[sujeto([miRNAs]), verbo([have]), complemento([been, widely, investigated, in, terms, of, cell, proliferation, and, differentiation])].
[sujeto(['Here', we, characterized, the, promoter, of, 'miR-206', in, chicken, and]), verbo([found]), complemento([that, the, preferable, promoter, was, located, in, 1200, bp, upstream, of, 'pri-miR-206'])].
[sujeto(['In', this, 'region,', many, key, transcription, 'factors,', including, 'MyoD,', 'c-Myb,', 'CEBPα/β,', 'AP-4,', 'RAP1,', 'Brn2,', 'GATA-1/2/3,', 'E47,', 'Sn,', upstream, stimulatory, factor, '(', 'USF)', and, 'CdxA,', were, predicted, to]), verbo([bind]), complemento([and, interact, with, 'miR-206', promoter])].
[sujeto(['Overexpression', of, 'MyoD', sharply]), verbo([increased]), complemento(['miR-206', expression, in, both, fibroblast, and, myoblast, 'cells,', and, also, the, regulation, in, the, myoblast, cells, was, much, 'stronger,', indicating, that, 'miR-206', was, regulated, by, 'MyoD', combined, with, other, muscle, specific, transcriptional, factors])].
[sujeto(['Interestingly,', the, motif]), verbo([bound]), complemento([by, 'MyoD', was, individually, destroyed, by, 'G-to-C', mutation, located, at, 419, bp, upstream, of, 'miR-206', precursor])].
[sujeto(['Thus,', this, mutation]), verbo([caused]), complemento([low, expression, of, 'miR-206'])].
[sujeto(['Additionally,', the, regulation, of, 'miR-206', on, embryo, muscle, mass, mainly, by]), verbo([increasing]), complemento(['MyoG', and, muscle, creatine, kinase, '(', 'MCK)', expression, '(', p, &, 'lt;', 0.05, ')', with, little, change, in, 'MyoD,', 'TMEM8C', and, myosin, heavy, chain, '(', 'MHC)'])].
[sujeto(['In', 'conclusion,', our, findings]), verbo([provide]), complemento([a, novel, mutation, destroying, the, promoter, activity, of, 'miR-206', in, birds, and, shed, new, light, to, understand, the, regulation, mechanism, of, 'miR-206', on, the, embryonic, muscle, growth])].
[sujeto(['Previously,', we, identified, five, 'POs,', designated, 'As-pro-PO', 'I-V,', from, the, mosquito, 'Armigeres', subalbatus, and, demonstrated, that, the, functions, of, 'As-pro-PO', 'I,', 'II', and, 'III,', were]), verbo([associated]), complemento([with, filarial, parasite, 'melanization,', blood, feeding, and, cuticle, 'formation,', respectively])].
[sujeto(['We']), verbo([found]), complemento([that, the, level, of, 'As-pro-PO', 'V', mRNA, in, mosquitoes, was, significantly, increased, after, microfilaria, challenge, or, blood, 'feeding,', and, decreased, to, normal, level, after, oviposition])].
[sujeto(['Knockdown', of, 'As-pro-PO', 'V', by, dsRNA, resulted, in, significant]), verbo([decreases]), complemento([in, the, degree, of, microfilaria, 'melanization,', egg, chronic, melanization, rates, and, egg, hatching, rates, in, 'Ar'])].
[sujeto(['Further', transfection, and, electrophoretic, 'mobility-shift', assays, verified, the, 'As-pro-PO', 'V', gene, might]), verbo([regulated]), complemento([by, both, 'AP-1,', a, putative, 'immune-related', regulatory, element, and, 'CdxA,', a, developmental, regulatory, element])].
[sujeto(['The']), verbo([binding]), complemento([of, 'AP-1', and, 'CdxA', motif, with, mosquito, nuclear, extracts, was, significantly, enhanced, after, microfilaria, challenge, and, 'blood-feeding', in, 'Ar'])].
[sujeto(['These', results, indicate, that, 'As-pro-PO', 'V', is, a, critical, enzyme, that, is]), verbo([required]), complemento([for, both, an, effective, melanization, immune, response, and, egg, chorion, melanization, in, this, mosquito])].
[sujeto(['Our', recent, 'genome-wide', association, study, '(', 'GWAS)', had, discovered, a, new, locus, at, 8, p23, '(', 'rs2738048)']), verbo([associated]), complemento([with, 'IgA', nephropathy, '(', 'IgAN)', in, 'Chinese', 'Han', 'patients,', implicating, the, 'DEFA', gene, family, within, this, locus, as, susceptibility, genes])].
[sujeto(['However,', it, is, still, unknown, whether, there, are, additional, variations, within, these, genes]), verbo([associated]), complemento([with, the, disease, susceptibility])].
[sujeto(['We']), verbo([found]), complemento([seven, 'SNPs', within, 'DEFA', genes, that, were, significantly, associated, with, 'IgAN,', including, rs2738048, discovered, in, our, previous, 'GWAS', '(', 'p = 0'])].
[sujeto(['Electrophoretic', mobility, shift, assays, and, luciferase, assays, demonstrated, that, fragments, containing, 'rs2738048,', rs2738081, and, rs6984215, were, transcription, factor]), verbo([binding]), complemento([sites, for, 'CTF,', 'SP1', and, 'CdxA,', 'respectively,', and, the, allele, status, of, rs2738048, and, rs6984215, could, significantly, change, the, luciferase, activity])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, polymorphisms, within, 'DEFA', genes, are, involved, in, gene, transcriptional, 'regulation,', and, this, may, have, some, effect, in, mediating, susceptibility, to, 'IgAN', in, southern, 'Chinese'])].
[sujeto(['Children', '(', 'n=488;', age, 'range:', 1.8, -, 6.0, 'y)', were, randomly]), verbo([recruited]), complemento([from, 'Montreal'])].
[sujeto([1, ')', were, positively]), verbo([associated]), complemento([with, 'BMC', and, aBMD, in, all, regression, 'models,', whereas, male, sex, contributed, positively, to, forearm, 'BMC', and, aBMD])].
[sujeto(['Having', a, 25, '(', 'OH)D', concentration, of, &, 'gt;75', 'nmol/L', positively]), verbo([associated]), complemento([with, forearm, and, whole, body, 'BMC', and, aBMD, '(', 'p<0'])].
[sujeto(['Helicobacter', pylori, encoded, 'CagA', is, presently, the, only, known, virulence, factor, that, is, injected, into, gastric, epithelial, cells, where, it, destroys, apical, junctional, complexes, and]), verbo([induces]), complemento([dedifferentiation, of, gastric, epithelial, 'cells,', leading, to, 'H'])].
[sujeto(['However,', little, is, known, about, the, molecular, mechanisms, by, which, 'CagA']), verbo([mediates]), complemento([these, changes])].
[sujeto(['Caudal-related', homeobox, 2, '(', 'Cdx2)', is, an, 'intestine-specific', transcription, factor, highly]), verbo([expressed]), complemento([in, multistage, tissues, of, dysplasia, and, cancer])].
[sujeto(['One', specific]), verbo([target]), complemento([of, 'Cdx2,', 'Claudin-2,', is, involved, in, the, regulation, of, tight, junction, '(', 'TJ)', permeability])].
[sujeto(['In', this, 'study,', our, findings, showed, that, the, activity, of, 'Cdx2']), verbo([binding]), complemento([to, 'Cdx', binding, sites, of, 'CdxA', '(', 'GTTTATG)', and, 'CdxB', '(', 'TTTTAGG)', of, probes, corresponding, to, 'claudin-2', flanking, region, increased, in, 'AGS', 'cells,', infected, with, 'CagA', positive, 'wild-type', strain, of, 'H'])].
[sujeto(['In', the, 'meantime,', we]), verbo([found]), complemento([that, 'TJs', of, 'AGS', 'cells,', infected, with, 'CagA', positive, 'wild-type', strain, of, 'H'])].
[sujeto(['pylori,', compared, to, 'CagA', negative, isogenic, 'mutant-type', 'strain,', were, more, severely, 'destroyed,']), verbo([leading]), complemento([to, wider, cell, 'gap,', interference, of, 'contact,', scattering, and, highly, elevated, migration, of, cells])].
[sujeto(['pylori-encoded', 'CagA', disrupts, 'TJs', and]), verbo([induces]), complemento([invasiveness, of, 'AGS', gastric, carcinoma, cells, via, 'Cdx2-dependent', targeting, of, 'Claudin-2'])].
[sujeto(['This']), verbo([provides]), complemento([a, new, mechanism, whereby, 'CagA', induced, dedifferentiation, of, 'AGS', 'cells,', leading, to, malignant, behavior, of, biology])].
[sujeto(['In', this, 'study,', 'real-time', polymerase, chain, reactions, and, 'Western', blot, assays, indicated, that, 'HMGB1', transcriptional, activity, and, protein, level, are]), verbo([increased]), complemento([in, 'Tax+-T', cells, '(', 'TaxP)'])].
[sujeto(['We']), verbo([found]), complemento([that, promoter, activity, in, 'Tax+-T', cells, to, be, higher, than, that, in, 'Tax--T', 'cells,', indicating, a, significant, increase, in, pHLuc6])].
[sujeto(['Bay11-7082', '(', 'NF-κB', 'inhibitor)', treatment, did, not, block, the]), verbo([enhancing]), complemento([effect])].
[sujeto(['Chromatin', immunoprecipitation, assays, revealed, that, 'Tax', was]), verbo([retained]), complemento([on, a, 'HMGB1', promoter, fragment, encompassing, -, 1163, to, -, 975])].
[sujeto(['Mutation', of, 'cis-', elements, for, 'C/EBP', reduced, significant, 'HMGB1', promoter, activity]), verbo([induced]), complemento([by, 'Tax'])].
[sujeto(['These', findings, indicate, that, 'Tax']), verbo([enhances]), complemento([the, expression, of, 'HMGB1', gene, at, the, transcriptional, 'level,', possibly, by, interacting, with, 'C/EBP'])].
[sujeto(['Interferon', regulatory, factor, 2, '(', 'IRF-2)', is, a, 'multi-functional', transcription, factor, in, the, 'IRF', family, exhibiting, both, transcriptional]), verbo([activating]), complemento([and, repressing, activities])].
[sujeto(['The', amino, acid, sequence, had, a, highly]), verbo([conserved]), complemento(['N-terminal', 'DBD', 'structure,', containing, characteristic, repeats, of, six, tryptophan, residues])].
[sujeto(['Only +2365T/C', 'SNP', was, significantly]), verbo([associated]), complemento([with, 'resistance/susceptibility', of, 'H'])].
[sujeto(['Among', 'them,', three, 'SNPs', including, 'A-99G,', 'A-86C,', and, 'A-49C', in, 'GPX', promoter, and, five, 'SNPs', including, 'A2841T,', 'C2847T,', 'G3146C,', 'A3150G,', and, 'G4645T', in, 'GPX', introns, were]), verbo([associated]), complemento([with, 'resistance/susceptibility', of, 'H'])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, the, polymorphic, loci, in, the, 'GPX', gene, could, be, potential, genetic, markers, for, future, molecular, selection, of, strains, resistant, to, diseases])].
[sujeto(['However,', these, approaches]), verbo([require]), complemento([the, use, of, sophisticated, and, expensive, 'serum-free', medium, supplemented, with, epithelial, growth, factor, '(', 'EGF),', 'Wnt', agonist, '(', 'R-spondin', 1, ')', ',', and, bone, morphogenetic, protein, inhibitor, '(', 'Noggin)', in, high, concentrations])].
[sujeto(['They']), verbo([have]), complemento([the, appearance, of, empty, spheres, and, comprise, cells, expressing, cytokeratin, '(', an, epithelial, cell, 'marker),', villin, '(', a, marker, of, 'enterocytes),', and, 'Sox-9', '(', a, transcription, factor, characteristic, of, progenitors, and, stem, cells, of, intestinal, 'crypts)'])].
[sujeto(['With', chicken, embryonic, tissue, as, a, source, of, 'organoids,', prostaglandin, 'E2', is, as, effective, as, 'R-spondin', 1, and, 'Noggin', in]), verbo([promoting]), complemento([sustained, growth, and, survival, of, epithelial, spheroids])].
[sujeto(['Specifically,', 'β-casein', is, a, major, component, of, 'cow,', goat, and, sheep, 'milk,', and, its, promoter]), verbo([has]), complemento([been, used, to, regulate, the, expression, of, transgenic, genes, in, the, mammary, gland, of, transgenic, animals])].
[sujeto(['We', estimated, the, transcriptional, activity, for, the, 5, '\'', -, proximal, region, with, or, without, intron, 1, of, the, porcine, 'β-casein', gene, in, 'HC11', cells]), verbo([stimulated]), complemento([with, lactogenic, hormones])].
[sujeto(['Taken', 'together,', these, findings]), verbo([suggest]), complemento([that, the, transcription, of, porcine, 'β-casein', gene, is, regulated, by, lactogenic, hormone, via, intron, 1, and, promoter, containing, a, mutant, 'TATA', box, '(', 'CATAAAA)', has, poor, porcine, 'β-casein', gene, activity])].
[sujeto(['To', examine, whether, 'PARK16,', which, was, recently, identified, as, a, protective, locus, for, 'Parkinson', disease, '(', 'PD)', in, 'Asian,', 'white,', and, 'South', 'American', 'populations,', is, also]), verbo([associated]), complemento([with, 'PD', in, the, genetically, homogeneous, 'Ashkenazi', 'Jewish', population])].
[sujeto(['Bioinformatic', analysis, defined, the, putative, promoter, region, of, 'RAB7L1', and, the, transcription, factor]), verbo([binding]), complemento([sites, that, are, potentially, affected, by, 2, of, the, tested, 'SNPs'])].
[sujeto(['All', tested, 'SNPs', were, significantly]), verbo([associated]), complemento([with, 'PD', '(', odds, 'ratios = 0'])].
[sujeto(['Two', of, 'them,', rs1572931, and, 'rs823144,', were, localized, to, the, putative, promoter, region, of, 'RAB7L1', and, their, sequence, variations, altered, the, predicted, transcription, factor]), verbo([binding]), complemento([sites, of, 'CdxA,', 'p300,', 'GATA-1,', 'Sp1,', and, 'c-Ets-1'])].
[sujeto(['Our', data, demonstrate, that, specific, 'SNP', variations, and, haplotypes, in, the, 'PARK16', locus, are]), verbo([associated]), complemento([with, reduced, risk, for, 'PD', in, 'Ashkenazim'])].
[sujeto(['Although', it, is, possible, that, alterations, in, the, putative, promoter, of, 'RAB7L1', are]), verbo([associated]), complemento([with, this, 'effect,', the, role, of, other, genes, in, this, locus, cannot, be, ruled, out])].
[sujeto(['It', is]), verbo([involved]), complemento([in, the, regulation, of, the, 'G1-phase', of, the, cell, cycle, and, is, considered, to, be, an, important, candidate, gene, for, selection, of, body, measurement, traits, through, 'marker-assisted', selection])].
[sujeto(['We', cloned, the, promoter, sequence, of, this, gene, in, bovines, and]), verbo([found]), complemento([it, to, share, high, similarity, with, that, of, the, human, 'CDK6', promoter])].
[sujeto(['A', 2271, -, bp, sequence, upstream, of, the, start, codon, in, the, bovine, 'CDK6', 5, '\'', -, flanking, sequence, is, rich, in, 'GC;', it, lacks, consensus, 'TATA', or, 'CAAT', 'box,', but, it, contains, several, 'MZF1']), verbo([binding]), complemento([sites])].
[sujeto(['Other', potential, 'cis-regulatory', elements, were]), verbo([found]), complemento([in, the, 5, '\'', -, flanking, 'region,', including, 'CdxA,', 'SRY,', 'p300,', 'GATA-1,', and, deltaE])].
[sujeto(['The', 'T-1075C', 'SNP', in, the, promoter, was]), verbo([found]), complemento([to, be, significantly, associated, with, body, length, and, heart, girth])].
[sujeto(['This', 'SNP', marker, was]), verbo([found]), complemento([to, be, significantly, associated, with, body, length, and, the, heart, girth, in, 737, individuals])].
[sujeto(['We', conclude, that, this, 'SNP', of, the, 'CDK6', gene]), verbo([has]), complemento([potential, as, a, genetic, marker, for, important, body, traits, in, bovine, reproduction, and, breeding])].
[sujeto(['The', aim, of, this, study]), verbo([has]), complemento([been, to, analyze, whether, 33, '%', radius, should, be, considered, the, recommended, area, to, assess, 'BMD', in, prostate, cancer, patients])].
[sujeto(['Normal', 'BMD', was]), verbo([found]), complemento([in, 17.7, '%', at, 33, '%', radius, and, 34.8, '%', at, cDXA])].
[sujeto(['The', 33, '%', radius, was, the, only, site, where, a, significant]), verbo([increase]), complemento([in, the, osteoporosis, rate, was, detected, in, patients, subjected, to, 'AS', compared, to, those, hormone, naïve, '(', 33, and, 13.8, '%', ')'])].
[sujeto(['The', 33, '%', radius, seems, more, sensible, than, the, central, skeleton, areas, to, detect, bone, mass]), verbo([loss]), complemento([in, patients, with, prostate, cancer])].
[sujeto(['Alkaline', phosphatases, are, ubiquitous, enzymes]), verbo([involved]), complemento([in, many, important, biological, processes])].
[sujeto(['Mammalian', 'tissue-nonspecific', alkaline, phosphatase]), verbo([has]), complemento([long, been, thought, to, feature, in, embryonic, development, and, bone, formation])].
[sujeto(['An', analysis, of, its, secondary, and, tertiary, structure, revealed, that, the, 'POALP', was]), verbo([conserved]), complemento([in, different, 'species,', but, one, disulfide, linkage, made, it, possible, to, adapt, to, 'low-temperature', environment])].
[sujeto(['The', 'ALP', activity, was]), verbo([found]), complemento([to, be, first, detectable, in, the, embryo, before, hatching])].
[sujeto(['These', findings]), verbo([suggest]), complemento([the, potential, role, of, 'POALP', in, nutrient, absorption, and, transportation])].
[sujeto(['To', evaluate, whether, these, genes, encode, enzymes, with, redundant, biological, 'functions,', each, gene, was, cloned, and]), verbo([expressed]), complemento([in, 'Escherichia', coli])].
[sujeto(['To', identify, the, amino, acid, residues, that, contribute, to, catalysis, and, substrate, specificity, within, this, family, of, 'enzymes,', the, roles, of]), verbo([conserved]), complemento([residues, '(', 'R177,', 'K214,', 'H215,', 'M251,', and, 'D286)', in, 'Xyl3B', were, probed, by, 'site-directed', mutagenesis])].
[sujeto(['Each', mutation]), verbo([led]), complemento([to, a, severely, decreased, catalytic, efficiency, without, a, change, in, the, overall, structure, of, the, mutant, enzymes])].
[sujeto(['Through', amino, acid, sequence, 'alignments,', an, amino, acid, residue, '(', 'E115)', 'that,', when, mutated, to, aspartic, 'acid,', resulted, in, a, 14, -, fold]), verbo([decrease]), complemento([in, the, 'k(cat)/K(m)', for, 'pNP-beta-d-xylopyranoside', '(', 'pNPX)', with, a, concurrent, 1.1, -, fold, increase, in, the, 'k(cat)/K(m)', for, 'pNP-beta-d-glucopyranoside', '(', 'pNPG)', was, identified])].
[sujeto(['Our', results, demonstrate, that, each, of, the, four, 'GH3', enzymes]), verbo([has]), complemento([evolved, to, perform, a, specific, role, in, lignopolysaccharide, hydrolysis, and, provide, insight, into, the, role, of, 'active-site', residues, in, catalysis, and, substrate, specificity, for, 'GH3', enzymes])].
[sujeto(['More', than, ten, 'bradykinin-related', peptides, and, their, cDNAs]), verbo([have]), complemento([been, identified, from, 'amphibians,', but, their, genes, are, unknown])].
[sujeto(['The', promoter, region, of, the, bradykinin, gene, contains, several, putative, recognition, sites, for]), verbo([nuclear]), complemento(['factors,', such, as, 'SRY,', 'GATA-1,', 'LYF-1,', 'DeltaE,', 'CDXA,', 'NKX-2'])].
[sujeto(['Interferon', regulatory, factor, 3, '(', 'IRF-3),', an, essential, transcriptional, regulator, of, the, interferon, 'genes,']), verbo([has]), complemento([been, implicated, in, virus, and, 'double-stranded', 'RNA', mediated, induction, of, 'IFN-α,', 'IFN-β', and, 'RANTES,', in, 'virus-induced', apoptosis, and, in, tumor, suppression])].
[sujeto(['Promoter', plays, an, important, role, in, the, regulation, of, gene, 'expression,', but, the, characterization, of, the, human, 'IRF-3', promoter]), verbo([has]), complemento([not, been, systematically, analyzed, in, 'HEK', 293, cells])].
[sujeto(['To', characterize, the, human, 'IRF-3', 'promoter,', we]), verbo([have]), complemento([isolated, a, genomic, clone, of, the, human, 'IRF-3', gene, promoter, region, containing, 1, ',', 0, nucleotides, of, the, 5, '\'', -, flanking, region])].
[sujeto(['This', region, contains, 'HSF,', 'E2F,', 'CdxA', and, 'c-Myb', transcription, factor]), verbo([binding]), complemento([sites])].
[sujeto(['The', 'E2F', sites, are, highly]), verbo([conserved]), complemento([among, 'IRF-3', promoter, regions, of, 'mouse,', rat, and, human])].
[sujeto(['Therefore,', it, was]), verbo([suggested]), complemento([that, this, 'E2F', site, may, be, essential, for, basal, promoter, activity])].
[sujeto(['Surprisingly,', mutation, of, this, 'E2F', site]), verbo([increased]), complemento([the, promoter, activity, by, 2, -, fold])].
[sujeto(['E2F1', transcription, factor, negatively]), verbo([regulates]), complemento([human, 'IRF-3', gene, promoter])].
[sujeto(['Although', the, requirement, for, 'RA', signaling, for, the, development, of, a, few, individual, endoderm, organs]), verbo([has]), complemento([been, established, a, systematic, assessment, of, its, activity, along, the, entire, 'antero-posterior', axis, has, not, been, performed, in, this, germ, layer])].
[sujeto(['These', results, imply, that, 'RA']), verbo([acts]), complemento([as, a, caudalizing, factor, in, a, graded, manner, in, pharyngeal, endoderm])].
[sujeto(['Posterior', foregut, and, midgut, organ, primordia, also]), verbo([require]), complemento(['RA,', but, exposing, endoderm, to, additional, 'RA', is, not, sufficient, to, expand, these, primordia, anteriorly])].
[sujeto(['Our', results, show, that, the, induction, of, 'CdxA,', a, midgut, 'marker,', and, pancreas, induction]), verbo([require]), complemento([direct, 'RA', signaling, in, endoderm])].
[sujeto(['Moreover,', communication, between, 'CdxA(+)', cells, is, necessary, to]), verbo([maintain]), complemento(['CdxA', 'expression,', therefore, synchronizing, the, cells, of, the, midgut, primordium])].
[sujeto(['We', further, show, that, the, 'RA', pathway]), verbo([acts]), complemento([synergistically, with, 'FGF4', in, endoderm, patterning, rather, than, mediating, 'FGF4', activity])].
[sujeto(['Gene', regulation, during, development, is, an, important, biological, activity, that]), verbo([leads]), complemento([to, synthesis, of, biomolecules, at, specific, locations, and, specific, times])].
[sujeto(['We', investigated, the, internal, promoter, of, tropomyosin, to, identify, sequences, that]), verbo([regulate]), complemento([expression, of, 'tmy-1', in, the, pharynx, and, intestine])].
[sujeto(['By', promoter, deletion, of, 'tmy-1', reporters, as, well, as, by, database, 'analyses,', a, 100, -, bp, fragment, that, contained]), verbo([binding]), complemento([sequences, for, a, 'GATA', 'factor,', for, a, chicken, 'CdxA', 'homolog,', and, for, a, forkhead, factor, was, identified])].
[sujeto(['Both', the, forkhead, and, 'CdxA']), verbo([binding]), complemento([sequences, contributed, to, pharyngeal, and, intestinal, expression])].
[sujeto(['We', showed, that, 'ELT-2', and, 'PHA-4', proteins]), verbo([interact]), complemento([directly, with, the, 'GATA', and, forkhead, binding, 'sequences,', 'respectively,', in, gel, mobility, shift, assays])].
[sujeto(['We']), verbo([found]), complemento([no, indication, of, a, synergistic, relation, between, 'ELT-2', and, 'PHA-4'])].
[sujeto(['Determination', of, the, developmental, fate, in, the, small, intestinal, epithelium, of, the, chicken, embryo]), verbo([has]), complemento([not, been, fully, analyzed, up, to, the, present])].
[sujeto(['The', small, intestinal, epithelium, reassociated, and, cultivated, with, the, proventricular, or, gizzard, mesenchyme, or, the, dermis]), verbo([expressed]), complemento([chicken, intestinal, fatty, acid, binding, 'protein,', sucrase, and, 'CdxA', as, occurs, during, the, normal, development, of, the, small, intestinal, epithelium])].
[sujeto(['The', presumptive, intestinal, endoderm, taken, from, an, earlier, stage, embryo, and]), verbo([associated]), complemento([and, cultivated, with, the, proventricular, or, gizzard, 'mesenchyme,', showed, gene, expression, patterns, which, were, the, same, as, those, found, in, normal, development])].
[sujeto(['However,', when, the, dermis, was, 'associated,', the, epithelium]), verbo([expressed]), complemento([sonic, 'hedgehog,', but, never, expressed, intestinal, 'epithelial-', or, stomach, 'epithelial-markers'])].
[sujeto(['ACS3', is, an, 'arachidonate-preferring', enzyme]), verbo([expressed]), complemento([in, a, wide, range, of, human, tissues, including, 'brain,', 'heart,', 'placenta,', 'prostate,', skeletal, 'muscle,', testis, and, thymus])].
[sujeto(['A', minimal, promoter, region]), verbo([required]), complemento([for, the, expression, of, the, human, 'ACS3', gene, in, melanoma, 'G361', cells, was, determined])].
[sujeto(['This', analysis, revealed, that, the, most, common, transcription, factor]), verbo([binding]), complemento([site, in, the, examined, collection, of, core, promoters, appears, to, be, initiator, '(', characterized, by, 'GEN_INI),', which, is, expected])].
[sujeto(['The', other, less, obvious, sites]), verbo([found]), complemento([were, 'Spz1,', 'E2F-1,', 'ZF5,', and, 'C/EBP'])].
[sujeto(['Interestingly,', the, 'TATA-box']), verbo([has]), complemento([been, found, in, only, 11.63, '%', of, all, examined, promoters])].
[sujeto(['These', additional, analyses, revealed, that, the, most, common, promoter, elements]), verbo([found]), complemento([also, include, 'AP-2,', 'CdxA,', 'Pax-2,', 'SRY,', 'STAT1', and, 'STAT5A'])].
[sujeto(['Spindle-checkpoint', genes]), verbo([have]), complemento([been, reported, to, be, mutated, in, several, human, 'cancers,', but, these, mutations, are, infrequent])].
[sujeto(['Recent']), verbo([reports]), complemento([suggest, that, the, hBUBR1, gene, may, play, an, important, role, in, mitotic, checkpoint, control, and, in, mitotic, checkpoint, impairment, in, human, cancers])].
[sujeto(['The', expression, of, 'BUBR1', was]), verbo([found]), complemento([to, be, 'up-regulated', in, all, of, these, cell, lines])].
[sujeto(['The', promoter, region, '(', 424, bp, upstream, from, exon, 1, ')', showed, promoter, activity, and, includes, multiple, transcription, factor, consensus]), verbo([binding]), complemento(['motifs,', including, those, for, 'Sp1,', 'Nkx-2,', 'CdxA,', 'SRY,', 'MyoD,', 'Ik-2,', 'HNF-3b,', 'Staf,', 'Oct-1,', 'Nkx-2,', 'v-Myb,', and, 'AML', 1, a])].
[sujeto(['Multiple', pathways]), verbo([leading]), complemento([to, activation, of, those, binding, factors, may, contribute, to, hBUBR1, gene, transcription])].
[sujeto(['Initiation', of, 'Hox', genes]), verbo([requires]), complemento([interactions, between, numerous, factors, and, signaling, pathways, in, order, to, establish, their, precise, domain, boundaries, in, the, developing, nervous, system])].
[sujeto(['There', are, distinct, differences, in, the, expression, and, regulation, of, members, of, 'Hox', genes, within, a, complex]), verbo([suggesting]), complemento([that, multiple, competing, mechanisms, are, used, to, initiate, their, expression, domains, in, early, embryogenesis])].
[sujeto(['In', this, 'study,', by, analyzing, the, response, of, 'HoxB', genes, to, both, 'RA', and, 'FGF', signaling, in, neural, tissue, during, early, chick, embryogenesis, '(', 'HH', stages, 7, -, 15, ')', ',', we]), verbo([have]), complemento([defined, two, distinct, groups, of, 'Hox', genes, based, on, their, reciprocal, sensitivity, to, 'RA', or, 'FGF', during, this, developmental, period])].
[sujeto(['We']), verbo([found]), complemento([that, the, expression, domain, of, 5, '\'', members, from, the, 'HoxB', complex, '(', 'Hoxb6-Hoxb9)', can, be, expanded, anteriorly, in, the, chick, neural, tube, up, to, the, level, of, the, otic, vesicle, following, 'FGF', treatment, and, that, these, same, genes, are, refractory, to, 'RA', treatment, at, these, stages])].
[sujeto(['Using', a, dominant, negative, form, of, a, 'Xenopus', 'Cdx', gene, '(', 'XcadEnR)', we]), verbo([found]), complemento([that, the, effect, of, 'FGF', treatment, on, 5, '\'', 'HoxB', genes, is, mediated, in, part, through, the, activation, and, function, of, 'CDX', activity])].
[sujeto(['We', demonstrated, by, in, ovo, electroporation, of, a, dominant, negative, retinoid, receptor, construct, '(', 'dnRAR)', that, retinoid, signaling, is]), verbo([required]), complemento([to, initiate, expression])].
[sujeto(['Elevating', 'CDX', activity, by, ectopic, expression, of, an]), verbo([activated]), complemento([form, of, a, 'Xenopus', 'Cdx', gene, '(', 'XcadVP16)', in, the, hindbrain, ectopically, activates, and, anteriorly, expands, 'Hoxb4', expression])].
[sujeto(['In', a, similar, 'manner,', when, ectopic, expression, of, 'XcadVP16', is, combined, with, 'FGF', 'treatment,', we]), verbo([found]), complemento([that, 'Hoxb9', expression, expands, anteriorly, into, the, hindbrain, region])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([a, model, 'whereby,', over, the, window, of, early, development, we, 'examined,', all, 'HoxB', genes, are, actually, competent, to, interpret, an, 'FGF', signal, via, a, 'CDX-dependent', pathway])].
[sujeto(['However,', mechanisms, that, axially, restrict, the, 'Cdx', domains, of, 'expression,', serve, to]), verbo([prevent]), complemento([3, '\'', genes, from, responding, to, 'FGF', signaling, in, the, hindbrain])].
[sujeto(['FGF', may]), verbo([have]), complemento([a, dual, role, in, both, modulating, the, accessibility, of, the, 'HoxB', complex, along, the, axis, and, in, activating, the, expression, of, 'Cdx', genes])].
[sujeto(['These', results, highlight, the, key, role, of, 'Cdx', genes, in, integrating, the, input, of, multiple, signaling, 'pathways,', such, as, 'FGFs', and, 'RA,', in, controlling, initiation, of, 'Hox', expression, during, development, and, the, importance, of, understanding, regulatory, 'events/mechanisms', that]), verbo([modulate]), complemento(['Cdx', expression])].
[sujeto(['Mouse', 'GLUT5', cDNA, and, a, 7.7, -, kb, genomic, fragment]), verbo([have]), complemento([been, isolated, and, characterized])].
[sujeto(['The', cDNA, sequence]), verbo([suggests]), complemento([mouse, 'GLUT5', is, composed, of, 501, amino, 'acids,', and, has, 69, -, 88, '%', amino, acid, identity, with, 'human,', 'rat,', and, rabbit, 'GLUT5'])].
[sujeto(['Expression', of, mouse, 'GLUT5', cRNA, in, 'Xenopus', laevis, oocytes, showed, that, 'GLUT5']), verbo([mediated]), complemento([fructose, 'transport,', with, a, 'K(t)', of, 13, mM])].
[sujeto(['In', agreement, with, studies, in, rats, and, 'rabbits,', mouse, small, intestinal, 'GLUT5', mRNA, expression, levels, were]), verbo([increased]), complemento([following, exposure, to, a, 65, '%', 'fructose-enriched', diet])].
[sujeto(['In', 'addition,', developmental, studies, showed, a, significant]), verbo([increase]), complemento([in, 'GLUT5', mRNA, expression, levels, in, adult, mouse, testis, when, compared, to, prepubertal, mouse, testis])].
[sujeto(['Moreover,', caudal, homeobox, gene, '(', 'CdxA),', upstream, stimulatory, factor, '(', 'USF),', and, 'sex-determining', region, of, 'Y', '(', 'SRY)']), verbo([binding]), complemento([sites, were, identified, in, the, 5, '\'', flanking, region, that, may, be, responsible, for, 'GLUT5\'s', expression, 'characteristics:', tissue, 'distribution,', sensitivity, to, dietary, fructose, in, the, small, 'intestine,', and, developmental, expression, in, the, testis])].
[sujeto(['To', investigate, the, mechanisms]), verbo([involved]), complemento([in, regulation, of, 'NHE3', gene, 'expression,', the, human, 'NHE3', promoter, region, was, cloned, and, characterized])].
[sujeto(['Deletion', of, a, fragment, containing, the, 'AP-2', and, 'Sp1', motifs, resulted, in, a, drastic]), verbo([decrease]), complemento([in, promoter, activity])].
[sujeto(['In', gel, mobility, shift, 'assays,', an, oligonucleotide, spanning, from, -, 78, to, -, 56, bp]), verbo([bound]), complemento([a, recombinant, 'AP-2,', and, the, corresponding, binding, activity, in, nuclear, extracts, was, supershifted, with, 'anti-AP2alpha', antibody])].
[sujeto(['Our', studies]), verbo([suggest]), complemento([that, the, 'NHE3', expression, is, regulated, by, a, combination, of, cis, elements, and, their, cognate, transcription, factors, that, include, the, 'AP-2', and, 'Sp1', family, members])].
[sujeto(['The', human, gene]), verbo([has]), complemento([now, been, isolated, and, characterized])].
[sujeto(['The', immunoglobulin, 'enhancer-binding', 'proteins,', 'E12', and, 'E47,', encoded, by, the, 'E2A', gene, belong, to, the, basic, 'helix-loop-helix', '(', 'bHLH)', family, of, regulatory, proteins, and]), verbo([act]), complemento([as, transcriptional, activators])].
[sujeto(['In', addition, to, their, critical, role, in, 'B-lymphocyte', 'development,', the, 'E12', and, 'E47', proteins]), verbo([have]), complemento([been, implicated, in, the, induction, of, myogenesis, as, heterodimeric, partners, of, myogenic, bHLH, 'proteins,', 'MyoD', and, myogenin])].
[sujeto(['Here', we, demonstrate, that, the, 'E2A', proteins, form, heterodimers, with, the, bHLH, oncoprotein, 'tal-1', in, myeloid, and, erythroid, cells, and, that, these, heterodimers, specifically]), verbo([bind]), complemento([to, the, 'CANNTG', 'DNA', motif])].
[sujeto(['Heterodimerization', with, 'tal-1']), verbo([represses]), complemento([transactivation, by, 'E47', and, could, function, to, prevent, the, expression, of, immunoglobulin, genes, in, cells, other, than, 'B', lymphocytes])].
[sujeto(['DNA']), verbo([binding]), complemento([by, 'E2A-tal-1', heterodimers, in, the, 'M1', mouse, myeloid, cell, line, is, abrogated, upon, terminal, macrophage, differentiation, induced, by, the, cytokine, interleukin, 6])].
[sujeto(['The']), verbo([loss]), complemento([of, 'E2A-tal-1', 'DNA', binding, is, correlated, with, elevated, expression, of, mRNA, encoding, the, dominant, negative, 'HLH', 'proteins,', 'Id1', and, particularly, 'Id2'])].
[sujeto(['Moreover,', recombinant, 'Id', proteins]), verbo([inhibit]), complemento([the, 'E2A-tal-1-specific', 'DNA', binding, activity, from, undifferentiated, 'M1', cells])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'E2A-tal-1', heterodimers, may, play, a, role, in, preventing, terminal, differentiation, in, the, myeloid, lineage, and, provide, a, possible, explanation, for, oncogenic, transformation, induced, by, ectopic, 'tal-1', expression, in, acute, 'T-cell', lymphoblastic, leukemias])].
[sujeto(['In', the, present, study, four, 'genes,', 'H-FABP', '(', heart, fatty, 'acid-binding', 'protein),', 'MASTR', '(', 'MEF2']), verbo([activating]), complemento([motif, and, 'SAP', domain, containing, transcriptional, 'regulator),', 'UCP3', '(', uncoupling, protein, 3, ')', and, 'MYOD1', '(', myogenic, differentiation, 1, ')', were, researched, in, 'Large', 'White', pigs])].
[sujeto([187, 'C>T']), verbo([have]), complemento([been, reported, to, be, associated, with, meat, quality, traits, in, pigs])].
[sujeto(['The', single, marker, association, analysis, showed, that, the, 'H-FABP', and, 'MASTR', genes, were]), verbo([associated]), complemento([with, 'IMF', '(', intramuscular, fat, 'content)', '(', 'P', &, 'lt;', 0.05, ')', ',', and, that, the, g])].
[sujeto(['Thus,', our, study, results]), verbo([suggested]), complemento([that, 'H-FABP', and, 'MASTR', polymorphisms, could, be, used, as, genetic, markers, in, the, 'marker-assisted', selection, towards, the, improvement, of, 'IMF', in, 'Large', 'White', pigs])].
[sujeto(['It', dorsalized, 'Xenopus', embryos, and, was]), verbo([expressed]), complemento([in, the, 'Spemann', organizer, during, early, gastrulation])].
[sujeto(['Frzb', was, secretable, and, could]), verbo([act]), complemento([across, cell, boundaries])].
[sujeto(['Furthermore,', 'Frzb', blocked, induction, of, 'MyoD,', an, action]), verbo([reported]), complemento([recently, for, a, 'dominant-negative', 'Xwnt-8'])].
[sujeto(['Frzb', coimmunoprecipitated, with, 'Wnt', 'proteins,']), verbo([providing]), complemento([direct, biochemical, evidence, for, 'Frzb-Wnt', interactions])].
[sujeto(['These', observations, implicate, 'Frzb', in, axial, patterning, and, support, the, concept, that, 'Frzb']), verbo([binds]), complemento([and, inactivates, 'Xwnt-8', during, 'gastrulation,', preventing, inappropriate, ventral, signaling, in, developing, dorsal, tissues])].
[sujeto(['Transcription', factors, containing, a, basic, 'helix-loop-helix', '(', 'bHLH)', motif]), verbo([regulate]), complemento([the, expression, of, 'tissue-specific', genes, in, a, number, of, mammalian, and, insect, systems])].
[sujeto(['Consequently,', 'Id', proteins]), verbo([inhibit]), complemento([binding, to, 'DNA', and, transcriptional, transactivation, by, heterodimerization, with, bHLH, proteins])].
[sujeto(['We']), verbo([report]), complemento([here, the, cDNA, sequence, of, a, novel, human, 'HLH', gene, '(', 'HGMW-approved', symbol, 'ID4)', that, lacks, the, basic, domain])].
[sujeto(['ID4', is, differentially]), verbo([expressed]), complemento([in, adult, organs, in, four, mRNA, 'molecules,', which, are, presumably, a, result, of, differential, splicing, 'and/or', alternative, usage, of, the, polyadenylation, sites])].
[sujeto(['Transfection', experiments, indicated, that, enforced, expression, of, 'Id-4H', protein]), verbo([inhibits]), complemento([the, 'trans-activation', of, the, muscle, creatine, kinase, 'E-box', enhancer, by, 'MyoD'])].
[sujeto(['The', three, ternary, complex, factors, '(', 'TCFs),', 'Net', '(', 'ERP/', 'SAP-2),', 'ELK-1', and, 'SAP-1,', are, highly, related, ets, oncogene, family, members, that]), verbo([participate]), complemento([in, the, response, of, the, cell, to, 'Ras', and, growth, signals])].
[sujeto(['Understanding', the, different, roles, of, these, factors, will]), verbo([provide]), complemento([insights, into, how, the, signals, result, in, coordinate, regulation, of, the, cell])].
[sujeto(['We', show, that, 'Net']), verbo([inhibits]), complemento([transcription, under, basal, 'conditions,', in, which, 'SAP-1a', is, inactive, and, 'ELK-1', stimulates])].
[sujeto(['Repression', is]), verbo([mediated]), complemento([by, the, 'NID,', the, 'Net', 'Inhibitory', 'Domain', of, about, 50, amino, 'acids,', which, autoregulates, the, 'Net', protein, and, also, inhibits, when, it, is, isolated, in, a, heterologous, fusion, protein])].
[sujeto(['Ras']), verbo([activates]), complemento(['Net', through, the, 'C-domain,', which, is, conserved, between, the, three, 'TCFs,', and, the, 'NID', is, an, efficient, inhibitor, of, 'Ras', activation])].
[sujeto(['The', 'NID,', as, well, as, more, 'C-terminal', 'sequences,']), verbo([inhibit]), complemento(['DNA', binding])].
[sujeto(['Net', is, more, refractory, to, 'DNA']), verbo([binding]), complemento([than, the, other, 'TCFs,', possibly, due, to, the, presence, of, multiple, inhibitory, elements])].
[sujeto(['The', sequence, resemblance, with, myogenic, factors]), verbo([suggested]), complemento([that, 'Net', may, form, complexes, with, the, same, partners])].
[sujeto(['Indeed,', we]), verbo([found]), complemento([that, 'Net', can, interact, in, vivo, with, the, basic, 'HLH', 'factor,', 'E47'])].
[sujeto(['We', propose, that, 'Net', is]), verbo([regulated]), complemento([at, the, level, of, its, latent, 'DNA-binding', activity, by, protein, interactions, 'and/or', phosphorylation])].
[sujeto(['The', identification, of, the, novel, inhibitory, domain]), verbo([provides]), complemento([a, new, inroad, into, exploring, the, different, roles, of, the, ternary, complex, factors, in, growth, control, and, transformation])].
[sujeto(['I-mfa', '(', inhibitor, of, the, 'MyoD', family, 'a)', is, a, transcription, modulator, that]), verbo([binds]), complemento([to, 'MyoD', family, members, and, inhibits, their, transcriptional, activities])].
[sujeto(['It', is, highly]), verbo([expressed]), complemento([in, the, sclerotome, and, plays, an, important, role, in, the, patterning, of, the, somite, early, in, development])].
[sujeto(['The', statistical, analyses, indicated, that, the, three, 'SNPs,', are]), verbo([associated]), complemento([with, the, phenotypic, traits, in, 'Luxi', '(', 'LX),', 'Qinchuan', '(', 'QC),', and, 'Jiaxian', '(', 'JX)', cattle, population, '(', 'P < 0'])].
[sujeto(['The', 'mutant-type', variants, were, superior, for, growth, 'traits;', the, heterozygote, diplotype, was]), verbo([associated]), complemento([with, higher, growth, traits, compared, to, 'wild-type', homozygote])].
[sujeto(['Our', results]), verbo([provide]), complemento([evidence, that, polymorphisms, in, the, 'I-mfa', gene, are, associated, with, growth, traits, and, may, be, used, for, 'marker-assisted', selection, in, beef, cattle, breeding, program])].
[sujeto(['Accumulating', evidence]), verbo([suggests]), complemento([that, 'Sirtuin', '(', 'Sirt)1', serves, a, significant, role, in, proliferation, and, differentiation, of, myoblast, 'cells;', however, the, signaling, mechanisms, involved, remain, to, be, established])].
[sujeto(['To', determine, if, 'MSTN', is]), verbo([involved]), complemento([in, the, regulation, of, myoblast, cell, proliferation, by, 'Sirt1,', the, present, study, administrated, the, 'Sirt1 activator', 'resveratrol,', inhibitor, nicotinamide, '(', 'NAM)', and, 'MSTN', inhibitor, 'SB431542 to', 'C2C12 myoblast', cells])].
[sujeto(['It', was, demonstrated, that, the, 'Sirt1 activator,', 'resveratrol,', 'repressed,', whereas, the, 'Sirt1 inhibitor,', 'NAM,']), verbo([enhanced]), complemento(['C2C12 myoblast', cells, proliferation, in, a, 'Sirt1‑dependent', manner])].
[sujeto(['Additionally,', resveratrol, upregulated, the, mRNA, expression, of, 'MyoD,', but]), verbo([inhibited]), complemento([the, expression, of, 'MSTN'])].
[sujeto(['Additionally,', 'NAM', significantly]), verbo([repressed]), complemento([the, expression, of, 'MyoD', and, the, phosphorylation, of, 'P107', '(', 'p‑P107),', but, enhanced, the, expression, of, 'MSTN', and, the, protein, expression, of, 'P107'])].
[sujeto(['Marek\'s', disease, '(', 'MD)', is, an, infectious, disease, of, chickens]), verbo([caused]), complemento([by, 'MD', virus, '(', 'MDV),', which, is, a, herpesvirus, that, initiates, tumor, formation])].
[sujeto(['Studies']), verbo([have]), complemento([indicated, that, microRNAs, '(', 'miRNAs)', are, linked, with, the, development, of, cancers, or, tumors])].
[sujeto(['The']), verbo([target]), complemento([genes, of, 'gga-miR-130a', were, predicted, using, 'TargetScan', and, miRDB, and, clustered, through, 'Gene', 'Ontology', analysis])].
[sujeto(['The']), verbo([target]), complemento([genes, were, validated, by, western, 'blot,', 'qRT-PCR,', and, a, dual, luciferase, reporter, assay])].
[sujeto(['Two']), verbo([target]), complemento(['genes,', homeobox, 'A3', '(', 'HOXA3)', and, 'MyoD', family, inhibitor, domain, containing, '(', 'MDFIC),', were, predicted, and, clustered, to, cell, proliferation])].
[sujeto(['Results', indicate, that, 'gga-miR-130a']), verbo([regulates]), complemento(['HOXA3', and, 'MDFIC', at, the, protein, level, but, not, at, the, mRNA, level])].
[sujeto(['Moreover,', the, 'gga-miR-130a']), verbo([binding]), complemento([sites, of, two, target, genes, have, been, confirmed])].
[sujeto(['We', conclude, that, 'gga-miR-130a', can]), verbo([arrest]), complemento(['MSB1', cell, proliferation, and, 'migration,', and, target, 'HOXA3', and, 'MDFIC,', which, are, both, involved, in, the, regulation, of, cell, proliferation])].
[sujeto(['Collectively,', 'gga-miR-130a', plays, a, critical, role, in, the, tumorigenesis]), verbo([associated]), complemento([with, chicken, 'MD'])].
[sujeto(['Extracellular', stimuli]), verbo([induce]), complemento([gene, expression, responses, through, intracellular, signaling, mediators])].
[sujeto(['To', investigate, the, global, gene, transcription, program]), verbo([regulated]), complemento([by, p38α, during, satellite, cell, differentiation, '(', 'myogenesis),', and, to, specifically, address, whether, this, regulation, occurs, through, direct, action, of, p38α, on, gene, 'promoters,', we, performed, a, combination, of, microarray, gene, expression, and, 'genome-wide', binding, analyses])].
[sujeto(['For', experimental, 'robustness,', two, myogenic, cellular, systems, with, genetic, and, chemical]), verbo([loss]), complemento([of, p38α, function, were, 'used:', '(', 1, ')', satellite, cells, derived, from, mice, with, 'muscle-specific', deletion, of, 'p38α,', and, '(', 2, ')', the, 'C2C12', murine, myoblast, cell, line, cultured, in, the, absence, or, presence, of, the, 'p38α/β', inhibitor, 'SB203580'])].
[sujeto(['We', show, that, p38α]), verbo([binds]), complemento([to, a, large, set, of, active, promoters, during, the, transition, of, myoblasts, from, proliferation, to, differentiation, stages])].
[sujeto(['p38α-bound', promoters, are, enriched, with]), verbo([binding]), complemento([motifs, for, several, transcription, 'factors,', with, 'Sp1,', 'Tcf3/E47,', 'Lef1,', 'FoxO4,', 'MyoD,', and, 'NFATc', standing, out, in, all, experimental, conditions])].
[sujeto(['Interestingly,', p38α, also]), verbo([associates]), complemento([with, genes, repressed, at, the, onset, of, 'differentiation,', thus, highlighting, the, relevance, of, 'p38-dependent', chromatin, regulation, for, transcriptional, activation, and, repression, during, myogenesis])].
[sujeto(['These', results, uncover, p38α, association, and, function, on, chromatin, at, novel, classes, of]), verbo([target]), complemento([genes, during, skeletal, muscle, cell, differentiation])].
[sujeto(['Acute', muscle, injury, and, physiological, stress, from, chronic, muscle, diseases, and, aging]), verbo([lead]), complemento([to, impairment, of, skeletal, muscle, function])].
[sujeto(['This', raises, the, question, of, whether, 'p53,', a, cellular, stress, 'sensor,']), verbo([regulates]), complemento([muscle, tissue, repair, under, stress, conditions])].
[sujeto(['By', investigating, muscle, differentiation, in, the, presence, of, genotoxic, 'stress,', we, discovered, that, p53]), verbo([binds]), complemento([directly, to, the, myogenin, promoter, and, represses, transcription, of, 'myogenin,', a, member, of, the, 'MyoD', family, of, transcription, factors, that, plays, a, critical, role, in, driving, terminal, muscle, differentiation])].
[sujeto(['This', reduction, of, myogenin, protein, is, observed, in, 'G1-arrested', cells, and]), verbo([leads]), complemento([to, decreased, expression, of, late, but, not, early, differentiation, markers])].
[sujeto(['In', response, to, acute, genotoxic, 'stress,', 'p53-mediated', repression, of, myogenin, reduces, 'post-mitotic']), verbo([nuclear]), complemento([abnormalities, in, terminally, differentiated, cells])].
[sujeto(['This', study]), verbo([reveals]), complemento([a, mechanistic, link, previously, unknown, between, p53, and, muscle, 'differentiation,', and, suggests, new, avenues, for, managing, 'p53-mediated', stress, responses, in, chronic, muscle, diseases, or, during, muscle, aging])].
[sujeto(['In', the, present, 'study,', we, performed, a, genome, wide, survey, of, candidate, genes, and, pathways]), verbo([associated]), complemento([with, individual, birth, weight, '(', 'IBW)', using, the, 'Illumina', 'PorcineSNP60', 'BeadChip', on, 24, high, '(', 'HEBV)', and, 24, low, estimated, breeding, value, '(', 'LEBV)', animals])].
[sujeto(['A', 'DSR', with, the, most, number, of, significant, 'SNPs', '(', including, 7, top, 0.1, '%', and, 31, top, 5, '%', 'SNPs)', was, located, on, 'SSC6,', while, another, 'DSR', with, the, largest, genetic, differences, in, 'F', 'ST', was]), verbo([found]), complemento([on, 'SSC18'])].
[sujeto(['These', regions, harbor, known, functionally, important, genes]), verbo([involved]), complemento([in, growth, and, 'development,', such, as, 'TNFRSF9', '(', tumor, necrosis, factor, receptor, superfamily, member, 9, ')', ',', 'CA6', '(', carbonic, anhydrase, 'VI)', and, 'MDFIC', '(', 'MyoD', family, inhibitor, domain, 'containing)'])].
[sujeto(['A', 'DSR', rich, in, imprinting, genes, appeared, on, 'SSC9,', which, included, 'PEG10', '(', paternally]), verbo([expressed]), complemento([10, ')', ',', 'SGCE', '(', 'sarcoglycan,', 'epsilon),', 'PPP1R9A', '(', protein, phosphatase, 1, ',', regulatory, subunit, 9, 'A)', and, 'ASB4', '(', ankyrin, repeat, and, 'SOCS', box, containing, 4, ')'])].
[sujeto(['More', 'importantly,', our, present, study]), verbo([provided]), complemento([evidence, to, support, six, quantitative, trait, loci, '(', 'QTL)', regions, for, pig, birth, 'weight,', six, 'QTL', regions, for, average, birth, weight, '(', 'ABW)', and, three, 'QTL', regions, for, litter, birth, weight, '(', 'LBW)', reported, previously, by, other, groups])].
[sujeto(['Furthermore,', gene, ontology, analysis, with, 183, genes, harbored, in, these, 27, 'DSRs']), verbo([suggested]), complemento([that, 'protein,', 'metal,', ion, and, 'ATP', 'binding,', viral, process, and, innate, immune, response, present, important, pathways, for, deciphering, their, roles, in, fetal, growth, or, development])].
[sujeto(['Overall,', our, study]), verbo([provides]), complemento([useful, information, on, candidate, genes, and, pathways, for, regulating, birth, weight, in, 'piglets,', thus, improving, our, understanding, of, the, genetic, mechanisms, involved, in, porcine, embryonic, or, fetal, development])].
[sujeto(['We']), verbo([have]), complemento([discovered, that, a, 'T-box', family, 'member,', 'TBX2,', is, highly, upregulated, in, tumor, cells, of, both, major, 'RMS', subtypes])].
[sujeto(['The', cell, cycle, regulator, p21, is]), verbo([required]), complemento([for, the, terminal, differentiation, of, skeletal, muscle, cells, and, is, silenced, in, 'RMS', cells])].
[sujeto(['We']), verbo([have]), complemento([found, that, 'TBX2', interacts, with, the, myogenic, regulatory, factors, 'MyoD', and, myogenin, and, inhibits, the, activity, of, these, factors])].
[sujeto(['TBX2', is]), verbo([expressed]), complemento([in, primary, myoblasts, and, 'C2C12', 'cells,', but, is, strongly, downregulated, upon, differentiation])].
[sujeto(['TBX2']), verbo([recruits]), complemento([the, histone, deacetylase, 'HDAC1', and, is, a, potent, inhibitor, of, the, expression, of, 'muscle-specific', genes, and, the, cell, cycle, 'regulators,', p21, and, p14])].
[sujeto(['TBX2']), verbo([promotes]), complemento([the, proliferation, of, 'RMS', cells, and, either, depletions, of, 'TBX2', or, dominant, negative, 'TBX2', upregulate, 'p21-', and, 'muscle-specific', genes])].
[sujeto(['Significantly,', depletion, or, interference, with, 'TBX2', completely]), verbo([inhibits]), complemento([tumor, growth, in, a, xenograft, 'assay,', highlighting, the, oncogenic, role, of, 'TBX2', in, 'RMS', cells])].
[sujeto(['Thus,', the, data, demonstrate, that, elevated, expression, of, 'TBX2', contributes, to, the, pathology, of, 'RMS', cells, by]), verbo([promoting]), complemento([proliferation, and, repressing, 'differentiation-specific', gene, expression])].
[sujeto(['These', results, show, that, deregulated, 'TBX2', serves, as, an, oncogene, in, 'RMS,']), verbo([suggesting]), complemento([that, 'TBX2', may, serve, as, a, new, diagnostic, marker, or, therapeutic, target, for, 'RMS', tumors])].
[sujeto(['I-mfa', null, mice]), verbo([have]), complemento([an, osteopenic, phenotype, characterized, by, increased, osteoclast, numbers, and, 'surface,', which, are, normalized, in, mice, lacking, both, 'Trpc1', and, 'I-mfa'])].
[sujeto(['In', vitro, differentiation, of, 'pre-osteoclasts', derived, from, 'I-mfa-deficient', mice]), verbo([leads]), complemento([to, an, increased, number, of, mature, osteoclasts, and, higher, bone, resorption, per, osteoclast])].
[sujeto(['Consistently,', whole, cell, currents]), verbo([activated]), complemento([in, response, to, the, depletion, of, intracellular, 'Ca(2+)', stores, are, larger, in, 'pre-osteoclasts', derived, from, 'I-mfa', 'knock-out', mice, compared, with, currents, in, wild, type, mice, and, normalized, in, cells, derived, from, double, mutant, 'mice,', suggesting, a, 'cell-autonomous', effect, of, 'I-mfa', on, 'TRPC1', in, these, cells])].
[sujeto(['Heterologous', expression, of, 'TRPC1ε', in, 'HEK293', cells, revealed, that, it, is, unique, among, all, known, 'TRPC1', isoforms, in, its, ability, to, amplify, the, activity, of, the, 'Ca(2+)', 'release-activated', 'Ca(2+)', '(', 'CRAC)', 'channel,']), verbo([mediating]), complemento(['store-operated', currents])].
[sujeto(['TRPC1ε', physically]), verbo([interacts]), complemento([with, 'Orai1,', the, 'pore-forming', subunit, of, the, 'CRAC', 'channel,', and, 'I-mfa', is, recruited, to, the, 'TRPC1ε-Orai1', complex, through, 'TRPC1ε', suppressing, 'CRAC', channel, activity])].
[sujeto(['We', propose, that, the, positive, and, negative, modulation, of, the, 'CRAC', channel, by, 'TRPC1ε', and, 'I-mfa,', 'respectively,', 'fine-tunes', the, dynamic, range, of, the, 'CRAC', channel]), verbo([regulating]), complemento([osteoclastogenesis])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, a, natural, compound, of, the, hydroxybenzoquinone, 'class,', 'embelin,', specifically, inhibits, 'H3Lys9', acetylation, in, mice, and, inhibits, recombinant, 'PCAF-mediated', acetylation, with, near, complete, specificity, in, vitro])].
[sujeto(['Furthermore,', using, 'embelin,', we]), verbo([have]), complemento([identified, the, gene, networks, that, are, regulated, by, 'PCAF', during, muscle, 'differentiation,', further, highlighting, the, broader, regulatory, functions, of, 'PCAF', in, muscle, differentiation, in, addition, to, the, regulation, via, 'MyoD', acetylation])].
[sujeto(['Ephrin-A5', is, a, chemotactic, molecule, that]), verbo([participates]), complemento([in, the, correct, positioning, and, formation, of, the, 'NMJ'])].
[sujeto(['Treatment', of, the, 'BSC', with, 'ephrin-A5']), verbo([causes]), complemento([a, reduction, '(', 'P', &, 'lt;', 0.05, ')', in, velocity, with, a, concomitant, increase, '(', 'P', &, 'lt;', 0.05, ')', in, directed, migration])].
[sujeto(['Ephrin-A5']), verbo([induced]), complemento([migration, appears, to, require, components, of, the, 'Ras', homolog, gene, family, member, 'A', '(', 'RhoA)', and, 'Rho-associated', protein, kinase, '(', 'ROCK)', signaling, machinery])].
[sujeto(['Supplementation', of, culture, media, with, a, chemical, 'ROCK', inhibitor]), verbo([suppressed]), complemento(['(', 'P', &, 'lt;', 0.05, ')', 'ephrin-A5', initiated, 'BSC', migration])].
[sujeto(['Twenty-four', hours, after, culture, 'establishment,', 'BSC', demonstrated, an]), verbo([increase]), complemento(['(', 'P', &, 'lt;', 0.05, ')', in, transwell, migration, toward, 'HGF'])].
[sujeto(['These', results, document, that, temporal, and, spatial, gradients, of, chemokines, and, growth, factors]), verbo([participate]), complemento([in, the, localization, of, 'BSC', within, the, niche])].
[sujeto(['The', class, 'IIa', histone, deacetylases, '(', 'HDACs)']), verbo([act]), complemento([as, transcriptional, repressors, by, altering, chromatin, structure, through, histone, deacetylation])].
[sujeto(['This', family, of, enzymes]), verbo([regulates]), complemento([muscle, development, and, 'phenotype,', through, regulation, of, 'muscle-specific', genes, including, myogenin, and, 'MyoD', '(', 'MYOD1)'])].
[sujeto(['More', 'recently,', class, 'IIa', 'HDACs']), verbo([have]), complemento([been, implicated, in, regulation, of, genes, involved, in, glucose, metabolism])].
[sujeto(['However,', the, effects, of, 'HDAC5', on, glucose, metabolism, and, insulin, action]), verbo([have]), complemento([not, been, directly, assessed])].
[sujeto(['Knockdown', of, 'HDAC5', in, human, primary, muscle, cells]), verbo([increased]), complemento([glucose, uptake, and, was, associated, with, increased, 'GLUT4', '(', 'SLC2A4)', expression, and, promoter, activity, but, was, associated, with, reduced, 'GLUT1', '(', 'SLC2A1)', expression])].
[sujeto(['The', effects, of, 'HDAC5', knockdown, on, glucose, metabolism, were, not, due, to, alterations, in, the, initiation, of, 'differentiation,', as, knockdown, of, 'HDAC5', after, the, onset, of, differentiation, also, resulted, in]), verbo([increased]), complemento([glucose, uptake, and, 'insulin-stimulated', glycogen, synthesis])].
[sujeto(['These', data, show, that, inhibition, of, 'HDAC5']), verbo([enhances]), complemento([metabolism, and, insulin, action, in, muscle, cells])].
[sujeto(['In', 'myotubes,', 'Scriptaid']), verbo([increased]), complemento([histone, 3, 'acetylation,', 'GLUT4', 'expression,', glucose, uptake, and, both, oxidative, and, 'non-oxidative', metabolic, flux])].
[sujeto(['Together,', these, data]), verbo([suggest]), complemento([that, 'HDAC5', regulates, muscle, glucose, metabolism, and, insulin, action, and, that, 'HDAC', inhibitors, can, be, used, to, modulate, these, parameters, in, muscle, cells])].
[sujeto(['Skeletal', muscle, differentiation, is]), verbo([regulated]), complemento([by, transcription, 'factors,', including, members, of, the, myogenic, regulatory, factor, '(', 'MRF)', family, and, many, signaling, pathways])].
[sujeto(['The', 'JAK1', and, 'JAK2', pathways, are, known, to, each]), verbo([have]), complemento([different, effects, on, myoblast, proliferation, and, 'differentiation;', 'however,', the, role, of, 'JAK3', in, myoblast, differentiation, remains, unclear])].
[sujeto(['During', myogenic, 'differentiation,', treatment, with, the, 'JAK3', inhibitor, 'WHIp154', significantly]), verbo([increased]), complemento([the, number, of, 'MHC-positive', multinucleated, myotubes, and, the, expressions, of, myosin, heavy, chain, '(', 'MHC),', myogenin, '(', 'MGN),', 'MyoD,', and, myogenic, enhancer, factor, 2, '(', 'MEF2)'])].
[sujeto(['Knockdown', of, the, 'JAK3', gene, using, siJAK3, also, significantly]), verbo([increased]), complemento(['MHC,', 'MGN', and, 'MyoD', mRNA, expressions, as, well, as, 'insulin-like', growth, 'factor-II', '(', 'IGF-II)', gene, expression])].
[sujeto(['During', 'differentiation,', 'JAK3', was, initially]), verbo([activated]), complemento([and, later, decreased])].
[sujeto(['Differentiation']), verbo([decreased]), complemento(['STAT1,', which, was, further, decreased, by, 'WHIp154'])].
[sujeto(['In', 'contrast,', 'STAT3', gradually, was, elevated, during, 'differentiation,', and, was]), verbo([increased]), complemento([by, 'JAK3', inhibition])].
[sujeto(['Moreover,', we]), verbo([found]), complemento([that, 'up-regulation', of, 'AKT', activity, and, 'down-regulation', of, 'ERK', activity, cooperated, to, accelerate, myogenic, differentiation])].
[sujeto(['Additionally,', 'JAK3', inhibition]), verbo([induced]), complemento([precocious, differentiation, and, played, important, roles, for, terminal, 'differentiation,', including, 'fusion,', which, is, involved, with, regulation, of, 'AKT', and, 'ERK', pathways])].
[sujeto(['Expression', of]), verbo([phosphorylated]), complemento(['Smad1/5/8,', which, is, an, indicator, of, 'BMP', 'activity,', was, higher, before, 'differentiation,', and, rapidly, decreased, after, differentiation, stimulation])].
[sujeto(['Treatment', with, inhibitors, of, 'BMP', type, 'I', receptors, or, noggin, in, 'C2C12', myoblasts, 'down-regulated', the, expression, of, myogenic, regulatory, 'factors,', such, as, 'Myf5', and, 'MyoD,']), verbo([leading]), complemento([to, impaired, myotube, formation])].
[sujeto(['Addition', of, 'BMP-2', during, the, myoblast, phase, also]), verbo([inhibited]), complemento([myotube, differentiation, through, the, 'down-regulation', of, 'Myf5', and, 'MyoD'])].
[sujeto(['A-83-01,', an, inhibitor, of, 'TGF-β', type, 'I', 'receptor,']), verbo([increased]), complemento([the, expression, of, 'Myf5', and, 'MyoD,', and, enhanced, myotube, formation])].
[sujeto(['The', present, results]), verbo([reveal]), complemento([that, endogenous, activities, of, the, 'TGF-β', family, are, changed, during, myogenesis, in, a, 'pathway-specific', 'manner,', and, that, the, activities, are, required, for, myogenesis])].
[sujeto(['Differentiation', often]), verbo([requires]), complemento([conversion, of, analogue, signals, to, a, stable, binary, output, through, positive, feedback])].
[sujeto(['Hedgehog', '(', 'Hh)', signalling]), verbo([promotes]), complemento([myogenesis, in, the, vertebrate, 'somite,', in, part, by, raising, the, activity, of, muscle, regulatory, factors, '(', 'MRFs)', of, the, 'Myod', family, above, a, threshold])].
[sujeto(['Hh', is, known, to]), verbo([enhance]), complemento(['MRF', expression])].
[sujeto(['Here', we, show, that, 'Hh', is, also, essential, at, a, second, step, that]), verbo([increases]), complemento(['Myod', protein, 'activity,', permitting, it, to, promote, 'Myogenin', expression])].
[sujeto(['Hh']), verbo([acts]), complemento([by, inducing, expression, of, cdkn1c, '(', 'p57(Kip2))', in, slow, muscle, precursor, 'cells,', but, neither, 'Hh', nor, 'Cdkn1c', is, required, for, their, cell, cycle, exit])].
[sujeto(['Myod', in, turn, 'up-regulates', 'cdkn1c,', thereby]), verbo([providing]), complemento([a, positive, feedback, loop, that, switches, myogenic, cells, to, terminal, differentiation])].
[sujeto(['We', show, here, that, 'OSM', potently]), verbo([inhibited]), complemento([myoblast, differentiation, mainly, by, activating, the, 'JAK1/STAT1/STAT3', pathway])].
[sujeto(['OSM', downregulated, myocyte, 'enhancer-binding', factor, 2, 'A', '(', 'MEF2A),', upregulated, the, expression, of, 'Id1', and, 'Id2,', and]), verbo([inhibited]), complemento([the, transcriptional, activity, of, 'MyoD', and, 'MEF2'])].
[sujeto(['In', 'addition,', 'OSM', also]), verbo([enhanced]), complemento([the, expression, of, 'STAT3', and, 'OSM', 'receptor,', which, constituted, a, positive, feedback, loop, to, further, amplify, 'OSM-induced', signaling])].
[sujeto(['Moreover,', we]), verbo([found]), complemento([that, 'STAT1', physically, associated, with, 'MEF2', and, repressed, its, transcriptional, 'activity,', which, could, account, for, the, 'OSM-mediated', repression, of, 'MEF2'])].
[sujeto(['Although', undetectable, in, normal, muscles, in, 'vivo,', 'OSM', was, rapidly]), verbo([induced]), complemento([on, muscle, injury, and, then, promptly, downregulated, just, before, the, majority, of, myoblasts, differentiate])].
[sujeto(['Prolonged', expression, of, 'OSM', in, muscles, compromised, the, regeneration, process, without, affecting, myoblast, 'proliferation,']), verbo([suggesting]), complemento([that, 'OSM', functions, to, prevent, proliferating, myoblasts, from, premature, differentiation, during, the, early, phase, of, muscle, regeneration])].
[sujeto(['Splitting', 'Fluc', into, 'N-', and, 'C-terminal', fragments, destroys, its, enzymatic, 'activity,', resulting, in, a, complete]), verbo([loss]), complemento([of, bioluminescence])].
[sujeto(['This']), verbo([led]), complemento([to, the, development, of, a, novel, labeling, strategy, for, imaging, 'protein–protein', interactions, in, 'vivo,', the, split, reporter, '(', 4, ')'])].
[sujeto(['In', this, 'method,', reporters, like, 'Fluc', are, dissected, into, two, fragments, and, fused, to, a, pair, of, proteins, '(', 'A', and, 'B)', that, strongly]), verbo([interact]), complemento([with, each, other])].
[sujeto(['The', interaction, between, protein, 'A', and, 'B', brings, the, 'N-', and, 'C-inteins', 'together,', resulting, in, the, joining, of, 'N-', and, 'C-terminal', fragments, of, 'Fluc', by, a, peptide, bond, and, a]), verbo([release]), complemento([of, a, fully, reconstituted, protein, 'Fluc'])].
[sujeto(['MyoD']), verbo([activates]), complemento([myogenesis, by, binding, directly, to, the, control, region, of, 'muscle-specific', 'genes,', and, it, converts, fibroblasts, into, skeletal, muscle])].
[sujeto(['The', helices, in, 'MyoD']), verbo([bind]), complemento([tightly, with, other, 'HLH', factors, such, as, 'Id', to, form, a, heterodimer])].
[sujeto(['Id,', also, known, as, an, inhibitor, of, differentiation, or, inhibitor, of, 'DNA', 'binding,', lacks, the, basic, domain, for, 'DNA']), verbo([binding]), complemento([and, acts, as, dominant, negative, regulator, in, myogenesis, or, other, cell, proliferations, '(', 6, ')'])].
[sujeto(['Id', 'protein-firefly', luciferase, 'N-fragment', &, 'amp;', firefly, luciferase, 'C-fragment-MyoD', protein, '(', 'Id-NFluc', &, 'amp;', 'CFluc-MyoD)', make, up, a, pair, of]), verbo([interacting]), complemento([proteins, attached, to, the, split, 'Fluc', fragments, '(', 7, ')'])].
[sujeto(['Kaposi\'s', 'sarcoma-associated', herpes, virus, '(', 'KSHV)-encoded', 'latency-associated']), verbo([nuclear]), complemento([antigen, '(', 'LANA)', protein, has, been, reported, to, interact, with, glycogen, synthase, kinase, 3, beta, '(', 'GSK-3beta)', and, to, negatively, regulate, its, 'activity,', leading, to, stimulation, of, 'GSK-3beta-dependent', 'beta-catenin', degradation])].
[sujeto(['We', show, here, that, the, 'I-mfa', domain, 'proteins,', 'HIC', '(', human, 'I-mfa', 'domain-containing', 'protein)', and, 'I-mfa', '(', inhibitor, of, 'MyoD', family, 'a),']), verbo([interacted]), complemento([in, vivo, with, 'LANA', through, their, 'C-terminal', 'I-mfa', domains])].
[sujeto(['This', interaction, affected, the, intracellular, localization, of, 'HIC,']), verbo([inhibited]), complemento([the, 'LANA-dependent', transactivation, of, a, 'beta-catenin-regulated', reporter, 'construct,', and, decreased, the, level, of, the, 'LANA'])].
[sujeto(['These', data]), verbo([reveal]), complemento([for, the, first, time, that, 'I-mfa', domain, proteins, interact, with, 'LANA', and, negatively, regulate, 'LANA-mediated', activation, of, 'Wnt', 'signaling-dependent', transcription, by, inhibiting, the, formation, of, the, 'LANA'])].
[sujeto(['MyoD', is, a, 'DNA-binding', protein, capable, of, specific, interactions, that]), verbo([involve]), complemento([the, 'helix-loop-helix', '(', 'HLH)', domain])].
[sujeto(['The', 'Id', family, consists, of, four, related, proteins, that, contain, a, highly]), verbo([conserved]), complemento([dimerization, motif, known, as, the, 'HLH', domain])].
[sujeto(['In', signaling, 'pathways,', 'Id', proteins]), verbo([act]), complemento([as, dominant, negative, antagonists, of, the, basic, 'helix-loop-helix', '(', 'bHLH)', family, of, transcription, factors, which, play, important, roles, in, cellular, 'development,', 'proliferation,', and, differentiation])].
[sujeto(['The', mechanism, of, 'Id', proteins, is, to, antagonize, bHLH, proteins, by]), verbo([binding]), complemento([as, dominant, negative, 'HLH', proteins, to, form, 'high-affinity', heterodimers, with, other, bHLH, 'proteins,', thereby, preventing, them, from, binding, to, 'DNA', and, inhibiting, transcription, of, 'differentiation-associated', genes])].
[sujeto(['The', goal, of, this, study, is, to, design, and, synthesize, peptide, fragments, of, 'MyoD', with, high, affinity, for, 'Id1', to, interrupt, the, interactions, among, 'Id1,', 'MyoD,', and, other, bHLH, 'DNA-binding', proteins, and, to]), verbo([inhibit]), complemento([the, proliferation, of, cancer, cells])].
[sujeto(['The', percentage, of, 'sub-G1', in, the, cell, cycle, of, the, cancer, cells, treated, with, 5, microM, of, 3, 'C', was, 'increased,', indicating, the]), verbo([induced]), complemento([apoptosis, of, cancer, cells, by, 3, 'C'])].
[sujeto(['Taken', 'together,', the, peptide, 3, 'C', is, a, promising]), verbo([lead]), complemento([compound, for, the, development, of, antiproliferative, agents])].
[sujeto(['Most', growth, factors]), verbo([stimulate]), complemento([myoblast, proliferation, and, prevent, 'differentiation,', whereas, 'insulin-like', growth, factors, '(', 'IGFs)', promote, myoblast, differentiation, through, the, phosphatidylinositol, 3, -, kinase, '(', 'PI3K)', pathway])].
[sujeto(['Subtilisin-like', proprotein, convertases, '(', 'SPCs)', are]), verbo([involved]), complemento([in, cell, growth, and, differentiation, via, activation, of, 'pro-growth', factors])].
[sujeto(['PACE4', mRNA, levels]), verbo([increased]), complemento([markedly, during, 'myogenesis,', whereas, the, expression, of, other, member, of, 'SPC', 'family,', furin, and, 'PC6,', remained, unchanged])].
[sujeto(['The', expression, of, shRNA]), verbo([targeting]), complemento(['PACE4,', but, not, 'furin,', suppressed, the, expression, of, the, 'muscle-specific', myosin, light, chain, '(', 'MLC)'])].
[sujeto(['Finally,', we, demonstrated, that, the, 'PI3K', inhibitor, 'LY294002', blocked, the, induction, of, 'PACE4', 'mRNA,', a, result, not, observed, when, another, myogenic, differentiation, 'inhibitor,', 'SB203580', '(', p38, 'MAP', kinase, 'inhibitor),', was, 'employed,', indicating, the, presence, of, a, positive, feedback, loop]), verbo([regulating]), complemento(['PACE4', expression])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'PACE4', plays, an, important, role, in, myogenic, differentiation, through, its, association, with, the, 'IGF-II', pathway])].
[sujeto(['Nuclear', localization, of, 'N', is, 'non-essential', for, 'PRRSV', replication, in, cultured, cells, but]), verbo([has]), complemento([been, shown, to, modulate, the, pathogenesis, of, virus, in, 'pigs,', suggesting, that, 'N', plays, an, accessory, role, in, the, nucleus, during, infection])].
[sujeto(['The', porcine, homolog, of, 'HIC', is, universally]), verbo([expressed]), complemento([in, pig, tissues, including, alveolar, macrophages])].
[sujeto(['The', 'I-mfa', domain, proteins, 'HIC', '(', also, known, as, 'MDFIC)', and, 'I-mfa', '(', also, known, as, 'MDFI)', are, candidate, tumor, suppressor, genes, that, are]), verbo([involved]), complemento([in, cellular, and, viral, transcriptional, regulation])].
[sujeto(['Here,', we, show, that, 'HIC', and, 'I-mfa', directly]), verbo([interact]), complemento([with, human, 'T-cell', leukemia, virus, 'type-1', '(', 'HTLV-1)', 'Tax', protein, in, vitro])].
[sujeto(['In', 'addition,', 'HIC', and, 'I-mfa']), verbo([repress]), complemento(['Tax-dependent', transactivation, of, an, 'HTLV-1', long, terminal, repeat, '(', 'LTR)', reporter, construct, in, 'COS-1,', 'Jurkat', and, 'high-Tax-producing', 'HTLV-1-infected', 'T', cells])].
[sujeto(['HIC', also]), verbo([interacts]), complemento([with, 'Tax', through, its, 'I-mfa', domain, in, vivo, and, represses, 'Tax-dependent', transactivation, of, 'HTLV-1', 'LTR', and, 'NF-κB', reporter, constructs, in, an, 'interaction-dependent', manner])].
[sujeto(['Furthermore,', we, show, that, 'HIC']), verbo([decreases]), complemento([the, nuclear, distribution, and, stimulates, the, proteasomal, degradation, of, 'Tax'])].
[sujeto(['These', data]), verbo([reveal]), complemento([that, 'HIC', specifically, interacts, with, 'HTLV-1', 'Tax', and, negatively, regulates, 'Tax', transactivational, activity, by, altering, its, subcellular, distribution, and, stability])].
[sujeto(['Furthermore,', 'genome-wide', 'DNA']), verbo([binding]), complemento([of, p53, was, analyzed, by, 'chromatin-immunoprecipitation', '(', 'ChIP-Seq)'])].
[sujeto(['Thereby,', we, identified, differentially]), verbo([regulated]), complemento([proteins, '(', 542, 'up,', 569, 'down),', mRNAs, '(', 1258, 'up,', 415, 'down),', miRNAs, '(', 111, 'up,', 95, 'down)', and, lncRNAs, '(', 270, 'up,', 123, 'down)'])].
[sujeto(['In', 'total,', we, detected, 133, direct, p53]), verbo([target]), complemento([genes, that, were, differentially, expressed, and, displayed, p53, occupancy, in, the, vicinity, of, their, promoter])].
[sujeto(['More', transcriptionally]), verbo([induced]), complemento([genes, displayed, occupied, p53, binding, sites, '(', 4.3, '%', 'mRNAs,', 7.2, '%', 'miRNAs,', 6.3, '%', 'lncRNAs,', 5.9, '%', 'proteins)', than, repressed, genes, '(', 2.4, '%', 'mRNAs,', 3.2, '%', 'miRNAs,', 0.8, '%', 'lncRNAs,', 1.9, '%', 'proteins),', suggesting, indirect, mechanisms, of, repression])].
[sujeto(['Moreover,', proteins]), verbo([repressed]), complemento([by, p53, significantly, overlapped, with, those, previously, shown, to, be, repressed, by, 'miR-34a'])].
[sujeto(['We', confirmed, 'up-regulation', of, the, novel, direct, p53]), verbo([target]), complemento([genes, 'LINC01021,', 'MDFI,', 'ST14', and, 'miR-486', and, showed, that, ectopic, 'LINC01021', expression, inhibits, proliferation, in, 'SW480', cells])].
[sujeto(['Furthermore,', 'KLF12,', 'HMGB1', and, 'CIT', mRNAs, were, confirmed, as, direct]), verbo([targets]), complemento([of, the, 'p53-induced', 'miR-34a,', 'miR-205', and, 'miR-486-5p,', respectively])].
[sujeto(['In', line, with, the]), verbo([loss]), complemento([of, p53, function, during, tumor, 'progression,', elevated, expression, of, 'KLF12,', 'HMGB1', and, 'CIT', was, detected, in, advanced, stages, of, cancer])].
[sujeto(['In', 'conclusion,', the, integration, of, multiple, omics, methods, allowed, the, comprehensive, identification, of, direct, and, indirect, effectors, of, p53, that]), verbo([provide]), complemento([new, insights, and, leads, into, the, mechanisms, of, 'p53-mediated', tumor, suppression])].
[sujeto(['However,', certain, patients, develop, drug, resistance, following, 'chemotherapy,', which, can]), verbo([lead]), complemento([to, disease, relapse, and, death])].
[sujeto(['Subgroups,', personalized, 'biomarkers,', and, therapy]), verbo([targets]), complemento([were, identified, using, cluster, analysis, of, differentially, expressed, genes])].
[sujeto(['We']), verbo([found]), complemento([that, 'basal-like', breast, cancer, could, be, further, divided, into, at, least, four, distinct, 'subgroups,', including, two, groups, at, risk, for, drug, resistance, and, two, groups, characterized, by, sensitivity, to, pharmacotherapy])].
[sujeto(['Therefore,', these, nine, differentially]), verbo([expressed]), complemento([genes, and, their, associated, functional, pathways, should, provide, the, basis, for, novel, personalized, clinical, treatments, of, 'basal-like', breast, cancer])].
[sujeto(['The', identified, hypermethylation, markers, in, 'CRC', patients, may]), verbo([have]), complemento([good, sensitivity, in, different, 'CRC', stages])].
[sujeto(['Whole', human, genome, oligo, microarray, was, applied, to, detect, the, differentially]), verbo([expressed]), complemento([genes, in, invasive, cells])].
[sujeto(['For', primary, cultured, invasive, 'cells,', differential, expressions, of, several, groups, of, common, genes, are, known, to]), verbo([have]), complemento([capacities, to, promote, proliferation, '(', 'CAV1,', 'IL6,', 'PLAT,', 'RRAD,', 'SRPX),', remodeling, of, extracellular, matrix, '(', 'COL1A1,', 'COL1A2,', 'NID2,', 'TNC,', 'RELN,', 'SPARC),', migration, '(', 'ACTG2,', 'CAV1,', 'CCL2,', 'CCL26,', 'CDC42EP3,', 'CNN1,', 'PHLDB2,', 'PLAT,', 'RRAD,', 'SRPX),', implantation, '(', 'IL6),', immune, escape, '(', 'CD70)', and, angiogenesis, '(', 'CCL2,', 'IL6,', 'IL18,', 'PLAT,', 'SLIT3)'])].
[sujeto(['In', 'conclusion,', the, characteristics, of, invasive, phenotype, 'HCC', cells, are, originated, from, differential, expressions, of, several, groups, of, genes, rather, than, few]), verbo([target]), complemento([genes])].
[sujeto(['Analysis', of, the, results, from, a, purchased, cell, line, may]), verbo([have]), complemento([bias, due, to, 'long-term', repeated, in, vitro, cultures])].
[sujeto(['Many', 'QTLs', for, fatness, traits]), verbo([have]), complemento([been, mapped, on, pig, chromosome, 7, q1])].
[sujeto(['Eight', novel, 'markers,', including, seven, 'SNPs', and, one, insertion, or, deletion, within, 'BTNL1,', 'COL21A1,', 'PPARD,', 'GLP1R,', 'MDFI,', 'GNMT,', 'ABCC10,', and, 'PLA2G7', 'genes,', as, well, as, two, previously]), verbo([reported]), complemento(['SNPs', in, 'SLC39A7', and, 'HMGA1', 'genes,', were, genotyped, in, 'Large', 'White', and, 'Meishan', pig, breeds])].
[sujeto(['Nine']), verbo([target]), complemento([genes, were, assayed, by, 'real-time', 'methylation-specific', polymerase, chain, reaction, '(', 'MSP)', in, 'bisulfite-treated', 'DNA', from, microdissected, frozen, specimens, of, 24, 'PanC', cases, and, 30, normal, colon, controls])].
[sujeto(['Combining', methylated, 'BMP3', and, mutant, 'KRAS']), verbo([increased]), complemento([stool, detection, over, either, marker, alone])].
[sujeto(['In', an, alkaline, 'medium,', the, chemiluminescence, '(', 'CL)', reaction, of, imidazole, derivatives, with, 'H(2)O(2)']), verbo([has]), complemento([been, investigated])].
[sujeto(['It', was, also]), verbo([found]), complemento([that, 'MDFI/H(2)O(2)', and, 't-BDFI/H(2)O(2)', systems, gave, strong, 'CL'])].
[sujeto(['Migraine', is]), verbo([associated]), complemento([with, an, increased, risk, for, cardiovascular, disease, '(', 'CVD)'])].
[sujeto(['We', performed, a, 'genome-wide', association, study, for, incident, 'CVD', events, during, 12, years, of, 'follow-up', among, 5, ',', 122, migraineurs]), verbo([participating]), complemento([in, the, 'population-based', 'Women\'s', 'Genome', 'Health', 'Study'])].
[sujeto(['No', 'SNP', was]), verbo([associated]), complemento([with, major, 'CVD,', ischemic, 'stroke,', myocardial, 'infarction,', or, 'CVD', death, at, the, 'genome-wide', 'level;', 'however,', five, 'SNPs', showed, association, with, 'p<5×10(-6)'])].
[sujeto(['Among', migraineurs, with, aura, rs7698623, in, 'MEPE', '(', 'OR', =, 6.37, ;, 95, '%', 'CI', 3.15, -, 12.9, ;, p, =, 2.7, '×10(-7))', and, rs4975709, in, 'IRX4', '(', 'OR', =, 5.06, ;, 95, '%', 'CI', 2.66, -, 9.62, ;, p, =, 7.7, '×10(-7))', appeared, to, be]), verbo([associated]), complemento([with, ischemic, 'stroke,', rs2143678, located, close, to, 'MDF1', with, major, 'CVD', '(', 'OR', =, 3.05, ;, 95, '%', 'CI', 1.98, -, 4.69, ;, p, =, 4.3, '×10(-7)),', and, the, intergenic, rs1406961, with, 'CVD', death, '(', 'OR', =, 12.33, ;, 95, '%', 'CI', 4.62, -, 32.87, ;, p, =, 5.2, '×10(-7))'])].
[sujeto(['Further,', rs1047964, in, 'BACE1', appeared, to, be]), verbo([associated]), complemento([with, 'CVD', death, among, women, with, any, migraine, '(', 'OR', =, 4.67, ;, 95, '%', 'CI', 2.53, -, 8.62, ;, p, =, 8.0, '×10(-7))'])].
[sujeto(['Our', results]), verbo([provide]), complemento([some, suggestion, for, an, association, of, five, 'SNPs', with, 'CVD', events, among, women, with, 'migraine;', none, of, the, results, was, 'genome-wide', significant])].
[sujeto(['The', 'I-mfa', domain, proteins, 'I-mfa', and, 'HIC', are, considered, to, be, candidate, tumor, suppressor, genes, and]), verbo([have]), complemento([been, shown, to, be, involved, in, transcriptional, regulation])].
[sujeto(['We', show, here, that, 'I-mfa', and, 'HIC', specifically]), verbo([interact]), complemento([with, 'SEI-1', through, their, 'C-terminal', 'I-mfa', domains, 'in vivo'])].
[sujeto(['This', interaction, affects, the, intracellular, localization, of, 'I-mfa', and]), verbo([requires]), complemento([the, region, of, 'SEI-1', between, 30, and, 90, amino, 'acids,', which, includes, its, 'SERTA', 'domain,', and, results, in, repression, of, its, intrinsic, transcriptional, activity])].
[sujeto(['I-mfa', also]), verbo([decreases]), complemento([the, levels, of, the, 'SEI-1·DP-1', complex, and, endogenous, 'Fbxw7', 'mRNA,', the, expression, of, which, is, coregulated, by, 'E2F·DP-1', and, 'SEI-1', in, an, 'interaction-dependent', manner, 'in vitro'])].
[sujeto(['In', 'addition,', 'I-mfa', also, specifically]), verbo([interacts]), complemento([with, other, 'SERTA', 'domain-containing', 'proteins,', including, 'SEI-2,', 'SEI-3,', 'SERTAD3', and, 'SERTAD4,', through, its, 'I-mfa', domain, 'in vivo'])].
[sujeto(['This', interaction, also, affects, the, intracellular, localization, of, 'I-mfa', and]), verbo([represses]), complemento([the, intrinsic, transcriptional, activities, of, 'SEI-2', and, 'SERTAD3,', which, are, also, involved, in, the, 'E2F-dependent', transcription])].
[sujeto(['These', data]), verbo([reveal]), complemento([for, the, first, time, that, 'I-mfa', domain, proteins, interact, with, 'SERTA', domain, proteins, and, negatively, regulate, their, transcriptional, activity])].
[sujeto(['Because', 'SEI-1,', 'SEI-2', and, 'SERTAD3,', whose, intrinsic, transcriptional, activities, are]), verbo([repressed]), complemento([by, 'I-mfa,', are, suggested, to, be, 'oncogenes,', 'I-mfa', domain, proteins, may, be, involved, in, their, oncogenic, functions, by, negatively, regulating, their, transcriptional, activities])].
[sujeto(['The', phenotypes, of, the, 'Scnm1Delta3-5', mutant, confirm, the, role, of, this, splice, factor, in, processing, the, 'Scn8a(medJ)', transcript, and]), verbo([provide]), complemento([a, new, allele, of, greater, severity, for, future, studies])].
[sujeto(['More', than, 1, /, 2, of, the, genes, aberrantly, hypermethylated, in, 'Panc-1', were, not]), verbo([expressed]), complemento([in, the, pancreatic, duct, '(', 'HPDE)', by, expression, array, analysis])].
[sujeto(['Promoter', and, 'CpG', island, array, analysis]), verbo([finds]), complemento([aberrant, methylation, of, hundreds, of, promoters, and, 'CpG', islands, in, pancreatic, cancer, cells])].
[sujeto(['A', commercial, chromogenic, agar, medium, '(', 'DFI)', was, supplemented, with, glucose, '(', 'mDFI)', to]), verbo([enhance]), complemento([the, specificity, of, 'Enterobacter', sakazakii, '(', 'E'])].
[sujeto(['In', these, patients, the, discriminatory, function, index, '(', 'DFI)', &, 'gt;', 32, ',']), verbo([has]), complemento([been, associated, with, a, mortality, rate, of, up, to, 50, '%'])].
[sujeto(['MELD', is, a, scale, that]), verbo([has]), complemento([been, recently, validated, as, independent, risk, factors, for, death, in, patients, who, are, candidates, for, liver, transplantation])].
[sujeto(['Wnt', regulation, of, muscle, development, is, thought, to, be]), verbo([mediated]), complemento([by, the, 'beta-catenin-TCF/LEF-dependent', canonical, pathway])].
[sujeto(['Here', we, demonstrate, that, 'beta-catenin,', not, 'TCF/LEF,', is]), verbo([required]), complemento([for, muscle, differentiation])].
[sujeto(['We', showed, that, 'beta-catenin']), verbo([interacts]), complemento([directly, with, 'MyoD,', a, basic, 'helix-loop-helix', transcription, factor, essential, for, muscle, differentiation, and, enhances, its, binding, to, 'E', box, elements, and, transcriptional, activity])].
[sujeto(['MyoD-mediated', transactivation, is]), verbo([inhibited]), complemento([in, muscle, cells, when, 'beta-catenin', is, deficient, or, the, interaction, between, 'MyoD', and, 'beta-catenin', is, disrupted])].
[sujeto(['We', identify, a, novel, interaction, of, 'Hand1', with, a, protein, that, contains, an, 'I-mfa', '(', inhibitor, of, myogenic, 'factor)', domain, that, anchors, 'Hand1', in, the, nucleolus, where, it, negatively]), verbo([regulates]), complemento(['Hand1', activity])].
[sujeto(['In', the, trophoblast, 'stem-cell', line, 'Rcho-1,', nucleolar, sequestration, of, 'Hand1', accompanies, sustained, cell, proliferation, and, 'renewal,', whereas]), verbo([release]), complemento([of, 'Hand1', into, the, nucleus, leads, to, its, 'activation,', thus, committing, cells, to, a, differentiated, 'giant-cell', fate])].
[sujeto(['Site-specific', phosphorylation, is]), verbo([required]), complemento([for, nucleolar, release, of, 'Hand1,', for, its, dimerization, and, biological, 'function,', and, this, is, mediated, by, the, 'non-canonical', 'polo-like', kinase, 'Plk4', '(', 'Sak)'])].
[sujeto(['Sak', is, 'co-expressed', in, 'Rcho-1', 'cells,', localizes, to, the, nucleolus, during, 'G2', and]), verbo([phosphorylates]), complemento(['Hand1', as, a, requirement, for, trophoblast, 'stem-cell', commitment, to, a, 'giant-cell', fate])].
[sujeto(['This', study, defines, a, novel, cellular, mechanism, for]), verbo([regulating]), complemento(['Hand1', that, is, a, crucial, step, in, the, 'stem-cell', differentiation, pathway])].
[sujeto(['Positive', transcription, elongation, factor, b, '(', 'P-TEFb)', 'complexes,', composed, of, 'cyclin-dependent', kinase, 9, '(', 'CDK9)', and, cyclin, 'T1', or, 'T2,', are, engaged, by, many, cellular, transcription, regulators, that]), verbo([activate]), complemento([or, inhibit, transcription, from, specific, promoters])].
[sujeto(['The', related, 'I-mfa', '(', inhibitor, of, 'MyoD', family, 'a)', and, 'HIC', '(', human, 'I-mfa-domain-containing)', proteins, function, in, myogenic, differentiation, and, embryonic, development, by]), verbo([participating]), complemento([in, the, 'Wnt', signaling, pathway])].
[sujeto(['We']), verbo([report]), complemento([that, 'I-mfa', is, a, novel, regulator, of, 'P-TEFb'])].
[sujeto(['Both', 'HIC', and, 'I-mfa']), verbo([interact]), complemento([through, their, homologous, 'I-mfa', domains, with, cyclin, 'T1', and, 'T2', at, two, binding, sites])].
[sujeto(['One', site, is, the, regulatory, 'histidine-rich', domain, that]), verbo([interacts]), complemento([with, 'CDK9', substrates, including, 'RNA', polymerase, 'II'])].
[sujeto(['The', second, site, contains, a, lysine, and, 'arginine-rich', motif, that, is, highly]), verbo([conserved]), complemento([between, the, two, 'T', cyclins])].
[sujeto(['This', site, overlaps, and, includes, the, previously, identified, 'Tat/TAR', recognition, motif, of, cyclin, 'T1']), verbo([required]), complemento([for, activation, of, human, immunodeficiency, virus, type, 1, '(', 'HIV-1)', transcription])].
[sujeto(['Their', 'I-mfa', domains, also]), verbo([bind]), complemento([the, activation, domain, of, 'HIV-1', 'Tat', and, inhibit, 'Tat-', and, 'P-TEFb-dependent', transcription, from, the, 'HIV-1', promoter])].
[sujeto(['Our', findings, link, 'I-mfa', and, 'HIC', to, viral, 'replication,', and]), verbo([suggest]), complemento([that, 'P-TEFb', is, modulated, in, the, 'Wnt', signaling, pathway])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, 'beta-catenin', interacts, with, a, transcription, suppressor, 'I-mfa', 'and,', through, this, 'interaction,', canonical, 'Wnt', signaling, could, relieve, 'I-mfa-mediated', suppression, of, myogenic, regulatory, factors, '(', 'MRFs)'])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento(['that,', based, on, this, 'interaction,', 'I-mfa-mediated', suppression, of, the, 'Wnt', transcription, factor, 'T-cell', 'factor/lymphoid', enhancing, 'factor-1', '(', 'TCF/LEF-1)', can, also, be, relieved])].
[sujeto(['Our', work, showed, that, knocking, down, endogenous, 'I-mfa', expression, mimics, canonical, 'Wnt', treatment, by]), verbo([inducing]), complemento([myogenesis, and, increasing, 'Wnt', reporter, gene, 'activity,', endogenous, 'Wnt', target, gene, expression, and, expression, of, 'MRFs', in, 'P19', cells])].
[sujeto(['In', 'addition,', we]), verbo([found]), complemento([that, 'beta-catenin', could, compete, with, 'I-mfa', for, binding, to, 'LEF-1', and, relieve, the, inhibitory, effects, of, 'I-mfa', in, overexpression, systems])].
[sujeto(['Furthermore,', canonical, 'Wnt', was, able, to, reduce, the, levels, of, endogenous, 'I-mfa']), verbo([associated]), complemento([with, 'LEF-1,', while, increasing, that, of, 'I-mfa', associated, with, 'beta-catenin'])].
[sujeto(['All', of, the, evidence, supports, a, conclusion, that, 'I-mfa', can]), verbo([suppress]), complemento([myogenesis, by, inhibiting, 'TCF/LEF-1', and, that, canonical, 'Wnt', signaling, may, relieve, the, suppression, through, elevating, 'beta-catenin', 'levels,', which, in, turn, relieve, 'I-mfa-mediated', suppression])].
[sujeto(['Cdkn1c', protein, levels, are, carefully]), verbo([regulated]), complemento([via, imprinting, and, other, epigenetic, mechanisms, affecting, both, the, promoter, and, distant, regulatory, 'elements,', which, restrict, its, expression, to, particular, developmental, phases, or, specific, cell, types])].
[sujeto(['Inappropriate', activation, of, these, regulatory, mechanisms]), verbo([leads]), complemento([to, 'Cdkn1c', 'silencing,', causing, growth, disorders, and, cancer])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, 'that,', in, skeletal, muscle, 'cells,', induction, of, 'Cdkn1c', expression, requires, the, binding, of, the, bHLH, myogenic, factor, 'MyoD', to, a, 'long-distance', regulatory, element, within, the, imprinting, control, region, 'KvDMR1'])].
[sujeto(['Interestingly,', 'MyoD']), verbo([binding]), complemento([to, 'KvDMR1', is, prevented, in, myogenic, cell, types, refractory, to, the, induction, of, 'Cdkn1c'])].
[sujeto(['We', show, that, treatment, with, the, 'DNA', demethylating, agent, 5, -, azacytidine, restores, the]), verbo([binding]), complemento([of, 'MyoD', to, 'KvDMR1', in, cells, refractory, to, 'Cdkn1c', induction])].
[sujeto(['This,', in, 'turn,']), verbo([promotes]), complemento([the, release, of, a, repressive, chromatin, loop, between, 'KvDMR1', and, 'Cdkn1c', promoter, 'and,', 'thus,', the, upregulation, of, the, gene])].
[sujeto(['Analysis', of, the, chromatin, status, of, 'Cdkn1c', promoter, and, 'KvDMR1', in, two, cell, types, showed, that, their, differential, responsiveness, to, the, 'MyoD-dependent', induction, of, the, gene, does, not]), verbo([involve]), complemento([just, their, methylation, status, 'but,', 'rather,', the, differential, 'H3', lysine, 9, dimethylation, at, 'KvDMR1'])].
[sujeto(['Finally,', we]), verbo([report]), complemento([that, the, same, histone, modification, also, marks, the, 'KvDMR1', region, of, human, cancer, cells, in, which, 'Cdkn1c', is, silenced])].
[sujeto(['On', the, basis, of, these, 'results,', we]), verbo([suggest]), complemento([that, the, epigenetic, status, of, 'KvDMR1', represents, a, critical, determinant, of, the, cell, 'type-restricted', expression, of, 'Cdkn1c', 'and,', 'possibly,', of, its, aberrant, silencing, in, some, pathological, conditions])].
[sujeto(['The', purpose, of, this, paper, was, to, study, the, effect, of, transforming, growth, factor, beta, '(', 'TGFβ)', signaling, pathway, on, 'reloading-mediated', restoration, of, disuse, muscle]), verbo([loss]), complemento([induced, by, hind, limb, suspension, in, rats])].
[sujeto(['Reloading']), verbo([increased]), complemento(['MyoD', mRNA, and, restored, the, decreased, gastrocnemius, 'weight/body', weight, 'ratio,', protein, concentration, of, 'gastrocnemius,', 'phospho-ERK2,', 'Pax7', and, the, increased, 'TGFβ1,', 'MSTN,', 'phospho-smad2/3,', 'phospho-p38,', 'phospho-JNK1/2,', and, p21, induced, by, hind, limb, suspension])].
[sujeto(['Disuse', muscle]), verbo([loss]), complemento([can, be, recovered, by, reloading, in, an, 'intensity-dependent', manner, through, canonical, and, noncanonical, 'TGFβ', signaling, pathways])].
[sujeto(['Pax7', and, 'MyoD', might, be, the, effectors, of, 'TGFβ', pathway, in]), verbo([mediating]), complemento([the, recovery, effect, of, reloading])].
[sujeto(['Transfection', with, 'in vitro']), verbo([transcribed]), complemento([mRNAs, is, a, safe, and, effective, tool, to, convert, somatic, cells, to, any, cell, type, of, interest])].
[sujeto(['One', caveat, of, mRNA, transfection, is, that, mRNAs, are]), verbo([recognized]), complemento([by, multiple, 'RNA-sensing', toll, like, receptors, '(', 'TLRs)'])].
[sujeto(['These', 'TLRs', can, both]), verbo([promote]), complemento([and, inhibit, cellular, reprogramming])].
[sujeto(['We', demonstrated, that, mRNA, transfection]), verbo([stimulated]), complemento(['TLR3', and, 'TLR7', and, induced, cytotoxicity, and, 'IFN-β', expression, in, human, and, mouse, fibroblasts])].
[sujeto(['Furthermore,', mRNA, transfection]), verbo([induced]), complemento([paracrine, inhibition, of, repeated, mRNA, transfection, through, type, 'I', 'IFNs'])].
[sujeto(['Repeated', liposomal, transfection, with, 'MyoD', mmRNAs, significantly]), verbo([enhanced]), complemento([myogenic, conversion, of, human, and, mouse, fibroblasts, compared, with, repeated, transfection, with, 'MyoD', mRNAs])].
[sujeto(['At', a, low, 'concentration,', 'TLR7/8', agonist, 'R848']), verbo([enhanced]), complemento(['MyoD', 'mmRNA-driven', conversion, of, human, fibroblasts, into, skeletal, muscle, 'cells,', whereas, high, concentrations, of, 'R848', inhibited, myogenic, conversion, of, fibroblasts])].
[sujeto(['Our', study]), verbo([suggests]), complemento([that, deliberate, control, of, 'TLR', signaling, is, a, key, factor, in, the, success, of, 'mRNA-driven', cellular, reprogramming])].
[sujeto(['Quercetin']), verbo([inhibited]), complemento([myeloperoxidase, '(', 'MPO)', and, 'N-acetyl-β-D-', glucosaminidase, '(', 'NAG)', 'activities,', cytokine, 'production,', oxidative, 'stress,', 'cyclooxygenase-2', '(', 'COX-2)', and, gp91phox, mRNA, expression, and, muscle, injury, '(', creatinine, kinase, '[', 'CK]', blood, levels, and, myoblast, determination, protein, '[', 'MyoD]', mRNA, 'expression)', as, well, as, inhibited, 'NFκB', activation, and, induced, 'Nrf2', and, 'HO-1', mRNA, expression, in, the, soleus, muscle])].
[sujeto(['Beyond']), verbo([inhibiting]), complemento([those, peripheral, 'effects,', quercetin, also, inhibited, spinal, cord, cytokine, 'production,', oxidative, stress, and, glial, cells, activation, '(', glial, fibrillary, acidic, protein, '[', 'GFAP]', and, ionized, 'calcium-binding', adapter, molecule, 1, '[', 'Iba-1]', mRNA, 'expression)'])].
[sujeto(['Muscle', regeneration, is, a, coordinated, process, that]), verbo([involves]), complemento([proliferation, and, differentiation, of, muscle, progenitor, cells])].
[sujeto(['Activation', of, 'MyoD', is, a, key, event, in, myogenic, 'differentiation,', which, is]), verbo([regulated]), complemento([by, 'p38 mitogen‑activated', protein, kinases, '(', 'MAPK)'])].
[sujeto(['Treatment', of, 'C2C12', myoblasts, with, 'DHC']), verbo([increased]), complemento([the, expression, levels, of, 'muscle‑specific', 'proteins,', including, 'MyoD,', myogenin, and, myosin, heavy, chain])].
[sujeto(['In', 'addition,', 'C2C12', myoblasts, exhibited]), verbo([enhanced]), complemento([multinucleated, myotube, formation, without, any, cytotoxicity])].
[sujeto(['Furthermore,', defects, in, 'differentiation‑induced', 'p38 MAPK', activation, and, myoblast, differentiation]), verbo([induced]), complemento([by, depletion, of, the, promyogenic, receptor, protein, 'Cdo', in, 'C2C12', myoblasts, were, restored, by, 'DHC', treatment])].
[sujeto(['In', 'conclusion,', these, results, indicated, that, 'DHC']), verbo([stimulates]), complemento(['p38 MAPK', 'activation,', which, can, enhance, heterodimerization, of, 'MyoD', and, 'E proteins,', thus, resulting, in, 'MyoD', activation, and, myoblast, differentiation])].
[sujeto(['These', findings]), verbo([suggested]), complemento([that, 'DHC', may, be, considered, a, potential, therapeutic, compound, for, the, improvement, of, muscle, stem, cell, regenerative, capacity, in, injured, muscle])].
[sujeto(['Skeletal', muscle, is, capable, of, robust, 'self-repair', following, mild, 'trauma,', yet, in, cases, of, traumatic, volumetric, muscle]), verbo([loss]), complemento(['(', 'VML),', where, more, than, 20, '%', of, a, 'muscle\'s', mass, is, 'lost,', this, capacity, is, overwhelmed])].
[sujeto(['Current', autogenic, whole, muscle, transfer, techniques, are, 'imperfect,', which]), verbo([has]), complemento([motivated, the, exploration, of, implantable, scaffolding, strategies])].
[sujeto(['We']), verbo([found]), complemento([that, the, repair, of, 'VML', injuries, using, 'DSM+MM', scaffolds, significantly, increased, recovery, of, peak, contractile, force, '(', 81, '±3%', of, normal, contralateral, 'muscle)', when, compared, to, unrepaired, 'VML', controls, '(', 62, '±4%)'])].
[sujeto(['Histological', findings, revealed, a, marked]), verbo([decrease]), complemento([in, collagen, dense, repair, tissue, formation, both, at, and, away, from, the, implant, site, for, 'DSM+MM', repaired, muscles])].
[sujeto(['The', addition, of, 'MM', to, 'DSM', significantly]), verbo([increased]), complemento(['MyoD', 'expression,', when, compared, to, isolated, 'DSM', treatment, '(', 21, fold, 'increase)', and, unrepaired, 'VML', '(', 37, 'fold)', controls])].
[sujeto(['Current', therapeutic, options, for, the, pediatric, cancer, rhabdomyosarcoma, '(', 'RMS)']), verbo([have]), complemento([not, improved, 'significantly,', especially, for, metastatic, 'RMS'])].
[sujeto(['The', signature, we, determined, could, discriminate, 'RMS', from, 'muscle,']), verbo([revealed]), complemento([a, subset, of, 'muscle-enriched', microRNA, '(', 'myomiR),', including, 'miR-22', which, was, strongly, underexpressed, in, tumors])].
[sujeto(['miR-22', was, physiologically]), verbo([induced]), complemento([during, normal, myogenic, differentiation, and, was, transcriptionally, regulated, by, 'MyoD,', confirming, its, identity, as, a, myomiR])].
[sujeto(['Once', introduced, into, 'RMS', 'cells,', 'miR-22']), verbo([decreased]), complemento([cell, 'proliferation,', 'anchorage-independent', 'growth,', invasiveness, and, promoted, apoptosis])].
[sujeto(['Moreover,', restoring, 'miR-22', expression, blocked, tumor, growth, and]), verbo([prevented]), complemento([tumor, dissemination, in, vivo])].
[sujeto(['Gene', expression, profiling, analysis, of, 'miR-22-expressing', cells]), verbo([suggested]), complemento(['TACC1', and, 'RAB5B', as, possible, direct, 'miR-22', targets])].
[sujeto(['Accordingly,']), verbo([loss]), complemento([and, gain, of, function, experiments, defined, the, biological, relevance, of, these, genes, in, 'RMS', pathogenesis])].
[sujeto(['In', previous, 'studies,', we]), verbo([have]), complemento([reported, that, phospholipase, 'C', '(', 'PLC)-β1', plays, a, crucial, role, in, myogenic, differentiation, and, we, determined, the, importance, of, its, catalytic, activity, for, the, initiation, of, this, process])].
[sujeto(['We', show, that, the, 'Inositol', 'Polyphosphate', 'Multikinase', '(', 'IPMK)', is, able, to]), verbo([promote]), complemento([myogenic, differentiation, since, its, overexpression, determines, the, 'up-regulation', of, several, myogenic, markers])].
[sujeto(['Moreover,', we, demonstrate, that, 'IPMK']), verbo([activates]), complemento([the, same, cyclin, 'D3', promoter, region, targeted, by, 'PLC-β1', and, that, 'IPMK-induced', promoter, activation, relies, upon, 'c-jun', binding, to, the, 'promoter,', as, we, have, shown, previously, for, 'PLC-β1'])].
[sujeto(['Furthermore,', our, data, shows, that, 'IPMK', overexpression]), verbo([causes]), complemento([an, increase, in, 'β-catenin', translocation, and, accumulation, to, the, nuclei, of, differentiating, myoblasts, resulting, in, higher, 'MyoD', activation])].
[sujeto(['Finally,', we, describe, that, 'PLC-β1', overexpression, determines, too, an]), verbo([increase]), complemento([in, 'β-catenin', translocation, and, that, 'PLC-β1,', 'IPMK', and, 'β-catenin', are, mediators, of, the, same, signaling, pathway, since, their, overexpression, results, in, cyclin, 'D3', and, myosin, heavy, chain, '(', 'MYH)', induction])].
[sujeto(['Pompe', disease, '(', 'PD)', is, a, lysosomal, disorder]), verbo([caused]), complemento([by, acid, 'α-glucosidase', '(', 'GAA)', deficiency])].
[sujeto(['We', previously, used, lentiviral, 'vector-mediated', 'GAA', gene, transfer, in, 'PD', 'patient-specific']), verbo([induced]), complemento([pluripotent, stem, cells])].
[sujeto(['Transcription', factor, 'EB', is, a, master, regulator, of, lysosomal, biogenesis, and, autophagy, that]), verbo([has]), complemento([recently, been, associated, with, muscular, 'pathology,', and, is, now, a, potential, therapeutic, target, in, 'PD', model, mice])].
[sujeto(['Here,', we, differentiated, skeletal, muscle, from, 'PD', 'patient-specific']), verbo([induced]), complemento([pluripotent, stem, cells, by, forced, 'MyoD', expression])].
[sujeto(['Thus,', our, findings, show, that, abnormal, lysosomal, biogenesis, is]), verbo([associated]), complemento([with, the, muscular, pathology, of, 'PD,', and, transcription, factor, 'EB', gene, transfer, is, effective, as, an, 'add-on', strategy, to, 'GAA', gene, transfer])].
[sujeto(['We', previously, demonstrated, that, histone, methyltransferase, 'KMT1A']), verbo([associates]), complemento([with, and, inhibits, 'MyoD', in, proliferating, 'myoblasts,', and, must, be, removed, to, allow, differentiation, to, proceed])].
[sujeto(['Conversely,', forced, activation, of, p38α, was, sufficient, to]), verbo([activate]), complemento(['MyoD', and, overcome, the, differentiation, blockade, in, 'KMT1A-overexpressing', 'C2C12', cells])].
[sujeto(['This', phosphorylation, was]), verbo([prevented]), complemento([by, the, inhibition, of, p38α])].
[sujeto(['A', ready, source, of, autologous, myogenic, cells, is, of, vital, importance, for, drug, screening, and, functional, genetic, studies, in, 'Duchenne', 'Muscular', 'Dystrophy', '(', 'DMD),', a, rare, disease]), verbo([caused]), complemento([by, a, variety, of, dystrophin, gene, mutations])].
[sujeto(['We', demonstrated, that, native, 'urine-derived', stem, cells]), verbo([express]), complemento([the, 'full-length', dystrophin, 'transcript,', and, that, the, dystrophin, mutation, was, retained, in, 'DMD', patient, 'cells,', although, the, dystrophin, protein, was, detected, solely, in, control, cells, following, myogenic, transformation, according, to, the, phenotype])].
[sujeto(['Notably,', we, also, showed, that, treatment, with, antisense, oligoribonucleotide, against, dystrophin, exon, 44]), verbo([induced]), complemento([skipping, in, both, native, and, 'MyoD-transformed', 'urine-derived', stem, cells, in, 'DMD,', with, a, therapeutic, 'transcript-reframing', 'effect,', as, well, as, visible, protein, restoration, in, the, latter])].
[sujeto(['Muscle', satellite, cells, can, proliferate, and, differentiate, into, 'myocytes;', this, biological, function]), verbo([has]), complemento([important, implications, for, muscle, 'development,', 'aging,', 'repair,', and, wasting, diseases])].
[sujeto(['Established', analytical, 'methods,', including, western, 'blotting,', 'PCR,', and, 'immunohistochemistry,']), verbo([has]), complemento([been, used, to, characterize, the, stages, of, satellite, cells, growth, and, development, but, there, is, currently, a, lack, of, methods, to, simultaneously, monitor, cell, proliferation, and, identify, changes, in, cell, properties, '(', i])].
[sujeto(['Image-based', flow, cytometry]), verbo([has]), complemento([the, capability, to, simultaneously, obtain, morphometric, 'data,', monitor, cell, 'division,', and, detect, expression, of, multiple, proteins, of, interest])].
[sujeto([3]), verbo([has]), complemento([a, profound, impact, on, chromatin, function, and, numerous, cellular, 'processes,', including, the, differentiation, of, muscle, cells])].
[sujeto([3]), verbo([have]), complemento([essential, roles, in, 'MyoD', regulation, during, myoblast, differentiation])].
[sujeto(['Here', we, show, that, 'HIRA', is]), verbo([phosphorylated]), complemento([by, 'Akt', 'kinase,', an, important, signaling, modulator, in, muscle, cells])].
[sujeto(['By', generating, a, phosphospecific, 'antibody,', we]), verbo([found]), complemento([that, a, significant, amount, of, 'HIRA', was, phosphorylated, in, myoblasts])].
[sujeto(['The', phosphorylation, level, of, 'HIRA', and, the, occupancy, of]), verbo([phosphorylated]), complemento([protein, on, muscle, genes, gradually, decreased, during, cellular, differentiation])].
[sujeto([3, deposition, and]), verbo([suppressed]), complemento([the, activation, of, muscle, genes, in, myotubes])].
[sujeto(['Our', data, show, that, 'HIRA', phosphorylation, limits, the, expression, of, myogenic, 'genes,', while, the, dephosphorylation, of, 'HIRA', is]), verbo([required]), complemento([for, proficient, 'H3'])].
[sujeto([3, deposition, and, gene, 'activation,', demonstrating, that, the, phosphorylation, switch, is, exploited, to]), verbo([modulate]), complemento(['HIRA/H3'])].
[sujeto([3, -]), verbo([mediated]), complemento([muscle, gene, regulation, during, myogenesis])].
[sujeto(['In', 'Duchenne', muscular, dystrophy, '(', 'DMD)', and, other, muscle, wasting, 'disorders,', cell, therapies, are, a, promising, route, for]), verbo([promoting]), complemento([muscle, regeneration, by, supplying, a, functional, copy, of, the, missing, dystrophin, gene, and, contributing, new, muscle, fibers])].
[sujeto([dFbs]), verbo([expressed]), complemento(['tamoxifen-inducible', 'MyoD', and, carried, a, 'mini-dystrophin', gene, driven, by, a, 'muscle-specific', promoter])].
[sujeto(['However,', treatment, with, 'PSC', gave, a, nearly, 'three-fold']), verbo([increase]), complemento([in, donor, cells, in, early, 'engraftment,', and, greatly, increased, the, number, of, 'donor-contributed', muscle, fibers, and, total, engrafted, area, in, transplanted, muscles])].
[sujeto(['Furthermore,', dystrophic, muscles, that, received, dFbs, with, 'PSC', displayed, reduced, injury, with, eccentric, contractions, and, an]), verbo([increase]), complemento([in, maximum, isometric, force])].
[sujeto(['Thus,']), verbo([enhancing]), complemento([survival, of, myogenic, cells, increases, engraftment, and, improves, structure, and, function, of, dystrophic, muscle])].
[sujeto(['The', 'excretory-secretory', products, '(', 'ESPs)']), verbo([released]), complemento([by, the, 'muscle-larvae', '(', 'ML)', stage, of, 'Trichinella', spiralis, have, been, suggested, to, be, involved, in, nurse, cell, formation])].
[sujeto(['However,', the, molecular, mechanisms, by, which, 'ML-ESPs']), verbo([modulate]), complemento([nurse, cell, formation, remain, unclear])].
[sujeto([spiralis, infection]), verbo([have]), complemento([not, been, characterized])].
[sujeto(['These', findings, indicated, that, 'CM']), verbo([inhibited]), complemento([myoblast, differentiation])].
[sujeto(['Conversely,', 'CM']), verbo([promoted]), complemento([myoblast, proliferation, and, increased, cyclin, 'D1', levels])].
[sujeto(['Taken', 'together,', results, of, our, study]), verbo([suggested]), complemento([that, 'CM', can, indirectly, influence, myoblast, differentiation, and, 'proliferation,', which, provides, a, new, method, for, the, elucidation, of, the, complex, mechanisms, involved, in, 'cell-parasite', and, 'cell-cell', interactions, during, 'T'])].
[sujeto(['The', transplantation, of, 'MDSCs', in, the, presence, of, a, transforming, growth, factor, β1, '(', 'TGF-β1)', antagonist, '(', 'losartan)', would, result, in]), verbo([decreased]), complemento([scar, tissue, formation, and, enhance, muscle, regeneration, after, contusion, injuries, in, a, mouse, model])].
[sujeto(['When', compared, with, 'MDSC', transplantation, 'alone,', 'MDSC/losartan', treatment, resulted, in, significantly]), verbo([decreased]), complemento([scar, 'formation,', an, increase, in, the, number, of, regenerating, 'myofibers,', and, improved, functional, recovery, after, muscle, contusions])].
[sujeto(['In', support, of, these, 'findings,', the, expression, levels, of, 'Smad7', and, 'MyoD', were, significantly]), verbo([increased]), complemento([in, the, group, treated, with, both, 'MDSCs', and, losartan])].
[sujeto(['When', compared, with, 'MDSCs', 'alone,', the, simultaneous, treatment, of, muscle, contusions, with, 'MDSCs', and, losartan, significantly, reduced, scar, 'formation,']), verbo([increased]), complemento([the, number, of, regenerating, 'myofibers,', and, improved, the, functional, recovery, of, 'muscle;', these, effects, were, 'caused,', at, least, in, 'part,', by, the, 'losartan-mediated', upregulation, of, 'Smad7', and, 'MyoD'])].
[sujeto(['Sarcopenic', 'obesity,', 'age-related', muscle, 'loss,', which, is, compensated, by, an]), verbo([increase]), complemento([in, fat, 'mass,', impairs, quality, of, life, in, elderly, people])].
[sujeto(['Although', the]), verbo([increase]), complemento([in, intramuscular, fat, is, associated, with, decreased, insulin, sensitivity, and, increased, metabolic, risk, 'factors,', the, origin, of, 'diabetes-associated', intramuscular, fat, has, not, been, elucidated])].
[sujeto(['Expression', of, a, myogenic, 'marker,', 'myoD,', was, lower, and, that, of, 'PDGF', receptor, alpha, and, 'CCAAT/enhancer']), verbo([binding]), complemento([protein, '(', 'CEBP)', alpha, was, higher, in, 'Ctx-injured', 'TA', of, 'KKAy', compared, with, that, of, 'C57BL/6'])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, γ, '(', 'PPARγ)', was, highly]), verbo([expressed]), complemento([in, 'fat-forming', lesions, in, older, 'KKAy'])].
[sujeto(['Treatment', with, 'all-trans', retinoic, acid]), verbo([prevented]), complemento([the, formation, of, intramuscular, 'fat;', 'however,', treatment, with, 'GW9662,', a, 'PPARγ', 'antagonist,', increased, the, fibrotic, change, in, muscle])].
[sujeto(['Diabetic', mice, showed, impaired, muscle, regeneration, with, fat, 'deposition,']), verbo([suggesting]), complemento([that, diabetes, may, enhance, sarcopenic, obesity, through, a, mechanism, involving, anomalous, 'fibro-adipocyte', progenitor, cell, differentiation])].
[sujeto(['Although', a, number, of, unique, features, of, 'EOMs', including, their, sparing, in, 'Duchenne', muscular, dystrophy]), verbo([have]), complemento([drawn, a, continuous, 'interest,', knowledge, about, these, hard, to, reach, muscles, is, still, limited])].
[sujeto(['The', goal, of, this, chapter, is, to]), verbo([provide]), complemento([detailed, methods, for, the, isolation, and, histological, analysis, of, mouse, 'EOMs'])].
[sujeto(['We', then]), verbo([provide]), complemento([a, detailed, description, with, 'step-by-step', images, of, our, procedure, for, isolating, '(', and, subsequently, 'cryosectioning)', 'EOMs', while, preserving, the, integrity, of, their, original, structural, organization])].
[sujeto(['Overall,', the, methods, described, in, this, chapter, should]), verbo([provide]), complemento([investigators, the, necessary, tools, for, entering, the, 'EOM', research, field, and, contribute, to, a, better, understanding, of, this, highly, specialized, muscle, group, and, its, complex, 'micro-anatomy'])].
[sujeto(['Adult', skeletal, muscle, is]), verbo([maintained]), complemento([and, repaired, by, resident, stem, cells, called, satellite, 'cells,', located, between, the, plasmalemma, of, a, muscle, 'fiber,', and, the, surrounding, basal, lamina])].
[sujeto(['When', 'needed,', satellite, cells, are]), verbo([activated]), complemento([to, form, proliferative, 'myoblasts,', that, then, differentiate, and, fuse, to, existing, muscle, 'fibers,', or, fuse, together, to, form, replacement, myofibers])].
[sujeto(['In', 'parallel,', a, proportion, of, satellite, cells, 'self-renew,', to]), verbo([maintain]), complemento([the, stem, cell, pool])].
[sujeto(['Co-immunostaining', of, skeletal, muscle, with, 'Pax7', and, laminin, allows, both, identification, of, satellite, 'cells,', and, the, myofiber, that, they, are]), verbo([associated]), complemento([with])].
[sujeto([2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin;', 'TCDD)']), verbo([cause]), complemento([cleft, palate, at, a, high, rate])].
[sujeto(['Runx2', and, osteopontin, immunoreactivity]), verbo([decreased]), complemento([in, the, 'TCDD-treated', palatal, 'bone,', and, 'MyoD', and, desmin, decreased, in, the, 'TCDD-treated', palatal, muscle])].
[sujeto(['TCDD', may]), verbo([suppress]), complemento([palatal, osteogenesis, and, myogenesis, via, 'AhR,', and, cause, cleft, palates, via, a, 'post-fusional', split, 'mechanism,', in, addition, to, a, failure, of, palatal, fusion])].
[sujeto(['Aryl', hydrocarbon, receptor, '(', 'AhR)']), verbo([nuclear]), complemento([translocator, '(', 'Arnt)', gene, has, been, isolated, and, characterized, from, a, mouse, genomic, 'DNA', library])].
[sujeto(['An', unusual, 'exon/intron', junctional, sequence, was]), verbo([found]), complemento([in, the, 11, th, intron, of, the, gene, that, begins, with, 'GC', at, its, 5, '\'', -, end])].
[sujeto(['The', gene, is, 'TATA-less', and]), verbo([has]), complemento([several, transcription, start, sites])].
[sujeto(['Of', 'all,', two, 'GC-boxes', displayed, the, most, dominant]), verbo([enhancing]), complemento([effects])].
[sujeto(['It', was, demonstrated, that, there, exist, specific, factors]), verbo([binding]), complemento([to, these, 'DNA', elements, in, the, nuclear, extracts, of, 'HeLa', cells])].
[sujeto(['Among', 'them,', 'Sp1', and, 'Sp3,', and, 'CAAT-box']), verbo([binding]), complemento(['factor-A', were, identified, to, bind, the, 'GC-boxes', and, 'CAAT-box,', respectively])].
[sujeto(['Expression', of, 'MyoD', in, 'HeLa', cells]), verbo([stimulated]), complemento([the, 'Arnt', promoter, activity, by, binding, to, the, 'E-box'])].
[sujeto(['The', 'AH-receptor', is, a, 'ligand-activated', transcription, factor, that]), verbo([regulates]), complemento([a, number, of, biological, responses, to, planar, aromatic, hydrocarbons])].
[sujeto(['Interest', in, this, receptor, is, related, to, its, role, in, the, toxic, action, of, a, variety, of, environmental, 'chemicals,', the, simplicity, and, elegance, of, the, murine, genetics, that]), verbo([led]), complemento([to, its, characterization, and, the, distinctive, mechanism, by, which, this, receptor, activates, gene, expression])].
[sujeto(['Recent', cloning, experiments]), verbo([have]), complemento([demonstrated, that, the, 'AH-receptor', is, structurally, related, to, the, 'Per,', 'ARNT', and, 'Sim', proteins])].
[sujeto(['In', the, 'AH-receptor,', this, domain, harbours, sequences]), verbo([involved]), complemento([in, the, formation, of, a, hydrophobic, pocket, that, bind, receptor, agonists])].
[sujeto(['Adjacent', to, the, 'PAS', domain, in, the, 'AH-receptor,', 'ARNT', and, 'Sim', proteins, is, a, 'basic/helix-loop-helix', '(', 'bHLH)', domain, that, appears, to]), verbo([mediate]), complemento([heterodimerization, and, sequence, specific, 'DNA', binding, properties])].
[sujeto(['The', observation, that, the, bHLH, domain, is, present, in, the, 'AH-receptor', and, the, 'ARNT', 'protein,', a, factor]), verbo([required]), complemento([for, proper, 'AH-receptor', 'function,', suggests, that, these, proteins, are, heterodimeric, partners, that, activate, gene, expression, in, a, manner, similar, to, 'Myc/Max', and, 'MyoD/E2A'])].
[sujeto(['The', objectives, of, this, review, are, to, describe, recent, experimental, results, in, this, field, and, to, use, this, information, to, develop, a, molecular, model, of, 'AH-receptor']), verbo([mediated]), complemento([signal, transduction])].
[sujeto(['A', cDNA, encoding, the, murine, 'Ah', receptor, '(', 'Ahb-1', allele, for, aromatic, hydrocarbon, 'responsiveness)']), verbo([has]), complemento([been, isolated, and, characterized])].
[sujeto(['Analysis', of, the, deduced, protein, sequence, revealed, a, region, with, similarity, to, the, basic, 'region/helix-loop-helix', '(', 'BR/HLH)', motif]), verbo([found]), complemento([in, many, transcription, factors, that, undergo, dimerization, for, function])].
[sujeto(['In', addition, to, the, 'BR/HLH', 'domain,', the, 'N-terminal', domain, of, the, 'Ah', receptor]), verbo([has]), complemento([extensive, sequence, similarity, to, the, human, 'ARNT', '(', aryl, hydrocarbon, receptor, nuclear, 'translocator)', protein, and, two, regulatory, proteins, of, 'Drosophila,', 'Sim', and, 'Per'])].
[sujeto(['Photoaffinity', labeling, and, peptide, mapping, studies, indicate, that, the, 'Ah', receptor]), verbo([binds]), complemento([agonist, at, a, domain, that, lies, within, this, conserved, 'N-terminal', domain])].
[sujeto(['The', 'Ah', receptor, appears, to, be, a, 'ligand-activated', transcription, factor, with, a, 'helix-loop-helix', motif, similar, to, those]), verbo([found]), complemento([in, a, variety, of, 'DNA-binding', 'proteins,', including, 'Myc', and, 'MyoD'])].
[sujeto(['The', protein, chaperone, heat, shock, protein, 90, '(', 'Hsp90)', is, a, major, regulator, of, different, transcription, factors, such, as, 'MyoD,', a, basic, helix, loop, helix, '(', 'bHLH)', 'protein,', and, the, 'bHLH-Per-aryl', hydrocarbon]), verbo([nuclear]), complemento([translocator, '(', 'ARNT)-Sim', '(', 'PAS)', factors, 'Sim', and, aryl, hydrocarbon, receptor, '(', 'Ahr)'])].
[sujeto(['The', transcription, factor, 'hypoxia-inducible', 'factor-1alpha', '(', 'HIF-1alpha),']), verbo([involved]), complemento([in, the, response, to, 'hypoxia,', also, belongs, to, the, 'bHLH-PAS', family])].
[sujeto(['Using', a, 'EGFP-HIF-1alpha', fusion, 'protein,', 'co-immunoprecipitation', experiments, evidenced, that, the, chimeric, protein]), verbo([expressed]), complemento([in, 'COS-7', cells, interacts, with, 'Hsp90', in, normoxia, but, not, in, hypoxia])].
[sujeto(['We', also, demonstrated, that, 'Hsp90']), verbo([interacts]), complemento([with, the, 'bHLH-PAS', domain, of, 'HIF-1alpha'])].
[sujeto(['At', 'last,', we, showed, that, 'Hsp90', activity, is, essential, for, 'HIF-1', activation, in, hypoxia, since, it, is]), verbo([inhibited]), complemento([in, the, presence, of, geldanamycin])].
[sujeto([1384, 'G>A', 'SNP', was]), verbo([associated]), complemento([with, litter, size, in, the, 'GZ', goats, '(', 'P<0'])].
[sujeto(['Luciferase', assay, analysis]), verbo([suggested]), complemento([that, the, 1384, 'A', allele, increased, luciferase, activity, when, compared, to, the, 1384, 'G', allele])].
[sujeto(['Functional', analysis]), verbo([suggested]), complemento([that, this, g])].
[sujeto([1384, 'G>A', 'SNP', may, be, an, important, genetic, regulator, of, 'KISS1', gene, expression, with, effects, on, downstream, processes, that, are]), verbo([modulated]), complemento([by, 'KISS1', gene, because, of, the, changes, of, methylation, and, transcription, 'factor-binding', sites])].
[sujeto(['Therefore,', the, current, study]), verbo([provides]), complemento([evidence, in, goats, for, genetic, markers, that, might, be, used, in, breeding, programs])].
[sujeto(['Doxorubicin', '(', 'Dox,', 'Adriamicin),', a, potent, broad, spectrum, anthracycline, anticancer, 'drug,', selectively]), verbo([inhibits]), complemento([muscle, specific, gene, expression, in, cardiac, cells, in, vivo, and, prevents, terminal, differentiation, of, skeletal, muscle, cells, in, vitro])].
[sujeto(['By']), verbo([inducing]), complemento([the, expression, of, the, 'helix-loop-helix', '(', 'HLH)', transcriptional, inhibitor, 'ld2,', 'Dox', represses, the, myogenic, function, of, the, 'MyoD', family, of, muscle, regulatory, factors, '(', 'MRFs)'])].
[sujeto(['In', many, cell, 'types,', terminal, differentiation, is, coupled, to, an, irreversible, exit, from, the, cell, cycle, and, 'MyoD', plays, a, critical, role, in, the, permanent, cell, cycle]), verbo([arrest]), complemento([of, differentiating, myocytes, by, upregulating, the, cyclin, dependent, kinase, inhibitor, '(', 'cdki)', p21])].
[sujeto(['In', 'Dox-treated', quiescent, 'myoblasts,', which, fail, to, differentiate, into, myotubes, under, permissive, culture, 'conditions,', serum, 're-stimulation']), verbo([induces]), complemento(['cyclin/cdk', 're-association', on, the, 'E2F/DP', complexes, and, this, correlates, with, an, evident, increase, in, 'E2F/DP', driven, transcription, and, 're-entry', of, myoblasts, into, the, cell, cycle])].
[sujeto(['Despite', 'Dox', ability, to]), verbo([activate]), complemento([the, 'DNA-damage', dependent, 'p53/p21', 'pathway,', when, induced, in, the, absence, of, 'MyoD', or, other, 'MRFs,', p21, fails, to, maintain, the, postmitotic, state, in, 'Dox-treated', myocytes, induced, to, differentiate])].
[sujeto(['Thus,', uncoupling, p21, induction, and, 'MyoD', activity, results, in, a, 'serum-reversible', cell, cycle, 'arrest,', indicating, that, 'MRF', specific, activation, of, 'cdki(s)', is]), verbo([required]), complemento([for, permanent, cell, cycle, arrest, in, differentiating, muscle, cells])].
[sujeto(['Duchenne', muscular, dystrophy, '(', 'DMD)', is, a, progressive, and, fatal, muscle, degenerating, disease]), verbo([caused]), complemento([by, a, dystrophin, deficiency])].
[sujeto(['Patient-derived', human]), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'hiPSCs)', are, a, promising, tool, for, drug, discovery])].
[sujeto(['Here,', we]), verbo([report]), complemento([an, in, vitro, evaluation, system, for, a, 'DMD', therapy, using, hiPSCs, that, recapitulate, the, primary, pathology, and, can, be, used, for, 'DMD', drug, screening])].
[sujeto(['However,', electric, stimulation, of, these, myotubes, for, in, vitro, contraction]), verbo([caused]), complemento([pronounced, calcium, ion, '(', 'Ca(2+))', influx, only, in, 'DMD', myocytes])].
[sujeto(['Restoration', of, dystrophin, by, the, 'exon-skipping', technique]), verbo([suppressed]), complemento([this, 'Ca(2+)', overflow, and, reduced, the, secretion, of, creatine, kinase, '(', 'CK)', in, 'DMD', myotubes])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, early, pathogenesis, of, 'DMD', can, be, effectively, modelled, in, skeletal, myotubes, induced, from, 'patient-derived', 'iPSCs,', thereby, enabling, the, development, and, evaluation, of, novel, drugs])].
[sujeto(['Patient-derived']), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'iPSCs)', have, opened, the, door, to, recreating, pathological, conditions, in, vitro, using, differentiation, into, diseased, cells, corresponding, to, each, target, tissue])].
[sujeto(['Yet', for, muscular, 'diseases,', a, method, for, reproducible, and, efficient, myogenic, differentiation, from, human, iPSCs, is]), verbo([required]), complemento([for, in, vitro, modeling])].
[sujeto(['Here,', we, introduce, a, myogenic, differentiation, protocol]), verbo([mediated]), complemento([by, inducible, transcription, factor, expression, that, reproducibly, and, efficiently, drives, human, iPSCs, into, myocytes])].
[sujeto(['This', differentiation, protocol, can, be, applied, widely, in, various, types, of, 'patient-derived', human, iPSCs, and]), verbo([has]), complemento([great, prospects, in, disease, modeling, particularly, with, inherited, diseases, that, require, studies, of, early, pathogenesis, and, drug, screening])].
[sujeto(['Overexpression', of, 'SIRT1', is, frequently, observed, in, various, types, of, 'cancers,']), verbo([suggesting]), complemento([its, potential, role, in, malignancies])].
[sujeto(['This']), verbo([suggests]), complemento([aberrant, 'CpG', 'DNA', methylation, as, the, mechanistic, background, for, malignant, 'SIRT1', elevation])].
[sujeto(['Our', work, also]), verbo([provides]), complemento([an, example, where, epigenetic, mechanisms, cause, the, 'group-wide', regulation, of, miRNAs, sharing, a, common, key, target])].
[sujeto(['The', 'ZHTc6-MyoD', embryonic, stem, cell, line]), verbo([expresses]), complemento([the, myogenic, transcriptional, factor, 'MyoD', under, the, control, of, a, 'tetracycline-inducible', promoter])].
[sujeto(['However,', a, small, fraction, does, not, 'differentiate,', instead, forming, colonies, that]), verbo([retain]), complemento([the, potential, for, myocyte, differentiation])].
[sujeto(['In', our, current, 'study,', we]), verbo([found]), complemento([that, parathyroid, hormone, type, 1, receptor, '(', 'PTH1R)', expression, in, 'colony-forming', cells, at, 13, days, after, differentiation, was, higher, than, that, in, the, undifferentiated, 'ZHTc6-MyoD', cells])].
[sujeto(['We', also]), verbo([found]), complemento([that, 'PTH1R', expression, was, required, for, myocyte, 'differentiation,', and, that, parathyroid, hormone, accelerated, the, differentiation])].
[sujeto(['Our', analysis, of, human, and, mouse, skeletal, muscle, tissues, showed, that, most, cells]), verbo([expressing]), complemento(['PTH1R', also, expressed, 'Pax7', and, 'CD34,', which, are, biomarkers, of, satellite, cells])].
[sujeto(['Furthermore,', we]), verbo([found]), complemento([that, parathyroid, hormone, treatment, significantly, improved, muscle, weakness, in, 'dystrophin-deficient', mdx, mice])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([indicating, that, 'PTH1R', and, 'PTH', accelerate, myocyte, differentiation])].
[sujeto([3, -, 'Methylcholanthrene', '(', 3, 'MC)']), verbo([induces]), complemento([tumor, formation, at, the, site, of, injection, in, the, hind, leg, of, mice, within, 110, days])].
[sujeto(['Recent']), verbo([reports]), complemento([reveal, that, the, transformation, of, normal, muscle, cells, to, atypical, cells, is, one, of, the, causes, for, tumor, 'formation,', however, the, molecular, mechanism, behind, this, process, is, not, well, understood])].
[sujeto(['Here,', we, show, in, an, in, vitro, study, that, 3, 'MC']), verbo([induces]), complemento([fragmentation, of, multinucleate, myotubes, into, viable, mononucleates])].
[sujeto(['Immunoblot', analysis]), verbo([reveals]), complemento([that, phosphorylation, of, myosin, regulatory, light, chain, '(', 'RLC20)', is, 5.6, '±0'])].
[sujeto(['Interestingly,', addition, of, the, myosin, light, chain, kinase, 'inhibitor,', 'ML-7,']), verbo([enhances]), complemento([the, 'fragmentation,', whereas, phosphatase, inhibitor, perturbs, the, 3, 'MC', induced, fragmentation, of, myotubes])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, decrease, in, 'RLC20', phosphorylation, may, be, associated, with, the, fragmentation, step, of, dedifferentiation])].
[sujeto(['The', establishment, of, human]), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'hiPSCs)', has, enabled, the, production, of, in, 'vitro,', 'patient-specific', cell, models, of, human, disease])].
[sujeto(['However,', myogenic, differentiation, of, hiPSCs]), verbo([has]), complemento([faced, 'obstacles,', 'namely,', low, efficiency, 'and/or', poor, reproducibility])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, 'rapid,', 'efficient,', and, reproducible, differentiation, of, hiPSCs, into, mature, myocytes])].
[sujeto(['Myocytes']), verbo([induced]), complemento([in, this, manner, reach, maturity, within, 2, weeks, of, differentiation, as, assessed, by, marker, gene, expression, and, functional, 'properties,', including, in, vitro, and, in, vivo, cell, fusion, and, twitching, in, response, to, electrical, stimulation])].
[sujeto(['Miyoshi', 'Myopathy', '(', 'MM)', is, a, congenital, distal, myopathy]), verbo([caused]), complemento([by, defective, muscle, membrane, repair, due, to, mutations, in, 'DYSFERLIN'])].
[sujeto(['Using', our]), verbo([induced]), complemento([differentiation, 'technique,', we, successfully, recreated, the, pathological, condition, of, 'MM', in, 'vitro,', demonstrating, defective, membrane, repair, in, 'hiPSC-derived', myotubes, from, an, 'MM', patient, and, phenotypic, rescue, by, expression, of, 'full-length', 'DYSFERLIN', '(', 'DYSF)'])].
[sujeto(['We']), verbo([target]), complemento([this, inducible, cassette, exchange, '(', 'ICE)', allele, to, the, '(', 'HPRT)', locus, and, demonstrate, recombination, in, murine, embryonic, stem, cells, '(', 'ESCs)', and, primary, cells, from, derivative, 'ICE', mice])].
[sujeto(['In', the, present, 'study,', methods, were, developed, to, expand, cultures, of, 'MSCs', and, to]), verbo([promote]), complemento([the, myogenic, differentiation, of, these, 'cells,', which, were, then, used, in, a, new, approach, for, the, treatment, of, 'DMD'])].
[sujeto(['The', transduction, of, 'CD271(+)', 'MSCs', with, 'MyoD']), verbo([caused]), complemento([myogenic, differentiation, in, vitro, and, the, formation, of, myotubes, expressing, late, myogenic, markers])].
[sujeto(['Despite', having, distinct, expression, patterns, and, phenotypes, in, mutant, 'mice,', the, myogenic, regulatory, factors, 'Myf5', and, 'MyoD']), verbo([have]), complemento([been, considered, to, be, functionally, equivalent])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, these, factors, have, a, different, response, to, 'DNA', 'damage,', due, to, the, presence, in, 'MyoD', and, absence, in, 'Myf5', of, a, consensus, site, for, 'Abl-mediated', tyrosine, phosphorylation, that, inhibits, 'MyoD', activity, in, response, to, 'DNA', damage])].
[sujeto(['Genotoxins', failed, to]), verbo([repress]), complemento([skeletal, myogenesis, in, 'MyoD-null', 'embryos;', reintroduction, of, 'wild-type', 'MyoD,', but, not, mutant, 'Abl', 'phosphorylation-resistant', 'MyoD,', restored, the, 'DNA-damage-dependent', inhibition, of, muscle, differentiation])].
[sujeto(['The', presence, of, a, 'DNA-damage-responsive', phosphorylation, motif, in, 'vertebrate,', but, not, in, invertebrate, 'MyoD']), verbo([suggests]), complemento([an, evolved, response, to, environmental, 'stress,', originated, from, basic, 'helix-loop-helix', gene, duplication, in, vertebrate, myogenesis])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, that, the, level, of, 'MyoD', expression, correlates, with, the, level, of, apoptosis, that, occurs, in, a, subpopulation, of, skeletal, myoblasts, induced, to, differentiate, by, serum, withdrawal])].
[sujeto(['Further,', using, a, fibroblast, cell, line]), verbo([expressing]), complemento([an, estrogen, 'receptor:MyoD', fusion, 'protein,', we, have, determined, that, addition, of, estrogen, sensitizes, these, fibroblasts, to, apoptosis, induced, by, serum, 'withdrawal,', or, by, treatment, with, etoposide, or, thapsigargin])].
[sujeto(['RNAi']), verbo([mediated]), complemento([silencing, of, 'MyoD', in, either, 23, 'A2', or, 'C2C12', myoblasts, renders, these, cells, resistant, to, apoptosis, induced, by, serum, 'withdrawal,', or, by, treatment, with, etoposide, or, thapsigargin])].
[sujeto(['Finally,', 'MyoD']), verbo([mediated]), complemento([regulation, of, the, apoptotic, response, to, these, various, 'stimuli,', in, both, myoblasts, and, 'fibroblasts,', correlates, with, the, level, of, induction, of, the, 'pro-apoptotic', 'Bcl2', family, member, 'PUMA'])].
[sujeto(['We', used, external, fixation, '(', 'EF),', as, a, clinically, relevant, 'model,', to]), verbo([gain]), complemento([insights, into, the, relationships, between, muscle, degenerative, and, regenerative, conditions, to, the, myogenic, properties, and, abundance, of, bona, fide, satellite, cells])].
[sujeto(['EF']), verbo([induced]), complemento([muscle, mass, 'loss;', declined, expression, of, the, muscle, specific, regulatory, factors, '(', 'MRFs)', 'Myf5,', 'MyoD,', 'myogenin,', and, also, of, satellite, cell, numbers, and, myogenic, differentiation, aptitude])].
[sujeto(['Tet']), verbo([enhanced]), complemento([the, expression, of, 'MRFs,', but, did, not, prevent, the, decline, of, the, satellite, cell, pool])].
[sujeto(['Together,', our, results, point, to, 'Tet', and, exercise, running, as, promising, and, relevant, approaches, for]), verbo([enhancing]), complemento([muscle, recovery, after, atrophy])].
[sujeto(['In', our, present, proof, of, principle, 'studies,', we]), verbo([have]), complemento([successfully, constructed, a, multilayered, culture, of, skeletal, muscle, 'cells,', derived, from, neonatal, satellite, 'cells,', that, are, distributed, in, a, 3, 'D', pattern, of, organization, that, mimics, many, of, the, features, of, intact, tissue])].
[sujeto(['In', myogenic, 'C(2)C(12)', 'cells,', 5, mM, creatine]), verbo([increased]), complemento([the, incorporation, of, labeled, '[', '(', 35, ')', 'S]methionine', into, sarcoplasmic, '(', +, 20, '%', ',', 'P', &, 'lt;', 0.05, ')', and, myofibrillar, proteins, '(', +, 50, '%', ',', 'P', &, 'lt;', 0.01, ')'])].
[sujeto(['Creatine', also]), verbo([promoted]), complemento([the, fusion, of, myoblasts, assessed, by, an, increased, number, of, nuclei, incorporated, within, myotubes, '(', +, 40, '%', ',', 'P', &, 'lt;', 0.001, ')'])].
[sujeto(['Expression', of, myosin, heavy, chain, type, 'II', '(', +, 1, ',', 300, '%', ',', 'P', &, 'lt;', 0.001, ')', ',', troponin, 'T', '(', +, 65, '%', ',', 'P', &, 'lt;', 0.01, ')', ',', and, titin, '(', +, 40, '%', ',', 'P', &, 'lt;', 0.05, ')', was]), verbo([enhanced]), complemento([by, creatine])].
[sujeto(['The', addition, of, 'rapamycin,', the, inhibitor, of, mammalian]), verbo([target]), complemento([of, 'rapamycin/70-kDa', ribosomal, 'S6', protein, kinase, '(', 'mTOR/p70(s6k))', 'pathway,', and, 'SB', 202190, ',', the, inhibitor, of, 'p38,', completely, blocked, differentiation, in, control, 'cells,', and, creatine, did, not, reverse, this, 'inhibition,', suggesting, that, the, 'mTOR/p70(s6k)', and, p38, pathways, could, be, potentially, involved, in, the, effect, induced, by, creatine, on, differentiation])].
[sujeto(['Creatine', also, affected, the, phosphorylation, state, of, p38, '(', -, 50, '%', at, 24, h, and, +, 70, '%', at, 96, 'h,', 'P', &, 'lt;', 0.05, ')', as, well, as, the]), verbo([nuclear]), complemento([content, of, its, downstream, targets, myocyte, enhancer, 'factor-2', '(', -, 55, '%', at, 48, h, and, +, 170, '%', at, 96, 'h,', 'P', &, 'lt;', 0.05, ')', and, 'MyoD', '(', +, 60, '%', ',', 'P', &, 'lt;', 0.01, ')'])].
[sujeto(['In', 'conclusion,', this, study, points, out, the, involvement, of, the, p38, and, the, 'Akt/PKB-p70(s6k)', pathways, in, the]), verbo([enhanced]), complemento([differentiation, induced, by, creatine, in, 'C(2)C(12)', cells])].
[sujeto(['The', hindlimbs, of, some, animals, in, each, group, were, irradiated, before, injury, to]), verbo([prevent]), complemento([proliferation, of, myogenic, cells, during, recovery])].
[sujeto(['Inhibiting', myogenesis]), verbo([prevented]), complemento([the, recovery, of, contractile, function, after, 'MR,', but, not, after, 1, 'R'])].
[sujeto(['Both', protocols]), verbo([caused]), complemento(['Evans', blue, dye, uptake, immediately, after, 'injury,', but, 'Evans', blue, dye, was, only, retained, in, fibers, for, several, days, after, 1, 'R'])].
[sujeto(['This']), verbo([suggests]), complemento([that, membranes, reseal, after, 1, 'R,', but, not, after, 'MR'])].
[sujeto(['The', mechanisms, that, underlie, recovery, after, injuries]), verbo([caused]), complemento([by, repeated, lengthening, contractions, and, injuries, caused, by, a, single, lengthening, contraction, are, different])].
[sujeto(['The', differences, may, be, important, when, planning]), verbo([targeted]), complemento([rehabilitation, strategies, for, each, type, of, injury])].
[sujeto(['Advanced', gene, 'therapy,', tissue, engineering, and, biopharmaceutical, manufacturing]), verbo([require]), complemento([sophisticated, and, 'well-balanced', multiregulated, multigene, interventions, to, reprogram, desired, mammalian, cell, phenotypes])].
[sujeto(['We']), verbo([have]), complemento([combined, the, streptogramin, '(', 'PIP)-', and, tetracycline, '(', 'TET)-responsive', gene, regulation, systems, for, independent, expression, control, of, the, differentiation, determinants, myoD, and, msx1, in, 'C2C12-derived', cells])].
[sujeto(['Different', 'dual-regulated', expression, scenarios, which]), verbo([induce]), complemento([either, 'both,', only, one, or, none, of, the, lineage, control, genes, triggered, differential, differentiation, and, precise, control, of, 'myogenic,', osteogenic, or, adipogenic, cell, phenotypes])].
[sujeto(['We']), verbo([reported]), complemento([previously, that, transcription, factor, nuclear, factor, '(', 'NF)-kappaB', is, constitutively, activated, in, human, and, murine, squamous, cell, carcinomas, '(', 'SCCs)'])].
[sujeto(['Remarkably,', 'NF-kappaB']), verbo([modulated]), complemento([the, expression, of, &, 'gt;60%', of, the, 308, genes, differentially, expressed, between, normal, keratinocytes, and, metastatic, 'SCCs'])].
[sujeto(['NF-kappaB', directly, or, indirectly]), verbo([modulated]), complemento([expression, of, programs, of, genes, functionally, linked, to, 'proliferation,', 'apoptosis,', 'adhesion,', and, angiogenesis])].
[sujeto(['NF-kappaB', 'DNA']), verbo([binding]), complemento([motifs, were, detected, in, the, promoter, of, approximately, 63, '%', of, genes, showing, increased, expression, and, 33, '%', of, the, genes, showing, decreased, expression])].
[sujeto(['The', 'ACTACAG', motif, implicated, in, the, 'NF-kappaB-dependent', 'down-regulation', of, mRNA, expression, of, 'MyoD', and, 'Sox9', was, detected, in, the, coding, portion, of, about, 15, '%', of, genes, showing]), verbo([increased]), complemento([or, decreased, expression])].
[sujeto(['Inactivation', of, 'NF-kappaB']), verbo([inhibited]), complemento([malignant, phenotypic, features, including, 'proliferation,', cell, 'survival,', 'migration,', 'angiogenesis,', and, tumorigenesis])].
[sujeto(['These', results]), verbo([provide]), complemento([evidence, that, 'NF-kappaB', is, an, important, modulator, of, gene, expression, programs, that, contribute, to, the, malignant, phenotype, of, 'SCC'])].
[sujeto(['In', the, present, study, optimized, 'HIV-1-based', vector, systems, that, display, efficient, doxycycline, '(', 'Dox)-dependent', transgene, expression, in, vitro, and, in, vivo]), verbo([have]), complemento([been, developed, through, the, modification, of, factors, that, contribute, to, basal, activity, levels])].
[sujeto(['Dissection', of, 'HIV-1', vectors, harboring, a, 'tTA-dependent', transgene, expression, cassette, revealed, several, mechanisms, that, account, for, 'Dox-independent', transgene, 'expression,', including, those]), verbo([mediated]), complemento([by, an, internal, 'CMV', 'promoter,', as, well, as, a, potential, contribution, from, fusion, proteins, generated, by, translational, readthrough])].
[sujeto(['Cell-substratum', interactions]), verbo([trigger]), complemento([key, signaling, pathways, that, modulate, growth, control, and, 'tissue-specific', gene, expression])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, abolishing, adhesive, interactions, by, suspension, culture, results, in, 'G(0)', arrest, of, myoblasts])].
[sujeto(['We']), verbo([report]), complemento([that, blocking, intracellular, transmission, of, 'adhesion-dependent', signals, in, adherent, cells, mimics, the, absence, of, adhesive, contacts])].
[sujeto(['Furthermore,', both, 'ML7', and, 'BDM']), verbo([suppressed]), complemento([expression, of, 'MyoD', and, 'myogenin,', induced, 'p27(kip1)', but, not, 'p21(cip1),', and, inhibited, differentiation])].
[sujeto(['Thus,', as, with, 'suspension-arrest,', inhibition, of, 'acto-myosin', contractility, in, adherent, cells]), verbo([led]), complemento([to, arrest, uncoupled, from, differentiation])].
[sujeto(['By', 'contrast,', 'wild-type', 'RhoA']), verbo([induced]), complemento(['arrest,', maintained, 'MyoD', and, activated, myogenin, and, p21, expression])].
[sujeto(['The', 'Rho', effector, kinase, 'ROCK', did, not, appear, to]), verbo([mediate]), complemento(['Rho\'s', effects, on, 'MyoD'])].
[sujeto(['Signals']), verbo([regulated]), complemento([by, 'MLCK', are, 'critical,', since, inhibition, of, 'MLCK', suppressed, 'MyoD', expression, but, inhibition, of, 'ROCK', did, not])].
[sujeto(['Inhibition', of, contractility]), verbo([suppressed]), complemento(['MyoD', but, did, not, reduce, actin, polymer, levels])].
[sujeto(['However,', actin, depolymerization, with, latrunculin, 'B']), verbo([inhibited]), complemento(['MyoD', expression])].
[sujeto(['Taken', 'together,', our, observations, indicate, that, actin, polymer, status, and, contractility]), verbo([regulate]), complemento(['MyoD', expression])].
[sujeto(['We']), verbo([suggest]), complemento([that, in, 'myoblasts,', the, 'Rho', pathway, and, regulation, of, 'acto-myosin', contractility, may, define, a, control, point, for, conditional, uncoupling, of, differentiation, and, the, cell, cycle])].
[sujeto(['Several', studies]), verbo([have]), complemento([already, demonstrated, that, 'micro-', and, 'milli-calpains', '(', 'CAPN', 1, -, 'CAPN', 2, ')', ',', 'calcium-dependent', intracellular, 'cysteine-proteases', are, involved, in, many, biological, phenomenon, including, muscle, growth, and, development])].
[sujeto(['More', 'particularly,', recent, studies]), verbo([have]), complemento([demonstrated, that, 'milli-calpain', is, implicated, in, myoblast, fusion])].
[sujeto(['Because', 'micro-', and, 'milli-calpains', do, not]), verbo([have]), complemento([the, same, intracellular, 'localization,', it, appears, likely, that, these, two, 'calcium-dependent', proteases, have, different, biological, roles, during, muscle, cell, differentiation])].
[sujeto(['We', 'therefore,']), verbo([have]), complemento([developed, a, muscle, cell, line, in, which, 'micro-calpain', is, 'over-expressed,', using, the, inducible, 'Tet', 'Regulated', 'Expression', 'System'])].
[sujeto(['The', present, study, shows, important]), verbo([decreases]), complemento([in, the, expression, level, of, ezrin, '(', 68, '%', ')', ',', vimentin, '(', 64, '%', ')', and, caveolin, 3, '(', 76, '%', ')', whereas, many, other, cytoskeletal, proteins, remain, remarkably, stable])].
[sujeto(['Concerning', the, myogenic, transcription, 'factors,', only, the, level, of, myogenin]), verbo([decreased]), complemento(['(', 59, '%', ')', after, the, 'over-expression', of, 'micro-calpain'])].
[sujeto(['Ultra', structural, studies]), verbo([have]), complemento([shown, that, the, myofibrils, formed, near, the, cell, periphery, are, normally, 'oriented,', lying, along, the, longitudinal, axis])].
[sujeto(['This', regularity, is, lost, progressively, towards, the, cell, center, where, the, cytoskeleton, presented, an]), verbo([increasing]), complemento([disorganization])].
[sujeto(['All', these, results, indicate, that, 'micro-calpain', is]), verbo([involved]), complemento([in, regulation, pathway, of, myogenesis, via, at, least, its, action, on, 'ezrin,', 'vimentin,', caveolin, 3, and, 'myogenin,', a, muscle, transcription, factor])].
[sujeto(['Skeletal', muscle, contractile, activity]), verbo([has]), complemento([been, implicated, in, many, aspects, of, muscle, cell, differentiation, and, maturation])].
[sujeto(['Much', of, the, research, in, this, area]), verbo([has]), complemento([depended, upon, costly, and, 'labor-intensive', cultures, of, isolated, primary, muscle, cells, because, widely, available, immortalized, muscle, cell, lines, often, do, not, display, a, high, level, of, either, spontaneous, or, stimulated, contractile, activity])].
[sujeto(['We', sought, to, develop, 'conditionally-immortalized', skeletal, muscle, cell, lines, that, would]), verbo([provide]), complemento([a, source, of, myofibers, that, exhibit, robust, spontaneous, contractile, activity, similar, to, primary, muscle, cultures])].
[sujeto(['Using', a, 'tetracycline-regulated', retroviral, vector]), verbo([expressing]), complemento([a, 'temperature-sensitive', 'T-antigen', to, infect, primary, 'myoblasts,', we, isolated, individual, clonal, muscle, precursor, cell, lines, that, have, characteristics, of, activated, satellite, cells, during, growth, and, rapidly, differentiate, into, mature, myotubes, with, spontaneous, contractile, activity, after, culture, in, 'non-transformation-permissive', conditions])].
[sujeto(['Nutrition', plays, a, key, role, in, the, maintenance, of, muscle, and, bone, 'mass,', and, dietary, protein, deficiency]), verbo([has]), complemento([in, particular, been, associated, with, catabolism, of, both, muscle, and, bone, tissue])].
[sujeto(['One', mechanism, thought, to, link, protein, deficiency, with]), verbo([loss]), complemento([of, muscle, mass, is, deficiency, in, specific, amino, acids, that, play, a, role, in, muscle, metabolism])].
[sujeto(['Adult', mice, '(', 12, 'mo)', were, fed, a, normal, diet, '(', 18, '%', 'protein),', as, well, as, diets, with, low, protein, '(', 8, '%', ')', supplemented, with]), verbo([increasing]), complemento([concentrations, '(', 50, ',', 100, ',', and, 200, 'uM)', of, kynurenine, '(', 'Kyn)', or, with, tryptophan, '(', 'Trp;', 1.5, 'mM)', for, 8, weeks])].
[sujeto(['Enzyme-linked', immunosorbent, assays, showed, significant]), verbo([increases]), complemento([in, skeletal, muscle, 'insulin-like', growth, 'factor-1,', 'leptin,', and, the, myostatin, antagonist, follistatin, with, 'Trp', supplementation])].
[sujeto(['In', 'vitro,', neither, amino, acid, affected, proliferation, of, 'myoprogenitors,', but, 'Trp']), verbo([increased]), complemento([the, expression, of, the, myogenic, markers, 'MyoD,', 'myogenin,', and, myosin, heavy, chain])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, dietary, amino, acids, can, directly, affect, molecular, signaling, in, skeletal, 'muscle,', further, indicating, that, dietary, manipulation, with, specific, amino, acids, could, potentially, attenuate, muscle, loss, with, dietary, protein, deficiency])].
[sujeto(['Brown', fat, or, brown, adipose, tissue, '(', 'BAT),']), verbo([found]), complemento([in, newborn, mammals, as, small, depots, localized, in, the, interscapular, 'region,', plays, a, prominent, role, in, regulating, thermogenesis, perinatally])].
[sujeto(['The', physiological, importance, of, functional, 'BAT']), verbo([has]), complemento([been, recently, reasserted, in, human, adults])].
[sujeto(['The']), verbo([increased]), complemento([adipocyte, proliferation, in, 'BAT', of, 'double-mutant', newborns, was, associated, with, overexpression, of, the, brown, 'fat-specific', marker, 'Ucp1'])].
[sujeto(['More', 'strikingly,', expression, of, the, master, key, gene, 'Prdm16']), verbo([involved]), complemento([in, the, switch, between, myogenic, and, brown, adipogenic, lineages, was, drastically, enhanced])].
[sujeto(['We', further, demonstrate, that, concomitant, 'Myod', and, 'Igf2', inactivation, accelerates, differentiation, of, a, brown, preadipocyte, cell, line, and]), verbo([induces]), complemento([lipid, accumulation, and, increased, 'Ucp1', and, 'Prdm16', expression])].
[sujeto(['These', results]), verbo([provide]), complemento([the, first, in, vivo, evidence, that, a, myogenic, regulator, together, with, a, growth, factor, act, simultaneously, but, through, independent, pathways, to, repress, 'Prdm16,', which, opens, potential, therapeutic, perspectives, for, human, metabolic, disorders])].
[sujeto(['Such', quadruplexes, were, implicated, in, the, regulation, of, gene, 'expression,', plausibly, by]), verbo([interacting]), complemento([with, transcription, factors])].
[sujeto(['We', showed, previously, that, homodimers, of, the, myogenic, transcription, factor, 'MyoD']), verbo([bound]), complemento([in, vitro, most, tightly, bimolecular, quadruplexes, of, promoter, sequences, of, 'muscle-specific', genes])].
[sujeto(['Here,', we, show, that, 'DNA', quadruplexes]), verbo([enhance]), complemento([in, vivo, 'MyoD', and, 'E-box-driven', expression, of, a, firefly, luciferase, '(', 'FL)', reporter, gene])].
[sujeto(['HEK293', cells, were, transfected, with, 'FL']), verbo([expressing]), complemento(['p4RTK-FL', vector, alone, or, together, with, 'MyoD', expressing, 'pEMSV-MyoD', 'plasmid,', with, quadruplexes, of, alpha7, integrin, or, sarcomeric, mitochondrial, creatine, kinase, '(', 'sMtCK)', muscle, gene, promoters, or, with, a, combination, thereof])].
[sujeto(['However,', together, with, 'MyoD,', quadruplex, 'DNA']), verbo([increased]), complemento([by, approximately, 35, -, fold, the, amounts, of, 'FL', mRNA, and, protein])].
[sujeto(['Without', affecting, its, 'expression,', 'DNA', quadruplexes]), verbo([bound]), complemento(['MyoD', in, the, cells])].
[sujeto(['Heterodimers', of, 'MRFs', with, 'E-proteins']), verbo([activate]), complemento(['muscle-specific', gene, expression, by, binding, to, 'E-box', motifs, 'd(CANNTG)', in, their, promoters, or, enhancers])].
[sujeto(['We', showed, previously, that, in, contrast, to, the, favored]), verbo([binding]), complemento([of, 'E-box', by, 'MyoD-E47', 'heterodimers,', homodimeric, 'MyoD', associated, preferentially, with, quadruplex, structures, of, regulatory, sequences, of, 'muscle-specific', genes])].
[sujeto(['To', inquire, whether, other, 'MRFs', shared, the, 'DNA']), verbo([binding]), complemento([preferences, of, 'MyoD,', the, 'DNA', affinities, of, 'hetero-', and, 'homo-dimeric', 'MyoD,', 'MRF4', and, 'Myogenin', were, compared])].
[sujeto(['Similarly', to, 'MyoD,', heterodimers, with, 'E47', of, 'MRF4', or, 'Myogenin']), verbo([bound]), complemento(['E-box', more, tightly, than, quadruplex, 'DNA'])].
[sujeto(['However,', unlike, homodimeric, 'MyoD', or, 'MRF4,', 'Myogenin', homodimers]), verbo([associated]), complemento([weakly, and, nonpreferentially, with, quadruplex, 'DNA'])].
[sujeto(['Thus,', 'Myogenin', with, an, implanted, 'MyoD', basic, region]), verbo([bound]), complemento([quadruplex, 'DNA', nearly, as, tightly, as, 'MyoD'])].
[sujeto(['We', speculate, that, the, dissimilar, interaction, of, 'MyoD', and, 'Myogenin', with, tetrahelical, domains, in, muscle, gene, promoters, may, differently]), verbo([regulate]), complemento([their, myogenic, activities])].
[sujeto(['Muscle', differentiation, and, expression, of, 'muscle-specific', proteins, are, initiated, by, the]), verbo([binding]), complemento([of, heterodimers, of, the, transcription, factor, 'MyoD', with, 'E2A', proteins, to, 'E-box', motif, 'd(CANNTG)', in, promoters, or, enhancers, of, 'muscle-specific', genes])].
[sujeto(['In', this, 'work,', we, identified, elements, in, 'MyoD', that]), verbo([bind]), complemento(['E-box', or, tetraplex, structures, of, promoter, sequences, of, the, 'muscle-specific', genes, alpha7, integrin, and, sarcomeric, 'Mitochondrial', 'Creatine', 'Kinase', '(', 'sMtCK)'])].
[sujeto(['Deletions', of, large, domains, of, the, 315, amino, acids, long, recombinant, 'MyoD', indicated, that, the]), verbo([binding]), complemento([site, for, both, 'E-box', and, tetraplex, 'DNA', is, its, basic, region, 'KRKTTNADRRKAATMRERRR', that, encompasses, the, three, underlined, clusters, of, basic, residues, designated, 'R(1),', 'R(2)', and, 'R(3)'])].
[sujeto(['By', 'contrast,', the, 'MyoD', deletion, mutants, 'Delta102-114,', 'DeltaR(3),', 'DeltaR(1)R(3)', or, 'DeltaR(2)R(3)']), verbo([maintained]), complemento([comparable, tetraplex, 'DNA-binding', capacity, as, reflected, by, the, similar, dissociation, constants, of, their, 'protein-DNA', complexes])].
[sujeto(['Only', deletion, of, all, three, basic, clusters, abolished, the]), verbo([binding]), complemento([of, tetraplex, 'DNA'])].
[sujeto(['Implications', of, the]), verbo([binding]), complemento([of, 'E-box', and, tetraplex, 'DNA', by, 'non-identical', 'MyoD', elements, are, considered])].
[sujeto(['We', therefore, perturbed, vascular, assembly, in, chick, limbs, by, overexpressing, 'VEGFA', and, demonstrated, that, ectopic, blood, vessels]), verbo([inhibit]), complemento([muscle, 'formation,', while, promoting, connective, tissue])].
[sujeto(['Conversely,', local, inhibition, of, vessel, formation, using, a, soluble, form, of, 'VEGFR1']), verbo([leads]), complemento([to, muscle, fusion])].
[sujeto(['The', endogenous, location, of, endothelial, cells, in, the, future, muscle, cleavage, zones, and, the, inverse, correlation, between, blood, vessels, and, muscle]), verbo([suggests]), complemento([that, vessels, are, involved, in, the, muscle, splitting, process])].
[sujeto(['We', also, identify, the, secreted, factor, 'PDGFB', '(']), verbo([expressed]), complemento([in, endothelial, 'cells)', as, a, putative, molecular, candidate, mediating, the, 'muscle-inhibiting', and, connective, 'tissue-promoting', functions, of, blood, vessels])].
[sujeto(['Finally,', we, propose, that, 'PDGFB']), verbo([promotes]), complemento([the, production, of, extracellular, matrix, and, attracts, connective, tissue, cells, to, the, future, splitting, 'site,', allowing, separation, of, the, muscle, masses, during, the, splitting, process])].
[sujeto(['Myogenic', transcription, is]), verbo([activated]), complemento([by, the, binding, of, heterodimers, of, the, basic, 'helix-loop-helix', proteins, 'MyoD', and, 'E12', or, 'E47', to, a, consensus, 'E-box', 'sequence,', 'd(CANNTG),', in, promoter, or, enhancer, regions, of, 'muscle-specific', genes])].
[sujeto(['Homodimers', of, 'MyoD']), verbo([bind]), complemento(['E-box', less, tightly, and, are, less, efficient, activators, of, transcription])].
[sujeto(['Here', we]), verbo([have]), complemento([shown, that, homodimers, of, 'full-length', recombinant, 'MyoD', formed, complexes, with, bimolecular, tetraplex, structures, of, 'muscle-specific', regulatory, sequences, but, not, with, their, 'double-stranded,', 'hairpin,', or, unimolecular, tetraplex, forms])].
[sujeto(['Preferential']), verbo([binding]), complemento([of, homodimeric, 'MyoD', to, bimolecular, tetraplex, 'DNA', structures, over, 'E-box', 'DNA', was, reflected, by, the, 18.7, -, 39.9, -, fold, lower, dissociation, 'constants,', 'Kd,', of, the, 'MyoD-tetraplex', 'DNA', complexes])].
[sujeto(['Similarly,', homodimers, of, the, 60, -, amino, acid, basic, 'helix-loop-helix', domain, of, 'MyoD']), verbo([bound]), complemento(['E-box', more, efficiently, and, tetraplex, 'DNA', less, efficiently, than, homodimers, of, 'full-length', 'MyoD'])].
[sujeto(['It', might, be, that, the, favored]), verbo([binding]), complemento([of, 'MyoD', homodimers, to, tetraplex, 'DNA', structures, lowers, their, ability, to, activate, 'muscle-specific', gene, 'transcription,', whereas, the, formation, of, 'MyoD-E47', heterodimers, and, their, preferential, binding, to, 'E-box', 'DNA', enhance, transcription])].
[sujeto(['The', myogenic, determination, protein, 'MyoD', was]), verbo([reported]), complemento([to, bind, to, a, tetrahelical, structure, of, 'guanine-rich', enhancer, sequence, of, muscle, creatine, kinase, '(', 'MCK)', more, tightly, than, to, its, target, 'E-box', motif, '[', 'K'])].
[sujeto([',', 267, ',', 13714, -, 13718, ']', ',']), verbo([suggesting]), complemento([that, tetraplex, structures, of, regulatory, sequences, of, 'muscle-specific', genes, could, contribute, to, transcriptional, regulation])].
[sujeto(['The', sMtCK, sequence, folded, into, a, hairpin, 'structure;', the, alpha7, integrin, oligonucleotide, generated, a, unimolecular, 'tetraplex;', and, sequences, from, all, three, genes]), verbo([associated]), complemento([to, generate, bimolecular, tetraplexes])].
[sujeto(['We', also, show, that, homodimeric, 'MyoD']), verbo([bound]), complemento([bimolecular, tetraplex, structures, of, 'muscle-specific', regulatory, sequences, more, efficiently, than, its, target, 'E-box', motif])].
[sujeto(['Forced', expression, of, the, bHLH, myogenic, 'factors,', 'Myf5', and, 'MyoD,', in, various, mammalian, cell, lines]), verbo([induces]), complemento([the, full, program, of, myogenic, differentiation])].
[sujeto(['However,', this, property]), verbo([has]), complemento([not, been, extensively, explored, in, vivo])].
[sujeto(['We']), verbo([have]), complemento([taken, advantage, of, the, chick, model, to, investigate, the, effect, of, electroporation, of, the, mouse, 'Myf5', and, 'MyoD', genes, in, the, embryonic, neural, tube])].
[sujeto(['We']), verbo([found]), complemento([that, misexpression, of, either, mouse, 'Myf5', or, 'MyoD', in, the, chick, neural, tube, leads, to, ectopic, skeletal, muscle, 'differentiation,', assayed, by, the, expression, of, the, myosin, heavy, chains, in, the, neural, tube, and, neural, crest, derivatives])].
[sujeto(['We', also, showed, that, the, endogenous, neuronal, differentiation, program, is]), verbo([inhibited]), complemento([under, the, influence, of, either, ectopic, mouse, 'Myf5', or, 'MyoD'])].
[sujeto(['We']), verbo([found]), complemento([that, 'MyoD', and, 'Myogenin', expression, can, be, activated, by, ectopic, mouse, 'Myf5', or, 'MyoD,', while, 'Myf5', expression, cannot, be, activated, either, by, mouse, 'MyoD', or, by, itself])].
[sujeto(['We', also, analysed, the, transcriptional, regulation, between, the, myogenic, factors, and, the, different, genes]), verbo([involved]), complemento([in, 'myogenesis,', such, as, 'Mef2c,', 'Pax3,', 'Paraxis,', 'Six1,', 'Mox1,', 'Mox2', and, 'FgfR4'])].
[sujeto(['Here,', we, investigated, the, effect, of]), verbo([increased]), complemento(['NDRG2', levels, on, the, 'proliferation,', differentiation, and, apoptosis, in, skeletal, muscle, cells, under, basal, and, stress, conditions])].
[sujeto(['NDRG2', overexpression]), verbo([increased]), complemento(['C2C12', myoblast, proliferation, and, the, expression, of, positive, cell, cycle, 'regulators,', 'cdk2,', cyclin, 'B', and, cyclin, 'D,', and, phosphorylation, of, 'Rb,', while, the, 'serine/threonine-deficient', 'NDRG2,', 3, 'A-NDRG2,', had, less, effect])].
[sujeto(['The', onset, of, differentiation, was]), verbo([enhanced]), complemento([by, 'NDRG2', as, determined, through, the, myogenic, regulatory, factor, expression, profiles, and, myocyte, fusion, index])].
[sujeto(['While', 'NDRG2', 'up-regulated', caspase, 3, /, 7, activities, during, 'differentiation,', no]), verbo([increase]), complemento([in, apoptosis, was, measured, by, 'TUNEL', assay, or, through, cleavage, of, caspase, 3, and, 'PARP', proteins])].
[sujeto(['During', 'H2O2', treatment, to]), verbo([induce]), complemento([oxidative, 'stress,', 'NDRG2', helped, protect, against, the, loss, of, proliferation, and, 'ER', stress, as, measured, by, 'GRP78', expression, with, 3, 'A-NDRG2', displaying, less, protection])].
[sujeto(['NDRG2', also, attenuated, apoptosis, by, reducing, cleavage, of, 'PARP', and, caspase, 3, and, expression, of, 'pro-apoptotic', 'Bax', while]), verbo([enhancing]), complemento([the, 'pro-survival', 'Bcl-2', and, 'Bcl-xL', levels])].
[sujeto(['Our', findings, show, that, 'NDRG2', overexpression]), verbo([increases]), complemento([myoblast, proliferation, and, caspase, 3, /, 7, activities, without, increasing, overall, differentiation])].
[sujeto(['Glucocorticoids']), verbo([cause]), complemento([secondary, osteoporosis, and, 'myopathy,', characterized, by, type, 'II', muscle, fiber, atrophy])].
[sujeto(['We', examined, whether, a, new, vitamin, 'D3', 'analogue,', 'eldecalcitol,', could]), verbo([inhibit]), complemento(['glucocorticoid-induced', osteopenia, or, myopathy, in, 'rats,', and, also, determined, the, effects, of, prednisolone, '(', 'PSL)', 'and/or', eldecalcitol, on, 'muscle-related', gene, expression])].
[sujeto(['Eldecalcitol', treatment, for, 4, &, 'nbsp;weeks']), verbo([maintained]), complemento([the, same, 'BMD', as, the, 'PSL + E', group])].
[sujeto(['After', 2, &, 'nbsp;weeks,', but, not, 4, &, 'nbsp;weeks,', eldecalcitol, treatment, significantly]), verbo([increased]), complemento(['Pax7', and, myogenin, mRNA, expression, in, gastrocnemius, 'muscle,', and, 'PSL', also, stimulated, myogenin, expression])].
[sujeto(['Eldecalcitol', appears, to]), verbo([increase]), complemento([muscle, volume, and, to, protect, against, femur, 'BMD', loss, in, 'PSL-administered', 'rats,', and, it, may, also, stimulate, myoblast, differentiation, into, early, myotubes])].
[sujeto(['Corticosteroids']), verbo([cause]), complemento([muscle, atrophy, by, acting, on, proteasomal, and, lysosomal, systems, and, by, affecting, pathways, related, to, muscular, 'trophysm,', such, as, the, 'IGF-1/PI-3k/Akt/mTOR'])].
[sujeto(['Omega-3', fatty, acid, '(', 'n-3)']), verbo([has]), complemento([been, used, beneficially, to, attenuate, muscle, atrophy, linked, to, sepsis, and, 'cachexia;', 'however,', its, effect, on, 'dexamethasone-induced', muscle, atrophy, has, not, been, evaluated])].
[sujeto(['Dexamethasone']), verbo([induced]), complemento([a, significant, loss, in, body, and, muscle, 'weight,', atrophy, in, type, 2, 'B', 'fibers,', and, decreased, expression, of, 'P-Akt,', 'P-GSK3β,', and, 'P-FOXO3a'])].
[sujeto(['N-3', supplementation, did, not, attenuate, the, negative, effects, of, dexamethasone, on, skeletal, 'muscle;', 'instead,', it]), verbo([caused]), complemento([atrophy, in, type, 1, ',', 2, 'A,', reduced, the, expression, of, 'Myogenin,', and, increased, the, expression, of, 'Atrogin-1'])].
[sujeto(['Myostatin', '(', 'MSTN)', is, primarily]), verbo([expressed]), complemento([in, muscle, and, plays, an, important, role, in, muscle, and, fat, development, in, pigs])].
[sujeto(['In', order, to, elucidate, whether, pig, 'MSTN', could, be]), verbo([regulated]), complemento([by, 'muscle-', and, 'fat-related', 'factors,', the, porcine, 'MSTN', promoter, was, amplified, and, cloned, into, 'pGL3-basic', 'vector,', and, transfected, into, cells, to, analyze, the, transcriptional, activity, of, promoter, with, 'muscle-', and, 'fat-related', factors, through, 'dual-luciferase', reporter, assays])].
[sujeto(['We']), verbo([found]), complemento([that, 'MSTN', promoter, transcriptional, activity, can, be, regulated, by, 'IBMX,', but, not, by, 'DIM'])].
[sujeto(['CCAAT/enhancer']), verbo([binding]), complemento([protein, '(', 'C/EBP)', α, and, 'C/EBPβ,', two, proteins, which, are, induced, by, 'DIM', during, adipogenesis, were, cotransfected, with, the, 1.7, -, kb, 'fragment,', 'respectively,', resulting, in, promoter, transcriptional, activity, downregulation])].
[sujeto(['Treating', the, fragment, with, rosiglitazone, which]), verbo([induce]), complemento([the, expression, of, peroxisome, 'proliferator-activated', receptor, γ, '(', 'PPARγ),', resulting, in, promoter, transcriptional, activity, upregulation])].
[sujeto(['The', purpose, of, this, review, is, to, discuss, novel, insight, into, mechanisms, of, 'glucocorticoid-regulated', muscle, 'wasting,', in, particular, the, role, of, transcription, factors, and]), verbo([nuclear]), complemento([cofactors])].
[sujeto(['Studies']), verbo([suggest]), complemento([that, 'glucocorticoid-induced', upregulation, of, the, transcription, factors, 'Forkhead', box, 'O', 1, and, 'CCAAT/enhancer-binding', protein, beta, and, downregulation, of, 'MyoD', and, myogenin, are, involved, in, 'glucocorticoid-induced', muscle, wasting])].
[sujeto(['In', 'addition,', 'glucocorticoid-induced', hyperacetylation]), verbo([caused]), complemento([by, increased, expression, of, the, nuclear, cofactor, p300, and, its, histone, acetyl, transferase, activity, and, decreased, expression, and, activity, of, histone, deacetylases, plays, an, important, role, in, 'glucocorticoid-induced', muscle, proteolysis, and, wasting])].
[sujeto(['Other', mechanisms, may, also, be]), verbo([involved]), complemento([in, 'glucocorticoid-induced', muscle, 'wasting,', including, insulin, resistance, and, 'store-operated', calcium, entry])].
[sujeto(['Novel', potential, strategies, to]), verbo([prevent]), complemento([or, treat, 'glucocorticoid-induced', muscle, wasting, include, the, use, of, small, molecule, histone, deacetylase, 'activators,', dissociated, glucocorticoid, receptor, 'agonists,', and, 11, 'beta-hydroxysteroid', dehydrogenase, type, 1, inhibitors])].
[sujeto(['An']), verbo([increased]), complemento([understanding, of, molecular, mechanisms, regulating, 'glucocorticoid-induced', muscle, wasting, will, help, develop, new, strategies, to, prevent, and, treat, this, debilitating, condition])].
[sujeto(['Long-term', corticosteroid, therapy]), verbo([causes]), complemento([myopathy, and, can, inhibit, regeneration, of, skeletal, muscle])].
[sujeto(['Single', myofibers, were, isolated, from, the, 'gastrocnemius,', centrifuged, to, mechanically]), verbo([activate]), complemento([satellite, 'cells,', and, maintained, in, culture, for, 48, h])].
[sujeto(['Supplementation', of, culture, media, with, the, nitric, oxide, 'donor,', diethylenetriamine, 'NONOate', '(', 'DETA-NO;', 5, -, 50, 'microM),']), verbo([caused]), complemento([a, 'dose-dependent', increase, in, the, number, of, 'myoD+', cells, arising, from, both, control, and, 'GC', myofibers, '(', 'P', &, 'lt;', 0.05, ')', ',', and, 10, and, 50, microM, 'DETA-NO', eliminated, the, 'GC-induced', deficit, in, myogenic, cells, '(', 'P', &, 'gt;', 0.05, ')'])].
[sujeto(['Nitric', oxide, production, could, be, an, important, therapeutic]), verbo([target]), complemento([for, the, prevention, of, corticosteroid, myopathy])].
[sujeto(['Glucocorticoid-induced', 'gene-1', '(', 'Gig1)', was, identified, in, a, yeast, 'one-hybrid', screen, for, factors, that]), verbo([interact]), complemento([with, the, 'MyoD', core, enhancer])].
[sujeto(['The', 'Gig1', gene, encodes, a, novel, 'C2H2', zinc, finger, protein, that, shares, a, high, degree, of, sequence, similarity, with, two, known, 'DNA']), verbo([binding]), complemento([proteins, in, 'humans,', 'Glut4', enhancer, factor, and, papillomavirus, binding, factor, '(', 'PBF)'])].
[sujeto(['The', 'DNA']), verbo([binding]), complemento([domain, of, 'Gig1,', which, contains, 'TCF-E-tail', 'CR1', and, 'CR2', motifs, shown, to, mediate, promoter, specificity, of, 'TCF-E-tail', 'isoforms,', was, mapped, to, a, 'C-terminal', domain, that, is, highly, conserved, in, 'Glut4', enhancer, factor, and, 'PBF'])].
[sujeto(['Gig1', was, also]), verbo([expressed]), complemento([in, a, subset, of, 'Scleraxis-positive', tendon, 'precursors/rudiments', of, the, 'limbs,', but, not, in, the, earliest, tendon, precursors, of, the, somite, '(', 'syndetome)', defined, by, 'Scleraxis', expression])].
[sujeto(['Skeletal', muscle, homoeostasis, is]), verbo([maintained]), complemento([by, a, variety, of, cytoprotective, mechanisms])].
[sujeto(['Since', ablation, of, the, 'TauT', '(', taurine, 'transporter)', gene, results, in, susceptibility, to, 'exercise-induced', muscle, weakness, in, 'vivo,', it]), verbo([has]), complemento([been, suggested, that, 'TauT', is, essential, for, skeletal, muscle, function])].
[sujeto(['Treatment', with, bFGF, '(', basic, fibroblast, growth, 'factor),', which]), verbo([inhibited]), complemento([muscle, 'differentiation,', abrogated, myogenic, induction, of, 'TauT'])].
[sujeto(['Database', analyses, identified, an, 'MEF2', '(', myocyte, enhancer]), verbo([binding]), complemento([factor, 2, ')', consensus, sequence, at, -, 844, in, the, rat, 'TauT', gene])].
[sujeto(['Electrophoretic', 'mobility-shift', assays, confirmed, that, 'MEF2']), verbo([bound]), complemento([to, the, 'MEF2', consensus, sequence, and, that, 'DNA-protein', complex, levels, were, increased, during, differentiation])].
[sujeto(['Importantly,', transfection, with, a, 'MyoD', expression, vector, markedly]), verbo([enhanced]), complemento(['TauT', promoter, activity, in, the, '(', 'non-myogenic)', 10, 'T1/2', cells])].
[sujeto(['Moreover,', 'co-transfection', with, an, 'MEF2', expression, vector, augmented, 'MyoD-induced', 'TauT', promoter, 'activity,']), verbo([suggesting]), complemento([that, 'MEF2', is, required, for, full, activation, of, 'TauT', expression])].
[sujeto(['Finally,', we, examined, the, effects, of, taurine, on, myotube, atrophy, to, clarify, the, biological, significance, of, the, 'up-regulation', of, 'TauT,', and, demonstrated, that, taurine, attenuated, muscle, atrophy]), verbo([induced]), complemento([by, dexamethasone])].
[sujeto(['TauT', expression, is]), verbo([regulated]), complemento([under, the, control, of, the, myogenic, 'programme,', and, we, propose, that, this, is, the, mechanism, for, 'taurine-mediated', resistance, to, muscle, atrophy])].
[sujeto(['Glucocorticoids']), verbo([have]), complemento([also, been, characterized, as, muscle, atrophying, agents])].
[sujeto(['However,', glucocorticoids, are, also, the, only, drugs]), verbo([reported]), complemento([to, have, a, beneficial, effect, on, the, treatment, of, muscle, degenerative, disorders])].
[sujeto(['Since', muscle, mass, relates, to, 'gender,', this, may, be, partially]), verbo([caused]), complemento([by, gender])].
[sujeto(['Male', rats, treated, with, dexamethasone, for, 14, days, '(', 1, mg, per, kg, body, 'weight)', showed]), verbo([increased]), complemento([levels, of, 'MyoD1,', myogenin, and, 'myf-5', compared, to, control, male, rats])].
[sujeto(['Female', rats, treated, with, dexamethasone, showed]), verbo([decreased]), complemento([expression, of, 'myf-6', compared, to, control, female, rats])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, dexamethasone, increase, satellite, 'cell-specific', 'MRF', activity, in, male, muscle, 'tissue,', which, is, suggested, to, be, associated, with, muscle, 'hypertrophy,', while, maintenance, of, muscle, tissue, is, affected, in, female, muscle, tissue])].
[sujeto(['Therefore,', we, conclude, that, both, basal, and, 'dexamethasone-induced', 'MRF', gene, mRNA, levels, are]), verbo([regulated]), complemento(['gender-specific'])].
[sujeto(['The', manner, in, which, growth, factors]), verbo([acting]), complemento([at, the, cell, surface, regulate, activity, of, myogenic, 'basic-helix-loop-helix', proteins, in, the, nucleus, and, thus, control, the, fate, of, committed, skeletal, myoblasts, remains, poorly, understood])].
[sujeto(['In', this, 'study,', we]), verbo([report]), complemento([that, immunoreactive, 'Gs', protein, 'alpha-subunits', '(', 'Gs', 'alpha)', localize, to, nuclei, of, proliferating, 'C2C12', myoblasts, but, not, to, nuclei, of, differentiated, postmitotic, 'C2C12', myotubes])].
[sujeto(['Dexamethasone-induced', expression, of]), verbo([activated]), complemento(['Gs', alpha, markedly, delayed, differentiation, in, comparison, with, uninduced, stably, transfected, 'cells,', which, differentiated, normally, in, 'mitogen-depleted', media])].
[sujeto(['Northern', blot, analysis, showed, that, impaired, differentiation, was]), verbo([associated]), complemento([with, delayed, 'up-regulation', of, 'MyoD', and, myogenin, and, delayed, 'down-regulation', of, 'Id,', a, dominant, negative, inhibitor, of, differentiation])].
[sujeto(['Similar', impairment, of, differentiation, could, not, be, reproduced, in, 'wild-type', 'C2C12', cells, by]), verbo([increasing]), complemento([intracellular, cAMP, either, with, forskolin, or, treatment, with, a, 'cell-permeable', cAMP, analog])].
[sujeto(['However,', treatment, of, myoblasts, with, cholera, toxin, markedly]), verbo([inhibited]), complemento([myogenic, differentiation])].
[sujeto(['Taken', 'together,', these, findings]), verbo([suggest]), complemento([a, novel, role, for, 'Gs', alpha, in, modulating, myogenic, differentiation])].
[sujeto(['After', treating, proliferating, cells, with, 'dexamethasone,', bmyf, transcripts, were]), verbo([induced]), complemento([approximately, fivefold, within, 1.5, -, 2.5, h])].
[sujeto(['Induction', of, bmyf, was, followed, 4, h, later, by, a, similar]), verbo([increase]), complemento([in, myogenin, transcripts, which, was, dependent, on, protein, synthesis])].
[sujeto(['The', 4, -, h, lag, before, the, myogenin, response]), verbo([suggested]), complemento([involvement, of, an, intermediate, factor])].
[sujeto(['However,', one, possible, 'factor,', 'myocyte-specific', enhancer]), verbo([binding]), complemento([factor, '(', 'MEF-2)', '(', a, known, enhancer, of, myogenin, promoter, 'activity)', was, neither, detectable, nor, inducible, by, dexamethasone, in, proliferating, cells])].
[sujeto(['There', was, also, a, transient, twofold]), verbo([increase]), complemento([in, mrf4, transcripts, by, dexamethasone, treatment, in, dividing, 'cells,', while, no, changes, were, detected, in, the, levels, of, 'Id,', 'E12,', or, 'TnC', messages])].
[sujeto(['We', conclude, that, ectopic, expression, of, 'MMTV-bmyf']), verbo([led]), complemento([to, activation, of, three, of, the, endogenous, myogenic, factor, genes, of, which, only, myogenin, showed, a, rapid, and, sustained, response, to, 'dexamethasone-mediated', induction, of, bmyf, in, dividing, cells])].
[sujeto(['Tissue', engineered, skeletal, muscle]), verbo([has]), complemento([potential, for, application, as, a, graft, source, for, repairing, soft, tissue, 'injuries,', a, model, for, testing, 'pharmaceuticals,', and, a, biomechanical, actuator, system, for, soft, robots])].
[sujeto(['However,', engineered, muscle, to, date]), verbo([has]), complemento([not, produced, forces, comparable, to, native, 'muscle,', limiting, its, potential, for, repair, and, for, use, as, an, in, vitro, model, for, pharmaceutical, testing])].
[sujeto(['In', this, 'study,', we, examined, the, trophic, effects, of, dexamethasone, '(', 'DEX),', a, glucocorticoid, that]), verbo([stimulates]), complemento([myoblast, differentiation, and, fusion, into, 'myotubes,', on, our, tissue, engineered, 'three-dimensional', skeletal, muscle, units, '(', 'SMUs)'])].
[sujeto(['These', optimized, 'SMUs', exhibited, formation, of, advanced, sarcomeric, structure, and, significant]), verbo([increases]), complemento([in, myotube, diameter, and, myotube, fusion, 'index,', compared, with, untreated, controls])].
[sujeto(['In', 'conclusion,', we]), verbo([have]), complemento([demonstrated, that, the, addition, of, 'DEX', to, our, process, of, engineering, skeletal, muscle, tissue, improves, 'myogenesis,', advances, muscle, 'structure,', and, increases, force, production, in, the, resulting, 'SMUs'])].
[sujeto(['Androgens,', known, mediators, of, overall, body, composition, and, specifically, skeletal, muscle, 'mass,']), verbo([have]), complemento([been, shown, to, regulate, 'MSCs'])].
[sujeto(['The', possible, overlapping, function, of, androgen, regulation, of, muscle, growth, and, 'MSC', activation]), verbo([has]), complemento([not, been, carefully, investigated, with, regards, to, muscle, regeneration])].
[sujeto(['In', an, in, vivo, muscle, atrophy, 'model,', androgen, 're-supplementation', significantly]), verbo([increased]), complemento([muscle, size, and, expression, of, 'IGF-1,', 'FST,', and, 'HGF,', while, significantly, decreasing, expression, of, 'GR'])].
[sujeto(['Biphasic', gene, expression, profiles, over, the, 7, -, day, 're-supplementation', period, identified, temporal, androgen, regulation, of, molecular]), verbo([targets]), complemento([involved, in, satellite, cell, engagement, into, myogenesis])].
[sujeto(['Modifications', in, the, androgen, signaling, gene, 'signature,', along, with, reduced, 'Pax7', and, 'MyoD', 'expression,']), verbo([suggested]), complemento([that, limited, 'MSC', activation, and, increased, inflammation, contributed, to, the, delayed, regeneration])].
[sujeto(['However,']), verbo([enhanced]), complemento(['MSC', activation, in, the, 'androgen-deplete', mouse, injury, model, was, driven, by, an, androgen, receptor, '(', 'AR)', agonist])].
[sujeto(['These', results]), verbo([provide]), complemento([novel, in, vitro, and, in, vivo, evidence, describing, molecular, targets, of, androgen, 'signaling,', while, also, increasing, support, for, translational, use, of, 'AR', agonists, in, skeletal, muscle, recovery, and, regeneration])].
[sujeto(['Recent', studies]), verbo([have]), complemento([demonstrated, that, 'HMB', inhibits, 'dexamethasone-induced', atrophy, in, cultured, 'myotubes,', but, its, effect, on, 'dexamethasone-induced', muscle, atrophy, has, not, been, determined, in, vivo])].
[sujeto(['Treatment', with, dexamethasone, weakened, grip, strengths, and]), verbo([increased]), complemento([muscle, damage, as, determined, by, increased, serum, creatine, kinase, levels, and, by, histological, analysis])].
[sujeto(['However,', 'HMB', supplementation, significantly]), verbo([prevented]), complemento([reductions, in, grip, 'strengths,', reduced, muscle, 'damage,', and, prevented, muscle, mass, and, protein, concentration, decrease, in, soleus, muscle])].
[sujeto(['Biochemical', analysis, demonstrated, that, dexamethasone, markedly]), verbo([increased]), complemento([levels, of, 'MuRF1', 'protein,', which, causes, the, ubiquitination, and, degradation, of, 'MyHC'])].
[sujeto(['Indeed,', dexamethasone, treatment]), verbo([decreased]), complemento(['MyHC', protein, expression, and, increased, the, 'ubiquitinated-MyHC', to, 'MyHC', ratio])].
[sujeto(['However,', 'HMB', supplementation]), verbo([caused]), complemento([the, 'down-regulations', of, 'MuRF1', protein, and, of, 'ubiquitinated-MyHC'])].
[sujeto(['Furthermore,', additional, experiments]), verbo([provided]), complemento([evidence, that, 'HMB', supplementation, inhibited, the, nuclear, translocation, of, 'FOXO1', induced, by, 'dexamethasone,', and, showed, increased, 'MyoD', expression, in, the, nuclear, fractions, of, soleus, muscles])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'HMB', supplementation, attenuates, 'dexamethasone-induced', muscle, wasting, by, regulating, 'FOXO1', transcription, factor, and, subsequent, 'MuRF1', expression])].
[sujeto(['Accordingly,', our, results]), verbo([suggest]), complemento([that, 'HMB', supplementation, could, be, used, to, prevent, steroid, myopathy])].
[sujeto(['Glucocorticoids', production, is]), verbo([increased]), complemento([in, many, pathological, conditions, that, are, associated, with, muscle, 'loss,', but, their, role, in, causing, muscle, wasting, is, not, fully, understood])].
[sujeto(['We']), verbo([have]), complemento([demonstrated, a, new, mechanism, of, 'glucocorticoid-induced', muscle, 'atrophy:', 'Dexamethasone', '(', 'Dex)', suppresses, satellite, cell, function, contributing, to, the, development, of, muscle, atrophy])].
[sujeto(['Specifically,', we]), verbo([found]), complemento([that, 'Dex', decreases, satellite, cell, proliferation, and, differentiation, in, vitro, and, in, vivo])].
[sujeto(['The', mechanism]), verbo([involved]), complemento(['Dex-induced', upregulation, of, myostatin, and, suppression, of, 'Akirin1,', a, promyogenic, gene])].
[sujeto(['When', myostatin, was]), verbo([inhibited]), complemento([in, 'Dex-treated', 'mice,', 'Akirin1', expression, increased, as, did, satellite, cell, 'activity,', muscle, regeneration, and, muscle, growth])].
[sujeto(['In', 'addition,', silencing, myostatin, in, myoblasts, or, satellite, cells]), verbo([prevented]), complemento(['Dex', from, suppressing, 'Akirin1', expression, and, cellular, proliferation, and, differentiation])].
[sujeto(['Finally,', overexpression, of, 'Akirin1', in, myoblasts]), verbo([increased]), complemento([their, expression, of, 'MyoD', and, myogenin, and, improved, cellular, proliferation, and, 'differentiation,', theses, improvements, were, no, longer, suppressed, by, 'Dex'])].
[sujeto(['We', conclude, that, glucocorticoids]), verbo([stimulate]), complemento([myostatin, which, inhibits, 'Akirin1', expression, and, the, reparative, functions, of, satellite, cells])].
[sujeto(['Thus,', inhibition, of, myostatin, or]), verbo([increasing]), complemento(['Akirin1', expression, could, lead, to, therapeutic, strategies, for, improving, satellite, cell, activation, and, enhancing, muscle, growth, in, diseases, associated, with, increased, glucocorticoid, production])].
[sujeto(['Annexin', 'A1', '(', 'ANXA1,', 'lipocortin-1)', is, a, 'glucocorticoid-regulated', 37, -, kDa, 'protein,', so, called, since, its, main, property, is, to]), verbo([bind]), complemento(['(', i])].
[sujeto(['Although', 'ANXA1']), verbo([has]), complemento([predominantly, been, studied, in, the, context, of, immune, responses, and, 'cancer,', the, protein, can, affect, a, larger, variety, of, biological, 'phenomena,', including, cell, proliferation, and, migration])].
[sujeto(['Our', previous, results, show, that, endogenous, 'ANXA1', positively]), verbo([modulates]), complemento([myoblast, cell, differentiation, by, promoting, migration, of, satellite, cells, 'and,', 'consequently,', skeletal, muscle, differentiation])].
[sujeto(['In', this, 'work,', we]), verbo([have]), complemento([evaluated, the, hypothesis, that, 'ANXA1', is, able, to, exert, effects, on, myoblast, cell, migration, acting, through, formyl, peptide, receptors, '(', 'FPRs)', following, changes, in, its, subcellular, localization, as, in, other, cell, types, and, tissues])].
[sujeto(['The', analysis, of, the, subcellular, localization, of, 'ANXA1', in, 'C2C12', myoblasts, during, myogenic, differentiation, showed, an, interesting]), verbo([increase]), complemento([of, extracellular, 'ANXA1', starting, from, the, initial, phases, of, skeletal, muscle, cell, differentiation])].
[sujeto(['Wound', healing, assay, experiments, showed, that, 'Ac2-26', peptide, is, able, to]), verbo([increase]), complemento([migration, of, 'C2C12', skeletal, muscle, cells, and, to, induce, cell, surface, translocation, and, secretion, of, 'ANXA1'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([a, role, for, 'ANXA1', as, a, highly, versatile, component, in, the, signaling, chains, triggered, by, the, proper, calcium, perturbation, that, takes, place, during, active, migration, and, differentiation, or, membrane, repair, since, the, protein, is, strongly, redistributed, onto, the, plasma, membranes, after, an, rapid, increase, of, intracellular, levels, of, 'Ca(2+)'])].
[sujeto(['These', properties, indicate, that, 'ANXA1', may, be]), verbo([involved]), complemento([in, a, novel, repair, mechanism, for, skeletal, muscle, and, may, have, therapeutic, implications, with, respect, to, the, development, of, 'ANXA1', mimetics])].
[sujeto(['Glucocorticoids', '(', 'GCs)', are]), verbo([involved]), complemento([in, the, muscle, wasting, caused, by, 'trauma,', 'inactivity,', and, stress])].
[sujeto(['The', results, showed, that, 'BM']), verbo([gain]), complemento([was, significantly, suppressed, by, 'DEX', treatment])].
[sujeto(['The', plasma, level, of, insulin, was]), verbo([increased]), complemento(['(', 'P<0'])].
[sujeto([5, ')', by, 'DEX', treatment, at, 'feeding,', whereas, 'IGF1', was]), verbo([decreased]), complemento(['(', 'P<0'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'GCs', suppress, 'IGF1', and, upregulate, myostatin, 'and/or', activated, myostatin, and, the, 'UBP', 'pathway,', which, might, be, the, source, of, the, effect, of, 'GCs', on, muscle, development])].
[sujeto(['We', investigated, the, expression, of, hepatocyte, growth, factor, '(', 'HGF),', which]), verbo([has]), complemento([mitogenic, and, 'anti-fibrotic', 'activities,', in, muscle, tissue, of, 'polymyositis/dermatomyositis', '(', 'PM/DM)', 'patients,', as, well, as, its, functional, roles, in, cultured, myoblasts])].
[sujeto(['Immunohistochemistry', in, muscle, from, 'PM/DM', patients, revealed, that, 'HGF', was]), verbo([expressed]), complemento([predominantly, on, infiltrating, mononuclear, cells, and, that, muscle, cells, expressed, the, receptor, 'c-met'])].
[sujeto(['Cultured', myoblasts, produced, 'HGF;', which, was]), verbo([increased]), complemento([by, 'IL-1alpha', but, suppressed, by, 'TGF-beta', and, dexamethasone])].
[sujeto(['Exogenous', 'HGF']), verbo([induced]), complemento([myoblast, proliferation, and, reduced, procollagen, type, 'I', production])].
[sujeto(['Furthermore,', 'HGF']), verbo([enhanced]), complemento([the, gene, expression, of, muscle, regulatory, factors, 'MyoD', and, 'Myf5,', while, suppressing, expression, of, 'fibrosis-related', 'genes,', connective, tissue, growth, factor, and, 'alpha-smooth', muscle, actin])].
[sujeto(['Various', signals, and, factors]), verbo([modulate]), complemento([this, 'process,', and, glucocorticoids, '(', 'GCs)', are, important, regulators, of, skeletal, muscle, metabolism])].
[sujeto(['We', show, that, 'glucocorticoid-induced', leucine, zipper, '(', 'GILZ),', a, 'GC-induced', 'gene,', and, the, newly, identified, isoform, long, 'GILZ', '(', 'L-GILZ)', are]), verbo([expressed]), complemento([in, skeletal, muscle, tissue, and, in, 'C2C12', myoblasts, where, 'GILZ/L-GILZ', maximum, expression, occurs, during, the, first, few, days, in, differentiation, medium])].
[sujeto(['Moreover,', we, observed, that, 'GC', treatment, of, 'myoblasts,', which]), verbo([increased]), complemento(['GILZ/L-GILZ', 'expression,', resulted, in, reduced, myotube, 'formation,', whereas, 'GILZ', and, 'L-GILZ', silencing, dampened, 'GC', effects])].
[sujeto(['Inhibition', of, differentiation]), verbo([caused]), complemento([by, 'GILZ/L-GILZ', overexpression, correlated, with, inhibition, of, 'MyoD', function, and, reduced, expression, of, myogenin])].
[sujeto(['Notably,', results, indicate, that, 'GILZ', and, 'L-GILZ']), verbo([bind]), complemento([and, regulate, 'MyoD/HDAC1', transcriptional, 'activity,', thus, mediating, the, 'anti-myogenic', effect, of, 'GCs'])].
[sujeto(['Atrophy', may, be, the, result, of]), verbo([increased]), complemento([catabolic, 'factors,', e])].
[sujeto(['Restraint', resulted, in, a, significant]), verbo([increase]), complemento([in, myostatin, which, was, significantly, reduced, with, 'Sutherlandia', treatment])].
[sujeto(['Restraint', also, resulted, in, a, significant, attenuation, of, the, 'PI3-Kinase/Akt', signaling, pathway, and]), verbo([increased]), complemento([apoptosis, which, was, reversed, with, 'Sutherlandia', treatment])].
[sujeto(['This', study, demonstrates, for, the, first, time, that, psychological, stress, elevates, markers, of, muscle, atrophy, and, 'apoptosis,', whilst, a, herbal, 'remedy,', 'Sutherlandia,']), verbo([inhibits]), complemento(['apoptosis,', and, signaling, pathways, associated, with, muscle, atrophy])].
[sujeto(['Myogenin', is, known, to, be, polyubiquitinated, by, 'SCF', '(', 'Skp1/Cullin', 1, /, 'F-box', 'protein)', followed, by, proteasomal, 'degradation,', though, the]), verbo([participating]), complemento(['F-box', protein, is, remaining, unidentified])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, myogenin, in, differentiated, myoblasts, is, destabilized, by, muscle, 'atrophy-inducing', dexamethasone, and, that, 'MAFbx', '(', muscle, atrophy, 'F-box', 'protein)', is, increased, in, atrophying, myotubes])].
[sujeto(['Myogenin', had, a, 'MAFbx-recognition', motif, and]), verbo([interacted]), complemento([with, 'MAFbx'])].
[sujeto(['MAFbx']), verbo([activated]), complemento([polyubiquitination, of, myogenin])].
[sujeto(['The', results, of, this, study]), verbo([suggest]), complemento([that, 'MAFbx', functions, as, an, 'F-box', protein, for, ubiquitination, of, myogenin])].
[sujeto(['Mechanical', ventilation, is, known, to]), verbo([induce]), complemento(['ventilator-induced', diaphragm, dysfunction])].
[sujeto(['Patients', submitted, to, mechanical, ventilation, often, receive, massive, doses, of, corticosteroids, that, may]), verbo([cause]), complemento([further, deterioration, of, diaphragm, function])].
[sujeto(['The', diaphragm, 'force-frequency', curve, was, shifted, downward, in, the, mechanical, ventilation, 'group,', but, this, deleterious, effect, was]), verbo([prevented]), complemento([when, corticosteroids, were, administered])].
[sujeto(['Diaphragm', 'cross-sectional', area, of, type, 'I', fibers, was, similarly]), verbo([decreased]), complemento([in, both, mechanical, ventilation, groups, while, atrophy, of, type, 'IIx/b', fibers, was, attenuated, after, corticosteroid, administration])].
[sujeto(['Plasma', cytokine, levels, were, unchanged, while, diaphragm, lipid, hydroperoxides, were, similarly]), verbo([increased]), complemento([in, both, mechanical, ventilation, groups])].
[sujeto(['Diaphragmatic', calpain, activity, was, significantly]), verbo([increased]), complemento([in, the, mechanical, ventilation, 'group,', but, calpain, activation, was, abated, with, corticosteroid, administration])].
[sujeto(['Inverse', correlations, were]), verbo([found]), complemento([between, calpain, activity, and, diaphragm, force])].
[sujeto(['Inhibition', of, the, calpain, system, is, most, likely, the, mechanism, by, which, corticosteroids]), verbo([induce]), complemento([this, protective, effect])].
[sujeto(['Accelerated', protein, degradation, via, the, 'ubiquitin-proteasome', pathway, is, the, principal]), verbo([cause]), complemento([of, skeletal, muscle, wasting, associated, with, common, human, disease, states, and, pharmacological, treatment, with, glucocorticoids])].
[sujeto(['Although', many, protein, regulatory, factors, essential, for, muscle, development, and, regeneration, are, degraded, via, the, ubiquitin, 'system,', little, is, known, about, the, mechanisms, and, regulation, of, this, pathway, that]), verbo([promote]), complemento([wasting, muscle])].
[sujeto(['Here,', we, demonstrate, 'that,', in, differentiated, 'myotubes,', 'glucocorticoid,', via, the, glucocorticoid, 'receptor,', selectively]), verbo([induces]), complemento([a, decrease, in, protein, abundance, of, 'MyoD,', a, master, switch, for, muscle, development, and, 'regeneration,', but, not, that, of, its, negative, regulator, 'Id1'])].
[sujeto(['This']), verbo([decrease]), complemento([in, 'MyoD', protein, results, from, accelerated, degradation, after, glucocorticoid, exposure])].
[sujeto(['Using', 'MyoD', and, 'Id1', mutants, deficient, in, either, 'N', 'terminus-dependent', or, internal, 'lysine-dependent', 'ubiquitination,', we, further, show, that, these, ubiquitination, pathways, of, 'MyoD', degradation, are]), verbo([regulated]), complemento([differently, from, those, of, 'Id1', degradation])].
[sujeto(['Specifically,', glucocorticoid]), verbo([activates]), complemento([the, 'N-terminal', ubiquitination, pathway, in, 'MyoD', degradation, in, 'myotubes,', without, concomitant, effects, on, 'Id1', degradation])].
[sujeto(['This', effect, of, glucocorticoid, on, 'MyoD', and, 'Id1', protein, degradation, is]), verbo([associated]), complemento([with, the, distinct, cellular, compartments, in, which, their, degradation, occurs])].
[sujeto(['UCP3', '(', uncoupling, 'protein-3)', is, a, mitochondrial, membrane, transporter]), verbo([expressed]), complemento([preferentially, in, skeletal, muscle])].
[sujeto(['Glucocorticoids']), verbo([activate]), complemento([the, transcription, of, the, ucp3, gene, through, a, glucocorticoid, 'receptor-binding', site, in, the, promoter, region])].
[sujeto(['Glucocorticoids', are, capable, of]), verbo([inducing]), complemento([ucp3, gene, transcription, independently, from, the, myogenic, regulatory, factor, 'MyoD,', in, contrast, with, the, transcriptional, activation, of, the, ucp3, gene, through, other, nuclear, hormone, receptors])].
[sujeto(['An', interplay, of, regulatory, factors]), verbo([modulates]), complemento([positively, '(', 'p300)', or, negatively, '(', histone, 'deacetylases)', the, action, of, glucocorticoids, on, ucp3, gene, transcription, via, histone, acetylation, or, deacetylation, 'processes,', respectively])].
[sujeto(['Among', 'them,', 'SIRT1']), verbo([acts]), complemento([as, a, major, repressor, of, ucp3, gene, expression, in, response, to, glucocorticoids])].
[sujeto(['The', action, of, 'SIRT1']), verbo([requires]), complemento([its, deacetylase, activity, and, results, in, histone, deacetylation, in, the, ucp3, promoter])].
[sujeto(['Moreover,', it]), verbo([involves]), complemento([a, specific, impairment, of, association, of, p300, with, the, glucocorticoid, receptor])].
[sujeto(['Agents']), verbo([activating]), complemento(['SIRT1,', such, as, 'resveratrol,', repress, ucp3, gene, expression])].
[sujeto(['Viral', oncoproteins, that, inactivate, the, retinoblastoma, tumor, suppressor, protein, '(', 'pRb)', family, both, block, skeletal, muscle, differentiation, and]), verbo([promote]), complemento([cell, cycle, progression])].
[sujeto(['To', clarify, the, dependence, of, terminal, differentiation, on, the, presence, of, the, different, 'pRb-related', 'proteins,', we]), verbo([have]), complemento([studied, myogenesis, using, isogenic, primary, fibroblasts, derived, from, mouse, embryos, individually, deficient, for, 'pRb,', 'p107,', or, p130])].
[sujeto(['When', ectopically]), verbo([expressed]), complemento([in, fibroblasts, lacking, 'pRb,', 'MyoD', induces, an, aberrant, skeletal, muscle, differentiation, program, characterized, by, normal, expression, of, early, differentiation, markers, such, as, myogenin, and, 'p21,', but, attenuated, expression, of, late, differentiation, markers, such, as, myosin, heavy, chain, '(', 'MHC)'])].
[sujeto(['Similar', defects, in, 'MHC', expression, were, not, observed, in, cells, lacking, either, p107, or, 'p130,', indicating, that, the, defect, is, specific, to, the]), verbo([loss]), complemento([of, pRb])].
[sujeto(['In', contrast, to, 'wild-type,', 'p107-deficient,', or, 'p130-deficient', differentiated, myocytes, that, are, permanently, withdrawn, from, the, cell, 'cycle,', differentiated, myocytes, lacking, pRb, accumulate, in, 'S', and, 'G2', phases, and]), verbo([express]), complemento([extremely, high, levels, of, cyclins, 'A', and, 'B,', 'cyclin-dependent', kinase, '(', 'Cdk2),', and, 'Cdc2,', but, fail, to, readily, proceed, to, mitosis])].
[sujeto(['Administration', of, 'caffeine,', an, agent, that, removes, inhibitory, phosphorylations, on, inactive, 'Cdc2/cyclin', 'B', 'complexes,', specifically]), verbo([induced]), complemento([mitotic, catastrophe, in, 'pRb-deficient', 'myocytes,', consistent, with, the, observation, that, the, majority, of, 'pRb-deficient', myocytes, arrest, in, 'S', and, 'G2'])].
[sujeto(['Together,', these, findings, indicate, that, pRb, is]), verbo([required]), complemento([for, the, expression, of, late, skeletal, muscle, differentiation, markers, and, for, the, inhibition, of, 'DNA', 'synthesis,', but, that, a, 'pRb-independent', mechanism, restricts, entry, of, differentiated, myocytes, into, mitosis])].
[sujeto(['PCAF', is, a, histone, acetyltransferase, that]), verbo([associates]), complemento([with, 'p300/CBP', and, competes, with, 'E1A', for, access, to, them])].
[sujeto(['While', exogenous, expression, of, 'PCAF', potentiates, both, 'MyoD-directed', transcription, and, myogenic, 'differentiation,', 'PCAF', inactivation, by, 'anti-PCAF', antibody, microinjection]), verbo([prevents]), complemento([differentiation])].
[sujeto(['MyoD']), verbo([interacts]), complemento([directly, with, both, 'p300/CBP', and, 'PCAF,', forming, a, multimeric, protein, complex, on, the, promoter, elements])].
[sujeto(['Exogenous', expression, of, 'PCAF', or, p300]), verbo([promotes]), complemento([p21, expression, and, terminal, 'cell-cycle', arrest])].
[sujeto(['PPARalpha', is, a]), verbo([nuclear]), complemento([receptor, important, for, lipid, and, glucose, metabolism])].
[sujeto(['It']), verbo([has]), complemento([been, suggested, that, in, brown, adipose, 'tissue,', 'PPARalpha', represses, the, expression, of, 'muscle-associated', 'genes,', in, this, way, potentially, acting, to, determine, cell, fate, in, brown, adipocytes])].
[sujeto(['Thus,', it, would, not, seem, that, 'PPARalpha']), verbo([represses]), complemento(['muscle-associated', 'genes,', but, 'PPARalpha', may, still, play, a, role, in, the, regulation, of, the, bifurcation, of, the, adipomyocyte, precursor, into, a, brown, adipocyte, or, myocyte, phenotype])].
[sujeto(['The', present, study]), verbo([has]), complemento([been, aimed, at, evaluating, comparatively, the, involvement, of, oxidative, stress, in, the, pathogenesis, of, skeletal, muscle, wasting, in, two, different, experimental, 'models:', rats, rendered, hyperglycemic, by, treatment, with, streptozotocin, and, rats, bearing, the, 'Yoshida', 'AH-130', ascites, hepatoma])].
[sujeto(['For', this, 'purpose,', both, tumor, bearers, and, diabetic, animals]), verbo([have]), complemento([been, treated, with, dehydroepiandrosterone, '(', 'DHEA),', a, multifunctional, steroid, endowed, with, multitargeted, antioxidant, properties])].
[sujeto(['The', 'hypercatabolism,', evaluated, in, terms, of, proteasome, activity, and, expression, of, 'atrogin-1', and, 'MuRF1,', is]), verbo([activated]), complemento([in, 'AH-130', 'rats,', whereas, it, is, lacking, in, 'streptozotocin-treated', rats])].
[sujeto(['Moreover,', we, demonstrate, that, the, role, of, oxidative, stress, can, interfere, with, muscle, wasting, through, different, 'mechanisms,', not, necessarily]), verbo([involving]), complemento(['NF-kappaB', activation])].
[sujeto(['SREBP-1', are, ubiquitously]), verbo([expressed]), complemento([transcription, 'factors,', strongly, expressed, in, lipogenic, tissues, where, they, regulate, several, metabolic, processes, like, fatty, acid, synthesis])].
[sujeto(['In', skeletal, 'muscle,', 'SREBP-1', proteins]), verbo([regulate]), complemento([the, expression, of, hundreds, of, 'genes,', and, we, previously, showed, that, their, overexpression, induced, muscle, atrophy, together, with, a, combined, lack, of, expression, of, myogenic, regulatory, factors])].
[sujeto(['Here', we, present, evidences, that, 'SREBP-1']), verbo([regulate]), complemento([muscle, protein, synthesis, through, the, downregulation, of, the, expression, of, 'MYOD1,', 'MYOG', and, 'MEF2C', factors])].
[sujeto(['In', myotubes, overexpressing, 'SREBP-1,', restoring, the, expression, of, myogenic, factors]), verbo([prevented]), complemento([atrophy, and, rescued, protein, 'synthesis,', without, affecting, 'SREBP-1', action, on, atrogenes, and, proteolysis])].
[sujeto(['Our', results, point, out, the, roles, of, 'MRFs', in, the, maintenance, of, the, protein, content, and, cell, size, in, adult, muscle, 'fibre,', and, contribute, to, decipher, the, mechanisms, by, which, 'SREBP-1']), verbo([regulate]), complemento([muscle, mass])].
[sujeto(['Interleukin-11', '(', 'IL-11)', is, a, pleiotropic, cytokine, that, supports, various, types, of, hematopoietic, cell, growth, and, is]), verbo([involved]), complemento([in, bone, resorption])].
[sujeto(['We']), verbo([report]), complemento([here, the, involvement, of, recombinant, human, 'IL-11', '(', 'rHuIL-11)', in, osteoblast, differentiation, in, mouse, mesenchymal, progenitor, 'cells,', 'C3H10T1/2'])].
[sujeto(['rHuIL-11', alone]), verbo([increased]), complemento([alkaline, phosphatase, '(', 'ALP)', activity, and, upregulated, expression, levels, of, osteocalcin, '(', 'OC),', bone, sialo, protein, '(', 'BSP),', and, parathyroid, hormone, receptor, '(', 'PTHR)', mRNA])].
[sujeto(['Recombinant', human, bone, morphogenetic, protein, '(', 'rHuBMP)-2']), verbo([increased]), complemento(['ALP', activity, and, mRNA, expression, of, these, genes, except, for, 'MyoD'])].
[sujeto(['The', expression, patterns, of, 'ALP', activity, and, 'osteoblast-specific', or, 'chondrocyte-specific', genes]), verbo([suggest]), complemento([that, 'rHuIL-11', may, be, involved, in, early, differentiation, of, osteoblasts, at, a, step, earlier, than, that, which, is, affected, by, 'rHuBMP-2'])].
[sujeto(['In', support, of, this, 'hypothesis,', combined, treatment, with, 'rHuIL-11', and, 'rHuBMP-2', synergistically]), verbo([increased]), complemento(['ALP', activity, and, mRNA, expression, of, 'OC', and, type, 'II', 'collagen,', 'rHuIL-11', also, abrogated, the, increased, levels, of, 'PPAR-gamma2,', aP2, mRNA, caused, by, 'rHuBMP-2'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'rHuIL-11', alone, and, in, combination, with, 'rHuBMP-2', can, induce, osteoblastic, differentiation, of, progenitor, cells, and, plays, an, important, role, in, osteogenesis])].
[sujeto(['Coumaric', acid, '(', 'CA)', is, a, phenolic, acid, of, the, hydroxycinnamic, acid, 'family,', and, it]), verbo([has]), complemento([many, biological, functions, such, as, 'anti-oxidant,', 'anti-inflammatory,', 'antidiabetic,', 'anti-ulcer,', 'anti-platelet,', 'anti-cancer', 'activities,', etc])].
[sujeto(['It', revealed, that, 'CA', treatment]), verbo([inhibited]), complemento([horse, 'serum-induced', skeletal, muscle, differentiation, as, evidenced, by, the, decreased, expression, of, early, myogenic, differentiation, markers, such, as, 'Myogenin', and, myoD, via, the, 'AMP', activated, protein, 'kinase-', alpha, 'AMPK-α', mediated, pathway])].
[sujeto(['Furthermore,', the, level, of, lipid, accumulation, and, changes, in, genes, and, protein, expressions, that, are]), verbo([associated]), complemento([with, lipogenesis, and, lipolysis, were, analyzed, in, 3, 'T3-L1', cells])].
[sujeto(['The', 'Oil', 'Red', 'O', staining, evidenced, that, 'CA', treatment]), verbo([inhibited]), complemento([lipid, accumulation, at, the, concentration, of, 0.1, and, 0.2, mM])].
[sujeto(['Furthermore,', coumaric, acid, treatment]), verbo([decreased]), complemento([the, expression, of, main, transcriptional, factors, such, as, 'CCAAT/enhancer', binding, 'protein-alpha', '(', 'C/EBP-α)', and, peroxisome, 'proliferator-activated', receptor, 'gamma-2', '(', 'PPAR-γ2)'])].
[sujeto(['Subsequently,', 'CA', treatment]), verbo([decreased]), complemento([the, expression, of, sterol, regulatory, element, binding, 'protein-1', '(', 'SREBP-1),', fatty, acid, synthase, '(', 'FAS),', acetyl, 'CoA', carboxylase, '(', 'ACC)', and, adiponectin])].
[sujeto(['Finally,', we, identified, conformational, changes]), verbo([induced]), complemento([by, 'CA', in, 'PPAR-γ2', using, computational, biology, tools])].
[sujeto(['It', revealed, that, 'CA', might, downregulate, the, 'PPAR-γ2', expression, by, directly]), verbo([binding]), complemento([with, amino, acids, of, 'PPAR-γ2', by, hydrogen, at, 3.26, distance, and, hydrophobic, interactions, at, 3.9, contact, distances])].
[sujeto(['These', data, indicated, that, 'CA']), verbo([suppressed]), complemento([skeletal, muscle, and, preadipocytes, differentiation, through, downregulation, of, the, main, transcriptional, factors, and, their, downstream, targets])].
[sujeto(['Both', cell, types, attached, and, were]), verbo([found]), complemento([evenly, distributed, within, the, material])].
[sujeto([1, ')', were]), verbo([increased]), complemento([compared, with, the, control, 'C2C12', cells])].
[sujeto(['Only', one, donor, showed, an]), verbo([increase]), complemento([in, the, osteogenic, markers, osteocalcin, '(', 'p=0'])].
[sujeto([1, ')', was]), verbo([found]), complemento([in, 'C2C12', cells])].
[sujeto([4, ')', ',', fatty, acid]), verbo([binding]), complemento([protein, 4, '(', 'FABP4)', '(', 'p=0'])].
[sujeto(['In', 'conclusion,', the, thermoresponsive, scaffold, was]), verbo([found]), complemento([suitable, for, 3, 'D', in, vitro, differentiation, toward, soft, tissue])].
[sujeto(['Ucp3', is, an, integral, protein, of, the, inner, mitochondrial, membrane, with, a, role, in, lipid, metabolism]), verbo([preventing]), complemento([deleterious, effects, of, fatty, acids, in, states, of, high, lipid, oxidation])].
[sujeto(['Ucp3', is]), verbo([expressed]), complemento([in, brown, adipose, tissue, and, skeletal, muscle, and, controlled, by, a, transcription, factor, complex, including, 'PPARalpha,', 'MyoD', and, the, histone, acetyltransferase, p300])].
[sujeto(['Several', studies]), verbo([have]), complemento([demonstrated, interaction, of, these, factors, with, chicken, ovalbumin, upstream, promoter, transcription, factor, 'II', '(', 'Coup-TFII)'])].
[sujeto(['This']), verbo([nuclear]), complemento([receptor, is, involved, in, organogenesis, and, other, developmental, processes, including, skeletal, muscle, 'development,', but, also, 'co-regulates', a, number, of, metabolic, genes])].
[sujeto(['In', reporter, gene, assays, 'Coup-TFII']), verbo([enhanced]), complemento([transactivation, of, the, 'Ucp3', promoter, conveyed, by, 'MyoD,', 'PPARalpha,', 'RXRalpha', 'and/or', p300])].
[sujeto(['Given', the, substantial, evidence, for, a, function, of, 'Ucp3', in, lipid, 'metabolism,', 'Coup-TFII', may, not, only, be, a, negative, regulator, of, glucose, responsive, genes, but, also, transactivate, genes]), verbo([involved]), complemento([in, lipid, metabolism])].
[sujeto(['Coping', with, reduced, energy, sources, entails, drastic, morphological, and, functional, changes, in, skeletal, 'muscle,', but, the, sequence, of, events]), verbo([required]), complemento([classification])].
[sujeto(['We']), verbo([found]), complemento([that, gastrocnemius, muscle, from, 'food-deprived', rats, shows, acute, rises, in, peroxisome, proliferator, activated, receptor, '(', 'PPAR)', gamma, coactivator, '(', 'PGC)', -, 1, 'alpha/PPAR', delta, nuclear, protein, and, myosin, heavy, chain, '(', 'MHC)', 'Ib', 'protein,', while, type, 'I', fibers, accumulate, and, the, muscle, tissue, appears, redder])].
[sujeto(['AMP', 'levels,', phosphorylation, of, both, 'AMP-activated', protein, kinase, '(', 'AMPK)', and, its, downstream]), verbo([target]), complemento([acetyl, coenzyme, 'A', carboxylase, '(', 'ACC)', are, induced, within, 6, h])].
[sujeto(['Rapidly']), verbo([increased]), complemento(['MyoD', mRNA, levels, are, followed, by, an, increase, in, uncoupling, protein, '(', 'UCP)', 3, '(', 'UCP3)', transcription])].
[sujeto(['Increased', serum, fatty, acid, levels, coincide, with]), verbo([increases]), complemento([in, mitochondrial, 'UCP3', protein, levels, and, fatty, acid, oxidation])].
[sujeto(['Accompanying', this, is, a]), verbo([decrease]), complemento([in, 'AMPK', 'phosphorylation,', reversible, upon, nicotinic, acid, 'treatment,', indicating, that, fatty, acids, may, modulate, this, 'kinase\'s', activity, after, the, metabolic, challenges, posed, by, food, deprivation])].
[sujeto(['The', transcription, factors, myogenin, and, 'MyoD']), verbo([have]), complemento([been, suggested, to, be, involved, in, maintaining, slow, and, fast, 'muscle-fiber', 'phenotypes,', 'respectively,', in, rodents])].
[sujeto(['The', training, evoked, the, expected, mRNA]), verbo([increase]), complemento([for, slow, 'fiber-specific', markers, myosin, heavy, chain, 'I', and, 3, -, 'hydroxyacyl-CoA', dehydrogenase, 'A,', whereas, an, mRNA, decrease, was, seen, for, fast, 'fiber-specific', markers, myosin, heavy, chain, 'IIx', and, glycerol, phosphate, dehydrogenase])].
[sujeto(['Although', the, slow, 'fiber-specific', markers, citrate, synthase, and, muscle, fatty, acid]), verbo([binding]), complemento([protein, did, not, display, a, significant, increase, in, 'mRNA,', they, did, tend, to, increase])].
[sujeto(['The', results, indicate, that, myogenin, is, indeed]), verbo([involved]), complemento([in, the, regulation, of, the, slow, oxidative, phenotype, in, human, skeletal, muscle, 'fibers,', whereas, 'MyoD', appears, to, have, a, more, complex, regulatory, function])].
[sujeto(['The', transcription, of, the, human, 'UCP3', '(', uncoupling, 'protein-3)', gene, in, skeletal, muscle, is, tightly]), verbo([regulated]), complemento([by, metabolic, signals, related, to, fatty, acid, availability])].
[sujeto(['However,', changes, in, thyroid, status, also]), verbo([modulate]), complemento(['UCP3', gene, 'expression,', albeit, by, unknown, mechanisms])].
[sujeto(['Treatment', of, human, 'UCP3', transgenic, mice, with, thyroid, hormones]), verbo([induced]), complemento([the, expression, of, the, human, gene, in, skeletal, muscle])].
[sujeto(['In', 'addition,', transient, transfection, experiments, demonstrate, that, thyroid, hormones]), verbo([activate]), complemento([the, transcription, of, the, human, 'UCP3', gene, promoter, when, 'MyoD', and, the, 'TR', '(', thyroid, hormone, 'receptor)', were, 'co-transfected'])].
[sujeto(['The', action, of, thyroid, hormones, on, 'UCP3', gene, transcription, is]), verbo([mediated]), complemento([by, the, binding, of, the, 'TR', to, a, proximal, region, in, the, 'UCP3', gene, promoter, that, contains, a, direct, repeat, structure])].
[sujeto(['An', intact, 'DNA', sequence, of, this, site, is]), verbo([required]), complemento([for, thyroid, hormone, responsiveness, and, 'TR', binding])].
[sujeto(['Chromatin', immunoprecipitation, assays, revealed, that, the, 'TR']), verbo([binds]), complemento([this, element, in, vivo])].
[sujeto(['In', 'summary,', 'UCP3', gene, transcription, is]), verbo([activated]), complemento([by, thyroid, hormone, treatment, in, 'vivo,', and, this, activation, is, mediated, by, a, 'TRE', '(', thyroid, hormone, response, 'element)', in, the, proximal, promoter, region])].
[sujeto(['Such', regulation]), verbo([suggests]), complemento([a, link, between, 'UCP3', gene, expression, and, the, effects, of, thyroid, hormone, on, mitochondrial, function, in, skeletal, muscle])].
[sujeto(['This', study, determined, whether, estradiol, '(', 'E2)', or, the, phytoestrogens, genistein, and, daidzein]), verbo([regulate]), complemento([expression, of, 'growth-related', and, lipogenic, genes, in, rainbow, trout])].
[sujeto(['In', 'liver,', expression, of, vitellogenin, '(', 'vtg)', and, estrogen, receptor, alpha, '(', 'era1)']), verbo([increased]), complemento([in, all, treatments, and, reflected, treatment, estrogenicity, '(', 'E2>genistein', '(', 50, 'μg/g)>genistein', '(', 5, 'μg/g)=daidzein', '(', 5, 'μg/g))'])].
[sujeto(['Estradiol', and, genistein, '(', 50, 'μg/g)', reduced, components, of, the, growth, hormone, '(', 'GH)/insulin-like', growth, factor, '(', 'IGF)', axis, in, 'liver,', including]), verbo([increased]), complemento([expression, of, 'IGF', binding, 'protein-2b1', '(', 'igfbp2b1)', and, reduced, igfbp5b1])].
[sujeto(['In', liver, 'E2', and, genistein, '(', 50, 'μg/g)', affected, expression, of, components, of, the, transforming, growth, factor, beta, signaling, 'mechanism,', reduced, expression, of, ppar, and, rxr, transcription, 'factors,', and]), verbo([increased]), complemento([expression, of, fatty, acid, synthesis, genes, 'srebp1,', 'acly,', 'fas,', 'scd1,', and, gpat, and, lipid, binding, proteins, fabp3, and, lpl])].
[sujeto(['In', muscle, 'E2', and, genistein, '(', 50, 'μg/g)']), verbo([increased]), complemento([era1, and, erb1, expression, and, decreased, erb2, expression])].
[sujeto(['Other', genes]), verbo([responded]), complemento([to, phytoestrogens, in, a, manner, that, suggested, regulation, by, estrogen, 'receptor-independent', 'mechanisms,', including, increased, 'ghr2,', 'igfbp2a,', 'igfbp4,', and, igfbp5b1])].
[sujeto(['Expression', of, muscle, regulatory, factors, pax7, and, myod, was]), verbo([increased]), complemento([by, 'E2', and, genistein])].
[sujeto(['These', data, indicate, that, genistein, and, daidzein, affect, expression, of, genes, in, rainbow, trout, that]), verbo([regulate]), complemento([physiological, mechanisms, central, to, growth, and, nutrient, retention])].
[sujeto(['p204,', an, 'interferon-inducible', p200, family, 'protein,']), verbo([inhibits]), complemento([rRNA, synthesis, in, fibroblasts, by, blocking, the, binding, of, the, upstream, binding, factor, transcription, factor, to, 'DNA'])].
[sujeto(['Here', we]), verbo([report]), complemento([that, among, 10, adult, mouse, tissues, 'tested,', the, level, of, p204, was, highest, in, heart, and, skeletal, muscles])].
[sujeto(['Leptomycin', 'B,', an, inhibitor, of]), verbo([nuclear]), complemento([export, that, blocked, myoblast, 'fusion,', inhibited, the, nuclear, export, 'signal-dependent', translocation, of, p204, to, the, cytoplasm])].
[sujeto(['The']), verbo([increase]), complemento([in, the, p204, level, during, myoblast, fusion, was, a, consequence, of, 'MyoD', transcription, factor, binding, to, several, 'MyoD-specific', sequences, in, the, gene, encoding, 'p204,', followed, by, transcription])].
[sujeto(['Overexpression', of, p204, '(', in, 'C2C12', myoblasts, carrying, an, inducible, p204, expression, 'plasmid)', accelerated, the, fusion, of, myoblasts, to, myotubes, in, differentiation, medium, and]), verbo([induced]), complemento([the, fusion, even, in, growth, medium])].
[sujeto(['The', level, of, p204, in, mouse, heart, muscle, strongly]), verbo([increased]), complemento([during, 'differentiation;', it, was, barely, detectable, in, 10])].
[sujeto([p204, is, the, second, p200, family, protein, '(', after, 'p202a)']), verbo([found]), complemento([to, be, involved, in, muscle, differentiation])].
[sujeto([')', 'These', results]), verbo([reveal]), complemento([that, p204, and, p202a, function, in, both, muscle, differentiation, and, interferon, action])].
[sujeto(['In', 'Duchenne', muscle, dystrophy, '(', 'DMD)', and, in, the, mdx, mouse, model, of, 'DMD,', a, lack, of, dystrophin]), verbo([leads]), complemento([to, myonecrosis, and, cardiorespiratory, failure])].
[sujeto(['Several', lines, of, evidence]), verbo([suggest]), complemento([a, detrimental, role, of, the, inflammatory, process, in, the, dystrophic, process])].
[sujeto(['Long-term', therapy, with, 'omega-3']), verbo([increased]), complemento([the, regulatory, protein, 'MyoD', and, muscle, regeneration, and, reduced, markers, of, inflammation, '(', 'TNF-α', and, 'NF-kB)', in, both, muscles, studied])].
[sujeto(['Assessments', included, bone, mineral, 'density/content', by, 'dual-energy', 'X-ray', 'absorptiometry,', muscle, wet, weight, '(', 'quadriceps)', and, expression, of, selected, genes]), verbo([regulating]), complemento([muscle, mass, and, protein, turnover])].
[sujeto(['Bone', mineral, content]), verbo([increased]), complemento([in, the, 'ALT', group, '(', +, 16, '%', ')', and, decreased, in, the, 'C', group, '(', -, 32, '%', ')'])].
[sujeto(['Mammalian']), verbo([target]), complemento([of, rapamycin, expression, was, higher, in, 'CH', than, 'ALT', and, 'ALTH'])].
[sujeto(['We']), verbo([have]), complemento([previously, 'shown,', that, the, leucine, 'metabolite,', 'β-hydroxy-β-methylbutyrate', '(', 'HMB)', suppresses, apoptotic, signaling, and, the, apoptotic, index, '(', the, ratio, of, apoptotic, positive, to, apoptotic, negative, 'myonuclei)', during, muscle, disuse, and, during, reloading, periods, after, disuse, in, aged, rats])].
[sujeto(['However,', it, was, not, clear, if, the, apoptotic, signaling, indexes, were, due, only, to, preservation, of, myonuclei, or, if, perhaps, the, total, myogenic, pool]), verbo([increased]), complemento([as, a, result, of, 'HMB-mediated', satellite, cell, proliferation, as, this, would, have, also, reduced, the, apoptotic, index])].
[sujeto(['HMB']), verbo([prevented]), complemento([the, functional, decline, in, maximal, plantar, flexion, isometric, force, production, during, the, reloading, 'period,', but, not, during, 'HLS'])].
[sujeto(['HMB-treatment']), verbo([enhanced]), complemento([the, proliferation, of, muscle, stem, cells, as, shown, by, a, greater, percentage, of, satellite, cells, that, had, proliferated, '(', more, 'BrdU', 'positive,', 'Pax-7', 'positive,', and, more, 'Pax7/Ki67', positive, 'nuclei)', and, as, a, 'result,', more, differentiated, stem, cells, were, present, '(', more, 'MyoD/myogenin', positive, 'myonuclei),', relative, to, total, 'myonuclei,', in, reloaded, plantaris, muscles, as, compared, to, reloaded, muscles, from, 'vehicle-treated', animals])].
[sujeto(['Furthermore', 'HMB']), verbo([increased]), complemento([the, nuclear, protein, abundance, of, proliferation, 'markers,', inhibitor, of, 'differentiation-2', and, cyclin, 'A,', as, compared, to, vehicle, treatment, in, reloaded, muscles])].
[sujeto(['Although', 'HMB']), verbo([increased]), complemento([phosphorylated, 'Akt', during, 'reloading,', other, mTOR, related, proteins, were, not, altered, by, 'HMB', treatment])].
[sujeto(['Enhanced', satellite, cell, proliferation]), verbo([leading]), complemento([to, increased, differentiated, myonuclei, should, increase, the, transcriptional, potential, to, support, muscle, hypertrophic, changes, and, functional, changes, in, sarcopenic, 'muscles,', and, this, could, partly, explain, the, reduced, apoptotic, index, in, 'HMB', treated, muscles])].
[sujeto(['Chronic', inflammation]), verbo([induces]), complemento([skeletal, muscle, wasting, and, cachexia])].
[sujeto(['In', arthritic, 'rats,', 'fenofibrate,', a, peroxisome, 'proliferator-activated', receptor, α, '(', 'PPARα', '(', 'PPARA))', 'agonist,', reduces, wasting, of, 'gastrocnemius,', a, predominantly, glycolytic, 'muscle,', by]), verbo([decreasing]), complemento([atrogenes, and, myostatin])].
[sujeto(['Considering', that, fenofibrate]), verbo([increases]), complemento([fatty, acid, 'oxidation,', the, aim, of, this, study, was, to, elucidate, whether, fenofibrate, is, able, to, prevent, the, effect, of, arthritis, on, serum, adipokines, and, on, 'soleus,', a, type, 'I', muscle, in, which, oxidative, metabolism, is, the, dominant, source, of, energy])].
[sujeto(['Arthritis', was]), verbo([induced]), complemento([by, injection, of, 'Freund\'s', adjuvant])].
[sujeto(['Arthritis']), verbo([decreased]), complemento([serum, 'leptin,', 'adiponectin,', and, insulin, '(', 'P<0'])].
[sujeto(['In', arthritic, 'rats,', fenofibrate, administration]), verbo([increased]), complemento([serum, concentrations, of, leptin, and, adiponectin])].
[sujeto(['Arthritis']), verbo([decreased]), complemento([soleus, 'weight,', 'cross-sectional', 'area,', fiber, 'size,', and, its, 'Ppar', α, mRNA, expression])].
[sujeto(['In', arthritic, 'rats,', fenofibrate]), verbo([increased]), complemento([soleus, 'weight,', fiber, 'size,', and, 'Ppar', α, expression, and, prevented, the, increase, in, 'Murf1', mRNA])].
[sujeto(['Fenofibrate']), verbo([decreased]), complemento(['myostatin,', whereas, it, increased, 'MyoD', '(', 'Myod1)', and, myogenin, expressions, in, the, soleus, of, control, and, arthritic, rats])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, in, oxidative, 'muscle,', fenofibrate, treatment, is, able, to, prevent, 'arthritis-induced', muscle, wasting, by, decreasing, 'Murf1', and, myostatin, expression, and, also, by, increasing, the, myogenic, regulatory, 'factors,', 'MyoD', and, myogenin])].
[sujeto(['Taking', into, account, the, beneficial, action, of, adiponectin, on, muscle, wasting, and, the, correlation, between, adiponectin, and, soleus, 'mass,', part, of, the, anticachectic, action, of, fenofibrate, may, be]), verbo([mediated]), complemento([through, stimulation, of, adiponectin, secretion])].
[sujeto(['Suboptimal', fetal, environments, due, to, inadequate, maternal, 'nutrition,', 'obesity,', inflammation, or, gestational, diabetes, expose, the, fetus, to, humoral, cues, that, alter, metabolism, and, growth, parameters]), verbo([leading]), complemento([to, metabolic, disturbances, later, in, life])].
[sujeto(['Maternal', obesity]), verbo([induces]), complemento([inflammation, in, the, fetus, causing, modifications, in, the, development, of, fetal, skeletal, muscle])].
[sujeto(['Changes', in, the, normal, course, of, myogenesis, may, arise, through, several, 'mechanisms:', changes, in, 'WNT/β-catenin', signaling, 'pathway,']), verbo([decreased]), complemento(['AMPK', activity, evoked, by, 'TNF-α,', increased, activity, of, 'NF-κB', in, response, to, 'inflammation,', which, leads, to, a, decrease, in, myogenic, factor, 'MyoD,', and, increased, expression, of, 'TGF', β1])].
[sujeto(['Modification', in, fetal, development]), verbo([associated]), complemento([with, maternal, obesity, is, attributed, to, epigenetic, changes])].
[sujeto(['These', adipocytes, stained, with, 'Oil-Red-O', and]), verbo([expressed]), complemento([the, terminal, differentiation, 'markers,', adipsin, and, fatty, acid, binding, protein, 4, ',', but, did, not, express, 'EYFP', and, were, therefore, not, of, satellite, cell, origin])].
[sujeto(['Satellite', cells, mutant, for, either, 'MyoD', or, 'Myf-5', also]), verbo([maintained]), complemento([myogenic, programming, in, culture, and, did, not, adopt, an, adipogenic, fate])].
[sujeto(['Under', 'adipogenesis-inducing', 'conditions,', satellite, cells, accumulated, cytoplasmic, lipid, but]), verbo([maintained]), complemento([myogenic, protein, expression, and, did, not, fully, execute, the, adipogenic, differentiation, 'program,', distinguishing, them, from, adipocytes, observed, in, muscle, fiber, cultures])].
[sujeto(['Although', iPS, cells, are, similar, to, embryonic, stem, '(', 'ES)', cells, in, their, 'pluripotency,', their, inherited, 'defects,', such, as, insertion, 'mutagenesis,', employment, of, 'oncogenes,', and, low, 'efficiency,']), verbo([associated]), complemento([with, the, reprogramming, procedure, have, hindered, their, clinical, application])].
[sujeto(['A', study]), verbo([has]), complemento([shown, that, valproic, acid, '(', 'VPA)', treatment, can, significantly, enhance, the, reprogramming, efficiency, and, avoid, the, usage, of, oncogenes])].
[sujeto(['To', understand, how, 'VPA', can]), verbo([enhance]), complemento(['pluripotency,', we, stably, transfected, an, 'Oct4', promoter, driven, luciferase, reporter, '(', 'Oct4-1'])].
[sujeto(['We']), verbo([found]), complemento([that, 'VPA', could, both, activate, 'Oct4', promoter, and, rescue, its, inhibition, by, retinoic, acid, '(', 'RA)'])].
[sujeto(['In', 'C2C12', 'myoblasts,', 'VPA', treatment, also]), verbo([enhanced]), complemento([endogenous, 'Oct4', expression, but, repressed, that, of, 'MyoD'])].
[sujeto(['Furthermore,', both, 'RARalpha', 'over-expression', and, mutation, of, a, proximal, hormone, response, element, '(', 'HRE)', blocked, the, activation, effect, of, 'VPA', on, 'Oct4', 'promoter,', implying, that, 'VPA', may, exert, its, activation, effect, through, factors]), verbo([targeting]), complemento([this, 'HRE'])].
[sujeto(['Taken', 'together,', these, observations, identify, a, molecular, mechanism, by, which, 'VPA', directly]), verbo([regulate]), complemento(['Oct4', expression, to, ensure, the, acquirement, and, maintenance, of, pluripotency])].
[sujeto(['We', demonstrate, that, 'PGD(2)', strongly]), verbo([inhibits]), complemento(['C2C12', myogenesis, as, measured, by, cell, 'fusion,', creatine, kinase, activity, and, 'MyoD,', myogenin, and, 'alpha-actin', expression])].
[sujeto(['Inhibition', of, myogenesis]), verbo([required]), complemento([micromolar, 'PGD(2)', concentrations, and, was, independent, of, the, known, 'PGD(2)', receptors, 'DP1', and, 'DP2'])].
[sujeto(['Unlike', its, cyclopentenone, derivative, 15, -, 'deoxy-Delta(12,14)-PGJ(2)', '(', 15, 'd-PGJ(2)),', 'PGD(2)', did, not, generate, toxic, mitochondrial, superoxide, indicating, that, the, inhibition, of, myogenesis, is, not]), verbo([mediated]), complemento([by, generation, of, high, concentrations, of, 'PGD(2)-derived', 15, 'd-PGJ(2)'])].
[sujeto(['Thus', our, observations]), verbo([provide]), complemento([evidence, for, a, novel, 'PGD(2)', signalling, mechanism, during, muscle, repair, exclusively, mediated, by, high, inflammatory, associated, 'PGD(2)', concentrations])].
[sujeto(['These', findings, indicate, a, complex, interplay, between, myoblasts, and, inflammatory, cells, during, the, repair, process, and]), verbo([have]), complemento([implications, for, the, use, of, 'non-steroidal', 'anti-inflammatory', drugs, in, the, treatment, of, muscle, injuries])].
[sujeto(['The', 't10,c12', 'CLA', 'isomer,', but, not, the, 'c9,t11', 'isomer,', significantly]), verbo([decreased]), complemento(['MIA', 'PaCa-2', proliferation, by, between, 15, '%', and, 19, '%'])].
[sujeto(['There', was, a, marked]), verbo([decrease]), complemento([in, muscle, 'MyoD', and, myogenin, expression, '(', 78, '%', and, 62, '%', ',', 'respectively),', but, no, change, in, either, 'Myf5', or, 'myostatin,', in, myotubes, grown, in, coculture, with, 'MIA', 'PaCa-2', cells])].
[sujeto(['Several-fold', significant]), verbo([increases]), complemento([in, 'CCL-2,', 'COX-2,', 'IL-8,', and, 'TNF-alpha', expression, in, myotubes, were, observed, with, 'MIA', 'PaCa-2', coculture])].
[sujeto(['The', 'c9,t11', 'CLA', isomer, significantly]), verbo([decreased]), complemento([basal, expression, of, 'TNF-alpha', in, myotubes, and, could, ameliorate, its, 'tumor-induced', rise])].
[sujeto(['The', study]), verbo([provides]), complemento([insight, into, the, 'anti-inflammatory', and, antiproliferative, actions, of, 'CLA', and, its, application, as, a, therapeutic, agent, in, inflammatory, disease, states])].
[sujeto(['Eicosapentaenoic', acid, '(', 'EPA)', is, an, 'omega-3', polyunsaturated, fatty, acid, that]), verbo([has]), complemento(['anti-inflammatory', and, anticachectic, actions])].
[sujeto(['The', aim, of, this, work, was, to, elucidate, whether, 'EPA', administration, is, able, to]), verbo([prevent]), complemento([an, 'arthritis-induced', decrease, in, body, weight, and, muscle, wasting, in, rats])].
[sujeto(['Arthritis', was]), verbo([induced]), complemento([by, intradermal, injection, of, 'Freund\'s', 'adjuvant;', 3, days, 'later,', nine, rats, received, 1, 'g/kg', 'EPA', or, coconut, oil, daily])].
[sujeto(['EPA', administration]), verbo([decreased]), complemento([the, external, signs, of, arthritis, and, paw, volume, as, well, as, liver, 'TNF-alpha', mRNA])].
[sujeto(['EPA', did, not, modify, 'arthritis-induced']), verbo([decrease]), complemento([in, food, intake, or, body, weight, gain])].
[sujeto(['However,', 'EPA', treatment]), verbo([prevented]), complemento(['arthritis-induced', increase, in, muscle, 'TNF-alpha', and, 'atrogin-1,', whereas, it, attenuated, the, decrease, in, gastrocnemius, weight, and, the, increase, in, 'MuRF1', mRNA])].
[sujeto(['Arthritis', not, only]), verbo([decreased]), complemento([myogenic, regulatory, factors, but, also, increased, 'PCNA,', 'MyoD,', and, myogenin, mRNA, in, the, gastrocnemius])].
[sujeto(['In', the, control, 'rats,', 'EPA', administration]), verbo([increased]), complemento(['PCNA', and, 'MyoD', mRNA, and, protein])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, in, experimental, 'arthritis,', in, addition, to, its, 'anti-inflammatory', 'effect,', 'EPA', treatment, attenuates, muscle, wasting, by, decreasing, 'atrogin-1', and, 'MuRF1', gene, expression, and, increasing, the, transcription, factors, that, regulate, myogenesis])].
[sujeto(['As', muscle, regeneration, comes, with, an, inflammatory, 'process,', it]), verbo([has]), complemento([been, proposed, that, the, inflammatory, cells, can, play, an, important, role, in, the, induction, of, muscle, fibres, regeneration])].
[sujeto(['The', data, obtained, showed, a, very, large]), verbo([decrease]), complemento([in, the, number, of, 'MyoD', 'positive/m-cadherin', positive, cells, in, the, ketoprofen, injected, group, compared, to, the, control, group])].
[sujeto(['Although', further, studies, are, needed, to, elucidate, the, sequence, of, biochemical, events, that]), verbo([induce]), complemento([a, reduction, of, 'MyoD', expression, due, to, 'ketoprofen,', the, results, demonstrate, that, prostaglandin, synthesis, is, required, for, the, induction, of, 'MyoD', expression, and, that, ketoprofen, can, affect, this, 'expression,', with, possible, adverse, effects, on, muscle, regeneration])].
[sujeto(['RT-PCR', showed, that, myoblasts]), verbo([expressed]), complemento([mRNA, for, 'LTB(4)', receptors, 'BLT1', and, 'BLT2,', and, 'LTB4', promoted, myoblast, proliferation, and, fusion])].
[sujeto(['U-75302,', a, specific, 'BLT1', 'inhibitor,', but, not, 'LY2552833,', a, specific, 'BLT2', 'inhibitor,', blocked, proliferation, and, differentiation, of, myoblasts]), verbo([induced]), complemento([by, 'LTB(4),', which, implies, the, involvement, of, the, 'BLT1', pathway])].
[sujeto(['Overall,', the, data]), verbo([suggest]), complemento([that, 'LTB(4)', contributes, to, muscle, regeneration, by, accelerating, proliferation, and, differentiation, of, satellite, cells])].
[sujeto(['Primary', alveolar, type, of, rhabdomyosarcoma, '(', 'RMS)', tumor, tissue, was, collected, from, the, tongue, of, a, 17, -, 'year-old', 'Japanese', woman, and, used, to, successfully, establish, a, rhabdomyosarcoma, cell, 'line,', which]), verbo([has]), complemento([been, designated, 'NUTOS'])].
[sujeto(['Side', effects, from, 'long-term', 'HAART', therapy, include]), verbo([loss]), complemento([of, muscle, mass])].
[sujeto(['Myoblasts', when, cultured, in, media, low, in, growth, factors, withdraw, from, the, cell, 'cycle,']), verbo([express]), complemento(['muscle-specific', differentiation, inducers, and, 'proteins,', and, fuse, to, form, myotubes])].
[sujeto(['The', neutral, 'protease,', 'calpain,', is]), verbo([required]), complemento([for, myotube, formation, and, 'RTV', decreased, calpain, activity, in, vitro])].
[sujeto(['We']), verbo([found]), complemento([lower, calpain, 'activity,', but, not, 'protein,', in, homogenates, of, 'RTV-treated', 'L6', cells, than, in, control, cultures])].
[sujeto(['Control', and, 'drug-related', 'L6', myoblasts, showed, identical]), verbo([decreases]), complemento([in, proliferating, cell, nuclear, antigens, expression, indicating, proliferation, arrest])].
[sujeto(['Similarly,', muscle, differentiation, inducers, 'MyoD', and, myogenin, and, their, downstream, 'target,', myosin, heavy, 'chain,', were]), verbo([expressed]), complemento([at, similar, levels, in, control, and, 'drug-treated', cells])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, protease, inhibitors, included, in, 'HAART', might, be, directly, involved, in, muscle, wasting, by, reducing, muscle, remodeling])].
[sujeto(['MyoD', and, 'Myf5', genes, are, selectively]), verbo([activated]), complemento([during, development, in, a, time, and, 'region-specific', manner, and, in, response, to, different, stimuli])].
[sujeto(['However,', molecules, that, specifically]), verbo([regulate]), complemento([the, expression, of, these, two, genes, and, the, pathways, involved, remain, to, be, determined])].
[sujeto(['We']), verbo([have]), complemento([recently, shown, that, the, serum, response, factor, '(', 'SRF),', a, transcription, factor, involved, in, activation, of, both, mitogenic, response, and, muscle, 'differentiation,', is, required, for, 'MyoD', gene, expression])].
[sujeto(['We']), verbo([have]), complemento([investigated, here, whether, 'SRF', is, also, involved, in, the, control, of, 'Myf5', gene, 'expression,', and, the, potential, role, of, upstream, regulators, of, 'SRF', 'activity,', the, 'Rho', family, 'G-proteins', including, 'Rho,', 'Rac,', and, 'CDC42,', in, the, regulation, of, 'MyoD', and, 'Myf5'])].
[sujeto(['We', show, that, inactivation, of, 'SRF', does, not, alter, 'Myf5', gene, 'expression,', whereas, it]), verbo([causes]), complemento([a, rapid, extinction, of, 'MyoD', gene, expression])].
[sujeto(['Furthermore,', we, show, that, 'RhoA,', but, not, 'Rac', or, 'CDC42,', is, also]), verbo([required]), complemento([for, the, expression, of, 'MyoD'])].
[sujeto(['Indeed,', blocking, the, activity, of, 'G-proteins', using, the, general, inhibitor, 'lovastatin,', or, more, specific, antagonists, of, 'Rho', proteins, such, as, 'C3-transferase', or, dominant, negative, 'RhoA', 'protein,', resulted, in, a, dramatic]), verbo([decrease]), complemento([of, 'MyoD', protein, levels, and, promoter, activity, without, any, effects, on, 'Myf5', expression])].
[sujeto(['We', further, show, that, 'RhoA-dependent', transcriptional, activation]), verbo([required]), complemento([functional, 'SRF', in, 'C2', muscle, cells])].
[sujeto(['These', data, illustrate, that, 'MyoD', and, 'Myf5', are]), verbo([regulated]), complemento([by, different, upstream, activation, pathways, in, which, 'MyoD', expression, is, specifically, modulated, by, a, 'RhoA/SRF', signaling, cascade])].
[sujeto(['Our', current, understanding, of, muscle, and, adipose, tissue, development]), verbo([has]), complemento([been, largely, restricted, to, the, study, of, murine, myogenic, and, adipogenic, cell, 'lines,', since, attempts, to, establish, these, cell, lines, from, other, species, have, met, with, only, limited, success])].
[sujeto(['Here', we]), verbo([report]), complemento([that, a, spontaneously, immortalized, bovine, embryonic, fibroblast, cell, line, '(', 'BEFS)', undergoes, differentiation, into, adipogenic, or, myogenic, lineages, when, ectopically, transduced, with, 'PPARgamma2', '(', an, adipogenic, lineage, 'determinant)', or, 'MyoD', '(', a, myogenic, lineage, 'determinant)', and, grown, in, adipogenic, and, myogenic, differentiation, culture, media, '(', 'ADCM', and, 'MDCM,', 'respectively)'])].
[sujeto(['We', also]), verbo([found]), complemento([that, 'PPARgamma2-overexpressing', 'BEFS', cells, '(', 'BEFS-PPARgamma2)', grown, in, 'ADCM', with, or, without, the, 'PPARgamma2', 'ligand,', 'troglitazone,', preferentially, differentiate, into, adipogenic, cells, in, the, presence, of, ectopic, 'MyoD', expression])].
[sujeto(['Ectopic', expression, of, 'PPARgamma2', in, the, inducible, 'MyoD-overepxressing', 'BEFS', cells, '(', 'BEFS-TetOn-MyoD)', completely]), verbo([suppresses]), complemento([myogenic, differentiation, and, leads, to, a, significant, increase, in, adipogenic, 'differentiation,', suggesting, that, the, adipogenic, differentiation, program, might, be, dominant])].
[sujeto(['Plasminogen', activators, 'urokinase-type', plasminogen, activator, '(', 'uPA)', and, 'tissue-type', plasminogen, activator, '(', 'tPA)', are, extracellular, proteases]), verbo([involved]), complemento([in, various, tissue, remodeling, processes])].
[sujeto(['In', 'contrast,', 'uPA-/-', mice, had, a, severe, regeneration, 'defect,', with]), verbo([decreased]), complemento([recruitment, of, 'blood-derived', monocytes, to, the, site, of, injury, and, with, persistent, myotube, degeneration])].
[sujeto(['A', similar, severe, regeneration, deficit, with, persistent, fibrin, deposition, was, also, reproducible, in, 'plasminogen-deficient', mice, after, 'injury,']), verbo([suggesting]), complemento([that, fibrinolysis, by, 'uPA-mediated', plasminogen, activation, plays, a, fundamental, role, in, skeletal, muscle, regeneration])].
[sujeto(['In', 'conclusion,', the, 'uPA-plasmin', system, is, identified, as, a, critical, component, of, the, mammalian, skeletal, muscle, regeneration, 'process,', possibly, because, it]), verbo([prevents]), complemento([intramuscular, fibrin, accumulation, and, contributes, to, the, adequate, inflammatory, response, after, injury])].
[sujeto(['To', identify, transcriptional, 'gene-networks']), verbo([involved]), complemento([in, the, early, in, vivo, response, of, liver, cells, to, radiation, exposure, and, improve, our, understanding, of, the, molecular, processes, responsible, for, tissue, radiosensitivity])].
[sujeto(['Other', genes]), verbo([regulated]), complemento([by, the, 'transformation-related', protein, 53, '(', 'Trp53/p53)', such, as, 'Bcl2-associated', 'X', protein, '(', 'Bax)', or, 'etoposide-induced-2'])].
[sujeto(['Grouping', differentially]), verbo([expressed]), complemento([genes, into, functional, categories, revealed, that, the, primary, response, of, liver, cells, to, radiation, exposure, was, the, enhancement, of, oxidoreductase, activity, and, inhibition, of, cell, 'proliferation,', involving, cell, cycle, progression, and, 'apoptosis-related', genes])].
[sujeto(['The', data]), verbo([provides]), complemento([evidence, of, gene, expression, modifications, associated, with, the, hepatic, response, to, radiation, exposure])].
[sujeto(['Overall,', our, expression, data, revealed, genes, and, cellular, pathways, that, might, help, to, improve, our, understanding, of, the, molecular, basis, underlying, tissue, radiosensitivity, and, to, identify, possible]), verbo([targets]), complemento([for, novel, therapeutic, strategies])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, 'PUMA', plays, a, pivotal, role, in, the, apoptosis, associated, with, skeletal, myoblast, differentiation, and, that, a, 'MyoD-dependent', mechanism, is, responsible, for, the, increased, expression, of, 'PUMA', in, these, cells])].
[sujeto(['Herein,', we]), verbo([report]), complemento([that, the, increased, expression, of, 'PUMA', under, these, conditions, involves, regulation, at, the, level, of, translation])].
[sujeto(['Specifically,', we]), verbo([have]), complemento([found, that, the, increase, in, 'PUMA', protein, levels, occurs, under, conditions, of, decreased, total, protein, 'synthesis,', 'eIF2-alpha', phosphorylation, and, hypophosphorylation, of, 'eIF4E-BP,', suggesting, that, 'PUMA', translation, is, proceeding, via, an, alternative, initiation, mechanism])].
[sujeto(['A', combination, of, in, vitro, and, ex, vivo, '(', 'cellular)', approaches]), verbo([has]), complemento([provided, evidence, suggesting, that, 'PUMA', mRNA, 5, '\'', 'UTR', harbors, an, 'Internal', 'Ribosome', 'Entry', 'Site', '(', 'IRES)', element])].
[sujeto(['Using', 'mono-', and, 'bi-cistronic', reporter, 'constructs,', we]), verbo([have]), complemento([delineated, an, mRNA, fragment, that, allows, for, 'cap-independent', translation, in, vitro, and, ex, vivo, '(', in, skeletal, 'myoblasts)', in, response, to, culture, in, differentiation, media, '(', 'DM),', or, in, response, to, treatment, with, the, 'DNA-damaging', 'agent,', etoposide])].
[sujeto(['Thus,', our, data]), verbo([has]), complemento([revealed, a, novel, 'IRES-mediated', regulation, of, 'PUMA', expression, in, several, cell, types, and, in, response, to, several, stimuli])].
[sujeto(['These', findings, contribute, to, our, understanding, and, potential, manipulation, of, any, developmental, or, therapeutic, scenario]), verbo([involving]), complemento(['PUMA'])].
[sujeto(['To']), verbo([prevent]), complemento([the, formation, of, differentiated, cells, with, genetic, 'instability,', we, hypothesized, that, genotoxic, stress, may, trigger, a, differentiation, checkpoint])].
[sujeto(['Here', we, show, that, exposure, to, genotoxic, agents]), verbo([causes]), complemento([a, reversible, inhibition, of, myogenic, differentiation])].
[sujeto(['Muscle-specific', gene, expression, is]), verbo([suppressed]), complemento([by, 'DNA-damaging', agents, if, applied, prior, to, differentiation, induction, but, not, after, the, differentiation, program, is, established])].
[sujeto(['The', myogenic, determination, 'factor,', 'MyoD', '(', encoded, by, 'Myod1),', is, a]), verbo([target]), complemento([of, the, differentiation, checkpoint, in, myoblasts])].
[sujeto(['The', inhibition, of, 'MyoD', by, 'DNA', damage]), verbo([requires]), complemento([a, functional, 'c-Abl', tyrosine, kinase, '(', encoded, by, 'Abl1),', but, occurs, in, cells, deficient, for, p53, '(', 'transformation-related', protein, 53, ',', encoded, by, 'Trp53)', or, 'c-Jun', '(', encoded, by, the, oncogene, 'Jun)'])].
[sujeto(['These', results, support, the, idea, that, genotoxic, stress, can]), verbo([regulate]), complemento(['differentiation,', and, identify, a, new, biological, function, for, 'DNA', 'damage-activated', signaling, network])].
[sujeto(['However,']), verbo([phosphorylated]), complemento(['IRS1(Ser636/639),', which, impedes, binding, of, downstream, effectors, and, the, negative, regulator, '(', 'PTEN)', of, 'PIP3,', was, increased, in, 'DEHP-exposed', groups])].
[sujeto(['Down-regulation', of, glucose, transporter, 4, '(', 'Glut4', '(', 'Slc2a4))', gene, expression, and]), verbo([increased]), complemento(['GLUT4(Ser488)', 'phosphorylation,', which, decreases, its, intrinsic, activity, and, translocation, towards, the, plasma, 'membrane,', were, recorded])].
[sujeto(['Chromatin', immunoprecipitation, assays, detected]), verbo([decreased]), complemento(['MYOD', binding, and, increased, histone, deacetylase, 2, interaction, towards, 'Glut4,', indicative, of, the, tight, chromatin, structure, at, the, 'Glut4', promoter])].
[sujeto(['Furthermore,', methylation, of, 'Glut4', at, the, 'MYOD-binding', site, was]), verbo([increased]), complemento([in, 'DEHP-exposed', groups])].
[sujeto(['These', findings, indicate, 'that,', gestational, 'DEHP', exposure, predisposes, 'F1', offspring, to, glucometabolic, dysfunction, at, adulthood, by, 'down-regulating', the, expression, of, critical, genes]), verbo([involved]), complemento([in, the, insulin, signalling, pathway])].
[sujeto(['Myogenic', differentiation, is, principally]), verbo([regulated]), complemento([by, activities, of, myogenic, regulatory, 'factors,', such, as, 'MyoD', and, 'myogenin,', leading, the, elongation, and, fusion, of, mononucleated, myoblasts, into, multinucleated, myotubes])].
[sujeto(['In', the, present, 'study,', myogenic, differentiation, of, 'C2C12', cells, was]), verbo([induced]), complemento([by, serum, deprivation, with, medium, containing, vehicle, or, 'DEHP', '(', 10, ',', 100, ',', 1, ',', 0, 'μg/ml)', for, 5, days])].
[sujeto(['This', in, vitro, study]), verbo([suggests]), complemento([that, 'DEHP', may, be, an, environmental, risk, factor, for, myogenesis])].
[sujeto(['For', reconstruction, or, repair, of, damaged, 'tissues,', an, artificially]), verbo([regulated]), complemento([switch, from, proliferation, to, differentiation, would, be, of, great, advantage])].
[sujeto(['To', achieve, conditional, 'myogenesis,', we]), verbo([expressed]), complemento(['MyoD', in, mouse, 'C3H', 10, 'T1/2', fibroblastic, 'cells,', using, a, gene, regulation, system, based, on, the, synthetic, steroid, 'RU', 486])].
[sujeto(['The', leucine, zipper, transcription, factors, cAMP, response, element]), verbo([binding]), complemento([protein, '(', 'CREB),', cAMP, response, element, modulatory, protein, '(', 'CREM)', and, activating, transcription, factor, 1, '(', 'ATF1)', bind, to, the, cAMP, response, element, '(', 'CRE)', with, the, palindromic, consensus, sequence, 'TGACGTCA'])].
[sujeto(['Their', transcriptional, activities, are, dependent, on, serine, phosphorylation]), verbo([induced]), complemento([by, various, extracellular, signals, such, as, 'hormones,', growth, factors, and, neurotransmitters])].
[sujeto(['The', importance, of, 'CREB', for, morphogenetic, processes, was, assessed, by, injection, of, 'RNA', encoding, a, 'dominant-negative', form, of, 'CREB', that, is, fused, to, a, truncated, progesterone, receptor, ligand]), verbo([binding]), complemento([domain])].
[sujeto(['In', this, fusion, 'protein,', a, 'dominant-negative', function, can, be]), verbo([induced]), complemento([by, application, of, the, synthetic, steroid, 'RU486', at, given, developmental, stages])].
[sujeto(['The', inhibition, of, 'CREB', at, blastula, and, early, gastrula, stages]), verbo([leads]), complemento([to, severe, posterior, defects, of, the, embryos, reflected, by, strong, spina, 'bifida,', whereas, the, inhibition, of, 'CREB', at, the, beginning, of, neurulation, resulted, in, stunted, embryos, with, microcephaly])].
[sujeto(['In', these, 'embryos,', initial, induction, of, neural, and, mesodermal, tissues, is, not, dependent, on, 'CREB', 'function,', as, genes, such, as, 'Otx2,', 'Krox20,', 'Shh', and, 'MyoD', are, still]), verbo([expressed]), complemento([in, injected, embryos])].
[sujeto(['But', the, expression, domains, of, 'Otx2', and, 'MyoD', were]), verbo([found]), complemento([to, be, distorted, reflecting, the, abnormal, development, in, both, neural, and, somitic, derivatives])].
[sujeto(['Testosterone', is, a, key, hormone]), verbo([regulating]), complemento([animal, growth, and, 'development,', which, promotes, skeletal, muscle, growth, and, inhibits, fat, 'deposition;', 'however,', the, underlying, mechanisms, remain, poorly, defined])].
[sujeto(['Because', canonical, 'Wingless', and, 'Int/β-catenin', signaling]), verbo([promotes]), complemento(['myogenesis,', we, hypothesized, that, testosterone, regulates, myogenesis, through, enhancing, the, 'β-catenin', signaling, pathway, and, the, expression, of, its, targeted, genes])].
[sujeto(['Trenbolone', treatment]), verbo([increased]), complemento([the, protein, levels, of, 'MyoD', and, myosin, heavy, 'chain,', as, well, as, the, androgen, receptor, content])].
[sujeto(['The', myogenic, effect, of, trenbolone, was, blocked, by, cyproterone, 'acetate,', a, specific, inhibitor, of, androgen, 'receptor,', showing, that, the, myogenic, effect, of, trenbolone, was]), verbo([mediated]), complemento([by, the, androgen, receptor])].
[sujeto(['Immunoprecipitation', showed, that, androgen, receptor, and, 'β-catenin', formed, a, 'complex,', which, was]), verbo([increased]), complemento([by, trenbolone, treatment])].
[sujeto(['Trenbolone']), verbo([activated]), complemento([adenosine, 'monophosphate-activated', protein, 'kinase,', which, might, phosphorylate, 'β-catenin', at, 'Ser552,', stabilizing, 'β-catenin'])].
[sujeto(['Indeed,', both, cytoplasmic, and]), verbo([nuclear]), complemento(['β-catenin', levels, were, increased, after, trenbolone, treatment])].
[sujeto(['As', a, 'result,', 'β-catenin-mediated', transcriptional, activity, was]), verbo([enhanced]), complemento([by, trenbolone, treatment])].
[sujeto(['In', 'conclusion,', these, data]), verbo([provide]), complemento([evidence, that, testosterone, increases, cellular, 'β-catenin', content, which, promotes, the, expression, of, 'β-catenin-targeted', genes, and, myogenesis, in, the, 'muscle-derived', stem, cells, of, cattle])].
[sujeto(['Two', kinds, of, proliferation, and, differentiation, patterns]), verbo([have]), complemento([been, obtained, in, the, resulting, clones])].
[sujeto(['When', 'SRF', antisense, 'RNA', expression, is]), verbo([induced]), complemento([in, proliferating, myoblasts, by, dexamethasone, 'treatment,', cell, growth, is, blocked, and, cyclin, 'A', concentration, drops])].
[sujeto(['When', 'SRF', antisense, 'RNA', synthesis, is]), verbo([induced]), complemento([in, arrested, confluent, myoblasts, cultured, in, a, differentiation, 'medium,', cell, fusion, is, blocked, and, synthesis, of, not, only, 'SRF', but, also, 'MyoD,', 'myogenin,', and, myosin, heavy, chain, is, inhibited])].
[sujeto(['Obesity', is, documented, to, be, a, state, of, chronic, mild, inflammation]), verbo([associated]), complemento([with, increased, macrophage, infiltration, into, adipose, tissue, and, liver, and, skeletal, muscle])].
[sujeto(['As', a, pleiotropic, inflammatory, 'mediator,', macrophage, migration, inhibitory, factor, '(', 'MIF)', is]), verbo([associated]), complemento([with, metabolic, 'disease,', so, 'MIF', may, signal, molecular, links, between, adipocytes, and, myocytes])].
[sujeto(['It', did, not, change, 'proliferation,', but, downregulated, cyclin, 'D1', and, 'CDK4,']), verbo([causing]), complemento([cell, accumulation, in, the, 'G1', phase])].
[sujeto([p21, protein, was]), verbo([increased]), complemento([significantly, and, 'MyoD,', 'MyoG,', and, p21, mRNA, also, increased, significantly, in, the, 'C2C12', cells, treated, with, 'ISO-1,', suggesting, that, inhibition, of, 'MIF', promotes, differentiation])].
[sujeto(['MIF']), verbo([inhibits]), complemento([the, myoblast, differentiation, by, affecting, the, cell, cycle, 'progression,', but, does, not, affect, proliferation])].
[sujeto(['Sequence', analysis, showed, that, the, 'full-length', 'FOXO3', 'CDS', is, 1467, &, 'nbsp;bp,', encoding, 488, amino, acids, and, is, highly]), verbo([conserved]), complemento([across, many, bird, species])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'FOXO3', plays, a, critical, role, in, the, proliferation, and, differentiation, of, duck, myoblasts])].
[sujeto(['Peroxiredoxin6', '(', 'Prdx6)', is, one, of, the, peroxiredoxin, '(', 'Prdxs)', family, members, that, play, an, important, role, in]), verbo([maintaining]), complemento([cell, homeostasis])].
[sujeto(['Our', previous, studies, demonstrated, that, 'Prdx6', was, significantly]), verbo([associated]), complemento([with, pig, meat, 'quality,', especially, meat, tenderness])].
[sujeto(['Several', regulatory, elements, including, 'CCAAT/enhancer-binding', proteinβ, '(', 'C/EBPβ),', 'Myogenic', 'Differentiation', '(', 'MyoD),', cAMP, response, element]), verbo([binding]), complemento([protein, '(', 'CREB),', stimulating, protein1, '(', 'Sp1)', and, heat, shock, factor, '(', 'HSF)', binding, sites, were, found, by, computational, analyses, together, with, luciferase, reporter, system])].
[sujeto(['Electrophoretic', mobility, shift, assays, '(', 'EMSA)', and, chromatin, immunoprecipitation, assays, '(', 'ChIP)', confirmed, that, 'C/EBPβ', and, 'CREB', could]), verbo([interact]), complemento([with, 'Prdx6', promoter])].
[sujeto(['Immuoprecipitation', results, also, showed, that, 'C/EBPβ', could]), verbo([interact]), complemento([with, 'Prdx6', in, vivo])].
[sujeto(['MyoD', and, 'MyoG', are, transcription, factors, that]), verbo([have]), complemento([essential, roles, in, myogenic, lineage, determination, and, muscle, differentiation])].
[sujeto(['These', analyses]), verbo([suggest]), complemento([that, the, evolution, of, 'MyoD', and, 'MyoG', was, driven, by, different, pathways])].
[sujeto(['Four', and, a, half, 'LIM', domain, protein, 3, '(', 'FHL3)']), verbo([regulates]), complemento([myoblasts, differentiation, and, gene, expression, by, acting, as, a, transcriptional, 'co-activator', or, 'co-repressor'])].
[sujeto(['However,', how, 'FHL3']), verbo([regulates]), complemento(['MyHC', expression, is, currently, not, clear])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, 'FHL3', 'down-regulated', the, expression, of, 'MyHC', 1, /, slow, and, 'up-regulated', the, expression, of, 'MyHC', 2, a, and, 'MyHC', 2, 'b,', whereas, no, significant, effect, was, found, on, 'MyHC', 2, x, expression])].
[sujeto(['MyoD', and]), verbo([phosphorylated]), complemento([cAMP, response, element, binding, protein, '(', 'pCREB)', played, important, roles, in, the, regulation, of, 'MyHC', 1, /, slow, and, 'MyHC', 2, a, expression, by, 'FHL3,', respectively])].
[sujeto(['FHL3', could]), verbo([interact]), complemento([with, 'MyoD,', 'CREB', and, pCREB, in, vivo])].
[sujeto([pCREB, had, stronger, interaction, with, the, cyclic, 'AMP-responsive', elements, '(', 'CRE)', of, the, 'MyHC', 2, a, promoter, compared, with, 'CREB,', and, 'FHL3', significantly, affected, the]), verbo([binding]), complemento([capacity, of, pCREB, to, 'CRE'])].
[sujeto(['We', established, a, model, in, which, 'FHL3']), verbo([promotes]), complemento([the, expression, of, 'MyHC', 2, a, through, 'CREB-mediated', transcription, and, inhibits, the, expression, of, 'MyHC', 1, /, slow, by, inhibiting, 'MyoD', transcription, activity, during, myogenesis])].
[sujeto(['Many', 'SET', domain, containing, proteins, and, several, 'PRDM', members]), verbo([have]), complemento([been, found, to, possess, histone, methyltransferase, 'activity,', yet, the, role, of, 'PRDM16', and, its, 'PR', domain, in, the, epigenetic, regulation, of, myogenic, and, adipogenic, genes, during, 'myoblasts/adipocytes', transdifferentiation, remains, unexplored])].
[sujeto(['In', this, 'study,', we, transfected, 'C2C12', myoblasts, to, stably]), verbo([express]), complemento(['PRDM16', and, observed, the, repression, of, myogenic, genes, and, activation, of, adipogenic, genes, at, both, proliferation, and, differentiation, stages])].
[sujeto(['Ectopic', 'PRDM16-induced', reprogramming, of, myogenic, and, adipogenic, genes, was]), verbo([associated]), complemento([with, the, hypermethylation, on, some, 'CpG', sites, in, the, enhancer, or, promoter, of, 'MyoD', and, 'myogenin,', but, the, methylation, status, of, 'PPARγ', promoter, was, not, affected])].
[sujeto(['C2C12', cells]), verbo([expressing]), complemento([truncated, 'PRDM16', lacking, 'PR', domain, '(', 'ΔPR-PRDM16)', demonstrated, attenuation, of, both, adipogenic, and, myogenic, 'potentials,', indicated, by, 'PPARγ', inactivation, and, decreased, triglyceride, 'deposition,', as, well, as, a, downregulation, of, 'MyoD,', 'MyHC', and, 'MCK', 'genes,', as, compared, with, 'C2C12', cells, expressing, intact, 'PRDM16'])].
[sujeto(['Furthermore,', 'C2C12', cells]), verbo([expressing]), complemento(['ΔPR-PRDM16', exhibited, significant, differences, in, histone, modifications, on, the, promoters, of, 'MyoD', and, 'PPARγ', genes])].
[sujeto(['Taken', 'together,', 'PRDM16-induced', 'C2C12', transdifferentiation, is]), verbo([associated]), complemento([with, alterations, in, 'CpG', methylation, of, myogenic, 'factors,', and, 'PR', domain, affects, both, myogenesis, and, adipogenesis, with, modified, histone, methylation, marks, on, 'MyoD', and, 'PPARγ', promoters])].
[sujeto(['Myostatin', '(', 'MSTN)', is, a, secreted, protein, belonging, to, the, transforming, growth, 'factor-β', '(', 'TGF-β)', family, that, is, primarily]), verbo([expressed]), complemento([in, skeletal, muscle, and, also, functions, in, adipocyte, maturation])].
[sujeto(['Studies']), verbo([have]), complemento([shown, that, 'MSTN', can, inhibit, adipogenesis, in, muscle, satellite, cells, '(', 'MSCs)', but, not, in, 'adipose-derived', stem, cells, '(', 'ADSCs)'])].
[sujeto(['However,', the, mechanism, by, which, 'MSTN', differently]), verbo([regulates]), complemento([adipogenesis, in, these, two, cell, types, remains, unknown])].
[sujeto(['To', investigate, whether, 'MSTN', differentially]), verbo([regulates]), complemento(['PPARγ', and, 'MyoD,', we, analyzed, 'PPARγ', and, 'MyoD', expression, by, assessing, 'mRNA,', protein, and, methylation, levels, in, 'ADSCs', and, 'MSCs', after, treatment, with, 100, 'ng/mL', 'MSTN', for, 0, ',', 24, ',', and, 48, h])].
[sujeto(['MyoD', expression, was, significantly]), verbo([increased]), complemento([in, 'ADSCs', and, decreased, in, 'MSCs'])].
[sujeto(['The', 'CpG', methylation, levels, of, the, 'PPARγ', and, 'MyoD', promoters, were]), verbo([decreased]), complemento([in, 'ADSCs', and, increased, in, 'MSCs'])].
[sujeto(['Therefore,', this, study, demonstrated, that, the, different, regulatory, adipogenic, roles, of, 'MSTN', in, 'ADSCs', and, 'MSCs']), verbo([act]), complemento([by, differentially, regulating, 'PPARγ', and, 'MyoD', expression])].
[sujeto(['Hyperplasia', and, hypertrophy, are, two, distinct, processes, of, skeletal, muscle, growth]), verbo([regulated]), complemento([by, four, myogenic, regulatory, factors, '(', 'MRFs,', contains, 'MyoD,', 'Myf5,', 'Mrf4', and, myogenin, '(', 'MyoG))', and, myostatin, '(', 'MSTN)'])].
[sujeto(['amblycephala,', the, diameter, scope, of, 'epaxial,', horizontal, septum, and, hypaxial, muscle, fibers, including, red, and, white, muscle, in, 2, -, 'year-old', fish, exhibited, broader, with, dramatic, reduction, in, frequency, distribution, of, &, 'lt;20', μm, 'diameter,', nevertheless, observable]), verbo([increase]), complemento([in, frequency, distribution, of, &, 'gt;50', μm, diameter])].
[sujeto(['Intermyofibrillar', '(', 'IM)', nuclei, were, also]), verbo([found]), complemento([except, numerous, subsarcolemmal, '(', 'SS)', nuclei, in, 2, -, 'year-old', 'fish,', whereas, only, 'SS', nuclei, were, observed, in, 1, -, 'year-old', fish])].
[sujeto(['Moreover,', we, observed, predominant]), verbo([increase]), complemento([in, the, mRNA, levels, of, 'MyoD,', 'Myf5,', 'Mrf4,', and, 'MSTN', during, muscle, development, of, fish, in, 2, -, 'year-old', fish, except, 'MyoG'])].
[sujeto(['Electrical', stimulation, is, often, used, to]), verbo([prevent]), complemento([muscle, atrophy, and, preserve, contractile, 'function,', but, its, effects, on, the, satellite, cell, population, after, nerve, injury, are, not, well, understood])].
[sujeto(['More', 'Pax7+/MyoD+', nuclei, in]), verbo([stimulated]), complemento([muscles, were, observed, than, in, 'non-stimulated', muscles])].
[sujeto([eMyHC, expression, was, elevated, in]), verbo([stimulated]), complemento([muscles, and, correlated, positively, with, enhanced, force, production])].
[sujeto(['Four', of, the, five, 'SNVs', were, significantly]), verbo([associated]), complemento([with, growth, performance, and, carcass, traits, of, the, cattle])].
[sujeto(['Statistical', analyses, of, combined, genotypes, indicated, that, some, combined, genotypes, were, significantly, or, highly, significantly]), verbo([associated]), complemento([with, growth, and, carcass, traits, in, the, 'Qinchuan', cattle, population])].
[sujeto([qPCR, analyses, also, showed, that, bovine, 'CSRP3', gene, was, exclusively]), verbo([expressed]), complemento([in, longissimus, dorsi, muscle, and, heart, tissues])].
[sujeto(['We']), verbo([found]), complemento([that, the, expression, levels, of, 'Tmod4', were, higher, in, skeletal, muscle, and, adipose, tissues])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, the, expression, of, 'Tmod4', was, decreased, in, myogenesis, while, increased, in, adipogenesis])].
[sujeto(['Then,', the, transcriptional, regulation, analysis, of, 'Tmod4', promoter, showed, that, 'Tmod4', could, be]), verbo([regulated]), complemento([directly, by, myogenic, factors, and, adipogenic, factors])].
[sujeto(['Furthermore,', the, roles, of, 'Tmod4', in, the, myogenesis, and, adipogenesis, were, confirmed, by, its, 'over-expression', in, 'C2C12', cells, and, 3, 'T3', 'cells,', which]), verbo([suggested]), complemento([that, 'Tmod4', could, promote, adipogenesis, by, 'up-regulating', the, adipogenic, factors, but, moderately, delay, the, myogenesis])].
[sujeto(['It', is, showed, that, the, expression, of, 'Tmod4', was]), verbo([activated]), complemento([in, adipogenesis, by, adipogenic, factors, while, inhibited, in, myogenesis, by, myogenic, factors])].
[sujeto(['Moreover,', 'Tmod4', could]), verbo([promote]), complemento([adipogenesis, by, 'up-regulating', the, expression, of, adipogenic, factors, while, moderately, delaying, the, myogenesis])].
[sujeto(['Our', study]), verbo([provides]), complemento([an, important, basis, for, further, understanding, the, regulation, and, function, of, porcine, 'Tmod4', in, muscle, and, fat, development])].
[sujeto(['Nectin-like', 'molecule-2', '(', 'Necl-2),', a, junction, 'molecule,', is, exclusively]), verbo([expressed]), complemento([by, spermatogenic, cells])].
[sujeto(['It']), verbo([mediates]), complemento([homophilic, interaction, between, germ, cells, and, heterophilic, interaction, between, 'Sertoli', and, germ, cells])].
[sujeto(['Knockout', studies]), verbo([have]), complemento([shown, that, loss, of, 'Necl-2', causes, male, 'infertility,', suggesting, 'Necl-2-based', cell, adhesion, is, crucial, for, spermatogenesis])].
[sujeto(['Transforming', growth, 'factor-βs', '(', 'TGF-βs)', are, crucial, for]), verbo([regulating]), complemento([cell, junction, restructuring, that, are, required, for, spermatogenesis])].
[sujeto(['In', the, present, 'study,', we, aim, to, investigate, the, mechanism, on, how, 'TGF-β1']), verbo([regulates]), complemento(['Necl-2', expression, to, achieve, timely, junction, restructuring, in, the, seminiferous, epithelium, during, spermatogenesis])].
[sujeto(['We']), verbo([have]), complemento([demonstrated, that, 'TGF-β1', reduces, 'Necl-2', mRNA, and, protein, levels, at, both, transcriptional, and, 'post-translational', levels])].
[sujeto(['Using', inhibitor, and, clathrin, 'shRNA,', we]), verbo([have]), complemento([revealed, that, 'TGF-β1', induces, 'Necl-2', protein, degradation, via, 'clathrin-dependent', endocytosis])].
[sujeto(['Mutational', studies, coupled, with, knockdown, experiments]), verbo([have]), complemento([shown, that, 'TGF-β1-induced', 'Necl-2', repression, requires, activation, of, 'Smad', proteins])].
[sujeto(['EMSA', and, 'ChIP', assays, further, confirmed, that, 'TGF-β1']), verbo([promotes]), complemento([the, binding, of, 'Smad', proteins, onto, 'MyoD', and, 'CCAATa', motifs, in, vitro, and, in, vivo])].
[sujeto(['Taken', 'together,', 'TGF-β1', is, a, potent, cytokine, that]), verbo([provides]), complemento([an, effective, mechanism, in, controlling, 'Necl-2', expression, in, the, testis, via, 'Smad-dependent', gene, repression, and, 'clathrin-mediated', endocytosis])].
[sujeto(['Semaphorin4d', '(', 'SEMA4D),', also, known, as, 'CD100,', an, oligodendrocyte, secreted, 'R-Ras', 'GTPase-activating', protein, '(', 'GAP),', affecting, axonal, growth, is]), verbo([involved]), complemento([in, a, range, of, processes, including, cell, 'adhesion,', 'motility,', 'angiogenesis,', immune, responses, and, tumour, progression])].
[sujeto(['This', study]), verbo([has]), complemento([focused, on, the, role, of, sema4d, in, the, development, and, expression, patterns, in, zebrafish, embryos, and, the, effect, of, its, suppression, on, development, using, 'sema4d-specific', antisense, 'morpholino-oligonucleotides'])].
[sujeto(['In', this, study, the, knockdown, of, 'sema4d,']), verbo([expressed]), complemento([at, all, developmental, 'stages,', lead, to, defects, in, the, hindbrain, and, trunk, structure, of, zebrafish, embryos])].
[sujeto(['In', 'addition,', these, phenotypes, appeared, to, be]), verbo([associated]), complemento([with, the, abnormal, expression, of, three, hindbrain, rhombomere, boundary, 'markers,', 'wnt1,', epha4a, and, foxb1])].
[sujeto(['Further,', a, notable]), verbo([increase]), complemento([of, cell, apoptosis, appeared, in, the, sema4d, knockdown, 'embryos,', while, no, obvious, reduction, in, cell, proliferation, was, observed])].
[sujeto(['Collectively,', these, data]), verbo([suggest]), complemento([that, sema4d, plays, an, important, role, in, the, development, of, the, hindbrain, and, skeletal, muscle])].
[sujeto(['Both', skeletal, muscle, and, tendon, are, closely]), verbo([associated]), complemento([during, their, development, and, both, can, bear, strong, mechanical, loading, dynamically])].
[sujeto(['Quantitatively,', 'MDCs']), verbo([expressed]), complemento([higher, levels, of, 'GDF-8,', collagens, 'III', and, 'VI', '(', p, &, 'lt;', 0.05, ')', ',', whereas, tenocytes, expressed, higher, levels, of, collagen, 'I,', scleraxis, and, tenomodulin, '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['Furthermore,', with, the]), verbo([increase]), complemento([of, implantation, 'time,', 'MDCs', gradually, lost, their, expression, of, myogenic, molecules, of, 'MyoD', and, desmin, and, gained, the, expression, of, 'tenomodulin,', a, marker, for, tenocytes])].
[sujeto(['It']), verbo([has]), complemento([been, suggested, that, mouse, lbx1, is, essential, for, directing, hypaxial, myogenic, precursor, cell, migration])].
[sujeto(['In', 'zebrafish,', the, expression, of, 'lbx1a,', 'lbx1b,', and, lbx2]), verbo([has]), complemento([been, observed, in, pectoral, fin, buds])].
[sujeto(['It']), verbo([has]), complemento([also, been, shown, that, knocking, down, endogenous, lbx2, in, zebrafish, embryos, diminishes, myoD, expression, in, the, pectoral, fin, bud])].
[sujeto(['Our', transplantation, studies, further, demonstrated, that, the, overexpression, of, lbx2, autonomously]), verbo([promotes]), complemento(['CE', movements])].
[sujeto(['We']), verbo([have]), complemento([demonstrated, that, application, of, the, wnt5b, 'MO,', a, 'dominant-negative', form, of, disheveled, '(', 'Dvl)', and, a, chemical, inhibitor, of, 'Rho-associated', kinase, 'Y27632', in, zebrafish, embryos, have, effects, reminiscent, that, are, of, the, 'CE', and, hypaxial, myogenesis, defects, observed, in, lbx2, morphants])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, the, key, noncanonical, 'Wnt', signaling, components, 'Wnt5,', 'Dvl,', and, 'RhoA', are, downstream, effectors, involved, in, the, regulative, roles, of, lbx2, in, 'CE', movement, and, hypaxial, myogenesis, during, zebrafish, embryogenesis])].
[sujeto(['It', encodes, for, skeletal, 'muscle-specific', transcription, factors, containing, highly]), verbo([conserved]), complemento([basic, 'helix-loop-helix', regions, that, perform, important, roles, in, the, 'initiation,', 'maintenance,', and, regulation, of, phenotypic, traits])].
[sujeto(['A', 'C→G', transversion, at, position, 624, was, detected, in, exon, 1, of, the, 'MyoD1', 'gene;', it]), verbo([causes]), complemento([an, amino, acid, substitution, '(', '(', 624, ')', 'serine/(624)cysteine)'])].
[sujeto(['Least', squares, analysis, showed, that, this, 'SNP', is, not, significantly]), verbo([associated]), complemento([with, back, fat, 'thickness,', eye, muscle, 'area,', intramuscular, 'fat,', or, marbling])].
[sujeto(['The', 'MyoD', mRNA]), verbo([expressed]), complemento([in, both, kinds, of, muscle, tissues, and, the, expression, profile, had, a, similar, 'trend,', although, the, expression, level, of, 'MyoD', in, the, breast, muscle, was, significantly, higher, than, that, in, the, leg, muscle, at, each, developmental, stages, '(', 'p<0'])].
[sujeto(['Results']), verbo([suggested]), complemento([that, 'MyoD', might, have, potential, functions, in, controlling, muscle, fiber, phenotype, during, the, secondary, myogenesis, of, muscle, development])].
[sujeto(['These', fundamental, works, may]), verbo([provide]), complemento([some, valuable, clues, for, knowing, the, roles, of, 'MyoD', in, the, myogenesis, and, the, muscle, fiber, type, differentiation, in, birds])].
[sujeto(['Mesenchymal', stromal, cells, '(', 'MSC)']), verbo([have]), complemento([been, thought, to, be, attractive, candidates, for, the, treatment, of, 'Duchenne', muscular, dystrophy, '(', 'DMD),', but, the, rate, of, 'MSC', myogenesis, is, very, low])].
[sujeto(['Adipogenic', differentiation, of, rMSC]), verbo([inhibited]), complemento([by, 'anti-Mstn', 'Ab', was, evaluated, by, 'Oil', 'Red', 'O', staining])].
[sujeto(['Five-azacytidine-mediated', myogenic, differentiation]), verbo([induced]), complemento([significant, endogenous, 'Mstn', expression])].
[sujeto(['Anti-Mstn', 'Ab', improved, the, expression, of, 'MyoD,', myogenin, and, 'MHC-alpha', and]), verbo([inhibited]), complemento([adipocyte, formation])].
[sujeto(['In', accordance, with, the]), verbo([increased]), complemento([motor, function, and, muscle, 'mass,', dystrophin, expression, had, increased])].
[sujeto(['Furthermore,', serum, 'CK', and, centrally, nucleated, fiber, '(', 'CNF)', levels]), verbo([decreased]), complemento(['slightly,', suggesting, specific, pathologic, features, of, the, dystrophic, muscle, were, partially, restored])].
[sujeto(['Using', 'anti-Mstn', 'Ab,', we]), verbo([found]), complemento([that, inhibition, of, 'Mstn', improved, myogenic, differentiation, of, rMSC, in, vitro, and, in, vivo])].
[sujeto(['A', combination, of, 'Mstn', blockade, and, 'MSC', transplantation, may]), verbo([provide]), complemento([a, pharmacologic, and, 'cell-based', strategy, for, the, treatment, of, 'DMD'])].
[sujeto(['To', explore, the, in, vitro, differentiation, of, the, rat, mesenchymal, stem, cells, '(', 'MSCs)', into, the, skeletal, muscle, cells]), verbo([induced]), complemento([by, the, myoblast, differentiation, factor, '(', 'MyoD)', and, 5, -, azacytidine])].
[sujeto(['The', differentiation, of, the, 3, rd, passage, of, 'MSCs', was]), verbo([induced]), complemento([by, the, combination, of, 5, -, 'azacytidine,', 'MyoD,', transforming, growth, factor, 'beta1,', and, the, 'insulin-like', growth, factor, 1])].
[sujeto(['Nine', days, after, the, 'induction,', the]), verbo([induced]), complemento(['MSCs', were, 'collected,', which, were, analyzed, with, the, 'MTT', 'chromatometry,', the, flow, 'cytometry,', and, the, immunohistochemistry])].
[sujeto(['The', primarily, cultured, 'MSCs', grew, as, a, colony, on, the, walls, of, the, culture, 'bottle;', after, the, culture, for, 5, -, 7, 'days,', the, cells, were, shaped, like, the, 'fibroblasts,', the, big, flat, polygonal, 'cells,', the, 'medium-sized', polygonal, 'cells,', and, the, small, triangle, 'cells;', after, the, culture, for, 12, 'days,', the, cells, were]), verbo([found]), complemento([to, be, 'fused,', spreading, all, over, the, bottle, 'bottom,', but, 'MSCs', were, unchanged, too, much, in, shape])].
[sujeto(['However,', after, the, culture, for, 7, 'days,', the, cells, grew, 'remarkably,', the, cell, volume]), verbo([increased]), complemento([gradually, in, a, form, of, 'ellipse,', fusiform, or, irregularity])].
[sujeto(['After', the, culture, for, 14, 'days,', the, proliferated, fusiform, cells, began, to]), verbo([increase]), complemento([in, a, great, amount])].
[sujeto(['After', the, culture, for, 18, -, 22, 'days,', the, myotubes]), verbo([increased]), complemento([in, number, and, 'volume,', with, the, nucleus, increased, in, 'number,', and, the, 'newly-formed', myotubes, and, the, fusiform, myoblst, grew, parallelly, and, separately])].
[sujeto(['The']), verbo([induced]), complemento(['MSCs', were, found, to, be, positive, for, desmin, and, specific, myoglobulin, of, the, skeletal, muscle])].
[sujeto(['The', flow, cytometry, showed, that, most, of, the, 'MSCs', and, the]), verbo([induced]), complemento(['MSCs', were, in, the, stages, of, 'G0/G1,', accounting, for, 79.4, '%', and, 62.9, '%', ',', 'respectively;', 'however,', the, cells, in, the, stages, of, 'G2/S', accounted, for, 20.6, '%', and, 36.1, '%'])].
[sujeto(['The', growth, curve, was, drawn, based, on, 'MTT,which', showed, that, 'MSCs', were, greater, in, the, growth, speed, than, the]), verbo([induced]), complemento(['MSCs'])].
[sujeto(['Heart', failure, was]), verbo([associated]), complemento([with, marked, effects, on, the, expression, of, 'Bmal1,', 'Clock', and, 'Rora', in, addition, to, several, 'non-circadian', genes, important, in, regulating, skeletal, muscle, phenotype, including, 'Mck,', 'Ttn', and, 'Mef2c'])].
[sujeto(['We']), verbo([found]), complemento([that, 'hypertensive/hypertrophic', 'SHR', showed, a, dampening, of, peak, 'Bmal1', and, 'Rev-erb', expression, in, the, 'liver,', and, the, 'clock-controlled', gene, 'Pgc1α', in, the, gastrocnemius])].
[sujeto(['In', 'addition,', the, 'core-clock', gene, 'Clock', and, the, 'muscle-specific,', 'clock-controlled', gene, 'Myod1,', no, longer]), verbo([maintained]), complemento([a, circadian, pattern, of, expression, in, gastrocnemius, from, the, hypertensive, 'SHR'])].
[sujeto(['These', findings]), verbo([provide]), complemento([a, framework, to, suggest, a, mechanism, whereby, chronic, heart, failure, leads, to, skeletal, muscle, 'pathologies;', prolonged, dysregulation, of, the, molecular, clock, in, skeletal, muscle, results, in, altered, 'Clock,', 'Pgc1α', and, 'Myod1', expression, which, in, turn, leads, to, the, 'mis-regulation', of, target, genes, important, for, mechanical, and, metabolic, function, of, skeletal, muscle])].
[sujeto(['In', 'vertebrates,', transcriptional, control, of, skeletal, muscle, genes, during, differentiation, is]), verbo([regulated]), complemento([by, enhancers, that, direct, the, combinatorial, binding, 'and/or', interaction, of, 'MEF2', and, the, bHLH, 'MyoD', family, of, myogenic, factors])].
[sujeto(['We']), verbo([have]), complemento([shown, that, 'Drosophila', 'MEF2', plays, a, role, similar, to, its, vertebrate, counterpart, in, the, regulation, of, the, 'Tropomyosin', 'I', gene, in, the, development, of, 'Drosophila', somatic, 'muscles,', 'however,', unlike, 'vertebrates,', 'Drosophila', 'MEF2', interacts, with, a, muscle, activator, region, that, does, not, have, binding, sites, for, myogenic, 'bHLH-like', factors, or, any, other, known, 'Drosophila', transcription, factors])].
[sujeto(['We', describe, here, the, isolation, and, characterization, of, a, component, of, the, muscle, activator, region, that, we]), verbo([have]), complemento([named, 'PDP1', '(', 'PAR', domain, protein, 1, ')'])].
[sujeto(['We', show, that, 'PDP1', is]), verbo([involved]), complemento([in, regulating, expression, of, the, 'Tropomyosin', 'I', gene, in, somatic, 'body-wall', and, pharyngeal, muscles, by, binding, to, 'DNA', sequences, within, the, muscle, activator, that, are, required, for, activator, function])].
[sujeto(['Mutations', that, eliminate, 'PDP1']), verbo([binding]), complemento([eliminate, muscle, activator, function, and, severely, reduce, expression, of, a, muscle, activator, plus, 'MEF2', 'mini-enhancer'])].
[sujeto(['These', and, previous, results]), verbo([suggest]), complemento([that, 'PDP1', may, function, as, part, of, a, larger, 'protein/DNA', complex, that, interacts, with, 'MEF2', to, regulate, transcription, of, 'Drosophila', muscle, genes])].
[sujeto(['Furthermore,', in, addition, to, being]), verbo([expressed]), complemento([in, the, mesoderm, that, gives, rise, to, the, somatic, 'muscles,', 'PDP1', is, also, expressed, in, the, mesodermal, fat, 'body,', the, developing, midgut, 'endoderm,', the, hindgut, and, 'Malpighian', 'tubules,', and, the, epidermis, and, central, nervous, 'system,', suggesting, that, 'PDP1', is, also, involved, in, the, terminal, differentiation, of, these, tissues])].
[sujeto(['Cellular', retinoic, acid]), verbo([binding]), complemento([protein, 2, '(', 'CRABP2),', a, member, of, a, family, of, specific, carrier, proteins, for, 'Vitamin', 'A,', belongs, to, a, family, of, small, cytosolic, lipid, binding, proteins])].
[sujeto(['Our', previous, study]), verbo([suggested]), complemento([that, 'CRABP2', was, involved, in, skeletal, muscle, 'development;', 'however,', the, molecular, function, and, regulatory, mechanism, of, 'CRABP2', in, myogenesis, remained, unclear])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, the, expression, of, the, 'CRABP2', gene, was, upregulated, during, 'C2C12', differentiation])].
[sujeto(['An', 'over-expression', assay, revealed, that, 'CRABP2']), verbo([promotes]), complemento([myogenic, transformation, by, regulating, the, cell, cycle, during, 'C2C12', differentiation])].
[sujeto(['The', region, from, -, 459, to, -, 4, bp, was, identified, as, the, core, promoter, and, contains, a, 'TATA', 'box,', a, 'GC', box, and]), verbo([binding]), complemento([sites, for, the, transcription, factors, 'MyoD', and, 'Sp1'])].
[sujeto(['Over-expression,', 'site-directed', mutagenesis, and, 'EMSA', assays, indicated, that, the, transcription, factors, 'MyoD', and, 'Sp1']), verbo([regulate]), complemento(['CRABP2', expression, and, promote, myoblast, differentiation, in, 'C2C12', cells])].
[sujeto(['The', myocyte, enhancer, factor, 2, 'C', '(', 'MEF2C)', is, a, member, of, the, 'MEF2', family, of, transcription, 'factors,']), verbo([involved]), complemento([in, skeletal, muscle, development])].
[sujeto(['In', this, study, we]), verbo([report]), complemento([the, cDNA, sequence, and, isolate, the, 5, '\'', upstream, region, of, the, mef2c, gene, from, porcine, genomic, 'DNA', using, 'PCR-based', 'GenomeWalker'])].
[sujeto(['No', typical, 'TATA,', 'GC', box, or, 'CAAT', box]), verbo([binding]), complemento([site, was, found, in, porcine, mef2c, 5, '\'', upstream, 'region,', whereas, some, potential, binding, sites, for, 'MyoD', '(', 'E-box),', 'MEF2', and, 'MBF1', were, present, in, the, proximal, upstream, region])].
[sujeto(['Co-transfection', assays, demonstrated, that, 'MBF1']), verbo([bound]), complemento([the, mef2c, promoter, and, inhibited, mef2c, expression])].
[sujeto(['These', results, may, be, useful, for, elucidating, the, regulation, mechanisms, of, 'mef2c,', which]), verbo([interacts]), complemento([with, other, factors, to, regulate, target, genes])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'SNPs', analysed, in, this, study, are, not, causative, 'mutations,', but, can, be, considered, as, markers, of, some, 'other,', still, unrevealed, genetic, polymorphism, that, influences, the, physiological, processes, and, phenotypic, traits, considered, in, this, study])].
[sujeto(['Tissue', factor, pathway, 'Inhibitor-2', '(', 'TFPI-2)', is]), verbo([associated]), complemento([with, extracellular, matrices, and, plays, a, major, role, in, cell, migration, and, tumor, invasion])].
[sujeto(['Moreover,', several, putative]), verbo([binding]), complemento([sites, for, transcription, factors, were, identified, '(', 'MyoD,', 'LYF1,', 'NF-Y,', 'GATA,', 'oct-1,', 'AP-1,', 'Sp1,', 'NF1,', 'NF-kappa', 'B', and, 'egr-1)'])].
[sujeto(['Luciferase', activity, consistently]), verbo([increased]), complemento([after, stimulation, of, 'JEG-3', cells, by, phorbol, 12, -, myristate, 13, -, acetate, indicating, that, 'NF1,', 'NF-kappa', 'B', and, 'egr-1/Sp1', binding, sites, are, crucial, in, inducible, 'TFPI-2', expression])].
[sujeto(['Moreover,', negative, regulatory, regions, included, 'AP-1']), verbo([binding]), complemento([sites, were, identified])].
[sujeto(['In', 'addition,', cotransfection, analysis, indicated, that, the, 'MyoD']), verbo([activates]), complemento([the, mouse, mafB, promoter, and, the, gene, is, positively, 'auto-regulated', by, its, own, product])].
[sujeto(['The', author]), verbo([reports]), complemento([the, isolation, and, analysis, of, genomic, clone, of, the, mouse, mafB, gene])].
[sujeto(['A', 'TATA-like', sequence, '(', 5, '\'', -, 'GATAAAA-3\')', and, an, inverted, 'CCAAT-box', '(', 5, '\'', -, 'ATTGG-3\')', were]), verbo([found]), complemento([to, be, located, at, nucleotide, -, 31, and, -, 86, ',', referring, to, the, transcription, initiation, 'site,', respectively])].
[sujeto(['Promoter', activity, of, the, 5, '\'', -, flanking, region, was, analyzed, by, reporter, transfection, 'assay,', which]), verbo([suggested]), complemento([that, these, segments, were, an, important, transcriptional, activator])].
[sujeto(['It', was, also]), verbo([suggested]), complemento([that, 'MyoD', transactivated, the, mouse, mafB, promoter, and, this, gene, was, positively, autoregulated, by, its, 'product,', 'MafB'])].
[sujeto(['For', the, mouse, 'UCP2,', the, region, near, the, 'transcription-initiation', site, lacked, the, typical, 'TATA', 'box,', but, was, 'GC-rich,', resulting, in, presence, of, several, potential, specificity, protein, 1, '(', 'Sp-1),', activator, protein, '(', 'AP)-1', and, 'AP-2']), verbo([binding]), complemento([sites])].
[sujeto(['The', putative, regulatory, motifs, for, 'muscle-regulatory', protein, '(', 'MyoD),', 'brown-fat', regulatory, 'element,', 'CCAAT', 'box,', 'cAMP-response', element, and, 'Y', box, were, also]), verbo([found]), complemento([in, the, mouse, 'UCP2', promoter, region, by, 'computer-assisted', analysis])].
[sujeto(['From', the, results, of, 'Northern-blot', analysis, and, transient, expression, 'assay,', we]), verbo([found]), complemento([that, the, mouse, 'UCP2', gene, responded, to, the, 'cAMP-dependent', protein, kinase, 'alpha-catalytic', subunit, signal, activation, at, the, transcription, level])].
[sujeto(['In', 'particular,', the, region, from, nt, -, 233, to, -, 34, significantly]), verbo([induced]), complemento(['PLAP', activity, in, the, cell, lines, derived, from, various, tissues, and, in, the, primary, culture, cells, of, rat, brown, adipose, 'tissue,', suggesting, that, this, region, is, most, important, for, the, ubiquitous, expression, of, mouse, 'UCP2', mRNA])].
[sujeto(['Furthermore,', it, was, shown, that, two, silencer, elements, were]), verbo([involved]), complemento([in, the, mouse, 'UCP2', 'gene;', one, was, located, between, nt, -, 2746, and, -, 602, ',', and, the, other, was, identified, in, intron, 1])].
[sujeto(['These', regions, deprived, the, enhancer, of, the, ability, to]), verbo([induce]), complemento(['PLAP', activity])].
[sujeto(['This', study, shows, a, fundamental, role, for, positive, and, negative, 'cis-acting', 'DNA', elements, in]), verbo([regulating]), complemento([the, basal, and, 'cAMP-induced', transcription, activity, of, the, mouse, 'UCP2', gene])].
[sujeto(['Uncoupling', protein, 3, '(', 'UCP3),', a, member, of, the, 'UCP', 'family,', mainly]), verbo([expressed]), complemento([in, skeletal, muscle, could, be, responsible, for, thermogenesis, in, humans])].
[sujeto(['We']), verbo([report]), complemento([the, hUCP3, transcription, initiation, on, a, 'G', located, 764, nucleotides, upstream, the, 'A', contained, in, the, first, translated, codon])].
[sujeto(['Therefore,', hUCP3, first, exon]), verbo([has]), complemento([669, bases, of, untranslated, sequence])].
[sujeto(['We', also]), verbo([report]), complemento([the, cloning, and, sequencing, of, seven, kilobases, from, the, gene, 5, '\'', end, and, analyze, the, features, of, the, potential, proximal, promoter])].
[sujeto(['The', 'MyoD', family]), verbo([binding]), complemento(['motif,', called, 'E-box,', is, the, most, abundant, on, this, region])].
[sujeto(['Other', 'muscle-specific', motives, present, in, the, potential, proximal, promoter, include, a, 'MEF2', site, as, well, as]), verbo([binding]), complemento([sequences, for, ubiquitous, factors, such, as, 'GC', box, and, two, 'CAAT', boxes])].
[sujeto(['Additionally,', three, putative, peroxisome, proliferator, and, one, thyroid, hormone, response, elements, '(', 'PPRE', and, 'TRE,', 'respectively)', are, 'found,', which]), verbo([suggest]), complemento([a, potential, role, for, the, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)', and, thyroid, hormone, in, human, 'UCP3', gene, expression])].
[sujeto(['The', aim, of, our, study, was, to, isolate, novel, 'gene(s)']), verbo([involved]), complemento([in, cell, differentiation, and, embryonic, liver, development])].
[sujeto(['Analysis', of, the, 'cded/lior', promoter, region, revealed, a, high, 'GC-content,', high, ratio, of, 'CpG/GpC,', multiple, 'GC-boxes,', the, lack, of, a, 'TATA', 'box,', 'CTF/NFI', 'element,', and, two, 'MyoD-MCK']), verbo([binding]), complemento([sites])].
[sujeto(['These', characteristics, are, also]), verbo([found]), complemento([in, several, genes, important, in, the, regulation, of, cell, growth, or, 'DNA', 'synthesis,', such, as, transforming, growth, 'factor-beta1,', 'c-Ha-ras,', nerve, growth, 'factor,', epidermal, growth, factor, 'receptor,', and, 'DNA', polymerase, beta])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'cded/lior', is, a, 'mesoderm/muscle-specific', transcript, that, may, be, involved, in, the, mesodermal, inductive, and, regulatory, interactions, required, for, liver, formation, and, embryonic, development])].
[sujeto(['We']), verbo([have]), complemento([mapped, two, transcriptional, start, sites, by, primer, extension])].
[sujeto(['This', sequence, contains, a]), verbo([conserved]), complemento(['GC', box, to, which, the, transcription, factor, 'Sp1', binds])].
[sujeto(['Reporter', gene, constructs, containing, a, 2, -, kilobase, pair, first, intron, fragment, of, the, myotonic, dystrophy, protein, kinase, gene]), verbo([enhances]), complemento([reporter, activity, up, to, 6, -, fold, in, the, human, rhabdomyosarcoma, myoblast, cell, line, 'TE32', but, not, in, 'NIH', 3, 'T3', fibroblasts])].
[sujeto(['Deletion', analysis, of, four, 'E-box', elements, within, the, first, intron]), verbo([reveal]), complemento([that, these, elements, contribute, to, enhancer, activity, similarly, in, 'TE32', myoblasts, and, 10, 'T1/2', fibroblasts])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'E-boxes', within, the, myotonic, dystrophy, protein, kinase, first, intron, mediate, interactions, with, upstream, promoter, elements, to, 'up-regulate', transcription, of, this, gene, in, myoblasts])].
[sujeto(['Glypicans', are, a, member, of, a, family, of, glycosylphosphatidylinositol, anchored, heparan, sulfate, proteoglycans, that, are]), verbo([expressed]), complemento([in, cell, and, development, specific, patterns])].
[sujeto(['One', of, the, genomic, clones, extended, approximately, 2.8, kb, 5, '\'', of, the, exon, 1, coding, 'sequence,', and, is, thus, likely, to, contain, sequences, that]), verbo([regulate]), complemento(['GPC1', gene, expression])].
[sujeto(['A', search, for, potential, transcription, factor]), verbo([binding]), complemento([sites, revealed, a, number, of, such, 'motifs,', including, 'Sp1', '(', 'GC', 'box),', 'NF-kappaB,', and, 'MyoD', '(', 'E-box)'])].
[sujeto(['Muscle', glycogen, phosphorylase, '(', 'MGP)', transcript, and, protein, levels]), verbo([increase]), complemento([during, skeletal, muscle, development, in, tandem, with, the, products, of, other, muscle, genes, responsible, for, glucose, and, glycogen, metabolism])].
[sujeto(['Three', of, the, 'E', box, motifs, in, the, 'MGP', proximal, promoter]), verbo([interacted]), complemento([with, 'C2C12', nuclear, proteins])].
[sujeto(['Mutational', analyses, of, the, 'MGP', promoter, demonstrated, that]), verbo([increased]), complemento([expression, in, 'C2C12', myotubes, did, not, require, any, of, the, 'E', box, motifs, or, the, 'CArG-like', element])].
[sujeto(['The', functional, studies]), verbo([suggest]), complemento([that, 'MGP', is, developmentally, regulated, during, myogenesis, by, alternative, pathways, that, utilize, unidentified, regulatory, elements, or, ancillary, factors])].
[sujeto(['One', alternately, spliced, exon, encodes, part, of, the, 'MYC-binding', 'domain,']), verbo([suggesting]), complemento([that, splicing, controls, the, 'MYC-binding', capacity, of, 'BIN1', polypeptides])].
[sujeto(['The', 'full-length', cDNA, encoding, the, murine, ryudocan, core, protein]), verbo([has]), complemento([now, been, cloned, and, sequenced])].
[sujeto(['The', promoter, region, of, the, mouse, gene, contains, various, 'cis-acting', 'elements,', including, a, 'TATA-like', box, and, a, 'GC', box, as, well, as, potential]), verbo([binding]), complemento([sites, for, the, transcription, factors, 'NF-IL6,', 'MyoD,', 'GATA,', 'C/EBP,', 'AP-2,', 'NF-kappaB,', 'AP-1,', and, 'Sp1'])].
[sujeto(['Deletion', analysis]), verbo([suggested]), complemento([that, the, proximal, promoter, region, including, the, 'TATA-like', 'box,', the, 'GC', 'box,', and, other, 'Sp1', binding, sites, was, required, for, full, transcriptional, activity])].
[sujeto(['These', findings, will, be, useful, for, the, study, of, ryudocan, gene, regulation, and, the, generation, of, mice, with]), verbo([targeted]), complemento([disruption, of, the, gene])].
[sujeto(['Mitogen-activated', protein, kinase, '(', 'MAPK)', or, extracellular, 'signal-regulated', kinase, are, ubiquitous, kinases]), verbo([conserved]), complemento([from, fungi, to, mammals])].
[sujeto(['Their', activity, is]), verbo([regulated]), complemento([by, phosphorylation, on, both, threonine, and, 'tyrosine,', and, they, play, a, crucial, role, in, the, regulation, of, proliferation, and, differentiation])].
[sujeto(['We']), verbo([report]), complemento([here, the, cloning, of, the, murine, p44, 'MAP', kinase, '(', extracellular, 'signal-regulated', kinase, 1, ')', 'gene,', the, determination, of, its, 'intron/exon', 'boundaries,', and, the, characterization, of, its, promoter])].
[sujeto(['The', gene, spans, approximately, eight, kilobases, '(', 'kb)', and, can, be, divided, into, nine, exons, and, eight, 'introns,', each, coding, region, exon, containing, from, one, to, three, of, the, highly]), verbo([conserved]), complemento([protein, kinase, domains])].
[sujeto(['Primer', extension, analysis]), verbo([reveals]), complemento([the, existence, of, two, major, start, sites, of, transcription, located, at, -, 183, and, -, 186, base, pairs, '(', 'bp)', as, well, as, four, discrete, start, sites, for, transcription, located, at, -, 178, ',', -, 192, ',', -, 273, ',', and, -, 292, bp, of, the, initiation, of, translation])].
[sujeto(['However,', the, start, site, region, lacks, 'TATA-like', sequences, but, does, contain, 'initiator-like', sequences, proximal, to, the, major, start, sites, obtained, by]), verbo([primer]), complemento([extension])].
[sujeto([1, kb, of, the, promoter, region]), verbo([has]), complemento([been, sequenced])].
[sujeto(['It', contains, three, putative, 'TATA', boxes, far, upstream, of, the, main, start, sites, 'region,', one, 'AP-1', 'box,', one, 'AP-2', 'box,', one, 'Malt', 'box,', one, 'GAGA', 'box,', one, half, 'serum-responsive', 'element,', and, putative]), verbo([binding]), complemento([sites, for, 'Sp1', '(', 'five),', 'GC-rich', binding, factor, '(', 'five),', 'CTF-NF1', '(', 'one),', 'Myb', '(', 'one),', p53, '(', 'two),', 'Ets-1', '(', 'one),', 'NF-IL6', '(', 'two),', 'MyoD', '(', 'two),', 'Zeste', '(', 'one),', and, hepatocyte, nuclear, 'factor-5', '(', 'one)'])].
[sujeto(['Progressive', deletions, of, the, approximately, 1, kb, '(', -, 1200, /, -, 78, ')', promoter, region, allowed, us, to, define, a, minimal, region, of, 186, bp, '(', -, 284, /, -, 78, ')', that]), verbo([has]), complemento([maximal, promoter, activity])].
[sujeto(['Within', this, 'context,', deletion, of, the, 'AP-2']), verbo([binding]), complemento([site, reduces, by, 30, -, 40, '%', the, activity, of, the, promoter])].
[sujeto(['(', 'ABSTRACT', 'TRUNCATED', 'AT', 400, 'WORDS)', rSkM2, is, a, 'tetrodotoxin-resistant', rat, skeletal, muscle, 'voltage-sensitive', sodium, channel, that, is]), verbo([expressed]), complemento([in, immature, and, denervated, skeletal, muscle, and, in, adult, heart])].
[sujeto(['We']), verbo([have]), complemento([isolated, a, 3.7, -, kb, gene, segment, that, contains, the, first, 'exon,', multiple, transcription, initiation, 'sites,', the, core, promoter, '(', nt, -, 102, to, +, 1, ')', ',', 'GC-rich', elements, '(', 'Sp1', recognition, 'sites),', three, overlapping, 'C-rich', motifs, '(', important, for, 'muscle-specific', expression, of, some, muscle, 'genes),', and, multiple, 'CANNTG', '(', 'E-box)', motifs, '(', 'MyoD', binding, 'sites)'])].
[sujeto(['A', deletion, analysis, of, the, 5, '\'', upstream, 2.8, -, kb, 'segment,', driving, the, rSkM2, core, 'promoter,']), verbo([has]), complemento([localized, a, 'muscle-restrictive', enhancer, element, '(', 'MRSE)', at, least, 2, kb, upstream, from, the, core, promoter])].
[sujeto(['Gel-shift', assays]), verbo([have]), complemento([identified, 'sequence-', and, 'cell-type-specific', proteins, that, bind, to, a, 16, -, bp, region, '(', -, 44, /, -, 29, ')', containing, 'C-rich', motifs])].
[sujeto(['Muscle-specific', complexes, formed, from, muscle, cell]), verbo([nuclear]), complemento([extracts, and, a, 16, -, bp, element, '(', -, 44, /, -, 29, ')', are, competed, by, unlabeled, -, 44, /, -, 29, oligonucleotide, but, not, by, several, mutant, oligonucleotides, that, implicate, nucleotides, -, 40, to, -, 38, and, -, 34, to, -, 32, in, the, binding, of, a, nuclear, protein, '(', designated, 'SkM2', transcription, factor, 1, ',', 'SkM2-TF1)'])].
[sujeto(['Vitamin', 'D', deficiency, and, advanced, glycation, end, products, '(', 'AGEs)', are]), verbo([suggested]), complemento([to, be, involved, in, the, pathogenesis, of, osteoporosis, and, sarcopenia])].
[sujeto(['We', previously, showed, that, osteoglycin, '(', 'OGN)', is, secreted, from, myoblasts, and]), verbo([stimulates]), complemento([osteoblastic, 'differentiation,', suggesting, that, it, plays, important, roles, in, the, interaction, between, muscle, and, bone])].
[sujeto([1, 'α,25-dihydroxyvitamin', 'D3', '(', 1, ',', 25, 'D)', and, 'eldecalcitol,', an, active, vitamin, 'D', 'analog,']), verbo([induced]), complemento([the, expression, of, 'MyoD,', myogenin, and, 'OGN,', and, these, effects, were, abolished, by, vitamin, 'D', receptor, '(', 'VDR)', suppression, by, siRNA, in, 'C2C12', cells])].
[sujeto(['Moreover,', conditioned, medium, from, 1, ',', 25, 'D-pretreated', 'C2C12', cells]), verbo([stimulated]), complemento([the, expression, of, type, 1, collagen, and, alkaline, phosphatase, in, 'MC3T3-E1', 'cells,', compared, to, control, medium, from, 1, ',', 25, 'D-untreated', 'C2C12', cells])].
[sujeto(['AGE2', and, 'AGE3']), verbo([suppressed]), complemento([the, expression, of, 'MyoD,', myogenin, and, 'OGN', in, 'C2C12', cells])].
[sujeto(['Active', vitamin, 'D', treatment, may, rescue, the, 'AGEs-induced', sarcopenia, as, well, as, -]), verbo([suppressed]), complemento([osteoblastic, differentiation, via, 'OGN', expression, in, myoblasts])].
[sujeto(['The', regulation, of, gene, expression, by, thyroid, hormone, '(', 'T3)']), verbo([involves]), complemento([binding, of, the, hormone, to, nuclear, receptors, '[', thyroid, hormone, receptor, '(', 'TR)]', acting, as, 'T3-dependent', transcription, factors, encoded, by, 'TRalpha', '(', 'NR1A1)', and, 'TRbeta', '(', 'NR1A2)', genes])].
[sujeto(['Several', 'TRalpha', variants]), verbo([have]), complemento([already, been, 'characterized,', but, only, some, of, them, display, 'T3', binding, activity])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([identified, another, 'transcript,', 'TRalpha-DeltaE6,', produced, by, alternative, splicing, with, microexon, 6, b, instead, of, exon, 6])].
[sujeto(['This', splicing]), verbo([leads]), complemento([to, the, synthesis, of, a, protein, devoid, of, a, hinge, domain])].
[sujeto(['Although', 'TRalpha-DeltaE6', did, not]), verbo([bind]), complemento(['DNA,', its, expression, induced, a, 'TRalpha1', sequestration, in, the, cytoplasm])].
[sujeto(['Functional', studies, demonstrated, that, 'TRalpha-DeltaE6']), verbo([inhibits]), complemento([the, transcriptional, activity, of, 'TRalpha1', and, retinoic, 'X', 'receptor-alpha,', but, not, of, retinoic, acid, 'receptor-alpha'])].
[sujeto(['We', also]), verbo([found]), complemento([that, 'TRalpha-DeltaE6', efficiently, decreased, the, ability, of, 'TRalpha', to, inhibit, 'MyoD', transcriptional, activity, during, myoblast, proliferation])].
[sujeto(['Consequently,', when, overexpressed, in, 'myoblasts,', it]), verbo([stimulated]), complemento([terminal, differentiation])].
[sujeto(['We']), verbo([suggest]), complemento([that, this, novel, 'TRalpha', variant, may, act, as, down, regulator, of, overall, 'T3', receptor, 'activity,', including, its, ability, to, repress, 'MyoD', transcriptional, activity, during, myoblast, proliferation])].
[sujeto(['Classical', 'ligand-activated']), verbo([nuclear]), complemento([receptors, '(', e])].
[sujeto([thyroid, hormone, 'receptor,', retinoic, acid, 'receptor),', orphan]), verbo([nuclear]), complemento([receptors, '(', e])].
[sujeto(['Rev-erbAalpha/beta),', 'Mad/Max', bHLH, '(', basic, helix, loop, 'helix)-LZ', 'proteins,', and, 'oncoproteins,', 'PLZF', and, 'LAZ3/BCL6,']), verbo([bind]), complemento(['DNA', and, silence, transcription, by, recruiting, a, repressor, complex, that, contains, 'N-CoR', '(', nuclear, receptor, 'corepressor)/SMRT', '(', silencing, mediator, of, retinoic, acid, and, thyroid, hormone, 'receptor),', 'Sin3A/B,', and, 'HDAc-1/-2', proteins])].
[sujeto(['The', function, of, the, 'corepressor,', 'N-CoR,', in, the, process, of, cellular, differentiation, and, coupled, phenotypic, 'acquisition,']), verbo([has]), complemento([not, been, investigated])].
[sujeto(['We', observed, that, the, mRNA, encoding, 'N-CoR', was]), verbo([suppressed]), complemento([as, proliferating, myoblasts, exited, the, cell, 'cycle,', and, formed, morphologically, and, biochemically, differentiated, myotubes])].
[sujeto(['Furthermore,', 'N-CoR', expression, efficiently]), verbo([inhibits]), complemento([the, 'myoD-mediated', myogenic, conversion, of, pluripotential, 'C3H10T1/2', cells])].
[sujeto(['We', demonstrate, that, 'MyoD-mediated', transactivation, and, activity, are]), verbo([repressed]), complemento([by, 'N-CoR'])].
[sujeto(['The', mechanism]), verbo([involves]), complemento([direct, interactions, between, 'MyoD', and, 'N-CoR;', 'moreover,', the, interaction, was, dependent, on, the, 'amino-terminal', repression, domain, '(', 'RD1)', of, 'N-CoR', and, the, bHLH, region, of, 'MyoD'])].
[sujeto(['Trichostatin', 'A', treatment, significantly]), verbo([stimulated]), complemento([the, activity, of, 'MyoD', by, approximately, 10, -, fold, and, inhibited, the, ability, of, 'N-CoR', to, repress, 'MyoD-mediated', 'transactivation,', consistent, with, the, involvement, of, the, corepressor, and, the, recruitment, of, a, histone, deacteylase, activity, in, the, process])].
[sujeto(['This', work, demonstrates, that, the, corepressor, 'N-CoR', is, a, key, regulator, of, 'MyoD', activity, and, mammalian, 'differentiation,', and, that, 'N-CoR']), verbo([has]), complemento([a, multifaceted, role, in, myogenesis])].
[sujeto(['Syndecan-1', is, an, integral, membrane, proteoglycan]), verbo([involved]), complemento([in, the, interaction, of, cells, with, extracellular, matrix, proteins, and, growth, factors])].
[sujeto(['It', is, transiently]), verbo([expressed]), complemento([in, several, condensing, mesenchymal, tissues, after, epithelial, induction])].
[sujeto(['The']), verbo([decrease]), complemento([in, 'syndecan-1', gene, expression, is, not, dependent, on, the, presence, of, 'E-boxes,', binding, sites, for, the, 'MyoD', family, of, transcription, factors, in, the, promoter, 'region,', or, myogenin, expression])].
[sujeto(['When', added, 'together,', 'however,', they]), verbo([induced]), complemento(['syndecan-1', expression])].
[sujeto(['Retinoic', 'acid,', an, inducer, of, 'myogenesis,']), verbo([inhibited]), complemento(['syndecan-1', expression, and, abolished, the, effect, of, the, growth, factors])].
[sujeto(['These', results, indicate, that, 'syndecan-1', expression, is, 'down-regulated', during, myogenesis, and, that, growth, factors, and, retinoic, acid]), verbo([modulate]), complemento(['syndecan-1', expression, by, a, mechanism, that, is, independent, of, myogenin])].
[sujeto(['Two', clonal, rat, rhabdomyosarcoma, cell, lines, 'BA-Han-1B', and, 'BA-Han-1C', with, different, capacities, for, myogenic, differentiation]), verbo([have]), complemento([been, examined, for, the, expression, of, muscle, regulatory, basic, 'helix-loop-helix', '(', 'bHLH)', proteins, of, the, 'MyoD', family])].
[sujeto(['Whereas', cells, of, the, 'BA-Han-1C', subpopulation, constitutively]), verbo([expressed]), complemento(['MyoD1', and, could, be, induced, to, differentiate, with, retinoic, acid, '(', 'RA),', 'BA-Han-1B', cells, did, not, express, any, of, the, myogenic, control, factors, and, appeared, to, be, largely, 'differentiation-defective'])].
[sujeto(['Upon', induction, with, 'RA,', 'BA-Han-1C', cells]), verbo([expressed]), complemento([also, 'myogenin,', in, contrast, to, 'BA-Han-1B', cells, which, never, activated, any, of, the, genes, encoding, muscle, bHLH, factors])].
[sujeto(['The', onset, of, myogenin, transcription, in, 'BA-Han-1C', cells]), verbo([required]), complemento([de, novo, protein, synthesis, and, 'DNA', replication, suggesting, that, 'RA', probably, did, not, act, directly, on, the, myogenin, gene])].
[sujeto(['Although', 'MyoD1', was]), verbo([expressed]), complemento([in, proliferating, 'BA-Han-1C', 'myoblasts,', 'muscle-specific', reporter, genes, were, not, activated, indicating, that, 'MyoD', was, biologically, inactive])].
[sujeto(['However,', transfections, with, plasmid]), verbo([expressing]), complemento([additional, 'MyoD1', protein, resulted, in, the, transactivation, of, muscle, genes, even, in, the, absence, of, 'RA'])].
[sujeto([mRNA, encoding, the, negative, regulatory, 'HLH', protein, 'Id', was]), verbo([expressed]), complemento([in, proliferating, 'BA-Han-1C', cells, and, disappeared, later, after, 'RA', induction, which, suggested, that, it, may, be, involved, in, the, regulation, of, 'MyoD1', activity])].
[sujeto(['In', 'fact,', stable, transfections, of, 'BA-Han-1C', cells, with, myogenin]), verbo([expressing]), complemento([plasmids, resulted, in, spontaneous, differentiation])].
[sujeto(['Together,', our, results]), verbo([suggest]), complemento([that, the, transformed, and, undifferentiated, phenotype, of, 'BA-Han-1C', rhabdomyosarcoma, cells, is, associated, with, the, inactivation, of, the, myogenic, factor, 'MyoD1', as, well, as, lack, of, myogenin, expression])].
[sujeto(['RA', alleviates, the, inhibition, of, myogenic, 'differentiation,', probably, by]), verbo([activating]), complemento(['MyoD', protein, and, myogenin, gene, transcription])].
[sujeto(['BA-Han-1B', cells, did, not]), verbo([respond]), complemento([to, 'RA', and, the, differentiated, phenotype, could, not, be, restored, by, overexpression, of, 'MyoD1', or, myogenin])].
[sujeto(['This', shows, that, 'FGF18']), verbo([induces]), complemento([expression, of, 'MyoD', and, 'ERK', phosphorylation, and, both, endogenous, and, 'FGF18', induced, 'MyoD', expression, is, inhibited, by, 'U0126'])].
[sujeto(['To', uncover, how, foxc1a]), verbo([regulates]), complemento([zebrafish, 'somitogenesis,', we, generated, foxc1a, 'knock-out', zebrafish, using, 'TALEN', '(', transcription, 'activator-like', effector, 'nuclease)', technology])].
[sujeto(['Analyses', on, the, expressions, of, the, key, genes, that, control, processes, of, somitogenesis, revealed, that, foxc1a, controlled, early, somitogenesis, by]), verbo([regulating]), complemento([the, expression, of, myod1])].
[sujeto(['In', the, somites, of, foxc1a, 'knock-out', 'embryos,', expressions, of, fgf8a, and, deltaC, were, 'abolished,', whereas, the, expression, of, aldh1a2, '(', responsible, for]), verbo([providing]), complemento([retinoic, acid, 'signaling)', was, significantly, increased])].
[sujeto(['Once', the]), verbo([increased]), complemento([retinoic, acid, level, in, the, foxc1a, null, embryos, was, reduced, by, knocking, down, 'aldh1a2,', the, reduced, expression, of, myod1, was, partially, rescued, by, resuming, expressions, of, fgf8a, and, deltaC, in, the, somites, of, the, mutant, embryos])].
[sujeto(['Moreover,', a, chromatin, immunoprecipitation, assay, on, zebrafish, embryos, revealed, that, 'Foxc1a']), verbo([bound]), complemento([aldh1a2, promoter, directly])].
[sujeto(['On', the, other, 'hand,', neither, knocking, down, fgf8a, nor]), verbo([inhibiting]), complemento(['Notch', signaling, affected, the, expression, of, 'aldh1a2,', although, knocking, down, fgf8a, reduced, expression, of, deltaC, in, the, somites, of, zebrafish, embryos, at, early, somitogenesis, and, vice, versa])].
[sujeto(['Only', then, do, they, begin, to, differentiate, and]), verbo([express]), complemento([markers, of, myogenic, commitment, and, determination, such, as, 'Myf5', and, 'MyoD'])].
[sujeto(['However', the, signals]), verbo([regulating]), complemento([this, process, remain, poorly, characterised])].
[sujeto(['We', show, that, 'FGF18,', which, is]), verbo([expressed]), complemento([in, the, distal, mesenchyme, of, the, limb, 'bud,', induces, premature, expression, of, both, 'Myf5', and, 'MyoD', and, that, blocking, 'FGF', signalling, also, inhibits, endogenous, 'MyoD', expression])].
[sujeto(['This', expression, is]), verbo([mediated]), complemento([by, 'ERK', 'MAP', kinase, but, not, 'PI3K', signalling])].
[sujeto(['We', also, show, that, retinoic, acid, '(', 'RA)', can]), verbo([inhibit]), complemento([the, myogenic, activity, of, 'FGF18', and, that, blocking, 'RA', signalling, allows, premature, induction, of, 'MyoD', by, 'FGF18', at, 'HH19'])].
[sujeto(['We', propose, a, model, where, interactions, between, 'FGF18', in, the, distal, limb, and, retinoic, acid, in, the, proximal, limb]), verbo([regulate]), complemento([the, timing, of, myogenic, gene, expression, during, limb, bud, development])].
[sujeto(['We']), verbo([have]), complemento([used, 'wild-type', and, transgenic, zebrafish, to, examine, the, role, of, 'RARγ'])].
[sujeto(['Treatment', of, zebrafish, embryos, with, an, 'RARγ-specific', agonist, reduced, somite, formation, and, axial, 'length,', which, was]), verbo([associated]), complemento([with, a, loss, of, hoxb13a, expression, and, 'less-clear', alterations, in, hoxc11a, or, myoD, expression])].
[sujeto(['There', was, a]), verbo([loss]), complemento([of, 'Sox', 9, -, immunopositive, neural, crest, 'stem/progenitor', cells, in, the, same, anterior, regions])].
[sujeto(['However,', there, was, no]), verbo([loss]), complemento([of, 'Tbx-5-immunopositive', lateral, plate, mesodermal, 'stem/progenitor', cells, and, the, block, was, reversed, by, agonist, washout, or, by, cotreatment, with, an, 'RARγ', antagonist])].
[sujeto(['Regeneration', of, the, caudal, fin, was, also, blocked, by, 'RARγ', agonist, 'treatment,', which, was]), verbo([associated]), complemento([with, a, loss, of, canonical, 'Wnt', signaling])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'RARγ', plays, an, essential, role, in, maintaining, 'stem/progenitor', cells, during, embryonic, development, and, tissue, regeneration, when, the, receptor, is, in, its, nonligated, state])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, pregnant, mice, treated, with, retinoic, acid, '(', +, 'RA)', produce, embryos, with, tongue, malformation, and, a, cleft, palate])].
[sujeto(['In', 'mock-', and, 'Wnt5a-transfected', 'C2C12', '(', 'Wnt5a-C2C12)', 'cells,', 'Wnt5a', overexpression, impaired, 'proliferation,', and]), verbo([maintained]), complemento(['Myf5', at, a, relative, high, level, after, 'RA', treatment])].
[sujeto(['These', data, support, the, hypothesis, that, the, 'Wnt5a/CaMKII', pathway, is, directly]), verbo([involved]), complemento([in, 'RA-induced', hypoplasia, and, disorder, of, tongue, muscles])].
[sujeto(['In', the, current, 'study,', we]), verbo([found]), complemento([that, α7, 'integrin-positive', human, skeletal, muscle, stem, cells, '(', 'α7(+)hSMSCs)', could, differentiate, into, the, odontoblast, lineage, under, specific, inductive, conditions, in, response, to, bone, morphogenetic, 'protein-4', '(', 'BMP-4)'])].
[sujeto(['Following', this, 'protocol,', 'α7(+)hSMSCs', were]), verbo([induced]), complemento([to, 'down-regulate', myogenic, genes, '(', 'MYOD', and, α7, 'integrin)', and, 'up-regulate', odontogenic, markers, including, dentin, 'sialophosphoprotein,', matrix, 'metalloproteinase-20', '(', 'enamelysin),', dentin, 'sialoprotein,', and, alkaline, phosphatase, but, not, osteoblastic, genes, '(', osteopontin, and, 'osteocalcin)'])].
[sujeto(['Interestingly,', using, siRNA, knockdown, strategies, revealed, that, the, 'differentiation-related', expression, of, the, α1, integrin, receptor, positively]), verbo([regulates]), complemento([the, expression, of, the, odontoblastic, markers, dentin, sialophosphoprotein, and, matrix, 'metalloproteinase-20'])].
[sujeto(['These', results, strongly]), verbo([suggest]), complemento([that, the, differentiation, of, 'α7(+)hSMSCs', along, the, odontogenic, lineage, is, dependent, on, the, concurrent, expression, of, α1, integrin])].
[sujeto(['When', buffalo, embryonic, stem, '(', 'ES)', 'cell-like', cells, that]), verbo([expressed]), complemento([surface, markers, 'SSEA-4,', 'TRA-1-60,', 'TRA-1-81,', 'CD9', and, 'CD90', and, intracellular, markers, 'OCT4,', 'SOX2', and, 'FOXD3,', as, shown, by, 'immunofluorescence,', and, that, expressed, 'REX-1', and, 'NUCLEOSTEMIN', as, confirmed, by, 'RT-PCR,', were, subjected, to, suspension, culture, in, hanging, drops, in, absence, of, 'LIF', and, buffalo, foetal, fibroblast, feeder, layer, 'support,', they, differentiated, to, form, 'three-dimensional', embryoid, bodies, '(', 'EBs)'])].
[sujeto(['The', cells, obtained, from, 'EBs', were]), verbo([found]), complemento([to, express, 'NF-68', and, 'NESTIN', '(', ectodermal, 'lineage),', 'BMP-4', and, 'α-skeletal', actin, '(', mesodermal, 'lineage),', and, 'α-fetoprotein,', 'GATA-4', and, 'HNF-4', '(', endodermal, 'lineage)'])].
[sujeto(['To', 'date,', it]), verbo([has]), complemento([proven, difficult, to, generate, skeletal, muscle, from, hESCs, in, high, yields, and, within, a, reasonable, timeframe])].
[sujeto(['Further,', a, 'hESC-derived', 'Pax3/7-positive', skeletal, muscle, progenitor, population]), verbo([has]), complemento([not, yet, been, described])].
[sujeto(['Previous', studies]), verbo([have]), complemento([shown, that, 'Pax3/7-positive', progenitor, cells, can, repopulate, the, satellite, cell, 'niche,', indicating, the, importance, of, this, population, for, therapy])].
[sujeto(['We', treated, hESCs, with, retinoic, acid, '(', 'RA)', and]), verbo([found]), complemento([an, enhancement, of, skeletal, 'myogenesis,', and, the, expression, of, the, myogenic, regulatory, factors, '(', 'MRFs)', 'MyoD', and, myogenin, by, day, 25])].
[sujeto(['Furthermore,', we]), verbo([found]), complemento([that, 'RA', treatment, expanded, the, muscle, progenitor, 'pool,', which, occurred, as, a, distinct, 'Pax3(+ve)', population, prior, to, 'MRF', expression])].
[sujeto(['Therefore,', we]), verbo([have]), complemento([identified, a, differentiation, pathway, in, hESCs, that, provides, a, skeletal, muscle, progenitor, population, which, can, undergo, myogenesis, more, efficiently])].
[sujeto(['The', contribution, of, 'PcG', proteins, to, cell, commitment, and, differentiation, relates, to, their, ability, to]), verbo([repress]), complemento([transcription, of, developmental, regulators, in, embryonic, stem, '(', 'ES)', cells, and, in, committed, cell, 'lineages,', including, skeletal, muscle, cells, '(', 'SMC)'])].
[sujeto(['PcG', proteins, are, preferentially, removed, from]), verbo([transcribed]), complemento(['regions,', but, the, underlying, mechanisms, remain, unclear])].
[sujeto(['Here,', 'PcG', proteins, are]), verbo([found]), complemento([to, occupy, and, repress, transcription, from, an, intronic, region, containing, the, microRNA, 'miR-214', in, undifferentiated, 'SMC'])].
[sujeto(['Once', 'transcribed,', 'miR-214', negatively, feeds, back, on, 'PcG', by]), verbo([targeting]), complemento([the, 'Ezh2', 3, '\'', 'UTR,', the, catalytic, subunit, of, the, 'PRC2', complex])].
[sujeto(['miR-214-mediated', 'Ezh2', protein, reduction, accelerates, 'SMC', differentiation, and]), verbo([promotes]), complemento([unscheduled, transcription, of, developmental, regulators, in, 'ES', cells])].
[sujeto(['While', retinoic, acid, '(', 'RA)', is, the, most, potent, small, molecule, enhancer, of, skeletal, myogenesis, in, stem, 'cells,', the, stage, and, mechanism, of, its, function]), verbo([has]), complemento([not, yet, been, elucidated])].
[sujeto(['Further,', the, intersection, of, 'RA', with, other, signalling, pathways, that]), verbo([stimulate]), complemento([or, inhibit, myogenesis, '(', such, as, 'Wnt', and, 'BMP4,', 'respectively)', is, unknown])].
[sujeto(['Thus,', the, purpose, of, this, study, is, to, examine, the, molecular, mechanisms, by, which, 'RA']), verbo([enhances]), complemento([skeletal, myogenesis, and, interacts, with, 'Wnt', and, 'BMP4', signalling, during, 'P19', or, mouse, embryonic, stem, '(', 'ES)', cell, differentiation])].
[sujeto(['Treatment', of, 'P19', or, mouse, 'ES', cells, with, low, levels, of, 'RA']), verbo([led]), complemento([to, an, enhancement, of, skeletal, myogenesis, by, upregulating, the, expression, of, the, mesodermal, 'marker,', 'Wnt3a,', the, skeletal, muscle, progenitor, factors, 'Pax3', and, 'Meox1,', and, the, myogenic, regulatory, factors, '(', 'MRFs)', 'MyoD', and, myogenin])].
[sujeto(['By', chromatin, 'immunoprecipitation,', 'RA', receptors, '(', 'RARs)']), verbo([bound]), complemento([directly, to, regulatory, regions, in, the, 'Wnt3a,', 'Pax3,', and, 'Meox1', genes, and, 'RA', activated, a, 'beta-catenin-responsive', promoter, in, aggregated, 'P19', cells])].
[sujeto(['Finally,', 'RA']), verbo([inhibited]), complemento([cardiomyogenesis, but, not, in, the, presence, of, 'BMP4'])].
[sujeto(['RA', can]), verbo([enhance]), complemento([skeletal, myogenesis, in, stem, cells, at, the, muscle, 'specification/progenitor', stage, by, activating, 'RARs', bound, directly, to, mesoderm, and, skeletal, muscle, progenitor, 'genes,', activating, 'beta-catenin', function, and, inhibiting, bone, morphogenetic, protein, '(', 'BMP)', signalling])].
[sujeto(['Thus,', a, signalling, pathway, can, function, at, multiple, levels, to, positively]), verbo([regulate]), complemento([a, developmental, program, and, can, function, by, abrogating, inhibitory, pathways])].
[sujeto(['Finally,', since, 'RA']), verbo([enhances]), complemento([skeletal, muscle, progenitor, 'formation,', it, will, be, a, valuable, tool, for, designing, future, stem, cell, therapies])].
[sujeto(['At', early, stages, of, limb, 'development,', 'RA', levels, are, highest, proximally, and]), verbo([regulate]), complemento([the, migration, of, myoblasts, into, the, limb])].
[sujeto(['As', the, premyogenic, progenitor, cells, migrate, into, the, limb, and, accumulate, in, premuscle, 'masses,', they]), verbo([express]), complemento(['Pax3', and, 'Meox2'])].
[sujeto(['Myogenic', differentiation, is, initiated, by, expression, of, 'Myf5', and, 'MyoD,', and, both, 'Pax3', and, 'Meox2', are]), verbo([required]), complemento([for, normal, 'Myf5', expression])].
[sujeto(['We', show, by]), verbo([loss]), complemento([of, function, using, the, inhibitor, 'citral,', that, 'RA', signalling, within, the, limb, bud, is, required, to, maintain, 'Pax3', and, 'Meox2', in, the, progenitor, and, 'Myf5', and, 'MyoD', in, the, differentiating, myoblasts])].
[sujeto(['RA', treatment, followed, by, exposure, to, triiodothyronine, '(', 'T3)', and, insulin]), verbo([induces]), complemento(['ES', cells, differentiation, into, adipocytes, and, skeletomyocytes])].
[sujeto(['On', the, other, 'hand,', 'OT', '(', 10, '(', -, 7, ')', 'M)', was]), verbo([reported]), complemento([to, inhibit, 3, 'T3', preadipocyte, maturation])].
[sujeto(['The', present, work, was, undertaken, to, determine, whether, 'P19', cells]), verbo([have]), complemento([an, adipogenic, potential, that, could, be, affected, by, 'OT'])].
[sujeto(['Levels', of, cTpnI, and, of, the, skeletal, marker, 'MyoD', were, almost, similar, in, both, 'protocols,', whereas, no, 'Oil-Red-O', staining, was]), verbo([associated]), complemento([with, the, cardiomyogenic, protocol])].
[sujeto(['Interestingly,', 'Oct3/4', pluripotency, marker, disappeared, in, the, adipogenic, protocol, but, remained]), verbo([expressed]), complemento([in, the, cardiomyogenic, one])].
[sujeto(['P19', cells, thus]), verbo([have]), complemento([an, adipogenic, potential, non, affected, by, 10, '(', -, 7, ')', 'M', 'OT'])].
[sujeto(['Retinoic', acid, '(', 'RA)']), verbo([has]), complemento([been, shown, to, regulate, muscle, differentiation, in, vitro])].
[sujeto(['Here,', we]), verbo([have]), complemento([investigated, the, role, of, 'RA', signalling, during, embryonic, myogenesis, in, zebrafish])].
[sujeto(['We']), verbo([have]), complemento([altered, 'RA', signalling, from, gastrulation, stages, onwards, by, either, inhibiting, endogenous, 'RA', synthesis, using, an, inhibitor, of, retinaldehyde, dehydrogenases, '(', 'DEAB)', or, by, addition, of, exogenous, 'RA'])].
[sujeto(['DEAB', reduces, expression, of, the, myogenic, markers, myoD, and, myogenin, in, 'somites,', whereas, 'RA']), verbo([induces]), complemento([increased, expression, of, these, genes, and, strongly, induces, premature, myoD, expression, in, the, presomitic, mesoderm, '(', 'psm)'])].
[sujeto(['The', expression, dynamics, of, myf5, in, presomitic, and, somitic, mesoderm]), verbo([suggest]), complemento([that, 'RA', promotes, muscle, 'differentiation,', a, role, supported, by, the, fact, that, 'RA', activates, expression, of, fast, 'myosin,', while, 'DEAB', represses, it])].
[sujeto(['We', show, that, fgf8, expression, in, somites, and, anterior, psm, is]), verbo([regulated]), complemento([by, 'RA,', and, find, that, in, the, absence, of, 'Fgf8', signalling, in, the, acerebellar, mutant, 'RA', fails, to, promote, myoD, expression])].
[sujeto(['We', propose, 'that,', in, the, developing, 'embryo,', localised, synthesis, of, 'RA', by, 'Raldh2', in, the, anterior, psm, and, in, somites]), verbo([activates]), complemento([fgf8, expression, which, in, turn, induces, the, expression, of, myogenic, genes, and, fast, muscle, differentiation])].
[sujeto(['We']), verbo([have]), complemento([already, shown, that, 'BTG1,', considered, as, an, antiproliferative, 'protein,', strongly, stimulates, myoblast, differentiation])].
[sujeto(['However,', the, mechanisms]), verbo([involved]), complemento([in, this, influence, remained, unknown])].
[sujeto(['In', cultured, 'myoblasts,', we]), verbo([found]), complemento([that, 'BTG1', stimulates, the, transcriptional, activity, of, nuclear, receptors, '(', 'T3', and, 'all-trans', retinoic, acid, receptors, but, not, 'RXRalpha', and, 'PPARgamma),', 'c-Jun', and, myogenic, factors, '(', 'CMD1,', 'Myf5,', 'myogenin)'])].
[sujeto(['Immunoprecipitation', experiments, performed, in, cells, or, using, in, 'vitro-synthesized', proteins, and, 'GST', 'pull-down', assays, established, that, 'BTG1', directly]), verbo([interacts]), complemento([with, 'T3', and, 'all-trans', retinoic, acid, receptors, and, with, avian, 'MyoD', '(', 'CMD1)'])].
[sujeto(['These', interactions, are]), verbo([mediated]), complemento([by, the, transactivation, domain, of, each, transcription, factor, and, the, 'A', box, and, 'C-terminal', part, of, 'BTG1'])].
[sujeto(['NCoR', presence]), verbo([induces]), complemento([the, ligand, dependency, of, the, interaction, with, nuclear, receptors])].
[sujeto(['Lastly,', deletion, of, 'BTG1']), verbo([interacting]), complemento([domains, abrogates, its, ability, to, stimulate, nuclear, receptors, and, 'CMD1', 'activity,', and, its, myogenic, influence])].
[sujeto(['In', 'conclusion,', 'BTG1', is, a, novel, important, coactivator]), verbo([involved]), complemento([in, the, regulation, of, myoblast, differentiation])].
[sujeto(['It', not, only]), verbo([stimulates]), complemento([the, activity, of, myogenic, 'factors,', but, also, of, nuclear, receptors, already, known, as, positive, myogenic, regulators])].
[sujeto(['On', the, basis, of, our, analysis, of, genes, on, the, cDNA, array, plus, the, data, from, our, 'RT-PCR', 'assays,', the, metabolic, adaptations, shown, by, rat, gastrocnemius, muscle, during, fasting, are, reflected, by, 'i)']), verbo([increased]), complemento([transcription, both, of, myosin, heavy, chain, '(', 'MHC)', 'Ib', '(', associated, with, type, 'I', 'fibers)', and, of, at, least, three, factors, involved, in, the, shift, toward, type, 'I', fibers, '[', 'p27kip1,', muscle, 'LIM', protein, '(', 'MLP),', cystein, rich, 'protein-2],', of, which, one, '(', 'MLP)', has, been, shown, to, enhance, the, activity, of, 'MyoD,', which, would, explain, the, known, increase, in, the, expression, of, skeletal, muscle, uncoupling, 'protein-3', '(', 'UCP3);', 'ii)', increased, lipoprotein, lipase, '(', 'LPL)', 'expression,', known, to, trigger, 'UCP3', 'transcription,', which, 'tends,', together, with, the, first, 'point,', to, underline, the, suggested, role, of, 'UCP3', in, mitochondrial, lipid, handling, '(', the, variations, under, the, first, point, and, this, one, have, not, been, observed, in, 'mice,', indicating, a, 'species-specific', regulation, of, these, 'mechanisms);', 'iii)', reduced, expression, of, the, 'muscle-specific', coenzyme, 'Q', '(', 'CoQ)7', 'gene,', which, is, necessary, for, mitochondrial, 'CoQ', 'synthesis,', together, with, an, increased, expression, of, mitochondrial, adenylate, kinase, 3, ',', which, inactivates, the, resident, key, enzyme, for, 'CoQ', 'synthesis,', 3, -, 'hydroxy-3-methylglutaryl', 'CoA', reductase, '(', 'HMGR),', the, mRNA, level, for, which, fell, during, 'fasting;', and, 'iv)', increased, transcription, of, components, of, the, proteasomal, pathways, involved, in, protein, 'degradation/turnover'])].
[sujeto(['Here,', we]), verbo([find]), complemento([that, correct, patterning, of, 'Hgf', expression, in, forelimb, buds, is, dependent, on, retinoic, acid, '(', 'RA)', synthesized, by, retinaldehyde, dehydrogenase, 2, '(', 'Raldh2)', expressed, proximally])].
[sujeto(['Met', and, 'MyoD', are]), verbo([expressed]), complemento([in, this, abnormal, 'domain,', indicating, that, myogenic, cell, migration, and, differentiation, are, occurring, in, the, absence, of, 'RA,', but, in, an, abnormal, location])].
[sujeto(['Expression', of, 'Bmp4,', an, inhibitor, of, 'Hgf', 'expression,', is]), verbo([increased]), complemento([and, shifted, anteroproximally, in, 'Raldh2(-/-)', limb, 'buds,', thus, encroaching, into, the, normal, expression, domain, of, 'Hgf'])].
[sujeto(['Our', studies]), verbo([suggest]), complemento([that, 'RA', signaling, provides, proximodistal, information, for, limb, buds, that, counterbalances, 'Bmp', 'signaling,', which, in, turn, helps, mediate, proximodistal, and, anteroposterior, patterning, of, 'Hgf', expression, to, correctly, direct, migration, of, 'Met-expressing', myogenic, precursor, cells])].
[sujeto(['Retinoids', '(', all, trans, and, 9, -, cis, retinoic, 'acid)', are, pleiotropic, regulators, of, cell, 'fate,', and]), verbo([have]), complemento([been, shown, to, regulate, the, expression, of, helix, loop, helix, transcription, factors, '(', e])].
[sujeto(['The', effects, of, retinoids, are]), verbo([mediated]), complemento([through, the, ligand, dependent, retinoic, acid, receptors, '(', 'RARs)', and, retinoid, 'X', receptors, '(', 'RXRs)'])].
[sujeto(['We']), verbo([have]), complemento([found, that, the, messenger, 'RNA', transcripts, encoding, 'RAR', are, repressed, during, differentiation, of, 'C2C12', myoblasts, 'while,', 'conversely,', 'RXR', mRNA, transcripts, are, induced, in, 'C2C12', myotubes])].
[sujeto(['The', 'Myf5', gene]), verbo([has]), complemento([both, in, vivo, and, in, vitro, expression, patterns, consistent, with, an, involvement, in, the, first, events, of, 'myogenesis,', such, as, acquisition, 'and/or', maintenance, of, myogenic, &, 'quot;determined"', phenotype])].
[sujeto(['We']), verbo([report]), complemento([here, that, retinoic, acid, '(', 'RA)', reduces, the, level, of, 'Myf5', message, in, both, mouse, 'C2', and, rat, 'L6', cell, 'lines,', probably, at, the, transcriptional, 'level,', because, 'Myf5', mRNA, stability, is, not, affected, by, 'RA'])].
[sujeto(['This', repression, is, dose, 'dependent,', starting, at, 0.1, microM, of, 'all-trans', 'RA,', and, is, not, abrogated, by, 'cycloheximide,']), verbo([suggesting]), complemento([a, direct, involvement, of, 'RA', receptors, in, the, control, of, 'Myf5', expression])].
[sujeto(['Furthermore,', we, compared, the, efficiency, of, natural, '(', 'all-trans', 'RA', and, 9, -, cis, 'RA)', or, synthetic, '(', 'TTNPB)', retinoids, that, differentially]), verbo([activate]), complemento([the, two, families, of, 'RA', 'receptors,', 'RA', receptors, and, retinoid, 'X-receptors', '(', 9, -, cis, 'RA)'])].
[sujeto(['As', 9, -, cis, 'RA', is, about, 10, times, more, efficient, than, 'all-trans', 'RA', in]), verbo([repressing]), complemento(['Myf5,', whereas, 'TTNPB,', which, preferentially, activates, 'RA', 'receptors,', is, far, less, 'potent,', our, data, provide, evidence, for, an, important, role, of, 'ligand-bound', retinoid, 'X-receptors', in, the, mediation, of, this, inhibition])].
[sujeto(['There', is]), verbo([increasing]), complemento([evidence, that, the, biological, activity, of, myostatin, '(', 'MSTN),', a, negative, regulator, of, muscle, 'growth,', is, affected, by, training, but, also, anabolic, steroids])].
[sujeto(['Md', treatment, resulted, in, a, significant, stimulation, of, anabolic, activity, of, the, levator, ani, 'muscle,', which, was, further]), verbo([increased]), complemento([by, 'training,', while, prostate, and, seminal, vesicle, weights, decreased, in, conformance, with, hormone, concentrations, of, 'LH', and, testosterone])].
[sujeto(['In', 'summary,', our, data, demonstrate, that, 'Md', treatment, of, intact, rats, results, in, anabolic, effects, which, are]), verbo([enhanced]), complemento([in, combination, with, physical, activity])].
[sujeto(['Interestingly,', the, anabolic, activity, on, the, levator, ani, was]), verbo([increased]), complemento([in, combination, with, 'training,', although, the, levator, ani, muscle, was, not, specifically, stimulated, by, our, training, protocol])].
[sujeto([gastrocnemius, and, 'soleus,', the, anabolic, effects, correlate, with, changes, in, the, expression, patterns, of, genes]), verbo([involved]), complemento([in, 'MSTN', signaling])].
[sujeto(['Our', data]), verbo([provide]), complemento([evidence, that, the, decrease, in, the, weight, of, 'androgen-sensitive', sexual, 'glands,', observed, after, 'Md', 'treatment,', is, caused, by, a, suppression, of, endogenous, testosterone, synthesis])].
[sujeto(['These', observations]), verbo([provide]), complemento([new, insights, into, the, molecular, mechanisms, of, the, interaction, between, anabolic, 'steroids,', training, and, 'MSTN', signaling, during, skeletal, muscle, adaptation])].
[sujeto(['We', recently]), verbo([reported]), complemento([increased, leg, lean, mass, and, strength, in, men, with, chronic, obstructive, pulmonary, disease, '(', 'COPD)', receiving, 10, wk, of, testosterone, '(', 'T)', and, leg, resistance, training, '(', 'R)', '(', 'Casaburi', 'R,', 'Bhasin', 'S,', 'Cosentino', 'L,', 'Porszasz', 'J,', 'Somfay', 'A,', 'Lewis', 'M,', 'Fournier', 'M,', 'Storer', 'T'])].
[sujeto(['While', no, significant, changes, in, fiber, 'CSAs', were, noted, across, 'groups,']), verbo([increased]), complemento([trends, were, observed, after, 10, 'wk,', and, significant, decrements, in, muscle, fiber, density, were, noted, in, all, treated, groups])].
[sujeto(['A', global]), verbo([increase]), complemento([in, all, myosin, heavy, chain, '(', 'MyHC)', mRNA, isoforms, was, observed, in, 'TR', patients])].
[sujeto(['Muscle', 'IGF-IEa', and, 'IGF-IEc', mRNAs, were, significantly]), verbo([increased]), complemento([with, 'TR', group])].
[sujeto(['Muscle', 'IGF-I', protein, was]), verbo([increased]), complemento([in, all, intervention, groups, '(', greatest, in, 'TR)'])].
[sujeto(['IGF']), verbo([binding]), complemento(['protein-4', mRNA, was, increased, with, 'TR'])].
[sujeto(['Myogenin', mRNA, was]), verbo([increased]), complemento([in, both, 'T', 'groups,', while, 'MyoD', and, myostatin, were, unchanged])].
[sujeto(['Muscle', atrophy, 'F-box', mRNA, tended, to]), verbo([increase]), complemento([with, 'TR'])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, the, combined, interventions, produced, an, enhanced, local, anabolic, milieu, driven, in, large, part, by, the, muscle, 'IGF', 'system,', despite, potentially, negative, biochemical, influences, present, in, 'COPD', patients])].
[sujeto(['Resting', serum, testosterone]), verbo([decreased]), complemento([significantly, '(', 'P', &, 'lt;', 0.01, ')', in, the, goserelin, group, from, 22.6, +, /, -, 1.6, '(', mean, +, /, -, s])].
[sujeto(['An', acute]), verbo([increase]), complemento([of, serum, testosterone, was, observed, during, the, final, 'ST', session, in, the, placebo, group, '(', 'P', &, 'lt;', 0.05, ')', ',', whereas, a, decreased, response, was, observed, in, the, goserelin, group, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto([mRNA, expression, of, 'IGF-IE(bc)', and, myogenin, 'increased,', while, expression, of, myostatin]), verbo([decreased]), complemento(['(', 'P', &, 'lt;', 0.01, ')', ;, 'however,', no, differences, were, observed, between, the, groups])].
[sujeto(['Muscle', strength, and, muscle, mass, showed, a, tendency, to]), verbo([increase]), complemento([more, in, the, placebo, group, than, in, the, goserelin, group, '(', 'P', =, 0.05, ')'])].
[sujeto(['Previous', studies, of, 'Delta', 4, -, 'androstene-3,17-dione', '(', 4, -, 'androstenedione)', administration, in, men]), verbo([have]), complemento([not, demonstrated, sustained, increments, in, testosterone, 'levels,', 'fat-free', mass, '(', 'FFM),', and, muscle, 'strength,', and, failure, to, demonstrate, 'androstenedione\'s', 'androgenic/anabolic', effects, has, stifled, efforts, to, regulate, its, sales])].
[sujeto(['To', determine, whether, 4, -, androstenedione]), verbo([has]), complemento(['androgenic/anabolic', 'properties,', we, evaluated, its, association, with, androgen, receptor, '(', 'AR)', and, its, effects, on, myogenesis, in, vitro])].
[sujeto(['AR']), verbo([nuclear]), complemento([translocation, and, myogenic, activity, of, androstenedione, were, evaluated, in, 'mesenchymal,', pluripotent, 'C3H10T1/2', 'cells,', in, which, androgens, stimulate, myogenesis, through, an, 'AR', pathway])].
[sujeto(['In', 'C3H10T1/2', 'cells,', 4, -, androstenedione]), verbo([caused]), complemento([nuclear, translocation, of, 'AR', and, stimulated, 'myogenesis,', as, indicated, by, a, 'dose-dependent', increase, in, myosin, heavy, chain, 'II+', myotube, area, and, 'up-regulation', of, 'MyoD', protein])].
[sujeto(['Administration', of, 1500, mg, 4, -, androstenedione, daily, to, hypogonadal, men, significantly]), verbo([increased]), complemento([serum, 'androstenedione,', total, and, free, 'testosterone,', 'estradiol,', and, estrone, levels, and, suppressed, 'SHBG', and, 'high-density', lipoprotein, cholesterol, levels])].
[sujeto([4, -, androstenedione, administration, was]), verbo([associated]), complemento([with, significant, gains, in, 'FFM', '(', +, 1.7, +, /, -, 0.5, 'kg;', 'P', =, 0.012, ')', and, muscle, strength, in, bench, press, '(', +, 4.3, +, /, -, 3.1, 'kg;', 'P', =, 0.006, ')', and, leg, press, exercises, '(', +, 18.8, +, /, -, 17.3, 'kg;', 'P', =, 0.045, ')'])].
[sujeto([4, -, androstenedione, is, an, androgen, that]), verbo([binds]), complemento(['AR,', induces, 'AR', nuclear, 'translocation,', and, promotes, myogenesis, in, 'vitro,', with, substantially, lower, potency, than, dihydrotestosterone])].
[sujeto([4, -, androstenedione, administration, in, high, doses, to, hypogonadal, men]), verbo([increases]), complemento([testosterone, 'levels,', 'FFM,', and, muscle, 'strength,', although, at, the, dose, 'tested,', the, anabolic, effects, in, hypogonadal, men, are, likely, because, of, its, conversion, to, testosterone])].
[sujeto(['Testosterone', supplementation]), verbo([increases]), complemento([skeletal, muscle, mass, and, decreases, fat, 'mass;', 'however,', the, underlying, mechanisms, are, unknown])].
[sujeto(['We', hypothesized, that, testosterone]), verbo([regulates]), complemento([body, composition, by, promoting, the, commitment, of, mesenchymal, pluripotent, cells, into, myogenic, lineage, and, inhibiting, their, differentiation, into, adipogenic, lineage])].
[sujeto(['Adipogenic', differentiation, was, assessed, by, adipocyte, counting, and, by, measurements, of, peroxisomal, 'proliferator-activated', receptor, gamma, 2, '(', 'PPAR', gamma, 2, ')', mRNA, and, 'PPAR', gamma, 2, protein, and, 'CCAAT/enhancer']), verbo([binding]), complemento([protein, alpha])].
[sujeto(['The', number, of, 'MyoD+', myogenic, cells, and, 'MHC+', myotubes, and, 'MyoD', and, 'MHC', mRNA, and, protein, levels]), verbo([increased]), complemento([dose, dependently, in, response, to, testosterone, and, 'DHT', treatment])].
[sujeto(['Both', testosterone, and, 'DHT']), verbo([decreased]), complemento([the, number, of, adipocytes, and, 'down-regulated', the, expression, of, 'PPAR', gamma, 2, mRNA, and, 'PPAR', gamma, 2, protein, and, 'CCAAT/enhancer', binding, protein, alpha])].
[sujeto(['Androgen', receptor, mRNA, and, protein, levels, were, low, at, baseline, but]), verbo([increased]), complemento([after, testosterone, or, 'DHT', treatment])].
[sujeto(['Therefore,', testosterone, and, 'DHT']), verbo([regulate]), complemento([lineage, determination, in, mesenchymal, pluripotent, cells, by, promoting, their, commitment, to, the, myogenic, lineage, and, inhibiting, their, differentiation, into, the, adipogenic, lineage, through, an, androgen, 'receptor-mediated', pathway])].
[sujeto(['The', observation, that, differentiation, of, pluripotent, cells, is, androgen, dependent]), verbo([provides]), complemento([a, unifying, explanation, for, the, reciprocal, effects, of, androgens, on, muscle, and, fat, mass, in, men])].
[sujeto(['Evidence']), verbo([has]), complemento([accumulated, that, suggests, that, 'insulin-like', growth, factors, '(', 'IGFs)', exert, a, positive, influence, on, myoblast, differentiation])].
[sujeto(['We']), verbo([have]), complemento([undertaken, to, study, the, signalling, events, required, for, differentiation, resulting, from, 'type-1', 'IGF', receptor, stimulation, in, 'C2', 'myoblasts,', where, autocrine, production, of, 'IGF-II', was, abolished, by, means, of, antisense, 'RNA'])].
[sujeto(['Exposure', of, the, cells, to, 'IGFs']), verbo([leads]), complemento([to, a, rapid, and, sustained, activation, of, 'phosphatidyl-inositol', 3, -, kinase, followed, by, the, expression, of, 'Myod,', myogenin, and, differentiation])].
[sujeto(['The', fungal, 'metabolite,', 'wortmannin,']), verbo([inhibits]), complemento([both, 'PI', 3, -, kinase, and, muscle, differentiation, with, an, 'IC', 50, in, the, nanomolar, range])].
[sujeto(['IGFs', are, also, known, to]), verbo([cause]), complemento([a, rapid, activation, of, 'MAP', kinase])].
[sujeto(['However,', the, synthetic, inhibitor, of, 'MEK,', 'PD098059,', which]), verbo([prevents]), complemento(['MAP', kinase, 'activation,', does, not, affect, myoblast, differentiation])].
[sujeto(['These', results]), verbo([provide]), complemento([evidence, that, 'PI', 3, -, 'kinase,', but, not, 'MAP', 'kinase,', is, required, for, 'insulin-like', growth, factor, 'receptor-dependent', differentiation, of, muscle, cells])].
[sujeto(['Skeletal', muscle, differentiation]), verbo([involves]), complemento([myoblast, 'alignment,', 'elongation,', and, fusion, into, multinucleate, 'myotubes,', together, with, the, induction, of, regulatory, and, structural, 'muscle-specific', genes])].
[sujeto(['Upon', serum, 'withdrawal,', 10, 'T1/2-MyoD', cells, formed, myotubes, and, showed]), verbo([increased]), complemento([levels, of, myogenin, and, p21])].
[sujeto(['In', 'contrast,', 'LY294002-treated', cells, exhibited, none, of, these, myogenic, characteristics, and]), verbo([maintained]), complemento([high, levels, of, 'Id,', a, negative, regulator, of, myogenesis])].
[sujeto(['The', 'cyclin-dependent-kinase', inhibitors, p21, and, p57, are, highly]), verbo([expressed]), complemento([in, skeletal, muscle, where, they, redundantly, control, cell, cycle, arrest, during, differentiation])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, p57, is, a, target, of, the, myogenic, factor, 'MyoD', in, cells, lacking, p21])].
[sujeto(['Here', we, show, that, 'MyoD']), verbo([induces]), complemento([p57, at, the, transcriptional, level, through, a, mechanism, different, from, that, involved, in, p21, 'regulation,', since, it, is, 'E-box-independent', and, requires, new, synthesized, 'protein(s)'])].
[sujeto(['We']), verbo([have]), complemento([identified, p73, family, members, as, the, factors, that, mediate, the, activation, of, p57, through, a, 165, bp, promoter, region])].
[sujeto(['The', levels, of, p73, 'alpha,', beta, and, delta, isoforms]), verbo([increase]), complemento([during, muscle, differentiation, both, in, 'MyoD-expressing', fibroblasts, and, in, spontaneously, differentiating, 'C2', myoblasts])].
[sujeto(['Finally,', each, of, the, isoforms, 'up-regulated', by, 'MyoD,', even, when, 'over-expressed', 'alone,', is, capable, of]), verbo([inducing]), complemento([p57, in, 'p21-lacking', fibroblasts])].
[sujeto(['In', 'contrast,', the, same, p73, 'isoforms,', either]), verbo([induced]), complemento([by, 'MyoD', or, exogenously, 'over-expressed,', are, unable, to, activate, the, expression, of, p57, in, 'p21-expressing', fibroblasts])].
[sujeto(['Our']), verbo([finding]), complemento([that, a, transfected, p57, 'promoter-reporter', 'construct,', unlike, the, endogenous, 'gene,', is, responsive, to, both, 'MyoD', and, p73, even, in, these, 'cells,', suggests, that, a, 'cis-acting', 'mechanism,', probably, involving, a, repressive, chromatin, 'structure,', prevents, the, induction, of, p57, in, 'p21-expressing', fibroblasts])].
[sujeto(['Myogenic', regulatory, factors, of, the, 'MyoD', family]), verbo([have]), complemento([the, ability, to, reprogram, differentiated, cells, toward, a, myogenic, fate])].
[sujeto(['In', this, 'study,', we, demonstrate, that, 'Six1', or, 'Six4', are]), verbo([required]), complemento([for, the, reprogramming, by, 'MyoD', of, mouse, embryonic, fibroblasts, '(', 'MEFs)'])].
[sujeto(['Using', microarray, 'experiments,', we]), verbo([found]), complemento([761, genes, under, the, control, of, both, 'Six', and, 'MyoD'])].
[sujeto(['Using', 'MyoD', 'ChIPseq', data, and, a, 'genome-wide', search, for, 'Six1/4', 'MEF3']), verbo([binding]), complemento(['sites,', we, found, significant, 'co-localization', of, binding, sites, for, 'MyoD', and, 'Six', proteins, on, over, a, thousand, mouse, genomic, 'DNA', regions])].
[sujeto(['The', combination, of, both, datasets, yielded, 82, genes, which, are, synergistically]), verbo([activated]), complemento([by, 'Six', and, 'MyoD,', with, 96, associated, 'MyoD+MEF3', putative, 'cis-regulatory', modules, '(', 'CRMs)'])].
[sujeto(['We', searched, putative]), verbo([binding]), complemento([sites, on, these, 'CRMs', using, available, databases, and, de, novo, search, of, conserved, motifs, and, demonstrated, that, the, 'Six/MyoD', synergistic, activation, takes, place, in, a, feedforward, way])].
[sujeto(['It']), verbo([involves]), complemento([the, recruitment, of, these, two, families, of, transcription, factors, to, their, 'targets,', together, with, partner, transcription, 'factors,', encoded, by, genes, that, are, themselves, activated, by, 'Six', and, 'MyoD,', including, 'Mef2,', 'Pbx-Meis', and, 'EBF'])].
[sujeto(['The', 'Peg3', '(', 'Paternally', 'Expressed', 'Gene', 3, ')', imprinted, domain, is, predicted, to, be]), verbo([regulated]), complemento([through, a, large, number, of, evolutionarily, conserved, regions, '(', 'ECRs)', that, are, localized, within, its, middle, 200, -, kb, region])].
[sujeto(['Phylogenetic', and, bioinformatic, analyses, further, revealed, that, several, 'cis-regulatory', motifs, are, frequently]), verbo([associated]), complemento([with, the, 'ECRs,', such, as, the, 'E', 'box,', 'PITX2,', 'NF-κB', and, 'RFX1', motifs])].
[sujeto(['A', series, of, subsequent, 'ChIP', experiments, demonstrated, that, the, trans, factor, 'MYOD', indeed]), verbo([binds]), complemento([to, the, 'E', box, of, several, 'ECRs,', further, suggesting, that, 'MYOD', may, play, significant, roles, in, the, transcriptional, control, of, the, 'Peg3', domain])].
[sujeto(['Emerging', studies, document, the, roles, of, long, 'non-coding', 'RNAs', '(', 'LncRNAs)', in]), verbo([regulating]), complemento([gene, expression, at, chromatin, level, but, relatively, less, is, known, how, they, regulate, 'DNA', methylation])].
[sujeto(['Here', we, identify, an, 'lncRNA,', 'Dum', '(', developmental, 'pluripotency-associated', 2, '(', 'Dppa2)', 'Upstream']), verbo([binding]), complemento(['Muscle', 'lncRNA)', in, skeletal, myoblast, cells])].
[sujeto(['The', expression, of, 'Dum', is, dynamically]), verbo([regulated]), complemento([during, myogenesis, in, vitro, and, in, vivo])].
[sujeto(['It', is, also, transcriptionally]), verbo([induced]), complemento([by, 'MyoD', binding, upon, myoblast, differentiation])].
[sujeto(['Functional', analyses, show, that, it]), verbo([promotes]), complemento([myoblast, differentiation, and, 'damage-induced', muscle, regeneration])].
[sujeto(['Mechanistically,', 'Dum', was]), verbo([found]), complemento([to, silence, its, neighboring, 'gene,', 'Dppa2,', in, cis, through, recruiting, 'Dnmt1,', 'Dnmt3a', and, 'Dnmt3b'])].
[sujeto(['Collectively,', we]), verbo([have]), complemento([identified, a, novel, lncRNA, that, interacts, with, 'Dnmts', to, regulate, myogenesis])].
[sujeto(['Wnt', proteins, are, secreted, cytokines, and, several, 'Wnts', are]), verbo([expressed]), complemento([in, the, developing, somites, and, surrounding, tissues])].
[sujeto(['These', 'Wnt', signals, received, by, somitic, cells, can]), verbo([lead]), complemento([to, activation, of, 'Pax3/Pax7', and, myogenic, regulatory, factors, '(', 'MRFs),', especially, 'Myf5', and, 'MyoD'])].
[sujeto(['However,', it, is, currently, unknown, whether, 'Wnts']), verbo([activate]), complemento(['Myf5', and, 'MyoD', through, direct, targeting, of, their, 'cis-regulatory', elements, or, via, indirect, pathways])].
[sujeto(['We']), verbo([found]), complemento([that, 'Wnt3a', activated, the, 'MyoD', proximal, 6.0, k, promoter, '(', 'P6P)', only, 'marginally,', but, highly, enhanced, the, activity, of, the, composite, 'P6P', plus, distal, enhancer, '(', 'DE)', reporter, through, canonical, and, 'non-canonical', pathways])].
[sujeto(['Further', screening, of, the, intervening, fragments, between, the, 'DE', and, the, 'P6P', identified, a, strong, 'Wnt-response', element, '(', 'WRE)', in, the, upstream, -, 8, to, -, 9, k, region, '(', 'L', 'fragment)', that]), verbo([acted]), complemento([independently, of, the, 'DE,', but, was, dependent, on, the, 'P6P'])].
[sujeto(['Deletion', of, a, 'Pax3/Pax7-targeted', site, in, the, 'L', fragment, significantly, reduced, its, response, to, 'Wnt3a,', implying, that, 'Wnt3a']), verbo([activates]), complemento([the, 'L', fragment, partially, through, 'Pax3/Pax7', action])].
[sujeto(['Binding', of, 'β-catenin', and, 'Pax7', to, their]), verbo([target]), complemento([sites, in, the, 'DE', and, the, 'L', fragment, respectively, was, also, demonstrated, by, 'ChIP'])].
[sujeto(['These', observations, demonstrated, the, first, time, that, 'Wnt3a', can, directly]), verbo([activate]), complemento(['MyoD', expression, through, targeting, 'cis-elements', in, the, 'DE', and, the, 'L', fragment])].
[sujeto(['MUNC', is, specifically]), verbo([expressed]), complemento([in, skeletal, muscle, and, exists, as, in, unspliced, and, spliced, 'isoforms,', and, its, 5, '\'', end, overlaps, with, the, 'cis-acting', distal, regulatory, region, '(', 'DRR)', of, 'MyoD'])].
[sujeto(['Stable', overexpression, of, 'MUNC', from, a, heterologous, promoter]), verbo([increased]), complemento([endogenous, 'MyoD,', 'Myogenin,', and, 'Myh3', '(', myosin, heavy, 'chain,', '[', 'MHC]', 'gene)', mRNAs, but, not, the, cognate, 'proteins,', suggesting, that, 'MUNC', can, act, in, trans, to, promote, gene, expression, but, that, this, activity, does, not, require, an, induction, of, 'MyoD', protein])].
[sujeto(['MUNC', also]), verbo([stimulates]), complemento([the, transcription, of, other, genes, that, are, not, recognized, as, 'MyoD-inducible', genes])].
[sujeto(['We', also, discovered, a, human, 'MUNC', that, is]), verbo([induced]), complemento([during, differentiation, of, myoblasts, and, whose, knockdown, decreases, 'differentiation,', suggesting, an, evolutionarily, conserved, role, of, 'MUNC', lncRNA, in, myogenesis])].
[sujeto(['Although', 'MUNC', overlaps, with, the, 'DRR', 'enhancer,', our, results]), verbo([suggest]), complemento([that, 'MUNC', is, not, a, classic, 'cis-acting', enhancer, 'RNA', '(', 'e-RNA)', acting, exclusively, by, stimulating, the, neighboring, 'MyoD', gene, but, more, like, a, promyogenic, lncRNA, that, acts, directly, or, indirectly, on, multiple, promoters, to, increase, myogenic, gene, expression])].
[sujeto(['However,', only, with, the, emergence, of, 'genome-wide', techniques]), verbo([has]), complemento([the, genuine, biological, scope, of, enhancers, begun, to, be, fully, uncovered])].
[sujeto(['Massive', scientific, efforts, of, multiple, laboratories, rapidly, advanced, the, overall, perception, that, enhancers, are, typified, by, common, epigenetic, characteristics, that, distinguish, their]), verbo([activating]), complemento([potential])].
[sujeto(['Broadly,', chromatin, modifiers, and, transcriptional, regulators, lay, down, the, essential, foundations, necessary, for, constituting, enhancers, in, their]), verbo([activated]), complemento([form])].
[sujeto(['Basing', on, 'genome-wide', 'ChIP-sequencing', of, 'enhancer-related', marks, we, identified, myogenic, enhancers, before, and, after, muscle, differentiation, and, discovered, that, 'MyoD', was]), verbo([bound]), complemento([to, nearly, a, third, of, 'condition-specific', enhancers])].
[sujeto(['Experimental', studies, that, tested, the, deposition, patterns, of, 'enhancer-related', epigenetic, marks, in, 'MyoD-null', myoblasts, revealed, the, high, dependency, that, a, specific, set, of, muscle, enhancers]), verbo([have]), complemento([towards, this, transcriptional, regulator])].
[sujeto(['Our', proposed, mechanistic, model]), verbo([suggests]), complemento([that, 'MyoD', is, involved, in, recruitment, of, methyltransferase, 'Set7,', acetyltransferase, p300, and, deposition, of, 'H3K4me1', and, 'H3K27ac', at, myogenic, enhancers])].
[sujeto(['In', 'addition,', 'MyoD']), verbo([binding]), complemento([at, enhancers, is, associated, with, 'PolII', occupancy, and, with, local, noncoding, transcription])].
[sujeto(['Modulation', of, muscle, enhancers, is]), verbo([suggested]), complemento([to, be, coordinated, via, transcription, factors, 'docking,', including, 'c-Jun', and, 'Jdp2', that, bind, to, muscle, enhancers, in, a, 'MyoD-dependent', manner])].
[sujeto(['We', hypothesize, that, distinct, transcription, factors, may]), verbo([act]), complemento([as, placeholders, and, mediate, the, assembly, of, newly, formed, myogenic, enhancers])].
[sujeto(['TBX1', encodes, a, transcription, factor, protein, that, contains, an, evolutionarily]), verbo([conserved]), complemento(['DNA', binding, domain, termed, the, 'T-box', that, is, shared, with, other, family, members])].
[sujeto(['All', 'T-box', 'proteins,', examined, so, 'far,']), verbo([bind]), complemento([to, similar, but, not, identical, consensus, 'DNA', 'sequences,', indicating, that, they, have, specific, binding, preferences])].
[sujeto(['In', contrast, to, other, 'TBX', family, members]), verbo([recognizing]), complemento([palindrome, 'sequences,', we, found, that, 'TBX1', preferentially, binds, to, a, tandem, repeat, of, 5, '\'', -, 'AGGTGTGAAGGTGTGA-3\''])].
[sujeto(['We', show, that, three, known, human, 'disease-causing', 'TBX1', missense, mutations, '(', 'F148Y,', 'H194Q', and, 'G310S)', do, not, alter]), verbo([nuclear]), complemento(['localization,', or, disrupt, binding, to, the, tandem, repeat, consensus, 'sequences,', but, they, reduce, transcriptional, activity, in, cell, culture, reporter, assays])].
[sujeto(['To', identify, 'Tbx1-downstream', 'genes,', we, performed, an, in, silico, genome, wide, analysis, of, potential, 'cis-acting', elements, in, 'DNA', and]), verbo([found]), complemento([strong, enrichment, of, genes, required, for, developmental, processes, and, transcriptional, regulation])].
[sujeto(['We']), verbo([found]), complemento([that, 'TBX1', binds, to, 19, different, loci, in, 'vitro,', which, may, correspond, to, putative, 'cis-acting', binding, sites])].
[sujeto(['In', situ, hybridization, coupled, with, luciferase, gene, reporter, assays, on, three, gene, 'loci,', 'Fgf8,', 'Bmper,', 'Otog-MyoD,', show, that, these, motifs, are, directly]), verbo([regulated]), complemento([by, 'TBX1', in, vitro])].
[sujeto(['Collectively,', the, present, studies, establish, new, insights, into, molecular, aspects, of, 'TBX1']), verbo([binding]), complemento([to, 'DNA'])].
[sujeto(['Its', transcription, is, mainly]), verbo([regulated]), complemento([by, peroxisome, 'proliferator-activated', receptors, '(', 'PPAR),', a, family, of, nuclear, hormone, receptors])].
[sujeto(['We', demonstrate]), verbo([binding]), complemento([of, 'SP1', and, 'SP3', to, this, element, which, is, adjacent, to, a, direct, repeat, 1, element, mediating, activation, of, 'UCP3', expression, by, 'PPARγ', agonists])].
[sujeto(['Transactivation']), verbo([mediated]), complemento([by, these, elements, is, interdependent, and, indispensable, for, 'UCP3', expression])].
[sujeto(['Systematic', deletion, uncovered, a, third]), verbo([binding]), complemento(['element,', a, putative, 'NF1', 'site,', in, close, proximity, to, the, 'SP1/3', and, 'PPARγ', binding, elements])].
[sujeto(['Data', mining, demonstrated]), verbo([binding]), complemento([of, 'MyoD', and, 'Myogenin', to, this, third, element, in, 'C2C12', 'cells,', 'and,', 'furthermore,', revealed, recruitment, of, p300])].
[sujeto(['Taken', 'together,', this, intronic, region, is, the, main, enhancer, driving, 'UCP3', expression, with, 'SP1/3', and, 'PPARγ', as, the, core, factors]), verbo([required]), complemento([for, expression])].
[sujeto(['Although', numerous, attempts]), verbo([have]), complemento([been, made, to, identify, these, 'combinations,', important, 'details,', such, as, mutual, positioning, of, the, factors, that, have, an, important, role, in, the, 'TF', 'interplay,', are, still, missing])].
[sujeto(['The', goal, of, the, present, work, is, in, silico, mapping, of, some, of, such]), verbo([associating]), complemento([factors, based, on, their, mutual, 'positioning,', using, computational, screening])].
[sujeto(['We']), verbo([have]), complemento([selected, the, process, of, myogenesis, as, a, study, 'case,', and, we, focused, on, 'TF', combinations, involving, master, myogenic, 'TF', 'Myogenic', differentiation, '(', 'MyoD)', with, other, factors, situated, at, specific, distances, from, it])].
[sujeto(['However,', we]), verbo([have]), complemento([also, found, novel, relationships, of, 'MyoD', with, other, factors, not, specific, for, muscle])].
[sujeto(['Additionally,', we]), verbo([have]), complemento([observed, that, 'MyoD', tends, to, associate, with, different, factors, in, proximal, and, distal, promoter, areas])].
[sujeto(['The', major, outcome, of, our, study, is, establishing, the, 'genome-wide', connection, between, biological, interactions, of, 'TFs', and, close, 'co-occurrence', of, their]), verbo([binding]), complemento([sites])].
[sujeto(['Identifying', gene, regulatory, elements, and, their]), verbo([target]), complemento([genes, in, vertebrates, remains, a, significant, challenge])].
[sujeto(['It', is, now]), verbo([recognized]), complemento([that, transcriptional, regulatory, sequences, are, critical, in, orchestrating, dynamic, controls, of, 'tissue-specific', gene, expression, during, vertebrate, development, and, in, adult, 'tissues,', and, that, these, elements, can, be, positioned, at, great, distances, in, relation, to, the, promoters, of, the, genes, they, control])].
[sujeto(['While', significant, progress]), verbo([has]), complemento([been, made, in, mapping, 'DNA', binding, regions, by, combining, chromatin, immunoprecipitation, and, next, generation, 'sequencing,', functional, validation, remains, a, limiting, step, in, improving, our, ability, to, correlate, in, silico, predictions, with, biological, function])].
[sujeto(['We', applied, this, method, to, 270, genes, highly]), verbo([expressed]), complemento([in, skeletal, muscle, and, predicted, 190, putative, 'cis-regulatory', modules])].
[sujeto(['We']), verbo([found]), complemento([45, '%', of, these, elements, expressed, only, in, the, fast, muscle, fibers, that, are, oriented, in, highly, organized, chevrons, in, the, 'Xenopus', laevis, tadpole])].
[sujeto(['Transcription', factor]), verbo([binding]), complemento([site, analysis, identified, &, 'gt;2', 'Mef2/MyoD', sites, within, '~200', bp, regions, in, 6, of, the, validated, 'enhancers,', and, systematic, mutagenesis, of, these, sites, revealed, that, they, are, critical, for, the, enhancer, function])].
[sujeto(['Skeletal', muscle, development, is, orchestrated, by, the, myogenic, regulatory, factor, 'MyoD,', whose, activity, is, blocked, in, myoblasts, by, proteins]), verbo([preventing]), complemento([its, nuclear, translocation, 'and/or', binding, to, 'G/C-centered', 'E-boxes', in, target, genes])].
[sujeto(['Recent', evidence, indicates, that, muscle, gene, expression, is, also]), verbo([regulated]), complemento([at, the, cis, level, by, differential, affinity, for, 'DNA', between, 'MyoD', and, other, 'E-box', binding, proteins, during, myogenesis])].
[sujeto(['MyoD']), verbo([binds]), complemento([to, 'G/C-centered', 'E-boxes,', enriched, in, muscle, differentiation, 'genes,', in, myotubes, but, not, in, myoblasts])].
[sujeto(['Here,', we, used, 'cell-based', and, in, vivo, 'Drosophila,', 'Xenopus', 'laevis,', and, mouse, models, to, show, that, 'ZEB1,', a, 'G/C-centered', 'E-box']), verbo([binding]), complemento([transcriptional, 'repressor,', imposes, a, temporary, 'stage-dependent', inhibition, of, muscle, gene, expression, and, differentiation, via, 'CtBP-mediated', transcriptional, repression])].
[sujeto(['We']), verbo([found]), complemento(['that,', contrary, to, 'MyoD,', 'ZEB1', binds, to, 'G/C-centered', 'E-boxes', in, muscle, differentiation, genes, at, the, myoblast, stage, but, not, in, myotubes])].
[sujeto(['Inhibition', of, muscle, genes, by, 'ZEB1', occurs, via, transcriptional, repression, and]), verbo([involves]), complemento([recruitment, of, the, 'CtBP', corepressor])].
[sujeto(['Lastly,', we, show, that, the, pattern, of, gene, expression]), verbo([associated]), complemento([with, muscle, differentiation, is, accelerated, in, 'ZEB1(-/-)', mouse, embryos])].
[sujeto(['The', 'up-regulation', of, the, cdk, inhibitor, p57kip2, plays, a, critical, role, in, coordinating, differentiation, and, growth]), verbo([arrest]), complemento([during, muscle, 'development,', as, well, as, in, other, tissues])].
[sujeto(['We']), verbo([have]), complemento([identified, an, unexpected, mechanism, by, which, 'MyoD', regulates, p57kip2, transcription, in, differentiating, muscle, cells])].
[sujeto(['We', show, that, the, induction, of, p57kip2]), verbo([requires]), complemento(['MyoD', binding, to, a, 'long-distance', element, located, within, the, imprinting, control, region, 'KvDMR1', and, the, consequent, release, of, a, chromatin, loop, involving, p57kip2, promoter])].
[sujeto(['We', also, show, that, 'differentiation-dependent', regulation, of, 'p57kip2,', while]), verbo([involving]), complemento([a, region, implicated, in, the, imprinting, 'process,', is, distinct, and, hierarchically, subordinated, to, the, imprinting, control])].
[sujeto(['These', findings, highlight, a, novel, 'mechanism,']), verbo([involving]), complemento([the, modification, of, higher, order, chromatin, 'structures,', by, which, 'MyoD', regulates, gene, expression])].
[sujeto(['Our', results, also]), verbo([suggest]), complemento([that, chromatin, folding, mediated, by, 'KvDMR1', could, account, for, the, highly, restricted, expression, of, p57kip2, during, development, 'and,', 'possibly,', for, its, aberrant, silencing, in, some, pathologies])].
[sujeto(['The', rate, of, predictive, success]), verbo([reveals]), complemento([striking, limitations, of, computational, regulatory, sequence, analysis, methods, for, 'CRM', discovery])].
[sujeto(['The', myosin, heavy, chain, 'gene,', 'MYH(M743-2),', is, highly]), verbo([expressed]), complemento([in, fast, muscle, fibers, of, torafugu, embryos, and, 'larvae,', suggesting, its, functional, roles, for, embryonic, and, larval, muscle, development])].
[sujeto(['However,', the, transcriptional, regulatory, mechanism]), verbo([involved]), complemento([in, its, expression, remained, unknown])].
[sujeto(['The', immunohistochemical, observation, revealed, that, the, zebrafish, larvae, from, the, stable, transgenic, line, consistently]), verbo([expressed]), complemento([enhanced, green, fluorescent, protein, '(', 'EGFP)', in, fast, muscle, fibers])].
[sujeto(['We', discovered, that, the, serum, response, factor, '(', 'SRF)-like']), verbo([binding]), complemento([sites, are, required, for, promoting, 'MYH(M743-2)', expression, and, myoblast, determining, factor, '(', 'MyoD)', and, myocyte, enhancer, 'factor-2', '(', 'MEF2)', binding, sites, participate, in, the, transcriptional, control, of, 'MYH(M743-2)', expression, in, fast, skeletal, muscles])].
[sujeto(['We', further, discovered, that, 'MyoD']), verbo([binding]), complemento(['sites,', but, not, 'MEF2,', participate, in, the, transcriptional, regulation, of, 'MYH(M743-2)', expression, in, pectoral, fin, and, craniofacial, muscles])].
[sujeto(['Skeletal', muscle, and, kidney, enriched, inositol, phosphatase, '(', 'SKIP)', was, identified, as, a, 5, '\'', -, inositol, phosphatase, that, hydrolyzes, 'PI(3,4,5)P3', to, 'PI(3,4)P2', that, negatively]), verbo([regulates]), complemento(['insulin-induced', phosphatidylinositol, 3, -, kinase, signaling, in, skeletal, muscle])].
[sujeto([5, ')', ',', and, allele, 'G', seemed, to, be]), verbo([associated]), complemento([with, an, increase, in, the, growth, trait])].
[sujeto(['Porcine', 'SKIP', was]), verbo([expressed]), complemento([abundantly, in, skeletal, muscle, tissue, and, was, transcriptionally, upregulated, during, skeletal, muscle, differentiation])].
[sujeto(['Analysis', of, the, porcine, 'SKIP', promoter, sequence, demonstrated, that, 'MyoD', was]), verbo([involved]), complemento([in, regulating, 'SKIP', mRNA, expression, in, 'myotubes,', partly, via, the, 'cis-acting', elements, in, 'SKIP', promoter])].
[sujeto(['In', 'summary,', we]), verbo([suggested]), complemento([that, 'SKIP', might, play, a, role, in, the, regulation, of, skeletal, muscle, development, in, pigs])].
[sujeto(['Diet-induced', weight]), verbo([loss]), complemento([is, affected, by, a, wide, range, of, 'factors,', including, genetic, variation])].
[sujeto(['Previously,', we]), verbo([reported]), complemento([a, strong, association, between, a, common, single, nucleotide, polymorphism, '(', 'SNP)', rs2419621, '(', 'C>T)', in, the, promoter, of, 'acyl-CoA', synthetase, long, chain, 5, '(', 'ACSL5),', rapid, weight, loss, in, obese, 'Caucasian', 'females,', and, elevated, 'ACSL5', mRNA, levels, in, skeletal, muscle, biopsies])].
[sujeto(['Here,', we, showed, by, electrophoretic, mobility, shift, assay, '(', 'EMSA)', that, the, 'T', allele, creates, a, functional, 'cis-regulatory', 'E-box', element, '(', 'CANNTG)', that, is]), verbo([recognized]), complemento([by, the, myogenic, regulatory, factor, 'MyoD'])].
[sujeto(['The', 'T', allele]), verbo([promoted]), complemento(['MyoD-dependent', activation, of, a, 1089, -, base, pair, 'ACSL5', promoter, fragment, in, nonmuscle, 'CV1', cells])].
[sujeto(['These', results]), verbo([reveal]), complemento([a, mechanism, for, elevated, transcription, of, 'ACSL5', in, skeletal, muscle, of, carriers, of, the, 'rs2419621(T)', 'allele,', associated, with, more, rapid, 'diet-induced', weight, loss])].
[sujeto(['In', the, current, 'study,', treatment, of, the, rat, osteogenic, cell, line, 'ROB-C26', cells, with, fibroblast, growth, factor, 8, '(', 'FGF8)']), verbo([stimulated]), complemento([alkaline, phosphatase, '(', 'ALP)', 'activity,', and, also, induced, the, expression, of, the, 'Runx2', transcription, 'factor,', and, increased, the, activity, of, a, luciferase, reporter, gene, containing, the, osteocalcin, '(', 'OCN)', promoter, and, six, copies, of, the, osteoblast, specific, 'cis-acting', element, 2, '(', 'OSE2)', response, element])].
[sujeto(['In', 'contrast,', 'FGF8', treatment, of, the, mouse, myoblast, cell, line, 'C2C12']), verbo([inhibited]), complemento([the, expression, of, desmin, and, the, synthesis, of, myotubes])].
[sujeto(['The', expression, of, 'MyoD,', 'Myogenin,', 'Foxc2,', and, 'Hand1', was, also]), verbo([decreased]), complemento([by, 'FGF8'])].
[sujeto(['Transient', expression, of, 'Foxc2', in, 'C2C12', cells]), verbo([induced]), complemento([the, expression, of, 'Hand1,', and, chromatin, immunoprecipitation, '(', 'ChIP)', analysis, indicated, that, 'Foxc2', binds, to, the, promoter, region, of, the, 'Hand1', gene])].
[sujeto(['These', results, indicated, that, 'Foxc2', is, directly]), verbo([involved]), complemento([in, the, regulation, of, 'Hand1', expression])].
[sujeto(['The', results, of, the, current, study, indicate, that, 'FGF8']), verbo([regulates]), complemento([myoblast, differentiation, through, the, regulation, of, 'MyoD', 'expression,', and, that, this, regulation, is, independent, of, 'Hand1', in, cultured, cells])].
[sujeto(['Facioscapulohumeral', muscular, dystrophy, '(', 'FSHD)', is]), verbo([caused]), complemento([by, an, unusual, deletion, with, neomorphic, activity])].
[sujeto(['This', deletion, derepresses, genes, in, 'cis;', however, which, candidate, gene]), verbo([causes]), complemento([the, 'FSHD', 'phenotype,', and, through, what, 'mechanism,', is, unknown])].
[sujeto(['We', compare, the, effects, of]), verbo([expressing]), complemento([variable, levels, of, each, 'FSHD', candidate, gene, on, myoblasts])].
[sujeto(['DUX4', expression, recapitulates, key, features, of, the, 'FSHD', molecular, 'phenotype,', including, repression, of, 'MyoD', and, its]), verbo([target]), complemento(['genes,', diminished, myogenic, 'differentiation,', repression, of, glutathione, redox, pathway, 'components,', and, sensitivity, to, oxidative, stress])].
[sujeto(['We', further, demonstrate, competition, between, 'DUX4', and, 'Pax3/Pax7:', when, either, 'Pax3', or, 'Pax7', is]), verbo([expressed]), complemento([at, high, 'levels,', 'DUX4', is, no, longer, toxic])].
[sujeto(['We', propose, a, hypothesis, for, 'FSHD', in, which, 'DUX4', expression, interferes, with, 'Pax7', in, satellite, 'cells,', and, inappropriately]), verbo([regulates]), complemento(['Pax', 'targets,', including, myogenic, regulatory, 'factors,', during, regeneration])].
[sujeto(['We', show, that, a, highly]), verbo([conserved]), complemento([17, -, bp, 'DNA', 'cis-acting', sequence, element, located, upstream, of, the, myogenin, promoter, '(', 'myogHCE)', is, essential, for, postnatal, repression, of, myogenin, in, transgenic, animals])].
[sujeto(['We', present, multiple, lines, of, evidence, supporting, the, idea, that, repression, is]), verbo([mediated]), complemento([by, the, 'Y-box', protein, 'MSY-3'])].
[sujeto(['Electroporation', in, vivo, shows, that, myogHCE, and, 'MSY-3', are]), verbo([required]), complemento([for, postnatal, repression])].
[sujeto(['We', further, show, 'that,', in, the, 'C2C12', cell, culture, 'system,', ectopic, 'MSY-3', can]), verbo([repress]), complemento(['differentiation,', while, reduced, 'MSY-3', promotes, premature, differentiation])].
[sujeto(['MSY-3']), verbo([binds]), complemento([myogHCE, simultaneously, with, the, homeodomain, protein, 'Pbx', in, postnatal, innervated, muscle])].
[sujeto(['We', therefore, propose, a, model, in, which, the, myogHCE, motif, operates, as, a, switch, by, specifying, opposing, 'functions;', one, that, was, shown, previously, is]), verbo([regulated]), complemento([by, 'MyoD', and, 'Pbx', and, it, specifies, a, chromatin, 'opening,', 'gene-activating', function, at, the, time, myoblasts, begin, to, 'differentiate;', the, other, includes, 'MYS-3', and, 'Pbx,', and, it, specifies, a, repression, function, that, operates, during, and, after, postnatal, muscle, maturation, in, vivo, and, in, myoblasts, before, they, begin, to, differentiate])].
[sujeto(['Cells', were, cultured, in, 'low-mitogen', differentiation, medium, to]), verbo([induce]), complemento([cell, 'differentiation,', with, or, without, the, addition, of, lactoferrin])].
[sujeto(['ALPase', activity]), verbo([increased]), complemento([after, the, addition, of, lactoferrin])].
[sujeto(['The', mRNA, expression, of, 'Runx2,', 'osteocalcin,', and, 'Sox9']), verbo([increased]), complemento([markedly, as, a, result, of, lactoferrin, 'treatment,', whereas, the, expression, of, 'MyoD,', 'desmin,', and, 'PPARgamma', decreased, significantly])].
[sujeto(['Western', blots, showed, that, lactoferrin, stimulation]), verbo([increased]), complemento(['Runx2', and, 'Sox9', 'proteins,', whereas, it, decreased, 'MyoD', and, 'PPARgamma', synthesis])].
[sujeto(['C2C12', cells]), verbo([expressed]), complemento([the, 'LRP1', lactoferrin, receptor])].
[sujeto(['De', novo, methylation, of, 'CpG', islands, within, the, promoters, of, eukaryotic, genes, is, often]), verbo([associated]), complemento([with, their, transcriptional, 'repression,', yet, the, methylation, of, 'CpG', islands, located, downstream, of, promoters, does, not, block, transcription])].
[sujeto(['The', rates, of, remethylation, of, both, 'CpG', islands, were]), verbo([associated]), complemento([with, time, but, not, with, the, rate, of, cell, 'division,', and, remethylation, of, the, p16, exon, 2, 'CpG', island, occurred, at, a, higher, rate, than, that, of, the, p16, promoter])].
[sujeto(['Remethylation', occurred, most, rapidly, in, the, 'p16,', 'PAX-6,', and, 'c-ABL', 'genes,', shown, to, be]), verbo([transcribed]), complemento([prior, to, drug, treatment])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, de, novo, methylation, is, not, restricted, to, the, 'S', phase, of, the, cell, cycle, and, that, transcription, through, 'CpG', islands, does, not, inhibit, their, remethylation])].
[sujeto([5, -, 'Azacytidine', '(', 5, -, 'aza-CR)', and, 5, -, 'aza-2\'-deoxycytidine', '(', 5, -, 'aza-CdR),', analogs, of, cytidine, modified, in, position, 5, ',', were, originally, developed, as, antitumor, 'agents,', and]), verbo([have]), complemento([been, useful, in, the, treatment, of, both, childhood, and, adult, leukemias])].
[sujeto(['These', agents, are, cytotoxic, per, 'se,', but, also]), verbo([induce]), complemento([differentiation, in, several, experimental, 'systems,', most, notably, the, induction, of, 'muscle,', 'adipocytes,', and, chondrocytes, in, cultures, of, 'drug-treated', mouse, embryo, fibroblasts])].
[sujeto(['The', mechanisms, underlying, this, 'drug-induced', differentiation]), verbo([have]), complemento([been, difficult, to, 'unravel,', a, fact, which, limits, the, rational, design, of, differentiation, therapy, as, a, modulator, of, cancer, using, these, agents])].
[sujeto(['Induction', of, new, developmental, pathways, in, cultured, cells]), verbo([involves]), complemento(['stable,', heritable, 'changes,', presumably, of, an, epigenetic, nature])].
[sujeto(['Since', 'DNA', methylation, is, believed, to, be]), verbo([involved]), complemento([at, some, level, in, the, regulation, of, gene, 'expression,', the, hypothesis, was, developed, that, changes, in, methylation, allowed, the, expression, of, new, genes, whose, activity, initiated, new, pathways, of, differentiation])].
[sujeto(['The', characterization, of, this, 'drug-induced', system, of, differentiation]), verbo([has]), complemento([therefore, opened, the, way, to, identifying, genes, directly, involved, in, the, initiation, or, modification, of, pathways, of, differentiation])].
[sujeto(['Expression', of, 'MyoD', in, myogenic, cell, lines]), verbo([has]), complemento([been, correlated, with, loss, of, methylation, at, specific, sites, in, the, 'genome,', but, the, critical, events, leading, to, expression, of, 'MyoD', and, muscle, differentiation, are, poorly, understood])].
[sujeto(['MyoD1', transfection]), verbo([induced]), complemento([the, synthesis, of, 'myosin,', 'desmin,', and, vimentin, without, substantially, altering, the, epidermal, differentiation, properties, '(', 'morphology,', keratin, 'profile)', in, vitro, nor, epidermal, morphogenesis, '(', formation, of, a, complex, stratified, squamous, 'epithelium)', in, surface, 'transplants,', demonstrating, the, stability, of, the, keratinocyte, phenotype])].
[sujeto(['The', present, study, evaluated, 'low-level', laser, therapy, '(', 'LLLT)', effects, on, some, physiological, pathways, that, may]), verbo([lead]), complemento([to, muscle, damage, or, regeneration, capacity, in, 'dystrophin-deficient', muscle, cells, of, mdx, 'mice,', the, experimental, model, of, 'Duchenne', muscular, dystrophy, '(', 'DMD)'])].
[sujeto(['The', mdx, 'LA', 24, and, mdx, 'LA', 48, groups, showed, significant]), verbo([increase]), complemento([in, cell, 'proliferation,', higher, diameter, in, muscle, cells, and, decreased, 'MyoD', levels, compared, to, the, mdx, group])].
[sujeto(['The', mdx, 'LA', 48, group, showed, significant]), verbo([increase]), complemento([in, 'Myosin', 'Heavy', 'Chain', levels, compared, to, the, untreated, mdx, and, mdx, 'LA', 24, groups])].
[sujeto(['The', mdx, 'LA', 24, and, mdx, 'LA', 48, groups, showed, significant]), verbo([increase]), complemento([in, '[', 'Ca2+]i'])].
[sujeto(['The', mdx, group, showed, significant]), verbo([increase]), complemento([in, 'H2O2', production, and, 4, -, 'HNE', levels, compared, to, the, 'Ctrl', group, and, 'LLLT', treatment, reduced, this, increase])].
[sujeto(['GSH', levels, and, 'GPx,', 'GR', and, 'SOD', activities]), verbo([increased]), complemento([in, the, mdx, group])].
[sujeto(['The', mdx, group, showed, significant]), verbo([increase]), complemento([in, the, 'TNF-α', and, 'NF-κB', 'levels,', which, in, turn, was, reduced, by, the, 'LLLT', treatment])].
[sujeto(['Together,', these, results]), verbo([suggest]), complemento([that, the, laser, treatment, improved, regenerative, capacity, and, decreased, inflammatory, response, and, oxidative, stress, in, dystrophic, muscle, 'cells,', indicating, that, 'LLLT', could, be, a, helpful, alternative, therapy, to, be, associated, with, other, treatment, for, dystrophinopathies])].
[sujeto(['It', is, known, that, 'non-cachectic', patients, with, chronic, obstructive, pulmonary, disease, '(', 'COPD)']), verbo([respond]), complemento([well, to, pulmonary, 'rehabilitation,', but, whether, cachectic, 'COPD', patients, are, capable, of, adaptive, responses, is, both, important, and, unknown])].
[sujeto(['Before', and, after, rehabilitation, vastus, lateralis, muscle, biopsies, were, analysed, morphologically, and, for, the, expression, of, muscle, remodelling, factors, '(', 'insulin-like', growth, factor, '(', 'IGF)-I,', myogenic, differentiation, factor, 'D', '(', 'MyoD),', tumour, necrosis, factor, '(', 'TNF)-alpha,']), verbo([nuclear]), complemento([factor, '(', 'NF)-kappaB', and, 'myostatin)', and, key, components, of, 'ubiquitin-mediated', proteolytic, systems, '(', muscle, ring, finger, protein, '(', 'MURF)-1', and, 'Atrogin-1)'])].
[sujeto(['Mean', muscle, fibre, 'cross-sectional', area]), verbo([increased]), complemento([in, both, 'groups,', but, significantly, less, in, cachectic, '(', 7, +, /, -, 2, '%', ')', than, in, 'non-cachectic', '(', 11, +, /, -, 2, '%', ')', patients])].
[sujeto(['Both', groups, equally]), verbo([decreased]), complemento([the, proportion, of, type, 'IIb', fibres, and, increased, muscle, 'capillary/fibre', ratio])].
[sujeto(['IGF-I', mRNA, expression]), verbo([increased]), complemento([in, both, 'groups,', but, 'IGF-I', protein, levels, increased, more, in, 'non-cachectic', 'COPD'])].
[sujeto(['Whilst', rehabilitation, had, no, effect, on, 'TNF-alpha', 'expression,', it]), verbo([decreased]), complemento([the, activation, of, the, transcription, factor, 'NF-kappaB', in, both, groups, by, the, same, amount])].
[sujeto(['Atrogin-1', and, 'MURF-1', expression, were]), verbo([increased]), complemento([in, cachectic, 'COPD,', but, it, was, decreased, in, 'non-cachectic', patients])].
[sujeto(['Cachectic', 'COPD', patients, partially]), verbo([retain]), complemento([the, capacity, for, peripheral, muscle, remodelling, in, response, to, rehabilitation, and, are, able, to, increase, exercise, capacity, as, much, as, those, without, 'cachexia,', even, if, they, exhibit, both, quantitative, and, qualitative, differences, in, the, type, of, muscle, fibre, remodelling, in, response, to, exercise, training])].
[sujeto(['Skeletal', muscle, wasting, commonly, occurs, in, patients, with, chronic, obstructive, pulmonary, disease, '(', 'COPD)', and]), verbo([has]), complemento([been, associated, with, the, presence, of, systemic, inflammation])].
[sujeto(['This', study, investigated, whether, rehabilitative, exercise, training]), verbo([decreases]), complemento([the, levels, of, systemic, or, local, muscle, inflammation, or, reverses, the, abnormalities, associated, with, muscle, deconditioning])].
[sujeto(['In', 'contrast,', there, was, a, significant]), verbo([increase]), complemento([in, mRNA, expression, of, 'IGF-I', '(', by, 67, '(', 22, ')', '%', ;, p, =, 0.044, ')', ',', 'MGF', '(', by, 67, '(', 15, ')', '%', ;, p, =, 0.002, ')', and, 'MyoD', '(', by, 116, '(', 30, ')', '%', ;, p, =, 0.001, ')'])].
[sujeto(['The']), verbo([increase]), complemento([observed, at, the, mRNA, level, was, also, seen, at, the, protein, level, for, 'IGF-I', '(', by, 72, '(', 36, ')', '%', ;, p, =, 0.046, ')', and, 'MyoD', '(', by, 67, '(', 21, ')', '%', ;, p, =, 0.012, ')'])].
[sujeto(['Pulmonary', rehabilitation, can]), verbo([induce]), complemento([peripheral, muscle, adaptations, and, modifications, in, factors, regulating, skeletal, muscle, hypertrophy, and, regeneration, without, decreasing, the, levels, of, systemic, or, local, muscle, inflammation])].
[sujeto(['This', pharmacological, treatment]), verbo([has]), complemento([been, demonstrated, to, induce, specific, apoptotic, death, in, monocytes, and, phagocytic, macrophages])].
[sujeto([',', 'MyoD', and, 'myogenin)', directly]), verbo([involved]), complemento([in, the, 'activation/proliferation', and, differentiation, of, muscle, precursor, cells, was, not, altered, by, the, clodronate, liposome, treatment])].
[sujeto(['The', repair, process, in, the, injured, muscle, of, clodronate, 'liposome-treated', mice, was, characterized, by, prolonged, clearance, of, necrotic, myofibers, and, a, tendency, for]), verbo([increased]), complemento([muscle, fat, accumulation, at, day, 9, and, 14, 'postinjury,', respectively])].
[sujeto(['In', 'conclusion,', a, significant, reduction, of, the, initial, 'monocyte/macrophage', influx, into, the, injured, muscle, is]), verbo([associated]), complemento([with, not, 'improved,', but, moderately, 'impaired,', repair, processes, after, skeletal, muscle, injury])].
[sujeto(['T(3)']), verbo([regulates]), complemento([energy, metabolism, by, stimulating, metabolic, rate, and, decreasing, metabolic, efficiency])].
[sujeto(['Within', 8, h, of, 'single-dose', 'T(3)', 'administration,', hypothyroid, rats, showed, a, rise, in, serum, fatty, acid, levels, concomitant, with, a, rapid]), verbo([increase]), complemento([in, 'UCP3', expression, in, gastrocnemius, 'muscle,', followed, by, inductions, of, peroxisome, proliferator, activated, receptor, delta, '(', 'PPARdelta)', '(', within, 24, 'h)', and, 'PPAR', target, gene, expression, '(', after, 24, 'h)'])].
[sujeto(['In', transfected, rat, 'L6', 'myoblasts,', only, the, rat, 'UCP3', promoter, positively]), verbo([responded]), complemento([to, 'T(3)', and, 'L165,041', together, in, the, presence, of, 'MyoD,', thyroid, hormone, receptor, beta1, '(', 'TRbeta1),', 'PPARdelta,', or, 'PPARdelta', plus, the, 'TR', dimerization, partner, retinoid, 'X', receptor, alpha])].
[sujeto(['Although', physical, interactions, with, other, receptors]), verbo([have]), complemento([been, 'reported,', heterodimeric, complexes, of, 'T(3)', nuclear, receptors, '(', 'TR)', with, retinoid, 'X', receptors, '(', 'RXRs)', are, considered, as, major, regulators, of, 'T(3)', target, gene, expression])].
[sujeto(['However,', despite, the, potent, 'T(3)', influence, in, proliferating, 'myoblasts,', 'RXR', isoforms, are, not]), verbo([expressed]), complemento([during, 'proliferation,', raising, the, question, of, the, nature, of, the, complex, involved, in, 'TRalpha', transcriptional, activity])].
[sujeto(['We']), verbo([have]), complemento([previously, established, that, 'c-Jun', induces, 'TRalpha1', transcriptional, activity, in, proliferating, myoblasts, not, expressing, 'RXR'])].
[sujeto(['This', regulation, is, specific, to, the, muscle, 'lineage,']), verbo([suggesting]), complemento([the, involvement, of, a, 'muscle-specific', factor])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, 'MyoD', expression, in, 'HeLa', cells, stimulates, 'TRalpha1', 'activity,', an, influence, potentiated, by, 'c-Jun', coexpression])].
[sujeto(['Similarly,', in, the, absence, of, 'RXR,', 'MyoD', or, 'c-Jun', overexpression, in, myoblasts]), verbo([induces]), complemento(['TRalpha1', transcriptional, activity, through, a, direct, repeat, 4, or, an, inverted, palindrome, 6, thyroid, hormone, response, element])].
[sujeto(['Furthermore,', we, demonstrated, that, 'TRalpha1', and, 'MyoD', physically]), verbo([interact]), complemento([in, the, hinge, region, of, the, receptor, and, the, transactivation, and, basic, helix, loop, helix, domains, of, 'MyoD'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, in, the, absence, of, 'RXR,', 'TRalpha1', transcriptional, activity, in, myoblasts, is, mediated, through, a, complex, including, 'MyoD', and, 'c-Jun'])].
[sujeto(['Mammals']), verbo([have]), complemento([two, major, isoforms, of, 'acetyl-CoA', carboxyase, '(', 'ACC)'])].
[sujeto(['ACCbeta', is, thought, to, control, fatty, acid, oxidation, by, means, of, the, ability, of, 'malonyl-CoA', to]), verbo([inhibit]), complemento([carnitine, 'palmitoyl-CoA', 'transferase-1', '(', 'CPT-1),', which, is, a, 'rate-limiting', enzyme, of, fatty, acid, oxidation, in, mitochondria])].
[sujeto(['Previously,', it, was]), verbo([reported]), complemento([that, 'MyoD', and, other, muscle, regulating, factors, '(', 'MRFs)', 'up-regulate', the, expression, of, 'ACCbeta', by, interactions, between, these, factors, and, several, 'cis-elements', of, 'ACCbeta', promoter])].
[sujeto(['We', described, here, that, 'ACCbeta', expression]), verbo([mediated]), complemento([by, 'MRFs', is, regulated, by, retinoic, acids])].
[sujeto(['Endogenous', expression, of, 'ACCbeta', in, differentiated, 'H9C2', myotube, was, significantly]), verbo([increased]), complemento([by, retinoic, acid, treatment])].
[sujeto(['However,', on, transient, transfection, assay, in, 'H9C2', 'myoblast,', 'ACCbeta', promoter, activity, was]), verbo([suppressed]), complemento([by, 'RXRalpha', and, more, severely, by, 'RARalpha'])].
[sujeto(['These', effects, on, 'ACCbeta', expression, in, myoblasts, and, myotubes, by, 'RXRalpha', and, 'RARalpha', seem, to, be]), verbo([mediated]), complemento([by, their, interactions, with, 'MRFs', because, no, consensus, sequence, for, 'RXRalpha', and, 'RARalpha', has, been, found, in, 'ACCbeta', promoter, and, retinoic, acid, receptors, did, not, affect, this, promoter, activities, by, itself])].
[sujeto(['In', transient, transfection, in, 'NIH3T3', 'fibroblast,', the, activation, of, 'ACCbeta', promoter, by, 'MyoD,', main, 'MRF', in, 'myoblast,', was, significantly]), verbo([suppressed]), complemento([by, 'RARalpha', and, to, a, less, extent, by, 'RXRalpha', while, the, 'RXRalpha', drastically, augmented, the, activation, by, 'MRF4,', major, 'MRF', in, myotube])].
[sujeto(['These', results, explained, that, retinoic, acids, differentially, affected, the, action, of, 'MRFs', according, to, their, types, and, 'RXRalpha', specially, elevates, the, expression, of, muscle, specific, genes, by]), verbo([stimulating]), complemento([the, action, of, 'MRF4'])].
[sujeto(['Rev-erbA', alpha, is, an, orphan, steroid, receptor, that, is]), verbo([expressed]), complemento([in, skeletal, muscle])].
[sujeto(['Rev-erbA', alpha]), verbo([binds]), complemento([to, 'single/tandem', copies, of, an, 'AGGTCA', 'motif,', is, transcribed, on, the, noncoding, strand, of, the, 'c-erbA-', alpha, gene, 'locus,', and, is, postulated, to, modulate, the, thyroid, hormone, '(', 'T3)', response])].
[sujeto(['T3']), verbo([induces]), complemento([terminal, muscle, differentiation, and, regulates, fiber, type, composition, via, direct, activation, of, the, 'muscle-specific', myoD, gene, family, '(', e])].
[sujeto(['The', myoD, gene, family, can, direct, the, fate, of, mesodermal, cell, lineages, and]), verbo([activate]), complemento([muscle, differentiation])].
[sujeto(['We', observed, abundant, levels, of, 'Rev-erbA', alpha, mRNA, in, dividing, 'C2C12', 'myoblasts,', which, were]), verbo([suppressed]), complemento([when, the, cells, differentiated, into, postmitotic, multinucleated, myotubes])].
[sujeto(['This']), verbo([decrease]), complemento([in, 'Rev-erbA', alpha, mRNA, correlated, with, the, appearance, of, 'muscle-specific', mRNAs, '(', e])].
[sujeto(['Constitutive', overexpression, of, full, length, 'Rev-erbA', alpha, cDNA, in, the, myogenic, cells, completely, abolished, 'differentiation,']), verbo([suppressed]), complemento([myoD, mRNA, 'levels,', and, abrogated, the, induction, of, myogenin, mRNA])].
[sujeto(['We', then, demonstrated, that, 1, ')', 'GAL4-REV-erbA', alpha, chimeras, that, contain, the, '\'', 'AB\'', region, and, lack, the, '\'', 'E\'', region]), verbo([activated]), complemento([transcription, of, 'GAL4', response, elements, in, the, presence, of, 8, -, 'Br-cAMP', and, 2, ')', the, 'ligand-binding', domain, '(', 'LBD)', contains, an, active, transcriptional, silencer])].
[sujeto(['Furthermore,', this, orphan, receptor, 1, ')', 'down-regulated', thyroid, hormone, receptor, '(', 'TR)/T3']), verbo([mediated]), complemento([transcriptional, activity, from, the, myogenin, promoter, and, thyroid, hormone, response, element, '(', 'TRE)', an, 2, ')', disrupted, 'TR', homodimer, and, 'TR/retinoid', 'X', receptor, '(', 'RXR)', heterodimer, formation, on, a, number, of, 'TREs', found, in, the, myoD, gene, family])].
[sujeto(['In', 'conclusion,', 'Rev-erbA', alpha, functions, as, a, negative, regulator, of, myogenesis, by]), verbo([targeting]), complemento([the, expression, of, the, myoD, gene, family])].
[sujeto(['The', mechanism, of, action, may]), verbo([involve]), complemento([inhibition, of, functional, 'TR/RXR', heterodimer, formation, on, critical, 'TREs', and, dominant, 'trans-repression', of, gene, expression])].
[sujeto(['COUP-TF', 'II', is, an, '\'', orphan, steroid, 'receptor\'', that]), verbo([binds]), complemento([a, wide, variety, of, 'AGGTCA', repeats, and, represses, thyroid, hormone, '(', 'T3)', and, retinoid, dependent, 'trans-activation;', 'however,', very, little, is, known, of, its, functional, 'and/or', developmental, role, during, mammalian, cell, differentiation])].
[sujeto(['T3', and, retinoids]), verbo([have]), complemento([been, demonstrated, to, promote, terminal, muscle, differentiation, via, activation, of, the, muscle, specific, myoD, gene, family, '(', 'myoD,', 'myogenin,', 'myf-5', and, 'MRF-4)'])].
[sujeto(['The', myoD, gene, family, can, direct, the, fate, of, mesodermal, cell, 'lineages,']), verbo([repress]), complemento(['proliferation,', activate, differentiation, and, the, contractile, phenotype])].
[sujeto(['Proliferating', 'C2C12', myoblasts]), verbo([expressed]), complemento(['COUP-TF', 'II', mRNA, which, was, repressed, when, cells, were, induced, to, differentiate, into, 'post-mitotic', multinucleated, myotubes, by, serum, withdrawal])].
[sujeto(['Concomitant', with, the]), verbo([decrease]), complemento([of, 'COUP-TF', 'II', mRNA, was, the, appearance, of, muscle, specific, mRNAs, '(', e])].
[sujeto(['We', show, that, 'Escherichia', coli]), verbo([expressed]), complemento([full, length, and, truncated, 'COUP-TF', 'II', bound, in, a, sequence, specific, manner, to, the, 'T3', response, elements, '(', 'TREs)', in, the, myoD, and, myogenin, regulatory, 'HLH', genes, '[', 'Olson', '(', 1992, ')', 'Dev'])].
[sujeto(['COUP-TF', 'II', diminished, the, homodimeric]), verbo([binding]), complemento([of, the, thyroid, hormone, receptor, and, the, heterodimeric, binding, of, thyroid, hormone, and, retinoid, 'X', receptor, complexes, to, these, 'TREs'])].
[sujeto(['Constitutive', 'over-expression', of, 'COUP-TF', 'II', cDNA, in, mouse, 'C2C12', myogenic, cells]), verbo([suppressed]), complemento([the, levels, of, myoD, mRNA, and, blocked, the, induction, of, myogenin, 'mRNA,', whereas, constitutive, expression, of, 'anti-sense', 'COUP-TF', 'II', cDNA, significantly, increased, the, steady, state, levels, of, myoD, mRNA, and, 'hyper-induced', myogenin, mRNA])].
[sujeto(['Triiodo-L-thyronine', treatment]), verbo([promotes]), complemento([terminal, muscle, differentiation, and, results, in, increased, 'MyoD', gene, transcription, in, myogenic, cell, 'lines;', furthermore, myoD, and, fast, myosin, heavy, chain, gene, expression, are, activated, in, rodent, slow, twitch, muscle, fibers, '(', 'Molecular', 'Endocrinology', 6, :, 1185, -, 1194, ',', 1992, ;, 'Development', 118, :, 1137, -, 1147, ',', 1993, ')'])].
[sujeto(['We']), verbo([have]), complemento([identified, a, 'T3', response, element, '(', 'TRE)', in, the, mouse, 'MyoD', promoter, between, nucleotide, positions, -, 337, and, -, 309, '(', 5, '\'', 'CTGAGGTCAGTACAGGCTGGAGGAGTAGA', 3, '\'', ')'])].
[sujeto(['This', sequence]), verbo([conferred]), complemento([an, appropriate, 'T3', response, to, an, enhancerless, 'SV40', promoter])].
[sujeto(['In', vitro]), verbo([binding]), complemento([studies, showed, that, the, thyroid, hormone, receptor, alpha, '(', 'TR', 'alpha)', formed, a, heterodimeric, 'complex,', with, either, the, retinoid, 'X', receptor, alpha, or, gamma, 1, isoforms, '(', 'RXR', 'alpha,', 'RXR', 'gamm),', on, the, 'MyoD', 'TRE', that, was, specifically, competed, by, other, well, characterised, 'TREs', and, not, by, other, response, elements])].
[sujeto(['EMSA', experiments, demonstrated, that, the]), verbo([nuclear]), complemento(['factor(s)', present, in, muscle, cells, that, bound, to, the, myoD, 'TRE', were, constitutively, expressed, during, 'myogenesis;', this, complex, was, competed, by, the, myosin, heavy, 'chain,', 'DR-4', and, 'PAL-0', 'TREs', in, a, sequence, specific, fashion])].
[sujeto(['Western', blot, analysis, indicated, that, 'TR', alpha, 1, was, constitutively]), verbo([expressed]), complemento([during, 'C2C12', differentiation])].
[sujeto(['Mutagenesis', of, the, myoD, 'TRE', indicated, that, the, sequence, of, the, direct, repeats, '(', 'AGGTCA)', and, the, 4, nucleotide, gap, were, necessary, for, efficient]), verbo([binding]), complemento([to, the, 'TR', 'alpha/RXR', alpha, heterodimeric, complex])].
[sujeto(['In', conclusion, our, data]), verbo([suggest]), complemento([that, the, 'TRE', in, the, helix, loop, helix, 'gene,', 'myoD,', is, a, target, for, the, direct, heterodimeric, binding, of, 'TR', alpha, and, 'RXR', 'alpha/gamma'])].
[sujeto(['These', results]), verbo([provide]), complemento([a, molecular, 'mechanism/model', for, the, effects, of, 'triiodo-L-thyronine', on, in, vitro, 'myogenesis;', the, activation, of, myoD, gene, expression, in, the, slow, twitch, fibres, and, the, cascade, of, myogenic, events, regulated, by, thyroid, hormone])].
[sujeto(['However,', whether, vitamin, 'D', directly, reduces, muscle, fiber, atrophy, or]), verbo([stimulates]), complemento([muscle, fiber, hypertrophy, remains, subject, of, debate])].
[sujeto(['We', show, that, myoblasts, not, only]), verbo([responded]), complemento([to, 1, ',', 25, '(', 'OH)2', 'D3', ',', but, also, to, the, precursor, 25, '(', 'OH)D3', by, increasing, their, 'VDR', mRNA, expression, and, reducing, their, proliferation])].
[sujeto(['In', differentiating, myoblasts, and, myotubes, 1, ',', 25, '(', 'OH)2', 'D3', as, well, as, 25, '(', 'OH)D3']), verbo([stimulated]), complemento(['VDR', mRNA, expression, and, in, myotubes, 1, ',', 25, '(', 'OH)2', 'D3', also, stimulated, 'MHC', mRNA, expression])].
[sujeto(['Interestingly,', both, myoblasts, and, myotubes]), verbo([expressed]), complemento(['CYP27B1', and, 'CYP24', mRNA, which, are, required, for, vitamin, 'D3', metabolism])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, skeletal, muscle, is, not, only, a, direct, target, for, vitamin, 'D3', 'metabolites,', but, is, also, able, to, metabolize, 25, '(', 'OH)D3', and, 1, ',', 25, '(', 'OH)2', 'D3'])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, the, expression, of, 'MyoD', mRNA, oscillates, over, 24, h, in, skeletal, muscle, and, that, the, circadian, clock, transcription, 'factors,', 'BMAL1', '(', brain, and, muscle, 'ARNT-like', 1, ')', and, 'CLOCK', '(', circadian, locomotor, output, cycles, 'kaput),', were, bound, to, the, core, enhancer, '(', 'CE)', of, the, 'MyoD', gene, in, vivo])].
[sujeto(['In', this, 'study,', we]), verbo([provide]), complemento([in, vivo, and, in, vitro, evidence, that, the, 'CE', is, necessary, for, circadian, expression, of, 'MyoD', in, adult, muscle])].
[sujeto(['Gel', shift, assays, identified, a]), verbo([conserved]), complemento(['non-canonical', 'E-box', within, the, 'CE', that, is, bound, by, 'CLOCK', and, 'BMAL1'])].
[sujeto(['Functional', analysis, revealed, that, this, 'E-box', was]), verbo([required]), complemento([for, full, activation, by, 'BMAL1/CLOCK', and, for, in, vitro, circadian, oscillation])].
[sujeto(['Expression', profiling, of, muscle, of, 'CE(loxP/loxP)', mice]), verbo([found]), complemento([approximately, 1300, genes, 'mis-expressed', relative, to, 'wild-type'])].
[sujeto(['The', results, of, this, work, identify, a, novel, element, in, the, 'MyoD', enhancer, that]), verbo([confers]), complemento([circadian, regulation, to, 'MyoD', in, skeletal, muscle, and, suggest, that, loss, of, circadian, regulation, leads, to, changes, in, myogenic, expression, and, downstream, mitochondrial, function])].
[sujeto(['Machado-Joseph', disease, '(', 'MJD)', is, a, neurodegenerative, 'disorder,']), verbo([caused]), complemento([by, the, expansion, of, the, '(', 'CAG)n', tract, in, the, 'MJD', gene])].
[sujeto(['The', mouse, 'Mjd', gene]), verbo([has]), complemento([a, structure, similar, to, that, of, its, human, counterpart, and, it, also, contains, a, 'TATA-less', promoter])].
[sujeto(['Its', 5, '\'', flanking, region, contains]), verbo([conserved]), complemento([putative, binding, regions, for, transcription, factors, 'Sp1,', 'USF,', 'Arnt,', 'Max,', 'E47,', and, 'MyoD'])].
[sujeto(['Upon', differentiation, of, 'P19', 'cells,', the, 'Mjd', gene, promoter, is, preferentially]), verbo([activated]), complemento([in, endodermal, and, mesodermal, 'derivatives,', including, cardiac, and, skeletal, 'myocytes;', and, less, so, in, neuronal, precursors])].
[sujeto(['Mouse', 'ataxin-3', is, ubiquitously]), verbo([expressed]), complemento([during, embryonic, development, and, in, the, 'adult,', with, strong, expression, in, regions, of, the, 'CNS', affected, in, 'MJD'])].
[sujeto(['It', is, particularly, abundant, in, all, types, of, muscle, and, in, ciliated, epithelial, 'cells,']), verbo([suggesting]), complemento([that, it, may, be, associated, with, the, cytoskeleton, and, may, have, an, important, function, in, cell, structure, 'and/or', motility])].
[sujeto(['Lysosomal', sialidase, is]), verbo([required]), complemento([for, the, catabolism, of, sialoglycoconjugates, such, as, gangliosides, and, deficiency, in, this, enzyme, results, in, the, autosomal, recessive, disease, sialidosis])].
[sujeto(['Furthermore,', we]), verbo([have]), complemento([shown, that, overexpression, of, human, sialidase, is, sufficient, to, clear, accumulated, ganglioside, in, 'Tay-Sachs', neuroglia, '[', 'Hum'])].
[sujeto(['In', this, 'paper,', we]), verbo([have]), complemento([characterized, the, 5, '\'', regulatory, region, of, the, mouse, lysosomal, sialidase, gene, in, order, to, understand, the, molecular, mechanisms, regulating, its, expression])].
[sujeto(['Expression', by, the, promoter, was]), verbo([found]), complemento([to, be, 'cell-type', restricted, and, required, at, least, 750, bp, upstream, of, the, 'ATG', for, 'high-level', expression])].
[sujeto(['Taken', 'together,', these, results, identify, 'cis-', and, 'trans-acting', factors]), verbo([involved]), complemento([in, the, regulation, of, sialidase, and, point, to, mechanisms, of, gene, upregulation])].
[sujeto(['Glycerol', kinase, '(', 'GK)', is, at, the, interface, of, fat, and, carbohydrate, metabolism, and]), verbo([has]), complemento([been, linked, to, obesity, and, type, 2, diabetes, mellitus, '(', 'T2DM)'])].
[sujeto(['Microarray', analysis, determined, that, there, were, 525, genes, that, were, differentially]), verbo([expressed]), complemento(['(', 1.2, -, 'fold,', p, 'value<0'])].
[sujeto(['Quantitative', 'PCR', '(', 'qPCR)', confirmed, the, differential, expression, of, genes, including, glycerol, kinase, '(', 'Gyk),', phosphatidylinositol, 3, -, kinase, regulatory, 'subunit,', polypeptide, 1, '(', p85, 'alpha)', '(', 'Pik3r1),', 'insulin-like', growth, factor, 1, '(', 'Igf1),', and, growth, factor, receptor]), verbo([bound]), complemento([protein, 2, -, associated, protein, 1, '(', 'Gab1)'])].
[sujeto(['Network', component, analysis, demonstrated, that, transcription, factor, activities, of, myogenic, differentiation, 1, '(', 'MYOD),', myogenic, regulatory, factor, 5, '(', 'MYF5),', myogenin, '(', 'MYOG),']), verbo([nuclear]), complemento([receptor, subfamily, 4, ',', group, 'A,', member, 1, '(', 'NUR77)', are, decreased, in, the, 'Gyk', 'KO', whereas, the, activity, of, paired, box, 3, '(', 'PAX3)', is, increased])].
[sujeto(['The', activity, of, 'MYOD', was, confirmed, using, a, 'DNA']), verbo([binding]), complemento([assay])].
[sujeto(['T3', treatment, '(', 'T1,', 1, 'mg;', 'T3,', 3, 'mg;', 'T10,', 10, 'mg/kg/day)', of, 'KK', mice, for, 4, days]), verbo([caused]), complemento([a, decrease, in, blood, glucose, level, by, 11, '%', ',', 25, '%', ',', and, 24, '%', ',', 'respectively,', without, affecting, body, weight])].
[sujeto(['Skeletal', muscle, of, mice, treated, with, 'T3', '(', 'T10)', showed, a, 98, '%']), verbo([increase]), complemento([in, the, mRNA, level, of, the, glucose, transporter, isotype, 4, '(', 'Glut4)'])].
[sujeto(['The', mRNA, level, of, a, muscle, cell, specific, differentiation, 'marker,', 'MyoD,', showed, a, significant]), verbo([increase]), complemento([in, the, 'T3', treatment, group, with, an, accompanying, enhancement, of, 'glyceraldehyde-3-phosphate', dehydrogenase, '(', 'GAPDH)', mRNA, level])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'T3', stimulates, muscle, cell, differentiation, in, 'vivo,', concomitant, with, a, stimulation, of, cellular, glucose, 'metabolism,', thus, decreasing, the, blood, glucose, level, in, hyperglycemic, 'KK', mice])].
[sujeto(['It', is, unclear, whether, insulin, resistance, is, a, primary, defect]), verbo([leading]), complemento([to, 'NIDDM', or, the, result, of, hyperinsulinemia, and, hyperglycemia])].
[sujeto(['These', cell, cultures]), verbo([expressed]), complemento([a, variety, of, 'muscle-specific', phenotypes, including, the, proteins, 'alpha-actinin', and, 'myosin,', 'muscle-specific', creatine, kinase, 'activity,', and, 'RNA', encoding, 'GLUT4,', 'MYF5,', 'MYOD1,', and, 'MYOGENIN'])].
[sujeto(['This', defect, in, insulin, action, is, stable, in, a, uniform, culture, environment, and, is]), verbo([retained]), complemento([over, time])].
[sujeto(['Class', 'II', 'HLH', 'proteins,', such, as, 'MyoD,', are]), verbo([expressed]), complemento([in, a, 'tissue-specific', manner])].
[sujeto(['Class', 'I', and, 'II', heterodimers, can]), verbo([bind]), complemento([to, 'E-boxes', '(', 'CANNTG)', and, regulate, lineage, commitments, of, embryonic, cells])].
[sujeto(['HHM', is, structurally, related, to, the, 'Id', family, and, was, highly]), verbo([expressed]), complemento([in, 'brain,', pituitary, 'gland,', 'lung,', 'heart,', 'placenta,', fetal, 'liver,', and, bone, marrow])].
[sujeto(['HHM', physically]), verbo([interacted]), complemento([with, 'E12', in, vitro, and, in, mammalian, cells])].
[sujeto(['Comparison', of, the, dominant, inhibitory, effects, of, 'HHM', and, 'Id2', on, the]), verbo([binding]), complemento([of, 'E12/MyoD', dimer, to, an, 'E-box', element, revealed, a, weaker, inhibition, by, 'HHM'])].
[sujeto(['However,', 'HHM', but, not, 'Id2', specifically]), verbo([inhibited]), complemento([the, luciferase, gene, activation, induced, by, hepatic, nuclear, factor, 4, '(', 'HNF4)', promoter])].
[sujeto(['The', 'HHM', was, transiently]), verbo([expressed]), complemento([during, 'stem-cell-driven', regeneration, of, the, liver, at, the, stage, in, which, the, early, basophilic, foci, of, hepatocytes, started, to, appear])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'HHM', is, a, novel, type, of, dominant, inhibitory, 'HLH', protein, that, might, modulate, 'liver-specific', gene, expression])].
[sujeto(['The', zebrafish, fushi, tarazu, 'factor-1a', '(', 'ff1a)', is, a, transcription, factor, belonging, to, the, 'NR5A', subgroup, of]), verbo([nuclear]), complemento([receptors])].
[sujeto(['The', 'NR5A', receptors]), verbo([bind]), complemento(['DNA', as, monomers, and, are, considered, to, be, orphans, due, to, their, ability, to, promote, transcription, of, downstream, genes, without, ligands])].
[sujeto(['In', 'zebrafish,', four, ff1, homologues, '(', 'Ff1a,', 'Ff1b,', 'Ff1c,', and, 'Ff1d)']), verbo([have]), complemento([been, identified, so, far])].
[sujeto(['Ff1a', is]), verbo([expressed]), complemento([in, the, somites, and, pronephric, ducts, during, somitogenesis, and, in, the, 'brain,', 'liver,', and, mandibular, arch, during, later, embryonic, stages])].
[sujeto(['In', adults, the, gene, is, highly]), verbo([expressed]), complemento([in, 'gonads,', 'liver,', and, 'intestine,', but, can, be, detected, in, most, tissues])].
[sujeto(['The', zebrafish, ff1a, dual, promoter, contains, several, 'GATA']), verbo([binding]), complemento([sites, and, 'E-boxes,', a, site, for, 'DR4,', 'XFD2,', 'MyoD,', 'Snail,', 'HNF3,', 'S8,', and, an, 'HMG-box', recognition, site, for, 'Sox9'])].
[sujeto(['In', a, first, attempt, to, dissect, the, ff1a, promoter, in, vivo, we]), verbo([have]), complemento([produced, first, generation, transgenes, in, order, to, determine, the, correlation, between, the, expression, of, the, endogenous, ff1a, gene, and, the, microinjected, ff1a, dual, promoter, coupled, to, the, pEGFP, reporter, vector])].
[sujeto(['Our', results, show, that, the, microinjected, constructs, are]), verbo([expressed]), complemento([in, the, correct, tissues])].
[sujeto(['MRF4', was, the, only, member, of, the, 'MyoD', family, that, was, concentrated, at, the, mature, 'NMJ,']), verbo([suggesting]), complemento([that, it, may, have, a, unique, role, in, the, maintenance, of, 'post-synaptic', specialization])].
[sujeto(['Three', potential, regulators, of, the, 'NMJ', were, identified, and, confirmed, by, 'real-time', 'PCR:', glia, maturation, factor, gamma, was, concentrated, at, the, 'NMJ', whereas, 'Unr', protein, and, protein, tyrosine, phosphatase, were]), verbo([repressed]), complemento([synaptically])].
[sujeto(['The', expression, of, transcription, factors, for, muscle, regeneration, '(', 'Pax3,', 'Pax7', and, 'MyoD)', was]), verbo([increased]), complemento([in, 'CWS', and, 'HE', compared, with, 'HMA', '(', 'p≤0'])].
[sujeto(['In', 'contrast,', the, expression, of, the, late, myogenic, differentiation, marker, 'MyoG', was, reduced, in, 'CWS', and, 'CWL', but]), verbo([increased]), complemento([in, 'HE', '(', 'p≤0'])].
[sujeto(['Bax', was, significantly]), verbo([increased]), complemento([in, 'CWS,', 'CWL', and, 'HE', '(', 'p≤0'])].
[sujeto(['Expression', of, the, oxidative, defense, genes, 'SOD2,', 'GCLM,', and, 'Nrf2', was]), verbo([decreased]), complemento([in, 'CWS', and, 'CWL', but, increased, in, 'HE', '(', 'p≤0'])].
[sujeto(['After', 'trauma,', 'SCs', leave, their, quiescent, state, to, enter, the, cell, cycle, and, undergo, multiple, rounds, of, 'proliferation,', a, process]), verbo([regulated]), complemento([by, 'MyoD'])].
[sujeto(['In', both, promoter, studies, with, myoblasts, and, a, mouse, model, of, muscle, injury, in, 'Nrf2-deficient', 'mice,', we, show, that, 'Nrf2', prolongs, 'SC', proliferation, by, 'up-regulating', 'MyoD', and]), verbo([suppresses]), complemento(['SC', differentiation, by, 'down-regulating', myogenin])].
[sujeto(['Moreover,', we, show, that, 'IL-6', and, 'HGF,', both, factors, that, facilitate, 'SC', 'activation,']), verbo([induce]), complemento(['Nrf2', activity, in, myoblasts])].
[sujeto(['Thus,', 'Nrf2', activity]), verbo([promotes]), complemento([muscle, regeneration, by, modulating, 'SC', proliferation, and, differentiation, and, thereby, provides, implications, for, tissue, regeneration])].
[sujeto(['Skeletal', muscle, redox, homeostasis, is, transcriptionally]), verbo([regulated]), complemento([by, nuclear, 'erythroid-2-p45-related', 'factor-2', '(', 'Nrf2)'])].
[sujeto(['Here,', we, hypothesize, that, 'age-dependent', decline, or, genetic, ablation, of, 'Nrf2']), verbo([leads]), complemento([to, accelerated, apoptosis, and, skeletal, muscle, degeneration])].
[sujeto(['Under', 'basal-physiological', 'conditions,', disruption, of, 'Nrf2', significantly, downregulates, antioxidants, and]), verbo([causes]), complemento([oxidative, stress])].
[sujeto(['Surprisingly,', 'Nrf2-null', mice, had]), verbo([enhanced]), complemento([antioxidant, capacity, identical, to, 'wild-type', '(', 'WT)', upon, acute, endurance, exercise, stress, '(', 'AEES),', suggesting, activation, of, 'Nrf2-independent', mechanisms, '(', i])].
[sujeto(['Analysis', of, prosurvival, pathways, in, the, basal, state]), verbo([reveals]), complemento([decreased, 'AKT', 'levels,', whereas, 'p-p53,', a, repressor, of, 'AKT,', was, increased, in, 'Nrf2-null', vs, 'WT', mice])].
[sujeto(['Upon', 'AEES,', 'AKT', and, 'p-AKT', levels, were, significantly, '(', p, &, 'lt;', 0.001, ')']), verbo([increased]), complemento(['(', &, 'gt;10-fold)', along, with, profound, downregulation, of, 'p-p53', '(', p, &, 'lt;', 0.01, ')', in, 'Nrf2-null', vs, 'WT', skeletal, 'muscle,', indicating, the, onset, of, prosurvival, mechanisms, to, compensate, for, the, loss, of, 'Nrf2', signaling])].
[sujeto(['However,', we]), verbo([found]), complemento([a, decreased, stem, cell, population, '(', 'PAX7)', and, 'MyoD', expression, '(', 'differentiation)', along, with, profound, activation, of, ubiquitin, and, apoptotic, pathways, in, 'Nrf2-null', vs, 'WT', mice, upon, 'AEES,', suggesting, that, compensatory, prosurvival, mechanisms, failed, to, overcome, the, programmed, cell, death, and, degeneration, in, skeletal, muscle])].
[sujeto(['The', 'Rho', family, 'GTPase', 'RhoA', is, known, to]), verbo([promote]), complemento(['myogenesis,', 'however,', the, mechanisms, controlling, its, regulation, in, myoblasts, have, yet, to, be, fully, elucidated])].
[sujeto(['We', show, here, that, the, 'SH2-containing', protein, tyrosine, 'phosphatase,', 'SHP-2,', functions, as, an, early, modulator, of, myogenesis, by]), verbo([regulating]), complemento(['RhoA'])].
[sujeto(['When', 'MyoD', was]), verbo([expressed]), complemento([in, fibroblasts, lacking, functional, 'SHP-2,', 'muscle-specific', gene, activity, was, impaired, and, abolition, of, 'SHP-2', expression, by, 'RNA', interference, inhibited, muscle, differentiation])].
[sujeto(['When', 'dephosphorylated,', 'p190-B', 'RhoGAP']), verbo([has]), complemento([been, shown, to, stimulate, the, activation, of, 'RhoA'])].
[sujeto(['Moreover,', overexpression, of, a, catalytically, inactive, mutant, of, 'SHP-2']), verbo([inhibited]), complemento(['p190-B', 'RhoGAP', tyrosyl, 'dephosphorylation,', 'RhoA', 'activity,', and, myogenesis])].
[sujeto(['These', observations, strongly]), verbo([suggest]), complemento([that, 'SHP-2', dephosphorylates, 'p190-B', 'RhoGAP,', leading, to, the, activation, of, 'RhoA'])].
[sujeto(['Collectively,', these, data]), verbo([provide]), complemento([a, mechanistic, basis, for, 'RhoA', activation, in, myoblasts, and, demonstrate, that, myogenesis, is, critically, regulated, by, the, actions, of, 'SHP-2', on, the, 'p190-B', 'Rho', 'GAP/RhoA', pathway])].
[sujeto(['Myogenesis', is, a, highly, ordered, process, that]), verbo([involves]), complemento([the, expression, of, 'muscle-specific', 'genes,', 'cell-cell', recognition, and, multinucleated, myotube, formation])].
[sujeto(['Although', protein, tyrosine, kinases]), verbo([have]), complemento([figured, prominently, in, 'myogenesis,', the, involvement, of, tyrosine, phosphatases, in, this, process, is, unknown])].
[sujeto(['SHP-2', is, an, 'SH2', 'domain-containing', tyrosine, 'phosphatase,', which, positively]), verbo([regulates]), complemento([growth, and, differentiation])].
[sujeto(['We', show, that, in, 'C2C12', 'myoblasts,', 'SHP-2', becomes, upregulated, early, on, during, myogenesis, and]), verbo([associates]), complemento([with, a, 120, kDa, 'tyrosyl-phosphorylated', complex])].
[sujeto(['We']), verbo([have]), complemento([identified, that, the, 120, kDa, complex, consists, of, the, 'SHP-2', 'substrate-1', '(', 'SHPS-1)', and, the, 'Grb2-associated', 'binder-1', '(', 'Gab-1)'])].
[sujeto(['Either', constitutive, expression, or, inducible, activation, of, 'MyoD', in, 10, 'T(1/2)', fibroblasts]), verbo([promotes]), complemento(['SHPS-1', tyrosyl, phosphorylation, and, its, association, with, 'SHP-2'])].
[sujeto(['It']), verbo([has]), complemento([been, shown, that, p38, 'mitogen-activated', protein, kinase, '(', 'MAPK)', activity, is, required, for, the, 'expression/activation', of, 'MyoD', and, 'MyoD-responsive', genes])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'SHPS-1/SHP-2', complex, formation, is, an, integral, signaling, component, of, skeletal, muscle, differentiation])].
[sujeto(['Shp-2', is, a, ubiquitously]), verbo([expressed]), complemento([tyrosine, phosphatase, with, two, 'SH2', domains])].
[sujeto(['Homozygous', mutant, mice, with, a]), verbo([targeted]), complemento([deletion, of, 65, amino, acid, residues, in, the, 'N-terminal', 'SH2', domain, of, 'Shp-2', die, in, utero, at, 'mid-gestation,', with, multiple, defects, in, mesodermal, patterning])].
[sujeto(['Further,', mutant, 'ES', cells, were, more, sensitive, than, 'wild-type', cells, to, the, differentiation]), verbo([suppressing]), complemento([effect, of, leukemia, inhibitory, factor, '(', 'LIF)'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, 'Shp-2', tyrosine, phosphatase, is, a, positive, regulator, for, both, cell, differentiation, and, 'proliferation,', in, contrast, to, the, 'Src-family', kinases, which, promote, cell, growth, but, block, differentiation])].
[sujeto(['Triiodothyronine', '(', 'T3)', positively]), verbo([regulates]), complemento([both, the, expression, of, the, 'MyoD', 'gene,', a, key, myogenic, 'regulator,', and, 'C2', muscle, cell, differentiation])].
[sujeto(['To', directly, examine, the, role, of, its]), verbo([nuclear]), complemento([receptors, in, the, control, of, 'myogenesis,', we, introduced, a, 'c-erbA', expression, vector, into, 'C2', muscle, cells, by, transient, or, stable, transfection])].
[sujeto(['Our', results, show, that, 'c-erbA', can, play, a, potent, role, in, the]), verbo([triggering]), complemento([of, muscle, terminal, differentiation, since, its, overexpression, leads, 'to:', '(', 1, ')', a, complete, abrogation, of, the, activity, of, the, myogenesis, inhibitor, 'AP-1', '(', 'fos/jun)', transcription, 'factor;', '(', 2, ')', an, enhanced, induction, of, 'MyoD', expression, upon, 'T3', 'treatment;', '(', 3, ')', the, acquisition, by, 'T3', of, the, ability, to, trigger, both, growth, arrest, and, terminal, differentiation, in, the, presence, of, large, amounts, of, serum, 'mitogens,', a, property, that, is, otherwise, specific, to, retinoic, acid, '(', 'RA)'])].
[sujeto(['Thus,', 'c-erbA', is, one, of, the, two, protooncogenes, '(', with, 'c-ski)', that]), verbo([acts]), complemento([as, positive, regulator, of, muscle, differentiation])].
[sujeto(['Furthermore,', the, fact, that, 'c-erbA', overexpression, allows, 'T3', to, largely, mimic, the, 'RA', effects, indicates, that, their, biological, differences, in, the, modulation, of, myogenic, program, primarily, rely, on, the, differential, expression, of, their, receptors, in, 'C2', muscle, cells, rather, than, on, an, intrinsic, specificity, of, their]), verbo([target]), complemento([genes])].
[sujeto(['RVR/Rev-erb', 'beta/BD73', is, an, orphan, steroid, receptor, that]), verbo([has]), complemento([no, known, ligand, in, the, &, 'quot;classical\'', sense])].
[sujeto(['RVR']), verbo([binds]), complemento([as, a, monomer, to, an, element, which, consists, of, an, 'A/T-rich', sequence, upstream, of, the, consensus, hexameric, 'half-site'])].
[sujeto(['However,', 'RVR', does, not]), verbo([activate]), complemento([transcription, and, blocks, transactivation, of, this, element, by, 'ROR/RZR'])].
[sujeto(['The', mechanism, of, 'RVR', action, remains, 'obscure,', hence, we, used, the, 'GAL4', hybrid, system, to, identify, and, characterize, an, active, transcriptional, silencer, in, the, ligand]), verbo([binding]), complemento([domain, '(', 'LBD)', of, 'RVR'])].
[sujeto(['Although', 'RVR', is]), verbo([expressed]), complemento([in, many, adult, 'tissues,', including, skeletal, 'muscle,', and, during, 'embryogenesis,', its, physiological, function, in, differentiation, and, mammalian, development, remains, unknown])].
[sujeto(['COUP-TF', 'II', and, 'Rev-erbA', 'alpha,']), verbo([have]), complemento([been, demonstrated, to, regulate, muscle, and, adipocyte, 'differentiation,', we, investigated, the, expression, and, functional, role, of, 'RVR', during, mouse, myogenesis])].
[sujeto(['In', 'C2C12', myogenic, 'cells,', 'RVR', mRNA, was, detected, in, proliferating, myoblasts, and, was]), verbo([suppressed]), complemento([when, the, cells, were, induced, to, differentiate, into, 'post-mitotic,', multinucleated, myotubes, by, serum, withdrawal])].
[sujeto(['This']), verbo([decrease]), complemento([in, 'RVR', mRNA, correlated, with, the, appearance, of, 'muscle-specific', markers, '(', e])].
[sujeto(['RVR', '\'']), verbo([loss]), complemento([of, 'function\'', studies, by, constitutive, 'over-expression', of, a, dominant, negative, 'RVR', delta, 'E', resulted, in, increased, levels, of, 'p21Cip1/Waf1', and, myogenin, mRNAs, after, serum, withdrawal])].
[sujeto(['In', 'conclusion,', our, studies, identified, a, potent, transcriptional, repression, domain, in, 'RVR,', characterized, critical, amino, acids, within, the, silencing, region, and]), verbo([provide]), complemento([evidence, for, the, physiological, role, of, 'RVR', during, myogenesis])].
[sujeto(['ER-alpha', mRNA, expression]), verbo([increased]), complemento([with, all, three, drug, treatments, '(', 'P', &, 'lt;', 0.05, ')', while, there, was, no, change, in, mRNA, expression, of, 'ER-beta', in, hSkM, cells])].
[sujeto([mRNA, expression, of, 'SRC']), verbo([increased]), complemento([and, 'SMRT', decreased, with, 'oestradiol,', 'TAM', and, 'RAL', in, hSkM, cells, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['Importantly,', mRNA, expression, of, 'MyoD']), verbo([increased]), complemento([with, oestradiol, and, decreased, with, 'TAM', and, 'RAL', in, hSkM, cells, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto([mRNA, expression, of, 'GLUT4']), verbo([increased]), complemento([with, oestradiol, and, 'RAL', and, decreased, with, 'TAM', in, hSkM, cells, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['These', findings, are, novel, in, that, they]), verbo([provide]), complemento([the, first, evidence, that, oestradiol, and, selective, 'ER', modulators, influence, 'ER-alpha', function, in, hSkM, cells])].
[sujeto(['This', demonstrates, the, importance, of, the, 'ER', and, alterations, in, its, 'coregulators,', to, potentially]), verbo([prevent]), complemento([sarcopenia, and, promote, muscle, growth, in, postmenopausal, women, using, these, forms, of, hormone, replacement, therapy])].
[sujeto(['Thyroid', hormone]), verbo([stimulates]), complemento([myoblast, 'differentiation,', through, an, inhibition, of, 'AP-1', activity, occurring, at, the, onset, of, differentiation])].
[sujeto(['In', this, study, we]), verbo([found]), complemento([that, the, 'T3', nuclear, receptor, 'c-ErbAalpha1', '(', 'T3Ralpha1)', is, involved, in, a, mechanism, preserving, the, duration, of, myoblast, proliferation])].
[sujeto(['Independently', of, the, hormone, 'presence,', 'T3Ralpha1']), verbo([represses]), complemento([avian, 'MyoD', transcriptional, activity])].
[sujeto(['Using', several, mutants, of, 'T3Ralpha1,', we]), verbo([found]), complemento([that, the, hinge, region, plays, a, crucial, role, in, the, inhibition, of, 'MyoD', activity])].
[sujeto(['Similarly,', the, 'T3', receptor, also]), verbo([represses]), complemento([myogenin, transcriptional, activity])].
[sujeto(['Therefore,', despite]), verbo([stimulating]), complemento([avian, myoblast, differentiation, by, a, 'T3-dependent', pathway, not, involving, myogenic, 'factors,', 'T3Ralpha1', contributes, to, maintain, an, optimal, myoblast, proliferation, period, by, inhibiting, 'MyoD', and, myogenin, activity])].
[sujeto(['When', the, gene, for, this, chimeric, protein, was]), verbo([expressed]), complemento([in, 'NIH', 3, 'T3', or, 10, 'T1/2', 'fibroblasts,', these, cells, displayed, 'hormone-dependent', induction, of, myogenesis])].
[sujeto(['Our', experiments, focused, on, cell, lines]), verbo([expressing]), complemento([estrogen, 'receptor-MyoD', chimeras])].
[sujeto(['Induction', of, these, lines, in, the, presence, of, estradiol, and, an, inhibitor, of, protein, 'synthesis,', 'cycloheximide,', resulted, in, the, activation, of, the, endogenous, myogenin, gene, but, did, not]), verbo([activate]), complemento([the, 'muscle-specific', creatine, kinase, or, cardiac, 'alpha-actin', gene])].
[sujeto(['This', result]), verbo([suggests]), complemento([that, 'MyoD', is, not, a, &, 'quot;direct"', activator, of, these, downstream, myogenic, genes, but, must, first, activate, myogenin, as, an, intermediary])].
[sujeto(['Once', muscle, is]), verbo([induced]), complemento([by, estrogen, 'receptor-MyoD', the, muscle, phenotype, is, very, stable, and, does, not, need, the, continued, presence, of, estradiol, for, its, maintenance])].
[sujeto(['The', leukocyte, adhesion, receptors, 'M290', '(', alpha, 'M290/beta', 7, ')', and, 'LPAM-1', '(', alpha, 4, beta, 7, ')', comprise, the, beta, 7, -, subfamily, of, 'integrins,', which, are, constitutively]), verbo([expressed]), complemento([on, subsets, of, lymphocytes, populating, the, mouse, small, intestine])].
[sujeto(['They', are]), verbo([induced]), complemento([de, novo, after, in, vitro, activation, of, lymphocytes, and, hence, may, serve, a, more, general, role, in, inflammation])].
[sujeto(['In', order, to, understand, how, beta, 7, integrins, are]), verbo([regulated]), complemento([during, an, immune, 'response,', we, isolated, and, characterized, the, promoter, region, of, the, beta, 7, gene])].
[sujeto(['Transfection', assays, with, a, luciferase, reporter, gene, revealed, that, 'cell-specific', expression, in, vitro, was]), verbo([retained]), complemento([in, a, 292, bp, 'sequence,', which, contained, several, consensus, binding, motifs, for, transcriptional, factors, preferentially, expressed, in, cells, of, the, lymphoid, lineages])].
[sujeto(['The', beta, 7, 'promoter,', like, its, alpha, 4, chain, 'partner,', contains, the, 'E', box, core, sequence, 'CACCTG']), verbo([found]), complemento([within, the, muscle, creatine, kinase, enhancer, which, binds, 'MyoD', in, vitro])].
[sujeto(['The', number, of, potential, 'DNA']), verbo([binding]), complemento([sites, for, transcriptional, factors, in, the, beta, 7, promoter, parallels, the, complex, regulation, of, expression, of, 'M290', and, 'LPAM-1', in, inflammation, and, gut, mucosal, immunity])].
[sujeto(['The', metamorphosis, of, anuran, amphibians, is]), verbo([induced]), complemento([by, thyroid, hormone, '(', 'TH)'])].
[sujeto(['The', cells]), verbo([expressed]), complemento([myoblast, markers, and, differentiated, into, myotubes, in, differentiation, medium])].
[sujeto(['XL-B4', cells]), verbo([expressing]), complemento([fluorescent, proteins, were, transplanted, into, tadpole, tails])].
[sujeto(['Exposure', of, 'XL-B4', cells, to, the, 'TH', triiodothyronine, '(', 'T3)', for, several, days, significantly]), verbo([induced]), complemento([apoptotic, cell, death])].
[sujeto(['We', then, examined, an, early, response, of, expression, of, genes]), verbo([involved]), complemento([in, apoptosis, or, myogenesis, to, 'T3'])].
[sujeto(['Treatment', of, the, cells, with, 'T3']), verbo([increased]), complemento([transcription, of, genes, for, matrix, 'metalloproteinase-9', '(', 'MMP-9)', and, thyroid, hormone, receptor, beta])].
[sujeto(['Interestingly,', the, 'T3-treatment', also]), verbo([increased]), complemento([myoD, 'transcripts,', but, decreased, the, amounts, of, myogenin, mRNA, and, myosin, heavy, chain])].
[sujeto(['These', results, indicated, that, 'T3', could, not, only]), verbo([induce]), complemento(['apoptosis,', but, also, attenuate, myogenesis, in, tadpole, tails, during, metamorphosis])].
[sujeto(['This', complex]), verbo([interacts]), complemento([physically, with, several, nuclear, receptors, through, the, 'TRAP220', 'subunit,', and, with, diverse, activators, through, other, subunits])].
[sujeto(['TRAP220']), verbo([has]), complemento([been, reported, to, show, 'ligand-enhanced', interaction, with, peroxisome, 'proliferator-activated', receptor, 'gamma(2)', '(', 'PPAR', 'gamma(2)),', a, nuclear, receptor, essential, for, adipogenesis])].
[sujeto(['Here', we, show, that, 'Trap220(-/-)', fibroblasts, are, refractory, to, 'PPAR', 'gamma(2)-stimulated', 'adipogenesis,', but, not, to, 'MyoD-stimulated', 'myogenesis,', and, do, not]), verbo([express]), complemento([adipogenesis, markers, or, 'PPAR', 'gamma(2)', target, genes])].
[sujeto(['Further', indicative, of, a, direct, role, for, 'TRAP220', in, 'PPAR', 'gamma(2)', function, via, the, 'TRAP', 'complex,', 'TRAP', functions, directly, as, a, transcriptional, coactivator, for, 'PPAR', 'gamma(2)', in, a, purified, in, vitro, system, and]), verbo([interacts]), complemento([with, 'PPAR', 'gamma(2)', in, a, 'ligand-', and, 'TRAP220-dependent', manner])].
[sujeto(['One', aspect, of, this, control, is, 'unquestioned:', circulating, 'GH']), verbo([acts]), complemento([on, the, liver, to, stimulate, expression, of, the, 'IGF-I', and, 'IGFBP3', 'genes,', substantially, increasing, the, levels, of, these, proteins, in, the, circulation])].
[sujeto(['It', also, seems, that, 'GH']), verbo([stimulates]), complemento([expression, of, 'IGF-I', genes, in, skeletal, 'muscle,', although, there, are, a, number, of, cases, in, which, skeletal, muscle, 'IGF-I', expression, is, elevated, in, the, absence, of, 'GH'])].
[sujeto(['It', is, substantially, less, clear, that, 'GH']), verbo([acts]), complemento([directly, on, skeletal, muscle, to, stimulate, its, 'growth;', the, presence, of, 'GH', receptor, mRNA, in, skeletal, muscle, is, well, 'established,', but, most, investigators, have, been, unsuccessful, in, demonstrating, any, specific, binding, of, 'GH', to, skeletal, muscle, or, to, myoblasts, in, culture])].
[sujeto(['It']), verbo([has]), complemento([been, equally, difficult, to, show, direct, actions, of, 'GH', on, cultured, muscle, 'cells;', the, only, positive, report, concludes, that, the, early, 'insulin-like', effects, of, 'GH', can, result, from, direct, interactions, between, 'GH', and, isolated, muscle, cells])].
[sujeto(['It', is, well, established, by, studies, in, a, number, of, laboratories, on, a, variety, of, systems, that, 'IGFs']), verbo([stimulate]), complemento([many, anabolic, responses, in, 'myoblasts,', as, they, do, in, other, cell, types])].
[sujeto(['IGFs']), verbo([have]), complemento([the, unusual, property, of, stimulating, both, proliferation, and, differentiation, of, 'myoblasts,', responses, that, are, generally, believed, to, be, mutually, 'exclusive;', in, 'myoblasts,', they, are, in, fact, temporally, separated])].
[sujeto(['The', stimulation, of, differentiation, by, 'IGF-I', is, '(', at, least, in, 'part)', a, result, of, substantially]), verbo([increased]), complemento([levels, of, the, mRNA, for, 'myogenin,', the, member, of, the, 'MyoD', family, most, directly, associated, with, terminal, myogenesis])].
[sujeto(['As', levels, of, myogenin, mRNA, 'rise,', those, of, 'myf-5', mRNA, '(', the, only, other, member, of, the, 'MyoD', family]), verbo([expressed]), complemento([significantly, in, 'L6', 'myoblasts)', fall, 'dramatically,', although, 'myf-5', expression, is, required, for, the, initial, elevation, of, myogenin])].
[sujeto(['The', effects, of, 'IGFs', are, significantly]), verbo([modulated]), complemento([by, 'IGFBPs', secreted, by, myoblasts, in, 'serum-free', 'medium,', inhibitory, 'IG-FBPs-4', and, -, 6, are, expressed, and, secreted, by, 'L6A1', 'myoblasts,', while, expression, of, 'IGFBP-5', rises, dramatically, as, differentiation, proceeds])].
[sujeto(['Even', if, exogenous, 'IGFs', are, not, added, to, the, 'low-serum', &, 'quot;differentiation"', 'medium,', myoblasts]), verbo([express]), complemento([sufficient, amounts, of, autocrine, 'IGF-II', to, stimulate, myogenesis, after, a, period, of, 'time;', some, myogenic, cell, 'lines,', '(', such, as, 'Sol', 8, ')', are, so, active, in, expressing, the, 'IGF-II', gene, that, it, is, not, possible, to, demonstrate, effects, of, exogenous, 'IGFs'])].
[sujeto(['This', autocrine, expression, of, 'IGFs', is, by, no, means, unique, to, skeletal, muscle, 'cells;', 'indeed,', it, is, so, widely, seen, in, cells]), verbo([responding]), complemento([to, mitogenic, stimuli, that, we, suggest, that, 'IGFs', can, be, viewed, as, extracellular, second, messengers, that, mediate, 'most,', if, not, 'all,', such, actions, of, agents, that, stimulate, cell, proliferation])].
[sujeto(['The', component, of, serum, that]), verbo([suppresses]), complemento(['IGF-II', gene, expression, under, &, 'quot;growth"', conditions, appears, to, be, the, 'IGFs', 'themselves,', which, exhibit, a, very, high, potency, in, the, feedback, inhibition, of, 'IGF-II', expression])].
[sujeto(['In', 'addition,', 'IGFs']), verbo([have]), complemento([effects, on, the, expression, of, other, genes, related, to, differentiation])].
[sujeto(['Treatment', of, 'L6A1', cell, with, 'IGFs']), verbo([suppresses]), complemento([their, expression, of, the, 'myogenesis-inhibiting', 'TGF', beta, s, with, a, time, course, consistent, with, an, initial, proliferative, step, followed, by, 'differentiation,', i])].
[sujeto([expression, is, first]), verbo([increased]), complemento([and, then, very, substantially, decreased])].
[sujeto(['It', is, not, established, that, this, plays, a, role, in, control, of, 'differentiation,', but, experiments, with, 'FGF', antisense, constructs]), verbo([suggests]), complemento([that, this, may, well, be, the, case])].
[sujeto(['Until', 'recently,', 'IGFs', were, the, only, circulating, agents, known, to]), verbo([stimulate]), complemento([myoblast, 'differentiation,', in, contrast, to, the, relatively, large, number, of, growth, factors, that, inhibit, the, process])].
[sujeto(['It', is, now, clear, that, thyroid, hormones, and, 'RA', also]), verbo([stimulate]), complemento(['myogenesis,', and, that, 'IL-15', enhances, the, stimulatory, eff, 'Mouse', embryonic, stem, '(', 'ES)', cells, grown, in, aggregates, give, rise, to, several, different, cell, 'types,', including, cardiac, muscle])].
[sujeto(['We', confirm, that, alpha, 6, 'B', is, constitutively]), verbo([expressed]), complemento([by, 'ES', cells])].
[sujeto(['Culturing', the, aggregates, under, conditions, that]), verbo([stimulate]), complemento(['(', transforming, growth, factor, beta, 1, 'supplement)', or, inhibit, '(', 'TGF', beta, 1, plus, 10, '(', -, 9, ')', 'M', retinoic, acid, 'supplement)', cardiac, muscle, differentiation, does, not, lead, to, any, qualitative, differences, in, the, timing, of, expression, of, these, 'genes,', but, quantitative, changes, cannot, be, excluded])].
[sujeto(['The', 'TGF', beta, 1, supplement, 'does,', 'however,']), verbo([lead]), complemento([to, a, relatively, greater, expression, of, alpha, 6, 'A', compared, to, alpha, 6, 'B', than, the, 'TGF', beta, 1, plus, 10, '(', -, 9, ')', 'M', 'RA', supplement, after, 6, days, in, 'culture,', suggesting, that, alpha, 6, 'A', expression, is, favoured, under, conditions, that, stimulate, cardiac, muscle, differentiation])].
[sujeto(['The', switch, towards, alpha, 6, 'A', expression, in, 'ES', cell, aggregates, is, paralleled, by, expression, of, the]), verbo([binding]), complemento([receptor, for, 'TGF', beta, '(', 'T', beta, 'RII)'])].
[sujeto(['The', initial, characterisation, of, differentiating, 'ES', cell, aggregates, in, terms, of, alpha, 6, 'A', integrin, subunit, expression]), verbo([suggests]), complemento([that, this, model, system, could, be, a, valuable, tool, in, the, study, of, the, role, of, the, alpha, 6, 'A', beta, 1, integrin, in, cardiac, muscle, differentiation])].
[sujeto(['By', using, the, reverse, 'transcriptase-polymerase', chain, 'reaction,', we]), verbo([have]), complemento([detected, expression, of, various, genes, before, and, after, differentiation, induction, with, four, different, agents, in, four, established, 'MRT', cell, lines, '(', 'TM87-16,', 'STM91-01,', 'TTC642,', and, 'TTC549)'])].
[sujeto(['Before', and, after, 'induction,', 'c-myc,', 'IGF-II,', 'IGF-I', 'receptor,', and, 'IGF-II', receptor, were, constitutively]), verbo([expressed]), complemento([by, all, four, cell, lines])].
[sujeto(['The', neurofilament, 'medium-size', '(', 'NF-M)', was, constitutively]), verbo([expressed]), complemento([by, the, 'TM87-16', and, 'TTC642,', and, the, 'S100', protein, alpha, subunit, was, expressed, by, 'TM87-16,', 'TTC642,', and, 'TTC549'])].
[sujeto(['Chromogranin', 'A', was]), verbo([expressed]), complemento([by, 'TM87-16', only, after, treatment, with, either, 'TPA', or, 'RA'])].
[sujeto(['MyoD,', 'N-myc,', tyrosine, 'hydroxylase,', 'N-CAM,', 'trkA,', and, the, 'S100', protein, beta, subunit, were, not]), verbo([expressed]), complemento([by, any, cell, line, before, or, after, induction, with, these, agents])].
[sujeto(['The', proliferating, cells, in, 'TM87-16', and, 'TTC642']), verbo([expressed]), complemento([mRNA, profiles, characteristic, of, neuroectoderm])].
[sujeto(['Positive', feedback, is, a, common, mechanism, enabling, biological, systems, to]), verbo([respond]), complemento([to, stimuli, in, a, 'switch-like', manner])].
[sujeto(['To', understand, why, this, motif, is, so, 'prevalent,', we, examined, its, properties, in, an, evolutionarily]), verbo([conserved]), complemento([transcriptional, regulatory, network, in, yeast, '(', 'Oaf1p/Pip2p)'])].
[sujeto(['We', demonstrate, that, the, asymmetry, in, positive, feedback]), verbo([confers]), complemento([a, competitive, advantage, and, allows, the, system, to, robustly, increase, its, responsiveness, while, precisely, tuning, the, response, to, a, consistent, level, in, the, presence, of, varying, stimuli])].
[sujeto(['This', study]), verbo([reveals]), complemento([evolutionary, advantages, for, the, 'ASSURE', 'motif,', and, mechanisms, for, 'control,', that, are, relevant, to, pharmacologic, intervention, and, synthetic, biology, applications])].
[sujeto(['The', uncoupling, 'protein-3', '(', 'UCP-3)', gene, encodes, for, a, mitochondrial, protein]), verbo([expressed]), complemento([preferentially, in, skeletal, muscle])].
[sujeto(['UCP-3', mRNA, is]), verbo([expressed]), complemento([in, cultured, muscle, cells, '(', 'C2C12', or, 'L6E9)', only, when, 'differentiated,', at, which, stage, 'UCP-3', is, highly, induced, by, 'all-trans', retinoic, acid, '(', 'RA)'])].
[sujeto(['Here', we]), verbo([report]), complemento([that, human, 'UCP-3', promoter, activity, is, dependent, on, 'MyoD', and, inducible, by, all, 'trans-RA'])].
[sujeto(['The', action, of, all, 'trans-RA', is]), verbo([increased]), complemento([by, 'co-transfection', with, 'RA', receptor, '(', 'RAR)'])].
[sujeto(['We']), verbo([have]), complemento([characterized, the, 'RA', response, element, that, controls, the, induction, by, 'RA', in, the, 5, '\'', noncoding, region, of, the, 'UCP-3', gene])].
[sujeto(['Deletion', and, 'point-mutation', analysis, of, the, 'hUCP-3', promoter]), verbo([led]), complemento([us, to, identify, a, 'direct-repeat', element, with, one, 'base-pair', spacing, '(', 'DR1)', at, position, -, 71, /, -, 59, responsible, for, the, induction, by, 'RA', of, the, activity, of, the, promoter])].
[sujeto(['This', 'DR1', element]), verbo([bound]), complemento([a, nuclear, protein, complex, from, muscle, cells, that, contain, 'RAR', and, retinoid, 'X', receptor, '(', 'RXR)'])].
[sujeto(['In', 'conclusion,', it]), verbo([has]), complemento([been, established, that, 'UCP-3', gene, promoter, activity, is, dependent, on, 'MyoD,', and, the, first, regulatory, pathway, for, 'UCP-3', gene, promoter, regulation, has, been, recognized, by, identifying, 'RA', as, a, transcriptional, activator, of, the, gene])].
[sujeto(['In', 'C2', 'myoblasts,', retinoic, acid, '(', 'RA)', is, an, efficient, inducer, of, both, growth]), verbo([arrest]), complemento([and, differentiation])].
[sujeto(['These', 'RA', effects, are]), verbo([mediated]), complemento([through, at, least, two, classes, of, retinoic, acid, receptors, '(', 'RARs', and, 'RXRs),', which, belong, to, the, nuclear, receptor, superfamily])].
[sujeto(['To', determine, the, role, played, by, each, 'RAR', or, 'RXR', family, in, this, model, 'system,', we]), verbo([have]), complemento([analysed, the, effects, of, 'RA', in, 'C2', myoblasts, expressing, a, dominant, negative, 'RAR', '(', 'dnRAR)', or, a, dominant, negative, 'RXR', '(', 'dnRXR)'])].
[sujeto(['The', stable, expression, of, dnRAR, or, dnRXR, in, 'C2', cells, delays, the, 'RA-induced', growth]), verbo([arrest]), complemento([and, 'differentiation,', an, effect, which, is, more, pronounced, in, 'C2-dnRXR', myoblasts])].
[sujeto(['Furthermore,', the, 'RA-inducible', expression, of, 'MyoD', gene, is, lost, in, 'C2-dnRXR', but, not, in, 'C2-dnRAR', 'cells,', indicating, that, each, family, of, retinoid, receptors, 'RAR', and, 'RXR', may]), verbo([regulate]), complemento([distinct, subsets, of, 'RA-responsive', genes])].
[sujeto(['Finally,', using, 'C2', cell, lines, with, different, retinoid, 'responsiveness,', we]), verbo([provided]), complemento([evidence, for, a, link, between, the, 'RXR', and, 'MyoD', families, in, the, process, of, myogenic, differentiation])].
[sujeto(['These', results, illustrate, a, critical, role, for, 'RA-receptors', in, 'RA-control', of, 'C2', myogenesis, and]), verbo([provide]), complemento([tools, for, studying, the, function, of, 'RA', and, its, receptors, during, vertebrate, development])].
[sujeto(['Betaglycan', is, a, 'membrane-anchored', proteoglycan, 'co-receptor', that]), verbo([binds]), complemento([transforming, growth, factor, beta, '(', 'TGF-beta)', via, its, core, protein, and, basic, fibroblast, growth, factor, through, its, glycosaminoglycan, chains])].
[sujeto(['The', mouse, betaglycan, gene, promoter, was, 'cloned,', and, its, sequence, showed, putative]), verbo([binding]), complemento([sites, for, 'SP1,', 'Smad3,', 'Smad4,', muscle, regulatory, factor, elements, such, as, 'MyoD', and, 'MEF2,', and, retinoic, acid, receptor])].
[sujeto(['We']), verbo([found]), complemento([that, 'MyoD,', but, not, 'myogenin,', stimulated, this, transcriptional, activity, even, in, the, presence, of, high, serum])].
[sujeto(['Betaglycan', promoter, activity, was]), verbo([increased]), complemento([by, 'RA', and, inhibited, by, the, three, isoforms, of, 'TGF-beta'])].
[sujeto(['Forced', expression, of, betaglycan, in, 'C(2)C(12)', myoblasts]), verbo([increases]), complemento([their, responsiveness, to, 'TGF-beta2,', suggesting, that, it, performs, a, 'TGF-beta', presentation, function, in, this, cell, lineage])].
[sujeto(['These', results, indicate, that, betaglycan, expression, is, 'up-regulated', during, myogenesis, and, that, 'MyoD', and, 'RA']), verbo([modulate]), complemento([its, expression, by, a, mechanism, that, is, independent, of, myogenin])].
[sujeto(['Based', on, the, findings, that, 'AT2', receptor, stimulation]), verbo([causes]), complemento([inhibition, of, 'proliferation,', and, that, other, antiproliferative, agents, such, as, transforming, growth, 'factor-beta,', retinoic, 'acid,', and, 'MyoD', act, via, repression, of, immediate, early, gene, '(', 'IEG)', 'expression,', this, study, was, aimed, at, elucidating, whether, downregulation, of, 'IEG', expression, is, also, part, of, the, 'AT2', receptor, coupled, signaling, mechanism])].
[sujeto(['Stimulation', of, angiotensin, 'AT2', receptors, in, the, rat, pheochromocytoma, cell, line, 'PC12', 'W', following, pretreatment, with, growth, factors, was, able, to, counteract, growth, factor]), verbo([induced]), complemento([proliferation, but, not, to, repress, growth, factor, induced, 'c-fos', and, 'c-jun', 'expression;', neither, did, 'AT2', receptor, stimulation, cause, an, induction, of, 'c-fos', expression])].
[sujeto(['We', conclude, 'that,', in, contrast, to, other, 'growth-inhibiting', 'agents,', the, antiproliferative, effect, of, angiotensin, 'II', via, the, 'AT2', receptor, is, not]), verbo([mediated]), complemento([by, repression, of, the, immediate, early, genes, 'c-fos', and, 'c-jun'])].
[sujeto(['Muscle', is]), verbo([found]), complemento([in, close, association, with, orthopaedic, 'injury,', however, its, capacity, to, make, a, cellular, contribution, to, bone, repair, remains, ambiguous])].
[sujeto(['To', exclude, the, prospect, that, osteoprogenitors, spontaneously]), verbo([express]), complemento(['MyoD', during, bone, 'repair,', we, created, a, metaphyseal, drill, hole, defect, in, the, tibia])].
[sujeto(['No', 'hAP+', staining, was, observed, in, this, model]), verbo([suggesting]), complemento([that, the, expression, of, 'MyoD', is, not, a, normal, event, for, endogenous, osteoprogenitors])].
[sujeto(['These', data, document, for, the, first, time, that, muscle, cells, can, play, a, significant, secondary, role, in, bone, repair, and, this, knowledge, may]), verbo([lead]), complemento([to, important, translational, applications, in, orthopaedic, surgery])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, 'β/δ', '(', 'PPARβ/δ)']), verbo([regulates]), complemento([postnatal, myogenesis, by, alleviating, myostatin, 'activity,', but, the, molecular, mechanisms, by, which, it, regulates, myogenesis, are, not, fully, understood])].
[sujeto(['C2C12', myoblasts, treated, with, a, 'PPARβ/δ', 'agonist,', 'GW0742', exhibit]), verbo([enhanced]), complemento([myotube, formation, and, 'muscle-specific', gene, expression])].
[sujeto(['GW0742', treatment, dramatically]), verbo([activates]), complemento([promyogenic, 'kinases,', p38MAPK, and, 'Akt,', in, a, 'dose-dependent', manner])].
[sujeto(['GW0742-stimulated', myoblast, differentiation, is]), verbo([mediated]), complemento([by, p38MAPK, and, 'Akt,', since, it, failed, to, restore, myoblast, differentiation, repressed, by, inhibition, of, p38MAPK, and, 'Akt'])].
[sujeto(['In', 'addition,', 'GW0742', treatment]), verbo([enhances]), complemento(['MyoD-reporter', activities])].
[sujeto(['Consistently,', overexpression, of, 'PPARβ/δ']), verbo([enhances]), complemento([myoblast, differentiation, accompanied, by, elevated, activation, of, p38MAPK, and, 'Akt'])].
[sujeto(['Collectively,', these, results]), verbo([suggest]), complemento([that, 'PPARβ/δ', enhances, myoblast, differentiation, through, activation, of, promyogenic, signaling, pathways])].
[sujeto(['To']), verbo([enhance]), complemento([the, 'PPARγ', 'signaling,', 'M3,', the, transactivation, domain, of, 'MyoD,', was, fused, to, 'PPARγ'])].
[sujeto(['Although', the, transduction, of, either, 'PPARγ', or, 'M3-PPARγ']), verbo([induced]), complemento([adipogenesis, in, 'myoblasts,', 'M3-PPARγ', drastically, induced, the, brown, adipocyte, markers, of, 'UCP1,', 'CIDEA,', and, 'PRDM16', by, 1, ',', 50, ',', 2.4, ',', and, 5.0, 'fold,', respectively, and, increased, mitochondria, contents, by, 4, 'fold,', compared, to, 'PPARγ'])].
[sujeto(['The', mRNA, expression, of, 'MyoD', tended, to]), verbo([increase]), complemento([with, days, of, gestation, '(', 'P', =, 0.06, ')'])].
[sujeto(['The', mRNA, expression, of, zinc, finger, protein, 423, '(', 'Zfp423;', 'P', &, 'lt;', 0.0001, ')', ',', 'C/EBPα', '(', 'P', =, 0.01, ')', ',', and, 'PPARγ', '(', 'P', &, 'lt;', 0.0001, ')', were]), verbo([enhanced]), complemento([in, 'ON', fetuses])].
[sujeto(['The', mRNA, expression, of, transforming, growth, factor, β, '(', 'TGF-β;', 'P', &, 'lt;', 0.0001, ')', ',', collagen, type, 'III,', α, 'I', '(', 'COL3A1;', 'P', &, 'lt;', 0.0001, ')', ',', and, collagen, content, '(', 'P', =, 0.01, ')', were]), verbo([increased]), complemento([in, 'ON', fetuses])].
[sujeto(['These', data, shows, that, maternal, overnutrition]), verbo([enhances]), complemento([fibrogenesis, and, likely, adipogenesis, without, compromising, myogenesis, in, fetal, skeletal, muscle, of, cattle])].
[sujeto(['Here', we, show, that, 'cross-antagonistic', mechanisms, of, actions, of, 'MyoD', and, 'PPARγ,', which, are, the, master, regulators, of, muscle, and, adipose, 'differentiation,', 'respectively,']), verbo([confer]), complemento([robustness, to, the, integrity, 'of cell', differentiation])].
[sujeto(['Simultaneous', expression, of, 'MyoD', and, 'PPARγ', in, mesenchymal, 'stem/stromal', cells]), verbo([led]), complemento([to, the, generation, of, a, mixture, of, multinucleated, myotubes, and, 'lipid-filled', adipocytes])].
[sujeto([',', 'lipid-filled', 'myotubes)', were, not, 'generated,']), verbo([suggesting]), complemento([that, these, differentiation, programs, are, mutually, exclusive])].
[sujeto(['Mechanistically,', although, exogenously]), verbo([expressed]), complemento(['MyoD', was, rapidly, degraded, in, adipocytes, through, 'ubiquitin-proteasome', 'pathways,', exogenously, expressed, 'PPARγ', was, not, downregulated, in, myotubes])].
[sujeto(['In', 'PPARγ-expressing', 'myotubes,', 'PPARγ-dependent', histone, hyperacetylation, was]), verbo([inhibited]), complemento([in, a, subset, of, adipogenic, gene, 'loci,', including, that, of, 'C/EBPα,', an, essential, effector, of, 'PPARγ'])].
[sujeto(['Thus,', the, 'cross-repressive', interactions, between, 'MyoD-', and, 'PPARγ-induced', differentiation, programs]), verbo([ensure]), complemento([discrete, 'cell-fate', decisions])].
[sujeto(['Real-time', polymerase, chain, reaction, '(', 'PCR)', analyses, revealed, significant, upregulation, of, the, myogenic, regulatory, factors, 'MyoD', and, myogenin, and, significant, downregulation, of, the, adipogenic, transcription, factors, peroxisome, 'proliferator-activated', 'receptor-γ', '(', 'PPARγ)', and, 'CCAAT/enhancer']), verbo([binding]), complemento(['protein-α', '(', 'CEBPα)', in, masseter, muscles, treated, with, 'Mst-siRNA-lipoplexes'])].
[sujeto(['The', duty, times, of, masseter, muscle, activity, exceeding, 5, '%', showed, a, slight, tendency, to]), verbo([increase]), complemento([in, both, wild, type, and, mdx, mice])].
[sujeto(['Therefore,', cationic, 'liposome-mediated', local, administration, of, 'Mst-siRNA', could]), verbo([increase]), complemento([muscular, size, and, improve, muscle, activity])].
[sujeto(['Administration', of, 'β2-agonists']), verbo([triggers]), complemento([skeletal, muscle, anabolism, and, hypertrophy])].
[sujeto(['Phosphorylation', of, 'Akt,', ribosomal, protein, 'S6,', '4E-BP1', and, 'ERK1/2', was]), verbo([increased]), complemento([at, day, 3, ',', but, returned, to, control, level, at, day, 10])].
[sujeto(['This', could]), verbo([lead]), complemento([to, a, transient, increase, in, protein, translation, and, could, explain, previous, studies, that, reported, increase, in, protein, synthesis, following, 'β2-agonist', administration])].
[sujeto(['Formoterol', administration, was, also]), verbo([associated]), complemento([with, a, significant, reduction, in, 'MAFbx/atrogin-1', mRNA, level, '(', day, 3, ')', ',', suggesting, that, formoterol, can, also, affect, protein, degradation, of, 'MAFbx/atrogin1', targeted, 'substrates,', including, 'MyoD', and, eukaryotic, initiation, 'factor-3f', '(', 'eIF3-f)'])].
[sujeto(['Surprisingly,', mRNA, level, of, 'autophagy-related', 'genes,', light, chain, 3, beta, '(', 'LC3b)', and, 'gamma-aminobutyric', acid, 'receptor-associated', 'protein-like', 1, '(', 'Gabarapl1),', as, well, as, lysosomal, 'hydrolases,', cathepsin, 'B', and, cathepsin, 'L,', was, significantly, and, transiently]), verbo([increased]), complemento([after, 1, 'and/or', 3, 'days,', suggesting, that, autophagosome, formation, would, be, increased, in, response, to, formoterol, administration])].
[sujeto(['However,', this]), verbo([has]), complemento([to, be, relativized, since, the, mRNA, level, of, 'Unc-51-like', kinase1, '(', 'Ulk1),', 'BCL2/adenovirus', 'E1B', interacting, protein3, '(', 'Bnip3),', and, transcription, factor, 'EB', '(', 'TFEB),', as, well, as, the, protein, content, of, 'Ulk1,', 'Atg13,', 'Atg5-Atg12', complex, and, 'p62/Sqstm1', remained, unchanged, or, was, even, decreased, in, response, to, formoterol, administration])].
[sujeto(['Human', 'Adipose', stem, cells, '(', 'ASCs)']), verbo([have]), complemento([been, reported, to, regenerate, muscle, fibers, and, reconstitute, the, pericytic, cell, pool, after, myogenic, differentiation, in, vitro])].
[sujeto(['Thirty', days, after, engraftment, in, 'mice,', we]), verbo([found]), complemento([that, 'NG2(+)', 'ASCs', underwent, a, complete, myogenic, 'differentiation,', fabricating, a, human, skeletal, muscle, 'tissue,', while, 'NG2(-)', 'ASCs', merely, formed, a, human, adipose, tissue])].
[sujeto(['Both', tissues, formed]), verbo([expressed]), complemento(['Class', 'I', 'HLA,', confirming, their, human, origin, and, excluding, any, contamination, by, murine, cells])].
[sujeto(['In', 'conclusion,', our, study]), verbo([provides]), complemento([novel, evidence, that, 'NG2(+)', 'ASCs', loaded, on, 'XHA', scaffolds, are, able, to, fabricate, a, human, skeletal, muscle, tissue, in, vivo, without, the, need, of, a, myogenic, 'pre-differentiation', step, in, vitro])].
[sujeto(['The', 'self-healing', potential, of, each, tissue, belongs, to, endogenous, stem, cells, residing, in, the, 'tissue;', 'however,', there, are, currently, no]), verbo([reports]), complemento([mentioned, for, the, isolation, of, human, rotator, 'cuff-derived', mesenchymal, stem, cells, '(', 'RC-MSCs)', since])].
[sujeto(['Similar', to, 'BM-MSCs,', 'RC-MSCs', were, demonstrated, to]), verbo([have]), complemento([the, potential, to, undergo, 'osteogenic,', 'adipogenic,', and, chondrogenic, differentiation])].
[sujeto(['Upon', induction, in, the, defined, 'media,', 'RC-MSCs', also]), verbo([expressed]), complemento(['lineage-specific', 'genes,', such, as, 'Runx', 2, and, osteocalcin, in, osteogenic, 'induction,', 'PPAR-γ', and, 'LPL', in, adipogenic, 'differentiation,', and, aggrecan, and, 'Col2a1', in, chondrogenic, differentiation])].
[sujeto(['The', multipotent, feature, of, 'RC-MSCs', in, the, myogenic, injury, model, was, further, strengthened, by, the]), verbo([increase]), complemento([in, myogenic, potential, both, in, vitro, and, in, vivo, when, compared, with, 'BM-MSCs'])].
[sujeto(['We', hypothesized, that, key, genes]), verbo([involved]), complemento([in, muscle, development, and, mitochondrial, biogenesis, would, be, altered, following, uteroplacental, insufficiency, in, rat, 'pups,', and, improving, postnatal, nutrition, by, 'cross-fostering', would, ameliorate, these, deficits])].
[sujeto(['In', both, 'sexes,', peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)-γ', 'coactivator-1α', '(', 'PGC-1α),', cytochrome, c, oxidase, subunits, 3, and, 4, '(', 'COX', 'III', and, 'IV)', and, myogenic, regulatory, factor, 4, expression]), verbo([increased]), complemento([from, late, gestation, to, postnatal, 'life,', whereas, mitochondrial, transcription, factor, 'A,', myogenic, differentiation, 1, '(', 'MyoD),', myogenin, and, 'insulin-like', growth, factor, 'I', '(', 'IGF-I)', decreased])].
[sujeto(['Foetal', growth, restriction]), verbo([increased]), complemento(['MyoD', mRNA, in, females, at, 'PN7,', whereas, in, males, 'IGF-I', mRNA, was, higher, at, 'E20', and, 'PN1'])].
[sujeto(['Cross-fostering', 'Restricted', pups, onto, a, 'Control', mother, significantly]), verbo([increased]), complemento(['COX', 'III', mRNA, in, males, and, 'COX', 'IV', mRNA, in, both, sexes, above, controls, with, little, effect, on, other, genes])].
[sujeto(['Developmental', age, appears, to, be, a, major, factor]), verbo([regulating]), complemento([skeletal, muscle, mitochondrial, and, developmental, 'genes,', with, growth, restriction, and, 'cross-fostering', having, only, subtle, effects])].
[sujeto(['Arthritis', is, a, chronic, inflammatory, illness, that]), verbo([induces]), complemento(['cachexia,', which, has, a, direct, impact, on, morbidity, and, mortality])].
[sujeto(['Fenofibrate,', a, selective, 'PPARα', activator, prescribed, to, treat, human, 'dyslipidemia,']), verbo([has]), complemento([been, reported, to, decrease, inflammation, in, rheumatoid, arthritis, patients])].
[sujeto(['Fenofibrate']), verbo([decreased]), complemento([external, signs, of, arthritis, and, liver, 'TNFα', and, blocked, 'arthritis-induced', decreased, in, 'PPARα', expression, in, the, gastrocnemius, muscle])].
[sujeto(['Arthritis']), verbo([decreased]), complemento([gastrocnemius, 'weight,', which, results, from, a, decrease, in, 'cross-section', area, and, myofiber, 'size,', whereas, fenofibrate, administration, to, arthritic, rats, attenuated, the, decrease, in, both, gastrocnemius, weight, and, fast, myofiber, size])].
[sujeto(['Fenofibrate', treatment]), verbo([prevented]), complemento(['arthritis-induced', increase, in, 'atrogin-1', and, 'MuRF1', expression, in, the, gastrocnemius])].
[sujeto(['Myostatin', expression, was, not, modified, by, 'arthritis,', but, fenofibrate]), verbo([decreased]), complemento([myostatin, expression, in, the, gastrocnemius, of, arthritic, rats])].
[sujeto(['Arthritis']), verbo([increased]), complemento([muscle, expression, of, 'MyoD,', 'PCNA,', and, myogenin, in, the, rats, treated, with, vehicle, but, not, in, those, treated, with, fenofibrate])].
[sujeto(['The', results, indicate, 'that,', in, experimental, 'arthritis,', fenofibrate]), verbo([decreases]), complemento([skeletal, muscle, atrophy, through, inhibition, of, the, 'ubiquitin-proteasome', system, and, myostatin])].
[sujeto(['About', 30, '%', of, the, total, single, 'cell-derived', colonies]), verbo([expressed]), complemento([adipogenic, potential, '(', defined, 'cytochemically)', when, 'BRL', was, present])].
[sujeto(['Notably,', 'however,', some, cells, exhibited, both, 'PPARgamma', and, 'Runx2']), verbo([nuclear]), complemento([labeling, with, concomitant, upregulation, of, expression, of, their, target, genes, with, 'BRL', treatment])].
[sujeto(['The', fact, that, some, 'ObL', cells]), verbo([maintain]), complemento([capacity, for, adipogenic, fate, selection, even, at, relatively, mature, developmental, stages, implies, an, unexpected, plasticity, with, important, implications, in, normal, and, pathological, bone, development])].
[sujeto(['Menopause,', the, 'age-related']), verbo([loss]), complemento([of, ovarian, hormone, 'production,', promotes, increased, adiposity, and, associated, metabolic, 'pathology,', but, molecular, mechanisms, remain, unclear])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, estrogen, increases, skeletal, muscle, 'PPARdelta', expression, in, 'vivo,', and, transgenic, mice, overexpressing, 'muscle-specific', 'PPARdelta', are, reportedly, protected, from, 'diet-induced', obesity])].
[sujeto(['Compared', to, 'SHM,', muscle, from, 'OVX', mice, displayed, significantly]), verbo([decreased]), complemento([expression, of, 'PPARdelta', '(', 3.4, -, 'fold),', 'FoxO1', '(', 4.5, -, 'fold),', 'PDK-4', '(', 2.3, -, 'fold),', and, 'UCP-2', '(', 1.8, -, 'fold)'])].
[sujeto(['Consistent', with, studies, indicating, 'PPARdelta', and, 'FoxO1']), verbo([regulate]), complemento([muscle, fiber, 'type,', we, observed, dramatic, 'OVX-specific', decreases, in, slow, isoforms, of, the, contractile, proteins, myosin, light, chain, '(', 11.1, -, 'fold)', and, troponin, 'C', '(', 11.8, -, 'fold)'])].
[sujeto(['In', 'addition,', muscles, from, 'OVX', mice]), verbo([expressed]), complemento([57, '%', less, myogenin, '(', drives, type, 'I', fiber, 'formation),', 2, -, fold, more, 'MyoD', '(', drives, type, 'II', fiber, 'formation),', and, 1.6, -, fold, less, musclin, '(', produced, exclusively, by, type, 'II', 'fibers)', than, 'SHM,', collectively, suggesting, a, shift, towards, less, type, 'I', oxidative, fibers])].
[sujeto(['Finally,', and, consistent, with, changes, in, 'PPARdelta', and, 'FoxO1', 'activity,', we, observed]), verbo([decreased]), complemento([expression, of, 'atrogin-1', '(', 2.3, -, 'fold)', and, 'MuRF-1', '(', 1.9, -, 'fold)', in, 'OVX', mice])].
[sujeto(['In', 'conclusion,', muscles, from, ovariectomized, mice, display]), verbo([decreased]), complemento(['PPARdelta', and, 'FoxO1', 'expression,', abrogated, expression, of, downstream, targets, involved, in, lipid, and, protein, 'metabolism,', and, gene, expression, profiles, indicating, less, type, 'I', oxidative, fibers])].
[sujeto(['SIRT3', deacetylases, and]), verbo([activates]), complemento([a, large, number, of, mitochondrial, enzymes, involved, in, the, respiratory, 'chain,', in, 'ATP', 'production,', and, in, both, the, citric, acid, and, urea, cycles])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, the, regulation, of, myoblast, differentiation, is, tightly, linked, to, mitochondrial, activity])].
[sujeto(['Since', 'SIRT3']), verbo([modulates]), complemento([mitochondrial, 'activity,', we, decide, to, address, its, role, during, myoblast, differentiation])].
[sujeto(['The', inhibition, of, 'SIRT3', expression]), verbo([mediated]), complemento([by, the, stable, integration, of, 'SIRT3', short, inhibitory, 'RNA', '(', 'SIRT3shRNA)', in, 'C2C12', 'myoblasts,', resulted, 'in:', 1, ')', abrogation, of, terminal, differentiation, -, as, evidenced, by, a, marked, decrease, in, the, myoblast, fusion, index, and, a, significant, reduction, of, 'Myogenin,', 'MyoD,', 'Sirtuin', 1, and, 'Troponin', 'T', protein, expression, -, restored, upon, 'MyoD', 'overexpression;', 2, ')', a, decrease, in, peroxisome, 'proliferator-activated', receptor, gamma, coactivator, 1, -, alpha, '(', 'PGC-1α)', and, citrate, synthase, protein, expression, reflecting, an, alteration, of, mitochondrial, 'density;', and, 3, ')', an, increased, production, of, reactive, oxygen, species, '(', 'ROS)', mirrored, by, the, decreased, activity, of, manganese, superoxide, dismutase, '(', 'MnSOD)'])].
[sujeto(['Altogether', our, data, demonstrate, that, 'SIRT3', mainly]), verbo([regulates]), complemento([myoblast, differentiation, via, its, influence, on, mitochondrial, activity])].
[sujeto(['Initial', force, production, '(', 1.6, +, /, -, 0.1, 'g/g', body, 'wt)', declined, 45, '%', within, 10, min, and, was]), verbo([maintained]), complemento([for, the, remainder, of, the, experiment])].
[sujeto(['An', 'immediate-early', growth, response, was, present, in, the, extensor, digitorum, longus, '(', 'EDL)', muscle, '(', 'FOS,', 'JUN,']), verbo([activating]), complemento([transcription, factor, 3, ',', and, musculoaponeurotic, fibrosarcoma, 'oncogene)', with, a, similar, but, attenuated, pattern, in, the, soleus, muscle])].
[sujeto(['Transcript', profiles, showed]), verbo([decreased]), complemento([fast, 'fiber-specific', mRNA, '(', myosin, heavy, chains, 2, 'A', and, 2, 'B,', fast, troponins, 'T(3)', and, 'I,', 'alpha-tropomyosin,', muscle, creatine, 'kinase,', and, 'parvalbumin)', and, increased, slow, transcripts, '(', myosin, heavy, 'chain-1beta/slow,', troponin, 'C', 'slow,', and, tropomyosin, 3, 'y)', in, the, 'EDL', versus, soleus, muscles])].
[sujeto(['Histological', analysis, of, the, 'EDL', revealed, glycogen, depletion, without, inflammatory, cell, infiltration, in]), verbo([stimulated]), complemento([versus, control, 'muscles,', whereas, ultrastructural, analysis, showed, no, evidence, of, myofiber, damage, after, stimulation])].
[sujeto(['Multiple', fiber, 'type-specific', transcription, factors, '(', tea, domain, family, member, 1, ',']), verbo([nuclear]), complemento([factor, of, activated, 'T', cells, 1, ',', peroxisome, 'proliferator-activated', 'receptor-gamma', 'coactivator-1alpha', and, -, 'beta,', circadian, locomotor, output, cycles, 'kaput,', and, 'hypoxia-inducible', 'factor-1alpha)', increased, in, the, 'EDL', along, with, transcription, factors, characteristic, of, embryogenesis, '(', 'Kruppel-like', factor, 4, ;, 'SRY', box, containing, 17, ;, transcription, factor, 15, ;, 'PBX/knotted', 1, homeobox, 1, ;, and, embryonic, 'lethal,', abnormal, 'vision)'])].
[sujeto(['No', established, in, vivo, satellite, cell, markers, or, genes]), verbo([activated]), complemento([in, our, parallel, experiments, of, satellite, cell, proliferation, in, vitro, '(', cyclins, 'A(2),', 'B(2),', 'C,', and, 'E(1)', and, 'MyoD)', were, differentially, increased, in, the, stimulated, muscles])].
[sujeto(['This', conversion, was]), verbo([associated]), complemento([with, the, expression, of, 'phenotype-specific', transcription, factors, from, resident, fiber, 'myonuclei,', including, the, activation, of, nascent, developmental, transcriptional, programs])].
[sujeto(['Ucp3', is, predominantly]), verbo([expressed]), complemento([in, skeletal, muscle, and, brown, adipose, tissue, and, is, regulated, by, a, transcription, factor, complex, involving, peroxisome, 'proliferator-activated', 'receptor-alpha,', 'MyoD,', and, 'COUP', transcription, factor, 'II'])].
[sujeto(['By', analysis, of, a, mutant, 'Djungarian', hamster, model, lacking, 'Ucp3', transcription, specifically, in, brown, adipose, 'tissue,', we, identified, a, putative, transcription, 'factor-binding', site, that]), verbo([confers]), complemento([tissue, specificity])].
[sujeto(['A', naturally, occurring, intronic, point, mutation, disrupting, this, site]), verbo([leads]), complemento([to, brown, adipose, 'tissue-specific', loss, of, 'Ucp3', expression, and, an, altered, body, weight, trajectory])].
[sujeto(['Our', findings]), verbo([provide]), complemento([insight, into, 'tissue-specific', 'Ucp3', regulation, 'and,', for, the, first, 'time,', unambiguously, demonstrate, that, changes, in, 'Ucp3', expression, can, interfere, with, body, weight, regulation])].
[sujeto(['Several', signaling, pathways]), verbo([have]), complemento([been, shown, to, regulate, the, lineage, commitment, and, terminal, differentiation, of, 'MSCs'])].
[sujeto(['Here,', we, conducted, a, comprehensive, analysis, of, the, 14, types, of, bone, morphogenetic, protein, '(', 'BMPs)', for, their, abilities, to]), verbo([regulate]), complemento([multilineage, specific, differentiation, of, 'MSCs'])].
[sujeto(['We']), verbo([found]), complemento([that, most, 'BMPs', exhibited, distinct, abilities, to, regulate, the, expression, of, 'Runx2,', 'Sox9,', 'MyoD,', and, 'PPARgamma2'])].
[sujeto(['Further', analysis, indicated, that, 'BMP-2,', 'BMP-4,', 'BMP-6,', 'BMP-7,', and, 'BMP-9', effectively]), verbo([induced]), complemento([both, adipogenic, and, osteogenic, differentiation, in, vitro, and, in, vivo])].
[sujeto(['Overexpression', of, 'Runx2']), verbo([enhanced]), complemento(['BMP-induced', osteogenic, 'differentiation,', whereas, knockdown, of, 'Runx2', expression, diminished, 'BMP-induced', bone, formation, with, a, decrease, in, adipocyte, accumulation, in, vivo])].
[sujeto(['Interestingly,', overexpression, of, 'PPARgamma2', not, only]), verbo([promoted]), complemento([adipogenic, 'differentiation,', but, also, enhanced, osteogenic, differentiation, upon, 'BMP-2,', 'BMP-6,', and, 'BMP-9', stimulation])].
[sujeto(['Conversely,', 'MSCs', with, 'PPARgamma2', knockdown, or, mouse, embryonic, fibroblasts, derived, from, 'PPARgamma2(-/-)', mice, exhibited, a, marked]), verbo([decrease]), complemento([in, adipogenic, 'differentiation,', coupled, with, reduced, osteogenic, differentiation, and, diminished, mineralization, upon, 'BMP-9', 'stimulation,', suggesting, that, 'PPARgamma2', may, play, a, role, in, 'BMP-induced', osteogenic, and, adipogenic, differentiation])].
[sujeto(['Thus,', it, is, important, to, understand, the, molecular, mechanism, behind, 'BMP-regulated', lineage, divergence, during, 'MSC', 'differentiation,', as, this, knowledge, could, help, us, to, understand, the, pathogenesis, of, skeletal, diseases, and, may]), verbo([lead]), complemento([to, the, development, of, strategies, for, regenerative, medicine])].
[sujeto(['Women', exhibit, an]), verbo([enhanced]), complemento([capability, for, lipid, metabolism, during, endurance, exercise, compared, with, men])].
[sujeto(['Nuclear', 'AMP-activated', protein, 'kinase-alpha', '(', 'alphaAMPK)', 'Thr(172)', '(', 'P', &, 'lt;', 0.001, ')', ',', histone, deacetylase, 5, '(', 'HDAC5)', 'Ser(498)', '(', 'P', &, 'lt;', 0.001, ')', ',', and, 'MEF2', 'Thr', '(', 'P', &, 'lt;', 0.01, ')', phosphorylation]), verbo([increased]), complemento([with, exercise])].
[sujeto(['Of', 'these,', 'MEF2A', mRNA]), verbo([increased]), complemento([25, '%', specifically, in, women, '(', 'P', &, 'lt;', 0.05, ')', ',', whereas, 'MEF2D', mRNA, tended, to, increase, in, men, '(', 'P', =, 0.11, ')'])].
[sujeto(['Although', minor, sex, differences, in, mRNA, expression, were, 'observed,', the, main]), verbo([finding]), complemento([of, the, present, study, was, the, implication, of, a, joint, signaling, action, of, 'AMPK,', 'HDAC5,', and, 'PGC1alpha', on, 'MEF2', in, the, immediate, regulatory, response, to, endurance, exercise])].
[sujeto(['In', skeletal, muscle, 'cells,', connexin43, '(', 'Cx43)']), verbo([has]), complemento([been, identified, as, the, major, 'connexin,', and, 'gap-junctional', communication, mediated, by, connexins, has, been, shown, to, be, required, for, their, myogenic, differentiation])].
[sujeto(['In', 'addition,', inhibition, of, connexin, function]), verbo([has]), complemento([been, shown, to, induce, transdifferentiation, of, osteoblasts, to, an, adipocytic, phenotype])].
[sujeto(['In', the, present, 'study,', we, examined, whether, the, inhibition, of, connexin, function, could]), verbo([induce]), complemento([phenotypic, changes, in, skeletal, muscle, cells])].
[sujeto(['Treatment', of, skeletal, muscle, cells, with, an, inhibitor, of, connexin, 'function,', 18, 'alpha-glycyrrhetinic', acid, '(', 'AGRA),', resulted, in, a, reduction, in, the, number, of, 'MyoD-positive', cells, and, complete, inhibition, of, myotube, 'formation,', concomitantly, with, an]), verbo([increase]), complemento([in, the, number, of, 'C/EBPalpha-positive', cells])].
[sujeto(['AGRA-treated', cells, cultured, in, adipogenic, differentiation, medium, could, give, rise, to, mature, adipocytes, that]), verbo([express]), complemento([both, 'PPARgamma', and, 'C/EBPalpha'])].
[sujeto(['The', presence, of, 'AGRA', during, adipogenic, differentiation, did, not]), verbo([inhibit]), complemento([adipogenesis, of, skeletal, muscle, cells])].
[sujeto(['These', results, indicate, that, inhibition, of, connexin, function]), verbo([induces]), complemento([phenotypic, changes, of, skeletal, muscle, cells, to, enter, adipogenesis])].
[sujeto(['Wnt3a', signaling]), verbo([induced]), complemento(['beta-catenin', nuclear, translocation, and, activated, the, 'Wnt', pathway, in, rMSC])].
[sujeto(['Moreover,', 'Wnt3a', signaling]), verbo([induced]), complemento([2.62, '%', and, 3.76, '%', of, 'rMSC-expressed', desmin, and, myosin, heavy, chain, after, being, cultured, in, myogenic, medium])].
[sujeto(['The', myogenic, differentiation, 'genes,', including, 'Pax7,', 'MyoD,', 'Myf5,', 'Myf4,', and, 'myogenin,', were]), verbo([activated]), complemento([after, 'Wnt3a', treatment])].
[sujeto(['On', the, other, 'hand,', 'Wnt3a']), verbo([inhibited]), complemento([the, adipogenic, differentiation, in, rMSC, through, the, downregulated, expression, of, 'CCAAT/enhancer-binding', protein, alpha, '(', 'C/EBPalpha)', and, peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPARgamma)'])].
[sujeto(['Furthermore,', 'Wnt3a']), verbo([promoted]), complemento([the, migration, capacity, of, rMSC])].
[sujeto(['The', results, indicate, that, 'Wnt3a', signaling, can]), verbo([induce]), complemento([myogenic, differentiation, in, rMSC])].
[sujeto(['Wnt3a', signaling, is, also]), verbo([involved]), complemento([in, the, regulation, of, the, proliferation, and, migration, of, rMSC])].
[sujeto(['These', results, could]), verbo([provide]), complemento([a, rational, foundation, for, 'cell-based', tissue, repair, in, humans])].
[sujeto(['Muscle', fibres]), verbo([have]), complemento([different, properties, with, respect, to, 'force,', contraction, 'speed,', 'endurance,', 'oxidative/glycolytic', capacity, etc])].
[sujeto(['It', is]), verbo([suggested]), complemento([that, changes, in, 'nerve-evoked', muscle, activity, lead, to, a, variety, of, activity, correlates, such, as, increases, in, free, intracellular, 'Ca(2+)', levels, caused, by, influx, across, the, cell, membrane, 'and/or', release, from, the, sarcoplasmatic, 'reticulum,', concentrations, of, metabolites, such, as, lipids, and, 'ADP,', hypoxia, and, mechanical, stress])].
[sujeto(['Such', correlates, are, detected, by, sensors, such, as, protein, kinase, 'C', '(', 'PKC),', 'calmodulin,', 'AMP-activated', kinase, '(', 'AMPK),', peroxisome, 'proliferator-activated', receptor, δ, '(', 'PPARδ),', and, oxygen, dependent, prolyl, hydroxylases, that]), verbo([trigger]), complemento([intracellular, signaling, cascades])].
[sujeto(['These', complex, cascades]), verbo([involve]), complemento([several, transcription, factors, such, as, nuclear, factor, of, activated, 'T-cells', '(', 'NFAT),', myocyte, enhancer, factor, 2, '(', 'MEF2),', myogenic, differentiation, factor, '(', 'myoD),', 'myogenin,', 'PPARδ,', and, sine, oculis, homeobox, 1, /, eyes, absent, 1, '(', 'Six1/Eya1)'])].
[sujeto(['These', factors, might]), verbo([act]), complemento([indirectly, by, inducing, gene, products, that, act, back, on, the, 'cascade,', or, as, ultimate, transcription, factors, binding, to, and, 'transactivating/repressing', genes, for, the, fast, and, slow, isoforms, of, various, contractile, proteins, and, of, metabolic, enzymes])].
[sujeto(['The', determination, of, size, and, force, is, even, more, complex, as, this]), verbo([involves]), complemento([not, only, intracellular, signaling, within, the, muscle, 'fibres,', but, also, muscle, stem, cells, called, satellite, cells])].
[sujeto(['Intercellular', signaling, substances, such, as, myostatin, and, 'insulin-like', growth, factor, 1, '(', 'IGF-1)', seem, to]), verbo([act]), complemento([in, a, paracrine, fashion])].
[sujeto(['Induction', of, hypertrophy, is, accompanied, by, the, satellite, cells, fusing, to, myofibres, and, thereby]), verbo([increasing]), complemento([the, capacity, for, protein, synthesis])].
[sujeto(['In', addition, to, changes, in, myonuclear, number, during, 'hypertrophy,', changes, in, muscle, fibre, size, seem, to, be]), verbo([caused]), complemento([by, alterations, in, 'transcription,', translation, '(', per, 'nucleus)', and, protein, degradation])].
[sujeto(['Treatment', of, 'C2C12', cells, with, the, 'PPARgamma', 'ligand,', 15, -, 'deoxy-Delta12,14-prostaglandin', 'J2', '(', 15, 'd-PGJ2),']), verbo([repressed]), complemento([morphologically, defined, myogenesis, and, reduced, endogenous, mRNA, levels, of, the, myogenic, differentiation, markers, 'MyoD,', 'myogenin,', and, 'alpha-actin'])].
[sujeto(['In', transient, transfection, 'assays,', 15, 'd-PGJ2', specifically]), verbo([inhibited]), complemento([the, expression, of, a, 'MyoD', 'promoter-luciferase', reporter, gene, '(', 'MyoDLuc)', in, a, cell, 'type-', and, 'promoter-specific', 'manner,', indicating, that, 15, 'd-PGJ2', functions, in, part, by, repressing, 'MyoD', gene, transcription])].
[sujeto(['The', inhibition, of, 'MyoD', gene, expression, by, 15, 'd-PGJ2', is]), verbo([mediated]), complemento([by, the, distal, region, of, the, 'MyoD', gene, promoter])].
[sujeto(['PPARgamma', on, its, own, also]), verbo([inhibited]), complemento(['MyoDLuc', expression, and, further, augmented, the, 15, 'd-PGJ2', response])].
[sujeto(['In', 'contrast,', 'L-805645', and, ciglitazone, did, not]), verbo([inhibit]), complemento(['MyoDLuc', expression, on, their, own, but, did, so, in, the, presence, of, ectopically, expressed, 'PPARgamma'])].
[sujeto(['Thus,', distinct, 'PPARgamma', ligands, may]), verbo([repress]), complemento(['MyoD', gene, expression, through, 'PPARgamma-dependent', and, -, independent, 'pathways,', and, 15, 'd-PGJ2', can, inhibit, the, myogenic, program, independent, of, its, cognate, 'receptor,', 'PPARgamma'])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, γ, '(', 'PPARγ)', is, a, key, transcription, factor, in, adipogenesis, and, can, be]), verbo([regulated]), complemento([by, 'adipogenesis-related', factors])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, 'over-expression', of, 'MyoD', enhanced, porcine, adipocyte, differentiation, and, 'up-regulated', 'PPARγ', 'expression,', whereas, small, interfering, 'RNA', against, 'MyoD', significantly, attenuated, porcine, adipocyte, differentiation, and, inhibited, 'PPARγ', expression])].
[sujeto(['Electrophoretic', mobility, shift, assays, and, chromatin, immunoprecipitation, further, showed, that, these, two, regions, are, 'MyoD-binding', 'sites,', both, in, vitro, and, in, 'vivo,', indicating, that, 'MyoD', directly]), verbo([interacts]), complemento([with, the, porcine, 'PPARγ', promoter])].
[sujeto(['Thus,', our, results, demonstrate, that, an, 'Enhancer', box, and, a]), verbo([binding]), complemento([site, for, a, cooperative, 'co-activator', of, 'MyoD', are, present, in, the, promoter, region, of, porcine, 'PPARγ;', 'furthermore,', 'MyoD', 'up-regulates', 'PPARγ', expression, and, promotes, porcine, adipocyte, differentiation])].
[sujeto(['Adenosine', monophosphate, '(', 'AMP)-activated', protein, kinase, '(', 'AMPK)', is]), verbo([inhibited]), complemento([in, 'SM', of, fetuses, born, to, obese, mothers])].
[sujeto(['Metformin', administration]), verbo([prevented]), complemento([these, changes, in, 'OB', offspring, 'SM'])].
[sujeto(['Mitochondrial', content, 'decreased,', and, activities, of, citrate, synthase, and, 'β-hydroxyacyl-CoA', dehydrogenase, also]), verbo([decreased]), complemento([in, 'OB', offspring, 'SM,', whereas, they, were, recovered, in, 'MET', offspring, 'SM'])].
[sujeto(['Efficacy', of, differentiated, 'MSCs', to, regenerate, cells, in, the, injured, tissues]), verbo([requires]), complemento([the, ability, to, maintain, the, differentiation, toward, the, desired, cell, fate])].
[sujeto(['Since', 'MSCs', represent, an, attractive, source, for, autologous, 'transplantation,', cellular, and, molecular, signaling, pathways, and, 'micro-environmental', changes]), verbo([have]), complemento([been, studied, in, order, to, understand, the, role, of, 'cytokines,', 'chemokines,', and, transcription, factors, on, the, differentiation, of, 'MSCs'])].
[sujeto(['The', differentiation, of, 'MSC', into, a, mesenchymal, lineage, is, genetically, manipulated, and]), verbo([promoted]), complemento([by, specific, transcription, factors, associated, with, a, particular, cell, lineage])].
[sujeto(['Recent', studies]), verbo([have]), complemento([explored, the, integration, of, transcription, 'factors,', including, 'Runx2,', 'Sox9,', 'PPARγ,', 'MyoD,', 'GATA4,', and, 'GATA6', in, the, differentiation, of, 'MSCs'])].
[sujeto(['Therefore,', the, overexpression, of, a, single, transcription, factor, in, 'MSCs', may]), verbo([promote]), complemento(['trans-differentiation', into, specific, cell, 'lineage,', which, can, be, used, for, treatment, of, some, diseases])].
[sujeto(['Recently,', understanding, the, underlying, genetic, bases, of, 'IMF']), verbo([has]), complemento([been, a, focus, particularly, in, the, beef, industry])].
[sujeto(['In', this, 'study,', with, the, deep, insights, of, ameliorating, the, beef, quality, by, genetic, 'means,', the, role, of, the, 'CCAAT/enhancer']), verbo([binding]), complemento([protein, alpha, '(', 'C/EBPα)', gene, was, investigated, by, 'over-expressing', 'C/EBPα', in, bovine, muscle, stem, cells, '(', 'MSCs)', to, initiate, the, adipogenic, program])].
[sujeto(['Prior', to, 'this,', bovine, 'MSCs', were, isolated, and]), verbo([induced]), complemento([to, differentiate, into, adipocytes, from, cells, that, were, exposed, to, dexamethasone, isobutylmethylxanthine, and, 'indomethacin;', the, presence, of, insulin, and, fetal, bovine, serum, was, examined])].
[sujeto(['Either', ectopic, expression, of, 'C/EBPα', or, treatment, with, dexamethasone, and, insulin]), verbo([induced]), complemento([the, accumulation, of, fat, droplets, and, the, expression, of, adipogenic, induction, genes, '(', 'LPL,', 'PPARγ,', 'C/EBPβ,', and, 'C/EBPδ)'])].
[sujeto(['This', study]), verbo([provides]), complemento([evidence, that, the, 'C/EBPα', gene, is, essential, for, cattle, adipose, tissue, growth, and, development])].
[sujeto(['Hence,', this]), verbo([finding]), complemento([can, contribute, to, improving, beef, carcass, quality])].
[sujeto(['Chemerin', is, an, 'adipocyte-secreted', adipokine, that]), verbo([regulates]), complemento([the, differentiation, and, metabolism, of, adipose, through, 'auto-/paracrine', signaling])].
[sujeto(['Its', function, in, the, differentiation, of, multipotent, myoblast, cells]), verbo([has]), complemento([thus, far, received, little, attention])].
[sujeto(['The', results, showed, that, 'Chemerin']), verbo([increased]), complemento(['ROS', levels, and, 'TG', content, of, 'C2C12', cells])].
[sujeto(['At', the, same, 'time,', the, mRNA, expressions, and, protein, concentrations, of, the, adipogenic, factors, 'PPARγ,', 'C/EBPα', and, 'UCP1', were, 'up-regulated,', while, the, muscle, specific, transcription, factors, 'MyoD,', 'Myogenin', and, 'MyHC', were]), verbo([decreased]), complemento([in, cultured, 'C2C12', cells])].
[sujeto(['In', 'conclusion,', the, adipokine, 'Chemerin']), verbo([promoted]), complemento([the, adipogenic, differentiation, potential, and, altered, the, fate, of, myoblast, cells, from, myogenesis, to, 'adipogenesis,', which, contributed, in, part, to, the, 'up-regulated', adipocyte, genes])].
[sujeto(['Our', study]), verbo([reveals]), complemento([the, importance, of, functional, 'Chemerin', signaling, in, adipogenesis, and, in, directing, the, differentiation, of, multipotent, myoblast, cells])].
[sujeto(['It']), verbo([has]), complemento([been, reported, that, the, 'lineage-specific', transcriptional, factors, including, 'Runt', related, transcription, factor, 2, '(', 'RUNX2),', 'Peroxisome', 'proliferator-activator', receptor, gamma, '(', 'PPARgamma)', and, 'Myogenic', differentiation, 1, '(', 'MyoD)', may, play, key, regulatory, roles, among, the, differentiation, of, 'MSCs'])].
[sujeto(['Recently,', researches]), verbo([have]), complemento([confirmed, that, the, 'Hippo', pathway, impacts, the, differentiation, fates, of, 'MSCs', through, regulating, the, activity, of, 'line-', 'age-specific', transcription, factors, by, the, 'Hippo', pathway, effectors, 'Tafazzin', '(', 'TAZ)', 'and/or', 'Yes-associated', protein, '(', 'YAP)'])].
[sujeto(['The', interaction, between, 'TAZ', and, 'RUNX2', boosts, the, osteogenic, processes, and]), verbo([promotes]), complemento(['MSCs', differentiating, into, osteoblast, lineage])].
[sujeto(['However,', 'PPARgamma']), verbo([binding]), complemento([to, 'TAZ', may, inhibit, the, adipocytes, 'differentiation,', and, thus, overexpression, of, 'TAZ', in, mesenchymal, stem, 'cell-like', cells, increases, the, expression, of, myogenic, genes, and, hastens, myofiber, formation, through, a, 'MyoD-dependent', manner])].
[sujeto([')', ',', and, mechanistic, stimuli, can, also, affect, the, fate, by]), verbo([regulating]), complemento([the, activity, of, 'TAZ/YAP'])].
[sujeto(['Compared', with, 'Chenghua', 'pigs,', development, and, maturation, of, fetal, skeletal, muscles, may, occur, earlier, in, 'Yorkshire', 'pigs,', but, the, negative, regulatory, effects, of, myostatin, may]), verbo([suppress]), complemento([muscle, development, at, the, later, stage])].
[sujeto(['The', following, parameters, were, 'measured:', cell, number, and, viability, by, laser, scanning, confocal, 'microscopy;', cell, proliferation, with, the, 'MTS', 'assay;', the, expression, of, a, panel, of, 18, genes, using, 'real-time', 'RT-PCR;', matrix, metalloproteinases, '(', 'MMPs)', 1, -, 3, ',', 'TIMP-1,', 'CTGF', and, 'FGF-2', protein, levels, in, supernatants, from, mechanically]), verbo([activated]), complemento([cultures, with, 'Enzyme-linked', immunosorbent, assays])].
[sujeto(['CTGF/FGF-2']), verbo([stimulated]), complemento([cell, proliferation, in, stationary, 'cultures,', but, relative, quantity, values, suggested, modest, effects, on, gene, expression])].
[sujeto(['Three-dimensional', tissue, constructs]), verbo([provide]), complemento([additional, complexity, to, monolayer, culture, 'systems,', and, suggest, some, of, the, assumptions, regarding, cell, 'growth,', differentiation, and, matrix, turnover, based, on, 'two-dimensional', cultures, may, not, apply, to, cells, in, 'three-dimensional', matrices])].
[sujeto(['The', five, cell, lines, were, transfected, with]), verbo([enhanced]), complemento([green, fluorescence, protein, gene, respectively, using, lipofection])].
[sujeto(['NS', and, 'AFS', cells, were]), verbo([induced]), complemento([to, differentiate, in, vitro])].
[sujeto(['The', five, cell, lines, were, used, for]), verbo([nuclear]), complemento([transfer])].
[sujeto(['The', results, showed, that, both, 'NS', and, 'AFS', cells]), verbo([expressed]), complemento(['POU5F1,', 'THY1', and, 'SOX2,', and, they, were, both, induced, to, differentiate, into, astrocyte, '(', 'GFAP+),', oligodendrocyte, '(', 'GalC+),', neuron, '(', 'NF+,', 'ENO2+,', and, 'MAP2+),', adipocyte, '(', 'LPL+', and, 'PPARG-D+),', osteoblast, '(', 'osteonectin+', and, 'osteocalcin+),', myocyte, '(', 'MYF6+', and, 'MYOD+),', and, endothelium, '(', 'PECAM1+,', 'CD34+,', 'CDH5+,', and, 'NOS3+)', respectively])].
[sujeto([5, ')', than, that, of, the, embryos, cloned, from, somatic, cells, '(', 'morula-blastocyst', rate, was, 16.27, -, 19.28, '%', and, pregnancy, rate, was, 0.0, '%', ')', ',', which]), verbo([suggests]), complemento([that, the, undifferentiated, state, of, the, donor, cells, increases, cloning, efficiency])].
[sujeto(['Skeletal', muscle, wasting, is, an, important, public, health, problem]), verbo([associated]), complemento([with, 'aging,', chronic, 'disease,', 'cancer,', kidney, 'dialysis,', and, 'HIV/AIDS'])].
[sujeto([1, ',', 25, -, 'Dihydroxyvitamin', 'D', '(', 1, ',', 25, -, 'D3),', the, active, form, of, vitamin, 'D,', is, widely]), verbo([recognized]), complemento([for, its, regulation, of, calcium, and, phosphate, homeostasis, in, relation, to, bone, development, and, maintenance, and, for, its, calcemic, effects, on, target, 'organs,', such, as, 'intestine,', 'kidney,', and, parathyroid, glands])].
[sujeto(['Emerging', evidence]), verbo([has]), complemento([shown, that, vitamin, 'D', administration, improves, muscle, performance, and, reduces, falls, in, vitamin, 'D-deficient', older, adults])].
[sujeto(['However,', little, is, known, of, the, underlying, mechanism, or, the, role, 1, ',', 25, -, 'D3', plays, in]), verbo([promoting]), complemento([myogenic, differentiation, at, the, cellular, 'and/or', molecular, level])].
[sujeto(['Addition', of, 1, ',', 25, -, 'D3', to, 'C(2)C(12)', myoblasts, 1, ')']), verbo([increased]), complemento([expression, and, nuclear, translocation, of, the, vitamin, 'D', 'receptor,', 2, ')', decreased, cell, 'proliferation,', 3, ')', decreased, 'IGF-I', 'expression,', and, 4, ')', promoted, myogenic, differentiation, by, increasing, 'IGF-II', and, follistatin, expression, and, decreasing, the, expression, of, 'myostatin,', the, only, known, negative, regulator, of, muscle, 'mass,', without, changing, growth, differentiation, factor, 11, expression])].
[sujeto(['Recent', studies, on, 'VDR', gene, knockout, mice, revealed, that, 'VDR', also]), verbo([regulates]), complemento([expression, of, the, 'MyoD', family, of, transcription, factors, in, skeletal, muscle])].
[sujeto(['Thus,', vitamin, 'D', and, 'Ca', appear, to]), verbo([regulate]), complemento(['proliferation,', maturation, and, function, of, skeletal, muscle, through, these, complex, actions])].
[sujeto(['In', an, earlier, 'study,', we]), verbo([reported]), complemento([on, the, linkage, relationships, of, 16, loci, on, mouse, chromosome, 7, and, the, homologous, relationship, between, this, chromosome, and, the, myotonic, dystrophy, gene, region, on, human, chromosome, 19])].
[sujeto(['Overexpression', of, multidrug, resistance, 1, '(', 'MDR1)', in, cancer, remains, one, of, the, major]), verbo([causes]), complemento([for, the, failure, of, chemotherapy])].
[sujeto(['In', the, present, 'study,', we]), verbo([found]), complemento([that, 'MyoD', and, 'PEA3', could, activate, 'P-glycoprotein', '(', 'P-gp)', expression, in, 'SGC7901', cells])].
[sujeto(['Knockdown', of, 'MyoD', and, 'PEA3', attenuated, 'MDR1', expression, and]), verbo([increased]), complemento([the, sensitivity, of, multidrug, resistant, cancer, cells, to, cytotoxic, drugs, that, were, transported, by, 'P-gp', in, 'SGC7901/VCR', cells])].
[sujeto(['MyoD', or, 'PEA3', could]), verbo([bind]), complemento([to, the, 'E-box', and, 'PEA3', sites, on, the, 'MDR1', promoter, and, activate, its, transcription])].
[sujeto(['The', regulation, of, 'MDR1', expression, by, 'MyoD', and, 'PEA3', may]), verbo([provide]), complemento([potential, ways, to, overcome, 'MDR', in, cancer, treatment])].
[sujeto(['We']), verbo([have]), complemento([characterized, the, promoter, methylation, profile, of, 82, genes, in, three, prostate, cancer, cell, lines, '(', 'LNCaP,', 'PC3,', and, 'DU145)', and, two, normal, prostate, cell, lines, '(', 'RWPE1', and, 'RWPE2)'])].
[sujeto(['Methylation']), verbo([binding]), complemento(['protein-purified', methylated, 'DNA', was, hybridized, on, the, membrane, and, detected, by, the, chemiluminescence, method])].
[sujeto(['In', 'addition,', promoter, methylation, was, detected, for, the, first, time, in]), verbo([target]), complemento([genes, such, as, 'RIOK3,', 'STAT5,', 'CASP8,', 'SRBC,', 'GAGE1,', and, 'NPAT'])].
[sujeto(['Overexpression', of, 'MDR1', in, breast, cancer, remains, a, major]), verbo([cause]), complemento([for, the, failure, of, chemotherapy])].
[sujeto(['In', the, present, 'report,', we]), verbo([find]), complemento(['UHRF1', plays, an, important, role, in, inhibiting, 'MDR1', promoter, activity, by, directly, binding, to, the, 'MDR1', promoter])].
[sujeto(['Knockdown', of, 'UHRF1']), verbo([activates]), complemento(['MDR1', promoter, activity, and, 'expression,', attenuates, the, binding, of, 'UHRF1', and, 'HDAC1', to, the, 'MDR1', promoter])].
[sujeto(['Overexpression', of, 'UHRF1', in, 'NCI/ADR-RES', cells, can]), verbo([induce]), complemento([deacetylation, of, histones, 'H3', and, 'H4', on, the, 'MDR1', 'promoter,', which, is, facilitated, by, recruitment, of, 'HDAC1', to, the, 'MDR1', promoter])].
[sujeto(['Loss', of, histone, acetylation, is, accompanied, by]), verbo([loss]), complemento([of, binding, of, the, key, transcription, 'factor,', 'MyoD,', 'CBP', and, 'p300,', locking, in, marked, suppression, of, 'MDR1,', increasing, sensitivity, of, 'MDR', cancer, cells, to, cytotoxic, drugs, that, are, transported, by, 'P-glycoprotein(P-gp)'])].
[sujeto(['The', inhibition, of, 'MDR1', expression, by, 'UHRF1', may]), verbo([provide]), complemento([potential, ways, to, overcome, multidrug, resistance, '(', 'MDR)', in, breast, cancer, treatment])].
[sujeto(['Fibroblast', growth, factor, 6, '(', 'FGF6)', is, selectively]), verbo([expressed]), complemento([during, muscle, development, and, regeneration])].
[sujeto(['FGF6', produced, in, genetically, engineered, mpc, was, 'active,']), verbo([inducing]), complemento([strong, morphological, 'changes,', altering, cell, adhesion, and, compromising, their, ability, to, differentiate, into, myotubes])].
[sujeto(['We', also]), verbo([report]), complemento([that, in, the, presence, of, 'FGF6,', the, minor, '(', 0.5, -, 2, '%', ')', subpopulation, of, cells, actively, excluding, 'Hoechst', 33342, in, a, 'verapamil-dependent', manner, '(', 'SP', 'phenotype)', was, increased, to, 15, -, 20, '%', and, the, expression, of, the, mdr1a, gene, '(', but, not, 'mdr1b)', was, upregulated, by, 400, -, fold])].
[sujeto(['Our', data, establish, a, previously, undescribed, link, between, 'FGF6--a', muscle, specific, growth, 'factor--and', a, multidrug, resistance, gene]), verbo([expressed]), complemento([in, stem, 'cells,', and, suggest, a, role, for, 'FGF6', in, the, maintenance, of, a, reserve, pool, of, progenitor, cells, in, the, skeletal, muscle])].
[sujeto(['To', establish, a, rabbit, model, for, investigating, the, effects, of, intermittent, cyclic, mechanical, tension, '(', 'ICMT)', on]), verbo([promoting]), complemento([degeneration, of, endplate, cartilage])].
[sujeto(['Multiple', strategies, were, employed, to, examine, degeneration, of, endplate, cartilage, and]), verbo([nuclear]), complemento([factor, '(', 'NF)-κB', signaling, pathway, activation])].
[sujeto(['Examination', of, hematoxylin, and, eosin, staining, of, sections, of, endplate, cartilage, showed, significant, damage, as, the, load, duration]), verbo([increased]), complemento([in, the, 'ICMT', loading, group])].
[sujeto(['Additionally,', 'ICMT', loading, can]), verbo([lead]), complemento([to, 'NF-κB', signaling, pathway, activation, as, well, as, degeneration, of, endplate, cartilage])].
[sujeto(['These', experiments, indicate, that, 'ICMT', contributes, to, the, activation, of, 'NF-κB', signaling, pathway, in, vivo, and, that, the, 'NF-κB', signaling, pathway, further, 'up-regulates', 'MMP13,']), verbo([leading]), complemento([to, degeneration, of, endplate, cartilage])].
[sujeto(['Although', oxidative, stress, is, implicated, in, 'SeMet', 'toxicity,', knowledge, gaps, remain, in, how, 'SeMet']), verbo([causes]), complemento([characteristic, spinal, deformities])].
[sujeto(['Gene', expression, studies, for, the, 'UPR']), verbo([suggest]), complemento([a, potential, role, for, 'CHOP', '(', 'c/ebp', homologous, 'protein)', induced, apoptosis, deformed, embryos, after, 5, μM, 'SeMet,', accompanied, by, a, significant, decrease, in, 'PDIA4', '(', protein, disulfide, isomerase, 'A4)', and, no, change, in, 'Dnajb9', '(', 'ER', 'DNA', 'J', 'Domain-Containing', 'Protein', 4, ')'])].
[sujeto(['This', expression, was, distinct, from, the, 'UPR']), verbo([induced]), complemento([by, 'well-studied', 'ER', stress, 'inducer,', 'tunicamycin,', which, robustly, activated, 'CHOP,', 'PDIA4', and, 'Dnajb9'])].
[sujeto(['Finally,', 'SeMet', treatment, significantly]), verbo([decreased]), complemento([transcripts, of, cartilage, 'development,', 'Sox9', '(', 'SRY', box, 9, ')', ',', while, increasing, 'Runx2', in, deformed, 'embryos,', without, altering, 'Twist', or, 'Collagen', 2, a1])].
[sujeto(['Results']), verbo([suggest]), complemento([that, oxidative, 'stress,', the, 'UPR', and, cell, death, play, key, roles, in, 'SeMet', induced, deformities, and, altered, skeletal, development, factors])].
[sujeto(['The', 'sex-determining', gene, 'SRY']), verbo([induces]), complemento(['SOX9', expression, in, the, testes, of, eutherian, mammals, via, two, pathways])].
[sujeto(['SRY']), verbo([binds]), complemento([to, 'testis-specific', enhancer, of, 'Sox9', '(', 'TESCO)', with, 'SF1', to, activate, 'SOX9', transcription])].
[sujeto(['SRY', also, 'up-regulates', 'ER71', 'expression,', and, 'ER71']), verbo([activates]), complemento(['Sox9', transcription])].
[sujeto(['After', the, initiation, of, testis, 'differentiation,', 'SOX9']), verbo([enhances]), complemento(['Amh', expression, by, binding, to, its, promoter, with, 'SF1'])].
[sujeto(['SOX8,', 'SOX9', and, 'SOX10,', members, of, the, 'SOXE', gene, 'family,', also]), verbo([enhance]), complemento([the, activities, of, the, 'Amh', promoter, and, 'TESCO'])].
[sujeto(['The', activity, of, the, 'AMH', promoter, was]), verbo([stimulated]), complemento([by, 'SOXE', genes, and, 'SF1'])].
[sujeto(['Mutant', 'AMH', 'promoters,', with, mutations, in, its, 'SOX', and, 'SF1']), verbo([binding]), complemento(['sites,', did, not, show, significant, activity, by, 'SOX9', and, 'SF1'])].
[sujeto(['These', results, indicate, that, 'AMH', expression, was]), verbo([regulated]), complemento([by, the, binding, of, 'SOX9', and, 'SF1'])].
[sujeto(['By', 'contrast,', 'SOXE', genes, could, not]), verbo([enhance]), complemento(['TESCO', activity])].
[sujeto(['Furthermore,', the, activity, of, the, 'SOX9', promoter, was]), verbo([enhanced]), complemento([by, 'ER71,', indicating, that, 'ER71', may, play, an, important, role, in, the, 'testis-specific', expression, of, 'SOX9'])].
[sujeto(['In', a, 46, ',', 'XY', 'individual,', the, presence, of, the, 'Y', chromosome, harboring, the, 'testis-determining', factor, '(', 'SRY)']), verbo([triggers]), complemento([testis, determination, and, differentiation])].
[sujeto(['In', a, 46, ',', 'XX', 'individual,', the, absence, of, 'SRY', along, with, the, activation, of, genes]), verbo([associated]), complemento([with, the, female, pathway, leads, to, ovarian, development])].
[sujeto(['The', latter, process]), verbo([has]), complemento([long, been, considered, as, a, default, pathway])].
[sujeto(['However,', recent, studies]), verbo([have]), complemento([cast, doubts, on, this, dogma])].
[sujeto(['Especial', attention, is, paid, to, 'FOXL2', whose, mutations, are, responsible, for, the, blepharophimosis, 'syndrome,', often]), verbo([associated]), complemento([with, female, 'infertility,', and, for, cancer])].
[sujeto(['We', highlight, the, cooperation, of, 'WNT4,', 'RSPO1', and, 'FOXL2', within, a, regulatory, network, and, the, need, for, further, research, to, better, understand, their, role, in, defining, and]), verbo([maintaining]), complemento([ovarian, identity])].
[sujeto(['Here,', we]), verbo([report]), complemento([a, rare, congenital, chromosomal, 'aberration,', 46, ',', 'X,dic(X;Y)(p22'])].
[sujeto(['A', cytogenetic, examination, of]), verbo([stimulated]), complemento([peripheral, blood, cells, revealed, the, constitutional, karyotype, 46, ',', 'X,dic(X;Y)(p22'])].
[sujeto(['A', 'CGH/SNP', array, '(', 'Illumina)', revealed, a]), verbo([gain]), complemento([of, 153, ',', 7, 'Mbp', of, the, 'X', chromosome, and, a, 803, -, kbp, microdeletion, '(', including, the, 'SHOX', 'gene),', which, were, also, confirmed, with, 'FISH'])].
[sujeto(['SHOX', encodes, a, transcriptional, factor, that]), verbo([regulates]), complemento([the, growth, of, the, long, bones])].
[sujeto(['The', deletion, of, the, 'SHOX', gene, together, with, the, 'Madelung', deformity, of, the, forearm, and, the, short, stature, of, the, proband]), verbo([led]), complemento([to, a, diagnosis, of, 'Léri-Weill', dyschondrosteosis, '(', 'LWD)'])].
[sujeto(['The']), verbo([gain]), complemento([of, almost, the, whole, 'X', chromosome, '(', 153, ',', 7, 'Mbp)', was, considered, a, variant, of, 'Klinefelter', syndrome, '(', 'KS)'])].
[sujeto(['We']), verbo([have]), complemento([reported, a, structural, aberration, of, the, sex, 'chromosomes,', 'dic(X;Y)(p22'])].
[sujeto(['The', related, genomic, imbalance, is]), verbo([associated]), complemento([with, two, known, hereditary, 'syndromes,', 'LWD', and, a, 'KS', 'variant,', identified, in, our, proband, at, an, advanced, age])].
[sujeto(['Because', the, breakpoints, did, not]), verbo([involve]), complemento([cancer, 'genes,', we, inferred, that, the, two, malignancies, in, the, proband, were, not, caused, by, this, abnormality])].
[sujeto(['The', addition, of, fibrin, protein, was, typically]), verbo([required]), complemento([to, achieve, a, similar, effect, on, 'M-ECM-adherent', monolayered, fibroblasts])].
[sujeto(['The', spheroid, fusion, process, was, followed, by, an]), verbo([increase]), complemento([in, cell, density, and, the, formation, of, tight, clusters])].
[sujeto(['The', fused, spheroids, continued, to]), verbo([maintain]), complemento([their, intracellular, 'ECM', turnover, and, proliferation, capacities])].
[sujeto(['A', model, is]), verbo([provided]), complemento([by, testis, determination, in, therian, mammals])].
[sujeto(['Mutations', in, human, 'SRY']), verbo([cause]), complemento([gonadal, dysgenesis, leading, to, 'XY', female, development, '(', 'Swyer', 'syndrome)'])].
[sujeto(['Here,', we]), verbo([have]), complemento([characterized, an, inherited, mutation, compatible, with, either, male, or, female, somatic, phenotypes, as, respectively, observed, in, an, 'XY', father, and, 'XY', daughter])].
[sujeto(['The', mutation, '(', a, 'crevice-forming', substitution, at, a]), verbo([conserved]), complemento([back, surface, of, the, 'SRY', 'high-mobility-group', 'box)', markedly, destabilizes, the, domain, but, preserves, specific, 'DNA', affinity, and, induced, 'DNA', bend, angle])].
[sujeto(['On', transient, transfection, of, diverse, human, and, rodent, cell, 'lines,', the, variant, 'SRY', exhibited, accelerated, proteasomal, degradation, '(', relative, to, 'wild-type)']), verbo([associated]), complemento([with, increased, 'ubiquitination;', in, vitro, susceptibility, to, 'ubiquitin-independent', '(', '″default″)', cleavage, by, the, 20, 'S', core, proteasome, was, unchanged])].
[sujeto(['Our', findings, define, a, novel, mechanism, of, impaired, 'organogenesis:', accelerated, 'ubiquitin-directed', proteasomal, degradation, of, a, master, transcription, factor]), verbo([leading]), complemento([to, a, developmental, decision, poised, at, the, edge, of, ambiguity])].
[sujeto(['In', this, commentary, we, briefly, summarize, early, work, on, circular, 'RNAs', derived, from, spliceosome]), verbo([mediated]), complemento([circularization])].
[sujeto(['We', highlight, how, this, early, work, inspired, work, on, the, basic, mechanisms, of]), verbo([nuclear]), complemento(['RNA', 'splicing,', the, possible, function, of, circular, 'RNAs', and, the, potential, uses, of, circular, 'RNAs', as, tools, in, biomedicine])].
[sujeto(['Recent', developments, in, the, study, of, circular, 'RNAs,', summarized, in, this, 'volume,']), verbo([have]), complemento([brought, these, questions, back, to, the, foreground])].
[sujeto(['SRY-related', 'HMG', box, '(', 'Sox)', genes, are, characterized, by, the, presence, of, a, 'DNA-binding', 'HMG', domain, and]), verbo([involved]), complemento([in, a, diverse, range, of, developmental, processes])].
[sujeto(['Two', core, promoters, in, 5, '\'', flanking, region, were, demonstrated, to, be, essential, for]), verbo([inducing]), complemento([transcriptional, regulatory, activity])].
[sujeto(['Interestingly,', 'EsSOXB2-1', protein, was, exclusively, localized, in, the, nucleus, of, spermatid, and, spermatozoa, even, at, the, end, of, acrosome, 'reaction,', and, was]), verbo([bound]), complemento([to, the, uncondensed, chromatin, in, nucleoplasm, of, mature, spermatozoa])].
[sujeto(['Knockdown', of, 'EsSoxB2-1', by, 'RNAi']), verbo([leads]), complemento([to, abnormal, transformation, of, the, nucleus, during, spermiogenesis])].
[sujeto(['Together,', these, findings, demonstrated, the, requirement, of, 'EsSoxB2-1', for, the, spermatozoa, nucleus, maturation, and, also]), verbo([suggested]), complemento([that, 'EsSoxB2-1', would, be, delivered, into, fertilized, eggs, along, with, chromatins, as, a, paternal, transcription, factor, for, regulating, early, embryonic, development])].
[sujeto(['Ossification', of, the, ligamentum, flavum, '(', 'OLF)', is, a, disorder, of, heterotopic, ossification, of, spinal, ligaments, and, is, the, main]), verbo([cause]), complemento([of, thoracic, spinal, canal, stenosis])].
[sujeto(['Previous', studies]), verbo([suggested]), complemento([that, 'miR-132-3p', negatively, regulates, osteoblast, differentiation])].
[sujeto(['However,', whether, 'miR-132-3p', is]), verbo([involved]), complemento([in, the, process, of, 'OLF', has, not, been, investigated])].
[sujeto(['In', this, 'study,', we, investigated, the, effect, of, 'miR-132-3p', and, its]), verbo([target]), complemento([genes, forkhead, box, 'O1', '(', 'FOXO1),', growth, differentiation, factor, 5, '(', 'GDF5)', and, 'SRY-box', 6, '(', 'SOX6)', on, the, osteogenic, differentiation, of, ligamentum, flavum, '(', 'LF)', cells])].
[sujeto(['We', demonstrated, that, 'miR-132-3p', was, 'down-regulated', during, the, osteogenic, differentiation, of, 'LF', cells, and, negatively]), verbo([regulated]), complemento([the, osteoblast, differentiation])].
[sujeto(['Further,', 'miR-132-3p']), verbo([targeted]), complemento(['FOXO1,', 'GDF5', and, 'SOX6', and, 'down-regulated', the, protein, expression, of, these, genes])].
[sujeto(['Meanwhile,', 'FOXO1,', 'GDF5', and, 'SOX6', were, 'up-regulated', after, osteogenic, differentiation, and, the, 'down-regulation', of, endogenous, 'FOXO1,', 'GDF5', or, 'SOX6']), verbo([suppressed]), complemento([the, osteogenic, differentiation, of, 'LF', cells])].
[sujeto(['In', 'addition,', we, also]), verbo([found]), complemento(['FOXO1,', 'GDF5', and, 'SOX6', expression, in, the, ossification, front, of, 'OLF', samples])].
[sujeto(['Overall,', these, results]), verbo([suggest]), complemento([that, 'miR-132-3p', inhibits, the, osteogenic, differentiation, of, 'LF', cells, by, targeting, 'FOXO1,', 'GDF5', and, 'SOX6'])].
[sujeto(['Monozygotic', twinning]), verbo([has]), complemento([not, previously, been, genetically, confirmed, in, the, dog])].
[sujeto(['This', case]), verbo([report]), complemento([describes, the, finding, of, two, viable, male, monozygotic, foetuses, within, one, placental, site, during, caesarean, section])].
[sujeto(['To', the, best, of, our, 'knowledge,', this, is, the, first]), verbo([report]), complemento([of, monozygotic, twinning, in, the, dog, confirmed, using, 'DNA', profiling])].
[sujeto(['The', 'SRY', gene, '(', 'SRY)']), verbo([provides]), complemento([instructions, for, making, a, transcription, factor, called, the, 'sex-determining', region, 'Y', protein])].
[sujeto(['The', 'sex-determining', region, 'Y', protein]), verbo([causes]), complemento([a, fetus, to, develop, as, a, male])].
[sujeto(['The', multiple, sequence, alignment, results, indicated, that, 'SRY', protein, sequences, from, 'Orcinus', orca, '(', killer, 'whale)', and, 'Tursiopsaduncus', '(', 'dolphin)']), verbo([have]), complemento([least, genetic, distance, of, 0.33, in, these, 15, species, and, are, 99.67, '%', identical, at, the, amino, acid, level])].
[sujeto(['Homosapiens', and, 'Pantroglodytes', '(', 'chimpanzee)']), verbo([have]), complemento([the, next, lowest, genetic, distance, of, 1.35, and, are, 98.65, '%', identical, at, the, amino, acid, level])].
[sujeto(['These', findings, indicate, that, the, 'SRY', proteins, are]), verbo([conserved]), complemento([in, the, 15, 'species,', and, their, evolutionary, relationships, are, similar])].
[sujeto(['Few']), verbo([reports]), complemento([demonstrate, occult, invasion, with, immunohistochemistry, 'staining,', which, were, discordant, with, reports, interpreting, such, staining, as, 'false-positive'])].
[sujeto(['Unequivocal', in, situ, melanoma, without]), verbo([associated]), complemento([nevi, or, regression, was, identified, using, a, consecutive, sample, of, 33, cases, plus, 1, index, case, in, an, academic, medical, center])].
[sujeto(['Occult', microinvasion, was, demonstrated, in, up, to, 'one-third', of, the, specimens, in, the, present, 'study,', which]), verbo([provides]), complemento([a, plausible, explanation, for, this, adverse, event])].
[sujeto(['Among', the, samples, of, 20, 'cases,', the, 'SRY', was]), verbo([found]), complemento([in, 11, cases, by, 'detecteion,', the, detection, results, were, consistent, with, sex, of, infants, after, 'delivery;', the, 'RASSF1A', was, amplified, all, in, samples, of, other, 9, cases, after, 'BstU1', 'cleavage,', which, confirmed, existance, of, cffDNA])].
[sujeto(['The', 'ABO', gene, detection, of, cffDNA, in, plasma, showed, that, out, of, 20, 'samples,', both, non, 'O', and, 'B', were, amplified, simultancously, in, 8, 'cases,']), verbo([suggesting]), complemento([the, 'B', blood, 'group;', the, non, 'O', was, 'amplified,', but, the, 'B', was, not, amplified, only, in, 5, 'cases,', suggesting, 'A', blood, 'group,', the, non, 'O', and, 'B', both, were, not, amplified, in, samples, of, 7, 'cases,', suggesting, 'O', blood, group])].
[sujeto(['The', present, study, demonstrated, that, 'T', cell, factor, 1, '(', 'TCF-1)', 'protein,', a, component, of, the, canonical, 'Wnt/β-catenin', signaling, 'pathway,', can]), verbo([regulate]), complemento([the, expression, of, 'runt-related', transcription, factor, 2, '(', 'runx2)', gene, and, 'Sry-related', 'HMG', box, 9, '(', 'sox9)', 'gene,', which, may, participate, in, the, differentiation, of, chondrosarcoma])].
[sujeto(['Dedifferentiated', chondrosarcoma, '(', 'DDCS)', is, a, special, variant, of, conventional, chondrosarcoma, '(', 'CCS),']), verbo([associated]), complemento([with, poor, survival, and, high, metastasis, rate])].
[sujeto(['Earlier,', high, expression, of, runx2, and, low, expression, of, sox9, were]), verbo([found]), complemento([in, 'DDCS', compared, with, 'CCS'])].
[sujeto(['Using', 'Western', blot, to, detect, clinical, tissue, samples, '(', including, 8, 'CCS', samples, and, 8, 'DDCS', 'samples)', and, immunohistochemistry, to, detect, 85, 'different-grade', chondrosarcoma, 'specimens,', a, high, expression, of, 'TCF-1', in, 'DDCS', tissues, was]), verbo([found]), complemento([compared, with, 'CCS', tissues])].
[sujeto(['Results', of, 'luciferase,', chromatin, 'immunoprecipitation,', and, gel, electrophoresis, mobility, shift, assays, demonstrated, that, 'TCF-1', protein, could]), verbo([bind]), complemento([to, the, promoter, of, runx2, gene, directly, and, sox9, gene, indirectly])].
[sujeto(['Hence,', it, could]), verbo([regulate]), complemento([expression, of, runx2, gene, positively, and, sox9, gene, negatively])].
[sujeto(['In', 'conclusion,', this, study, proved, that, 'TCF-1']), verbo([participates]), complemento([in, the, dedifferentiation, of, 'DDCS,', which, may, be, mediated, by, runx2, gene, and, sox9, gene])].
[sujeto(['Also,', 'TCF-1', can, be, of, important, prognostic, value, and, a, promising, therapeutic]), verbo([target]), complemento([for, 'DDCS', patients])].
[sujeto(['The', present, case]), verbo([report]), complemento([describes, a, 6, -, year, old, subfertile, pony, 'mare,', which, became, pregnant, after, the, eleventh, artificial, insemination])].
[sujeto(['The', examination, of, the, ovaries, and, the, uterus, did, not]), verbo([reveal]), complemento([any, abnormal, clinical, findings, and, the, mare, showed, a, regular, oestrous, cycle])].
[sujeto(['It']), verbo([has]), complemento([been, reported, that, 5, -, azacytidine, suppresses, the, biological, behavior, of, esophageal, cancer, cells])].
[sujeto(['In', this, 'study,', using, 'Transwell', invasion, and, cell, proliferation, 'assays,', we, demonstrated, that, 5, -, azacytidine, significantly]), verbo([inhibited]), complemento([the, metastasis, and, proliferation, of, 'EC9706', 'cells,', and, upregulated, the, expression, of, 'cadherin 1 (CDH1)', and, 'SRY-box', containing, 'gene 17 (SOX17)'])].
[sujeto(['Moreover,', the, inhibition, of, the, metastasis, of, the, 5, -, 'azacytidine-treated', 'EC9706', cells, was, impaired, following, transfection, with, siRNA]), verbo([targeting]), complemento(['CDH1 (CDH1 siRNA),', and, the, inhibition, of, cell, proliferation, was, attenuated, following, the, downregulation, of, 'SOX17', by, siRNA, targeting, 'SOX17 (SOX17 siRNA)'])].
[sujeto(['Furthermore,', 5, -, azacytidine, remarkably, reduced, the, 'CDH1', and, 'SOX17', promoter, methylation, 'levels,']), verbo([suggesting]), complemento([that, 5, -, azacytidine, upregulates, the, expression, of, 'SOX17', and, 'CDH1', by, inhibiting, the, methylation, of, the, 'SOX17', and, 'CDH1', promoter])].
[sujeto(['The', findings, of, our, study, confirm, that, 5, -, azacytidine]), verbo([suppresses]), complemento([the, proliferation, and, metastasis, of, 'EC9706', esophageal, cancer, cells, by, upregulating, the, expression, of, 'CDH1', and, 'SOX17'])].
[sujeto(['The', 'X', 'Chromosome']), verbo([has]), complemento([a, rich, and, conserved, gene, 'content,', while, the, 'Y', 'Chromosome', has, lost, most, of, its, genes])].
[sujeto(['In', the, 'Transcaucasian', mole, vole, 'Ellobius', 'lutescens,', the, 'Y', 'Chromosome', including, 'Sry']), verbo([has]), complemento([been, 'lost,', and, both, females, and, males, have, a, 17, ',', 'X', diploid, karyotype])].
[sujeto(['Similarly,', the, closely, related, 'Ellobius', 'talpinus,']), verbo([has]), complemento([a, 54, ',', 'XX', karyotype, in, both, females, and, males])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, sequencing, and, assembly, of, the, 'E'])].
[sujeto(['The', results, indicate, that, the]), verbo([loss]), complemento([of, the, 'Y', 'Chromosome', in, 'E'])].
[sujeto([lutescens, can, carry, one, and, the, same, 'X', 'Chromosome', with, a, largely]), verbo([conserved]), complemento([gene, 'content,', including, all, genes, known, to, function, in, 'X', 'Chromosome', inactivation])].
[sujeto(['The', availability, of, the, genomes, of, these, mole, vole, species]), verbo([provides]), complemento([unique, models, to, study, the, dynamics, of, sex, chromosome, evolution])].
[sujeto(['Somatic', cell]), verbo([nuclear]), complemento([transfer, '(', 'SCNT)', provides, an, excellent, model, for, studying, epigenomic, reprogramming, during, mammalian, development])].
[sujeto(['Our', results, demonstrate, that, incomplete, demethylation, on, the, 'SRY', gene, is, the, driving]), verbo([cause]), complemento([of, 'XY(DSD)', in, these, 'XY', 'DSD', 'dogs,', indicating, a, central, role, of, epigenetic, regulation, in, sex, determination])].
[sujeto(['No', mutation, was]), verbo([found]), complemento([in, the, 'SRY', gene])].
[sujeto(['The', karyotype, of, patients, carrying, 'idic(Y)(p)', seems, 'unstable,', and, female, patients]), verbo([have]), complemento([the, characteristics, of, short, stature, and, secondary, sexual, hypoplasia])].
[sujeto(['Here,', we, replaced, 'Sry', by, transgenic, activation, of, its, downstream]), verbo([target]), complemento(['Sox9,', and, 'Eif2s3y,', by, transgenic, overexpression, of, its, 'X', 'chromosome-encoded', homolog, 'Eif2s3x'])].
[sujeto(['During', its, final, 'phase,', 'spermiogenesis,', haploid, round, spermatids, undergo, cellular, differentiation, into, 'spermatozoa,', which]), verbo([involves]), complemento([extensive, restructuring, of, cell, 'morphology,', 'DNA,', and, epigenome])].
[sujeto(['An', analytical, evaluation, using, blood, samples, from, patients, with, leukemia, showed, that, the, while, blood, cell, '(', 'WBC)', depletion, and, 'NRBC']), verbo([loss]), complemento([rates, of, the, positive, enrichment, process, were, 93.98, &, 'nbsp;%', and, 6.02, &, 'nbsp;%,', respectively])].
[sujeto(['Gonadoblastoma', '(', 'GB),', a, rare, in, situ, germ, cell, tumor, derived, from, sex, cord, and, germ, 'cells,', is, closely]), verbo([associated]), complemento([with, gonadal, dysgenesis])].
[sujeto(['Increasing', studies, show, that, the, formation, of, 'GB', is, closely, related, to, genes]), verbo([regulating]), complemento([sexual, differentiation, and, determination, '(', e])].
[sujeto(['Here', we, describe, the, clinical, and, pathological, 'features,', diagnosis, and, treatment, of, 'GB,', and, also, summarize, the, molecular, genetic, and, epigenetic, mechanisms, underlying, the, gonadal, abnormalities, that]), verbo([lead]), complemento([to, 'GB'])].
[sujeto(['We', analyze, and, construct, the, common, gene, regulatory, networks, related, to, the, development, of, 'GB,', and, describe, some, obstacles, and, deficiencies, in, current, studies, to]), verbo([provide]), complemento([innovative, perspectives, on, further, studying, the, pathological, and, molecular, mechanisms, of, 'GB'])].
[sujeto(['Sex', determination, in, mammals]), verbo([requires]), complemento([expression, of, the, 'Y-linked', gene, 'Sry', in, the, bipotential, genital, ridges, of, the, 'XY', embryo])].
[sujeto(['Here,', we, analysed, 'Sry', flanking, sequences, across, many, 'species,', using, newly, available, genome, sequences, and, computational, 'tools,', to, better, understand, 'Sry\'s', genomic, context, and, to, identify]), verbo([conserved]), complemento([regions, predictive, of, functional, roles])].
[sujeto(['We', identified, 'position-specific', conservation, of]), verbo([binding]), complemento([motifs, for, multiple, transcription, factor, 'families,', including, 'GATA', binding, factors, and, 'Oct/Sox', dimers])].
[sujeto(['In', contrast, with, the, landscape, of, extremely, low, sequence, conservation, around, the, 'Sry', coding, 'region,', our, analysis, highlighted, a, strongly]), verbo([conserved]), complemento([interval, of, '~106 bp', within, the, 'Sry', promoter, '(', which, we, term, the, 'Sry', 'Proximal', 'Conserved', 'Interval,', 'SPCI)'])].
[sujeto(['We', further]), verbo([report]), complemento([that, inverted, repeats, flanking, murine, 'Sry', are, much, larger, than, previously, recognised])].
[sujeto(['The', unusually, fast, pace, of, sequence, drift, on, the, 'Y', chromosome, sharpens, the, likely, functional, significance, of, both, the, 'SPCI', and, the, identified]), verbo([binding]), complemento(['motifs,', providing, a, basis, for, future, studies, of, the, 'role(s)', of, these, elements, in, 'Sry', regulation])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([in, the, scientific, literature, of, an, 'SRY-positive', hermaphrodite, 'Holstein', cattle, with, continuous, ovarian, cycles])].
[sujeto(['In', mouse, 'XY', 'gonads,', 'SRY']), verbo([induces]), complemento(['SOX9', upregulation, and, subsequent, 'FGF9', expression, by, embryonic, day, 11.5, '(', 'E11'])].
[sujeto([5, ')', ',']), verbo([leading]), complemento([to, the, differentiation, of, 'Sertoli', cells])].
[sujeto(['These', 2, ovarian, 'factors,', together, with, retinoic, acid, '(', 'RA)', 'action,']), verbo([promote]), complemento([feminization, partially, through, the, repression, of, the, masculinizing, activities, of, 'SOX9,', 'FGF9', and, 'DMRT1'])].
[sujeto(['At', 'birth,', the, oocyte, nests, break, down, into, single, oocytes, surrounded, by, granulosa, 'cells,']), verbo([leading]), complemento([to, the, assembly, of, primordial, follicles])].
[sujeto(['Animal', researches, and, clinical, studies]), verbo([have]), complemento([supported, the, relevance, between, phthalates, exposure, and, testicular, dysgenesis, syndrome, '(', 'TDS)'])].
[sujeto(['DEHP', exposure, resulted, in, significant, reduction, in, mRNA, of, 'Sry', during, sex, determination, from, gestation, day, '(', 'GD)', 11.0, to, 11.5, in, male, fetal, 'mice,', and, the]), verbo([increasing]), complemento([of, 'Sry', expression, to, threshold, level, on, 'GD', 11.5, was, delayed])].
[sujeto(['Taken', 'together,', the, results]), verbo([suggest]), complemento([that, the, potential, mechanism, of, gonadal, development, disorder, by, 'DEHP', may, origin, from, repression, of, important, male, sex, determination, signaling, 'pathway,', involving, 'Gadd45g', '→', 'Gata4', '→', 'Sry', '→', 'Sox9'])].
[sujeto(['The', results, would]), verbo([promote]), complemento([a, better, understanding, of, the, association, between, phthalate, esters, '(', 'PAEs)', exposure, and, the, reductive, disorder])].
[sujeto(['The', 'SOX9', gene]), verbo([has]), complemento([been, identified, as, a, major, factor, in, testis, development, in, mammals, after, it, is, activated, by, the, 'SRY', gene])].
[sujeto(['However,', duplication, of, the, gene, itself, in, some, mammalian, 'species,', or, of, a, 'well-delimited', upstream, '\'', 'RevSex\'', region, in, 'humans,']), verbo([has]), complemento([been, shown, to, result, in, testis, development, in, the, absence, of, the, 'SRY', gene])].
[sujeto(['Contrary', to, what, is, observed, in, the, current, dog, genome, 'assembly,', we]), verbo([found]), complemento([that, the, genomic, organization, is, quite, similar, to, that, reported, in, humans, and, other, mammalian, 'species,', including, the, position, of, the, 'RevSex', region, in, respect, to, 'SOX9'])].
[sujeto(['The', analysis, of, the]), verbo([conserved]), complemento([sequences, within, this, region, in, 7, mammalian, species, facilitated, the, highlighting, of, a, consensus, sequence, for, 'SRY', binding])].
[sujeto(['This', new, information, could, help, in, the, identification, of, evolutionarily]), verbo([conserved]), complemento([elements, relevant, for, 'SOX9', gene, 'regulation,', and, could, provide, valid, targets, for, mutation, analysis, in, 'XY', 'DSD', patients])].
[sujeto(['Diagnosis', of, fetal, gender, early, in, pregnancy, is, very, useful, as, it, would]), verbo([prevent]), complemento([invasive, fetal, sampling, in, almost, half, the, cases, at, risk, of, inheriting, 'X-linked', disorders, or, those, affecting, sexual, differentiation])].
[sujeto(['Noninvasive', prenatal, diagnosis, '(', 'NIPD)', using, circulating, 'cell-free', fetal, '(', 'cff)', 'DNA', from, maternal, circulation]), verbo([has]), complemento([emerged, as, a, useful, alternative, to, existing, methods, for, prenatal, diagnosis, of, gender])].
[sujeto(['Sex-reversal', cases, in, humans, and, genetic, models, in, mice]), verbo([have]), complemento([revealed, that, the, fate, of, the, bipotential, gonad, hinges, upon, the, balance, between, 'pro-testis', 'SOX9', and, 'pro-ovary', 'beta-catenin', pathways])].
[sujeto(['In', the, absence, of, 'Sox9', and, 'beta-catenin,', both, 'XX', and, 'XY', gonads, progressively, lean, toward, the, testis, 'fate,', indicating, that, expression, of, certain, 'pro-testis', genes]), verbo([requires]), complemento([the, repression, of, the, 'beta-catenin', 'pathway,', rather, than, a, direct, activation, by, 'SOX9'])].
[sujeto(['XY)', affects, this, 'process,', we, compared, the, transcriptomes, of, 'Sox9/beta-catenin', mutant, gonads, and]), verbo([found]), complemento([that, early, molecular, changes, underlying, the, 'XY-specific', masculinization, involve, the, expression, of, 'Sry', and, 21, 'SRY', direct, target, 'genes,', such, as, 'Sox8', and, 'Cyp26b1'])].
[sujeto(['These', results, imply, that, when, both, 'Sox9', and, 'beta-catenin', are, 'absent,', 'Sry', is, capable, of]), verbo([activating]), complemento([other, 'pro-testis', genes, and, drive, testis, differentiation])].
[sujeto(['Our', findings, not, only]), verbo([provide]), complemento([insight, into, the, mechanism, of, sex, 'determination,', but, also, identify, candidate, genes, that, are, potentially, involved, in, disorders, of, sex, development])].
[sujeto(['This']), verbo([report]), complemento([describes, a, disorder, of, the, sexual, development, in, a, beagle, dog, resulting, in, an, intersex, condition])].
[sujeto(['Testosterone', levels, that, were, within, the, male, reference, ranges, before, surgery]), verbo([decreased]), complemento([to, basal, levels, postsurgically])].
[sujeto(['The', stem, cell, marker, 'OCT4', is, frequently]), verbo([expressed]), complemento([in, 'HCCs,', and, its, expression, correlates, with, those, of, putative, cancer, stem, cell, '(', 'CSC)', markers, and, 'CSC', properties])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, 'Sry', is, involved, in, tumor, malignancy, in, rodent, 'HCCs'])].
[sujeto(['Ectopic', expression, of, 'SRY']), verbo([increased]), complemento([multiple, stem, cell, 'factors,', including, 'OCT4', and, 'CD13'])].
[sujeto(['The', 'OCT4', promoter, contained, 'SRY-binding', sites, that, were, directly]), verbo([activated]), complemento([by, 'SRY'])].
[sujeto(['In', 'HCC-derived', 'cells,', 'SRY', knockdown]), verbo([decreased]), complemento(['OCT4', expression, and, cancer, 'stem-like', phenotypes, such, as, 'self-renewal,', 'chemoresistance,', and, tumorigenicity])].
[sujeto(['Conversely,', 'OCT4', and, 'SRY', overexpression]), verbo([promoted]), complemento([cancer, 'stem-like', phenotypes])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'SRY', is, involved, in, the, maintenance, of, cancer, 'stem-like', characteristics, through, 'OCT4'])].
[sujeto(['Noteworthily,', 'SRY', was, highly]), verbo([expressed]), complemento([in, some, hHCC, patients])].
[sujeto(['Gender', role, and, gender, identity, are]), verbo([reported]), complemento([as, male])].
[sujeto(['SRY,', the, gene, that, encodes, the, 'sex-determining', region, 'Y', 'protein,', is, the, principal, gene, known, to, be]), verbo([associated]), complemento([with, 46, ',', 'XX', testicular, 'DSD'])].
[sujeto(['Rearrangements', in, or, around, 'SOX9', and, 'SOX3', detected, by, 'CMA,', or, rarely, 'karyotype,']), verbo([have]), complemento([recently, been, reported, in, a, few, 'cases;', at, least, one, more, 'as-yet-unknown', gene, at, another, locus, is, implicated])].
[sujeto(['Treatment', of, 'manifestations:', 'Similar', to, that, for, other]), verbo([causes]), complemento([of, testosterone, deficiency])].
[sujeto(['After', age, 14, 'years,', 'low-dose', testosterone, therapy, is, initiated, and, gradually]), verbo([increased]), complemento([to, reach, adult, levels])].
[sujeto(['Surveillance:', 'Monitor', for, testosterone, effects, during, testosterone, replacement, 'therapy,', including, prostate, size, and, 'prostate-specific', antigen, '(', 'PSA)', in, 'adults;', routine, monitoring, of, 'hematocrit,', lipid, 'profile,', and, liver, function, 'tests;', bone, mineral, density, determination, by, bone, densitometry, '(', 'DEXA)', 'annually,', if, osteopenia]), verbo([has]), complemento([been, diagnosed])].
[sujeto(['Autosomal', dominant, inheritance]), verbo([has]), complemento([been, documented, for, familial, cases, thought, to, be, caused, by, 'CNV', in, or, around, 'SOX9'])].
[sujeto(['The', mode, of, inheritance, of, other, 'SRY-negative', 46, ',', 'XX', testicular, 'DSD', is, not, 'known,', but, autosomal, recessive, inheritance]), verbo([has]), complemento([been, postulated])].
[sujeto(['Mixed', gonadal, dysgenesis, '(', 'MGD)', is, a, disorder, of, sexual, development, that, typically]), verbo([has]), complemento([a, mosaic, 45, ',', 'X/46,XY', karyotype])].
[sujeto(['To', assess, genetic, mutations, and]), verbo([associated]), complemento([somatic, anomalies, in, a, series, of, patients, with, 46, ',', 'XY', gonadal, dysgenesis, '(', 'GD)'])].
[sujeto(['A', mutation, was]), verbo([found]), complemento([in, 7, patients, of, whom, 2, had, family, history, of, reproductive, problems, and, 5, had, associated, somatic, anomalies])].
[sujeto(['Among', the, three, other, patients, with]), verbo([associated]), complemento([anomalies, and, no, 'mutation,', two, had, ectodermal, dysplasia, and, one, had, leukemia])].
[sujeto(['Müllerian', structures, can, be]), verbo([found]), complemento([in, some, cases, only, by, histologic, 'examination,', which, should, be, coupled, to, preventive, gonadectomy, because, of, the, risk, of, tumor, formation])].
[sujeto(['The', 'RNA']), verbo([binding]), complemento([motif, protein, 38, '(', 'RBM38,', also, known, as, 'RNPC1)', plays, a, pivotal, role, in, regulating, a, wide, range, of, biological, 'processes,', from, cell, proliferation, and, cell, cycle, arrest, to, cell, myogenic, differentiation])].
[sujeto(['It', was, originally]), verbo([recognized]), complemento([as, an, 'oncogene,', and, was, frequently, found, to, be, amplified, in, 'prostate,', ovarian, and, colorectal, 'cancer,', chronic, lymphocytic, 'leukemia,', colon, 'carcinoma,', esophageal, 'cancer,', dog, lymphomas, and, breast, cancer])].
[sujeto(['In', the, present, 'study,', the, complete, 'RNPC1', gene, was, identified, in, a, number, of, vertebrate, 'genomes,']), verbo([suggesting]), complemento([that, 'RNPC1', exists, in, all, types, of, 'vertebrates,', including, 'fish,', 'amphibians,', birds, and, mammals])].
[sujeto(['A', total, of, 34, functionally, relevant, single, nucleotide, polymorphisms, '(', 'SNPs),', including, 14, 'SNPs']), verbo([causing]), complemento([missense, 'mutations,', 8, exonic, splicing, enhancer, 'SNPs', and, 12, 'SNPs', causing, nonsense, 'mutations,', were, identified, in, the, human, 'RNPC1', gene])].
[sujeto(['RNPC1', was]), verbo([found]), complemento([to, be, expressed, in, 'bladder,', 'blood,', 'brain,', 'breast,', 'colorectal,', 'eye,', head, and, 'neck,', 'lung,', 'ovarian,', skin, and, soft, tissue, cancer])].
[sujeto(['We']), verbo([found]), complemento([that, the, association, between, the, expression, of, 'RNPC1', and, prognosis, varied, in, different, types, of, 'cancer,', and, even, in, the, same, type, of, cancer, from, the, different, databases, used])].
[sujeto(['This']), verbo([suggests]), complemento([that, the, function, of, 'RNPC1', in, these, tumors, may, be, multidimensional])].
[sujeto(['The', sex, determining, region, 'Y', '(', 'SRY)-box', 5, '(', 'Sox5),', 'runt-related', transcription, factor, 3, '(', 'RUNX3),', 'CCAAT', displacement, protein, 1, '(', 'CUTL1),', 'v-rel', avian, reticuloendotheliosis, viral, oncogene, homolog, '(', 'Rel)A,', peroxisome, 'proliferator-activated', receptor, γ, isoform, 2, '(', 'PPARγ2)', and]), verbo([activating]), complemento([transcription, factor, 6, '(', 'ATF6)', regulatory, transcription, factor, binding, sites, were, identified, in, the, upstream, '(', 'promoter)', region, of, the, 'RNPC1', 'gene,', and, may, thus, be, involved, in, the, effects, of, 'RNPC1', in, tumors])].
[sujeto(['The', upstream, region, of, the, 'XFGF8', gene, contains, two, putative]), verbo([binding]), complemento([sites, for, the, 'SRY', '(', 'sex-determining', region, 'Y)-box', 2, '(', 'SOX2)', transcription, factor])].
[sujeto(['Furthermore,', 'Xenopus', 'SOX2', '(', 'XSOX2)', physically]), verbo([interacted]), complemento([with, the, 'SOX2-binding', motif, within, the, upstream, region, of, the, 'XFGF8', gene, in, vitro, and, in, vivo])].
[sujeto(['Depletion', of, endogenous, 'XSOX2', resulted, in]), verbo([loss]), complemento([of, 'XFGF8', gene, expression, in, 'midbrain-hindbrain', 'junction,', auditory, 'placode,', lens, placode, and, forebrain, in, developing, 'Xenopus', embryos])].
[sujeto(['Collectively,', our, results]), verbo([suggest]), complemento([that, 'XSOX2', directly, upregulates, 'XFGF8', gene, expression, in, the, early, embryonic, development, of, 'Xenopus'])].
[sujeto(['Nuclear', receptor, subfamily, 5, ',', group, 'A,', member, 1, '(', 'NR5A1', previously, known, as, 'SF-1/AD4BP)', is, a, transcription, factor]), verbo([involved]), complemento([in, the, development, of, 'adrenal/gonadal', tissues, and, steroidogenic, lineage, cell, differentiation, in, adult, somatic, stem, cells])].
[sujeto(['To', understand, the, cellular, signaling, network, that]), verbo([regulates]), complemento(['NR5A1', gene, 'expression,', loss, of, function, screening, with, an, siRNA, kinome, 'library,', and, gain, of, function, screening, with, an, addressable, 'full-length', cDNA, library, representing, one, quarter, of, the, human, genome, was, carried, out])].
[sujeto(['The', 'NR5A1', gene, expression, was]), verbo([activated]), complemento([in, mesenchymal, stem, cells, by, siRNA, directed, against, protein, kinase, 'C', '(', 'PKC)-delta,', 'erb-B3,', 'RhoGAP', '(', 'ARHGAP26),', and, hexokinase, 2, ',', none, of, which, were, previously, known, to, be, involved, in, the, 'NR5A1', gene, expression])].
[sujeto(['In', 'addition,', the]), verbo([gain]), complemento([of, function, studies, indicated, that, 'sex-determining', region, 'Y', '(', 'SRY)-box', 15, '(', 'SOX15),', 'TEA', domain, family, member, 4, ',', 'KIAA1257', '(', a, gene, of, unknown, 'function),', 'ADAM', metallopeptidase, with, thrombospondin, type, 1, motif, 6, ',', 'Josephin', domain, containing, 1, ',', centromere, 'protein,', 'TATA', 'box-binding', 'protein-associated', factor, 5, -, like, 'RNA', 'polymerase,', and, inducible, 'T-cell', 'co-stimulator', activate, 'NR5A1', gene, expression])].
[sujeto(['These', results]), verbo([provide]), complemento([new, insights, into, the, molecular, mechanisms, of, 'NR5A1', gene, expression])].
[sujeto(['Seven', different, sets, of, oligonucleotide, 'primers,', sex, determining, region, 'Y', '(', 'SRY),', zinc, finger, gene, on, the, 'Y', chromosome, '(', 'ZFY),', testis, specific, protein, 'Y', '(', 'TSPY),', 'DYZ3,', 'DYF49S1,', 'RNA']), verbo([binding]), complemento([motif, protein, '(', 'RBM),', and, 'DYZ1,', spanning, on, centromeres, and, short, and, long, arms, of, the, 'Y', chromosome, were, used, for, 'PCR'])].
[sujeto(['The', 'leucine-zipper', and, 'HMG-box', motif, were, almost, completely]), verbo([conserved]), complemento([between, these, homologues])].
[sujeto([rSox6, '(', rat, 'Sox6)', was, specifically]), verbo([expressed]), complemento([in, the, neonatal, brain, and, adult, testis, with, 'Northern', blotting])].
[sujeto(['The', rSox6, was]), verbo([expressed]), complemento([in, the, neonatal, brain, and, adult, testis, as, well, as, by, 'Northern', blotting, and, also, expressed, in, the, adult, eyeball, and, slightly, in, the, ovary])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([identified, a, new, human, 'SOX', 'gene,', 'SOX13,', as, encoding, the, type, 1, diabetes, 'autoantigen,', islet, cell, antigen, 12, '(', 'ICA12)'])].
[sujeto(['Deletion', mapping, of, the, antibody, epitopes, showed, that, the, autoantibodies, were, primarily, directed, against, an, epitope]), verbo([requiring]), complemento([the, majority, of, the, protein])].
[sujeto(['Recombinant', 'SOX13', protein]), verbo([bound]), complemento([to, the, 'SOX', consensus, 'DNA', motif, 'AACAAT,', and, binding, was, inhibited, by, homodimer, formation])].
[sujeto(['These', 'observations-along', with, the, known, molecular, interactions, of, the, closely, related, 'protein,', rainbow, trout, 'Sox23-suggest', that, 'SOX13', may, be]), verbo([activated]), complemento([for, nuclear, import, and, 'DNA', binding, through, heterodimer, formation])].
[sujeto(['In', 'conclusion,', we]), verbo([have]), complemento([identified, 'ICA12', as, the, putative, transcription, factor, 'SOX13', and, demonstrated, an, increased, frequency, of, autoantibody, reactivity, in, sera, from, type, 1, diabetic, subjects, compared, with, type, 2, diabetic, and, healthy, control, subjects])].
[sujeto(['Leydig', cells, and, 'Sertoli', cells, of, the, testes, produce, hormones, that]), verbo([cause]), complemento([male, 'differentiation,', if, receptors, are, present])].
[sujeto(['The', 'Y', chromosomal, 'SRY', gene, '(', sex, determining, 'Region', 'Y', 'gene)']), verbo([acts]), complemento([as, 'TDF', and, is, required, for, regular, male, sex, determination])].
[sujeto(['SRY', represents, a, transcription, factor, belonging, to, the, superfamily, of, genes, sharing, the, 'HMG-box', 'motif(high-mobility', 'group-box),', which]), verbo([acts]), complemento([as, 'DNA', binding, region])].
[sujeto(['The', glycine, at, codon, 95, is, highly]), verbo([conserved]), complemento([between, the, family, of, 'HMG-box', proteins, and, between, species])].
[sujeto(['This', point, mutation]), verbo([has]), complemento([not, been, described, earlier, and, brings, the, total, number, of, 'SRY', mutations, described, so, far, to, 36, ',', each, mutation, being, unique])].
[sujeto(['The', present, data]), verbo([provide]), complemento([further, evidence, to, support, the, functional, importance, of, the, putative, 'DNA', binding, activity, of, the, 'SRY', 'HMG-box', domain])].
[sujeto(['In', vertebrates, several, proteins, containing, a, covalently]), verbo([bound]), complemento([selenocysteine, residue, have, been, identified])].
[sujeto(['The', protein, was, traced, in, rat, 'plasma,', but, its, role]), verbo([has]), complemento([not, been, worked, out, so, far])].
[sujeto(['Selenoprotein', 'P', was, also]), verbo([found]), complemento([to, be, expressed, in, 'testis,', 'brain,', 'gut,', and, hematopoietic, cells])].
[sujeto(['One', 'TATA', motif, 38, bp, upstream, to, exon, 1]), verbo([suggests]), complemento([transcription, of, selp, by, 'RNA', polymerase, 'II'])].
[sujeto(['Within', the, 1116, bp, upstream, of, exon, 1, four, hepatic]), verbo([nuclear]), complemento([factor, 3, beta, '(', 'HNF3beta)', binding, motifs, were, 'found,', which, is, in, line, with, 'liver-specific', expression, of, selenoprotein, 'P'])].
[sujeto(['Two', 'BRN-2', motifs, suitable, for, the]), verbo([binding]), complemento([of, 'brain-specific', regulatory, factors, correlated, to, the, selenoprotein, 'P', expression, in, the, cerebellum])].
[sujeto(['Selenoprotein', 'P', was, also]), verbo([expressed]), complemento([in, 'Leydig', cells, which, could, be, regulated, by, binding, proteins, docking, to, the, 'SRY', motifs, present, in, the, promoter, region])].
[sujeto(['The', methodology]), verbo([involved]), complemento([a, combination, of, polymerase, chain, reaction, '(', 'PCR)', and, nested, 'PCR', followed, by, 'Southern', blot, analysis, of, three, genes, the, sex, determining, region, 'Y', '(', 'SRY),', testis, specific, protein, 'Y', encoded, '(', 'TSPY)', and, 'RNA', binding, motif, protein, '(', 'RBM)', '(', previously, designated, as, 'YRRM)', and, nine, additional, 'STSs', spanning, all, seven, intervals, of, the, 'Y', chromosome])].
[sujeto(['The', methodology]), verbo([has]), complemento([a, high, sensitivity, as, it, detects, one, 46, ',', 'XY', cell, among, 10, '(', 5, ')', 46, ',', 'XX', cells])].
[sujeto(['Reliability', was]), verbo([ensured]), complemento([by, taking, several, precautions, to, avoid, false, positive, results])].
[sujeto(['We']), verbo([report]), complemento([the, results, of, screening, 50, 'TS', patients, and, the, identification, of, cryptic, 'Y', chromosome, material, in, 12, '(', 24, '%', ')', of, them])].
[sujeto(['Karyotypes', were, divided, in, four, 'groups:', 5, '(', 23.8, '%', ')', patients, out, of, the, 21, 'TS', patients, which]), verbo([have]), complemento([the, 45, ',', 'X', karyotype, '(', group, 'A)', also, have, cryptic, 'Y', 'sequences;', none, '(', 0, '%', ')', of, the, 7, patients, who, have, karyotypes, with, anomalies, on, one, of, the, 'X', chromosomes, have, 'Y', mosaicism, '(', group, 'B);', 1, '(', 6.3, '%', ')', of, the, 16, patients, with, a, mosaic, karyotype, have, 'Y', material, '(', group, 'C);', and, 6, '(', 100, '%', ')', out, of, 6, patients, with, a, supernumerary, marker, chromosome, '(', 'SMC)', have, 'Y', chromosome, sequences, '(', group, 'D)'])].
[sujeto(['This', study, used, a, reliable, and, sensitive, methodology, to, identify, the, presence, of, 'Y', chromosome, material, in, 'TS', patients, thus]), verbo([providing]), complemento([not, only, a, better, estimate, of, a, 'patient\'s', risk, in, developing, either, gonadoblastoma, or, another, form, of, gonadal, tumor, but, also, the, overall, incidence, of, cryptic, 'Y', mosaicism])].
[sujeto(['Regrowing', neurites, grew, atop, this, 'layer,', forming, 'non-uniform', patterns, that, were, similar, to, those, formed, by, endogenously]), verbo([expressed]), complemento(['laminin-1,', entactin, and, integrin, 'beta4,', but, not, fibronectin, or, tenascin])].
[sujeto(['In', cultures, grown, for, 42, h, and]), verbo([maintained]), complemento([in, three, different, growth, 'media,', all, regrowing, neurites, were, preferentially, associated, with, 'spindle-shaped', nonneural, cells])].
[sujeto(['The', spontaneous, and, preferential, association, of, neurites, in, culture, with, mitotic, 'Schwann', cells, highlights, the, potential, contribution, 'neurite-Schwann', cell, interactions, may]), verbo([have]), complemento([in, promoting, the, growth, and, regrowth, of, damaged, spiral, ganglion, neurons, in, the, cochlea])].
[sujeto(['Although', the, miRNAs, are]), verbo([involved]), complemento([in, breast, cancer, 'development,', their, axis, with, the, transcription, factors, that, show, therapeutic, potential, in, breast, cancer, is, largely, unknown])].
[sujeto(['Recently,', we, demonstrated, that, 'agonist-activated', 'Ahr']), verbo([induced]), complemento([a, highly, conserved, miRNA, 'cluster,', named, 'miR-212/132,', in, murine, cellular, immune, compartment])].
[sujeto(['Therefore,', current, study, was, performed, to, examine, if, this, miRNA, cluster]), verbo([mediates]), complemento([the, 'anti-metastatic', properties, of, 'Ahr', agonists])].
[sujeto(['The', 2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD)', and, 3, ',', 3, '\'', -, diindolylmethane, '(', 'DIM)', were, used, to]), verbo([activate]), complemento(['Ahr', in, 'MDA-MB-231', and, 'T47D', breast, cancer, cells])].
[sujeto(['Chromatin', immunoprecipitation, '(', 'ChIP)', assay, was, used, to, identify, the]), verbo([binding]), complemento(['site(s)', for, 'Ahr', on, 'miR-212/132', promoter])].
[sujeto(['For', prediction, of, potentially]), verbo([target]), complemento([gene, of, the, miRNA, 'cluster,', bioinformatics, analysis, was, carried, 'out,', and, to, test, 'targeting,', luciferase, activity, was, quantified])].
[sujeto(['The', 'miR-212/132', cluster, was, transcriptionally]), verbo([activated]), complemento([in, 'MDA-MB-231', and, 'T47D', cells, by, 'TCDD', and, 'DIM,', and, this, activation, was, regulated, by, 'Ahr'])].
[sujeto(['A', reciprocal, correlation, was, identified, between, 'Ahr', 'agonists-induced', 'miR-212/132', and, the, 'pro-metastatic', 'SRY-related', 'HMG-box4', '(', 'SOX4),', and, a, new, specific]), verbo([binding]), complemento([sites, for, 'miR-212/132', were, identified, on, the, untranslated, region, '(', 3, '\'', 'UTR)', of, 'SOX4'])].
[sujeto(['Further', in, vivo, studies, demonstrated, that, the, 'Ahr-miR-212/132-SOX4', module, was]), verbo([induced]), complemento([by, 'Ahr', activation])].
[sujeto(['Taken', 'together,', the, findings]), verbo([provide]), complemento([the, first, evidences, of, the, synergistic, 'anti-metastatic', properties, of, 'miR-212/132', cluster, through, suppression, of, 'SOX4'])].
[sujeto(['Also,', current, study]), verbo([suggest]), complemento([a, new, 'miRNA-based', mechanism, elucidating, the, 'anti-metastatic', properties, of, 'Ahr', 'agonists,', suggesting, possibility, of, using, 'miR-212/132', to, control, metastasis, in, breast, cancer, patients])].
[sujeto(['Goldfish', '(', 'Carassius', 'auratus)', and, zebrafish, '(', 'Danio', 'rerio)']), verbo([have]), complemento([utility, as, complementary, models, for, understanding, the, molecular, basis, and, functional, significance, of, exaggerated, neural, estrogen, biosynthesis])].
[sujeto(['Multiple', cytochrome, 'P450', aromatase, '(', 'P450arom)', cDNAs, that, derive, from, separate, gene, loci, '(', cyp19a, and, 'cyp19b)', are, differentially]), verbo([expressed]), complemento([in, brain, '(', 'P450aromB>A)', and, ovary, '(', 'P450aromA>B)', and, have, a, different, developmental, program, '(', 'B>A)', and, response, to, estrogen, upregulation, '(', 'B', 'only)'])].
[sujeto(['As', measured, by]), verbo([increased]), complemento(['P450aromB', 'mRNA,', a, functional, estrogen, response, system, is, first, detected, 24, -, 48, h, 'post-fertilization', '(', 'hpf),', consistent, with, the, onset, of, estrogen, receptor, '(', 'ER)', expression, '(', 'alpha,', 'beta,', and, 'gamma)'])].
[sujeto(['The', 5, '\'', -, flanking, region, of, the, cyp19b, gene]), verbo([has]), complemento([a, 'TATA', 'box,', two, estrogen, response, elements, '(', 'EREs),', an, 'ERE', 'half-site', '(', 'ERE1/2),', a, nerve, growth, factor, 'inducible-B', protein, '(', 'NGFI-B)/Nur77', responsive, element, '(', 'NBRE)', binding, 'site,', and, a, sequence, identical, to, the, zebrafish, 'GATA-2', gene, neural, specific, enhancer])].
[sujeto(['The', cyp19a, promoter, region]), verbo([has]), complemento(['TATA', and, 'CAAT', 'boxes,', a, steroidogenic, 'factor-1', '(', 'SF-1)', binding, 'site,', and, two, aryl, hydrocarbon, receptor, '(', 'AhR)/AhR', nuclear, translocator, factor, '(', 'ARNT)', binding, motifs])].
[sujeto(['Both', genes]), verbo([have]), complemento([multiple, potential, 'SRY/SOX', binding, sites, '(', 16, and, 8, in, cyp19b, and, 'cyp19a,', 'respectively)'])].
[sujeto(['Luciferase', reporters]), verbo([have]), complemento([basal, promoter, activity, in, 'GH3', 'cells,', but, differences, '(', 'a>b)', are, opposite, to, fish, pituitary, '(', 'b>a)'])].
[sujeto(['When', microinjected, into, fertilized, zebrafish, 'eggs,', a, cyp19b, 'promoter-driven', green, fluorescent, protein, '(', 'GFP)', reporter, '(', but, not, 'cyp19a)', is]), verbo([expressed]), complemento([in, neurons, of, 30, -, 48, hpf, 'embryos,', most, prominently, in, retinal, ganglion, cells, '(', 'RGCs)', and, their, projections, to, optic, tectum])].
[sujeto(['Further', studies, are]), verbo([required]), complemento([to, identify, functionally, relevant, 'cis-elements', and, cellular, 'factors,', and, to, determine, the, regulatory, role, of, estrogen, in, neurodevelopment])].
[sujeto(['Diet', and, microbiome, derived, indole, derivatives, are, known, to]), verbo([activate]), complemento([the, ligand, induced, transcription, 'factor,', the, 'Aryl', hydrocarbon, 'Receptor', '(', 'AhR)'])].
[sujeto(['While', the, current, understanding, of, 'AhR', biology]), verbo([has]), complemento([confirmed, its, role, in, mucosal, 'lymphocytes,', its, function, in, intestinal, antigen, presenting, cells, '(', 'APCs)', is, poorly, understood])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, 'Cre-mediated', deletion, of, 'AhR', in, 'CD11c-expressing', cells, in, 'C57/BL6', mice, is, associated, with, altered, intestinal, epithelial, morphogenesis, in, vivo])].
[sujeto(['Moreover,', when, 'co-cultured', with, 'AhR-deficient', 'DCs', ex, 'vivo,', intestinal, organoids, showed, reduced, 'SRY', '(', sex, determining, region, 'Y)-box', 9, and]), verbo([increased]), complemento(['Mucin', 2, 'expression,', which, correlates, with, reduced, 'Paneth', cells, and, increased, goblet, cell, 'differentiation,', similar, to, the, data, obtained, in, vivo])].
[sujeto(['Further,', characterization, of, intestinal, 'APC', 'subsets,', devoid, of, 'AhR,', revealed, an, expression, pattern]), verbo([associated]), complemento([with, aberrant, intrinsic, 'Wnt', pathway, regulation])].
[sujeto(['At', a, functional, 'level,', the]), verbo([loss]), complemento([of, 'AhR', in, 'APCs', resulted, in, a, dysfunctional, epithelial, 'barrier,', associated, with, a, more, aggressive, chemically, induced, colitis, compared, to, wild, type, animals])].
[sujeto(['Our', results, are, consistent, with, a, model, whereby, the, 'AhR', signalling, pathway, may]), verbo([participate]), complemento([in, the, regulation, of, innate, immunity, through, intestinal, epithelium, development, and, mucosal, immunity])].
[sujeto(['In', the, 'male,', testosterone, '(', 'T)', secreted, by, the, developing, testes, defeminizes, 'LH']), verbo([release]), complemento(['mechanisms;', 'conversely,', perinatal, 'AhR', activation, by, 2, ',', 3, ',', 7, ',', 8, ',', -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD)', blocks, defeminization])].
[sujeto(['To', better, understand, developmental, mechanisms, altered, by, 'TCDD', 'exposure,', we, first, verified, that, neonatal, 'TCDD', exposure, in, male, rats]), verbo([prevented]), complemento([the, loss, of, 'AVPV', 'GABA/glutamate', neurons, that, are, critical, for, 'female-typical', 'LH', surge, release])].
[sujeto(['In', 'addition,', upstream, regulatory, analysis]), verbo([suggests]), complemento([that, both, estrogen, receptors, '(', 'ER)', and, androgen, receptors, '(', 'AR)', regulate, genes, targeted, by, 'TCDD'])].
[sujeto(['Of', the, 23, mRNAs]), verbo([found]), complemento([to, be, changed, by, 'TCDD', at, least, 2, -, fold, '(', 'p<0'])].
[sujeto([5, ')', ',', most]), verbo([participate]), complemento([in, the, functions, identified, in, our, bioinformatics, analyses])].
[sujeto(['Several,', including, matrix, metallopeptidase, 9, and, 'SRY-box', 11, '(', 'Sox11),', are, known]), verbo([targets]), complemento([of, 'E2'])].
[sujeto(['CUG', triplet, 'repeat,', 'RNA']), verbo([binding]), complemento([protein, 2, '(', 'cugbp2)', is, particularly, interesting, because, it, is, 'sex-specific,', oppositely, regulated, by, estradiol, '(', 'E2)', and, 'TCDD'])].
[sujeto(['Moreover,', it]), verbo([regulates]), complemento([the, 'post-transcriptional', processing, of, molecules, previously, linked, to, sexual, differentiation, of, the, brain])].
[sujeto(['These', findings]), verbo([provide]), complemento([new, insights, into, how, 'TCDD', may, interfere, with, defeminization, of, 'LH', release, patterns])].
[sujeto(['Two', 'P450arom', mRNAs, which, derive, from, separate, gene, loci, '(', cyp19a, and, 'cyp19b)', are, differentially]), verbo([expressed]), complemento([in, brain, '(', 'b>a)', and, ovary, '(', 'a>b)', and, have, a, different, developmental, program, '(', 'b>a)', and, estrogen, upregulation, '(', b, 'only)'])].
[sujeto(['Sequence', analysis, of, the, cyp19b, gene, approximately, 1.8, kb, upstream, of, the, transcription, start, site, revealed, a, 'TATA', box, at, nucleotide, '(', 'nt)', -, 30, ',', two, estrogen, responsive, elements, '(', 'EREs;', nt, -, 351, and, -, 211, ')', and, a, consensus]), verbo([binding]), complemento([site, '(', 'NBRE)', for, nerve, growth, factor, 'inducible-B', protein, '(', 'NGFI-B/Nur77)', at, -, 286, ',', which, includes, another, 'ERE', 'half-site'])].
[sujeto(['Also', present, were, a, sequence, at, nt, -, 399, '(', 'CCCTCCT)']), verbo([required]), complemento([for, neural, specificity, of, the, zebrafish, 'GATA-2', 'gene,', and, 16, copies, of, an, 'SRY/SOX', binding, motif])].
[sujeto(['The', 5, '\'', -, flanking, region, '(', approximately, 1.0, 'kb)', of, the, cyp19a, gene, had, 'TATA', '(', nt, -, 48, ')', and, 'CAAT', '(', nt, -, 71, ')', 'boxes,', a, steroidogenic, 'factor-1', '(', 'SF-1)']), verbo([binding]), complemento([site, '(', nt, -, 265, ')', ',', eight, copies, of, the, 'SRY/SOX', 'motif,', and, two, copies, of, a, recognition, site, for, binding, the, arylhydrocarbon, receptor, '(', 'AhR)/AhR', nuclear, translocator, factor, '(', 'ARNT)', heterodimer])].
[sujeto(['Tandem', analysis, of, cyp19a, and, cyp19b, promoters, in, living, zebrafish, embryos, can, be, a, useful, approach, for, identifying, 'cis-elements', and, cellular, factors]), verbo([involved]), complemento([in, the, correct, 'tissue-specific,', 'spatial,', temporal, and, estrogen, regulated, expression, of, aromatase, genes, during, 'CNS', and, gonadal, development])].
[sujeto(['ELISA', and, 'RT-PCR', were, used, to, measure, protein, and, mRNA, 'levels,', 'respectively,', of]), verbo([nuclear]), complemento([factor, '(', 'NF)-κB,', 'IL-1β,', 'IL-6', and, 'TNF-α'])].
[sujeto(['Donor', cell, numbers]), verbo([decreased]), complemento([over, time])].
[sujeto(['Pretreatment', with, triptolide, improved, graft, survival, both, 24, '(', 29.3, ±, 0.9, '%', ')', and, 72, h, '(', 17.5, ±, 1.2, '%', ')', after, transplantation, of, 'MSCs', and, resulted, in, a, 2.5, -, fold]), verbo([increase]), complemento([in, the, total, cell, number, 72, h, after, cell, transplantation])].
[sujeto(['The', mechanism, underlying, this, effect]), verbo([involves]), complemento([attenuating, the, inflammatory, response, via, inhibition, of, the, 'NF-κB', signaling, pathway])].
[sujeto(['Many', papers]), verbo([have]), complemento([shown, that, 'SRY', '(', 'sex-determining', region, 'Y)-box', '(', 'SOX)', family, genes, serve, as, either, tumor, suppressor, genes, '(', 'TSGs)', or, oncogenes, by, regulating, the, 'Wnt', signaling, pathway, in, different, cancers])].
[sujeto(['We']), verbo([have]), complemento([demonstrated, recently, that, epigenetic, silencing, of, 'SOX1', gene, occurs, frequently, in, cervical, cancer])].
[sujeto(['Overexpression', of, 'SOX1']), verbo([inhibited]), complemento([cell, 'proliferation,', anchorage, 'independency,', and, invasion, in, vitro])].
[sujeto(['SOX1']), verbo([suppressed]), complemento([tumor, growth, in, nonobese, 'diabetic/severe', combined, immunodeficiency, mice])].
[sujeto(['After', induction, of, 'SOX1', by, doxycycline, '(', 'DOX),', 'SOX1']), verbo([inhibited]), complemento([cell, growth, and, invasion, in, the, inducible, system])].
[sujeto(['SOX1']), verbo([inhibited]), complemento(['TCF-dependent', transcriptional, activity, and, the, 'Wnt', target, genes])].
[sujeto(['SOX1', also]), verbo([repressed]), complemento([the, invasive, phenotype, by, regulating, the, expression, of, 'invasion-related', genes])].
[sujeto(['Taken', 'together,', these, data]), verbo([suggest]), complemento([that, 'SOX1', can, function, as, a, tumor, suppressor, partly, by, interfering, with, 'Wnt/β-catenin', signaling, in, cervical, cancer])].
[sujeto(['BM-derived', 'MSCs', were, detected, by, 'RT-PCR', of, 'CD29', and, were, then, infused, into, the, tail, vein, of, female, rats, that, received, 'CCl4', injection, to]), verbo([induce]), complemento([liver, fibrosis])].
[sujeto(['MSCs', and, 'SIMV']), verbo([decreased]), complemento([liver, procollagens, 'I', and, 'III,', 'TIMP-1', and, endoglin, gene, 'expressions,', 'TGF-β1', 'immunostaining,', and, serum, liver, function, tests, compared, with, the, 'CCl4', group])].
[sujeto(['MMP-1', expression, was]), verbo([increased]), complemento([in, the, 'CCl4/MSCs', group])].
[sujeto(['Our', recent, studies]), verbo([have]), complemento([demonstrated, that, 'SRY', '(', sex, determining, region, 'Y)-box', 1, '(', 'SOX1)', and, secreted, 'frizzled-related', proteins, are, concomitantly, 'promoter-hypermethylated,', and, this, might, lead, to, abnormal, activation, of, the, 'Wnt', signaling, pathway, in, 'HCC'])].
[sujeto(['SOX1', encodes, a, transcription, factor]), verbo([involved]), complemento([in, the, regulation, of, embryonic, development, and, cell, fate, determination])].
[sujeto(['Overexpression', of, 'SOX1', by, a, constitutive, or, inducible, approach, could]), verbo([suppress]), complemento([cell, 'proliferation,', colony, 'formation,', and, invasion, ability, in, 'HCC', cell, 'lines,', as, well, as, tumor, growth, in, nonobese, 'diabetic/severe', combined, immunodeficiency, mice])].
[sujeto(['We', used, a, 'T', cell, factor, '(', 'TCF)-responsive', luciferase, reporter, assay, and, western, blot, analysis, to, prove, that, 'SOX1', could]), verbo([regulate]), complemento(['TCF-responsive', transcriptional, activity, and, inhibit, the, expression, of, 'Wnt', downstream, genes])].
[sujeto(['Furthermore,', we, used, glutathione, 'S-transferase', 'pull-down,', 'co-immunoprecipitation,', and, confocal, microscopy, to, demonstrate, that, 'SOX1', could]), verbo([interact]), complemento([with, 'β-catenin', but, not, with, the, 'β-catenin/TCF', complex])].
[sujeto(['Moreover,', restoration, of, the, expression, of, 'SOX1']), verbo([induces]), complemento([significant, cellular, senescence, in, 'Hep3B', cells])].
[sujeto(['MSCs', were, mainly, distributed, in, the, glomerular, capillaries, at, the, time, points, of, 6, h, and, 48, 'h,', but, the, number, of, 'MSCs', in, glomerular, capillaries]), verbo([decreased]), complemento([and, those, in, renal, mesenchyma, increased, at, the, time, points, from, 10, d, to, 60, d, 'gradually,', then, tended, to, a, steady, 'state,', meanwhile, it, showed, a, stable, increasing, trend, in, renal, tubule])].
[sujeto(['Cell', colony, of, 'MSCs', could, be]), verbo([found]), complemento([in, mesenchyma, with, a, slowed, down, increasing, between, 30, d, to, 60, 'd,', but, the, increasing, in, tubule, was, still, steady])].
[sujeto(['MSCs', transplantation]), verbo([has]), complemento([beneficial, effects, on, 'CAAN,', which, is, possibly, related, with, the, reduction, of, 'PTC'])].
[sujeto(['The', results, indicate, that, 'X-', or, 'Y-linked', genes]), verbo([have]), complemento([direct, 'effects,', not, mediated, by, gonadal, 'secretions,', on, sex, differences, in, two, different, types, of, acute, nociception])].
[sujeto(['Recent', studies]), verbo([have]), complemento([shown, that, hematopoietic, bone, marrow, '(', 'BM)', 'stem/progenitor', cells, can, give, rise, to, hepatocytes, in, 'diseased/damaged', liver])].
[sujeto(['One', study]), verbo([has]), complemento([reported, that, 'BM', cells, can, transdifferentiate, into, liver, 'progenitor/oval', 'cells,', but, it, has, not, been, proven, that, the, latter, can, repopulate, the, liver])].
[sujeto(['To', answer, this, 'question,', we]), verbo([have]), complemento([lethally, irradiated, female, 'DPP4(-)', mutant, 'F344', rats, and, transplanted, them, with, 50, million, 'wild-type', male, 'F344', 'BM', cells])].
[sujeto(['A', 'real-time', 'PCR-based', gene, expression, survey, was, performed, on, isolated, 'European']), verbo([sea]), complemento([bass, follicles, from, primary, growth, to, late, vitellogenesis])].
[sujeto([',', the, beginning, of, the, secondary, growth, 'phase)', showed, elevated, mRNA, amounts, of, follicle]), verbo([stimulating]), complemento([hormone, receptor, '(', 'fshr)', and, 'anti-Mullerian', hormone])].
[sujeto(['Early-to-mid', vitellogenic, follicles, showed, high, mRNA, levels, of, fshr, and, cytochrome, 'P450,', family, 19, ',', subfamily, 'A,', polypeptide, 1, a, while, 'mid-to-late', vitellogenic, follicles]), verbo([expressed]), complemento([increasing, transcript, amounts, of, luteinizing, 'hormone/choriogonadotropin', 'receptor,', steroidogenic, acute, regulatory, 'protein,', and, estrogen, receptors, 1, and, 2, a])].
[sujeto(['The', expression, of, 'biliary/progenitor', markers, by, hepatocellular, carcinoma, '(', 'HCC)', is, often]), verbo([associated]), complemento([with, poor, prognosis, and, stem, 'cell-like', behaviors, of, tumor, cells])].
[sujeto(['Hepatocellular', adenomas, '(', 'HCA)', also, often]), verbo([express]), complemento(['biliary/progenitor', markers, and, frequently, act, as, precursor, lesions, for, 'HCC'])].
[sujeto(['However,', the, cell, of, origin, of, 'HCA', and, 'HCC', that]), verbo([expresses]), complemento([these, markers, still, remains, unclear])].
[sujeto(['Therefore,', to, evaluate, if, mature, hepatocytes, give, rise, to, 'HCA', and, 'HCC', 'tumors,', and, to, understand, the, molecular, pathways]), verbo([involved]), complemento([in, 'tumorigenesis,', we, 'lineage-labeled', hepatocytes, by, injecting, 'adeno-associated', virus, '(', 'AAV)', containing, 'thyroxine-binding', globulin, '(', 'TBG)', promoter, 'driven-Cre', into, 'Rosa(YFP)', mice])].
[sujeto(['We', treated, 'AAV-TBG-Cre;Rosa(YFP)', mice, with, diethylnitrosamine, '(', 'DEN)', followed, by, multiple, injections, of, carbon, tetrachloride, '(', 'CCl4', ')', to]), verbo([induce]), complemento([carcinogenesis, and, 'fibrosis,', and, found, that, 'HCA', and, 'HCC', nodules, were, 'YFP(+)', 'lineage-labeled', and, also, positive, for, osteopontin, '(', 'Opn),', 'SRY', '(', sex, determining, region, 'Y)-box', 9, '(', 'Sox9),', and, epithelial, cell, adhesion, molecule, '(', 'EpCAM),', and, enriched, for, transcripts, of, 'biliary/progenitor', markers, such, as, 'Prom1,', 'Cd44,', and, 'Dlk1'])].
[sujeto(['None', of, the, tumor, nodules]), verbo([expressed]), complemento(['YFP,', indicating, that, 'Foxl1-expressing', cells, are, not, the, cell, of, origin, for, 'hepatotoxin-induced', liver, tumors])].
[sujeto(['By', contrast, with, the, 'mouse,', 'SRY', is, primarily]), verbo([expressed]), complemento([in, most, cells, of, 'XY', 'genital-ridges', and, not, solely, in, 'pre-Sertoli', cells])].
[sujeto(['Between', cord, formation, and, 'prepuberty,', 'SRY', remains]), verbo([expressed]), complemento([in, both, 'Sertoli', and, germinal, cells])].
[sujeto(['Unlike', the, germinal, 'lineage,', 'SRY', continues, to, be, highly]), verbo([expressed]), complemento([in, adult, 'Sertoli', cells, with, a, typical, nuclear, staining])].
[sujeto(['Our', data, indicate, that, in, 'goat,', the, role, of, 'SRY', may, not, be, limited, to, testis, determination, and, could]), verbo([have]), complemento([other, functions, in, testicular, maintenance, and, hence, male, fertility])].
[sujeto(['To', evaluate, 'SRY', phylogenic, conservation, in, regards, to, its, 'function,', we]), verbo([expressed]), complemento([the, goat, gene, '(', 'gSRY)', in, 'XX', transgenic, mouse, gonads])].
[sujeto(['Here,', we, show, that, gSRY]), verbo([induces]), complemento([testis, 'formation,', despite, a, goat, expression, profile])].
[sujeto(['Our', results, demonstrate, that, 'sex-reversal', can, be]), verbo([induced]), complemento([in, 'XX-mice', by, a, 'non-mouse', 'SRY', thus, suggesting, a, conserved, molecular, mechanism, of, action, of, this, 'testis-determining', gene, across, mammalian, species])].
[sujeto(['In', 'mammals,', the, 'Y-located', 'SRY', gene, is, known, to]), verbo([induce]), complemento([testis, formation, from, the, indifferent, gonad])].
[sujeto(['It', is, now, assumed, that, 'SRY']), verbo([acts]), complemento([upstream, of, 'SOX9', in, the, sex, determination, 'cascade,', but, the, regulatory, link, which, should, exist, between, these, two, genes, remains, unknown])].
[sujeto(['Studies', on, 'XX', sex, reversal, in, polled, goats, '(', 'PIS', 'mutation:', 'Polled', 'Intersex', 'Syndrome)']), verbo([have]), complemento([led, to, the, discovery, of, a, 'female-specific', locus, crucial, for, ovarian, differentiation])].
[sujeto(['The', 'FOXL2', expression, profile, of, mice, is, similar, to, that, described, in, goats, in, accordance, with, a]), verbo([conserved]), complemento([role, of, this, ovarian, differentiating, gene, in, mammals])].
[sujeto(['On', the, 'contrary,', the, 'PISRT1', expression, profile, is, different, between, mice, and, 'goats,']), verbo([suggesting]), complemento([different, mechanisms, of, the, primary, switch, in, the, testis, determination, process, within, mammals])].
[sujeto(['By', 'definition,', the, 'DNA']), verbo([binding]), complemento([domain, of, 'SOX', genes, is, at, least, 50, '%', identical, to, the, 79, amino, acid, 'HMG', domain, of, the, 'SRY', gene])].
[sujeto(['We']), verbo([report]), complemento([here, two, 'HMG-box', sequences, from, two, microbat, species, '(', 'R'])].
[sujeto(['Pipistrellus)', which, were, 'PCR', amplified, using, a]), verbo([primer]), complemento([pair, specific, to, the, mouse, 'Sry', 'HMG-box'])].
[sujeto(['The', high, percentage, of, identity, of, this, sequences, with, the, human, and, mouse, 'SOX30', 'HMG-box']), verbo([suggests]), complemento([that, they, are, the, 'SOX30', 'HMG-box', for, these, two, bat, species])].
[sujeto(['This', fragment, contains, two]), verbo([binding]), complemento([sites, for, the, 'Serendipity', '(', 'Sry)', d, zinc, finger, 'activator,', that, mediate, its, cooperative, binding])].
[sujeto(['Further', analysis, showed, that, the, bcd, promoter, configuration, is, decisive, for, 'Sry', d]), verbo([activating]), complemento([function])].
[sujeto(['Replacement', of, sdbs, by]), verbo([binding]), complemento([sites, for, 'Sry', 'b,', the, 'Sry', d, 'paralog,', restores, bcd, transcription, in, sry, d, mutant, 'ovaries,', demonstrating, that, the, functional, divergence, between, these, two, proteins, during, evolution, was, mainly, driven, by, changes, in, their, 'DNA-specific', recognition, 'properties,', resulting, in, the, control, of, separate, developmental, pathways])].
[sujeto(['The', drug, discovery, research, for, cholestatic, liver, diseases]), verbo([has]), complemento([been, hampered, by, the, lack, of, a, 'well-established', human, cholangiocyte, model])].
[sujeto(['Functional', 'cholangiocyte-like', cells, differentiated, from, human]), verbo([induced]), complemento([pluripotent, stem, '(', 'iPS)', cells, are, expected, to, be, a, promising, candidate, for, such, 'research,', but, there, remains, no, 'well-established', method, for, differentiating, cholangiocytes, from, human, iPS, cells])].
[sujeto(['In', this, 'study,', we, searched, for, a, suitable, extracellular, matrix, to]), verbo([promote]), complemento([cholangiocyte, differentiation, from, human, iPS, 'cells,', and, found, that, both, laminin, 411, and, laminin, 511, were, suitable, for, this, purpose])].
[sujeto(['The', gene, expression, levels, of, the, cholangiocyte, 'markers,', aquaporin, 1, '(', 'AQP1),', 'SRY-box', 9, '(', 'SOX9),', cystic, fibrosis, transmembrane, conductance, regulator, '(', 'CFTR),', 'G', 'protein-coupled', bile, acid, receptor, 1, '(', 'GPBAR1),', 'Jagged', 1, '(', 'JAG1),', secretin, receptor, '(', 'SCTR),', and, 'γ-glutamyl', transferase, '(', 'GGT1)', were]), verbo([increased]), complemento([by, using, laminin, 411, or, laminin, 511, as, a, matrix])].
[sujeto(['In', 'addition,', the, percentage, of, 'AQP1-positive', cells, was]), verbo([increased]), complemento([from, 61.8, '%', to, 92.5, '%', by, using, laminin, 411, or, laminin, 511])].
[sujeto(['Furthermore,', the, diameter, and, number, of, cysts, consisted, of, 'cholangiocyte-like', cells, were]), verbo([increased]), complemento([when, using, either, matrix])].
[sujeto(['After', partial, hepatectomy, '(', 'PH),', diethylnitrosamine, '(', 'DEN)', was, administered, to]), verbo([induce]), complemento([liver, fibrosis])].
[sujeto(['Transplanted', cells, proliferated, and, differentiated, into, hepatocytes, and, bile, duct, epithelial, cells, with, 30, '%', -, 50, '%', repopulation, in, the, liver, fibrosis]), verbo([induced]), complemento([by, 'DEN', after, 3, mo])].
[sujeto(['Transplanted', 'FLEP', cells, proliferate, and, differentiate, into, hepatocytes, and, bile, duct, epithelial, cells, with, high, repopulation, capacity, in, the, fiberized, liver]), verbo([induced]), complemento([by, 'DEN,', which, restores, liver, function, and, reduces, liver, fibrosis])].
[sujeto(['Both', patients, and, controls, had, to]), verbo([have]), complemento([male, 'offspring,', and, no, history, of, miscarriages, or, blood, 'transfusions;', they, could, not, be, twins])].
[sujeto(['Y-chromosome', sequences, were]), verbo([found]), complemento([in, three, of, the, four, 'PBC', women, with, associated, systemic, sclerosis])].
[sujeto(['This', discrepancy, may]), verbo([suggest]), complemento([that, not, only, fetal, cells, but, also, fragments, of, fetal, 'DNA', are, present, in, maternal, circulation])].
[sujeto(['This', study, aimed, to, evaluate, whether, female, adult, offspring, born, with, intrauterine, growth, retardation]), verbo([induced]), complemento([by, prenatal, nicotine, exposure, '(', 'PNE)', are, susceptible, to, osteoarthritis, '(', 'OA)', and, to, explore, the, underlying, programming, mechanisms])].
[sujeto(['The', female, adult, offspring, with, or, without, 'PNE', were, forced, with, a, strenuous, treadmill, running, for, 6, wk, to]), verbo([induce]), complemento(['OA'])].
[sujeto(['For', adult, 'offspring,']), verbo([increased]), complemento([cartilage, destruction, and, accelerated, 'OA', progression, were, observed, in, the, 'PNE', group, with, 'running;', the, expression, of, α1, chain, of, type, 'II', collagen, '(', 'Col2A1),', 'aggrecan,', 'SRY-type', high, mobility, group, box, 9, '(', 'Sox9),', and, 'IGF1', signaling, molecules, in, the, cartilage, of, 'PNE', offspring, were, decreased])].
[sujeto(['For', 'fetuses,', elevated, serum, corticosteroid, and, nicotine, levels, and]), verbo([suppressed]), complemento(['IGF1', levels, were, 'observed;', expression, of, 'Col2A1,', 'aggrecan,', 'Sox9,', and, 'IGF1', were, reduced])].
[sujeto(['In', 'conclusion,', 'PNE']), verbo([increases]), complemento([the, susceptibility, of, adult, offspring, to, 'OA;', the, potential, mechanism, involves, 'IGF1', 'low-functional', programming, in, articular, cartilage, caused, directly, by, the, action, of, nicotine, on, 'α4β2-nAChR'])].
[sujeto(['Prenatal', stress, is, known, to]), verbo([cause]), complemento([intrauterine, fetal, growth, 'retardation,', and, is, also, associated, with, various, 'long-term', effects, in, the, form, of, metabolic, and, neurodevelopmental, diseases, in, adults])].
[sujeto(['Many', of, the, diseases]), verbo([associated]), complemento([with, prenatal, stress, exhibit, a, sex, bias])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, administration, of, the, synthetic, 'glucocorticoid,', dexamethasone, '(', 'Dex),', at, embryonic, days, 7.5, ',', 8.5, ',', and, 9.5, ',', induces, embryonic, growth, restriction, in, a, 'sex-dependent', manner, in, a, mouse, model])].
[sujeto(['During', male, gonadal, 'development,', 'sex-determining', 'genes,', such, as, 'Sry,', 'Sox9,', and, other, downstream, 'genes,', were]), verbo([found]), complemento([to, be, dysregulated, in, response, to, prenatal, 'Dex,', whereas, the, genes, for, the, ovarian, pathway, were, affected, to, a, lesser, degree, in, females])].
[sujeto(['In', 'addition,', fetal, testosterone, concentrations, were]), verbo([decreased]), complemento([by, prenatal, exposure, to, 'Dex,', in, parallel, with, reduced, numbers, of, 3, 'β-hydroxysteroid', dehydrogenase, '(', 3, 'β-HSD)-positive', cells, in, the, embryonic, testis])].
[sujeto(['We', believe, these, studies]), verbo([provide]), complemento([valuable, insights, into, possible, mechanisms, responsible, for, 'sex-specific', responses, to, prenatal, stress])].
[sujeto(['The', knowledge, that, diverse, populations, of, dopaminergic, neurons, within, the, ventral, tegmental, area, '(', 'VTA)', can, be, distinguished, in, terms, of, their, 'molecular,', electrophysiological, and, functional, 'properties,', as, well, as, their, differential, projections, to, cortical, and, subcortical, regions]), verbo([has]), complemento([significance, for, key, brain, 'functions,', such, as, the, regulation, of, 'motivation,', working, memory, and, sensorimotor, control])].
[sujeto(['Almost', without, 'exception,', this, understanding]), verbo([has]), complemento([evolved, from, landmark, studies, performed, in, the, male, sex])].
[sujeto(['This', may, be, driven, by, sex, differences, in, the, hormonal, environment, during, adulthood, '(', '\'', 'activational\'', 'effects)', and, development, '(', perinatal, 'and/or', pubertal, '\'', 'organizational\'', 'effects),', as, well, as, genetic, 'factors,', especially, the, 'SRY', gene, on, the, 'Y', chromosome, in, 'males,', which, is]), verbo([expressed]), complemento([in, a, 'sub-population', of, adult, midbrain, dopaminergic, neurons])].
[sujeto(['Stress', and, stress, 'hormones,', especially, 'glucocorticoids,', are, important, factors, which]), verbo([interact]), complemento([with, the, 'VTA', dopaminergic, systems, in, order, to, achieve, behavioral, adaptation, and, enable, the, individual, to, cope, with, environmental, change])].
[sujeto(['This', may]), verbo([have]), complemento([enduring, consequences, for, individual, resilience, or, susceptibility, to, pathophysiological, change, induced, by, stressors, in, later, 'life,', with, potential, translational, significance, for, sex, bias, commonly, found, in, disorders, involving, dysfunction, of, the, mesocorticolimbic, dopaminergic, systems])].
[sujeto(['Prenatal', dexamethasone, '(', 'DEX)', treatment]), verbo([has]), complemento([been, proposed, since, 1984, to, prevent, genital, virilization, in, girls, with, congenital, adrenal, hyperplasia, '(', 'CAH)'])].
[sujeto(['It', avoided, prenatal, 'DEX', in, 68, '%', of, 'males,', and, this, percentage]), verbo([increased]), complemento([over, the, years])].
[sujeto(['DEX', was]), verbo([maintained]), complemento([until, prenatal, diagnosis, in, 'non-CAH', females])].
[sujeto(['Virilization', was]), verbo([prevented]), complemento([in, 12, 'CAH', girls, treated, at, the, latest, at, 6, weeks, gestation, and, minimized, in, 3, girls, treated, between, 6, and, 7, weeks, gestation])].
[sujeto(['Prenatal', 'DEX', should, be]), verbo([maintained]), complemento([to, prevent, virilization, and, traumatic, surgery, in, 'CAH', girls, after, informed, consent, and, information, provided, to, families, about, the, benefit, to, risk, ratio, in, limiting, hyperandrogenism, during, fetal, life])].
[sujeto(['Our', large, multicentric, 'French', cohort]), verbo([has]), complemento([helped, to, better, assess, the, risks, previously, reported])].
[sujeto(['Normal', male, sex, development]), verbo([requires]), complemento([the, 'SRY', gene, on, the, 'Y', 'chromosome,', the, regression, of, 'Müllerian', structures, via, 'anti-Müllerian', hormone, '(', 'AMH)', 'signalling,', the, development, of, the, 'Wolffian', duct, system, into, normal, male, internal, genital, structures, consequent, to, testosterone, secretion, by, the, testicular, 'Leydig', 'cells,', and, 'finally,', sufficient, activation, of, testosterone, to, dihydrotestosterone, by, 5, 'alpha-reductase'])].
[sujeto(['Recent', studies, in, human, fetal, development]), verbo([have]), complemento([demonstrated, the, early, fetal, expression, of, the, adrenocorticotrophic, hormone, '(', 'ACTH)', receptor, and, all, steroidogenic, components, necessary, for, the, biosynthesis, of, cortisol])].
[sujeto(['These', findings]), verbo([provide]), complemento([compelling, evidence, for, the, assumed, pathogenesis, of, congenital, adrenal, hyperplasia, '(', 'CAH)', due, to, 21, -, hydroxylase, 'deficiency,', diminished, feedback, to, the, pituitary, due, to, glucocorticoid, 'deficiency,', subsequent, 'ACTH', 'excess,', and, 'up-regulation', of, adrenal, androgen, production, with, subsequent, virilization])].
[sujeto(['Thus', 'CAH', teaches, important, lessons, from, 'nature,']), verbo([providing]), complemento([privileged, insights, into, the, window, of, human, sexual, 'differentiation,', and, particularly, highlighting, the, importance, of, steroidogenesis, in, the, process, of, human, sexual, differentiation])].
[sujeto(['Mutations', in, the, gene, encoding, 110, -, hydroxylase, '(', 'CYPI]BJ)', are, the, second, most, common]), verbo([cause]), complemento([of, congenital, adrenal, hyperplasia, '(', 'CAH),', a, disorder, characterized, by, adrenal, insufficiency, and, virilization, of, female, external, genitalia])].
[sujeto(['We', describe, a, new, case, of, 1113, -, hydroxylase, 'CAH']), verbo([caused]), complemento([by, donor, splice, site, mutation, in, the, 'CYPllB1', gene])].
[sujeto(['In', a, previous]), verbo([reported]), complemento([case, a, donor, splice, mutation, was, identified, for, the, first, time, at, the, same, position, codon, 318, of, the, 'CYPIIB1', gene])].
[sujeto(['To', clarify, the, complexity, of, possible, interactions, between, two, distinct, 'ligands,', 'PTH', and, 'PTHrP,', and, their, common, receptor, in, the, intact, 'organism,', and, to, identify, as, yet, unrecognized, roles, for, 'PTH', in, normal, 'physiology,', we]), verbo([have]), complemento([cloned, and, characterized, the, structural, 'organization,', nucleotide, sequence, and, transcriptional, regulation, of, the, murine, gene, encoding, 'PTH'])].
[sujeto(['Comparison', of, the, murine, preproPTH, sequence, with, other, mammalian, forms, of, the, protein, shows, it, to, be, highly]), verbo([conserved]), complemento([and, to, share, limited, structural, similarity, to, 'PTHrP', at, the, 'amino-terminal', 'region,', a, domain, critical, for, binding, and, activation, of, their, common, receptor])].
[sujeto(['Putative']), verbo([binding]), complemento([motifs, for, the, transcription, factors, 'sex-determining', region, 'Y', gene, 'product,', transcriptional, repressor, 'CDP,', hepatic, nuclear, factor, 3, 'beta,', 'GATA-binding', factor, 1, ',', glucocorticoid, 'receptor,', 'SRY-related', high, mobility, group, box, protein, 5, and, cAMP, response, element, binding, protein, were, identified, in, the, 5, '\'', flanking, region, of, the, 'Pth', gene])].
[sujeto(['When', placed, upstream, of, a, reporter, 'gene,', these, sequences, failed, to]), verbo([confer]), complemento([transcriptional, regulation, in, response, to, 1, ',', 25, '(', 'OH)(2)', vitamin, 'D(3),', but, responded, positively, to, the, addition, of, isoproterenol, and, forskolin])].
[sujeto(['Acutely', rejecting, allografts, showed, a, dense, mononuclear, infiltrate, consisting, of]), verbo([activated]), complemento(['CD4(+)', and, 'CD8(+)', 'T', cells, with, some, macrophages])].
[sujeto(['SOX9', is, a, transcription, factor, that]), verbo([activates]), complemento([type, 'II', procollagen, '(', 'Col2a1)', gene, expression, during, chondrocyte, differentiation])].
[sujeto(['Glucocorticoids', are, also, known, to]), verbo([promote]), complemento([chondrocyte, differentiation, via, unknown, molecular, mechanisms])].
[sujeto(['Sox9', mRNA, was]), verbo([expressed]), complemento([at, high, levels, in, these, chondrocytes])].
[sujeto(['Treatment', with, 'DEX']), verbo([enhanced]), complemento(['Sox9', mRNA, expression, within, 24, h, and, this, effect, was, observed, at, least, up, to, 48, h])].
[sujeto(['Western', blot, analysis, revealed, that, 'DEX', also]), verbo([enhanced]), complemento([the, levels, of, 'SOX9', protein, expression])].
[sujeto(['Treatment', with, 'DEX']), verbo([enhanced]), complemento(['Col2a1', mRNA, expression, in, these, chondrocytes, and, 'furthermore,', 'DEX', enhanced, the, activity, of, 'Col2-CAT', '(', chloramphenicol, 'acetyltransferase)', construct, containing, a, 1.6, kb, intron, fragment, where, 'chondrocyte-specific', 'Sry/Sox-', consensus, sequence, is, located])].
[sujeto(['The']), verbo([enhancing]), complemento([effect, of, 'DEX', was, specific, to, 'SOX9,', as, 'DEX', did, not, alter, the, levels, of, 'Sox6', mRNA, expression])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'DEX', promotes, chondrocyte, differentiation, through, enhancement, of, 'SOX9'])].
[sujeto(['Consequently,', each, invertebrate, gene]), verbo([has]), complemento([been, amplified, to, the, maximum, of, four, paralogous, genes, in, 'vertebrates:', the, 'one-to-four', rule])].
[sujeto(['When', this, rule, is, applied, to, genes, pertinent, to, gonadal, development, and, 'differentiation,', the, following, 'emerged:', '(', 'i)', 'Two', closely, related, 'zinc-finger', transcription, factor, genes, in, invertebrates]), verbo([have]), complemento([been, amplified, to, two, paralogous, groups, in, vertebrates])].
[sujeto(['Interestingly,', 'EGR1', and, 'WT1']), verbo([act]), complemento([as, antagonists, of, each, other, in, nephroblastic, cells])].
[sujeto(['Its', ancient, origin]), verbo([suggests]), complemento([that, 'SRY', once, became, extinct, in, earlier, 'vertebrates,', only, to, revive, itself, in, the, mammalian, ancestor])].
[sujeto(['(', 'iv)', 'Inasmuch', as, four, paralogues, of, one, invertebrate]), verbo([nuclear]), complemento([receptor, gene, have, differentiated, to, receptors, of, 'androgen,', 'mineralocorticoid,', glucocorticoid, and, 'progesterone,', there, should, at, most, be, four, paralogous, 'estrogen-receptor', genes, in, the, vertebrate, genome])].
[sujeto(['It', is, likely, that, one, of, them, plays, a, pivotal, role, in, the, 'estrogen-dependent', 'sex-determining', mechanism, so, commonly]), verbo([found]), complemento([among, 'reptiles,', amphibians, and, fish])].
[sujeto(['Alleles', of, the, 'sex-determining', genes, and, the, genes, of, the, other, genetic, systems, which]), verbo([participate]), complemento([in, regulation, of, reproduction, may, be, responsible, for, this, variability])].
[sujeto(['We']), verbo([have]), complemento([found, nearly, twofold, interstrain, differences, in, testosterone, levels, in, the, blood, of, male, rat, fetuses, of, 2, strains])].
[sujeto(['The', rats, with, higher, testosterone, levels, during, intrauterine, development]), verbo([have]), complemento([higher, rates, of, sexual, maturation, and, sexual, activity, in, future, life])].
[sujeto(['Genetic', differences, were, also]), verbo([found]), complemento([in, sensitivity, of, fetal, testosterone, to, disruptive, influences])].
[sujeto(['Consequently,', each, invertebrate, gene]), verbo([has]), complemento([been, amplified, to, the, maximum, of, four, paralogous, genes, in, 'vertebrates:', the, 'one-to-four', rule])].
[sujeto(['When', this, rule, is, applied, to, genes, pertinent, to, gonadal, development, and, 'differentiation,', the, following, 'emerged:', '(', 'i)', 'Two', closely, related, 'zinc-finger', transcription, factor, genes, in, invertebrates]), verbo([have]), complemento([been, amplified, to, two, paralogous, groups, in, vertebrates])].
[sujeto(['Interestingly,', 'EGR1', and, 'WT1']), verbo([act]), complemento([as, antagonists, of, each, other, in, nephroblastic, cells])].
[sujeto(['Its', ancient, origin]), verbo([suggests]), complemento([that, 'SRY', once, became, extinct, in, earlier, 'vertebrates,', only, to, revive, itself, in, the, mammalian, ancestor])].
[sujeto(['(', 'iv)', 'Inasmuch', as, four, paralogues, of, one, invertebrate]), verbo([nuclear]), complemento([receptor, gene, have, differentiated, to, receptors, of, 'androgen,', 'mineralocoticoid,', glucocorticoid, and, 'progesterone,', there, should, at, most, be, four, paralogous, 'estrogen-receptor', genes, in, the, vertebrate, genome])].
[sujeto(['It', is, likely, that, one, of, them, plays, a, pivotal, role, in, the, 'estrogen-dependent', 'sex-determining', mechanism, so, commonly]), verbo([found]), complemento([among, 'reptiles,', amphibians, and, fish])].
[sujeto(['A', de, novo, apparently, balanced, translocation]), verbo([involving]), complemento([chromosomes, 8, and, 20, was, found, in, a, 14, -, 'year-old', boy, with, minor, 'anomalies,', mild, skeletal, abnormalities, and, ambiguous, external, genitalia, including, perineoscrotal, 'hypospadias,', rudimentary, fused, labioscrotal, 'folds,', bilateral, 'cryptorchidism,', and, small, penis])].
[sujeto(['No', signs, of, other, conditions, known, to, be]), verbo([associated]), complemento([with, structural, anomalies, of, either, chromosome, 8, or, 20, were, present, and, incomplete, masculinisation, of, the, external, genitalia, appears, to, be, the, main, component, of, the, phenotype])].
[sujeto(['Coding', sequences, of, the, 'sex-determining', gene, '(', 'SRY)', and, androgen, receptor, gene, '(', 'AR)', were]), verbo([found]), complemento([to, be, identical, to, those, of, a, normal, male, excluding, their, role, in, the, cause, of, the, present, condition])].
[sujeto(['Since', several, other]), verbo([reports]), complemento([describe, the, association, of, hypospadias, and, hypertelorism, with, deletions, or, translocations, involving, 8, 'q,', we, suggest, that, a, locus, necessary, for, male, sex, differentiation, is, located, at, distal, 8, q])].
[sujeto(['Although', the, etiologies, of, true, hermaphroditism, and, mixed, gonadal, dysgenesis, remain, 'elusive,', most, gene, defects, in, female, pseudohermaphroditism, or, 'CAH']), verbo([have]), complemento([been, pinpointed, to, the, 21, -, hydroxylase, gene])].
[sujeto(['Incomplete', masculinization]), verbo([has]), complemento([been, found, to, be, due, to, defects, in, the, androgen, 'receptor,', 5, 'alpha-reductase,', or, enzymes, in, the, pathway, from, cholesterol, to, testosterone])].
[sujeto(['SRY', point, mutations]), verbo([have]), complemento([been, implicated, in, 46, 'XY', pure, gonadal, dysgenesis])].
[sujeto(['Retained', müllerian, ducts]), verbo([have]), complemento([been, attributed, to, point, mutations, in, the, 'MIS', 'gene;', those, with, normal, 'MIS', levels, should, be, expected, to, have, receptor, deficits])].
[sujeto(['The', proper, care, of, these, complex, patients]), verbo([requires]), complemento([that, the, physician, be, a, scientist, as, well, as, a, clinician, and, a, skilled, technician])].
[sujeto(['Di-(2-ethylhexyl)', phthalate, '(', 'DEHP)', is, a, plasticizer, with, endocrine, disrupting, properties, that, is]), verbo([found]), complemento([ubiquitously, in, the, environment, as, well, as, in, human, amniotic, 'fluid,', umbilical, cord, 'blood,', human, 'milk,', 'semen,', and, saliva])].
[sujeto(['It', is, used, in, the, industry, to, add, flexibility, to, polyvinyl, 'chloride-derived', plastics, and, its, wide, spread, use, and, presence]), verbo([has]), complemento([resulted, in, constant, human, exposure, through, fetal, development, and, postnatal, life])].
[sujeto(['Epidemiological', studies]), verbo([have]), complemento([suggested, an, association, between, phthalate, exposures, and, human, reproductive, effects, in, infant, and, adult, populations])].
[sujeto(['The', present, review, focuses, on, these, novel, 'findings,', which]), verbo([suggest]), complemento([that, 'DEHP', exerts, more, complex, and, broader, disruptive, effects, on, the, endocrine, system, and, metabolism, than, previously, thought])].
[sujeto(['To']), verbo([report]), complemento([a, translocation, between, chromosomes, 3, and, 4, :, 46, ',', 'XY,t(3;4)(p25;q31'])].
[sujeto(['G-banding', of, his, chromosomes, showed, that, the, patient, had, a, balanced, translocation]), verbo([involving]), complemento([chromosomes, 3, and, 4, :, 46, ',', 'XY,t(3;4)(p25;q31'])].
[sujeto(['This', karyotype]), verbo([finding]), complemento([was, confirmed, by, 'FISH'])].
[sujeto(['Although', no, such, association]), verbo([has]), complemento([been, reported, to, 'date,', we, think, that, the, severe, hypospadias, in, our, case, might, be, associated, with, this, translocation])].
[sujeto(['Polymorphisms', 'C-824T', and, 'A-581G', were, located, in, highly]), verbo([conserved]), complemento([regions, and, were, predicted, to, disrupt, known, transcriptional, control, motifs, myocyte, enhancer, 'factor-2', '(', 'MEF2),', 'sex-determining', region, 'Y', '(', 'SRY),', and, forkhead, box, 'D1', '(', 'FOXD1)', at, 'C-824T', and, 'G/C-rich', binding, factors, specificity, protein, 1, '(', 'SP1),', activating, 'enhancer-binding', protein, 2, '(', 'AP2)],', early, growth, response, protein, 1, '(', 'EGR1)', at, 'A-581G'])].
[sujeto(['We', further, probed, the, functional, significance, of, 'C-824T', and, 'A-581G', by, cotransfection, of, 'trans-activating', factors, in, 'cella;', 'MEF2,', 'SRY,', and, 'FOXD1', differentially]), verbo([activated]), complemento(['C-824T,', whereas, the, 'G/C-rich', binding, factors, 'SP1,', 'AP2,', and, 'EGR1', differentially, activated, 'A-581G'])].
[sujeto(['At', 'C-824T,', factor, 'MEF2']), verbo([acted]), complemento([in, a, directionally, coordinate, fashion, '(', at, 'T>C)', to, explain, the, in, vivo, trait, 'associations,', whereas, at, 'A-581G,', factors, 'SP1,', 'AP2,', and, 'EGR1', displayed, similar, differential, actions, '(', at, 'G>A)'])].
[sujeto(['Finally,', chromatin, immunoprecipitation, demonstrated, that, the, endogenous, factors]), verbo([bound]), complemento([to, the, motifs, in, cella])].
[sujeto(['MEF2,', 'FOXD1,', and, 'SRY', contribute, to, functional, differences, in, 'C-824T', 'expression,', whereas, 'SP1,', 'AP2,', and, 'EGR1']), verbo([mediate]), complemento([those, of, 'A-581G'])].
[sujeto(['The', 'SRY', effect, on, 'TH', transcription]), verbo([suggests]), complemento([a, mechanism, whereby, male, and, female, sex, may, differ, in, sympathetic, activity, and, hence, blood, pressure])].
[sujeto(['This', fatty, acid]), verbo([has]), complemento([profound, and, diverse, effects, on, liver, metabolism])].
[sujeto(['The', levels, of, 'AST,', 'ALT', and, 'ALP', in, the, serum, of, rats, with, 'APAP-induced', liver, injury, were, significantly]), verbo([increased]), complemento([and, returned, to, the, levels, in, control, group, by, day, six])].
[sujeto(['The', 'APAP-induced']), verbo([decrease]), complemento([in, albumin, was, significantly, improved, in, rats, through, cell, 'therapy,', when, compared, with, that, in, the, 'APAP-alone', treated, rats])].
[sujeto(['Depending', on, multiple, signaling, 'cues,', in, about, half, of, the, 'individuals,', the, juvenile, ovaries, degenerate, or, undergo, apoptosis, to, initiate, testes, development, while, the, other, half]), verbo([maintains]), complemento([the, oogenic, pathway])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, activation, of, 'NFκB', and, prostaglandin, synthase, 2, '(', 'ptgs2)', results, in, 'female-biased', sex, ratios])].
[sujeto(['Prostaglandin', synthase, and, prostaglandins, are]), verbo([involved]), complemento([in, multiple, physiological, 'functions,', including, cell, survival, and, apoptosis])].
[sujeto(['On', further, 'evaluation,', we, observed, that, exposure, with, the, prostaglandin, 'D2', '(', 'PGD2)', analogue, 'BW-245C']), verbo([induced]), complemento(['SRY-box', containing, gene, 9, a, '(', 'sox9a)', and, resulted, in, 'male-biased', sex, ratios])].
[sujeto(['On', the, other, 'hand,', prostaglandin, 'E2', '(', 'PGE2)', treatment, resulted, in, 'female-biased', sex, ratios, and]), verbo([involved]), complemento([activation, of, 'NFκB', and, the, 'β-catenin', pathway, as, well, as, inhibition, of, sox9])].
[sujeto(['In', this, 'study,', we, show, that, 'PGD2', and, 'PGE2', can, program, the, gonads, to, either, the, testis, or, the, ovary, differentiation, 'pathways,', indicating, that, prostaglandins, are]), verbo([involved]), complemento([in, the, regulation, of, zebrafish, gonadal, differentiation])].
[sujeto(['Valproic', acid, also]), verbo([inhibits]), complemento([histone, deacetylase, 'activity,', which, is, associated, with, histone, hyperacetylation, and, changes, in, gene, expression])].
[sujeto(['Reverse', 'transcription-polymerase', chain, reaction, analysis, revealed, a, significant]), verbo([increase]), complemento([in, conserved, dopamine, neurotrophic, factor, '(', 'CDNF)', and, glial, cell, 'line-derived', neurotrophic, factor, mRNA, 'expression,', after, treatment, with, clinically, relevant, concentrations, of, 'VPA', '(', 0.5, or, 1.0, 'mM)', for, 24, hr])].
[sujeto(['In', 'addition,', significant]), verbo([increases]), complemento([in, the, mRNA, levels, of, the, early, dopaminergic, neuron, 'marker,', nuclear, 'receptor-related', protein, 1, '(', 'Nurr1),', and, the, transcriptional, 'regulator,', early, growth, response, protein, 1, '(', 'Egr1),', were, observed, after, treatment, with, 'VPA', for, 24, hr])].
[sujeto([2, cells, after, 'VPA', treatment, for, 24, hr, or, 48, 'hr,']), verbo([suggesting]), complemento([involvement, of, an, epigenetic, mechanism, in, the, observed, gene, induction, by, this, drug])].
[sujeto(['These', findings, support, a, role, for, 'VPA', in]), verbo([modulating]), complemento([neurotrophic, and, differentiation, factor, 'expression,', in, keeping, with, its, reported, neuroprotective, and, neurodevelopmental, effects])].
[sujeto(['The', potential, of, 'MSC', for, mesenchymal, differentiation]), verbo([has]), complemento([been, well, documented, in, different, animal, models, predominantly, on, rodents])].
[sujeto(['Plastic-adherent', bMSC, isolated, from, fetal, 'BM']), verbo([maintained]), complemento([a, 'fibroblast-like', morphology, under, monolayer, culture, conditions])].
[sujeto(['These', cells]), verbo([expressed]), complemento([high, levels, of, 'MSC', surface, markers, '(', 'CD73,', 'CD90,', and, 'CD105)', and, low, levels, of, hematopoietic, surface, markers, '(', 'CD34', and, 'CD45)'])].
[sujeto(['Culture', of, bMSC, under, osteogenic, conditions, during, a, 27, -, day, period]), verbo([induced]), complemento(['up-regulation', of, the, osteocalcin, '(', 'OC)', gene, expression, and, alkaline, phosphatase, '(', 'ALPL)', 'activity,', and, promoted, mineralization, of, the, matrix])].
[sujeto(['Increasing', supplementation, levels, of, ascorbic, acid, to, culture, media]), verbo([enhanced]), complemento([osteogenic, differentiation, of, 'bMSC;', 'whereas,', reduction, of, 'FBS', supplementation, compromised, osteogenesis])].
[sujeto([bMSC]), verbo([increased]), complemento([expression, of, 'cartilage-specific', genes, aggrecan, '(', 'ACAN),', collagen, 2, 'A1', '(', 'COL2A1)', and, 'SRY', '(', 'sex-determining', region, 'Y)', box, 9, '(', 'SOX9)', at, 'Day', 21, of, chondrogenic, differentiation])].
[sujeto(['Treatment', of, bMSC, with, adipogenic, factors]), verbo([increased]), complemento([levels, of, fatty, 'acid-binding', protein, 2, '(', 'AP2)', mRNA, and, accumulation, of, lipid, vacuoles, after, 18, &, 'nbsp;days', of, culture])].
[sujeto(['NANOG', mRNA, levels, in, differentiating, bMSC, were, not, affected, during, adipogenic, 'culture;', 'however,', osteogenic, and, chondrogenic, conditions]), verbo([induced]), complemento([higher, and, lower, 'levels,', respectively])].
[sujeto(['The', simplicity, of, isolation, and, the, differentiation, potential]), verbo([suggest]), complemento([that, bMSC, from, 'abattoir-derived', fetal, 'BM', are, appropriate, candidate, for, investigating, 'MSC', biology, and, for, eventual, applications, for, regenerative, therapy])].
[sujeto(['H-REV107']), verbo([has]), complemento([been, shown, to, express, at, high, levels, in, differentiated, tissues, of, 'post-meiotic', testicular, germ, cells])].
[sujeto(['Prostaglandin', 'D2', '(', 'PGD2)', is, conjectured, to]), verbo([induce]), complemento(['SRY-related', 'high-mobility', group, box, 9, '(', 'SOX9)', expression, and, subsequent, 'Sertoli', cell, differentiation])].
[sujeto(['To', 'date,', the, function, of, 'H-rev107', in, differentiated, testicular, cells]), verbo([has]), complemento([not, been, well, defined])].
[sujeto(['In', the, 'study,', we]), verbo([found]), complemento([that, 'H-rev107', was, 'co-localized', with, prostaglandin, 'D2', synthase, '(', 'PTGDS)', and, enhanced, the, activity, of, 'PTGDS,', resulting, in, increase, of, 'PGD2', production, in, testis, cells])].
[sujeto(['Furthermore,', when, 'H-rev107', was]), verbo([expressed]), complemento([in, human, 'NT2/D1', testicular, cancer, 'cells,', cell, migration, and, invasion, were, inhibited])].
[sujeto(['Also,', silencing, of, 'PTGDS', would, reduce, 'H-rev107-mediated']), verbo([increase]), complemento([in, 'PGD2,', 'cAMP,', and, 'SOX9'])].
[sujeto(['These', results, revealed, that, 'H-rev107,', through, 'PTGDS,']), verbo([suppressed]), complemento([cell, migration, and, invasion])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, the, 'PGD2-cAMP-SOX9', signal, pathway, might, play, an, important, role, in, 'H-rev107-mediated', cancer, cell, invasion, in, testes])].
[sujeto(['RIG1', is]), verbo([expressed]), complemento([in, high, levels, in, 'well-differentiated', 'tissues,', but, its, expression, is, decreased, in, cancer, tissues, and, cancer, cell, lines])].
[sujeto(['We']), verbo([found]), complemento(['RIG1', to, be, highly, expressed, in, testicular, cells])].
[sujeto(['When', 'RIG1', was]), verbo([expressed]), complemento([in, 'NT2/D1', testicular, cancer, 'cells,', neither, cell, death, nor, cell, viability, was, affected])].
[sujeto(['However,', 'RIG1', significantly]), verbo([inhibited]), complemento([cell, migration, and, invasion, in, 'NT2/D1', cells])].
[sujeto(['We']), verbo([found]), complemento([that, prostaglandin, 'D2', synthase, '(', 'PTGDS)', interacted, with, 'RIG1', using, yeast, 'two-hybrid', screens])].
[sujeto(['Further,', we]), verbo([found]), complemento(['PTGDS', to, be, 'co-localized', with, 'RIG1', in, 'NT2/D1', testis, cells])].
[sujeto(['This', indicated, that, 'RIG1', can]), verbo([enhance]), complemento(['PTGDS', activity])].
[sujeto(['Silencing', of, 'PTGDS', expression, significantly]), verbo([decreased]), complemento(['RIG1-mediated', cAMP, and, 'PGD2', production])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'RIG1', will, suppress, cell, 'migration/invasion', through, the, 'PGD2', signaling, pathway])].
[sujeto(['In', 'conclusion,', 'RIG1', can]), verbo([interact]), complemento([with, 'PTGDS', to, enhance, its, function, and, to, further, suppress, 'NT2/D1', cell, migration, and, invasion])].
[sujeto(['Our', study]), verbo([suggests]), complemento([that, 'RIG1-PGD2', signaling, might, play, an, important, role, in, cancer, cell, suppression, in, the, testis])].
[sujeto(['Afterwards', the, expression, of, 'Sox9', is]), verbo([maintained]), complemento([by, a, positive, feedback, loop, with, 'Fgf9', and, prostaglandin, 'D2', as, well, as, by, autoregulative, ability, of, 'Sox9'])].
[sujeto(['If', these, factors, reach, high, 'concentrations,', then, 'Sox9', 'and/or', 'Fgf9', may]), verbo([inhibit]), complemento([the, female, pathway])].
[sujeto(['Surprisingly,', 'splicing,']), verbo([nuclear]), complemento(['transport,', and, extramatrix, proteins, may, be, involved, in, sex, determination])].
[sujeto(['In', the, mouse, 'XY', 'gonad,', 'SOX9', upregulates, 'Fgf9,', which, initiates, a, 'Sox9/Fgf9', feedforward, 'loop,', and, 'Sox9', expression, is]), verbo([stimulated]), complemento([by, the, prostaglandin, 'D2', '(', 'PGD2)', producing, lipocalin, prostaglandin, 'D', synthase, '(', 'L-PGDS,', or, 'PTDGS)', 'enzyme,', which, accelerates, commitment, to, the, male, pathway])].
[sujeto(['In', an, attempt, to, decipher, the, genetic, relationships, between, 'Sox9', and, the, 'L-Pgds/PGD2', pathway, during, mouse, testicular, 'organogenesis,', we]), verbo([found]), complemento([that, ablation, of, 'Sox9', at, the, onset, or, during, the, time, window, of, expression, in, embryonic, 'Sertoli', cells, abolished, 'L-Pgds', transcription])].
[sujeto(['In', this, 'study,', we, demonstrated, genetically, that, the, 'L-Pgds/PGD2', pathway]), verbo([acts]), complemento([as, a, second, amplification, loop, of, 'Sox9', expression])].
[sujeto(['These', data]), verbo([suggest]), complemento(['that,', once, activated, and, maintained, by, 'SOX9,', production, of, testicular, 'L-PGDS', leads, to, the, accumulation, of, 'PGD2,', which, in, turn, activates, 'Sox9', transcription, and, nuclear, translocation, of, 'SOX9'])].
[sujeto(['This', mechanism]), verbo([participates]), complemento([together, with, 'FGF9', as, an, amplification, system, of, 'Sox9', gene, expression, and, activity, during, mammalian, testicular, organogenesis])].
[sujeto(['However,', expression, of, the, transcription, factor, 'SRY', initiates, male, development, and]), verbo([induces]), complemento(['patterning,', 'proliferation,', and, epithelialization, specific, to, the, testis])].
[sujeto(['These', mechanisms]), verbo([have]), complemento([recently, been, shown, to, both, promote, the, male, fate, and, simultaneously, repress, ovarian, development])].
[sujeto(['After', their, 'specification,', 'Sertoli', cells, epithelialize, and, surround, the, male, germ, line, to, form, large, looping, structures]), verbo([bound]), complemento([by, extracellular, matrix])].
[sujeto(['To']), verbo([ensure]), complemento([that, 'Sertoli', cells, differentiate, in, sufficient, numbers, to, induce, normal, testis, 'development,', the, early, testis, produces, prostaglandin, 'D(2)', '(', 'PGD(2)),', which, recruits, cells, of, the, supporting, cell, lineage, to, a, 'Sertoli', cell, fate])].
[sujeto(['Here', we, show, that, the, gene, encoding, prostaglandin, 'D', synthase, '(', 'Pgds),', the, enzyme, that, produces, 'PGD(2),', is]), verbo([expressed]), complemento([in, 'Sertoli', cells, immediately, after, the, onset, of, 'Sox9', expression])].
[sujeto(['Promoter', analysis, in, silico, and, in, vitro, identified, a, paired, 'SOX/SRY']), verbo([binding]), complemento([site])].
[sujeto(['Interestingly,', only, 'SOX9,', and, not, 'SRY,', was, able, to]), verbo([bind]), complemento([as, a, dimer, to, this, site, and, transactivate, the, 'Pgds', promoter])].
[sujeto(['Finally,', chromatin, immunoprecipitation, proved, that, 'SOX9', but, not, 'SRY']), verbo([binds]), complemento([to, the, 'Pgds', promoter, in, vivo])].
[sujeto(['We']), verbo([have]), complemento([raised, an, antibody, specifically, recognizing, endogenous, mouse, 'SRY', protein, and, used, it, to, investigate, the, molecular, and, cellular, mode, of, action, of, 'SRY', in, testis, determination])].
[sujeto(['We']), verbo([find]), complemento([that, expression, of, 'SRY', protein, closely, mirrors, the, expression, of, 'Sry', mRNA, in, mouse, genital, ridges, and, is, detectable, for, 6, to, 8, h, after, the, mRNA, ceases, to, be, detectable])].
[sujeto(['The', subset, of, somatic, cells, that]), verbo([expresses]), complemento(['SRY', begins, to, express, 'SOX9', almost, immediately])].
[sujeto(['Since', these, 'SOX9-positive', cells, go, on, to, develop, as, 'Sertoli', 'cells,', it, appears, that, 'SRY', expression, marks, the, 'pre-Sertoli', cell, lineage, and]), verbo([leads]), complemento([to, 'up-regulation', of, 'Sox9', expression, 'cell-autonomously'])].
[sujeto(['However,', a, small, proportion, of, 'SOX9-positive', cells, did, not, appear, to]), verbo([express]), complemento(['SRY,', possibly, reflecting, the, additional, involvement, of, paracrine, signaling, in, activating, 'Sox9', transcription, in, these, cells])].
[sujeto(['Finally,', we, showed, by, employing, specific, inhibitors, that, the, causative, signaling, molecule, is, prostaglandin, 'D2', '(', 'PGD2)', and, that, 'PGD2', can]), verbo([induce]), complemento(['Sox9', transcription, in, cultured, 'XX', gonads])].
[sujeto(['Our', data, indicate, a, mechanism, whereby, 'Sry', uses, both, a, 'cell-autonomous', mechanism, and, a, 'PGD2-mediated', signaling, mechanism, to]), verbo([stimulate]), complemento([expression, of, 'Sox9', and, induce, the, differentiation, of, 'Sertoli', cells, in, vivo])].
[sujeto(['During', mammalian, gonadal, 'development,']), verbo([nuclear]), complemento(['import/export', of, the, transcription, factor, 'SOX9', is, a, critical, step, of, the, 'Sry-initiated', 'testis-determining', cascade])].
[sujeto(['In', this, 'study,', we, identify, a, molecular, mechanism, contributing, to, the, 'SOX9']), verbo([nuclear]), complemento([translocation, in, 'NT2/D1', 'cells,', which, is, mediated, by, the, prostaglandin, 'D2', '(', 'PGD2)', signalling, pathway, via, stimulation, of, its, 'adenylcyclase-coupled', 'DP1', receptor])].
[sujeto(['We']), verbo([find]), complemento([that, activation, of, 'cAMP-dependent', protein, kinase, 'A', '(', 'PKA)', induces, phosphorylation, of, 'SOX9', on, its, two, 'S64', and, 'S181', 'PKA', 'sites,', and, its, nuclear, localization, by, enhancing, 'SOX9', binding, to, the, nucleocytoplasmic, transport, protein, importin, beta])].
[sujeto(['We', thus, propose, a, new, step, in, the, 'sex-determining', cascade, where, 'PGD2']), verbo([acts]), complemento([as, an, autocrine, factor, inducing, 'SOX9', nuclear, translocation, and, subsequent, 'Sertoli', cell, differentiation])].
[sujeto(['We']), verbo([have]), complemento([examined, specific, genes, whose, expression, is, altered, during, apoptosis, induced, by, prostaglandin, '(', 'PG)A2', and, 'Delta12-PGJ2', in, human, hepatocellular, carcinoma, 'Hep3B', cells])].
[sujeto(['Using', mRNA, differential, 'display,', we]), verbo([have]), complemento([identified, two, 'genes:', one, is, specifically, 'up-regulated', and, encodes, for, human, 'Sox-4', '(', 'Sry-HMG', box, 'gene)', and, the, other, is, significantly, 'down-regulated', and, is, the, human, homolog, of, yeast, 'Ssf-1,', a, novel, splicing, factor])].
[sujeto(['Interestingly,', 'Sox-4', was, highly]), verbo([expressed]), complemento([in, subcutaneous, tumors, grown, in, nude, mice, as, a, xenograft, from, 'Hep3B', cells])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, expression, of, 'Sox-4', may, be, related, to, the, apoptosis, pathway, leading, to, cell, death, as, well, as, to, 'tumorigenesis,', and, that, 'Ssf-1', gene, may, serve, as, a, negative, regulator, of, 'PGA2/Delta12-PGJ2-mediated', 'Hep3B', cell, apoptosis])].
[sujeto(['We', describe, a, method, for, rapid, and, efficient, polymerase, chain, reaction, '(', 'PCR)', amplification, of, specific]), verbo([target]), complemento(['DNA', sequences, directly, from, cells, fixed, in, 3, :, 1, 'methanol-acetic', acid, '(', 'Carnoy\'s', 'fixative)', for, routine, cytogenetic, analysis])].
[sujeto(['No', differences, in, quality, of, amplification, products, were]), verbo([found]), complemento([between, 'PCR', templates, obtained, from, fresh, tissues, or, from, cells, fixed, for, varying, lengths, of, time, in, 'Carnoy\'s', fixative])].
[sujeto(['This', technique]), verbo([has]), complemento([the, following, 'advantages:', '(', 1, ')', it, allows, retrospective, studies, of, genetic, disorders, from, archived, 'specimens;', '(', 2, ')', it, requires, only, a, limited, number, of, 'cells;', '(', 3, ')', it, is, rapid, and, 'simple;', and, '(', 4, ')', it, avoids, multistep, procedures, required, in, extraction, of, the, 'DNA'])].
[sujeto(['Transforming', growth, factor, β, 1, '(', 'Tgfβ1)', is]), verbo([involved]), complemento([in, the, progression, of, renal, fibrosis])].
[sujeto(['According', to, recent, 'observations,', ammonium, chloride, '(', 'NH4Cl)']), verbo([prevented]), complemento(['phosphate-induced', vascular, 'remodeling,', effects, involving, decrease, of, 'Tgfβ1', expression, and, inhibition, of, 'Tgfβ1-dependent', signaling])].
[sujeto(['The', present, 'study,', 'thus,', explored, whether, 'NH4Cl', influences, renal, 'Tgfβ1-induced', 'pro-fibrotic', signaling, in, obstructive, nephropathy]), verbo([induced]), complemento([by, unilateral, ureteral, obstruction, '(', 'UUO)'])].
[sujeto(['UUO', was]), verbo([induced]), complemento([for, seven, days, in, 'C57Bl6', mice, with, or, without, additional, treatment, with, 'NH4Cl', '(', 0.28, 'M', in, drinking, 'water)'])].
[sujeto(['UUO']), verbo([increased]), complemento([renal, mRNA, expression, of, 'Tgfb1,', 'Tgfβ-activated', kinase, 1, '(', 'Tak1)', protein, abundance, and, 'Smad2', phosphorylation, in, the, nuclear, fraction, of, the, obstructed, kidney, 'tissues,', effects, blunted, in, 'NH4Cl', treated, mice, as, compared, to, control, treated, mice])].
[sujeto(['The', mRNA, levels, of, the, transcription, factors]), verbo([nuclear]), complemento([factor, of, activated, 'T', cells, 5, '(', 'Nfat5)', and, 'SRY', '(', sex, determining, region, 'Y)-box', 9, '(', 'Sox9)', as, well, as, of, tumor, necrosis, factor, α, '(', 'Tnfα),', interleukin, 6, '(', 'Il6),', plasminogen, activator, inhibitor, 1, '(', 'Pai1)', and, 'Snai1', were, 'up-regulated', in, the, obstructed, kidney, tissues, following, 'UUO,', effects, again, significantly, ameliorated, following, 'NH4Cl', treatment])].
[sujeto(['Furthermore,', the]), verbo([increased]), complemento([protein, and, mRNA, expression, of, 'α-smooth', muscle, actin, '(', 'α-Sma),', fibronectin, and, collagen, type, 'I', in, the, obstructed, kidney, tissues, following, 'UUO', were, significantly, attenuated, following, 'NH4Cl', treatment])].
[sujeto(['Sixty-five', percent, of, fibroblast, colonies, '(', 55, of, 85, ')', isolated, from, female, heart, allografts]), verbo([expressed]), complemento([the, male, sry, gene])].
[sujeto(['Cardiac', fibroblasts, are]), verbo([activated]), complemento([and, exist, in, a, profibrogenic, microenvironment, in, allografts, undergoing, chronic, rejection])].
[sujeto(['A', substantial, proportion, of, intragraft, fibroblasts, are]), verbo([recruited]), complemento([from, allograft, recipients, in, this, experimental, model, of, chronic, cardiac, allograft, rejection])].
[sujeto(['To']), verbo([gain]), complemento([more, insights, into, the, function, of, specific, genes, in, these, complex, 'processes,', the, expression, of, multiple, candidates, needs, to, be, 'assessed,', preferably, on, the, protein, level])].
[sujeto(['Here,', we, developed, a]), verbo([targeted]), complemento([proteomics, method, based, on, selected, reaction, monitoring, '(', 'SRM)', to, study, the, candidate, 'sex-related', proteins, in, zebrafish, which, were, selected, based, on, a, global, proteomics, analysis, of, adult, gonads, and, representational, difference, analysis, of, male, and, female, 'DNA,', as, well, as, on, published, information, on, zebrafish, and, other, vertebrates])].
[sujeto(['Evidence', on, protein, expression, was, obtained, for, the, first, time, for, several, candidate, genes, previously, studied, only, on, the, mRNA, level, or]), verbo([suggested]), complemento([by, bioinformatic, predictions])].
[sujeto(['Tuba1b', '(', tubulin, alpha, 1, 'b),', initially, included, in, the, study, as, one, of, the, potential, housekeeping, 'proteins,', was]), verbo([found]), complemento([to, be, preferentially, expressed, in, the, adult, testis, with, nearly, absent, expression, in, the, ovary])].
[sujeto(['The', revealed, changes, in, protein, expression, patterns]), verbo([associated]), complemento([with, gonad, differentiation, suggest, that, several, of, the, examined, 'proteins,', especially, 'Ilf2', and, 'Ilf3', '(', interleukin, 'enhancer-binding', factors, 2, and, 3, ')', ',', 'Raldh3', '(', retinaldehyde, dehydrogenase, type, 3, ')', ',', 'Zgc:195027', '(', low, density, 'lipoprotein-related', receptor, protein, 3, ')', and, 'Sept5a', '(', septin, 5, 'a),', may, play, a, specific, role, in, the, sexual, differentiation, in, zebrafish])].
[sujeto(['We']), verbo([report]), complemento([that, mMSC, 'Feeder', 'Layer', and, the, combination, of, 'VEGF,', 'SCF', and, 'TPO', strongly, promote, hematopoietic, differentiation])].
[sujeto(['The', results, showed, that, the, cells]), verbo([induced]), complemento([from, 'ES-D3', expressed, hematopoietic, progenitor, antigens, '(', 'CD34', and, 'CD117),', myelocyte, cell, antigen, '(', 'CD11b),', erythrocyte, cell, antigen, '(', 'Ter119),', and, transcription, factors, '(', 'Flk-1,', 'GATA-2,', 'SCL,', 'beta-H1', and, 'beta-major)'])].
[sujeto(['Furthermore,', those]), verbo([induced]), complemento([differentiated, cells, were, injected, into, female, 'C57BL/6', mice, which, were, treated, with, high, dose, topotecan, chemotherapy, to, restore, part, of, their, blood, system, function])].
[sujeto(['We', observed, rapid, white, blood, cell, 'recovery,', which]), verbo([suggested]), complemento([that, the, infusion, of, differentiated, cells, has, a, positive, impact, on, hematopoiesis])].
[sujeto(['Emerging', data]), verbo([suggest]), complemento([that, cancer, stem, cells, '(', 'CSCs)', exist, in, equilibrium, with, differentiated, cells, and, that, stochastic, transitions, between, these, states, can, account, for, tumor, heterogeneity, and, drug, resistance])].
[sujeto(['These', tumor, spheres, were]), verbo([found]), complemento([to, have, higher, aldehyde, dehydrogenase, '(', 'ALD)', cell, fractions, and, increased, expression, of, 'Kruppel-like', factor, 4, ',', 'SRY', '(', sex, determining, region, 'Y)-box', 2, ',', and, 'Nanog', and, were, resistant, to, 'γ-radiation,', 5, -, 'fluorouracil,', 'cisplatin,', and, etoposide, treatment, compared, with, monolayer, culture, cells])].
[sujeto(['ALDHigh', clones, showed]), verbo([increased]), complemento(['EGF', receptor, '(', 'EGFR)', and, 'insulin-like', growth, 'factor-1', receptor, '(', 'IGF-1R)', 'phosphorylation,', with, increased, activation, of, downstream, pathways, compared, with, 'ALDLow', clones])].
[sujeto(['Taken', 'together,', these, results, show, that, 'HNSCC', 'CSCs', exhibit, 'plasticity,', with, the, maintenance, of, the, stem, cell, fraction, dependent, on, the, 'EGFR', and, 'IGF-1R', pathways, and, potentially, amenable, to]), verbo([targeted]), complemento([therapeutics])].
[sujeto(['True', hermaphrodite, '(', 'TH)', is, genetically, a, heterogenous, condition]), verbo([causing]), complemento([ovarian, and, testicular, tissue, development, in, the, same, individual])].
[sujeto(['We']), verbo([report]), complemento([here, the, first, case, of, pure, 'NGCO', in, the, right, ovotestis, of, a, 23, -, 'year-old', 45, ',', 'XO/46X,X', 'sex-determining', region, 'Y', chromosome, '(', 'SRY)-negative', 'TH'])].
[sujeto(['The', patient]), verbo([responded]), complemento([well, to, radical, surgery, with, 'bleomycin,', 'etoposide,', cisplatin, '(', 'BEP)', regimen])].
[sujeto(['We', also, hypothesize, that, some, mutations, of, an, 'X-linked', or, autosomal, gene]), verbo([lead]), complemento([to, testicular, determination, in, 'SRY-negative', 'TH', patients])].
[sujeto(['In', the, past, 15, 'years,', anomalies, of, male, sexual, differentiation]), verbo([have]), complemento([greatly, increased, in, both, wildlife, and, humans, in, different, parts, of, the, world])].
[sujeto(['Environmental', endocrine, disruptors]), verbo([have]), complemento([been, implicated, in, the, dramatic, rise, in, neonatal, ambiguous, genitalia, with, variable, rates, of, 'severity,', such, as, 'micropenis,', 'cryptorchidism,', and, isolated, or, associated, hypospadias])].
[sujeto(['Because', most, environmental, 'pollutants,', such, as, organochlorine, 'pesticides,', polychlorinated, 'biphenyls,', dioxins, and, 'furans,', alkylphenol, 'polyetholyethoxylates,', and, phytoestrogens, and, 'phtalates,']), verbo([have]), complemento([estrogenic, and, antiandrogenic, 'activity,', they, are, able, to, interfere, with, normal, fetal, male, sexual, differentiation])].
[sujeto(['All', had, normal, testosterone, production, after, human, chorionic, gonadotrophin, stimulation, 'testing,']), verbo([suggesting]), complemento([androgen, resistance, or, 'so-called', idiopathic, 'MPH'])].
[sujeto(['Since', environmental, pollutants, are, known, for, their, estrogenic, activity, and, can, be]), verbo([released]), complemento([progressively, from, the, adipose, tissue, where, they, 'accumulate,', we, detected, their, presence, by, measuring, the, estrogenic, bioactivity, of, the, 'newborns\'', serum, with, a, recently, developed, ultrasensitive, bioassay])].
[sujeto(['We']), verbo([found]), complemento([higher, estrogenic, bioactivity, in, these, newborns, than, in, controls])].
[sujeto(['In', 'conclusion,', the, maternal, exposure, to, environmental, pollutants, during, pregnancy, and, high, estrogenic, bioactivity, in, the, 'newborns\'', serum, highly]), verbo([suggest]), complemento([that, ambiguous, genitalia, are, related, to, fetal, exposure, to, endocrine, disruptors])].
[sujeto(['Mice', may, share, similar, mechanism, with, human, underlying, reproductive, toxicity]), verbo([induced]), complemento([by, 'di(2-ethylhexyl)', phthalate, '(', 'DEHP),', which, is, not, supposed, to, be, associated, with, decreased, testicular, testosterone])].
[sujeto(['After', in, utero, 'DEHP', 'exposure,']), verbo([loss]), complemento([of, 'Sertoli', cells, and, germ, cells, were, observed, in, the, male, pups, at, postnatal, days, 21])].
[sujeto(['And', 'SRY-related', 'HMG', box, 9, '(', 'SOX9),', 'Fibroblast', growth, 'factor-9', '(', 'FGF9),', and, 'Double-sex', and, 'Mab-3', related, transcripttion, factor, 1, '(', 'DMRT1)', proteins, were, significantly, downregulated, by, 'DEHP', at, 2, 'mg/kg/d', and, 'above,']), verbo([suggesting]), complemento([the, depression, of, 'Sertoli', cell, differentiation])].
[sujeto(['Furthermore,', the, 'testosterone-independent', pathway]), verbo([regulating]), complemento(['Sertoli', cells, differentiation, was, disturbed, in, fetus, by, 'DEHP', at, 2, 'mg/kg/d', and, above, during, the, critical, time, window, of, sex, 'determination,', involving, 'Gadd45g', '→', 'Gata4/Fog2', '→', 'Sry', '→', 'Sox9', '→', 'Fgf9', 'The', results, suggest, that, in, utero, 'DEHP', exposure, damaged, 'Sertoli', cells, in, the, postnatal, life, of, mice, offspring, via, disturbance, of, the, differentiation, regulating, 'pathway,', potentially, inducing, declines, in, spermatogenesis])].
[sujeto(['Insulin-like', androgenic, gland, hormone, gene, '(', 'IAG)', is, a, sex, regulator, specifically]), verbo([expressed]), complemento([in, male, 'crustaceans,', controlling, the, male, sexual, 'differentiation,', spermatogenesis, and, reproductive, strategy])].
[sujeto(['Our', previous, study]), verbo([reported]), complemento([the, cloning, and, characterization, of, the, prawn, 'Macrobrachium', nipponense, 'IAG', '(', 'MnIAG)'])].
[sujeto(['In', this, 'study,', we, further, identified, a, 2214, -, bp, 'MnIAG', 5, '\'', -, flanking, 'region,', and, analyzed, its, transcription, factor]), verbo([binding]), complemento([sites, and, transcriptional, activity])].
[sujeto(['The', results, showed, that, there, were, two, potential, promoter, core, 'sequences,', three, 'TATA', boxes, and, one, 'CAAT', box, existing, in, the, 'MnIAG', 5, '\'', -, flanking, region, as, well, as, many, potential, transcription, factor]), verbo([binding]), complemento(['sites,', such, as, 'SRY,', 'Sox-5,', 'GATA-1,', etc])].
[sujeto(['Notably,', the, transcriptional, activity, was, weak, in, this, 'region,', and, a, negative, regulatory, region, was]), verbo([found]), complemento([in, -, 604, to, -, 231, bp])].
[sujeto([nipponense, yeast, libraries, and, identified, proteins]), verbo([interacting]), complemento([with, the, 'MnIAG', protein, by, yeast, two, hybridization, assay])].
[sujeto(['The', identification, of, 'MnIAG', putative, regulatory, region, and, proteins, that]), verbo([interact]), complemento([with, 'IAG', will, facilitate, our, understanding, of, the, regulatory, role, of, 'MnIAG', and, provide, a, foundation, for, deep, insight, into, the, prawn, sex, differentiation, mechanism, and, signaling, transduction, pathways])].
[sujeto(['To', identify, differentially]), verbo([expressed]), complemento([genes, '(', 'DEGs)', and, find, associated, pathways, that, may, function, as, targets, of, lung, cancer])].
[sujeto(['Besides,', novel, genes]), verbo([associated]), complemento([with, lung, cancer, were, identified, by, 'co-expression', analysis])].
[sujeto(['Then,', 'GO', enrichment, and, transcription]), verbo([binding]), complemento([site, analysis, were, performed, on, these, 'DEGs,', and, novel, genes, were, predicted, using, 'DAVID'])].
[sujeto(['Finally,', 'PPI', network, was, constructed, by, 'String', software, in, order, to, get, the, hub, codes]), verbo([involved]), complemento([in, cancer, carcinoma])].
[sujeto(['The', transcription, biding, site, analysis, showed, that, these, genes, were]), verbo([regulated]), complemento([by, 'LHX3,', 'HNF3B,', 'CDP,', 'HFH1,', 'FOXO4,', 'STAT,', 'SOX5,', 'MEF2,', 'FOXO3', and, 'SRY'])].
[sujeto(['Hub', codes, as, 'BUB1B,', 'MAD2L', and, 'TOP2A', may, play, as]), verbo([target]), complemento([genes, in, lung, carcinoma, in, the, result, of, 'PPI', network, analysis])].
[sujeto(['Newly', predicted, genes, and, hub, codes, can, perform, as]), verbo([target]), complemento([genes, for, diagnose, and, clinical, therapy, of, lung, cancer])].
[sujeto(['Single', nucleotide, polymorphisms, '(', 'SNPs)', are, an, important]), verbo([cause]), complemento([of, functional, variation, in, proteins, leading, to, tumorigenesis])].
[sujeto(['After', preprocessing, of, raw, 'data,', 'GC-associated', 'SNPs', were, identified, using, the, 'Cochran-Armitage', trend, 'test,', and, differentially]), verbo([expressed]), complemento([genes, '(', 'DEGs)', were, screened, out, using, the, limma, package, in, 'R'])].
[sujeto(['Significant', 'DEGs', with, risk]), verbo([associated]), complemento(['SNP', loci, were, screened, using, the, 'Fisher', combination, test])].
[sujeto(['Gene', ontology, function, and, pathway, enrichment, analyses, were, performed, for, 'DEGs', with, risk]), verbo([associated]), complemento(['SNP', loci, by, 'GenCLip', online, tool])].
[sujeto(['Transcriptional', regulatory, analysis, was, also, conducted, for, transcription, factor, and]), verbo([target]), complemento(['DEGs'])].
[sujeto(['A', total, of, 79, 'DEGs', with, risk]), verbo([associated]), complemento(['SNP', loci, were, identified, from, 'GC', samples, compared, with, normal, controls])].
[sujeto(['Additionally,', 'DEGs', were, significantly]), verbo([involved]), complemento([in, the, 'NO1', 'pathway,', including, 'actin,', alpha, 1, ',', skeletal, muscle, '(', 'ACTA1)'])].
[sujeto(['In', the, regulatory, 'network,', transcription, factor, forkhead, box, 'L1', '(', 'FOXL1)']), verbo([regulated]), complemento([26, 'DEGs', with, risk, associated, 'SNP', 'loci,', including, 'Iroquois', homeobox, 1, '(', 'IRX1)', 'rs11134044,', sex, determining, region, 'Y', '(', 'SRY)-box1', '(', 'SOX1)', rs9549447, and, msh, homeobox, 1, '(', 'MSX1)', rs41451149])].
[sujeto(['IRX1,', 'SOX1', and, 'MSX1', with, risk]), verbo([associated]), complemento(['SNP', loci, may, serve, as, candidate, biomarkers, for, diagnosis, and, prognosis, of, 'GC'])].
[sujeto(['We']), verbo([report]), complemento([a, case, of, a, 14, -, 'year-old', male, with, microorchidism, and, mild, bilateral, gynecomastia, who, referred, to, our, hospital, because, of, abnormal, gender, characteristics])].
[sujeto(['This', study, adds, a, new, case, of, 'SRY-negative', 46, ',', 'XX', testicular, disorder, of, sex, development, and, further, verifies, the, view, that, the, absence, of, major, regions, from, the, 'Y', chromosome]), verbo([leads]), complemento([to, an, incomplete, masculine, 'phenotype,', abnormal, hormone, levels, and, infertility])].
[sujeto(['Although', members, of, 'SOX', family]), verbo([have]), complemento([been, well, documented, for, their, essential, roles, in, embryonic, 'development,', cell, proliferation, and, 'disease,', the, functional, role, and, molecular, mechanism, of, 'SOX30', in, cancer, are, largely, unexplored])].
[sujeto(['SOX30', was]), verbo([expressed]), complemento([in, normal, and, 'peri-tumoral', lung, tissues, in, which, 'SOX30', was, 'unmethylated,', but, was, silenced, or, downregulated, in, lung, cancer, cell, lines, and, primary, lung, tumor, tissues, harboring, a, hypermethylated, 'SOX30'])].
[sujeto(['De-methylation', experiments, further, confirmed, that, silence, of, 'SOX30', was]), verbo([regulated]), complemento([by, its, hypermethylation])].
[sujeto(['Ectopic', expression, of, 'SOX30']), verbo([induces]), complemento([cancer, cell, apoptosis, with, inhibiting, proliferation, in, vitro, and, represses, tumor, formation, in, 'vivo,', whereas, knockdown, of, 'SOX30', demonstrates, a, reversed, effect, both, in, vitro, and, in, vivo])].
[sujeto(['At', the, molecular, 'level,', the, antitumorigenic, effect, of, 'SOX30', is]), verbo([mediated]), complemento([by, directly, binding, to, 'CACTTTG', '(', +, 115, to, +, 121, ')', of, p53, promoter, region, and, activating, p53, 'transcription,', suggesting, that, 'SOX30', is, a, novel, transcriptional, activating, factor, of, p53])].
[sujeto(['Overall,', these, findings, demonstrate, that, 'SOX30', is, a, novel, epigenetic, silenced, tumor, suppressor]), verbo([acting]), complemento([through, direct, regulation, of, p53, transcription, and, expression])].
[sujeto(['This', study]), verbo([provides]), complemento([novel, insights, on, the, mechanism, of, tumorigenesis, in, lung, cancer])].
[sujeto(['We']), verbo([report]), complemento([on, a, patient, with, a, 47, ',', 'XXY', karyotype, who, presents, a, normal, female, 'phenotype,', which, is, an, extremely, rare, observation, worldwide])].
[sujeto(['Type', 'B', ultrasound, scans, and, other, tests]), verbo([suggested]), complemento([that, her, ovaries, had, completely, failed])].
[sujeto(['Microsatellite', 'DNA', marker, analysis, revealed, that, the, 2, 'X', chromosomes, were, derived, from, her, mother, and, that, this, abnormality, was]), verbo([caused]), complemento([by, 'non-disjunction', of, the, maternal, 'X', chromosomes, during, meiosis, 'II'])].
[sujeto(['This', paper, is, the, first]), verbo([report]), complemento([of, a, 47, ',', 'XXY', female, with, ovarian, failure])].
[sujeto(['This', study, adds, cases, on, the, five, new, 46, ',', 'XX', male, individuals, with, 'SRY-positive', and, further, verifies, the, view, that, the, presence, of, 'SRY', gene, and, the, absence, of, major, regions, in, 'Y', chromosome, should]), verbo([lead]), complemento([to, the, expectance, of, a, completely, masculinised, 'phenotype,', abnormal, hormone, levels, and, infertility])].
[sujeto(['In', recent, 'years,', 'up-regulation', of, 'SOX11']), verbo([has]), complemento([been, detected, in, various, types, of, solid, tumors])].
[sujeto(['In', this, 'study,methylation-specific', 'PCR', and, real, time, quantitative, 'PCR']), verbo([have]), complemento([been, applied, to, investigate, the, effect, of, promoter, methylation, of, the, 'SOX11', gene, on, 'SOX11', expression, in, the, nasopharyngeal, carcinoma, and, chronic, inflammation, tissues])].
[sujeto(['SOX11', mRNA, and, protein, were, 're-expressed,', 'SOX11', gene, was, 'demethylated,', and, growth, and, invasion, of, cells, were]), verbo([inhibited]), complemento([in, 'CNE2', cell, line, after, 5, -, 'aza-2\'-deoxycytidine', treatment])].
[sujeto(['MiR-375', is, an, important, small, 'non-coding', 'RNA', that, is, specifically]), verbo([expressed]), complemento([in, islet, cells, of, the, pancreas])].
[sujeto(['miR-375', is]), verbo([required]), complemento([for, normal, pancreatic, genesis, and, influences, not, only, 'β-cell', mass, but, also, 'α-cell', mass])].
[sujeto(['When', human, embryonic, stem, cells, '(', 'hESCs)', differentiate, into, endodermal, 'lineages,', 'miR-375', is, highly]), verbo([expressed]), complemento([in, the, definitive, 'endoderm,', which, suggests, that, 'miR-375', may, have, a, distinct, role, in, early, development])].
[sujeto(['miR-375', plays, an, important, role, in, the, complex, regulatory, network, of, pancreatic, 'development,', which, could, be]), verbo([regulated]), complemento([by, pancreatic, 'genes,', such, as, 'NeuroD1,', 'Ngn3,', 'Pdx1', and, 'Hnf6;', 'additionally,', 'miR-375', regulates, genes, related, to, pancreas, 'development,', cell, growth, and, proliferation, and, insulin, secretion, genes, to, exert, its, function])].
[sujeto(['Because', of, the, special, role, of, 'miR-375,', it, may, be, a, potential]), verbo([target]), complemento([to, treat, diabetes])].
[sujeto(['Antagonising', 'miR-375', may]), verbo([enhance]), complemento([the, effects, of, 'exendin-4', in, 'patients,', and, controlling, the, expression, of, 'miR-375', could, assist, mature, 'hESCs-derived', 'β-cells'])].
[sujeto(['Ovarian-specific', promoter, '(', 'OSP)', is, a, 'tissue-specific', promoter, only]), verbo([expressed]), complemento([in, the, ovary, to, regulate, its, development])].
[sujeto(['Bioinformatics', analysis, indicated, that, the, fragment, contained, multiple, transcription, factor]), verbo([binding]), complemento(['sites,', such, as, 'SRY,', 'HSF,', 'AP-1,', 'C/EBP,', 'CAAT,', 'TATA,', and, so, 'on,', and, the, nucleotide, sequence, of, 'OSP', shared, 99, '%', and, 97, '%', similarity, with, those, of, 'OSP-1', and, 'OSP-2', in, rat])].
[sujeto(['In', 'summary,', we, successfully, extracted, dairy, goat, 'OSP', and, identified, its, transcriptional, 'activity,', which, in, part, shed, light, on, the, study, of, 'ovarian-specific', transcription, and]), verbo([provided]), complemento([further, insights, into, the, development, and, regulation, of, dairy, 'goat\'s', ovary, as, well])].
[sujeto(['Long', noncoding, 'RNAs', '(', 'lncRNAs)']), verbo([have]), complemento([been, attracting, immense, research, 'interest,', while, only, a, handful, of, lncRNAs, have, been, characterized, thoroughly])].
[sujeto(['Their', involvement, in, the, fundamental, cellular, processes, including]), verbo([regulate]), complemento([gene, expression, at, 'epigenetics,', 'transcription,', and, 'post-transcription', highlighted, a, central, role, in, cell, homeostasis])].
[sujeto(['Here,', we, give, a, systematic, and, comprehensive, summary, of, the, existing, knowledge, of, lncRNAs, in, order, to]), verbo([provide]), complemento([a, better, understanding, of, this, new, studying, field])].
[sujeto(['In', this, 'review,', we, also, highlighted, recent, studies, related, lncRNAs, in, central, nervous, system, '(', 'CNS)', development, and, neurodegenerative, 'diseases,', including, 'Alzheimer\'s', disease, '(', 'AD),', 'Parkinson\'s', disease, '(', 'PD),', 'Huntington\'s', disease, '(', 'HD)', and, amyotrophic, lateral, sclerosis, '(', 'ALS),', and, elucidated, some, specific, lncRNAs, which, may, be, important, for, understanding, the, pathophysiology, of, neurodegenerative, 'diseases,', also]), verbo([have]), complemento([the, potential, as, therapeutic, targets])].
[sujeto(['Recently,', 'genome-wide', association, studies]), verbo([have]), complemento([implicated, 'SOX5', as, a, candidate, gene, for, susceptibility, to, four, 'cardiac-related', 'endophenotypes:', higher, resting, heart, rate, '(', 'HR),', the, electrocardiographic, 'PR', 'interval,', atrial, fibrillation, and, left, ventricular, mass])].
[sujeto(['We']), verbo([have]), complemento([determined, that, human, 'SOX5', has, a, highly, conserved, 'Drosophila', 'ortholog,', 'Sox102F,', and, have, employed, transgenic, 'Drosophila', models, to, quantitatively, measure, cardiac, function, in, adult, flies])].
[sujeto(['For', this, 'purpose,', we]), verbo([have]), complemento([developed, a, 'high-speed', and, 'ultrahigh-resolution', optical, coherence, tomography, imaging, 'system,', which, enables, rapid, 'cross-sectional', imaging, of, the, heart, tube, over, various, cardiac, cycles, for, the, measurement, of, cardiac, structural, and, dynamical, parameters, such, as, 'HR,', dimensions, and, areas, of, heart, 'chambers,', cardiac, wall, thickness, and, wall, velocities])].
[sujeto(['We']), verbo([have]), complemento([found, that, the, silencing, of, 'Sox102F', resulted, in, a, significant, decrease, in, 'HR,', heart, chamber, size, and, cardiac, wall, 'velocities,', and, a, significant, increase, in, cardiac, wall, thickness, that, was, accompanied, by, disrupted, myofibril, structure, in, adult, flies])].
[sujeto(['In', 'addition,', the, silencing, of, 'Sox102F', in, the, wing]), verbo([led]), complemento([to, increased, 'L2,', 'L3', and, wing, marginal, veins, and, increased, and, disorganized, expression, of, 'wingless,', the, central, component, of, the, 'Wnt', signaling, pathway])].
[sujeto(['This', implicates, an, important, functional, role, for, 'SOX5', in, heart, and]), verbo([suggests]), complemento([that, the, alterations, in, 'SOX5', levels, may, contribute, to, the, pathogenesis, of, multiple, cardiac, diseases, or, traits])].
[sujeto(['The', aim]), verbo([has]), complemento([been, to, set, up, a, rapid, and, accurate, microarray, assay, using, sandwich, mode, for, sex, determination, of, bovine, preimplantation, embryos])].
[sujeto(['This']), verbo([suggests]), complemento([that, the, oligonucleotide, microarray, method, of, 'SRY', gene, analysis, can, be, used, in, early, sex, prediction, of, bovine, embryos, in, breeding, programs])].
[sujeto(['The', 'Sry-containing', protein, 'Sox2', initially, was, known, to]), verbo([regulate]), complemento([the, 'self-renewal', of, the, mouse, and, human, embryonic, stem, cells, '(', 'ESCs)'])].
[sujeto(['It', is, also, important, for, the, maintenance, of, stem, cells, in, multiple, adult, tissues, including, the, brain, and, 'trachea,', and, it, is, one, of, the, key, transcription, factors, for, establishing]), verbo([induced]), complemento([pluripotent, stem, cells])].
[sujeto(['Recently,', overexpression, and, gene, amplification, of, 'Sox2']), verbo([have]), complemento([been, associated, with, the, development, of, squamous, cell, carcinoma, in, multiple, tissues, such, as, the, lung, and, esophagus])].
[sujeto(['These', different, roles, for, 'Sox2']), verbo([involve]), complemento([a, complicated, regulatory, networks, consisting, of, 'microRNAs,', kinases, and, signaling, molecules])].
[sujeto(['While', the, levels, of, 'Sox2', are]), verbo([modulated]), complemento([transcriptionally, and, 'translationally,', 'post-translational', modification, is, also, important, for, the, various, functions, of, 'Sox2'])].
[sujeto(['In', 'clinics,', high, levels, of, 'Sox2', are, correlated, with, poor, prognosis, and]), verbo([increased]), complemento([proliferation, of, cancer, stem, cells])].
[sujeto(['Therefore']), verbo([targeting]), complemento(['Sox2', can, be, potentially, explored, for, a, new, therapeutic, avenue, to, treat, cancers])].
[sujeto(['We', will, also, review, the, main, upstream, and, downstream]), verbo([targets]), complemento([of, 'Sox2,', which, can, be, potentially, used, as, therapeutic, measures, to, treat, cancer, with, abnormal, levels, of, 'Sox2'])].
[sujeto(['In', the, present, 'study,']), verbo([increased]), complemento([expression, levels, of, 'COL9A1', were, identified, in, the, abductor, hallucis, muscle, of, 'ICTEV', patients, compared, with, those, in, control, samples])].
[sujeto(['The', 'COL9A1', gene, is]), verbo([regulated]), complemento([by, 'SRY', '(', 'sex‑determining', region, 'Y)‑box', 9, '(', 'SOX9)'])].
[sujeto([mRNA, and, protein, expression, levels, of, 'SOX9', were, detected, by, 'real‑time', polymerase, chain, reaction, and, western, blot, 'analysis,', respectively, and, were]), verbo([found]), complemento([to, be, significantly, higher, in, 'ICTEV', muscle, samples, compared, with, those, in, control, samples])].
[sujeto(['Intestinal', metaplasia, began, to]), verbo([express]), complemento(['CEACAM1', and, showed, more, membranous, staining, of, 'CEACAM1', than, normal, mucosa, and, hyperplastic, polyps, '(', 'P', =])].
[sujeto(['SOX9', expression, significantly]), verbo([increased]), complemento([from, nonneoplastic, lesions, to, neoplastic, 'lesions,', and, 'CEACAM1', expression, patterns, markedly, 'changed;', their, coexpression, also, showed, signally, elevated, suggesting, that, 'SOX9,', as, a, transcriptional, 'regulator,', play, important, roles, in, the, changing, of, 'CEACAM1', expression, 'patterns,', which, might, promote, the, tumor, progression])].
[sujeto(['Stem', cell, transplantation]), verbo([has]), complemento([become, a, promising, therapeutic, approach, for, the, treatment, of, myocardial, infarction, '(', 'MI)'])].
[sujeto(['However,', the, poor, survival, of, the, donor, cells, after, transplantation]), verbo([has]), complemento([restricted, its, therapeutic, efficacy])].
[sujeto(['Hydrogen', sulfide, '(', 'H(2)S),', one, gaseous, signaling, 'molecule,']), verbo([has]), complemento([been, applied, to, inhibit, cell, apoptosis, and, promote, cell, survival])].
[sujeto(['Preconditioning', 'MSCs', with, 200, 'µmol/L', 'NaHS', '(', as, the, donor, of, 'H(2)S)', for, 30, min]), verbo([decreased]), complemento([the, 'hypoxia-induced', cell, apoptosis, in, vitro])].
[sujeto(['The', mechanisms, contributing, to, the, beneficial, effects, of, 'H(2)S', on, 'MSCs', were]), verbo([associated]), complemento([with, increased, levels, of, phosphorylated, 'Akt', '(', 'pAkt),', phosphorylated, 'Erk1/2', '(', 'pErk1/2)', and, phosphorylated, glycogen, synthase, 'kinase-3β', '(', 'pGSK-3β)', in, 'MSCs'])].
[sujeto(['Furthermore,', transplantation, of, the, 'H(2)S-pretreated', 'MSCs', reduced, the, infarct, size, and]), verbo([increased]), complemento([left, ventricular, '(', 'LV)', 'function,', as, judged, by, transthoracic, echocardiography])].
[sujeto(['In', 'conclusion,', 'H(2)S', preconditioning, effectively]), verbo([promotes]), complemento(['MSCs', survival, under, ischemic, injury, and, helps, cardiac, repair, after, 'MI,', which, has, great, clinical, significance])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, the, observed, complex, 'DSD', phenotype, is, the, result, of, somatic, gonosomal, mosaicism, and, 'UPD', despite, a, normal, blood, karyotype])].
[sujeto(['The', discovery, of, the, role, of, a, 'teleost-specific', aquaporin, '(', 'Aqp1ab)', during, the, process, of, oocyte, hydration, in, marine, fish, producing, pelagic, '(', 'floating)', 'eggs,', recently, confirmed, by, molecular, 'approaches,']), verbo([has]), complemento([revealed, that, this, mechanism, is, more, sophisticated, than, initially, thought])].
[sujeto(['Recent', phylogenetic, and, genomic, studies]), verbo([suggest]), complemento([that, 'Aqp1ab', likely, evolved, by, tandem, duplication, from, a, common, ancestor, and, further, neofunctionalized, in, oocytes, for, water, transport])].
[sujeto(['Investigations', into, the, regulation, of, 'Aqp1ab', during, oogenesis, indicate, that, the, mRNA, and, protein, product, are, highly, accumulated, during, early, oocyte, 'growth,', possibly, through, the, transcriptional, activation, of, the, aqp1ab, promoter, by, the, classical]), verbo([nuclear]), complemento([progesterone, receptor, and, perhaps, by, 'Sry-related', high, mobility, group, '[', 'HMG]-box', '(', 'Sox)', transcription, factors])].
[sujeto(['During', oocyte, growth, and, 'maturation,', 'Aqp1ab', intracellular, trafficking, may, be]), verbo([regulated]), complemento([by, phosphorylation, 'and/or', dephosphorylation, of, specific, 'C-terminal', residues, in, 'Aqp1ab,', as, well, as, by, 'signal-mediated', sorting, processes])].
[sujeto(['These', mechanisms, possibly]), verbo([regulate]), complemento([the, temporal, insertion, of, 'Aqp1ab', into, the, oocyte, plasma, membrane, during, oocyte, 'hydration,', although, the, intracellular, signaling, pathways, involved, are, yet, unknown])].
[sujeto(['Interestingly,', in, some, freshwater, species, that, spawn, partially, hydrated, 'eggs,', high, accumulation, of, transcripts, encoding, functional, 'Aqp1ab', channels]), verbo([have]), complemento([also, been, found, in, the, ovary])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, 'Aqp1ab-mediated', mechanism, for, oocyte, hydration, is, likely, conserved, in, teleosts])].
[sujeto(['One', of, the, most, dramatic, differences]), verbo([involves]), complemento([estrogen, positive, 'feedback,', which, leads, to, ovulation])].
[sujeto(['Estradiol']), verbo([stimulated]), complemento([both, '[', 'Ca2+]i', release, and, progesterone, synthesis, in, hypothalamic, astrocytes, from, adult, female, mice])].
[sujeto(['Surface', biotinylation, demonstrated, mERα, in, both, female, and, male, 'astrocytes,', but, only, in, female, astrocytes, did, estradiol, treatment]), verbo([increase]), complemento([insertion, of, the, receptor, into, the, 'membrane,', a, necessary, step, for, maximal, '[', 'Ca2+]i', release])].
[sujeto(['The', trafficking, of, mERα, in, 'female,', but, not, 'male,', astrocytes, further]), verbo([suggests]), complemento([that, cell, signaling, mechanisms, are, sexually, differentiated])].
[sujeto(['SOX-9,', an, essential, factor, for, male, sexual, 'development,', can, be]), verbo([induced]), complemento([by, prostaglandin, 'D2', in, a, 'Sry-independent', mechanism])].
[sujeto(['Recent', data]), verbo([suggest]), complemento([that, the, hedgehog, pathway, is, involved, in, the, differentiation, of, normal, 'Sertoli', and, 'Leydig', cells])].
[sujeto(['The', purpose, of, our, study, was, to, investigate, the, mechanisms]), verbo([involved]), complemento([in, the, differentiation, of, ovarian, sex, 'cord-stromal', tumour, '(', 'SCST)', cells])].
[sujeto(['Sertoli', cells]), verbo([expressed]), complemento(['anti-Mullerian', hormone, '(', 'AMH),', 'SOX-9,', prostaglandin, 'D', synthase, '(', 'Pgds)', and, 'bcl-2', '(', in, four, of, four, 'cases);', sonic, hedgehog, '(', 'Shh)', and, p53, '(', in, three, of, four, 'cases)', and, androgen, receptors, '(', 'AR;', in, one, of, four, 'cases)'])].
[sujeto(['Leydig', cells]), verbo([expressed]), complemento(['Shh', and, 'AR', '(', two, of, two, 'cases),', while, they, showed, no, expression, of, 'p53,', 'bcl-2', and, 0, '%', 'Ki-67', index])].
[sujeto(['Granulosa', cells]), verbo([expressed]), complemento(['AMH,', 'Pgds,', 'Shh,', estrogen, 'receptors,', progesterone, 'receptors,', 'AR', and, 'bcl-2', '(', in, two, of, two, 'cases)', and, p53, '(', in, one, of, two, 'cases)'])].
[sujeto(['Further', investigation, is]), verbo([required]), complemento([to, clarify, the, role, of, the, molecules, outlined, above, in, the, histogenesis, of, ovarian, 'SCST,', as, 'Pgds-mediated', 'SOX-9', upregulation, could, provide, a, reasonable, explanation, for, the, presence, of, testicular, differentiation, in, ovarian, 'SCST'])].
[sujeto(['This', result]), verbo([suggests]), complemento([that, sexual, differentiation, of, 'PR', expression, in, these, regions, is, likely, controlled, mainly, by, gonadal, 'hormones,', not, by, the, genetic, sex, of, the, brain, cells])].
[sujeto(['No', differences, in, 'PRir', were, detected, between, 'wild-type', 'XY', mice, with, the, 'Sry', gene, on, the, 'Y-chromosome', and, 'XY', mice, with, the, 'Sry', 'transgene,']), verbo([suggesting]), complemento([that, testicular, hormones, produced, in, these, two, genotypes, have, comparable, effects, on, neural, tissue])].
[sujeto(['In', the, absence, of, 'Sry,', or, if, 'Sry', is]), verbo([expressed]), complemento([at, insufficient, 'levels,', the, support, cell, precursors, differentiate, as, granulosa, 'cells,', thus, initiating, the, ovarian, pathway])].
[sujeto(['We', demonstrate, that, the, transcription, factor, 'GATA4', and, its, 'co-factor', 'FOG2', are]), verbo([required]), complemento([for, gonadal, differentiation])].
[sujeto(['Mouse', fetuses, homozygous, for, a, null, allele, of, 'Fog2', or, homozygous, for, a]), verbo([targeted]), complemento([mutation, in, 'Gata4', '(', 'Gata4(ki))', that, abrogates, the, interaction, of, 'GATA4', with, 'FOG', 'co-factors', exhibit, abnormalities, in, gonadogenesis])].
[sujeto(['We']), verbo([found]), complemento([that, 'Sry', transcript, levels, were, significantly, reduced, in, 'XY', 'Fog2(-/-)', gonads, at, 'E11'])].
[sujeto(['In', 'addition,', three, genes, crucial, for, normal, 'Sertoli', cell, function, '(', 'Sox9,', 'Mis', and, 'Dhh)', and, three, 'Leydig', cell, steroid, biosynthetic, enzymes, '(', 'p450scc,', 3, betaHSD, and, 'p450c17)', were, not]), verbo([expressed]), complemento([in, 'XY', 'Fog2(-/-)', and, 'Gata(ki/ki)', 'gonads,', whereas, 'Wnt4,', a, gene, required, for, normal, ovarian, 'development,', was, expressed, ectopically])].
[sujeto(['By', 'contrast,', 'Wt1', and, 'Sf1,', which, are]), verbo([expressed]), complemento([prior, to, 'Sry', and, necessary, for, gonad, development, in, both, 'sexes,', were, expressed, normally, in, both, types, of, mutant, 'XY', gonads])].
[sujeto(['These', results, indicate, that, 'GATA4', and, 'FOG2', and, their, physical, interaction, are]), verbo([required]), complemento([for, normal, gonadal, development])].
[sujeto(['Here,', we]), verbo([report]), complemento([a, 'SLCT', with, intermediate, differentiation, in, a, 23, -, 'year-old', woman, investigated, by, light, 'microscopy,', immunohistochemistry, for, intermediate, 'filaments,', and, sex, steroid, hormone, receptors, '(', 'SSHR),', as, well, as, by, polymerase, chain, reaction, '(', 'PCR)', for, the, presence, of, the, 'sex-determining', region, 'Y', gene, '(', 'SRY)'])].
[sujeto(['Our', investigation, shows, that, the, 'SCs', of, 'SLCT']), verbo([express]), complemento([progesterone, and, androgen, receptors, as, well, as, cytokeratins, and, vimentin])].
[sujeto(['Thus,', our, results]), verbo([provide]), complemento([strong, evidence, for, a, close, histogenetic, relationship, between, the, 'SLCT', and, the, female, 'gonocyte-supporting', 'cell,', the, granulosa, cell, '(', 'GC)'])].
[sujeto(['To', study, the, process, of, mammalian, sex, determination, and, in, particular, to, further, understand, the, mechanisms, of, transcriptional, regulation, of, the, 'SRY', 'gene,', we]), verbo([have]), complemento([isolated, a, 4.5, -, kilobase, '(', 'kb)', pig, 'SRY', 5, '\'', flanking, sequence])].
[sujeto(['To', facilitate, the, in, vitro, analysis, of, these, 'sequences,', we]), verbo([have]), complemento([generated, a, porcine, genital, ridge, '(', 'PGR)', cell, line, '(', 900000000000.0, ')', that, expresses, 'SRY', as, well, as, 'SOX9,', steroidogenic, 'factor-1', '(', 'SF-1),', and, 'DAX1'])].
[sujeto(['Via']), verbo([primer]), complemento([extension, analysis, on, 'RNA', from, this, cell, 'line,', a, transcription, start, site, for, porcine, 'SRY', was, identified, at, -, 661, base, pairs, '(', 'bps)', 5, '\'', from, the, translation, initiation, site])].
[sujeto(['Deletion', studies, of, the, 'SRY', 5, '\'', flanking, sequences, in, 'PGR', 900000000000.0, cells, demonstrated, that, -, 1.4, kb, of, 5, '\'', flanking, sequences]), verbo([retained]), complemento([full, transcriptional, activity, compared, with, the, -, 4.5, kb, 'fragment,', but, that, transcriptional, activity, fell, when, further, deletions, were, made])].
[sujeto(['Sequences', downstream, of, the, transcriptional, start, site, are, important, for, promoter, 'activity,', because, deleting]), verbo([transcribed]), complemento([but, not, translated, sequences, eliminated, promoter, activity])].
[sujeto(['Sequence', analysis, of, the, -, 1.4, kb, fragment, identified, two, potential]), verbo([binding]), complemento([sites, for, 'SF-1,', at, -, 1369, and, at, -, 290, from, the, 'ATG'])].
[sujeto(['To', address, the, role, of, 'SF-1', transactivation, in, 'SRY', promoter, 'activity,', mutagenesis, studies, of, the, potential, 'SF-1']), verbo([binding]), complemento([sites, were, performed, and, revealed, that, these, sites, were, indeed, important, for, 'SRY', promoter, activity])].
[sujeto(['Gel', shift, assays, confirmed, that, the, upstream, site, was]), verbo([recognized]), complemento([by, mouse, 'SF-1', protein])].
[sujeto(['The', purpose, of, this, study, is, to, understand, whether, naturally, occurring, genetic, variation, in, the, promoter, of, chromogranin, 'B', '(', 'CHGB),', a, major, constituent, of, catecholamine, storage, 'vesicles,', is, functional, and]), verbo([confers]), complemento([risk, for, cardiovascular, disease])].
[sujeto(['Previously,', we]), verbo([found]), complemento([that, genetic, variation, at, 'CHGB', influenced, autonomic, 'function,', with, association, maximal, toward, the, 5, '\'', region])].
[sujeto(['The', 'A-296C', disrupted, a, 'c-FOS', 'motif,', exhibiting, differential, mobility, shifting, to, chromaffin, cell]), verbo([nuclear]), complemento([proteins, during, 'EMSA,', binding, of, endogenous, 'c-FOS', on, 'ChIP,', and, differential, response, to, exogenous, 'c-FOS'])].
[sujeto(['The', common, 'CHGB', promoter, variants, 'A-296C', and, 'A-261T,', and, their, consequent, 'haplotypes,', alter]), verbo([binding]), complemento([of, specific, transcription, factors, to, influence, gene, expression, in, cella, as, well, as, 'BP', in, vivo])].
[sujeto(['Involvement', of, the, 'sex-specific', factor, 'SRY']), verbo([suggests]), complemento([a, novel, mechanism, for, development, of, sexual, dimorphism, in, 'BP'])].
[sujeto(['Trophoblast', migration, into, the, maternal, circulation, is]), verbo([increased]), complemento([in, preeclampsia, and, can, trigger, the, endothelial, dysfunction, that, characterizes, the, clinical, disease])].
[sujeto(['We', hypothesised, that, '\'', fetal, 'trafficking\'', is]), verbo([increased]), complemento([in, women, with, severe, preeclampsia, and, that, the, quantity, of, trafficking, is, greater, in, women, with, more, severe, disease])].
[sujeto(['No', correlation, was]), verbo([found]), complemento([between, the, quantity, of, fetal, 'DNA', and, disease, severity])].
[sujeto(['Catsper', genes, are, exclusively]), verbo([expressed]), complemento([in, the, testis, during, 'spermatogenesis,', but, the, function, and, regulation, of, the, corresponding, promoter, regions, are, unknown])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, cloning, and, characterization, of, the, promoter, regions, in, the, human, and, murine, 'Catsper1', genes])].
[sujeto(['We', also]), verbo([found]), complemento([that, the, immediate, upstream, region, and, the, first, exon, in, the, human, 'CATSPER1', gene, negatively, regulate, transcriptional, activity])].
[sujeto(['In', the, murine, 'Catsper1', 'promoter,']), verbo([binding]), complemento([sites, for, transcription, factors, 'SRY,', 'SOX9', and, 'CREB', were, protected, by, the, presence, of, nuclear, testis, proteins, in, 'DNAse', degradation, assays])].
[sujeto(['SOX9', is, a, member, of, the, 'SOX', '[', 'Sry-related', 'high-mobility', group, '(', 'HMG)', 'box]', family, and, is]), verbo([required]), complemento([for, the, development, and, differentiation, of, multiple, cell, lineages])].
[sujeto(['The', 'SOX9', expression]), verbo([increased]), complemento([from, 'non-neoplastic', mucosa, to, early, cancer])].
[sujeto(['Three', of, six, cell, lines, had]), verbo([increased]), complemento([methylation, through, 'EBV', infection, and, decreased, 'SOX9', expression])].
[sujeto(['In', the, adult, 'testis,', 'Sertoli', cells, '(', 'SCs)', are, the, epithelial, supporting, cells, of, the, seminiferous, tubules, that]), verbo([provide]), complemento([germ, cells, '(', 'GCs)', with, the, required, nutrients, and, structural, and, regulatory, support, to, complete, spermatogenesis])].
[sujeto(['SCs', also, form, the, 'blood-testis', 'barrier,', phagocytose, apoptotic, spermatocytes, and, cell, debris, derived, from, 'spermiogenesis,', and, produce, and, secrete, numerous, paracrine, and, endocrine, signals]), verbo([involved]), complemento([in, different, regulatory, processes])].
[sujeto(['They', are, the, first, cells, to, differentiate, in, the, embryonic, 'XY', gonadal, primordium, and, are]), verbo([involved]), complemento([in, the, regulation, of, 'testis-specific', differentiation, 'processes,', such, as, prevention, of, 'GC', entry, into, 'meiosis,', 'Leydig', and, peritubular, myoid, cell, 'differentiation,', and, regression, of, the, 'Müllerian', 'duct,', the, anlagen, of, the, 'uterus,', 'oviducts,', and, the, upper, part, of, the, vagina])].
[sujeto(['Expression', of, the, 'Y-linked', gene, 'SRY', in, 'pre-SCs', initiates, a, genetic, cascade, that]), verbo([leads]), complemento([to, 'SC', differentiation, and, subsequently, to, testis, development])].
[sujeto(['Since', the, identification, of, the, 'SRY', 'gene,', many, 'Sertoli-specific', transcription, factors, and, signals, underlying, the, molecular, mechanisms, of, early, testis, differentiation]), verbo([have]), complemento([been, identified])].
[sujeto(['Here,', we, review, the, state, of, the, art, of, the, molecular, interactions, that, commit, the, supporting, cell, lineage, of, the, gonadal, primordium, to, differentiate, as, 'SCs', and, the, subsequent, 'Sertoli-specific', signaling, pathways]), verbo([involved]), complemento([in, early, testis, differentiation])].
[sujeto(['Epithelial-mesenchymal', transition, '(', 'EMT)', changes, polarized, epithelial, cells, into, migratory, phenotypes]), verbo([associated]), complemento([with, loss, of, 'cell-cell', adhesion, molecules, and, cytoskeletal, rearrangements])].
[sujeto(['In', 'particular,', the, promoter, sequences, of, differentially]), verbo([expressed]), complemento([genes, and, their, transcription, factors, were, analyzed, to, identify, potential, binding, sites, and, partners])].
[sujeto(['The', four, most, frequent, 'cis-regulatory', elements, '(', 'CREs)', in, 'up-regulated', genes, were, 'SRY,', 'FTS-1,', 'Evi-1,', and, 'GC-Box,', and, 'RNA', inhibition, of, the, four, transcription, 'factors,', 'Atf2,', 'Klf10,', 'Sox11,', and, 'SP1,', most, frequently]), verbo([binding]), complemento([these, 'CREs,', establish, their, importance, in, the, initiation, and, propagation, of, 'EMT'])].
[sujeto(['Our', results, identify, new, transcriptional, interactions, with, high, frequency, 'CREs', that]), verbo([modulate]), complemento([the, stability, of, cellular, 'plasticity,', and, may, serve, as, targets, for, modulating, these, transitional, states, in, fibroblasts])].
[sujeto(['The', past, few, years]), verbo([have]), complemento([seen, an, enormous, increase, in, the, knowledge, of, the, signaling, pathways, and, the, transcription, factors, that, control, endochondral, bone, development])].
[sujeto(['Recent', studies, of, rare, chondrodysplasias, that, exhibit, disproportionate, dwarfism, due, to, the, impairment, of, endochondral, ossification]), verbo([have]), complemento([identified, many, responsible, genes, and, have, clarified, pathogenic, mechanisms, of, these, diseases, by, using, molecular, genetics, and, biology])].
[sujeto(['Waardenburg', syndrome, '(', 'WS)', is, an, 'auditory-pigmentary', disorder, that, exhibits, varying, combinations, of, sensorineural, hearing]), verbo([loss]), complemento([and, abnormal, pigmentation, of, the, hair, and, skin])].
[sujeto(['WS', type, 4, '(', 'WS4),', a, subtype, of, 'WS,', is, characterized, by, the, presence, of, the, aganglionic, megacolon, and, is]), verbo([associated]), complemento([with, mutations, in, the, gene, encoding, either, endothelin, 3, ',', endothelin, receptor, type, 'B', '(', 'EDNRB),', or, 'Sry-box', 10, '(', 'SOX10)'])].
[sujeto(['Here,', we]), verbo([provide]), complemento([evidence, that, 'SOX10', regulates, the, expression, of, 'EDNRB', gene, in, human, 'melanocyte-lineage', 'cells,', as, judged, by, 'RNA', interference, and, chromatin, immunoprecipitation, analyses])].
[sujeto(['Human', melanocytes, preferentially]), verbo([express]), complemento([the, 'EDNRB', transcripts, derived, from, the, conventional, 'EDNRB', promoter])].
[sujeto(['Moreover,', a, transcription, factor, 'Sp1']), verbo([enhances]), complemento([the, degree, of, the, 'SOX10-mediated', transactivation, of, the, 'EDNRB', promoter, through, these, 'cis-acting', elements])].
[sujeto(['Furthermore,', we]), verbo([have]), complemento([shown, that, the, 'EDNRB', promoter, is, heavily, methylated, in, 'HeLa', human, cervical, cancer, 'cells,', lacking, 'EDNRB', 'expression,', but, not, in, melanocytes, and, 'HMV-II', melanoma, cells])].
[sujeto(['The', expression, of, 'EDNRB', became, detectable, in, 'HeLa', cells, after, treatment, with, a, demethylating, 'reagent,', 5, '\'', -, 'aza-2\'-deoxycytidine,', which, was, further]), verbo([enhanced]), complemento([in, the, transformed, cells, 'over-expressing', 'SOX10'])].
[sujeto(['We', therefore]), verbo([suggest]), complemento([that, 'SOX10,', alone, or, in, combination, with, 'Sp1,', regulates, transcription, of, the, 'EDNRB', 'gene,', thereby, ensuring, appropriate, expression, level, of, 'EDNRB', in, human, melanocytes])].
[sujeto(['The', 'Wilms', tumor, 1, '(', 'WT1)', gene, product, may]), verbo([regulate]), complemento([the, 'mullerian-inhibiting', substance, '(', 'MIS)', 'gene,', because, mutations, in, 'WT1', can, cause, persistence, of, the, mullerian, duct, in, men])].
[sujeto(['In', the, present, 'study,', we, show, by, gel, shift, and, chromatin, immunoprecipitation, assays, that, 'WT1']), verbo([bound]), complemento([to, a, 'GC-rich', sequence, in, the, murine, 'Mis', promoter])].
[sujeto(['The', 'WT1,', 'SRY', box, protein, 9, ',', and, steroidogenic, factor, 1, could, synergistically]), verbo([activate]), complemento([the, 'Mis', 'promoter,', and, at, least, two, factors, were, necessary, for, minimal, activation])].
[sujeto(['The', deficiency, of, this, hydrolase]), verbo([causes]), complemento([a, disorder, known, as, mucopolysaccharidosis, type, 'IIIA,', characterized, by, a, profound, neurological, deterioration])].
[sujeto(['Human', and, mouse, 'exon-intron', structures, were]), verbo([reported]), complemento([without, any, characterization, of, their, promoter, regions, '[', 'DNA', 'Res'])].
[sujeto(['The', 5, '\'', -, flanking, region, was, shown, to, contain, a, 'GC-rich', region, and, putative]), verbo([binding]), complemento([sites, for, the, transcription, factors, 'SRY,', 'MZF1', and, 'Nkx-2'])].
[sujeto(['Finally,', the, 3, '\'', -, untranslated, region, of, the, mouse, sulphamidase, gene, was, isolated, and]), verbo([found]), complemento([to, be, longer, than, the, region, identified, in, the, human, gene])].
[sujeto(['Genetic', analysis]), verbo([has]), complemento([implicated, a, number, of, gene, products, essential, for, this, 'process,', which, include, 'Sry,', 'WT1,', 'SF-1,', and, 'DAX-1'])].
[sujeto(['We']), verbo([have]), complemento([sought, to, better, define, the, role, of, 'WT1', in, this, process, by, identifying, downstream, targets, of, 'WT1', during, normal, gonadal, development])].
[sujeto(['We']), verbo([have]), complemento([noticed, that, in, the, developing, murine, gonadal, 'ridge,', wt1, expression, precedes, expression, of, 'Dax-1,', a, nuclear, receptor, gene])].
[sujeto(['We', also, demonstrate, that, 'WT1', can]), verbo([activate]), complemento([the, 'Dax-1', promoter])].
[sujeto(['Footprinting', 'analysis,', transient, 'transfections,', promoter, 'mutagenesis,', and, mobility, shift, assays]), verbo([suggest]), complemento([that, 'WT1', regulates, 'Dax-1', via, 'GC-rich', binding, sites, found, upstream, of, the, 'Dax-1', 'TATA', box])].
[sujeto(['We', show, that, two, 'WT1-interacting', 'proteins,', the, product, of, a, 'Denys-Drash', syndrome, allele, of, wt1, and, prostate, apoptosis, 'response-4', 'protein,']), verbo([inhibit]), complemento(['WT1-mediated', transactivation, of, 'Dax-1'])].
[sujeto(['In', 'addition,', we, demonstrate, that, 'WT1', can]), verbo([activate]), complemento([the, endogenous, 'Dax-1', promoter])].
[sujeto(['Determination', of, 41.2, kb, of, 'Y', chromosome, genomic, sequence]), verbo([has]), complemento([been, made, from, a, cosmid, that, spans, the, 'Yp', pseudoautosomal, boundary, and, includes, 18.5, kb, of, sequence, from, the, 'patient-defined', 'sex-determining', region, of, the, 'Y', chromosome])].
[sujeto(['An', 'AceDB', database, of, the, sequence, and, the, analysis, data]), verbo([have]), complemento([been, produced, as, a, resource, for, studies, of, the, evolution, and, population, genetics, of, the, 'Y', chromosome])].
[sujeto(['Indeed,', no, coding, regions, other, than, those, previously]), verbo([reported]), complemento([can, be, detected, anywhere, in, the, 41, kb])].
[sujeto(['The', 'Y-specific', and, pseudoautosomal, portions, of, this, sequence]), verbo([have]), complemento([different, repeat, sequence, and, 'GC', 'contents:', this, may, have, relevance, both, to, the, events, defining, the, pseudoautosomal, boundary, and, to, the, course, of, sequence, evolution, in, the, absence, of, recombination])].
[sujeto(['In', 'contrast,', meiotic, entry, is, actively]), verbo([prevented]), complemento([in, the, fetal, testis, at, this, developmental, 'time-point'])].
[sujeto(['It']), verbo([has]), complemento([previously, been, shown, that, 'RA-treatment', mediates, initiation, of, meiosis, in, human, fetal, ovary, ex, vivo])].
[sujeto(['Continued', proliferation, of, cells, without, signs, of]), verbo([increased]), complemento([apoptosis, was, observed, after, 2, weeks, of, culture])].
[sujeto(['In', cultured, fetal, ovaries, treated, with, 'RA,', an]), verbo([increased]), complemento([number, of, meiotic, germ, cells, '(', 'P', &, 'lt;', 0.05, ')', and, 'DMRT1-positive', oogonia, initiating, meiosis, '(', 'P', &, 'lt;', 0.05, ')', was, 'observed,', which, is, in, agreement, with, a, previous, study])].
[sujeto(['In', fetal, 'testes,', 'RA-treatment', resulted, in, a]), verbo([decreased]), complemento([number, of, gonocytes, '(', 'P', &, 'lt;', 0.05, ')', ',', a, reduced, percentage, of, proliferating, gonocytes, '(', 'P', &, 'lt;', 0.05, ')', ',', altered, expression, pattern, of, the, somatic, cell, markers, 'AMH', and, 'COUP-TFII,', as, well, as, disrupted, seminiferous, cord, structure, and, testis, morphology])].
[sujeto(['Our', novel]), verbo([finding]), complemento([of, disrupted, fetal, testis, development, after, treatment, with, 'RA', indicates, that, abnormal, meiosis, regulation, can, potentially, cause, gonadal, dysgenesis])].
[sujeto(['The', authors]), verbo([have]), complemento([no, conflicts, of, interest])].
[sujeto(['Elastic', 'net-Cox\'s', proportional, regression, hazards, model, '(', 'EN-COX)', was, used, to, identify, the, prognostic]), verbo([associated]), complemento([factors])].
[sujeto(['Then,', the]), verbo([target]), complemento([genes, of, the, obtained, miRNAs, were, predicted, followed, by, function, prediction])].
[sujeto(['The']), verbo([target]), complemento([genes, of, 'miRNA-342', such, as, 'B-cell', 'CLL/lymphoma', 2, '(', 'BCL2)', were, mainly, enriched, in, the, biological, process, related, to, cellular, metabolic, process, and, 'Disease', 'Ontology', terms, of, lymphoma])].
[sujeto(['The']), verbo([target]), complemento([genes, of, 'miRNA-93', were, mainly, enriched, in, the, pathway, of, 'G1', phase])].
[sujeto(['These', prognostic, markers, such, as, 'miRNA-93,', 'miRNA-342,', 'RARA,', 'MAFF,', 'SOX4,', and, 'BCL2', may, be, used, as]), verbo([targets]), complemento([for, 'TPC', chemoprevention])].
[sujeto(['In', 'XY', 'gonads,', 'sex-determining', region, 'Y', '(', 'SRY)']), verbo([triggers]), complemento([fibroblast, growth, factor, 9, '(', 'FGF9)', expression, in, somatic, cells])].
[sujeto(['FGF', 'signaling,', together, with, downstream, 'nodal/activin', 'signaling,']), verbo([promotes]), complemento([male, differentiation, in, 'XY', germ, cells, by, suppressing, retinoic, acid, '(', 'RA)-dependent', meiotic, entry, and, inducing, 'male-specific', genes])].
[sujeto(['However,', the, mechanism, by, which, 'nodal/activin', signaling]), verbo([regulates]), complemento(['XY', 'PGC', fate, is, unknown])].
[sujeto(['We']), verbo([found]), complemento([that, conditional, deletion, of, 'Smad2,', but, not, 'Smad3,', from, 'XY', 'PGCs', led, to, a, loss, of, 'male-specific', gene, expression])].
[sujeto(['Moreover,', suppression, of, 'RA', signaling, did, not, rescue, 'male-specific', gene, expression, in, 'Smad2-mutant', 'testes,', indicating, that, 'SMAD2', signaling]), verbo([promotes]), complemento([male, differentiation, in, a, 'RA-independent', manner])].
[sujeto(['By', 'contrast,', we]), verbo([found]), complemento([that, p38, signaling, has, an, important, role, in, the, suppression, of, 'RA', signaling])].
[sujeto(['The', 'Smad2', deletion, did, not, disrupt, the, p38, signaling, pathway, even, though, 'Nodal', expression, was, significantly, 'reduced,']), verbo([suggesting]), complemento([that, p38, was, not, regulated, by, nodal, signaling, in, 'XY', 'PGCs'])].
[sujeto(['Additionally,', the, inhibition, of, p38, signaling, in, the, 'Smad2-mutant', testes, severely, impeded, 'XY', 'PGC', differentiation, and]), verbo([induced]), complemento([meiosis])].
[sujeto(['Firstly,', the, peak, of, 'SRY', gene, expression, that, is, observed, in, early, differentiated, 'XY', gonads, in, numerous, mammals, was, also, seen, in, the, 'rabbit,', but, this, expression, was]), verbo([maintained]), complemento([at, a, high, level, until, the, end, of, puberty])].
[sujeto(['Thirdly,', the, expression, of, 'STRA8', and, 'DMC1', genes, '(', which, are, known, to, be, specifically]), verbo([expressed]), complemento([in, germ, cells, during, 'meiosis)', was, enhanced, in, 'XX', gonads, around, birth, but, also, slightly, and, significantly, in, 'XY', gonads, at, the, same, 'time,', even, though, no, meiosis, occurs, in, 'XY', gonad, at, this, stage])].
[sujeto(['SRY,', as, a, founder, member, of, 'SOX', 'family,']), verbo([has]), complemento([been, long, believed, to, be, involved, in, the, development, of, sexual, gonads, by, triggering, signaling, cascades, which, lead, to, the, formation, of, testis, or, ovary, from, bipotential, gonads])].
[sujeto(['In', order, to]), verbo([gain]), complemento([further, insight, into, the, possible, roles, of, 'SRY', during, 'development,', we, looked, into, possible, 'SRY-regulated', genes, and, their, levels, of, expression, in, a, human, embryonic, carcinoma, cell, 'line,', named, 'NTera2,', before, and, after, induction, of, differentiation])].
[sujeto(['The', results, showed, that, incorporation, of, 'SRY', in, both, groups, of, genes, was]), verbo([increased]), complemento([after, induction, of, differentiation])].
[sujeto(['Besides,', lower, expression, of, 'OCT4,', 'SOX2,', and, 'NANOG', and, higher, expression, of, 'PAX6', and, 'NESTIN', genes, in, differentiated, cells]), verbo([suggest]), complemento([that, 'SRY', may, act, as, a, transcription, repressor, for, 'pluripotency-associated', genes, and, as, a, transcription, activator, for, 'differentiation-related', genes])].
[sujeto(['We', show, that, mice, fed, excess, vitamin, 'A', develop, aortic, valve, stenosis, and, leaflet, calcification]), verbo([associated]), complemento([with, increased, expression, of, osteogenic, genes, and, decreased, expression, of, cartilaginous, markers])].
[sujeto(['Using', a, pharmacological, 'approach,', we, show, that, 'RA-mediated', 'Sox9', repression, and, calcification, is]), verbo([regulated]), complemento([by, classical, 'RA', signaling, and, requires, both, 'RA', and, retinoid, 'X', receptors])].
[sujeto(['Our', studies, demonstrate, that, excess, vitamin, 'A', dietary, intake]), verbo([promotes]), complemento([heart, valve, calcification, in, vivo])].
[sujeto(['Therefore']), verbo([suggesting]), complemento([that, hypervitaminosis, 'A', could, serve, as, a, new, risk, factor, of, calcific, aortic, valve, disease, in, the, human, population])].
[sujeto(['Y(Tir)', '(', mice, with, 'Y', chromosome, from, a, strain, in, 'Tirano,', 'Italy,', and, autosomes, and, 'X-chromosomes', from, the, 'B6', 'strain)', mice]), verbo([provide]), complemento([an, excellent, model, for, analysing, sex, development, that, occurs, during, gonadal, 'differentiation;', 'however,', the, molecular, mechanisms, that, contribute, to, sex, reversal, are, unclear])].
[sujeto(['Our', aim]), verbo([has]), complemento([been, to, establish, which, molecular, events, participate, in, this, sex, reversal])].
[sujeto(['The', pattern, of, gene, expression, related, to, testicular, '[', 'Sry', '(', 'sex-determining', region, of, the, 'Y', 'chromosome),', 'Sox9', '(', 'Sry-related', 'high-mobility', group, box, gene, 9, ')', and, 'Mis', '(', 'Müllerian-inhibiting', 'substance)]', and, ovarian, '[', 'Wnt4', '(', 'Wingless-type', 'MMTV', '(', 'murine-mammary-tumour', 'virus)', integration, site, 'family,', member, 4, ')', ',', 'Rspo1', '(', 'cysteine-rich', secretory, protein, containing, a, thrombospondin, type, 1, 'repeat)', and, 'Stra8', '(']), verbo([stimulated]), complemento([by, retinoic, acid, gene, 8, ')', ']', differentiation, was, analysed, by, applying, immunofluorescence, and, 'real-time', 'RT-PCR', '(', reverse, 'transcription-PCR),', focusing, on, 'XY', gonads, from, the, 'B6'])].
[sujeto(['Y(Tir)', 'strain,', both, at, the, transcript, and, protein, 'level,']), verbo([inducing]), complemento([differentiation, of, ovaries, and, 'ovotestes,', but, not, the, formation, of, the, 'testes,', which, were, normal])].
[sujeto(['Our', results, indicate, that, the, expression, of, testicular, genes, is]), verbo([inhibited]), complemento([at, various, 'levels,', permitting, the, expression, of, ovarian, genes, such, as, 'Wnt4,', 'Stra8', and, 'Rspo1'])].
[sujeto(['Correlation', analysis, indicated, that, an, ovary, differentiation, pathway, is]), verbo([activated]), complemento([when, the, testicular, differentiation, pathway, is, inhibited])].
[sujeto(['The', unexpected, action, of, 'SRY', in, the, control, of, voluntary, movement, in, male, rodents]), verbo([suggests]), complemento([a, role, in, the, regulation, of, dopamine, transmission, and, 'dopamine-related', disorders, with, gender, 'bias,', such, as, 'Parkinson\'s', disease])].
[sujeto(['Retinoic', 'acid-induced', differentiation, of, human, precursor, 'NT2', cells, into, dopaminergic, cells]), verbo([increased]), complemento([expression, of, 'TH,', 'NURR1,', 'D2', 'R', and, 'SRY'])].
[sujeto(['Conversely,', 'SRY', 'over-expression']), verbo([increased]), complemento(['TH,', 'DDC,', 'DBH,', 'D2', 'R', and, 'MAO-A', 'levels,', accompanied, by, increased, extracellular, dopamine, levels])].
[sujeto(['A', luciferase, assay, demonstrated, that, 'SRY']), verbo([activated]), complemento([a, 4.6, kb, 5, '\'', upstream, regulatory, region, of, the, human, 'TH', 'promoter/nigral', enhancer])].
[sujeto(['Combined,', these, results]), verbo([suggest]), complemento([that, 'SRY', plays, a, role, as, a, positive, regulator, of, catecholamine, synthesis, and, metabolism, in, the, human, male, midbrain])].
[sujeto(['This', ancillary, genetic, mechanism, might, contribute, to, gender, bias, in, 'fight-flight', behaviours, in, men, or, their]), verbo([increased]), complemento([susceptibility, to, dopamine, 'disorders,', such, as, 'Parkinson\'s', disease, and, schizophrenia])].
[sujeto(['Therefore,', identification, of, factors]), verbo([regulating]), complemento([the, expression, of, the, 'Cyp26b1', gene, is, an, important, goal, in, reproductive, biology])].
[sujeto(['In', the, mouse, gonadal, somatic, cell, line, 'TM3,', transfection, of, constructs]), verbo([expressing]), complemento(['SOX9', and, 'SF1', activated, 'Cyp26b1', 'expression,', independently, of, the, positive, regulator, 'RA'])].
[sujeto(['In', embryonic, gonads, deficient, in, 'SOX9', or, 'SF1,', 'Cyp26b1', expression, was]), verbo([decreased]), complemento([relative, to, 'wild-type', '(', 'WT)', 'controls,', as, measured, by, quantitative, 'RT-PCR', '(', 'qRT-PCR)'])].
[sujeto(['Furthermore,', 'qRT-PCR', showed, that, 'Cyp26b1', 'up-regulation', by, 'SOX9/SF1', was, attenuated, by, the, ovarian, transcription, factor, 'Forkhead', box, 'L2', '(', 'FOXL2)', in, 'TM3', 'cells,', whereas, in, 'Foxl2-null', 'mice,', 'Cyp26b1', expression, in, 'XX', gonads, was]), verbo([increased]), complemento(['∼20-fold', relative, to, 'WT', controls])].
[sujeto(['These', data, support, the, hypothesis, that, 'SOX9', and, 'SF1']), verbo([ensure]), complemento([the, male, fate, of, germ, cells, by, 'up-regulating', 'Cyp26b1', and, that, 'FOXL2', acts, to, antagonize, 'Cyp26b1', expression, in, ovaries])].
[sujeto(['The', 'SRY-related', transcription, factor, 'Sox9', is]), verbo([expressed]), complemento([in, developing, and, mature, heart, 'valves,', and, its, function, is, required, for, expression, of, 'cartilage-associated', 'proteins,', similar, to, its, role, in, chondrogenesis])].
[sujeto(['In', addition, to, 'cartilage-associated', 'defects,', mice, with, reduced, sox9, function, develop, skeletal, bone, 'prematurely;', 'however,', the, ability, of, sox9, deficiency, to]), verbo([promote]), complemento([ectopic, osteogenic, phenotypes, in, heart, valves, has, not, been, examined])].
[sujeto(['This', study, aims, to, determine, the, role, of, 'Sox9', in]), verbo([maintaining]), complemento([connective, tissue, homeostasis, in, mature, heart, valves, using, in, vivo, and, in, vitro, approaches])].
[sujeto(['Using', histological, and, molecular, 'analyses,', we]), verbo([report]), complemento(['that,', from, 3, months, of, 'age,', 'Sox9(fl/+);Col2a1-cre', mice, develop, calcific, lesions, in, heart, valve, leaflets, associated, with, increased, expression, of, 'bone-related', genes, and, activation, of, inflammation, and, matrix, remodeling, processes])].
[sujeto(['Furthermore,', we, show, that, retinoic, acid, treatment, in, mature, heart, valves, is, sufficient, to]), verbo([promote]), complemento([calcific, processes, in, 'vitro,', which, can, be, attenuated, by, 'Sox9', overexpression])].
[sujeto(['This', study]), verbo([provides]), complemento([insight, into, the, molecular, mechanisms, of, heart, valve, calcification, and, identifies, reduced, 'Sox9', function, as, a, potential, genetic, basis, for, calcific, valvular, disease])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, characterization, of, the, 'SOX3', promoter, and, demonstrated, that, the, general, transcription, factors, 'NF-Y', '(', nuclear, 'factor-Y),', 'Sp1', '(', specificity, protein, 1, ')', and, 'USF', '(', upstream, stimulatory, 'factor)', are, involved, in, transcriptional, regulation, of, 'SOX3', promoter, activity])].
[sujeto(['In', the, present, study, we]), verbo([provide]), complemento([the, first, evidence, that, the, 'TALE', '(', 'three-amino-acid', loop, 'extension)', transcription, factors, 'PBX1', '(', 'pre-B-cell', leukaemia, homeobox, 1, ')', and, 'MEIS1', '(', myeloid, ecotropic, viral, integration, site, 1, 'homologue)', participate, in, regulating, human, 'SOX3', gene, expression, in, 'NT2/D1', cells, by, direct, interaction, with, the, consensus, 'PBX/MEIS-binding', 'site,', which, is, conserved, in, all, mammalian, orthologue, promoters, analysed])].
[sujeto(['PBX1', is, present, in, the, protein, complex, formed, at, this, site, with]), verbo([nuclear]), complemento([proteins, from, uninduced, 'cells,', whereas, both, 'PBX1', and, 'MEIS1', proteins, were, detected, in, the, complex, created, with, extract, from, 'RA', '(', retinoic, 'acid)-induced', 'NT2/D1', cells])].
[sujeto(['Finally,', we, demonstrated, that, overexpressed, 'PBX1', and, 'MEIS1']), verbo([increased]), complemento([endogenous, 'SOX3', protein, expression, in, both, uninduced, and, 'RA-induced', 'NT2/D1', cells])].
[sujeto(['With', the, results, of, the, present, 'study,', for, the, first, 'time,', we]), verbo([have]), complemento([established, a, functional, link, between, the, 'TALE', 'proteins,', 'PBX1', and, 'MEIS1,', and, expression, of, the, human, 'SOX3', gene])].
[sujeto(['This', link, is, of, particular, interest, since, both, 'TALE', family, members, and, members, of, the, 'SOX', superfamily, are]), verbo([recognized]), complemento([as, important, developmental, regulators])].
[sujeto(['Balanced', production, and, degradation, of, retinoids, is, important, in]), verbo([regulating]), complemento([development, of, several, organ, systems, in, the, vertebrate, embryo])].
[sujeto(['Among', 'these,', it, is, known, that, retinoic, acid, '(', 'RA),', and, the, 'retinoid-catabolyzing', enzyme, 'CYP26B1', together]), verbo([regulate]), complemento([the, 'sex-specific', behavior, of, germ, cells, in, developing, mouse, gonads])].
[sujeto(['We']), verbo([report]), complemento([here, that, the, gene, encoding, a, cytosolic, 'class-1', aldehyde, 'dehydrogenase,', 'ALDH1A1,', a, weak, catalyst, of, 'RA', 'production,', is, strongly, expressed, in, a, 'male-specific', manner, in, somatic, cells, of, the, developing, mouse, 'testis,', beginning, shortly, after, 'Sry', expression, is, first, detectable])].
[sujeto(['This', expression, pattern, is]), verbo([conserved]), complemento([in, the, developing, male, gonad, of, the, chicken, and, is, dependent, on, the, 'testis-specific', transcription, factor, 'SOX9'])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, low, levels, of, 'RA', may, be, required, for, early, developmental, events, in, the, 'testis,', or, that, 'Aldh1a1', expression, in, the, fetus, may, prefigure, a, later, requirement, for, 'ALDH1A1', in, regulating, spermatogenesis, postnatally])].
[sujeto(['DAX-1', '(', 'DSS-AHC', 'Critical', 'Region', on, the, 'X', 'Chromosome-1)', is, a, member, of, the]), verbo([nuclear]), complemento([hormone, receptor, superfamily, that, has, an, important, role, in, steroidogenesis, and, gonadogenesis])].
[sujeto(['We', show, here, that, 'DAX-1', is, able, to]), verbo([inhibit]), complemento([splicing, in, in, vivo, and, in, vitro, splicing, 'assays,', and, this, inhibition, is, relieved, by, the, addition, of, 'SOX6'])].
[sujeto(['SOX6', appears, to]), verbo([inhibit]), complemento([the, interaction, between, 'DAX-1', and, the, splicing, 'machinery,', thus, providing, a, likely, mechanism, for, functional, interference])].
[sujeto(['We', conclude, that, 'DAX-1', and, 'SOX6', proteins, 'interact,']), verbo([have]), complemento([overlapped, expression, in, the, 'testis,', and, act, antagonistically, during, 'pre-mRNA', splicing])].
[sujeto(['Mammalian', gonad, differentiation]), verbo([involves]), complemento([sexually, dimorphic, 'cell-fate', decisions, within, the, bipotential, gonadal, primordia])].
[sujeto(['Testis', differentiation, is, initiated, by, a, 'center-to-poles', wave, of, 'Sry', expression, that]), verbo([induces]), complemento([supporting, cell, precursors, '(', 'SCPs)', to, become, 'Sertoli', rather, than, granulosa, cells])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, 1700106, 'J16Rik', and, 'Sprr2d', may, have, important, roles, in, early, gonad, 'development,', and, are, consistent, with, the, hypothesis, that, ovarian, 'SCP', differentiation, occurs, in, a, 'center-to-poles', wave, with, similar, timing, to, that, of, testicular, 'SCP', differentiation])].
[sujeto(['Different', genes]), verbo([express]), complemento([in, different, phases, and, tend, to, change, with, the, time])].
[sujeto(['The', functions, of, some, 'genes,', such, as, 'SRY,', 'SOX9,', 'SOX8,', 'DAX1,', and, 'FGF9,']), verbo([have]), complemento([already, been, defined, in, male, gonadal, morphogenesis])].
[sujeto(['This', paper, presents, a, review, of, the, genes]), verbo([involved]), complemento([in, the, formation, of, the, male, gonad, in, mammals])].
[sujeto(['This', highly]), verbo([conserved]), complemento([function, is, retained, in, birds, and, is, supported, by, the, high, levels, of, 'AMH', expression, in, developing, testes])].
[sujeto(['Mammalian', 'AMH', expression, is]), verbo([regulated]), complemento([by, a, combination, of, transcription, 'factors,', the, most, important, being, 'Sry-type', 'high-mobility-group', box, transcription, 'factor-9', '(', 'SOX9)'])].
[sujeto(['In', the, chicken, 'embryo,', 'however,', 'AMH', mRNA, expression, precedes, that, of, 'SOX9,']), verbo([leading]), complemento([to, the, view, that, 'AMH', may, play, a, more, central, role, in, avian, testicular, development])].
[sujeto(['AMH']), verbo([caused]), complemento([the, gonads, of, both, sexes, to, develop, as, small, and, undeveloped, structures, at, both, embryonic, and, adult, stages])].
[sujeto(['A', similar, gonadal, phenotype, was, also, observed, in, 'males,', with, a, complete]), verbo([loss]), complemento([of, both, 'Sertoli', 'cells,', disrupted, 'SOX9', expression, and, gonadal, steroidogenesis])].
[sujeto(['At', sexual, maturity, both, sexes, showed, a, female, external, phenotype, but]), verbo([retained]), complemento([sexually, dimorphic, body, weights, that, matched, their, genetic, sexes])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'AMH', does, not, operate, as, an, early, testis, activator, in, the, chicken, but, can, affect, downstream, 'events,', such, as, sex, steroid, hormone, production])].
[sujeto(['In', 'addition,', this, study]), verbo([provides]), complemento([a, unique, opportunity, to, assess, chicken, sexual, development, in, an, environment, of, sex, hormone, 'deficiency,', demonstrating, the, importance, of, both, hormonal, signaling, and, direct, cell, autonomous, factors, for, somatic, sex, identity, in, birds])].
[sujeto(['The', 'phenotype,', ultrasonographic, 'examination,', hormone, 'status,', cytogenetic, evaluation, and, molecular, diagnostics]), verbo([lead]), complemento([to, the, diagnosis, of, an, 'XY', testicular, disorder, of, sexual, development, '(', 'DSD)', due, to, a, complete, androgen, insensitivity, syndrome])].
[sujeto(['To', our, knowledge, this, is, the, first]), verbo([report]), complemento([about, a, thoroughbred, in, racing, sports, with, an, 'XY', testicular, disorder, of, sexual, development])].
[sujeto(['To', 'date,', intersex, racing, horses]), verbo([have]), complemento([never, been, described, in, thoroughbreds, or, a, regulation, for, intersexes, in, regard, to, horse, races, has, been, issued])].
[sujeto(['The', establishment, of, social, hierarchies, is, a, naturally, 'occurring,', evolutionarily]), verbo([conserved]), complemento([phenomenon, with, a, 'well-established', impact, on, fitness, and, health])].
[sujeto(['Together,', our, results, demonstrate, a, 'sex-specific', mechanism, underlying, social, 'hierarchy,', in, which, both, males, and, females]), verbo([retain]), complemento([the, functional, capacity, to, adapt, their, social, strategy])].
[sujeto(['More', 'generally,', we, expect, the, automated, tube, test, to]), verbo([provide]), complemento([an, important, complementary, approach, for, both, fundamental, and, translational, studies, of, social, behavior])].
[sujeto(['In', 'teleosts,', the, expression, of, steroidogenic, enzymes, and, related, transcription, factor, genes, occurs, in, a, 'stage-', and, 'tissue-specific', manner]), verbo([causing]), complemento([sexual, development])].
[sujeto(['The', role, of, 'sox3,', an, evolutionary, ancestor, of, 'SRY,']), verbo([has]), complemento([not, been, studied, in, detail])].
[sujeto(['Developing', and, mature, testis, showed, higher, sox3, expression, than, ovary, of, corresponding, 'stages,', and, more, sox3, transcripts, were]), verbo([found]), complemento([during, the, spawning, phase, of, the, seasonal, reproductive, cycle])].
[sujeto(['Expression', of, sox3, was, upregulated, by, hCG, after, in, vivo, and, in, vitro, 'induction,']), verbo([suggesting]), complemento([that, gonadotropins, might, stimulate, it])].
[sujeto(['Sox3', could, also, be]), verbo([found]), complemento([in, the, zona, radiata, of, developing, and, mature, oocytes])].
[sujeto(['These', results]), verbo([suggest]), complemento([a, possible, role, for, 'Sox3', in, the, regulation, of, testicular, development, and, function])].
[sujeto(['Criteria']), verbo([suggested]), complemento(['XY', 'DSD', include, overt, genital, 'ambiguity,', apparent, 'female/male', genitalia, with, 'inguinal/labial', 'mass,', apparent, male, genitalia, with, unilateral, or, bilateral, 'non-palpable', 'testes,', micropenis, and, isolated, hypospadias, or, with, undescended, testis])].
[sujeto(['Numerous', spermatogenic, cells, were, observed, in, the, 'semen,', and, approximately, 60, '%', of, the, cells, examined, in, semen, were, primary, 'spermatocytes,', showing, spermatogenic]), verbo([arrest]), complemento([at, the, primary, spermatocyte, level])].
[sujeto(['This', is, the, first, case]), verbo([reported]), complemento([with, a, nonmosaic, 46, ',', 'X,', i, '(', 'Y)', '(', p11])].
[sujeto(['Aberrations', in, pseudoautosomal, region, 1, on, the, rearranged, 'Y', chromosome, may, result, in, the, deficiency, of, 'X-Y', pairing, or, 'recombination,', ultimately]), verbo([lead]), complemento([to, the, spermatogenic, failure])].
[sujeto(['Whilst', gonadal, hormones, can, substantially, influence, sexual, differentiation, of, the, 'brain,', recent, findings]), verbo([have]), complemento([suggested, that, 'sex-linked', genes, may, also, directly, influence, neurodevelopment])].
[sujeto(['Over', a, 24, hour, 'period,', 'XX', and, 'XY', gonadally, female, mice, '(', lacking, 'Sry)', exhibited, greater, horizontal, locomotor, activity, and, reduced, food, consumption, per, unit, bodyweight, than, 'XX', and, 'XY', gonadally, male, mice, '(', possessing, 'Sry);', in, two, behavioural, tests, '(', the, elevated, plus, and, zero, 'mazes)', 'XX', and, 'XY', gonadally, female, mice, showed, evidence, for]), verbo([increased]), complemento(['anxiety-related', behaviours, relative, to, 'XX', and, 'XY', gonadally, male, mice])].
[sujeto(['The', present, data]), verbo([suggest]), complemento(['that:', 'i)', the, 'male-specific', factor, 'Sry', may, influence, activity, and, feeding, behaviours, in, 'mice,', and, 'ii)', dissociable, feeding, and, 'anxiety-related', murine, phenotypes, may, be, differentially, modulated, by, 'Sry', and, by, other, 'sex-linked', genes])].
[sujeto(['Our', results, may]), verbo([have]), complemento([relevance, for, understanding, the, molecular, underpinnings, of, sexually, dimorphic, behavioural, phenotypes, in, healthy, men, and, 'women,', and, in, individuals, with, abnormal, sex, chromosome, constitutions])].
[sujeto(['Here,', we]), verbo([report]), complemento([about, a, 30, years, old, male, subject, with, vanishing, testis, 'syndrome,', feminization, and, gynecomastia])].
[sujeto(['Follicle']), verbo([stimulating]), complemento([hormone, '(', 'FSH)', and, 'Leutinizing', hormone, '(', 'LH)', levels, were, elevated, whereas, testosterone, was, below, normal, and, 'anti-mullerian-hormone', level, was, undetectable, in, the, patient])].
[sujeto(['The', chromosomal, analysis, and, 'DNA', analysis, of, 'SRY', and, 'ZFY,', 'DAX-I,', 'AZFa,', 'AZFb,', 'AZFc', and, heterochromatic, region, of, 'Y', chromosome, with, 'STS']), verbo([primer]), complemento(['(', 'sY160)', were, done, to, detect, any, genetic, changes, at, specified, sites, '(', both, at, chromosomal, and, molecular, 'level)'])].
[sujeto(['PCR', amplification, of, 'SRY,', 'ZFY,', 'DAX-I,', 'AZFa,', 'AZFb,', 'AZFc', gene, and, 'Y', chromosome, heterochromatic, region, using, 'STS']), verbo([primer]), complemento(['sY(160)', did, not, reveal, any, microdeletions])].
[sujeto(['The', 'anti-mullerian-hormone', level, was, undetectable, indicating, that, the, patient, 'didn\'t']), verbo([have]), complemento([any, testicular, tissue, in, scrotum])].
[sujeto(['Increased', levels, of, 'FSH,', 'LH', and, reversed, 'androgen:', estrogen, ratio, might]), verbo([have]), complemento([given, rise, to, gynecomastia, in, the, patient])].
[sujeto(['The', torsion, of, testis, might]), verbo([have]), complemento([caused, vascular, occlusion, and, thereby, regression, of, testicular, tissue, 'occurred,', but, the, exact, genetic, condition, yet, to, understand])].
[sujeto(['Post-surgery', subjects, showed, reduced, 'androgens,', a, marked]), verbo([increase]), complemento([in, 'LH', and, 'FSH', and, normal, 'PRL'])].
[sujeto(['There', was, a, marked]), verbo([increase]), complemento([in, the, baseline, and, 'post-stimulation', 'GH', values, in, 6, of, the, 13, 'pre-surgery', 'patients,', peaking, at, 'T15'])].
[sujeto(['Qualitative', analysis, of, the, 'AZFa,', 'AZFb,', and, 'AZFc', regions, did, not]), verbo([reveal]), complemento([any, microdeletions, in, any, subject])].
[sujeto(['This', gender, disorder, does, not, seem, to, be]), verbo([associated]), complemento([with, any, molecular, mutations, of, some, of, the, main, genes, involved, in, sexual, differentiation])].
[sujeto(['With', 'aging,', this, cardiovascular, protection, in, women, is, lost, and, this, may, be, related, to]), verbo([loss]), complemento([of, estrogen, postmenopause, but, the, possible, contribution, of, other, sex, hormones, needs, to, be, further, examined])].
[sujeto(['Restoration', of, these, 'RAS', depressor, pathways, in, older, 'women,', or, 'up-regulation', of, these, in, 'males,', represents, a, therapeutic]), verbo([target]), complemento([that, is, worth, pursuing])].
[sujeto(['An', irregularity, in, any, of, these, three, steps, can]), verbo([lead]), complemento([to, a, disorder, in, sexual, development, '(', 'DSD)'])].
[sujeto(['All', seven, 'XX', 'sex-reversed', dogs, were]), verbo([found]), complemento([to, be, negative, for, the, 'SRY', gene, by, polymerase, chain, reaction])].
[sujeto(['The', basal, plasma, 'LH', concentration]), verbo([increased]), complemento([significantly, after, 'GnRH', administration, in, all, dogs, with, 'DSD'])].
[sujeto(['An', early, investigation, and, management, op, cryptorchidism, are, essential, for, the, diagnosis, of]), verbo([associated]), complemento(['pathologies,', because, 'intra-abdominal', testis, are, associated, with, infertility, and, neoplasic, risk])].
[sujeto(['The', authors, describe, a, case, of, late, presentation, of, cryptorchidism]), verbo([associated]), complemento([with, genetic, disorder])].
[sujeto(['With', this, case]), verbo([report]), complemento([the, authors, intend, to, enhance, the, need, of, early, management, of, cryptorchidism, and, short, 'stature,', in, order, to, improve, the, prognosis])].
[sujeto(['The', measurements, of, luteinizing, 'hormone,', follicle]), verbo([stimulating]), complemento(['hormone,', testosterone, and, 'ir-inhibin', showed, a, tendency, to, increase, gradually, from, 'April'])].
[sujeto(['In', 'autopsy,', immature, symmetrical, subcutaneous, testes, were]), verbo([found]), complemento([in, the, inguinal, regions])].
[sujeto(['The', authors]), verbo([report]), complemento([a, case, of, a, dysgenetic, male, pseudohermaphroditism, with, a, 45, ',', 'X/46,XY', karyotype, in, a, mosaic, 'form,', which, was, diagnosed, in, an, infant])].
[sujeto(['Surgical', removal, of, the, dysgenetic, testicular, tissue, located, in, the, abdominal, cavity, and, its, histological, evaluation]), verbo([provides]), complemento([separation, of, mixed, gonadal, 'dysgenesis,', dysgenetic, male, 'pseudohermaphroditism,', bilateral, gonadal, dysgenesis, and, ovotestis, in, the, 45, ',', 'X/46,XY', mosaic, cases])].
[sujeto(['An', accurate, evaluation, is, necessary, for, a, correct, sex, assignment, and, for, surgical, intervention, to]), verbo([prevent]), complemento([neoplastic, degeneration, of, the, dysgenetic, gonad])].
[sujeto(['To', describe, a, rare, case, of, 45, ',', 'X', 'Turner\'s', syndrome, with, elevated, 'T', and, clitoromegaly]), verbo([caused]), complemento([by, ovarian, hilus, cell, hyperplasia])].
[sujeto(['An', 11, -, 'and-a-half-year-old', girl, with, 45, ',', 'X', karyotype, showed, signs, of, accelerated, growth, and, clitoromegaly, and, was]), verbo([found]), complemento([to, have, elevated, serum, 'T'])].
[sujeto(['Ovarian', hilus, cell, hyperplasia, is, an, extremely, rare]), verbo([cause]), complemento([of, virilization, in, 'Turner\'s', syndrome])].
[sujeto(['Data', in, the, rat]), verbo([have]), complemento([suggested, the, 'male-specific', 'Y-chromosome', gene, 'Sry', to, contribute, to, balance, between, these, two, 'axes,', but, why, the, 'testis-determining', gene, has, these, functions, remains, unknown])].
[sujeto(['A', combination, of, in, silico, 'genetic/protein', 'comparisons,', functional, luciferase, assays, for, promoters, of, the, human, 'RAS,', and, 'RNA-Seq', profiling, in, rat, were, used, to, address, if, regulation, of, 'Sry', on, the, 'RAS', is]), verbo([conserved]), complemento([in, the, homologous, 'X-chromosome', 'gene,', 'Sox3'])].
[sujeto(['The', regulation, by, both, 'SRY', and, 'SOX3', on, the, 'MAS', promoter, indicates, a, cis, regulation, through, multiple, 'SOX']), verbo([binding]), complemento([sites])].
[sujeto(['Sry', transcripts, are]), verbo([found]), complemento([in, all, analyzed, male, rat, tissues, including, the, 'kidney,', while, 'Sox3', transcripts, are, found, only, in, the, brain, and, 'testis,', suggesting, that, the, primary, tissue, for, renin, production, '(', 'kidney)', can, only, be, regulated, by, 'SRY', and, not, 'SOX3'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'SRY', regulation, of, the, 'RAS', is, partially, shared, with, its, 'X-chromosome', homolog, 'SOX3,', but, 'SRY', gained, a, 'sex-specific', control, in, the, kidney, for, the, 'rate-limiting', step, of, the, 'RAS,', potentially, resulting, in, 'male-specific', blood, pressure, regulation])].
[sujeto(['Mammalian', sex, determination, hinges, on, the, development, of, ovaries, or, 'testes,', with, testis, fate, being]), verbo([triggered]), complemento([by, the, expression, of, the, transcription, factor, 'sex-determining', region, 'Y', '(', 'Sry)'])].
[sujeto(['Several', epigenetic, 'modifiers,', transcription, factors, and, kinases, are, implicated, in]), verbo([regulating]), complemento(['Sry', 'transcription,', but, it, remains, unclear, whether, or, how, this, farrago, of, factors, acts, 'co-ordinately'])].
[sujeto(['Here', we, review, our, current, understanding, of, 'Sry', regulation, and]), verbo([provide]), complemento([a, model, that, assembles, all, known, regulators, into, three, 'modules,', each, converging, on, a, single, transcription, factor, that, binds, to, the, 'Sry', promoter])].
[sujeto(['We', also, discuss, potential, future, avenues, for, discovering, the, 'cis-elements', and, 'trans-factors']), verbo([required]), complemento([for, 'Sry', regulation])].
[sujeto(['The', 'Y-chromosomal', gene, 'SRY']), verbo([acts]), complemento([as, the, primary, trigger, for, male, sex, determination, in, mammalian, embryos])].
[sujeto(['However,', the, 'cis-sequences']), verbo([involved]), complemento([in, regulation, of, 'Sry', have, not, been, 'identified,', precluding, a, test, of, this, hypothesis])].
[sujeto(['To', avoid, problems]), verbo([associated]), complemento([with, conventional, pronuclear, injection, of, 'transgenes,', we, used, a, published, strategy, designed, to, yield, 'single-copy', transgene, integration, at, a, 'defined,', transcriptionally, 'open,', autosomal, 'locus,', 'Col1a1'])].
[sujeto(['None', of, the, 'Sry', transgenes, tested, was]), verbo([expressed]), complemento([at, levels, compatible, with, activation, of, 'Sox9', or, 'XX', sex, reversal])].
[sujeto(['Our', findings, indicate, either, that, the, 'Col1a1', locus, does, not]), verbo([provide]), complemento([an, appropriate, context, for, the, correct, expression, of, 'Sry', 'transgenes,', or, that, the, 'cis-sequences', required, for, 'Sry', expression, in, the, developing, gonads, lie, beyond, 8, kb, 5, '\'', of, the, 'TSS'])].
[sujeto(['The', full, length, of, 'ZP3', cDNA, was, firstly, characterized, and, its, tissue, distribution, revealed, that, 'ZP3', mRNA, was, predominantly]), verbo([expressed]), complemento([in, ovary, of, 'G'])].
[sujeto(['The', 5, '\'', flanking, regions, of, 'ZP2', and, 'ZP3', were, isolated, and, the, comparison, of, transcription, factors, in, the, regions, of, 'ZP2', and, 'ZP3']), verbo([suggested]), complemento([that, the, disparity, for, the, responsiveness, of, 'ZP2', and, 'ZP3', to, 'EE2', could, partly, be, a, result, of, differential, 'cis-elements', such, as, 'oocyte-specific', protein, '(', 'Osp1)', binding, sites, 'or/and', 'sex-determining', region, 'Y', '(', 'SRY)', binding, site])].
[sujeto(['To']), verbo([provide]), complemento([a, summary, of, the, recent, major, advances, in, the, field, of, molecular, genetics, and, understanding, of, psychosexual, 'development,', as, these, developments, have, resulted, in, changes, in, terminology, and, classification, of, disorders, of, sexual, differentiation, '(', 'DSD)/intersex;', and, to, provide, a, quick, and, simplified, review, of, the, basic, information])].
[sujeto(['The', newly, proposed, terminology, and, classification]), verbo([has]), complemento([eliminated, some, confusion, for, both, patient, and, 'family,', as, well, as, among, health, professionals])].
[sujeto(['The', new, advances]), verbo([have]), complemento([facilitated, the, categorisation, of, gonadal, malignancy, in, patients, with, 'DSD', into, 'high-,', 'intermediate-', and, 'low-risk', groups])].
[sujeto(['More', molecular, genetics, studies, will, allow, a, better, understanding, of, the]), verbo([causes]), complemento([of, each, condition, of, 'DSD'])].
[sujeto([',', 'Swyer', 'syndrome),', 'SRY', 'mutations,', residing, in, the, 'HMG', '(', 'High', 'Mobility', 'Group)', 'domain,', are]), verbo([found]), complemento([to, affect, nuclear, transport, or, binding, to, and, bending, of, 'DNA'])].
[sujeto(['Mutations', in, 'SRY', as, well, as, 'WT1', can]), verbo([lead]), complemento([to, diminished, expression, and, function, of, 'SRY,', resulting, in, 'sub-optimal', 'SOX9', 'expression,', 'Sertoli', cell, formation, and, subsequent, lack, of, proper, testicular, development])].
[sujeto(['Embryonic', germ, cells, residing, in, this, unfavourable, 'micro-environment']), verbo([have]), complemento([an, increased, risk, for, malignant, transformation])].
[sujeto(['Occurrence', of, a, delayed, progressive, kidney, failure, '(', focal, segmental, glomerular, 'sclerosis)']), verbo([triggered]), complemento([analysis, of, 'WT1,', revealing, a, pathogenic, 'splice-site', mutation, in, intron, 9])].
[sujeto(['Analysis', of, the, 'SRY', gene, in, an, additional, five, 'FS', cases, did, not]), verbo([reveal]), complemento([any, mutations])].
[sujeto(['The', case, presented, shows, the, importance, of, 'multi-gene', based, diagnosis, of, 'DSD', 'patients,', allowing, early, diagnosis, and, 'treatment,', thus]), verbo([preventing]), complemento([putative, development, of, an, invasive, cancer])].
[sujeto(['SRY', is, a, transcription, factor, and, together, with, 'SF1', it, directly, 'up-regulates', the, expression, of, the, pivotal, 'sex-determining', gene, 'Sox9', via, a, 1.3, -, kb, 'cis-regulatory', element, '(', 'TESCO)', which, contains, an, evolutionarily]), verbo([conserved]), complemento([region, '(', 'ECR)', of, 180, &, 'nbsp;bp'])].
[sujeto(['Remarkably,', several, rodent, species, appear, to, determine, sex, in, the, absence, of, 'Sry', and, a, 'Y', 'chromosome,', including, the, mole, voles, 'Ellobius', lutescens, and, 'Ellobius', 'tancrei,', whereas, 'Ellobius', fuscocapillus, of, the, same, genus]), verbo([retained]), complemento(['Sry'])].
[sujeto(['We']), verbo([have]), complemento([cloned, and, sequenced, 1.1, &, 'nbsp;kb', of, 'E'])].
[sujeto([lutescens, might, still, be]), verbo([regulated]), complemento([via, 'TESCO'])].
[sujeto(['We']), verbo([have]), complemento([also, cloned, and, sequenced, the, 'ECRs', of, 'E'])].
[sujeto(['While', the, three, 'Ellobius', 'ECRs', are, highly, similar, '(', 94, -, 97, '%', sequence, 'identity),', they, all, display, a, 14, -, bp, deletion, '(', 'Δ14)', removing, a, highly]), verbo([conserved]), complemento(['SOX/TCF', site])].
[sujeto(['Introducing', 'Δ14', into, mouse, 'TESCO']), verbo([increased]), complemento([both, basal, activity, and, 'SF1-mediated', activation, of, 'TESCO', in, 'HEK293T', cells])].
[sujeto(['We', propose, a, model, whereby, 'Δ14', may]), verbo([have]), complemento([triggered, 'up-regulation', of, 'Sox9', in, 'XX', gonads, leading, to, destabilization, of, the, 'XY/XX', 'sex-determining', mechanism, in, 'Ellobius'])].
[sujeto([fuscocapillus, could]), verbo([have]), complemento([independently, stabilized, their, sex, determination, mechanisms, by, 'Sry-independent', and, 'Sry-dependent', 'approaches,', respectively])].
[sujeto(['The', mechanism, of, donor, choice]), verbo([ensuring]), complemento([that, switching, occurs, primarily, and, productively, to, the, opposite, 'type,', called, 'directionality,', is, largely, unknown])].
[sujeto(['A', previously, 'unrecognized,', shorter, swi2, 'mRNA,', a, truncated, form, of, the, 'swi2,', was, 'identified,', and, its, expression]), verbo([requires]), complemento([the, 'mat1-Mc', function])].
[sujeto(['We', also]), verbo([found]), complemento([that, the, abp1, gene, '(', human, 'CENPB', 'homolog)', controls, directionality, through, swi2, regulation])].
[sujeto(['Sex', determining, region, 'Y', '(', 'SRY)-box', 2, '(', 'SOX2)', anophthalmia, syndrome, is, an, autosomal, dominant, disorder, manifesting, as, severe, developmental, eye, malformations]), verbo([associated]), complemento([with, 'brain,', 'esophageal,', 'genital,', and, kidney, abnormalities])].
[sujeto(['The', syndrome, is, usually]), verbo([caused]), complemento([by, de, novo, mutations, or, deletions, in, the, transcription, factor, 'SOX2'])].
[sujeto(['In', keeping, with, several, genetic, 'disorders,', we]), verbo([found]), complemento([that, 'SOX2', mutations, were, associated, with, older, parental, age, and, the, difference, was, statistically, significant, for, mothers, '(', 'p=0'])].
[sujeto(['With', the, current, sample, 'size,', there, was, no, evidence, that, sequence, variants, in, cis, surrounding, 'SOX2']), verbo([confer]), complemento([susceptibility, to, either, mutations, or, deletions])].
[sujeto(['CD133']), verbo([has]), complemento([been, recognized, as, a, specific, cell, surface, marker, for, cancer, stem, cells, in, various, 'tumors,', although, its, biological, functions, and, transcriptional, regulation, remain, unclear])].
[sujeto(['We']), verbo([found]), complemento([that, the, 'CD133', expression, level, was, 'up-regulated', in, the, lung, cancer, cell, lines, 'N417,', 'H358,', and, 'A549,', when, these, cell, lines, were, cultured, under, hypoxic, conditions])].
[sujeto(['Among', the, five, promoters, '(', 'P1-P5)', of, human, 'CD133', gene, 'loci,', 'P1', promoter, was, most, strongly]), verbo([associated]), complemento([with, 'hypoxia-induced', promoter, activity, of, 'CD133', gene, expression])].
[sujeto(['The', chromatin, immunoprecipitation, assay, further, confirmed, the, direct]), verbo([binding]), complemento([of, 'Octamer', biding, 'trans-cription', factor, 3, /, 4, '(', 'OCT4)', 'and/or', 'SRY-box', containing, 'gene 2', '(', 'SOX2)', to, the, 'P1', promoter, region, of, 'CD133', gene, loci])].
[sujeto(['In', 'addition,', the, enhancement, of, both, 'OCT4', and, 'SOX2', expression, by, the, α, subunit, of, 'hypoxia-inducible', factors, '(', 'HIF1α', and, 'HIF2α)', was]), verbo([required]), complemento([for, 'hypoxia-induced', 'CD133', expression])].
[sujeto(['Knockdown', of, 'OCT4', or, 'SOX2', expression, in, 'N417', cells, with, stabilized, 'HIF1α', 'and/or', 'HIF2α', abolished, 'CD133P1', 'activity,', while, ectopic, 'OCT4', or, 'SOX2', expression]), verbo([triggers]), complemento(['CD133P1', activity, in, the, absence, of, 'HIF1α', or, 'HIF2α'])].
[sujeto(['Thus,', in, the, hypoxic, 'conditions,', 'OCT4', and, 'SOX2,', both, of, which, are]), verbo([induced]), complemento([by, 'HIF1α/HIF2α'])].
[sujeto([',', sets, of]), verbo([expressed]), complemento([transcription, 'factors,', define, the, gene, expression, capabilities, of, cells, in, animal, development])].
[sujeto(['Here', we, explore, the, functional, significance, of, an, unprecedented, example, of, regulatory, state, conservation, from, the, cnidarian, 'Nematostella', to, 'Drosophila,']), verbo([sea]), complemento(['urchin,', 'fish,', and, mammals])].
[sujeto(['Our', probe, is, a, deeply]), verbo([conserved]), complemento(['cis-regulatory', 'DNA', module, of, the, 'SRY-box', 'B2', '(', 'soxB2),', recognizable, at, the, sequence, level, across, many, phyla])].
[sujeto(['Transphyletic', 'cis-regulatory', 'DNA', transfer, experiments]), verbo([reveal]), complemento([that, the, plesiomorphic, control, function, of, this, module, may, have, been, to, respond, to, a, regulatory, state, associated, with, neuronal, differentiation])].
[sujeto(['By', introducing, expression, constructs, driven, by, this, module, from, any, phyletic, source, into, the, genomes, of, diverse, developing, 'animals,', we, discover, that, the, regulatory, state, to, which, it]), verbo([responds]), complemento([is, used, at, different, levels, of, the, neurogenic, developmental, 'process,', including, patterning, and, development, of, the, vertebrate, forebrain, and, neurogenesis, in, the, 'Drosophila', optic, lobe, and, brain])].
[sujeto(['The', regulatory, state]), verbo([recognized]), complemento([by, the, conserved, 'DNA', sequence, may, have, been, redeployed, to, different, levels, of, the, developmental, regulatory, program, during, evolution, of, complex, central, nervous, systems])].
[sujeto(['Since', on, the, canine, chromosome, 23, '(', 'CFA23)', 3, genes, '(', 'FOXL2,PISRT1', and, 'CTNNB1)']), verbo([involved]), complemento([in, the, sex, determination, process, are, 'present,', further, cytogenetic, 'FISH', studies, were, carried, out, with, the, use, of, 'BAC', probes, specific, for, this, chromosome])].
[sujeto(['It', was]), verbo([found]), complemento([that, a, pericentromeric, fragment, of, 'CFA23', was, deleted, as, a, result, of, the, centric, fusion])].
[sujeto(['Acquired', during, early, 'development,', the, cell, 'type-specific', epigenotype, is]), verbo([maintained]), complemento([by, cellular, memory, mechanisms, that, involve, epigenetic, modifications])].
[sujeto(['Here', we, present, the, epigenetic, status, of, the, euchromatic, region, of, the, human, 'Y', chromosome, that]), verbo([has]), complemento([mostly, been, ignored, in, earlier, whole, genome, epigenetic, mapping, studies])].
[sujeto(['Using', 'ChIP-on-chip', 'approach,', we, mapped, 'H3K9ac,', 'H3K9me3,', 'H3K27me3', modifications, and, 'CTCF']), verbo([binding]), complemento([sites, while, 'DNA', methylation, analysis, of, selected, 'CpG', islands, was, done, using, bisulfite, sequencing])].
[sujeto(['The', combination, of, histone, and, 'DNA', 'modifications,', along, with, 'CTCF', association, in, some, 'cases,']), verbo([reveals]), complemento([the, transcriptional, potential, of, all, protein, coding, genes, including, the, 'sex-determining', gene, 'SRY', and, the, oncogene, 'TSPY'])].
[sujeto(['We', also, observe, preferential, association, of, histone, marks, with, different, tandem, 'repeats,']), verbo([suggesting]), complemento([their, importance, in, genome, organization, and, gene, regulation])].
[sujeto(['Individuals', with, rare, cytogenetic, variants]), verbo([have]), complemento([contributed, to, our, understanding, of, the, genetics, of, sex, development, and, its, disorders])].
[sujeto(['Here,', we]), verbo([report]), complemento([on, a, child, with, a, de, novo, 12, ;, 17, 'translocation,', 46, ',', 'XX,t(12;17)(q14'])].
[sujeto(['Thus,', the, 12, ;, 17, translocation, removed, part, of, the, 'SOX9', 'cis-regulatory', region, and, replaced, it, with, a, regulatory, element, from, pseudogene, 'LOC204010', or, the, next, 'gene,', 'Deynar,', of, chromosome, 12, ',', potentially]), verbo([causing]), complemento(['up-regulation', of, the, 'testis-determining', 'SOX9', gene, during, gonadal, development, and, the, phenotype, of, 46, ',', 'XX', testicular, 'DSD'])].
[sujeto(['To']), verbo([gain]), complemento([further, insights, on, the, genetic, divergence, and, the, 'species-specific', characteristics, of, the, 'follicle-stimulating', hormone, receptor, '(', 'FSHR),', we, cloned, 946, bp, of, the, 5, '\'', -, flanking, region, of, the, 'FSHR', gene, from, the, volcano, mouse, '(', 'Neotomodon', alstoni, 'alstoni),', and, compared, its, features, with, those, from, other, mammalian, species])].
[sujeto(['The', low, transcription, levels, detected, in, 'MSC-1', cells, probably, reflect, the, recruitment, of, 'Sertoli', 'cells-specific']), verbo([nuclear]), complemento([factors, that, repress, transcription, of, the, 'FSHR', gene])].
[sujeto(['Functional', analysis, of, a, series, of, progressive, 5, '\'', -, deletion, mutants, identified, regions]), verbo([involved]), complemento([in, positive, and, negative, transcriptional, regulation, as, well, as, the, strongest, minimal, promoter, spanning, 260, bp, upstream, the, translation, initiation, site])].
[sujeto(['The', identification, of, inhibitory]), verbo([nuclear]), complemento([transcription, 'factors,', which, are, apparently, expressed, in, 'MSC-1', 'cells,', may, contribute, to, a, better, understanding, of, the, transcriptional, regulation, of, the, 'FSHR', gene])].
[sujeto(['Thus', 'far,', only, a, handful, of, direct]), verbo([target]), complemento([genes, are, known, for, this, transcription, factor, limiting, our, understanding, of, the, biological, network, it, governs])].
[sujeto(['We', describe, identification, of, multiple, direct, regulatory]), verbo([target]), complemento([genes, of, 'Sox10', through, a, procedure, based, on, function, and, conservation])].
[sujeto(['By', combining, 'RNA', interference, technique, and, 'DNA', microarray, 'technology,', we]), verbo([have]), complemento([identified, a, set, of, genes, that, show, significant, 'down-regulation', upon, introduction, of, 'Sox10', specific, siRNA, into, 'Schwannoma', cells])].
[sujeto(['Subsequent', comparative, genomics, analyses]), verbo([led]), complemento([to, potential, binding, sites, for, 'Sox10', protein, conserved, across, several, mammalian, species, within, the, genomic, region, proximal, to, these, genes])].
[sujeto(['Multiple', sites, belonging, to, 4, different, genes, '(', proteolipid, 'protein,', 'Sox10,', extracellular, superoxide, 'dismutase,', and, 'pleiotrophin)', were, shown, to, directly]), verbo([interact]), complemento([with, 'Sox10', by, chromatin, immunoprecipitation, assay])].
[sujeto(['In', 'sum,', the, process, of, combining, differential, expression, profiling, and, comparative, genomics, successfully]), verbo([led]), complemento([to, further, defining, the, role, of, 'Sox10,', a, critical, transcription, factor, for, the, development, of, peripheral, glia])].
[sujeto(['The', 'Sry-related', 'high-mobility-group', box, transcription, factor, 'Sox9']), verbo([recruits]), complemento([the, redundant, 'L-Sox5', and, 'Sox6', proteins, to, effect, 'chondrogenesis,', but, the, mode, of, action, of, the, trio, remains, unclear])].
[sujeto(['We', identify, here, a, highly]), verbo([conserved]), complemento([359, -, bp, sequence, 10, kb, upstream, of, the, 'Agc1', gene, for, 'aggrecan,', a, most, essential, cartilage, proteoglycan, and, key, marker, of, chondrocyte, differentiation])].
[sujeto(['The', chondrogenic, trio, is]), verbo([required]), complemento([and, sufficient, to, mediate, the, activity, of, this, enhancer])].
[sujeto(['It']), verbo([acts]), complemento(['directly,', 'Sox9', binding, to, a, critical, 'cis-acting', element, and, 'L-Sox5/Sox6', binding, to, three, additional, 'elements,', which, are, cooperatively, needed])].
[sujeto(['Upon']), verbo([binding]), complemento([to, their, specific, 'sites,', 'L-Sox5/Sox6', increases, the, efficiency, of, 'Sox9', binding, to, its, own, recognition, site, and, thereby, robustly, potentiates, the, ability, of, 'Sox9', to, activate, the, enhancer])].
[sujeto(['L-Sox5/Sox6', similarly, secures, 'Sox9']), verbo([binding]), complemento([to, 'Col2a1', '(', encoding, 'collagen-2)', and, other, 'cartilage-specific', enhancers])].
[sujeto(['This', study, thus, uncovers, critical, 'cis-acting', elements, and, transcription, factors, driving, 'Agc1', expression, in, cartilage, and]), verbo([increases]), complemento([understanding, of, the, mode, of, action, of, the, chondrogenic, 'Sox', trio])].
[sujeto(['Several', genes, or, loci]), verbo([associated]), complemento([with, plasma, 'HDL-cholesterol', levels, have, been, identified, on, autosomes, and, the, 'X', chromosome])].
[sujeto(['In', 'contrast,', genes, or, loci, on, the, 'Y', chromosome]), verbo([have]), complemento([not, attracted, significant, attention, hitherto])].
[sujeto(['We', obtained, the, following, results, from, the, genotype, data, on, 30, single, nucleotide, polymorphisms, '(', 'SNPs),', including, nonsynonymous, and, synonymous, 'SNPs', and, 9, polymorphisms, in, 'Sry:', '(', 1, ')', 'Variation', in, rs46947134, of, 'Uty', was, significantly]), verbo([associated]), complemento([with, plasma, 'HDL-cholesterol', levels])].
[sujeto(['(', 2, ')', 'A', 'CAG', repeat, number, polymorphism, in, 'Sry', was, significantly]), verbo([associated]), complemento([with, plasma, 'HDL-cholesterol', levels])].
[sujeto(['We', identified, several, variants]), verbo([associated]), complemento([with, plasma, 'HDL-cholesterol', levels])].
[sujeto(['Because', the, physiological, significance, of, various, 'Y-linked', genes, remains, 'unclear,', the, results, of, this, study, will]), verbo([provide]), complemento([further, insights, into, the, functions, of, 'Y-linked', genes, in, lipid, metabolism])].
[sujeto(['Excess', cardiovascular, risk, in, men, compared, with, women]), verbo([has]), complemento([been, suggested, to, be, partly, explained, by, effects, of, the, 'Y', chromosome])].
[sujeto(['However,', inconsistent, results]), verbo([have]), complemento([been, reported, on, the, 'Y', 'chromosome\'s', genetic, influence, on, blood, pressure, and, lipid, levels])].
[sujeto(['The', prevalence, of, hypertension, tended, to, be, higher, in, 'YAP(+)', than, in, 'YAP(-)', 'men,', and, this, tendency, was]), verbo([found]), complemento([to, be, stronger, among, men, aged, 65, years, or, older])].
[sujeto(['In', 'conclusion,', 'Y', chromosome, polymorphisms, '(', 'YAP,', 'M175', and, 'SRY+465)', do, not, appear, to, be]), verbo([associated]), complemento([with, cardiovascular, risk, factors, in, 'Japanese', men])].
[sujeto(['Studies', using, much, larger, sample, sizes, 'and/or', additional, independent, samples, will, be]), verbo([required]), complemento([for, definitive, conclusions])].
[sujeto(['In', 'addition,', their, effects, on, the, inflammatory, changes]), verbo([induced]), complemento([in, 'LDL-receptor', mice, fed, a, 'Western', diet, following, influenza, 'A', infection, were, studied])].
[sujeto(['When', apolipoprotein, 'AI', mimetic, peptides, synthesized, from, either, 'D-', or, 'L-amino', acids, were, administered, to, 'LDL-receptor', null, 'mice,', only, peptides, synthesized, from, 'D-amino', acids, were, stable, in, the, circulation, and]), verbo([enhanced]), complemento([the, ability, of, 'high-density', lipoprotein, '(', 'HDL)', to, protect, 'LDL', against, oxidation])].
[sujeto(['Administration', of, the, peptide, 'D-4F', to, 'LDL-receptor', null, mice, and, apoE, null, mice]), verbo([decreased]), complemento([lesion, size])].
[sujeto(['Additionally,', in, 'LDL', receptor, null, mice, after, influenza, 'infection,', 'D-4F', treatment]), verbo([increased]), complemento([plasma, 'HDL', levels, and, paraoxonase, 'activity,', and, inhibited, increased, in, 'LDL-cholesterol', and, peak, levels, of, 'interleukin-6', 'post-infection'])].
[sujeto(['Injection', of, female, mice, with, male, 'macrophages,', and, subsequent, measurement, of, the, male, '\'', 'sry\'', 'gene,', revealed, a, marked]), verbo([increase]), complemento([in, macrophage, traffic, into, the, aortic, arch, after, infection, that, was, prevented, by, administration, of, 'D-4F'])].
[sujeto(['This', indicates, 'that:', '(', 'i)', oral, 'D-4F']), verbo([has]), complemento([powerful, 'anti-atherosclerotic', 'properties,', and, '(', 'ii)', the, loss, of, the, 'anti-inflammatory', properties, of, 'HDL', after, influenza, infection, in, mice, is, associated, with, increased, arterial, macrophage, traffic, that, can, be, prevented, by, administration, of, 'D-4F'])].
[sujeto(['We']), verbo([reported]), complemento([that, 'HDL', loses, its, antiinflammatory, properties, during, acute, influenza, 'A', infection, in, 'mice,', and, we, hypothesized, that, these, changes, might, be, associated, with, increased, trafficking, of, macrophages, into, the, artery, wall])].
[sujeto(['D-4F', treatment]), verbo([increased]), complemento([plasma, 'HDL', cholesterol, and, paraoxonase, activity, compared, with, 'PBS', and, inhibited, increases, in, 'LDL', cholesterol, and, peak, levels, of, 'interleukin-6', after, infection])].
[sujeto(['Injection', of, female, mice, with, male, 'macrophages,', which, were, detected, with, 'real-time', polymerase, chain, reaction, to, measure, the, male, 'Sry', 'gene,', revealed, a, marked]), verbo([increase]), complemento([in, macrophage, traffic, into, the, aortic, arch, and, innominate, arteries, after, infection, that, was, prevented, by, administration, of, 'D-4F'])].
[sujeto(['We', conclude, that]), verbo([loss]), complemento([of, antiinflammatory, properties, of, 'HDL', after, influenza, infection, in, mice, is, associated, with, increased, arterial, macrophage, traffic, that, can, be, prevented, by, administration, of, 'D-4F'])].
[sujeto(['Endothelial', progenitor, cells, '(', 'EPCs)']), verbo([provide]), complemento([paracrine, support, to, the, vascular, endothelium, and, may, also, replace, damaged, or, senescent, endothelial, cells])].
[sujeto(['We', hypothesized, that, the, number, of, 'CFU-ECs', derived, from, maternal, blood, are]), verbo([decreased]), complemento([in, women, with, preeclampsia, compared, to, normal, pregnancy])].
[sujeto(['Previous', work]), verbo([suggested]), complemento([that, there, were, 'X-linked', 'parent-of-origin', effects, on, the, phenotype])].
[sujeto(['Eighty-three', percent, of, 45, ',', 'X']), verbo([retained]), complemento([their, maternal, 'X', '(', 'X(m)),', whereas, 64, '%', 46, 'Xi(Xq)', retained, their, paternal, 'X', '(', 'X(p),', 'P', &, 'lt;', 0.001, ')'])].
[sujeto(['Kidney', malformations, were, exclusively]), verbo([found]), complemento([in, 'X(m)', patients, '(', 'P', =, 0.03, ')'])].
[sujeto(['The', 'X(m)', group, had, lower, total, and, 'low-density', lipoprotein, cholesterol, '(', 'P', &, 'lt;', 0.003, ')', ',', and, higher, body, mass, index, sd, score, '(', 'P', =, 0.03, ')', that, was, not]), verbo([maintained]), complemento([after, 'GH', treatment])].
[sujeto(['The', parental, origin, of, the, missing, short, arm, of, the, 'X', chromosome]), verbo([has]), complemento([an, impact, on, 'overweight,', 'kidney,', 'eye,', and, 'lipids,', which, suggests, a, potential, effect, of, an, 'as-yet-undetermined', 'X', chromosome, gene, imprinting])].
[sujeto(['The', critical, role, of, monocyte, recruitment, in, atherogenesis]), verbo([has]), complemento([been, appreciated, for, some, time])].
[sujeto(['However,', until, 'recently,', there]), verbo([have]), complemento([been, no, sufficiently, sensitive, methods, for, measuring, rates, of, monocyte, recruitment, to, the, arterial, wall, in, vivo])].
[sujeto(['We']), verbo([have]), complemento([developed, a, novel, highly, sensitive, 'method,', based, on, the, polymerase, chain, 'reaction,', for, quantitatively, tracking, 'DNA-marked', monocytes, and, have, adapted, it, for, use, in, mice])].
[sujeto(['In', control, low, density, lipoprotein, 'receptor-negative', 'mice,', monocyte, recruitment]), verbo([decreased]), complemento([slightly, but, significantly, as, lesions, progressed])].
[sujeto(['Intrauterine', exposure, to, 5, -, 'AZA-2\'-deoxycytidine', '(', 5, -, 'AZA-CdR)', alters, gene, expression]), verbo([causing]), complemento(['malformations,', abnormal, 'post-natal', growth, and, altered, reproductive, capacity])].
[sujeto(['While', normal, presence, of, 'Sry', gene, was, 'observed,', mating, behavior, was, altered, in, exposed, males]), verbo([suggesting]), complemento([that, the, reproductive, alteration, could, be, attributed, to, a, behavioral, phenomenon])].
[sujeto(['The', tissues, from, the, tumor, and, its, periphery, carry, a, significantly]), verbo([increased]), complemento([number, of, 'SRY', copies, compared, to, its, neighboring, common, breast, tissue, '(', p, =, 0.005, ')'])].
[sujeto(['We']), verbo([found]), complemento([a, heterogeneous, distribution, of, fetal, microchimerism, in, breast, cancer, environment])].
[sujeto(['Are', 'Y-chromosome', microdeletions]), verbo([associated]), complemento([with, 'SHOX', 'haploinsufficiency,', thus, representing, a, risk, of, skeletal, anomalies, for, the, carriers, and, their, male, 'descendents?', 'The', present, study, shows, that, 'SHOX', haploinsufficiency, is, unlikely, to, be, associated, with, 'Y-chromosome', microdeletions])].
[sujeto(['Y-chromosome', microdeletions, are, not, commonly, known, as, a, major, molecular, genetic]), verbo([cause]), complemento([of, any, pathological, condition, except, spermatogenic, failure])].
[sujeto(['However,', it]), verbo([has]), complemento([been, recently, proposed, that, they, are, associated, not, only, with, infertility, but, also, with, anomalies, in, the, pseudoautosomal, regions, '(', 'PAR),', among, which, 'SHOX', haploinsufficiency, stands, out, with, a, frequency, of, 5.4, '%', in, microdeletion, carriers, bearing, a, normal, karyotype])].
[sujeto(['This']), verbo([finding]), complemento([implies, that, sons, fathered, by, men, with, 'Y-chromosome', defects, will, not, only, exhibit, fertility, 'problems,', but, might, also, suffer, from, 'SHOX-related', conditions])].
[sujeto(['No', 'SHOX', deletions, were]), verbo([found]), complemento([in, any, of, the, examined, subjects, '(', patients, as, well, as, 'controls),', thus, excluding, an, association, with, 'SHOX', haploinsufficiency])].
[sujeto(['This', might]), verbo([suggest]), complemento([that, 'Y-chromosome', microdeletions, have, a, higher, incidence, for, 'SHOX', 'duplications,', irrespective, of, the, 'patient\'s', karyotype])].
[sujeto(['The', number, of, controls, analyzed, is, rather, low, to, assess, whether, the, 'SHOX', duplications]), verbo([found]), complemento([in, the, two, men, with, 'Y-chromosome', microdeletions, and, a, normal, karyotype, represent, a, neutral, polymorphism, or, are, actually, associated, with, the, presence, of, the, microdeletion])].
[sujeto(['Our', results, imply, that, deletion, carriers]), verbo([have]), complemento([no, augmented, risk, of, 'SHOX-related', pathologies, '(', short, stature, and, skeletal, 'anomalies)', and, indicate, that, there, is, no, need, for, radical, changes, in, genetic, counseling, of, 'Yq', microdeletion, carriers, attempting, 'ART,', since, the, only, risk, established, so, far, for, their, male, offspring, remains, impaired, spermatogenesis])].
[sujeto(['The', specifics, of, the, interstrain, variation, in, spermatogenetic, parameters, indicated, that, a, physiological, compensatory, mechanism]), verbo([increases]), complemento([certain, spermatogenetic, parameters, when, other, ones, are, low, to, maintain, male, fertility, at, a, level, sufficient, for, successful, reproduction])].
[sujeto(['The']), verbo([decreases]), complemento([in, proportion, of, motile, sperms, and, in, their, velocity, were, attributed, to, mutations, '(', 'I63T', and, 'W133L)', of, the, 'Sry', gene, in, the, 'DD/He', strain])].
[sujeto(['Clinical', indications, for, fetal, sex, determination, include, risk, of, 'X-linked', 'disorders,', a, family, history, of, conditions]), verbo([associated]), complemento([with, ambiguous, development, of, the, external, 'genitalia,', and, some, fetal, ultrasound, findings])].
[sujeto(['It', is, usually, performed, in, the, first, trimester, from, fetal, material, obtained, through, 'CVS', and, is]), verbo([associated]), complemento([with, an, approximately, 1, '%', risk, of, miscarriage])].
[sujeto(['A', multiplex, 'PCR', was, performed, for, the, simultaneous, amplification, of]), verbo([target]), complemento([sequences, of, 'SRY', and, 'DYS14', from, chromosome, 'Y,', along, with, 'RASSF1A', and, 'ACTB', sequences])].
[sujeto(['In', the, clinical, 'studies,', fetal, sex, was, correctly, diagnosed, in, 16, 'pregnancies,', and, one, case, was]), verbo([reported]), complemento([as, inconclusive])].
[sujeto(['SNV', analysis, showed, 'DAZ1/DAZ2', deletion, in, all, those, with, 'gr/gr', and, those, with, 'b1/b3', 'deletion,', 'DAZ3/DAZ4', deletion, in, those, with, 'b2/b3', 'deletion,', and, 'DAZ-SNV', sY587, deletion, in, 1, case, of, 'sY1291,', sY1197, 'deletion,', but, no, 'DAZ', deletion, was]), verbo([found]), complemento([in, 1, case, of, 'b1/b2', deletion])].
[sujeto(['The', most, common, genetic]), verbo([causes]), complemento([of, spermatogenic, failure, are, sex, chromosomal, abnormalities, '(', most, frequently, 'Klinefelter\'s', 'syndrome)', and, deletions, of, the, azoospermia, factor, '(', 'AZF)', regions, '(', 'AZFa,', 'AZFb,', and, 'AZFc)', of, the, 'Y', chromosome])].
[sujeto(['Several', studies]), verbo([have]), complemento([proposed, that, partial, 'AZFc', 'deletions/duplications', may, be, a, risk, factor, for, spermatogenic, impairment])].
[sujeto(['We', describe, a, multiplex, quantitative, 'fluorescent-polymerase', chain, reaction, '(', 'QF-PCR)', method, that, allows, simultaneous, detection, of, these, genetic]), verbo([causes]), complemento([and, risk, factors, of, male, infertility])].
[sujeto(['The', consequences, of, such, rearrangements, are, not, only]), verbo([loss]), complemento([but, also, gain, of, specific, genes])].
[sujeto(['One', hundred, and, fifty, three, haplotypes]), verbo([have]), complemento([been, discovered, in, the, human, 'Y', chromosome])].
[sujeto(['Among', 'them,', 16, gene, products]), verbo([have]), complemento([been, discovered, in, the, azoospermia, factor, region, '(', 'AZF)', and, are, related, to, spermatogenesis])].
[sujeto(['It']), verbo([has]), complemento([been, discovered, that, one, subset, of, gene, rearrangements, on, the, 'Y', 'chromosome,', &, 'quot;micro-deletions",', is, a, major, cause, of, male, infertility, in, some, populations])].
[sujeto(['Six', 'AZFs', of, the, 'Y', chromosome]), verbo([have]), complemento([been, discovered, including, 'AZFa,', 'AZFb,', 'AZFc,', and, their, combinations, 'AZFbc,', 'AZFabc,', and, partial, 'AZFc', called, 'AZFc/gr/gr'])].
[sujeto(['Different', deletions, in, 'AZF']), verbo([lead]), complemento([to, different, content, spermatogenesis, loss, from, teratozoospermia, to, infertility, in, different, populations, depending, on, their, 'Y', haplotypes])].
[sujeto(['This', article, describes, the, structure, of, the, human, 'Y', chromosome, and, investigates, the]), verbo([causes]), complemento([of, 'micro-deletions', and, their, relationship, with, male, infertility, from, the, view, of, chromosome, evolution])].
[sujeto(['Regardless', of, the, exact, 'mechanism,', 'however,', all, these, animals, would, exhibit, a, 'sex-specific', gene, expression, 'inequality,', due, to, the, different, number, of, 'X', 'chromosomes,', a, phenomenon]), verbo([inhibited]), complemento([by, a, series, of, genetic, and, epigenetic, regulatory, events, described, as, &, 'quot;dosage', 'compensation"'])].
[sujeto(['Since', adequate, available, data, is, currently, restricted, to, 'worms,', flies, and, 'mammals,', while, for, other, groups, of, 'animals,', such, as, 'reptiles,', fish, and, birds, it, is, very, 'limited,', it, is, not, yet, clear, whether, this, is, an, evolutionary]), verbo([conserved]), complemento([mechanism])].
[sujeto(['However', certain, striking, similarities]), verbo([have]), complemento([already, been, observed, among, evolutionary, distant, 'species,', such, as, 'Drosophila', melanogaster, and, 'Mus', musculus])].
[sujeto([the, ratio, of, autosomes, to, gonosomes, '(', a, process, well, understood, in, 'flies,', but, still, hypothesized, in, 'mammals),', 'b)', the, implication, of, 'non-translated,', 'sex-specific,', regulatory, 'RNAs', '(', roX, and, 'Xist,', 'respectively)', as, key, elements, in, this, process, and, the, location, of, similar, mediators, in, the, 'Z', chromosome, of, chicken, 'c)', the, inclusion, of, a, chromatin, modification, epigenetic, final, 'step,', which]), verbo([ensures]), complemento([that, gene, expression, remains, stably, regulated, throughout, the, affected, area, of, the, gonosome])].
[sujeto(['This', review, summarizes, these, points, and, proposes, a, possible, role, for, comparative, 'genetics,', as, they, seem, to, constitute, proof, of]), verbo([maintained]), complemento([cell, economy, '(', by, using, the, same, basic, regulatory, elements, in, various, different, 'scenarios)', throughout, numerous, centuries, of, evolutionary, history])].
[sujeto(['We']), verbo([found]), complemento([significantly, more, 'LH', but, not, 'FSH', peaks, per, 24, 'h,', as, estimated, by, the, 'Weibull', lambda, analysis])].
[sujeto(['In', this, group, of, patients, with, severe, hypergonadotropic, hypogonadism, due, to, a, supernumerary, 'X', 'chromosome,', higher, 'basal,', 'pulsatile,', and, total, 'LH', and, 'FSH', secretion, were]), verbo([associated]), complemento([with, significantly, more, 'LH', peaks, per, 24, h, in, comparison, with, healthy, controls])].
[sujeto(['Thus,', our, data, indicate, that, in, patients, with, 'Klinefelter', syndrome, and, 'XX', male, karyotypes, the, entire, 'hypothalamic-pituitary-gonadal', axis]), verbo([has]), complemento([undergone, functional, changes])].
[sujeto(['We']), verbo([report]), complemento([on, a, 13, -, 'year-old', boy, presenting, with, left, scrotal, hemorrhage])].
[sujeto(['A', variety, of, such, regulatory, mechanisms]), verbo([have]), complemento([been, described, so, far, and, some, of, the, more, extensively, studied, ones, are, being, discussed])].
[sujeto(['Another', model, organism, whose, sex, depends, on, the, 'X:A', 'ratio,', 'Caenorhabditis', 'elegans,']), verbo([has]), complemento([furthermore, to, provide, for, the, brief, period, of, spermatogenesis, in, hermaphrodites, '(', 'XX)', without, the, benefit, of, the, &, 'quot;male"', genes, of, the, sex, determination, pathway])].
[sujeto(['Many', reptiles]), verbo([have]), complemento([no, discernible, sex, determining, genes])].
[sujeto(['Their', sexual, fate, is, determined, by, the, temperature, of, the, environment, during, the, thermosensitive, period, '(', 'TSP)', of, 'incubation,', which]), verbo([regulates]), complemento([aromatase, activity])].
[sujeto(['However,', we]), verbo([have]), complemento([yet, to, decipher, which, of, the, two, '(', 'Z', or, 'W)', is, responsible, for, the, choice, between, males, and, females])].
[sujeto(['Similar', observations]), verbo([have]), complemento([been, described, not, only, in, 'mammals,', but, also, in, other, 'vertebrates,', emphasizing, the, need, for, further, study, of, both, normal, hormonal, regulators, of, sexual, phenotype, and, patterns, of, 'epigenetic/environmental', disruption])].
[sujeto(['This', is, due, to, the, distinct, content, of, the, 'X', and, 'Y-chromosomes', in, both, genes, and, regulatory, 'sequences,', 'SRY', being, the, key, regulator, 'Hormones', '(', 'AMH,', 'testosterone,', 'Insl3)', secreted, by, the, foetal, testis, '(', gonadal, sexual, 'dimorphism),', impede, 'Müller', duct, 'development,', masculinize, 'Wolff', duct, derivatives, and, are]), verbo([involved]), complemento([in, testicular, descent, '(', hormonal, sexual, 'dimorphism)'])].
[sujeto(['Intervertebral', disc, degeneration, is, the]), verbo([leading]), complemento([cause, of, chronic, back, pain])].
[sujeto(['Hypoxia']), verbo([induced]), complemento(['SDC4', mRNA, and, protein, expression, by, '~2'])].
[sujeto(['While', the, activity, of, the, 'SDC4', promoter, containing, hypoxia, response, element, '(', 'HRE)', was]), verbo([induced]), complemento([2, -, fold, '(', 'P<0'])].
[sujeto([5, ')', ',', the, 'HRE', mutation]), verbo([decreased]), complemento([the, activity, by, 40, '%', in, hypoxia])].
[sujeto(['Transfections', with, plasmids, coding, 'prolyl-4-hydroxylase', domain, protein, 2, '(', 'PHD2)', and, 'ShPHD2', show, that, hypoxic, expression, of, 'SDC4', mRNA, and, protein, is]), verbo([regulated]), complemento([by, 'PHD2', through, controlling, 'hypoxia-inducible', factor, 1, α, '(', 'HIF-1α)', levels])].
[sujeto(['Although', overexpression, of, 'HIF-1α', significantly]), verbo([increased]), complemento(['SDC4', protein, 'levels,', stable, suppression, of, 'HIF-1α', and, 'HIF-1β', decreased, 'SDC4', expression, by, 50, '%', in, human, 'NP', cells])].
[sujeto(['Finally,', suppression, of, 'SDC4', 'expression,', as, well, as, 'HS', 'function,', resulted, in, an, '~2-fold']), verbo([increase]), complemento([in, 'sex-determining', region, 'Y', '(', 'SRY)-box', 9, '(', 'Sox9)', 'mRNA,', and, protein, '(', 'P<0'])].
[sujeto([5, ')', and, simultaneous]), verbo([increase]), complemento([in, 'Sox9', transcriptional, activity, and, target, gene, expression])].
[sujeto(['Taken', 'together,', our, findings]), verbo([suggest]), complemento([that, in, healthy, 'discs,', 'SDC4,', through, its, 'HS', side, 'chains,', contributes, to, maintenance, of, the, hypoxic, tissue, niche, by, controlling, baseline, expression, of, 'Sox9'])].
[sujeto(['We']), verbo([report]), complemento([isolation, of, novel, splice, variants, of, chicken, 'Neuronal', 'Per-Arnt-Sim', domain, protein, 3, '(', 'cNPAS3)', gene, distinct, from, the, previously, predicted, cNPAS3, at, the, 5, '\'', end])].
[sujeto(['We', also, show, that, the, alternative, splicing, pattern, of, 'NPAS3', is]), verbo([conserved]), complemento([between, chicken, and, human])].
[sujeto(['RNA', in, situ, hybridization, indicated, that, the, expression, of, cNPAS3, in, the, developing, central, nervous, system, '(', 'CNS)', is, limited, to, the, ventricular, zone, and, only, partially, overlaps, with, that, of, chicken, 'Reelin', '(', 'cReelin),', the, only, known, regulatory]), verbo([target]), complemento([gene, of, 'NPAS3', in, the, adult, brain])].
[sujeto(['Epidermal', keratinocytes]), verbo([respond]), complemento([to, extracellular, influences, by, activating, cytoplasmic, signal, transduction, pathways, that, change, gene, expression])].
[sujeto(['Using', 'pathway-specific', transcriptional, 'profiling,', we, identified, the, genes]), verbo([regulated]), complemento([by, two, such, 'pathways,', p38, and, 'ERK'])].
[sujeto(['We', used, 'SB203580', and, 'PD98059', as, specific, inhibitors, and, 'Affymetrix', 'Hu133Av2', 'microarrays,', to, identify, the, genes]), verbo([regulated]), complemento([after, 1, ',', 4, ',', 24, ',', and, 48, h, and, compared, them, to, genes, regulated, by, 'JNK'])].
[sujeto(['Both', pathways]), verbo([promote]), complemento([epidermal, 'differentiation;', 'however,', there, is, a, surprising, disconnect, between, the, expression, of, steroid, synthesis, enzymes, and, differentiation, markers])].
[sujeto(['The', p38, pathway]), verbo([induces]), complemento([the, expression, of, extracellular, matrix, and, 'proliferation-associated', 'genes,', while, suppressing, 'microtubule-associated', genes])].
[sujeto(['The', 'ERK', pathway]), verbo([induces]), complemento([nuclear, envelope, and, mRNA, splicing, 'proteins,', while, suppressing, steroid, synthesis, and, mitochondrial, energy, production, enzymes])].
[sujeto(['Transcription', factors, 'SRY,', 'c-FOS,', and, 'N-Myc', are, the, principal]), verbo([targets]), complemento([of, the, p38, 'pathway,', 'Elk-1', 'SAP1', and, 'HLH2', of, 'ERK,', while, 'FREAC-4,', 'ARNT', and, 'USF', are, shared])].
[sujeto(['The', results]), verbo([suggest]), complemento([a, list, of, targets, potentially, useful, in, therapeutic, interventions, in, cutaneous, diseases, and, wound, healing])].
[sujeto(['Here', we, describe, how, the, interaction, between, 'Hhex', '(', hematopoietically]), verbo([expressed]), complemento(['homeobox)', and, 'SOX13', '(', 'SRY-related', high, mobility, group, box, transcription, factor, 13, ')', ',', modulates, 'Wnt/TCF', pathway, activity])].
[sujeto(['Hhex', is, a, homeodomain, factor]), verbo([expressed]), complemento([in, multiple, 'endoderm-derived', 'tissues,', like, the, 'liver,', where, it, is, essential, for, proper, development])].
[sujeto(['The', pleiotropic, expression, of, 'Hhex', during, embryonic, development, and, its, dual, role, as, a, transcriptional, repressor, and, activator]), verbo([suggest]), complemento([the, presence, of, different, 'tissue-specific', partners, capable, of, modulating, its, activity, and, function])].
[sujeto(['While', searching, for, developmentally]), verbo([regulated]), complemento(['Hhex', 'partners,', we, set, up, a, yeast, 'two-hybrid', screening, using, an, 'E9'])].
[sujeto(['We']), verbo([found]), complemento([that, 'SOX13', interacts, directly, with, 'full-length', 'Hhex,', and, we, delineated, the, interaction, domains, within, the, two, proteins])].
[sujeto(['SOX13', is, known, to]), verbo([repress]), complemento(['Wnt/TCF', signaling, by, interacting, with, 'TCF1'])].
[sujeto(['That', it, arises, from, embryonic, epiblast, cells, prior, to, gastrulation]), verbo([suggests]), complemento([that, it, may, retain, a, reservoir, of, stem, cells, throughout, pregnancy])].
[sujeto(['We']), verbo([found]), complemento([that, human, amniotic, epithelial, cells, '(', 'hAECs)', harvested, from, 'term-delivered', fetal, membranes, express, mRNA, and, proteins, present, in, human, embryonic, stem, cells, '(', 'hESCs),', including, 'POU', 'domain,', class, 5, ',', transcription, factor, 1, ;, 'Nanog', 'homeobox;', 'SRY-box', 2, ;, and, 'stage-specific', embryonic, 'antigen-4'])].
[sujeto(['In', keeping, with, possible, stem, 'cell-like', 'activity,', hAECs, were, also, 'clonogenic,', and, primary, hAEC, cultures, could, be]), verbo([induced]), complemento([to, differentiate, into, 'cardiomyocytic,', 'myocytic,', 'osteocytic,', adipocytic, '(', 'mesodermal),', 'pancreatic,', hepatic, '(', 'endodermal),', 'neural,', and, astrocytic, '(', 'neuroectodermal)', cells, in, 'vitro,', as, defined, by, 'phenotypic,', mRNA, 'expression,', 'immunocytochemical,', 'and/or', ultrastructural, characteristics])].
[sujeto(['Last,', using, flow, cytometry, we]), verbo([have]), complemento([shown, that, only, a, very, small, proportion, of, primary, hAECs, contain, class, 'IA', and, class, 'II', human, leukocyte, antigens, '(', 'HLAs),', consistent, with, a, low, risk, of, tissue, rejection])].
[sujeto(['These', observations]), verbo([suggest]), complemento([that, the, term, 'amnion,', an, abundant, and, easily, accessible, 'tissue,', may, be, a, useful, source, of, multipotent, stem, cells, that, possess, a, degree, of, immune, privilege])].
[sujeto(['Cells', showed]), verbo([increased]), complemento([hepatic, associated, gene, expression, of, 'alpha-fetoprotein', '(', 'AFP),', 'Albumin', '(', 'Alb),', 'Glucose-6-phosphatase', '(', 'G6Pc),', 'SRY', '(', sex, determining, region, 'Y)-box', 9, '(', 'Sox9),', hepatic, nuclear, factors, '(', 'HNF1a,', 'HNF1β,', 'HNF3β,', 'HNF4α,', 'HNF6,', 'Epithelial', cell, adhesion, molecule, '(', 'EpCAM),', 'Leucine-rich', 'repeated-containing', 'G-protein', coupled, receptor, 5, -, positive, '(', 'Lgr5)', and, 'Tyrosine', aminotransferase, '(', 'TAT)'])].
[sujeto(['Cells', showed]), verbo([decreased]), complemento(['fibrogenesis,', hepatic, stellate, cell, 'infiltration,', 'Kupffer', cells, and, inflammatory, cytokines])].
[sujeto(['In', 'addition,', grafted, 'MLpvNG2(+)', cells, could, mobilize, endogenous, 'stem/progenitors', to]), verbo([participate]), complemento([in, liver, repair])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'MLpvNG2(+)', cells, may, be, novel, adult, liver, progenitors, that, participate, in, liver, regeneration])].
[sujeto(['In', a, logistic, regression, model]), verbo([involving]), complemento(['demographic,', anthropometric, and, metabolic, 'variables,', only, diabetes, duration, was, significantly, associated, with, 'anti-SOX-13', 'positivity,', especially, for, duration, &, 'gt;', 5, years, '(', 'P', &, 'lt;', 0.002, ')'])].
[sujeto(['Whilst', the, frequency, of, 'anti-SOX-13', may, be]), verbo([increased]), complemento([in, some, populations, of, diabetic, 'patients,', this, reactivity, does, not, usefully, distinguish, 'Type', 1, from, 'Type', 2, diabetes])].
[sujeto(['However,', the, association, with, diabetes, duration]), verbo([suggests]), complemento([that, 'anti-SOX-13', may, be, a, 'non-specific', marker, of, tissue, damage, associated, with, chronic, hyperglycaemia])].
[sujeto(['Despite', its, essential, function, during, endoderm, formation, and, 'differentiation,', few, direct]), verbo([targets]), complemento([of, 'SOX17', are, known])].
[sujeto(['To', identify]), verbo([targets]), complemento([of, 'SOX17,', we, isolated, 'SOX17', binding, sites, with, a, chromatin, immunoprecipitation, '(', 'ChIP)-cloning', screen])].
[sujeto(['SOX17-ChIP', identified, zinc, finger, protein, 202, '(', 'Zfp202)', as, a, direct]), verbo([target]), complemento([of, 'SOX17', during, endoderm, differentiation, of, 'F9', embryonal, carcinoma, cells])].
[sujeto(['A', sequence, in, the, first, intron, of, 'Zfp202']), verbo([activated]), complemento([transcription, in, differentiated, 'F9', 'cells,', and, overexpression, of, 'Sox17', increased, the, transcriptional, activity, of, this, sequence])].
[sujeto(['SOX17']), verbo([binds]), complemento([to, a, site, within, this, sequence, in, electrophoretic, mobility, shift, 'assays,', and, mutation, of, this, site, decreases, the, transcriptional, activation])].
[sujeto(['Zfp202', is]), verbo([induced]), complemento([concomitantly, with, 'Sox17', during, endoderm, differentiation, of, 'F9', cells])].
[sujeto(['We', also, show, that, 'ZFP202']), verbo([represses]), complemento(['Hnf4a,', which, has, been, reported, for, the, human, ortholog, 'ZNF202'])].
[sujeto(['Identifying']), verbo([targets]), complemento([of, 'SOX17', will, help, to, elucidate, the, molecular, basis, of, endoderm, differentiation, and, may, provide, a, better, understanding, of, the, role, of, endoderm, in, patterning, the, other, germ, layers])].
[sujeto(['We', hypothesized, that, 'estrogen,', directly, or, 'indirectly,']), verbo([regulates]), complemento([genes, responsible, for, somatic, cell, differentiation, and, steroidogenesis])].
[sujeto(['ArKO', ovaries]), verbo([expressed]), complemento([estrogen, receptors, alpha, and, 'beta,', and, 'LH', 'receptor,', indices, of, estrogen, responsiveness, in, the, ovary])].
[sujeto(['E2']), verbo([decreased]), complemento([serum, 'FSH', and, 'LH', and, increased, uterine, weights, of, 10, -, 'wk-old', 'ArKO', mice])].
[sujeto(['Placebo-treated', 'ArKO', ovaries]), verbo([have]), complemento([increased, 'Sox9', '(', 15, -, 'fold;', 'P', &, 'lt;', 0.001, ')', ',', 'Müllerian-inhibiting', substance, '(', 2.9, -, 'fold),', 'Lrh-1', '(', 7.7, -, 'fold),', and, 'dosage-sensitive', sex, reversal, adrenal, hypoplasia, congenital, critical, region, on, the, 'X', chromosome, gene, 1, '(', 12, -, 'fold)', expression, compared, with, 'Wt', at, 10, wk])].
[sujeto(['Consistent', with]), verbo([increased]), complemento([serum, 'T', levels, and, 'Leydig', cells, in, their, 'ovaries,', 'placebo-treated', 'ArKO', ovaries, had, increased, 17, 'alpha-hydroxylase,', 17, 'beta-hydroxysteroid', dehydrogenase, 'type-3,', and, 17, 'beta-hydroxysteroid', dehydrogenase, 'type-1', expression, compared, with, 'Wt', at, 10, wk])].
[sujeto(['E2', treatment, for, 3, wk, improved, the, ovarian, 'phenotype,']), verbo([decreased]), complemento([development, of, 'Sertoli', 'cells,', decreased, the, expression, of, 'Sox9,', 'Lrh-1,', and, the, steroidogenic, enzymes, in, 'ArKO', 'ovaries,', and, induced, ovulation, in, some, cases])].
[sujeto(['In', 'conclusion,', the, expression, of, the, genes]), verbo([regulating]), complemento([somatic, cell, differentiation, is, directly, or, indirectly, responsive, to, estrogen])].
[sujeto(['We', aimed, to, identify, the, genetic]), verbo([cause]), complemento([in, a, cohort, of, 11, unrelated, cases, and, two, sisters, with, 46, ',', 'XX', 'SRY-negative', '(', 'ovo)testicular', disorders, of, sex, development, '(', 'DSD)'])].
[sujeto(['Whole-exome', sequencing, '(', n, =, 9, ')', ',']), verbo([targeted]), complemento([resequencing, '(', n, =, 4, ')', ',', and, haplotyping, were, performed])].
[sujeto(['The', 'Arg92', residue, is, highly]), verbo([conserved]), complemento([and, located, in, the, 'Ftz-F1', 'region,', probably, involved, in, 'DNA-binding', specificity, and, stability])].
[sujeto(['Transcriptomics', in, 'patient-derived', lymphocytes, showed, upregulation, of, 'MAMLD1,', a, direct, 'NR5A1']), verbo([target]), complemento([previously, associated, with, 46, ',', 'XY', 'DSD'])].
[sujeto(['We', propose, 'NR5A1,', previously]), verbo([associated]), complemento([with, 46, ',', 'XY', 'DSD', and, 46, ',', 'XX', primary, ovarian, 'insufficiency,', as, a, novel, gene, for, 46, ',', 'XX', '(', 'ovo)testicular', 'DSD'])].
[sujeto(['(', 'Arg92Trp)', results, in]), verbo([decreased]), complemento([inhibition, of, the, male, developmental, pathway, through, downregulation, of, female, antitestis, 'genes,', thereby, tipping, the, balance, toward, testicular, differentiation, in, 46, ',', 'XX', individuals])].
[sujeto([ff1d, is, a, novel, zebrafish, 'FTZ-F1', gene, with, sequence, characteristics, indicating, similar, basic, regulatory, mechanisms, as, the, previously, characterized, ff1, based, on, the, presence, of, an, 'FTZ-F1', box, in, the, 'DNA']), verbo([binding]), complemento([domain, and, an, interactive, domain, '(', 'I-Box)', and, an, 'AF-2', in, the, ligand, binding, domain])].
[sujeto(['The', highest, sequence, similarity, was]), verbo([found]), complemento([between, ff1d, and, ff1b, '(', 'NR5A4),', a, gene, previously, shown, to, be, a, functional, homolog, to, the, steroidogenic, factor, 1, '(', 'SF-1)'])].
[sujeto(['SF-1', is, crucial, in, mammalian, steroidogenesis, and, in, sex, determination, by]), verbo([regulating]), complemento([the, 'anti-Mullerian', hormone, '(', 'AMH)'])].
[sujeto(['In', 'fish,', 'AMH']), verbo([has]), complemento([not, been, described, previously])].
[sujeto(['AMH', was, detected, in, growing, 'oocytes,', the, ovarian, follicular, layer, and, testicular, 'Sertoli', 'cells,', similar, to, the, mammalian, 'pattern,']), verbo([suggesting]), complemento([a, conserved, role, between, zebrafish, and, mammalian, 'AMH'])].
[sujeto(['Comparison', of, sequences, and, expression, patterns, indicate, that, ff1d, is, a, new, candidate, for, sex, determination, and, differentiation, in, a, way, similar, to, 'SF-1,', possibly]), verbo([involving]), complemento(['AMH'])].
[sujeto(['The', study, of, naturally, occurring, mutations, in, humans, and]), verbo([induced]), complemento([mutations, in, mice, that, cause, sex, reversal, has, been, instrumental, in, the, cloning, and, functional, analysis, of, genes, involved, in, gonadal, differentiation])].
[sujeto(['Several', genes]), verbo([required]), complemento([for, this, complex, developmental, process, have, now, been, identified])].
[sujeto(['The', genes, 'LIM1,', 'WT1', and, 'FTZ-F1']), verbo([have]), complemento([been, demonstrated, to, be, involved, in, the, formation, of, the, gonads, prior, to, their, differentiation, as, testes, or, ovaries])].
[sujeto(['Subsequent', 'sex-specific', gonadal, differentiation, appears, to, be]), verbo([mediated]), complemento([by, the, 'SRY', and, 'SOX9', genes, in, the, 'testis,', and, the, 'DAX-1', gene, in, the, ovary])].
[sujeto(['Mammals']), verbo([have]), complemento([two, genes, '(', 'SRY', and, 'DMT1)', for, testis, 'formation-androgenesis,', an, 'anti-testis', 'gene,', 'DAX1,', an, 'anti-Müllerian', duct, 'hormone,', and, steroid, sex, hormones])].
[sujeto(['However,', the, statement, that, insects, do, not]), verbo([have]), complemento([sex, hormones, loses, much, of, its, credibility, if, one, considers, '(', 1, ')', the, classical, endocrinological, work, on, sexual, differentiation, in, the, firefly, 'Lampyris', and, in, the, hevea, tussock, moth, 'Orgyia;', '(', 2, ')', the, recent, identification, of, an, androgenic, hormone, and, its, role, in, sex, determination, in, the, isopod, 'Armadillidium;', '(', 3, ')', the, similarity, between, steroidogenic, factor, 1, '(', 'SF-1)', of, mammals, and, fushi, tarazu, factor, 1, '(', 'FTZ-F1)', of, 'Drosophila;', and, '(', 4, ')', the, steroidogenic, effect, of, gonadotropins, secreted, by, the, brain, of, female, locusts, and, mosquitoes, and, of, male, gypsy, moth])].
[sujeto(['In', 'mammals,', the, presence, of, 'SRY,', the, 'sex-determining', gene, located, on, the, 'Y', chromosome, is]), verbo([required]), complemento([to, induce, the, gonadal, anlage, to, differentiate, as, a, 'testis,', whereas, its, absence, leads, to, the, development, of, an, ovary])].
[sujeto(['We']), verbo([report]), complemento([here, the, characterization, by, 5, '\'', and, 3, '\'', 'RACE', analysis, of, several, 'SRY', transcripts, which, are, expressed, in, the, ovine, male, developing, gonads])].
[sujeto(['These', transcripts, were, not, detected, in, any, other, fetal, tissues, and, were]), verbo([expressed]), complemento([only, in, the, genital, portion, of, the, urogenital, ridge])].
[sujeto(['The', temporal, profile, of, 'SRY', expression, analyzed, by, 'RT-PCR']), verbo([suggests]), complemento([that, in, the, sheep, fetus, the, role, of, 'SRY', is, not, limited, to, initiating, 'Sertoli', cell, differentiation, as, in, mice])].
[sujeto(['In', addition, to, 'SRY,', other, genes, are, known, to, be]), verbo([involved]), complemento([in, mammalian, sex, 'determination:', 'Wilms\'', tumor, gene, 'WT-1,', steroidogenic, factor, gene, 'Ftz-F1', '(', 'SF-1)', and, 'anti-Müllerian', hormone, '(', 'AMH)'])].
[sujeto(['In', 'female,', we]), verbo([have]), complemento([observed, the, presence, of, 'SF-1', transcripts, from, the, undifferentiated, stage, until, birth])].
[sujeto(['These', data]), verbo([reveal]), complemento([significant, differences, between, rodent, and, ruminant, models, concerning, the, 'sex-determining', pathway])].
[sujeto(['However,', the, indifferent, gonad]), verbo([has]), complemento([two, 'options,', to, form, either, a, testis, or, an, 'ovary,', and, mutations, of, this, tissue, usually, produce, sex, reversal, or, sterility, which, is, not, lethal, for, the, individual])].
[sujeto(['The', studies, of, human, patients, showing, different, types, of, sex, 'reversal,', in, combination, with, the, use, of, transgenic, mice, 'and/or', gene]), verbo([targeting]), complemento(['disruption,', have, led, to, the, isolation, of, several, genes, important, for, sex, development])].
[sujeto(['However,', the, mammalian, sex, differentiation, pathway]), verbo([requires]), complemento([the, function, of, a, number, of, additional, genes, which, we, are, now, trying, to, identify, with, the, help, of, mRNA, differential, display, technique])].
[sujeto(['The', 'male-specific', region, of, 'chromosome-Y', '(', 'MSY)', contributes, to, phenotypes, outside, of, testis, development, and]), verbo([has]), complemento([a, high, rate, of, evolution, between, mammalian, species])].
[sujeto(['With', a, lack, of, genomic, 'crossover,', 'MSY', is, one, of, the, few, genomic, areas, under, similar, variation, and, evolutionary, selection, in, inbred, and, outbred, animal, 'populations,', allowing, for, an, assessment, of, evolutionary, mechanisms, to]), verbo([translate]), complemento([between, the, populations])].
[sujeto(['We']), verbo([have]), complemento([shown, that, '(', 1, ')', 'MSY', of, rat, has, nine, autosomal, gene, transposition, events, with, 'strain-specific', 'selection;', '(', 2, ')', sequence, variants, in, 'MSY', occur, with, a, 1.98, -, fold, higher, number, of, variants, than, other, chromosomes, in, seven, sequenced, rat, 'strains;', '(', 3, ')', 'Sry,', the, most, studied, 'MSY', 'gene,', has, undergone, extensive, gene, 'duplications,', driving, ubiquitous, expression, not, seen, in, human, or, 'mouse;', '(', 4, ')', the, expression, profile, of, 'Sry', in, the, rat, is, driven, by, the, insertion, of, the, 'Sry2', copy, into, an, intron, of, the, ubiquitously, expressed, 'Kdm5d', gene, in, antisense, 'orientation,', but, due, to, several, loss, of, function, mutations, in, the, 'Sry2', 'protein,', nuclear, localization, and, transcriptional, control, are, 'decreased;', '(', 5, ')', expression, of, 'Sry', copies, other, than, 'Sry2', in, the, rat, overlaps, with, the, expression, profile, for, human, 'SRY;', '(', 6, ')', gene, duplications, and, sequence, variants, '(', 'P76T)', of, 'Sry', can, be, selected, for, phenotypes, such, as, high, blood, pressure, and, androgen, receptor, signaling, within, inbred, 'mating;', and, most, 'importantly,', '(', 7, ')', per, chromosome, 'size,', 'MSY', contributes, to, higher, 'strain-specific', phenotypic, variation, relative, to, all, other, 'chromosomes,', with, 53, phenotypes, showing, both, a, male, to, female, and, consomic, cross, significance])].
[sujeto(['In', 'particular,', chondrogenic, differentiation]), verbo([has]), complemento([never, been, deeply, investigated])].
[sujeto(['Both', populations]), verbo([expressed]), complemento([mesenchymal, but, not, endothelial, and, hematopoietic, 'markers,', even, though, we, observed, a, lower, expression, of, human, leukocyte, antigen, '(', 'HLA)', 'I', in, 'CB-MSCs'])].
[sujeto(['Adipose', 'tissue-derived', stem, cells, '(', 'ADSCs)']), verbo([have]), complemento([shown, potential, for, the, treatment, of, nerve, injuries])].
[sujeto(['Most', previous, efforts]), verbo([have]), complemento([aimed, at, stimulating, regeneration, by, using, 'neural-differentiation', 'protocols,', but, the, potential, of, undifferentiated, 'ADSCs', to, enhance, axonal, growth, as, well, as, their, ability, to, transdifferentiate, in, situ, have, been, poorly, investigated])].
[sujeto(['In', this, 'study,', using, a, rat, sciatic, nerve, model, we, show, that, 'ADSCs,', transplanted, in, an, artificial, nerve, 'conduit,']), verbo([stimulate]), complemento([axonal, outgrowth, from, the, proximal, nerve, stump, and, evoke, greater, 'Schwann', cell, '(', 'SC)', 'proliferation/intrusion', in, the, distal, stump])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, any, regenerative, effect, of, transplanted, 'ADSCs', is, more, likely, to, be, mediated, by, an, initial, boost, of, released, growth, factors, 'and/or', by, an, indirect, effect, on, endogenous, 'SCs', activity])].
[sujeto(['Using', a, 'cell-free', degradation, assay, and, 'site-directed', 'mutagenesis,', we]), verbo([report]), complemento([here, that, the, three, 'PEST', motifs, of, 'c-fos', are, not, required, for, rapid, cleavage, by, calpains])].
[sujeto(['Here', we]), verbo([report]), complemento([the, analysis, of, an, unexplored, sequence, inside, the, 'bone-specific', distal, promoter, 'F', '(', 'PF)', with, respect, to, the, regulation, of, 'ERalpha', gene, expression, in, bone])].
[sujeto(['It', contains, a, 'TA', reach, 'box,', a, conventional, 'CAAT', box, and, potential, regulatory, elements, for, many, transcription, 'factors,', including, 'Cbfa1', '[', 'OSE2', '(', 'osteoblast-specific', 'element)', core]), verbo([binding]), complemento(['factor],', 'GATA-1', '[', '(', 'A/T)GATA(A/G)', binding, 'protein],', 'Sox5', '[', 'sex-determining', region, 'Y', '(', 'SRY)-type', 'HMG', bOX, 'protein,', belonging, to, a, subfamily, of, 'DNA-binding', proteins, with, an, 'HMG', 'domain],', 'Sry,', 'AP1', '(', activator, protein, 1, ')', and, 'CP2', '(', activator, of, 'gamma-globin)'])].
[sujeto(['It', is, able, to, strongly]), verbo([activate]), complemento([the, luciferase, reporter, gene, in, 'MG-63', 'osteoblastic-like', 'cells,', but, not, in, 'MCF7', 'breast-cancer', cells])].
[sujeto(['This', is, in, agreement, with, different, transcripts, that, we]), verbo([found]), complemento([in, the, two, cell, types])].
[sujeto(['The', footprinting, and, electrophoretic, 'mobility-shift', assays, '(', 'EMSAs)', showed, 'that,', inside, the, region, 'analysed,', there, were, some, sequences, that, specifically, reacted, to]), verbo([nuclear]), complemento([proteins, isolated, from, 'MG-63', cells])].
[sujeto(['In', 'particular,', we, identified, two, 'regions,', named, 'PF', a, and, 'PF', 'b,', that, do, not, present]), verbo([binding]), complemento([sites, for, known, transcription, factors, and, that, are, involved, in, a, strong, 'DNA-protein', interaction, in, 'MG-63,', but, not, in, 'MCF7,', cells])].
[sujeto(['The', analysis, of, three, transcription, factors, '(', 'GATA-1,', 'Sry', and, 'Sox)', that, might]), verbo([bind]), complemento([the, identified, footprinted, areas, suggested, a, possible, indirect, role, of, these, proteins, in, the, regulation, of, 'ERalpha', gene, expression, in, bone])].
[sujeto(['These', data]), verbo([provide]), complemento([evidence, for, different, promoter, usage, of, the, 'ERalpha', gene, through, the, recruitment, of, 'tissue-specific', transcription, activators, and, 'co-regulators'])].
[sujeto(['Formation', of, a, testis]), verbo([requires]), complemento([the, interaction, of, 'gene-products', and, hormones, '(', 'androgens)', on, pluripotent, tissue])].
[sujeto(['Sertoli', cells, make, a, number, of, substances, that, affect, testicular, development, and, 'function,', particularly, 'anti-Müllerian', 'hormone,', which]), verbo([inhibits]), complemento([female, oviduct, formation, from, the, 'Müllerian', 'anlage,', inhibits, aromatase, activity, to, stop, estrogen, 'production,', and, possibly, stimulates, androgen, production, by, 'Leydig', cells])].
[sujeto(['Although', information, concerning, paracrine, and, autocrine, regulation, of, the, avian, testis, by, these, substances, is, 'sparse,', much, can, be, learned, from, mammalian, 'studies,', in, which, putative, roles, of, each, of, these, substances]), verbo([have]), complemento([been, established])].
[sujeto(['How', 'Sertoli', cells]), verbo([cause]), complemento([directed, apoptosis, of, spermatogonia, using, the, 'Fas-ligand,', 'Fas-receptor', pathway, is, 'reviewed,', as, well, as, ways, to, circumvent, this, process])].
[sujeto(['Sex', differentiation, in, organisms, is, correlated, to, sex, steroid, production, and, receptor, signaling, pathways]), verbo([involving]), complemento([androgens, and, estrogens])].
[sujeto(['The', objectives, of, this, study, were, to, determine, whether, genes, related, to, steroid, 'biosynthesis,', steroid, receptor, 'signaling,', and, those, related, to, sex, differentiation, were]), verbo([expressed]), complemento([in, 'pre-differentiated', fathead, minnow, '(', 'FHM)', 'embryos,', an, ecotoxicological, model])].
[sujeto(['The', majority, of, transcripts, 'investigated,', for, example, 'estrogen,', 'androgen,', and, thyroid, receptors, as, well, as, steroid, biosynthesis, 'transcripts,', were]), verbo([expressed]), complemento([within, the, first, 72, hours, of, 'development;', exceptions, were, star, '(', steroidogenic, acute, regulatory, 'protein)', and, 'cyp19a,', which, did, not, have, detectable, expression, until, 5, dpf, '(', 'pre-hatch)'])].
[sujeto(['Transcripts', that]), verbo([increased]), complemento([in, relative, mRNA, abundance, over, the, first, two, weeks, of, development, included, 'ar,', 'dax1,', 'hsd11b2,', 'hsd17b,', cyp19a, and, thra])].
[sujeto(['Additional', studies, are]), verbo([required]), complemento([to, determine, their, relative, roles, in, male, and, female, differentiation, during, these, early, developmental, periods])].
[sujeto(['One', set, of, 'sense/antisense', primers, is, used, to, amplify, the, experimental, transgene, '(', androgen, receptor, gene, in, this, 'case),', the, second, set, for, the, mouse, 'Y-chromosome-specific', 'SRY', 'gene,', and, the, third, set, for, the, beta, subunit, of, the, thyroid]), verbo([stimulating]), complemento([hormone, '(', 'TSH', 'beta),', an, internal, control])].
[sujeto(['Dax-1', '[', 'dosage-sensitive', sex, 'reversal-adrenal', hypoplasia, congenita, critical, region, on, the, 'X', 'chromosome,', gene, 1, '(', 'NR0B1)]', is, an, orphan]), verbo([nuclear]), complemento([receptor, acting, as, a, suppressor, of, 'Ad4', binding, 'protein/steroidogenic', factor, 1, '[', 'Ad4BP/SF-1', '(', 'NR5A1)]', and, as, an, 'anti-Sry', factor, in, the, process, of, gonadal, sex, differentiation])].
[sujeto(['The', roles, of, these]), verbo([nuclear]), complemento([receptors, in, the, differentiation, of, the, gonads, and, the, adrenal, cortex, have, been, established, through, studies, of, the, mutant, phenotype, in, both, mice, and, humans])].
[sujeto(['Reporter', gene, analysis, revealed, that, 'Dax-1', gene, transcription, was]), verbo([activated]), complemento([by, 'beta-catenin,', a, key, 'signal-transducing', protein, in, the, 'Wnt', 'pathway,', acting, in, synergy, with, 'Ad4BP/SF-1'])].
[sujeto(['These', results, were, supported, by, in, vivo, observations, using, 'Wnt4', 'gene-disrupted', 'mice,', in, which, 'Dax-1', gene, expression, was]), verbo([decreased]), complemento([significantly, in, sexually, differentiating, female, gonads])].
[sujeto(['We', thus, conclude, that, 'Wnt4', signaling]), verbo([mediates]), complemento([the, increased, expression, of, 'Dax-1', as, the, ovary, becomes, sexually, differentiated])].
[sujeto(['Here,', we, explored, the, role, of, the, neuropeptide, 'orexin,', a, respiratory, homeostasis, 'modulator,', in, growth, retardation]), verbo([induced]), complemento([in, an, upper, airway, obstructed, '(', 'AO)', rat, model])].
[sujeto(['The', 'AO', group, gained, 46, '%', less, body, weight, compared, to, the, control, 'group,', despite, elevated, food, 'intake;', plasma, ghrelin]), verbo([increased]), complemento([by, 275, '%', and, leptin, level, decreased, by, 44, '%'])].
[sujeto(['The', impediment, of, bone, elongation, and, bone, mass, was, followed, by, a, 200, '%']), verbo([increase]), complemento([in, 'OX1R', and, 38, '%', reduction, of, local, 'GP', ghrelin, proteins, and, growth, hormone, secretagogue, receptor, 1, a])].
[sujeto(['Sry-related', transcription, factor, nine, '(', 'Sox9),', a, molecule]), verbo([mediating]), complemento([cartilage, 'ossification,', was, downregulated, and, the, level, of, transcription, factor, peroxisome, 'proliferator-activated', receptor, gamma, was, 'upregulated,', explaining, the, bone, architecture, abnormalities])].
[sujeto(['In', 'AO', 'animals,']), verbo([enhanced]), complemento([expression, of, orexin, and, 'OX1R', plays, a, role, in, respiratory, induced, sleep, and, growth, abnormalities])].
[sujeto(['The', purpose, of, this, study, was, to, investigate, whether, suppression, of, 'Wnt', signaling, pathway, by, 'PPARγ', gene, affects]), verbo([target]), complemento(['SOX9', gene, expression])].
[sujeto(['High', expression, of, 'PPARγ', '(', p, &, 'lt;', 0.05, ')', for, transfection, recombinant, plasmid, group]), verbo([induced]), complemento([obviously, decreased, expression, of, 'β-catenin', '(', p, &, 'lt;', 0.05, ')', ',', whereas, 'SOX9', expression, decreased, significantly, '(', p, &, 'lt;', 0.05, ')', compared, with, the, transfection, empty, vector, group, and, normal, comparison, group])].
[sujeto(['PPARγ', can]), verbo([suppress]), complemento(['β-catenin', expression, in, 'Wnt', signaling, pathway, and, its, downstream, effector, 'SOX9', expression, in, gastric, cancer, cells])].
[sujeto(['We']), verbo([have]), complemento([shown, earlier, that, peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPARγ)', agonists, inhibit, the, expansion, of, 'BTSCs', in, 'T98G', and, 'U87MG', glioma])].
[sujeto(['We']), verbo([found]), complemento([that, 'PPARγ', 'agonists,', ciglitazone, and, 15, -, 'deoxy-Δ(12,14)-ProstaglandinJ(2),', inhibited, cell, viability, and, proliferation, of, 'T98G-', and, 'DB29-BTSCs'])].
[sujeto(['They', also]), verbo([inhibited]), complemento(['Sox2', while, enhancing, 'Nanog', expression, in, 'BTSCs'])].
[sujeto(['These', findings, highlight, that, 'PPARγ', agonists]), verbo([inhibit]), complemento(['BTSC', proliferation, in, association, with, altered, expression, of, 'Sox2,', 'Nanog,', and, other, stemness, genes])].
[sujeto(['Therefore,']), verbo([targeting]), complemento([stemness, genes, in, 'BTSCs', could, be, a, novel, strategy, in, the, treatment, of, glioblastoma])].
[sujeto(['We', established, a, mammary, epithelial, cell, line, with, a, genotype, of, 'PBPLoxP/LoxP', by]), verbo([expressing]), complemento([an, active, form, of, 'Notch4'])].
[sujeto(['Null', mutation, of, 'PBP']), verbo([caused]), complemento([severe, growth, inhibition, of, the, 'Notch4-immortalized', mammary, cells])].
[sujeto(['We']), verbo([found]), complemento([that, truncated, 'PBP', without, the, two, 'LXXLL', motifs, could, reverse, the, growth, inhibition, due, to, the, deficiency, of, endogenous, 'PBP,', indicating, that, signalling, through, nuclear, receptors, is, unlikely, to, be, responsible, for, the, growth, inhibition, as, the, result, of, 'PBP', deficiency])].
[sujeto(['The', 're-expression', of, 'SOX10', was, capable, of, reversing, the, growth, inhibition, due, to, 'PBP', 'deficiency,', whereas]), verbo([suppressed]), complemento([expression, of, 'SOX10', inhibited, the, growth, of, 'Notch4-immortalized', mammary, cells])].
[sujeto(['Further', studies, revealed, 'PBP', is, directly]), verbo([recruited]), complemento([to, the, enhancer, of, the, 'SOX10', 'gene,', indicating, that, 'SOX10', is, a, direct, target, gene, of, 'PBP'])].
[sujeto(['We', conclude, that, 'PBP', is, essential, for, the, growth, of, 'Notch4-immortalized', mammary, cells, by]), verbo([activating]), complemento(['SOX10', 'expression,', providing, a, potential, molecular, mechanism, through, which, 'PBP', regulates, the, growth, of, mammary, 'stem/progenitor', cells])].
[sujeto(['MicroRNA-124', contributes, to, neurogenesis, through]), verbo([regulating]), complemento([its, 'targets,', but, its, expression, both, in, the, brain, of, 'Huntington\'s', disease, mouse, models, and, patients, is, decreased])].
[sujeto(['However,', the, effects, of, 'microRNA-124', on, the, progression, of, 'Huntington\'s', disease]), verbo([have]), complemento([not, been, reported])].
[sujeto(['Results', from, this, study, showed, that, 'microRNA-124']), verbo([increased]), complemento([the, latency, to, fall, for, each, 'R6/2', 'Huntington\'s', disease, transgenic, mouse, in, the, rotarod, test])].
[sujeto([5, -, 'Bromo-2\'-deoxyuridine', '(', 'BrdU)', staining, of, the, striatum, shows, an]), verbo([increase]), complemento([in, neurogenesis])].
[sujeto(['In', 'addition,', 'brain-derived', neurotrophic, factor, and, peroxisome, 'proliferator-activated', receptor, gamma, coactivator, 1, -, alpha, protein, levels, in, the, striatum, were]), verbo([increased]), complemento([and, 'SRY-related', 'HMG', box, transcription, factor, 9, protein, level, was, decreased])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'microRNA-124', slows, down, the, progression, of, 'Huntington\'s', disease, possibly, through, its, important, role, in, neuronal, differentiation, and, survival])].
[sujeto(['A', total, of, 6, 'SNPs', and, one, 4, bp, insertion, variation, in, the, promoter, region, of, the, bovine, 'PPARGC1A', gene, were, 'identified:', 'SNP', -, 259, 'T>A,', -, 301, '_-298insCTTT,', -, 915, 'A>G,', -, 1175, 'T>G,', -, 1590, 'C>T,', -, 1665, 'C>T', and, -, 1690, 'G>A,', which, are, in, the]), verbo([binding]), complemento([sites, of, some, important, transcription, 'factors:', 'sex-determining', region, 'Y', '(', 'SRY),', 'myeloid-specific', zinc, 'finger-1', '(', 'MZF-1)', and, octamer, factor, 1, '(', 'Oct-1)'])].
[sujeto(['It', is, expected, that, these, polymorphisms, may]), verbo([regulate]), complemento(['PPARGC1A', gene, transcription, and, might, have, consequences, at, a, regulatory, level])].
[sujeto(['The', transcription, factor, 'Sox9', '(', 'SRY-related', high, mobility, 'group-Box', gene, 9, ')']), verbo([regulates]), complemento([chondrocyte, differentiation, and, 'cartilage-specific', expression, of, 'genes,', such, as, 'Col2a1', '(', collagen, type, 'II', 'alpha1)'])].
[sujeto(['However,', 'Sox9', expression, is, detected, not, only, in, chondrogenic, tissue, but, also, in, nonchondrogenic, 'tissues,']), verbo([suggesting]), complemento([the, existence, of, a, molecular, 'partner(s)', required, for, 'Sox9', to, control, chondrogenesis, and, chondrogenic, gene, expression])].
[sujeto(['Here,', we]), verbo([report]), complemento([identification, of, peroxisome, 'proliferator-activated', receptor, gamma, 'co-activator', 1, alpha, '(', 'PGC-1alpha)', as, a, coactivator, for, 'Sox9', during, chondrogenesis])].
[sujeto(['Expression', of, 'PGC-1alpha', is]), verbo([induced]), complemento([at, chondrogenesis, sites, during, mouse, embryonic, limb, development, and, during, chondrogenesis, in, human, 'MSC', cultures])].
[sujeto(['PGC-1alpha', directly]), verbo([interacts]), complemento([with, 'Sox9', and, promotes, 'Sox9-dependent', transcriptional, 'activity,', suggesting, that, 'PGC-1alpha', acts, as, a, transcriptional, coactivator, for, 'Sox9'])].
[sujeto(['Consistent', with, this, 'finding,', 'PGC-1alpha', disruption, in, 'MSC', by, small, interfering, 'RNA']), verbo([inhibits]), complemento(['Col2a1', expression, during, chondrogenesis])].
[sujeto(['Furthermore,', overexpression, of, both, 'PGC-1alpha', and, 'Sox9']), verbo([induced]), complemento([expression, of, chondrogenic, 'genes,', including, 'Col2a1,', followed, by, chondrogenesis, in, the, 'MSC', and, developing, chick, limb])].
[sujeto(['Together,', our, results]), verbo([suggest]), complemento([a, transcriptional, mechanism, for, chondrogenesis, that, is, coordinated, by, 'PGC-1alpha'])].
[sujeto(['A', recent, paper, demonstrated, that, decellularized, extracellular, matrix, '(', 'DECM)', deposited, by, 'synovium-derived', stem, cells, '(', 'SDSCs),', especially, from, fetal, 'donors,', could, rejuvenate, human, adult, 'SDSCs', in, both, proliferation, and, chondrogenic, 'potential,', in, which, expanded, cells, and, corresponding, culture, substrate, '(', such, as, 'DECM)', were]), verbo([found]), complemento([to, share, a, mutual, reaction, in, both, elasticity, and, protein, profiles, '(', see, ref])].
[sujeto(['It', seems, that, young, 'DECM', may, assist, in, the, development, of, culture, strategies, that, optimize, proliferation, and]), verbo([maintain]), complemento([&, 'quot;stemness"', of, mesenchymal, stem, cells, '(', 'MSCs),', helping, to, overcome, one, of, the, primary, difficulties, in, 'MSC-based', regenerative, therapies])].
[sujeto(['The', three, mouse, models, were, 'i)', 'XSxr(a)O', in, which, the, 'Yp-derived', 'Tp(Y)1Ct(Sxr-a)', sex, reversal, factor]), verbo([provides]), complemento([an, almost, complete, 'Yp', gene, 'complement,', 'ii)', 'XSxr(b)O,Eif2s3y', males, in, which, 'Tp(Y)1Ct(Sxr-b)', has, a, deletion, completely, or, partially, removing, eight, 'Yp', genes, -, the, 'Yp', gene, 'Eif2s3y', has, been, added, as, a, transgene, to, support, spermatogonial, 'proliferation,', and, 'iii)', 'XOSry,Eif2s3y', males, in, which, the, 'Sry', transgene, directs, gonad, development, along, the, male, pathway])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([used, the, same, mouse, models, analysed, at, 6, weeks, of, age, to, investigate, potential, 'Yp', gene, involvement, in, spermiogenesis])].
[sujeto(['We']), verbo([found]), complemento([that, all, three, mouse, models, produce, haploid, and, diploid, spermatids, and, that, the, diploid, spermatids, showed, frequent, duplication, of, the, developing, acrosomal, cap, during, the, early, stages])].
[sujeto(['Most', 'strikingly,', in, 'XOSry,Eif2s3y', 'males,', spermatid, development]), verbo([arrested]), complemento([at, round, spermatid, step, 7, so, that, no, sperm, head, restructuring, or, tail, development, was, observed])].
[sujeto(['We', conclude, that, 'Sxr(a)', '(', and, therefore, 'Yp)', includes, genetic, information, essential, for, sperm, morphogenesis, and, that, this, is, partially]), verbo([retained]), complemento([in, 'Sxr(b)'])].
[sujeto(['Most', of, our, current, knowledge, on, mammalian, sex, 'determination,', the, genetic, process, by, which, the, gonadal, primordia, are, committed, to, differentiate, as, either, testes, or, 'ovaries,']), verbo([has]), complemento([derived, mainly, from, the, study, of, 'sex-reversed', mice, obtained, by, direct, genetic, manipulation])].
[sujeto(['However,', there, are, also, numerous, cases, of, natural, exceptions, to, normal, gonad, development, which]), verbo([have]), complemento([been, described, in, a, variety, of, 'mammals,', including, both, domestic, and, wild, species])].
[sujeto(['These', studies, are, necessary, to, elucidate, particular, aspects, of, mammalian, gonad, development, in, some, instances, and, to, understand, how, the, genetic, mechanisms, controlling, gonad, development]), verbo([have]), complemento([evolved])].
[sujeto(['Sxr(b)', is, an, 'Sxr(a)-derived', variant, in, which, a, deletion]), verbo([has]), complemento([removed, six, 'Y', 'short-arm', genes, and, created, a, 'Zfy2/Zfy1', fusion, gene, spanning, the, deletion, breakpoint, '[', 4, ',', 5, ']'])].
[sujeto(['XSxr(b)O', males]), verbo([have]), complemento([spermatogonial, arrest, that, can, be, overcome, by, the, 're-addition', of, 'Eif2s3y', from, the, deletion, as, a, 'transgene;', 'however,', 'XSxr(b)OEif2s3y', transgenic, males, do, not, show, the, expected, elimination, of, 'MI', spermatocytes, in, response, to, the, univalent, '[', 6, ']'])].
[sujeto(['Here', we, show, that, these, 'XSxr(b)OEif2s3y', males]), verbo([have]), complemento([an, impaired, apoptotic, response, with, completion, of, the, first, meiotic, 'division,', but, there, is, no, second, meiotic, division])].
[sujeto(['These', findings]), verbo([provide]), complemento([further, insight, into, the, basis, for, the, much, lower, transmission, of, chromosomal, errors, originating, at, the, first, meiotic, division, in, men, than, in, women, '[', 7, ']'])].
[sujeto(['Investigations', in, mice]), verbo([suggest]), complemento([that, the, 'Y-chromosomal', genes, affect, certain, behaviors])].
[sujeto(['Here,', we, studied, whether, a, part, of, the, 'Y', 'chromosome,', the, 'Sxr', 'locus,']), verbo([has]), complemento([an, effect, on, induction, of, motivation, for, parental, care, '(', pup, 'retrieval)', or, of, parental, aggression, towards, pups, '(', 'infanticide)'])].
[sujeto(['The']), verbo([induced]), complemento([pup, retrieval, or, infanticide, behaviors, were, 'genotype-dependent'])].
[sujeto(['Further,', it]), verbo([induces]), complemento([infanticide, to, a, level, higher, than, that, of, 'XX', females, but, significantly, lower, than, that, of, normal, males, '(', 'XY)'])].
[sujeto(['Hence,', we]), verbo([suggest]), complemento([that, genes, outside, the, 'sex-determining', region, of, the, 'Y', chromosome, 'and/or', genes, on, autosomes, are, necessary, for, manifestation, of, full, 'male-type', parental, behavior])].
[sujeto(['In', the, absence, of, any, other, 'mutations,', testis, differentiation, in, 'XXSxr', fetuses, is, essentially, normal, and, only, one]), verbo([report]), complemento([of, an, 'XXSxr', fetus, with, ovotestes, is, in, the, literature])].
[sujeto(['We']), verbo([report]), complemento([that, 84, '%', '(', 21, /, 25, ')', of, 13, days, postcoitum, 'XXSxr', fetuses, on, the, 'B6', inbred, genomic, background, have, ovotestes])].
[sujeto(['Ovotestes', were]), verbo([found]), complemento([in, fetuses, from, both, 'Sxra', and, 'Sxrb', variants])].
[sujeto(['Examination', of, fetuses, older, than, 13, dpc]), verbo([suggests]), complemento([that, the, presence, of, ovotestes, is, transient, in, most, fetuses])].
[sujeto(['The', development, of, ovotestes, is]), verbo([associated]), complemento([with, the, inbred, background, and, is, exacerbated, by, the, dominant, spotting, oncogene, allele, 'KitW-42J'])].
[sujeto(['We', propose, that, spreading, of, 'X-inactivation', into, the, 'Sxr', region, resulting, in]), verbo([loss]), complemento([of, 'Sry', expression, is, more, extensive, in, 'B6-Sxr', strains])].
[sujeto(['Earlier', cytogenetic, observations, had]), verbo([suggested]), complemento([that, the, deletions, resulted, from, asymmetrical, meiotic, recombination, between, the, 'Y', and, the, homologous, 'Sxr', 'region,', but, no, direct, evidence, for, this, hypothesis, was, available])].
[sujeto(['We']), verbo([have]), complemento([now, analyzed, the, offspring, of, 'XSxr/Y', males, carrying, an, evolutionarily, divergent, 'Mus', musculus, domesticus, 'Y', 'chromosome,', which, permits, detection, and, characterization, of, such, recombination, events])].
[sujeto(['This', analysis]), verbo([has]), complemento([enabled, the, derivation, of, a, recombination, map, of, 'Yp', and, 'Sxr,', also, demonstrating, the, orientation, of, 'Yp', with, respect, to, the, 'Y', centromere])].
[sujeto(['The', mapping, data]), verbo([have]), complemento([established, that, 'Rbm,', the, murine, homologue, of, a, gene, family, cloned, from, the, human, 'Y', 'chromosome,', lies, between, 'Sry', and, the, centromere])].
[sujeto(['Analysis', of, two, additional, 'XY', female, lines, shows, that, asymmetrical, 'Yp-Sxr', recombination]), verbo([leading]), complemento([to, 'XY', female, sex, reversal, results, in, deletion, of, 'Rbm', sequences])].
[sujeto(['This']), verbo([suggests]), complemento([that, the, rearrangement, arose, from, a, recombination, event, involving, the, distal, 'Y', telomere, 'sequences,', i])].
[sujeto([',', within, the, 'telomere,', a, structure, historically, assumed, to, be, incapable, of]), verbo([participating]), complemento([in, chromosome, rearrangements])].
[sujeto(['The', 'Sxr', '(', 'sex-reversed)', 'region,', a, fragment, of, the, 'Y', chromosome, short, 'arm,', can]), verbo([cause]), complemento([chromosomally, female, 'XXSxr', or, 'XSxrO', mice, to, develop, as, sterile, males])].
[sujeto(['The', original, 'Sxr', 'region,', termed, 'Sxra,', 'encodes:', 'Tdy,', the, primary, 'sex-determining', 'gene;', 'Hya,', the, controlling, or, structural, locus, for, the, minor, transplantation, antigen, 'H-Y;', 'gene(s)', controlling, the, expression, of, the, serologically, detected, male, antigen, '(', 'SDMA);', 'Spy,', a, 'gene(s)']), verbo([required]), complemento([for, the, survival, and, proliferation, of, 'A', spermatogonia, during, 'spermatogenesis;', 'Zfy-1/Zfy-2,', 'zinc-finger-containing', genes, of, unknown, 'function;', and, 'Sry,', which, is, probably, identical, to, 'Tdy'])].
[sujeto(['We']), verbo([report]), complemento([here, the, isolation, of, a, new, 'testis-specific', 'gene,', 'Sby,', mapping, to, the, 'DNA', deleted, from, the, 'Sxrb', region, '(', the, delta, 'Sxrb', 'interval)'])].
[sujeto(['Sby']), verbo([has]), complemento([extensive, homology, to, the, 'X-linked', human, 'ubiquitin-activating', enzyme, 'E1'])].
[sujeto(['The', critical, role, of, this, enzyme, in]), verbo([nuclear]), complemento(['DNA', replication, together, with, the, 'testis-specific', expression, of, 'Sby', suggests, 'Sby', as, a, candidate, for, the, spermatogenic, gene, 'Spy'])].
[sujeto(['According', to, our, 'results,', the, most, useful, markers, for, these, chromosomal, variants, were, the, genes]), verbo([found]), complemento([in, the, pseudoautosomic, regions, 1, and, 2, '(', 'PAR1', and, 'PAR2),', because, differences, in, gene, dosage, '(', relative, 'quantification)', between, groups, were, more, evident, in, 'SHOX', and, 'VAMP7', gene, expression])].
[sujeto(['Therefore,', we, conclude, that, these, markers, are, useful, for, early, detection, in, aneuploidies]), verbo([involving]), complemento([sex, chromosomes])].
[sujeto(['This', calcification, shares, features, with, osteogenesis, and, may]), verbo([involve]), complemento([osteogenic, factors])].
[sujeto(['Compared', with, 'DCC-resistant', 'C57BL/6', 'mice,', a, significant]), verbo([increase]), complemento([in, 'Opn', transcription, was, demonstrated, in, necrotic, lesions, of, both, 'DCC-susceptible', 'C3H/He', and, 'B6'])].
[sujeto(['Significant']), verbo([increases]), complemento([in, gene, expression, were, also, demonstrated, for, the, transcription, factors, runt, 'domain-containing', transcription, factor, 2, '(', 'Runx2),', vitamin, 'D', receptor, '(', 'Vdr),', 'SRY', '(', 'sex-determining', region, 'Y)-box', 9, 'protein,', and, 'Nfkb1', in, 'C3H/He', mice, versus, 'C57BL/6', controls])].
[sujeto(['However,', only, 'Runx2', remained, significantly]), verbo([increased]), complemento([in, the, 'B6'])].
[sujeto(['Luciferase', assay, use]), verbo([increased]), complemento(['Opn', promoter, 'activity,', which, was, demonstrated, after, overexpression, of, 'Runx2'])].
[sujeto(['A', 'poly-T', stretch, insertion, was, identified, to, stabilize, the]), verbo([binding]), complemento([of, 'Runx2,', thus, significantly, enhancing, 'Opn', promoter, activity])].
[sujeto(['This', 'Runx2-mediated', activation, was, further]), verbo([enhanced]), complemento([by, cotransfection, with, 'Vdr'])].
[sujeto(['Our', data]), verbo([suggest]), complemento([a, key, role, of, 'Runx2', in, the, regulation, of, 'Opn', in, a, model, of, cardiovascular, calcification, and, demonstrate, a, synergistic, cooperation, of, 'Runx2', and, 'Vdr'])].
[sujeto(['The', order, of, the, 'Y-linked', type, 'I', markers, was, 'STS-Y,', 'SRY', and, 'ZFY', 'These', orders, are, the, same, arrangements, as]), verbo([reported]), complemento([for, the, human, 'X-', and, 'Y-chromosomes,', supporting, the, conservation, of, genomic, organization, between, the, human, and, the, horse, sex, chromosomes])].
[sujeto(['Regional', ordering, of, 'X-linked', type, 'I', and, microsatellite, markers]), verbo([provides]), complemento([the, first, integration, of, type, 'I', and, type, 'II', markers, in, the, horse, 'X', chromosome])].
[sujeto(['Rainbow', darter, '(', 'Etheostoma', 'caeruleum)', is, a, small, benthic, fish, species]), verbo([found]), complemento([in, 'North', 'America', that, are, abundant, and, distributed, throughout, the, 'Grand', 'River', 'watershed,', 'ON,', 'Canada'])].
[sujeto(['There', were, no, changes, in, condition, 'factor;', 'however,', there, was, a, significant]), verbo([increase]), complemento([in, 'LSI', and, a, decrease, in, 'GSI', in, fish, inhabiting, downstream, environments, when, compared, with, fish, collected, from, the, reference, site])].
[sujeto(['In', the, 'gonad,', there, were, sex, specific, differences, for, genes, related, to, sexual, 'differentiation;', dmrt1, was, only]), verbo([expressed]), complemento([in, males, whereas, foxl2, and, sox9, were, highly, expressed, in, females, compared, to, males])].
[sujeto(['Conversely,', esrb, was, not, differentially]), verbo([expressed]), complemento([between, sexes, or, among, sites])].
[sujeto(['This', study, is, the, first, to]), verbo([report]), complemento([on, gene, expression, changes, in, the, rainbow, 'darter,', with, emphasis, on, the, differences, in, transcript, abundance, between, sexes, and, how, these, changes, relate, to, exposures, to, 'MWWEs'])].
[sujeto(['Molecular', approaches, are, being, investigated, for, their, potential, application, to, field, 'ecotoxicology,', and, molecular, bioassays, for, 'relevant,', sentinel, species, in, environmental, monitoring, programs, are]), verbo([required]), complemento([to, better, understand, the, impact, of, anthropogenic, impacts, on, species, at, risk, in, river, systems])].
[sujeto(['The']), verbo([increasing]), complemento([relevance, of, the, cancer, stem, cell, '(', 'CSC)', hypothesis, and, the, impact, of, 'CSC-associated', markers, in, the, carcinogenesis, of, solid, tumours, may, provide, potential, prognostic, implications, in, lung, cancer])].
[sujeto(['We', observed, that, 'ALDH', and, 'OCT4A', were]), verbo([associated]), complemento([with, nodal, status, '(', 'ALDH,', 'P', =, 0.05, ;, 'OCT4A,', 'P', =, 0.03, ')', having, lower, mRNA, levels, in, tumours, with, lymph, node, 'metastasis,', 'N+,', compared, with, that, in, 'N0'])].
[sujeto(['High', 'OCT4A', levels, were, significantly, correlated, with, tumour, size, of, &, 'lt;3', 'cm,']), verbo([decrease]), complemento([in, tumours, &, 'gt;3', cm, '(', 'P', =, 0.03, ')'])].
[sujeto(['Our', study]), verbo([reveals]), complemento([that, 'CSC-associated', 'markers:', 'OCT4A,', 'CD133', and, 'ALDH', are, involved, in, the, initial, phase, of, carcinogenesis, of, 'LAC,', and, can, be, used, as, predictors, of, early, stage, 'LAC', and, poor, 'disease-free', intervals])].
[sujeto(['Allopatric', diversification, driven, by, geological, or, climatic, processes]), verbo([has]), complemento([been, identified, as, the, main, mechanism, shaping, present, faunal, distribution, on, the, island])].
[sujeto(['Tarsiers,', small, nocturnal, primates, with, possible, evidence, of, an, 'Eocene', fossil, record, on, the, 'Asian', 'mainland,', are, at, present, exclusively]), verbo([found]), complemento([in, insular, 'Southeast', 'Asia'])].
[sujeto(['We']), verbo([found]), complemento([that, their, arrival, at, the, 'Proto-Sulawesi', archipelago, coincided, with, initial, 'Miocene', tectonic, uplift, and, hypothesize, that, tarsiers, dispersed, over, the, region, in, distinct, waves])].
[sujeto(['This', 'congruence,', 'however,']), verbo([has]), complemento([partially, been, superimposed, by, 'taxon-specific', dispersal, patterns])].
[sujeto(['Whereas', similar, disorders, and, 'similar-looking', coat, colour, phenotypes, sometimes]), verbo([have]), complemento([a, different, genetic, background, '(', e])].
[sujeto(['The', human, predilection, for, fancy, phenotypes, that, ignore, disorders, and, genetic, defects, is, a, major, driving, force, for, the]), verbo([increase]), complemento([of, pleiotropic, effects, in, domestic, species, and, laboratory, subjects, since, domestication, has, commenced, approximately, 18, ',', 0, years, ago])].
[sujeto(['We', hypothesized, that, bone, marrow, derived, 'Sca-1+', stem, cells, '(', 'BM', 'Sca-1+)', transduced, with, multiple, therapeutic, cytokines, with, diverse, effects, will]), verbo([induce]), complemento([faster, angiomyogenic, differentiation, in, the, infarcted, myocardium])].
[sujeto(['BM', 'Sca-1+', were, purified, from, transgenic, male, mice]), verbo([expressing]), complemento(['GFP'])].
[sujeto(['LDH', and, 'TUNEL', assays, showed]), verbo([enhanced]), complemento([survival, of, 'GFSca-1+', under, lethal, anoxia, '(', 'p<0'])].
[sujeto(['MTS', assay, showed, significant]), verbo([increased]), complemento([cell, proliferation, in, 'GFSca-1+', '(', 'p<0'])].
[sujeto(['Immunostaining', for, vWF, showed]), verbo([increased]), complemento([blood, vessel, density, in, both, 'peri-infarct', and, infarct, regions, in, 'group-3'])].
[sujeto(['This', study, used, genomewide, 'array-CGH', in, microdissected, specimens, to, map, genetic, alterations]), verbo([found]), complemento([in, primary, 'OSCC', and, neck, lymph, node, metastases])].
[sujeto(['The', highest, frequencies, of]), verbo([gains]), complemento([were, detected, in, 'LMYC,', 'REL,', 'TERC,', 'PIK3CA,', 'MYB,', 'MDR1,', 'HRAS,', 'GARP,', 'CCND2,', 'FES,', 'HER2,', 'SIS,', and, 'SRY'])].
[sujeto(['The', highest, frequencies, of]), verbo([losses]), complemento([were, detected, in, 'p44S10,', 'TIF1,', 'LPL,', 'MTAP,', 'BMI1,', 'EGR2,', and, 'MAP2K5'])].
[sujeto(['Higher', 'FGF4', immunoreactivity, in, primary, 'OSCC', is]), verbo([associated]), complemento([with, a, worse, prognosis])].
[sujeto(['Our', study]), verbo([suggests]), complemento([that, precise, genomic, profiling, can, be, useful, in, determining, gene, number, changes, in, 'OSCC'])].
[sujeto(['ABCC4', gene, on, chromosome, 13, ',', 'TYMS', gene, on, chromosome, 18, ',', 'DSCR3', gene, on, chromosome, 21, ',', 'HPRT2', gene, on, chromosome, 'X,', and, 'SRY', gene, on, 'Y', chromosome, were, used, as, the]), verbo([target]), complemento(['genes,', with, 'GAPDH', gene, on, chromosome, 12, as, the, control, gene])].
[sujeto(['The', ratio, of, the]), verbo([target]), complemento([gene, on, chromosome, 13, to, the, control, gene, showed, a, significant, difference, between, the, normal, karyotype, group, '(', 0.9, -, or, +, 0.31, ')', and, trisome, group, '(', 1.39, -, or, +, 0.12, ',', 'P=0'])].
[sujeto(['The', expression, of, the]), verbo([target]), complemento([gene, on, the, 'Y', chromosome, was, not, detected, in, normal, females, '(', 46, ',', 'XX),', and, a, significant, difference, in, the, expression, was, found, between, normal, male, group, '(', 46, ',', 'XY)', and, 47, ',', 'XYY', group, '(', 1.57, -, or, +, 0.54, vs, 3.08, -, or, +, 0.15, ',', 'P=0'])].
[sujeto(['Fetoprotein', transcription, factor, '(', 'FTF)', is, an, orphan]), verbo([nuclear]), complemento([receptor, that, activates, the, 'alpha(1)-fetoprotein', gene, during, early, liver, developmental, growth])].
[sujeto(['Here', we, sought, to, define, better, the, position, of, 'FTF', in, transcriptional, cascades]), verbo([leading]), complemento([to, hepatic, differentiation])].
[sujeto(['The', mFTF, transcription, initiation, site, was, located, in, adult, liver, at, 238, nucleotides, from, the, first, translation, initiator, 'codon,', with, six, canonical, 'GATA,', 'E', 'box,', and, 'Nkx', motifs, clustered, between, -, 50, /, -, 140, base, pairs, '(', 'bp)', from, the, cap, 'site;', 'DNA/protein']), verbo([binding]), complemento([assays, also, pinpointed, an, 'HNF4-binding', element, at, +, 36, bp, and, an, 'FTF-binding', element, at, -, 257, bp])].
[sujeto(['Transfection', assays, and, point, mutations, showed, that, the, mFTF, promoter, is]), verbo([activated]), complemento([by, 'GATA,', 'HNF4alpha,', 'FTF,', 'Nkx,', and, basic, 'helix-loop-helix', 'factors,', with, marked, cooperativity, between, 'GATA', and, 'HNF4alpha'])].
[sujeto(['Three', genes, encoding, transcription, factors, critical, to, early, hepatic, 'differentiation,', 'Hnf3beta,', 'Hnf4alpha,', and, 'Hnf1alpha,', each, contain, dual, 'FTF-binding', elements, in, their, proximal, 'promoters,', and, all, three, promoters, are]), verbo([activated]), complemento([by, 'FTF', in, transfection, assays])].
[sujeto(['Direct', 'DNA']), verbo([binding]), complemento([action, and, cooperativity, was, demonstrated, between, 'FTF', and, 'HNF3beta', on, the, 'Hnf3beta', promoter, and, between, 'FTF', and, 'HNF4alpha', on, the, 'Hnf1alpha', promoter])].
[sujeto(['These', combined, results]), verbo([suggest]), complemento([that, 'FTF', is, an, early, intermediary, between, endodermal, specification, signals, and, downstream, genes, that, establish, and, amplify, the, hepatic, phenotype])].
[sujeto(['The', majority, of, mutations, were, 'novel,']), verbo([loss]), complemento([of, function, '(', 'LOF)', '(', 78.4, '%', ')', 'mutations,', and, most, disrupted, the, 'DNA-binding', domain, '(', 58.8, '%', ')'])].
[sujeto(['Mutation', status, was]), verbo([associated]), complemento([with, tumor, grade, and, not, associated, with, survival, outcomes])].
[sujeto(['Most', tumors]), verbo([expressed]), complemento(['FOXA2', at, both, the, mRNA, and, protein, level])].
[sujeto(['In', those, tumors, with, 'mutations,', the, majority, of, cases]), verbo([expressed]), complemento([both, alleles])].
[sujeto(['The', pattern, of, 'FOXA2', mutations, and, expression, in, tumors]), verbo([suggests]), complemento([complex, regulation, and, a, haploinsufficient, or, 'dominant-negative', tumor, suppressor, function])].
[sujeto(['Insulin', is, a, crucial, mediator, of, the, glucose, and, lipid, metabolism, that]), verbo([has]), complemento([been, implicated, in, atherosclerotic, and, inflammatory, processes])].
[sujeto(['Important', mediators, of, insulin, signaling, such, as, 'Liver', 'X', 'Receptors', '(', 'LXRs)', and, 'Forkhead', 'Box', 'A2', '(', 'FOXA2)', are, known, to]), verbo([regulate]), complemento(['apoA-I', expression, in, liver])].
[sujeto(['Forkhead', 'Box', 'O1', '(', 'FOXO1)', is, a, 'well-known']), verbo([target]), complemento([of, insulin, signaling, and, a, key, mediator, of, oxidative, stress, response])].
[sujeto(['Low', doses, of, insulin, were, shown, to]), verbo([activate]), complemento(['apoA-I', expression, in, human, hepatoma, 'HepG2', cells])].
[sujeto(['Treatment', of, 'HepG2', cells, with, high, doses, of, insulin, '(', 48, 'hours,', 100, 'nM)']), verbo([suppresses]), complemento(['apoA-I', gene, expression])].
[sujeto(['FOXO1', forms, a, complex, with, 'LXRβ', and, insulin, treatment, impairs, 'FOXO1/LXRβ', complex]), verbo([binding]), complemento([to, hepatic, enhancer, and, triggers, its, nuclear, export])].
[sujeto(['Insulin', as, well, as, 'LXR', ligand, 'TO901317']), verbo([enhance]), complemento([the, interaction, between, 'FOXA2,', 'LXRα', and, hepatic, enhancer])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, high, doses, of, insulin, downregulate, 'apoA-I', gene, expression, in, 'HepG2', cells, through, redistribution, of, 'FOXO1/LXRβ', 'complex,', 'FOXA2', and, 'LXRα', on, hepatic, enhancer, of, 'apoA-I', gene])].
[sujeto(['Genes', significantly]), verbo([associated]), complemento([with, baseline, seizure, frequency, on, likelihood, ratio, test, were, identified, based, on, &, 'gt;0'])].
[sujeto(['Expression', levels, of, forty, genes, were, significantly]), verbo([associated]), complemento([with, baseline, seizure, frequency])].
[sujeto(['Of', the, seven, most, 'significant,', four]), verbo([have]), complemento([been, linked, to, other, neurologic, diseases])].
[sujeto(['Expression', levels]), verbo([associated]), complemento([with, high, seizure, frequency, included, low, expression, of, 'Homeobox', 'A10,', 'Forkhead', box, 'A2,', 'Lymphoblastic', leukemia, derived, sequence, 1, ',', 'HGF', 'activator,', 'Kelch', repeat, and, 'BTB', '(', 'POZ)', domain, containing, 11, ',', 'Thanatos-associated', protein, domain, containing, 8, and, 'Heparin', sulfate, '(', 'glucosamine)', 3, -, 'O-sulfotransferase', 3, 'A1'])].
[sujeto(['Four', of, the, seven, discussed]), verbo([have]), complemento([been, previously, related, to, other, neurologic, diseases])].
[sujeto(['Future', investigation, of, these, genes, could, establish, new, biomarkers, for, predicting, 'epileptogenicity,', and, could]), verbo([have]), complemento([significant, implications, for, diagnosis, and, management, of, temporal, lobe, 'epilepsy,', as, well, as, epilepsy, pathogenesis])].
[sujeto(['Pancreatic', cancer, is, the, fourth]), verbo([leading]), complemento([cause, of, cancer, death, in, the, 'United', 'States'])].
[sujeto(['Restoration', of, 'miR-1291', expression]), verbo([inhibited]), complemento([pancreatic, cancer, cell, 'proliferation,', which, was, associated, with, cell, cycle, arrest, and, enhanced, apoptosis])].
[sujeto(['Furthermore,', 'miR-1291', sharply]), verbo([suppressed]), complemento([the, tumorigenicity, of, 'PANC-1', cells, in, mouse, models])].
[sujeto(['Through', computational, and, experimental, studies, we, further, identified, that, forkhead, box, protein, 'A2', '(', 'FOXA2),', a, transcription, factor, governing, 'AGR2', 'expression,', was, a, direct]), verbo([target]), complemento([of, 'miR-1291'])].
[sujeto(['These', results, connect, 'miR-1291', to, the, 'FOXA2-AGR2', regulatory, pathway, in, the, suppression, of, pancreatic, cancer, cell, proliferation, and, 'tumorigenesis,']), verbo([providing]), complemento([new, insight, into, the, development, of, 'miRNA-based', therapy, to, combat, pancreatic, cancer])].
[sujeto(['Since', 'LAL-deficient', '(', 'Lal', '(', -, /, -, ')', ')', mice, suffer, from, progressive]), verbo([loss]), complemento([of, adipose, tissue, and, severe, accumulation, of, lipids, in, hepatic, 'lysosomes,', we, hypothesised, that, 'LAL', deficiency, triggers, alternative, energy, 'pathway(s)'])].
[sujeto(['Despite']), verbo([loss]), complemento([of, adipose, 'tissue,', 'Lal', '(', -, /, -, ')', mice, show, enhanced, glucose, clearance, during, insulin, and, glucose, tolerance, tests, and, have, increased, uptake, of, '[', '(', 3, ')', 'H]2-deoxy-D-glucose', into, skeletal, muscle, compared, with, 'wild-type', mice])].
[sujeto(['We', observed, 84, '%']), verbo([decreased]), complemento([plasma, leptin, levels, and, significantly, reduced, hepatic, 'ATP,', 'glucose,', glycogen, and, glutamine, concentrations, in, fed, 'Lal', '(', -, /, -, ')', mice])].
[sujeto(['Markedly', reduced, hepatic, 'acyl-CoA', concentrations]), verbo([decrease]), complemento([the, expression, of, peroxisome, 'proliferator-activated', receptor, α, '(', 'PPARα)', target, genes])].
[sujeto(['However,', treatment, of, 'Lal', '(', -, /, -, ')', mice, with, the, 'PPARα', agonist, fenofibrate, further]), verbo([decreased]), complemento([plasma, 'TG', '(', and, hepatic, glucose, and, 'glycogen)', concentrations, in, 'Lal', '(', -, /, -, ')', mice])].
[sujeto(['Depletion', of, hepatic]), verbo([nuclear]), complemento([factor, 4, α, and, forkhead, box, protein, a2, in, fasted, 'Lal', '(', -, /, -, ')', mice, might, be, responsible, for, reduced, expression, of, microsomal, 'TG', transfer, 'protein,', defective, 'VLDL', synthesis, and, drastically, reduced, plasma, 'TG', levels])].
[sujeto(['We', conclude, that]), verbo([decreased]), complemento([plasma, 'VLDL', production, enhances, glucose, uptake, into, skeletal, muscle, to, compensate, for, the, lack, of, energy, supply])].
[sujeto(['Genome-wide', association, studies, '(', 'GWAS)', of, type, 2, diabetes, '(', 'T2D)']), verbo([have]), complemento([discovered, a, number, of, loci, that, contribute, to, susceptibility, to, the, disease])].
[sujeto(['Future', challenges, include, elucidation, of, functional, mechanisms, through, which, these, 'GWAS-identified', loci]), verbo([modulate]), complemento(['T2D', disease, risk])].
[sujeto(['The', aim, of, the, present, study, was, to, comprehensively, characterize, 'T2D']), verbo([associated]), complemento([single, nucleotide, polymorphisms, '(', 'SNPs)', and, genes, through, computational, approaches])].
[sujeto(['Computational', biology, approaches, used, in, the, present, study, included, comparative, genomic, analyses, and, functional, annotation, using, 'GWAS3D', and, 'RegulomeDB,', investigation, of, the, effects, of, 'T2D-associated', 'SNPs', on, miRNA]), verbo([binding]), complemento([and, protein, 'phosphorylation,', and, gene, 'ontology,', pathway, 'enrichment,', 'protein-protein', interaction, '(', 'PPI)', networks, and, functional, module, analysis, of, 'T2D-associated', genes, from, previously, published, 'GWAS'])].
[sujeto(['Computational', analysis, identified, a, number, of, 'T2D', 'GWAS-associated', 'SNPs', that, were, located, at, protein]), verbo([binding]), complemento(['sites,', including, 'CCCTC-binding', factor, '(', 'CTCF),', 'E1A', binding, protein, p300, '(', 'EP300),', hepatocyte, nuclear, factor, 4, alpha, '(', 'HNF4A),', transcription, factor, 7, like, 2, '(', 'TCF7L2),', forkhead, box, 'A1', '(', 'FOXA1)', and, 'A2', '(', 'FOXA2),', and, potentially, affected, the, binding, of, miRNAs, and, protein, phosphorylation])].
[sujeto(['The', results]), verbo([provide]), complemento([objectives, and, clues, for, future, experimental, studies, and, further, insights, into, the, molecular, pathogenesis, of, 'T2D'])].
[sujeto(['Mutations', in, hepatocyte]), verbo([nuclear]), complemento([factor, 1, transcription, factors, '(', 'HNF1α/β)', are, associated, with, diabetes])].
[sujeto(['However,', they, also]), verbo([have]), complemento([an, important, role, in, the, biology, of, many, other, 'tissues,', including, the, intestine])].
[sujeto(['We', used, chromatin, immunoprecipitation, followed, by, direct, sequencing, '(', 'ChIP-seq)', to, identify, 'HNF1']), verbo([binding]), complemento([sites, 'genome-wide'])].
[sujeto(['Direct']), verbo([targets]), complemento([of, 'HNF1', were, validated, using, conventional, 'ChIP', assays, and, confirmed, by, 'siRNA-mediated', depletion, of, 'HNF1,', followed, by, 'RT-qPCR'])].
[sujeto(['Gene', ontology, process, enrichment, analysis, of, the, 'HNF1']), verbo([targets]), complemento([identified, multiple, processes, with, a, role, in, intestinal, epithelial, cell, 'function,', including, properties, of, the, cell, 'membrane,', cellular, response, to, 'hormones,', and, regulation, of, biosynthetic, processes])].
[sujeto(['Approximately', 50, '%', of, 'HNF1']), verbo([binding]), complemento([sites, were, also, occupied, by, other, members, of, the, intestinal, transcriptional, 'network,', including, hepatocyte, nuclear, factor, 4, 'A', '(', 'HNF4A),', caudal, type, homeobox, 2, '(', 'CDX2),', and, forkhead, box, 'A2', '(', 'FOXA2)'])].
[sujeto(['Depletion', of, 'HNF1', in, 'Caco2', cells]), verbo([increases]), complemento(['FOXA2', abundance, and, decreases, levels, of, 'CDX2,', illustrating, the, coordinated, activities, of, the, network])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'HNF1', plays, an, important, role, in, regulating, intestinal, epithelial, cell, 'function,', both, directly, and, through, interactions, with, other, intestinal, transcription, factors])].
[sujeto(['The', transcription, factor, forkhead, box, protein, 'A2', '(', 'FOXA2,', also, known, as, hepatocyte]), verbo([nuclear]), complemento([factor, 3, β, or, transcription, factor, 3, 'β),', has, been, found, to, play, pivotal, roles, in, multiple, phases, of, mammalian, 'life,', from, the, early, development, to, the, 'organofaction,', and, subsequently, in, homeostasis, and, metabolism, in, the, adult])].
[sujeto(['In', the, embryonic, development, 'period,', 'FOXA2', is]), verbo([require]), complemento([d, for, the, formation, of, the, primitive, node, and, 'notochord,', and, its, absence, results, in, embryonic, lethality])].
[sujeto(['Leukotriene', pathway, and, signal, transducers, and, activators, of, transcription, 6, pathway, may]), verbo([mediate]), complemento([this, inflammation, through, recruitment, and, activation, of, denditric, cell, during, lung, developments])].
[sujeto(['FOXA2', is, a, potential, treatment]), verbo([target]), complemento([for, lung, diseases, with, 'Th2', inflammation, and, goblet, cell, 'hyperplasia,', such, as, asthma, and, chronic, obstructive, pulmonary, disease])].
[sujeto(['In', this, 'study,', by, using, a, combination, of, chemical, inhibition, and, genetic, approaches, in, zebrafish, and, murine, 'cells,', we, identify, a, mechanism, by, which, cPLA2α]), verbo([promotes]), complemento([cell, proliferation])].
[sujeto(['We', identified, 2, cpla2α, genes, in, 'zebrafish,', cpla2αa, and, 'cpla2αb,', with]), verbo([conserved]), complemento([phospholipase, activity])].
[sujeto(['In', 'zebrafish,']), verbo([loss]), complemento([of, cpla2α, expression, or, inhibition, of, cpla2α, activity, diminished, 'G1', progression, through, the, cell, cycle])].
[sujeto(['We', further, show, that, 'PGE2,', through, 'PI3K/AKT', 'activation,']), verbo([promoted]), complemento(['Forkhead', box, protein, 'O1', '(', 'FOXO1)', phosphorylation, and, 'FOXO1', nuclear, export])].
[sujeto(['This']), verbo([led]), complemento([to, 'up-regulation', of, cyclin, 'D1', and, 'down-regulation', of, 'p27(Kip1),', thus, promoting, 'G1', progression])].
[sujeto(['Finally,', using, pharmacologic, 'inhibitors,', we, show, that, 'cPLA2α,', rapidly, accelerated, fibrosarcoma, '(', 'RAF)/MEK/ERK,', and, 'PI3K/AKT', signaling, pathways, cooperatively]), verbo([regulate]), complemento(['G1', progression, in, response, to, 'platelet-derived', growth, factor, stimulation])].
[sujeto(['In', 'summary,', these, data, indicate, that, 'cPLA2α,', through, its, phospholipase, 'activity,', is, a, critical, effector, of, 'G1', phase, progression, through, the, cell, cycle, and]), verbo([suggest]), complemento([that, pharmacological, targeting, of, this, enzyme, may, have, important, therapeutic, benefits, in, disease, mechanisms, that, involve, excessive, cell, 'proliferation,', in, 'particular,', cancer, and, proliferative, glomerulopathies])].
[sujeto(['The']), verbo([nuclear]), complemento(['receptor,', pregnane, 'X', receptor, '(', 'PXR),', is, a, key, transcription, factor, for, the, 'xenobiotic-induced', expression, of, genes, associated, with, various, liver, functions])].
[sujeto(['Recently,', we]), verbo([reported]), complemento([that, 'PXR', activation, stimulates, 'xenobiotic-induced', hepatocyte, proliferation])].
[sujeto(['In', the, present, 'study,', we, investigated, whether, 'PXR', activation, also]), verbo([stimulates]), complemento([growth, 'factor-mediated', hepatocyte, proliferation])].
[sujeto(['In', 'G0', 'phase-synchronized,', immortalized, mouse, 'hepatocytes,', serum, or, epidermal, growth, factor, treatment]), verbo([increased]), complemento([cell, growth, and, this, growth, was, augmented, by, the, expression, of, mouse, 'PXR', and, 'co-treatment', with, pregnenolone, 16, 'α-carbonitrile', '(', 'PCN),', a, 'PXR', ligand])].
[sujeto(['In', a, liver, regeneration, model, using, carbon, 'tetrachloride,', 'PCN', treatment]), verbo([enhanced]), complemento([the, 'injury-induced', increase, in, the, number, of, 'Ki-67-positive', nuclei, as, well, as, 'Ccna2', and, 'Ccnb1', mRNA, levels, in, 'wild-type', '(', 'WT)', but, not, 'Pxr-null', mice])].
[sujeto(['Chronological', analysis, of, this, model, demonstrated, that, 'PCN', treatment, shifted, the, maximum, cell, proliferation, to, an, earlier, time, point, and]), verbo([increased]), complemento([the, number, of, 'M-phase', cells, at, those, time, points])].
[sujeto(['In', 'WT', but, not, 'Pxr-null', 'mice,', 'PCN', treatment, reduced, hepatic, mRNA, levels, of, genes]), verbo([involved]), complemento([in, the, suppression, of, 'G0/G1-', and, 'G1/S-phase', 'transition,', e])].
[sujeto(['Analysis', of, the, 'Rbl2', promoter, revealed, that, 'PXR', activation]), verbo([inhibited]), complemento([its, 'Forkhead', box, 'O3', '(', 'FOXO3)-mediated', transcription])].
[sujeto(['Finally,', the, 'PXR-mediated', enhancement, of, hepatocyte, proliferation, was]), verbo([inhibited]), complemento([by, the, expression, of, dominant, active, 'FOXO3', 'in vitro'])].
[sujeto(['The', results, of, the, present, study]), verbo([suggest]), complemento([that, 'PXR', activation, stimulates, growth, 'factor-mediated', hepatocyte, proliferation, in, 'mice,', at, least, in, 'part,', through, inhibiting, 'FOXO3', from, accelerating, 'cell-cycle', progression])].
[sujeto(['The']), verbo([binding]), complemento([activity, of, 'H3/H4', histone, on, the, 'Ets-1', 'promoter,', and, that, of, forkhead, box, '(', 'FOX)A2,', 'FOXO1', and, 'Ets-1', on, the, 'Pdx-1', promoter, was, measured, by, chromatin, immunoprecipitation, and, quantitative, 'real-time', 'PCR', assay])].
[sujeto(['High', glucose]), verbo([induced]), complemento([upregulation, of, 'Ets-1', expression, and, hyperacetylation, of, histone, 'H3', and, 'H4', at, the, 'Ets-1', gene, promoter, in, beta, cells])].
[sujeto(['Ets-1', overexpression, dramatically]), verbo([suppressed]), complemento([insulin, secretion, and, biosynthesis, both, in, vivo, and, in, vitro])].
[sujeto(['Besides,', 'Ets-1', overexpression]), verbo([increased]), complemento([the, activity, of, 'FOXO1', but, decreased, that, of, 'FOXA2', binding, to, the, pancreatic, and, duodenal, homeobox, 1, '(', 'PDX-1)', homology, region, 2, '(', 'PH2),', resulting, in, inhibition, of, 'Pdx-1', promoter, activity, and, downregulation, of, 'PDX-1', expression, and, activity])].
[sujeto(['In', 'addition,', high, glucose]), verbo([promoted]), complemento([the, interaction, of, 'Ets-1', and, 'FOXO1,', and, the, activity, of, 'Ets-1', binding, to, the, 'Pdx-1', promoter])].
[sujeto(['Importantly,', 'PDX-1', overexpression, reversed, the, defect, in, pancreatic, beta, cells]), verbo([induced]), complemento([by, 'Ets-1', 'excess,', while, knockdown, of, 'Ets-1', prevented, 'hyperglycaemia-induced', dysfunction, of, pancreatic, beta, cells])].
[sujeto(['Our', observations]), verbo([suggest]), complemento([that, 'Ets-1', links, glucotoxicity, to, pancreatic, beta, cell, dysfunction, through, inhibiting, 'PDX-1', expression, in, type, 2, diabetes])].
[sujeto(['Cellular', metabolism, is, increasingly]), verbo([recognized]), complemento([as, a, controller, of, immune, cell, fate, and, function])].
[sujeto(['MicroRNA-33', '(', 'miR-33)']), verbo([regulates]), complemento([cellular, lipid, metabolism, and, represses, genes, involved, in, cholesterol, 'efflux,', 'HDL', 'biogenesis,', and, fatty, acid, oxidation])].
[sujeto(['Macrophage-specific', 'Mir33', deletion]), verbo([increased]), complemento([oxidative, 'respiration,', enhanced, spare, respiratory, 'capacity,', and, induced, an, 'M2', macrophage, 'polarization-associated', gene, profile])].
[sujeto(['Furthermore,', 'miR-33-mediated', 'M2', polarization]), verbo([required]), complemento(['miR-33', targeting, of, the, energy, sensor, 'AMP-activated', protein, kinase, '(', 'AMPK),', but, not, cholesterol, efflux])].
[sujeto(['Notably,', 'miR-33', inhibition]), verbo([increased]), complemento([macrophage, expression, of, the, retinoic, 'acid-producing', enzyme, aldehyde, dehydrogenase, family, 1, ',', subfamily, 'A2', '(', 'ALDH1A2)', and, retinal, dehydrogenase, activity, both, in, vitro, and, in, a, mouse, model])].
[sujeto(['Consistent', with, the, ability, of, retinoic, acid, to, foster, inducible, 'Tregs,', 'miR-33-depleted', macrophages, had, an]), verbo([enhanced]), complemento([capacity, to, induce, forkhead, box, 'P3', '(', 'FOXP3)', expression, in, naive, 'CD4(+)', 'T', cells])].
[sujeto(['Collectively,', these, results]), verbo([reveal]), complemento([that, 'miR-33', regulates, macrophage, inflammation, and, demonstrate, that, 'miR-33', antagonism, is, 'atheroprotective,', in, 'part,', by, reducing, plaque, inflammation, by, promoting, 'M2', macrophage, polarization, and, 'Treg', induction])].
[sujeto(['IL-13']), verbo([increases]), complemento([mucin, '(', 'MUC)', 5, 'AC,', the, major, component, of, airway, 'mucus,', in, airway, epithelial, cells])].
[sujeto(['According', to, the, 'literature,', 'IL-13', receptor, activation]), verbo([leads]), complemento([to, 'STAT6', activation, and, consequent, induction, of, chloride, channel, accessory, 1, '(', 'CLCA1)', gene, 'expression,', associated, with, the, induction, of, 'MUC5AC'])].
[sujeto(['Heme', 'oxygenase-1', '(', 'HO-1)', is, an, enzyme, that, catalyzes, oxidation, of, heme, to, 'biliverdin,', and]), verbo([has]), complemento(['anti-inflammatory', and, 'anti-oxidant', properties])].
[sujeto(['We', examined, the, effects, of, 'HO-1', on, mucin, production, and, goblet, cell, hyperplasia]), verbo([induced]), complemento([by, 'IL-13'])].
[sujeto(['Hemin', '(', 4, 'μM)', significantly]), verbo([increased]), complemento(['HO-1', protein, expression, '(', p, b, 0.01, ')', and, 'HO-1', mRNA, expression, '(', p, b, 0.001, ')'])].
[sujeto(['IL-13', significantly]), verbo([increased]), complemento([goblet, 'cells,', 'MUC5AC', protein, secretion, '(', p, b, 0.01, ')', and, 'MUC5AC', mRNA, '(', p, b, 0.001, ')', ',', and, these, were, decreased, by, hemin, by, way, of, 'HO-1'])].
[sujeto(['Hemin']), verbo([decreased]), complemento([the, expression, of, 'CLCA1', mRNA, '(', p, b, 0.05, ')', and, it, was, reversed, by, 'SnPP-IX,', but, could, not, suppress, 'IL-13-induced', phosphorylation, of, 'STAT6', or, 'SAM', pointed, 'domain-containing', 'ETS', transcription, factor, '(', 'SPDEF)', and, 'Forkhead', box, 'A2', '(', 'FOXA2)', mRNA, expression])].
[sujeto(['In', 'summary,', 'HO-1', overexpression]), verbo([suppressed]), complemento(['IL-13-induced', goblet, cell, hyperplasia, and, 'MUC5AC', 'production,', and, involvement, of, 'CLCA1', in, the, mechanism, was, suggested])].
[sujeto(['To', show, the, efficient, generation, of, 'hepatocyte-like', cells, '(', 'HLCs)', differentiated, from, the]), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'iPSCs)', of, rats])].
[sujeto(['Then', fibroblast, growth, factor, 4, and, bone, morphogenetic, protein, 2, were, added, to, the, culture, medium, and, used, to]), verbo([induce]), complemento([hepatic, differentiation])].
[sujeto(['After', endodermal, 'induction,', the, differentiated, cells]), verbo([expressed]), complemento([endodermal, markers, forkhead, box, protein, 'A2', and, 'SRY-box', containing, gene, 17, at, the, mRNA, and, protein, levels])].
[sujeto(['These', differentiated, cells]), verbo([expressed]), complemento([hepatic, markers, including, 'α-fetoprotein,', albumin, 'CK8,', 'CK18,', 'CK19,', and, transcription, factor, 'HNF-4α'])].
[sujeto(['In', 'addition,', the, cells]), verbo([expressed]), complemento([functional, proteins, such, as, 'α1-antitrypsin,', cytochrome, 'P450', 1, 'A2', and, 'CYP', 3, 'A4'])].
[sujeto(['They']), verbo([acted]), complemento([like, healthy, hepatic, 'cells,', storing, glycogen, and, taking, up, indocyanine, green, and, 'low-density', lipoproteins])].
[sujeto(['Also,', the, rates, of, urea, synthesis, '(', 20, d, 1.202, ±, 0.08, 'mg/dL', vs, 0, d, 0.317, ±, 0.021, 'mg/dL,', 'P', &, 'lt;', 0.01, ')', and, albumin, secretion, '(', 20, d, 1.601, ±, 0.102, 'mg/dL', vs, 0, d, 0.313, ±, 0.015, 'mg/dL,', 'P', &, 'lt;', 0.01, ')']), verbo([increased]), complemento([significantly, as, differentiation, progressed])].
[sujeto(['Hepatocyte-like', cells, differentiated, from, human, pluripotent, stem, cells, '(', such, as, human, embryonic, stem, '(', 'ES)', cells, and]), verbo([induced]), complemento([pluripotent, stem, '(', 'iPS)', 'cells)', are, expected, to, be, utilized, in, drug, screening])].
[sujeto(['To']), verbo([enhance]), complemento([this, hepatocyte, differentiation, 'efficiency,', 'hepatocyte-related', transcription, 'factors,', such, as, forkhead, box, protein, 'A2', '(', 'FOXA2)', and, hepatocyte, nuclear, factor, 1, alpha, '(', 'HNF1α),', were, overexpressed, during, the, hepatocyte, differentiation, process])].
[sujeto(['In', 'addition,', to]), verbo([enhance]), complemento([the, functions, of, 'hepatocyte-like', 'cells,', these, cells, were, cultured, in, three, dimensional, '(', 3, 'D)', conditions, using, a, 'Nanopillar', plate])].
[sujeto(['Various', hepatic, 'functions,', including, albumin, secretion, and, drug, metabolism, 'capacities,', of, the, 'hepatocyte-like', cells, were, significantly]), verbo([enhanced]), complemento([by, performing, 3, 'D', cell, culture])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, method, of, hepatocyte, differentiation, could, be, improved, by, using, gene, transfer, and, 3, 'D', cell, culture, technologies])].
[sujeto(['The', enterohormone, 'glucagon-like', 'peptide-1', '(', 'GLP-1)', is]), verbo([required]), complemento([to, amplify, 'glucose-induced', insulin, secretion, that, facilitates, peripheral, glucose, utilisation])].
[sujeto(['Alteration', in, 'GLP-1', secretion, during, obesity]), verbo([has]), complemento([been, reported, but, is, still, controversial])].
[sujeto(['Due', to, the, high, adaptability, of, intestinal, cells, to, environmental, 'changes,', we, hypothesised, that, the, density, of, 'GLP-1-producing', cells, could, be, modified, by, nutritional, factors, to]), verbo([prevent]), complemento([the, deterioration, of, metabolic, condition, in, obesity])].
[sujeto(['Mice', fed, a, 'HFD', for, 8, weeks, displayed, an]), verbo([increase]), complemento([in, 'GLP-1-positive', cells, in, the, jejunum, and, colon, accordingly, to, 'GLP-1', secretion])].
[sujeto(['Moreover,', genetically, obese, 'ob/ob', mice, did, not, show, alteration, of, 'GLP-1-positive', cell, density, in, the, jejunum, or, 'colon,']), verbo([suggesting]), complemento([that, obesity, per, se, is, not, sufficient, to, trigger, the, mechanism])].
[sujeto(['The', higher, 'L-cell', density, in, 'HFD-fed', mice]), verbo([involved]), complemento([a, rise, in, 'L-cell', terminal, differentiation, as, witnessed, by, the, increased, expression, of, transcription, factors, downstream, of, neurogenin3, '(', 'Ngn3)'])].
[sujeto(['We']), verbo([suggest]), complemento([that, the, observed, increase, in, 'GLP-1-positive', cell, density, triggered, by, high, fat, consumption, in, humans, and, mice, might, favour, insulin, secretion, and, therefore, constitute, an, adaptive, response, of, the, intestine, to, balance, 'diet-induced', insulin, resistance])].
[sujeto(['Despite', the, better, prognosis, of, embryonal, 'RMS,', patients, in, the, 'E2', are, likely, to]), verbo([have]), complemento([a, poor, prognosis])].
[sujeto(['It']), verbo([has]), complemento([been, shown, that, acetylcholine, is, both, a, neurotransmitter, and, acts, as, a, local, 'mediator,', produced, by, airway, cells, including, epithelial, cells])].
[sujeto(['In', vivo, studies]), verbo([have]), complemento([demonstrated, an, indirect, role, for, acetylcholine, in, epithelial, cell, differentiation])].
[sujeto(['Human', airway, epithelial, cells]), verbo([expressed]), complemento([all, components, of, the, 'non-neuronal', cholinergic, 'system,', suggesting, acetylcholine, production])].
[sujeto(['Differentiation', into, goblet, cells, was, barely]), verbo([induced]), complemento([after, air, exposure])].
[sujeto(['Therefore,', 'IL-13', '(', 1, 'ng/mL)', was, used, to]), verbo([induce]), complemento([goblet, cell, metaplasia])].
[sujeto(['IL-13']), verbo([induced]), complemento(['MUC5AC-positive', cells, '(', 5, -, 'fold)', and, goblet, cells, '(', 14, -, 'fold),', as, assessed, by, 'histochemistry,', and, 'MUC5AC', gene, expression, '(', 105, -, 'fold)'])].
[sujeto(['These', effects, were, partly]), verbo([prevented]), complemento([by, tiotropium, '(', 47, -, 92, '%', ')'])].
[sujeto(['Goblet', cell, metaplasia, was]), verbo([induced]), complemento([by, 'IL-13', in, a, 'dose-dependent', 'manner,', which, was, inhibited, by, tiotropium])].
[sujeto(['In', 'addition,', tiotropium, reversed, goblet, cell, metaplasia]), verbo([induced]), complemento([by, 2, weeks, of, 'IL-13', exposure])].
[sujeto(['IL-13']), verbo([decreased]), complemento([forkhead, box, protein, 'A2', '(', 'FoxA2)', expression, '(', 1.6, -, 'fold)', and, increased, 'FoxA3', '(', 3.6, -, 'fold)', and, 'SAM-pointed', 'domain-containing', 'ETS', transcription, factor, '(', 'SPDEF)', '(', 5.2, -, 'fold)', expression])].
[sujeto(['Tiotropium']), verbo([prevented]), complemento([the, effects, on, 'FoxA2', and, 'FoxA3,', but, not, on, 'SPDEF'])].
[sujeto(['We', demonstrate, that, tiotropium]), verbo([has]), complemento([no, effects, on, epithelial, cell, differentiation, after, air, 'exposure,', but, inhibits, and, reverses, 'IL-13-induced', goblet, cell, 'metaplasia,', possibly, via, 'FoxA2', and, 'FoxA3'])].
[sujeto(['Their', importance, in]), verbo([regulating]), complemento([biological, processes, in, the, lung, and, liver, is, extensively, 'characterized,', though, much, less, is, known, about, their, role, in, intestine])].
[sujeto(['FOXA2']), verbo([binding]), complemento([sites, 'genome-wide', were, determined, by, 'ChIP-seq', and, direct, targets, of, the, factor, were, validated, by, 'ChIP-qPCR', and, 'siRNA-mediated', depletion, of, 'FOXA1/2', followed, by, 'RT-qPCR'])].
[sujeto(['Depletion', of, both, 'FOXA1', and, 'FOXA2']), verbo([led]), complemento([to, a, significant, reduction, in, the, expression, of, multiple, transmembrane, proteins, including, ion, channels, and, 'transporters,', which, form, a, network, that, is, essential, for, maintaining, normal, ion, and, solute, transport])].
[sujeto(['One', of, the]), verbo([targets]), complemento([was, the, adenosine, 'A2B', 'receptor,', and, reduced, receptor, mRNA, levels, were, associated, with, a, functional, decrease, in, intracellular, cyclic, 'AMP'])].
[sujeto(['We', also, observed, that, 30, '%', of, 'FOXA2']), verbo([binding]), complemento([sites, contained, a, 'GATA', motif, and, that, 'FOXA1/A2', depletion, reduced, 'GATA-4,', but, not, 'GATA-6', protein, levels])].
[sujeto(['These', data, show, that, 'FOXA2', plays, a, pivotal, role, in]), verbo([regulating]), complemento([intestinal, epithelial, cell, function])].
[sujeto(['Moreover,', that, the, 'FOXA', and, 'GATA', families, of, transcription, factors, may, work, cooperatively, to]), verbo([regulate]), complemento([gene, expression, 'genome-wide', in, the, intestinal, epithelium])].
[sujeto(['Apolipoprotein', 'M', '(', 'ApoM)', is, a, novel, apolipoprotein, that, was, discovered, in, 1999, and, is]), verbo([bound]), complemento([primarily, to, 'high-density', lipoproteins, '(', 'HDLs)', in, the, plasma])].
[sujeto(['Multiple', factors, may, influence, its, expression, at, both, the, 'post-transcriptional', and, the, transcriptional, levels, both, in, vivo, and, ex, vivo, as, 'follows:', hepatocyte]), verbo([nuclear]), complemento(['factor-1α,', 4, α, '(', 'HNF-1α,', 4, 'α),', liver, receptor, 'homolog-1', '(', 'LRH-1),', forkhead, box, 'A2', '(', 'Foxa2)', and, platelet, activating, factor, '(', 'PAF)', upregulate, its, 'expression;', liver, 'X', receptor, '(', 'LXR),', retinoid, 'X', receptor, '(', 'RXR),', farnesoid, 'X', receptor, '(', 'FXR),', small, heterodimer, partner, '(', 'SHP)', and, the, majority, of, cytokines, downregulate, its, expression])].
[sujeto(['Structurally,', there, exists, a, characterized, hydrophobic]), verbo([binding]), complemento([pocket, within, the, apoM, 'protein,', which, enables, it, to, bind, functional, lipids, such, as, 'Sphingosine-1-Phosphate', '(', 'S1P)'])].
[sujeto(['Functionally,', it, facilitates, the, formation, of, 'preβ-HDL', and]), verbo([enhances]), complemento([an, avalanche, of, atheroprotective, effects, exerted, by, 'HDL'])].
[sujeto(['Moreover,', in, patients, with, 'diabetes,', the, levels, of, plasma, apoM, may, 'decrease,', whereas, the, augmentation, of, apoM]), verbo([decreases]), complemento([plasma, glucose, levels, and, magnifies, the, secretion, of, insulin])].
[sujeto(['We', show, characteristic, morphological, changes, corresponding, to, 'epithelial-mesenchymal', transition, '(', 'EMT)', program, fulfillment, in, 'PANC1', cell, line]), verbo([stimulated]), complemento([with, 'TGFβ1'])].
[sujeto(['We', show, 5, -, and, 28, -, fold]), verbo([increase]), complemento([in, 'SNAI1', and, 'SNAI2', expression, levels, and, 25, -, and, 15, -, fold, decrease, in, 'CDH1', and, 'KRT8', expression, 'levels,', 'respectively,', which, confirms, the, 'EMT-program', fulfillment])].
[sujeto(['We', demonstrate, downregulation, of, expression, of, pancreatic, master, genes, 'SOX9,', 'FOXA2,', and, 'GATA4', '(', 2, -, ',', 5, -, ',', and, 4, -, 'fold,', 'respectively)', and, absence, of, significant, changes, in, 'HES1,', 'NR5A2,', and, 'GATA6', expression, levels, in, the, cells]), verbo([stimulated]), complemento([with, 'TGFβ1'])].
[sujeto([1, ',', and, 'ONECUT1', 'genes,', which, are, inactive, in, 'PANC1', cell, line, after, the, 'EMT']), verbo([stimulated]), complemento([by, 'TGFβ1'])].
[sujeto(['Consequently,', the, contribution, of, 'intestine-enriched', factors]), verbo([expressed]), complemento([within, 'BO', to, oncogenesis, is, unclear])].
[sujeto(['Herein,', using, transcriptomics, we, define, the, 'intestine-enriched', genes]), verbo([expressed]), complemento([in, 'meta-profiles', of, 'BO', and, 'OAC'])].
[sujeto(['Interestingly,', 77, '%', of, the, genes, differentially]), verbo([expressed]), complemento([in, a, 'meta-profile', of, 'BO', were, similarly, expressed, in, intestinal, tissues])].
[sujeto(['Furthermore,', 85, '%', of, this, 'intestine-like', signature, was]), verbo([maintained]), complemento([upon, transition, to, 'OAC'])].
[sujeto(['Simulated', acid, reflux, was, observed, to]), verbo([induce]), complemento([the, expression, of, both, 'NR5A2', and, 'GATA6'])].
[sujeto(['Abrogation', of, 'NR5A2-GATA6', expression, in, conjunction, with, 'BCL-XL', 'co-silencing', resulted, in, synergistically]), verbo([increased]), complemento([sensitivity, to, chemotherapeutics, and, 'photo-dynamic', therapeutics])].
[sujeto(['These', findings, characterize, the, 'intestine-like', signature]), verbo([associated]), complemento([with, 'IM', which, may, have, important, consequences, to, adenocarcinogenesis])].
[sujeto(['Transcription', factors, that, play, key, roles, in]), verbo([regulating]), complemento([pancreatic, progenitor, state, have, been, 'identified,', but, the, chromatin, regulators, that, help, establishing, and, maintaining, pancreatic, fate, are, less, well, known])].
[sujeto(['We', show, that, 'Setd7', is]), verbo([expressed]), complemento([in, the, prospective, pancreatic, endoderm, of, 'Xenopus', and, mouse, embryos, prior, to, 'Pdx1', induction])].
[sujeto(['Importantly,', we, demonstrate, that, setd7, is, sufficient, and]), verbo([required]), complemento([for, pancreatic, cell, fate, specification, in, 'Xenopus', 'Functional', and, biochemical, approaches, in, 'Xenopus', and, mouse, endoderm, support, that, 'Setd7', modulates, methylation, marks, at, pancreatic, regulatory, 'regions,', possibly, through, interaction, with, the, transcription, factor, 'Foxa2'])].
[sujeto(['Together,', these, results, demonstrate, that, 'Setd7']), verbo([acts]), complemento([as, a, central, component, of, the, transcription, complex, initiating, the, pancreatic, program])].
[sujeto(['Recently,', the, 'US', 'FDA']), verbo([has]), complemento([approved, &, 'quot;vagal', blocking, therapy, or, 'vBLoc®', 'therapy"', as, a, new, treatment, for, obesity])].
[sujeto(['Rats', were, implanted, with, 'VBLOC,', an, 'intra-abdominal', electrical, device, with]), verbo([leads]), complemento([placed, around, gastric, vagal, trunks, through, an, abdominal, incision, and, controlled, by, wireless, device])].
[sujeto(['VBLOC', reduced, body, weight, and, food, 'intake,', which, was]), verbo([associated]), complemento([with, increased, satiety, but, not, with, decreased, hunger])].
[sujeto(['Brain', activities, in, response, to, 'VBLOC', included]), verbo([increased]), complemento([gene, expression, of, leptin, and, 'CCKb', 'receptors,', 'interleukin-1β,', tumor, necrosis, 'factor,', and, transforming, growth, factor, β1, in, the, 'brainstem;', increased, 'CCK,', 'somatostatin,', and, tyrosine, hydroxylase, in, the, 'hippocampus;', increased, 'NPY,', 'AgRP,', and, 'Foxa2', in, the, 'hypothalamus;', and, reduced, 'CCKb', 'receptor,', melanocortin, 4, 'receptor,', and, insulin, receptor, in, the, hypothalamus])].
[sujeto(['Based', on, the, present, 'study,', we, may]), verbo([suggest]), complemento([that, 'VBLOC', induces, satiety, through, vagal, 'signaling,', leading, to, reduced, food, intake, and, loss, of, body, weight])].
[sujeto(['Because', the, original, 'N27', cell, line]), verbo([has]), complemento([been, passaged, many, 'times,', the, line, has, become, a, mixture, of, cell, types, with, highly, variable, expression, of, 'TH'])].
[sujeto(['In', the, current, 'study,', we]), verbo([have]), complemento([performed, multiple, rounds, of, clonal, cultures, and, have, identified, a, dopaminergic, cell, clone, expressing, high, levels, of, 'TH', and, the, dopamine, transporter, '(', 'DAT)'])].
[sujeto(['We']), verbo([have]), complemento([named, this, new, clone, 'N27-A'])].
[sujeto(['Nearly', 100, '%', of, 'N27-A', cells]), verbo([express]), complemento(['TH,', 'DAT', and, 'Tuj1'])].
[sujeto(['Western', blots]), verbo([have]), complemento([confirmed, that, 'N27-A', cells, have, three, to, four, times, the, levels, of, 'TH', and, 'DAT', compared, to, the, previous, mixed, population, in, 'N27'])].
[sujeto(['Further', analysis]), verbo([has]), complemento([shown, that, the, new, clone, expresses, the, dopamine, neuron, transcription, factors, 'Nurr1,', 'En1,', 'FoxA2', and, 'Pitx3'])].
[sujeto(['The', 'N27-A', cells]), verbo([express]), complemento([the, vesicular, monoamine, transporter, '(', 'VMAT2),', but, do, not, express, 'dopamine-beta-hydroxylase', '(', 'DβH),', the, enzyme, responsible, for, converting, dopamine, to, norepinephrine])].
[sujeto(['Functional', analysis]), verbo([has]), complemento([shown, that, 'N27-A', cells, are, more, sensitive, than, 'N27', cells, to, neurotoxins, taken, up, by, the, dopamine, transporter, such, as, 6, -, hydroxydopamine, and, 1, -, 'methyl-4-phenylpyridine', '(', 'MPP+)'])].
[sujeto(['The', 'DAT', inhibitor, nomifensine, can, block, 'MPP+']), verbo([induced]), complemento([toxicity])].
[sujeto(['The', 'N27-A', cells, show, dopamine]), verbo([release]), complemento([under, basal, and, depolarization, conditions])].
[sujeto(['We', conclude, that, the, new, 'N27-A', clone, of, the, immortalized, rat, dopaminergic, cell, line, 'N27', should]), verbo([provide]), complemento([an, improved, in, vitro, model, for, 'Parkinson\'s', disease, research])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF4α),', a, critical, transcription, 'factor,', plays, an, essential, role, in, the, entire, process, of, liver, development])].
[sujeto(['In', hepatocyte, culture, 'medium,', 'HNF4α-transduced', 'MSCs', '(', 'E7-hHNF4α', 'cells)', strongly]), verbo([expressed]), complemento([the, albumin, '(', 'ALB),', 'CYP2B6,', 'alpha-1', antitrypsin, '(', 'AAT),', and, 'FOXA2', mRNA, and, exhibited, morphology, markedly, similar, to, that, of, mature, hepatocytes])].
[sujeto(['Approximately', 28, '%', of, 'E7-hHNF4α', cells]), verbo([expressed]), complemento([both, 'ALB', and, 'AAT'])].
[sujeto(['Furthermore,', these, 'E7-hHNF4α', cells, via, superior, mesenteric, vein, '(', 'SMV)', injection]), verbo([expressed]), complemento([human, 'ALB', in, mouse, chronic, injured, liver])].
[sujeto(['In', 'conclusion,', this, study, represents, a, novel, strategy, by, directly]), verbo([inducing]), complemento(['hepatocyte-like', cells, from, 'MSCs'])].
[sujeto(['The', ultraweb, 'NF']), verbo([caused]), complemento([better, proliferation, and, characterization, of, 'MSCs'])].
[sujeto(['MSCs', transplantation, significantly, improved, liver, 'functions,']), verbo([increased]), complemento([hepatic, 'HGF', and, 'Bcl-2', 'levels,', whereas, decreased, serum, 'fibronectin,', hepatic, 'TNF-α', and, 'TGF-β1', levels])].
[sujeto(['Hepatic', 'HNF4α,', 'FOXa2,', 'CYP7a1', genes, expression, were]), verbo([enhanced]), complemento([while, 'β-5-Tub', and, 'AFP', genes, expression, were, depressed])].
[sujeto(['ELOVL', family, member, 6, ',', elongation, of, very, long, chain, fatty, acids, '(', 'Elovl6)', is, a, microsomal, 'enzyme,', which]), verbo([regulates]), complemento([the, elongation, of, 'C12-16', saturated, and, monounsaturated, fatty, acids])].
[sujeto(['Elovl6']), verbo([has]), complemento([been, shown, to, be, associated, with, various, pathophysiologies, including, insulin, 'resistance,', 'atherosclerosis,', and, 'non-alcoholic', steatohepatitis])].
[sujeto(['Histological', analysis, revealed, a, reduced, length, of, proliferating, and, an, elongated, length, of, hypertrophic, chondrocyte, 'layer,', and]), verbo([decreased]), complemento([trabecular, bone, in, 'Elovl6-/-', mice, compared, with, controls])].
[sujeto(['These', results, were, presumably, due, to, a, modest]), verbo([decrease]), complemento([in, chondrocyte, proliferation, and, accelerated, differentiation, of, cells, of, the, chondrocyte, lineage])].
[sujeto(['Consistent', with, the]), verbo([increased]), complemento([length, of, the, hypertrophic, chondrocyte, layer, in, 'Elovl6-/-', 'mice,', 'Collagen10α1', was, identified, as, one, of, the, most, affected, genes, by, ablation, of, 'Elovl6', in, chondrocytes])].
[sujeto(['Furthermore,', this, elevated, expression, of, 'Collagen10α1', of, 'Elovl6-null', chondrocytes, was, likely]), verbo([associated]), complemento([with, increased, levels, of, 'Foxa2/a3', and, 'Mef2c', mRNA, expression])].
[sujeto(['Relative']), verbo([increases]), complemento([in, protein, levels, of, nuclear, 'Foxa2', and, cytoplasmic, histone, deacethylase, 4, /, 5, /, 7, were, also, observed, in, 'Elovl6', knockdown, cells, of, the, chondrocyte, lineage])].
[sujeto(['Collectively,', our, data]), verbo([suggest]), complemento([that, 'Elovl6', plays, a, critical, role, for, proper, development, of, embryonic, growth, plate])].
[sujeto(['Studies', in, cultured, cell, lines, and, mice]), verbo([have]), complemento([shown, a, loss, of, 'ZIC2', function, is, the, pathogenic, mechanism, but, the, molecular, details, of, this, 'ZIC2', requirement, remain, elusive])].
[sujeto(['An', intact, 'NODAL', signal, transduction, pathway, and, functional, 'ZIC2', are, both]), verbo([required]), complemento([for, 'PrCP', establishment])].
[sujeto(['We', now, show, that, 'ZIC2']), verbo([acts]), complemento([downstream, of, the, 'NODAL', signal, during, 'PrCP', development])].
[sujeto(['ZIC2', physically]), verbo([interacts]), complemento([with, 'SMAD2', and, 'SMAD3,', the, receptor, activated, proteins, that, control, transcription, in, a, 'NODAL', dependent, manner])].
[sujeto(['Together', 'SMAD3', and, 'ZIC2']), verbo([regulate]), complemento(['FOXA2', transcription, in, cultured, cells, and, 'Zic2', also, controls, the, foxA2, expression, during, 'Xenopus', development])].
[sujeto(['Variant', forms, of, the, 'ZIC2', 'protein,']), verbo([associated]), complemento([with, 'HPE', in, man, or, 'mouse,', are, deficient, in, their, ability, to, influence, 'SMAD-dependent', transcription])].
[sujeto(['These', findings]), verbo([reveal]), complemento([a, new, mechanism, of, 'NODAL', signal, transduction, in, the, mammalian, node, and, provide, the, first, molecular, explanation, of, how, 'ZIC2', 'loss-of-function', precipitates, 'HPE'])].
[sujeto(['Although', much, attention]), verbo([has]), complemento([been, given, to, explore, its, clinical, 'application,', research, of, the, basic, mechanisms, of, 'HE4', in, ovarian, cancer, are, still, unclear])].
[sujeto(['In', the, present, 'study,', we]), verbo([provide]), complemento([fundamental, data, to, identify, 'full-scale', differentially, expressed, genes, '(', 'DEGs)', in, response, to, 'HE4', by, use, of, human, 'whole-genome', microarrays, in, human, epithelial, ovarian, cancer, cell, line, 'ES-2', following, overexpression, and, silencing, of, 'HE4'])].
[sujeto(['We']), verbo([found]), complemento([that, a, total, of, 717, &, 'nbsp;genes', were, upregulated, and, 898, &, 'nbsp;genes', were, downregulated, in, the, 'HE4-overexpressing', cells, vs])].
[sujeto(['These', 'DEGs', were]), verbo([involved]), complemento([in, 'MAPK,', steroid, 'biosynthesis,', cell, 'cycle,', the, p53, hypoxia, 'pathway,', and, focal, adhesion, pathways])].
[sujeto(['Interaction', network, analysis, predicted, that, the, genes]), verbo([participated]), complemento([in, the, regulatory, connection])].
[sujeto(['We']), verbo([found]), complemento([that, 'SERPIND1', may, act, as, a, potential, oncogene, in, the, development, of, ovarian, cancer])].
[sujeto(['These', identified, genes, may]), verbo([provide]), complemento([a, theoretical, basis, for, investigations, of, the, underlying, molecular, mechanism, of, 'HE4', in, ovarian, cancer])].
[sujeto(['The', soluble, form, of, activin, 'A', '(', 'Act)']), verbo([has]), complemento([been, widely, used, as, an, in, vitro, inducer, of, definitive, endoderm, '(', 'DE)'])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([developed, a, nanofibrous, poly, '(', 'ɛ-caprolactone)', 'substrate,', biofunctionalized, with, 'Act,', for, directed, differentiation, of, hESCs, into, 'DE'])].
[sujeto(['The', nanofibers, with, covalent, iAct, significantly]), verbo([increased]), complemento([expression, levels, of, the, endodermal, markers, 'SOX17,', 'FOXA2,', and, 'CXCR4,', compared, with, physically, adsorbed, 'Act', '(', 'aAct)', or, without, 'Act', '(', 'noAct)'])].
[sujeto(['In', 'addition,', iAct]), verbo([retained]), complemento([its, bioactivity, after, storage, for, five, days, in, the, absence, of, cell, seeding])].
[sujeto(['Hypoxia']), verbo([has]), complemento([been, demonstrated, to, play, an, important, role, in, embryonic, formation, and, development, and, to, modulate, stem, cell, differentiation])].
[sujeto(['However,', the, influence, of, oxygen, tension, on, thyroid, differentiation]), verbo([has]), complemento([not, been, studied])].
[sujeto(['In', this, 'study,', we, used, murine]), verbo([induced]), complemento([pluripotent, stem, '(', 'iPS)', cells, for, thyroid, cell, differentiation, under, normoxic, and, hypoxic, conditions, and, compared, differentiation, efficiency, in, 'morphology,', 'function,', gene, and, protein, expression, under, both, conditions])].
[sujeto(['We']), verbo([found]), complemento([that, hypoxia, promoted, adhesion, and, outgrowth, of, embryoid, bodies, '(', 'EBs)', derived, from, murine, iPS, cells])].
[sujeto([1, ')', was]), verbo([increased]), complemento([by, hypoxia, at, both, gene, and, protein, levels, during, 'early-mid', differentiation, stages, '(', 'p<0'])].
[sujeto(['In', 'addition,', functional, iodide, uptake, by, differentiated, cells, was, also]), verbo([increased]), complemento([after, hypoxia])].
[sujeto(['Thyroid', differentiation, from, iPS, cells, is]), verbo([enhanced]), complemento([under, hypoxia, and, this, may, involve, hypoxia, inducible, factors, '(', 'HIFs)', and, their, downstream, gene, 'FGF2'])].
[sujeto(['Our', data, offer, a, foundation, for, understanding, thyroid, development, and]), verbo([provide]), complemento([a, potentially, more, efficient, way, to, use, cell, therapy, for, treating, thyroid, deficiency])].
[sujeto([:, 'The', progressive, death, of, dopamine, producing, neurons, in, the, substantia, nigra, pars, compacta, is, the, principal]), verbo([cause]), complemento([of, symptoms, of, 'Parkinson\'s', disease, '(', 'PD)'])].
[sujeto(['Stem', cells]), verbo([have]), complemento([potential, therapeutic, use, in, replacing, these, cells, and, restoring, function])].
[sujeto(['To', this, 'end,', we, differentiated, baboon, 'fibroblast-derived']), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'biPSCs)', into, dopaminergic, neurons, with, the, application, of, specific, morphogens, and, growth, factors])].
[sujeto(['We', confirmed, that, 'biPSC-derived', dopaminergic, neurons, resemble, those]), verbo([found]), complemento([in, the, human, midbrain, based, on, cell, 'type-specific', expression, of, dopamine, markers, 'TH', and, 'GIRK2'])].
[sujeto(['Using', the, reverse, transcriptase, quantitative, polymerase, chain, 'reaction,', we, also, showed, that, 'biPSC-derived', dopaminergic, neurons]), verbo([express]), complemento(['PAX6,', 'FOXA2,', 'LMX1A,', 'NURR1,', and, 'TH', genes, characteristic, of, this, cell, type, in, vivo])].
[sujeto(['Finally,', we, showed, that, 'biPSC-derived', neurons]), verbo([released]), complemento([catecholamines, in, response, to, electrical, stimulation])].
[sujeto(['Functional', dopamine, neurons, were, produced, from, baboon]), verbo([induced]), complemento([pluripotent, stem, 'cells,', and, their, properties, were, compared, to, baboon, midbrain, cells, in, vivo])].
[sujeto(['The', baboon]), verbo([has]), complemento([advantages, as, a, clinically, relevant, model, in, which, to, optimize, the, efficacy, and, safety, of, stem, 'cell-based', therapies, for, neurodegenerative, 'diseases,', such, as, 'Parkinson\'s', disease])].
[sujeto(['However,', it, is, currently, unclear, how, these, embryonic, tissue, interactions, can, be]), verbo([translated]), complemento([into, a, defined, differentiation, protocol, for, human, embryonic, stem, cells])].
[sujeto(['Activin', 'A']), verbo([has]), complemento([been, proposed, to, direct, 'DE', into, a, 'SOX2-positive', 'foregut-like', cell, type])].
[sujeto(['We', show, in, contrast, to, previous, studies, that, the, generation, of, the, foregut, marked, by, 'SOX2/FOXA2', 'double-positive', cells, does, not, depend, on, activin, 'A/TGF-β-signaling', but, is]), verbo([mediated]), complemento([by, the, inhibition, of, 'Wnt-', and, 'BMP-signaling'])].
[sujeto(['Retinoic', acid, can, posteriorize, and, at, the, same, time, dorsalize, the, foregut, toward, a, 'PDX1-positive', pancreatic, duodenal, cell, type, whereas, active, 'Wnt/beta-catenin', signaling, synergistically, with, 'FGF-2,', 'BMP-4,', and, 'RA']), verbo([induces]), complemento([the, formation, of, 'CDX2-positive', posterior, endoderm])].
[sujeto(['Thus,', these, results]), verbo([provide]), complemento([new, insights, into, the, mechanisms, behind, cell, specification, of, human, 'DE', derived, from, pluripotent, stem, cells])].
[sujeto(['While', orthotopic, transplantation, into, the, testis]), verbo([promotes]), complemento([seminomatous, growth, of, the, 'seminoma-like', cell, line, 'TCam-2,', ectopic, xenotransplantation, into, the, flank, initiates, reprogramming, into, an, 'EC-like', fate])].
[sujeto(['During', this, 'reprogramming,', 'BMP', signaling, is, 'inhibited,']), verbo([leading]), complemento([to, induction, of, 'NODAL', 'signaling,', upregulation, of, pluripotency, factors, and, downregulation, of, seminoma, 'markers,', like, 'SOX17'])].
[sujeto(['In', 'contrast,', the, pioneer, factor, 'FOXA2', and, its]), verbo([target]), complemento([genes, were, 'upregulated,', suggesting, that, 'FOXA2', might, play, an, important, role, in, induction, of, 'non-seminomatous', differentiation])].
[sujeto(['The', lipophilic, statin, lovastatin]), verbo([decreases]), complemento([cholesterol, synthesis, and, is, a, safe, and, effective, treatment, for, the, prevention, of, cardiovascular, diseases])].
[sujeto(['We']), verbo([found]), complemento([that, lovastatin, treatment, delayed, 'NANOG', downregulation, during, ectodermal, and, endodermal, differentiation])].
[sujeto(['Exposure', of, hES, cells, to, lovastatin]), verbo([led]), complemento([to, a, minor, decrease, in, the, expression, of, 'SSEA-3', and, a, significant, reduction, in, 'CD133', expression])].
[sujeto(['By', analyzing, hES, with, and, without, 'CD133,', we, discovered, that, 'CD133', expression, is]), verbo([required]), complemento([for, proper, formation, of, embryoid, bodies])].
[sujeto(['Mammalian', anterior, gradient, 2, '(', 'AGR2),', an, endoplasmic, reticulum, '(', 'ER)', protein, 'disulfide-isomerase', '(', 'PDI),', is]), verbo([involved]), complemento([in, cancer, cell, growth, and, 'metastasis,', asthma, and, inflammatory, bowel, disease, '(', 'IBD)'])].
[sujeto(['Mice', lacking, 'Agr2', exhibit]), verbo([decreased]), complemento(['Muc2', protein, in, intestinal, goblet, 'cells,', abnormal, 'Paneth', cell, 'development,', ileitis, and, colitis])].
[sujeto(['Despite', its, importance, in, cancer, biology, and, inflammatory, 'diseases,', the, mechanisms]), verbo([regulating]), complemento([agr2, expression, in, the, gastrointestinal, tract, remain, unclear])].
[sujeto(['No', 'EGFP', expression, was, detected, in, the, intestinal, goblet, cells, of, 'Tg(HREM:EGFP)', or, 'Tg(FHREM:EGFP)', embryos, with, mutated, 'HRE', or, 'FHRE,', whereas, 'EGFP', was]), verbo([expressed]), complemento([in, the, pharynx, of, 'Tg(HREM:EGFP),', but, not, 'Tg(FHREM:EGFP),', embryos])].
[sujeto(['Morpholino', knockdown, of, foxa1, '(', forkhead, box, 'A1)', reduced, agr2, levels, in, the, 'pharynx,', whereas, knockdown, of, foxa2, or, hif1ab]), verbo([decreased]), complemento([intestinal, agr2, expression, and, affected, the, differentiation, and, maturation, of, intestinal, goblet, cells])].
[sujeto(['These', results, demonstrate, that, 'Foxa1']), verbo([regulates]), complemento([agr2, expression, in, the, 'pharynx,', whereas, both, 'Foxa2', and, 'Hif1ab', control, agr2, expression, in, intestinal, goblet, cells, to, regulate, maturation, of, these, cells])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, exposure, to, phenyl, ethyl, alcohol, '(', 'PEA)', causes, an, increase, in, the, expression, of, the, transcription, factor, otx2, in, the, olfactory, epithelium, '(', 'OE)', of, juvenile, 'zebrafish,', and, this, change, is, correlated, with, the, formation, of, an, odor, memory, of, 'PEA'])].
[sujeto(['Subsequent', in, silico, analysis, uncovered, 'Hnf3b']), verbo([binding]), complemento([sites, closely, associated, with, 'Otx2', binding, sites, in, the, regions, flanking, the, 'ORs'])].
[sujeto(['Analysis', by, quantitative, polymerase, chain, reaction, and, 'RNA-seq', of, 'OR', expression, in, developing, zebrafish, exposed, to, different, isoforms, of, 'PEA', showed, that, a, subset, of, 'ORs', containing, both, 'Otx2/Hnf3b']), verbo([binding]), complemento([sites, were, downregulated, only, in, 'βPEA-exposed', juveniles, and, this, change, persisted, through, adult, life])].
[sujeto(['Localization', of, 'OR', expression, by, in, situ, hybridization, indicates, the, downregulation, occurs, at, the, level, of, 'RNA', and, not, the, number, of, cells]), verbo([expressing]), complemento([a, given, receptor])].
[sujeto(['Finally,', analysis, of, immediate, early, gene, expression, in, the, 'OE', did, not]), verbo([reveal]), complemento([changes, in, 'c-fos', expression, in, response, to, either, αPEA, or, βPEA])].
[sujeto(['SSCs', first, changed, into, hepatic, 'stem-like', cells, since, they, resembled, hepatic, oval, cells, in, morphology, and]), verbo([expressed]), complemento(['Ck8,', 'Ck18,', 'Ck7,', 'Ck19,', 'OV6,', and, albumin])].
[sujeto(['Notably,', these, differentiated, cells, acquired, functional, attributes, of, 'hepatocyte-like', cells, because, they, secreted, 'albumin,', synthesized, 'urea,', and, uptake, and]), verbo([released]), complemento([indocyanine, green])].
[sujeto(['Moreover,', phosphorylation, of, 'ERK1/2', and, 'Smad2/3', rather, than, 'Akt', was]), verbo([activated]), complemento([in, hepatic, stem, cells, and, mature, hepatocytes])].
[sujeto(['This', study, thus]), verbo([provides]), complemento([an, invaluable, source, of, mature, hepatocytes, for, treating, 'liver-related', diseases, and, drug, toxicity, screening, and, offers, novel, insights, into, mechanisms, of, liver, development, and, cell, reprogramming])].
[sujeto(['This', gene]), verbo([has]), complemento([a, 'CpG', island, extending, 2500, bp, from, the, translational, start, 'site;', 'however,', studies, characterizing, its, transcriptional, regulation, have, not, been, conducted])].
[sujeto(['Two', transcripts, for, 'DAPK', were, identified, that, code, for, a, single, 'protein,', while, being]), verbo([regulated]), complemento([by, two, promoters])].
[sujeto(['The', previously, identified, 'DAPK', transcript, designated, as, exon, 1, transcript, was]), verbo([expressed]), complemento([at, levels, 3, -, fold, greater, than, the, alternate, exon, 1, b, transcript])].
[sujeto(['Sequencing', the, 'DAPK', 'CpG', island, in, tumor, cell, lines, revealed, 'dense,', but, heterogenous, methylation, of, 'CpGs', that, blocked, access, of, the, 'CP2', and, 'HNF3B', proteins, that, in, 'turn,', was]), verbo([associated]), complemento([with, loss, of, transcription, that, was, restored, by, treatment, with, 5, -, 'aza-2\'-deoxycytidine'])].
[sujeto(['Growing', evidence, indicates, that, microRNAs]), verbo([have]), complemento([a, significant, role, in, tumor, development, and, may, constitute, robust, biomarkers, for, cancer, diagnosis, and, prognosis])].
[sujeto(['We']), verbo([report]), complemento([that, 'miR-122', is, specifically, repressed, in, a, subset, of, primary, tumors, that, are, characterized, by, poor, prognosis])].
[sujeto(['We', further, show, that, the]), verbo([loss]), complemento([of, 'miR-122', expression, in, tumor, cells, segregates, with, specific, gene, expression, profiles, linked, to, cancer, 'progression,', namely, the, suppression, of, hepatic, phenotype, and, the, acquisition, of, invasive, properties])].
[sujeto(['We', identify, 'liver-enriched', transcription, factors, as, central, regulatory, molecules, in, the, gene, networks]), verbo([associated]), complemento([with, loss, of, 'miR-122,', and, provide, evidence, suggesting, that, 'miR-122', is, under, the, transcriptional, control, of, 'HNF1A,', 'HNF3A', and, 'HNF3B'])].
[sujeto(['We', further, show, that]), verbo([loss]), complemento([of, 'miR-122', results, in, an, increase, of, cell, migration, and, invasion, and, that, restoration, of, 'miR-122', reverses, this, phenotype])].
[sujeto(['One', known, genetic, mechanism, for, transient, neonatal, diabetes, is]), verbo([loss]), complemento([of, methylation, at, 6, q24])].
[sujeto(['The', etiology, of, prune, belly, sequence, is, unknown, but, a, genetic, 'defect,', affecting, the, mesoderm, from, which, the, triad, abdominal, muscle, 'hypoplasia,', urinary, tract, 'abnormalities,', and, cryptorchidism, 'develop,']), verbo([has]), complemento([been, suggested])].
[sujeto(['The', proband, had]), verbo([loss]), complemento([of, methylation, at, the, 6, q24, locus, 'TNDM', and, also, at, the, loci, 'IGF2R,', 'DIRAS3,', and, 'PEG1,', while, the, other, family, 'members,', including, the, healthy, monozygotic, 'twin,', had, normal, findings])].
[sujeto(['The']), verbo([loss]), complemento([of, methylation, on, chromosome, 6, q24, and, elsewhere, may, indicate, a, generalized, maternal, hypomethylation, 'syndrome,', which, accounts, for, both, transient, neonatal, diabetes, and, prune, belly, sequence])].
[sujeto(['Mammalian', 'tissue-', 'and/or', 'time-specific', transcription, is, primarily]), verbo([regulated]), complemento([in, a, combinatorial, fashion, through, interactions, between, a, specific, set, of, transcriptional, regulatory, factors, '(', 'TRFs)', and, their, cognate, 'cis-regulatory', elements, located, in, the, regulatory, regions])].
[sujeto(['In', exploring, the, 'DNA', regions, and, 'TRFs']), verbo([involved]), complemento([in, combinatorial, transcriptional, 'regulation,', we, noted, that, individual, knockdown, of, a, set, of, human, 'liver-enriched', 'TRFs', such, as, 'HNF1A,', 'HNF3A,', 'HNF3B,', 'HNF3G', and, 'HNF4A', resulted, in, perturbation, of, the, expression, of, several, single, 'TRF', 'genes,', such, as, 'HNF1A,', 'HNF3G', and, 'CEBPA', genes])].
[sujeto(['We', thus, searched, the, potential]), verbo([binding]), complemento([sites, for, these, five, 'TRFs', in, the, highly, conserved, genomic, regions, around, these, three, 'TRF', genes, and, found, several, putative, combinatorial, regulatory, regions])].
[sujeto(['Chromatin', immunoprecipitation, analysis, revealed, that, almost, all, of, the, putative, regulatory, 'DNA', regions, were]), verbo([bound]), complemento([by, the, 'TRFs', as, well, as, two, coactivators, '(', 'CBP', and, 'p300)'])].
[sujeto(['EMSA', demonstrated, specific, bindings, of, these, 'HNFs', to, the]), verbo([target]), complemento(['DNA', region])].
[sujeto(['The', 'liver-specific', activity, of, 'ENII', is]), verbo([regulated]), complemento([by, multiple, 'liver-enriched', transcription, 'factors,', including, 'LRH-1/hB1F,', 'HNF1,', 'HNF3b,', 'HNF4', and, 'C/EBP'])].
[sujeto(['In', this, 'study,', we, demonstrate, a, functional, synergism, between, the, orphan]), verbo([nuclear]), complemento([receptor, 'LRH-1/hB1F', and, the, homeoprotein, 'HNF1', in, 'up-regulating', the, 'liver-specific', activity, of, 'ENII'])].
[sujeto(['We']), verbo([have]), complemento([defined, the, activation, domains, in, hB1F, and, 'HNF1', that, contribute, to, the, synergism])].
[sujeto(['We', further, show, that, hB1F, and, 'HNF1', can]), verbo([interact]), complemento([directly, in, vitro, and, have, mapped, the, domains, required, for, this, interaction])].
[sujeto(['Angiotensin', 'II']), verbo([has]), complemento([been, shown, to, exert, complex, effects, on, proximal, tubular, cell, function, and, growth])].
[sujeto(['We', used, 'DNA', microarrays, to, analyze, multiple, gene, expression, responses, to]), verbo([increasing]), complemento([angiotensin, 'II', concentrations])].
[sujeto(['Coordinated', changes, were, observed, in, genes, of, the, hepatocyte]), verbo([nuclear]), complemento([factor, 3, family, '(', 'NHF3;', 'HNF3A,', 'HNF3B', and, 'HNF3G),', in, the, 'E2F', genes, '(', 'E2F1,', 'E2F3)', and, the, interferon, regulatory, factors, 'IRF1', and, 'IRF5'])].
[sujeto(['Three', genes]), verbo([involved]), complemento([in, the, dampening, of, oxidative, stress, were, enhanced])].
[sujeto(['Taken', 'together,', brief, exposure, of, human, tubular, epithelial, cells, to, angiotensin, 'II', elicited, a, marked, induction, of]), verbo([nuclear]), complemento(['factors,', antioxidant, genes, and, hormones, and, hormone, receptor, genes])].
[sujeto(['We']), verbo([have]), complemento([discovered, two, 'single-nucleotide', polymorphisms, in, the, 5, '\'', flanking, region, of, the, 'HFE', gene])].
[sujeto(['When', a, 'T', was, present, at, -, 970, ',', a, 'C', was, always]), verbo([found]), complemento([at, -, 467])].
[sujeto(['The', less, common, -, 467, mutation, was]), verbo([found]), complemento([in, almost, 12, chromosomes, that, bore, the, 845, 'G-->A', '(', 'C282Y)', mutation, and, was, significantly, more, prevalent, in, chromosomes, containing, the, 187, 'C-->G', '(', 'H63D)', mutation])].
[sujeto(['The', tighter, association, of, the, -, 467, polymorphism, with, the, 'C282Y', mutation, is, consistent, with, other, data, that]), verbo([suggest]), complemento([that, the, 'C282Y', mutation, has, occurred, relatively, recently, and, that, the, 'H63D', mutation, is, considerably, older])].
[sujeto(['DNase', 'I', footprinting, from, mouse, cells, revealed, that, several, potential, 'cis-elements', were, occupied, by]), verbo([nuclear]), complemento([proteins])].
[sujeto(['Our', data]), verbo([provide]), complemento([insight, into, the, regulatory, mechanisms, that, govern, the, expression, of, the, 'MAP1A', gene])].
[sujeto(['Mutations', in, genes, encoding, hepatocyte]), verbo([nuclear]), complemento([factor, '(', 'HNF)', are, responsible, for, three, of, the, five, subtypes, of, 'maturity-onset', diabetes, of, the, young, '(', 'MODY)'])].
[sujeto(['This', observation, and, molecular, studies, indicate, that, the, 'HNF', network, is]), verbo([required]), complemento([for, normal, function, of, pancreatic, 'beta-cells'])].
[sujeto(['This']), verbo([suggests]), complemento([that, transcription, factors, involved, in, this, complex, network, are, candidates, for, genetic, defects, in, 'MODY'])].
[sujeto(['All', of, the, five, known, 'MODY', 'genes,', 'HNF-4alpha,', 'glucokinase,', 'HNF-1alpha,', 'HNF-1beta,', and, 'IPF1,', were, previously, excluded, as, being, the]), verbo([cause]), complemento([of, diabetes, in, these, families])].
[sujeto(['Familial', segregation, studies, and, linkage, analysis, showed, that, genetic, variation, in, the, 'HNF-3beta', gene, is, unlikely, to, be, the]), verbo([cause]), complemento([of, 'early-onset', type, 2, diabetes, in, these, 'Caucasian', families])].
[sujeto(['Mutations', in, the, transcription, factors, hepatocyte]), verbo([nuclear]), complemento([factor, '(', 'HNF)-4alpha', and, -, 1, 'alpha,', insulin, promoter, 'factor-1,', and, 'HNF-1beta', are, the, causes, of, four, forms, of, 'maturity-onset', diabetes, of, the, young, '(', 'MODY1', and, 3, -, 5, ',', 'respectively)'])].
[sujeto(['The', 'winged-helix', transcription, factor, 'HNF-3beta']), verbo([has]), complemento([been, implicated, in, the, regulation, of, expression, of, each, of, these, 'MODY', 'genes,', suggesting, that, mutations, in, the, 'HNF-3beta', gene, '(', 'HNF3B)', may, also, cause, 'MODY'])].
[sujeto(['We']), verbo([have]), complemento([tested, this, hypothesis, by, screening, a, panel, of, 57, unrelated, 'Japanese', subjects, with, a, clinical, diagnosis, of, 'MODY', for, mutations, in, 'HNF3B'])].
[sujeto(['This', analysis, revealed, four, frequent, polymorphisms, that, were, not]), verbo([associated]), complemento([with, 'MODY,', including, one, in, the, promoter, region, '(', -, 213, 'A/G),', two, silent, mutations, in, the, codons, for, 'Ala', 97, '(', 291, 'C/T)', and, 'Gly', 279, '(', 837, 'A/G),', and, one, in, the, 3, '\'', -, untranslated, region, '(', 1424, 'C/T)'])].
[sujeto(['Two', rare, substitutions, in, the, 5, '\'', -, untranslated, 'region,', -, 156, 'C/T', and, -, 67, 'A/C,', were]), verbo([found]), complemento([in, a, heterozygous, state, in, two, 'subjects,', and, two, subjects, were, heterozygous, for, putative, missense, 'mutations,', 'S109N', '(', 326, 'G', &, 'gt;', 'A)', and, 'A328V', '(', 983, 'C>T)'])].
[sujeto(['The', two, missense, mutations, were, not]), verbo([found]), complemento([in, 106, normal, chromosomes, from, nondiabetic, subjects])].
[sujeto(['It', was, not, possible, to, test, for, 'co-segregation', of, these, mutations, with, diabetes, and, 'thus,', it, is, unclear, whether, or, not, these, mutations, can]), verbo([cause]), complemento(['MODY'])].
[sujeto(['The', results, of, our, study]), verbo([suggest]), complemento([that, mutations, in, 'HNF3B', are, not, a, common, cause, of, 'MODY', in, 'Japanese', subjects])].
[sujeto(['Small', heterodimer, partner, '(', 'SHP;', 'NR0B2)', is, an, atypical, orphan]), verbo([nuclear]), complemento([receptor, and, acts, as, a, coregulator, of, various, nuclear, receptors])].
[sujeto(['Herein,', we, examined, a, novel, cross, talk, between, 'SHP', and, a, forkhead, transcription, factor, 'HNF3', '(', hepatocyte]), verbo([nuclear]), complemento([factor, 3, /, 'Foxa'])].
[sujeto(['Transient', transfection, assay, demonstrated, that, 'SHP']), verbo([inhibited]), complemento([the, transcriptional, activity, of, all, three, isoforms, of, 'HNF3,', 'HNF3alpha,', 'beta,', and, gamma])].
[sujeto(['In', vivo, and, in, vitro, protein, interaction, studies, showed, that, 'SHP', physically]), verbo([interacted]), complemento([with, 'HNF3'])].
[sujeto(['Adenovirus-mediated', overexpression, of, 'SHP', significantly]), verbo([decreased]), complemento([the, mRNA, levels, of, 'glucose-6-phosphase', '(', 'G6Pase),', cholesterol, 7, -, 'alpha-hydroxylase', '(', 'CYP7A1),', and, phosphoenolpyruvate, carboxykinase, '(', 'PEPCK)', in, 'HepG2', cells, and, rat, primary, hepatocytes])].
[sujeto(['Moreover,', the, mRNA, level, of, 'G6Pase', was, notably]), verbo([increased]), complemento([by, 'down-regulation', of, 'SHP', with, small, interfering, 'RNA'])].
[sujeto(['Interestingly,', 'HNF3', transactivity, was, still]), verbo([repressed]), complemento([by, 'SHPDelta128-139', that, fails, to, repress, nuclear, receptors])].
[sujeto(['Mapping', of, interaction, domain, revealed, that, 'SHP']), verbo([interacted]), complemento([with, forkhead, 'DNA', binding, domain, of, 'HNF3alpha'])].
[sujeto(['Gel', mobility, shift, and, chromatin, immunoprecipitation, assays, demonstrated, that, 'SHP']), verbo([inhibits]), complemento(['DNA', binding, of, 'HNF3'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'SHP', is, involved, in, the, regulation, of, 'G6Pase,', 'CYP7A1,', and, 'PEPCK', gene, expression, via, novel, mechanism, of, inhibition, of, 'HNF3', activity, and, expand, the, role, of, 'SHP', as, a, coregulator, of, other, family, of, transcription, factors, in, addition, to, nuclear, receptors])].
[sujeto(['We']), verbo([have]), complemento([developed, a, protocol, of, differentiation, of, human, embryonic, stem, cells, '(', 'ES)', towards, 'hepatocyte-like', cells, '(', 'ES-Hep)'])].
[sujeto(['Using', a, set, of, human, adult, markers, including, 'CAAT/enhancer']), verbo([binding]), complemento([protein, '(', 'C/EBPalpha),', hepatocyte, nuclear, factor, 4, /, 7, ratio, '(', 'HNF4alpha1/HNF4alpha7),', cytochrome, 'P450', 7, 'A1', '(', 'CYP7A1),', 'CYP3A4', and, constitutive, androstane, receptor, '(', 'CAR),', and, fetal, markers, including, 'alpha-fetoprotein,', 'CYP3A7', and, glutathione, 'S-transferase', 'P1,', we, analyzed, the, expression, of, a, panel, of, 41, genes, in, 'ES-Hep', comparatively, with, human, adult, primary, 'hepatocytes,', adult, and, fetal, liver])].
[sujeto(['When', compared, with, 'hepatocyte-like', cells, derived, from, adult, liver, non, parenchymal, epithelial, '(', 'NPE)', cells, '(', 'NPE-Hep),', 'ES-Hep']), verbo([expressed]), complemento([several, adult, and, fetal, liver, makers, at, much, greater, levels, '(', at, least, one, order, of, 'magnitude),', consistent, with, greater, expression, of, 'liver-enriched', transcription, factors, 'Forkhead', box, 'A2,', 'C/EBPalpha,', 'HNF4alpha', and, 'HNF6'])].
[sujeto(['Finally', we, showed, that, 'lentivirus-mediated', expression, of, xenoreceptor, 'CAR', in, 'ES-Hep']), verbo([induced]), complemento([the, expression, of, several, detoxification, genes, including, 'CYP2B6,', 'CYP2C9,', 'CYP3A4,', 'UDP-glycosyltransferase', 1, 'A1,', solute, carriers, 21, 'A6,', as, well, as, biotransformation, of, 'midazolam,', a, 'CYP3A4-specific', substrate])].
[sujeto(['We']), verbo([found]), complemento([that, the, hepatic, differentiation, of, maGSCs, was, induced, by, the, 'OP9', 'co-culture', system, in, comparison, to, the, gelatin, culture])].
[sujeto(['Furthermore,', we, showed, that, the, combination, of, 'OP9', 'co-culture', with, activin, 'A', resulted, in, the]), verbo([increased]), complemento([expression, of, endodermal, and, early, hepatic, markers, 'Gata4,', 'Sox17,', 'Foxa2,', 'Hnf4,', 'Afp,', and, 'Ttr', compared, to, differentiated, cells, on, gelatin, or, on, 'OP9', alone])].
[sujeto(['These', generated, hepatic, cells, successfully, demonstrated, in, vitro, functions]), verbo([associated]), complemento([with, mature, 'hepatocytes,', including, albumin, and, urea, 'secretion,', glycogen, 'storage,', and, uptake, of, 'low-density', lipoprotein])].
[sujeto(['Specification', of, these, progenitors, with, bone, morphogenetic, 'protein-4', in, combination, with, basic, fibroblast, growth, factor, and, activin, 'A', results, in, the, development, of, hepatic, populations, highly, enriched, '(', 45, -, 70, '%', ')', for, cells, that]), verbo([express]), complemento([the, 'alpha-fetoprotein', and, albumin, proteins])].
[sujeto(['These', cells, also]), verbo([express]), complemento([transcripts, of, 'Afp,', 'Alb1,', 'Tat,', 'Cps1,', 'Cyp7a1', and, 'Cyp3a11;', they, secrete, 'albumin,', store, 'glycogen,', show, ultrastructural, characteristics, of, mature, 'hepatocytes,', and, are, able, to, integrate, into, and, proliferate, in, injured, livers, in, vivo, and, mature, into, hepatocytes, expressing, dipeptidyl, peptidase, 'IV', or, fumarylacetoacetate, hydrolase])].
[sujeto(['Together,', these, findings, establish, a, developmental, pathway, in, embryonic, stem, cell, differentiation, cultures, that]), verbo([leads]), complemento([to, efficient, generation, of, cells, with, an, immature, hepatocytic, phenotype])].
[sujeto(['Corneal', epithelium, is]), verbo([maintained]), complemento([by, a, population, of, stem, cells, '(', 'SCs)', that, have, not, been, identified, by, specific, molecular, markers])].
[sujeto(['The', objective, of, this, study, was, to]), verbo([find]), complemento([new, putative, markers, for, these, 'SCs', and, to, identify, associated, molecular, pathways])].
[sujeto(['RT²-PCR-A', results, indicated, an]), verbo([increased]), complemento([or, decreased, expression, in, 21, and, 24, 'genes,', 'respectively,', in, cells, from, the, corneal, 'SC', niche, compared, to, cells, from, the, central, corneal, epithelium])].
[sujeto(['Functional', analysis, by, proprietary, software]), verbo([found]), complemento([4, different, associated, pathways, and, a, novel, network, with, the, highest, upregulated, genes, in, the, corneal, 'SC', niche])].
[sujeto(['This']), verbo([led]), complemento([to, the, identification, of, specific, 'molecules,', chemokine, '(', 'C-X-C', 'motif)', ligand, 12, '(', 'CXCL12),', 'islet-1', transcription, factor, 'LIM/homeodomain', '(', 'ISL1),', 'collagen-type', 'II', alpha, 1, '(', 'COL2A),', neural, cell, adhesion, molecule, 1, '(', 'NCAM1),', aggrecan, '(', 'ACAN),', forkhead, box, 'A2', '(', 'FOXA2),', 'Gap', junction, protein, beta, 1, /, connexin, 32, '(', 'GJB1/Cnx32),', and, 'Msh', homeobox, 1, '(', 'MSX1),', that, could, be, used, to, recognize, putative, corneal, epithelial, 'SCs', grown, in, culture, and, intended, for, transplantation])].
[sujeto(['Knowledge', of, these, gene, and, molecular, pathways]), verbo([has]), complemento([provided, a, better, understanding, of, the, signaling, molecular, pathways, associated, with, 'progenitor-rich', limbal, epithelium])].
[sujeto(['FoxO1']), verbo([binds]), complemento([to, insulin, response, elements, located, in, the, promoters, of, 'insulin-like', growth, 'factor-binding', protein, 1, '(', 'IGFBP1)', and, 'glucose-6-phosphatase', '(', 'G6Pase),', activating, their, expression])].
[sujeto(['Insulin-mediated', phosphorylation, of, 'FoxO1']), verbo([promotes]), complemento([cytoplasmic, 'translocation,', inhibiting, 'FoxO1-mediated', transactivation])].
[sujeto(['We']), verbo([have]), complemento([previously, demonstrated, that, 'FoxO1', opens, and, remodels, chromatin, assembled, from, the, 'IGFBP1', promoter, via, a, highly, conserved, winged, helix, motif])].
[sujeto(['This', 'finding,', which, established, 'FoxO1', as, a, &, 'quot;pioneer"', 'factor,']), verbo([suggested]), complemento([a, model, whereby, 'FoxO1', chromatin, remodeling, at, regulatory, targets, facilitates, binding, and, recruitment, of, additional, regulatory, factors])].
[sujeto(['However,', the, impact, of, 'FoxO1', phosphorylation, on, its, ability, to]), verbo([bind]), complemento([chromatin, and, the, effect, of, 'FoxO1', loss, on, recruitment, of, neighboring, transcription, factors, at, its, regulatory, targets, in, liver, chromatin, is, unknown])].
[sujeto(['In', this, 'study,', we, demonstrate, that, an, amino, acid, substitution, that, mimics, 'insulin-mediated', phosphorylation, of, a, serine, in, the, winged, helix, 'DNA']), verbo([binding]), complemento([motif, curtails, 'FoxO1', nucleosome, binding])].
[sujeto(['We', also, demonstrate, that, 'shRNA-mediated']), verbo([loss]), complemento([of, 'FoxO1', binding, to, the, 'IGFBP1', and, 'G6Pase', promoters, in, 'HepG2', cells, significantly, reduces, binding, of, 'RNA', polymerase, 'II', and, the, pioneer, factors, 'FoxA1/A2'])].
[sujeto(['Knockdown', of, 'FoxA1', similarly, reduced]), verbo([binding]), complemento([of, 'RNA', polymerase, 'II', and, 'FoxO1'])].
[sujeto(['Reduction', in, acetylation, of, histone, 'H3', 'Lys-27', accompanies]), verbo([loss]), complemento([of, 'FoxO1', and, 'FoxA1/A2', binding])].
[sujeto(['Interdependent']), verbo([binding]), complemento([of, 'FoxO1', and, 'FoxA1/A2', possibly, entails, cooperative, binding, because, 'FoxO1', and, 'FoxA1/A2', facilitate, one, 'another\'s', binding, to, 'IGFPB1', promoter, 'DNA'])].
[sujeto(['These', results, illustrate, how, transcription, factors, can, nucleate, transcriptional, events, in, chromatin, in, response, to, signaling, events, and]), verbo([suggest]), complemento([a, model, for, regulation, of, hepatic, glucose, metabolism, through, interdependent, 'FoxO/FoxA', binding])].
[sujeto([5, mouse, 'brain,', we]), verbo([found]), complemento([that, 'Shh', and, its, receptor, 'Ptch1', define, two, adjacent, mutually, exclusive, gene, expression, 'domains:', 'Shh+Ptch1-', and, 'Shh-Ptch1+'])].
[sujeto(['These', two, domains, are]), verbo([associated]), complemento([respectively, with, 'Foxa2', and, 'Gata3,', two, transcription, factors, that, play, key, roles, in, specifying, them])].
[sujeto(['Important', 'Gata3']), verbo([targets]), complemento([include, 'Slit2', and, 'Slit3,', which, are, involved, in, the, process, of, axon, 'guidance,', as, well, as, 'Slc18a1,', 'Th', and, 'Qdpr,', which, are, associated, with, neurotransmitter, synthesis, and, release])].
[sujeto(['By', 'contrast,', 'Foxa2', both, 'up-regulates', the, genes]), verbo([expressed]), complemento([in, the, 'Shh+Ptch1-', domain, and, 'down-regulates', the, genes, characteristic, of, the, 'Shh-Ptch1+', domain])].
[sujeto(['Our', work]), verbo([provides]), complemento([the, first, 'genome-wide', characterization, of, the, gene, regulatory, network, involved, in, the, 'Shh', pathway, that, underlies, pattern, formation, in, the, early, mouse, brain])].
[sujeto(['The', aryl, hydrocarbon, receptor, '(', 'AhR)', is, a, 'ligand-activated', transcription, factor, that]), verbo([mediates]), complemento([diverse, dioxin, toxicities])].
[sujeto(['While', the, acute, effects, of, activation, of, the, 'AhR', pathway, by, 2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD)']), verbo([have]), complemento([been, a, focus, of, past, 'study,', the, role, of, this, pathway, in, normal, physiology, and, ageing, is, unclear])].
[sujeto(['Adult', pregnant, 'Lewis', rat, dams, were, dosed, with, corn, oil, vehicle, or, 'TCDD', '(', 50, 'ng/kg-week', by, 'gavage)', on, days, 14, and, 21, of, gestation, and, 'post-natal', days, 7, and, 14, to]), verbo([provide]), complemento([in, utero, and, lactational, '(', 'IUL)', exposure, to, pups])].
[sujeto(['Data', analysis, revealed, an, accelerated, onset, of, acyclicity, by, 5, months, in, all, groups]), verbo([involving]), complemento(['IUL', exposure, of, the, developing, ovary, to, 'TCDD'])].
[sujeto([17, 'beta-oestradiol', was, significantly]), verbo([decreased]), complemento([in, animals, receiving, 'TCDD', during, 'IUL', exposure, of, the, 'H-H', axis])].
[sujeto(['This', study]), verbo([reveals]), complemento([a, particular, sensitivity, of, the, developing, ovary, to, 'TCDD', leading, to, early, loss, of, reproductive, function, with, age])].
[sujeto(['Xenobiotic', and, drug, metabolism, and, transport, are, managed, by, a, large, number, of, genes, coordinately]), verbo([regulated]), complemento([by, at, least, three, nuclear, receptors, or, 'xenosensors:', aryl, hydrocarbon, receptor, '(', 'AhR),', constitutive, androstane, receptor, '(', 'CAR,', 'NR1I3),', and, pregnane, 'X', receptor, '(', 'PXR,', 'NR1I2)'])].
[sujeto(['Initially', characterized, as, 'xenosensors,', it, is, now, evident, that, 'CAR', and, 'PXR', also]), verbo([trigger]), complemento([pleiotropic, effects, on, liver, function])].
[sujeto(['Recent', studies]), verbo([have]), complemento([shown, the, existence, of, crosstalk, between, xenosensors, and, other, nuclear, receptors, or, transcription, factors, controlling, endogenous, signaling, pathways, which, regulate, physiological, functions])].
[sujeto(['Such', crosstalks, explain, clinical, observations, and]), verbo([provide]), complemento([molecular, mechanisms, allowing, understanding, how, xenobiotics, and, drugs, may, affect, physiological, functions, and, provoke, endocrine, disruptions])].
[sujeto(['Cytochrome', 'P450', 2, 'A2', '(', 'CYP2A2)', is, an, adult, 'male-specific', rat, liver, steroid, hydroxylase, whose, 'sex-dependent', expression, is]), verbo([regulated]), complemento([at, the, transcriptional, level, by, sexually, dimorphic, pituitary, growth, hormone, '(', 'GH)', secretory, patterns])].
[sujeto(['In', contrast, to, 'CYP2C11', and, other, 'male-specific,', plasma, 'GH', 'pulse-inducible', liver, 'genes,', 'CYP2A2', is, highly]), verbo([expressed]), complemento([in, hypophysectomized, rat, 'liver,', despite, the, absence, of, 'GH', stimulation])].
[sujeto(['A', further, approximately, 2.5, -, fold]), verbo([increase]), complemento([in, activity, was, obtained, by, cotransfection, of, hepatocyte, nuclear, factor, '(', 'HNF)', 3, gamma, or, 'HNF4alpha'])].
[sujeto(['CYP2A2', promoter, activity, was]), verbo([inhibited]), complemento([approximately, 85, '%', by, transfection, of, 'HNF3beta', or, 'HNF6,', both, of, which, are, more, highly, expressed, in, female, than, male, liver, and, can, strongly, 'trans-activate', the, 'female-specific', 'CYP2C12', promoter])].
[sujeto(['By', 'contrast,', 'STAT5b', synergistically]), verbo([enhanced]), complemento([the, transcriptional, activity, of, 'HNF4alpha', toward, two, other, 'male-specific', liver, target, 'genes,', 'Cyp2d9', and, 'CYP8B1'])].
[sujeto(['Furthermore,', 'STAT5b', in, combination, with, the, 'HNF4alpha', coactivator, peroxisome, 'proliferator-activated', receptor, gamma, 'coactivator-1alpha', strongly]), verbo([enhanced]), complemento([the, transcriptional, activity, of, 'HNF4alpha', toward, 'CYP8B1', but, not, toward, 'CYP2A2'])].
[sujeto(['These', findings, support, the, hypothesis, that, 'sex-dependent', 'HNFs', contribute, to, the, sexually, dimorphic, expression, of, 'CYP2A2', and, other, liver, 'CYPs', and, highlight, the, ability, of, 'STAT5b', to]), verbo([act]), complemento([in, concert, with, 'HNF4alpha', to, regulate, select, 'male-specific', liver, 'CYP', genes])].
[sujeto(['In', particular, the, parenchymal, liver, cells, or, hepatocytes, are]), verbo([targeted]), complemento([since, they, are, the, major, sites, of, drug, transport, and, of, metabolite, formation, and, thus, also, the, place, where, not, only, 'detoxification,', but, also, activation, of, new, chemical, '(', 'NCE)', and, biological, '(', 'NBE)', entities, may, occur])].
[sujeto(['However,', within, a, few, 'days,', they, undergo, dedifferentiation, with]), verbo([loss]), complemento([of, 'liver-specific', 'functionality,', including, xenobiotic, biotransformation, 'capacity,', making, them, only, suitable, for, 'short-term', applications])].
[sujeto(['A', plausible, alternative, to, primary, hepatocyte, cultures, that, can, be]), verbo([maintained]), complemento([for, longer, periods, of, time, could, be, the, use, of, 'liver-derived', epithelial, cell, lines, and, their, optimized, derivatives])].
[sujeto(['Undifferentiated', rLEC, stably]), verbo([express]), complemento([the, hepatic, progenitor, markers, 'CEBPA,', 'FOXA2,', 'GJA1,', 'ONECUT1,', 'KRT18', and, 'KRT19', for, at, least, 15, consecutive, passages, after, cryopreservation])].
[sujeto(['Upon', sequential, exposure, to, hepatogenic, growth, factors, and, 'cytokines,', rLEC, generate, functional, hepatic, 'progeny,']), verbo([expressing]), complemento([mature, hepatic, markers, including, 'Alb,', 'Ahr,', 'Car,', 'C/ebpα,', 'Cx32,', 'Foxa2,', 'Hnf1α,', 'Hnf1β', and, 'Onecut1'])].
[sujeto(['rLEC-derived', hepatic, cells, also, acquire, the, ability, to, store, 'glycogen,']), verbo([express]), complemento([genes, encoding, for, key, hepatic, enzymes, as, shown, by, 'Affymetrix', microarray, 'data,', and, display, stable, 'CYP1A1/2-', and, 'CYP2B1/2-dependent', activities, for, several, weeks, at, levels, comparable, to, those, observed, in, cultured, primary, rat, hepatocytes])].
[sujeto(['Many', different, markers]), verbo([have]), complemento([been, attributed, to, these, 'cells,', but, their, nature, still, remains, obscure])].
[sujeto(['This', study, is, a, detailed, gene, expression, analysis, aimed, at]), verbo([revealed]), complemento([their, identity, and, repopulating, in, vivo, capacity])].
[sujeto(['Oval', cells, were]), verbo([activated]), complemento([in, 2, -, 'acetylaminofluorene-treated', rats, subjected, to, partial, hepatectomy, or, in, 'D-galactosamine-treated', rats])].
[sujeto(['We']), verbo([found]), complemento([that, 'EpCAM(+)', and, 'Thy-1(+)', cells, represent, two, different, populations, of, cells, in, the, oval, cell, niche])].
[sujeto(['EpCAM(+)', cells]), verbo([express]), complemento([the, classical, oval, cell, markers, '(', 'alpha-fetoprotein,', 'cytokeratin-19,', 'OV-1', 'antigen,', a6, 'integrin,', and, connexin, 43, ')', ',', cell, surface, markers, recently, identified, by, us, '(', 'CD44,', 'CD24,', 'EpCAM,', aquaporin, 5, ',', 'claudin-4,', secretin, 'receptor,', 'claudin-7,', 'V-ros', sarcoma, virus, oncogene, homolog, 1, ',', cadherin, 22, ',', 'mucin-1,', and, 'CD133),', and, 'liver-enriched', transcription, factors, '(', forkhead, box, 'q,', forkhead, box, 'a2,', onecut, 1, ',', and, transcription, factor, 2, ')'])].
[sujeto(['Oval', cells, do, not]), verbo([express]), complemento([previously, reported, hematopoietic, stem, cell, markers, 'Thy-1,', 'c-kit,', and, 'CD34', or, the, neuroepithelial, marker, neural, cell, adhesion, molecule, 1])].
[sujeto(['However,', oval, cells]), verbo([express]), complemento([a, number, of, mesenchymal, markers, including, 'vimentin,', 'mesothelin,', bone, morphogenetic, protein, 7, ',', and, 'Tweak', receptor, '(', tumor, necrosis, factor, receptor, 'superfamily,', member, 12, 'A)'])].
[sujeto(['A', group, of, novel, differentially]), verbo([expressed]), complemento([oval, cell, genes, is, also, presented])].
[sujeto(['Transplantation', experiments]), verbo([reveal]), complemento([that, 'EpCAM(+)', cells, are, true, progenitors, capable, of, repopulating, injured, rat, liver])].
[sujeto(['We']), verbo([have]), complemento([shown, that, 'EpCAM(+)', oval, cells, are, bipotential, adult, hepatic, epithelial, progenitors])].
[sujeto(['These', cells, display, a, mixed, 'epithelial/mesenchymal', phenotype, that]), verbo([has]), complemento([not, been, recognized, previously])].
[sujeto(['Here', we]), verbo([report]), complemento([that, 'BCa', cells, are, dependent, on, a, mechanism, to, supply, precursors, for, intracellular, lipid, production, derived, from, extracellular, sources, and, that, the, endothelial, lipase, '(', 'LIPG)', fulfils, this, function])].
[sujeto(['LIPG', is, ubiquitously, and, highly]), verbo([expressed]), complemento([under, the, control, of, 'FoxA1', or, 'FoxA2', in, all, 'BCa', subtypes])].
[sujeto(['The', downregulation, of, either, 'LIPG', or, 'FoxA', in, transformed, cells, results, in]), verbo([decreased]), complemento([proliferation, and, impaired, synthesis, of, intracellular, lipids])].
[sujeto(['Limited', adult, dopaminergic, neurogenesis]), verbo([has]), complemento([led, to, novel, therapeutic, strategies, such, as, transplantation, of, dopaminergic, precursors, '(', 'DPs)'])].
[sujeto(['Here,', we, demonstrate, the, direct, conversion, of, mouse, fibroblasts, into]), verbo([induced]), complemento(['DPs', '(', 'iDPs)', by, ectopic, expression, of, 'Brn2,', 'Sox2', and, 'Foxa2'])].
[sujeto(['After', transplantation, into, 'MPTP-lesioned', 'mice,', iDPs, differentiated, into, 'DA', 'neurons,', functionally, alleviated, the, motor, 'deficits,', and, reduced, the]), verbo([loss]), complemento([of, striatal, 'DA', neuronal, axonal, termini])].
[sujeto(['We', propose, that, the, iDPs, from, direct, reprogramming]), verbo([provides]), complemento([a, safe, and, efficient, cell, source, for, 'PD', treatment])].
[sujeto(['Farnesol', is, a, 'non-cyclic', sesquiterpene, '(', 'isoprenoid)']), verbo([found]), complemento([in, the, essential, oils, of, many, plants])].
[sujeto(['Therefore,', farnesyltransferase, is, a]), verbo([target]), complemento([for, drug, development, to, inhibit, 'Ras'])].
[sujeto(['Tumors', frequently, develop, resistance, towards, standard, 'chemotherapies,', and, thus, novel, agents, are, urgently]), verbo([required]), complemento([that, bypass, the, 'cross-resistance', evoked, by, established, anticancer, drugs])].
[sujeto(['Remarkably,', none, of, these, genes]), verbo([conferred]), complemento([resistance, to, 'farnesol,', indicating, that, this, compound, may, be, useful, for, the, treatment, of, otherwise, 'drug-resistant', and, refractory, tumors, expressing, these, mechanisms, of, resistance])].
[sujeto(['Among', the, candidates, were, genes]), verbo([involved]), complemento([in, apoptosis, '(', 'STAB2,', 'NUMBL),', regulation, of, transcription, '(', 'CDYL,', 'FOXA2)', and, diverse, other, functional, groups, '(', 'INE1,', 'CTRL,', 'MRS2,', 'NEB,', 'LMO7,', 'C9orf3,', 'EHBP1)'])].
[sujeto(['The', fact, that, these, genes, are, not]), verbo([associated]), complemento([with, resistance, to, traditional, anticancer, drugs, suggests, farnesol, may, possess, a, novel, mechanism, of, 'action,', and, consequently, might, bypass, drug, resistance, to, established, chemotherapeutics])].
[sujeto(['We']), verbo([targeted]), complemento([the, reverse, tetracycline, controlled, transactivator, '(', 'rtTA)', to, the, 'Foxa2', locus, '(', 'Foxa2(ITA))', to, generate, a, system, for, regulating, 'Cre-recombinase', activity, within, 'Foxa2', expression, 'domains,', including, the, 'endoderm,', 'notochord,', and, floor, plate, of, early, mouse, embryos])].
[sujeto(['The', use, of, an, internal, ribosomal, entry, site, to, obtain, rtTA, expression, preserves, 'Foxa2', function, of, the]), verbo([targeted]), complemento([allele])].
[sujeto(['This', system, will]), verbo([provide]), complemento([a, useful, tool, for, manipulating, gene, expression, in, 'endoderm,', 'notochord,', and, floor, 'plate,', all, of, which, are, tissues, with, important, structural, and, patterning, functions, during, embryogenesis])].
[sujeto(['Since', the, lung, is, repeatedly, subjected, to, injury, by, pathogens, and, 'toxicants,', maintenance, of, pulmonary, homeostasis]), verbo([requires]), complemento([rapid, repair, of, its, epithelial, surfaces])].
[sujeto(['Expression', of, transcription, factors, active, in, morphogenesis, and, differentiation, of, the, embryonic, 'lung,', including, 'beta-catenin,', 'Foxa2,', 'Foxj1,', and, 'Sox', family, members, '(', 'Sox17', and, 'Sox2),', was, dynamically]), verbo([regulated]), complemento([during, repair, and, redifferentiation, of, the, bronchiolar, epithelium, after, naphthalene, injury])].
[sujeto(['Squamous', cells, derived, from, ciliated, cells, spread, beneath, injured, 'Clara', cells, within, 6, -, 12, h, after, 'injury,']), verbo([maintaining]), complemento([the, integrity, of, the, epithelium])].
[sujeto(['Agonists', for, the]), verbo([nuclear]), complemento([receptor, peroxisomal, 'proliferator-activated', 'receptor-gamma', '(', 'PPARgamma)', and, its, heterodimeric, 'partner,', retinoid, 'X', receptor, '(', 'RXR),', are, effective, agents, for, the, treatment, of, type, 2, diabetes])].
[sujeto(['To']), verbo([gain]), complemento([insight, into, the, antidiabetic, action, of, these, 'compounds,', we, treated, female, 'Zucker', diabetic, rats, '(', 'ZFF)', with, 'AGN194204,', which, we, show, to, be, a, 'homodimer-specific', 'RXR', 'agonist,', or, the, 'PPARgamma', 'agonist,', troglitazone])].
[sujeto(['AGN194204', had, no, effect, on, peripheral, glucose, 'utilization,', whereas, troglitazone]), verbo([increased]), complemento(['insulin-stimulated', glucose, utilization, by, 50, '%', ',', glucose, uptake, into, skeletal, muscle, by, 85, '%', ',', and, de, novo, skeletal, muscle, glycogen, synthesis, by, 300, '%'])].
[sujeto(['Troglitazone']), verbo([increased]), complemento([skeletal, muscle, 'Irs-1', and, 'phospho-Akt', levels, following, in, vivo, insulin, 'treatment,', whereas, 'AGN194204', increased, hepatic, 'Irs-2', and, insulin, stimulated, 'phospho-Akt', in, liver])].
[sujeto(['Gene', profiles, of, 'AGN194204-treated', mouse, liver, analyzed, by, 'Ingenuity', 'Pathway', 'Analysis', identified]), verbo([increases]), complemento([in, fatty, acid, synthetic, 'genes,', including, 'Srebp-1', and, fatty, acid, 'synthase,', a, pathway, previously, shown, to, be, induced, by, 'RXR', agonists])].
[sujeto(['A', network, of, 'down-regulated', genes, containing, 'Foxa2,', 'Foxa3,', and, 'G-protein', subunits, was, 'identified,', and]), verbo([decreases]), complemento([in, these, mRNA, levels, were, confirmed, by, quantitative, reverse, 'transcription-PCR'])].
[sujeto(['Treatment', of, 'HepG2', cells, with, 'AGN194204', resulted, in, inhibition, of, 'glucagon-stimulated', cAMP, accumulation]), verbo([suggesting]), complemento([the, 'G-protein', 'down-regulation', may, provide, an, additional, mechanism, for, hepatic, insulin, sensitization, by, 'RXR'])].
[sujeto(['These', studies, demonstrate, distinct, molecular, events]), verbo([lead]), complemento([to, insulin, sensitization, by, high, affinity, 'RXR', and, 'PPARgamma', agonists])].
[sujeto(['Although']), verbo([expressed]), complemento([in, all, cells, at, the, early, 'stages,', in, the, adult, it, is, mainly, restricted, to, the, 'beta-cell'])].
[sujeto(['DNase', 'I', footprinting, analysis, revealed, two, protected, 'regions,', one]), verbo([binding]), complemento([the, transcription, factors, 'SP1', and, 'SP3', and, the, other, hepatocyte, nuclear, factor, 3, beta, '(', 'HNF-3beta)', and, 'HNF-1alpha'])].
[sujeto(['Cotransfection', experiments]), verbo([suggest]), complemento([that, 'HNF-3beta,', 'HNF-1alpha,', and, 'SP1', are, positive, regulators, of, the, 'herein-described', human, 'PDX-1', enhancer, element])].
[sujeto(['Furthermore,', mutations, within, each, motif, abolished, the]), verbo([binding]), complemento([of, the, corresponding, 'factor(s)', and, dramatically, impaired, the, enhancer, 'activity,', therefore, suggesting, cooperativity, between, these, factors])].
[sujeto(['To', address, the, question, whether, these, enzymatic, alterations, result, from, specific, changes, in, the, levels, of, 'hepatocyte-enriched']), verbo([nuclear]), complemento([factors, '(', 'HNF),', we, analysed, the, mRNA, levels, of, six, different, 'HNFs', '(', 'HNF-1alpha,', 'beta,', 'HNF-3alpha,', 'beta,', 'gamma,', and, 'HNF-4)', by, 'RNase', protection, assay, in, chemically, induced, liver, tumours, and, corresponding, normal, liver, tissue, from, mice, of, three, different, strains])].
[sujeto(['When', compared, with, the, normal, liver, 'tissue,', 'HNF-1beta,', 'HNF-3alpha', and, 'HNF-3beta', showed, unchanged, expression, levels, in, the, various, liver, 'tumours,', which, 'HNF-1alpha', and, 'HNF-4', mRNAs, were, lowered, by, 20, -, 30, '%', ',', and, 'HNF-3gamma', mRNA, was]), verbo([increased]), complemento([by, 50, '%'])].
[sujeto(['We']), verbo([found]), complemento([a, substantial, reduction, in, cancer, risk, '(', 'OR', 0.39, ;, 95, '%', 'CI', 0.25, -, 0.61, ;, 'Pinteraction', =, 0.029, ')', associated, with, combined, genotypes, for, 'CYP2A13', 'R257C', and, a, functionary, regulatory, variant, in, the, cis, element, of, 'ABCB1', synergistically, targeted, by, 'GATA', binding, protein, 6, and, 'FOXA2'])].
[sujeto(['Genetic', manipulation, of, 'FOXA2', consistently, influenced, its]), verbo([binding]), complemento([to, and, transactivation, of, the, promoters, of, 'CYP2A13,', 'UGT2B17,', and, 'ABCB1,', whose, mRNA, and, protein, expressions, were, all, consistently, correlated, with, those, of, 'FOXA2', in, both, tumorous, and, normal, lung, tissues])].
[sujeto(['We', previously, identified, polymorphisms, in, pregnane, 'X', receptor, '(', 'PXR)', and, 'ATP-binding', cassette, subfamily, 'B', member, 1, '(', 'ABCB1)']), verbo([associated]), complemento([with, 'CYP3A4', mRNA, levels, in, small, cohorts, of, human, livers])].
[sujeto(['We', resequenced, hepatic]), verbo([nuclear]), complemento(['factor-3-beta', '(', 'HNF3beta,', 'FoxA2),', 'HNF4alpha,', 'HNF3gamma', '(', 'FoxA3),', nuclear, receptor, corepressor, 2, '(', 'NCoR2),', and, regions, of, the, 'CYP3A4', promoter, and, genotyped, informative, 'single-nucleotide', polymorphisms, in, 'PXR', and, 'ABCB1', in, the, same, livers])].
[sujeto(['A', common, silent, polymorphism, and, a, polymorphic, trinucleotide, '(', 'CCT)', repeat, in, 'FoxA2', were]), verbo([associated]), complemento([with, 'CYP3A4', expression])].
[sujeto(['The', transcriptional, activity, of, the, 'FoxA2', polymorphic, 'CCT', repeat, alleles, '(', 'wild-type,', n, =, 14, and, 'variant,', n, =, 13, ',', 15, ',', and, 19, ')', when, assayed, by, luciferase, reporter, transactivation, assays, was, greatest, for, the, 'wild-type', 'repeat,', with, deviations, from, this, number, having]), verbo([decreased]), complemento([transcriptional, activity])].
[sujeto(['This', corresponded, with, higher, expression, of, 'FoxA2', mRNA, and, its]), verbo([targets]), complemento(['PXR', and, 'CYP3A4', in, human, livers, with, '(', 'CCT)', n, =, 14, genotypes])].
[sujeto(['Nuclear', receptors, constitutive, 'active/androstane', receptor, '(', 'CAR)', and, pregnane, 'X', receptor, '(', 'PXR)', were, originally, characterized, as, transcription, factors]), verbo([regulating]), complemento([the, hepatic, genes, that, encode, drug, metabolizing, enzymes])].
[sujeto(['Recent', works]), verbo([have]), complemento([now, revealed, that, these, nuclear, receptors, also, play, the, critical, roles, in, modulating, hepatic, energy, metabolism])].
[sujeto(['While', 'CAR', and, 'PXR', directly]), verbo([bind]), complemento([to, their, response, sequences, 'phenobarbital-responsive', enhancer, module, '(', 'PBREM)', and, xenobiotic, responsive, enhancer, module, '(', 'XREM)', in, the, promoter, of, target, genes, to, increase, drug, 'metabolism,', the, receptors, also, cross, talk, with, various, hormone, responsive, transcription, factors, such, as, forkhead, box, 'O1', '(', 'FoxO1),', forkhead, box, 'A2', '(', 'FoxA2),', 'cAMP-response', element, binding, 'protein,', and, peroxisome, proliferator, activated, receptor, gamma, coactivator, 1, alpha, '(', 'PGC', 1, 'alpha)', to, decrease, energy, metabolism, through, 'down-regulating', 'gluconeogenesis,', fatty, acid, oxidation, and, ketogenesis, and, 'up-regulating', lipogenesis])].
[sujeto(['In', 'addition,', 'CAR']), verbo([modulates]), complemento([thyroid, hormone, activity, by, regulating, type, 1, deiodinase, in, the, regenerating, liver])].
[sujeto(['Cytochrome', 'P450', 3, 'A4', '(', 'CYP3A4)', is, the, major, cytochrome, 'P450', present, in, adult, human, liver, and, is]), verbo([involved]), complemento([in, the, metabolism, of, over, 50, '%', of, therapeutic, compounds, currently, in, use])].
[sujeto(['Since', expression, levels, of, 'CYP3A4', are]), verbo([regulated]), complemento([by, many, of, these, 'compounds,', this, raises, the, potential, for, 'drug-drug', interactions, and, subsequent, altered, efficacy, or, toxicity, of, the, individual, compounds, at, the, dose, prescribed])].
[sujeto(['To', examine, this, we]), verbo([have]), complemento([used, 'DNase', 'I', footprinting, and, bioinformatic, analysis, to, identify, putative, transcription, factor, binding, sites, within, the, 250, base, pairs, of, promoter, proximal, to, the, transcription, start, site])].
[sujeto(['We', identified, several, protected, fragments, within, this, region, that, corresponded, to, putative]), verbo([binding]), complemento([sites, for, 'Sp1,', 'AP2,', 'CCAAT/enhancer', binding, protein, '(', 'C/EBPalpha),', and, hepatic, nuclear, 'factor-3', '(', 'HNF3),', as, well, as, confirming, previously, identified, 'C/EBPalpha,', pregnane, 'X', receptor, '(', 'PXR),', and, 'HNF3', binding, sites])].
[sujeto(['Sequential', 'site-directed', mutagenesis, of, 'C/EBPalpha,', 'Sp1,', 'HNF3,', and, 'PXR']), verbo([binding]), complemento([sites, was, next, used, to, examine, the, role, of, these, sites, in, basal, 'CYP3A4', expression])].
[sujeto(['Disruption', of, the, 'C/EBPalpha,', 'HNF3,', and, 'PXR']), verbo([binding]), complemento([sites, all, affected, basal, expression])].
[sujeto(['Disruption', of, any, of, these, sites, either]), verbo([led]), complemento([to, an, altered, pattern, of, activation, by, the, 'xenobiotic,', as, altered, maximal, 'activation,', or, altered, the, 'EC(50)', value, of, activation])].
[sujeto(['Chicken', 'CYP2H1', promoter, constructs]), verbo([express]), complemento([strongly, in, chick, embryo, hepatocytes, at, a, level, comparable, with, that, of, 'Rous', sarcoma, viral, promoter])].
[sujeto(['We']), verbo([have]), complemento([identified, the, transcription, factors, responsible, for, the, active, 'CYP2H1', promoter])].
[sujeto(['Protein']), verbo([binding]), complemento([to, these, sites, was, established, by, gel, mobility, shift, assays])].
[sujeto(['The', promoter, was, also, active, in, mammalian, 'HepG2', and, 'COS-1', cell, lines, where, expression, was, dependent, on, the, identified, transcription, factor]), verbo([binding]), complemento([sites, but, promoter, activity, in, the, 'HeLa', cells, was, low])].
[sujeto(['Transactivation', experiments, revealed, that, promoter, expression, could, be]), verbo([activated]), complemento([through, the, appropriate, binding, sites, by, exogenously, expressed, rat, 'HNF-1alpha', or, 'HNF-1beta,', rat, 'HNF-3alpha', or, 'HNF-3beta', and, chicken, 'C/EBP', alpha])].
[sujeto(['By', 'comparison,', in, vivo, expression, of, this, gene, in, uninduced, chick, embryo, hepatocytes, is, low, but, markedly]), verbo([increased]), complemento([by, phenobarbital])].
[sujeto(['BMP4', is, preferentially]), verbo([expressed]), complemento([in, 'diffuse-type', gastric, cancer, cells])].
[sujeto(['Human', 'BMP4', gene, was]), verbo([found]), complemento([consisting, of, six, 'exons,', including, novel, exon, 1, 'C,', and, known, exons, 1, '(', 1, 'A', or, 'I),', 1, 'B', '(', 'II),', 2, '(', 'III),', 3, '(', 'IV)', and, 4, '(', 'V)'])].
[sujeto(['The', 5, '\'', -, flanking, region, of, exon, 1, and, exon, 1, 'itself,', but, not, exons, 1, 'C', and, 1, 'B,', were, well]), verbo([conserved]), complemento([between, human, 'BMP4', and, rodent, 'Bmp4', genes])].
[sujeto(['FOXA2,', 'OLF1,', and, 'MYC-binding', sites, were]), verbo([conserved]), complemento([among, the, major, promoter, region, of, 'human,', 'baboon,', 'cow,', 'bat,', mouse, and, rat, 'BMP4', orthologs])].
[sujeto(['Capicua', '(', 'CIC)']), verbo([has]), complemento([been, implicated, in, pathogenesis, of, spinocerebellar, ataxia, type, 1, and, cancer, in, 'mammals;', 'however,', the, in, vivo, physiological, functions, of, 'CIC', remain, largely, unknown])].
[sujeto(['Here', we, show, that, 'Cic', hypomorphic, '(', 'Cic-L(-/-))', mice]), verbo([have]), complemento([impaired, bile, acid, '(', 'BA)', homeostasis, associated, with, induction, of, proinflammatory, cytokines])].
[sujeto(['We', discovered, that, several, drug, metabolism, and, 'BA', transporter, genes, were, 'down-regulated', in, 'Cic-L(-/-)', 'liver,', and, that, 'BA', was]), verbo([increased]), complemento([in, the, liver, and, serum, whereas, bile, was, decreased, within, the, gallbladder, of, 'Cic-L(-/-)', mice])].
[sujeto(['We', also]), verbo([found]), complemento([that, levels, of, proinflammatory, cytokine, genes, were, 'up-regulated', in, 'Cic-L(-/-)', liver])].
[sujeto(['Consistent', with, this, 'finding,', levels, of, hepatic, transcriptional, 'regulators,', such, as, hepatic]), verbo([nuclear]), complemento([factor, 1, alpha, '(', 'HNF1α),', 'CCAAT/enhancer-binding', protein, beta, '(', 'C/EBPβ),', forkhead, box, protein, 'A2', '(', 'FOXA2),', and, retinoid, 'X', receptor, alpha, '(', 'RXRα),', were, markedly, decreased, in, 'Cic-L(-/-)', mice])].
[sujeto(['Moreover,', induction, of, tumor, necrosis, factor, alpha, '(', 'Tnfα)', expression, and]), verbo([decrease]), complemento([in, the, levels, of, 'FOXA2,', 'C/EBPβ,', and, 'RXRα', were, found, in, 'Cic-L(-/-)', liver, before, 'BA', was, 'accumulated,', suggesting, that, inflammation, might, be, the, cause, for, the, cholestasis, in, 'Cic-L(-/-)', mice])].
[sujeto(['Our', findings, indicate, that, 'CIC', is, a, critical, regulator, of, 'BA', 'homeostasis,', and, that, its, dysfunction, might, be]), verbo([associated]), complemento([with, chronic, liver, disease, and, metabolic, disorders])].
[sujeto(['ATP']), verbo([binding]), complemento([cassette, transporter, 'A1', '(', 'ABCA1)', plays, a, key, role, in, the, biogenesis, of, 'HDL', by, promoting, the, efflux, of, cellular, cholesterol, and, phospholipids, to, lipid, free, 'apoA-I'])].
[sujeto(['Mutations', in, the, 'ABCA1', gene]), verbo([cause]), complemento(['Tangier', disease, which, is, characterized, by, near, or, complete, absence, of, circulating, plasma, 'HDL'])].
[sujeto(['We', show, that, the, 'ABCA1', promoter, contains, three, 'FOXA2']), verbo([binding]), complemento([elements, in, the, proximal, region])].
[sujeto(['Two', of, the, sites, are, localized, in, a, region, of, the, 'ABCA1', promoter, enriched, in]), verbo([binding]), complemento([elements, for, transcriptional, repressor, proteins, whereas, the, third, site, is, the, core, of, the, 'TATA', element, of, the, 'ABCA1', promoter])].
[sujeto(['Inhibition', of, 'FOXA2']), verbo([binding]), complemento([to, the, 'ABCA1', promoter, by, 'site-directed', mutagenesis, or, 'FOXA2', gene, expression, by, siRNA, was, associated, with, increased, 'ABCA1', promoter, activity, and, protein, levels])].
[sujeto(['Overexpression', of, 'FOXA2']), verbo([inhibited]), complemento([both, the, constitutive, 'ABCA1', gene, expression, as, well, as, 'ABCA1', gene, induction, by, oxysterols, and, retinoids, via, nuclear, receptors, 'LXRα/RXRα'])].
[sujeto(['In', 'summary,', the, present, study, identifies, transcription, factor, 'FOXA2', as, a, negative, modulator, of, 'ABCA1', gene, expression, in, hepatic, cells, and]), verbo([reveals]), complemento([a, novel, mechanism, of, transcriptional, repression, by, 'FOXA2', which, involves, the, 'TATA', element, of, the, 'ABCA1', gene])].
[sujeto(['Cytokine', signaling]), verbo([has]), complemento([been, connected, to, regulation, of, metabolism, and, energy, balance])].
[sujeto(['Numerous', cytokine, gene, expression, changes, are]), verbo([stimulated]), complemento([by, accumulation, of, bile, acids, in, livers, of, young, 'Foxa2', 'liver-conditional', null, mice])].
[sujeto(['We']), verbo([found]), complemento([that, loss, of, 'Foxa2', in, the, liver, results, in, a, premature, aging, 'phenotype,', including, significant, weight, 'gain,', reduced, food, 'intake,', and, decreased, energy, expenditure])].
[sujeto(['We', show, that, 'Foxa2', antagonizes, the, mammalian]), verbo([target]), complemento([of, rapamycin, '(', 'mTOR)', 'pathway,', resulting, in, increased, hepatic, lipogenesis, and, adiposity])].
[sujeto(['While', much, prior, work]), verbo([has]), complemento([focused, on, adipose, tissue, in, 'obesity,', we, discovered, a, novel, 'age-onset', obesity, phenotype, in, a, model, where, gene, deletion, occurs, only, in, the, 'liver,', underscoring, the, importance, of, the, role, hepatic, lipogenesis, plays, in, the, development, of, obesity])].
[sujeto(['We', recently]), verbo([reported]), complemento([a, novel, role, for, 'Foxa2', in, bile, acid, metabolism])].
[sujeto(['The', winged, helix, transcription, factor, 'Foxa2', is]), verbo([required]), complemento([to, prevent, intrahepatic, cholestasis, and, liver, injury, in, mice, fed, a, cholic, 'acid-enriched', diet])].
[sujeto(['Here,', we, use, functional, genomics, to, study, how, 'Foxa2']), verbo([regulates]), complemento([its, targets, in, a, cholic, 'acid-dependent', manner])].
[sujeto(['We']), verbo([found]), complemento([that, multiple, signaling, pathways, essential, for, the, hepatic, response, to, acute, liver, injury, are, impaired, in, livers, of, 'Foxa2-deficient', 'mice,', suggesting, that, the, deletion, of, 'Foxa2', in, the, hepatocyte, affects, the, liver, on, a, large, scale])].
[sujeto(['We', also, discovered, distinct, 'feed-forward', regulatory, loops, controlling, 'Foxa2-dependent']), verbo([targets]), complemento([in, a, cholic, 'acid-dependent', or, -, independent, manner])].
[sujeto(['We', show, that, 'Foxa2']), verbo([interacts]), complemento([with, different, transcription, factors, to, achieve, gene, expression, responses, appropriate, for, each, physiologic, state])].
[sujeto(['Homeostatic', regulation, of, bile, acid, metabolism, and, biliary, lipid, secretion, is, critical, to]), verbo([prevent]), complemento([enterohepatic, diseases])].
[sujeto([',', 2008, ')', show, that]), verbo([loss]), complemento([of, forkhead, box, transcription, factor, 'Foxa2', in, the, liver, leads, to, hepatic, injury, due, to, downregulation, in, the, expression, levels, of, bile, acid, transporters, and, detoxification, enzymes])].
[sujeto(['Dysregulation', of, bile, acid, homeostasis, can]), verbo([lead]), complemento([to, cholestatic, liver, disease, and, endoplasmic, reticulum, '(', 'ER)', stress])].
[sujeto(['We', show, by, global, location, analysis, '(', '\'', 'ChIP-on-chip\')', and, cell, 'type-specific', gene, ablation, that, the, winged, helix, transcription, factor, 'Foxa2', is]), verbo([required]), complemento([for, normal, bile, acid, homeostasis])].
[sujeto(['As']), verbo([suggested]), complemento([by, the, location, 'analysis,', deletion, of, 'Foxa2', in, hepatocytes, in, mice, using, the, 'Cre-lox', system, leads, to, decreased, transcription, of, genes, encoding, bile, acid, transporters, on, both, the, basolateral, and, canalicular, 'membranes,', resulting, in, intrahepatic, cholestasis])].
[sujeto(['In', 'addition,', we, show, that, expression, of, 'FOXA2', is, markedly]), verbo([decreased]), complemento([in, liver, samples, from, individuals, with, different, cholestatic, 'syndromes,', suggesting, that, reduced, 'FOXA2', abundance, could, exacerbate, the, injury])].
[sujeto(['Microsomal', epoxide, hydrolase, '(', 'mEH)', is, a, bifunctional, protein, that, plays, a, central, role, in, carcinogen, metabolism, and, is, also, able, to]), verbo([mediate]), complemento([the, 'sodium-dependent', uptake, of, bile, acids, into, hepatocytes])].
[sujeto(['Studies']), verbo([have]), complemento([identified, a, subject, '(', 'S-1)', with, extremely, elevated, serum, bile, salt, levels, in, the, absence, of, observable, hepatocellular, 'injury,', suggesting, a, defect, in, bile, acid, uptake])].
[sujeto(['Sequence', analysis, of, the, mEH, gene, '(', 'EPHX1)', revealed, a, point, mutation, at, an, upstream, 'HNF-3', site, '(', allele, 'I)', and, in, intron, 1, '(', allele, 'II),', which, resulted, in, a, significant]), verbo([decrease]), complemento([in, 'EPHX1', promoter, activity, in, transient, transfection, assays])].
[sujeto(['Gel', shift, assays, using, a, radiolabeled, oligonucleotide, from, each, region, resulted, in, specific, transcription, factor]), verbo([binding]), complemento(['patterns,', which, were, altered, in, the, presence, of, the, mutation])].
[sujeto(['These', studies, demonstrate, that, the, expression, of, mEH, is, greatly, reduced, in, a, patient, with, 'hypercholanemia,']), verbo([suggesting]), complemento([that, mEH, participates, in, 'sodium-dependent', bile, acid, uptake, in, human, liver, where, its, absence, may, contribute, to, the, etiology, of, this, disease])].
[sujeto(['We', previously, generated, a, transgenic, mouse, line, '(', 'T-77)', in, which]), verbo([increased]), complemento([hepatic, expression, of, the, hepatocyte, nuclear, 'factor-3beta', '(', 'HNF-3beta)', protein, was, used, to, assess, its, role, in, 'hepatocyte-specific', gene, transcription])].
[sujeto(['These', postnatal, liver, defects, were]), verbo([associated]), complemento([with, diminished, expression, of, hepatocyte, genes, involved, in, gluconeogenesis, and, bile, acid, transport, as, well, as, reduced, levels, of, hepatocyte, transcription, factors])].
[sujeto(['In', this, 'study,', we, show, that, mouse, tail, vein, injections, of, adenovirus]), verbo([expressing]), complemento([the, rat, 'HNF-3beta', '(', 'AdHNF3beta)', cDNA, efficiently, increased, its, levels, throughout, the, liver, lobule, and, recapitulated, the, 'T-77', transgenic, liver, phenotype, within, several, days, postinfection])].
[sujeto(['Likewise,', the, 'AdHNF3beta-infected', liver, phenotype, was]), verbo([associated]), complemento([with, reduced, hepatic, expression, of, genes, involved, in, glucose, 'homeostasis,', bile, acid, 'transport,', and, bilirubin, 'conjugation,', which, were, not, found, with, control, adenovirus, infections])].
[sujeto(['These', studies, show, that, 'adenovirus-mediated', gene, transfer, is, an, effective, method, for, rapid, hepatic]), verbo([increases]), complemento([in, transcription, factor, levels, to, determine, in, vivo, target, genes])].
[sujeto(['In', 'contrast,', 'AdHNF3alpha-infected', liver, displayed, only, a, transient, reduction, in, hepatic, glycogen, levels, and, was]), verbo([associated]), complemento([with, less, severe, decreases, in, hepatic, expression, of, gluconeogenic, and, bilirubin, metabolism, genes])].
[sujeto(['Consistent', with, these, 'findings,', only, 'T-77', transgenic, and, 'AdHNF3beta-infected', liver, exhibited, diminished, hepatic, expression, of, the, 'HNF-6', transcription, 'factor,']), verbo([suggesting]), complemento([that, reduced, 'HNF-6', levels, contribute, to, diminished, 'HNF-3beta-specific', transcriptional, activity])].
[sujeto(['The', winged, helix, transcription, 'factor,', hepatocyte]), verbo([nuclear]), complemento(['factor-3beta', '(', 'HNF-3beta),', mediates, the, 'hepatocyte-specific', transcription, of, numerous, genes, important, for, liver, function])].
[sujeto(['However,', the, in, vivo, role, of, 'HNF-3beta', in]), verbo([regulating]), complemento([these, genes, remains, unknown, because, homozygous, null, 'HNF3beta', mouse, embryos, die, in, utero, prior, to, liver, formation])].
[sujeto(['In', order, to, examine, the, regulatory, function, of, 'HNF-3beta,', we, created, transgenic, mice, in, which, the, -, 3, -, kb, transthyretin, promoter, functions, to]), verbo([increase]), complemento([hepatocyte, expression, of, the, rat, 'HNF-3beta', protein])].
[sujeto(['The', retarded, growth, phenotype, is, likely, due, to, a, 20, -, fold]), verbo([increase]), complemento([in, hepatic, expression, of, 'insulin-like', growth, factor, binding, protein, 1, '(', 'IGFBP-1),', which, results, in, elevated, levels, in, serum, of, 'IGFBP-1', and, limits, the, biological, availability, of, 'IGFs', required, for, postnatal, growth])].
[sujeto(['The', defects, in, glycogen, storage, and, serum, bile, acids, coincide, with, diminished, postnatal, expression, of, hepatocyte, genes]), verbo([involved]), complemento([in, gluconeogenesis, '(', phosphoenolpyruvate, carboxykinase, and, glycogen, 'synthase)', and, sinusoidal, bile, acid, uptake, '(', 'Ntcp),', respectively])].
[sujeto(['These', transgenic, studies, represent, the, first, in, vivo, demonstration, that, the, 'HNF-3beta', transcriptional, network]), verbo([regulates]), complemento([expression, of, 'hepatocyte-specific', genes, required, for, bile, acid, and, glucose, 'homeostasis,', as, well, as, postnatal, growth])].
[sujeto(['Transcription', factors, forkhead, box, '(', 'Fox)O1', and, pancreatic, and, duodenal, 'homeobox-1', '(', 'PDX-1)', are]), verbo([involved]), complemento([in, dexamethasone, '(', 'DEX)-induced', dysfunction, in, pancreatic, 'β-cells'])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, 'DEX', markedly, increased, 'FoxO1', mRNA, and, protein, 'expression,', whereas, it, decreased, 'PDX-1', mRNA, and, protein, expression, in, a, 'dose-', and, 'time-dependent', manner])].
[sujeto(['Further', study, showed, that, 'FoxA2', was]), verbo([involved]), complemento([in, regulation, of, 'FoxO1', and, 'PDX-1', expression, in, 'DEX-induced', pancreatic, 'β-cells', dysfunction])].
[sujeto(['Interestingly,', we, demonstrated, for, the, first, time, that, 'FoxA2', could]), verbo([bind]), complemento([to, the, 'FoxO1', gene, promoter, and, positively, regulate, 'FoxO1', expression])].
[sujeto(['Moreover,', we]), verbo([found]), complemento([that, 'DEX', increased, the, activity, of, 'FoxA2', binding, to, the, 'FoxO1', promoter, but, decreased, the, activity, of, 'FoxA2', binding, to, the, 'PDX-1', promoter, of, 'RINm5F', cells])].
[sujeto(['Knockdown', of, 'FoxA2', by, 'RNA', interference]), verbo([inhibited]), complemento(['FoxO1', expression, and, restored, 'PDX-1', expression, in, pancreatic, 'β-cells', treated, with, 'DEX'])].
[sujeto(['Together,', the, results, of, the, present, study, demonstrated, that, 'FoxA2', could, dynamically]), verbo([regulate]), complemento(['FoxO1', and, 'PDX-1', expression, in, pancreatic, 'β-cells', treated, with, 'DEX,', which, provides, new, important, information, on, the, transcriptional, regulation, of, 'FoxO1', and, 'PDX-1', in, 'DEX-induced', pancreatic, 'β-cells'])].
[sujeto(['Insulin', can]), verbo([inhibit]), complemento([the, stimulatory, effect, of, glucocorticoid, hormones, on, the, transcription, of, genes, coding, for, enzymes, involved, in, glucose, metabolism])].
[sujeto(['We']), verbo([reported]), complemento([earlier, that, insulin, inhibits, the, 'glucocorticoid-stimulated', transcription, of, the, gene, coding, for, liver, 6, -, 'phosphofructo-2-kinase', '(', 'PFK-2)'])].
[sujeto(['To', elucidate, the, mechanism, of, these, hormonal, 'effects,', we]), verbo([have]), complemento([studied, the, regulatory, regions, of, the, 'PFK-2', gene, in, transfection, experiments])].
[sujeto(['We']), verbo([found]), complemento([that, both, glucocorticoids, and, insulin, act, via, the, glucocorticoid, response, unit, '(', 'GRU)', located, in, the, first, intron])].
[sujeto(['Footprinting', experiments, showed, that, the, 'GRU']), verbo([binds]), complemento([not, only, the, glucocorticoid, receptor, '(', 'GR),', but, also, ubiquitous, '[', nuclear, factor, 'I', '(', 'NF-I)]', and, 'liver-enriched', '[', hepatocyte, nuclear, factor, '(', 'HNF)-3,', 'HNF-6,', 'CAAT/enhancer', binding, protein, '(', 'C/EBP)]', transcription, factors])].
[sujeto(['Site-directed', mutational, analysis, of, the, 'GRU', revealed, that, these, factors]), verbo([modulate]), complemento([glucocorticoid, action, but, that, none, of, them, seems, to, be, individually, involved, in, the, inhibitory, effect, of, insulin])].
[sujeto(['We', did, not]), verbo([find]), complemento([an, insulin, response, element, in, the, 'GRU,', but, we, showed, that, insulin, targets, the, 'GR'])].
[sujeto(['Insulin-induced', inhibition, of, the, glucocorticoid, stimulation]), verbo([required]), complemento([the, 'ligand-binding', domain, of, the, 'GR'])].
[sujeto(['Finally,', the, 'insulin-signaling', cascade]), verbo([involved]), complemento([was, independent, of, the, 'phosphatidylinositol-3-kinase', and, 'mitogen-activated', protein, kinase, pathways])].
[sujeto(['Together,', these, results]), verbo([suggest]), complemento([that, insulin, acts, on, the, 'PFK-2', gene, via, another, pathway, and, targets, either, the, 'GR', in, its, 'ligand-binding', domain, or, a, cofactor, interacting, with, this, domain])].
[sujeto(['The', rate, of, transcription, of, the, hepatic, phosphoenolpyruvate, carboxykinase, '(', 'PEPCK)', and, 'insulin-like', growth, 'factor-binding', protein, 1, '(', 'IGFBP-1)', genes, is]), verbo([stimulated]), complemento([by, glucocorticoids, and, inhibited, by, insulin])].
[sujeto(['In', both, 'cases,', the, effect, of, insulin, is, 'dominant,', since, it]), verbo([suppresses]), complemento([both, basal, and, 'glucocorticoid-stimulated', 'PEPCK', or, 'IGFBP-1', gene, transcription])].
[sujeto(['Analyses', of, both, promoters, by, transfection, of, 'PEPCK', or, 'IGFBP-1-chloramphenicol', acetyltransferase, fusion, genes, into, rat, hepatoma, cells]), verbo([has]), complemento([led, to, the, identification, of, insulin, response, sequences, '(', 'IRSs)', in, both, genes])].
[sujeto(['The', core, 'IRS,', 'T(G/A)TTTTG,', is, the, same, in, both, 'genes,', but, the, 'PEPCK', promoter]), verbo([has]), complemento([a, single, copy, of, this, element, whereas, the, 'IGFBP-1', promoter, has, two, copies, arranged, as, an, inverted, palindrome])].
[sujeto(['The', 'IGFBP-1', 'IRS', and, 'PEPCK', 'IRS', both]), verbo([bind]), complemento([the, alpha, and, beta, forms, of, hepatic, nuclear, factor, 3, '(', 'HNF-3),', although, the, latter, does, so, with, a, 'sixfold-lower', relative, affinity])].
[sujeto(['Both', the, 'PEPCK', and, the, 'IGFBP-1', 'IRSs', also, function, as, accessory, factor]), verbo([binding]), complemento([sites, required, for, the, full, induction, of, gene, transcription, by, glucocorticoids])].
[sujeto(['A', combination, of, transient, transfection, and, 'DNA']), verbo([binding]), complemento([studies, suggests, that, 'HNF-3', is, the, accessory, factor, that, supports, 'glucocorticoid-induced', gene, transcription])].
[sujeto(['In', both, 'genes,', the, 'HNF-3']), verbo([binding]), complemento([site, overlaps, the, 'IRS', core, 'motif(s)'])].
[sujeto(['A', model, in, which, insulin, is, postulated, to]), verbo([mediate]), complemento([its, negative, effect, on, 'glucocorticoid-induced', 'PEPCK', and, 'IGFBP-1', gene, transcription, indirectly, by, inhibiting, 'HNF-3', action, is, proposed])].
[sujeto(['Using', conditional, gene, ablation, during, a, later, phase, of, liver, 'development,', we, show, here, that, deletion, of, both, 'Foxa1', and, 'Foxa2', '(', 'Foxa1/2)', in, the, embryonic, liver]), verbo([caused]), complemento([hyperplasia, of, the, biliary, tree])].
[sujeto(['The', glucocorticoid, receptor, is, a, negative, regulator, of, 'IL-6', 'transcription;', in, the, absence, of, 'Foxa1/2,', the, glucocorticoid, receptor, failed, to]), verbo([bind]), complemento([to, the, 'IL-6', 'promoter,', causing, enhanced, 'IL-6', expression])].
[sujeto(['Thus,', after, liver, 'specification,', 'Foxa1/2', are]), verbo([required]), complemento([for, normal, bile, duct, development, through, prevention, of, excess, cholangiocyte, proliferation])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, 'Foxa1/2', function, as, terminators, of, bile, duct, expansion, in, the, adult, liver, through, inhibition, of, 'IL-6', expression])].
[sujeto(['We', show, here, 'that,', in, 'HepG2', hepatoma, 'cells,', 'EGF', '(', epidermal, growth, 'factor)']), verbo([inhibits]), complemento([basal, mouse, 'G6Pase', fusion, gene, transcription])].
[sujeto(['Several', studies]), verbo([have]), complemento([shown, that, insulin, represses, basal, mouse, 'G6Pase', fusion, gene, transcription, through, 'FOXO1', '(', forkhead, box, 'O1),', but, 'Stoffel', and, colleagues, have, recently, suggested, that, insulin, can, also, regulate, gene, transcription, through, 'FOXA2', '(', forkhead, box, 'A2)', '[', 'Wolfrum,', 'Asilmaz,', 'Luca,', 'Friedman', and, 'Stoffel', '(', 2003, ')', 'Proc'])].
[sujeto(['A', combined, 'GR', '(', glucocorticoid, 'receptor)-FOXA2']), verbo([binding]), complemento([site, is, located, between, -, 185, and, -, 174, in, the, mouse, 'G6Pase', promoter, overlapping, two, 'FOXO1', binding, sites, located, between, '(', -, 188, and, -, 182, ')', and, '(', -, 174, and, -, 168, ')'])].
[sujeto(['Selective', mutation, of, the, 'FOXO1']), verbo([binding]), complemento([sites, reduced, the, effect, of, 'insulin,', whereas, mutation, of, the, 'GR/FOXA2', binding, site, had, no, effect, on, the, insulin, response])].
[sujeto(['In', 'contrast,', selective, mutation, of, the, 'FOXO1', and, 'GR/FOXA2']), verbo([binding]), complemento([sites, both, reduced, the, effect, of, 'EGF'])].
[sujeto(['The', effect, of, these, mutations, was, 'additive,', since, the, combined, mutation, of, both, 'FOXO1', and, 'GR/FOXA2']), verbo([binding]), complemento([sites, reduced, the, effect, of, 'EGF', to, a, greater, extent, than, the, individual, mutations])].
[sujeto(['These', results]), verbo([suggest]), complemento(['that,', in, 'HepG2', 'cells,', 'GR', 'and/or', 'FOXA2', are, required, for, the, inhibition, of, basal, 'G6Pase', gene, transcription, by, 'EGF', but, not, insulin])].
[sujeto(['EGF', also]), verbo([inhibits]), complemento([hepatic, 'G6Pase', gene, expression, in, 'vivo,', but, in, cultured, hepatocytes, 'EGF', has, the, opposite, effect, of, stimulating, 'expression,', an, observation, that, may, be, explained, by, a, switch, in, 'ErbB', receptor, 'sub-type', expression, following, hepatocyte, isolation])].
[sujeto(['At', the, transcriptional, 'level,', maturation, is, controlled, by, the, actions, of, a, group, of, transcription, factors]), verbo([mediating]), complemento([gene, expression, in, the, lung])].
[sujeto(['A', network, of, transcription, factors]), verbo([regulates]), complemento([gene, expression, in, the, respiratory, 'epithelium,', which, then, influences, cell, maturation, throughout, the, lung])].
[sujeto(['Glucocorticoids', '(', via, the, glucocorticoid, 'receptor),']), verbo([acting]), complemento([primarily, in, the, pulmonary, 'mesenchyme,', influence, maturation, in, the, respiratory, epithelium])].
[sujeto(['Elucidation', of, the, intersecting, pathways, controlling, perinatal, lung, function, may]), verbo([provide]), complemento([opportunities, to, induce, pulmonary, maturation, in, preterm, infants, at, risk, for, respiratory, distress, syndrome, before, 'birth,', and, will, help, identify, genes, and, processes, important, for, various, aspects, of, lung, function])].
[sujeto(['Activation', of, the, genes, encoding, gluconeogenic, enzymes, is]), verbo([mediated]), complemento([by, 'hormone-responsive', transcription, factors, such, as, the, cyclic, 'AMP', response, element, binding, protein, '(', 'CREB)', and, the, glucocorticoid, receptor, '(', 'GR)'])].
[sujeto(['Here', we, show, using, 'cell-type-specific', gene, ablation, that, the, winged, helix, transcription, factor, 'Foxa2', is]), verbo([required]), complemento([for, activation, of, the, hepatic, gluconeogenic, program, during, fasting])].
[sujeto(['Specifically,', 'Foxa2']), verbo([promotes]), complemento([gene, activation, both, by, cyclic, 'AMP,', the, second, messenger, for, 'glucagon,', and, glucocorticoids])].
[sujeto(['Foxa2']), verbo([mediates]), complemento([these, effects, by, enabling, recruitment, of, 'CREB', and, 'GR', to, their, respective, target, sites, in, chromatin])].
[sujeto(['We', conclude, that, 'Foxa2', is]), verbo([required]), complemento([for, execution, of, the, hepatic, gluconeogenic, program, by, integrating, the, transcriptional, response, of, the, hepatocyte, to, hormonal, stimulation])].
[sujeto(['They', significantly]), verbo([suppress]), complemento([glucocorticoid, induction, of, tyrosine, aminotransferase, '(', 'TAT)', in, the, liver, of, sensitive, animals, and, have, minor, effect, on, the, induction, of, this, enzyme, in, the, liver, of, resistant, animals, '(', 3, '\'', -, 'MeDAB-treated', mice, and, 'OAT-treated', 'rats)'])].
[sujeto(['The', inhibitory, effect, of, these, carcinogens, is, realized, at, the, level, of, gene, transcription, '(']), verbo([decreased]), complemento([accumulation, of, 'TAT', 'mRNA)'])].
[sujeto(['This', effect, is]), verbo([mediated]), complemento([via, reduction, of, 'DNA-binding', activity, of, transcription, factor, 'HNF3', '(', without, decrease, of, its, 'content)', without, any, involvement, of, the, glucocorticoid, receptor])].
[sujeto(['It', was, shown, that, carcinogens, influence, 'DNA-binding', activity, of, 'HNF3', via, an, unknown]), verbo([nuclear]), complemento([factor])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento(['factor-3', '(', 'HNF-3)', belongs, to, a, large, family, of, forkhead, transcription, factors, and, is, made, up, of, three, members, '(', 'HNF-3alpha,', -, 3, beta, and, -, 3, 'gamma)'])].
[sujeto(['It']), verbo([has]), complemento([been, shown, that, 'HNF-3', regulates, a, number, of, metabolically, important, genes])].
[sujeto(['However,', the, mechanisms, underlying, this, regulation, of, 'HNF-3', activity, by, hormones, and, nutrition]), verbo([have]), complemento([not, yet, been, well, elucidated])].
[sujeto(['The', 'protein-free', diet, and, gluten, diet]), verbo([caused]), complemento([a, 3])].
[sujeto([7, -, fold]), verbo([increase]), complemento([in, 'HNF-3g', mRNA, in, the, liver, and, did, not, affect, the, mRNA, level, of, either, 'HNF-3alpha', or, 'HNF-3beta'])].
[sujeto(['Daily', administration, of, dexamethasone]), verbo([caused]), complemento([the, mRNA, levels, of, 'HNF-3alpha', and, 'HNF-3beta', to, increase, '(', 2.3, -, and, 1.4, -, 'fold,', 'respectively),', but, had, no, effect, on, the, 'HNF-3gamma', mRNA, level])].
[sujeto(['Insulin', replacement, in, the, diabetic, rats]), verbo([decreased]), complemento([both, mRNA, levels, in, a, 'dose-dependent', manner])].
[sujeto(['These', results, show, that, the, genes, of, the, three, members, of, the, 'HNF-3', family]), verbo([respond]), complemento([differently, to, hormonal, and, nutritional, factors, suggesting, that, the, activities, of, 'HNF-3', members, are, 'regulated,', at, least, in, 'part,', by, the, levels, of, their, gene, expression])].
[sujeto(['Hypersensitivity', to, acetylcholinesterase, inhibitors, '(', 'anti-AChEs)']), verbo([causes]), complemento([severe, nervous, system, symptoms, under, low, dose, exposure])].
[sujeto(['Two', contiguous, 'mutations,', a, 'T-->A', 'substitution,', disrupting, a, putative, glucocorticoid, response, 'element,', and, a, 4, -, bp, 'deletion,', abolishing, one, of, two, adjacent, 'HNF3']), verbo([binding]), complemento(['sites,', were, identified, 17, kb, upstream, of, the, transcription, start, site])].
[sujeto(['Electromobility', shift, 'assays,', transfection, studies, and, measurements, of, 'AChE', levels, in, immortalized, lymphocytes, as, well, as, in, peripheral, blood, from, both, carriers, and, 'non-carriers,', revealed, functional, relevance, for, this, mutation, both, in, vitro, and, in, vivo, and, showed, it, to]), verbo([increase]), complemento(['AChE', 'expression,', probably, by, alleviating, competition, between, the, two, hepatocyte, nuclear, factor, 3, binding, sites])].
[sujeto(['Moreover,', 'AChE-overexpressing', transgenic, 'mice,', unlike, normal, 'FVB/N', 'mice,', displayed, 'anti-AChE', hypersensitivity, and, failed, to, transcriptionally]), verbo([induce]), complemento(['AChE', production, following, exposure, to, 'anti-AChEs'])].
[sujeto(['Glucocorticoids']), verbo([stimulate]), complemento([gluconeogenesis, by, increasing, the, rate, of, transcription, of, genes, that, encode, gluconeogenic, enzymes, such, as, phosphoenolpyruvate, carboxykinase, '(', 'PEPCK)', and, 'glucose-6-phosphatase'])].
[sujeto(['Previous', studies]), verbo([have]), complemento([shown, that, hepatic, nuclear, factor, 3, '(', 'HNF3)', is, required, as, an, accessory, factor, for, several, 'glucocorticoid-stimulated', 'genes,', including, 'PEPCK'])].
[sujeto(['These', results]), verbo([provide]), complemento([direct, evidence, that, members, of, the, 'HNF3', family, are, required, for, proper, regulation, of, hepatic, gluconeogenesis])].
[sujeto(['Expression', of, the, rat, cytosolic, aspartate, aminotransferase, gene, is]), verbo([stimulated]), complemento([by, glucocorticoids, and, repressed, by, insulin, in, the, liver])].
[sujeto(['The', regulation, by, insulin, and, part, of, the, glucocorticoid, effect, are]), verbo([mediated]), complemento([by, a, distal, region, in, the, promoter])].
[sujeto(['A', 142, bp, fragment, '(', -, 1844, to, -, 1702, ')']), verbo([confers]), complemento([hormonal, sensitivity, to, the, heterologous, thymidine, kinase, promoter, in, 'transient-transfection', assays, in, 'H4IIEC3', hepatoma, cells])].
[sujeto(['Footprinting', and, 'gel-shift', assays, showed, that, several]), verbo([nuclear]), complemento([proteins, bind, to, this, region, at, conserved, 'CCAAT-enhancer', binding, protein, '(', 'C/EBP),', activator, protein, '(', 'AP-1)', and, 'E-box', sequences])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento(['factor-3alpha', '(', 'HNF-3)alpha', and, beta, bind, to, sequences, upstream, of, a, 'glucocorticoid-responsive', element, '(', 'GRE)', 'half-site', as, demonstrated, by, supershift, experiments])].
[sujeto(['Nuclear', factor, 'I', '(', 'NFI)-like', proteins]), verbo([bind]), complemento([downstream, of, the, 'GRE', 'half-site'])].
[sujeto(['The', effect, of, insulin, was, not]), verbo([prevented]), complemento([by, any, single, mutation, in, the, 'IRE-like', sites])].
[sujeto(['However,', mutation, of, two, 'IRE', sites, '(', namely, 'IREc', and, 'd)']), verbo([prevented]), complemento([the, insulin, effect, although, only, marginally, affecting, the, glucocorticoid, effect])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, the, effect, of, insulin, is, due, to, a, complex, interplay, of, factors, requiring, the, synergistic, contribution, of, at, least, two, sites, and, underline, the, contribution, of, 'HNF-3', and, 'NFI-like', proteins])].
[sujeto(['Complete', induction, of, hepatic, phosphoenolpyruvate, carboxykinase, '(', 'PEPCK)', gene, transcription, by, glucocorticoids]), verbo([requires]), complemento([a, complex, glucocorticoid, response, unit, '(', 'GRU)'])].
[sujeto(['The', 'GRU', is, comprised, of, two, glucocorticoid, receptor, '(', 'GR)-binding', sites, '(', 'GR1', and, 'GR2)', and, four, accessory, 'factor-binding', sites, '[', 'AF1,', 'AF2,', 'AF3,', and, cAMP, response, element, '(', 'CRE)]', that]), verbo([bind]), complemento([distinct, transcription, factors])].
[sujeto(['Hepatic']), verbo([nuclear]), complemento([factor, 4, '(', 'HNF4)', and, chicken, ovalbumin, upstream, promoter, transcription, factor, '(', 'COUP-TF)', bind, to, the, 'AF1', element, and, account, for, 'AF1', activity])].
[sujeto(['Members', of, the, hepatic]), verbo([nuclear]), complemento([factor, 3, '(', 'HNF3)', family, bind, to, the, 'AF2', element, and, provide, 'AF2', activity])].
[sujeto(['We', also, identified, the, domains, of, 'HNF4', and, 'HNF3', beta, that, are]), verbo([required]), complemento([for, the, 'AF1', and, 'AF2', 'activities,', respectively])].
[sujeto(['The', 'carboxy-terminal', transactivation, domain, of, 'HNF4', '(', amino, acids, 128, -, 374, ')']), verbo([confers]), complemento([most, of, the, 'AF1', 'activity,', while, the, carboxyterminal, transactivation, domain, of, 'HNF3', beta, '(', amino, acids, 361, -, 458, ')', mediates, 'AF2', activity])].
[sujeto(['These', domains, of, 'HNF4', and, 'HNF3', beta, appear, to]), verbo([have]), complemento([distinct, roles, in, the, response, to, 'glucocorticoids,', as, there, are, unique, structural, requirements, for, 'each,', as, judged, by, the, failure, of, most, other, classes, of, transactivation, domains, to, serve, as, accessory, factors])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, regulation, of, the, 'PEPCK', gene, by, glucocorticoids, requires, specific, interactions, between, 'GR,', accessory, 'factors,', and, 'coactivators,', and, that, the, transactivation, domains, of, 'AF1', and, 'AF2', are, of, fundamental, importance, in, the, assembly, of, this, multiprotein, complex])].
[sujeto(['A', single, 'far-upstream', enhancer, is, sufficient, to]), verbo([confer]), complemento(['hepatocyte-specific,', 'glucocorticoid-', and, cyclic, 'AMP-inducible', periportal, expression, to, the, carbamoylphosphate, synthetase, 'I', '(', 'CPS)', gene])].
[sujeto(['To', identify, the, mechanism, of, 'hormone-dependent', 'activation,', the, composition, and, function, of, the, enhancer]), verbo([have]), complemento([been, analyzed])].
[sujeto(['The', in, vivo, relevance, of, the, transcription, factors]), verbo([interacting]), complemento([with, the, enhancer, in, the, regulation, of, 'CPS', expression, in, the, liver, was, assessed, by, the, analysis, of, knockout, mice])].
[sujeto(['A', strong, reduction, of, 'CPS', mRNA, levels, was, observed, in, glucocorticoid, 'receptor-', and, 'C/EBPalpha-deficient', 'mice,', whereas, the, 'CPS', mRNA, was, normally]), verbo([expressed]), complemento([in, 'C/EBPbeta', knockout, mice, and, in, 'HNF3alpha', and, -, gamma, 'double-knockout', mice])].
[sujeto(['Here', we, characterize, a, composite, enhancer, which, directs, 'STF-1', expression, to, pancreatic, islet, cells, via, two, functional, elements, that]), verbo([recognize]), complemento([the, nuclear, factors, 'HNF-3beta', and, 'BETA-2'])].
[sujeto(['In', keeping, with, their, inhibitory, effects, on, islet, cell, 'maturation,', glucocorticoids, were]), verbo([found]), complemento([to, repress, 'STF-1', gene, expression, by, interfering, with, 'HNF-3beta', activity, on, the, 'islet-specific', enhancer])].
[sujeto(['Overexpression', of, 'HNF-3beta']), verbo([suppressed]), complemento([glucocorticoid, 'receptor-mediated', inhibition, of, the, 'STF-1', 'gene,', and, our, results, suggest, that, the, expansion, of, pancreatic, islet, precursor, cells, during, development, may, be, restricted, by, hormonal, cues, which, regulate, 'STF-1', gene, expression])].
[sujeto(['Transcription', of, the, hepatic, phosphoenolpyruvate, carboxykinase, gene, is]), verbo([stimulated]), complemento([by, glucocorticoids, and, inhibited, by, insulin])].
[sujeto(['The', glucocorticoid, response, is]), verbo([mediated]), complemento([by, a, complex, glucocorticoid, response, unit, that, consists, of, two, glucocorticoid, receptor, '(', 'GR)-binding', sites, '(', 'GR1', and, 'GR2)', and, two, accessory, 'factor-binding', sites, '(', 'AF1', and, 'AF2)'])].
[sujeto(['The', complete, unit, is]), verbo([required]), complemento([for, the, full, glucocorticoid, response])].
[sujeto(['The', dominant, insulin, effect, is]), verbo([mediated]), complemento([in, part, through, an, insulin, response, sequence, that, is, coincident, with, the, 'AF2', element])].
[sujeto(['Members', of, the, hepatic]), verbo([nuclear]), complemento([factor, 3, '(', 'HNF3)', and, 'CCAAT', enhancer, binding, protein, '(', 'C/EBP)', families, bind, to, the, 'AF2', 'element;', 'however,', there, is, no, correlation, between, binding, of, these, factors, and, the, ability, of, the, 'AF2', element, to, mediate, an, insulin, response])].
[sujeto(['We', show, here, that]), verbo([binding]), complemento([of, 'HNF3', does, correlate, with, the, stimulation, of, the, glucocorticoid, response, by, the, 'AF2', element, and, that, 'C/EBP', is, apparently, not, involved, in, this, effect])].
[sujeto(['This', requirement, for, 'HNF3', is, quite, specific, since, the, substitution, of, elements, known, to]), verbo([enhance]), complemento([the, action, of, the, 'GR', in, other, promoters, fails, to, recapitulate, 'AF2', accessory, factor, activity])].
[sujeto(['Based', on, current, and, previous, 'observations,', the, glucocorticoid, response, unit, consists, of, four, 'DNA', elements, that]), verbo([bind]), complemento([four, different, proteins])].
[sujeto(['These', 'are:', 'AF1', '(', hepatic]), verbo([nuclear]), complemento([factor, 4, /, chicken, ovalbumin, upstream, promoter, transcription, 'factor),', 'AF2', '(', 'HNF3),', 'GR1', '(', 'GR),', and, 'GR2', '(', 'GR)'])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 3, '(', 'HNF3)', recognizes, two, apparently, distinct, classes, of, sequence])].
[sujeto(['However,', a, detailed, mutational, analysis, of, a, representative]), verbo([binding]), complemento([site, of, each, class, reveals, that, these, sequences, display, common, features])].
[sujeto(['Particularly,', our, study]), verbo([reveals]), complemento([that, the, 'DNA', site, used, for, this, structural, analysis, is, too, short, to, account, for, all, 'HNF3-DNA', interactions])].
[sujeto(['The', better, knowledge, of, the, sequence, determinant]), verbo([recognized]), complemento([by, 'HNF3', has, allowed, us, to, analyze, its, function, in, the, glucocorticoid, response, of, the, rat, tyrosine, aminotransferase, '(', 'TAT)', gene])].
[sujeto(['This', response, is]), verbo([mediated]), complemento([through, a, complex, array, of, neighboring, and, overlapping, transcription, factor, binding, sites])].
[sujeto(['Furthermore,', 'HNF3', beta, overexpression, results, in, a, stimulation, of, the, glucocorticoid, response, that, is, dependent, on, the, integrity, of, its]), verbo([binding]), complemento([sites])].
[sujeto(['We', also, show, that, the, relative, level, of, 'HNF3', determines, the, extent, of, the, contribution, of, one, of, the, glucocorticoid, receptor]), verbo([binding]), complemento([sites])].
[sujeto(['Glucocorticoids']), verbo([stimulate]), complemento([and, insulin, inhibits, hepatic, production, of, 'IGFBP-1', at, the, level, of, gene, transcription])].
[sujeto(['We']), verbo([have]), complemento([reported, that, both, the, 'IGFBP-1', and, 'PEPCK', 'IRSs', bind, hepatocyte, nuclear, 'factor-3', '(', 'HNF-3)', proteins, '[', 1, ']'])].
[sujeto(['We', now]), verbo([report]), complemento([that, 'IRSs', from, the, 'IGFBP-1', and, 'PEPCK,', as, well, as, an, 'IRS', which, also, binds, 'HNF-3', in, the, rat, tyrosine, aminotransferase, '(', 'TAT)', 'gene,', also, interact, with, another, 'DNA/protein', complex, in, gel, shift, studies])].
[sujeto(['Of', 'note,', a, 250, -, fold, excess, of, an, oligo, containing, a, 'C/EBP']), verbo([binding]), complemento([site, '(', but, not, other, 'AT-rich', 'sequences)', inhibits, the, formation, of, this, complex, in, gel, shift, assays])].
[sujeto(['Similarly,', preincubation, with, 'CHOP,', a, truncated, member, of, the, 'C/EBP', family, which, contains, a, 'beta-leucine', zipper, 'domain,', does, not]), verbo([prevent]), complemento([or, alter, the, mobility, of, this, novel, 'DNA/protein', 'complex,', indicating, that, components, of, this, complex, do, not, form, heterodimers, with, 'beta-ZIP', proteins])].
[sujeto(['We', conclude, that, 'HNF-3', proteins, and, this, novel, 'C/EBP-related', 'DNA/protein', complex, may, play, an, important, role, in]), verbo([mediating]), complemento([interactions, between, glucocorticoids, and, insulin, in, the, regulation, of, 'IGFBP-1', and, perhaps, multiple, hepatic, genes])].
[sujeto(['An', insulin, response, element, '(', 'IRE)']), verbo([has]), complemento([been, identified, approximately, 100, base, pairs, '(', 'bp)', 5, '\'', to, the, transcription, start, site, of, the, human, 'insulin-like', growth, factor, binding, 'protein-1', '(', 'hIGFBP-1)', gene])].
[sujeto(['This', cis, element, appears, crucial, to, the, multihormonal, regulation, of, 'hIGFBP-1', expression, in, 'liver,', since, '(', 'i)', an, intact, 'IRE', is]), verbo([required]), complemento([for, maximal, stimulation, of, 'hIGFBP-1', promoter, activity, by, 'dexamethasone,', and, '(', 'ii)', the, 'IRE', confers, insulin, inhibition, of, both, basal, and, 'dexamethasone-stimulated', 'hIGFBP-1', promoter, activity])].
[sujeto(['Further', progress, in, understanding, how, the, 'IRE']), verbo([confers]), complemento([insulin, and, glucocorticoid, effects, requires, identification, of, transcription, factors, confering, effects, of, these, hormones])].
[sujeto(['D-site']), verbo([binding]), complemento([protein, '(', 'DBP),', and, members, of, the, hepatic, nuclear, factor, 3, '(', 'HNF', 3, ')', and, high, mobility, group, 'I/Y', '(', 'HMG', 'I/Y)', protein, 'families,', each, known, to, bind, 'DNA', elements, similar, in, sequence, to, the, 'IRE,', were, tested, for, 'IRE', binding])].
[sujeto(['Additional', studies, are]), verbo([required]), complemento([to, establish, whether, binding, of, any, of, these, proteins, to, the, 'IRE', is, important, to, the, regulation, of, 'hIGFBP-1', expression, by, insulin, 'and/or', glucocorticoids])].
[sujeto(['IGF']), verbo([binding]), complemento(['protein-1', is, an, important, 'short-term', modulator, of, 'IGF', bioavailability])].
[sujeto(['Hepatic', transcription, of, 'IGFBP-1', is]), verbo([increased]), complemento([by, glucocorticoids, and, suppressed, by, insulin])].
[sujeto(['This', insulin, response, sequence, contains, a, sequence, highly, related, '(', 10, /, 12, 'bases)', to, a, consensus, 'HNF-3']), verbo([binding]), complemento([sequence])].
[sujeto(['Gel', shift, and, supershift, studies, confirm, that, this, sequence]), verbo([binds]), complemento(['HNF-3', 'alpha,', beta, and, gamma])].
[sujeto(['Co-expression', of, 'HNF-3', beta]), verbo([enhances]), complemento(['IGFBP-1', promoter, activity, in, 'NIH-3T3', cells])].
[sujeto(['Mutation', of, this, 'HNF-3']), verbo([binding]), complemento([sequence, disrupts, this, effect, as, well, as, the, ability, of, glucocorticoids, to, stimulate, and, of, insulin, to, inhibit, 'IGFBP-1', promoter, activity, in, 'H4IIE', and, 'HepG2', hepatoma, cells])].
[sujeto(['HNF-3']), verbo([binding]), complemento([at, this, site, may, play, an, important, role, in, the, multihormonal, regulation, of, hepatic, 'IGFBP-1', gene, expression])].
[sujeto(['Studies']), verbo([have]), complemento([shown, 'over-expression', of, 'GLUT2', in, diabetic, conditions])].
[sujeto(['Ferulic', acid, '(', 'FA)', is, an, antidiabetic, phenolic, phytocompound, which, is]), verbo([reported]), complemento([to, regulate, 'GLUT4', in, vitro])].
[sujeto(['Male', 'Wistar', rats, were, divided, into, 5, 'groups:', 'control,', diabetic, '(', diabetes, was]), verbo([induced]), complemento([by, giving, high, fat, diet, and, high, fructose, water, for, 60, 'days),', diabetic, rats, treated, with, 'FA', '(', 50, 'mg/kg', body, 'weight/day,', orally, for, 30, 'days),', diabetic, rats, treated, with, metformin, '(', 50, 'mg/kg', body, 'weight/day,', orally, for, 30, 'days)', and, control, rats, treated, with, 'FA', '(', 50, 'mg/kg', body, 'weight/day', orally, for, 30, 'days)'])].
[sujeto(['Glucose', uptake, and, 'oxidation,', expression, of, 'GLUT2', and]), verbo([binding]), complemento([of, transcription, factors, -, 'SREBP1c,', 'HNF1α', and, 'HNF3β', with, 'GLUT2', gene, promoter, were, studied])].
[sujeto(['Over-expression', of, 'GLUT2', in, hepatic, tissue, was]), verbo([found]), complemento([in, high, fat, and, 'fructose-', induced, 'type-2', diabetic, animals])].
[sujeto(['Foxa2', '(', 'Hnf3beta)', is, a, 'winged-helix/forkhead', transcription, factor, that]), verbo([regulates]), complemento([gene, expression, in, the, 'liver,', pancreatic, islets, and, adipocytes])].
[sujeto(['It', is]), verbo([required]), complemento([for, the, maintenance, of, glucose, and, lipid, homeostasis])].
[sujeto(['Hyperinsulinemia-mediated', inactivation, of, 'Foxa2', by]), verbo([nuclear]), complemento([exclusion, has, recently, been, implicated, in, the, development, of, liver, steatosis, and, insulin, resistance, in, three, animal, models, of, diabetes])].
[sujeto(['These', abnormalities, were, cured, by, 'adenovirus-mediated', expression, of, a, constitutively, active, form, of, 'Foxa2', containing, a, mutated, 'T156', phosphorylation, 'site,', which]), verbo([increases]), complemento([fatty, acid, oxidation, and, reduces, its, biosynthesis])].
[sujeto(['Accordingly,', the, prevention, of, phosphorylation, of, 'Foxa2', was]), verbo([suggested]), complemento([as, a, pharmacological, target, for, the, treatment, of, obesity, and, diabetes])].
[sujeto(['In', 'particular,', 'growth-restricted', infants, or, infants, born, prematurely, may, develop, a, severe, form, of, intestinal, inflammation, known, as, necrotizing, enterocolitis, '(', 'NEC),', which]), verbo([has]), complemento([a, high, mortality])].
[sujeto(['Milk']), verbo([provides]), complemento([a, multitude, of, proteins, with, 'anti-inflammatory', properties, and, in, this, review, we, gather, together, some, recent, significant, advances, regarding, the, isolation, and, proteomic, identification, of, these, minor, constituents, of, both, human, and, bovine, milk])].
[sujeto(['We', introduce, the, process, of, 'inflammation,', with, a, focus, on, the, immature, 'gut,', and, describe, how, a, multitude, of, milk, proteins]), verbo([act]), complemento([against, the, inflammatory, process, according, to, both, in, vitro, and, in, vivo, studies])].
[sujeto(['Nonalcoholic', fatty, liver, disease, '(', 'NAFLD)', is, a, common, liver, disease, whose, prevalence]), verbo([has]), complemento([increased, markedly])].
[sujeto(['We']), verbo([reported]), complemento([previously, that, fatty, acid, synthesis, was, enhanced, in, 'NAFLD', with, the, accumulation, of, fatty, acids])].
[sujeto(['To', clarify, the, 'disorder,', we, evaluated, the, expression, of, genes]), verbo([regulating]), complemento([fatty, acid, synthesis, by, 'real-time', 'PCR', using, samples, from, 'NAFLD', '(', 'n=22)', and, normal, liver, '(', 'control;', 'n=10)'])].
[sujeto(['SREBP-1c', is, positively]), verbo([regulated]), complemento([by, insulin, signaling, 'pathways,', including, insulin, receptor, substrate, '(', 'IRS)-1', and, -, 2])].
[sujeto(['In', 'NAFLD,', 'IRS-1', expression, was]), verbo([enhanced]), complemento([and, correlated, positively, with, 'SREBP-1c', expression])].
[sujeto(['In', 'contrast,', 'IRS-2', expression]), verbo([decreased]), complemento([by, 50, '%', and, was, not, correlated, with, 'SREBP-1c'])].
[sujeto(['Forkhead', box, protein, 'A2', '(', 'Foxa2)', is, a, positive, regulator, of, fatty, acid, oxidation, and, is, itself, negatively]), verbo([regulated]), complemento([by, 'IRSs'])].
[sujeto(['Foxa2', expression]), verbo([increased]), complemento([in, 'NAFLD', and, showed, a, negative, correlation, with, 'IRS-2,', but, not, with, 'IRS-1,', expression])].
[sujeto(['It', is, known, that, 'SREBP-1c', is, negatively]), verbo([regulated]), complemento([by, 'AMP-activated', protein, kinase, '(', 'AMPK)', but, expression, levels, of, 'AMPK', in, 'NAFLD', were, almost, equal, to, those, of, the, controls])].
[sujeto(['These', data, indicate, 'that,', in, 'NAFLD,', insulin, signaling, via, 'IRS-1']), verbo([causes]), complemento([the, 'up-regulation', of, 'SREBP1-c,', leading, to, the, increased, synthesis, of, fatty, acids, by, the, 'hepatocytes;', negative, feedback, regulation, via, 'AMPK', does, not, occur, and, the, activation, of, 'Foxa2,', following, a, decrease, of, 'IRS-2,', 'up-regulates', fatty, acid, oxidation])].
[sujeto(['The', 'Forkhead', box, '(', 'Fox)', transcription, factor, 'Foxa2', '(', 'HNF-3beta)', and, related, family, members, 'Foxa1', '(', 'HNF-3alpha)', and, 'Foxa3', '(', 'HNF-3gamma)']), verbo([act]), complemento([in, concert, with, other, hepatocyte, nuclear, factors, '(', 'HNF)', to, coordinately, regulate, 'liver-specific', gene, expression])].
[sujeto(['To', circumvent, the, hepatic, functional, redundancy, of, the, 'Foxa', 'proteins,', we, used, the, 'T-77', transgenic, '(', 'TG)', mouse, line, in, which, the, -, 3, -, kb, transthyretin, '(', 'TTR)', promoter, functioned, to]), verbo([increase]), complemento([hepatocyte, expression, of, the, 'Foxa2', cDNA])].
[sujeto(['Adult', 'TG', mice, exhibited, reduced, hepatic, glycogen, and, progressive, liver, 'injury,', but]), verbo([maintained]), complemento([normal, serum, levels, of, 'glucose,', 'insulin,', and, glucagon])].
[sujeto(['The', postnatal, 'TG', mice, displayed, significant, reduction, in, serum, glucose, levels, and, in, hepatocyte, glycogen, storage, without]), verbo([increased]), complemento([serum, levels, of, ketone, bodies, and, free, fatty, acid, suggesting, that, they, are, not, undergoing, a, starvation, response])].
[sujeto(['We', show, that, 'TG', liver, developed, a, substantial, transient, 'steatosis,', which, reached, a, maximum, at, postnatal, day, 5, and, is]), verbo([associated]), complemento([with, increased, expression, of, hepatic, genes, involved, in, fatty, acid, and, triglyceride, 'synthesis,', lipid, 'beta-oxidation,', and, amino, acid, biosynthesis])].
[sujeto(['In', 'conclusion,', our, model, proposes, that, in, response, to, reduction, in, hepatocyte, glycogen, 'storage,', the, 'TTR-Foxa2', 'TG', mice, survive, by]), verbo([maintaining]), complemento([sufficient, serum, levels, of, glucose, through, gluconeogenesis, using, deaminated, amino, acids, with, dicarboxylate, products, of, peroxisomal, lipid, 'beta-oxidation', shuttled, through, the, tricarboxylic, acid, cycle])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, hepatitis, 'C', virus, '(', 'HCV)', infection, modulates, the, expression, of, forkhead, box, transcription, 'factors,', including, 'FoxO1', and, 'FoxA2,', which, play, key, roles, in, gluconeogenesis, and, 'β-oxidation', of, fatty, 'acid,', respectively])].
[sujeto(['The', aim, of, the, present, study, was, to, determine, the, role, of, forkhead, box, transcription, factors, in]), verbo([modulating]), complemento([lipid, metabolism])].
[sujeto([5, cells]), verbo([increased]), complemento([expression, of, sterol, regulatory, element, binding, protein, 1, c, '(', 'SREBP-1c)', and, its, downstream, 'target,', fatty, acid, synthase, '(', 'FASN),', which, are, key, proteins, involved, in, lipid, synthesis])].
[sujeto(['Knockdown', of, 'FoxO1', by, small, interfering, 'RNA', in, 'HCV-infected', cells, significantly]), verbo([decreased]), complemento(['SREBP-1c', and, 'FASN', expression])].
[sujeto([5, cells, significantly]), verbo([decreased]), complemento([the, expression, of, 'medium-chain', acyl, coenzyme, 'A', dehydrogenase, '(', 'MCAD)', and, 'short-chain', acyl, coenzyme, 'A', dehydrogenase, '(', 'SCAD),', involved, in, the, regulation, of, 'β-oxidation', of, fatty, acids])].
[sujeto(['Oil', red, 'O', and, neutral, lipid, staining, indicated, that, 'HCV', infection, significantly]), verbo([increases]), complemento([lipid, accumulation, compared, to, that, in, the, 'mock-infected', control])].
[sujeto(['This', was, further, verified, by, the]), verbo([increased]), complemento([expression, of, 'perilipin-2', and, decreased, activity, of, 'hormone-sensitive', lipase, '(', 'HSL)', in, 'HCV-infected', 'hepatocytes,', implying, increased, accumulation, of, neutral, lipids])].
[sujeto(['Knockdown', of, 'FoxO1', and, ectopic, expression, of, 'FoxA2', significantly]), verbo([decreased]), complemento(['HCV', replication])].
[sujeto(['Taken', 'together,', these, results]), verbo([suggest]), complemento([that, 'HCV', modulates, forkhead, box, transcription, factors, which, together, increase, lipid, accumulation, and, promote, viral, replication])].
[sujeto(['Hepatic', steatosis, is, a, frequent, complication]), verbo([associated]), complemento([with, chronic, 'HCV', infection])].
[sujeto(['Its', presence, is, a, key, prognostic, indicator]), verbo([associated]), complemento([with, the, progression, to, hepatic, fibrosis, and, hepatocellular, carcinoma])].
[sujeto(['Several', mechanisms]), verbo([have]), complemento([been, proposed, to, account, for, the, development, of, steatosis, and, fatty, liver, during, 'HCV', infection])].
[sujeto(['We', observed, that, 'HCV', infection]), verbo([increases]), complemento([expression, of, both, 'SREBP-1c', and, 'FASN'])].
[sujeto(['Further', investigation]), verbo([suggested]), complemento([that, the, expression, of, 'SREBP-1c', and, 'FASN', is, controlled, by, the, transcription, factor, 'FoxO1', during, 'HCV', infection])].
[sujeto(['In', 'addition,', 'HCV', infection, significantly]), verbo([decreased]), complemento([both, 'MCAD', and, 'SCAD', 'expression,', which, is, controlled, by, 'FoxA2'])].
[sujeto(['HCV', infection, also]), verbo([increased]), complemento([lipid, droplet, 'accumulation,', increased, 'perilipin-2', 'expression,', and, decreased, 'HSL', activity])].
[sujeto(['Thus,', knockdown, of, 'FoxO1', '(']), verbo([decreased]), complemento(['lipogenesis)', and, overexpression, of, 'FoxA2', '(', increased, 'β-oxidation)', resulted, in, a, significant, disruption, of, the, platform, 'and,', 'hence,', a, decrease, in, 'HCV', genome, replication])].
[sujeto(['Thus,']), verbo([targeting]), complemento([of, 'FoxO1', and, 'FoxA2', might, be, useful, in, developing, a, therapeutic, approach, against, 'HCV', infection])].
[sujeto(['Dietary', 'n-3', polyunsaturated, fatty, acid, '(', 'n-3', 'PUFA)', supplementation, is, postulated, to]), verbo([have]), complemento([positive, effects, on, fertility])].
[sujeto(['The', impact, of, dietary, 'n-3', 'PUFA', supplementation, on, physiological, and, biochemical, processes]), verbo([involved]), complemento([in, reproduction, is, likely, to, be, associated, with, significant, alterations, in, gene, expression, in, key, reproductive, tissues, which, is, in, turn, regulated, by, transcription, factors])].
[sujeto(['Furthermore,', oPOSSUM, was, employed, to, identify, transcription, factors]), verbo([involved]), complemento([in, gene, expression, changes, due, to, supplementary, 'PUFA'])].
[sujeto(['The', human, liver, fatty, acid]), verbo([binding]), complemento([protein, '(', 'hFABP1)', participates, in, cellular, 'long-chain', fatty, acid, trafficking, and, regulation, of, lipid, metabolism, and, changes, in, hFABP1, are, associated, with, an, increased, risk, for, type, 2, 'diabetes,', cardiovascular, disease, '(', 'CVD),', and, metabolic, syndromes])].
[sujeto(['TFSEARCH', and, 'TESS', programs, were, used, to, predict, potential, transcription, factor]), verbo([binding]), complemento([sites])].
[sujeto(['Two', putative]), verbo([binding]), complemento([sites, for, the, 'liver-enriched', transcription, factors, hepatocyte, nuclear, factor, 3, β, '(', 'HNF3β)', and, 'CCAAT/enhancer', binding, protein, α, '(', 'C/EBPα)', were, identified, in, 'the -255 nt', 'to -155 nt', hFABP1, promoter, region])].
[sujeto(['In', 'addition,', the, electrophoretic, mobility, shift, assay, '(', 'EMSA)', and, chromatin, immunoprecipitation, assay, '(', 'ChIP)', revealed, that, these]), verbo([binding]), complemento([sites, were, recognized, by, 'HNF3β', and, 'C/EBPα', respectively])].
[sujeto(['Overexpression', of, 'HNF3β', and, 'C/EBPα']), verbo([enhanced]), complemento([the, transcription, of, hFABP1, and, consequently, improved, the, protein, level, of, hFABP1, 'in HepG2', 'cells,', while, knockdown, of, 'HNF3β', and, 'C/EBPα', showed, the, inverse, effects])].
[sujeto(['Taken', 'together,', the, hFABP1, gene, is, highly]), verbo([transcribed]), complemento([in, 'liver-derived', 'cells,', and, regulated, predominantly, by, 'liver-enriched', transcription, factors, 'HNF3β', and, 'C/EBPα'])].
[sujeto(['Glucose', disposal]), verbo([induces]), complemento([a, signal, that, modulates, the, transcriptional, regulation, of, genes, involved, in, the, glycolysis, and, lipogenesis, pathways])].
[sujeto(['By', microarray, 'analysis,', we, observed, that, critical, genes, such, as, 'liver-type', pyruvate, 'kinase,', malic, 'enzyme,', fatty, acid, 'synthase,', and, 'stearoyl-CoA', desaturase, 1, were]), verbo([enhanced]), complemento(['multiple-fold,', whereas, genes, involved, in, mitochondrial, fatty, acid, oxidation, and, the, 'Krebs', cycle, were, downregulated])].
[sujeto(['Despite', the]), verbo([increase]), complemento([in, expression, of, fatty, acid, synthesis, genes, and, the, presence, of, 'steatosis,', no, major, alterations, to, the, levels, of, genes, involved, in, 'VLDL', assembly, and, 'secretion,', such, as, diacylglycerol, acyltransferases, 1, and, 2, and, microsomal, triglyceride, transfer, 'protein,', were, observed])].
[sujeto(['Overall,', our, data]), verbo([suggest]), complemento([that, the, gene, expression, pattern, induced, by, glucose, metabolism, favors, fatty, acid, storage, in, the, liver, rather, than, secretion, into, the, circulation])].
[sujeto(['Lack', of, surfactant, lipids, and, proteins, in, the, lungs]), verbo([causes]), complemento([respiratory, distress, 'syndrome,', a, common, cause, of, morbidity, and, mortality, in, preterm, infants])].
[sujeto(['We', show, that, 'C/EBPalpha', plays, a, crucial, role, in, the, maturation, of, the, respiratory, epithelium, in, late, 'gestation,', being]), verbo([required]), complemento([for, the, production, of, surfactant, lipids, and, proteins, necessary, for, lung, function])].
[sujeto(['Deletion', of, the, 'Cebpa', gene, in, respiratory, epithelial, cells, in, fetal, mice]), verbo([caused]), complemento([respiratory, failure, at, birth])].
[sujeto(['Normal', synthesis, of, surfactant, lipids, and, 'proteins,', including, 'SP-A,', 'SP-B,', 'SP-C,', 'SP-D,', 'ABCA3', '(', a, lamellar, body]), verbo([associated]), complemento(['protein)', and, 'FAS', '(', precursor, of, fatty, acid, 'synthesis)', were, dependent, upon, expression, of, the, 'C/EBPalpha', in, respiratory, epithelial, cells])].
[sujeto(['Deletion', of, the, 'Cebpa', gene]), verbo([caused]), complemento([increased, expression, of, 'Tgfb2,', a, growth, factor, that, inhibits, lung, epithelial, cell, proliferation, and, differentiation])].
[sujeto(['Normal', expression, of, 'C/EBPalpha']), verbo([required]), complemento(['Titf1', and, 'Foxa2,', transcription, factors, that, also, play, an, important, role, in, perinatal, lung, differentiation])].
[sujeto(['C/EBPalpha']), verbo([participates]), complemento([in, a, transcriptional, network, that, is, required, for, the, regulation, of, genes, mediating, perinatal, lung, maturation, and, surfactant, homeostasis, that, is, necessary, for, adaptation, to, air, breathing, at, birth])].
[sujeto(['Changes', in, the, circulating, concentrations, of, these, hormones, signal, fed, or, starvation, states, and, elicit, 'counter-regulatory', responses, that]), verbo([maintain]), complemento([normoglycaemia])].
[sujeto(['Here', we, show, that, in, normal, 'mice,', plasma, insulin]), verbo([inhibits]), complemento([the, forkhead, transcription, factor, 'Foxa2', by, nuclear, exclusion, and, that, in, the, fasted, '(', low, 'insulin)', state, 'Foxa2', activates, transcriptional, programmes, of, lipid, metabolism, and, ketogenesis])].
[sujeto(['In', these, 'mice,', adenoviral, expression, of, 'Foxa2T156A,', a, 'nuclear,', constitutively, active, 'Foxa2', that, cannot, be]), verbo([inhibited]), complemento([by, 'insulin,', decreases, hepatic, triglyceride, 'content,', increases, hepatic, insulin, 'sensitivity,', reduces, glucose, 'production,', normalizes, plasma, glucose, and, significantly, lowers, plasma, insulin])].
[sujeto(['These', changes, are]), verbo([associated]), complemento([with, increased, expression, of, genes, encoding, enzymes, of, fatty, acid, 'oxidation,', ketogenesis, and, glycolysis])].
[sujeto(['Chronic', hyperinsulinaemia, in, 'insulin-resistant', syndromes, results, in, the, cytoplasmic, localization, and, inactivation, of, 'Foxa2,', thereby]), verbo([promoting]), complemento([lipid, accumulation, and, insulin, resistance, in, the, liver])].
[sujeto(['Pharmacological', intervention, to]), verbo([inhibit]), complemento([phosphorylation, of, 'Foxa2', may, be, an, effective, treatment, for, type, 2, diabetes])].
[sujeto(['Liver', fatty, acid]), verbo([binding]), complemento([protein, '(', 'L-FABP)', is, a, small, protein, that, is, thought, to, play, an, important, role, in, the, intracellular, binding, and, trafficking, of, long, chain, fatty, acids, in, the, liver])].
[sujeto(['Expression', of, the, gene, encoding, the, zebrafish, liver, fatty, acid]), verbo([binding]), complemento([protein, is, regulated, by, a, 435, -, bp, distal, region, '(', -, 1944, to, -, 1510, ')', of, the, 'L-FABP', promoter])].
[sujeto(['The', 435, -, bp, sequence, region]), verbo([has]), complemento([two, distinct, liver, regulatory, 'elements,', 'A', '(', -, 1944, to, -, 1623, ')', and, 'B', '(', -, 1622, to, -, 1510, ')', ',', and, contains, multiple, putative, consensus, binding, sites])].
[sujeto(['The', importance, of, the, 'HNF-1alpha', consensus]), verbo([binding]), complemento([site, in, the, 'A', element, and, the, 'HNF-3beta', consensus, binding, site, in, the, 'B', element, within, the, 435, -, bp, distal, region, of, the, 'L-FABP', promoter, region, suggests, that, combinatorial, interactions, between, multiple, regulatory, factors, are, responsible, for, the, gene, expression, of, 'L-FABP', in, the, liver])].
[sujeto(['Nonalcoholic', steatohepatitis, '(', 'NASH)', is, one, of, the, most, frequent]), verbo([causes]), complemento([of, abnormal, liver, dysfunction, associated, with, synthesis, and, oxidation, of, fatty, acids])].
[sujeto(['As', a, result, of, the]), verbo([decrease]), complemento([of, 'AdipoR1/R2', 'expression,', the, messenger, 'RNA', expression, levels, of, genes, located, downstream, of, 'AdipoR1/R2,', adenosine, 'monophosphate-activated', protein, kinase, 'α1/α2,', which, inhibits, fatty, acid, 'synthesis,', and, peroxisome, 'proliferator-activated', receptor, 'α,', which, activates, fatty, acid, 'oxidation,', also, decreased])].
[sujeto(['Expression', level, of, sterol, regulatory, element]), verbo([binding]), complemento(['protein-1c', was, found, to, be, 'elevated,', suggesting, the, 'up-regulation', of, 'IRS-1,', and, resulted, in, increased, fatty, acid, synthesis])].
[sujeto(['Furthermore,']), verbo([increase]), complemento([of, forkhead, box, protein, 'A2', expression, was, 'observed,', which, might, be, associated, with, the, 'down-regulation', of, 'IRS-2,', facilitating, fatty, acid, oxidation])].
[sujeto(['Taken', 'together,']), verbo([increased]), complemento([synthesis, and, oxidation, of, fatty, acids, by, 'up-', or, 'down-regulation', of, 'AdipoR', or, 'IRS', may, contribute, to, the, progression, of, 'NASH'])].
[sujeto(['The', prevalence, of, diabetes]), verbo([has]), complemento([exponentially, increased, in, recent, decades, due, to, environmental, factors, such, as, nocturnal, lifestyle, and, 'aging,', both, of, which, influence, the, amount, of, melatonin, produced, in, the, pineal, gland])].
[sujeto(['Intriguingly,', treatment, of, 'C2C12', cells, with, melatonin, '(', 1, 'nm)']), verbo([stimulated]), complemento([glucose, uptake, twofold, increase])].
[sujeto(['Melatonin-stimulated', glucose, transport, was]), verbo([inhibited]), complemento([with, 'co-treatment', with, the, melatonin, receptor, antagonist, luzindole])].
[sujeto(['Melatonin', also]), verbo([increased]), complemento([the, phosphorylation, level, of, insulin, receptor, 'substrate-1', '(', 'IRS-1)', and, the, activity, of, phosphoinositide, 3, -, kinase, '(', 'PI-3-kinase)'])].
[sujeto(['In', 'addition,', melatonin]), verbo([increased]), complemento([the, expression, level, of, forkhead, box, 'A2,', which, was, recently, discovered, to, regulate, fatty, acid, oxidation, and, to, be, inhibited, by, insulin])].
[sujeto(['In', 'summary,', melatonin]), verbo([stimulates]), complemento([glucose, transport, to, skeletal, muscle, cells, via, 'IRS-1/PI-3-kinase', 'pathway,', which, 'implies,', at, the, molecular, 'level,', its, role, in, glucose, homeostasis, and, possibly, in, diabetes])].
[sujeto(['Apolipoprotein', 'M', '(', 'apoM),', as, a, novel, apolipoprotein, which, is, mainly]), verbo([expressed]), complemento([in, liver, and, kidney, 'tissues,', is, associated, with, development, and, progression, of, atherosclerosis, and, diabetes])].
[sujeto(['Our', group]), verbo([have]), complemento([recently, shown, that, 'Dihydrocapsaicin(DHC)can', significantly, decrease, atherosclerotic, plaque, formation, in, 'apoE-/-', mice])].
[sujeto(['We']), verbo([found]), complemento([that, 'DHC', markedly, decreased, expression, of, apoM, at, both, mRNA, and, protein, level, in, 'HepG2', cells, in, a, 'dose-dependent', and, 'time-dependent', manner])].
[sujeto(['Expression', of, 'Foxa2', was]), verbo([decreased]), complemento([while, expression, of, 'LXRα', was, increased, by, 'DHC', treatment, in, 'HepG2', cells])].
[sujeto(['In', 'addittion,', overexpression, of, 'Foxa2', markedly, compensated, the, inhibition, effect]), verbo([induced]), complemento([by, 'DHC', on, apoM, expression])].
[sujeto(['LXRα', small, interfering, 'RNA', significantly, abolished, the, inhibition, effect, which]), verbo([induced]), complemento([by, 'DHC', on, apoM, expression])].
[sujeto(['DHC', could, 'down-regulate', apoM, expression, through]), verbo([inhibiting]), complemento(['Foxa2', expression, and, enhancing, 'LXRα', expression, in, 'HepG2', cells])].
[sujeto(['Previous', studies]), verbo([have]), complemento([reported, the, differentiation, of, mesodermal, 'MSCs', into, endodermal, and, ectodermal, cell, types, beyond, their, embryonic, 'lineages,', including, hepatocytes, and, neurons])].
[sujeto(['In', the, present, 'study,', we, demonstrated, that, valproic, acid, '(', 'VPA),', which, is, a, histone, deacetylase, 'inhibitor,']), verbo([induced]), complemento([an, increase, in, the, expression, of, endodermal, genes, including, 'CXCR4,', 'SOX17,', 'FOXA1,', 'FOXA2,', 'GSC,', 'c-MET,', 'EOMES,', and, 'HNF-1β', in, human, umbilical, cord, derived, 'MSCs', '(', 'hUCMSCs)'])].
[sujeto(['In', 'addition,', we]), verbo([found]), complemento([that, 'VPA', is, able, to, increase, these, endodermal, genes, in, hUCMSCs, by, activating, signal, transduction, of, 'AKT', and, 'ERK'])].
[sujeto(['VPA', pretreatment]), verbo([increased]), complemento([hepatic, differentiation, at, the, expense, of, adipogenic, differentiation])].
[sujeto(['The', effects, of, 'VPA', on]), verbo([modulating]), complemento([hUCMSCs, fate, were, diminished, by, blocking, 'AKT', and, 'ERK', activation, using, specific, signaling, inhibitors])].
[sujeto(['Together,', our, results]), verbo([suggest]), complemento([that, 'VPA', contributes, to, the, lineage, conversion, of, hUCMSCs, to, hepatic, cell, fate, by, upregulating, the, expression, of, endodermal, genes, through, 'AKT', and, 'ERK', activation])].
[sujeto(['Foxa2', is, a, member, of, the, 'Forkhead', family, of]), verbo([nuclear]), complemento([transcription, factors, that, is, highly, expressed, in, respiratory, epithelial, cells, of, the, developing, and, mature, lung])].
[sujeto(['Foxa2', is]), verbo([required]), complemento([for, normal, airway, epithelial, 'differentiation,', and, its, deletion, causes, 'goblet-cell', metaplasia, and, 'Th2-mediated', pulmonary, inflammation, during, postnatal, development])].
[sujeto(['Foxa2', expression, is]), verbo([inhibited]), complemento([during, aeroallergen, sensitization, and, after, stimulation, with, 'Th2', 'cytokines,', when, its, loss, is, associated, with, 'goblet-cell', metaplasia])].
[sujeto(['During', the, first, 2, weeks, after, 'birth,', the]), verbo([loss]), complemento([of, 'Foxa2', increases, the, production, of, leukotrienes, '(', 'LTs)', and, 'Th2', cytokines, in, the, lungs, of, 'Foxa2', 'gene-targeted', mice])].
[sujeto(['Foxa2', expression]), verbo([inhibited]), complemento([15, -, lipoxygenase, '(', 'Alox15)', and, increased, 'Alox5', 'transcription,', each, encoding, key, lipoxygenases, associated, with, asthma])].
[sujeto(['The', inhibition, of, the, cysteinyl, 'LT', '(', 'CysLT)', signaling, pathway, by, montelukast]), verbo([inhibited]), complemento(['IL-4,', 'IL-5,', 'eotaxin-2,', and, regulated, upon, activation, normal, 'T', cell, expressed, and, presumably, secreted, expression, in, the, developing, lungs, of, 'Foxa2', 'gene-targeted', mice])].
[sujeto(['Montelukast']), verbo([inhibited]), complemento([the, expression, of, genes, regulating, mucus, 'metaplasia,', including, 'Spdef,', 'Muc5ac,', 'Foxa3,', and, 'Arg2'])].
[sujeto(['Foxa2', plays, a, 'cell-autonomous', role, in, the, respiratory, 'epithelium,', and, is]), verbo([required]), complemento([for, the, suppression, of, 'Th2', immunity, and, mucus, metaplasia, in, the, developing, lung, in, a, process, determined, in, part, by, its, regulation, of, the, 'CysLT', pathway])].
[sujeto(['Circulating', levels, of, insulin, and, glucagon, reflect, the, nutritional, state, of, animals, and, elicit, regulatory, responses, in, the, liver, that]), verbo([maintain]), complemento([glucose, and, lipid, homeostasis])].
[sujeto(['The', transcription, factor, 'Foxa2']), verbo([activates]), complemento([lipid, metabolism, and, ketogenesis, during, fasting, and, is, inhibited, via, 'insulin-PI3K-Akt', 'signaling-mediated', phosphorylation, at, 'Thr156', and, nuclear, exclusion])].
[sujeto(['Here', we, show, 'that,', in, 'addition,', 'Foxa2', is, acetylated, at, the]), verbo([conserved]), complemento([residue, 'Lys259', following, inhibition, of, histone, deacetylases, '(', 'HDACs)', class, 'I-III', and, the, cofactors, p300, and, 'SirT1', are, involved, in, 'Foxa2', acetylation, and, 'deacetylation,', respectively])].
[sujeto(['Physiologically,', fasting, states, and, glucagon, stimulation, are, sufficient, to]), verbo([induce]), complemento(['Foxa2', acetylation])].
[sujeto(['Introduction', of, the, 'acetylation-mimicking', '(', 'K259Q)', or, -, deficient, '(', 'K259R)', mutations]), verbo([promotes]), complemento([or, inhibits, 'Foxa2', 'activity,', 'respectively,', and, adenoviral, expression, of, 'Foxa2-K259Q', augments, expression, of, genes, involved, in, fatty, acid, oxidation, and, ketogenesis])].
[sujeto(['Our', study]), verbo([reveals]), complemento([a, molecular, mechanism, by, which, glucagon, signaling, activates, a, fasting, response, through, acetylation, of, 'Foxa2'])].
[sujeto(['It']), verbo([has]), complemento([been, reported, that, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)-γ', and, their, synthetic, ligands, have, direct, effects, on, pancreatic, 'β-cells'])].
[sujeto(['We', investigated, whether, 'PPAR-γ', activation]), verbo([stimulates]), complemento([insulin, secretion, through, the, 'up-regulation', of, 'GPR40', in, pancreatic, 'β-cells'])].
[sujeto(['PPAR-γ', activation, with, 'RGZ', 'and/or', adenoviral, 'PPAR-γ', overexpression]), verbo([increased]), complemento([free, fatty, acid, '(', 'FFA)', receptor, 'GPR40', 'expression,', and, increased, insulin, secretion, and, intracellular, calcium, 'mobilization,', and, was, blocked, by, the, 'PLC', 'inhibitors,', 'GPR40', 'RNA', 'interference,', and, 'GLUT2', 'RNA', interference])].
[sujeto(['As', a, downstream, signaling, pathway, of, intracellular, calcium, 'mobilization,', the]), verbo([phosphorylated]), complemento([levels, of, 'CaMKII', and, 'CREB,', and, the, downstream, 'IRS-2', and, 'phospho-Akt', were, significantly, increased])].
[sujeto(['Despite', of, insulin, receptor, 'RNA', 'interference,', the, levels, of, 'IRS-2', and, 'phospho-Akt', was, still]), verbo([maintained]), complemento([with, 'PPAR-γ', activation])].
[sujeto(['In', 'addition,', the, 'β-cell', specific, gene, 'expression,', including, 'Pdx-1', and, 'FoxA2,']), verbo([increased]), complemento([in, a, 'GPR40-', and, 'GLUT2-dependent', manner])].
[sujeto(['The', levels, of, 'GPR40,']), verbo([phosphorylated]), complemento(['CaMKII', and, 'CREB,', and, 'β-cell', specific, genes, induced, by, 'RGZ', were, blocked, by, 'GW9662,', a, 'PPAR-γ', antagonist])].
[sujeto(['Finally,', 'PPAR-γ', activation, 'up-regulated', 'β-cell', gene, expressions, through, 'FoxO1']), verbo([nuclear]), complemento(['exclusion,', independent, of, the, insulin, signaling, pathway])].
[sujeto(['Based', on, immunohistochemical, 'staining,', the, 'GLUT2,', 'IRS-2,', 'Pdx-1,', and, 'GPR40', were, more, strongly]), verbo([expressed]), complemento([in, islets, from, 'RGZ-treated', 'OLETF', rats, compared, to, control, islets])].
[sujeto(['These', observations]), verbo([suggest]), complemento([that, 'PPAR-γ', activation, with, 'RGZ', 'and/or', adenoviral, overexpression, increased, intracellular, calcium, 'mobilization,', insulin, 'secretion,', and, 'β-cell', gene, expression, through, 'GPR40', and, 'GLUT2', gene, 'up-regulation'])].
[sujeto(['The', 'Foxa', subfamily, of, winged, 'helix/forkhead', box, '(', 'Fox)', transcription, factors, comprises, three, members, which, play, important, roles, in, controlling, both, metabolism, and, homeostasis, through, the, regulation, of, multiple]), verbo([target]), complemento([genes, in, the, 'liver,', pancreas, and, adipose, tissue])].
[sujeto(['In', the, mouse, 'liver,', 'Foxa2', is]), verbo([repressed]), complemento([by, insulin, and, mediates, fasting, responses])].
[sujeto(['Unlike', 'Foxa2', 'however,', the, role, of, 'Foxa1', in, the, liver]), verbo([has]), complemento([not, yet, been, investigated, in, detail])].
[sujeto(['Results', demonstrate, that, 'Foxa1', is, a, potent, inhibitor, of, hepatic, triglyceride, 'synthesis,', accumulation, and, secretion, by]), verbo([repressing]), complemento([the, expression, of, multiple, target, genes, of, these, pathways, '(', e])].
[sujeto(['Moreover,', 'Foxa1']), verbo([represses]), complemento([the, fatty, acid, transporter, protein, 'FATP2', and, lowers, fatty, acid, uptake])].
[sujeto(['Foxa1', also]), verbo([increases]), complemento([the, breakdown, of, fatty, acids, by, inducing, peroxisomal, fatty, acid, 'β-oxidation', and, ketone, body, synthesis])].
[sujeto(['Finally,', 'Foxa1', is, able, to, largely, 'up-regulate', 'UCP1,', thereby, dissipating, energy, and, consistently]), verbo([decreasing]), complemento([the, mitochondria, membrane, potential])].
[sujeto(['We', also]), verbo([report]), complemento([that, human, and, rat, 'NAFL', have, a, reduced, 'Foxa1', 'expression,', possibly, through, a, protein, kinase, 'C-dependent', pathway])].
[sujeto(['However,', 'Foxa1', is, 'down-regulated', in, human, and, rat, 'NAFL', 'and,', 'therefore,']), verbo([increasing]), complemento(['Foxa1', levels, could, protect, from, steatosis])].
[sujeto(['Altogether,', we]), verbo([suggest]), complemento([that, 'Foxa1', could, be, a, novel, therapeutic, target, for, 'NAFL', disease, and, insulin, resistance])].
[sujeto(['The', factors, responsible]), verbo([provoke]), complemento([both, insulin, resistance, and, pancreatic, beta, cell, dysfunction, but, remain, to, be, fully, identified])].
[sujeto(['We']), verbo([report]), complemento([a, combination, of, molecular, events, in, human, and, mouse, pancreatic, beta, 'cells,', induced, by, elevated, levels, of, free, fatty, acids, or, by, administration, of, a, 'high-fat', diet, with, associated, 'obesity,', that, comprise, a, pathogenic, pathway, to, diabetes])].
[sujeto(['Elevated', concentrations, of, free, fatty, acids]), verbo([caused]), complemento([nuclear, exclusion, and, reduced, expression, of, the, transcription, factors, 'FOXA2', and, 'HNF1A', in, beta, cells])].
[sujeto(['Protection', from, disease, was]), verbo([conferred]), complemento([by, enforced, beta, 'cell-specific', 'GnT-4a', protein, glycosylation, and, involved, the, maintenance, of, glucose, transporter, expression, and, the, preservation, of, glucose, transport])].
[sujeto(['Recent', success, in, pancreatic, islet, transplantation]), verbo([has]), complemento([energized, the, field, to, discover, an, alternative, source, of, stem, cells, with, differentiation, potential, to, beta, cells])].
[sujeto(['Generation', of, 'glucose-responsive,', 'insulin-producing', beta, cells, from, 'self-renewing,', pluripotent, human, 'ESCs', '(', 'hESCs)']), verbo([has]), complemento([immense, potential, for, diabetes, treatment])].
[sujeto(['We']), verbo([report]), complemento([here, the, development, of, a, novel, 'serum-free', protocol, to, generate, 'insulin-producing', 'islet-like', clusters, '(', 'ILCs)', from, hESCs, grown, under, 'feeder-free', conditions])].
[sujeto(['Disclosure', of, potential, conflicts, of, interest, is]), verbo([found]), complemento([at, the, end, of, this, article])].
[sujeto(['A', study, by, 'Wolfrum', and, 'Stoffel', '(', 2006, ')', shows, that, the, forkhead, protein, 'Foxa2']), verbo([stimulates]), complemento([hepatic, 'VLDL', production, in, concert, with, the, coactivator, 'PGC-1beta', and, that, insulin, inhibits, this, process, by, inactivating, 'Foxa2'])].
[sujeto(['Forkhead', transcription, factor, 'Foxa2']), verbo([activates]), complemento([genes, involved, in, hepatic, lipid, metabolism, and, is, regulated, by, insulin])].
[sujeto(['Activation', of, 'Foxa2', in, the, liver]), verbo([leads]), complemento([to, increased, oxidation, and, secretion, of, fatty, acids, in, the, form, of, triacylglycerols, '(', 'TAGs),', a, process, impaired, in, type, 2, diabetes])].
[sujeto(['Adenoviral', expression, of, 'Foxa2', and, 'Pgc-1beta', in, livers, of, 'ob/ob', mice, results, in]), verbo([decreased]), complemento([hepatic, 'TAG', content, and, increased, plasma, 'TAG', concentrations])].
[sujeto(['In', 'addition,', the, concerted, action, of, 'Foxa2/Pgc-1beta']), verbo([activates]), complemento([genes, in, mitochondrial, beta, oxidation, and, enhances, fatty, acid, metabolism])].
[sujeto(['Furthermore,', 'Foxa2/Pgc-1beta']), verbo([induce]), complemento([the, expression, of, microsomal, transfer, 'protein,', thereby, increasing, 'apoB-containing', 'VLDL', secretion])].
[sujeto(['This', process, is]), verbo([inhibited]), complemento([by, insulin, through, a, 'Foxa2-dependent', mechanism])].
[sujeto(['These', data, demonstrate, that, 'Foxa2/Pgc-1beta']), verbo([regulate]), complemento([hepatic, lipid, homeostasis, by, affecting, the, clearance, rate, of, fatty, acids, through, oxidation, 'and/or', secretion, of, lipids, in, response, to, insulin])].
[sujeto(['The', 'SNPs', most, consistently]), verbo([associated]), complemento([with, 'CYP3A4', phenotypic, measures, were, a, 44477, 'T>C(-1359)', promoter, 'SNP', '(', in, linkage, disequilibrium, with, 'SNP', 463970, ',', a, 6, -, base, pair, deletion, in, intron, 1, 'a,', and, 'SNP', 46551, ',', a, 'C', nucleotide, insertion, in, intron, 1, 'b);', 'SNP', 63396, 'C>T', in, intron, 1, '(', in, linkage, disequilibrium, with, 'SNP', 63704, 'A>G,', a, 63813, '(', 'CAAA)(CA)', variable, 'repeat,', and, 'SNP', 65104, 'T>C);', and, 'SNP', 56348, 'C>A,', 'SNP', 69789, 'A>G,', and, 'SNP', 66034, 'T>C'])].
[sujeto(['Donor', livers, with, the, variant, 'PXR', alleles, had, altered, hepatic, expression, of, 'PXR']), verbo([targets]), complemento([compared, with, livers, with, 'PXR', 'wild-type', alleles])].
[sujeto(['These', results, identified, 'PXR', promoter, and, intron, 1, 'SNPs']), verbo([associated]), complemento([with, 'PXR', target, gene, expression, '(', 'CYP3A4)', in, donor, livers, and, cultured, hepatocytes, and, that, a, striking, number, of, the, linked, intron, 1, 'SNPs', will, affect, putative, binding, sites, for, hepatic, nuclear, factor, 3, beta, '(', 'FOXA2),', a, transcription, factor, linked, with, 'PXR', expression])].
[sujeto(['In', this, 'study,', a, subpopulation, of, 'CSCs', of, ovarian, carcinoma, was, isolated, and, the, genes, differentially]), verbo([expressed]), complemento([in, these, cells, were, identified, to, characterize, 'CSCs', and, to, find, candidate, biomarkers])].
[sujeto(['Overexpression', of, 'LEF1,', 'VAV3,', and, 'NKX3-2', was, significantly]), verbo([associated]), complemento([with, distant, metastasis, by, immunohistochemistry])].
[sujeto(['The', further, functional, assay, revealed, that, 'VAV3', knockdown]), verbo([regulated]), complemento(['CSC', activation, and, ovarian, cancer, cell, proliferation, and, sensitized, paclitaxel, '(', 'PTX)-resistant', cancer, cells, to, 'PTX', treatment])].
[sujeto(['Hepatocyte-like', cells, differentiated, from, human, embryonic, stem, cells, '(', 'hESCs)', and]), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'hiPSCs)', can, be, utilized, as, a, tool, for, screening, for, hepatotoxicity, in, the, early, phase, of, pharmaceutical, development])].
[sujeto(['We']), verbo([have]), complemento([recently, reported, that, hepatic, differentiation, is, promoted, by, sequential, transduction, of, 'SOX17,', 'HEX,', and, 'HNF4α', into, 'hESC-', or, 'hiPSC-derived', 'cells,', but, further, maturation, of, 'hepatocyte-like', cells, is, required, for, widespread, use, of, drug, screening])].
[sujeto(['The', combination, of, two, transcription, 'factors,', 'FOXA2', and, 'HNF1α,']), verbo([promoted]), complemento([efficient, hepatic, differentiation, from, hESCs, and, hiPSCs])].
[sujeto(['The', expression, profile, of, 'hepatocyte-related', genes, '(', such, as, genes, encoding, cytochrome, 'P450', 'enzymes,', conjugating, 'enzymes,', hepatic, 'transporters,', and, hepatic]), verbo([nuclear]), complemento(['receptors)', achieved, with, 'FOXA2', and, 'HNF1α', transduction, was, comparable, to, that, obtained, in, primary, human, hepatocytes])].
[sujeto(['The', objectives, of, this, study, were, to, examine, the, effects, of, 'P4', on, androgen, production, in, the, mature, teleost, testis, and, to, identify, molecular, signaling, cascades]), verbo([regulated]), complemento([by, 'P4', to, improve, understanding, of, its, role, in, male, reproduction])].
[sujeto(['P4', significantly]), verbo([increased]), complemento([testosterone, '(', 'T)', production, in, the, 'FHM', testis, but, did, not, affect, 11, -, ketotestosterone])].
[sujeto(['There', was, also, a, 20, '%']), verbo([increase]), complemento([in, a, gene, network, for, 'follicle-stimulating', hormone, secretion, and, an, 18, '%', decrease, in, genes, involved, in, vasopressin, signaling])].
[sujeto(['star,', 'cyp19a,', 11, 'bhsd)', were, not, significantly, affected, by, 'P4', treatments, in, this, 'study,', and, it, is, hypothesized, that, 'pre-existing', molecular, machinery, may, be, more]), verbo([involved]), complemento([in, the, increased, production, of, 'T', rather, than, the, de, novo, expression, of, 'steroid-related', transcripts, and, receptors])].
[sujeto(['There', was, a, significant]), verbo([decrease]), complemento([in, prostaglandin, 'E', synthase, 3, b, '(', 'cytosolic)', '(', 'ptges3b)', after, treatment, with, 'P4,', suggesting, that, there, is, cross, talk, between, 'P4', and, prostaglandin, pathways, in, the, reproductive, testis])].
[sujeto(['P4']), verbo([has]), complemento([a, role, in, regulating, steroid, production, in, the, male, testis, and, may, do, so, by, modulating, gene, networks, related, to, endocrine, 'pathways,', such, as, 'Igf1,', 'Tnfr,', and, vasopressin])].
[sujeto(['Three', distinct, hepatocyte]), verbo([nuclear]), complemento(['factor-3', '(', 'HNF-3)', proteins, '(', 'alpha,', 'beta,', and, 'gamma)', regulate, the, transcription, of, numerous, 'liver-enriched', genes])].
[sujeto(['The', 'HNF-3', proteins]), verbo([bind]), complemento(['DNA', via, a, homologous, winged, helix, motif, common, to, a, number, of, proteins, known, to, be, critical, for, determination, events, in, embryogenesis])].
[sujeto(['We']), verbo([have]), complemento([demonstrated, previously, that, two, binding, sites, in, the, -, 184, 'HNF-3', beta, promoter, are, recognized, by, widely, distributed, factors, and, that, there, is, also, a, critical, autoregulatory, 'site,', we, identified, a, binding, site, for, a, 'cell-specific', 'factor,', 'LF-H3', 'beta,', that, may, function, in, restricting, 'HNF-3', beta, gene, expression, to, hepatocytes])].
[sujeto(['Our', present, study, demonstrates, that, members, of, the, 'C/EBP', and, proline, and, acidic, amino, 'acid-rich', subfamilies, of, basic, region, leucine, zipper, transcription, factors]), verbo([bind]), complemento([the, 'LF-H3', beta, 'site,', and, cotransfection, of, 'HepG2', cells, shows, that, these, factors, are, able, to, activate, an, 'HNF-3', beta, promoter, reporter, construct])].
[sujeto(['The', 'LF-H3', 'beta-C/EBP']), verbo([binding]), complemento([sequence, also, confers, 'HNF-3', beta, promoter, stimulation, in, response, to, interleukin, '(', 'IL)-1', and, 'IL-6'])].
[sujeto(['Upstream', of, this, 'HNF-3', beta, proximal, promoter, 'region,', an, 'IFN-stimulated', response, element, core, sequence, '(', -, 231, to, -, 210, ')', was]), verbo([found]), complemento([that, mediates, transcriptional, induction, by, 'IFN-gamma', but, not, 'IFN-alpha'])].
[sujeto(['Consistent', with, this, 'finding,', we, observed, that, 'IFN-gamma', induction]), verbo([requires]), complemento([ongoing, protein, synthesis])].
[sujeto(['HNF-3beta', joins, the, 'C/EBP', family, on, the, list, of, 'liver-enriched', transcription, 'factors,', the, expression, of, which, is]), verbo([modulated]), complemento([by, cytokines])].
[sujeto(['FOXH1', and, 'FOXO1', mRNAs, are]), verbo([expressed]), complemento([in, human, embryonic, stem, '(', 'ES)', cells])].
[sujeto(['Deregulation', of, 'FOX', family, genes]), verbo([leads]), complemento([to, congenital, 'disorders,', diabetes, 'mellitus,', or, carcinogenesis])].
[sujeto(['Expression', 'profiles,', genetic, alterations, and, epigenetic, changes, of, 'FOX', family, genes, as, well, as]), verbo([binding]), complemento([proteins, and, target, genes, of, 'FOX', family, transcription, factors, should, be, comprehensively, investigated, to, develop, novel, therapeutics, and, preventives, for, human, diseases])].
[sujeto(['Embryonic', heart, development, is, a, very, complicated, process]), verbo([regulated]), complemento([precisely, by, a, network, composed, of, many, genes, and, signaling, pathways, in, time, and, space])].
[sujeto(['Forkhead', box, '(', 'Fox,', 'FOX)', proteins, are, a, family, of, transcription, factors, characterized, by, the, presence, of, an, evolutionary]), verbo([conserved]), complemento([&, 'quot;forkhead"or', &, 'quot;winged-helix"', 'DNA-binding', domain, and, able, to, organize, temporal, and, spatial, gene, expression, during, development])].
[sujeto(['They', are]), verbo([involved]), complemento([in, a, wide, variety, of, cellular, 'processes,', such, as, cell, cycle, 'progression,', 'proliferation,', 'differentiation,', 'migration,', metabolism, and, 'DNA', damage, response])].
[sujeto(['An', abundance, of, studies, in, model, organisms, and, systems]), verbo([has]), complemento([established, that, 'Foxa2,', 'Foxc1/c2,', 'Foxh1', and, 'Foxm1,', 'Foxos', and, 'Foxps', are, important, components, of, the, signaling, pathways, that, instruct, cardiogenesis, and, embryonic, heart, 'development,', playing, paramount, roles, in, heart, development])].
[sujeto(['The', previous, studies, also]), verbo([have]), complemento([demonstrated, that, mutations, in, some, of, the, forkhead, box, genes, and, the, aberrant, expression, of, forkhead, box, gene, are, heavily, implicated, in, the, congenital, heart, disease, '(', 'CHD)', of, humans])].
[sujeto(['This', review, primarily, focuses, on, the, current, understanding, of, heart, development]), verbo([regulated]), complemento([by, forkhead, box, transcription, factors, and, molecular, genetic, mechanisms, by, which, forkhead, box, factors, modulate, heart, development, during, embryogenesis, and, organogenesis])].
[sujeto(['Higher', identities, of, amino, acid, sequences, and]), verbo([conserved]), complemento(['exon-intron', organizations, were, found, between, 'LcGnRH3', and, other, 'GnRH3', genes])].
[sujeto(['For', 'example,', two, specific, residues, '(', 'V', and, 'A)', were]), verbo([found]), complemento([in, the, family, 'Sciaenidae,', and, the, unique, 75, -, 72, bp, type, of, the, open, reading, frame, 2, and, 3, existed, in, the, family, 'Cyprinidae'])].
[sujeto(['Analysis', of, the, 2576, bp, promoter, fragment, of, 'LcGnRH3', showed, a, number, of, transcription, factor]), verbo([binding]), complemento(['sites,', such, as, 'AP1,', 'CREB,', 'GATA-1,', 'HSF,', 'FOXA2,', and, 'FOXL1'])].
[sujeto(['The', 'aspartate-histidine-histidine-cysteine', '(', 'DHHC)', protein, family, shares, a, 50, -, amino, acid, 'cysteine-rich', domain, with, a]), verbo([conserved]), complemento(['DHHC', signature, motif])].
[sujeto(['Several', 'DHHC', family, members]), verbo([have]), complemento([been, implicated, in, neuronal, differentiation, and, synaptic, plasticity])].
[sujeto(['And', disruptions, to, their, function, can]), verbo([lead]), complemento([to, disease, in, the, nervous, system])].
[sujeto(['In', the, 'meanshile,', mutant, zdhhc15b, zebrafish, was]), verbo([associated]), complemento([with, poor, learning, behavior, as, detected, by, 'T-maze', testing])].
[sujeto(['Consistent', with, the]), verbo([decreased]), complemento([number, of, 'DA', neurons, following, 'knock-down', of, 'zdhhc15b,', the, expression, of, fate, 'determination-related', transcription, factors, such, as, 'nurr1,', 'foxA2,', and, lmx1a, were, also, reduced, in, morphant, zebrafish])].
[sujeto(['Our', results]), verbo([reveal]), complemento([that, zdhhc15b, controls, 'DA', neuronal, fate, decisions, by, regulating, differentiation, but, not, progenitor, cell, proliferation, or, 'DA', neuronal, survival])].
[sujeto(['Laminin', 411, is, a, key, component, of, the, basement, membrane, and, is]), verbo([involved]), complemento([in, the, regulation, of, cell, 'differentiation;', 'however,', little, is, known, about, a, role, of, laminin, 411, in, the, regulation, of, 'IPC', differentiation, from, human, 'MSCs'])].
[sujeto(['To', evaluate, potential, therapeutic, efficacy, of, 'IPCs']), verbo([induced]), complemento([from, 'UC-MSCs,', a, 'type-1', diabetes, '(', 'T1DM)', rat, model, was, generated, using, streptozotocin])].
[sujeto(['Laminin', 411, markedly]), verbo([induced]), complemento([the, expression, of, the, genes, 'Foxa2', and, 'Sox17,', markers, for, pancreatic, precursor, 'cells,', efficiently, induced, 'IPC', differentiation, from, 'MSCs,', and, 'up-regulated', insulin, expression, at, both, mRNA, and, protein, levels])].
[sujeto(['Furthermore,', the, expression, of, the, genes, known, to, govern, insulin, expression, including, 'Pdx1', and, 'Ngn3', was, markedly]), verbo([induced]), complemento([by, laminin, 411, ',', which, suggests, that, 'Pdx1', and, 'Ngn3', signaling, pathways, are, involved, in, laminin, 411, 'induced-insulin', expression, machinery])].
[sujeto(['More', 'importantly,', administration, of, laminin, 411, -]), verbo([induced]), complemento(['IPCs', rapidly, and, significantly, 'down-regulated', fasting, blood, glucose, 'levels,', significantly, reduced, the, 'HbA1c', concentration, and, markedly, improved, the, symptoms, and, survival, of, 'T1DM', rats])].
[sujeto(['Our', results, demonstrate, that, laminin, 411]), verbo([acts]), complemento([as, a, potent, differentiation, inducer, of, 'IPCs', from, 'UC-MSCs', via, the, 'Pdx1', and, 'Ngn3', signaling, pathways])].
[sujeto(['These', novel]), verbo([finding]), complemento([highlights, a, potential, clinical, application, of, laminin, 411, 'induced-IPCs', in, the, treatment, of, 'T1DM,', which, calls, for, further, studies])].
[sujeto(['The', results, showed, that, most, frequent]), verbo([gains]), complemento([included, 8, q24])].
[sujeto([33, and]), verbo([losses]), complemento([in, 8, p23])].
[sujeto([1, -, p12, and]), verbo([gains]), complemento([of, 7, p12])].
[sujeto([1, -, q34, were]), verbo([associated]), complemento([with, positive, lymph, node, status, and, advanced, clinical, stage, '(', 'stages III and IV)'])].
[sujeto([2, -, 25.3]), verbo([gain]), complemento([was, more, frequent, in, patients, with, distant, metastasis])].
[sujeto(['Integrated', analysis, indicated, that, overexpression, of, 'PDP1,', 'TRIB1,', 'C13orf27,', 'FOXA2,', 'PMEPA1', and, 'PHACTR3', was]), verbo([associated]), complemento([with, 'gains,', and, underexpression, of, 'FHOD,', 'SMAD4', and, 'BCL2', was, associated, with, losses])].
[sujeto(['Dlx5', and, 'Dlx6', are, two, closely]), verbo([associated]), complemento([homeobox, genes, which, code, for, transcription, factors, involved, in, the, control, of, steroidogenesis, and, reproduction])].
[sujeto(['DLX5/6', are, also, strongly]), verbo([expressed]), complemento([by, the, human, endometrium, but, their, function, in, the, uterus, is, unknown])].
[sujeto(['The', involvement, of, 'DLX5/6', in, human, uterine, pathology, is]), verbo([suggested]), complemento([by, their, strong, downregulation, in, endometriotic, lesions, and, upregulation, in, endometrioïd, adenocarcinomas])].
[sujeto(['In', 'Dlx5/6', mutant, 'uteri,', the, expression, of, genes]), verbo([involved]), complemento([in, gland, formation, '(', 'Foxa2)', and, in, epithelial, remodelling, during, implantation, '(', 'Msx1)', is, significantly, reduced])].
[sujeto(['Furthermore,', we, show, that, 'DLX5', is, highly]), verbo([expressed]), complemento([in, human, endometrial, glandular, epithelium, and, that, its, expression, is, affected, in, endometriosis])].
[sujeto(['Given', their, importance, for, female, 'reproduction,', 'DLX5', and, 'DLX6', must, be, regarded, as, interesting]), verbo([targets]), complemento([for, future, clinical, research])].
[sujeto(['The', definitive, role, of, 'Wnt7a', in, postnatal, uterine, development, and, adult, function]), verbo([requires]), complemento([a, conditional, 'knockout,', because, global, deletion, disrupts, müllerian, duct, 'patterning,', 'specification,', and, cell, fate, in, the, fetus])].
[sujeto(['The', 'Wnt7a-null', uterus, appears, to, be, posteriorized, because, of, developmental, defects, in, the, 'embryo,', as, evidenced, by, the, stratified, luminal, epithelium, that, is, normally]), verbo([found]), complemento([in, the, vagina, and, the, presence, of, short, and, uncoiled, oviducts])].
[sujeto(['During', embryonic, 'development,', 'Foxa2', is]), verbo([required]), complemento([for, the, formation, of, the, node, and, 'notochord,', and, ablation, of, this, gene, results, in, defects, in, 'gastrulation,', neural, tube, 'patterning,', and, gut, morphogenesis])].
[sujeto(['Foxa2']), verbo([has]), complemento([been, shown, to, be, expressed, specifically, in, the, glandular, epithelium, of, the, murine, uterus])].
[sujeto(['Pgr(cre/+)', 'Foxa2(loxP/loxP)', mice, also, showed, a, severe, impairment, of, the, uterus, to]), verbo([respond]), complemento([to, the, artificial, induction, of, the, decidual, response])].
[sujeto(['The']), verbo([loss]), complemento([of, endometrial, glands, resulted, in, the, reduction, of, leukemia, inhibitory, factor, '(', 'Lif)', expression])].
[sujeto(['This', analysis, demonstrates, that, 'Foxa2']), verbo([regulates]), complemento([endometrial, gland, development, and, that, mice, with, a, loss, of, endometrial, glands, cannot, support, implantation, in, part, due, to, the, loss, of, 'LIF,', which, is, a, requisite, for, fertility, in, the, mouse])].
[sujeto(['The', oval, cells, are, thought, to, be, the, progeny, of, a, liver, stem, cell, compartment, and, strong, evidence, now, exists, indicating, that, these, cells, can]), verbo([participate]), complemento([in, liver, regeneration, by, differentiating, into, different, hepatic, lineages])].
[sujeto(['To', better, understand, the, regulation, of, this, process, we]), verbo([have]), complemento([studied, the, expression, of, 'liver-enriched', transcriptional, factors, '(', 'HNF1', alpha, and, 'HNF1', 'beta,', 'HNF3', 'alpha,', 'HNF3', 'beta,', and, 'HNF3', 'gamma,', 'HNF4,', 'C/EBP,', 'C/EBP', 'beta,', and, 'DBP)', in, an, experimental, model, of, oval, cell, proliferation, and, differentiation, and, compared, the, expression, of, these, factors, to, that, observed, during, late, stages, of, hepatic, ontogenesis])].
[sujeto(['The', 'steady-state', mRNA, levels, of, four, '(', 'HNF1', 'alpha,', 'HNF3', 'alpha,', 'HNF4,', and, 'C/EBP', 'beta)', &, 'quot;liver-enriched"', transcriptional, factors, gradually]), verbo([decrease]), complemento([during, the, late, period, of, embryonic, liver, development, while, three, factors, '(', 'HNF1', 'beta,', 'HNF3', 'beta,', and, 'DBP)', increase])].
[sujeto(['However,', during, early, stages, of, oval, cell, proliferation, both, small, and, large, bile, ducts, start, to]), verbo([express]), complemento(['HNF1', alpha, and, 'HNF1', 'beta,', 'HNF3', 'gamma,', 'C/EBP,', and, 'DBP', but, not, 'HNF4'])].
[sujeto(['At', the, later, stages, all, of, these, factors, are, also, highly]), verbo([expressed]), complemento([in, the, proliferating, oval, cells])].
[sujeto(['Based', on, these, data, we]), verbo([suggest]), complemento([that, the, upregulation, of, the, &, 'quot;establishment"', factors, '(', 'HNF1', and, -, 3, ')', may, be, an, important, step, in, oval, cell, activation])].
[sujeto(['Furthermore,', the, data]), verbo([suggest]), complemento([that, 'HNF4', may, be, responsible, for, the, final, commitment, of, a, small, portion, of, the, oval, cells, to, differentiate, into, hepatocytes, which, form, the, basophilic, foci, and, eventually, regenerate, the, liver, parenchyma])].
[sujeto(['However,', the, underlying, genetic, mechanism]), verbo([associated]), complemento([with, vitamin, 25, '(', 'OH)D', concentrations, is, poorly, understood])].
[sujeto(['We', earlier]), verbo([reported]), complemento([a, very, high, prevalence, of, vitamin, 'D', deficiency, associated, with, an, increased, risk, for, type, 2, diabetes, and, obesity, in, a, 'Punjabi', 'Sikh', diabetic, cohort, as, part, of, the, 'Asian', 'Indian', diabetic, heart, study, '(', 'AIDHS)'])].
[sujeto(['Here', we]), verbo([have]), complemento([performed, the, first, 'genome-wide', association, study, '(', 'GWAS)', of, serum, 25, '(', 'OH)D', on, 3538, individuals, from, this, 'Punjabi', 'Sikh', population])].
[sujeto([47, '×10(-9)]', between, 'FOXA2', and, 'SSTR4', was, identified, to, be]), verbo([associated]), complemento([with, 25, '(', 'OH)D', levels])].
[sujeto([36, '×10(-6)]', was]), verbo([found]), complemento([within, the, regulatory, region, of, the, 'IVL', gene, on, chromosome, 1, q21])].
[sujeto(['Additionally,', our, study, replicated, 3, of, 5, known, 'GWAS', genes]), verbo([associated]), complemento([with, 25, '(', 'OH)D', concentrations, including, 'GC', '(', 'p=0'])].
[sujeto([19, ')']), verbo([reported]), complemento([in, 'Europeans', and, the, 'DAB1', '(', 'p=0'])].
[sujeto([3, ')', ',']), verbo([reported]), complemento([in, 'Hispanics'])].
[sujeto(['Identification', of, novel, association, signals, in, biologically, plausible, regions, with, 25, '(', 'OH)D', metabolism, will]), verbo([provide]), complemento([new, molecular, insights, on, genetic, drivers, of, vitamin, 'D', status, and, its, implications, in, health, disparities])].
[sujeto(['Evidence']), verbo([suggests]), complemento([that, the, cytokine, interferon, '(', 'IFN)-γ', released, by, natural, killer, and, 'CD4(+)', 'T', cells, contributes, to, the, conjunctival, goblet, cell, '(', 'GC)', loss, in, dry, eye])].
[sujeto(['The', purpose, of, this, study, was, to, investigate, if, topical, neutralization, of, 'IFN-γ']), verbo([prevents]), complemento([or, alleviates, 'GC', loss, in, an, experimental, desiccating, stress, '(', 'DS)', model, of, dry, eye])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, topical, 'IFN-γ', neutralization, significantly, decreased, 'DS-induced', conjunctival, 'GC', loss])].
[sujeto(['This', was, accompanied, by]), verbo([decreased]), complemento([epithelial, 'apoptosis,', and, increased, 'IL-13', and, decreased, 'FoxA2', expression, in, the, forniceal, conjunctiva])].
[sujeto(['Similar', to, the, donor, 'mice,', topical, 'IFN-γ', neutralization]), verbo([decreased]), complemento([conjunctival, 'GC', 'loss,', suppressed, apoptosis, and, increased, 'IL-13', expression, in, adoptive, transfer, recipients])].
[sujeto(['In', 'summary,', this, study, demonstrated, that, topical, neutralization, of, 'IFN-γ']), verbo([prevents]), complemento(['GC', loss, via, modulating, apoptosis, and, maintaining, 'IL-13', signaling])].
[sujeto(['Activation', of, sonic, hedgehog, '(', 'HH)', signaling, pathway]), verbo([has]), complemento([been, implicated, in, aggressiveness, and, progression, of, gastrointestinal, tumors])].
[sujeto(['We', planned, this, study, to, identify, a, subgroup, of, gastric, cancer, '(', 'GC)', patients, with, 'HH', activation, and, to, assess, the, effect, of, a, 'HH', inhibitor, in, 'HH']), verbo([activated]), complemento(['GC', in, vitro])].
[sujeto(['We', surveyed, 'HH', pathway, activation, among, 512, 'GC', specimens, for, protein, expression, of, various]), verbo([target]), complemento([genes, involved, in, 'HH', 'pathway:', 'Indian', hedgehog, '(', 'IHH),', 'patched-1', '(', 'PTCH1),', smoothened, '(', 'SMO),', 'GLI2,', and, 'FOXA2'])].
[sujeto(['This', is, the, largest]), verbo([report]), complemento([to, analyze, the, hedgehog, pathway, in, 'GC'])].
[sujeto(['PTCH1', overexpression, was, an, independent, prognostic, factor, for, survival, and, 'SMO', overexpression, which, was]), verbo([found]), complemento([in, 12.0, '%', of, 'GC', patients, might, be, the, potential, predictive, marker, of, 'HH', inhibitor])].
[sujeto(['Intestinal', cell, kinase, '(', 'ICK;', 'GeneID', 22858, ')', is, a]), verbo([conserved]), complemento(['MAPK', and, 'CDK-like', kinase, that, is, widely, expressed, in, human, tissues])].
[sujeto(['Data', from, the, 'Cancer', 'Genome', 'Anatomy', 'Project', indicated, 'ICK', mRNA, is]), verbo([increased]), complemento([in, 'cancer,', and, that, its, expression, correlated, with, expression, of, mRNA, for, an, uncharacterized, 'F-box', 'protein,', 'FBX9', '(', 'GeneID:', 26268, ')'])].
[sujeto(['Results', from, deletions, and, truncations, defined, a, minimal, promoter, for, 'ICK,', and, revealed, that, repressors, and, enhancers, differentially]), verbo([regulate]), complemento(['ICK', versus, 'FBX9', promoter, activity])].
[sujeto(['FOXA1', and, 'FOXA2']), verbo([increase]), complemento([luciferase, activity, of, a, minimal, promoter, 10, -, 20, fold, in, 'HEK293T', cells])].
[sujeto(['The', expression, of, 'beta-catenin']), verbo([increased]), complemento([activity, of, the, minimal, promoter, approximately, 10, fold])].
[sujeto([3, ',', 'NM_016513)', are]), verbo([expressed]), complemento([in, low, copy, number, and, increased, in, some, breast, 'cancers,', using, a, ten, base, tag, 5, '\'', -, 'TCAACCTTAT-3\'', specific, for, both, 'ICK', transcripts])].
[sujeto(['ICK', and, 'FBX9', are, divergently]), verbo([transcribed]), complemento([from, a, bidirectional, promoter, that, is, 'GC-rich', and, contains, a, 'CpG', island])].
[sujeto(['These', data, are, consistent, with, functions, that]), verbo([have]), complemento([been, proposed, for, 'ICK', in, development, and, in, proliferation, or, survival, of, some, breast, and, colon, cancers])].
[sujeto(['WNT5A', is, a, 'cancer-associated', gene]), verbo([involved]), complemento([in, invasion, and, metastasis, of, 'melanoma,', breast, 'cancer,', pancreatic, 'cancer,', and, gastric, cancer])].
[sujeto(['SNAI1', '(', 'Snail),', 'CD44,', 'G3BP2,', and, 'YAP1', are, 'WNT5A']), verbo([target]), complemento([genes])].
[sujeto(['We', and, other, groups, previously]), verbo([reported]), complemento([that, 'IL6-', or, 'LIF-induced', signaling, through, 'JAK-STAT3', signaling, cascade, is, involved, in, 'WNT5A', upregulation, '(', 'STAT3-WNT5A', signaling, 'loop)'])].
[sujeto(['The', 'WNT5A', gene, was]), verbo([found]), complemento([to, encode, two, isoforms, by, using, alternative, first, exons, 1, 'A', and, 1, 'B'])].
[sujeto(['Quadruple', 'Smad-binding', elements, '(', 'SBEs),', single, 'Sp1-binding', site, '(', 'GC-box),', 'PPARgamma-binding', 'site,', 'C/EBP-binding', site, and, 'bHLH-binding', site, within, the, promoter, 'A', 'region,', 5, '\'', -, adjacent, to, exon, 1, 'A,', were]), verbo([conserved]), complemento([in, human, 'WNT5A,', chimpanzee, 'WNT5A,', mouse, 'Wnt5a,', and, rat, 'Wnt5a'])].
[sujeto(['NF-kappaB-binding', 'site,', 'CUX1-binding', 'site,', double, 'SBEs', and, double, 'GC-boxes', within, the, promoter, 'B', 'region,', 5, '\'', -, adjacent, to, exon, 1, 'B,', were]), verbo([conserved]), complemento([in, mammalian, 'WNT5A', orthologs])].
[sujeto(['Quadruple', 'FOX-binding', sites, and, double, 'SBEs', within, 'ultra-conserved', intron, 1, were, also]), verbo([conserved]), complemento([in, mammalian, 'WNT5A', orthologs])].
[sujeto(['Quadruple', 'FOX-binding', sites, rather, than, 'GLI-binding', site, revealed, that, 'Hedgehog', signals]), verbo([induce]), complemento(['WNT5A', upregulation, indirectly, via, 'FOX', family, 'members,', such, as, 'FOXA2,', 'FOXC2,', 'FOXE1,', 'FOXF1', and, 'FOXL1'])].
[sujeto(['TGFbeta', signals, were]), verbo([found]), complemento([to, upregulate, 'WNT5A', expression, directly, through, the, 'Smad', 'complex,', and, also, indirectly, through, 'Smad-induced', 'CUX1', and, 'MAP3K7-mediated', 'NF-kappaB'])].
[sujeto(['Together', these, facts, indicate, that, 'WNT5A', is]), verbo([transcribed]), complemento([based, on, multiple, 'mechanisms,', such, as, 'NF-kappaB,', 'Hedgehog,', 'TGFbeta,', and, 'Notch', signaling, cascades])].
[sujeto(['The', endostatin, precursor, collagen, 'XVIII', is]), verbo([expressed]), complemento([at, high, levels, in, human, 'livers,', the, main, source, being, hepatocytes])].
[sujeto(['We']), verbo([have]), complemento([studied, the, regulatory, elements, in, the, promoter, 2, of, the, 'Col18a1', gene, that, directs, the, transcription, of, the, 'NC1-517', variant, of, collagen, 'alpha1(XVIII),', which, is, the, main, form, expressed, in, the, liver])].
[sujeto(['Gel-shift', analyses, showed, that, 'HNF3,', 'NF1/CTF,', and, 'Sp1-like', sites, specifically]), verbo([recognized]), complemento([nuclear, factors])].
[sujeto(['Super-shift', experiments, indicated, that, 'HNF3beta', was, the, major, form, of, 'HNF3']), verbo([interacting]), complemento([with, the, 'HNF3/NF1', site])].
[sujeto(['The', 'well-differentiated', hepatoma, cell, line, mhATFS315, transfected, with, a, truncated, form, of, 'HNF3beta,', which, competitively, blocks, 'HNF3', transactivating, 'activity,']), verbo([expressed]), complemento([the, 'Col18a1gene', at, a, very, low, level])].
[sujeto(['Taken', 'together,', these, data, strongly]), verbo([suggest]), complemento([that, 'Col18a1', is, a, 'liver-specific', gene])].
[sujeto(['Furthermore,', 'gel-shift', analyses, performed, with]), verbo([nuclear]), complemento([factors, prepared, from, 'well-differentiated', hepatocellular, carcinomas, showed, increased, 'HNF3/NF1', binding, activity, compared, with, normal, livers])].
[sujeto(['Consequently,', the, precursor, of, endostatin, might, be, differently]), verbo([expressed]), complemento([according, to, the, differentiated, 'and/or', transformed, state, of, hepatocytes])].
[sujeto(['Long', noncoding, 'RNAs', '(', 'lncRNAs)', are, thought, to, play, important, roles, in]), verbo([regulating]), complemento([gene, 'transcription,', but, few, have, 'well-defined', expression, patterns, or, known, biological, functions, during, mammalian, development])].
[sujeto(['Using', a, conservative, pipeline, to, identify, lncRNAs, that]), verbo([have]), complemento([important, biological, 'functions,', we, identified, 363, lncRNAs, in, the, lung, and, foregut, endoderm])].
[sujeto([1, -]), verbo([associated]), complemento([noncoding, intergenic, 'RNA)', and, 'LL34,', play, distinct, roles, in, endoderm, development, by, controlling, expression, of, critical, developmental, transcription, factors, and, 'pathways,', including, retinoic, acid, signaling])].
[sujeto(['In', 'particular,', we, show, that, 'LL18/NANCI']), verbo([acts]), complemento([upstream, of, 'Nkx2'])].
[sujeto([1, and, downstream, from, 'Wnt', signaling, to]), verbo([regulate]), complemento([lung, endoderm, gene, expression])].
[sujeto(['These', studies]), verbo([reveal]), complemento([that, lncRNAs, play, an, important, role, in, foregut, and, lung, endoderm, development, by, regulating, multiple, aspects, of, gene, 'transcription,', often, through, regulation, of, transcription, factor, expression])].
[sujeto(['Our', goal, is, to, decipher, which, 'DNA', sequences, are]), verbo([required]), complemento([for, 'tissue-specific', expression, of, epididymal, genes])].
[sujeto(['These', are, differently]), verbo([regulated]), complemento([and, regionalized, in, the, epididymis])].
[sujeto(['To', define, further, the, fragments]), verbo([regulating]), complemento([gene, 'expression,', the, 'Lcn5', promoter, was, examined, in, transgenic, mice, and, immortalized, epididymal, cell, lines])].
[sujeto(['Transient', transfection, analysis, revealed, that, a, transcription, factor, forkhead, box, 'A2', '(', 'Foxa2)']), verbo([interacts]), complemento([with, androgen, receptor, and, binds, to, the, 100, bp, fragment, of, the, 'Lcn5', promoter, between, 1.2, kb, and, 1.3, kb, and, that, 'Foxa2', expression, inhibits, 'androgen-dependent', induction, of, the, 'Lcn5', promoter, activity])].
[sujeto(['Immunohistochemistry', indicated, a, restricted, expression, of, 'Foxa2', in, the, epididymis, where, endogenous, 'Lcn5', gene, expression, is]), verbo([suppressed]), complemento([and, that, the, 'Foxa2', inhibition, of, the, 'Lcn5', promoter, is, consistent, with, the, lack, of, expression, of, 'Lcn5', in, the, corpus, and, cauda])].
[sujeto(['Our', approach]), verbo([provides]), complemento([a, basic, strategy, for, further, analysis, of, the, epididymal, lipocalin, gene, regulation, and, flexible, control, of, epididymal, function])].
[sujeto(['The', relative, lack, of, successful, pancreatic, differentiation, of, human, embryonic, stem, cells, '(', 'hESCs)', may]), verbo([suggest]), complemento([that, directed, differentiation, of, hESCs, into, definitive, endoderm, and, subsequent, commitment, towards, a, pancreatic, fate, are, not, readily, achieved])].
[sujeto(['The', patterns, of, gene, expression, and, protein, production]), verbo([associated]), complemento([with, embryonic, germ, layers, and, pancreatic, endoderm, were, analysed, by, 'RT-PCR', and, immunostaining])].
[sujeto(['The', population, of, pancreatic, endodermal, cells, that, produced, 'PDX1', was, significantly]), verbo([increased]), complemento([at, the, expense, of, ectodermal, 'differentiation,', and, a, subset, of, the, 'PDX1-positive', cells, also, produced, 'FOXA2,', 'caudal-type', homeobox, transcription, factor, 2, '(', 'CDX2),', and, nestin, '(', 'NES)'])].
[sujeto(['After', 'transplantation,', the, 'PDX1-positive', cells, further, differentiated, into, mature, cell, types, producing, insulin, and, 'glucagon,', resulting, in, amelioration, of, hyperglycaemia, and, weight]), verbo([loss]), complemento([in, 'streptozotocin-treated', diabetic, mice])].
[sujeto(['Here,', we]), verbo([reported]), complemento([that, the, 1.8, -, kb, 'Lcn5', promoter, confers, epididymis, 'region-specific', gene, expression, in, transgenic, mice])].
[sujeto(['Between', the, 1.2, -, kb, to, 1.3, -, kb, 'region,', two, androgen, receptor, '(', 'AR)']), verbo([binding]), complemento([sites, were, identified])].
[sujeto(['Adjacent', to, 'AR']), verbo([binding]), complemento(['sites,', a, 'Foxa2', '[', 'Fox', '(', 'Forkhead', 'box)', subclass, 'A]', binding, site, was, confirmed, by, gel, shift, assay])].
[sujeto(['Similar', 'Foxa']), verbo([binding]), complemento([sites, were, also, found, on, the, promoters, of, human, and, rat, 'Lcn5,', indicating, the, 'Foxa', binding, site, is, conserved, among, species])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, among, the, three, members, of, 'Foxa', 'family,', 'Foxa1', and, 'Foxa3', were, absent, in, the, epididymis, whereas, 'Foxa2', was, detected, in, epididymal, principal, cells])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, 'Foxa2', displays, a, 'region-specific', expression, pattern, along, the, 'epididymis:', no, staining, observed, in, initial, 'segment,', light, staining, in, proximal, 'caput,', gradiently, heavier, staining, in, middle, and, distal, 'caput,', and, strongest, staining, in, corpus, and, 'cauda,', regions, with, little, or, no, expression, of, 'Lcn5'])].
[sujeto(['In', transient, transfection, 'experiments,', 'Foxa2', expression]), verbo([inhibits]), complemento(['AR', induction, of, the, 'Lcn5', 'promoter,', which, is, consistent, with, the, lack, of, expression, of, 'Lcn5', in, the, corpus, and, cauda])].
[sujeto(['One', would, hypothesize, that, disrupting, this, process]), verbo([provides]), complemento([an, ideal, approach, to, male, 'contraception,', since, it, would, not, interfere, with, testicular, endocrine, output, or, sperm, production])].
[sujeto(['To', achieve, this, 'purpose,', we, studied, a, cluster, of, 'epididymis-specific', lipocalin, genes, for, understanding, the, specific, mechanisms]), verbo([involved]), complemento([in, the, control, of, gene, expression, in, the, epididymis])].
[sujeto(['We']), verbo([have]), complemento([identified, six, 'epididymis-specific', lipocalin, genes, that, are, differently, regulated, and, regionalized, in, the, epididymis])].
[sujeto(['Lipocalin', 5, '[', 'Lcn5', or, epididymal, retinoic, 'acid-binding', protein, '(', 'E-RABP)]', is, a, member, of, this, 'epididymis-specific', lipocalin, gene, 'cluster,', which]), verbo([binds]), complemento([hydrophobic, molecules, such, as, retinoic, acid])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, the, 5, kb, promoter, fragment, of, the, 'Lcn5', gene, confers, both, 'androgen-dependent', regulation, and, 'epididymis-specific', gene, expression, in, transgenic, mice, whereas, 0.6, kb, promoter, fragment, does, not])].
[sujeto(['To', further, narrow, down, the, important, 'cis-regulatory', elements, that]), verbo([regulate]), complemento([gene, expression, in, the, 'epididymis,', we, studied, the, 'Lcn5', promoter, in, both, transgenic, mice, and, immortalized, epididymal, cells])].
[sujeto(['We']), verbo([have]), complemento([found, that, 1.8, kb, promoter, fragment, of, the, 'Lcn5', gene, was, sufficient, for, 'tissue-', and, 'region-specific', expression, in, transgenic, 'mice,', and, that, a, transcription, factor, 'Forkhead', box, 'A2', '(', 'Foxa2)', interacts, with, the, androgen, receptor, and, binds, to, the, 100, bp, fragment, of, the, 'Lcn5', promoter, between, 1.2, and, 1.3, kb])].
[sujeto(['Our']), verbo([finding]), complemento([provides, a, framework, for, further, analysis, of, the, epididymal, lipocalin, gene, regulation, and, modulated, control, of, 'epididymis-specific', expression])].
[sujeto(['Human', embryonic, stem, cells, '(', 'hESCs)']), verbo([retain]), complemento([the, extraordinary, capacity, to, differentiate, into, different, cell, types, of, an, adult, 'organism,', including, pancreatic, 'β-cells'])].
[sujeto(['For', this, particular, 'lineage,', although, a, lot, of, effort]), verbo([has]), complemento([been, made, in, the, last, ten, years, to, achieve, an, efficient, and, reproducible, differentiation, 'protocol,', it, was, not, until, recently, that, this, aim, was, roughly, accomplished])].
[sujeto(['Our', results, indicate, that, treatment, of, hESCs, '(', 'HS-181)', with, 'activin-A']), verbo([induced]), complemento([definitive, endoderm, differentiation, as, detected, by, the, expression, of, 'SOX17', and, 'FOXA2'])].
[sujeto(['Addition', of, retinoic, acid, '(', 'RA),', 'Noggin', and, 'Cyclopamine']), verbo([promoted]), complemento([pancreatic, differentiation, as, indicated, by, the, expression, of, the, early, pancreatic, progenitor, markers, 'ISL1,', 'NGN3', and, 'PDX1'])].
[sujeto(['Moreover,', during, maturation, in, suspension, 'culture,', differentiating, cells, assembled, in, 'islet-like', 'clusters,', which]), verbo([expressed]), complemento([specific, endocrine, markers, such, as, 'PDX1,', 'SST,', 'GCG', and, 'INS'])].
[sujeto(['Similar', results, were, confirmed, with, the, human]), verbo([induced]), complemento(['Pluripotent', 'Stem', 'Cell', '(', 'hiPSC)', line, 'MSUH-001'])].
[sujeto(['Finally,', differentiation, protocols, incorporating, 'RSV', treatment, yielded, numerous, 'insulin-positive', 'cells,']), verbo([induced]), complemento([significantly, higher, 'PDX1', expression, and, were, able, to, transiently, normalize, glycaemia, when, transplanted, in, streptozotocin, '(', 'STZ)', induced, diabetic, mice, thus, promoting, its, survival])].
[sujeto(['It', was, recently]), verbo([reported]), complemento([that, human, periapical, cysts, '(', 'hPCys),', a, commonly, occurring, odontogenic, cystic, lesion, of, inflammatory, 'origin,', contain, mesenchymal, stem, cells, '(', 'MSCs)', with, the, capacity, for, 'self-renewal', and, multilineage, differentiation])].
[sujeto(['In', this, 'study,', periapical, inflammatory, cysts, were, compared, with, dental, pulp, to, determine, whether, this, tissue, may, be, an, alternative, accessible, tissue, source, of, 'MSCs', that]), verbo([retain]), complemento([the, potential, for, neurogenic, differentiation])].
[sujeto(['Flow', cytometry, and, immunofluorescence, analysis, indicated, that, 'hPCy-MSCs', and, dental, pulp, stem, cells, spontaneously]), verbo([expressed]), complemento([the, 'neuron-specific', protein, 'β-III', tubulin, and, the, neural, 'stem-/astrocyte-specific', protein, glial, fibrillary, acidic, protein, '(', 'GFAP)', in, their, basal, state, before, differentiation, occurs])].
[sujeto(['After', exposure, to, neurogenic, differentiation, conditions, '(', neural, media, containing, epidermal, growth, factor, '[', 'EGF],', basic, fibroblast, growth, factor, '[', 'bFGF],', and, retinoic, 'acid),', the, 'hPCy-MSCs', showed]), verbo([enhanced]), complemento([expression, of, 'β-III', tubulin, and, 'GFAP', 'proteins,', as, well, as, increased, expression, of, neurofilaments, 'medium,', neurofilaments, 'heavy,', and, 'neuron-specific', enolase, at, the, transcript, level])].
[sujeto(['The', present, study, demonstrated, for, the, first, time, that, 'hPCy-MSCs']), verbo([have]), complemento([a, predisposition, toward, the, neural, phenotype, that, is, increased, when, exposed, to, neural, differentiation, 'cues,', based, on, upregulation, of, a, comprehensive, set, of, proteins, and, genes, that, define, neuronal, cells])].
[sujeto(['In', 'conclusion,', these, results]), verbo([provide]), complemento([evidence, that, 'hPCy-MSCs', might, be, another, optimal, source, of, 'neural/glial', cells, for, 'cell-based', therapies, to, treat, neurologic, diseases])].
[sujeto(['We', previously]), verbo([reported]), complemento([the, in, vitro, differentiation, of, human, embryonic, stem, cells, '(', 'hESCs)', into, pancreatic, endoderm])].
[sujeto(['Sequential', treatment, with, 'Wnt3a,', activin, 'A,', and, noggin]), verbo([induced]), complemento([a, transient, upregulation, of, 'T', and, 'MixL1,', followed, by, increased, expression, of, endodermal, 'genes,', including, 'FOXA2,', 'SOX17,', and, 'CXCR4'])].
[sujeto(['We', also, show, that, inhibition, of, sonic, hedgehog, signaling, by, 'bFGF/activin', βB, and, cotreatment, with, 'VEGF', and, 'FGF7', produced, many, 3, 'D', cellular, clusters, that]), verbo([express]), complemento([both, 'SOX17', and, 'PDX1'])].
[sujeto(['We']), verbo([found]), complemento([for, the, first, time, that, proteoglycans, and, 'vimentin(+)', mesenchymal, cells, were, mainly, localized, in, 'hESC-derived', 'PDX1(+)', clusters])].
[sujeto(['Importantly,', treatment, with, 'chlorate,', an, inhibitor, of, proteoglycan, 'sulfation,', together, with, inhibition, of, 'Notch', signaling, significantly]), verbo([increased]), complemento([the, expression, of, 'Neurog3', and, 'NeuroD1,', promoting, a, transition, from, 'PDX1(+)', progenitor, cells, toward, mature, pancreatic, endocrine, cells])].
[sujeto(['Purified', 'dithizone(+)', 3, 'D', aggregates, generated, by, our, refined, protocol, produced, pancreatic, hormones, and]), verbo([released]), complemento([insulin, in, response, to, both, glucose, and, pharmacological, drugs, in, vitro])].
[sujeto(['Furthermore,', the, 'islet-like', 3, 'D', aggregates]), verbo([decreased]), complemento([blood, glucose, levels, and, continued, to, exhibit, pancreatic, features, after, transplantation, into, diabetic, mice])].
[sujeto(['Retinoic', acid, '(', 'RA)']), verbo([has]), complemento([diverse, biological, effects])].
[sujeto(['The', liver, stores, vitamin, 'A,', generates, 'RA,', and]), verbo([expresses]), complemento([receptors, for, 'RA'])].
[sujeto(['The', current, study, examines, the, hepatic]), verbo([binding]), complemento([profile, of, two, 'RA', receptor, 'isoforms,', 'RARA', '(', 'RARα)', and, 'RARB', '(', 'RARβ),', in, response, to, 'RA', treatment, in, mouse, livers])].
[sujeto(['Each']), verbo([expressed]), complemento([unique, and, common, 'bindings,', implying, their, redundant, and, specific, roles])].
[sujeto(['RARB']), verbo([has]), complemento([higher, 'RA', responsiveness, than, 'RARB'])].
[sujeto(['RAR', frequently]), verbo([bound]), complemento([the, consensus, hormone, response, element, '[', 'HRE;', '(', 'A/G)G(G/T)TCA],', which, often, contained, the, motifs, assigned, to, 'SP1,', 'GABPA,', and, 'FOXA2,', suggesting, potential, interactions, between, those, transcriptional, factors])].
[sujeto(['Functional', annotation, coupled, with, principle, component, analysis, revealed, that, the, function, of, 'RAR']), verbo([target]), complemento([genes, were, motif, dependent])].
[sujeto(['RAR']), verbo([target]), complemento([genes, are, enriched, in, various, biological, processes])].
[sujeto(['The', hepatic, 'RAR', 'genome-wide']), verbo([binding]), complemento([data, can, help, us, understand, the, global, molecular, mechanisms, underlying, 'RAR', and, 'RA-mediated', gene, and, pathway, regulation])].
[sujeto(['Moreover,', in, 'Step', 'III,', the]), verbo([induced]), complemento([cells, expressed, pancreatic, markers, such, as, 'amylase,', carboxypeptidase, 'A', and, chymotrypsinogen, 'B,', which, were, similar, to, those, in, normal, human, pancreas])].
[sujeto(['From', day, 8, in, 'Step', 'III,', cells, immunohistochemically, positive, for, amylase, and, for, carboxypeptidase, 'A,', a, pancreatic, exocrine, cell, 'product,', were]), verbo([induced]), complemento([by, 'FGF7'])].
[sujeto(['Thus,', our, 'three-step', culture, protocol, for, human, 'ES', cells, effectively]), verbo([induces]), complemento([the, differentiation, of, 'amylase-', and, 'carboxypeptidase-A-containing', pancreatic, exocrine, cells])].
[sujeto(['Sox17,', 'GATA4,', 'GATA6,', 'FoxA2,', 'HEX,', 'HNF4α', and, 'C/EBPα', were]), verbo([expressed]), complemento([in, fetal, and, adult, liver, 'cells,', but, not, in, iPS, cells])].
[sujeto(['Sox17,', 'GATA6', and, 'HNF4α', were]), verbo([expressed]), complemento([after, exposure, a, combination, of, oncostatin, 'M,', epidermal, growth, 'factor,', retinoic, 'acid,', dexamethasone, and, 'ITS', '(', 'OERDITS)'])].
[sujeto(['When', iPS, cells, were, introduced, with, 'FoxA2,', 'GATA4,', 'HEX', and, 'C/EBPα', and, cultured, with, 'OERDITS', for, 8, 'days,', the, cells]), verbo([expressed]), complemento(['α-fetoprotein,', 'δ-like', '(', 'Dlk)-1', and, 'γ-glutamyl', transpeptidase, '(', 'GTP),', and, 'ICG', uptake, was, observed])].
[sujeto(['Generation', of, 'PP', cells, from, adipose, 'tissue-derived', mesenchymal, stem, cells, '(', 'AD-MSCs)', would]), verbo([provide]), complemento([an, unlimited, source, of, 'PP', cells])].
[sujeto(['Here', we, developed, a, 2, -, step, stepwise, 'protocol,', which]), verbo([induced]), complemento(['AD-MSCs', to, generate, 'FOXA2-', or, 'SOX17-positive', definitive, endoderm, '(', 'DE)', '(', 5, 'days)', and, pancreatic, and, duodenal, homeobox, gene, 1, '(', 'PDX1)-positive', 'PP', cells, '(', 4, -, 6, 'days)'])].
[sujeto(['By', mimicking, the, developmental, progress, in, embryonic, 'development,', we, optimized, the, timing, and, combination, of, cytokines, to]), verbo([activate]), complemento([the, key, signaling, pathways, during, pancreatic, development])].
[sujeto(['We']), verbo([found]), complemento([that, activating, the, 'Nodal/Activin', signal, with, 'Activin', 'A', could, induce, differentiation, of, 'AD-MSCs', toward, 'DE,', which, could, be, further, promoted, by, the, 'Wnt', signaling, pathway, activator, 'Wnt3a'])].
[sujeto(['Subsequently,', the, 'Wnt', signaling, pathway, inhibitor, 'Dkk1', along, with, retinoic, 'acid/FGF2', '(', 60, 'ng/mL)', further]), verbo([induced]), complemento(['AD-MSC-derived', 'DE', cells, to, differentiate, into, 'PDX1-positive', 'PP', cells])].
[sujeto(['It', might]), verbo([provide]), complemento([an, unlimited, source, of, autologous, 'PP', cells, for, pancreatic, diseases])].
[sujeto(['One', of, the, earliest, 'epithelial-to-mesenchymal', transitions, in, mouse, embryogenesis]), verbo([involves]), complemento([the, differentiation, of, inner, cell, mass, cells, into, primitive, and, then, into, parietal, endoderm])].
[sujeto(['Our', previous, work, on, how, primitive, endoderm, develops, revealed, that, the, 'Wnt6', gene, is, upregulated, by, 'RA,']), verbo([leading]), complemento([to, the, activation, of, the, canonical, 'WNT-β-catenin', pathway])].
[sujeto(['The', mechanism, by, which, 'Wnt6', is]), verbo([regulated]), complemento([was, not, 'determined,', but, in, silico, analysis, of, the, human, 'WNT6', promoter, region, had, suggested, that, the, 'GATA6', and, 'FOXA2', transcription, factors, might, be, involved, '[', 1, ']'])].
[sujeto(['More', 'specifically,', overexpression, of, 'Gata6', or, 'Foxa2', alone]), verbo([induced]), complemento([molecular, and, morphological, markers, of, primitive, 'endoderm,', which, occurred, concomitantly, with, the, upregulation, of, the, 'Wnt6', gene])].
[sujeto(['Gata6-', or, 'Foxa2-overexpressing', cells, were, also]), verbo([found]), complemento([to, have, increased, levels, in, 'T-cell', factor, '(', 'TCF)-dependent', 'transcription,', and, when, these, cells, were, treated, with, 'db-cAMP,', they, developed, into, parietal, endoderm])].
[sujeto(['Chromatin', immunoprecipitation, analysis, revealed, that, 'GATA6', and, 'FOXA2', were]), verbo([bound]), complemento([to, the, 'Wnt6', 'promoter,', and, overexpression, studies, showed, that, these, transcription, factors, were, sufficient, to, switch, on, the, gene, expression, of, a, 'Wnt6', reporter, construct])].
[sujeto(['Together,', these, results]), verbo([provide]), complemento([evidence, for, the, direct, regulation, of, 'Wnt6', that, leads, to, the, activation, of, the, canonical, 'WNT-β-catenin', pathway, and, subsequent, induction, of, primitive, extraembryonic, endoderm])].
[sujeto(['The', results, obtained, demonstrated, that, neural, rosette, forming, cells]), verbo([respond]), complemento([to, 'RA', with, clear, 'concentration-dependent', 'morphological,', and, gene, expression, changes, remarkably, similar, to, those, induced, in, 'vivo,', in, the, developing, neural, 'tube,', by, 'RA', exposure])].
[sujeto(['This', strict, correspondence, indicates, that, the, neural, rosette, protocol, described, is, capable, of, detecting, specific, teratogenic, mechanisms]), verbo([causing]), complemento([perturbations, of, early, neural, development, and, therefore, represents, a, promising, alternative, test, for, human, prenatal, developmental, toxicity])].
[sujeto(['Mouse', embryonic, stem, cells, '(', 'ESCs)', can, be]), verbo([induced]), complemento([to, form, pancreatic, exocrine, 'enzyme-producing', cells, in, vitro, in, a, stepwise, fashion, that, recapitulates, the, development, in, vivo])].
[sujeto(['Based', upon, the, mouse, 'ESC', 'model,', we]), verbo([have]), complemento([induced, the, in, vitro, formation, of, pancreatic, exocrine, 'enzyme-producing', cells, from, hESCs])].
[sujeto(['In', 'Stage', 1, ',', embryoid, bodies, '(', 'EBs)', were, formed, from, dissociated, hESCs, and, then, treated, with, the, growth, factor, activin, 'A,', which]), verbo([promoted]), complemento([the, expression, of, 'Foxa2', and, 'Sox17', 'mRNAs,', markers, of, definitive, endoderm])].
[sujeto(['In', 'Stage', 2, ',', the, cells, were, treated, with, 'all-trans', retinoic, acid, which]), verbo([promoted]), complemento([the, transition, to, cells, that, expressed, gut, tube, endoderm, mRNA, marker, 'HNF1b'])].
[sujeto(['In', 'Stage', 3, ',', the, cells, were, treated, with, fibroblast, growth, factor, 7, '(', 'FGF7),', which]), verbo([induced]), complemento([expression, of, 'Pdx1', typical, of, pancreatic, progenitor, cells])].
[sujeto(['In', 'Stage', 4, ',', treatment, with, 'FGF7,', 'glucagon-like', peptide, 1, ',', and, nicotinamide]), verbo([induced]), complemento([the, expression, amylase, '(', 'AMY)', 'mRNA,', a, marker, for, mature, pancreatic, exocrine, cells])].
[sujeto(['These', cells, also]), verbo([expressed]), complemento([other, exocrine, secretory, proteins, including, 'elastase,', carboxypeptidase, 'A,', 'chymotrypsin,', and, pancreatic, lipase, in, culture])].
[sujeto(['The', homeobox, gene, 'Noto', is]), verbo([expressed]), complemento([in, the, node, and, its, derivative, the, notochord])].
[sujeto(['Here', we, use, a]), verbo([targeted]), complemento(['Noto-GFP', reporter, to, isolate, and, characterize, 'node/notochord-like', cells, derived, from, mouse, embryonic, stem, cells])].
[sujeto(['We']), verbo([find]), complemento([very, few, 'Noto-expressing', cells, after, spontaneous, differentiation])].
[sujeto(['However,', the, number, of, 'Noto-expressing', cells, was]), verbo([increased]), complemento([when, using, 'Activin', 'A', to, induce, a, 'Foxa2-', and, 'Brachyury-expressing', progenitor, 'population,', whose, further, differentiation, into, 'Noto-expressing', cells, was, improved, by, simultaneous, inhibition, of, 'BMP,', 'Wnt,', and, retinoic, acid, signaling])].
[sujeto(['Noto-GFP(+)', cells]), verbo([expressed]), complemento([the, 'node/notochord', markers, 'Noto,', 'Foxa2,', 'Shh,', 'Noggin,', 'Chordin,', 'Foxj1,', and, 'Brachyury;', showed, a, vacuolarization, characteristic, of, notochord, 'cells;', and, can, integrate, into, midline, structures, when, grafted, into, 'Hensen\'s', node, of, gastrulating, chicken, embryos])].
[sujeto(['The', produced, cells, were, analyzed, by, quantitative, 'PCR,', immunohistochemistry, and, static, insulin]), verbo([release]), complemento([assay, for, markers, of, trilaminar, 'embryo,', and, pancreas])].
[sujeto(['Differentiated', cells, displayed]), verbo([increased]), complemento(['Sox17', and, 'Foxa2', expression, consistent, with, definitive, endoderm, production])].
[sujeto(['Various', assays, revealed, that, the, cell, clusters, generated, by, this, protocol]), verbo([express]), complemento([markers, of, the, pancreatic, lineage, including, insulin, 'I,', insulin, 'II,', 'C-peptide,', 'PDX-1,', carboxypeptidase, 'E,', 'pan-cytokeratin,', 'amylase,', 'glucagon,', 'PAX6,', 'Ngn3', and, 'Nkx6'])].
[sujeto(['This', protocol, using, 'all-trans-retinoic', 'acid,', 'DBcAMP,', in, the, absence, of, embryoid, 'bodies,', generated, cells, that]), verbo([have]), complemento([features, of, definitive, endoderm, that, may, serve, as, pancreatic, endocrine, precursors])].
[sujeto(['We', developed, a, differentiation, protocol, that, gradually]), verbo([induced]), complemento([the, formation, of, mouse, pancreatic, exocrine, cells, from, embryonic, stem, cells, '(', 'ESCs)'])].
[sujeto(['This', process, mimicked, in, vivo, pancreatic, development, by, directing, cells, through, definitive, endoderm, '(', 'DE),', gut, tube, 'endoderm,', and, pancreatic, progenitor, cells, to, differentiated, cells, that]), verbo([expressed]), complemento([pancreatic, exocrine, enzymes])].
[sujeto(['Treatment', of, embryoid, bodies, with, activin, 'A']), verbo([induced]), complemento([the, formation, of, 'DE', cells, that, expressed, marker, mRNAs, 'Goosecoid', and, 'Mixl1', and, that, were, 'double-positive', with, 'Foxa2', and, 'Sox17', proteins])].
[sujeto(['Subsequent', treatment, of, the, 'DE', cells, by, retinoic, acid]), verbo([induced]), complemento([the, formation, of, gut, tube, endoderm, cells, that, expressed, the, specific, marker, 'Hnf1b'])].
[sujeto(['Fibroblast', growth, factor, 7, '(', 'FGF7)']), verbo([promoted]), complemento([differentiation, of, 'PDX1-expressing', pancreatic, progenitor, cells, that, also, expressed, 'Foxa2', 'mRNA,', an, endodermal, 'marker,', suggesting, derivation, from, the, 'DE', cells])].
[sujeto(['Exocrine', cell, differentiation, was]), verbo([induced]), complemento([with, 'FGF7,', 'glucagon-like', 'peptide-1,', and, nicotinamide])].
[sujeto(['The', differentiated, cells]), verbo([expressed]), complemento([mature, pancreatic, exocrine, cell, 'mRNAs,', such, as, 'Amylase,', 'Elastase,', and, 'Carboxypeptidase', 'A'])].
[sujeto(['Active', amylase, was]), verbo([released]), complemento([into, the, medium])].
[sujeto(['Moreover,', 'FGF7', was]), verbo([associated]), complemento([with, differentiation, of, pancreatic, exocrine, cells])].
[sujeto(['The', findings]), verbo([reported]), complemento([here, offer, a, novel, and, effective, process, to, develop, pancreatic, exocrine, cells, from, 'ESCs'])].
[sujeto(['The', cardinal, motor, symptoms, of, 'Parkinson\'s', disease, '(', 'PD)', are]), verbo([caused]), complemento([by, the, vulnerability, to, dysfunction, and, degeneration, of, ventral, midbrain, '(', 'VM)', dopaminergic, '(', 'DA)', neurons])].
[sujeto(['Here', we, demonstrate, a, combination, of, three, modifications, that, were]), verbo([required]), complemento([to, produce, 'VM', 'DA', neurons])].
[sujeto(['Thirdly,', early, exposure, to, 'FGF8a,', rather, than, 'Fgf8b,', and, 'WNT1', was]), verbo([required]), complemento([for, robust, differentiation, of, the, 'FOXA2(+)', floor, 'plate-like', human, neural, progenitor, cells, into, 'FOXA2(+)', 'DA', neurons])].
[sujeto(['In', 'summary,', this, new, human, 'ES', and, iPS, cell, differentiation, protocol, using, 'FGF8a,', 'WNT1,', low, dose, retinoic, acid, and, a, high, activity, form, of, 'SHH', can, generate, human, 'VM', 'DA', neurons, that, are]), verbo([required]), complemento([for, relevant, new, 'bioassays,', drug, discovery, and, cell, based, therapies, for, 'PD'])].
[sujeto(['Hepatic', 'pre-induction', was, performed, by, activinA, and, 'FGF4', resulting, in]), verbo([enhanced]), complemento(['SOX17', and, 'FOXA2', expression])].
[sujeto(['By', tracing, the, fate, of, the, 'molecule\'s', label, via, isotopomer, analysis, using, '(', 13, ')', 'C', 'NMR', 'spectroscopy,', formation, of, both, glycogen, and, some, gluconeogenetic, activity, could, be, observed]), verbo([providing]), complemento([evidence, of, a, 'hepatocyte-like', glucose, metabolism, in, differentiated, 'USSC'])].
[sujeto(['Similarly,', pluripotent, embryonic, stem, cells, can, be]), verbo([induced]), complemento([to, differentiate, in, vitro, into, specific, phenotypes, in, response, to, morphogen, treatment])].
[sujeto(['Degradable', 'PLGA', microspheres]), verbo([releasing]), complemento([retinoic, acid, were, incorporated, directly, within, 'EBs', and, induced, the, formation, of, cystic, spheroids, uniquely, resembling, the, phenotype, and, structure, of, early, streak, mouse, embryos, '(', 'E6'])].
[sujeto(['Higher', order, chromatin, structures, across, the, genome, are]), verbo([maintained]), complemento([in, part, by, the, architectural, proteins, 'CCCTC', binding, factor, '(', 'CTCF)', and, the, cohesin, 'complex,', which, 'co-localize', at, many, sites, across, the, genome])].
[sujeto(['Here,', we, examine, the, role, of, these, proteins, in]), verbo([mediating]), complemento([chromatin, structure, at, the, cystic, fibrosis, transmembrane, conductance, regulator, '(', 'CFTR)', gene])].
[sujeto(['CFTR', encompasses, nearly, 200, kb, flanked, by, 'CTCF-binding', 'enhancer-blocking', insulator, elements, and, is]), verbo([regulated]), complemento([by, 'cell-type-specific', intronic, 'enhancers,', which, loop, to, the, promoter, in, the, active, locus])].
[sujeto(['SiRNA-mediated', depletion, of, 'CTCF', or, the, cohesin, 'component,', 'RAD21,', showed, that, these, two, factors]), verbo([have]), complemento([distinct, roles, in, regulating, the, higher, order, organization, of, 'CFTR'])].
[sujeto(['CTCF']), verbo([mediates]), complemento([the, interactions, between, 'CTCF/cohesin', binding, 'sites,', some, of, which, have, 'enhancer-blocking', insulator, activity])].
[sujeto(['Disruption', of, the, 'three-dimensional', structure, of, the, 'CFTR', gene, by, depletion, of, 'CTCF', or, 'RAD21']), verbo([increases]), complemento([gene, 'expression,', which, is, accompanied, by, alterations, in, histone, modifications, and, 'TF', occupancy, across, the, 'locus,', and, causes, internalization, of, the, gene, from, the, nuclear, periphery])].
[sujeto(['The', forkhead, box, 'A', transcription, 'factors,', 'FOXA1', and, 'FOXA2,', function, as, pioneer, factors, to, open, condensed, chromatin, and, facilitate]), verbo([binding]), complemento([of, other, proteins])].
[sujeto(['Here', we, show, that, concurrent, depletion, of, 'FOXA1', and, 'FOXA2']), verbo([represses]), complemento(['CFTR', expression, and, alters, the, 'three-dimensional', architecture, of, the, active, locus, by, diminishing, interactions, between, the, promoter, and, intronic, 'cis-acting', elements])].
[sujeto(['Moreover,']), verbo([loss]), complemento([of, 'FOXA1/A2', suppresses, the, recruitment, of, other, members, of, the, transcriptional, network, including, 'HNF1', and, 'CDX2,', to, multiple, 'cis-elements'])].
[sujeto(['These', data]), verbo([reveal]), complemento([a, complex, molecular, mechanism, underlying, the, role, of, 'FOXA1/A2', in, achieving, high, levels, of, 'CFTR', expression, in, intestinal, epithelial, cells])].
[sujeto(['This', sequence, contains, an, 'intestine-selective', enhancer, and]), verbo([associates]), complemento([with, enhancer, signature, 'proteins,', such, as, 'p300,', in, addition, to, 'tissue-specific', 'TFs', '(', transcription, 'factors)'])].
[sujeto(['In', the, present, study, we, identify, critical, 'TFs', that, are]), verbo([recruited]), complemento([to, this, element, and, demonstrate, their, importance, in, regulating, 'CFTR', expression])].
[sujeto(['In', vitro, 'DNase', 'I', footprinting, and, 'EMSAs', '(', electrophoretic, 'mobility-shift', 'assays)', identified, four, 'cell-type-selective', regions, that]), verbo([bound]), complemento(['TFs', in, vitro])].
[sujeto(['ChIP', '(', chromatin, 'immunoprecipitation)', identified, 'FOXA1/A2', '(', forkhead, box, 'A1/A2),', 'HNF1', '(', hepatocyte]), verbo([nuclear]), complemento([factor, 1, ')', and, 'CDX2', '(', 'caudal-type', homeobox, 2, ')', as, in, vivo, 'trans-interacting', factors])].
[sujeto(['Mutation', of, their]), verbo([binding]), complemento([sites, in, the, intron, 11, core, compromised, its, enhancer, activity, when, measured, by, reporter, gene, assay])].
[sujeto(['Moreover,', siRNA, '(', small, interfering, 'RNA)-mediated', knockdown, of, 'CDX2']), verbo([caused]), complemento([a, significant, reduction, in, endogenous, 'CFTR', transcription, in, intestinal, 'cells,', suggesting, that, this, factor, is, critical, for, the, maintenance, of, high, levels, of, 'CFTR', expression, in, these, cells])].
[sujeto(['The', 'ChIP', data, also, demonstrate, that, these, 'TFs']), verbo([interact]), complemento([with, multiple, 'cis-regulatory', elements, across, the, 'CFTR', 'locus,', implicating, a, more, global, role, in, intestinal, expression, of, the, gene])].
[sujeto(['A', main, challenge, of, modern, biology, is, to, understand, how, specific, constellations, of, genes, are]), verbo([activated]), complemento([to, differentiate, cells, and, give, rise, to, distinct, tissues])].
[sujeto(['This', study, focuses, on, elucidating, how, gene, expression, is, initiated, in, the, 'notochord,', an, axial, structure, that]), verbo([provides]), complemento([support, and, patterning, signals, to, embryos, of, humans, and, all, other, chordates])].
[sujeto(['Although', numerous, notochord, genes]), verbo([have]), complemento([been, 'identified,', the, regulatory, 'DNAs', that, orchestrate, development, and, propel, evolution, of, this, structure, by, eliciting, notochord, gene, expression, remain, mostly, 'uncharted,', and, the, information, on, their, configuration, and, recurrence, is, still, quite, fragmentary])].
[sujeto(['We']), verbo([found]), complemento([that, most, 'Ciona', notochord, 'CRMs', relied, upon, variable, combinations, of, binding, sites, for, the, transcription, factors, 'Brachyury', 'and/or', 'Foxa2,', which, can, act, either, synergistically, or, independently, from, one, another])].
[sujeto(['Notably,', one, of, these, 'CRMs', contains, a, 'Brachyury']), verbo([binding]), complemento([site, juxtaposed, to, an, '(', 'AC)', 'microsatellite,', an, unusual, arrangement, also, found, in, 'Brachyury-bound', regulatory, regions, in, mouse])].
[sujeto(['In', 'contrast,', different, subsets, of, 'CRMs', relied, upon]), verbo([binding]), complemento([sites, for, transcription, factors, of, widely, diverse, families])].
[sujeto(['Surprisingly,', we]), verbo([found]), complemento([that, neither, 'intra-genomic', nor, interspecific, conservation, of, binding, sites, were, reliably, predictive, hallmarks, of, notochord, 'CRMs'])].
[sujeto(['Both', caloric, restriction, '(', 'CR)', and, resveratrol, '(', 'RSV)']), verbo([have]), complemento([beneficial, effects, on, obesity])].
[sujeto(['However,', the, biochemical, pathways, that]), verbo([mediate]), complemento([these, beneficial, effects, might, be, complex, and, interconnected, and, have, not, been, fully, elucidated])].
[sujeto(['To']), verbo([reveal]), complemento([the, common, therapeutic, mechanism, of, 'CR', and, 'RSV,', we, performed, a, comparative, transcriptome, analysis, of, adipose, tissues, from, 'diet-induced', obese, '(', 'DIO)', zebrafish, and, obese, humans])].
[sujeto(['We', identified, nine, genes, in, 'DIO', zebrafish, and, seven, genes, in, obese, humans, whose, expressions, were]), verbo([regulated]), complemento([by, 'CR', and, 'RSV'])].
[sujeto(['Although', the, gene, lists, did, not, overlap, except, for, one, 'gene,', the, gene, ontologies, enriched, in, the, gene, lists, were, highly, 'overlapped,', and, included, genes]), verbo([involved]), complemento([in, adipocyte, 'differentiation,', lipid, storage, and, lipid, metabolism])].
[sujeto(['EP300', is, a, histone, and, lysyl, acetyltransferase, that]), verbo([modulates]), complemento([the, function, of, histone, and, various, proteins, including, 'CEBPB,', 'CEBPD,', 'FOXA1,', and, 'FOXA2'])].
[sujeto(['The', reduction, of, adiposity, by, 'C646', was, not, significantly, different, from, that]), verbo([induced]), complemento([by, 'RSV', or, 'co-treatment', of, 'C646', and, 'RSV'])].
[sujeto(['Recent', studies, indicate, that, 'DNA', methylation, can, be, used, to, identify, transcriptional, 'enhancers,', but, no, systematic, approach]), verbo([has]), complemento([been, developed, for, 'genome-wide', identification, and, analysis, of, enhancers, based, on, 'DNA', methylation])].
[sujeto(['We', identified, networks]), verbo([regulated]), complemento([by, known, cancer, drivers, such, as, 'GATA3', and, 'FOXA1', '(', breast, 'cancer),', 'SOX17', and, 'FOXA2', '(', endometrial, 'cancer),', and, 'NFE2L2,', 'SOX2,', and, 'TP63', '(', squamous, cell, lung, 'cancer)'])].
[sujeto(['We', propose, 'ELMER', as, a, powerful, new, paradigm, for, understanding, the, 'cis-regulatory', interface, between, 'cancer-associated', transcription, factors, and, their, functional]), verbo([target]), complemento([genes])].
[sujeto(['Midbrain', dopamine, neuronal, progenitors, develop, into, heterogeneous, subgroups, of, 'neurons,', such, as, substantia, nigra, pars, 'compacta,', ventral, tegmental, area, and, retrorubal, 'field,', that]), verbo([regulate]), complemento([motor, 'control,', motivated, and, addictive, behaviours])].
[sujeto(['The', development, of, midbrain, dopamine, neurons]), verbo([has]), complemento([been, extensively, 'studied,', and, these, studies, indicate, that, complex, 'cross-regulatory', interactions, between, extrinsic, and, intrinsic, molecules, regulate, a, precise, temporal, and, spatial, programme, of, neurogenesis, in, midbrain, dopamine, progenitors])].
[sujeto(['To', elucidate, direct, molecular, interactions, between, multiple, regulatory, factors, during, neuronal, differentiation, in, 'mice,', we, characterised, 'genome-wide']), verbo([binding]), complemento([sites, of, the, 'forkhead/winged', helix, transcription, factor, 'Foxa1,', which, functions, redundantly, with, 'Foxa2', to, regulate, the, differentiation, of, mDA, neurons])].
[sujeto(['Interestingly,', our, studies, identified, a, rostral, brain, floor, plate, 'Neurog2', enhancer, that]), verbo([requires]), complemento([direct, input, from, 'Otx2,', 'Foxa1,', 'Foxa2', and, an, 'E-box', transcription, factor, for, its, transcriptional, activity])].
[sujeto(['Furthermore,', the, chromatin, remodelling, factor, 'Smarca1', was, shown, to, function, downstream, of, 'Foxa1', and, 'Foxa2', to]), verbo([regulate]), complemento([differentiation, from, immature, to, mature, midbrain, dopaminergic, neurons])].
[sujeto(['Our', 'genome-wide', 'Foxa1-bound', 'cis-regulatory', sequences, from, 'ChIP-Seq', and, 'Foxa1/2', candidate]), verbo([target]), complemento([genes, from, 'RNA-Seq', analyses, of, embryonic, midbrain, dopamine, cells, also, provide, an, excellent, resource, for, probing, mechanistic, insights, into, gene, regulatory, networks, involved, in, the, differentiation, of, midbrain, dopamine, neurons])].
[sujeto(['To', identify, the, transcriptional, regulators, of, 'MafA,', we, examined, various, transcription, 'factors,', which, are, potentially]), verbo([involved]), complemento([in, β, cell, differentiation])].
[sujeto(['An', 'adenovirus-mediated', overexpression, study, clearly, demonstrated, that, 'Onecut1']), verbo([suppresses]), complemento([the, promoter, activity, of, 'MafA', through, the, 'Foxa2-binding', 'cis-element', on, the, 'MafA', enhancer, region, '(', named, area, 'A)'])].
[sujeto(['However,', 'ChIP', analysis, showed, that, 'Foxa2', but, not, 'Onecut1', could, directly]), verbo([bind]), complemento([to, area, 'A'])].
[sujeto(['Furthermore,', overexpression, of, 'Onecut1']), verbo([inhibited]), complemento([the, binding, of, 'Foxa2', onto, area, 'A', upon, 'ChIP', analysis])].
[sujeto(['Importantly,', insertion, of, a, mutation, in, the, 'Foxa2-binding', site, of, area, 'A', significantly]), verbo([decreased]), complemento([the, promoter, activity, of, 'MafA'])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'Onecut1', suppresses, 'MafA', gene, expression, through, the, 'Foxa2-binding', site])].
[sujeto(['In', 'addition,', 'Onecut1', expression, was, significantly]), verbo([increased]), complemento([in, the, islets, of, diabetic, 'db/db', 'mice,', whereas, 'MafA', expression, was, markedly, decreased])].
[sujeto(['These', in, vivo, experiments, also]), verbo([suggest]), complemento([that, 'Onecut1', is, a, negative, regulator, of, 'MafA', gene, expression])].
[sujeto(['This', study, implicates, the, novel, role, of, 'Onecut1', in, the, control, of, normal, β, cell, differentiation, and, its, involvement, in, β, cell, dysfunction, under, diabetic, conditions, by]), verbo([suppressing]), complemento(['MafA', gene, expression])].
[sujeto(['We']), verbo([have]), complemento([shown, previously, that, 'Clock,', microsomal, triglyceride, transfer, protein, '(', 'MTP),', and, nocturnin, are, involved, in, the, circadian, regulation, of, intestinal, lipid, absorption])].
[sujeto(['Plasma', triglyceride, in, 'apoAIV(-/-)', mice, showed, diurnal, variations, similar, to, 'apoAIV(+/+)', 'mice;', 'however,', the]), verbo([increases]), complemento([in, plasma, triglyceride, at, night, were, significantly, lower, in, these, mice])].
[sujeto(['Conversely,', apoAIV, overexpression]), verbo([increased]), complemento(['MTP', mRNA, in, hepatoma, 'cells,', indicating, transcriptional, regulation])].
[sujeto(['Mechanistic', studies, revealed, that, sequences, between, -, 204, /, -, 775, bp, in, the, 'MTP', promoter]), verbo([respond]), complemento([to, apoAIV, and, that, apoAIV, enhances, expression, of, 'FoxA2', and, 'FoxO1', transcription, factors, and, their, binding, to, the, identified, cis, elements, in, the, 'MTP', promoter, at, night])].
[sujeto(['These', data, indicate, that, apoAIV]), verbo([modulates]), complemento([diurnal, changes, in, lipid, absorption, by, regulating, forkhead, transcription, factors, and, 'MTP', and, that, inhibition, of, apoAIV, expression, might, reduce, plasma, lipids])].
[sujeto(['It', is, not, clear, to, what, extent, 'cell-specific', features, determine, the]), verbo([binding]), complemento([capacity, of, seven, 'STAT', members, and, to, what, degree, they, share, genetic, targets])].
[sujeto(['We', determined, that, the, genomic]), verbo([binding]), complemento([capacity, of, 'STATs', is, primarily, defined, by, the, cell, type, and, to, a, lesser, extent, by, individual, family, members])].
[sujeto(['For', 'example,', the, overlap, of, shared]), verbo([binding]), complemento([sites, between, 'STATs', 3, and, 5, in, 'T', cells, is, greater, than, that, between, 'STAT5', in, 'T', cells, and, 'non-T', cells])].
[sujeto(['Even', for, the, top, 1, ',', 0, highly, enriched, 'STAT']), verbo([binding]), complemento(['sites,', '~15%', of, 'STAT5', binding, sites, in, mouse, female, liver, are, shared, by, other, 'STATs', in, different, cell, types, while, in, 'T', cells, '~90%', of, 'STAT5', binding, sites, are, 'co-occupied', by, 'STAT3,', 'STAT4', and, 'STAT6'])].
[sujeto(['In', 'addition,', we, identified, 116, 'cis-regulatory', modules, '(', 'CRM),', which, are]), verbo([recognized]), complemento([by, all, 'STAT', members, across, cell, types, defining, a, common, 'JAK-STAT', signature])].
[sujeto(['Lastly,', in, liver, 'STAT5']), verbo([binding]), complemento([significantly, coincides, with, binding, of, the, 'cell-specific', transcription, factors, 'HNF4A,', 'FOXA1', and, 'FOXA2', and, is, associated, with, 'cell-type', specific, gene, transcription])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, genomic, binding, of, 'STATs', is, primarily, determined, by, the, cell, type, and, further, specificity, is, achieved, in, part, by, juxtaposed, binding, of, 'cell-specific', transcription, factors])].
[sujeto(['MafA', and, 'Pdx1', represent, critical, transcriptional, regulators]), verbo([required]), complemento([for, the, maintenance, of, pancreatic, islet, 'β-cell', function])].
[sujeto(['The', in, vivo, 'β-cell-enriched', expression, pattern, of, these, genes, is, principally, directed, by, islet, transcription, factors]), verbo([binding]), complemento([within, conserved, 'Region', 3, '(', base, pairs, '(', 'bp)', -, 8118, /, -, 7750, ')', of, 'MafA', and, 'Area', 'II', '(', bp, -, 2153, /, -, 1923, ')', of, the, 'Pdx1', gene])].
[sujeto(['Comprehensive', mutational, analysis, of]), verbo([conserved]), complemento(['MafA', 'Region', 3, revealed, two, new, 'β-cell', 'line-specific', 'cis-activation', 'elements,', termed, 'Site', 4, '(', bp, -, 7997, to, -, 7988, ')', and, 'Site', 12, '(', bp, -, 7835, to, -, 7826, ')'])].
[sujeto(['Gel', mobility, and, antibody, 'super-shift', analysis, identified, 'Pdx1', as, the, 'Site', 4]), verbo([binding]), complemento(['factor,', while, an, 80, -, 88, kilodalton, '(', 'kDa)', 'β-cell', 'line-enriched', protein, complex, bound, 'Site', 12, and, similar, aligned, nucleotides, within, 'Pdx1', 'Area', 'II'])].
[sujeto(['The', 80, -, 88, kDa, activator, was, also]), verbo([found]), complemento([in, adult, mouse, islet, extract])].
[sujeto(['The', vertebrate, organizer, and, notochord]), verbo([have]), complemento(['conserved,', essential, functions, for, embryonic, development, and, patterning])].
[sujeto(['Some', 'CRMs']), verbo([have]), complemento([been, conserved, throughout, vertebrates, and, likely, represent, ancestral, regulatory, 'networks,', while, others, have, diverged, beyond, recognition, but, still, function, over, a, wide, evolutionary, range])].
[sujeto(['Here', we, identify, and, characterize, a, 'mammalian-specific', 'CRM']), verbo([required]), complemento([for, node, and, notochord, specific, '(', 'NNC)', expression, of, 'NOTO,', a, transcription, factor, essential, for, node, 'morphogenesis,', nodal, cilia, movement, and, establishment, of, laterality, in, mouse])].
[sujeto(['Three', subregions, in, 'NOCE', together]), verbo([mediated]), complemento([full, activity, in, vivo])].
[sujeto(['NOCE', represents, a, 'novel,', 'mammal-specific', 'CRM']), verbo([required]), complemento([for, the, highly, restricted, 'Noto', expression, in, the, node, and, nascent, notochord, and, thus, regulates, normal, node, development, and, function])].
[sujeto(['The', transcription, factors, 'Foxa1', and, 'Foxa2']), verbo([promote]), complemento([the, specification, of, midbrain, dopaminergic, '(', 'mDA)', neurons, and, the, floor, plate])].
[sujeto(['Whether', their, role, is, direct]), verbo([has]), complemento([remained, unclear, as, they, also, regulate, the, expression, of, 'Shh,', which, has, similar, roles])].
[sujeto(['This', identified, 9160, 'high-quality', 'Foxa2']), verbo([binding]), complemento([sites, associated, with, 5409, 'genes,', providing, mechanistic, insights, into, 'Foxa2-mediated', positive, and, negative, regulatory, events])].
[sujeto(['Foxa2']), verbo([regulates]), complemento([directly, and, positively, key, determinants, of, mDA, 'neurons,', including, 'Lmx1a,', 'Lmx1b,', 'Msx1', and, 'Ferd3l,', while, negatively, inhibiting, transcription, factors, expressed, in, ventrolateral, midbrain, such, as, 'Helt,', 'Tle4,', 'Otx1,', 'Sox1', and, 'Tal2'])].
[sujeto(['Furthermore,', 'Foxa2', negatively]), verbo([regulates]), complemento([extrinsic, and, intrinsic, components, of, the, 'Shh', signaling, 'pathway,', possibly, by, binding, to, the, same, enhancer, regions, of, 'co-regulated', genes, as, 'Gli1'])].
[sujeto(['Foxa2', also]), verbo([regulates]), complemento([the, expression, of, floor, plate, factors, that, control, axon, trajectories, around, the, midline, of, the, 'embryo,', thereby, contributing, to, the, axon, guidance, function, of, the, floor, plate])].
[sujeto(['This', work, represents, the, first, comprehensive, characterization, of, 'Foxa2']), verbo([targets]), complemento([in, mDA, progenitors, and, provides, a, framework, for, elaborating, gene, regulatory, networks, in, a, functionally, important, progenitor, population])].
[sujeto(['The', 'G6PC2', gene, encoding, 'islet-specific', 'glucose-6-phosphatase', related, protein, '(', 'IGRP)']), verbo([has]), complemento([a, common, promoter, 'variant,', rs573225, '(', -, 231, 'G/A),', located, within, a, 'Foxa', binding, site])].
[sujeto(['In', 'vitro,', the, 'G', allele, showed, a, higher, affinity, for]), verbo([binding]), complemento(['Foxa2', transcription, factor, and, increased, 'G6PC2', promoter, activity])].
[sujeto(['Foxa2']), verbo([binding]), complemento([is, modified, if, the, 'C', adjacent, to, the, 'G', allele, is, methylated])].
[sujeto(['IGI', was]), verbo([associated]), complemento([with, rs573225, by, linear, regression, analysis, and, was, 30, '%', greater, in, 'AA', or, 'AG', than, in, 'GG', obese, children])].
[sujeto([rs573225, was, also]), verbo([associated]), complemento([with, fasting, glucose])].
[sujeto([rs573225, is, a, functional, 'cis-regulatory', '(', 'epi)-single-nucleotide', polymorphism, '(', 'SNP)', of, 'G6PC2']), verbo([associated]), complemento([with, 'glucose-insulin', homeostasis, in, obese, 'children,', likely, to, explain, the, results, of, recent, 'genome-wide', association, studies, in, nondiabetic, adults])].
[sujeto(['Here,', we, use, 'genome-wide', location, analysis, for, 'Foxa2', to, identify, its]), verbo([targets]), complemento([in, the, adult, liver])].
[sujeto(['We', then, show, by, computational, analyses, that, 'Foxa2', containing, 'cis-regulatory', modules, are, not, constructed, from, a, random, assortment, of]), verbo([binding]), complemento([sites, for, other, transcription, factors, expressed, in, the, 'liver,', but, rather, that, their, composition, depends, on, the, strength, of, the, 'Foxa2', consensus, site, present])].
[sujeto(['We', not, only]), verbo([provide]), complemento([a, better, understanding, of, the, mechanisms, of, 'Foxa2', regulation, but, also, introduce, a, novel, method, for, identification, of, different, 'cis-regulatory', modules, involving, a, single, factor])].
[sujeto(['The', 'cis-regulatory', regions, of, many, developmental, regulators, and, transcription, factors, are, believed, to, be, highly]), verbo([conserved]), complemento([in, the, genomes, of, vertebrate, 'species,', suggesting, specific, regulatory, mechanisms, for, these, gene, classes])].
[sujeto(['Synthetic', enhancers, containing, the, two, essential, regions, in, front, of, a, 'TATA-box', drive, expression, in, the, notochord, while, concatemerization, of, the, subregions, alone, is, not, 'sufficient,', indicating, that, the, combination, of, the, two, sequence, elements, is]), verbo([required]), complemento([for, notochord, expression])].
[sujeto(['This']), verbo([suggests]), complemento([that, the, regulatory, grammar, itself, does, not, dictate, the, high, evolutionary, conservation, between, these, orthologous, 'cis-regulatory', sequences])].
[sujeto(['Foxa1', and, 'Foxa2', forkhead, box, transcription, factors, '(', 'TFs)']), verbo([participate]), complemento([in, transcriptional, programs, governing, intestinal, cell, differentiation])].
[sujeto(['Down-regulation', of, 'Foxa1', and, 'Foxa2', by, 'RNA', interference, in, cultured, intestinal, cells]), verbo([decreased]), complemento(['Muc2', mRNA, level, by, 'half,', and, abolished, 'Muc2', protein, expression])].
[sujeto(['Chromatin', immunoprecipitation, and, gel, shift, assays, showed, that, these, two, 'TFs', directly]), verbo([bind]), complemento([to, the, 'Muc2', promoter])].
[sujeto(['Co-transfection', experiments, indicated, that, both, 'TFs']), verbo([activate]), complemento([the, 'Muc2', promoter, and, that, mutations, of, three, 'Foxa', 'cis-elements', inhibit, 'Muc2', transactivation])].
[sujeto(['To', identify, transcription, factors, that]), verbo([regulate]), complemento(['ABCA3', expression, in, the, 'lung,', we, identified, by, bioinformatic, and, functional, analyses, two, positive, regulatory, 'regions,', located, between, bp, -, 2591, and, -, 1102, and, bp, -, 1102, and, +, 11, ',', relative, to, the, exon, 1, of, the, 'Abca3', gene, promoter])].
[sujeto(['The', distal, cassette, contains, consensus, sequences, predicting]), verbo([binding]), complemento([to, lung, transcription, factors, including, 'FOXA2,', 'CCAAT/enhancer', binding, 'protein-alpha', '(', 'C/EBPalpha),', 'GATA-6,', thyroid, transcription, 'factor-1', '(', 'TTF-1', or, 'Nkx2'])].
[sujeto([1, ')', ',', and]), verbo([nuclear]), complemento([factor, of, activated, 'T', 'cells-c3', '(', 'NFATc3)'])].
[sujeto(['FOXA2,', 'C/EBPalpha,', 'GATA-6,', 'TTF-1,', and, 'NFATc3']), verbo([increased]), complemento([the, activity, of, the, 'Abca3', luciferase, construct, in, a, 'dose-dependent', manner])].
[sujeto(['The', distal, cassette]), verbo([conferred]), complemento([activation, by, 'FOXA2,', 'C/EBPalpha,', 'GATA-6,', 'TTF-1,', and, 'NFATc3', in, a, 'position-', and, 'orientation-independent', 'manner,', serving, as, an, 'enhancer-like', regulatory, element])].
[sujeto(['The', proximal, 'Abca3', promoter, region, contained, multiple, sterol, responsive, element, '(', 'SRE)']), verbo([binding]), complemento([sites])].
[sujeto(['SRE']), verbo([binding]), complemento([protein, '(', 'SREBP)-1c', significantly, increased, the, activity, of, the, 'Abca3', luciferase, construct, in, a, 'dose-dependent', 'manner,', whereas, 'SREBP-1a', and, 'SREBP-2', did, not, influence, the, 'Abca3', promoter, activity])].
[sujeto(['Chromatin', immunoprecipitation, '(', 'ChIP)', analyses, demonstrated, the]), verbo([binding]), complemento([of, 'SREBP-1c,', 'C/EBPalpha,', and, 'TTF-1', to, their, respective, regulatory, elements])].
[sujeto(['Conditional', deletion, of, 'SREBP', 'cleavage-activating', protein, '(', 'Scap)', in, respiratory, epithelial, cells, in, the, mouse, lung, in, vivo]), verbo([inhibited]), complemento([the, expression, of, 'SREBPs', in, concert, with, 'Abca3'])].
[sujeto(['Abca3', gene, expression, is]), verbo([mediated]), complemento([by, discrete, 'cis-acting', cassettes, that, mediate, pulmonary, 'cell-', and, 'lipid-sensitive', pathways, regulating, surfactant, homeostasis])].
[sujeto(['However,', disruption, of, either, the, -, 803, /, -, 795, or, the, -, 408, /, -, 403, site, did, not, affect, reporter, gene, activity, in, 'NIH', 3, 'T3', 'cells,']), verbo([suggesting]), complemento([that, this, promoter, fragment, is, subjected, to, 'cell-specific', regulation])].
[sujeto(['The']), verbo([nuclear]), complemento([proteins, that, bound, to, these, -, 803, /, -, 795, and, -, 408, /, -, 403, sites, were, identified, by, gel, retardation, assays, as, 'HNF3beta', '(', hepatocyte, nuclear, factor, 3, 'beta)/Foxa2', '(', 'forkhead/winged', helix, transcription, factor, 'box2)', and, 'USFs', '(', upstream, stimulatory, 'factors),', 'USF1', and, 'USF2,', respectively])].
[sujeto(['Chromatin', immunoprecipitation, assays, using, antisera, against, 'HNF3beta/Foxa2,', 'USF1', and, 'USF2', demonstrated, that, endogenous, 'HNF3beta/Foxa2']), verbo([binds]), complemento([to, the, -, 803, /, -, 795, 'Foxa2', 'site,', and, 'USF1', and, 'USF2', bind, to, the, -, 408, /, -, 403, 'E-box', respectively, in, 'vivo,', consistent, with, the, gel, retardation, assay, results])].
[sujeto(['Although', there, are, weak]), verbo([binding]), complemento([sites, located, at, regions, -, 904, and, -, 572, for, 'PDX1', '(', pancreatic, duodenal, 'homeobox-1),', a, transcription, factor, that, controls, expression, of, 'beta-cell-specific', 'genes,', it, did, not, appear, to, regulate, 'PC', expression, in, 'INS-1', cells, in, the, context, of, the, 1.2, kb, promoter, fragment])].
[sujeto(['The', results, presented, here, show, that, 'Foxa2', and, 'USFs']), verbo([regulate]), complemento([the, distal, promoter, of, the, rat, 'PC', gene, in, a, 'cell-specific', manner])].
[sujeto(['We', aimed, to, investigate, whether, vascular, endothelial, growth, factor, '(', 'VEGF)', influences, apolipoprotein, 'M', '(', 'ApoM)', expression, and, 'pre-β-high-density', lipoprotin, '(', 'HDL)', 'formation,', and, whether, forkhead, box, 'A2', '(', 'Foxa2)', and, 'Nur77', are]), verbo([involved]), complemento([in, this, process])].
[sujeto(['We', analyzed, the, serum, 'VEGF', concentrations, of, 264, adults, who, underwent, a, medical, checkup, and]), verbo([found]), complemento([that, 'VEGF', concentration, was, positively, correlated, with, serum, 'triglyceride,', total, 'cholesterol,', 'LDL', cholesterol, '(', 'LDL-C),', 'very-low-density', lipoprotein, cholesterol, '(', 'VLDL-C),', and, 'ApoB', 'concentrations,', but, was, negatively, correlated, with, serum, 'high-density', lipoprotein, cholesterol, '(', 'HDL-C)', and, 'ApoM', concentrations])].
[sujeto(['At', the, same, 'time,', expression, of, 'Foxa2', was, also, 'inhibited,', whereas, expression, of, 'Nur77', was]), verbo([increased]), complemento([by, treatment, with, 'VEGF'])].
[sujeto(['In', 'addition,', siRNA, knockdown, of, 'Nur77', significantly, compensated, for, the, inhibitory, effect, of, 'VEGF', on, 'Foxa2', 'expression,', whereas, the, 'Nur77', agonist, cytosporone, 'B']), verbo([led]), complemento([to, the, downregulation, of, 'Foxa2', expression, more, significantly, than, 'VEGF'])].
[sujeto(['Moreover,', overexpression, of, a, 'Nur77', transgene, in, 'C57BL/6', mice, resulted, in]), verbo([decreased]), complemento([serum, 'ApoM', and, 'pre-β-HDL', 'levels,', whereas, 'si-Nur77-treated', mice, displayed, upregulated, serum, 'ApoM', and, 'pre-β-HDL', levels])].
[sujeto(['These', results]), verbo([provide]), complemento([evidence, that, 'VEGF', may, first, downregulate, expression, of, 'Foxa2', by, enhancing, 'Nur77', activity, and, then, decrease, expression, of, 'ApoM', and, 'pre-β-HDL', formation])].
[sujeto(['More', 'precisely,', we, 'observe,', in, patients, with, type, 2, 'diabetes,', an]), verbo([increased]), complemento([production, of, 'VLDL(1)', particles, that, is, potentially, detrimental, by, generating, atherogenic, 'remnants,', small, dense, 'LDL', particles, and, 'triglyceride-rich', 'HDL', particles])].
[sujeto(['Several', pathophysiological, factors, are, responsible, for]), verbo([increased]), complemento(['VLDL', 'production,', in, type, 2, diabetes])].
[sujeto(['Indeed,', defective, activation, of, 'PI3-kinase,', secondary, to, insulin, 'resistance,', is]), verbo([associated]), complemento([with, a, reduction, of, apoB, degradation, in, the, 'hepatocytes,', a, rise, in, 'MTP', expression, '(', by, increasing, nuclear, transcription, factors, 'Fox01', and, 'Foxa2)', and, an, increased, activity, of, phospholipase, 'D1', and, 'ARF-1,', which, are, involved, in, 'VLDL(1)', formation])].
[sujeto(['Moreover,', peripheral, insulin, resistance, is, responsible, for]), verbo([increased]), complemento([lipolysis, of, adipose, tissue, leading, to, augmented, portal, flux, of, 'FFA', to, the, liver, 'and,', as, a, 'consequence,', activation, of, 'VLDL', production])].
[sujeto(['In', 'addition,']), verbo([increased]), complemento([de, novo, lipogenesis, is, observed, in, type, 2, diabetes])].
[sujeto(['This', is, secondary, to]), verbo([increased]), complemento([activation, of, 'SREBP-1c', '(', 'Sterol', 'Regulatory', 'Element-Binding', 'Protein-1c),', mainly, by, 'Endoplasmic', 'Reticulum', 'stress,', and, of, 'ChREBP', '(', 'Carbohydrate', 'Responsive', 'Element', 'Binding', 'Protein),', mainly, by, hyperglycemia])].
[sujeto(['Furthermore,']), verbo([decreased]), complemento([plasma, adiponectin, observed, in, type, 2, 'diabetes,', may, also, play, a, role, in, increased, 'VLDL', production, by, decreasing, liver, 'AMP-kinase', activation, and, by, increasing, plasma, 'FFA', levels, as, a, consequence, of, reduced, muscle, 'FFA', oxidation])].
[sujeto(['They', are, among, the, earliest, to]), verbo([bind]), complemento([quiescent, 'genes,', which, they, activate, in, conjunction, with, other, transcription, factors])].
[sujeto(['Here', we, confirmed, by, chromatin, immunoprecipitation, that, 'FoxA2', is, one, of, the, factors]), verbo([bound]), complemento([to, the, 'promoter-proximal', enhancer, of, the, gene, encoding, apolipoprotein, 'AI', '(', a, component, of, high, density, 'lipoprotein)', and, that, it, functions, in, synergy, with, the, nuclear, receptor, hepatocyte, nuclear, 'factor-4alpha'])].
[sujeto(['Furthermore,', toward, identifying, additional, cofactors, that, could, potentially]), verbo([regulate]), complemento(['FoxA2', 'activity,', we, identified, 'DNA-dependent', protein, kinase, '(', 'DNA-PK)', as, a, 'FoxA2-associated', factor, upon, affinity, purification, of, 'epitope-tagged', 'FoxA2'])].
[sujeto(['We', show, that, 'FoxA2,']), verbo([found]), complemento([to, be, a, phosphoprotein, in, 'vivo,', is, also, an, efficient, substrate, for, 'DNA-PK,', which, targets, serine, 283])].
[sujeto(['This', residue, is, contained, within, a]), verbo([conserved]), complemento(['serine-glutamine', phosphorylation, signal, for, 'DNA-PK,', located, within, the, 'C-terminal', third, of, the, 'polypeptide,', just, distal, to, its, 'winged-helix', 'DNA', binding, domain])].
[sujeto(['We', establish, that, this, residue, is, critical, for, 'FoxA2', function, because, 'FoxA2', bearing, a, mutation, at, this, site, is, severely, compromised, in, its, ability, to]), verbo([activate]), complemento([a, reporter, gene, under, the, control, of, its, cognate, 'DNA-binding', site, '(', apoAI, site, 'B)'])].
[sujeto(['Complementary', experiments, rule, out, that, this, mutation, compromises, the, ability, of, 'FoxA2', to, either, translocate, to, the, nucleus, or, to]), verbo([bind]), complemento([site, 'B'])].
[sujeto(['Obesity,', 'diabetes,', insulin, 'resistance,', and, hyperinsulinemia, are, frequently]), verbo([associated]), complemento([with, a, cluster, of, closely, related, lipid, abnormalities, such, as, low, plasma, levels, of, high, density, lipoprotein, '(', 'HDL)', and, elevated, levels, of, 'triglyceride,', both, known, to, increase, the, risk, of, developing, atherosclerotic, disease])].
[sujeto(['Here', we, demonstrate, that, 'insulin,', through, a, 'Foxa2-mediated', 'mechanism,']), verbo([inhibited]), complemento([the, expression, of, apolipoprotein, 'M', '(', 'apoM),', an, important, determinant, of, plasma, 'pre-beta-HDL', and, 'alpha-HDL', concentrations])].
[sujeto(['Obese', mice, had]), verbo([decreased]), complemento([apoM, expression, and, plasma, 'pre-beta-HDL', levels, due, to, inactivation, of, 'Foxa2', in, hyperinsulinemic, states])].
[sujeto(['Nuclear', reexpression, of, 'Foxa2', with, a, 'phosphorylation-deficient', mutant, 'Foxa2T156A', '(', 'Ad-T156A)']), verbo([activated]), complemento([apoM, expression, and, increased, plasma, 'pre-beta-HDL', and, 'alpha-HDL', levels])].
[sujeto(['In', 'contrast,', haploinsufficient, 'Foxa2(+/-)', mice, exhibited]), verbo([decreased]), complemento([hepatic, apoM, expression, and, plasma, 'pre-beta-HDL', and, 'HDL', levels])].
[sujeto(['The']), verbo([increase]), complemento([in, plasma, 'HDL', levels, and, 'pre-beta-HDL', formation, by, 'Foxa2', was, mediated, exclusively, by, 'apoM,', as, constitutive, active, expression, of, 'Foxa2', in, 'apoM(-/-)', mice, had, no, effect, on, plasma, 'HDL', levels])].
[sujeto(['Our', results, identify, a, fundamental, mechanism, by, which, insulin]), verbo([regulates]), complemento([plasma, 'HDL', levels, in, physiological, and, 'insulin-resistant', states, and, thus, have, important, implications, for, novel, therapeutic, approaches, to, prevent, atherosclerosis])].
[sujeto(['Apolipoprotein', '(', 'apo)A-I', alone, or, as, a, component, of, high, density, lipoprotein, particles]), verbo([has]), complemento([antiatherogenic, properties])].
[sujeto(['Results', in, rats, showed, that, levels, of, serum, 'apoA-I', 'protein,', hepatic, 'mRNA,', and, transcription, of, the, gene, were]), verbo([decreased]), complemento([to, 39, '%', ',', 18, '%', ',', and, 38, '%', ',', 'respectively,', in, 180, -, 'day-old', animals, compared, to, those, of, newborn, rats])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, a, nuclear, 'mechanism(s)', may, account, for, the, decline, in, 'apoA-I', expression])].
[sujeto(['Accordingly,', we, examined, hepatic]), verbo([nuclear]), complemento([binding, activity, to, four, specific, 'cis-acting', elements, of, the, rat, 'apoA-I', promoter])].
[sujeto(['There', were, 'age-dependent', changes, of]), verbo([binding]), complemento([activity, to, two, proximal, 'sites,', 'B', and, 'C,', but, not, to, the, more, distal, 'elements,', 'IRCE', and, 'A'])].
[sujeto(['Decreased', 'B-site']), verbo([binding]), complemento([activity, correlated, with, lower, mRNA, levels, encoding, the, 'activator,', 'HNF-3beta'])].
[sujeto(['The', 'age-dependent', change, in, the, pattern, of]), verbo([binding]), complemento([to, site, 'C', was, due, to, a, switch, from, the, 'activator,', 'HNF-4,', to, the, 'repressor,', 'ARP-1'])].
[sujeto(['Estrogen', replacement, therapy]), verbo([increases]), complemento([plasma, concentrations, of, high, density, lipoprotein, and, its, major, protein, 'constituent,', apolipoprotein, 'AI', '(', 'apoAI)'])].
[sujeto(['Studies', with, animal, model, 'systems,', 'however,']), verbo([suggest]), complemento([opposite, effects])].
[sujeto(['In', 'HepG2', cells, stably]), verbo([expressing]), complemento([estrogen, receptor, alpha, '(', 'ERalpha),', 17, 'beta-estradiol', '(', 'E2)', potently, inhibited, apoAI, mRNA, steady, state, levels])].
[sujeto(['ApoAI', promoter, deletion, mapping, experiments, indicated, that, 'ERalpha', plus, 'E2']), verbo([inhibited]), complemento([apoAI, activity, through, the, 'liver-specific', enhancer])].
[sujeto(['Although', the, 'ERalpha', 'DNA']), verbo([binding]), complemento([domain, was, essential, but, not, sufficient, for, apoAI, enhancer, 'inhibition,', 'ERalpha', binding, to, the, apoAI, enhancer, could, not, be, detected, by, electrophoretic, mobility, shift, assays])].
[sujeto(['Expression', of, the, 'ERalpha', coactivator, 'RIP140', dramatically]), verbo([repressed]), complemento([apoAI, enhancer, function, in, cotransfection, 'experiments,', suggesting, that, 'RIP140', may, also, function, as, a, coactivator, on, the, apoAI, enhancer])].
[sujeto(['At', low, ratios, of, 'RIP140', to, 'ERalpha,', 'E2']), verbo([repressed]), complemento([apoAI, enhancer, 'activity,', whereas, at, high, ratios, this, repression, was, reversed])].
[sujeto(['Recently,']), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'iPSCs)', derived, from, the, reprogramming, of, somatic, 'fibroblasts,', have, been, shown, to, resemble, embryonic, stem, '(', 'ES)', cells, in, that, they, have, pluripotent, properties, and, the, potential, to, differentiate, into, all, cell, lineages, in, 'vitro,', including, hepatocytes])].
[sujeto(['We']), verbo([have]), complemento([established, a, rapid, and, efficient, differentiation, protocol, that, is, able, to, generate, functional, 'hepatocyte-like', cells, from, human, iPSCs])].
[sujeto(['Human', embryonic, stem, cells, '(', 'hESCs)']), verbo([provide]), complemento([a, new, source, for, hepatocyte, production, in, translational, medicine, and, cell, replacement, therapy])].
[sujeto(['The']), verbo([reported]), complemento(['hESC-derived', 'hepatocyte-like', cells, '(', 'HLCs)', were, commonly, generated, on, 'Matrigel,', a, mouse, cell, 'line-derived', extracellular, matrix, '(', 'ECM)'])].
[sujeto(['In', comparison, with, 'Matrigel,', the, differentiated, 'HLCs', on, both, 'ECMs']), verbo([expressed]), complemento([similar, levels, of, 'hepatocyte-specific', 'genes,', secreted, 'α-fetoprotein,', and, metabolized, 'ammonia,', showed, glycogen, storage, activity, as, well, as, 'low-density', lipoprotein, and, indocyanine, green, uptake])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, the, 'xeno-free', and, 'cost-benefit', matrix, may, be, applicable, in, bioartificial, livers, and, also, may, facilitating, a, clinical, application, of, human, pluripotent, stem, 'cell-derived', hepatocytes, in, the, future])].
[sujeto(['The', generation, of]), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'iPSCs)', is, an, innovative, 'personalized-regenerative', 'technology,', which, can, transform, 'own-self', somatic, cells, into, embryonic, stem, '(', 'ES)-like', 'cells,', which, have, the, potential, to, differentiate, into, all, cell, types, of, three, dermal, lineages])].
[sujeto(['We', showed, that, 'FMSNs', of, various, surface, charges, could, be, efficiently, internalized, by, iPSCs, without]), verbo([causing]), complemento([cytotoxicity])].
[sujeto(['Notably,', 'positive-charged', 'FMSN']), verbo([enhanced]), complemento([cellular, uptake, efficiency, and, retention, time])].
[sujeto(['Moreover,', when, using, 'positive-charged', 'FMSN', to, deliver, hepatocyte]), verbo([nuclear]), complemento([factor, 3, β, '(', 'HNF3β)', plasmid, 'DNA', '(', 'pDNA),', the, treated, iPSCs, exhibited, significantly, improved, definitive, endoderm, formation, and, further, quickly, differentiated, into, 'hepatocyte-like', cells, with, mature, functions, '(', 'low-density', lipoprotein, uptake, and, glycogen, 'storage)', within, 2, weeks, in, vitro])].
[sujeto(['These', findings]), verbo([reveal]), complemento([the, multiple, advantages, of, 'FMSNs', to, serve, as, ideal, vectors, not, only, for, stem, cell, labeling, but, also, for, safe, gene, delivery, to, promote, the, production, of, 'hepatocyte-like', cells, from, iPSCs])].
[sujeto(['The', nature, of, extranuclear, estrogen, elements]), verbo([has]), complemento([not, been, elucidated, so, 'far;', classical, or, alternatively, transcribed, 'ER', isoforms, '(', 'ERα36,', 'ERα46)', anchored, to, the, plasma, membrane, and, 'GPR30', '(', 'GPER1)', have, been, reported, to, exert, early, estrogen, actions])].
[sujeto(['Two', different, clusters, of, transcripts, could, be, 'identified:', '(', 1, ')', the, majority, of, transcripts, were]), verbo([inhibited]), complemento([by, both, 'ICI182,780', and, 'G15,', suggesting, an, interaction, of, 'E2-BSA', with, a, common, 'ER-related', 'element,', or, a, direct, 'ER-GPER1', 'interaction;', '(', 2, ')', a, small, number, of, 'G15-only', modified, 'transcripts,', in, two, cell, lines, '(', 'T47D', and, 'SKBR3', 'cells),', indicative, of, specific, 'GPER1-related', effects])].
[sujeto(['The', latter, transcripts, were, significantly, related, to, pathways, including, 'FOXA2/FOXA3', transcription, factor, 'networks,', 'RNA-Polymerases', 'Transcription', 'Regulation', and, lipid, 'metabolism,', while, 'ICI/G15']), verbo([inhibited]), complemento([transcripts, affected, pathways, related, to, 'apoptosis,', erythropoietin, 'signaling,', metabolic, effects, through, the, citric, acid, 'cycle,', 'IL-4', and, 'IL-5', mediated, events, and, homologous, 'DNA', recombination])].
[sujeto(['Here,', we, show, that, the]), verbo([nuclear]), complemento([hormone, 'receptors,', hepatocyte, nuclear, factor, 4, and, retinoid, 'X', receptor, alpha, plus, peroxisome, 'proliferator-activated', receptor, 'alpha,', support, 'HBV', replication, in, nonhepatic, cells, by, controlling, pregenomic, 'RNA', 'synthesis,', indicating, these, 'liver-enriched', transcription, factors, control, a, unique, molecular, switch, restricting, viral, tropism])].
[sujeto(['In', 'contrast,', hepatocyte]), verbo([nuclear]), complemento([factor, 3, antagonizes, nuclear, hormone, 'receptor-mediated', viral, 'replication,', demonstrating, distinct, regulatory, roles, for, these, 'liver-enriched', transcription, factors])].
[sujeto(['The', signalling, molecule, 'Sonic', hedgehog, is]), verbo([involved]), complemento([in, a, multitude, of, distinct, patterning, processes, during, vertebrate, embryogenesis])].
[sujeto(['We', show, here, that, misexpression, of, axial]), verbo([leads]), complemento([to, ectopic, activation, of, sonic, hedgehog, expression, in, the, 'zebrafish,', suggesting, that, axial, is, a, regulator, of, sonic, hedgehog, transcription])].
[sujeto(['This', effect, is]), verbo([mediated]), complemento([by, two, 'Axial', '(', 'HNF3beta)', recognition, sequences])].
[sujeto(['We', furthermore, identified, a, retinoic, acid, response, element, '(', 'RARE)', in, the, sonic, hedgehog, upstream, region, which, can, be]), verbo([bound]), complemento([by, retinoic, acid, receptor, '(', 'RAR)', and, retinoid, 'X', receptor, '(', 'RXR)', heterodimers, in, vitro, and, confers, retinoic, acid, inducibility, to, the, sonic, hedgehog, promoter, in, the, 'HeLa', cell, system])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, both, 'Axial', '(', 'HNF3beta)', and, retinoic, acid, receptors, are, direct, regulators, of, the, sonic, hedgehog, gene])].
[sujeto(['Human', 'CYP3A7', and, 'CYP3A4', are]), verbo([expressed]), complemento([in, fetal, and, adult, 'livers,', 'respectively,', although, the, 5, '\'', -, flanking, regions, of, the, two, genes, show, 90, '%', homology])].
[sujeto(['Transfection', studies, using, a, series, of, the, 'CYP3A7', or, 'CYP3A4', 'promoter-luciferase', chimeric, genes, identified, a]), verbo([nuclear]), complemento([factor, kappaB, '(', 'NF-kappaB)-like', element, between, nucleotides, -, 2326, and, -, 2297, that, conferred, the, transcriptional, activation, of, the, 'CYP3A7', gene])].
[sujeto(['A', gel, shift, assay, using]), verbo([nuclear]), complemento([extracts, from, 'HepG2', cells, showed, that, 'Sp1', and, 'Sp3', bound, to, the, 'NF-kappaB-like', element, of, the, 'CYP3A7', but, not, 'CYP3A4', gene])].
[sujeto(['Additionally,', introduction, of, mutations, into]), verbo([binding]), complemento([sites, for, hepatocyte, nuclear, factor, 3, 'beta,', upstream, stimulatory, factor, 1, ',', and, a, basic, transcription, element, in, the, proximal, promoter, attenuated, luciferase, activity, to, 20, '%', of, the, level, seen, with, the, intact, 'CYP3A7', promoter])].
[sujeto(['Thus,', we, conclude, that, the, expression, of, the, 'CYP3A7', gene, in, 'HepG2', cells, is, cooperatively]), verbo([regulated]), complemento([by, 'Sp1,', 'Sp3,', hepatocyte, nuclear, factor, 3, 'beta,', and, upstream, stimulatory, factor, 1])].
[sujeto(['In', the, present, 'study,', we]), verbo([have]), complemento([used, reporter, gene, analysis, and, 'semi-quantitative', 'RT-PCR', to, establish, that, 'insulin,', 'glucagon,', 'glucagon-like', 'peptide-1', '(', 'GLP-1)', and, the, 'GLP-1', derivatives, 'GLP(7-36)Amide', and, 'Exendin-4', all, stimulate, 'IAPP', promoter, 'activity,', as, well, as, endogenous, 'IAPP', mRNA, levels, in, isolated, islets, of, 'Langerhans'])].
[sujeto(['In', 'contrast,', somatostatin, had, no, 'effect,', and, whilst, the, inflammatory, cytokines, 'TNF-alpha,', 'IL-1alpha', and, 'IL-1beta', had, no, effect, on, promoter, 'activity,', they, all]), verbo([decreased]), complemento(['IAPP', mRNA, levels, in, isolated, islets])].
[sujeto(['Finally,', utilising, a, series, of, deletion, reporter, gene, constructs, of, the, human, 'IAPP', gene, 'promoter,', we, used, overexpression, studies, to, establish, that, 'HNF-3beta', '(', 'FoxA2)', negatively]), verbo([regulates]), complemento([the, 'IAPP', 'promoter,', whilst, the, 'MODY3', transcription, factor, 'HNF-1alpha', positively, regulates, promoter, activity])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, '(', 'HNF)-1alpha', plays, a, central, role, in, intestinal, and, hepatic, gene, regulation, and, is, required, for, hepatic, expression, of, the, liver, fatty, acid, binding, protein, gene, '(', 'Fabpl)'])].
[sujeto(['An', 'Fabpl', transgene, was, directly]), verbo([activated]), complemento([through, cognate, sites, by, 'HNF-1alpha', and, 'HNF-1beta,', as, well, as, five, other, endodermal, 'factors:', 'CDX-1,', 'C/EBPbeta,', 'GATA-4,', 'FoxA2,', and, 'HNF-4alpha'])].
[sujeto(['HNF-1alpha']), verbo([activated]), complemento([the, 'Fabpl', transgene, by, as, much, as, 60, -, fold, greater, in, the, presence, of, the, other, five, endodermal, factors, than, in, their, 'absence,', accounting, for, up, to, 'one-half', the, total, transgene, activation, by, the, group, of, six, factors])].
[sujeto(['This', degree, of, synergistic, interaction]), verbo([suggests]), complemento([that, multifactor, cooperativity, is, a, critical, determinant, of, endodermal, gene, activation, by, 'HNF-1alpha'])].
[sujeto(['Mutations', in, 'HNF-1alpha', that, result, in, maturity, onset, diabetes, of, the, young, '(', 'MODY3)']), verbo([provide]), complemento([evidence, for, the, in, vivo, significance, of, these, synergistic, interactions])].
[sujeto(['An', 'R131Q', 'HNF-1alpha', 'MODY3', mutant, exhibits, complete]), verbo([loss]), complemento([of, synergistic, activation, in, concert, with, the, other, endodermal, transcription, factors, despite, 'wild-type', transactivation, ability, in, their, absence])].
[sujeto(['Selective']), verbo([loss]), complemento([of, synergy, with, other, endodermal, transcription, factors, accompanied, by, retention, of, native, transactivation, ability, in, an, 'HNF-1alpha', 'MODY', mutant, suggests, in, vivo, significance, for, cooperative, synergy])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, '(', 'HNF)-3beta,', a, transcription, factor, expressed, in, pancreatic, beta, 'cells,', is, an, upstream, regulator, of, 'HNF-1alpha/MODY3,', 'HNF-4alpha/MODY1', and, 'IPF1/MODY5', genes])].
[sujeto(['Our', previous, screening, of, 'MODY', subjects, showed, that, mutations, in, the, 'HNF-3beta', gene, are, not, a, common]), verbo([cause]), complemento([of, this, form, of, diabetes, in, the, 'Japanese'])].
[sujeto(['We', tested, the, hypothesis, that, mutations, in, the, 'HNF-3beta', gene]), verbo([cause]), complemento(['late-onset', 'Type', 'II', '(', 'non-insulin-dependent)', diabetes, mellitus, in, this, population])].
[sujeto(['The', 'A86T', mutation, in, the, 'HNF-3beta', gene, might, be]), verbo([involved]), complemento([in, the, development, of, 'late-onset', 'Type', 'II', diabetes, in, a, small, group, of, 'Japanese', people])].
[sujeto(['The', genes, encoding, the, functionally, related, hepatocyte]), verbo([nuclear]), complemento([factors, 'HNF-1alpha', and, 'HNF-4alpha', play, a, critical, role, in, normal, pancreatic, 'beta-cell', function])].
[sujeto(['The', transcriptional, hierarchy, of, 'HNFs']), verbo([suggests]), complemento([that, other, proteins, of, the, regulatory, cascade, might, be, responsible, for, other, forms, of, 'MODY', 'and/or', 'late-onset', type, 2, diabetes])].
[sujeto(['In', this, 'study,', we, show, that, 'HNF-3alpha,', -, 3, 'beta,', -, 3, 'gamma,', -, 4, 'gamma,', and, -, 6, are]), verbo([expressed]), complemento([in, pancreatic, 'beta-cells'])].
[sujeto(['We']), verbo([report]), complemento([the, identification, and, characterization, of, simple, tandem, repeat, 'DNA', polymorphisms, in, the, genes, encoding, 'HNF-3alpha,', -, 3, 'beta,', -, 3, 'gamma,', -, 4, 'gamma,', and, -, 6, and, the, mapping, of, 'HNF-6', to, chromosome, bands, 15, q21])].
[sujeto(['In', diabetes, 'mellitus,', hepatic, and, tubular, glucose, output]), verbo([has]), complemento([been, related, to, 'Slc2a2/GLUT2', 'overexpression;', and, controlling, the, expression, of, this, gene, may, be, an, important, adjuvant, way, to, improve, glycemic, homeostasis])].
[sujeto(['Thus,', the, present, study, investigated, transcriptional, mechanisms]), verbo([involved]), complemento([in, the, 'diabetes-induced', overexpression, of, the, 'Slc2a2', gene])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factors, 1, α, and, 4, α, '(', 'HNF-1α', and, 'HNF-4α),', forkhead, box, 'A2', '(', 'FOXA2),', sterol, regulatory, element, binding, 'protein-1c', '(', 'SREBP-1c)', and, the, 'CCAAT-enhancer-binding', protein, '(', 'C/EBPβ)', mRNA, expression, '(', 'RT-PCR)', and, binding, activity, into, the, 'Slc2a2', promoter, '(', electrophoretic, mobility, 'assay)', were, analyzed, in, the, liver, and, kidney, of, diabetic, and, 6, -, day, 'insulin-treated', diabetic, rats])].
[sujeto(['Slc2a2/GLUT2', expression]), verbo([increased]), complemento([by, more, than, 50, '%', '(', 'P<0'])].
[sujeto(['Similarly,', the, mRNA, expression, and, the]), verbo([binding]), complemento([activity, of, 'HNF-1α,', 'HNF-4α', and, 'FOXA2', increased, by, 50, to, 100, '%', '(', 'P<0'])].
[sujeto(['Neither', the, 'Srebf1', and, 'Cebpb', mRNA, 'expression,', nor, the, 'SREBP-1c', and, 'C/EBP-β']), verbo([binding]), complemento([activity, was, altered, in, diabetic, rats])].
[sujeto(['HNF-1α,', 'HNF-4α', and, 'FOXA2', transcriptional, factors, are]), verbo([involved]), complemento([in, 'diabetes-induced', overexpression, of, 'Slc2a2', gene, in, the, liver, and, kidney])].
[sujeto(['These', data, point, out, that, these, transcriptional, factors, are, important]), verbo([targets]), complemento([to, control, 'GLUT2', expression, in, these, 'tissues,', which, can, contribute, to, glycemic, homeostasis, in, diabetes])].
[sujeto(['The', human, gene, 'MUC4', encodes, a, large, transmembrane, mucin, that, is, developmentally]), verbo([regulated]), complemento([and, expressed, along, the, undifferentiated, pseudostratified, 'epithelium,', as, early, as, 6.5, weeks, during, fetal, development])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factors, '(', 'HNF),', forkhead, box, 'A', '(', 'FOXA),', 'GATA,', and, 'caudal-related', homeobox, transcription, factors, '(', 'TFs)', are, known, to, control, cell, differentiation, of, gut, endoderm, 'derived-tissues', during, embryonic, development])].
[sujeto(['Experiments', using, small, interfering, 'RNA,', cell, 'co-transfection,', and, 'site-directed', mutagenesis, indicated, that, 'MUC4', is]), verbo([regulated]), complemento([at, the, transcriptional, level, by, 'CDX-1', and, -, 2, ',', 'HNF-1', alpha, and, -, 1, 'beta,', 'FOXA1/A2,', 'HNF-4', alpha, and, -, 4, 'gamma,', and, 'GATA-4,', -, 5, ',', and, -, 6, factors, in, a, 'cell-specific', manner])].
[sujeto(['Altogether,', these, results, demonstrate, that, 'MUC4', is, a]), verbo([target]), complemento([gene, of, endodermal, 'TFs', and, thus, point, out, an, important, role, for, these, 'TFs', in, regulating, 'MUC4', expression, during, epithelial, differentiation, during, 'development,', 'cancer,', and, repair])].
[sujeto(['The']), verbo([cause]), complemento([of, organ, failure, is, enigmatic, for, many, degenerative, 'diseases,', including, 'end-stage', liver, disease])].
[sujeto(['Here,', using, a, 'CCl4-induced', rat, model, of, irreversible, and, fatal, hepatic, 'failure,', which, also, exhibits, terminal, changes, in, the, extracellular, 'matrix,', we, demonstrated, that, chronic, injury, stably, reprograms, the, critical, balance, of, transcription, factors, and, that, diseased, and, dedifferentiated, cells, can, be, returned, to, normal, function, by, 're-expression', of, critical, transcription, 'factors,', a, process, similar, to, the, type, of, reprogramming, that]), verbo([induces]), complemento([somatic, cells, to, become, pluripotent, or, to, change, their, cell, lineage])].
[sujeto(['Forced', 're-expression', of, the, transcription, factor, 'HNF4α']), verbo([induced]), complemento([expression, of, the, other, 'hepatocyte-expressed', transcription, 'factors;', restored, functionality, in, terminally, diseased, hepatocytes, isolated, from, 'CCl4-treated', 'rats;', and, rapidly, reversed, fatal, liver, failure, in, 'CCl4-treated', animals, by, restoring, diseased, hepatocytes, rather, than, replacing, them, with, new, hepatocytes, or, stem, cells])].
[sujeto(['Together,', the, results, of, our, study, indicate, that, disruption, of, the, transcription, factor, network, and, cellular, dedifferentiation, likely]), verbo([mediate]), complemento([terminal, liver, failure, and, suggest, reinstatement, of, this, network, has, therapeutic, potential, for, correcting, organ, failure, without, cell, replacement])].
[sujeto(['We', recently, demonstrated, that, 'β-cells', become, hypoxic, under, high, glucose, conditions, due, to]), verbo([increased]), complemento([oxygen, consumption, and, that, the, pancreatic, islets, of, diabetic, mice, but, not, those, of, control, mice, are, moderately, hypoxic])].
[sujeto(['In', the, present, 'study,', moderate, hypoxia]), verbo([induced]), complemento([a, hypoxic, response, in, 'MIN6', 'cells,', as, evidenced, by, increased, levels, of, 'HIF-1α', protein, and, target, genes])].
[sujeto(['Most', of, the, 'hypoxia-induced', gene, downregulation, in, 'MIN6', cells, was, not, affected, by, the, suppression, of, 'HIF-1α,']), verbo([suggesting]), complemento([a, 'HIF-1-independent', mechanism])].
[sujeto(['Moderate', hypoxia, also]), verbo([induced]), complemento([apoptosis, in, 'MIN6', cells])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, hypoxia, is, a, novel, stressor, of, 'β-cells', and, that, hypoxic, stress, may, play, a, role, in, the, deterioration, of, 'β-cell', function])].
[sujeto(['Siah2-dependent', expression, and, activity, of, 'HIF-1α']), verbo([regulate]), complemento([its, availability, to, form, a, transcriptional, complex, with, 'FoxA2,', resulting, in, expression, of, specific, target, 'genes,', including, 'Hes6,', 'Sox9', and, 'Jmjd1a,', whose, 'co-expression', is, sufficient, for, formation, of, 'NE', tumors, and, 'NE', lesions, in, 'PCa'])].
[sujeto(['These', studies]), verbo([provide]), complemento([novel, markers, to, diagnose, and, monitor, formation, of, 'NE', lesions, and, 'NE', tumors])].
[sujeto(['Furthermore,', defining, the, regulatory, axis, consisting, of, 'Siah2', and, 'HIF-1α/FoxA2', cooperation]), verbo([suggests]), complemento([novel, therapeutic, modalities, to, treat, these, most, aggressive, forms, of, prostate, cancer])].
[sujeto(['Here', we, review, current, understanding, of, 'Siah', role, in, control, of, hypoxia, and, prostate, tumor, development, and, highlight, potential, approaches, for]), verbo([targeting]), complemento([components, along, 'Siah-regulated', pathways])].
[sujeto(['Formation', of, 'NE', prostate, tumors, in, the, 'TRAMP', mouse, model, was]), verbo([suppressed]), complemento([in, mice, lacking, the, ubiquitin, ligase, 'Siah2,', which, regulates, 'HIF-1alpha', availability])].
[sujeto(['Cooperation', between, 'HIF-1alpha', and, 'FoxA2,', a, transcription, factor]), verbo([expressed]), complemento([in, 'NE', 'tissue,', promotes, recruitment, of, p300, to, transactivate, select, 'HIF-regulated', 'genes,', 'Hes6,', 'Sox9,', and, 'Jmjd1a'])].
[sujeto(['These', 'HIF-regulated', genes, are, highly]), verbo([expressed]), complemento([in, metastatic, 'PCa', and, required, for, 'hypoxia-mediated', 'NE', 'phenotype,', metastasis, in, 'PCa,', and, the, formation, of, 'NE', tumors])].
[sujeto(['Tissue-specific', expression, of, 'FoxA2', combined, with, 'Siah2-dependent', 'HIF-1alpha', availability, enables, a, transcriptional, program]), verbo([required]), complemento([for, 'NE', prostate, tumor, development, and, 'NE', phenotype, in, 'PCa'])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, 'PGC-1alpha-mediated', upregulation, of, 'beta-cell', sterol, element, binding, protein, '(', 'SREBP)', gene, expression, impairs, insulin, secretion, via, increased, transcription, of, uncoupling, protein, 2, '(', 'UCP2)'])].
[sujeto(['PGC-1beta,', in, contrast, to, 'PGC-1alpha,', directly]), verbo([binds]), complemento([to, and, acts, as, a, 'co-activator', of, 'SREBPs', and, the, forkhead, transcription, factor, 2, 'A', '(', 'FOXA2)', involved, in, pancreas, development, and, function])].
[sujeto(['In', comparison, to, 'controls,', mRNA, levels, of, all, genes, studied, except, for, 'FOXA2', and, 'FOXO1', were]), verbo([increased]), complemento([in, islets, of, 'obese,', 'fa/fa', 'ZDF', rats])].
[sujeto(['PGC-1beta', as, well, as, 'SREBP-1c', and, -, 2]), verbo([increased]), complemento([transcription, from, the, 'UCP2', promoter, in, 'INS-1E', cells])].
[sujeto(['Transient', transfection, of, 'PGC-1beta-specific', siRNAs, significantly]), verbo([decreased]), complemento(['SREBP-2-mediated', transcriptional, activation, of, the, 'UCP2', gene])].
[sujeto(['Furthermore', 'PGC-1beta,', 'SREBP-1c,', and, 'FOXA2', overexpression, augmented, granuphilin, promoter, 'activity,', whereas, 'siRNA-mediated', gene, knockdown, of, 'PGC-1beta', reduced, the, effects, of, 'SREBP-1c', and, 'FOXA2', on, granuphilin, gene, transcription, and, significantly]), verbo([increased]), complemento(['glucose-stimulated', insulin, release, from, 'INS-1E', cells])].
[sujeto(['Morphological', changes, that, occur, during, pancreatic, endocrine, cell, differentiation]), verbo([have]), complemento([been, shown, in, rodent, systems, to, be, dependent, on, sequential, alterations, in, transcription, factor, expression])].
[sujeto(['However,', similar, data, for, humans]), verbo([have]), complemento([been, limited])].
[sujeto(['The', aim, of, the, present, study, was, to]), verbo([provide]), complemento([a, connection, between, pancreatic, 'morphology,', transcription, factor, gene, expression, and, protein, localisation, during, human, fetal, development])].
[sujeto(['We', observed, a, significant]), verbo([decrease]), complemento([in, pancreatic, duodenal, homeobox, 1, '(', 'PDX-1)(+)/cytokeratin', 19, '(', +, ')', cells, '(', p, &, 'lt;', 0.001, ')', ',', with, a, simultaneous, increase, in, 'PDX-1(+)/insulin(+)', cells, from, 8, to, 21, weeks, '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['Increased', 'PDX-1/insulin', 'co-localisation', within, islet, clusters, was, 'noted,', while, no, 'co-expression', of, 'PDX-1', with, glucagon, was, 'found,']), verbo([suggesting]), complemento([that, loss, of, 'PDX-1', is, essential, for, alpha, cell, formation])].
[sujeto(['Co-localisation', of, 'NGN3', with, 'PDX-1,', insulin, and, glucagon, was, noted, during, early, 'development,', with, significant]), verbo([decreases]), complemento([in, middle, and, late, stages, '(', p, &, 'lt;', 0.001, ')'])].
[sujeto(['Our', microarray, and, 'co-localisation', analyses, of, transcription, factors, linked, to, 'NGN3', demonstrated, that, 'ISL1', transcription, factor, '(', 'ISL1),', neurogenic, differentiation, 1, '(', 'NEUROD1),', 'NK2', related, transcription, factor, 'related,', locus, 2, '(', 'NKX2-2)', and, paired, box, gene, 6, '(', 'PAX6)', were, upregulated, during, development, and, present, in, all, four, endocrine, cell, 'types,', while, 'NK6', related, transcription, factor, 'related,', locus, 1, '(', 'NKX6-1)', was]), verbo([expressed]), complemento([exclusively, in, beta, cells])].
[sujeto(['This', study, is, an, important, step, towards, identifying, key, molecular, factors]), verbo([involved]), complemento([in, development, of, the, human, fetal, endocrine, pancreas])].
[sujeto(['We', demonstrate, that, the]), verbo([binding]), complemento([sites, for, highly, conserved, transcription, factors, vary, extensively, between, human, and, mouse])].
[sujeto(['We', mapped, the]), verbo([binding]), complemento([of, four, 'tissue-specific', transcription, factors, '(', 'FOXA2,', 'HNF1A,', 'HNF4A', and, 'HNF6)', to, 4, ',', 0, orthologous, gene, pairs, in, hepatocytes, purified, from, human, and, mouse, livers])].
[sujeto(['Despite', the]), verbo([conserved]), complemento([function, of, these, 'factors,', from, 41, '%', to, 89, '%', of, their, binding, events, seem, to, be, species, specific])].
[sujeto(['When', the, same, protein]), verbo([binds]), complemento([the, promoters, of, orthologous, 'genes,', approximately, 'two-thirds', of, the, binding, sites, do, not, align])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factors, '(', 'HNF)', play, a, critical, role, in, development, of, the, liver])].
[sujeto(['This', in, vivo, model]), verbo([has]), complemento([allowed, us, to, investigate, the, fundamental, mechanisms, underlying, 'HCC', progression])].
[sujeto(['A', complete]), verbo([loss]), complemento([of, cell, 'polarity,', a, decrease, in, 'cell-cell', and, 'cell-extracellular', matrix, '(', 'ECM)', 'adhesion,', elevation, of, telomerase, 'activity,', and, extinction, of, 'liver-specific', gene, expression, accompanies, tumor, progression])].
[sujeto(['Forced', 're-expression', of, 'HNF4alpha1', in, cultured, fgHCC, cells, reversed, the, progressive, phenotype, and]), verbo([induced]), complemento([fgHCC, cells, to, 're-establish', an, epithelium, and, reform, 'cell-ECM', contacts])].
[sujeto(['Moreover,', fgHCC, cells, that]), verbo([expressed]), complemento(['HNF4alpha1', also, 're-established', expression, of, the, profile, of, liver, transcription, factors, and, hepatic, genes, that, are, associated, with, a, differentiated, hepatocyte, phenotype])].
[sujeto(['In', 'conclusion,']), verbo([loss]), complemento([of, 'HNF4', expression, is, an, important, determinant, of, 'HCC', progression])].
[sujeto(['Forced', expression, of, this, factor, can]), verbo([promote]), complemento([reversion, of, tumors, toward, a, less, invasive, highly, differentiated, 'slow-growing', phenotype])].
[sujeto(['Down-regulation', of, constitutive, hepatic, cytochrome, 'P450', '(', 'P450)', mRNAs, by, bacterial, endotoxin, '(', 'lipopolysaccharide,', 'LPS)', or, other, inflammatory, stimuli]), verbo([has]), complemento([been, documented, 'extensively,', but, the, contribution, of, transcriptional, suppression, to, this, effect, is, poorly, understood])].
[sujeto(['Injection', of, curcumin, significantly]), verbo([inhibited]), complemento([the, rapid, transcriptional, suppression, of, 'CYP2E1,', and, blocked, that, of, 'CYP3A2'])].
[sujeto(['These', effects, seemed, to, be, independent, of, inhibition, of]), verbo([nuclear]), complemento(['factor-kappaB', '(', 'NF-kappaB)', activation, by, 'curcumin,', because, induction, of, known, 'NF-kappaB-regulated', genes, was, not, attenuated])].
[sujeto(['One', hour, after, 'LPS', 'injection,', the, 'DNA-binding', activities, of, hepatocyte]), verbo([nuclear]), complemento([factor, '(', 'HNF)1alpha,', 'HNF3beta,', and, 'HNF4alpha', were, reduced, to, 73, ',', 72, ',', and, 53, '%', ',', 'respectively,', of, control, values])].
[sujeto(['The']), verbo([nuclear]), complemento([abundances, of, 'Sp1,', 'liver-enriched', transcriptional, inhibitory, protein, '(', 'LIP),', 'HNF1alpha,', and, 'HNF3beta', were, 'unchanged,', whereas, the, abundance, of, 'HNF4alpha', was, reduced, to, 87, '%', of, control, levels])].
[sujeto(['Differentiation', of, hepatocytes, is, reflected, by, their, expression, of, hepatic, functional, proteins, in, the, mouse, 'embryo,', and, 'liver-enriched', transcription, factors, '(', 'LETFs)']), verbo([have]), complemento([been, shown, to, regulate, hepatic, functional, genes, strictly])].
[sujeto(['Previous']), verbo([reports]), complemento([demonstrated, that, the, level, of, 'LETF', expression, is, altered, in, 'HCC', or, preneoplastic, nodules, compared, with, noncancerous, tissues])].
[sujeto(['These', findings]), verbo([suggested]), complemento([that, 'HNF-4', alpha, and, 'HNF-1', alpha, are, useful, markers, to, assess, the, degree, of, 'HCC', 'differentiation,', which, we, suggest, could, be, evaluated, objectively, by, the, quantitative, analysis, of, 'HNFs', and, 'C/EBP', alpha, in, 'HCCs'])].
[sujeto(['Overexpression', of, prothrombin]), verbo([leads]), complemento([to, an, increased, risk, of, venous, thrombosis])].
[sujeto(['The', aim, of, our, study, was, to, localize, the, regions, within, the, prothrombin, enhancer, responsible, for, its, 'activity,', to, identify, the, proteins]), verbo([binding]), complemento([to, these, 'regions,', and, to, establish, their, functional, importance])].
[sujeto(['Putative', transcription, factor, '(', 'TF)']), verbo([binding]), complemento([sites, were, evaluated, by, electrophoretic, mobility, shift, assays])].
[sujeto(['The', functional, importance, of, each, 'TF']), verbo([binding]), complemento([site, was, evaluated, by, site, directed, mutagenesis, and, transient, transfection, of, the, mutant, constructs])].
[sujeto(['Analysis', of, this, region, revealed, putative]), verbo([binding]), complemento([sites, for, hepatocyte, nuclear, factor, 'HNF4,', 'HNF3-beta', and, specificity, 'protein(Sp)1'])].
[sujeto(['We', identified, six, different, 'TFs']), verbo([binding]), complemento([to, three, evolutionary, conserved, sites, in, the, 'enhancer:', 'HNF4-alpha', '(', site, 1, ')', ',', 'HNF1-alpha,', 'HNF3-beta', and, an, as, yet, unidentified, 'TF', '(', site, 2, ')', and, the, ubiquitously, expressed, 'TFs', 'Sp1', and, 'Sp3', '(', site, 3, ')'])].
[sujeto(['Mutagenesis', studies, showed, that]), verbo([loss]), complemento([of, binding, of, 'HNF3-beta', resulted, in, a, considerable, decrease, of, enhancer, 'activity,', whereas, loss, of, 'HNF4-alpha', or, 'Sp1/Sp3', resulted, in, milder, reductions])].
[sujeto(['Six', different, 'TFs', are, able, to]), verbo([bind]), complemento([to, this, region])].
[sujeto(['A', possible, role, of, hepatocyte]), verbo([nuclear]), complemento([factor, 1, '(', 'HNF1)', or, 'HNF3,', a, predominant, 'trans-acting', factors, of, hepatic, or, pancreatic, 'beta-cells,', was, examined, on, the, tissue, specific, interdependent, expression, of, glucokinase, '(', 'GK)', in, 'liver,', 'H4IIE,', 'HepG2,', 'HIT-T15', and, 'MIN6', cell, line])].
[sujeto(['The', tissues, or, cell, lines, known, to]), verbo([express]), complemento(['GK', showed, abundant, levels, of, 'HNF1', and, 'HNF3', mRNA, as, observed, in, 'liver,', 'H4IIE,', 'HepG2,', 'HIT-T15', and, 'MIN6', 'cells,', whereas, they, were, not, detected, in, 'brain,', 'heart,', 'NIH', 3, 'T3,', 'HeLa', cells])].
[sujeto(['The', promoter, of, glucokinase, contains, several, 'HNF3', consensus, sequences, and, are, well]), verbo([conserved]), complemento([in, 'human,', mouse, and, rat])].
[sujeto(['Transfection', of, the, glucokinase, promotor, linked, with, luciferase, reporter, to, liver, or, pancreatic, beta, cell, lines, showed, high]), verbo([interacting]), complemento([activities, with, 'HNF1', and, 'HNF3,', whereas, minimal, activities, were, detected, in, the, cells, expressing, very, low, levels, of, 'HNFs'])].
[sujeto(['The']), verbo([binding]), complemento([of, 'HNF1', or, 'HNF3', to, the, 'GK', promoter, genes, was, confirmed, by, electrophoretic, mobility, shift, assay, '(', 'EMSA)'])].
[sujeto(['During', hepatic, 'proliferation,', expression, of, hepatocyte]), verbo([nuclear]), complemento([factors, '(', 'HNF)1alpha,', 'HNF4,', 'C/EBP', 'alpha,', and, 'C/EBP', beta, mRNAs, was, 'depressed,', whereas, that, of, 'HNF3alpha', and, 'HNF3beta', transcripts, was, enhanced])].
[sujeto(['The', mitoinhibitory, 'agents,', 'IL-1beta,', 'IL-6,', 'TGF-beta,', and, activin, 'A,', were, examined, to, determine, whether, they, could]), verbo([induce]), complemento([differentiation, of, proliferating, hepatocytes, as, shown, in, cells, treated, with, 'DMSO'])].
[sujeto(['Although', these, factors]), verbo([inhibited]), complemento([cell, 'growth,', the, cells, did, not, differentiate])].
[sujeto(['Therefore,', hepatic, differentiation]), verbo([requires]), complemento([not, only, inhibition, of, 'DNA', synthesis, but, also, induction, of, appropriate, transcription, factors])].
[sujeto(['Liver-specific', gene, expression, in, adult, hepatocytes, relies, on, four, families, of, evolutionary]), verbo([conserved]), complemento([transcription, factors, that, are, 'liver-enriched', but, not, restricted, to, this, tissue])].
[sujeto(['These', factors, function, in, unique, 'combinations,', often, 'synergistically,', to]), verbo([stimulate]), complemento(['cell-specific', transcription])].
[sujeto(['Each', family, is, composed, of, several, members, displaying, 'similar,', if, not, 'identical,', 'DNA', recognition, properties, and, sharing, structural, homology, in, their, 'DNA']), verbo([binding]), complemento([domains])].
[sujeto(['The', consequences, of, inactivating, different, family, members, in, the, mouse, by, homologous, 'recombination,', together, with, recent, studies, of, their, 'regulation,']), verbo([suggest]), complemento([a, model, for, liver, differentiation, involving, a, regulatory, network, rather, than, a, completely, hierarchical, genetic, circuitry])].
[sujeto(['We', investigated, transacting, factors]), verbo([binding]), complemento([to, the, 'cis-element', important, in, 'tissue-specific', expression, of, the, human, glucose, transporter, type, 2, isoform, '(', 'GLUT2)', gene])].
[sujeto(['DNase', 'I', footprinting, and, electrophoretic, mobility, shift, assay, indicated, that, site, 'C', contained, one]), verbo([binding]), complemento([site, for, hepatocyte, nuclear, factor, 1, '(', 'HNF1)', and, two, binding, sites, for, 'HNF3'])].
[sujeto(['The', mutations, at, positions, +, 101, and, +, 103, ',', which, are, considered, to, be, critical, in]), verbo([binding]), complemento(['HNF1', and, 'HNF3,', resulted, in, a, 53, '%', decrease, in, promoter, 'activity,', whereas, the, mutation, of, the, proximal, 'HNF3', binding, site, '(', +, 115, and, +, 117, ')', reduced, promoter, activity, by, 28, '%'])].
[sujeto(['The', mutations, of, these, four, sites, resulted, in, marked]), verbo([decrease]), complemento(['(', 70, '%', ')', in, promoter, activity, as, well, as, diminished, bindings, of, 'HNF1', and, 'HNF3'])].
[sujeto(['A', to, 'G', 'mutation,', which]), verbo([causes]), complemento([conversion, of, the, 'HNF1', and, 'HNF3', binding, sequence, to, the, 'NF-Y', binding, 'site,', resulted, in, a, 22, '%', decrease, in, promoter, activity])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'HNF1alpha', and, 'HNF3beta', may, be, the, most, important, players, in, the, 'tissue-specific', expression, of, the, human, 'GLUT2', gene])].
[sujeto(['Within', the, liver, acinus, the, majority, of, genes, are]), verbo([expressed]), complemento([in, an, ascending, or, descending, gradient, from, the, portal, to, the, central, vein])].
[sujeto(['The', regulatory, factors]), verbo([involved]), complemento([in, this, spatial, pattern, of, gene, expression, are, still, poorly, understood])].
[sujeto(['Many', liver, genes, are]), verbo([regulated]), complemento([by, 'liver-enriched', transcription, factors])].
[sujeto(['Here', we]), verbo([report]), complemento([on, mRNA, distribution, of, four, transcription, factors, in, cell, lysates, obtained, from, either, the, periportal, or, the, perivenous, region, after, 'zone-specific', digitonin, infusion, and, by, 'in-situ', hybridization])].
[sujeto(['The', moderate, acinar, zonation, of, the, mRNAs, of, these, transcription, factors]), verbo([suggests]), complemento([that, at, best, they, could, modulate, but, not, govern, the, zonated, expression, of, liver, genes, in, the, mature, liver])].
[sujeto(['alpha-Fetoprotein', '(', 'AFP)', and, transthyretin, '(', 'TTR)', transcripts]), verbo([increased]), complemento([at, the, stage, when, embryoid, bodies, began, to, form, 'yolk-sac-like', structures, and, were, expressed, strongly, thereafter])].
[sujeto(['Expression', of, hepatocyte]), verbo([nuclear]), complemento([factor, '(', 'HNF)', 4, ',', a, variant, form, of, 'HNF1', '(', also, called, 'HNF1beta),', and, 'HNF3beta', started, before, the, onset, of, 'AFP', and, 'TTR', expression])].
[sujeto(['Serum', albumin, '(', 'ALB)', transcript, was, only]), verbo([found]), complemento([in, late, large, cystic, 'EBs'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, patterns, of, endoderm, gene, expression, during, 'EB', development, reflect, the, order, found, during, mouse, development, in, 'vivo,', and, 'EB', formation, may, serve, as, an, in, vitro, system, to, study, the, differentiation, process])].
[sujeto(['Transcription', of, 'hepatocyte-specific', genes]), verbo([requires]), complemento([the, interaction, of, their, regulatory, regions, with, several, nuclear, factors])].
[sujeto(['Among', them, is, the, hepatocyte]), verbo([nuclear]), complemento([factor, 3, '(', 'HNF3)', 'family,', composed, of, the, 'HNF3', 'alpha,', 'HNF3', 'beta,', and, 'HNF3', gamma, 'proteins,', which, are, expressed, in, the, liver, and, have, very, similar, fork, head, 'DNA', binding, domains])].
[sujeto(['The', regulatory, regions, of, numerous, 'hepatocyte-specific', genes, contain, 'HNF3']), verbo([binding]), complemento([sites])].
[sujeto(['Cells', were, stably, transfected, with, a, vector, allowing, the, synthesis, of, an, 'HNF3', beta, fragment, consisting, of, the, fork, head, 'DNA']), verbo([binding]), complemento([domain, without, the, transactivating, 'amino-', and, 'carboxy-terminal', domains])].
[sujeto(['The', truncated, protein, was, located, in, the, nuclei, of, cultured, hepatoma, cells, and, competed, with, endogenous, 'HNF3', proteins, for]), verbo([binding]), complemento([to, cognate, 'DNA', sites])].
[sujeto(['Overproduction', of, this, truncated, 'protein,', lacking, any, transactivating, 'activity,']), verbo([induced]), complemento([a, dramatic, decrease, in, the, expression, of, 'liver-specific', 'genes,', including, those, for, 'albumin,', 'transthyretin,', 'transferrin,', phosphoenolpyruvate, 'carboxykinase,', and, aldolase, 'B,', whereas, the, expression, of, the, 'L-type', pyruvate, kinase, 'gene,', containing, no, 'HNF3', binding, 'sites,', was, unaltered])].
[sujeto(['Thus,', the, transactivating, domains, of, 'HNF3', proteins, are, needed, for, the, proper, expression, of, a, set, of, 'liver-specific', genes, but, not, for, expression, of, the, genes, encoding, transcription, factors]), verbo([found]), complemento([in, differentiated, hepatocytes])].
[sujeto(['The', influence, of, hepatocyte]), verbo([nuclear]), complemento([factor, 3, '(', 'HNF3)', on, the, level, of, transcriptional, activity, from, the, four, hepatitis, 'B', virus, promoters, was, investigated, by, 'transient-transfection', analysis, in, the, dedifferentiated, hepatoma, cell, 'line,', 'HepG2'])].
[sujeto(['It', was]), verbo([found]), complemento([that, the, large, surface, antigen, promoter, 'and,', to, a, much, lesser, 'extent,', the, nucleocapsid, promoter, were, transactivated, in, the, presence, of, 'HNF3'])].
[sujeto(['The', complex, formed, with, 'Huh7', cell, extract, comigrated, with, exogenously]), verbo([expressed]), complemento(['HNF3', beta, in, 'HeLa', 'S3', extracts, and, was, specifically, inhibited, from, forming, by, the, addition, of, 'HNF3', beta, antiserum])].
[sujeto(['The', promoter, element, which, appears, to]), verbo([mediate]), complemento([the, 'HNF3', transactivation, was, functionally, mapped, by, mutational, analysis, to, a, region, between, nucleotides, -, 65, and, -, 54, relative, to, the, transcriptional, start, site])].
[sujeto(['A', synthetic, promoter, construct, containing, this, 'HNF3-binding', site, was, able, to]), verbo([mediate]), complemento([transactivation, by, 'HNF3', beta])].
[sujeto(['These', and, previous, results]), verbo([suggest]), complemento([that, the, hepatitis, 'B', virus, large, surface, antigen, promoter, is, regulated, by, at, least, two, 'liver-enriched', transcription, 'factors,', 'HNF1', and, 'HNF3,', which, together, may, contribute, to, the, differentiated, liver, cell, type, specificity, of, this, promoter])].
[sujeto(['The', transthyretin, '(', 'TTR)', gene, is]), verbo([regulated]), complemento([by, two, 'DNA', regions, which, elicit, 'hepatocyte-specific', 'expression:', a, proximal, promoter, and, distal, enhancer])].
[sujeto(['The', 'TTR', promoter, and, enhancer, are, composed, of, at, least, eight, 'DNA']), verbo([binding]), complemento([sites, for, three, different, hepatocyte, nuclear, factors, '(', 'HNF),', 'CCAAT/enhancer', binding, protein, '(', 'C/EBP),', and, 'AP-1/cJun'])].
[sujeto(['Site', directed, mutations, within, each, of, the, 'HNF']), verbo([binding]), complemento([sites, in, the, 'TTR', promoter, were, introduced, to, evaluate, their, contribution, to, transcriptional, activity, in, hepatoma, cells])].
[sujeto(['The', data, indicate, that, the, strong, affinity, 'HNF-3-S']), verbo([binding]), complemento([site, '(', -, 106, to, -, 94, ')', is, absolutely, required, for, 'TTR', promoter, activity, since, several, mutations, in, this, site, eliminate, 'TTR', expression, in, the, context, of, its, enhancer])].
[sujeto(['In', 'contrast,', when, we, deleted, the, 'TTR', enhancer, from, these, 'HNF', mutant, 'constructs,', 'TTR', expression]), verbo([decreased]), complemento([to, undetectable, levels])].
[sujeto(['This', result]), verbo([suggests]), complemento([cooperation, between, the, factors, binding, to, the, 'TTR', promoter, and, enhancer, regions])].
[sujeto(['These', results, also, demonstrate, that, the, 'HNF3-S', site, alone, is, not, sufficient, to]), verbo([activate]), complemento(['TTR', 'transcription,', but, rather, requires, the, participation, of, three, 'cell-specific', factors, to, elicit, minimal, promoter, activity])].
[sujeto(['To', investigate, the, regulation, of, genes, whose, expression, is, enriched, in, liver, we, studied, expression, of, the, albumin, and, transthyretin, '(', 'TTR)', genes, in, a, series, of, rat, hepatoma, cell, lines, '(', 'FaO,', 'C2,', 'C2rev7,', and, 'H5)', that]), verbo([express]), complemento([these, genes, at, different, rates])].
[sujeto(['The', level, of, expression, of, albumin, and, 'TTR', was, compared, to, the, expression, and, 'DNA-binding', activity, of, four, transcription, 'factors,', 'HNF1/LFB1,', 'C/EBP,', 'HNF3,', and, 'HNF4,', that, are]), verbo([found]), complemento([at, high, concentrations, in, liver])].
[sujeto(['The', hepatocyte]), verbo([nuclear]), complemento(['factors,', 'Hnf1a', and, 'Hnf4a,', in, addition, to, playing, key, roles, in, determining, hepatocyte, 'fate,', have, been, implicated, as, candidate, 'lineage-determining', transcription, factors, in, the, kidney, proximal, tubule, '(', 'PT)', '[', 'Martovetsky', et])].
[sujeto(['Mouse', embryonic, fibroblasts, '(', 'MEFs)', transduced, with, 'Hnf1a', and, 'Hnf4a', form, tight, junctions, and]), verbo([express]), complemento([multiple, 'PT', drug, transporters, '(', e])].
[sujeto(['In', 'contrast,', the, coexpression, '(', with, 'Hnf1a', and, 'Hnf4a)', of, 'GATA']), verbo([binding]), complemento([protein, 4, '(', 'Gata4),', as, well, as, the, forkhead, box, transcription, 'factors,', 'Foxa2', and, 'Foxa3,', in, 'MEFs', not, only, downregulates, 'PT', markers, but, also, leads, to, upregulation, of, several, hepatocyte, 'markers,', including, 'albumin,', 'apolipoprotein,', and, transferrin])].
[sujeto(['Thus,', the, presence, of, 'Gata4', and, 'Foxa2/Foxa3', appears, to, alter, the, effect, of, 'Hnf1a', and, 'Hnf4a', by, an, 'as-yet', unidentified, 'mechanism,']), verbo([leading]), complemento([toward, the, generation, of, more, 'hepatocyte-like', cells, as, opposed, to, cells, exhibiting, 'PT', characteristics])].
[sujeto(['These', findings]), verbo([provide]), complemento([valuable, 'insight,', not, only, into, the, 'developmental,', and, perhaps, 'organotypic,', regulation, of, drug, 'transporters,', 'drug-metabolizing', 'enzymes,', and, tight, 'junctions,', but, also, for, regenerative, medicine, strategies, aimed, at, restoring, the, function, of, the, liver, 'and/or', kidney, '(', acute, kidney, 'injury,', 'AKI;', chronic, kidney, 'disease,', 'CKD)'])].
[sujeto(['To', investigate, the, molecular, mechanism, for, their, 'diversities,', we, test, the, hypothesis, that, large, and, small, 'BEC']), verbo([have]), complemento([disparity, in, their, target, gene, response, to, their, transcriptional, 'regulator,', the, biliary, 'cell-enriched', hepatocyte, nuclear, factor, 'HNF6'])].
[sujeto(['The', expression, of, the, major, 'HNF', '(', 'HNF6,', 'OC2,', 'HNF1b,', 'HNF1a,', 'HNF4a,', 'C/EBPb,', and, 'Foxa2)', and, representative, biliary, transport]), verbo([target]), complemento([genes, that, are, 'HNF', dependent, were, compared, between, 'SV40-transformed', 'BEC', derived, from, large, '(', 'SV40LG)', and, small, '(', 'SV40SM)', 'ducts,', before, and, after, treatment, with, recombinant, adenoviral, vectors, expressing, 'HNF6', '(', 'AdHNF6)', or, control, 'LacZ', cDNA, '(', 'AdLacZ)'])].
[sujeto(['Large', and, small, 'BEC', were, isolated, from, mouse, liver, treated, with, growth, 'hormone,', a, known, transcriptional, activator, of, 'HNF6,', and, the, effects, on, selected]), verbo([target]), complemento([genes, were, examined])].
[sujeto(['This', was]), verbo([associated]), complemento([with, 2.7, -, and, 4, -, fold, higher, baseline, expression, of, 'HNF1a-', and, 'HNF4a-regulated', ntcp, and, oatp1, 'genes,', respectively])].
[sujeto(['The', net, effects, were, upregulation, of, 'HNF6']), verbo([target]), complemento([gene, glucokinase, and, of, 'Foxa2,', 'HNF1a,', and, 'HNF4a', target, genes, 'oatp1,', 'ntcp,', and, mrp2, over, 'AdLacZ', control, in, both, 'cells,', but, with, higher, levels, in, 'AdH6-SV40SM', over, 'AdH6-SV40LG', of, 'glucokinase,', 'oatp1,', 'ntcp,', and, mrp2, '(', by, 1.8, -, ',', 3.4, -, ',', 2.4, -, ',', and, 2.5, -, 'fold,', 'respectively)'])].
[sujeto(['In', 'vivo,', growth, 'hormone-mediated']), verbo([increase]), complemento([in, 'HNF6', expression, was, associated, with, similar, higher, upregulation, of, glucokinase, and, mrp2, in, cholangiocytes, from, small, vs])].
[sujeto(['Small', and, large, 'BEC']), verbo([have]), complemento([a, distinct, profile, of, hepatocyte, transcription, factor, and, cognate, target, gene, 'expression,', as, well, as, differential, strength, of, response, to, transcriptional, 'regulation,', thus, providing, a, potential, molecular, basis, for, their, divergent, function])].
[sujeto(['We', developed, a, method, for, estimating, the, positional, distribution, of, transcription, factor, '(', 'TF)']), verbo([binding]), complemento([sites, using, 'ChIP-chip', 'data,', and, applied, it, to, recently, published, experiments, on, binding, sites, of, nine, 'TFs:', 'OCT4,', 'SOX2,', 'NANOG,', 'HNF1A,', 'HNF4A,', 'HNF6,', 'FOXA2,', 'USF1', and, 'CREB1'])].
[sujeto(['The', number, of]), verbo([target]), complemento([genes, of, each, 'TF', ranges, from, few, hundred, to, several, thousand])].
[sujeto(['We']), verbo([found]), complemento([that, for, each, of, the, nine, 'TFs', the, estimated, binding, site, distribution, is, closely, approximated, by, a, mixture, of, two, 'components:', a, narrow, 'peak,', localized, within, 300, -, bp, upstream, of, the, 'TSS,', and, a, distribution, of, almost, uniform, density, within, the, tested, region])].
[sujeto(['Using', 'Gene', 'Ontology', '(', 'GO)', and, 'Enrichment', 'analysis,', we, were, able, to]), verbo([associate]), complemento(['(', for, each, of, the, 'TFs', 'studied)', the, target, genes, of, both, types, of, binding, with, known, biological, processes])].
[sujeto(['Most', 'GO', terms, were, enriched, either, among, the, proximal]), verbo([targets]), complemento([or, among, those, with, a, uniform, distribution, of, binding, sites])].
[sujeto(['For', 'example,', the, three, 'stemness-related', 'TFs']), verbo([have]), complemento([several, hundred, target, genes, that, belong, to, '\'', 'development\'', and, '\'', 'morphogenesis\'', whose, binding, sites, belong, to, the, uniform, distribution])].
[sujeto(['\'', 'Credible', 'sets\'', of, the, variants, most, likely, to, drive, each, distinct, signal, mapped, predominantly, to, noncoding, 'sequence,', implying, that, association, with, 'T2D', is]), verbo([mediated]), complemento([through, gene, regulation])].
[sujeto(['Credible', set, variants, were, enriched, for, overlap, with, 'FOXA2', chromatin, immunoprecipitation]), verbo([binding]), complemento([sites, in, human, islet, and, liver, 'cells,', including, at, 'MTNR1B,', where, fine, mapping, implicated, rs10830963, as, driving, 'T2D', association])].
[sujeto(['We', confirmed, that, the, 'T2D', risk, allele, for, this, 'SNP']), verbo([increases]), complemento(['FOXA2-bound', enhancer, activity, in, 'islet-', and, 'liver-derived', cells])].
[sujeto(['We', observed, 'allele-specific', differences, in, 'NEUROD1']), verbo([binding]), complemento([in, 'islet-derived', 'cells,', consistent, with, evidence, that, the, 'T2D', risk, allele, increases, islet, 'MTNR1B', expression])].
[sujeto(['MicroRNAs', are, a, class, of, negative, regulators, of, gene, 'expression,', which]), verbo([have]), complemento([been, shown, to, be, involved, in, the, development, of, endocrine, pancreas, and, in, the, regulation, of, insulin, secretion])].
[sujeto(['Since', type, 2, diabetes, '(', 'T2D)', is, characterized, by, beta, cell, 'dysfunction,', we, aimed, at, evaluating, expression, levels, of, 'miR-124a', and, 'miR-375,', both]), verbo([involved]), complemento([in, the, control, of, beta, cell, 'function,', in, human, pancreatic, islets, obtained, from, 'T2D', and, from, 'age-matched', 'non-diabetic', organ, donors])].
[sujeto(['In', 'addition,', 'miR-124a', silencing, in, 'MIN6', pseudoislets, resulted, in]), verbo([increased]), complemento([expression, of, predicted, target, genes, '(', 'Mtpn,', 'Foxa2,', 'Flot2,', 'Akt3,', 'Sirt1', and, 'NeuroD1)', involved, in, beta, cell, function])].
[sujeto(['For', 'Mtpn', and, 'Foxa2,', we, further, demonstrated, the, actual]), verbo([binding]), complemento([of, 'miR-124a', to, their, 3, 'UTR', sequences, by, luciferase, assay])].
[sujeto(['We', uncovered, a, major, hyperexpression, of, 'miR-124a', in, 'T2D', 'islets,', whose, silencing, resulted, in]), verbo([increased]), complemento([expression, of, target, genes, of, major, importance, for, beta, cell, function, and, whose, overexpression, impaired, 'glucose-stimulated', insulin, 'secretion,', leading, to, the, hypothesis, that, an, altered, 'miR-124a', expression, may, contribute, to, beta, cell, dysfunction, in, type, 2, diabetes])].
[sujeto(['Many', of, the, type, 2, diabetes, loci, identified, through, 'genome-wide', association, studies, localize, to, 'non-protein-coding', intronic, and, intergenic, regions, and, likely, contain, variants, that]), verbo([regulate]), complemento([gene, transcription])].
[sujeto(['To']), verbo([gain]), complemento([insight, into, the, molecular, mechanisms, underlying, the, association, 'signal,', we, used, open, 'chromatin,', histone, modifications, and, transcription, factor, 'ChIP-seq', data, sets, from, type, 2, 'diabetes-relevant', cell, types, to, identify, 'SNPs', overlapping, predicted, regulatory, regions])].
[sujeto(['Using', electromobility, shift, and, supershift, assays, we, demonstrated, that, the, rs11257655, risk, allele, showed, 'allele-specific']), verbo([binding]), complemento([to, 'FOXA1', and, 'FOXA2'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, rs11257655, affects, transcriptional, activity, through, altered, binding, of, a, protein, complex, that, includes, 'FOXA1', and, 'FOXA2,', providing, a, potential, molecular, mechanism, at, this, 'GWAS', locus])].
[sujeto(['MicroRNAs', '(', 'miRNAs)']), verbo([have]), complemento([emerged, as, biomarkers, of, metabolic, 'status,', etiological, factors, in, complex, 'disease,', and, promising, drug, targets])].
[sujeto(['Recent']), verbo([reports]), complemento([suggest, that, miRNAs, are, critical, regulators, of, pathways, underlying, the, pathophysiology, of, type, 2, diabetes])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'miR-29', is, an, important, regulatory, factor, in, normal, metabolism, and, may, represent, a, novel, therapeutic, target, in, type, 2, diabetes, and, related, metabolic, syndromes])].
[sujeto(['In', order, to, explore, how, common, genetic, variants]), verbo([associated]), complemento([with, 'T2D', correlate, with, body, mass, index, '(', 'BMI),', we, examined, the, influence, of, 25, 'T2D', associated, loci, on, obesity, risk])].
[sujeto(['We', used, 5056, individuals, '(', 2528, 'sib-pairs)']), verbo([recruited]), complemento([in, 'Indian', 'Migration', 'Study', and, conducted, within, 'sib-pair', analysis, for, six, obesity, phenotypes])].
[sujeto(['We']), verbo([found]), complemento([associations, of, variants, in, 'CXCR4', '(', 'rs932206)', and, 'HHEX', '(', 'rs5015480)', with, higher, body, mass, index, '(', 'BMI)', '(', 'β=0'])].
[sujeto(['CXCR4', variant, was, also, strongly]), verbo([associated]), complemento([with, body, fat, '(', 'β=0'])].
[sujeto(['In', 'summary,', we, establish, the, role, of, 'T2D']), verbo([associated]), complemento([loci, in, influencing, the, measures, of, obesity, in, 'Indian', 'population,', suggesting, common, underlying, pathophysiology, across, populations])].
[sujeto(['Dietary', 'Se', deficiency]), verbo([decreased]), complemento(['(', 'P', &, 'lt;', 0.05, ')', 'OE', islet, mRNA, levels, of, 2, key, transcriptional, activators, '(', 'Beta2', and, 'Foxa2)', and, removed, genotype, differences, in, islet, mRNA, levels, of, 7, genes, '(', 'Beta2,', 'Cfos,', 'Foxa2,', 'Pregluc,', 'Ins1,', 'p53,', and, 'Sur1)', related, to, insulin, synthesis, and, secretion])].
[sujeto(['Dietary', 'Se', deficiency, also]), verbo([decreased]), complemento(['(', 'P', &, 'lt;', 0.05, ')', blood, glucose, and, hepatic, lipid, concentrations, in, the, 'WT', mice])].
[sujeto(['This', alleviation, resulted, from]), verbo([modulating]), complemento([the, expression, 'and/or', function, of, proinsulin, 'genes,', lipogenesis, 'rate-limiting', enzyme, 'genes,', and, key, glycolysis, and, gluconeogenesis, enzymes, in, 'islets,', 'liver,', and, muscle])].
[sujeto(['Variations', within, the, 'FOXA', family]), verbo([have]), complemento([been, studied, for, a, putative, contribution, to, the, risk, of, type, 2, diabetes, '(', 'T2D),', and, recently, the, minor, 'T-allele', of, 'FOXA2', rs1209523, was, reported, to, associate, with, decreased, fasting, plasma, glucose, levels, in, a, study, using, a, weighted, false, discovery, rate, control, procedure, to, enhance, the, statistical, power, of, genome, wide, association, studies, in, detecting, associations, between, 'low-frequency', variants, and, a, given, trait])].
[sujeto(['Thus,', the, primary, aim, of, this, study, was, to, investigate, whether, the, minor, 'T-allele', of, rs1205923, in, 'FOXA2']), verbo([associated]), complemento([with, 1, ')', decreased, fasting, plasma, glucose, and, 2, ')', a, lower, risk, of, developing, 'T2D'])].
[sujeto(['Secondly,', we, investigated, whether, rs1205923, in, 'FOXA2']), verbo([associated]), complemento([with, other, 'glucose-related', phenotypes])].
[sujeto(['We', examined, for, associations, of, the, 'FOXA2', genotype, with, fasting, plasma, glucose, and, estimates, of, insulin]), verbo([release]), complemento([and, insulin, sensitivity, following, an, oral, glucose, tolerance, test, in, 6, ',', 162, 'Danish', individuals, from, the, 'population-based', 'Inter99', study, while, association, with, 'T2D', risk, was, assessed, in, 10, ',', 196, 'Danish', individuals, including, four, different, study, populations])].
[sujeto(['The', 'FOXA2', rs1209523, was, not]), verbo([associated]), complemento([with, fasting, plasma, glucose, '(', effect, size, '(', 'β)', =, -, 0.03, 'mmol/l', '(', 95, '%', 'CI:', -, 0.07, ;, 0.01, ')', ',', p, =, 0.2, ')', in, 'glucose-tolerant', individuals, from, the, general, 'Danish', population])].
[sujeto(['Also,', several, indices, of, insulin]), verbo([release]), complemento([and, 'β-cell', function, were, associated, with, the, minor, 'T-allele', of, 'FOXA2', rs1209523, in, 'non-obese', individuals])].
[sujeto(['Insulin', secretion, by, the, pancreatic, beta, cell, is, critical, to]), verbo([maintain]), complemento([glucose, homeostasis])].
[sujeto(['During', the, last, few, 'years,', several, beta, 'cell-specific', transcription, factors, that]), verbo([regulate]), complemento([insulin, synthesis, and, secretion, in, response, to, glucose, have, been, discovered])].
[sujeto(['These', factors, are]), verbo([regulated]), complemento([not, only, in, their, expression, by, other, 'genes,', but, also, in, their, activity, by, other, proteins, and, by, 'post-translational', 'modifications,', therefore, participating, in, physiologically, important, signaling, pathways, of, the, beta, cell])].
[sujeto(['We']), verbo([found]), complemento([a, strong, association, of, '(', 'TCC)(', n, ')', common, allele, 'A5', with, type, 2, diabetes, '[', 'OR', =, 1.66, '(', 95, '%', 'CI', 1.36, -, 2.04, ',', p, =, 5.9, x, 10, '(', -, 7, ')', ')', for, 'A5', 'homozygotes]'])].
[sujeto(['Obese', individuals, with, 'A5A5', genotype, had]), verbo([enhanced]), complemento([risk, when, segregated, from, 'normal-weight', subjects, '[', 'OR', =, 1.92, '(', 95, '%', 'CI', 1.47, -, 2.51, ')', ',', p, =, 1.6, x, 10, '(', -, 6, ')', ']'])].
[sujeto(['A5', was, also, nominally]), verbo([associated]), complemento([with, higher, fasting, glucose, '(', p, =, 0.02, ')', and, lower, fasting, insulin, '(', p, =, 0.0028, ')', and, 'C-peptide', '(', p, =, 0.036, ')', levels, among, controls])].
[sujeto(['At', the, rs1055080, 'locus,', 'GG', was]), verbo([found]), complemento([to, provide, reduced, risk, among, 'normal-weight', subjects, '[', 'OR', =, 0.59, '(', 95, '%', 'CI', 0.4, -, 0.88, ')', ',', p, =, 0.011, ']'])].
[sujeto(['For', the, first, time, we, demonstrated, that, 'FOXA2', variants, may, affect, risk, of, type, 2, diabetes, and, metabolic, traits, in, 'North', 'India,', however, replication, analyses, in, other, cohorts, are]), verbo([required]), complemento([to, confirm, the, findings])].
[sujeto(['We', demonstrated, that, 'long-term', treatment, with, 'ISV', improves, glucose, 'homeostasis,']), verbo([increases]), complemento([insulin, 'sensitivity,', lowers, plasma, triglycerides, and, lowers, weight, in, the, diabetic, 'KKAy', mice])].
[sujeto(['We']), verbo([have]), complemento([now, generated, mice, that, lack, the, lambda, isoform, of, 'PKC', in, pancreatic, beta, cells, '(', 'betaPKClambda(-/-)', 'mice)', and, show, that, these, animals, manifest, impaired, glucose, tolerance, and, hypoinsulinemia])].
[sujeto(['Furthermore,', insulin, secretion, in, response, to, high, concentrations, of, glucose, was, 'impaired,', whereas, the, basal, rate, of, insulin]), verbo([release]), complemento([was, 'increased,', in, islets, isolated, from, 'betaPKClambda(-/-)', mice])].
[sujeto(['The', abundance, of, mRNAs, for, 'Glut2', and, 'HNF3beta', was, reduced, in, islets, of, 'betaPKClambda(-/-)', 'mice,', and, the, expression, of, genes]), verbo([regulated]), complemento([by, 'HNF3beta', was, also, affected, '(', that, of, 'Sur1', and, 'Kir6'])].
[sujeto(['These', results, indicate, that, 'PKClambda', plays, a, prominent, role, in, regulation, of, 'glucose-induced', insulin, secretion, by]), verbo([modulating]), complemento([the, expression, of, genes, important, for, beta, cell, function])].
[sujeto(['Liver', is, a, vital, organ, and]), verbo([retains]), complemento([its, regeneration, capability, throughout, 'adulthood,', which, requires, contributions, from, different, cell, 'populations,', including, liver, precursors, and, intrahepatic, stem, cells])].
[sujeto(['Using', retroviral, system, to, stably]), verbo([express]), complemento(['SV40', 'T', antigen, flanked, with, 'Cre/LoxP', 'sites,', we, establish, a, repertoire, of, iHP, clones, with, varied, differentiation, potential])].
[sujeto(['The', iHP, cells]), verbo([maintain]), complemento(['long-term', proliferative, activity, and, express, varied, levels, of, progenitor, markers, '(', 'Pou5f1/Oct4', and, 'Dlk)', and, hepatocyte, markers, '(', 'AFP,', 'Alb', and, 'ApoB)'])].
[sujeto(['Five', representative, iHP, clones]), verbo([express]), complemento(['hepatic/pancreatic', transcription, factors, 'HNF3α/Foxa1,', 'HNF3β/Foxa2,', and, 'HNF4α/MODY1'])].
[sujeto(['Dexamethasone', is, shown, to]), verbo([promote]), complemento([the, expression, of, hepatocyte, markers, 'AFP', and, 'TAT,', along, with, 'ICG-uptake', and, glycogen, storage, functions, in, the, iHP, clones])].
[sujeto(['Molecular', defects, of, the, genes, for, transcription, 'factors,', hepatocyte]), verbo([nuclear]), complemento([factor, '(', 'HNF)-4', 'alpha,', 'HNF-1', 'alpha,', 'HNF-1', beta, and, insulin, promoter, 'factor-1', cause, 'maturity-onset', diabetes, of, the, young, '(', 'MODY1,', 3, ',', 5, ',', and, 4, ',', 'respectively)'])].
[sujeto(['This']), verbo([suggests]), complemento([the, 'HNF-related', transcription, cascade, is, important, in, insulin, secretion, which, is, induced, by, glucose])].
[sujeto(['When', these, 'EBs', are, treated, with, 'tamoxifen,', the, 'Oct4']), verbo([expressing]), complemento([cells, switch, from, a, red, to, a, green, fluorescence, 'color,', and, this, is, maintained, thereafter, by, all, their, progeny])].
[sujeto(['Markers', of, the, early, body, 'axis,', 'Brachyury', '(', 'BRA)', and, 'FOXA2,', usually, showed, a, concentration, of, positive, cells, in, one, region, of, the, 'EB,', but, the, morphology, is, not, predictable, and, there, are, also, scattered, cells]), verbo([expressing]), complemento([these, markers])].
[sujeto(['BRA,', which, marks, the, early, 'mesoderm,', node, and, 'notochord,', arises, in, 'Oct4']), verbo([expressing]), complemento([cells, on, days, 3, -, 4])].
[sujeto(['FOXA2,', which, marks, the, floor, plate, of, the, neural, tube, and, definitive, 'endoderm,', as, well, as, the, node, and, 'notochord,', arises, at, the, same, time, but, mostly, in, cells, that]), verbo([have]), complemento([already, lost, 'Oct4', expression])].
[sujeto(['The']), verbo([nuclear]), complemento([hormone, receptors, hepatocyte, nuclear, factor, 4, '(', 'HNF4)', and, the, retinoid, 'X', alpha, '(', 'RXRalpha)', plus, the, peroxisome, 'proliferator-activated', receptor, alpha, '(', 'PPARalpha)', heterodimer, support, hepatitis, 'B', virus, '(', 'HBV)', replication, in, nonhepatoma, cells])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 3, '(', 'HNF3)', inhibits, nuclear, hormone, 'receptor-mediated', viral, replication])].
[sujeto(['Inhibition', of, 'HBV', replication, by, 'HNF3beta', is]), verbo([associated]), complemento([with, the, preferential, reduction, in, the, level, of, the, pregenomic, 'RNA', compared, with, that, of, precore, 'RNA'])].
[sujeto(['Hepatitis', 'B', e, antigen, '(', 'HBeAg),', encoded, by, the, precore, 'RNA,']), verbo([mediates]), complemento([part, of, the, inhibition, of, viral, replication, by, 'HNF3beta'])].
[sujeto(['Therefore,', transcriptional, interference]), verbo([mediated]), complemento([by, 'HNF3', may, also, regulate, 'HBV', 'RNA', synthesis, and, viral, replication])].
[sujeto(['The', transcription, factors, of, the, hepatocyte]), verbo([nuclear]), complemento([factor, 3, '(', 'HNF3)', 'family,', which, are, active, in, the, 'liver,', are, expressed, early, during, endoderm, differentiation])].
[sujeto(['Overexpression', of, 'HNF3beta', '(', and, to, a, lesser, extent, of, 'HNF3alpha)']), verbo([induced]), complemento([the, expression, of, genes, associated, with, endodermal, 'lineage,', 'namely,', the, genes, for, 'CFTR', and, 'albumin,', but, did, not, induce, the, expression, of, genes, involved, in, late, endoderm, 'differentiation,', such, as, the, genes, for, 'PEPCK', and, 'alpha1-antitrypsin'])].
[sujeto(['Moreover,', expression, of, 'HNF1beta', was, highly]), verbo([induced]), complemento([in, 'HNF3-overexpressing', 'cells,', while, expression, of, 'HNF1alpha', and, 'HNF4', was, only, mildly, induced, in, these, cells])].
[sujeto(['Therefore,', 'HNF3alpha', and, -, beta, seem, to, be]), verbo([involved]), complemento([in, early, endoderm, differentiation, of, 'ES', cells, and, together, with, other, developmental, factors, are, apparently, needed, for, the, induction, of, the, endodermal, lineage, in, vivo])].
[sujeto(['The', 'tissue-specific', transcription, factors, of, the, hepatocyte]), verbo([nuclear]), complemento(['factor-4', '(', 'HNF4),', hepatocyte, nuclear, 'factor-3', '(', 'HNF3),', and, liver, factor, 'B1', '(', 'LFB1)', families, are, thought, to, play, a, role, in, the, development, of, internal, organs, and, in, the, 'tissue-specific', expression, of, many, distinct, genes])].
[sujeto(['We']), verbo([have]), complemento([now, constructed, derivatives, of, these, proteins, by, introducing, the, 'hormone-binding', domain, of, the, estrogen, receptor, and, show, that, in, transient, transfections, these, chimeric, proteins, act, as, 'estrogen-inducible', transcription, factors, with, the, 'DNA', sequence, specificity, of, the, original, factors])].
[sujeto(['These', chimeric, transcription, factors, are, differently, affected, by, the, partial, estrogen, antagonist, 4, -, hydroxytamoxifen, and, the, pure, antiestrogen, 'N-n-butyl-11-(3,17-dihydroxy-estra-1,3,5(10)-trien-', 7, 'alpha-yl)N-methyl-undecamide', '(', 'ICI', 164384, ')', ;, 4, -, hydroxytamoxifen, 'activates,', at, least, 'partially,', all, the, chimeric, factors, and, the, estrogen, 'receptor,', while, 'ICI', 164384, surprisingly]), verbo([activates]), complemento([the, transcription, factors, derived, from, 'HNF3', and, 'LFB1', and, inhibits, only, the, estrogen, receptor, and, the, 'HNF4', derivative])].
[sujeto(['Recent', work]), verbo([has]), complemento([shown, that, overexpression, of, 'lineage-specific', transcription, factors, can, directly, cause, cells, phenotypic, 'changes,', including, 'differentiation,', 'trans-differentiation,', and, 'de-differentiation'])].
[sujeto(['We', hypothesized, that, 'lentivirus-mediated', constitutive, expression, of, forkhead, box, 'A2', '(', 'Foxa2)', and, hepatocyte]), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'Hnf4a)', could, promote, inducing, mouse, 'ESCs', to, 'hepatocyte-likes', cells])].
[sujeto(['First,', 'ESC', lines, that, stably]), verbo([expressed]), complemento(['Foxa2,', 'Hnf4a,', or, 'Foxa2/Hnf4a', were, constructed, via, lentiviral, expression, vectors])].
[sujeto(['However,', with, some, assistance, from]), verbo([inducing]), complemento(['factors,', 'Foxa2', significantly, increased, the, hepatic, differentiation, of, 'ESCs,', whereas, the, expression, of, 'Hnf4a', alone, or, 'Foxa2/Hnf4a', could, not])].
[sujeto(['Differentiated', 'CCE-Foxa2', cells, were, more, superior, in]), verbo([expressing]), complemento([several, 'liver-specific', markers, and, 'protein,', storing, glycogen, than, differentiated, 'CCE', cells])].
[sujeto(['Here,', we]), verbo([found]), complemento([that, 'FOXA', members, are, directly, and, indirectly, involved, in, 'HBV', replication, in, human, hepatic, cells])].
[sujeto(['In', 'addition,', 'FOXA1', and, 'FOXA2']), verbo([suppressed]), complemento([nuclear, hormone, 'receptors,', such, as, 'HNF4α,', that, are, related, to, 'HBV', replication])].
[sujeto(['However,', it, remains, unclear, how, 'lineage-specifying', transcription, 'factors,', which, are, often]), verbo([expressed]), complemento([in, both, progenitor, and, mature, cell, 'populations,', influence, cell, differentiation])].
[sujeto(['Using', in, vivo, mouse, liver, development, as, a, 'model,', we, identified, thousands, of, enhancers, that, are]), verbo([bound]), complemento([by, the, master, regulators, 'HNF4A', and, 'FOXA2', in, a, 'differentiation-dependent', 'manner,', subject, to, chromatin, 'remodeling,', and, associated, with, differentially, expressed, target, genes])].
[sujeto(['Enhancers', exclusively, occupied, in, the, embryo, were]), verbo([found]), complemento([to, be, responsive, to, developmentally, regulated, 'TEAD2', and, coactivator, 'YAP1'])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, 'Hippo', signaling, may, affect, hepatocyte, differentiation, by, influencing, 'HNF4A', and, 'FOXA2', interactions, with, temporal, enhancers])].
[sujeto(['Here,', we, develop, two, novel, strategies, to, combine, epigenomic, data, with, transcriptomic, profiles, in, humans, or, mice, to, prioritize, potential, candidate, 'SNPs']), verbo([associated]), complemento([with, lipid, levels, by, 'genome-wide', association, study, '(', 'GWAS)'])].
[sujeto(['This', method]), verbo([recognized]), complemento([the, known, 'SORT1', rs12740374, regulatory, 'SNP', associated, with, 'LDL-cholesterol,', and, highlighted, candidate, functional, 'SNPs', at, 15, additional, lipid, loci])].
[sujeto(['This', approach, identified, 'SNPs', in, specific, transcription, factor]), verbo([binding]), complemento([sites, that, are, located, near, target, genes, of, these, transcription, factors])].
[sujeto(['We', show, that, 'FOXA2', transcription, factor]), verbo([binding]), complemento([sites, are, enriched, at, 'lipid-associated', loci, and, experimentally, validate, that, alleles, of, one, such, proxy, 'SNP', located, near, the, 'FOXA2', target, gene, 'BIRC5', show, allelic, differences, in, 'FOXA2-DNA', binding, and, enhancer, activity])].
[sujeto(['These', methods, can, be, used, to, generate, testable, hypotheses, for, many, 'non-coding', 'SNPs']), verbo([associated]), complemento([with, complex, diseases, or, traits])].
[sujeto(['Here', we, use, conditional, murine, genetics, to, determine, how, the, identity, of, lung, epithelial, cells, changes, upon]), verbo([loss]), complemento([of, their, master, 'cell-fate', regulator])].
[sujeto(['Nkx2-1', deletion, in, normal, and, neoplastic, lungs]), verbo([causes]), complemento([not, only, loss, of, pulmonary, identity, but, also, conversion, to, a, gastric, lineage])].
[sujeto(['Nkx2-1', is, likely, to]), verbo([maintain]), complemento([pulmonary, identity, by, recruiting, transcription, factors, 'Foxa1', and, 'Foxa2', to, 'lung-specific', 'loci,', thus, preventing, them, from, binding, gastrointestinal, targets])].
[sujeto(['Nkx2-1-negative', murine, lung, tumors, mimic, mucinous, human, lung, 'adenocarcinomas,', which]), verbo([express]), complemento([gastric, markers])].
[sujeto(['Loss', of, the, gastrointestinal, transcription, factor, 'Hnf4α']), verbo([leads]), complemento([to, derepression, of, the, embryonal, 'proto-oncogene', 'Hmga2', in, 'Nkx2-1-negative', tumors])].
[sujeto(['These', observations]), verbo([suggest]), complemento([that, loss, of, both, active, and, latent, differentiation, programs, is, required, for, tumors, to, reach, a, 'primitive,', poorly, differentiated, state])].
[sujeto(['One', mechanism, by, which, 'TCF7L2', could, influence, expression, of, genes]), verbo([involved]), complemento([in, diverse, diseases, is, by, binding, to, distinct, regulatory, regions, in, different, tissues])].
[sujeto(['We', identified, 116, ',', 0, 'non-redundant', 'TCF7L2']), verbo([binding]), complemento(['sites,', with, only, 1, ',', 864, sites, common, to, the, six, cell, lines])].
[sujeto(['Using', 'ChIP-seq,', we, showed, that, many, genomic, regions, that, are, marked, by, both, 'H3K4me1', and, 'H3K27Ac', are, also]), verbo([bound]), complemento([by, 'TCF7L2,', suggesting, that, 'TCF7L2', plays, a, critical, role, in, enhancer, activity])].
[sujeto(['Bioinformatic', analysis, of, the, cell, 'type-specific', 'TCF7L2']), verbo([binding]), complemento([sites, revealed, enrichment, for, multiple, transcription, 'factors,', including, 'HNF4alpha', and, 'FOXA2', motifs, in, 'HepG2', cells, and, the, 'GATA3', motif, in, 'MCF7', cells])].
[sujeto(['Interestingly,', in, 'MCF7', cells, the, 'TCF7L2', motif, is, enriched, in, most, 'TCF7L2', sites, but, is, not, enriched, in, the, sites]), verbo([bound]), complemento([by, both, 'GATA3', and, 'TCF7L2'])].
[sujeto(['This', analysis]), verbo([suggested]), complemento([that, 'GATA3', might, tether, 'TCF7L2', to, the, genome, at, these, sites])].
[sujeto(['To', test, this, 'hypothesis,', we, depleted, 'GATA3', in, 'MCF7', cells, and, showed, that, 'TCF7L2']), verbo([binding]), complemento([was, lost, at, a, subset, of, sites])].
[sujeto(['RNA-seq', analysis]), verbo([suggested]), complemento([that, 'TCF7L2', represses, transcription, when, tethered, to, the, genome, via, 'GATA3'])].
[sujeto(['Our', studies, demonstrate, a, novel, relationship, between, 'GATA3', and, 'TCF7L2,', and]), verbo([reveal]), complemento([important, insights, into, 'TCF7L2-mediated', gene, regulation])].
[sujeto(['However,', previous, studies]), verbo([have]), complemento([shown, that, the, hepatic, program, can, also, be, activated, in, 'non-hepatic', lineage, cells, after, exposure, to, particular, stimuli, or, fusion, with, hepatocytes])].
[sujeto(['These', unexpected, findings]), verbo([suggest]), complemento([that, factors, critical, to, hepatocyte, differentiation, exist, and, become, activated, to, induce, 'hepatocyte-specific', properties, in, different, cell, types])].
[sujeto(['The']), verbo([induced]), complemento(['hepatocyte-like', '(', 'iHep)', cells, have, multiple, 'hepatocyte-specific', features, and, reconstitute, damaged, hepatic, tissues, after, transplantation])].
[sujeto(['The', generation, of, iHep, cells, may]), verbo([provide]), complemento([insights, into, the, molecular, nature, of, hepatocyte, differentiation, and, potential, therapies, for, liver, diseases])].
[sujeto(['To', investigate, the, gene, expression, pattern, of, hepatocyte]), verbo([nuclear]), complemento([factor, 6, '(', 'HNF6)', and, other, 'liver-enriched', transcription, factors, in, various, segments, of, the, human, intestine, to, better, understand, the, differentiation, of, the, gut, epithelium])].
[sujeto(['Protein', expression, of, major, 'liver-enriched', transcription, factors, was, determined, by, 'Western', blotting, while, the, 'DNA']), verbo([binding]), complemento([of, 'HNF6', was, investigated, by, electromobility, shift, assays])].
[sujeto(['The', gene, expression, patterning, of, 'liver-enriched', transcription, factors, differed, in, the, various, segments, of, the, human, intestine, with, 'HNF6', gene, expression, being, most, abundant, in, the, duodenum, '(', 'P', &, 'lt;', 0.05, ')', whereas, expression, of, the, zinc, finger, protein, 'GATA4', and, of, the, 'HNF6']), verbo([target]), complemento([gene, 'ALDH3A1', was, most, abundant, in, the, jejunum, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['Likewise,', expression, of, 'FOXA2', and, the, splice, variants, 2, and, 4, of, 'HNF4alpha', were, most, abundantly]), verbo([expressed]), complemento([in, the, jejunum, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['The', expression, of, 'HNF6', and, of, genes]), verbo([targeted]), complemento([by, this, 'factor,', i])].
[sujeto([neurogenin, 3, '(', 'NGN3)', was, most, abundant, in, the, jejunum, followed, by, the, ileum, and, the, colon, while, 'DNA']), verbo([binding]), complemento([activity, of, 'HNF4alpha', and, of, 'NGN3', was, confirmed, by, electromobility, shift, assays, to, an, optimized, probe])].
[sujeto(['Furthermore,', 'Western', blotting]), verbo([provided]), complemento([evidence, of, the, expression, of, several, 'liver-enriched', transcription, factors, in, cultures, of, colon, epithelial, 'cells,', albeit, at, different, levels])].
[sujeto(['To']), verbo([gain]), complemento([insight, into, the, transcriptional, networks, regulating, the, function, of, these, 'tissues,', we, globally, identify, binding, sites, for, 'FOXA2', in, adult, mouse, islets, and, 'liver,', 'PDX1', in, 'islets,', and, 'HNF4A', in, liver])].
[sujeto(['Because', most, eukaryotic, transcription, factors]), verbo([bind]), complemento([thousands, of, 'loci,', many, of, which, are, thought, to, be, 'inactive,', methods, that, can, discriminate, functionally, active, binding, events, are, essential, for, the, interpretation, of, 'genome-wide', transcription, factor, binding, data])].
[sujeto(['By', analyzing, our]), verbo([binding]), complemento([and, histone, methylation, data, in, combination, with, comprehensive, gene, expression, 'data,', we, show, that, 'H3K4me1', enrichment, profiles, discriminate, transcription, factor, occupied, loci, into, three, 'classes:', those, that, are, functionally, 'active,', those, that, are, poised, for, 'activation,', and, those, that, reflect, 'pioneer-like', transcription, factor, activity])].
[sujeto(['Furthermore,', we, demonstrate, that, the]), verbo([regulated]), complemento([presence, of, 'H3K4me1-marked', nucleosomes, at, transcription, factor, occupied, promoters, and, enhancers, controls, their, 'activity,', implicating, both, 'tissue-specific', transcription, factor, binding, and, nucleosome, remodeling, complex, recruitment, in, determining, 'tissue-specific', gene, expression])].
[sujeto(['Gene', expression, is]), verbo([regulated]), complemento([by, combinations, of, transcription, 'factors,', which, can, be, mapped, to, regulatory, elements, on, a, 'genome-wide', scale, using, 'ChIP', experiments])].
[sujeto(['In', a, previous, 'ChIP-chip', study, of, 'USF1', and, 'USF2', we]), verbo([found]), complemento([evidence, also, of, binding, of, 'GABP,', 'FOXA2', and, 'HNF4a', within, the, enriched, regions])].
[sujeto(['Here,', we]), verbo([have]), complemento([applied, 'ChIP-seq', for, these, transcription, factors, and, identified, 3064, peaks, of, enrichment, for, 'GABP,', 7266, for, 'FOXA2', and, 18783, for, 'HNF4a'])].
[sujeto(['Distal', elements, with, 'USF2', signal, was, frequently]), verbo([bound]), complemento([also, by, 'HNF4a', and, 'FOXA2'])].
[sujeto(['GABP', peaks, were]), verbo([found]), complemento([at, transcription, start, 'sites,', whereas, 94, '%', of, 'FOXA2', and, 90, '%', of, 'HNF4a', peaks, were, located, at, other, positions])].
[sujeto(['We', developed, a, method, to, accurately, define, 'TFBS', within, 'peaks,', and]), verbo([found]), complemento([the, predicted, sites, to, have, an, elevated, conservation, level, compared, to, peak, 'centers;', however, the, majority, of, bindings, were, not, evolutionary, conserved])].
[sujeto(['An', interaction, between, 'HNF4a', and, 'GABP', was, seen, at, 'TSS,', with, 'one-third', of, the, 'HNF4a', positive, promoters, being]), verbo([bound]), complemento([also, by, 'GABP,', and, this, interaction, was, verified, by, 'co-immunoprecipitations'])].
[sujeto(['ChIP-seq', data, are, enriched, in]), verbo([binding]), complemento([sites, for, the, protein, immunoprecipitated])].
[sujeto(['Some', sequences, may, also, contain]), verbo([binding]), complemento([sites, for, a, coregulator])].
[sujeto(['Biologists', are, interested, in, knowing, which, coregulatory, factor, motifs, may, be, present, in, the, sequences]), verbo([bound]), complemento([by, the, protein, 'ChIP\'ed'])].
[sujeto(['When', applied, to, a, mouse, liver, 'Foxa2', 'ChIP-seq', dataset]), verbo([involving]), complemento([~, 12, 0, 400, -, bp, 'sequences,', coMOTIF, identified, 'co-occurrence', of, 'Foxa2', with, 'Hnf4a,', 'Cebpa,', 'E-box,', 'Ap1/Maf', or, 'Sp1', motifs, in, '~6-33%', of, these, sequences])].
[sujeto(['These', motifs, are, either, known, as, 'liver-specific', transcription, factors, or]), verbo([have]), complemento([an, important, role, in, liver, function])].
[sujeto(['It', was, established, that, genes, 'Gata6,', 'Foxa2', and, 'Hnf4a', were, specifically]), verbo([expressed]), complemento([in, vole, extraembryonic, endoderm, 'cells,', while, 'Cdx2', and, 'Handl', 'genes,', in, trophoblast, stem, cells])].
[sujeto(['During', 'organogenesis,', the, winged, helix, hepatocyte]), verbo([nuclear]), complemento([factor, 3, beta, '(', 'HNF-3beta)', protein, participates, in, regulating, gene, transcription, in, the, developing, 'esophagus,', 'trachea,', 'liver,', 'lung,', 'pancreas,', and, intestine])].
[sujeto(['Squamous', tumours, are, enriched, for, 'TP53', and, 'KDM6A', 'mutations,', upregulation, of, the, 'TP63∆N', transcriptional, 'network,', hypermethylation, of, pancreatic, endodermal, 'cell-fate', determining, genes, and]), verbo([have]), complemento([a, poor, prognosis])].
[sujeto(['Pancreatic', progenitor, tumours, preferentially]), verbo([express]), complemento([genes, involved, in, early, pancreatic, development, '(', 'FOXA2/3,', 'PDX1', and, 'MNX1)'])].
[sujeto(['ADEX', tumours, displayed, upregulation, of, genes, that]), verbo([regulate]), complemento([networks, involved, in, 'KRAS', 'activation,', exocrine, '(', 'NR5A2', and, 'RBPJL),', and, endocrine, differentiation, '(', 'NEUROD1', and, 'NKX2-2)'])].
[sujeto(['Immunogenic', tumours, contained, upregulated, immune, networks, including, pathways]), verbo([involved]), complemento([in, acquired, immune, suppression])].
[sujeto(['The', orphan]), verbo([nuclear]), complemento([receptor, 'NR5A2', is, necessary, for, the, 'stem-like', properties, of, the, epiblast, of, the, 'pre-gastrulation', embryo, and, for, cellular, and, physiological, homeostasis, of, 'endoderm-derived', organs, postnatally])].
[sujeto(['At', 'birth,', the, 'NR5A2-deficient', pancreas]), verbo([has]), complemento([defects, in, all, three, epithelial, 'tissues:', a, partial, loss, of, endocrine, 'cells,', a, disrupted, ductal, tree, and, a, &, 'gt;90%', deficit, of, acini])].
[sujeto(['In', 'particular,', 'Nr5a2', and, 'Ptf1a', establish, mutually, reinforcing, regulatory, interactions, and, collaborate, to, control, developmentally]), verbo([regulated]), complemento([pancreatic, genes, by, binding, to, shared, transcriptional, regulatory, regions])].
[sujeto(['Nr5a2', controls, several, temporally, distinct, stages, of, pancreatic, development, that]), verbo([involve]), complemento([regulatory, mechanisms, relevant, to, pancreatic, oncogenesis, and, the, maintenance, of, the, exocrine, phenotype])].
[sujeto(['Curcumin', '(', 'diferuloylmethane),', a, golden, pigment, from, 'turmeric,']), verbo([has]), complemento([been, linked, with, 'antioxidant,', 'anti-inflammatory,', 'anticancer,', 'antiviral,', 'antibacterial,', and, antidiabetic, properties])].
[sujeto(['Most', of, the, these, activities]), verbo([have]), complemento([been, assigned, to, 'methoxy,', 'hydroxyl,', 'α,β-unsaturated', carbonyl, moiety, or, to, diketone, groups, present, in, curcumin])].
[sujeto(['Various', studies]), verbo([suggest]), complemento([that, curcumin, is, a, more, potent, antioxidant, than, 'THC;', curcumin, '(', but, not, 'THC)', can, bind, and, inhibit, numerous, targets, including, 'DNA', '(', 'cytosine-5)-methyltransferase-1,', heme, 'oxygenase-1,', 'Nrf2,', 'β-catenin,', 'cyclooxygenase-2,', 'NF-kappaB,', inducible, nitric, oxide, 'synthase,', nitric, 'oxide,', amyloid, 'plaques,', reactive, oxygen, 'species,', vascular, endothelial, growth, 'factor,', cyclin, 'D1,', 'glutathione,', 'P300/CBP,', 5, -, 'lipoxygenase,', cytosolic, phospholipase, 'A2,', prostaglandin, 'E2,', inhibitor, of, 'NF-kappaB', 'kinase-1,', -, 2, ',', 'P38MAPK,', 'p-Tau,', tumor, necrosis, 'factor-α,', forkhead, box, 'O3a,', 'CRAC;', curcumin, can, inhibit, tumor, cell, growth, and, suppress, cellular, entry, of, viruses, such, as, influenza, 'A', virus, and, hepatitis, 'C', virus, much, more, effectively, than, 'THC;', curcumin, affects, membrane, 'mobility;', and, curcumin, is, also, more, effective, than, 'THC', in, suppressing, 'phorbol-ester-induced', tumor, promotion])].
[sujeto(['Other', 'studies,', 'however,']), verbo([suggest]), complemento([that, 'THC', is, superior, to, curcumin, for, induction, of, 'GSH', 'peroxidase,', 'glutathione-S-transferase,', 'NADPH:', quinone, 'reductase,', and, quenching, of, free, radicals])].
[sujeto(['Most', studies]), verbo([have]), complemento([indicated, that, 'THC', exhibits, higher, antioxidant, 'activity,', but, curcumin, exhibits, both, 'pro-oxidant', and, antioxidant, properties])].
[sujeto(['The', aim, of, the, study, was, to, determine, whether, metformin]), verbo([regulates]), complemento([hepatic, gluconeogenesis, through, the, orphan, nuclear, receptor, small, heterodimer, partner, '(', 'SHP;', 'NR0B2)'])].
[sujeto(['Hepatic', 'SHP', gene, expression, was]), verbo([induced]), complemento([by, 'metformin,', 5, -, 'aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside', '(', 'AICAR),', and, 'Ad-AMPK'])].
[sujeto(['Metformin']), verbo([inhibited]), complemento([hepatocyte, nuclear, 'factor-4alpha-or', 'FoxA2-mediated', promoter, activity, of, 'PEPCK', and, 'G6Pase,', and, the, inhibition, was, blocked, with, siRNA, 'SHP'])].
[sujeto(['Additionally,', 'SHP', knockdown, by, adenovirus, containing, siRNA, 'SHP']), verbo([inhibited]), complemento(['metformin-mediated', repression, of, 'cAMP/dexamethasone-induced', hepatic, gluconeogenic, gene, expression])].
[sujeto(['Furthermore,', oral, administration, of, metformin]), verbo([increased]), complemento(['SHP', mRNA, levels, in, 'B6-Lep(ob/ob)', mice])].
[sujeto(['Overexpression', of, 'SHP', by, 'Ad-SHP']), verbo([decreased]), complemento([blood, glucose, levels, and, hepatic, gluconeogenic, gene, expression, in, 'B6-Lep(ob/ob)', mice])].
[sujeto(['We']), verbo([have]), complemento([concluded, that, metformin, inhibits, hepatic, gluconeogenesis, through, 'AMPK-dependent', regulation, of, 'SHP'])].
[sujeto(['Transdifferentiattion', potential, of, mesenchymal, stem, cells, '(', 'MSCs)', into, 'insulin-producing', cells, '(', 'IPCs)']), verbo([has]), complemento([been, suggested, recently])].
[sujeto(['In', order, to, 'differentiate,', 'MSCs', were]), verbo([induced]), complemento([by, selection, of, 'nestin-expressing', cells, and, treatment, with, 100, 'μg/mL', 'MPE'])].
[sujeto(['In', 'contrast,', a, crosstalk, between, 'FOXA2', and, 'TCF7L2', transcription, 'factors,', 'DNA-PK', 'complex,', 'KAT2B', protein, positively]), verbo([interacting]), complemento([with, 'PDX-1,', 'CREB1,', 'EP300', resulted, in, the, induction, of, 'IPC', and, following, insulin, production])].
[sujeto(['In', 'conclusion,', we]), verbo([report]), complemento([an, 'efficient,', 'simple,', and, easy, method, for, production, of, functional, 'IPCs', from, 'MSCs', by, 'MPE', treatment])].
[sujeto(['Lung', cancer, is, the]), verbo([leading]), complemento([cause, of, 'cancer-mediated', death])].
[sujeto(['Although', various, therapeutic, approaches, are, used, for, lung, cancer, 'treatment,', these, mainly]), verbo([target]), complemento([the, tumor, suppressor, p53, transcription, 'factor,', which, is, involved, in, apoptosis, and, cell, cycle, arrest])].
[sujeto(['However,', 'p53-targeted', therapies]), verbo([have]), complemento([limited, application, in, lung, 'cancer,', since, p53, is, found, to, be, mutated, in, more, than, half, of, lung, cancers])].
[sujeto(['In', this, 'study,', we, propose, tumor, suppressor, 'FOXA2', as, an, alternative]), verbo([target]), complemento([protein, for, therapies, against, lung, cancer, and, reveal, a, possible, 'FOXA2-centered', transcriptional, regulation, network, by, identifying, new, target, genes, and, binding, partners, of, 'FOXA2', by, using, various, screening, techniques])].
[sujeto(['The', genes, encoding, 'Glu/Asp-rich', 'carboxy-terminal', domain, 2, '(', 'CITED2),']), verbo([nuclear]), complemento([receptor, subfamily, 0, ',', group, 'B,', member, 2, '(', 'NR0B2),', cell, adhesion, molecule, 1, '(', 'CADM1)', and, 'BCL2-associated', 'X', protein, '(', 'BAX)', were, identified, as, putative, target, genes, of, 'FOXA2'])].
[sujeto(['Additionally,', the, proteins, including, highly, similar, to, heat, shock, protein, 'HSP', 90, -, beta, '(', 'HSP90A),', heat, shock, 70, &, 'nbsp;kDa', protein, 1, 'A', variant, '(', 'HSPA1A),', histone, deacetylase, 1, '(', 'HDAC1)', and, 'HDAC3', were, identified, as, novel]), verbo([interacting]), complemento([partners, of, 'FOXA2'])].
[sujeto(['Moreover,', we, showed, that, 'FOXA2-dependent', promoter, activation, of, 'BAX', and, p21, genes, is, significantly, reduced, via, physical, interactions, between, the, identified]), verbo([binding]), complemento([partners, and, 'FOXA2'])].
[sujeto(['These', results]), verbo([provide]), complemento([opportunities, to, understand, the, 'FOXA2-centered', transcriptional, regulation, network, and, novel, therapeutic, targets, to, modulate, this, network, in, 'p53-deficient', lung, cancer])].
[sujeto(['Enterocytes', of, the, jejunum]), verbo([express]), complemento([several, genes, related, to, 'digestion/absorption', of, nutrients, and, ions, when, these, cells, rapidly, differentiate, from, crypt, to, villus, cells])].
[sujeto(['Several', transcriptional, factors, such, as, 'Pdx1,', 'Foxa2', and, 'Thra', were]), verbo([expressed]), complemento([in, the, 'crypt,', whereas, 'Klf15', was, highly, expressed, during, the, 'crypt-villus', transition])].
[sujeto(['Subsets', of, genes, related, to, the, digestion, and, absorption, of, 'starch/sucrose', and, dietary, fat, as, well, as, their, transcriptional, 'factors/co-factors', are]), verbo([expressed]), complemento([in, the, specific, locations, along, the, 'crypt-villus', axis])].
[sujeto(['The', jejunum, may, absorb, nutrients, effectively, by, simultaneously]), verbo([expressing]), complemento([subsets, of, genes, along, the, 'villus-crypt', axis])].
[sujeto(['Thyroid', carcinoma, cells, often, do, not]), verbo([express]), complemento(['thyroid-specific', genes, including, sodium, iodide, symporter, '(', 'NIS),', thyroperoxidase, '(', 'TPO),', thyroglobulin, '(', 'TG),', and, 'thyrotropin-stimulating', hormone, receptor, '(', 'TSHR)'])].
[sujeto(['Treatment', of, thyroid, carcinoma, cells, '(', four, papillary, and, two, anaplastic, cell, 'lines)', with, histone, deacetylase, inhibitors, '(', 'SAHA', or, 'VPA)', modestly]), verbo([induced]), complemento([the, expression, of, the, 'NIS', gene])].
[sujeto(['The', promoter, regions, of, the, 'thyroid-specific', genes, contained]), verbo([binding]), complemento([sites, for, hepatocyte, nuclear, factor, 3, beta, '(', 'HNF3', 'beta)/forkhead', box, 'A2', '(', 'FoxA2),', thyroid, transcription, factor, 1, '(', 'TTF-1),', and, 'CCAAT/enhancer', binding, protein, '(', 'C/EBP', 'beta)'])].
[sujeto(['Quantitative', reverse, 'transcription-polymerase', chain, reaction, '(', 'RT-PCR)', showed]), verbo([decreased]), complemento([expression, of, 'HNF3', 'beta/FoxA2', and, 'TTF-1', mRNA, in, papillary, thyroid, carcinoma, cell, 'lines,', when, compared, with, normal, thyroid, cells])].
[sujeto(['Forced', expression, of, these, genes, in, papillary, thyroid, carcinoma, cells]), verbo([inhibited]), complemento([their, growth])].
[sujeto(['Furthermore,', the, 'CpG', island, in, the, promoter, region, of, 'HNF3', 'beta/FoxA2', was, aberrantly, 'methylated;', and, treatment, with, 5, -, 'aza-2-deoxycytidine', '(', 5, -, 'Az)']), verbo([induced]), complemento([its, expression])].
[sujeto(['Subcellular', fractionation, of, papillary, thyroid, carcinoma, cell, lines, also, demonstrated, high, levels, of, expression, of, 'C/EBP', beta, in, the, 'cytoplasm,']), verbo([suggesting]), complemento([that, a, large, proportion, of, 'C/EBP', beta, protein, is, inappropriately, localised, in, the, cytoplasm])].
[sujeto(['In', 'summary,', these, findings]), verbo([reveal]), complemento([novel, abnormalities, in, thyroid, carcinoma, cells])].
[sujeto(['The', mechanisms, controlling, thyrocyte, development, during, embryonic, stem, '(', 'ES)', cell, differentiation]), verbo([have]), complemento([only, been, partially, 'elucidated,', although, previous, studies, have, suggested, the, participation, of, thyroid, stimulating, hormone, '(', 'TSH)', in, these, processes])].
[sujeto(['To', further, define, the, role, of, 'TSH', in, this, 'context,', we]), verbo([have]), complemento([studied, a, murine, 'ES', cell, line, in, which, green, fluorescent, protein, '(', 'GFP)', cDNA, is, targeted, to, the, 'TSH', receptor, '(', 'TSHR)', 'gene,', linking, the, expression, of, 'GFP', to, the, transcription, of, the, endogenous, 'TSHR', gene])].
[sujeto(['We', demonstrate, 'that,', in, the, initial, stages, of, embryoid, body, 'formation,', activin, 'A', and, 'TSH']), verbo([induce]), complemento([the, differentiation, of, definitive, endoderm, and, thyrocyte, progenitors, expressing, 'Sox17,', 'Foxa2,', and, 'TSHR'])].
[sujeto(['Our', data]), verbo([suggest]), complemento(['that,', despite, the, fact, that, 'TSH', is, important, for, the, induction, and, specification, of, thyrocytes, from, 'ES', 'cells,', insulin, and, 'IGF-1', are, crucial, for, thyrocyte, maturation])].
[sujeto(['Our', method]), verbo([provides]), complemento([a, powerful, in, vitro, differentiation, model, for, studying, the, mechanisms, of, early, thyrocyte, lineage, development])].
[sujeto(['Previous', studies, from, our, group]), verbo([have]), complemento([shown, that, 'Foxa1', is, expressed, in, the, prostate, and, interacts, with, the, androgen, receptor, '(', 'AR)', to, regulate, 'prostate-specific', genes, such, as, 'prostate-specific', antigen, '(', 'PSA)', and, probasin, '(', 'PB)'])].
[sujeto(['We']), verbo([report]), complemento([here, that, 'Foxa2', but, not, 'Foxa1', is, expressed, in, the, epididymis])].
[sujeto(['Further,', 'Foxa2']), verbo([interacts]), complemento([with, the, 'AR', to, regulate, the, mouse, epididymal, retinoic, acid, binding, protein, '(', 'mE-RABP)', 'gene,', an, 'epididymis-specific', gene])].
[sujeto(['Overexpression', of, 'Foxa2']), verbo([suppresses]), complemento([androgen, activation, of, the, 'mE-RABP', promoter, while, overexpression, of, 'Foxa2', with, 'prostate-specific', promoters, activates, gene, expression, in, an, 'androgen-independent', manner])].
[sujeto(['GST', 'pull-down', assays, determined, that, both, 'Foxa1', and, 'Foxa2', physically]), verbo([interact]), complemento([with, the, 'DNA', binding, domain, of, the, 'AR'])].
[sujeto(['The', interaction, between, 'Foxa', proteins, and, 'AR', was, further, confirmed, by, 'gel-shift', assays, where, 'Foxa', protein, was]), verbo([recruited]), complemento([to, 'AR', binding, oligomers, even, when, 'Foxa', binding, sites, were, not, 'present,', and, 'AR', was, recruited, to, 'Foxa', binding, oligomers, even, in, the, absence, of, an, 'AR', binding, site])].
[sujeto(['Given', that, 'Foxa1', and, 'Foxa2', proteins, are]), verbo([expressed]), complemento([differentially, in, the, prostate, and, 'epididymis,', these, data, suggest, that, the, 'Foxa', proteins, have, distinct, effects, on, 'AR-regulated', genes, in, different, male, reproductive, accessory, organs])].
[sujeto(['Secondary', neurulation, and, axis, formation]), verbo([involve]), complemento([differentiation, of, the, tail, bud, mesenchyme])].
[sujeto(['We']), verbo([report]), complemento([a, detailed, analysis, of, gene, expression, in, the, caudal, region, of, day, 10, mouse, embryos, during, primary, neuropore, closure])].
[sujeto(['Genes', selected, for, study, include, those]), verbo([involved]), complemento([in, the, key, events, of, gastrulation, and, neurulation, at, earlier, stages, and, more, cranial, levels])].
[sujeto(['Specifically,', we]), verbo([report]), complemento([continuity, of, expression, of, the, genes, 'Wnt5a,', 'Wnt5b,', 'Evx1,', 'Fgf8,', 'RARgamma,', 'Brachyury,', and, 'Hoxb1', from, primitive, streak, and, node, into, subpopulations, of, the, tail, bud, and, caudal, axial, structures])].
[sujeto(['The', patterns, of, expression, of, 'Wnt5a,', 'Hoxb1,', 'Brachyury,', 'RARgamma,', and, 'Evx1,', together, with, observations, on, 'proliferation,']), verbo([reveal]), complemento([that, the, caudal, mesoderm, is, organised, at, a, molecular, level, into, distinct, domains, delineated, by, longitudinal, and, transverse, borders, before, histological, differentiation])].
[sujeto(['Expression', of, 'Wnt5a', in, the, ventral, ectodermal, ridge, supports, previous, evidence, that, this, structure, is]), verbo([involved]), complemento([in, 'epithelial-mesenchymal', interaction])].
[sujeto(['These', results]), verbo([provide]), complemento([a, foundation, for, understanding, the, mechanisms, facilitating, transition, from, primary, to, secondary, body, axis, 'formation,', as, well, as, the, factors, involved, in, defective, spinal, neurulation])].
[sujeto(['Treatment', of, pseudoglandular, stage, fetal, lungs, in, vitro, with, the, 'pan-retinoic', acid, receptor, '(', 'pan-RAR)', 'antagonist,', 'BMS493,', reduces, retinoic, acid, receptor, beta, '(', 'Rarb)', gene, expression, within, the, proximal, bronchial, tubules, and]), verbo([increases]), complemento([explant, bud, formation])].
[sujeto(['Treatment', with, retinoic, acid, '(', 'RA)']), verbo([increases]), complemento(['Rarb', expression, and, reduces, explant, bud, formation, through, a, signaling, mechanism, involving, 'RARbeta'])].
[sujeto(['Together', these, data]), verbo([suggest]), complemento([that, 'RA', through, 'RARbeta', provides, morphogenetic, stabilizing, activity, to, the, proximal, tubules, during, lung, branching, morphogenesis])].
[sujeto(['We', demonstrate, that, 'Rarb', isoform, transcripts, are, the, only, known, 'Rar', transcripts, to, specifically, localize, to, the, proximal, tubules, and, that, 'RAREhsp68lacZ', reporter, transgene, activity]), verbo([reveals]), complemento([endogenous, 'RA', signaling, activity, within, these, same, proximal, tubules])].
[sujeto(['We', therefore, discuss, an, 'interbud/proximal', tubule, signaling, niche]), verbo([involving]), complemento([feedback, between, 'Rarb', expression, and, 'Raldh1-mediated', synthesis, of, 'RA'])].
[sujeto(['We']), verbo([suggest]), complemento([that, this, feedback, favors, interbud, morphogenetic, stability, by, increasing, expression, of, morphoregulatory, molecules, such, as, 'TGFbeta3', and, 'Foxa2,', thus, promoting, bronchial, tubule, formation, rather, than, continual, budding, and, branching])].
[sujeto(['Transcriptional', changes]), verbo([suggest]), complemento([that, derepression, of, the, nuclear, receptors, 'PPARα,', 'PPARγ,', and, 'LXRα', in, aged, mouse, liver, leads, to, activation, of, targets, regulating, lipid, synthesis, and, 'storage,', whereas, 'age-dependent', changes, in, nucleosome, occupancy, are, associated, with, binding, sites, for, both, known, regulators, '(', forkhead, factors, and, nuclear, 'receptors)', and, candidates, associated, with, nuclear, lamina, '(', 'Hdac3', and, 'Srf)', implicated, to, govern, metabolic, function, of, aging, liver])].
[sujeto(['Winged-helix', transcription, factor, 'Foxa2', and]), verbo([nuclear]), complemento([receptor, corepressor, 'Hdac3', exhibit, a, reciprocal, binding, pattern, at, 'PPARα', targets, contributing, to, gene, expression, changes, that, lead, to, steatosis, in, aged, liver])].
[sujeto(['The', winged, helix, protein, 'FOXA2', and, the]), verbo([nuclear]), complemento([receptor, peroxisome, 'proliferator-activated', 'receptor-γ', '(', 'PPARγ)', are, highly, 'conserved,', regionally, expressed, transcription, factors, '(', 'TFs)', that, regulate, networks, of, genes, controlling, complex, metabolic, functions])].
[sujeto(['Cistrome', analysis, for, 'Foxa2', in, mouse, liver, and, 'PPARγ', in, mouse, adipocytes]), verbo([has]), complemento([previously, produced, 'consensus-binding', sites, that, are, nearly, identical, to, those, used, by, the, corresponding, 'TFs', in, human, cells])].
[sujeto(['We']), verbo([report]), complemento([here, 'that,', despite, the, conservation, of, the, canonical, binding, 'motif,', the, great, majority, of, binding, regions, for, 'FOXA2', in, human, liver, and, for, 'PPARγ', in, human, adipocytes, are, not, in, the, orthologous, locations, corresponding, to, the, mouse, 'genome,', and, vice, versa])].
[sujeto(['Of', 'note,', 'TF']), verbo([binding]), complemento([can, be, absent, in, one, species, despite, sequence, 'conservation,', including, motifs, that, do, support, binding, in, the, other, 'species,', demonstrating, a, major, limitation, of, in, silico, binding, site, prediction])].
[sujeto(['Whereas', only, approximately, 10, '%', of]), verbo([binding]), complemento([sites, are, 'conserved,', 'gene-centric', analysis, reveals, that, about, 50, '%', of, genes, with, nearby, 'TF', occupancy, are, shared, across, species, for, both, hepatic, 'FOXA2', and, adipocyte, 'PPARγ'])].
[sujeto(['Thus,', 'species-specific', strategies, underlie, the, biological, functions, of, metabolic, 'TFs', that, are, highly]), verbo([conserved]), complemento([across, mammalian, species])].
[sujeto(['Analysis', of, factor]), verbo([binding]), complemento([in, multiple, species, may, be, necessary, to, distinguish, apparent, 'species-unique', noise, and, reveal, functionally, relevant, information])].
[sujeto(['Regular', use, of, 'beta(2)-adrenoceptor', agonists, may]), verbo([enhance]), complemento(['non-specific', airway, responsiveness, and, inflammation])].
[sujeto(['In', earlier, experimental, 'studies,', we, showed, that, prolonged, in, vitro, fenoterol, exposure]), verbo([induced]), complemento([airway, sensitization, via, perturbed, epithelial, regulation, of, bronchoconstriction])].
[sujeto(['Fenoterol', exposure, significantly]), verbo([enhanced]), complemento(['CD8(+)-T', and, differentiated, 'CD138(+)-B-cells', infiltration, into, the, 'bronchi,', especially, the, subepithelial, area])].
[sujeto(['Increase', in, 'CD8', or, 'CD138', 'labeling-intensity', strongly, correlated, with, rise, in, maximal, contraction, to, 'endothelin-1']), verbo([induced]), complemento([by, fenoterol, exposure])].
[sujeto(['In', 'summary,', our, results, show, that, fenoterol]), verbo([modulates]), complemento([the, 'T', and, 'B', cells, chemotaxis, possibly, via, the, epithelial, chemokine, secretion, in, isolated, bronchi, from, 'ex-smokers'])].
[sujeto(['They', also]), verbo([suggest]), complemento([that, the, infiltration, of, resident, 'T', and, 'B', cells, into, the, subepithelial, area, is, associated, with, an, increase, in, airway, responsiveness, due, to, fenoterol, exposure])].
[sujeto(['While', both, drugs]), verbo([have]), complemento([been, shown, to, improve, 'insulin-sensitive', glucose, 'uptake,', the, direct, effects, of, these, drugs, on, pancreatic, beta, cells, is, only, now, beginning, to, be, clarified])].
[sujeto(['Western', blot, and, gel, retardation, analyses, were, used, to, examine, the, effects, of, both, drugs, on, the, regulation, of, 'IPF1', protein, 'production,']), verbo([nuclear]), complemento([accumulation, and, 'DNA', binding, activity, in, both, 'Min6', cells, and, isolated, rat, islets, of, 'Langerhans'])].
[sujeto(['Over', 24, 'h,', rosiglitazone]), verbo([promoted]), complemento([the, nuclear, accumulation, of, 'IPF1', and, forkhead, homeobox, 'A2', '(', 'FOXA2),', independently, of, glucose, 'concentration,', and, stimulated, a, 'two-fold', increase, in, the, activity, of, the, 'Ipf1', gene, promoter, '(', 'p<0'])].
[sujeto(['Stimulation', of, the, 'Ipf1', promoter, by, rosiglitazone, was, unaffected, by, the, presence, of, the, peroxisome, proliferator]), verbo([activated]), complemento([receptor, gamma, antagonist, 'GW9662'])].
[sujeto(['Metformin']), verbo([stimulated]), complemento(['IPF1', nuclear, accumulation, and, 'DNA', binding, activity, in, a, 'time-dependent', 'manner,', with, maximal, effects, observed, after, 2, h])].
[sujeto(['Metformin', and, rosiglitazone]), verbo([have]), complemento([direct, effects, on, beta, cell, gene, 'expression,', suggesting, that, these, agents, may, play, a, previously, unrecognised, role, in, the, direct, regulation, of, pancreatic, beta, cell, function])].
[sujeto(['Upon', drug, 'activation,', the]), verbo([nuclear]), complemento([pregnane, 'X', receptor, '(', 'PXR)', regulates, not, only, hepatic, drug, but, also, energy, metabolism])].
[sujeto(['Using', 'Pxr(-/-)', 'mice,', we]), verbo([have]), complemento([now, investigated, the, 'PXR-mediated', repression, of, lipid, metabolism, in, the, fasting, livers])].
[sujeto(['Reflecting', these, 'up-', and, 'down-regulations', and, consistent, with]), verbo([decreased]), complemento([energy, 'metabolism,', the, levels, of, hepatic, triglycerides, and, of, serum, 3, -, hydroxybutylate, were, increased, and, 'decreased,', 'respectively,', in, the, 'PCN-treated', 'Pxr(+/+)', mice])].
[sujeto(['Using', gel, 'shift,', glutathione, 'S-transferase', 'pull-down', and, 'cell-based', reporter, 'assays,', we, then, examined, whether, 'PXR', could, 'cross-talk', with, the, insulin, response, forkhead, factor, 'FoxA2', to]), verbo([repress]), complemento([the, transcription, of, the, 'Cpt1a', and, 'Hmgcs2', 'genes,', because, 'FoxA2', activates, these, genes, in, fasting, liver])].
[sujeto(['PXR', directly]), verbo([bound]), complemento([to, 'FoxA2', and, repressed, its, activation, of, the, 'Cpt1a', and, 'Hmgcs2', promoters])].
[sujeto(['Moreover,', 'ChIP', assays, showed, that, 'PCN', treatment, attenuated, the]), verbo([binding]), complemento([of, 'FoxA2', to, these, promoters, in, fasting, 'Pxr(+/+)', but, not, 'Pxr(-/-)', mice])].
[sujeto(['These', results, are, consistent, with, the, conclusion, that, 'PCN-activated', 'PXR']), verbo([represses]), complemento(['FoxA2-mediated', transcription, of, 'Ctp1a', and, 'Hmgcs2', genes, in, fasting, liver])].
[sujeto(['Streptozotocin', '(', 'STZ),', a, 'glucosamine-nitrosourea', 'compound,']), verbo([has]), complemento([potent, genotoxic, effects, on, pancreatic, 'β-cells', and, is, frequently, used, to, induce, diabetes, in, experimental, animals])].
[sujeto(['Glucagon-like', 'peptide-1', '(', 'GLP-1)']), verbo([has]), complemento(['β-cell', protective, effects, and, is, known, to, preserve, 'β-cells', from, 'STZ', treatment])].
[sujeto(['At', 1, week, after, multiple, 'low-dose', 'STZ', 'administrations,', pancreatic, 'β-cells', showed, impaired, insulin, 'expression,', while]), verbo([maintaining]), complemento([expression, of, nuclear, 'Nkx6'])].
[sujeto(['STZ', treatment, also]), verbo([suppressed]), complemento([expression, of, a, wide, range, of, genes, linked, with, key, 'β-cell', functions, or, diabetes, 'development,', such, as, 'G6pc2,', 'Slc2a2', '(', 'Glut2),', 'Slc30a8,', 'Neurod1,', 'Ucn3,', 'Gad1,', 'Isl1,', 'Foxa2,', 'Vdr,', 'Pdx1,', 'Fkbp1b', and, 'Abcc8,', suggesting, global, 'β-cell', defects, in, 'STZ-treated', islets])].
[sujeto(['The', 'Tmem229B,', 'Prss53', and, 'Ttc28', genes, were, highly]), verbo([expressed]), complemento([in, untreated, islets, and, strongly, suppressed, by, 'STZ,', suggesting, their, potential, roles, in, 'β-cell', function])].
[sujeto(['Given', the, 'pro-β-cell-survival', effects, of, 'Cxcl12', '(', 'Sdf-1)', in]), verbo([inducing]), complemento(['GLP-1', production, in, 'α-cells,', pancreatic, 'GLP-1-mediated', 'Cxcl13', induction, might, also, play, a, crucial, role, in, maintaining, the, integrity, of, 'β-cells', in, damaged, islets])].
[sujeto(['Although', the, negative, regulation, of, gene, expression, by, insulin]), verbo([has]), complemento([been, widely, 'studied,', the, transcription, factors, responsible, for, the, insulin, effect, are, still, unknown])].
[sujeto(['The', purpose, of, this, work, was, to, explore, the, molecular, mechanisms]), verbo([involved]), complemento([in, the, insulin, repression, of, the, 5, -, aminolevulinate, synthase, '(', 'ALAS)', gene])].
[sujeto(['By', transient, transfection, 'assays,', we, determined, that, hepatic]), verbo([nuclear]), complemento([factor, 3, '(', 'HNF3)', and, nuclear, factor, 1, '(', 'NF1)', are, necessary, for, an, appropriate, expression, of, the, 'ALAS', gene])].
[sujeto(['Electrophoretic', mobility, shift, assay, and, 'Southwestern', blotting, indicate, that, 'HNF3']), verbo([binds]), complemento([to, the, 'ALAS', promoter])].
[sujeto(['Mutational', analysis, of, this, region, revealed, that, 'IRE', disruption, abrogates, insulin, 'action,', whereas, mutation, of, the, 'HNF3', element]), verbo([maintains]), complemento([hormone, responsiveness])].
[sujeto(['This', dissociation, between, 'HNF3']), verbo([binding]), complemento([and, insulin, action, suggests, that, 'HNF3beta', is, not, the, sole, physiologic, mediator, of, 'insulin-induced', transcriptional, repression])].
[sujeto(['Furthermore,', 'Southwestern', blotting, assay, shows, that, at, least, two, polypeptides, other, than, 'HNF3beta', can]), verbo([bind]), complemento([to, 'ALAS', promoter, and, that, this, binding, is, dependent, on, the, integrity, of, the, 'IRE'])].
[sujeto(['We', propose, a, model, in, which, insulin, exerts, its, negative, effect, through, the, disturbance, of, 'HNF3beta']), verbo([binding]), complemento([or, transactivation, 'potential,', probably, due, to, specific, phosphorylation, of, this, transcription, factor, by, 'Akt'])].
[sujeto(['The', posttranslational, modification, of, 'HNF3', would, allow, the]), verbo([binding]), complemento([of, a, protein, complex, that, recognizes, the, core, 'IRE'])].
[sujeto(['These', results]), verbo([provide]), complemento([a, potential, mechanism, for, the, 'insulin-mediated', repression, of, 'IRE-containing', promoters])].
[sujeto(['The', first, mouse, model, for, 'PHHI']), verbo([has]), complemento([a, conditional, deletion, of, the, gene, encoding, the, 'winged-helix', transcription, factor, 'Foxa2', '(', 'Forkhead', box, 'a2,', formerly, 'Hepatocyte', nuclear, factor, 3, 'beta)', in, pancreatic, beta, cells])].
[sujeto(['Using', isolated, 'islets,', we]), verbo([found]), complemento([that, 'Foxa2', deficiency, resulted, in, excessive, insulin, release, in, response, to, amino, acids, and, complete, loss, of, 'glucose-stimulated', insulin, secretion])].
[sujeto(['Most', 'PHHI', cases, are]), verbo([associated]), complemento([with, mutations, in, 'SUR1', '(', 'Sulfonylurea', receptor, 1, ')', or, 'KIR6'])].
[sujeto(['We', utilized, expression, profiling, to, identify, additional]), verbo([targets]), complemento([of, 'Foxa2'])].
[sujeto(['Strikingly,', one, of, these, 'genes,', 'Hadhsc,', encodes, 'short-chain', 'L-3-hydroxyacyl-coenzyme', 'A', 'dehydrogenase,', deficiency, of, which]), verbo([has]), complemento([been, shown, to, cause, 'PHHI', in, humans])].
[sujeto(['Hadhsc', is, a, direct]), verbo([target]), complemento([of, 'Foxa2,', as, demonstrated, by, cotransfection, as, well, as, in, vivo, chromatin, immunoprecipitation, experiments, using, isolated, islets])].
[sujeto(['Thus,', we]), verbo([have]), complemento([established, 'Foxa2', as, an, essential, activator, of, genes, that, function, in, multiple, pathways, governing, insulin, secretion])].
[sujeto(['Our', recent, efforts]), verbo([led]), complemento([to, a, successful, production, of, chimeric, 'pre-miR-27b', in, bacteria, using, a, transfer, 'RNA', '(', 'tRNA)-based', recombinant, 'RNA', 'technology,', but, at, very, low, expression, levels])].
[sujeto(['Consequently,', recombinant, 'tRNA/mir-1291', reduced, the, protein, levels, of, 'miR-1291']), verbo([target]), complemento(['genes,', including, 'ABCC1,', 'FOXA2,', and, 'MeCP2,', as, compared, with, cells, transfected, with, the, same, doses, of, control, 'methionyl-tRNA', scaffold, with, a, sephadex, aptamer, '(', 'tRNA/MSA)'])].
[sujeto(['In', 'addition,', 'tRNA-carried', 'pre-miR-1291']), verbo([suppressed]), complemento([the, growth, of, 'MCF-7', and, 'PANC-1', cells, in, a, 'dose-dependent', 'manner,', and, significantly, enhanced, the, sensitivity, of, 'ABCC1-overexpressing', 'PANC-1', cells, to, doxorubicin])].
[sujeto(['These', results, indicate, that, recombinant, 'miR-1291', agent, is, effective, in, the, modulation, of]), verbo([target]), complemento([gene, expression, and, 'chemosensitivity,', which, may, provide, insights, into, 'high-yield', bioengineering, of, new, ncRNA, agents, for, pharmacoepigenetics, research])].
[sujeto(['The', organic, anion, transporting, polypeptides, '(', 'OATPs)']), verbo([mediate]), complemento([the, uptake, of, numerous, amphipathic, compounds, into, hepatocytes])].
[sujeto(['The', expression, of, 'OATP8', was]), verbo([decreased]), complemento([in, 60, '%', of, 'HCC', compared, to, surrounding, 'non-tumor', liver, 'tissue,', on, both, the, mRNA, and, protein, levels])].
[sujeto(['Expression', of, the, 'liver-enriched', transcription, factor, hepatocyte]), verbo([nuclear]), complemento([factor, 3, beta, '(', 'HNF3beta)', was, increased, in, 70, '%', of, 'HCC', and, correlated, inversely, with, 'OATP8', mRNA, '(', 'r=-0'])].
[sujeto(['In', contrast, to, 'OATP8,', expression, of, 'OATP-C', was, not, significantly]), verbo([decreased]), complemento([in, 'HCC'])].
[sujeto(['In', transfected, 'Huh7', 'cells,', 'OATP8', promoter, activity, was]), verbo([inhibited]), complemento([by, 70, '%', when, 'HNF3beta', was, cotransfected])].
[sujeto(['An', 'HNF3beta']), verbo([binding]), complemento([site, was, located, at, nt, -, 39, /, -, 23, by, 'EMSA'])].
[sujeto(['The', 'OATP-C', promoter, was, not]), verbo([inhibited]), complemento([by, 'HNF3beta'])].
[sujeto(['HNF3beta']), verbo([represses]), complemento([transcription, of, the, 'OATP8', but, not, the, 'OATP-C', 'gene,', providing, a, mechanism, for, reduced, expression, of, 'OATP8', in, 'HCC'])].
[sujeto(['Mouse', embryonic, stem, '(', 'ES)', cells, are, clonal, cell, lines, derived, from, the, inner, cell, mass, of, developing, blastocysts, and]), verbo([have]), complemento(['multi-lineage', differentiation, ability])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, 'ES', cells, can, be, made, to, differentiate, into, hepatocytes, possessing, high, metabolic, activities, by, transfection, of, hepatocyte, nuclear, 'factor-3beta', '(', 'HNF-3beta)'])].
[sujeto(['The', expression, of, organic, anion, transporting, polypeptide, 1, '(', 'oatp1),', multidrug, 'resistance-associated', protein, 1, '(', 'mrp1),', 'mrp2,', 'mrp3,', and, ugt1a1, was, not, seen, in, the, undifferentiated, 'HNF-3beta-ES', cells, by, 'RT-PCR,', whereas, all, were]), verbo([expressed]), complemento([in, differentiating, 'HNF-3beta-ES', cells])].
[sujeto(['An', immunofluorescence, examination, revealed, that, oatp1, was, 'co-located', with, 'desmoplakin,', a, marker, for, the, basolateral, '(', 'sinusoidal)', 'membrane,', and, mrp2, was, 'co-localized', with, 'CD26,', a, marker, for, the, apical, '(', 'canalicular)', 'membrane,', though, they, were, both]), verbo([expressed]), complemento([throughout, most, of, the, cell, membranes])].
[sujeto(['They']), verbo([express]), complemento([endodermal, transcription, factors, '(', e])].
[sujeto(['Transfer', into, distinct, culture, 'conditions,', each, comprised, of, a, specific, mix, of, hormones, and, matrix, 'components,', yields, either, cords, of, hepatocytes, '(']), verbo([express]), complemento(['albumin,', 'CYP3A4,', and, 'transferrin),', branching, ducts, of, cholangiocytes, '(', expressing, anion, 'exchanger-2-AE2', and, 'CFTR),', or, regulatable, 'C-peptide', secreting, 'neoislet-like', clusters, '(', expressing, 'glucagon,', 'insulin)', and, accompanied, by, changes, in, gene, expression, correlating, with, the, adult, fate])].
[sujeto(['The', phenotypes, and, availability, from, all, age, donors]), verbo([suggest]), complemento([that, these, 'stem/progenitors', have, considerable, potential, for, regenerative, therapies, of, 'liver,', bile, 'duct,', and, pancreatic, diseases, including, diabetes])].
[sujeto(['RUNX1']), verbo([loss]), complemento([in, 'ER(+)', mammary, epithelial, cells, increases, 'β-catenin,', deregulates, mitosis, and, stimulates, cell, proliferation, and, expression, of, stem, cell, markers])].
[sujeto(['However,', it, does, not]), verbo([stimulate]), complemento(['LEF/TCF,', 'c-Myc', or, 'CCND1,', and, it, does, not, accelerate, 'G1/S', cell, cycle, phase, transition])].
[sujeto(['Finally,', 'RUNX1', 'loss-mediated', deregulation, of, 'β-catenin', and, mitosis, is, ameliorated, by, 'AXIN1', stabilization, in, 'vitro,', highlighting, 'AXIN1', as, a, potential]), verbo([target]), complemento([for, the, management, of, 'ER(+)', breast, cancer])].
[sujeto(['AML1-ETO', is, the, most, common, fusion, oncoprotein]), verbo([causing]), complemento([acute, myeloid, leukemia, '(', 'AML),', a, disease, with, a, 5, -, year, survival, rate, of, only, 24, '%'])].
[sujeto(['While', known, for, decades, to, be, the, translational, product, of, a, chimeric, gene, created, by, the, stable, chromosome, translocation, 't(8;21)(q22;q22),', it, is, not, known, how, 'AML1-ETO', achieves, its, native, and, functional, conformation, or, whether, this, process, can, be]), verbo([targeted]), complemento([for, therapeutic, benefit])].
[sujeto(['We', demonstrate, that, a, folding, intermediate, of, 'AML1-ETO']), verbo([binds]), complemento([to, 'TRiC', 'directly,', mainly, through, its, 'β-strand', 'rich,', 'DNA-binding', domain, '(', 'AML-(1-175)),', with, the, assistance, of, 'HSP70'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'TRiC', contributes, to, 'AML1-ETO', proteostasis, through, specific, interactions, between, the, 'oncoprotein\'s', 'DNA-binding', 'domain,', which, may, be, targeted, for, therapeutic, benefit])].
[sujeto(['Acute', myeloid, leukemia, '(', 'AML)', 1, -, 'Evi-1', is, a, chimeric, gene, generated, by, the, t, '(', 3, ;, 21, ')', '(', 'q26;', 'q22)', 'translocation,', which]), verbo([leads]), complemento([into, malignant, transformation, of, hematopoietic, stem, cells, by, unclear, mechanisms])].
[sujeto(['This', in, vivo, study, aimed, to, establish, a, stable, line, of, zebrafish]), verbo([expressing]), complemento([the, human, 'RUNX1-Evi-1', fusion, gene, under, the, control, of, a, heat, 'stress-inducible', bidirectional, 'promoter,', and, investigate, its, roles, in, hematopoiesis, and, hematologic, malignancies])].
[sujeto(['Consequently,', primitive, hematopoiesis, was]), verbo([enhanced]), complemento([by, upregulation, of, gata2, and, 'scl,', while, erythropoiesis, was, downregulated, due, to, the, suppression, of, gata1])].
[sujeto([1, ',', but, it, was]), verbo([inhibited]), complemento([along, with, the, low, expression, of, mpo])].
[sujeto(['Microarray', analysis, demonstrated, that, 'RUNX1-Evi-1', not, only, upregulated, 'proteasome,', cell, 'cycle,', 'glycolysis/gluconeogenesis,', tyrosine, 'metabolism,', drug, 'metabolism,', and, 'PPAR', 'pathway,', but, also]), verbo([suppressed]), complemento([transforming, growth, factor, 'β,', 'Jak-STAT,', 'DNA', 'replication,', mismatch, 'repair,', p53, 'pathway,', 'JNK', signaling, 'pathway,', and, nucleotide, excision, repair])].
[sujeto(['Factors', in, cell, proliferation, were, obviously]), verbo([suppressed]), complemento([after, 3, -, day, treatment, with, histone, deacetylase, 'inhibitor,', valproic, acid])].
[sujeto(['Accordingly,', higher, proportion, of, 'G1']), verbo([arrest]), complemento([and, apoptosis, were, manifested, by, the, propidium, iodide, staining])].
[sujeto(['RUNX1-Evi-1', may]), verbo([promote]), complemento([proliferation, and, apoptosis, resistance, of, primitive, hematopoietic, 'cell,', and, inhibit, the, differentiation, of, myeloid, cells, with, the, synergy, of, different, pathways, and, factors])].
[sujeto(['VPA', may, be, a, promising, choice, in, the, molecular]), verbo([targeting]), complemento([therapy, of, 'RUNX1-Evi-1-related', leukemia])].
[sujeto(['Two', distantly, located, promoter, regions]), verbo([regulate]), complemento([the, dynamic, expression, of, 'RUNX', genes, during, 'development:', distal, 'P1', and, proximal, 'P2', promoters])].
[sujeto(['We']), verbo([have]), complemento([recently, described, that, 'β-catenin', increases, total, 'Runx1', mRNA, levels, in, human, 'CD34(+)', hematopoietic, progenitors, and, enhances, spatial, proximity, with, its, translocation, partner, 'ETO'])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, induction, of, 'Wnt/β-catenin', signaling, in, 'HL60', and, 'Jurkat', 'leukemia-derived', cell, lines, and, 'CD34(+)', progenitors, selectively, activate, the, production, of, the, longer, distal, 'P1-Runx1', mRNA, isoform])].
[sujeto(['Gain-', and, 'loss-of-function', experiments, revealed, that, the, differential]), verbo([increase]), complemento([in, 'P1-Runx1', expression, is, accomplished, through, a, minimal, 'β-catenin', responsive, region, that, includes, a, highly, conserved, 'TCF/LEF-binding', 'element,', located, -, 20, /, -, 16, bp, upstream, of, the, canonical, distal, 'P1-Runx1', transcription, start, site])].
[sujeto(['We', conclude, that, the, distal, 'P1-Runx1', promoter, is, a, direct, transcriptional]), verbo([target]), complemento([of, 'Wnt/β-catenin', signaling, that, may, be, important, in, normal, hematopoiesis, or, its, transition, into, malignant, stem, cells, during, the, onset, or, progression, of, leukemia])].
[sujeto(['The', generation, of, diverse, neuronal, subtypes]), verbo([involves]), complemento([specification, of, neural, progenitors, 'and,', 'subsequently,', postmitotic, neuronal, 'differentiation,', a, relatively, poorly, understood, process])].
[sujeto(['NGF', signals, through, the, 'ERK/MAPK', pathway, to]), verbo([promote]), complemento([expression, of, 'Cbfb', but, not, 'Runx1', prior, to, maturation, of, nonpeptidergic, nociceptors])].
[sujeto(['Thus,', an, 'NGF/TrkA-MAPK-CBFβ', pathway, converges, with, 'Islet1-Runx1', signaling, to]), verbo([promote]), complemento(['Runx1/CBFβ', holocomplex, formation, and, nonpeptidergic, nociceptor, maturation])].
[sujeto(['Convergence', of, extrinsic, and, intrinsic, signals, to, control, heterodimeric, transcription, factor, complex, formation]), verbo([provides]), complemento([a, robust, mechanism, for, postmitotic, neuronal, subtype, specification])].
[sujeto(['The', 't(8;21)', and, 'Inv(16)', translocations, disrupt, the, normal, function, of, core]), verbo([binding]), complemento([factors, alpha, '(', 'CBFA)', and, beta, '(', 'CBFB),', respectively])].
[sujeto(['Both', translocations, are]), verbo([associated]), complemento([with, favorable, clinical, outcomes, after, intensive, 'chemotherapy,', and, given, the, perceived, mechanistic, 'similarities,', patients, with, these, translocations, are, frequently, referred, to, as, having, 'CBF-AML'])].
[sujeto(['It', remains, uncertain, as, to, 'whether,', 'collectively,', these, translocations, are, mechanistically, the, same, or, impact, different, pathways, in, subtle, ways, that]), verbo([have]), complemento([both, biological, and, clinical, significance])].
[sujeto(['A', total, of, 1291, genes, in, 't(8;21)', and, 474, genes, in, 'Inv(16)', were, differentially]), verbo([expressed]), complemento([relative, to, the, 'NK', 'controls,', with, 198, genes, differentially, expressed, in, both, subtypes])].
[sujeto(['The', majority, of, these, genes, '(', 175, /, 198, ;, binomial, test, 'p-value', &, 'lt;', 10, '(', -, 30, ')', ')', are, consistent, in, expression, changes, among, the, two, subtypes]), verbo([suggesting]), complemento([the, expression, profiles, are, more, similar, between, the, 'CBF', cohorts, than, in, the, 'NK', cohort])].
[sujeto(['Our', analysis, also, revealed, alternative, splicing, events, '(', 'ASEs)', differentially]), verbo([expressed]), complemento([across, 'subtypes,', with, 337, 't(8;21)-specific', and, 407, 'Inv(16)-specific', 'ASEs', 'detected,', the, majority, of, which, were, acetylated, proteins, '(', p, =, 1.5, x, 10, '(', -, 51, ')', and, p, =, 1.8, x, 10, '(', -, 54, ')', for, the, two, 'subsets)'])].
[sujeto(['In', addition, to, known, 'fusions,', we, identified, and, verified, 16, de, novo, fusions, in, 43, 'patients,', including, three, fusions]), verbo([involving]), complemento(['NUP98', in, six, patients])].
[sujeto(['Clustering', of, differentially]), verbo([expressed]), complemento([genes, indicated, that, the, homeobox, '(', 'HOX)', gene, 'family,', including, two, transcription, factors, '(', 'MEIS1', and, 'NKX2-3)', were, 'down-regulated', in, 'CBF', compared, to, 'NK', samples])].
[sujeto(['This']), verbo([finding]), complemento([supports, existing, data, that, the, dysregulation, of, 'HOX', genes, play, a, central, role, in, biology, 'CBF-AML', hematopoiesis])].
[sujeto(['These', data]), verbo([provide]), complemento([comprehensive, transcriptome, profiling, of, 'CBF-AML', and, delineate, genes, and, pathways, that, are, differentially, 'expressed,', providing, insights, into, the, shared, biology, as, well, as, differences, in, the, two, 'CBF', subsets])].
[sujeto(['Chromosomal', translocations, are, frequently]), verbo([associated]), complemento([with, a, wide, variety, of, 'cancers,', particularly, hematologic, malignancies])].
[sujeto(['We']), verbo([report]), complemento([here, that, 'Wnt/β-catenin', signaling, increases, the, expression, of, 'ETO', and, 'RUNX1', genes, in, human, hematopoietic, progenitors])].
[sujeto(['We']), verbo([found]), complemento([that, 'β-catenin', is, rapidly, recruited, into, 'RNA', polymerase, 'II', transcription, factories, '(', 'RNAPII-Ser5)', and, that, 'ETO', and, 'RUNX1', genes, are, brought, into, close, spatial, proximity, upon, 'Wnt3a', induction])].
[sujeto(['Notably,', 'long-term', treatment, of, cells, with, 'Wnt3a']), verbo([induces]), complemento([the, generation, a, frequent, 'RUNX1-ETO', translocation, event])].
[sujeto(['Thus,', 'Wnt/β-catenin', signaling]), verbo([induces]), complemento([transcription, and, translocation, of, 'RUNX1', and, 'ETO', fusion, gene, 'partners,', opening, a, novel, window, to, understand, the, 'onset/development', of, leukemia])].
[sujeto(['Th-inducing', 'Pox', virus, and, zinc, 'finger/Krüppel-like', factor, '(', 'ThPOK)', is, a, key, commitment, factor, for, 'CD4(+)', lineage, 'T', cells, and, is, essential, for, the, maintenance, of, 'CD4', lineage, 'integrity;', 'thus,', the, expression, of, 'ThPOK']), verbo([has]), complemento([to, be, tightly, controlled])].
[sujeto(['In', this, 'article,', we, demonstrate, that, 'Myc-associated', zinc, 'finger-related', factor, '(', 'MAZR)', and, 'Runt-related', transcription, factor, 1, '(', 'Runx1)', together]), verbo([repressed]), complemento(['ThPOK', in, preselection, 'double-positive', 'thymocytes,', whereas, 'MAZR', acted, in, synergy, with, 'Runx3', in, the, repression, of, 'ThPOK', in, 'CD8(+)', 'T', cells])].
[sujeto(['Furthermore,', 'MAZR-Runx1', and, 'MAZR-Runx3', 'double-mutant', mice, showed]), verbo([enhanced]), complemento([derepression, of, 'Cd4', in, 'double-negative', thymocytes, and, in, 'CD8(+)', 'T', cells, in, comparison, with, 'Runx1', or, 'Runx3', 'single-deficient', 'mice,', 'respectively,', indicating, that, 'MAZR', modulates, 'Cd4', silencing])].
[sujeto(['Finally,', retroviral, 'Cre-mediated', conditional, deletion, of, 'MAZR', in, peripheral, 'CD8(+)', 'T', cells]), verbo([led]), complemento([to, the, derepression, of, 'ThPOK,', thus, showing, that, 'MAZR', is, also, part, of, the, molecular, machinery, that, maintains, a, repressed, state, of, 'ThPOK', in, 'CD8(+)', 'T', cells])].
[sujeto(['However,', the, molecular, mechanisms]), verbo([involved]), complemento([in, regulating, the, differentiation, and, function, of, 'MDSCs', remain, largely, unclear])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, inhibition, of, microRNA, '(', 'miR)-9', promoted, the, differentiation, of, 'MDSCs', with, significantly, reduced, immunosuppressive, function, whereas, overexpression, of, 'miR-9', markedly, enhanced, the, function, of, 'MDSCs'])].
[sujeto(['Notably,', knockdown, of, 'miR-9', significantly, impaired, the, activity, of, 'MDSCs', and]), verbo([inhibited]), complemento([the, tumor, growth, of, 'Lewis', lung, carcinoma, in, mice])].
[sujeto(['Moreover,', 'miR-9']), verbo([regulated]), complemento(['MDSCs', differentiation, by, targeting, the, 'runt-related', transcription, factor, 1, ',', an, essential, transcription, factor, in, regulating, 'MDSC', differentiation, and, function])].
[sujeto(['Furthermore,', the, 'CREB', was]), verbo([found]), complemento([to, regulate, 'miR-9', expression, in, 'MDSCs'])].
[sujeto(['Taken', 'together,', our, findings]), verbo([have]), complemento([identified, a, critical, role, of, 'miR-9', in, regulating, the, differentiation, and, function, of, 'MDSCs'])].
[sujeto(['Acute', stimulation, of, 'nucleotide-binding', oligomerization, domain, 2, '(', 'NOD2),', the, 'Crohn\'s', 'disease-associated', sensor, of, bacterial, 'peptidoglycan,']), verbo([induces]), complemento([cytokines])].
[sujeto(['However,', chronic, 'NOD2', stimulation, in, macrophages]), verbo([decreases]), complemento([cytokines, upon, pattern, recognition, receptor, '(', 'PRR)', 'restimulation;', cytokine, attenuation, to, 'PRR', stimulation, is, similarly, observed, in, intestinal, macrophages])].
[sujeto(['The', role, for, the, transcriptional, repressors, 'Twist1', and, 'Twist2', in]), verbo([regulating]), complemento(['PRR-induced', cytokine, outcomes, is, poorly, understood, and, has, not, been, reported, for, 'NOD2'])].
[sujeto(['We']), verbo([found]), complemento([that, 'Twist1', and, 'Twist2', were, required, for, optimal, cytokine, downregulation, during, acute, 'and,', 'particularly,', chronic, 'NOD2', stimulation, of, human, macrophages])].
[sujeto(['Consistently,', 'Twist1', and, 'Twist2', expression, was]), verbo([increased]), complemento([after, chronic, 'NOD2', 'stimulation;', this, increased, expression, was, 'IL-10', and, 'TGF-β', dependent])].
[sujeto(['Although', 'Twist1', and, 'Twist2', did, not, coregulate, each, 'other\'s', 'expression,', they, cooperated, to]), verbo([enhance]), complemento([binding, to, cytokine, promoters, after, chronic, 'NOD2', stimulation])].
[sujeto(['Moreover,', 'Twist1', and, 'Twist2', contributed, to]), verbo([enhance]), complemento([expression, and, promoter, binding, of, the, proinflammatory, inhibitor, 'c-Maf', and, the, transcriptional, repressor, 'Bmi1'])].
[sujeto(['Furthermore,', with, chronic, 'NOD2', 'stimulation,', 'Twist1', and, 'Twist2', contributed, to, the]), verbo([decreased]), complemento([expression, and, cytokine, promoter, binding, of, the, transcriptional, activators, activating, transcription, factor, 4, ',', 'C/EBPα,', 'Runx1,', and, 'Runx2'])].
[sujeto(['Finally,', 'NOD2', synergized, with, additional, 'PRRs', to]), verbo([increase]), complemento(['Twist1', and, 'Twist2', expression, and, 'Twist-dependent', pathways])].
[sujeto(['Therefore,', after, chronic, 'NOD2', stimulation, 'Twist1', and, 'Twist2', coordinate, the, regulation, of, both, transcriptional, activators, and, 'repressors,', thereby]), verbo([mediating]), complemento([optimal, cytokine, downregulation])].
[sujeto(['A', recent, study]), verbo([has]), complemento([shown, that, transcriptional, regulators, of, core, binding, factor, '(', 'Cbf)', β2, and, 'promotor-1-transcribed', 'Runt-related', transcription, factor, 1, '(', 'P1-Runx1)', are, required, for, the, differentiation, of, 'CD3-CD4+CD45+', lymphoid, tissue, inducer, '(', 'LTi)', 'cells,', which, initiate, and, trigger, the, developmental, program, of, 'PPs,', but, the, involvement, of, this, pathway, in, 'NALT', and, 'TALT', development, remains, to, be, elucidated])].
[sujeto(['Here', we]), verbo([report]), complemento([that, 'Cbfβ2', plays, an, essential, role, in, 'NALT', and, 'TALT', development, by, regulating, 'LTi', cell, trafficking, to, the, 'NALT', and, 'TALT', anlagens])].
[sujeto(['Cbfβ2', was]), verbo([expressed]), complemento([in, 'LTi', cells, in, all, three, types, of, 'MALT', examined])].
[sujeto(['Indeed,', similar, to, the, previous]), verbo([finding]), complemento([for, 'PPs,', we, found, that, 'Cbfβ2-/-', mice, lacked, 'NALT', and, 'TALT', lymphoid, structures])].
[sujeto(['We', exploited, a, pluripotent, hematopoietic, 'stem/progenitor', cell, 'line,', 'EML1,', and, generated, a, cell, line, '(', 'EML-TA)', stably]), verbo([expressing]), complemento([the, 'TEL-AML1', fusion, protein])].
[sujeto(['Global', gene, expression, profiling, of, 'EML1', cells, at, different, stages, of, 'B-lymphoid', 'differentiation,', compared, with, 'EML-TA,', identified, the, interferon, '(', 'IFN)α/β', pathway, as, a, primary]), verbo([target]), complemento([of, repression, by, 'TEL-AML1'])].
[sujeto(['In', 'particular,', expression, and, phosphorylation, of, 'interferon-regulatory', factor, 3, '(', 'IRF3)', was]), verbo([decreased]), complemento([in, 'EML-TA', 'cells;', 'strikingly,', stable, expression, of, 'IRF3', restored, the, capacity, of, 'EML-TA', cells, to, differentiate, into, mature, 'B-cells'])].
[sujeto(['The', ability, of, 'TEL-AML1', to, block, 'B-cell', differentiation, and, downregulate, the, 'IRF3-IFNα/β', pathway, was, confirmed, in, mouse, and, human, primary, hematopoietic, precursor, cells, '(', 'Lin-', and, 'CD34+', 'cells,', 'respectively),', and, in, a, 'patient-derived', cell, line]), verbo([expressing]), complemento(['TEL-AML1', '(', 'REH)'])].
[sujeto(['Furthermore,', treatment, of, 'TEL-AML1']), verbo([expressing]), complemento([cells, with, 'IFNα/β', was, sufficient, to, overcome, the, maturation, block])].
[sujeto(['Our', data]), verbo([provide]), complemento([new, insight, on, 'TEL-AML1', function, and, may, offer, a, new, therapeutic, opportunity, for, 'B-ALL'])].
[sujeto(['High', mutation, frequencies, of, 'RUNX1', gene, in, chronic, myelomonocytic, leukemia, '(', 'CMML)', and, myelodysplastic, syndromes, '(', 'MDS)']), verbo([have]), complemento([been, 'described,', whereas, the, biologic, significances, of, the, mutations, were, not, investigated])].
[sujeto(['Then,', we, studied, the, 'DNA', and, 'CBFβ']), verbo([binding]), complemento([abilities, of, all, the, 'RUNX1', mutants, identified, by, using, electrophoretic, mobility, shift, assay, and, 'co-immunoprecipitation', 'assay,', and, also, determined, their, activities, on, target, 'C-FMS', gene, induction, by, 'Western', blotting, and, luciferase, reporter, assay])].
[sujeto(['Previously,', it, was, proposed, that, 'CBFβ-SMMHC']), verbo([acts]), complemento([by, dominantly, repressing, the, transcription, factor, 'RUNX1', '(', 'Runt-related', protein, 1, ')', ',', but, we, recently, showed, that, 'CBFβ-SMMHC', has, activities, that, are, independent, of, 'RUNX1', repression])].
[sujeto(['In', 'addition,', we, showed, that, a, modified, 'CBFβ-SMMHC', with]), verbo([decreased]), complemento(['RUNX1-binding', activity, accelerates, leukemogenesis])].
[sujeto(['To', test, 'this,', we, generated, mice]), verbo([expressing]), complemento(['Cbfb-MYH11', in, a, 'Runx1-deficient', 'background,', resulting, from, either, homozygous, 'Runx1-null', alleles, '(', 'Runx1(-/-))', or, a, single, 'dominant-negative', 'Runx1', allele, '(', 'Runx1(+/lz))'])].
[sujeto(['We']), verbo([found]), complemento([that, loss, of, 'Runx1', activity, rescued, the, differentiation, defects, induced, by, 'Cbfb-MYH11', during, primitive, hematopoiesis])].
[sujeto(['During', definitive, 'hematopoiesis,', 'RUNX1']), verbo([loss]), complemento([also, significantly, reduced, the, proliferation, and, differentiation, defects, induced, by, 'Cbfb-MYH11'])].
[sujeto(['The', transcription, factor, fusion, 'CBFβ-SMMHC', '(', core]), verbo([binding]), complemento([factor, β, and, the, 'smooth-muscle', myosin, heavy, 'chain),', expressed, in, 'AML', with, the, chromosome, inversion, 'inv(16)(p13q22),', outcompetes, 'wild-type', 'CBFβ', for, binding, to, the, transcription, factor, 'RUNX1,', deregulates, 'RUNX1', activity, in, 'hematopoiesis,', and, induces, 'AML'])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, development, of, a, 'protein-protein', interaction, 'inhibitor,', 'AI-10-49,', that, selectively, binds, to, 'CBFβ-SMMHC', and, disrupts, its, binding, to, 'RUNX1'])].
[sujeto(['Treatment', of, primary, 'inv(16)', 'AML', patient, blasts, with, 'AI-10-49']), verbo([triggers]), complemento([selective, cell, death])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, direct, inhibition, of, the, oncogenic, 'CBFβ-SMMHC', fusion, protein, may, be, an, effective, therapeutic, approach, for, 'inv(16)', 'AML,', and, they, provide, support, for, transcription, factor, targeted, therapy, in, other, cancers])].
[sujeto([1, +, ')', 'Th1', cells]), verbo([induced]), complemento([colitis, in, 'Rag(-/-)', mice, after, adoptive, transfer, and, converted, into, 'IL-17(+)', 'Th17,', but, not, 'Foxp3(+)', 'Treg', cells, in, the, inflamed, intestines])].
[sujeto(['TGF-β', and, 'IL-6,', but, not, 'IL-1β', and, 'IL-23,']), verbo([regulated]), complemento(['Th1', conversion, into, 'Th17', cells])].
[sujeto(['TGF-β', induction, of, transcriptional, factor, 'Runx1', is, crucial, for, the, 'conversion,', since, silencing, 'Runx1', by, siRNA]), verbo([inhibited]), complemento(['Th1', conversion, into, 'Th17', cells])].
[sujeto(['Furthermore,', 'TGF-β']), verbo([enhanced]), complemento([histone, 'H3K9', acetylation, but, inhibited, 'H3K9', trimethylation, of, 'Runx1-', and, 'ROR-γt-binding', sites, on, 'il-17', or, rorc, gene, in, 'Th1', cells])].
[sujeto(['We', conclude, that, 'Th1', cells, convert, into, 'Th17', cells, under, inflammatory, conditions, in, 'intestines,', which, is, possibly]), verbo([mediated]), complemento([by, 'TGF-β', induction, of, 'Runx1'])].
[sujeto(['Cooperative', assemblies, of, transcription, factors, '(', 'TFs)', on]), verbo([target]), complemento([gene, enhancers, coordinate, cell, 'proliferation,', fate, 'specification,', and, differentiation, through, precise, and, complicated, transcriptional, mechanisms])].
[sujeto(['Chemical', 'modifications,', such, as, 'phosphorylation,', of, 'TFs']), verbo([induced]), complemento([by, cell, signaling, further, modulate, the, dynamic, cooperativity, of, 'TFs'])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, various, 'Ets1-containing', 'TF-DNA', complexes, respond, differently, to, 'calcium-induced', phosphorylation, of, 'Ets1,', which, is, known, to, inhibit, 'Ets1-DNA', binding])].
[sujeto(['Crystallographic', analysis, of, a, complex, comprising, 'Ets1,', 'Runx1,', and, 'CBFβ', at, the, 'TCRα', enhancer, revealed, that, 'Ets1', acquires, robust]), verbo([binding]), complemento([stability, in, the, 'Runx1', and, 'DNA-complexed', 'state,', via, allosteric, mechanisms])].
[sujeto(['This', allows]), verbo([phosphorylated]), complemento(['Ets1', to, be, retained, at, the, 'TCRα', enhancer, with, 'Runx1,', in, contrast, to, other, 'Ets1', target, gene, enhancers, including, 'mb-1', and, 'stromelysin-1'])].
[sujeto(['This', study]), verbo([provides]), complemento([a, 'structure-based', model, for, 'cell-signaling-dependent', regulation, of, target, 'genes,', mediated, via, chemical, modification, of, 'TFs'])].
[sujeto(['The', 2, genes, 'RUNX1', and, 'SP7', resulted, differently]), verbo([expressed]), complemento([in, cells, cultured, on, metallic, supports, if, compared, with, the, expression, recorded, for, 'OIC'])].
[sujeto(['However,', the, mechanism, by, which, 'Cbfβ']), verbo([regulates]), complemento([cartilage, and, bone, development, remains, unclear])].
[sujeto(['Surprisingly,', the, mutant, mice, had, 'under-developed', larynx, and, tracheal, 'cartilage,']), verbo([causing]), complemento([alveolus, defects, that, led, to, death, shortly, after, birth, from, suffocation])].
[sujeto(['Importantly,', we, showed, that, 'Cbfβ', was]), verbo([expressed]), complemento([throughout, the, skeleton, during, both, embryonic, and, postnatal, 'development,', which, explains, the, 'multiple-skeletal', defects, observed, in, the, mutant, mice])].
[sujeto(['Notably,', 'Cbfβ,', 'Runx1', and, 'Runx2', displayed, different, expression, patterns, in, the, growth, plates, of, the, 'wild-type', 'mice,', indicating, that, 'Cbfβ/Runx1', complex, and, 'Cbfβ/Runx2', complex, may]), verbo([regulate]), complemento([chondrocyte, proliferation, and, 'hypertrophy,', 'respectively,', in, a, spatial, and, temporal, manner])].
[sujeto(['Collectively,', the, results, demonstrate, that, 'Cbfβ']), verbo([mediates]), complemento([cartilage, and, bone, development, by, interacting, with, 'Runx1', and, 'Runx2', to, regulate, the, expressions, of, 'Col', 'X', and, 'Osx', for, chondrocyte, and, osteoblast, development])].
[sujeto(['These', findings, not, only]), verbo([reveal]), complemento([a, critical, role, for, 'Cbfβ', in, cartilage, and, bone, development, but, also, facilitate, the, design, of, novel, therapeutic, approaches, for, skeletal, diseases])].
[sujeto(['Core']), verbo([binding]), complemento([factor, '(', 'CBF)', is, a, heterodimeric, transcription, factor, complex, composed, of, a, 'DNA-binding', 'subunit,', one, of, three, 'runt-related', transcription, factor, '(', 'RUNX)', 'factors,', and, a, 'non-DNA', binding, 'subunit,', 'CBFβ'])].
[sujeto(['CBFβ', is, critical, for, 'DNA']), verbo([binding]), complemento([and, stability, of, the, 'CBF', transcription, factor, complex])].
[sujeto(['In', the, 'ovary,', the, 'LH', surge]), verbo([increases]), complemento([the, expression, of, 'Runx1', and, 'Runx2', in, periovulatory, 'follicles,', implicating, a, role, for, 'CBFs', in, the, periovulatory, process])].
[sujeto(['The', mutant, female, mice, exhibited, significant, reductions, in, 'fertility,', with, smaller, litter, 'sizes,']), verbo([decreased]), complemento([progesterone, during, 'gestation,', and, fewer, cumulus, oocyte, complexes, collected, after, an, induced, superovulation])].
[sujeto(['Cbfβ', knockdown, mice, also, exhibited]), verbo([decreased]), complemento([expression, of, key, genes, within, the, corpora, lutea, and, morphological, changes, in, the, ovarian, 'structure,', including, the, presence, of, large, antral, follicles, well, into, the, luteal, phase])].
[sujeto(['Overall,', these, data]), verbo([suggest]), complemento([a, role, for, 'CBFs', as, significant, regulators, of, gene, 'expression,', ovulatory, 'processes,', and, luteal, development, in, the, ovary])].
[sujeto(['Core']), verbo([binding]), complemento([factor, β, '(', 'Cbfβ)', is, a, partner, protein, of, 'Runx', family, transcription, factors, with, minimally, characterized, function, in, cartilage])].
[sujeto(['Here', we, address, the, role, of, 'Cbfβ', in, cartilage, by, generating, 'chondrocyte-specific', 'Cbfβ-deficient', mice, '(', 'Cbfb(Δch/Δch)', ')', from, 'Cbfb-floxed', mice, crossed, with, mice]), verbo([expressing]), complemento(['Cre', from, the, 'Col2a1', promoter])].
[sujeto(['Cbfb(Δch/Δch)', mice, died, soon, after, birth, and, exhibited, delayed, endochondral, bone, 'formation,', shorter, appendicular, skeleton, length, with]), verbo([increased]), complemento([proliferative, 'chondrocytes,', and, nearly, absent, hypertrophic, chondrocyte, zones])].
[sujeto(['Immunohistochemical', and, quantitative, 'real-time', 'PCR', analyses, showed, that, the, number, and, size, of, proliferative, chondrocytes]), verbo([increased]), complemento([and, the, expression, of, chondrocyte, maturation, markers, at, the, growth, 'plates,', including, 'Runx2,', 'osterix,', and, 'osteopontin,', significantly, diminished, in, 'Cbfb(Δch/Δch)', mice, compared, to, wild, type, mice])].
[sujeto(['Mechanistically,', 'Cbfβ', deficiency, in, chondrocytes]), verbo([caused]), complemento([a, decrease, of, protein, levels, of, 'Runx', transcription, factors, by, accelerating, 'polyubiquitination-mediated', proteosomal, degradation, in, vitro])].
[sujeto(['Indeed,', 'Runx2', and, 'Runx3,', but, not, 'Runx1,']), verbo([decreased]), complemento([in, 'Cbfb(Δch/Δch)', mice])].
[sujeto(['Runx2', is]), verbo([required]), complemento([for, osteoblast, differentiation, and, chondrocyte, 'maturation,', and, haplodeficiency, of, 'RUNX2', causes, cleidocranial, 'dysplasia,', which, is, characterized, by, open, fontanelles, and, sutures, and, hypoplastic, clavicles])].
[sujeto(['Cbfb', forms, a, heterodimer, with, 'Runx', family, proteins, and]), verbo([enhances]), complemento([their, 'DNA-binding', capacity])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, the, partial, rescue, of, hematopoiesis, in, 'Cbfb(-/-)', mice, revealed, the, requirement, of, 'Cbfb', in, skeletal, development])].
[sujeto(['The', differentiation, of, chondrocytes, and, osteoblasts, were, severely]), verbo([inhibited]), complemento([in, 'vitro,', and, the, reporter, activities, of, 'Ihh,', 'Col10a1,', and, 'Bglap2', promoter, constructs, were, reduced, in, 'Cbfb(fl/fl/Cre)', chondrocytes, or, osteoblasts])].
[sujeto(['These', findings, indicate, that, 'Cbfb', is]), verbo([required]), complemento([for, skeletal, development, by, regulating, chondrocyte, differentiation, and, proliferation, and, osteoblast, 'differentiation;', that, 'Cbfb', plays, an, important, role, in, the, stabilization, of, 'Runx', family, 'proteins;', and, that, 'Runx2', protein, stability, is, less, dependent, on, 'Cbfb', in, calvariae, than, in, cartilaginous, limb, skeletons])].
[sujeto(['Cytogenetics']), verbo([provide]), complemento([reliable, risk, stratification, for, 'treatment:', high, hyperdiploidy, and, 'ETV6-RUNX1', are, good, 'risk,', whereas, 'BCR-ABL1,', 'MLL', 'rearrangements,', and, hypodiploidy, are, poor, risk])].
[sujeto(['With', advancing, technologies, in, 'array-based', approaches, '(', single, nucleotide, polymorphism, 'arrays)', and, 'next-generation', sequencing, to, study, the, 'genome,']), verbo([increasing]), complemento([numbers, of, new, genetic, changes, are, being, discovered])].
[sujeto(['Whether', they]), verbo([have]), complemento([a, link, to, outcome, is, the, most, important, factor, for, refinement, of, risk, factors, in, relation, to, clinical, trials])].
[sujeto(['For', several, newly, identified, 'abnormalities,', including, intrachromosomal, amplification, of, chromosome, 21, '(', 'iAMP21),', that, are]), verbo([associated]), complemento([with, a, poor, prognosis, with, standard, 'therapy,', appropriately, modified, treatment, has, significantly, improved, outcome])].
[sujeto(['After', the, successful, use, of, tyrosine, kinase, inhibitors, in, the, treatment, of, 'BCR-ABL1-positive', acute, lymphoblastic, 'leukemia,', patients, with, alternative, 'ABL1', translocations, and, rearrangements]), verbo([involving]), complemento(['PDGFRB', may, benefit, from, treatment, with, tyrosine, kinase, inhibitors])].
[sujeto(['Other', 'aberrations,', for, 'example,', 'CRLF2', overexpression, and, 'JAK2', 'mutations,', are, also]), verbo([providing]), complemento([potential, novel, therapeutic, targets, with, the, prospect, of, reduced, toxicity])].
[sujeto(['Inactivating', 'RUNX1', mutations]), verbo([have]), complemento([frequently, been, found, in, patients, with, myelodysplastic, syndrome, '(', 'MDS)', and, cytogenetically, normal, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['However,', no, somatic, 'RUNX1', alteration, was]), verbo([found]), complemento([in, 'AMLs', with, leukemogenic, fusion, 'proteins,', such, as, 'core-binding', factor, '(', 'CBF)', leukemia, and, 'MLL', fusion, 'leukemia,', raising, the, possibility, that, 'RUNX1', could, actually, promote, the, growth, of, these, leukemia, cells])].
[sujeto(['Using', normal, human, cord, blood, cells, and, those]), verbo([expressing]), complemento([leukemogenic, fusion, 'proteins,', we, discovered, a, dual, role, of, 'RUNX1', in, myeloid, leukemogenesis])].
[sujeto(['RUNX1', overexpression]), verbo([inhibited]), complemento([the, growth, of, normal, cord, blood, cells, by, inducing, myeloid, 'differentiation,', whereas, a, certain, level, of, 'RUNX1', activity, was, required, for, the, growth, of, 'AML1-ETO', and, 'MLL-AF9', cells])].
[sujeto(['Using', a, mouse, genetic, 'model,', we, also, showed, that, the, combined]), verbo([loss]), complemento([of, 'Runx1/Cbfb', inhibited, leukemia, development, induced, by, 'MLL-AF9'])].
[sujeto(['RUNX2', could, compensate, for, the]), verbo([loss]), complemento([of, 'RUNX1'])].
[sujeto(['The', survival, effect, of, 'RUNX1', was]), verbo([mediated]), complemento([by, 'BCL2', in, 'MLL', fusion, leukemia])].
[sujeto(['Inhibiting', 'RUNX1', activity, rather, than]), verbo([enhancing]), complemento([it, could, be, a, promising, therapeutic, strategy, for, 'AMLs', with, leukemogenic, fusion, proteins])].
[sujeto(['This', translocation]), verbo([causes]), complemento([expression, of, the, 'RUNX1-ETO', '(', 'AML1-ETO)', fusion, 'protein,', which, cooperates, with, additional, mutations, in, leukemia, development])].
[sujeto(['We']), verbo([report]), complemento([here, that, interferons, '(', 'IFNs)', and, 'IFN-stimulated', genes, are, a, group, of, genes, consistently, 'up-regulated', by, 'RUNX1-ETO', in, both, human, and, murine, models])].
[sujeto(['Addition', of, exogenous, 'IFN', in, vitro, significantly, reduces, the]), verbo([increase]), complemento([in, 'self-renewal', potential, induced, by, both, 'RUNX1-ETO', and, its, leukemogenic, splicing, isoform, 'RUNX1-ETO9a'])].
[sujeto(['Finally,']), verbo([loss]), complemento([of, type, 'I', 'IFN', signaling, via, knockout, of, 'Ifnar1', significantly, accelerates, leukemogenesis, in, a, 't(8;21)', murine, model])].
[sujeto(['This', demonstrates, the, role, of]), verbo([increased]), complemento(['IFN', signaling, as, an, important, factor, inhibiting, 't(8;21)', fusion, protein, function, and, leukemia, development, and, supports, the, use, of, type, 'I', 'IFNs', in, the, treatment, of, 'AML'])].
[sujeto(['Lymphoid', 'enhancer-binding', factor, 1, '(', 'LEF1)', is, a, downstream, effector, of, the, 'Wnt/β-catenin', signaling, pathway, and, its, dysregulation, is]), verbo([associated]), complemento([with, a, number, of, malignant, diseases, such, as, leukemia])].
[sujeto(['Moreover,', we]), verbo([provide]), complemento([the, first, evidence, that, primary, 'AML', samples, with, 'AML1-ETO', or, 'PML-RARα', have, a, higher, 'LEF1', level, compared, with, those, without, each, fusion, gene])].
[sujeto(['High', 'LEF1', level, was]), verbo([associated]), complemento([with, a, favorable, 'relapse-free', survival, in, patients, with, 'FLT3-ITD', 'wild-type'])].
[sujeto(['No', consecutive, analysis, of, 'BAALC', and, 'WT1', expressions]), verbo([associated]), complemento([with, 'core-binding', factor, 'AML', '(', 'CBF-AML)', from, diagnosis, to, hematopoietic, stem, cell, transplantation, '(', 'HSCT)', has, yet, been, reported])].
[sujeto(['A', subgroup, of, 't(8;21)', showing, higher, 'BAALC', and, 'WT1', expressions, at, 'post-HSCT', were, also]), verbo([associated]), complemento([with, inferior, 'OS', '(', 'P', =, 0.018, ',', 0.015, ')', and, higher, 'CIR', rates, '(', 'P', =, 0.019, ',', 0.011, ')'])].
[sujeto(['Developing', novel, therapies, that]), verbo([suppress]), complemento(['self-renewal', of, leukemia, stem, cells, may, reduce, the, likelihood, of, relapses, and, extend, 'long-term', survival, of, patients, with, acute, myelogenous, leukemia, '(', 'AML)'])].
[sujeto(['AML1-ETO', '(', 'AE)', is, an, oncogene, that, plays, an, important, role, in]), verbo([inducing]), complemento(['self-renewal', of, hematopoietic, 'stem/progenitor', cells, '(', 'HSPCs),', leading, to, the, development, of, leukemia, stem, cells])].
[sujeto(['Previously,', using, a, zebrafish, model, of, 'AE', and, a, 'whole-organism', chemical, suppressor, 'screen,', we]), verbo([have]), complemento([discovered, that, 'AE', induces, specific, hematopoietic, phenotypes, in, embryonic, zebrafish, through, a, cyclooxygenase, '(', 'COX)-2', and, 'β-catenin-dependent', pathway])].
[sujeto(['Here,', we, show, that, 'AE', also]), verbo([induces]), complemento([expression, of, the, 'Cox-2', gene, and, activates, 'β-catenin', in, mouse, bone, marrow, cells])].
[sujeto(['Inhibition', of, 'COX']), verbo([suppresses]), complemento(['β-catenin', activation, and, serial, replating, of, 'AE(+)', mouse, 'HSPCs'])].
[sujeto(['In', 'addition,', treatment, with, 'nimesulide,', a, 'COX-2', selective, 'inhibitor,', dramatically]), verbo([suppresses]), complemento([xenograft, tumor, formation, and, inhibits, in, vivo, progression, of, human, leukemia, cells])].
[sujeto(['In', 'summary,', our, data, indicate, an, important, role, of, a, 'COX/β-catenin-dependent', signaling, pathway, in, tumor, 'initiation,', 'growth,', and, 'self-renewal,', and, in]), verbo([providing]), complemento([the, rationale, for, testing, potential, benefits, from, common, 'COX', inhibitors, as, a, part, of, 'AML', treatments])].
[sujeto(['It', is, known, that, leukemia, patients, with, extramedullary, infiltration, '(', 'EMI)']), verbo([have]), complemento([a, worse, prognosis, than, patients, without, it])].
[sujeto(['Recent', data, indicate, that, the, amyloid, precursor, protein, '(', 'APP)', is]), verbo([involved]), complemento([in, cell, 'adhesion,', 'motility,', and, proliferation])].
[sujeto(['The', expression, of, 'APP', and, its, prognostic, significance, in, acute, myeloid, leukemia, '(', 'AML)']), verbo([have]), complemento([not, been, studied])].
[sujeto(['Transwell', data, show, that, 'siRNA/APP', substantially, impairs, cell, 'migration,', but, it, does, not]), verbo([inhibit]), complemento([cell, proliferation])].
[sujeto(['Furthermore,', by, quantitative, 'real-time', polymerase, chain, reaction, and, 'Western', 'blot,', we]), verbo([found]), complemento([that, 'siRNA/APP', decreases, 'MMP-2', expression, in, vitro])].
[sujeto(['Our', study]), verbo([provides]), complemento([a, novel, clue, that, 'APP', is, involved, in, the, extramedullary, infiltration, of, leukemia, by, 'MMP-2'])].
[sujeto(['Secreted-frizzled', related, proteins, '(', 'SFRPs)', are, modulators, of, the, 'Wnt', signaling, pathway, that, is, closely]), verbo([involved]), complemento([in, normal, and, malignant, hematopoiesis])].
[sujeto(['Epigenetic', deregulation, of, 'Wnt', modulators]), verbo([leading]), complemento([to, aberrant, signaling, has, been, reported, in, adult, patients, with, acute, myeloid, leukemia, '(', 'AML),', but, its, occurrence, in, childhood, patients, with, 'AML', and, the, role, of, individual, modulators, are, unclear])].
[sujeto(['In', this, 'study,', we, examined, 'SFRP1,', 'SFRP2,', 'SFRP4,', and, 'SFRP5', promoter, methylation, in, 83, patients, with, 'AML', '(', 59, children, and, 24, 'adults)', and]), verbo([found]), complemento([preferential, 'SFRP1', methylation, and, mRNA, 'down-regulation', in, the, prognostically, favorable, subgroup, of, 'AML', with, 't(8;21)', translocation])].
[sujeto(['Mechanistically,', we, further, demonstrated, that, 'RUNX1-ETO,', the, 't(8;21)', fusion, 'product,', specifically]), verbo([bound]), complemento([the, 'SFRP1', promoter, and, repressed, its, transcription, via, a, consensus, 'RUNX', binding, site])].
[sujeto(['In', 't(8;21)-leukemia', 'cells,', 'SFRP1', selectively]), verbo([inhibited]), complemento([canonical, 'Wnt', signaling, and, cellular, proliferation, that, were, associated, with, concomitant, 'down-regulation', of, 'Wnt/β-catenin', target, 'genes,', including, 'CCND1', and, 'MYC'])].
[sujeto(['Taken', 'together,', we, identified, 'SFRP1', as, a, transcriptional, repression]), verbo([target]), complemento([of, the, 't(8;21)', fusion, protein, and, demonstrated, a, novel, mechanism, of, 'Wnt', activation, in, a, specific, subtype, of, 'AML'])].
[sujeto(['The', 'mixed-lineage', leukemia, '(', 'MLL)', 'H3K4', methyltransferase, 'protein,', and, the, heterodimeric, 'RUNX1/CBFβ', transcription, factor, 'complex,', are, critical, for, definitive, and, adult, 'hematopoiesis,', and, both, are, frequently]), verbo([targeted]), complemento([in, human, acute, leukemia])].
[sujeto(['We', identified, a, physical, and, functional, interaction, between, 'RUNX1', '(', 'AML1)', and, 'MLL', and, show, that, both, are]), verbo([required]), complemento([to, maintain, the, histone, lysine, 4, trimethyl, mark, '(', 'H3K4me3)', at, 2, critical, regulatory, regions, of, the, 'AML1', target, gene, 'PU'])].
[sujeto(['Similar', to, 'CBFβ,', we, show, that, 'MLL']), verbo([binds]), complemento([to, 'AML1', abrogating, its, 'proteasome-dependent', degradation])].
[sujeto(['Furthermore,', a, subset, of, previously, uncharacterized, 'frame-shift', and, missense, mutations, at, the, 'N', terminus, of, 'AML1,']), verbo([found]), complemento([in, 'MDS', and, 'AML', 'patients,', impairs, its, interaction, with, 'MLL,', resulting, in, loss, of, the, 'H3K4me3', mark, within, 'PU'])].
[sujeto([1, regulatory, 'regions,', and]), verbo([decreased]), complemento(['PU'])].
[sujeto(['The', interaction, between, 'MLL', and, 'AML1']), verbo([provides]), complemento([a, mechanism, for, the, 'sequence-specific', binding, of, 'MLL', to, 'DNA,', and, identifies, 'RUNX1', target, genes, as, potential, effectors, of, 'MLL', function])].
[sujeto(['The', genetic, origins, of, the, development, of, malignant, haematological, disorders]), verbo([have]), complemento([been, established, at, the, beginning, of, the, 80, ies])].
[sujeto(['Systematic', characterization, of, chromosomal, structural, abnormalities, 'and,', more, recently, by, 'DNA', microarray, approaches, and, sequencing, of, tumour, genomes]), verbo([have]), complemento([allowed, the, identification, of, a, large, number, of, genes, that, are, mutated, during, malignant, transformation, in, humans])].
[sujeto(['Functional', studies, of, these, human, oncogenes]), verbo([have]), complemento([shown, that, most, of, them, were, not, able, to, transform, a, haematologic, progenitor, when, acting, alone, and, that, cooperation, with, other, oncogenic, events, was, required])].
[sujeto(['From', these, 'data,', the, development, of, efficient, therapeutic, approaches, will, be, possible, by]), verbo([targeting]), complemento([the, early, oncogenic, events, which, are, at, the, origin, of, the, malignant, transformation])].
[sujeto(['To', identify, genes, and, components]), verbo([associated]), complemento([with, this, oncogene, we, used, 'Drosophila', as, a, genetic, model])].
[sujeto(['Expression', of, 'AML1-ETO']), verbo([caused]), complemento([an, expansion, of, hematopoietic, precursors, in, 'Drosophila,', which, expressed, high, levels, of, reactive, oxygen, species, '(', 'ROS)'])].
[sujeto(['Mutations', in, functional, domains, of, the, fusion, protein]), verbo([suppress]), complemento([the, proliferative, phenotype])].
[sujeto(['In', a, genetic, 'screen,', we]), verbo([found]), complemento([that, inactivation, of, 'EcRB1', or, activation, of, 'Foxo', and, superoxide, 'dismutase-2', '(', 'SOD2)', suppress, the, 'AML1-ETO-induced', phenotype, by, reducing, 'ROS', expression, in, the, precursor, cells])].
[sujeto(['Our', studies, indicate, that, 'ROS', is, a, signaling, factor]), verbo([promoting]), complemento([maintenance, of, normal, as, well, as, the, aberrant, myeloid, precursors, and, suggests, the, importance, of, antioxidant, enzymes, and, their, regulators, as, targets, for, further, study, in, the, context, of, leukemia])].
[sujeto(['Although', 'NF-E2', levels, correlate, with, 'JAK2(V671F)', allele, burden, in, some, 'PV', 'cohorts,', the, molecular, mechanism]), verbo([causing]), complemento([aberrant, 'NF-E2', expression, has, not, been, described])].
[sujeto(['Here', we, show, that, 'NF-E2', expression, is, also]), verbo([increased]), complemento([in, patients, with, essential, thrombocythemia, and, primary, myelofibrosis, independent, of, the, presence, of, the, 'JAK2(V617F)', mutation])].
[sujeto(['Characterization', of, the, 'NF-E2', promoter, revealed, multiple, functional]), verbo([binding]), complemento([sites, for, 'AML1/RUNX-1'])].
[sujeto(['Chromatin', immunoprecipitation, demonstrated, 'AML1']), verbo([binding]), complemento([to, the, 'NF-E2', promoter, in, vivo])].
[sujeto(['Moreover,', 'AML1']), verbo([binding]), complemento([to, the, 'NF-E2', promoter, was, significantly, increased, in, granulocytes, from, 'PV', patients, compared, with, healthy, controls])].
[sujeto(['RNAi-mediated', suppression, of, either, 'AML1', or, of, its]), verbo([binding]), complemento([partner, 'CBF-beta', significantly, decreased, 'NF-E2', expression])].
[sujeto(['Moreover,', expression, of, the, leukemic, fusion, protein, 'AML/ETO', drastically]), verbo([decreased]), complemento(['NF-E2', protein, levels])].
[sujeto(['Our', data, identify, 'NF-E2', as, a, novel, 'AML1']), verbo([target]), complemento([gene, and, delineate, a, role, for, aberrant, 'AML1', expression, in, mediating, elevated, 'NF-E2', expression, in, 'MPN', patients])].
[sujeto(['The', acquisition, of, the, 'critical,', secondary, 'CNAs']), verbo([requires]), complemento([some, 'Darwinian', selective, advantage, to, expand, numbers, of, cells, at, 'risk,', and, the, cytokine, 'TGF', beta, is, able, to, exercise, this, function])].
[sujeto(['The', clonal, architecture, of, 'ALL']), verbo([has]), complemento([been, investigated, by, single, cell, analysis, with, multicolor, probes, to, mutant, genes])].
[sujeto(['The', data]), verbo([reveal]), complemento([not, a, linear, sequence, of, mutation, acquisition, with, clonal, succession, but, rather, considerable, complexity, with, a, 'tree-like', or, branching, structure, of, genetically, distinct, subclones, very, reminiscent, of, 'Darwin\'s', original, 1837, evolutionary, divergence, diagram])].
[sujeto(['This', evolutionary, pattern]), verbo([has]), complemento([important, implications, for, stem, cells, in, 'ALL,', for, the, origins, of, relapse, and, for, therapeutic, targeting])].
[sujeto(['However,', optimal, sampling, intervals]), verbo([have]), complemento([not, been, defined, and, are, likely, to, vary, according, to, the, underlying, molecular, lesion])].
[sujeto(['Combination', of, conventional, chromosome, analysis, '(', 'CCA)', and, 'FISH']), verbo([provides]), complemento([higher, sensitivity, in, detecting, these, genetic, 'abnormalities,', and, it, is, effective, to, apply, several, 'FISH', probes, as, a, profile, test])].
[sujeto(['Naturally', arising, regulatory, 'T', '(', 'Treg)', cells]), verbo([express]), complemento([the, transcription, factor, 'FoxP3,', which, critically, controls, the, development, and, function, of, 'Treg', cells])].
[sujeto(['FoxP3']), verbo([interacts]), complemento([with, another, transcription, factor, 'Runx1', '(', also, known, as, 'AML1)'])].
[sujeto(['Here,', we, showed, that, 'Treg', 'cell-specific', deficiency, of, 'Cbfbeta,', a, cofactor, for, all, 'Runx', 'proteins,', or, that, of, 'Runx1,', but, not, 'Runx3,']), verbo([induced]), complemento(['lymphoproliferation,', autoimmune, 'disease,', and, hyperproduction, of, 'IgE'])].
[sujeto(['The', 'Runx', complex]), verbo([bound]), complemento([to, more, than, 3000, gene, loci, in, 'Treg', 'cells,', including, the, 'Foxp3', regulatory, regions, and, the, 'Il4', silencer])].
[sujeto(['In', 'addition,', knockdown, of, 'RUNX1', showed, that, 'RUNX1', is]), verbo([required]), complemento([for, the, optimal, regulation, of, 'FoxP3', expression, in, human, 'T', cells])].
[sujeto(['Interestingly,', both, 'CBF', leukemia, fusion, proteins, and, 'miR-17,', which]), verbo([targets]), complemento(['RUNX1-3\'UTR,', negatively, affect, a, common, core, 'RUNX1-miRNA', mechanism, that, forces, myeloid, cells, into, an, 'undifferentiated,', 'KIT-induced,', proliferating, state])].
[sujeto(['In', the, second, part, of, this, study, we, took, advantage, of, the, conservation, of, the, core, 'RUNX1-miRNA', mechanism, in, mouse, and, 'human,', to, mechanistically, demonstrate, in, a, mouse, myeloid, cell, model, that]), verbo([increased]), complemento(['KIT-induced', proliferation, is, per, se, a, mechanism, sufficient, to, delay, myeloid, differentiation])].
[sujeto(['In', the, first, part, of, this, study, we]), verbo([found]), complemento([that, stable, 'miR-17', upregulation, 'affects,', like, the, 'CBF-AML', fusion, proteins, '(', 'RUNX1-MTG8', or, 'CBFB-MYH11),', a, core, 'RUNX1-miRNA', mechanism, leading, to, 'KIT-induced', proliferation, of, 'differentiation-arrested', 'U937', myeloid, cells])].
[sujeto(['The', integrated, information, gathered, from, the, two, myeloid, cell, models, shows, that, 'RUNX1']), verbo([regulates]), complemento([myeloid, differentiation, not, only, by, direct, transcriptional, regulation, of, coding, and, 'non-coding', myeloid, differentiation, functions, '(', e])].
[sujeto(['miR-223),', but, also, by]), verbo([modulating]), complemento(['KIT-induced', proliferation, via, 'non-coding', miRNAs, '(', e])].
[sujeto(['On', the, other, 'hand,', the, extent, of, 'KIT-induced', proliferation, itself, can]), verbo([modulate]), complemento([myeloid, differentiation, of, cells, with, wild, type, 'RUNX1', function])].
[sujeto(['CBFβ', and, 'RUNX1', form, a, 'DNA-binding', heterodimer, and, are, both]), verbo([required]), complemento([for, hematopoietic, stem, cell, '(', 'HSC)', generation, in, mice])].
[sujeto(['However,', the, nascent, 'HSCs', were, not]), verbo([released]), complemento([from, the, 'aorta-gonad-mesonephros', '(', 'AGM)', 'region,', as, evidenced, by, the, accumulation, of, 'runx1(+)', cells, in, the, 'AGM', that, could, not, enter, circulation])].
[sujeto(['Finally,', we]), verbo([found]), complemento([that, cbfb, was, downstream, of, the, 'Notch', pathway, during, 'HSC', development])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, runx1, and, cbfb, are, required, at, 2, different, steps, during, early, 'HSC', development])].
[sujeto(['CBFβ', is, not]), verbo([required]), complemento([for, nascent, 'HSC', emergence, but, is, required, for, the, release, of, 'HSCs', from, 'AGM', into, circulation])].
[sujeto(['Despite', the, absolute, requirements, for, these, factors, in, the, development, of, hematopoietic, stem, cells, and, 'lymphocytes,', their, roles, in, the, development, of, bone, marrow, progenitor, subsets]), verbo([have]), complemento([not, been, defined])].
[sujeto(['Besides', the]), verbo([loss]), complemento([of, 'DC', 'progenitors,', 'pan-hematopoietic', 'Cbfb-deficient', mice, also, lack, 'CD105(+)', erythroid, 'progenitors,', leading, to, severe, anemia, at, 3, to, 4, months, of, age])].
[sujeto(['RUNX1/CBFβ', '(', core]), verbo([binding]), complemento([factor, '[', 'CBF])', is, a, heterodimeric, transcription, factor, complex, that, is, frequently, involved, in, chromosomal, 'translocations,', point, 'mutations,', or, deletions, in, acute, leukemia])].
[sujeto(['The', mixed, lineage, leukemia, '(', 'MLL)', gene, is, also, frequently]), verbo([involved]), complemento([in, chromosomal, translocations, or, partial, tandem, duplication, in, acute, leukemia])].
[sujeto(['The', 'MLL', protein]), verbo([interacts]), complemento([with, 'RUNX1', and, prevents, 'RUNX1', from, 'ubiquitin-mediated', degradation])].
[sujeto(['RUNX1/CBFβ']), verbo([recruits]), complemento(['MLL', to, regulate, downstream, target, genes])].
[sujeto(['However,', the, functional, consequence, of, 'MLL', fusions, on, 'RUNX1/CBFβ', activity]), verbo([has]), complemento([not, been, fully, understood])].
[sujeto(['We', confirmed, this]), verbo([finding]), complemento([in, 'Mll-Af9', 'knock-in', mice, and, human, 'M4/M5', acute, myeloid, leukemia, '(', 'AML)', cell, 'lines,', with, or, without, 'MLL', 'translocations,', showing, that, 'MLL', translocations, cause, a, hypomorph, phenotype, of, 'RUNX1/CBFβ'])].
[sujeto(['Overexpression', of, 'RUNX1']), verbo([inhibits]), complemento([the, development, of, 'AML', in, 'Mll-Af9', 'knock-in', 'mice;', 'conversely,', further, reducing, 'Runx1/Cbfβ', levels, accelerates, 'MLL-AF9-mediated', 'AML', in, bone, marrow, transplantation, assays])].
[sujeto(['These', data]), verbo([reveal]), complemento([a, newly, defined, negative, regulation, of, 'RUNX1/CBFβ', by, 'MLL', fusion, proteins, and, suggest, that, targeting, 'RUNX1/CBFβ', levels, may, be, a, potential, therapy, for, 'MLLs'])].
[sujeto(['The', human, immunodeficiency, virus, '(', 'HIV)-1', protein, 'Vif']), verbo([has]), complemento([a, central, role, in, the, neutralization, of, host, innate, defences, by, hijacking, cellular, proteasomal, degradation, pathways, to, subvert, the, antiviral, activity, of, host, restriction, 'factors;', 'however,', the, underlying, mechanism, by, which, 'Vif', achieves, this, remains, unclear])].
[sujeto(['Here', we]), verbo([report]), complemento([a, crystal, structure, of, the, 'Vif-CBF-β-CUL5-ELOB-ELOC', complex])].
[sujeto(['The', structure]), verbo([reveals]), complemento([that, 'Vif,', by, means, of, two, 'domains,', organizes, formation, of, the, pentameric, complex, by, interacting, with, 'CBF-β,', 'CUL5', and, 'ELOC'])].
[sujeto(['The', larger, domain, '(', 'α/β', 'domain)', of, 'Vif']), verbo([binds]), complemento([to, the, same, side, of, 'CBF-β', as, 'RUNX1,', indicating, that, 'Vif', and, 'RUNX1', are, exclusive, for, 'CBF-β', binding])].
[sujeto(['Together,', our, data]), verbo([reveal]), complemento([the, structural, basis, for, 'Vif', hijacking, of, the, 'CBF-β', and, 'CUL5', 'E3', ligase, 'complex,', laying, a, foundation, for, rational, design, of, novel, 'anti-HIV', drugs])].
[sujeto(['Different', mechanisms, for, 'CBFβ-MYH11', function, in, acute, myeloid, leukemia, with, 'inv(16)']), verbo([have]), complemento([been, proposed, such, as, tethering, of, 'RUNX1', outside, the, 'nucleus,', interference, with, transcription, factor, complex, assembly, and, recruitment, of, histone, 'deacetylases,', all, resulting, in, transcriptional, repression, of, 'RUNX1', target, genes])].
[sujeto(['Here,', through, 'genome-wide', 'CBFβ-MYH11-binding', site, analysis, and, quantitative, interaction, 'proteomics,', we]), verbo([found]), complemento([that, 'CBFβ-MYH11', localizes, to, 'RUNX1', occupied, 'promoters,', where, it, interacts, with, 'TAL1,', 'FLI1', and, 'TBP-associated', factors, '(', 'TAFs)', in, the, context, of, the, hematopoietic, transcription, factors, 'ERG,', 'GATA2', and, 'PU'])].
[sujeto(['Transcriptional', analysis, revealed, that, upon, fusion, protein, 'knockdown,', a, small, subset, of, the, 'CBFβ-MYH11']), verbo([target]), complemento([genes, show, increased, 'expression,', confirming, a, role, in, transcriptional, repression])].
[sujeto(['However,', the, majority, of, 'CBFβ-MYH11']), verbo([target]), complemento(['genes,', including, genes, implicated, in, hematopoietic, stem, cell, 'self-renewal', such, as, 'ID1,', 'LMO1', and, 'JAG1,', are, actively, transcribed, and, repressed, upon, fusion, protein, knockdown])].
[sujeto(['Together', these, results]), verbo([suggest]), complemento([an, essential, role, for, 'CBFβ-MYH11', in, regulating, the, expression, of, genes, involved, in, maintaining, a, stem, cell, phenotype])].
[sujeto(['The', rare, but, recurrent, 'RUNX1-USP42', fusion, gene, is, the, result, of, a, 't(7;21)(p22;q22)', chromosomal, translocation, and]), verbo([has]), complemento([been, described, in, 6, cases, of, acute, myeloid, leukemia, '(', 'AML)', and, one, case, of, refractory, anemia, with, excess, of, blast])].
[sujeto(['The', bone, marrow, cells, in, the, present, case, also, had, a, 5, q, 'deletion,', and, it, was, revealed, that, 5, out, of, the, 8]), verbo([reported]), complemento([cases, '(', including, the, present, 'case)', with, 't(7;21)(p22;q22)/RUNX1-USP42', also, had, cytogenetic, abnormalities, of, 5, q])].
[sujeto(['Most', patients, with, acute, myeloid, leukemia, '(', 'AML)', and, genetic, rearrangements]), verbo([involving]), complemento([the, core, binding, factor, '(', 'CBF)', have, favorable, prognosis])].
[sujeto(['In', 'contrast,', a, minority, of, them, still]), verbo([have]), complemento([a, high, risk, of, leukemia, recurrence])].
[sujeto(['In', multivariate, 'analyses,', leukocyte, count, above, 20, &, 'nbsp;× 10(9)', /, 'L,', 'BAALC', 'over-expression,', and, high, copy, numbers, of, 'RUNX1-RUNXT1', or, 'CBFB-MYH11', after, induction, chemotherapy, '(', 'CT)']), verbo([led]), complemento([to, increased, relapse, rate])].
[sujeto(['Regarding', 'OS,', age, &, 'gt;50 yr,', leukocyte, count, above, 20, &, 'nbsp;× 10(9)', /, 'L,', and]), verbo([increased]), complemento(['MN1', expression, were, adverse, features])].
[sujeto(['Core']), verbo([binding]), complemento([factor, '(', 'CBF)-positive', acute, myeloid, leukemia, '(', 'AML)', presents, a, favorable, 'prognosis,', except, for, patients, with, 'KIT', 'mutation,', especially, 'D816', mutation])].
[sujeto(['The', study, patients, consisted, of, 121, patients, with, 'CBF', 'AML', '(', 82, patients, with, 'RUNX1/RUNX1T1', '[', 67.8, &, 'nbsp;%]', and, 39, patients, with, 'CBFB/MYH11', '[', 32.2, &, 'nbsp;%])']), verbo([recruited]), complemento([from, eight, institutions, in, 'Korea'])].
[sujeto(['The', presence, of, 'KIT', 'D816', mutation, was]), verbo([associated]), complemento([with, adverse, outcomes, for, the, 'event-free', survival, '(', p, =, 0.03, ')', and, for, the, overall, survival, '(', p, =, 0.02, ')'])].
[sujeto(['Core']), verbo([binding]), complemento([factor, '(', 'CBF)', 'leukemias,', those, with, translocations, or, inversions, that, affect, transcription, factor, genes, 'RUNX1', or, 'CBFB,', account, for, '~24%', of, adult, acute, myeloid, leukemia, '(', 'AML)', and, 25, '%', of, pediatric, acute, lymphocytic, leukemia, '(', 'ALL)'])].
[sujeto(['Current', treatments, for, 'CBF', leukemias, are]), verbo([associated]), complemento([with, significant, morbidity, and, 'mortality,', with, a, 5, -, y, survival, rate, of, '~50%'])].
[sujeto(['We', hypothesize, that, the, interaction, between, 'RUNX1', and, 'CBFβ', is, critical, for, 'CBF', leukemia, and, can, be]), verbo([targeted]), complemento([for, drug, development])].
[sujeto(['Ro5-3335,', a, benzodiazepine, identified, from, the, 'screen,', was, able, to]), verbo([interact]), complemento([with, 'RUNX1', and, 'CBFβ', 'directly,', repress, 'RUNX1/CBFB-dependent', transactivation, in, reporter, 'assays,', and, repress, 'runx1-dependent', hematopoiesis, in, zebrafish, embryos])].
[sujeto(['Our', data, thus, confirmed, that, 'RUNX1-CBFβ', interaction, can, be]), verbo([targeted]), complemento([for, leukemia, treatment, and, we, have, identified, a, promising, lead, compound, for, this, purpose])].
[sujeto(['The', clinical, value, of, serial, minimal, residual, disease, '(', 'MRD)', monitoring, in, core]), verbo([binding]), complemento([factor, '(', 'CBF)', acute, myeloid, leukemia, '(', 'AML)', by, quantitative, 'RT-PCR', was, prospectively, assessed, in, 278, patients, '[', 163, with, 't(8;21)', and, 115, with, 'inv(16)]', entered, in, the, 'United', 'Kingdom', 'MRC', 'AML', 15, trial])].
[sujeto(['During', 'follow-up,', 'cut-off', 'MRD', thresholds, in, 'BM', and, 'PB']), verbo([associated]), complemento([with, a, 100, '%', relapse, rate, were, 'identified:', for, 't(8;21)', patients, 'BM', &, 'gt;', 500, 'copies,', 'PB', &, 'gt;', 100, 'copies;', for, 'inv(16)', 'patients,', 'BM', &, 'gt;', 50, copies, and, 'PB', &, 'gt;', 10, copies])].
[sujeto(['Breast', carcinoma, is, the]), verbo([leading]), complemento([cause, of, 'cancer-related', mortality, in, women, 'worldwide,', with, an, estimated, 1.38, million, new, cases, and, 458, ',', 0, deaths, in, 2008, alone])].
[sujeto(['Recurrent', somatic, alterations, in, breast, cancer]), verbo([have]), complemento([been, 'described,', including, mutations, and, copy, number, 'alterations,', notably, 'ERBB2', 'amplifications,', the, first, successful, therapy, target, defined, by, a, genomic, aberration])].
[sujeto(['Previous', 'DNA', sequencing, studies, of, breast, cancer, genomes]), verbo([have]), complemento([revealed, additional, candidate, mutations, and, gene, rearrangements])].
[sujeto(['Here', we]), verbo([report]), complemento([the, 'whole-exome', sequences, of, 'DNA', from, 103, human, breast, cancers, of, diverse, subtypes, from, patients, in, 'Mexico', and, 'Vietnam', compared, to, 'matched-normal', 'DNA,', together, with, 'whole-genome', sequences, of, 22, breast, 'cancer/normal', pairs])].
[sujeto(['Furthermore,', we]), verbo([have]), complemento([identified, a, recurrent, 'MAGI3-AKT3', fusion, enriched, in, 'triple-negative', breast, cancer, lacking, oestrogen, and, progesterone, receptors, and, 'ERBB2', expression])].
[sujeto(['The', 'MAGI3-AKT3', fusion]), verbo([leads]), complemento([to, constitutive, activation, of, 'AKT', 'kinase,', which, is, abolished, by, treatment, with, an, 'ATP-competitive', 'AKT', 'small-molecule', inhibitor])].
[sujeto(['Osteoarthritis', '(', 'OA)', is, a, degenerative, joint, disease, that]), verbo([involves]), complemento([the, destruction, of, articular, cartilage, and, eventually, leads, to, disability])].
[sujeto(['Molecules', that]), verbo([promote]), complemento([the, selective, differentiation, of, multipotent, mesenchymal, stem, cells, '(', 'MSCs)', into, chondrocytes, may, stimulate, the, repair, of, damaged, cartilage])].
[sujeto(['Using', an, 'image-based', 'high-throughput', 'screen,', we, identified, the, small, molecule, 'kartogenin,', which]), verbo([promotes]), complemento([chondrocyte, differentiation, '(', median, effective, concentration, =, 100, 'nM),', shows, chondroprotective, effects, in, 'vitro,', and, is, efficacious, in, two, 'OA', animal, models])].
[sujeto(['Kartogenin']), verbo([binds]), complemento([filamin, 'A,', disrupts, its, interaction, with, the, transcription, factor, 'core-binding', factor, β, subunit, '(', 'CBFβ),', and, induces, chondrogenesis, by, regulating, the, 'CBFβ-RUNX1', transcriptional, program])].
[sujeto(['This', work]), verbo([provides]), complemento([new, insights, into, the, control, of, chondrogenesis, that, may, ultimately, lead, to, a, stem, 'cell-based', therapy, for, osteoarthritis])].
[sujeto(['Yet', the, mechanisms, that]), verbo([target]), complemento(['PRCs', to, specific, loci, in, mammalian, cells, remain, incompletely, understood])].
[sujeto(['In', this, study, we, show, that, 'Bmi1,', a, core, component, of, 'Polycomb', 'Repressive', 'Complex', 1, '(', 'PRC1),']), verbo([binds]), complemento([directly, to, the, 'Runx1/CBFβ', transcription, factor, complex])].
[sujeto(['Genome-wide', studies, in, megakaryocytic, cells, demonstrate, significant, chromatin, occupancy, overlap, between, the, 'PRC1', core, component, 'Ring1b', and, 'Runx1/CBFβ', and, functional, regulation, of, a, considerable, fraction, of, commonly]), verbo([bound]), complemento([genes])].
[sujeto(['We', also, show, that, 'Ring1b', occupies, key, 'Runx1']), verbo([binding]), complemento([sites, in, primary, murine, thymocytes, and, that, this, occurs, via, 'PRC2-independent', mechanisms])].
[sujeto(['Genetic', depletion, of, 'Runx1', results, in, reduced, 'Ring1b']), verbo([binding]), complemento([at, these, sites, 'in vivo'])].
[sujeto(['These', findings]), verbo([provide]), complemento([evidence, for, 'site-specific', 'PRC1', chromatin, recruitment, by, core, binding, transcription, factors, in, mammalian, cells])].
[sujeto(['The', identification, of, minimal, residual, disease, '(', 'MRD)']), verbo([has]), complemento([led, to, substantial, improvements, in, early, recognition, of, the, recurrence, of, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['Besides,', more, than, 50, '%', of, all, 'AML', patients, lack, one, of, these, specific, 'sequences,', so, it, is, crucial, to, identify, molecular]), verbo([targets]), complemento([applicable, for, the, majority, of, patients])].
[sujeto(['These', features]), verbo([have]), complemento([led, to, its, adoption, for, 'MRD', detection, using, 'RQ-PCR'])].
[sujeto(['A', 'European', 'LeukemiaNet', 'Study']), verbo([found]), complemento([the, magnitude, of, 'WT1', log, reduction, after, induction, chemotherapy, to, be, an, independent, predictor, of, relapse])].
[sujeto(['Finally,', some, authors]), verbo([translated]), complemento([the, use, of, 'WT1', in, the, clinic, giving, donor, lymphocytes, infusions, to, patients, with, increasing, 'WT1-mRNA', levels, after, allogeneic, stem, cell, transplantation, and, obtaining, an, improvement, of, survival, in, this, subset])].
[sujeto(['Data', collected, on, 'WT1', expression, over, the, past, years]), verbo([provided]), complemento([evidence, for, the, use, of, this, molecular, marker, to, stratify, 'high-risk', 'AML', patients])].
[sujeto(['NanoString', nCounter, system, is, a, novel, 'probe-based', gene, expression, platform, capable, of, measuring, up, to, 800]), verbo([targets]), complemento([with, advantages, of, 'reproducibility,', 'accuracy,', and, sample, type, flexibility])].
[sujeto(['To', examine, the, value, of, minimal, residual, disease, '(', 'MRD)', by, multiparameter, flow, cytometry, '(', 'MFC)', in, core]), verbo([binding]), complemento([factor, '(', 'CBF)', acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto([1, ',', 0.01, to, 0.1, ',', 0.1, to, 1, ',', 1, to, 10, ',', and, &, 'gt;10%,', and]), verbo([reporting]), complemento(['MFC', '(', 'sensitivity,', 0.1, '%', -, 0.01, '%', ')', as, positive, or, 'negative,', κ, coefficient, test, showed, no, agreement, between, 'qRT-PCR', and, 'MFC', in, 'BM', samples, obtained, postinduction, '(', n, =, 44, ',', κ, =, 0.041, ')', ',', and, only, weak, agreement, during, consolidation, '(', n, =, 108, ',', κ, =, 0.083, ')', ',', 'maintenance/follow-up', '(', n, =, 107, ',', κ, =, 0.164, ')', ',', and, salvage, chemotherapy, '(', n, =, 24, ',', 0.376, ')'])].
[sujeto([1, '%', was]), verbo([associated]), complemento([with, lower, and, '≥10%', with, higher, 'AML', relapse, risk, '(', 'P', =])].
[sujeto(['In', the, latter, group, with, intermediate, 'qRT-PCR', 'results,', 'MFC']), verbo([provided]), complemento([prognostic, value, for, relapse, '(', 'P', =, 0.006, ')'])].
[sujeto(['The', most, common, subgroups, were, 'KMT2A', rearrangement, '(', 29, '%', ')', ',', normal, karyotype, '(', 15, '%', ')', ',', 'RUNX1-RUNX1T1', '(', 10, '%', ')', ',', deletions, of, 5, 'q,', 7, q, 'and/or', 17, p, '(', 9, '%', ')', ',', myeloid, leukaemia]), verbo([associated]), complemento([with, 'Down', syndrome, '(', 7, '%', ')', ',', 'PML-RARA', '(', 7, '%', ')', and, 'CBFB-MYH11', '(', 5, '%', ')'])].
[sujeto(['Single', nucleotide, polymorphism, array, '(', 'SNP-A)', analysis, and, exon, sequencing, of, 100, 'genes,', performed, in, 52, and, 40, 'cases,', respectively, '(', 39, 'overlapping),', revealed, '≥1', aberration, in, 89, '%', ;, when, adding, cytogenetic, 'data,', this, frequency]), verbo([increased]), complemento([to, 98, '%'])].
[sujeto(['Twenty-two', genes, were]), verbo([targeted]), complemento([by, focal, 'CNAs,', including, 'AEBP2', and, 'PHF6', deletions, and, genes, involved, in, 'AML-associated', gene, fusions])].
[sujeto(['In', 'total,', 60, mutations, were]), verbo([found]), complemento([in, 30, 'genes,', primarily, those, encoding, signalling, proteins, '(', 47, '%', ')', ',', transcription, factors, '(', 25, '%', ')', ',', or, epigenetic, modifiers, '(', 13, '%', ')'])].
[sujeto(['It', is]), verbo([required]), complemento([for, fetal, liver, hematopoiesis, and, skeletal, development])].
[sujeto(['Cbfb']), verbo([has]), complemento([two, functional, 'isoforms,', 'Cbfb1', and, 'Cbfb2,', which, are, formed, by, alternative, splicing])].
[sujeto(['Intramembranous', and, endochondral, ossification, was, retarded, and, chondrocyte, and, osteoblast, differentiation, was]), verbo([inhibited]), complemento([in, 'Cbfb2(-/-)', embryos, but, not, in, 'Cbfb1(-/-)', embryos])].
[sujeto(['Furthermore,', the, amounts, of, 'Runx', proteins, and, 'Cbfb', in, 'Cbfb2(-/-)', embryos, differed, similarly, among, skeletal, 'tissues,', 'livers,', and, 'thymuses,']), verbo([suggesting]), complemento([that, 'Runx', proteins, and, 'Cbfb', are, mutually, required, for, their, stability])].
[sujeto(['Although', 'Cbfb1(-/-)', embryos, developed, 'normally,', 'Cbfb1']), verbo([induced]), complemento([chondrocyte, and, osteoblast, differentiation, and, enhanced, 'DNA', binding, of, 'Runx2', more, efficiently, than, 'Cbfb2'])].
[sujeto(['Cbfb2', was, more, 'abundant,', but, 'Cbfb1', was, more, potent, for]), verbo([enhancing]), complemento(['Runx2', activity])].
[sujeto(['Although', only, 'Cbfb2']), verbo([loss]), complemento([generated, overt, skeletal, 'phenotypes,', both, may, play, major, roles, in, skeletal, development, with, functional, redundancy])].
[sujeto(['Genetic', alterations, such, as, chromosomal, 'translocations,', copy, number, variations, and, point, mutations]), verbo([have]), complemento([been, widely, reported, to, result, in, the, malfunction, of, 'RUNX', transcription, factors])].
[sujeto(['Leukemias', arising, from, such, alterations, in, 'RUNX', family, genes, are, collectively, termed, core]), verbo([binding]), complemento([factor, '(', 'CBF)', leukemias])].
[sujeto(['Over', the, 'years,', retroviral, 'transduction-transplantation', assays, and, 'transgenic,', knockin, and, knockout, mouse, models, alone, or, in, combination, with, mutagenesis]), verbo([have]), complemento([been, used, to, study, the, roles, of, 'RUNX', alterations, in, leukemogenesis])].
[sujeto(['Although', successful, in]), verbo([inducing]), complemento(['leukemia,', the, existing, assays, and, models, possess, many, inherent, limitations])].
[sujeto(['A', 'CBF', leukemia, model, which]), verbo([induces]), complemento([leukemia, with, complete, penetrance, and, short, latency, would, be, ideal, as, a, platform, for, drug, discovery])].
[sujeto(['Here,', we, summarize, the, currently, available, mouse, models, which]), verbo([have]), complemento([been, utilized, to, study, 'CBF', 'leukemias,', discuss, the, advantages, and, limitations, of, individual, experimental, 'systems,', and, propose, suggestions, for, improvements, of, mouse, models])].
[sujeto(['In', a, patient, with, acute, myeloid, leukemia, '(', 'AML)', following, 'therapy,']), verbo([finding]), complemento(['≥5%', bone, marrow, '(', 'BM)', blasts, is, highly, concerning, for, 'residual/relapsed', disease])].
[sujeto(['The', receptor, tyrosine, kinase, 'KIT', is]), verbo([expressed]), complemento([in, the, vast, majority, of, these, acute, myeloid, leukemias, and, frequent, activating, 'KIT', gene, mutations, have, been, associated, with, a, higher, risk, of, relapse])].
[sujeto(['The', disappearance, of, 'KIT', gene, mutations, at, relapse]), verbo([suggests]), complemento([that, clonal, devolution, may, in, part, explain, the, absence, of, efficacy, observed, with, 'single-agent', dasatinib, in, these, patients, '(', n])].
[sujeto(['In', acute, myeloid, leukaemia, '(', 'AML),', the, presence, of, 't(8;21)(q22;q22)', and, 'inv(16)(p13q22)/t(16;16)(p13;q22)', 'and/or', the, corresponding, molecular, rearrangements, 'RUNX1/RUNX1T1', and, 'CBFB/MYH11', '[', collectively, referred, to, as, core]), verbo([binding]), complemento([factor, '(', 'CBF)', 'AML]', predict, for, a, more, favourable, outcome, in, patients, receiving, 'cytarabine-anthracycline', based, induction, and, upon, achievement, of, complete, 'remission,', 'high-dose', cytarabine, consolidation, chemotherapy])].
[sujeto(['Clinical', studies, with]), verbo([targeting]), complemento([compounds, '(', e])].
[sujeto([gemtuzumab, 'ozogamicin,', 'dasatinib)', added, to, intensive, chemotherapy, appear, beneficial, both, in, younger, and, older, 'patients,', albeit, the, latter, continue, to]), verbo([have]), complemento([a, significantly, worse, outcome, than, the, former])].
[sujeto(['Regularly', molecular, monitoring, of, disease, during, remission, may]), verbo([provide]), complemento([a, strategy, for, early, therapeutic, intervention, before, overt, relapse])].
[sujeto(['Core-binding', factor, acute, myeloid, leukemia, '(', 'CBF-AML)', -, including, 'AML', with, 't(8;21)', and, 'AML', with, 'inv(16)', -, accounts, for, about, 15, '%', of, adult, 'AML', and, is]), verbo([associated]), complemento([with, a, relatively, favorable, prognosis])].
[sujeto(['Due', to, similarities, between, their, molecular, and, prognostic, 'features,', 't(8;21)', and, 'inv(16)-AML', are, usually, grouped, and]), verbo([reported]), complemento([together, in, clinical, studies])].
[sujeto(['However,', considerable, experimental, evidences]), verbo([have]), complemento([highlighted, that, they, represent, two, distinct, entities, and, should, be, considered, separately, for, further, studies])].
[sujeto(['The', diagnostics, of, leukemia, relies, upon, 'multi-parametric', approach]), verbo([involving]), complemento([a, number, of, different, pathology, disciplines, such, as, flow, 'cytometry,', 'histopathology,', cytogenetics, and, molecular, genetics, '[', fluorescent, in, situ, hybridization, '(', 'FISH)', and, polymerase, chain, reaction, '(', 'PCR)]'])].
[sujeto(['In', the, last, two, 'decades,', several, studies]), verbo([have]), complemento([reported, observations, that, 'PFG', are, present, in, healthy, population, and, not, necessarily, result, in, leukemia])].
[sujeto(['The', first, such, study, by, 'Limpens', and, colleagues, on, 't(14/18)/', 'BCL2-JH', '[', 1, ']', and, next, in, line, '[', 2, ',', 3, ']']), verbo([led]), complemento([to, many, questions, regarding, the, significance, of, these, chromosomal, translocations, in, leukemogenesis])].
[sujeto(['Translocation', 't(8;21)/', 'AML1', 'ETO', was]), verbo([found]), complemento([in, 4.4, '%', of, patients, with, a, mean, age, of, 45.4, 'years,', while, none, of, these, patients, was, older, than, 55, years])].
[sujeto(['Translocation', 't(15;17)/', 'PMLRARA', was]), verbo([found]), complemento([in, 5.5, '%', of, patients, with, a, mean, age, of, 52.6, years, and, an, almost, equal, distribution, between, younger, and, older, patients])].
[sujeto(['The', 'MLL', gene, rearrangements, were]), verbo([found]), complemento([in, 6.6, '%', of, 'patients,', the, -, 5, /, 5, 'q-', 'and/', or, -, 7, /, 7, 'q-', aberrations, in, 7.7, '%', of, 'patients,', while, the, most, frequent, genetic, abnormality, in, our, study, was, trisomy, 8, '(', 10, '%', ')'])].
[sujeto(['Moreover,', we]), verbo([found]), complemento([a, favorable, clinical, outcome, in, patients, expressing, fusion, genes, 'AML1-ETO', or, 'PMLRARA', in, contrast, to, an, adverse, clinical, outcome, with, few, remissions, and, death, in, 'AML', patients, with, 'MLL,', -, 5, 'q/', -, 5, and, -, 7, 'q/', 7, -])].
[sujeto(['Finally,', an, intermediate, prognosis, was]), verbo([found]), complemento([in, patients, with, trisomy, 8])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([a, good, congruence, with, published, literature, on, the, incidence, and, prognostic, value, of, several, well, established, 'AML-associated', genetic, aberrations])].
[sujeto(['The', multiplex, 'RT-nPCR', used, in, this, study, can, 'quickly,', effectively, and, accurately, screen, the, fusion, genes, in, 'AML', 'patients,', which, can]), verbo([provide]), complemento([important, evidence, for, assessing, diagnosis, and, 'treatment,', and, also, provide, necessary, information, for, minimal, residual, disease, '(', 'MRD)', and, prognosis])].
[sujeto(['Within', the, past, few, 'years,', the, invention, of, 'next-generation', sequencing]), verbo([has]), complemento([revealed, several, new, genes, associated, with, tumor, formation, and, 'development,', for, example, 'DNMT3a'])].
[sujeto(['PCR', amplification, of, the, entire, coding, region, of, 'DNMT3a', was, performed, using, 23, overlapping]), verbo([primer]), complemento([pairs, in, 57, patients, who, were, diagnosed, in, 'Blood', 'Disease', 'Hospital', of, 'Chinese', 'Academy', of, 'Medical', 'Sciences,', then, the, directly, sequencing, was, underwent])].
[sujeto(['The', results, showed, that, no, 'DNMT3a', mutation, was]), verbo([found]), complemento([in, these, patients, including, the, hotspot, 'R882'])].
[sujeto(['But', 'AML1/ETO', mutation, was]), verbo([found]), complemento([in, 10, 'patients,', 'CBFB/MYH11', mutation, in, 3, 'patients,', 'PML/RARa', mutation, in, 13, 'patients,', 'FLT3/ITD', mutation, in, 5, 'patients,', 'FLT3/TKD', mutation, in, 1, 'patient,', 'PML/RARa', and, 'FLT3/TKD', mutation, coexisted, in, 2, patients])].
[sujeto(['Most', sensitive, methodology, to, detect, 'MRD', is, molecular, polymerase, chain, reaction, '(', 'PCR)', but, its, applicability, is, restricted, to, 'AML', with, 'leukemia-specific', molecular]), verbo([targets]), complemento(['(', e])].
[sujeto(['To', realize, the, methodology, that, better, identify, high, risk, 'patients,', an, analysis, of, 'sensitivity,', 'specificity,', predictive, values, '(', 'PV)', and, likelihood, ratio, '(', 'LR)', was]), verbo([provided]), complemento([and, similar, results, were, showed])].
[sujeto([1, ;, 'q22);', 'CBFB-MYH11', chromosomal, 'rearrangements,', but, whether, the, mutation, is, indicative, of]), verbo([associated]), complemento(['SM', is, unclear])].
[sujeto(['Five', of, the, eight, cases, carried, the, mutation, in, a, cell, fraction, below, 'one-tenth', of, the, blast, cell, 'fraction,', thus]), verbo([suggesting]), complemento([that, 'KIT', mutation, is, often, a, late, event, in, leukemogenesis])].
[sujeto(['The', presence, of, the, 'KIT', 'D816V', mutation, in, the, 'CBF', 'AML', subgroup, can, therefore, not, be, considered, indicative, of]), verbo([associated]), complemento(['SM'])].
[sujeto(['The', rearrangements, 't(8;21)', and, 'inv(16)']), verbo([involve]), complemento([the, 'RUNX1/RUNX1T1', '(', 'AML1-ETO', ')', and, 'CBFB/MYH11', 'genes,', respectively])].
[sujeto(['The', 't(8;21)', and, 'inv(16)', subtypes, of, 'AML']), verbo([have]), complemento([been, usually, grouped, and, reported, together, in, clinical, 'studies;', 'however,', recent, studies, have, demonstrated, 'genetic,', 'clinical,', and, prognostic, 'differences,', supporting, the, notion, that, they, represent, 2, distinct, biologic, and, clinical, entities])].
[sujeto(['No', correlation, was, observed, between, incidence, and, age, except, for, 'BCR-ABL', p210, 'fusion,', the, incidence, of, which, rises, with]), verbo([increasing]), complemento([age])].
[sujeto(['To', our, 'knowledge,', the, presence, of, 'PML-RARA', and, 'CBFB-MYH11', in, healthy, individuals]), verbo([has]), complemento([not, been, previously, described])].
[sujeto(['The', present, study]), verbo([provides]), complemento([further, evidence, for, the, presence, of, 'LLA', genetic, alterations, in, healthy, individuals, and, suggests, that, these, mutations, are, not, themselves, sufficient, for, malignant, transformation])].
[sujeto(['AML1-ETO', fusion, gene, transcript, was]), verbo([found]), complemento([in, 14, patients, '(', 19, '%', ')'])].
[sujeto(['Duplication', of, 'FLT3', gene, was]), verbo([found]), complemento([in, 4, '(', 5.3, '%', ')', cases])].
[sujeto(['Analysis', of, 'MRD', level, in, subsequent, time, points, showed, systematic]), verbo([decrease]), complemento([of, number, of, fusion, gene, transcript, copies, and, gene, 'WT1', expression])].
[sujeto(['To', establish, the, rate, of, molecular, marker, presence, in, 'AML', in, children, and, the, influence, of, the, presence, of, 'MRD', on, the, treatment, results, as, 'well,', the, study]), verbo([has]), complemento([to, be, conducted, on, a, larger, group, of, patients, with, longer, 'follow-up'])].
[sujeto(['Many', oncogenetic, aberrations, in, acute, leukemias, result, in, a, fusion, 'gene,', which, is]), verbo([transcribed]), complemento([into, fusion, transcripts, and, translated, into, fusion, 'proteins,', which, are, assumed, to, play, a, critical, role, in, the, oncogenetic, process])].
[sujeto(['So', 'far,', we]), verbo([have]), complemento([been, able, to, design, such, fusion, protein, immunobead, assays, for, 'BCR-ABL,', 'PML-RARA,', 'TEL-AML1,', 'E2A-PBX1,', 'MLL-AF4,', 'AML1-ETO', and, 'CBFB-MYH11'])].
[sujeto(['The', novel, immunobead, assay, will, enable, fast, and, easy, classification, of, acute, leukemia, patients, that]), verbo([express]), complemento([fusion, proteins])].
[sujeto(['Fluorescence', in, situ, hybridization, '(', 'FISH)', analysis, can]), verbo([provide]), complemento([important, information, in, the, management, of, patients, with, hematologic, malignancies])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, performing, 'FISH', in, addition, to, 'G-banded', karyotype, may, contribute, little, additional, genetic, information, in, 'AML', and, 'MDS,', whereas, routine, 'FISH', analysis, appears, to, be, an, efficient, screening, method, in, 'ALL', and, 'MM'])].
[sujeto(['In', a, 'large-scale', miRNA, expression, profiling, analysis, of, 435, human, miRNAs, in, 52, acute, myeloid, leukemia, '(', 'AML)', 'samples,', we]), verbo([found]), complemento([that, 'miR-126', and, its, minor, counterpart, in, 'biogenesis,', 'namely,', 'miR-126*,', were, specifically, aberrantly, overexpressed, in, core, binding, factor, '(', 'CBF)', 'AMLs', including, both, 't(8;21)/AML1-ETO', and, 'inv(16)/CBFB-MYH11', samples])].
[sujeto(['Our', in, vitro, 'gain-', and, 'loss-of-function', experiments, showed, that, forced, expression, of, 'miR-126']), verbo([inhibited]), complemento([apoptosis, and, increased, the, viability, of, 'AML', 'cells,', whereas, the, opposite, effect, was, observed, when, endogenous, expression, of, 'miR-126', was, knocked, down])].
[sujeto(['In', 'addition,', through, in, vitro, 'colony-forming/replating', 'assays,', we, demonstrated, that, forced, expression, of, 'miR-126']), verbo([enhanced]), complemento([proliferation, and, 'colony-forming/replating', capacity, of, mouse, normal, bone, marrow, progenitor, cells, alone, and, 'particularly,', in, cooperation, with, 'AML1-ETO,', a, fusion, gene, resulting, from, 't(8;21)'])].
[sujeto(['Aberrant', promoter, 'DNA', methylation]), verbo([has]), complemento([been, shown, to, play, a, role, in, acute, myeloid, leukemia, '(', 'AML)', pathophysiology])].
[sujeto(['Methylation', signatures, were]), verbo([associated]), complemento([with, the, presence, of, a, specific, cytogenetic, status])].
[sujeto(['The', presence, of, 'MLL', rearrangements, in, 'HSPC']), verbo([induced]), complemento([the, methylation, profile, observed, in, the, 'MLL-positive', primary, samples])].
[sujeto(['Our', study]), verbo([provides]), complemento([a, comprehensive, epigenetic, profiling, of, 'AML,', identifies, new, clinical, markers, for, cases, with, a, normal, 'karyotype,', and, reveals, relevant, biological, information, related, to, the, role, of, fusion, proteins, on, the, methylation, signature])].
[sujeto(['Inv(16)(p13q22)', is]), verbo([associated]), complemento([with, acute, myeloid, leukemia, subtype, 'M4Eo', that, is, characterized, by, the, presence, of, myelomonocytic, blasts, and, atypical, eosinophils])].
[sujeto(['CBF', beta, normally]), verbo([interacts]), complemento([with, 'RUNX1', to, form, a, transcriptionally, active, nuclear, complex])].
[sujeto(['The', 'CBF', 'beta-SMMHC', fusion, protein, is, capable, of]), verbo([binding]), complemento([to, 'RUNX1', and, form, dimers, and, multimers, through, its, myosin, tail])].
[sujeto(['Previous', results, from, transgenic, mouse, models, show, that, 'Cbfb-MYH11', is, able, to]), verbo([inhibit]), complemento([dominantly, 'Runx1', function, in, 'hematopoiesis,', and, is, a, key, player, in, the, pathogenesis, of, leukemia])].
[sujeto(['In', recent, 'years,', molecular, and, cellular, biological, studies]), verbo([have]), complemento([led, to, the, proposal, of, several, models, to, explain, the, function, of, 'CBF', 'beta-SMMHC'])].
[sujeto(['Core-binding', factor, beta, '(', 'CBFbeta,', also, called, polyomavirus, enhancer]), verbo([binding]), complemento([protein, 2, beta, '(', 'PEBP2B))', is, associated, with, an, inversion, of, chromosome, 16, and, is, associated, with, acute, myeloid, leukemia, in, humans])].
[sujeto(['CBFbeta', forms, a, heterodimer, with, 'RUNX1', '(', 'runt-related', transcription, factor, 1, ')', ',', which]), verbo([has]), complemento([a, 'DNA', binding, domain, homologous, to, the, 'pair-rule', protein, runt, in, 'Drosophila', melanogaster])].
[sujeto(['Haploinsufficiency', of, another, 'runt-related', 'protein,', 'RUNX2', '(', also, called, 'CBFA1),']), verbo([causes]), complemento([cleidocranial, dysplasia, in, humans, and, is, essential, in, skeletal, development, by, regulating, osteoblast, differentiation, and, chondrocyte, maturation])].
[sujeto(['Mice', deficient, in, 'Cbfb', '(', 'Cbfb(-/-))', die, at, 'midgestation,', so, the, function, of, 'Cbfbeta', in, skeletal, development]), verbo([has]), complemento([yet, to, be, ascertained])].
[sujeto(['Electrophoretic', mobility, shift, assays, and, reporter, assays, showed, that, 'Cbfbeta', was, necessary, for, the, efficient, 'DNA']), verbo([binding]), complemento([of, 'Runx2', and, for, 'Runx2-dependent', transcriptional, activation])].
[sujeto(['These', findings, indicate, that, 'Cbfbeta', is]), verbo([required]), complemento([for, the, function, of, 'Runx2', in, skeletal, development])].
[sujeto(['AML1/RUNX1', is, an, essential, transcription, factor]), verbo([involved]), complemento([in, the, differentiation, of, hematopoietic, cells])].
[sujeto(['AML1']), verbo([binds]), complemento([to, the, 'Runt-binding', 'double-stranded', 'DNA', element, '(', 'RDE)', of, target, genes, through, its, 'N-terminal', 'Runt', domain])].
[sujeto(['In', a, previous, 'study,', we, obtained, 'RNA', aptamers, against, the, 'AML1', 'Runt', domain, by, systematic, evolution, of, ligands, by, exponential, enrichment, and, revealed, that, 'RNA', aptamers, exhibit, higher, affinity, for, the, 'Runt', domain, than, that, for, 'RDE', and, possess, the, 5, '\'', -, 'GCGMGNN-3\'', and, 5, '\'', -, 'N\'N\'CCAC-3\'']), verbo([conserved]), complemento([motif, '(', 'M:', 'A', or, 'C;', 'N', and, 'N\'', form, 'Watson-Crick', base, 'pairs)', that, is, important, for, 'Runt', domain, binding])].
[sujeto(['In', this, 'study,', to, understand, the, structural, basis, of, recognition, of, the, 'Runt', domain, by, the, aptamer, 'motif,', the, solution, structure, of, a, 22, -, mer, 'RNA', was, determined, using]), verbo([nuclear]), complemento([magnetic, resonance])].
[sujeto(['Structural', analysis, of, the, aptamer, motif, indicated, that, the, aptamer]), verbo([binds]), complemento([to, the, 'Runt', domain, by, mimicking, the, 'RDE', sequence, and, structure])].
[sujeto(['Our', data, should]), verbo([enhance]), complemento([the, understanding, of, the, structural, basis, of, 'DNA', mimicry, by, 'RNA', molecules])].
[sujeto(['Runt-related', transcription, factor, 2, '(', 'Runx2)', and, muscle, segment, homeobox, homolog, 2, -]), verbo([interacting]), complemento([nuclear, target, '(', 'MINT)', '(', 'Spen', 'homolog)', are, transcriptional, regulators, critical, for, mammalian, development])].
[sujeto(['MINT']), verbo([enhances]), complemento(['Runx2', activation, of, osteocalcin, '(', 'OC)', fibroblast, growth, factor, '(', 'FGF)', response, element, in, an, 'FGF2-dependent', fashion, in, 'C3H10T1/2', cells])].
[sujeto(['Although', the, 'MINT', 'N-terminal', 'RNA', recognition, motif, domain, 'contributes,', the, muscle, segment, homeobox, homolog, 2, -]), verbo([interacting]), complemento([domain, is, sufficient, for, 'Runx2', activation])].
[sujeto(['Conversely,', phosphomimetic, 'Asp', substitution, of, these, 'AD3', 'Ser/Thr', residues]), verbo([enhanced]), complemento([activation, by, 'MINT'])].
[sujeto(['Systematic', screening, with, 'PDPK', inhibitors, identified, that, the, casein, 'kinase-2/homeodomain-interacting', protein, kinase, '(', 'HIPK)/dual', specificity, tyrosine, phosphorylation]), verbo([regulated]), complemento([kinase, inhibitor, 2, -, 'dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole', '(', 'DMAT),', but, not, 'ERK,', 'c-Jun', 'N-terminal', 'kinase,', 'p38MAPK,', or, other, casein, 'kinase-2', 'inhibitors,', abrogated, 'Runx2-,', 'MINT-,', and, 'FGF2-activation'])].
[sujeto(['HIPK3', and, 'Runx2', coprecipitate, after, in, vitro, 'transcription-translation,', and, recombinant, 'HIPK3']), verbo([recognizes]), complemento(['Runx2', 'AD3', as, kinase, substrate])].
[sujeto(['Furthermore,', 'DMAT', treatment, and, 'HIPK3', 'RNAi']), verbo([inhibited]), complemento(['MINT+FGF2', activation, of, 'Runx2', 'AD3,', and, nuclear, 'HIPK3', colocalized, with, 'MINT'])].
[sujeto(['Thus,', 'HIPK3']), verbo([participates]), complemento([in, 'MINT+FGF2', regulation, of, 'Runx2', 'AD3', activity, and, controls, 'Runx2-dependent', 'OC', expression])].
[sujeto(['Expression', of, the, 'IL-7R', 'alpha-chain', '(', 'IL-7Ralpha)', is, strictly]), verbo([regulated]), complemento([during, the, development, and, maturation, of, lymphocytes])].
[sujeto(['Glucocorticoids', '(', 'GC)']), verbo([have]), complemento([pleiotypic, effects, on, the, growth, and, function, of, lymphocytes])].
[sujeto(['Although', 'GC']), verbo([have]), complemento([been, reported, to, induce, the, transcription, of, 'IL-7Ralpha', gene, in, human, 'T', 'cells,', its, molecular, mechanism, is, largely, unknown])].
[sujeto(['This', effect, does, not]), verbo([require]), complemento([protein, synthesis, de, 'novo,', because, protein, synthesis, inhibitors, do, not, block, the, process])].
[sujeto(['Mouse', 'IL-7Ralpha', promoter]), verbo([has]), complemento([striking, homology, with, human, and, 'rat,', containing, consensus, motifs, of, 'Ikaros,', 'PU'])].
[sujeto(['In', 'addition,', a]), verbo([conserved]), complemento([noncoding, sequence, '(', 'CNS)', of, approximately, 270, bp, was, found, 3.6, -, kb, upstream, of, the, 'promoter,', which, was, designated, as, 'CNS-1'])].
[sujeto(['Importantly,', we, show, by, reporter, assay, that, the, 'IL-7Ralpha', promoter]), verbo([has]), complemento([specific, transcription, activity, in, 'T', cells])].
[sujeto(['We', also, demonstrate, that, 'GR']), verbo([binds]), complemento([to, the, 'GR', motif, by, 'EMSA'])].
[sujeto(['In', 'addition,', by, chromatin, immunoprecipitation, 'assay,', we, show, that, 'GR', is, rapidly]), verbo([recruited]), complemento([to, endogenous, 'CNS-1', chromatin, after, 'GC', stimulation])].
[sujeto(['These', results, demonstrate, that, 'GR']), verbo([binds]), complemento([to, the, 'GR', motif, in, the, 'CNS-1', region, after, 'GC', stimulation, and, then, activates, the, transcription, of, the, 'IL-7Ralpha', promoter])].
[sujeto(['The', 'RUNX3', gene, belongs, to, the, runt, domain, family, of, transcription, factors, that]), verbo([act]), complemento([as, master, regulators, of, gene, expression, in, major, developmental, pathways])].
[sujeto(['Two', large]), verbo([conserved]), complemento(['CpG', islands, were, found, within, both, 'genes,', one, around, exon, 2, and, the, other, at, the, beginning, of, exon, 6])].
[sujeto(['RUNX1,', 'RUNX2', and, 'RUNX3', gene, products]), verbo([bind]), complemento([to, the, same, 'DNA', 'motif,', hence, their, temporal, and, spatial, expression, during, development, should, be, tightly, regulated])].
[sujeto(['Structure/function', analysis, showed, that, two, promoter, 'regions,', designated, 'P1', and, 'P2,']), verbo([regulate]), complemento(['RUNX3', expression, in, a, cell, 'type-specific', manner])].
[sujeto(['Transfection', experiments, demonstrated, that, both, promoters, were, highly, active, in, the, 'GM1500', 'B-cell', 'line,', which, endogenously]), verbo([expresses]), complemento(['RUNX3,', but, were, inactive, in, the, 'K562', myeloid, cell, 'line,', which, does, not, express, 'RUNX3'])].
[sujeto(['We', specified, 43, genes, which, are, most, suitable, as, molecular, markers, of, 'PTC,', among, them, some, 'well-known', 'PTC', markers, '(', 'MET,', fibronectin, 1, ',', dipeptidylpeptidase, 4, ',', or, adenosine, 'A1', 'receptor)', and, potential, new, ones, '(', 'UDP-galactose-4-epimerase,', cadherin, 16, ',', gap, junction, protein, 3, ',', 'sushi,', 'nidogen,', and, 'EGF-like', domains, 1, ',', inhibitor, of, 'DNA']), verbo([binding]), complemento([3, ',', 'RUNX1,', leiomodin, 1, ',', 'F-box', protein, 9, ',', and, tripartite, 'motif-containing', 58, ')'])].
[sujeto(['Both', aging, rat, muscle, and, 'Sarco', mouse, muscle, exhibited, marked, 'fiber-type', 'grouping,', consistent, with, repeating, cycles, of, denervation, and, 'reinnervation,', yet, in, 'VO', 'muscle,', rapsyn, at, the, endplate]), verbo([increased]), complemento([and, was, associated, with, only, a, 10, &, 'nbsp;%', decline, in, acetylcholine, receptor, '(', 'AChR)', 'intensity,', whereas, in, 'Sarco', 'mice,', there, was, a, decline, in, rapsyn, and, a, 25, &, 'nbsp;%', decrease, in, 'AChR', intensity])].
[sujeto(['In', the, 'Sarco', 'mice,', there, were, much, smaller]), verbo([increases]), complemento([in, denervation, transcripts, '(', 0, -, 3.5, -, 'fold)', and, accumulation, of, very, small, fibers, '(', 2, -, 6, &, 'nbsp;%)', compared, to, the, 'VO', 'rat,', suggesting, a, reduced, capacity, for, reinnervation, in, aging, muscle])].
[sujeto(['Despite', the, marked, persistent, denervation, in, the, 'VO', rat, 'muscle,', transcripts, of, neurotrophins]), verbo([involved]), complemento([in, promoting, axonal, sprouting, following, denervation, exhibited, no, 'increase,', and, several, miRNAs, predicted, to, suppress, neurotrophins, were, elevated, in, 'VO', rat])].
[sujeto(['Our', results, support, the, hypothesis, that, the, accumulation, of, denervated, fibers, with, aging, is, due, to, failed, reinnervation, and, that, this, may, be, affected, by, a, limited, neurotrophin, response, that]), verbo([mediates]), complemento([axonal, sprouting, following, denervation])].
[sujeto(['An', appropriate, inflammatory, response, plays, critical, roles, in, eliminating, 'pathogens,', whereas, an, excessive, inflammatory, response, can]), verbo([cause]), complemento([tissue, damage])].
[sujeto(['Overexpression', of, 'RUNX1']), verbo([promoted]), complemento(['IL-1β', and, 'IL-6', production, in, response, to, 'LPS', stimulation])].
[sujeto(['Moreover,', 'RUNX1']), verbo([interacted]), complemento([with, the, 'NF-κB', subunit, 'p50,', and, coexpression, of, 'RUNX1', with, p50, further, enhanced, the, 'NF-κB', luciferase, activity])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'RUNX1', may, be, a, new, potential, target, for, resolving, 'TLR4-associated', uncontrolled, inflammation, and, preventing, sepsis])].
[sujeto(['Based', on, this, 'data,', it, was]), verbo([suggested]), complemento([that, the, 'well-recognized', 'phenotype-ameliorating', role, assigned, to, positive, 'XmnI', could, be, associated, with, its, linked, elements, in, the, 'LCR'])].
[sujeto(['To', investigate, the, functional, significance, of, polymorphisms, at, the, 5, '\'', 'HS4-LCR,', we, studied, its, influence, on]), verbo([binding]), complemento([of, transcription, factors])].
[sujeto(['Web-based', predictions, of, transcription, factor]), verbo([binding]), complemento([revealed, a, binding, site, for, 'runt-related', transcription, factor, 1, '(', 'RUNX1),', when, the, allele, at, the, center, of, the, palindrome, '(', 'TGGGG(A/G)CCCCA)', was, 'A', but, not, when, it, was, 'G'])].
[sujeto(['Furthermore,', electromobility, shift, assay, '(', 'EMSA)', presented, evidence, in, support, of, 'allele-specific']), verbo([binding]), complemento([of, 'RUNX1', to, 5, '\'', 'HS4'])].
[sujeto(['Considering', that, 'RUNX1', is, a, 'well-known', regulator, of, 'hematopoiesis,', these, preliminary, data]), verbo([suggest]), complemento([the, importance, of, further, studies, to, confirm, this, interaction, and, consequently, investigate, its, functional, and, phenotypical, relevance])].
[sujeto(['These', studies, could, help, us, to, understand, the, molecular, mechanism, behind, the, phenotype, modifying, role, of, the, 5, '\'', 'HS4-LCR', polymorphic, palindromic, region, '(', 'rs16912979),', which]), verbo([has]), complemento([been, observed, in, previous, studies])].
[sujeto(['Aberrant', expression, of, long, noncoding, 'RNAs']), verbo([has]), complemento([recently, been, reported, in, tumorigenesis, and, plays, a, pivotal, role, in, regulating, malignant, behavior, of, cancers])].
[sujeto(['Knockdown', of, 'HCP5']), verbo([inhibited]), complemento([the, malignant, biological, behavior, of, glioma, cells, by, reducing, 'proliferation,', migration, and, 'invasion,', and, inducing, apoptosis])].
[sujeto(['HCP5']), verbo([regulated]), complemento([the, malignant, behavior, of, glioma, cells, by, binding, to, 'microRNA-139,', which, functions, as, a, tumor, suppressor])].
[sujeto(['Moreover,', knockdown, of, 'HCP5', 'down-regulated', 'Runt-related', transcription, factor, 1, ',', a, direct, and, functional, downstream]), verbo([target]), complemento([of, 'microRNA-139', that, is, involved, in, 'microRNA-139-mediated', 'tumor-suppressive', effects, in, glioma, cells])].
[sujeto(['Runt-related', transcription, factor, 1]), verbo([increased]), complemento([promoter, activities, and, upregulated, expression, of, the, oncogenic, gene, astrocyte, elevated, 'gene-1', '(', 'AEG-1)'])].
[sujeto(['Runt-related', transcription, factor, 1, also]), verbo([increased]), complemento([the, promoter, activities, and, expression, of, 'HCP5,', which, showed, a, positive, feedback, loop, in, regulating, the, malignant, behavior, of, glioma, cells])].
[sujeto(['In', 'conclusion,', this, study, demonstrated, that, the, 'HCP5-microRNA-139-', 'Runt-related', transcription, factor, 1, feedback, loop, plays, a, pivotal, role, in]), verbo([regulating]), complemento([the, malignant, behavior, of, glioma, 'cells,', which, may, provide, a, potential, therapeutic, strategy, for, treating, glioma])].
[sujeto(['Chromosomal', abnormalities]), verbo([lead]), complemento([to, the, development, of, hematologic, malignancies, such, as, 'Myelodysplastic', 'Syndrome', '(', 'MDS)'])].
[sujeto(['Known', chromosomal, changes]), verbo([causing]), complemento(['MDS', include, deletion, of, the, long, arm, of, chromosome, 5, ',', 'runt-related', transcription, factor, 1, '(', 'RUNX1)', also, known, as, acute, myeloid, leukemia, 1, protein, '(', 'AML1),', and, very, rarely, fusion, genes, involving, 'RUNX1', at, 't(5;21)(q15;q22)'])].
[sujeto(['Therapy', was, started, with, 'Lenalidomide']), verbo([leading]), complemento([to, normal, blood, counts])].
[sujeto(['We']), verbo([report]), complemento([a, new, case, of, 't(5;21)(q15;q22)', involving, the, 'RUNX1', gene, and, 'del(5)(q13q33)', in, a, 'MDS', 'patient,', a, combination, of, chromosomal, abnormalities, heretofore, not, reported, in, the, literature])].
[sujeto(['RUNX1', rearrangement, is, usually]), verbo([associated]), complemento([with, an, adverse, prognosis, in, 'AML', and, 'MDS'])].
[sujeto(['Deletions', of, 5, q, are, typically]), verbo([associated]), complemento([with, poor, prognosis, in, 'AML,', however, it, is, usually, associated, with, a, favorable, prognosis, in, 'MDS'])].
[sujeto(['Our', patient]), verbo([responded]), complemento([very, well, to, 'Lenalidomide', therapy, with, achievement, of, 'CR'])].
[sujeto(['Lenalidomide', is, approved, for, treatment, of, anemia, in, low, and, intermediate, risk, 'MDS', with, del, '(', 5, 'q),', however, based, on, a, search, of, literature, it, seems, that, 'RUNX1', mutations, are, also, more, prominent, in, patients, who]), verbo([have]), complemento([responded, to, 'Lenalidomide', therapy])].
[sujeto(['Hence,', it, is, conceivable, that, our, patient, started, with, a, 5, q, minus, syndrome, and, then, acquired, the, second, hit, 'RUNX1', translocation]), verbo([leading]), complemento([to, an, accelerated, phase, of, myeloid, neoplasm, or, refractory, anemia, with, excess, 'blasts,', type, 1])].
[sujeto(['Hence,', the, temporal, relationship, between, acquisition, of, del, 5, q, and, 'RUNX1', rearrangement, may]), verbo([have]), complemento([influenced, the, clinical, outcome, and, possibly, response, to, therapy])].
[sujeto(['AAA', is]), verbo([caused]), complemento([by, segmental, weakening, of, the, aortic, walls, and, progressive, aortic, dilation, leading, to, the, eventual, rupture, of, the, 'aorta,', accompanied, by, intense, inflammation])].
[sujeto(['Additionally,', studies]), verbo([have]), complemento([indicated, a, close, relationship, between, the, pathogenesis, and, progression, of, 'AAA', and, cellular, immune, responses, in, aneurysm, wall, tissue])].
[sujeto(['There', are, no, proven, clinical, management, strategies, or, 'pharmaco-therapeutics', to]), verbo([prevent]), complemento(['AAA', progression, once, an, 'AAA', has, been, detected])].
[sujeto(['Moreover,', so, far, no, biomarkers]), verbo([have]), complemento([been, established, to, indicate, the, disease, status, of, 'AAA'])].
[sujeto(['Hence,', understanding, the, pathogenesis, of, 'AAA']), verbo([has]), complemento([recently, become, an, increasing, priority, in, basic, and, translational, vascular, research])].
[sujeto(['The', results, of, elevated, expression, of, 'RUNX', genes, and, their, relationships, in, the, 'AAA', tissues]), verbo([suggest]), complemento([the, involvement, of, conserved, 'Runt-related', genes, in, the, pathophysiology, of, 'AAA', development])].
[sujeto(['Th17', and]), verbo([associated]), complemento(['IL-17', were, involved, in, the, pathogenesis, of, 'ITP'])].
[sujeto(['Runt-related', transcription, factor, 1, '(', 'RUNX1),', a, member, of, the, runt, 'domain-containing', family, of, transcription, 'factors,', is]), verbo([required]), complemento([for, 'Th17', differentiation])].
[sujeto(['Whether', 'RUNX1', was]), verbo([involved]), complemento([in, the, pathogenesis, of, 'ITP', remains, poorly, understood])].
[sujeto(['Furthermore,', a, significantly, positive, correlation, of, 'RUNX1', with, 'RORγt', was]), verbo([found]), complemento([in, active, 'ITP', patients])].
[sujeto(['In', 'conclusion,', 'RUNX1', was]), verbo([associated]), complemento([with, the, pathogenesis, of, 'ITP', possibly, through, regulation, of, 'Th17', cell, differentiation, and, therapeutically, targeting, it, might, be, a, novel, approach, in, 'ITP', treatment])].
[sujeto(['Runt-related', transcription, factor, 1, '(', 'Runx1),', a, master, regulator, of, 'hematopoiesis,', is]), verbo([expressed]), complemento([in, preosteoclasts])].
[sujeto(['Previously', we, evaluated, the, bone, phenotype, of, 'CD11b-Cre', 'Runx1(fl/fl)', mice, and, demonstrated]), verbo([enhanced]), complemento([osteoclasts, and, decreased, bone, mass, in, males])].
[sujeto(['Both', female, and, male, 'LysM-Cre', 'Runx1(fl/fl)', mice, had]), verbo([decreased]), complemento([trabecular, bone, mass, '(', 72, '%', decrease, in, bone, volume, 'fraction)', and, increased, osteoclast, number, '(', 2, -, 3, 'times)', '(', 'P', &, 'lt;'])].
[sujeto(['We', also, demonstrated, that]), verbo([loss]), complemento([of, 'Runx1', in, pluripotential, myeloid, precursors, with, 'LysM-Cre', did, not, alter, the, number, of, myeloid, precursor, cells, in, bone, marrow, or, their, ability, to, differentiate, into, phagocytizing, or, 'antigen-presenting', cells])].
[sujeto(['This', study, demonstrates, that, abrogation, of, 'Runx1', in, multipotential, myeloid, precursor, cells, significantly, and, specifically]), verbo([enhanced]), complemento([the, ability, of, receptor, activator, of, nuclear, 'factor-κB', ligand, to, stimulate, osteoclast, formation, and, fusion, in, female, and, male, mice, without, affecting, other, myeloid, cell, fates])].
[sujeto(['In', 'turn,']), verbo([increased]), complemento([osteoclast, activity, in, 'LysM-Cre', 'Runx1(fl/fl)', mice, likely, contributed, to, a, decrease, in, bone, mass])].
[sujeto(['These', dramatic, effects, were, not, due, to]), verbo([increased]), complemento([osteoclast, precursors, in, the, deleted, mutants, and, argue, that, inhibition, of, 'Runx1', in, multipotential, myeloid, precursor, cells, is, important, for, osteoclast, formation, and, function])].
[sujeto(['Previously,', we, showed, that, 'SMAD4', and, 'runt-related', transcription, factor, 1, '(', 'RUNX1)', were, independently]), verbo([required]), complemento([for, 'MDE', to, express, 'ΔNp63'])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, vaginal, mesenchyme, directs, vaginal, epithelial, cell, fate, in, 'MDE', through, paracrine, activation, of, fibroblast, growth, factor, '(', 'FGF)', 'receptor-MAPK', pathway])].
[sujeto(['In', the, developing, reproductive, 'tract,', 'FGF7', and, 'FGF10', were, enriched, in, vaginal, 'mesenchyme,', whereas, 'FGF', receptor, 2, 'IIIb', was]), verbo([expressed]), complemento([in, epithelia, of, both, the, uterus, and, vagina])].
[sujeto(['In', 'vitro,', 'FGF10', in, combination, with, bone, morphogenetic, protein, 4, and, activin, 'A', '(', 'ActA)', was, sufficient, to]), verbo([induce]), complemento(['ΔNp63', in, 'MDE,', and, 'ActA', was, essential, for, induction, of, 'RUNX1', through, 'SMAD-independent', pathways])].
[sujeto(['Accordingly,', inhibition, of, type, 1, receptors, for, activin, in, neonatal, mice]), verbo([induced]), complemento([uterine, differentiation, in, vaginal, epithelium, by, 'down-regulating', 'RUNX1,', whereas, conditional, deletion, of, 'Smad2', and, 'Smad3', had, no, effect, on, vaginal, epithelial, differentiation])].
[sujeto(['In', 'conclusion,', vaginal, epithelial, cell, fate, in, 'MDE', is]), verbo([induced]), complemento([by, 'FGF7/10-MAPK,', bone, morphogenetic, protein, 4, -, 'SMAD,', and, 'ActA-RUNX1', pathway, 'activities,', and, the, disruption, in, any, one, of, these, pathways, results, in, conversion, from, vaginal, to, uterine, epithelial, cell, fate])].
[sujeto(['Osseo', genic, lineage, differentiation, was, also, tested, by, means, of, the, 'catenin-β1', 'immunofluorescence,']), verbo([induced]), complemento(['osteoblasts,', which, represented, the, internal, control])].
[sujeto(['The', 'RUNX1', and, 'SP7', expressions, in, the]), verbo([induced]), complemento([osteoblasts, prove, to, be, 'different,', compared, with, cells, cultured, on, metallic, supports])].
[sujeto(['Present', results]), verbo([suggested]), complemento([that, different, titanium, surfaces, might, induce, some, differences, in, terms, of, gene, expression])].
[sujeto(['However,', the, 'TEL-AML1', copies, in, her, blood, still]), verbo([increased]), complemento([and, she, died, with, leukemia, relapse, after, additional, 'CAR-T', cell, infusion])].
[sujeto(['CAR-T', therapy, is, a, novel, therapeutic, approach, that, could, be, useful, for, patients, with, relapsed, and, refractory, 'B-ALL', who]), verbo([have]), complemento([failed, all, other, treatment, options])].
[sujeto(['Homoharringtonine', combined, aclarubicin, and, cytarabine, '(', 'HAA)']), verbo([has]), complemento([been, demonstrated, to, achieve, a, high, remission, rate, and, provide, a, survival, advantage, in, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['The', median, fold]), verbo([decrease]), complemento([of, the, 'RUNX1/RUNX1T1', transcript, level, was, 200, '(', 1, -, 358000, ')', ',', and, 16.7, '%', '(', 5, /, 30, ')', patients, achieved, &, 'gt;3', log, decrease, after, one, cycle, of, the, 'HAA', regimen])].
[sujeto(['A', network, of, 'lineage-specific', transcription, factors, and, microRNAs, tightly]), verbo([regulates]), complemento([differentiation, of, hematopoietic, stem, cells, along, the, distinct, lineages])].
[sujeto(['We']), verbo([found]), complemento([that, the, hematopoietic, master, regulator, 'RUNX1', controls, the, expression, of, certain, 'microRNAs,', of, importance, during, 'erythroid/megakaryocytic', differentiation])].
[sujeto(['In', 'particular,', we, show, that, the, erythorid, 'miR144/451', cluster, is, epigenetically]), verbo([repressed]), complemento([by, 'RUNX1', during, megakaryopoiesis])].
[sujeto(['Furthermore,', the, leukemogenic, 'RUNX1/ETO', fusion, protein, transcriptionally]), verbo([represses]), complemento([the, 'miR144/451', 'pre-microRNA'])].
[sujeto(['Thus', 'RUNX1/ETO', contributes, to]), verbo([increased]), complemento([expression, of, miR451, target, genes, and, interferes, with, normal, gene, expression, during, differentiation])].
[sujeto(['Furthermore,', we, observed, that, inhibition, of, 'RUNX1/ETO', in, 'Kasumi1', cells, and, in, 'RUNX1/ETO', positive, primary, acute, myeloid, leukemia, patient, samples]), verbo([leads]), complemento([to, 'up-regulation', of, 'miR144/451'])].
[sujeto(['RUNX1', '(', 'AML1)', amplification, in, patients, with, 'B-cell', acute, lymphoblastic, leukemia, '(', 'B-ALL)']), verbo([has]), complemento([been, associated, with, poor, survival, for, unclear, reasons])].
[sujeto(['Our', anecdotal, experience]), verbo([suggests]), complemento([that, children, with, 'B-ALL', and, 'RUNX1', amplification, might, be, predisposed, to, thrombosis])].
[sujeto(['The', 'RUNX1', isoforms, derived, from, 'P2', are]), verbo([expressed]), complemento([in, a, variety, of, 'tissues,', but, expression, of, 'P1-derived', isoform, is, restricted, to, cells, of, hematopoietic, lineage])].
[sujeto(['Here', we]), verbo([report]), complemento([regulation, of, 'P1-derived', 'RUNX1', mRNA, by, 'RUNX1', protein])].
[sujeto(['In', silico, analysis, of, 'P1', promoter, revealed, presence, of, two, evolutionary]), verbo([conserved]), complemento(['RUNX', 'motifs,', 0.6, kb, upstream, of, the, transcription, start, 'site,', and, three, 'RUNX', motifs, within, 170, bp, of, the, 5, '\'', 'UTR'])].
[sujeto(['Mutation', or, deletion, of, 'RUNX', motifs, in, the, 'UTR']), verbo([enhances]), complemento([basal, activity, of, the, 'RUNX1', promoter])].
[sujeto(['Chromatin', immunoprecipitation, revealed, that, 'RUNX1', protein, is]), verbo([recruited]), complemento([to, these, sites])].
[sujeto(['We', also, demonstrate, that, 'RUNX1', protein]), verbo([regulates]), complemento([transcription, of, endogenous, 'RUNX1', mRNA, in, 'T-cell'])].
[sujeto(['Finally', we, show, that, 'SCL', transcription, factor, is]), verbo([recruited]), complemento([to, regions, containing, 'RUNX', motifs, in, the, promoter, and, the, 'UTR', and, regulates, activity, of, the, 'RUNX1', 'P1', promoter, in, vitro])].
[sujeto(['Thus,', multiple, lines, of, evidence, show, that, 'RUNX1', protein]), verbo([regulates]), complemento([its, own, gene, transcription])].
[sujeto(['For', acute, myeloid, 'leukemia,', we, identified, a, 'MEGS', with, five, genes, '(', 'FLT3,', 'IDH2,', 'NRAS,', 'KIT,', and, 'TP53)', and, a, 'MEGS', '(', 'NPM1,', 'TP53,', and, 'RUNX1)', whose, mutation, status, was, strongly]), verbo([associated]), complemento([with, survival, '(', p, =, 6.7, ×, 10, '(', -, 4, ')', ')'])].
[sujeto(['For', breast, 'cancer,', we, identified, a, significant, 'MEGS', consisting, of, 'TP53', and, four, infrequently, mutated, genes, '(', 'ARID1A,', 'AKT1,', 'MED23,', and, 'TBL1XR1),']), verbo([providing]), complemento([support, for, their, role, as, cancer, drivers])].
[sujeto(['Transmissible', gastroenteritis, virus, '(', 'TGEV),', belonging, to, the, coronaviridae, 'family,', is, the, key]), verbo([cause]), complemento([of, the, fatal, diarrhea, of, piglets, and, results, in, many, pathological, processes])].
[sujeto(['During', the, process, of, apoptosis]), verbo([induced]), complemento([by, 'TGEV', infection, in, 'PK-15', 'cells,', the, 'miR-27b', is, notably, 'down-regulated'])].
[sujeto(['Thus,', we, speculate, that, 'miR-27b', is]), verbo([involved]), complemento([in, regulating, the, process, of, apoptosis, in, 'PK-15', cells])].
[sujeto(['In', this, study, we, demonstrated, that, the, 'over-expression', of, 'miR-27b']), verbo([led]), complemento([to, the, inhibition, of, 'TGEV-induced', 'apoptosis,', reduction, of, 'Bax', protein, 'level,', and, decrease, of, 'caspase-3', and, -, 9, activities])].
[sujeto(['Conversely,', silencing, of, 'miR-27b', by, 'miR-27b', inhibitors]), verbo([enhanced]), complemento([apoptosis, via, 'up-regulating', 'Bax', expression, and, promoting, the, activities, of, 'caspase-3', and, -, 9, in, 'TGEV-infected', cells])].
[sujeto(['Subsequently,', the, 'runt-related', transcription, factor, 1, '(', 'RUNX1)', is, a, candidate]), verbo([target]), complemento([of, 'miR-27b', predicted, by, bioinformatics, search])].
[sujeto(['We', further, identified, that, the, 'miR-27b', directly]), verbo([bound]), complemento([to, the, 3, '\'', 'UTR', of, 'RUNX1', mRNA, and, suppressed, 'RUNX1', 'expression,', which, indicates, 'RUNX1', is, the, direct, target, gene, of, 'miR-27b'])].
[sujeto(['The', 'over-expression', of, 'RUNX1']), verbo([increased]), complemento([apoptosis, and, knockdown, 'RUNX1blocked', apoptosis, of, 'viral-infected', cells, via, regulating, 'Bax', expression, and, the, activities, of, 'caspase-3', and, -, 9])].
[sujeto(['Our', data]), verbo([reveal]), complemento([that, 'miR-27b', may, repress, the, mitochondrial, pathway, of, apoptosis, by, targeting, 'RUNX1,', indicating, that, 'TGEV', may, induce, apoptosis, via, 'down-regulating', 'miR-27b', and, that, 'miR-27b', may, act, as, a, target, for, therapeutic, intervention])].
[sujeto(['Despite', its, 'prevalence,', the, exact, genomic]), verbo([targets]), complemento([of, 'E/R', have, remained, elusive])].
[sujeto(['We', evaluated, gene, loci, and, enhancers]), verbo([targeted]), complemento([by, 'E/R', 'genome-wide', in, precursor, 'B', acute, leukemia, cells, using, global, 'run-on', sequencing, '(', 'GRO-seq)'])].
[sujeto(['We', show, that, expression, of, the, 'E/R', fusion]), verbo([leads]), complemento([to, widespread, repression, of, 'RUNX1-motif', containing, enhancers, at, its, target, gene, loci])].
[sujeto(['Moreover,', multiple, 'super-enhancers', from, 'CD19/CD20-lineage', were]), verbo([repressed]), complemento([implicating, a, role, in, impediment, of, lineage, commitment])].
[sujeto(['In', 'effect,', the, expression, of, several, genes]), verbo([involved]), complemento([in, 'B', cell, signaling, and, adhesion, was, 'downregulated,', and, the, repression, depended, on, the, 'wild-type', 'DNA-binding', 'Runt', domain, of, 'RUNX1'])].
[sujeto(['The', results]), verbo([provide]), complemento([a, comprehensive, 'genome-wide', mapping, between, 'E/R-regulated', key, regulatory, elements, and, genes, in, precursor, 'B', cell, leukemia, that, disrupt, normal, 'B', lymphopoiesis])].
[sujeto(['Down', syndrome, '(', 'DS)', is, the]), verbo([leading]), complemento([genetic, cause, of, mental, retardation, and, is, caused, by, a, third, copy, of, human, chromosome, 21])].
[sujeto(['The', different, pathologies, of, 'DS']), verbo([involve]), complemento([many, tissues, with, a, distinct, array, of, neural, phenotypes])].
[sujeto(['Our', results, show, that, neural, progenitor, cells, '(', 'NPCs)', differentiated, from, five, independent, 'DS-ESC', lines, display]), verbo([increased]), complemento([apoptosis, and, downregulation, of, forehead, developmental, genes])].
[sujeto(['Analysis', of, differentially]), verbo([expressed]), complemento([genes, suggested, 'RUNX1', as, a, key, transcription, regulator, in, 'DS-NPCs'])].
[sujeto(['Using', genome, editing, we, were, able, to, disrupt, all, three, copies, of, 'RUNX1', in, 'DS-ESCs,']), verbo([leading]), complemento([to, downregulation, of, several, 'RUNX1', target, developmental, genes, accompanied, by, reduced, apoptosis, and, neuron, migration])].
[sujeto(['Galectin-3', '(', 'Gal-3)']), verbo([has]), complemento([been, implicated, in, pancreatic, ductal, adenocarcinoma, '(', 'PDAC),', and, its, candidacy, as, a, therapeutic, target, has, been, evaluated])].
[sujeto(['Gal-3', is, widely, upregulated, in, 'tumors,', and, its, expression, is]), verbo([associated]), complemento([with, the, development, and, malignancy, of, 'PDAC'])].
[sujeto(['In', the, present, 'study,', we, demonstrate, that, a, 'polysaccharide,', 'RN1,', purified, from, the, flower, of, 'Panax', notoginseng]), verbo([binds]), complemento([to, 'Gal-3', and, suppresses, its, expression])].
[sujeto(['In', 'addition,', 'RN1', markedly]), verbo([inhibits]), complemento(['PDAC', cells, growth, in, 'vitro,', in, vivo, and, in, 'patient-derived', xenografts])].
[sujeto(['Mechanistically,', 'RN1']), verbo([binds]), complemento([to, epidermal, growth, factor, receptor, '(', 'EGFR)', and, 'Gal-3,', thereby, disrupting, the, interaction, between, 'Gal-3', and, 'EGFR', and, downregulating, 'extracellular-related', kinase, '(', 'ERK)', phosphorylation, and, the, transcription, factor, of, 'Gal-3,', 'Runx1', expression])].
[sujeto(['Inhibiting', the, expression, of, 'Runx1', by, 'RN1,']), verbo([suppresses]), complemento(['Gal-3', expression, and, inactivates, 'Gal-3-associated', signaling, 'pathways,', including, the, 'EGFR/ERK/Runx1,', 'BMP/smad/Id-3', and, 'integrin/FAK/JNK', signaling, pathways])].
[sujeto(['In', 'addition,', 'RN1', can, also]), verbo([bind]), complemento([to, bone, morphogenetic, protein, receptors, '(', 'BMPR1A', and, 'BMPR2)', and, block, the, interaction, between, 'Gal-3', and, the, 'BMPRs'])].
[sujeto(['Thus,', our, results]), verbo([suggest]), complemento([that, a, novel, 'Gal-3', inhibitor, 'RN1', may, be, a, potential, candidate, for, human, 'PDAC', treatment, via, multiple, targets, and, multiple, signaling, pathways])].
[sujeto(['BCP-ALL', are, believed, to, be]), verbo([arrested]), complemento([at, the, 'pre-BCR', checkpoint, independent, of, 'pre-BCR', expression])].
[sujeto(['However,', the, cellular, stage, at, which, 'BCP-ALL', are]), verbo([arrested]), complemento([and, whether, this, relates, to, expression, of, the, 'pre-BCR', components, '(', 'IGHM,', 'IGLL1', and, 'VPREB1)', is, still, unclear])].
[sujeto(['Moreover,', analyzing, six, 'BCP-ALL', data, sets, '(', n, =, 733, ')', ',', we, demonstrate, that, 'TCF3-PBX1', 'ALL']), verbo([express]), complemento([high, levels, of, 'IGHM,', 'IGLL1', and, 'VPREB1,', and, are, arrested, at, the, 'pre-B', stage])].
[sujeto(['By', 'contrast,', 'ETV6-RUNX1', 'ALL']), verbo([express]), complemento([low, levels, of, 'IGHM', or, 'VPREB1,', and, are, arrested, at, the, 'pro-B', stage])].
[sujeto(['Irrespective', of, 'subtype,', 'ALL', with, high, levels, of, 'IGHM,', 'IGLL1', and, 'VPREB1', are]), verbo([arrested]), complemento([at, the, 'pre-B', stage, and, correlate, with, good, prognosis, in, 'high-risk', pediatric, 'BCP-ALL', '(', n, =, 207, ')'])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, 'BCP-ALL', are, arrested, at, different, cellular, 'stages,', which, relates, to, the, expression, pattern, of, the, 'pre-BCR', components, that, could, serve, as, prognostic, markers, for, 'high-risk', pediatric, 'BCP-ALL', patients])].
[sujeto(['The', genetic, basis, of, myelodysplastic, syndromes, '(', 'MDS)', is, 'heterogeneous,', and, various, combinations, of, somatic, mutations, are]), verbo([associated]), complemento([with, different, clinical, phenotypes, and, outcomes])].
[sujeto(['Somatic', mutation, in, 'ASXL1,', 'RUNX1,', or, 'TP53', is, independently]), verbo([associated]), complemento([with, unfavorable, outcomes, and, shorter, survival, after, allogeneic, 'HSCT', for, patients, with, 'MDS', and, 'MDS/AML'])].
[sujeto(['In', 'contrast,', congenital, disorders]), verbo([caused]), complemento([by, a, single, genetic, mutation, are, ideal, candidates, for, deriving, iPSCs])].
[sujeto(['We']), verbo([have]), complemento([been, investigating, the, molecular, mechanisms, underlying, leukemia, and, 'MDS', by, implementing, iPSC, technology])].
[sujeto(['Familial', platelet, disorder, '(', 'FPD)', is, a, rare, autosomal, dominant, disorder, characterized, by, thrombocytopenia, and, a, high, propensity, for, developing, acute, 'leukemia,', which, is]), verbo([caused]), complemento([by, heterozygous, mutation, of, 'RUNX1'])].
[sujeto(['We']), verbo([have]), complemento([successfully, established, iPSCs, from, three, distinct, 'FPD', pedigrees, and, examined, the, responsible, defect, during, hematopoietic, development])].
[sujeto(['A', novel, role, for, phenotypic, transcription, factors, in, very, early, differentiation, was, recently, observed, and, merits, further, study, to, elucidate, what, role, this, precocious, expression, may]), verbo([have]), complemento([in, development])].
[sujeto(['This', early, 'RUNX1', expression, spike]), verbo([provides]), complemento([a, paradigm, for, precocious, expression, of, a, phenotypic, transcription, factor, that, invites, detailed, mechanistic, study, to, fully, understand, its, biological, importance])].
[sujeto(['We']), verbo([found]), complemento([an, overall, greater, mutational, burden, and, more, driver, mutations, in, 'T-cell', 'ALL', '(', 'T-ALL)', patients, compared, to, 'B-cell', precursor, 'ALL', '(', 'BCP-ALL)', patients])].
[sujeto(['Specifically', in, 'BCP-ALL,', we, identified, 'ATRX', as, a, novel, putative, driver, gene, and, uncovered, an, association, between, somatic, mutations, in, the, 'Notch', signaling, pathway, at, 'ALL', diagnosis, and]), verbo([increased]), complemento([risk, of, relapse])].
[sujeto(['The', genes, highlighted, in, our, study, were, frequently]), verbo([involved]), complemento([in, epigenetic, 'regulation,', associated, with, germline, susceptibility, to, 'ALL,', and, present, in, minor, subclones, at, diagnosis, that, became, dominant, at, relapse])].
[sujeto(['We', observed, a, high, degree, of, clonal, heterogeneity, and, evolution, between, diagnosis, and, relapse, in, both, 'BCP-ALL', and, 'T-ALL,', which, could]), verbo([have]), complemento([implications, for, the, treatment, efficiency])].
[sujeto(['Five', clinically, actionable, variants, were]), verbo([reported]), complemento([to, the, pregnant, 'women,', including, haploinsufficiency, of, 'RUNX1,', a, mosaicism, for, segmental, chromosome, 13, 'deletion,', an, unbalanced, 'translocation,', and, two, interstitial, chromosome, 'X', deletions])].
[sujeto(['Shotgun', sequencing, of, cfDNA, not, only, enables, the, detection, of, fetal, aneuploidies, but, also]), verbo([reveals]), complemento([the, presence, of, maternal, 'CNVs'])].
[sujeto(['Interrogating', the, maternal, 'CNV', landscape, can, improve, overall, pregnancy, 'management,', and, we, propose]), verbo([reporting]), complemento([those, variants, if, clinically, relevant])].
[sujeto(['The', identification, and]), verbo([reporting]), complemento([of, such, 'CNVs', pose, novel, counseling, dilemmas, that, warrant, further, discussions, and, development, of, societal, guidelines])].
[sujeto(['To', orchestrate, the, genomic, response, to, cellular, stress, 'signals,', p53]), verbo([recognizes]), complemento([and, binds, to, 'DNA', containing, specific, and, 'well-characterized', 'p53-responsive', elements, '(', 'REs)'])].
[sujeto(['Therefore,', the, identification, and, characterization, of, a, 'species-specific', p53, 'Binding', sistes, '(', 'BS)', consensus, sequence, and, of, the]), verbo([associated]), complemento([target, genes, may, help, to, provide, new, insights, into, the, evolution, of, the, p53, regulatory, networks, across, different, species])].
[sujeto(['Here,', we, designed, and, biochemically, validated, a, computational, approach, to, identify, novel, p53]), verbo([target]), complemento([genes, in, 'Danio', rerio, genome])].
[sujeto(['Screening', all, the, 'Danio', rerio, genome, by, 'pattern-matching-based', 'analysis,', we]), verbo([found]), complemento([p53, 'RE-like', patterns, proximal, to, 979, annotated, 'Danio', rerio, genes])].
[sujeto(['Prioritization', analysis, identified, a, subset, of, 134, candidate, 'pattern-related', 'genes,', 31, of, which]), verbo([have]), complemento([been, investigated, in, further, biochemical, assays])].
[sujeto(['Our', study, identified, 'runx1,', 'axin1,', 'traf4a,', 'hspa8,', 'col4a5,', 'necab2,', and, dnajc9, genes, as, novel, direct, p53]), verbo([targets]), complemento([and, 12, additional, 'p53-controlled', genes, in, 'Danio', rerio, genome])].
[sujeto(['The', proposed, combinatorial, approach, resulted, to, be, highly, sensitive, and, robust, for, identifying, new, p53]), verbo([target]), complemento([genes, also, in, additional, animal, species])].
[sujeto(['Aspirin']), verbo([prevents]), complemento([cardiovascular, disease, and, colon, 'cancer;', however, 'aspirin\'s', inhibition, of, platelet, 'COX-1', only, partially, explains, its, diverse, effects])].
[sujeto(['Here', we]), verbo([report]), complemento([that, 60, '%', of, 'ARS', transcripts, are, regulated, by, 'RUNX1', -, a, hematopoietic, transcription, factor, -, and, 48, '%', of, 'ARS', gene, promoters, contain, a, 'RUNX1', binding, site])].
[sujeto(['Megakaryocytic', cells, exposed, to, aspirin, and, its, metabolite, '(', salicylic, 'acid,', a, weak, 'COX-1', 'inhibitor)', showed, up, regulation, in, the, 'RUNX1', 'P1', isoform, and, 'MYL9,', which, is, transcriptionally]), verbo([regulated]), complemento([by, 'RUNX1'])].
[sujeto(['In', human, 'subjects,', 'RUNX1', 'P1', expression, in, blood, and, 'RUNX1-regulated', platelet, 'proteins,', including, 'MYL9,', were, 'aspirin-responsive', and]), verbo([associated]), complemento([with, platelet, function])].
[sujeto(['In', cardiovascular, disease, patients, 'RUNX1', 'P1', expression, was]), verbo([associated]), complemento([with, death, or, 'MI'])].
[sujeto(['RUNX1']), verbo([acts]), complemento([as, a, tumor, suppressor, gene, in, gastrointestinal, malignancies])].
[sujeto(['We', show, that, 'RUNX1', 'P1', expression, is]), verbo([associated]), complemento([with, colon, cancer, free, survival, suggesting, a, role, for, 'RUNX1', in, 'aspirin\'s', protective, effect, in, colon, cancer])].
[sujeto(['Our', studies]), verbo([reveal]), complemento([an, effect, of, aspirin, on, 'RUNX1', and, gene, expression, that, may, additionally, explain, 'aspirin\'s', effects, in, cardiovascular, disease, and, cancer])].
[sujeto(['We', investigated, genetic, factors]), verbo([associated]), complemento([with, 'thiopurine-induced', leukopenia, in, patients, with, 'IBD'])].
[sujeto(['A', 'genome-wide', association, study, '(', 'GWAS)', was, conducted, in, 'thiopurine-treated', patients, with, 'IBD,', followed, by, 'high-throughput', sequencing, of, genes, identified, as, significant, in, the, 'GWAS', or, those]), verbo([involved]), complemento([in, thiopurine, metabolism, '(', 'n=331)'])].
[sujeto(['Significant', loci]), verbo([associated]), complemento([with, 'thiopurine-induced', leukopenia, were, validated, in, two, additional, replication, cohorts, '(', 'n=437', and, 'n=330)'])].
[sujeto(['The', 'GWAS', identified, two, loci]), verbo([associated]), complemento([with, 'thiopurine-induced', leukopenia, '(', 'rs16957920,', 'FTO', 'intron;', 'rs2834826,', 'RUNX1', 'intergenic)'])].
[sujeto(['High-throughput']), verbo([targeted]), complemento([sequencing, indicated, that, an, 'FTO', coding, variant, '(', 'rs79206939,', p])].
[sujeto(['A134T)', linked, to, rs16957920, is]), verbo([associated]), complemento([with, 'thiopurine-induced', leukopenia])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, the, hypomorphic, 'FTO', p])].
[sujeto(['A134T', variant, is]), verbo([associated]), complemento([with, 'thiopurine-induced', leukopenia])].
[sujeto(['These', results, shed, light, on, the, novel, physiological, role, of, 'FTO', and]), verbo([provide]), complemento([a, potential, pharmacogenetic, biomarker, for, thiopurine, therapy])].
[sujeto(['In', 1994, ',', 'Braddock', and, 'Carey', first]), verbo([reported]), complemento([two, unrelated, girls, with, a, new, multiple, malformation, syndrome])].
[sujeto(['Since', that, 'time,', there]), verbo([have]), complemento([been, multiple, other, reported, patients, with, a, similar, phenotype])].
[sujeto(['In', 'addition,', several]), verbo([reports]), complemento([of, thrombocytopenia, and, developmental, delay, have, been, documented, in, association, with, deletions, in, the, 'Down', syndrome, critical, region, at, 21, q22])].
[sujeto(['The', similarity, of, the]), verbo([reported]), complemento([cases, with, deletions, involving, 21, q22, with, the, clinical, presentation, of, the, two, patients, with, 'Braddock-Carey', syndrome, resulted, in, a, reinvestigation, of, the, genetic, etiology, of, these, two, patients, 20, years, after, the, original, study])].
[sujeto(['This', investigation]), verbo([provides]), complemento([evidence, that, the, etiology, of, this, and, other, &, 'quot;Fanconi-like"', disorders, represent, a, newly, recognized, contiguous, gene, deletion, syndrome, involving, 21, q22, and, 'specifically,', the, 'RUNX1', gene])].
[sujeto(['Induction', of, selectin, ligands, on, 'T', cells, is, controlled, primarily, by, 'cytokines,', including, 'TGF-β1,', and]), verbo([requires]), complemento([p38α, 'MAPK,', but, transcriptional, mechanisms, that, underlie, 'cytokine-driven', selectin, ligand, expression, are, poorly, understood])].
[sujeto(['In', this, 'study,', we, 'show,', using, mice, with, conditional, deletions, of, the, 'TGF-β1-responsive', transcription, factors, 'Smad2,', 'Smad3,', or, 'Smad4,', that, induction, of, selectin, ligands, on, 'CD4', cells, in, response, to, 'TGF-β1']), verbo([requires]), complemento(['Smad4', plus, either, 'Smad2', or, 'Smad3'])].
[sujeto(['Analysis', of, 'CD4', cells, from, mice, with, only, one, functional, 'Smad4', allele, revealed, a, sharp, gene, dosage, 'effect,']), verbo([suggesting]), complemento([the, existence, of, a, threshold, of, 'TGF-β1', signal, strength, required, for, selectin, ligand, induction])].
[sujeto(['Both', 'Smad4', plus, either, 'Smad2', or, 'Smad3', were, selectively]), verbo([required]), complemento([for, induction, of, 'Fut7', and, 'Gcnt1,', glycosyltransferases, critical, for, selectin, ligand, 'biosynthesis,', but, they, were, not, required, for, 'St3gal4', or, 'St3gal6', induction])].
[sujeto(['Smad4', plus, either, 'Smad2', or, 'Smad3', were, also]), verbo([required]), complemento([for, induction, of, 'Runx', transcription, factors, by, 'TGF-β1'])].
[sujeto(['In', 'contrast,', enforced, expression, of, 'Runx1,', 'Runx2,', or, 'Runx3', failed, to, restore, differentiation, of, 'TGF-β1-dependent', 'Th', cell, 'lineages,', including, 'Th17,', 'Th9,', and]), verbo([induced]), complemento([regulatory, 'T', cells])].
[sujeto(['These', results, show, that, 'Smads', are, directly]), verbo([required]), complemento([for, 'Th', cell, differentiation, independent, of, 'Runx', induction, but, only, indirectly, required, via, 'Runx2', for, 'TGF-β1-induced', selectin, ligand, induction, on, murine, 'CD4', 'T', cells])].
[sujeto(['The', plethora, of, knowledge, gained, on, myelodysplastic, syndromes, '(', 'MDS),', a, heterogeneous, 'pre-malignant', disorder, of, hematopoietic, stem, 'cells,', through, sequencing, of, several, pathway, genes]), verbo([has]), complemento([unveiled, molecular, pathogenesis, and, its, progression, to, 'AML'])].
[sujeto(['Evolution', of, phenotypic, classification, and, 'risk-stratification', based, on, peripheral, cytopenias, and, blast, count]), verbo([has]), complemento([moved, to, 'five-tier', 'risk-groups', solely, concerning, chromosomal, aberrations])].
[sujeto(['Increased', frequency, of, complex, 'abnormalities,', which, is]), verbo([associated]), complemento([with, genetic, 'instability,', defines, the, subgroup, of, worst, prognosis, in, 'MDS'])].
[sujeto(['Recent', discoveries, on, mutations, in, 'RNA-splicing', machinery, '(', 'SF3B1,', 'SRSF2,', 'ZRSR2,', 'U2AF1,', 'U2AF2);', 'DNA', methylation, '(', 'TET2,', 'DNMT3A,', 'IDH1/2);', chromatin, modification, '(', 'ASXL1,', 'EZH2);', transcription, factor, '(', 'TP53,', 'RUNX1);', signal, 'transduction/kinases', '(', 'FLT3,', 'JAK2);', 'RAS', pathway, '(', 'KRAS,', 'NRAS,', 'CBL,', 'NF1,', 'PTPN11);', cohesin, complex, '(', 'STAG2,', 'CTCF,', 'SMC1A,', 'RAD21);', 'DNA', repair, '(', 'ATM,', 'BRCC3,', 'DLRE1C,', 'FANCL);', and, other, pathway, genes]), verbo([have]), complemento([given, insights, into, the, independent, effects, and, interaction, of, 'co-occurrence', of, mutations, on, 'disease-phenotype'])].
[sujeto(['RNA-splicing', and, 'DNA', methylation, mutations, appeared, to, occur, early, and, are]), verbo([reported]), complemento([as, '\'', 'founder\'', mutations, in, over, 50, '%', 'MDS', patients])].
[sujeto(['TET2', 'mutation,', through, altered, 'DNA', 'methylation,']), verbo([has]), complemento([been, found, to, have, independent, prognostic, response, to, hypomethylating, agents])].
[sujeto(['Moreover,', presence, of, 'DNMT3A,', 'TET2', and, 'ASXL1', mutations, in, normal, elderly, individuals, forms, the, basis, of, understanding, that, accumulation, of, somatic, mutations, may, not]), verbo([cause]), complemento([direct, 'disease-development;', 'however,', cooperation, with, other, mutations, in, the, genes, that, are, frequently, mutated, in, myeloid, and, other, hematopoietic, cancers, might, result, in, clonal, expansion, through, 'self-renewal', 'and/or', proliferation, of, hematopoietic, stem, cells])].
[sujeto(['Identification', of, small, molecules, as, inhibitors, of, epigenetic, mutations]), verbo([has]), complemento([opened, avenues, for, tailoring, targeted, drug, development])].
[sujeto(['Inversion', of, chromosome, 16, '(', 'inv(16))', generates, the, 'CBFβ-SMMHC', fusion, protein, and, is]), verbo([found]), complemento([in, nearly, all, patients, with, acute, myeloid, leukemia, subtype, 'M4', with, 'Eosinophilia', '(', 'M4Eo)'])].
[sujeto(['Recently,', there]), verbo([have]), complemento([been, important, advances, in, defining, the, role, of, 'CBFβ-SMMHC', and, its, binding, 'partners,', the, transcription, factor, 'RUNX1', and, the, histone, deacetylase, 'HDAC8'])].
[sujeto(['Importantly,', initial, trials, demonstrate, that, small, molecules]), verbo([targeting]), complemento([these, binding, partners, are, effective, against, 'CBFβ-SMMHC', induced, leukemia])].
[sujeto(['In', this, study, we, sought, to, identify, genetic, factors]), verbo([associated]), complemento([with, the, presenting, white, blood, cell, '(', 'WBC)', count, in, 'B-precursor', acute, lymphoblastic, leukemia, '(', 'BP-ALL)'])].
[sujeto(['Using', 'ETV6-RUNX1-positive', 'BP-ALL', patient, 'samples,', a, homogeneous, 'subtype,', we, identified, 16, differentially]), verbo([expressed]), complemento([genes, based, on, the, presenting, 'WBC', count, '(', &, 'lt;', 50, ',', 0, /, cumm, vs, &, 'gt;', 50, ',', 0, ')'])].
[sujeto(['We', further, confirmed, that, 'IL1R1,', 'BCAR3,', 'KCNH2,', 'PIR,', and, 'ZDHHC23', were, differentially]), verbo([expressed]), complemento([in, a, larger, cohort, of, 'ETV6-RUNX1-negative', 'BP-ALL', patient, samples])].
[sujeto(['Further', studies, in, leukemia, cell, line, models, will, better, delineate, the, role, of, these, genes, in]), verbo([regulating]), complemento([the, white, blood, cell, count, and, potentially, identify, new, therapeutic, targets])].
[sujeto([cCD3, was, not]), verbo([expressed]), complemento([in, both, groups])].
[sujeto(['ASXL2', mutation, may, be, a, new, event, that, can, cooperate, with, 'AML1-ETO', to]), verbo([induce]), complemento([leukemia])].
[sujeto(['ASXL2', gene, mutations, and, 'c-kit', gene, mutations, may, not]), verbo([have]), complemento([a, specific, correlation, between, them])].
[sujeto(['Human', endogenous, retrovirus, '(', 'HERV)', sequences, make, up, '~8%', of, the, human, genome, and]), verbo([increased]), complemento([expression, of, some, 'HERV', proteins, has, been, observed, in, various, pathologies, including, leukaemia, and, multiple, sclerosis])].
[sujeto(['However,', little, is, known, about, the, function, of, these, 'HERV', proteins, or, environmental, factors, which]), verbo([regulate]), complemento([their, expression])].
[sujeto(['Cell', proliferation, and, cell, toxicity, assays, were, carried, out, on, human, acute, 'T', lymphoblastic, leukaemia, '(', 'MOLT-4)', and, 'Fanconi', anaemia]), verbo([associated]), complemento([acute, myeloid, leukaemia, '(', 'FA-AML1)', cells, treated, with, two, different, sizes, of, 'AgNPs', '(', 7, nm, and, 50, nm, 'diameter)'])].
[sujeto(['Syncytin-1', mRNA, and, protein, were]), verbo([induced]), complemento([by, both, 7, and, 50, nm, 'AgNPs', in, both, cell, types, yet, with, different, kinetics])].
[sujeto(['In', 'summary,', the, observation, that, 'AgNPs']), verbo([induce]), complemento([expression, of, 'syncytin-1', in, 'FA-AML1', and, 'MOLT-4', cells, at, doses, as, little, as, 5, 'µg/ml', is, grounds, for, concern, since, this, protein, is, 'up-regulated', in, both, malignant, and, neurodegenerative, diseases])].
[sujeto(['Considering', the, widespread, use, of, 'AgNPs', in, the, environment, it, is, clear, that, their, ability, to]), verbo([induce]), complemento(['syncytin-1', should, be, investigated, further, in, other, cell, types])].
[sujeto(['Histone', deacetylases, '(', 'HDACs)', critically]), verbo([regulate]), complemento([gene, expression, by, determining, the, acetylation, status, of, histones])].
[sujeto(['In', 'addition,', studies]), verbo([have]), complemento([increasingly, focused, on, the, activities, of, 'HDACs,', especially, involving, 'non-histone', 'proteins,', and, their, various, biological, effects])].
[sujeto(['Aberrant', 'HDAC', expression, observed, in, several, kinds, of, human, tumors, makes, 'HDACs', potential]), verbo([targets]), complemento([for, cancer, treatment])].
[sujeto(['Several', preclinical, studies]), verbo([have]), complemento([suggested, that, 'HDAC', inhibitors, exhibit, some, efficacy, in, the, treatment, of, acute, myelogenous, leukemia, '(', 'AML)', with, 'AML1-ETO,', which, mediates, transcriptional, repression, through, its, interaction, with, a, complex, including, 'HDAC1'])].
[sujeto(['Recurrent', mutations, in, epigenetic, regulators, are]), verbo([found]), complemento([in, 'T-cell', lymphomas, '(', 'TCLs),', and, 'HDAC', inhibitors, and, hypomethylating, agents, were, shown, to, act, cooperatively, in, the, treatment, of, 'TCLs'])].
[sujeto(['Preclinical', modeling]), verbo([has]), complemento([suggested, that, persistent, activation, of, the, signal, transducer, and, activator, of, transcription, '(', 'STAT)', signaling, pathway, could, serve, as, a, useful, biomarker, of, resistance, to, 'HDAC', inhibitor, in, patients, with, cutaneous, 'TCL'])].
[sujeto(['Panobinostat,', a, 'pan-HDAC', 'inhibitor,', in, combination, with, bortezomib, and, 'dexamethasone,']), verbo([has]), complemento([achieved, longer, 'progression-free', survival, in, patients, with, 'relapsed/refractory', multiple, myeloma, '(', 'MM)', than, the, placebo, in, combination, with, bortezomib, and, dexamethasone])].
[sujeto(['Panobinostat']), verbo([inhibited]), complemento(['MM', cell, growth, by, degrading, protein, phosphatase, 3, catalytic, subunit, α, '(', 'PPP3CA),', a, catalytic, subunit, of, calcineurin])].
[sujeto(['This', degradation, was]), verbo([suggested]), complemento([to, be, mediated, by, the, blockade, of, the, chaperone, function, of, heat, shock, protein, 90, '(', 'HSP90)', due, to, 'HDAC6', inhibition])].
[sujeto(['Furthermore,', 'PPP3CA', was]), verbo([suggested]), complemento([as, a, common, target, of, panobinostat, and, bortezomib])].
[sujeto(['A', frequent, concomitant, event, is, the]), verbo([loss]), complemento([of, the, residual, 'ETV6', allele, suggesting, a, critical, role, for, the, 'ETV6', transcriptional, repressor, in, the, etiology, of, this, cancer])].
[sujeto(['However,', the, precise, mechanism, through, which]), verbo([loss]), complemento([of, functional, 'ETV6', contributes, to, disease, pathogenesis, is, still, unclear])].
[sujeto(['To', investigate, the, impact, of, 'ETV6']), verbo([loss]), complemento([on, the, transcriptional, network, and, to, identify, new, transcriptional, targets, of, 'ETV6,', we, used, whole, transcriptome, analysis, of, both, 'pre-B', leukemic, cell, lines, and, patients, combined, with, chromatin, immunoprecipitation])].
[sujeto(['Using', this, integrative, 'approach,', we, identified, 4, novel, direct, 'ETV6']), verbo([target]), complemento(['genes:', 'CLIC5,', 'BIRC7,', 'ANGPTL2', and, 'WBP1L'])].
[sujeto(['To', further, evaluate, the, role, of, chloride, intracellular, channel, protein, 'CLIC5', in, 'leukemogenesis,', we, generated, cell, lines, overexpressing, 'CLIC5', and, demonstrated, an]), verbo([increased]), complemento([resistance, to, hydrogen, 'peroxide-induced', apoptosis])].
[sujeto(['We', further, described, the, implications, of, 'CLIC5\'s', ion, channel, activity, in, 'lysosomal-mediated', cell, 'death,', possibly, by]), verbo([modulating]), complemento([the, function, of, transferrin, receptor, with, which, it, 'co-localizes', intracellularly])].
[sujeto(['For', the, first, 'time,', we, showed, that]), verbo([loss]), complemento([of, 'ETV6', leads, to, significant, overexpression, of, 'CLIC5,', which, in, turn, leads, to, decreased, 'lysosome-mediated', apoptosis])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, heightened, 'CLIC5', activity, could, promote, a, permissive, environment, for, 'oxidative-stress', induced, 'DNA', damage, accumulation, and, thereby, contribute, to, leukemogenesis])].
[sujeto(['CD56(+)', 'AML', patients]), verbo([respond]), complemento([poorly, to, 'treatment,', frequently, relapse, after, complete, remission, and, have, a, low, survival, rate])].
[sujeto(['The', interval, of, 'MRD', detection, should, be, shortened, to]), verbo([find]), complemento([out, relapse, earlier])].
[sujeto(['CD19(+)', 'AML', patients]), verbo([have]), complemento([a, good, treatment, outcome, and, often, accompanies, with, 'AML1/ETO', fusion, 'gene,', which, is, known, to, be, a, good, prognostic, marker])].
[sujeto(['Acute', myeloid, leukemia, '(', 'AML)', carrying, 't(8;21)(q22;q22)', or, 'inv(16)/t(16;16)(p13;q22)', is, classified, as, core]), verbo([binding]), complemento([factor, '(', 'CBF)-AML', and, accounts, for, approximately, 15, '%', of, 'AML'])].
[sujeto(['C-KIT', mutation, can, be, detected, in, 17, '~46%', of, 'CBF-AML', and, is]), verbo([associated]), complemento([with, poor, prognosis])].
[sujeto(['C-KIT', mutation, is, a, crucial, hit, and, cooperates, with, 'AML1-ETO', resulting, from, 't(8;21)(q22;q22)', to]), verbo([cause]), complemento([overt, 'AML'])].
[sujeto(['Tyrosine', kinase, inhibitors, '(', 'TKI)']), verbo([targeting]), complemento(['c-KIT,', such, as, 'imatinib,', has, been, used, successfully, to, treat, 'c-KIT', driven, 'gastro-intestinal', stromal, tumors])].
[sujeto(['However', the, effect, of, 'TKI', on, 'c-KIT', driven, 'leukemia,', including, 'CBF-AML', and, systemic, mastocytosis, '(', 'SM),']), verbo([has]), complemento([not, been, satisfactory])].
[sujeto(['BPR1J373', is, a, 5, -, 'phenylthiazol-2-ylamine-pyriminide', derivative]), verbo([targeting]), complemento([multiple, tyrosine, kinases])].
[sujeto(['It', was, shown, to]), verbo([inhibit]), complemento([cell, proliferation, and, induce, apoptosis, in, 'AML', cells, with, constitutively, activated, 'c-KIT', via, inhibiting, 'c-KIT', phosphorylation, and, its, downstream, signals])].
[sujeto(['The', compound]), verbo([induced]), complemento([apoptosis, by, mitochondrial, intrinsic, pathway, through, upregulation, of, proapoptotic, proteins, 'Bax', and, 'Bak', and, caspase, 8, and, 9, activation, in, 'c-KIT', mutant, 'Kasumi-1', cells])].
[sujeto(['Furthermore,', it]), verbo([induced]), complemento([cell, cycle, arrest, via, targeting, aurora, kinase, 'B', in, 'c-KIT', wild, type, 'KG-1', cells])].
[sujeto(['BPR1J373', was, shown, to, effectively]), verbo([suppress]), complemento(['c-KIT', phosphorylation, of, 'D816V', mutation, by, treating, 'c-KIT-null', 'COS-1', cells, transfected, with, 'c-KIT', 'D816V', mutant, plasmid])].
[sujeto(['In', 'conclusion,', 'BPR1J373']), verbo([inhibits]), complemento([cell, proliferation, of, 'c-KIT', driven, 'AML', cells, via, induction, of, apoptosis, and, cell, cycle, arrest])].
[sujeto(['Human', 'CD34+', hematopoietic, stem, and, progenitor, cells, '(', 'HSPC)']), verbo([expressing]), complemento([fusion, protein, 'AML1-ETO', '(', 'AE),', generated, by, the, 't(8;21)(q22;q22)', 'rearrangement,', manifest, enhanced, 'self-renewal', and, dysregulated, differentiation, without, leukemic, 'transformation,', representing, a, 'pre-leukemia', stage])].
[sujeto(['However,', 'AE', expression, alone, is, not, sufficient, to]), verbo([maintain]), complemento([high, telomerase, activity, to, immortalize, human, 'HSPC', 'cells,', which, may, hamper, transformation])].
[sujeto(['Enforced', expression, of, hTERT, immortalized, human, 'AE', 'pre-leukemia', cells, in, a, 'telomere-lengthening', independent, 'manner,', and, improved, the, 'pre-leukemia', stem, cell, function, by]), verbo([enhancing]), complemento([cell, proliferation, and, survival])].
[sujeto(['AE-hTERT', cells]), verbo([retained]), complemento([cytokine, dependency, and, 'multi-lineage', differentiation, potential, similar, to, parental, 'AE', clones])].
[sujeto(['The', presence, of, 'AML1-ETO', '(', 'RUNX1-CBF2T1),', a, fusion, oncoprotein, resulting, from, a, 't(8;21)', chromosomal, 'translocation,']), verbo([has]), complemento([been, implicated, as, a, necessary, but, insufficient, event, in, the, development, of, a, subset, of, acute, myeloid, leukemias, '(', 'AML)'])].
[sujeto(['While', 'AML1-ETO', prolongs, survival, and]), verbo([inhibits]), complemento([differentiation, of, hematopoietic, stem, cells, '(', 'HSC),', other, contributory, events, are, needed, for, cell, proliferation, and, leukemogenesis])].
[sujeto(['We']), verbo([have]), complemento([postulated, that, specific, tumor, suppressor, genes, keep, the, leukemic, potential, of, 'AML1-ETO', in, check])].
[sujeto(['In', studying, 'del(9q),', one, of, the, most, common, concomitant, chromosomal, abnormalities, with, 't(8;21),', we, identified, the]), verbo([loss]), complemento([of, an, apparent, tumor, 'suppressor,', 'TLE4,', that, appears, to, cooperate, with, 'AML1-ETO', to, confer, a, leukemic, phenotype])].
[sujeto(['We', show, that, the]), verbo([loss]), complemento([of, 'TLE4', confers, proliferative, advantage, to, leukemic, 'cells,', simultaneous, with, an, upregulation, of, a, 'pro-', inflammatory, signature, mediated, through, aberrant, increases, in, 'Wnt', signaling, activity])].
[sujeto(['It']), verbo([has]), complemento([been, reported, that, amyloid, precursor, 'protein (APP)', promotes, cell, proliferation, and, metastasis, in, various, types, of, solid, cancers])].
[sujeto(['In', our, previous, 'study,', we, showed, that, 'APP', is, highly]), verbo([expressed]), complemento([and, regulates, leukemia, cell, migration, in, 'AML1‑ETO-positive (AE)', leukemia])].
[sujeto(['Whether', 'APP', is]), verbo([involved]), complemento([in, the, regulation, of, 'AE', leukemia, cell, proliferation, or, apoptosis, is, unclear])].
[sujeto([1, ')', and]), verbo([increased]), complemento([levels, of, 'c-KIT', expression, '(', 'P=0'])].
[sujeto([1, ')', ',', was, significantly]), verbo([increased]), complemento([when, the, 'APP', gene, was, knocked, 'down,', concomitant, with, reduced, levels, of, 'anti-apoptotic', protein, 'Bcl-2', and, increased, levels, of, 'caspase-3 and -9,', 'however,', no, apparent, change, was, observed, in, the, cell, cycle, distribution, '(', 'P>0'])].
[sujeto(['Moreover,', the, knockdown, of, 'APP', markedly]), verbo([decreased]), complemento(['c-KIT', expression, at, both, the, transcription, '(', as, evidenced, by, qPCR, 'analysis)', and, translation, '(', as, confirmed, by, 'CD117', assay, and, western, blot, 'analysis)', 'levels,', as, well, as, 'p-AKT', and, its, downstream, targets, including, 'NF-κB,', p53, and, 'Bcl-2'])].
[sujeto(['Chromosomal', translocation, 8, ;, 21, is]), verbo([found]), complemento([in, 40, '%', of, the, 'FAB', 'M2', subtype, of, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['The', resultant, 'in-frame', fusion, protein, 'AML1-ETO', '(', 'AE)']), verbo([acts]), complemento([as, an, initiating, oncogene, for, leukemia, development])].
[sujeto(['Full', activity, was, realized, only, upon]), verbo([increased]), complemento([fusion, protein, expression])].
[sujeto(['In', the, context, of, 'AE,', 'AE9a', did, not, show, selection, for]), verbo([increased]), complemento(['expression,', affirming, observations, of, human, 't(8;21)', patient, samples, where, 'full-length', 'AE', is, the, dominant, protein, detected])].
[sujeto(['Mechanistically,', 'AE9a', showed, defective, transcriptional, regulation, of, 'AE']), verbo([target]), complemento([genes, that, was, partially, corrected, at, high, expression])].
[sujeto(['MicroRNAs', '(', 'miRNAs)', are, a, class, of, small, endogenous, 'non-coding', 'RNAs', that, play, important, regulatory, roles, by]), verbo([targeting]), complemento([mRNAs, for, cleavage, or, translational, repression])].
[sujeto([miRNAs]), verbo([act]), complemento([in, diverse, biological, processes, including, 'development,', cell, 'growth,', 'apoptosis,', and, hematopoiesis])].
[sujeto(['The', miRNA, expression, is]), verbo([associated]), complemento([with, specific, cytogenetic, changes, and, can, also, be, used, to, discriminate, between, the, different, subtypes, of, leukemia, in, acute, lymphoblastic, leukemia, with, common, 'translocations,', it, is, shown, that, the, miRNAs, have, the, potential, to, be, used, for, clinical, diagnosis, and, prognosis])].
[sujeto(['Although', the, 'TALE', family, homeodomain, factor, 'Meis1']), verbo([has]), complemento([been, linked, to, 'malignancy,', a, role, for, 'MEIS2', is, less, clear])].
[sujeto(['Here,', we, demonstrate, that, 'MEIS2', is]), verbo([expressed]), complemento([at, high, levels, in, patients, with, 'AML1-ETO-positive', acute, myeloid, leukemia, and, that, growth, of, 'AML1-ETO-positive', leukemia, depends, on, 'MEIS2', expression])].
[sujeto(['In', 'mice,', 'MEIS2', collaborates, with, 'AML1-ETO', to]), verbo([induce]), complemento([acute, myeloid, leukemia])].
[sujeto(['MEIS2']), verbo([binds]), complemento([strongly, to, the, 'Runt', domain, of, 'AML1-ETO,', indicating, a, direct, interaction, between, these, transcription, factors])].
[sujeto(['High', expression, of, 'MEIS2', impairs, repressive, 'DNA']), verbo([binding]), complemento([of, 'AML1-ETO,', inducing, increased, expression, of, genes, such, as, the, druggable, 'proto-oncogene', 'YES1'])].
[sujeto(['It']), verbo([causes]), complemento([acute, myeloid, leukemia, '(', 'AML)', by, dysregulating, the, expression, of, genes, critical, for, myeloid, cell, development, and, differentiation, and, recently, has, been, reported, to, bind, multiple, subunits, of, the, mammalian, cytosolic, chaperonin, 'TRiC', '(', or, 'CCT),', primarily, through, its, 'DNA', binding, domain, '(', 'AML1-175)'])].
[sujeto(['Our', structure]), verbo([reveals]), complemento([that, 'AML1-175', associates, directly, with, a, specific, subset, of, 'TRiC', subunits, in, the, open, conformation])].
[sujeto(['Here', we, show, that, salicylate, specifically]), verbo([inhibits]), complemento(['CBP', and, p300, lysine, acetyltransferase, activity, in, vitro, by, direct, competition, with, 'acetyl-Coenzyme', 'A', at, the, catalytic, site])].
[sujeto(['We', used, a, chemical, 'structure-similarity', search, to, identify, another, 'anti-inflammatory', 'drug,', 'diflunisal,', that]), verbo([inhibits]), complemento([p300, more, potently, than, salicylate])].
[sujeto(['Finally,', we]), verbo([found]), complemento([that, diflunisal, suppressed, the, growth, of, 'p300-dependent', leukemia, cell, lines, expressing, 'AML1-ETO', fusion, protein, in, vitro, and, in, vivo])].
[sujeto(['The', 'IGF2', mRNA]), verbo([binding]), complemento([protein, 1, '(', 'IGF2BP1)', belongs, to, a, family, of, regulatory, 'RNA-binding', proteins, and, controls, 'stability,', transport, or, translation, of, its, target, transcripts])].
[sujeto(['Re-expression', of, 'IGF2BP1', is, frequently]), verbo([found]), complemento([in, different, tumors, and, has, been, associated, with, aggressive, disease, phenotypes])].
[sujeto(['IGF2BP1']), verbo([has]), complemento([also, been, identified, to, be, exclusively, specific, for, 't(12;21)(p13;q22)-positive', acute, lymphoblastic, leukemia, '(', 'ALL)', but, biological, significance, of, 'IGF2BP1', overexpression, has, not, been, investigated, to, date])].
[sujeto(['We']), verbo([have]), complemento([recently, reported, that, 'ETV6/RUNX1', transcript, is, a, target, of, 'RNA-binding', protein, 'IGF2BP1', in, 't(12;21)(p13;q22)-positive', 'ALL', suggesting, a, direct, role, of, 'IGF2BP1', in, 'ETV6/RUNX1-mediated', leukemogenesis])].
[sujeto(['To', address, this, question, we]), verbo([have]), complemento([employed, stable, clones, of, 'REH', cells, -, a, model, cell, line, of, 't(12;21)(p13;q22)-positive', 'ALL', -, with, downregulated, 'IGF2BP1', expression])].
[sujeto(['Here', we, show, that, downregulation, of, 'IGF2BP1', impairs, proliferation, by, attenuating, cell, cycle, progression, and]), verbo([increasing]), complemento([the, rate, of, spontaneous, cell, death])].
[sujeto(['We', also]), verbo([provide]), complemento([evidence, that, downregulation, of, 'IGF2BP1', induce, reduction, of, 'STAT3', mRNA, levels, and, augments, sensitivity, to, 'STAT3', selective, inhibitor, 'S3I-201'])].
[sujeto(['Here', we, demonstrate, that, 'Ikaros', also]), verbo([regulates]), complemento(['Th17', differentiation, through, its, ability, to, promote, expression, of, multiple, 'Th17', 'lineage-determining', 'genes,', including, 'Ahr,', 'Runx1,', 'Rorc,', 'Il17a,', and, 'Il22'])].
[sujeto(['In', naive, 'cells,', 'Ikaros', is]), verbo([required]), complemento([to, limit, repressive, chromatin, modifications, at, these, gene, 'loci,', thus, maintaining, the, potential, for, expression, of, the, 'Th17', gene, program])].
[sujeto(['Additionally,', 'Ikaros']), verbo([represses]), complemento([the, expression, of, genes, that, limit, 'Th17', 'development,', including, 'Foxp3', and, 'Tbx21'])].
[sujeto(['These', data, define, new]), verbo([targets]), complemento([of, the, action, of, 'Ikaros', and, indicate, that, 'Ikaros', plays, a, critical, role, in, 'CD4+', 'T', cell, differentiation, by, integrating, specific, cytokine, cues, and, directing, epigenetic, modifications, that, facilitate, activation, or, repression, of, relevant, genes, that, drive, 'T', cell, lineage, choice])].
[sujeto(['Forced', expression, of, the, transcription, factor, 'HoxB4']), verbo([has]), complemento([been, shown, to, enhance, the, 'self-renewal', capacity, of, mouse, bone, marrow, hematopoietic, stem, cells, '(', 'HSCs)', and, confer, a, 'long-term', repopulating, capacity, to, yolk, sac, and, embryonic, stem, '(', 'ES)', 'cell-derived', hematopoietic, precursors])].
[sujeto(['The', results, revealed, many, of, the, genes, essential, for, 'HSC', development, to, be, direct]), verbo([targets]), complemento([of, 'HoxB4,', such, as, 'Runx1,', 'Scl/Tal1,', 'Gata2,', and, 'Gfi1'])].
[sujeto(['HoxB4', tended, to]), verbo([activate]), complemento([the, 'transcription,', but, the, 'down-regulation', of, a, significant, portion, of, direct, targets, suggested, its, function, to, be, 'context-dependent'])].
[sujeto(['Our', list, of, 'HoxB4']), verbo([targets]), complemento([also, provides, novel, candidate, regulators, for, 'HSCs'])].
[sujeto(['AML1-ETO', fusion, protein, is, a, product, of, chromosome, translocation, 't(8;21)', frequently, occurred, in, acute, myeloid, leukemia, '(', 'AML),', but, its, sole, expression, appears, to, fail, to]), verbo([cause]), complemento([overt, leukemia, in, vivo])].
[sujeto(['AML1-ETO', fusion, protein, was, conditionally]), verbo([induced]), complemento([in, engineered, 'U937-A/E', 9, /, 14, /, 18, cells])].
[sujeto(['Our', results, showed, that, 'AML1-ETO', induction, significantly]), verbo([increased]), complemento([the, formation, of, carcinogen, 'benzopyrene-DNA', adducts, in, leukemic, cells])].
[sujeto(['In', line, with, the, 'effect,', we, also]), verbo([found]), complemento([that, 'AML1-ETO', induction, upregulated, 'CYP1A1', 'expression,', which, was, dependent, on, 'AML1-binding', motif, in, the, promotor, of, 'CYP1A1', gene])].
[sujeto(['Additionally,', 'AML1-ETO', protein, also]), verbo([increased]), complemento(['AhR', 'expression,', a, 'ligand-activated', transcription, factor, that, mediates, 'PAHs-induced', 'CYP1A1', gene, expression])].
[sujeto(['These', 'data,', combined, with, its, inhibitory, effect, on, 'DNA', repair, as]), verbo([reported]), complemento(['previously,', propose, that, the, presence, of, 'AML1-ETO', increases, the, susceptibility, of, cells, to, chemical, 'carcinogens,', which, favors, the, development, of, additional, genetic, alterations])].
[sujeto(['Cytogenetically', normal, acute, myeloid, leukemia, '(', 'CN-AML)', patients, harboring, 'RUNX1', mutations]), verbo([have]), complemento([a, dismal, prognosis, with, 'anthracycline/cytarabine-based', chemotherapy])].
[sujeto(['Tail', vein, injection, of, 'CG-SH', into, 'NOD', scid, gamma, mice]), verbo([led]), complemento([to, leukemic, engraftment, in, the, bone, 'marrow,', 'spleen,', and, peripheral, blood, within, 6, weeks])].
[sujeto(['Single', nucleotide, polymorphism, '(', 'SNP)', rs11671784, is, in, the, loop, of, 'pre-miR-27a', and, the, 'G/A', variation, can, significantly]), verbo([decrease]), complemento([mature, 'miR-27a', expression])].
[sujeto(['In-vitro', study, was, performed, to, explore, the, mechanism, of, 'chemo-sensitivity', and, the, downstream]), verbo([target]), complemento([of, 'miR-27a', by, using, bladder, cancer, cell, lines])].
[sujeto(['This', study, identified, a, causative, relationship, between, rs11671784, 'G/A', 'variation,', lowered, 'miR-27a', 'expression,']), verbo([increased]), complemento(['RUNX-1', expression, and, following, weakened, 'chemo-sensitivity'])].
[sujeto([rs11671784, 'G', allele]), verbo([has]), complemento([significantly, stronger, effect, over, 'A', allele, in, promoting, 'chemo-sensitivity', in, bladder, cancer])].
[sujeto(['miR-27a']), verbo([mediates]), complemento([chemotherapy, at, least, partially, through, reducing, 'P-gp', expression, and, increasing, apoptosis])].
[sujeto(['In', 'addition,', 'RUNX-1', is, a, novel, direct]), verbo([target]), complemento([of, 'miR-27a,', which, is, involved, in, its, regulation, of, 'chemo-sensitivity', in, bladder, cancer])].
[sujeto(['The', presence, of, 'FISH(+)CD34(+)CD38(-)', cells, before, consolidation, was, negatively]), verbo([associated]), complemento([with, cumulative, incidence, of, relapse, '(', 64, vs, 18, '%', ',', 'P', =])].
[sujeto([5, ')', ',', and]), verbo([retained]), complemento([prognostic, significance, for, 'RFS', in, multivariate, analysis])].
[sujeto(['EPs', can, revert, to, 'SCs', upon, 'injury,', but, whether, this, dedifferentiation, occurs, in, normal, 'HF', homeostasis, '(', hair, 'cycle)', and, the, mechanisms]), verbo([regulating]), complemento([both, differentiation, and, dedifferentiation, are, unclear])].
[sujeto(['Here,', we, use, lineage, 'tracing,']), verbo([gain]), complemento([of, 'function,', transcriptional, 'profiling,', and, functional, assays, to, examine, the, role, of, observed, endogenous, 'Runx1', level, changes, in, the, hair, cycle])].
[sujeto(['We']), verbo([find]), complemento([that, forced, 'Runx1', expression, induces, hair, degeneration, '(', 'catagen)', and, simultaneously, promotes, changes, in, the, quiescent, bulge, 'SC', transcriptome, toward, a, cell, state, resembling, the, 'EP', 'HG', fate])].
[sujeto(['We', propose, that, 'SC', differentiation, and, dedifferentiation, are, likely, to, occur, during, normal, 'HF', degeneration, and, niche, restructuring, in, response, to, changes, in, endogenous, 'Runx1', levels]), verbo([associated]), complemento([with, 'SC', location, with, respect, to, the, niche])].
[sujeto(['Rearrangements']), verbo([involving]), complemento([the, 'RUNX1', gene, account, for, approximately, 15, '%', of, balanced, translocations, in, 'therapy-related', acute, myeloid, leukemia, '(', 't-AML)', patients, and, are, one, of, the, most, common, genetic, abnormalities, observed, in, 't-AML'])].
[sujeto(['Drugs']), verbo([targeting]), complemento([the, topoisomerase, 'II', '(', 'TOP2)', enzyme, are, implicated, in, 't-AML;', 'however,', the, mechanism, is, not, well, understood, and, to, date, a, single, 'RUNX1-RUNX1T1', 't-AML', breakpoint, junction, sequence, has, been, published])].
[sujeto(['Here', we]), verbo([report]), complemento([an, additional, five, breakpoint, junction, sequences, from, 't-AML', patients, with, the, 'RUNX1-', 'RUNX1T1', translocation])].
[sujeto(['Using', a, leukemia, cell, line, 'model,', we, show, that, 'TOP2', beta, '(', 'TOP2B)', is]), verbo([required]), complemento([for, induction, of, 'RUNX1', chromosomal, breaks, by, the, 'TOP2', poison, etoposide, and, 'that,', while, 'TOP2', alpha, '(', 'TOP2A)', and, 'TOP2B', proteins, are, both, present, on, 'RUNX1', and, 'RUNX1T1', 'chromatin,', only, the, 'TOP2B', enrichment, reached, significance, following, etoposide, exposure, at, a, region, on, 'RUNX1', where, translocations, occur])].
[sujeto(['Specifically,', we, identified, a, 'TOP2B-dependent']), verbo([increase]), complemento([in, the, number, of, nuclei, displaying, juxtaposed, 'RUNX1', and, 'RUNX1T1', loci, following, etoposide, treatment])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([found, for, the, first, time, that, 'Runt-related', transcription, factor, 1, '(', 'RUNX1)', contributes, to, 'p53-dependent', 'DNA', damage, response])].
[sujeto(['Upon', adriamycin, '(', 'ADR)', 'exposure,', p53, as, well, as, 'RUNX1', were, strongly]), verbo([induced]), complemento([in, 'p53-proficient', 'HCT116', and, 'U2OS', 'cells,', which, were, closely, associated, with, significant, transactivation, of, p53, target, 'genes,', such, as, 'p21(WAF)(1),', 'BAX,', 'NOXA,', and, 'PUMA'])].
[sujeto(['RUNX1', was, exclusively]), verbo([expressed]), complemento([in, the, cell, nucleus, and, formed, a, complex, with, p53, in, response, to, 'ADR'])].
[sujeto(['Chromatin', immunoprecipitation, assay, demonstrated, that, p53, together, with, 'RUNX1', are, efficiently]), verbo([recruited]), complemento([onto, p53, target, gene, promoters, following, 'ADR', 'exposure,', indicating, that, 'RUNX1', is, involved, in, 'p53-mediated', transcriptional, regulation])].
[sujeto(['Indeed,', forced, expression, of, 'RUNX1']), verbo([stimulated]), complemento([the, transcriptional, activity, of, p53, in, response, to, 'ADR'])].
[sujeto(['Consistent', with, these, 'observations,', knockdown, of, 'RUNX1', attenuated, 'ADR-mediated', induction, of, p53]), verbo([target]), complemento([genes, and, suppressed, 'ADR-dependent', apoptosis])].
[sujeto(['Furthermore,', 'RUNX1', was]), verbo([associated]), complemento([with, p300, histone, 'acetyltransferase,', and, 'ADR-dependent', acetylation, of, p53, at, 'Lys-373/382', was, markedly, inhibited, in, 'RUNX1', knockdown, cells])].
[sujeto(['In', 'addition,', knockdown, of, 'RUNX1', resulted, in, a, significant]), verbo([decrease]), complemento([in, the, amount, of, 'p53-p300', complex, following, 'ADR', exposure])].
[sujeto(['Taken', 'together,', our, present, results, strongly]), verbo([suggest]), complemento([that, 'RUNX1', is, required, for, the, stimulation, of, p53, in, response, to, 'DNA', damage, and, also, provide, novel, insight, into, understanding, the, molecular, mechanisms, behind, 'p53-dependent', 'DNA', damage, response])].
[sujeto(['The', 5, -, year, cumulative, incidence, of, relapse, was, 19.4, '%', and, testes, were, more, frequently]), verbo([involved]), complemento([in, 'ETV6/RUNX1-positive', relapses, '(', 'P=0'])].
[sujeto(['In', univariate, 'analysis,', female, gender, was]), verbo([associated]), complemento([with, a, poor, 'survival,', whereas, site, of, 'relapse,', age, at, 'diagnosis,', leukocytosis, and, consolidation, strategy, had, no, effect])].
[sujeto(['In', multivariate, 'analysis,', only, the, duration, of, first, remission, remained]), verbo([associated]), complemento([with, outcome])].
[sujeto(['We']), verbo([found]), complemento([an, excellent, outcome, for, patients, with, 'ETV6/RUNX1-positive', leukemia, relapses, that, occurred, more, than, 36, months, after, diagnosis])].
[sujeto(['Here', we]), verbo([report]), complemento([that, triptolide, inhibits, cell, proliferation, and, induces, apoptosis, in, a, 'dose-', and, 'time-dependent', manner, of, 't(8;21)-bearing', 'Kasumi-1,', 'SKNO-1', and, 'CD34+', cells, harvested, from, bone, marrow, samples, of, patients, with, 't(8;21)', leukemia])].
[sujeto(['We', show, that, triptolide]), verbo([triggers]), complemento([cleavage, of, the, resultant, 'AML1-ETO', fusion, protein, of, 't(8;21),', and, causes, downregulation, of, 'C-KIT', followed, by, inhibition, of, 'JAK-STAT', signaling])].
[sujeto(['Triptolide', downregulates, p65, and]), verbo([inhibits]), complemento([the, 'DNA-binding', activity, of, 'NF-κB'])].
[sujeto(['Culture', with, 'BMP-2', or, 'BMP-6+AA']), verbo([increased]), complemento(['ALP', activity, of, 'PDLCs,', suggesting, their, 'osteo-inductive', effects])].
[sujeto(['However,', longer, duration, of, culture, showed, neither, of, the, 'BMPs']), verbo([induced]), complemento([in, vitro, mineralization])].
[sujeto(['In', 'contrast,', 'OS', were, able, to]), verbo([increase]), complemento(['ALP', activity, and, 'OPN', 'expressions,', and, also, induced, in, vitro, mineralization])].
[sujeto(['The', mineralization, ability, was, not]), verbo([enhanced]), complemento([by, the, addition, of, 'BMP-2', or, 'BMP-6'])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, addition, of, 'BMP-2', or, 'BMP-6', to, 'OS', may, not, enhance, an, osteogenic, differentiation, of, hPDLCs])].
[sujeto(['Runx1,', a, 'Runt', domain, transcription, 'factor,', controls, the, differentiation, of, nociceptors, that]), verbo([express]), complemento([the, neurotrophin, receptor, 'Ret,', regulates, the, expression, of, many, ion, channels, and, 'receptors,', and, controls, the, 'lamina-specific', innervation, pattern, of, nociceptive, afferents, in, the, spinal, cord])].
[sujeto(['We']), verbo([activated]), complemento([ectopic, expression, of, 'Runx1a', in, cultured, 'NCSCs', using, the, 'Tet-ON', gene, regulatory, system, during, the, formation, of, neurospheres, and, analyzed, the, proportion, of, neurons, and, glial, cells, originating, from, 'NCSCs'])].
[sujeto(['Offsprings', in, which, 'Runx1a', had, been]), verbo([activated]), complemento([showed, retarded, growth, and, displayed, 'megacolon,', pigment, 'defects,', and, dystrophic, dorsal, root, ganglia])].
[sujeto(['In', the, neuropathic, pain, 'model,', the, threshold, for, mechanical, sensitivity, was, markedly]), verbo([increased]), complemento([following, activation, of, 'Runx1a'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'Runx1a', has, a, specific, role, in, 'NCSC', development, and, that, modulation, of, 'Runx1a', activity, may, reduce, mechanical, hypersensitivity, associated, with, neuropathic, pain])].
[sujeto(['We']), verbo([report]), complemento([a, case, of, a, 31, -, 'year-old', female, with, a, positive, 'RUNX1/CBFA2T1', '(', alias, 'AML1/ETO)', fusion, gene, and, a, karyotype, with, a, 't(2;21;8)(p12;q22;q22)'])].
[sujeto(['Although', variant, translocations]), verbo([involving]), complemento([chromosome, region, 2, p12, have, never, been, reported, 'before,', we, suppose, this, translocation, may, be, responsible, for, the, clinical, manifestation, and, prognosis, of, this, case])].
[sujeto(['The', translocation, 't(16;21)']), verbo([involving]), complemento(['RUNX1', '(', 'AML1)', and, resulting, in, the, 'RUNX1-CBFA2T3', fusion, is, a, rare, but, recurrent, abnormality, mostly, found, in, 'therapy-related', acute, myeloid, leukemia, '(', 't-AML)', associated, with, agents, targeting, topoisomerase, 'II', '(', topo, 'II)'])].
[sujeto(['This', study]), verbo([suggests]), complemento([a, wider, distribution, in, the, human, 'genome,', and, particularly, at, genes, involved, in, chromosome, translocations, observed, in, 't-AML,', of, 'DNA', regions, '(', 'hotspot)', targeted, by, specific, topo, 'II', drugs])].
[sujeto(['The', median, copy, number, of, the, 'RUNX1/MTG8', 'transcript,', measured, after, each, treatment, course]), verbo([decreased]), complemento([over, time])].
[sujeto(['However,', an]), verbo([increase]), complemento([in, the, 'MRD', level, was, documented, in, three, patients, after, the, second, 'consolidation,', and, all, of, them, subsequently, relapsed])].
[sujeto(['But', no, data]), verbo([have]), complemento([been, available, up, to, date, concerning, mutual, positioning, of, these, particular, genes, in, the, nucleus, of, a, living, cell, as, well, as, the, mechanism, of, their, rapprochement, and, realignment])].
[sujeto(['Here', we, show, that, there, is, no, proximity, between, these, two, genes, in, the, primary, nuclei, of, normal, human, male, fibroblasts, and, moreover, that, these, genes, are, located, in, different]), verbo([nuclear]), complemento([layers])].
[sujeto(['But', we, further, show, that, treatment, of, cells, with, 'VP-16', '(', 'etoposide),', an, inhibitor, of, 'DNA', topoisomerase, 'II', widely, used, in, anticancer, 'chemotherapy,']), verbo([causes]), complemento([the, 'ETO', gene, repositioning, which, allows, 'AML1', and, 'ETO', genes, to, be, localized, in, the, same, nuclear, layer])].
[sujeto(['Finally,', inhibition, of, 'ETO', gene, repositioning, by, 2, ',', 3, -, butanedione, monoxime, '(', 'BDM)']), verbo([suggests]), complemento([that, this, process, depends, on, nuclear, myosin])].
[sujeto(['Mesenchymal', stem, cells, '(', 'MSC)']), verbo([have]), complemento([been, derived, from, different, cultured, human, 'tissues,', including, bone, 'marrow,', adipose, 'tissue,', amniotic, fluid, and, umbilical, cord, blood])].
[sujeto(['Only', recently, it, was]), verbo([suggested]), complemento([that, 'MSC', descended, from, perivascular, 'cells,', the, latter, being, defined, as, 'CD146⁺', 'neuro-glial', proteoglycan, '(', 'NG)2⁺', 'platelet-derived', growth, 'factor-Rβ⁺', 'ALP⁺', 'CD34⁻', 'CD45⁻', von, 'Willebrand', factor, '(', 'vWF)⁻', 'CD144⁻'])].
[sujeto(['Moreover,', foetal, 'HUC', perivascular, cells, '(', 'HUCPC)']), verbo([express]), complemento([the, embryonic, cell, markers, specific, embryonic, 'antigen-4,', 'Runx1', and, 'Oct-4', and, can, be, cultured, over, the, long, term])].
[sujeto(['The', secretory, profile, exhibited, by, foetal, 'HUCPC', in, the, migration, assay]), verbo([suggested]), complemento([a, paracrine, effect, that, could, be, exploited, in, various, clinical, conditions, including, lung, disorders])].
[sujeto(['The', 'tick-borne', protozoan, parasite, 'Theileria', annulata]), verbo([causes]), complemento([a, debilitating, disease, of, cattle, called, 'Tropical', 'Theileriosis'])].
[sujeto(['The', parasite, predominantly, invades, bovine, macrophages, '(', m, 'phi)', and]), verbo([induces]), complemento([host, cell, transformation, by, a, mechanism, that, has, not, been, fully, elucidated])].
[sujeto(['Infection', is]), verbo([associated]), complemento([with, loss, of, characteristic, m, phi, functions, and, phenotypic, 'markers,', indicative, of, host, cell, 'de-differentiation'])].
[sujeto(['We']), verbo([have]), complemento([investigated, the, effect, of, 'T'])].
[sujeto(['The', 'up-regulation', of, 'c-maf', mRNA, levels, observed, during, bovine, monocyte, differentiation, to, m, phi, was]), verbo([suppressed]), complemento([by, 'T'])].
[sujeto(['annulata-infected', cells, with, the, theileriacidal, drug, buparvaquone]), verbo([induced]), complemento(['up-regulation', of, 'c-maf', and, 'mafB,', which, correlated, with, altered, expression, of, 'down-stream', target, 'genes,', e])].
[sujeto([annulata, infection, is]), verbo([associated]), complemento([with, the, suppression, of, the, transcription, 'factors,', 'Pu'])].
[sujeto([1, and, 'RUNX1,', and, colony]), verbo([stimulating]), complemento([factor, 1, receptor, '(', 'CSF1R)', which, are, also, involved, in, the, regulation, of, 'monocyte/m', phi, differentiation])].
[sujeto(['We', believe, these, results]), verbo([provide]), complemento([the, first, direct, evidence, that, 'T'])].
[sujeto([annulata]), verbo([modulates]), complemento([the, host, m, phi, differentiation, 'state,', which, may, diminish, the, defence, capabilities, of, the, infected, cell, 'and/or', promote, cell, proliferation])].
[sujeto(['The', 't(8;21)', chromosomal, translocation]), verbo([activates]), complemento([aberrant, expression, of, the, 'AML1-ETO', '(', 'AE)', fusion, protein, and, is, commonly, associated, with, core, binding, factor, acute, myeloid, leukaemia, '(', 'CBF', 'AML)'])].
[sujeto(['Combining', a, conditional, mouse, model, that, closely, resembles, the, slow, evolution, and, the, mosaic, 'AE', expression, pattern, of, human, 't(8;21)', 'CBF', 'AML', with, global, transcriptome, 'sequencing,', we]), verbo([find]), complemento([that, disease, progression, was, characterized, by, two, principal, pathogenic, mechanisms])].
[sujeto(['We', also]), verbo([find]), complemento([that, both, 'HSC', and, 'lineage-restricted', granulocyte, macrophage, progenitors, '(', 'GMPs)', acquired, leukaemic, stem, cell, '(', 'LSC)', potential, being, capable, of, initiating, and, maintaining, the, disease])].
[sujeto(['Finally,', our, data, demonstrate, that, 'long-term', expression, of, 'AE']), verbo([induces]), complemento([an, indolent, myeloproliferative, disease, '(', 'MPD)-like', myeloid, leukaemia, phenotype, with, complete, penetrance, and, that, acute, inactivation, of, 'AE', function, is, a, potential, novel, therapeutic, option])].
[sujeto(['MicroRNA']), verbo([regulate]), complemento([the, activity, of, 'protein-coding', genes, including, those, involved, in, hematopoietic, cancers])].
[sujeto(['T-cell,', 'MLL-rearranged,', 'TEL-AML1-positive,', 'E2A-PBX1-positive', and, hyperdiploid, acute, lymphoblastic, 'leukemia,', with, the, exception, of, 'BCR-ABL-positive', and, '\'', 'B-other\'', acute, lymphoblastic, leukemias, '(', defined, as, precursor, 'B-cell', acute, lymphoblastic, leukemia, not, carrying, the, foregoing, cytogenetic, 'aberrations),', were]), verbo([found]), complemento([to, have, unique, 'microRNA-signatures', that, differed, from, each, other, and, from, those, of, healthy, hematopoietic, cells])].
[sujeto(['Strikingly,', the, microRNA, signature, of, 'TEL-AML1-positive', and, hyperdiploid, cases, partly, 'overlapped,', which, may]), verbo([suggest]), complemento([a, common, underlying, biology])].
[sujeto(['No', discriminative, microRNA, were]), verbo([found]), complemento([for, prednisolone, response, and, only, one, microRNA, was, linked, to, resistance, to, 'L-asparaginase'])].
[sujeto(['A', combined, expression, profile, based, on, 14, microRNA, that, were, individually]), verbo([associated]), complemento([with, 'prognosis,', was, highly, predictive, of, clinical, outcome, in, pediatric, acute, lymphoblastic, leukemia, '(', 5, -, year, 'disease-free', survival, of, 89.4, '%', '±7%', versus, 60.8, '±12%,', 'P=0'])].
[sujeto(['Functional', studies, of, discriminative, and, prognostically, important, microRNA, may]), verbo([provide]), complemento([new, insights, into, the, biology, of, pediatric, acute, lymphoblastic, leukemia])].
[sujeto(['CD20', is]), verbo([expressed]), complemento([in, approximately, 'one-', half, of, pediatric, acute, lymphoblastic, leukemia, '(', 'ALL)', cases, with, 'B-cell', precursor, '(', 'BCP)', origin])].
[sujeto(['CD20-positivity', significantly]), verbo([increased]), complemento([from, 45, '%', in, initial, samples, to, 81, '%', at, 'end-induction', '(', day, 15, ',', 71, '%', ')'])].
[sujeto(['In', 'vitro,', 'CD20', 'up-regulation', significantly]), verbo([enhanced]), complemento([rituximab, cytotoxicity, and, could, be, elicited, on, prednisolone, incubation])].
[sujeto(['In', 'conclusion,', 'CD20', 'up-regulation', is, frequently]), verbo([induced]), complemento([in, 'BCP-ALL', during, 'induction,', and, this, translates, into, an, acquired, state, of, higher, sensitivity, to, rituximab])].
[sujeto(['The', 'Wilms\'', tumour, gene, 1, '(', 'WT1)', protein, is, highly]), verbo([expressed]), complemento([in, most, leukaemias])].
[sujeto(['Co-expression', of, 'WT1', and, the, fusion, protein, 'AML1-ETO', in, mice, rapidly]), verbo([induces]), complemento([acute, myeloid, leukaemia, '(', 'AML)'])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, the, fusion, protein, 'BCR/ABL1', increases, expression, of, 'WT1', mRNA, and, protein, via, the, 'phosphatidylinositol-3', kinase, '(', 'PI3K)-Akt', pathway])].
[sujeto(['Inhibition', of, 'BCR/ABL1', or, 'PI3K', activity, strongly]), verbo([suppressed]), complemento([transcription, from, 'WT1', 'promoter/enhancer', reporters])].
[sujeto(['Forced', expression, of, 'BCR/ABL1', in, normal, human, progenitor, 'CD34+', cells]), verbo([increased]), complemento(['WT1', mRNA, and, 'protein,', further, supporting, the, notion, of, 'BCR/ABL1-driven', expression, of, 'WT1', in, human, haematopoietic, cells])].
[sujeto(['Forced', expression, of, 'WT1', in, 'K562', cells]), verbo([provided]), complemento([protection, against, cytotoxic, effects, of, the, 'ABL1', tyrosine, kinase, inhibitor, 'imatinib,', as, judged, by, effects, on, viability, measured, by, trypan, blue, 'exclusion,', metabolic, 'activity,', annexin, 'V', and, 'DAPI', '(', 4, '\'', ',', 6, -, 'diamidino-2-phenylindole)', staining])].
[sujeto(['None', of, the, isoforms]), verbo([provided]), complemento([any, detectable, protection, against, apoptosis, induced, by, arsenic, trioxide, and, only, very, weak, protection, against, 'etoposide,', indicating, that, 'WT1', interferes, with, specific, apoptotic, signalling, pathways])].
[sujeto(['Our', data, demonstrate, that, 'WT1', expression, is]), verbo([induced]), complemento([by, oncogenic, signalling, from, 'BCR/ABL1', and, that, 'WT1', contributes, to, resistance, against, apoptosis, induced, by, imatinib])].
[sujeto(['c-MET', was]), verbo([found]), complemento([to, be, expressed, in, normal, 'B', cells, and, in, 'B-ALL', patients, with, the, 't(12;21)', 'TEL-AML1', 'translocation,', but, it, is, not, expressed, in, the, most, part, of, 'B-ALL', without, the, 't(12;21)'])].
[sujeto(['We', also]), verbo([found]), complemento([that, 'c-MET,', related, to, proliferation, and, protection, from, 'apoptosis,', is, associated, with, the, 'pro-apoptotic', protein, 'FAS', in, 'TEL-AML1', 'B-ALL', cells, and, in, normal, 'B', lymphocytes])].
[sujeto(['REH', cells]), verbo([stimulated]), complemento([with, 'IL-3', and, treated, with, doxorubicin, did, not, undergo, apoptosis, more, than, nonstimulated, 'cells,', demonstrating, that, increased, proliferation, in, itself, is, not, directly, related, to, the, higher, apoptotic, sensitivity, observed, with, 'HGF', stimulation])].
[sujeto(['These', results, indicate, that, 'c-MET', activation]), verbo([enhances]), complemento([specifically, 'FAS-mediated', apoptosis, in, 'TEL-AML1', 'ALL', cells, 'and,', considering, that, the, 'c-MET/FAS', complex, is, present, only, in, normal, 'B', lymphocytes, and, in, 'TEL-AML1', 'leukemias,', this, implies, that, it, may, have, an, important, contribution, in, cellular, homeostasis, and, in, high, sensitivity, of, 'TEL-AML1', 'ALL', to, chemotherapeutic, regimens])].
[sujeto(['Further', 'follow-up', of, this, patient, and, the, analysis, of, a, larger, number, of, children, are, needed, to, define, whether, the]), verbo([gains]), complemento([of, the, specific, extra, chromosomes, modify, the, good, prognosis, that, 't(8;21)', confers, to, this, subgroup, of, 'AML'])].
[sujeto(['AML1-ETO', fusion, 'protein,', a, product, of, 'leukemia-related', chromosomal, translocation, 't(8;21),', was]), verbo([reported]), complemento([to, upregulate, expression, of, 'connexin-43', '(', 'Cx43),', a, member, of, gap, 'junction-constituted', connexin, family])].
[sujeto(['By', bioinformatic, 'analysis,', here, we, showed, that, there, are, two, putative, 'AML1-binding', consensus, sequences, followed, by, two]), verbo([activated]), complemento([protein, '(', 'AP)1', sites, in, the, 5, '\'', -, flanking, region, upstream, to, 'Cx43', gene])].
[sujeto(['AML1-ETO', could, directly]), verbo([bind]), complemento([to, these, two, 'AML1-binding', sites, in, electrophoretic, mobility, shift, 'assay,', but, luciferase, reporter, assay, revealed, that, the, 'AML1', binding, sites, were, not, indispensable, for, 'Cx43', induction, by, 'AML1-ETO', protein])].
[sujeto(['In', 'agreement,', 'AML1-ETO', overexpression, in, leukemic, 'U937', cells]), verbo([activated]), complemento(['c-Jun', 'N-terminal', kinase, '(', 'JNK),', while, its, specific, inhibitor, 'SP600125', effectively, abrogated, 'AML1-ETO-induced', 'Cx43', 'expression,', indicating, that, 'JNK', signaling, pathway, contributes, to, 'AML1-ETO', induced, 'Cx43', expression])].
[sujeto(['Chromosome', rearrangements, are, believed, to]), verbo([cause]), complemento([the, secondary, leukemias, which, constitute, frequent, complications, of, antitumor, chemotherapy, with, topoisomerase, 'II-specific', drugs])].
[sujeto(['Here', we, show, that, inhibition, of, 'DNA', topoisomerase, 'II', in, cultured, cells]), verbo([stimulates]), complemento([association, of, components, of, the, 'non-homologous', end, joining, system, with, a, known, breakpoint, cluster, region, of, the, human, 'AML1', 'gene,', suggesting, that, errors, of, 'DNA', repair, during, 'NHEJ', may, be, the, cause, of, illegitimate, recombination, in, cells, treated, with, topoisomerase, 'II', poisons])].
[sujeto(['Carcinogens\'', failure, to, be, degraded, by, 'CYP2B6', may]), verbo([cause]), complemento(['DNA', injury, and, cancer])].
[sujeto(['We']), verbo([recruited]), complemento([300, patients, including, 164, cases, of, acute, myeloid, leukemia, '(', 'AML),', 96, cases, of, acute, lymphoblastic, leukemia, '(', 'ALL,', including, 17, cases, of, 'T-ALL', and, 79, cases, of, 'B-ALL),', 40, cases, of, 'MDS,', as, well, as, 348, unrelated, umbilical, cord, blood, as, the, controls])].
[sujeto(['T', allele, of, 'CYP2B6', 516, 'G>T', 'SNP', may, be, one, of, the, risk, factors, predisposing, to, the, pathogenesis, of, a, majority, of, 'ALL', and, 'AML,', but]), verbo([has]), complemento([no, relationship, with, 'B-ALL', and, leukemia, with, or, without, chromosome, abnormalities])].
[sujeto(['Runx1', and, 'Notch', signaling, are]), verbo([involved]), complemento([in, this, 'process,', with, 'Notch', signaling, decreasing, with, time, in, 'HCs'])].
[sujeto(['Inhibiting', 'Notch', signaling, readily]), verbo([increases]), complemento(['HC', production, in, mouse, and, chicken, embryos])].
[sujeto(['In', the, 'mouse,', 'however, this']), verbo([increase]), complemento([is, transient])].
[sujeto(['Collectively,', we, show, complementary, roles, of, hemogenic, 'ECs', and, mesenchymal, compartments, in]), verbo([triggering]), complemento([aortic, hematopoiesis])].
[sujeto(['The', subaortic, mesenchyme]), verbo([induces]), complemento(['Runx1', expression, in, 'hemogenic-primed', 'ECs', and, collaborates, with, 'Notch', dynamics, to, control, aortic, hematopoiesis])].
[sujeto(['On', the, other, 'hand,', dexamethasone, can]), verbo([induce]), complemento([apoptosis, in, these, cells, at, low, 'concentrations,', whereas, other, myelomonocytic, leukemia, cell, lines, tested, were, resistant, to, 'glucocorticoid-induced', apoptosis])].
[sujeto(['Glucocorticoids', might]), verbo([induce]), complemento([the, apoptosis, of, some, types, of, 'AML', 'cells,', just, like, that, of, some, lymphoid, leukemia, cells])].
[sujeto(['Naturally', arising, 'CD25+CD4+', regulatory, 'T', cells, '(', 'T(R)', 'cells)', are, engaged, in, the, maintenance, of, immunological, 'self-tolerance', and, immune, homeostasis, by]), verbo([suppressing]), complemento([aberrant, or, excessive, immune, 'responses,', such, as, autoimmune, disease, and, allergy])].
[sujeto(['T(R)', cells, specifically]), verbo([express]), complemento([the, transcription, factor, 'Foxp3,', a, key, regulator, of, 'T(R)-cell', development, and, function])].
[sujeto(['Ectopic', expression, of, 'Foxp3', in, conventional, 'T', cells, is, indeed, sufficient, to]), verbo([confer]), complemento([suppressive, 'activity,', repress, the, production, of, cytokines, such, as, 'interleukin-2', '(', 'IL-2)', and, 'interferon-gamma', '(', 'IFN-gamma),', and, upregulate, 'T(R)-cell-associated', molecules, such, as, 'CD25,', cytotoxic, 'T-lymphocyte-associated', 'antigen-4,', and, 'glucocorticoid-induced', 'TNF-receptor-family-related', protein])].
[sujeto(['However,', the, method, by, which, 'Foxp3', controls, these, molecular, events]), verbo([has]), complemento([yet, to, be, explained])].
[sujeto(['Here', we, show, that, the, transcription, factor, 'AML1', '(', acute, myeloid, leukaemia, 1, ')', /, 'Runx1', '(', 'Runt-related', transcription, factor, 1, ')', ',', which, is, crucially]), verbo([required]), complemento([for, normal, haematopoiesis, including, thymic, 'T-cell', 'development,', activates, 'IL-2', and, 'IFN-gamma', gene, expression, in, conventional, 'CD4+', 'T', cells, through, binding, to, their, respective, promoters])].
[sujeto(['In', natural, 'T(R)', 'cells,', 'Foxp3']), verbo([interacts]), complemento([physically, with, 'AML1'])].
[sujeto(['Several', lines, of, evidence, support, a, model, in, which, the, interaction]), verbo([suppresses]), complemento(['IL-2', and, 'IFN-gamma', 'production,', upregulates, 'T(R)-cell-associated', 'molecules,', and, exerts, suppressive, activity])].
[sujeto(['Infection', of, newborn, inbred, 'NMRI', mice, with, 'Akv']), verbo([induced]), complemento([35, '%', plasma, cell, proliferations, '(', 'PCPs)', '(', consistent, with, 'plasmacytoma),', 33, '%', diffuse, large, 'B-cell', 'lymphomas,', 25, '%', follicular, 'B-cell', lymphomas, and, few, splenic, marginal, zone, and, small, 'B-cell', lymphomas])].
[sujeto(['Additional', mutation, of]), verbo([binding]), complemento([sites, for, the, glucocorticoid, 'receptor,', 'Ets,', 'Runx,', or, basic, 'helix-loop-helix', transcription, factors, in, the, proviral, 'U3', 'region,', 'however,', shifted, disease, induction, to, almost, exclusively, 'PCPs,', but, had, no, major, influence, on, tumor, latency, periods])].
[sujeto(['Southern', analysis, of, immunoglobulin, rearrangements, and, ecotropic, provirus, integration, patterns, showed, that, many, of, the, 'tumors/cell', proliferations]), verbo([induced]), complemento([by, each, virus, were, polyclonal])].
[sujeto(['Our', results, indicate, that, enhancer, mutations, weaken, the, ability, of, 'Akv', to]), verbo([induce]), complemento([mature, 'B-cell', lymphomas, prior, to, the, plasma, cell, 'stage,', whereas, development, of, plasma, cell, proliferations, is, less, dependent, of, viral, enhancer, strength])].
[sujeto(['Myeloblasts', in, the, peripheral, blood]), verbo([increased]), complemento([43, months, after, the, onset, of, 'NHL'])].
[sujeto(['Translocation', '(', 2, ;, 21, ')', '(', 'q21;q22)']), verbo([has]), complemento([not, been, described, previously, to, our, knowledge])].
[sujeto(['The', disrupted, 'AML1', gene, resulting, from, two, 21, q22, rearrangements, may, be]), verbo([involved]), complemento([in, the, pathogenesis, of, 'AML', in, the, present, case])].
[sujeto(['In', this, 'study,', we, present, a, remarkable, clonal, cell, 'line,', 32080, ',', derived, from, a, 'CD2-Lmo2-', transgenic, 'T-cell', leukemia, with, differentiation]), verbo([arrest]), complemento([at, the, transition, from, the, intermediate, single, positive, to, double, positive, stages, of, 'T-cell', development])].
[sujeto(['There', was, 'cell-to-cell', 'variability,', with, some, cells]), verbo([expressing]), complemento([no, 'CD4', and, others, expressing, high, 'CD4'])].
[sujeto(['Lmo2', knockdown]), verbo([decreased]), complemento(['CD4', 'expression,', while, inhibition, of, intracellular, 'NOTCH1', or, histone, deacetylase, activity, induced, 'CD4', expression])].
[sujeto(['Enforced', expression, of, 'RUNX1']), verbo([repressed]), complemento(['CD4', expression])].
[sujeto(['We', analyzed, the, 'CD4', locus, by, 'Histone', 3, chromatin, immunoprecipitation, and]), verbo([found]), complemento([silencing, marks, in, the, 'CD4(-)', cells, and, activating, marks, in, the, 'CD4(+)', population])].
[sujeto(['Retrospective', findings, indicated, that, 't-AML/MDS']), verbo([associated]), complemento([genetic, aberrations, can, be, observed, directly, after, exposure, to, chemotherapy, and, can, precede, 't-AML', by, several, months])].
[sujeto(['Clonal', aberrations, were]), verbo([found]), complemento([in, three, patients])].
[sujeto(['Sustained', high, expression, of, 'TEL-AML1']), verbo([participated]), complemento([in, and, maintained, the, occurrence, of, 'GC', resistance])].
[sujeto(['Inhibition', of, 'TEL-AML1', may]), verbo([provide]), complemento([a, new, therapeutic, approach, to, reverse, 'GC', resistance])].
[sujeto(['Recurrent']), verbo([losses]), complemento([affected, chromosomal, regions, 12, 'p13,', 6, 'q21,', 15, q15])].
[sujeto([2, ',', whereas]), verbo([gains]), complemento([occurred, in, regions, 21, q22, and, 12, p])].
[sujeto(['Loss', of, 12, p13, including, 'CDKN1B', was]), verbo([associated]), complemento([with, a, shorter, remission, duration, '(', 'P=0'])].
[sujeto(['Distribution', of, 'X-chromosomal', copy, number, alterations, was, 'gender-specific:', whole, 'X-chromosome']), verbo([loss]), complemento([occurred, exclusively, in, 'females,', gain, of, 'Xq', only, in, males])].
[sujeto([3, ')', was]), verbo([associated]), complemento([with, a, poor, response, to, induction, treatment, '(', 'P=0'])].
[sujeto(['To', probe, the, effects, of, dexamethasone, '(', 'DEX)', combined, with, histone, deacetylase, '(', 'HDAC)', inhibitor, vorinostat, on]), verbo([inhibiting]), complemento([proliferation, and, inducing, differentiation, and, apoptosis, in, 'Kasumi-1', leukemia, 'cells,', and, its, possible, mechanisms, in, order, to, provide, a, theoretical, basis, for, the, treatment, of, 'AML1-ETO', positive, 'AML'])].
[sujeto(['Treatment', with, the, combination, of, 'DEX', and, vorinostat, for, 48, h]), verbo([led]), complemento([to, statistically, significant, differences, of, inhibited, proliferation, '[', '(', 42.06, '±8'])].
[sujeto([20, ')', '%', ']', ',']), verbo([increased]), complemento([differentiation, '[', '(', 52.83, '±8'])].
[sujeto(['Also', significant, ubiquitination, and]), verbo([decreased]), complemento(['AML1-ETO', protein, in, 'Kasumi-1', cells, after, the, combination, treatment, over, single, agent, or, control, were, observed])].
[sujeto(['The', results, indicated, that, 'DEX', and, vorinostat, could, synergistically]), verbo([inhibit]), complemento([the, 'Kasumi-1', cells, 'proliferation,', induce, 'Kasumi-1', cells, differentiation, and, apoptosis, through, ubiquitination, and, degradation, of, 'AML1-ETO'])].
[sujeto(['The', 'ETV6/RUNX1', '(', 'E/R)', gene, fusion, is, generated, by, the, 't(12;21)', and]), verbo([found]), complemento([in, approximately, 25, '%', of, childhood, 'B-cell', precursor, acute, lymphoblastic, leukemia])].
[sujeto(['To', investigate, this, 'issue,', we]), verbo([suppressed]), complemento([the, endogenous, 'E/R', fusion, protein, with, lentivirally, transduced, short, hairpin, 'RNA', in, the, leukemia, cell, lines, 'REH', and, 'AT-2,', and, found, a, distinct, reduction, of, proliferation, and, cell, survival])].
[sujeto(['In', line, with, the, observed, concurrent, inactivation, of, the, phosphoinositide, 3, -, kinase, '(', 'PI3K)/AKT/mammalian']), verbo([target]), complemento([of, rapamycin, '(', 'mTOR)', 'pathway,', pharmacological, inhibition, diminished, the, phosphorylation, of, 'AKT', and, ribosomal, protein, 'S6,', and, significantly, increased, the, apoptosis, rate, in, 'E/R-positive', leukemias])].
[sujeto(['Collectively,', these, data, demonstrate, that, the, 'E/R', fusion, protein]), verbo([activates]), complemento([the, 'PI3K/AKT/mTOR', pathway, and, is, indispensible, for, disease, maintenance])].
[sujeto(['Importantly,', these, results]), verbo([provide]), complemento([a, first, rationale, and, justification, for, targeting, the, fusion, gene, and, the, 'PI3K/AKT/mTOR', pathway, therapeutically])].
[sujeto(['To']), verbo([gain]), complemento([insight, into, the, relapse, 'mechanisms,', we, analyzed, single, nucleotide, polymorphism, arrays, for, 'DNA', copy, number, aberrations, '(', 'CNAs)', in, 18, matched, diagnosis, and, relapse, leukemias])].
[sujeto(['Moreover,', we, identified, 'recurrent,', mainly, nonoverlapping, deletions]), verbo([associated]), complemento([with, 'glucocorticoid-mediated', apoptosis, targeting, the, 'Bcl2', modifying, factor, '(', 'BMF)', '(', 'n=3),', glucocorticoid, receptor, 'NR3C1', '(', 'n=4),', and, components, of, the, mismatch, repair, pathways, '(', 'n=3)'])].
[sujeto(['They', were, all]), verbo([associated]), complemento([with, 'leukemias,', which, poorly, responded, to, treatment])].
[sujeto(['With', rare, 'exception,', 'however,', the, resultant, protein, products]), verbo([have]), complemento([remained, largely, intractable, as, pharmacologic, targets])].
[sujeto(['One', example, is, 'AML1-ETO,', the, most, common, translocation]), verbo([reported]), complemento([in, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['Gene', expression, signatures, were, used, as, surrogates, for, the, expression, versus]), verbo([loss]), complemento([of, the, translocation, in, 'AML1-ETO-expressing', cells])].
[sujeto(['In', addition, to]), verbo([modulating]), complemento([the, 'AML1-ETO', 'signature,', both, classes, induced, evidence, of, 'differentiation,', dramatically, inhibited, cell, 'viability,', and, ultimately, induced, apoptosis, via, 'on-target', activity])].
[sujeto(['This', work]), verbo([suggests]), complemento([a, role, for, 'DHFR', inhibitors, and, corticosteroids, in, treating, patients, with, 'AML1-ETO-positive', disease])].
[sujeto(['We', explored, the, mechanisms]), verbo([leading]), complemento([to, the, distinct, overexpression, of, 'EPOR', as, well, as, the, effects, of, 'EPO', signaling, on, 'ETV6/RUNX1-positive', acute, lymphoblastic, leukemias])].
[sujeto(['We', show, here, that, ectopic, expression, of, 'ETV6/RUNX1']), verbo([induced]), complemento(['EPOR', 'up-regulation'])].
[sujeto(['Exposure', to, 'EPO']), verbo([increased]), complemento([proliferation, and, survival, of, 'ETV6/RUNX1-positive', leukemias, in, 'vitro,', whereas, blocking, its, binding, site, did, not, alter, cell, survival])].
[sujeto(['The', latter, was, not]), verbo([caused]), complemento([by, activating, mutations, in, the, 'EPOR', but, might, be, triggered, by, constitutive, activation, of, phosphatidylinositol, 3, -, 'kinase/Akt,', the, major, signaling, pathway, of, 'EPOR', in, these, cells])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, 'ETV6/RUNX1', leads, to, 'EPOR', 'up-regulation', and, that, activation, by, 'EPO', might, be, of, relevance, to, the, biology, of, this, leukemia, subtype])].
[sujeto([20, ']', ',', while, no, differences, were]), verbo([found]), complemento([between, two, groups, in, 'age,', gender, 'ratio,', initial, platelet, 'count,', percentage, of, blast, in, bone, 'marrow,', immunophenotypes, and, the, expression, of, myeloid, antigen, 'CD13,', 'CD33', and, 'CD34'])].
[sujeto(['The', load, of, leukemia, cells, in, 'TEL-AML1', positive, patients, is, significantly, smaller, than, its, 'counterparts,', and, the, blast, cells, in, 'TEL-AML1', positive, patients, are, more, sensitive, to, 'prednisone,', indicating, childhood, 'ALL', with, 'TEL-AML1', fusion, gene]), verbo([has]), complemento([a, favorable, prognosis])].
[sujeto(['This']), verbo([report]), complemento([suggests, that, a, subset, of, 'CD7+', 'T-cell', leukemias, without, mature, 'T-cell', antigens, '(', 'CD4-,', 'CD8-)', are, minimally, differentiated, and, can, relapse, as, 'AML'])].
[sujeto(['This', study, analyzes, the, relationship, between, the, mRNA, expression, of, the, genes, and, fusion, products]), verbo([involved]), complemento([in, 't(12;21),', in, vitro, sensitivity, to, 'prednisolone,', 'vincristine,', and, 'L-asparaginase,', and, 'long-term', clinical, outcome, in, 't(12;21)+', acute, lymphoblastic, leukemia, '(', 'ALL)', patients])].
[sujeto(['The', 'TEL-AML1', fusion, product, was]), verbo([expressed]), complemento([in, all, 't(12;21)+', 'cases,', whereas, the, reciprocal, fusion, product, 'AML1-TEL', was, expressed, in, only, 76, '%'])].
[sujeto(['High', expression, levels, of, 'TEL-AML1', '[', hazard, ratio, '(', 'HR),', 1.3, ;, 95, '%', confidence, interval, '(', 95, '%', 'CI),', 1.1, -, 1.57, ;, 'P', =, 0.003, ']', ',', 'AML1-TEL', '(', 'HR,', 4.9, ;, 95, '%', 'CI,', 1.99, -, 12.4, ;, 'P', =, 0.001, ')', and, 'AML1', '(', 'HR,', 1.1, ;, 95, '%', 'CI,', 1.03, -, 1.22, ;, 'P', =, 0.006, ')', were]), verbo([associated]), complemento([with, a, poor, 'long-term', clinical, outcome, within, 't(12;21)+', 'ALL'])].
[sujeto(['Acute', lymphoblastic, leukemia, '(', 'ALL)', can, be, cured, with, combination, chemotherapy, in, over, 75, '%', of, 'children,', but, the]), verbo([cause]), complemento([of, treatment, failure, in, the, remaining, patients, is, unknown])].
[sujeto(['We', determined, the, sensitivity, of, 'ALL', cells, to, individual, antileukemic, agents, in, 441, patients, and, used, a, 'genome-wide', approach, to, identify, 45, genes, differentially]), verbo([expressed]), complemento([in, 'ALL', exhibiting, crossresistance, to, 'prednisolone,', 'vincristine,', 'asparaginase,', and, daunorubicin])].
[sujeto(['We', also, identified, a, distinct, phenotype, of, discordant, resistance, to, asparaginase, and, vincristine, and, 139, genes, whose, expression, was]), verbo([associated]), complemento([with, this, novel, phenotype])].
[sujeto(['We']), verbo([report]), complemento([a, case, of, de, novo, acute, lymphoblastic, leukemia, with, tandem, amplification, of, the, 'AML1', gene, located, in, a, chromosome, marker, that, originated, from, chromosome, 21, and, a, long, 'event-free', survival])].
[sujeto(['t(12;21)(p1', 3, ;, 'q22),', the, most, frequent, chromosomal, translocation]), verbo([found]), complemento([in, childhood, acute, lymphoblastic, leukemia, '(', 'ALL),', occurs, in, approximately, 25, '%', of, 'B-lineage', 'ALL', cases, and, has, been, claimed, to, carry, a, good, prognosis])].
[sujeto(['Al', though, patients, with, 't(12;21)-positive', 'ALL']), verbo([have]), complemento([been, claimed, to, have, a, good, 'outcome,', these, data, indicate, that, this, does, not, reflect, a, high, sensitivity, to, 'prednisolone,', 'vincristine,', and, doxorubicin, given, during, induction, therapy])].
[sujeto(['The', 'TEL-AML1', fusion, which, results, from, a, cryptic, 't(12;21)', translocation, is, the, most, frequently, occurring, genetic, abnormality, in, childhood, acute, lymphoblastic, leukemia, '(', 'ALL)', and]), verbo([has]), complemento([been, associated, with, an, excellent, treatment, outcome])].
[sujeto(['TEL-AML1(+)', 'ALL', cells]), verbo([expressed]), complemento([higher, levels, of, the, 'pro-apoptotic', protein, 'Fas', and, lower, levels, of, the, 'anti-apoptotic', protein, 'Bcl2', than, 'TEL-AML1(-)', 'ALL', 'cells,', as, determined, by, confocal, laser, scanning, microscopy])].
[sujeto(['This', study]), verbo([provides]), complemento([novel, mechanistic, insights, regarding, the, chemosensitivity, of, 'TEL-AML1(+)', 'ALL', cells, and, provides, a, cogent, explanation, for, the, excellent, 'leukemia-free', survival, outcome, of, children, with, 'TEL-AML1(+)', 'ALL', treated, on, contemporary, chemotherapy, programs])].
[sujeto(['The', polyomavirus, enhancer]), verbo([binding]), complemento([protein, 2, '(', 'PEBP2)/core', binding, factor, '(', 'CBF)', is, a, transcription, factor, composed, of, two, 'subunits,', alpha, and, beta])].
[sujeto(['The', gene, encoding, the, beta, subunit, is, disrupted, by, 'inv(16),', resulting, in, the, formation, of, a, chimeric, 'protein,', 'beta-SMMHC,', which, is]), verbo([associated]), complemento([with, acute, myelogenous, leukemia])].
[sujeto(['To', understand, the, effect, of, 'beta-SMMHC', on, 'PEBP2-mediated', 'transactivation,', we, used, a, luciferase, assay, system, in, which, contribution, of, both, the, alpha, and, beta, subunits, was, absolutely]), verbo([required]), complemento([to, activate, transcription])].
[sujeto(['Using', this, 'system,', we]), verbo([found]), complemento([that, the, minimal, region, of, the, beta, subunit, required, for, transactivation, resides, between, amino, acid, 1, and, 135, ',', which, is, known, to, dimerize, with, the, alpha, subunit])].
[sujeto(['Furthermore', 'beta-SMMHC', blocked, the, synergistic, transcription, achieved, by, 'PEBP2', and, 'CCAAT/enhancer']), verbo([binding]), complemento([protein, alpha])].
[sujeto(['By', using, a, construct, in, which, the, 'PEBP2', alpha, subunit, was, fused, to, the, glucocorticoid, receptor, ligand]), verbo([binding]), complemento(['domain,', we, demonstrated, that, coexpressed, 'beta-SMMHC', tightly, sequestered, the, alpha, subunit, in, the, cytoplasm, and, blocked, 'dexamethasone-dependent', nuclear, translocation, of, the, alpha, subunit])].
[sujeto(['Thus,', the, result, suggess, that, 'beta-SMMHC']), verbo([inhibits]), complemento(['PEBP2-mediated', transcription, via, cytoplasmic, sequestration, of, the, alpha, subunit])].
[sujeto(['Lastly', proliferation, of, 'ME-1', cells, that, harbor, 'inv(16)', was, blocked, by, an, antisense, oligonucleotide, complementary, to, the, junction, of, the, chimeric, 'mRNA,']), verbo([suggesting]), complemento([that, 'beta-SMMHC', contributes, to, leukemogenesis, by, blocking, the, differentiation, of, myeloid, cells])].
[sujeto(['We', previously, showed, 'that,', among, patients, treated, on, 'St', 'Jude', 'protocols,', 'TEL', rearrangement, independently]), verbo([conferred]), complemento([an, excellent, prognosis])].
[sujeto(['Thus,', the, presence, of, a, rearranged, 'TEL', gene, is, also]), verbo([associated]), complemento([with, an, improved, survival, among, patients, treated, with, 'antimetabolite-based', therapy])].
[sujeto(['Our', results, indicate, that, all, newly, diagnosed, 'ALL', patients, should, be, screened, for, 'TEL', gene, rearrangements, and]), verbo([suggest]), complemento([that, these, patients, are, candidates, for, less, intensive, therapy])].
[sujeto(['Hematopoietic', stem, and, progenitor, cell, '(', 'HSPC)', specification, is]), verbo([regulated]), complemento([by, numerous, defined, factors, acting, locally, within, the, hemogenic, 'niche;', 'however,', it, is, unclear, whether, production, can, 'adapt to', fluctuating, systemic, needs])].
[sujeto(['Exposure', to, serotonin, or, the, reuptake, inhibitor, fluoxetine]), verbo([increased]), complemento([runx1, expression, and, 'Flk1(+)/cMyb(+)', 'HSPCs', independent, of, peripheral, innervation])].
[sujeto(['Significantly,', developmental, 'hypoxia,', as, indicated, by, 'Hif1α', 'function,']), verbo([induced]), complemento([the, 'HPA/I', axis, and, cortisol, production])].
[sujeto(['Our', data, establish, that, embryonic, 'HSC', production]), verbo([responds]), complemento([to, physiologic, stress, via, 'CNS-derived', serotonin, synthesis, and, central, feedback, regulation, to, control, 'HSC', numbers])].
[sujeto(['In', 58, '%', of, 'samples,', we]), verbo([found]), complemento([deletions, in, various, glucocorticoid, signaling, 'pathway-associated', 'genes,', but, only, 'NR3C1', and, 'ETV6', deletions, prevailed, in, minimal, residual, disease, poor, responding, and, subsequently, relapsing, cases, '(', 'p<0'])].
[sujeto(['The', leukemic, cells, from, these, five, patients, demonstrated]), verbo([increased]), complemento([in, vitro, resistance, to, asparaginase, compared, to, those, from, the, other, 11, patients, '(', p, =, 0.009, ')'])].
[sujeto(['From', the, present, case, 'series,', the, demonstrated, in, vitro, resistance, to, chemotherapeutic, agents, may]), verbo([have]), complemento([a, prognostic, value, in, children, with, 'ALL', before, comprehensive, minimal, residual, disease, measurement, is, available])].
[sujeto(['The', prognosis, for, older, adolescents, and, young, adults, with, acute, lymphoblastic, leukemia, '(', 'ALL)']), verbo([has]), complemento([been, historically, much, worse, than, that, for, younger, patients])].
[sujeto(['The', 89, older, adolescents, were, significantly, more, likely, to]), verbo([have]), complemento(['T-cell', 'ALL,', the, 't(4;11)(MLL-AF4),', and, detectable, minimal, residual, disease, during, or, at, the, end, of, remission, 'induction;', they, were, less, likely, to, have, the, 't(12;21)(ETV6-RUNX1)', compared, with, younger, patients])].
[sujeto(['The', 'Runx', genes, are, important, in, development, and, 'cancer,', where, they, can]), verbo([act]), complemento([either, as, oncogenes, or, tumour, suppressors])].
[sujeto(['We', compared, the, effects, of, ectopic, 'Runx', expression, in, established, 'fibroblasts,', where, all, three, genes, produce, an, indistinguishable, phenotype, entailing, epithelioid, morphology, and]), verbo([increased]), complemento([cell, survival, under, stress, conditions])].
[sujeto(['Gene', array, analysis, revealed, a, strongly, overlapping, transcriptional, 'signature,', with, no, examples, of, opposing, regulation, of, the, same]), verbo([target]), complemento([gene])].
[sujeto(['A', common, set, of, 50, highly]), verbo([regulated]), complemento([genes, was, identified, after, further, filtering, on, regulation, by, inducible, 'RUNX1-ER'])].
[sujeto(['This', set, revealed, a, strong, bias, toward, genes, with, annotated, roles, in, cancer, and, 'development,', and, a, preponderance, of]), verbo([targets]), complemento([encoding, extracellular, or, surface, 'proteins,', reflecting, the, marked, effects, of, 'Runx', on, cell, adhesion])].
[sujeto(['Furthermore,', in, silico, prediction, of, resistance, to, glucocorticoid, growth, inhibition, was, confirmed, in, fibroblasts, and, lymphoid, cells]), verbo([expressing]), complemento([ectopic, 'Runx'])].
[sujeto(['Although', two, direct, 'Runx', activation]), verbo([target]), complemento([genes, were, repressed, '(', 'Ncam1', and, 'Rgc32),', the, fusion, proteins, appeared, to, disrupt, the, regulation, of, downregulated, targets, '(', 'Cebpd,', 'Id2', and, 'Rgs2)', rather, than, impose, constitutive, repression])].
[sujeto(['These', results, elucidate, the, oncogenic, potential, of, the, 'Runx', family, and]), verbo([reveal]), complemento([novel, targets, for, therapeutic, inhibition])].
[sujeto(['The', study]), verbo([recruited]), complemento([309, hospitalized, patients, '(', 187, male, and, 122, 'female)', with, childhood, 'ALL,', the, 'sex,', 'age,', initial, 'WBC', 'count,', 'immunophenotype,', chromosome, and, gene, expression, were, recorded])].
[sujeto(['Acute', lymphoblastic, leukemia, '(', 'ALL)', with, distinct, fusion, transcripts]), verbo([has]), complemento([unique, clinical, features])].
[sujeto(['T-ALL', was]), verbo([associated]), complemento([with, a, high, 'WBC,', increased, 'age,', more, central, nervous, system, 'involvement,', a, poor, prednisone, 'response,', and, high, 'MRD,', with, a, 5, -, year, 'EFS', of, 68.4, ±, 5.2, '%'])].
[sujeto(['Therefore,', this, study]), verbo([suggests]), complemento([that, a, fusion, 'gene-specific', chemotherapy, regimen, 'and/or', targeted, therapy, should, be, developed, to, improve, further, the, cure, rate, of, pediatric, 'ALL'])].
[sujeto(['Early', 'B', cell, factor, '(', 'EBF)', family, members, are, transcription, factors, known, to]), verbo([have]), complemento([important, roles, in, several, aspects, of, vertebrate, 'neurogenesis,', including, 'commitment,', migration, and, differentiation])].
[sujeto(['Knowledge', of, how, 'EBF', family, members, contribute, to, neurogenesis, is, limited, by, a, lack, of, detailed, understanding, of, genes, that, are, transcriptionally]), verbo([regulated]), complemento([by, these, factors])].
[sujeto(['We', performed, a, microarray, screen, in, 'Xenopus', animal, caps, to, search, for]), verbo([targets]), complemento([of, 'EBF', transcriptional, 'activity,', and, identified, candidate, targets, with, multiple, 'roles,', including, transcription, factors, of, several, classes])].
[sujeto(['We', determined, 'that,', among, the, most, upregulated, candidate, genes, with, expected, neuronal, 'functions,', most]), verbo([require]), complemento(['EBF', activity, for, some, or, all, of, their, 'expression,', and, most, have, overlapping, expression, with, ebf, genes])].
[sujeto(['We', also]), verbo([found]), complemento([that, the, candidate, target, genes, that, had, the, most, strongly, overlapping, expression, patterns, with, ebf, genes, were, predicted, to, be, direct, transcriptional, targets, of, 'EBF', transcriptional, activity])].
[sujeto(['The', identification, of, candidate]), verbo([targets]), complemento([that, are, transcription, factor, 'genes,', including, 'nscl-1,', emx1, and, 'aml1,', improves, our, understanding, of, how, 'EBF', proteins, participate, in, the, hierarchy, of, transcription, control, during, neuronal, 'development,', and, suggests, novel, mechanisms, by, which, 'EBF', activity, promotes, migration, and, differentiation])].
[sujeto(['Large', progress]), verbo([has]), complemento([been, made, in, the, treatment, of, acute, lymphoblastic, leukemia, '(', 'ALL)', of, childhood, and, adolescence, over, the, past, 30, years])].
[sujeto(['Event-free', survival, '(', 'pEFS)', of, the, total, group, was, significantly]), verbo([associated]), complemento([with, age])].
[sujeto(['The', most, unfavorable, outcome, was]), verbo([found]), complemento([in, infancy, and, the, best, results, were, achieved, at, toddler, and, 'pre-school', age])].
[sujeto(['Beyond', 5, y, of, 'age,', survival, probability]), verbo([decreased]), complemento(['(', pEFS, at, 8, 'y:', &, 'lt;', 1, y, =, 0.45, ;, 1, -, 5, y, =, 0.82, ;, 6, -, 9, y, =, 0.75, ;, 10, -, 14, y, =, 0.63, ;, &, 'gt;', or, =, 15, y, =, 0.59, ')'])].
[sujeto(['The', incidence, was, constant, after, a, peak, in, the, first, year, of, 'life,', yet, the, percentage, of, 'CD10', negativity]), verbo([increased]), complemento([with, rising, age, in, this, subgroup])].
[sujeto(['We']), verbo([report]), complemento([a, case, of, acute, myeloblastic, leukemia, '(', 'AML)-M2', '(', by, 'French-American-British', 'classification)', with, 't(8;21)', '(', 'q22:q22)', that, was, complicated, with, severe, pneumonia])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, patient, acquired, 'morphological,', cytogenetic])].
[sujeto(['Haematopoietic', stem, and, progenitor, cell, '(', 'HSPC)', transplant, is, a, widely, used, treatment, for, 'life-threatening', conditions, such, as, 'leukaemia;', 'however,', the, molecular, mechanisms]), verbo([regulating]), complemento(['HSPC', engraftment, of, the, recipient, niche, remain, incompletely, understood])].
[sujeto(['We', use, this, system, to, conduct, a, chemical, 'screen,', and, identify, epoxyeicosatrienoic, acids, '(', 'EETs)', as, a, family, of, lipids, that]), verbo([enhance]), complemento(['HSPC', engraftment])].
[sujeto(['The', 'pro-haematopoietic', effects, of, 'EETs', were]), verbo([conserved]), complemento([in, the, developing, zebrafish, 'embryo,', where, 11, ',', 12, -, 'EET', promoted, 'HSPC', specification, by, activating, a, unique, activator, protein, 1, '(', 'AP-1)', and, runx1, transcription, program, autonomous, to, the, haemogenic, endothelium])].
[sujeto(['This', effect]), verbo([required]), complemento([the, activation, of, the, 'phosphatidylinositol-3-OH', kinase, '(', 'PI(3)K)', 'pathway,', specifically, 'PI(3)Kγ'])].
[sujeto(['In', adult, 'HSPCs,', 11, ',', 12, -, 'EET']), verbo([induced]), complemento([transcriptional, 'programs,', including, 'AP-1', 'activation,', which, modulate, several, cellular, 'processes,', such, as, 'migration,', to, promote, engraftment])].
[sujeto(['Furthermore,', we, demonstrate, that, the, 'EET', effects, on]), verbo([enhancing]), complemento(['HSPC', homing, and, engraftment, are, conserved, in, mammals])].
[sujeto(['Our', study, establishes, a, new, method, to, explore, the, molecular, mechanisms, of, 'HSPC', 'engraftment,', and, discovers, a, previously, 'unrecognized,', evolutionarily]), verbo([conserved]), complemento([pathway, regulating, multiple, haematopoietic, generation, and, regeneration, processes])].
[sujeto(['EETs', may]), verbo([have]), complemento([clinical, application, in, marrow, or, cord, blood, transplantation])].
[sujeto(['On', the, one, 'hand,', autophagy, might, be]), verbo([induced]), complemento([as, a, prosurvival, response, to, 'therapy,', thereby, reducing, treatment, efficiency])].
[sujeto(['Here,', we, investigated, these, opposing, roles, of, autophagy, in, 't(8;21)', acute, myeloid, leukemia, '(', 'AML)', 'cells,', which]), verbo([express]), complemento([the, most, frequently, occurring, 'AML', fusion, 'oncoprotein,', 'AML1-eight-twenty-one', '(', 'ETO)'])].
[sujeto(['We', demonstrate, that, autophagy, is]), verbo([induced]), complemento([by, 'AML1-ETO-targeting', 'drugs,', such, as, the, histone, deacetylase, inhibitors, '(', 'HDACis)', valproic, acid, '(', 'VPA)', and, vorinostat])].
[sujeto(['Furthermore,', we, show, that, autophagy, does, not]), verbo([mediate]), complemento([degradation, of, 'AML1-ETO', but, rather, has, a, prosurvival, role, in, 'AML', 'cells,', as, inhibition, of, autophagy, significantly, reduced, the, viability, and, 'colony-forming', ability, of, 'HDACi-treated', 'AML', cells])].
[sujeto(['Combined', treatment, with, 'HDACis', and, autophagy, inhibitors, such, as, chloroquine, '(', 'CQ)']), verbo([led]), complemento([to, a, massive, accumulation, of, ubiquitinated, proteins, that, correlated, with, increased, cell, death])].
[sujeto(['Finally,', we, show, that, 'VPA']), verbo([induced]), complemento([autophagy, in, 't(8;21)', 'AML', patient, 'cells,', and, combined, treatment, with, 'CQ', enhanced, cell, death])].
[sujeto(['Hematopoiesis', -, the, process, by, which, blood, cells, are, formed, -]), verbo([has]), complemento([been, studied, intensely, for, over, a, century, using, a, variety, of, model, systems])].
[sujeto(['Over', the, last, 'decade,', the, zebrafish]), verbo([has]), complemento([come, to, the, forefront, as, a, new, model, in, hematopoiesis, 'research,', as, it, allows, the, use, of, 'large-scale', 'genetics,', chemical, screens, and, transgenics])].
[sujeto(['This', comparative, approach, to, understanding, hematopoiesis]), verbo([has]), complemento([led, to, fundamental, knowledge, about, the, process, and, to, the, development, of, new, therapies, for, disease])].
[sujeto(['Here,', we]), verbo([provide]), complemento([a, broad, overview, of, vertebrate, hematopoiesis])].
[sujeto(['Peroxisome', 'proliferator-activated', 'receptor-gamma', '(', 'PPARγ)']), verbo([regulates]), complemento([both, glucose, metabolism, and, bone, mass])].
[sujeto(['Evidence']), verbo([suggests]), complemento([that, the, therapeutic, modulation, of, 'PPARγ', with, synthetic, agonists, activity, may, elicit, undesirable, effects, on, bone])].
[sujeto(['In', the, presence, of, 15, 'd-PGJ2', it, was, possible, to, visualize, mineralized, nodules, in, the, extracellular, matrix, confirmed, with, the]), verbo([increased]), complemento(['RUNX', mRNA, expression])].
[sujeto([15, 'd-PGJ2', at, small, doses]), verbo([increased]), complemento([the, osteoblast, activity, and, the, 'bone-related', proteins, expression])].
[sujeto(['VGLUT3-expressing', unmyelinated, 'low-threshold', mechanoreceptors, '(', 'C-LTMRs)', are, proposed, to]), verbo([mediate]), complemento([pleasant, touch, 'and/or', 'pain,', but, the, molecular, programs, controlling, 'C-LTMR', development, are, unknown])].
[sujeto(['We', then]), verbo([found]), complemento([that, 'VGLUT3-persistent', neurons, express, the, runt, domain, transcription, factor, 'Runx1'])].
[sujeto(['Furthermore,', 'Runx1', is]), verbo([required]), complemento([to, establish, mechanosensitivity, in, 'C-LTMRs,', by, controlling, the, expression, of, the, mechanically, gated, ion, channel, 'Piezo2'])].
[sujeto(['These', findings, appear, to, argue, against, the, recently, proposed, role, of, 'VGLUT3', in, 'C-LTMRs', in]), verbo([mediating]), complemento([mechanical, hypersensitivity, induced, by, nerve, injury, or, inflammation])].
[sujeto(['Thus,', our, studies]), verbo([provide]), complemento([new, insight, into, the, genetic, program, controlling, 'C-LTMR', development, and, call, for, a, revisit, for, the, physiological, functions, of, 'C-LTMRs'])].
[sujeto(['We', analyzed, the, activity, of, the, histone, deacetylase, inhibitor, '(', 'HDACi)', 'suberoyl-anilide', hydroxamic, acid, '(', 'SAHA)', on, 'Kasumi-1', acute, myeloid, leukemia, '(', 'AML)', cells]), verbo([expressing]), complemento(['AML1/ETO'])].
[sujeto(['SAHA', and, 'VPA']), verbo([induced]), complemento([histone, 'H3', and, 'H4', 'acetylation,', myeloid, differentiation, and, massive, early, apoptosis])].
[sujeto(['The', latter, effects, were, not, determined, by, either, drug, in, 'AML', cell, 'lines,', such, as, 'NB4', or, 'THP-1,', not]), verbo([expressing]), complemento(['AML1/ETO'])].
[sujeto(['SAHA', was, more, rapid, and, effective, than, 'VPA', in]), verbo([increasing]), complemento(['H3', and, 'H4', acetylation, in, total, 'Kasumi-1', cell, lysates, and, more, effective, than, 'VPA', in, inducing, acetylation, of, 'H4K8,', 'H4K12,', 'H4K16', residues])].
[sujeto(['At', the, promoter, of, 'IL3,', a, 'transcriptionally-silenced']), verbo([target]), complemento([of, 'AML1/ETO,', 'SAHA', was, also, more, rapid, than, 'VPA', in, inducing, total, 'H4,', 'H4K5,', 'H4K8', and, 'H3K27', 'acetylation,', while, 'VPA', was, more, effective, than, 'SAHA', at, later, times, in, inducing, acetylation, of, total, 'H4,', 'H4K12,', 'H4K16,', as, well, as, total, 'H3'])].
[sujeto(['Consistent', with, these, 'differences,', 'SAHA']), verbo([induced]), complemento([the, expression, of, 'IL3', mRNA, more, rapidly, than, 'VPA,', while, the, effect, of, 'VPA', was, delayed])].
[sujeto(['Our', results]), verbo([led]), complemento([to, include, 'SAHA,', an, 'FDA-approved', 'drug,', among, the, 'HDACi', active, in, the, 'AML1/ETO-expressing', 'AML', cells])].
[sujeto(['We']), verbo([have]), complemento([examined, the, effect, of, 'all-trans', retinoic, acid, '(', 'ATRA)', on, growth, and, differentiation, of, 'preadipocytes,', and, on, adipokine, gene, expression, in, mature, adipocytes, using, human, preadipocyte, cell, 'model,', 'AML-I'])].
[sujeto(['Both', 'ATRA', and, 9, -, cis, 'RA']), verbo([induced]), complemento([growth, arrest, in, 'AML-I', preadipocyte, at, between, 50, and, 100, 'µM,', which, was, accompanied, by, apoptosis])].
[sujeto(['Western', blotting, showed, a]), verbo([loss]), complemento([of, 'NF-κB,', 'Bcl-2', and, 'p-Akt,', and, the, accumulation, of, 'Bad', and, 'Akt', in, cytoplasm, of, 'ATRA-treated', 'AML-I', preadipocytes])].
[sujeto(['Exposure', of, 'AML-I', to, 'ATRA', or, 9, -, cis, 'RA']), verbo([increased]), complemento([intracellular, lipid, accumulation, in, a, 'time-dependent', manner, compared, to, 'vehicle-treated', cells])].
[sujeto(['Expression', of, fatty, acid, synthase, '(', 'FAS)', and, peroxisome, 'proliferator-activated', 'receptor-γ', '(', 'PPAR-γ)', proteins, was]), verbo([increased]), complemento([in, 'ATRA-treated', cells])].
[sujeto(['Thus,', both, 'ATRA', and, 9, -, cis, 'RA']), verbo([promoted]), complemento(['differentiation,', inhibited, proliferation, and, induced, apoptosis, in, 'AML-I', preadipocytes])].
[sujeto(['ATRA', also]), verbo([modulated]), complemento([adipokine, expression, by, increasing, the, mRNA, level, of, adipocytokines, '(', 'adiponectin,', leptin, and, 'LPL),', and, by, inhibiting, 'PAI-1', mRNA, expression, in, mature, 'AML-I', adipocytes])].
[sujeto(['The', data]), verbo([suggest]), complemento([that, 'ATRA', exerts, a, wide, range, of, 'effects--growth', 'arrest,', 'apoptosis,', lipogenesis, and, modulation, of, adipokine, gene, 'expression--during', the, maturation, of, preadipocytes, into, adipocytes])].
[sujeto(['Valproic', acid, '(', 'VPA)']), verbo([has]), complemento([extensive, effects, on, leukemic, blasts, through, its, inhibition, of, histone, deacetylases])].
[sujeto(['In', 't(8;21)', 'AML,', leukemogenesis, is, supposed, to, be]), verbo([induced]), complemento([via, aberrant, recruitment, of, histone, deacetylases])].
[sujeto(['VPA']), verbo([induced]), complemento([apoptosis, in, 'AML1/ETO-positive', and, 'MLL-AF4-positive', cells, in, a, 'dose-dependent', manner])].
[sujeto(['VPA']), verbo([increased]), complemento([the, expression, of, 'AML1', target, genes, -, 'PU'])].
[sujeto(['AML1/ETO-positive', leukemia, shows, specific, mechanism, of, 'VPA', residing, from, differentiation, followed, by, apoptosis, that, is, accompanied, by, an]), verbo([increase]), complemento([in, the, expression, of, repressed, 'AML1', target, genes])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, 'AML1/ETO-positive', patients, might, derive, the, greatest, benefit, from, 'VPA', treatment])].
[sujeto(['Haploinsufficiency', of, 'RUNX1', '(', also, known, as, 'CBFA2/AML1)', is]), verbo([associated]), complemento([with, familial, 'thrombocytopenia,', platelet, 'dysfunction,', and, predisposition, to, acute, leukemia])].
[sujeto(['We']), verbo([have]), complemento([reported, on, a, patient, with, thrombocytopenia, and, impaired, 'agonist-induced', 'aggregation,', 'secretion,', and, protein, phosphorylation, associated, with, a, 'RUNX1', mutation])].
[sujeto(['Expression', profiling, of, platelets, revealed, approximately, 5, -, fold]), verbo([decreased]), complemento([expression, of, 12, -, lipoxygenase, '(', 12, -, 'LO,', gene, 'ALOX12),', which, catalyzes, 12, -, hydroxyeicosatetraenoic, acid, production, from, arachidonic, acid])].
[sujeto(['We', hypothesized, that, 'ALOX12', is, a, direct, transcriptional]), verbo([target]), complemento([gene, of, 'RUNX1'])].
[sujeto(['In', present, 'studies,', 'agonist-induced', platelet, 12, -, 'HETE', production, was]), verbo([decreased]), complemento([in, the, patient])].
[sujeto(['In', luciferase, reporter, studies, in, human, erythroleukemia, 'cells,', mutation, of, each, site]), verbo([decreased]), complemento(['activity;', overexpression, of, 'RUNX1', 'up-regulated', promoter, 'activity,', which, was, abolished, by, mutation, of, 'RUNX1', sites])].
[sujeto(['Gel', shift, 'studies,', including, with, recombinant, 'protein,', revealed, 'RUNX1']), verbo([binding]), complemento([to, each, site])].
[sujeto(['Chromatin', immunoprecipitation, revealed, in, vivo, 'RUNX1']), verbo([binding]), complemento([in, the, region, of, interest])].
[sujeto([siRNA, knockdown, of, 'RUNX1']), verbo([decreased]), complemento(['RUNX1', and, 12, -, 'LO', proteins])].
[sujeto(['ALOX12', is, a, direct, transcriptional]), verbo([target]), complemento([of, 'RUNX1'])].
[sujeto(['Our', studies]), verbo([provide]), complemento([further, proof, of, principle, that, platelet, expression, profiling, can, elucidate, novel, alterations, in, platelets, with, inherited, dysfunction])].
[sujeto(['Compared', with, control, 'group,', the, expression, level, of, 'AML1', mRNA, significantly]), verbo([increased]), complemento([in, a, 'dose-dependent', manner])].
[sujeto(['Compared', with, control, 'group,', the, expression, level, of, cyclin, 'D2', mRNA, significantly]), verbo([decreased]), complemento([when, 'kasumi-1', cells, had, been, treated, with, 3, 'mmol/L', 'VPA', as, well, as, 'kasumi-1', cells, were, treated, with, different, concentrations, of, 'VPA', for, 3, days])].
[sujeto(['In', 'conclusion,', 'VPA', could, remove, transcription, inhibition, of, 'AML1-ETO', fusion, 'protein,']), verbo([increase]), complemento([transcription, of, 'AML1', and, 'down-regulate', mRNA, expression, of, 'AML1', target, gene, cyclin, 'D2', through, 'HDAC', inhibiting, activity])].
[sujeto(['RUNX1-related', chimeras, generated, by, the, chromosomal, translocations]), verbo([repress]), complemento([transcriptional, activity, of, 'wild-type', 'RUNX1', by, recruiting, the, 'co-repressor/histone', deacetylase, complex])].
[sujeto(['Thus,', histone, deacetylase, inhibitors, are, expected, to, restore, normal, functions, of, 'wild-type', 'RUNX1', and, thereby, affect, the, growth, and, differentiation, ability, of, leukemic, cells]), verbo([expressing]), complemento([the, chimera])].
[sujeto(['We', investigated, the, in, vitro, effects, of, histone, deacetylase, 'inhibitors,', trichostatin, 'A', and, valproic, 'acid,', on, human, leukemic, cell, lines, such, as, 'SKNO-1', and, 'Kasumi-1']), verbo([expressing]), complemento(['RUNX1/ETO,', 'Reh', expressing, 'TEL/RUNX1', and, 'SKH-1', 'co-expressing', 'RUNX1/EVI1', and, 'BCR/ABL'])].
[sujeto(['We', also, employed, 'K562', cells]), verbo([expressing]), complemento(['BCR/ABL', without, such, a, chimera, as, a, control])].
[sujeto(['Treatment', with, each, inhibitor]), verbo([increased]), complemento([acetylated, histone, 4, in, all, of, these, cell, lines])].
[sujeto(['Interestingly,', proliferation, of, 'SKNO-1,', 'Kasumi-1,', 'SKH-1', and, 'Reh', cells, was, significantly]), verbo([suppressed]), complemento([after, 3, -, day, culture, with, trichostatin, 'A', or, valproic, 'acid,', when, compared, to, that, of, 'K562', cells])].
[sujeto(['We', observed, cell, cycle]), verbo([arrest]), complemento([and, apoptotic, induction, in, the, 'RUNX1', 'chimera-expressing', cells, by, the, propidium, iodide, staining])].
[sujeto(['We', propose, histone, deacetylase, inhibitors, to, be, an, attractive, choice, in, the, molecular]), verbo([targeting]), complemento([therapy, of, 'RUNX1-related', leukemia])].
[sujeto(['Contrary', to, its, role, in, 'HDAC2', 'degradation,', the, 'E3-ligase', 'RLIM', does, not]), verbo([target]), complemento(['AML1-ETO', and, 'PML-RARalpha', for, 'ubiquitin-dependent', elimination])].
[sujeto(['The', former]), verbo([requires]), complemento([the, induction, of, 'UbcH8', expression, and, each, of, these, processes, might, be, beneficial, for, leukemia, treatment])].
[sujeto(['Our', observations, shed, light, on, the, mechanism, determining, the, interplay, between, 'E2-conjugases,', 'E3-ligases,', and, their, substrates, and]), verbo([suggest]), complemento([a, strategy, for, utilizing, the, ubiquitylation, machinery, in, a, therapeutic, setting])].
[sujeto(['Here,', we, show, that, chemicals, that]), verbo([enhance]), complemento([prostaglandin, '(', 'PG)', 'E2', synthesis, increased, 'HSC', 'numbers,', and, those, that, block, prostaglandin, synthesis, decreased, stem, cell, numbers])].
[sujeto(['The', cyclooxygenases, responsible, for, 'PGE2', synthesis, were]), verbo([required]), complemento([for, 'HSC', formation])].
[sujeto(['In', murine, embryonic, stem, cell, differentiation, 'assays,', 'PGE2']), verbo([caused]), complemento([amplification, of, multipotent, progenitors])].
[sujeto(['Furthermore,', ex, vivo, exposure, to, stabilized, 'PGE2']), verbo([enhanced]), complemento([spleen, colony, forming, units, at, day, 12, post, transplant, and, increased, the, frequency, of, 'long-term', repopulating, 'HSCs', present, in, murine, bone, marrow, after, limiting, dilution, competitive, transplantation])].
[sujeto(['The']), verbo([conserved]), complemento([role, for, 'PGE2', in, the, regulation, of, vertebrate, 'HSC', homeostasis, indicates, that, modulation, of, the, prostaglandin, pathway, may, facilitate, expansion, of, 'HSC', number, for, therapeutic, purposes])].
[sujeto(['Histone', deacetylase, inhibitor, valproic, acid, '(', 'VPA)', was, recently, shown, to]), verbo([enhance]), complemento([proliferation, and, 'self-renewal', of, normal, hematopoietic, stem, 'cells,', raising, the, possibility, that, 'VPA', may, also, support, growth, of, leukemic, progenitor, cells, '(', 'LPC)'])].
[sujeto(['Here,', 'VPA']), verbo([maintains]), complemento([a, significantly, higher, proportion, of, 'CD34+', 'LPC', and, colony, forming, units, compared, to, control, cultures, in, six, 'AML', 'samples,', but, selectively, reduces, leukemic, cell, numbers, in, another, 'AML', sample, with, expression, of, 'AML1/ETO'])].
[sujeto(['Our', data]), verbo([suggest]), complemento([a, differential, effect, of, 'VPA', on, the, small, population, of, 'AML', progenitor, cells, and, the, bulk, of, aberrantly, differentiated, blasts, in, the, majority, of, 'AML', samples, tested])].
[sujeto(['In', 't(8;21)', acute, myeloid, leukemia, '(', 'AML),', the, 'AML1/ETO', fusion, protein]), verbo([promotes]), complemento([leukemogenesis, by, recruiting, class, 'I', histone, deacetylase, '(', 'HDAC)-containing', repressor, complex, to, the, promoter, of, 'AML1', target, genes])].
[sujeto(['Valproic', acid, '(', 'VPA),', a, commonly, used, antiseizure, and, mood, stabilizer, 'drug,']), verbo([has]), complemento([been, shown, to, cause, growth, arrest, and, induce, differentiation, of, malignant, cells, via, 'HDAC', inhibition])].
[sujeto(['VPA']), verbo([causes]), complemento([selective, proteasomal, degradation, of, 'HDAC2', but, not, other, class, 'I', 'HDACs', '(', i])].
[sujeto(['Therefore,', we, raised, the, question, of, whether, this, drug, can, effectively]), verbo([target]), complemento([the, leukemogenic, activity, of, the, 'AML1/ETO', fusion, protein, that, also, recruits, 'HDAC1,', a, key, regulator, of, normal, and, aberrant, histone, acetylation])].
[sujeto(['We']), verbo([report]), complemento([here, that, 'VPA', treatment, disrupts, the, 'AML1/ETO-HDAC1', physical, 'interaction,', stimulates, the, global, dissociation, of, 'AML1/ETO-HDAC1', complex, from, the, promoter, of, 'AML1/ETO', target, 'genes,', and, induces, relocation, of, both, 'AML1/ETO', and, 'HDAC1', protein, from, nuclear, to, perinuclear, region])].
[sujeto(['Furthermore,', we, show, that, mechanistically, these, effects]), verbo([associate]), complemento([with, a, significant, inhibition, of, 'HDAC', 'activity,', histone, 'H3', and, 'H4', 'hyperacetylation,', and, recruitment, of, 'RNA', polymerase, 'II,', leading, to, transcriptional, reactivation, of, target, genes, '(', i])].
[sujeto(['Ultimately,', these, pharmacological, effects, resulted, in, significant, antileukemic, activity]), verbo([mediated]), complemento([by, partial, cell, differentiation, and, 'caspase-dependent', apoptosis])].
[sujeto(['Taken', 'together,', these, data, support, the, notion, that, 'VPA', might, effectively]), verbo([target]), complemento(['AML1/ETO-driven', leukemogenesis, through, disruption, of, aberrant, 'HDAC1', function, and, that, 'VPA', should, be, integrated, in, novel, therapeutic, approaches, for, 'AML1/ETO-positive', 'AML'])].
[sujeto(['The', fusion, protein, 'TEL-AML1', in, 't(12;21)+', acute, lymphoblastic, leukemia, '(', 'ALL)']), verbo([recruits]), complemento(['co-repressors', and, histone, deacetylases, '(', 'HDAC),', which, transrepress, 'AML1', target, genes])].
[sujeto(['Normal', bone, marrow, cells, were, more, resistant, to, 'HDAC', inhibitor, 'FK228']), verbo([induced]), complemento([cell, killing, than, were, cells, from, 'ALL', patients, with, or, without, 't(12;21)'])].
[sujeto(['FK228']), verbo([induced]), complemento([differentiation, in, 'ALL,', irrespective, of, the, presence, of, 't(12;21)'])].
[sujeto(['Acute', myeloid, leukemia, 1, '(', 'AML1),', also, denoted, 'Runx1,', is, a, transcription, factor, essential, for, 'hematopoiesis,', and, the, 'AML1', gene, is, the, most, common]), verbo([target]), complemento([of, chromosomal, translocations, in, human, leukemias])].
[sujeto(['AML1']), verbo([binds]), complemento([to, sequences, present, in, the, regulatory, regions, of, a, number, of, 'hematopoiesis-specific', 'genes,', including, certain, cytokines, such, as, granulocyte, macrophage, 'colony-stimulating', factor, '(', 'GM-CSF)', 'up-regulated', after, 'T', cell, receptor, stimulation])].
[sujeto(['Here', we, show, that, both, subunits, of, the, 'Ca(2+)/calmodulin-dependent', protein, phosphatase, calcineurin, '(', 'CN),', which, is]), verbo([activated]), complemento([upon, 'T', cell, receptor, 'stimulation,', interact, directly, with, the, 'N-terminal', runt, homology, 'domain-containing', part, of, 'AML1'])].
[sujeto(['The', regulatory, 'CN', subunit]), verbo([binds]), complemento(['AML1', with, a, higher, affinity, and, in, addition, also, interacts, with, the, isolated, runt, homology, domain])].
[sujeto(['The', related, 'Runx2', transcription, 'factor,', which, is, essential, for, bone, 'formation,', also]), verbo([interacts]), complemento([with, 'CN'])].
[sujeto(['A', constitutively, active, derivative, of, 'CN', is, shown, to]), verbo([activate]), complemento([synergistically, the, 'GM-CSF', 'promoter/enhancer', together, with, 'AML1', or, 'Runx2'])].
[sujeto(['We', also]), verbo([provide]), complemento([evidence, that, relief, of, the, negative, effect, of, the, 'AML1', sites, is, important, for, 'Ca(2+)', activation, of, the, 'GM-CSF', 'promoter/enhancer', and, that, 'AML1', overexpression, increases, this, 'Ca(2+)', activation])].
[sujeto(['Both', subunits, of, 'CN']), verbo([interact]), complemento([with, 'AML1', in, coimmunoprecipitation, 'analyses,', and, confocal, microscopy, analysis, of, cells, expressing, 'fluorescence-tagged', protein, derivatives, shows, that, 'CN', can, be, recruited, to, the, nucleus, by, 'AML1', in, vivo])].
[sujeto(['Mutant', analysis, of, the, 'GM-CSF', promoter, shows, that, the, 'Ets1']), verbo([binding]), complemento([site, of, the, promoter, is, essential, for, the, synergy, between, 'AML1', and, 'CN', in, 'Jurkat', 'T', cells])].
[sujeto(['Analysis', of, the, effects, of, inhibitors, of, the, protein, kinase, glycogen, synthase, 'kinase-3beta', and, in, vitro, 'phosphorylation/dephosphorylation', analysis, of, 'Ets1']), verbo([suggest]), complemento([that, glycogen, synthase, 'kinase-3beta-phosphorylated', 'Ets1', is, a, target, of, 'AML1-recruited', 'CN', phosphatase, at, the, 'GM-CSF', promoter])].
[sujeto(['Posttranslational', modification, by, small, 'ubiquitin-like', modifier, '(', 'SUMO)', conjugation]), verbo([regulates]), complemento([the, subnuclear, localization, of, several, 'proteins;', 'however,', 'SUMO', modification, has, not, been, directly, linked, to, nuclear, export])].
[sujeto(['The', 'ETS', '(', 'E-Twenty-Six)', family, member, 'TEL', '(', 'ETV6)', is, a, transcriptional, repressor, that, can]), verbo([inhibit]), complemento(['Ras-dependent', colony, growth, in, soft, agar, and, induce, cellular, aggregation, of, 'Ras-transformed', cells])].
[sujeto(['TEL', is, frequently, disrupted, by, chromosomal, translocations, such, as, the, 't(12;21),', which, is]), verbo([associated]), complemento([with, nearly, 'one-fourth', of, pediatric, 'B', cell, acute, lymphoblastic, leukemia])].
[sujeto(['In', the, vast, majority, of, 't(12;21)-containing', 'cases,', the, second, allele, of, 'TEL', is, 'deleted,']), verbo([suggesting]), complemento([that, inactivation, of, 'TEL', contributes, to, the, disease])].
[sujeto(['Although', 'TEL', functions, in, the, nucleus, as, a, 'DNA-binding', transcriptional, 'repressor,', it]), verbo([has]), complemento([also, been, detected, in, the, cytoplasm])].
[sujeto(['TEL', is, posttranslationally, modified, by, sumoylation, at, lysine, 99, within, a, highly]), verbo([conserved]), complemento([domain, '(', the, &, 'quot;pointed"', 'domain)'])].
[sujeto(['Mutation', of, the, 'sumo-acceptor', lysine, or, mutations, within, the, pointed, domain, that, affect, sumoylation, impair]), verbo([nuclear]), complemento([export, of, 'TEL'])].
[sujeto(['Mutation', of, lysine, 99, also, results, in, an]), verbo([increase]), complemento([in, 'TEL', transcriptional, 'repression,', presumably, because, of, decreased, nuclear, export])].
[sujeto(['We', propose, that, the, ability, of, 'TEL', to]), verbo([repress]), complemento([transcription, and, suppress, growth, is, regulated, by, sumoylation, and, nuclear, export])].
[sujeto(['AML1', may, play, a, role, in, growth, and, differentiation, of, cells, along, erythroid, 'and/or', megakaryocytic, 'lineages,', because, a, significant, level, of, the, 'AML1', gene, is]), verbo([expressed]), complemento([in, these, cells])].
[sujeto(['We', overexpressed, 'AML1a', '(', without, the, 'transcription-activating', 'domain)', and, 'AML1b', '(', with, the, 'domain)', proteins, in, 'K562', leukemia, 'cells,', which, can, be]), verbo([induced]), complemento([to, differentiate, into, 'hemoglobin-producing', cells, and, megakaryocytes])].
[sujeto(['On', the, other, 'hand,', 'AML1b']), verbo([conferred]), complemento([a, similar, 'differentiation-inducing', capacity, upon, 'K562', cells, transfected, with, vector, alone])].
[sujeto(['AML1a', expression, was]), verbo([associated]), complemento([with, enhanced, sensitivity, to, megakaryocytic, differentiation, induced, by, phorbol, ester])].
[sujeto(['These', results]), verbo([provide]), complemento([evidence, that, 'AML1', proteins, play, a, role, in, erythroid, and, megakaryocytic, differentiation])].
[sujeto(['Cannabinoids', '(', 'CB)']), verbo([modulate]), complemento([adult, hematopoietic, stem, and, progenitor, cell, '(', 'HSPCs)', 'function,', 'however,', impact, on, the, 'production,', 'expansion,', or, migration, of, embryonic, 'HSCs', is, currently, uncharacterized])].
[sujeto(['Here,', using, chemical, and, genetic, approaches]), verbo([targeting]), complemento(['CB-signaling', in, 'zebrafish,', we, show, that, 'CB', receptor, '(', 'CNR)', 2, ',', but, not, 'CNR1,', regulates, embryonic, 'HSC', development])].
[sujeto(['During', 'HSC', specification, in, the, 'aorta-gonad-mesonephros', '(', 'AGM)', 'region,', 'CNR2', stimulation, by, 'AM1241']), verbo([increased]), complemento(['runx1;cmyb(+)', 'HSPCs,', through, heightened, 'proliferation,', whereas, 'CNR2', antagonism, decreased, 'HSPC', 'number;', 'FACS', analysis, and, absolute, 'HSC', counts, confirmed, and, quantified, these, effects])].
[sujeto(['Epistatic', investigations, showed, 'AM1241', significantly, upregulated, 'PGE2', synthesis, in, a, 'Ptgs2-dependent', manner, to]), verbo([increase]), complemento(['AGM', 'HSCs'])].
[sujeto(['Using', a, candidate, approach, for, 'HSC', migration, and, retention, 'factors,', 'P-selectin', was, identified, as, the, functional]), verbo([target]), complemento([of, 'CNR2', regulation])].
[sujeto(['Together,', these, data]), verbo([suggest]), complemento(['CNR2-signaling', optimizes, the, 'production,', 'expansion,', and, migration, of, embryonic, 'HSCs', by, modulating, multiple, downstream, signaling, pathways])].
[sujeto(['Valproic', acid, '(', 'VPA)', exhibits, important, pharmacological, properties, but]), verbo([has]), complemento([been, reported, to, trigger, side, 'effects,', notably, on, the, hematological, system])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, 'VPA', affects, hematopoietic, homeostasis, by, inhibiting, erythroid, differentiation, and, promoting, myeloid, and, megakaryocyte, differentiation])].
[sujeto(['Here,', we, analyzed, the, effect, of, 'VPA', on, regulatory, factors]), verbo([involved]), complemento([in, 'erythro-megakaryocytic', differentiation, 'pathways,', including, transcription, factors, and, microRNAs, '(', 'miRs)'])].
[sujeto(['We', demonstrate, that, 'VPA']), verbo([inhibited]), complemento([erythroid, differentiation, in, erythropoietin, '(', 'Epo)-stimulated', 'TF1', leukemia, cells, and, 'CD34(+)/hematopoietic', stem, cells, '(', 'HSCs)', and, in, 'aclacinomycin-(Acla)-treated', 'K562', cells])].
[sujeto(['Mir-144/451', gene, expression, was]), verbo([decreased]), complemento([in, all, erythroid, and, megakaryocyte, models, in, correlation, with, 'GATA-1', inhibition])].
[sujeto(['In', 'Epo-stimulated', 'CD34(+)/HSCs,', 'VPA']), verbo([induced]), complemento([the, expression, of, the, 'ETS', family, transcription, factors, 'PU'])].
[sujeto([1, ',', 'ETS-1,', 'GABP-α,', 'Fli-1', and, 'GATA-2,', which, are, all, known, to, be, negative, regulators, of, 'erythropoiesis,', while, it]), verbo([promoted]), complemento([the, megakaryocytic, pathway])].
[sujeto([1, and, 'ETS-1', expression, were]), verbo([induced]), complemento([in, correlation, with, 'miR-155', 'inhibition;', 'however,', the, 'GATA-1/PU'])].
[sujeto(['Using', megakaryoblastic, 'Meg-01', 'cells,', we, demonstrated, that, 'VPA']), verbo([induced]), complemento([megakaryocyte, morphological, features, and, 'CD61', expression])].
[sujeto(['GATA-2', and, 'miR-27a', expression, were]), verbo([increased]), complemento([in, correlation, with, a, decrease, in, 'RUNX1', mRNA, 'expression,', suggesting, megakaryocyte, differentiation])].
[sujeto(['Finally,', by, using, valpromide, and, the, 'Class', 'I', 'HDACi', 'MS-275,', we, validated, that, the, 'well-described', 'HDACi', activity, of, 'VPA', is, not]), verbo([required]), complemento([in, the, inhibitory, effect, on, erythropoiesis])].
[sujeto(['Overall,', this]), verbo([report]), complemento([shows, that, 'VPA', modulates, the, 'erythro-megakaryocytic', differentiation, program, through, regulatory, 'micro-networks', involving, 'GATA', and, 'ETS', transcription, factors, and, 'miRNAs,', notably, the, 'GATA-1/miR-144/451', axis])].
[sujeto(['Molecular', mechanisms, that, are]), verbo([associated]), complemento([with, 'age-related', denervation, and, loss, of, skeletal, muscle, mass, and, function, '(', 'sarcopenia)', are, described, for, female, 'C57Bl/6J', mice, aged, 3, ',', 15, ',', 24, ',', 27, and, 29, months, '(', 'm)'])].
[sujeto(['Changes', in, mRNAs, and, proteins]), verbo([associated]), complemento([with, myofibre, denervation, and, protein, metabolism, in, ageing, muscles, are, 'reported,', across, the, transition, from, healthy, adult, myofibres, to, sarcopenia, that, occurs, between, 15, and, 24, m])].
[sujeto(['This', onset, of, sarcopenia, at, 24, 'm,', corresponded, with]), verbo([increased]), complemento([expression, of, genes, associated, with, neuromuscular, junction, denervation, including, 'Chnrg,', 'Chrnd,', 'Ncam1,', 'Runx1,', 'Gadd45a', and, 'Myog'])].
[sujeto(['Sarcopenia', in, quadriceps, muscles, also, coincided, with]), verbo([increased]), complemento([protein, levels, for, 'Igf1', 'receptor,', 'Akt', and, ribosomal, protein, 'S6', '(', 'Rps6)', with, increased, phosphorylation, of, 'Rps6', '(', 'Ser235/236)', and, elevated, 'Murf1', mRNA, and, 'protein,', but, not, 'Fbxo32:', many, of, these, changes, are, also, linked, to, denervation])].
[sujeto(['Global', transcription, profiling, via, microarray, analysis, confirmed, these, functional, themes, and, highlighted, additional, themes, that, may, be, a, consequence, of, pathology]), verbo([associated]), complemento([with, 'sarcopenia,', including, changes, in, fatty, acid, 'metabolism,', extracellular, matrix, structure, and, protein, catabolism])].
[sujeto(['Ageing', was, also]), verbo([associated]), complemento([with, increased, global, gene, expression, 'variance,', consistent, with, decreased, control, of, gene, regulation])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, the, patients, of, both, myelodysplastic, syndromes, and, chronic, myeloid, leukaemia, with, 'BMI1', overexpression, had, a, higher, risk, in, malignant, myeloid, progression])].
[sujeto(['In', vitro, gene, transfection, studies, showed, that, 'BMI1']), verbo([inhibited]), complemento([cell, myeloid, and, erythroid, differentiation, induced, by, 12, -, 'O-tetradecanoyl', 'phorbol-13-acetate', '(', 'TPA)', and, histone, deacetylase, inhibitor, sodium, butyrate, respectively])].
[sujeto(['BMI1', also, resisted, apoptosis]), verbo([induced]), complemento([by, arsenic, trioxide])].
[sujeto(['By', using, chromatin, immunoprecipitation, '(', 'ChIP)', collaborated, with, secondary, generation, sequencing, and, verified, by, 'ChIP-PCR,', we]), verbo([found]), complemento([that, 'BMI1', directly, bound, to, the, promoter, region, of, 'Zmym3,', which, encodes, a, component, of, histone, 'deacetylase-containing', complexes])].
[sujeto(['In', 'addition,', as, one, of, the, downstream]), verbo([target]), complemento([genes, of, this, 'complex,', 'c-fos', was, activated, with, increasing, histone, acetylation, when, 'ZMYM3', was, suppressed, in, the, 'Bmi1-transfected', cells])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, 'BMI1', may, reprogramme, the, histone, acetylation, profile, in, multiple, genes, through, either, indirect, or, direct, binding, effects, which, probably, contributes, to, the, malignant, progression, of, myeloid, progenitor, cells])].
[sujeto(['Nickel', '(', 'Ⅱ)', is, a, toxic, and, carcinogenic, metal, which]), verbo([induces]), complemento([a, redox, imbalance, following, oxidative, stress])].
[sujeto(['Nuclear', factor, 'erythroid-2', related, factor, 2, '(', 'Nrf2)', is, a, redox, factor, that]), verbo([regulates]), complemento(['oxidation/reduction', status, and, consequently, mediates, cytoprotective, responses, against, exposure, to, environmental, toxicants])].
[sujeto(['In', this, 'study,', we, investigated, the, protective, roles, of, the, 'Nrf2', gene, against, oxidative, stress, and, 'DNA', damage]), verbo([induced]), complemento([by, nickel, at, 'sub-lethal', doses])].
[sujeto(['Under', nickel, exposure, 'conditions,', we, detected, significantly]), verbo([increased]), complemento([intracellular, 'ROS', 'generation,', in, addition, to, higher, amounts, of, 'DNA', damage, using, comet, assay, and, 'γ-H2AX', immunofluorescence, staining, in, 'Nrf2', lacking, 'cells,', as, compared, to, 'Nrf2', 'wild-type', cells])].
[sujeto(['In', 'addition,', we, attempted, to, identify, potential, nickel, and, 'Nrf2-responsive']), verbo([targets]), complemento([and, the, relevant, pathway])].
[sujeto(['Additionally,', using, bioinformatics, 'tool,', we]), verbo([found]), complemento([that, these, genes, functioned, principally, in, a, variety, of, molecular, 'processes,', including, oxidative, stress, 'response,', 'necrosis,', 'DNA', repair, and, cell, survival])].
[sujeto(['Although', exposure, to, 'SPs', is]), verbo([associated]), complemento([with, reproductive, toxicity, in, 'mammals,', limited, information, is, available, regarding, the, effects, of, 'SPs', on, female, ovulatory, function])].
[sujeto(['Bifenthrin', '(', 'BF),', a, 'broad-spectrum', type, 'I', 'SP,']), verbo([has]), complemento([been, widely, used, for, pest, control, for, two, decades])].
[sujeto(['Our', in, vivo, studies, demonstrated, that, 'short-term', administration, of, 'BF', to, 'gonadotropin-primed', rats, disrupted, the, expression, of, 'LH-responsible', ovulatory, 'genes,']), verbo([suggesting]), complemento([that, 'BF', has, similar, disrupting, effects, on, in, vitro, and, in, vivo, 'LH', signaling])].
[sujeto(['Importantly,', we]), verbo([found]), complemento([that, 'BF', blocked, 'LH-inducible', prostaglandin, 'E2', '(', 'PGE2)', accumulation, in, cultured, medium, of, granulosa, cells])].
[sujeto(['Forskolin']), verbo([stimulated]), complemento(['PTGS2', expression, was, decreased, by, treatment, with, 'BF,', indicating, that, 'BF', may, inhibit, 'LH-induced', 'PTGS2', expression, through, the, protein, kinase, 'A', '(', 'PKA)-mediated', signaling, pathway])].
[sujeto(['Taken', 'together,', our, present, study, firstly, shows, the, systemic, disrupting, effects, of, 'BF', on, the, network, of, ovulatory, gene, expression, patterns, as, well, as, prostaglandin, 'synthesis,', and]), verbo([suggest]), complemento([that, exposure, to, 'BF', may, increase, the, risk, of, ovulatory, dysfunction, in, females])].
[sujeto(['Most', of, the, recurrent, karyotypic, rearrangements, in, 'AML']), verbo([have]), complemento([been, defined, as, distinct, disease, entities, in, the, 2008, 'World', 'Health', 'Organization', '(', 'WHO)', classification])].
[sujeto(['In', this, paper, we]), verbo([report]), complemento([an, 'AML', case, showing, a, novel, 't(4;16)(q25;q23'])].
[sujeto([1, ')', rearrangement]), verbo([causing]), complemento([the, activation, of, epidermal, growth, factor, '(', 'EGF)', and, elongation, of, 'long-chain', fatty, acids, family, member, 6, '(', 'ELOVL6)', 'genes,', rather, than, the, generation, of, a, novel, fusion, gene])].
[sujeto(['It']), verbo([has]), complemento([been, proposed, that, inhibitors, of, an, 'oncogene\'s', effects, on, multipotent, hematopoietic, progenitor, cell, differentiation, may, change, the, properties, of, the, leukemic, stem, cells, and, complement, the, clinical, use, of, cytotoxic, drugs])].
[sujeto(['This', approach, may, open, doors, for, developing, therapeutics]), verbo([targeting]), complemento([oncogene, function, within, leukemic, stem, cells])].
[sujeto(['A', thorough, investigation, of, these, mechanisms, and, the, response, to, pharmacologic, modifiers, will]), verbo([provide]), complemento([a, better, understanding, of, the, role, of, histone, acetylation, in, leukemogenesis])].
[sujeto(['The', combined, approach, was, used, to, follow, the, dynamics, of, 'H4', acetylation, in, 'Kasumi-1', cells, harboring, the, fusion, gene, 'AML1/ETO', shown, to, aberrantly]), verbo([recruit]), complemento([histone, deacetylases, '(', 'HDACs)'])].
[sujeto(['Gene', transcription, is]), verbo([regulated]), complemento([by, a, complex, series, of, epigenetic, 'modifications,', i])].
[sujeto(['On', the, other, 'hand,', methylation, of, the, promoter, regions, of, some, genes, by, 'DNA', methyltransferases, '(', 'DNMT)']), verbo([leads]), complemento([to, transcriptional, silencing, and, is, a, common, mechanism, to, regulate, gene, expression])].
[sujeto(['In', normal, eukaryotic, 'cells,', 'DNA', methylation, and, histone, acetylation, are, interdependent, and]), verbo([maintain]), complemento(['equilibrium,', allowing, temporal, expression, of, genes])].
[sujeto(['In', leukemic, 'cells,', hypermethylation, of, 'CpG', islands, in, the, promoter, region, of, genes, critical, for, cell, cycle, and, maturation, is, 'frequent,', and, 'DNMTs', were]), verbo([found]), complemento([to, be, 'overexpressed,', findings, paralleled, by, evidence, of, transcriptional, repression, of, downstream, genes])].
[sujeto(['Therefore,', the, combination, of, 'HDAC', and, 'DNMT', inhibitors]), verbo([has]), complemento([been, considered, to, be, a, possible, therapeutic, approach, to, restore, normal, gene, expression, in, acute, myeloid, leukemia, '(', 'AML)', and, other, diseases])].
[sujeto(['Histone', acetylation, as, measured, by, flow, cytometry, was]), verbo([increased]), complemento([following, treatment, with, 'D1', and, the, combination, of, 'D1', and, decitabine])].
[sujeto(['Addition', of, 'D1', alone, or, in, combination, with, decitabine, also]), verbo([led]), complemento([to, inhibition, of, cell, proliferation, and, induction, of, apoptosis])].
[sujeto(['Thus,', treatment, of, 'AML', with, 'HDAC', inhibitors, such, as, 'D1', and, 'DNMT', inhibitors, such, as, decitabine, might]), verbo([have]), complemento([clinical, benefit, for, 'patients,', especially, these, presenting, subtypes, of, 'AML,', like, 'AML1/ETO,', in, which, the, leukemogenic, mechanism, involves, corepressor, protein, complexes, containing, 'HDAC', and, 'DNMT'])].
[sujeto(['RUNX/AML', transcription, factors, are, critical, regulators, of, cell, growth, and, differentiation, in, multiple, lineages, and]), verbo([have]), complemento([been, linked, to, human, cancers, including, acute, myelogenous, leukemia, '(', 'RUNX1),', as, well, as, breast, '(', 'RUNX2)', and, gastric, cancers, '(', 'RUNX3)'])].
[sujeto(['RUNX', proteins, are]), verbo([targeted]), complemento([to, gene, regulatory, 'micro-environments', within, the, nucleus, via, a, specific, subnuclear, targeting, signal])].
[sujeto(['The', 'taxol-dependent', cytoplasmic, accumulation, of, 'RUNX2', is]), verbo([inhibited]), complemento([by, leptomycin, 'B,', which, blocks, 'CRM-1', dependent, nuclear, 'export,', and, is, not, affected, by, the, protein, synthesis, inhibitor, cycloheximide])].
[sujeto(['Using', biochemical, 'assays,', we, show, that, endogenous, 'RUNX2']), verbo([associates]), complemento([with, stabilized, microtubules, in, a, 'concentration-dependent', manner, and, that, the, 'RUNX2', amino, terminus, mediates, the, microtubule, association])].
[sujeto(['In', soluble, fractions, of, 'cells,', 'RUNX2', 'co-immunoprecipitates', alpha, tubulin]), verbo([suggesting]), complemento([that, microtubule, binding, involves, the, 'alpha/beta', tubulin, subunits])].
[sujeto(['We', conclude, that, 'RUNX2']), verbo([associates]), complemento([with, microtubules, and, shuttles, between, the, nucleus, and, the, cytoplasm])].
[sujeto(['We', propose, that, 'nuclear-cytoplasmic', shuttling, of, 'RUNX2', may]), verbo([modulate]), complemento([its, transcriptional, 'activity,', as, well, as, its, ability, to, interface, with, signal, transduction, pathways, that, are, integrated, at, 'RUNX2', containing, subnuclear, sites])].
[sujeto(['It', is, possible, that, 'taxol-induced', acute, depletion, of, the]), verbo([nuclear]), complemento([levels, of, 'RUNX2', 'and/or', other, cell, growth, regulatory, factors, may, represent, an, alternative, pathway, by, which, taxol, exerts, its, biological, effects, during, cancer, chemotherapies])].
[sujeto(['Additionally,', electrophoretic, mobility, shift, assays]), verbo([have]), complemento([shown, that, the, palindrome, could, bind, the, 'RUNX1', component, in, nuclear, extracts, of, myeloid, cell, lines, exclusively, through, its, 'RUNX', motif])].
[sujeto(['The', palindrome, was]), verbo([found]), complemento([in, five, additional, human, 'genes,', two, of, which, '(', 'MYH11', and, 'MLLT1)', have, been, linked, to, chromosomal, rearrangements, leading, to, leukemia])].
[sujeto(['The', data, presented, here]), verbo([have]), complemento(['implicated,', for, the, first, 'time,', 'RUNX/AML', in, the, regulation, of, the, uPA, gene])].
[sujeto(['To', assess, whether, dopamine, receptor, 2, agonists, reduced, the, size, of, peritoneal, lesions, in, women, with, endometriosis, and, elucidate, whether, affectation, of, vascular, endothelial, growth, factor, '(', 'VEGF)/VEGF', receptor, 2, '(', 'VEGFR2)-dependent', angiogenesis, was]), verbo([mediating]), complemento([the, observed, effects])].
[sujeto(['Hyperprolactinemic', patients, '(', n, =, 9, ')', with, endometriosis]), verbo([requiring]), complemento([a, first, surgical, intervention, '(', 'L1)', and, benefiting, from, a, 'second-look', laparoscopy, '(', 'L2)', were, evaluated])].
[sujeto(['Quinagolide']), verbo([induced]), complemento([a, 69.5, '%', reduction, in, the, size, of, the, 'lesions,', with, 35, '%', vanishing, completely])].
[sujeto(['By', interfering, with, 'angiogenesis,']), verbo([enhancing]), complemento(['fibrinolysis,', and, reducing, 'inflammation,', quinagolide, reduces, or, eliminates, peritoneal, endometriotic, lesions, in, women, with, endometriosis])].
[sujeto(['The', 't(12;21)', chromosomal, 'translocation,']), verbo([targeting]), complemento([the, gene, encoding, the, 'RUNX1', transcription, 'factor,', is, observed, in, 25, '%', of, pediatric, acute, lymphoblastic, leukemia, '(', 'ALL)', and, is, an, initiating, event, in, the, disease])].
[sujeto(['This', study, revealed, 2, critical, functions, of, 'Runx1:', '(', 1, ')', to]), verbo([promote]), complemento([survival, and, development, of, progenitors, specified, to, the, 'B-cell', 'lineage,', a, function, that, can, be, substituted, by, ectopic, 'Bcl2', 'expression,', and, '(', 2, ')', to, enable, the, developmental, transition, through, the, 'pre-B', stage, triggered, by, the, 'pre-B-cell', antigen, receptor, '(', 'pre-BCR)'])].
[sujeto(['Gene', expression, analysis, and, genomewide, 'Runx1', occupancy, studies, support, the, hypothesis, that, 'Runx1', reinforces, the, transcription, factor, network, governing, early, 'B-cell', survival, and, development, and, specifically]), verbo([regulates]), complemento([genes, encoding, members, of, the, 'Lyn', kinase, subfamily, '(', key, integrators, of, 'interleukin-7', and, 'pre-BCR', 'signaling)', and, the, 'stage-specific', transcription, factors, 'SpiB', and, 'Aiolos', '(', critical, downstream, effectors, of, 'pre-BCR', 'signaling)'])].
[sujeto(['Interrogation', of, expression, databases, of, 257, 'ALL', samples, demonstrated, the, specific, 'down-regulation', of, the, 'SPIB', and, 'IKZF3', genes, '(', the, latter, encoding, 'AIOLOS)', in, 't(12;21)', 'ALL,']), verbo([providing]), complemento([novel, insight, into, the, mechanism, by, which, the, translocation, blocks, 'B-cell', development, and, promotes, leukemia])].
[sujeto(['A', causative, role, for, single, nucleotide, polymorphisms, '(', 'SNPs)', in, many, genetic, disorders]), verbo([has]), complemento([become, evident, through, numerous, 'genome-wide', association, studies])].
[sujeto(['Differential', transcription, factor]), verbo([binding]), complemento([at, a, 'SNP', resulting, in, altered, gene, expression, is, one, possible, mechanism])].
[sujeto(['Here', we, apply, 'PWAS', '(', &, 'quot;proteome-wide', analysis, of, 'SNPs"),', a, methodology, based, on, quantitative, mass, spectrometry, that, enables, rapid, screening, of, 'SNPs', for, differential, transcription, factor, 'binding,', to, 12, 'SNPs', that, are, highly]), verbo([associated]), complemento([with, type, 1, diabetes, at, the, 'IL2RA', 'locus,', encoding, the, 'interleukin-2', receptor, 'CD25'])].
[sujeto(['We']), verbo([report]), complemento(['differential,', 'allele-specific', binding, of, the, transcription, factors, 'RUNX1,', 'LEF1,', 'CREB,', and, 'TFAP4', to, 'IL2RA', 'SNPs', 'rs12722508*A,', 'rs12722522*C,', 'rs41295061*A,', and, 'rs2104286*A', and, demonstrate, the, functional, influence, of, 'RUNX1', at, rs12722508, by, reporter, gene, assay])].
[sujeto(['The', cytokines, 'TGFβ', and, 'IL-6']), verbo([promote]), complemento([the, development, of, 'Th17', cells, that, produce, 'IL-17,', an, inflammatory, cytokine, not, expressed, by, other, 'T', helper, lineages])].
[sujeto(['We', show, that, the, +, 28, -, kb, noncoding, sequence, cooperates, with, 'STAT3,', 'RORγt,', and, 'Runx1', to]), verbo([enhance]), complemento([transcription, from, both, il17a, and, il17f, promoters])].
[sujeto(['This', enhancer, and, both, promoters, exhibited, 'Th17', 'lineage-specific', 'DNA', 'demethylation,', accompanied, by, demethylation, of, lysine, 27, of, histone, 'H3', '(', 'H3K27)', and]), verbo([increased]), complemento(['H3K4', methylation])].
[sujeto(['Loss', of, 'DNA', methylation, tended, to, occur, at, 'STAT3', consensus, 'elements,', and, we, show, that, methylation, of, one, of, these, elements, in, the, il17a, promoter, directly]), verbo([inhibits]), complemento(['STAT3', binding, and, transcriptional, activity])].
[sujeto(['These', results, demonstrate, that, 'TGFβ', and, 'IL-6', synergize, to, epigenetically, poise, the, il17, loci, for, expression, in, 'Th17', 'cells,', and]), verbo([suggest]), complemento([a, general, mechanism, by, which, active, 'STAT3', may, be, epigenetically, excluded, from, 'STAT3-responsive', genes, in, 'non-Th17', lineages])].
[sujeto(['Here', we, show, that, optimal, transcription, of, the, gene, encoding, interleukin, 17, '(', 'Il17)']), verbo([required]), complemento([a, 2, -, kilobase, promoter, and, at, least, one, conserved, noncoding, '(', 'enhancer)', 'sequence,', 'CNS-5'])].
[sujeto(['Both', 'cis-regulatory', elements, contained, regions, that]), verbo([bound]), complemento([the, transcription, factors, 'RORgammat', and, 'Runx1'])].
[sujeto(['Runx1', influenced, 'T(H)-17', differentiation, by]), verbo([inducing]), complemento(['RORgammat', expression, and, by, binding, to, and, acting, together, with, 'RORgammat', during, 'Il17', transcription])].
[sujeto(['However,', 'Runx1', also]), verbo([interacts]), complemento([with, the, transcription, factor, 'Foxp3,', and, this, interaction, was, necessary, for, the, negative, effect, of, 'Foxp3', on, 'T(H)-17', differentiation])].
[sujeto(['Thus,', our, data, support, a, model, in, which, the, differential, association, of, 'Runx1', with, 'Foxp3', and, with, 'RORgammat']), verbo([regulates]), complemento(['T(H)-17', differentiation])].
[sujeto(['Although', previous, studies]), verbo([have]), complemento([revealed, the, roles, of, cytokine, signaling, and, of, transcription, factors, during, differentiation, of, 'Th1', or, 'Th2', 'cells,', it, is, unclear, how, the, exclusive, expression, pattern, of, each, hallmark, cytokine, is, established])].
[sujeto(['The', 'DNaseI', hypersensitivity, site, 'IV', within, the, mouse, 'Il4', locus, plays, an, important, role, in, the, repression, of, 'Il4', expression, in, 'Th1', 'cells,', and, it]), verbo([has]), complemento([been, named, the, 'Il4', silencer])].
[sujeto(['Using', 'Cbf', 'beta-', or, 'Runx3-deficient', 'T', 'cells,', we, show, that]), verbo([loss]), complemento([of, 'Runx', complex, function, results, in, derepression, of, 'IL-4', in, 'Th1', cells])].
[sujeto(['Furthermore,', enforced, expression, of, 'GATA-3', in, 'Th1', cells]), verbo([inhibited]), complemento([binding, of, 'Runx', complexes, to, the, 'Il4', silencer])].
[sujeto(['Interestingly,', 'T', 'cell-specific', inactivation, of, the, 'Cbf', beta, gene, in, mice]), verbo([led]), complemento([to, elevated, serum, immunoglobulin, 'E', and, airway, infiltration])].
[sujeto(['These', results, demonstrate, critical, roles, of, 'Runx', complexes, in]), verbo([regulating]), complemento([immune, 'responses,', at, least, in, 'part,', through, the, repression, of, the, 'Il4', gene])].
[sujeto(['T-cell', acute, lymphoblastic, leukemia, '(', 'T-ALL)', is, characterized, as, a, 'high-risk', stratified, disease]), verbo([associated]), complemento([with, frequent, 'relapse,', chemotherapy, 'resistance,', and, a, poorer, prognostic, outlook, than, 'B-precursor', 'ALL'])].
[sujeto(['Many', of, the, challenges, in, treating, 'T-ALL', reflect, the, lack, of, prognostic, cytogenetic, or, molecular, abnormalities, on, which, to, base, 'therapy,', including]), verbo([targeted]), complemento([therapy])].
[sujeto(['Notch1']), verbo([activating]), complemento([mutations, were, identified, in, more, than, 50, '%', of, 'T-ALL', cases, and, can, be, therapeutically, targeted, with, 'γ-secretase', inhibitors, '(', 'GSIs)'])].
[sujeto(['Mutant', 'Notch1', can]), verbo([activate]), complemento([cMyc, and, 'PI3K-AKT-mTOR1', signaling, in, 'T-ALL'])].
[sujeto(['In', 'T-ALLs', with, 'wild-type', phosphatase, and, tensin, homolog, deleted, on, chromosome, ten, '(', 'PTEN),', 'Notch1', transcriptionally]), verbo([represses]), complemento(['PTEN,', an, effect, reversible, by, 'GSIs'])].
[sujeto(['Notch1', also]), verbo([promotes]), complemento([growth, factor, receptor, '(', 'IGF1R', and, 'IL7Rα)', signaling, to, 'PI3K-AKT'])].
[sujeto(['Notch1', itself, might]), verbo([regulate]), complemento([posttranslational, inactivation, of, 'PTEN'])].
[sujeto(['PP2A', is]), verbo([activated]), complemento([by, 'Notch1', in, 'PTEN-null', 'T-ALL', 'cells,', and, 'GSIs', reduce, 'PP2A', activity, and, increase, phosphorylation, of, 'AKT,', 'AMPK,', and, p70S6K])].
[sujeto(['Myeloid', and, lymphoid, neoplasms, with, abnormalities, of, fibroblast, growth, factor, receptor, 1, gene, '(', 'FGFR1)', are, a, rare, and, aggressive, disease, group, that, harbors, translocations, of, 'FGFR1', with, at, least, 14]), verbo([recognized]), complemento([partner, genes])].
[sujeto(['We']), verbo([report]), complemento([a, case, of, a, patient, with, a, novel, 't(17;21)(p13;q22)', with, 'RUNX1', rearrangement, and, trilineage, blasts])].
[sujeto(['To', our, 'knowledge,', this, is, the, first]), verbo([reported]), complemento([case, of, a, myeloid, and, lymphoid, neoplasm, with, abnormalities, of, 'FGFR1', with, 't(17;21)(p13;q22)', and, trilineage, blasts])].
[sujeto(['Four', years, 'before,']), verbo([he]), complemento([had, received, combination, chemotherapy, including, etoposide, for, seminoma])].
[sujeto(['Thus,', acute, leukemia, with, 't(1;21)', and, 'RUNX1', rearrangement, could, be]), verbo([associated]), complemento([with, 'B/myeloid', mixed, phenotype, as, well, as, previous, topoisomerase, 'II', inhibitor, therapy, and, poor, prognoses])].
[sujeto(['Using', 'semi-quantitative', 'PCR-based', 'approach,', we]), verbo([have]), complemento([shown, that, the, breakpoint, cluster, region, of, the, 'AML1', gene, was, associated, with, the, nuclear, matrix])].
[sujeto(['We']), verbo([have]), complemento([demonstrated, that, inhibition, of, topoisomerase, 'II', by, etoposide, stimulates, the, appearance, of, histone, gammaH2AX, 'foci,', an, indicator, for, the, presence, of, 'DNA', 'double-strand', breaks])].
[sujeto(['Furthermore,', the, major, part, of, these, foci, was]), verbo([associated]), complemento([with, the, nuclear, matrix])].
[sujeto(['We', also, visualized]), verbo([nuclear]), complemento(['matrix--associated', multiprotein, complexes, involved, in, topoisomerase, 'II--induced', 'DNA', 'double-strand', break, repair])].
[sujeto(['Colocalization', studies]), verbo([have]), complemento([demonstrated, that, these, complexes, included, the, principal, components, of, the, 'non-homologous', end, joining, repair, system, '(', 'Ku80,', 'DNA-PKcs', and, 'DNA', ligase, 'IV)'])].
[sujeto(['Thus,', it, is, reasonable, to]), verbo([suggest]), complemento([that, the, 'non-homologous', 'DNA', end, joining, is, a, possible, mechanism, of, topoisomerase, 'II--induced', chromosomal, rearrangements])].
[sujeto(['The', 't(3;21)(q26;q22)', translocation, is]), verbo([associated]), complemento([with, myeloid, leukemias, and, results, in, a, chimeric, oncoprotein, containing, 'AML1/RUNX1', variably, fused, to, 'EAP,', 'MDS1,', 'and/or', 'EVI1'])].
[sujeto(['The', current, study, describes, what, to, the, 'authors\'', knowledge, is, the, first, large, case, series]), verbo([reported]), complemento([to, date, of, 26, 't(3;21)(q26;q22)-associated', 'leukemias,', in, which, 24, cases, arose, after, chemotherapy])].
[sujeto(['Eight', patients, with, chronic, myeloproliferative, disorders, '(', 'CMPD)', were]), verbo([found]), complemento([to, have, 't(3;21)', with, 't(9;22)', as, the, sole, cytogenetic, 'abnormality;', in, 5, other, patients, this, was, accompanied, by, trisomy, 8])].
[sujeto(['The', ability, of, topoisomerase, 2, inhibitors, to]), verbo([induce]), complemento(['DNA', breakage, is, well, recognized])].
[sujeto(['Previous', 'studies,', 'however,']), verbo([have]), complemento([concentrated, on, the, effects, on, individual, genes])].
[sujeto(['We']), verbo([found]), complemento(['MLL', to, be, more, susceptible, to, 'etoposide-induced', cleavage, than, 'RUNX1', and, 'MLLT3,', with, maximum, cleavage, at, a, lower, drug, concentration])].
[sujeto(['In', 'conclusion,', we]), verbo([found]), complemento([that, the, presence, of, the, 't(12;21)', translocation, in, childhood, precursor, 'B-ALL', is, associated, with, a, high, tumor, cell, sensitivity, to, doxorubicin, and, etoposide])].
[sujeto(['High', throughput, techniques, should, now, be, used, to, elucidate, the, cellular, mechanisms, by, which, 'ETV6/RUNX1', gene, fusion, is, linked, to]), verbo([increased]), complemento([sensitivity, to, these, drugs])].
[sujeto(['Recent', findings, that, 'site-specific', cleavage, of, the, 'MLL', gene, can, be]), verbo([induced]), complemento([by, chemotherapeutic, agents, such, as, 'topoisomerase-II', inhibitors, suggest, that, apoptogenic, agents, can, cause, chromosomal, translocations, in, hematopoietic, cells])].
[sujeto(['Short-term', culture, of, immature, 'B', cell, lines, in, the, presence, of, apoptogenic, stimuli, such, as, serum, 'starvation,', 'etoposide,', or, salicylic, acid]), verbo([induced]), complemento(['double-strand', breaks, '(', 'DSBs)', in, intron, 5, of, the, 'TEL', gene, and, intron, 1, of, the, 'AML1', gene])].
[sujeto(['DSBs', within, the, 'TEL', gene, were, also]), verbo([associated]), complemento([with, fusion, to, other, unknown, 'genes,', presumably, as, a, result, of, chromosomal, translocation])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, breakage, and, fusion, of, 'TEL', and, 'AML1', may, be, relatively, common, events, and, that, sublethal, apoptotic, signals, could, play, a, role, in, initiating, leukemogenesis, via, the, promotion, of, 'DNA', damage])].
[sujeto(['A', distinct, population, of, 'therapy-related', acute, myeloid, leukemia, '(', 't-AML)', is, strongly]), verbo([associated]), complemento([with, prior, administration, of, topoisomerase, 'II', '(', topo, 'II)', inhibitors])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, 'site-specific', cleavage, within, the, 'MLL', bcr, can, be, induced, by, either, catalytic, topo, 'II', 'inhibitors,', genotoxic, chemotherapeutic, agents, which, do, not, target, topo, 'II,', or, nongenotoxic, stimuli, of, apoptotic, cell, 'death,', suggesting, that, this, 'site-specific', cleavage, is, part, of, a, generalized, cellular, response, to, an, apoptotic, stimulus])].
[sujeto(['We', also, show, that, 'site-specific', cleavage, within, the, 'MLL', bcr, can, be, linked, to, the, 'higher-order', chromatin, fragmentation, that, occurs, during, the, initial, stages, of, 'apoptosis,', possibly, through, cleavage, of, 'DNA', loops, at, their, anchorage, sites, to, the]), verbo([nuclear]), complemento([matrix])].
[sujeto(['In', 'addition,', we, show, that, 'site-specific', cleavage, is]), verbo([conserved]), complemento([between, 'species,', as, specific, 'DNA', cleavage, can, also, be, demonstrated, within, the, murine, 'MLL', locus])].
[sujeto(['Lastly,', 'site-specific', cleavage, during, apoptosis, can, also, be, identified, at, the, 'AML1', 'locus,', a, locus, which, is, also, frequently]), verbo([involved]), complemento([in, chromosomal, rearrangements, present, in, 't-AML', patients])].
[sujeto(['In', 'conclusion,', these, results]), verbo([suggest]), complemento([the, potential, involvement, of, 'higher-order', chromatin, fragmentation, which, occurs, as, a, part, of, a, generalized, apoptotic, response, in, a, mechanism, leading, to, chromosomal, translocation, of, the, 'MLL', and, 'AML1', genes, and, subsequent, 't-AML'])].
[sujeto(['Altered', regulation, of, many, transcription, factors]), verbo([has]), complemento([been, shown, to, be, important, in, the, development, of, leukemia])].
[sujeto(['TWIST2']), verbo([modulates]), complemento([the, activity, of, a, number, of, important, transcription, factors, and, is, known, to, be, a, regulator, of, hematopoietic, differentiation])].
[sujeto(['We']), verbo([found]), complemento([that, 'TWIST2', was, inactivated, in, more, than, 50, '%', of, cases, of, childhood, and, adult, acute, lymphoblastic, leukemia, through, promoter, hypermethylation, and, that, this, epigenetic, regulation, was, especially, prevalent, in, 'RUNX1-ETV6-driven', cases])].
[sujeto(['Furthermore,', 're-expression', of, 'TWIST2', resulted, in]), verbo([increased]), complemento([sensitivity, to, the, chemotherapeutic, agents, 'etoposide,', daunorubicin, and, dexamethasone, and, 'TWIST2', hypermethylation, was, almost, invariably, found, in, relapsed, adult, acute, lymphoblastic, leukemia, '(', 91, '%', of, samples, 'hypermethylated)'])].
[sujeto(['This', study]), verbo([suggests]), complemento([a, dual, role, for, epigenetic, inactivation, of, 'TWIST2', in, acute, lymphoblastic, 'leukemia,', initially, through, altering, cell, growth, and, survival, properties, and, subsequently, by, increasing, resistance, to, chemotherapy])].
[sujeto(['Decreasing', use, of, prophylactic, cranial, irradiation, in, the, period, 1997, -, 2008, was, not]), verbo([associated]), complemento([with, increased, rates, of, 'CNS', 'relapse,', prompting, complete, omission, of, prophylactic, cranial, irradiation, from, 'TPOG', 'protocols,', beginning, in, 2009])].
[sujeto(['Higher', leukocyte, count, and, 't(9;22)']), verbo([retained]), complemento([prognostic, significance, in, both, 'TPOG-97', and, 'TPOG-2002', by, multivariate, analysis])].
[sujeto(['Although', 'long-term', outcome, in, 'TPOG', clinical, trials, is, comparable, with, results, being]), verbo([reported]), complemento(['worldwide,', the, persistent, strength, of, certain, prognostic, variables, and, the, lower, frequencies, of, favorable, outcome, 'predictors,', such, as, 'ETV6-RUNX1', and, hyperdiploidy, &, 'gt;50,', in, 'Taiwanese', children, warrant, renewed, effort, to, cure, a, higher, proportion, of, patients, while, preserving, their, quality, of, life])].
[sujeto(['MLL', gene, fusions, are, the, hallmark, of, more, than, 70, '%', of, 'therapy-related', leukemias, '(', 't-ML)']), verbo([associated]), complemento([with, topoisomerase, 'II', inhibitors, '(', e])].
[sujeto([',', 'etoposide)', and]), verbo([cause]), complemento([leukemia, in, murine, transgenic, models])].
[sujeto(['The', fusion, points, in, 'Mll', chimeric, products]), verbo([induced]), complemento([by, etoposide, were, localized, to, a, 1.5, kb, region, between, exons, 9, and, 11, ',', analogous, to, the, 'MLL', breakpoint, cluster, region, in, human, leukemia])].
[sujeto(['One', partner, was, 'Runx1,', the, murine, homologue, of, the, transcription, factor, 'AML-1,', a]), verbo([target]), complemento([of, human, translocations, in, 'therapy-related', leukemia])].
[sujeto(['These', findings, indicate, that, etoposide]), verbo([triggers]), complemento([the, formation, of, 'Mll', gene, 'fusions,', a, critical, step, for, the, development, of, 'treatment-induced', leukemic, transformation])].
[sujeto(['The', effect, of, intensified, therapy, on, the, importance, of, currently]), verbo([recognized]), complemento([phenotypic, and, genotypic, determinants, of, outcome, was, assessed, in, 2090, children, enrolled, on, the, 'Medical', 'Research', 'Council', 'United', 'Kingdom', acute, lymphoblastic, leukaemia, 'XI', '(', 'MRC', 'UKALL', 'XI)', protocol])].
[sujeto(['Reverse', 'transcriptase-polymerase', chain, reaction, '(', 'RT-PCR)', methods, often, detect, the, 'AML1/MTG8', fusion, transcript, even, in, acute, myelogenous, leukemia, '(', 'AML)', patients, with, 't(8;21)', who]), verbo([have]), complemento([been, in, 'long-term', remission])].
[sujeto(['Southern', blot, analysis, of, bone, marrow, cells, did, not, detect, rearrangement, of, the, 'AML1', 'gene,', 'however,', fluorescence, in, situ, hybridization, '(', 'FISH)', analysis, of, bone, marrow, cells, at, interphase, and, metaphase, revealed, a, translocational, splitting, between, chromosome, 21]), verbo([involving]), complemento(['AML1', gene, and, chromosome, 16])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, breakpoint, is, not, located, in, the, breakpoint, cluster, region, for, 't(8;21)'])].
[sujeto(['Treatment-related', acute, myeloid, leukemia, '(', 't-AML)', following, successful, therapy, of, a, primary, malignancy]), verbo([has]), complemento([been, recognized, with, increasing, frequency, among, cancer, survivors, over, the, past, several, years])].
[sujeto(['Many', of, these, 't-AML', cases, are]), verbo([associated]), complemento([with, the, use, of, intensive, chemotherapy, regimens, that, employ, one, or, more, agents, which, target, eukaryotic, topoisomerase, 'II', '(', topo, 'II),', and, demonstrate, 'non-random', chromosomal, translocations, involving, either, the, 'MLL', '(', 'ALL-1,', 'HRX)', gene, at, 11, q23, or, the, 'AML1', gene, at, 21, q22])].
[sujeto(['Although', many, investigators]), verbo([have]), complemento([speculated, that, these, translocations, are, induced, by, the, therapeutic, use, of, topo, 'II', 'inhibitors,', the, molecular, sequence, of, events, by, which, topo, 'II', inhibitors, might, induce, a, chromosomal, translocation, are, not, well, understood])].
[sujeto(['This', 'DNA', 'cleavage,', which, maps, to, a, region, of, the, 'AML1', locus, frequently, disrupted, by, chromosomal, 'translocations,', can, be]), verbo([induced]), complemento([in, several, cell, 'lines,', with, multiple, different, topo, 'II', 'inhibitors,', indicating, that, this, phenomenon, is, not, restricted, to, a, specific, cell, type, or, specific, topo, 'II', inhibitor])].
[sujeto(['It', is, conceivable, that, 'site-specific', 'double-strand', 'DNA', cleavage, within, the, 'AML1', locus]), verbo([induced]), complemento([by, topo, 'II', inhibitors, represents, the, initial, molecular, event, leading, to, a, chromosomal, translocation, and, 't-AML'])].
[sujeto(['The', purposes, of, this, study, were, to, investigate, the, possible, molecular, mechanisms, of, 'miR-18a']), verbo([regulating]), complemento([the, permeability, of, 'blood-tumor', barrier, '(', 'BTB)', via, 'down-regulated', expression, and, distribution, of, 'runt-related', transcription, factor, 1, '(', 'RUNX1)'])].
[sujeto(['The', overexpression, of, 'miR-18a', significantly, impaired, the, integrity, and]), verbo([increased]), complemento([the, permeability, of, 'BTB,', which, respectively, were, detected, by, 'TEER', and, 'HRP', flux, 'assays,', accompanied, by, 'down-regulated', mRNA, and, protein, expressions, and, distributions, of, 'ZO-1,', occludin, and, 'claudin-5', in, 'GECs'])].
[sujeto(['Dual-luciferase', reporter, assay, was, carried, out, and, revealed, 'RUNX1', is, a]), verbo([target]), complemento([gene, of, 'miR-18a'])].
[sujeto(['Most', 'important,', 'miR-18a', and, 'RUNX1', could, reversely]), verbo([regulate]), complemento([the, permeability, of, 'BTB', as, well, as, the, expressions, and, distributions, of, 'ZO-1,', occludin, and, 'claudin-5'])].
[sujeto(['Finally,', chromatin, immunoprecipitation, verified, that, 'RUNX1']), verbo([interacted]), complemento([with, &, 'quot;TGGGGT"', 'DNA', sequence, in, promoter, region, of, 'ZO-1,', occludin, and, 'claudin-5', respectively])].
[sujeto(['Taken', 'together,', our, present, study, indicated, that, 'miR-18a']), verbo([increased]), complemento([the, permeability, of, 'BTB', via, 'RUNX1', mediated, 'down-regulation', of, tight, junction, related, proteins, 'ZO-1,', occludin, and, 'claudin-5,', which, would, attract, more, attention, to, 'miR-18a', and, 'RUNX1', as, potential, targets, of, drug, delivery, across, 'BTB', and, provide, novel, strategies, for, glioma, treatment])].
[sujeto(['Recently', a, putative, link, to, breast, cancer]), verbo([has]), complemento([started, to, 'emerge,', however, the, function, of, 'RUNX1', in, breast, cancer, is, still, unknown])].
[sujeto(['RUNX1', was]), verbo([associated]), complemento([with, progesterone, receptor, '(', 'PR)-positive', tumours, '(', 'P<0'])].
[sujeto([1, ')', 'T-lymphocytic', 'infiltrate,']), verbo([increased]), complemento([tumour, 'CD138+plasma', cell, '(', 'P<0'])].
[sujeto(['RUNX1', expression, did, not, influence, outcome, of, oestrogen, receptor, '(', 'ER)-positive', or, 'HER2-positive', 'disease,', however, on, univariate, analysis, a, high, 'RUNX1', protein, was, significantly]), verbo([associated]), complemento([with, poorer, 'cancer-specific', survival, in, patients, with, 'ER-negative', '(', 'P<0'])].
[sujeto(['Of', 'relevance,', triple, negative, breast, cancer, currently, lacks, good, biomarkers, and, patients, with, this, subtype, do, not, benefit, from, the, option, of]), verbo([targeted]), complemento([therapy, unlike, patients, with, 'ER-positive', or, 'HER2-positive', disease])].
[sujeto(['Recent', genomic, studies]), verbo([have]), complemento([provided, a, refined, genetic, map, of, acute, lymphoblastic, leukemia, '(', 'ALL)', and, increased, the, number, of, potential, prognostic, markers])].
[sujeto(['Studies']), verbo([have]), complemento([suggested, that, myeloid, fate, choice, is, primarily, regulated, by, transcription, 'factors;', 'however,', new, intrinsic, regulators, and, their, underlying, mechanisms, remain, to, be, elucidated])].
[sujeto(['Runx1', is]), verbo([induced]), complemento([by, high, 'Pu'])].
[sujeto([1, level]), verbo([required]), complemento([for, balanced, fate, commitment, to, neutrophils, versus, macrophages])].
[sujeto(['Mammals']), verbo([have]), complemento([two, principal, types, of, fat])].
[sujeto(['Recent', studies]), verbo([have]), complemento([demonstrated, that, brown, adipocytes, arise, in, vivo, from, a, 'Myf5-positive,', myoblastic, progenitor, by, the, action, of, 'Prdm16', '(', 'PR', domain, containing, 16, ')'])].
[sujeto(['Blocking', 'miR-193b', 'and/or', 'miR-365', in, primary, brown, preadipocytes, markedly, impaired, brown, adipocyte, adipogenesis, by]), verbo([enhancing]), complemento(['Runx1t1', '(', 'runt-related', transcription, factor, 1, ;, translocated, 'to,', 1, ')', 'expression,', whereas, myogenic, markers, were, significantly, induced])].
[sujeto(['Forced', expression, of, 'Mir193b', 'and/or', 'Mir365', in, 'C2C12', myoblasts, blocked, the, entire, programme, of, 'myogenesis,', 'and,', in, adipogenic, 'conditions,', 'miR-193b']), verbo([induced]), complemento([myoblasts, to, differentiate, into, brown, adipocytes])].
[sujeto(['Our', results, demonstrate, that, 'Mir193b-365', serves, as, an, essential, regulator, for, brown, fat, 'differentiation,', in, part, by]), verbo([repressing]), complemento([myogenesis])].
[sujeto(['Mutations', of, isocitrate, dehydrogenase, 1, '(', 'IDH1)']), verbo([have]), complemento([recently, been, reported, in, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['We', analyzed, 416, 'Chinese', 'AML', patients, and]), verbo([found]), complemento([28, patients, '(', 6.7, '%', ')', carried, this, mutation])].
[sujeto(['The', 'IDH1', mutations, were]), verbo([associated]), complemento([with, 'NPM1', mutations, '(', 'P=0'])].
[sujeto(['For', 'AML', with, 'AML1-ETO', fusion, 'gene,', 'IDH1(mut)', patients, may]), verbo([have]), complemento([worse, 'disease-free', survival, '(', 'DFS)', than, 'IDH1(wild-type)', patients])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([a, higher, expression, level, of, 'AML1a', in, acute, lymphoblastic, leukemia, and, acute, myeloid, leukemia, '(', 'AML)-M2', patients, in, comparison, to, the, controls])].
[sujeto(['Additionally,', 'AML1a']), verbo([represses]), complemento([transcription, of, promoter, of, macrophage, 'colony-stimulating', factor, receptor, mediated, by, 'AML1b,', indicating, that, 'AML1a', antagonized, the, effect, of, 'AML1b'])].
[sujeto(['Untreated,', the, disease, progresses, to, accelerate, phase, and, blast, crisis, in, which, hematopoietic, differentiation]), verbo([has]), complemento([become, arrested])].
[sujeto(['CML', progression, is, frequently]), verbo([associated]), complemento([with, cytogenetic, evidence, of, clonal, 'evolution,', defined, as, additional, chromosomal, aberrations])].
[sujeto(['We', here]), verbo([report]), complemento([a, 'CML', resistant, to, tyrosine, kinase, inhibitors, that, rapidly, progressed, to, blastic, phase])].
[sujeto(['These', genomic, rearrangements, were, confirmed, by, 'FISH', with, probes]), verbo([targeting]), complemento([the, deletion, on, chromosome, 21, '(', 24, 'kb),', and, with, 'BAC', probes, flanking, the, deletion, on, 1, p36, '(', 220, 'kb)'])].
[sujeto(['However,', no, cryptic, 't(1;21)(p36;q22)', 'and/or', 'RUNX1-PRDM16', were, 'detected,']), verbo([suggesting]), complemento([that, these, deletions, are, the, residual, hallmarks, of, a, more, complex, mechanism, of, chromosomal, 'rearrangement,', as, indicated, by, the, additional, inversion, of, the, region, bounded, by, 1, p36])].
[sujeto(['At', the, molecular, 'level,', these, abnormalities]), verbo([lead]), complemento([to, the, overexpression, of, the, 'PR-domain', negative, oncogenic, isoform, of, 'PRDM16,', associated, with, two, deleted, copies, within, the, runt, domain, of, 'C-teminal', aberrant, 'RUNX1'])].
[sujeto(['In', the, present, 'research,', we]), verbo([found]), complemento([that, 'AML1-ETO', is, able, to, inhibit, 'Sp1', transactivity])].
[sujeto(['We', also]), verbo([found]), complemento([that, this, inhibition, of, 'Sp1', transactivity, by, 'AML1-ETO', is, achieved, by, interaction, between, 'Sp1', and, 'RUNT', domain, of, 'AML1'])].
[sujeto(['Since', 'Sp1', is]), verbo([involved]), complemento([in, hematopoietic, cell, 'differentiation,', we, proposed, that, 'AML1-ETO', promotes, leukemogenesis, by, blocking, cell, differentiation, through, inhibition, of, 'Sp1', transactivity])].
[sujeto(['We', previously, discovered, a, novel, 'trans-tail', histone, code]), verbo([involving]), complemento([monomethylated, histone, 'H4', lysine, 20, '(', 'H4K20)', and, 'H3', lysine, 9, '(', 'H3K9);', 'however,', the, mechanisms, that, establish, this, code, and, its, function, in, transcription, were, unknown])].
[sujeto(['In', this, 'report,', we, demonstrate, that, 'H3K9', monomethylation, is, dependent, upon, the, 'PR-Set7', 'H4K20', monomethyltransferase, but, independent, of, its, catalytic, 'function,', indicating, that, 'PR-Set7']), verbo([recruits]), complemento([an, 'H3K9', monomethyltransferase, to, establish, the, 'trans-tail', histone, code])].
[sujeto(['We', determined, that, this, histone, code, is]), verbo([involved]), complemento([in, a, transcriptional, regulatory, pathway, in, vivo, whereby, monomethylated, 'H4K20', binds, the, 'L3MBTL1', repressor, protein, to, repress, specific, 'genes,', including, 'RUNX1,', a, critical, regulator, of, hematopoietic, differentiation])].
[sujeto(['The', selective]), verbo([loss]), complemento([of, monomethylated, 'H4K20', at, the, 'RUNX1', promoter, resulted, in, the, displacement, of, 'L3MBTL1', and, a, concomitant, increase, in, 'RUNX1', transcription])].
[sujeto(['Importantly,', the, lack, of, monomethylated, 'H4K20', in, the, human, 'K562', multipotent, cell, line, was, specifically]), verbo([associated]), complemento([with, spontaneous, megakaryocytic, 'differentiation,', in, 'part,', by, activating, 'RUNX1'])].
[sujeto(['Our', findings, demonstrate, that, this, newly, described, repression, pathway, is]), verbo([required]), complemento([for, regulating, proper, megakaryopoiesis, and, suggests, that, it, is, likely, to, function, similarly, in, other, multipotent, cell, types, to, regulate, specific, differentiation, pathways])].
[sujeto(['The', 't(12;21)(p13;q22)', translocation, is]), verbo([found]), complemento([in, 20, to, 25, '%', of, cases, of, childhood, 'B-lineage', acute, lymphoblastic, leukemia, '(', 'B-ALL)'])].
[sujeto(['We']), verbo([report]), complemento([an, analysis, of, gene, expression, in, 60, children, with, 'B-lineage', 'ALL', using, 'Agilent', whole, genome, 'oligo-chips', '(', 44, 'K-G4112A)', 'and/or', real, time, 'RT-PCR'])].
[sujeto(['Microarray', analyses, of, 26, samples, allowed, the, identification, of, genes, differentially]), verbo([expressed]), complemento([between, the, 'TEL/AML1-positive', and, negative, 'ALL', groups])].
[sujeto(['Gene', enrichment, analysis, defined, five, enriched, 'GO', 'categories:', cell, 'differentiation,', cell, 'proliferation,', 'apoptosis,', cell, motility, and, response, to, 'wounding,']), verbo([associated]), complemento([with, 14, genes, -, 'RUNX1,', 'TCFL5,', 'TNFRSF7,', 'CBFA2T3,', 'CD9,', 'SCARB1,', 'TP53INP1,', 'ACVR1C,', 'PIK3C3,', 'EGFL7,', 'SEMA6A,', 'CTGF,', 'LSP1,', 'TFPI', -, highlighting, the, biology, of, the, 'TEL/AML1', 'sub-group'])].
[sujeto(['Gene', expression, analyses, of, leukemia, cells, from, 60, children, with, 'TEL/AML1-positive', and, -, negative, 'B-lineage', 'ALL']), verbo([led]), complemento([to, the, identification, of, five, biological, 'processes,', associated, with, 14, validated, genes, characterizing, and, highlighting, the, biology, of, the, 'TEL/AML1-positive', 'ALL', 'sub-group'])].
[sujeto(['Of', the, 62, 'patients,', 23, '(', 37.1, '%', ')', were]), verbo([found]), complemento([to, carry, 13, different, fusion, genes])].
[sujeto(['The', patients, with, immunophenotype, of, 'Pre-B-ALL', were]), verbo([found]), complemento([to, 'carry:', 'TEL/AML1(3', 'cases);', 'E2A/PBX1,', 'E2A/HLF,', 'TLS/ERG,', 'MLL/AF4,', 'MLL/AF9,', 'MLL/AF10,', 'MLL/AFX-MLL/AF6-MLL/ELL,', 'MLL/AF6-MLL/ELL,', dupMLL, '(', one, case, for, 'each);', and, 'HOX11', '(', 6, 'cases)'])].
[sujeto(['The', patients, with, immunophenotype, of, 'Pre-T-ALL', were]), verbo([found]), complemento([to, 'carry:', 'TAL1D', '(', 4, 'cases,', one, is, also, found, to, have, 'HOX11', 'expression);', and, 'HOX11', '(', 2, 'cases)'])].
[sujeto(['Multiplex', 'RT-PCR', combined, with, chromosome, analysis, and, immunophenotyping, can]), verbo([provide]), complemento([reliable, and, helpful, information, for, the, 'diagnosis,', therapy, evaluation, and, prognosis, prediction, in, childhood, 'ALL,', which, may, also, serve, as, a, basis, on, which, to, implement, the, criteria, of, 'WHO', classification])].
[sujeto(['It', is, useful, for]), verbo([revealed]), complemento([whole, gene, expression, profile, and, has, a, great, potentiality, in, the, era, of, functional, genomics])].
[sujeto(['It']), verbo([provides]), complemento([an, alternative, method, of, studies, on, gene, expression, which, is, at, least, as, good, as, 'LacZ', staining, and, immunohistochemistry])].
[sujeto(['EVI1', is, also]), verbo([expressed]), complemento([as, part, of, a, fusion, transcript, with, the, transcription, factor, 'AML1', in, the, 't(3;21)(q26;q22),', associated, with, myeloid, leukemia])].
[sujeto(['MDS1', is, located, at, 3, q26, 170, -, 400, kb, upstream, '(', 'telomeric)', of, 'EVI1', in, the, chromosomal, region, in, which, some, of, the, breakpoints, 5, '\'', of, 'EVI1']), verbo([have]), complemento([been, mapped])].
[sujeto(['MDS1']), verbo([has]), complemento([been, identified, as, a, single, gene, as, well, as, a, previously, unreported, 'exon(s)', of, 'EVI1', 'We', have, analyzed, the, relationship, between, 'MDS1', and, 'EVI1', to, determine, whether, they, are, two, separate, genes])].
[sujeto(['In', this, 'report,', we, present, evidence, indicating, that, 'MDS1', exists, in, normal, tissues, both, as, a, unique, transcript, and, as, a, normal, fusion, transcript, with, 'EVI1,', with, an, additional, 188, codons, at, the, 5, '\'', end, of, the, previously]), verbo([reported]), complemento(['EVI1', open, reading, frame])].
[sujeto(['This', additional, region]), verbo([has]), complemento([about, 40, '%', homology, at, the, amino, acid, level, with, the, 'PR', domain, of, the, 'retinoblastoma-interacting', 'zinc-finger', protein, 'RIZ'])].
[sujeto(['These', results, are, important, in, view, of, the, fact, that, 'EVI1', and, 'MDS1', are]), verbo([involved]), complemento([in, leukemia, associated, with, chromosomal, translocation, breakpoints, in, the, region, between, these, genes])].
[sujeto(['We', aim, to, search, 'non-protein', coding, regions, of, key, hematopoiesis, transcription, factors, for, genetic, variations]), verbo([associated]), complemento([with, acute, myeloid, leukemia, susceptibility])].
[sujeto(['Rs2249650', and, rs2268276, at, 'RUNX1', intron, 5.2, enhancer, were]), verbo([found]), complemento([to, be, associated, with, acute, myeloid, leukemia, susceptibility])].
[sujeto(['Supershift', assay, indicated, that, one, potential]), verbo([binding]), complemento([protein, was, 'PU'])].
[sujeto(['It', is, a, process, tightly]), verbo([regulated]), complemento([by, many, intrinsic, and, extrinsic, 'factors,', including, transcriptional, factors, and, signaling, molecules])].
[sujeto(['Here', we, show, that, 'miR-144']), verbo([regulates]), complemento([hematopoiesis, and, vascular, development, in, zebrafish])].
[sujeto(['Overexpression', of, 'miR-144']), verbo([inhibited]), complemento([primitive, hematopoiesis, as, demonstrated, by, a, reduced, number, of, circulating, blood, 'cells,', reduced, 'o-dianisidine', staining, of, 'hemoglobin,', and, reduced, expression, of, 'hbαe1,', 'hbβe1,', gata1, and, pu])].
[sujeto(['Overexpression', of, 'miR-144', also]), verbo([inhibited]), complemento([definitive, hematopoiesis, as, shown, by, reduced, expression, of, runx1, and, 'c-myb'])].
[sujeto(['Mechanistically,', 'miR-144']), verbo([regulates]), complemento([hematopoiesis, by, repressing, expression, of, meis1, involved, in, hematopoiesis])].
[sujeto(['Both', 'real-time', 'RT-PCR', and, 'Western', blot, analyses, showed, that, overexpression, of, 'miR-144']), verbo([repressed]), complemento([expression, of, meis1])].
[sujeto(['Bioinformatic', analysis, predicts, a]), verbo([target]), complemento([binding, sequence, for, 'miR-144', at, the, 3, '\'', -, 'UTR', of, meis1])].
[sujeto(['Deletion', of, the, 'miR-144']), verbo([target]), complemento([sequence, eliminated, the, repression, of, meis1, expression, mediated, by, 'miR-144'])].
[sujeto(['Finally,', because, meis1, is]), verbo([involved]), complemento([in, vascular, 'development,', we, tested, the, effect, of, 'miR-144', on, vascular, development])].
[sujeto(['These', findings, establish, 'miR-144', as, a, novel, miRNA, that]), verbo([regulates]), complemento([hematopoiesis, and, vascular, development, by, repressing, expression, of, meis1])].
[sujeto(['Studies', implicate, a, potential, role, for, 'EAF1', in, 'MLL-ELL']), verbo([induced]), complemento(['leukemogenesis;', however, the, biological, function, of, 'EAF1', in, this, process, remains, unknown])].
[sujeto(['In', this, 'study,', we, show, that, knockdown, of, zebrafish, eaf1, by, morpholinos]), verbo([caused]), complemento([serious, defects, in, both, primitive, and, definitive, hematopoiesis])].
[sujeto(['Using', microarray, 'analysis,', we, identified, foxo3b, as, a]), verbo([target]), complemento([gene, suppressed, by, eaf1])].
[sujeto(['Ectopic', expression, of, foxo3b, in, embryos, mimicked, the, phenotypes, exhibited, in, eaf1, 'morphants,', except, that, foxo3b, had, no, effect, on, runx1, and, 'c-myb', expression, while, eaf1, morphants, did, not]), verbo([express]), complemento([these, markers, in, the, ventral, wall, of, dorsal, aorta])].
[sujeto(['Subsequent', experiments, showed, that, a, dominant, negative, form, of, 'Foxo3b', '(', 'dn-foxo3b)', partially, restored, primitive, hematopoietic, defects, in, eaf1, 'morphants,']), verbo([suggesting]), complemento([that, foxo3b, might, serve, as, a, key, factor, for, mediating, eaf1, function, in, primitive, hematopoiesis])].
[sujeto(['Furthermore,', we, observed, that, foxo3b]), verbo([inhibited]), complemento([the, transcriptional, activity, of, gata1, and, spi1, through, 'protein-protein', interaction])].
[sujeto(['Our', findings, not, only]), verbo([suggest]), complemento([a, function, of, eaf1, on, hematopoiesis, in, 'vivo,', but, also, reveal, a, novel, regulatory, 'pathway,', 'eaf1-foxo3b-gata1/spi1,', that, may, shed, light, on, the, role, of, 'EAF1', in, 'MLL-ELL', induced, leukemogenesis])].
[sujeto(['After', investigating, common, acute, 'leukemia-related', mutations, in, 17, 'genes,', 12, of, 31, '(', 39, '%', ')', patients, were]), verbo([found]), complemento([to, have, at, least, one, 'mutation,', classified, 'with:', 'IKZF1', deletion, '(', 4, of, 31, ')', ',', and, 'EZH2', '(', 3, of, 31, ')', ',', 'ASXL1', '(', 3, of, 31, ')', ',', 'ETV6', '(', 2, of, 31, ')', ',', 'NOTCH1', '(', 1, of, 31, ')', ',', and, 'TET2', '(', 1, of, 31, ')', mutations])].
[sujeto(['Benzidine', 'staining,', 'semi-quantitative', 'RT-PCR,', 'Western', blot, and, microarray, methods, were, used, to, survey, the, effects, of, 'APS', on]), verbo([inducing]), complemento([erythroid, differentiation, and, the, changes, of, gene, expression, profile, in, 'K562', cells])].
[sujeto(['These', differential, expression, genes, generally]), verbo([regulate]), complemento([protein, 'binding,', cellular, metabolic, 'process,', the, cell, 'proliferation,', and, transcriptional, activator, activity])].
[sujeto(['Our', studies, indicate, that, 'APS', indicate, potent, activities, on, the, erythroid, differentiation, by]), verbo([modulating]), complemento([genes, of, 'LMO2,', 'Klf1,', 'Klf3,', 'Runx1,', 'EphB4', and, 'Sp1,', increasing, 'gamma-globin', mRNA, expression, and, fetal, hemoglobin, synthesis, in, 'K562', cells])].
[sujeto(['Recent', advances]), verbo([have]), complemento([demonstrated, that, the, differentiated, somatic, cells, could, be, reprogrammed, into, pluripotent, state])].
[sujeto(['Consequently,', the, reprogrammed, somatic, cells, recapitulate, the, capacity, to, differentiate, into, specific, cell, lineages, under, appropriate, culture, 'conditions,', which]), verbo([provides]), complemento([unlimited, cell, sources, for, cell, 'transplantation-based', therapy])].
[sujeto(['In', the, present, 'study,', testicular, 'Sertoli', cells, were, successfully, reprogrammed, into, pluripotent, stem, cells, through, somatic, cell]), verbo([nuclear]), complemento([transfer, '(', 'SCNT)'])].
[sujeto([were, dynamically]), verbo([expressed]), complemento([during, the, differentiation, of, the, reprogrammed, somatic, cells, in, vitro])].
[sujeto(['KIT', mutations, may, be]), verbo([associated]), complemento([with, a, poor, prognosis, in, 't(8;21)', 'AML'])].
[sujeto(['AML1-ETO', fusion, gene, and, mutated, 'KIT']), verbo([act]), complemento([as, &, 'quot;two-hit"', factors, in, 'Kasumi-1', cells])].
[sujeto(['Our', results, confirmed, that, 'Hsp90', and, mutated, 'KIT', were, valid, molecular]), verbo([targets]), complemento([in, the, therapy, of, 'AML'])].
[sujeto(['The', 'TGF-beta1/SMAD', signaling, pathway, usually]), verbo([participates]), complemento([in, a, wide, range, of, cellular, processes, such, as, 'growth,', 'proliferation,', differentiation, and, apoptosis])].
[sujeto(['Upon']), verbo([binding]), complemento([on, 'TGF-beta1,', the, dimerized, 'TGF-beta', type, 'II', receptors, recruit, and, phosphorylate, the, 'TGF-beta', type, 'I', 'receptors,', which, phosphorylate, the, 'receptor-regulated', 'SMAD', '(', 'SMAD2', and, 'SMAD3)', presented, by, the, 'SMAD', anchor, for, receptor, activation])].
[sujeto(['The']), verbo([phosphorylated]), complemento(['receptor-regulated', 'SMAD', form, heterologous, complexes, with, the, 'common-mediator', 'SMAD', '(', 'SMAD4)', and, subsequently, translocate, into, the, 'nucleus,', where, they, interact, with, other, transcription, factors, to, regulate, the, expression, of, target, genes])].
[sujeto(['This', 'multi-functional', signaling, pathway]), verbo([modulated]), complemento([by, various, elements, with, complex, mechanisms, at, different, levels, is, also, inevitably, involved, in, cancer])].
[sujeto(['The', constitutively, active, tyrosine, kinase, produced, by, the, specific, 'Bcr-Abl', fusion, gene, on, the, 'Philadelphia', chromosome, can]), verbo([enhance]), complemento([the, resistance, of, malignant, cells, to, 'TGF-beta1-induced', growth, inhibition, and, 'apoptosis,', which, contributes, to, enhancement, of, proteasomal, degradation, of, p27])].
[sujeto(['However,', overexpression, of, the, 'EVI1', 'gene,', which, is, also]), verbo([caused]), complemento([by, 'Bcr-Abl,', can, recruit, the, 'C-terminal', binding, protein, and, histone, deacetylase, to, prevent, the, 'MH2', domain, on, 'SMAD3'])].
[sujeto(['The', later, is, essential, for, transcription, activation, on]), verbo([target]), complemento([genes, and, leads, to, blockage, of, the, 'TGF-beta1/SMAD', signaling, pathway])].
[sujeto(['Some', studies]), verbo([have]), complemento([indicated, that, certain, therapeutic, agents, applied, in, clinical, treatment, can, inhibit, proliferation, and, promote, differentiation, of, leukemia, cells, by, way, of, modulation, of, the, 'TGF-beta1/SMAD', signal, pathway])].
[sujeto(['For', 'example,', arsenic, trioxide, can]), verbo([promote]), complemento([specific, degradation, of, the, 'AML1/MDS1/EVI1', oncoprotein, and, inhibit, the, proliferation, of, leukemia, cells])].
[sujeto(['The', tyrosine, kinase, inhibitor, in, the]), verbo([target]), complemento([therapy, of, chronic, myeloid, leukemia, can, effectively, inhibit, the, tyrosine, kinase, activity, of, 'Bcr-Abl', and, induce, suppression, on, the, 'TGF-beta1/SMAD', signaling, pathway])].
[sujeto(['The', 'TGF-beta1/SMAD', signaling, pathway, plays, an, important, role, in, chronic, myeloid, leukemia, cells, and]), verbo([leads]), complemento([the, leukemia, cells, to, growth, 'inhibition,', differentiation, and, apoptosis])].
[sujeto(['Since', it, is, a, complex, signaling, pathway, widely]), verbo([involved]), complemento([in, many, aspects, of, cellular, 'activities,', further, study, and, comprehensive, analysis, of, the, 'TGF-beta1/SMAD', signaling, pathway, are, imperative, and, will, have, a, guiding, significance, in, research, and, clinical, applications])].
[sujeto(['Acute', myeloid, leukemia, '(', 'AML)', arises, from, genetic, changes, at, the, level, of, stem, 'cell,', various, mutations]), verbo([have]), complemento([been, 'elucidated,', including, 'AML1-ETO', fusion, gene, has, been, shown, as, the, representative, target, of, cellular, transformation, for, 'LSCs', originating, from, hematopoietic, stem, cells, '(', 'HSCs)', compartment])].
[sujeto(['And', the, interaction]), verbo([mediated]), complemento([by, adhesion, molecules, between, 'LSCs', and, niche, played, a, role, in, chemoresistance, of, 'LSCs'])].
[sujeto(['Therefore,', study, on, the, 'LSCs', surface, makers, related, to, niche, is, helpful, for, the, potential]), verbo([target]), complemento([therapy, in, the, future])].
[sujeto(['Furthermore,', 'AML1/ETO', fusion, signals, and, 'MDR1', expression, were, detected, on, the, 'CD34(+)/CD38(-)/CD123(+)', 'LSCs', populations]), verbo([expressing]), complemento(['N-Cadherin', and, 'Tie2'])].
[sujeto(['The', detection, rate, of, clonal, chromosomal, aberrations, was]), verbo([enhanced]), complemento([to, 59.5, '%', by, combined, application, of, multiplex, 'RT-PCR', and, karyotype, analysis])].
[sujeto(['Whereas', 'Evi-1a', is, widely]), verbo([recognized]), complemento([as, an, 'oncoprotein,', a, role, for, 'Evi-1c,', which, has, an, additional, 'PR', domain, in, the, 'amino-terminus', of, 'Evi-1a,', in, 'leukemogenesis,', has, not, been, elucidated, thus, far])].
[sujeto(['Aberrant', oligomerization, of, transcription, factors]), verbo([has]), complemento([recently, emerged, as, a, prevalent, mechanism, for, activating, their, oncogenic, potential, in, hematopoietic, malignancies])].
[sujeto(['Remarkably,', 'Evi-1c']), verbo([has]), complemento([lost, the, ability, to, interact, with, 'CtBP,', a, transcriptional, corepressor, that, associates, with, 'Evi-1a'])].
[sujeto(['As', a, 'consequence,', the, ability, of, 'Evi-1c', to]), verbo([repress]), complemento([transforming, growth, 'factor-beta', '(', 'TGF-beta)', signaling, is, significantly, abrogated])].
[sujeto(['These', results, identify, a, novel, function, of, a, 'PR', domain, to]), verbo([regulate]), complemento([oligomerization, of, transcription, factors, and, suggest, that, 'homo-oligomerization', may, play, a, critical, role, in, corepressor, recruitment, by, the, 'Evi-1', proteins])].
[sujeto(['In', 'addition,', we]), verbo([found]), complemento([that, the, chimeric, oncoprotein, acute, myelocytic, leukemia, '(', 'AML)1-Evi-1,', generated, in, 't(3;21)', 'leukemia,', also, forms, 'homo-oligomers', and, 'hetero-oligomers', with, 'Evi-1a,', while, it, did, not, interact, with, 'Evi-1c'])].
[sujeto(['Consistent', with, the, 'results,', repression, of, 'TGF-beta', by, 'AML1-Evi-1', was, significantly]), verbo([enhanced]), complemento([by, 'Evi-1a,', whereas, it, was, hardly, affected, by, the, presence, of, 'Evi-1c'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, oligomerization, may, contribute, to, the, oncogenic, potential, of, 'Evi-1-containing', proteins])].
[sujeto(['The', '(', 8, ;, 21, ')', translocation, between, the, 'AML1', and, 'ETO', genes, is, seen, in, approximately, 12, -, 15, '%', of, all, acute, myeloid, leukemia, '(', 'AML)', and, is, a, frequently, observed, nonrandom, genetic, alteration]), verbo([associated]), complemento([with, 'AML'])].
[sujeto(['The', 'ETO', moiety, was, shown, to]), verbo([interact]), complemento([with, the, nuclear, receptor, 'co-repressor', '(', 'N-CoR)', 'complex,', which, includes, mSin3A, and, the, histone, 'deacetylase,', 'HDAC1'])].
[sujeto(['In', order, to, characterize, the, interaction, between, 'ETO', and, 'N-CoR,', mutants, of, either, protein, were, constructed, and, tested, for]), verbo([binding]), complemento([in, both, yeast, 'two-hybrid', and, immunoprecipitation, assays])].
[sujeto(['We']), verbo([found]), complemento([that, two, domains, of, human, 'N-CoR,', amino, acid, residues, 988, -, 1126, and, 1551, -, 1803, ',', were, necessary, for, interaction, with, 'ETO'])].
[sujeto(['Previously,', we, and, other, investigators, had]), verbo([reported]), complemento([that, two, unusual, zinc, finger, motifs, at, the, 'C-terminus', of, 'ETO', mediated, binding, to, 'N-CoR'])].
[sujeto(['Here,', using, mammalian, 'two-hybrid', 'assays,', we]), verbo([found]), complemento([that, transcription, repression, by, 'ETO', was, substantially, decreased, when, either, zinc, finger, motif, of, 'ETO', is, deleted, or, mutated])].
[sujeto(['Characterization', of, the, 'ETO', interaction, domains, within, human, 'N-CoR', and, of, the, transcription, domains, of, 'ETO', is, a, first, step, in, designing]), verbo([targeted]), complemento([molecular, therapy, for, 't(8;21)', 'AML'])].
[sujeto(['The', complex, variants, of, 't(8;21)']), verbo([involving]), complemento([chromosomes, 8, and, 21, as, well, as, a, variable, chromosome, account, for, 1.1, -, 5, '%', of, acute, myeloid, leukemia, '(', 'AML)', patients])].
[sujeto(['This', paper]), verbo([reports]), complemento([a, case, of, 'AML-M2', with, 't(8;21;8)', translocation, for, the, first, time])].
[sujeto(['A', novel, variant, translocation, 't(8;20)(q22;p13)', detected, by, karyotype, analysis, of, bone, marrow, cells, using, 'R-', and, 'G-banding', 'techniques,', is]), verbo([reported]), complemento([in, a, case, of, 'M2-acute', myeloid, leukaemia, '(', 'AML)'])].
[sujeto(['RT-PCR', revealed, no, 'AML1/ETO', fusion, 'transcript,', but, the, 'wild-type', 'ETO-3\'', was]), verbo([expressed]), complemento([in, the, bone, marrow, cells, suggesting, that, 't(8;20)', is, a, true, simple, variant, translocation, of, 't(8;21),', and, that, a, fusion, gene, consisting, of, 'ETO', and, an, unidentified, gene, located, in, band, 20, p13, may, exist, in, our, case])].
[sujeto(['Further', study, is]), verbo([required]), complemento([to, clarify, the, entity, of, the, assumed, fusion, gene])].
[sujeto(['As', a, single, biopsy, might, not, represent, the, full, biologic, complexity, of, the, 'tumor,', we]), verbo([have]), complemento([analyzed, immunohistochemically, four, different, cores, obtained, from, each, primary, tumor, within, the, cohort, of, 364, patients, with, endometrial, cancer, '(', 'EC)'])].
[sujeto(['The', following, proteins, were, 'examined:', estrogen, receptor, 1, '(', 'ESR1),', progesterone, 'receptor,', epidermal, growth, factor, 'receptor,', 'v-erb-b2', erythroblastic, leukemia, viral, oncogene, homolog, 2, ',', receptor, 'tyrosine-protein', kinase, 'erbB-3,', 'v-erb-b2', avian, erythroblastic, leukemia, viral, oncogene, homolog, 4, ',', 'phosphatidylinositol-4,5-bisphosphate', 3, -, 'kinase,']), verbo([phosphorylated]), complemento(['v-akt', murine, thymoma, viral, oncogene, homolog, 1, ',', 'v-myc', avian, myelocytomatosis, viral, oncogene, 'homolog,', 'DNA', topoisomerase, 'II', alpha, 170, kDa, '(', 'TOP2A),', 'cyclin-dependent', kinase, inhibitor, 2, 'A', '(', 'CDKN2A),', tumor, protein, 'p53,', 'RAD21', 'homolog,', 'S'])].
[sujeto(['Particularly', strong, correlation, was]), verbo([found]), complemento([between, 'TOP2A', and, 'CDKN2A', heterogeneity, and, higher, stage, of, the, disease, '(', 'P', =])].
[sujeto(['A', widely, accepted, dualistic, 'model,', which]), verbo([has]), complemento([been, established, on, a, morphological, 'basis,', differentiates, 'EC', into, two, broad, 'categories:', 'Type', 'I', 'oestrogen-dependent', adenocarcinoma, with, an, endometrioid, morphology, and, 'Type', 'II', 'non-oestrogen-dependent', 'EC', with, a, serous, papillary, or, clear, cell, morphology])].
[sujeto(['Molecular', genetic, evidence, indicates, that, endometrial, 'carcinoma,', as, described, in, other, 'malignancies,', likely, develops, as, the, result, of, a, stepwise, accumulation, of, alterations, in, cellular, regulatory, 'pathways,', such, as, oncogene, activation, and, tumor, suppressor, gene, 'inactivation,', which]), verbo([lead]), complemento([to, dysfunctional, cell, growth])].
[sujeto(['In', type, 'I', endometrioid, endometrial, 'cancer,', 'PTEN', gene, silencing, in, conjunction, with, defects, in, 'DNA', mismatch, repair, 'genes,', as, evidenced, by, the, microsatellite, instability, 'phenotype,', or, mutations, in, the, 'K-ras', 'and/or', 'beta-catenin', 'genes,', are]), verbo([recognized]), complemento([major, 'alterations,', which, define, the, progression, of, the, normal, endometrium, to, 'hyperplasia,', to, endometrial, intraepithelial, 'neoplasia,', and, then, on, to, carcinoma])].
[sujeto(['Nevertheless,', despite, the, great, effort, made, to, establish, a, 'molecularly-based', histological, 'classification,', the, following, issues, must, still, be, 'clarified:', what]), verbo([triggers]), complemento([the, tumor, cells, to, invade, the, myometrium, and, what, causes, vascular, or, lymphatic, 'dissemination,', finally, culminating, in, 'metastasis?', 'RUNX1,', a, transcription, 'factor,', was, recently, identified, as, one, of, the, most, highly, 'over-expressed', genes, in, a, microarray, study, of, invasive, endometrial, carcinoma])].
[sujeto(['Another', candidate, 'gene,', which, may, be]), verbo([associated]), complemento([with, an, initial, switch, to, myometrial, 'infiltration,', is, the, transcription, factor, 'ETV5/ERM'])].
[sujeto(['These', 'studies,', as, well, as, those, conducted, for, other, genes, possibly]), verbo([involved]), complemento([in, the, mitotic, checkpoint, as, a, major, mechanism, of, carcinogenesis, in, 'non-endometrioid', endometrial, 'cancer,', could, help, in, understanding, the, differences, in, the, biology, and, the, clinical, outcome, among, histological, types])].
[sujeto(['The', 'LH', surge]), verbo([induces]), complemento([specific, transcription, factors, that, regulate, the, expression, of, a, myriad, of, genes, in, periovulatory, follicles, to, bring, about, ovulation, and, luteinization])].
[sujeto(['The', present, study, determined, 1, ')', the, localization, of, 'RUNX1,', a]), verbo([nuclear]), complemento([transcription, 'factor,', 2, ')', regulation, of, 'Runx1', mRNA, 'expression,', and, 3, ')', its, potential, function, in, rat, ovaries])].
[sujeto(['Treatments', with, 'hCG,', 'forskolin,', or, phorbol, 12, myristate, 13, -, acetate]), verbo([stimulated]), complemento(['Runx1', mRNA, expression])].
[sujeto(['The', effects, of, hCG, were, reduced, by, inhibitors, of, protein, kinase, 'A,', 'MAPK', 'kinase,', or, p38, 'kinase,', indicating, that, 'Runx1', expression, is]), verbo([regulated]), complemento([by, the, 'LH-initiated', activation, of, these, signaling, mediators])].
[sujeto(['In', 'addition,', 'hCG-induced', 'Runx1', mRNA, expression, was]), verbo([inhibited]), complemento([by, a, progesterone, receptor, antagonist, and, an, epidermal, growth, factor, receptor, tyrosine, kinase, 'inhibitor,', whereas, amphiregulin, stimulated, 'Runx1', mRNA, 'expression,', demonstrating, that, the, expression, is, mediated, by, the, activation, of, the, progesterone, receptor, and, epidermal, growth, factor, receptor])].
[sujeto(['Finally,', knockdown, of, 'Runx1', mRNA, by, small, interfering, 'RNA']), verbo([decreased]), complemento([progesterone, secretion, and, reduced, levels, of, mRNA, for, 'Cyp11a1,', 'Hapln1,', 'Mt1a,', and, 'Rgc32'])].
[sujeto(['The', hormonally]), verbo([regulated]), complemento([expression, of, 'Runx1', in, periovulatory, 'follicles,', its, involvement, in, progesterone, 'production,', and, regulation, of, preovulatory, gene, expression, suggest, important, roles, of, 'RUNX1', in, the, periovulatory, process])].
[sujeto(['RNA', expression, of, 42, 'genes,', including, 24, putative, genes]), verbo([associated]), complemento([with, plasma, 'E2', 'levels,', seven, proliferation, genes, and, 'RANKL', was, measured])].
[sujeto(['Expression', of, 'PGR,', 'TFF1,', 'GREB1', and, 'PDZK1', followed, the, previously]), verbo([reported]), complemento(['pattern:', a, higher, level, in, 'W2', compared, to, 'W1', while, 'W3', had, an, intermediate, 'value,', mirroring, changes, in, plasma, estradiol])].
[sujeto(['The', 'TGF-β', signaling, pathway]), verbo([has]), complemento([a, significant, role, in, breast, cancer, initiation, and, promotion, by, regulating, various, cellular, processes])].
[sujeto(['We', evaluated, whether, genetic, variation, in, eight, genes, '(', 'TGF-β1,', 'TGF-β2,', 'TGF-βR1,', 'TGF-βR2,', 'TGF-βR3,', 'RUNX1,', 'RUNX2,', and, 'RUNX3)', is]), verbo([associated]), complemento([with, breast, cancer, risk, in, women, from, the, 'Breast', 'Cancer', 'Health', 'Disparities', 'Study'])].
[sujeto(['After', adjustment, for, multiple, 'comparisons,', two, 'SNPs', were, significantly]), verbo([associated]), complemento([with, breast, cancer, 'risk:', 'RUNX3', '(', rs906296, 'ORCG/GG', =, 1.15, 95, '%', 'CI', 1.04, -, 1.26, ')', and, 'TGF-β1', '(', rs4803455, 'ORCA/AA', =, 0.89, 95, '%', 'CI', 0.81, -, 0.98, ')'])].
[sujeto(['RUNX3', '(', 'rs906296)', and, 'TGF-βR2', '(', 'rs3773644)', were]), verbo([associated]), complemento([with, risk, in, 'pre-menopausal', women, '(', p, adj, =, 0.002, and, 0.02, ',', 'respectively)', and, in, those, with, intermediate, to, high, 'NA', ancestry, '(', p, adj, =, 0.04, and, 0.01, ',', 'respectively)'])].
[sujeto(['Four', 'RUNX', 'SNPs', were]), verbo([associated]), complemento([with, increased, risk, of, 'ER-', tumors])].
[sujeto(['Results']), verbo([provide]), complemento([evidence, that, genetic, variation, in, 'TGF-β', and, 'RUNX', genes, are, associated, with, breast, cancer, risk])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([of, significant, associations, between, genetic, variants, in, 'TGF-β', and, 'RUNX', genes, and, breast, cancer, risk, among, women, of, 'NA', ancestry])].
[sujeto(['Genes', upregulated, in, 'G', +, 'E', +, 'H(trt)', encode, 'for:', proteins, that, are]), verbo([involved]), complemento([in, prostaglandin, synthesis, '(', 'Ptgs2,', 'Pla2g4a,', and, 'Runx1)', and, cholesterol, biosynthesis, '(', 'Hmgcr,', 'Sc4mol,', and, 'Dhcr24);', receptors, that, allow, cholesterol, uptake, '(', 'Ldlr', and, 'Scarb1),', regulate, progesterone, synthesis, '(', 'Star),', and, inactivate, estrogen, '(', 'Sult1e1);', and, downstream, effectors, of, 'LH', signal, '(', 'Pgr,', 'Cebpb,', 'Creb3l1,', 'Areg,', 'Ereg,', and, 'Adamts1)'])].
[sujeto(['Conversely,', 'G', +, 'E', +, 'H(trt)', downregulated, genes, encoding, proteins]), verbo([involved]), complemento(['in:', 'DNA', replication, and, cell, cycle, progression, '(', 'Ccne2,', 'Orc5l,', 'Rad50,', and, 'Mcm6);', reproductive, developmental, 'process;', and, granulosa, cell, expansion, '(', 'Gdf9,', 'Bmp15,', 'Amh,', 'Amhr2,', 'Bmpr1b,', 'Tgfb2,', 'Foxl2,', 'Pde3a,', 'Esr2,', 'Fshr,', 'Ybx2,', 'Ccnd2,', 'Ccnb1ip1,', and, 'Zp3);', maternal, effect, genes, required, for, embryo, development, '(', 'Zar1,', 'Npm2,', 'Nlrp5,', 'Dnmt1,', 'H1foo,', and, 'Zfp57);', amino, acid, 'degradation;', and, ketogenesis, '(', 'Hmgcs2,', and, 'Cpt1b)'])].
[sujeto(['These', results, from, the, rat, show, that, hormones, used, for, estrus, synchronization, '(', 'G(trt))', and, ovarian, hyper, stimulation, '(', 'G', +, 'E(trt))', had, minimal, effects, on, gene, 'expression,', whereas, induction, of, ovulation, '(', 'G', +, 'E', +, 'H(trt))']), verbo([caused]), complemento([major, changes, in, gene, expression, of, rat, 'COCs'])].
[sujeto(['This', study]), verbo([provides]), complemento([comprehensive, information, about, regulated, genes, during, late, follicle, development, and, ovulation, induction])].
[sujeto(['Response', gene, to, complement, 32, '(', 'Rgc32)']), verbo([has]), complemento([recently, been, suggested, to, be, expressed, in, the, ovary, and, regulated, by, 'RUNX1,', a, transcription, factor, in, periovulatory, follicles])].
[sujeto(['In', the, present, 'study,', we, determined, the, expression, profile, of, the, 'Rgc32', gene, in, the, rodent, ovary, throughout, the, reproductive, cycle, and, the, regulatory, 'mechanism(s)']), verbo([involved]), complemento([in, 'Rgc32', expression, during, the, periovulatory, period])].
[sujeto(['Further', studies, using, hormonally]), verbo([induced]), complemento([luteal, and, luteolysis, models, revealed, a, transient, increase, in, levels, of, 'Rgc32', mRNA, at, the, time, of, functional, regression, of, the, 'CL'])].
[sujeto(['The', effect, of, human, chorionic, gonadotropin, on, 'Rgc32', expression, was, mimicked, by, 'forskolin,', but, not, phorbol, 12, -, myristate, 13, -, 'acetate,', and, was]), verbo([mediated]), complemento([by, the, activation, of, progesterone, receptors, and, the, epidermal, growth, 'factor-signaling', pathway])].
[sujeto(['The', mechanism, by, which, 'RUNX1']), verbo([regulates]), complemento(['Rgc32', expression, was, investigated, using, chromatin, immunoprecipitation, and, 'Rgc32', 'promoter-luciferase', reporter, assays])].
[sujeto(['Data', from, these, assays, revealed, direct]), verbo([binding]), complemento([of, 'RUNX1', in, the, 'Rgc32', promoter, region, in, vivo, as, well, as, the, involvement, of, 'RUNX', binding, sites, in, the, transactivation, of, the, 'Rgc32', promoter, in, vitro])].
[sujeto(['In', 'summary,', the, present, study, demonstrated, the, 'spatial/temporal-specific', expression, of, 'Rgc32', in, the, 'ovary,', and]), verbo([provided]), complemento([evidence, of, 'LH-initiated', and, 'RUNX1-mediated', expression, of, 'Rgc32', gene, in, luteinizing, granulosa, cells])].
[sujeto(['Herein', we, document, that, epidermal, growth, factor, '(', 'EGF)-like', factors, amphiregulin, '(', 'Areg),', epiregulin, '(', 'Ereg),', and, betacellulin, '(', 'Btc)', are]), verbo([induced]), complemento([in, cumulus, oocyte, complexes, '(', 'COCs)', by, autocrine, and, paracrine, mechanisms, that, involve, the, actions, of, prostaglandins, '(', 'PGs)', and, progesterone, receptor, '(', 'PGR)'])].
[sujeto(['In', cultured, 'COCs,', 'FSH/forskolin']), verbo([induced]), complemento(['Areg', mRNA, within, 0.5, h, that, peaked, at, 4, 'h,', a, process, blocked, by, inhibitors, of, p38MAPK, '(', 'SB203580),', 'MAPK', kinase, '(', 'MEK)', 1, '(', 'PD98059),', and, 'PTGS2', '(', 'NS398)', but, not, protein, kinase, 'A', '(', 'PKA)', '(', 'KT5720)'])].
[sujeto(['Conversely,', 'AREG', but, not, 'FSH']), verbo([induced]), complemento(['Ptsg2', mRNA, at, 0.5, h, with, peak, expression, of, 'Ptgs2', and, 'Areg', mRNAs, at, 4, 'h,', processes, blocked, by, the, 'EGF', receptor, tyrosine, kinase, inhibitor, 'AG1478', '(', 'AG),', 'PD98059,', and, 'NS398'])].
[sujeto(['Phorbol', 12, -, myristate, 13, -, acetate, '(', 'PMA)', and, adenovirally]), verbo([expressed]), complemento(['PGRA', synergistically, induced, 'Areg', mRNA, in, granulosa, cells])].
[sujeto(['In', 'COCs,', 'AREG', not, only]), verbo([induced]), complemento([genes, that, impact, matrix, formation, but, also, genes, involved, in, steroidogenesis, '(', 'StAR,', 'Cyp11a1)', and, immune, 'cell-like', functions, '(', 'Pdcd1,', 'Runx1,', 'Cd52)'])].
[sujeto(['PGs']), verbo([acting]), complemento([via, 'PTGER2', in, cumulus, cells, provide, a, 'secondary,', autocrine, pathway, to, regulate, expression, of, 'Areg', in, 'COCs', showing, critical, functional, links, between, 'G', 'protein-coupled', receptor, and, growth, factor, receptor, pathways, in, ovulating, follicles])].
[sujeto(['High', and, low, molecular, weight, '(', 'LMW)', tropomyosin, 'isoforms,', by, regulation, of, actin, 'filaments,']), verbo([have]), complemento([a, major, role, in, the, regulation, of, cell, behaviour])].
[sujeto(['Expression', of, 'LMW', isoforms, from, the, 'TPM1', and, 'TPM3', genes]), verbo([have]), complemento([an, important, role, in, these, effects, but, the, regulation, of, their, expression, is, unknown])].
[sujeto(['The', effect, of, mutating, candidate, transcription, factor]), verbo([binding]), complemento([sites, identified, an, 'AML1-like', transcription, factor, binding, site, in, 'TPM1', and, a, cAMP, response, element, in, 'TPM3'])].
[sujeto(['Downstream', from, the, primary, activation, sequence, in, 'TPM1', was, a, repressor, region, corresponding, to, two, 'Sp/KLF', family]), verbo([binding]), complemento(['GC', boxes])].
[sujeto(['Band', shift, assays, confirmed, that, deletion, of, these, sites, altered, transcription, factor]), verbo([binding]), complemento([and, 'ChIP', assays, confirmed, the, presence, of, 'AML1', and, 'CREB', at, the, 'TPM1', and, 'TPM3', activation, sequences, in, the, respective, promoters])].
[sujeto(['Expression', of, 'LMW', isoforms, from, 'TPM1', and, 'TPM3', genes, is]), verbo([regulated]), complemento([very, differently])].
[sujeto(['This', facilitates, regulation, of, the, many, cell, processes]), verbo([involving]), complemento([these, proteins])].
[sujeto(['In', situations, where, these, proteins]), verbo([have]), complemento([a, critical, 'role,', such, as, cancer, 'metastasis,', it, also, facilitates, specific, intervention])].
[sujeto(['MTG16,', 'MTGR1', and, 'ETO', are]), verbo([nuclear]), complemento([transcriptional, corepressors, of, the, human, 'ETO', protein, family])].
[sujeto(['We', tried, to, identify, structural, and, functional, promoter, elements, of, 'MTG16', and, 'MTGR1', genes, in, order, to]), verbo([find]), complemento([associations, between, their, regulation, and, hematopoiesis])].
[sujeto(['Mutation', of, an, evolutionary]), verbo([conserved]), complemento(['GATA', -, 301, consensus, binding, site, repressed, promoter, function])].
[sujeto(['Furthermore,', results, from, in, vitro, 'antibody-enhanced', electrophoretic, mobility, shift, assay, and, in, vivo, chromatin, immunoprecipitation, indicated]), verbo([binding]), complemento([of, 'GATA-1', to, the, 'GATA', -, 301, site])].
[sujeto(['Furthermore,', expression, of, the, transcription, factor, 'HERP2,', which]), verbo([represses]), complemento(['GATA-1,', produced, strong, inhibition, of, the, 'MTG16', promoter, reporter, consistent, with, a, role, of, 'GATA-1', in, transcriptional, activation])].
[sujeto(['The', 'TATA-less', and, 'CCAAT-less', 'MTGR1', promoter]), verbo([retained]), complemento([most, of, the, transcriptional, activity, within, a, -, 308, to, -, 207, bp, region, with, a, 'GC-box-rich', sequence, containing, multiple, 'SP1', binding, sites, reminiscent, of, a, housekeeping, gene, with, constitutive, expression])].
[sujeto(['However,', mutations, of, individual, 'SP1']), verbo([binding]), complemento([sites, did, not, repress, promoter, 'function;', multiple, active, 'SP1', binding, sites, may, be, required, to, safeguard, constitutive, 'MTGR1', transcriptional, activity])].
[sujeto(['The', observed, repression, of, 'MTG16/MTGR1', promoters, by, the, leukemia]), verbo([associated]), complemento(['AML1-ETO', fusion, gene, may, have, a, role, in, hematopoietic, dysfunction, of, leukemia])].
[sujeto(['An', evolutionary]), verbo([conserved]), complemento(['GATA', binding, site, is, critical, in, transcriptional, regulation, of, the, 'MTG16', promoter])].
[sujeto(['Our', results, demonstrate, that, the, 'ETO', homologue, promoters, are]), verbo([regulated]), complemento([differently, consistent, with, hematopoietic, 'cell-type-', specific, expression, and, function])].
[sujeto(['We']), verbo([found]), complemento([that, 'Sp1', could, bind, to, the, 'guanine-cytosine', '(', 'GC)-stretch', of, the, 'EEN', promoter, and, was, critical, for, the, normal, 'EEN', 'expression,', whereas, the, 'leukemia-associated', fusion, protein, 'AML1-ETO', could, aberrantly, transactivate, the, 'EEN', gene, through, an, 'AML1', binding, site])].
[sujeto(['Of', 'note,', overexpressed, 'EEN', showed, oncogenic, 'properties,', such, as, transforming, potential, in, 'NIH3T3', 'cells,']), verbo([stimulating]), complemento([cell, 'proliferation,', and, increasing, the, activity, of, transcriptional, factor, 'AP-1'])].
[sujeto(['Retroviral', transduction, of, 'EEN']), verbo([increased]), complemento(['self-renewal', and, proliferation, of, murine, hematopoietic, progenitor, cells])].
[sujeto(['Moreover,', 'Kasumi-1', and, 'HL60-cell', growth, was]), verbo([inhibited]), complemento([with, 'down-regulation', of, 'EEN', by, 'RNAi'])].
[sujeto(['These', findings, demonstrate, that, 'EEN', might, be, a, common]), verbo([target]), complemento([in, 2, major, types, of, 'AML', associated, with, 'MLL', or, 'AML1', 'translocations,', and, overexpression, of, 'EEN', may, play, an, essential, role, in, leukemogenesis])].
[sujeto(['The', objective, of, this, study, was, to, identify, elements]), verbo([regulating]), complemento([specific, expression, of, 'Mona/Gads', in, human, 'T', cell, and, myelomonocytic, cell, lines])].
[sujeto(['Deletion', analysis, and, electrophoresis, mobility, shift, assay, identified, several, cis, regulatory, 'elements:', overlapping, initiator, 'sequences,', one, interferon, response, 'factor-2', '(', 'IRF-2)-binding', site, at, position, -, 154, ',', one, 'GC', box]), verbo([recognized]), complemento([by, 'Sp1', and, 'Sp3', at, position, -, 52, ',', and, two, acute, myeloid, leukemia, '(', 'AML)-1', binding, sites, at, positions, -, 70, and, -, 13])].
[sujeto(['Site-directed', mutagenesis, experiments, indicated, a, key, role, of, 'AML-1', for, driving, 'Mona', expression, in, 'T', cells, and, myeloid, 'cells,', and, involvement, of, 'Sp1/Sp3', and, 'IRF-2', transcription, factors, to]), verbo([modulate]), complemento(['Mona', expression, in, a, 'cell-specific', manner])].
[sujeto(['miR-215', was]), verbo([reported]), complemento([to, be, downregulated, and, functioned, as, a, tumor, suppressor, in, several, cancers])].
[sujeto(['Ectopic', expression, of, 'miR-215', in, 'GES-1', and, 'HGC-27', cells, '(', low, 'miR-215', 'expression)']), verbo([promoted]), complemento([cell, 'growth,', 'migration,', 'invasion,', and, 'metastasis,', and, these, were, reversed, in, 'NCI-N87', cells, '(', high, 'miR-215', 'expression)', after, 'miR-215', downregulation])].
[sujeto(['Potential']), verbo([target]), complemento([genes, of, 'miR-215', were, predicted, and, 'RUNX1,', a, transcription, factor, and, a, tumor, 'suppressor,', was, confirmed, to, be, potential, target, according, to, luciferase, studies])].
[sujeto(['miR-215']), verbo([promotes]), complemento([malignant, progression, of, 'GC', by, targeting, 'RUNX1,', and, 'RUNX1', can, partially, reverse, 'miR-215', effects])].
[sujeto(['Latent', 'TGF-beta']), verbo([binding]), complemento([proteins, '(', 'LTBPs)', are, extracellular, matrix, 'glycoproteins,', which, are, essential, for, the, targeting, and, activation, of, 'TGF-betas'])].
[sujeto(['LTBP-3']), verbo([regulates]), complemento([the, bioavailability, of, 'TGF-beta', especially, in, the, bone])].
[sujeto(['To', understand, the, regulation, of, 'LTBP-3', 'expression,', we]), verbo([have]), complemento([isolated, and, characterized, the, promoter, region, of, human, 'LTBP-3', gene])].
[sujeto(['The', 'GC-rich', 'TATA-less', promoter, contained, several, transcription, initiation, sites, and, putative]), verbo([binding]), complemento([sites, for, multiple, sequence, specific, transcription, factors, including, 'Sp1,', 'AP-1,', 'c-Ets,', 'MZF-1,', 'Runx1', and, members, of, the, 'GATA-family'])].
[sujeto(['Reporter', gene, analyses, of, the, promoter, indicated, that, it, was, more, active, in, 'MG-63', than, in, 'Saos-2', osteosarcoma, 'cells,']), verbo([suggesting]), complemento([that, it, is, regulated, as, the, endogenous, gene])].
[sujeto(['TGF-beta1']), verbo([stimulated]), complemento([the, transcriptional, activity, of, 'LTBP-3', promoter, in, 'MG-63', 'cells,', while, certain, other, 'bone-derived', growth, factors, and, hormones, were, ineffective])].
[sujeto(['TGF-beta1']), verbo([increased]), complemento(['LTBP-3', mRNA, levels, accordingly])].
[sujeto(['Analyses', of, deletion, constructs, of, the, promoter, and, mutational, deletion, of, specific, transcription, factor]), verbo([binding]), complemento([sites, indicated, that, 'Smad3/4', and, 'AP-1', binding, sites, mediated, the, 'TGF-beta1', response])].
[sujeto(['The', involvement, of, 'AP-1', activity, was, further, indicated, by]), verbo([decreased]), complemento(['TGF-beta', responsiveness, of, the, 'LTBP-3', promoter, in, the, presence, of, a, 'MEK/Erk', signaling, pathway, inhibitor])].
[sujeto(['Our', results]), verbo([suggest]), complemento([an, important, new, role, for, 'TGF-beta1', in, the, regulation, of, its, binding, 'protein,', 'LTBP-3'])].
[sujeto([4, ',', designated, the, human, leukocyte, receptor, 'complex,', and, are, predominantly]), verbo([expressed]), complemento([on, myeloid, lineage, cells])].
[sujeto(['Inhibitory', 'ILT2', and, 'ILT4', both]), verbo([have]), complemento([a, similar, genomic, 'structure,', in, which, the, approximately, 160, -, bp, 5, '\'', -, flanking, regions, function, as, core, promoters, with, critically, important, 'PU'])].
[sujeto([1]), verbo([binding]), complemento([sites])].
[sujeto(['Additionally,', 'ILT4', transcription, is, tightly]), verbo([regulated]), complemento([by, chromatin, modifications, accompanied, by, histone, 'acetylation,', which, strictly, controls, expression, within, myeloid, lineage, cells])].
[sujeto([1, and, 'Runx1']), verbo([binding]), complemento([sites, are, 'essential,', but, a, downstream, heat, shock, element, also, augments, promoter, activity])].
[sujeto(['Thus,', each, 'ILT', is]), verbo([regulated]), complemento([by, a, distinct, transcriptional, 'mechanism,', although, 'PU'])].
[sujeto([1]), verbo([acts]), complemento([as, a, common, 'trans-acting', factor])].
[sujeto(['We', also]), verbo([found]), complemento([that, human, 'CMV', infection, strongly, 'trans-activates', inhibitory, 'ILT2', and, 'ILT4', genes, through, the, expression, of, 'immediate-early', proteins])].
[sujeto(['Tnk1/Kos1', is, a, 'non-receptor', protein, tyrosine, kinase]), verbo([found]), complemento([to, be, a, tumor, suppressor])].
[sujeto(['It', negatively]), verbo([regulates]), complemento([cell, growth, by, indirectly, suppressing, 'Ras', activity])].
[sujeto(['We', identified, and, characterized, the, critical, 'cis-elements']), verbo([required]), complemento([for, 'Tnk1/Kos1\'s', promoter, activity])].
[sujeto(['Deletion', analysis, of, the, 'm-Tnk1', promoter]), verbo([reveals]), complemento([the, presence, of, both, positive, '(', -, 25, to, -, 151, ')', and, negative, '(', -, 151, to, -, 1201, ')', regulatory, regions])].
[sujeto(['The', three, 'GC', boxes, which]), verbo([bind]), complemento(['Sp1', and, 'Sp3', with, high, 'affinity,', an, 'AP2', site, '(', that, overlaps, with, an, 'AML1', 'site)', and, a, 'MED1', site, comprise, the, necessary, 'cis-elements', of, the, proximal, promoter, required, for, both, constitutive, and, inducible, 'Tnk1/Kos1', expression])].
[sujeto(['Importantly,', results]), verbo([reveal]), complemento([that, cellular, stress, reverses, the, repression, of, 'Tnk1/Kos1', and, induces, its, expression, through, increased, high, affinity, interactions, between, nuclear, proteins, 'Sp1,', 'Sp3,', 'AP2', and, 'MED1', for, the, 'm-Tnk1', promoter])].
[sujeto(['These', findings]), verbo([provide]), complemento([a, mechanism, by, which, the, 'm-Tnk1', promoter, can, be, dynamically, regulated, during, normal, growth])].
[sujeto(['They']), verbo([suggest]), complemento([that, prenatal, pesticide, exposures, may, be, causal, factors, for, the, generation, of, 'leukemia-associated', chromosomal, translocations])].
[sujeto(['The', main, start, sites, were]), verbo([found]), complemento([at, -, 591, ',', -, 577, ',', -, 560, and, -, 541, nucleotides, 5, '\'', of, the, 'AUG'])].
[sujeto(['Comparison', of, the, rat, sequences, with, the, human, sequences, from, the, 'Human', 'Genome', 'Data', 'Bank', revealed, that, the, 5, '\'', 'UTR', exon, 2, was, extremely]), verbo([conserved]), complemento([with, 95.8, '%', sequence, 'identity,', as, were, the, initial, 640, bp, of, 5, '\'', flanking, 'sequences,', with, 78, '%', sequence, identity])].
[sujeto(['Chromosomal', rearrangements, of, trkC]), verbo([have]), complemento([been, recently, reported, in, congenital, fibrosarcoma, and, it, has, been, proposed, that, abnormal, activation, of, this, gene, might, be, involved, in, tumor, development])].
[sujeto(['To', facilitate, the, search, for, new, mutations, and, rearrangements, in, the, human, trkC, locus, we]), verbo([have]), complemento([partially, characterized, its, genomic, organization, by, restriction, mapping, and, have, obtained, the, complete, 'intron-exon', structure])].
[sujeto(['Analysis', of, the, 5, '\'', flanking, region, revealed, the, absence, of, 'TATA', 'box,', a, very, high, content, in, 'C/G', compatible, with, a, 'CpG', island, and, the, presence, of, putative]), verbo([binding]), complemento([sites, for, the, 'AP1,', 'AP2,', 'GC,', 'ATF,', 'BRN2,', 'AML1', and, 'Nkx2'])].
[sujeto(['Upon', recognition, of, viral, components, by, pattern, recognition, 'receptors,', including, 'TLRs', and, retinoic, 'acid-inducible', gene, 'I-like', 'helicases,', cells, are]), verbo([activated]), complemento([to, produce, type, 'I', 'IFN,', which, plays, key, roles, in, host, antiviral, innate, immune, response])].
[sujeto(['However,', excessive, 'IFN', production, may]), verbo([induce]), complemento([immune, 'disorders,', and, the, mechanisms, responsible, for, the, regulation, of, type, 'I', 'IFN', production, have, attracted, much, attention])].
[sujeto(['Furthermore,', type, 'I', 'IFN']), verbo([activates]), complemento([the, downstream, 'IFN/JAK/STAT', pathway, to, modulate, expression, of, a, set, of, genes, against, viral, 'infection,', but, whether, these, genes, can, feedback, regulate, type, 'I', 'IFN', production, is, poorly, understood])].
[sujeto(['In', this, 'study,', by, screening, the, microRNAs]), verbo([modulated]), complemento([by, viral, infection, in, 'macrophages,', we, identified, that, microRNA, '(', 'miR)-27a', was, significantly, downregulated, via, the, 'IFN/JAK/STAT1/runt-related', transcription, factor, 1, pathway])].
[sujeto(['Inducible', downregulation, of, 'miR-27a,', in, 'turn,', negatively]), verbo([regulated]), complemento([vesicular, stomatitis, 'virus-triggered', type, 'I', 'IFN', 'production,', thus, promoting, vesicular, stomatitis, virus, replication, in, macrophages])].
[sujeto(['Mechanistically,', we]), verbo([found]), complemento([that, 'miR-27a', directly, targeted, sialic, 'acid-binding', 'Ig-like', lectin, '(', 'Siglec)1', and, 'E3', ubiquitin, ligase, tripartite, 'motif-containing', protein, 27, '(', 'TRIM27),', both, of, which, were, previously, verified, as, negative, regulators, of, type, 'I', 'IFN', production])].
[sujeto(['Furthermore,', we, constructed, &, 'quot;Sponge"', transgenic, mice, against, 'miR-27a', expression, and]), verbo([found]), complemento([that, 'Siglec1', and, 'TRIM27', expression, were, elevated, whereas, type, 'I', 'IFN', production, was, inhibited, and, viral, replication, was, aggregated, in, vivo])].
[sujeto(['Therefore,', type, 'I', 'IFN-induced', downregulation, of, 'miR-27a', can, upregulate, 'Siglec1', and, 'TRIM27', 'expression,', feedback]), verbo([inhibiting]), complemento([type, 'I', 'IFN', production, in, antiviral, innate, response])].
[sujeto(['Our', study, outlines, a, new, negative, way, to, feedback]), verbo([regulate]), complemento([type, 'I', 'IFN', production])].
[sujeto(['Advances', in, molecular, research]), verbo([have]), complemento([greatly, improved, our, understanding, of, the, leukemogenesis, in, 'AML'])].
[sujeto(['While', 'loss-of-function', mutations, in, 'DNMT3A', are, highly, recurrent, in, acute, myeloid, leukemia, '(', 'AML),', 'DNMT3A', mutations, are, almost, never]), verbo([found]), complemento([in, 'AML', patients, with, translocations, that, create, oncogenic, fusion, genes, such, as, 'PML-RARA,', 'RUNX1-RUNX1T1,', and, 'MLL-AF9'])].
[sujeto(['Here,', we, explored, how, 'DNMT3A', is]), verbo([involved]), complemento([in, the, function, of, these, fusion, genes])].
[sujeto(['We', used, retroviral, vectors, to]), verbo([express]), complemento(['PML-RARA,', 'RUNX1-RUNX1T1,', or, 'MLL-AF9', in, bone, marrow, cells, derived, from, 'WT', or, 'DNMT3A-deficient', mice])].
[sujeto(['Additionally,', we, examined, the, phenotypes, of, hematopoietic, cells, from, 'Ctsg-PML-RARA', 'mice,', which]), verbo([express]), complemento(['PML-RARA', in, early, hematopoietic, progenitors, and, myeloid, 'precursors,', with, or, without, 'DNMT3A'])].
[sujeto(['We', determined, that, the, methyltransferase, activity, of, 'DNMT3A,', but, not, 'DNMT3B,', is]), verbo([required]), complemento([for, aberrant, 'PML-RARA-driven', 'self-renewal', ex, vivo, and, that, 'DNMT3A', is, dispensable, for, 'RUNX1-RUNX1T1-', and, 'MLL-AF9-driven', 'self-renewal'])].
[sujeto(['Furthermore,', both, the, 'PML-RARA-driven', competitive, transplantation, advantage, and, development, of, acute, promyelocytic, leukemia, '(', 'APL)']), verbo([required]), complemento(['DNMT3A'])].
[sujeto(['Together,', these, findings]), verbo([suggest]), complemento([that, 'PML-RARA', requires, 'DNMT3A', to, initiate, 'APL', in, mice])].
[sujeto(['Acute', myeloid, leukemia, '(', 'AML)', is, mostly, driven, by, oncogenic, transcription, 'factors,', which]), verbo([have]), complemento([been, classically, viewed, as, intractable, targets, using, 'small-molecule', inhibitor, approaches])].
[sujeto(['Here', we, demonstrate, that, 'AML', driven, by, repressive, transcription, 'factors,', including, 'AML1-ETO', '(', encoded, by, the, fusion, oncogene, 'RUNX1-RUNX1T1)', and, 'PML-RARα', fusion, oncoproteins, '(', encoded, by, 'PML-RARA)', are, extremely, sensitive, to, poly, '(', 'ADP-ribose)', polymerase, '(', 'PARP)', 'inhibition,', in, part, owing, to, their]), verbo([suppressed]), complemento([expression, of, key, homologous, recombination, '(', 'HR)-associated', genes, and, their, compromised, 'DNA-damage', response, '(', 'DDR)'])].
[sujeto(['Intriguingly,', genetic, or, pharmacological, inhibition, of, an, 'MLL', downstream, 'target,', 'HOXA9,', which]), verbo([activates]), complemento([expression, of, various, 'HR-associated', 'genes,', impairs, 'DDR', and, sensitizes, 'MLL', leukemia, to, 'PARP', inhibitors, '(', 'PARPis)'])].
[sujeto(['Conversely,', 'HOXA9', overexpression]), verbo([confers]), complemento(['PARPi', resistance, to, 'AML1-ETO', and, 'PML-RARα', transformed, cells])].
[sujeto(['Together,', these, studies, describe, a, potential, utility, of, 'PARPi-induced', synthetic, lethality, for, leukemia, treatment, and]), verbo([reveal]), complemento([a, novel, molecular, mechanism, governing, 'PARPi', sensitivity, in, 'AML'])].
[sujeto(['Here,', we, identified, 'Mtss1', expression, to, be]), verbo([increased]), complemento([in, 'AML', subsets, with, favorable, 'outcome,', while, suppressed, in, high, risk, 'AML', patients])].
[sujeto(['Mechanistically,', 'MTSS1', expression, was, negatively]), verbo([regulated]), complemento([by, 'FLT3-ITD', signaling, but, enhanced, by, the, 'AML1-ETO', fusion, protein])].
[sujeto(['DNMT3B,', a, negative, regulator, of, 'MTSS1,', showed, strong]), verbo([binding]), complemento([to, the, 'MTSS1', promoter, in, 'PML-RARA', positive, but, not, 'AML1-ETO', positive, 'cells,', suggesting, that, 'AML1-ETO', leads, to, derepression, of, 'MTSS1'])].
[sujeto(['Pharmacological', treatment, of, 'AML', cell, lines, carrying, the, 'FLT3-ITD', mutation, with, the, specific, 'FLT3', inhibitor, 'PKC-412']), verbo([caused]), complemento([upregulation, of, 'MTSS1'])].
[sujeto(['Moreover,', treatment, of, acute, promyelocytic, cells, '(', 'APL)', with, 'all-trans', retinoic, acid, '(', 'ATRA)']), verbo([increased]), complemento(['MTSS1', mRNA, levels])].
[sujeto(['Taken', 'together,', our, findings]), verbo([suggest]), complemento([that, 'MTSS1', might, have, a, 'context-dependent', function, and, could, act, as, a, tumor, 'suppressor,', which, is, pharmacologically, targetable, in, 'AML', patients])].
[sujeto(['Here', we, show, that, both, oncogenic, proteins, specifically, downregulate, the, expression, of, 'CD48,', a, ligand, of, the, natural, killer, '(', 'NK)', cell]), verbo([activating]), complemento([receptor, 2, 'B4,', thereby, leading, to, decreased, killing, by, 'NK', cells])].
[sujeto(['We', demonstrate, that, this, process, is, histone, deacetylase, '(', 'HDAC)-dependent,', that, it, is]), verbo([mediated]), complemento([through, the, downregulation, of, 'CD48', messenger, 'RNA,', and, that, treatment, with, 'HDAC', inhibitors, '(', 'HDACi)', restores, the, expression, of, 'CD48'])].
[sujeto(['Furthermore,', by, using, chromatin, immunoprecepitation, '(', 'ChIP)', 'experiments,', we, show, that, 'AML1-ETO', directly]), verbo([interacts]), complemento([with, 'CD48'])].
[sujeto(['Finally,', we, show, that, 'AML', patients, who, are, carrying, these, specific, translocations]), verbo([have]), complemento([low, expression, of, 'CD48'])].
[sujeto(['Delineating', the, mechanism, or, mechanisms, that]), verbo([regulate]), complemento([the, specification, of, hemogenic, endothelial, cells, from, primordial, endothelium, is, critical, for, optimizing, their, derivation, from, human, stem, cells, for, clinical, therapies])].
[sujeto(['We', previously, determined, that, retinoic, acid, '(', 'RA)', is]), verbo([required]), complemento([for, hemogenic, 'specification,', as, well, as, 'cell-cycle', 'control,', of, endothelium, during, embryogenesis])].
[sujeto(['Herein,', we, define, the, molecular, signals, downstream, of, 'RA', that]), verbo([regulate]), complemento([hemogenic, endothelial, cell, development, and, demonstrate, that, 'cell-cycle', control, is, required, for, this, process])].
[sujeto(['We']), verbo([found]), complemento([that, 're-expression', of, 'c-Kit', in, 'RA-deficient', '(', 'Raldh2(-/-))', primordial, endothelium, induced, 'Notch', signaling, and, p27, 'expression,', which, restored, 'cell-cycle', control, and, rescued, hemogenic, endothelial, cell, specification, and, function])].
[sujeto(['Thus,', 'RA', regulation, of, hemogenic, endothelial, cell, specification]), verbo([requires]), complemento(['c-Kit,', notch, 'signaling,', and, 'p27-mediated', 'cell-cycle', control])].
[sujeto(['Both', radiation, and, chemotherapeutic, drugs]), verbo([induce]), complemento([autophagy, in, tumor, 'cells,', and, whether, this, contributes, to, cell, death, or, survival, is, debated])].
[sujeto(['Although', a, prodeath, role]), verbo([has]), complemento([been, reported, in, certain, 'contexts,', 'treatment-induced', autophagy, often, exerts, a, prosurvival, function, by, preventing, apoptosis, and, delaying, necrosis])].
[sujeto(['Interestingly,', a, more, specific, role, of, autophagy]), verbo([has]), complemento([been, demonstrated, in, certain, subtypes, of, leukemia])].
[sujeto(['The', fusion, oncoproteins, 'PML-RARA', and, 'BCR-ABL,', the, main, oncogenic, drivers, of, acute, promyelocytic, leukemia, and, chronic, myeloid, leukemia, '(', 'CML),', 'respectively,']), verbo([have]), complemento([recently, been, identified, as, autophagy, substrates, and, their, degradation, by, autophagy, shown, to, contribute, to, treatment])].
[sujeto(['However,', this, does, not, seem, to, be, a, general, feature, of, leukemic, fusion, 'oncoproteins,', as, we, recently]), verbo([found]), complemento([that, 'AML1-ETO,', the, most, frequently, occurring, acute, myeloid, leukemia, '(', 'AML)', fusion, 'protein,', is, not, an, autophagy, substrate])].
[sujeto(['ATRA']), verbo([enhances]), complemento([hematopoietic, stem, cell, 'self-renewal', through, retinoic, acid, receptor, '(', 'RAR)γ', activation, while, promoting, differentiation, of, committed, myeloid, progenitors, through, 'RARα', activation])].
[sujeto(['Its', lack, of, success, in, the, treatment, of, 'non-APL', acute, myeloid, leukemia, '(', 'AML)', may, be, related, to, 'ATRA\'s', 'non-selectivity', for, the, 'RARα', and, 'RARγ', 'isotypes,', and, specific, 'RARα', activation, may, be, more, beneficial, in]), verbo([promoting]), complemento([myeloid, differentiation])].
[sujeto(['Morphological', and, flow, cytometric, analysis, confirmed, a, predominantly, immature, myeloid, population, in, the, 'ATRA-treated', 'AE', cells, while, the, 'NRX195183-treated', cells, demonstrated, an]), verbo([increase]), complemento([in, the, mature, myeloid, population])].
[sujeto(['Similarly,', 'NRX195183', treatment]), verbo([promoted]), complemento([myeloid, differentiation, in, an, 'AE9a', in, vivo, murine, model])].
[sujeto(['In', the, 'ATRA-treated', 'AE', 'cells,', gene, expression, analyses, revealed, functional, networks]), verbo([involving]), complemento(['SERPINE1', and, bone, morphogenetic, protein, 2, ;, 'AKT', phosphorylation, was, upregulated])].
[sujeto(['Chromatin', accessibility, plays, a, key, role, in]), verbo([regulating]), complemento([cell, type, specific, gene, expression, during, hematopoiesis, but, has, also, been, suggested, to, be, aberrantly, regulated, during, leukemogenesis])].
[sujeto(['Z', as, a, histone, modification, generally]), verbo([associated]), complemento([with, these, accessible, 'regions,', whereas, unsupervised, clustering, analysis, of, other, chromatin, 'features,', including, 'DNA', 'methylation,', 'H2A'])].
[sujeto(['Of', 'these,', 'PML-RARα']), verbo([binding]), complemento([was, found, specifically, at, accessible, chromatin, regions, characterized, by, p300, binding, and, hypoacetylated, histones])].
[sujeto(['Together,', our, results]), verbo([suggest]), complemento([that, oncofusion, proteins, localize, to, accessible, regions, and, that, chromatin, accessibility, together, with, p300, binding, and, histone, acetylation, characterize, 'AML1-ETO', and, 'PML-RARα', binding, sites])].
[sujeto(['Leukemia,', a, group, of, hematological, malignancies, characterized, by, abnormal, 'proliferation,']), verbo([decreased]), complemento(['apoptosis,', and, blocked, differentiation, of, hematopoietic, 'stem/progenitor', 'cells,', is, a, disease, involving, dynamic, change, in, the, genome])].
[sujeto(['Chromosomal', translocation, and, point, mutation, are, the, major, mechanisms, in, 'leukemia,', which]), verbo([lead]), complemento([to, production, of, oncogenes, with, dominant, gain, of, function, and, tumor, suppressor, genes, with, recessive, loss, of, function])].
[sujeto(['The', past, two, to, three, decades]), verbo([have]), complemento([witnessed, tremendous, success, in, development, of, targeted, therapies, for, acute, and, chronic, myeloid, leukemia, caused, by, the, three, fusion, proteins])].
[sujeto(['Here,', we, review, the, therapeutic, efficacies, and, the, mechanisms, of, action, of]), verbo([targeted]), complemento([therapies, for, myeloid, leukemia, and, show, how, this, strategy, significantly, improve, the, clinical, outcome, of, patients, and, even, turn, acute, promyelocytic, leukemia, from, highly, fatal, to, highly, curable])].
[sujeto(['Our', previous, study, showed, that, the, differentiation, and, apoptosis, of, 'Kasumi-1']), verbo([induced]), complemento([by, sodium, phenylbutyrate, '(', 'PB),', were, accompanied, by, significant, upregulation, of, 'PIG7', and, 'AML1b', '(', one, of, the, 'AML1', 'isoforms)'])].
[sujeto(['The', specific, 'AML1-binding', site]), verbo([required]), complemento([for, 'p53-induced', gene, 7, '(', 'PIG7)', transactivation, was, located, between, nucleotides, -, 1511, and, -, 1503, in, the, 'PIG7', promoter])].
[sujeto(['Overexpression', of, 'PIG7', could]), verbo([induce]), complemento([the, apoptosis, and, differentiation, of, 'Kasumi-1', and, 'SKNO-1', 'cells,', but, showed, less, effect, on, 'NB4', cells, directly])].
[sujeto(['In', 'conclusion,', 'PIG7', could, be, transactivated, by, 'AML1,', which, subsequently]), verbo([induces]), complemento([differentiation, and, apoptosis, of, leukemia, 'cells,', especially, those, with, 'AML1-ETO', fusion, gene])].
[sujeto([22, of, the, 40, 'AML', cases, were]), verbo([found]), complemento([to, carry, 7, types, of, cytogenetic, abnormalities, by, multiprobe, 'FISH', panel, including, 'AML1/ETO', transfusion, 'gene,', 'PML-RARa', transfusion, 'gene,', 'MLL', 'breakapart,', 'P53', 'deletion,', 'Del', '(', 5, 'q),', 'Del7q', and, trisomy, 8])].
[sujeto(['The', 'leukaemia-specific', fusion, oncoprotein, 'RUNX1/RUNX1T1', '(', 'AML1/ETO),', resulting, from, the, chromosomal, translocation, '(', 8, ;, 21, ')', in, acute, myeloid, leukaemia, '(', 'AML),', imposes, a, striking, 'genotype-phenotype', relationship, upon, this, distinct, subtype, of, 'AML,', which, is]), verbo([mediated]), complemento([by, 'multiple,', 'co-ordinate', downstream, effects, induced, by, this, chimeric, transcription, factor])].
[sujeto(['We', previously, identified, the, 'LAT2', 'gene,', encoding, the, adaptor, molecule, 'LAT2', '(', 'NTAL,', 'LAB),', which, is]), verbo([phosphorylated]), complemento([by, 'KIT', and, has, a, role, in, mast, cell, and, 'B-cell', 'activation,', as, a, target, of, the, repressor, activity, of, 'RUNX1/RUNX1T1'])].
[sujeto(['In', 'contrast,', in, a, cohort, of, 43, 'AML', 'patients,', higher, levels, of, 'LAT2', were]), verbo([associated]), complemento([with, myelomonocytic, features])].
[sujeto(['In', previous, 'studies,', we]), verbo([found]), complemento([that, the, deficiency, of, sensory, and, motor, neurons, was, a, primary, defect, associated, with, the, spinal, malformation])].
[sujeto(['Upon', prenatal, treatment, of, spina, bifida, through, in, utero, stem, cell, transplantation, in, a, retinoic, 'acid-induced', spina, bifida, rat, 'model,', we]), verbo([found]), complemento([that, the, mesenchymal, stem, cell, '(', 'MSCs)', 'survived,', 'migrated,', and, differentiated, into, cells, of, a, neural, lineage])].
[sujeto(['Some', of, the, transplanted, 'MSCs']), verbo([expressed]), complemento([sensory, neuron, cell, specific, phenotypes])].
[sujeto(['The', percentage, of, 'Brn3a-positive', neurons, in, 'DRG', was, also]), verbo([increased]), complemento([after, transplantation])].
[sujeto(['Our', results, indicate, that, the, transplantation, of, 'MSCs', into, the, spinal, cord, could]), verbo([promote]), complemento([the, transplanted, 'MSCs', and, the, surrounding, cells, to, differentiate, toward, a, sensory, neuron, cell, fate, and, to, play, an, important, role, in, protecting, sensory, neurons, in, 'DRG'])].
[sujeto(['The', 'ETS', transcription, factor, 'ERG']), verbo([has]), complemento([been, implicated, as, a, major, regulator, of, both, normal, and, aberrant, hematopoiesis])].
[sujeto(['Here,', we, show, that, 'FUS-ERG']), verbo([acts]), complemento([in, the, context, of, a, heptad, of, proteins, '(', 'ERG,', 'FLI1,', 'GATA2,', 'LYL1,', 'LMO2,', 'RUNX1', and, 'TAL1)', central, to, proper, expression, of, genes, involved, in, maintaining, a, stem, cell, hematopoietic, phenotype])].
[sujeto(['Moreover,', in, 't(16;21)', 'FUS-ERG', 'co-occupies', genomic, regions]), verbo([bound]), complemento([by, the, nuclear, receptor, heterodimer, 'RXR:RARA', inhibiting, target, gene, expression, and, interfering, with, hematopoietic, differentiation])].
[sujeto(['Together,', the, results]), verbo([suggest]), complemento([that, 'FUS-ERG', acts, as, a, transcriptional, repressor, of, the, retinoic, acid, signaling, pathway])].
[sujeto(['All-trans', retinoic, acid, '(', 'ATRA)', is, well, established, as, differentiation, therapy, for, acute, promyelocytic, leukemia, '(', 'APL)', in, which, the, 'PML-RARα', '(', promyelocytic, 'leukemia-retinoic', acid, receptor, 'α)', fusion, protein]), verbo([causes]), complemento([blockade, of, the, retinoic, acid, '(', 'RA)', 'pathway;', 'however,', in, types, of, acute, myeloid, leukemia, '(', 'AML)', other, than, 'APL,', the, mechanism, of, 'RA', pathway, inactivation, is, not, fully, understood])].
[sujeto(['Treatment', with, 'ATRA']), verbo([induced]), complemento([significant, myeloid, differentiation, accompanied, by, upregulation, of, 'RARα,', 'C/EBPα,', 'C/EBPɛ', and, 'PU'])].
[sujeto([1, upstream, regulatory, region, '(', 'URE)', and, 'RUNX1+24/+25', intronic, enhancer, was, higher, in, 'MLL-AF9-positive', cells, than, in, 'MLL-AF4-positive', 'cells,', and]), verbo([inhibiting]), complemento(['lysine-specific', demethylase, 1, ',', which, acts, as, a, histone, demethylase, 'inhibitor,', reactivated, 'ATRA', sensitivity, in, 'MLL-AF4-positive', cells])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, level, of, 'H3K4me2', in, the, 'RARα', 'gene-promoter', 'region,', 'PU'])].
[sujeto(['Our', findings]), verbo([provide]), complemento([insight, into, the, mechanisms, of, 'ATRA', sensitivity, in, 'AML', and, novel, treatment, strategies, for, 'ATRA-resistant', 'AML'])].
[sujeto(['The', genetic, diagnostics]), verbo([have]), complemento([become, an, essential, component, in, the, initial, 'work-up', for, disease, 'classification,', prognostication, and, prediction])].
[sujeto(['More', and, more, promising, molecular]), verbo([targeted]), complemento([therapeutics, are, becoming, available])].
[sujeto(['With', the, advent, of, the, next, generation, sequencing, technologies, it, is, expected, that, new, therapeutic]), verbo([targets]), complemento([will, be, identified])].
[sujeto(['These', insights, will]), verbo([lead]), complemento([to, a, further, individualization, of, 'AML', therapy])].
[sujeto(['It', is, concluded, that, the, 'CD200', antigen, expression, in, 'AML', may]), verbo([associate]), complemento([with, a, poor, prognosis, of, patients])].
[sujeto(['Although', 'all-trans', retinoic, acid, '(', 'ATRA)']), verbo([has]), complemento([been, successfully, introduced, to, treat, acute, promyelocytic, leukemia, '(', 'APL),', it, is, rather, ineffective, in, 'non-APL', 'AML'])].
[sujeto(['In', our, present, 'study,', 1200, 'off-patent', marketed, drugs, and, natural, compounds, that]), verbo([have]), complemento([been, approved, by, the, 'Food', and, 'Drug', 'Administration', '(', 'FDA)', were, screened, for, 'anti-leukemia', activity, using, the, retrovirus, 'transduction/transformation', assay, '(', 'RTTA)'])].
[sujeto(['Furazolidone', '(', 'FZD)', was, shown, to]), verbo([inhibit]), complemento([bone, marrow, transformation, mediated, by, several, leukemia, fusion, 'proteins,', including, 'AML1-ETO'])].
[sujeto(['Furazolidone']), verbo([has]), complemento([been, used, in, the, treatment, of, certain, bacterial, and, protozoan, infections, in, human, and, animals, for, more, than, sixty, years])].
[sujeto(['FZD', displayed, potent, antiproliferative, properties, at, submicromolar, concentrations, and]), verbo([induced]), complemento([apoptosis, in, 'AML', cell, lines])].
[sujeto(['Importantly,', 'FZD', treatment, of, certain, 'AML', cells]), verbo([induced]), complemento([myeloid, cell, differentiation, by, morphology, and, flow, cytometry, for, 'CD11b', expression])].
[sujeto(['Furthermore,', 'FZD', treatment, resulted, in]), verbo([increased]), complemento([stability, of, tumor, suppressor, p53, protein, in, 'AML', cells])].
[sujeto(['Our', in, vitro, results]), verbo([suggest]), complemento([furazolidone, as, a, novel, therapeutic, strategy, in, 'AML', patients])].
[sujeto(['CMTM5']), verbo([has]), complemento([been, shown, to, exhibit, tumor, suppressor, 'activities,', 'however,', its, role, in, leukemia, is, unclear])].
[sujeto(['Herein', we, firstly]), verbo([reported]), complemento([the, expression, and, function, of, 'CMTM5', in, myeloid, leukemia])].
[sujeto(['Ectopic', expression, of, 'CMTM5-v1', strongly]), verbo([inhibited]), complemento([the, proliferation, of, 'K562', and, 'MEG-01', cells])].
[sujeto(['Therefore,', 'CMTM5', may, be]), verbo([involved]), complemento([in, the, pathomechanism, of, myeloid, leukemias])].
[sujeto(['The', biologic, functions, of, 'AML1', and, 'AML3']), verbo([have]), complemento([been, well, 'characterized;', 'however,', the, functional, role, of, 'AML2', remains, unknown])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, 'AML2', protein, expressed, predominantly, in, cells, of, hematopoietic, origin, is, a, nuclear, serine, phosphoprotein, associated, with, the, nuclear, 'matrix,', and, its, expression, is, not, cell, 'cycle-related'])].
[sujeto(['In', 'HL-60', cells, 'AML2', expression, can, be]), verbo([induced]), complemento([by, all, three, natural, 'retinoids,', 'all-trans-retinoic', acid, '(', 'RA),', 13, -, 'cis-RA,', and, 9, -, 'cis-RA', in, a, 'dose-dependent', manner])].
[sujeto(['A', synthetic, retinoic, acid, 'derivative,', 4, 'HPR,', which, neither]), verbo([activates]), complemento(['RA', receptor, '(', 'RAR)', alpha, nor, retinoic, 'X', receptor, alpha, was, unable, to, induce, the, expression, of, 'AML2'])].
[sujeto(['A', 'RAR-selective', 'activator,', 'TTNPB,']), verbo([induced]), complemento(['AML2', expression, similar, to, 'RA'])].
[sujeto(['Our', study, further, showed, that, 'AGN193109,', a, potent, 'RARalpha', 'antagonist,']), verbo([suppressed]), complemento(['AML2', expression, induced, by, 'RA', and, that, a, retinoic, 'X', receptor, pan, agonist, 'AGN194204', had, no, effect, on, its, expression])].
[sujeto(['Taken', 'together,', these, studies, conclusively, demonstrated, that, the, expression, of, 'AML2', in, 'HL-60', cells, is]), verbo([regulated]), complemento([through, the, 'RARalpha-specific', signaling, pathway])].
[sujeto(['Based', on, these, studies, we, hypothesize, that, 'AML2', expression, is, normally]), verbo([regulated]), complemento([by, 'retinoid/vitamin', 'D', nuclear, receptors, mainly, through, the, 'RARalpha-dependent', signaling, pathway, and, that, it, may, play, a, role, in, hematopoietic, cell, differentiation])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, 'runt-related', transcription, factor, '(', 'RUNX1)', could, be, a, key, molecule, for, the, 'androgen-dependence', of, prostate, cancer])].
[sujeto(['We']), verbo([found]), complemento(['RUNX1', is, a, target, of, 'AR', and, regulated, positively, by, androgen])].
[sujeto(['Our', 'RUNX1', 'ChIP-seq', analysis, indicated, that, 'RUNX1', is]), verbo([recruited]), complemento([to, 'AR', binding, sites, by, interacting, with, 'AR'])].
[sujeto(['In', 'androgen-dependent', 'cancer,']), verbo([loss]), complemento([of, 'RUNX1', impairs, 'AR-dependent', transcription, and, cell, growth])].
[sujeto(['The', 'RUNX1', promoter, is]), verbo([bound]), complemento([by, enhancer, of, zeste, homolog, 2, '(', 'EZH2)', and, is, negatively, regulated, by, histone, 'H3', lysine, 27, '(', 'K27)', trimethylation])].
[sujeto(['In', clinical, prostate, cancer, 'samples,', the, 'RUNX1', expression, level, is, negatively]), verbo([associated]), complemento([with, 'EZH2', and, that, 'RUNX1', loss, correlated, with, poor, prognosis])].
[sujeto(['These', results, indicated, the, significance, of, 'RUNX1', for, 'androgen-dependency', and, that]), verbo([loss]), complemento([of, 'RUNX1', could, be, a, key, step, for, the, progression, of, prostate, cancer])].
[sujeto(['Mutant', 'MAP3K1', was]), verbo([associated]), complemento([with, luminal, 'A', 'status,', 'low-grade', histology, and, low, proliferation, 'rates,', whereas, mutant, 'TP53', was, associated, with, the, opposite, pattern])].
[sujeto(['Distinct', phenotypes, in, 'oestrogen-receptor-positive', breast, cancer, are]), verbo([associated]), complemento([with, specific, patterns, of, somatic, mutations, that, map, into, cellular, pathways, linked, to, tumour, 'biology,', but, most, recurrent, mutations, are, relatively, infrequent])].
[sujeto(['Prospective', clinical, trials, based, on, these, findings, will]), verbo([require]), complemento([comprehensive, genome, sequencing])].
[sujeto(['In', this, 'report,', we]), verbo([have]), complemento([investigated, the, relationship, between, androgen, levels, and, prostate, tumorigenesis, in, 'Nkx3'])].
[sujeto([',', 7, 'months),', we]), verbo([have]), complemento([found, that, prolonged, exposure, of, 'Nkx3'])].
[sujeto(['We']), verbo([found]), complemento([that, prostate, tumors, from, the, 'Low-T', mutant, mice, share, a, similar, gene, expression, profile, as, 'androgen-independent', prostate, tumors, from, these, mutant, 'mice,', which, includes, the, deregulated, expression, of, several, genes, that, are, 'up-regulated', in, human, 'hormone-refractory', prostate, 'cancer,', such, as, 'Vav3', and, 'Runx1'])].
[sujeto(['We', propose, that, exposure, to, reduced, androgens, may]), verbo([promote]), complemento([prostate, tumorigenesis, by, selecting, for, molecular, events, that, promote, more, 'aggressive,', 'hormone-refractory', tumors])].
[sujeto(['The', 't(8;21)', translocation, is, the, most, widespread, genetic, defect]), verbo([found]), complemento([in, human, acute, myeloid, leukemia])].
[sujeto(['Here', we, show, that, the, local, exon, combinatorics, of, the, 'RUNX1-RUNX1T1', gene, follows, a, 'power-law', behavior, and, '(', 'i)', the, vast, majority, of, exons]), verbo([has]), complemento([a, low, 'ECI,', '(', 'ii)', only, a, small, part, is, represented, by, &, 'quot;exons-hubs"', of, splicing, with, very, high, 'ECI', 'values,', and, '(', 'iii)', it, is, 'scale-free', and, very, sensitive, to, targeted, skipping, of, &, 'quot;exons-hubs"'])].
[sujeto(['Half-life', of, these, transcripts, is]), verbo([increased]), complemento([due, to, the, deregulation, of, some, key, genes, of, the, 'nonsense-mediated', decay, system, in, leukemia, cells])].
[sujeto(['Altogether,', our, results, show, that, alternative, splicing, of, the, 'RUNX1-RUNX1T1', transcripts, follows, strict, rules, and, that, the, 'power-law', component, of, the, fusion, gene, organization]), verbo([confers]), complemento([a, high, flexibility, to, this, process])].
[sujeto(['There']), verbo([has]), complemento([been, considerable, interest, in, identifying, a, 'cis-regulatory', element, that, targets, gene, expression, to, stem, cells])].
[sujeto(['Such', an, 'element,', termed, stem, cell, 'enhancer,', holds, the, promise, of]), verbo([providing]), complemento([important, insights, into, the, transcriptional, programs, responsible, for, inherent, stem, 'cell-specific', properties, such, as, 'self-renewal', capacity])].
[sujeto(['A', series, of, candidate, enhancers]), verbo([have]), complemento([been, identified, for, hematopoietic, stem, cells, '(', 'HSCs)'])].
[sujeto(['Human', 'RUNX1', gene, is, one, of, the, most, frequent]), verbo([target]), complemento([for, chromosomal, translocations, associated, with, acute, myeloid, leukemia, '(', 'AML)', and, acute, lymphoid, leukemia, '(', 'ALL)'])].
[sujeto(['No', homologous, sequences]), verbo([have]), complemento([been, found, at, the, recombination, 'regions;', but, 'DNase', 'I', hypersensitive, sites, '(', 'DHS)', have, been, mapped, to, the, areas, of, the, genes, involved, in, 't(8;21)'])].
[sujeto(['Presence', of, 'DHS', sites, is, commonly]), verbo([associated]), complemento([with, regulatory, elements, such, as, 'promoters,', enhancers, and, 'silencers,', among, others])].
[sujeto(['Our', genomic, analysis, identified, nine]), verbo([conserved]), complemento(['non-coding', sequences, that, are, evolutionarily, conserved, among, 'rat,', mouse, and, human])].
[sujeto(['Our', results, demonstrate, that, the, identified, regions, can, indeed]), verbo([regulate]), complemento([transcription, of, a, reporter, gene, in, a, distance, and, position, independent, 'manner;', 'moreover,', their, transcriptional, effect, is, cell, type, specific])].
[sujeto(['We']), verbo([have]), complemento([identified, nine, conserved, non, coding, sequence, that, are, harbored, in, intron, 5, of, the, 'RUNX1', gene])].
[sujeto(['We']), verbo([have]), complemento([also, demonstrated, that, two, of, these, regions, can, regulate, transcriptional, activity, in, vitro])].
[sujeto(['Taken', together, our, results]), verbo([suggest]), complemento([that, intron, 5, of, the, 'RUNX1', gene, contains, multiple, potential, 'cis-regulatory', elements])].
[sujeto(['In', all, 'vertebrates,', the, 'Runx1', gene, is]), verbo([transcribed]), complemento([from, two, 'promoters:', a, proximal, promoter, '(', 'P2),', and, a, distal, promoter, '(', 'P1)'])].
[sujeto(['We', previously]), verbo([found]), complemento([that, runx1, expression, in, a, specific, hematopoietic, cell, population, in, zebrafish, embryos, depends, on, cohesin])].
[sujeto(['Here', we, show, that, zebrafish, runx1, is, directly]), verbo([bound]), complemento([by, cohesin, and, 'CCCTC', binding, factor, '(', 'CTCF)', at, the, 'P1', and, 'P2', 'promoters,', and, within, the, intron, between, 'P1', and, 'P2'])].
[sujeto(['Cohesin', initiates, expression, of, runx1, in, the, posterior, lateral, mesoderm, and, influences, promoter, 'use,', while, 'CTCF']), verbo([represses]), complemento([its, expression, in, the, newly, emerging, cells, of, the, tail, bud])].
[sujeto(['The', intronic]), verbo([binding]), complemento([sites, for, cohesin, and, 'CTCF', coincide, with, histone, modifications, that, confer, 'enhancer-like', 'properties,', and, two, of, the, 'cohesin/CTCF', sites, behaved, as, insulators, in, an, in, vivo, assay])].
[sujeto(['The', identified, cohesin, and, 'CTCF']), verbo([binding]), complemento([sites, are, likely, to, be, 'cis-regulatory', elements, '(', 'CREs)', for, runx1, since, they, also, recruit, 'RNA', polymerase, 'II', '(', 'RNAPII)'])].
[sujeto(['We', propose, that, cohesin, and, 'CTCF']), verbo([have]), complemento([distinct, functions, in, the, regulation, of, runx1, during, zebrafish, 'embryogenesis,', and, that, these, regulatory, functions, are, likely, to, involve, runx1, intronic, 'CREs'])].
[sujeto(['Cohesin', '(', but, not, 'CTCF)', depletion]), verbo([enhanced]), complemento(['RUNX1', expression, in, a, human, leukemia, cell, 'line,', suggesting, conservation, of, 'RUNX1', regulation, through, evolution])].
[sujeto([1]), verbo([has]), complemento([been, shown, to, cause, a, shift, in, myelomonocytic, progenitor, fate])].
[sujeto(['Such', activity]), verbo([has]), complemento([been, demonstrated, to, be, a, tightly, controlled, mechanism, regulating, a, wide, variety, of, protein, functions, under, both, normal, physiological, and, pathological, conditions])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, that, a, conformational, change, in, 'Runx2', induced, by, 'Pin1', is, essential, for, its, function, in, osteogenesis, in, vitro, and, in, vivo])].
[sujeto(['In', this, 'study,', we, show, that, the, 'Pin1-mediated', conformational, change, in, 'Runx1']), verbo([enhances]), complemento([its, acetylation, and, stabilization, 'and,', 'consequently,', enhances, its, transacting, activity])].
[sujeto(['The']), verbo([increased]), complemento([acetylation, of, 'Runx1', represses, 'PU'])].
[sujeto(['Conversely,', the, lack, of, '(', or, the, inhibition, 'of)', 'Pin1']), verbo([increases]), complemento(['PU'])].
[sujeto(['Pin1', 'KO', mice]), verbo([have]), complemento([an, increased, 'CD11b(+)', /, 'F4/80(+)', cell, population, and, 'F4/80', protein, expression, in, spleen])].
[sujeto(['From', our, 'data,', we, can, conclude, that, the, conformational, change, in, 'Runx1']), verbo([induced]), complemento([by, 'Pin1', represses, 'PU'])].
[sujeto([1, is, a, crucial, factor, in, acute, myeloid, leukemia, '(', 'AML),', and, 'Pin1', may, thus, be, a, useful]), verbo([target]), complemento([for, controlling, 'PU'])].
[sujeto(['The', transcription, factor, 'Runx1', '(', 'AML1)', is, a, central, regulator, of, hematopoiesis, and, is]), verbo([required]), complemento([for, the, formation, of, definitive, hematopoietic, stem, cells, '(', 'HSCs)'])].
[sujeto(['Runx1', is, alternatively]), verbo([expressed]), complemento([from, two, 'promoters:', the, proximal, '(', 'P2)', prevails, during, primitive, 'hematopoiesis,', while, the, distal, '(', 'P1)', dominates, in, definitive, 'HSCs'])].
[sujeto(['Although', some, transcription, factor]), verbo([binding]), complemento([sites, and, 'cis-regulatory', elements, have, been, 'identified,', a, mechanistic, explanation, for, the, alternative, promoter, usage, remains, elusive])].
[sujeto(['In', 'vivo,', we]), verbo([find]), complemento([loss, of, methylation, correlated, with, the, primitive, to, definitive, transition, at, the, 'P1', promoter])].
[sujeto(['In', 'vitro,', 'hypomethylation,', acquisition, of, active, chromatin, 'modifications,', and]), verbo([increased]), complemento([transcriptional, activity, at, 'P1', are, promoted, by, direct, interaction, with, 'HOXB4,', a, transcription, factor, that, confers, definitive, repopulation, status, on, primitive, hematopoietic, progenitors])].
[sujeto(['Despite', such, widespread, 'involvements,', the, relationship, between, 'RUNX1', and, 'MLL']), verbo([has]), complemento([never, been, appreciated])].
[sujeto(['Recently,', we, showed, that, 'RUNX1', physically, and, functionally]), verbo([interacts]), complemento([with, 'MLL,', thereby, regulating, the, epigenetic, status, of, critical, 'cis-regulatory', elements, for, hematopoietic, genes])].
[sujeto(['This', newly, unveiled, interaction, between, the, two, most, prevalent, leukemia, genes]), verbo([has]), complemento([solved, a, 'long-standing', 'conundrum:', 'leukemia-associated', 'RUNX1', 'N-terminal', point, mutants, that, exhibit, no, obvious, functional, abnormalities, in, classical, assays, for, the, assessment, of, transcriptional, activities])].
[sujeto(['These', mutants, turned, out, to, be, defective, in, 'MLL', interaction, and, subsequent, epigenetic, modifications, that, can, be, examined, by, the, 'histone-modification', status, of, 'cis-regulatory', elements, in, the]), verbo([target]), complemento([genes])].
[sujeto(['RUNX1/MLL']), verbo([binding]), complemento([confirms, the, importance, of, 'RUNX1', function, as, an, epigenetic, regulator])].
[sujeto(['These', new, findings, would]), verbo([enhance]), complemento([our, understanding, on, the, mechanistic, basis, for, leukemia, development, and, may, provide, a, novel, direction, for, therapeutic, applications])].
[sujeto(['Overexpression', of, the, brain, and, acute, 'leukemia,', cytoplasmic, '(', 'BAALC)', gene, is, implicated, in, myeloid, leukemogenesis, and]), verbo([associated]), complemento([with, poor, outcome, in, both, acute, myeloid, leukemia, '(', 'AML)', and, acute, lymphoblastic, leukemia, patients])].
[sujeto(['Additionally,', high, 'BAALC', expression, occurs, in, 'glioblastoma,', 'melanoma,', and, childhood, gastrointestinal, stroma, 'tumors,']), verbo([suggesting]), complemento([an, oncogenic, role, for, 'BAALC'])].
[sujeto(['We', show, that, 'BAALC', overexpression, occurs, in, the, presence, of, the, 'T', allele, of, 'SNP', 'rs62527607[GT],', which, creates, a]), verbo([binding]), complemento([site, for, the, activating, 'RUNX1', transcription, factor, in, the, 'BAALC', promoter, region])].
[sujeto(['Thus,', we, identify, a, heritable, genomic, feature, predisposing, to, overexpression, of, an, 'oncogene,', thereby, possibly]), verbo([leading]), complemento([to, enhanced, 'AML', leukemogenesis])].
[sujeto(['Our', findings, further]), verbo([suggest]), complemento([that, genomic, variants, might, become, useful, tools, in, the, practice, of, personalized, medicine])].
[sujeto(['However,', the, 'cis-regulatory', mechanisms]), verbo([modulating]), complemento([the, 'Runx1', gene, expression, remain, to, be, elucidated])].
[sujeto(['Herewith,', we]), verbo([report]), complemento([the, identification, of, an, intronic, 'Runx1', 'enhancer,', 'Runx1', +, 24, mouse, conserved, noncoding, element, '(', 'mCNE),', using, a, combinatorial, in, silico, approach, involving, comparative, genomics, and, retroviral, integration, sites, mapping])].
[sujeto(['The', 'Runx1', +, 24, mCNE, was]), verbo([found]), complemento([to, possess, 'hematopoietic-specific', enhancer, activity, in, both, zebrafish, and, mouse, models])].
[sujeto([1, is, critical, for, multiple, hematopoietic, 'lineages,', but, different, leukocyte, types]), verbo([require]), complemento([strictly, distinct, patterns, of, 'PU'])].
[sujeto([1, is]), verbo([required]), complemento([early, for, 'T-cell', lineage, development, but, then, must, be, repressed, by, a, 'stage-specific', mechanism, correlated, with, commitment])].
[sujeto(['Other', lineages]), verbo([require]), complemento(['steady,', low, expression, or, upregulation])].
[sujeto(['However,', the, 'URE', is, dispensable, for, most, 'Sfpi1', downregulation, in, early, 'T', 'cells,', and, we, show, that, it]), verbo([retains]), complemento([enhancer, activity, in, immature, 'T-lineage', cells, even, where, endogenous, 'Sfpi1', is, repressed])].
[sujeto(['We', now, present, evidence, for, another, complex, of]), verbo([conserved]), complemento([noncoding, elements, that, mediate, 'discrete,', 'cell-type-specific', regulatory, features, of, 'Sfpi1,', including, a, myeloid, 'cell-specific', activating, element, and, a, 'separate,', 'pro-T-cell-specific', silencer, element])].
[sujeto(['T-cell-specific', repression]), verbo([requires]), complemento(['Runx1', acting, through, multiple, nonconsensus, sites, in, the, silencer, core])].
[sujeto(['These', newly, characterized, sites]), verbo([recruit]), complemento(['Runx1', binding, in, early, 'T', cells, in, vivo, and, define, a, functionally, specific, scaffold, for, 'dose-dependent,', 'Runx-mediated', repression])].
[sujeto(['The', 'Eight-Twenty-One', '(', 'ETO)']), verbo([nuclear]), complemento(['co-repressor', gene, belongs, to, the, 'ETO', homologue, family, also, containing, 'Myeloid', 'Translocation', 'Gene', on, chromosome, 16, '(', 'MTG16)', and, myeloid, translocation, 'Gene-Related', protein, 1, '(', 'MTGR1)'])].
[sujeto(['Normal', functions, of, 'ETO', homologues]), verbo([have]), complemento([as, yet, not, been, examined])].
[sujeto(['Strong', 'ETO', promoter, activity, was, specifically, observed, upon, transfection, of, a, promoter, reporter, construct, into, 'erythroid/megakaryocytic', 'cells,', which]), verbo([have]), complemento([endogeneous, 'ETO', gene, activity])].
[sujeto(['An', evolutionary]), verbo([conserved]), complemento([region, of, 228, bp, revealed, potential, 'cis-elements', involved, in, transcription, of, 'ETO'])].
[sujeto(['Disruption', of, the, evolutionary]), verbo([conserved]), complemento(['GATA', -, 636, consensus, binding, site, repressed, transactivation, and, disruption, of, the, 'ETS1', -, 705, consensus, binding, site, enhanced, activity, of, the, 'ETO', promoter])].
[sujeto(['The', promoter, was]), verbo([stimulated]), complemento([by, overexpression, of, 'GATA-1', into, 'erythroid/megakaryocytic', cells])].
[sujeto(['Electrophoretic', mobility, shift, assay, with, 'erythroid/megakaryocytic', cells, showed, specific]), verbo([binding]), complemento([of, 'GATA-1', to, the, 'GATA', -, 636, site])].
[sujeto(['Furthermore,', results, from, chromatin, immunoprecipitation, showed, 'GATA-1']), verbo([binding]), complemento([in, vivo, to, the, conserved, region, of, the, 'ETO', promoter, containing, the, -, 636, site])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, the, 'GATA', -, 636, site, may, have, a, role, in, activation, of, the, 'ETO', gene, activity, in, cells, with, 'erythroid/megakaryocytic', potential])].
[sujeto(['Leukemia']), verbo([associated]), complemento(['AML1-ETO', strongly, suppressed, an, 'ETO', promoter, reporter, in, 'erythroid/megakaryocytic', cells])].
[sujeto(['We', demonstrate, that, the, 'GATA-1', transcription, factor]), verbo([binds]), complemento([and, transactivates, the, 'ETO', proximal, promoter, in, an, 'erythroid/megakaryocytic-specific', manner])].
[sujeto(['G2', accumulation, '(', 'G2A)', is, a, 'G-protein', coupled, 'receptor,']), verbo([activated]), complemento([by, several, ligands, and, 'stimuli,', such, as, lysophosphatidylcholine, '(', 'LPC),', extracellular, low, pH, and, oxidized, phospholipids, including, 9, -, and, 13, -, hydroxyoctadecadienoic, 'acid,', and, has, been, implicated, in, mediating, inflammatory, process, under, oxidative, conditions])].
[sujeto(['In', the, course, of, the, 'analysis,', we]), verbo([found]), complemento([that, two, transcriptional, 'variants,', 'hG2A-a', and, -, 'b,', are, produced, by, alternative, 'splicing,', resulting, in, the, production, of, 'N-terminal', different, hG2A, proteins, with, similar, sensitivity, to, low, pH, and, 'LPC'])].
[sujeto(['Using', a, monocytic, cell, line, 'THP-1', as, a, 'model,', transcription, of, hG2A, was, precisely, 'examined,', and, we, demonstrated, that, it, is, dependent, both, on, the, chromatin, structure, around, 'TSS,', and, on, the]), verbo([binding]), complemento([of, the, transcription, factors, '(', 'c/EBPalpha', and, 'beta,', 'Runx1', and, 'Pu'])].
[sujeto(['However,', the, molecular, mechanisms]), verbo([regulating]), complemento([first, the, priming, and, then, maintenance, of, gene, expression, within, one, developmental, pathway, are, essentially, unknown])].
[sujeto(['The', hematopoietic, system, represents, a, powerful, experimental, model, to, address, these, questions, and, here, we]), verbo([have]), complemento([focused, on, a, regulatory, circuit, playing, a, central, role, in, 'myelopoiesis:', the, transcription, factor, 'PU'])].
[sujeto([1, ',', its]), verbo([target]), complemento([gene, 'colony-stimulating-factor', 1, receptor, '(', 'Csf1r),', and, key, upstream, regulators, such, as, 'RUNX1'])].
[sujeto(['We']), verbo([find]), complemento([that, during, 'ontogeny,', chromatin, unfolding, precedes, the, establishment, of, active, histone, marks, and, the, formation, of, stable, transcription, factor, complexes, at, the, 'Pu'])].
[sujeto([1, locus, and, we, show, that, chromatin, remodeling, is]), verbo([mediated]), complemento([by, the, transient, binding, of, 'RUNX1', to, 'Pu'])].
[sujeto(['By', 'contrast,', chromatin, reorganization, of, 'Csf1r']), verbo([requires]), complemento([prior, expression, of, 'PU'])].
[sujeto(['Once', the, full, hematopoietic, program, is, 'established,', stable, transcription, factor, complexes, and, active, chromatin, can, be]), verbo([maintained]), complemento([without, 'RUNX1'])].
[sujeto(['Recently,', we, identified, the, 'Runx1', +, 23, enhancer, that]), verbo([targets]), complemento([reporter, gene, expression, to, the, first, emerging, 'HSCs', of, the, mouse, embryo, when, linked, to, the, heterologous, hsp68, promoter])].
[sujeto(['Endogenous', 'Runx1', is]), verbo([transcribed]), complemento([from, 2, alternative, 'promoters,', 'P1', and, 'P2'])].
[sujeto(['Here,', we, examined, the, in, vivo, 'cis-regulatory', potential, of, these, alternative, promoters, and, asked, whether, they]), verbo([act]), complemento([with, and, contribute, to, the, spatiotemporal, specific, expression, of, the, 'Runx1', +, 23, enhancer])].
[sujeto(['Our', results, firmly, establish, 'that,', in, contrast, to, zebrafish, 'runx1,', mouse, 'Runx1', promoter, sequences, do, not]), verbo([confer]), complemento([any, hematopoietic, specificity, in, transgenic, embryos])].
[sujeto(['Yet,', both, mouse, promoters]), verbo([act]), complemento([with, the, +, 23, enhancer, to, drive, reporter, gene, expression, to, sites, of, 'HSC', emergence, and, 'colonization,', in, a, +, 23, -, specific, pattern])].
[sujeto(['The', 'Runt', homology, domain, '(', 'Runx)', defines, a, metazoan, family, of, 'sequence-specific', transcriptional, regulatory, proteins, that, are, critical, for, animal, development, and, causally]), verbo([associated]), complemento([with, a, variety, of, mammalian, cancers])].
[sujeto(['The']), verbo([sea]), complemento([urchin, 'Runx', gene, 'SpRunt-1', is, expressed, throughout, the, blastula, stage, 'embryo,', and, is, required, globally, during, embryogenesis, for, cell, survival, and, differentiation])].
[sujeto(['Depletion', of, 'SpRunt-1', by, morpholino, 'antisense-mediated', knockdown]), verbo([causes]), complemento([a, blastula, stage, deficit, in, cell, 'proliferation,', as, shown, by, bromodeoxyuridine, '(', 'BrdU)', incorporation, and, direct, cell, counts])].
[sujeto(['Chromatin', immunoprecipitation, '(', 'ChIP)', indicates, that, 'Runx']), verbo([target]), complemento([sites, within, 5, '\'', sequences, flanking, 'cyclinD,', wnt6, and, wnt8, are, directly, bound, by, 'SpRunt-1', protein, at, late, blastula, stage])].
[sujeto(['Furthermore,', experiments, using, a, green, fluorescent, protein, '(', 'GFP)', reporter, transgene, show, that, the, 'blastula-stage', operation, of, a, 'cis-regulatory', module, previously, shown, to, be]), verbo([required]), complemento([for, wnt8, expression, '(', 'Minokawa', et, al])].
[sujeto(['Finally,', inhibitor, studies, and, immunoblot, analysis, show, that, 'SpRunt-1', protein, levels, are, negatively]), verbo([regulated]), complemento([by, glycogen, synthase, kinase, '(', 'GSK)-3'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'Runx', expression, and, 'Wnt', signaling, are, mutually, linked, in, a, feedback, circuit, that, controls, cell, proliferation, during, development])].
[sujeto(['The', transcription, factor, 'Runx1/AML1', is, an, important, regulator, of, hematopoiesis, and, is, critically]), verbo([required]), complemento([for, the, generation, of, the, first, definitive, hematopoietic, stem, cells, '(', 'HSCs)', in, the, major, vasculature, of, the, mouse, embryo])].
[sujeto(['In', this, 'study,', we, used, a, combination, of, comparative, genomics, and, chromatin, analysis, to, identify, a, highly]), verbo([conserved]), complemento([531, -, bp, enhancer, located, at, position, +, 23.5, in, the, first, intron, of, the, 224, -, kb, mouse, 'Runx1', gene])].
[sujeto(['Transcription', factor]), verbo([binding]), complemento([in, vivo, and, analysis, of, the, mutated, enhancer, in, transient, transgenic, mouse, embryos, implicate, 'Gata2', and, 'Ets', proteins, as, critical, factors, for, its, function])].
[sujeto(['We', also, show, that, the, 'SCL/Lmo2/Ldb-1', complex, is]), verbo([recruited]), complemento([to, the, enhancer, in, vivo])].
[sujeto(['Importantly,', transplantation, experiments, demonstrate, that, the, intronic, 'Runx1', enhancer]), verbo([targets]), complemento([all, definitive, 'HSCs', in, the, mouse, 'embryo,', suggesting, that, it, functions, as, a, crucial, 'cis-regulatory', element, that, integrates, the, 'Gata,', 'Ets,', and, 'SCL', transcriptional, networks, to, initiate, 'HSC', generation])].
[sujeto([1, is]), verbo([activated]), complemento([in, hematopoietic, stem, cells, and, is, expressed, in, mast, 'cells,', 'B', 'cells,', 'granulocytes,', and, macrophages, but, is, switched, off, in, 'T', cells])].
[sujeto(['Many', of, the, transcription, factors]), verbo([regulating]), complemento(['Pu'])].
[sujeto([1]), verbo([have]), complemento([been, 'identified,', but, little, is, known, about, how, they, organize, 'Pu'])].
[sujeto([1, was]), verbo([bound]), complemento([by, a, set, of, transcription, factors, different, from, that, in, myeloid, cells, and, adopted, alternative, chromatin, architectures])].
[sujeto([1, chromatin, at, the, 'URE', was, open, and, the, same, transcription, factor]), verbo([binding]), complemento([sites, were, occupied, as, in, 'B', cells])].
[sujeto(['The', transcription, factor, 'RUNX1', was]), verbo([bound]), complemento([to, the, 'URE', in, precursor, 'cells,', but, binding, was, 'down-regulated', in, maturing, cells])].
[sujeto([1, -]), verbo([expressing]), complemento([cells])].
[sujeto(['Our', results]), verbo([provide]), complemento([important, insights, into, how, 'overlapping,', but, 'different,', sets, of, transcription, factors, program, 'tissue-specific', chromatin, structures, in, the, hematopoietic, system])].
[sujeto(['Mutations', in, mouse, and, human, 'Nfe2,', 'Fli1', and, 'Runx1']), verbo([cause]), complemento([thrombocytopenia])].
[sujeto(['Enhancers', with, 'H3K4me2-marked', nucleosome, pairs, were, most, enriched, for, 'NF-E2,', 'FLI', and, 'RUNX', sequence, 'motifs,']), verbo([suggesting]), complemento([that, this, 'TF', triad, controls, much, of, the, late, 'MK', program])].
[sujeto(['ChIP-seq', revealed, 'NF-E2', occupancy, near, previously, implicated]), verbo([target]), complemento(['genes,', whose, expression, is, compromised, in, 'Nfe2-null', 'cells,', and, many, other, genes, that, become, active, late, in, 'MK', differentiation])].
[sujeto(['FLI', and, 'RUNX', were, also, the, motifs, most, enriched, near, 'NF-E2']), verbo([binding]), complemento([sites, and, 'ChIP-seq', implicated, 'FLI1', and, 'RUNX1', in, activation, of, late, 'MK,', including, 'NF-E2-dependent,', genes])].
[sujeto(['Histones', showed, limited, activation, in, regions, of, single, 'TF', 'binding,', while, enhancers, that]), verbo([bind]), complemento(['NF-E2', and, either, 'RUNX1,', 'FLI1', or, both, 'TFs', gave, the, highest, signals, for, 'TF', occupancy, and, 'H3K4me2;', these, enhancers, associated, best, with, genes, activated, late, in, 'MK', maturation])].
[sujeto(['These', findings]), verbo([provide]), complemento([a, rich, dataset, of, 'TF', and, chromatin, dynamics, in, primary, 'MK', and, explain, why, individual, 'TF', losses, cause, thrombopocytopenia])].
[sujeto(['CCR3', is, a, chemokine, receptor, that]), verbo([mediates]), complemento([the, accumulation, of, allergic, inflammatory, 'cells,', including, eosinophils, and, 'Th2', 'cells,', at, inflamed, sites])].
[sujeto([1, on, transcription, of, the, gene, in, 'EoL-1', eosinophilic, cells, and, 'Jurkat', 'T', 'cells,', both, of, which]), verbo([expressed]), complemento([functional, surface, 'CCR3', and, these, two, transcription, factors])].
[sujeto([1, siRNA, resulted, in, a, modest]), verbo([decrease]), complemento([in, 'CCR3', reporter, activity, in, both, cell, 'types,', compared, with, transfection, of, 'GATA-1', siRNA])].
[sujeto(['Cotransfection', of, the, two, siRNAs]), verbo([led]), complemento([to, inhibition, in, an, additive, manner])].
[sujeto(['EMSA', analysis, showed, that, 'RUNX1,', in, 'particular,']), verbo([bound]), complemento([to, its, binding, motifs])].
[sujeto([1, -]), verbo([binding]), complemento([sites, exhibited, reduced, reporter, activities])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'RUNX1', and, 'PU'])].
[sujeto([1]), verbo([participate]), complemento([in, transcriptional, regulation, of, the, 'CCR3', gene])].
[sujeto(['Although', at, a, terminal, differentiation, 'stage,', hypertrophic, chondrocytes]), verbo([have]), complemento([been, implicated, as, the, principal, engine, of, bone, growth])].
[sujeto(['Abnormal', chondrocyte, hypertrophy]), verbo([has]), complemento([been, seen, in, many, skeletal, dysplasia, and, osteoarthritis])].
[sujeto(['However,', how, the, type, 'X', collagen, gene, is]), verbo([regulated]), complemento([during, chondrocyte, hypertrophy, has, not, been, fully, elucidated])].
[sujeto(['We']), verbo([have]), complemento([recently, demonstrated, that, 'Runx2', interaction, with, a, 150, -, bp, mouse, 'Col10a1', 'cis-enhancer', is, required, but, not, sufficient, for, its, hypertrophic, 'chondrocyte-specific', reporter, expression, in, transgenic, 'mice,', suggesting, requirement, of, additional, 'Col10a1', regulators])].
[sujeto(['In', this, 'study,', we]), verbo([report]), complemento([in, silico, sequence, analysis, of, this, 150, -, bp, enhancer, and, identification, of, its, multiple, binding, 'factors,', including, 'AP1,', 'MEF2,', 'NFAT,', 'Runx1', and, 'TBX5'])].
[sujeto(['We']), verbo([have]), complemento([also, performed, mass, spectrometry, analysis, and, detected, 'EF1-alpha,', 'Fus,', 'GdF7', and, 'Runx3', as, components, of, the, specific, complex, formed, by, the, 'cis-enhancer', and, nuclear, extracts, from, hypertrophic, 'MCT', '(', mouse, chondrocytes, immortalized, with, large, 'T', 'antigen)', cells, that, express, 'Col10a1', abundantly])].
[sujeto(['Notably,', some, of, the, candidate, genes, are, differentially]), verbo([expressed]), complemento([in, hypertrophic, 'MCT', cells, and, have, been, associated, with, chondrocyte, hypertrophy, and, 'Runx2,', an, indispensible, 'Col10a1', regulator])].
[sujeto(['We', identified, a, 'robust,', 'genome-wide', mechanism, of, 'MEG-specific', lineage, priming, by, a, previously, described, 'stem/progenitor', 'cell-expressed', transcription, factor, heptad, '(', 'GATA2,', 'LYL1,', 'TAL1,', 'FLI1,', 'ERG,', 'RUNX1,', 'LMO2)']), verbo([binding]), complemento([to, 'MEG-associated', 'cis-regulatory', modules, '(', 'CRMs)', in, multipotential, progenitors])].
[sujeto(['This', is, followed, by, 'genome-wide', 'GATA', factor, switching, that]), verbo([mediates]), complemento([further, induction, of, 'MEG-specific', genes, following, lineage, commitment])].
[sujeto(['Our', findings]), verbo([reveal]), complemento([important, new, insights, into, how, 'ERY', and, 'MEG', lineages, arise, from, a, common, bipotential, progenitor, via, overlapping, and, divergent, functions, of, shared, hematopoietic, transcription, factors])].
[sujeto(['During', the, last, 'decades,', many, studies]), verbo([have]), complemento([investigated, the, transcriptional, and, epigenetic, regulation, of, lineage, decision, in, the, hematopoietic, system])].
[sujeto(['These', efforts]), verbo([led]), complemento([to, a, model, in, which, extrinsic, signals, and, intrinsic, cues, establish, a, permissive, chromatin, context, upon, which, a, regulatory, network, of, transcription, factors, and, epigenetic, modifiers, act, to, guide, the, differentiation, of, hematopoietic, lineages])].
[sujeto(['These', networks, include, 'lineage-specific', factors, that, further, modify, the, epigenetic, landscape, and]), verbo([promote]), complemento([the, generation, of, specific, cell, types])].
[sujeto(['The', process, of, 'B', lymphopoiesis]), verbo([requires]), complemento([a, set, of, transcription, 'factors,', including, 'Ikaros,', 'PU'])].
[sujeto(['The', expression, of, 'EBF1', is, initiated, by, the, combined, action, of, 'E2A', and, 'FoxO1,', and, it, is, further]), verbo([enhanced]), complemento([and, maintained, by, several, positive, feedback, loops, that, include, 'Pax-5', and, 'IL-7', signaling])].
[sujeto(['EBF1']), verbo([acts]), complemento([in, concert, with, 'Ikaros,', 'PU'])].
[sujeto(['EBF1', and, 'Pax-5', also, collaborate, to]), verbo([repress]), complemento([alternative, cell, fates, and, lock, cells, into, the, 'B-lineage', fate])].
[sujeto(['In', addition, to, the, functions, of, 'EBF1', in, establishing, and]), verbo([maintaining]), complemento(['B-cell', 'identity,', 'EBF1', is, required, to, coordinate, differentiation, with, cell, proliferation, and, survival])].
[sujeto(['Through', the, use, of, alternative, promoters, 'and/or', alternative, 'splicing,', each, of, the, elephant, shark, 'Runx', genes]), verbo([expresses]), complemento([multiple, isoforms, similar, to, their, orthologs, in, human, and, other, bony, vertebrates])].
[sujeto(['The', syntenic, blocks, of, genes, at, the, elephant, shark, 'Runx', gene, loci, are, highly]), verbo([conserved]), complemento([in, 'human,', but, represented, by, shorter, conserved, blocks, in, zebrafish, indicating, a, higher, degree, of, rearrangements, in, this, teleost, fish])].
[sujeto(['Analysis', of, promoter, regions, revealed, conservation, of]), verbo([binding]), complemento([sites, for, transcription, 'factors,', including, two, tandem, binding, sites, for, 'Runx', that, are, totally, conserved, in, the, distal, promoter, regions, of, elephant, shark, 'Runx1-3'])].
[sujeto(['Several']), verbo([conserved]), complemento([noncoding, elements, '(', 'CNEs),', which, are, putative, 'cis-regulatory', 'elements,', and, miRNA, binding, sites, were, identified, in, the, elephant, shark, and, human, 'Runx', gene, loci])].
[sujeto(['Some', of, these, 'CNEs', and, miRNA]), verbo([binding]), complemento([sites, are, absent, in, teleost, fishes, such, as, zebrafish, and, fugu])].
[sujeto(['In', 'summary,', our, analysis]), verbo([reveals]), complemento([that, the, genomic, organization, and, expression, profiles, of, 'Runx', genes, were, already, complex, in, the, common, ancestor, of, jawed, vertebrates])].
[sujeto(['MicroRNAs', '(', 'miRs)']), verbo([have]), complemento([emerged, as, critical, modulators, of, immune, 'responses,', but, little, is, known, about, their, transcriptional, regulation, and, tissue, specificity])].
[sujeto(['miR-142', is, specifically]), verbo([expressed]), complemento([in, hematopoietic, tissues, and, plays, an, important, role, in, regulating, immunity])].
[sujeto([1, ',', 'C/EBPβ,', and, 'Runx1', transcription, factor]), verbo([binding]), complemento([sites, are, conserved, and, constitutively, occupied, by, the, respective, transcription, factors, in, the, 'miR-142', gene, promoter, only, in, the, hematopoietic, cells])].
[sujeto(['Furthermore,', 'TLR4', stimulation]), verbo([enhanced]), complemento(['miR-155', whereas, experiments, with, knockdown, and, mimic, expression, of, 'miR-155', demonstrated, that, 'miR-155', negatively, regulates, 'miR-142-3p', expression, by, targeting, 'PU'])].
[sujeto(['Thus,', 'TLR4', stimulation]), verbo([represses]), complemento(['PU'])].
[sujeto([1, ',', resulting, in, downregulation, of, 'miR-142', and]), verbo([increased]), complemento([expression, of, 'IL-6'])].
[sujeto(['These', results, collectively]), verbo([reveal]), complemento([the, direct, 'cis-acting', sequences, of, 'miR-142', specific, promoter, and, that, transcription, factor, 'PU'])].
[sujeto(['The', gene, encoding, the, receptor, for, macrophage, 'colony-stimulating', factor, '(', 'CSF-1R)', is]), verbo([expressed]), complemento([exclusively, in, cells, of, the, myeloid, lineages, as, well, as, trophoblasts])].
[sujeto(['A']), verbo([conserved]), complemento([element, in, the, second, 'intron,', 'Fms-Intronic', 'Regulatory', 'Element', '(', 'FIRE),', is, essential, for, 'macrophage-specific', transcription, of, the, gene])].
[sujeto(['However,', the, molecular, details, of, how, 'FIRE', activity, is]), verbo([regulated]), complemento([and, how, it, impacts, the, 'Csf1r', promoter, have, not, been, characterised])].
[sujeto(['Here', we, show, that, agents, that, 'down-modulate', 'Csf1r', mRNA, transcription]), verbo([regulated]), complemento([promoter, activity, altered, the, occupancy, of, key, 'FIRE', 'cis-acting', elements, including, 'RUNX1,', 'AP1,', and, 'Sp1', binding, sites])].
[sujeto(['We', demonstrate, that, 'FIRE']), verbo([acts]), complemento([as, an, 'anti-sense', promoter, in, macrophages, and, reversal, of, 'FIRE', orientation, within, its, native, context, greatly, reduced, enhancer, activity, in, macrophages])].
[sujeto(['These', results, demonstrate, that, 'FIRE', is, an, 'orientation-specific']), verbo([transcribed]), complemento([enhancer, element])].
[sujeto(['Chromosome', anomalies, were]), verbo([found]), complemento([in, the, 'BM', of, three, 'patients,', without, any, morphological, evidence, of, 'MDS:', 1, ')', an, acquired, complex, rearrangement, of, chromosome, 21, in, a, boy, with, severe, aplastic, anaemia, '(', 'SAA);', the, rearrangement, caused, the, loss, of, exons, 2, -, 8, of, the, 'RUNX1', gene, with, subsequent, hypoexpression])].
[sujeto([2, ')', a, constitutional, complex, rearrangement, of, chromosome, 21, in, a, girl, with, congenital, 'thrombocytopenia;', the, rearrangement]), verbo([led]), complemento([to, 'RUNX1', disruption, and, hypoexpression])].
[sujeto([3, ')', an, acquired, paracentric, inversion, of, chromosome, 1, ',', in, which, two, regions, at, the, breakpoints, were, shown, to, be, 'lost,', in, a, boy, with, aplastic, 'anaemia;', the, 'MPL', 'gene,', localized, in, chromosome, 1, short, arms, was, not, mutated, neither, 'disrupted,', but, its, expression, was, severely, 'reduced:', we, postulate, that, the, aplastic, anaemia, was, due, to, position, effects]), verbo([acting]), complemento([both, in, cis, and, in, 'trans,', and, causing, 'Congenital', 'Amegakaryocytic', 'Thrombocytopenia', '(', 'CAMT)'])].
[sujeto(['The', anomaly, may, be, either, acquired, or, 'constitutional,', and, it, may]), verbo([act]), complemento([by, 'deletion/disruption', of, the, 'gene,', or, by, position, effects])].
[sujeto(['Expression', of, 'AML1', is]), verbo([regulated]), complemento([at, the, level, of, transcription, by, two, 'promoters,', distal, '(', 'D)', and, proximal, '(', 'P),', that, give, rise, to, mRNAs, bearing, two, distinct, 5, '\'', untranslated, regions, '(', 5, '\'', 'UTRs)', '(', 'D-UTR', and, 'P-UTR)'])].
[sujeto(['Here', we, show, that, these, 5, '\'', 'UTRs']), verbo([act]), complemento([as, translation, regulators, in, vivo])].
[sujeto(['Transfections', and, in, vitro, assays, with, bicistronic, constructs, demonstrate, that, the, 'D-UTR']), verbo([mediates]), complemento(['cap-dependent', translation, whereas, the, 'P-UTR', mediates, 'cap-independent', translation, and, contains, a, functional, internal, ribosome, entry, site, '(', 'IRES)'])].
[sujeto(['The', 'IRES-containing', bicistronic, constructs, are, more, active, in, hematopoietic, cell, lines, that, normally]), verbo([express]), complemento([the, 'P-UTR-containing', mRNAs])].
[sujeto(['Furthermore,', we, show, that, the, 'IRES-dependent', translation]), verbo([increases]), complemento([during, megakaryocytic, differentiation, but, not, during, erythroid, 'differentiation,', of, 'K562', cells])].
[sujeto(['These', results, strongly]), verbo([suggest]), complemento([that, the, function, of, the, 'P-UTR', 'IRES-dependent', translation, in, vivo, is, to, tightly, regulate, the, translation, of, 'AML1', mRNAs])].
[sujeto(['The', data, show, that, 'AML1', expression, is]), verbo([regulated]), complemento([through, usage, of, alternative, promoters, coupled, with, 'IRES-mediated', translation, control])].
[sujeto(['Myeloperoxidase', '(', 'MPO)', is, an, important, antibacterial, enzyme]), verbo([found]), complemento([only, in, granulocytes, and, monocytes])].
[sujeto(['The', human, 'MPO', gene, is]), verbo([transcribed]), complemento([early, during, myelogenesis, but, 'MPO', 'RNA', synthesis, ceases, at, the, end, of, the, promyelocyte, stage, of, myeloid, maturation])].
[sujeto([the, enhancer]), verbo([confers]), complemento(['TPA-', or, 'DMSO-responsiveness', upon, either, endogenous, or, exogenous, promoters])].
[sujeto(['Gelshift', competition, and, supershift, experiments, demonstrated, the]), verbo([binding]), complemento([of, the, alpha, subunit, of, the, transcription, factor, 'AML1', to, this, site, in, 'HL-60', cells])].
[sujeto(['Vascular', calcification, is, an, active, deposition, process, of, calcium, phosphate, which, resembles, bone, formation, and, is, highly]), verbo([regulated]), complemento([by, 'osteoblast-like', cells])].
[sujeto(['In', study, 'III,', we, investigated, whether, 'A7r5', aortic, smooth, muscle, cells, were]), verbo([induced]), complemento([into, 'osteoblast-like', phenotypes, by, incubation, with, or, without, 80, 'μg/mL', of, 'RAW264'])].
[sujeto(['Both', animal, and, cell, studies, consistently, demonstrated, that, the, 'CML/RAGE', axis, may, first, initiate, the, apoptosis, of, macrophages, in, atherosclerotic, lesions, and, then]), verbo([induce]), complemento(['BMP-2-cbfα1-ALP-calcification', cascade, in, a, 'high-lipid,', 'apoptosis-coexisting', environment])].
[sujeto(['The', 'CML/RAGE', axis, may, play, an, important, role, in, atherosclerotic, calcification, of, diabetes, through, the, mechanism, that]), verbo([induces]), complemento([the, apoptosis, of, macrophages, followed, by, the, osteogenic, differentiation, of, aortic, smooth, muscle, cells])].
[sujeto(['ETV6-RUNX1', fusion, '[', 't(12;21)(p13;q22)]', occurs, in, 25, '%', of, childhood, 'B-cell', precursor, acute, lymphoblastic, leukemia, '(', 'BCP-ALL)', and, is]), verbo([associated]), complemento([with, a, favorable, outcome])].
[sujeto(['Additional', abnormalities]), verbo([involving]), complemento(['der(21)t(12;21)', and, nonrearranged, chromosome, 12, are, well, characterized, but, aberrations, involving, the, 'der(12)t(12;21)', have, rarely, been, described])].
[sujeto(['This']), verbo([led]), complemento([to, the, formation, of, the, following, 'chromosome:', 'der(12)(21qter→21q22'])].
[sujeto(['In', 'conclusion,', this, study]), verbo([has]), complemento([defined, novel, abnormalities, in, 'ETV6-RUNX1', 'BCP-ALL,', which, implicate, new, genes, involved, in, leukemogenesis])].
[sujeto(['We', further, demonstrated, that, four, of, these, 'genes,', 'CXCR3,', 'PGDS,', 'GPR98', and, 'CBS,', consistently]), verbo([responded]), complemento([to, cycloleucine, treatment, in, additional, experiments, over, a, range, of, concentrations])].
[sujeto(['We', carried, out, 'gene-specific', 'DNA', methylation, analysis, on, five, 'genes,', including, 'CBS,', and]), verbo([found]), complemento([no, evidence, that, 'DNA', methylation, changes, were, mediating, the, gene, expression, changes, observed])].
[sujeto(['This', indicates, that, apart, from, their, role, in, the, immune, 'response,', it, is, likely, that, these, gene, products, may, also]), verbo([have]), complemento([a, role, to, play, in, the, cellular, response, to, folate, status])].
[sujeto(['The', 'Wnt/β-catenin', signaling, pathway]), verbo([has]), complemento([a, crucial, role, in, embryonic, 'development,', stem, cell, maintenance, and, human, disease])].
[sujeto(['By', screening, a, synthetic, chemical, library, of, lycorine, 'derivatives,', we, identified, 4, -, 'ethyl-5-methyl-5,6-dihydro-[1,3]dioxolo[4,5-j]phenanthridine', '(', 'HLY78)', as, an, activator, of, the, 'Wnt/β-catenin', signaling, 'pathway,', which]), verbo([acts]), complemento([in, a, 'Wnt', 'ligand-dependent', manner])].
[sujeto(['HLY78']), verbo([targets]), complemento([the, 'DIX', domain, of, 'Axin', and, potentiates, the, 'Axin-LRP6', 'association,', thus, promoting, 'LRP6', phosphorylation, and, 'Wnt', signaling, transduction])].
[sujeto(['Moreover,', we, identified, the, critical, residues, on, 'Axin', for, 'HLY78']), verbo([binding]), complemento([and, showed, that, 'HLY78', may, weaken, the, autoinhibition, of, 'Axin'])].
[sujeto(['In', 'addition,', 'HLY78']), verbo([acts]), complemento([synergistically, with, 'Wnt', in, the, embryonic, development, of, zebrafish, and, increases, the, expression, of, the, conserved, hematopoietic, stem, cell, '(', 'HSC)', 'markers,', runx1, and, 'cmyb,', in, zebrafish, embryos])].
[sujeto(['Collectively,', our, study, not, only]), verbo([provides]), complemento([new, insights, into, the, regulation, of, the, 'Wnt/β-catenin', signaling, pathway, by, a, 'Wnt-specific', small, molecule, but, also, will, facilitate, therapeutic, 'applications,', such, as, 'HSC', expansion])].
[sujeto(['Although', 'Hoxa9', and, 'Meis1', can]), verbo([bind]), complemento(['DNA', as, 'heterodimers,', both, can, also, heterodimerize, with, 'Pbx', proteins])].
[sujeto(['Thus,', while, their, coactivation, may, result, from, the, necessity, to]), verbo([bind]), complemento([promoters, as, 'heterodimers,', it, may, also, result, from, the, necessity, of, altering, independent, biochemical, pathways, that, cooperate, to, generate, 'AML,', either, as, monomers, or, as, heterodimers, with, 'Pbx', proteins])].
[sujeto(['Here', we, demonstrate, that, constitutive, expression, of, 'Hoxa9', in, primary, murine, marrow, immortalizes, a, late, myelomonocytic, 'progenitor,']), verbo([preventing]), complemento([it, from, executing, terminal, differentiation, to, granulocytes, or, monocytes, in, the, presence, of, 'granulocyte-macrophage', 'colony-stimulating', factor, '(', 'GM-CSF)', or, 'interleukin-3'])].
[sujeto(['The', 'Hoxa9-immortalized', progenitor, exhibited, a, promyelocytic, transcriptional, 'profile,']), verbo([expressing]), complemento(['PU'])].
[sujeto([1, ',', 'AML1,', 'c-Myb,', 'C/EBP', 'alpha,', and, 'C/EBP', epsilon, as, well, as, their]), verbo([target]), complemento(['genes,', the, receptors, for, 'GM-CSF,', 'G-CSF,', and, 'M-CSF', and, the, primary, granule, proteins, myeloperoxidase, and, neutrophil, elastase])].
[sujeto(['G-CSF', obviated, the, differentiation, block, of, 'Hoxa9,']), verbo([inducing]), complemento([neutrophilic, differentiation, with, accompanying, expression, of, neutrophil, gelatinase, 'B', and, upregulation, of, gp91phox])].
[sujeto(['M-CSF', also, obviated, the, differentiation, 'block,']), verbo([inducing]), complemento([monocytic, differentiation, with, accompanying, expression, of, the, macrophage, 'acetyl-low-density', lipoprotein, scavenger, receptor, and, 'F4/80', antigen])].
[sujeto(['Therefore,', 'Hoxa9', evokes, a, 'cytokine-selective', block, in, differentiation, by, a, mechanism, that, does, not]), verbo([require]), complemento(['Meis', gene, expression, or, interaction, with, 'Pbx', through, the, 'PIM'])].
[sujeto(['The', 't(16;21)(q24;q22)', translocation, is, a, rare, but, recurrent, chromosomal, abnormality]), verbo([associated]), complemento([with, 'therapy-related', myeloid, malignancies, and, a, variant, of, the, 't(8;21)', translocation, in, which, the, 'AML1', gene, on, chromosome, 21, is, rearranged])].
[sujeto(['Here', we]), verbo([report]), complemento([the, molecular, definition, of, this, chromosomal, aberration, in, four, patients])].
[sujeto(['The', 'AML1-CBFbeta', transcription, factor, complex, is, essential, for, the, definitive, hematopoiesis, of, all, lineages, and, is, the, most, frequent]), verbo([target]), complemento([of, chromosomal, rearrangements, in, human, leukemia])].
[sujeto(['In', the, 't(8;21)', translocation]), verbo([associated]), complemento([with, acute, myeloid, leukemia, '(', 'AML),', the, 'AML1(CBFA2/PEBP2alphaB)', gene, is, juxtaposed, to, the, 'MTG8(ETO/CDR)', gene])].
[sujeto(['We', show, here, that, the, resultant, 'AML1-MTG8', gene, product, specifically, and, strongly]), verbo([interacts]), complemento([with, an, 85, -, kDa, phosphoprotein])].
[sujeto(['Comparison', of, amino, acid, sequences, among, 'MTGR1,', 'MTG8,', and, 'Nervy', revealed, four, evolutionarily]), verbo([conserved]), complemento([regions, '(', 'NHR1', to, 'NHR4)'])].
[sujeto(['Ectopic', expression, of, 'AML1-MTG8', in, 'L-G', murine, myeloid, progenitor, cells]), verbo([inhibits]), complemento([differentiation, to, mature, neutrophils, and, induces, cell, proliferation, in, response, to, granulocyte, 'colony-stimulating', factor, '(', 'G-CSF)'])].
[sujeto(['Immunoprecipitation', analysis, indicates, that, this, region, is]), verbo([required]), complemento([for, 'AML1-MTG8', to, form, a, stable, complex, with, 'MTGR1'])].
[sujeto(['Overexpression', of, 'MTGR1']), verbo([stimulates]), complemento(['AML1-MTG8', to, induce, 'G-CSF-dependent', proliferation, of, 'L-G', cells, and, to, interfere, with, 'AML1-dependent', transcription])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'AML1-MTG8', could, function, as, a, complex, with, 'MTGR1', and, that, the, complex, might, be, important, in, promoting, leukemogenesis])].
[sujeto(['The', translocation, '(', 8, ;, 21, ')', is, a, chromosome, abnormality]), verbo([associated]), complemento([with, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['In', this]), verbo([report]), complemento([we, demonstrate, the, use, of, a, highly, specific, 'dual-colour', 'FISH', method, for, the, detection, of, 't(8;21)', on, interphase, cells])].
[sujeto(['AML1,', a, gene, encoding, a, protein, of, the, 'PEBP2/CBF', family, of, transcription, factors, is, disrupted, by, translocations]), verbo([associated]), complemento([with, human, leukemia])].
[sujeto(['In', the, 't(8;21)', acute, myelogenous, leukemia, '(', 'AML),', 'AML1', was]), verbo([found]), complemento([fused, to, a, gene, on, chromosome, 8, that, we, designated, 'CDR', '(', also, known, as, 'ETO', and, 'MTG8)'])].
[sujeto(['Signals', were]), verbo([found]), complemento([in, group, 1, on, chromosomes, 21, and, 21, 'q+,', in, group, 2, on, chromosomes, 21, ',', 21, 'q+', and, 8, 'q-', and, in, group, 3, on, chromosomes, 21, and, 8, 'q-'])].
[sujeto(['Thus', regardless, of, the, heterogeneity]), verbo([suggested]), complemento([by, 'FISH,', all, the, breakpoints, in, the, 'AML1', gene, were, clustered, in, the, same, intro, between, exons, 5, and, 6])].
[sujeto(['AML1', contains, a, region, of, sequence, homology, to, the, 'Drosophila', runt, gene, and, the, mouse, polyomavirus, enhancer]), verbo([binding]), complemento([protein, 'PEBP2', alpha, gene])].
[sujeto(['Deletion', of, the, long, arm, of, chromosome, 9, ',', 'del(9q),', is, a, recurring, chromosomal, aberration, in, acute, myeloid, leukemia, '(', 'AML)', that, is, frequently]), verbo([associated]), complemento([with, 't(8;21)'])].
[sujeto(['We']), verbo([found]), complemento([no, homozygous, loss, at, any, locus, tested])].
[sujeto(['The', results, of, our, studies, are, consistent, with, a, model, of, tumor, suppression]), verbo([mediated]), complemento([by, haploinsufficiency, of, critical, genes, in, 'del(9q)', 'AML'])].
[sujeto(['Tumor', cells, xenografted, could, not, be]), verbo([found]), complemento([in, other, tissues, than, in, inoculation, 'area,', and, still, harbored, the, specific, 't(8;21)', and, 'AML1-ETO', fusion, gene])].
[sujeto(['The', expression, of, 'CD11b', and, 'CD13', antigen, of, the, tumor, cells, was]), verbo([increased]), complemento([in, xenografted, mice, model, treated, with, 'PB', when, compared, with, the, control, \, '[', '(', 12.08, +, /, -, 1.02, ')', '%', and, '(', 54.91, +, /, -, 2.72, ')', '%', \, ']', ',', respectively, '(', 'P', &, 'lt;', 0.01, ')', ',', and, tumor, cells, showed, a, cell, cycle, arrest, with, increased, 'G(0)/G(1)-phase', cells, and, decreased, 'S-phase', cells])].
[sujeto(['PB']), verbo([inhibited]), complemento([the, growth, of, 'Kasumi-1', xenograft, tumor, by, inducing, tumor, cell, apoptosis, and, 'differentiation,', and, suppressing, its, angiogenesis, in, vivo])].
[sujeto([5, -, 'Aza-CdR', could, significantly]), verbo([enhance]), complemento([the, antitumor, activity, of, 'PB'])].
[sujeto(['A', 'proto-oncogene,', 'MTG8', '(', 'ETO/CDR),', is, disrupted, in, the, 't(8;21)', translocation]), verbo([associated]), complemento([with, acute, myeloid, 'leukemia,', and, the, gene, 'product,', 'MTG8,', is, a, phosphoprotein, capable, of, cell, transformation, in, concert, with, 'v-H-ras'])].
[sujeto(['To', obtain, insight, into, functional, regulation, of, 'MTG8', by, 'phosphorylation,', we, studied, protein, kinases, that]), verbo([interact]), complemento(['with,', and, 'phosphorylate,', 'MTG8', in, vitro])].
[sujeto(['Recombinant', 'MTG8', protein, was, first]), verbo([found]), complemento([to, be, associated, with, two, 'serine/threonine', protein, kinases, in, cell, extracts, from, both, 'HEL', cells, and, a, leukemic, cell, line, carrying, 't(8;21)'])].
[sujeto(['A', cytoplasmic, protein, kinase, of, 61, kDa, '(', 'MTG8N-kinase)']), verbo([phosphorylated]), complemento([the, 'amino-terminal', of, 'MTG8,', and, another, of, 52, kDa, '(', 'MTG8C-kinase)', phosphorylated, the, 'carboxyl-terminal', domain])].
[sujeto(['In', 'addition,', we, demonstrated, that, heat, shock, protein, 90, '(', 'HSP90)', specifically]), verbo([binds]), complemento([to, the, 'amino-terminal', domain, of, 'MTG8', in, vitro, and, in, vivo])].
[sujeto(['The', 't(8;21)', translocation]), verbo([associated]), complemento([with, acute, myeloid, leukemia, '(', 'AML)', disrupts, two, 'genes,', the, 'AML1', gene, also, known, as, the, core, binding, factor, 'A2', '(', 'CBFA2)', on, chromosome, 21, ',', and, a, gene, on, chromosome, 8, ',', hereafter, referred, to, as, 'MTG8,', but, also, known, as, 'CDR', and, 'ETO'])].
[sujeto(['Extensive', information, is, available, on, 'AML1,', a, member, of, the, 'CBF', family, of, transcription, 'factors,', containing, a, highly]), verbo([conserved]), complemento(['domain,', the, runt, 'box,', of, the, 'Drosophila', segmentation, gene, runt])].
[sujeto(['This', gene, is, essential, for, the, hematopoietic, development, and, is]), verbo([found]), complemento([disrupted, in, several, leukemias])].
[sujeto(['In', 'addition,', we]), verbo([found]), complemento([a, region, encompassing, aa, 443, -, 514, predicted, to, have, a, significant, propensity, to, form, coiled, coil, structures])].
[sujeto(['MTG8', displays, a, high, degree, of, similarity, with, 'nervy,', a, homeotic]), verbo([target]), complemento([gene, of, 'Drosophila,', expressed, in, the, nervous, system])].
[sujeto(['Human', and, mouse, 'wild-type', 'MTG8', are, also, highly]), verbo([expressed]), complemento([in, brain, relative, to, other, tissues])].
[sujeto(['Immunohistochemical', experiments, in, a, 12.5, -, 'day-old', mouse, embryo, clearly, showed, that, the, protein, was]), verbo([expressed]), complemento([in, the, neural, cells, of, the, developing, brain, and, the, spinal, cord])].
[sujeto(['In', primary, cultures, of, hippocampal, neurons, of, 2, -, 3, 'day-old', 'mice,', 'MTG8', was]), verbo([found]), complemento([in, the, 'nucleus,', in, the, cytoplasm, and, as, fine, granules, in, the, neurites])].
[sujeto(['The', evidence, of, 'MTG8', in, the, nucleus, and, cytoplasm, of, neural, cells]), verbo([suggests]), complemento([a, specific, mechanism, regulating, the, subcellular, localization, of, the, protein])].
[sujeto(['In', the, translocation, '(', 8, ;, 21, ')', '(', 'q22;q22)']), verbo([associated]), complemento([with, acute, myelogenous, leukemia, '(', 'AML),', part, of, the, long, arm, of, chromosome, 8, is, reciprocally, translocated, onto, chromosome, 21])].
[sujeto(['To', isolate, fusion, transcripts, of, 'AML1,', and, an, as, yet, unidentified, gene, on, chromosome, 8]), verbo([involved]), complemento([in, the, 'rearrangement,', we, used, rapid, amplification, of, cDNA, ends, '(', 'RACE)', and, primers, for, 'AML1', exons, 5, and, 6])].
[sujeto(['A', fusion, transcript, was, identified, by, 3, '\'', 'RACE', in, the, 'RNA', of, 't(8;21)', leukemic, cells, that, also]), verbo([express]), complemento([multiple, normal, 'AML1', transcripts])].
[sujeto(['This']), verbo([finding]), complemento([makes, it, possible, to, detect, the, translocation, at, the, molecular, 'level,', thus, improving, the, diagnosis, and, monitoring, of, the, disease, in, leukemic, patients])].
[sujeto(['It']), verbo([has]), complemento([been, demonstrated, that, 'KRAS', mutations, represent, about, 90, '%', of, 'cancer-associated', 'mutations,', and, that, 'KRAS', mutations, play, an, essential, role, in, neoplastic, transformation])].
[sujeto(['Cancer-associated', 'RAS', mutations, occur, frequently, in, acute, myeloid, leukemia, '(', 'AML),']), verbo([suggesting]), complemento([a, functional, role, for, 'Ras', in, leukemogenesis])].
[sujeto(['The', phosphorylation, of, 'MEK/ERK', was, significantly]), verbo([enhanced]), complemento([in, the, 'AML1/ETO', +, 'Kras', group])].
[sujeto(['The', similar, results, of, the, 'AML1/ETO', +, 'Nras', group, were, consistent, with, those]), verbo([reported]), complemento([previously])].
[sujeto(['Co-transduction', of, 'Kras(G12D)', and, 'AML1/ETO']), verbo([induces]), complemento([acute, monoblastic, leukemia])].
[sujeto(['Since', expression, of, mutant, 'K-ras', alone, was, insufficient, to]), verbo([induce]), complemento(['leukemia,', this, model, may, be, useful, for, investigating, the, 'multi-step', leukemogenesis, model, of, human, leukemia])].
[sujeto(['Acute', leukemia, is, the, most, common, malignancy, in, 'children,', being, mostly, produced, by, such, chromosomal, abnormalities, as, translocations, or, inversions]), verbo([causing]), complemento([gene, fusion])].
[sujeto(['To', detect, three, fusion, genes, that]), verbo([have]), complemento([been, proven, very, important, in, patient, 'classification:', 't(9:22)p190,', 't(4:11)', and, 't(12:21)'])].
[sujeto(['We']), verbo([found]), complemento(['t(9:22)p190', in, two, 'patients,', 't(4:11)', in, two, patients, and, 't(12:21)', in, one, patient])].
[sujeto(['Day', 33, can, still, be, considered, the, reference, time, in, the, evaluation, of, treatment, 'response;', patients, with, 'BCR-ABL', seem, to]), verbo([have]), complemento([a, worse, prognosis, than, those, who, do, not, have, this, translocation])].
[sujeto(['A', complex, 120, -, base, pair, 'enhancer,', derived, from, the, mouse, 'sex-limited', protein, '(', 'Slp)', 'gene,', is]), verbo([activated]), complemento([solely, by, the, androgen, receptor, '(', 'AR)', in, specific, 'tissues,', although, it, contains, a, hormone, response, element, recognized, by, several, steroid, receptors])].
[sujeto(['The', generation, of, this, transcriptional, specificity]), verbo([has]), complemento([been, ascribed, to, the, interactions, of, the, receptor, with, 'tissue-specific', nonreceptor, factors, bound, to, accessory, sites, within, the, enhancer])].
[sujeto(['Protein-DNA', interaction, assays, revealed, two, factors]), verbo([binding]), complemento([the, 5, '\'', part, of, the, enhancer, that, differ, widely, in, abundance, between, cells, showing, 'AR-specific', activation, of, the, 'Slp', element, compared, with, those, that, also, permit, activation, by, glucocorticoid, receptor, '(', 'GR)'])].
[sujeto(['The', factor, designated, 'B', formed, a, complex, centered, on, the, sequence, 'TGTGGT,', a, core, motif]), verbo([recognized]), complemento([by, members, of, the, 'AML/CBFalpha', transcription, factor, family])].
[sujeto(['This', complex, was, competed, by, a, high, affinity]), verbo([binding]), complemento([site, specific, for, 'AML/CBFalpha', and, was, specifically, supershifted, by, an, antibody, to, 'AML3/CBFalpha1,', placing, factor, 'B', within, the, 'AML3/CBFalpha1', subclass])].
[sujeto(['Interestingly,', this, factor, was, shown, to]), verbo([bind]), complemento([to, a, second, site, in, the, 3, '\'', part, of, the, 'enhancer,', positioned, between, the, two, critical, 'AR', binding, sites])].
[sujeto(['These', data, demonstrate, that, 'AML3/CBFalpha1', is, functionally]), verbo([required]), complemento([for, hormonal, induction, of, the, 'Slp', enhancer, and, that, 'direct,', preferential, 'protein-protein', interactions, may, contribute, to, 'AR-specific', activation])].
[sujeto(['These', results, demonstrate, an, intriguing, role, of, 'AML3/CBFalpha1', in, 'steroid-', as, well, as, 'tissue-specific', activation, of]), verbo([target]), complemento([genes])].
[sujeto(['Overexpression', of, vegf, and, notch, is, sufficient, to]), verbo([induce]), complemento(['HSCs', in, the, tbx16, 'mutant,', despite, a, lack, of, axial, vascular, organization])].
[sujeto(['The', most, proximal, 'HSC', 'mutants,', such, as, 'hdac1,', were]), verbo([found]), complemento([to, have, no, defect, in, vessel, or, artery, formation])].
[sujeto(['Further', analysis, demonstrated, that, hdac1]), verbo([acts]), complemento([downstream, of, 'Notch', signaling, but, upstream, or, in, parallel, to, runx1, to, promote, 'AGM', hematopoiesis])].
[sujeto(['Together,', our, results, establish, a, hierarchy, of, signaling, programs]), verbo([required]), complemento([and, sufficient, for, 'HSC', emergence, in, the, 'AGM'])].
[sujeto(['The', interaction, of]), verbo([nuclear]), complemento([and, mitochondrial, genes, is, an, essential, feature, in, maintenance, of, normal, cellular, function])].
[sujeto(['Of', 82, structural, subunits, that, make, up, the, oxidative, phosphorylation, system, in, the, 'mitochondria,', mitochondrial, 'DNA', '(', 'mtDNA)', encodes, 13, subunits, and, rest, of, the, subunits, are, encoded, by]), verbo([nuclear]), complemento(['DNA'])].
[sujeto(['Mutations', in, mitochondrial, genes, encoding, the, 13, subunits]), verbo([have]), complemento([been, reported, in, a, variety, of, cancers])].
[sujeto(['However,', little, is, known, about, the]), verbo([nuclear]), complemento([response, to, impairment, of, mitochondrial, function, in, human, cells])].
[sujeto(['Our', study]), verbo([suggests]), complemento([that, depletion, of, mtDNA, results, in, oxidative, 'stress,', causing, increased, lipid, peroxidation, in, breast, cancer, cells])].
[sujeto(['Using', a, cDNA, microarray, we, compared, differences, in, the]), verbo([nuclear]), complemento([gene, expression, profile, between, a, breast, cancer, cell, line, '(', parental, 'Rho+)', and, its, 'Rho0', derivative, impaired, in, mitochondrial, function])].
[sujeto(['Expression', of, several]), verbo([nuclear]), complemento([genes, involved, in, cell, 'signaling,', cell, 'architecture,', energy, 'metabolism,', cell, 'growth,', apoptosis, including, general, transcription, factor, 'TFIIH,', 'v-maf,', 'AML1,', was, induced, in, 'Rho0', cells])].
[sujeto(['Mitochondrial', impairment, in, breast, cancer, cells, results, in, altered, expression, of]), verbo([nuclear]), complemento([genes, involved, in, 'signaling,', cellular, 'architecture,', 'metabolism,', cell, growth, and, 'differentiation,', and, apoptosis])].
[sujeto(['These', genes, may]), verbo([mediate]), complemento([the, cross, talk, between, mitochondria, and, the, nucleus])].
[sujeto(['Breast', tissue, is, among, the, most, sensitive, tissues, to, the, carcinogenic, actions, of, ionizing, radiation, and, epidemiological, studies]), verbo([have]), complemento([linked, radiation, exposure, to, breast, cancer])].
[sujeto(['Functional', analysis, of, the, upregulated, genes, mapped, to, cell, proliferation, and, cancer, related, canonical, pathways, such, as, '\'', 'ERK/MAPK', 'signaling\',', '\'', 'CDK5', 'signaling\',', and, '\'', 14, -, 3, -, 3, -]), verbo([mediated]), complemento(['signaling\''])].
[sujeto(['Interestingly,', the, downregulated, genes, mapped, to, fewer, canonical, pathways]), verbo([involved]), complemento([in, cell, proliferation])].
[sujeto(['Results', from, 'qRT-PCR', on, five, selected, differentially]), verbo([expressed]), complemento([genes, confirmed, microarray, data])].
[sujeto(['The', 'PCR', data, on, 'PPP4c,', 'ELF1,', 'MAPK12,', 'PLCG1,', and, 'E2F6', showed, similar, trend, in, up, and, downregulation, as]), verbo([has]), complemento([been, observed, with, the, microarray])].
[sujeto(['Exposure', to, a, clinically, relevant, radiation, dose]), verbo([led]), complemento([to, 'long-term', activation, of, mammary, gland, genes, involved, in, proliferative, and, metabolic, 'pathways,', which, are, known, to, have, roles, in, carcinogenesis])].
[sujeto(['When', considered, along, with, downregulation, of, a, number, of, tumor, suppressor, 'genes,', our, study]), verbo([has]), complemento([implications, for, breast, cancer, initiation, and, progression, after, therapeutic, radiation, exposure])].
[sujeto(['Alteration', of, 'lineage-specific', transcriptional, programs, for, hematopoiesis]), verbo([causes]), complemento([differentiation, block, and, promotes, leukemia, development])].
[sujeto(['AML1/ETO']), verbo([participates]), complemento([in, a, protein, complex, with, the, 'RA', receptor, alpha, '(', 'RARalpha)', at, 'RA', regulatory, regions, on, 'RARbeta2,', which, is, a, key, 'RA', target, gene, mediating, 'RA', 'activity/resistance', in, cells])].
[sujeto(['At', these, 'sites,', 'AML1/ETO']), verbo([recruits]), complemento([histone, 'deacetylase,', 'DNA', 'methyltransferase,', and, 'DNA-methyl-CpG', binding, activities, that, promote, a, repressed, chromatin, conformation])].
[sujeto(['Finally,', 'RARbeta2', is, commonly, silenced, by, hypermethylation, in, primary, 'AML', blasts, but, not, in, normal, hematopoietic, 'precursors,', thus]), verbo([suggesting]), complemento([a, role, for, the, epigenetic, repression, of, the, 'RA', signaling, pathway, in, myeloid, leukemogenesis])].
[sujeto(['Acute', myeloid, leukemia, '(', 'AML)-associated', chromosomal, translocations, result, in, formation, of, chimeric, transcription, 'factors,', such, as, 'PML/RARalpha,', 'PLZF/RARalpha,', and, 'AML-1/ETO,', of, which, the, components, are]), verbo([involved]), complemento([in, regulation, of, transcription, by, chromatin, modeling, through, histone, 'acetylation/deacetylation'])].
[sujeto(['The', leukemic, differentiation, block, is, attributed, to, deregulated, transcription]), verbo([caused]), complemento([by, these, chimeric, fusion, 'proteins,', which, aberrantly, recruit, 'histone-deacetylase', '(', 'HDAC)', activity])].
[sujeto(['In', the, absence, of, 'ligand,', the, transcriptional, activity, of, 'TR', and, 'RAR', is, silenced, by, recruitment, of, 'HDAC', activity, through]), verbo([binding]), complemento([to, corepressors])].
[sujeto(['In', the, presence, of, 'ligand,', 'TR', and, 'RAR']), verbo([activate]), complemento([transcription, by, releasing, 'HDAC', activity, and, by, recruiting, 'histone-acetyltransferase', activity])].
[sujeto(['Here', we]), verbo([report]), complemento([that, 'VDR', binds, corepressors, in, a, 'ligand-dependent', manner, and, that, inhibition, of, 'HDAC', activity, increases, 'VitD(3)', sensitivity, of, 'HL-60', cells])].
[sujeto(['Nevertheless,', the, inhibition, of, 'HDAC', activity, is, unable, to, overcome, the, block, of, 'VitD(3)-induced', differentiation]), verbo([caused]), complemento([by, 'PLZF/RARalpha', expression])].
[sujeto(['Here', we, demonstrate, that, the, expression, of, the, translocation, products, 'PML/RARalpha', and, 'PLZF/RARalpha', impairs, the, localization, of, 'VDR', in, the, nucleus, by]), verbo([binding]), complemento([to, 'VDR'])].
[sujeto(['Furthermore,', the, overexpression, of, 'VDR', in, 'U937', cells]), verbo([expressing]), complemento(['AML-related', translocation, products, completely, abolishes, the, block, of, 'VitD(3)-induced', differentiation])].
[sujeto(['Taken', together, these, data, indicate, that, the, 'AML-associated', translocation, products, block, differentiation, not, only, by, interfering, with, 'chromatin-modeling', but, also, by, sequestering, factors]), verbo([involved]), complemento([in, the, differentiation, signaling, 'pathways,', such, as, 'VDR', in, the, 'VitD(3)-induced', differentiation])].
[sujeto(['The', retinoic, acid, receptors, '(', 'RARs)', 'alpha,', 'beta2,', and, gamma]), verbo([regulate]), complemento([specific, subsets, of, target, genes, during, 'all-trans', retinoic, acid, '(', 'RA)', induced, differentiation, of, 'F9', teratocarcinoma, stem, cells])].
[sujeto(['Our', goal, was, to, analyze, the, 'Tie1', 'gene,', which, encodes, a, surface, receptor, tyrosine, kinase]), verbo([expressed]), complemento([in, the, hematovascular, system])].
[sujeto(['We', showed, that, 'RARgamma,', but, not, 'RARalpha', or, 'RARbeta2,', is]), verbo([required]), complemento([for, 'Tie1', promoter, activation, by, 'RA'])].
[sujeto(['Treatment', with, a, 'RARgamma', selective, agonist, plus, a, retinoid, 'X', receptor, agonist, '(', 'LGD1069)']), verbo([increased]), complemento(['Tie1', mRNA, levels, by, 11, -, +, /, -, 2.5, -, fold, 48, hours, after, 'RA', addition, in, 'F9', 'WT,', but, not, in, 'F9', 'RARgamma-/-', 'cells,', by, quantitative, reverse, transcription, polymerase, chain, reaction])].
[sujeto(['RA']), verbo([increased]), complemento(['GATA4', transcripts, by, 12, -, +, /, -, 1, -, fold, in, 'F9', 'WT', at, 48, 'hours,', but, not, in, 'F9', 'RARgamma-/-', cells])].
[sujeto(['In', 'addition,', transfection, of, a, 'GATA4', expression, vector]), verbo([increased]), complemento(['Tie1', 'promoter/luciferase', activity, in, both, 'RA-treated', 'F9', 'WT', and, 'RARgamma-/-', cells])].
[sujeto(['Tie1', promoter, deletion, analyses, indicated, that, a, region, of, the, promoter, that, possessed, multiple, 'GATA', sites]), verbo([mediated]), complemento([the, 'RA-associated', 'Tie1', transcriptional, increase])].
[sujeto(['The', biological, effects, of, 'all-trans-retinoic', acid, '(', 'RA),', a, major, active, metabolite, of, 'retinol,', are, mainly]), verbo([mediated]), complemento([through, its, interactions, with, retinoic, acid, receptor, '(', 'RARs', 'alpha,', 'beta,', 'gamma)', and, retinoid, 'X', receptor, '(', 'RXRs', 'alpha,', 'beta,', 'gamma)', heterodimers])].
[sujeto(['RAR/RXR', heterodimers]), verbo([activate]), complemento([transcription, by, binding, to, 'RA-response', elements, '(', 'RAREs', or, 'RXREs)', in, the, promoters, of, primary, target, genes])].
[sujeto(['Murine', 'F9', teratocarcinoma, stem, cells]), verbo([have]), complemento([been, widely, used, as, a, model, for, cellular, differentiation, and, 'RA', signaling, during, embryonic, development])].
[sujeto(['We', identified, and, characterized, genes, that, are, differentially]), verbo([expressed]), complemento([in, 'F9', wild, type, '(', 'Wt)', and, 'F9', 'RARgamma-/-', 'cells,', with, and, without, 'RA', 'treatment,', through, the, use, of, 'oligonucleotide-based', microarrays])].
[sujeto(['Our', data, indicate, that, 'RARgamma,', in, the, absence, of, exogenous, 'RA,']), verbo([modulates]), complemento([gene, expression])].
[sujeto(['Other', 'genes,', such, as, 'Runx1,', were]), verbo([expressed]), complemento([at, lower, levels, in, both, 'F9', 'RARbeta2-/-', and, 'RARgamma-/-', cell, lines, than, in, 'F9', 'Wt', and, 'RARalpha-/-'])].
[sujeto(['Genes', specifically]), verbo([induced]), complemento([by, 'RA', at, 6, h, with, the, protein, synthesis, inhibitor, cycloheximide, in, 'F9', 'Wt,', but, not, in, 'RARgamma-/-', 'cells,', included, 'Hoxa3,', 'Hoxa5,', 'Gas1,', 'Cyp26a1,', 'Sfrp2,', 'Fbp2,', and, 'Emp1'])].
[sujeto(['These', genes, represent, specific, primary, 'RARgamma']), verbo([targets]), complemento([in, 'F9', cells])].
[sujeto(['Several', genes, in, the, 'Wnt', signaling, pathway, were]), verbo([regulated]), complemento([by, 'RARgamma'])].
[sujeto(['The', study, revealed, nine, transcription, factors, presenting, enriched, motifs, for, these, gene, 'promoters,', five, of, which, are, implicated, in, cellular, growth, '(', 'ELK1,', 'ELK4,', 'RUNX1,', 'HOX11-CTF1,', 'TAL1-ternary', complex, factor, 3, ')', and, four, in, mitochondrial, biogenesis, '(']), verbo([nuclear]), complemento([respiratory, 'factor-1', '(', 'NRF-1),', 'GABPA,', 'PPARG-RXRA', and, 'estrogen-related', receptor, alpha, '(', 'ESRRA))'])].
[sujeto(['Exploring', the, thyroid, 'tumours,', we]), verbo([found]), complemento([that, 'DAP3', mRNA, and, protein, expression, is, upregulated, in, tumours, presenting, a, mitochondrial, biogenesis, compared, with, the, normal, tissue])].
[sujeto(['DAP3', may]), verbo([participate]), complemento([in, mitochondrial, maintenance, and, play, a, role, in, the, balance, between, mitochondrial, homoeostasis, and, tumourigenesis])].
[sujeto(['Acute', myeloid, leukemia, '(', 'AML),', a, class, of, prevalent, hematopoietic, 'malignancies,', is]), verbo([caused]), complemento([by, the, acquisition, of, gene, mutations, that, confer, deregulated, 'proliferation,', impaired, differentiation, and, a, survival, advantage, of, hematopoietic, progenitors])].
[sujeto(['More', 'recently,', we]), verbo([reported]), complemento([that, cobalt, chloride, '(', 'CoCl(2))/iron', chelator, desferrioxamine, '(', 'DFO)-mimicked', hypoxia, or, moderate, hypoxia, '(', 2, '%', and, 3, '%', 'O(2))', can, directly, trigger, differentiation, of, many, subtypes, of, 'AML', cells])].
[sujeto(['Additionally,', these, 'hypoxia-simulating', agents, selectively]), verbo([stimulate]), complemento([differentiation, in, acute, promyelocytic, leukemic, cells, induced, by, arsenic, 'trioxide,', an, effective, 'second-line', drug, for, this, unique, type, of, leukemia])].
[sujeto(['Furthermore,', 'HIF-1alpha', and, two, hematopoietic, transcription, factors, 'CCAAT/enhancer']), verbo([binding]), complemento([protein, alpha, '(', 'C/EBPalpha)', and, 'Runx1/AML1', interact, directly, with, each, other])].
[sujeto(['Such', interactions]), verbo([increase]), complemento([the, transcriptional, activities, of, 'C/EBPalpha', and, 'Runx1/AML1,', while, 'C/EBPalpha', competes, with, 'HIF-1beta', for, direct, binding, to, 'HIF-1alpha', 'protein,', and, significantly, inhibits, the, 'DNA-binding', ability, of, 'HIF-1'])].
[sujeto(['We']), verbo([found]), complemento([that, 'Tcf7', is, the, most, 'down-regulated', transcription, factor, when, 'CD34+', cells, switch, into, 'CD34-', 'cells,', using, 'RNA-Seq'])].
[sujeto(['We', subsequently, identified, the]), verbo([target]), complemento([genes, bound, by, 'TCF7,', using, 'ChIP-Seq'])].
[sujeto(['We', show, that, 'TCF7', and, 'RUNX1', '(', 'AML1)']), verbo([bind]), complemento([to, each, 'other\'s', promoter, regions, and, that, 'TCF7', is, necessary, for, the, production, of, the, short, 'isoforms,', but, not, the, long, isoforms, of, 'RUNX1,', suggesting, that, 'TCF7', and, the, short, isoforms, of, 'RUNX1', function, coordinately, in, regulation])].
[sujeto(['Tcf7', 'knock-down', experiments, and, 'Gene', 'Set', 'Enrichment', 'Analyses']), verbo([suggest]), complemento([that, 'TCF7', plays, a, dual, role, in, promoting, the, expression, of, genes, characteristic, of, 'self-renewing', 'CD34+', cells, while, repressing, genes, activated, in, partially, differentiated, 'CD34-', state])].
[sujeto(['Using', 'genome-wide', and, functional, 'approaches,', we, investigated, the]), verbo([binding]), complemento(['properties,', transcriptional, role, and, chromatin, environment, of, 'Ets1', during, this, transition])].
[sujeto(['We']), verbo([found]), complemento([that, while, 'Ets1', binding, at, distal, sites, was, associated, with, active, genes, at, both, 'DN', and, 'DP', 'stages,', its, enhancer, activity, was, attained, at, the, 'DP', 'stage,', as, reflected, by, levels, of, the, core, transcriptional, hallmarks, 'H3K4me1/3,', 'RNA', 'Polymerase', 'II', and, eRNA])].
[sujeto(['Coincidentally,', 'Ets1']), verbo([associates]), complemento([more, specifically, with, 'Runx1', in, 'DN', and, with, 'TCF1', in, 'DP', cells])].
[sujeto(['We', also]), verbo([provide]), complemento([evidence, that, 'Ets1', predominantly, binds, distal, 'nucleosome-occupied', regions, in, 'DN', and, 'nucleosome-depleted', regions, in, 'DP'])].
[sujeto(['Finally', and, 'importantly,', we, demonstrate, that, 'Ets1']), verbo([induces]), complemento([chromatin, remodeling, by, displacing, 'H3K4me1-marked', nucleosomes])].
[sujeto(['Our', results, thus]), verbo([provide]), complemento([an, original, model, whereby, the, ability, of, a, transcription, factor, to, bind, nucleosomal, 'DNA', changes, during, differentiation, with, consequences, on, its, cognate, enhancer, activity])].
[sujeto(['LEF/TCFs']), verbo([have]), complemento([a, 'DNA', 'sequence-specific', 'high-mobility', group, '(', 'HMG)', box, that, binds, 'Wnt', response, elements, '(', 'WREs)'])].
[sujeto(['The', &, 'quot;E', 'tail"', isoforms, of, 'TCFs', are, alternatively, spliced, to, include, a, second, 'DNA']), verbo([binding]), complemento([domain, called, the, 'C-clamp'])].
[sujeto(['We', show, that, induction, of, a, dominant, negative, 'C-clamp', version, of, 'TCF1', '(', 'dnTCF1E)']), verbo([induces]), complemento([p21, expression, and, a, stall, in, the, growth, of, 'DLD1', colon, cancer, cells])].
[sujeto(['Induction', of, a, 'C-clamp', mutant, did, not, efficiently]), verbo([induce]), complemento(['p21,', nor, did, it, stall, cell, growth])].
[sujeto(['Microarray', analysis, revealed, that, induction, of, p21, by, 'wild-type', dnTCF1E, '(', 'dnTCF1E(WT))', correlated, with, a]), verbo([decrease]), complemento([in, expression, of, multiple, p21, suppressors, that, act, at, multiple, levels, from, transcription, '(', 'SP5,', 'YAP1,', and, 'RUNX1),', 'RNA', stability, '(', 'MSI2),', and, protein, stability, '(', 'CUL4A)'])].
[sujeto(['We', show, that, the, 'C-clamp', is, a, 'sequence-specific', 'DNA']), verbo([binding]), complemento([domain, that, can, make, contacts, with, 5, '\'', -, 'RCCG-3\'', elements, upstream, or, downstream, of, 'WREs'])].
[sujeto(['The', 'C-clamp-RCCG', interaction, was, critical, for, 'TCF1E-mediated', transcriptional, control, of, 'p21-connected']), verbo([target]), complemento([gene, promoters])].
[sujeto(['Our', results, indicate, that, a, 'rapid-response', 'WNT/p21', circuit, is, driven, by, 'C-clamp']), verbo([target]), complemento([gene, selection])].
[sujeto(['CBFbeta', is, the, 'non-DNA']), verbo([binding]), complemento([subunit, of, the, core, binding, factors, '(', 'CBFs)'])].
[sujeto(['Here', we, show, that, 'CBFbeta', is, also]), verbo([required]), complemento([at, very, early, stages, of, natural, killer, '(', 'NK)-cell', development])].
[sujeto(['Therefore,', the, ability, of, the, prethymic, cell, to]), verbo([respond]), complemento([appropriately, to, 'Notch', is, dependent, on, 'CBFbeta,', and, both, signals, converge, to, activate, the, 'T-cell', developmental, program])].
[sujeto(['Although', a, number, of, transcription, factors, '(', 'TFs)']), verbo([have]), complemento([been, identified, that, play, a, pivotal, role, in, the, development, of, hematopoietic, 'lineages,', only, little, is, known, about, factors, that, may, influence, development, and, lineage, commitment, of, natural, killer, '(', 'NK)', or, 'NK-like', 'T', '(', 'NKT)-cells'])].
[sujeto(['AML1,', 'E2A,', 'ETS1,', 'IKAROS', and, 'IRF1', were]), verbo([found]), complemento([to, be, positive, for, all, cell, lines, tested, whereas, 'GATA1', turned, out, to, be, universally, negative])].
[sujeto(['Although', 'genome-wide', association, studies, '(', 'GWAS)']), verbo([have]), complemento([identified, a, significant, number, of, 'single-nucleotide', polymorphisms, '(', 'SNPs)', associated, with, many, complex, human, 'traits,', the, susceptibility, loci, identified, so, far, can, explain, only, a, small, fraction, of, the, genetic, risk])].
[sujeto(['Previously,', we]), verbo([reported]), complemento([a, 'model-free', 'Generalized', 'Multifactor', 'Dimensionality', 'Reduction', '(', 'GMDR)', approach, for, detecting, 'G×G', in, both, dichotomous, and, quantitative, phenotypes])].
[sujeto(['Of', these, core, 'SNPs,', 11, in, 'FTO,', 'TSPAN8,', and, 'TCF7L2']), verbo([have]), complemento([been, reported, to, be, associated, with, 'T2D,', 'obesity,', or, 'both,', providing, an, independent, replication, of, previously, reported, 'SNPs'])].
[sujeto([',', 'L3MBTL3,', 'CELF4,', and, 'RUNX1,', for, 'T2D,', a]), verbo([finding]), complemento([that, warrants, further, investigation, with, independent, samples])].
[sujeto(['We']), verbo([found]), complemento([differential, 'DNA', methylation, of, genes, in, biological, pathways, including, 'mitogen-activated', protein, kinase, '(', 'MAPK),', 'insulin,', and, calcium, signaling, '(', 'P', '≤', 0.007, ')', and, of, individual, genes, with, known, function, in, 'muscle,', including, 'MAPK1,', 'MYO18B,', 'HOXC6,', and, the, 'AMP-activated', protein, kinase, subunit, 'PRKAB1', in, skeletal, muscle, of, 'FH(+)', compared, with, 'FH(-)', men])].
[sujeto(['DNA', methylation, of, genes, in, retinol, metabolism, and, calcium, signaling, pathways, '(', 'P', &, 'lt;', 3, ×, 10, '(', -, 6, ')', ')', and, with, known, functions, in, muscle, and, 'T2D', including, 'MEF2A,', 'RUNX1,', 'NDUFC2,', and, 'THADA']), verbo([decreased]), complemento([after, exercise])].
[sujeto(['Methylation', of, these, human, promoter, regions]), verbo([suppressed]), complemento([reporter, gene, expression, in, vitro])].
[sujeto(['These', findings]), verbo([provide]), complemento([new, insights, into, how, genetic, background, and, environment, can, alter, the, human, epigenome])].
[sujeto(['LCRs']), verbo([have]), complemento([been, identified, in, many, immunologically, important, gene, 'loci,', including, one, between, the, 'TCRdelta/TCRalpha', gene, segments, and, the, ubiquitously, expressed, 'Dad1', gene])].
[sujeto(['How', a, ubiquitously, active, element, can]), verbo([participate]), complemento([in, 'tissue-restricted', 'LCR', activity, is, not, clear])].
[sujeto(['In', 'isolation,', the, activity, in, this, region]), verbo([suppresses]), complemento([position, effect, transgene, silencing, in, many, tissues])].
[sujeto(['A', combination, of, in, vivo, footprint, examination, of, this, element, in, widely, active, transgene, and, 'EMSAs', revealed, 'tissue-unrestricted', factor, occupancy, patterns, and]), verbo([binding]), complemento([of, several, ubiquitously, expressed, transcription, factors])].
[sujeto(['We', identified, 'tissue-restricted', 'AML-1', and, 'Elf-1', as, proteins, that, potentially]), verbo([act]), complemento([via, this, element])].
[sujeto(['These', data, demonstrate, that, a, widely, active, 'LCR', module, can, synergize, with, other, 'LCR', components, to, produce, 'tissue-specific', 'LCR', activity, through, differential, protein, occupancy, and, function, and]), verbo([provide]), complemento([evidence, to, support, a, role, for, this, 'LCR', module, in, the, regulation, of, both, 'TCR', and, 'Dad1', genes])].
[sujeto(['Cannabinoid', receptor, type, 2, '(', 'CB2)', activation, is, recently]), verbo([reported]), complemento([to, promote, proliferation, of, some, types, of, resident, stem, cells, '(', e])].
[sujeto(['This', study, aims, to, explore, the, role, and, possible, mechanisms, of, 'CB2', receptor, activation, in]), verbo([enhancing]), complemento([myocardial, repair])].
[sujeto(['Our', results, revealed, that, 'CB2', receptor, agonist, 'AM1241', can, significantly]), verbo([increase]), complemento(['CPCs', by, 'c-kit', and, 'Runx1', staining, in, ischemic, myocardium, as, well, as, improve, cardiomyocyte, proliferation])].
[sujeto(['AM1241', also]), verbo([decreased]), complemento([serum, levels, of, 'MDA,', 'TNF-α', and, 'IL-6', after, 'MI'])].
[sujeto(['Moreover,', 'AM1241', treatment, markedly]), verbo([increased]), complemento(['p-Akt', and, 'HO-1', 'expression,', and, promoted, 'Nrf-2', nuclear, translocation])].
[sujeto(['In', 'conclusion,', 'AM1241', could]), verbo([induce]), complemento([myocardial, regeneration, and, improve, cardiac, 'function,', which, might, be, associated, with, 'PI3K/Akt/Nrf2', signaling, pathway, activation])].
[sujeto(['Our', findings, may]), verbo([provide]), complemento([a, promising, strategy, for, cardiac, endogenous, regeneration, after, 'MI'])].
[sujeto(['The', 'NFE2', protein, forms, heterodimers, with, small, 'MAF', 'proteins,', and, the, resulting, complex]), verbo([binds]), complemento([to, regulatory, elements, in, a, large, number, of, target, genes])].
[sujeto(['In', contrast, to, other, 'CNC', transcription, family, members, including, 'NFE2L1', '(', 'NRF1),', 'NFE2L2', '(', 'NRF2)', and, 'NFE2L3', '(', 'NRF3),', which, are, widely, 'expressed,', earlier, studies, had]), verbo([suggested]), complemento([that, the, major, sites, of, 'NFE2', expression, are, hematopoietic, cells])].
[sujeto(['Based', on, cell, culture, studies, it, was, proposed, that, this, protein]), verbo([acts]), complemento([as, a, critical, regulator, of, globin, gene, expression])].
[sujeto(['Indeed,', absence, of, 'NFE2']), verbo([led]), complemento([to, severely, impaired, platelet, production])].
[sujeto(['Surprisingly,', it, was, recently]), verbo([found]), complemento([that, 'NFE2', also, has, a, role, in, 'non-hematopoietic', 'tissues,', such, as, the, 'trophoblast,', in, which, it, is, also, 'expressed,', as, well, as, the, 'bone,', opening, the, door, to, new, research, areas, for, this, transcription, factor])].
[sujeto(['Important', strides]), verbo([have]), complemento([been, made, with, respect, to, the, clinical, significance, of, 'NFE2,', linking, this, transcription, factor, to, hematological, disorders, such, as, polycythemias])].
[sujeto(['Abstract', 'Endothelial', progenitor, cells, '(', 'EPCs)']), verbo([have]), complemento([been, demonstrated, to, be, effective, for, the, treatment, of, cardiovascular, diseases])].
[sujeto(['However,', the, differentiation, process, from, circulation, to, adhesion]), verbo([has]), complemento([not, been, clarified, because, circulating, 'EPCs', rarely, attached, to, dishes, in, 'EPC', cultures, previously])].
[sujeto(['The', bioactivities, of, 'adhesion,', 'proliferation,', 'migration,', tube, 'formation,', and, differentiated, type, of, 'EPC', colony, formation]), verbo([increased]), complemento([in, 'EPCs', exposed, to, dextran])].
[sujeto(['The', surface, protein, expression, rate, of, the, endothelial, markers, vascular, endothelial, growth, factor, '(', 'VEGF)-R1/2,', 'VE-cadherin,', 'Tie2,', 'ICAM1,', 'VCAM1,', and, integrin, 'αv/β3']), verbo([increased]), complemento([in, 'EPCs', exposed, to, dextran])].
[sujeto(['The', mRNA, levels, of, 'VEGF-R1/2,', 'VE-cadherin,', 'Tie2,', endothelial, nitric, oxide, 'synthase,', 'MMP9,', and, 'VEGF']), verbo([increased]), complemento([in, 'EPCs', treated, with, dextran])].
[sujeto(['Those', of, 'endothelium-related', transcription, factors, 'ID1/2,', 'FOXM1,', 'HEY1,', 'SMAD1,', 'FOSL1,', 'NFkB1,', 'NRF2,', 'HIF1A,', 'EPAS1']), verbo([increased]), complemento([in, 'dextran-treated', 'EPCs;', 'however,', those, of, 'hematopoietic-', and, 'antiangiogenic-related', transcription, factors, 'TAL1,', 'RUNX1,', 'c-MYB,', 'GATA1/2,', 'ERG,', 'FOXH1,', 'HHEX,', 'SMAD2/3', decreased, in, 'dextran-exposed', 'EPCs'])].
[sujeto(['Inhibitor', analysis, showed, that, 'PI3K/Akt,', 'ERK1/2,', 'JNK,', and, p38, signal, transduction, pathways, are]), verbo([involved]), complemento([in, the, differentiation, in, response, to, dextran])].
[sujeto(['In', 'conclusion,', dextran]), verbo([induces]), complemento([differentiation, of, circulating, 'EPCs', in, terms, of, 'adhesion,', 'migration,', 'proliferation,', and, vasculogenesis])].
[sujeto(['The', differentiation, mechanism, in, response, to, dextran, is]), verbo([regulated]), complemento([by, multiple, signal, transductions, including, 'PI3K/Akt,', 'ERK1/2,', 'JNK,', and, p38])].
[sujeto(['To', understand, the, role, of, 'ETO', and, 'AML1-ETO', in, the, pathogenesis, of, 'AML,', the, full, length, cDNAs, of, 'ETO', and, 'AML1-ETO', were, cloned, and, antibodies, against, 'AML1', and, 'ETO', proteins]), verbo([have]), complemento([been, developed, in, our, laboratory])].
[sujeto(['Western', blot, analysis, showed, that, 'ETO', and, 'AML1-ETO', were, identified, as, 70, kDa, and, 94, kDa, 'proteins,', 'respectively,', and, that, both, 'proteins,', like, 'AML1,', were]), verbo([associated]), complemento([with, the, nuclear, matrix])].
[sujeto(['To', examine, whether, the, 't(8;21)-positive', 'AMLs']), verbo([expressed]), complemento([a, 94, -, kDa, 'AML1-ETO,', protein, fractions, isolated, from, leukemia, blasts, of, 10, patients, with, 't(8;21)-positive', 'AML', and, the, 'Kasumi-1', cells, were, analyzed, by, 'Western', blotting])].
[sujeto(['We']), verbo([found]), complemento([that, 'AML1-ETO', blocked, the, erythroid, differentiation, of, 'K562', cells, induced, by, low, doses, of, 'Ara-C'])].
[sujeto(['The', 't(8;21)', is]), verbo([associated]), complemento([with, 12, -, 15, '%', of, acute, myelogenous, leukemias, of, the, 'M2', subtype])].
[sujeto(['AML1', encodes, a, 'DNA']), verbo([binding]), complemento(['factor;', the, 'ETO', protein, product, is, less, well, 'characterized,', but, is, thought, to, be, a, transcription, factor])].
[sujeto(['ETO-2', is, also]), verbo([expressed]), complemento([in, myeloid, and, erythroid, cell, lines])].
[sujeto(['We', confirmed, the]), verbo([nuclear]), complemento([localization, of, 'ETO-2', and, demonstrated, that, domain, 'III', and, the, 'zinc-finger', region, are, not, required, for, nuclear, localization])].
[sujeto(['We', further, showed, that, a, region, within, 'ETO,', containing, domain, 'II,']), verbo([mediates]), complemento([dimerization, among, family, members])].
[sujeto(['This', region, is]), verbo([conserved]), complemento([in, the, oncoprotein, 'AML-1/ETO'])].
[sujeto(['Macrophages', are, immune, cells]), verbo([involved]), complemento([in, various, biological, processes, including, host, 'defence,', 'homeostasis,', 'differentiation,', and, organogenesis])].
[sujeto(['Disruption', of, macrophage, biology]), verbo([has]), complemento([been, linked, to, increased, pathogen, 'infection,', inflammation, and, malignant, diseases])].
[sujeto(['Differential', gene, expression, observed, in, monocytic, differentiation, is, primarily]), verbo([regulated]), complemento([by, interacting, transcription, factors, '(', 'TFs)'])].
[sujeto(['Current', research]), verbo([suggests]), complemento([that, microRNAs, '(', 'miRNAs)', degrade, and, repress, translation, of, 'mRNA,', but, also, may, target, genes, involved, in, differentiation])].
[sujeto(['We', focus, on, getting, insights, into, the, transcriptional, circuitry]), verbo([regulating]), complemento([miRNA, genes, expressed, during, monocytic, differentiation])].
[sujeto(['A', set, of, 'TF-->miRNA', associations, was, derived, from, predicted, 'TF']), verbo([binding]), complemento([sites, in, promoter, regions, of, miRNA, genes])].
[sujeto(['Our', analysis, identified, 12, 'TFs', that, potentially, play, a, central, role, in]), verbo([regulating]), complemento([miRNAs, throughout, the, differentiation, process])].
[sujeto(['Six', of, these, 12, 'TFs', '(', 'ATF2,', 'E2F3,', 'HOXA4,', 'NFE2L1,', 'SP3,', and, 'YY1)']), verbo([have]), complemento([not, previously, been, described, to, be, important, for, monocytic, differentiation])].
[sujeto(['Subsequently,', we]), verbo([have]), complemento([identified, 12, candidate, key, controllers, of, miRNAs, during, this, differentiation, process])].
[sujeto(['AML1/RUNX1', mutations]), verbo([have]), complemento([been, reported, frequently, in, myelodysplastic, syndrome, '(', 'MDS)', 'patients,', especially, those, diagnosed, with, refractory, anemia, with, excess, blast, '(', 'RAEB),', 'RAEB', in, transformation, '(', 'RAEBt),', or, 'AML', following, 'MDS', '(', these, categories, are, defined, as, 'MDS/AML)'])].
[sujeto(['AML1', mutations, were, significantly]), verbo([associated]), complemento([with, -, 7, /, 7, 'q-,', whereas, 'MDS/AML', patients, without, 'AML1', mutations, showed, a, high, frequency, of, -, 5, /, 5, 'q-', and, a, complex, karyotype])].
[sujeto(['Furthermore,', blast, cells, of, the, 'AML1-mutated', patients]), verbo([expressing]), complemento([surface, 'c-KIT,', and, 'SHP-2', mutants, contributed, to, prolonged, and, enhanced, extracellular, 'signal-regulated', kinase, activation, following, stem, cell, factor, stimulation])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'MDS/AML', arising, from, 'AML1/RUNX1', mutations, has, a, significant, association, with, -, 7, /, 7, 'q-', 'alteration,', and, frequently, involves, 'RTK-RAS', signaling, pathway, activation])].
[sujeto(['SHP-2', is]), verbo([required]), complemento([during, 'development,', and, germline, mutations, in, 'PTPN11,', the, gene, encoding, 'SHP-2,', cause, 'Noonan', syndrome])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, 'PTPN11', lesions, occur, in, childhood, acute, lymphoblastic, leukemia, '(', 'ALL)'])].
[sujeto(['Our', findings]), verbo([provide]), complemento([evidence, for, a, wider, role, of, 'PTPN11', lesions, in, 'leukemogenesis,', but, also, suggest, a, 'lineage-related', and, differentiation, 'stage-related', contribution, of, these, lesions, to, clonal, expansion])].
[sujeto(['Dysfunction', of, 'FOXP3', in, human, is]), verbo([associated]), complemento([with, fatal, autoimmune, disease, known, as, 'immunodysregulation,', 'polyendocrinopathy,', 'enteropathy,', 'X-linked', syndrome, '(', 'IPEX)', or, 'X-linked', 'autoimmunity-allergic', disregulation, syndrome, '(', 'XLAAD)'])].
[sujeto(['FOXP3', also, can]), verbo([act]), complemento([as, a, breast, tumor, suppressor, of, the, 'v-erb-b2', erythroblastic, leukemia, viral, oncogene, homolog, 2, '(', 'neuro/glioblastoma', derived, oncogene, homolog, '(', 'avian))', '(', 'Her2/neu)', gene])].
[sujeto(['While', the, suppressive, functions, of, 'FOXP3', in]), verbo([maintaining]), complemento([the, immune, balance, between, tolerance, and, autoimmunity, are, 'obvious,', the, underlying, molecular, mechanism, remains, almost, entirely, undefined])].
[sujeto(['Recent', studies, indicate, that, 'FOXP3', may, form, a, dynamic, superamolecular, complex, with, a, variety, of, molecular, partners, including, transcription, factors, and, enzymatic, proteins, to]), verbo([regulate]), complemento([transcription])].
[sujeto(['How', the, 'FOXP3', ensemble, changes, in, response, to, 'T-cell', receptor, signals, 'and/or', proinflammatory, signal, remains, unclear, although, work, from, this, laboratory]), verbo([has]), complemento([revealed, its, complexity])].
[sujeto(['Structural', information, on, 'FOXP3', complex, may, offer, novel, functional, 'insights,', as, well, as, facilitate, the, development, of, rational, means, to]), verbo([modulate]), complemento([regulatory, 'T-cell', function, in, various, human, diseases])].
[sujeto(['The', silencing, mediator, of, retinoic, and, thyroid, hormone, receptors, '(', 'SMRT)', 'co-repressor']), verbo([recruits]), complemento([histone, deacetylases, '(', 'HDAC)', and, mediates, transcriptional, repression, by, interacting, with, various, transcription, factors])].
[sujeto(['We', recently]), verbo([reported]), complemento([that, 'Flt3-ITD', interferes, with, the, transcriptional, and, biological, action, of, promyelocytic, leukaemia, zinc, finger, transcriptional, repressor, by, dissociating, it, from, 'SMRT'])].
[sujeto(['Mammalian', 'two-hybrid', assays, demonstrated, that, this, protein]), verbo([interacts]), complemento([with, 'SMRT'])].
[sujeto(['Furthermore,', this, 'AML1B-SMRT', interaction, was, disrupted, by, the, overexpression, of, 'Flt3-ITD,']), verbo([leading]), complemento([to, the, reduction, of, 'AML1B', repression, activity])].
[sujeto(['Additionally,', we, showed, 'AML1B', repression, 'target,', p21, '(', 'WAF1/CIP1),', was, aberrantly]), verbo([expressed]), complemento([in, 'Flt3-ITD', stably, expressed, 'BaF3', cells])].
[sujeto(['They', differentiate, through, interaction, of, their, 'Valpha14-Jalpha18', invariant, 'TCRalpha', chains, with, 'CD1d']), verbo([expressed]), complemento([on, 'double-positive', '(', 'DP)', thymocytes])].
[sujeto(['Although', their, development]), verbo([has]), complemento([been, shown, to, be, thymus, 'dependent,', their, developmental, pathway, has, not, been, definitively, established])].
[sujeto(['Their', development, is, absolutely, dependent, on, 'Runx1', and, 'ROR(gamma)t,', transcription, factors, that, 'influence,', but, are, not]), verbo([required]), complemento(['for,', development, of, conventional, 'T', cells])].
[sujeto(['Our', results, indicate, that, even, though, 'CD1d']), verbo([binding]), complemento(['DP', thymocytes, have, yet, to, be, 'observed,', 'Valpha14-Jalpha18', rearrangement, in, these, cells, is, required, for, development, of, iNKT, cells])].
[sujeto(['Primary', aggressive, bone, tumors, had, copy, number]), verbo([gains]), complemento([of, 17.8, '±12'])].
[sujeto([7, '%', in, the, 'genome,', and]), verbo([losses]), complemento([of, 17.3, '±11'])].
[sujeto([4, '%', in, 287]), verbo([target]), complemento([clones, '(', threshold, for, each, 'DCNA:', '≦085,', 1.15, '≦)'])].
[sujeto(['Metastatic', lesion, showed]), verbo([increased]), complemento([9, 'DCNAs', of, remarkable, change, '(', 'm/p', ratio, '≧1'])].
[sujeto(['Our', results, may]), verbo([provide]), complemento([several, entry, points, for, the, identification, of, candidate, genes, associated, with, aggressive, change, of, bone, tumors])].
[sujeto(['Little', is, known, about, the, genetic, variants]), verbo([associated]), complemento([with, trabecular, and, cortical, vBMD, in, 'humans,', although, both, may, be, important, for, determining, bone, strength, and, osteoporotic, risk])].
[sujeto(['In', the, current, 'analysis,', we, tested, the, hypothesis, that, there, are, genetic, variants]), verbo([associated]), complemento([with, trabecular, and, cortical, vBMD, at, the, femoral, neck, by, genotyping, 4608, tagging, and, potentially, functional, 'single-nucleotide', polymorphisms, '(', 'SNPs)', in, 383, bone, metabolism, candidate, genes, in, 822, 'Caucasian', men, aged, 65, years, or, older, from, the, 'Osteoporotic', 'Fractures', in, 'Men', 'Study', '(', 'MrOS)'])].
[sujeto(['We', identified, 'SNPs', in, five, genes, '(', 'IFNAR2,', 'NFATC1,', 'SMAD1,', 'HOXA,', and, 'KLF10)', that, were, robustly]), verbo([associated]), complemento([with, cortical, vBMD, and, 'SNPs', in, nine, genes, '(', 'APC,', 'ATF2,', 'BMP3,', 'BMP7,', 'FGF18,', 'FLT1,', 'TGFB3,', 'THRB,', and, 'RUNX1)', that, were, robustly, associated, with, trabecular, vBMD])].
[sujeto(['There', was, no, overlap, between, genes]), verbo([associated]), complemento([with, cortical, vBMD, and, trabecular, vBMD])].
[sujeto(['Two', transcription, 'factors,', the, 'helix-loop-helix', inhibitor, 'Id2', and, the, retinoic, 'acid-related', orphan, receptor, γt, '(', 'Rorγt),']), verbo([have]), complemento([been, shown, to, be, crucial, for, 'LTi', cell, development])].
[sujeto(['In', this, 'study,', we]), verbo([report]), complemento([impaired, lymphoid, tissue, organogenesis, in, mice, in, which, the, function, of, 'Runx1/Cbfβ', transcription, factor, complexes, was, attenuated, by, the, loss, of, either, the, distal, 'promoter-derived', 'Runx1', or, 'Cbfβ2', variant, protein])].
[sujeto(['We']), verbo([found]), complemento([that, 'LTi', progenitors, in, fetal, 'liver,', defined, previously, as, a, lineage, 'marker-negative', α4β7, integrin, '(', 'α4β7)(+)', 'IL-7R', 'α-chain', '(', 'IL-7Rα)(+)', 'population,', can, be, subdivided, into, 'Rorγt-expressing', 'IL-7Rα(high)', cells, and, nonexpressing, 'IL-7Rα(mid)', cells])].
[sujeto(['Whereas', 'Id2', and, 'Rorγt', are]), verbo([required]), complemento([to, direct, 'α4β7(+)IL-7Rα(mid)', cells, to, become, 'α4β7(+)IL-7Rα(high)', 'cells,', 'Runx1/Cbfβ2', complexes, are, necessary, for, the, emergence, of, 'α4β7(+)IL-7Rα(mid)', cells])].
[sujeto(['In', 'addition,', the]), verbo([loss]), complemento([of, 'Cbfβ2,', but, not, 'P1-Runx1,', resulted, in, an, inefficient, upregulation, of, 'Rorγt', in, residual, 'α4β7(+)IL-7Rα(+)', 'LTi', cells, at, anlagen])].
[sujeto(['Our', results, thus, revealed, that, 'Runx1/Cbfβ2', complexes]), verbo([regulate]), complemento([the, differentiation, of, 'LTi', cells, at, two, 'stages:', an, early, specification, of, hematopoietic, progenitors, toward, the, 'LTi', lineage, and, a, subsequent, activation, of, 'Rorγt', expression, at, anlagen])].
[sujeto(['Chemical', 'biology,', using, small, molecules, as, probes, to, study, the, cellular, signaling, 'network,']), verbo([has]), complemento([developed, rapidly, in, recent, years])].
[sujeto(['The', interaction, between, chemistry, and, biology, not, only]), verbo([provides]), complemento([new, insight, into, the, understanding, of, cellular, 'activities,', but, also, generates, new, lead, compounds, for, the, treatment, of, diseases])].
[sujeto(['Abnormalities', in, these, proteins, may]), verbo([cause]), complemento([the, dysregulation, of, hematopoiesis, and, even, the, occurrence, of, leukemia])].
[sujeto(['Ubiquitin-mediated', protein, degradation, represents, a, critical, mechanism, in]), verbo([regulating]), complemento([the, cellular, levels, and, functions, of, these, proteins])].
[sujeto(['Thus,']), verbo([targeting]), complemento([protein, degradation, has, been, emerging, as, an, important, strategy, to, conquer, malignant, diseases])].
[sujeto(['Leukotriene', 'B(4)', 'type-1', receptor, '(', 'BLT1),', which, plays, a, role, in, various, inflammatory, 'diseases,', is, exclusively]), verbo([expressed]), complemento([in, peripheral, 'leukocytes,', which, suggests, that, its, expression, is, stringently, regulated])].
[sujeto(['Here', we]), verbo([report]), complemento([that, acute, myeloid, leukemia, 1, '(', 'AML1/Runx1)', is, involved, in, the, enhancement, of, 'BLT1', expression, in, leukocytes])].
[sujeto(['In', retinoic, acid, '(', 'RA)-stimulated', human, promyelocytic, leukemia, '(', 'HL-60)', 'cells,', the, transcription, of, the, 'BLT1', gene, was]), verbo([found]), complemento([to, be, significantly, activated])].
[sujeto(['RA', did, not, directly]), verbo([modulate]), complemento([the, 'BLT1', 'promoter,', suggesting, enhancers, in, other, loci])].
[sujeto(['DNase', 'I-hypersensitivity', analyses, revealed, an]), verbo([activated]), complemento(['region,', termed, 'AE-BLex,', at, the, 'intron-I:exon-II', boundary])].
[sujeto(['AE-BLex']), verbo([acts]), complemento([as, an, enhancer, for, the, 'BLT1', promoter, and, possesses, 2, 'AML1', recognition, sites])].
[sujeto(['We', demonstrated, that, the, enhancement, of, 'BLT1', expression, during, the, 'RA-induced', differentiation, of, 'HL-60', cells, is, due, to, a, loosening, of, the, chromatin, structure, around, 'AE-BLex,', which]), verbo([leads]), complemento([to, the, incremental, binding, of, 'AML1'])].
[sujeto(['The', 'AML1/AE-BLex', complex, was, confirmed, in, other, 'BLT1-']), verbo([expressing]), complemento([leukemia, cell, lines, and, human, peripheral, leukocytes])].
[sujeto(['Thus,', 'AML1']), verbo([enhances]), complemento(['BLT1', expression, by, binding, to, 'AE-BLex,', which, is, accessible, in, leukocytes])].
[sujeto(['Acute', myeloid, leukemia, '(', 'AML)']), verbo([associated]), complemento([translocations, often, cause, gene, fusions, that, encode, oncofusion, proteins])].
[sujeto(['Although', many, of, the, breakpoints]), verbo([involved]), complemento([in, chromosomal, translocations, have, been, 'cloned,', in, most, cases, the, role, of, the, chimeric, proteins, in, tumorigenesis, is, not, elucidated])].
[sujeto(['Here', we, will, discuss, the, fusion, proteins, of, the, 4, most, common, translocations]), verbo([associated]), complemento([with, 'AML', as, well, as, the, common, molecular, mechanisms, that, these, four, and, other, fusion, proteins, utilize, to, transform, progenitor, cells])].
[sujeto(['Recurrent', balanced, translocations, are, generally]), verbo([recognized]), complemento([to, be, a, major, parameter, for, prognostication, in, acute, myeloid, leukaemia, '(', 'AML)'])].
[sujeto(['Patients', with, these, mutations]), verbo([have]), complemento([a, good, prognosis, unlike, abnormalities, in, chromosome, 5, or, 7, or, 'FLT3', genes])].
[sujeto(['Therefore,', we, screened, the, 'AmL', patients, for, known, specific, genetic, abnormalities, that, could]), verbo([lead]), complemento([to, more, definitive, prognoses])].
[sujeto(['The', prevalence, of, bcr3, '(', short, 'isoform)', was, higher, '(', 62, '%', ')', than, that, of, bcr1, '(', long, 'isoform)', '(', 38, '%', ')', and, no, correlation, was]), verbo([found]), complemento([with, 'age,', sex, or, white, blood, cell, count])].
[sujeto(['Thus,', patients, with, 'APL', who]), verbo([have]), complemento(['FLT3', mutation, appear, to, have, a, poorer, prognosis])].
[sujeto(['ERG', and, 'FLI1', are, closely, related, members, of, the, 'ETS', family, of, transcription, factors, and]), verbo([have]), complemento([been, identified, as, essential, factors, for, the, function, and, maintenance, of, normal, hematopoietic, stem, cells])].
[sujeto(['Here', 'genome-wide', analysis, revealed, that, both, 'ERG', and, 'FLI1', occupy, similar, genomic, regions, as, 'AML1-ETO', in, 't(8;21)', 'AMLs', and, identified, 'ERG/FLI1', as, proteins, that, facilitate]), verbo([binding]), complemento([of, oncofusion, protein, complexes])].
[sujeto(['In', 'addition,', we, demonstrate, that, 'ERG', and, 'FLI1']), verbo([bind]), complemento([the, 'RUNX1', promoter, and, that, 'shRNA-mediated', silencing, of, 'ERG', leads, to, reduced, expression, of, 'RUNX1', and, 'AML1-ETO,', consistent, with, a, role, of, 'ERG', in, transcriptional, activation, of, these, proteins])].
[sujeto(['Finally,', we, identify, 'H3', acetylation, as, the, epigenetic, mark, preferentially]), verbo([associated]), complemento([with, 'ETS', factor, binding])].
[sujeto(['This', intimate, connection, between, 'ERG/FLI1']), verbo([binding]), complemento([and, 'H3', acetylation, implies, that, one, of, the, molecular, strategies, of, oncofusion, 'proteins,', such, as, 'AML1-ETO', and, 'PML-RAR-α,', involves, the, targeting, of, histone, deacetylase, activities, to, 'ERG/FLI1', bound, hematopoietic, regulatory, sites])].
[sujeto(['To', establish, a, 'real-time', quantitative, reverse, transcriptase, polymerase, chain, reaction, '(', 'RQ-RT-PCR)', for, quantitative, detection, of, the, common, molecular, markers, that]), verbo([have]), complemento([affirmative, clinical, significance, in, the, acute, and, chronic, leukemia, 'patients,', and, evaluate, its, significance, in, diagnosing, leukemias, and, monitoring, minimal, residual, disease, '(', 'MRD)'])].
[sujeto(['Different', levels, of, transcription, of, corresponding, fusion, genes, are]), verbo([found]), complemento([in, various, subtypes, of, leukemias, at, 'diagnosis,', among, which, the, level, of, 'AML1-ETO', was, higher, and, 'PML-RAR', alpha, lower])].
[sujeto(['Detection', of, fusion, transcript, levels, in, untreated, leukemia, patients, not, only]), verbo([provides]), complemento([baseline, for, minimal, residual, disease, monitoring, and, treatment, evaluation, but, also, enable, the, comparison, in, 'inter-laboratory', data])].
[sujeto(['The', acute, promyelocytic, 'leukemia-specific', 'PML-RARalpha', fusion, protein, is, a, 'dominant-negative', transcriptional, repressor, of, retinoic, acid, receptor, '(', 'RAR)']), verbo([target]), complemento(['genes,', which, recruits, 'HDAC', and, corepressor, proteins, and, inhibits, coactivators])].
[sujeto(['Another', oncogenic, transcription, 'factor,', 'AML1-ETO,', was, proposed, to]), verbo([cause]), complemento([an, 'HDAC-dependent', repression, of, 'RAR', target, genes])].
[sujeto(['The', 'RAR']), verbo([target]), complemento(['RARbeta2', gene, has, been, reported, to, be, frequently, silenced, by, hypermethylation, in, many, types, of, cancer, cells])].
[sujeto(['PML-RARalpha', positive, 'NB4', and, its, 'ATRA-resistant', subvariant, 'MR2', and, 'AML1-ETO']), verbo([expressing]), complemento(['Kasumi-1', cells, had, heterozygous, methylation, of, 'RARbeta2'])].
[sujeto(['Although', 'DNA', methyltransferase, inhibitor, 5, -, 'aza-2\'-deoxycytidine', partially, reversed, 'RARbeta2', 'CpG', methylation, in, these, 'cells,', it, did, not, significantly]), verbo([enhance]), complemento(['ATRA-induced', 'RARbeta2', mRNA, expression, and, induction, of, maturation])].
[sujeto(['However,', the, histone, acetylase, inhibitor, 'SAHA', combined, with, 'ATRA', significantly]), verbo([reactivated]), complemento(['RARbeta2', mRNA, both, in, 'NB4', and, 'MR2', cells, with, degradation, of, 'PML-RARalpha,', which, was, associated, with, maturation])].
[sujeto(['In', 'contrast,', 'SAHA', did, not, affect, 'AML1-ETO', levels, and, failed, to]), verbo([induce]), complemento(['RARbeta2', expression, and, maturation, in, 'Kasumi-1', cells])].
[sujeto(['These', results, demonstrate, that, oncogenic, 'PML-RARalpha', and, 'AML1-ETO', translocations, are, rarely]), verbo([associated]), complemento([with, 'RARbeta2', promoter, methylation, in, primary, 'AML', samples])].
[sujeto(['Bone', marrow, samples, from, 161, cases, of, leukemia, and, 8, cases, of, myelodysplastic, syndrome, '(', 'MDS)', were]), verbo([involved]), complemento([in, the, study])].
[sujeto(['Ten', fusion, genes, were, detected, in, 115, cases, of, 'leukemia,', including, 'AML1/ETO,', 'PML/RAR', 'alpha,', 'PLZF/RAR', 'alpha,', 'dupMLL,', 'MLL/AF6,', 'MLL/AF10,', 'CBFbeta/MYH11,', 'BCR/ABL,', 'Hox11,', and, 'EVI1', 'BCR/ABL', was, positive, in, all, the, 52, cases, of, chronic, myeloid, 'leukemia;', 'PML/RAR', alpha, was]), verbo([found]), complemento([in, 21, of, 25, acute, promyelocytic, leukemia, '(', 'APL),', and, 'PLZF/RAR', alpha, was, detected, in, one, case, of, 'APL'])].
[sujeto(['MLL', aberrations, were]), verbo([found]), complemento([in, 16, 'AL,', in, which, all, 'MLL/AF6', translocation, existed, in, 'M5', subtype, with, classic, monoblastic, characters])].
[sujeto(['Fusion', genes, were, also]), verbo([found]), complemento([in, 2, 'MDS', 'cases,', of, which, 'AML1/ETO', 'positive-MDS-RAEB', progressed, to, 'AML', rapidly])].
[sujeto(['Screening', of, common, fusion, genes, by, multiplex, 'RT-PCR', is, an, important, tool, which, could]), verbo([provide]), complemento([useful, and, reliable, molecular, genetic, information, for, the, diagnosis, and, treatment, of, leukemia])].
[sujeto(['Many', studies]), verbo([have]), complemento([assessed, the, clinical, significance, of, the, detection, of, minimal, residual, disease, '(', 'MRD)', in, acute, leukemia])].
[sujeto(['Thus', 'far,', many, studies]), verbo([have]), complemento([suggested, that, 'MRD', detection, to, evaluate, the, response, to, chemotherapy, is, useful, for, predicting, the, prognosis, of, childhood, acute, lymphoblastic, leukemia, '(', 'ALL)'])].
[sujeto(['However,', few, studies]), verbo([have]), complemento([reported, on, the, significance, of, 'MRD', in, childhood, acute, myeloid, leukemia, '(', 'AML),', because, of, small, numbers, of, patients, and, limited, availability, of, 'MRD', markers])].
[sujeto(['The', 'AML1/MTG8', fusion, gene, was]), verbo([expressed]), complemento([in, 8, 'patients,', 'PML/RAR', alpha, was, expressed, in, 3, 'patients,', and, 'MYH11/CBF', beta, was, expressed, in, 1, patient])].
[sujeto(['On', the, other, 'hand,', 1, of, the, 2, patients, who, continued, on, chemotherapy, continued, to, be, 'MRD', 'positive,']), verbo([suggesting]), complemento([a, 'graft-versus-leukemia', effect, in, allogeneic, 'SCT'])].
[sujeto(['The', 3, -, year, 'event-free', survival, in, de, novo, 'AML', was, 69.4, '%', +, /, -, 9.8, '%', '(', n, =, 26, ')', ',', a, result, that, is, encouraging, and, superior, to, other]), verbo([reported]), complemento([outcomes])].
[sujeto(['Thus,', an, 'MRD-based', treatment, strategy, together, with, conventional, risk, factors, appears, to, be]), verbo([required]), complemento([for, further, improving, the, outcomes, of, 'AML'])].
[sujeto(['Expression', of, 'AML', fusion, proteins, in, transgenic, mice]), verbo([increases]), complemento([the, risk, of, myeloid, 'leukemias,', suggesting, that, they, induce, a, preleukemic, state])].
[sujeto(['We']), verbo([expressed]), complemento(['AML1/ETO,', 'PML/RAR,', and, 'PLZF/RAR', in, 'U937', hemopoietic, precursor, cells, and, measured, global, gene, expression, using, oligonucleotide, chips])].
[sujeto(['We', identified, 1, ',', 555, genes]), verbo([regulated]), complemento([concordantly, by, at, least, two, fusion, proteins, that, were, further, validated, in, patient, samples, and, finally, classified, according, to, available, functional, information])].
[sujeto(['Strikingly,', we]), verbo([found]), complemento([that, 'AML', fusion, proteins, induce, genes, involved, in, the, maintenance, of, the, stem, cell, phenotype, and, repress, 'DNA', repair, 'genes,', mainly, of, the, base, excision, repair, pathway])].
[sujeto(['Functional', studies, confirmed, that, ectopic, expression, of, fusion, proteins, constitutively]), verbo([activates]), complemento([pathways, leading, to, increased, stem, cell, renewal, '(', e])].
[sujeto([',', the, 'Jagged1/Notch', 'pathway)', and]), verbo([provokes]), complemento([accumulation, of, 'DNA', damage])].
[sujeto(['Mutations', in, signal, transduction, 'molecules,', which]), verbo([regulate]), complemento([cell, differentiation, and, 'proliferation,', are, involved, in, the, development, of, leukemia])].
[sujeto(['BCR/ABL']), verbo([found]), complemento([in, chronic, myelogenous, leukemia, '(', 'CML)', is, a, hallmark, of, the, constitutively, active, forms, of, cytoplasmic, tyrosine, kinases])].
[sujeto(['Downstream', of, the, tyrosine, kinase, is, the, 'RAS', 'GTP-binding', 'protein,', and, genetic, mutations, related, to, this, protein]), verbo([have]), complemento([been, found, in, a, wide, variety, of, malignant, tumors, including, hematopoietic, tumors])].
[sujeto(['In', the, 'nucleus,', transcription, 'factor-encoding', genes, are, frequently, detected, as, the]), verbo([targets]), complemento([of, chromosomal, translocations, found, in, specific, types, of, leukemias])].
[sujeto(['Another', example, of, abnormal, transcription, factors, is, 'PML/RAR', alpha, generated, by, t, '(', 15, ;, 17, ')', translocation]), verbo([found]), complemento([in, acute, promyelocytic, leukemia])].
[sujeto(['Mutations', or, deletions, of, tumor, suppressor, genes, are, frequently]), verbo([found]), complemento([in, cell, cycle, regulators, such, as, 'p53,', 'RB', and, p16, genes])].
[sujeto(['Therefore,', mutations, of, any, molecules]), verbo([involved]), complemento([in, the, signal, transduction, pathways, from, growth, factor, receptors, to, inside, the, nucleus, are, thought, to, contribute, to, neoplastic, transformation, of, hematopoietic, cells])].
[sujeto(['To', present, a, special, case, with, the, karyotype, and, molecular, marker, of, acute, myeloid, leukemia, '(', 'AML)-M2', who, was]), verbo([induced]), complemento([to, complete, remission, by, 'all-trans', retinoic, acid, '(', 'ATRA)', alone])].
[sujeto(['After', primarily, cultured, bone, marrow, cells, from, the, iliac, aspiration, were, tested, for, in, vitro]), verbo([induced]), complemento(['differentiation,', the, patient, was, treated, with, oral, 'all-trans', retinoic, acid, 'alone,', 60, mg, per, day, until, complete, remission, was, achieved])].
[sujeto(['The', characteristic, chromosomal, aberration, for, 'M3,', the, 't(15;17)', reciprocal, 'translocation,', was, not]), verbo([found]), complemento([while, a, 't(8;21)', translocation, was, verified])].
[sujeto(['Primary', cultured, bone, marrow, cells, can, be, fully]), verbo([induced]), complemento([to, terminal, differentiation, after, 4, days, exposure, to, 'ATRA'])].
[sujeto(['A', hematological, complete, remission, was, achieved, after, 40, days, treatment, with, 'ATRA', as, a, single, therapeutic, 'agent,']), verbo([suggesting]), complemento([an, alternative, pathway, mediating, 'ATRA-induced', myeloid, differentiation])].
[sujeto(['A', leukemia, patient, with, a, subtype, other, than, 'M3,', such, as, 'M2', in, this, 'case,', may, also, be]), verbo([induced]), complemento([to, complete, remission, by, the, mechanism, of, 'ATRA-induced', terminal, differentiation])].
[sujeto(['This', implies, that, there, may, be, a, pathway, other, than, 'PML/RAR', alpha, fusion, gene, product, which]), verbo([mediates]), complemento(['ATRA-induced', myeloid, maturation, in, leukemia, cells])].
[sujeto(['This', effect, is, due, to, the, ability, of, the, 'ETO', portion, of, the, protein, to]), verbo([recruit]), complemento(['co-repressors', to, promoters, of, 'AML-1', target, genes])].
[sujeto(['The', 't(11;17)(q21;q23)-associated', acute, promyelocytic, leukemia, creates, the, promyelocytic, leukemia, zinc, finger, 'PLZFt/RAR', alpha, fusion, protein, 'and,', in, a, similar, 'manner,']), verbo([inhibits]), complemento(['RAR', alpha, target, gene, expression, and, myeloid, differentiation])].
[sujeto(['PLZF', is]), verbo([expressed]), complemento([in, hematopoietic, progenitors, and, functions, as, a, growth, suppressor, by, repressing, cyclin, 'A2', and, other, targets])].
[sujeto(['This', effect, was, dependent, on, the, presence, of, the, 'ETO', zinc, finger, 'domain,', which]), verbo([recruits]), complemento(['corepressors,', and, could, not, be, rescued, by, overexpression, of, 'co-repressors', that, normally, enhance, 'PLZF', repression])].
[sujeto(['AML-1/ETO', also, excluded, 'PLZF', from, the]), verbo([nuclear]), complemento([matrix, and, reduced, its, ability, to, bind, to, its, cognate, 'DNA-binding', site])].
[sujeto(['Finally,', 'ETO']), verbo([interacted]), complemento([with, 'PLZF/RAR', alpha, and, enhanced, its, ability, to, repress, through, the, 'RARE'])].
[sujeto([2000, ;, 96, :, 3939, -, 3947, ')', 'RAR', and, 'AML1', transcription, factors, are]), verbo([found]), complemento([in, leukemias, as, fusion, proteins, with, 'PML', and, 'ETO,', respectively])].
[sujeto(['Association', of, 'PML-RAR', and, 'AML1-ETO', with, the]), verbo([nuclear]), complemento([corepressor, '(', 'N-CoR)/histone', deacetylase, '(', 'HDAC)', complex, is, required, to, block, hematopoietic, differentiation])].
[sujeto(['We', show, that, 'PML-RAR', and, 'AML1-ETO', exist, in, vivo, within, high, molecular, weight, '(', 'HMW)']), verbo([nuclear]), complemento(['complexes,', reflecting, their, oligomeric, state])].
[sujeto(['Oligomerization']), verbo([requires]), complemento(['PML', or, 'ETO', 'coiled-coil', regions, and, is, responsible, for, abnormal, recruitment, of, 'N-CoR,', transcriptional, 'repression,', and, impaired, differentiation, of, primary, hematopoietic, precursors])].
[sujeto(['The', 'Wilms', tumor, gene, '(', 'WT1)']), verbo([has]), complemento([been, reported, to, be, a, prognostic, factor, and, a, marker, for, the, detection, of, minimal, residual, disease, '(', 'MRD)', in, acute, leukemia])].
[sujeto(['Here', we, studied, minimal, residual, disease, '(', 'MRD)', of, patients, with, acute, myeloid, leukemia, '(', 'AML)', who]), verbo([have]), complemento(['PML/RAR', alpha, or, 'AML1/ETO', as, well, as, the, phenotypic, analysis, of, lymphocyte, subsets, involved, in, antitumor, immunity])].
[sujeto(['Basically,', the, total, percentage, of, the, 'CD4+,', 'CD8+', and, 'CD56+', cell, populations, in, the, 'BM', was]), verbo([increased]), complemento([and, in, the, following, 'order:', 'MRD-/LT', 'patients,', normal, 'volunteers,', 'MRD+/LT', patients, and, 'MRD+', or, -, /, 'ST', patients])].
[sujeto(['Sequence', analysis, revealed, that, the, promoter, of, gcfoxp3, contains, 'AP-1,', 'AML-1/Runx1,', 'NF-κb', and, 'GATA-3']), verbo([binding]), complemento(['sites,', which, positively, or, negatively, regulate, mammalian, foxp3, expression])].
[sujeto(['In', 'addition,', the, intron, 'II', of, gcfoxp3, contains, some, putative]), verbo([binding]), complemento([sites, including, 'AP-1,', 'NFAT,', 'Smad3,', 'RAR,', 'CREB/ATF', and, 'FOXO1,', which, are, corresponding, to, their, locations, in, the, proximal, intronic, enhancers, of, human, foxp3])].
[sujeto(['In', an, in, vivo, model, of, grass, 'carp,', an, immunosuppressive, agent, rapamycin, was, showed, to]), verbo([stimulate]), complemento([gcfoxp3, mRNA, expression, in, 'thymus,', 'gill,', head, kidney, and, spleen, after, bacterial, challenge])].
[sujeto(['Moreover,', rapamycin]), verbo([increased]), complemento([gcFoxp3, protein, levels, with, an, additive, manner, in, the, infected, fish])].
[sujeto(['These', findings, support, the, involvement, of, fish, 'Foxp3', in, immune, response, and, highlight, a, possible, signaling, pathway, that]), verbo([regulates]), complemento([teleost, 'Foxp3', expression])].
[sujeto(['Terminal', differentiation, of, blood, cells]), verbo([requires]), complemento([the, concerted, action, of, a, series, of, transcription, factors, that, are, expressed, at, specific, stages, of, maturation, and, function, in, a, 'cell-type', and, 'dosage-dependent', manner])].
[sujeto(['A', role, for, 'PIR', in, myeloid, differentiation]), verbo([has]), complemento([not, to, date, been, reported])].
[sujeto(['In', this, study, we, show, that, 'PIR', expression, is, significantly]), verbo([repressed]), complemento([in, a, large, proportion, of, acute, myeloid, leukemias, '(', 'AMLs),', regardless, of, subtype, or, underlying, karyotypic, abnormalities])].
[sujeto(['We', show, that, 'PIR', expression]), verbo([increases]), complemento([during, in, vitro, myeloid, differentiation, of, primary, hematopoietic, precursor, 'cells,', and, that, ablation, of, 'PIR', in, the, 'U937', myelomonocytic, cell, line, or, in, murine, primary, hematopoietic, precursor, cells, results, in, impairment, of, terminal, myeloid, differentiation])].
[sujeto(['Gene', expression, profiling, of, 'U937', cells, after, knockdown, of, 'PIR', revealed]), verbo([increased]), complemento([expression, of, genes, associated, with, the, early, phases, of, 'hematopoiesis,', in, 'particular,', homeobox, 'A', '(', 'HOXA)', genes])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'PIR', is, required, for, terminal, myeloid, 'maturation,', and, its, downregulation, may, contribute, to, the, differentiation, arrest, associated, with, 'AML'])].
[sujeto(['A', number, of, molecular]), verbo([targets]), complemento([have, been, identified, in, 'leukemia,', based, on, the, understanding, of, signaling, pathways, controlling, cell, 'differentiation,', 'proliferation,', 'apoptosis,', and, malignant, transformation])].
[sujeto(['Growth', factors, and, integrins]), verbo([interact]), complemento([with, their, receptors, and, activate, signaling, cascades, with, intimate, interconnections])].
[sujeto(['The', specific, niches, within, the, bone, marrow, microenvironment, may]), verbo([provide]), complemento([a, sanctuary, for, subpopulations, of, leukemic, cells, to, escape, 'chemotherapy-induced', death, and, acquire, drug, resistance])].
[sujeto(['Investigations', into, bone, marrow, 'stroma-leukemia', crosstalk, may, result, in, the, development, of, strategies, against, the, acquisition, of, a, 'chemo-resistant', phenotype, and]), verbo([enhance]), complemento([the, efficacy, of, therapies, in, leukemia])].
[sujeto(['In', recent, 'studies,', we, proposed, novel, therapeutic, interventions]), verbo([targeting]), complemento([the, 'microenvironment/leukemia', interaction, focusing, on, 'SDF1/CXCR4,', 'ILK/PI3K/Akt,', 'TGF-beta,', and, 'Notch', signaling])].
[sujeto(['Gene', transcriptional, activity, is]), verbo([regulated]), complemento([by, chromatin, modification, and, 'DNA', methylation])].
[sujeto(['The', transcription, of]), verbo([target]), complemento([genes, is, initiated, following, the, ligation, of, these, 'receptors,', recruitment, of, 'co-activators,', and, replacement, of, repressors])].
[sujeto(['We', demonstrated, that, histone, acetylation, by, the, 'PPARgamma', agonist, 'CDDO,', 'RAR/RXR', agonist, 'ATRA,', 'and/or', histone, deacetylase, inhibitors, '(', 'HDACIs)', reversed, the, silenced, 'RARbeta', and, 'MDR1', genes, in, acute, promyelocytic, 'leukemia,', and, that, 'HDACI']), verbo([induced]), complemento([apoptosis, with, phagocytosis, through, the, induction, of, 'Annexin', 'A1', in, 'AML1/ETO-positive', acute, myelocytic, leukemia, '(', 'AML)', cells])].
[sujeto(['Finally,', we, emphasize, the, potential, applications, of, research, findings, and, methods, in, the, fields, of, clinical, 'medicine,', molecular, 'diagnosis,', and]), verbo([targeting]), complemento([therapy])].
[sujeto(['To', investigate, the, expression, level, of, preferentially]), verbo([expressed]), complemento([antigen, of, melanoma, '(', 'PRAME)', mRNA, in, newly, diagnosed, acute, myeloid, leukemia, '(', 'AML)', patients, and, evaluate, its, usefulness, for, detecting, minimal, residual, disease, '(', 'MRD)'])].
[sujeto(['PRAME', mRNA, levels, were, detected, in, bone, marrow, samples, from, 142, newly, diagnosed, 'AML', patients, '(', 72, of, them, 'didn\'t']), verbo([express]), complemento([any, specific, fusion, 'gene)', by, 'TaqMan', based, 'real-time', quantitative, 'PCR', 'methods,', and, were, serially, monitored, in, 60, bone, marrow, samples, from, 9, 'follow-up', patients, '(', 2, of, them, without, specific, fusion, 'gene),', including, 3, in, continuous, complete, 'remission,', 6, in, hematological, relapse])].
[sujeto([abl, was, selected, as, control, 'gene,', 'PRAME', and, 'AML1-ETO', mRNA, levels, were]), verbo([expressed]), complemento([by, their, 'copies/abl', copies, in, percentage])].
[sujeto(['All', 'NBM', samples]), verbo([expressed]), complemento(['PRAME', mRNA, and, the, upper, limit, was, 0.28, '%'])].
[sujeto(['For', all, newly, diagnosed, 'AML', 'patients,', median, 'PRAME', mRNA, level, was, 3.97, '%', '(', 0.0, '%', -, 714.97, '%', ')', ',', 76.8, '%', of, them, was, higher, than, 0.28, '%', ',', 54.9, '%', had, over, 1, -, log]), verbo([increasing]), complemento([and, 26.1, '%', had, over, 2, -, log, increasing])].
[sujeto(['AML1-ETO', '(', +, ')', 'M2', patients]), verbo([expressed]), complemento([the, highest, levels, '(', all, 'P<0'])].
[sujeto(['PRAME', mRNA, levels, in, 3, hematological, relapsed, patients]), verbo([increased]), complemento([above, 0.28, '%', 1, -, 4, months, ahead, 'relapse,', and, in, other, 3, relapsed, patients, the, levels, never, decreased, to, normal, range, even, in, remission])].
[sujeto(['PRAME', mRNA, could, be, used, to, monitor, 'MRD', for, 'AML', patients, with, higher, than, normal, 'levels,', and, it]), verbo([increases]), complemento([over, or, persistently, higher, than, normal, range, predicts, hematological, relapse])].
[sujeto(['Basophilic', crisis, and, eosinophilia, are, well]), verbo([recognized]), complemento([features, of, advanced, chronic, myeloid, leukaemia])].
[sujeto(['In', this, 'patient,', who, initially, suffered, from, chronic, myelomonocytic, 'leukaemia,', basophils]), verbo([increased]), complemento([to, 48, '%', and, eosinophils, up, to, 31, '%', at, the, time, of, progression])].
[sujeto(['Mixed', lineage, crisis, was, not, accompanied, by, an]), verbo([increase]), complemento([in, blast, cells, or, organomegaly])].
[sujeto(['Basophils', were, thus]), verbo([found]), complemento([to, be, 'CD123+,', 'CD203c+,', 'BB1+,', 'KIT-', 'cells,', and, to, express, a, functional, 'IgE-receptor'])].
[sujeto(['Among', the, other, patients, with, 'MDS', 'examined,', 4, '(', 1.2, '%', ')', were]), verbo([found]), complemento([to, have, marked, basophilia, '(', &, 'gt;or=', 20, '%', ')', and, 7, '(', 2.1, '%', ')', were, found, to, have, massive, eosinophilia, '(', &, 'gt;or=', 20, '%', ')', ',', whereas, 'mixed-lineage', crisis, was, detected, in, none, of, them])].
[sujeto(['Histone', deacetylases, '(', 'HDACs)']), verbo([regulate]), complemento([transcription, and, specific, 'functions,', such, as, tumor, suppression, by, 'p53,', and, are, frequently, altered, in, cancer])].
[sujeto(['Inhibitors', of, 'HDACs', '(', 'HDACI)', possess, 'anti-tumor', activity, and, are, well, 'tolerated,']), verbo([suggesting]), complemento([that, they, might, develop, into, a, specific, strategy, for, cancer, treatment])].
[sujeto(['Indeed,', 'HDACIs']), verbo([have]), complemento([successfully, entered, clinical, 'trials,', but, the, molecular, basis, for, their, selective, 'anti-tumor', activities, is, not, clear])].
[sujeto(['Recent', work, on, leukemias]), verbo([expressing]), complemento([the, 'PML-RAR', or, 'AML1-ETO', 'oncogenes,', known, to, initiate, leukemogenesis, through, deregulation, of, 'HDACs,', shows, that, 'HDACIs', induce, massive, 'blast-cell', apoptosis])].
[sujeto(['Significantly,', normal, myeloid, progenitors, are, not, sensitive, to, 'HDACI-induced', apoptosis, and, oncogene, expression, is, not, sufficient, to]), verbo([confer]), complemento(['HDACI-sensitivity', to, normal, 'cells,', demonstrating, that, sensitivity, to, 'HDACI', is, a, property, of, the, fully, transformed, phenotype])].
[sujeto(['In', the, last, twenty, 'years,', using, 'all-trans', retinoic, acid, '(', 'ATRA)', as, a, differentiation, 'inducer,', 'Shanghai', 'Institute', of, 'Hematology']), verbo([has]), complemento([achieved, an, important, breakthrough, in, the, treatment, of, acute, promyelocytic, leukemia, '(', 'APL),', which, realized, the, theory, of, reversing, phenotype, of, cells, and, provided, a, successful, model, of, differentiation, therapy, in, cancers])].
[sujeto(['The', ability, of, 'ATRA', to, modify, the, recruitment, of]), verbo([nuclear]), complemento([receptor, 'co-repressor', with, 'PML-RAR', alpha, but, not, 'PLZF-RAR', alpha, caused, by, the, variant, chromosome, translocation, elucidated, the, therapeutic, mechanism, of, 'ATRA', from, the, molecular, level, and, provides, new, insight, into, 'transcription-modulating', therapy])].
[sujeto(['Since', 1994, ',', our, group]), verbo([has]), complemento([successfully, applied, arsenic, trioxide, '(', 'As(2)O(3))', in, treating, relapsed, 'APL', 'patients,', with, the, complete, remission, rate, of, 70, '%', -, 80, '%'])].
[sujeto(['Low-dose', 'As(2)O(3)']), verbo([induced]), complemento([partial, differentiation, of, 'APL', 'cells,', while, the, higher, dose, induced, apoptosis])].
[sujeto(['As(2)O(3)']), verbo([binds]), complemento([ubiquitin, like, 'SUMO-1', through, the, lysine, 160, of, 'PML,', resulting, in, the, degradation, of, 'PML-RAR', alpha])].
[sujeto(['Taken', 'together,', 'ATRA', and, 'As(2)O(3)']), verbo([target]), complemento([the, transcription, factor, 'PML-RAR', 'alpha,', the, former, by, retinoic, acid, receptor, and, the, latter, by, 'PML', 'sumolization,', both, induce, 'PML-RAR', alpha, degradation, and, 'APL', cells, differentiation, and, apoptosis])].
[sujeto(['Because', of, the, different]), verbo([acting]), complemento(['pathways,', 'ATRA', and, 'As(2)O(3)', have, no, 'cross-resistance', and, can, be, used, as, combination, therapy])].
[sujeto(['Based', on, the, great, success, of, the, pathogenetic, gene]), verbo([target]), complemento([therapy, in, 'APL,', this, strategy, may, extend, to, other, leukemias])].
[sujeto(['Combination', of, 'Gleevec', and, arsenic, agents, in, treating, chronic, myeloid, leukemia]), verbo([has]), complemento([already, make, a, figure, both, in, clinical, and, laboratory, 'research,', aiming, at, counteracting, the, abnormal, tyrosine, kinase, activity, of, 'ABL', and, the, degradating, 'BCR-ABL', fusion, protein])].
[sujeto(['In', acute, myeloid, leukemia, 'M(2b),', using, new]), verbo([target]), complemento([therapy, degradating, 'AML1-ETO', fusion, protein, and, reducing, the, abnormal, tyrosine, kinase, activity, of, 'c-kit', will, also, lead, to, new, therapeutic, management, in, acute, leukemias])].
[sujeto(['Histone', deacetylases, '(', 'HDACs)']), verbo([regulate]), complemento([transcription, and, specific, cellular, 'functions,', such, as, tumor, suppression, by, 'p53,', and, are, frequently, altered, in, cancer])].
[sujeto(['We', investigated, the, effects, of, 'HDACIs', on, leukemias]), verbo([expressing]), complemento([the, 'PML-RAR', or, 'AML1-ETO', 'oncoproteins,', known, to, initiate, leukemogenesis, through, deregulation, of, 'HDACs'])].
[sujeto(['Here', we]), verbo([report]), complemento(['that:', '(', 'i)', 'HDACIs', induce, apoptosis, of, leukemic, 'blasts,', although, oncogene, expression, is, not, sufficient, to, confer, 'HDACI', sensitivity, to, normal, 'cells;', '(', 'ii)', apoptosis, is, p53, independent, and, 'depends,', both, in, vitro, and, in, 'vivo,', upon, activation, of, the, death, receptor, pathway, '(', 'TRAIL', and, 'Fas', signaling, 'pathways);', '(', 'iii)', 'TRAIL,', 'DR5,', 'FasL', and, 'Fas', are, upregulated, by, 'HDACIs', in, the, leukemic, 'cells,', but, not, in, normal, hematopoietic, progenitors])].
[sujeto(['The', speed, of, 'FISH', is, very, valuable, in, 'AML-M3/M3v', because, 'PML/RAR+', patients]), verbo([require]), complemento([specific, therapy])].
[sujeto(['Furthermore,', we]), verbo([suggest]), complemento(['FISH', screening, in, 'failed,', complex, or, suboptimal, quality, chromosome, and, specific, 'FISH', analysis, for, 5, 'q,', 7, 'q,', 12, 'p,', 17, 'p,', 'inv(16),', 't(11q23)', in, order, to, implement, 'CBA', accuracy])].
[sujeto(['Genes,', such, as, those, of, 'mixed-lineage', 'leukaemia,', 'AML1', and, retinoic, acid, receptor, 'alpha,']), verbo([have]), complemento([been, found, to, be, aberrantly, fused, to, different, 'partners,', which, often, encode, transcription, factors, or, other, chromatin, modifying, 'enzymes,', in, numerous, types, of, acute, lymphoid, and, myeloid, leukaemias])].
[sujeto(['These', chimeric, fusion, 'oncoproteins,', generated, by, reciprocal, chromosomal, 'translocations,', are, responsible, for, chromatin, alterations, on]), verbo([target]), complemento([genes, whose, expression, is, critical, to, stem, cell, development, or, lineage, specification, in, haematopoiesis])].
[sujeto(['Alterations', in, the, '\'', histone, 'code\'', or, in, the, 'DNA', methylation, content, occur, as, consequence, of, aberrant]), verbo([targeting]), complemento([of, the, corresponding, enzymatic, activities])].
[sujeto(['Several', lines, of, evidence]), verbo([suggest]), complemento([similar, pathogenetic, mechanisms, for, these, fusion, proteins])].
[sujeto(['We', used, 'high-density', oligonucleotide, arrays, to, identify, shared]), verbo([target]), complemento([genes, in, inducibly, transfected, 'U937', cells, expressing, 'AML1-ETO,', 'PML-RARalpha,', or, 'PLZF-RARalpha'])].
[sujeto(['All', three, fusion, proteins, significantly]), verbo([repressed]), complemento([the, expression, of, 38, genes, and, induced, the, expression, of, 14, genes])].
[sujeto(['Several', of, the]), verbo([regulated]), complemento([genes, were, associated, with, 'Wnt', signaling])].
[sujeto(['One', of, 'these,', plakoglobin, '(', 'gamma-catenin),', was]), verbo([induced]), complemento([on, the, mRNA, and, protein, level, by, all, three, fusion, proteins])].
[sujeto(['The', plakoglobin, promoter, was, cloned, and, shown, to, be]), verbo([induced]), complemento([by, 'AML1-ETO,', with, promoter, activation, depending, on, the, corepressor, and, histone, deacetylase, binding, domains])].
[sujeto(['The', induction, of, plakoglobin, by, 'AML', fusion, proteins]), verbo([led]), complemento([to, downstream, signaling, and, transactivation, of, 'TCF-', and, 'LEF-dependent', 'promoters,', including, the, 'c-myc', 'promoter,', which, was, found, to, be, bound, by, plakoglobin, in, vivo, after, 'AML1-ETO', expression])].
[sujeto(['beta-Catenin', protein, levels, and, 'TCF', and, 'LEF']), verbo([target]), complemento([genes, such, as, 'c-myc', and, cyclin, 'D1', were, found, to, be, induced, by, the, fusion, proteins])].
[sujeto(['On', the, functional, 'level,', a, dominant, negative, 'TCF']), verbo([inhibited]), complemento([colony, growth, of, 'AML1-ETO-positive', 'Kasumi', 'cells,', whereas, plakoglobin, transfection, into, myeloid, 32, 'D', cells, enhanced, proliferation, and, clonal, growth])].
[sujeto(['Transduction', of, plakoglobin, into, primitive, murine, hematopoietic, progenitor, cells, preserved, the, immature, phenotype, during, colony, 'growth,']), verbo([suggesting]), complemento([enhanced, 'self-renewal'])].
[sujeto(['These', data]), verbo([provide]), complemento([evidence, that, activation, of, 'Wnt', signaling, is, a, common, feature, of, several, balanced, translocations, in, 'AML'])].
[sujeto(['We']), verbo([report]), complemento([a, case, of, acute, myeloid, leukemia, 'FAB-type', 2, with, a, translocation, 't(15;17)(q22;q12)', 'On', the, basis, of, the, cytological, 'findings,', a, translocation, 't(8;21)(q22;q22)', was, suspected])].
[sujeto(['Oncogene', amplification, resulting, in, aberrant, 'expression,', although, common, in, solid, 'tumors,', is, rare, in, acute, myeloid, leukemia, '(', 'AML)', and, is, mostly]), verbo([associated]), complemento([with, amplification, of, 'MYC,', 'RUNX1,', and, 'MLL', genes])].
[sujeto(['Retinoic', acid, receptor, alpha, '(', 'RARA)', and, other]), verbo([target]), complemento([sequences, at, 17, p11])].
[sujeto([2, often, represent, the, amplicons]), verbo([expressed]), complemento([in, breast, 'cancer,', not, in, 'AML'])].
[sujeto(['Fluorescence', in, situ, hybridization, '(', 'FISH)', analysis, showed, amplification, of, 'RARA,']), verbo([loss]), complemento([of, 7, 'q,', monosomy, 7, ',', loss, of, 'DEK', '(', 6, 'p23),', and, additional, copies, of, 'NUP214', '(', 9, 'q34)', and, 'MLL', '(', 11, 'q23)'])].
[sujeto(['Additional', case]), verbo([reports]), complemento([are, necessary, to, assess, whether, 'RARA', amplification, in, hematologic, malignancies, serves, as, an, independent, prognostic, factor])].
[sujeto(['The', use, of, genetically, engineered, mice, '(', 'GEM)']), verbo([have]), complemento([been, critical, in, understanding, disease, states, such, as, 'cancer,', and, none, more, so, than, acute, myelogenous, leukaemia, '(', 'AML),', a, disease, characterized, by, over, 100, distinct, chromosomal, translocations])].
[sujeto(['A', substantial, proportion, of, cases, exhibiting, recurrent, reciprocal, translocations, at, 'diagnosis,', such, as, 't(8;21)', or, 't(15;17)']), verbo([have]), complemento([been, exhaustively, studied, and, are, currently, employed, in, clinical, diagnosis])].
[sujeto(['Furthermore,', little, emphasis]), verbo([has]), complemento([been, paid, to, the, effect, of, chromosomal, translocations, other, than, recurrent, genetic, 'abnormalities,', with, no, models, reflecting, the, multiple, abnormalities, observed, in, 'high-risk', cases, of, 'AML', accounting, for, 8, -, 10, '%', of, adult, 'AML'])].
[sujeto(['The', latter]), verbo([have]), complemento([been, used, to, great, effect, in, defining, the, transforming, properties, of, chromosomal, translocation, products, such, as, 'MLL', '(', found, in, 5, -, 6, '%', of, all, 'AML', 'cases)', and, 'NUP98', '(', denoting, poor, prognosis, in, 'therapy-related', 'disease)', and, particularly, when, 'co-transduced', with, bad, prognostic, factors, such, as, 'Flt3', mutations])].
[sujeto(['Finally,', we, comment, on, the, emergence, of, newer, transduction, 'technologies,', which, can]), verbo([regulate]), complemento([the, level, of, expression, to, defined, cell, lineages, in, both, primary, murine, and, human, 'xenografts,', and, discuss, how, combining, multiple, genetic, 'modalities,', more, relevant, models, of, this, complex, disease, are, being, generated])].
[sujeto([1, gene, mutations, were, identified, in, some, patients, with, acute, myeloid, leukemia, '(', 'AML)', and, as, several, oncogenic, products, '(', 'AML1-ETO,', promyelocytic, 'leukemia-retinoic', acid, receptor, 'alpha,', 'FMS-like', receptor, tyrosine, kinase, 3, internal, tandem, 'duplication)', are]), verbo([associated]), complemento([with, 'PU'])].
[sujeto(['In', 'NB4', cells, we, obtained]), verbo([increases]), complemento([in, 'PU'])].
[sujeto([1, mRNA, and, 'protein,', comparable, to]), verbo([increases]), complemento([obtained, with, 'all-trans', retinoic, 'acid-stimulation'])].
[sujeto(['Transduced', cells, showed]), verbo([increased]), complemento([myelomonocytic, surface, antigen, 'expression,', decreased, proliferation, rates, and, increased, apoptosis])].
[sujeto([1, should, therefore, constitute, an, interesting]), verbo([target]), complemento([for, therapeutic, intervention, in, 'AML'])].
[sujeto(['MEF', is, an, 'ETS-related', transcription, factor, with, strong, transcriptional]), verbo([activating]), complemento([activity, that, affects, hematopoietic, stem, cell, behavior, and, is, required, for, normal, 'NK', cell, and, 'NK', 'T-cell', development])].
[sujeto(['The', 'MEF', '(', also, known, as, 'ELF4)', gene, is]), verbo([repressed]), complemento([by, several, 'leukemia-associated', fusion, transcription, factor, proteins, '(', 'PML-retinoic', acid, receptor, alpha, and, 'AML1-ETO),', but, it, is, also, activated, by, retroviral, insertion, in, several, cancer, models])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, cyclin, 'A-dependent', phosphorylation, of, 'MEF', largely, restricts, its, activity, to, the, 'G(1)', phase, of, the, cell, 'cycle;', we, now, show, that, 'MEF', is, a, 'short-lived', protein, whose, expression, level, also, peaks, during, late, 'G(1)', phase])].
[sujeto(['Mutagenesis', studies, show, that, the, rapid, turnover, of, 'MEF', in, 'S', phase, is, dependent, on, the, specific, phosphorylation, of, threonine, 643, and, serine, 648, at, the, 'C', terminus, of, 'MEF', by, cdk2, and, on, the, 'Skp1/Cul1/F-box', '(', 'SCF)', 'E3', ubiquitin, ligase, complex, 'SCF(Skp2),', which]), verbo([targets]), complemento(['MEF', for, ubiquitination, and, proteolysis])].
[sujeto(['Overexpression', of, 'MEF', drives, cells, through, the, 'G(1)/S', 'transition,', thereby]), verbo([promoting]), complemento([cell, proliferation])].
[sujeto(['The', tight, regulation, of, 'MEF', levels, during, the, cell, cycle, contributes, to, its, effects, on]), verbo([regulating]), complemento([cell, cycle, entry, and, cell, proliferation])].
[sujeto(['Cellular', and, systemic, 'O(2)', concentrations, are, tightly]), verbo([regulated]), complemento([to, maintain, delicate, oxygen, homeostasis])].
[sujeto(['Although', the, roles, of, hypoxia, in, solid, tumors]), verbo([have]), complemento([been, widely, 'studied,', few, studies, were, reported, regarding, the, possible, effects, of, hypoxia, on, leukemic, cells])].
[sujeto(['Here,', we, showed, for, the, first, time, that, low, concentrations, of, cobalt, chloride, '(', 'CoCl(2)),', a, 'hypoxia-mimicking', 'agent,', and, 2, -, 3, '%', 'O(2)']), verbo([triggered]), complemento([differentiation, of, various, subtypes, of, human, acute, myeloid, leukemic, '(', 'AML)', cell, 'lines,', including, 'NB4,', 'U937', and, 'Kasumi-1', 'cells,', 'respectively,', from, 'M3,', 'M5', and, 'M2b-type', 'AML,', but, 'CoCl(2)', did, not, modulate, 'AML', 'subtype-specific', fusion, proteins, promyelocytic, 'leukemia-retinoic', acid, receptor, alpha, '(', 'PML-RARalpha)', and, 'AML1-ETO'])].
[sujeto(['Treatment', with, 'CoCl(2)', also]), verbo([induced]), complemento([primary, leukemic, cells, from, some, 'AML', patients, to, undergo, differentiation])].
[sujeto(['Similar', to, what, occurs, in, solid, tumor, 'cells,', 'CoCl(2)-mimicked', hypoxia, also]), verbo([increased]), complemento([the, level, of, 'hypoxia-inducible', factor, '(', 'HIF)-1alpha', protein, and, its, 'DNA-binding', activity, in, leukemic, cells])].
[sujeto(['The', 'CoCl(2)', induction, of, 'HIF-1alpha', protein, and, its, 'DNA-binding', activity, were]), verbo([inhibited]), complemento([by, 3, -, 'morpholinosydnonimine,', which, also, blocked, 'CoCl(2)-induced', cell, differentiation, in, leukemic, cells])].
[sujeto(['These', results]), verbo([provide]), complemento([an, insight, into, a, possible, link, of, hypoxia, or, 'HIF-1alpha', and, leukemic, cell, 'differentiation,', and, are, possibly, of, significance, to, explore, clinical, potentials, of, hypoxia, or, 'hypoxia-mimicking', agents, and, novel, 'target-based', drugs, for, differentiation, therapy, of, leukemia])].
[sujeto(['Significant', levels, of, 'WT1', gene, were]), verbo([expressed]), complemento([in, all, leukemia, patients, and, for, 'CML', the, levels, increased, as, the, clinical, phase, progressed])].
[sujeto(['Patients', with, less, than, 0.6, levels, had, significantly, higher, rates, of, complete, remission, '(', 'CR),', 'disease-free', 'survival,', and, overall, survival, than, those, with, &, 'gt;', or, =, 0.6, 'levels,', whereas, 'CR', could, not, be]), verbo([induced]), complemento([in, any, of, the, 7, patients, with, acute, leukemia, having, greater, than, 1.0, levels, of, 'WT1', gene, expression])].
[sujeto(['In', 2, other, 'patients,', the, 'WT1', mRNA, gradually]), verbo([increased]), complemento([after, discontinuation, of, chemotherapy])].
[sujeto(['However,', the, development, of, 'therapy-related', myeloid, neoplasms, '(', 't-MN)', is, being]), verbo([reported]), complemento([with, increasing, frequency, in, patients, successfully, treated, for, 'APL'])].
[sujeto(['We', attempted, to, clarify, the, different, clinical, features, and, hematologic, findings, between, 't-MN', and, relapse, 'cases,', and, to, identify, gene, alterations]), verbo([involved]), complemento([in, 't-MN'])].
[sujeto(['Cytogenetic', abnormalities, or, point, mutations, of, the, 'hematopoiesis-specific', genes, are, frequently]), verbo([found]), complemento([in, patients, with, 'AML,', and, these, genetic, aberrations, are, closely, associated, with, the, pathophysiology, of, the, disease])].
[sujeto(['Molecular', pathogenesis, of, 'AML']), verbo([has]), complemento([been, disclosed, through, analyses, of, such, gene, 'aberrations,', including, 'AML1', and, 'MLL', 'abnormalities,', 'PML-RARA', chimeric, 'gene,', activating, mutations, of, 'FLT3,', and, 'EVI-1', abnormalities])].
[sujeto(['Through', prediction, of, prognosis, and]), verbo([targeted]), complemento(['therapy,', this, knowledge, on, pathogenesis, of, 'AML', has, been, applied, to, the, clinical, 'practice,', and, further, investigation, should, improve, the, outcome, of, therapy, for, 'AML', in, the, future])].
[sujeto(['A', reciprocal, translocation]), verbo([involving]), complemento([chromosomes, 15, and, 17, ',', 't(15;17)(q22;q21),', is, a, characteristic, feature, of, 'APL', that, represents, approximately, 5, -, 8, '%', of, 'AML'])].
[sujeto(['Nonetheless,', 'therapy-related', myelodysplastic, 'syndrome-acute', myelogenous, leukemia, '(', 't-MDS/AML)']), verbo([has]), complemento([been, reported, as, a, rare, complication, of, chemotherapy, in, 'APL'])].
[sujeto(['Submicroscopic', deletions, of, genes, in, recurrent, chromosomal, rearrangements, occur, frequently, in, hematologic, 'malignancies,', but, their, incidences]), verbo([have]), complemento([not, been, reported, clearly])].
[sujeto(['We']), verbo([report]), complemento([the, first, 'dry-reagent,', 'disposable,', dipstick, test, for, molecular, screening, of, seven, chromosomal, translocations, associated, with, acute, and, chronic, leukemia])].
[sujeto(['The', dipstick, assay, with, appropriate, probes, can, be, used, for, identification, of, the, fusion, transcripts]), verbo([involved]), complemento([in, the, translocation])].
[sujeto(['This', chromosomal, translocation, is]), verbo([associated]), complemento([with, de, novo, and, 'therapy-related', acute, myeloid, leukemia, and, with, the, blast, crisis, of, chronic, myelogenous, leukemia])].
[sujeto(['The', mechanisms, by, which, 'AME']), verbo([induces]), complemento([a, neoplastic, transformation, in, bone, marrow, cells, are, unknown])].
[sujeto(['AME']), verbo([interacts]), complemento([with, the, corepressors, 'CtBP', and, 'HDAC1,', and, it, was, shown, that, 'AME', is, a, repressor, in, contrast, to, the, parent, transcription, factors, 'AML1', and, 'ME,', which, are, transcription, activators])].
[sujeto(['Studies', with, murine, bone, marrow, progenitors, indicated, that, the, introduction, of, a, point, mutation, that, destroys, the, 'CtBP-binding', consensus, impairs, but, does, not, abolish, the, disruption, of, cell, differentiation, and, replication]), verbo([associated]), complemento([with, 'AME', 'expression,', suggesting, that, additional, events, are, required])].
[sujeto(['We']), verbo([report]), complemento([that, 'AME', is, also, able, to, oligomerize, and, displays, a, complex, pattern, of, 'self-interaction', that, involves, at, least, three, oligomerization, 'regions,', one, of, which, is, the, distal, zinc, finger, domain])].
[sujeto(['Although', the, deletion, of, this, short, domain, does, not, preclude, the, 'self-interaction', of, 'AME,', it, significantly, reduces, the, differentiation, defects]), verbo([caused]), complemento([in, vitro, by, 'AME', in, primary, murine, bone, marrow, progenitors])].
[sujeto(['The', addition, of, a, point, mutation, that]), verbo([inhibits]), complemento(['CtBP', binding, completely, abrogates, the, effects, of, 'AME', on, 'differentiation,', suggesting, that, 'AME', induces, hematopoietic, differentiation, defects, through, at, least, two, separate, but, cooperating, pathways])].
[sujeto(['Fluorescence', in, situ, hybridization, '(', 'FISH)', can, detect, minor, genetic, changes, that, cytogenetic, analysis, may, 'miss;', 'however,', there, are, few]), verbo([reports]), complemento([on, the, kinds, of, genetic, changes, that, show, large, discrepancies, between, results, obtained, with, 'FISH', versus, 'G-banding', techniques])].
[sujeto(['Given', these, 'results,', all, patients, with, known, genetic, changes, should]), verbo([have]), complemento(['FISH', analysis, in, 'follow-up,', for, an, accurate, assessment, of, the, likelihood, of, complete, remission, or, recurrence])].
[sujeto(['Eight', patients, showed]), verbo([increasing]), complemento([levels, of, expression, during, 'follow-up', and, all, had, relapse])].
[sujeto(['By', combining, the, transcription, ratios, at, these, 2, 'checkpoints,', a, new, powerful, prognostic, score]), verbo([has]), complemento([been, established])].
[sujeto(['This', was, due, to, the, apparent]), verbo([loss]), complemento([of, the, 3, '\'', part, of, 'RUNX1'])].
[sujeto(['Since', chromosome, number, abnormalities, may, be]), verbo([associated]), complemento([with, submicroscopic, gene, 'rearrangements,', it, should, be, important, to, search, for, them, for, a, better, understanding, of, mechanisms, of, 'leukemogenesis,', and, to, understand, the, prognostic, heterogeneity, in, leukemic, patients, with, aneusomies, without, apparent, chromosome, structure, rearrangements])].
[sujeto(['We', sought, to, understand, the, structure, and]), verbo([gain]), complemento([insight, into, the, fusion, process, between, 'AML1', and, 'ETO', by, sequencing, genomic, fusions, in, 17, primary, childhood, 'AMLs', and, two, cell, lines, with, 't(8;21)'])].
[sujeto(['All', patients, with, available, 'RNA']), verbo([expressed]), complemento([an, 'AML1-ETO', mRNA, fusion, between, exon, 5, of, 'AML1', and, exon, 2, of, 'ETO'])].
[sujeto(['Breakpoints', in, general, displayed, similar, complexity, of, 'duplications,', 'deletions,', and, insertions, to, other, common, pediatric, leukemia, translocations, '(', 'TEL-AML1,', 'MLL-AF4,', 'PML-RARA,', 'CBFB-MYH11)', that, we, and, others]), verbo([have]), complemento([analyzed])].
[sujeto(['Genetic', features, and, clinical, implications, due, to, the, encoded, chimeric, neoproteins]), verbo([causing]), complemento([malignant, haematopoietic, disorders, are, reviewed])].
[sujeto(['A', pivotal, regulatory, network, of, 18, miRNA, and, 16]), verbo([targets]), complemento([was, identified])].
[sujeto(['The', combination, of, inversely]), verbo([expressed]), complemento([miRNAs, and, targets, improved, diagnostic, accuracy])].
[sujeto(['In', a, clinical, feature, 'analysis,', several, miRNAs, '(', 'miR-34a,', 'miR-424,', 'miR-20b,', and, 'miR-152)', and, genes, '(', 'CCNE2,', 'COL4A1,', 'TRAF6,', and, 'HSP90B1)', were]), verbo([associated]), complemento([with, aggressive, clinical, 'features,', which, have, not, previously, been, reported])].
[sujeto(['Our', study, not, only, identified, a, pivotal, miRNA, regulatory, network]), verbo([associated]), complemento([with, 'PTC', but, also, provided, evidence, that, miRNAs, and, target, genes, can, be, used, as, biomarkers, in, 'PTC', diagnosis, and, clinical, risk, evaluation])].
[sujeto(['Transcriptional', dysregulation, is]), verbo([associated]), complemento([with, haematological, malignancy])].
[sujeto([1, downregulation, 'and/or', dysfunction]), verbo([has]), complemento([been, described, in, human, 'AML', patients, carrying, the, fusion, oncogenes, 'RUNX1-ETO', and, 'PML-RARA'])].
[sujeto(['To', study, the, transcriptional, programmes]), verbo([associated]), complemento([with, compromised, 'PU'])].
[sujeto([1, induction]), verbo([caused]), complemento([transition, from, leukaemia, phenotype, to, monocytic, differentiation])].
[sujeto(['Global']), verbo([binding]), complemento([maps, for, 'PU'])].
[sujeto([1]), verbo([retains]), complemento(['DNA-binding', 'ability,', but, the, induction, of, 'wild-type', protein, dramatically, increases, both, the, number, and, the, height, of, 'PU'])].
[sujeto([1, -]), verbo([binding]), complemento([peaks])].
[sujeto(['Correlating', chromatin, immunoprecipitation, '(', 'ChIP)', 'Seq', with, gene, expression, 'data,', we]), verbo([found]), complemento([that, 'PU'])].
[sujeto([1, recruitment, coupled, with]), verbo([increased]), complemento([histone, acetylation, induces, gene, expression, and, activates, a, 'monocyte/macrophage', transcriptional, programme])].
[sujeto([1, induction, also]), verbo([caused]), complemento([the, reorganisation, of, a, subgroup, of, 'CEBPA', binding, peaks])].
[sujeto([1]), verbo([target]), complemento([gene, set, defined, in, our, model, allows, the, stratification, of, primary, human, 'AML', 'samples,', shedding, light, on, both, known, and, novel, 'AML', subtypes, that, may, be, driven, by, 'PU'])].
[sujeto(['The', lack, of, molecular, diagnosis, in, the, field, of, cancer, in, 'Iraq']), verbo([has]), complemento([motivated, us, to, perform, a, genetic, analysis, of, pediatric, acute, myelogenous, leukemia, '(', 'AML),', including, class, 'I', and, 'II', aberrations])].
[sujeto(['The', recent, 'World', 'Health', 'Organization', classification]), verbo([recognizes]), complemento([different, subtypes, of, acute, myeloid, leukemia, '(', 'AML)', according, to, the, presence, of, several, recurrent, genetic, abnormalities])].
[sujeto(['Detection', of, these, abnormalities, and, other, molecular, changes, is, of]), verbo([increasing]), complemento([interest, because, it, contributes, to, a, refined, diagnosis, and, prognostic, assessment, in, 'AML', and, enables, monitoring, of, minimal, residual, disease])].
[sujeto(['We']), verbo([have]), complemento([developed, a, novel, 'real-time', 'RT-PCR', assay, to, simultaneously, detect, 15, 'AML-associated', rearrangements, that, is, a, simple, and, easily, applicable, method, for, use, in, clinical, diagnostic, laboratories])].
[sujeto(['Accordingly,', 'del(20q)', as, an, isolated, abnormality, must, be, distinguished, from, cases, in, which, it, is]), verbo([associated]), complemento([with, other, chromosomal, rearrangements, for, a, better, stratification, of, prognosis])].
[sujeto(['We']), verbo([report]), complemento([a, case, of, an, isolated, 'del(20q)', abnormality, with, additional, genomic, aberrations, identified, using, 'whole-genome', single, nucleotide, polymorphism, array, '(', 'SNP-A)-based', karyotyping])].
[sujeto(['Using', 'FISH,', other, rearrangements, such, as, 'BCR/ABL1,', 'RUNX1/RUNX1T1,', 'PML/RARA,', 'CBFB/MYH11,', and, 'MLL', were]), verbo([found]), complemento([to, be, negative])].
[sujeto(['SNP-A', identified, an, additional, copy, neutral]), verbo([loss]), complemento([of, heterozygosity, '(', 'CN-LOH)', in, the, 11, q13])].
[sujeto(['Unexpectedly,', the, terminal, regions, showed]), verbo([gain]), complemento([on, chromosome, 20, q])].
[sujeto(['The', patient, did, not, achieve, complete, 'remission;', 8, months, 'later,']), verbo([he]), complemento([died, from, complications, of, leukemic, cell, infiltrations, into, the, central, nervous, system])].
[sujeto(['This', study]), verbo([suggests]), complemento([that, a, presumably, isolated, chromosomal, abnormality, by, 'MC', may, have, additional, genomic, 'aberrations,', including, 'CN-LOH,', which, could, be, associated, with, a, poor, prognosis])].
[sujeto(['Multiplex', reverse, transcription, polymerase, chain, reaction, '(', 'mRT-PCR)']), verbo([has]), complemento([recently, emerged, as, an, alternative, to, cytogenetics])].
[sujeto(['However,', false, negative, results, were]), verbo([found]), complemento([in, three, cases, who, have, 'inv(16),', 't(4;11)', or, 't(11;19)(q23;p13'])].
[sujeto(['This', 'mRT-PCR', assay, is, a, useful, screening, tool, in, acute, leukemia, because, it]), verbo([provides]), complemento([rapid, and, reliable, detection, of, clinically, important, chimeric, transcripts])].
[sujeto(['In', 'addition,', cryptic, translocations]), verbo([provide]), complemento([additional, genetic, information, that, could, be, clinically, useful])].
[sujeto(['Molecular', mutations]), verbo([have]), complemento([been, analyzed, to, subdivide, 'AML', with, normal, karyotype, into, prognostic, subsets])].
[sujeto(['Based', on, 'Cox', regression, and, 'Kaplan-Meier', 'analyses,', 5, distinct, prognostic, subgroups, were, 'identified:', '(', 1, ')', very, 'favorable:', 'PML-RARA', rearrangement, '(', n, =, 29, ')', or, 'CEPBA', double, mutations, '(', n, =, 42, ;, overall, survival, '[', 'OS]', at, 3, 'years:', 82.9, '%', ')', ;, '(', 2, ')', 'favorable:', 'RUNX1-RUNX1T1', '(', n, =, 35, ')', ',', 'CBFB-MYH11', '(', n, =, 31, ')', ',', or, 'NPM1', mutation, without, 'FLT3-ITD', '(', n, =, 186, ;, 'OS', at, 3, 'years:', 62.6, '%', ')', ;, '(', 3, ')', 'intermediate:', none, of, the, mutations]), verbo([leading]), complemento([to, assignment, into, groups, 1, ',', 2, ',', 4, ',', or, 5, '(', n, =, 235, ;, 'OS', at, 3, 'years:', 44.2, '%', ')', ;, '(', 4, ')', 'unfavorable:', 'MLL-PTD', 'and/or', 'RUNX1', mutation, 'and/or', 'ASXL1', mutation, '(', n, =, 203, ;, 'OS', at, 3, 'years:', 21.9, '%', ')', ;, and, '(', 5, ')', very, 'unfavorable:', 'TP53', mutation, '(', n, =, 80, ;, 'OS', at, 3, 'years:', 0, '%', ;, 'P', &, 'lt;'])].
[sujeto(['This', comprehensive, molecular, characterization]), verbo([provides]), complemento([a, more, powerful, model, for, prognostication, than, cytogenetics])].
[sujeto(['From', the, authors, review, it, is, evident, that, this, phenomenon]), verbo([has]), complemento([both, theoretical, and, practical, '(', 'diagnostic,', 'prognostic,', and, 'therapeutic)', significance])].
[sujeto(['Integrated', 'mRNA-miRNA', functional, analyses]), verbo([reveal]), complemento(['that:', 1, ')', several, very, highly, expressed, genes, '(', e])].
[sujeto([',', 'miR-152,', 'miR-146b,', 'miR-339-5p)', in, 'MNs', are]), verbo([associated]), complemento([with, one, important, cellular, 'process-axon', 'guidance;', 2, ')', some, very, highly, expressed, mitogenic, pathway, genes, '(', e])].
[sujeto([',', 'miR-370,', 'miR-9,', 'miR-672)', in, 'NBCs', are]), verbo([associated]), complemento([with, cancer, pathways])].
[sujeto(['These', results]), verbo([provide]), complemento([a, library, of, negative, mRNAmiRNA, networks, that, are, likely, involved, in, the, cellular, processes, of, differentiation, and, division])].
[sujeto(['Murine', studies, directly, link, primary, acute, myeloid, leukaemia, '(', 'AML)', and]), verbo([decreased]), complemento(['PU'])].
[sujeto(['Similarly,', a, 'radiation-induced', chromosome, 2, deletion, and, subsequent, 'Sfpi1', point, mutation, in, the, remaining, allele]), verbo([lead]), complemento([to, murine, 'radiation-induced', 'AML'])].
[sujeto(['This', review]), verbo([provides]), complemento([an, 'up-to-date', overview, on, our, current, understanding, of, the, involvement, of, 'PU'])].
[sujeto(['It', is, concluded, that, the, 'Msi2', mRNA]), verbo([expresses]), complemento([in, leukamia, stem, 'cells,', the, high, expression, of, 'Msi2', mRNA, has, been, found, in, newly, diagnosed, 'AML', 'patients,', especially, in, 'M1,', 'M4', and, 'M5', 'patients,', the, high, expression, also, has, been, observed, in, patients, with, 'CD34(+)'])].
[sujeto(['The', results, showed, that, the, 'NPM1', mutation, was]), verbo([found]), complemento([in, 14.1, '%', samples, '(', 55, /, 389, ')'])].
[sujeto(['It', is, concluded, that, 'AML', with, 'NPM1', mutation]), verbo([has]), complemento([distinct, clinical, features])].
[sujeto(['It', is, important, to, identify, these, transcripts, as, they]), verbo([provide]), complemento([useful, prognostic, information, to, the, treating, clinician])].
[sujeto(['Acquired', somatic, mutations, of, 'IDH1', and, 'IDH2']), verbo([have]), complemento([recently, been, reported, in, some, types, of, brain, tumors, and, a, small, proportion, of, acute, myeloid, leukemia, '(', 'AML)', cases])].
[sujeto(['Two', missense, mutations, were]), verbo([found]), complemento([in, 'IDH2-mutated', 'cases;', p])].
[sujeto(['Older', age, and, higher, median, platelet, counts, were, significantly]), verbo([associated]), complemento([with, 'IDH2', mutations, although, the, clinical, impact, of, either, 'IDH1', or, 'IDH2', mutations, on, 'patients\'', overall, survival, could, not, be, observed])].
[sujeto(['No', patients, concurrently, carried, both, 'IDH1', and, 'IDH2', mutations]), verbo([suggesting]), complemento([that, these, mutations, were, mutually, exclusive])].
[sujeto(['Our', present, data, failed, to, support, the, prognostic, relevance, of, 'IDH', mutations, although, alterations, of, these, metabolic, genes, potentially]), verbo([have]), complemento([an, important, role, in, leukemia, development])].
[sujeto(['Chromatin', modifications, at, both, histones, and, 'DNA', are, critical, for]), verbo([regulating]), complemento([gene, expression])].
[sujeto(['Mis-regulation', of, such, epigenetic, marks, can]), verbo([lead]), complemento([to, pathological, 'states;', 'indeed,', cancer, affecting, the, hematopoietic, system, is, frequently, linked, to, epigenetic, abnormalities])].
[sujeto(['Further,', we, discuss, how, chromosomal, translocations]), verbo([leading]), complemento([to, fusion, proteins, can, aberrantly, regulate, gene, transcription, through, chromatin, modifications, within, the, hematopoietic, system])].
[sujeto(['PML-RARa,', 'AML1-ETO', and, 'MLL-fusions', are, examples, of, fusion, proteins, that, 'mis-regulate', epigenetic, modifications, '(', either, directly, or, 'indirectly),', which, can]), verbo([lead]), complemento([to, acute, myeloblastic, leukemia, '(', 'AML)'])].
[sujeto(['An', 'in-depth', understanding, of, the, mechanisms, behind, the, 'mis-regulation', of, epigenetic, modifications, that]), verbo([lead]), complemento([to, the, development, and, progression, of, 'AMLs', could, be, critical, for, designing, effective, treatments])].
[sujeto(['Seven', genes, '(', 'RARB,', 'BVES,', 'CDKN2A,', 'KCNH5,', 'RASSF1,', 'CDH13,', and, 'RUNX)', were]), verbo([found]), complemento([to, be, methylated, significantly, more, frequently, in, tumor, tissues, than, in, noncancerous, tissues])].
[sujeto(['Only', methylation, of, 'CCND2', and, 'APC', was, frequently, detected, in, both, cancerous, and, noncancerous, 'tissues,', supporting, the, hypothesis, that, the, methylation, of, these, two, genes, is, a, preneoplastic, change, and, may, be]), verbo([associated]), complemento([with, tobacco, smoking, exposure])].
[sujeto(['Detection', of, methylation, of, these, genes, in, blood, might]), verbo([have]), complemento([utility, in, monitoring, and, detecting, tumor, recurrence, in, 'early-stage', 'NSCLC', after, curative, surgical, resection])].
[sujeto(['MOZ-TIF2', and, 'MOZ-CBP', are, leukemogenic, fusion, proteins]), verbo([associated]), complemento([with, 'therapy-induced', acute, myeloid, leukemia])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, 'MOZ-TIF2', inhibits, transcription, by, 'CREB-binding', protein, '(', 'CBP)/p300-dependent', activators, such, as, nuclear, receptors, and, p53])].
[sujeto(['Here', we]), verbo([have]), complemento([shown, that, 'MOZ-TIF2', associates, with, the, 'RARbeta2', promoter, in, 'vivo,', resulting, in, altered, recruitment, of, 'CBP/p300,', aberrant, histone, 'modification,', and, 'down-regulation', of, the, 'RARbeta2', gene])].
[sujeto(['In', 'contrast,', 'MOZ-TIF2', 'up-regulated', transcription]), verbo([mediated]), complemento([by, the, 'MOZ/MYST3-dependent', activator, 'AML1/RUNX1'])].
[sujeto(['Both', wild, type, 'MOZ', and, 'MOZ-TIF2', were]), verbo([found]), complemento([to, colocalize, with, 'AML1,', and, 'MOZ-TIF2', was, recruited, to, an, 'AML1', target, promoter])].
[sujeto(['A', 'MOZ-CBP', fusion, protein, showed, similar, functions, to, 'MOZ-TIF2', in, that, it]), verbo([inhibited]), complemento([retinoic, acid, 'receptor-mediated', transcription, but, enhanced, 'AML1', reporter, activation])].
[sujeto(['Although', it, contains, almost, the, entire, 'CBP', 'sequence,', 'MOZ-CBP', does, not, appear, to]), verbo([associate]), complemento([with, 'PML', bodies])].
[sujeto(['In', 'summary,', our, results, indicate, that, leukemogenic, 'MOZ', fusion, proteins]), verbo([have]), complemento([differential, effects, on, the, activities, of, 'CBP-dependent', and, 'MOZ-dependent', activators, because, of, their, ability, to, alter, cofactor, recruitment, and, chromatin, modification, at, target, promoters])].
[sujeto(['Studies']), verbo([have]), complemento([shown, that, the, fusion, alone, is, insufficient, for, the, initiation, of, 'leukemia;', additional, genetic, changes, are, required])].
[sujeto(['TBL1XR1', is, a, key, component, of, the, 'SMRT', and, 'N-CoR', compressor, 'complexes,', which, control, 'hormone-receptor']), verbo([mediated]), complemento([gene, expression])].
[sujeto(['Differential', expression, of, the, retinoic, acid]), verbo([target]), complemento(['genes,', 'RARB,', 'CRABP1,', and, 'CRABP2,', indicated, that, deletion, of, 'TBL1XR1', compromised, the, function, of, 'SMRT/N-CoR', in, the, appropriate, control, of, gene, expression])].
[sujeto(['We']), verbo([provide]), complemento([evidence, that, implicates, this, deletion, in, the, inappropriate, control, of, gene, expression, in, these, patients])].
[sujeto(['The']), verbo([target]), complemento([of, the, interaction, between, 'TBL1XR1', and, the, signaling, pathways, described, here, may, be, exploited, in, cancer, therapy])].
[sujeto(['IL-13', is, a, central, mediator, of, airway, responsiveness, and, mucus, expression, in, patients, with, allergic, airway, 'inflammation,', and, 'IL-13', is, currently, a, therapeutic]), verbo([target]), complemento([for, asthma])].
[sujeto(['However,', little, is, known, about, how, 'IL-13']), verbo([regulates]), complemento([human, 'CD4(+)', 'T-cell', lineages, because, 'IL-13', receptor, '(', 'IL-13R)', 'α1,', a, subunit, of, 'IL-13R,', has, not, previously, been, reported, to, exist, on, human, 'T', cells])].
[sujeto(['We', sought, to, determine, whether, human, 'CD4(+)', 'T(H)17', cells]), verbo([express]), complemento(['IL-13Rα1', and, whether, 'IL-13', regulates, 'T(H)17', cytokine, production])].
[sujeto(['Naive', human, 'CD4(+)', cells, were, isolated, from, whole, 'blood,']), verbo([activated]), complemento([with, 'anti-CD3', and, 'anti-CD28,', and, polarized, to, 'T(H)1,', 'T(H)2,', 'T(H)17,', or, induced, regulatory, 'T', cells, in, the, presence, of, 'IL-13', '(', 0, -, 10, 'ng/mL)'])].
[sujeto(['T(H)17', 'cells,', but, not, 'T(H)0,', 'T(H)1,', 'T(H)2,', or]), verbo([induced]), complemento([regulatory, 'T', 'cells,', expressed, 'IL-13Rα1'])].
[sujeto(['IL-13', neither]), verbo([inhibited]), complemento(['IFN-γ', production, from, 'T(H)1', cells, nor, inhibited, 'IL-4', production, from, 'T(H)2', cells])].
[sujeto(['IL-13Rα1', is]), verbo([expressed]), complemento([on, human, 'CD4(+)', 'T(H)17', 'cells,', and, 'IL-13', attenuates, 'IL-17A', production, at, polarization, and, restimulation])].
[sujeto(['Although', 'IL-13', is, an, attractive, therapeutic]), verbo([target]), complemento([for, decreasing, symptoms, associated, with, 'asthma,', these, results, suggest, that, therapies, inhibiting, 'IL-13', production, could, have, adverse, side, effects, by, increasing, 'IL-17A', production])].
[sujeto(['Gene', methylation, and, other, epigenetic, modifications, of, gene, regulation]), verbo([have]), complemento([been, implicated, in, the, growth, of, ovarian, 'cancer,', but, the, clinical, significance, of, such, modifications, in, the, 'Notch', pathway, in, 'high-grade', serous, ovarian, cancer, '(', 'HGS-OvCa)', is, not, well, understood])].
[sujeto(['We', also]), verbo([found]), complemento([a, significant, inverse, relationship, between, miRNAs, and, mRNA, expression, for, 'CCND1,', 'PPARG,', and, 'RUNX1'])].
[sujeto(['By', further, analyzing, the, effect, of, miRNAs, on, gene, expression, and, 'OS,', we]), verbo([found]), complemento([that, patients, with, higher, levels, of, 'CCND1,', 'PPARG,', and, 'RUNX1', expression, and, lower, expression, levels, of, their, respective, miRNAs, '(', 502, -, 5, 'p,', 128, ',', and, 215, /, 625, ')', had, significantly, poorer, 'OS'])].
[sujeto(['Epigenetic', alterations, of, multiple, 'Notch']), verbo([target]), complemento([genes, and, pathway, interacting, genes, '(', 'PPARG,', 'CCND1,', and, 'RUNX1)', may, relate, to, activation, of, this, pathway, and, poor, survival, of, patients, with, 'HGS-OvCa'])].
[sujeto([microRNAs, '(', 'miRNAs)', play, key, roles, in]), verbo([modulating]), complemento([a, variety, of, cellular, processes, through, repression, of, their, mRNA, targets])].
[sujeto(['In', skeletal, 'muscle,', miRNAs, are, known, to, be]), verbo([involved]), complemento([in, myoblast, proliferation, and, differentiation])].
[sujeto(['We', identified, a, set, of, miRNAs, that, was, highly]), verbo([expressed]), complemento([in, 'SP', cells, as, compared, with, 'MP', cells])].
[sujeto(['One', 'miRNA,', 'miR-128a,', was, elevated, in, expression, in, 'SP', 'cells,', but]), verbo([decreased]), complemento([in, expression, during, continued, culture, in, vitro])].
[sujeto(['Overexpression', of, 'miR-128a', in, 'SP', cells, resulted, in]), verbo([inhibited]), complemento([cell, proliferation])].
[sujeto(['The', differentiation, potential, of, 'SP', cells, was, also]), verbo([decreased]), complemento([when, 'miR-128a', was, overexpressed])].
[sujeto(['MiR-128a', was]), verbo([found]), complemento([to, regulate, the, target, genes, involved, in, the, regulation, of, 'adipogenic-,', 'osteogenic-', and, myogenic, genes, that, 'include:', 'PPARγ,', 'Runx1,', and, 'Pax3'])].
[sujeto(['Overexpression', of, 'miR-128a']), verbo([suppressed]), complemento([the, activity, of, a, luciferase, reporter, fused, to, the, 3, '\'', -, untranslated, region, of, each, gene])].
[sujeto(['These', results, demonstrate, that, 'miR-128a', contributes, to, the, maintenance, of, the, quiescent, 'state,', and, it]), verbo([regulates]), complemento([cellular, differentiation, by, repressing, individual, genes, in, 'SP', cells])].
[sujeto(['Secreted', 'frizzled-related', protein, 1, '(', 'Sfrp1)', is, highly]), verbo([expressed]), complemento([by, stromal, cells, maintaining, hematopoietic, stem, cells, '(', 'HSCs)'])].
[sujeto(['Sfrp1']), verbo([loss]), complemento([in, stromal, cells, increases, production, of, hematopoietic, 'progenitors,', and, in, knockout, 'mice,', dysregulates, hemostasis, and, increases, 'Flk2-', 'Cd34-', 'Lin-', 'Sca1+', 'Kit+', '(', 'LSK)', cell, numbers, in, bone, marrow])].
[sujeto(['Also,', 'LSK', and, multipotent, progenitors, '(', 'MPPs)', resided, mainly, in, the, 'G0/G1', phase, of, cell, 'cycle,', with, an, accompanying]), verbo([decrease]), complemento([in, intracellular, 'beta-catenin', levels])].
[sujeto(['Gene-expression', studies, showed, a, concomitant]), verbo([decrease]), complemento(['Ccnd1', and, 'Dkk1', in, 'Cd34-', 'LSK', cells, and, increased, expression, of, 'Pparg,', 'Hes1,', and, 'Runx1', in, 'MPP'])].
[sujeto(['Transplantation', experiments, showed, no, intrinsic, effect, of, 'Sfrp1']), verbo([loss]), complemento([on, the, number, of, 'HSCs', or, their, ability, to, engraft, irradiated, recipients])].
[sujeto(['In', 'contrast,', serial, transplantations, of, 'wild-type', 'HSCs', into, 'Sfrp1(-/-)', mice, show, a, progressive]), verbo([decrease]), complemento([of, 'wild-type', 'LSK', and, 'MPP', numbers])].
[sujeto(['Our', results, demonstrate, that, 'Sfrp1', is]), verbo([required]), complemento([to, maintain, 'HSC', homeostasis, through, extrinsic, regulation, of, 'beta-catenin'])].
[sujeto(['The', aim, of, this, study, was, to, characterize, differentially]), verbo([expressed]), complemento([genes, in, the, normal, and, 'adriamycin-induced', 'CGN', rats, by, microarray, 'analysis,', and, to, determine, the, potential, molecular, mechanisms, of, 'CGN', pathogenesis])].
[sujeto(['KEGG,', 'Gene', 'Ontology', '(', 'GO)', 'analyze,', 'LIMMA,', 'String', and, 'Cytoscape', software, were, applied, to, screen, and, analyze, differentially]), verbo([regulated]), complemento([genes])].
[sujeto([2334, differentially]), verbo([regulated]), complemento([genes, were, identified, including, 1294, 'up-regulated', genes, and, 1040, 'down-regulated', genes])].
[sujeto(['Exposure', to, replication, competent, and, 'single-round', 'VSV-G', pseudotyped, 'HIV', strains]), verbo([provide]), complemento([evidence, that, superior, 'HIV', replication, in, 'Th1Th17', vs])].
[sujeto(['Th1', cells, was]), verbo([regulated]), complemento([by, mechanisms, located, at, entry, and, 'post-entry', levels])].
[sujeto(['Gene', 'Set', 'Enrichment', 'Analysis', revealed, pathways, enriched, in, 'Th1Th17', '(']), verbo([nuclear]), complemento(['receptors,', 'trafficking,', 'p38/MAPK,', 'NF-κB,', 'p53/Ras,', 'IL-23)', vs])].
[sujeto(['Differentially']), verbo([expressed]), complemento([genes, were, classified, into, biological, categories, using, 'Gene', 'Ontology'])].
[sujeto(['Th1Th17', cells]), verbo([expressed]), complemento([typical, 'Th17', markers, '(', 'IL-17A/F,', 'IL-22,', 'CCL20,', 'RORC,', 'IL-26,', 'IL-23R,', 'CCR6)', and, transcripts, functionally, linked, to, regulating, cell, trafficking, '(', 'CEACAM1,', 'MCAM),', activation, '(', 'CD28,', 'CD40LG,', 'TNFSF13B,', 'TNFSF25,', 'PTPN13,', 'MAP3K4,', 'LTB,', 'CTSH),', transcription, '(', 'PPARγ,', 'RUNX1,', 'ATF5,', 'ARNTL),', apoptosis, '(', 'FASLG),', and, 'HIV', infection, '(', 'CXCR6,', 'FURIN)'])].
[sujeto(['The']), verbo([nuclear]), complemento([receptor, 'PPARγ', was, preferentially, expressed, by, 'Th1Th17', cells])].
[sujeto(['PPARγ', 'RNA', interference, significantly]), verbo([increased]), complemento(['HIV', replication, at, levels, 'post-entry', and, prior, 'HIV-DNA', integration])].
[sujeto(['Finally,', the, activation, of, 'PPARγ', pathway, via, the, agonist, 'Rosiglitazone']), verbo([induced]), complemento([the, nuclear, translocation, of, 'PPARγ', and, a, robust, inhibition, of, viral, replication])].
[sujeto(['Th1', cells, demonstrated, that, 'HIV', permissiveness, is]), verbo([associated]), complemento([with, a, superior, state, of, cellular, activation, and, limited, antiviral, properties, and, identified, 'PPARγ', as, an, intrinsic, negative, regulator, of, viral, replication])].
[sujeto(['Therefore,']), verbo([triggering]), complemento(['PPARγ', pathway, via, 'non-toxic', agonists, may, contribute, to, limiting, covert, 'HIV', replication, and, disease, progression, during, antiretroviral, treatment])].
[sujeto(['The', 'wingless-Int', '(', 'WNT)', pathway]), verbo([has]), complemento([an, essential, role, in, cell, regulation, of, hematopoietic, stem, cells, '(', 'HSC)'])].
[sujeto(['For', 'Acute', 'Myeloid', 'Leukemia', '(', 'AML),', the, malignant, counterpart, of, 'HSC,', currently, only, a, selective, number, of, genes, of, the, 'WNT', pathway, are, analyzed, by, using, either, gene, expression, or, 'DNA-methylation', profiles, for, the, identification, of, prognostic, markers, and, potential, candidate]), verbo([targets]), complemento([for, drug, therapy])].
[sujeto(['It', is, known, that, mRNA, expression, is, controlled, by, 'DNA-methylation', and, that, specific, patterns, can, infer, the, ability, to, differentiate, biological, 'differences,', thus, a, combined, analysis, using, all, 'WNT', annotated, genes, could]), verbo([provide]), complemento([more, insight, in, the, 'WNT', signaling])].
[sujeto(['Our', results]), verbo([provide]), complemento([novel, insights, in, 'WNT', signaling, in, 'AML,', we, discovered, new, and, previously, identified, prognostic, markers, and, a, refinement, of, the, patient, groups])].
[sujeto(['Limited', evidence, is, available, about, the, specific, miRNA, networks, that]), verbo([regulate]), complemento([differentiation, of, specific, immune, cells])].
[sujeto(['In', this, 'study,', we, characterized, miRNA, expression, and]), verbo([associated]), complemento([alterations, in, expression, with, putative, mRNA, targets, that, are, critical, during, differentiation, of, macrophages])].
[sujeto(['We', identified, 112, miRNAs, with, expression, patterns, that, were, differentially]), verbo([regulated]), complemento([5, -, fold, or, more, during, 'BMDM', development])].
[sujeto(['With', 'TargetScan', and, 'MeSH', 'databases,', we, identified, 1267, transcripts]), verbo([involved]), complemento([in, 30, canonical, pathways, linked, to, macrophage, biology, as, potentially, regulated, by, these, specific, 112, miRNAs])].
[sujeto([1, ',', and, 14, miRNAs]), verbo([target]), complemento([the, nuclear, receptor, 'PPARα', and, 'PPARγ'])].
[sujeto(['This', novel, information]), verbo([provides]), complemento([an, important, reference, resource, for, further, study, of, the, functional, links, between, miRNAs, and, their, target, mRNAs, for, the, regulation, of, differentiation, and, function, of, macrophages])].
[sujeto([',', aerobic, and, 'resistance)', into, one, training, 'protocol,']), verbo([providing]), complemento([stimuli, meant, to, increase, muscle, 'strength,', aerobic, capacity, and, mass])].
[sujeto(['As', disuse, is]), verbo([associated]), complemento([with, decrements, in, 'strength,', aerobic, capacity, and, muscle, size, concurrent, training, is, an, attractive, modality, for, rehabilitation])].
[sujeto(['We']), verbo([recruited]), complemento([18, young, adults, '(', 10, '♂,', 8, '♀)', to, determine, if, order, of, exercise, mode, during, concurrent, training, would, differentially, affect, gene, 'expression,', protein, content, and, measures, of, strength, and, aerobic, capacity, after, 2, weeks, of, 'knee-brace', induced, disuse])].
[sujeto(['Concurrent', exercise, sessions, were, performed, 3, 'x/week', for, 6, weeks, at, gradually]), verbo([increasing]), complemento([intensities, either, with, endurance, exercise, preceding, '(', 'END>RES)', or, following, '(', 'RES>END)', resistance, exercise])].
[sujeto(['Concurrent', exercise, altered, the, expression, of, genes]), verbo([involved]), complemento([in, mitochondrial, biogenesis, '(', 'PGC-1α,', 'PRC,', 'PPARγ),', hypertrophy, '(', 'PGC-1α4,', 'REDD2,', 'Rheb)', and, atrophy, '(', 'MuRF-1,', 'Runx1),', increased, electron, transport, chain, complex, protein, 'content,', citrate, synthase, and, mitochondrial, cytochrome, c, oxidase, enzyme, 'activity,', muscle, 'mass,', maximum, isometric, strength, and, 'VO', 2, peak])].
[sujeto(['In', 'conclusion,', concurrent, exercise, training, is, an, effective, modality, for, the, rehabilitation, of, the]), verbo([loss]), complemento([of, skeletal, muscle, 'mass,', maximum, 'strength,', and, peak, aerobic, capacity, resulting, from, 'disuse,', regardless, of, the, order, in, which, the, modes, of, exercise, are, performed])].
[sujeto(['A', new, class, of, inflammatory, 'CD4(+)', 'T', cells, that, produce, 'interleukin-17', '(', 'IL-17)', '(', termed, 'Th17)']), verbo([has]), complemento([been, 'identified,', which, plays, a, critical, role, in, numerous, inflammatory, conditions, and, autoimmune, diseases])].
[sujeto(['The', active, form, of, vitamin, 'D,', 1, ',', 25, -, dihydroxyvitamin, 'D(3)', '[', 1, ',', 25, '(', 'OH)(2)D(3)],']), verbo([has]), complemento([a, direct, repressive, effect, on, the, expression, of, 'IL-17A', in, both, human, and, mouse, 'T', cells])].
[sujeto(['The', mechanism, of, 1, ',', 25, '(', 'OH)(2)D(3)', repression, of, 'IL-17A', expression, was]), verbo([found]), complemento([to, be, transcriptional, 'repression,', mediated, by, the, vitamin, 'D', receptor, '(', 'VDR)'])].
[sujeto(['Transcription', 'assays,', gel, 'shifting,', and, chromatin, immunoprecipitation, '(', 'ChIP)', assays, indicate, that, the, negative, effect, of, 1, ',', 25, '(', 'OH)(2)D(3)', on, 'IL-17A']), verbo([involves]), complemento([blocking, of, nuclear, factor, for, activated, 'T', cells, '(', 'NFAT),', recruitment, of, histone, deacetylase, '(', 'HDAC),', sequestration, of, 'Runt-related', transcription, factor, 1, '(', 'Runx1)', by, 1, ',', 25, '(', 'OH)(2)D(3)/VDR,', and, a, direct, effect, of, 1, ',', 25, '(', 'OH)(2)D(3)', on, induction, of, 'Foxp3'])].
[sujeto(['Our', results, describe, novel, mechanisms, and, new, concepts, with, regard, to, vitamin, 'D', and, the, immune, system, and]), verbo([suggest]), complemento([therapeutic, targets, for, the, control, of, autoimmune, diseases])].
[sujeto(['Osteopontin', '(', 'OPN),', a, glycosylated, phosphoprotein, that]), verbo([binds]), complemento(['calcium,', is, present, in, bone, extracellular, matrix, and, has, been, reported, to, modulate, both, mineralization, and, bone, resorption])].
[sujeto(['In', this, 'study,', we, addressed, possible, 'cross-talk', between, 'VDR', and, 'Runx2', in]), verbo([regulating]), complemento(['OPN', transcription])].
[sujeto([1, ',', 25, -, 'Dihydroxyvitamin', 'D(3)', '(', 1, ',', 25, '(', 'OH)(2)D(3))', or, 'Runx2']), verbo([stimulated]), complemento(['OPN', transcription, '(', mouse, 'OPN', promoter, -, 777, /, +, 79, ')', 2, -, 3, -, fold])].
[sujeto(['In', 'ROS', 17, /, 2.8, and, 'MC3T3-E1', cells, that, contain, endogenous, 'Runx2,', 'AML-1/ETO,', which]), verbo([acts]), complemento([as, a, repressor, of, 'Runx2,', significantly, inhibited, 1, ',', 25, '(', 'OH)(2)D(3)', induction, of, 'OPN', 'transcription,', 'OPN', 'mRNA,', and, protein, expression])].
[sujeto(['Chromatin', immunoprecipitation, analyses, showed, that, 1, ',', 25, '(', 'OH)(2)D(3)', can]), verbo([enhance]), complemento(['VDR', and, 'Runx2', recruitment, on, the, 'OPN', 'promoter,', further, indicating, cooperation, between, these, two, factors, in, the, regulation, of, 'OPN'])].
[sujeto(['In', osteoblastic, 'cells,', 'Hes-1,', a, downstream, factor, of, the, 'Notch', signaling, 'pathway,', was]), verbo([found]), complemento([to, enhance, basal, and, 1, ',', 25, '(', 'OH)(2)D(3)-induced', 'OPN', transcription])].
[sujeto(['This', enhancement, was]), verbo([inhibited]), complemento([by, 'AML-1/ETO,', an, inhibitor, of, 'Runx2'])].
[sujeto(['Immunoprecipitation', assays, indicated, that, 'Hes-1', and, 'Runx2']), verbo([interact]), complemento([and, that, 1, ',', 25, '(', 'OH)(2)D(3)', can, enhance, this, interaction])].
[sujeto(['Taken', 'together,', these, findings, define, novel, mechanisms]), verbo([involving]), complemento([the, intersection, of, three, 'pathways,', 'Runx2,', 1, ',', 25, '(', 'OH)(2)D(3),', and, 'Notch', 'signaling,', that, play, a, major, role, in, the, regulation, of, 'OPN', in, osteoblastic, cells, and, therefore, in, the, process, of, bone, remodeling])].
[sujeto(['The', mineralized, skeleton, is, a, major, evolutionary, novelty, that]), verbo([has]), complemento([contributed, to, the, impressive, morphological, diversifications, of, the, vertebrates])].
[sujeto(['We', now]), verbo([have]), complemento([a, rather, complete, view, of, the, events, underlying, 'osteogenesis,', from, a, 'cellular,', 'molecular,', 'genetic,', and, epigenetic, perspective])].
[sujeto(['Because', this, knowledge, is, still, largely, restricted, to, 'mammals,', it, is, 'difficult,', if, not, 'impossible,', to, deduce, the, evolutionary, history, of, the, regulatory, network]), verbo([involved]), complemento([in, osteoblasts, specification, and, differentiation])].
[sujeto(['In', this, 'study,', we, focused, on, the, transcriptional, regulators, 'Runx2', and, 'VDR', '(', the, 'Vitamin', 'D', 'Receptor)', 'that,', in, 'mammals,', directly]), verbo([interact]), complemento([together, and, stabilize, complexes, of, 'co-activators', and, chromatin, 'remodellers,', thereby, allowing, the, transcriptional, activation, of, target, genes, involved, in, extracellular, matrix, mineralization])].
[sujeto(['Using', a, combination, of, 'functional,', 'biochemical,', and, histological, 'approaches,', we]), verbo([have]), complemento([asked, if, the, interaction, observed, between, 'Runx2', and, 'VDR', represents, a, recent, mammalian, 'innovation,', or, if, it, results, from, more, ancient, changes, that, have, occurred, deep, in, the, vertebrate, lineage])].
[sujeto(['Using', immunohistochemistry, and, in, situ, hybridization, in, developing, embryos, of, 'chick,', frog, and, teleost, 'fishes,', we]), verbo([have]), complemento([revealed, that, the, 'co-expression', of, 'Runx2', and, 'VDR', in, skeletal, elements, has, been, particularly, strengthened, in, the, lineage, leading, to, amniotes])].
[sujeto(['We', show, that, the, teleost, 'Runx2', orthologue, as, well, as, the, three, mammalian, 'Runx1,', 'Runx2', and, 'Runx3', paralogues, are, able, to, 'co-immunoprecipitate', with, the, 'VDR', protein, present, in]), verbo([nuclear]), complemento([extracts, of, rat, osteoblasts, stimulated, with, 1, 'alpha,25-dihydroxyvitamin', 'D3'])].
[sujeto(['In', 'addition,', the, teleost, 'Runx2', can]), verbo([activate]), complemento([the, transcription, of, the, mammalian, osteocalcin, promoter, in, transfection, 'experiments,', and, this, response, can, be, further, enhanced, by, 1, 'alpha,25-dihydroxyvitamin', 'D3'])].
[sujeto(['Finally,', using, 'pull-down', experiments, between, recombinant, 'proteins,', we, show, that, the, 'VDR', homologue, from, 'teleosts,', but, not, from, 'ascidians,', is, able, to, directly]), verbo([interact]), complemento([with, the, mammalian, 'Runx2', homologue])].
[sujeto(['We', propose, an, evolutionary, scenario, for, the, assembly, of, the, molecular, machinery]), verbo([involving]), complemento(['Runx2', and, 'VDR', in, vertebrates])].
[sujeto(['In', the, last, common, ancestor, of, actinopterygians, and, 'sacropterygians,', the, three, 'Runx', paralogues, possessed, the, potential, to, physically, and, functionally]), verbo([interact]), complemento([with, the, 'VDR', protein])].
[sujeto(['Therefore,', 1, 'alpha,25-dihydroxyvitamin', 'D3', might]), verbo([have]), complemento([been, able, to, modulate, the, transcriptional, activity, of, 'Runx1,', 'Runx2', or, 'Runx3', in, the, tissues, expressing, 'VDR'])].
[sujeto(['After', the, split, from, 'amphibians,', in, the, lineage]), verbo([leading]), complemento([to, 'amniotes,', 'Runx2', and, 'VDR', became, robustly, 'co-expressed', in, developing, skeletal, 'elements,', and, their, regulatory, interaction, was, incorporated, in, the, genetic, program, involved, in, the, specification, and, differentiation, of, osteoblasts])].
[sujeto(['These', small, 'RNAs', exert, their, function, assembled, in, the, 'RNA-induced', silencing, complexes, '(', 'RISCs),', where, members, of, 'Argonaute', '(', 'Ago)', family, of, proteins]), verbo([provide]), complemento([a, unique, platform, for, target, recognition, and, gene, silencing])].
[sujeto(['Here,', by, using, myeloid, cell, lines, and, primary, 'blasts,', we, show, that, 'Ago2']), verbo([has]), complemento([a, key, role, in, human, monocytic, cell, fate, determination, and, in, 'LPS-induced', inflammatory, response, of, 1, ',', 25, -, dihydroxyvitamin, 'D3', '(', 'D3)-treated', myeloid, cells])].
[sujeto(['The', silencing, of, 'Ago2', impairs, the, 'D3-dependent', 'miR-17-5p/20a/106a,', 'miR-125b', and, 'miR-155', 'downregulation,', the, accumulation, of, their, translational]), verbo([targets]), complemento(['AML1,', 'VDR', and, 'C/EBPβ', and, monocytic, cell, differentiation])].
[sujeto(['Moreover,', we, show, that, 'Ago2', is]), verbo([recruited]), complemento([on, 'miR-155', host, gene, promoter, and, on, the, upstream, region, of, an, overlapping, antisense, 'lncRNA,', determining, their, epigenetic, 'silencing,', and, 'miR-155', downregulation])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, 'RUNX1', haploinsufficiency, collaborates, with, the, 'BCR-ABL1', oncogene, in, this, leukemia])].
[sujeto(['The', description, of, this, atypical, gene, fusion, is, an, important, addition, to, the, characterization, of, the, pathogenomic, mechanisms]), verbo([leading]), complemento([to, 'RUNX1', structural, and, functional, alterations])].
[sujeto(['Furthermore,', our, data, strongly]), verbo([suggests]), complemento([that, inadequate, dosage, of, this, gene, plays, an, essential, role, in, leukemogenesis])].
[sujeto(['AML1-ETO', is, a, 'DNA']), verbo([binding]), complemento([transcription, factor, and, has, been, demonstrated, to, play, a, critical, role, in, promoting, leukemogenesis])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, the, effect, of, 'AML1-ETO', on, the, promoter, of, multidrug, 'resistance-1', '(', 'MDR1)', 'gene,', a, known, 'AML1-ETO', 'target,', is, highly, cell, type, specific])].
[sujeto(['Besides', observing, repression, of, the, 'MDR1', promoter, in, 'C33A', and, 'CV-1', cells, as]), verbo([reported]), complemento(['previously,', 'AML1-ETO', strongly, activated, the, promoter, in, 'K562', and, 'B210', cells])].
[sujeto(['More', 'importantly,', this, activation]), verbo([required]), complemento([both, the, 'AML1', and, 'ETO', portions, of, the, fusion, 'protein,', but, did, not, depend, on, the, 'AML1', binding, site, in, 'MDR1', promoter])].
[sujeto(['Furthermore,', results, from, promoter, deletion, analysis, and, chromatin, immunoprecipitation, assays]), verbo([suggested]), complemento([that, this, activation, effect, was, likely, through, the, influence, of, the, general, transcription, machinery, rather, than, 'promoter-specific', factors])].
[sujeto(['Based', on, these, 'data,', we, propose, that, 'AML1-ETO', may]), verbo([have]), complemento([opposing, effects, on, gene, expression, depending, on, the, various, conditions, of, the, cellular, environment])].
[sujeto(['TEL/AML1-positive', 'ALL']), verbo([has]), complemento([a, favorable, 'prognosis,', and, one, possible, reason, is, that, this, subtype, of, 'ALL', rarely, shows, drug, resistance])].
[sujeto(['AML1/ETO,', another, 'AML1-containing', chimeric, 'protein,']), verbo([has]), complemento([been, shown, to, transcriptionally, repress, the, activity, of, the, multidrug, 'resistance-1', '(', 'MDR-1)', gene, 'promoter;', 'thus,', we, examined, whether, 'TEL/AML1', also, represses, 'MDR-1', gene, 'expression,', possibly, preventing, the, emergence, of, multidrug, resistance])].
[sujeto(['In', this, 'study,', we, show, that, the, 'TEL/AML1', protein]), verbo([binds]), complemento([to, the, consensus, 'AML1', binding, site, in, the, 'MDR-1', promoter, and, transcriptionally, represses, its, activity])].
[sujeto(['Furthermore,', we]), verbo([report]), complemento([that, 'MDR-1', mRNA, levels, in, leukemic, cells, obtained, from, 'TEL/AML1-positive', 'ALL', patients, are, lower, than, those, from, 'TEL/AML1-negative', 'ALL', patients])].
[sujeto(['Thus,', 'TEL/AML1', protein]), verbo([acts]), complemento([as, a, transcriptional, repressor, of, 'MDR-1', gene, 'expression,', and, although, 'TEL/AML1', has, been, implicated, in, 'leukemogenesis,', its, effects, on, the, 'MDR-1', gene, may, contribute, to, the, excellent, prognosis, of, 'TEL/AML1-positive', 'ALL', with, current, therapy])].
[sujeto(['Here', we]), verbo([report]), complemento([that, there, is, significant, association, between, rheumatoid, arthritis, and, the, organic, cation, transporter, gene, 'SLC22A4', '(', 'P', =, 3.4e-5, ')'])].
[sujeto(['We', show, that, expression, of, 'SLC22A4', is, specific, to, hematological, and, immunological, tissues, and, that, 'SLC22A4', is, also, highly]), verbo([expressed]), complemento([in, the, inflammatory, joints, of, mice, with, 'collagen-induced', arthritis])].
[sujeto(['A', 'SNP', in, 'RUNX1', is, also, strongly]), verbo([associated]), complemento([with, rheumatoid, arthritis, '(', 'P', =, 0.00035, ')'])].
[sujeto(['Our', data, indicate, that, the, regulation, of, 'SLC22A4', expression, by, 'RUNX1', is]), verbo([associated]), complemento([with, susceptibility, to, rheumatoid, 'arthritis,', which, may, represent, an, example, of, an, epistatic, effect, of, two, genes, on, this, disorder])].
[sujeto(['However,', the, mechanisms, by, which, these, proteins]), verbo([act]), complemento([remain, obscure])].
[sujeto(['Here', we, demonstrate, that, the, multidrug, resistance, 1, '(', 'MDR-1)', promoter, is, a]), verbo([target]), complemento([for, 'AML/ETO', transcriptional, repression])].
[sujeto(['We']), verbo([have]), complemento([defined, two, domains, in, 'AML/ETO', that, are, required, for, repression, of, basal, transcription, from, the, 'MDR-1', 'promoter:', a, hydrophobic, heptad, repeat, '(', 'HHR)', motif, and, a, conserved, zinc, finger, '(', 'ZnF)', domain, termed, the, 'MYND', domain])].
[sujeto(['The', 'HHR']), verbo([mediates]), complemento([formation, of, 'AML/ETO', homodimers, and, 'AML/ETO-ETO', heterodimers])].
[sujeto(['Single', serine, substitutions, at]), verbo([conserved]), complemento([cysteine, residues, within, the, predicted, 'ZnFs', also, abrogate, transcriptional, repression])].
[sujeto(['Finally,', we, observe, that, 'AML/ETO', can, also]), verbo([inhibit]), complemento(['Ets-1', activation, of, the, 'MDR-1', 'promoter,', indicating, that, 'AML/ETO', can, disrupt, both, basal, and, 'Ets-1-dependent', transcription])].
[sujeto(['The', most, extensively, studied, protein]), verbo([involved]), complemento([in, multidrug, resistance, '(', 'MDR)', is, the, transmembrane, glycoprotein, 'P', '(', 'P-gp),', the, product, of, the, multidrug, resistance, gene, 1, '(', 'MDR1)'])].
[sujeto(['MDR1/P-gp', overexpression, is, frequently, observed, in, hematological, 'malignancies,', especially, in, acute, 'leukemia,', and]), verbo([has]), complemento([been, reported, to, correlate, with, poor, prognosis, in, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['No', such, difference, was]), verbo([found]), complemento([when, analyzing, peripheral, blood, samples])].
[sujeto(['In', 'Caucasians,', the, most, prominent, association, was]), verbo([found]), complemento([with, promoter, 'SNP', rs10489759, in, the, 'LOC647132', pseudogene, on, chromosome, 1, '(', 'p=7'])].
[sujeto(['In', 'addition,', 'SNP', rs4748153, in, the, immune, response, gene, 'PRKCQ', '(', protein, kinase, 'C,', 'theta)', was, significantly]), verbo([associated]), complemento([with, neutralizing, antibody, levels, '(', 'p=2'])].
[sujeto(['This', study]), verbo([has]), complemento([identified, candidate, 'SNPs', that, may, be, important, in, regulating, humoral, immunity, to, smallpox, vaccination])].
[sujeto(['Heterozygous', individuals, '(', 'C/T)']), verbo([have]), complemento([intermediate, activity, and, homozygotes, for, the, variant, allele, '(', 'T/T)', are, deficient, in, 'NQO1', activity])].
[sujeto(['In', previous, 'studies,', genotypes]), verbo([conferring]), complemento([lower, 'NQO1', activity, have, been, associated, with, an, increased, risk, of, acute, 'leukemia,', particularly, infant, leukemia, carrying, 'MLL/AF4', fusion, genes])].
[sujeto(['When', compared, to, the, healthy, control, 'group,', only, children, with, 'Burkitt\'s', lymphoma, significantly, more, often, had, 'NQO1', genotypes]), verbo([associated]), complemento([with, lower, 'NQO1', activity, '(', odds, 'ratio,', 1.81, ;, 'p=0'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, in, our, population, the, 'NQO1', 'C609T', polymorphism, does, not, confer, an, increased, risk, of, the, investigated, entities, of, childhood, 'ALL'])].
[sujeto(['However,', there, may, be, a]), verbo([modulating]), complemento([role, for, 'NQO1', in, the, pathogenesis, of, pediatric, sporadic, 'Burkitt\'s', lymphoma])].
[sujeto(['The', risk, of, developing, childhood, leukemia]), verbo([has]), complemento([been, associated, with, gene, polymorphisms, that, decrease, the, activity, of, detoxifying, metabolic, enzymes, and, enzymes, involved, in, systemic, oxidative, stress])].
[sujeto(['PON1', rs854560, '(', 'L55M)', was]), verbo([associated]), complemento([with, an, increased, risk, of, developing, childhood, leukemia, '(', 'LM', +, 'MM,', 'OR', 1.93, ',', 95, '%', 'CI', 1.32, -, 2.81, ')'])].
[sujeto(['The', 'PON1', rs662, 'R192R', genotype, had, a, statistically, significant]), verbo([decreased]), complemento([frequency, in, 'ALL', '(', 'OR', 0.64, ',', 95, '%', 'CI', 0.43, -, 0.93, ')'])].
[sujeto(['Infant', 'ALL', cases, were, more, likely, to, harbor, homozygous, 'PON1', rs854560, alleles, than, controls, '(', 'OR', 1.72, ',', 95, '%', 'CI', 1.03, -, 2.89, ')', ;, at, least, one, 'M', allele, was]), verbo([associated]), complemento([with, an, increased, risk, of, 'ALL', in, children, older, than, 1, year, '(', 'OR', 1.99, ',', 95, '%', 'CI', 1.17, -, 3.3, ')'])].
[sujeto(['The', 'NQO1', rs1800566, '(', 'C609T),', 'PON1', rs854560, '(', 'L55M),', and, 'PON1', rs662, '(', 'Q192R)', polymorphisms, modified, risk, depending, on, leukemia, subtype, '(']), verbo([decreased]), complemento([in, 'AML,', increased, and, decreased, in, 'ALL,', 'respectively),', age, 'strata,', and, variant, genotype, combinations])].
[sujeto(['Analyses', of, chromosomal, translocation, and, inversion, breakpoints, in, sporadic, acute, myeloid, leukemias]), verbo([have]), complemento([identified, many, transcription, factors, as, playing, a, role, in, leukemogenesis])].
[sujeto(['Studies', of, families, with, a, 'Mendelian', predisposition, to, hematological, malignancies]), verbo([have]), complemento([identified, the, gene, coding, for, the, transcription, factor, 'RUNX1', as, a, 'leukemia-predisposing', gene, involved, in, the, first, steps, of, leukemogenesis])].
[sujeto(['Although', 'CBFB', forms, a, 'core-binding', factor, transcriptional, complex, with, 'RUNX1,', previous, analyses]), verbo([have]), complemento([excluded, the, 'CBFB', gene, as, the, 'leukemia-predisposing', gene, in, these, families])].
[sujeto(['The', presence, of, 'NQO1', polymorphisms, may]), verbo([suggest]), complemento([a, role, for, this, gene, in, disease, risk, modification, in, these, families])].
[sujeto(['Despite', the, fact, that, 'BCP-ALL', with, 'ETV6-RUNX1', usually, results, in, a, very, good, 'prognosis,', the, sibs, experienced, divergent, 'outcomes;', a, remarkable, difference, in, one, child, that, presented, a, more, aggressive, disease, was, higher, leukocytosis]), verbo([associated]), complemento([with, 'IKZF1', deletion])].
[sujeto(['The', familial, pattern, of, 'ETV6', was, tested, by, the, 12, p, microsatellite, analysis, and, demonstrated, that, deletions, occurred, in, one, child, but, not, the, 'other,', while, heterozygous, patterns, were]), verbo([found]), complemento([in, the, parents])].
[sujeto(['Altogether,', our, data]), verbo([suggest]), complemento([that, genetic, predisposition, aligned, with, chance, haa, an, additive, effect, in, 'BCP-ALL', outcome])].
[sujeto(['These', data]), verbo([have]), complemento([led, to, the, suggestion, that, some, infant, leukemia, may, arise, via, transplacental, fetal, exposures, during, pregnancy, to, substances, that, form, cleavable, complexes, with, topoisomerase, 'II', and, induce, illegitimate, recombination, of, the, 'MLL', gene])].
[sujeto(['MLL-rearranged', leukemias, were, more, likely, to]), verbo([have]), complemento([genotypes, with, low, 'NQO1', function, '(', heterozygous, 'CT', or, homozygous, 'TT', at, nucleotide, 609, ')', than, controls, '(', odds, 'ratio,', 2.5, ;, 'P', =, 0.015, ')'])].
[sujeto(['In', the, subset, of, infant, leukemias, that, had, 'MLL-AF4', fusion, genes, '(', n, =, 21, ')', ',', the, bias]), verbo([increase]), complemento([in, low, or, null, function, 'NQO1', genotypes, was, more, pronounced, '(', odds, 'ratio,', 8.12, ;, 'P', =, 0.00013, ')'])].
[sujeto(['These', data, support, the, idea, of, a, novel, causal, mechanism, in, infant, leukemia]), verbo([involving]), complemento([genotoxic, exposure, in, utero, and, modulation, of, impact, on, a, selective, target, gene, by, an, inherited, allele, encoding, a, 'rate-limiting', step, in, a, carcinogen, detoxification, pathway])].
[sujeto(['Transcripts', significantly, enriched, in, 'Th17', versus, 'Th1', were, previously]), verbo([associated]), complemento([with, the, regulation, of, 'TCR', signaling, '(', 'ZAP-70,', 'Lck,', and, 'CD96)', and, 'Th17', polarization, '(', 'RORγt,', 'ARNTL,', 'PTPN13,', and, 'RUNX1)'])].
[sujeto(['Functional', studies, demonstrated, an]), verbo([increased]), complemento([ability, of, 'Th17', versus, 'Th1', cells, to, respond, to, 'TCR', triggering, in, terms, of, 'NF-κB', nuclear, 'translocation/DNA-binding', activity, and, proliferation])].
[sujeto(['The', transcriptional, program, of, 'Th17', cells, includes, molecules]), verbo([regulating]), complemento(['HIV', replication, at, multiple, 'post-entry', steps, that, may, represent, potential, targets, for, novel, therapies, aimed, at, protecting, 'Th17', cells, from, infection, and, subsequent, depletion, in, 'HIV-infected', subjects])].
[sujeto(['BACKGROUND:', 'Polymorphisms', in, several, genes, '(', 'NOD2,', 'MDR1,', 'SLC22A4)']), verbo([have]), complemento([been, associated, with, susceptibility, to, 'Crohn\'s', disease])].
[sujeto(['Identification', of, the, remaining, 'Crohn\'s', susceptibility, genes, is, essential, for, the, development, of, 'disease-specific']), verbo([targets]), complemento([for, immunotherapy])].
[sujeto(['Using', gene, expression, 'analysis,', we, identified, a, differentially]), verbo([expressed]), complemento([gene, on, 5, 'q33,', the, colony, stimulating, factor, 1, receptor, '(', 'CSF1R)', 'gene,', and, hypothesized, that, it, is, a, 'Crohn\'s', susceptibility, gene])].
[sujeto(['The', 'CSF1R', gene, is]), verbo([involved]), complemento([in, monocyte, to, macrophage, differentiation, and, in, innate, immunity])].
[sujeto(['METHODS:', 'Patients']), verbo([provided]), complemento([informed, consent, prior, to, entry, into, the, study, as, approved, by, the, 'Institutional', 'Review', 'Board', at, 'LSU', 'Health', 'Sciences', 'Center'])].
[sujeto(['RESULTS:', 'A', single, nucleotide, polymorphism, '(', 'A2033T)', near, a, 'Runx1']), verbo([binding]), complemento([site, in, the, eleventh, intron, of, the, colony, stimulating, factor, 1, receptor, was, identified])].
[sujeto(['CONCLUSIONS:', 'We', conclude, that, the, colony]), verbo([stimulating]), complemento([factor, receptor, 1, gene, may, be, a, susceptibility, gene, for, 'Crohn\'s', disease])].
[sujeto(['To', investigate, retinoblastoma, '(', 'Rb)']), verbo([associated]), complemento([protein, 46, '(', 'RbAp46)', gene, expression, levels, in, bone, marrow, '(', 'BM)', cells, of, leukemia, patients])].
[sujeto(['No', statistic, difference, was]), verbo([found]), complemento([between, the, 'CR', group, and, control, 'group,', or, between, the, newly, diagnosed, group, and, relapsed, group])].
[sujeto(['RbAp46', expression, levels, in, 'ALs', and, 'CML-BC', were, strikingly, higher, than, that, in, 'non-leukemias', and, 'CML-CP,', and, might]), verbo([participate]), complemento([in, leukemogenesis])].
[sujeto(['The', structure, of, 'Mhp1', was, previously, solved, in, three, different, conformations]), verbo([providing]), complemento([insight, into, the, molecular, basis, of, the, alternating, access, mechanism])].
[sujeto(['We', show, precisely, where, 5, -, substituted, hydantoin, substrates]), verbo([bind]), complemento([in, an, extended, configuration, at, the, interface, of, the, bundle, and, hash, domains])].
[sujeto(['Metal', ions, play, crucial, roles, in, numerous, biological, 'processes,', facilitating, biochemical, reactions, by]), verbo([binding]), complemento([to, various, proteins])].
[sujeto(['An']), verbo([increasing]), complemento([body, of, evidence, suggests, that, neurotoxicity, associated, with, exposure, to, nonessential, metals, '(', e])].
[sujeto([',', 'Pb(2+))']), verbo([involves]), complemento([disruption, of, synaptic, 'activity,', and, these, observed, effects, are, associated, with, the, ability, of, 'Pb(2+)', to, interfere, with, 'Zn(2+)', and, 'Ca(2+)-dependent', functions])].
[sujeto(['In', this, 'review,', we, first, discuss, potential, neuronal, 'Ca(2+)']), verbo([binding]), complemento([protein, '(', 'CaBP)', targets, for, 'Pb(2+)', such, as, calmodulin, '(', 'CaM),', 'synaptotagmin,', neuronal, calcium, 'sensor-1', '(', 'NCS-1),', 'N-methyl-d-aspartate', receptor, '(', 'NMDAR)', and, family, 'C', of, 'G-protein', coupled, receptors, '(', 'cGPCRs),', and, their, involvement, in, 'Ca(2+)-signalling', pathways])].
[sujeto(['We', then, compare, metal]), verbo([binding]), complemento([properties, between, 'Ca(2+)', and, 'Pb(2+)', to, understand, the, structural, implications, of, 'Pb(2+)', binding, to, 'CaBPs'])].
[sujeto([',', 'NMR', and, fluorescence, 'spectroscopy)', of, 'Pb(2+)']), verbo([binding]), complemento([are, discussed, to, investigate, the, molecular, mechanism, behind, 'Pb(2+)', toxicity])].
[sujeto(['These', studies, identify, an, 'opportunistic,', allosteric]), verbo([binding]), complemento([of, 'Pb(2+)', to, 'CaM,', which, is, distinct, from, ionic, displacement])].
[sujeto(['Together,', these, data]), verbo([suggest]), complemento([three, potential, modes, of, 'Pb(2+)', activity, related, to, molecular, 'and/or', neural, 'toxicity:', '(', 'i)', 'Pb(2+)', can, occupy, 'Ca(2+)-binding', 'sites,', inhibiting, the, activity, of, the, protein, by, structural, 'modulation,', '(', 'ii)', 'Pb(2+)', can, mimic, 'Ca(2+)', in, the, binding, 'sites,', falsely, activating, the, protein, and, perturbing, downstream, 'activities,', or, '(', 'iii)', 'Pb(2+)', can, bind, outside, of, the, 'Ca(2+)-binding', 'sites,', resulting, in, the, allosteric, modulation, of, the, protein, activity])].
[sujeto(['Moreover,', the, data, further]), verbo([suggest]), complemento([that, even, low, concentrations, of, 'Pb(2+)', can, interfere, at, multiple, points, within, the, neuronal, 'Ca(2+)', signalling, pathways, to, cause, neurotoxicity])].
[sujeto(['NCS-1', is, a, multispecific, protein]), verbo([interacting]), complemento([with, a, number, of, binding, partners, in, both, 'calcium-dependent', and, independent, 'manners,', and, acting, in, a, variety, of, cellular, processes, in, which, it, has, been, linked, to, a, number, of, disorders, such, as, schizophrenia, and, autism])].
[sujeto(['Unlike', what]), verbo([has]), complemento([been, observed, with, the, 'Ca(2+)-bound', 'state,', the, presence, of, 'Mg(2+)', allows, both, the, 'N-', and, 'C-domain', to, fold, through, 'all-or-none', transitions, with, similar, refolding, rates])].
[sujeto(['In', the, absence, of, divalent, 'ions,', 'NCS-1', unfolds, and, refolds, reversibly, in, a, 'two-state', reaction]), verbo([involving]), complemento([only, the, 'C-domain,', whereas, the, 'N-domain', has, no, detectable, transitions])].
[sujeto(['Overall,', the, results, allowed, us, to, trace, the, progression, of, 'NCS-1', folding, along, its, energy, landscapes, and]), verbo([provided]), complemento([a, solid, platform, for, understanding, the, conformational, dynamics, of, similar, 'EF-hand', proteins])].
[sujeto(['In', 'cardiomyocytes,', intracellular, calcium, '(', 'Ca2+)', transients, are, elicited, by, electrical, and, receptor, 'stimulations,']), verbo([leading]), complemento([to, muscle, contraction, and, gene, 'expression,', respectively])].
[sujeto(['Although', such, elevations, of, 'Ca2+levels', '(', '[', 'Ca2+])', also, occur, in, the, 'nucleus,', the, precise, mechanism, of]), verbo([nuclear]), complemento(['[', 'Ca2+]', regulation, during, different, kinds, of, 'stimuli,', and, its, relationship, with, cytoplasmic, '[', 'Ca2+]', regulation, are, not, fully, understood])].
[sujeto(['We', confirmed, that]), verbo([nuclear]), complemento(['Ca2+', transients, were, elicited, by, both, electrical, and, receptor, stimulations, in, neonatal, mouse, ventricular, myocytes])].
[sujeto(['Kinetic', analysis, revealed, that, electrical, 'stimulation-elicited']), verbo([nuclear]), complemento(['Ca2+', transients, are, slower, than, cytoplasmic, 'Ca2+', 'transients,', and, chelating, cytoplasmic, 'Ca2+', abolished, nuclear, 'Ca2+', 'transients,', suggesting, that, nuclear, 'Ca2+', are, mainly, derived, from, the, cytoplasm, during, electrical, stimulation])].
[sujeto(['On', the, other, 'hand,', receptor, stimulation, such, as, with, 'insulin-like', growth, 'factor-1', '(', 'IGF-1)', preferentially]), verbo([increased]), complemento([nuclear, '[', 'Ca2+]', compared, to, cytoplasmic, '[', 'Ca2+]'])].
[sujeto(['Experiments', using, inhibitors, revealed, that, electrical, and, receptor, 'stimulation-elicited', 'Ca2+', transients, were, mainly]), verbo([mediated]), complemento([by, ryanodine, receptors, and, inositol, 1, ',', 4, ',', 5, -, trisphosphate, receptors, '(', 'IP3Rs),', 'respectively,', suggesting, different, mechanisms, for, the, two, signals])].
[sujeto(['Furthermore,', 'IGF-1-elicited']), verbo([nuclear]), complemento(['Ca2+', transient, amplitude, was, significantly, lower, in, myocytes, lacking, neuronal, 'Ca2+', 'sensor-1', '(', 'NCS-1),', a, 'Ca2+', binding, protein, implicated, in, 'IP3R-mediated', pathway, in, the, heart])].
[sujeto(['These', results]), verbo([suggest]), complemento([a, novel, mechanism, for, receptor, 'stimulation-induced', nuclear, '[', 'Ca2+]', regulation, mediated, by, 'IP3R', and, 'NCS-1', that, may, further, 'fine-tune', cardiac, 'Ca2+', signal, regulation])].
[sujeto(['Sensing', and]), verbo([regulating]), complemento([intracellular, levels, of, calcium, are, essential, for, proper, cellular, function])].
[sujeto(['Neuronal', calcium, 'sensor-1', '(', 'NCS-1)', is, a, member, of, the, highly]), verbo([conserved]), complemento([neuronal, calcium, sensor, family])].
[sujeto(['Although', 'NCS-1']), verbo([has]), complemento([been, associated, with, psychiatric, conditions, including, 'autism,', bipolar, disorder, and, 'schizophrenia,', it, is, unclear, which, role, 'NCS-1', plays, in, behavior])].
[sujeto(['To', understand, the, involvement, of, 'NCS-1', in, psychiatric, 'conditions,', we]), verbo([provided]), complemento([a, comprehensive, behavioral, characterization, of, 'NCS-1', knockout, '(', 'KO)', mice])].
[sujeto(['These', data, implicate, 'NCS-1', in, exploratory, 'activity,', memory, and, 'mood-related', 'behaviors,']), verbo([suggesting]), complemento([that, 'NCS-1', gene, ablation, may, result, in, phenotypic, abnormalities, associated, with, neuropsychiatric, disorders])].
[sujeto(['Certain', thermoreceptor, neurons, are, sensitive, to, tiny, thermal, fluctuations, '(', 0.01, °, 'C', or, 'less)', and]), verbo([maintain]), complemento([their, sensitivity, across, a, wide, range, of, ambient, temperatures, through, a, process, of, 'adaptation,', but, understanding, of, the, biochemical, basis, for, this, performance, is, rudimentary])].
[sujeto(['Here,', we, use, in, vivo, 'whole-cell', 'patch-clamp', recording, from, 'AFD', to, show, that]), verbo([loss]), complemento([of, 'GCY-8,', but, not, of, 'GCY-18', or, 'GCY-23,', reduces, or, eliminates, 'ThRCs,', identifying, this, rGC, as, a, crucial, signaling, element])].
[sujeto(['We']), verbo([provide]), complemento([evidence, that, the, conserved, neuronal, calcium, sensor, 1, protein, also, regulates, the, threshold, for, 'ThRC', activation, and, propose, a, signaling, network, to, account, for, 'ThRC', activation, and, adaptation])].
[sujeto(['Because', 'PDEs', play, essential, roles, in, diverse, biological, 'processes,', including, vertebrate, phototransduction, and, 'olfaction,', and, regulation, of, smooth, muscle, contractility, and, cardiovascular, 'function,', this, study]), verbo([has]), complemento([broad, implications, for, understanding, how, extraordinary, sensitivity, and, dynamic, range, is, achieved, in, cyclic, 'nucleotide-based', signaling, networks])].
[sujeto(['Neuronal', calcium, 'sensor-1', '(', 'NCS-1)', is, a, small, calcium]), verbo([binding]), complemento([protein, that, plays, a, key, role, in, the, internalization, and, desensitization, of, activated, 'D2', dopamine, receptors, '(', 'D2Rs)'])].
[sujeto(['Here,', we]), verbo([have]), complemento([used, fluorescence, anisotropy, '(', 'FA)', and, a, panel, of, 'NCS-1', 'EF-hand', variants, to, interrogate, the, interaction, between, the, 'D2R', and, 'NCS-1'])].
[sujeto(['(', 1, ')', 'FA', titration, experiments, indicate, that, at, low, 'D2R', peptide, concentrations, 'calcium-loaded', 'NCS-1']), verbo([binds]), complemento([to, the, 'D2R', peptide, in, a, monomeric, form])].
[sujeto(['At', high, 'D2R', peptide, 'concentrations,', the, 'FA', titration, data, are, best, fit, by, a, model, in, which, the, 'D2R', peptide]), verbo([binds]), complemento([two, 'NCS-1', monomers, sequentially, in, a, cooperative, fashion])].
[sujeto(['(', 2, ')', 'Competition', 'FA', experiments, in, which, unlabeled, 'D2R', peptide, was, used, to, compete, with, labeled, peptide, for]), verbo([binding]), complemento([to, 'NCS-1', shifted, titration, curves, to, higher, 'NCS-1', 'concentrations,', suggesting, that, the, binding, of, 'NCS-1', to, the, 'D2R', is, highly, specific, and, that, binding, occurs, in, a, cooperative, fashion])].
[sujeto(['(', 3, ')', 'N-Terminally', myristoylated, 'NCS-1']), verbo([dimerizes]), complemento([in, a, 'calcium-dependent', manner])].
[sujeto(['(', 4, ')', 'Co-immunoprecipitation', experiments, in, 'HEK-293', confirm, that, 'NCS-1', can, oligomerize, in, cell, lysates, and, that, oligomerization, is, dependent, on, calcium]), verbo([binding]), complemento([and, requires, functionally, intact, 'EF-hand', domains])].
[sujeto(['(', 5, ')', 'Ca(2+)/Mg(2+)', 'FA', titration, experiments, revealed, that, 'NCS-1', 'EF-hands', 2, -, 4, '(', 'EF2-4)', contributed, to]), verbo([binding]), complemento([with, the, 'D2R', peptide])].
[sujeto(['EF2', appears, to]), verbo([have]), complemento([the, highest, affinity, for, 'Ca(2+),', and, occupancy, of, this, site, is, sufficient, to, promote, 'high-affinity', binding, of, the, 'NCS-1', monomer, to, the, 'D2R', peptide])].
[sujeto(['Finally,', we, propose, a, structural, model, that, predicts, that, the, 'D2R', peptide]), verbo([binds]), complemento([to, the, first, 60, residues, of, 'NCS-1'])].
[sujeto(['We']), verbo([report]), complemento([the, effects, of, binding, of, 'Mg(2+)', to, the, second, 'Ca(2+)-binding', domain, '(', 'CBD2)', of, the, 'sodium-calcium', exchanger])].
[sujeto(['CBD2', is, known, to]), verbo([bind]), complemento([two, 'Ca(2+)', ions, using, its, 'Ca(2+)-binding', sites, 'I', and, 'II'])].
[sujeto(['Here,', we, show, by]), verbo([nuclear]), complemento([magnetic, resonance, '(', 'NMR),', circular, 'dichroism,', isothermal, titration, 'calorimetry,', and, mutagenesis, that, 'CBD2', also, binds, 'Mg(2+)', at, both, 'sites,', but, with, significantly, different, affinities])].
[sujeto(['The', results, from, 'Mg(2+)-Ca(2+)', competition, experiments, show, that, 'Ca(2+)', can, replace, 'Mg(2+)', from, site, 'I,', but, not, site, 'II,', and, that, 'Mg(2+)']), verbo([binding]), complemento([affects, the, affinity, for, 'Ca(2+)'])].
[sujeto(['Furthermore,', thermal, unfolding, circular, dichroism, data, demonstrate, that, 'Mg(2+)']), verbo([binding]), complemento([stabilizes, the, domain])].
[sujeto(['NMR', chemical, shift, perturbations, and, '(', 15, ')', 'N', relaxation, data]), verbo([reveal]), complemento([that, 'Mg(2+)-bound', 'CBD2', adopts, a, state, intermediate, between, the, apo, and, fully, 'Ca(2+)-loaded', forms])].
[sujeto(['We']), verbo([found]), complemento([that, '~20%', of, the, residues, in, the, protein, access, alternative, conformations, in, 'non-myr', 'case,', which, increases, to, '~28%', for, myr, 'NCS-1'])].
[sujeto(['Besides,', residues, responsible, for, the, absence, of, 'Ca²(+)-myristoyl', switch, are, also]), verbo([found]), complemento([accessing, alternative, states])].
[sujeto(['This', observation, prompts, us, to, conclude, that, this, may]), verbo([lead]), complemento([to, differences, in, their, individual, conformational, flexibility, and, has, implications, on, the, functionality])].
[sujeto(['Theoretical', simulations]), verbo([reveal]), complemento([that, these, 'low-energy', excited, states, are, within, an, energy, band, of, 2, -, 4, 'kcal/mol', with, respect, to, the, native, state])].
[sujeto(['NCS-1']), verbo([has]), complemento([one, cryptic, '(', 'EF1)', and, three, functional, '(', 'EF2,', 'EF3,', and, 'EF4)', 'EF-hand', motifs])].
[sujeto(['In', this, 'work,', we, determined, the, specificity, of, 'Ca(2+)']), verbo([binding]), complemento([using, 'NMR', and, 'EF-hand', mutants])].
[sujeto(['Ca(2+)', 'titration,', as, monitored, by, '[', '(', 15, ')', 'N,(1)H]', heteronuclear, single, quantum, 'coherence,']), verbo([suggests]), complemento([that, 'Ca(2+)', binds, to, the, 'EF2', and, 'EF3', almost, 'simultaneously,', followed, by, 'EF4'])].
[sujeto(['Our', 'NMR', data]), verbo([suggest]), complemento([that, 'Mg(2+)', binds, to, 'EF2', and, 'EF3,', thereby, classifying, them, as, structural, 'sites,', whereas, 'EF4', is, a, 'Ca(2+)-specific', or, regulatory, site])].
[sujeto(['This', was, further, corroborated, using, an, 'EF2/EF3-disabled', 'mutant,', which]), verbo([binds]), complemento([only, 'Ca(2+)', and, not, 'Mg(2+)'])].
[sujeto(['Ca(2+)']), verbo([binding]), complemento([induces, conformational, rearrangements, in, the, protein, by, reversing, 'Mg(2+)-induced', changes, in, 'Trp', fluorescence, and, surface, hydrophobicity])].
[sujeto(['Under', current, 'clamp,', 'UTP']), verbo([increased]), complemento([action, potential, '(', 'AP)', firing, in, response, to, depolarizing, current, 'steps,', depolarized, the, resting, 'potential,', decreased, the, threshold, current, required, to, fire, an, 'AP,', and, decreased, 'spike-frequency', adaptation])].
[sujeto(['Like', 'bradykinin,', but, unlike, 'muscarinic,', purinergic, stimulation]), verbo([induced]), complemento([rises, in, intracellular, '[', 'Ca(2+)](i)'])].
[sujeto(['As', for, 'bradykinin,', purinergic, stimulation, did, not]), verbo([suppress]), complemento(['I(Ca),', unless, neuronal, calcium, 'sensor-1', '(', 'NCS-1)', activity, was, blocked, by, a, 'dominant-negative', 'NCS-1', construct])].
[sujeto(['Our', results, indicate, that, 'P2Y', receptors]), verbo([modulate]), complemento(['M-type', channels, in, 'SCG', cells, via, 'IP(3)-mediated', '[', 'Ca(2+)](i)', signals, in, concert, with, 'CaM', and, not, by, depletion, of, 'phosphatidylinositol-4,', 5, -, biphosphate])].
[sujeto(['In', this, 'study,', we, demonstrate, that, an, 'EF-hand', 'Ca2+-binding', protein, neuronal, 'Ca2+', 'sensor-1', '(', 'NCS-1),', one, of, the, key, proteins, for, various, neuronal, 'functions,', also]), verbo([acts]), complemento([as, an, important, survival, factor])].
[sujeto(['Overexpression', of, 'NCS-1', rendered, cultured, neurons, more, tolerant, to, cell, death]), verbo([caused]), complemento([by, several, kinds, of, 'stressors,', whereas, the, 'dominant-negative', mutant, '(', 'E120Q)', accelerated, it])].
[sujeto(['In', 'addition,', 'NCS-1', proteins]), verbo([increased]), complemento([upon, treatment, with, glial, cell, 'line-derived', neurotrophic, factor, '(', 'GDNF)', and, mediated, 'GDNF', survival, signal, in, an, 'Akt', '(', but, not, 'MAPK)-dependent', manner])].
[sujeto(['Furthermore,', 'NCS-1', is, significantly, 'up-regulated', in, response, to, 'axotomy-induced', injury, in, the, dorsal, motor, nucleus, of, the, vagus, neurons, of, adult, rats, in, 'vivo,', and, adenoviral, overexpression, of, 'E120Q', resulted, in, a, significant]), verbo([loss]), complemento([of, surviving, 'neurons,', suggesting, that, 'NCS-1', is, involved, in, an, antiapoptotic, mechanism, in, adult, motor, neurons])].
[sujeto(['We', propose, that, 'NCS-1', is, a, novel, 'survival-promoting', factor, 'up-regulated', in, injured, neurons, that]), verbo([mediates]), complemento([the, 'GDNF', survival, signal, via, the, phosphatidylinositol, 3, -, 'kinase-Akt', pathway])].
[sujeto(['The', 'calcium-', and, 'sodium-permeable', transient, receptor, potential, channel, 'TRPC5']), verbo([has]), complemento([an, inhibitory, role, in, neuronal, outgrowth, but, the, mechanisms, governing, its, activity, are, poorly, understood])].
[sujeto(['Here', we, propose, a, mechanism]), verbo([involving]), complemento([the, neuronal, calcium, 'sensor-1', '(', 'NCS-1)', protein])].
[sujeto(['Inhibitory', mutants, of, 'TRPC5', and, 'NCS-1']), verbo([enhance]), complemento([neurite, outgrowth, similarly])].
[sujeto(['Mutant', 'NCS-1', does, not]), verbo([inhibit]), complemento(['surface-expression', of, 'TRPC5', but, generally, suppresses, channel, 'activity,', irrespective, of, whether, it, is, evoked, by, 'carbachol,', store, 'depletion,', lanthanides, or, elevated, intracellular, calcium])].
[sujeto(['NCS-1', and, 'TRPC5', are, in, the, same, protein, complex, in, rat, brain, and, 'NCS-1', directly]), verbo([binds]), complemento([to, the, 'TRPC5', 'C-terminus'])].
[sujeto(['The', data]), verbo([suggest]), complemento(['protein-protein', interaction, between, 'NCS-1', and, 'TRPC5,', and, involvement, of, this, protein, complex, in, retardation, of, neurite, outgrowth])].
[sujeto(['This', work, tested, the, theory, that, neuronal, calcium, 'sensor-1', '(', 'NCS-1)']), verbo([has]), complemento([effects, on, neurotransmitter, release, beyond, its, actions, on, membrane, channels])].
[sujeto(['Exogenous,', myristoylated, 'NCS-1']), verbo([stimulated]), complemento([nerve, ending, phosphatidylinositol, 4, -, phosphate, '[', 'PI(4)P]', 'synthesis,', but, 'non-myristoylated-NCS-1', did, not])].
[sujeto(['The', 'N-terminal', peptide, of, 'NCS-1', interfered, with, 'PI(4)P', 'synthesis,', and, with, spontaneous, and, 'Ca(2+)-evoked']), verbo([release]), complemento([of, both, '[', '(', 3, ')', 'H]-norepinephrine', '(', 'NA)', and, '[', '(', 14, ')', 'C]-glutamate', '(', 'glu)', in, a, 'concentration-dependent', manner])].
[sujeto(['An', antibody, raised, against, the, 'N-terminal', of, 'NCS-1']), verbo([inhibited]), complemento([perforated, nerve, ending, 'PI(4)P', 'synthesis,', but, the, 'C-terminal', antibody, had, no, effects])].
[sujeto(['Antibodies', against, the, 'N-', and, 'C-termini', of, 'NCS-1']), verbo([caused]), complemento([significant, increases, in, 'mini/spontaneous/stimulation-independent', release, of, '[', '(', 3, ')', 'H]-NA', from, perforated, nerve, 'endings,', but, had, no, effect, on, '[', '(', 14, ')', 'C]-glu', release])].
[sujeto(['These', results, support, the, idea, that, 'NCS-1', facilitates, nerve, ending, neurotransmitter]), verbo([release]), complemento([and, phosphoinositide, production, via, 'PI4K', and, localizes, these, effects, to, the, 'N-terminal', of, 'NCS-1'])].
[sujeto(['Combined', with, previous, work, on, the, regulation, of, channels, by, 'NCS-1,', the, data, are, consistent, with, the, hypothesis, that, a, 'NCS-1-PI4K', '(', 'NP,', 'neuropotentiator)', complex, may, serve, as, an, essential, linker, between, lipid, and, protein, metabolism, to]), verbo([regulate]), complemento([membrane, traffic, and, 'co-ordinate', it, with, ion, fluxes, and, plasticity, in, the, nerve, ending])].
[sujeto(['Dopamine', 'receptor-interacting', proteins, constitute, a, part, of, the, dopamine, system, that, is]), verbo([involved]), complemento([in, regulation, of, dopamine, 'receptor-associated', intracellular, signaling])].
[sujeto(['All']), verbo([increases]), complemento([in, protein, levels, were, correlated, with, those, of, corresponding, messages])].
[sujeto(['Also,', 'up-regulation', of, both, calcyon, and, 'NCS-1', in, the, cortex, of, schizophrenia, patients, can, be, attributed, largely, to, an]), verbo([enhanced]), complemento([transcription, or, reduced, degradation, of, their, messages])].
[sujeto(['Finally,', our, findings]), verbo([suggest]), complemento([that, elevations, in, the, expressions, of, calcyon, and, 'NCS-1', in, schizophrenia, may, have, the, same, underlying, cause])].
[sujeto(['SOS3']), verbo([activates]), complemento([the, 'SOS2', protein, 'kinase,', which, activates, various, ion, transporters])].
[sujeto(['SOS3', was, cloned, into, a, plasmid, and]), verbo([expressed]), complemento([in, 'Escherichia', 'coli,', allowing, purification, of, the, protein, to, homogeneity])].
[sujeto(['A', promising, 'molecular-replacement', solution]), verbo([has]), complemento([been, found, using, neuronal, 'calcium-sensor', 1, as, the, search, model])].
[sujeto(['Interestingly,', no, solution, was]), verbo([found]), complemento([using, 'AtCBL2', '(', 'A'])].
[sujeto(['Neuronal', calcium, 'sensor-1', '(', 'NCS-1),', a, 'Ca(2+)-binding', 'protein,', plays, an, important, role, in, the, modulation, of, neurotransmitter]), verbo([release]), complemento([and, phosphatidylinositol, signaling, pathway])].
[sujeto(['Here,', we, present, the, role, of, myristoylation, of, 'NSC-1', in, governing, 'Ca(2+)']), verbo([binding]), complemento([and, 'Ca(2+)-induced', conformational, changes, in, 'NCS-1', as, compared, with, the, role, in, the, nonmyristoylated, protein])].
[sujeto(['The', '(', 45, ')', 'Ca']), verbo([binding]), complemento([and, isothermal, titration, calorimetric, data, show, that, myristoylation, increases, the, degree, of, 'cooperativity;', 'thus,', the, myristoylated, 'NCS-1', binds, 'Ca(2+)', more, strongly, '(', with, three, 'Ca(2+)', binding, 'sites)', than, the, 'non-myristoylated', one, '(', with, two, 'Ca(2+)', binding, 'sites)'])].
[sujeto(['Although', the, changes, in, the, 'far-UV', 'CD', upon, 'Ca(2+)']), verbo([binding]), complemento([were, not, seen, in, 'E120Q', mutant, '(', disabling, 'EF-hand', 3, ')', ',', the, 'near-UV', 'CD', changes, in, conformation, also, were, not, influenced, by, this, mutation])].
[sujeto(['The', difference, in, the]), verbo([binding]), complemento([affinity, of, myristoylated, and, 'non-myristoylated', proteins, to, 'Ca(2+)', also, was, reflected, by, 'Trp', fluorescence])].
[sujeto([8, -, 'Anilino-1-naphthalene', sulfonic, acid]), verbo([binding]), complemento([data, showed, solvation, of, the, myristoyl, group, in, the, presence, of, 'Ca(2+),', which, could, be, attributed, to, the, 'myristoyl-dependent', conformational, changes, in, 'NCS-1'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, myristoylation, influences, the, protein, conformation, and, 'Ca(2+)', 'binding,', which, might, be, crucial, for, its, physiological, functions])].
[sujeto(['recoverin,', 'neurocalcins,', and, 'frequenin)', are]), verbo([expressed]), complemento([at, highest, levels, in, excitable, 'cells,', and, some, of, them, regulate, desensitization, of, 'G', 'protein-coupled', receptors])].
[sujeto(['Ncs1p']), verbo([binds]), complemento([three, 'Ca2+', ions, at, saturation, with, an, apparent, affinity, of, 2, microm, and, 'Hill', coefficient, of, 1.9])].
[sujeto(['Subcellular', fractionation, experiments, showed, that, myristoylation, and, 'Ca2+']), verbo([binding]), complemento([by, 'Ncs1p', are, essential, for, its, translocation, from, cytoplasm, to, membranes])].
[sujeto(['Analysis', of, 'Ncs1p', mutants, lacking, myristoylation, '(', 'Ncs1p(G2A))', or, deficient, in, 'Ca2+']), verbo([binding]), complemento(['(', 'Ncs1p(E84Q/E120Q/E168Q))', revealed, that, 'Ca2+', binding, was, essential, for, both, 'phenotypes,', while, myristoylation, was, less, critical])].
[sujeto(['Exogenous', 'cAMP,', a, key, regulator, for, sexual, 'development,']), verbo([suppressed]), complemento([conjugation, and, sporulation, of, 'ncs1Delta,', suggesting, involvement, of, 'Ncs1p', in, the, adenylate, cyclase, pathway, turned, on, by, the, 'glucose-sensing', 'G', 'protein-coupled', receptor, 'Git3p'])].
[sujeto(['In', 'contrast,', the, 'Ca2+-intolerance', of, ncs1Delta, was, not, affected, by, cAMP, or, 'recoverin,']), verbo([suggesting]), complemento([that, the, two, ncs1Delta, phenotypes, are, mechanistically, independent])].
[sujeto(['We', propose, that, 'Schizosaccharomyces', pombe, 'Ncs1p', negatively]), verbo([regulates]), complemento([sporulation, perhaps, by, controlling, 'Ca2+-dependent', desensitization, of, 'Git3p'])].
[sujeto(['Ca2+', ions, play, a, crucial, role, not, only, as, the]), verbo([trigger]), complemento([for, neurotransmitter, 'release,', but, also, in, other, aspects, of, brain, 'function,', such, as, 'short-term', and, 'long-term', modulation, of, synaptic, 'efficacy,', which, may, underlie, certain, forms, of, learning, and, memory])].
[sujeto(['The', actions, of, 'Ca2+', are]), verbo([mediated]), complemento([by, 'Ca(2+)-binding', 'proteins,', including, a, group, of, proteins, known, as, neuronal, calcium, sensor, '(', 'NCS)', proteins])].
[sujeto(['Some', members, of, this, 'family,', such, as, recoverin, and, guanylate, 'cyclase-activating', 'protein,', are, only]), verbo([expressed]), complemento([in, photoreceptor, cells, and, have, been, implicated, in, the, control, of, visual, transduction, 'pathways,', while, the, functional, roles, of, the, other, members, are, largely, unknown])].
[sujeto(['NCS-1', is, an, 'N-terminally', myristoylated, protein, that, contains, four, 'EF-hand', 'motifs,', three, of, which, are, able, to]), verbo([bind]), complemento(['Ca2+', in, the, submicromolar, range])].
[sujeto(['Overexpression', of, 'NCS-1']), verbo([has]), complemento([been, shown, to, enhance, evoked, neurotransmitter, 'release,', 'paired-pulse', facilitation, and, exocytosis, in, several, neuronal, and, neuroendocrine, cell, types])].
[sujeto(['Recent', experiments]), verbo([suggest]), complemento([that, 'NCS-1', interacts, directly, with, phosphatidylinositol, 4, -, hydroxykinase, in, yeast, as, well, as, mammalian, 'cells,', suggesting, that, it, may, enhance, neuronal, secretion, by, modulating, cellular, trafficking, steps, in, a, 'phosphoinositide-dependent', manner])].
[sujeto(['In', 'contrast,', an, involvement, of, 'NCS-1', in, the, expression, and, regulation, of, 'voltage-gated', 'Ca2+', channels, and, 'K+', channels]), verbo([has]), complemento([also, been, 'proposed,', which, may, be, 'attributed,', at, least, in, 'part,', to, the, effects, of, 'NCS-1', on, vesicular, trafficking, pathways])].
[sujeto(['The', present, review, describes, current, knowledge, about, the, cellular, functions, and, molecular, mechanisms, by, which, 'NCS-1', may]), verbo([regulate]), complemento([neurotransmitter, release])].
[sujeto(['The', crystal, structure, of, 'AtCBL2']), verbo([has]), complemento([been, determined, at, 2.1, 'A', resolution])].
[sujeto(['The', two, calcium, ions, are, coordinated, in, the, first, and, fourth, 'EF-hand', 'motifs,', whereas, the, second, and, third, 'EF-hand', motifs, are]), verbo([maintained]), complemento([in, the, open, form, by, internal, hydrogen, bonding, without, coordination, of, calcium, ions])].
[sujeto(['Both', a, possible, site, and, a, possible, mechanism, for, the]), verbo([target]), complemento([binding, to, 'AtCBL2', are, discussed, based, on, the, 'three-dimensional', structure])].
[sujeto(['The', 'null-mutants', had, normal, growth, and, pathogenicity, similar, to, the, parental, 'strain,', but, their, growth, was]), verbo([suppressed]), complemento([in, high, concentrations, of, 'Ca2+', or, acidic, conditions])].
[sujeto(['Neuronal', calcium, sensor, '(', 'NCS)', 'proteins,', a, 'sub-branch', of, the, 'EF-hand', 'superfamily,', are]), verbo([expressed]), complemento([in, the, brain, and, retina, where, they, transduce, calcium, signals, and, are, genetically, linked, to, degenerative, diseases])].
[sujeto(['The', amino, acid, sequences, of, 'NCS', proteins, are, highly]), verbo([conserved]), complemento([but, their, physiological, functions, are, quite, distinct])].
[sujeto(['Retinal', recoverin, and, guanylate, cyclase]), verbo([activating]), complemento([proteins, '(', 'GCAPs)', both, serve, as, calcium, sensors, in, retinal, rod, 'cells,', neuronal, frequenin, '(', 'NCS1)', modulates, synaptic, activity, and, neuronal, 'secretion,', 'K(+)', channel, interacting, proteins, '(', 'KChIPs)', regulate, ion, channels, to, control, neuronal, 'excitability,', and, 'DREAM', '(', 'KChIP3)', is, a, transcriptional, repressor, that, regulates, neuronal, gene, expression])].
[sujeto(['Here', we, review, the, molecular, structures, of, myristoylated, forms, of, 'NCS1,', 'recoverin,', and, 'GCAP1', that, all, look, very, 'different,']), verbo([suggesting]), complemento([that, the, sequestered, myristoyl, group, helps, to, refold, these, highly, homologous, proteins, into, very, different, structures])].
[sujeto(['The', molecular, structure, of, 'NCS']), verbo([target]), complemento([complexes, have, been, solved, for, recoverin, bound, to, rhodopsin, kinase, '(', 'RK),', 'NCS-1', bound, to, phosphatidylinositol, 4, -, 'kinase,', and, 'KChIP1', bound, to, 'A-type', 'K(+)', channels])].
[sujeto(['We', propose, that, 'N-terminal', myristoylation, is, critical, for, shaping, each, 'NCS', family, member, into, a, different, 'structure,', which, upon, 'Ca(2+)-induced', extrusion, of, the, myristoyl, group, exposes, a, unique, set, of, previously, masked, residues, that]), verbo([interact]), complemento([with, a, particular, physiological, target])].
[sujeto(['Neuronal', calcium, sensor, '(', 'NCS)', 'proteins,', a, 'sub-branch', of, the, calmodulin, 'superfamily,', are]), verbo([expressed]), complemento([in, the, brain, and, retina, where, they, transduce, calcium, signals, and, are, genetically, linked, to, degenerative, diseases])].
[sujeto(['The', amino, acid, sequences, of, 'NCS', proteins, are, highly]), verbo([conserved]), complemento([but, their, physiological, functions, are, quite, distinct])].
[sujeto(['Retinal', recoverin, and, guanylate, cyclase]), verbo([activating]), complemento([proteins, '(', 'GCAPs)', both, serve, as, calcium, sensors, in, retinal, rod, 'cells,', neuronal, frequenin, '(', 'NCS1)', modulate, synaptic, activity, and, neuronal, 'secretion,', 'K+', channel, interacting, proteins, '(', 'KChIPs)', regulate, ion, channels, to, control, neuronal, 'excitability,', and, 'DREAM', '(', 'KChIP3)', is, a, transcriptional, repressor, that, regulates, neuronal, gene, expression])].
[sujeto(['Here', we, review, the, molecular, structures, of, myristoylated, forms, of, 'NCS1,', 'recoverin,', and, 'GCAP1', that, all, look, very, 'different,']), verbo([suggesting]), complemento([that, the, sequestered, myristoyl, group, helps, to, refold, these, highly, homologous, proteins, into, very, different, structures])].
[sujeto(['The', molecular, structure, of, 'NCS']), verbo([target]), complemento([complexes, have, been, solved, for, recoverin, bound, to, rhodopsin, 'kinase,', 'NCS-1', bound, to, phosphatidylinositol, 4, -, 'kinase,', and, 'KChIP1', bound, to, 'A-type', 'K+', channels])].
[sujeto(['We', propose, the, idea, that, 'N-terminal', myristoylation, is, critical, for, shaping, each, 'NCS', family, member, into, a, unique, 'structure,', which, upon, 'Ca2+-induced', extrusion, of, the, myristoyl, group, exposes, a, unique, set, of, previously, masked, 'residues,', thereby, exposing, a, distinctive, ensemble, of, hydrophobic, residues, to]), verbo([associate]), complemento([specifically, with, a, particular, physiological, target])].
[sujeto(['This', includes, information, on, the, variety, of, exchangers, that]), verbo([have]), complemento([been, described, and, their, regulatory, properties])].
[sujeto(['Parts', of, the, 'NCS1', molecule]), verbo([involved]), complemento([in, regulation, and, ion, transport, have, been, 'elucidated,', and, initial, information, on, the, topology, and, structure, is, available])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, 2.85, -, angstrom, resolution, structure, of, the, 'NCS1', 'benzyl-hydantoin', 'transporter,', 'Mhp1,', from, 'Microbacterium', liquefaciens])].
[sujeto(['The', structures, of, the, 'outward-facing', open, and, 'substrate-bound', occluded, conformations, were, 'solved,', showing, how, the, 'outward-facing', cavity, closes, upon]), verbo([binding]), complemento([of, substrate])].
[sujeto(['Comparisons', with, the, leucine, transporter, 'LeuT(Aa)', and, the, galactose, transporter, vSGLT]), verbo([reveal]), complemento([that, the, 'outward-', and, 'inward-facing', cavities, are, symmetrically, arranged, on, opposite, sides, of, the, membrane])].
[sujeto(['The', reciprocal, opening, and, closing, of, these, cavities, is, synchronized, by, the, inverted, repeat, helices, 3, and, 8, ',']), verbo([providing]), complemento([the, structural, basis, of, the, alternating, access, model, for, membrane, transport])].
[sujeto(['However,', the, presence, of, a, 'calcium-myristoyl', switch, in, 'NCS1', and, its, role, in, the, membrane]), verbo([binding]), complemento([are, controversial])].
[sujeto(['Two']), verbo([binding]), complemento([parameters, are, calculated, from, monolayer, 'measurements:', the, maximum, insertion, 'pressure,', up, to, which, protein, binding, is, energetically, 'favorable,', and, the, 'synergy,', reporting, attractive, or, repulsive, interactions, with, the, lipid, monolayers])].
[sujeto(['Binding', membrane, measurements, performed, in, the, presence, of, myristoylated, 'NCS1']), verbo([reveal]), complemento([better, binding, interactions, for, phospholipids, composed, of, phosphoethanolamine, polar, head, groups, and, unsaturated, fatty, acyl, chains])].
[sujeto(['In', the, absence, of, 'calcium,', the, membrane]), verbo([binding]), complemento([measurements, are, drastically, modified, and, suggest, that, the, protein, is, more, strongly, bound, to, the, membrane])].
[sujeto(['Indeed,', the]), verbo([binding]), complemento([of, calcium, by, three, 'EF-hand', motifs, of, 'NCS1', leads, to, a, conformation, change])].
[sujeto(['The', 'N-terminal', peptide, of, 'NCS1', is, composed, of, two, amphiphilic, helices]), verbo([involved]), complemento([in, the, membrane, interactions, of, 'NCS1'])].
[sujeto(['Moreover,', the, presence, of, the, myristoyl, group]), verbo([has]), complemento([a, weak, influence, on, the, membrane, binding, of, 'NCS1', suggesting, the, absence, of, a, 'calcium-myristoyl', switch, mechanism, in, this, protein])].
[sujeto(['The', myristoylation, could, thus]), verbo([have]), complemento([a, structural, role, required, in, the, 'folding/unfolding', of, 'NCS1', which, is, essential, to, its, multiple, biological, functions])].
[sujeto(['We']), verbo([found]), complemento([elevated, expression, of, neuronal, calcium, sensor, 1, '(', 'Ncs1)', and, dopamine, 'type-2', receptors, upon, 'self-directed', 'exploration,', in, concert, with, increased, neuronal, activity, in, the, hippocampal, dentate, gyrus, and, area, 'CA3,', as, well, as, the, nucleus, accumbens])].
[sujeto(['We', probed, further, into, the, learning, bonus, by, developing, a, point, mutant, mouse, '(', 'Ncs1(P144S/P144S))', harboring, a, destabilized, 'NCS-1', 'protein,', and]), verbo([found]), complemento([this, line, lacked, the, equivalent, 'self-directed', exploration, learning, bonus])].
[sujeto(['These', results, are, potentially, relevant, for, augmenting, learning, and, memory, in, health, and, 'disease,', and]), verbo([provide]), complemento([the, basis, for, further, molecular, and, circuit, analyses, in, this, direction])].
[sujeto(['NCS1', '(', neuronal, calcium, 'sensor-1)', is, a, 'Ca(2+)-myristoyl', switch, protein, of, the, 'NCS', protein, family]), verbo([involved]), complemento([in, synaptic, plasticity, and, neurotransmission, via, 'Ca(2+)-dependent', regulation, of, dopamine, 'D2', receptor, and, associated, 'Gprotein', coupled, receptor, kinase, '(', 'GRK)-2'])].
[sujeto(['Overexpression', of, 'NCS1', in, synaptic, terminals, results, in, accumulation, of, 'membrane-bound', protein, and, its, redundant, regulatory, activity]), verbo([associated]), complemento([with, neurological, disorders])].
[sujeto(['Here,', we]), verbo([have]), complemento([demonstrated, that, bovine, photoreceptors, contain, 'NCS1', that, is, capable, of, a, partially, irreversible, interaction, with, isolated, photoreceptor, membranes, and, implicated, in, 'Ca(2+)-dependent', binding, and, regulation, of, 'GRK1', in, vitro])].
[sujeto(['Using', 'NCS1-', recoverin, 'C-terminal', chimeric, construct, '(', 'NR),', it, was]), verbo([found]), complemento([that, the, 'Ca(2+)-myristoyl', switch, of, 'NCS1', is, affected, by, its, 'C-terminal', segment, downstream, the, fourth, 'EF-loop', of, the, 'protein,', which, is, variable, within, the, 'NCS', family])].
[sujeto(['NR']), verbo([retains]), complemento([structural, stability, and, sensitivity, to, 'Ca(2+),', but, interacts, with, photoreceptor, membranes, with, lower, affinity, in, a, 'Ca(2+)-', dependent, fully, reversible, manner, and, displays, altered, 'GRK1', modulation])].
[sujeto(['These', data, combined, with, fluorescent, probing, of, surface, hydrophobicity, of, 'NCS1,', 'NR', and, recoverin]), verbo([suggest]), complemento([that, the, 'C-terminal', segment, of, 'NCS1', regulates, reuptake, of, myristoyl, group, under, 'Ca(2+)-free', conditions, and, participates, in, organization, of, the, 'target-binding', pocket, of, the, protein])].
[sujeto(['We', point, out, a, putative, role, of, 'NCS1', in, photoreceptors, as, a, modulator, of, 'GRK', activity, and, propose]), verbo([targeting]), complemento([of, the, 'C-terminal', segment, of, 'NCS1', as, an, appropriate, way, for, selective, suppression, of, excessive, membrane, accumulation, and, aberrant, activity, of, the, protein, in, neurons, associated, with, central, nervous, system, dysfunctions])].
[sujeto(['EF-hand', calcium, sensors]), verbo([respond]), complemento([structurally, to, changes, in, intracellular, 'Ca(2+)', 'concentration,', triggering, diverse, cellular, responses, and, resulting, in, broad, interactomes])].
[sujeto(['Two', intermediate, structures]), verbo([induced]), complemento([by, 'Ca(2+)', binding, to, the, 'EF-hands', were, observed, during, refolding])].
[sujeto(['Molecular', dynamics, results]), verbo([reveal]), complemento([the, atomistic, details, of, the, unfolding, process, and, rationalize, the, different, domain, stabilities, during, mechanical, unfolding])].
[sujeto(['Our', results, emphasize, that, 'NCS1']), verbo([has]), complemento([evolved, a, remarkable, complex, interdomain, cooperativity, and, a, fundamentally, different, folding, mechanism, compared, to, structurally, related, proteins])].
[sujeto(['Neuronal', calcium, 'sensor-1', '(', 'NCS-1)']), verbo([regulates]), complemento([various, neuronal, functions])].
[sujeto(['Although', it, is]), verbo([expressed]), complemento([in, the, 'heart,', very, little, is, known, about, its, cardiac, functions])].
[sujeto(['NCS-1', was, highly]), verbo([expressed]), complemento([in, young, 'hearts,', and, its, deletion, decreased, survival, and, contractile, function, in, young, mice])].
[sujeto(['This', was, due, to, reduced, 'Ca(2+)/calmodulin-dependent', protein, kinase, 'II', '(', 'CaMKII)', activity, in, 'Ncs1(-/-)', 'myocytes,', which]), verbo([led]), complemento([to, reduced, sarcoplasmic, reticulum, 'Ca(2+)', uptake, and, release])].
[sujeto(['NCS-1', physically, and, functionally]), verbo([interacted]), complemento([with, inositol, 1, ',', 4, ',', 5, -, trisphosphate, receptors, '(', 'IP(3)Rs)', in, the, heart])].
[sujeto(['In', 'addition,', 'IP(3)R', stimulation, resulted, in, phosphorylation, of, 'CaMKII-δ,', which, was]), verbo([enhanced]), complemento([by, 'NCS-1', overexpression])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, a, functional, link, exists, between, 'NCS-1,', 'IP(3)R', 'function,', and, 'CaMKII', activation, that, may, affect, global, 'Ca(2+)', signals, in, the, immature, heart])].
[sujeto(['Furthermore,', 'NCS-1', was, upregulated, in, hypertrophic, 'hearts,', and, 'hormone-induced', hypertrophy, was, largely]), verbo([prevented]), complemento([in, 'Ncs1(-/-)', hearts])].
[sujeto(['Inhibitors', of, 'IP(3)Rs,', 'CaMKII,', and, calcineurin, all]), verbo([prevented]), complemento(['NCS-1-induced', 'hypertrophy,', which, suggests, the, involvement, of, these, pathways])].
[sujeto(['NCS-1', is, an, important, regulator, of, immature, heart, function, and, 'hypertrophy,', and, it, functions, in, part, by]), verbo([promoting]), complemento(['IP(3)R', 'function,', followed, by, 'CaMKII-dependent', signal, activation])].
[sujeto(['Adult', cortical, neurons, forming, the, corticospinal, tract, '(', 'CST)', normally]), verbo([have]), complemento([low, levels, of, the, neuronal, calcium, 'sensor-1', '(', 'NCS1)', protein])].
[sujeto(['In', primary, cultured, adult, cortical, 'neurons,', the, 'lentivector-induced', overexpression, of, 'NCS1']), verbo([induces]), complemento([neurite, sprouting, associated, with, increased, 'phospho-Akt', levels])].
[sujeto(['When', the, 'PI3K/Akt', signalling, pathway, was, pharmacologically]), verbo([inhibited]), complemento([the, 'NCS1-induced', neurite, sprouting, was, abolished])].
[sujeto(['In', injured, corticospinal, 'neurons,', overexpression, of, 'NCS1']), verbo([induced]), complemento([axonal, sprouting, and, regeneration, and, also, neuroprotection])].
[sujeto(['These', findings, demonstrate, that]), verbo([increasing]), complemento([the, levels, of, intracellular, 'NCS1', in, injured, and, uninjured, central, neurons, enhances, their, intrinsic, anatomical, plasticity, within, the, injured, adult, central, nervous, system])].
[sujeto(['Many', neurodevelopmental, genes, were]), verbo([increased]), complemento([during, scarless, repair, on, 'post-injury', days, 1, and, 3])].
[sujeto(['Neuropeptide', 'Y', 'Receptor', type, 'I,', cJun, related, 'Transcription', 'Factor', '(', 'junD),', 'Synaptophysin,', 'SNAP', 25, ',', 'Neuronal', calcium, sensor, 1, '(', 'NCS1),', neural, 'visine-like', calcium]), verbo([binding]), complemento([protein, 1, '(', 'NVP1),', nerve, growth, 'factor-induced', gene, 'A', '(', 'NGFI-A/EGR1),', 'VGF8A', 'protein,', 'p27kip1,', and, members, of, the, 'GABA', and, serotonin, family, each, had, 2, -, to, 3, -, fold, expression, increases, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['We', speculate, that, fetal, skin, cells]), verbo([express]), complemento([neurotrophins, during, skin, development, that, regulate, peripheral, neuron, formation])].
[sujeto(['During', injury, these, factors]), verbo([promote]), complemento([the, survival, and, regeneration, of, peripheral, 'neurons;', this, interaction, of, 'neuropeptides,', neuropeptide, 'receptors,', and, neurotrophins, may, modulate, the, fetal, scarless, repair, mechanisms, in, response, to, injury])].
[sujeto(['Identification', of, these, neurodevelopmental, candidate, genes]), verbo([provides]), complemento([insight, for, new, investigation, into, mechanisms, regulating, scarless, healing])].
[sujeto(['Neuronal', calcium, sensor, '(', 'NCS)', proteins]), verbo([regulate]), complemento([signal, transduction, and, are, highly, conserved, from, yeast, to, humans])].
[sujeto(['Ncs1p', expression]), verbo([increases]), complemento([approximately, 100, -, fold, when, fission, yeast, grows, in, high, extracellular, 'Ca(2+)', '(', &, 'gt;0'])].
[sujeto(['Transcriptional', reporter, assays, show, that, ncs1, promoter, activity]), verbo([increased]), complemento([30, -, fold, when, extracellular, 'Ca(2+)', was, raised, to, 0.1, 'M', and, was, highly, 'Ca(2+)-specific'])].
[sujeto(['The', 'Ca(2+)-responsive', ncs1, promoter, region, consists, of, 130, nucleotides, directly, upstream, from, the, start, codon, and, contains, tandem, repeats, of, the, 'sequence,', 5, '\'', -, 'caact-3\',', that]), verbo([binds]), complemento([to, 'Prz1p'])].
[sujeto(['The', 'Ca(2+)-sensitive', ncs1Delta, phenotype, is, rescued, by, a, yam8, null, 'mutation,']), verbo([suggesting]), complemento([a, possible, interaction, between, 'Ncs1p', and, the, 'Ca(2+)', 'channel,', 'Yam8p'])].
[sujeto(['Ca(2+)', uptake, and, 'Ncs1p']), verbo([binding]), complemento([to, yeast, membranes, are, both, decreased, in, 'yam8Delta,', suggesting, 'Ca(2+)-induced', binding, of, 'Ncs1p', to, 'Yam8p', results, in, channel, closure])].
[sujeto(['We', propose, that, 'Ncs1p']), verbo([promotes]), complemento(['Ca(2+)', tolerance, in, fission, 'yeast,', in, part, by, cytosolic, 'Ca(2+)', buffering, and, perhaps, by, negatively, regulating, the, 'Yam8p', 'Ca(2+)', channel])].
[sujeto(['Here', we, show, that, 'inducible,', modest, overexpression, of, neuronal, calcium, sensor, 1, '(', 'Ncs1)', selectively, in, the, adult, murine, dentate, gyrus, '(', 'DG)']), verbo([promotes]), complemento([a, specific, form, of, exploratory, behavior])].
[sujeto(['The', mice, also, display, a, selective, facilitation, of, 'long-term', potentiation, '(', 'LTP)', in, the, medial, perforant, path, and, a, selective, enhancement, in, 'rapid-acquisition', spatial, 'memory,', phenotypes, that, are, reversed, by, direct, application, of, a, 'cell-permeant', peptide, '(', 'DNIP)', designed, to, interfere, with, 'NCS-1']), verbo([binding]), complemento([to, the, dopamine, 'type-2', receptor, '(', 'D2R)'])].
[sujeto(['These', data, demonstrate, a, role, for, 'NCS-1', and, 'D2R', in, 'DG', plasticity, and]), verbo([provide]), complemento([insight, for, understanding, how, the, 'DG', contributes, to, the, origin, of, exploration, and, spatial, memory, acquisition])].
[sujeto(['Parkinson\'s', disease, '(', 'PD),', the, second, most, frequent, neurodegenerative, disorder, at, old, 'age,', can, be]), verbo([caused]), complemento([by, elevated, expression, or, the, 'A53T', missense, mutation, of, the, presynaptic, protein, 'alpha-synuclein', '(', 'SNCA)'])].
[sujeto(['We']), verbo([have]), complemento([previously, demonstrated, that, a, functional, dopamine, 'D2', receptor, promoter, variant, '(', 'DRD2', -, 141, 'Ins/Del)', predicts, response, to, nicotine, replacement, therapy, '(', 'NRT)'])].
[sujeto(['The', present, study, extends, this]), verbo([finding]), complemento([in, the, same, population, of, 363, 'NRT-treated', 'subjects,', by, examining, variation, in, the, gene, encoding, the, neuronal, calcium, 'sensor-1', protein, '(', 'FREQ),', which, functions, to, regulate, 'D2', receptor, desensitization])].
[sujeto(['This', result]), verbo([suggests]), complemento([that, the, interaction, between, variation, in, the, 'DRD2', and, 'FREQ', 'genes,', which, both, encode, components, of, the, 'D2', dopamine, receptor, signal, transduction, 'pathway,', impacts, the, efficacy, of, 'NRT'])].
[sujeto(['Phenotypic', heterogeneity, of, cancer, cells, is]), verbo([caused]), complemento([not, only, by, genetic, and, epigenetic, alterations, but, also, by, stochastic, variation, of, intracellular, signaling, molecules])].
[sujeto(['Using', cells, that, stably]), verbo([express]), complemento(['Förster', resonance, energy, transfer, '(', 'FRET)', 'biosensors,', we, show, here, a, correlation, between, a, temporal, fluctuation, in, the, activity, of, 'Rac1', and, the, invasive, properties, of, 'C6', glioma, cells])].
[sujeto(['By', using, 'long-term', 'time-lapse', 'imaging,', we]), verbo([found]), complemento([that, 'Rac1', activity, in, 'C6', glioma, cells, fluctuated, over, a, timescale, that, was, substantially, longer, than, that, of, the, replication, cycle])].
[sujeto(['Among', the, 14, genes, that, were, most]), verbo([associated]), complemento([with, the, term, '\'', 'membrane\'', '(', 'membrane-related', 'genes)', in, 'Rac1(high)', 'cells,', we, identified, four, genes, that, were, associated, with, glioma, invasion, and, 'Rac1', activity, by, using, siRNA, knockdown, experiments])].
[sujeto(['Among', the, transcription, factors, upregulated, in, 'Rac1(high)', 'cells,', 'Egr2', was]), verbo([found]), complemento([to, positively, regulate, expression, of, the, four, 'membrane-related', 'invasion-associated', genes])].
[sujeto(['The', identified, signaling, network, might]), verbo([cause]), complemento([the, fluctuations, in, 'Rac1', activity, and, the, heterogeneity, in, the, invasive, capacity, of, glioma, cells])].
[sujeto(['This', protein]), verbo([has]), complemento([an, important, role, in, the, regulation, of, neurotransmitter, release, per, 'synapse,', axonal, growth, and, bouton, formation])].
[sujeto(['Here,', we]), verbo([have]), complemento([investigated, the, factors, involved, in, this, unusual, feature, by, examining, the, molecular, evolution, of, the, two, frq, genes, in, 'Drosophila', and, the, evolutionary, dynamics, of, 'NCS', family, in, a, large, set, of, bilaterian, species])].
[sujeto(['Surprisingly,', we]), verbo([have]), complemento([found, no, amino, acid, replacements, fixed, across, the, twelve, 'Drosophila', species, surveyed])].
[sujeto(['In', 'contrast,', synonymous, substitutions]), verbo([have]), complemento([been, prevalent, in, the, evolution, of, the, coding, region, of, frq1, and, 'frq2,', indicating, the, presence, of, strong, functional, constraints, following, gene, duplication])].
[sujeto(['Despite', 'that,', we]), verbo([have]), complemento([detected, that, significant, evolutionary, rate, acceleration, had, occurred, in, 'Frq1', in, early, times, from, the, 'duplication,', in, which, positive, selection, '(', likely, promoting, functional, 'diversification)', had, probably, an, important, role])].
[sujeto(['The', analysis, of, sequence, conservation, and, 'DNA', topology, at, the, 'non-coding', regions, of, both, genes]), verbo([has]), complemento([allowed, the, identification, of, 'DNA', regions, candidates, to, be, 'cis-regulatory', elements])].
[sujeto(['The', results]), verbo([reveal]), complemento([a, possible, mechanism, of, regulatory, diversification, between, frq1, and, frq2])].
[sujeto(['Selected', amino, acid, substitutions, in, 'Frq1', likely, contributed, to, the, functional, divergence, between, the, two, 'duplicates,', 'which,', in, 'turn,', should]), verbo([have]), complemento([diverged, in, their, regulation, by, 'ecdysone-induced', early, genes])].
[sujeto(['A', variety, of, 'Ca2+']), verbo([binding]), complemento([proteins, are, known, to, play, an, integral, role, in, catecholamine, release, from, synapses, as, well, as, secretory, 'cells,', such, as, chromaffin, cells])].
[sujeto(['The', 'Drosophila', protein, frequenin, and, its, mammalian, homolog, neuronal, 'Ca2+', 'sensor-1', '(', 'NCS-1)', belong, to, a, family, of, 'Ca2+', sensors, with, 'EF', hands, that]), verbo([bind]), complemento(['Ca2+', and, then, interact, with, other, proteins])].
[sujeto(['Frequenin/NCS-1']), verbo([has]), complemento([been, shown, to, enhance, exocytotic, activity, in, addition, to, altering, 'Ca2+', channel, regulation])].
[sujeto(['To', better, understand, how, 'NCS-1']), verbo([regulates]), complemento(['stimulus-secretion', 'coupling,', bovine, chromaffin, cells, were, infected, with, 'Semliki', 'Forest', virus, '(', 'SFV)', vectors, containing, the, rat, 'NCS-1', gene])].
[sujeto(['Exocytosis', elicited, by, membrane, depolarization, was, not, significantly, different, between, cells, infected, with, 'SFV']), verbo([expressing]), complemento([green, fluorescent, protein, '(', 'GFP)', or, 'GFP', plus, 'NCS-1,', except, that, the, overexpression, of, 'NCS-1', resulted, in, a, faster, rundown, in, exocytosis])].
[sujeto(['When', cells, were]), verbo([stimulated]), complemento([with, 'histamine,', 'NCS-1', overexpression, led, to, higher, 'exocytosis,', as, well, as, '[', 'Ca2+]i', elevation])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'NCS-1', may, regulate, cellular, activity, through, the, modulation, of, the, phosphatidylinositol, signaling, pathway])].
[sujeto(['Neuronal', calcium, 'sensor-1', '(', 'NCS-1', 'Var1)', is, a, 'calcium-binding', protein]), verbo([expressed]), complemento([in, most, tissues])].
[sujeto(['Because', alterations, in, the, level, of, expression, of, 'NCS-1', 'Var1', and, the, expression, of, 'NCS-1', variants]), verbo([have]), complemento([been, correlated, with, several, neurological, 'diseases,', the, relative, expression, and, functional, role, of, 'NCS-1', 'Var2', was, examined])].
[sujeto(['We']), verbo([found]), complemento([that, 'NCS-1', 'Var2', mRNA, levels, are, not, found, in, mouse, tissues, and, are, expressed, at, levels, '~1000-fold', lower, than, 'NCS-1', 'Var1', in, three, different, human, cell, lines, '(', 'SHSY5Y,', 'HEK293,', 'MB231)'])].
[sujeto(['The', calcium]), verbo([binding]), complemento([affinity, is, '~100', times, weaker, in, purified, 'NCS-1', 'Var2', than, 'NCS-1', 'Var1'])].
[sujeto(['Because', truncation, of, 'NCS-1', 'Var1']), verbo([has]), complemento([been, linked, to, functional, changes, in, 'neurons,', we, determined, whether, the, differing, properties, of, the, 'NCS-1', variants, could, potentially, contribute, to, the, altered, cell, function])].
[sujeto(['In', contrast, to, previous]), verbo([reports]), complemento([showing, that, overexpression, of, 'NCS-1', 'Var1', increases, 'calcium-dependent', 'processes,', functional, differences, in, cells, overexpressing, 'NCS-1', 'Var2', were, undetectable, in, assays, for, cell, 'growth,', cell, death, and, drug, '(', 'paclitaxel)', potency])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'NCS-1', 'Var1', is, the, primary, functional, version, of, 'NCS-1'])].
[sujeto(['Neuronal', calcium, 'sensor-1', '(', 'NCS-1)']), verbo([mediates]), complemento([changes, in, cellular, function, by, regulating, various, target, proteins])].
[sujeto(['Many', potential]), verbo([targets]), complemento([have, been, identified, but, the, physiological, significance, of, only, a, few, has, been, established])].
[sujeto(['Mutants', with, defects, in, four, potential, 'NCS-1']), verbo([targets]), complemento(['(', 'arf-1'])].
[sujeto([1]), verbo([acting]), complemento([in, the, same, pathway])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'ARF-1'])].
[sujeto([1]), verbo([interacts]), complemento([with, 'NCS-1', in, 'AIY', neurons, and, potentially, 'pifk-1', in, the, 'Ca(2+)', signaling, pathway, that, leads, to, inhibited, locomotion, at, an, elevated, temperature])].
[sujeto(['Neuronal', calcium, 'sensor-1', '(', 'NCS-1)', protein]), verbo([has]), complemento([orthologues, from, 'Saccharomyces', cerevisiae, to, human, with, highly, conserved, amino, acid, sequences])].
[sujeto(['This']), verbo([leads]), complemento([us, to, investigate, the, temperature, effects, on, the, conformational, dynamics, of, human, 'NCS-1', at, 310, and, 316, 'K', by, 'all-atom', molecular, dynamics, '(', 'MD)', simulations, and, dynamic, community, network, analysis])].
[sujeto(['The', dynamic, community, network, analysis]), verbo([suggests]), complemento([that, the, interdomain, correlation, is, 'weakened,', and, the, intradomain, coupling, is, strengthened, at, 316, 'K'])].
[sujeto(['This', study]), verbo([suggests]), complemento([that, the, elevated, temperature, affects, the, conformational, dynamics, of, human, 'NCS-1', protein])].
[sujeto(['Comparison', of, the, structural, dynamics, of, 'R102Q', mutant, and, 'Δ176-190', truncated, 'NCS-1']), verbo([suggests]), complemento([that, the, structural, and, dynamical, response, of, 'NCS-1', protein, to, elevated, temperature, may, be, one, of, its, intrinsic, functional, properties])].
[sujeto(['Calcium', sensors, detect, intracellular, calcium, changes, and]), verbo([interact]), complemento([with, downstream, targets, to, regulate, many, functions])].
[sujeto(['Neuronal', 'Calcium', 'Sensor-1', '(', 'NCS-1)', or, 'Frequenin', is, widely]), verbo([expressed]), complemento([in, the, nervous, 'system,', and, involved, in, 'neurotransmission,', synaptic, plasticity, and, learning])].
[sujeto(['NCS-1']), verbo([interacts]), complemento([with, and, regulates, dopamine, 'D2', receptor, '(', 'D2R)', internalization, and, is, implicated, in, disorders, like, schizophrenia, and, substance, abuse])].
[sujeto(['We', show, that, 'Ncs-1', deletion, in, the, mouse]), verbo([decreases]), complemento([willingness, to, work, for, food])].
[sujeto(['Moreover,', 'Ncs-1', knockout, mice]), verbo([have]), complemento([significantly, lower, 'activity-dependent', dopamine, release, in, the, nucleus, accumbens, core, in, acute, slice, recordings])].
[sujeto(['In', 'contrast,', food, 'preference,']), verbo([responding]), complemento([for, conditioned, 'reinforcement,', ability, to, represent, changes, in, reward, 'value,', and, locomotor, response, to, amphetamine, are, not, impaired])].
[sujeto(['These', studies, identify, novel, roles, for, 'NCS-1', in]), verbo([regulating]), complemento(['activity-dependent', striatal, dopamine, release, and, aspects, of, motivated, behavior])].
[sujeto(['The', present, study, aimed, to, examine, the, effects, of, chronic, social, defeat, stress, on, the, dopamine, receptors, and, proteins]), verbo([involved]), complemento([in, 'post-endocytic', trafficking, pathways])].
[sujeto(['We', observed]), verbo([increased]), complemento([expression, of, 'D2S,', 'D2L', and, 'D2Rs', dimers, in, the, prefrontal, cortex, '(', 'PFC)', of, susceptible, 'and/or', unsusceptible, mice, compared, with, controls])].
[sujeto(['The', present, study, demonstrated, that, chronic, social, defeat, stress]), verbo([induced]), complemento([increased, expression, of, 'D2S,', 'D2L,', and, 'D2R', dimers, in, the, 'PFC', of, susceptible, 'and/or', unsusceptible, mice])].
[sujeto(['Neuronal', calcium, 'sensor-1', '(', 'NCS-1)', protein]), verbo([has]), complemento([been, implicated, in, multiple, neuronal, functions, by, binding, partners, mostly, through, a, largely, exposed, hydrophobic, crevice, '(', 'HC)'])].
[sujeto(['In', the, absence, of, a, 'ligand,', the, 'C-terminal', tail, '(', loop, 'L3,', residues, 'D176', to, 'V190)']), verbo([binds]), complemento([directly, to, the, 'HC', pocket, as, a, ligand, 'mimetic,', occupying, the, 'HC', and, regulating, its, conformational, stability])].
[sujeto(['A', recent, experimental, study]), verbo([reported]), complemento([that, 'L3', deletion, resulted, in, global, structure, destabilization])].
[sujeto(['Our', cumulative, 2, μs, 'MD', simulations, demonstrated, that, 'L3', deletion]), verbo([increased]), complemento([the, structural, flexibility, of, the, 'C-domain', and, the, distant, 'N-domain'])].
[sujeto(['These', conformational, changes]), verbo([caused]), complemento([by, 'C-terminal', tail, truncation, may, affect, the, regulation, of, target, interactions])].
[sujeto(['Our', study]), verbo([provides]), complemento([atomic, details, of, the, conformational, dynamics, effects, of, the, 'C-terminal', tail, on, human, wild, type, 'NCS-1'])].
[sujeto(['The', preferential, degeneration, of, 'Substantia', nigra, dopamine, midbrain, neurons, '(', 'SN', 'DA)']), verbo([causes]), complemento([the, 'motor-symptoms', of, 'Parkinson\'s', disease, '(', 'PD)'])].
[sujeto([1, 'T-type', 'channels,', and, their, modulation, of, 'SN', 'DA', 'activity-pattern', and, 'D2-AR-sensitisation,']), verbo([provide]), complemento([new, insights, into, flexible, 'age-', and, 'calcium-dependent', 'activity-control', of, 'SN', 'DA', neurons, and, its, pharmacological, modulation])].
[sujeto(['It']), verbo([interacts]), complemento([with, both, the, 'G-protein-coupled', receptor, '(', 'GPCR)', dopamine, 'D2', receptor, '(', 'D2R),', regulating, its, internalization, and, surface, 'expression,', and, the, cognate, kinases, 'GRK1', and, 'GRK2'])].
[sujeto(['Determination', of, the, crystal, structures, of, 'Ca(2+)/NCS-1', alone, and, in, complex, with, peptides, derived, from, 'D2R', and, 'GRK1']), verbo([reveals]), complemento([that, the, differential, recognition, is, facilitated, by, the, conformational, flexibility, of, the, 'C-lobe-binding', site])].
[sujeto(['We']), verbo([find]), complemento([that, two, copies, of, the, 'D2R', peptide, bind, within, the, hydrophobic, crevice, on, 'Ca(2+)/NCS-1,', but, only, one, copy, of, the, 'GRK1', peptide, binds])].
[sujeto(['The', different]), verbo([binding]), complemento([modes, are, made, possible, by, the, 'C-lobe-binding', site, of, 'NCS-1,', which, adopts, alternative, conformations, in, each, complex])].
[sujeto(['C-terminal', residues, 'Ser-178-Val-190']), verbo([act]), complemento([in, concert, with, the, flexible, 'EF3/EF4', loop, region, to, effectively, form, different, 'peptide-binding', sites])].
[sujeto(['Removal', of, 'Ser-178-Val-190', generated, a, 'C-terminal', truncation, mutant, that, formed, a, 'dimer,', indicating, that, the, 'NCS-1', 'C-terminal', region]), verbo([prevents]), complemento(['NCS-1', oligomerization])].
[sujeto(['We', propose, that, the, flexible, nature, of, the, 'C-terminal', region, is, essential, to, allow, it, to]), verbo([modulate]), complemento([its, 'protein-binding', sites, and, adapt, its, conformation, to, accommodate, both, ligands])].
[sujeto(['This', appears, to, be, driven, by, the, variability, of, the, conformation, of, the, 'C-lobe-binding', 'site,', which]), verbo([has]), complemento([ramifications, for, the, target, specificity, and, diversity, of, 'NCS-1'])].
[sujeto(['Many', members, of, the, neuronal, calcium, sensor, '(', 'NCS)', protein, family]), verbo([have]), complemento([a, striking, coexistence, of, two, 'characteristics,', that, 'is,', 'N-myristoylation', and, the, cryptic, 'EF-1', motif])].
[sujeto(['We', investigated, the, rationale, behind, this, correlation, in, neuronal, calcium, 'sensor-1', '(', 'NCS-1)', by, restoring, 'Ca(2+)']), verbo([binding]), complemento([ability, of, the, disabled, 'EF-1', loop, by, appropriate, mutations])].
[sujeto(['The', concurrence, of, canonical, 'EF-1', and, 'N-myristoylation', considerably]), verbo([decreased]), complemento([the, overall, 'Ca(2+)', 'affinity,', conformational, 'flexibility,', and, functional, activation, of, downstream, effecter, molecules, '(', i])].
[sujeto(['Of', a, particular, 'note,', 'Ca(2+)']), verbo([induced]), complemento([conformational, change, '(', which, is, the, first, premise, for, a, 'CaBP', to, be, considered, as, 'sensor)', is, considerably, reduced, in, myristoylated, proteins, in, which, 'Ca(2+)-binding', to, 'EF-1', is, restored])].
[sujeto(['Moreover,', 'Ca(2+),', which, otherwise, augments, the, enzymatic, activity, of, 'PI4Kβ', '(']), verbo([modulated]), complemento([by, 'NCS-1),', leads, to, a, further, decline, in, the, modulated, 'PI4Kβ', activity, by, myristoylated, mutants, '(', with, canonical, 'EF-1)', pointing, toward, a, loss, of, 'Ca(2+)', signaling, and, specificity, at, the, structural, as, well, as, functional, levels])].
[sujeto(['The', pharmacological, significance, of, the, adenosine, 'A2A', receptor, '(', 'A2AR)-dopamine', 'D2', receptor, '(', 'D2R)', heteromer, is, well, established, and, it, is, being, considered, as, an, important]), verbo([target]), complemento([for, the, treatment, of, 'Parkinson’s', disease, and, other, neuropsychiatric, disorders])].
[sujeto(['This', depends, on, the, ability, of, low, and, high, 'Ca2+', levels, to]), verbo([promote]), complemento([a, selective, interaction, of, the, heteromer, with, the, neuronal, 'Ca2+-binding', proteins, 'NCS-1', and, 'calneuron-1,', respectively])].
[sujeto(['These', 'Ca2+-binding', proteins, differentially]), verbo([modulate]), complemento([allosteric, interactions, within, the, 'A2AR-D2R', 'heteromer,', which, constitutes, a, unique, cellular, device, that, integrates, extracellular, '(', adenosine, and, 'dopamine)', and, intracellular, '(', 'Ca+2)', signals, to, produce, a, specific, functional, response])].
[sujeto(['Facilitation', and, inactivation, of, 'P/Q-type', 'Ca2+', currents]), verbo([mediated]), complemento([by, 'Ca2+/calmodulin', binding, to, 'Ca(V)2'])].
[sujeto(['Other', calcium, sensor, proteins, displace, calmodulin, from, its]), verbo([binding]), complemento([site, and, differentially, modulate, 'P/Q-type', 'Ca2', +, 'currents,', resulting, in, diverse, patterns, of, 'short-term', synaptic, plasticity])].
[sujeto(['Neuronal', calcium, 'sensor-1', '(', 'NCS-1,', 'frequenin)']), verbo([has]), complemento([been, shown, to, enhance, synaptic, 'facilitation,', but, the, underlying, mechanism, is, unclear])].
[sujeto(['We']), verbo([report]), complemento([here, that, 'NCS-1', directly, interacts, with, 'IQ-like', motif, and, 'calmodulin-binding', domain, in, the, 'C-terminal', domain, of, 'Ca(V)2'])].
[sujeto(['Expression', of, 'NCS-1', in, presynaptic, superior, cervical, ganglion, neurons]), verbo([has]), complemento([no, effect, on, synaptic, 'transmission,', eliminating, effects, of, this, calcium, sensor, protein, on, endogenous, 'N-type', 'Ca2+', currents, and, the, endogenous, neurotransmitter, release, machinery])].
[sujeto(['However,', in, superior, cervical, ganglion, neurons]), verbo([expressing]), complemento(['wild-type', 'Ca(V)2'])].
[sujeto([1, 'channels,', 'co-expression', of, 'NCS-1']), verbo([induces]), complemento([facilitation, of, synaptic, transmission, in, response, to, paired, pulses, and, trains, of, depolarizing, 'stimuli,', and, this, effect, is, lost, in, 'Ca(V)2'])].
[sujeto(['These', results]), verbo([reveal]), complemento([that, 'NCS-1', directly, modulates, 'Ca(V)2'])].
[sujeto([1, channels, to]), verbo([induce]), complemento(['short-term', synaptic, facilitation, and, further, demonstrate, that, 'CaS', proteins, are, crucial, in, 'fine-tuning', 'short-term', synaptic, plasticity])].
[sujeto(['In', the, same, 'disorders,']), verbo([increased]), complemento([neuronal, calcium, sensor, 'protein-1', '(', 'NCS-1)', expression, was, reported, in, a, series, of, postmortem, studies])].
[sujeto(['These', disorders, are, also, characterized, by, sleep, 'dysregulation,']), verbo([suggesting]), complemento([a, role, for, the, reticular, activating, system, '(', 'RAS)'])].
[sujeto(['The', discovery, of, 'gamma-band', activity, in, the, pedunculopontine, nucleus, '(', 'PPN),', the, cholinergic, arm, of, the, 'RAS,', revealed, that, such, activity, was]), verbo([mediated]), complemento([by, 'high-threshold', calcium, channels, that, are, regulated, by, 'NCS-1'])].
[sujeto(['We', hypothesized, that, 'NCS-1', normally]), verbo([regulates]), complemento(['gamma-band', oscillations, through, these, calcium, channels, and, that, excessive, levels, of, 'NCS-1,', such, as, would, be, expected, with, 'overexpression,', decrease, 'gamma-band', activity])].
[sujeto(['We']), verbo([found]), complemento([that, 'PPN', neurons, in, rat, brain, slices, manifested, 'gamma-band', oscillations, that, were, increased, by, low, levels, of, 'NCS-1', but, suppressed, by, high, levels, of, 'NCS-1'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'NCS-1', overexpression, may, be, responsible, for, the, decrease, in, 'gamma-band', activity, present, in, at, least, some, schizophrenia, and, bipolar, disorder, patients])].
[sujeto(['Neuronal', calcium, 'sensor-1', '(', 'NCS-1)', protein]), verbo([has]), complemento([a, variety, of, different, neuronal, functions, and, interacts, with, multiple, binding, partners, mostly, through, a, large, 'solvent-exposed', hydrophobic, crevice, '(', 'HC)'])].
[sujeto(['A', single, 'R102Q', mutation, in, human, 'NCS-1', protein, was, demonstrated, to, be]), verbo([associated]), complemento([with, autism, disease])].
[sujeto(['Solution', 'NMR', study]), verbo([reported]), complemento([that, this, 'R102Q', mutant, had, 'long-range', chemical, shift, effects, on, the, 'HC', and, the, 'C-terminal', tail, '(', 'L3)'])].
[sujeto(['To', understand, the, influence, of, the, 'R102Q', mutation, on, the, 'HC', and, 'L3', of, 'NCS-1,', we]), verbo([have]), complemento([investigated, the, conformational, dynamics, and, the, structural, flexibility, of, wild, type, '(', 'WT)', 'NCS-1', and, its, 'R102Q', mutant, by, conducting, extensive, 'all-atom', molecular, dynamics, '(', 'MD)', simulations])].
[sujeto(['On', the, basis, of, six, independent, 450, ns, 'MD', 'simulations,', we]), verbo([have]), complemento([found, that, the, 'R102Q', mutation, in, 'NCS-1', protein, '(', 1, ')', dramatically, reduces, the, flexibility, of, loops, 'L2', and, 'L3,', '(', 2, ')', facilitates, 'L3', in, a, more, extended, state, to, occupy, the, hydrophobic, crevice, to, a, larger, 'extent,', '(', 3, ')', significantly, affects, the, intersegment, salt, 'bridges,', and, '(', 4, ')', changes, the, subspace, of, the, free, energy, landscape, of, 'NCS-1', protein])].
[sujeto(['These', results]), verbo([reveal]), complemento([the, important, role, of, salt, bridges, on, the, structural, properties, of, 'NCS-1', protein, and, that, 'R102Q', mutation, disables, the, dynamic, relocation, of, 'C-terminus,', which, may, block, the, binding, of, 'NCS-1', protein, to, its, receptors])].
[sujeto(['This', study, may]), verbo([provide]), complemento([structural, insights, into, the, autistic, spectrum, disorder, associated, with, 'R102Q', mutation])].
[sujeto(['In', response, to, channel, opening, and, 'Ca(2+)', 'influx,', specific, 'Ca(2+)-binding', proteins]), verbo([associate]), complemento([with, cytoplasmic, regulatory, domains, of, the, 'P/Q', channel, to, modulate, subsequent, channel, opening])].
[sujeto(['The', ubiquitous, 'Ca(2+)-sensing', protein, calmodulin, '(', 'CaM)']), verbo([regulates]), complemento([the, activity, of, all, types, of, mammalian, 'voltage-gated', 'Ca(2+)', 'channels,', including, the, 'P/Q', 'class,', by, direct, binding, to, specific, regulatory, motifs])].
[sujeto(['More', 'recently,', experimental, evidence]), verbo([has]), complemento([highlighted, a, role, for, additional, 'Ca(2+)-binding', 'proteins,', particularly, of, the, 'CaBP', and, 'NCS', families, in, the, regulation, of, 'P/Q', channels])].
[sujeto(['NCS-1', is, a, protein]), verbo([found]), complemento([from, yeast, to, humans, and, that, regulates, a, diverse, number, of, cellular, functions])].
[sujeto(['Physiological', and, genetic, evidence, indicates, that, 'NCS-1']), verbo([regulates]), complemento(['P/Q', channel, 'activity,', including, 'calcium-dependent', 'facilitation,', although, a, direct, physical, association, between, the, proteins, has, yet, to, be, demonstrated])].
[sujeto(['Using', distinct, but, complementary, 'approaches,', including, in, vitro]), verbo([binding]), complemento([of, bacterially, expressed, recombinant, 'proteins,', fluorescence, 'spectrophotometry,', isothermal, titration, 'calorimetry,', nuclear, magnetic, 'resonance,', and, expression, of, fluorescently, tagged, proteins, in, mammalian, 'cells,', we, show, direct, binding, and, demonstrate, that, 'CaM', can, compete, for, it])].
[sujeto([1, association, might, add, to, the, complexity, of, calcium, channel, regulation]), verbo([mediated]), complemento([by, other, known, 'calcium-sensing', proteins, and, how, this, might, help, to, 'fine-tune', neurotransmission, in, the, mammalian, central, nervous, system])].
[sujeto(['Here', we, use, 'single-molecule', optical, tweezers, to, monitor, misfolding, reactions, of, the, human, neuronal, calcium, 'sensor-1,', a, multispecific, 'EF-hand', protein]), verbo([involved]), complemento([in, neurotransmitter, release, and, linked, to, severe, neurological, diseases])].
[sujeto(['We', directly, observed, two, misfolding, trajectories]), verbo([leading]), complemento([to, distinct, kinetically, trapped, misfolded, conformations])].
[sujeto(['The', relative, probability, of, the, different, trajectories, could, be, affected, by]), verbo([modulating]), complemento([the, relaxation, rate, of, applied, 'force,', demonstrating, an, unprecedented, 'real-time', control, over, the, 'free-energy', landscape, of, a, protein])].
[sujeto(['Remarkably', for, a, calcium, 'sensor,', we]), verbo([found]), complemento([that, higher, calcium, concentrations, increased, the, lifetimes, of, the, misfolded, 'conformations,', slowing, productive, folding, to, the, native, state])].
[sujeto(['Central', nervous, system, dysfunction, secondary, to, sepsis, is]), verbo([associated]), complemento([with, local, generation, of, 'pro-', and, 'anti-inflammatory', 'cytokines,', impaired, cerebral, 'microcirculation,', disturbance, of, 'neurotransmitters,', 'apoptosis,', and, cognitive, impairment])].
[sujeto(['It', is, known, that, during, the, process, of, learning, and, memory, formation, several, pathways, are]), verbo([involved]), complemento([such, as, dopaminergic, and, cholinergic, systems])].
[sujeto(['Thus,', the, objective, of, this, study, is, to, evaluate, the, neuronal, calcium, sensor, '(', 'NCS-1)', and, 'dopamine-cAMP']), verbo([regulated]), complemento([phosphoprotein, of, 32, ',', 0, kDa, '(', 'DARPP-32)', expression, as, well, as, 'brain-derived', neurotrophic, factor, '(', 'BDNF)', and, nerve, growth, factor, '(', 'NGF)', levels, in, prefrontal, cortex, and, hippocampus, of, rats, 12, ',', 24, ',', and, 48, h, after, sepsis, induction])].
[sujeto(['After', 12, and, 24, 'h,', there, was, an]), verbo([increase]), complemento([of, 'NGF', levels, in, 'hippocampus;', and, up, to, 48, 'h,', a, decrease, of, 'NCS-1', expression, in, prefrontal, 'cortex,', a, decrease, of, 'BDNF', levels, in, hippocampus, and, an, increase, of, 'NGF', levels, in, hippocampus])].
[sujeto(['In', 'conclusion,', we, believe, that, the, low, expression, of, 'NCS-1', in, prefrontal, cortex, and, low, levels, of, 'BDNF', in, hippocampus, may, be]), verbo([associated]), complemento([with, the, pathophysiology, of, cognitive, impairment, during, sepsis, and, a, putative, role, of, the, dopaminergic, system])].
[sujeto(['Identification', of, the, molecules]), verbo([involved]), complemento([in, cell, 'death/survival', pathways, is, important, for, understanding, the, mechanisms, of, cell, loss, in, cardiac, 'disease,', and, thus, is, clinically, relevant])].
[sujeto(['Ca(2+)-dependent', signals, are, often]), verbo([involved]), complemento([in, these, pathways])].
[sujeto(['Here,', we]), verbo([found]), complemento([that, neuronal, 'Ca(2+)-sensor-1', '(', 'NCS-1),', a, 'Ca(2+)-binding', 'protein,', has, an, important, role, in, cardiac, survival, during, stress])].
[sujeto(['Although', oxidative, stress, elevated, mitochondrial, proton, 'leak,', which, exerts, a, protective, effect, by]), verbo([inhibiting]), complemento([the, production, of, reactive, oxygen, species, in, 'WT', 'myocytes,', this, response, was, considerably, diminished, in, 'Ncs1(-/-)', 'cardiomyocytes,', and, this, would, be, a, major, reason, for, cell, death])].
[sujeto(['Consistently,', 'H2O2-induced']), verbo([loss]), complemento([of, mitochondrial, membrane, 'potential,', a, critical, early, event, in, cell, 'death,', was, accelerated, in, 'Ncs1(-/-)', myocytes])].
[sujeto(['Activation', of, 'stress-induced', 'Ca(2+)-dependent', survival, 'pathways,', such, as, 'Akt', and, 'PGC-1α', '(', which]), verbo([promotes]), complemento([mitochondrial, biogenesis, and, 'function),', was, diminished, in, 'Ncs1(-/-)', hearts])].
[sujeto(['Overall,', these, data, demonstrate, that, 'NCS-1', contributes, to, stress, tolerance, in, cardiomyocytes, at, least, in, part, by]), verbo([activating]), complemento([certain, 'Ca(2+)-dependent', survival, pathways, that, promote, mitochondrial, 'biosynthesis/function', and, detoxification, pathways])].
[sujeto(['Neuronal', calcium, sensor, '(', 'NCS)', proteins, transduce, 'Ca2+', signals, and, are, highly]), verbo([conserved]), complemento([from, yeast, to, humans])].
[sujeto(['We', determined, 'NMR', structures, of, the, 'NCS-1', homolog, from, fission, yeast, '(', 'Ncs1),', which]), verbo([activates]), complemento([a, phosphatidylinositol, 4, -, kinase])].
[sujeto(['Ncs1', contains, an, 'α-NH2-linked', myristoyl, group, on, a, long, 'N-terminal', arm, and, four, 'EF-hand', 'motifs,', three, of, which]), verbo([bind]), complemento(['Ca2+,', assembled, into, a, compact, structure])].
[sujeto(['Thus,', a, unique, remodeling, of, each, 'NCS', protein, by, its, myristoyl, 'group,', and, 'Ca2+-dependent', unmasking, of, different, 'residues,', may, explain, how, each, family, member]), verbo([recognizes]), complemento([distinct, target, proteins])].
[sujeto(['The']), verbo([increasing]), complemento([incidence, of, reproductive, 'anomalies,', described, as, testicular, dysgenesis, 'syndrome,', is, thought, to, be, related, to, the, exposure, of, the, population, to, chemicals, in, the, environment])].
[sujeto(['Bisphenol', 'A', '(', 'BPA)', and, 'di(2-ethylhexyl)phthalate', '(', 'DEHP),', which]), verbo([have]), complemento([hormonal, and, antihormonal, 'activity,', have, attracted, public, attention, due, to, their, presence, in, consumer, products])].
[sujeto(['Results', showed, that, prenatal, exposures, to, test, chemicals, exerted, variable, effects, on, steroidogenic, factor, 1, and, 'GATA']), verbo([binding]), complemento([protein, 4, protein, expression, and, increased, '(', 'P', &, 'lt;'])].
[sujeto(['Pituitary', 'LHβ', and, 'FSHβ', subunit, protein, expression, was]), verbo([increased]), complemento(['(', 'P', &, 'lt;'])].
[sujeto([5, ')', in, 'BPA-', and, 'DEHP-exposed', prepubertal, male, rats, but, were]), verbo([decreased]), complemento(['(', 'P', &, 'lt;'])].
[sujeto(['Exposure', to, both, 'BPA', and, 'DEHP', in, utero]), verbo([inhibited]), complemento(['(', 'P', &, 'lt;'])].
[sujeto(['Together', the, present, data]), verbo([suggest]), complemento([that, altered, developmental, programming, in, the, testes, associated, with, chemical, exposures, are, related, to, the, disruption, of, sexual, differentiation, events, and, 'DNA', methylation, patterns])].
[sujeto(['The', inactivation, of, p53, creates, a, major, challenge, for]), verbo([inducing]), complemento([apoptosis, in, cancer, cells])].
[sujeto(['An', attractive, strategy, is, to, identify, and, subsequently]), verbo([target]), complemento([the, survival, signals, in, p53, defective, cancer, cells])].
[sujeto(['The', inhibition, of, this, signal]), verbo([induces]), complemento([apoptosis, in, cancer, cells, but, not, 'non-transformed', cells])].
[sujeto(['Using', the, 'CRISPR', 'technology,', we, demonstrate, that, p53]), verbo([loss]), complemento([enhances, the, apoptosis, caused, by, 'RUNX2', knockdown])].
[sujeto(['Mechanistically,', 'RUNX2']), verbo([provides]), complemento([the, survival, signal, partially, through, inducing, 'MYC', transcription])].
[sujeto(['Cancer', cells]), verbo([have]), complemento([high, levels, of, activating, histone, marks, on, the, 'MYC', locus, and, concomitant, high, 'MYC', expression])].
[sujeto(['RUNX2', knockdown]), verbo([decreases]), complemento([the, levels, of, these, histone, modifications, and, the, recruitment, of, the, 'Menin/MLL1', '(', mixed, lineage, leukemia, 1, ')', complex, to, the, 'MYC', locus])].
[sujeto(['Two', inhibitors, of, the, 'Menin/MLL1', complex]), verbo([induce]), complemento([apoptosis, in, p53, defective, cancer, cells])].
[sujeto(['Together,', we, identify, a, 'RUNX2-mediated', epigenetic, mechanism, of, the, survival, of, p53, defective, cancer, cells, and]), verbo([provide]), complemento([a, 'proof-of-principle', that, the, inhibition, of, this, epigenetic, axis, is, a, promising, strategy, to, kill, p53, defective, cancer, cells])].
[sujeto(['Osteoblastic', differentiation, is]), verbo([regulated]), complemento([by, various, 'factors,', including, hormones, and, transcription, factors])].
[sujeto(['Runt-related', transcription, factor, 2, '(', 'Runx2)', is, an, essential, player, in, osteoblastogenesis, and, transactivates, its, molecular]), verbo([target]), complemento([by, creating, a, protein, complex, with, its, 'hetero-dimeric', partner, core, binding, factor, beta, '(', 'Cbfb)'])].
[sujeto(['The', expression, of, 'miR-145']), verbo([increased]), complemento([during, 'osteoblastogenesis,', indicating, that, 'miR-145', works, as, an, inhibitor, of, osteoblastogenesis])].
[sujeto(['Stable', expression, of, 'miR-145']), verbo([decreased]), complemento([endogenous, 'Cbfb', expression, and, inhibited, 'osteoblastogenesis,', in, cooperation, with, 'miR-34c'])].
[sujeto(['Furthermore,', 'miR-145']), verbo([decreased]), complemento([bone, regeneration, in, vivo])].
[sujeto(['Our', results, indicate, that, 'miR-145', physiologically]), verbo([regulates]), complemento([osteoblast, differentiation, and, bone, formation, via, 'Cbfb', expression, by, forming, a, regulatory, microRNA, network])].
[sujeto(['Subsets', of, innate, lymphoid, cells, '(', 'ILCs)', reside, in, the, mucosa, and]), verbo([regulate]), complemento([immune, responses, to, external, pathogens])].
[sujeto(['Here', we]), verbo([report]), complemento([that, the, transcription, factor, 'Runx3', was, essential, for, the, normal, development, of, 'ILC1', and, 'ILC3', cells, but, not, of, 'ILC2', cells])].
[sujeto(['Runx3', was]), verbo([required]), complemento([for, expression, of, the, transcription, factor, 'RORγt', and, its, downstream, 'target,', the, transcription, factor, 'AHR,', in, 'ILC3', cells])].
[sujeto(['Damage', to, these, cells, can, severely, impact, cell, development, and]), verbo([has]), complemento([the, potential, to, cause, 'diseases,', such, as, leukemia])].
[sujeto(['Leukemia-causing', chromosomal, rearrangements]), verbo([have]), complemento([largely, been, studied, in, the, context, of, radiation, exposure, and, are, formed, by, a, 'multi-step', 'process,', including, an, initial, 'DNA', breakage, and, fusion, of, the, free, 'DNA', ends])].
[sujeto(['Exposure', of, 'HSPCs', to, 'non-cytotoxic', levels, of, environmental, chemicals, or, chemotherapeutic, agents]), verbo([causes]), complemento(['DNA', breakage, at, preferential, sites, in, the, human, 'genome,', including, the, 'leukemia-related', genes, 'MLL', and, 'CBFB'])].
[sujeto(['Though', 'benzene,', 'etoposide,', and, doxorubicin]), verbo([have]), complemento([previously, been, linked, to, leukemia, 'formation,', this, is, the, first, study, to, demonstrate, a, role, for, 'DEN', in, the, generation, of, 'DNA', breakage, at, 'leukemia-specific', sites])].
[sujeto(['These', data]), verbo([suggest]), complemento([a, role, for, 'long-term', environmental, chemical, or, residual, chemotherapeutic, drug, exposure, in, generation, of, 'DNA', breakage, at, sites, with, a, propensity, to, form, 'leukemia-causing', gene, rearrangements])].
[sujeto(['Existing', 'qRT-PCR', methods, are, well, established, and, in, widespread, use, in, clinical, laboratories, but, they, are, laborious, and]), verbo([require]), complemento([the, generation, of, standard, curves])].
[sujeto(['We', compared, the, data, obtained, using, the, plasmid, calibrator, method, to, commercially, available, assays, using, standard, curves, and]), verbo([found]), complemento([that, the, results, obtained, by, both, methods, are, comparable, over, a, broad, range, of, values, with, similar, sensitivities])].
[sujeto(['Our', method]), verbo([has]), complemento([the, advantage, of, simplicity, and, is, therefore, lower, in, cost, and, may, be, less, subject, to, errors, that, may, be, introduced, during, the, generation, of, standard, curves])].
[sujeto(['Polymorphisms', in, miRNA, genes, could, potentially, alter, various, biological, processes, by, influencing, the, processing, and, '(', 'or)']), verbo([target]), complemento([selection, of, miRNAs])].
[sujeto(['Association', analysis, with, chicken, carcass, and, growth, traits, showed, that, the, 'SNP', was, significantly]), verbo([associated]), complemento([with, carcass, 'weight,', evisceration, 'weight,', breast, muscle, 'weight,', leg, muscle, 'weight,', and, body, weight, at, 8, weeks, of, 'age,', as, well, as, some, body, size, indexes, including, shank, 'girth,', chest, 'breadth,', breast, bone, 'length,', and, body, slanting, 'length,', in, the, 'Gushi-Anka', 'F2', resource, population])].
[sujeto(['Subsequently,', using, 'dual-luciferase']), verbo([report]), complemento(['assay,', we, verified, that, 'miR-1666', could, perform, its, function, through, targeting, of, the, 'CBFB', gene])].
[sujeto(['It', may, further, affect, the, function, of, 'miR-1666', through, the]), verbo([target]), complemento([gene, 'CBFB,', hence, it, is, associated, with, chicken, growth, traits])].
[sujeto(['As', the, patient, had, no, history, of, exposure, to, topoisomerase, 'II', 'inhibitors,', among, her, previously, used, 'chemotherapeutics,', the, topoisomerase, 'I', 'inhibitor,', 'irinotecan,', was, speculated, to, be, the, most, plausible]), verbo([cause]), complemento([of, 't-AML', in, this, case])].
[sujeto(['The', present, case]), verbo([suggests]), complemento([that, irinotecan, may, cause, 't-AML', resembling, that, associated, with, topoisomerase, 'II', inhibitors])].
[sujeto(['CBF-β', is]), verbo([required]), complemento([for, 'HIV-1', 'Vif', 'function,', as, it, increases, the, 'steady-state', level, of, the, 'HIV-1', 'Vif', protein, to, promote, host, restriction, factor, 'APOBEC3', degradation])].
[sujeto(['However,', the, precise, mechanism, by, which, 'CBF-β']), verbo([promotes]), complemento(['HIV-1', 'Vif', levels, remains, unclear])].
[sujeto(['In', the, present, 'study,', we]), verbo([provided]), complemento([evidences, that, 'CBF-β', promoted, 'steady-state', levels, of, 'HIV-1', 'Vif', by, inhibiting, the, degradation, of, 'HIV-1', 'Vif', through, the, proteasome, pathway])].
[sujeto(['Our', results]), verbo([reveal]), complemento([a, new, mechanism, by, which, a, cellular, protein, supports, viral, infectivity, by, inhibiting, viral, protein, degradation])].
[sujeto(['This', process, is, counteracted, by, 'Vif', '(', viral, infectivity, 'factor)', of, 'lentiviruses,', which]), verbo([binds]), complemento(['APOBEC3s', and, promotes, their, degradation])].
[sujeto(['CBF-β', '(', core]), verbo([binding]), complemento([factor, subunit, 'β)', is, an, essential, 'co-factor', for, the, function, of, human, immunodeficiency, virus, type, 1, 'Vif', to, degrade, human, 'APOBEC3s'])].
[sujeto(['These', findings]), verbo([suggested]), complemento([that, primate, lentiviruses, have, adapted, to, use, 'CBF-β,', an, evolutionary, stable, 'protein,', to, counteract, 'APOBEC3', proteins, of, their, hosts, after, diverging, from, other, lentiviruses])].
[sujeto(['Here', we]), verbo([provide]), complemento([the, 'loss-of-function', genetic, evidence, that, 'Runx', signaling, affects, postnatal, development, of, the, submandibular, gland, '(', 'SMG)'])].
[sujeto(['Core']), verbo([binding]), complemento([factor, β, '(', 'Cbfb)', is, a, cotranscription, factor, which, forms, a, heterodimer, with, 'Runx', proteins])].
[sujeto(['Cbfb', was, specifically]), verbo([expressed]), complemento([in, the, duct, 'epithelium,', specifically, in, the, 'SMG'])].
[sujeto(['Epithelial', 'Cbfb', deficiency, resulted, in]), verbo([decrease]), complemento([in, the, size, of, the, 'SMG', and, in, the, saliva, secretion, on, postnatal, day, 35])].
[sujeto(['Because', the, circulating, testosterone, or, tissue, dihydrotestosterone, levels, were, not, affected, in, the, 'Cbfb', 'mutants,', it, appears, that, 'Runx/Cbfb', signaling]), verbo([regulate]), complemento([androgen, receptor, 'pathway,', but, does, not, affect, the, circulating, testosterone, levels, or, the, enzymatic, conversion, to, 'DHT'])].
[sujeto(['Core']), verbo([binding]), complemento([factor, beta, '(', 'Cbfβ),', the, partner, protein, of, 'Runx', family, transcription, 'factors,', enhances, 'Runx', function, by, increasing, the, binding, of, 'Runx', to, 'DNA'])].
[sujeto(['Here,', we, address, a, direct, role, of, 'Cbfβ', in, skeletal, homeostasis, by, generating, 'osteoblast-specific', 'Cbfβ-deficient', mice, '(', 'Cbfb(Δob/Δob)', ')', from, 'Cbfb-floxed', mice, crossed, with, mice]), verbo([expressing]), complemento(['Cre', from, the, 'Col1a1', promoter])].
[sujeto(['Although', the, number, of, osteoblasts, remained, 'unchanged,', the, number, of, active, osteoblasts]), verbo([decreased]), complemento([in, 'Cbfb(Δob/Δob)', mice, and, resulted, in, lower, mineral, apposition, rate])].
[sujeto(['Immunohistochemical', and, quantitative, 'real-time', 'PCR', analyses, showed, that, the, expression, of, osteogenic, 'markers,', including, 'Runx2,', 'osterix,', 'osteocalcin,', and, 'osteopontin,', was, significantly]), verbo([repressed]), complemento([in, 'Cbfb(Δob/Δob)', mice, compared, with, 'wild-type', mice])].
[sujeto(['The', mechanism, was, revealed, by, forced, expression, of, 'Cbfβ,', which]), verbo([increased]), complemento(['Runx2', protein, levels, in, vitro, by, inhibiting, 'polyubiquitination-mediated', proteosomal, degradation])].
[sujeto(['Bacterial', translation, initiation, factor, 'IF2', complexed, with, 'GTP']), verbo([binds]), complemento([to, the, 30, 'S', ribosomal, 'subunit,', promotes, ribosomal, binding, of, 'fMet-tRNA,', and, favors, the, joining, of, the, small, and, large, ribosomal, subunits, yielding, a, 70, 'S', initiation, complex, ready, to, enter, the, translation, elongation, phase])].
[sujeto(['Within', the, 'IF2', molecule, subdomain, 'G3,', which, is, believed, to, play, an, important, role, in, the, 'IF2-30S', 'interaction,', is, positioned, between, the, 'GTP-binding', 'G2', and, the, 'fMet-tRNA']), verbo([binding]), complemento(['C-terminal', subdomains])].
[sujeto(['In', this, study, the, solution, structure, of, subdomain, 'G3', of, 'Geobacillus', stearothermophilus, 'IF2']), verbo([has]), complemento([been, elucidated])].
[sujeto(['In', line, with, its, role, as, linker, between, 'G3', and, subdomain, 'C1,', this, helix]), verbo([has]), complemento([no, 'well-defined', orientation, but, is, endowed, with, a, dynamic, nature])].
[sujeto(['Structural', comparisons]), verbo([have]), complemento([resulted, in, a, model, that, describes, the, interaction, between, 'IF2-G3', and, the, 30, 'S', ribosomal, subunit])].
[sujeto(['The', extrinsic, arm, contains]), verbo([binding]), complemento([sites, for, 'NADH,', the, primary, electron, acceptor, 'FMN,', and, seven, 'iron-sulfur', clusters, that, form, a, pathway, for, electrons, linking, 'FMN', to, the, terminal, electron, 'acceptor,', 'ubiquinone,', which, is, bound, in, a, tunnel, in, the, region, of, the, junction, between, the, arms])].
[sujeto(['The', membrane, arm, contains, four, 'antiporter-like', 'domains,', energetically, coupled, to, the, quinone, site, and]), verbo([involved]), complemento([in, pumping, protons, from, the, matrix, into, the, intermembrane, space, contributing, to, the, proton, motive, force])].
[sujeto(['Seven', of, the, 'subunits,', forming, the, core, of, the, membrane, 'arm,', are]), verbo([translated]), complemento([from, mitochondrial, 'genes,', and, the, remaining, 'subunits,', the, products, of, nuclear, 'genes,', are, imported, from, the, cytosol])].
[sujeto(['The', 'DNA', methylation, status, of, the, candidate, genes, was, analyzed, by, 'methylation-specific', polymerase, chain, reaction, assays, to, evaluate, the, relationship, between, bladder, cancer, and]), verbo([target]), complemento([gene, methylation, status, in, the, urine, sediments, of, participants])].
[sujeto(['Injury', was]), verbo([induced]), complemento([by, clamping, the, gluteus, maximus, and, medius, '(', group, 'M)', or, osteotomy, of, greater, trochanter, '(', group, 'O)', on, the, right, 'hip,', as, well, as, combined, muscle, injury, and, osteotomy, of, greater, trochanter, '(', group, 'M+O)'])].
[sujeto(['Osteogenic', 'm-progenitors', in, group, 'O']), verbo([increased]), complemento([the, expression, of, bone, morphogenetic, protein, 2, and, also, bone, morphogenetic, protein, antagonist, differential, 'screening-selected', gene, aberrative, in, neuroblastoma])].
[sujeto(['CD56,', representing, myogenic, 'progenitors,', was, highly]), verbo([expressed]), complemento([in, the, 'm-progenitors', isolated, from, group, 'M', '(', day, 10, ')', ',', but, 'm-progenitors', of, group, 'M+O', '(', day, 10, ')', exhibited, the, highest, expression, of, 'platelet-derived', growth, factor, receptor, α, '(', 'PDGFR-α),', a, marker, of, 'muscle-derived', mesenchymal, stem, cells, '(', 'M-MSCs)'])].
[sujeto(['Most', 'likely,', 'M-MSCs,', rather, than, myogenic, 'progenitors,', in, the, 'm-progenitors']), verbo([participate]), complemento([in, 'HO', formation])].
[sujeto(['The', study, also]), verbo([found]), complemento([that, 'muscle-derived', mesenchymal, stem, 'cells,', but, not, myogenic, 'progenitors,', are, involved, in, the, formation, of, 'HO'])].
[sujeto(['Bone', 'formation,', a, highly]), verbo([regulated]), complemento([developmental, 'process,', involves, osteoblast, 'differentiation,', which, is, controlled, by, different, important, transcription, factors])].
[sujeto(['Recent', evidence]), verbo([has]), complemento([suggested, possible, negative, regulation, of, inhibitors, of, growth, '(', 'ING)', 1, b, on, the, osteoblast, marker, expression])].
[sujeto(['The', aim, of, this, study, is, to, examine, the, detailed, mechanism, by, which, the, activity, of, 'ING1b']), verbo([inhibits]), complemento([osteoblast, differentiation])].
[sujeto(['In', the, current, 'study,', we, investigated, the, function, and, mechanism, by, which, 'ING1b']), verbo([inhibits]), complemento([osteoblast, differentiation, using, 'C3H10T1/2', mesenchymal, stem, cells, and, 'MC3T3-E1', preosteoblasts])].
[sujeto(['Real-time', polymerase, chain, reaction, and, 'Western', blotting, showed, that, 'ING1b', was]), verbo([decreased]), complemento([during, osteoblast, differentiation, and, 'ING1b', overexpression, markedly, decreased, alkaline, phosphatase, '(', 'ALP)', 'activity,', 'runt-related', transcription, factor, 2, '(', 'Runx2)', 'expression,', and, collagen, type, 1, 'synthesis,', whereas, 'ING1b', silencing, significantly, upregulated, 'ALP', 'activity,', 'Runx2', 'expression,', and, collagen, type, 1, synthesis])].
[sujeto(['Further', studies, indicated, that, 'ING1b']), verbo([suppressed]), complemento([the, expression, of, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)-β/δ', in, a, 'hypoxia-inducible', factor, '(', 'HIF)', 1, 'α-dependent', 'manner,', while, 'ING1b', silencing, significantly, increased, the, expression, of, 'PPAR-β/δ', and, 'HIF1α'])].
[sujeto(['Moreover,', 'PPAR-β/δ', or, 'HIF1α', silencing, significantly]), verbo([inhibited]), complemento(['ALP', 'activity,', 'Runx2', 'expression,', and, collagen, type, 1, synthesis])].
[sujeto(['These', results, demonstrated, that, 'ING1b', is, an, important, regulator, of, osteoblast, differentiation, and]), verbo([suppresses]), complemento(['PPAR-β/δ'])].
[sujeto(['Our', study, may]), verbo([provide]), complemento([additional, insight, into, osteoblast, differentiation, and, offer, a, potential, new, molecular, target, for, osteoporosis])].
[sujeto(['β-GP']), verbo([induced]), complemento([an, increase, in, the, expression, of, 'BMP2,', 'Runx2,', and, 'β-catenin'])].
[sujeto(['BMP2,', 'Runx2,', and, 'β-catenin', levels, and, the, calcium, content]), verbo([decreased]), complemento([when, the, cells, were, cultured, with, 'rmKlotho;', 'however,', the, levels, of, each, were, upregulated, after, treatment, with, the, 'LiCl'])].
[sujeto(['Klotho', can, ameliorate, the, calcification, and, osteogenic, transition, of, 'VSMCs']), verbo([induced]), complemento([by, 'β-GP'])].
[sujeto(['The', mechanism, of, 'Klotho', in]), verbo([preventing]), complemento([calcification, in, 'VSMCs', may, be, partially, mediated, by, the, inhibition, of, the, 'Wnt/β-catenin', signaling, pathway])].
[sujeto(['The', temporomandibular, joint, '(', 'TMJ)', is, a, small, synovial, joint, at, which, the, mandible, articulates, with, the, skull, during, movements]), verbo([involved]), complemento([in, speaking, and, mastication])].
[sujeto(['This', review, summarizes, our, current, knowledge, of, genes, that]), verbo([regulate]), complemento([the, formation, of, primary, components, of, the, 'TMJ,', as, well, as, genes, that, regulate, postnatal, growth, of, the, 'TMJ'])].
[sujeto(['Although', the, 'TMJ', is]), verbo([regulated]), complemento([by, some, of, the, same, genes, that, are, important, in, limb, 'joints,', others, appear, unique, to, the, 'TMJ', or, have, different, actions])].
[sujeto(['Runx2,', a, master, regulator, of, osteoblast, 'differentiation,', is, tightly]), verbo([regulated]), complemento([at, both, transcriptional, and, 'post-translational', levels])].
[sujeto(['Post-translational', modifications, such, as, phosphorylation, and, ubiquitination]), verbo([have]), complemento([differential, effects, on, 'Runx2', functions])].
[sujeto(['Here,', we, show, that, the, reduced, expression, and, functions, of, 'Runx2', upon, its, phosphorylation, by, 'GSK3β', are]), verbo([mediated]), complemento([by, its, 'ubiquitin-mediated', degradation, through, 'E3', ubiquitin, ligase, 'Fbw7α'])].
[sujeto(['Fbw7α', through, its, 'WD', domain]), verbo([interacts]), complemento([with, 'Runx2', both, in, a, heterologous, '(', 'HEK293T', 'cells)', system, as, well, as, in, osteoblasts])].
[sujeto(['Furthermore,', overexpression, of, either, 'Fbw7α', or, 'GSK3β', was, sufficient, to, 'down-regulate', endogenous, 'Runx2', expression, and, 'function;', 'however,', both, failed, to]), verbo([inhibit]), complemento([endogenous, 'Runx2', when, either, of, them, was, depleted, in, osteoblasts])].
[sujeto(['Fbw7α-mediated', inhibition, of, 'Runx2', expression, also]), verbo([led]), complemento([to, reduced, 'Runx2', transactivation, and, osteoblast, differentiation])].
[sujeto(['In', 'contrast,', inhibition, of, 'Fbw7α', restored, 'Runx2', levels, and]), verbo([promoted]), complemento([osteoblast, differentiation])].
[sujeto(['We', also, observed, reciprocal, expression, levels, of, 'Runx2', and, 'Fbw7α', in, models, of, bone]), verbo([loss]), complemento([such, as, lactating, '(', physiological, bone, loss, 'condition)', and, ovariectomized, '(', induction, of, surgical, 'menopause)', animals, that, show, reduced, 'Runx2', and, enhanced, 'Fbw7α,', whereas, this, was, reversed, in, the, 'estrogen-treated', ovariectomized, animals])].
[sujeto(['In', 'addition,', methylprednisolone, '(', a, synthetic, 'glucocorticoid)', treatment, to, neonatal, rats, showed, a, temporal]), verbo([decrease]), complemento([in, 'Runx2', with, a, reciprocal, increase, in, 'Fbw7', in, their, calvarium])].
[sujeto(['Taken', 'together,', these, data, demonstrate, that, 'Fbw7α', negatively]), verbo([regulates]), complemento([osteogenesis, by, targeting, 'Runx2', for, 'ubiquitin-mediated', degradation, in, a, 'GSK3β-dependent', manner, and, thus, provides, a, plausible, explanation, for, 'GSK3β-mediated', bone, loss, as, described, before])].
[sujeto(['By', 6, 'mo,', heterotopic, cartilage, had, formed, in, the, discs, and]), verbo([expressed]), complemento([cartilage, hypertrophic, markers, 'Runx2', and, 'ColX'])].
[sujeto(['Bone', morphogenetic, protein, '(', 'BMP)', signaling, was]), verbo([activated]), complemento([with, the, ectopic, chondrogenic, cells, and, 'chondrocytes,', as, indicated, by, phosphorylated, 'Smad', 1, /, 5, /, 8, nuclear, staining, and, by, elevated, expression, of, 'Bmp2,', 'Bmpr1b,', 'Bmpr2,', and, 'BMP', signaling, target, genes])].
[sujeto(['Likewise,', we]), verbo([found]), complemento([that, upon, treatment, with, recombinant, human, 'BMP', 2, in, 'high-density', micromass, 'culture,', mutant, disc, cells, differentiated, into, chondrocytes, and, synthesized, cartilage, matrix, more, robustly, than, control, cells])].
[sujeto(['Unexpectedly,', we]), verbo([found]), complemento([that, 'Prg4', was, expressed, at, 'joint-associated', 'sites,', including, 'disc/muscle', insertion, and, 'muscle/bone', 'interface,', and, all, these, structures, were, abnormal, in, 'Prg4', mutants])].
[sujeto(['Our', data, indicate, that, 'Prg4', is, needed, for, 'TMJ', disc, integrity, and, function, and, that, its, absence]), verbo([leads]), complemento([to, ectopic, chondrogenesis, and, cartilage, formation, in, conjunction, with, abnormal, 'BMP', signaling])].
[sujeto(['Our', findings, imply, that, the, 'BMP', signaling, pathway, could, be, a, potential, therapeutic]), verbo([target]), complemento([for, prevention, or, inhibition, of, ectopic, cartilage, formation, in, 'TMJ', disease])].
[sujeto(['Berberine', '(', 'BBR)']), verbo([has]), complemento([recently, been, reported, to, be, extensively, used, for, musculoskeletal, disorders, such, as, osteoporosis, through, enhancing, osteogenic, 'differentiation,', inhibiting, osteoclastogenesis, and, bone, resorption, and, repressing, adipogenesis])].
[sujeto(['Although', canonical, 'Wnt', signaling, plays, a, crucial, role, in]), verbo([suppressing]), complemento([bone, 'marrow-derived', mesenchymal, stem, cells, '(', 'MSCs)', commitment, to, the, chondrogenic, and, adipogenic, lineage, and, enhancing, osteogenic, 'differentiation,', no, previous, reports, have, shown, an, association, between, 'BBR-induced', osteogenesis, and, 'Wnt/β-catenin', signaling, pathway])].
[sujeto(['Increasing', concentration, of, 'BBR', '(', 3, ',', 10, and, 30, 'μM)']), verbo([promoted]), complemento([osteogenic, differentiation, and, osteogenic, genes, expression, after, incubation, for, various, days, compared, with, 'DMSO', 'group,', whereas, expression, levels, of, chondrogenic, and, adipogenic, related, marker, genes, were, dramatically, suppressed])].
[sujeto(['After', treated, with, 10, μM, 'BBR', for, 7, 'days,', 'β-catenin,', 'OPN', and, 'OCN', expression, were, significantly, 'induced,', which, could, be, effectively]), verbo([suppressed]), complemento([by, the, addition, of, 'DKK-1', or, 'β-catenin', siRNA, 'β-catenin'])].
[sujeto(['Interestingly,', the, expression, level, of, 'Runx2', gene, was, also]), verbo([decreased]), complemento([by, inhibiting, the, transduction, of, 'Wnt/β-catenin', signaling])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'BBR', can, stimulate, osteogenic, differentiation, of, 'MSCs', not, only, by, enhancing, 'Runx2', expression, but, also, by, activating, canonical, 'Wnt/β-catenin', signaling, 'pathway,', and, canonical, 'Wnt/β-catenin', signaling, pathway, is, in, part, responsible, for, 'BBR-induced', osteogenic, differentiation, of, 'MSCs', in, vitro])].
[sujeto(['BBR', is, a, potential, pharmaceutical, medicine, by]), verbo([enhancing]), complemento([osteogenic, differentiation, for, bone, 'disorders,', such, as, osteoporosis])].
[sujeto(['Elucidating', the, molecular, mechanisms, responsible, for, osteogenesis, of, human, 'adipose-derived', mesenchymal, stem, cells, '(', 'hADSCs)', will]), verbo([provide]), complemento([deeper, insights, into, the, regulatory, mechanisms, of, this, process, and, help, develop, more, efficient, methods, for, 'cell-based', therapies])].
[sujeto(['The', endogenous, expression, of, 'miR-26a']), verbo([increased]), complemento([during, the, osteogenic, differentiation])].
[sujeto(['The', overexpression, of, 'miR-26a']), verbo([promoted]), complemento([hADSC, 'osteogenesis,', whereas, osteogenesis, was, repressed, by, 'miR-26a', knockdown])].
[sujeto(['Additionally,', 'miR-26a', directly]), verbo([targeted]), complemento([the, 3, '\'', 'UTR', of, the, 'GSK3β,', suppressing, the, expression, of, 'GSK3β', protein])].
[sujeto(['Similar', to, the, effect, of, overexpressing, 'miR-26a,', the, knockdown, of, 'GSK3β']), verbo([promoted]), complemento([osteogenic, 'differentiation,', whereas, 'GSK3β', overexpression, inhibited, this, 'process,', suggesting, that, 'GSK3β', acted, as, a, negative, regulator, of, hADSC, osteogenesis])].
[sujeto(['Furthermore,', 'GSK3β', influences, 'Wnt', signalling, pathway, by]), verbo([regulating]), complemento(['β-catenin,', and, subsequently, altered, the, expression, of, its, downstream, target, 'C/EBPα'])].
[sujeto(['In', 'turn,', 'C/EBPα', transcriptionally]), verbo([regulated]), complemento([the, expression, of, 'miR-26a', by, physically, binding, to, the, 'CTDSPL', promoter, region])].
[sujeto(['Our', findings]), verbo([provided]), complemento([new, insights, into, the, function, of, 'miR-26a', and, the, mechanisms, underlying, osteogenesis, of, hADSCs])].
[sujeto(['The', 'membrane-anchored', glycoprotein, 'RECK', '(', 'reversion-inducing', 'cysteine-rich', protein, with, 'Kazal', 'motifs)']), verbo([inhibits]), complemento([expression, and, activity, of, certain, matrix, metalloproteinases, '(', 'MMPs),', thereby, suppressing, tumor, cell, metastasis])].
[sujeto(['RNA', interference, of, 'RECK', in, hMSCs, revealed, that, endogenous, 'RECK']), verbo([suppresses]), complemento([the, transcription, and, biosynthesis, of, tissue, inhibitor, of, metalloproteinases, '(', 'TIMP)-2', but, does, not, influence, the, expression, of, 'MMP-2,', 'MMP-9,', membrane, type, '(', 'MT)1-MMP', and, 'TIMP-1', in, these, cells])].
[sujeto(['Knockdown', of, 'RECK', in, hMSCs]), verbo([promoted]), complemento([monolayer, regeneration, and, chemotactic, migration, of, 'hMSCs,', as, demonstrated, by, scratch, wound, and, chemotaxis, assay, analyses])].
[sujeto(['The', latter, was, determined, by, analysis, of, the, 'β-catenin']), verbo([target]), complemento([genes, 'Dickkopf1', '(', 'DKK1),', axis, inhibition, protein, 2, '(', 'AXIN2),', 'runt-related', transcription, factor, 2, '(', 'RUNX2)', and, a, 'luciferase-based', 'β-catenin-activated', reporter, '(', 'BAR)', assay])].
[sujeto(['Our', findings, demonstrate, that, 'RECK', is, a, regulator, of, hMSC, functions]), verbo([suggesting]), complemento([that, modulation, of, 'RECK', may, improve, the, development, of, 'hMSC-based', therapeutical, approaches, in, regenerative, medicine])].
[sujeto(['Protein', structure, and, function]), verbo([have]), complemento([been, remarkably, conserved, throughout, evolution, and, 'BMP2', transcription, has, been, proposed, to, be, tightly, 'regulated,', although, few, data, is, available])].
[sujeto(['In', this, work, we]), verbo([report]), complemento([the, cloning, and, functional, analysis, of, gilthead, seabream, 'BMP2', promoter])].
[sujeto(['As', in, other, 'vertebrates,', seabream, 'BMP2', gene]), verbo([has]), complemento([a, 5, '′', 'non-coding', 'exon,', a, feature, already, present, in, 'DPP', 'gene,', the, fruit, fly, ortholog, of, vertebrate, 'BMP2', 'gene,', and, maintained, throughout, evolution])].
[sujeto(['In', silico, analysis, of, seabream, 'BMP2', promoter, revealed, several]), verbo([binding]), complemento([sites, for, bone, and, cartilage, related, transcription, factors, '(', 'TFs)', and, their, functionality, was, evaluated, using, 'promoter-luciferase', constructions, and, 'TF-expressing', vectors])].
[sujeto(['Runt-related', transcription, factor, 3, '(', 'RUNX3)', was, shown, to, negatively]), verbo([regulate]), complemento(['BMP2', transcription, and, combination, with, the, core, binding, factor, β, '(', 'CBFβ)', further, reduced, transcriptional, activity, of, the, promoter])].
[sujeto(['Although', to, a, lesser, 'extent,', myocyte, enhancer, factor, 2, 'C', '(', 'MEF2C)', had, also, a, negative, effect, on, the, regulation, of, 'BMP2', gene, 'transcription,', when]), verbo([associated]), complemento([with, 'SRY', '(', sex, determining, region, 'Y)-box', 9, '(', 'SOX9b)'])].
[sujeto(['Finally,', 'v-ets', avian, erythroblastosis, virus, 'E26', oncogene, homolog, 1, '(', 'ETS1)', was, able, to, slightly]), verbo([enhance]), complemento(['BMP2', transcription])].
[sujeto(['Data']), verbo([reported]), complemento([here, provides, new, insights, toward, the, better, understanding, of, the, transcriptional, regulation, of, 'BMP2', gene, in, a, bone, and, cartilage, context])].
[sujeto(['We']), verbo([have]), complemento([recently, shown, that, 'inv(16)', results, in, fusion, of, 'CBFB/PEBP2B,', a, gene, encoded, at, 16, q22, to, 'MYH11,', a, smooth, muscle, myosin, heavy, chain, gene, encoded, at, 16, p13])].
[sujeto(['In', this, study, we]), verbo([have]), complemento([examined, a, series, of, 37, of, these, cases, using, reverse, 'transcriptase-polymerase', chain, reaction, '(', 'RT-PCR)', to, detect, expression, of, a, hybrid, 'CBFB/MYH11', transcript])].
[sujeto(['The', organic, nitrogen, content]), verbo([decreased]), complemento(['sharply,', in, the, early, 'phase,', with, an, increase, in, ammonium, concentration])].
[sujeto(['Notably', the, reduction, in, organic, nitrogen, was, significantly, higher, than, the]), verbo([increase]), complemento([in, 'NH4(+)', which, can, be, attributed, to, the, volatilization, of, 'NH4(+)', under, alkaline, pH])].
[sujeto(['The', 'nitrate-N', concentration]), verbo([decreased]), complemento([sharply, from, soil, with, a, concomitant, increase, in, water, column])].
[sujeto(['However', the, reduction, of, nitrate, in, soil, was, significantly, higher, than, the]), verbo([increase]), complemento([in, water, column])].
[sujeto(['The', initial, 'NH4(+)-N', concentration, in, the, soil, was, very, low, and, it]), verbo([increased]), complemento([gradually, during, purification, due, to, increasing, soil, cation, exchange, capacity])].
[sujeto(['Thus', by, trapping, 'NH4(+)', ion, soil, contributes, towards]), verbo([preventing]), complemento([contamination, of, water])].
[sujeto(['Thus', at, 'EKW,', the, cumulative, activities, in, water, and, soil]), verbo([involved]), complemento([in, nitrogen, dynamics, lead, to, overall, reduction, of, the, oxygen, demand, and, contribute, towards, efficient, sewage, purification])].
[sujeto(['Their', biological, functions, are, linked, to, their, particular, chemical, 'properties:', they, play, a, role, in, structuring, macromolecules, 'and/or']), verbo([act]), complemento([as, 'co-factors', catalyzing, diverse, biochemical, reactions])].
[sujeto(['These', metal, ions, are, also, essential, for, microbial, pathogens, during, 'infection:', they, are]), verbo([involved]), complemento([in, bacterial, metabolism, and, various, virulence, factor, functions])].
[sujeto([aeruginosa, is, a, medically, significant, 'Gram-negative', bacterial, opportunistic, pathogen, that, can]), verbo([cause]), complemento([severe, chronic, lung, infections, in, cystic, fibrosis, patients, and, that, is, responsible, for, nosocomial, infections, worldwide])].
[sujeto(['We']), verbo([have]), complemento([studied, the, influences, of, grain, size, on, 'P', doping, in, 'Si-NCs'])].
[sujeto(['Free', carrier, 'concentration,', which, is]), verbo([provided]), complemento([by, activated, 'P', 'atoms,', decreases, with, decreasing, grain, size, due, to, increasing, formation, energy, and, activation, energy, of, 'P', atoms, incorporated, in, 'Si-NCs'])].
[sujeto(['Furthermore,', we]), verbo([have]), complemento([studied, the, 'P', locations, inside, 'Si-NCs', and, hydrogen, passivation, of, 'P', in, the, form, of, 'P-Si-H', complexes, using, the, 'first-principles', method])].
[sujeto(['These', results]), verbo([provide]), complemento([valuable, understanding, of, 'P', doping, in, 'Si-NCs'])].
[sujeto(['The', electron, transfer, from, the, excited, 'Cu(dtc)2', complex, to, a, solvent, molecule]), verbo([leads]), complemento([to, the, appearance, of, the, primary, 'intermediate,', the, '[', 'ClCu(dtc)(dtcCHCl2)]', 'complex,', where, a, dtcCHCl2, molecule, is, coordinated, with, a, copper, ion, via, one, sulfur, atom])].
[sujeto(['Arabidopsis', thaliana, possess, 20, glutamate, 'receptor-like', genes, '(', 'AtGLRs)', in, its, genome, which, are]), verbo([involved]), complemento([in, many, functions, including, light, signal, transduction, and, calcium, homeostasis])].
[sujeto([thaliana]), verbo([have]), complemento([been, studied, in, silico])].
[sujeto(['In', two, genes, namely, 'AT2G17260', and, 'AT4G35290,', presence, of, 'RAV1-A']), verbo([binding]), complemento([site, motif, in, the, promoter, coupled, with, results, from, gene, ontology, annotation, indicate, their, role, in, stomatal, movement, through, abscisic, acid, signaling])].
[sujeto(['Five', of, these, genes]), verbo([have]), complemento([shown, 'G-protein-coupled', 'γ-aminobutyric', acid, '(', 'GABA)', receptor, activity, indicating, a, possible, interaction, between, 'AtGLRs', and, 'GABA'])].
[sujeto(['Structurally,', all, of, them, were, similar, while, differences, were]), verbo([found]), complemento([regarding, electrostatic, surfaces, as, well, as, surface, hydrophobicity])].
[sujeto(['Results', of, this, study]), verbo([provide]), complemento([a, comprehensive, reference, regarding, 'AtGLRs', for, further, analysis, regarding, the, 'structure,', 'function,', and, evolution, of, the, glutamate, receptors, in, plants])].
[sujeto(['Spinel', cobalt, oxide]), verbo([has]), complemento([been, proposed, undergoing, multiple, 'steps\'', reaction, during, electrochemical, lithiation, process])].
[sujeto(['In', this, 'work,', we]), verbo([have]), complemento([utilized, a, 'low-angle', annular, 'dark-field', scanning, transmission, electron, microscopy, method, to, visualize, the, dynamical, reaction, process, in, real, time, and, study, the, reaction, homogeneity, at, different, rates])].
[sujeto(['We']), verbo([reveal]), complemento([a, 'two-step\'s', reaction, at, single, particle, level, which, includes, initial, intercalation, reaction, followed, by, conversion, reaction])].
[sujeto(['At', the, high, 'rate,', a, quick, intercalation, reaction, starts, and, it, may]), verbo([cause]), complemento([the, intermediate, phase, being, overwhelmed, by, following, conversion, reaction, while, at, the, low, 'rate,', the, conversion, reaction, starts, after, the, intercalation, reaction, fully, finished])].
[sujeto(['This', work, may]), verbo([provide]), complemento([microscopic, insights, to, the, reaction, dynamics, at, 'non-equilibrium', conditions, and, highlighted, the, effect, of, lithium, diffusion, rate, on, the, overall, reaction, homogeneity, as, well, as, the, performance])].
[sujeto(['Due', to, the, 'self-charging', and, the, capacity, 'regeneration,', the, trajectories]), verbo([have]), complemento([the, property, of, multimodality])].
[sujeto(['The', method, is, demonstrated, to, be, effective, for, prediction, by, the, excellent, predictive, result, of, the, experiments, on, the, two, commercial, and, chargeable, 'Type', 1850, 'Lithium-ion', 'batteries,']), verbo([provided]), complemento([by, 'NASA'])].
[sujeto(['In', this, article, we]), verbo([report]), complemento([the, synthesis, and, structure, of, the, new, 'Co(II)', complex, 'Et4N[Co(II)(hfac)3]', '(', 'I)', '(', hfac, =, 'hexafluoroacetylacetonate)', exhibiting, 'single-ion', magnet, '(', 'SIM)', behavior])].
[sujeto(['Mycobacterium', tuberculosis, protein, kinase, 'G', '(', 'PknG)', is, a, 82, &, 'nbsp;kDa', multidomain, 'eukaryotic-like', 'serine/threonine', kinase]), verbo([mediating]), complemento([the, survival, of, pathogenic, mycobacteria, within, host, macrophages])].
[sujeto(['The', 'N-terminal', sequence, preceding, the, catalytic, kinase, domain, contains, an, approximately, 75, residues, long, 'tail,', which, was, predicted, to, show, no, regulatory, secondary, structure, '(', 1, -, 75, &, 'nbsp;= NORS)', but, harbors, the, major, in, vivo, phosphorylation, site, '(', 'T63),', and, a, 'rubredoxin-like', metal]), verbo([binding]), complemento([motif, '(', 74, -, 147, &, 'nbsp;= RD)'])].
[sujeto(['In', the, reduced, rubredoxin, 'motif,', four]), verbo([conserved]), complemento([cysteine, residues, that, are, present, as, two, 'C-X-X-C-G', motifs, coordinate, a, metal, ion])].
[sujeto(['The', cysteines, are, further]), verbo([involved]), complemento([in, sensing, the, redox, environment, to, regulate, 'PknG', catalytic, activity])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, '(', 1, ')', 'H,', '(', 13, ')', 'C,', and, '(', 15, ')', 'N', resonance, assignments, of, the, highly, dynamic, unstructured, 'N-terminal', region, 'NORS', and, the, 'RD', in, the, 'reduced,', metal, 'bound,', presumably, folded, and, the, 'oxidized,', 'presumably unfolded', state])].
[sujeto(['Chemical', shifts]), verbo([have]), complemento([been, deposited, at, the, 'BioMagResBank', under, the, 'BMRB', accession, numbers, 26, ',', 28, for, the, 'His-PknG1-147', with, the, 'RD', in, 'reduced,', metal, bound, 'state,', 26, ',', 27, for, 'His-PknG1-75,', and, 26, ',', 30, and, 26, ',', 29, for, 'PknG74-147', either, in, the, 'reduced,', metal, bound, or, oxidized, 'state,', respectively])].
[sujeto(['Different', electrochemical, methods, including, galvanostatic, charge, discharge, experiments, and, cyclic, voltammetry]), verbo([have]), complemento([been, applied, to, study, the, system, performance])].
[sujeto(['This', nanosensor, platform, offers, a, novel, method, for, future, development, of, ratiometric, fluorescent, probes, for]), verbo([targeting]), complemento([other, 'analytes,', like, 'ions,', 'metabolites,and', other, biomolecules, in, biosamples])].
[sujeto(['A', series, of, new, 'two-dimensional', coordination, framework, 'materials,', based, on, 'Ag(I)-N', bond, 'formation,']), verbo([has]), complemento([been, synthesized, and, structurally, characterized, by, single, crystal, methods])].
[sujeto(['In', all, 'cases,', 'L1', ligands, are]), verbo([found]), complemento([to, be, fully, 'saturated,', in, terms, of, metal, ion, 'binding,', with, both, sets, of, pyridyl, and, imino, 'N', atoms, 'involved,', though, in, 1, and, 2, ',', crystallographically, independent, 'L1', moieties, also, display, 'pyridyl-only', binding])].
[sujeto(['Either', solvent, '(', 1, ')', or, the, anion, '(', 2, and, 3, ')']), verbo([acts]), complemento([as, a, terminal, ligand, to, support, interlayer, interactions, in, the, solid, state])].
[sujeto(['Despite', the, relatively, labile, 'nature,', typical, of, such, 'Ag(I)-N', 'bonds,', 'solvent-based', exfoliation, of, crystals, of, 3, was, shown, to]), verbo([provide]), complemento([dispersions, of, 'large,', 'μm(2),', flakes, which, readily, deposit, on, oxide, surfaces, as, 'single-molecule', 'sheets,', as, revealed, by, atomic, force, microscopy])].
[sujeto(['High', quality, 'Gd2O3', 'NPs', are, usually, synthesized, through, a, 'non-hydrolytic', route, which]), verbo([requires]), complemento(['post-synthetic', modification, to, render, the, 'NPs', water, soluble])].
[sujeto(['The', current, challenge, is, to, obtain, aqueous, 'Gd2O3', 'NPs', with, high, colloidal, stability, and]), verbo([enhanced]), complemento([r, 1, relaxivity])].
[sujeto(['Such', a, coating, layer]), verbo([provided]), complemento(['(', 'i)', superior, aqueous, 'stability,', '(', 'ii)', 'biocompatibility,', as, well, as, '(', 'iii)', 'multi-modality', '(', conjugation, with, fluorescence, 'dye)'])].
[sujeto(['In', 'contrast,', a, thicker, polymeric, layer, coating]), verbo([prevents]), complemento(['Gd(3+)', ions, 'leakage,', thus, improving, its, biocompatibility])].
[sujeto(['We', present, the, structure, of, an, asymmetric, 'RNA', loop, that]), verbo([binds]), complemento([metal, ions, and, has, an, essential, function, in, a, bacteriophage, packaging, motor])].
[sujeto(['Prohead', 'RNA', is, a, noncoding, 'RNA', that, is]), verbo([required]), complemento([for, genome, packaging, activity, in, 'phi29-like', bacteriophage])].
[sujeto(['The', loops, in, 'GA1', and, phi29, bacteriophage, share, a]), verbo([conserved]), complemento([adenine, that, forms, a, base, 'triple,', although, the, structural, context, for, the, base, triple, differs])].
[sujeto(['NMR', relaxation, studies, and, femtosecond, 'time-resolved', fluorescence, spectroscopy]), verbo([reveal]), complemento([the, dynamic, behavior, of, the, loop, in, the, metal, ion, bound, and, unbound, forms])].
[sujeto(['The', mechanism, of, metal, ion]), verbo([binding]), complemento([appears, to, be, an, induced, conformational, change, between, two, dynamic, ensembles, rather, than, a, conformational, capture, mechanism])].
[sujeto(['These', results]), verbo([provide]), complemento([experimental, benchmarks, for, computational, models, of, 'RNA-metal', ion, interactions])].
[sujeto(['The', n, =, 4, ',', 13, ',', 22, magic, number, species]), verbo([have]), complemento([cuboid, ground, state, structures, and, exhibit, elevated, abundance, in, 'ESI', mass, spectra])].
[sujeto(['Experiments', on, singly, charged, clusters]), verbo([reveal]), complemento([that, the, loss, of, small, neutrals, is, the, dominant, fragmentation, pathway])].
[sujeto(['The', 'MD', data]), verbo([reveal]), complemento([that, the, prevalence, of, these, dissociation, channels, is, linked, to, the, presence, of, 'short-lived', intermediates, where, a, relatively, compact, core, structure, carries, a, small, '[', 'NaCl]', i, protrusion])].
[sujeto(['Fragmentation', events, of, this, type, are, kinetically, favored, over, other, dissociation, channels, that, would]), verbo([require]), complemento([the, 'quasi-simultaneous', rupture, of, multiple, electrostatic, contacts])].
[sujeto(['The', 'CID', behavior, of, 'NaCl', cluster, ions, bears, interesting, analogies, to, that, of, collisionally]), verbo([activated]), complemento([protein, complexes])].
[sujeto(['Overall,', it, appears, that, 'MD', simulations, represent, a, valuable, tool, for, deciphering, the, dissociation, of, noncovalently]), verbo([bound]), complemento([systems, in, the, gas, phase])].
[sujeto(['A', 'Synapt', 'G2-S', mass, spectrometer]), verbo([has]), complemento([been, modified, to, allow, photointeraction, of, ions, post, the, mobility, cell])].
[sujeto(['For', this, work, we]), verbo([have]), complemento([employed, a, single, wavelength, 'laser,', which, irradiates, at, 266, nm])].
[sujeto(['Further,', we]), verbo([have]), complemento([incorporated, ion, mobility, and, subsequent, drift, time, gating, into, the, 'UVPD', method, allowing, the, separate, analysis, of, 'm/z-coincident', 'species,', both, conformers, and, multimers])].
[sujeto(['Each', mobility, selected, form]), verbo([has]), complemento([a, different, '\'', 'fingerprint\'', dissociation, 'spectrum,', both, predominantly, containing, b, and, y, fragments])].
[sujeto(['Differences', in, the, intensities, of, various]), verbo([loss]), complemento([channels, between, the, two, species, were, revealed])].
[sujeto(['The', smaller, conformer, of, melittin]), verbo([has]), complemento([less, cleavage, sites, along, the, peptide, backbone, than, the, larger, conformer, suggesting, considerable, structural, differences])].
[sujeto(['We', also, show, how, this, modified, instrument, facilitates]), verbo([activated]), complemento([electron, photodissociation])].
[sujeto(['A', series, of, 'LiMn1-x-yFexVyPO4', '(', 'LMFVP)', nanomaterials]), verbo([have]), complemento([been, synthesized, using, a, 'pilot-scale', continuous, hydrothermal, synthesis, process, '(', 'CHFS)', and, evaluated, as, high, voltage, cathodes, in, 'Li-ion', batteries, at, a, production, rate, of, 0.25, kg, 'h-1'])].
[sujeto(['The', rapid, synthesis, and, screening, approach]), verbo([has]), complemento([allowed, the, specific, capacity, of, the, high, 'Mn', content, olivines, to, be, 'optimized,', particularly, at, high, discharge, rates])].
[sujeto(['This', mechanism]), verbo([involves]), complemento([the, formation, of, seed, 'Ag@Co', nanoparticles, by, 'InterMatrix', 'Synthesis', and, subsequent, overgrowth, after, incubation, at, a, low, temperature, in, chloride, and, phosphate, solutions])].
[sujeto(['These', ions]), verbo([promote]), complemento([the, dissolution, and, recrystallization, in, an, ordered, configuration, of, 'pre-synthetized', nanoparticles, initially, embedded, in, 'negatively-charged', polymeric, matrices])].
[sujeto(['During', 'recrystallization,', silver, ions, aggregate, in, 'AgCl@Co', 'fractal-like', 'structures,', then, evolve, into]), verbo([regular]), complemento([polycrystalline, solid, nanostructures, '(', e])].
[sujeto(['CS)', in, a, single, crystallization, step, on, specific, regions, of, the, ion, exchange, resin, '(', 'IER)', which]), verbo([maintain]), complemento([the, integrity, of, polycrystalline, nanocubes])].
[sujeto(['Thus,', this, synthesis, protocol, may, be, easily, expanded, to, the, composition, of, other, nanoparticles]), verbo([providing]), complemento([an, 'interesting,', cheap, and, simple, alternative, for, cubic, structure, formation, and, isolation])].
[sujeto(['Large', 'PCSs', for, backbone, 'N-H', resonances, observed, for, 'M8-CAM-tagged', human, ubiquitin, mutant, 'proteins,', which, were, introduced, into, 'HeLa', cells, by, 'electroporation,', demonstrated, that, this, approach, readily]), verbo([provides]), complemento([the, useful, information, enabling, the, determination, of, protein, 'structures,', relative, orientations, of, domains, and, protein, complexes, within, human, cultured, cells])].
[sujeto(['We', previously, demonstrated, that, aquaporin, '(', 'AQP)1,', a, member, of, the, water, channel, family, of, 'proteins,', was]), verbo([expressed]), complemento([in, 'PASMCs', and, was, necessary, for, 'hypoxia-induced', 'migration;', 'however,', the, mechanism, by, which, 'AQP1', controls, this, response, is, unclear])].
[sujeto(['The', 'C-terminal', tail, of, 'AQP1', contains, putative, calcium, '(', 'EF-hand)', and, protein]), verbo([binding]), complemento([sites])].
[sujeto(['Thus,', we, wanted, to, explore, whether, the, 'C-terminal', tail, or, the, 'EF-hand', motif, of, 'AQP1', was]), verbo([required]), complemento([for, migration, and, proliferation])].
[sujeto(['In', subsequent, 'experiments,', 'wild-type', 'AQP1,', 'AQP1', lacking, the, entire, cytoplasmic, 'C-terminal', 'tail,', or, 'AQP1', with, a, mutation, in, the, 'EF-hand', motif, were]), verbo([expressed]), complemento([in, 'PASMCs', using, adenoviral, constructs])].
[sujeto(['For', all, 'AQP1', 'constructs,', infection]), verbo([increased]), complemento(['AQP1', protein, 'levels,', water, 'permeability,', and, the, change, in, cell, volume, induced, by, hypotonic, challenge])].
[sujeto(['Infection', with, 'wild-type', and, 'EF-hand', mutated, 'AQP1,', but, not, 'C-terminal-deleted', 'AQP1,']), verbo([increased]), complemento(['PASMC', migration, and, proliferation])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'AQP1', controls, proliferation, and, migration, in, 'PASMCs', and, that, the, mechanism, requires, the, 'C-terminal', tail, of, the, protein, but, is, independent, of, water, transport, or, the, 'EF-hand', motif])].
[sujeto(['Microglial', cells]), verbo([respond]), complemento([to, various, factors, which, are, produced, following, nerve, injury, of, multiple, aetiologies, and, contribute, to, the, development, of, neuronal, disease])].
[sujeto(['Chemokine', '(', 'C-C', 'motif)', ligand, 1, '(', 'CCL-1),', a, 'well-characterized', chemokine, secreted, by]), verbo([activated]), complemento(['T', 'cells,', has, been, shown, to, play, an, important, role, in, neuropathic, pain, induced, by, nerve, injury, and, is, also, produced, in, various, cell, types, in, the, 'CNS,', especially, in, dorsal, root, ganglia, '(', 'DRG)'])].
[sujeto(['We', first, showed, that, 'CCR-8,', a, specific, receptor, for, 'CCL-1,', was]), verbo([expressed]), complemento([on, primary, cultured, 'microglia,', as, well, as, on, astrocytes, and, 'neurons,', and, was, upregulated, in, the, presence, of, 'CCL-1'])].
[sujeto(['CCL-1', at, concentration, of, 1, 'ng/ml']), verbo([induced]), complemento(['chemotaxis,', increased, motility, at, a, higher, concentration, '(', 100, 'ng/ml),', and, increased, proliferation, and, phagocytosis, of, cultured, microglia])].
[sujeto(['CCL-1', also]), verbo([activated]), complemento([microglia, 'morphologically,', promoted, mRNA, levels, for, 'brain-derived', neurotrophic, factor, '(', 'BDNF)', and, 'IL-6,', and, increased, the, release, of, nitrite, from, microglia])].
[sujeto(['These', indicate, that, 'CCL-1']), verbo([has]), complemento([a, role, as, a, mediator, in, 'neuron-glia', 'interaction,', which, may, contribute, to, the, development, of, neurological, 'diseases,', especially, in, neuropathic, pain])].
[sujeto(['Studies']), verbo([involving]), complemento(['Toll-like', receptor, 3, '(', 'TLR3)-deficient', mice, suggest, that, this, receptor, binds, 'double-stranded', 'RNA'])].
[sujeto(['In', the, present, 'study,', we, analyzed, 'ligand/receptor', interactions, and, 'receptor-proximal', events]), verbo([leading]), complemento([to, 'TLR3', activation])].
[sujeto(['Furthermore,', inactive, mutants, had, a, dominant, negative, 'effect,']), verbo([suggesting]), complemento([that, the, signaling, module, is, a, multimer])].
[sujeto(['The', synthetic, 'double-stranded', 'RNAs', 'poly(I-C)', and, 'poly(A-U)']), verbo([induced]), complemento([calcium, mobilization, in, a, 'TLR3-CD32', stably, transfected, 'U937', clone, but, not, in, control, cells, transfected, with, other, constructs])].
[sujeto(['An', 'anti-TLR3', antibody, also]), verbo([induced]), complemento(['Ca(2+)', flux, but, only, when, 'cross-linked', by, a, secondary, 'anti-immunoglobulin', 'antibody,', confirming, that, multimerization, by, the, ligand, is, a, requirement, for, signaling])].
[sujeto(['The', inhibitors, of, lysosome, 'maturation,', bafilomycin, and, 'chloroquine,']), verbo([inhibited]), complemento([the, 'poly(I-C)-induced', biological, response, in, immune, 'cells,', showing, that, 'TLR3', interacted, with, its, ligand, in, acidic, subcellular, compartments])].
[sujeto(['These', observations, demonstrate, that, engagement, of, 'TLR3', by, 'poly(I-C)', at, an, acidic, 'pH,', probably, in, early, phagolysosomes, or, 'endosomes,']), verbo([induces]), complemento([receptor, aggregation, leading, to, signaling])].
[sujeto(['Here', for, the, first, 'time,', we, discovered, that, a, chicken, fast, 'TnT', isoform, with, a, unique, 'Tx', motif, '(', 'HEEAH)(n)']), verbo([binds]), complemento([calcium])].
[sujeto(['The', metal]), verbo([binding]), complemento([behavior, of, this, 'TnT', isoform, was, first, investigated, using, terbium, as, a, calcium, analogue, due, to, its, more, readily, detectable, fluorescence, variation, upon, 'TnT', binding])].
[sujeto(['Both', intact, 'TnT', and, 'TnT', 'N-terminal', fragment, '(', 'TnT', 'N47)']), verbo([bound]), complemento([terbium, with, high, affinity, indicating, that, the, 'N-terminal', sequence, was, the, site, of, binding])].
[sujeto(['Since', terbium, often, substitutes, at, 'calcium-binding', 'sites,', radioactive, calcium, was, tested, and]), verbo([found]), complemento([to, bind, both, intact, 'TnT', and, 'TnT', 'N47'])].
[sujeto(['Fluorescence', measurements, using, the, 'calcium-sensitive', fluorescent, 'dye,', calcium, green, 5, 'N,', confirmed, that, calcium]), verbo([bound]), complemento([to, the, tertiary, complex, of, 'TnT', and, the, tropomyosin, dimer, with, a, fast, 'on-rate', '(', 10, '(', 6, ')', -, 10, '(', 7, ')', 'M(-1)', 's(-1))', as, detected, in, 'stopped-flow', analysis])].
[sujeto(['Consistent', with, these, 'observations,', computational, predictions]), verbo([suggest]), complemento([that, 'TnT', 'N47', might, fold, into, an, elongated, structure, with, at, least, one, 'high-affinity', metal, ion, binding, pocket, comprised, primarily, of, the, 'Tx', motif, sequence, and, several, lower, affinity, binding, sites])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'TnT', may, play, a, role, in, modulating, the, 'calcium-mediated', regulatory, process, of, striated, muscle, contraction])].
[sujeto(['Electron', paramagnetic, resonance, '(', 'EPR)', spectroscopy, was, used, to, investigate, changes, in, dynamics, of, 'spin-labeled', nucleotides, in, the, 'TAR', 'RNA', '(', 'U23,', 'U25,', 'U38,', and, 'U40)', upon]), verbo([binding]), complemento([to, 'cations,', 'argininamide,', and, two, peptides, derived, from, the, 'Tat', protein])].
[sujeto(['Nearly', identical, changes, in, dynamics, were, obtained, for, either, calcium, or, sodium, 'ions,', indicating, the, absence, of, a, 'calcium-specific', structural, change, for, the, 'TAR', 'RNA', in, solution, that, had, previously, been]), verbo([suggested]), complemento([by, crystallographic, data])].
[sujeto(['Similar', dynamic, signatures, were, obtained, for, two, 'Tat-derived', peptides, that]), verbo([have]), complemento([the, same, important, binding, determinant, '(', 'R52)', and, similar, binding, affinities, to, the, 'TAR', 'RNA'])].
[sujeto(['Calmodulin-like', domain, protein, kinases, '(', 'CDPKs)', are, a, family, of, 'calcium-', but, not, 'calmodulin-dependent', protein, kinases]), verbo([found]), complemento([in, a, wide, variety, of, plants, and, in, protists])].
[sujeto(['RNA', blot, analysis, showed, that, the, three, 'CDPKs', were]), verbo([expressed]), complemento([in, most, plant, tissues, examined, and, in, 'suspension-cultured', soybean, cells])].
[sujeto(['Recombinant', 'CDPKalpha,', -, 'beta,', and, -, gamma]), verbo([phosphorylated]), complemento([peptide, substrates, containing, the, 'four-residue', motif, 'R/K-X-X-S/T,', but, 'CDPKalpha', was, the, most, selective, for, residues, outside, of, the, motif])].
[sujeto(['The', 'CDPKs', were]), verbo([inhibited]), complemento([by, the, general, protein, kinase, inhibitors, 'K252a', and, staurosporine, and, by, calphostin, 'C,', which, is, an, inhibitor, of, protein, kinase, 'C'])].
[sujeto(['In', the, presence, of, the, peptide, substrate, 'syntide-2', the, 'Kd', of, 'CDPKalpha']), verbo([decreased]), complemento([to, 0.6, microM])].
[sujeto(['The', concentrations, of, 'Ca2+']), verbo([required]), complemento([for, 'half-maximal', activity, '(', 'K0'])].
[sujeto(['These', results, show, that, members, of, the, 'CDPK', family, differ, in, biochemical, properties, and, support, the, hypothesis, that, each, isoform, may]), verbo([have]), complemento([a, distinct, role, in, calcium, signal, transduction])].
[sujeto([cDNA, clones, encoding, a, 'soluble,', 'calcium-dependent,', 'melibiose-binding', lectin, from, 'Xenopus', laevis, oocytes]), verbo([have]), complemento([been, 'isolated,', 'characterized,', and, expressed, in, bacteria])].
[sujeto(['This', lectin]), verbo([has]), complemento([been, shown, by, others, to, be, localized, in, oocyte, cortical, granules, where, it, ultimately, is, released, and, participates, in, the, formation, of, the, fertilization, envelope])].
[sujeto(['A', lectin, with, similar, specificity]), verbo([has]), complemento([been, purified, by, others, from, blastula, and, immunolocalized, to, specific, locations, in, developing, 'embryos,', which, suggests, it, may, also, function, after, fertilization, in, regulating, cell, adhesion, and, migration])].
[sujeto(['We']), verbo([have]), complemento([used, melibiose, affinity, chromatography, to, isolate, the, oocyte, lectin, '(', monomer, molecular, masses, of, about, 45, and, 43, 'kDa)', and, shown, that, after, exhaustive, treatment, with, 'N-glycanase,', only, one, major, protein, band, at, 35, kDa, was, 'observed,', suggesting, that, a, single, polypeptide, with, variable, 'N-linked', glycosylation, is, expressed, in, the, oocyte])].
[sujeto(['Although', this, 'lectin,', termed, 'XL35,']), verbo([requires]), complemento([calcium, ions, for, oligosaccharide, 'binding,', its, sequence, does, not, contain, the, sequence, motif, defined, for, &, 'quot;C-type"', lectins])].
[sujeto(['A', 6, -, 'Histagged', from, of, the, lectin, was]), verbo([expressed]), complemento([in, 'E'])].
[sujeto(['Northern', blot, analysis, demonstrated, that, the, lectin, mRNA, is]), verbo([expressed]), complemento([in, oocytes, and, remains, at, relatively, high, levels, through, late, 'gastrulae,', continuing, until, tadpole, stages])].
[sujeto(['The', persistence, of, the, lectin, 'mRNA,', coupled, with, results, from, earlier, 'studies,', strongly]), verbo([suggests]), complemento([that, 'XL35', is, zygotically, expressed, and, functions, during, morphogenesis])].
[sujeto(['Here,', the, nsdC, '(', never, in, sexual, 'development)', 'gene-encoding', a, putative, transcription, factor, carrying, a, novel, type, of, 'zinc-finger', 'DNA-binding', domain, consisting, of, two, 'C(2)H(2)\'s', and, a, 'C(2)HC', motif, that, are, highly]), verbo([conserved]), complemento([in, most, fungi, but, not, in, plants, or, 'animals-was', investigated])].
[sujeto(['While', the, deletion, of, nsdC, resulted, in, the, complete]), verbo([loss]), complemento([of, fruiting, body, formation, under, all, conditions, favoring, sexual, 'development,', overexpression, of, nsdC, not, only, enhanced, formation, of, fruiting, bodies, '(', 'cleistothecia)', but, also, overcame, inhibitory, effects, of, certain, stresses, on, cleistothecial, 'development,', implying, that, 'NsdC', is, a, key, positive, regulator, of, sexual, development])].
[sujeto(['Deletion', of, nsdC, also, retarded, vegetative, growth, and, hyperactive, asexual, 'sporulation,']), verbo([suggesting]), complemento([that, 'NsdC', is, necessary, not, only, for, sexual, development, but, also, for, regulating, asexual, sporulation, negatively])].
[sujeto(['Overexpression', of, veA, or, nsdD, does, not, rescue, the, failure, of, fruiting, body, formation]), verbo([caused]), complemento([by, nsdC, deletion])].
[sujeto(['Furthermore,', nsdC, expression, is, not, affected, by, either, 'VeA', or, 'NsdD,', and, vice, 'versa,', indicating, that, 'NsdC']), verbo([regulates]), complemento([sexual, development, independently, of, 'VeA', or, 'NsdD'])].
[sujeto(['The', 'Crithidia', fasciculata, cycling, sequence]), verbo([binding]), complemento([protein, '(', 'CSBP)', binds, with, high, specificity, to, sequence, elements, in, several, mRNAs, that, accumulate, periodically, during, the, cell, cycle])].
[sujeto(['Mutations', in, these, sequence, elements, abolish, both, cycling, of, the, mRNA, and]), verbo([binding]), complemento([of, 'CSBP'])].
[sujeto(['Two', 'genes,', 'CSBPA', and, 'CSBPB,', encoding, putative, subunits, of, 'CSBP']), verbo([have]), complemento([been, cloned, and, were, found, to, be, present, in, tandem, on, the, same, 'DNA', molecule, and, to, be, closely, related])].
[sujeto(['Both', 'CSBPA', and, 'CSBPB', proteins]), verbo([have]), complemento([a, predicted, 'coiled-coil', domain, near, the, 'N', terminus, and, a, novel, histidine, and, cysteine, motif, near, the, 'C', terminus])].
[sujeto(['The', latter, motif, is]), verbo([conserved]), complemento([in, other, trypanosomatid, species])].
[sujeto(['Gel', sieving, chromatography, and, glycerol, gradient, sedimentation, results, indicate, that, 'CSBP']), verbo([has]), complemento([a, molecular, mass, in, excess, of, 200, kDa, and, an, extended, structure])].
[sujeto(['Recombinant', 'CSBPA', and, 'CSBPB', also]), verbo([bind]), complemento([specifically, to, the, cycling, sequence, and, together, can, be, reconstituted, to, give, an, 'RNA', gel, shift, similar, to, that, of, purified, 'CSBP'])].
[sujeto(['Proteins', in, cell, extracts]), verbo([bind]), complemento([to, an, 'RNA', probe, containing, six, copies, of, the, cycling, sequence])].
[sujeto(['The', 'RNA-protein', complexes, contain, both, 'CSBPA', and, 'CSBPB,', and, the]), verbo([binding]), complemento([activity, cycles, in, near, synchrony, with, target, mRNA, levels])].
[sujeto(['CSBPA', and, 'CSBPB', mRNA, and, protein, levels, show, little, variation, throughout, the, cell, 'cycle,']), verbo([suggesting]), complemento([that, additional, factors, are, involved, in, the, cyclic, binding, to, the, cycling, sequence, elements])].
[sujeto(['We']), verbo([report]), complemento([the, isolation, and, characterization, of, a, mutant, of, 'Escherichia', coli, unable, to, grow, aerobically, on, 'non-fermentable', 'substrates,', except, for, very, slow, growth, on, glycerol])].
[sujeto(['Comparison', of, the, inferred, amino, acid, sequence, of, 'UbiG', with, the, sequence, of, other, 'S-adenosylmethionine', '(', 'AdoMet)-dependent', methyltransferases]), verbo([reveals]), complemento([a, highly, conserved, 'AdoMet-binding', region])].
[sujeto(['Generally,', potassium, stabilizes, 'guanine-quartet', assemblies, to, a, larger, extent, than, 'sodium;', in, this, article, we]), verbo([report]), complemento([about, a, 'higher-order', 'G4', structure, more, stable, in, sodium, than, in, potassium])].
[sujeto(['The', 'multi-subunit', 'RNA', 'Import', 'Complex', '(', 'RIC)', from, mitochondria, of, the, kinetoplastid, protozoon, 'Leishmania', tropica]), verbo([induces]), complemento([translocation, of, tRNAs, across, artificial, or, natural, 'membranes,', but, the, nature, of, the, translocation, pore, remains, unknown])].
[sujeto(['R3']), verbo([induced]), complemento([translocation, of, tRNA, into, liposomes, when, the, pH, of, the, medium, was, lowered, to, '∼6', in, the, absence, of, 'ATP'])].
[sujeto(['R3-mediated', tRNA, translocation, could, also, be]), verbo([induced]), complemento([at, neutral, pH, by, a, 'K(+)', diffusion, potential, with, an, optimum, of, 60, -, 70, mV])].
[sujeto(['Point', mutations, in, the, 'Cys2-His2', 'Fe-binding', motif, of, 'RIC6,', which, is, homologous, to, the, respiratory, 'Complex', 'III', 'Fe-S', 'protein,', abrogated, import]), verbo([induced]), complemento([by, low, pH, but, not, by, 'K(+)', diffusion, potential])].
[sujeto(['These', results, indicate, that, the, 'R3', complex, forms, a, pore, that, is, gated, by, a, 'proton-generated', membrane, potential, and, that, the, 'Fe-S']), verbo([binding]), complemento([region, of, 'RIC6', has, a, role, in, proton, translocation])].
[sujeto([tropica, thus, contains, a, novel, macromolecular, channel, distinct, from, the, mitochondrial, protein, import, pore, that, is, apparently]), verbo([involved]), complemento([in, tRNA, import, in, some, species])].
[sujeto(['With', high]), verbo([binding]), complemento([affinity, and, distinct, pharmacological, 'functions,', animal, toxins, are, powerful, ligands, to, investigate, the, 'structure-function', relationships, of, 'voltage-gated', ion, channels])].
[sujeto(['Jingzhaotoxin-I', '(', 'JZTX-I)', is, an, important, neurotoxin, from, the, tarantula, 'Chilobrachys', jingzhao, venom, that]), verbo([inhibits]), complemento([both, sodium, and, potassium, channels])].
[sujeto(['In', our, previous, 'work,', 'JZTX-I,', as, a, gating, 'modifier,', is, able, to]), verbo([inhibit]), complemento([activation, of, the, potassium, channel, subtype, 'Kv2'])].
[sujeto(['However,', its]), verbo([binding]), complemento([site, on, 'Kv2'])].
[sujeto(['In', this, 'study,', using, 'Ala-scanning', mutagenesis, 'strategy,', we, demonstrated, that, four, residues, '(', 'I273,', 'F274,', 'E277,', and, 'K280)', in, 'S3b-S4', motif, contributed, to, the, formation, of, 'JZTX-I']), verbo([binding]), complemento([site])].
[sujeto(['The', mutations, 'I273A,', 'F274A,', 'E277A,', and, 'K280A', reduced, toxin]), verbo([binding]), complemento([affinity, by, 6, -, ',', 10, -, ',', 8, -, ',', and, 7, -, 'fold,', respectively])].
[sujeto(['Taken', together, with, our, previous, data, that, 'JZTX-I', accelerated, channel, 'deactivation,', these, results]), verbo([suggest]), complemento([that, 'JZTX-I', inhibits, 'Kv2'])].
[sujeto(['Employing', a, 100, -, fold, 'NH₄+', gradient, amiloride, applied, to, the, luminal, side]), verbo([inhibited]), complemento([the, influx, in, a, 'dose-dependent', 'manner,', with, a, maximal, inhibition, of, 75, '%', at, 20, mmol, 'L⁻¹', and, an, estimated, 'IC50', =, 2, mmol, 'L⁻¹'])].
[sujeto(['Amiloride', also]), verbo([caused]), complemento([a, 'dose-dependent', but, smaller, decrease, in, the, 'short-circuit', current, '(', 'I(sc))'])].
[sujeto(['Using', molecular, methods, full, and, partial, sequence, information, of, two, putative, 'cation/proton', exchangers, '(', 'MsNHE8,', 'MsNHE7,', 9, ')', were, 'obtained,', both, containing, the, characteristic, amiloride]), verbo([binding]), complemento([motif])].
[sujeto(['In', 'contrast,', in, this, tissue, high, expression, levels, of, the, 'V-ATPase', '(', 'D', 'subunit)', were, 'detected,', likely, the, sole, pump, responsible, for, energizing, goblet, cell, 'K+', 'excretion,', but, also]), verbo([involved]), complemento([in, columnar, cell, ammonia, uptake])].
[sujeto([3, was, most, readily, detected, in, kidney, and, was, also]), verbo([expressed]), complemento([in, pancreas, &, 'gt;', lung])].
[sujeto(['The', most, remarkable, difference, between, the, two, polypeptides, is, that, the, 'Walker', 'Type', 'A', consensus]), verbo([binding]), complemento([motif, present, in, both, 'Kir1'])].
[sujeto([2, was, not]), verbo([conserved]), complemento([in, the, 'Kir1'])].
[sujeto([2, polypeptide, in, 'Xenopus', oocytes, resulted, in, the, synthesis, of, a, 'K+-selective', channel, that, exhibited, an, inwardly, rectifying, 'current-voltage', relationship, and, was]), verbo([inhibited]), complemento([by, external, 'Ba2+', and, 'Cs+'])].
[sujeto([2, current, amplitude, was, reduced, by, &, 'gt;85%', when, the, pH, was]), verbo([decreased]), complemento([from, pH, 7.4, to, 5.9, using, the, 'membrane-permeant', buffer, acetate, but, was, relatively, unaffected, when, pH, was, similarly, lowered, using, 'membrane-impermeant', biphthalate])].
[sujeto(['The', inhibition, by, intracellular, protons, was, 'voltage-independent', with, an, 'IC50', of, pH, 6.2, and, a, 'Hill', coefficient, of, 1.9, ',']), verbo([suggesting]), complemento([the, cooperative, binding, of, 2, protons, to, the, intracellular, face, of, the, channel])].
[sujeto(['An', 'ATP']), verbo([binding]), complemento([motif, which, is, characteristic, of, this, subfamily, was, also, conserved])].
[sujeto(['The', weak, rectification, of, sWIRK, is, significant, in, that, it]), verbo([has]), complemento([a, negatively, charged, residue, '(', 'glutamate)', in, the, 'M2', region, which, is, reported, to, cause, strong, inward, rectification])].
[sujeto(['Monocytes,', separated, from, human, peripheral, 'blood,', were, preincubated, with, different, polycyclic, aromatic, hydrocarbons, '(', 'PAHs)', for, 24, h, and, the, production, of, superoxide, ions, '(', 'O*2-)', was, then, measured, using, as, a]), verbo([stimulating]), complemento([agent, phorbol, 12, -, myristate, 13, -, acetate])].
[sujeto(['A', significantly]), verbo([enhanced]), complemento(['O*2-', production, is, only, observed, when, the, cells, are, treated, with, 'benzo[a]pyrene', '(', 'B[a]P);', 'benzo[e]pyrene,', 'benzo[a]anthracene', and, 3, -, methylcholanthrene, induce, a, small, but, not, significant, increase, of, 'O*2-'])].
[sujeto(['Anthracene']), verbo([has]), complemento([no, 'effect,', while, phenanthrene, slightly, inhibits])].
[sujeto(['The', priming, activity, of, 'B[a]P', is, unrelated, to, variations, in, intracellular, 'Ca2+', '(', '[', 'Ca2+]i),', as, demonstrated, by, the, inability, of, 'B[a]P', to]), verbo([increase]), complemento(['[', 'Ca2+]i', concentration, in, both, monocytes, and, the, promonocytic, cell, line, 'U937'])].
[sujeto(['Furthermore,', in, monocytes, the, 'sarcoplasmic/endoplasmic', reticulum, 'Ca2+', -, 'ATPase', 'inhibitor,', 'thapsigargin,', which, can]), verbo([increase]), complemento(['[', 'Ca2+]i', evokes, a, 'differentiation-like', event, associated, with, a, decrease, in, the, production, of, superoxide, ions])].
[sujeto(['These', results, further, support, that, the]), verbo([enhancing]), complemento([activity, of, 'B[a]P', on, monocytes, superoxide, production, is, not, mediated, by, an, increase, of, '[', 'Ca2+]i'])].
[sujeto(['In', 'contrast,', the, role, of, the, aryl, hydrocarbon, receptor, '(', 'AhR)', in, 'B[a]P-induced', superoxide, ion, enhancement, is]), verbo([suggested]), complemento([by, the, inhibitory, effect, of, the, specific, antagonist, 'alpha-naphthoflavone', '(', 'alphaNF),', while, the, tumor, necrosis, factor, '(', 'TNF-alpha)', is, not, involved, in, the, phenomenon])].
[sujeto(['Thus,', the, interaction, of, 'B[a]P', with, its, cytosolic, receptor, and, either, the, metabolism, of, the, compound, into, reactive, intermediates, or, the, 'over-expression', of, some, unknown, genes, seem, to, be]), verbo([involved]), complemento([in, an, essential, step, in, this, process])].
[sujeto(['This', paper]), verbo([reports]), complemento([the, results, from, in, vitro, experiments, utilizing, vital, fluorescent, probes, and, biochemical, assays, to, examine, the, effects, of, 2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin', '(', 2, ',', 3, ',', 7, ',', 8, -, 'TCDD)', and, related, compounds, in, primary, rat, astroglia, in, an, effort, to, identify, the, cellular, 'site(s)', involved, in, toxicity])].
[sujeto(['Application', of, 100, nM, 2, ',', 3, ',', 7, ',', 8, -, 'TCDD,', a, strong, 'Ah', receptor, 'agonist,', resulted, in, altered, astroglial, intracellular, 'Ca2+,', a, significant]), verbo([decrease]), complemento([in, 'glutathione,', a, disrupted, mitochondrial, membrane, 'potential,', a, significant, decrease, in, glutamine, synthetase, immunoreactivity, and, eventual, loss, of, pH, maintenance])].
[sujeto(['These', 'findings,', coupled, with, the, identification, of, the, 9, -, 10, 'S', cytosolic, 'Ah', receptor, in, cultured, rat, 'astroglia,', are, consistent, with, typical, 'structure-activity', relationships, observed, for, other, 'Ah', receptor]), verbo([mediated]), complemento([responses])].
[sujeto(['However,', the, time, course, of, the, 'Ca2+,', as, well, as, other, responses, observed, in, this, 'study,']), verbo([suggest]), complemento([that, the, above, effects, may, not, necessarily, involved, the, formation, of, the, nuclear, 'Ah', receptor, complex])].
[sujeto(['We']), verbo([have]), complemento([used, 'X-ray', crystallography, and, 'small-angle', 'X-ray', scattering, to, examine, and, compare, the, crystal, structure, of, amlodipine, and, its, location, in, cardiac, sarcolemmal, lipid, bilayers, with, that, of, uncharged, dihydropyridines, '(', 'DHPs)', such, as, nimodipine])].
[sujeto(['Crystallographic', analysis, demonstrated, that, the, 'DHP', ring, of, amlodipine, is, considerably, more, planar, than, that, of, 'nimodipine,', that, amlodipine]), verbo([has]), complemento([a, greater, torsion, angle, between, the, 'DHP', and, aryl, 'rings,', and, that, the, protonated, amino, group, extends, away, from, the, 'DHP', ring, structure])].
[sujeto(['Despite', the, positive, charge, of, amlodipine, at, physiological, 'pH,', membrane, electron, density, profile, structures, showed, amlodipine, to]), verbo([have]), complemento([a, 'time-averaged', location, near, the, hydrocarbon, 'core/water', interface, similar, to, that, observed, for, several, uncharged, 'DHPs'])].
[sujeto(['This', location, may, also]), verbo([provide]), complemento([an, appropriate, conformation, and, orientation, for, amlodipine, binding, to, its, receptor, site, at, this, depth, in, the, membrane])].
[sujeto(['Finally,', we]), verbo([have]), complemento([measured, the, nonspecific, partitioning, of, amlodipine, into, native, sarcoplasmic, reticulum, membranes, from, rabbit, skeletal, muscle, and, compared, these, data, with, those, for, the, uncharged, 'DHPs'])].
[sujeto(['These', data]), verbo([suggest]), complemento([differences, in, membrane, interactions, for, 'amlodipine,', compared, with, uncharged, 'DHPs,', that, may, be, correlated, with, its, novel, pharmacodynamic, and, pharmacokinetic, profile])].
[sujeto(['The', in, vitro, stability, of, the, 'Ah', receptor, from, rat, hepatic, cytosol, was, evaluated, by, '[', 3, 'H]TCDD']), verbo([binding]), complemento(['studies,', gel, 'filtration,', and, sucrose, density, gradient, ultracentrifugation])].
[sujeto(['Protease', inhibitors, did, not, reduce, and, dilution, slightly]), verbo([increased]), complemento([the, inactivation, rate, at, 20, degrees, 'C'])].
[sujeto(['Recovery', and, 20, degrees, 'C', stability]), verbo([decreased]), complemento([with, increasing, ionic, strength])].
[sujeto(['Specific']), verbo([binding]), complemento([was, markedly, pH, 'dependent,', with, maximum, recovery, at, 7.6])].
[sujeto(['Analysis', of, the, pH, curve]), verbo([suggested]), complemento([that, cysteine, sulfhydryl, groups, may, be, involved, in, 'TCDD', binding])].
[sujeto(['Dithiothreitol', '(', 1, 'mM)', maximized, recovery, and, 20, degrees, 'C', 'stability,', and, addition, of, the, thiol, largely]), verbo([reactivated]), complemento([binding, sites, lost, from, cytosol, prepared, without, it])].
[sujeto(['Glycerol', '(', 10, '%', 'v/v)', and, 'EDTA', '(', 1.5, 'mM)', maximized, recovery, of, specific, 'binding,', but, both]), verbo([decreased]), complemento([20, degrees, 'C', stability, in, a, 'concentration-dependent', manner])].
[sujeto(['Calcium', chloride, '(', 4, 'mM)']), verbo([increased]), complemento([stability, at, 20, degrees, 'C', by, approximately, 20, '%', ',', and, retarded, the, characteristic, shift, in, sedimentation, coefficient, from, approximately, 9, to, approximately, 6, 'S', in, 'high-salt', sucrose, gradients])].
[sujeto(['The', fact, that, sodium, molybdate, '(', 20, 'mM)']), verbo([decreased]), complemento([recovery, and, 20, degrees, 'C', stability, when, dithiothreitol, was, present, but, slightly, increased, stability, in, its, absence, suggested, an, antagonism, between, the, two, compounds])].
[sujeto(['Molybdate', mitigated, the, inactivation]), verbo([induced]), complemento([by, 0.4, 'M', 'KCl,', an, effect, which, may, be, related, to, the, observation, of, dual, peaks, in, 'molybdate-containing', 'high-salt', sucrose, gradients])].
[sujeto(['These', data, indicate, that, thermal, inactivation, of, the, unoccupied, rat, hepatic, 'Ah', receptor, primarily, may, be, due, to, physical, rather, than, enzymatic, 'processes;', '(', 'ii)', sulfhydryl, 'oxidation,', removal, of, low, molecular, weight, cytosolic, 'components,', and, high, ionic, strength, result, in, rapid, rates, of, inactivation, at, 20, degrees, 'C;', and, '(', 'iii)', the, large, degree, of, protection]), verbo([conferred]), complemento([by, 'TCDD', binding, implies, a, very, tight, 'ligand-receptor', 'interaction,', and, as, such, accords, with, 'TCDDs', extraordinary, potency, and, persistence, in, producing, its, toxic, and, biochemical, effects])].
[sujeto(['Asthma', may, be]), verbo([induced]), complemento([by, chemical, 'sensitisers,', via, mechanisms, that, are, still, poorly, understood])].
[sujeto(['Since', potent, chemical, 'sensitisers,', such, as, 'toluene-2,4-diisocyanate', '(', 'TDI),', are, also, sensory, 'irritants,', it, is]), verbo([suggested]), complemento([that, 'chemical-induced', asthma, relies, on, 'neuro-immune', mechanisms])].
[sujeto(['In', vitro, intracellular, calcium, imaging, and, 'patch-clamp', recordings, in, 'TRPA1-', and, 'TRPV1-expressing', 'Chinese', hamster, ovarian, cells, showed, that, 'TDI']), verbo([activates]), complemento([murine, 'TRPA1,', but, not, 'TRPV1'])].
[sujeto(['Using', an, in, vivo, 'model,', in, which, an, airway, challenge, with, 'TDI']), verbo([induces]), complemento(['AHR', in, 'TDI-sensitised', 'C57Bl/6', 'mice,', we, demonstrated, that, 'AHR', does, not, 'develop,', despite, successful, 'sensitisation,', in, 'Trpa1', and, 'Trpv1', knockout, 'mice,', and, 'wild-type', mice, pretreated, with, a, 'TRPA1', blocker, or, a, substance, 'P', receptor, antagonist])].
[sujeto(['The', results, showed, that, the, generation, of, reactive, oxygen, species, '(', 'ROS),', the]), verbo([release]), complemento([of, cytochrome, c, and, 'DNA', fragmentation, were, 'caspase-dependent,', and, 'Ca(2+)', was, involved, in, calpain, activation, and, phosphatidylserine, '(', 'PS)', exposure, in, '(', '∙)OH-induced', carp, erythrocytes])].
[sujeto(['Moreover,', the, results]), verbo([suggested]), complemento([that, caspases, were, involved, in, 'PS', 'exposure,', and, 'Ca(2+)', was, involved, in, 'DNA', fragmentation, in, '(', '∙)OH-induced', fish, erythrocytes])].
[sujeto(['The', results, displayed, that, 'Ala,', 'Cit,', 'Pro', and, 'Ala10Pro4Cit1', effectively]), verbo([suppressed]), complemento(['ROS', 'generation,', cytochrome, c, 'release,', activation, of, 'caspase-3,', 'caspase-8', and, 'caspase-9', at, the, physiological, 'concentrations,', prevented, 'Ca(2+)', 'influx,', calpain, 'activation,', 'PS', 'exposure,', 'DNA', fragmentation, and, the, degradation, of, the, cytoskeleton, and, oxidation, of, membrane, and, hemoglobin, '(', 'Hb)', and, increased, activity, of, 'anti-hydroxyl', radical, '(', 'AHR)', in, '(', '∙)OH-induced', carp, erythrocytes])].
[sujeto(['Ala10Pro4Cit1', produced, a, synergistic, effect, of]), verbo([inhibited]), complemento([oxidative, stress, and, apoptosis, in, fish, erythrocytes])].
[sujeto(['The', studies, supported, the, use, of, 'Gln,', 'Ala,', 'Cit', and, 'Pro', as, oxidative, stress, and, apoptosis, inhibitors, in, mammal, cells, and, the, hypothesis, that, the]), verbo([inhibited]), complemento([effects, of, 'Gln', on, oxidative, stress, and, apoptosis, are, at, least, partly, dependent, on, that, of, its, metabolites, in, mammalian])].
[sujeto(['Mineral', and, bone, disease, '(', 'CKD-MBD),', disorders, of, mineral, 'metabolism,', is]), verbo([associated]), complemento([with, mortality, and, cardiovascular, disease, in, dialysis, patients])].
[sujeto(['We', also, examined, the, association, between, achieve, 'K/DOQI', 'guidelines\'']), verbo([targets]), complemento([and, clinical, outcomes])].
[sujeto(['From', a, total, of, 284, hemodialysis, 'patients,', none, of, the, baseline, mineral, values, is]), verbo([associated]), complemento([with, mortality, and, cardiovascular, 'event,', except, hyperphosphatemia])].
[sujeto(['Compared', to, patients, achieved, 'K/DOQI', 'guidelines\'', 'targets,', time, average, hyperphosphatemia, is]), verbo([associated]), complemento([with, 'MACE', and, first, cardiovascular, event, '[', the, adjusted, hazard, ratios, '(', 'AHRs)', are, 6.343, and, 3.278, ')', ;, whereas, time, average, hypercalcemia, is, associated, with, 'MACE', marginally, '(', the, 'AHR', is, 5.964, ')'])].
[sujeto(['The', 'AHRs', for, mortality, in, those, who, only, met, 'PTH']), verbo([targets]), complemento([and, none, of, the, mineral, value, targets, are, 1.73, and, 1.74, ',', whereas, the, 'AHRs', for, cardiovascular, events, in, those, who, met, only, 'Ca,', only, 'PTH,', and, none, of, the, targets, are, 1.73, ',', 1.81, and, 2.54, '(', all, ps, &, 'lt;', 0.05, ')'])].
[sujeto(['Time-average', phosphate, is]), verbo([associated]), complemento([with, cardiovascular, events, after, initiation, of, dialysis])].
[sujeto(['TRPA1,', a, member, of, the, 'TRP', channel, 'superfamily,', is, a, 'chemo-sensitive', cation, channel, that, can, be]), verbo([activated]), complemento([by, a, variety, of, external, and, internal, 'stimuli,', leading, to, the, influx, of, 'Ca(2+)'])].
[sujeto(['Functional', 'TRPA1', channels]), verbo([have]), complemento([been, identified, in, neuronal, and, 'non-neuronal', tissues, of, the, 'lung,', including, 'ASM'])].
[sujeto(['In', the, 'airways,', these, channels, can]), verbo([regulate]), complemento([the, release, of, mediators, that, are, markers, of, airway, inflammation, in, asthma, and, 'COPD'])].
[sujeto(['For,', 'example,', 'TRPA1', controls, 'cigarette-smoke-induced', inflammatory, mediator]), verbo([release]), complemento([and, 'Ca(2+)', mobilization, in, vitro, and, in, 'vivo,', a, response, tied, to, disease, pathology, in, 'COPD'])].
[sujeto(['Recent', work]), verbo([has]), complemento([revealed, that, pharmacological, or, genetic, inhibition, of, 'TRPA1', inhibits, the, 'allergen-induced', airway, inflammation, in, vitro, and, airway, 'hyper-responsiveness', '(', 'AHR)', in, vivo])].
[sujeto(['Airway', hyperresponsiveness, '(', 'AHR)', in, asthma, is, predominantly]), verbo([caused]), complemento([by, increased, sensitivity, of, bronchial, smooth, muscle, cells, '(', 'BSMCs)', to, stimuli])].
[sujeto(['The', sarcoplasmic, reticulum, '(', 'SR)-Ca(2+)']), verbo([release]), complemento(['channel,', known, as, ryanodine, receptor, '(', 'RyR),', mediates, the, contractive, response, of, 'BSMCs', to, stimuli])].
[sujeto(['Asthmatic', 'serum,', 'IL-5,', 'IL-13,', and, 'TNF-α']), verbo([enhance]), complemento([the, calcium, response, of, 'BSMCs', to, contractile, agonists, and, cause, dissociation, of, 'FKBP12'])].
[sujeto([6, from, 'RyR2', and, a]), verbo([decrease]), complemento([in, 'FKBP12'])].
[sujeto([6, in, 'BSMCs']), verbo([causes]), complemento([a, decrease, in, the, association, of, 'RyR2', with, 'FKBP12'])].
[sujeto([6, and, an]), verbo([increase]), complemento([in, the, calcium, response, of, 'BSMCs'])].
[sujeto([6]), verbo([increases]), complemento([the, association, of, 'FKBP12'])].
[sujeto([6, with, 'RyR2,']), verbo([decreases]), complemento([the, calcium, response, of, 'BSMCs,', and, normalizes, airway, responsiveness, in, 'OVA-sensitized', and, -, challenged, rats])].
[sujeto([6, from, 'RyR2', in, 'BSMCs', is, responsible, for, the]), verbo([increased]), complemento([calcium, response, contributing, to, 'AHR', in, asthma])].
[sujeto(['Intracellular', 'Ca(2+)', dynamics, of, airway, smooth, muscle, cells, '(', 'ASMC)']), verbo([mediate]), complemento(['ASMC', contraction, and, 'proliferation,', and, thus, play, a, key, role, in, airway, 'hyper-responsiveness', '(', 'AHR)', and, remodelling, in, asthma])].
[sujeto(['The', model, confirms, that, 'SOCE', is, elicited, upon, sufficient, 'Ca(2+)', depletion, of, the, sarcoplasmic, reticulum, '(', 'SR),', while, 'receptor-operated', '[', 'Ca(2+)', entry, '(', 'ROCE)', is]), verbo([inhibited]), complemento([in, such, conditions])].
[sujeto(['SOCE', 'up-regulation', may, thus, contribute, to, 'AHR', by]), verbo([increasing]), complemento([the, 'Ca(2+)', oscillation, frequency, that, in, turn, regulates, 'ASMC', contraction])].
[sujeto(['The', model, also]), verbo([provides]), complemento([an, explanation, for, the, failure, of, the, 'SERCA', pump, blocker, 'CPA', to, clamp, the, cytosolic, 'Ca(2+)', of, 'ASMC', in, lung, 'slices,', by, showing, that, 'CPA', is, unable, to, maintain, the, 'SR', empty, of, 'Ca(2+)'])].
[sujeto(['This', prediction, is, confirmed, by, experimental, data, from, mouse, lung, 'slices,', and, strongly]), verbo([suggests]), complemento([that, 'CPA', only, partially, inhibits, 'SERCA', in, 'ASMC'])].
[sujeto(['Prior', fractures, and, alcoholism, independently]), verbo([increased]), complemento([fracture, risk, significantly])].
[sujeto(['We']), verbo([have]), complemento([evaluated, the, influence, of, the, microfluidic, environment, on, renal, cell, functionality])].
[sujeto(['The', transcriptomic, and, proteomic, integration, revealed, that, the, ion, transporters]), verbo([involved]), complemento([in, 'calcium,', 'phosphate,', and, sodium, homoeostasis, and, several, genes, involved, in, 'H(+)', transporters, and, pH, regulation, were, 'up-regulated', in, microfluidic, biochips])].
[sujeto(['Concerning', drug, 'metabolism,', we]), verbo([found]), complemento(['Phase', 'I', '(', 'CYP', 'P450),', 'Phase', 'II', enzymes, '(', 'GST),', various, multidrug, resistance, genes, '(', 'MRP),', and, 'Phase', 'III', transporters, '(', 'SLC)', were, also, 'up-regulated', in, the, biochips])].
[sujeto(['Furthermore,', the, study, shows, that, those, inductions, were, correlated, with, the, induction, of, the, 'Ahr', and, 'Nrf-2', dependent, 'pathways,', which, results, in, a, global, cytoprotective, response]), verbo([induced]), complemento([by, the, microenvironment])].
[sujeto(['Microfluidic', biochips, may, thus]), verbo([provide]), complemento([an, important, insight, into, exploring, xenobiotic, injury, and, transport, modifications, in, this, type, of, bioartificial, microfluidic, kidney])].
[sujeto(['Finally,', the, investigation, demonstrated, that, combining, the, transcriptomic, and, proteomic, analyses, obtained, from, a, cell, &, 'quot;on', 'chip"', culture, would]), verbo([provide]), complemento([a, pertinent, new, tool, in, the, mechanistic, interpretation, of, cellular, mechanisms, for, predicting, kidney, cell, toxicity, and, renal, clearance, in, vitro])].
[sujeto([1, ')']), verbo([increased]), complemento([after, sensitization, along, with, an, increase, in, '[', 'Ca2+]i', levels, in, leukocytes, and, tracheal, smooth, muscle, 'cells,', higher, rates, of, '(', 45, ')', 'Ca', and, '(', 22, ')', 'Na', influx, in, leukocytes, and, higher, '(', 86, ')', 'Rb', influx, rates, in, tracheal, smooth, muscle, 'cells,', and, increased, levels, of, lipid, peroxides, in, plasma])].
[sujeto(['In', guineapig, model, of, asthma, sensitization, to, allergen]), verbo([increased]), complemento([the, membrane, permeability, to, calcium, and, 'sodium,', and, intracellular, calcium, levels])].
[sujeto(['In', a, 'Cox', regression, model, with, control, for, known, 'confounders,']), verbo([increased]), complemento([pfmdr1, copy, number, was, associated, with, an, attributable, hazard, ratio, '(', 'AHR)', for, treatment, failure, of, 6.3, '(', 95, '%', 'CI', 2.9, -, 13.8, ',', 'p<0'])].
[sujeto(['Single', nucleotide, polymorphisms, in, pfmdr1, were]), verbo([associated]), complemento([with, increased, mefloquine, susceptibility, in, 'vitro,', but, not, in, vivo])].
[sujeto(['Amplification', in, pfmdr1, is, the, main]), verbo([cause]), complemento([of, resistance, to, mefloquine, in, falciparum, malaria])].
[sujeto(['Genes', that, encode, parasite, transport, proteins, maybe]), verbo([involved]), complemento([in, export, of, drugs, and, so, cause, resistance])].
[sujeto(['In', this, study, we, show, that]), verbo([increase]), complemento([in, copy, number, of, 'pfmdr1,', a, gene, encoding, a, parasite, transport, 'protein,', is, the, best, overall, predictor, of, treatment, failure, with, mefloquine])].
[sujeto(['Inside-out', patches, from, 'AHR', showed, normal, activation, with, exogenous, 'cGMP-dependent', protein, kinase, 'I', '(', 'cGKI),']), verbo([suggesting]), complemento([no, abnormality, downstream, of, cGKI])].
[sujeto(['This', was, substantiated, by, showing, the, following, in, 'AHR:', '(', 1, ')', reduced, effect, of, the, 'cGKIalpha-selective', activator, 8, -, 'APT-cGMP;', '(', 2, ')', reduced, total, cGKI, protein, '(', both, 'isoforms),', but, an]), verbo([increase]), complemento([in, cGKIbeta, protein, in, quantitative, immunofluorescence, and, 'Western', 'blots;', '(', 3, ')', similar, changes, in, cGKI, isoforms, immunoisolated, with, 'Maxi-K', 'channels;', and, '(', 4, ')', a, large, increase, in, cGKIbeta, mRNA, and, a, decrease, in, cGKIalpha, mRNA, in, 'real-time', 'PCR', and, 'Northern', blots])].
[sujeto(['Embryonic', stem, cells, are, pluripotent, cells, derived, from, the, inner, cell, mass, of, mouse, blastocysts, that]), verbo([have]), complemento([been, shown, to, differentiate, spontaneously, into, cell, types, representing, all, three, germ, layers])].
[sujeto(['This', study, shows, that, 'ES', cells, were]), verbo([induced]), complemento([to, differentiate, in, vitro, into, mineralized, osteoblasts, under, the, influence, of, ascorbic, 'acid,', 'beta-glycerophosphate', and, 1, 'alpha,25-OH', vitamin, 'D3'])].
[sujeto(['The', activity, of, alkaline, 'phosphatase,', an, early, osteoblast, 'marker,', was]), verbo([found]), complemento([to, be, increased, around, day, 12, of, culture])].
[sujeto(['The', 'osteoblast-specific', transcription, factor, 'Cbfa1', was]), verbo([induced]), complemento([a, few, days, earlier])].
[sujeto(['The', expression, of, osteopontin, and, 'osteonectin,', both, being]), verbo([involved]), complemento([in, binding, calcium, ions, and, hydroxyapatite, during, mineralization, 'processes,', as, well, as, of, collagen, type, 'I,', representing, by, far, the, most, predominant, collagen, in, vertebrate, 'organisms,', is, enhanced, at, the, beginning, of, the, second, culture, week, upon, addition, of, supplements])].
[sujeto(['In', the, third, week, of, 'culture,', treated, cells, showed, a, second, peak, of, 'osteopontin,', osteonectin, and, collagen, type, 'I', 'expression,', osteopontin, and, osteonectin, being]), verbo([stimulated]), complemento([3, -, 4, -, fold, and, collagen, type, 'I', being, induced, 6, -, fold, over, control, values])].
[sujeto(['Alkaline', phosphatase, '(', 'ALP)', expression, was]), verbo([enhanced]), complemento([at, the, beginning, of, the, third, week, of, culture, and, was, found, to, be, increased, again, at, later, stages, of, culture, at, days, 27, -, 34])].
[sujeto(['The', in, vitro, differentiation, of, mouse, embryonic, stem, cells, into, osteoblasts, may]), verbo([provide]), complemento([a, suitable, model, for, studying, the, molecular, processes, of, osteoblastic, development, in, vivo])].
[sujeto(['We', tested, the, hypothesis, that, an, elevated, 'potassium-42', '(', '(', 42, ')', 'K(+))', efflux, '(', highly, dependent, on, 'Ca(2+))', and, an]), verbo([increase]), complemento([in, the, sensitivity, of, contraction, and, '(', 42, ')', 'K(+)', efflux, to, norepinephrine, '(', 'NE)', in, conduit, arteries, of, 'aldosterone-salt', hypertensive, rats, '(', 'AHR)', extended, to, 'smaller,', distributing, arteries])].
[sujeto(['In', 'contrast,', the, sensitivity, of, the, contractile, and, '(', 42, ')', 'K(+)', efflux, responses, to, 'NE', was]), verbo([enhanced]), complemento([in, 'SMA', from, 'AHR', compared, to, 'CSR'])].
[sujeto(['We', compared, the]), verbo([binding]), complemento([profiles, and, contractile, mechanisms, of, putative, muscarinic, 'M1', agonists, 'McN-A-343', and, 'AHR-602', with, those, of, carbachol, in, smooth, muscle, of, 'guinea-pig', taenia, caeci])].
[sujeto(['McN-A-343', and, 'AHR-602,', as, well, as, 'carbachol,', completely, displaced, the, 'atropine-sensitive']), verbo([binding]), complemento([of, '[', 3, 'H]-quinuclidinyl', benzilate, to, muscarinic, receptors, present, in, the, membrane, preparation])].
[sujeto(['In', the, presence, of, 2.2, mM, extracellular, 'Ca2+,', 'McN-A-343', and, 'AHR-602']), verbo([induced]), complemento([contraction, corresponding, to, 79, and, 85, '%', ',', 'respectively,', of, the, maximal, contraction, to, 0.1, mM, carbachol])].
[sujeto(['Contractions']), verbo([induced]), complemento([by, these, agents, were, mediated, via, activation, of, the, muscarinic, receptor, subtype, that, had, a, high, affinity, for, 4, -, 'DAMP', '(', 'M3', 'selective)', but, a, low, affinity, for, pirenzepine, '(', 'M1', 'selective)', and, 'AF-DX', 116, '(', 'M2', 'selective)'])].
[sujeto(['These', contractions, were]), verbo([inhibited]), complemento([by, an, 'L-type', 'Ca2+', channel, 'blocker,', verapamil])].
[sujeto(['Application', of, 'McN-A-343', or, 'AHR-602']), verbo([inhibited]), complemento([the, 'carbachol-induced', contraction, in, 'Ca(2+)-free', 'solution,', and, this, inhibition, was, surmounted, by, a, higher, concentration, of, carbachol])].
[sujeto(['After', treatment, with, propylbenzilylcholine, 'mustard,', carbachol]), verbo([induced]), complemento([contraction, only, in, the, presence, of, extracellular, 'Ca2+'])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, in, the, taenia, caeci, there, is, a, greater, receptor, reserve, for, muscarinic, 'M3', 'receptor-mediated', 'Ca2+', influx, than, for, 'M3', mediated, 'Ca2+', release])].
[sujeto(['The', compounds, 'McN-A-343', and, 'AHR-602', are, agonists, of, the, 'Ca2+', influx, 'pathway,', but, do, not, appear, to]), verbo([stimulate]), complemento([the, 'Ca2+', release, pathway])].
[sujeto(['We', determined, whether, the, impaired, 'endothelium-dependent', relaxation, in, 'aldosterone-salt', hypertensive, rats, '(', 'AHR)', is]), verbo([associated]), complemento([with, a, decreased, free, 'Ca2+', '(', '[', 'Ca2+]i)', response, in, endothelial, cells])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, depressed, endothelial, '[', 'Ca2+]i', responses, to, acetylcholine, may, be, involved, in, the, impaired, 'endothelium-dependent', relaxation, in, aorta, from, 'AHR'])].
[sujeto(['Recent', studies]), verbo([have]), complemento([shown, that, crude, oil, exposure, affects, cardiac, development, in, fish, by, disrupting, 'excitation-contraction', '(', 'EC)', coupling])].
[sujeto(['We', previously]), verbo([found]), complemento([that, eggs, of, 'Atlantic', haddock, '(', 'Melanogrammus', 'aeglefinus)', bind, dispersed, oil, 'droplets,', potentially, leading, to, more, profound, toxic, effects, from, uptake, of, polycyclic, aromatic, hydrocarbons, '(', 'PAHs)'])].
[sujeto(['We', quantified, effects, on, cardiac, function, and, 'morphogenesis,', characterized, novel, craniofacial, 'defects,', and, examined, the, expression, of, genes, encoding, potential]), verbo([targets]), complemento([underlying, cardiac, and, craniofacial, defects])].
[sujeto(['The', specific, nature, of, the, craniofacial, abnormalities]), verbo([suggests]), complemento([that, crude, oil, may, target, common, craniofacial, and, cardiac, precursor, cells, either, directly, or, indirectly, by, affecting, ion, channels, and, intracellular, calcium, in, particular])].
[sujeto(['Furthermore,', 'down-regulation', of, genes, encoding, specific, components, of, the, 'EC', coupling, machinery]), verbo([suggests]), complemento([that, crude, oil, disrupts, 'excitation-transcription', coupling, or, normal, feedback, regulation, of, ion, channels, blocked, by, 'PAHs'])].
[sujeto(['Novel', methods, for, preserving, primary, teeth, can, help, to]), verbo([maintain]), complemento([their, 'developmental,', 'esthetic,', and, functional, capabilities])].
[sujeto(['The', aim, of, this, study, was, to, assess, the, success, of, the, repair, of, bony, 'defects,']), verbo([caused]), complemento([by, 'pre-treatment', 'perforations,', with, a, mixture, of, three, antibiotics, combined, with, simvastatin, '(', 3, 'Mixtatin)', compared, to, 'MTA', in, hopeless, primary, molars])].
[sujeto(['By', the, end, of, 24, months, in, 3, 'Mixtatin', 'group,', 31, '(', 96.8, '%', ')', teeth, revealed, no, clinical, signs, or, symptoms, with]), verbo([arrested]), complemento([resorption, progress, in, radiographs])].
[sujeto(['Radiographic', and, clinical, healing, occurred, more, successfully, following, 3, 'Mixtatin', treatment, compared, to, treatment, with, 'MTA,', it, may]), verbo([lead]), complemento([to, a, paradigm, shift, in, the, pulpal, treatment, of, primary, teeth, in, the, future])].
[sujeto(['This', article]), verbo([reports]), complemento([a, clinical, case, of, a, 9, -, 'year-old', boy, with, a, traumatic, injury, to, the, maxillary, central, incisors, 24, hours, after, a, fall, in, his, schoolyard])].
[sujeto(['Two', endpoints, were, 'used:', '(', 1, ')', the, concentration, dependent, potential, to]), verbo([induce]), complemento([early, afterdepolarizations, in, the, simulated, action, potential, and, '(', 2, ')', the, 'arrhythmia-like', disruption, in, the, simulated, 'pseudo-ECG', signals])].
[sujeto(['Overactivation', of, neuronal, 'N-methyl-D-aspartate', receptors, '(', 'NMDARs)']), verbo([causes]), complemento([excitotoxicity, and, is, necessary, for, neuronal, death])].
[sujeto(['In', the, classical, 'view,', these, 'ligand-gated', 'Ca(2+)-permeable', ionotropic, receptors]), verbo([require]), complemento(['co-agonists', and, membrane, depolarization, for, activation])].
[sujeto(['We']), verbo([report]), complemento([that, 'NMDARs', signal, during, ligand, binding, without, activation, of, their, ion, conduction, pore])].
[sujeto(['Pharmacological', pore, block, with, 'MK-801,', physiological, pore, block, with, 'Mg(2+)', or, a, 'Ca(2+)-impermeable', 'NMDAR', variant]), verbo([prevented]), complemento(['NMDAR', 'currents,', but, did, not, block, excitotoxic, dendritic, blebbing, and, secondary, currents, induced, by, exogenous, 'NMDA'])].
[sujeto(['NMDARs,', 'Src', kinase, and, 'Panx1', form, a, signaling, 'complex,', and, activation, of, 'Panx1']), verbo([required]), complemento([phosphorylation, at, 'Y308'])].
[sujeto(['Our', observations]), verbo([provide]), complemento([insights, into, a, new, signaling, modality, of, 'NMDARs', that, has, 'broad-reaching', implications, for, brain, physiology, and, pathology])].
[sujeto(['In', 'addition,a', new, concept]), verbo([has]), complemento([been, proposed, &, 'quot;CKD-MBD"'])].
[sujeto(['The', main, therapeutic]), verbo([target]), complemento([for, 'CKD-MBD', becomes, the, phosphate, control])].
[sujeto(['The', purpose, of, the, present, study, was, to, evaluate, the, effect, of, common, pediatric, liquid, medicines, on, surface, roughness, and, tooth, structure]), verbo([loss]), complemento([and, to, evaluate, the, pH, values, of, these, medicines, at, room, and, cold, temperatures, in, vitro])].
[sujeto(['Despite', the, low, pH, values, of, all, evaluated, 'medicines,', only, 'Alivium®,', 'Clavulin®,', and, 'Claritin®']), verbo([increased]), complemento([linear, surface, 'roughness,', and, only, 'Claritin®', demonstrated, the, in, vitro, capacity, to, produce, significant, tooth, structure, loss])].
[sujeto(['Drug', resistance, in, 'Plasmodium', falciparum]), verbo([has]), complemento([posed, an, obstacle, to, effective, treatment, and, challenges, many, malaria, control, programmes, in, endemic, areas])].
[sujeto(['On', day, 0, ',', of, the, 94, evaluated, 'samples,', 'wild-type', alleles, were, identified, in, 73.4, '%', '(', n, =, 69, ')', for, pfmdr1, 'N86Y', position, and, only, one, sample, carried, the, mutant, allele, '(', 'Y)', for, pfmdr1, 1246, ;, 14, '%', of, these, samples, showed]), verbo([increased]), complemento([pfmdr1, copy, 'number;', 100, '%', '(', n, =, 21, ')', had, 'wild-type', allele, of, k13, gene, in, all, the, studied, positions])].
[sujeto(['These', results, showed, changes, in, parasite, profile, susceptibility, to, 'AL', in, comparison, to, the, baseline, data, from, 2002, to, 2004, and, on, the, genotyping, 'characteristics;', the, clinical, outcome, after, treatment, with, 'AL', did, not, link, a, particular, genotype, with, treatment, 'failure;', observed, changes, do, not]), verbo([provide]), complemento([sufficient, evidence, for, a, treatment, policy, 'change,', but, they, suggest, that, a, carefully, monitoring, is, needed, in, this, area])].
[sujeto(['Few', 'BKCa', channel, openers]), verbo([have]), complemento([been, accepted, for, clinical, development])].
[sujeto(['Using', 'voltage-ramp', 'protocols,', 'GoSlo-SR5-130']), verbo([caused]), complemento([currents, to, activate, at, more, negative, potentials, in, a, 'concentration-dependent', 'manner,', shifting, the, 'half-maximal', activation, voltage, potential, to, the, left, on, the, voltage, axis])].
[sujeto(['GoSlo-SR5-130', also, resulted, in, an]), verbo([increase]), complemento([in, the, activity, of, spontaneous, transient, outward, currents, in, myocytes, isolated, from, 'CCSM,', and, this, effect, was, reversed, by, iberiotoxin])].
[sujeto(['Isometric', tension, recording, of, strips, of, rabbit, corpus, cavernosum, showed, that, 'GoSlo-SR5-130']), verbo([inhibited]), complemento([spontaneous, contractions, in, a, 'concentration-dependent', manner])].
[sujeto(['This', effect, was, reversed, in, the, presence, of, 'iberiotoxin,']), verbo([suggesting]), complemento([that, 'GoSlo-SR5-130', exerts, its, effect, through, 'BKCa', channels])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'GoSlo-SR5-130', is, an, effective, tool, for, the, study, of, 'BKCa', channels, and, that, these, channels, can, modulate, 'CCSM', activity, and, are, possible, targets, for, the, treatment, of, erectile, dysfunction])].
[sujeto(['The', formation, of, a, ternary, 'antibiotic-metal-clay', complex, is, hypothesized, as, the, primary, adsorption, mechanism, responsible, for, the]), verbo([increased]), complemento([adsorption, of, tetracycline, antibiotics, on, smectites, in, the, presence, of, divalent, metal, cations, under, circumneutral, and, higher, pH, conditions])].
[sujeto(['To', evaluate, this, 'hypothesis,', we, conducted, a, spectroscopic, investigation, of, oxytetracycline, '(', 'OTC)']), verbo([interacting]), complemento([with, 'Na-montmorillonite', in, the, presence, and, absence, of, 'Ca', or, 'Mg', salts, at, pH, 6, and, pH, 8])].
[sujeto(['Despite', a, 'two-fold']), verbo([increase]), complemento([in, 'OTC', adsorbed, in, the, presence, of, 'Ca', or, 'Mg,', both, 'solid-state', nuclear, magnetic, resonance, and, infrared, signatures, of, the, 'OTC', functional, groups, involved, in, metal, complexation, implied, that, the, formation, of, an, 'inner-sphere', ternary, complexation, was, not, significant, in, stabilizing, the, adsorbate, structures])].
[sujeto(['The', spectroscopic, data, further, indicated, that, the, 'positively-charged', amino, group]), verbo([mediated]), complemento([the, 'OTC', adsorption, both, in, the, absence, and, presence, of, the, divalent, metal, cations])].
[sujeto(['Focusing', on, the, experiments, with, 'Mg,', 'X-ray', diffraction, analysis, revealed, that, the, 'metal-promoted', adsorption, was, coupled, with, an]), verbo([increased]), complemento([intercalation, of, 'OTC', within, the, montmorillonite, layers])].
[sujeto(['The', simulations, uncovered, the, evolution, of, segregated, interstratification, patterns, that, demonstrated, how]), verbo([increased]), complemento([access, to, smectite, interlayers, in, the, presence, of, the, divalent, metal, cations, enhanced, adsorption, of, 'OTC'])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, specific, aqueous, structures, of, the, clay, crystallites, in, response, to, the, 'co-presence', of, 'Mg', and, 'OTC', in, solution, served, as, precursors, to, the, interlayer, trapping, of, the, antibiotic, species])].
[sujeto(['Secondary', hyperparathyroidism, is, almost, a, constant, feature, in, chronic, kidney, disease, '(', 'CKD)', patients]), verbo([maintained]), complemento([on, hemodialysis, '(', 'HD)'])].
[sujeto(['Recent', studies]), verbo([provide]), complemento([conflicting, data, on, the, 'benefits,', efficacy, and, tolerance, of, cinacalcet, as, 'first-line', therapy, for, the, treatment, of, secondary, hyperparathyroidism, in, 'CKD'])].
[sujeto(['We', used, the]), verbo([targets]), complemento([of, 'Chronic', 'Kidney', 'Disease:', 'Outcomes', 'Quality', 'Initiative', '(', 'K/DOQI)', clinical, guidelines, as, optimal, target, of, serum, 'iPTH,', calcium, and, phosphate])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, treatment, of, 'CKD', 'patients,', having, moderate, to, severe, secondary, 'hyperparathyroidism,', with, 'low-dose', cinacalcet, is, effective, and, well, tolerated])].
[sujeto(['Adenosine', diphosphate, ribose, '(', 'ADPR),', a, product, of, 'β-NAD+', metabolism, generated, by, the, multifunctional, enzyme, 'CD38,', is]), verbo([recognized]), complemento([as, a, novel, signaling, molecule])].
[sujeto(['CD38-dependent', pathways]), verbo([have]), complemento([been, characterized, in, pulmonary, artery, smooth, muscle, cells, '(', 'PASMCs);', however, the, physiological, function, of, extracellular, 'ADPR', is, unclear])].
[sujeto(['ADPR', elicited, 'concentration-dependent']), verbo([increase]), complemento([in, '[', 'Ca2+]i', with, a, fast, transient, and, a, sustained, phase, in, 'PASMCs'])].
[sujeto(['The', sustained, phase, was, abolished, by, 'Ca2+', removal, and]), verbo([inhibited]), complemento([by, the, 'non-selective', cation, channel, blocker, 'SKF-96365,', but, was, unaffected, by, 'TRPM2', antagonists, or, nifedipine])].
[sujeto(['The', purinergic, receptor, '(', 'P2X)', antagonist, 'pyridoxal-phosphate-6-azophenyl-2\',', 4, '\'', -, disulfonate]), verbo([inhibited]), complemento([partially, the, transient, and, the, sustained, 'Ca2+', 'response,', while, the, 'P2(XY)', inhibitor, suramin, and, the, phospholipase, 'C', inhibitor, 'U73122', abolished, the, sustained, 'Ca2+', influx])].
[sujeto(['By', 'contrast,', 'ATP', and, 'ADP']), verbo([activated]), complemento(['Ca2+', response, exhibited, a, high, and, a, low, affinity, 'component,', and, the, pharmacological, profile, of, 'ATP-induced', 'Ca2+', response, was, distinctive, from, that, of, 'ADPR'])].
[sujeto(['BrdU', incorporation, assay, showed, that, 'ADPR']), verbo([caused]), complemento([significant, inhibition, whereas, 'ATP', caused, slight, stimulation, of, 'PASMC', proliferation])].
[sujeto(['RT-PCR', analysis]), verbo([found]), complemento([that, almost, all, 'P2X', and, 'P2Y', subtypes, are, expressed, in, 'PAs'])].
[sujeto(['ADPR', and, 'ATP']), verbo([activate]), complemento(['Ca2+', responses, through, different, combinations, of, multiple, purinergic, receptor, 'subtypes;', and, extracellular, 'ADPR', may, exert, an, 'autocrine/paracrine', action, via, purinergic, receptors, on, 'PASMCs'])].
[sujeto(['The', phenolic, abietane, diterpene, component, of, rosemary, and, 'sage,', carnosic, 'acid,', may, either]), verbo([induce]), complemento([or, inhibit, apoptosis, of, nucleated, cells])].
[sujeto(['The', mechanisms]), verbo([involved]), complemento([in, the, effects, of, carnosic, acid, include, altered, mitochondrial, function, and, gene, expression])].
[sujeto(['Cellular', mechanisms]), verbo([involved]), complemento([in, the, stimulation, of, eryptosis, include, oxidative, 'stress,', increase, of, cytosolic, 'Ca2+', activity, '(', '[', 'Ca2+]i),', and, ceramide, formation])].
[sujeto(['The', present, study, 'explored,', whether, and, how, carnosic, acid]), verbo([induces]), complemento([eryptosis])].
[sujeto(['A', 48, hours, exposure, of, human, erythrocytes, to, carnosic, acid, significantly]), verbo([increased]), complemento([the, percentage, of, 'annexin-V-binding', cells, '(', 2.5, 'µg/ml),', significantly, decreased, forward, scatter, '(', 10, 'µg/ml),', significantly, increased, 'Fluo3', fluorescence, '(', 10, 'µg/ml),', significantly, increased, ceramide, abundance, '(', 10, 'µg/ml),', significantly, increased, hemolysis, '(', 10, 'µg/ml),', but, significantly, decreased, 'DCFDA', fluorescence, '(', 10, 'µg/ml)'])].
[sujeto(['Carnosic', acid]), verbo([triggers]), complemento([cell, shrinkage, and, phospholipid, scrambling, of, the, human, erythrocyte, cell, 'membrane,', an, effect, paralleled, by, 'and/or', in, part, due, to, 'Ca2+', entry, and, increased, ceramide, abundance])].
[sujeto(['Glycogen', synthase, kinase, '(', 'GSK)-3', is, a, ubiquitously]), verbo([expressed]), complemento([kinase, inhibited, by, 'insulin-dependent', 'Akt/PKB/SGK'])].
[sujeto(['Mice']), verbo([expressing]), complemento(['Akt/PKB/SGK-resistant', 'GSK3α/GSK3β', '(', 'gsk3(KI))', exhibit, enhanced, sympathetic, nervous, activity, and, phosphaturia, with, decreased, bone, density])].
[sujeto(['Hormones']), verbo([participating]), complemento([in, phosphate, homeostasis, include, fibroblast, growth, factor, '(', 'FGF)-23,', a, 'bone-derived', hormone, that, inhibits, 1, ',', 25, -, dihydroxyvitamin, 'D3', '(', 1, ',', 25, '(', 'OH)2D3;', 'calcitriol)', formation, and, phosphate, reabsorption, in, the, kidney, and, counteracts, vascular, calcification, and, aging])].
[sujeto(['FGF23', secretion, is]), verbo([stimulated]), complemento([by, the, sympathetic, nervous, system])].
[sujeto(['Propranolol', treatment]), verbo([decreased]), complemento([serum, 'FGF23', and, loss, of, renal, calcium, and, phosphate, and, increased, serum, phosphate, concentration, in, 'gsk3(KI)', mice])].
[sujeto(['We', conclude, that, 'Akt/PKB/SGK-sensitive', 'GSK3', inhibition]), verbo([participates]), complemento([in, the, regulation, of, 'FGF23', 'release,', 1, ',', 25, '(', 'OH)2D3', 'formation,', and, thus, mineral, 'metabolism,', by, controlling, the, activity, of, the, sympathetic, nervous, system])].
[sujeto(['To', observe, the, effects, of, calcium, hydroxide, 'Ca(OH)₂and', 'Hoshino\'s', 'paste(a', mixture, of, 'metronidazole,', 'ciprofloxacin,', and, 'minocycline)', on, the, proliferation, of, porcine, dental, papilla, cells, '(', 'pDPCs),', and, to]), verbo([provide]), complemento([some, theoretical, basis, for, the, choice, of, root, canal, disinfection, drugs, for, pulp, revascularization, treatment])].
[sujeto(['Meanwhile,', cell, proliferation, was]), verbo([inhibited]), complemento([by, 'Hoshino\'s', paste])].
[sujeto(['Each', concentration, of, 'Ca(OH)₂in', the, study]), verbo([has]), complemento([no, effect, on, pDPCs, 'proliferation,', while, 'Hoshino\'s', paste, can, inhibit, cell, proliferation])].
[sujeto(['Although', the, actin, cytoskeleton, is, vital, for, carcinogenesis, and, subsequent, 'pathology,', no, 'microfilament-directed', agent]), verbo([has]), complemento([been, approved, for, cancer, chemotherapy])].
[sujeto(['One', of, the, most, studied, classes, of, 'microfilament-directed', agents]), verbo([has]), complemento([been, the, 'cytochalasins,', mycotoxins, known, to, disrupt, the, formation, of, actin, polymers])].
[sujeto(['In', 'addition,', 'verapamil,', a, calcium, ion, channel, blocker, known, to, reverse, 'P-glycoprotein', '(', 'P-gp)']), verbo([mediated]), complemento([drug, 'resistance,', was, used, in, combination, with, multiple, cytochalasin, congeners, to, determine, whether, drug, sensitivity, could, be, increased])].
[sujeto(['While', multidrug, resistant, 'SKVLB1', had]), verbo([increased]), complemento([drug, tolerance, '(', was, more, 'resistant)', to, most, cytochalasin, congeners, in, comparison, to, drug, sensitive, 'SKOV3,', the, level, of, resistance, was, 10, to, 1000, -, fold, less, for, the, cytochalasins, than, for, any, of, the, clinically, approved, agents])].
[sujeto(['While', cytochalasins, did, not, appear, to, alter, the, expression, of, 'ATP']), verbo([binding]), complemento([cassette, '(', 'ABC)', 'transporters,', several, cytochalasins, appeared, to, inhibit, the, activity, of, 'ABC', 'transporter-mediated', efflux, of, rhodamine, 123, '(', 'Rh123),', suggesting, that, these, congeners, do, have, affinity, for, drug, efflux, pumps])].
[sujeto(['Cytochalasins', also, appeared, to, significantly]), verbo([decrease]), complemento([the, 'F/G-actin', ratio, in, both, drug, sensitive, and, drug, resistant, 'cells,', indicative, of, marked, microfilament, inhibition])].
[sujeto(['The', cytotoxicity, of, most, cytochalasin, congeners, could, be]), verbo([increased]), complemento([with, the, addition, of, 'verapamil,', and, the, drug, sensitivity, of, resistant, 'SKVLB1', to, the, clinically, approved, antineoplastic, agents, could, be, increased, with, the, addition, of, cytochalasins])].
[sujeto(['Cytochalasins', appear, to]), verbo([inhibit]), complemento([the, activity, of, 'P-gp', and, potentially, other, 'ABC', 'transporters,', and, may, have, novel, activity, against, multidrug, resistant, neoplastic, cells, that, overexpress, drug, efflux, proteins])].
[sujeto(['It']), verbo([has]), complemento([been, shown, that, the, regulatory, mechanisms, of, 'Ca(2+)', signaling, between, tumor, and, normal, cells, are, 'different,', providing, new, insight, into, the, pharmacological, modulation, of, anticancer, drugs])].
[sujeto(['The', results, showed, that, the, growth, 'inhibition,', necrosis, and, apoptosis, 'rates,', as, well, as, intracellular, 'Ca(2+)', concentrations, '(', '[', 'Ca(2+)]i)']), verbo([induced]), complemento([by, '[', 'Ca(2+)]e', in, 'HepG2', cells, were, higher, than, those, in, 'L02', cells])].
[sujeto(['Moreover,', '[', 'Ca(2+)]e', was, able, to, selectively]), verbo([enhance]), complemento(['ADM-induced', growth, 'inhibition,', apoptosis, and, necrosis, in, 'HepG2', 'cells,', but, not, in, 'L02', cells])].
[sujeto(['ADM', and, '[', 'Ca(2+)]a', 'co-treatment', had, a, significant, interaction, effect, to]), verbo([increase]), complemento(['[', 'Ca(2+)]i', in, both, cell, 'lines,', although, there, was, no, significant, difference, in, '[', 'Ca(2+)]i', between, the, two, cells])].
[sujeto(['To', further, elucidate, the, mechanisms]), verbo([involved]), complemento([in, the, selective, promotion, of, '[', 'Ca(2+)]e', in, 'HepG2', and, 'L02', 'cells,', the, levels, of, these, apoptosis, regulatory, proteins, '(', 'bcl-2,', bax, and, 'procaspase-3)', and, the, 'caspase-3', activity, following, treatment, of, 'HepG2', and, 'L02', cells, with, 'ADM', 'or/and', '[', 'Ca(2+)]a', were, investigated])].
[sujeto(['The', results, showed, that, treating, 'HepG2', cells, with, '[', 'Ca(2+)]a', and, 'ADM']), verbo([increased]), complemento([the, level, of, bax, protein, and, 'caspase-3', activity, while, decreasing, the, level, of, 'bcl-2', 'protein,', compared, with, treatment, with, 'ADM', alone])].
[sujeto(['These', results, indicate, that, hepatoma, 'HepG2', cells, are, more, sensitive, to, '[', 'Ca2+]e', than, normal, hepatic, 'L02', cells, and, that, '[', 'Ca(2+)]a', can, selectively]), verbo([enhance]), complemento(['ADM-induced', cell, death, in, 'HepG2', cells])].
[sujeto(['The', mechanism, of, this, intensive, 'pro-apoptotic', effect, can, be, ascribed, to, 'up-regulation', of, bax, and, the, simultaneous, 'down-regulation', of, 'bcl-2,', followed, by, the, switch, from, 'procaspase-3', to, 'caspase-3,', which]), verbo([executed]), complemento([apoptosis])].
[sujeto(['The', present, data]), verbo([suggest]), complemento([the, potency, of, the, calcium, ion, as, an, enhancer, of, 'ADM'])].
[sujeto(['Peptide-based', supramolecular, hydrogels]), verbo([have]), complemento([been, comprehensively, investigated, in, biomaterial, applications, because, of, their, unique, 'bioactivity,', 'biofunctionality,', and, biocompatible, features])].
[sujeto(['The', morphology, of, the, nanofibrous, network, constructions, and, the]), verbo([binding]), complemento([forces, exhibited, from, the, hydrogel, demonstrated, that, the, combination, of, two, mechanisms, successfully, enhanced, the, mechanical, stability, through, the, formation, of, a, densely, entangled, fibrous, network, of, peptide, multimers, that, is, attributed, to, the, 'AuNP', linkage, and, 'Ca(2+)-induced', agglomeration])].
[sujeto(['UV-vis', spectrophotometry, and, fluorescence, analysis, were, also, used, to, demonstrate, the]), verbo([enhanced]), complemento([stability, of, the, hydrogel, under, various, conditions, such, as, 'thermal,', solvent, 'erosion,', pH, value, and, sonication])].
[sujeto(['All', results, indicate, that, the, presence, of, 'AuNPs', and, 'Ca(2+)', can, strengthen, the, prepared, hydrogel, by, more, than, doubling, the, diameter, of, 'NapFFC', 'nanofibers,', enabling, the, formation, of, stronger, frameworks, and, slowing, the]), verbo([release]), complemento([of, components])].
[sujeto(['Herein', we]), verbo([report]), complemento([a, rapid, and, green, strategy, for, the, preparation, of, amorphous, calcium, phosphate, mesoporous, microspheres, '(', 'ACP-MSs)', using, adenosine, 5, '\'', -, diphosphate, disodium, salt, '(', 'ADP)', as, an, organic, phosphorus, source, by, a, 'microwave-assisted', hydrothermal, method])].
[sujeto(['Unfortunately,', the, cocktail, assay, had, to, be, split, because, of, interferences, during, incubation]), verbo([caused]), complemento([by, substrates, or, 'metabolites,', but, the, mixture, of, both, incubates, could, be, analyzed, in, one, analytical, run])].
[sujeto(['Qunidine,', trimethoprim, and, 'α-naphthoflavone', could, significantly]), verbo([inhibit]), complemento([the, disappearance, of, 'Imp;', meanwhile, 'ketoconazole,', sulfaphenazole, and, qunidine, could, inhibit, the, disappearance, of, 'Ost'])].
[sujeto(['CYP1A,', 'CYP2C', are]), verbo([involved]), complemento([in, the, metabolism, of, 'Imp', and, 'CYP3A', mediates, the, metabolism, of, 'Ost', in, rat, liver, microsomes])].
[sujeto(['In', human, liver, 'microsomes,', 'CYP1A2,', 'CYP2C8,', 'CYP2D6', are]), verbo([involved]), complemento([in, the, metabolism, of, 'Imp;', 'CYP3A4', is, involved, in, the, metabolism, of, 'Ost', at, all, the, tested, concentrations, of, 'Ost,', while, 'CYP2C9,', 'CYP2D6', mediate, the, metabolism, at, high, concentration, of, 'Ost'])].
[sujeto(['Cytochrome', 'P450', enzymes, '(', 'CYPs)', in, the, liver, metabolize, drugs, prior, to, 'excretion,', with, different, enzymes]), verbo([acting]), complemento([at, different, molecular, motifs])].
[sujeto(['We', investigated, which, enzymes, were]), verbo([involved]), complemento([using, human, liver, microsomes, and, 12, 'cDNA-expressed', human, 'CYPs'])].
[sujeto(['Both', ketoconazole, and, troleandomycin, '(', 'CYP3A', 'inhibitors)', almost, completely]), verbo([inhibited]), complemento([the, formation, of, 7, -, 'OH-', and, 6, -, 'OH-NBL'])].
[sujeto(['Similarly,', 'α-naphthoflavone', '(', 'CYP1A1', 'inhibitor)', and, furafylline, '(', 'CYP1A2', 'inhibitor)', significantly]), verbo([decreased]), complemento([the, formation, of, 4, '\'', -, 'OH-NBL'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'CYP1A2', and, 'CYP3A4', are, the, key, enzymes, in, human, liver, mediating, the, oxidative, demethylation, of, 'NBL', in, the, 'B-ring', and, 'A-ring,', respectively])].
[sujeto(['Identification', of, cytochrome, 'P450', isoforms, '(', 'CYPs)']), verbo([involved]), complemento([in, flourofenidone, '(', 5, -, 'methyl-1-(3-fluorophenyl)-2-[1H]-pyridone,', 'AKF-PD)', 5, -, methylhydroxylation, was, carried, out, using, human, liver, microsomes, and, 'cDNA-expressed', human, 'CYPs', '(', 'supersomes)'])].
[sujeto(['The', production, of, 'AKF-PD', 5, -, methylhydroxylation, metabolite, was, completely]), verbo([inhibited]), complemento([by, 'a-naphthoflavone', '(', a, 'CYP1A2', 'inhibitor)', with, the, 'IC50', value, of, 0.12, μM, in, human, liver, microsomes])].
[sujeto(['Potential', 'drug-drug', interactions]), verbo([involving]), complemento(['CYP1A2', may, be, noticed, when, 'AKF-PD', is, used, combined, with, 'CYP1A2', inducers, or, inhibitors])].
[sujeto(['The', following, human, 'CYP', inhibitors]), verbo([caused]), complemento([little, or, no, inhibition, of, 'CYP2A', as, defined, by, a, 'K(i)', &, 'gt;', 200, 'μm:', quinidine, '(', 'CYP2D6),', troleandomycin, '(', 'CYP3A4),', and, sulfaphenazole, '(', 'CYP2C9)'])].
[sujeto(['In', the, absence, of, a, preincubation, 'period,', 8, -, 'MOP']), verbo([inhibited]), complemento([the, 7, -, hydroxylation, of, coumarin, with, a, 'K(i)', value, of, 1.1, 'μm,', which, decreased, to, 0.1, μm, when, 8, -, 'MOP', was, preincubated, with, pig, liver, microsomes, for, 3, min])].
[sujeto(['α-Naphthoflavone']), verbo([inhibited]), complemento([the, 7, -, hydroxylation, of, coumarin, with, a, 'K(i)', value, of, 32, 'μm,', which, did, not, increase, ability, to, inhibitor, 'CYP2A', when, 'α-naphthoflavone', was, preincubated, with, pig, liver, microsomes, for, 3, min])].
[sujeto(['These', results, of, this, study]), verbo([suggest]), complemento([that, 8, -, 'MOP', is, a, 'potent,', 'mechanism-based', inhibitor, of, pig, 'CYP2A', activity, in, pig, liver, microsomes])].
[sujeto(['The', results, of, the, inhibition, and, correlation, studies, strongly]), verbo([suggest]), complemento([that, the, turkey, 'CYP2A6', ortholog, 'and,', to, a, lesser, 'extent,', the, 'CYP1A1', 'ortholog,', are, involved, in, the, bioactivation, of, aflatoxin, 'B1', in, turkey, liver, microsomes])].
[sujeto(['This', is, the, first, study]), verbo([reporting]), complemento([the, role, of, 'CYP2A6', in, the, bioactivation, of, 'AFB1', in, an, avian, species, and, the, role, of, 'CYP1A1', in, any, species])].
[sujeto(['Incubation', of, 'PAP-1', with, 'SD', rat, liver, microsomes, rendered, the, same, five, major, metabolites, in, a, nicotinamide, adenine, dinucleotide, phosphate, '(', 'NADPH)-dependent', manner]), verbo([suggesting]), complemento([that, cytochrome, 'P450', '(', 'CYP)', enzymes, are, involved, in, 'PAP-1', metabolism])].
[sujeto(['Of', the, five, metabolites, 'M3,', 'M4,', and, 'M5', were]), verbo([found]), complemento([to, inhibit, 'Kv1'])].
[sujeto([3, -, inactive, 'M1', as, the, major, phase, 'I', 'metabolite,', and]), verbo([suggest]), complemento([that, hydroxylation, and, 'O-dealkylation', are, the, major, pathways, of, 'PAP-1', metabolism])].
[sujeto(['In', 'conclusion,', the, results, from, this, study, indicate, that, 'HepaRG', cells, could]), verbo([provide]), complemento([a, suitable, alternative, to, pHH, in, pharmaceutical, research, and, development, for, metabolism, studies, such, as, 'CYP', induction, or, 'sub-chronic', to, chronic, hepatotoxicity, studies])].
[sujeto(['Metabolism', plays, an, important, role, in, the, toxic, effects]), verbo([caused]), complemento([by, 3, ',', 4, -, methylenedioxymethamphetamine, '(', 'MDMA)'])].
[sujeto(['Most', research]), verbo([has]), complemento([focused, on, the, involvement, of, 'CYP2D6', enzyme, in, 'MDMA', 'bioactivation,', and, less, is, known, about, the, contribution, of, other, cytochrome, 'P450', '(', 'P450)', and, phase, 'II', metabolism])].
[sujeto(['MDMA']), verbo([acts]), complemento([as, inhibitor, of, its, own, metabolism, with, a, relative, potency, of, inhibition, of, 'CYP2D>CYP3A>', 'CYP1A', in, rat, liver, microsomes, and, in, human, liver, '[', immortalized, human, liver, epithelial, cells, '(', 'THLE)]', cells, transfected, with, individual, 'CYP1A2,', 'CYP3A4,', or, 'CYP2D6'])].
[sujeto(['MDMA', metabolism, by, 'CYP2D6', significantly]), verbo([increased]), complemento(['cytotoxicity,', which, was, counteracted, by, 'CYP2D6', inhibition, by, quinidine])].
[sujeto(['Inhibition', of, 'COMT', by, 2, '\'', -, 'fluoro-3,4-dihydroxy-5-nitrobenzophenone', '(', 'Ro-41-0960)', and, 'GST', by, buthionine, sulfoximine, showed, that, 'COMT', is, mainly]), verbo([involved]), complemento([in, detoxification, of, 'CYP2D6-formed', 'MDMA', 'metabolites,', whereas, glutathione, '(', 'GSH)', is, mainly, involved, in, detoxification, of, 'CYP3A4-formed', 'MDMA', metabolites])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, 'CYP2D6', as, well, as, 'CYP3A4', play, an, important, role, in, 'MDMA', bioactivation])].
[sujeto(['Recent', guidance, from, the, 'US', 'Food', and, 'Drug', 'Administration', '(', 'USFDA)']), verbo([has]), complemento([advocated, testing, of, 'time-dependent', inhibition, of, cytochrome, 'P450', '(', 'CYP),', which, can, be, addressed, by, performing, 'IC(50)', shift, as, well, as, 'K(I)/k(inact)', determinations])].
[sujeto(['For', rapid]), verbo([acting]), complemento(['inhibitors,', such, as, 'azamulin/CYP3A4', and, tienilic, 'acid/CYP2C9,', the, 'IC(50)', shifts, were, similar, at, both, time, points, suggesting, a, short, maximum, 'pre-incubation', time, with, closely, spaced, time, points, for, the, 'K(I)/k(inact)', assay])].
[sujeto(['Slow']), verbo([acting]), complemento([inhibitors, '(', such, as, 'verapamil/CYP3A4', or, 'S-fluoxetine/CYP2C19)', showed, an, increase, in, 'IC(50)', shift, between, 10, and, 30, min, suggesting, a, longer, maximum, 'pre-incubation', time, with, wider, spacing, of, time, points, for, 'K(I)/k(inact)'])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, that, the, metabolism, of, 'S-carvedilol', in, 'beta-naphthoflavone', '(', 'beta-NF)-treated', 'Caco-2', cells, is, faster, than, that, of, 'R-carvedilol'])].
[sujeto(['The', expression, of, cytochrome, 'P450', '(', 'CYP)', 1, 'A1', and, 'CYP1A2', 'mRNA,', but, not, 'CYP2D6,', 'CYP3A4,', and, 'CYP2C9', 'mRNA,', was]), verbo([increased]), complemento([in, 'beta-NF-treated', 'Caco-2', 'cells,', as, compared, with, 'non-treated', cells])].
[sujeto(['Furafylline,', an, inhibitor, of, the, 'CYP1A', 'subfamily,']), verbo([decreased]), complemento([the, metabolism, of, 'S-carvedilol', in, 'Caco-2', cells, cultured, on, plastic, dishes])].
[sujeto(['On', the, other, 'hand,', the, oxidation, of, 'S-carvedilol', in, microsomes, of, 'beta-NF-treated', 'Caco-2', cells, was, faster, than, that, of, 'R-carvedilol,', and, furafylline]), verbo([decreased]), complemento([the, oxidative, activity, of, 'S-carvedilol'])].
[sujeto(['These', findings]), verbo([suggested]), complemento([that, the, 'CYP1A', subfamily, was, responsible, for, the, stereoselective, metabolism, of, carvedilol, in, 'beta-NF-treated', 'Caco-2', cells])].
[sujeto(['One', hydroxyl, metabolite, of, ginkgolide, 'B', were, identified, in, rat, liver, 'microsomes,', and, quinidine, uncompetitively]), verbo([inhibited]), complemento([the, formation, of, the, 'metabolite;', its, inhibitor, constant, '(', 'Ki)', value, for, the, inhibition, of, hydroxyl, metabolite, was, estimated, to, be, 8, 'micromol/L,', while, 'alpha-naphthoflavone,', 'ketoconazole,', 'sulfaphenazole,', and, diethyldithiocarbamate, had, no, inhibitory, effects])].
[sujeto(['In', experiments, with, 'HLM', from, 'CYP2D6', and, 'CYP2C19', poor, 'metabolizers,', 'HO-MPBP', formation, was]), verbo([found]), complemento([to, be, 78, and, 79, '%', lower, in, comparison, with, pooled, 'HLM,', respectively])].
[sujeto(['From', these, 'data,', it, can, be, concluded, that, polymorphically]), verbo([expressed]), complemento(['CYP2D6', is, mainly, responsible, for, 'MPBP', hydroxylation])].
[sujeto(['The', 'IC50s', '(', micromol, x, 'L(-1))', were, in, good, agreement, with, those, obtained, with, individual, substrates, '(', 'alpha-naphthoflavone,', 0.18, vs, 0.26, ;, 'quinidine,', 0.058, 5, vs, 0.058, 4, ;, 'sulfaphenazole,', 0.48, vs, 0.45, ;, 'fluconazol,', 17.5, vs, 11.4, ;, 'ketoconazole,', 0.22, vs, 0.24, ')', and, with, previously]), verbo([reported]), complemento([values, in, the, literature])].
[sujeto(['The', formation, of, 3, -, hydroxypilocarpine, in, human, liver, microsomes, was, strongly]), verbo([inhibited]), complemento(['(', &, 'gt;90%)', by, 200, microM, coumarin])].
[sujeto(['The', highest, formation, activity, was]), verbo([expressed]), complemento([by, recombinant, 'CYP2A6'])].
[sujeto(['To', identify, the, major, human, cytochrome, 'P450', '(', 'P450)']), verbo([participating]), complemento([in, rutaecarpine, oxidative, 'metabolism,', human, liver, microsomes, and, 'bacteria-expressed', recombinant, human, 'P450', were, studied])].
[sujeto(['Microsomal', 10, -, and, 3, -, hydroxylation, activities, were, strongly]), verbo([inhibited]), complemento([by, ketoconazole])].
[sujeto(['The', 11, -, and, 12, -, hydroxylation, activities, were]), verbo([inhibited]), complemento([by, 'alpha-naphthoflavone,', 'quinidine,', and, ketoconazole])].
[sujeto(['These', results, indicated, that, multiple, hepatic, 'P450s', including, 'CYP1A2,', 'CYP2D6,', and, 'CYP3A4']), verbo([participate]), complemento([in, rutaecarpine, hydroxylations])].
[sujeto(['The', major, metabolite, 10, -, hydroxyrutaecarpine]), verbo([decreased]), complemento(['CYP1A1,', 'CYP1A2,', and, 'CYP1B1', activities, with, respective, 'IC(50)', values, of, 2.56, +, /, -, 0.04, ',', 2.57, +, /, -, 0.11, ',', and, 0.09, +, /, -, 0.01, 'microM,', suggesting, that, product, inhibition, might, occur, during, rutaecarpine, hydroxylation])].
[sujeto(['The', metabolite, profile, and, kinetic, properties, of, rutaecarpine, hydroxylation, by, human, 'P450s']), verbo([provide]), complemento([important, information, relevant, to, the, clinical, application, of, rutaecarpine, and, 'E'])].
[sujeto(['Identification', of, cytochrome, 'P-450', isoenzymes, '(', 'CYPs)']), verbo([involved]), complemento([in, perazine, 5, -, sulphoxidation, and, 'N-demethylation', was, carried, out, using, human, liver, microsomes, and, 'cDNA-expressed', human, 'CYPs', '(', 'Supersomes)'])].
[sujeto(['alpha-Naphthoflavone', '(', a, 'CYP1A2', 'inhibitor)', and, ketoconazole, '(', a, 'CYP3A4', 'inhibitor)', significantly]), verbo([decreased]), complemento([the, rate, of, perazine, 5, -, 'sulphoxidation,', while, ticlopidine, '(', a, 'CYP2C19', 'inhibitor)', strongly, reduced, the, rate, of, perazine, 'N-demethylation', in, human, liver, microsomes])].
[sujeto(['Ethoxyresorufin', 'O-deethylase', activity, in, deer, was, markedly]), verbo([inhibited]), complemento([by, 'alpha-naphthoflavone,', but, was, relatively, resistant, to, inhibition, by, furafylline])].
[sujeto(['Coumarin', 7, -, hydroxylase, was]), verbo([inhibited]), complemento([by, 8, -, methoxypsoralen])].
[sujeto(['Western', blot, analysis, using, antibodies, to, rat, 'CYP1A', recognised, a, 'single,', highly]), verbo([expressed]), complemento([protein])].
[sujeto(['In', 'contrast,', when, antibodies, to, rat, 'CYP2E1', were, 'used,', a, highly]), verbo([expressed]), complemento([single, protein, was, observed])].
[sujeto(['In', 'summary,', this, is, the, first, study, showing, that, deer, liver]), verbo([expresses]), complemento([all, 'xenobiotic-metabolising', cytochrome, 'P450', 'families,', but, the, level, of, expression, differs, from, that, of, the, rat])].
[sujeto(['The', results, show, that, 'CYP1A2', activity, was, markedly]), verbo([induced]), complemento([by, 'beta-naphthoflavone', '(', on, average, 13, -, 'fold,', n, =, 28, 'preparations),', and, weakly, induced, by, phenobarbital, '(', 1.9, -, 'fold,', n, =, 25, ')', and, rifampin, '(', 2.3, -, 'fold,', n, =, 22, ')', ;, 'CYP2A6', activity, tended, to, be, increased, with, phenobarbital, '(', n, =, 7, ')', and, rifampin, '(', n, =, 3, ')', 'treatments,', but, the, effects, were, not, statistically, 'significant;', 'CYP2B6', was, induced, by, phenobarbital, '(', 6.5, -, 'fold,', n, =, 13, ')', and, rifampin, '(', 13, -, 'fold,', n, =, 14, ')', ;, 'CYP2C8', was, induced, by, phenobarbital, '(', 4.0, -, 'fold,', n, =, 4, ')', and, rifampin, '(', 5.2, -, 'fold,', n, =, 4, ')', ;, 'CYP2C9', was, induced, by, phenobarbital, '(', 1.8, -, 'fold,', n, =, 14, ')', and, rifampin, '(', 3.5, -, 'fold,', n, =, 10, ')', ;, 'CYP2C19', was, markedly, induced, by, rifampin, '(', 37, -, 'fold,', n, =, 10, ')', ',', but, relatively, modestly, by, phenobarbital, '(', 7, -, 'fold,', n, =, 9, ')', ;, 'CYP2D6', was, not, significantly, induced, by, phenobarbital, '(', n, =, 5, ')', or, rifampin, '(', n, =, 5, ')', ;, 'CYP2E1', was, induced, by, phenobarbital, '(', 1.7, -, 'fold,', n, =, 5, ')', ',', rifampin, '(', 2.2, -, 'fold,', n, =, 5, ')', ',', and, isoniazid, '(', 2.3, -, 'fold,', n, =, 5, ')', ;, 'and,', 'CYP3A4', was, induced, by, phenobarbital, '(', 3.3, -, 'fold,', n, =, 42, ')', and, rifampin, '(', 10, -, 'fold,', n, =, 61, ')', ',', but, not, by, 'beta-naphthoflavone'])].
[sujeto(['Based', on, these, 'observations,', we, generalize, that, 'beta-naphthoflavone']), verbo([induces]), complemento(['CYP1A2', and, isoniazid, induces, 'CYP2E1,', whereas, rifampin, 'and,', to, a, lesser, extent, 'phenobarbital,', tend, to, significantly, and, consistently, induce, enzymes, of, the, 'CYP2A,', 'CYP2B,', 'CYP2C,', 'CYP2E,', and, 'CYP3A', subfamilies, but, not, the, 2, 'D', subfamily])].
[sujeto(['Treatment', with, 'BNF', significantly]), verbo([induced]), complemento([mean, levels, of, 'CYP1A2', apoprotein, to, 160, '%', of, levels, in, 72, -, h, control, '(', no, test, 'compound)', human, liver, slice, microsomes])].
[sujeto(['NaPB', significantly]), verbo([induced]), complemento([levels, of, 'CYP3A4', apoprotein, to, 255, '%', of, control, and, 'RIF', significantly, induced, levels, of, 'CYP2C19', and, 'CYP3A4', apoproteins, to, 265, and, 330, '%', of, 'control,', respectively])].
[sujeto(['In', 'addition,', treatment, with, 'RIF']), verbo([increased]), complemento([levels, of, 'CYP2A6', apoprotein, to, 205, '%', of, 'control,', and, treatment, with, both, 'NaPB', and, 'RIF', increased, levels, of, 'CYP2B6', apoprotein, to, 370, and, 615, '%', of, 'control,', respectively])].
[sujeto(['However,', these]), verbo([increases]), complemento([were, not, statistically, 'significant,', owing, to, a, variable, response, between, liver, slice, preparations, from, different, 'subjects,', this, being, apparent, for, all, inducible, 'P450s'])].
[sujeto(['In', 'contrast,', none, of, the, compounds, examined, significantly]), verbo([increased]), complemento([levels, of, 'CYP2C8,', 'CYP2C9,', 'CYP2D6,', 'CYP2E1,', and, 'CYP4A11', apoproteins])].
[sujeto(['The', aryl, hydrocarbon, receptor, '(', 'AHR)', is, a, 'ligand-activated', transcription, factor, that]), verbo([mediates]), complemento([the, toxicity, of, 'dioxins,', but, also, plays, important, physiological, 'roles,', which, are, only, beginning, to, unfold])].
[sujeto(['Previous', studies]), verbo([have]), complemento([surprisingly, unveiled, that, low, doses, of, the, potent, 'AHR', agonist, 'TCDD', induce, a, strong, and, persistent, avoidance, of, novel, food, items, in, rats])].
[sujeto(['Here,', we, further, examined, the, involvement, of, the, 'AHR', in, the, avoidance, response, in, 'Sprague-Dawley', rats, with, three, established, 'AHR', 'agonists:', 6, -, 'formylindolo(3,2-b)carbazole', '(', 'FICZ),', 'β-naphthoflavone', '(', 'BNF)', and, 'benzo[a]pyrene', '(', 'BaP);', with, a, novel, selective, 'AHR', modulator, '(', 'C2);', and, with, an, activator, of, another]), verbo([nuclear]), complemento(['receptor,', 'CAR:', 2, ',', 4, ',', 6, -, 'tryphenyldioxane-1,3', '(', 'TPD)'])].
[sujeto(['As', sensitive, indices, of, 'AHR', or, 'CAR', 'activity,', we, used, 'Cyp1a1', and, 'Cyp2b1', gene, 'expression,', as, they, 'are,', 'respectively,', the, 'drug-metabolizing', enzymes, specifically]), verbo([regulated]), complemento([by, them])].
[sujeto(['We', further, attempted, to, address, the, roles, played, by]), verbo([enhanced]), complemento([neophobia, and, conditioned, taste, aversion, '(', 'CTA)', in, the, avoidance, behaviour])].
[sujeto(['All', 'AHR', agonists]), verbo([triggered]), complemento([practically, total, avoidance, of, novel, 'chocolate,', but, the, durations, varied])].
[sujeto(['Hence,', the, avoidance, response, appears, to, specifically]), verbo([involve]), complemento([the, 'AHR', instead, of, being, triggered, by, induction, of, intestinal, or, hepatic, nuclear, receptor, signalling, in, general])].
[sujeto(['Moreover,', this, behavioural, change, in, rats, seems, to, contain, elements, of, both, 'CTA', and]), verbo([enhanced]), complemento(['neophobia,', but, further, clarification, of, this, is, still, required])].
[sujeto(['Endosulfan']), verbo([induced]), complemento(['time-dependent', reduction, in, the, 'HK', somatic, index, and, 'histo-pathological', changes, in, renal, and, hemopoietic, components, of, the, organ])].
[sujeto(['At', cellular, 'level,', exposure, to, endosulfan]), verbo([led]), complemento([to, death, of, 'HK', leucocytes])].
[sujeto(['We']), verbo([report]), complemento([that, 'β-endosulfan', accumulates, more, readily, in, the, 'HK'])].
[sujeto(['Depuration', studies]), verbo([suggested]), complemento([the, persistence, of, 'ESS', in, the, 'HK'])].
[sujeto(['Pre-treatment', of, 'HKL', with, 'CYP1A', specific, inhibitor, 'α-Naphthoflavone', '(', 'ANF)']), verbo([led]), complemento([to, reduction, in, 'CYP1A', 'mRNA,', protein, 'levels,', and, inhibited, 'ESS', formation, together, implicating, the, role, of, 'CYP1A', on, endosulfan, metabolism])].
[sujeto(['Collectively,', our, findings]), verbo([suggest]), complemento([that, 'HK', plays, an, important, role, in, endosulfan, metabolism])].
[sujeto(['We', propose, that, endosulfan]), verbo([induces]), complemento([the, activation, of, 'CYP1A', in, 'HK', which, led, to, the, generation, of, persistent, 'metabolite,', 'ESS,', resulting, in, immunotoxicity])].
[sujeto(['The', activities, of, 'ethoxyresorufin-O-deethylation', '(', 'EROD)', and, 'erythromycin-N-demethylation', '(', 'ERND)']), verbo([increased]), complemento([significantly, '(', 'P<0'])].
[sujeto(['However,', in, further, experiments, on, the, formation, of, 'CF,', the, level, of, 'EF', 'N-deethylation', was, significantly]), verbo([induced]), complemento([by, 'RIF', and, inhibited, by, ketoconazole, '(', 'KTZ)', for, 'CYP3A', but, had, no, influence, for, 'CYP1A,', 'BNF', and, berberine, chloride, '(', 'BER)'])].
[sujeto(['The', aryl, hydrocarbon, receptor, '(', 'AhR)', is, a, ligand]), verbo([activated]), complemento([transcriptional, 'regulator,', which, governs, key, biological, processes, including, detoxification, of, carcinogens])].
[sujeto(['Thus,', 'β-NF', can]), verbo([induce]), complemento([the, representative, detoxifying, enzyme, cytochrome, 'P4501A1,', thereby, enhancing, the, detoxification, potential])].
[sujeto(['We']), verbo([found]), complemento([that, supramolecular, complexation, of, 'β-NF', with, the, synthetic, 6, ',', 6, '\'', -, 'thiobis(methylene)-β-cyclodextrin', '(', 'β-CD-S)', dimer, significantly, enhanced, 'β-NF\'s', role, as, an, 'AhR', agonist])].
[sujeto(['The', water, solubility, of, 'β-NF', was]), verbo([increased]), complemento([to, 469, fold, by, effective, supramolecular, complexation, with, the, 'β-CD-S', 'dimer,', and, caused, significant, induction, of, cytochrome, 'P4501A1'])].
[sujeto(['In', 'summary,', supramolecular, complexation, of, 'β-NF', with, 'β-CD-S', dimer, greatly]), verbo([enhanced]), complemento(['bio-availability', of, 'β-NF', as, an, 'AhR', agonist])].
[sujeto(['Our', findings]), verbo([provide]), complemento([an, 'easy,', 'non-destructive,', and, alternative, approach, to, enhance, the, 'bio-availability', of, therapeutics])].
[sujeto(['At', week, 4, ',', 'BNF', and, 'LMG']), verbo([increased]), complemento([cell, proliferation, together, with, 'hepatotoxicity,', while, 'CRB', did, not])].
[sujeto(['Additionally,', 'BNF', and, 'CRB', reduced, the, number, of, cells]), verbo([expressing]), complemento(['phosphorylated-histone', 'H3', in, both, ubiquitin, 'D', '(', 'UBD)(+)', cells, and, 'Ki-67(+)', proliferating, 'cells,', suggesting, development, of, spindle, checkpoint, 'dysfunction,', regardless, of, cell, proliferation, activity])].
[sujeto(['At', week, 6, ',', examined, 'hepatocarcinogens/tumor', promoters]), verbo([increased]), complemento([preneoplastic, hepatic, foci, expressing, glutathione, 'S-transferase', placental, form])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, some, 'hepatocarcinogens/tumor', promoters, increase, their, toxicity, after, 'post-initiation', 'treatment,', causing, regenerative, cell, proliferation])].
[sujeto(['This']), verbo([suggests]), complemento([that, facilitation, of, cell, proliferation, and, disruption, of, spindle, checkpoint, function, are, induced, by, different, mechanisms, during, hepatocarcinogenesis])].
[sujeto(['Four', weeks, of, 'post-initiation', treatment, may, be, sufficient, to]), verbo([induce]), complemento(['hepatocarcinogen/tumor', 'promoter-specific', cellular, responses])].
[sujeto(['Molecular', docking, study, was, performed, to, further, explore, the]), verbo([binding]), complemento([site, of, 'FKA', on, 'CYP450', isoforms])].
[sujeto(['The', chemical, inhibition, experiments, showed, that, the, metabolic, clearance, rate, of, 'Flavokawain', 'A']), verbo([decreased]), complemento([to, 19.84, '%', ',', 50.38, '%', ',', and, 67.02, '%', of, the, control, in, the, presence, of, 'ketoconazole,', sulfamethoxazde, and, 'a-naphthoflavone'])].
[sujeto(['The', study, showed, that, 'Flavokawain', 'A']), verbo([has]), complemento([varying, inhibitory, effect, on, 'CYP450', enzymes, and, 'CYP3A2', was, the, principal, 'CYP', isoform, contributing, to, the, metabolism, of, 'Flavokawain', 'A'])].
[sujeto(['Our', results]), verbo([provided]), complemento([a, basis, for, better, understanding, the, biotransformation, of, 'FKA', and, prediction, of, 'drug-drug', interaction, of, 'FKA'])].
[sujeto(['CYP1B1', is, a, promising, drug]), verbo([target]), complemento([for, developing, novel, drugs, against, hormonal, cancers, and, hypertension])].
[sujeto(['We']), verbo([have]), complemento([developed, a, novel, in, silico, approach, for, design, of, selective, 'CYP1B1', inhibitors])].
[sujeto(['The']), verbo([binding]), complemento([free, energies, and, 'HB', percentage, occupancy, calculations, of, 94, compounds, of, cluster, 1, have, verified, the, docking, results, using, 'MD'])].
[sujeto(['The', final, filtered]), verbo([lead]), complemento([candidates, consist, of, compounds, sandwiched, between, phenylalanine, 'π-π', stacking, and, less, than, 6, &, 'nbsp;Å', from, heme, '(', 'Fe)', for, enzymatic, action])].
[sujeto(['Germline', competent, 'PGCs', can, be, developed, as, a, 'cell-based', system, for, genetic, modification, in, 'chickens,', which]), verbo([provides]), complemento([a, valuable, tool, for, transgenic, technology, with, both, research, and, industrial, applications])].
[sujeto(['The', aryl, hydrocarbon, receptor, '(', 'AHR)', is, a, 'ligand-activated', transcription, factor, that, besides]), verbo([mediating]), complemento([toxic, responses, to, environmental, contaminants, plays, pivotal, physiological, roles, in, various, biological, processes])].
[sujeto(['Since', a, novel, compound, that]), verbo([acts]), complemento([as, an, antagonist, of, this, receptor, has, been, reported, to, promote, expansion, of, hematopoietic, stem, 'cells,', we, conducted, the, present, study, with, the, aim, of, determining, whether, addition, of, an, established, 'AHR', antagonist, to, the, standard, culture, medium, used, nowadays, for, in, vitro, chicken, 'PGCs', culture, improves, ex, vivo, expansion])].
[sujeto(['We']), verbo([have]), complemento([found, that, addition, of, 'α-naphthoflavone', in, culture, medium, promotes, the, amplification, of, undifferentiated, cells, and, that, this, effect, is, exerted, by, the, blockade, of, 'AHR', action])].
[sujeto(['Our', results, constitute, the, first]), verbo([report]), complemento([of, the, successful, use, of, a, readily, available, 'AHR', antagonist, to, improve, avian, 'PGCs', 'expansion,', and, they, further, extend, the, knowledge, of, the, effects, of, 'AHR', modulation, in, undifferentiated, cells])].
[sujeto(['High', affinity, aryl, hydrocarbon, receptor, '(', 'AHR)', 'ligands,', such, as, certain, polychlorinated, biphenyls, and, 2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD),']), verbo([cause]), complemento([severe, cardiac, teratogenesis, in, fish, embryos])].
[sujeto(['Moderately', strong, 'AHR', 'agonists,', for, example, 'benzo[a]pyrene', and, 'β-naphthoflavone,', are, capable, of]), verbo([causing]), complemento([similar, cardiotoxic, 'effects,', particularly, when, coupled, with, cytochrome, 'P450', 1, 'A', '(', 'CYP1A)', inhibitors, '(', e])].
[sujeto(['Additionally,', some, weaker, 'AHR', agonists, '(', 'carbaryl,', 2, -, 'methylindole,', 3, -, 'methylindole,', and, 'phenanthrene)', are, known, to, also]), verbo([cause]), complemento([cardiotoxicity, in, zebrafish, '(', 'Danio', 'rerio)', embryos, when, coupled, with, 'FL;', 'however,', the, cardiotoxic, effects, were, not, mediated, specifically, by, 'AHR', stimulation])].
[sujeto(['This', study, was, performed, to, determine, if, binary, exposure, to, weak, 'AHR', agonists, and, 'FL', were, also, capable, of]), verbo([causing]), complemento([cardiotoxicity, in, 'Atlantic', killifish, 'Fundulus', heteroclitus, embryos])].
[sujeto(['Carbaryl,', 'indigo,', and, indirubin]), verbo([induced]), complemento([the, highest, 'CYP1', activity, levels, in, naïve, killifish, 'embryos,', but, no, significant, 'CYP1', induction, was, observed, in, the, 'PAH-adapted', killifish])].
[sujeto(['Embryos', were, coexposed, to, subteratogenic, levels, of, each, agonist, and, 500, 'μg/L', 'FL', to, assess, if, binary, administration, could]), verbo([cause]), complemento([cardiotoxicity])].
[sujeto(['Indigo', and, indirubin, coupled, with, 'FL']), verbo([caused]), complemento([cardiac, teratogenesis, in, naïve, 'killifish,', but, coexposures, did, not, produce, cardiac, chamber, abnormalities, in, the, 'PAH-adapted', population])].
[sujeto(['Knockdown', of, 'AHR2', in, naïve, killifish, embryos, did, not]), verbo([prevent]), complemento([cardiac, teratogenesis])].
[sujeto(['The', data]), verbo([suggest]), complemento([a, unique, mechanism, of, cardiotoxicity, that, is, not, driven, by, 'AHR2', activation])].
[sujeto(['In', the, present, 'study,', we, investigated, the, effect, of, 3, -, methylcholanthrene, '(', 3, 'MC)', on, sexual, maturity, and, the, ability, of, 'α-naphthoflavone', '(', 'αNF)', to]), verbo([prevent]), complemento([this, action])].
[sujeto(['No', differences, were]), verbo([found]), complemento([in, body, 'weight,', ovarian, 'weight,', day, of, vaginal, 'opening,', or, the, establishment, of, the, estrous, cycle, among, the, different, groups, of, rats])].
[sujeto(['Also,', 3, 'MC']), verbo([inhibited]), complemento([the, ovulation, rate, and, induced, an, overexpression, of, both, the, 'Cyp1a1', and, 'Cyp1b1', 'genes,', measured, by, chromatin, immunoprecipitation, assay])].
[sujeto(['The', daily, treatment, with, αNF, alone]), verbo([increased]), complemento([the, number, of, follicles, in, most, of, the, stages, analyzed, when, compared, with, controls])].
[sujeto(['Moreover,', the, αNF, treatment]), verbo([prevented]), complemento([completely, not, only, the, 3, 'MC-induced', decrease, in, all, types, of, follicles, but, also, the, 3, 'MC-induced', overexpression, of, 'Cyp', enzymes, and, the, genetic, damage, in, bone, marrow, cells, and, oocytes])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, '(', 'i)', daily, exposure, to, 3, 'MC', during, the, pubertal, period, destroys, the, follicle, reserve, and, alters, the, ovulation, 'rate;', '(', 'ii)', the, 3, 'MC', action, seems, to, be, mediated, by, an, aryl, hydrocarbon, 'receptor-dependent', 'mechanism;', '(', 'iii)', daily, administration, of, αNF, has, a, clear, stimulatory, action, on, the, ovarian, 'function;', and, '(', 'iv)', αNF, may, prevent, both, the, systemic, and, gonadal, 3, 'MC-induced', toxicity])].
[sujeto(['Dystrophin', 'Dp71,', the, smallest, product, encoded, by, the, 'Duchenne', muscular, dystrophy, 'gene,', is, ubiquitously]), verbo([expressed]), complemento([in, all, 'non-muscle', cells])].
[sujeto(['Although', 'Dp71', is]), verbo([involved]), complemento([in, various, cellular, 'processes,', the, mechanisms, underlying, its, expression, have, been, little, studied])].
[sujeto(['In', the, present, study, we, aimed, at, identifying, 'DNA', elements, and, transcription, factors]), verbo([involved]), complemento([in, 'Dp71', expression, in, hepatic, cells])].
[sujeto(['Using', 'EMSAs', and, 'ChIP,', we, showed, that, the, 'Sp1', '(', specificity, protein, 1, ')', ',', 'Sp3', '(', specificity, protein, 3, ')', and, 'YY1', '(', 'Yin', and, 'Yang', 1, ')', transcription, factors]), verbo([bind]), complemento([to, the, 'Dp71', promoter, region])].
[sujeto(['Knockdown', of, 'Sp1,', 'Sp3', and, 'YY1 in', hepatic, cells]), verbo([increased]), complemento([endogenous, 'Dp71', 'expression,', but, reduced, 'Dp71', promoter, activity])].
[sujeto(['Further,', higher, levels, of, the, more, potent, hepatotoxic, metabolite, desethylamiodarone, were, detected, in, 'CYP3A4', or, 'CYP1A1']), verbo([expressed]), complemento([cells])].
[sujeto(['The', 'CYP3A4', inhibitor, ketoconazole, and, the, 'CYP1A1', inhibitor, 'α-naphthoflavone', drastically]), verbo([inhibited]), complemento([the, metabolism, of, amiodarone, to, desethylamiodarone])].
[sujeto(['FICZ', is, a, proposed, physiological, 'AHR', ligand, that]), verbo([induces]), complemento([its, own, degradation, as, part, of, a, regulatory, negative, feedback, loop])].
[sujeto(['In', vitro, studies, in, cells, show, that, 'CYP1', inhibition, in, the, presence, of, 'FICZ', results, in]), verbo([enhanced]), complemento(['AHR', 'activation,', suggesting, that, 'FICZ', accumulates, in, the, cell, when, its, metabolism, is, blocked])].
[sujeto(['Embryos', were, injected, with, morpholino, antisense, oligonucleotides]), verbo([targeting]), complemento(['CYP1A', '(', 'CYP1A-MO),', 'Ahr2,', or, a, combination, of, both])].
[sujeto(['In', 'CYP1A-MO-injected', 'embryos,', 'however,', 'FICZ', dramatically]), verbo([increased]), complemento(['mortality,', incidence, and, severity, of, pericardial, edema, and, circulation, 'failure,', reduced, hatching, 'frequency,', blocked, swim, bladder, 'inflation,', and, strongly, potentiated, expression, of, 'Ahr2-regulated', genes])].
[sujeto(['These', effects, were, substantially, reduced, in, embryos, with, a, combined, knockdown, of, 'Ahr2', and, 'CYP1A,', indicating, that, the, toxicity, was]), verbo([mediated]), complemento([at, least, partly, by, 'Ahr2'])].
[sujeto(['HPLC', analysis, of, 'FICZ-exposed', embryos, showed]), verbo([increased]), complemento([levels, of, 'FICZ', after, concomitant, 'CYP1A-MO', injection, or, αNF, 'co-exposure'])].
[sujeto(['Together,', these, results, show, that, a, functioning, 'CYP1/AHR', feedback, loop, is, crucial, for, regulation, of, 'AHR', signaling, by, a, potential, physiological, ligand, in, vivo, and, further, highlights, the, role, of, 'CYP1', enzymes, in]), verbo([regulating]), complemento([biological, effects, of, 'FICZ'])].
[sujeto(['Here,', we, 're-optimized', the, substrate, cocktail, method, to]), verbo([increase]), complemento([the, reliability, and, accuracy, of, screening, for, candidate, compounds, and, expanded, the, method, from, a, direct, 'CYP', inhibition, assay, to, a, 'time-dependent', inhibition, '(', 'TDI)', assay])].
[sujeto(['The', inhibition, curve, profiles, and, 'IC50', values, of, 7, 'CYP', inhibitors, were, approximate, when, a, single, substrate, and, the, substrate, cocktail, were, 'tested,', and, were, consistent, with, the, previously]), verbo([reported]), complemento([values])].
[sujeto(['The', development, of, a, 'high-throughput', tool, is]), verbo([required]), complemento([for, screening, of, environmental, pollutants, and, assessing, their, impacts, on, aquatic, animals])].
[sujeto(['ECOD', activity, was]), verbo([inhibited]), complemento([in, planarians, exposed, to, 10, and, 100, μM, rifampicin, or, carbamazepine, for, 24, h])].
[sujeto(['The', objective, of, this, study, was, to, evaluate, how, 'β-naphthoflavone']), verbo([interacts]), complemento([with, lipopolysaccharide, '(', 'LPS)', and, polyinosinic, 'acid:', polycytidylic, acid, '(', poly, 'I:', 'C)', induced, innate, immune, parameters, as, well, as, phase, 'I', and, phase, 'II', detoxification, enzymes, in, head, kidney, cells, isolated, from, 'Atlantic', cod])].
[sujeto(['The', results, showed, that, 'β-naphthoflavone', '(', 25, &, 'nbsp;nM),', with, and, without, 'LPS,', significantly]), verbo([induced]), complemento([cytochrome, 'P450', '(', 'cyp1c)', transcription, in, cod, head, kidney, cells])].
[sujeto(['β-naphthoflavone', '(', 100, &, 'nbsp;nM)', in, the, presence, of, the, virus, 'mimic,', poly, 'I:', 'C,', also]), verbo([increased]), complemento([cyp1c1transcription])].
[sujeto(['LPS']), verbo([induced]), complemento(['cyp1c1,', cyclooxygenase, 2, '(', 'cox2),', interleukin, 1, β, '(', 'IL-1β),', interleukin, 6, '(', 'IL-6)', and, interleukin, 8, '(', 'IL-8)', 'transcription,', genes, that, were, not, affected, by, the, tested, 'β-naphthoflavone', concentrations, alone])].
[sujeto(['However,', 'β-naphthoflavone', '(', 25, and, 50, &, 'nbsp;nM)', strengthened, 'LPS']), verbo([induced]), complemento([cox2, and, 'IL-8', transcription])].
[sujeto(['Cod', head, kidney, cells, exposed, to, 'β-naphthoflavone', concentrations, ranging, from, 25, to, 100, &, 'nbsp;nM,', with, and, without, 'LPS', or, poly, 'I:', 'C,']), verbo([expressed]), complemento(['AhR', protein])].
[sujeto(['LPS', or, 'β-naphthoflavone', '(', 5, -, 50, &, 'nbsp;nM)', significantly]), verbo([induced]), complemento([leukotriene, 'B4', '(', 'LTB4)', secretion, compared, to, control])].
[sujeto(['In', 'conclusion,', this, study]), verbo([suggests]), complemento([that, 'β-naphthoflavone', could, interfere, with, 'LPS', induced, immune, cell, signaling, in, cod, head, kidney, cells])].
[sujeto(['Obesity', is, an, increasingly, urgent, global, 'problem,', 'yet,', little, is, known, about, its]), verbo([causes]), complemento([and, less, is, known, how, obesity, can, be, effectively, treated])].
[sujeto(['The', 'AHR', is, a, 'ligand-activated']), verbo([nuclear]), complemento([receptor, that, regulates, genes, involved, in, a, number, of, biological, 'pathways,', including, xenobiotic, metabolism, and, 'T', cell, polarization])].
[sujeto(['This', study, was, an, investigation, into, whether, inhibition, of, the, 'AHR']), verbo([prevents]), complemento(['Western', 'diet-based', obesity])].
[sujeto(['Using', an, 'AHR-directed,', 'luciferase-expressing', mouse, hepatocyte, cell, 'line,', we, show, that, the, transforming, growth, factor, β1, '(', 'TGFβ1)', signaling, pathway, via, 'PI3K', and, 'NF-κB', and, the, 'toll-like', receptor, 2, /, 4, '(', 'TLR2/4)', signaling, pathway]), verbo([stimulated]), complemento([by, oxidized, 'low-density', lipoproteins, via, 'NF-κB,', each, induce, luciferase, 'expression;', 'however,', 'TLR2/4', signaling, was, significantly, reduced, by, inhibition, of, 'IDO1'])].
[sujeto(['At', physiological, 'levels,', kynurenine, but, not, kynurenic, acid, '(', both, tryptophan, metabolites, and, known, 'AHR', 'agonists)']), verbo([activated]), complemento(['AHR-directed', luciferase, expression])].
[sujeto(['We', propose, a, 'hepatocyte-based', 'model,', in, which, kynurenine, production, is]), verbo([increased]), complemento([by, enhanced, 'IDO1', activity, stimulated, by, 'TGFβ1', and, 'TLR2/4', 'signaling,', via, 'PI3K', and, 'NF-κB,', to, perpetuate, a, cycle, of, 'AHR', activation, to, cause, 'obesity;', and, inhibition, of, the, 'AHR,', in, 'turn,', blocks, the, 'cycle\'s', output, to, prevent, obesity])].
[sujeto(['The', 'AHR', with, its, broad, ligand]), verbo([binding]), complemento([specificity, is, a, promising, candidate, for, a, potentially, simple, therapeutic, approach, for, the, prevention, and, treatment, of, obesity, and, associated, complications])].
[sujeto(['TCDD', successfully]), verbo([induced]), complemento([cleft, palate])].
[sujeto(['FA', and, 'α-naphthoflavone', may, reduce, the, generation, of, reactive, oxygen, 'species,']), verbo([inhibit]), complemento(['MEE', apoptosis, through, 'anti-oxidation,', and, increase, filopodia, and, 'MEE', movement])].
[sujeto(['This', may, result, in, restoration, of, the, ultrastructure, of, the, palatal, surface, to, a, normal, 'state,']), verbo([leading]), complemento([to, the, fusion, and, formation, of, complete, palate, in, 'TCDD-treated', fetal, mice])].
[sujeto(['By', using, 'Western', blot, and, immunofluorescence, 'staining,', we, unexpectedly]), verbo([found]), complemento([that, 'SKF-525A', at, 2, -, 20, &, 'nbsp;μM', caused, remarkable, accumulation, of, 'microtubule-associated', protein, light, chain, 3, 'II', '(', 'LC3-II)', in, primary, rat, hepatocytes, at, 1, ',', 4, and, 24, &, 'nbsp;h,', indicating, that, autophagy, was, disrupted])].
[sujeto(['SKF-525A', showed, no, effects, on, chloroquine]), verbo([induced]), complemento(['LC3-II', 'accumulation,', suggesting, that, autophagic, flux, was, 'blocked,', which, is, further, supported, by, the, increased, level, of, the, p62, protein, after, 'SKF-525A', treatment])].
[sujeto(['These', findings]), verbo([provide]), complemento([novel, insights, into, the, mechanisms, by, which, various, 'CYP', inhibitors, differentially, affect, a, same, 'drug\'s', toxicity, in, hepatocytes])].
[sujeto(['The', data, also, indicate, that, 'SKF-525A', is, not, an, ideal, chemical, inhibitor, for, probing, the, relation, between, 'CYP']), verbo([mediated]), complemento([metabolism, and, toxicity, in, primary, hepatocytes])].
[sujeto(['Alkylated', polycyclic, aromatic, hydrocarbons, '(', 'alkyl-PAHs)', are, the, predominant, form, of, 'PAHs', in, crude, 'oils,', of, 'which,', 3, -, 5, ring, 'alkyl-PAH', may]), verbo([cause]), complemento(['dioxin-like', toxicity, to, early, life, stages, of, fish])].
[sujeto(['The', results, showed, that, 'ANF', significantly]), verbo([inhibited]), complemento([the, induction, of, 'CYP1A', activity, by, 'retene;', 'however,', 'ANF', interacted, with, retene, to, induce, significant, developmental, toxicity, and, genotoxicity, at, 10, ',', 100, ',', and, 200, &, 'nbsp;μg/L', '(', p, &, 'lt;', 0.01, ')'])].
[sujeto(['The', interactions, of, retene, with, 'ANF', indicate, that, 'CYP1A', inhibition, was, possibly]), verbo([act]), complemento([through, different, mechanisms, to, produce, similar, developmental, effects, and, genotoxicity])].
[sujeto(['Therefore,', elevated, toxicity, of, 'alkyl-phenanthrene', under, 'CYP1A', inhibitor]), verbo([suggested]), complemento([that, the, ecotoxicity, of, 'PAHs', in, coastal, water, may, have, underestimated, the, threat, of, 'PAHs', to, fish, or, ecosystem])].
[sujeto(['Mesaconitine', and, 6, metabolites, 'M1-M6', were]), verbo([found]), complemento([in, the, incubation, system])].
[sujeto(['We', investigated, four, 'CYP', subfamilies, '(', 'CYP1A,', 'CYP2D,', 'CYP2C,', and, 'CYP3A)', that, are]), verbo([involved]), complemento([in, 90, '%', of, all, metabolic, drug, transformations, and, identified, four, amino, acid, interaction, networks, associated, with, specific, 'CYP', 'functionalities,', i])].
[sujeto(['Interestingly,', we, did, not, detect, any, 'co-evolved', 'substrate-binding', 'network,']), verbo([suggesting]), complemento([that, substrate, recognition, is, specific, for, each, subfamily])].
[sujeto(['Analysis', of, the, membrane]), verbo([binding]), complemento([networks, revealed, that, different, 'CYP', proteins, adopt, different, 'membrane-bound', 'orientations,', consistent, with, the, differing, substrate, preference, for, each, isoform])].
[sujeto(['The', catalytic, networks, were]), verbo([associated]), complemento([with, conservation, of, catalytic, function, among, 'CYP', 'isoforms,', whereas, the, dimerization, network, was, specific, to, different, 'CYP', isoforms])].
[sujeto(['We', further, applied, 'low-temperature', 'ATD', simulations, to, verify, proposed, allosteric, sites]), verbo([associated]), complemento([with, the, 'heme-binding', network, and, their, role, in, regulating, metabolic, fate])].
[sujeto(['The', metabolic, activities]), verbo([associated]), complemento([with, 'CYP1A,', 'CYP2B,', 'CYP2C,', 'CYP2D,', 'CYP2E', and, 'CYP3A', were, measured])].
[sujeto(['The', activities]), verbo([associated]), complemento([with, 'CYP3A', and, 'CYP2B', were, higher, than, the, activities, of, the, other, measured, 'CYPs'])].
[sujeto(['Species', differences, were]), verbo([found]), complemento([in, the, baseline, metabolism, of, these, substrates])].
[sujeto(['Killifish']), verbo([have]), complemento([significantly, higher, metabolic, rates, for, all, tested, substrates, except, 7, -, benzyloxyquinoline, and, 7, -, 'benzyloxy-4-trifluoromethylcoumarin', '(', both, mammalian, 'CYP3A', 'substrates);', significant, differences, were, also, seen, between, male, and, female, killifish])].
[sujeto(['Treatment', with, 'dexamethasone,', 'pregnenolone-16alpha-carbonitrile,', and, rifampicin, did, not]), verbo([cause]), complemento(['broad,', measurable, 'CYP', induction, in, either, fish, species])].
[sujeto(['In', 'trout,', dexamethasone, '(', 100, mg, 'kg(-1))', significantly]), verbo([induced]), complemento([3, -, 'cyano-7-ethoxycoumarin', metabolism, and, rifampicin, '(', 100, mg, 'kg(-1))', induced, the, dealkylation, of, 7, -, 'methoxyresorufin,', although, both, were, highly, variable])].
[sujeto(['Overall,', 'dexamethasone,', 'pregnenolone-16alpha-carbonitrile', and, rifampicin, did, not, appear, to, consistently]), verbo([increase]), complemento(['CYP', activity, in, fish])].
[sujeto(['Trout', treated, with, 10, or, 50, mg, 'kg(-1)', 'beta-naphthoflavone', '(', 'BNF),', a, 'CYP1A', 'inducer,', showed, significantly]), verbo([induced]), complemento([activity, across, almost, all, substrates, 'tested,', exceptions, being, 7, -, 'benzyloxyquinoline,', 7, -, 'benzyloxy-4-trifluoromethylcoumarin', and, dibenzylfluorescein])].
[sujeto([7, -, 'Methoxy-4-(aminomethyl)coumarin,', a, typical, 'CYP2D', substrate, in, 'mammals,', was, not, metabolized, by, untreated, fish, liver, 'microsomes;', 'however,', treatment, with, 'BNF', significantly]), verbo([induced]), complemento([the, metabolism, of, this, substrate, in, trout])].
[sujeto(['Induced', substrate, metabolism, in, 'BNF-treated', microsomes, was, only, correlated, across, selective, 'substrates,']), verbo([suggesting]), complemento([that, 'BNF', induces, multiple, 'CYPs', in, fish, liver])].
[sujeto(['When', used, in, the, 'elderly,', 'Ginkgo']), verbo([has]), complemento([a, high, potential, for, interactions, with, cardiovascular, drugs])].
[sujeto(['CYP1A1,', 1, 'A2,', 2, 'B1/2,', and, 3, 'A1', activities, and, gene, expression, in, the, rat, liver, were, significantly]), verbo([increased]), complemento([in, a, 'dose-dependent', manner, by, pretreatment, with, 'EGb', 761])].
[sujeto(['The', formation, of, 'NDP', from, propranolol, in, liver, microsomes, was, significantly]), verbo([inhibited]), complemento([by, 'alpha-naphthoflavone', '(', 'ANF,', a, selective, 'CYP1A2', 'inhibitor),', but, not, by, quinidine, '(', a, 'CYP2D', 'inhibitor)'])].
[sujeto(['These', results, indicated, that, 'EGb', 761, pretreatment]), verbo([decreased]), complemento([the, plasma, concentrations, of, propranolol, by, accelerated, conversion, of, parental, drug, to, 'NDP', due, to, induction, of, 'CYP1A2'])].
[sujeto(['EGb', 761, pretreatment, also, significantly]), verbo([induced]), complemento(['CYP2B1/2', and, 'CYP3A1,', suggesting, potential, interactions, with, substrate, drugs, for, these, two, enzymes])].
[sujeto(['Intact', cells, more, closely, reflect, the, environment, to, which, 'CYP', substrates, and, inhibitors, are, exposed, in, the, 'liver,', and, it, may, therefore, be, desirable, to, assess, the, potential, of, a, drug, to]), verbo([cause]), complemento(['CYP', inhibition, in, isolated, hepatocytes])].
[sujeto(['Quinine,', 'quinidine,', 'pyrilamine,', 'propafenone,', 'verapamil,', ketoconazole, and, terfenadine]), verbo([inhibited]), complemento([dextromethorphan, 'O-demethylation', in, rat, liver, microsomes, and, hepatocytes, with, 'IC50', values, in, the, low, micromolar, range])].
[sujeto(['The', 'cell-associated', concentrations, of, quinine, and, quinidine, were]), verbo([found]), complemento([to, be, significantly, higher, than, those, in, the, extracellular, 'medium,', suggesting, that, intracellular, accumulation, may, potentiate, the, effect, of, these, compounds])].
[sujeto(['The', ethoxyresorufin, 'O-deethylase', activity, was, markedly]), verbo([inhibited]), complemento([by, furafylline, and, 'a-naphthoflavone,', and, coumarin, 7, -, hydroxylase, by, 8, -, methoxypsoralen])].
[sujeto(['Immunoblot', analysis, employing, antibodies, to, human, 'CYP2D6', and, rat, 'CYP4A1', revealed, in, both, cases, a, 'single,', poorly]), verbo([expressed]), complemento([immunoreacting, band, in, bovine, microsomes])].
[sujeto(['Earlier', studies]), verbo([have]), complemento([shown, that, members, of, the, cytochrome, 'P4501', '(', 'CYP1)', enzyme, family, are, constitutively, 'expressed,', and, are, elevated, in, the, livers, of, ringed, seals, '(', 'Phoca', 'hispida)', and, grey, seals, '(', 'Halichoerus', 'grypus)', living, in, the, heavily, polluted, 'Baltic', 'Sea'])].
[sujeto(['However,', antibodies, to, human, and, rodent, 'CYP2B,', 'CYP2C', and, 'CYP2E', forms, did, not]), verbo([recognize]), complemento([any, proteins, in, these, seal, species])].
[sujeto(['Both', activities, were, elevated, in, the, 'Baltic', seal, 'populations,', showed, a, strong, positive, correlation, with, 'CYP1A', activity, and, were, at, least, partly]), verbo([inhibited]), complemento([by, a, typical, 'CYP1A', 'inhibitor,', 'alpha-naphthoflavone'])].
[sujeto(['Testosterone', 6, 'beta-hydroxylation,', a, 'CYP3A', 'marker,', showed, a, relatively, high, level, of, activity, in, the, livers, of, both, seal, species, and, was, potently]), verbo([inhibited]), complemento([by, 'ketoconazole,', a, 'CYP3A-selective', inhibitor])].
[sujeto(['We', conclude, tentatively, that, 'CYP2A-', and, 'CYP3A-like', enzymes, are]), verbo([expressed]), complemento([in, ringed, and, grey, 'seals,', but, that, 'CYP2B-', and, 'CYP2C-like', ones, are, not])].
[sujeto(['Stereoselective', metabolism, of, cibenzoline, 'succinate,', an, oral, antiarrhythmic, 'drug,', was, investigated, on, hepatic, microsomes, from, humans, and, rats, and, microsomes, from, cells]), verbo([expressing]), complemento([human, cytochrome, 'P450s', '(', 'CYPs)'])].
[sujeto(['The', total, 'CL(int)', for, the, formation, of, the, four, main, metabolites, from, 'S(-)-', and, 'R(+)-cibenzoline', was, 1.47, and, 1.64, 'microl/min/mg,', 'respectively,']), verbo([suggesting]), complemento([that, the, total, 'CL(int)', in, 'R(+)-enantiomer', was, slightly, greater, than, that, in, 'S(-)-enantiomer', in, human, liver, microsomes])].
[sujeto(['The', 'M1', formation, from, 'R(+)-cibenzoline', was, highly, correlated, with, bufuralol, 1, '\'', -, hydroxylation, and, 'CYP2D6', content, and, was]), verbo([inhibited]), complemento([by, 'quinidine,', a, potent, inhibitor, of, 'CYP2D6'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, 'M1', formation, from, 'R(+)-cibenzoline', was, catalyzed, by, 'CYP2D6'])].
[sujeto(['Ketoconazole,', which, is, a, potent, inhibitor, of, 'CYP3A4/5,', had, a, strong, inhibitory, effect, on, their, 'formation,', and, the, 'M4', formation, from, 'R(+)-cibenzoline', was]), verbo([inhibited]), complemento([by, quinidine, by, 45, '%'])].
[sujeto(['The', formation, of, 'M2', was, also]), verbo([inhibited]), complemento([by, quinidine, by, 46, to, 52, '%', at, lower, cibenzoline, enantiomers, '(', 5, 'microM),', whereas, the, inhibition, by, quinidine, was, not, observed, at, a, higher, substrate, concentration, '(', 100, 'microM)'])].
[sujeto(['In', male, rat, liver, 'microsomes,', ketoconazole, and, quinidine]), verbo([inhibited]), complemento([the, formation, of, the, main, 'metabolites,', 'M1', and, 'M3,', &, 'gt;74%', and, 44, to, 59, '%', ',', respectively])].
[sujeto(['These', results]), verbo([provide]), complemento([evidence, that, 'CYP3A', and, 'CYP2D', play, a, major, role, in, the, stereoselective, metabolism, of, cibenzoline, in, humans, and, male, rats])].
[sujeto(['Using', 12, typical, 'CYP', 'inhibitors,', it, was]), verbo([found]), complemento([that, nifedipine, '(', 'CYP3A', 'inhibitor)', and, haloperidol, '(', 'CYP2D', 'inhibitor)', showed, significant, inhibition, towards, the, 'N1-oxidation', of, 'BA', and, 'NBAs'])].
[sujeto(['PB', and, 'RIF']), verbo([increased]), complemento([the, levels, of, 'CYP3A', apoprotein, and, 'mRNA,', whereas, 'BNF', 'down-regulated', 'CYP3A', and, related, activities])].
[sujeto(['PB', and, 'RIF', treatment, resulted, in]), verbo([increased]), complemento([ethylmorphine, 'N-demethylation', and, testosterone, 'hydroxylation,', which, appears, to, be, the, result, of, 'CYP3A', induction])].
[sujeto(['Similar']), verbo([inducing]), complemento([effects, were, observed, for, 'tolbutamide,', a, marker, substrate, for, 'CYP2C'])].
[sujeto(['The', role, of, different, cytochrome, 'P450', isozymes, '(', 'CYP)', in, the, 'N-demethylation', of, chlorimipramine, and, chlorpromazine]), verbo([has]), complemento([been, investigated, in, liver, microsomes, from, rats, by, studying, the, effects, of, multiple, subchronic, doses, of, 'chlorimipramine,', 'chlorpromazine,', phenobarbital, and, 'beta-naphthoflavone', on, the, 'N-demethylation', of, 'ethylmorphine,', 'mono-N-demethyl-chlorimipramine', and, chlorpromazine, and, on, the, hydroxylation, of, aniline])].
[sujeto(['Multiple', doses, of, chlorimipramine]), verbo([increased]), complemento([the, capacity, of, microsomes, to, 'N-demethylate', ethylmorphine, '(', 9.8, +, /, -, 0.73, and, 6.08, +, /, -, 0.06, nmol, 'min(-1)', '(', mg, 'protein)(-1)', for, 'chlorimipramine-treated', and, control, 'rats,', 'respectively)', as, well, as, itself, '(', 4.65, +, /, -, 0.25, and, 3.1, +, /, -, 0.33, nmol, 'min(-1)', '(', mg, 'protein)(-1),', 'respectively)'])].
[sujeto(['Multiple', doses, of, chlorpromazine]), verbo([induced]), complemento(['aniline-hydroxylase', activity, '(', 1.11, +, /, -, 0.16, and, 0.94, +, /, -, 0.06, nmol, 'min(-1)', '(', mg, 'protein)(-1)', for, chlorimipramine, and, control, 'microsomes,', 'respectively)', but, the, capacity, to, 'N-demethylate', itself, was, unchanged])].
[sujeto(['Phenobarbital', treatment]), verbo([induced]), complemento([ethylmorphine, 'N-demethylation', 'activity,', but, did, not, affect, 'N-demethylation', 'activity,', towards, chlorimipramine, and, chlorpromazine])].
[sujeto(['The', capacity, to, 'N-demethylate', either, chlorimipramine, or, chlorpromazine, was]), verbo([increased]), complemento([by, treatment, with, either, phenobarbital, or, 'beta-naphthoflavone'])].
[sujeto(['In', control, 'microsomes,', sulphaphenazole, markedly]), verbo([inhibited]), complemento([both, 'chlorimipramine-N-mono-', and, 'di-N-demethylation,', whereas, quinidine, markedly, inhibited, the, rate, of, formation, of, chlorpromazine])].
[sujeto(['The', 'CYP2C', and, 'CYP2D', subfamilies, seem, to, be]), verbo([involved]), complemento([in, the, mono, 'N-demethylation', of, chlorimipramine, and, 'chlorpromazine,', respectively])].
[sujeto(['Moreover', the, 'CYP1A', and, 'CYP2B', subfamilies, might]), verbo([participate]), complemento([in, the, 'N-demethylation', of, either, chlorimipramine, or, chlorpromazine])].
[sujeto(['This', could]), verbo([have]), complemento([important, implications, in, the, clinical, use, of, chlorimipramine, and, chlorpromazine, in, view, of, the, genetic, polymorphism, of, 'CYP2C', and, 'CYP2D', isozymes, in, man])].
[sujeto(['The', accumulation, of, 'DTZ', metabolites, in, serum, occurs, during, prolonged, therapy, and]), verbo([leads]), complemento([to, decreased, 'DTZ', elimination])].
[sujeto(['This', study, assessed, the, role, of, human, 'CYPs', in, microsomal, 'DTZ', oxidation, and, the, capacity, of, 'DTZ', metabolites, to]), verbo([inhibit]), complemento([specific, 'CYP', activities])].
[sujeto(['DTZ', oxidation, was, correlated, with, testosterone, 6, 'beta-hydroxylation', '(', r, =, 0.82, ')', 'and,', to, a, lesser, 'extent,', tolbutamide, hydroxylation, '(', r, =, 0.59, ')', but, not, with, activities]), verbo([mediated]), complemento([by, 'CYP1A2', or, 'CYP2E1'])].
[sujeto(['The', 'CYP3A4', inhibitors, ketoconazole, and, troleandomycin]), verbo([decreased]), complemento([microsomal, 'DTZ', 'oxidation,', but, inhibitors, or, substrates, of, 'CYP2C,', 'CYP2D', and, 'CYP2E1', produced, no, inhibition])].
[sujeto(['Some', inhibition, was, produced, by, 'alpha-naphthoflavone,', a, chemical, that]), verbo([inhibits]), complemento(['CYP1As', and, also, interacts, with, 'CYP3A4'])].
[sujeto(['In', further, 'experiments,', the, capacities, of, 'DTZ', and, three, metabolites, to]), verbo([modulate]), complemento([human, 'CYP', 1, 'A2,', 20.0, ',', 2, 'C9', and, 3, 'A4', activities, were, evaluated, in, vitro])].
[sujeto(['DTZ', and, its, 'N-desmethyl', and, 'N,N-didesmethyl', metabolites, selectively]), verbo([inhibited]), complemento(['CYP3A4', 'activity,', whereas, 'O-desmethyl', 'DTZ', was, not, inhibitory])].
[sujeto(['CYP3A4', inhibition, was]), verbo([enhanced]), complemento([when, 'DTZ', and, 'N-desmethyl', 'DTZ', underwent, biotransformation, in, 'NADPH-supplemented', hepatic, microsomes, in, 'vitro,', supporting, the, contention, that, inhibitory, metabolites, may, be, generated, in, situ])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'N-demethylated', metabolites, of, 'DTZ', may, contribute, to, 'CYP3A4', inhibition, in, 'vivo,', especially, under, conditions, in, which, 'N-desmethyl', 'DTZ', 'accumulates,', such, as, during, prolonged, 'DTZ', therapy])].
[sujeto(['After', establishing, a, lack, of, interaction, between, these, compounds, the, effects, of, the]), verbo([inducing]), complemento([agents, were, investigated])].
[sujeto(['beta-naphthoflavone', also]), verbo([induced]), complemento([caffeine, plasma, clearance, but, did, not, affect, microsomal, caffeine, 1, -, and, 3, -, demethylation, rates])].
[sujeto(['In', contrast, with, 'beta-naphthoflavone', 'treatment,', phenobarbital, treatment, resulted, in, an]), verbo([increase]), complemento([of, microsomal, caffeine, 1, -, and, 3, -, demethylation, rates])].
[sujeto(['Sulphaphenazole', was]), verbo([found]), complemento([to, be, a, more, potent, inhibitor, of, tolbutamide, hydroxylation, than, sulphadimethoxine])].
[sujeto(['As', 'expected,', the, microsomal, 'aniline-4-hydroxylation', rate, '(', 'CYP2E)', was]), verbo([increased]), complemento([after, isoniazid, treatment])].
[sujeto(['The', microsomal, testosterone, 6, 'beta-hydroxylation', rate, '(', 'CYP3A)', was]), verbo([increased]), complemento([after, phenobarbital, and, triacetyloleandomycin, treatment])].
[sujeto(['Antipyrine', plasma, clearance, was, also]), verbo([increased]), complemento([after, phenobarbital, treatment])].
[sujeto(['Quinidine,', a, specific, inhibitor, of, 'CYP2D6,']), verbo([inhibited]), complemento([propranolol, 4, -, and, 5, -, hydroxylase, activities, selectively, and, in, a, 'concentration-dependent', manner])].
[sujeto(['alpha-Naphthoflavone,', a, potent, inhibitor, of, 'CYP1A2,']), verbo([inhibited]), complemento([all, of, the, propranolol, oxidation, 'activities,', and, the, 'IC50', value, for, 'N-desisopropylase', activity, was, much, smaller, than, the, values, for, 'ring-hydroxylase', activities])].
[sujeto(['Antibody', directed, to, 'CYP2D']), verbo([inhibited]), complemento([propranolol, 4, -, and, 5, -, hydroxylase, activities, by, 70, '%', at, an, 'antibody/microsomal', protein, ratio, of, 1.0])].
[sujeto(['Anti-CYP2C9', antibody, did, not]), verbo([inhibit]), complemento([any, activity, determined])].
[sujeto(['Pretreatment', with, the, 'CYP1A', 'inducer,', 'beta-naphthoflavone', '(', 'BNF),']), verbo([increased]), complemento([theophylline, clearance, 4.5, -, fold, '(', p, &, 'lt;', 0.001, ')', ',', and, the, 'CYP1A', 'inhibitor,', 'alpha-naphthoflavone,', significantly, attenuated, the, 'BNF', effect])].
[sujeto(['Pretreatment', with, 'phenobarbital,', an, inducer, of, 'CYP2B/C', in, 'rats,', had, a, far, more, modest, 'effect,']), verbo([increasing]), complemento([theophylline, clearance, only, 1.6, -, fold, '(', p, &, 'lt;', 0.005, ')'])].
[sujeto(['The', 'phenobarbital-mediated']), verbo([increase]), complemento([in, theophylline, clearance, was, attenuated, by, 'orphenadrine,', a, 'CYP2B/C', inhibitor])].
[sujeto(['While', the, powerful, 'CYP3A', inducer, clotrimazole, did, not]), verbo([increase]), complemento([theophylline, 'clearance,', 'troleandomycin,', an, inhibitor, of, 'CYP3A,', did, slow, theophylline, clearance, by, about, 25, '%', '(', p, &, 'lt;', 0.002, ')'])].
[sujeto(['Together,', these, findings]), verbo([suggest]), complemento([that, 'CYP1A', is, principally, responsible, for, the, overall, oxidation, of, theophylline, in, 'rats,', and, that, 'CYP2B/C', probably, also, mediates, some, theophylline, oxidation])].
[sujeto(['The', cytochrome, 'P450', isozymes, catalyzing, the, oxidation, of, the, methylenedioxyphenyl, compounds, methylenedioxybenzene, '(', 'MDB)', and, methylenedioxyamphetamine, '(', 'MDA)']), verbo([have]), complemento([been, investigated, in, rabbit, liver, preparations])].
[sujeto(['Formation', of, catechol, and, sesamol, from, 'MDB', in, microsomal, incubation, mixtures, was]), verbo([enhanced]), complemento([about, 5, -, and, 3, -, 'fold,', 'respectively,', by, pretreatment, of, the, rabbits, with, 'phenobarbital,', which, induced, 'CYP2B4', and, 'CYP4B1'])].
[sujeto(['The', cytochrome, 'P450', isozyme, responsible, for, aromatic, hydroxylation, of, 'MDB', was]), verbo([induced]), complemento([by, 'beta-naphthoflavone', and, was, inhibited, by, 'alpha-naphthoflavone'])].
[sujeto(['However,', 'MDA', competitively]), verbo([inhibited]), complemento([the, 'N-demethylation', of, erythromycin])].
[sujeto(['Antibodies', against, 'CYP2B4,', but, not, those, against, 'CYP4B1,']), verbo([caused]), complemento([a, marked, inhibition, of, the, demethylenation, and, aromatic, hydroxylation, of, 'MDB'])].
[sujeto(['Antibodies', against, 'CYP2C3', did, not]), verbo([inhibit]), complemento([the, demethylenation, of, 'MDA,', nor, did, substrates, or, inhibitors, of, the, 'CYP2D', family, except, for, bufuralol])].
[sujeto(['Reconstitution', experiments, with, 'CYP2B4']), verbo([suggested]), complemento([that, 'phenobarbital-inducible', complex, formation, from, 'MDA', was, not, due, to, the, carbene, pathway, involving, the, methylenedioxy, group, but, was, due, to, oxidation, of, the, amino, group])].
[sujeto(['The', results]), verbo([suggested]), complemento([that, one, or, more, constitutive, isoforms, '(', probably, 'unknown)', of, cytochrome, 'P450', present, in, rabbit, liver, microsomes, are, primarily, responsible, for, 'MDA', demethylenation, but, that, 'CYP3A6', contributes, slightly])].
[sujeto(['Brassica', carinata, '(', 'Ethiopian', 'mustard)']), verbo([has]), complemento([previously, been, identified, as, a, potential, crop, species, suitable, for, marginal, land, in, the, 'North', 'American', prairies, due, to, its, relatively, high, salt, tolerance])].
[sujeto(['Generally,', the, height, of, the, 'BS', line, was, greater, than, the, 'YS', line, under, both, salt, 'treatments,', indicating]), verbo([enhanced]), complemento([salt, tolerance, of, the, 'BS', line])].
[sujeto(['For', 'example,', tryptophan, and, formate, levels]), verbo([increased]), complemento([in, the, 'YS', line, after, four, weeks, of, 100, mM, salt, 'treatment,', while, proline, and, threonine, levels, varied, uniquely, compared, to, other, metabolites, of, the, lines])].
[sujeto(['Together,', the, data, indicate, that, the, 'brown-seeded', line]), verbo([has]), complemento([greater, sodium, tolerance, than, the, 'yellow-seed', 'line,', provide, clues, to, the, biochemical, underpinnings, for, the, phenotypic, 'variation,', and, highlight, the, utility, of, 'B'])].
[sujeto(['KYNA']), verbo([has]), complemento([also, been, shown, to, scavenge, hydroxyl, radicals, '(', 'OH)', under, controlled, conditions, of, free, radical, production])].
[sujeto(['The', scavenging, ability, of, 'KYNA', '(']), verbo([expressed]), complemento([as, 'IC(50)', 'values)', was, as, 'follows:', 'OH=O(2)(-)>ONOO(-)'])].
[sujeto(['Both', 'FeSO(4)', and, 3, -, 'NPA']), verbo([increased]), complemento([lipid, peroxidation, '(', 'LP)', and, 'ROS', formation, in, a, significant, manner, in, these, 'preparations,', whereas, 'KYNA', significantly, reduced, these, markers])].
[sujeto(['An']), verbo([increase]), complemento([in, 'ROS', formation, was, induced, by, 'FeSO(4)', in, forebrain, and, cerebellum, in, a, 'time-dependent', 'manner,', and, 'KYNA', reduced, this, effect, in, a, 'concentration-dependent', manner])].
[sujeto(['A', 3, -, fold]), verbo([increase]), complemento([in, 'LP', and, a, 2, -, fold, increase, in, 'ROS', formation, were, seen, after, exposure, to, 'FeSO(4),', whereas, 'KYNA', attenuated, these, effects, in, a, 'concentration-dependent', manner])].
[sujeto(['FeSO(4)']), verbo([increased]), complemento([the, striatal, 'OH', 'production,', while, 'KYNA', mitigated, this, effect])].
[sujeto(['Altogether,', these, data, strongly]), verbo([suggest]), complemento([that, 'KYNA,', in, addition, to, be, a, 'well-known', antagonist, acting, on, nicotinic, and, 'NMDA', 'receptors,', can, be, considered, as, a, potential, endogenous, antioxidant])].
[sujeto(['In', 'CKD,', 'however,', an, inadequate, renal, clearance, of, indoxyl, sulfate]), verbo([leads]), complemento([to, its, elevated, serum, levels])].
[sujeto(['The', oral, adsorbent, 'AST-120', reduces, the, serum, levels, of, indoxyl, sulfate, by, adsorbing, indole, in, the, intestines, and]), verbo([stimulating]), complemento([its, excretion, into, feces])].
[sujeto(['I']), verbo([have]), complemento([proposed, a, protein, metabolite, theory, by, which, endogenous, protein, metabolites, such, as, indoxyl, sulfate, play, a, significant, role, in, the, progression, of, 'CKD'])].
[sujeto(['A', progressive, decline, in, the, glomerular, filtration, rate]), verbo([leads]), complemento([to, increased, serum, levels, of, endogenous, protein, metabolites, such, as, indoxyl, 'sulfate,', and, to, the, adverse, effects, of, their, overload, on, the, remnant, nephrons])].
[sujeto(['Indoxyl', sulfate]), verbo([stimulates]), complemento([progressive, both, tubulointerstitial, fibrosis, and, glomerular, sclerosis, by, increasing, the, expression, of, transforming, growth, 'factor-beta1,', a, tissue, inhibitor, of, 'metalloproteinase-1', and, proalpha1, '(', 'I)', 'collagen,', leading, to, a, further, loss, of, nephrons])].
[sujeto(['Moreover,', indoxyl, sulfate]), verbo([induces]), complemento([oxidative, stress, in, tubular, 'cells,', mesangial, 'cells,', vascular, smooth, muscle, 'cells,', endothelial, cells, and, osteoblasts, as, well, as, stimulating, aortic, calcification, in, hypertensive, 'rats,', it, is, also, involved, in, the, progression, of, 'CKD,', cardiovascular, disease, '(', 'CVD)', and, osteodystrophy])].
[sujeto(['Tryptophan', '(', 'TRP),', an, essential, amino, 'acid,', is]), verbo([bound]), complemento([mostly, to, albumin, in, plasma])].
[sujeto(['However,', it, is]), verbo([reported]), complemento([that, binding, is, inhibited, by, indoles, that, accumulate, in, uremic, plasma])].
[sujeto(['We', therefore, investigated, whether, 'AST-120', recovers, 'TRP']), verbo([binding]), complemento([to, plasma, proteins, and, improves, the, nutritional, state, of, uremic, patients])].
[sujeto(['The', in, vitro]), verbo([binding]), complemento([ratio, of, 'TRP', to, bovine, serum, albumin, '(', 'BSA)', was, measured, in, the, presence, of, 'IS', by, the, equilibrium, dialysis, technique])].
[sujeto(['IS']), verbo([inhibited]), complemento([in, vitro, binding, of, 'TRP', to, 'BSA', in, a, 'dose-dependent', manner])].
[sujeto(['However,', a, 2, -, week, administration, of, 'AST-120', significantly, reduced, 'IS', levels, from, 1.79, +, /, -, 1.01, to, 1.15, +, /, -, 0.85, 'mg/dL', '(', 'N', 'group,', 0.06, +, /, -, 0.01, 'mg/dL),']), verbo([increased]), complemento([total, 'TRP', levels, '(', 1.16, +, /, -, 0.18, 'mg/dL),', and, improved, the, 'TRP', plasma, 'protein-binding', ratio, to, 83.1, '%', +, /, -, 3.8, '%', ',', whereas, total, protein, and, albumin, levels, remained, unchanged])].
[sujeto(['After', 2, months, of, 'AST-120', 'administration,', serum, albumin, and, transferrin, levels]), verbo([increased]), complemento([significantly])].
[sujeto(['Serum', concentration, of, indoxyl, sulfate, is, markedly]), verbo([increased]), complemento([as, an, inhibitor, of, 'drug-binding', in, uremic, patients, as, compared, with, healthy, subjects])].
[sujeto(['Since', indoxyl, sulfate, is]), verbo([bound]), complemento([to, serum, 'albumin,', it, cannot, be, removed, efficiently, by, 'hemodialysis,', and, it, tends, to, accumulate, in, uremic, serum])].
[sujeto(['To', determine, if, oral, 'sorbent,', 'AST-120,', could, adsorb, indole, in, intestine, and, then]), verbo([decrease]), complemento([serum, concentration, of, indoxyl, 'sulfate,', it, was, administered, to, nephrectomized, uremic, rats])].
[sujeto(['Serum', concentration, of, indoxyl, sulfate, was, markedly]), verbo([decreased]), complemento([in, uremic, rats, fed, with, oral, sorbent, as, compared, with, control, uremic, rats])].
[sujeto(['However,', serum, concentrations, of, creatinine, and, urea, nitrogen, were, not, significantly]), verbo([decreased]), complemento([in, the, uremic, rats, fed, with, oral, sorbent, as, compared, with, the, control, uremic, rats])].
[sujeto(['Serum', concentration, of, tryptophan, was, not]), verbo([decreased]), complemento([but, rather, increased, in, the, uremic, rats, fed, with, oral, sorbent, as, compared, with, the, control, uremic, rats])].
[sujeto(['Concentration', of, indoxyl, sulfate, in, bile, of, a, uremic, rat, was, much, lower, than, that, in, the, uremic, 'serum,']), verbo([suggesting]), complemento([that, the, adsorption, of, indoxyl, sulfate, in, intestine, is, not, a, major, mechanism, of, decreasing, the, serum, concentration, of, indoxyl, sulfate])].
[sujeto(['These', results, demonstrate, that, oral, 'sorbent,', 'AST-120,', can]), verbo([decrease]), complemento([serum, concentration, of, indoxyl, sulfate, in, uremia, due, to, adsorption, of, indole, in, intestine])].
[sujeto(['Among', 'them,', haplotype, 'H4', was, positively]), verbo([associated]), complemento([with, 'high-altitude', adaptation, whereas, haplotypes, 'H6,', 'H7', and, 'H8', had, negative, association, with, 'high-altitude', adaptation])].
[sujeto(['The', 'Median-joining', profile]), verbo([suggested]), complemento([that, haplotype, 'H5', had, the, ancestral, position, to, the, other, haplotypes, but, had, no, significant, relationship, with, 'high-altitude', adaptation])].
[sujeto(['Results', also]), verbo([suggested]), complemento([that, chickens, with, 'A', allele, at, m])].
[sujeto(['It']), verbo([suggests]), complemento([that, the, synonymous, mutation, m])].
[sujeto(['A', 3, ',', 345, -, bp, fragment, of, 'Dictyostelium', discoideum, mitochondrial, 'DNA', '(', 'mtDNA)']), verbo([has]), complemento([been, sequenced])].
[sujeto(['This', fragment, contained, the, 80, -, kDa, subunit, of, complex, 'I', '(', 'NADH:ubiquinone', 'oxidoreductase),', encoding, a, predicted, amino, acid, sequence, of, 688, residues, and, a, molecular, mass, of, 79, ',', 805, daltons, which, is]), verbo([nuclear]), complemento([encoded, in, other, metazoa])].
[sujeto(['Both', the, 80, -, kDa, subunit, and, the, 'ORF104', were, hydrophilic, and, highly, 'charged,']), verbo([suggesting]), complemento([they, are, not, membrane, 'associated,', unlike, most, mitochondrially, encoded, proteins, in, the, metazoa])].
[sujeto(['The', large, size, of, the, mitochondrial, genome, '(', 54, 'kb),', the, lack, of, intergenic, 'sequence,', and, the, apparent, use, of, the, universal, code]), verbo([suggest]), complemento(['D'])].
[sujeto([discoideum, mtDNA, may, encode, many, primitive, genes, that, are]), verbo([nuclear]), complemento([encoded, in, higher, organisms])].
[sujeto(['Mitochondrial', 'DNA', disease, is, one, of, the, most, common, groups, of, inherited, neuromuscular, disorders, and, frequently]), verbo([associated]), complemento([with, marked, phenotypic, and, genotypic, heterogeneity])].
[sujeto(['Molecular', genetic, testing, identified, a, 'previously-reported', 'pathogenic,', heteroplasmic, mutation, in, the, 'mitochondrial-encoded', transfer, 'RNA', tryptophan, '(', 'MT-TW)', gene, which, based, on, family, studies, was, likely, to]), verbo([have]), complemento([arisen, de, novo, in, our, patient])].
[sujeto(['Interestingly,', we, documented, an]), verbo([increase]), complemento([in, the, mutant, mtDNA, heteroplasmy, level, in, her, second, biopsy, '(', 72, '%', compared, to, 56, '%', ')', ',', reflecting, the, progression, of, clinical, disease])].
[sujeto(['All', three, affected, siblings, were]), verbo([found]), complemento([to, be, homoplasmic, for, an, m])].
[sujeto([5559, 'A>G', mutation]), verbo([causes]), complemento([a, reduction, in, the, steady, state, levels, of, 'tRNA(Trp)', and, this, decrease, likely, affects, the, stability, of, other, mitochondrial, 'RNAs', in, the, patient, fibroblasts])].
[sujeto(['We', observe, accumulation, of, an, unprocessed, transcript, containing, 'tRNA(Trp),']), verbo([decreased]), complemento([de, novo, protein, synthesis, and, consequently, lowered, steady, state, levels, of, mitochondrial, 'DNA-encoded', proteins, that, compromise, mitochondrial, respiration])].
[sujeto([5559, 'A>G', mutation, at, homoplasmic, levels]), verbo([causes]), complemento(['LS', in, association, with, severe, 'multi-organ', disease, '(', 'LS-plus)', as, a, consequence, of, dysfunctional, mitochondrial, 'RNA', metabolism])].
[sujeto(['Numerous', pathogenic, mutations, responsible, for, mitochondrial, diseases]), verbo([have]), complemento([been, identified, in, mitochondrial, 'DNA', '(', 'mtDNA)-encoded', tRNA, genes])].
[sujeto(['We']), verbo([found]), complemento([a, 'disease-causative', 'mutation,', m])].
[sujeto(['This', mutation, firstly, disturbed, the, translation, machinery, of, mitochondrial, 'tRNA(Trp)', and]), verbo([induced]), complemento([mitochondrial, respiratory, 'dysfunction,', followed, by, severely, injured, mitochondrial, homeostasis])].
[sujeto(['We', also, demonstrated, 'cell-type-specific', disease, phenotypes, using, 'patient-derived']), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'iPSCs)', carrying, '~100', '%', mutant, m])].
[sujeto(['Significant']), verbo([loss]), complemento([of, terminally, differentiated, 'iPSC-derived', 'neurons,', but, not, their, 'stem/progenitor', 'cells,', was, detected, most, likely, due, to, serious, mitochondrial, dysfunction, triggered, by, m])].
[sujeto(['Our', 'iPSC-based', disease, models, would, be, widely, available, for, understanding, the, &, 'quot;definite"', 'genotype-phenotype', relationship, of, affected, tissues, and, organs, in, various, mitochondrial, diseases]), verbo([caused]), complemento([by, heteroplasmic, mtDNA, 'mutations,', as, well, as, for, further, drug, discovery, applications])].
[sujeto(['We']), verbo([report]), complemento([a, patient, harboring, a, de, novo, m])].
[sujeto(['Our', proband, had, an, earlier, onset, and, more, severe, phenotype, than, the, first]), verbo([reported]), complemento([patient, harboring, the, same, mutation])].
[sujeto(['Mitochondrial', '(', 'mt)', 'DNA-associated', 'Leigh', syndrome, and, 'NARP', '(', neurogenic, muscle, 'weakness,', 'ataxia,', and, retinitis, 'pigmentosa)', are, part, of, a, continuum, of, progressive, neurodegenerative, disorders]), verbo([caused]), complemento([by, abnormalities, of, mitochondrial, energy, generation])].
[sujeto(['Decompensation', '(', often, with, elevated, lactate, levels, in, blood, 'and/or', 'CSF)', during, an, intercurrent, illness, is, typically]), verbo([associated]), complemento([with, psychomotor, retardation, or, regression])].
[sujeto(['MT-ATP6,', 'MT-TL1,', 'MT-TK,', 'MT-TW,', 'MT-TV,', 'MT-ND1,', 'MT-ND2,', 'MT-ND3,', 'MT-ND4,', 'MT-ND5,', 'MT-ND6,', and, 'MT-CO3', are, the, mitochondrial, genes, in, which, pathogenic, variants, are, known, to]), verbo([cause]), complemento(['mtDNA-associated', 'Leigh', syndrome])].
[sujeto(['MT-ATP6', is, the, only, gene, in, which, pathogenic, variants, are, known, to]), verbo([cause]), complemento(['NARP'])].
[sujeto(['Approximately', 10, '%', of, individuals, with, 'Leigh', syndrome]), verbo([have]), complemento([either, the, m])].
[sujeto([8993, 'T>C', 'MT-ATP6', pathogenic, 'variant;', approximately, 10, '%', -, 20, '%']), verbo([have]), complemento([pathogenic, variants, in, other, mitochondrial, genes])].
[sujeto(['The', proportion, of, individuals, with, 'NARP', who]), verbo([have]), complemento([a, detectable, pathogenic, variant, at, 'MT-ATP6', nucleotide, 8993, is, unknown, but, likely, greater, than, 50, '%', ;, a, 'T-to-G', transversion, '(', m])].
[sujeto([8993, 'T>C)']), verbo([has]), complemento([also, been, described])].
[sujeto(['Anticongestive', therapy, may, be]), verbo([required]), complemento([for, cardiomyopathy])].
[sujeto(['Surveillance:', 'Neurologic,', 'ophthalmologic,', and, cardiologic, evaluations, at]), verbo([regular]), complemento([intervals, to, monitor, progression, and, appearance, of, new, symptoms])].
[sujeto(['The', mother, of, a, proband, usually]), verbo([has]), complemento([the, mtDNA, pathogenic, variant, and, may, or, may, not, have, symptoms])].
[sujeto(['In', most, 'cases,', the, mother]), verbo([has]), complemento([a, much, lower, mutant, load, than, the, proband, and, usually, remains, asymptomatic, or, develops, only, mild, symptoms])].
[sujeto(['Occasionally', the, mother]), verbo([has]), complemento([a, substantial, mutant, load, and, develops, severe, symptoms, in, adulthood])].
[sujeto(['Prenatal', diagnosis, and, preimplantation, genetic, diagnosis, for, couples, at]), verbo([increased]), complemento([risk, of, having, children, with, mitochondrial, 'DNA-associated', 'Leigh', syndrome, and, 'NARP', is, possible, by, analysis, of, mtDNA, extracted, from, 'non-cultured', fetal, cells, or, from, single, 'blastomeres,', 'respectively;', 'however,', the, use, of, molecular, genetic, test, results, to, predict, 'long-term', outcome, is, difficult])].
[sujeto(['Mitochondrial', 'DNA', '(', 'mtDNA)', defects, were, known, to, be]), verbo([associated]), complemento([with, a, large, spectrum, of, human, diseases, and, patients, might, present, wide, range, of, clinical, features, with, various, combinations])].
[sujeto(['Mutations', in, mitochondrial, 'tRNAs,', rRNAs, and, 'protein-coding', genes, or, 'large-scale', rearrangements]), verbo([have]), complemento([been, implicated, in, several, cytopathies])].
[sujeto(['Mitochondrial', 'myopathies,', usually, maternally, inherited, group, of, neuromuscular, diseases]), verbo([caused]), complemento([by, mitochondrial, dysfunction, occurring, before, the, age, of, 20, years, and, often, begin, with, exercise, 'intolerance,', muscle, weakness, and, neurodevelopmental, retardation])].
[sujeto([5521, 'G>A', mutation, in, the, 'D-stem', region, of, the, 'tRNA(Trp)', gene, which, could]), verbo([lead]), complemento([to, a, disruption, of, the, secondary, structure, of, this, tRNA, and, affect, the, 'tRNA-ribosome', interaction, with, a, consequent, decrease, in, the, rate, of, synthesis, of, mitochondrial, proteins])].
[sujeto(['Mutations', in, the, mitochondrial, 'genome,', and, in, particular, the, 'mt-tRNAs,', are, an, important]), verbo([cause]), complemento([of, human, disease])].
[sujeto(['Through', the, application, of, the, pathogenicity, scoring, 'system,', we]), verbo([have]), complemento([classified, six, of, these, variants, as, &, 'quot;definitely', 'pathogenic"', mutations, '(', m])].
[sujeto(['Combined', oxidative, phosphorylation, '(', 'OXPHOS)', system, deficiencies, are, a, group, of, mitochondrial, disorders, that, are]), verbo([associated]), complemento([with, a, range, of, clinical, phenotypes, and, genetic, defects])].
[sujeto(['Our', results, show, that, these, 'tRNA(Trp)', and, 'tRNA(Arg)', mutations]), verbo([cause]), complemento([the, combined, 'OXPHOS', deficiencies, in, the, 'patients,', adding, to, the, still, expanding, group, of, pathogenic, mitochondrial, tRNA, mutations])].
[sujeto(['In', this, 'study,', we, performed, a, systematic, sequence, analysis, of, mitochondrial, genes]), verbo([associated]), complemento([with, 'LS', in, 'Tunisian', patients])].
[sujeto(['We', revealed, the, presence, of, 34]), verbo([reported]), complemento(['polymorphisms,', nine, novel, nucleotide, variants, and, two, new, mutations, '(', 'T5523G', and, 'A5559G)', in, the, tested, patients])].
[sujeto(['These', two, mutations, were, localized, in, two]), verbo([conserved]), complemento([regions, of, the, 'tRNA(Trp)', and, 'affect,', 'respectively,', the, 'D-stem', and, the, 'T-stem', of, the, mitochondrial, tRNA, leading, to, a, disruption, of, the, secondary, structure, of, this, tRNA])].
[sujeto(['We']), verbo([report]), complemento([here, the, first, mutational, screening, of, mitochondrial, mutations, in, 'Tunisian', patients, with, 'Leigh', syndrome, which, described, two, novel, mutations, associated, with, this, disorder])].
[sujeto(['There', were, significant]), verbo([increases]), complemento([in, the, levels, of, 'kynurenine,', kynurenic, 'acid,', anthranilic, acid, and, 3, -, 'hydroxy-kynurenine', '(', 3, -, 'HK)', in, the, maternal, brain, after, 5, &, 'nbsp;h', but, not, 24, &, 'nbsp;h,', while, the, embryos, exhibited, high, levels, of, 'kynurenine,', kynurenic, acid, and, anthranilic, acid, after, 5, &, 'nbsp;h', which, were, maintained, at, 24, &, 'nbsp;h', 'post-treatment'])].
[sujeto(['At', 24, &, 'nbsp;h', there, was, also, a, strong, trend, to, an]), verbo([increase]), complemento([in, quinolinic, acid, levels, '(', 'P = 0'])].
[sujeto(['The', results, confirm, the, marked]), verbo([increase]), complemento([in, the, accumulation, of, some, neuroactive, kynurenines, when, 'KMO', is, 'inhibited,', and, 're-emphasise', the, potential, importance, of, changes, in, anthranilic, acid])].
[sujeto(['When', brains, were, examined, from, young, mice, heterozygous, for, the, meCP2, gene, -, a, potential, model, for, 'Rett', syndrome, -, no, differences, were, noted, from, control, 'mice,']), verbo([suggesting]), complemento([that, the, proposed, roles, for, kynurenines, in, autism, spectrum, disorder, are, not, relevant, to, 'Rett', 'syndrome,', supporting, its, recognition, as, a, 'distinct,', 'independent,', condition])].
[sujeto(['Radiation', exposure, to, immune, system]), verbo([induces]), complemento([imbalance, in, cytokines, expression, involved, in, 'Th1/Th2', homeostasis, perturbations])].
[sujeto(['However,', 'NATG', pretreatment, to, irradiated, 'HEK293T', cells, '(', that, did, not]), verbo([express]), complemento(['NK-1Receptor)', did, not, provide, significant, survival, suggesting, 'NK-1R', involvement, in, 'NATG', mediated, radioprotection])].
[sujeto([1, murine, macrophages, exhibited]), verbo([increased]), complemento(['IFN-γ', levels, '(', '∼90%)', with, significant, decrease, in, 'TNF-α', at, 24, h, as, compared, to, irradiated, cells])].
[sujeto(['Further,', significant]), verbo([decrease]), complemento(['(', '∼20%)', in, 'IL-10', and, 'IL-2', '(', '∼26%)', levels, was, observed, in, irradiated, macrophages, pretreated, with, 'NATG', as, compared, to, only, irradiated, cells])].
[sujeto(['Hence,', 'NATG', 'pre-treatment', to, irradiated, macrophages]), verbo([induced]), complemento(['IFN-γ,', 'IL-17A', and, 'IL-12', 'expression,', 'whereas,', suppresses, 'TNF-α,', 'IL-10', and, 'IL-2', expressions])].
[sujeto(['The', structures, of, these, compounds, were, characterized, by]), verbo([nuclear]), complemento([magnetic, resonance, and, mass, spectrometry, analysis, and, comparing, with, literature])].
[sujeto(['It', was]), verbo([suggested]), complemento([that, further, work, should, be, carried, out, to, 'isolate,', 'purify,', and, characterize, the, active, constituents, responsible, for, the, activity, of, these, plants])].
[sujeto(['Cancer', cell, metabolism]), verbo([has]), complemento([received, increasing, attention])].
[sujeto(['Despite', a, boost, in, the, application, of, clinical, metabolic, profiling, '(', 'CMP)', in, cancer, 'patients,', a, 'meta-analysis']), verbo([has]), complemento([not, been, performed])].
[sujeto(['The', primary, goal, of, this, study, was, to, assess, whether, public, accessibility, of, metabolomics, data, and, identification, and]), verbo([reporting]), complemento([of, metabolites, were, sufficient, to, assess, which, metabolites, were, consistently, altered, in, cancer, patients])].
[sujeto(['This', analysis, confirmed, 'well-known']), verbo([increases]), complemento([in, glycolytic, 'metabolites,', but, also, unveiled, unprecedented, changes, in, other, metabolites, such, as, ketone, bodies, and, amino, acids, '(', 'histidine,', 'tryptophan)'])].
[sujeto(['However,', this, study, also, highlighted, that, insufficient, public, accessibility, of, metabolomics, 'data,', and, inadequate, metabolite, identification, and]), verbo([reporting]), complemento([hamper, the, discovery, potential, of, 'meta-analyses', of, 'CMP', 'studies,', calling, for, improved, standardization, of, metabolomics, studies])].
[sujeto(['KA']), verbo([activated]), complemento(['Trp', 2, ',', 3, -, dioxygenase, '(', 'TDO),', possibly, by, increasing, liver, 3, -, 'HAA,', but, inhibited, kynurenine, aminotransferase, '(', 'KAT)', and, kynureninase, activities, with, 3, -, 'HK', as, substrate])].
[sujeto([3, -, 'HK']), verbo([inhibited]), complemento([kynureninase, activity, from, 3, -, 'HK'])].
[sujeto([3, -, 'HAA']), verbo([stimulated]), complemento(['TDO,', but, inhibited, kynureninase, activity, from, 'K', and, 3, -, 'HK'])].
[sujeto(['Trp', '(', 50, 'mg/kg)']), verbo([increased]), complemento([kynurenine, metabolite, concentrations, and, 'KAT', from, 'K,', and, exerted, a, temporary, stimulation, of, 'TDO'])].
[sujeto(['The', kynureninase, inhibitors, 'BSZ', and, 'CBD', also]), verbo([inhibited]), complemento(['KAT,', but, stimulated, 'TDO'])].
[sujeto(['BSZ', abolished, or, strongly]), verbo([inhibited]), complemento([the, 'Trp-induced', increases, in, liver, 'Trp', and, kynurenine, metabolites])].
[sujeto(['As', to, 'schizophrenia,', research, into, the, pathophysiology]), verbo([has]), complemento([focused, on, 'dopamine,', 'brain-derived', neurotrophic, 'factor,', and, glutamate, signaling, in, 'which,', concerning, the, 'latter,', the, 'N-methyl-d-aspartate', receptor, plays, a, crucial, role])].
[sujeto(['Glutamate', levels, were]), verbo([increased]), complemento([in, both, patient, groups, as, compared, to, controls])].
[sujeto(['Nicotinamide,', a, naturally, occurring, nutrient, that, is]), verbo([maintained]), complemento([through, the, dietary, intakes, of, vitamin, 'B3', and, 'tryptophan,', has, been, used, in, the, treatment, of, some, skin, conditions, including, atopic, eczema])].
[sujeto(['Maternal', nicotinamide, and, related, metabolite, concentrations, were, not]), verbo([associated]), complemento([with, offspring, atopic, eczema, at, age, 6, months])].
[sujeto(['Higher', concentrations, of, nicotinamide, and, anthranilic, acid, 'were,', 'however,']), verbo([associated]), complemento([with, a, lower, risk, of, eczema, at, age, 12, months, '(', odds, ratios, 0.69, ',', 95, '%', 'CI', 0.53, -, 0.91, /, 'SD', 'change,', 'P', =, 0.007, and, 0.63, ',', 0.48, -, 0.83, ',', 'P', =, 0.001, ',', 'respectively)'])].
[sujeto(['Research', on, the, neurobiology, of, the, kynurenine, pathway]), verbo([has]), complemento([suffered, years, of, relative, obscurity, because, tryptophan, 'degradation,', and, its, involvement, in, both, physiology, and, major, brain, 'diseases,', was, viewed, almost, exclusively, through, the, lens, of, the, 'well-established', metabolite, serotonin])].
[sujeto(['With']), verbo([increasing]), complemento([recognition, that, kynurenine, and, its, metabolites, can, affect, and, even, control, a, variety, of, classic, neurotransmitter, systems, directly, and, 'indirectly,', interest, is, expanding, rapidly])].
[sujeto(['Moreover,', kynurenine, pathway, metabolism, itself, is]), verbo([modulated]), complemento([in, conditions, such, as, infection, and, 'stress,', which, are, known, to, induce, major, changes, in, 'well-being', and, 'behaviour,', so, that, kynurenines, may, be, instrumental, in, the, etiology, of, psychiatric, and, neurological, disorders])].
[sujeto(['In', 'particular,']), verbo([targeting]), complemento([the, kynurenine, pathway, with, new, specific, agents, may, make, it, possible, to, prevent, disease, by, appropriate, pharmacological, or, genetic, manipulations])].
[sujeto(['The', kynurenine, '(', 'KYN)', pathway, '(', 'KP)', is, a, major, degradative, pathway, of, the, amino, 'acid,', 'L-tryptophan', '(', 'TRP),', that, ultimately]), verbo([leads]), complemento([to, the, anabolism, of, the, essential, pyridine, 'nucleotide,', nicotinamide, adenine, dinucleotide])].
[sujeto(['Dendritic', cells, '(', 'DCs)']), verbo([have]), complemento([been, shown, to, mediate, immunoregulatory, roles, that, mediated, by, 'TRP', catabolism])].
[sujeto(['However,', characterization, of, the, 'KP', in, human, 'DCs']), verbo([has]), complemento([so, far, only, been, partly, delineated])].
[sujeto(['It', is, critical, to, understand, which, 'KP', enzymes, are]), verbo([expressed]), complemento([and, which, 'KP', metabolites, are, produced, to, be, able, to, understand, their, regulatory, effects, on, the, immune, response])].
[sujeto(['Our', results, show, that, the, 'KP', is, entirely]), verbo([expressed]), complemento([in, human, 'MDDC'])].
[sujeto(['Following', activation, of, the, 'KP', using, interferon, 'gamma,', 'MDDCs', can]), verbo([mediate]), complemento([apoptosis, of, 'T', h, cells, in, vitro])].
[sujeto(['Understanding', the, molecular, mechanisms]), verbo([regulating]), complemento(['KP', metabolism, in, 'MDDCs', may, provide, renewed, insight, for, the, development, of, novel, therapeutics, aimed, at, modulating, immunological, effects, and, peripheral, tolerance])].
[sujeto([untreated, 'rats;', 193, were, altered, by, the, antibiotic, treatments, with, a, tendency, towards]), verbo([decreased]), complemento([metabolite, levels])].
[sujeto(['Both', antibiotic, treatments]), verbo([decreased]), complemento([the, severity, of, an, induced, myocardial, infarction, in, vivo, by, 27, '%', and, 29, '%', ',', respectively])].
[sujeto(['We', then, determined, whether, microbial, metabolites, of, the, amino, acids, 'phenylalanine,', tryptophan, and, tyrosine, were, linked, to]), verbo([decreased]), complemento([severity, of, myocardial, infarction])].
[sujeto(['Oral', or, intravenous, pretreatment, of, rats, with, these, amino, acid, metabolites, abolished, the]), verbo([decrease]), complemento([in, infarct, size, conferred, by, vancomycin])].
[sujeto(['Inhibition', of, 'JAK-2', '(', 'AG-490,', 10, 'μM),', 'Src', kinase, '(', 'PP1,', 20, 'μM),', 'Akt/PI3', kinase, '(', 'Wortmannin,', 100, 'nM),', 'p44/42', 'MAPK', '(', 'PD98059,', 10, 'μM),', p38, 'MAPK', '(', 'SB203580,', 10, 'μM),', or, 'KATP', channels, '(', 'glibenclamide,', 3, 'μM)', abolished, cardioprotection, by, 'vancomycin,', indicating, microbial, metabolites, are]), verbo([interacting]), complemento([with, cell, surface, receptors, to, transduce, their, signals, through, 'Src', 'kinase,', cell, survival, pathways, and, 'KATP', channels])].
[sujeto(['These', inhibitors]), verbo([have]), complemento([no, effect, on, myocardial, infarct, size, in, untreated, rats])].
[sujeto(['This', study, links, gut, microbiota, metabolites, to, severity, of, myocardial, infarction, and, may]), verbo([provide]), complemento([future, opportunities, for, novel, diagnostic, tests, and, interventions, for, the, prevention, of, cardiovascular, disease])].
[sujeto(['Although', the, results, indicate, the, most, pronounced, effect, in, 'T3', plants, as, compared, to, 'T1', and, 'T2', 'plants,', even, just, leaf, exposure, to, 'CdONPs']), verbo([has]), complemento([the, potential, to, induce, changes, in, plant, metabolism])].
[sujeto(['To', examine, whether, delirium, in, hip, fracture, patients, was]), verbo([associated]), complemento([with, changes, in, the, levels, of, amino, acids, 'and/or', monoamine, metabolites, in, cerebrospinal, fluid, '(', 'CSF)', and, serum])].
[sujeto(['Higher', 'CSF', levels, of, monoamine, precursors, in, hip, fracture, patients, with, delirium]), verbo([suggest]), complemento([a, higher, monoaminergic, activity, in, the, central, nervous, system, during, delirium, in, this, patient, group])].
[sujeto(['However,', there]), verbo([have]), complemento([been, no, data, regarding, these, parameters, in, patients, on, peritoneal, dialysis, compared, to, those, undergoing, hemodialysis, or, kidney, transplantation])].
[sujeto(['IDO', levels, were]), verbo([increased]), complemento([in, the, 'PD,', 'HD,', and, 'KT', groups, compared, to, the, control, group])].
[sujeto(['The', concentration, of, kynurenine, was, significantly]), verbo([increased]), complemento([in, the, 'PD', group, compared, to, the, other, groups, '(', p, &, 'lt;', 0.01, ')'])].
[sujeto(['The', 'kynurenine/tryptophan', ratio, was]), verbo([increased]), complemento([in, the, 'PD', group, compared, to, the, other, groups, '(', all, p, &, 'lt;', 0.01, ')'])].
[sujeto(['TAS', levels, in, the, 'PD', and, 'HD', groups, were, significantly]), verbo([decreased]), complemento([compared, to, the, control, group, '(', both, p, &, 'lt;', 0.05, ')'])].
[sujeto(['TAS', levels, in, the, 'PD', group, were, significantly]), verbo([decreased]), complemento([compared, to, the, 'KT', group])].
[sujeto(['The', results, showed, that, 'IDO', levels, were]), verbo([increased]), complemento([in, peritoneal, dialysis, and, hemodialysis, patients, and, in, renal, transplant, 'recipients,', while, oxidative, stress, was, found, to, be, related, to, 'IDO', activity, and, was, most, increased, in, the, patients, on, peritoneal, dialysis])].
[sujeto(['Dicathais', orbita, is, a, mollusc, of, the, 'Muricidae', family, and, is, well, known, for, the, production, of, the, expensive, dye, 'Tyrian', purple, and, its, brominated, precursors, that]), verbo([have]), complemento([anticancer, 'properties,', in, addition, to, choline, esters, with, 'muscle-relaxing', properties])].
[sujeto(['Annotation', with, reference, to, the, 'Nr,', 'Swiss-Prot', and, 'Kyoto', 'Encyclopedia', of, 'Genes', and, 'Genomes', '(', 'KEGG)', databases, identified, 'candidate-coding', regions, in, 76, ',', 152, of, these, 'contigs,', with, transcripts, for, many, enzymes, in, various, metabolic, pathways]), verbo([associated]), complemento([with, secondary, metabolite, biosynthesis, represented])].
[sujeto([orbita]), verbo([expresses]), complemento([a, number, of, genes, associated, with, 'indole,', sulfur, and, histidine, metabolism, pathways, that, are, relevant, to, 'Tyrian', purple, precursor, 'biosynthesis,', and, many, of, which, were, not, found, in, the, fully, annotated, genomes, of, three, other, molluscs, in, the, 'KEGG', database])].
[sujeto(['These', transcriptome, data]), verbo([provide]), complemento([a, significant, molecular, resource, for, gastropod, research, in, general, and, 'Tyrian', purple, producing, 'Muricidae', in, particular])].
[sujeto(['Biochemical', pathway, analysis, was, conducted, to]), verbo([gain]), complemento([understanding, of, underlying, pathways, involved, in, the, 'SLE', pathogenesis])].
[sujeto(['We']), verbo([found]), complemento([an, increased, oxidative, activity, in, 'SLE,', supported, by, increased, xanthine, oxidase, activity, and, an, increased, turnover, in, the, urea, cycle])].
[sujeto(['The', most, discriminatory, metabolite, observed, was, 'tryptophan,', with]), verbo([decreased]), complemento([levels, in, 'SLE', patients, compared, to, control, groups])].
[sujeto(['There']), verbo([has]), complemento([been, a, recent, interest, in, the, broader, physiological, importance, of, multispecific, &, 'quot;drug"', transporters, of, the, 'SLC', and, 'ABC', transporter, families])].
[sujeto(['The', partly, validated, reconstructed, network, is, also, consistent, with, a, major, role, for, 'OAT1', in]), verbo([modulating]), complemento([metabolic, and, signaling, pathways, involving, uric, 'acid,', gut, microbiome, 'products,', and, 'so-called', uremic, toxins, accumulating, in, chronic, kidney, disease])].
[sujeto(['The', fact, that, 'OAT1', can, affect, many, systemic, biological, pathways]), verbo([suggests]), complemento([that, 'drug-metabolite', interactions, need, to, be, considered, beyond, simple, competition, for, the, drug, transporter, itself, and, may, explain, aspects, of, 'drug-induced', metabolic, syndrome])].
[sujeto(['Our', approach, should]), verbo([provide]), complemento([novel, mechanistic, insights, into, the, role, of, 'OAT1', and, other, drug, transporters, implicated, in, metabolic, diseases, like, 'gout,', 'diabetes,', and, chronic, kidney, disease])].
[sujeto(['It', is, well, established, that, the, 'renin-angiotensin', system, '(', 'RAS)', is, present, in, the, brain, and, that, glutamate]), verbo([activates]), complemento([the, brain, centers, responsible, for, blood, pressure, control])].
[sujeto(['An', antagonist, of, 'glutamate,', kynurenic, acid, '(', 'KYNA)', was, shown, to]), verbo([decrease]), complemento([blood, pressure, after, intracerebral, administration])].
[sujeto(['Among', the, examined, 'angiotensin-converting', enzyme, 'inhibitors,', lisinopril]), verbo([increased]), complemento(['KYNA', 'production,', perindopril, was, 'ineffective,', and, ramipril, decreased, 'KYNA', synthesis, in, rat, brain, cortical, slices])].
[sujeto(['Lisinopril']), verbo([increased]), complemento(['KAT', 'I', activity, and, perindopril, did, not, affect, it])].
[sujeto(['Neither', lisinopril, nor, perindopril, affected, 'KAT', 'II', 'activity,', but, ramipril]), verbo([decreased]), complemento(['KAT', 'II', activity, in, the, rat, brain, cortex, in, vitro])].
[sujeto(['Our', study]), verbo([reveals]), complemento([that, 'angiotensin-converting', enzyme, inhibitors, show, various, influences, on, 'KYNA', production, in, rat, brain, cortical, slices, and, activity, of, 'KATs'])].
[sujeto(['Several', 'KP', metabolites, play, distinct, physiological, 'roles,', often, linked, to, immune, system, 'functions,', and, may, also, be, causally]), verbo([involved]), complemento([in, human, diseases, including, neurodegenerative, 'disorders,', schizophrenia, and, cancer])].
[sujeto(['Pharmacological', manipulation, of, the, 'KP']), verbo([has]), complemento([therefore, become, an, active, area, of, drug, development])].
[sujeto(['To']), verbo([target]), complemento([the, pathway, 'effectively,', it, is, important, to, understand, how, specific, 'KP', enzymes, control, levels, of, the, bioactive, metabolites, in, vivo])].
[sujeto(['Here,', we, conducted, a, comprehensive, biochemical, characterization, of, mice, with, a]), verbo([targeted]), complemento([deletion, of, either, tryptophan, 2, ',', 3, -, dioxygenase, '(', 'TDO)', or, indoleamine, 2, ',', 3, -, dioxygenase, '(', 'IDO),', the, two, initial, 'rate-limiting', enzymes, of, the, 'KP'])].
[sujeto(['Although', our, study, revealed, several, unexpected, downstream, effects, on, 'KP', metabolism, in, both, knockout, 'mice,', the, results, were, essentially, consistent, with, 'TDO-mediated', control, of, basal, 'KP', metabolism, and, a, role, of, 'IDO', in, phenomena]), verbo([involving]), complemento([stimulation, of, the, immune, system])].
[sujeto(['The', anion]), verbo([binding]), complemento([properties, of, these, receptors, can, be, tuned, through, electronic, switching, to, stabilize, a, conformation, displaying, high, affinity, for, the, dihydrogenphosphate, and, pyrophosphate, anions, '(', as, the, tetrabutylammonium, 'salts)', in, chloroform])].
[sujeto(['Loss', of, the, 'C-1', and, 'C-5', carbon, moieties, during, the, formation, of, 3, -, 'mercaptobutan-2-one']), verbo([suggests]), complemento([two, different, mechanisms, leading, to, the, key, intermediate, 'butane-2,3-dione'])].
[sujeto(['The', photosensitizing, properties, of, 'tolmetin,', 5, -, '(', 'p-toluoyl)-1-methyl-2-pyrrolyacetic', acid, '(', 'TLM),']), verbo([have]), complemento([been, studied, in, vitro, following, the, lysis, of, erythrocytes, in, phosphate, buffer, suspensions, irradiated, with, 'UVA', light, in, the, presence, of, the, drug])].
[sujeto(['It', was]), verbo([found]), complemento([that, the, phototoxic, properties, of, the, drug, are, negligible, in, nitrogen, and, significant, in, aerated, 'medium,', but, that, they, decrease, in, 'oxygen-saturated', solution])].
[sujeto(['The', comparison, between, the, photohaemolysis, and, photolysis, results, and, the, effect, of, suitable, additives, such, as, sodium, 'azide,', 'mannitol,', butylated, 'hydroxy-anisole,', reduced, 'glutathione,', superoxide, dismutase, and, copper, '(', 'II)']), verbo([suggest]), complemento([that, the, phototoxicity, of, 'TLM', can, be, attributed, essentially, to, singlet, oxygen, in, the, first, step, and, to, its, photoproducts, when, they, accumulate, and, compete, with, the, starting, drug, in, light, absorption])].
[sujeto(['In', the, molecular, modelling, 'study,', compound, 9, i, was]), verbo([bound]), complemento([in, to, the, active, pocket, of, 'EGFR', with, four, hydrogen, bonds, and, two, 'π-cation', interactions, having, minimum, binding, energy, 'ΔGb=-54'])].
[sujeto(['In', the, molecular, modeling, 'study,', compound, 7, k, was]), verbo([bound]), complemento([in, to, the, active, pocket, of, 'EGFR', with, three, hydrogen, bond, and, one, 'π-cation', interaction, with, minimum, binding, energy, 'ΔGb', =, -, 54.6913, 'kcal/mol,', as, well, as, compound, 7, b, was, bound, in, to, the, active, site, of, 'FabH', with, hydrogen, bond, and, 'π-sigma', interactions, with, minimum, binding, energy, 'ΔGb', =, -, 45.9125, 'kcal/mol'])].
[sujeto(['Mechanistically,', metformin]), verbo([interacts]), complemento([with, many, protein, kinases, and, transcription, factors, that, alter, the, expression, of, numerous, downstream, target, genes, governing, lipid, 'metabolism,', cell, 'proliferation,', and, drug, metabolism])].
[sujeto(['The', constitutive, androstane, receptor, '(', 'CAR,', 'NR1i3),', a, known, xenobiotic, 'sensor,']), verbo([has]), complemento([recently, been, recognized, as, a, novel, signaling, 'molecule,', in, that, its, activation, could, be, regulated, by, protein, kinases, in, addition, to, the, traditional, ligand, binding])].
[sujeto(['We', show, that, metformin, could]), verbo([suppress]), complemento(['drug-induced', expression, of, 'CYP2B6', '(', a, typical, target, gene, of, 'CAR)', by, modulating, the, phosphorylation, status, of, 'CAR'])].
[sujeto(['In', human, 'hepatocytes,', metformin, robustly]), verbo([suppressed]), complemento([the, expression, of, 'CYP2B6', induced, by, both, indirect, '(', 'phenobarbital)', and, direct, 'CITCO', '[', 6, -, '(', 4, -, 'chlorophenyl)imidazo[2,1-b]1,3thiazole-5-carbaldehyde', 'O-(3,4-dichlorobenzyl)oxime]', activators, of, human, 'CAR'])].
[sujeto(['Mechanistic', investigation, revealed, that, metformin, specifically]), verbo([enhanced]), complemento([the, phosphorylation, of, 'threonine-38', of, 'CAR,', which, blocks, 'CAR', nuclear, translocation, and, activation])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, metformin, is, a, potent, repressor, of, 'drug-induced', 'CYP2B6', expression, through, specific, inhibition, of, human, 'CAR', activation])].
[sujeto(['These', compounds]), verbo([inhibited]), complemento([the, growth, of, 'ErbB-2', 'over-expressing', human, tumor, cell, lines, '(', 'BT474,', 'N87,', and, 'SK-BR-3)', in, vitro])].
[sujeto(['Compound', 15, emerged, as, a, key]), verbo([lead]), complemento([and, showed, significant, ability, to, inhibit, growth, 'factor-induced', receptor, phosphorylation, in, 'SK-BR-3', cells, '(', 'IC(50)=54', 'nM)', and, cellular, proliferation, in, vitro, '(', 'IC(50)=14,', 58, ',', and, 58, nM, for, 'BT474,', 'N87,', and, 'SK-BR-3', 'respectively)'])].
[sujeto(['This', work]), verbo([has]), complemento([now, been, extended, by, using, 6, -, ',', 7, -, ',', and, 8, -, quinolinecarbaldehyde, to, prepare, 23, new, 'quinoline-tyrphostins', 1, -, 23])].
[sujeto(['The', order, of, potency, was, 7, -, &, 'gt;', 6, &, 'gt;', 8, -, substituted, 'quinoline,', which, indicates, that]), verbo([increased]), complemento([activity, of, the, 7, -, substituted, quinolines, is, associated, with, electron, deficiency, at, the, 7, -, position, in, the, quinoline, ring])].
[sujeto(['Compounds', 1, -, 23, showed, similar, 'IC50', values, against, the, 'MCF7', and, 'MCF7/ADR', cell, lines, '(', the, latter, shows, fourfold]), verbo([increased]), complemento([protein, tyrosine, kinase, 'activity)', except, for, the, compounds, 1, and, 15, formed, from, 6, -, quinolinecarbaldehyde, and, malononitrile, and, 7, -, quinolinecarbaldehyde, and, 'cyanoacetamide,', which, showed, a, significant, '(', 11, -, and, 42, -, 'fold,', 'respectively)', increase, in, potency, against, the, 'MCF7/ADR', cell, line])].
[sujeto(['Furthermore,', no, association, was]), verbo([found]), complemento([between, growth, inhibition, and, inhibition, of, the, 'EGFR', protein, tyrosine, kinase, '(', 'PTK),', using, a, 'cell-free', assay])].
[sujeto(['In', 'addition,', new, compounds, were, prepared, from, 2, -, and, 4, -, quinolinecarbaldehyde, with, extended, conjugation, in, the, side, chains, '(', 24, -, 27, ')', or, with, methoxypolyethoxyethyl, esters, in, the, side, chain, to]), verbo([increase]), complemento([water, solubility, '(', 28, and, 29, ')'])].
[sujeto(['No', association, was]), verbo([found]), complemento([between, inhibition, of, 'PTK', and, growth, 'inhibition,', again, indicating, that, their, mode, of, action, may, not, be, specific, for, the, 'EGF', receptor])].
[sujeto(['The', channel, was, originally, identified, as, a, 'volume-regulated', ion, channel, that, can, be]), verbo([activated]), complemento([upon, reduction, of, the, extracellular, osmolality])].
[sujeto(['Later,', the, channel, was, proposed, to, be]), verbo([involved]), complemento([in, the, modulation, of, insulin, release, in, pancreatic, islets])].
[sujeto(['However,', new, evidence]), verbo([has]), complemento([uncovered, a, role, of, 'TRPM3', as, a, thermosensitive, nociceptor, channel, implicated, in, the, detection, of, noxious, heat])].
[sujeto(['The', channel, is, functionally]), verbo([expressed]), complemento([in, a, subset, of, neurons, of, the, somatosensory, system, and, can, be, activated, by, heat])].
[sujeto(['In', somatosensory, 'neurons,', 'TRPM3']), verbo([has]), complemento([been, implicated, in, temperature, perception, and, inflammatory, 'hyperalgesia,', whereas, in, pancreatic, 'β-cells', the, channel, has, been, linked, to, 'glucose-induced', insulin, release])].
[sujeto(['In', 'cells,', it, is]), verbo([activated]), complemento([by, heat, and, chemical, 'agonists,', including, pregnenolone, sulfate, '(', 'PS)', and, nifedipine, '(', 'Nif)'])].
[sujeto(['We']), verbo([found]), complemento([that, 'phosphatidylinositol-4,5-bisphosphate', '(', 'PIP2)', or, clotrimazole, is, necessary, for, channel, opening, by, 'PS'])].
[sujeto(['Unlike', 'PS,', the, presence, of, 'Nif', alone, sufficed, to]), verbo([induce]), complemento(['TRPM3', activity, and, demonstrated, distinct, gating, behavior])].
[sujeto(['We', also, performed, an, extensive, thermodynamic, analysis, of, 'TRPM3', activation, and]), verbo([found]), complemento([that, 'TRPM3', exhibited, slight, temperature, sensitivity, in, the, bilayers])].
[sujeto(['We', confirmed, its, direct, gating, by, 'PS', and, 'PIP2,', but]), verbo([found]), complemento([a, lack, of, the, strong, intrinsic, temperature, sensitivity, common, to, other, thermosensitive, 'TRP', channels])].
[sujeto(['The', major, organic, 'solvent-extractable', metabolites, of, 'BP']), verbo([found]), complemento([in, the, extracellular, culture, medium, were, primarily, the, diols, with, smaller, quantities, of, phenols, and, quinones])].
[sujeto(['Clotrimazole']), verbo([inhibited]), complemento([the, generation, of, organic, 'solvent-soluble', and, 'water-soluble', conjugates, in, a, 'dose-dependent', manner])].
[sujeto(['The', in, vitro, metabolism, of, 'BP', by, microsomes, prepared, from, control, and, 'benz[a]anthracene', '(', 'BA)-induced', cultured, keratinocytes, was, also]), verbo([inhibited]), complemento([by, clotrimazole, with, greater, inhibitory, effect, on, 'BA-induced', keratinocytes, especially, with, respect, to, the, formation, of, diols, and, quinones])].
[sujeto(['The', 'enzyme-mediated', covalent]), verbo([binding]), complemento([of, 'BP', to, mouse, keratinocyte, 'DNA', and, protein, was, also, substantially, diminished, by, clotrimazole, in, a, 'dose-dependent', fashion])].
[sujeto(['The', activity, in, vitro, of, 'miconazole,', 'clotrimazole,', 'econazole,', sodium, 'omadine,', and, sodium, thiosulphate, against, 'Pityrosporum', orbiculare, was]), verbo([found]), complemento([to, correlate, with, the, good, clinical, results, these, drugs, produce, in, tinea, versicolor])].
[sujeto(['The', monooxygenase, activity, was]), verbo([inhibited]), complemento([by, carbon, 'monoxide,', phenylisocyanide, and, 'anti-NADPH-cytochrome', 'P-450', reductase, 'IgG,', but, not, by, 'anti-cytochrome', b5, 'IgG'])].
[sujeto(['The', enzymatic, activity]), verbo([inhibited]), complemento([by, carbon, monoxide, was, photoreversibly, restored, by, light, of, a, wavelength, of, around, 450, nm])].
[sujeto(['The', microsomal, monooxygenase, activity]), verbo([induced]), complemento([by, phenobarbital, or, ethanol, were, more, effective, than, that, by, 3, -, 'methylcholanthrene,', clotrimazole, or, 'beta-naphthoflavone'])].
[sujeto(['The', treatment, of, vaginal, infection, at, week, 28, with, the, topical, association, of, 'metronidazole+clotrimazole,']), verbo([led]), complemento([to, both, the, eradication, of, vaginal, infections, and, the, restoration, of, the, vaginal, microbiota, in, 72, '%', of, the, 'cases,', bringing, the, level, of, risk, of, pPROM, similar, to, that, of, women, without, vaginal, infection, at, week, 28])].
[sujeto(['Furthermore,', data]), verbo([suggested]), complemento([the, possible, benefits, of, the, topical, treatment, with, 'metronidazole+clotrimazole', in, pregnancy, to, eradicate, 'infections,', restore, the, normal, microbiota, and, reduce, the, risk, of, pPROM])].
[sujeto(['Physicochemical', parameters, '(', globule, 'size,', zeta, 'potential,', drug, 'content,', viscosity, and, 'pH),', and, in, vitro]), verbo([release]), complemento([of, 'CME', were, studied])].
[sujeto(['The', developed, 'CME', displayed, an, average, globule, size, less, than, 50, nm, and, a, positive, surface, 'charge,', acceptable, 'physico-chemical', 'behavior,', and, exhibited, sustained, drug]), verbo([release]), complemento([in, 'in-vitro', study])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, positively, charged, chitosan, coated, microemulsions, could, be, used, as, novel, topical, formulation, for, its, ability, to, retain, on, the, skin, and, its, ability, to, sustain, the, release, of, the, drug])].
[sujeto(['Mint,', 'basil,', 'lavender,', tea, tree, 'oil,', winter, savory, and, oregano, essential, oils]), verbo([inhibited]), complemento([both, the, growth, and, the, activity, of, 'C'])].
[sujeto(['Damages']), verbo([induced]), complemento([by, essential, oils, at, the, cellular, level, were, stronger, than, those, caused, by, clotrimazole])].
[sujeto(['Some', infections]), verbo([have]), complemento([been, reported, to, be, tolerant, to, conventional, 'treatments,', especially, in, immunosuppressed, patients])].
[sujeto(['New', studies]), verbo([have]), complemento([suggested, that, 'ozone,', which, is, the, allotropic, form, of, 'oxygen,', may, have, antifungal, effects])].
[sujeto(['Results', '•', 'Ozone', and, clotrimazole, both, reduced, symptoms, significantly, and]), verbo([led]), complemento([to, a, negative, culture, for, vaginal, candidiasis, '(', 'P', &, 'lt;'])].
[sujeto(['However,', clotrimazole]), verbo([decreased]), complemento([the, burning, sensation, significantly, more, than, did, ozone, '(', 'P', &, 'lt;'])].
[sujeto(['Conclusions', '•', 'Considering', the, potential, efficacy, of, ozonated, olive, oil, in, the, improvement, of, the, clinical, and, paraclinical, aspects, of, treatment, of, patients, with, vulvovaginal, 'candidiasis,', the, research, team]), verbo([suggests]), complemento([that, the, treatment, can, be, an, effective, topical, treatment, for, those, patients])].
[sujeto(['After', culturing, with, different, concentrations, of, ligustrazine, or, the, inhibitor, of, 'AKT', '(', 'LY294002)', for, 72, 'h,', cell, 'viability,', clone, formation, 'numbers,', and, levels, of, phosphatidyl, inositol, 3, -, kinase, '(', 'PI3K),', 'p-AKT,', and, 'p-mammalian']), verbo([target]), complemento([of, rapamycin, '(', 'mTOR)', were, determined])].
[sujeto(['Both', the, cell, viability, and, clone, formation, numbers, were, significantly]), verbo([inhibited]), complemento([by, application, of, 'LY294002'])].
[sujeto(['CONCLUSIONS', 'Our', results]), verbo([suggest]), complemento([that, ligustrazine, combined, with, holistic, nursing, is, an, effective, treatment, of, pressure, sores])].
[sujeto(['The', protective, effect, may, be]), verbo([associated]), complemento([with, the, promotion, of, cell, growth, by, activation, of, the, 'PI3K/AKT', pathway])].
[sujeto(['Results', indicated, the, presence, of, two, of, the]), verbo([targeted]), complemento(['COXIBs', in, real, samples, of, sewage, 'sludge,', the, highest, average, concentration, '(', 22, 'ngg(-1))', corresponding, to, celecoxib])].
[sujeto(['MRP3', expression, in, the, human, liver, is, low, under, normal, physiologic, conditions, but, is]), verbo([induced]), complemento([by, drug, treatment])].
[sujeto(['Although', several, studies]), verbo([have]), complemento([identified, a, region, necessary, for, the, basal, transcription, of, 'MRP3,', no, region, that, responds, to, drugs, has, been, reported])].
[sujeto(['Among', typical]), verbo([nuclear]), complemento([receptor, 'ligands,', clotrimazole, dramatically, enhanced, 'MRP3', reporter, activity, in, 'HepG2', 'cells,', whereas, rifampicin, had, no, effect])].
[sujeto(['Overexpression', of, the, pregnane, 'X', receptor, did, not]), verbo([enhance]), complemento(['clotrimazole-mediated', transcription])].
[sujeto(['We']), verbo([found]), complemento([that, clotrimazole, was, toxic, to, 'HepG2', cells, and, we, therefore, investigated, whether, 'mitogen-activated', protein, kinase, '(', 'MAPK)', activation, is, involved, in, the, transactivation, of, 'MRP3', by, clotrimazole])].
[sujeto([p38, 'MAPK', inhibitor, 'SB203580', '[', 4, -, '(', 4, -, 'fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole]']), verbo([suppressed]), complemento(['MRP3', mRNA, expression, induced, by, 'clotrimazole,', whereas, 'c-Jun', 'N-terminal', kinase, inhibitor, 'SP600125', '(', 1, ',', 9, -, 'pyrazoloanthrone)', and, extracellular, 'signal-regulated', kinase, inhibitor, 'PD98059', '[', 2, -, '(', 2, -, 'amino-3-methoxyphenyl)-4H-1-benzopyran-4-one]', did, not])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, activation, of, the, p38, 'MAPK', pathway, induces, the, transcriptional, activation, of, 'MRP3'])].
[sujeto(['In', this, 'study,', three, different, polymeric, coatings, are, investigated, for, their, ability, to, stabilize, amorphous, films, of, the, model, drug, clotrimazole, and, to, protect, against, thermally]), verbo([induced]), complemento([transitions])].
[sujeto(['Optical', microscopy, and, 'X-ray', diffraction, data]), verbo([reveal]), complemento([that, at, ambient, conditions, of, about, 22, °, 'C,', any, of, these, iCVD, layers, extends, the, lifetime, of, the, amorphous, state, significantly])].
[sujeto(['At', higher, temperatures, '(', 50, or, 70, °, 'C),', the, 'p-PFDA', coating, is, unable, to]), verbo([provide]), complemento(['protection,', while, the, 'p-HEMA', and, 'p-MAA', strongly, reduce, the, crystallization, rate])].
[sujeto(['Furthermore,', 'p-HEMA', and, 'p-MAA', selectively, facilitate, a, preferential, alignment, of, clotrimazole, 'and,', 'interestingly,', even]), verbo([suppress]), complemento([crystallization, upon, a, 'temporary,', rapid, temperature, increase, '(', 3, °, 'C/min,', up, to, 150, °, 'C)'])].
[sujeto(['The', results, of, this, study, demonstrate, how, a, polymeric, 'coating,', synthesized, directly, on, top, of, an, amorphous, 'phase,', can]), verbo([act]), complemento([as, a, stabilizing, agent, against, crystalline, 'transitions,', which, makes, this, approach, interesting, for, a, variety, of, applications])].
[sujeto(['Further', studies, of, 'PM', in, 'HaCaT', cells]), verbo([suggest]), complemento([its, 'DNA', damaging, potential, which, may, lead, to, apoptosis])].
[sujeto(['Generation', of, reactive, oxygen, and, nitrogen, species, following, 'PM', exposure, may, be, an, early, event, in, the, 'PM']), verbo([induced]), complemento([apoptosis])].
[sujeto(['In', 'addition,', the, activity, of, cytochrome, 'P450', '(', 'CYP450),', the, key, xenobiotic, metabolism, 'enzyme,', was]), verbo([found]), complemento([to, be, increased, following, 'PM', exposure, indicating, its, role, in, 'PM', induced, toxicity])].
[sujeto(['Interestingly,', we]), verbo([found]), complemento([that, the, use, of, these, inhibitors, significantly, suppressed, the, 'PM', induced, apoptosis, in, 'HaCaT', 'cells,', which, confirm, the, crucial, role, of, 'CYP1B1', in, the, toxic, manifestation, of, 'PM'])].
[sujeto(['Taken', 'together;', this, study, first, time]), verbo([reports]), complemento([the, possible, health, hazards, of, 'PM', from, industrial, areas, of, 'Odisha,', 'India'])].
[sujeto(['The', 'CYP26s', are, responsible, for, metabolizing, retinoic, acid, and, play, an, important, role, in]), verbo([maintaining]), complemento([homeostatic, levels, of, retinoic, acid])].
[sujeto(['Given', the, ability, of, 'CYP2C8', to, metabolize, retinoic, 'acid,', we, evaluated, the, potential, for, 'CYP2C8', inhibitors, to, also]), verbo([inhibit]), complemento(['CYP26'])].
[sujeto(['An', evaluation, of, 'IC50\'s', versus, in, vivo, 'Cmax', values]), verbo([suggests]), complemento([that, inhibitors, such, as, clotrimazole, or, fluconazole, may, interact, with, 'CYP26', at, clinically, relevant, concentrations, and, may, alter, levels, of, retinoic, acid])].
[sujeto(['These', findings]), verbo([provide]), complemento([insight, into, drug, interactions, resulting, in, elevated, retinoic, acid, concentrations, and, expand, upon, the, pharmacophore, of, 'CYP26', inhibition])].
[sujeto(['However,', a, larger, study, is]), verbo([required]), complemento([to, draw, more, solid, conclusions])].
[sujeto(['Probiotic', use, was]), verbo([associated]), complemento([with, a, 'three-fold', reduction, in, the, adjusted, risk, of, recurrence, '(', 'HR', '[', 95, &, 'nbsp;%CI]:', 0.3, '[', 0.1, -, 0.91, ']', ;, 'P', =, 0.033, ')'])].
[sujeto(['Similar', findings, were]), verbo([found]), complemento([at, six, months, after, azole, treatment, in, women, with, 'RVVC'])].
[sujeto(['Overall,', good, compliance, with, the, probiotic, was]), verbo([reported]), complemento([for, 91.3, &, 'nbsp;%', of, women])].
[sujeto(['The', study]), verbo([suggests]), complemento([that, 'follow-up', therapy, with, vaginal, tablets, with, 'L'])].
[sujeto([plantarum, 'I1001', could]), verbo([increase]), complemento([the, effectiveness, of, 'single-dose', 500, &, 'nbsp;mg', clotrimazole, at, preventing, recurrence, of, 'VVC,', an, effect, that, was, also, observed, in, women, with, recurrent, vulvovaginal, candidiasis, '(', 'RVVC)', after, six, months, of, azole, treatment])].
[sujeto(['These', complexes, were, characterized, by, a, combination, of, elemental, 'analysis,', molar, 'conductivity,', infrared, and, 'UV-vis', 'spectroscopy,', '(', 1, ')', 'H,', '(', 13, ')', 'C{(1)H}', and, '(', 31, ')', 'P{(1)H}']), verbo([nuclear]), complemento([magnetic, resonance, 'techniques,', cyclic, voltammetry, and, mass, spectroscopy])].
[sujeto(['Bovine', serum, albumin]), verbo([binding]), complemento(['constants,', which, were, in, the, range, of, 1.3, -, 36.0, '×10(4)M(-1),', and, thermodynamic, parameters, suggest, spontaneous, interactions, with, this, protein, by, electrostatic, forces, due, to, the, positive, charge, of, the, complexes])].
[sujeto(['DNA', interactions, studied, by, spectroscopic, 'titration,', viscosity, 'measurements,', gel, 'electrophoresis,', circular, 'dichroism,', ethidium, bromide, displacement, and, reactions, with, guanosine, and, guanosine, monophosphate, indicated, the, 'DNA']), verbo([binding]), complemento([affinity, primarily, through, 'non-covalent', interactions])].
[sujeto(['The', antimicrobial, activity, assays, of, the, complexes]), verbo([provided]), complemento([evidence, that, they, are, potential, agents, against, mycobacterial, 'infections,', specifically, against, 'Mycobacterium', tuberculosis, 'H37Rv'])].
[sujeto(['A', validation, set, composed, of, 12, mixtures, containing, different, ratios, of, the, three, analytes, was, used, to, evaluate, the, predictive, power, of, the]), verbo([suggested]), complemento([models])].
[sujeto(['Additionally,', the, work, highlighted, the, effect, of, 'GA', on]), verbo([increasing]), complemento([the, predictive, power, of, 'PLS', and, 'ANN', models])].
[sujeto(['TRPM2', channels]), verbo([have]), complemento([been, suggested, to, play, a, role, in, ischemic, neuronal, 'injury,', specifically, in, males])].
[sujeto(['A', major, hindrance, to, 'TRPM2', research]), verbo([has]), complemento([been, the, lack, of, specific, 'TRPM2', inhibitors])].
[sujeto(['Fluorescent', calcium, imaging, '(', 'Fluo5F)', was, used, to, determine, inhibitor, efficacy, of, the, 'TRPM2', peptide, inhibitor, '(', 'tat-M2NX)', in, 'HEK293', cells, stably]), verbo([expressing]), complemento([hTRPM2])].
[sujeto(['TRPM2', inhibition, by, 'tat-M2NX', was, observed, by]), verbo([decreased]), complemento(['Ca(2+)', influx, following, 'H2O2', exposure, human, 'TRPM2', expressing, cells])].
[sujeto(['Administration', of, 'tat-M2NX', 3, h, after, reperfusion]), verbo([provided]), complemento([significant, protection, to, males, when, analyzed, at, 24, h, or, 4, days, after, 'MCAO'])].
[sujeto(['These', data, demonstrate, the, development, of, a, new, peptide, inhibitor, of, 'TRPM2', channels, that]), verbo([provides]), complemento([protection, from, ischemic, stroke, in, young, adult, and, aged, male, animals, with, a, clinically, relevant, therapeutic, window])].
[sujeto(['It', is, a, multifactorial, disease]), verbo([associated]), complemento([with, numerous, nutritional, deficiencies, as, well, as, reproductive, issues, and, increased, risk, to, thyroid, 'disease,', kidney, failure, and, cancer])].
[sujeto(['Celiac', disease, is]), verbo([associated]), complemento([with, imbalances, in, gut, bacteria, that, can, be, fully, explained, by, the, known, effects, of, glyphosate, on, gut, bacteria])].
[sujeto(['Characteristics', of, celiac, disease, point, to, impairment, in, many, cytochrome, 'P450', 'enzymes,', which, are]), verbo([involved]), complemento([with, detoxifying, environmental, 'toxins,', activating, vitamin, 'D3,', catabolizing, vitamin, 'A,', and, maintaining, bile, acid, production, and, sulfate, supplies, to, the, gut])].
[sujeto(['Glyphosate', is, known, to]), verbo([inhibit]), complemento([cytochrome, 'P450', enzymes])].
[sujeto(['Deficiencies', in, 'iron,', 'cobalt,', 'molybdenum,', copper, and, other, rare, metals]), verbo([associated]), complemento([with, celiac, disease, can, be, attributed, to, 'glyphosate\'s', strong, ability, to, chelate, these, elements])].
[sujeto(['Deficiencies', in, 'tryptophan,', 'tyrosine,', methionine, and, selenomethionine]), verbo([associated]), complemento([with, celiac, disease, match, 'glyphosate\'s', known, depletion, of, these, amino, acids])].
[sujeto(['Celiac', disease, patients]), verbo([have]), complemento([an, increased, risk, to, 'non-Hodgkin\'s', 'lymphoma,', which, has, also, been, implicated, in, glyphosate, exposure])].
[sujeto(['Reproductive', issues]), verbo([associated]), complemento([with, celiac, 'disease,', such, as, 'infertility,', 'miscarriages,', and, birth, 'defects,', can, also, be, explained, by, glyphosate])].
[sujeto(['Glyphosate', residues, in, wheat, and, other, crops, are, likely]), verbo([increasing]), complemento([recently, due, to, the, growing, practice, of, crop, desiccation, just, prior, to, the, harvest])].
[sujeto(['This']), verbo([suggests]), complemento([that, selenium, derived, from, these, compounds, converge, to, a, common, metabolic, pool])].
[sujeto(['If', more, than, 80, '%', of, the, activity, administered, is]), verbo([found]), complemento([in, the, gall, 'bladder,', disturbed, absorption, of, bile, acids, in, the, terminal, ileum, can, be, excluded])].
[sujeto(['Values', smaller, than, 80, '%', ',', 'however,', do, not]), verbo([provide]), complemento([proof, of, disturbed, absorption])].
[sujeto(['BAAT']), verbo([has]), complemento([a, dual, localization, to, the, cytosol, and, 'peroxisomes,', possibly, due, to, an, inefficient, 'carboxy-terminal', peroxisomal, targeting, signal, '(', 'PTS),', -, 'serine-glutamine-leucine', '(', -, 'SQL)'])].
[sujeto(['Amidation', activity, of, 'BAAT', and, 'BAAT', lacking, the, final, two, amino, acids, '(', 'AAs)', '(', 'BAAT-S)', were, 'similar,', whereas, the, activity, of, 'BAAT', with, a, canonical, 'PTS', sequence, '(', 'BAAT-SKL)', was]), verbo([increased]), complemento([&, 'gt;2'])].
[sujeto(['BAAT-S', immunoprecipitated, when, incubated, with, peroxisomal, biogenesis, factor, 5, '(', 'Pex5)', and, rabbit, 'anti-Pex5', 'antibodies;', 'however,', deleting, the, final, 12, 'AAs']), verbo([prevented]), complemento([coimmunoprecipitation, with, 'Pex5,', indicating, the, 'Pex5', interaction, involves, more, than, the, -, 'SQL', sequence])].
[sujeto(['These', results, indicate, that, even, small, changes, in, the, carboxy, terminus, of, 'BAAT', can]), verbo([have]), complemento([significant, effects, on, activity, and, substrate, specificity])].
[sujeto(['Serum', bile, acids, '(', 'BAs)', are, elevated, following, bariatric, surgery, and]), verbo([have]), complemento([emerged, as, a, potential, 'glucose-lowering', beneficial, factor])].
[sujeto(['Duodenal-jejunal', bypass, '(', 'DJB),', sleeve, gastrectomy, '(', 'SG),', and, sham, operation, were, performed, in, diabetic, rats]), verbo([induced]), complemento([by, 'high-fat', diet, '(', 'HFD)', and, streptozotocin, '(', 'STZ)'])].
[sujeto(['They', also, resulted, in]), verbo([increased]), complemento([serum, 'BAs,', especially, the, 'taurine-conjugated', 'BAs', by, elevated, conjugation])].
[sujeto(['No', obvious, difference, was, detected, between, 'DJB', and, 'SG', except, that, 'SG', achieved]), verbo([decreased]), complemento([weight, gain, and, food, intake])].
[sujeto(['The', preferentially, elevated, serum, 'taurine-conjugated', 'BAs', were, similar, after, different, bariatric, 'surgeries,', and, the]), verbo([enhanced]), complemento([conjugation, of, 'BAs', in, the, liver, might, account, for, the, changed, serum, 'BAs', profiles])].
[sujeto(['Alcoholic', liver, disease, '(', 'ALD)', is, one, of, the, major]), verbo([causes]), complemento([of, liver, morbidity, and, mortality, worldwide])].
[sujeto(['Chronic', alcohol, consumption]), verbo([leads]), complemento([to, development, of, liver, pathogenesis, encompassing, 'steatosis,', 'inflammation,', 'fibrosis,', 'cirrhosis,', and, in, extreme, 'cases,', hepatocellular, carcinoma])].
[sujeto(['Moreover,', 'ALD', may, also]), verbo([associate]), complemento([with, cholestasis])].
[sujeto(['Emerging', evidence, now]), verbo([suggests]), complemento([that, farnesoid, 'X', receptor, '(', 'FXR)', and, bile, acids, also, play, important, roles, in, 'ALD'])].
[sujeto(['Taken', 'together,', reduced, 'BA', conjugate, formation, in, 'day-3', 'SCRH', results, in, lower, intracellular, glycine, conjugate, 'concentrations,', explaining]), verbo([decreased]), complemento([toxicity, of, '(', 'C)DCA', in, 'day-3', versus, 'day-1', 'SCRH'])].
[sujeto(['Our', data]), verbo([provide]), complemento([for, the, first, time, a, direct, link, between, 'BA', toxicity, and, glycine, conjugate, exposure, in, 'SCRH'])].
[sujeto(['The', final, step, in, bile, acid, synthesis]), verbo([involves]), complemento([conjugation, with, glycine, and, 'taurine,', which, promotes, a, high, intraluminal, micellar, concentration, to, facilitate, lipid, absorption])].
[sujeto(['We', identified, the, genetic, defect, that]), verbo([causes]), complemento([this, disorder, using, mass, spectrometry, analysis, of, 'urine,', 'bile,', and, serum, samples, and, sequence, analysis, of, the, genes, encoding, bile, 'acid-CoA:amino', acid, 'N-acyltransferase', '(', 'BAAT)', and, bile, 'acid-CoA', ligase, '(', 'SLC27A5)'])].
[sujeto(['Levels', of, urinary, bile, acids, were]), verbo([increased]), complemento(['(', 432, ±, 248, 'μmol/L)', and, predominantly, excreted, in, unconjugated, forms, '(', 79.4, '%', ±, 3.9, '%', ')', and, as, sulfates, and, glucuronides])].
[sujeto(['Based', on, a, study, of, 10, pediatric, 'patients,', genetic, defects, that, disrupt, bile, acid, amidation]), verbo([cause]), complemento(['fat-soluble', vitamin, deficiency, and, growth, 'failure,', indicating, the, importance, of, bile, acid, conjugation, in, lipid, absorption])].
[sujeto(['Cholate-CoA', ligase, '(', 'CCL)', and, bile, 'acid-CoA:', amino, acid, 'N-acyltransferase', '(', 'BAAT)', sequentially]), verbo([mediate]), complemento(['bile-acid', amidation])].
[sujeto(['Defects', can]), verbo([cause]), complemento([intrahepatic, cholestasis])].
[sujeto(['Distinction']), verbo([has]), complemento([required, gene, sequencing])].
[sujeto(['The', importance, of, peroxisomes, in, lipid, metabolism, is, now, well, established, and, peroxisomes, contain, approximately, 60, enzymes]), verbo([involved]), complemento([in, these, lipid, metabolic, pathways])].
[sujeto(['Several', 'acyl-CoA', thioesterase, enzymes, '(', 'ACOTs)']), verbo([have]), complemento([been, identified, in, peroxisomes, that, catalyze, the, hydrolysis, of, 'acyl-CoAs', '(', 'short-,', 'medium-,', 'long-', and, very, 'long-chain),', bile, 'acid-CoAs,', and, methyl, 'branched-CoAs,', to, the, free, fatty, acid, and, coenzyme, 'A'])].
[sujeto(['A', number, of, acyltransferase, 'enzymes,', which, are, structurally, and, functionally, related, to, 'ACOTs,']), verbo([have]), complemento([also, been, identified, in, 'peroxisomes,', which, conjugate, '(', or, 'amidate)', bile, 'acid-CoAs', and, 'acyl-CoAs', to, amino, 'acids,', resulting, in, the, production, of, amidated, bile, acids, and, fatty, acids])].
[sujeto(['The', function, of, 'ACOTs', is, to]), verbo([act]), complemento([as, auxiliary, enzymes, in, the, 'α-', and, 'β-oxidation', of, various, lipids, in, peroxisomes])].
[sujeto(['In', 'addition,', 'BAAT', is]), verbo([required]), complemento([for, reconjugation, of, bile, salts, in, the, enterohepatic, circulation])].
[sujeto(['Treatment', of, 'D(4)CA-exposed', hepatocytes, with, 30, -, 150, 'μg/mL', digitonin]), verbo([led]), complemento([to, the, complete, release, of, 'D(4)CA,', 'D(4)GCA,', and, glyceraldehyde, 3, -, phosphate, dehydrogenase, '(', 'GAPDH)', '(', cytosolic, 'marker)'])].
[sujeto(['Full']), verbo([release]), complemento([of, 'D(4)TCA,', 'catalase,', and, 'BAAT', was, only, observed, at, 500, 'μg/mL', 'digitonin,', indicating, the, presence, of, 'D(4)TCA', in, 'membrane-enclosed', organelles])].
[sujeto(['Expression', of, 'caveolin-1', in, hepatocytes, is, relatively, 'low,', and, it]), verbo([has]), complemento([been, suggested, to, also, reside, at, other, subcellular, locations, than, the, plasma, membrane])].
[sujeto(['Recently,', we]), verbo([found]), complemento([that, the, peroxisomal, membrane, contains, lipid, microdomains])].
[sujeto(['Like', 'caveolin-1,', hepatic, peroxisomes, are]), verbo([involved]), complemento([in, lipid, metabolism])].
[sujeto(['Green', fluorescent, protein, '(', 'GFP)-tagged', 'caveolin-1', was]), verbo([expressed]), complemento([in, rat, hepatocytes])].
[sujeto(['Cell', fractionation, and, microscopic, analyses]), verbo([reveal]), complemento([that, 'caveolin-1', colocalizes, with, peroxisomal, marker, proteins, '(', 'catalase,', the, 70, kDa, peroxisomal, membrane, protein, 'PMP70,', the, adrenoleukodystrophy, protein, 'ALDP,', 'Pex14p,', and, the, bile, 'acid-coenzyme', 'A:amino', acid, 'N-acyltransferase', 'BAAT)', in, rat, hepatocytes])].
[sujeto(['Artificially']), verbo([expressed]), complemento(['GFP-caveolin-1', accumulated, in, 'catalase-positive', organelles])].
[sujeto(['Peroxisomal', 'caveolin-1', is]), verbo([associated]), complemento([with, 'detergent-resistant', microdomains])].
[sujeto(['Caveolin-1', expression, is, strongly]), verbo([repressed]), complemento([by, the, peroxisome, 'proliferator-activated', 'receptor-alpha', agonist, fenofibric, acid])].
[sujeto(['Caveolin-1', is, not]), verbo([required]), complemento([for, peroxisome, 'biogenesis,', but, this, unique, subcellular, location, may, determine, its, important, role, in, hepatocyte, proliferation, and, lipid, metabolism])].
[sujeto(['We']), verbo([have]), complemento([used, photobleaching, in, live, cells, expressing, green, fluorescent, protein, '(', 'GFP)-fusion', proteins, to, show, that, imported, bona, fide, peroxisomal, matrix, proteins, are, retained, in, the, peroxisome])].
[sujeto(['Using', this, technique, we]), verbo([found]), complemento([that, 'GFP', tagged, bile, 'acid-CoA:amino', acid, 'N-acyltransferase', '(', 'BAAT)', was, exclusively, localized, in, the, cytosol, in, 'HeLa', cells])].
[sujeto(['We', conclude, that, the, cytosolic, localization, was, due, to, its, carboxyterminal, 'non-consensus', peroxisomal]), verbo([targeting]), complemento([signal, '(', -, 'SQL)', since, mutation, of, the, -, 'SQL', to, -, 'SKL', resulted, in, 'BAAT', being, efficiently, imported, into, peroxisomes])].
[sujeto(['The', absence, or, presence, of, a, cytosolic, pool, of, 'BAAT']), verbo([has]), complemento([important, implications, for, the, intracellular, transport, of, 'unconjugated/deconjugated', bile, salts])].
[sujeto(['In', 'addition,', green, fluorescent, protein, '(', 'GFP)-tagged', rat, 'Baat', '(', 'rBaat)', and, human, 'BAAT', '(', 'hBAAT)', were, transiently]), verbo([expressed]), complemento([in, primary, rat, hepatocytes, and, human, fibroblasts])].
[sujeto(['Endogenous', hBAAT, and, rBaat, were]), verbo([found]), complemento([to, specifically, localize, to, peroxisomes, in, human, and, rat, 'hepatocytes,', respectively])].
[sujeto(['Significant', amounts, of, 'GFP-tagged', hBAAT, or, rBaat, were, detected, in, the, cytosol, only, when, coexpressed, with, 'DsRed-SKL,']), verbo([suggesting]), complemento([that, 'hBAAT/rBaat', and, 'DsRed-SKL', compete, for, the, same, peroxisomal, import, machinery])].
[sujeto(['When']), verbo([expressed]), complemento([in, 'fibroblasts,', 'GFP-tagged', hBAAT, localized, to, the, 'cytosol,', confirming, earlier, observations])].
[sujeto(['In', recent, 'years,', human, genetic, and, molecular, studies]), verbo([have]), complemento([identified, several, 'genes,', the, disruption, of, which, results, in, cholestasis])].
[sujeto(['Mutations', in, 'BAAT,', 'TJP2', '(', 'ZO-2),', and, 'EPHX1']), verbo([have]), complemento([been, identified, in, patients, with, hypercholanemia])].
[sujeto(['A', 'CLDN1', mutation, was, recently]), verbo([reported]), complemento([in, patients, with, 'ichthyosis,', leukocyte, 'vacuoles,', alopecia, and, sclerosing, cholangitis, '(', 'ILVASC),', and, 'North', 'American', 'Indian', childhood, cirrhosis, '(', 'NAIC)', is, associated, with, a, missense, mutation, in, 'CIRH1A'])].
[sujeto(['Alagille', syndrome, patients, carry, mutations, in, 'JAG1,', and, mutations, in, 'VPS33B']), verbo([have]), complemento([been, identified, in, patients, with, 'arthrogryposis,', renal, dysfunction, and, cholestasis, syndrome, '(', 'ARC)'])].
[sujeto(['Identification', of, these, 'genes,', and, characterization, of, the, proteins, they, 'encode,', is]), verbo([enhancing]), complemento([our, understanding, of, the, biology, of, the, enterohepatic, circulation, in, health, and, disease])].
[sujeto(['We', show, here, that, 'FHC', in, 'Amish', individuals, is]), verbo([associated]), complemento([with, mutations, in, tight, junction, protein, 2, '(', encoded, by, 'TJP2,', also, known, as, 'ZO-2)', and, bile, acid, 'Coenzyme', 'A:', amino, acid, 'N-acyltransferase', '(', encoded, by, 'BAAT)'])].
[sujeto(['The', mutation, of, 'TJP2,', which, occurs, in, the, first, 'PDZ', 'domain,', reduces, domain, stability, and, ligand]), verbo([binding]), complemento([in, vitro])].
[sujeto(['Previous', studies, showed, glucose, and, insulin, signaling, can]), verbo([regulate]), complemento([bile, acid, '(', 'BA)', metabolism, during, fasting, or, feeding])].
[sujeto(['This', study, showed, that, 40, '%', 'CR']), verbo([increased]), complemento([the, 'BA', pool, size, '(', 162, '%', ')', as, well, as, total, 'BAs', in, 'serum,', 'gallbladder,', and, small, intestinal, contents])].
[sujeto(['In', 'addition,', 'CR', &, 'quot;dose-dependently"']), verbo([increased]), complemento([the, concentrations, of, 'tauro-cholic', acid, '(', 'TCA)', and, many, secondary, 'BAs', '(', produced, by, intestinal, 'bacteria)', in, 'serum,', such, as, 'tauro-deoxycholic', acid, '(', 'TDCA),', 'DCA,', lithocholic, 'acid,', 'ω-muricholic', acid, '(', 'ωMCA),', and, hyodeoxycholic, acid])].
[sujeto(['Notably,', 40, '%', 'CR']), verbo([increased]), complemento(['TDCA', by, over, 1000, '%', '(', 'serum,', 'liver,', and, 'gallbladder)'])].
[sujeto(['Interestingly,', 40, '%', 'CR']), verbo([increased]), complemento([the, proportion, of, 12, 'α-hydroxylated', 'BAs', '(', 'CA', and, 'DCA),', which, correlated, with, improved, glucose, tolerance, and, lipid, parameters])].
[sujeto(['The', 'CR-induced']), verbo([increase]), complemento([in, 'BAs', correlated, with, increased, expression, of, 'BA-synthetic', '(', 'Cyp7a1)', and, conjugating, enzymes, '(', 'BAL),', and, the, ileal, 'BA-binding', protein, '(', 'Ibabp)'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'CR', increases, 'BAs', in, male, mice, possibly, through, orchestrated, increases, in, 'BA', synthesis, and, conjugation, in, liver, as, well, as, intracellular, transport, in, ileum])].
[sujeto(['Several', studies]), verbo([have]), complemento([demonstrated, that, fish, oil, may, affect, the, bile, acid, metabolism, as, well, as, lipid, 'metabolism,', whereas, only, scarce, data, are, available])].
[sujeto(['Hepatic', mRNA, expression, of, lipids, '(', 'Abcg5/8,', multidrug, resistance, gene, product, 2, ')', and, bile, acids, transporters, '(', bile, salt, export, 'pump,', multidrug, resistance]), verbo([associated]), complemento([protein, 2, and, 3, ',', organic, solute, transporter, 'α)', was, induced, in, fish, 'oil-fed', mice])].
[sujeto(['Hepatic', 'Cyp8b1,', 'Cyp27a1', and, bile, acid, 'CoA', :, amino, acid, 'N-acyltransferase', were]), verbo([increased]), complemento([in, fish, 'oil-fed', mice, compared, with, 'soybean-oil', fed, mice])].
[sujeto(['Besides,', intestinal, cholesterol, '(', 'Abcg5/8)', and, bile, acid, transporters, '(', multidrug, resistance]), verbo([associated]), complemento([protein, 2, and, organic, solute, transporter, 'α)', were, induced, in, fish, 'oil-fed', mice])].
[sujeto(['Fish', oil]), verbo([induced]), complemento([the, expression, of, cholesterol, and, bile, acid, transporters, not, only, in, liver, but, in, intestine])].
[sujeto(['The', upregulation, of, 'Abcg5/g8', by, fish, oil, is]), verbo([caused]), complemento([by, an, increase, in, cellular, 27, -, 'HOC', through, 'Cyp27a1', induction])].
[sujeto(['To', test, the, hypothesis, that, dexamethasone, '(', 'Dex)', treatment, would, restore, rat, hepatic, bile, acid, coenzyme, 'A-amino', acid, 'N-acyltransferase', '(', 'rBAT)', expression, in, septic, rats, after, cecal, ligation, and, puncture, by]), verbo([increasing]), complemento([expression, of, retinoic, acid, 'X', receptor, alpha, '(', 'RXRalpha),', we, assessed, survival, rate, and, bile, and, bile, salt, concentration, in, the, 'Dex-treated', septic, group, and, compared, these, results, with, those, for, a, nontreated, septic, 'group,', a, 'Dex-treated', nonseptic, 'group,', and, a, sham, group])].
[sujeto(['Dexamethasone', treatment, '(', 0.01, 'mg/kg)', significantly, improved, the, survival, rate, and]), verbo([increased]), complemento([the, bile, and, bile, salt, concentration, in, the, bile, ducts, of, septic, rats, '(', 'P', =, &, 'lt;0'])].
[sujeto(['In', our, assessment, of, bile, 'salt-related', 'genes,', during, 'sepsis,', there, were]), verbo([decreases]), complemento([in, protein, and, mRNA, expression, of, rBAT, and, cholesterol, 7, 'alpha-hydroxylase', '(', 'CYP7A1)'])].
[sujeto(['Treatment', with, 'Dex', restored, expression, of, rBAT, and, 'RXR[alpha]', but, not, 'CYP7A1,', bile, salt, export, 'pump,', or, multidrug, resistance]), verbo([associated]), complemento([protein, 2, '(', 'MRP2)'])].
[sujeto(['In', an, experiment, to, confirm, our, 'findings,', 'RXR[alpha]', siRNA, was]), verbo([found]), complemento([to, significantly, block, 'Dex-induced', increases, in, expression, of, rBAT, in, hepatocytes, taken, from, septic, rats, '(', 'P', &, 'lt;', 0.01, ')'])].
[sujeto(['Dex', restored, the, expression, of, rBAT, in, septic, rats, by]), verbo([enhancing]), complemento(['RXR[alpha],', a, process, that, might, explain, the, mechanism, underlying, 'Dex\'s', anticholestatic, effect])].
[sujeto(['MS,', with, or, without, 'pre-analysis', peptide, 'fractionation,', can, be, used, to, decipher, the, residues, on, proteins, where, oxidative, modifications]), verbo([caused]), complemento([by, 'peroxynitrite,', singlet, oxygen, or, electrophilic, lipids, have, occurred])].
[sujeto(['Dose-response', inactivation, by, 4, 'HNE', '(', 4, -, 'hydroxynonenal)', of, hBAT, '(', human, bile, acid, 'CoA:amino', acid, 'N-acyltransferase)', and, 'CKBB', '(', cytosolic, brain, isoform, of, creatine, 'kinase)', is]), verbo([associated]), complemento([with, 'site-specific', modifications])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, future, in, vivo, studies, should, carefully, assess, the, critical, sites, that, are, modified, rather, than, using, antibodies, that, do, not, distinguish, between, different, modified, sites])].
[sujeto(['In', the, present, 'study,', protein, carbonylation, of, 'BAT,', consistent, with, modification, by, reactive, oxygen, species, and, their, 'products,', was]), verbo([increased]), complemento([in, hepatic, homogenates, of, apolipoprotein, 'E', 'knock-out', mice])].
[sujeto(['Because', two, of, these, amino, acids, '(', 'Cys', and, 'His)', are, members, of, the, catalytic, triad, of, human, 'BAT,', it, was, proposed, that, 4, 'HNE', would]), verbo([cause]), complemento([inactivation, of, this, enzyme])].
[sujeto(['The', data, revealed, that, the, 'active-site', 'His', '(', 'His362)', 'dose-dependently', formed, a, 4, 'HNE', 'adduct,', contributing, to]), verbo([loss]), complemento([of, 'activity,', although, 4, 'HNE', adducts, on, other, residues, may, also, contribute])].
[sujeto(['Sepsis']), verbo([causes]), complemento([intrahepatic, cholestasis, and, leads, to, hepatic, failure])].
[sujeto(['Expression', of, rat, hepatic, bile, acid, coenzyme, 'A-amino', acid, 'N-acyltransferase', '(', 'rBAT),', a, major, enzyme, for, the, conjugation, of, bile, 'acids,', is, significantly]), verbo([decreased]), complemento([during, sepsis])].
[sujeto(['During', 'sepsis,']), verbo([nuclear]), complemento([receptors, and, translocation, of, 'RXR-alpha', from, cytosol, to, nucleus, decrease])].
[sujeto(['Polymicrobial', sepsis, was]), verbo([induced]), complemento([in, rats, by, cecal, ligation, and, puncture, '(', 'CLP)'])].
[sujeto(['Post-CLP']), verbo([decreases]), complemento([were, observed, in, mRNA, levels, of, rBAT, '(', 6, 'h),', protein, levels, of, rBAT, '(', 6, 'h),', 'RXR-alpha', '(', 6, 'h),', and, 'FXR', '(', 9, 'h)'])].
[sujeto(['DNA']), verbo([binding]), complemento([activity, of, 'FXR/RXR', significantly, decreased, at, 6, h, after, 'CLP'])].
[sujeto(['Dexamethasone', reversed, 'sepsis-inhibited', 'RXR-alpha', expression, and, the]), verbo([binding]), complemento([activity, of, 'FXR/RXR', to, rBAT, 'DNA', as, well, as, rBAT, protein, expression])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, suppression, of, rBAT, occurs, at, the, transcriptional, 'level,', and, the, decrease, in, 'RXR-alpha', by, septic, insult, may, play, a, critical, role, in, rBAT, suppression, at, the, early, stage, of, polymicrobial, sepsis])].
[sujeto(['In', male, and, female, 'rats,', 65, -, 75, '%', of, total, liver, 'BAT', activity, was]), verbo([found]), complemento([in, the, 'cytosol,', 15, -, 17, '%', was, found, in, the, 'peroxisomes,', and, 5, -, 10, '%', was, found, in, the, heavy, mitochondrial, fraction])].
[sujeto(['After', clofibrate, 'treatment,', male, rats, displayed, an]), verbo([increase]), complemento([in, peroxisomal, 'BAT', specific, activity, and, a, decrease, in, cytosolic, 'BAT', specific, 'activity,', whereas, females, showed, an, opposite, response])].
[sujeto(['These', data, support, the, novel]), verbo([finding]), complemento([that, clofibrate, treatment, does, not, directly, regulate, 'BAT', activity, but, does, alter, the, subcellular, localization, of, 'BAT'])].
[sujeto(['The', farnesoid, 'X', receptor, '(', 'Fxr)', controls, bile, acid, homeostasis, by, coordinately]), verbo([regulating]), complemento([the, expression, of, synthesizing, enzymes, '(', 'Cyp7a1,', 'Cyp8b1),', conjugating, enzymes, '(', 'Bal,', 'Baat)', and, transporters, in, the, ileum, '(', 'Asbt,', 'Ostα/β)', and, liver, '(', 'Ntcp,', 'Bsep,', 'Ostβ)'])].
[sujeto(['Circulating', bile, acids, are]), verbo([increased]), complemento([during, pregnancy, due, to, 'hormone-mediated', disruption, of, 'Fxr', signaling])].
[sujeto(['While', this, adaptation]), verbo([enhances]), complemento([lipid, 'absorption,', elevated, bile, acids, may, predispose, women, to, develop, maternal, cholestasis])].
[sujeto(['Treatment', of, pregnant, mice, with, 'GW4064']), verbo([induced]), complemento([ileal, 'Fgf15,', 'Shp', and, 'Ostα/β', 'mRNAs,', and, restored, hepatic, 'Shp,', 'Bal,', 'Ntcp,', and, 'Bsep', back, to, 'vehicle-treated', virgin, levels])].
[sujeto(['Pregnant', mice, exhibited, 2.5, -, fold]), verbo([increase]), complemento([in, 'Cyp7a1', mRNA, compared, to, virgin, 'controls,', which, was, reduced, by, 'GW4064'])].
[sujeto(['Similarly', treatment, of, mouse, primary, hepatocytes, with, plasma, isolated, from, pregnant, mice]), verbo([induced]), complemento(['Cyp7a1', mRNA, by, nearly, 3, -, fold, as, compared, to, virgin, 'plasma,', which, could, be, attenuated, by, 'co-treatment', with, either, 'GW4064', or, recombinant, 'FGF19', protein])].
[sujeto(['Collectively,', these, data]), verbo([reveal]), complemento([that, repressed, activity, of, intestinal, and, hepatic, 'Fxr', in, 'pregnancy,', as, previously, 'demonstrated,', may, be, restored, by, pharmacological, activation])].
[sujeto(['This', study]), verbo([provides]), complemento([the, basis, for, a, novel, approach, to, restore, bile, acid, homeostasis, in, patients, with, maternal, cholestasis])].
[sujeto(['Evidence', indicates, that, the, polymorphisms, in, genes]), verbo([involved]), complemento([in, bile, acid, metabolism, may, play, an, important, role, in, the, development, of, 'anti-tuberculosis', 'drug-induced', hepatotoxicity, '(', 'ATDH)', in, tuberculosis, '(', 'TB)', patients, treated, with, 'anti-tuberculosis', drugs])].
[sujeto(['Significant', differences, were]), verbo([found]), complemento([in, genotype, distributions, of, rs1457043, in, 'CYP7A1', between, patients, with, and, those, without, 'ATDH', '(', 'P', =, 0.014, ')'])].
[sujeto(['Genetic', polymorphisms, of, 'CYP7A1', may, be]), verbo([associated]), complemento([with, susceptibility, to, 'ATDH', in, the, 'Chinese', population])].
[sujeto(['Using', 'two-stage', receiver, operating, characteristic, '(', 'ROC)', 'analysis,', 18, metabolites, were]), verbo([recognized]), complemento([as, potential, biomarkers, related, to, 'CUMS-induced', depression, via, 12, metabolic, pathways])].
[sujeto(['Subsequently,', we, detected, the, mRNA, expressions, levels, of, 'apoptosis-associated', genes, such, as, 'Bax', and, 'Bcl-2', and, four, key, enzymes, including, 'Pla2g15,', 'Pnpla6,', 'Baat', and, 'Gad1']), verbo([involved]), complemento([in, phospholipid, and, primary, bile, acid, biosynthesis, in, liver, tissues, of, 'CUMS', rats, by, 'real-time', 'qRT-PCR', assay])].
[sujeto(['Results', of, 'liver-targeted', metabonomics, and, mRNA, expression, demonstrated, that, 'CUMS-induced', depression]), verbo([leads]), complemento([to, variations, in, hepatic, metabolic, profile, and, gene, 'expression,', and, ultimately, results, in, liver, injury])].
[sujeto(['Bile', acids, '(', 'BAs)', are, not, only, digestive, surfactants, but, also, important, cell, signaling, 'molecules,', which]), verbo([stimulate]), complemento([several, signaling, pathways, to, regulate, some, important, biological, processes])].
[sujeto(['The', 'bile-acid-activated']), verbo([nuclear]), complemento(['receptor,', farnesoid, 'X', receptor, '(', 'FXR),', plays, a, pivotal, role, in, regulating, bile, 'acid,', lipid, and, glucose, homeostasis, as, well, as, in, regulating, the, inflammatory, 'responses,', barrier, function, and, prevention, of, bacterial, translocation, in, the, intestinal, tract])].
[sujeto(['As', 'expected,', 'FXR', is]), verbo([involved]), complemento([in, the, pathophysiology, of, a, wide, range, of, diseases, of, gastrointestinal, 'tract,', including, inflammatory, bowel, 'disease,', colorectal, cancer, and, type, 2, diabetes])].
[sujeto(['Intrahepatic', cholestasis, is, a, clinical, syndrome, with, systemic, and, intrahepatic, accumulation, of, excessive, toxic, bile, acids, that, ultimately]), verbo([cause]), complemento([hepatobiliary, injury])].
[sujeto(['AB23A', treatment, 'dose-dependently', protected, against, liver, injury]), verbo([induced]), complemento([by, 'ANIT', through, reducing, hepatic, uptake, and, increasing, efflux, of, bile, acid, via, 'down-regulation', of, hepatic, uptake, transporters, '(', 'Ntcp)', and, 'up-regulation', of, efflux, transporter, '(', 'Bsep,', 'Mrp2', and, 'Mdr2)', expression])].
[sujeto(['Furthermore,', 'AB23A', reduced, bile, acid, synthesis, through]), verbo([repressing]), complemento(['Cyp7a1', and, 'Cyp8b1,', increased, bile, acid, conjugation, through, inducing, 'Bal,', 'Baat', and, bile, acid, metabolism, through, an, induction, in, gene, expression, of, 'Sult2a1'])].
[sujeto(['The', 'GR']), verbo([regulates]), complemento(['BA', 'homeostasis;', 'however,', the, impact, of, impaired, 11, 'β-HSD1', activity, remained, unknown])].
[sujeto(['Gene', expression, analyses, revealed]), verbo([decreased]), complemento([expression, of, the, 'BA-CoA', ligase, 'Fatp5,', suggesting, impaired, 'BA', amidation])].
[sujeto(['Reduced', organic, 'anion-transporting', 'polypeptide-1A1', '(', 'Oatp1a1)', and]), verbo([enhanced]), complemento([organic, 'solute-transporter-β', '(', 'Ostb)', mRNA, expression, were, observed, in, livers, from, global, 11, 'β-HSD1-deficient', mice])].
[sujeto(['The', impact, of, 11, 'β-HSD1-deficiency', on, 'BA', homeostasis, seems, to, be, 'GR-independent', because, intrahepatic, corticosterone, and, 'GR']), verbo([target]), complemento([gene, expression, were, not, substantially, decreased, in, livers, from, global, knockout, mice])].
[sujeto(['The', liver, is, a, major, organ, that, stores, 'RA']), verbo([suggesting]), complemento([that, retinoids, play, an, important, role, in, the, function, of, hepatocytes])].
[sujeto(['In', our, previous, 'studies,', we]), verbo([have]), complemento([demonstrated, the, involvement, of, small, heterodimer, partner, '(', 'SHP)', in, 'RA-induced', signaling, in, a, 'non-transformed', hepatic, cell, line, 'AML', 12])].
[sujeto(['In', the, present, 'study,', we]), verbo([have]), complemento([identified, several, critical, genes, in, lipid, homeostasis, '(', 'Apoa1,', 'Apoa2', and, 'ApoF)', that, are, repressed, by, 'RA-treatment', in, a, 'SHP', dependent, 'manner,', in, vitro, and, also, in, vivo, with, the, use, of, the, 'SHP', null, mice])].
[sujeto(['In', a, similar, 'manner,', 'RA', also]), verbo([represses]), complemento([several, critical, genes, involved, in, bile, acid, metabolism, '(', 'Cyp7a1,', 'Cyp8b1,', 'Mdr2,', 'Bsep,', 'Baat', and, 'Ntcp)', via, upregulation, of, 'SHP'])].
[sujeto(['Collectively', our, data]), verbo([suggest]), complemento([that, 'SHP', plays, a, major, role, in, 'RA-induced', potential, changes, in, pathophysiology, of, metabolic, disorders, in, the, liver])].
[sujeto(['Bile', acids, '(', 'BAs)']), verbo([have]), complemento([many, physiological, roles, and, exhibit, both, toxic, and, protective, influences, within, the, liver])].
[sujeto(['Alterations', in, the, 'BA', profile, may, be, the, result, of, disease]), verbo([induced]), complemento([liver, injury])].
[sujeto(['Increased', mRNA, expression, of, 'BAAT', and, 'CYP7B1', was, observed, in, contrast, to]), verbo([decreased]), complemento(['CYP8B1', expression, in, 'NASH', samples])].
[sujeto(['The', 'BA', metabolomic, profile, of, 'NASH', livers, exhibited, an]), verbo([increase]), complemento([in, taurine, together, with, elevated, levels, of, conjugated, 'BA', 'species,', taurocholic, acid, '(', 'TCA)', and, taurodeoxycholic, acid, '(', 'TDCA)'])].
[sujeto(['Conversely,', cholic, acid, '(', 'CA)', and, glycodeoxycholic, acid, '(', 'GDCA)', were]), verbo([decreased]), complemento([in, 'NASH', liver])].
[sujeto(['These', findings]), verbo([reveal]), complemento([a, potential, shift, toward, the, alternative, pathway, of, 'BA', synthesis, during, 'NASH,', mediated, by, increased, mRNA, and, protein, expression, of, 'CYP7B1'])].
[sujeto(['Treatment', with, glucocorticoids, '(', 'GCs)', may]), verbo([cause]), complemento([adverse, 'effects,', including, cholestasis])].
[sujeto(['The', ability, of, 'dexamethasone,', prednisolone, and, budesonide, to, affect, the, liver, handling, of, bile, acids, '(', 'BAs)']), verbo([has]), complemento([been, investigated])].
[sujeto(['In', rats, treated, with, 'GCs', for, 4, 'days,', altered, serum, and, bile, 'BA', 'levels,', changed, conjugation, 'pattern,', and, delayed, and]), verbo([decreased]), complemento([ability, to, 'conjugate/secrete', exogenously, administered, 'deoxycholate,', were, found, using, 'HPLC-MS/MS'])].
[sujeto(['RT-QPCR', analyses, revealed, that, 'GC', treatment, also]), verbo([induced]), complemento([a, 'down-regulation', of, liver, nuclear, receptors, '(', 'Fxr,', 'Gr', and, 'Shp),', transporters, '(', 'Ntcp,', 'Mrp4', and, 'Bcrp)', and, enzymes, '(', 'Cyp7a1', and, 'Baat),', whereas, 'Bsep,', 'Mrp2', and, 'Cyp27a1', were, 'up-regulated'])].
[sujeto(['In', 'HepG2', 'cells,', 'GCs']), verbo([induced]), complemento([a, decreased, expression, of, 'FXR', and, 'SHP,', and, inhibited, the, regulatory, effect, of, 'GW4064', on, 'FXR-target', genes])].
[sujeto(['In', 'Alexander', 'cells,', only, when, they, were, transfected, with, 'FXR+RXR,', 'GW4064']), verbo([caused]), complemento(['up-regulation', of, 'SHP', and, 'OSTβ,', and, a, 'down-regulation', of, 'CYP27A1'])].
[sujeto(['Co-transfection', of, 'Alexander', cells, with, 'IR-1-Luc', and, 'FXR+RXR', revealed, that, 'GCs', did, not]), verbo([inhibit]), complemento([but, moderately, enhanced, 'FXR', activity])].
[sujeto(['Moreover,', 'GCs']), verbo([have]), complemento([a, synergistic, effect, on, 'GW4064-induced', 'FXR', 'activation,', whereas, chenodeoxycholate, and, 'GW4064', have, an, additive, effect])].
[sujeto(['In', 'conclusion,', 'GCs', are, able, to, directly, or, indirectly]), verbo([activate]), complemento(['FXR', but, they, also, 'antagonize,', through, 'FXR-independent', 'mechanisms,', the, expression, of, 'FXR', and, 'FXR', target, genes, involved, in, the, hepatic, handling, of, 'BAs'])].
[sujeto(['During', 'pregnancy,', proper, hepatobiliary, transport, and, bile, acid, synthesis, protect, the, liver, from, cholestatic, injury, and]), verbo([regulate]), complemento([the, maternal, and, fetal, exposure, to, bile, 'acids,', 'drugs,', and, environmental, chemicals])].
[sujeto([mRNAs, of, the, bile, acid, synthetic, enzymes, in, the, classic, 'pathway,', 'Cyp7a1', and, 8, 'b1,']), verbo([increased]), complemento([in, pregnant, 'mice,', whereas, mRNA, and, protein, expression, of, enzymes, in, the, alternative, pathway, of, bile, acid, synthesis, '(', 'Cyp27a1', and, 39, 'a1)', and, conjugating, enzymes, '(', 'Bal', and, 'Baat)', decreased])].
[sujeto(['In', 'conclusion,', pregnancy]), verbo([caused]), complemento([a, global, downregulation, of, most, hepatic, 'transporters,', which, began, as, early, as, 'GD7', for, some, genes, and, was, maximal, by, 'GD14', and, 17, ',', and, was, inversely, related, to, increasing, concentrations, of, circulating, 17, 'β-estradiol', and, progesterone, as, pregnancy, progressed])].
[sujeto(['Born', at, 27, weeks, 'gestation,', a, child, of, consanguineous, parents, of, 'Pakistani', origin]), verbo([required]), complemento([prolonged, parenteral, nutrition])].
[sujeto(['No', mutations, were]), verbo([found]), complemento([in, 'BAAT,', encoding, bile, 'acid-CoA', :, aminoacid, 'N-acyl', transferase])].
[sujeto([1012, 'C', &, 'gt;', 'T', in, 'SLC27A5,', predicted, to, alter, a, highly]), verbo([conserved]), complemento(['amino-acid', residue, '(', p])].
[sujeto([1772, 'A', &, 'gt;', 'G', in, 'ABCB11,', predicted, to, alter, a, highly]), verbo([conserved]), complemento(['amino-acid', residue, '(', p])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([of, a, mutation, in, 'SLC27A5'])].
[sujeto(['The', amidation, defect, may]), verbo([have]), complemento([contributed, to, cholestatic, liver, disease, in, the, setting, of, 'prematurity,', parenteral, 'nutrition,', and, homozygosity, for, an, 'ABCB11', mutation])].
[sujeto(['This']), verbo([increases]), complemento([their, aqueous, 'solubility,', particularly, in, the, acidic, environment, of, the, upper, part, of, the, small, intestine])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF4alpha)', has, an, important, role, in, regulating, the, expression, of, 'liver-specific', genes])].
[sujeto(['Because', bile, acids, are, produced, from, cholesterol, in, liver, and, many, enzymes]), verbo([involved]), complemento([in, their, biosynthesis, are, preferentially, expressed, in, 'liver,', the, role, of, 'HNF4alpha', in, the, regulation, of, bile, acid, production, was, examined])].
[sujeto(['Mice', lacking, hepatic, 'HNF4alpha', expression, exhibited, markedly]), verbo([decreased]), complemento([expression, of, the, very, long, chain, 'acyl-CoA', 'synthase-related', gene, '(', 'VLACSR),', a, mouse, candidate, for, bile, 'acid-CoA', 'ligase,', and, 'BAT'])].
[sujeto(['This', was]), verbo([associated]), complemento([with, markedly, elevated, levels, of, unconjugated, and, 'glycine-conjugated', bile, acids, in, gallbladder])].
[sujeto(['HNF4alpha', was]), verbo([found]), complemento([to, bind, directly, to, the, mouse, 'VLACSR', and, 'BAT', gene, 'promoters,', and, the, promoter, activities, were, dependent, on, 'HNF4alpha-binding', sites, and, 'HNF4alpha', expression])].
[sujeto(['Rat', liver, 'BAT', '(', 'rBAT)', cDNA, was, isolated, from, a, rat, liver, lambdaZAP, cDNA, library, and]), verbo([expressed]), complemento([in, 'Sf9', insect, cells, using, a, baculoviral, vector])].
[sujeto(['Similar', to, 'hBAT,']), verbo([expressed]), complemento([rBAT, was, capable, of, forming, both, taurine, and, glycine, conjugates, with, 'cholyl-CoA'])].
[sujeto(['Treatment', of, rats, with, 'clofibrate,', a, known, peroxisomal, 'proliferator,', significantly]), verbo([induced]), complemento([rBAT, 'activity,', 'message,', and, immunoreactive, protein, in, rat, liver])].
[sujeto(['Peroxisomal', membrane, 'protein-70,', a, marker, for, 'peroxisomes,', was, also]), verbo([induced]), complemento([by, 'clofibrate,', whereas, rBAL, activity, and, protein, amount, were, not, affected])].
[sujeto(['The', farnesoid, 'X', receptor, '(', 'FXR;', 'NR1H4)']), verbo([regulates]), complemento([bile, acid, and, lipid, homeostasis, by, acting, as, an, intracellular, bile, 'acid-sensing', transcription, factor])].
[sujeto(['Several', identified, 'FXR']), verbo([target]), complemento([genes, serve, critical, roles, in, the, synthesis, and, transport, of, bile, acids, as, well, as, in, lipid, metabolism])].
[sujeto(['Here', we, used, 'Affymetrix', 'micro-array', and, 'Northern', analysis, to, demonstrate, that, two, enzymes]), verbo([involved]), complemento([in, conjugation, of, bile, acids, to, taurine, and, 'glycine,', namely, bile, 'acid-CoA', synthetase, '(', 'BACS)', and, bile, 'acid-CoA:', amino, acid, 'N-acetyltransferase', '(', 'BAT)', are, induced, by, 'FXR', in, rat, liver])].
[sujeto(['The', response, elements, resemble, the, consensus, 'FXR']), verbo([binding]), complemento([site, consisting, of, two, nuclear, receptor, 'half-sites', organized, as, an, inverted, repeat, and, separated, by, a, single, nucleotide, '(', 'IR-1)'])].
[sujeto(['These', response, elements, directly]), verbo([bind]), complemento(['FXR/retinoid', 'X', receptor, '(', 'RXR)', heterodimers, and, confer, the, activity, of, 'FXR', ligands, in, transient, transfection, experiments])].
[sujeto(['Further', mutational, analysis, confirms, that, the, 'IR-1', sequence, of, the, 'BACS', and, 'BAT', genes]), verbo([mediate]), complemento([transactivation, by, 'FXR/RXR', heterodimers])].
[sujeto(['Finally,', 'Fisher', rats, treated, with, the, synthetic, 'FXR', ligand, 'GW4064', clearly, show]), verbo([increased]), complemento([transcript, levels, of, both, the, 'BACS', and, 'BAT', mRNA])].
[sujeto(['These', studies, demonstrate, a, mechanism, by, which, 'FXR']), verbo([regulates]), complemento([bile, acid, 'amidation,', a, critical, component, of, the, enterohepatic, circulation, of, bile, acids])].
[sujeto(['Enzymatically', active, mBAT, was]), verbo([expressed]), complemento([in, 'E'])].
[sujeto(['Immunoblot', analysis, of]), verbo([expressed]), complemento([mBAT, with, rabbit, 'anti-human', 'BAT', polyclonal, antibodies, detected, a, single, protein, with, a, molecular, mass, of, approximately, 45, ',', 0, daltons])].
[sujeto(['Cytosol', from, cells, transformed, with, 'mBAT#9/pKK233-2', possessed, significant, amounts, of, 'BAT-catalyzed', conjugating, activity, with, taurine, as, substrate, but, the]), verbo([expressed]), complemento([enzyme, did, not, use, glycine, or, 'fluoro-beta-alanine', as, substrates])].
[sujeto(['These', results, indicate, that, a, 'taurine-specific', form, of, 'BAT']), verbo([has]), complemento([been, cloned, and, expressed, from, mouse, liver])].
[sujeto(['Kan-1/rBAT', mRNA, was, mainly]), verbo([expressed]), complemento([in, the, livers, of, adult, rats, and, rats, immediately, 'after,', but, not, 'before,', birth])].
[sujeto(['It', was]), verbo([expressed]), complemento([in, the, 'hepatocytes,', the, sinusoidal, endothelial, cells, and, the, 'Kupffer', cells, of, the, liver])].
[sujeto(['After', partial, 'hepatectomy,', the, levels, of, 'Kan-1/rBAT', mRNA]), verbo([decreased]), complemento([at, 6, and, 12, h, in, the, regenerating, liver])].
[sujeto(['In', a, sepsis, 'model,', hepatic, expression, of, 'Kan-1/rBAT', mRNA]), verbo([decreased]), complemento([at, 6, and, 12, h, after, caecal, ligation, and, puncture])].
[sujeto(['The', kinetics, of, 'Kan-1/rBAT', mRNA, expression]), verbo([suggests]), complemento([that, it, may, play, a, role, in, 'acute-phase', reactions])].
[sujeto(['In', order, to, establish, whether, a, single, enzyme, in, human, liver, was, capable, of, conjugating, bile, acids, with, both, glycine, and, 'taurine,', a, cDNA, encoding, human, liver, bile, 'acid-CoA:amino', acid, 'N-acyltransferase', '(', 'hBAT)']), verbo([has]), complemento([been, isolated, and, characterized])].
[sujeto(['The', identity, of, the, cDNA, was, confirmed, by, the, following, 'findings:', 1, ')', the, open, reading, frame, began, with, an, 'ATG', codon, and, was, followed, by, a, nucleotide, sequence, 'which,', when, 'translated,', corresponded, exactly, to, the, first, 17, 'NH2-terminal', amino, acids, of, purified, human, liver, 'BAT;', 2, ')', cytosol, of, 'Escherichia', coli, 'XL1-Blue', cells, transfected, with, hBAT8, subcloned, into, an, expression, 'vector,', 'pKK233-2,', demonstrated, significant, enzymatic, activity, for, the, conjugation, of, both, taurine, and, glycine, with, cholic, 'acid;', 3, ')', bacterial, expression, of, hBAT8, generated, a, protein, that, comigrated, with, hBAT, from, human, liver, during, 'SDS-polyacrylamide', gel, electrophoresis, and, 'cross-reacted', with, a, specific, polyclonal, rabbit, 'anti-hBAT', antibody, during, immunoblot, 'analysis;', 4, ')', kinetic, characteristics, of, the]), verbo([expressed]), complemento([enzyme, were, very, similar, to, those, reported, for, purified, liver, 'BAT'])].
[sujeto(['Bile', acid, 'CoA', synthetase]), verbo([has]), complemento([been, discovered, in, rat, kidney])].
[sujeto(['This', 'peak,', when, incubated, with, purified, bile, acid, 'CoA:', amino, acid, 'N-acyltransferase', '(', 'BAT)', from, human, liver, and, either, taurine, or, 'glycine,']), verbo([led]), complemento([to, the, formation, of, 'CDC-taurine', or, 'CDC-glycine,', respectively])].
[sujeto(['This', activity, appeared, specific, for, bile, acids, as, it, was, not]), verbo([inhibited]), complemento([by, benzoic, acid, or, salicylic, 'acid,', known, substrates, for, other, rat, kidney, 'CoA', synthetases])].
[sujeto(['This', demonstrates, that, the, kidney]), verbo([has]), complemento([the, potential, for, bile, acid, metabolism, and, may, have, a, role, in, bile, acid, physiology])].
[sujeto(['A', novel, location, of, the, 'bile-acid-conjugating', enzyme, bile, 'acid-CoA:amino', acid, 'N-acyltransferase', '(', 'BAT)']), verbo([has]), complemento([been, discovered, in, the, cytosolic, fraction, of, rat, kidney])].
[sujeto(['Immunoblot', analysis, using, a, human, liver, 'anti-BAT', polyclonal, antibody, indicated, that, rat, kidney, 'BAT']), verbo([has]), complemento([the, same, molecular, mass, as, rat, liver, 'BAT'])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, kidney, has, a, role, in, bile, acid, metabolism, and, physiology])].
[sujeto(['Maintenance', of, body, temperature, in, 'cold-exposed', animals]), verbo([requires]), complemento([induction, of, thermogenesis, and, management, of, fuel])].
[sujeto(['Here,', we, demonstrated, that, reducing, ambient, temperature, attenuated, 'diet-induced', obesity, '(', 'DIO),', which, was]), verbo([associated]), complemento([with, increased, iBAT, thermogenesis, and, a, plasma, bile, acid, profile, similar, to, that, of, 'germ-free', mice])].
[sujeto(['Gut', microbiota, was, characterized, by]), verbo([increased]), complemento([levels, 'of Adlercreutzia,', 'Mogibacteriaceae,', 'Ruminococcaceae,', and, 'Desulfovibrio', and, reduced, levels, of, 'Bacilli,', 'Erysipelotrichaceae,', and, the, genus, 'rc4-4'])].
[sujeto(['These', genera]), verbo([have]), complemento([been, associated, with, leanness, and, 'obesity,', respectively])].
[sujeto(['Thus,', a, 'microbiota-liver-BAT', axis, may]), verbo([mediate]), complemento([protection, against, obesity, at, reduced, temperature])].
[sujeto(['Hypoxia,', a, common, feature, of, advanced, 'HCC,']), verbo([has]), complemento([been, shown, to, modulate, the, evolution, of, the, tumor, microenvironment])].
[sujeto(['Human', 'HCC', cell, lines, '(', 'Huh-BAT,', 'SNU-475)', were, cocultured, with, an]), verbo([activated]), complemento([human, hepatic, stellate, cell, line, '(', 'HSCs;', 'LX-2)', under, either, normoxic, or, hypoxic, conditions])].
[sujeto(['Expression', of, 'CD31', and]), verbo([phosphorylated]), complemento(['(', 'p-)', 'Akt', in, 'HCC', tissues, was, detected, by, immunohistochemistry])].
[sujeto(['Coculturing', 'HCC', cells, with, 'HSCs', under, hypoxic, conditions]), verbo([enhanced]), complemento([their, 'proliferation,', 'migration,', and, resistance, to, bile, acid, '(', 'BA)-induced', apoptosis, compared, to, coculturing, under, normoxic, conditions])].
[sujeto(['Under', 'hypoxia,', of, various, 'HSC-derived', growth, 'factors,', 'PDGF-BB', was, the, most, 'up-regulated,']), verbo([leading]), complemento([to, the, activation, of, the, phosphatidylinositol, 3, -, kinase, '(', 'PI3K)/Akt', pathway, in, 'HCC', cells])].
[sujeto(['Immunohistochemical', study, also, revealed, that, 'p-Akt', was, highly]), verbo([expressed]), complemento([in, 'hypoxic,', hypovascular, 'HCC', as, compared, to, hypervascular, 'HCC'])].
[sujeto(['In', 'conclusion,', hypoxic, 'HSC-derived', 'PDGF-BB']), verbo([stimulates]), complemento([the, proliferation, of, 'HCC', cells, through, activation, of, the, 'PI3K/Akt', 'pathway,', while, the, inhibition, of, 'PDGF-BB', or, 'PI3K/Akt', pathways, enhances, apoptotic, cell, death])].
[sujeto(['The', number, of, obese, patients]), verbo([has]), complemento([increased, annually, worldwide])].
[sujeto(['Miglitol', is, an, 'alpha-glucosidase', inhibitor, '(', 'αGI)', that, is, commonly, used, as, an, 'anti-diabetic', 'drug,', and, there, is, growing, evidence, that, it, also]), verbo([has]), complemento(['anti-obesity', effects])].
[sujeto(['Miglitol']), verbo([has]), complemento([been, shown, to, reduce, body, weight, and, ameliorate, insulin, resistance, in, both, clinical, trials, with, adult, patients, and, in, rodent, models, of, obesity])].
[sujeto(['Although', the, specific, mechanism, of, action, of, this, effect, remains, 'unclear,', some, mechanisms]), verbo([have]), complemento([been, suggested, through, experimental, results])].
[sujeto(['Miglitol']), verbo([has]), complemento([been, shown, to, inhibit, adipogenesis, of, white, adipocytes, in, 'vitro,', activate, brown, adipose, tissue, '(', 'BAT)', in, 'mice,', influence, bile, acid, metabolism, in, 'mice,', and, regulate, the, secretion, of, incretin, hormones, in, humans])].
[sujeto(['A', unique, advantage, of, miglitol, is, that, it, is, already, used, as, an, 'anti-diabetic', drug, with, no, severe, side, 'effects,', whereas, many, of, the, 'anti-obesity', drugs, developed, to, date]), verbo([have]), complemento([been, withdrawn, because, of, their, severe, side, effects])].
[sujeto(['In', this, 'review,', we]), verbo([provide]), complemento([an, overview, of, the, state, of, research, on, miglitol, for, obesity, 'treatment,', emphasizing, that, it, warrants, more, detailed, attention])].
[sujeto(['The', interest, in, brown, adipose, tissue, '(', 'BAT)', as, a]), verbo([target]), complemento([to, combat, metabolic, disease, has, recently, been, renewed, with, the, discovery, of, functional, 'BAT', in, humans])].
[sujeto(['In', 'rodents,', 'BAT', can, be]), verbo([activated]), complemento([by, bile, 'acids,', which, activate, type, 2, iodothyronine, deiodinase, '(', 'D2)', in, 'BAT', via, the, 'G-coupled', protein, receptor, 'TGR5,', resulting, in, increased, oxygen, consumption, and, energy, expenditure])].
[sujeto(['Treatment', of, 12, healthy, female, subjects, with, 'CDCA', for, 2, days, resulted, in]), verbo([increased]), complemento(['BAT', activity])].
[sujeto(['Whole-body', energy, expenditure, was, also]), verbo([increased]), complemento([upon, 'CDCA', treatment])].
[sujeto(['In', vitro, treatment, of, primary, human, brown, adipocytes, derived, with, 'CDCA', or, specific, 'TGR5', agonists]), verbo([increased]), complemento([mitochondrial, uncoupling, and, 'D2', 'expression,', an, effect, that, was, absent, in, human, primary, white, adipocytes])].
[sujeto(['These', findings, identify, bile, acids, as, a]), verbo([target]), complemento([to, activate, 'BAT', in, humans])].
[sujeto(['Vitamin', 'C', is, known, to]), verbo([have]), complemento([hepatoprotective, 'effects,', but, their, underlying, mechanisms, are, 'unclear,', especially, those, associated, with, hepatic, fibrosis])].
[sujeto(['Here,', we, analyzed, the, impact, of, vitamin, 'C', on, bile, acid]), verbo([induced]), complemento([hepatocyte, apoptosis, in, vitro, and, lithocholic, acid, '(', 'LCA)-induced', liver, injury, in, vitamin, 'C-insufficient', 'Gulo(-/-)', 'mice,', which, cannot, synthesize, vitamin, 'C', similarly, to, humans])].
[sujeto(['When', 'Huh-BAT', cells, were, treated, with, bile, 'acid,', apoptosis, was]), verbo([induced]), complemento([by, endoplasmic, reticulum, 'stress-related', 'JNK', activation, but, vitamin, 'C', attenuated, bile, 'acid-induced', hepatocyte, apoptosis, in, vitro])].
[sujeto(['In', our, in, vivo, 'experiments,', 'LCA', feeding]), verbo([increased]), complemento([plasma, marker, of, cholestasis, and, resulted, in, more, extensive, liver, damage, and, hepatic, fibrosis, by, more, prominent, apoptotic, cell, death, and, recruiting, more, intrahepatic, inflammatory, 'CD11b(+)', cells, in, the, liver, of, vitamin, 'C-insufficient', 'Gulo(-/-)', mice, compared, to, wild, type, mice, which, have, minimal, hepatic, fibrosis])].
[sujeto(['However,', when, vitamin, 'C', was, supplemented, to, vitamin, 'C-insufficient', 'Gulo(-/-)', 'mice,', hepatic, fibrosis, was, significantly, attenuated, in, the, liver, of, vitamin, 'C-sufficient', 'Gulo(-/-)', mice, like, in, wild, type, mice, and, this, hepatoprotective, effect, of, vitamin, 'C', was, thought, to, be]), verbo([associated]), complemento([with, both, decreased, hepatic, apoptosis, and, necrosis])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, vitamin, 'C', had, hepatoprotective, effect, against, cholestatic, liver, injury])].
[sujeto(['Little', information, on, these, lipases]), verbo([has]), complemento([been, obtained, and, only, the, major, secreted, 'lipase,', namely, 'YLLIP2,', had, been, biochemically, and, structurally, characterized])].
[sujeto(['It']), verbo([has]), complemento([no, apparent, regioselectivity, in, 'TAG', 'hydrolysis,', thus, generating, glycerol, and, 'FFAs', as, final, lipolysis, products])].
[sujeto(['YLLIP8', properties, are, distinct, from, those, of, the, 1, ',', 3, -, regioselective, 'YLLIP2,']), verbo([acting]), complemento([optimally, at, acidic, pH])].
[sujeto(['The', canine, 'SNAP', 'Bile', 'Acids', 'Test', '(', 'SNAP-BAT)']), verbo([provides]), complemento([an, 'immediate,', 'semi-quantitative', measurement, of, bile, acid, concentrations, 'in-house'])].
[sujeto(['Agreement', of, the, 'SNAP-BAT', with, the, enzymatic, method]), verbo([has]), complemento([not, been, extensively, investigated])].
[sujeto(['After', verifying, 'intra-assay', precision, of, the, 'SNAP-BAT,', a, prospective, analysis, was, performed, using, blood, samples, collected, from, 56, dogs, suspected, to]), verbo([have]), complemento([liver, disease])].
[sujeto(['The', 'SNAP-BAT', is, a, highly, 'accurate,', 'semi-quantitative', test, that, yields, immediate, 'results,', and]), verbo([has]), complemento([very, little, 'intra-assay', 'variability,', particularly, for, results, &, 'gt;30', 'µmol/L'])].
[sujeto(['Brown', adipose, tissue, '(', 'BAT)']), verbo([has]), complemento([the, unique, ability, to, oxidize, fatty, acids, to, generate, 'heat,', a, process, termed, thermogenesis])].
[sujeto(['The', mitochondrial, uncoupling, protein, 1, is, predominantly]), verbo([expressed]), complemento([in, 'BAT', and, controls, the, thermogenetic, properties, of, this, tissue])].
[sujeto(['Since']), verbo([activated]), complemento(['BAT', dissipates, 'energy,', it, is, considered, beneficial, in, controlling, 'metabolism,', i])].
[sujeto(['Indeed,', humans, with, a, higher, 'BMI']), verbo([have]), complemento([less, active, 'BAT'])].
[sujeto(['Endocrine', factors, such, as, thyroid, 'hormone,', sex, steroid, hormones, and, glucocorticoids, can]), verbo([modulate]), complemento(['BAT', activity])].
[sujeto(['Since', the, intestinal, tract]), verbo([has]), complemento([emerged, as, an, endocrine, organ, regulating, energy, balance, and, glucose, 'homeostasis,', this, review, will, discuss, how, 'gut-derived', hormones, and, other, intestinal, 'tract-related', factors, such, as, bile, acids, modulate, 'BAT', activity])].
[sujeto(['Emphasis', will, be, put, on, whether, these, hormones]), verbo([regulate]), complemento(['BAT', directly, or, via, the, central, nervous, system])].
[sujeto(['In', 'summary,', it, can, be, globally, stated, that, anorexigenic, gut, hormones]), verbo([stimulate]), complemento(['BAT', while, orexigenic, gut, hormones, inhibit, 'BAT', activity])].
[sujeto(['How', these, hormones]), verbo([modulate]), complemento(['BAT', and, whether, this, is, via, a, direct, 'and/or', central, effect, is, largely, unknown])].
[sujeto(['Novel', insights, about, 'gut-derived', factors, such, as, bile, acids]), verbo([suggest]), complemento([that, they, also, affect, 'BAT', activity])].
[sujeto(['Thyroid', hormone, '(', 'TH)', is]), verbo([required]), complemento([for, normal, development, as, well, as, regulating, metabolism, in, the, adult])].
[sujeto(['The', thyroid, hormone, receptor, '(', 'TR)', 'isoforms,', α, and, 'β,', are, differentially]), verbo([expressed]), complemento([in, tissues, and, have, distinct, roles, in, 'TH', signaling])].
[sujeto(['D2', is]), verbo([expressed]), complemento([in, the, 'hypothalamus,', white, 'fat,', brown, adipose, tissue, '(', 'BAT),', and, skeletal, muscle, and, is, required, for, adaptive, thermogenesis])].
[sujeto(['The', thyroid, gland, is]), verbo([regulated]), complemento([by, thyrotropin, releasing, hormone, '(', 'TRH)', and, thyroid, stimulating, hormone, '(', 'TSH)'])].
[sujeto(['In', addition, to, 'TRH/TSH', regulation, by, 'TH', 'feedback,', there, is, central, modulation, by, nutritional, 'signals,', such, as, 'leptin,', as, well, as, peptides]), verbo([regulating]), complemento([appetite])].
[sujeto(['The', nutrient, status, of, the, cell]), verbo([provides]), complemento([feedback, on, 'TH', signaling, pathways, through, epigentic, modification, of, histones])].
[sujeto(['TR']), verbo([regulates]), complemento([cholesterol, and, carbohydrate, metabolism, through, direct, actions, on, gene, expression, as, well, as, 'cross-talk', with, other, nuclear, 'receptors,', including, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR),', liver, 'X', receptor, '(', 'LXR),', and, bile, acid, signaling, pathways])].
[sujeto(['TH']), verbo([modulates]), complemento([hepatic, insulin, 'sensitivity,', especially, important, for, the, suppression, of, hepatic, gluconeogenesis])].
[sujeto(['The', role, of, 'TH', in]), verbo([regulating]), complemento([metabolic, pathways, has, led, to, several, new, therapeutic, targets, for, metabolic, disorders])].
[sujeto(['Besides', their, role, in, lipid, 'absorption,', bile, acids, '(', 'BAs)', can]), verbo([act]), complemento([as, signalling, molecules])].
[sujeto(['Cholic', acid, was, shown, to, counteract, obesity, and]), verbo([associated]), complemento([metabolic, disorders, in, 'high-fat-diet', '(', 'cHF)-fed', mice, while, enhancing, energy, expenditure, through, induction, of, mitochondrial, uncoupling, protein, 1, '(', 'UCP1)', and, activation, of, 'non-shivering', thermogenesis, in, brown, adipose, tissue, '(', 'BAT)'])].
[sujeto(['To']), verbo([induce]), complemento([obesity, and, associated, metabolic, 'disorders,', male, 2, -, 'month-old', 'C57BL/6J', mice, were, fed, cHF, '(', 35, '%', lipid, wt, 'wt(-1),', mainly, corn, 'oil)', for, 4, months])].
[sujeto(['In', the, 8, -, week, 'reversion,', the, 'CDCA', intervention, resulted, in, a, 'dose-dependent', reduction, of, 'obesity,', dyslipidaemia, and, glucose, 'intolerance,', which, could, be, largely, explained, by, a, transient]), verbo([decrease]), complemento([in, food, intake])].
[sujeto(['The', 3, -, week, reversion, revealed, mild, 'CDCA-dependent', and, food, 'intake-independent', induction, of, 'UCP1-mediated', thermogenesis, in, interscapular, 'BAT,', negligible]), verbo([increase]), complemento([of, 'UCP1', in, subcutaneous, 'WAT', and, a, shift, from, carbohydrate, to, lipid, oxidation])].
[sujeto(['The', hydrophobic, bile, 'acid,', deoxycholic, acid, '(', 'DC),', can]), verbo([induce]), complemento([apoptosis, in, hepatocytes])].
[sujeto(['DC']), verbo([induced]), complemento([apoptosis, in, 'NTCP-positive', 'HCC', 'cells,', especially, under, hypoxic, conditions])].
[sujeto(['In', 'NTCP-negative', 'HCC', 'cells,', simultaneous, treatment, with, 'DC', and, cyclooxygenase, inhibitor, markedly]), verbo([decreased]), complemento([aggressive, cellular, behaviors, via, the, inhibition, of, 'NF-κB/COX-2/IL-8', pathways])].
[sujeto(['Increased', serum, bile, salt, levels]), verbo([have]), complemento([been, associated, to, a, 'single-nucleotide', polymorphism, in, the, bile, salt, export, pump, '(', 'BSEP;', 'ABCB11)', in, several, acquired, cholestatic, liver, diseases, but, there, is, little, evidence, in, alcoholic, liver, disease, '(', 'ALD)'])].
[sujeto(['Furthermore,', a, crosstalk, between, vitamin, 'D', and, bile, acid, synthesis]), verbo([has]), complemento([recently, been, discovered])].
[sujeto(['Whether', this, crosstalk]), verbo([has]), complemento([an, influence, on, the, course, of, 'ALD', is, unclear, to, date])].
[sujeto(['We', conclude, that, 'ABCB11', and, 'NR1I1', polymorphisms, are, obviously, not]), verbo([associated]), complemento([with, development, of, cirrhosis, in, patients, with, 'ALD'])].
[sujeto(['To', examine, how, 'high-mobility', group, box, 1, '(', 'HMGB1)']), verbo([regulates]), complemento([hepatocyte, apoptosis, 'and,', 'furthermore,', to, determine, whether, glycyrrhizin, '(', 'GL),', a, known, 'HMGB1', 'inhibitor,', prevents, 'HMGB1-induced', hepatocyte, apoptosis])].
[sujeto(['HMGB1']), verbo([increased]), complemento([cellular, apoptosis, in, 'Huh-BAT', cells])].
[sujeto(['HMGB1']), verbo([led]), complemento([to, increased, cytochrome, c, release, from, mitochondria, into, the, 'cytosol,', and, induced, the, cleavage, of, procaspase, 3])].
[sujeto(['GL', also]), verbo([prevented]), complemento(['HMGB1-induced', cytochrome, c, release, and, p38, activation, in, 'Huh-BAT', cells])].
[sujeto(['The', present, study, demonstrated, that, 'HMGB1']), verbo([promoted]), complemento([hepatocyte, apoptosis, through, a, 'p38-dependent', mitochondrial, pathway])].
[sujeto(['Kaki-tannin,', a, highly, 'polymerized-tannin', from, the, young, fruits, of, persimmon, '(', 'Diospyros', kaki, '\'', 'Hachiya\'),']), verbo([has]), complemento([been, shown, to, have, bile, 'acid-binding', activity])].
[sujeto(['Kaki-tannin']), verbo([induced]), complemento([a, 2, -, fold, increase, in, fecal, bile, acid, excretion, and, was, significantly, effective, in, the, prevention, of, a, rise, in, plasma, 'cholesterol,', 'triglyceride,', and, insulin, levels])].
[sujeto(['Kaki-tannin', treatment, also]), verbo([prevented]), complemento([fatty, liver])].
[sujeto(['The', genes, related, to, cholesterol, 'metabolism,', including, 3, -, 'hydroxy-3-methylglutaryl-coenzyme', 'A', reductase, and, sterol, regulatory, 'element-binding', protein, 2, ',', were]), verbo([increased]), complemento([in, the, liver, of, the, 'kaki-tannin', group])].
[sujeto(['Interestingly,', the, uncoupling, 'protein-1', '(', 'UCP1)', gene, and, the, 'UCP3', gene, were, significantly]), verbo([increased]), complemento([in, the, 'BAT', of, the, 'kaki-tannin', 'group,', which, was, also, confirmed, at, the, protein, level])].
[sujeto(['The', expression, of, 'TGR5', and, its, function, are, distinct, from, the, previously, identified]), verbo([nuclear]), complemento([bile, acid, 'receptor,', farnesoid, 'X', receptor, '(', 'FXR)'])].
[sujeto(['These', two, bile, acid, receptors, complement, with, each, other, for]), verbo([maintaining]), complemento([bile, acid, homeostasis, and, mediating, bile, acid, signaling])].
[sujeto(['Both', receptors, are, also, shown, to, play, roles, in]), verbo([regulating]), complemento([inflammation, and, glucose, metabolism])].
[sujeto(['An', interesting]), verbo([finding]), complemento([for, 'TGR5', is, its, role, in, energy, metabolism])].
[sujeto(['The', discovery, of, 'TGR5', expression, in, brown, adipocyte, tissues, '(', 'BATs)', and, the, recent, demonstration, of, 'BAT', in, adult, human, body]), verbo([suggest]), complemento([a, potential, approach, to, combat, obesity, by, targeting, 'TGR5', to, increase, thermogenesis])].
[sujeto(['We', summarize, here, the, latest]), verbo([finding]), complemento([of, 'TGR5', 'research,', especially, its, role, in, energy, metabolism, and, glucose, homeostasis])].
[sujeto(['We', investigated, one, of, these, pathways]), verbo([involving]), complemento([acute, 'cholestasis,', immediate, portal, 'hyperpressure,', and, arginine, vasopressin, '(', 'AVP)', secretion])].
[sujeto(['Acute', cholestasis, '(', mimicked, by, 'BDL', or, 'BA', 'injection)', as, well, as, portal, hyperpressure, '(', mimicked, by, 'PVS)', independently]), verbo([activated]), complemento(['SON', and, 'AVP', secretion])].
[sujeto(['BA', accumulated, in, the, brain, after, 'PH', or, 'BDL,', and, 'TGR5', was]), verbo([expressed]), complemento([in, 'SON'])].
[sujeto(['SON', activation, was, mimicked, by, the, 'TGR5', agonist, 'OA', and]), verbo([inhibited]), complemento([in, 'TGR5', 'KO', mice, after, 'BDL'])].
[sujeto(['After', 'PH', in, 'rodents,', acute, cholestasis, and, portal, 'hypertension,', via, the, nervous, and, endocrine, 'routes,']), verbo([stimulate]), complemento([the, secretion, of, 'AVP', that, may, protect, the, liver, against, shear, stress, and, bile, acids, overload])].
[sujeto(['Data', in, living, donors]), verbo([suggest]), complemento([that, this, pathway, may, also, operate, in, humans])].
[sujeto(['Aliphatic', glucosinolate, biosynthesis, is, highly, 'compartmentalized,']), verbo([requiring]), complemento([import, of, 2, -, keto, acids, or, amino, acids, into, chloroplasts, for, side, chain, elongation, and, export, of, the, resulting, compounds, into, the, cytosol, for, conversion, into, glucosinolate])].
[sujeto(['Aliphatic', glucosinolate, biosynthesis, in, 'Arabidopsis', thaliana, is]), verbo([regulated]), complemento([by, three, 'R2R3-MYB', transcription, 'factors,', the, major, player, being, 'High', 'Aliphatic', 'Glucosinolate', 1, '(', 'HAG1/MYB28)'])].
[sujeto(['Furthermore,', two, isopropylmalate, isomerases, 'genes,', 'IPMI1', and, 'IPMI2,', and, the, isopropylmalate, dehydrogenase, 'gene,', 'IPMDH1,', were, identified, as]), verbo([targets]), complemento([of, 'HAG1/MYB28', and, the, corresponding, proteins, localized, to, 'plastids,', suggesting, a, role, in, plastidic, chain, elongation, reactions])].
[sujeto(['The', bat5, mutant, chemotype, was, rescued, by]), verbo([induced]), complemento([overexpression, of, 'BAT5'])].
[sujeto(['Feeding', experiments, using, 2, -, keto, acids, and, amino, acids, of, different, chain, length]), verbo([suggest]), complemento([that, 'BAT5', is, a, plastidic, transporter, of, '(', 'chain-elongated)', 2, -, keto, acids])].
[sujeto(['Mechanical', stimuli, and, methyl, jasmonate, transiently]), verbo([induced]), complemento(['BAT5', expression, in, inflorescences, and, leaves])].
[sujeto(['The', secondary, bile, acid, lithocholic, acid, '(', 'LCA)', and, its, derivatives]), verbo([act]), complemento([as, selective, modulators, of, the, vitamin, 'D', receptor, '(', 'VDR),', although, their, structures, fundamentally, differ, from, that, of, the, natural, hormone, 1, 'α,25-dihydroxyvitamin', 'D3', '(', 1, ',', 25, '(', 'OH)2D3)'])].
[sujeto(['The', complexes, of, the, 'ligand-binding', domain, of, rat, 'VDR', '(', 'VDR-LBD)', with, 'LCA', and, its, derivatives, revealed, that, the, ligands]), verbo([bound]), complemento([to, the, same, 'ligand-binding', pocket, '(', 'LBP)', of, 'VDR-LBD', that, 1, ',', 25, '(', 'OH)2D3', binds, 'to,', but, in, the, opposite, 'orientation;', their, 'A-ring', was, positioned, at, the, top, of, the, 'LBP,', whereas, their, acyclic, tail, was, located, at, the, bottom, of, the, 'LBP'])].
[sujeto(['Recently,', zebrafish, 'VDR']), verbo([has]), complemento([been, reported, to, have, the, second, 'LBP', on, the, outside, of, the, canonical, 'LBP,', although, its, physiological, function, is, unclear])].
[sujeto(['The', vitamin, 'D', receptor, '(', 'VDR),', an, endocrine]), verbo([nuclear]), complemento([receptor, for, 1, 'α,25-dihydroxyvitamin', 'D3,', acts, also, as, a, bile, acid, sensor, by, binding, lithocholic, acid, '(', 'LCA)'])].
[sujeto(['The', crystal, structure, of, the, zebrafish, 'VDR', ligand]), verbo([binding]), complemento([domain, in, complex, with, 'LCA', and, the, 'SRC-2', coactivator, peptide, reveals, the, binding, of, two, 'LCA', molecules, by, 'VDR'])].
[sujeto(['One', 'LCA']), verbo([binds]), complemento([to, the, canonical, 'ligand-binding', 'pocket,', and, the, second, 'one,', which, is, not, fully, 'buried,', is, anchored, to, a, site, located, on, the, 'VDR', surface])].
[sujeto(['Despite', the, low, affinity, of, the, alternative, 'site,', the]), verbo([binding]), complemento([of, the, second, molecule, promotes, stabilization, of, the, active, receptor, conformation])].
[sujeto(['The', unique]), verbo([binding]), complemento([mode, of, 'LCA', provides, clues, for, the, development, of, new, chemical, compounds, that, target, alternative, binding, sites, for, therapeutic, applications])].
[sujeto(['Vitamin', 'D', receptor, '(', 'VDR)']), verbo([mediates]), complemento([vitamin, 'D', signaling, involved, in, bone, 'metabolism,', cellular, growth, and, 'differentiation,', cardiovascular, 'function,', and, bile, acid, regulation])].
[sujeto(['Mice', with, an, 'intestine-specific', disruption, of, 'VDR', '(', 'Vdr(ΔIEpC))']), verbo([have]), complemento([abnormal, body, 'size,', colon, 'structure,', and, imbalance, of, bile, acid, metabolism])].
[sujeto(['Lithocholic', acid, '(', 'LCA),', a, secondary, bile, acid, that]), verbo([activates]), complemento(['VDR,', is, among, the, most, toxic, of, the, bile, acids, that, when, overaccumulated, in, the, liver, causes, hepatotoxicity])].
[sujeto(['Because', cytochrome, 'P450', 3, 'A4', '(', 'CYP3A4)', is, a]), verbo([target]), complemento([gene, of, 'VDR-involved', bile, acid, 'metabolism,', the, role, of, 'CYP3A4', in, 'VDR', biology, and, bile, acid, metabolism, was, investigated])].
[sujeto(['VDR', deficiency, in, the, intestine, of, the, 'Vdr(ΔIEpC)', mice, exacerbates, 'LCA-induced', hepatotoxicity, manifested, by]), verbo([increased]), complemento([necrosis, and, 'inflammation,', due, in, part, to, 'over-accumulation', of, hepatic, bile, acids, including, taurocholic, acid, and, taurodeoxycholic, acid])].
[sujeto(['This', study]), verbo([reveals]), complemento([that, intestinal, 'CYP3A4', protects, against, 'LCA', hepatotoxicity])].
[sujeto(['The', secondary, bile, acid, lithocholic, acid, '(', 'LCA)', and, its, derivatives]), verbo([act]), complemento([as, selective, modulators, of, the, vitamin, 'D', receptor, '(', 'VDR),', although, their, structures, fundamentally, differ, from, that, of, the, natural, hormone, 1, 'α,25-dihydroxyvitamin', 'D3', '[', 1, ',', 25, '(', 'OH)2D3)]'])].
[sujeto(['Here,', we]), verbo([have]), complemento([determined, the, crystal, structures, of, the, 'ligand-binding', domain, of, rat, 'VDR', '(', 'VDR-LBD)', in, ternary, complexes, with, a, synthetic, partial, peptide, of, the, coactivator, 'MED1', '(', mediator, of, 'RNA', polymerase, 'II', transcription, subunit, 1, ')', and, four, 'ligands,', 'LCA,', 3, -, keto, 'LCA,', 'LCA', 'acetate,', and, 'LCA', 'propionate,', with, the, goal, of, elucidating, their, agonistic, mechanism])].
[sujeto(['LCA', and, its, derivatives]), verbo([bind]), complemento([to, the, same, 'ligand-binding', pocket, '(', 'LBP)', of, 'VDR-LBD', that, 1, ',', 25, '(', 'OH)2D3', binds, 'to,', but, in, the, opposite, 'orientation;', their, 'A-ring', is, positioned, at, the, top, of, the, 'LBP,', whereas, their, acyclic, tail, is, located, at, the, bottom, of, the, 'LBP'])].
[sujeto(['The', hormonal, metabolite, of, vitamin, 'D,', 1, 'α,25-dihydroxyvitamin', 'D(3)', '(', 1, ',', 25, 'D),', initiates, biological, responses, via]), verbo([binding]), complemento([to, the, vitamin, 'D', receptor, '(', 'VDR)'])].
[sujeto(['When', occupied, by, 1, ',', 25, 'D,', 'VDR']), verbo([interacts]), complemento([with, the, retinoid, 'X', receptor, '(', 'RXR)', to, form, a, heterodimer, that, binds, to, vitamin, 'D', responsive, elements, in, the, region, of, genes, directly, controlled, by, 1, ',', 25, 'D'])].
[sujeto(['By']), verbo([recruiting]), complemento([complexes, of, either, coactivators, or, 'corepressors,', 'ligand-activated', 'VDR-RXR', modulates, the, transcription, of, genes, encoding, proteins, that, promulgate, the, traditional, functions, of, vitamin, 'D,', including, signaling, intestinal, calcium, and, phosphate, absorption, to, effect, skeletal, and, calcium, homeostasis])].
[sujeto(['Thus,', vitamin, 'D', action, in, a, particular, cell, depends, upon, the, metabolic, production, or, delivery, of, sufficient, concentrations, of, the, 1, ',', 25, 'D', 'ligand,', expression, of, adequate, 'VDR', and, 'RXR', coreceptor, 'proteins,', and, 'cell-specific', programming, of, transcriptional, responses, to]), verbo([regulate]), complemento([select, genes, that, encode, proteins, that, function, in, mediating, the, effects, of, vitamin, 'D'])].
[sujeto(['For', 'example,', 1, ',', 25, 'D']), verbo([induces]), complemento(['RANKL,', 'SPP1', '(', 'osteopontin),', and, 'BGP', '(', 'osteocalcin)', to, govern, bone, mineral, 'remodeling;', 'TRPV6,', 'CaBP(9k),', and, claudin, 2, to, promote, intestinal, calcium, 'absorption;', and, 'TRPV5,', 'klotho,', and, 'Npt2c', to, regulate, renal, calcium, and, phosphate, reabsorption])].
[sujeto([',', lithocholic, 'acid,', docosahexaenoic, 'acid,', and, 'curcumin,']), verbo([have]), complemento([been, reported])].
[sujeto(['The', active, form, of, vitamin, 'D,', 1, 'α,25-dihydroxyvitamin', 'D(3)', '[', 1, ',', 25, '(', 'OH)(2)D(3)],']), verbo([binds]), complemento([to, the, vitamin, 'D', receptor, '(', 'VDR)', and, regulates, various, physiological, and, pharmacological, processes])].
[sujeto(['Secondary', bile, 'acids,', such, as, lithocholic, acid, '(', 'LCA),', also]), verbo([act]), complemento([as, endogenous, 'VDR', ligands])].
[sujeto(['Hairless', '(', 'HR)']), verbo([acts]), complemento([as, a, coregulator, of, 'VDR', through, a, direct, interaction])].
[sujeto(['HR', mutations]), verbo([confer]), complemento([an, alopecia, phenotype, similar, to, 'VDR', mutations, in, mice, and, 'humans,', but, the, underlying, molecular, mechanisms, have, not, been, elucidated])].
[sujeto(['We', examined, the, effect, of, 'HR', on, 'VDR', activation]), verbo([induced]), complemento([by, 1, ',', 25, '(', 'OH)(2)D(3)', and, 'LCA'])].
[sujeto(['HR']), verbo([repressed]), complemento(['VDR', transactivation, induced, by, both, 1, ',', 25, '(', 'OH)(2)D(3)', and, 'LCA'])].
[sujeto(['HR', also]), verbo([repressed]), complemento([transactivation, of, 'VDR', 'E269A', and, 'R391A', 'mutants,', but, less, effectively, than, that, of, 'wild-type', 'VDR'])].
[sujeto(['These', residues, are]), verbo([involved]), complemento([in, retinoid, 'X', receptor, '(', 'RXR)', heterodimer, allosteric, 'communication,', through, which, information, from, ligands, is, transmitted, to, dimer, and, coactivator, interfaces])].
[sujeto(['In', the, presence, of, 'HR', 'cotransfection,', 'LCA']), verbo([activated]), complemento([these, 'VDR', mutants, more, effectively, than, 'wild-type', 'VDR'])].
[sujeto(['In', mammalian, 'two-hybrid', 'assays,', 'HR']), verbo([enhanced]), complemento([the, association, of, 'VDR', with, a, 'corepressor,', nuclear, receptor, corepressor])].
[sujeto(['Interestingly,', 'HR', knockdown, in, 'keratinocyte-derived', 'HaCaT', cells]), verbo([increased]), complemento(['ligand-induced', cytochrome, 'P450,', family, 24, ',', subfamily, 'A,', polypeptide, 1, '(', 'CYP24A1)', expression, but, suppressed, expression, of, cathelicidin, antimicrobial, 'peptide,', indicating, that, 'HR', acts, not, only, as, a, corepressor, but, also, as, a, coactivator])].
[sujeto(['HR', may, be, a, 'VDR', modulator, that, affects, the, 'RXR', allosteric, communication, network, in, order, to]), verbo([regulate]), complemento([transcription, in, a, 'gene-selective', manner])].
[sujeto(['The', vitamin, 'D', receptor, '(', 'VDR)']), verbo([mediates]), complemento([vitamin, 'D', signaling, in, numerous, physiological, and, pharmacological, 'processes,', including, bone, and, calcium, 'metabolism,', cellular, growth, and, 'differentiation,', 'immunity,', and, cardiovascular, function])].
[sujeto(['Although', transcriptional, regulation, by, 'VDR']), verbo([has]), complemento([been, investigated, 'intensively,', an, understanding, of, 'ligand-selective', dynamic, 'VDR', conformations, remains, elusive])].
[sujeto(['In', the, absence, of, 'ligand,', 'VDR', homodimers, were, preferred, to, 'RXR', heterodimers, and, were]), verbo([associated]), complemento([with, 'SMRT'])].
[sujeto([1, ',', 25, '(', 'OH)(2)D(3)']), verbo([induced]), complemento([heterodimerization, with, 'RXR,', dissociation, of, 'SMRT,', and, association, of, 'SRC-1'])].
[sujeto(['LCA', and, 'ADTT']), verbo([induced]), complemento([those, effects, to, a, lesser, extent, at, concentrations, that, did, not, induce, expression, of, the, 'VDR', target, gene, 'CYP24A1', in, human, embryonic, kidney, '(', 'HEK)', 293, cells])].
[sujeto(['Unlike', in, 'HEK293', 'cells,', 'ADTT']), verbo([increased]), complemento(['CYP24A1', expression, in, 'HCT116', cells, and, increased, the, association, of, 'VDR', and, 'SMRT', on, the, 'CYP24A1', promoter])].
[sujeto(['The', results, indicate, that, 'ligand-selective', conformation, may]), verbo([lead]), complemento([to, unique, cofactor, complex, formation, in, a, cell, 'context-dependent', manner])].
[sujeto(['Nuclear', receptors, '(', 'NRs)', are, 'ligand-activated', transcription, factors, that]), verbo([regulate]), complemento([the, expression, of, genes, involved, in, biologically, important, processes])].
[sujeto(['The', human, vitamin, 'D', receptor, '(', 'hVDR)', is, a, member, of, the, 'NR', superfamily, and, is, responsible, for]), verbo([maintaining]), complemento([calcium, and, phosphate, homeostasis])].
[sujeto(['This', receptor, is]), verbo([activated]), complemento([by, its, natural, 'ligand,', 1, 'α,', 25, -, dihydroxyvitamin, 'D(3)', '(', 1, 'α,', 25, '(', 'OH)(2)D(3)),', as, well, as, bile, acids, such, as, lithocholic, acid, '(', 'LCA)'])].
[sujeto(['Disruption', of, molecular, interactions, between, the, hVDR, and, its, natural, ligand, result, in, adverse, 'diseases,', such, as, 'rickets,', making, this, receptor, a, good]), verbo([target]), complemento([for, drug, discovery])].
[sujeto(['Previous', mutational, analyses, of, the, hVDR]), verbo([have]), complemento([mainly, focused, on, residues, lining, the, 'receptor\'s', ligand, binding, pocket, '(', 'LBP)', and, techniques, such, as, alanine, scanning, mutagenesis, and, 'site-directed', mutagenesis])].
[sujeto(['In', this, 'work,', a, rationally, designed, hVDR, library, using, randomized, codons, at, selected, positions]), verbo([provides]), complemento([insight, into, the, role, of, residue, 'C410,', particularly, on, activation, of, the, receptor, by, various, ligands])].
[sujeto(['A', 'variant,', 'C410Y,', was, engineered, to]), verbo([bind]), complemento(['LCA', with, increased, sensitivity, '(', 'EC(50)', value, of, 3, μM, and, a, 34, -, fold, 'activation)', in, mammalian, cell, culture, assays])].
[sujeto(['Furthermore,', this, variant, displayed, activation, with, a, novel, small, 'molecule,', cholecalciferol, '(', 'chole)', which, does, not]), verbo([activate]), complemento([the, 'wild-type', 'receptor,', with, an, 'EC(50)', value, of, 4, μM, and, a, 25, -, fold, activation])].
[sujeto(['The', presence, of, a, bulky, residue, at, this, 'position,', such, as, a, tyrosine, or, 'phenylalanine,', may, contribute, towards, molecular, interactions, that, allow, for, the]), verbo([enhanced]), complemento([activation, with, 'LCA', and, novel, activation, with, chole])].
[sujeto(['Additional', bulk, at, the, same, end, of, the, 'pocket,', such, as, in, the, case, of, the, variant, 'H305F;', 'C410Y']), verbo([enhances]), complemento([the, 'receptor\'s', sensitivity, for, these, ligands, 'further,', perhaps, due, to, the, filling, of, a, cavity])].
[sujeto(['The', human, vitamin, 'D', receptor, '(', 'hVDR)', is, a, member, of, the]), verbo([nuclear]), complemento([receptor, 'superfamily,', involved, in, calcium, and, phosphate, 'homeostasis;', hence, implicated, in, a, number, of, 'diseases,', such, as, 'Rickets', and, 'Osteoporosis'])].
[sujeto(['This', receptor]), verbo([binds]), complemento([1, 'α,25-dihydroxyvitamin', 'D(3)', '(', also, referred, to, as, 1, ',', 25, '(', 'OH)(2)D(3))', and, other, known, 'ligands,', such, as, lithocholic, acid])].
[sujeto(['Specific', interactions, between, the, receptor, and, ligand, are, crucial, for, the, function, and, activation, of, this, 'receptor,', as, implied, by, the, single, point, 'mutation,', 'H305Q,']), verbo([causing]), complemento([symptoms, of, 'Type', 'II', 'Rickets'])].
[sujeto(['A', hVDR, 'mutant,', 'H305F,', was, engineered, with]), verbo([increased]), complemento([sensitivity, towards, lithocholic, 'acid,', with, an, 'EC(50)', value, of, 10, μM, and, 40, '±14', fold, activation, in, mammalian, cell, 'assays,', while, maintaining, 'wild-type', activity, with, 1, ',', 25, '(', 'OH)(2)D(3)'])].
[sujeto(['Furthermore,', via, random, 'mutagenesis,', a, hVDR, 'mutant,', 'H305F/H397Y,', was, discovered, to]), verbo([bind]), complemento([a, novel, small, 'molecule,', 'cholecalciferol,', a, precursor, in, the, 1, 'α,25-dihydroxyvitamin', 'D(3)', biosynthetic, 'pathway,', which, does, not, activate, 'wild-type', hVDR])].
[sujeto(['This', 'variant,', 'H305F/H397Y,']), verbo([binds]), complemento([and, activates, in, response, to, cholecalciferol, concentrations, as, low, as, 100, 'nM,', with, an, 'EC(50)', value, of, 300, nM, and, 70, '±11', fold, activation, in, mammalian, cell, assays])].
[sujeto(['In', silico, docking, analysis, of, the, variant, displays, a, dramatic, conformational, shift, of, cholecalciferol, in, the, ligand]), verbo([binding]), complemento([pocket, in, comparison, to, the, docked, analysis, of, cholecalciferol, with, 'wild-type', hVDR])].
[sujeto(['This', shift, is, hypothesized, to, be, due, to, the, introduction, of, two, bulkier, 'residues,']), verbo([suggesting]), complemento([that, the, addition, of, these, bulkier, residues, introduces, molecular, interactions, between, the, ligand, and, 'receptor,', leading, to, activation, with, cholecalciferol])].
[sujeto(['The', farnesoid, 'X', receptor, '(', 'FXR),', pregnane, 'X', receptor, '(', 'PXR),', and, vitamin, 'D', receptor, '(', 'VDR)', are, three, closely, related]), verbo([nuclear]), complemento([hormone, receptors, in, the, 'NR1H', and, 1, 'I', subfamilies, that, share, the, property, of, being, activated, by, bile, salts])].
[sujeto(['Bile', salts, vary, significantly, in, structure, across, vertebrate, 'species,']), verbo([suggesting]), complemento([that, receptors, binding, these, molecules, may, show, adaptive, evolutionary, changes, in, response])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, 'FXRs', from, the, sea, lamprey, '(', 'Petromyzon', 'marinus)', and, zebrafish, '(', 'Danio', 'rerio)', are, activated, by, planar, bile, alcohols, found, in, these, two, species])].
[sujeto(['In', this, 'report,', we, characterize, 'FXR,', 'PXR,', and, 'VDR', from, the, 'green-spotted', pufferfish, '(', 'Tetraodon', 'nigriviridis),', an, actinopterygian, fish, that, unlike, the, zebrafish]), verbo([has]), complemento([a, bile, salt, profile, similar, to, humans])].
[sujeto(['Tetraodon', 'FXR']), verbo([has]), complemento([a, ligand, selectivity, profile, very, similar, to, human, 'FXR,', with, strong, activation, by, the, synthetic, ligand, 'GW4064', and, by, the, primary, bile, acid, chenodeoxycholic, acid])].
[sujeto(['Homology', modelling, and, docking, studies]), verbo([suggest]), complemento([a, 'ligand-binding', pocket, architecture, more, similar, to, human, and, rat, 'FXRs', than, to, lamprey, or, zebrafish, 'FXRs'])].
[sujeto(['Tetraodon', 'PXR', was]), verbo([activated]), complemento([by, a, variety, of, bile, acids, and, 'steroids,', although, not, by, the, larger, synthetic, ligands, that, activate, human, 'PXR', such, as, rifampicin])].
[sujeto(['We', also, demonstrate, that, 'VDRs', from, the, pufferfish, and, 'Japanese', medaka, were]), verbo([activated]), complemento([by, small, secondary, bile, acids, such, as, lithocholic, 'acid,', whereas, the, 'African', clawed, frog, 'VDR', was, not])].
[sujeto(['Our', studies]), verbo([provide]), complemento([further, evidence, of, the, relationship, between, both, 'FXR,', 'PXR,', and, 'VDR', ligand, selectivity, and, 'cross-species', variation, in, bile, salt, profiles])].
[sujeto(['Zebrafish', and, 'green-spotted', pufferfish]), verbo([provide]), complemento([a, clear, contrast, in, having, markedly, different, primary, bile, salt, profiles, '(', planar, bile, alcohols, for, zebrafish, and, sterically, bent, bile, acids, for, the, 'pufferfish)', and, receptor, selectivity, that, matches, these, differences, in, endogenous, ligands])].
[sujeto(['Our', observations, to, date, present, an, integrated, picture, of, the, 'co-evolution', of, bile, salt, structure, and, changes, in, the]), verbo([binding]), complemento([pockets, of, three, nuclear, hormone, receptors, across, the, species, studied])].
[sujeto(['Introduction', of, the, 1, 'alpha-hydroxyl', group, into, 25, -, hydroxyvitamin, 'D3', '(', 2, ')', to, produce, 1, 'alpha,25-dihydroxyvitamin', 'D3', '(', 1, ')']), verbo([increases]), complemento([the, 'VDR', binding, affinity, by, approximately, 1000, -, fold])].
[sujeto(['We', speculated, that, the, carboxylic, acid, of, lithocholic, acid, could, be]), verbo([recognized]), complemento([by, 'Arg-274', in, the, 'ligand-binding', domain, of, 'VDR'])].
[sujeto(['Vitamin', 'D', receptor, '(', 'VDR)', is]), verbo([activated]), complemento([by, natural, 'ligands,', 1, 'alpha,', 25, -, 'dihydroxy-vitamin', 'D(3)', '[', 1, 'alpha,25(OH)(2)-D(3)]', and, lithocholic, acid, '(', 'LCA)'])].
[sujeto(['Our', previous, study, shows, that, 'VDR', is]), verbo([expressed]), complemento([in, human, 'hepatocytes,', and, 'VDR', ligands, inhibit, bile, acid, synthesis, and, transcription, of, the, gene, encoding, cholesterol, 7, 'alpha-hydroxylase', '(', 'CYP7A1)'])].
[sujeto(['Confocal', immunofluorescent, microscopy, imaging, and, immunoblot, analysis, showed, that, 'LCA', and, 1, 'alpha,', 25, '(', 'OH)(2)-D(3)']), verbo([induced]), complemento([intracellular, translocation, of, 'VDR', from, the, cytosol, to, the, nucleus, and, also, plasma, membrane, where, 'VDR', colocalized, with, 'caveolin-1'])].
[sujeto(['VDR', ligands]), verbo([induced]), complemento([tyrosine, phosphorylation, of, 'c-Src', and, 'VDR', and, their, interaction])].
[sujeto(['Kinase', assays, showed, that, 'VDR', ligands, specifically]), verbo([activated]), complemento([the, 'c-Raf/MEK1/2/extracellular', 'signal-regulated', kinase, '(', 'ERK)', 1, /, 2, 'pathway,', which, stimulates, serine, phosphorylation, of, 'VDR', and, hepatocyte, nuclear, 'factor-4alpha,', and, their, interaction])].
[sujeto(['Mammalian', 'two-hybrid', assays, showed, a, 'VDR', 'ligand-dependent', interaction, of]), verbo([nuclear]), complemento([receptor, 'corepressor-1', and, silencing, mediator, of, retinoid, and, thyroid, with, 'VDR/retinoid', 'X', 'receptor-alpha', '(', 'RXRalpha)'])].
[sujeto(['In', 'conclusion,', 'VDR', ligands]), verbo([activate]), complemento([membrane, 'VDR', signaling, to, activate, the, 'MEK1/2/ERK1/2', 'pathway,', which, stimulates, nuclear, 'VDR/RXRalpha', recruitment, of, corepressors, to, inhibit, 'CYP7A1', gene, transcription, in, human, hepatocytes])].
[sujeto(['This', membrane, 'VDR-signaling', pathway, may, be]), verbo([activated]), complemento([by, bile, acids, to, inhibit, bile, acid, synthesis, as, a, rapid, response, to, protect, hepatocytes, from, cholestatic, liver, injury])].
[sujeto(['The']), verbo([nuclear]), complemento([vitamin, 'D', receptor, '(', 'VDR)', mediates, the, actions, of, 1, ',', 25, -, dihydroxyvitamin, 'D(3)', '(', 1, ',', 25, 'D)', to, regulate, gene, transcription])].
[sujeto(['Recently,', the, secondary, bile, 'acid,', lithocholate, '(', 'LCA),', was]), verbo([recognized]), complemento([as, a, novel, 'VDR', ligand])].
[sujeto(['CM', '(', 10, '(', -, 5, ')', 'M)']), verbo([activated]), complemento([transcription, of, a, luciferase, plasmid, containing, the, distal, vitamin, 'D', responsive, element, '(', 'VDRE)', from, the, human, 'CYP3A4', gene, at, levels, comparable, to, 1, ',', 25, 'D', '(', 10, '(', -, 8, ')', 'M)', in, transfected, human, colon, cancer, cells, '(', 'Caco-2)'])].
[sujeto(['While', 'CM', also]), verbo([activated]), complemento([transcription, via, a, retinoid, 'X', receptor, '(', 'RXR)', responsive, 'element,', activation, of, the, glucocorticoid, receptor, '(', 'GR)', by, 'CM', was, negligible])].
[sujeto(['Competition']), verbo([binding]), complemento([assays, with, radiolabeled, 1, ',', 25, 'D', confirmed, that, 'CM', binds, directly, to, 'VDR'])].
[sujeto(['In', mammalian, 'two-hybrid', assays, employing, transfected, 'Caco-2', 'cells,', 'CM', '(', 10, '(', -, 5, ')', 'M)']), verbo([increased]), complemento([the, ability, of, 'VDR', to, recruit, its, heterodimeric, 'partner,', 'RXR,', and, steroid, receptor, 'coactivator-1', '(', 'SRC-1)'])].
[sujeto(['Real-time', 'PCR', studies, revealed, that, 'CM-bound', 'VDR', can]), verbo([activate]), complemento(['VDR', target, genes, 'CYP3A4,', 'CYP24,', p21, and, 'TRPV6', in, 'Caco-2', cells])].
[sujeto(['Numerous', studies]), verbo([have]), complemento([shown, chemoprotection, by, 'CM', against, intestinal, cancers, via, a, variety, of, mechanisms])].
[sujeto(['Small', intestine, and, colon, are, important, 'VDR-expressing', tissues, where, 1, ',', 25, 'D']), verbo([has]), complemento([known, anticancer, properties, that, 'may,', in, 'part,', be, elicited, by, activation, of, 'CYP-mediated', xenobiotic, detoxification, 'and/or', 'up-regulation', of, the, tumor, suppressor, p21])].
[sujeto(['Our', results]), verbo([suggest]), complemento([the, novel, hypothesis, that, 'nutritionally-derived', 'CM', facilitates, chemoprevention, via, direct, binding, 'to,', and, activation, 'of,', 'VDR'])].
[sujeto(['The', activity, of, 'beta-catenin,', commonly, dysregulated, in, human, colon, 'cancers,', is]), verbo([inhibited]), complemento([by, the, vitamin, 'D', receptor, '(', 'VDR),', and, this, mechanism, is, postulated, to, explain, the, putative, 'anti-cancer', activity, of, vitamin, 'D', metabolites, in, the, colon])].
[sujeto(['We']), verbo([report]), complemento([herein, that, 'beta-catenin-mediated', transcription, is, most, effectively, suppressed, by, the, 'VDR', 'FokI', variant, 'F/M4', when, 1, ',', 25, 'D', is, limiting])].
[sujeto(['Using', 'Caco-2', colorectal, cancer, '(', 'CRC)', 'cells,', it, was, observed, that, 'VDR', 'ligands,', 1, ',', 25, 'D', and, 'LCA,', both]), verbo([suppress]), complemento(['beta-catenin', transcriptional, 'activity,', though, 1, ',', 25, 'D', exhibited, significantly, greater, inhibition])].
[sujeto(['Moreover,', 1, ',', 25, 'D,', but, not, 'LCA,']), verbo([suppressed]), complemento([endogenous, expression, of, the, 'beta-catenin', target, gene, 'DKK-4', independent, of, 'VDR', 'DNA-binding', activity])].
[sujeto(['These', results, support, 'beta-catenin', sequestration, away, from, endogenous, gene]), verbo([targets]), complemento([by, 1, ',', 25, 'D-VDR'])].
[sujeto(['This', activity, is, most, efficiently]), verbo([mediated]), complemento([by, the, 'FokI', gene, variant, 'F/M4,', a, 'VDR', allele, previously, associated, with, protection, against, 'CRC'])].
[sujeto(['Interestingly,', we]), verbo([found]), complemento([the, inhibition, of, 'beta-catenin', activity, by, 1, ',', 25, 'D-VDR', was, significantly, enhanced, by, 'wild-type', 'APC'])].
[sujeto(['These', results]), verbo([reveal]), complemento([a, previously, unrecognized, role, for, 1, ',', 25, 'D-VDR', in, 'APC/beta-catenin', cross, talk])].
[sujeto(['Collectively,', these, findings, strengthen, evidence, favoring, a, direct, effect, on, the, 'Wnt-signaling', molecule, 'beta-catenin', as, one, 'anti-cancer']), verbo([target]), complemento([of, 1, ',', 25, 'D-VDR', action, in, the, colorectum])].
[sujeto(['The', vitamin, 'D', receptor, '(', 'VDR)']), verbo([regulates]), complemento([the, expression, of, drug, metabolizing, enzymes, and, transporters, in, intestine, and, 'liver,', but, the, regulation, of, 'VDR', expression, in, intestine, and, liver, is, incompletely, understood])].
[sujeto([1, ',', 25, '(', 'OH)(2)D(3)']), verbo([induced]), complemento(['VDR', expression, in, rat, ileum, and, 'liver,', and, human, ileum, but, not, in, liver])].
[sujeto(['Chenodeoxycholic', acid, '(', 'CDCA),', but, not, lithocholic, acid, '(', 'LCA)', and, 'GW4064']), verbo([induced]), complemento(['VDR', mRNA, expression, in, rat, ileum, and, liver])].
[sujeto(['The', 'PKCalpha', 'activator,', 'phorbol-12-myristate-13-acetate', '(', 'PMA)']), verbo([induced]), complemento([the, expression, of, 'VDR', in, the, rat, 'liver,', and, the, induction, of, 'VDR', by, 1, ',', 25, '(', 'OH)(2)D(3)', and, 'CDCA', was, inhibited, by, the, 'PKCalpha', 'inhibitor,', bisindolyl, maleimide, 'I', '(', 'Bis', 'I)'])].
[sujeto(['These', results, show, that, the, expression, of, 'VDR', is, likely, to, be]), verbo([regulated]), complemento([by, 'PKC', but, not, by, 'FXR', or, 'VDR', activation, at, least, in, the, rat, liver])].
[sujeto(['The', 'VDR']), verbo([mediated]), complemento([induction, of, its, target, genes, 'CYP3A1', and, 'CYP3A2', by, 1, ',', 25, '(', 'OH)(2)D(3)', or, 'LCA', in, the, rat, ileum, was, strongly, reduced, in, the, presence, of, 'CDCA', despite, the, higher, 'VDR', expression])].
[sujeto(['Thus,', 'CDCA', might, potentiate, the, toxicity, of, 'LCA', by]), verbo([inhibiting]), complemento([its, metabolism])].
[sujeto(['Cathelicidin', is, an, antimicrobial, peptide, '(', 'AMP)', and, signaling, molecule, in, innate, immunity, and, a, direct]), verbo([target]), complemento([of, 1, ',', 25, -, dihydroxyvitamin, 'D3', '(', 1, ',', 25, 'D3)', in, primary, human, keratinocytes, '(', 'NHEK)'])].
[sujeto(['We']), verbo([found]), complemento([increased, expression, of, cathelicidin, mRNA, and, peptide, in, 'NHEK,', in, 'Caco-2', colon, cells, no, effect, was, observed, after, 'LCA', stimulation])].
[sujeto(['The', 'VDR', as, well, as, 'MEK-ERK', signaled, the, upregulation, of, cathelicidin, in, 'NHEK']), verbo([induced]), complemento([by, 'LCA'])].
[sujeto(['Based', on, these, observations, 'LCA-like', molecules]), verbo([targeting]), complemento([cathelicidin, could, be, designed, for, the, treatment, of, cutaneous, diseases, that, are, characterized, by, disturbed, cathelicidin, expression])].
[sujeto(['Calcitriol,', an, active, vitamin, 'D', 'metabolite,']), verbo([has]), complemento([a, limited, application, in, bone, repair, because, of, its, undesirable, hypercalcaemic, action])].
[sujeto(['However', it]), verbo([has]), complemento([emerged, that, lithocholic, acid, '(', 'LCA)', is, a, 'non-calcaemic', vitamin, 'D', receptor, ligand, but, whether, this, steroid, can, support, osteoblast, maturation, has, not, been, reported])].
[sujeto(['The', 'co-stimulation', of, cells, with, 'LCA,', 'LCA', acetate, or, 'LCA', acetate, methyl, ester, '(', 0.5, -, 5, 'microM)', and, lysophosphatidic, acid, '(', 'LPA,', 20, 'microM)', resulted, in, 'clear,', synergistic]), verbo([increases]), complemento([in, 'MG63', maturation, that, was, both, time, and, dose, dependent])].
[sujeto(['Cells', grown, upon, both, titanium, and, 'hydroxyapatite,', two, widely, used, implant, 'materials,']), verbo([responded]), complemento([well, to, 'co-treatment', with, 'LCA', acetate, '(', 5, 'microM)', and, 'LPA', '(', 20, 'microM)', as, demonstrated, by, 'stark,', synergistic, increases, in, 'ALP', activity])].
[sujeto(['Synergistic']), verbo([increases]), complemento([in, 'ALP', 'activity,', and, therefore, osteoblast, 'maturation,', were, observed, for, 'MG63', cells, 'co-stimulated', with, 'LCA', acetate, '(', 5, 'microM)', and, either, epidermal, growth, factor, '(', 10, 'ng/ml)', or, transforming, growth, 'factor-beta', '(', 10, 'ng/ml)'])].
[sujeto(['Ligands']), verbo([acting]), complemento([on, either, the, farnesoid, 'X', receptor, or, pregnane, 'X', receptor, could, not, substitute, for, the, action, of, 'LCA', acetate, on, 'MG63', maturation])].
[sujeto(['Lithocholate', is, able, to]), verbo([act]), complemento([as, a, calcitriol, surrogate, in, generating, mature, osteoblasts])].
[sujeto(['Given', that, 'LCA', is, 'non-calcaemic', it, is, likely, to]), verbo([find]), complemento([an, application, in, bone, 'repair/regeneration', by, aiding, matrix, calcification, at, implant, sites])].
[sujeto(['The', vitamin, 'D', receptor, '(', 'VDR)', is, a]), verbo([nuclear]), complemento([receptor, for, the, active, form, of, vitamin, 'D(3)', and, mediates, regulation, of, calcium, homeostasis])].
[sujeto(['Bile', 'acids,', such, as, lithocholic, 'acid,']), verbo([have]), complemento([been, identified, as, additional, endogenous, 'VDR', ligands])].
[sujeto(['The', in, vivo, role, of, 'VDR', in, bile, acid, metabolism]), verbo([has]), complemento([not, been, elucidated])].
[sujeto([1, 'alpha(OH)D(3)', administration, also]), verbo([decreased]), complemento([plasma, bile, acids, in, mice, fed, bile, 'acids,', such, as, 'DCA'])].
[sujeto(['The', effect, of, 1, 'alpha(OH)D(3)', administration, in]), verbo([decreasing]), complemento([liver, bile, acid, composition, was, observed, in, mice, under, fasting, conditions, and, was, associated, with, increased, urinary, excretion, and, increased, expression, of, bile, acid, 'transporters,', such, as, renal, multidrug, 'resistance-associated', protein, 4])].
[sujeto(['These', findings, indicate, that, pharmacological, activation, of, 'VDR']), verbo([enhances]), complemento([metabolism, of, bile, 'acids,', especially, urinary, excretion])].
[sujeto(['The', results, confirm, that, 'VDR']), verbo([acts]), complemento([a, regulator, of, bile, acid, metabolism, in, vivo])].
[sujeto(['OSTalpha', and, 'OSTbeta', mRNA, 'expression,', quantified, by, 'qRT-PCR,', in, rat, 'jejunum,', 'ileum,', colon, and, 'liver,', and, in, human, ileum, and, liver, was, positively]), verbo([regulated]), complemento([by, 'FXR', and, 'GR', ligands])].
[sujeto(['In', 'contrast,', the, 'VDR', 'ligand,', 1, ',', 25, '(', 'OH)2D3']), verbo([decreased]), complemento([the, expression, of, 'rOSTalpha-rOSTbeta', in, rat, 'intestine,', but, had, no, effect, on, human, 'ileum,', and, rat, and, human, liver, slices])].
[sujeto(['Lithocholic', acid, '(', 'LCA)']), verbo([decreased]), complemento([the, expression, of, rOSTalpha, and, rOSTbeta, in, rat, ileum, but, induced, 'OSTalpha-OSTbeta', expression, in, rat, liver, 'slices,', and, human, ileum, and, liver, slices])].
[sujeto(['This', study]), verbo([suggest]), complemento(['that,', apart, from, 'FXR', 'ligands,', the, 'OSTalpha', and, 'OSTbeta', genes, are, also, regulated, by, 'VDR', and, 'GR', ligands, and, not, by, 'PXR', ligands])].
[sujeto(['This', study, show, that, 'VDR', ligands, exerted, different, effects, on, 'OSTalpha-OSTbeta', in, the, rat, and, human, intestine, and, liver, compared, with, other]), verbo([nuclear]), complemento(['receptors,', 'FXR,', 'PXR,', and, 'GR,', pointing, to, 'species-', and, 'organ-specific', differences, in, the, regulation, of, 'OSTalpha-OSTbeta', genes])].
[sujeto(['The', expression, of, human, 'ABCB1']), verbo([has]), complemento([recently, been, reported, to, be, under, the, control, of, nuclear, receptor, 'NR1I', subfamily, 'members,', pregnane, 'X', receptor, '(', 'PXR,', 'NR1I2)', and, constitutive, androstane, receptor, '(', 'CAR,', 'NR1I3)'])].
[sujeto(['Here,', we]), verbo([have]), complemento([investigated, the, involvement, of, another, 'NR1I', 'member,', vitamin, 'D', receptor, '(', 'VDR,', 'NR1I1),', in, 'ABCB1', expression])].
[sujeto(['In', the, human, colorectal, adenocarcinoma, cell, line, 'LS174T,', which, abundantly]), verbo([expresses]), complemento(['VDR,', both, 1, 'alpha,25-dihydroxyvitamin', 'D(3)', '(', 1, ',', 25, -, 'VD3)', and, lithocholic, acid, '(', 'LCA)', increased, 'ABCB1', mRNA, levels])].
[sujeto(['Reporter', gene, assays, in, 'LS174T', cells, with, constructs, containing, various, lengths, of, the, 'ABCB1', regulatory, region, revealed, that, the, region, containing, multiple]), verbo([nuclear]), complemento([receptor, binding, motifs, located, at, -, 7.8, kilobases, '[', termed, nuclear, 'receptor-responsive', module, '(', 'NURREM)],', to, which, 'PXR', and, 'CAR', also, 'bind,', is, essential, for, the, 'VDR-mediated', 'ABCB1', transactivation])].
[sujeto(['Further', reporter, assays, with, constructs, containing, truncated, 'NURREM', and, gel, shift, assays]), verbo([suggested]), complemento([simultaneous, binding, of, multiple, 'VDR/retinoid', 'X', receptor, alpha, heterodimers, to, 'NURREM'])].
[sujeto(['In', human, hepatoma, 'HepG2', 'cells,', in, contrast, with, 'LS174T', 'cells,', 1, ',', 25, -, 'VD3']), verbo([activated]), complemento([the, 'ABCB1', transcription, only, in, the, presence, of, ectopically, expressed, 'VDR'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, 'NR1I', subfamily, members, regulate, the, 'ABCB1', expression, sharing, the, binding, sites, within, 'NURREM', and, that, the, physiologically, produced, 'LCA', and, 1, ',', 25, -, 'VD3', may, modulate, the, 'ABCB1', expression, in, human, 'intestines,', possibly, associated, with, interindividual, variations, of, 'ABCB1', expression])].
[sujeto(['It']), verbo([has]), complemento([been, reported, that, quercetin, is, an, activator, of, rat, vitamin, 'D', receptor, '(', 'rVDR)'])].
[sujeto(['Quercetin,', 3, -, 'hydroxyflavone,', 'galangin,', 'datiscetin,', 'kaempferol,', 'morin,', 'isorhamnetin,', 'tamarixetin,', 'myricetin,', and, syringetin, did, not]), verbo([activate]), complemento(['rVDR,', 'mVDR,', or, hVDR, in, 'HEK-293', and, 'HepG2', cells, transfected, with, the, corresponding, receptor, expression, plasmid, and, either, the, secreted, phosphoprotein, 1, '(', 'Spp1)', or, cytochrome, 'P450', 24, 'A1', '(', 'CYP24A1)', reporter, 'plasmid,', when, compared, to, the, respective, empty, vector, control, group, transfected, with, one, or, the, other, reporter, plasmid, and, treated, with, one, of, the, flavonols])].
[sujeto(['Control', analysis, indicated, that, lithocholic, acid, and, 1, 'α,25-dihydroxyvitamin', 'D3,', but, not, 'rifampicin,']), verbo([activated]), complemento(['rVDR,', 'mVDR,', and, hVDR])].
[sujeto(['As', shown, in, transfected, 'HEK293', and, 'HepG2', 'cells,', the, flavonols, did, not, influence, hVDR, ligand]), verbo([binding]), complemento([domain, 'transactivation,', steroid, receptor, 'coactivator-1', 'recruitment,', or, hVDR, target, gene, expression, '(', transient, receptor, potential, cation, channel, 6, and, 'CYP24A1)', in, 'hVDR-expressing', 'Caco-2', or, 'LS180', cells])].
[sujeto(['A', systematic, study, with, phase, 1, and, phase, 2, metabolites, of, cholesterol, and, vitamin, 'D', was, conducted, to, determine, whether, their, biological, activity, is]), verbo([mediated]), complemento([by, the, vitamin, 'D', receptor, '(', 'VDR)'])].
[sujeto(['Biochemical', and, 'cell-based', assays, were, used, to, demonstrate, that, hydroxylated, 'LCA', analogs, were, not, able, to]), verbo([bind]), complemento(['VDR'])].
[sujeto(['This', excludes, 'VDR', from]), verbo([mediating]), complemento([their, biological, and, pharmacological, activities])].
[sujeto(['LCA', 'Gluc', 'II']), verbo([increased]), complemento([the, expression, of, 'CYP24A1', in, 'DU145', cancer, cells, especially, in, the, presence, of, the, endogenous, 'VDR', ligand, 1, ',', 25, '(', 'OH)2D3'])].
[sujeto(['For', the, first, 'time,', we, showed, that, calcitroic, 'acid,', the, assumed, inactive, final, metabolite, of, vitamin, 'D,', was, able, to]), verbo([activate]), complemento(['VDR-mediated', transcription, to, a, higher, magnitude, than, bile, acid, 'LCA'])].
[sujeto(['Bile', acids, are, hormones, that]), verbo([regulate]), complemento([their, own, 'synthesis,', 'transport,', in, addition, to, glucose, and, lipid, 'homeostasis,', and, energy, balance])].
[sujeto(['The', affinity, of, secondary, bile, acid, metabolites, to, host]), verbo([nuclear]), complemento([receptors, is, 'described,', the, potential, of, secondary, bile, acids, to, promote, 'tumors,', and, the, potential, of, bile, acids, to, serve, as, therapeutic, agents, are, discussed])].
[sujeto(['This', process, is, under, tight, regulation, by]), verbo([nuclear]), complemento([receptor, signaling])].
[sujeto(['Bile', 'acids,', produced, from, 'cholesterol,', can, alter, gene, expression, in, the, liver, and, small, intestine, via]), verbo([activating]), complemento([the, nuclear, receptors, farnesoid, 'X', receptor, '(', 'FXR;', 'NR1H4),', pregnane, 'X', receptor, '(', 'PXR;', 'NR1I2),', vitamin, 'D', receptor, '(', 'VDR;', 'NR1I1),', 'G', protein, coupled, receptor, 'TGR5,', and, other, cell, signaling, pathways, '(', 'JNK1/2,', 'AKT', and, 'ERK1/2)'])].
[sujeto(['Among', these, 'controls,', 'FXR', is, known, to, be, a, major, bile, 'acid-responsive', 'ligand-activated', transcription, factor, and, a, crucial, control, element, for]), verbo([maintaining]), complemento([bile, acid, homeostasis])].
[sujeto(['FXR']), verbo([has]), complemento([a, high, affinity, for, several, major, endogenous, bile, 'acids,', notably, cholic, 'acid,', deoxycholic, 'acid,', chenodeoxycholic, 'acid,', and, lithocholic, acid])].
[sujeto(['By']), verbo([responding]), complemento([to, excess, bile, 'acids,', 'FXR', is, a, bridge, between, the, liver, and, small, intestine, to, control, bile, acid, levels, and, regulate, bile, acid, synthesis, and, enterohepatic, flow])].
[sujeto(['FXR', is, highly]), verbo([expressed]), complemento([in, the, liver, and, 'gut,', relative, to, other, 'tissues,', and, contributes, to, the, maintenance, of, 'cholesterol/bile', acid, homeostasis, by, regulating, a, variety, of, metabolic, enzymes, and, transporters])].
[sujeto(['The']), verbo([nuclear]), complemento([receptor, superfamily, of, 'ligand-activated', transcription, factors, plays, a, central, role, in, the, regulation, of, cellular, responses, to, chemical, challenge])].
[sujeto(['Nuclear', receptors, are]), verbo([activated]), complemento([by, a, wide, range, of, both, endogenous, and, exogenous, 'chemicals,', and, their, target, genes, include, those, involved, in, the, metabolism, and, transport, of, the, activating, chemical])].
[sujeto(['Such']), verbo([target]), complemento([gene, 'activation,', 'thus,', acts, to, remove, the, stimulating, xenobiotic, or, to, maintain, homeostatic, levels, of, endogenous, chemicals])].
[sujeto(['Using', 'DNA', microarray, technology, we]), verbo([have]), complemento([examined, the, transcriptome, response, of, primary, rat, hepatocytes, to, two, nuclear, receptor, 'ligands:', 'Pregnenalone-16α-carbonitrile', '(', 'PCN),', a, xenobiotic, 'PXR', 'agonist,', and, lithocholic, 'acid,', an, endogenous, mixed, 'PXR/VDR/FXR', agonist])].
[sujeto(['We', demonstrate, that, despite, differences, in, the, profile, of]), verbo([activated]), complemento([nuclear, 'receptors,', transcriptome, responses, for, these, two, ligands, are, broadly, similar, at, lower, 'concentrations,', indicating, a, conserved, general, response])].
[sujeto(['However,', as, concentrations, of]), verbo([stimulating]), complemento([ligand, 'rises,', the, transcriptome, responses, 'diverge,', reflecting, a, need, for, specific, responses, to, the, two, stimulating, chemicals])].
[sujeto(['Finally,', we, demonstrate, a, novel, 'feed-back', loop, for, 'PXR,', whereby, 'ligand-activation', of, 'PXR']), verbo([suppresses]), complemento([transcription, of, the, 'PXR', 'gene,', acting, to, attenuate, 'PXR', protein, expression, levels, at, higher, ligand, concentrations])].
[sujeto(['Through', in, silico, simulation, we, demonstrate, that, this, 'feed-back', loop, is, an, important, factor, to]), verbo([prevent]), complemento([hyperexpression, of, 'PXR', target, genes, such, as, 'CYP3A', and, confirm, these, findings, in, vitro])].
[sujeto(['This', novel, insight, into, the, regulation, of, the, 'PXR-mediated', regulatory, signal, networks]), verbo([provides]), complemento([a, potential, mechanistic, rationale, for, the, robustness, in, steroid, homeostasis, within, the, cell])].
[sujeto(['The', effects, of, the, secondary, bile, 'acid,', lithocholic, acid, '(', 'LCA),', a, 'VDR,', 'FXR', and, 'PXR', 'ligand,', on, the, regulation, of, bile, acid, metabolism, '(', 'CYP3A', 'isozymes),', synthesis, '(', 'CYP7A1),', and, transporter, proteins, '(', 'MRP3,', 'MRP2,', 'BSEP,', 'NTCP)', as, well, as]), verbo([nuclear]), complemento([receptors, '(', 'FXR,', 'PXR,', 'LXRα,', 'HNF1α,', 'HNF4α', and, 'SHP)', were, studied, in, rat, and, human, 'precision-cut', intestine, and, liver, slices, at, the, mRNA, level])].
[sujeto(['LCA']), verbo([induced]), complemento([rCYP3A1, and, rCYP3A9, in, the, rat, 'jejunum,', ileum, and, 'colon,', rCYP3A2, only, in, the, 'ileum,', rCYP3A9, expression, in, the, 'liver,', and, 'CYP3A4', in, the, human, ileum, but, not, in, liver])].
[sujeto(['LCA']), verbo([induced]), complemento([the, expression, of, rMRP2, in, the, colon, but, not, in, the, jejunum, and, ileum, but, did, not, affect, rMRP3, expression, along, the, length, of, the, rat, intestine])].
[sujeto(['In', human, ileum, 'slices,', 'LCA']), verbo([induced]), complemento([hMRP3, and, hMRP2, expression])].
[sujeto(['In', rat, liver, 'slices,', 'LCA']), verbo([decreased]), complemento(['rCYP7A1,', rLXRα, and, rHNF4α, 'expression,', induced, rSHP, 'expression,', but, did, not, affect, rBSEP, or, rNTCP, 'expression;', whereas, in, the, human, 'liver,', a, small, but, significant, decrease, was, found, for, hHNF1α, expression])].
[sujeto(['These', data]), verbo([suggests]), complemento([profound, species, differences, in, the, effects, of, 'LCA', on, bile, acid, 'transport,', synthesis, and, detoxification])].
[sujeto(['The', vitamin, 'D', receptor, '(', 'VDR)', is, a, transcriptional, factor, responsive, to, 1, 'alpha,25-dihydroxyvitamin', 'D(3)', and, lithocholic, 'acid,', and]), verbo([induces]), complemento([expression, of, drug, metabolizing, enzymes, 'CYP3A4,', 'CYP2B6', and, 'CYP2C9'])].
[sujeto(['The', single, nucleotide, polymorphisms, '(', 'SNPs)', that]), verbo([increase]), complemento(['VDR', expression, or, 'activity,', -, 29649, 'G>A,', 2, 'T>C', and, 1592, '(', '(', *, ')', 308, ')', 'C>A', tagging, linked, variations, in, the, 3, '\'', -, 'UTR,', were, detected, at, 0.43, ',', 0.636, ',', and, 0.318, allele, 'frequencies,', respectively])].
[sujeto(['Another', 'SNP,', -, 26930, 'A>G,', with, reduced, 'VDR', transcription, was]), verbo([found]), complemento([at, a, 0.028, frequency])].
[sujeto(['The', 'NR1I', subfamily, of]), verbo([nuclear]), complemento([hormone, receptors, includes, the, 1, ',', 25, -, '(', 'OH)(2)-vitamin', 'D(3)', receptor, '(', 'VDR;', 'NR1I1),', pregnane, 'X', receptor, '(', 'PXR;', 'NR1I2),', and, constitutive, androstane, receptor, '(', 'CAR;', 'NR1I3)'])].
[sujeto(['PXR', and, 'VDR', are]), verbo([found]), complemento([in, diverse, vertebrates, from, fish, to, mammals, while, 'CAR', is, restricted, to, mammals])].
[sujeto(['Current', evidence]), verbo([suggests]), complemento([that, the, 'CAR', gene, arose, from, a, duplication, of, an, ancestral, 'PXR', 'gene,', and, that, 'PXR', and, 'VDR', arose, from, duplication, of, an, ancestral, 'gene,', represented, now, by, a, single, gene, in, the, invertebrate, 'Ciona', intestinalis])].
[sujeto(['Aside', from, the, 'high-affinity', effects, of, 1, ',', 25, -, '(', 'OH)(2)-vitamin', 'D(3)', on, 'VDRs,', the, 'NR1I', subfamily, members, are, functionally, united, by, the, ability, to]), verbo([bind]), complemento([potentially, toxic, endogenous, compounds, with, low, affinity, and, initiate, changes, in, gene, expression, that, lead, to, enhanced, metabolism, and, elimination, '(', e])].
[sujeto(['The', detoxification, role, of, 'VDR', seems, limited, to, sensing, high, concentrations, of, certain, toxic, bile, 'salts,', such, as, lithocholic, 'acid,', whereas, 'PXR', and, 'CAR']), verbo([have]), complemento([the, ability, to, recognize, structurally, diverse, compounds])].
[sujeto(['PXR', and, 'CAR', show, the, highest, degree, of, 'cross-species', variation, in, the, 'ligand-binding', domain, of, the, entire, vertebrate]), verbo([nuclear]), complemento([hormone, receptor, 'superfamily,', suggesting, adaptation, to, 'species-specific', ligands])].
[sujeto(['This', review, examines, the, insights, that, phylogenetic, and, experimental, studies]), verbo([provide]), complemento([into, the, function, of, 'VDR,', 'PXR,', and, 'CAR,', and, how, the, functions, of, these, receptors, have, expanded, to, evolutionary, advantage, in, humans, and, other, animals])].
[sujeto(['To']), verbo([prevent]), complemento([the, development, of, 'adiposity-associated', metabolic, 'diseases,', early, biomarkers, are, needed])].
[sujeto(['Urine', and, plasma, metabolomics, fingerprints]), verbo([have]), complemento([been, successfully, associated, with, metabolic, dysfunctions])].
[sujeto(['Fat', resistance, '(', 'FR)', was]), verbo([found]), complemento([to, be, associated, with, higher, urinary, levels, of, acylglycines, and, leucine])].
[sujeto(['After', 'HF', feeding, for, 10, 'weeks,', 'FS', mice, tended, to]), verbo([have]), complemento([lower, plasma, levels, of, 'β-hydroxybutyrate', than, 'FR', ones])].
[sujeto(['Suspicion', of, fibromyalgia, arises, when, a, patient]), verbo([has]), complemento([pain, at, multiple, locations, that, cannot, be, attributed, to, trauma, or, 'inflammation,', and, when, the, pain, is, especially, musculoskeletal])].
[sujeto(['In', 'addition,', one, can, also, attempt, to]), verbo([increase]), complemento(['mobility,', avoid, 'overloading,', and, improve, physical, condition, and, the, level, of, 'activity,', and, to, activate, 'problem-solving', skills])].
[sujeto(['Less', invasive, surgical, '(', 'LIS)', procedures, are, potentially]), verbo([associated]), complemento([with, a, lower, risk, of, 'complications;', 'however,', little, is, known, regarding, the, complications, after, 'LIS', procedures, for, the, treatment, of, spinal, metastases])].
[sujeto(['The', secondary, objective, was, to, identify, factors]), verbo([associated]), complemento([with, the, occurrence, of, complications, and, survival])].
[sujeto(['The', median, operating, time, was, 122, '(', range, 57, -, 325, ')', minutes, with, a, median, blood]), verbo([loss]), complemento([of, 100, &, 'nbsp;ml', '(', based, on, 41, 'subjects)'])].
[sujeto(['Prolonged', operating, time, was, independently]), verbo([associated]), complemento([with, an, increased, risk, of, complications])].
[sujeto(['A', complication, rate, of, 18, &, 'nbsp;%', was]), verbo([found]), complemento([after, 'PPSF', for, unstable, spinal, metastases])].
[sujeto(['Potential', advantages, of, less, invasive, treatment, are, limited, blood]), verbo([loss]), complemento([and, high, early, ambulation, rate])].
[sujeto(['Following', the, use, of, the, oral, 'rinse,', a, significant, decline, was]), verbo([found]), complemento([of, the, extent, to, which, the, participants, reported, to, take, into, account, their, oral, odor, when, meeting, a, person, for, the, first, time])].
[sujeto(['Both', studies, identified, a, subgroup, of, individuals, '(', 9.1, '%', and, 28.1, '%', 'respectively)', who]), verbo([reported]), complemento([to, keep, a, certain, distance, when, meeting, other, 'people,', despite, a, &, 'quot;fresh"', 'self-perceived', oral, odor])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, 'self-perceived', oral, odor, negatively, affects, social, 'interactions,', and, that, adequate, management, of, halitosis, has, the, potential, to, improve, such, interactions])].
[sujeto(['International', literature]), verbo([reveals]), complemento([no, consensus, on, which, and, how, many, characteristics, and, risk, indicators, must, be, present, to, diagnose, '(', nursing, 'home-acquired)', pneumonia, and, aspiration, pneumonia])].
[sujeto(['The', aim, of, this, survey, was, to, reach, consensus, among, a, panel, of, clinical, medical, experts, in, geriatrics, and, pulmonology, about, the, characteristics]), verbo([required]), complemento([for, diagnosing, 'pneumonia,', and, about, the, risk, indicators, needed, to, consider, the, diagnosis, aspiration, pneumonia, in, nursing, home, residents, with, pneumonia])].
[sujeto(['No', consensus, was, reached, about, characteristics, and, the, number, of, characteristics]), verbo([required]), complemento([for, diagnosing, '(', nursing, 'home-acquired)', pneumonia])].
[sujeto(['However,', 57, '%', agreed, that, 'dyspnea,', 'fever,', deterioration, of, general, 'functioning,', tachypnea, and, crepitation, with, auscultation, are, the, most, important, characteristics, and, the, responses, by, the, participants]), verbo([suggested]), complemento([that, two, or, three, characteristics, should, be, present])].
[sujeto(['No', final, consensus, could, be, reached, about, which, and, how, many, characteristics, are]), verbo([required]), complemento([for, diagnosing, pneumonia, in, nursing, home, residents])].
[sujeto(['The', objective, of, 'Atraumatic', 'Restorative', 'Treatment', is, to]), verbo([prevent]), complemento([carious, lesion, development, and, to, stop, its, progression])].
[sujeto(['An', accurately, placed, 'sealant-restoration']), verbo([prevents]), complemento([remaining, cariogenic, bacteria, from, reigniting, the, process, of, decay, and, allows, the, residual, carious, dentine, to, remineralise])].
[sujeto(['To', achieve, good, results, using, 'Atraumatic', 'Restorative', 'Treatment,', an, oral, healthcare, provider, should, complete, a, programme, of, instruction, and]), verbo([have]), complemento([command, of, sufficient, knowledge, of, 'cariology,', the, principles, of, treatment, and, the, available, restorative, materials])].
[sujeto(['Pneumonia', is, an, important]), verbo([cause]), complemento([of, death, in, care, home, residents])].
[sujeto(['Written', and, informed, consent, will, be, obtained, from, all]), verbo([participating]), complemento([care, homes, and, residents])].
[sujeto(['The', trial]), verbo([has]), complemento([been, registered, in, the, 'Netherlands', in, the, 'National', 'Trial', 'Register:', 'TC=3515'])].
[sujeto(['Among', other, 'things,', this, thesis, aimed, at]), verbo([finding]), complemento([a, method, of, measuring, older, 'people\'s', adaptability, to, removable, complete, dentures])].
[sujeto(['Subsequently,', only, a, few, research, projects, on, this, topic]), verbo([have]), complemento([been, carried, out])].
[sujeto(['During', the, last, 'decades,', inquiries, into, a, method, of, measuring, treatment, effectiveness]), verbo([has]), complemento([focused, on, older, 'people\'s', quality, of, life, and, general, health, condition])].
[sujeto(['Subsequent', to, this, dissertation, no, comparable, research]), verbo([has]), complemento([been, carried, out, in, the, 'Netherlands', or, abroad])].
[sujeto(['As', soon, as, older, people, who, are, living, at, home, become, 'dependent,', they, will]), verbo([require]), complemento([support])].
[sujeto(['The', prevalence, of, 'NAFLD']), verbo([increased]), complemento([from, 5.3, '%', to, 18.8, '%', in, women, younger, than, 45, years, versus, women, aged, 45, to, 55, years, and, rose, to, 27.8, '%', in, women, older, than, 55, years])].
[sujeto(['Multiple', regression, analyses, showed, that]), verbo([increased]), complemento(['BMI', and, low, aspartate, 'aminotransferase-to-alanine', aminotransferase, ratio, were, closely, related, to, 'NAFLD', in, women, of, different, 'ages,', whereas, increasing, 'BMI,', 'BAAT', 'score,', 'age,', high, 'triglycerides,', alanine, 'aminotransferase,', and, low, aspartate, 'aminotransferase-to-alanine', aminotransferase, ratio, were, all, closely, related, to, 'NAFLD', in, obese, women])].
[sujeto(['Obese', and, postmenopausal, women]), verbo([have]), complemento([a, high, prevalence, of, 'NAFLD', and, severe, metabolic, disorders])].
[sujeto(['Although', oat, '(', 1, ',', 3, :, 1, ',', 4, ')', -, 'β-glucan', '(', 'BG)']), verbo([has]), complemento([been, shown, to, decrease, blood, cholesterol, in, intervention, 'trials,', the, detailed, mechanism, is, not, yet, 'defined,', but, restricted, reabsorption, of, bile, acids, '(', 'BAs)', has, been, hypothesized])].
[sujeto(['Using', pigs, as, a, model, for, humans, we, demonstrated, 'that,', compared, to, the, 'control,', 'BG', added, to, the, diet, for, 26, d]), verbo([caused]), complemento([decreases, of, 24, '%', in, blood, total, 'BAs', '(', 'TBAs),', 34, '%', in, total, cholesterol, '(', 'TC),', and, 57, '%', in, 'LDL', cholesterol, '(', 'LDL-C)', '(', 'P', &, 'lt;', 0.01, ')', ;, decreases, of, 20, '%', 'TBA', in, the, midjejunum, and, terminal, ileum, '(', 'P', &, 'lt;', 0.01, ')', ;, increases, of, 80, '%', in, cecal, total, neutral, sterols, '(', 'TNSs)', including, cholesterol, '(', 'P', &, 'lt;', 0.01, ')', ;, a, 50, '%', reduction, in, 'BA', active, transport, across, ex, vivo, ileum, after, 40, min, '(', 'P', &, 'lt;', 0.001, ')', ;, and, 32, '%', decrease, in, jejunal, microvilli, heights, with, apparent, increased, goblet, cell, activity])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, 'BG', not, only, physically, hinders, the, active, reabsorption, of, 'BAs', and, uptake, of, 'cholesterol,', but, also, changes, the, 'BAs', profile, with, lower, circulating, levels, without, excess, excretion, in, the, 'feces,', thus, resulting, in, reduced, blood, 'TC', and, 'LDL-C'])].
[sujeto(['Fermentation', of, sterols, reaching, the, colon]), verbo([enhanced]), complemento([production, of, therapeutic, ursodeoxycholic, 'acid,', suppressed, toxic, lithocholic, 'acid,', and, decreased, the, possibility, of, cholesterol, absorption, by, transforming, the, latter, into, 'coprostanol,', a, nonabsorbable, 'NS'])].
[sujeto(['Reduction', in, circulating, bile, acid, and, restricted, diffusion, across, the, intestinal, epithelium, are]), verbo([associated]), complemento([with, a, decrease, in, blood, cholesterol, in, the, presence, of, oat, 'β-glucan'])].
[sujeto(['To']), verbo([increase]), complemento([the, efficiency, of, 'winery-derived', biomass, 'biodegradation,', grape, pomace, was, ultrasonicated, for, 20, min, in, the, presence, of, 0.25, 'M,', 0.5, 'Mand1'])].
[sujeto(['Thus,', the, combination, of, sonication, 'pre-treatment', and, enzymatic, degradation]), verbo([has]), complemento([the, potential, to, considerably, improve, the, breakdown, of, agricultural, biomass, and, produce, commercially, useful, compounds, in, markedly, less, time, '(', &, 'lt;40h)', with, respect, to, biological, only, degradation, '(', 16, 'days)'])].
[sujeto(['G-protein-coupled', bile, acid, receptor, 1, ',', also, known, as, 'TGR5', is, known, to, be]), verbo([involved]), complemento([in, glucose, homeostasis])].
[sujeto(['In', animal, 'models,', treatment, with, a, 'TGR5', agonist]), verbo([induces]), complemento([incretin, secretion, to, reduce, hyperglycemia])].
[sujeto(['Betulinic', 'acid,', a, triterpenoid, present, in, the, leaves, of, white, 'birch,']), verbo([has]), complemento([been, introduced, as, a, selective, 'TGR5', agonist])].
[sujeto(['However,', direct, activation, of, 'TGR5', by, betulinic, acid]), verbo([has]), complemento([not, yet, been, reported])].
[sujeto(['Betulinic', acid, 'dose-dependently']), verbo([increases]), complemento([glucose, uptake, by, 'CHO-K1', cells, transfected, with, 'TGR5', 'only,', which, can, be, considered, an, alternative, method, instead, of, radioligand, binding, assay])].
[sujeto(['Additionally,', signals, coupled, to, 'TGR5', activation, are, also]), verbo([increased]), complemento([by, betulinic, acid, in, cells, transfected, with, 'TGR5'])].
[sujeto(['In', 'NCI-H716', 'cells,', which, endogenously]), verbo([express]), complemento(['TGR5,', betulinic, acid, induces, 'glucagon-like', peptide, secretion, via, increasing, calcium, levels])].
[sujeto(['Similar', to, the, positive, control, lithocholic, 'acid,', which, is, the, established, agonist, of, 'TGR5,', betulinic, acid]), verbo([has]), complemento([been, characterized, as, a, useful, agonist, of, 'TGR5', and, can, be, used, to, activate, 'TGR5', in, the, future])].
[sujeto(['Recently,', we]), verbo([reported]), complemento([the, crystal, structure, of, human, 'NAPE-PLD', and, discovered, specific, binding, sites, for, the, bile, acid, deoxycholic, acid])].
[sujeto(['Chenodeoxycholic', acid, and, 'glyco-', or, 'tauro-dihydroxy', conjugates, can, also]), verbo([bind]), complemento([to, 'NAPE-PLD', and, drive, its, activation])].
[sujeto(['The', only, natural, monohydroxy, bile, 'acid,', lithocholic, 'acid,', shows, an, affinity, of, '∼20', μM, and]), verbo([acts]), complemento([instead, as, a, reversible, inhibitor, '(', 'IC50', '≈', 68, 'μM)'])].
[sujeto(['Overall,', these, findings]), verbo([provide]), complemento([important, insights, into, the, allosteric, regulation, of, the, enzyme, mediated, by, bile, acid, cofactors, and, reveal, that, 'NAPE-PLD', responds, primarily, to, the, number, and, position, of, their, hydroxyl, groups])].
[sujeto(['Intestinal', bacteria, are]), verbo([involved]), complemento([in, bile, acid, '(', 'BA)', deconjugation, 'and/or', dehydroxylation, and, are, responsible, for, the, production, of, secondary, 'BA'])].
[sujeto(['However,', an]), verbo([increase]), complemento([in, the, production, of, secondary, 'BA', modulates, the, intestinal, microbiota, due, to, the, bactericidal, effects, and, promotes, cancer, risk, in, the, liver, and, colon])].
[sujeto(['The', ingestion, of, 'Bacillus', coagulans, improves, constipation, via, the, activation, of, bowel, movement, to]), verbo([promote]), complemento([defaecation, in, 'humans,', which, may, alter, 'BA', metabolism, in, the, intestinal, contents])].
[sujeto(['BA', secretion, is]), verbo([promoted]), complemento([with, 'high-fat', diet, 'consumption,', and, the, ratio, of, cholic, acid, '(', 'CA):chenodeoxycholic', acid, in, primary, 'BA', increases, with, ageing])].
[sujeto(['In', 'CA-fed', 'rats,', soya, pulp, significantly]), verbo([increased]), complemento([the, production, of, secondary, 'BA', such, as, deoxycholic, acid, and, 'ω-muricholic', 'acids,', and, soya, pulp, ingestion, alleviated, problems, related, to, plasma, adiponectin, and, gut, permeability, in, rats, fed, the, 'CA', diet])].
[sujeto([coagulans, and, soya, pulp, successfully]), verbo([suppressed]), complemento([the, increased, production, of, secondary, 'BA', in, 'CA-fed', rats, compared, with, soya, pulp, 'itself,', without, impairing, the, beneficial, effects, of, soya, pulp, ingestion])].
[sujeto(['In', 'conclusion,', it, is, possible, that, a, combination, of, prebiotics, and, probiotics, can, be, used, to, avoid, an, unnecessary]), verbo([increase]), complemento([in, the, production, of, secondary, 'BA', in, the, large, intestine, without, impairing, the, beneficial, functions, of, prebiotics])].
[sujeto(['With', the]), verbo([increasing]), complemento([importance, of, 'BAs,', analytical, methods, for, their, quantification, and, screening, have, been, developed])].
[sujeto(['However,', due, to, the, diverse, range, and, variety, of, 'BAs', with, different, activation, 'potency,', a, 'simple,', 'effective,', and, sensitive, method, is]), verbo([required]), complemento([to, screen, 'BAs', for, accurate, quantification, and, identification])].
[sujeto(['Using', this, 'method,', along, with, the, accurate, quantification, of, 19]), verbo([targeted]), complemento(['BAs,', 22, unknown, 'BAs', were, detected, and, characterized, by, their, fragmentation, patterns])].
[sujeto(['Through', statistical, 'analysis,', we]), verbo([found]), complemento([that, as, the, rats, 'aged,', unconjugated, 'BAs', and, 'glycine-conjugated', 'BAs', decreased, or, were, 'unaffected,', while, 'taurine-conjugated', 'BAs', were, increased, in, general])].
[sujeto(['Among', the, unknown, 'BAs,', 5, of, the, 'taurine-conjugated', 'BAs', 'increased,', while, a, 'glycine-conjugated', 'BA', 'decreased,', in, agreement, with, the, trends, of, the]), verbo([targeted]), complemento(['BAs'])].
[sujeto(['The', crystal, structure, of, a, 'Li(+)', salt, of, a, glucosyl, derivative, of, lithocholic, acid, '(', lithium, 3, 'α-(α-d-glucopyranosyl)-5β-cholan-24-oate)']), verbo([has]), complemento([been, solved])].
[sujeto(['Monolayers,', having, a, hydrophobic, interior, and, hydrophilic, 'edges,', are]), verbo([recognized]), complemento([in, the, crystal, structure])].
[sujeto(['A', fourth, 'molecule,', located, in, this, 'monolayer,', is]), verbo([involved]), complemento([in, the, coordination, of, the, cation, through, the, carboxylate, ion, by, an, electrostatic, 'interaction,', thus, completing, a, distorted, tetrahedron])].
[sujeto(['Water', and, acetone, are, also]), verbo([involved]), complemento([in, the, hydrogen, bond, network])].
[sujeto(['A', hierarchical, organization, can, be]), verbo([recognized]), complemento([in, the, 'crystal,', the, helical, assembly, along, 21, screw, axes, being, 'left-handed'])].
[sujeto(['No', significant, differences, were]), verbo([found]), complemento([in, the, levels, of, fecal, urosodeoxycholic, acid, among, the, three, groups, '(', 'P>0'])].
[sujeto(['Fecal', secondary, colonic, bile, 'acids,', deoxycholic, acid, and, lithocholic, 'acid,', are, in]), verbo([decrease]), complemento([in, children, with, 'HSP', at, the, acute, 'stage,', which, may, be, involved, in, the, pathogenesis, and, treatment, outcomes, of, 'HSP'])].
[sujeto(['The', principal, reactions]), verbo([involved]), complemento([were, '(', 1, ')', decarbonylation, of, conjugated, 12, -, 'oxo-Δ(9(11))-derivatives', using, in, situ, generated, monochloroalane, '(', 'AlH2Cl)', prepared, from, 'LiAlH4', and, 'AlCl3,', '(', 2, ')', epoxidation, of, the, deoxygenated, 'Δ(9(11))-enes', using, 'm-chloroperbenzoic', acid, catalyzed, by, 4, ',', 4, '\'', -, 'thiobis-(6-tert-butyl-3-methylphenol),', '(', 3, ')', subsequent, 'Markovnikov', 9, 'α-hydroxylation', of, the, 'Δ(9(11))-enes', with, 'AlH2Cl,', and, '(', 4, ')', selective, oxidation, of, the, primary, hydroxyl, group, at, 'C-24', in, the, resulting, 3, 'α,9α,24-triol', and, 3, 'α,7α,9α,24-tetrol', to, the, corresponding, 'C-24', carboxylic, acids, using, sodium, chlorite, '(', 'NaClO2)', in, the, presence, of, a, catalytic, amount, of, 2, ',', 2, ',', 6, ',', 6, -, tetramethylpiperidine, 1, -, oxyl, free, radical, '(', 'TEMPO)', and, sodium, hypochlorite, '(', 'NaOCl)'])].
[sujeto(['The', 3, 'α,7α,9α-trihydroxy-5β-cholan-24-oic', acid]), verbo([has]), complemento([been, reported, to, be, present, in, the, bile, of, the, 'Asian', 'bear,', and, its, 7, -, deoxy, derivative, is, likely, to, be, a, bacterial, metabolite])].
[sujeto(['After', 'UDCA', 'administration,', 2, -, hour, postprandial, concentrations, of, both, 'UDCA', and, chenodeoxycholic, acid, significantly]), verbo([increased]), complemento(['(', 'P < '])].
[sujeto(['These', data, do, not, support, recent, suggestions, that]), verbo([enhanced]), complemento([biotransformation, of, 'UDCA', to, the, hepatotoxic, secondary, bile, acid, lithocholic, occurs, when, patients, with, 'CFLD', are, treated, with, relatively, high, doses, of, 'UDCA'])].
[sujeto(['Enzyme-mediated', protein, modification, often]), verbo([requires]), complemento([large, amounts, of, 'biocatalyst,', adding, significant, costs, to, the, process, and, limiting, industrial, applications])].
[sujeto(['A', proline, variant, of, an, evolved, sortase, 'A', '(', 'SrtA', 7, 'M)', was, 'N-terminally', labeled, with, lithocholic, acid, '(', 'LA)-an', inexpensive, bile, acid, that, exhibits, strong]), verbo([binding]), complemento([to, 'β-cyclodextrin', '(', 'βCD)'])].
[sujeto(['The', 'LA-Pro-SrtA', 7, 'M', conjugate]), verbo([retained]), complemento([full, enzymatic, 'activity,', even, after, multiple, rounds, of, recycling])].
[sujeto(['The', bidirectional, effects, between, intestinal, microbiota, '(', 'IM)', and, bile, acids, '(', 'BA)']), verbo([suggest]), complemento([that, dysbiosis, may, be, accompanied, by, an, altered, bile, acid, '(', 'BA)', 'homeostasis,', which, in, turn, can, contribute, to, the, metabolic, dysregulation, seen, in, 'NAFLD'])].
[sujeto(['Bacteroidetes', and, 'Clostridium', leptum, counts, were]), verbo([decreased]), complemento([in, in, a, subset, of, 16, patients, with, 'NASH', compared, to, 25, 'HC,', after, adjusting, for, body, mass, index, and, 'weight-adjusted', calorie, intake, '(', p, =, 0.028, and, p, =, 0.03, ',', 'respectively)'])].
[sujeto(['In', adults, with, 'NAFLD,', dysbiosis, is]), verbo([associated]), complemento([with, altered, 'BA', 'homeostasis,', which, renders, them, at, increased, risk, of, hepatic, injury])].
[sujeto(['We', hypothesized, that, bile, acids]), verbo([activate]), complemento([alveolar, epithelial, cells, '(', 'AECs)', and, lung, 'fibroblasts,', which, may, be, regulated, by, 'FXR', activation])].
[sujeto(['LCA,', 'DCA', and, 'CDCA', reduced, cell, viability, and]), verbo([increased]), complemento([intracellular, reactive, oxygen, species, '(', 'ROS)', production, in, 'A549', cells])].
[sujeto(['They', all]), verbo([induced]), complemento(['EMT,', as, shown, by, enhanced, 'α-SMA', and, vimentin, and, decreased, 'E-cadherin', levels])].
[sujeto(['LCA', directly]), verbo([induced]), complemento([differentiation, of, lung, fibroblasts, to, myofibroblasts])].
[sujeto(['All', three, bile, acids]), verbo([promoted]), complemento([cellular, migration, but, not, proliferation, of, lung, fibroblasts])].
[sujeto(['Differentiation', and, proliferation, were]), verbo([enhanced]), complemento([in, lung, fibroblasts, exposed, to, conditioned, medium, from, bile, 'acid-stimulated', 'A549', 'cells,', which, contained, increased, levels, of, profibrotic, factors])].
[sujeto(['TGF-β/Smad3', signaling, was, also]), verbo([involved]), complemento([in, the, bile, 'acid-induced', 'EMT', and, lung, fibroblast, differentiation])].
[sujeto(['Bile', acid, microaspiration, may]), verbo([promote]), complemento([the, development, of, pulmonary, fibrosis, by, inducing, activation, of, 'AECs', and, lung, fibroblasts, via, 'FXR-dependent', and, independent, pathways])].
[sujeto(['Methyl', 3, 'α-acetoxy-7-oxo-cholanate', '(', 1, ')', ',', methyl, 3, 'α-acetoxy-12-oxo-cholanate', '(', 2, ')', and, methyl, 3, 'α,7α-diacetoxy-12-oxo-cholanate', '(', 3, ')', were, subjected, to, 'Baeyer-Villiger', oxidation, to]), verbo([provide]), complemento([homolactones, '(', 7, -, 9, ')', or, to, the, 'Beckmann', rearrangement, of, the, corresponding, oximes, to, give, homolactams, '(', 16, -, 18, ')'])].
[sujeto(['Among', these, 'compounds,', 7, ',', 9, and, 16, were]), verbo([found]), complemento([to, have, the, significant, 'activity,', with, 'IC50', values, '⩽3μM', against, 'α-2,6-(N)-ST', 'selectively,', which, are, 5, -, fold, lower, than, that, of, 'Lith-O-Asp'])].
[sujeto(['Given', the, reality, that, 'LCA', and, its, 'analogue,', 'Lith-O-Asp,']), verbo([have]), complemento([been, revealed, to, improve, inhibitory, efficacy, of, 'ST', and, to, have, a, wide, range, of, antimetastatic, activities, in, different, human, cancer, 'cells,', the, 'up-to-date', findings, have, noteworthy, pharmacological, significance, as, they, open, a, promising, path, to, the, improvement, of, a, prospective, molecular, targeted, application, of, modified, 'LCA', analogues, as, agents, for, the, treatment, of, cancer, metastasis])].
[sujeto(['Here,', the, singular, 'self-assembling', properties, of, dansyl, and, naproxen, derivatives, of, 'CA', '(', 3, 'β-Dns-CA', and, 3, 'β-NPX-CA,', 'respectively)']), verbo([have]), complemento([been, demonstrated, on, the, basis, of, their, photoactive, properties])].
[sujeto(['Thus,', the, emission, spectra, of, 3, 'β-Dns-CA', registered, at]), verbo([increasing]), complemento([concentrations, '(', 25, -, 140, 'μM)', showed, a, remarkable, 'non-linear', enhancement, in, the, emission, intensity, accompanied, by, a, hypsochromic, shift, of, the, maximum, and, up, to, a, 'three-fold', increase, in, the, singlet, lifetime])].
[sujeto(['In', the, case, of, 3, 'β-NPX-CA,', when, the, 'NPX', relative, triplet, lifetime, was, plotted, against, 'concentration,', a, marked]), verbo([increase]), complemento(['(', up, to, 'two-fold)', was, observed, at, 40, -, 70, 'μM,', indicating, the, formation, of, new, 3, 'β-NPX-CA', assemblies, at, ca])].
[sujeto(['A', lower]), verbo([increase]), complemento([in, the, emission, was, observed, for, 3, 'β-NPX-CA', in, the, 'mixture,', while, a, huge, increase, was, experienced, by, 3, 'β-Dns-CA', in, the, same, concentration, range, '(', up, to, 60, μM, 'total)'])].
[sujeto(['A', partial, intermolecular, energy, transfer, from, 'NPX', to, 'Dns,', consistent, with, their]), verbo([reported]), complemento([singlet, 'energies,', was, 'revealed,', pointing, to, the, formation, of, extremely, fluorescent, hybrid, assemblies, at, 5, -, 10, μM, '(', total, 'concentration)'])].
[sujeto(['We', showed, that, dihydroxy, 'BAs,', but, not, the, monohydroxy, 'BA', lithocholic, acid, '(', 'LCA),']), verbo([stimulate]), complemento(['Cl(-)', secretion, in, human, colonic, 'T84', cells, '(', 'Ao', 'M,', 'Sarathy', 'J,', 'Domingue', 'J,', 'Alrefai', 'WA,', 'Rao', 'MC'])].
[sujeto(['While', 'LCA', '(', 50, 'μM,', 15, 'min)', drastically, '(', &, 'gt;90%)']), verbo([inhibited]), complemento(['FSK-stimulated', 'short-circuit', current, '(', 'Isc),', it, did, not, alter, 'carbachol-stimulated', 'Isc', 'LCA', did, not, alter, basal, 'Isc,', transepithelial, 'resistance,', cell, 'viability,', or, cytotoxicity])].
[sujeto(['LCA\'s', inhibitory, effect, was, dose, 'dependent,']), verbo([acted]), complemento([faster, from, the, apical, 'membrane,', 'rapid,', and, not, immediately, reversible])].
[sujeto(['LCA', also]), verbo([prevented]), complemento([the, 'Isc', stimulated, by, the, 'cAMP-dependent', secretagogues, 8, -, 'bromo-cAMP,', 'lubiprostone,', or, chenodeoxycholic, acid, '(', 'CDCA)'])].
[sujeto(['While', 'LCA', alone, had, no, effect, on, intracellular, cAMP, concentration, '(', '[', 'cAMP]i),', it]), verbo([decreased]), complemento(['FSK-stimulated', '[', 'cAMP]i', by, 90, '%'])].
[sujeto(['Although', 'LCA']), verbo([caused]), complemento([a, small, increase, in, intracellular, 'Ca(2+)', concentration, '(', '[', 'Ca(2+)]i),', chelation, by, 'BAPTA-AM', did, not, reverse, 'LCA\'s', effect, on, 'Isc', 'LCA', action, does, not, appear, to, involve, known, 'BA', 'receptors,', farnesoid, 'X', 'receptor,', vitamin, 'D', 'receptor,', muscarinic, acetylcholine, receptor, 'M3,', or, bile, 'acid-specific', transmembrane, 'G', 'protein-coupled', receptor, 5])].
[sujeto(['LCA', significantly]), verbo([increased]), complemento(['ERK1/2', 'phosphorylation,', which, was, completely, abolished, by, the, 'MEK', inhibitor, 'PD-98059'])].
[sujeto(['Surprisingly', 'PD-98059', did, not, reverse, 'LCA\'s', effect, on, 'Isc', 'Finally,', although, 'LCA', had, no, effect, on, basal, 'Isc,', nystatin, permeabilization, studies, showed, that, 'LCA', both]), verbo([stimulates]), complemento([an, apical, cystic, fibrosis, transmembrane, conductance, regulator, 'Cl(-)', current, and, inhibits, a, basolateral, 'K(+)', current])].
[sujeto(['In', 'summary,', 50, μM, 'LCA', greatly]), verbo([inhibits]), complemento(['cAMP-stimulated', 'Cl(-)', 'secretion,', making, low, doses, of, 'LCA', of, potential, therapeutic, interest, for, diarrheal, diseases])].
[sujeto(['Colorectal', cancer, '(', 'CRC)', is, one, of, the, most, frequent]), verbo([causes]), complemento([of, cancer, death, worldwide, and, is, associated, with, adoption, of, a, diet, high, in, animal, protein, and, saturated, fat])].
[sujeto(['Saturated', fat]), verbo([induces]), complemento([increased, bile, secretion, into, the, intestine])].
[sujeto(['Epidemiological', evidence]), verbo([suggests]), complemento(['CRC', is, associated, with, increased, levels, of, 'DCA', in, 'serum,', 'bile,', and, stool])].
[sujeto(['Mechanisms', by, which, secondary, bile, acids]), verbo([promote]), complemento(['CRC', are, explored])].
[sujeto(['Thus,', taurocholic, acid]), verbo([has]), complemento([the, potential, to, stimulate, intestinal, bacteria, capable, of, converting, taurine, and, cholic, acid, to, hydrogen, sulfide, and, deoxycholic, 'acid,', a, genotoxin, and, 'tumor-promoter,', respectively])].
[sujeto(['In', bovine, aortic, endothelial, 'cells,', treatment, with, a, bile, acid, having, a, high, affinity, to, 'TGR5,', taurolithocholic, acid, '(', 'TLCA),', significantly]), verbo([increased]), complemento(['NO', production])].
[sujeto(['TLCA']), verbo([increased]), complemento([endothelial, 'NO', 'synthase(ser1177)', phosphorylation, in, human, umbilical, vein, endothelial, cells])].
[sujeto(['This', response, was, accompanied, by]), verbo([increased]), complemento(['Akt(ser473)', phosphorylation, and, intracellular, 'Ca(2+)'])].
[sujeto(['Inhibition', of, these, signals, significantly]), verbo([decreased]), complemento(['TLCA-induced', 'NO', production])].
[sujeto(['In', human, umbilical, vein, endothelial, 'cells,', 'TLCA', significantly, reduced, tumor, necrosis, 'factor-α-induced', adhesion, of, 'monocytes,', vascular, cell, adhesion, 'molecule-1', 'expression,', and, activation, of]), verbo([nuclear]), complemento(['factor-κB'])].
[sujeto(['TLCA', also]), verbo([inhibited]), complemento(['lipopolysaccharide-induced', monocyte, adhesion, to, mesenteric, venules, in, vivo])].
[sujeto(['TGR5', agonism]), verbo([induces]), complemento(['NO', production, via, 'Akt', activation, and, intracellular, 'Ca(2+)', increase, in, vascular, endothelial, 'cells,', and, this, function, inhibits, monocyte, adhesion, in, response, to, inflammatory, stimuli])].
[sujeto(['Steroid', and, 'Xenobiotic', 'Receptor', '(', 'SXR)', belongs, to]), verbo([nuclear]), complemento([receptor, superfamily])].
[sujeto(['Recently,', we]), verbo([have]), complemento([demonstrated, that, vitamin, 'K2', also, serves, as, a, ligand, for, 'SXR', and, activation, of, 'SXR', by, vitamin, 'K2', suppressed, proliferation, and, motility, of, hepatocellular, carcinoma, '(', 'HCC)', cells])].
[sujeto(['To', analyze, function, of, 'SXR', in, 'HCC', 'cells,', we, overexpressed, exogenous, 'SXR', 'double-tagged', with, 'FLAG', and, 'HA', in, a, 'HCC', cell, 'line,', 'HepG2', 'cells,', and, purified, 'SXR-binding', molecules, by, immunoprecipitation, from, the]), verbo([nuclear]), complemento([extracts, of, these, cells])].
[sujeto(['Several']), verbo([binding]), complemento([molecules, were, identified, by, 'TOF-MS', analyses])].
[sujeto(['Then,', we]), verbo([have]), complemento([shown, that, 'AF2', domain, of, 'SXR', is, necessary, for, binding, with, 'PROX1'])].
[sujeto(['We', further, demonstrated, that, 'PROX1', negatively]), verbo([regulated]), complemento([the, transcriptional, activity, of, 'SXR', by, promoter, analyses, of, 'SXR', target, gene])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'PROX1', could, negatively, regulate, 'SXR', signals, in, some, tumor, 'cells,', such, as, 'HCC', 'cells,', where, both, 'SXR', and, 'PROX1', are, expressed])].
[sujeto(['In', 'cholestasis,', 'LCA', levels]), verbo([increase]), complemento([in, the, liver, and, intestine])].
[sujeto(['The', objective, of, this, study, is, to, test, the, hypothesis, that, 'VDR', plays, a, role, in]), verbo([inhibiting]), complemento([cholesterol, 7, 'alpha-hydroxylase', '(', 'CYP7A1)', gene, expression, and, bile, acid, synthesis, in, human, hepatocytes])].
[sujeto(['Immunoblot', analysis]), verbo([has]), complemento([detected, 'VDR', proteins, in, the, nucleus, of, the, human, hepatoma, cell, line, 'HepG2', and, human, primary, hepatocytes])].
[sujeto([1, 'alpha,', 25, -, 'Dihydroxy-vitamin', 'D(3)', or, 'LCA', 'acetate-activated', 'VDR']), verbo([inhibited]), complemento(['CYP7A1', mRNA, expression, and, bile, acid, 'synthesis,', whereas, small, interfering, 'RNA', to, 'VDR', completely, abrogated, 'VDR', inhibition, of, 'CYP7A1', mRNA, expression, in, 'HepG2', cells])].
[sujeto(['Electrophoretic', mobility, shift, assay, and, mutagenesis, analyses]), verbo([have]), complemento([identified, the, negative, 'VDR', response, elements, that, bind, 'VDR/retinoid', 'X', receptor, alpha, in, the, human, 'CYP7A1', promoter])].
[sujeto(['Mammalian', 'two-hybrid,', 'coimmunoprecipitation,', glutathione, 'S-transferase', 'pull-down,', and, chromatin, immunoprecipitation, assays, show, that, 'ligand-activated', 'VDR', specifically]), verbo([interacts]), complemento([with, hepatocyte, nuclear, factor, 4, alpha, '(', 'HNF4alpha)', to, block, 'HNF4alpha', interaction, with, coactivators, or, to, compete, with, 'HNF4alpha', for, coactivators, or, to, compete, for, binding, to, 'CYP7A1', 'chromatin,', which, results, in, the, inhibition, of, 'CYP7A1', gene, transcription])].
[sujeto(['This', study, shows, that, 'VDR', is]), verbo([expressed]), complemento([in, human, hepatocytes, and, may, play, a, critical, role, in, the, inhibition, of, bile, acid, 'synthesis,', thus, protecting, liver, cells, during, cholestasis])].
[sujeto(['Toxic', bile, acids]), verbo([induce]), complemento([hepatocyte, 'apoptosis,', for, which, p53, and, cyclin, 'D1', have, been, implicated, as, underlying, mediators])].
[sujeto(['Both', p53, and, cyclin, 'D1', are]), verbo([targets]), complemento([of, 'c-Myc,', which, is, also, 'up-regulated', in, cholestasis])].
[sujeto(['Myc-Max', typically]), verbo([activates]), complemento([transcription, via, 'E-box', binding])].
[sujeto(['Mnt-Max', also]), verbo([binds]), complemento([the, 'E-box', sequence, but, serves, as, a, repressor, and, inhibits, the, enhancer, activity, of, 'Myc-Max'])].
[sujeto(['Following', common, bile, duct, ligation, or, left, hepatic, bile, duct, 'ligation,', the, expression, of, 'p53,', 'c-Myc,', and, cyclin, 'D1']), verbo([increased]), complemento(['markedly,', whereas, 'Mnt', expression, decreased])].
[sujeto(['Nuclear']), verbo([binding]), complemento([activity, of, 'Myc', to, the, 'E-box', element, of, p53, and, cyclin, 'D1', 'increased,', whereas, that, of, 'Mnt', decreased, in, a, 'time-dependent', fashion])].
[sujeto(['Lithocholic', acid, '(', 'LCA)', treatment, of, primary, human, hepatocytes, and, 'HuH-7', cells]), verbo([induced]), complemento([a, similar, switch, from, 'Mnt', to, 'Myc', and, increased, p53, and, cyclin, 'D1', promoter, activity, and, endogenous, p53, and, cyclin, 'D1', expression, and, apoptosis])].
[sujeto(['Blocking', 'c-Myc', induction, in, 'HuH-7', cells]), verbo([prevented]), complemento([the, 'LCA-mediated', increase, in, p53, and, cyclin, 'D1', expression, and, reduced, apoptosis])].
[sujeto(['Lowering', 'Mnt', expression, further]), verbo([enhanced]), complemento(['LCA\'s', inductive, effect, on, p53, and, cyclin, 'D1'])].
[sujeto(['Bile', 'duct-ligated', mice, treated, with, a, lentivirus, harboring, 'c-myc', small, interfering, 'RNA', were, protected, from, hepatic, induction, of, p53, and, cyclin, 'D1,', a, switch, from, 'Mnt', to, 'Myc']), verbo([nuclear]), complemento([binding, to, 'E-box,', and, hepatocyte, apoptosis])].
[sujeto(['Lipophilic', bile, acids, are]), verbo([suggested]), complemento([to, be, involved, in, the, endogenous, expression, of, 'CYP3A4', in, human, and, experimental, animals, as, ligands, of, nuclear, receptors])].
[sujeto(['To', verify, the]), verbo([nuclear]), complemento([receptor, 'specificity,', the, bile, 'acid-mediated', induction, of, 'CYP3A4', has, been, studied, in, vitro, and, in, vivo, in, the, present, study])].
[sujeto(['Lithocholic', acid, '(', 'LCA)', strongly]), verbo([enhanced]), complemento([the, activities, of, the, 'CYP3A4', reporter, 'gene,', which, contained, multiple, nuclear, receptor, binding, 'elements,', in, both, 'HepG2', and, 'LS174T', cells])].
[sujeto(['The', introduction, of, small, interfering, 'RNA', for, human, vitamin, 'D', receptor, '(', 'VDR),', but, not, for, human, pregnane, 'X', 'receptor,', reduced, the, 'LCA-induced', activation, of, the, reporter, gene, in, these, 'cells,']), verbo([suggesting]), complemento([the, major, role, of, 'VDR', in, the, 'LCA', induction, of, 'CYP3A4'])].
[sujeto(['Consistently,', oral, administration, of, 'LCA', '(', 100, 'mg/kg/day', for, 3, 'days)']), verbo([increased]), complemento(['Cyp3a', protein, levels, in, the, intestine, but, not, in, the, 'liver,', where, a, negligible, level, of, 'VDR', mRNA, is, detected])].
[sujeto(['In', mice, with, the, adenovirally]), verbo([expressed]), complemento(['VDR,', 'LCA', treatment, '(', 100, or, 400, 'mg/kg/day', for, 3, 'days)', resulted, in, the, enhanced, reporter, activities, and, increased, levels, of, 'Cyp3a', proteins, in, the, liver])].
[sujeto(['Oxidative', 'stress,']), verbo([causing]), complemento([necrotic, and, apoptotic, cell, 'death,', is, associated, with, bile, acid, toxicity])].
[sujeto(['Using', liver, '(', 'HepG2,', 'Hepa1c1c7,', and, primary, human, 'hepatocytes)', and, intestinal, '(', 'C2bbe1,', a, 'Caco-2', 'subclone)', 'cells,', we, demonstrated, that, toxic, bile, 'acids,', such, as, lithocholic, acid, '(', 'LCA)', and, chenodeoxycholic, 'acid,']), verbo([induced]), complemento([the, nuclear, factor, '(', 'erythroid-2', 'like)', factor, 2, '(', 'Nrf2)', target, 'genes,', especially, the, 'rate-limiting', enzyme, in, glutathione, '(', 'GSH)', biosynthesis, '[', glutamate, cysteine, ligase, modulatory, subunit, '(', 'GCLM)', and, glutamate, cysteine, ligase, catalytic, subunit, '(', 'GCLC)]', and, thioredoxin, reductase, 1])].
[sujeto(['Nrf2', activation, and, induction, of, 'Nrf2']), verbo([target]), complemento([genes, were, also, evident, in, vivo, in, the, liver, of, 'CD-1', mice, treated, 7, to, 8, h, or, 4, days, with, 'LCA'])].
[sujeto(['Silencing', of, 'Nrf2', via, 'small-interfering', 'RNA']), verbo([suppressed]), complemento([basal, and, bile, 'acid-induced', mRNA, levels, of, the, 'above-mentioned', genes])].
[sujeto(['Consistent', with, 'this,', overexpression, of, 'Nrf2', 'enhanced,', but, 'dominant-negative', 'Nrf2', 'attenuated,', 'Nrf2']), verbo([target]), complemento([gene, induction, by, bile, acids])].
[sujeto(['The', activation, of, 'Nrf2-antioxidant', responsive, element, '(', 'ARE)', transcription, machinery, by, bile, acids, was, confirmed, by]), verbo([increased]), complemento([nuclear, accumulation, of, 'Nrf2,', enhanced, 'ARE-reporter', 'activity,', and, increased, 'Nrf2', binding, to, 'ARE'])].
[sujeto(['It', is, noteworthy, that, 'Nrf2', silencing]), verbo([increased]), complemento([cell, susceptibility, to, 'LCA', 'toxicity,', as, evidenced, by, reduced, cell, viability, and, increased, necrosis, and, apoptosis])].
[sujeto(['Concomitant', with, 'GCLC/GCLM', 'induction,', cellular, 'GSH', was, significantly]), verbo([increased]), complemento([in, bile, 'acid-treated', cells])].
[sujeto(['In', 'summary,', this, study]), verbo([provides]), complemento([molecular, evidence, linking, bile, acid, toxicity, to, oxidative, stress])].
[sujeto(['Nrf2', is, centrally]), verbo([involved]), complemento([in, counteracting, such, oxidative, stress, by, enhancing, adaptive, antioxidative, 'response,', particularly, 'GSH', 'biosynthesis,', and, hence, cell, survival])].
[sujeto(['Treatment', with, 0.5, '%', 'CDCA', diet]), verbo([decreased]), complemento([hepatic, 'Sult2a', to, 20, '%', of, the, control, in, 'wild-type', 'mice,', but, increased, the, content, in, 'FXR-null', mice])].
[sujeto(['Liver', 'Sult2a1', '(', 'St2a4)', mRNA, levels, were, reduced, to, 26, '%', in, 'wild-type', mice, after, feeding, of, a, 'CDCA', 'diet,', while, no]), verbo([decrease]), complemento([was, observed, on, 'Sult2a1', mRNA, levels, in, 'FXR-null', mice, after, 'CDCA', feeding])].
[sujeto([523, ')', was]), verbo([found]), complemento([between, hepatic, 'Sult2a', protein, content, and, small, heterodimer, partner, '(', 'SHP)', mRNA, level])].
[sujeto(['PCN-mediated']), verbo([increase]), complemento([in, 'Sult2a', protein, levels, were, attenuated, by, 'CDCA', feeding, in, 'wild-type', 'mice,', but, not, in, 'FXR-null', mice])].
[sujeto(['Human', 'SULT2A1', protein, and, mRNA, levels, were]), verbo([decreased]), complemento([in, 'HepG2', cells, treated, with, the, 'FXR', 'agonists,', 'CDCA', or, 'GW4064', in, 'dose-dependent', 'manners,', although, 'SHP', mRNA, levels, were, increased])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'SULT2A', is, negatively, regulated, through, 'CDCA-mediated', 'FXR', activation, in, mice, and, humans])].
[sujeto(['So', 'far,', a, bile, 'acid-CoA', cleaving, activity]), verbo([has]), complemento([not, been, assessed, in, the, research, of, bile, acid, amidation, in, human, liver])].
[sujeto(['In', this, 'work,', a, bile, 'acid-CoA', cleaving, activity]), verbo([has]), complemento([been, demonstrated, at, a, rate, that, may, influence, the, concentration, of, bile, 'acid-CoA', 'thioesters,', free, bile, acids, and, amidated, bile, acids, within, the, hepatocyte])].
[sujeto(['The', thioesterases, may]), verbo([have]), complemento([an, indirect, regulatory, function, on, the, bile, acid, synthesis, and, are, important, for, the, regulation, of, bile, acid, synthesis, by, providing, free, chenodeoxycholic, 'acid,', the, most, potent, activator, of, the, farnesoid, 'X', receptor])].
[sujeto(['The', formation, of, 'chenodeoxycholyl-D-cystenolic', acid, was]), verbo([decreased]), complemento([by, the, addition, of, various, concentrations, of, taurine, to, the, incubation, mixture])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, bile, 'acid-CoA:', amino, acid, 'N-acyltransferase', in, red, seabream, is, not, able, to, distinguish, taurine, and, 'D-cysteinolic', acid, as, the, 'substrate,', probably, because, of, their, structural, similarity])].
[sujeto(['Consequently,', 'D-cystenolic', acid, conjugated, bile, acids]), verbo([found]), complemento([in, the, bile, of, wild, red, seabream, were, thought, to, be, synthesized, in, the, liver, of, the, fish, utilizing, the, unusual, amino, 'acid,', which, originated, from, 'foods,', prior, to, secretion, into, the, bile])].
[sujeto(['The', liver, is, the, central, organ]), verbo([involved]), complemento([in, lipid, metabolism])].
[sujeto(['Dyslipidemia', and, its, related, 'disorders,', including, 'non-alcoholic', fatty, liver, disease, '(', 'NAFLD),', obesity, and, other, metabolic, 'diseases,', are, of]), verbo([increasing]), complemento([public, health, concern, due, to, their, increasing, prevalence, in, the, population])].
[sujeto(['Besides', their, 'well-characterized', functions, in, cholesterol, homoeostasis, and, nutrient, 'absorption,', bile, acids, are, also, important, metabolic, regulators, and, function, as, signaling, hormones, by]), verbo([activating]), complemento([specific, nuclear, 'receptors,', 'G-protein', coupled, 'receptors,', and, multiple, signaling, pathways])].
[sujeto(['Recent', studies, identified, a, new, signaling, pathway, by, which, conjugated, bile, acids, '(', 'CBA)']), verbo([activate]), complemento([the, extracellular, regulated, protein, kinases, '(', 'ERK1/2)', and, protein, kinase, 'B', '(', 'AKT)', signaling, pathway, via, 'sphingosine-1-phosphate', receptor, 2, '(', 'S1PR2)'])].
[sujeto(['This', review, focuses, on, recent, findings, related, to, the, role, of, bile, 'acids/S1PR2-mediated', signaling, pathways, in]), verbo([regulating]), complemento([hepatic, lipid, metabolism])].
[sujeto(['The']), verbo([increasing]), complemento([prevalence, of, this, disease, requires, novel, therapeutic, approaches, to, prevent, disease, progression])].
[sujeto(['Synthetic', farnesoid, 'X', receptor, '(', 'FXR)', agonists]), verbo([have]), complemento([been, developed, to, specifically, target, these, receptors, for, therapeutic, use, in, 'NAFLD', patients])].
[sujeto(['Here,', we, present, a, review, of, bile, acid, physiology, and, how, agonism, of, 'FXR', receptors]), verbo([has]), complemento([been, examined, in, 'pre-clinical', and, clinical, 'NAFLD'])].
[sujeto(['Early', evidence]), verbo([suggests]), complemento([a, potential, role, for, synthetic, 'FXR', agonists, in, the, management, of, 'NAFLD;', 'however,', additional, studies, are, needed, to, clarify, their, effects, on, lipid, and, glucose, parameters, in, humans])].
[sujeto(['The', farnesoid, 'X', receptor, '(', 'FXR)', and, the, liver, x, receptors, '(', 'LXRs)', are, bile, 'acid-activated', receptors, that, are, highly]), verbo([expressed]), complemento([in, the, enterohepatic, tissues])].
[sujeto(['We']), verbo([have]), complemento([investigated, the, effects, of, ileal, interposition, '(', 'IT),', a, surgical, relocation, of, the, distal, ileum, into, the, proximal, 'jejunum,', on, 'FXR', and, 'LXRs', in, rats])].
[sujeto(['Seven', months, after, 'surgery,', blood, concentrations, of, total, bile, 'acids,', taurocholic, 'acid,', an, 'FXR', 'ligand,', and, taurohyocholic, 'acid,', an, 'LXRα', 'ligand,', were, significantly]), verbo([increased]), complemento([by, 'IT', '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['In', 'contrast,', liver, and, intestinal, concentrations, of, conjugated, and, nonconjugated, bile, acids, were]), verbo([decreased]), complemento(['(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['These', changes, were]), verbo([associated]), complemento([with, a, robust, induction, of, 'FXR', and, 'FXR-regulated', genes, in, the, 'intestine,', including, 'Fgf15,', a, negative, regulator, of, bile, acid, synthesis])].
[sujeto(['IT']), verbo([repressed]), complemento([the, liver, expression, of, 'glucose-6-phosphatase', '(', 'G6PC)', and, phosphoenolpyruvate, carboxykinase, '(', 'Pepck),', two, gluconeogenetic, 'genes,', along, with, the, expression, of, 'LXRα', and, its, target, genes, sterol, regulatory, 'element-binding', protein, '(', 'Srebp)', 1, c, and, fatty, acid, synthase, '(', 'Fas)', in, the, liver])].
[sujeto(['Whether', confirmed, in, human, 'settings,', these, results, support, the, association, of, pharmacological, therapies, with, bariatric, surgeries, to, exploit, the, selective, activation, of, intestinal]), verbo([nuclear]), complemento([receptors])].
[sujeto(['Endoplasmic', reticulum, '(', 'ER)', stress]), verbo([has]), complemento([been, implicated, in, the, pathogenesis, of, nonalcoholic, steatohepatitis])].
[sujeto(['The', 'ER', stress, response, is]), verbo([activated]), complemento([in, the, livers, of, mice, fed, a, 'methionine-', and, 'choline-deficient', '(', 'MCD)', 'diet,', yet, the, role, of, 'ER', stress, in, the, pathogenesis, of, 'MCD', 'diet-induced', steatohepatitis, is, unknown])].
[sujeto(['TUDCA', and, 'PBA', effectively, attenuated, the, 'ER', stress, response, in, 'MCD', 'diet-fed', 'mice,', as, evidenced, by, reduced, protein, levels, of]), verbo([phosphorylated]), complemento([eukaryotic, initiation, factor, 2, α, and, phosphorylated, 'JNK', and, suppression, of, mRNA, levels, of, 'CCAAT/enhancer', binding, protein, homologous, 'protein,', 'glucose-regulated', protein, 78, 'kDa,', and, 'X-box', binding, protein, 1])].
[sujeto(['However,', 'PBA', and, 'TUDCA', did, not]), verbo([decrease]), complemento(['MCD', 'diet-induced', hepatic, steatosis])].
[sujeto(['MCD', 'diet-induced', hepatic, 'inflammation,', as, evidenced, by]), verbo([increased]), complemento([plasma, alanine, aminotransferase, and, induction, of, hepatic, 'TNFα', 'expression,', was, also, not, reduced, by, 'PBA', or, 'TUDCA'])].
[sujeto(['ER', chemical, chaperones, reduce, 'MCD', 'diet-induced', 'ER', 'stress,', yet, they, do, not, improve, 'MCD', 'diet-induced', hepatic, 'steatosis,', 'inflammation,', or, activation, of, genes]), verbo([associated]), complemento([with, fibrosis])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, although, the, 'ER', stress, response, is, activated, by, the, 'MCD', 'diet,', it, does, not, have, a, primary, role, in, the, pathogenesis, of, 'MCD', 'diet-induced', steatohepatitis])].
[sujeto(['Human', ileal, bile, acid]), verbo([binding]), complemento([protein, '(', 'I-BABP),', a, member, of, the, family, of, intracellular, lipid, binding, 'proteins,', is, thought, to, play, a, role, in, the, enterohepatic, circulation, of, bile, salts])].
[sujeto(['Previously,', we]), verbo([have]), complemento([shown, by, 'stopped-flow', fluorescence, analysis, that, positive, binding, cooperativity, exhibited, by, 'I-BABP', in, its, interactions, with, glycocholate, '(', 'GCA)', and, glycochenodeoxycholate, '(', 'GCDA),', the, two, primary, bile, salts, in, 'humans,', is, related, to, a, slow, conformational, change, in, the, protein])].
[sujeto(['In', this, 'study,', we, used, backbone, '(', 15, ')', 'N', relaxation]), verbo([nuclear]), complemento([magnetic, resonance, '(', 'NMR)', techniques, to, obtain, 'residue-specific', information, about, the, internal, dynamics, of, apo, 'I-BABP', and, the, doubly, ligated, 'I-BABP:GCA:GCDA', complex, on, various, time, scales])].
[sujeto(['According', to, our, 'NMR', 'data,', bile, salt]), verbo([binding]), complemento([is, accompanied, by, a, slight, rigidification, of, the, '(', 15, ')', 'N-(1)H', bond, vectors, on, the, picosecond, to, nanosecond, time, 'scale,', with, most, pronounced, changes, occurring, in, the, 'C-D', region])].
[sujeto(['According', to, the, 'NMR', 'measurements,', the, helical, cap, region, may]), verbo([have]), complemento([a, less, crucial, role, in, mediating, ligand, entry, and, release, than, what, has, been, indicated, for, fatty, acid, binding, proteins])].
[sujeto(['Although', human, immunodeficiency, virus, '(', 'HIV)-related', morbidity, and, mortality, rates, in, patients, treated, with, a, combination, of, high, active, antiretroviral, therapy, '(', 'HAART)']), verbo([have]), complemento(['declined,', significant, 'metabolic/vascular', adverse, effects, associated, with, the, long, term, use, of, 'HIV', protease, inhibitors, '(', 'PIs)', have, emerged, as, a, significant, side, effect])].
[sujeto(['Here', we, illustrate, that]), verbo([targeting]), complemento([the, bile, acid, sensor, farnesoid, 'X', receptor, '(', 'FXR)', protects, against, dyslipidemia, and, vascular, injury, induced, 'HIV-PIs', in, rodents])].
[sujeto(['Administration', of, the, 'HIV', 'PI', ritonavir, to, wild, type, mice]), verbo([increased]), complemento([plasma, triacylglycerols, and, cholesterol, levels, and, this, effect, was, exacerbated, by, dosing, ritonavir, to, mice, harbouring, a, disrupted, 'FXR'])].
[sujeto(['Dyslipidemia']), verbo([induced]), complemento([by, ritonavir, associated, with, a, shift, in, the, liver, expression, of, signature, 'genes,', 'Sterol', 'Regulatory', 'Element-Binding', 'Protein', '(', 'SREBP)-1', and, fatty, acid, synthase])].
[sujeto(['Treating', wild, type, mice, with, the, 'FXR', agonist, '(', chenodeoxycholic, 'acid,', 'CDCA)', protected, against, development, of, dyslipidemia]), verbo([induced]), complemento([by, ritonavir])].
[sujeto(['Administration', of, ritonavir, to, 'ApoE(-/-)', 'mice,', a, strain, that, develop, spontaneously, 'atherosclerosis,']), verbo([increased]), complemento([the, extent, of, aortic, plaques, without, worsening, the, dyslipidemia])].
[sujeto(['FXR', activation, 'counter-regulated', induction, of, 'expression/activity', of, 'CD36']), verbo([caused]), complemento([by, 'HIV-PIs', in, circulating, monocytes, and, aortic, plaques])].
[sujeto(['In', macrophages, cell, 'lines,', 'CDCA', attenuated, 'CD36', induction, and, uptake, of, acetylated, 'LDL']), verbo([caused]), complemento([by, ritonavir])].
[sujeto(['Natural', and, synthetic, 'FXR', ligands, reduced, the]), verbo([nuclear]), complemento([translocation, of, 'SREBP1c', caused, by, ritonavir])].
[sujeto(['Activation', of, the, bile, acid, sensor, 'FXR', protects, against, dyslipidemia, and, atherosclerotic]), verbo([caused]), complemento([by, 'ritonavir,', a, widely, used, 'HIV', 'PI'])].
[sujeto(['From', a, mechanistic, stand, point, it, appears, that, besides, reducing, the, liver, expression, of, genes]), verbo([involved]), complemento([in, fatty, acid, 'synthesis,', 'FXR', activation, 'counter-regulates', the, 'expression/activity', of, 'CD36', on, monocytes])].
[sujeto(['FXR', ligands, might, hold, promise, in, the, treatment, dyslipidemia]), verbo([induced]), complemento([by, ritonavir])].
[sujeto(['Bile', acids]), verbo([have]), complemento([been, shown, to, modulate, energy, metabolism])].
[sujeto(['The', protective, effects, of, the, bile, acid, treatment, were]), verbo([associated]), complemento([with, a, downregulation, of, tumor, necrosis, factor, '(', 'TNF)α,', sterol, regulatory, 'element-binding', protein, '(', 'SREBP)1,', 'FAS', mRNA, 'expression,', and, lipid, peroxidation, in, the, 'liver,', whereas, hepatic, farnesoid, 'X', receptor, '(', 'FXR)', or, short, heterodimer, partner, '(', 'SHP)', protein, concentration, did, not, differ, between, groups, fed, fructose])].
[sujeto(['Taken', 'together,', these, data]), verbo([suggest]), complemento([that, bile, acids, prevent, 'fructose-induced', hepatic, steatosis, in, mice, through, mechanisms, involving, protection, against, the, 'fructose-induced', translocation, of, intestinal, bacterial, endotoxin])].
[sujeto(['Free-fatty', acids, '(', 'FFAs)', are, 'well-characterized', factor, for]), verbo([causing]), complemento([production, of, inflammatory, factors, and, insulin, resistance, in, adipocytes])].
[sujeto(['Using', cultured, 'adipocytes,', we, demonstrate, that, 'FFAs', can]), verbo([activate]), complemento([endoplasmic, reticulum, '(', 'ER)', stress, pathway, by, examination, of, 'ER', stress, sensor, activation, and, marker, gene, expression])].
[sujeto(['The', key, downstream]), verbo([target]), complemento([of, 'FFA-induced', 'ER', stress, is, 'IκB', kinase, β, '(', 'IKKβ),', a, master, kinase, for, regulating, expression, of, inflammatory, genes])].
[sujeto(['Consistently,', overexpression, of, 'IKKβ', in, 3, 'T3-L1', 'CAR', adipocytes]), verbo([causes]), complemento([inflammation, and, insulin, resistance])].
[sujeto(['In', 'addition,', 'IKKβ', overexpression]), verbo([has]), complemento([profound, effect, on, adipocyte, lipid, 'metabolism,', including, inhibition, of, lipogenesis, and, promotion, of, lipolysis])].
[sujeto(['Furthermore,']), verbo([increased]), complemento([endogenous, 'IKKβ', expression, and, activation, is, also, observed, in, isolated, primary, adipocytes, from, mice, injected, with, lipids, or, fed, on, 'high-fat', diet, '(', 'HFD)', acutely])].
[sujeto(['Diet-induced', obesity, is]), verbo([associated]), complemento([with, proteinuria, and, glomerular, disease, in, humans, and, rodents])].
[sujeto(['We']), verbo([have]), complemento([shown, that, in, mice, fed, a, 'high-fat', 'diet,', increased, renal, expression, of, the, transcriptional, factor, 'sterol-regulatory', element, binding, 'protein-1', '(', 'SREBP-1)', plays, a, critical, role, in, renal, lipid, accumulation, and, increases, the, activity, of, proinflammatory, cytokines, and, profibrotic, growth, factors])].
[sujeto(['In', the, current, 'study,', we]), verbo([have]), complemento([determined, a, key, role, of, the, farnesoid, 'X', receptor, '(', 'FXR)', in, modulating, renal, 'SREBP-1', 'activity,', glomerular, 'lesions,', and, proteinuria])].
[sujeto(['We']), verbo([found]), complemento([that, feeding, a, 'Western-style', diet, to, 'DBA/2J', mice, results, in, 'proteinuria,', podocyte, 'loss,', mesangial, 'expansion,', renal, lipid, 'accumulation,', and, increased, expression, of, proinflammatory, 'factors,', oxidative, 'stress,', and, profibrotic, growth, factors])].
[sujeto(['Treatment', of, these, mice, with, the, highly, selective, and, potent, 'FXR-activating', ligand, 6, -, 'alpha-ethyl-chenodeoxycholic', acid, '(', 'INT-747)', ameliorates, triglyceride, accumulation, by]), verbo([modulating]), complemento([fatty, acid, synthesis, and, 'oxidation,', improves, 'proteinuria,', prevents, podocyte, 'loss,', mesangial, 'expansion,', accumulation, of, extracellular, matrix, 'proteins,', and, increased, expression, of, profibrotic, growth, factors, and, fibrosis, 'markers,', and, modulates, inflammation, and, oxidative, stress])].
[sujeto(['Our', results, therefore, indicate, that, 'FXR', activation, could, represent, an, effective, therapy, for, treatment, of, abnormal, renal, lipid, metabolism, with]), verbo([associated]), complemento(['inflammation,', oxidative, 'stress,', and, kidney, pathology, in, patients, affected, by, obesity])].
[sujeto(['The', farnesoid, 'X', receptor, '(', 'FXR)', is, a, member, of, the]), verbo([nuclear]), complemento([receptor, superfamily, that, functions, as, an, endogenous, sensor, for, bile, acids, and, regulates, cholesterol, and, fatty, acid, metabolism])].
[sujeto(['INT-747', administration, to, 'ApoE-/-', mice, reduced, aortic, expression, of, 'IL-1beta,', 'IL-6,', and, 'CD11b', 'mRNA,', while, it, upregulated, the, expression, of, 'FXR', and, its]), verbo([target]), complemento(['gene,', the, small, heterodimer, partner, '(', 'SHP)'])].
[sujeto(['FXR', activation, reduced, the, liver, expression, of, sterol, regulatory, element]), verbo([binding]), complemento([protein, 1, 'c,', resulting, in, reduced, triglyceride, and, cholesterol, content, in, the, liver, and, amelioration, of, hyperlipidemia])].
[sujeto(['We']), verbo([found]), complemento([that, 'FXR', and, 'SHP', are, expressed, in, the, aorta, and, macrophages, and, that, 'FXR', ligands, might, have, utility, in, prevention, and, treatment, of, atherosclerotic, lesions])].
[sujeto(['This', effect, is]), verbo([caused]), complemento([by, an, increase, in, the, transcription, of, genes, involved, in, fatty, acid, synthesis])].
[sujeto(['CDCA']), verbo([inhibits]), complemento(['T0-901317-induced', 'ACCalpha', transcription, by, suppressing, the, enhancer, activity, of, a, 'LXR', response, unit, '(', -, 101, to, -, 71, 'bp)', that, binds, 'LXR', and, 'sterol-regulatory', element, binding, 'protein-1', '(', 'SREBP-1)'])].
[sujeto(['We', also, demonstrate, that, 'CDCA']), verbo([decreases]), complemento([the, expression, of, 'SREBP-1', in, the, nucleus, and, the, acetylation, of, histone, 'H3', and, 'H4', at, the, 'ACCalpha', 'LXR', response, unit])].
[sujeto(['The', 'CDCA-mediated', reduction, in, 'ACCalpha', expression, is]), verbo([associated]), complemento([with, a, decrease, in, the, expression, of, peroxisome, 'proliferator-activated', receptor, gamma, 'coactivator-1alpha', '(', 'PGC-1alpha)', and, small, heterodimer, partner, and, an, increase, in, the, expression, of, fibroblast, growth, 'factor-19', '(', 'FGF-19)'])].
[sujeto(['Ectopic', expression, of, 'FGF-19']), verbo([decreases]), complemento(['T0-901317-induced', 'ACCalpha', expression])].
[sujeto(['Inhibition', of, p38, 'mitogen-activated', protein, kinase, '(', 'MAPK)', 'and/or', extracellular, 'signal-regulated', kinase, '(', 'ERK)']), verbo([suppresses]), complemento([the, effects, of, 'CDCA', on, the, expression, of, 'ACCalpha,', 'SREBP-1,', 'PGC-1alpha,', and, 'FGF-19'])].
[sujeto(['These', results, demonstrate, that, 'CDCA']), verbo([inhibits]), complemento(['T0-901317-induced', 'ACCalpha', transcription, by, suppressing, the, activity, of, 'LXR', and, 'SREBP-1'])].
[sujeto(['We', postulate, that, p38, 'MAPK,', 'ERK,', 'PGC-1alpha,', and, 'FGF-19', are, components, of, the, signaling, 'pathway(s)']), verbo([mediating]), complemento([the, regulation, of, 'ACCalpha', gene, transcription, by, 'CDCA'])].
[sujeto(['Farnesoid', 'X', receptor, '(', 'FXR),', the, receptor, for, bile, 'acids,', including, chenodeoxycholic, acid, '(', 'CDCA),', is, a, member, of, the]), verbo([nuclear]), complemento([receptor, 'superfamily,', which, also, includes, the, receptors, for, retinoic, 'acid,', vitamin, 'D', '(', 'D3),', thyroid, 'hormone,', thiazolidinedione, and, 22, '(', 'R)-hydroxycholesterol'])].
[sujeto(['Here,', we]), verbo([have]), complemento([evaluated, the, effects, of, a, series, of, ligands, and, their, receptors, on, the, promoter, activity, induced, by, 'CDCA/FXR'])].
[sujeto(['The', kidney, cell, 'line,', 'CV1,', was, cotransfected, with, 'FXR-expression', plasmid, and, the, 'luciferase-based', reporter, gene, that]), verbo([has]), complemento([a, thymidine, kinase, promoter, fused, to, the, canonical, 'FXR-responsive', element, or, the, natural, promoter, for, the, small, heterodimer, partner, '(', 'SHP),', bile, salt, export, pump, '(', 'BSEP),', and, ileum, bile, acid, '(', 'I-BABP)', gene])].
[sujeto(['D3', and, its, receptor, '(', 'VDR)']), verbo([inhibited]), complemento([the, transactivation, of, all, four, reporter, constructs, that, are, enhanced, by, 'CDCA/FXR'])].
[sujeto(['The', transcription, factor, farnesoid, 'X', receptor, '(', 'FXR)']), verbo([has]), complemento([recently, been, implicated, in, the, control, of, hepatic, triglyceride, production])].
[sujeto(['controls)', due, to]), verbo([increased]), complemento([hepatic, lipoprotein, production])].
[sujeto(['This', could, be, largely, attributed, to]), verbo([enhanced]), complemento([hepatic, de, novo, 'lipogenesis,', as, indicated, by, increased, expression, of, sterol, regulatory, 'element-binding', 'protein-1,', fatty, acid, 'synthase,', and, 'steaoryl-CoA', 'desaturase-1'])].
[sujeto(['Lipoprotein', analysis, demonstrated, that, the]), verbo([increase]), complemento([in, plasma, triglycerides, occurred, in, the, 'VLDL', density, 'range,', whereas, increases, in, 'VLDL,', 'IDL/LDL,', and, 'HDL', cholesterol, accounted, for, the, elevated, plasma, cholesterol, concentrations])].
[sujeto(['Addition', of, 0.1, '%', 'CDCA', to, the, 'high-fructose', diet]), verbo([decreased]), complemento([hepatic, de, novo, lipogenesis, and, consequently, triglyceride, production, and, prevented, the, increases, in, plasma, triglycerides, and, cholesterol, '(', -, 40, and, -, 18, '%', ',', 'P', =, 0.03, and, 0.03, vs])].
[sujeto(['CDCA-treated', animals, had, lower, 'VLDL', triglycerides, and]), verbo([decreased]), complemento(['VLDL', and, 'IDL/LDL', cholesterol, plasma, concentrations])].
[sujeto(['These', data, demonstrate, that, activation, of, 'FXR', with, 'CDCA', effectively, lowers, plasma, triglyceride, and, cholesterol, 'concentrations,', mainly, by]), verbo([decreasing]), complemento([de, novo, lipogenesis, and, hepatic, secretion, of, 'triglyceride-rich', lipoproteins])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, alpha, '(', 'PPARalpha)', is, a]), verbo([nuclear]), complemento([receptor, that, controls, expression, of, genes, involved, in, lipid, metabolism, and, is, activated, by, fatty, acids, and, hypolipidaemic, fibrates])].
[sujeto(['Fibrates']), verbo([induce]), complemento([the, hepatic, expression, of, murine, multidrug, resistance, 2, '(', 'Mdr2', ')', ',', encoding, the, canalicular, phospholipid, translocator])].
[sujeto(['The', physiological, role, of, 'PPARalpha', in, regulation, of, 'Mdr2', and, other, genes]), verbo([involved]), complemento([in, bile, formation, is, unknown])].
[sujeto(['We']), verbo([found]), complemento([no, differences, in, hepatic, expression, of, the, 'ATP', binding, cassette, transporter, genes, 'Mdr2,', 'Bsep', '(', bile, salt, export, 'pump),', 'Mdr1a', /, 1, 'b,', 'Abca1', and, 'Abcg5', /, 'Abcg8', '(', implicated, in, cholesterol, 'transport),', the, bile, 'salt-uptake', systems, 'Ntcp', '(', 'Na(+)-taurocholate', 'co-transporting', polypeptide, 'gene)', and, 'Oatp1', '(', organic, 'anion-transporting', polypeptide, 1, 'gene)', or, in, bile, formation, between, 'wild-type', and, 'Ppar', 'alpha((-/-))', mice])].
[sujeto(['Exposure', of, cultured, 'wild-type', mouse, hepatocytes, to, 'PPARalpha', agonists, specifically]), verbo([induced]), complemento(['Mdr2', mRNA, levels, and, did, not, affect, expression, of, 'Mdr1a', /, 1, b])].
[sujeto(['Altered', transporter, expression, in, 'fibrate-treated', 'wild-type', mice, was]), verbo([associated]), complemento([with, a, approximately, 400, '%', increase, in, bile, 'flow:', secretion, of, phospholipids, and, cholesterol, was, increased, only, during, 'high-bile-salt', infusions])].
[sujeto(['The', induction, of, 'Mdr2', mRNA, and, 'Mdr2', protein, levels, by, fibrates, is]), verbo([mediated]), complemento([by, 'PPARalpha,', while, the, induction, of, 'Mdr1a', /, 1, b, in, vivo, probably, reflects, a, secondary, phenomenon, related, to, chronic, 'PPARalpha', activation])].
[sujeto(['The']), verbo([finding]), complemento([that, expression, of, a, cholesterol, 7, 'alpha-hydroxylase', '(', 'CYP7A1)', transgene, in, cultured, rat, hepatoma, cells, caused, a, coordinate, increase, in, lipogenesis, and, secretion, of, 'apoB-containing', lipoproteins, led, to, the, hypothesis, that, hepatic, production, of, 'apoB-containing', lipoproteins, may, be, linked, to, the, expression, of, 'CYP7A1', '(', 'Wang,', 'S'])].
[sujeto(['To', examine, this, hypothesis, in, 'vivo,', a, transgene, encoding, 'CYP7A1', driven, by, the, constitutive, 'liver-specific', enhancer, of, the, human, apoE, gene, was]), verbo([expressed]), complemento([in, 'C56BL/6', mice])].
[sujeto(['The', expression, of, 'CYP7A1', mRNA, '(', 20, -, 'fold),', protein, '(', approximately, 10, -, 'fold),', and, enzyme, activity, '(', 5, -, 'fold)', was, markedly]), verbo([increased]), complemento([in, transgenic, mice, compared, with, 'non-transgenic', littermates])].
[sujeto(['The', bile, acid, pool, of, 'CYP7A1', transgenic, mice, was, doubled, mainly, due, to]), verbo([increased]), complemento([hydrophobic, dihydroxy, bile, acids])].
[sujeto(['CYP7A1', transgenic, mice, also, displayed, a, &, 'gt;2-fold']), verbo([increase]), complemento([in, hepatic, production, and, secretion, of, 'triglyceride-rich', 'apoB-containing', lipoproteins])].
[sujeto(['Despite', the]), verbo([increased]), complemento([hepatic, secretion, of, 'apoB-containing', lipoproteins, in, 'CYP7A1', 'mice,', plasma, levels, of, triglycerides, and, cholesterol, were, not, significantly, increased])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, the, 5, -, fold, increased, expression, of, the, low, density, lipoprotein, receptor, displayed, by, the, livers, of, 'CYP7A1', transgenic, mice, was, sufficient, to, compensate, for, the, 2, -, fold, increase, production, of, 'apoB-containing', lipoproteins])].
[sujeto(['A', 24, h, incubation, of, 'Caco-2', cells, in, a, medium, containing, either, bile, or, bile, acids, resulted, in, a, remarkable, 7.5, -, fold]), verbo([increase]), complemento([in, the, 'I-BABP', mRNA, level, over, the, control, level])].
[sujeto(['Bile', acid, treatment]), verbo([increased]), complemento([the, level, of, 'I-BABP', mRNA, in, 'Caco-2', cells, in, a, 'time-', and, 'dose-dependent', manner])].
[sujeto(['Western', blot, analysis, showed, that, this, induction]), verbo([led]), complemento([to, increase, in, cytosolic, 'I-BABP'])].
[sujeto(['Pretreatment', by, actinomycin, 'D', or, cycloheximide, completely]), verbo([inhibited]), complemento([the, 'up-regulation', of, 'I-BABP', expression, by, bile, acid])].
[sujeto(['Bile', 'acids,', especially, lipophilic, bile, 'acids,']), verbo([increase]), complemento([the, 'I-BABP', expression, in, 'Caco-2-cells,', suggesting, that, luminal, bile, acids, play, an, important, role, in, regulating, the, 'I-BABP', gene, expression])].
[sujeto(['Hydrophobic', bile, acids]), verbo([have]), complemento([been, implicated, in, the, pathogenesis, of, cholestatic, liver, injury])].
[sujeto(['The', hypothesis, that, hydrophobic, bile, acid, toxicity, is]), verbo([mediated]), complemento([by, oxidant, stress, in, an, in, vivo, rat, model, was, tested, in, this, study])].
[sujeto([bolus, of, 'TCDC', '(', 10, 'mumol/100', g, 'weight),', serum, aspartate, aminotransferase, '(', 'AST)', and, alanine, aminotransferase, '(', 'ALT)', levels, 'peaked,', hepatic, mitochondria, showed, evidence, of]), verbo([increased]), complemento([lipid, 'peroxidation,', and, serum, bile, acid, analysis, was, consistent, with, a, cholestatic, injury])].
[sujeto(['Treatment', with, parenteral, 'alpha-tocopherol', was]), verbo([associated]), complemento([with, a, 60, '%', -, 70, '%', reduction, in, 'AST', and, 'ALT', 'levels,', improved, 'histology,', and, a, 60, '%', reduction, in, mitochondrial, lipid, peroxidation, in, rats, receiving, 'TCDC'])].
[sujeto(['These', data, show, that, hepatocyte, injury, and, oxidant, damage, to, mitochondria]), verbo([caused]), complemento([by, i])].
[sujeto(['While', 'I-', and, 'L-FABPc', gene, transcription, commence, in, late, fetal, life, coincident, with, initial, cytodifferentiation, of, the, mouse, gut, 'epithelium,', the, ileal, gene, is]), verbo([activated]), complemento(['later,', at, the, 'suckling/weaning', transition, '(', postnatal, day, 12, ')'])].
[sujeto(['The', ileal, location, and, developmental, pattern, of, expression]), verbo([suggested]), complemento([that, this, protein, may, play, a, role, in, the, intracellular, transport, of, bile, salts, in, the, ileal, epithelium])].
[sujeto(['To', test, this, 'hypothesis,', we]), verbo([expressed]), complemento([the, porcine, ileal, peptide, '(', 'PIP)', in, 'Escherichia', 'coli,', purified, it, to, apparent, 'homogeneity,', and, analyzed, its, binding, properties, for, bile, acids, and, fatty, acids, using, 13, 'C', 'NMR', spectroscopy])].
[sujeto(['Like', 'I-FABPc,', 'PIP']), verbo([binds]), complemento([palmitate, and, oleate, with, a, 1, :, 1, molar, stoichiometry])].
[sujeto(['However,', unlike, 'I-FABPc', 'PIP']), verbo([binds]), complemento([chenodeoxycholate])].
[sujeto(['In', 'addition,', the, presence, of, chenodeoxycholate, blocks, fatty, acid]), verbo([binding]), complemento([to, 'PIP,', but, not, to, 'I-FABPc'])].
[sujeto(['Experiments', were, performed, using, isolated, mucosal, cells, from, the, rat, jejunum, or, using, the, perfused, jejunum, in, the, anesthetized, rat, to, test, whether, lipophilic, unconjugated, dihydroxy, bile, acids, are, absorbed, from, the, proximal, small, intestine, via, the, same, carrier, mechanism]), verbo([involved]), complemento([in, the, uptake, of, long, chain, fatty, acids])].
[sujeto(['With', isolated, jejunal, mucosal, 'cells,', the, cellular, uptake, rate, of, deoxycholic, acid, or, chenodeoxycholic, acid]), verbo([increased]), complemento([linearly, with, 'time,', showed, no, evidence, of, 'saturation,', and, was, not, decreased, by, the, presence, of, a, monospecific, antibody, to, the, membrane, fatty, acid, binding, protein])].
[sujeto(['In', 'contrast,', oleate, uptake, was, 'saturable,', was]), verbo([inhibited]), complemento([by, the, same, 'antibody,', but, was, not, affected, by, the, presence, of, chenodeoxycholic, acid, or, deoxycholic, acid])].
[sujeto(['Bile', acid, uptake, by, isolated, enterocytes, occurred, at, 'one-eighth', the, rate, of, fatty, acid, uptake, if]), verbo([expressed]), complemento([in, relation, to, total, solute, 'concentration;', if, expressed, in, relation, to, monomeric, 'concentration,', initial, bile, acid, uptake, was, four, orders, of, magnitude, slower, than, fatty, acid, uptake])].
[sujeto(['In', the, isolated, perfused, jejunal, 'segment,', chenodeoxycholic, acid, and, deoxycholic, acid, uptake, was, not, influenced, by, the, presence, of, the, antibody, to, membrane, fatty, acid]), verbo([binding]), complemento(['protein,', whereas, absorption, of, oleate, was, inhibited, by, more, than, 70, '%'])].
[sujeto(['These', experiments, indicate, that, absorption, of, unconjugated, lipophilic, dihydroxy, bile, acids, in, the, rodent, jejunum, does, not]), verbo([involve]), complemento([the, carrier, mediated, uptake, mechanism, involved, in, the, absorption, of, long, chain, fatty, 'acids--the', mechanism, is, likely, to, be, passive, nonionic, diffusion])].
[sujeto(['A', 'micro-partition', centrifugal, ultrafiltration, technique]), verbo([has]), complemento([been, used, to, monitor, the, percentage, of, '[', 14, 'C]glycocholate,', '[', 3, 'H]glycochenodeoxycholate', and, '[', 3, 'H]glycochenodeoxycholate-3-sulphate', bound, to, serum, proteins, of, patients, with, cholestatic, liver, disease])].
[sujeto(['In', comparison, with, normal, individuals, the, percentage, of]), verbo([binding]), complemento([of, '[', 14, 'C]glycocholate', 'and,', to, a, lesser, 'extent,', of, '[', 3, 'H]glycochenodeoxycholate', and, '[', 3, 'H]glycochenodeoxycholate-3-sulphate', was, reduced])].
[sujeto(['The']), verbo([binding]), complemento([of, '[', 14, 'C]glycocholate', was, inversely, related, to, the, serum, bile, salt, and, bilirubin, concentrations])].
[sujeto(['In', 'contrast,', the]), verbo([binding]), complemento([of, '[', 3, 'H]glycochenodeoxycholate', and, '[', 3, 'H]glycochenodeoxycholate-3-sulphate', were, not, altered, by, the, severity, of, the, cholestasis])].
[sujeto(['Studies', in, vitro, indicated, that, the, reduction, in, the]), verbo([binding]), complemento([of, '[', 14, 'C]glycocholate', in, cholestatic, liver, disease, was, not, due, to, high, concentrations, of, bile, 'salts,', unconjugated, bilirubin, or, fatty, acids])].
[sujeto(['Consistent', with, this, 'observation,', treatment, of, mice, with, 'FXR-specific', agonists, '(', 'GSK2324', or, 'GW4064)', rapidly]), verbo([increased]), complemento([hepatic, levels, of, 'Srebp-2', 'mRNA,', precursor, sterol, response, element, binding, protein, 2, '(', 'pSREBP-2)', 'protein,', and, 'miR-33'])].
[sujeto(['Furthermore,', 'miR-33', 'targets,', that, include, 'ABCA1', '(', 'ATP']), verbo([binding]), complemento([cassette, transporter, 'A1),', 'NSF', '(', 'N-ethylmaleimide-sensitive', 'factor),', and, 'CPT1', '(', carnitine, palmitoyltransferase, 1, ')', ',', were, all, reduced, in, 'GSK2324-treated', mice])].
[sujeto(['In', 'contrast,', neither]), verbo([nuclear]), complemento(['SREBP-2', protein, '(', 'nSREBP-2)', nor, 'SREBP-2', target, genes, were, induced, after, 'FXR', activation])].
[sujeto(['The', inability, to, process, 'pSREBP-2', to, 'nSREBP-2', is, likely, a, consequence, of, the, induction, of, insulin, 'INSIG-2A', '(']), verbo([induced]), complemento([gene, 2, 'A)', by, 'FXR', agonists])].
[sujeto(['Finally,', we, show, that, 'FXR-dependent', induction, of, both, 'Srebp-2', and, 'miR-33', is, ablated, in, 'Scap(-/-)', mice, that, lack]), verbo([nuclear]), complemento(['SREBP-2'])].
[sujeto(['We', demonstrate, that, the, activation, of, 'FXR', uncouples, the, expression, of]), verbo([nuclear]), complemento(['SREBP-2', and, 'miR-33,', and, the, regulation, of, their, respective, target, genes])].
[sujeto(['Further,', we, conclude, that, the, 'FXR', 'agonist-dependent']), verbo([increase]), complemento([in, 'miR-33', requires, transcription, of, the, 'Srebp-2', gene])].
[sujeto(['Farnesoid', 'X', receptor, '(', 'FXR,', 'NR1H4),', a]), verbo([nuclear]), complemento([receptor, '(', 'NR)', highly, expressed, in, the, 'liver,', 'intestine,', 'kidney,', adrenal, glands, and, other, 'cholesterol-rich', 'tissues,', functions, as, the, master, regulator, for, bile, acid, homeostasis])].
[sujeto(['FXR,', which]), verbo([regulates]), complemento([the, expression, of, genes, encoding, proteins, involved, in, cholesterol, 'homeostasis,', plays, an, essential, role, in, regulating, 'cholesterol,', 'lipid,', and, glucose, metabolism])].
[sujeto(['Recently,', some, 'FXR', agonists, are]), verbo([reported]), complemento([to, have, low, selectivity, on, 'NRs,', which, forces, the, researchers, to, move, their, eyes, onto, the, development, of, 'FXR', antagonists, with, high, selectivity])].
[sujeto(['The', development, of, 'non-steroidal', 'FXR', antagonists, with, different, scaffolds, including, 'AGN34,', 'tuberatolides,', 'atractylenolides,', 'andrographolides,', 'GW4064', derivatives, and, 1, ',', 3, ',', 4, -, 'trisubstitutedpyrazolones,']), verbo([provides]), complemento([us, a, prospect, for, the, therapy, of, in, 'ammation,', metabolic, 'syndrome,', 'diabetes,', cholesterol, 'gallstones,', and, cancer])].
[sujeto(['Farnesoid', 'X', receptor, '(', 'FXR,', 'NR1H4)', is, a, 'ligand-activated', transcription, 'factor,', belonging, to, the]), verbo([nuclear]), complemento([receptor, superfamily])].
[sujeto(['FXR', is, highly]), verbo([expressed]), complemento([in, the, liver, and, is, essential, in, regulating, bile, acid, homeostasis])].
[sujeto(['FXR', deficiency, is, implicated, in, numerous, liver, diseases, and, mice, with, modulation, of, 'FXR']), verbo([have]), complemento([been, used, as, animal, models, to, study, liver, physiology, and, pathology])].
[sujeto(['We']), verbo([have]), complemento([reported, 'genome-wide', binding, of, 'FXR', in, mice, by, chromatin, immunoprecipitation, -, deep, sequencing, '(', 'ChIP-seq),', with, results, indicating, that, 'FXR', may, be, involved, in, regulating, diverse, pathways, in, liver])].
[sujeto(['ChIP-seq', showed, similar, profiles, of, 'genome-wide', 'FXR']), verbo([binding]), complemento([in, humans, and, mice, in, terms, of, motif, analysis, and, pathway, prediction])].
[sujeto(['In', 'summary,', we]), verbo([have]), complemento([established, 'genome-wide', human, 'FXR', binding, and, transcriptome, profiles])].
[sujeto(['Farnesoid', 'X', receptor, '(', 'FXR,', 'NR1H4)', is, a, member, of, a]), verbo([nuclear]), complemento([receptor, 'superfamily,', which, plays, important, roles, in, bile, acid, 'homeostasis,', lipoprotein, and, glucose, 'metabolism,', and, hepatic, regeneration])].
[sujeto(['GW4064', is, a, potent, and, selective, 'FXR', agonist, and]), verbo([has]), complemento([become, a, tool, compound, to, probe, the, physiological, functions, of, 'FXR'])].
[sujeto(['Here,', we]), verbo([report]), complemento([a, computational, study, of, 'GW4064', unbinding, pathways, from, 'FXR', by, using, several, molecular, dynamics, '(', 'MD)', simulation, techniques])].
[sujeto(['Based', on, the, crystal, structure, of, 'FXR', in, complex, with, 'GW4064,', conventional, 'MD', was, first, used, to, refine, the]), verbo([binding]), complemento([and, check, the, stability, of, 'GW4064', in, the, 'FXR', pocket])].
[sujeto(['The']), verbo([nuclear]), complemento([receptor, farnesoid, 'X', receptor, alpha, '(', 'FXRalpha,', 'NR1H4)', is, activated, by, bile, acids, in, multiple, species, including, 'mouse,', 'rat,', and, human, and, in, this, study, we, have, identified, two, isoforms, of, 'Fxralpha', in, 'Japanese', medaka, '(', 'Oryzias', 'latipes),', a, small, freshwater, teleost])].
[sujeto(['A', 'Gal4DBD-FxralphaLBD', fusion, construct, was]), verbo([activated]), complemento([by, 'chenodeoxycholic,', 'cholic,', deoxycholic, and, lithocholic, 'acids,', and, the, synthetic, agonist, 'GW4064', in, transient, transactivation, assays])].
[sujeto(['Activation', of, the, 'Gal4DBD-FxralphaLBD', fusion, construct, was]), verbo([enhanced]), complemento([by, addition, of, 'PGC-1alpha,', as, demonstrated, through, titration, assays])].
[sujeto(['Surprisingly,', when, the, 'full-length', versions, of, the, two, 'Fxralpha', isoforms, were, compared, in, transient, transfection, 'assays,', 'Fxralpha2', was]), verbo([activated]), complemento([by, 'C(24)', bile, acids, and, 'GW4064,', while, 'Fxralpha1', was, not, significantly, activated, by, any, of, the, compounds, tested])].
[sujeto(['Furthermore,', mammalian, 'two-hybrid', studies, demonstrated, the, ability, of, 'Fxralpha2,', but, not, 'Fxralpha1,', to]), verbo([interact]), complemento([with, 'PGC-1alpha', and, 'SRC-1,', and, supported, our, results, from, the, transient, transfection, reporter, gene, activation, assays])].
[sujeto(['These', data, demonstrate, that, both, mammalian, and, teleost, 'FXR', '(', 'Fxralpha2', 'isoform)', are]), verbo([activated]), complemento([by, primary, and, secondary, bile, acids])].
[sujeto(['The', small, freshwater, 'teleost,', medaka, '(', 'Oryzias', 'latipes),']), verbo([has]), complemento([a, history, of, usage, in, studies, of, chronic, toxicity, of, liver, and, biliary, system])].
[sujeto(['Recent', progress, with, this, model]), verbo([has]), complemento([focused, on, defining, the, medaka, hepatobiliary, system])].
[sujeto(['Here', we, investigate, critical, liver, function, and, toxicity, by, examining, the, in, vivo, role, and, function, of, the, farnesoid, 'X', receptor, alpha, '(', 'FXRalpha,', 'NR1H4),', a, member, of, the]), verbo([nuclear]), complemento([receptor, superfamily, that, plays, an, essential, role, in, the, regulation, of, bile, acid, homeostasis])].
[sujeto(['Activation', of, medaka, 'Fxralpha', in, vivo, with, 'GW4064', '(', a, strong, 'FXRalpha', 'agonist)', resulted, in, modification, of, gene, expression, for, defined, 'FXRalpha', gene]), verbo([targets]), complemento([including, the, bile, salt, export, 'protein,', small, heterodimer, 'partner,', and, cytochrome, 'P450', 7, 'A1'])].
[sujeto(['This']), verbo([report]), complemento([of, hepatobiliary, injury, following, 'GW4064', exposure, extends, previous, investigations, of, the, intrahepatic, biliary, system, in, 'medaka,', reveals, sensitivity, to, toxicant, 'exposure,', and, illustrates, the, need, for, added, resolution, in, detection, and, interpretation, of, toxic, responses, in, this, vertebrate])].
[sujeto(['The', farnesoid, 'X', receptor, '(', 'FXR,', 'NR1H4)', belongs, to, the]), verbo([nuclear]), complemento([receptor, superfamily, and, is, activated, by, bile, acids, such, as, chenodeoxycholic, 'acid,', or, synthetic, ligands, such, as, 'GW4064'])].
[sujeto(['Posttranslational', modifications]), verbo([regulating]), complemento([its, activity, have, not, been, investigated, yet])].
[sujeto(['Here,', we, demonstrate, that, 'calcium-dependent', protein, kinase, 'C', '(', 'PKC)', inhibition, impairs, 'ligand-mediated', regulation, of, 'FXR']), verbo([target]), complemento([genes])].
[sujeto(['Moreover,', in, a, transactivation, 'assay,', we, show, that, 'FXR', transcriptional, activity, is]), verbo([modulated]), complemento([by, 'PKC'])].
[sujeto(['Furthermore,', phorbol, 12, -, myristate, 13, -, acetate, ',', a, 'PKC', 'activator,']), verbo([induces]), complemento([the, phosphorylation, of, endogenous, 'FXR', in, 'HepG2', cells, and, 'PKCalpha', phosphorylates, in, vitro, 'FXR', in, its, 'DNA-binding', domain, on, 'S135', and, 'S154'])].
[sujeto(['In', contrast, to, 'wild-type', 'FXR,', mutant, 'FXRS135AS154A', displays, an, impaired, 'PKCalpha-induced', transactivation, and, a]), verbo([decreased]), complemento(['ligand-dependent', 'FXR', transactivation])].
[sujeto(['Finally,', phosphorylation, of, 'FXR', by, 'PKC']), verbo([promotes]), complemento([the, recruitment, of, peroxisomal, 'proliferator-activated', receptor, gamma, coactivator, 1, alpha])].
[sujeto(['In', 'conclusion,', these, findings, show, that, the, phosphorylation, of, 'FXR']), verbo([induced]), complemento([by, 'PKCalpha', directly, modulates, the, ability, of, agonists, to, activate, 'FXR'])].
[sujeto(['The', farnesoid, 'X', 'receptor/bile', acid, receptor, '(', 'FXR;', 'NR1H4)', is, a, 'ligand-activated', transcription, factor, that]), verbo([regulates]), complemento([bile, acid, and, lipid, 'homeostasis,', and, is, highly, expressed, in, enterohepatic, tissue])].
[sujeto(['FXR', is, also]), verbo([expressed]), complemento([in, vascular, tissue])].
[sujeto(['We']), verbo([have]), complemento([investigated, whether, 'FXR', regulates, inflammation, and, migration, in, vascular, smooth, muscle, cells])].
[sujeto(['The', 'FXR']), verbo([target]), complemento(['gene,', small, heterodimer, partner, '(', 'SHP),', was, induced, in, vascular, smooth, muscle, cells, after, treatment, with, synthetic, 'FXR', 'ligands,', 'GW4064,', or, 6, 'alpha-ethyl-chenodeoxycholic', acid])].
[sujeto(['FXR', ligands]), verbo([induced]), complemento([smooth, muscle, cell, death, and, downregulated, interleukin, '(', 'IL)-1beta-induced', inducible, nitric, oxide, synthase, and, 'cyclooxygenase-2', expression])].
[sujeto(['In', 'addition,', 'FXR', ligands]), verbo([suppressed]), complemento([smooth, muscle, cell, migration, stimulated, by, 'platelet-derived', growth, 'factor-BB'])].
[sujeto(['Reporter', gene, assays, showed, that, 'FXR', ligands]), verbo([activated]), complemento([an, 'FXR', reporter, gene, and, suppressed, 'IL-1beta-induced', nuclear, factor, '(', 'NF)-kappaB', activation, and, iNOS, in, a, manner, that, required, functional, 'FXR', and, 'SHP'])].
[sujeto(['Our', observations]), verbo([suggest]), complemento([that, a, 'FXR-SHP', pathway, may, be, a, novel, therapeutic, target, for, vascular, 'inflammation,', 'remodeling,', and, atherosclerotic, plaque, stability])].
[sujeto(['The']), verbo([nuclear]), complemento([receptor, 'FXRalpha', '(', 'NR1H4)', plays, a, pivotal, role, in, maintaining, bile, salt, and, lipid, homeostasis, by, functioning, as, a, bile, salt, sensor, in, mammals])].
[sujeto(['In', 'contrast,', 'FXRbeta', '(', 'NR1H5)', from, mouse, is]), verbo([activated]), complemento([by, lanosterol, and, does, not, share, common, ligands, with, 'FXRalpha'])].
[sujeto(['There', is, an, extra, sequence, in, the, middle, of, the, sFxr, ligand]), verbo([binding]), complemento([domain, '(', 'LBD)', compared, with, the, 'LBD', of, 'FXRalpha'])].
[sujeto(['Luciferase', reporter, assays, demonstrated, that, sFxr]), verbo([responds]), complemento([weakly, to, scymnol, 'sulfate,', bile, 'salts,', and, synthetic, 'FXRalpha', 'ligands,', in, striking, difference, from, human, 'FXRalpha', '(', 'hFXRalpha)'])].
[sujeto(['Together,', these, results, indicate, that, 'FXR', is, an, ancient]), verbo([nuclear]), complemento([receptor, and, suggest, that, 'FXRalpha', may, have, acquired, ligand, specificity, for, bile, acids, later, in, evolution, by, deletion, of, a, sequence, from, its, 'LBD'])].
[sujeto(['Acquisition', of, this, property, may, be, an, example, of, molecular, 'exploitation,', where, an, older, molecule, is]), verbo([recruited]), complemento([for, a, new, functional, role])].
[sujeto(['The', farnesoid, 'X', receptor, '(', 'FXR,', 'NR1H4)', is, a, bile, 'acid-responsive']), verbo([nuclear]), complemento([receptor, that, plays, critical, roles, in, the, transcriptional, regulation, genes, involved, in, 'cholesterol,', bile, 'acid,', 'triglyceride,', and, carbohydrate, metabolism])].
[sujeto(['By', microarray, analysis, of, hepatic, genes, from, female, 'Zucker', diabetic, fatty, '(', 'ZDF)', rats, treated, with, the, 'FXR', agonist, 'GW4064,', we]), verbo([have]), complemento([identified, dimethylarginine, 'dimethylaminohydrolase-1', '(', 'DDAH1)', as, an, 'FXR', target, gene])].
[sujeto(['Sequence', analysis, of, the, 'DDAH1', gene]), verbo([reveals]), complemento([the, presence, of, an, 'FXR', response, element, '(', 'FXRE)', located, 90, kb, downstream, of, the, transcription, initiation, site, and, within, the, first, intron])].
[sujeto(['Functional', analysis, of, the, putative, 'FXRE', demonstrated, 'GW4064', 'dose-dependent', transcriptional, activation, from, the, 'element,', and, we]), verbo([have]), complemento([demonstrated, that, the, 'FXRE', sequence, binds, the, 'FXR-RXR', heterodimer])].
[sujeto(['In', vivo, administration, of, 'GW4064', to, female, 'ZDF', rats]), verbo([promoted]), complemento([a, 'dose-dependent', and, &, 'gt;6-fold', increase, in, hepatic, 'DDAH1', gene, expression])].
[sujeto(['These', findings]), verbo([provide]), complemento([a, mechanism, by, which, 'FXR', may, increase, 'endothelium-derived', nitric, oxide, levels, through, modulation, of, serum, 'ADMA', levels, via, direct, regulation, of, hepatic, 'DDAH1', gene, expression])].
[sujeto(['Several', putative, 'FXR']), verbo([target]), complemento([genes, were, 'identified,', including, the, organic, solute, transporters, alpha, and, beta, '(', 'OSTalpha', and, 'OSTbeta)'])].
[sujeto(['These', 'FXREs', are]), verbo([conserved]), complemento([in, both, mouse, genes])].
[sujeto(['Treatment', of, 'wild-type', mice, with, 3, -, '(', 2, ',', 6, -, 'dichlorophenyl)-4-(3\'-carboxy-2-chloro-stilben-4-yl)-oxymethyl-5-isopropyl-isoxazole', '(', 'GW4064),', a, synthetic, 'FXR', 'agonist,']), verbo([induced]), complemento(['OSTalpha', and, 'OSTbeta', mRNAs, in, the, intestine, and, kidney])].
[sujeto(['Both', mRNAs, were, also]), verbo([induced]), complemento([when, 'wild-type,', but, not, 'FXR-deficient', '(', 'FXR-/-),', adrenals, were, cultured, in, the, presence, of, 'GW4064'])].
[sujeto(['OSTalpha', and, 'OSTbeta', mRNA, levels, were, also]), verbo([induced]), complemento([in, the, adrenals, and, kidneys, of, 'wild-type,', but, not, 'FXR-/-,', mice, after, the, increase, of, plasma, bile, acids, in, response, to, the, hepatotoxin, 'alpha-naphthylisothiocyanate'])].
[sujeto(['Finally,', overexpression, of, human, 'OSTalpha', and, 'OSTbeta', facilitated, the, uptake, of, conjugated, chenodeoxycholate, and, the, activation, of, 'FXR']), verbo([target]), complemento([genes])].
[sujeto(['These', results, demonstrate, that, 'OSTalpha', and, 'OSTbeta', are, novel, 'FXR']), verbo([target]), complemento([genes, that, are, expressed, in, the, adrenal, 'gland,', 'kidney,', and, intestine])].
[sujeto(['The', farnesoid, 'X', receptor, '(', 'FXR;', 'NR1H4)', is, a]), verbo([nuclear]), complemento([hormone, receptor, that, functions, as, the, bile, acid, receptor])].
[sujeto(['In', addition, to, the, critical, role, 'FXR', plays, in, bile, acid, metabolism, and, 'transport,', it]), verbo([regulates]), complemento([a, variety, of, genes, important, in, lipoprotein, metabolism])].
[sujeto(['Treatment', of, either, 'H4IIE', or, 'MH1C1', rat, hepatoma, cell, lines, as, well, as, primary, rat, or, human, hepatocytes, with, 'FXR', agonists]), verbo([led]), complemento([to, stimulation, of, 'PEPCK', mRNA, expression, to, levels, comparable, to, those, obtained, with, glucocorticoid, receptor, agonists])].
[sujeto(['In', addition, to]), verbo([inducing]), complemento(['PEPCK', expression, in, primary, 'hepatocytes,', 'FXR', agonists, stimulated, glucose, output, to, levels, comparable, to, those, observed, with, a, glucocorticoid, receptor, agonist])].
[sujeto(['Consistent', with, these, 'observations,', treatment, of, 'C57BL6', mice, with, 'GW4064', significantly]), verbo([increased]), complemento([hepatic, 'PEPCK', expression])].
[sujeto(['Activation', of, 'FXR', initiated, a, cascade]), verbo([involving]), complemento([induction, of, peroxisome, 'proliferator-activated', receptor, alpha, and, 'TRB3', expression, that, is, consistent, with, stimulation, of, 'PEPCK', gene, expression, via, interference, with, a, pathway, that, may, involve, 'Akt-dependent', phosphorylation, of, 'Forkhead/winged', helix, transcription, factor, '(', 'FOXO1)'])].
[sujeto(['The', 'FXR-peroxisome', 'proliferator-activated', receptor, 'alpha-TRB3', pathway, was]), verbo([conserved]), complemento([in, rat, hepatoma, cell, 'lines,', 'mice,', as, well, as, primary, human, hepatocytes])].
[sujeto(['Thus,', in, addition, to, its, role, in, the, regulation, of, lipid, 'metabolism,', 'FXR']), verbo([regulates]), complemento([carbohydrate, metabolism])].
[sujeto(['Syndecan-1', '(', 'SDC1),', a, transmembrane, heparan, sulfate, proteoglycan, that]), verbo([participates]), complemento([in, the, binding, and, internalization, of, extracellular, 'ligands,', was, identified, in, a, screen, designed, to, isolate, genes, that, are, regulated, by, the, farnesoid, 'X-receptor', '(', 'FXR,', 'NR1H4)'])].
[sujeto(['Treatment', of, human, hepatocytes, with, either, naturally, occurring, '(', chenodeoxycholic, 'acid)', or, synthetic, '(', 'GW4064)', 'FXR', ligands, resulted, in, both, induction, of, 'SDC1', mRNA, and]), verbo([enhanced]), complemento(['binding,', 'internalization,', and, degradation, of, low, density, lipoprotein])].
[sujeto(['Transient', transfection, 'assays,', using, 'wild-type', and, mutant, 'SDC1', 'promoter-luciferase', 'genes,']), verbo([led]), complemento([to, the, identification, of, a, nuclear, hormone, 'receptor-binding', hexad, arranged, as, a, direct, repeat, separated, by, one, nucleotide, '(', 'DR-1)', in, the, proximal, promoter, that, was, necessary, and, sufficient, for, activation, by, 'FXR'])].
[sujeto(['The', 'wild-type,', but, not, a, mutated, 'DR-1', 'element,']), verbo([conferred]), complemento(['FXR', responsiveness, to, a, heterologous, thymidine, kinase, 'promoter-reporter', gene])].
[sujeto(['Four', murine, 'FXR', isoforms]), verbo([have]), complemento([been, identified, recently, that, differ, either, at, their, amino, terminus, 'and/or', by, the, presence, or, absence, of, four, amino, acids, in, the, hinge, region])].
[sujeto(['Interestingly,', the, activities, of, the, human, 'SDC1', 'promoter-reporter', constructs, were, highly]), verbo([induced]), complemento([by, the, two, 'FXR', isoforms, that, do, not, contain, the, 'four-amino', acid, insert, and, were, unresponsive, to, the, isoforms, containing, the, four, amino, acids])].
[sujeto(['Thus,', current, studies, demonstrate, that, hepatic, 'SDC1', is]), verbo([induced]), complemento([in, an, 'FXR', 'isoform-specific', manner])].
[sujeto(['The', multidrug, 'resistance-associated', protein, 2, '(', 'MRP2,', 'ABCC2),']), verbo([mediates]), complemento([the, efflux, of, several, conjugated, compounds, across, the, apical, membrane, of, the, hepatocyte, into, the, bile, canaliculi])].
[sujeto(['We', identified, 'MRP2', in, a, screen, designed, to, isolate, genes, that, are]), verbo([regulated]), complemento([by, the, farnesoid, 'X-activated', receptor, '(', 'FXR,', 'NR1H4)'])].
[sujeto(['MRP2', mRNA, levels, were]), verbo([induced]), complemento([following, treatment, of, human, or, rat, hepatocytes, with, either, naturally, occurring, '(', chenodeoxycholic, 'acid)', or, synthetic, '(', 'GW4064)', 'FXR', ligands])].
[sujeto(['In', 'addition,', we]), verbo([have]), complemento([shown, that, 'MRP2', expression, is, regulated, by, the, pregnane, 'X', receptor, '(', 'PXR,', 'NR1I2)', and, constitutive, androstane, receptor, '(', 'CAR,', 'NR1I3)'])].
[sujeto(['PXR,', 'CAR,', and, 'FXR']), verbo([bound]), complemento([with, high, affinity, to, this, element, as, heterodimers, with, the, retinoid, 'X', receptor, alpha, '(', 'RXRalpha,', 'NR2B1)'])].
[sujeto(['Luciferase', activity, was]), verbo([induced]), complemento([in, a, 'PXR-,', 'CAR-,', or, 'FXR-dependent', manner])].
[sujeto(['Furthermore,', the, isolated, 'ER-8', element, was, capable, of]), verbo([conferring]), complemento(['PXR,', 'CAR,', and, 'FXR', responsiveness, on, a, heterologous, thymidine, kinase, promoter])].
[sujeto(['Mutation', of, the, 'ER-8', element, abolished, the]), verbo([nuclear]), complemento([receptor, response])].
[sujeto(['These', studies, demonstrate, that, 'MRP2', is]), verbo([regulated]), complemento([by, three, distinct, nuclear, receptor, signaling, pathways, that, converge, on, a, common, response, element, in, the, 5, '\'', -, flanking, region, of, this, gene])].
[sujeto(['Chemical', genomics, is, the, name, we]), verbo([have]), complemento([given, to, the, analysis, of, gene, function, through, use, of, small, molecule, chemical, tools])].
[sujeto(['Orphan']), verbo([nuclear]), complemento([receptors, are, ideally, suited, to, this, technique, of, functional, 'analysis,', since, their, activity, as, transcription, factors, is, regulated, by, small, hydrophobic, ligands])].
[sujeto(['GW4064', is, a, potent, and, selective, nonsteroidal, ligand, for, the]), verbo([nuclear]), complemento([bile, acid, receptor, 'FXR', '(', 'NR1H4)'])].
[sujeto(['Using', 'GW4064', as, a, chemical, 'tool,', we]), verbo([have]), complemento([identified, genes, regulated, by, 'FXR', in, the, 'liver,', including, those, involved, in, bile, acid, synthesis, and, transport])].
[sujeto(['We']), verbo([have]), complemento([also, discovered, that, 'PXR', '(', 'NR1I2)', is, a, lithocholic, acid, receptor, that, controls, the, biosynthesis, and, metabolism, of, bile, acids])].
[sujeto(['These', functions]), verbo([suggest]), complemento([that, potent, 'PXR', and, 'FXR', ligands, may, offer, a, new, approach, to, the, treatment, of, cholestatic, liver, disease])].
[sujeto(['As', a, novel, mediator, of, hepatic, very, 'low-density', lipoproteins, '(', 'VLDL)', 'secretion,', phospholipase, 'A2', 'G12B', '(', 'PLA2G12B)', is, transcriptionally]), verbo([regulated]), complemento([by, hepatocyte, nuclear, 'factor-4', alpha, '(', 'HNF-4α)'])].
[sujeto(['Farnesoid', 'X', receptor, '(', 'FXR)', plays, a, critical, role, in]), verbo([maintaining]), complemento([bile, acids, and, triglycerides, '(', 'TG)', homeostasis])].
[sujeto(['Here', we]), verbo([report]), complemento([that, 'FXR', regulates, serum, 'TG', level, in, part, through, 'PLA2G12B'])].
[sujeto(['Activation', of, 'FXR', by, chenodeoxycholic, acid, '(', 'CDCA)', or, 'GW4064', significantly]), verbo([decreased]), complemento(['PLA2G12B', expression, in, 'HepG2', cells])].
[sujeto(['PLA2G12B', expression, was, transcriptionally]), verbo([repressed]), complemento([due, to, an, 'FXR-mediated', 'up-regulation', of, small, heterodimer, partner, '(', 'SHP)', which, functionally, suppresses, 'HNF-4α', activity])].
[sujeto(['We']), verbo([found]), complemento([that, hepatic, 'PLA2G12B', expression, was, suppressed, and, serum, 'TG', level, reduced, in, high, fat, diet, mice, treated, with, 'CDCA'])].
[sujeto(['Our', data, demonstrate, that, activation, of, 'FXR']), verbo([promotes]), complemento(['TG', 'lowering,', not, only, by, decreasing, de, novo, lipogenesis, but, also, reducing, hepatic, secretion, of, 'TG-rich', 'VLDL', particles, in, part, through, suppressing, 'PLA2G12B', expression])].
[sujeto(['Several', 'isoxazole-containing', series, of, 'FXR', agonists]), verbo([have]), complemento([been, published, over, the, last, 15, 'years,', subsequent, to, the, prototypical, amphiphilic, '\'', 'hammerhead\'-type', structure, that, was, originally, laid, out, by, 'GW4064,', the, first, potent, synthetic, 'FXR', agonist])].
[sujeto(['The', resulting, compounds, all, demonstrated, high, potencies, at, the]), verbo([target]), complemento([receptor, 'FXR', but, with, considerable, differences, in, their, physicochemical, and, in, vivo, profiles])].
[sujeto(['The', 'structure-activity', relationships, for, key, chemical, features, that]), verbo([have]), complemento([a, major, impact, on, the, in, vivo, pharmacology, of, this, series, are, discussed])].
[sujeto(['HBV', enters, hepatocytes, by]), verbo([binding]), complemento([to, sodium, taurocholate, cotransporting, polypeptide, '(', 'NTCP),', the, genome, of, which, contains, 2, active, farnesoid, 'X', receptor, '(', 'FXR)', α, response, elements, that, participate, in, 'HBV', transcriptional, activity])].
[sujeto(['In', 'HepaRG', 'cells,', 'FXR', agonists, '(', 6, -, ethyl, chenodeoxycholic, acid, and, 'GW4064),', but, no, 'antagonist,', and, an, 'FXR-unrelated', bile, salt]), verbo([inhibited]), complemento([viral, 'mRNA,', 'DNA,', and, protein, production, '(', 'IC50,', 0.1, -, 0.5, 'μM)', and, reduced, covalently, closed, circular, 'DNA', pool, size])].
[sujeto(['These', effects, were, independent, of, the, 'NTCP', inhibitor, 'cyclosporine-A,', which]), verbo([suggests]), complemento([inhibition, occurred, at, a, postentry, step])].
[sujeto(['Infection', of, these, cells]), verbo([increased]), complemento([expression, of, 'FXR', and, modified, expression, of, 'FXR-regulated', genes, 'SHP,', 'APOA1,', 'NTCP,', 'CYP7A1,', and, 'CYP8B1', with, a, more, pronounced, effect, in, 'PHHs', than, in, 'HepaRG', cells])].
[sujeto(['In', the, present, 'study,', we, for, the, first, time, tested, the, effect, of, farnesoid, 'X', receptor, '(', 'FXR)', agonists, 'GW4064', and, 'CDCA', '(', chenodeoxycholic, 'acid)', in, combination, with, cisplatin, '(', 'CDDP)', on]), verbo([increasing]), complemento([the, chemosensitivity, in, 'BTC'])].
[sujeto(['Our', results, show, that, 'co-treatment', of, 'CDDP', with, 'FXR', agonists, remarkably]), verbo([enhance]), complemento([chemosensitivity, of, 'BTC', cells])].
[sujeto(['Mechanistically,', we]), verbo([found]), complemento([that, activation, of, 'FXR', induced, expression, of, small, heterodimer, partner, '(', 'SHP),', which, in, turn, inhibited, signal, transducer, and, activator, of, transcription, 3, '(', 'STAT3)', phosphorylation, and, resulted, in, 'down-regulation', of, 'Bcl-xL', expression, in, 'BTC', 'cells,', leading, to, increased, susceptibility, to, 'CDDP'])].
[sujeto(['Moreover,', the, experiments, on, 'tumor-bearing', mice, showed, that, 'GW4064/CDDP', 'co-treatment']), verbo([inhibited]), complemento([the, tumor, growth, in, vivo, by, 'up-regulating', 'SHP', expression, and, 'down-regulating', 'STAT3', phosphorylation])].
[sujeto(['These', results]), verbo([suggest]), complemento(['CDDP', in, combination, with, 'FXR', agonists, could, be, a, potential, new, therapeutic, strategy, for, 'BTC'])].
[sujeto(['Cholestasis', is, characterized, by, accumulation, of, bile, acids, and, 'inflammation,']), verbo([causing]), complemento([hepatocellular, damage])].
[sujeto(['Bile', acid, preconditioning, did, not]), verbo([induce]), complemento([significant, levels, of, necrosis, in, 'GCDCA-challenged', 'HepG2'])].
[sujeto(['GCDCA-,', 'CDCA-', and, 'GW4064-', preconditioning]), verbo([enhanced]), complemento(['ABCB11', mRNA, 'levels,', but, in, contrast, to, the, bile, 'acids,', 'GW4064', did, not, significantly, reduce, 'GCDCA-induced', 'caspase-3/7', activity])].
[sujeto(['The', 'GCDCA', challenge, strongly]), verbo([increased]), complemento([intracellular, levels, of, this, bile, 'acid,', which, was, not, lowered, by, 'GCDCA-preconditioning'])].
[sujeto(['As', an, important, regulator, of, the, crosstalk, between, breast, cancer, cells, and, 'CAFs,', the, cytokine, leptin]), verbo([has]), complemento([been, associated, to, breast, carcinogenesis])].
[sujeto(['The']), verbo([nuclear]), complemento(['Farnesoid', 'X', 'Receptor-(FXR)', seems, to, exert, an, oncosuppressive, role, in, different, 'tumors,', including, breast, cancer])].
[sujeto(['Herein,', we, 'demonstrated,', for, the, first, 'time,', that, the, synthetic, 'FXR', agonist, 'GW4064,']), verbo([inhibiting]), complemento([leptin, 'signaling,', affects, the, 'tumor-promoting', activities, of, 'CAFs', in, breast, malignancy])].
[sujeto(['GW4064']), verbo([inhibited]), complemento(['growth,', motility, and, invasiveness, induced, by, leptin, as, well, as, by, 'CAF-conditioned', media, in, different, breast, cancer, cell, lines])].
[sujeto(['These', effects, rely, on, the, ability, of]), verbo([activated]), complemento(['FXR', to, increase, the, expression, of, the, suppressor, of, the, cytokine, signaling, 3, '(', 'SOCS3)', leading, to, inhibition, of, 'leptin-activated', signaling, and, downregulation, of, 'leptin-target', genes])].
[sujeto(['Interestingly,', 'GW4064-treated', tumors, exhibited]), verbo([decreased]), complemento([levels, of, 'leptin-regulated', proteins, along, with, a, strong, staining, intensity, for, 'SOCS3'])].
[sujeto(['Thus,', 'FXR', ligands, might, represent, an, emerging, potential, 'anti-cancer', therapy, able, to, block, the, tumor, supportive, role, of]), verbo([activated]), complemento([fibroblasts, within, the, breast, microenvironment])].
[sujeto(['Vascular', farnesoid, 'X', receptor, '(', 'FXR)', ligands]), verbo([have]), complemento([been, shown, previously, to, regulate, vascular, tension])].
[sujeto(['This', study, investigated, whether, 'FXR', activation]), verbo([regulates]), complemento([vasoreactivity, via, the, angiotensin, 'II', '(', 'Ang', 'II)', type, 2, receptor, '(', 'AT2', 'R)', and, the, 'kallikrein-kinin', system, in, rat, aortic, vascular, endothelial, cells, '(', 'RAECs)'])].
[sujeto(['It', was]), verbo([found]), complemento([that, the, 'FXR', agonists, 'GW4064', and, 'INT-747,', in, a, 'dose-dependent', 'manner,', increased, the, protein, abundance, of, 'AT2', 'R,', 'B2', 'R', and, 'SHP-1', and, decreased, that, of, 'AT1', 'R'])].
[sujeto(['Moreover,', it, was]), verbo([found]), complemento([that, 'GW4064', and, 'INT-747', upregulated, expression, of, eNOS, and, enhanced, 'NOS', 'activity,', which, attenuated, vasoconstriction, and, induced, 'vasodilation,', respectively])].
[sujeto(['The', current, work]), verbo([suggests]), complemento([that, 'FXR', regulates, vascular, tension, by, controlling, the, 'eNOS-NO', system, via, activation, of, a, pathway, mediated, by, 'AT2', 'R-B2', 'R', pathway, in, 'RAECs'])].
[sujeto(['To', assess, the, effect, of, farnesoid, 'X', receptor, '(', 'FXR),', a, bile, acid]), verbo([nuclear]), complemento(['receptor,', on, renal, proximal, tubular, 'cells,', primary, cultured, mouse, kidney, proximal, tubular, cells, were, treated, with, 'GW4064', '(', a, 'FXR', 'agonist)', or, 'DMSO', '(', as, 'controls)', overnight])].
[sujeto(['Analysis', of, gene, expression, in, the, proximal, tubular, cells, by, whole, genome, microarrays, indicated, that, 'FXR', activation]), verbo([induced]), complemento([genes, involved, in, fatty, acid, degradation, and, oxidation, reduction])].
[sujeto(['Among', 'them,', genes]), verbo([involved]), complemento([in, glutathione, metabolism, were, mostly, induced])].
[sujeto(['Here', we, describe, in, details, the, contents, and, quality, controls, for, the, gene, expression, and, related, results]), verbo([associated]), complemento([with, the, data, uploaded, to, 'Gene', 'Expression', 'Omnibus', '(', accession, number, 'GSE70296)'])].
[sujeto(['The', farnesoid, 'X', receptor, '(', 'FXR)']), verbo([regulates]), complemento([bile, 'acid,', lipid, and, glucose, metabolism])].
[sujeto(['Here', we, show, that, treatment, of, mice, with, 'glycine-β-muricholic', acid, '(', 'Gly-MCA)']), verbo([inhibits]), complemento(['FXR', signalling, exclusively, in, 'intestine,', and, improves, metabolic, parameters, in, mouse, models, of, obesity])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'Gly-MCA', may, be, a, candidate, for, the, treatment, of, metabolic, disorders])].
[sujeto(['Thus,']), verbo([loss]), complemento([of, nutrition, caused, by, serum, starvation, in, cells, could, induce, formation, of, reactive, oxygen, species, '(', 'ROS),', resulting, in, cell, death])].
[sujeto(['This', study, investigated, the, effect, of, 'LQ,', metformin, '[', an, activator, of]), verbo([activated]), complemento(['AMP-activated', protein, kinase, '(', 'AMPK)]', and, 'GW4064', '[', a, ligand, of, farnesoid, 'X', receptor, '(', 'FXR)]', on, mitochondrial, dysfunction, and, oxidative, stress, induced, by, serum, deprivation, as, well, as, its, molecular, 'mechanism,', as, assessed, by, immunoblot, and, flow, cytometer, assays])].
[sujeto(['Serum', deprivation, in, 'HepG2,', 'H4IIE', and, 'AML12', cells, successfully]), verbo([induced]), complemento([oxidative, stress, and, 'apoptosis,', as, indicated, by, depletion, of, 'glutathione,', formation, of, 'ROS,', and, altered, expression, of, 'apoptosis-related', proteins, such, as, 'procaspase-3,', 'poly(ADP-ribose)', 'polymerase,', and, 'Bcl-2'])].
[sujeto(['However,', 'LQ', pretreatment, significantly, blocked, these, pathological, changes, and, mitochondrial, dysfunction]), verbo([caused]), complemento([by, serum, deprivation])].
[sujeto(['Moreover,', 'LQ']), verbo([activated]), complemento(['AMPK', in, 'HepG2', cells, and, mice, 'liver,', as, shown, by, phosphorylation, of, 'AMPK', and, 'ACC,', and, this, activation, was, mediated, by, its, upstream, kinase, '(', i])].
[sujeto(['Experiments', using, a, chemical, inhibitor, of, 'AMPK', with, 'LKB1-deficient', 'Hela', cells, revealed, the, role, of, the, 'LKB1-AMPK', pathway, in, cellular, protection]), verbo([conferred]), complemento([by, 'LQ'])].
[sujeto(['LQ', also]), verbo([induced]), complemento([protein, and, mRNA, expression, of, both, 'FXR', as, well, as, small, heterodimer, 'partner,', which, is, important, since, treatment, with, 'FXR', ligand, 'GW4064', protected, hepatocytes, against, cell, death, and, mitochondrial, damage, induced, by, serum, deprivation])].
[sujeto(['AMPK', activators, such, as, 'LQ', can, protect, hepatocytes, against, oxidative, hepatic, injury, and, mitochondrial, dysfunction]), verbo([induced]), complemento([by, serum, 'deprivation,', and, the, beneficial, effect, might, be, mediated, through, the, 'LKB1', pathway, as, well, as, 'FXR', induction])].
[sujeto(['Maternal', obesity, is]), verbo([associated]), complemento([with, dysregulation, of, glucose, and, lipid, metabolism, with, consequent, exposure, of, the, fetus, to, an, abnormal, metabolic, milieu])].
[sujeto(['It', is]), verbo([recognized]), complemento([that, maternal, obesity, predisposes, offspring, to, chronic, kidney, disease, '(', 'CKD)'])].
[sujeto(['We', aimed, to, determine, whether, the]), verbo([nuclear]), complemento(['Farnesoid', 'X', receptor, '(', 'FXR),', known, to, play, a, role, in, maintaining, homeostasis, of, glucose, and, lipid, 'metabolism,', is, involved, in, renal, injury, in, offspring, of, obese, mothers])].
[sujeto(['Glucose', intolerance, in, the, offspring, of, obese, mothers, was, evident, at, 'weaning,', with]), verbo([associated]), complemento([downregulation, of, renal, 'FXR', expression, and, upregulation, of, monocyte, chemoattractant, 'protein-1', '(', 'MCP-1)', and, transforming, growth, 'factor-β1', '(', 'TGF-β1)'])].
[sujeto(['HK2', cells, exposed, to, high, glucose, had, reduced, 'FXR', expression, and]), verbo([increased]), complemento(['MCP-1,', 'TGF-β1,', fibronectin, and, collagen, 'IV', 'expression,', which, was, reversed, in, the, presence, of, 'GW4064'])].
[sujeto(['This', was]), verbo([associated]), complemento([with, the, downregulation, of, the, renal, 'FXR', expression, suggesting, a, potential, protective, role, for, 'FXR'])].
[sujeto(['An', area, of]), verbo([increasing]), complemento([interest, is, metabolic, 'reprogramming,', whereby, 'drug-induced', alterations, in, the, metabolic, landscape, of, a, tumour, slow, tumour, growth, 'and/or', increase, sensitivity, to, existing, therapeutics])].
[sujeto(['Nuclear', receptors, are, transcription, factors, central, to, the, expression, of, metabolic, and, transport, 'proteins,', and, thus, represent, potential]), verbo([targets]), complemento([for, metabolic, reprogramming])].
[sujeto(['We', show, that, activation, of, the]), verbo([nuclear]), complemento([receptor, 'FXR,', either, by, its, endogenous, ligand, 'CDCA', or, the, synthetic, 'GW4064,', leads, to, cell, death, in, four, breast, cancer, cell, lines, with, distinct, 'phenotypes:', 'MCF-10A', '(', 'normal),', 'MCF-7', '(', receptor, 'positive),', 'MDA-MB-231', and, 'MDA-MB-468', '(', triple, 'negative)'])].
[sujeto(['Finally,', we, demonstrate, that, 'FXR', agonists, do, not]), verbo([stimulate]), complemento([migration, in, breast, cancer, cell, 'lines,', an, important, potential, adverse, effect])].
[sujeto(['The', bile, acid, '(', 'BA)-sensing']), verbo([nuclear]), complemento(['receptor,', farnesoid, 'X', receptor, '(', 'FXR),', regulates, postprandial, metabolic, 'responses,', including, inhibition, of, 'BA', 'synthesis,', by, inducing, the, intestinal, 'hormone,', fibroblast, growth, factor, '(', 'FGF)15', '(', 'FGF19', in, 'human)'])].
[sujeto(['In', this, 'study,', we, tested, a, novel, hypothesis, that, 'FXR', not, only]), verbo([induces]), complemento([intestinal, 'FGF15', but, also, primes, the, liver, for, effectively, responding, to, the, signal, by, transcriptional, induction, of, the, obligate, coreceptor, for, 'FGF15,', 'β-Klotho', '(', 'βKL)'])].
[sujeto(['Activation', of, 'FXR', by, a, synthetic, 'agonist,', 'GW4064,', in, mice]), verbo([increased]), complemento([occupancy, of, 'FXR', and, its, 'DNA-binding', 'partner,', retinoid, 'X', 'receptor-α,', at, 'FGF15-signaling', component, 'genes,', particularly, 'βKL,', and, induced, expression, of, these, genes])].
[sujeto(['Interestingly,', mRNA, levels, of, 'Fgfr4,', the, 'FGF15', 'receptor,', were, not]), verbo([increased]), complemento([by, 'GW4064,', but, protein, levels, increased, as, a, result, of, 'βKL-dependent', increased, protein, stability])].
[sujeto(['Both', 'FGF', receptor, 4, and, βKL, protein, levels, were, substantially]), verbo([decreased]), complemento([in, 'FXR-knockout', '(', 'KO)', 'mice,', and, 'FGF19', 'signaling,', monitored, by, phosphorylated, 'ERK,', was, blunted, in, 'FXR-KO', 'mice,', 'FXR-KO', mouse, 'hepatocytes,', and, 'FXR-down-regulated', human, hepatocytes])].
[sujeto(['In', 'mice,', transient, inductions, of, intestinal, 'Fgf15', and, hepatic, βKL, were, temporally, correlated, after, 'GW4064', 'treatment,', and, pretreatment, of, hepatocytes, with, 'GW4064', before, 'FGF19', treatment]), verbo([enhanced]), complemento(['FGF19', 'signaling,', which, was, abolished, by, transcriptional, inhibition, or, βKL, 'down-regulation'])].
[sujeto(['Visfatin,', a, recently, discovered, 'adipocytokine,']), verbo([has]), complemento([been, shown, to, have, an, important, role, in, the, pathogenesis, of, diabetic, nephropathy, '(', 'DN)'])].
[sujeto(['The', farnesoid, 'X', receptor, '(', 'FXR),', a, 'ligand-activated']), verbo([nuclear]), complemento(['receptor,', plays, a, protective, role, in, 'DN'])].
[sujeto(['The', regulation, between, 'FXR', and, visfatin, and, their, interaction, in, 'DN']), verbo([has]), complemento([not, been, well, established])].
[sujeto(['In', this, 'study,', we]), verbo([reported]), complemento([that, 'FXR', agonist, 'GW4064', reduced, high, glucose, induced, human, mesangial, cells, '(', 'HMCs)', 'inflammation,', fibrosis, and, proliferation, by, downregulating, visfatin, 'expression,', which, can, be, blunted, by, exogenous, visfatin, treatment])].
[sujeto(['Moreover,', luciferase, reporter, assay, showed, 'FXR']), verbo([regulated]), complemento([visfatin, transcription, activity, probably, by, binding, to, the, -, 1607, bp, and, -, 1192, bp, region, of, the, visfatin, promoter])].
[sujeto(['In', vivo, study, also, showed, that, 'GW4064', ameliorated, the, progression, of, 'DN', in, 'db/db', mice, with, a]), verbo([decreased]), complemento([visfatin, expression])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'FXR', activation, delayed, the, progression, of, diabetic, nephropathy, and, this, effect, is, through, downregulating, visfatin])].
[sujeto(['Suppressor', of, cytokine, signaling, 3, '(', 'SOCS3)', is, regarded, as, a, vital, repressor, in, the, liver, carcinogenesis, mainly, by]), verbo([inhibiting]), complemento([signal, transducer, and, activator, of, transcription, 3, '(', 'STAT3)', activity])].
[sujeto(['Farnesoid', 'X', 'Receptor', '(', 'FXR),', highly]), verbo([expressed]), complemento([in, 'liver,', has, an, important, role, in, protecting, against, hepatocellular, carcinoma, '(', 'HCC)'])].
[sujeto(['However,', it, is, unclear, whether, the, tumor, suppressive, activity, of, 'FXR']), verbo([involves]), complemento([the, regulation, of, 'SOCS3'])].
[sujeto(['In', the, present, 'study,', we]), verbo([found]), complemento([that, activation, of, 'FXR', by, its, specific, agonist, 'GW4064', in, 'HCC', cells, inhibited, cell, 'growth,', induced, cell, cycle, arrest, at, 'G1', 'phase,', elevated, p21, expression, and, repressed, 'STAT3', activity])].
[sujeto(['Reporter', assay, revealed, that, 'FXR', activation]), verbo([enhanced]), complemento([the, transcriptional, activity, of, 'SOCS3', promoter])].
[sujeto(['Electrophoretic', mobility, shift, assay, '(', 'EMSA)', and, chromatin, immunoprecipitation, '(', 'ChIP)', assay, displayed, that, 'FXR', directly]), verbo([bound]), complemento([to, 'IR9', 'DNA', motif, within, 'SOCS3', promoter, region])].
[sujeto(['The', in, vivo, study, in, nude, mice, showed, that, treatment, with, 'FXR', ligand, 'GW4064', could, decelerate, the, growth, of, 'HCC', 'xenografts,', 'up-regulate', 'SOCS3', and, p21, expression, and]), verbo([inhibit]), complemento(['STAT3', phosphorylation, in, the, xenografts])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, induction, of, 'SOCS3', may, be, a, novel, mechanism, by, which, 'FXR', exerts, its, 'anti-HCC', 'effects,', and, the, 'FXR-SOCS3', signaling, may, serve, as, a, new, potential, target, for, the, 'prevention/treatment', of, 'HCC'])].
[sujeto(['The', farnesoid, 'X', receptor, '(', 'FXR)', signaling, pathway, is, known, to, be]), verbo([involved]), complemento([in, the, metabolism, of, bile, 'acid,', glucose, and, lipid])].
[sujeto(['In', the, present, 'study,', we, demonstrated, that, 400, &, 'nbsp;µmol/l', deoxycholic, acid, '(', 'DCA)', stimulation]), verbo([promotes]), complemento([the, proliferation, of, normal, human, gastric, epithelial, cells, '(', 'GES-1)'])].
[sujeto(['In', 'addition,', 'DCA']), verbo([activated]), complemento(['FXR', and, increased, the, expression, of, intestinal, metaplasia, 'genes,', including, 'caudal-related', homeobox, transcription, factor, 2, '(', 'Cdx2)', and, 'mucin 2', '(', 'MUC2)'])].
[sujeto([also, 'enhanced/reduced', the]), verbo([nuclear]), complemento(['factor-κB', '(', 'NF-κB)', activity, and, binding, of, the, 'Cdx2', promoter, region, and, 'NF-κB,', the, most, common, subunit, p50, protein])].
[sujeto(['Taken', 'together,', the, results, indicated, that, 'DCA', is, capable, of]), verbo([modulating]), complemento([the, expression, of, 'Cdx2', and, the, downstream, 'MUC2', via, the, nuclear, receptor, 'FXR-NF-κB', activity, in, normal, gastric, epithelial, cells])].
[sujeto(['FXR', signaling, pathway, may, therefore, be]), verbo([involved]), complemento([in, the, intestinal, metaplasia, of, human, gastric, mucosa])].
[sujeto([',']), verbo([has]), complemento([multiple, pharmacological, 'properties,', including, 'anti-inflammatory,', 'immune-modulatory,', and, 'anti-proliferative', activities])].
[sujeto(['The', expression, of, 'FXR', and, its]), verbo([target]), complemento([genes, were, detected, by, 'Western', blot, and, 'qRT-PCR'])].
[sujeto(['The', transient, overexpression, of, 'FXR', protected, against, 'triptolide-induced', cell, 'death,', whereas, 'FXR', knockdown, with, a, specific, small, interfering, 'RNA', resulted, in]), verbo([increased]), complemento([cytotoxicity])].
[sujeto(['Moreover,', the, livers, of, 'GW4064-treated', mice, showed]), verbo([increased]), complemento([expression, of, 'FXR', and, several, related, target, genes, involved, in, phase, 'II', and, phase, 'III', xenobiotic, metabolism])].
[sujeto(['Taken', 'together,', these, results, indicate, that, activation, of, 'FXR', attenuates, 'triptolide-induced', hepatotoxicity, and]), verbo([provide]), complemento([direct, implications, for, the, development, of, novel, therapeutic, strategies, against, 'triptolide-induced', hepatotoxicity])].
[sujeto(['Farnesoid', 'X', receptor, α, '(', 'FXRα)', as, a, bile, acid, sensor, plays, potent, roles, in, multiple, metabolic, 'processes,', and, its, antagonist]), verbo([has]), complemento([recently, revealed, special, interests, in, the, treatment, of, metabolic, 'disorders,', although, the, underlying, mechanisms, still, remain, unclear])].
[sujeto(['Here,', we, identified, that, the, small, molecule, 'N-benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino)', benzamide, '(', 'NDB)', functioned, as, a, selective, antagonist, of, human, 'FXRα', '(', 'hFXRα),', and, the, crystal, structure, of, hFXRα, ligand]), verbo([binding]), complemento([domain, '(', 'hFXRα-LBD)', in, complex, with, 'NDB', was, analyzed])].
[sujeto(['It', was, unexpectedly, discovered, that, 'NDB']), verbo([induced]), complemento([rearrangements, of, helix, 11, '(', 'H11)', and, helix, 12, '(', 'H12,', 'AF-2)', by, forming, a, homodimer, of, 'hFXRα-LBD,', totally, different, from, the, active, conformation, in, monomer, 'state,', and, the, binding, details, were, further, supported, by, the, mutation, analysis])].
[sujeto(['Moreover,', functional, studies, demonstrated, that, 'NDB', effectively, antagonized, the, 'GW4064-stimulated', 'FXR/RXR', interaction, and, 'FXRα']), verbo([target]), complemento([gene, expression, in, primary, mouse, 'hepatocytes,', including, the, small, heterodimer, partner, '(', 'SHP)', and, 'bile-salt', export, pump, '(', 'BSEP);', 'meanwhile,', administration, of, 'NDB', to, 'db/db', mice, efficiently, decreased, the, gene, expressions, of, phosphoenolpyruvate, carboxykinase, '(', 'PEPCK),', glucose, 6, -, phosphatase, '(', 'G6-pase),', small, heterodimer, 'partner,', and, 'BSEP'])].
[sujeto(['It', is, expected, that, our, first, analyzed, crystal, structure, of, 'hFXRα-LBD·NDB', will, help, expound, the, antagonistic, mechanism, of, the, 'receptor,', and, 'NDB', may]), verbo([find]), complemento([its, potential, as, a, lead, compound, in, 'anti-diabetes', research])].
[sujeto(['We']), verbo([found]), complemento([that, chenodeoxy, cholic, acid, '(', 'CDCA)', reduced, the, amount, of, 'HIF-1α', protein, only, under, physiological, hypoxia, but, not, under, severe, hypoxia, without, decreasing, its, mRNA, level])].
[sujeto(['By', using, a, proteasome, inhibitor, 'MG132', and, a, translation, inhibitor, 'cyclohexamide,', we, showed, that, 'CDCA', reduced, 'HIF-1α', protein, by]), verbo([decreasing]), complemento([its, translation, but, not, by, enhancing, its, degradation])].
[sujeto(['The', following, findings, indicated, that, farnesoid, 'X', receptor, '(', 'FXR),', a, 'CDCA', receptor, and, its]), verbo([target]), complemento(['gene,', 'Small', heterodimer, partner, '(', 'SHP)', are, not, involved, in, this, effect, of, 'CDCA'])].
[sujeto(['Distinctly', from, 'CDCA,', 'MG132']), verbo([prevented]), complemento(['SHP', and, an, exogenous, 'FXR', 'agonist,', 'GW4064', from, reducing, 'HIF-1α', protein])].
[sujeto(['Furthermore', a, 'FXR', 'antagonist,', guggulsterone, failed, to]), verbo([prevent]), complemento(['CDCA', from, decreasing, 'HIF-1α', protein])].
[sujeto(['These', findings]), verbo([suggested]), complemento([that, 'CDCA', and, guggulsterone, reduced, the, translation, of, 'HIF-1α', in, a, mechanism, which, 'FXR', and, 'SHP', are, not, involved])].
[sujeto(['This', study]), verbo([reveals]), complemento([novel, therapeutic, functions, of, traditional, nontoxic, 'drugs,', 'CDCA', and, 'guggulsterone,', as, inhibitors, of, 'HIF-1α', protein])].
[sujeto(['It', is, a, highly, polymorphic, enzyme, and, subject, to, marked, inhibition, by, a, number, of, 'drugs,']), verbo([causing]), complemento([a, large, interindividual, variability, in, drug, clearance, and, drug, response, and, 'drug-drug', interactions])].
[sujeto(['The', expression, and, activity, of, 'CYP2D6', are]), verbo([regulated]), complemento([by, a, number, of, 'physiological,', pathological, and, environmental, factors, at, 'transcriptional,', 'post-transcriptional,', translational, and, epigenetic, levels])].
[sujeto(['DNA', hypermethylation, and, histone, modifications, can]), verbo([repress]), complemento([the, expression, of, 'CYP2D6'])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento(['factor-4α', binds, to, a, directly, repeated, element, in, the, promoter, of, 'CYP2D6', and, thus, regulates, the, expression, of, 'CYP2D6'])].
[sujeto(['Small', heterodimer, partner]), verbo([represses]), complemento([hepatocyte, nuclear, 'factor-4α-mediated', transactivation, of, 'CYP2D6'])].
[sujeto(['GW4064,', a, farnesoid, 'X', receptor, 'agonist,']), verbo([decreases]), complemento([hepatic, 'CYP2D6', expression, and, activity, while, increasing, small, heterodimer, partner, expression, and, its, recruitment, to, the, 'CYP2D6', promoter])].
[sujeto(['Recent', 'genome-wide', association, studies]), verbo([have]), complemento([identified, a, large, number, of, genes, that, can, regulate, 'CYP2D6'])].
[sujeto(['Pregnancy']), verbo([induces]), complemento(['CYP2D6', via, unknown, mechanisms])].
[sujeto(['Renal', or, liver, 'diseases,', smoking, and, alcohol, use]), verbo([have]), complemento([minor, to, moderate, effects, only, on, 'CYP2D6', activity])].
[sujeto(['Post-translational', modifications, such, as, phosphorylation, of, 'CYP2D6', 'Ser135']), verbo([have]), complemento([been, 'observed,', but, the, functional, impact, is, unknown])].
[sujeto(['Further', functional, and, validation, studies, are, needed, to, clarify, the, role, of]), verbo([nuclear]), complemento(['receptors,', epigenetic, factors, and, other, factors, in, the, regulation, of, 'CYP2D6'])].
[sujeto(['TGR5', is, known, to]), verbo([regulate]), complemento([the, 'BA', homeostasis, and, energy, metabolism])].
[sujeto(['Here', we]), verbo([report]), complemento([that, 'TGR5', is, involved, in, mediating, the, 'anti-obesity', and, 'anti-hyperglycemia', effect, of, a, natural, 'compound,', oleanolic, acid])].
[sujeto(['By', comparing, the, miRNA, profiles, between, wild, type, and, 'TGR5-/-', livers, after, 'OA', 'treatment,', we, identified, 'miR-26a', as, a, novel, downstream]), verbo([target]), complemento([gene, of, 'TGR5', activation])].
[sujeto(['The', expression, of, 'miR-26a', in, the, liver, was]), verbo([induced]), complemento([in, a, 'TGR5-dependent', manner, after, feeding, the, mice, with, a, bile, acid, diet])].
[sujeto(['TGR5', activation, strongly]), verbo([increased]), complemento([the, expression, of, 'miR-26a', in, 'macrophages,', including, the, 'Kupffer', cells, in, the, liver])].
[sujeto(['We', further, demonstrated, that, 'JNK', pathway, was]), verbo([required]), complemento([for, 'miR-26a', induction, by, 'TGR5', activation])].
[sujeto(['These', results, unravel, a, new, mechanism, by, which, bile, acid, receptor, 'TGR5']), verbo([activates]), complemento([a, miRNA, gene, expression])].
[sujeto(['Farnesoid', 'X', receptor, '(', 'FXR)', functions, as, a, regulator, of, bile, acid, and, lipid, homeostasis, and, is]), verbo([recognized]), complemento([as, a, promising, therapeutic, target, for, metabolic, diseases])].
[sujeto(['The', biologic, function, of, 'FXR', is]), verbo([mediated]), complemento([in, part, by, a, small, heterodimer, partner, '(', 'SHP);', 'ligand-activated', 'FXR', enhances, 'SHP', 'expression,', and, 'SHP', in, turn, represses, the, activity, of, multiple, transcription, factors])].
[sujeto(['In', human, 'hepatocytes,', treatment, of, 'GW4064', '(', 1, 'μM)', for, 48, hours, resulted, in, a, 75, '%']), verbo([decrease]), complemento([in, 'CYP3A4', mRNA, expression, and, a, 25, '%', decrease, in, 'CYP3A4', 'activity,', accompanied, by, '∼3-fold', increase, in, 'SHP', mRNA, expression])].
[sujeto(['In', 'HepG2', 'cells,', 'SHP']), verbo([repressed]), complemento([transactivation, of, 'CYP3A4', promoter, by, pregnane, 'X', receptor, '(', 'PXR),', constitutive, androstane, receptor, '(', 'CAR),', and, glucocorticoid, receptor])].
[sujeto(['Interestingly,', 'GW4064', did, not]), verbo([repress]), complemento([expression, of, 'CYP2B6,', another, target, gene, of, 'PXR', and, 'CAR;', 'GW4064', enhanced, 'CYP2B6', promoter, activity])].
[sujeto(['In', 'conclusion,', 'GW4064']), verbo([represses]), complemento(['CYP3A4', expression, in, human, 'hepatocytes,', potentially, through, upregulation, of, 'SHP', expression, and, subsequent, repression, of, 'CYP3A4', promoter, activity])].
[sujeto(['Clinically', significant, 'drug-drug', interaction]), verbo([involving]), complemento(['FXR', agonists, and, 'CYP3A4', substrates, may, occur])].
[sujeto(['FXR', is]), verbo([activated]), complemento([by, bile, 'acids,', 'RXRα', by, the, vitamin, 'A-derivative', 9, -, cis, retinoic, acid, '(', 9, 'cRA)'])].
[sujeto(['Remarkably,', 9, cRA]), verbo([inhibits]), complemento([binding, of, 'FXR/RXRα', to, its, response, 'element,', an, inverted, 'repeat-1', '(', 'IR-1)'])].
[sujeto(['Still,', most, 'FXR/RXRα']), verbo([target]), complemento([genes, are, maximally, expressed, in, the, presence, of, both, 'ligands,', including, the, small, heterodimer, partner, '(', 'SHP)'])].
[sujeto([hSHP, promoter, elements, lacking, the, previously, identified, 'IR-1', '(', -, 291, /, -, 279, ')', largely]), verbo([maintained]), complemento([their, activation, by, 'FXR/CDCA,', but, were, unresponsive, to, 9, cRA])].
[sujeto(['Pull', down, assays, revealed, a, direct]), verbo([binding]), complemento([of, 'FXR', to, the, -, 122, /, -, 69, 'sequence,', which, was, abrogated, by, 'site-specific', mutations, in, a, binding, site, for, the, liver, receptor, 'homolog-1', '(', 'LRH-1)', at, -, 78, /, -, 70])].
[sujeto(['LRH-1', did, not]), verbo([increase]), complemento(['FXR/RXRα-mediated', activation, of, hSHP, promoter, activity])].
[sujeto(['FXR/CDCA-activated', expression, of, 'SHP', is, primarily]), verbo([mediated]), complemento([through, direct, binding, to, an, 'LRH-1', binding, 'site,', which, is, not, modulated, by, 'LRH-1', and, unresponsive, to, 9, cRA])].
[sujeto([9, 'cRA-induced', expression, of, 'SHP']), verbo([requires]), complemento([the, 'IR-1', that, overlaps, with, a, direct, 'repeat-2', '(', 'DR-2)', and, 'DR-4'])].
[sujeto(['Hepatitis', 'B', virus, '(', 'HBV)', genome, transcription, is, highly, dependent, on, 'liver-enriched,', metabolic]), verbo([nuclear]), complemento([receptors, '(', 'NRs)'])].
[sujeto(['Among', 'others,', 'NR', farnesoid, 'X', receptor, α, '(', 'FXRα)']), verbo([enhances]), complemento(['HBV', core, promoter, activity, and, pregenomic, 'RNA', synthesis])].
[sujeto(['Interestingly,', two, 'food-withdrawal-induced', 'FXRα', 'modulators,', peroxisome, 'proliferator-activated', 'receptor-γ', coactivator, 1, α, '(', 'PGC-1α)', and, deacetylase, 'SIRT1,']), verbo([have]), complemento([been, found, to, be, associated, with, 'HBV', genomes, ex, vivo])].
[sujeto(['Whereas', 'PGC-1α', induction, was, shown, to]), verbo([increase]), complemento(['HBV', 'replication,', the, effect, of, 'SIRT1', on, 'HBV', transcription, remains, unknown])].
[sujeto(['Here,', we, showed, 'that,', in, 'hepatocarcinoma-derived', 'Huh-7', 'cells,', combined, activation, of, 'FXRα', by, 'GW4064', and, 'SIRT1', by, activator, 3]), verbo([increased]), complemento(['HBV', core, 'promoter-controlled', luciferase, expression, by, 25, -, 'fold,', compared, with, a, 10, -, fold, increase, with, 'GW4064', alone])].
[sujeto(['Using', cell, lines, differentially]), verbo([expressing]), complemento(['FXRα', in, overexpression, and, silencing, 'experiments,', we, demonstrated, that, 'SIRT1', activated, the, core, promoter, in, an, 'FXRα-', and, 'PGC-1α-dependent', manner])].
[sujeto(['Thus,', we, identified, a, subnetwork, of, metabolic, factors]), verbo([regulating]), complemento(['HBV', 'replication,', strengthening, the, hypothesis, that, transcription, of, 'HBV', and, metabolic, genes, is, similarly, controlled])].
[sujeto(['The', phenotype, of, male, knockout, mice, for, the, 'NaS1', sodium, sulfate, cotransporter, includes, hyposulfatemia, and]), verbo([increased]), complemento([hepatic, expression, of, mouse, cytoplasmic, sulfotransferase, 'Sult2a', and, 'Sult3a1'])].
[sujeto(['Here', we]), verbo([report]), complemento([that, in, 8, -, 'week-old', female, 'NaS1-null', 'mice,', hepatic, 'Sult2a1', mRNA, levels, were, '∼51-fold', higher, than, they, were, in, a, 'wild-type', liver, but, expression, of, no, other, 'Sult', was, affected])].
[sujeto(['When', a, reporter, plasmid, containing, at, least, 233, nucleotides, '(', 'nt)', of, 'Sult2a1', 5, '\'', -, flanking, sequence, was, transfected, into, 'shPAPSS1/2', 'cells,', reporter, activity, was, significantly]), verbo([increased]), complemento([relative, to, the, activity, that, was, seen, for, reporters, containing, 179, or, fewer, nucleotides])].
[sujeto(['Mutation', of, an, 'IR0', '(', inverted, repeat, of, 'AGGTCA,', with, 0, intervening, 'bases)']), verbo([nuclear]), complemento([receptor, motif, at, nt, -, 191, to, 180, significantly, attenuated, the, 'PAPSS1/2', 'knockdown-mediated', increase])].
[sujeto(['PAPSS1/2', knockdown, significantly]), verbo([activated]), complemento([farnesoid, 'X', receptor, '(', 'FXR),', 'retinoid-related', orphan, 'receptor,', and, pregnane, 'X', receptor, responsive, 'reporters,', and, treatment, with, the, 'FXR', agonist, 'GW4064', '[', 3, -, '(', 2, ',', 6, -, 'dichlorophenyl)-4-(3\'-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole]', increased, 'Sult2a1', promoter, activity, when, the, 'IR0', was, intact])].
[sujeto(['We', propose, that, hyposulfatemia]), verbo([leads]), complemento([to, hepatic, 'PAPS', 'depletion,', which, causes, loss, of, 'SULT2A1', activity, and, results, in, accumulation, of, nonsulfated, bile, acids, and, 'FXR', activation])].
[sujeto(['Because', of, the, 'anti-inflammatory', actions, of, farnesoid, 'X', receptor, '(', 'FXR)', 'agonists,', 'FXR']), verbo([has]), complemento([received, much, attention, as, a, potential, therapeutic, target])].
[sujeto(['However,', the, molecular, mechanisms, of, actions]), verbo([have]), complemento([not, yet, been, elucidated])].
[sujeto(['In', the, present, 'study,', we]), verbo([reported]), complemento([that, in, the, animal, model, of, 'LPS-induced', liver, 'injury,', administration, of, the, 'FXR', natural, ligand, 'CDCA', could, attenuate, hepatocyte, inflammatory, 'damage,', reduce, transaminase, 'activities,', suppress, inflammation, mediators, '(', 'IL-6,', 'TNF-α', and, 'ICAM-1)', expression, and, inhibit, 'STAT3', phosphorylation])].
[sujeto(['These', protective, effects, of, 'FXR', were, accompanied, by, an]), verbo([increased]), complemento([expression, of, suppressor, of, cytokine, signaling, 3, '(', 'SOCS3),', which, is, a, negative, feedback, regulator, of, 'cytokine-STAT3', signaling])].
[sujeto(['Moreover', we, observed, both, natural, ligand, 'CDCA', and, synthetic, ligand, 'GW4064', could, upregulate, 'SOCS', 3, expression, by]), verbo([enhancing]), complemento([the, promoter, activity, in, hepatocytes])].
[sujeto(['These', results]), verbo([suggest]), complemento([modulation, of, 'SOCS3', expression, may, represent, a, novel, mechanism, through, which, 'FXR', activation, could, selectively, affect, cytokine, bioactivity, in, inflammation, response])].
[sujeto(['Emerging', evidence, indicates, that]), verbo([nuclear]), complemento([receptors, play, a, critical, regulatory, role, in, cardiovascular, 'physiology/pathology'])].
[sujeto(['Recently,', 'farnesoid-X-receptor', '(', 'FXR),', a, member, of, the, metabolic]), verbo([nuclear]), complemento([receptor, 'superfamily,', has, been, demonstrated, to, be, expressed, in, vascular, 'cells,', with, important, roles, in, vascular, 'physiology/pathology'])].
[sujeto(['Natural', and, synthetic, 'FXR', agonists, upregulated, cardiac, 'FXR', 'expression,']), verbo([stimulated]), complemento([myocyte, 'apoptosis,', and, reduced, myocyte, viability, 'dose-', and, 'time-dependently'])].
[sujeto(['Pharmacological', inhibition, or, genetic, ablation, of, 'FXR', significantly, reduced, myocardial, apoptosis, by, 29.0, -, 53.4, '%', ',']), verbo([decreased]), complemento([infarct, size, by, 23.4, -, 49.7, '%', ',', and, improved, cardiac, function, in, 'ischaemic/reperfused', myocardium])].
[sujeto(['These', results, demonstrate, that]), verbo([nuclear]), complemento([receptor, 'FXR', acts, as, a, novel, functional, receptor, in, cardiac, 'tissue,', regulates, apoptosis, in, 'cardiomyocytes,', and, contributes, to, 'MI/R', injury])].
[sujeto(['Bile', acids, are]), verbo([recognized]), complemento([as, metabolic, modulators])].
[sujeto(['Oral', administration, of, 264, 'W94', for, two, wk]), verbo([increased]), complemento([fecal, bile, acid, concentrations, and, elevated, 'non-fasting', plasma, total, 'Glp-1'])].
[sujeto(['Treatment', of, 264, 'W94', significantly]), verbo([decreased]), complemento(['HbA1c', and, 'glucose,', and, prevented, the, drop, of, insulin, levels, typical, of, 'ZDF', rats, in, a, 'dose-dependent', manner])].
[sujeto(['An', oral, glucose, tolerance, test, revealed, up, to, 'two-fold']), verbo([increase]), complemento([in, plasma, total, 'Glp-1', and, 'three-fold', increase, in, insulin, in, 264, 'W94', treated, 'ZDF', rats, at, doses, sufficient, to, achieve, glycemic, control])].
[sujeto(['Tissue', mRNA, analysis, indicated, a]), verbo([decrease]), complemento([in, farnesoid, 'X', receptor, '(', 'Fxr)', activation, in, small, intestines, and, the, liver, but, 'co-administration', of, a, 'Fxr', agonist, '(', 'GW4064)', did, not, attenuate, 264, 'W94', induced, glucose, lowering, effects])].
[sujeto(['In', 'summary,', our, results, demonstrate, that, inhibition, of, 'Asbt']), verbo([increases]), complemento([bile, acids, in, the, distal, 'intestine,', promotes, 'Glp-1', release, and, may, offer, a, new, therapeutic, strategy, for, type, 2, diabetes, mellitus])].
[sujeto(['The', 'Farnesoid', 'X', 'Receptor', '(', 'FXR)', is, a, bile, acids, sensor, and, member, of, the]), verbo([nuclear]), complemento([receptor, superfamily])].
[sujeto(['Activation', of, 'FXR', lowers, plasma, triacylglycerols, and, glucose, levels, through, a, mechanism, that]), verbo([involves]), complemento([both, the, repression, of, key, regulatory, genes, in, the, liver, and, the, modulation, of, insulin, sensitivity, in, peripheral, tissues])].
[sujeto(['In', the, present, study, we]), verbo([have]), complemento([investigated, whether, administering, obese, '(', 'fa/fa)', 'Zucker', 'rats,', a, genetic, model, of, obesity, associated, with, dyslipidemia, and, insulin, 'resistance,', with, an, 'FXR', ligand, protects, against, 'lipid-induced', cardiomyopathy])].
[sujeto(['FXR', is]), verbo([expressed]), complemento([in, neonatal, cardiomyocytes, and, the, treatment, with, 'FXR', 'agonists,', chenodeoxycholic, acid, '(', 'CDCA),', and, 'GW4064,', increased, the, mRNA, expression, of, 'FXR', and, its, canonical, target, 'gene,', the, small, heterodimer, partner, '(', 'SHP),', as, well, as, 'proliferator-activated', receptor, alpha, 'PPARα,', 'acyl-CoA', oxidase, '(', 'AOX)', and, pyruvate, dehydrogenase, kinase, '(', 'PDK-4)'])].
[sujeto(['The', 'histological-pathological', analysis, of, hearts, demonstrated, that, treatment, with, the, 'FXR', ligand, reduced, lipid, heart, content]), verbo([decreased]), complemento([the, rate, of, 'apoptosis,', fibrosis, scores, and, restored, heart, insulin, signalling])].
[sujeto(['Chronic', 'CDCA', 'administration,', in, the, 'heart,']), verbo([induced]), complemento(['PPARα', and, 'PPARα-regulated', genes, involved, in, 'β-oxidation'])].
[sujeto(['The', striking, benefit, of, this, therapy, on, cardiac, function, in, this, model, warrants, an, effort, to, determine, whether, a, counterpart, of, this, activity]), verbo([translates]), complemento([in, human, settings])].
[sujeto(['The', aim, of, this, study, was, to, identify, novel, lymphatic, 'metastasis-associated', markers, and, therapeutic]), verbo([targets]), complemento([for, pancreatic, cancer])].
[sujeto(['DNA', microarray, study, was, carried, out, to, identify, genes, differentially]), verbo([expressed]), complemento([between, 17, pancreatic, cancer, tissues, with, lymph, node, metastasis, and, 17, pancreatic, cancer, tissues, without, lymph, node, metastasis])].
[sujeto(['Farnesoid', 'X', receptor, overexpression, in, pancreatic, cancer, tissues, with, lymph, node, metastasis, is]), verbo([associated]), complemento([with, poor, patient, survival])].
[sujeto(['Moreover,', 'GW4064-mediated', 'FXR', activation]), verbo([increased]), complemento([cell, migration, and, invasion])].
[sujeto(['Sirtuin', 1, '(', 'SIRT1)', is, a, 'NAD-dependent', deacetylase, that, is, critically]), verbo([involved]), complemento([in, diverse, cellular, processes, including, metabolic, 'disease,', 'cancer,', and, possibly, aging])].
[sujeto(['Despite', extensive, studies, on, 'SIRT1', 'function,', how, 'SIRT1', levels, are]), verbo([regulated]), complemento([remains, relatively, unknown])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, the, nuclear, bile, acid, receptor, farnesoid, 'X', receptor, '(', 'FXR)', inhibits, 'microRNA-34a', '(', 'miR-34a)', in, the, 'liver,', which, results, in, a, positive, regulation, of, 'SIRT1', levels])].
[sujeto(['Activation', of, 'FXR', by, the, synthetic, agonist, 'GW4064']), verbo([decreases]), complemento([hepatic, 'miR-34a', levels, in, normal, 'mice,', and, 'consistently,', hepatic, 'miR-34a', levels, are, elevated, in, 'FXR-null', mice])].
[sujeto(['FXR']), verbo([induces]), complemento([expression, of, small, heterodimer, partner, '(', 'SHP),', an, orphan, nuclear, receptor, and, transcriptional, 'corepressor,', which, in, turn, results, in, repression, of, 'p53,', a, key, activator, of, the, 'miR-34a', 'gene,', by, inhibiting, p53, occupancy, at, the, promoter])].
[sujeto(['MiR-34a']), verbo([decreased]), complemento(['SIRT1', levels, by, binding, to, the, 3, '\'', -, untranslated, region, of, 'SIRT1', 'mRNA,', and, 'adenovirus-mediated', overexpression, of, 'miR-34a', substantially, decreased, 'SIRT1', protein, levels, in, mouse, liver])].
[sujeto(['Remarkably,', 'miR-34a', levels, were, 'elevated,', and, 'SIRT1', protein, levels, were, reduced, in, 'diet-induced', obese, 'mice,', and, 'FXR', activation, in, these, mice, reversed, the, 'miR-34a', and, 'SIRT1', 'levels,', indicating, an, intriguing, link, among, 'FXR', 'activation,']), verbo([decreased]), complemento(['miR-34a,', and, 'subsequently,', increased, 'SIRT1', levels])].
[sujeto(['Our', study, demonstrates, an, unexpected, role, of, the, 'FXR/SHP', pathway, in, controlling, 'SIRT1', levels, via, 'miR-34a', inhibition, and, that, elevated, 'miR-34a', levels, in, obese, mice, contribute, to]), verbo([decreased]), complemento(['SIRT1', levels])].
[sujeto(['Essential', fatty, acid, '(', 'EFA)', deficiency, in, mice]), verbo([has]), complemento([been, associated, with, increased, bile, 'production,', which, is, mainly, determined, by, the, enterohepatic, circulation, '(', 'EHC)', of, bile, salts])].
[sujeto(['To', establish, the, mechanism, underlying, the]), verbo([increased]), complemento([bile, 'production,', we, characterized, in, detail, the, 'EHC', of, bile, salts, in, 'EFA-deficient', mice, using, stable, isotope, 'technique,', without, interrupting, the, normal, 'EHC'])].
[sujeto(['Farnesoid', 'X', receptor, '(', 'FXR)']), verbo([has]), complemento([been, proposed, as, an, important, regulator, of, bile, salt, synthesis, and, homeostasis])].
[sujeto(['EFA', 'deficiency-enhanced', bile, flow, and, biliary, bile, salt, secretion, were]), verbo([associated]), complemento([with, elevated, bile, salt, pool, size, and, synthesis, rate, '(', +, 146, and, +, 42, '%', ',', 'respectively,', 'P', &, 'lt;', 0.05, ')', ',', despite, increased, ileal, bile, salt, reabsorption, '(', +, 228, '%', ',', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['Bile', flow, and, biliary, secretion, were]), verbo([enhanced]), complemento([to, the, same, extent, in, 'EFA-deficient', 'wild-type', and, 'Fxr(-/-)', 'mice,', indicating, contribution, of, other, factors, besides, 'FXR', in, regulation, of, 'EHC', during, 'EFA', deficiency])].
[sujeto(['In', 'conclusion,', our, data, indicate, that, 'EFA', deficiency, is]), verbo([associated]), complemento([with, interrupted, negative, feedback, of, bile, salt, 'synthesis,', possibly, because, of, reduced, ileal, 'Fgf15', expression])].
[sujeto(['Farnesoid', 'X', receptor, '(', 'FXR)', is, a, bile, 'acid-sensing']), verbo([nuclear]), complemento([receptor, that, controls, bile, acid, homeostasis])].
[sujeto(['It']), verbo([has]), complemento([been, suggested, that, downregulation, of, 'FXR', contributes, to, the, pathogenesis, of, an, inherited, disorder, of, bile, secretion, caused, by, mutations, in, 'ATP8B1'])].
[sujeto(['We']), verbo([have]), complemento([investigated, the, relationship, between, 'ATP8B1', knockdown, and, 'FXR', downregulation, in, the, human, hepatoblastoma, cell, line, 'HepG2'])].
[sujeto(['Transfection', of, 'HepG2', cells, with, 'ATP8B1', small, interfering, 'RNA', '(', 'siRNA)', duplexes]), verbo([led]), complemento([to, a, 60, '%', reduction, in, the, endogenous, levels, of, 'ATP8B1', mRNA, and, protein, and, a, concomitant, decrease, in, 'FXR', mRNA, and, protein, 'content,', as, well, as, in, 'FXR', phosphorylation])].
[sujeto(['This']), verbo([decrease]), complemento([was, accompanied, by, a, marked, reduction, in, mRNA, levels, of, a, subset, of, 'FXR', 'targets,', such, as, bile, salt, export, pump, '(', 'ABCB11),', small, heterodimer, 'partner,', and, uridine, 5, '\'', -, 'diphosphate-glucuronosyltransferase'])].
[sujeto(['ATP8B1', inhibition, specifically]), verbo([targeted]), complemento(['FXR', since, mRNA, expression, of, other, prominent, nuclear, 'receptors,', such, as, pregnane, 'X', receptor, and, constitutive, androstane, 'receptor,', or, 'liver-enriched', transcription, 'factors,', such, as, hepatocyte, nuclear, factor, 1, alpha, '(', 'HNF-1alpha)', and, 'HNF-4alpha,', was, not, altered])].
[sujeto(['The', expression, of, other, key, genes]), verbo([involved]), complemento([in, bile, acid, 'synthesis,', 'detoxification,', and, transport, also, remained, unchanged, upon, 'ATP8B1', knockdown])].
[sujeto(['Supporting', the, specificity, of, the, 'effect,', 'siRNA-mediated', silencing, of, 'ABCB11,', whose, defect, is]), verbo([associated]), complemento([with, another, inherited, disorder, of, bile, 'secretion,', did, not, affect, 'FXR', expression])].
[sujeto(['Treatment', with, the, synthetic, 'FXR', agonist, 'GW4064', was, able, to, partially, neutralize, 'ATP8B1', 'siRNA-mediated', 'FXR', downregulation, and, fully, counteract, inhibition, of, 'FXR']), verbo([target]), complemento([genes])].
[sujeto(['The', farnesoid, 'X', receptor, '(', 'FXR),', a, member, of, the]), verbo([nuclear]), complemento([hormone, receptor, 'superfamily,', plays, an, essential, role, in, the, regulation, of, enterohepatic, circulation, and, lipid, homeostasis])].
[sujeto(['In', this, 'study,', we]), verbo([report]), complemento([that, two, synthetic, 'FXR', 'agonists,', 'WAY-362450', and, 'GW4064,', suppressed, 'interleukin-6-induced', 'CRP', expression, in, human, 'Hep3B', hepatoma, cells])].
[sujeto(['Knockdown', of, 'FXR', by, short, interfering, 'RNA', attenuated, the, inhibitory, effect, of, the, 'FXR', agonists, and, also]), verbo([increased]), complemento([the, ability, of, 'interleukin-6', to, induce, 'CRP', production])].
[sujeto(['These', data]), verbo([provide]), complemento([new, evidence, for, direct, 'anti-inflammatory', properties, of, 'FXR'])].
[sujeto(['Mouse', fibroblast, growth, factor, 15, '(', 'FGF15)', and, human, ortholog, 'FGF19']), verbo([have]), complemento([been, identified, as, the, bile, 'acid-induced', intestinal, factors, that, mediate, bile, acid, feedback, inhibition, of, cholesterol, 7, 'alpha-hydroxylase', gene, '(', 'C', 'YP7A1)', transcription, in, mouse, liver])].
[sujeto(['Chenodeoxycholic', acid, '(', 'CDCA)', and, the, farnesoid, 'X', receptor, '(', 'FXR)-specific', agonist, 'GW4064', strongly]), verbo([induced]), complemento(['FGF19', but, inhibited, 'CYP7A1', messenger, 'RNA', '(', 'mRNA)', levels, in, primary, human, hepatocytes])].
[sujeto(['FGF19', strongly, and, rapidly]), verbo([repressed]), complemento(['CYP7A1', but, not, small, heterodimer, partner, '(', 'SHP)', mRNA, levels])].
[sujeto(['Kinase', inhibition, and, phosphorylation, assays, revealed, that, the, 'mitogen-activated', protein, 'kinase/extracellular', 'signal-regulated', kinase, 1, /, 2, '(', 'MAPK/Erk1/2)', pathway, played, a, major, role, in]), verbo([mediating]), complemento(['FGF19', inhibition, of, 'CYP7A1'])].
[sujeto(['Interestingly,', 'CDCA']), verbo([stimulated]), complemento([tyrosine, phosphorylation, of, the, 'FGF', receptor, 4, '(', 'FGFR4)', in, hepatocytes])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, bile, 'acid-activated', 'FXR', is, able, to, induce, 'FGF19', in, hepatocytes, to, inhibit, 'CYP7A1', by, an, 'autocrine/paracrine', mechanism])].
[sujeto(['The', hepatic, 'FGF19/FGFR4/Erk1/2', pathway, may]), verbo([inhibit]), complemento(['CYP7A1', independent, of, 'SHP'])].
[sujeto(['In', addition, to]), verbo([inducing]), complemento(['FGF19', in, the, 'intestine,', bile, acids, in, hepatocytes, may, activate, the, liver, 'FGF19/FGFR4', signaling, pathway, to, inhibit, bile, acid, synthesis, and, prevent, accumulation, of, toxic, bile, acid, in, human, livers])].
[sujeto(['Particularly', little, information, is, available, about, a, role, of]), verbo([nuclear]), complemento([receptors, in, the, regulation, of, decorin, expression])].
[sujeto(['In', the, present, 'study,', we]), verbo([report]), complemento([that, activation, of, vascular, 'FXR', by, a, specific, ligand, resulted, in, upregulation, of, decorin, at, the, levels, of, both, mRNA, and, protein])].
[sujeto(['FXR', appears, to]), verbo([induce]), complemento([decorin, expression, at, a, transcriptional, level, because, '(', 1, ')', upregulation, of, decorin, mRNA, expression, was, abolished, by, the, treatment, of, a, transcription, 'inhibitor,', actinomycin, 'D;', and, '(', 2, ')', decorin, promoter, activity, was, significantly, increased, by, activation, of, 'FXR'])].
[sujeto(['Functional', analysis, of, human, decorin, promoter, identified, an, imperfect, inverted, repeat, 'DNA', 'motif,', 'IR8', '(', -, 2313, 'TGGTCAtagtgtcaTGACCT-2294),', as, a, likely, 'FXR-responsive', element, that, is]), verbo([involved]), complemento([in, decorin, regulation])].
[sujeto(['During', fasting, and, in, type, 'I', 'diabetes,', elevated, levels, of, peroxisome, 'proliferator-activated', receptor, 'gamma-coactivator-1alpha', '(', 'PGC-1alpha)']), verbo([induce]), complemento([expression, of, the, 'Cyp7A1', gene, and, overexpression, of, 'PGC-1alpha', in, hepatoma, cells, stimulates, bile, acid, synthesis])].
[sujeto(['Using', 'Ad-PGC-1alpha-RNA', interference, to]), verbo([induce]), complemento([acute, disruption, of, 'PGC-1alpha', in, 'mice,', here, we, show, that, 'PGC-1alpha', is, necessary, for, 'fasting-mediated', induction, of, 'CYP7A1'])].
[sujeto(['Co-immunoprecipitation', and, promoter, activation, studies]), verbo([reveal]), complemento([that, the, induction, of, 'CYP7A1', is, mediated, by, direct, interaction, between, 'PGC-1alpha', and, the, 'AF2', domain, of, liver, receptor, 'homolog-1', '(', 'LRH-1)'])].
[sujeto(['We', also, show, that, transactivation, of, 'PGC-1alpha', and, 'LRH-1', is]), verbo([repressed]), complemento([by, the, small, heterodimer, partner, '(', 'SHP)'])].
[sujeto(['Treatment', of, mice, with, 'GW4064,', a, synthetic, agonist, for, farnesoid, 'X', 'receptor,']), verbo([induced]), complemento(['SHP', expression, and, decreased, both, the, recruitment, of, 'PGC-1alpha', to, the, 'Cyp7A1', promoter, and, the, 'fasting-induced', expression, of, 'CYP7A1', mRNA])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'PGC-1alpha', is, an, important, 'co-activator', for, 'LRH-1', and, that, 'SHP', targets, the, interaction, between, 'LRH-1', and, 'PGC-1alpha', to, inhibit, 'CYP7A1', expression])].
[sujeto(['Overall,', these, studies]), verbo([provide]), complemento([further, evidence, for, the, important, role, of, 'PGC-1alpha', in, bile, acid, homeostasis, and, suggest, that, pharmacological, targeting, of, farnesoid, 'X', receptor, in, vivo, can, be, used, to, reverse, the, increase, in, 'CYP7A1', associated, with, adverse, metabolic, conditions])].
[sujeto(['The', transcription, of, the, gene, '(', 'CYP7A1)', encoding, cholesterol, 7, 'alpha-hydroxylase,', a, key, enzyme, in, cholesterol, 'homeostasis,', is]), verbo([repressed]), complemento([by, bile, acids, via, multiple, mechanisms, involving, members, of, the, nuclear, receptor, superfamily])].
[sujeto(['Here,', we, describe, a, regulatory, mechanism, that, can, be, exploited, for]), verbo([modulating]), complemento([bile, acid, synthesis])].
[sujeto(['By', dissecting, the, mechanisms, of, 'CYP7A1', 'transcription,', we]), verbo([found]), complemento([that, bile, acids, stimulate, the, sequential, recruitment, of, the, histone, deacetylases, '(', 'HDACs)', 7, ',', 3, ',', and, 1, ',', and, of, the, corepressor, 'SMRTalpha', '(', silencing, mediator, of, retinoid, and, thyroid, 'receptors-alpha)', and, the, nuclear, corepressor])].
[sujeto(['Bile', 'acids,', but, not, the, farnesoid, 'X', 'receptor-selective', agonist, 'GW4064,']), verbo([increase]), complemento([the, nuclear, concentration, of, 'HDAC7,', which, promotes, the, assembly, of, a, repressive, complex, that, ultimately, represses, 'CYP7A1', transcription])].
[sujeto(['Interestingly,', despite, its, high, basal, expression, 'level,', small, heterodimer, partner, '(', 'SHP)', is]), verbo([associated]), complemento([with, the, 'CYP7A1', promoter, only, at, a, later, stage, of, bile, acid, repression])].
[sujeto(['Gene', silencing, with, small, interfering, 'RNA', confirms, that, 'HDAC7', is, the, key, factor]), verbo([required]), complemento([for, the, repression, of, 'CYP7A1', 'transcription,', whereas, knockdown, of, 'SHP', does, not, prevent, the, 'down-regulation', of, 'CYP7A1'])].
[sujeto(['Administration', of, the, 'HDAC', inhibitors, valproic, acid, or, trichostatin, 'A', to, genetically, hypercholesterolemic, mice]), verbo([increases]), complemento(['Cyp7a1', messenger, 'RNA', and, bile, acid, synthesis, and, consequently, markedly, reduces, total, plasma, and, 'low-density', lipoprotein, cholesterol])].
[sujeto(['By', using, a, combination, of, 'molecular,', 'cellular,', and, animal, 'models,', our, study, highlights, the, importance, of, 'HDACs', in, the, feedback, regulation, of, 'CYP7A1', transcription, and, identifies, these, enzymes, as, potential]), verbo([targets]), complemento([to, modulate, bile, acid, synthesis, and, for, the, treatment, of, hypercholesterolemia])].
[sujeto(['All', root, canal, sealers]), verbo([induced]), complemento([the, expression, of, 'MMP-2', in, 'MRC5', fibroblasts])].
[sujeto(['AH', 'Plus', had, the, highest, cytotoxicity, amongst, the, tested, 'sealers,', but, all, were]), verbo([associated]), complemento([with, cytotoxic, effects])].
[sujeto(['White', smoke, inhalation, is, an, uncommon, but, potentially, deadly]), verbo([cause]), complemento([of, acute, lung, injury])].
[sujeto(['No', clinical, spectrum, or, treatment, protocol]), verbo([have]), complemento([been, developed])].
[sujeto(['Twenty-five', percent, of, these, patients, had, severe, acute, lung, injury]), verbo([requiring]), complemento([artificial, ventilation, support])].
[sujeto(['The', intrinsic]), verbo([cause]), complemento([of, thymic, involution, is, still, undefined])].
[sujeto(['However,', transgenic, 'mice,', with]), verbo([increased]), complemento(['GC', sensitivity, and, over, expression, of, 'GC', 'receptors,', display, delayed, 'age-associated', thymic, involution])].
[sujeto(['This', fact]), verbo([suggests]), complemento([that, other, substances, may, affect, thymic, involution])].
[sujeto(['Among', 'them,', both, isoforms, of, metallothioneins, '(', 'MTs)', 'I+II', and, 'III', are, the, major, candidates, because, their, increments]), verbo([leads]), complemento([to, organ, atrophy, in, constant, stress, and, are, induced, by, 'IL-6,', which, increases, in, ageing])].
[sujeto(['Enhanced', 'MTs', in, ageing, allows, constant, sequester, of, zinc, ions, and, no, subsequent, zinc]), verbo([release]), complemento([leading, to, low, zinc, ion, bioavailability, for, thymic, efficiency])].
[sujeto(['Thus,', we]), verbo([have]), complemento([investigated, the, 'MTmRNA', '(', 'I+II', and, 'III)', in, the, thymus, from, 'young,', old, and, very, old, mice])].
[sujeto(['RESULTS:', 'Both', isoforms, of, 'MTmRNA', and, 'IL-6mRNA']), verbo([increase]), complemento([in, old, thymus, coupled, with, low, zinc, ion, 'bioavailability,', reduced, 'TECs', 'proliferation,', impaired, thymulin, activity, and, enhanced, plasma, corticosterone, in, comparison, with, young])].
[sujeto(['Concomitantly,', good, zinc, ion, 'bioavailability,']), verbo([maintained]), complemento(['TECs', 'proliferation,', satisfactory, thymulin, activity, and, reduced, corticosterone, are, observed, in, very, old, mice])].
[sujeto(['CONCLUSIONS:', 'The', concomitant, increments, by, high, 'IL-6', of, both, 'MT', isoforms, in, the, thymus, from, old, mice, may, be]), verbo([involved]), complemento([in, thymic, involution, because, provoking, low, zinc, ion, 'bioavailability,', which, is, relevant, for, thymic, efficiency])].
[sujeto(['By', 'contrast,', the, limited, increments, of, 'MTs', by, low, 'IL-6']), verbo([induce]), complemento([good, zinc, ion, bioavailability, and, satisfactory, thymic, efficiency, in, very, old, mice])].
[sujeto(['Therefore,', abnormal]), verbo([increased]), complemento(['MTs', may, provoke, complete, thymic, involution, during, ageing, and, the, possible, appearance, of, 'age-related', diseases])].
[sujeto(['Nitric', oxide, '(', 'NO)', is, a, potent, intercellular, mediator, of, 'melanogenesis,', whereas, metallothionein, '(', 'MT)', is, an, inducible, intracellular, antioxidant, that]), verbo([has]), complemento([been, reported, to, scavenge, 'NO'])].
[sujeto(['Further,', an, 'NO-stimulated']), verbo([increase]), complemento([of, tyrosinase, activity, in, melanocytes, was, remarkably, 'suppressed,', when, 'MT', was, induced, prior, to, 'NO', stimulation])].
[sujeto(['Melanogenesis', was, also, 'suppressed,', when, dexamethasone, was, used, to]), verbo([induce]), complemento(['MT'])].
[sujeto(['However,', an, 'NO-stimulated']), verbo([increase]), complemento([of, tyrosinase, expression, was, not, suppressed, at, the, gene, and, protein, 'level,', when, 'MT', was, induced, in, melanocytes])].
[sujeto(['Melanosome', fractions, were, prepared, from, 'melanocytes,', whose, melanogenesis, was]), verbo([suppressed]), complemento([by, the, induction, of, 'MT'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'MT', induction, may, be, effective, to, suppress, melanogenesis, stimulated, by, 'NO', as, well, as, other, 'melanogens,', and, these, suppressive, effects, might, be, due, to, a, direct, inhibition, of, tyrosinase, activity, in, melanosome, and, not, a, scavenging, effect, of, 'NO'])].
[sujeto(['They', are, rich, in, 'sulphur--20', residues, for, 'cysteine,', are]), verbo([found]), complemento([in, cytosol, and, nuclei, of, eucaryotic, cells])].
[sujeto(['MT-I', and, 'MT-II', are]), verbo([found]), complemento([in, all, animal, 'tissues,', 'MT-III', and, 'MT-IV--in', the, brain])].
[sujeto(['MT', molecule]), verbo([involve]), complemento([two, 'domains,', alpha, and, beta])].
[sujeto(['MT', gene, promoter]), verbo([have]), complemento([response, elements, to, metals, '(', 'MRE),', to, glucocorticoids, '(', 'GRE)', and, to, oxidative, 'agents,', electrophilic, compounds, and, xenobiotics, '(', 'ARE)'])].
[sujeto(['Expression', and, synthesis, of, 'MT', are]), verbo([induced]), complemento([for, heavy, metals, '(', 'Zn,', 'Cu,', 'Cd', and, so, 'Hg,', 'Pb,', 'As,', 'Ni,', 'Ag', a])].
[sujeto(['Other', inductors]), verbo([act]), complemento([more, or, less, actively, as, 'stress-agents'])].
[sujeto(['Zinc', stabilizes, 'MT', 'molecule,']), verbo([enhances]), complemento([some, of, their, functional, activities, as, a, scavenger, of, metal, 'ions,', of, free, 'radicals,', toxins, and, xenobiotics])].
[sujeto(['All', extracts, of, 'N2', completely]), verbo([inhibited]), complemento([cell, metabolism, '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['Similar', effects, were]), verbo([provoked]), complemento([by, the, first, three, eluates, of, 'Endomethasone,', but, the, 24, -, h, extract, irritated, cells, significantly, less, '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['A', significant, inhibition, of, mitochondrial, activity, was]), verbo([induced]), complemento([by, the, first, '(', 3, 'T3)', or, the, first, and, second, eluate, '(', periodontal, ligament, 'fibroblasts)', of, 'AH', 'Plus', '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['The', subsequent, eluates, of, this, sealer, and, all, extracts, of, 'Apexit', did, not]), verbo([reveal]), complemento([any, cytotoxic, potency])].
[sujeto(['Pronounced', cytotoxic, effects, were, only]), verbo([caused]), complemento([by, 'N2-extracts', in, both, cell, cultures, '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['Furthermore,', statistically, significant, cytotoxic, alterations, were, also]), verbo([induced]), complemento([by, 10, -, week, eluates, of, 'Endomethasone', '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['Enzyme', 'activity,', reflected, by, the, rate, of, conversion, of, cortisol, to, 'cortisone,', was, inactivated, by, 'NEM', '(', 'IC(50)=10', 'microM),', while, the, activity, was, markedly]), verbo([increased]), complemento([by, the, sulfhydryl, protecting, reagent, dithiothreitol, '(', 'DTT;', 'EC(50)=1', 'mM)'])].
[sujeto(['Taken', 'together,', these, results]), verbo([suggested]), complemento([that, the, sulfhydryl, '(', 'SH)', 'group(s)', of, the, microsomal, 11, 'beta-HSD2', may, be, critical, for, enzyme, activity])].
[sujeto([5, 'microM),', but, through, a, novel, mechanism, not]), verbo([involving]), complemento([the, 'SH', groups])].
[sujeto(['In', 'addition,', prior, incubation, of, human, placental, microsomes, with, 'NAD(+)', '(', 'cofactor)', but, not, cortisol, '(', 'substrate)', resulted, in, a, 'concentration-dependent']), verbo([increase]), complemento(['(', 'EC(50)=8', 'microM)', in, 11, 'beta-HSD2', 'activity,', indicating, that, binding, of, 'NAD(+)', to, the, microsomal, 11, 'beta-HSD2', facilitated, the, conversion, of, cortisol, to, cortisone])].
[sujeto(['Thus,', this]), verbo([finding]), complemento([substantiates, the, previously, proposed, concept, that, a, compulsorily, ordered, ternary, complex, mechanism, may, operate, for, 11, 'beta-HSD2,', with, 'NAD(+)', binding, 'first,', followed, by, a, conformational, change, allowing, cortisol, binding, with, high, affinity])].
[sujeto(['Collectively,', the, present, results]), verbo([suggest]), complemento([that, cellular, mechanisms, of, 'SH', group, modification, and, intracellular, levels, of, 'Zn(2+)', may, play, an, important, role, in, regulation, of, placental, 11, 'beta-HSD2', activity])].
[sujeto(['It']), verbo([has]), complemento([been, hypothesized, that, they, play, a, role, in, the, function, of, 'zinc-dependent', signal, transduction, proteins, and, transcription, factors])].
[sujeto(['We', investigated, the, capacity, of, zinc, and, other, metal, ions, and, conditions, to]), verbo([increase]), complemento([both, 'Zn-associated', 'MT', levels, and, the, receptiveness, of, cells, to, transcriptional, activation, mediated, by, the, 'zinc-dependent', glucocorticoid, receptor, '(', 'GR)'])].
[sujeto(['We', 'studied,', in, a, 'GR-responsive', mouse, 'mammary-tumor', cell, 'line,', the, ability, of, dexamethasone, '(', 'DEX)', to]), verbo([stimulate]), complemento([transcription, of, a, chloramphenicol, acetyltransferase, '(', 'CAT)', gene, controlled, by, a, mouse, 'mammary-tumor', virus, promoter])].
[sujeto(['However,', 0.05, to, 0.5, microM, 'CdCl(2)', had, no, effect, on, 'CAT', 'activity,', despite, an]), verbo([increase]), complemento([in, 'Cd-associated', 'MT'])].
[sujeto(['These', results, may, reflect, a, functional, difference, between, 'zinc-associated', 'MT,', and, 'MT']), verbo([associated]), complemento([with, other, metals])].
[sujeto(['Although', absolute, amounts, of, 'MT', were, unchanged, by, these, two, 'treatments,', a, higher, percentage, of, total, cellular, zinc, was]), verbo([associated]), complemento([with, the, 'MT', protein, fractions, after, treatment])].
[sujeto(['Metallothionein', '(', 'MT)', is, thought, to]), verbo([have]), complemento([an, antioxidant, function, and, is, strongly, expressed, during, activation, of, thermogenesis, and, increased, oxidative, stress, in, brown, adipose, tissue, '(', 'BAT)'])].
[sujeto(['Immunohistochemical', analysis, of, 'BAT', from, rats, exposed, to, 4, degrees, 'C', for, 24, h, showed, that, 'MT', and, uncoupling, protein, 1, '(', 'UCP1)', were, coexpressed, in, differentiated, 'adipocytes,', and, both, cytoplasmic, and]), verbo([nuclear]), complemento([localization, of, 'MT', was, observed])].
[sujeto(['Administration', of, norepinephrine, to, rats, and, isoproterenol, to, mice]), verbo([stimulated]), complemento(['MT', and, 'UCP1', expression, in, 'BAT,', implying, a, sympathetically, mediated, pathway, for, 'MT', induction])].
[sujeto(['In', 'mice,', 'zinc,', and, particularly, 'dexamethasone,']), verbo([induced]), complemento(['MT-2', expression, in, 'BAT', and, liver])].
[sujeto(['Surprisingly,', zinc, also]), verbo([induced]), complemento(['UCP1', in, 'BAT,', suggesting, that, elevated, zinc, may, induce, thermogenesis])].
[sujeto(['Their', hepatic, contents, after, exposure, to, stress, were, elevated, to, twice, the, basal, level, with, 24, 'h,', resulting, in, more, than, a, 3, -, fold]), verbo([increase]), complemento([at, 144, 'h,', whereas, their, renal, contents, gradually, increased, after, 24, h, and, reached, the, same, level, as, that, in, the, liver, around, 96, h])].
[sujeto(['Both', proteins, mainly]), verbo([bound]), complemento([zinc, in, their, endogenous, forms, and, showed, different, immunogenicity, to, rat, and, rabbit, 'MTs'])].
[sujeto(['Dexamethasone,', a, potent, inducer, for, 'MT', synthesis, in, 'mammals,']), verbo([induced]), complemento([the, production, of, both, isoforms, in, crucian, 'carp,', whereas, cadmium, and, zinc, ions, prominently, induced, the, synthesis, of, 'ccMT-2'])].
[sujeto(['These', results, indicate, that, crucian, carp]), verbo([have]), complemento([the, ability, to, produce, 'MTs', in, response, to, various, kinds, of, environmental, stress, and, that, violent, 'air-pumping', stress, in, crucian, carp, may, induce, 'MT', 'synthesis,', in, 'part,', via, the, release, of, endogenous, 'factor(s),', such, as, glucocorticoids])].
[sujeto(['With']), verbo([increasing]), complemento([time, on, 'dialysis,', the, membrane, may, become, compromised, resulting, in, decreased, dialysing, capacity])].
[sujeto(['We']), verbo([have]), complemento([pursued, an, innovative, 'strategy,', i])].
[sujeto([genetic, modification, of, the, mesothelial, cell, to, change, the, properties, of, the, membrane, to, potentially, improve, its, dialysing, capacity, and, 'longevity,', and]), verbo([have]), complemento([demonstrated, the, feasibility, of, this, approach, in, a, rat, model, of, ex, vivo, gene, transfer])].
[sujeto(['The', potential, to]), verbo([regulate]), complemento([transgene, expression, in, this, model, is, examined, here])].
[sujeto(['Rat', peritoneal, mesothelial, cells, '(', 'MCs)', were, stably, modified, to]), verbo([express]), complemento([human, growth, hormone, '(', 'hGH)', under, control, of, the, heavy, metal, ion, and, 'glucocorticoid-regulatable', murine, 'metallothionein-1', promoter])].
[sujeto(['The', effect, of, zinc, and, the, synthetic, glucocorticoid, dexamethasone, on, hGH, expression, was, analysed, in, 'MC', clones]), verbo([maintained]), complemento([in, continuous, passage, or, stationary, 'phase,', and, in, our, rat, model, of, ex, vivo, gene, transfer])].
[sujeto([2, -, 200, -, 'fold)']), verbo([increases]), complemento([in, hGH, production])].
[sujeto(['Our', results, demonstrate, the, modulation, of, transgene, expression, in, 'MCs', in, vitro, and, in, 'vivo,', and]), verbo([suggest]), complemento([the, potential, for, the, regulation, of, gene, expression, in, a, genetically, modified, mesothelium, that, may, ultimately, be, used, for, the, delivery, of, therapeutic, proteins, to, maintain, peritoneal, membrane, viability, in, the, peritoneal, dialysis, patient])].
[sujeto(['Since', 'Ras', proteins, are, essential, intermediates, of, some, 'insulin-like', growth, factor, 'I', '(', 'IGF-I)/insulin', signaling, 'pathways,', we, examined, whether, 'Ras', proteins]), verbo([mediate]), complemento([the, 'IGF-I-induced', uncoupling, protein, expression])].
[sujeto(['IGF-I', treatment, of, fetal, brown, adipocytes, cotransfected, with, inducible, gene, constructs, of, 'SV40', large, 'T', antigen, '(', 'SV40LTag)', and, a, transforming, ras, gene]), verbo([induced]), complemento([uncoupling, protein, expression, '(', 'UCP)', in, the, absence, of, expression, of, the, transfected, genes])].
[sujeto(['The', expression, of, the, 'dexamethasone-inducible', transforming, ras, gene, alone, or, in, combination, with, the, 'Zn-inducible', 'SV40LTag', mimicked, the, 'IGF-I', effect]), verbo([inducing]), complemento(['UCP', expression, and, 'IGF-I', did, not, induce, it, further])].
[sujeto(['However,', the, expression, of, the, 'Zn-inducible', 'SV40LTag', did, not]), verbo([increase]), complemento(['UCP', expression, in, the, absence, of, 'IGF-I'])].
[sujeto(['Expression', of, the, transfected, ras, oncogene, also]), verbo([induced]), complemento(['IGF-I', and, 'IGF-I', receptor, 'mRNAs,', whereas, expression, of, 'SV40LTag', did, not, increase, them])].
[sujeto(['Specific', 'IGF-I']), verbo([binding]), complemento([was, also, specifically, increased, by, expression, of, the, transfected, ras, oncogene, but, was, not, affected, by, expression, of, the, 'SV40LTag', construct])].
[sujeto(['These', results, indicate, that, 'Ras', proteins]), verbo([mediate]), complemento([the, 'IGF-I-induced', effect, on, 'UCP', expression, and, play, a, role, in, the, expression, of, 'IGF-I', and, 'IGF-I', receptor])].
[sujeto(['Therefore,', an, 'IGF-I', 'autocrine/paracrine', loop, might, be, implicated, in, the, process, of, thermogenic, differentiation, of, brown, adipose, tissue, by, a, new, mechanism, unlike, that]), verbo([induced]), complemento([by, norepinephrine])].
[sujeto(['For', each, material, there, was, a]), verbo([increased]), complemento([rate, of, tertiary, dentine, formation, in, the, second, period, '(', 29, -, 49, 'days)', compared, to, the, first, period, '(', 0, -, 28, 'days)'])].
[sujeto(['All', the, materials]), verbo([caused]), complemento([odontoblast, 'destruction,', altered, ground, substance, production, and, alterations, in, the, calcification, process])].
[sujeto(['Patients', with, 'ESRD']), verbo([have]), complemento([multiple, alterations, of, thyroid, hormone, metabolism, in, the, absence, of, concurrent, thyroid, disease])].
[sujeto(['These', may, include, elevated, basal, 'TSH', 'values,', which, may, transiently]), verbo([increase]), complemento([to, greater, than, 10, 'mU/liter,', blunted, 'TSH', response, to, 'TRH,', diminished, or, absent, 'TSH', diurnal, 'rhythm,', altered, 'TSH', 'glycosylation,', and, impaired, 'TSH', and, 'TRH', clearance, rates])].
[sujeto(['In', 'addition,', serum, total, and, free, 'T3', and, 'T4', values, may, be, 'reduced,', free, rT3, levels, are, elevated, while, total, values, are, 'normal,', serum]), verbo([binding]), complemento([protein, concentrations, may, be, 'altered,', and, 'disease-specific', inhibitors, reduce, serum, 'T4', binding])].
[sujeto(['Thyroid', hormone, metabolism, normalizes, with, renal, 'transplantation;', 'however,', glucocorticoid, therapy, may]), verbo([induce]), complemento([additional, changes])].
[sujeto(['ESRD', patients, may]), verbo([have]), complemento([an, increased, frequency, of, 'goiter,', thyroid, 'nodules,', thyroid, 'carcinoma,', and, hypothyroidism])].
[sujeto(['Goiter', and, hypothyroidism, may, be]), verbo([induced]), complemento([by, iodide, 'excess,', due, to, reduced, renal, iodide, 'excretion,', and, may, be, reversed, with, iodide, restriction, in, some, patients])].
[sujeto(['The']), verbo([increased]), complemento([frequency, of, thyroid, nodules, and, malignancies, in, 'ESRD', may, relate, to, secondary, hyperparathyroidism])].
[sujeto(['ESRD', patients, with, hyperthyroidism, or, follicular, neoplasms]), verbo([require]), complemento([reduced, dosages, of, 'Na', 131, -, 'I', depending, upon, 'type,', 'frequency,', and, duration, of, dialysis, therapy])].
[sujeto(['Of', 'non-metal', 'MT', inducers, 'tested,', sodium, butyrate]), verbo([caused]), complemento([a, low, level, induction, of, 'MT', while, 'interleukin-1', had, no, effect, on, basal, 'MT', levels])].
[sujeto([1, ',', 25, -, dihydroxyvitamin, 'D']), verbo([increased]), complemento(['MT', induction])].
[sujeto(['The', steroid, hormone, dexamethasone]), verbo([caused]), complemento([a, reduction, in, basal, and, induced, 'MT', levels])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'MT', regulation, in, growth, plate, chondrocytes, differs, significantly, from, what, is, known, in, other, cell, types, and, that, this, difference, may, be, related, to, the, mineralization, of, this, tissue])].
[sujeto(['MT-I', and, 'MT-II', are]), verbo([found]), complemento([in, all, tissues, of, the, 'body,', while, 'MT-III', exists, only, in, brain])].
[sujeto(['Regulation', of, 'MT-I', and, 'MT-III', mRNA, was, studied, in, brain, and, liver, of, control, 'C57BL/6J', mice, and, mice, given, chemicals, known, to]), verbo([increase]), complemento(['MT-I,', 'namely,', lipopolysaccharide, '(', 'LPS),', zinc, chloride, '(', 'Zn),', cadmium, chloride, '(', 'Cd),', dexamethasone, '(', 'Dex),', 'ethanol,', and, kainic, acid, '(', 'KA)'])].
[sujeto(['Northern', blot, analysis, revealed, that, 'MT-I', mRNA, levels, in, liver, were]), verbo([induced]), complemento([dramatically, '(', 12, -, 27, -, fold, over, basal, 'levels)', by, all, of, the, 'chemicals,', while, in, brain, only, 'LPS', produced, an, increase, in, 'MT-I', mRNA, '(', 2, -, 'fold)'])].
[sujeto(['MT-I', mRNA, 'signal,', which, was, most, abundant, in, the, glial, cells, of, the, 'Purkinje', cell, layer, of, the, cerebellum, in, control, 'mice,', appeared, to, be]), verbo([enhanced]), complemento([in, mice, given, the, 'MT-I', inducers, '(', 'LPS,', 'Zn,', 'Cd,', 'Dex,', 'ethanol,', and, 'KA)'])].
[sujeto(['MT-I', mRNA, hybridization, signal, was, also]), verbo([enhanced]), complemento([in, the, olfactory, bulbs, from, 'LPS-', and, 'Cd-treated', 'mice,', while, this, signal, was, present, but, weak, in, control, brains])].
[sujeto(['Signals', for, 'MT-III', in, hippocampus, appeared, to, be, reduced, by, 'KA,', 'Dex', and, 'LPS', 'treatment,', while, in, the, cortical, 'region,', 'MT-III', mRNA, signals, appeared, to, be]), verbo([enhanced]), complemento([by, 'KA,', 'Cd,', and, ethanol, treatment])].
[sujeto(['In', 'conclusion,', both, 'MT-I', and, 'MT-III', expression, in, brain, appears, to, be]), verbo([modulated]), complemento([by, exogenous, 'treatment,', 'however,', the, changes, are, small, in, relation, to, those, observed, in, liver])].
[sujeto(['A', common, strongly, ordered, 'multi-step-pattern', of, endogenous, 'DNA', degradation, was]), verbo([induced]), complemento([in, rat, liver, nuclei, and, intact, 'thymocytes,', prepared, in, the, presence, of, chelating, agents, and, incubated, in, the, presence, of, 'CaCl2', 'and/or', 'MgCl2'])].
[sujeto(['ZnCl2', completely]), verbo([inhibited]), complemento([advanced, genome, cleavage, to, 'oligo-', and, mononucleosomal, 'DNA', without, affecting, the, initial, generation, of, large, 'DNA', fragments])].
[sujeto(['The', similar, pattern, of, 'DNA', degradation, was, observed, in, thymocytes, treated, with, dexamethasone, and, with, the, topoisomerase, 'II', inhibitor, 'VM-26,', the, agents, known, to]), verbo([induce]), complemento([apoptosis])].
[sujeto(['The', effect, of, 'VM-26', strongly]), verbo([suggests]), complemento([the, involvement, of, topoisomerase, 'II', in, generation, of, large, 'DNA', fragments])].
[sujeto(['Detachment', of, chromatin, from, the]), verbo([nuclear]), complemento([matrix, attachment, regions, may, be, one, of, the, possible, mechanisms, of, switching, off, the, genome, function, and, triggering, the, 'multi-step', process, of, endogenous, chromatin, degradation, thus, leading, to, cell, death, in, terminal, differentiation, or, 'stress-induced', apoptosis])].
[sujeto(['The', levels, of, intracellular, free, 'Ca(II)', and, 'Zn(II)', during, dexamethasone, '(', 'dex)-induced', apoptosis, in, 'CEM', cell, lines, were, determined, by, 19, 'F']), verbo([nuclear]), complemento([magnetic, resonance, '(', 'NMR),', using, the, fluorinated, intracellular, chelator, 1, ',', 2, -, 'bis-(2-', 'amino-5-fluorophenoxy)ethane-N,N,N\',N\'-tetraacetic', acid, '(', 5, -, 'FBAPTA)'])].
[sujeto(['Dex']), verbo([caused]), complemento([a, continuous, increase, in, the, 'Ca(II)', level, in, 'dex-sensitive', 'CEM-C7', 'cells,', while, in, 'CEM-C1', cells, dex, caused, an, initial, increase, in, the, 'Ca(II)', level, which, in, approximately, 36, h, was, restored, to, its, normal, value])].
[sujeto(['The', intracellular, 'Ca(II)', level, in, 'CEM-4R4', cells, was, not, significantly, affected, by, 'dex,', while, that, of, 'CEM-ICR27', cells]), verbo([decreased]), complemento([after, dex, incubation])].
[sujeto(['No', detectable, level, of, intracellular, 'Zn(II)', was]), verbo([found]), complemento([in, the, other, cell, lines])].
[sujeto(['Incubation', with, &, 'lt;', 100, microM, 'Zn(II)', did, not]), verbo([inhibit]), complemento(['dex-induced', apoptosis, in, 'CEM-C7', cells, '(', e])].
[sujeto(['Treatment', with, approximately, 250, microM, 'Zn(II)']), verbo([caused]), complemento([significant, decrease, in, growth, rate, in, all, cell, lines, and, prevented, 'dex-induced', 'DNA', degradation, in, 'CEM-C7', cells])].
[sujeto(['A', calibrated, amount, of, 'Ca(II)', ionophore, '(', 'A23187),', used, to]), verbo([increase]), complemento(['Ca(II)', concentrations, up, to, the, 'dex-induced', 'levels,', did, not, induce, 'DNA', degradation, in, 'CEM-C7', or, 'CEM-C1', cells])].
[sujeto(['While', elevation, of, intracellular, 'Ca(II)', by, itself, is, not, sufficient, to, initiate, apoptosis, in, 'CEM-C7', 'cells,', the, results]), verbo([reported]), complemento([here, suggest, that, 'Ca(II)', is, involved, in, the, killing, mechanism, as, a, secondary, factor])].
[sujeto(['The', combination, of, dex, and, ionophore]), verbo([caused]), complemento([significant, 'DNA', degradation, in, 'CEM-C1', 'cells,', which, normally, showed, resistance, to, each, compound, individually])].
[sujeto(['The', combination, of, dex, and, the, 'Zn(II)', chelator, phenanthroline, also]), verbo([caused]), complemento([extensive, 'DNA', degradation, in, the, normally, 'dex-resistant', 'CEM-C1', 'cells,', suggesting, that, 'Zn(II)', plays, a, role, in, the, dex, resistance, of, these, cells])].
[sujeto(['It']), verbo([has]), complemento([been, found, that, 'adrenaline,', prednisolone, and, pilocarpine, caused, the, multidirectional, changes, of, these, metals, content, in, cells, and, in, extracellular, space])].
[sujeto(['In', this, significant]), verbo([increase]), complemento([of, zinc, concentration, by, 33, -, 42, '%', ',', 'magnesium--by', 33, -, 50, '%', ',', and, also, decrease, of, copper, content, by, 25, -, 50, '%', was, observed, in, granulocytes, of, animals, after, adrenal, hormones, injections])].
[sujeto(['Under', the, influence, of, cholinomimetics, content, of, zinc, and, magnesium, were, essential]), verbo([decreased]), complemento([in, granulocytes, of, the, 'rabbits,', by, 58, '%', and, by, 33, '%', 'respectively,', and, content, of, copper, was, risen, by, 43, '%', '(', 'P', &, 'lt;', 0.001, ')'])].
[sujeto(['Adrenaline', and, prednisolone, prescription]), verbo([caused]), complemento([a, significant, decrease, of, zinc, concentration, by, 20, -, 24, '%', ',', 'magnesium--by', 22, -, 33, '%', ',', and, increase, of, copper, content, by, 36, -, 43, '%'])].
[sujeto(['Pilocarpine', injection]), verbo([caused]), complemento([a, decrease, of, zinc, and, magnesium, content, by, 28, and, 33, '%', '(', 'P', &, 'lt;', 0.01, ')', 'respectively,', and, an, increase, of, copper, concentration, by, 43, '%', '(', 'P', &, 'lt;', 0.001, ')'])].
[sujeto(['Human', 'CBG']), verbo([mediates]), complemento([the, targeted, release, of, cortisol, at, sites, of, inflammation, through, cleavage, of, its, reactive, center, loop, '(', 'RCL)', by, neutrophil, elastase])].
[sujeto(['The', 'RCLs', of, 'SERPIN', family, members, are]), verbo([targeted]), complemento([by, diverse, endogenous, and, exogenous, 'proteases,', including, several, bacterial, proteases])].
[sujeto(['This', proteolytic, activity, was]), verbo([inhibited]), complemento([by, zinc, chelators, and, occurred, most, efficiently, at, pH, 7, and, elevated, physiological, temperature, '(', 'ie,', 41, °, 'C)'])].
[sujeto(['This', metalloprotease, cleaves, the, 'CBG', 'RCL', at, a, major, 'site,', distinct, from, that]), verbo([targeted]), complemento([by, neutrophil, elastase])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, humoral, responses, to, 'P'])].
[sujeto([aeruginosa, infection, are, influenced, by, this, 'pathogen\'s', ability, to, secrete, a, protease, that]), verbo([promotes]), complemento([the, release, of, the, 'anti-inflammatory', 'steroid,', 'cortisol,', from, its, plasma, transport, protein])].
[sujeto(['The', influence, of, cell, numbers, on, 'peroxide-(tertiary', butylhydroperoxide, '(', 'tBHP)', or, hydrogen, 'peroxide-(HP))', or, 'zinc-(zinc', 'chloride)']), verbo([induced]), complemento([oxidative, stress, was, assessed, in, alveolar, 'epithelial-like', cell, lines, in, this, work])].
[sujeto(['Glucocorticoid', pretreatment, seems, to]), verbo([increase]), complemento([toxicity, of, 'HP', in, 'A549', monolayers, according, to, the, lowered, protein, 'content,', while, toxicity, might, be, changed, by, a, different, way, when, cells, are, incubated, as, cell, suspensions])].
[sujeto(['No', explanation, as, a, cell, culture, artificial, effect, was, 'observed,', therefore, we, assume, the]), verbo([increased]), complemento([toxicity, after, glucocorticoid, pretreatment, occurs, in, vivo, as, well])].
[sujeto(['Exposure', to, environmental, toxicants, can, alter, a, range, of, cellular, functions]), verbo([involved]), complemento([in, the, immune, response])].
[sujeto(['Previously,', it]), verbo([has]), complemento([been, reported, that, 'MT1', has, several, immunosuppressive, properties])].
[sujeto(['Furthermore,', we, earlier, showed, that, functionally, tolerogenic, dendritic, cells, '(', 'DCs)']), verbo([expressed]), complemento([increased, mRNA, levels, of, 'MT1'])].
[sujeto(['Alternatively,', 'ZnCl2-treated', murine, 'DCs', transport, 'MT1', to, the, cell, surface, are, tolerogenic, and]), verbo([promote]), complemento([the, expansion, of, 'T', cells, with, a, regulatory, phenotype])].
[sujeto(['Additionally,', we]), verbo([have]), complemento([found, a, new, mechanism, for, tolerogenic, 'DCs', to, exert, their, immune, regulatory, function])].
[sujeto(['The', aim, of, this, study, was, to, evaluate, the, biocompatibility, in, rat, subcutaneous, connective, tissue, of, a, new, zinc, oxide, endodontic, sealer, '(', 'Endomethasone', 'N)', compared, to, those]), verbo([provided]), complemento([by, 'Endofill', and, 'Sealer', 26])].
[sujeto(['Independently', of, the, 'sealer,', the, tissue, behavior, showed, a, tendency, to]), verbo([decrease]), complemento([the, irritation, effect, over, time])].
[sujeto(['It', can, be, concluded, that, all, sealers, are, 'irritant,', but, its, toxicity]), verbo([decreased]), complemento([with, time])].
[sujeto(['Endomethásone', 'N', showed, biocompatible, characteristics, comparable, with, those]), verbo([provided]), complemento([by, 'Endofill', and, 'Sealer', 26])].
[sujeto(['Arsenic', '(', 'As)', is, considered, a, top, environmental, chemical, of, human, health, because, it]), verbo([has]), complemento([been, linked, to, adverse, health, effects, including, 'cancer,', 'diabetes,', cardiovascular, 'disease,', and, reproductive, and, developmental, problems])].
[sujeto(['In', several, cell, culture, and, animal, 'models,', 'As']), verbo([acts]), complemento([as, an, endocrine, 'disruptor,', which, may, underlie, many, of, its, health, effects])].
[sujeto(['In', those, 'studies,', low, 'iAs(+3)', concentrations, '(', 0.1, -, 0.7, 'μM)']), verbo([stimulated]), complemento(['hormone-inducible', 'transcription,', whereas, somewhat, higher, but, still, 'non-cytotoxic', levels, '(', 1, -, 3, 'μM)', inhibited, transcription])].
[sujeto(['Recent', evidence]), verbo([suggests]), complemento(['that,', compared, with, 'iAs,', methylated, forms, may, have, distinct, biochemical, effects])].
[sujeto(['Here,', fluorescence, polarization, '(', 'FP)', experiments, utilizing, 'purified,', 'hormone-bound', human, glucocorticoid, '(', 'GR)', and, progesterone, receptor, '(', 'PR)']), verbo([have]), complemento([demonstrated, that, neither, inorganic, '(', 'iAs(+3))', nor, dimethylated, '(', 'DMA(+3))', species, of, trivalent, 'As', affect, receptor, interactions, with, glucocorticoid, 'DNA', response, elements, '(', 'GREs)'])].
[sujeto(['However,', monomethylated, forms, '(', 'monomethylarsenite,', 'MMA(+3)', and, monomethylarsonic, 'diglutathione,', 'MADG)', strongly]), verbo([inhibit]), complemento(['GR-GRE', and, 'PR-GRE', binding])].
[sujeto(['Additionally,', speciation, studies, of, 'iAs(+3)-treated', 'H4IIE', rat, hepatoma, cells, show, 'that,', under, treatment, conditions, that]), verbo([cause]), complemento([inhibition, of, 'hormone-inducible', gene, 'transcription,', the, intracellular, concentration, of, 'MADG', is, sufficient, to, inhibit, 'GR-GRE', and, 'PR-GRE', interactions, in, vivo])].
[sujeto(['These', results, indicate, that, 'arsenic\'s', inhibitory, endocrine, disruption, effects, are, probably]), verbo([caused]), complemento([in, part, by, methylated, 'metabolites\'', disruption, of, 'SR', ability, to, bind, 'DNA', response, elements, that, are, crucial, to, 'hormone-driven', gene, transcription])].
[sujeto(['A', remarkable, dentin, bridge, formation, was]), verbo([found]), complemento([in, all, groups])].
[sujeto(['No', pulp, necrosis, was]), verbo([found]), complemento([in, any, tooth, of, the, four, groups])].
[sujeto(['Pathological', reactions, of, the, pulp, were]), verbo([found]), complemento([in, 25, '%', ',', 40, '%', ',', 20, '%', ',', and, 100, '%', of, groups, 1, ',', 2, ',', 3, ',', and, 4, ',', respectively])].
[sujeto(['Differences', between, study, and, control, groups, were]), verbo([found]), complemento([statistically, significant, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['All', materials, used, in, this, study, were, biocompatible, and]), verbo([suggested]), complemento([to, be, studied, further, on, human, teeth])].
[sujeto(['It', was, observed, that, 'CH', and, 'CTZ', paste]), verbo([induced]), complemento([severe, 'inflammation,', a, large, amount, of, necrotic, 'tissue,', 'lymphocytes,', foreign, body, cells, and, bone, 'resorption,', while, 'Guedes', 'Pinto', 'Paste', induced, little, or, no, inflammation, in, the, 4, -, week, observation, period])].
[sujeto(['The', drug]), verbo([release]), complemento([from, 'temperature-responsive', 'NP', could, be, controllable, by, changing, the, temperature])].
[sujeto(['Moreover,', we]), verbo([found]), complemento([this, effect, to, be, useful, for, controlling, the, stealthiness, by, changing, the, temperature])].
[sujeto(['Present', 'temperature-responsive', 'NPs']), verbo([have]), complemento([successfully, exhibited, 'thermo-responsive', drug, release, and, intracellular, uptake, while, possessing, a, biodegradable, character])].
[sujeto(['Dehydration']), verbo([has]), complemento([a, profound, influence, on, neuroexcitability])].
[sujeto(['Water', deprivation]), verbo([led]), complemento([to, downregulation, of, janus, kinase, and, microtubule, interacting, protein, 1, ',', neuronal, 'PAS', domain, protein, 4, ',', 'thrombomodulin,', purinergic, receptor, 'P2Y', -, 'G-protein', coupled, 13, 'gene,', gap, junction, protein, beta, 1, ',', neurotrophin, 3, ',', hyaluronan, and, proteoglycan, link, protein, 1, ',', 'G', 'protein-coupled', receptor, 19, ',', 'CD93', 'antigen,', forkhead, box, 'P1,', suppressor, of, cytokine, signaling, 3, ',', 'apelin,', 'immunity-related', 'GTPase', family, 'M,', serine, '(', or, 'cysteine)', peptidase, inhibitor, clade, 'B', member, 1, 'a,', serine, '(', or, 'cysteine)', peptidase, inhibitor, clade, 'H', member, 1, ',', glutathion, peroxidase, 8, '(', 'putative),', discs, large, '(', 'Drosophila)', 'homolog-associated', protein, 1, ',', zinc, finger, and, 'BTB', domain, containing, 3, ',', and, 'H2A', histone, family, member, 'V'])].
[sujeto(['In', 'conclusion,', water, deprivation, influences, the, transcription, of, a, wide, variety, of, genes, in, the, 'brain,', which, may]), verbo([participate]), complemento([in, the, orchestration, of, brain, responses, to, water, deprivation])].
[sujeto(['The', results, were]), verbo([expressed]), complemento([as, a, bacterial, survival, index, '(', 'BSI)', when, compared, to, the, unexposed, control])].
[sujeto(['In', previous, experiments, an]), verbo([increase]), complemento([in, 'zinc-mediated', toxicity, was, found, after, pretreatment, of, alveolar, epithelial, type, 'II-like', cells, with, glucocorticoids])].
[sujeto(['Pretreatment', of, cells, with, 7.5, 'micromol/l', 'DEX', for, 72, h]), verbo([decreased]), complemento([cellular, glutathione, content, in, both, cell, lines])].
[sujeto(['Furthermore', compared, to, not, pretreated, cells, toxicity, of, both, peroxides, was]), verbo([increased]), complemento([in, 'A549', 'cells,', while, in, 'L2', cells, only, toxicity, of, tBHP, was, significantly, increased, by, the, glucocorticoid, pretreatment])].
[sujeto(['HP', toxicity, only, showed, a, tendency, to, be]), verbo([increased]), complemento([in, 'L2', cells, after, 'DEX', pretreatment])].
[sujeto(['The', results, point, to, a, 'glucocorticoid-dependent']), verbo([increased]), complemento([oxidative, stress, of, alveolar, epithelial, type, 'II', cells, as, antagonised, by, antioxidative, enzymes, such, as, catalase, 'and/or', preferentially, by, the, glutathione, system])].
[sujeto(['Solid', nanoparticles, consisting, of, biodegradable, polymers]), verbo([have]), complemento([emerged, as, a, promising, carrier, for, various, 'drugs,', but, unfortunately, the, encapsulation, of, drugs, remains, challenging])].
[sujeto(['It', was]), verbo([found]), complemento([that, 'BP', formed, an, ionic, complex, with, zinc, at, a, certain, pH, range, obtained, by, addition, of, diethanolamine])].
[sujeto(['These', results, strongly]), verbo([suggested]), complemento([that, the, encapsulation, was, promoted, by, zinc, creating, an, ionic, bridge, between, a, carboxyl, group, on, 'PLA/PLGA', and, a, phosphate, group, on, 'BP'])].
[sujeto(['The']), verbo([binding]), complemento([of, arsenite, '(', 'As(III))', and, monomethylarsenite, '(', 'MMAIII)', to, the, 'DNA-binding', domain, of, the, glucocorticoid, receptor, '(', 'GR-DBD)', and, their, competition, with, the, two, required, 'Zn2+', ions, of, this, domain, have, been, investigated, with, isothermal, titration, calorimetry, '(', 'ITC)', and, circular, dichroism, '(', 'CD)'])].
[sujeto(['The']), verbo([binding]), complemento([thermodynamics, indicate, that, 'MMAIII,', but, not, 'arsenite,', is, able, to, compete, with, one, of, the, two, 'Zn2+', ions])].
[sujeto(['This']), verbo([has]), complemento([been, confirmed, by, monitoring, arsenite, and, 'MMAIII', titrations, of, 'Zn2GR-DBD', with, 'CD'])].
[sujeto(['Only', 'MMAIII', is, able, to, eliminate, the, 'Zn-stabilized', secondary, 'structure,', consistent, with, partial, or, complete, displacement, of, at, least, one, 'Zn2+', ion, 'and,', 'therefore,']), verbo([loss]), complemento([of, 'GR-DBD', competence, to, bind, to, the, 'DNA', of, its, recognition, 'site,', the, glucocorticoid, response, element, '(', 'GRE)'])].
[sujeto(['Zinc-mediated', toxicity]), verbo([has]), complemento([been, linked, to, cellular, glutathione, content, in, isolated, cells])].
[sujeto(['In', 'addition,', treatment, of, alveolar, epithelial, type, 'II', cells, with, glucocorticoids, diminishes, cellular, glutathione, 'content,', and, this, is, followed, by, an]), verbo([increase]), complemento([in, 'zinc-mediated', toxicity])].
[sujeto(['The', question, arises, whether, an]), verbo([increase]), complemento([in, glutathione, synthesis, might, decrease, 'zinc-mediated', toxicity])].
[sujeto(['Furthermore', only, in, one, '(', of, 'three)', cell, line, tested, a, significant]), verbo([increase]), complemento([in, 'GSH', content, by, 'NAC', as, compared, to, 'NADC', treatment, was, achieved])].
[sujeto(['Furthermore', the]), verbo([increased]), complemento(['zinc-mediated', toxicity, due, to, hydrocortisone, was, abolished, in, the, alveolar, epithelial, cell, lines, by, the, 'NADC/NAC', treatment])].
[sujeto(['The', 'International', 'Agency', for, 'Research', on, 'Cancer']), verbo([has]), complemento([recently, classified, formaldehyde, as, carcinogenic, to, human, beings])].
[sujeto(['After', consideration, of, a, review, of, extensively, searched, 'literature,', a, protocol, and, key, points, document]), verbo([have]), complemento([been, developed, to, assist, clinicians, in, their, treatment, planning])].
[sujeto([randomized, controlled, 'trials)', are]), verbo([required]), complemento([to, enable, us, to, identify, acceptable, alternatives, which, can, replace, formocresol])].
[sujeto(['Polymorphic', variants, in, several, molecules]), verbo([involved]), complemento([in, the, glomerular, function, and, drug, metabolism, have, been, implicated, in, the, pathophysiology, of, pediatric, idiopathic, nephrotic, syndrome, '(', 'INS),', but, the, results, remain, inconsistent])].
[sujeto(['We', analyzed, the, association, of, eleven, allelic, variants, in, eight, genes, '(', 'angiopoietin-like', 4, '(', 'ANGPTL4),', glypican, 5, '(', 'GPC5),', 'interleukin-13', '(', 'IL-13),', macrophage, migration, inhibitory, factor, '(', 'MIF),', neural, nitric, oxide, synthetase, '(', 'nNOS),', multidrug, 'resistance-1', '(', 'MDR1),', 'glucocorticoid-induced', 'transcript-1', '(', 'GLCCI1),', and]), verbo([nuclear]), complemento([receptor, 'subfamily-3', '(', 'NR3C1))', in, 100, 'INS', patients, followed, up, till, adulthood])].
[sujeto(['While', 'MDR1', variant, genotype, distribution]), verbo([associated]), complemento([with, different, medication, 'regimes,', the, other, analyzed, gene, variants, showed, only, little, or, marginal, clinical, relevance, in, 'INS'])].
[sujeto(['We', tested, the, hypothesis, that, prenatal, stress, and, the]), verbo([decrease]), complemento([of, hippocampal, 'Nurr1', alter, offspring, behavioral, responses, in, the, forced, swimming, test, '(', 'FST)'])].
[sujeto(['Results', showed, that, the]), verbo([decrease]), complemento([of, hippocampal, 'Nurr1', after, the, antisense, 'ODN', in, adult, 'NPS', rats, induces, immobility, '(', indicating, 'depressive-like', 'behavior)'])].
[sujeto(['The', 'PS', adult, 'rats,', including, the, group, with]), verbo([decreased]), complemento([hippocampal, 'Nurr1,', presented, low, immobility, in, the, 'FST'])].
[sujeto(['This', low, immobility, was, concordant, with, maintenance, of, 'Nurr1', and, 'Bdnf', expression, levels, in, the, three, analyzed, brain, 'regions;', 'Nr3c1', gene, expression, was, also]), verbo([maintained]), complemento([in, the, 'PFC', and, hypothalamus])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'Nurr1', and, associated, genes, could, participate, in, the, brain, modifications, induced, by, prenatal, 'stress,', allowing, active, coping, '(', 'resilience)', with, acute, stress, in, adulthood])].
[sujeto(['Eighty-two', children, '(', 56, 'boys/26', 'girls,', mean, age, 9.6, ±, 3.2, 'years)', with, 'moderate-severe', asthma, exacerbation, were, genotyped, for, eight, 'single-nucleotide', polymorphisms, that, were, a, priori]), verbo([associated]), complemento([with, 'ICS', response, in, chronic, asthma, 'treatment:', glucocorticosteroid, receptor, '(', 'NR3C1)', 'rs41423247;', 'corticotrophin-releasing', hormone, receptor1, '(', 'CRHR1)', 'rs242939,', 'rs242941,', and, 'rs1876828;', 'T-box', 21, '(', 'TBX21)', 'rs2240017;', 'glucocorticoid-induced', transcript, 1, '(', 'GLCCl1);', and, 'T', gene, rs3099266, and, rs2305089])].
[sujeto(['Homozygosity', for, the, 'G', allele, at, rs41423247, of, the, glucocorticosteroid, receptor, '(', 'NR3C1)', gene, is]), verbo([associated]), complemento([with, a, higher, improvement, in, 'FEV1', at, 4, h, in, children, with, 'moderate-to-severe', asthma, exacerbation, treated, with, 'high-dose', 'ICS'])].
[sujeto(['This', observation, may]), verbo([have]), complemento([important, clinical, implications, especially, for, children, who, use, systemic, steroids, frequently, for, recurrent, asthma, exacerbations])].
[sujeto([11, 'β-hydroxysteroid', dehydrogenase, 1, '(', 11, 'β-HSD1)', inhibitors]), verbo([have]), complemento([been, shown, to, treat, type, 2, diabetes, '(', 'T2D)'])].
[sujeto(['T2D', was]), verbo([induced]), complemento([by, feeding, with, high, fat, diet, plus, injection, of, streptozocin, '(', 30, 'mg/kg)'])].
[sujeto(['Liver', 'Nr3c1,', 'Col1a1,', 'Col3a1,', 'Fn1,', 'Timp1,', and, 'Timp2', were]), verbo([increased]), complemento([in, 'T2D', rats])].
[sujeto(['T2D', liver, showed, significant, fibrosis, with, the]), verbo([increases]), complemento([of, 'α-smooth', muscle, actin, and, fibronectin])].
[sujeto(['Previously', we]), verbo([have]), complemento([shown, that, prenatal, moderate, arsenic, exposure, '(', 50, 'ppb)', disrupts, glucocorticoid, receptor, '(', 'GR)', programming, and, that, these, changes, continue, into, adolescence, in, males])].
[sujeto(['However,', it, was, not, clear, what, the, molecular, mechanisms, were]), verbo([promoting]), complemento([these, 'GR', programming, changes, or, if, these, changes, occurred, in, 'arsenic-exposed', females])].
[sujeto(['Compared', to, 'males,', females, were, resistant, to, arsenic]), verbo([induced]), complemento([changes, in, 'GR,', 11, 'β-Hsd-1', and, 11, 'β-Hsd-2', protein, levels, despite, observed, elevations, in, 'Nr3c1', and, 'Hsd11b2', mRNA])].
[sujeto(['This', 'sex-specific', effect, was, not, due, to, differences, in, the, methylation, of, the, 'GR', promoter, as, methylation, of, the, 'Nr3c1', gene, was, either, unchanged, '(', region, containing, the, 'egr-1']), verbo([binding]), complemento(['site)', or, similarly, reduced, '(', region, containing, the, 'SP-1', transcription, factor, binding, 'site)', in, both, males, and, females, exposed, to, arsenic])].
[sujeto(['Arsenic', did, produce, sex, and, 'age-specific', changes, in, the, methylation, of, 'Hsd11b1', 'gene,', producing]), verbo([increased]), complemento([methylation, in, females, at, 'E14', and, decreased, methylation, at, 'E18'])].
[sujeto(['It', is, possible, that, this, greater, 'anti-oxidative', capacity, within, the, females]), verbo([provides]), complemento([protection, against, low, to, moderate, arsenate])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, the, 'GR', signaling, system, in, female, offspring, was, not, as, affected, by, prenatal, arsenic, and, predicts, that, female, 'arsenic-exposed', mice, should, have, normal, 'GR', feedback, regulation])].
[sujeto(['Gender,', genetic, 'makeup,', and, prior, experience]), verbo([interact]), complemento([to, determine, physiological, responses, to, an, external, perceived, stressor])].
[sujeto(['Two', hundred, 'thirty-two', healthy, participants, were]), verbo([recruited]), complemento([and, underwent, the, experiment])].
[sujeto(['The', seCPT, group, had, a, clear, stress, 'reaction;', salivary, cortisol, levels, and, peak, systolic, and, diastolic, blood, pressure, all]), verbo([increased]), complemento([significantly, compared, to, the, control, group])].
[sujeto(['Higher', 'promoter-wide', methylation, levels, were]), verbo([associated]), complemento([with, decreased, baseline, blood, 'pressure,', and, when, incorporated, into, a, linear, mixed, effect, model, significantly, predicted, lower, systolic, and, diastolic, blood, pressure, evolution, over, time, in, response, to, the, experimental, manipulation])].
[sujeto(['The', underlying, genotype, significantly, predicted, methylation, 'levels;', 'particularly,', the, homozygous, 'BclI', minor, allele, was]), verbo([associated]), complemento([with, higher, methylation, in, promoter, 1, 'H', '(', p, =, 0.042, ')'])].
[sujeto(['The', seCPT]), verbo([induced]), complemento([a, strong, cardiovascular, and, 'HPA', axis, 'response,', and, both, systems, were, affected, by, the, functional, genetic, 'variants,', although, methylation, also, predicted, blood, pressure, reactivity])].
[sujeto(['Obesity', is]), verbo([associated]), complemento([with, hepatic, mitochondrial, dysfunction])].
[sujeto(['The', relationship, between, glucocorticoids, '(', 'GCs)', and, obesity]), verbo([has]), complemento([also, been, demonstrated, in, several, researches])].
[sujeto(['Both', the, translocation, of, 'GR', '(', 'NR3C1)', into, mitochondria, and, the]), verbo([binding]), complemento([of, 'GR', to, the, mtDNA, were, lower, in, the, liver, of, 'HFD', mice])].
[sujeto(['The', 'PGC1α', mRNA, 'expression,', protein, 'content,', and, translocation, into, mitochondria, were, also]), verbo([found]), complemento([to, be, 'reduced,', with, the, lower, 'GR', binding, to, the, promoter, region, of, 'PGC1α', in, the, liver, of, 'HFD', mice])].
[sujeto(['GR,', as, a, transcription, 'factor,', may, take, an, important, role, in, the, regulation, of, mitochondrial, oxidative, phosphorylation, in, the, 'HFD', mice, by]), verbo([interacting]), complemento([with, 'PGC1α', and, controlling, mtDNA, expression])].
[sujeto(['Clock', gene]), verbo([regulates]), complemento([the, circadian, rhythm, of, various, physiological, functions])].
[sujeto(['The', expression, of, clock, gene]), verbo([has]), complemento([been, shown, to, be, attenuated, by, certain, 'drugs,', resulting, in, a, rhythm, disorder])].
[sujeto(['The', purpose, of, this, study, was, to, investigate, the, influence, of, 'MMC', on, clock, gene, expression, in, 'fibroblasts,', the]), verbo([target]), complemento([cells, of, 'MMC'])].
[sujeto(['Following', 'MMC', 'treatment,', 'Bmal1', mRNA, levels, was, significantly, 'decreased,', whereas, 'Dbp,', 'Per1,', and, 'Rev-erbα', mRNA, levels, were, significantly]), verbo([increased]), complemento([in, the, mouse, fibroblast, cell, line, 'NIH3T3', cells])].
[sujeto(['MMC']), verbo([suppressed]), complemento([the, induction, of, 'Per1', mRNA, by, dexamethasone, '(', 'DEX),', ligand, of, 'GR,', in, 'NIH3T3', cells])].
[sujeto(['MMC', also]), verbo([modulated]), complemento([the, 'DEX-driven', circadian, oscillations, of, 'Per2::Luciferase', bioluminescence, in, 'mouse-derived', ocular, fibroblasts])].
[sujeto(['The', present, findings]), verbo([suggest]), complemento([that, 'MMC', combined, with, trabeculectomy, could, increase, the, risk, for, a, local, circadian, 'rhythm-disorder', at, the, ocular, surface])].
[sujeto(['In', human, 'patients,', response, to, corticosteroid, therapy]), verbo([has]), complemento([been, correlated, with, the, presence, of, certain, polymorphisms, of, the, glucocorticoid, receptor, gene, '(', 'NR3C1)'])].
[sujeto(['Depending', on, the, polymorphism, 'present,', patients, may, show, either]), verbo([increased]), complemento([sensitivity, to, 'glucocorticoid-induced', adverse, effects, or, resistance, to, their, therapeutic, effects])].
[sujeto(['The', amino, acid, changes]), verbo([caused]), complemento([by, c])].
[sujeto(['We', conclude, that, 'NR3C1', polymorphisms, occur, in, dogs, and, may]), verbo([cause]), complemento([individual, variation, in, response, to, corticosteroid, therapy])].
[sujeto(['Changes', in, methylation, levels, of, stress, reactivity, genes, such, as, the, glucocorticoid, receptor, gene, '(', 'NR3C1)', can, be]), verbo([induced]), complemento([by, adversity])].
[sujeto(['Higher', 'NR3C1', methylation, levels]), verbo([have]), complemento([been, associated, with, a, reduced, 'NR3C1', 'expression,', possibly, leading, to, impaired, negative, feedback, regulation, of, the, 'HPA-axis'])].
[sujeto(['In', this, study, we, tested, whether, methylation, levels, of, 'NR3C1', were]), verbo([associated]), complemento([with, 'HPA-axis', 'regulation,', operationalized, as, cortisol, responses])].
[sujeto(['Higher', 'NR3C1', methylation, levels, were]), verbo([associated]), complemento([with, a, flattened, cortisol, recovery, 'slope,', indicating, a, delayed, recovery, time])].
[sujeto(['Cortisol', response, activation, was, not]), verbo([associated]), complemento([with, 'NR3C1', methylation])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, methylation, of, 'NR3C1', may, impair, negative, feedback, of, the, 'HPA-axis', in, adolescents])].
[sujeto(['This', study, also]), verbo([found]), complemento([that, the, global, methylation, status, of, 'PBMCs', in, 'SLE', patients, was, obviously, lower, than, healthy, 'controls,', and, it, was, related, to, the, elevated, 'GADD45α', mRNA, expression, in, 'SLE', patients])].
[sujeto(['These', conclusions]), verbo([have]), complemento([to, be, certified, by, 'larger-scale', clinical, studies])].
[sujeto(['The', transcription, factor, 'E-twenty-six', version, 5, '(', 'ETV5)']), verbo([has]), complemento([been, linked, with, obesity, in, 'genome-wide', association, studies])].
[sujeto(['Moreover,', 'ETV5-deficient', mice, '(', 'knockout;', 'KO)']), verbo([have]), complemento([reduced, body, 'weight,', lower, fat, 'mass,', and, are, resistant, to, 'diet-induced', 'obesity,', directly, linking, 'ETV5', to, the, regulation, of, energy, balance, and, metabolism])].
[sujeto(['ETV5', is]), verbo([expressed]), complemento([in, hypothalamic, brain, regions, that, regulate, both, metabolism, and, 'HPA', axis, 'activity,', suggesting, that, 'ETV5', may, also, modulate, 'HPA', axis, function])].
[sujeto(['ETV5', deficiency]), verbo([increased]), complemento([both, 'pre-', and, 'post-stress', plasma, 'corticosterone,', suggesting, that, loss, of, 'ETV5', elevated, glucocorticoid, tone])].
[sujeto(['Consistent', with, this, 'idea,', 'ETV5', 'KO', mice]), verbo([have]), complemento([reduced, thymus, 'weight,', suggestive, of, increased, 'glucocorticoid-induced', thymic, involution])].
[sujeto(['ETV5', deficiency, also]), verbo([decreased]), complemento([the, mRNA, expression, of, glucocorticoid, receptor, '(', 'GR),', mineralocorticoid, receptor, '(', 'MR),', and, vasopressin, receptor, 1, 'A', in, the, 'hypothalamus,', without, altering, 'vasopressin,', 'corticotropin-releasing', 'hormone,', or, oxytocin, mRNA, expression])].
[sujeto(['Dexamethasone', reduced, plasma, corticosterone, in, both, 'ETV5', 'KO', and, 'WT', 'mice,']), verbo([suggesting]), complemento([that, glucocorticoid, negative, feedback, was, unaltered, by, 'ETV5', deficiency])].
[sujeto(['In', 'summary,', these, data]), verbo([suggest]), complemento([that, the, 'obesity-associated', transcription, factor, 'ETV5', normally, acts, to, diminish, circulating, glucocorticoids])].
[sujeto(['We', studied, the, association, between, the, presence, of, glucocorticoid, receptor, '(', 'GR)', and, 'glucocorticoid-induced', transcript, 1, '(', 'GLCCI1)', gene, 'polymorphisms,', which]), verbo([modulate]), complemento(['GC', 'sensitivity,', and, baseline, disease, activity, score, '(', 'DAS)', and, efficacy, of, 'GC', bridging, therapy, in, 'RA'])].
[sujeto(['In', vivo, 'GC', sensitivity, was]), verbo([expressed]), complemento([as, the, relative, decrease, in, 'DAS', following, 2, &, 'nbsp;weeks', of, standardized, 'GC', therapy])].
[sujeto(['All', patients, were, genotyped, for, the, 'GR', polymorphisms, 'BclI', '(', 'rs41423247),', 'N363S', '(', 'rs6195),', 9, β, '(', 'rs6198),', 'ER22/23EK', '(', 'rs6189 + rs6190),', and, the, 'GLCCI1', variant, rs37972, and, subsequently, divided, in, groups, carrying, a, polymorphism]), verbo([associated]), complemento([with, increased, 'GC', sensitivity, '(', 'BclI-G', 'allele,', 'N363S-G', 'allele,', 'GLCCI1-C', 'allele)', or, decreased, 'GC', sensitivity, '(', 9, 'β-G', 'allele,', 'ER22/23EK-A/A', 'allele,', 'GLCCI1-T', 'allele)'])].
[sujeto(['Differences', in, baseline, 'DAS', and, relative]), verbo([decrease]), complemento([in, 'DAS', in, the, different, genotype, groups, were, analyzed, using, analysis, of, covariance, and, linear, regression])].
[sujeto(['Baseline', 'DAS', was, higher, in, patients, who, carried, polymorphisms, of, the, 'GR', and, 'GLCCI1', genes]), verbo([associated]), complemento([with, decreased, 'GC', sensitivity])].
[sujeto(['GLCCI1', 'genotype,', but, not, 'GR', 'genotypes,', was]), verbo([associated]), complemento([with, improvement, in, 'DAS', in, male, patients, with, 'RA'])].
[sujeto(['The', 'GLCCI1', gene, minor, allele, '(', 'rs37972)', may, be]), verbo([associated]), complemento([with, less, efficient, 'GC', bridging, therapy, in, male, 'RA', patients])].
[sujeto(['Carriers', of, the, 'BclI-G,', 'N363S-G,', or, 'GLCCI1-C', alleles, had, lower, levels, of, baseline, disease, 'activity,']), verbo([suggesting]), complemento([a, role, for, the, 'GLCCI1', and, 'GR', gene, in, regulation, of, 'GC', sensitivity, to, endogenously, produced, cortisol])].
[sujeto(['GCs', after]), verbo([binding]), complemento([to, the, glucocorticoid, receptor, '(', 'GR)', form, the, complex, '(', transcription, 'factor),', which, acts, on, promoter, and, regulatory, parts, of, genes, enhancing, the, expression, of, 'anti-inflammatory', proteins, and, decreasing, the, proinflammatory, protein, 'synthesis,', including, numerous, cytokines, mediating, inflammation, in, the, course, of, asthma])].
[sujeto(['Non-sensitivity', or, resistance, to, 'GCs', favours, an]), verbo([increase]), complemento([in, the, 'TGF-β', expression])].
[sujeto(['This', cytokine, plays, a, central, role, in, asthma]), verbo([inducing]), complemento([fibroblast, differentiation, and, extracellular, matrix, synthesis])].
[sujeto(['GCs', reduce, 'TGF-β', 1, and, 'TGF-β', 2, production, and, significantly]), verbo([decrease]), complemento([the, expression, of, upregulated, 'TGF-β', 1, and, 'TGF-β', 2, mRNA, induced, by, exogenous, 'TGF-β'])].
[sujeto(['A', total, of, 173, patients, with, asthma, and, 163, healthy, volunteers]), verbo([participated]), complemento([in, the, study])].
[sujeto(['The', significance, of, 'AA', and, 'GG', genotypes, of, 'Tth111I', 'SNP', in]), verbo([increasing]), complemento([and, decreasing, the, level, of, the, 'TGF-β', 1, mRNA, expression, was, demonstrated])].
[sujeto(['The', 'N363S', 'SNP', 'AA', genotype, of, 'NR3C1', gene, statistically, significantly, influenced, the]), verbo([increase]), complemento([in, the, level, of, the, 'TGF-β', 1, mRNA, expression])].
[sujeto(['In', the, case, of, the, occurrence, of, 'Tth111I', and, 'N363S', polymorphic, forms, of, the, gene, 'studied,', a, reduced, ability, of, 'GCs', to]), verbo([inhibit]), complemento([the, 'TGF-β', 1, expression, can, be, observed])].
[sujeto(['Maternal', smoking, is, one, of, the, most, important, modifiable, risk, factors, for, low, 'birthweight,', which, is, strongly]), verbo([associated]), complemento([with, increased, cardiometabolic, disease, risk, in, adulthood])].
[sujeto(['Maternal', smoking, reduces, the, levels, of, the, methyl, donor, vitamin, 'B12', and, is]), verbo([associated]), complemento([with, altered, 'DNA', methylation, at, birth])].
[sujeto(['Altered', 'DNA', methylation, may, be, an, important, mechanism, underlying]), verbo([increased]), complemento([disease, 'susceptibility;', 'however,', the, extent, to, which, this, can, be, induced, in, the, developing, fetus, is, unknown])].
[sujeto(['In', addition, to, identifying, baseline, sex, 'differences,', we]), verbo([found]), complemento([that, maternal, smoking, was, associated, with, 'sex-specific', alterations, of, fetal, liver, vitamin, 'B12,', plasma, homocysteine, and, expression, of, enzymes, in, the, 1, -, carbon, cycle, in, fetal, liver])].
[sujeto(['Our', unique, data, strengthen, studies, linking, in, utero, exposures, to, altered, 'DNA', methylation, by, 'showing,', for, the, first, 'time,', that, such, changes, are, present, in, fetal, life, and, in, a, key, metabolic]), verbo([target]), complemento(['tissue,', human, fetal, liver])].
[sujeto(['However,', glucocorticoid, resistance, often]), verbo([leads]), complemento([to, suboptimal, asthma, control])].
[sujeto(['Pre-treatment', with, tumor, necrosis, 'factor-α', '(', 'TNF)', or, 'interleukin-1β']), verbo([inhibited]), complemento(['dexamethasone-induced', mRNA, expression, of, the, putative, 'anti-inflammatory', genes, 'RGS2', and, 'TSC22D3,', or, just, 'TSC22D3,', in, primary, human, airway, epithelial, and, smooth, muscle, 'cells,', respectively])].
[sujeto(['However,', neither, inhibitor, affected, 'TNF-dependent']), verbo([loss]), complemento([of, 'dexamethasone-induced', 'CDKN1C', or, 'TSC22D3', mRNA])].
[sujeto(['Full', and, partial, agonists, showed, various, degrees, of, agonism, on, 'RGS2', and, 'TSC22D3', 'expression,', but, were, equally, effective, at]), verbo([inducing]), complemento(['CDKN1C', and, 'DUSP1,', and, did, not, affect, the, repression, of, 'CDKN1C', or, 'TSC22D3', expression, by, 'TNF'])].
[sujeto(['Chronic', stress, alters, the, 'hypothalamic-pituitary-adrenal', 'axis,']), verbo([increases]), complemento([gut, 'motility,', and, increases, the, perception, of, visceral, pain])].
[sujeto(['We', investigated, whether, epigenetic, mechanisms]), verbo([regulate]), complemento([chronic, 'stress-induced', visceral, pain, in, the, peripheral, nervous, systems, of, rats])].
[sujeto(['Chronic', stress, was]), verbo([associated]), complemento([with, increased, methylation, of, the, 'Nr3c1', promoter, and, reduced, expression, of, this, gene, in, 'L6-S2,', but, not, 'L4-L5,', 'DRGs'])].
[sujeto(['Stress', also, was]), verbo([associated]), complemento([with, 'up-regulation', in, 'DNMT1-associated', methylation, of, the, 'Cnr1', promoter, and, 'down-regulation', of, 'glucocorticoid-receptor-mediated', expression, of, 'CNR1', in, 'L6-S2,', but, not, 'L4-L5,', 'DRGs'])].
[sujeto(['Concurrently,', chronic, stress]), verbo([increased]), complemento([expression, of, the, histone, acetyltransferase, 'EP300', and, increased, histone, acetylation, at, the, 'Trpv1', promoter, and, expression, of, the, 'TRPV1', receptor, in, 'L6-S2', 'DRG', neurons])].
[sujeto(['Knockdown', of, 'DNMT1', and, 'EP300', in, 'L6-S2', 'DRG', neurons, of, rats, reduced, 'DNA', methylation, and, histone, 'acetylation,', 'respectively,', and]), verbo([prevented]), complemento([chronic, 'stress-induced', increases, in, visceral, pain])].
[sujeto(['Chronic', stress]), verbo([increases]), complemento(['DNA', methylation, and, histone, acetylation, of, genes, that, regulate, visceral, pain, sensation, in, the, peripheral, nervous, system, of, rats])].
[sujeto(['Type', 1, diabetes, is, a, multifactorial, inflammatory, disease, that, develops, as, a, result, of, deregulated, immune, 'responses,']), verbo([causing]), complemento([progressive, autoimmune, destruction, of, 'insulin-producing', beta, cells, of, pancreas])].
[sujeto(['Prophylactic', in, vivo, therapy, with, 'CpdA']), verbo([conferred]), complemento([protection, against, development, of, immunoinflammatory, diabetes, in, mice, by, dampening, the, 'M1/Th1/Th17', immune, response, and, switching, it, towards, an, 'anti-inflammatory', 'M2/Th2/Treg', 'profile,', thus, preserving, beta, cell, function])].
[sujeto(['Anti-diabetic', properties, of, 'CpdA', are]), verbo([mediated]), complemento([through, modulation, of, immune, 'cell-mediated', 'pathways,', but, without, triggering, adverse, events])].
[sujeto(['These', findings]), verbo([provide]), complemento([basic, information, for, the, therapeutic, use, of, selective, 'GR', agonists, in, the, amelioration, of, 'islet-directed', autoimmunity])].
[sujeto(['Glucocorticoids']), verbo([act]), complemento([on, the, glucocorticoid, receptor, '(', 'NR3C1)', to, repress, inflammatory, gene, expression])].
[sujeto(['IL1B', rapidly]), verbo([induced]), complemento(['DUSP1', expression, and, 'RNA', silencing, revealed, a, transient, role, in, feedback, inhibition, of, 'MAPKs', and, inflammatory, gene, expression])].
[sujeto(['With', 'dexamethasone,', which]), verbo([induced]), complemento(['DUSP1', 'expression,', plus, 'IL1B', '(', 'co-treatment),', 'DUSP1', expression, was, further, enhanced])].
[sujeto(['Whereas,', 'CCL20', mRNA, was, not]), verbo([repressed]), complemento([by, dexamethasone, at, 1, 'h,', repression, of, 'CCL2,', 'CXCL3,', 'IL6,', and, 'IL8', was, 'unaffected,', and, 'PTGS2', repression, was, partially, affected, by, 'DUSP1', knockdown])].
[sujeto(['Therefore', this, also, illustrates, key, roles, for, 'DUSP1-independent', effectors, in]), verbo([mediating]), complemento(['glucocorticoid-dependent', repression])].
[sujeto(['Because', 'GR', expression]), verbo([increases]), complemento([in, a, subset, of, primary, prostate, cancer, '(', 'PC)', following, androgen, deprivation, 'therapy,', we, sought, to, determine, whether, 'GR', activation, can, contribute, to, resistance, to, 'AR-directed', therapy])].
[sujeto(['Cell', lines, stably]), verbo([expressing]), complemento(['GR', '(', 'NR3C1)-targeted', shRNA, or, ectopic, 'SGK1-Flag', were, also, studied, in, vivo])].
[sujeto(['In', 'addition,', 'GR', activation]), verbo([increased]), complemento(['prostate-specific', antigen, '(', 'PSA)', secretion, and, induced, 'SGKI', and, 'MKP1/DUSP', gene, expression])].
[sujeto(['We', studied, several, 'PC', models, before, and, following, treatment, with, androgen, blockade, and]), verbo([found]), complemento([that, increased, 'GR', expression, and, activity, contributed, to, 'tumor-promoting', 'PC', cell, viability])].
[sujeto(['Increased', 'GR-regulated', 'SGK1', expression, 'appears,', at, least, in, 'part,', to]), verbo([mediate]), complemento([enhanced, 'PC', cell, survival])].
[sujeto(['Women']), verbo([reporting]), complemento([childhood, abuse, victimization, exhibited, higher, mean, 'NR3C1', methylation, levels, than, nonabused, 'women,', with, a, clear, 'dose-response', relationship])].
[sujeto(['NR3C1', mean, methylation, was, higher, among, women, who]), verbo([reported]), complemento([childhood, abuse])].
[sujeto(['Initial']), verbo([reports]), complemento([of, large, differences, in, methylation, level, in, genomic, regulatory, 'regions,', coupled, with, clear, gene, expression, data, in, both, imprinted, genes, and, malignant, 'diseases,', provided, easily, dissected, molecular, mechanisms, for, switching, genes, on, or, off])].
[sujeto(['However,', a, more, subtle, process, is, becoming, 'evident,', where, small, '(', &, 'lt;10 %)', changes, to, intermediate, methylation, levels, are]), verbo([associated]), complemento([with, complex, disease, phenotypes])].
[sujeto(['This']), verbo([has]), complemento([resulted, in, two, clear, methylation, paradigms])].
[sujeto(['Our', initial, expectation, of, rapidly, identifying, mechanisms, linking, environmental, exposure, to, a, disease, phenotype]), verbo([led]), complemento([to, numerous, 'observational/association', studies, being, performed])].
[sujeto(['Although', this, expectation, remains, 'unmet,', there, is, now, a, growing, body, of, literature, on, specific, 'genes,']), verbo([suggesting]), complemento([wide, ranging, transcriptional, and, translational, consequences, of, such, subtle, methylation, changes])].
[sujeto(['Data', from, the, glucocorticoid, receptor, '(', 'NR3C1)']), verbo([has]), complemento([shown, that, a, complex, interplay, between, 'DNA', 'methylation,', extensive, 5, '\'', 'UTR', 'splicing,', and, microvariability, gives, rise, to, the, overall, level, and, relative, distribution, of, total, and, 'N-terminal', protein, isoforms, generated])].
[sujeto(['Additionally,', the, presence, of, multiple, 'AUG', translation, initiation, codons, throughout, the, 'complete,', processed, mRNA, enables, translation, 'variability,', hereby]), verbo([enhancing]), complemento([the, translational, isoforms, and, the, resulting, protein, isoform, 'diversity,', providing, a, clear, link, between, small, changes, in, 'DNA', methylation, and, significant, changes, in, protein, isoforms, and, cellular, locations])].
[sujeto(['The', aim, of, the, present, investigation, was, to, examine, the, effect, of, inhibition, of, endoplasmic, reticulum, stress, 'signaling,']), verbo([mediated]), complemento([by, 'IRE1', '(', inositol, requiring, enzyme, 1, ')', ',', which, is, a, central, mediator, of, the, unfolded, protein, response, on, the, expression, of, genes, encoding, glucocorticoid, receptor, '(', 'NR3C1)', and, some, related, proteins, '(', 'SGK1,', 'SGK3,', 'NCOA1,', 'NCOA2,', 'ARHGAP35,', 'NNT)', and, their, hypoxic, regulation, in, 'U87', glioma, cells, for, evaluation, of, their, possible, significance, in, the, control, of, the, glioma, growth])].
[sujeto(['We']), verbo([have]), complemento([also, shown, that, hypoxia, increases, the, expression, of, 'NR3C1,', 'SGK1,', 'NCOA2,', 'ARHGAP35,', and, 'NNT', genes, but, decreases, 'SGK3', and, 'NCOA1', genes, expression, in, control, glioma, cells])].
[sujeto(['Moreover,', the, inhibition, of, both, enzymatic, activities, '(', kinase, and, 'endoribonuclease)', of, 'IRE1', in, 'U87', glioma, cells]), verbo([enhances]), complemento([the, eff, ect, of, hypoxia, on, the, expression, of, 'SGK1,', 'SGK3,', and, 'NNT', 'genes,', but, decreases, the, sensitivity, of, 'NR3C1', gene, to, hypoxic, condition])].
[sujeto(['Results', of, this, investigation, demonstrate, that, inhibition, of, 'IRE1', signaling, enzyme, function, affects, the, expression, of, 'NR3C1,', 'SGK1,', 'SGK3,', 'NCOA1,', 'NCOA2,', 'ARHGAP35,', and, 'NNT', genes, in, 'U87', glioma, cells, in, gene, specific, manner, and, that, all, these, genes, are]), verbo([regulated]), complemento([by, hypoxia, preferentially, through, 'IRE1', signaling, pathway, of, the, endoplasmic, reticulum, stress])].
[sujeto(['Genetic', variations, in, the, glucocorticoid, receptor, '(', 'GR)', and, the, mineralocorticoid, receptor, '(', 'MR)']), verbo([have]), complemento([been, associated, with, maladaptive, stress, responses, and, major, depressive, disorder, '(', 'MDD)'])].
[sujeto(['In', a, 'case-control', study, 'design,', we, examined, whether, single, nucleotide, polymorphisms, '(', 'SNPs)', and, haploid, genotype, '(', 'haplotype)', associations, of, 'MR', gene, 'NR3C2,', 'GR', gene, 'NR3C1', and, genes, of, 'GR', chaperone, molecules, 'FK506']), verbo([binding]), complemento([protein, 5, '(', 'FKBP5)', and, 'corticotrophin-releasing', hormone, receptor, 1, '(', 'CRHR1)', differed, between, healthy, subjects, '(', 'n = 634)', and, inpatients, with, major, depressive, disorder, '(', 'n = 412)'])].
[sujeto(['In', 'contrast,', 'NR3C2,', 'FKBP5', and, 'CRHR1', polymorphisms, were, not, significantly]), verbo([associated]), complemento([with, 'MDD'])].
[sujeto(['Our', results, support, the, notion, of, an, association, between, variants, of, 'GR-related', genes, in, women, and, the, pathophysiology, of, 'depression:', females, suffering, from, 'MDD', showed, a, more, than, three, times, higher, frequency, of, the, 'T/C', polymorphism, compared, to, 'controls,', which, thus, seems, to]), verbo([increase]), complemento([the, vulnerability, to, depression, in, females])].
[sujeto(['The', endocrine, mechanisms, that]), verbo([lead]), complemento([to, initiation, of, parturition, in, dogs, are, still, not, fully, understood])].
[sujeto(['The', prepartum, luteolysis, is]), verbo([associated]), complemento([with, increased, prostaglandin, '(', 'PG)', 'F2α', 'secretion;', 'however,', there, is, no, 'pregnancy-', or, 'parturition-related', increase, in, estrogens])].
[sujeto(['Moreover,', unlike, in, other, mammalian, 'species,', in, the, 'dog,']), verbo([increased]), complemento([peripartum, levels, of, cortisol, measured, sporadically, in, maternal, peripheral, blood, are, not, mandatory, for, normal, parturition])].
[sujeto(['The', 'Ut/Pl', expression, of, 'GR/NR3C1', did, not, change, significantly, from, 'pre-implantation', until, 'mid-gestation;', 'however,', it, was, strongly]), verbo([induced]), complemento([during, the, prepartum, luteolysis])].
[sujeto(['Compartmentalization', studies, within, the, 'Ut/Pl', 'units,']), verbo([involving]), complemento(['placenta,', endometrium, and, myometrium, 'separately,', performed, at, the, prepartum, luteolysis, revealed, the, highest, 'GR/NR3C1-mRNA', levels, in, placenta, compared, with, endometrium, and, myometrium])].
[sujeto(['In', 'conclusion,']), verbo([increased]), complemento([expression, of, 'GR/NR3C1', during, normal, 'parturition,', but, not, following, 'antigestagen-treatment,', suggest, that, it, is, not, required, for, initiating, the, signaling, cascade, of, 'PG', synthesis, leading, to, the, induction, of, parturition, in, the, dog])].
[sujeto(['The', 'hypothalamic-pituitary-adrenal', '(', 'HPA)', axis]), verbo([has]), complemento([been, implicated, in, the, pathophysiology, of, a, variety, of, mood, and, cognitive, disorders])].
[sujeto(['Neuroendocrine', studies]), verbo([have]), complemento([demonstrated, 'HPA', axis, overactivity, in, major, 'depression,', a, relationship, of, 'HPA', axis, activity, to, cognitive, performance, and, a, potential, role, of, 'HPA', axis, genetic, variation, in, cognition])].
[sujeto(['After', all, 'DEX', 'doses,', a, lower, number, of, 'MetS', patients]), verbo([suppressed]), complemento(['PF', and, 'SF', compared, to, controls])].
[sujeto(['MetS', patients, exhibited]), verbo([decreased]), complemento(['HPA', sensitivity, to, glucocorticoid, feedback])].
[sujeto(['Variation', in, genes]), verbo([regulating]), complemento([the, 'HPA', axis, -, particularly, the, glucocorticoid, receptor, -, may, facilitate, adaptation, to, changing, climatic, conditions, by, altering, expression])].
[sujeto(['Although', we]), verbo([find]), complemento([some, evidence, of, positive, 'selection,', substitution, rate, is, negatively, correlated, with, variance, in, precipitation])].
[sujeto(['This']), verbo([suggests]), complemento([climatic, cycling, in, 'sub-Saharan', 'Africa', may, have, resulted, in, lower, substitution, rates, to, maintain, a, successful, coping, strategy])].
[sujeto(['Altered', 'DNA', methylation, '(', 'DNAm)', levels, of, 'hypothalamic-pituitary-adrenal', '(', 'HPA)', axis, genes]), verbo([has]), complemento([been, associated, with, exposure, to, childhood, maltreatment, '(', 'CM)', and, 'depression;', 'however,', it, is, unknown, whether, 'CM', and, depression, have, joint, and, potentially, interacting, effects, on, the, glucocorticoid, receptor, '(', 'NR3C1)', 'DNAm'])].
[sujeto(['Both', 'CM', and, 'MDD', were, significant, predictors, of, 'NR3C1', 'DNAm:', 'CM', was]), verbo([associated]), complemento([with, an, increase, in, 'DNAm', in, an, 'EGR1', transcription, factor, binding, site, '(', 'TFBS),', whereas, 'MDD', was, associated, with, a, decrease, in, 'DNAm', downstream, of, the, 'TFBS'])].
[sujeto(['CM', alone, was]), verbo([associated]), complemento([with, significantly, lower, 'NR3C1', 'GE'])].
[sujeto(['Our']), verbo([report]), complemento([of, 'CM', is, a, retrospective, 'self-report', of, 'abuse,', which, may, introduce, recall, bias])].
[sujeto(['CM', and, 'MDD', are, both]), verbo([associated]), complemento([with, altered, 'DNAm', levels, in, the, 'NR3C1', promoter, 'region,', however, the, location, and, direction, of, effects, differ, between, the, two, 'exposures,', and, the, functional, 'effects,', as, measured, by, 'GE,', appear, to, be, limited, to, 'CM', exposure, alone])].
[sujeto(['We', examined, whether, 'DNA', methylation, of, the, glucocorticoid, receptor, 'gene,', 'NR3C1,', was]), verbo([associated]), complemento([with, experiences, of, stress, by, an, expectant, mother, and, fearfulness, in, her, infant])].
[sujeto(['Mothers']), verbo([reported]), complemento([on, prenatal, stress, and, infant, temperament, when, infants, were, 5, months, old, '(', n, =, 68, ')'])].
[sujeto(['Exploratory', 'sex-specific', analysis, revealed, a, 'trend-level', association, between, prenatal, stress, and]), verbo([increased]), complemento([methylation, of, 'NR3C1', exon, 1, 'F', for, 'female,', but, not, 'male,', infants])].
[sujeto(['In', 'addition,']), verbo([increased]), complemento([methylation, was, significantly, associated, with, greater, fearfulness, for, females])].
[sujeto(['Results']), verbo([suggest]), complemento([an, 'experience-dependent', pathway, to, fearfulness, for, female, infants, via, epigenetic, modification, of, the, glucocorticoid, receptor, gene])].
[sujeto(['RT-qPCR']), verbo([requires]), complemento([a, suitable, set, of, internal, control, genes, '(', 'ICGs)', for, an, accurate, normalization])].
[sujeto(['The', use, of, a, different, subset, 'ICGs', out, of, the, 7, 'investigated,', although, not, statistically, affected, by, the, 'conditions,', biased, the, 'results,', as, demonstrated, through, changes, in, expression, of, glucocorticoid, receptor, '(', 'NR3C1)', mRNA, as, a]), verbo([target]), complemento([gene])].
[sujeto(['Cancer', diagnosis, is]), verbo([associated]), complemento([with, an, increased, suicide, 'risk,', particularly, within, the, first, 1, &, 'nbsp;year', after, diagnosis, of, cancer])].
[sujeto(['Abnormal', function, of, the, 'hypothalamic-pituitary-adrenal', axis]), verbo([has]), complemento([been, implicated, in, the, pathophysiology, of, depression, and, suicide])].
[sujeto(['Subjects', carrying, the, 'GG', genotype, of, 'Bcl-1', polymorphism, were, at]), verbo([increased]), complemento([risk, of, early, suicide, when, compared, to, those, carrying, the, 'CC', genotype, '(', 'OR', 3.8, ',', 95, &, 'nbsp;%', 'CI', 1.02, -, 14.16, ',', 'p = '])].
[sujeto(['Similarly,', those, individuals, carrying, the, 'GG', genotype, '(', recessive, 'mode)', had, an]), verbo([increased]), complemento([risk, of, early, suicide, relative, to, the, 'CC', or, 'CG', genotype, '(', 'OR', 3.71, ',', 95, &, 'nbsp;%', 'CI', 1.03, -, 13.43, ',', 'p = '])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, the, 'NR3C1', 'Bcl-1', polymorphisms, may, be, involved, in, the, susceptibility, to, suicide, within, the, first, year, after, cancer, diagnosis, among, cancer, patients, in, 'Korean', population])].
[sujeto(['Since', depression]), verbo([has]), complemento([been, associated, to, dysregulation, of, the, 'hypothalamic-pituitary-adrenal', 'axis,', this, study, evaluated, the, effects, of, 'SNPs', in, 'stress-related', genes, on, depressive, symptoms, of, crack, cocaine, addicts, at, early, abstinence, and, over, the, detoxification, treatment, '(', 4, 'th,', 11, th, and, 18, th, day, post, 'admission)'])].
[sujeto(['A', significant, main, effect, of, 'NR3C1-rs41423247', was, 'found,', where, the, 'C', minor, allele]), verbo([increased]), complemento([depressive, symptoms, at, early, abstinence])].
[sujeto(['This', analysis]), verbo([suggests]), complemento([that, the, presence, of, at, least, one, 'C', allele, is, worse, at, early, 'abstinence,', while, only, 'CC', genotype, appears, to, increase, depressive, symptoms, at, late, abstinence])].
[sujeto(['Also,', a, slight, effect, of, rs41423247, 'C', minor, allele]), verbo([increasing]), complemento([the, number, of, 're-hospitalizations', after, 2.5, years, was, found, '(', 'P=0'])].
[sujeto(['These', findings, are, in, agreement, with, previous, studies]), verbo([reporting]), complemento([an, influence, of, rs41423247, on, sensitivity, to, glucocorticoids, and, further, elucidate, its, resulting, effects, on, 'depressive-related', traits])].
[sujeto(['The', glucocorticoid, receptor, plays, a, pivotal, role, in, the, 'brain\'s', response, to, 'stress;', a, haplotype, of, functional, polymorphisms, in, the, 'NR3C1', gene, encoding, this, receptor]), verbo([has]), complemento([been, associated, with, 'attention-deficit', hyperactivity, disorder, '(', 'ADHD)'])].
[sujeto(['The', serotonin, transporter, '(', 5, -, 'HTT)', gene, polymorphism, 5, -, 'HTTLPR', is, known, to, influence, the, relation, between, stress, exposure, and, 'ADHD', 'severity,', which, may, be, partly, because, of, its]), verbo([reported]), complemento([effects, on, glucocorticoid, levels])].
[sujeto(['Neuroimaging,', genetic, and, stress, exposure, questionnaire, data, were, available, for, 539, adolescents, and, young, adults]), verbo([participating]), complemento([in, the, multicenter, 'ADHD', cohort, study, 'NeuroIMAGE', '(', average, 'age:', 17.2, 'years)'])].
[sujeto(['We']), verbo([found]), complemento([that, individuals, carrying, the, 'ADHD', risk, haplotype, of, 'NR3C1', showed, significantly, more, positive, relation, between, stress, exposure, and, 'ADHD', severity, than, 'non-carriers'])].
[sujeto(['The']), verbo([reported]), complemento([interplay, between, 'NR3C1', and, 5, -, 'HTT', may, further, explain, some, of, the, heterogeneity, between, studies, regarding, the, role, of, these, genes, and, 'hypothalamic-pituitary-adrenal', axis, activity, in, 'ADHD'])].
[sujeto(['We', examine, the, literature, addressing, associations, between, adverse, maternal, 'exposures,', perinatal, outcomes, and, methylation, of, key, genes]), verbo([regulating]), complemento([placental, cortisol, metabolism])].
[sujeto(['We', followed, 'Cochrane\'s', 'PRISMA']), verbo([reporting]), complemento([guidelines, '(', 2009, ')'])].
[sujeto(['NR3C1', and, 'HSD11', β, methylation, were]), verbo([associated]), complemento([with, adverse, infant, 'neurobehavior,', stress, 'response,', blood, pressure, and, physical, development])].
[sujeto(['In', utero, exposure, to, maternal, 'stress,', 'nutrition,', 'preeclampsia,', smoking, and, diabetes, were]), verbo([associated]), complemento([with, altered, 'NR3C1', and, 'HSD11', β, methylation])].
[sujeto(['NR3C1', and, 'HSD11', β, methylation, are, useful, biomarkers, of, specific, environmental, stressors]), verbo([associated]), complemento([with, important, perinatal, outcomes, that, determine, pediatric, and, adult, disease, risk])].
[sujeto(['Early', adversity]), verbo([increases]), complemento([risk, for, developing, psychopathology])].
[sujeto(['Mounting', evidence]), verbo([suggests]), complemento([that, early, adversity, is, associated, with, 'GR', promoter, methylation, and, gene, expression])].
[sujeto(['Few', studies]), verbo([have]), complemento([examined, links, between, 'GR', promoter, methylation, and, 'psychopathology,', and, findings, to, date, have, been, mixed])].
[sujeto(['Healthy', adult, participants, '(', 'N=340)', who, were, free, of, psychotropic, medications]), verbo([reported]), complemento([on, their, childhood, experiences, of, maltreatment, and, parental, death, and, desertion])].
[sujeto(['Childhood', adversity, and, a, history, of, past, 'substance-use', disorder, and, current, or, past, depressive, or, anxiety, disorders, were]), verbo([associated]), complemento([with, lower, levels, of, 'NR3C1', promoter, methylation, across, the, region, as, a, whole, and, at, individual, 'CpG', sites, '(', 'P<0'])].
[sujeto(['The', number, of, adversities, was, negatively]), verbo([associated]), complemento([with, 'NR3C1', methylation, in, participants, with, no, lifetime, disorder, '(', 'P=0'])].
[sujeto(['This']), verbo([finding]), complemento([stands, in, contrast, to, our, prior, 'work,', but, is, consistent, with, emerging, 'findings,', suggesting, complexity, in, the, regulation, of, this, gene])].
[sujeto(['Three', hundred, and, 'twenty-eight', patients, with, asthma, and, 60, healthy, volunteers, were]), verbo([recruited]), complemento([to, this, study])].
[sujeto(['The']), verbo([target]), complemento(['SNPs', were, genotyped, by, polymerase, chain, reaction, '(', 'PCR)-high', resolution, melting, and, 'PCR-restriction', fragment, length, polymorphism])].
[sujeto(['Neither', of, these, differences, were]), verbo([found]), complemento([to, be, statistically, significant])].
[sujeto(['In', 'conclusion,', 'SNPs', in, 'NR3C1', were, not, significantly]), verbo([associated]), complemento([with, asthma, in, patients, from, the, 'Henan', 'Province'])].
[sujeto(['Epigenetic', mechanisms]), verbo([regulating]), complemento([expression, of, the, glucocorticoid, receptor, gene, '(', 'NR3C1)', promoter, may, influence, behavioral, and, biological, aspects, of, stress, response, in, human, infants])].
[sujeto(['The', presence, of, high, fundamental, frequency, in, cry, '(', above, 1, 'kHz)']), verbo([has]), complemento([been, linked, to, poor, vocal, tract, 'control,', poor, regulation, of, stress, 'response,', and, may, be, an, indicator, or, poor, neurobehavioral, integrity])].
[sujeto(['In', primary, acute, lymphoblastic, leukemia, cells, exhibiting, de, novo, resistance, to, 'glucocorticoids,', we, recently, discovered]), verbo([decreased]), complemento([promoter, methylation, of, caspase, 1, '(', 'CASP1)', and, 'NLR', 'family,', pyrin, domain, containing, 3, '(', 'NLRP3),', which, resulted, in, increased, 'transcription,', constitutive, 'NALP3', '(', 'NACHT,', 'LRR', and, 'PYD', 'domains-containing', protein, 3, ')', inflammasome, 'activation,', and, caspase, 1, -, mediated, cleavage, of, the, glucocorticoid, receptor])].
[sujeto(['Stimulants', of, 'protease-activated', receptor, '(', 'PAR)(2)']), verbo([promote]), complemento([the, generation, of, the, bronchoprotective, prostanoid, prostaglandin, '(', 'PG)', 'E(2)', by, airway, epithelial, cells])].
[sujeto(['In', 'contrast,', glucocorticoids, reduce, the, levels, of, 'PGE(2)', in, airway, epithelial, cell, cultures, by, concomitantly]), verbo([inhibiting]), complemento([pathways, required, for, 'PGE(2)', synthesis, and, facilitating, pathways, involved, in, 'PGE(2)', inactivation])].
[sujeto(['The', aim, of, this, study, was, to, determine, whether, glucocorticoids]), verbo([inhibited]), complemento(['PAR(2)-mediated,', 'PGE(2)-dependent', responses, in, epithelial, cell, 'cultures,', in, intact, airway, 'preparations,', and, in, whole, animals])].
[sujeto(['In', cultures, of, 'A549', 'cells,', a, 'PAR(2)-activating', peptide, 'SLI-GRL-NH(2)', produced, concentration, and, 'time-dependent']), verbo([increases]), complemento([in, 'PGE(2)', 'levels,', which, were, significantly, enhanced, after, exposure, to, lipopolysaccharide, '(', 'LPS)'])].
[sujeto(['However,', 'SLIGRL-NH(2)-induced']), verbo([increases]), complemento([in, 'PGE(2)', levels, were, abolished, by, pretreatment, of, cells, with, the, 'glucocorticoid,', dexamethasone])].
[sujeto(['In', mouse, isolated, tracheal, 'preparations,', 'SLIGRL-NH(2)', and, 'PGE(2)']), verbo([induced]), complemento(['concentration-dependent', relaxation, responses, that, were, unaffected, by, 'dexamethasone,', irrespective, of, whether, dexamethasone, exposure, occurred, in, vitro, or, in, vivo])].
[sujeto(['Intranasal', administration, of, 'LPS', produced, a, pronounced]), verbo([increase]), complemento([in, the, numbers, of, neutrophils, recovered, from, the, bronchoalveolar, lavage, fluid, of, 'BALB/c', mice])].
[sujeto(['In', the, combined, presence, of, dexamethasone, and, 'f-LIGRL-NH(2)', or, dexamethasone, and, 'PGE(2),', the, number, of, neutrophils, was]), verbo([suppressed]), complemento([further, '(', 80, -, 83, '%', 'lower)'])].
[sujeto(['The', results, showed, that, overfeeding]), verbo([induced]), complemento([a, greater, increase, in, body, weight, '(', 'p=0'])].
[sujeto([36, ')']), verbo([increased]), complemento([more, in, the, 2.3, /, 2.3, kb, than, in, the, 4.5, /, 2.3, kb, subjects])].
[sujeto(['The', 2.3, /, 2.3, kb, genotype, was, also]), verbo([associated]), complemento([with, a, greater, increase, in, abdominal, visceral, fat, '(', 'p=0'])].
[sujeto(['In', 'conclusion,', 2.3, /, 2.3, kb, subjects, of, the, 'GRL', 'Bcl', 'I', polymorphism, experience, greater]), verbo([increases]), complemento([in, body, 'weight,', blood, pressure, and, cholesterol, levels, as, well, as, visceral, fat, than, 4.5, /, 2.3, kb, subjects, in, response, to, overfeeding])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, overfeeding, induces, an, atherogenic, profile, in, subjects, who, are, homozygotes, for, the, 2.3, kb, allele])].
[sujeto([placebo, in, both, 'studies),', 12.1, '%', with, mesalamine, 2.4, 'g,', and, 12.6, '%', with, budesonide, controlled, ileal]), verbo([release]), complemento([capsules, 9, mg])].
[sujeto(['A', 12, -, month, maintenance, therapy, study]), verbo([suggested]), complemento([that, budesonide, 'MMX', 6, mg, may, prolong, time, to, clinical, 'relapse:', 'Median', time, was, &, 'gt;1', year, with, budesonide, 'MMX', 6, mg, versus, 181, days, '(', p, =, 0.02, ')', with, 'placebo;', 'however,', further, studies, are, needed])].
[sujeto(['Cumulative', safety, and, tolerability, of, budesonide, 'MMX,', a, 'once-daily', oral, corticosteroid, for]), verbo([inducing]), complemento([mild, to, moderate, ulcerative, colitis, 'remission,', was, examined])].
[sujeto(['Patients', randomised, to, budesonide, 'MMX', 9, mg, '[', n, =, 288, ']', ',', 6, mg, '[', n, =, 254, ']', ',', or, placebo, '[', n, =, 293, ']', had, similar, rates, of, adverse, events, '[', 'AEs]', '[', 27.1, '%', ',', 24.8, '%', ',', and, 23.9, '%', ',', 'respectively]', and, serious, 'AEs', '[', 2.4, '%', ',', 2.0, '%', ',', and, 2.7, '%', ',', 'respectively];', 'treatment-related', 'AEs', and, serious, 'AEs', were]), verbo([reported]), complemento([by, 11.8, '%', and, 13.5, '%', ',', and, 5.9, '%', and, 2.2, '%', ',', 'respectively,', of, patients, receiving, budesonide, 'MMX', 3, mg, '[', n, =, 17, ']', or, 'open-label', budesonide, 'MMX', 9, mg, '[', n, =, 89, ']'])].
[sujeto(['Budesonide', 'MMX', was, not]), verbo([associated]), complemento([with, an, overall, increased, risk, for, 'glucocorticoid-related', adverse, effects])].
[sujeto(['Budesonide', 'MMX', 9, mg, was]), verbo([associated]), complemento([with, normal, mean, cortisol, concentrations, at, final, visit, and, an, 'AE', incidence, comparable, to, placebo])].
[sujeto(['Overall,', budesonide, 'MMX', was, safe, and, well, tolerated, for]), verbo([inducing]), complemento([remission, of, patients, with, mild, to, moderate, ulcerative, colitis])].
[sujeto(['In', the, year, before, 'enrollment,', more, 'infliximab-', than, 'other-treatments-only-treated', patients]), verbo([required]), complemento([surgical, intervention, '(', 17.4, '%', vs])].
[sujeto(['In', multivariate, logistic, regression, 'analyses,', treatment, with, prednisone, '(', hazard, ratio, '(', 'HR)', =, 2.14, ',', 95, '%', confidence, interval, '(', 'CI)', =, 1.55, ',', 2.95, ;, 'P', &, 'lt;', 0.001, ')', or, narcotic, analgesics, '(', 'HR', =, 1.79, ',', 95, '%', 'CI', =, 1.29, ',', 2.48, ;, 'P', &, 'lt;', 0.001, ')', and, age, '(', 'HR', =, 1.08, ',', 95, '%', 'CI', =, 1.07, ',', 1.09, ;, 'P', &, 'lt;', 0.001, ')', were]), verbo([associated]), complemento([with, increased, mortality, risk])].
[sujeto(['Neither', infliximab, nor, immunomodulator, treatment, was]), verbo([associated]), complemento([with, increased, mortality, risk])].
[sujeto(['Factors', independently]), verbo([associated]), complemento([with, serious, infections, included, 'moderate-to-severe', disease, activity, '(', 'HR', =, 2.24, ',', 95, '%', 'CI', =, 1.57, ',', 3.19, ;, 'P', &, 'lt;', 0.001, ')', ',', narcotic, analgesic, treatment, '(', 'HR', =, 1.98, ',', 95, '%', 'CI', =, 1.44, ',', 2.73, ;, 'P', &, 'lt;', 0.001, ')', ',', prednisone, therapy, '(', 'HR', =, 1.57, ',', 95, '%', 'CI', =, 1.17, ',', 2.1, ;, 'P', =, 0.002, ')', ',', and, infliximab, treatment, '(', 'HR', =, 1.43, ',', 95, '%', 'CI', =, 1.11, ',', 1.84, ;, 'P', =, 0.006, ')'])].
[sujeto(['An']), verbo([increased]), complemento([risk, of, serious, infection, with, infliximab, was, 'observed,', although, 'CD', severity, and, use, of, prednisone, or, narcotic, analgesics, carried, higher, risks])].
[sujeto(['Aim', 'To', evaluate, 'budesonide\'s', safety, profile, in, 'CD', 'patients,', in, 'particular,', incidences, of, clinically, important, 'AEs', known, to, be]), verbo([associated]), complemento([with, systemic, 'GCSs'])].
[sujeto(['Incidence', rates, were, 'similar,', except, for, higher, incidence, of, endocrine, disorders, in, budesonide, versus, placebo, patients, '(', 'P', =, 0.0042, ')']), verbo([caused]), complemento([by, a, higher, overall, occurrence, of, cutaneous, 'GCS', symptoms, '(', 'P', =, 0.0036, ')', in, the, budesonide, 'group;', differences, in, individual, symptoms, were, nonsignificant])].
[sujeto(['Occurrence', of, clinically, important, or, serious, 'AEs']), verbo([associated]), complemento([with, systemic, 'GCSs,', including, 'sepsis,', 'cataracts,', adrenal, insufficiency, was, rare, and, similar, between, groups])].
[sujeto(['Budesonide', treatment, for, up, to, 1, year, is, 'well-tolerated', in, 'CD', 'patients,', with, an, 'AE', profile, similar, to, placebo, and, only, rare, occurrences, of, clinically, important, 'AEs']), verbo([associated]), complemento([with, systemic, 'GCSs'])].
[sujeto(['Glucocorticoid', receptors, '(', 'GRs)', are, cytoplasmaticreceptors]), verbo([regulating]), complemento([the, expression, of, cortisol, and, bind, to, specific, sites, on, chromatin])].
[sujeto(['These', data, showed, a, significant]), verbo([increase]), complemento([in, body, 'weight,', body, mass, 'index,', abdominal, 'obesity,', fasting, 'glucose,', 'insulin,', and, homeostasis, model, assessment, over, the, 5, -, year, 'follow-up', among, homozygotes, for, the, rare, 'BclI', allele])].
[sujeto(['The', 'N363S', carrier, 'DMD', patients, showed, a, trend, towards, a, later, age, at]), verbo([loss]), complemento([of, ambulation, in, comparison, with, 'non-carrier', patients])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, the, 'N363S', 'GRL', polymorphism, may, be, implicated, in, the, long, term, response, to, glucocorticoids])].
[sujeto(['The', 'Crohn\'s', &, 'amp;', 'Colitis', 'Foundation', of, 'America', '(', 'CCFA)']), verbo([has]), complemento([indicated, that, its, recommendations, are, intended, to, serve, as, reference, points, for, clinical, 'decision-making,', not, as, rigid, 'standards,', 'limits,', or, rules])].
[sujeto(['Previous', studies]), verbo([have]), complemento([linked, the, 'N363S', variant, of, the, 'GRL', gene, to, increased, glucocorticoid, effects, such, as, higher, body, 'fat,', a, lower, 'lean-body', mass, and, a, larger, insulin, response, to, dexamethasone])].
[sujeto(['However,', contradictory, findings]), verbo([have]), complemento([been, also, reported, about, the, association, between, this, variant, and, obesity, phenotypes])].
[sujeto(['Although', certain, genotypic, effects, could, be, 'population-specific,', we, conclude, that, there, is, no, compelling, evidence, that, the, 'N363S', polymorphism, of, the, 'GRL', gene, is]), verbo([associated]), complemento([with, either, average, 'BMI', or, obesity, risk])].
[sujeto(['In', multivariate, logistic, regression, 'analysis,', only, prednisone, was]), verbo([associated]), complemento([with, an, increased, mortality, risk, '(', odds, ratio, '[', 'OR],', 2.1, ;, 95, '%', 'CI,', 1.15, -, 3.83, ;, 'P='])].
[sujeto(['Although', the, unadjusted, analysis, showed, an]), verbo([increased]), complemento([risk, for, infection, with, infliximab, 'use,', multivariate, logistic, regression, analysis, suggested, that, infliximab, was, not, an, independent, predictor, of, serious, infections, '(', 'OR,'])].
[sujeto(['Factors', independently]), verbo([associated]), complemento([with, serious, infections, included, prednisone, use, '(', 'OR,', 2.21, ;, 95, '%', 'CI,', 1.46, -, 3.34, ;, 'P<'])].
[sujeto(['The']), verbo([increased]), complemento([risk, for, serious, infection, observed, with, infliximab, likely, was, owing, to, disease, severity, and, prednisone, use])].
[sujeto(['In', order, to, investigate, whether, the, variances, in, the, candidate, genes, '(', 'Insulin', receptor, substrate, 'IRS-1,', 'beta3-adrenergic', receptor, 'ADRB3,', 3, 'beta-hydro-xysteroid', dehydrogenase, 'HSD3B2,', glucocorticoid, receptor, 'GRL', and, 21, -, hydroxylase, 'CYP21)', which, affect, the, metabolism, of, adrenal, steroids, hormone, and, body, 'composition,', are]), verbo([associated]), complemento([with, precocious, puberty, in, 'Chinese', girls])].
[sujeto(['Among', these, six, activity, 'SNPs', in, five, candidate, 'genes,', 'IRS-1', 972, 'R', was, statistically]), verbo([associated]), complemento([with, the, onset, time, of, puberty, in, 'Chinese', girls])].
[sujeto(['In', order, to, confirm, whether, the, candidate, genes]), verbo([have]), complemento([any, other, activity, 'SNPs', that, are, associated, with, the, onset, time, of, puberty, in, 'Chinese', 'girls,', resequencing, of, these, candidate, genes, is, needed, in, following, time])].
[sujeto(['We', examined, 'biological,', 'psychological,', and, genetic, determinants]), verbo([associated]), complemento([with, weight, maintenance, '(', 'WM)', after, weight, loss])].
[sujeto(['BW']), verbo([loss]), complemento([was, 7.0, +, /, -, 3.1, kg])].
[sujeto(['Compared', with, unsuccessful, 'subjects,', successful, subjects, had, a, higher]), verbo([increase]), complemento([in, dietary, restraint, over, time, '(', 4.8, +, /, -, 5.0, and, 1.8, +, /, -, 3.9, ',', 'respectively;', 'P', &, 'lt;', 0.01, ')', but, significantly, less, sensation, of, general, hunger, '(', -, 4.0, +, /, -, 4.9, and, -, 1.2, +, /, -, 2.7, ',', 'respectively;', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['The', more, successful, genotypes, showed, a, higher, baseline, body, mass, index, and, waist, circumference, '(', 'PPARgamma2),', a, greater]), verbo([decrease]), complemento([in, disinhibition, of, dietary, restraint, '(', 'GRL),', and, less, sensation, of, hunger, '(', 'GRL)'])].
[sujeto(['Management', strategies, for, 'Crohn\'s', must, therefore, be]), verbo([targeted]), complemento([toward, lifelong, 'management,', taking, into, consideration, not, only, the, 'short-term', but, also, the, 'long-term', aspects, of, the, disease])].
[sujeto(['Male', and, female, preadolescents, and, adolescents, who]), verbo([participated]), complemento([in, phase, 1, of, the, 'Québec', 'Family', 'Study,', and, who, were, retested, about, 12, yr, 'later,', were, recruited, and, subdivided, on, the, basis, of, a, genetic, variant, within, the, intron, 2, of, the, glucocorticoid, receptor, '(', 'GRL', 'IVS2-BclI)'])].
[sujeto(['The']), verbo([increase]), complemento([in, sc, adiposity, over, the, 12, -, yr, 'follow-up', period, in, the, 4.5, /, 2.3, genotype, female, subgroup, was, more, than, twice, that, observed, in, the, 4.5, /, 4.5, and, the, 2.3, /, 2.3, genotype, subgroups, '(', 'P', &, 'lt;', 0.01, ')'])].
[sujeto(['In', 'conclusion,', this, study]), verbo([suggests]), complemento([that, a, significant, interaction, effect, exists, between, variation, in, the, glucocorticoid, receptor, gene, and, body, fat, gain, in, female, subjects, experiencing, the, transition, between, adolescence, and, adulthood])].
[sujeto(['Further', research, 'will,', 'however,', be, necessary, to, characterize, the, lifestyle, factors]), verbo([promoting]), complemento([fat, 'accumulation,', over, 'time,', among, genetically, susceptible, individuals])].
[sujeto(['It', is, confirmed, that, the, 4.5, kb, allele, of, the, 'GRL', 'BclI', polymorphism, is]), verbo([associated]), complemento([with, a, higher, amount, of, abdominal, visceral, fat, '(', 'AVF)', depot, '(', 'P', for, 'trend<0'])].
[sujeto(['Furthermore,', the, alpha, 2, -, 'ADR', 'Dra', 'I', variant, is]), verbo([associated]), complemento([with, lower, 'cross-sectional', areas, of, abdominal, total, '(', 'P=0'])].
[sujeto(['There', is, an, association, between, the, 'GRL', 'BclI', polymorphism, and]), verbo([increased]), complemento(['AVF', levels, independent, of, the, level, of, total, body, fat])].
[sujeto(['The', alpha, 2, -, 'ADR', 'DraI', variant, is]), verbo([associated]), complemento([with, a, lower, 'cross-sectional', area, of, abdominal, total, fat])].
[sujeto(['Numerous', interactions, between, 'GRL', and, 'ADR', markers, on, overall, adiposity, and, total, abdominal, fat, as, well, as, between, 'GRL,', 'LPL', and, 'ADR', genes, on, overall, 'adiposity,', abdominal, total, and, visceral, fat]), verbo([suggest]), complemento([that, the, genetic, architecture, of, body, fat, content, and, adipose, tissue, distribution, is, complex, although, some, 'genes,', like, 'GRL,', may, have, ubiquitous, effects])].
[sujeto(['The', purpose, of, this, review, is, to, explore, the, evidence, accumulated, thus, far, that]), verbo([suggests]), complemento([a, genetic, component, to, the, observed, variation, in, abdominal, visceral, fat, '(', 'AVF)', levels])].
[sujeto(['The', precise, determination, of, 'AVF', levels, in, humans, is, limited, to, methods, such, as, computerized, tomography, and, magnetic, resonance, 'imaging;', 'thus,', few, studies]), verbo([have]), complemento([examined, the, role, of, genetic, factors, on, this, phenotype])].
[sujeto(['However,', after, adjustment, for, total, fat, mass, the, support, for, a, major, gene, was, 'reduced,']), verbo([suggesting]), complemento([that, a, major, gene, which, affects, fat, mass, may, also, affect, 'AVF', either, directly, '(', 'pleiotropy),', or, indirectly])].
[sujeto(['The', search, for, candidate, genes, that, may, impact, 'AVF', levels, is, in, its, 'infancy,', and, few, candidate, genes]), verbo([have]), complemento([been, identified])].
[sujeto(['However,', the, glucocorticoid, receptor, '(', 'GRL),', ss3, adrenergic, receptor, '(', 'ADRB3),', and, fatty, acid]), verbo([binding]), complemento([protein, 2, '(', 'FABP2)', genes, have, been, significantly, associated, with, 'AVF', or, 'intra-abdominal', fat, levels, in, humans])].
[sujeto(['In', 'addition,', three, quantitative, trait, loci, obtained, from, crosses, of, 'mice,', the, 'Do2,', 'Mob4,', and, 'Qbw1', loci]), verbo([have]), complemento([been, linked, with, mesenteric, or, abdominal, fat, and, are, thus, considered, positional, candidate, genes, for, 'AVF', levels])].
[sujeto(['The', search, for, candidate, genes, or, random, genetic, markers]), verbo([associated]), complemento([with, 'AVF', levels, is, a, challenging, prospect])].
[sujeto(['We']), verbo([have]), complemento([utilized, a, 'cross-sectional', association, approach, to, investigate, sporadic, breast, cancer])].
[sujeto(['Several', polymorphic, regions, within, the, 'ESRalpha', gene]), verbo([have]), complemento([been, 'identified,', and, some, alleles, of, these, polymorphisms, have, been, found, to, occur, at, increased, levels, in, 'breast-cancer', patients])].
[sujeto(['Additionally,', variations, in, 'GRL']), verbo([have]), complemento([the, potential, to, disrupt, cell, transcription, and, may, be, associated, with, cancer, formation])].
[sujeto(['Our', results, indicate, that, specific, alleles, of, the, 'ESR', gene, '(', alpha, 'subtype)', and, a, marker, for, the, 'GRL', gene, locus, are]), verbo([associated]), complemento([with, sporadic, 'breast-cancer', development, in, the, tested, 'Caucasian', population, and, justify, further, investigation, of, the, role, of, these, and, other, nuclear, steroid, receptors, in, the, etiology, of, breast, cancer])].
[sujeto(['To', identify, genetic, markers]), verbo([associated]), complemento([with, premature, pubarche, in, children, and, hyperandrogenism, in, adolescent, girls])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, the, development, of, 'PP', and, 'HA', can, be, associated, with, the, occurrence, of, multiple, sequence, variants, at, five, susceptibility, 'loci,', especially, steroidogenic, enzyme, genes])].
[sujeto(['Gene-gene', interaction, effects, were]), verbo([found]), complemento([between, 'GRL', and, 'alpha2-ADR', genes, for, 'low-density', lipoprotein, cholesterol, '(', '[', 'LDL-C]', 'P', =])].
[sujeto(['Higher-order', interaction, effects]), verbo([involving]), complemento(['GRL,', 'LPL,', and, 'ADR', markers, were, observed, for, the, plasma, insulin, area, '(', 'P', =])].
[sujeto(['In', 'conclusion,', multiple, interactions, among, 'GRL,', 'LPL,', and, 'ADR', gene, markers, contribute, to, insulin, metabolism, and, perhaps, to, lipid, 'levels,', while, no, significant, effect, is]), verbo([found]), complemento([for, each, gene, separately])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'gene-gene', interaction, effects, could, play, a, role, in, the, etiology, of, risk, factors, for, common, chronic, diseases])].
[sujeto(['Steroid', hormones, and, their]), verbo([nuclear]), complemento([receptors, play, a, major, role, in, the, development, and, progression, of, breast, cancer])].
[sujeto(['MCF-7', cells, are, 'triple-positive', breast, cancer, cells]), verbo([expressing]), complemento([estrogen, receptor, '(', 'ER),', progesterone, receptor, '(', 'PR),', and, glucocorticoid, receptor, '(', 'GR)'])].
[sujeto(['MTT', assay, results, show, that, 'E2', or, 'P4']), verbo([induced]), complemento([the, cell, proliferation, by, more, than, 35, &, 'nbsp;%,', and, 'Dex', decreased, the, proliferation, by, 26, &, 'nbsp;%'])].
[sujeto(['E2', and, 'P4', are]), verbo([found]), complemento([to, increase, 'ERα', by, more, than, twofold, and, 'c-Jun,', 'c-Fos,', and, 'Fra-1', 'AP-1', 'TFs', by, more, than, 1.7, -, 'fold,', while, 'Dex', shows, opposite, effect, of, 'E2-', or, 'P4-induced', effect, as, well, as, effect, on, the, expression, of, nuclear, receptors, and, 'AP-1', factors])].
[sujeto(['E2', antagonist, 'Fulvestrant', '(', 'ICI', 182, ',', 780, ')']), verbo([found]), complemento([to, reduce, proliferation, and, 'E2-induced', expression, of, 'AP1-TFs,', while, 'P4', or, 'Dex', antagonist, 'Mifepristone', '(', 'RU486)', is, found, to, block, 'GR-mediated', expression, of, 'NRs', and, 'AP-1', mRNAs])].
[sujeto(['Results']), verbo([suggest]), complemento([that, 'E2', and, 'P4', act, 'synergistically,', and, 'Dex', acts, as, an, antagonist, of, 'E2', and, 'P4'])].
[sujeto(['Our', results, showed, that, chronic, but, not, acute, morphine, downregulated, the, expression, of]), verbo([nuclear]), complemento(['GR', protein, and, 'GR', exon, 17, variant, 'mRNA,', and, upregulated, the, methylation, of, 'GR', 17, exon, promoter, in, the, hippocampus, of, rats])].
[sujeto(['In', 'contrast,', pretreatment, of, 5, -, aza, into, rat, hippocampus, reversed, chronic, 'morphine-induced', hypermethylation, of, 'GR', 17, promoter, and]), verbo([decrease]), complemento([in, 'GR', expression])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, chronic, morphine, induced, hypermethylation, of, 'GR', 17, 'promoter,', which, then, downregulated, the, expression, of, hippocampal, 'GR,', and, was, thus, involved, in, chronic, 'morphine-induced', dysfunction, of, the, 'HPA', axis, and, the, modulation, of, morphine, dependence])].
[sujeto(['Moreover,', chronic, 'morphine-induced', hypermethylation, of, 'GR', 17, promoter, may, be, at, least, partially, due, to, the]), verbo([increase]), complemento([in, hippocampal, 'DNMT', 1, expression, and, its, binding, at, 'GR', 17, promoter, in, the, rat, hippocampus])].
[sujeto(['High', intake, of, dietary, fructose]), verbo([causes]), complemento([perturbation, in, lipid, metabolism, and, provokes, 'lipid-induced', insulin, resistance])].
[sujeto(['A', rise, in, glucocorticoids, '(', 'GCs)']), verbo([has]), complemento([recently, been, suggested, to, be, involved, in, 'fructose-induced', insulin, resistance])].
[sujeto(['Insulin', resistance, was]), verbo([induced]), complemento([in, mice, by, administering, a, 'high-fructose', diet, '(', 'HFrD)', for, 60, days])].
[sujeto(['Mifepristone', '(', 'RU486),', a, 'GC', 'antagonist,', was, administered, to, 'HFrD-fed', mice, for, the, last, 18, 'days,', and, the, intracellular, and, extracellular, 'GC', 'levels,', the, glucocorticoid, receptor, '(', 'GR)', activation, and, the, expression, of, 'GC-regulated', genes]), verbo([involved]), complemento([in, lipid, metabolism, were, examined])].
[sujeto(['HFrD', elevated, the, intracellular, 'GC', content, in, both, liver, and, adipose, tissue, and]), verbo([enhanced]), complemento([the, 'GR', nuclear, translocation])].
[sujeto(['The', levels, of, free, fatty, acids, and, triglycerides, in, plasma, were, 'elevated,', accompanied, by]), verbo([increased]), complemento([plasma, insulin, and, glucose, levels, and, decreased, hepatic, glycogen, content])].
[sujeto(['Treatment', with, 'RU486', reduced, plasma, lipid, 'levels,', tissue, 'GC', levels, and, the, expression, of, 'GC-targeted', genes]), verbo([involved]), complemento([in, lipid, 'accumulation,', and, it, improved, insulin, sensitivity])].
[sujeto(['This', study, demonstrated, that, 'HFrD-induced', lipid, accumulation, and, insulin, resistance, are]), verbo([mediated]), complemento([by, enhanced, 'GC', in, liver, and, adipose, tissue, and, that, 'GC', antagonism, might, reduce, 'fructose-induced', lipid, abnormalities, and, insulin, resistance])].
[sujeto(['The', glucocorticoid, receptor, '(', 'GR)']), verbo([binds]), complemento([as, a, homodimer, to, genomic, response, 'elements,', which, have, particular, sequence, and, shape, characteristics])].
[sujeto(['Rather,', mutating, the, dimerization, interface, mitigates, 'DNA-induced', changes, in, both, activity, and, 'structure,', arguing, for, a, role, of, 'DNA-induced', structural, changes, in]), verbo([modulating]), complemento(['GR', activity])].
[sujeto(['Together,', our, study, shows, that, 'DNA', sequence, identity, of, genomic]), verbo([binding]), complemento([sites, modulates, 'GR', activity, downstream, of, 'binding,', which, may, play, a, role, in, achieving, regulatory, specificity, towards, individual, target, genes])].
[sujeto(['Recently,', 'however,', evidence]), verbo([has]), complemento([emerged, that, suggests, the, presence, of, rapid, 'non-genomic', 'GR-dependent', signaling, pathways, within, the, 'brain,', though, their, existence, in, spinal, and, peripheral, nociceptive, neurons, remains, elusive])].
[sujeto(['In', this, 'paper,', we, aim, to, systemically, identify, 'GR', within, the, spinal, cord, and, 'periphery,', to, verify, their, putative, membrane, location, and, to, characterize, possible, 'G', protein, coupling, and, pain]), verbo([modulating]), complemento([properties])].
[sujeto(['GR', saturation]), verbo([binding]), complemento([revealed, that, these, receptors, are, linked, to, the, cell, membrane, of, sensory, neurons, 'and,', upon, 'activation,', they, trigger, membrane, targeted, '[', '(', 35, ')', 'S]GTPγS', 'binding,', indicating, 'G', protein, coupling, to, a, putative, receptor])].
[sujeto(['Overall,', this, study]), verbo([provides]), complemento([firm, evidence, for, a, novel, neuronal, mechanism, of, 'GR', agonists, that, is, 'rapid,', 'non-genomic,', dependent, on, membrane, binding, and, 'G', protein, 'coupling,', and, acutely, modulates, nociceptive, 'behavior,', thus, unraveling, a, yet, unconsidered, mechanism, of, pain, relief])].
[sujeto(['Chronic', stress]), verbo([induces]), complemento([altered, energy, metabolism, and, plays, important, roles, in, the, etiology, of, 'depression,', in, which, the, glucocorticoid, negative, feedback, is, disrupted, due, to, imbalanced, glucocorticoid, receptor, '(', 'GR)', functions])].
[sujeto(['In', this, 'study,', we, investigated, the, role, of, 'AMP-activated', protein, kinase, '(', 'AMPK),', the, key, enzyme]), verbo([regulating]), complemento([cellular, energy, 'metabolism,', and, related, signaling, pathways, in, chronic, 'stress-induced', 'GR', dysregulation])].
[sujeto(['In', cultured, rat, cortical, 'astrocytes,', glucocorticoid, treatment]), verbo([decreased]), complemento([the, 'level,', which, was, accompanied, by, the, decreased, expression, of, liver, kinase, 'B1', '(', 'LKB1)', and, reduced, phosphorylation, of, 'AMPK'])].
[sujeto(['Glucocorticoid-induced', effects, were, attenuated, by, 'glucocorticoid-inducible', kinase, 1, '(', 'SGK1)', inhibitor, 'GSK650394,', which, also]), verbo([inhibited]), complemento([glucocorticoid, induced, phosphorylation, of, 'Forkhead', box, 'O3a', '(', 'FOXO3a)'])].
[sujeto(['Taken', 'together,', these, results]), verbo([suggest]), complemento([that, chronic, stress, activates, 'SGK1', and, suppresses, the, expression, of, 'LKB1', via, inhibitory, phosphorylation, of, 'FOXO3a'])].
[sujeto(['Downregulated', 'LKB1', contributes, to, reduced, activation, of, 'AMPK,']), verbo([leading]), complemento([to, the, dephosphorylation, of, 'HDAC5', and, the, suppression, of, transcription, of, 'GR'])].
[sujeto(['Antidepressants']), verbo([increase]), complemento([hippocampal, neurogenesis, by, activating, the, glucocorticoid, receptor, '(', 'GR),', but, excessive, 'GR', activation, impairs, hippocampal, 'neurogenesis,', suggesting, that, normal, 'GR', function, is, crucial, for, hippocampal, neurogenesis])].
[sujeto(['Baicalin', was]), verbo([reported]), complemento([to, regulate, the, expression, of, 'GR', and, facilitate, hippocampal, 'neurogenesis,', but, the, underlying, molecular, mechanisms, are, still, unknown])].
[sujeto(['We']), verbo([found]), complemento([that, oral, administration, of, baicalin, '(', 40, ',', 80, or, 160, 'mg/kg)', for, 4, weeks, alleviated, several, chronic, 'CORT-induced', 'anxiety/depression-like', behaviors])].
[sujeto(['Baicalin', also]), verbo([increased]), complemento(['Ki-67-', and, 'DCX-positive', cells, to, restore, chronic, 'CORT-induced', suppression, of, hippocampal, neurogenesis])].
[sujeto(['Moreover,', baicalin, normalized, the, chronic, 'CORT-induced']), verbo([decrease]), complemento([in, 'GR', protein, 'levels,', the, increase, in, 'GR', nuclear, translocation, and, the, increase, in, 'GR', phosphorylation, at, 'Ser203', and, 'Ser211'])].
[sujeto(['Finally,', chronic, 'CORT', exposure]), verbo([increased]), complemento([the, level, of, 'FK506-binding', protein, 51, '(', 'FKBP5)', and, of, phosphorylated, 'serum-', and, 'glucocorticoid-inducible', kinase, 1, '(', 'SGK1)', at, 'Ser422', and, 'Thr256,', whereas, baicalin, normalized, these, changes])].
[sujeto(['Together,', our, findings]), verbo([suggest]), complemento([that, baicalin, improves, 'anxiety/depression-like', behaviors, and, promotes, hippocampal, neurogenesis])].
[sujeto(['Diet-induced', obesity]), verbo([causes]), complemento([chronic, 'macrophage-driven', inflammation, in, white, adipose, tissue, '(', 'WAT)', leading, to, insulin, resistance])].
[sujeto(['We', recently]), verbo([reported]), complemento([that, a, nuclear, receptor, 'cofactor-glucocorticoid', receptor, '(', 'GR)-interacting', protein, '(', 'GRIP)1-cooperates', with, 'GR', to, repress, inflammatory, genes])].
[sujeto(['Thus,', 'GRIP1', is, a, critical, regulator, of, 'immunometabolism,', which, engages, distinct, transcriptional, mechanisms, to, coordinate, the, balance, between, macrophage, populations, and, ultimately]), verbo([promote]), complemento([metabolic, homeostasis])].
[sujeto(['Glucocorticoids', '(', 'GCs)', are]), verbo([involved]), complemento([in, stress, and, circadian, 'regulation,', and, produce, many, actions, via, the, 'GC', receptor, '(', 'GR),', which, is, classically, understood, to, function, as, a, nuclear, transcription, factor])].
[sujeto(['However,', the]), verbo([nuclear]), complemento([genome, is, not, the, only, genome, in, eukaryotic, cells])].
[sujeto(['Recent', work]), verbo([has]), complemento([established, 'that,', in, the, brain, and, other, 'systems,', the, 'GR', is, translocated, from, the, cytosol, to, the, mitochondria, and, that, stress, and, corticosteroids, have, a, direct, influence, on, mtDNA, transcription, and, mitochondrial, physiology])].
[sujeto(['To', determine, if, stress, affects, mitochondrially]), verbo([transcribed]), complemento([mRNA, '(', 'mtRNA)', 'expression,', we, exposed, adult, male, rats, to, both, acute, and, chronic, immobilization, stress, and, examined, mtRNA, expression, using, quantitative, 'RT-PCR'])].
[sujeto(['We']), verbo([found]), complemento([that, acute, stress, had, a, main, effect, on, mtRNA, expression, and, that, expression, of, 'NADH', dehydrogenase, 1, ',', 3, ',', and, 6, '(', 'ND-1,', 'ND-3,', 'ND-6)', and, 'ATP', synthase, 6, '(', 'ATP-6)', genes, was, significantly, 'down-regulated'])].
[sujeto(['Chronic', stress]), verbo([induced]), complemento([a, significant, 'up-regulation', of, 'ND-6', expression])].
[sujeto(['ChIP', sequencing, of, 'GR', showed, that, corticosterone, treatment]), verbo([induced]), complemento([a, 'dose-dependent', association, of, the, 'GR', with, the, control, region, of, the, mitochondrial, genome])].
[sujeto(['It']), verbo([modulates]), complemento([stress, condition, by, regulating, antioxidant, responses, and, apoptosis, in, the, immune, cells])].
[sujeto(['Stress']), verbo([causes]), complemento([increased, glucocorticoid, level, that, acts, through, glucocorticoid, receptor, '(', 'GR)', and, is, translocated, into, nucleus, under, regulation, of, 'HSP90', based, chaperone, machinery])].
[sujeto(['Melatonin', influences, glucocorticoid, and, 'GR']), verbo([mediated]), complemento([stress, condition, in, 'rodents,', but, till, date, there, are, no, reports, which, could, suggest, the, effect, of, melatonin, treatment, on, 'GR', mediated, apoptosis, and, inhibition, of, 'Nrf-2/hemeoxygenase-1', '(', 'HO-1)', induced, antioxidant, status, in, immunocompetent, cells, '(', peripheral, blood, mononuclear, 'cells;', 'PBMCs)'])].
[sujeto(['Therefore,', in, the, present, 'study,', we, considered, 'GR']), verbo([mediated]), complemento([inhibition, of, 'Nrf2', and, 'HO-1', along, with, 'anti-apoptotic', 'Bcl-2', expression, in, 'PBMCs'])].
[sujeto(['The', 'PBMCs', were, treated, with, synthetic, 'glucocorticoid;', dexamethasone, '(', 'Dex)', and, melatonin, '(', 'Mel),', to, explore, the, effect, of, melatonin, treatment, in, regulation, of, 'GR']), verbo([mediated]), complemento([apoptosis, and, inhibition, of, antioxidant, status, in, immune, cells])].
[sujeto(['It', was, noted, that, melatonin, treatment]), verbo([retained]), complemento(['GR', into, cytoplasm, by, inhibiting, the, dissociation, of, 'HSP90', from, 'GR-HSP90', complex, and, enhanced, expression, of, 'Nrf2/HO-1', and, 'Bcl-2', expression])].
[sujeto(['This']), verbo([led]), complemento([to, increased, 'HO-1', expression, and, elevated, 'Bcl-2', led, to, increased, 'Bcl-2/Bax', ratio, that, might, ultimately, enhanced, the, cellular, antioxidant, response, and, survival, under, glucocorticoid, mediated, stress, condition])].
[sujeto(['Our', observations]), verbo([suggest]), complemento([that, the, declined, 'GR', nuclear, translocation, upon, melatonin, treatment, might, be, responsible, for, the, 'up-regulation', of, 'Nrf2', mediated, 'HO-1', activity, and, increased, 'Bcl-2/Bax', ratio, in, 'PBMCs', to, maintain, the, immune, homeostasis, under, stress, condition])].
[sujeto(['Glucocorticoid', receptor, '(', 'GR)', signaling]), verbo([has]), complemento([recently, been, shown, to, play, a, direct, role, in, the, regulation, of, cardiomyocyte, function])].
[sujeto(['Functional', studies, showed, that, 'GR', regulation, of, 'Klf13', is, critical, to, protect, cardiomyocytes, from, 'DNA', damage, and, cell, death]), verbo([induced]), complemento([by, 'cobalt(II)', chloride, hexahydrate, '(', 'CoCl2·6H2O)', and, the, antineoplastic, drug, doxorubicin])].
[sujeto(['These', results, established, a, novel, role, for, 'GR', and, 'KLF13', signaling, in, adult, cardiomyocytes, with, potential, clinical, implications, for, the, prevention, of, cardiotoxicity]), verbo([induced]), complemento([heart, failure])].
[sujeto(['We', investigated, whether, 'pre-pubertal', '(', postnatal, day, '[', 'P]', 35, ')', and, 'post-pubertal', adolescent, '(', 'P45)', and, adult, '(', 'P75)', male, rats, differed, in, 'stressor-induced', hormonal, responses, and, in, glucocorticoid, receptor, '(', 'GR)', translocation, because, it]), verbo([has]), complemento([been, proposed, that, negative, feedback, is, maturing, in, adolescence, and, may, be, a, basis, for, the, prolonged, activation, of, the, 'HPA', axis, in, adolescents, compared, with, adults])].
[sujeto(['After', 30, min, of, restraint, 'stress,', plasma, concentrations, of, corticosterone, and, progesterone]), verbo([increased]), complemento([to, a, greater, extent, in, the, adolescents, than, in, the, adults])].
[sujeto(['Whereas', restraint, stress]), verbo([increased]), complemento([concentrations, of, testosterone, in, adult, 'males,', concentrations, decreased, in, adolescents])].
[sujeto(['In', all, three, age, 'groups,', restraint, stress, reduced, 'GR', expression, in, the, cytosol, and]), verbo([increased]), complemento([expression, in, the, nucleus, within, the, 'hippocampus,', and, the, increase, in, nuclear, 'GR', was, greater, in, 'pre-pubertal', adolescents, compared, with, adults])].
[sujeto(['In', a, separate, set, of, rats, we, investigated, age, differences, in, hippocampal, mRNA, expression, of, corticosteroid, receptors, '(', 'MR', and, 'GR)', and, of, chaperones, '(', 'FKBP5,', 'FKBP4,', 'BAG-1),', which, are, known, to]), verbo([modulate]), complemento([their, 'activity,', at, baseline, and, after, restraint, stress])].
[sujeto(['Restraint', stress]), verbo([decreased]), complemento([the, expression, of, 'GR', and, increased, the, expression, of, 'FKBP5', 'mRNA,', and, age, was, not, a, significant, factor])].
[sujeto(['Higher', expression, of, 'FKBP4', mRNA, was]), verbo([found]), complemento([at, 'P35', than, at, 'P75'])].
[sujeto(['Most', research, of, 'HPA', function, in, adolescent, rats]), verbo([has]), complemento([involved, 'pre-pubertal', 'rats;', the, present, findings, indicate, that, despite, their, increase, in, gonadal, 'function,', responses, to, stressors, in, 'P45', rats, are, more, like, those, of, 'pre-pubertal', than, adult, rats])].
[sujeto(['The', greater, 'stressor-induced', 'GR', translocation, in, 'pre-pubertal', adolescents, parallels, their, greater]), verbo([release]), complemento([of, corticosterone, in, response, to, 'stressors,', which, may, contribute, to, the, enhanced, sensitivity, of, adolescent, rats, to, the, effects, of, chronic, stress, exposures, compared, with, adults])].
[sujeto(['Glucocorticoid', receptor, '(', 'GR)', is, a, classic, member, of, the]), verbo([nuclear]), complemento([receptor, superfamily, and, plays, pivotal, roles, in, human, physiology, at, the, level, of, gene, regulation])].
[sujeto(['Various', constellations, of, cellular, cofactors, are]), verbo([required]), complemento([to, associate, with, 'GR', to, 'activate/repress', genes])].
[sujeto(['The', effects, of, specific, ligands, on, the, 'AF2', structure, and, consequent, preferential]), verbo([binding]), complemento([of, 'co-activators', or, 'co-repressors', have, helped, our, understanding, of, the, mechanisms, involved])].
[sujeto(['We', believe, that, this, is, because, work, so, far]), verbo([has]), complemento([largely, avoided, detailed, examination, of, the, contributions, of, 'AF1', to, overall, 'GR', actions])].
[sujeto(['It']), verbo([has]), complemento([been, shown, that, the, 'GR', containing, only, the, 'N-terminal', domain, '(', 'NTD)', and, the, 'DNA-binding', domain, '(', 'GR500)', is, constitutively, quite, active, in, stimulating, transcription, from, simple, promoters])].
[sujeto(['Lack', of, this, information]), verbo([has]), complemento([hampered, our, complete, understanding, of, how, 'GR', regulates, its, target, 'gene(s)'])].
[sujeto(['The', major, obstacle, in, determining, 'GR500', structure]), verbo([has]), complemento([been, due, to, its, intrinsically, disordered, 'NTD', 'conformation,', frequently, found, in, transcription, factors])].
[sujeto(['In', this, 'study,', we, tested, whether, a, naturally, occurring, 'osmolyte,', 'trehalose,', can]), verbo([promote]), complemento([functionally, ordered, conformation, in, 'GR500'])].
[sujeto(['The', 'UV-B', photoreceptor, 'UV', 'RESISTANCE', 'LOCUS', 8, '(', 'UVR8)']), verbo([promotes]), complemento(['UV-B', acclimation, and, tolerance, in, 'Arabidopsis', thaliana, 'UVR8', localizes, to, both, cytosol, and, 'nucleus,', but, its, main, activity, is, assumed, to, be, nuclear])].
[sujeto(['UV-B', photoreception]), verbo([stimulates]), complemento([nuclear, accumulation, of, 'UVR8', in, a, presently, unknown, manner])].
[sujeto(['Here,', we, show, that, 'CONSTITUTIVELY', 'PHOTOMORPHOGENIC', 1, '(', 'COP1)', is]), verbo([required]), complemento([for, 'UV-B-induced', nuclear, accumulation, of, 'UVR8,', but, bypassing, the, 'COP1', requirement, for, 'UVR8', nuclear, accumulation, did, not, rescue, the, cop1, mutant, 'UV-B', phenotype])].
[sujeto(['Using', a, glucocorticoid, receptor, '(', 'GR)-based', fusion, protein, system, to, conditionally, localize, 'GR-UVR8', to, the, 'nucleus,', we]), verbo([have]), complemento([demonstrated, that, both, photoactivation, and, nuclear, localization, of, 'UVR8', are, required, for, 'UV-B-induced', photomorphogenic, responses])].
[sujeto(['In', 'contrast,', there, was, no, 'UV-B', response, when, 'UV-B-activated', 'UVR8', was, artificially]), verbo([retained]), complemento([in, the, cytosol])].
[sujeto(['In', agreement, with, a, predominantly]), verbo([nuclear]), complemento(['activity,', constitutively, active, 'UVR8(W285A)', accumulated, in, the, nucleus, also, in, the, absence, of, 'UV-B'])].
[sujeto(['Furthermore,', 'GR-COP1', expression, lines]), verbo([suggested]), complemento([that, 'UV-B-activated', 'UVR8', can, be, coimported, into, the, nucleus, by, 'COP1'])].
[sujeto(['Our', data, strongly, support, localization, of, 'UVR8', signaling, in, the, nucleus, and, a, dual, role, for, 'COP1', in, the, regulation, of, 'UV-B-induced', 'UVR8']), verbo([nuclear]), complemento([accumulation, and, in, 'UVR8-mediated', 'UV-B', signaling])].
[sujeto(['Glucocorticoid', receptor, '(', 'GR)', overexpression, is]), verbo([associated]), complemento([with, poor, prognosis, 'ER-negative', breast, cancer])].
[sujeto(['GR', antagonism, with, mifepristone]), verbo([increases]), complemento(['chemotherapy-induced', breast, cancer, cell, 'death,', therefore, we, conducted, a, phase, 'I', clinical, trial, of, mifepristone, and, 'nab-paclitaxel', in, advanced, breast, cancer])].
[sujeto(['All', were]), verbo([found]), complemento([to, have, a, twofold, or, greater, increase, in, serum, cortisol, after, mifepristone, 'administration,', reflecting, effective, 'GR', inhibition])].
[sujeto(['Pharmacokinetic', data]), verbo([suggest]), complemento([an, interaction, between, 'nab-paclitaxel', and, mifepristone, in, some, patients])].
[sujeto(['Immunohistochemical', staining, for, 'GR']), verbo([found]), complemento([six, of, nine, tumors, were, 'GR-positive'])].
[sujeto(['GR', appears, to, be, a, promising]), verbo([target]), complemento([in, 'TNBC,', and, 'GR', inhibition, plus, chemotherapy, produces, manageable, toxicity])].
[sujeto(['While', neutropenia, was, observed, in, 'some,', a, 'nab-paclitaxel', dose, of, 100, &, 'nbsp;mg/m(2)', plus, mifepristone, 300, &, 'nbsp;mg', was]), verbo([found]), complemento([to, be, 'tolerable,', and, a, randomized, phase, 'II', trial, of, 'nab-paclitaxel', 'with/without', mifepristone, is, planned, in, 'GR-positive', advanced, 'TNBC'])].
[sujeto(['Nesfatin-1,', a, recently, identified, satiety, molecule, derived, from, nucleobindin, 2, '(', 'NUCB2),', is]), verbo([associated]), complemento([with, visceral, hypersensitivity, in, rats, and, is, expressed, in, the, amygdala])].
[sujeto(['We', tested, the, hypothesis, that, 'nesfatin-1', expression, in, the, amygdala, is]), verbo([involved]), complemento([in, the, pathogenesis, of, irritable, bowel, syndrome, '(', 'IBS)', visceral, hypersensitivity])].
[sujeto(['Rats', subjected, to, 'MS', showed, a, significantly]), verbo([increased]), complemento([mean, abdominal, withdrawal, reflex, '(', 'AWR)', score, and, electromyographic, '(', 'EMG)', activity, at, 40, ',', 60, ',', and, 80, mmHg, colorectal, distension])].
[sujeto([mRNA, and, protein, expression, of, 'nesfatin-1/NUCB2', in, the, amygdala, were]), verbo([increased]), complemento([in, 'MS', 'rats,', but, not, in, 'NH', rats])].
[sujeto(['In', 'MS', 'rats,', 'AWR', scores, and, 'EMG', activity, were, significantly]), verbo([decreased]), complemento([after, 'anti-nesfatin-1/NUCB2', injection])].
[sujeto(['In', normal, 'rats,', mean, 'AWR', 'score,', 'EMG', 'activity,', and, corticosterone, expression, were, significantly]), verbo([increased]), complemento([after, 'nesfatin-1', injection, into, the, amygdala])].
[sujeto(['Elevated', expression, of, 'nesfatin-1/NUCB2', in, the, amygdala, in, 'MS', rats]), verbo([suggests]), complemento([a, potential, role, in, the, pathogenesis, of, visceral, 'hypersensitivity,', which, could, potentially, take, place, via, activation, of, 'GR', and, 'MR', signaling, pathways])].
[sujeto(['Glucocorticoid', receptor, '(', 'GR)', activation]), verbo([has]), complemento([been, shown, to, reduce, adult, hippocampal, progenitor, cell, proliferation, and, neurogenesis])].
[sujeto(['By', 'contrast,', mineralocorticoid, receptor, '(', 'MR)', signaling, is]), verbo([associated]), complemento([with, neuronal, survival, in, the, dentate, gyrus, of, the, 'hippocampus,', and, impairment, of, hippocampal, 'MR', has, been, linked, to, pathological, 'conditions,', such, as, depression, or, neurodegenerative, disorders])].
[sujeto(['Here,', we, aimed, to, further, clarify, the, protective, role, of, 'MR', in, adult, hippocampal, neurons, by, studying, the, survival, and, proliferative, effects, of, the, highly, potent, 'MR', agonist, fludrocortisone, '(', 'Fludro)', in, adult, rat, hippocampal, progenitor, cells, '(', 'AHPs),', along, with, the]), verbo([associated]), complemento([signaling, mechanisms])].
[sujeto(['Fludro,', which, upregulated, 'MR', but, not, 'GR', 'expression,']), verbo([increased]), complemento([survival, and, proliferation, and, prevented, apoptosis, in, 'AHPs', cultured, in, growth, 'factor-deprived', medium])].
[sujeto(['Moreover,', they]), verbo([involved]), complemento([signaling, through, 'cAMP/protein', kinase, 'A', '(', 'PKA)/cAMP', response, 'element-binding', 'protein,', phosphoinositide, 3, -, kinase, '(', 'PI3K)/Akt', and, its, downstream, targets, glycogen, synthase, 'kinase-3β', '(', 'GSK-3β)', and, mammalian, target, of, rapamycin])].
[sujeto(['Furthermore,', 'Fludro', attenuated, the, detrimental, effects, of, 'amyloid-β', peptide, 1, -, 42, '(', 'Aβ1-42)', on, cell, 'survival,', 'proliferation,', and, apoptosis, in, 'AHPs,', and]), verbo([increased]), complemento([the, phosphorylation, of, both, 'PI3K/Akt', and, 'GSK-3β,', which, was, reduced, by, 'Aβ1-42'])].
[sujeto(['Overall,', these, results, are, the, first, to, show, the, protective, and, proliferative, role, of, 'Fludro', in, 'AHPs,']), verbo([suggesting]), complemento([the, potential, therapeutic, importance, of, targeting, 'MR', for, increasing, hippocampal, neurogenesis, and, for, treating, neurodegenerative, diseases])].
[sujeto(['Here', we, examined, the, effects, of, three, gold, '(', 'I)', 'mixed-ligand', complexes, with, the, general, formula, '[', 'Au(Ln)(PPh3)]', '(', 1, ',', 2, ',', 3, ')']), verbo([involving]), complemento([triphenylphosphine, '(', 'PPh3)', and, a, deprotonated, form, of, 'O-substituted', derivatives, of, 9, -, deazahypoxanthine, '(', 'Ln)', on, the, transcriptional, activity, of, aryl, hydrocarbon, receptor, '(', 'AhR),', androgen, receptor, '(', 'AR),', glucocorticoid, receptor, '(', 'GR),', thyroid, receptor, '(', 'TR),', pregnane, 'X', receptor, '(', 'PXR)', and, vitamin, 'D', receptor, '(', 'VDR),', employing, gene, reporter, assays])].
[sujeto(['In', 'addition,', we, measured, mRNA, '(', 'RT-PCR)', and, protein, '(', western, 'blot)', expression, of]), verbo([target]), complemento([genes, for, those, 'receptors,', including, 'drug-metabolizing', 'P450s,', in, primary, human, hepatocytes, and, cancer, cell, lines, 'LS180', and, 'HepG2'])].
[sujeto(['All', the, compounds, slightly, and, 'dose-dependently']), verbo([activated]), complemento(['PXR', and, 'AhR,', and, moderately, induced, 'CYP3A4', and, 'CYP1A1/2', genes, in, human, hepatocytes, and, 'LS180 cells'])].
[sujeto(['Both', basal, and, thyroid, 'hormone-inducible', transcriptional, activity, of, 'TR', was, 'dose-dependently']), verbo([increased]), complemento([by, all, tested, compounds])].
[sujeto(['In', 'contrast,', the, expression, of, 'SPOT14', mRNA, was]), verbo([decreased]), complemento([by, tested, compounds, in, human, hepatocytes, and, 'HepG2', cells])].
[sujeto(['Early', life, stress, '(', 'ES)', significantly]), verbo([increases]), complemento([predisposition, to, psychopathologies])].
[sujeto(['Cannabinoids', may]), verbo([cause]), complemento([cognitive, deficits, and, exacerbate, the, effects, of, 'ES'])].
[sujeto(['Nevertheless,', the, endocannabinoid, system]), verbo([has]), complemento([been, suggested, as, a, therapeutic, target, for, the, treatment, of, 'stress-', and, 'anxiety-related', disorders])].
[sujeto(['WIN', administered, during, late, adolescence]), verbo([prevented]), complemento([these, 'stress-induced', impairments, and, reduced, anxiety, levels])].
[sujeto(['Differences', in, recognition, memory, and, in, the, expression, of, 'GRs', and, 'CB1r', in, the, fear, circuit]), verbo([suggest]), complemento([sex, differences, in, the, mechanism, underlying, coping, with, stress])].
[sujeto(['The', 'PTPN11', 'gene,', encoding, the, tyrosine, phosphatase, 'SHP-2,', is, overexpressed, in, rheumatoid, arthritis, '(', 'RA)', 'fibroblast-like', synoviocytes, '(', 'FLS)', compared, with, osteoarthritis, '(', 'OA)', 'FLS', and]), verbo([promotes]), complemento(['RA', 'FLS', invasiveness])].
[sujeto(['Using', computational, 'methods,', we, identified, a, putative, enhancer, in, 'PTPN11', intron, 1, ',', which, contained, a, glucocorticoid, 'receptor-']), verbo([binding]), complemento(['(', 'GR-binding)', motif])].
[sujeto(['RA', 'FLS', stimulation, with, the, glucocorticoid, dexamethasone]), verbo([induced]), complemento(['GR', binding, to, the, enhancer, and, 'PTPN11', expression])].
[sujeto(['Glucocorticoid', responsiveness, of, 'PTPN11', was, significantly, higher, in, 'RA', 'FLS', than, 'OA', 'FLS', and]), verbo([required]), complemento([the, differentially, methylated, 'CpGs', for, full, enhancer, function])].
[sujeto(['Our', findings, demonstrate, how, abnormal, epigenetic, regulation, of, a, pathogenic, gene, determines, 'FLS', behavior, and, demonstrate, that]), verbo([targeting]), complemento(['SHP-2', or, the, 'SHP-2', pathway, could, be, a, therapeutic, strategy, for, 'RA'])].
[sujeto(['In', the, interest, of, investigating, glucocorticoid, actions, in, the, cornea, of, the, 'eye,', we, established, that, multiple, cell, types, in, mouse, corneas]), verbo([express]), complemento([functional, glucocorticoid, receptor, '(', 'GR)', with, corneal, epithelial, cells, having, robust, expression])].
[sujeto(['Over', 4000, genes, were, significantly]), verbo([regulated]), complemento([within, 6, &, 'nbsp;h', of, dexamethasone, 'treatment,', and, genes, associated, with, cell, 'movement,', cytoskeletal, remodeling, and, permeability, were, highly, regulated])].
[sujeto(['These', functional, alterations, were]), verbo([associated]), complemento([with, cytoskeletal, remodeling, at, the, wounded, edge, of, a, 'scratch-wounded', monolayer])].
[sujeto(['However,', glucocorticoid, treatment, improved, the, organization, of, 'tight-junction', proteins, and]), verbo([enhanced]), complemento([the, epithelial, barrier, function])].
[sujeto(['These', effects, are, primarily, attributed, to, glucocorticoid, receptor, transrepressional, activities, but, with, concomitant, receptor, transactivation]), verbo([associated]), complemento([with, considerable, side, effects])].
[sujeto(['Triterpenoids']), verbo([have]), complemento([structural, similarities, with, glucocorticoids, and, exhibit, 'anti-inflammatory', and, apoptotic, activities, via, mechanisms, that, are, not, 'well-defined'])].
[sujeto(['We', showed, that, echinocystic, acid, and, its, glucoside]), verbo([induced]), complemento([glucocorticoid, receptor, nuclear, translocation, by, 75, '%', and, 55, '%'])].
[sujeto(['They']), verbo([suppressed]), complemento([the, nuclear, 'factor-kappa', beta, transcriptional, activity, by, 20, '%', and, 70, '%', ',', 'respectively,', whereas, they, have, no, glucocorticoid, receptor, transactivation, capability, and, stimulatory, effect, on, the, expression, of, the, phosphoenolopyruvate, carboxykinase, target, gene, in, 'HeLa', cells])].
[sujeto(['Induced', fit, docking, calculations, predicted, favorable]), verbo([binding]), complemento([in, the, ligand, binding, domain, and, structural, characteristics, which, can, be, considered, consistent, with, the, experimental, observations])].
[sujeto(['Further,', glucocorticoids, exert, apoptotic, 'activities;', we]), verbo([have]), complemento([demonstrated, here, that, the, echinocystic, acids, in, combination, with, the, synthetic, 'glucocorticoid,', 'dexamethasone,', induce, apoptosis])].
[sujeto(['The', postnatal, light, environment, that, a, mouse, experiences, during, the, critical, first, 3, postnatal, weeks]), verbo([has]), complemento(['long-term', effects, on, both, its, circadian, rhythm, output, and, clock, gene, expression])].
[sujeto(['Furthermore,', data, from, our, lab]), verbo([suggest]), complemento([that, postnatal, light, may, also, impact, the, 'hypothalamic-pituitary-adrenal', '(', 'HPA)', 'axis,', which, is, a, key, regulator, of, stress])].
[sujeto(['Results', showed, that, 'LL-', and, 'DD-raised', mice, exhibited]), verbo([decreased]), complemento(['GR', expression, in, the, 'hippocampus,', increased, plasma, corticosterone, concentration, at, the, onset, of, the, dark, phase, and, a, depressive, phenotype, when, exposed, to, 'LD', cycles, later, in, life])].
[sujeto(['Furthermore,', 'LL-raised', mice, showed]), verbo([increased]), complemento(['corticotrophin-releasing', hormone, mRNA, expression, in, the, paraventricular, nucleus, of, the, hypothalamus])].
[sujeto(['Taken', 'together,', these, data]), verbo([suggest]), complemento([that, altered, postnatal, light, environments, have, 'long-term', effects, on, the, 'HPA', axis, and, the, circadian, 'system,', which, can, lead, to, altered, stress, responses, and, a, depressive, phenotype, in, adulthood])].
[sujeto(['Adaptation', to, fasting]), verbo([involves]), complemento([both, 'Glucocorticoid', 'Receptor', '(', 'GRα)', and, 'Peroxisome', 'Proliferator-Activated', 'Receptor', α, '(', 'PPARα)', activation])].
[sujeto(['Given', both, receptors, can, physically]), verbo([interact]), complemento([we, investigated, the, possibility, of, a, 'genome-wide', 'cross-talk', between, activated, 'GR', and, 'PPARα,', using, 'ChIP-', and, 'RNA-seq', in, primary, hepatocytes])].
[sujeto(['Our', data]), verbo([reveal]), complemento([extensive, chromatin, 'co-localization', of, both, factors, with, cooperative, induction, of, genes, controlling, 'lipid/glucose', metabolism])].
[sujeto(['Key', 'GR/PPAR', 'co-controlled', genes, switched, from, transcriptional, antagonism, to, cooperativity, when, moving, from, short, to, prolonged, hepatocyte, 'fasting,', a, phenomenon, coinciding, with, gene, promoter, recruitment, of]), verbo([phosphorylated]), complemento(['AMP-activated', protein, kinase, '(', 'AMPK)', and, blocked, by, its, pharmacological, inhibition])].
[sujeto(['Long-term', fasting, in, mice, showed]), verbo([enhanced]), complemento([phosphorylation, of, liver, 'AMPK', and, 'GRα', 'Ser211'])].
[sujeto(['Phospho-AMPK', chromatin, recruitment, at, liver]), verbo([target]), complemento(['genes,', observed, upon, prolonged, fasting, in, 'mice,', is, dampened, by, refeeding])].
[sujeto(['Taken', 'together,', our, results, identify, 'phospho-AMPK', as, a, molecular, switch, able, to, cooperate, with]), verbo([nuclear]), complemento([receptors, at, the, chromatin, level, and, reveal, a, novel, adaptation, mechanism, to, prolonged, fasting])].
[sujeto(['Glucocorticoids', '(', 'GCs)', used, as, inflammation, suppressors]), verbo([have]), complemento([harmful, side, 'effects,', including, induction, of, hepatic, steatosis])].
[sujeto(['We', demonstrated, that, granulocytic, '(', 'G)-MDSC', accumulation]), verbo([mediated]), complemento([the, effects, of, 'GCs', on, the, fatty, 'liver,', in, which, activating, transcription, factor, 3, '(', 'ATF3)', /, 'S100A9', signaling, plays, an, important, role])].
[sujeto(['Adoptive', transfer, of, 'GC-induced', or, 'ATF3-deficient', 'G-MDSCs']), verbo([promoted]), complemento([lipid, accumulation, in, the, 'liver,', while, depletion, of, 'G-MDSCs', alleviated, these, effects])].
[sujeto(['Mechanistic', studies, showed, that, in, 'MDSCs,', 'ATF3', was, transrepressed, by, 'GC', receptor, 'GR', through, direct]), verbo([binding]), complemento([to, the, negative, 'GR', response, element, '(', 'nGRE)'])].
[sujeto(['S100A9', is, the, major, transcriptional]), verbo([target]), complemento([of, 'ATF3', in, 'G-MDSCs'])].
[sujeto(['Silencing', 'S100A9', clearly, alleviated, 'G-MDSCs', expansion, and, hepatic, steatosis]), verbo([caused]), complemento([by, 'ATF3', deficiency, or, 'GC', treatment])].
[sujeto(['Our', study, uncovers, an, important, role, of, 'G-MDSCs', in, 'GC-induced', hepatic, 'steatosis,', in, which, 'ATF3', may]), verbo([have]), complemento([potential, therapeutic, implications])].
[sujeto(['Transcriptional', and, chromatin, regulations]), verbo([mediate]), complemento([the, liver, response, to, nutrient, availability])].
[sujeto(['The', role, of, chromatin, factors]), verbo([involved]), complemento([in, hormonal, regulation, in, response, to, fasting, is, not, fully, understood])].
[sujeto(['We']), verbo([have]), complemento([identified, 'SETDB2,', a, 'glucocorticoid-induced', putative, epigenetic, 'modifier,', as, a, positive, regulator, of, 'GR-mediated', gene, activation, in, liver])].
[sujeto(['Insig2a']), verbo([increases]), complemento([during, fasting, to, limit, lipid, 'synthesis,', but, the, mechanism, of, induction, is, unknown])].
[sujeto(['INSIG2', is, a, negative, regulator, of, 'SREBP,', and, acute, glucocorticoid, treatment]), verbo([decreased]), complemento([active, 'SREBP', during, refeeding, or, in, livers, of, 'Ob/Ob', 'mice,', both, systems, of, elevated, 'SREBP-1c-driven', lipogenesis])].
[sujeto(['Overall,', these, studies, identify, a, 'GR-SETDB2', regulatory, axis, of, hepatic, transcriptional, reprogramming, and, identify, 'SETDB2', as, a, potential]), verbo([target]), complemento([for, metabolic, disorders, with, aberrant, glucocorticoid, actions])].
[sujeto(['The', glucocorticoid, receptor, '(', 'GR)']), verbo([binds]), complemento([the, human, genome, at, &, 'gt;10,000', sites, but, only, regulates, the, expression, of, hundreds, of, genes])].
[sujeto(['To', determine, 'the functional', effect, of, each, 'site,', we, measured, 'the glucocorticoid', '(', 'GC)', responsive, activity, of, nearly, all, 'GR']), verbo([binding]), complemento([sites, '(', 'GBSs)', captured, using, chromatin, immunoprecipitation, '(', 'ChIP)', in, 'A549', cells])].
[sujeto(['The', responsive, sites, were, defined, by, direct, 'GR']), verbo([binding]), complemento([via, 'a GC response', element, '(', 'GRE)', and, exclusively, increased, 'reporter-gene', expression])].
[sujeto(['We', further, show, that, those, interactions, can, synergistically]), verbo([modulate]), complemento([the, activity, of, direct, 'GBSs', and, may, therefore, play, a, major, role, in, driving, gene, activation, in, response, to, 'GCs'])].
[sujeto(['Transcription', factors, '(', 'TFs)', are, effectors, of, cell, signaling, pathways, that]), verbo([regulate]), complemento([gene, expression])].
[sujeto(['TF', networks, are, highly, 'interconnected;', one, signal, can]), verbo([lead]), complemento([to, changes, in, many, 'TF', 'levels,', and, one, 'TF', level, can, be, changed, by, many, different, signals])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, parallel, analysis, of, temporal, 'TF', level, changes, due, to, multiple, stimuli, in, distinct, cell, types])].
[sujeto(['We']), verbo([have]), complemento([analyzed, 'short-term', dynamic, changes, in, the, levels, of, nuclear, factor, 'kappa-light-chain-enhancer', of, activated, 'B', cells, '(', 'NF-kB),', signal, transducer, and, activator, of, transcription, 3, '(', 'Stat3),', cAMP, response, 'element-binding', protein, '(', 'CREB),', glucocorticoid, receptor, '(', 'GR),', and, 'TATA', binding, protein, '(', 'TBP),', in, breast, and, liver, cancer, cells, after, tumor, necrosis, 'factor-alpha', '(', 'TNF-α)', and, palmitic, acid, '(', 'PA)', exposure])].
[sujeto(['GR', levels, were, unchanged, in, response, to, 'TNF-α', stimulation, and]), verbo([increased]), complemento([in, response, to, 'PA', treatment])].
[sujeto(['Our', results, show, significant, overlap, in, signaling, initiated, by, 'TNF-α', and, by, 'PA,', with, the, exception, that, the, events]), verbo([leading]), complemento([to, 'PA-mediated', cytotoxicity, likely, also, include, induction, of, 'GR', signaling])].
[sujeto(['Glucocorticoid-induced', osteoporosis, '(', 'GIO)', is, one, of, the, major, side, effects, of, 'long-term', glucocorticoid, '(', 'GC)', therapy]), verbo([mediated]), complemento([mainly, via, the, suppression, of, bone, formation, and, osteoblast, differentiation, independently, of, 'GC', receptor, '(', 'GR)', dimerization])].
[sujeto(['In', 'vivo,', abrogation, of, 'Dicer-dependent', miRNA, biogenesis, in, osteoblasts]), verbo([led]), complemento([to, growth, retardation, and, impaired, bone, formation])].
[sujeto(['In', 'line,', differentiation, of, 'Dicer', deficient, osteoblasts, was]), verbo([suppressed]), complemento([to, the, same, extent, as, wild, type, cells, by, 'GC', treatment])].
[sujeto(['Systemic', corticosteroid, concentration, depends, largely, on, activity, of, the, 'hypothalamic-pituitary-adrenal', '(', 'HPA)', 'axis,', but, glucocorticoid, can, also, be, regenerated, from, intrinsically, inert, metabolites, by, the, enzyme, 11, 'β-hydroxysteroid', dehydrogenase, type, 1, '(', 11, 'β-HSD1),', selectively]), verbo([increasing]), complemento([glucocorticoid, levels, within, cells, and, tissues])].
[sujeto(['Extensive', studies]), verbo([have]), complemento([revealed, roles, for, glucocorticoid, regeneration, by, 11, 'β-HSD1', in, 'liver,', 'adipose,', brain, and, other, 'tissues,', but, until, recently, there, has, been, little, focus, on, the, heart])].
[sujeto(['We', also, consider, the, potential, of, 11, 'β-HSD1', as, a, therapeutic]), verbo([target]), complemento([to, enhance, repair, following, myocardial, infarction, and, to, prevent, the, development, of, cardiac, remodeling, and, heart, failure])].
[sujeto(['Factors', that]), verbo([regulate]), complemento([physiological, feedback, by, pulses, of, glucocorticoids, on, the, 'hypothalamic-pituitary', unit, are, sparsely, defined, in, humans, in, relation, to, 'gluco-', or, mineralocorticoid, receptor, 'pathways,', 'gender,', age, and, the, 'sex-steroid', milieu])].
[sujeto(['Despite', feedback, 'imposition,', 'CRH-AVP-stimulated', 'ACTH', secretion, was, also]), verbo([increased]), complemento([by, mifepristone, and, not, by, eplerenone])].
[sujeto([6, ')', and, more]), verbo([regular]), complemento(['(', 'P=0'])].
[sujeto(['Pulsatile', cortisol, feedback, on, 'ACTH', secretion, in, this, paradigm, is]), verbo([mediated]), complemento([by, the, glucocorticoid, 'receptor,', in, part, acting, at, the, level, of, the, 'pituitary,', and, influenced, by, sex])].
[sujeto(['Fetal', membranes]), verbo([express]), complemento([abundant, 11, 'β-hydroxysteroid', dehydrogenase, 1, '(', 11, 'β-HSD1)', which, converts, inert, cortisone, to, active, cortisol])].
[sujeto(['By', using, cultured, human, primary, amnion, 'fibroblasts,', we, demonstrated, 'that,', in, addition, to, induction, of, the, key, enzymes]), verbo([involved]), complemento([in, prostaglandin, 'E2', '(', 'PGE2)', 'synthesis,', cortisol, stimulated, 11, 'β-HSD1', and, inhibited, 'LOX', reciprocally])].
[sujeto(['Cortisone', also]), verbo([inhibited]), complemento(['LOX', 'expression,', which, was, abolished, by, inhibition, of, 11, 'β-HSD1'])].
[sujeto(['Chromatin', immunoprecipitation, assay, revealed, that, cortisol]), verbo([increased]), complemento(['GR', binding, to, 'LOX', promoter])].
[sujeto(['Moreover,']), verbo([increased]), complemento([cortisol, and, 11, 'β-HSD1', abundance, and, decreased, 'LOX', abundance, were, observed, in, human, amnion, tissue, following, 'labor-initiated', spontaneous, rupture, of, membranes])].
[sujeto(['Phosphatidylinositol-4', kinase, 'III', β, '(', 'PI4KB)', and, 'oxysterol-binding', protein, '(', 'OSBP)', family, 'I']), verbo([have]), complemento([been, identified, as, the, major, targets, of, 'anti-enterovirus', drug, candidates])].
[sujeto(['Resistance', mutations, in, poliovirus, '(', 'PV)', to, these, inhibitors]), verbo([have]), complemento([been, identified, in, viral, 3, 'A', 'protein,', represented, by, a, 'G5318A', '(', 3, 'A-Ala70Thr)', 'mutation,', but, the, mechanism, of, viral, resistance, to, host, 'PI4KB/OSBP', inhibitors, remained, unknown])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, a, 'G5318A', mutation, enhances, the, basal, levels, of, phosphatidylinositol, 4, -, phosphate, '(', 'PI4P)', and, of, the, 3, 'A', protein, and, decreases, the, levels, of, the, 3, 'AB', protein, during, 'PV', replication])].
[sujeto(['The', 3, 'A', protein]), verbo([acted]), complemento([as, a, major, effector, responsible, for, the, resistance, to, 'PI4KB', 'inhibitor,', but, did, not, enhance, the, 'PI4KB', activity, in, vitro, in, contrast, to, the, 2, 'C,', 2, 'BC,', 3, 'AB,', and, 3, 'D', proteins])].
[sujeto(['The', 3, 'AB', protein]), verbo([acted]), complemento([as, the, primary, target, of, a, 'G5318A', mutation, and, also, as, an, effector])].
[sujeto(['We', identified, novel, resistance, mutations, to, a, 'PI4KB', inhibitor, '[', 'C5151U', '(', 3, 'A-T14M)', and, 'C5366U', '(', 3, 'A-H86Y)', 'mutations]', and]), verbo([found]), complemento([that, there, is, a, positive, correlation, between, the, extent, of, the, resistance, phenotype, and, the, levels, of, the, 3, 'A', proteins])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, the, 3, 'A', protein, overproduced, by, enhanced, processing, of, the, 3, 'AB', protein, with, the, resistance, mutations, overcomes, the, inhibitory, effect, of, 'PI4KB', inhibitor, on, 'PV', replication, independently, of, the, hyperactivation, of, the, 'PI4KB/OSBP', pathway])].
[sujeto(['Like', all, 'positive-sense', 'RNA', 'viruses,', hepatitis, 'C', virus, '(', 'HCV)']), verbo([induces]), complemento([host, membrane, alterations, for, its, replication])].
[sujeto(['We']), verbo([found]), complemento([that, 'HCV', replication, organelles, are, continuously, generated, de, novo, at, spatially, distinct, sites, from, preformed, ones])].
[sujeto(['This', process, is, accompanied, by, accumulated, intracellular, membrane, 'alteration,']), verbo([increased]), complemento([cholesterol, 'delivery,', 'NS5A', 'phosphorylation,', and, positive, strand, 'RNA', 'content,', and, by, eventual, association, with, 'HCV', core, protein, around, 'LDs'])].
[sujeto(['Generation', of, spatially, segregated, foci]), verbo([requires]), complemento([viral, 'NS5A', and, the, host, factors, phosphatidylinositol, 4, -, kinase, 'PI4KA', and, 'oxysterol-binding', 'protein,', while, association, of, foci, with, 'LDs', requires, cholesterol])].
[sujeto(['Thus,', our, results]), verbo([reveal]), complemento([that, 'HCV', replication, organelles, are, not, static, 'structures,', but, instead, are, continuously, generated, and, dynamically, change, in, composition, and, possibly, also, in, function])].
[sujeto(['Oxsterol']), verbo([binding]), complemento(['protein-related', protein, 4, '(', 'ORP4)', is, essential, for, cell, 'proliferation,', but, the, underlying, mechanism, is, unclear])].
[sujeto(['ORP4', is]), verbo([expressed]), complemento([as, three, 'variants,', 'ORP4L,', 'ORP4M', and, 'ORP4S'])].
[sujeto(['Here,', we]), verbo([reported]), complemento([that, silencing, of, 'ORP4L', with, specific, small, interfering, 'RNA', '(', 'siRNA)', inhibited, the, proliferation, of, human, cervical, cancer, cell, lines, 'C33A,', 'HeLa', and, 'CaSki,', the, reverse, effect, being, observed, in, 'ORP4L', overexpressing, cells])].
[sujeto(['For', molecular, 'insight,', we]), verbo([found]), complemento([that, 'ORP4L', maintained, intracellular, 'Ca2+', homeostasis])].
[sujeto(['Through', this, 'mechanism,', 'ORP4L']), verbo([activated]), complemento([nuclear, factor, of, activated, 'T', cells, '(', 'NFAT)', activity, and, thus, promoted, expression, of, a, gene, cluster, which, supported, cell, proliferation])].
[sujeto(['Furthermore,', 'ORP4L', knockdown, markedly]), verbo([inhibited]), complemento([tumor, growth, in, a, 'C33A', cell, xenograft, mouse, model])].
[sujeto(['To', 'conclude,', our, results]), verbo([reveal]), complemento([that, 'ORP4L', promotes, cell, proliferation, through, maintaining, intracellular, 'Ca2+', homeostasis])].
[sujeto(['Oxysterols', are, 27, -, carbon, oxidized, derivatives, of, cholesterol, or, 'by-products', of, cholesterol, biosynthesis, which, can]), verbo([induce]), complemento([cell, apoptosis, in, addition, to, a, number, of, other, bioactions])].
[sujeto(['ORP8', is, a, member, of, the, oxysterol]), verbo([binding]), complemento([protein, '(', 'OSBP)-related', protein, '(', 'ORP)', 'family,', implicated, in, cellular, lipid, 'homeostasis,', migration, and, organization, of, the, microtubule, cytoskeleton])].
[sujeto(['Here', we]), verbo([reported]), complemento([that, 25, -, hydroxycholesterol, '(', 25, -, 'OHC)', induced, apoptosis, of, the, hepatoma, cell, lines, 'HepG2', and, 'Huh7', via, 'ER', stress, response, 'pathway,', and, 'ORP8', overexpression, resulted, in, a, similar, cell, response, as, 25, -, 'OHC,', indicating, a, putative, functional, relationship, between, oxysterol, cytotoxicity, and, 'ORP8'])].
[sujeto(['Further', experiments, demonstrated, that, 'ORP8', overexpression, significantly]), verbo([enhanced]), complemento([the, 25, -, 'OHC', effect, on, 'ER', stress, and, apoptosis, in, 'HepG2', cells])].
[sujeto(['Taken', 'together,', the, present, study]), verbo([suggests]), complemento([that, 'ORP8', may, mediate, the, cytotoxicity, of, 25, -, 'OHC'])].
[sujeto(['An', important, question, is, whether, or, not, 'LTPs', are, able, to, convey, lipids, to, create, and]), verbo([maintain]), complemento([the, lipid, gradients, observed, between, organelles])].
[sujeto(['Compounds', called, 'ORPhilins', block, 'PI4P/sterol', exchange, and]), verbo([have]), complemento([thereby, powerful, antiviral, 'activities,', indicating, in, turn, that, some, 'ORP/Osh', proteins, might, be, relevant, pharmaceutical, targets])].
[sujeto(['We']), verbo([found]), complemento([that, 'ORP1L', localized, to, the, 'Coxiella', 'PV', within, 12, h, of, infection, through, a, process, requiring, the, 'Coxiella', 'Dot/Icm', 'Type', 4, 'B', secretion, 'system,', which, secretes, effector, proteins, into, the, host, cell, cytoplasm, where, they, manipulate, trafficking, and, signalling, pathways])].
[sujeto(['The', 'ORP1L', 'N-terminal', ankyrin, repeats, were, necessary, and, sufficient, for, 'PV', 'localization,', indicating, that, 'ORP1L']), verbo([binds]), complemento([a, 'PV', membrane, protein])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'ORP1L', is, specifically, recruited, by, the, bacteria, to, the, 'Coxiella', 'PV,', where, it, influences, 'PV', membrane, dynamics, and, interactions, with, the, 'ER'])].
[sujeto(['Here', we]), verbo([provide]), complemento([genetic, evidence, for, the, critical, involvement, of, 'EMCV', protein, 3, 'A', in, this, process])].
[sujeto(['In', the, presence, of, 'PI4KA', 'inhibitors,', the, mutants, no, longer]), verbo([induced]), complemento(['PI4P,', 'OSBP,', or, cholesterol, accumulation, at, 'ROs,', which, aggregated, into, large, cytoplasmic, clusters])].
[sujeto(['This']), verbo([report]), complemento([may, contribute, to, a, better, understanding, of, the, roles, of, 'PI4KA', and, 'OSBP', in, membrane, modifications, induced, by, '(', +, ')', 'RNA', viruses])].
[sujeto(['IMPORTANCE', 'Positive-strand', 'RNA', viruses]), verbo([modulate]), complemento([lipid, homeostasis, to, generate, 'unique,', membranous, &, 'quot;replication', 'organelles"', '(', 'ROs)', where, viral, genome, replication, takes, place])].
[sujeto(['Hepatitis', 'C', 'virus,', encephalomyocarditis, virus, '(', 'EMCV),', and, enteroviruses]), verbo([have]), complemento([convergently, evolved, to, hijack, host, phosphatidylinositol, 4, -, kinases, '(', 'PI4Ks),', which, produce, 'PI4P', 'lipids,', to, recruit, 'oxysterol-binding', protein, '(', 'OSBP),', a, 'PI4P-binding', protein, that, shuttles, cholesterol, to, 'ROs'])].
[sujeto(['Remarkably,', the, mutations]), verbo([conferred]), complemento([resistance, to, 'PI4K', but, not, 'OSBP', 'inhibitors,', thereby, uncoupling, the, levels, of, dependency, of, 'EMCV', 'RNA', replication, on, 'PI4K', and, 'OSBP'])].
[sujeto(['This', work, may, contribute, to, a, deeper, understanding, of, the, roles, of, 'PI4K/PI4P', and, 'OSBP/cholesterol', in, membrane, modifications]), verbo([induced]), complemento([by, 'positive-strand', 'RNA', viruses])].
[sujeto(['ER-MVB', contacts, additionally, function, in, epidermal, growth, factor, receptor, '(', 'EGFR)', tyrosine, kinase, downregulation, by]), verbo([providing]), complemento([sites, where, the, 'ER-localized', 'phosphatase,', 'PTP1B,', interacts, with, endocytosed, 'EGFR', before, the, receptor, is, sorted, onto, intraluminal, vesicles, '(', 'ILVs)'])].
[sujeto(['Here', we, show, that, these, contacts, are, tethered, by, annexin, 'A1', and, its, 'Ca(2+)-dependent', 'ligand,', 'S100A11,', and, form, a, subpopulation, of, differentially]), verbo([regulated]), complemento([contact, sites, between, the, 'ER', and, endocytic, organelles])].
[sujeto(['This', sterol, traffic, depends, on, interaction, between, 'ER-localized', 'VAP', and, endosomal, 'oxysterol-binding', protein, 'ORP1L,', and, is]), verbo([required]), complemento([for, the, formation, of, 'ILVs', within, the, 'MVB', and, thus, for, the, spatial, regulation, of, 'EGFR', signaling])].
[sujeto(['The', 'oxysterol-binding', protein, '(', 'OSBP)-related', proteins, 'ORP5', and, 'ORP8']), verbo([have]), complemento([been, shown, recently, to, transport, phosphatidylserine, '(', 'PS)', from, the, endoplasmic, reticulum, '(', 'ER)', to, the, plasma, membrane, '(', 'PM)', at, 'ER-PM', contact, sites])].
[sujeto(['PS', is, also, transferred, from, the, 'ER', to, mitochondria, where, it]), verbo([acts]), complemento([as, precursor, for, mitochondrial, 'PE', synthesis])].
[sujeto(['Here,', we, show, 'that,', in, addition, to, 'ER-PM', contact, 'sites,', 'ORP5', and, 'ORP8', are, also, localized, to, 'ER-mitochondria', contacts, and]), verbo([interact]), complemento([with, the, outer, mitochondrial, membrane, protein, 'PTPIP51'])].
[sujeto(['A', functional, lipid, transfer, '(', 'ORD)', domain, was]), verbo([required]), complemento([for, this, localization])].
[sujeto(['Interestingly,', 'ORP5', and, 'ORP8', depletion]), verbo([leads]), complemento([to, defects, in, mitochondria, morphology, and, respiratory, function])].
[sujeto(['Sera', of, the, carriers, displayed, a, reduced, capacity, to]), verbo([act]), complemento([as, cholesterol, efflux, acceptors, '(', 'p < 0'])].
[sujeto(['C39X', carrier, showed, reduced, cholesterol, efflux, to, 'lipid-free', 'apoA-I', but, not, to, mature, 'HDL', 'particles,']), verbo([suggesting]), complemento([a, specific, defect, in, 'ABCA1-mediated', efflux, pathway])].
[sujeto(['In', hepatic, 'cells,', 'GFP-OSBPL1A', partially, 'co-localized', in, endosomes, containing, fluorescent, 'apoA-I,']), verbo([suggesting]), complemento([that, 'OSBPL1A', may, regulate, the, intracellular, handling, of, 'apoA-I'])].
[sujeto(['The', 'GFP-OSBPL1A-39X', mutant, protein, remained, in, the, cytosol, and, failed, to]), verbo([interact]), complemento([with, 'Rab7,', which, normally, recruits, 'OSBPL1A', to, late, 'endosomes/lysosomes,', suggesting, that, this, mutation, represents, a, 'loss-of-function'])].
[sujeto(['Our', observations]), verbo([provide]), complemento([evidence, that, a, familial, 'loss-of-function', mutation, in, 'OSBPL1A', affects, the, first, step, of, the, reverse, cholesterol, transport, process, and, associates, with, a, low, 'HDL-C', phenotype])].
[sujeto(['This']), verbo([suggests]), complemento([that, rare, mutations, in, 'OSBPL', genes, may, contribute, to, dyslipidemias])].
[sujeto(['Lipids', are, precisely, distributed, in, cell, 'membranes,', along, with]), verbo([associated]), complemento([proteins, defining, organelle, identity])].
[sujeto(['Recent', findings]), verbo([reveal]), complemento([that, proteins, of, the, 'oxysterol-binding', protein, 'related-proteins', '(', 'ORP)/oxysterol-binding', homology, '(', 'Osh)', family, are, not, all, just, sterol, 'transporters/sensors:', some, can, bind, either, phosphatidylinositol, 4, -, phosphate, '(', 'PtdIns(4)P)', and, sterol, or, 'PtdIns(4)P', and, phosphatidylserine, '(', 'PS),', exchange, these, lipids, between, 'membranes,', and, thereby, use, phosphoinositide, metabolism, to, create, cellular, lipid, gradients])].
[sujeto(['The', endoplasmic, reticulum, '(', 'ER)', makes, abundant, contacts, with, 'endosomes,', and, the, numbers, of, contact, sites]), verbo([increase]), complemento([as, endosomes, mature])].
[sujeto(['It', is, already, clear, that, such, contact, sites]), verbo([have]), complemento([diverse, compositions, and, 'functions,', but, in, this, 'mini-review', we, will, focus, on, two, particular, 'types of', 'ER-endosome', contact, sites, that, regulate, endosome, positioning])].
[sujeto(['Formation', of, 'ER-endosome', contact, sites, that, contain, the, 'cholesterol-binding', protein, 'oxysterol-binding', 'protein-related', protein, 1, 'L', '(', 'ORP1L)', is, coordinated, with]), verbo([loss]), complemento([of, the, 'minus-end-directed', microtubule, motor, 'Dynein', from, endosomes])].
[sujeto(['We', discuss, the, possibility, that, formation, of, these, two, 'types of', contact, sites, is, coordinated, as, a, '\'', 'gear-shift\'', mechanism, for, endosome, 'motility,', and, we, review, evidence, that, 'Kinesin-1-mediated', motility, of, late, endosomes, '(', 'LEs)', to, the, cell, periphery]), verbo([promotes]), complemento([outgrowth, of, neurites, and, other, protrusions])].
[sujeto(['The', mutated, 'OSBPL2', '(', 'OMIM:', 606731, ')', ',', encoding, oxysterol]), verbo([binding]), complemento(['protein-like', protein, 2, ',', was, recently, identified, as, a, novel, causative, gene, for, autosomal, dominant, nonsyndromic, hearing, loss, '(', 'ADNSHL)'])].
[sujeto(['We']), verbo([reported]), complemento([the, expression, patterns, of, 'Osbpl2', in, 'zebrafish,', in, order, to, further, understand, the, role, of, 'OSBPL2', in, hearing, formation, and, development])].
[sujeto(['Bioinformatics', analysis, indicates, that, zebrafish]), verbo([has]), complemento([two, homologues, of, 'Osbpl2', gene, '(', 'Osbpl2a', and, 'Osbpl2b)', and, 'Osbpl2b', is, the, orthologous, gene, of, human, 'OSBPL2'])].
[sujeto(['The', zygotical, expression, of, the, two, genes]), verbo([has]), complemento([not, been, started, at, 11, -, somite, stage])].
[sujeto(['At', 24, h, 'post-fertilization', '(', 'hpf),', both, 'Osbpl2a', and, 'Osbpl2b', are]), verbo([found]), complemento([at, ventricle, zone, of, 'brain,', 'however,', the, expression, level, of, 'Osbpl2a', is, higher, than, that, of, 'Osbpl2b'])].
[sujeto(['At', 72, 'hpf,', 'Osbpl2b', is, only]), verbo([found]), complemento([at, liver, 'primordium,', while, 'Osbpl2a', is, not, detected, anywhere, obviously])].
[sujeto(['At', 96, 'hpf,', 'Osbpl2b', is]), verbo([found]), complemento([at, pharyngeal, 'arches,', 'liver,', digestive, tract, and, otic, 'vesicle,', while, 'Osbpl2a', remains, undetected])].
[sujeto(['Osbpl2b', was, demonstrated, to, be, the, orthologous, gene, of, human, 'OSBPL2,', which]), verbo([has]), complemento([strong, maternal, 'expression,', while, 'Osbpl2a', was, detected, without, obvious, maternal, expression])].
[sujeto(['We', review, data]), verbo([suggesting]), complemento([that, several, pathways, may, operate, in, 'parallel,', including, membrane, transport, routes, and, membrane, contact, sites, '(', 'MCSs)'])].
[sujeto(['There', is]), verbo([increasing]), complemento([appreciation, that, 'MCSs', provide, an, important, mechanism, for, intermembrane, lipid, transfer])].
[sujeto(['In', late, 'endosome-ER', 'contacts,', three, protein, bridges]), verbo([involving]), complemento([oxysterol, binding, protein, related, protein, '(', 'ORP)1L-vesicle', associated, membrane, 'protein-associated', protein, '(', 'VAP),', steroidogenic, acute, regulatory, protein, '(', 'StAR)D3-VAP', and, 'ORP5-NPC1', proteins, have, been, reported])].
[sujeto(['Studies', for, lipid, transfer, via, 'MCSs']), verbo([have]), complemento([been, most, advanced, in, 'Saccharomyces', cerevisiae])].
[sujeto(['Recently,', a, new, 'sterol-binding', protein, family]), verbo([conserved]), complemento([between, yeast, and, man, was, identified])].
[sujeto(['Increasing', insights, into, the, role, of, 'MCSs', in, directional, sterol, delivery, between, membranes, propose, that, they, might]), verbo([provide]), complemento([routes, for, 'LDL-cholesterol', transfer, to, the, 'ER'])].
[sujeto(['Future', work, should]), verbo([reveal]), complemento([which, specific, contacts, may, operate, for, 'this,', and, how, they, are, controlled, by, cholesterol, homeostatic, machineries])].
[sujeto(['Here', we, show, that, expression, of, mutant, 'PSS1', enzymes]), verbo([decreased]), complemento([phosphatidylinositol, 4, -, phosphate, '(', 'PI4P)', levels, both, in, the, 'Golgi', and, the, plasma, membrane, '(', 'PM)', by, activating, the, 'Sac1', phosphatase, and, altered, 'PI4P', cycling, at, the, 'PM'])].
[sujeto(['Oxysterol-binding', 'protein-related', protein, 8, ',', which, was, recently, identified, as, a, 'PI4P-PS', exchanger, between, the, 'ER', and, 'PM,', showed, 'PI4P-dependent', membrane, association, that, was, significantly]), verbo([decreased]), complemento([by, expression, of, 'PSS1', mutant, enzymes])].
[sujeto(['Our', studies]), verbo([reveal]), complemento([that, 'PS', synthesis, is, tightly, coupled, to, 'PI4P-dependent', 'PS', transport, from, the, 'ER'])].
[sujeto(['Consequently,', 'PSS1', mutations, not, only, affect, cellular, 'PS', levels, and, distribution, but, also]), verbo([lead]), complemento([to, a, more, complex, imbalance, in, lipid, homeostasis, by, disturbing, 'PI4P', metabolism])].
[sujeto(['Oxysterol']), verbo([binding]), complemento(['protein-related', protein, 2, '(', 'ORP2)', is, a, lipid, binding, protein, that, has, been, implicated, in, various, cellular, 'processes,', including, lipid, 'sensing,', cholesterol, 'efflux,', and, endocytosis])].
[sujeto(['We', recently, identified, 'ORP2', as, a, member, of, a, protein, complex, that]), verbo([regulates]), complemento([glucocorticoid, biosynthesis])].
[sujeto(['Herein,', we, examine, the, effect, of, silencing, 'ORP2', on, adrenocortical, function, and, show, that, the, 'ORP2', knockdown, cells, exhibit, reduced, amounts, of, multiple, steroid, 'metabolites,', including, 'progesterone,', 11, -, 'deoxycortisol,', and, 'cortisol,', but]), verbo([have]), complemento([increased, concentrations, of, 'androgens,', and, estrogens])].
[sujeto(['Moreover,', silencing, 'ORP2']), verbo([suppresses]), complemento([the, expression, of, most, proteins, required, for, cortisol, production, and, reduces, the, expression, of, steroidogenic, factor, 1, '(', 'SF1)'])].
[sujeto(['ORP2', silencing, also]), verbo([increases]), complemento([cellular, 'cholesterol,', concomitant, with, decreased, amounts, of, 22, -, hydroxycholesterol, and, 7, -, 'ketocholesterol,', two, molecules, that, have, been, shown, to, bind, to, 'ORP2'])].
[sujeto(['Further,', we, show, that, 'ORP2']), verbo([binds]), complemento([to, liver, 'X', receptor, '(', 'LXR)', and, is, required, for, nuclear, 'LXR', expression])].
[sujeto(['LXR', and, 'ORP2', are]), verbo([recruited]), complemento([to, the, 'CYP11B1', promoter, in, response, to, cAMP, signaling])].
[sujeto(['Additionally,', 'ORP2', is]), verbo([required]), complemento([for, the, expression, of, other, 'LXR', target, 'genes,', including, 'ABCA1', and, the, 'LDL', receptor, '(', 'LDLR)'])].
[sujeto(['In', 'summary,', we, establish, a, novel, role, for, 'ORP2', in]), verbo([regulating]), complemento([steroidogenic, capacity, and, cholesterol, homeostasis, in, the, adrenal, cortex])].
[sujeto(['MicroRNAs', exert, potent, effects, on, biological, 'pathways,', including, cholesterol, 'metabolism,', by]), verbo([repressing]), complemento([genes, with, related, functions])].
[sujeto(['We', reasoned, that, this, mode, of, pathway, regulation, could, be, exploited, to, identify, novel, genes]), verbo([involved]), complemento([in, cholesterol, homeostasis])].
[sujeto(['Here,', we, identify, 'oxysterol-binding', 'protein-like', 6, '(', 'OSBPL6)', as, a, novel]), verbo([target]), complemento([of, 2, miRNA, hubs, regulating, cholesterol, 'homeostasis:', 'miR-33', and, 'miR-27b'])].
[sujeto(['Characterization', of, 'OSBPL6', revealed, that, it, is, transcriptionally]), verbo([regulated]), complemento([in, macrophages, and, hepatocytes, by, liver, 'X', receptor, and, in, response, to, cholesterol, loading, and, in, mice, and, nonhuman, primates, by, 'Western', diet, feeding])].
[sujeto(['Subcellular', localization, studies, showed, that, 'ORP6', is]), verbo([associated]), complemento([with, the, endolysosomal, network, and, endoplasmic, 'reticulum,', suggesting, a, role, for, 'ORP6', in, cholesterol, trafficking, between, these, compartments])].
[sujeto(['Accordingly,', knockdown, of, 'OSBPL6', results, in, aberrant, clustering, of, endosomes, and]), verbo([promotes]), complemento([the, accumulation, of, free, cholesterol, in, these, 'structures,', resulting, in, reduced, cholesterol, esterification, at, the, endoplasmic, reticulum])].
[sujeto(['Conversely,', 'ORP6', overexpression]), verbo([enhances]), complemento([cholesterol, trafficking, and, efflux, in, macrophages, and, hepatocytes])].
[sujeto(['These', studies, identify, 'ORP6', as, a, novel, regulator, of, cholesterol, trafficking, that, is, part, of, the, 'miR-33', and, 'miR-27b']), verbo([target]), complemento([gene, networks, that, contribute, to, the, maintenance, of, cholesterol, homeostasis])].
[sujeto(['Cholesterol', is, kept, high, in, the, plasma, membrane, '(', 'PM)', because, it, is, essential, for, its, barrier, 'function,', while, low, levels, are]), verbo([found]), complemento([in, the, endoplasmic, reticulum, '(', 'ER)', where, cholesterol, mediates, feedback, control, of, its, own, synthesis, by, 'sterol-sensor', proteins])].
[sujeto(['The', 'ER→Golgi→PM', concentration, gradient, of, cholesterol, in, mammalian, 'cells,', and, ergosterol, in, 'yeast,', appears, to, be, sustained, by, specific, intracellular, transport, 'processes,', which, are, mostly]), verbo([mediated]), complemento([by, lipid, transfer, proteins, '(', 'LTPs)'])].
[sujeto(['A', mutation, in, 'VAPB']), verbo([causes]), complemento([a, familial, form, of, 'Amyotrophic', 'Lateral', 'Sclerosis'])].
[sujeto(['The', mutant, protein, '(', 'VAPB-P56S)', is, aggregate, prone, and, blocks, retrograde, traffic, from, the, endoplasmic, reticulum, '(', 'ER)', 'Golgi', intermediate, compartment, '(', 'ERGIC)', including, trafficking, to, the]), verbo([nuclear]), complemento([envelope, '(', 'NE)'])].
[sujeto(['Here', we]), verbo([report]), complemento([a, morphological, screen, where, overexpression, of, oxysterol, binding, 'protein-related', 'protein-3', '(', 'ORP3)', rescued, the, mutant, 'VAPB', phenotype])].
[sujeto(['Knockdown', of, 'ORP3', or, 'VAPB']), verbo([increased]), complemento([the, intracellular, level, of, phosphatidylinositol, 4, -, phosphate, '(', 'PtdIns4P)'])].
[sujeto(['Decreasing', 'PtdIns4P', levels, by]), verbo([inhibiting]), complemento([its, synthesis, reduced, the, severity, of, the, mutant, 'VAPB-induced', membrane, expansions, and, restored, 'Emerin', trafficking, to, the, 'NE'])].
[sujeto(['Thus,', 'VAPB', and, its]), verbo([interacting]), complemento([partners, cooperatively, regulate, protein, trafficking, through, the, 'ERGIC', by, modulating, 'PtdIns4P', levels])].
[sujeto(['Oxysterol-binding', protein, '(', 'OSBP)', and, its, related, protein, 'homologs,', 'ORPs,', constitute, a]), verbo([conserved]), complemento([family, of, 'lipid-binding/transfer', proteins, '(', 'LTPs)', expressed, ubiquitously, in, eukaryotes])].
[sujeto(['ORPs']), verbo([have]), complemento([been, implicated, as, intracellular, lipid, sensors, or, transporters])].
[sujeto(['Most', 'ORPs', carry]), verbo([targeting]), complemento([determinants, for, the, endoplasmic, reticulum, '(', 'ER)', and, 'non-ER', organelle, membrane])].
[sujeto(['Such', sites]), verbo([have]), complemento([roles, in, lipid, transport, and, 'metabolism,', control, of, 'Ca(2+)', 'fluxes,', and, signaling, events])].
[sujeto(['ORPs', are, postulated, either, to, transport, lipids, over, 'MCSs', to]), verbo([maintain]), complemento([the, distinct, lipid, compositions, of, organelle, 'membranes,', or, to, control, the, activity, of, 'enzymes/protein', complexes, with, functions, in, signaling, and, lipid, metabolism])].
[sujeto(['Transport', of, 'PI4P', followed, by, its, hydrolysis, would, in, this, model]), verbo([provide]), complemento([the, energy, for, transfer, of, the, other, lipid, against, its, concentration, gradient])].
[sujeto(['Several', 'ORPs', are]), verbo([reported]), complemento([to, modulate, vesicle, transport, along, the, secretory, or, endocytic, pathways])].
[sujeto(['Moreover,', antagonists, of, certain, 'ORPs']), verbo([inhibit]), complemento([cancer, cell, proliferation])].
[sujeto(['Thus,', 'ORPs', are, 'LTPs,', which]), verbo([mediate]), complemento([interorganelle, lipid, transport, and, coordinate, lipid, signals, with, a, variety, of, cellular, regimes])].
[sujeto(['Whether', or, not, 24, -, hour, ambulatory, 'BP', monitoring, and, pulse, wave, velocity, '(', 'PWV)', add, insight, to, the, issue]), verbo([has]), complemento([also, been, examined])].
[sujeto(['The', largest, differences, between, oSBP, and, cSBP, correspond, to, the, isolated, systolic, 'HTN', '(', 'ISH)', 'group,', in, which, only, 25, '%', of, subjects]), verbo([have]), complemento([high, 'cBP,', in, contrast, to, 50, '%', of, the, 'systo-diastolic', 'HTN', '(', 'SDH)', group])].
[sujeto(['To']), verbo([gain]), complemento([insights, from, a, large, 'dataset,', we, investigated, safety, and, performance, of, the, 'EnligHTN™', 'Renal', 'Denervation', 'System', '(', 'St'])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([of, pooled, data, from, the, 'EnligHTN', 'I-III', trials, through, 24, -, months])].
[sujeto(['VAP', '(', 'VAPA', and, 'VAPB)', is, an, evolutionarily]), verbo([conserved]), complemento([endoplasmic, reticulum, '(', 'ER)-anchored', protein, that, helps, generate, tethers, between, the, 'ER', and, other, membranes, through, which, lipids, are, exchanged, across, adjacent, bilayers])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, by, regulating, 'PI4P', levels, on, 'endosomes,', 'VAP', affects, 'WASH-dependent', actin, nucleation, on, these, organelles, and, the, function, of, the, 'retromer,', a, protein, coat, responsible, for, 'endosome-to-Golgi', traffic])].
[sujeto(['VAP', is]), verbo([recruited]), complemento([to, retromer, budding, sites, on, endosomes, via, an, interaction, with, the, retromer, 'SNX2', subunit])].
[sujeto(['These', results]), verbo([reveal]), complemento([a, role, of, 'PI4P', in, 'retromer-/WASH-dependent', budding, from, endosomes])].
[sujeto(['Collectively,', our, data, show, how, the, 'ER', can, control, budding, dynamics, and, association, with, the, cytoskeleton, of, another, membrane, by, direct, contacts]), verbo([leading]), complemento([to, bilayer, lipid, modifications])].
[sujeto(['The', mean, supSBP, and, supDBP, were]), verbo([found]), complemento([to, be, lower, than, 'OSBP', and, 'ODBP', '(', 130.9, '±14'])].
[sujeto([52.7, '%', ;, p, &, 'lt;', 0.0001, ')', and, the, additive, value, derived, mostly, from, its, higher, predictive, power, of, identifying, patients, with]), verbo([increased]), complemento(['night-time', 'BP'])].
[sujeto(['The', supine, blood, pressure, '≥', 130, /, 80, mm, 'Hg', was]), verbo([found]), complemento([to, be, a, specific, and, sensitive, threshold, for, hypertension])].
[sujeto(['Nucleic', acids, added, to, one, compartment, traverse, the, 'pore,', and]), verbo([modulate]), complemento([the, current, in, a, 'sequence-dependent', manner])].
[sujeto(['The', data, indicate, that, the, 'α-HL', constriction, 'zone/β-barrel']), verbo([interacts]), complemento([strongly, with, both, 'OsBp', and, the, base])].
[sujeto(['A', 23, nucleotide, long, oligo, with, four, 'dT(OsBp)', traverses, 18, -, times, 'slower,', and, the, same, oligo, with, nine, '(', 'dT+dC)(OsBp)', moieties, traverses, 84, -, times, slower, compared, to, 'dA20,']), verbo([suggesting]), complemento([an, average, rate, of, 40, or, 180, 'μs/base,', respectively])].
[sujeto(['Increasing', evidence]), verbo([suggests]), complemento([that, 'oxysterol-binding', 'protein-related', proteins, '(', 'ORPs)', localize, at, membrane, contact, 'sites,', which, are, 'high-capacity', platforms, for, 'inter-organelle', exchange, of, small, molecules, and, information])].
[sujeto(['ORPs', can, simultaneously]), verbo([associate]), complemento([with, the, two, apposed, membranes, and, transfer, lipids, across, the, interbilayer, gap])].
[sujeto(['Analogously,', yeast, 'Osh6p']), verbo([mediates]), complemento([the, transport, of, phosphatidylserine, from, the, endoplasmic, reticulum, to, the, plasma, membrane, in, exchange, for, 'PI4P,', and, 'ORP5', and, -, 8, are, suggested, to, execute, similar, functions, in, mammalian, cells])].
[sujeto(['ORPs', may, share, the, capacity, to]), verbo([bind]), complemento(['PI4P', within, their, 'ligand-binding', 'domain,', prompting, the, hypothesis, that, bidirectional, transport, of, a, phosphoinositide, and, another, lipid, may, be, a, common, theme, among, the, protein, family])].
[sujeto(['Arterial', hypertension, '(', 'AH)', may, be, related, to, fluid, 'retention,']), verbo([increased]), complemento([vascular, resistance, or, hyperdynamic, heart, function])].
[sujeto(['This', analysis]), verbo([involved]), complemento([272, patients, '(', average, 'age:', 44.1, ±, 10.8, 'years)', with, 'AH'])].
[sujeto(['The', results, were, evaluated, separately, in, subgroups, derived, from, median, of, 'MBP', '(', 110, 'mmHg):', with, slightly]), verbo([increased]), complemento(['(', '\'', 'SI_BP\')', and, more, increased, 'BP', '(', '\'', 'MI_BP\')'])].
[sujeto(['The', comparison, in, the, 'SI_BP', subgroup, did, not]), verbo([reveal]), complemento([such, significant, differences])].
[sujeto(['This', effect, is, more, pronounced, in, patients, with, higher, baseline, 'BP,', while, in, those, with, slightly]), verbo([increased]), complemento(['BP', the, empiric, approach, seems, comparable, to, 'ICG'])].
[sujeto([25, -, 'Hydroxycholesterol', '(', 25, 'OH)', competitively]), verbo([inhibits]), complemento([this, exchange, reaction, in, vitro, and, causes, the, constitutive, localization, of, 'OSBP', at, the, 'ER/Golgi', interface, and, 'PI-4P-dependent', recruitment, of, ceramide, transfer, protein, '(', 'CERT)', for, sphingomyelin, synthesis])].
[sujeto(['Treatment', of, fibroblasts, or, 'Chinese', hamster, ovary, '(', 'CHO)', cells, with, 25, 'OH']), verbo([caused]), complemento([a, 50, -, 70, '%', reduction, in, 'Golgi-associated', immunoreactive, 'PI-4P', that, correlated, with, 'Golgi', localization, of, 'OSBP'])].
[sujeto(['In', 'contrast,', 25, 'OH']), verbo([caused]), complemento([an, 'OSBP-dependent', enrichment, in, 'Golgi', 'PI-4P', that, was, detected, with, a, pleckstrin, homology, domain, probe])].
[sujeto(['The', 'PI-4P', and, sterol]), verbo([binding]), complemento([activities, of, 'OSBP', were, both, required, for, 25, 'OH', activation, of, sphingomyelin, 'synthesis,', suggesting, that, 25, 'OH', must, be, exchanged, for, 'PI-4P', to, be, concentrated, at, contact, sites])].
[sujeto(['We', propose, a, model, wherein, 25, 'OH', activation, of, 'OSBP']), verbo([promotes]), complemento([the, binding, and, retention, of, 'PI-4P', at, 'ER-Golgi', contact, sites])].
[sujeto(['This', pool, of, 'PI-4P', specifically]), verbo([recruits]), complemento([pleckstrin, homology, 'domain-containing', proteins, involved, in, lipid, transfer, and, 'metabolism,', such, as, 'CERT'])].
[sujeto(['MicroRNA-124', '(', 'miR-124),', a, 'brain-specific', miRNA, 'molecule,']), verbo([has]), complemento([been, implicated, in, stimulating, neurite, outgrowth, and, elongation, during, neuronal, differentiation])].
[sujeto(['However,', the, direct]), verbo([target]), complemento([genes, and, the, mechanisms, of, 'miR-124-induced', neurite, outgrowth, are, poorly, understood])].
[sujeto(['In', this, 'study,', we, demonstrated, that, 'miR-124', directly]), verbo([targeted]), complemento([and, downregulated, the, endogenous, expression, of, 'oxysterol-binding', protein, '(', 'OSBP)'])].
[sujeto(['A', previous, study]), verbo([found]), complemento([that, the, expression, of, 'miR-124', increased, during, brain, development])].
[sujeto(['In', the, present, 'study,', we, demonstrated, that, the, expression, of, 'OSBP']), verbo([decreased]), complemento([during, the, development, of, the, 'C57BL/6', mouse, 'cortex,', which, was, negatively, correlated, with, 'miR-124', expression])].
[sujeto(['OSBP', knockdown, using, specific, shRNAs]), verbo([promoted]), complemento([neurite, outgrowth, and, elongation, in, both, 'Neuro-2a', cells, and, primary, cultured, mouse, cortical, neurons])].
[sujeto(['Conversely,', 'OSBP', overexpression, strongly]), verbo([repressed]), complemento([the, neurite, 'elongation-enhancing', effect, of, 'miR-124', in, 'Neuro-2a', cells])].
[sujeto(['Our', results]), verbo([suggested]), complemento([that, 'OSBP', may, be, a, target, and, downstream, effector, of, 'miR-124', for, regulating, neurite, outgrowth, and, elongation])].
[sujeto(['In', this, 'study,', we, evaluated, the, tumor, 'selectivity,', cellular, 'internalization,', and, biological, activity, of, a, 'cell-permeable', ovarian, cancer, 'cell-specific', therapeutic, protein, consisting, of, 'TAT-OSBP', and, constitutively, active, 'MKK6(E),', an, upstream, kinase, of, the, p38, signaling, pathway, that]), verbo([mediates]), complemento([cellular, apoptosis])].
[sujeto(['TAT-OSBP-MKK6(E)', fusion, protein]), verbo([inhibited]), complemento([cancer, cell, growth, to, varying, 'degrees,', with, the, highest, level, of, inhibition, in, 'HO8910', cells])].
[sujeto(['Moreover,', 'TAT-OSBP-MKK6(E)', significantly]), verbo([induced]), complemento([apoptosis, of, 'HO8910', cells])].
[sujeto(['Our', results, demonstrate, that, 'TAT-OSBP-MKK6(E)', is, a, novel, artificially, designed, 'molecule,', which]), verbo([induces]), complemento([apoptosis, and, selectively, targets, human, ovarian, carcinoma, 'HO8910', cells])].
[sujeto(['Our', study]), verbo([provides]), complemento([novel, insights, that, may, aid, in, the, development, of, a, new, generation, of, anticancer, drugs])].
[sujeto(['Vesicle-associated', membrane, 'protein-associated', protein, '(', 'VAP)', is, an, endoplasmic, reticulum, '(', 'ER)-resident', integral, membrane, protein, that, controls, a, nonvesicular, mode, of, ceramide, and, cholesterol, transfer, from, the, 'ER', to, the, 'Golgi', complex, by]), verbo([interacting]), complemento([with, ceramide, transfer, protein, and, 'oxysterol-binding', protein, '(', 'OSBP),', respectively])].
[sujeto(['We']), verbo([report]), complemento([that, 'VAP', and, its, interacting, proteins, are, required, for, the, processing, and, secretion, of, pancreatic, adenocarcinoma, 'up-regulated', 'factor,', whose, transport, from, the, 'trans-Golgi', network, '(', 'TGN)', to, the, cell, surface, is, mediated, by, transport, carriers, called, &, 'quot;carriers', of, the, 'trans-Golgi', network, to, the, cell, 'surface"', '(', 'CARTS)'])].
[sujeto(['In', 'VAP-depleted', 'cells,', diacylglycerol, level, at, the, 'TGN', was]), verbo([decreased]), complemento([and, 'CARTS', formation, was, impaired])].
[sujeto(['We']), verbo([found]), complemento([that, 'VAP', forms, a, complex, with, not, only, 'OSBP', but, also, 'Sac1', phosphoinositide, phosphatase, at, specialized, 'ER', subdomains, that, are, closely, apposed, to, the, 'trans-Golgi/TGN,', most, likely, reflecting, membrane, contact, sites])].
[sujeto(['Accumulating', evidence]), verbo([suggests]), complemento([that, picornaviruses, from, different, genera, use, different, strategies, to, generate, viral, replication, organelles, '(', 'ROs)'])].
[sujeto(['We']), verbo([reveal]), complemento([that, the, 'EMCV', nonstructural, protein, 3, 'A', interacts, with, and, is, responsible, for, 'PI4KA', recruitment, to, viral, 'ROs'])].
[sujeto(['PI4P', lipids, and, cholesterol, are, shown, to, be]), verbo([required]), complemento([for, the, global, organization, of, the, 'ROs', and, for, viral, genome, replication])].
[sujeto(['In', 'conclusion,', we, describe, for, the, first, time, a, cellular, pathway]), verbo([involved]), complemento([in, the, biogenesis, of, cardiovirus, 'ROs'])].
[sujeto(['Remarkably,', the, same, pathway, was]), verbo([reported]), complemento([to, promote, formation, of, the, replication, sites, of, hepatitis, 'C', 'virus,', a, member, of, the, 'Flaviviridae', 'family,', but, not, other, picornaviruses, or, flaviviruses])].
[sujeto(['Lipid', transfer, between, cell, membrane, bilayers, at, contacts, between, the, endoplasmic, reticulum, '(', 'ER)', and, other, membranes, help, to]), verbo([maintain]), complemento([membrane, lipid, homeostasis])].
[sujeto(['We']), verbo([found]), complemento([that, two, similar, 'ER', integral, membrane, 'proteins,', 'oxysterol-binding', protein, '(', 'OSBP)-related', protein, 5, '(', 'ORP5)', and, 'ORP8,', tethered, the, 'ER', to, the, plasma, membrane, '(', 'PM)', via, the, interaction, of, their, pleckstrin, homology, domains, with, phosphatidylinositol, 4, -, phosphate, '(', 'PI4P)', in, this, membrane])].
[sujeto(['Gain-', and, 'loss-of-function', experiments, showed, that, 'ORP5', and, 'ORP8', could]), verbo([mediate]), complemento(['PI4P/PS', countertransport, between, the, 'ER', and, the, 'PM,', thus, delivering, 'PI4P', to, the, 'ER-localized', 'PI4P', phosphatase, 'Sac1', for, degradation, and, 'PS', from, the, 'ER', to, the, 'PM'])].
[sujeto(['We', previously, synthesized, a, 'MAPK', 'kinase-recombinant', fusion, 'protein,', 'MAP2K6-FP,', that, contains, three, 'domains:', a, protein, transduction, domain, 'TAT,', a, human, ovarian, cancer, 'HO8910', 'cell-specific']), verbo([binding]), complemento([peptide, '(', 'OSBP),', and, a, potential, 'anti-tumor', effector, domain, 'MKK6', '(', 'E)'])].
[sujeto(['The', combination, treatment, resulted, in, significantly, altered, 'caspase-3,', vascular, endothelial, growth, factor, '(', 'VEGF),', and, proliferating, cell]), verbo([nuclear]), complemento([antigen, expression, compared, to, treatment, with, the, single, agents, '(', 'P<0'])].
[sujeto(['Both', 'MAP2K6-FP', and, paclitaxel, can]), verbo([inhibit]), complemento([cell, proliferation, and, induce, apoptosis, in, ovarian, cancer, 'HO8910', cells])].
[sujeto(['Interestingly,', the, combination, of, 'MAP2K6-FP', and, paclitaxel, had, a, synergistic, antitumor, effect, on, 'HO8910', 'cells,', which]), verbo([induced]), complemento([apoptosis, by, increasing, 'caspase-3', expression, and, decreasing, 'VEGF', expression])].
[sujeto(['Intrahepatic', cholestasis, of, pregnancy, '(', 'ICP)', is, a, disorder, of, bile, acid, '(', 'BA)', 'synthesis,', 'excretion,', and, 'metabolism,', with, systemic, accumulation, of, 'BAs,', which, can]), verbo([lead]), complemento([to, 'prematurity,', fetal, 'distress,', and, intrauterine, death])].
[sujeto(['Our', findings]), verbo([provide]), complemento([the, 'ERα-centered', hypothesis, on, the, mechanisms, of, 'ICP'])].
[sujeto(['Lipoprotein', particle, sizing, by, proton]), verbo([nuclear]), complemento([magnetic, resonance, '(', 'H(1)', 'NMR)', was, available, for, 432, subjects])].
[sujeto(['TC,', 'LDL-C,', and, 'ApoB', were]), verbo([associated]), complemento([with, higher, levels, of, all, oxysterols, '(', all, p, &, 'lt;', 0.05, ')', in, 'HC'])].
[sujeto(['In', 'MS,', 'LDL-C', was]), verbo([associated]), complemento([with, higher, levels, of, 24, -, 'HC,', 25, -, 'HC,', 7, -, 'KC,', and, 7, 'α-HC', '(', all, p, &, 'lt;', 0.05, ')', ',', while, 'TC', and, 'ApoB', were, associated, with, increased, levels, of, all, oxysterols, '(', all, p, &, 'lt;', 0.005, ')'])].
[sujeto(['Using', an, oral, feed, regimen, of, pure, 28, -, 'HB,', we, noted, a]), verbo([decrease]), complemento([of, 16, &, 'nbsp;%', in, 'liver,', 17.1, &, 'nbsp;%', in, kidney, and, 9.3, &, 'nbsp;%', in, testicular, 'HMGCR', enzyme, 'activity,', 25, &, 'nbsp;%', in, 'HMGCR', gene, expression, and, 44, &, 'nbsp;%', in, the, activity, of, pure, human, 'HMGCR', due, to, this, plant, oxysterol])].
[sujeto(['In', silico, docking, studies, yielded]), verbo([binding]), complemento([metrics, for, 28, -, 'HB-HMGCR', lower, than, for, 'HMGCoA-HMGCR,', indicating, stronger, binding, of, 'HMGCR', by, this, ligand])].
[sujeto([28, -, 'HB', exerts, differential, effects, on, rat, tissue, 'HMGCR,', down]), verbo([regulates]), complemento([liver, 'HMGCR', gene, expression, and, significantly, inhibits, 'HMGCR', activity])].
[sujeto(['Among', the, various, metabolites, produced, by, 'tumors,', we, recently, showed, that, cholesterol, oxidized, 'products,', namely, 'oxysterols,', favor, tumor, growth, through, the, inhibition, of, 'DC', migration, toward, lymphoid, organs, and, by]), verbo([promoting]), complemento([the, recruitment, of, 'pro-tumor', neutrophils, within, the, tumor, microenvironment])].
[sujeto(['In', 'particular,', we, tested, efficacy, and, safety, of, different, administration, 'schedules,', and, of, 'immunotherapy-based', combination, of, a, class, of, 'compounds,', namely, zaragozic, 'acids,', which]), verbo([inhibit]), complemento([cholesterol, pathway, downstream, of, mevalonate, 'formation,', thus, leaving, intact, the, formation, of, the, 'isoprenoids,', which, are, required, for, the, maturation, of, proteins, involved, in, the, immune, cell, function])].
[sujeto(['We', show, that, zaragozic, acids]), verbo([inhibit]), complemento([the, in, vivo, growth, of, the, 'RMA', lymphoma, and, the, 'Lewis', lung, carcinoma, '(', 'LLC)', without, inducing, side, effects])].
[sujeto(['Tumor', growth, inhibition]), verbo([requires]), complemento([an, intact, immune, 'system,', as, immunodeficient, 'tumor-bearing', mice, do, not, respond, to, zaragozic, acid, treatment])].
[sujeto(['Of', 'note,', the, effect, of, zaragozic, acids, is, accompanied, by, a, marked, reduction, in, the, 'LXR']), verbo([target]), complemento([genes, 'Abcg1,', 'Mertk,', 'Scd1', and, 'Srebp-1c', in, the, tumor, microenvironment])].
[sujeto(['The', widespread, involvement, of, the, 'Hedgehog', '(', 'Hh)', signaling, pathway, in, human, malignancies]), verbo([has]), complemento([driven, efforts, to, develop, 'Hh', pathway, inhibitors, as, 'anti-cancer', agents])].
[sujeto(['However,', several, such, 'Smo', antagonists]), verbo([have]), complemento([failed, in, clinical, trials, to, benefit, patients, with, cancers, that, arise, from, aberrant, 'Hh', signaling, '(', which, often, bypasses, 'Smo)'])].
[sujeto(['In', this, 'study,', we]), verbo([report]), complemento([that, a, naturally, occurring, 'oxysterol,', 20, 'α,', 22, '(', 'R)-dihydroxycholesterol', '(', 'Oxy16),', a, known, metabolite, in, the, biosynthesis, of, steroid, 'hormones,', strongly, inhibits, 'Hh', signaling, induced, in, 'C3H10T1/2', embryonic, fibroblasts, and, 'NIH3T3-E1', fibroblasts, through, a, mechanism, that, is, independent, of, liver, 'X', receptor, '(', 'LXR)', activation])].
[sujeto(['We', demonstrate, that, 'Oxy16']), verbo([inhibits]), complemento(['Hh', signaling, in, 'Suppressor', of, 'Fused', '(', 'Sufu)', null, mouse, embryonic, fibroblast, '(', 'MEF)', 'cells,', indicating, that, its, inhibitory, effect, on, 'Hh', signaling, is, epistatic, to, 'Sufu'])].
[sujeto(['We', further, demonstrate, that, 'Oxy16']), verbo([inhibits]), complemento(['Gli1', transcriptional, activity, in, 'NIH3T3-E1', cells, overexpressing, 'Gli1', and, a, 'Gli-dependent', reporter, construct])].
[sujeto(['Altogether,', data, presented, here]), verbo([suggest]), complemento([that, 'Oxy16', may, be, a, suitable, starting, point, for, the, development, of, new, drugs, that, inhibit, 'Hh', signaling, downstream, of, 'Smo'])].
[sujeto(['By']), verbo([targeting]), complemento([aberrant, 'Hh', 'signaling,', such, novel, 'Hh', pathway, inhibitors, could, significantly, broaden, the, range, of, clinical, applications, compared, to, existing, 'Smo', antagonists])].
[sujeto(['Furthermore,', the, present, study, adds, a, new, facet, to, the, spectrum, of, 'Hh', pathway, modulation, that, naturally, occurring, oxysterol, derivatives, are, capable, 'of,', ranging, from, allosteric, activation, of, the, pathway, via, 'Smo']), verbo([binding]), complemento([to, inhibition, of, the, pathway, downstream, of, 'Smo'])].
[sujeto(['Liver', 'X', receptors, '(', 'LXRs)', are]), verbo([nuclear]), complemento([receptors, that, play, central, roles, in, the, transcriptional, control, of, lipid, metabolism])].
[sujeto(['The', ability, of, 'LXRs', to, integrate, metabolic, and, inflammation, signalling, makes, them, attractive]), verbo([targets]), complemento([for, intervention, in, human, metabolic, diseases])].
[sujeto(['Several', oxidized, metabolites, of, cholesterol, '(', 'oxysterols)', are, endogenous, 'LXR', 'ligands,', that]), verbo([modulate]), complemento([their, transcriptional, responses])].
[sujeto(['This', change, in, the, activity, profile, is]), verbo([triggered]), complemento([by, a, disruption, of, a, key, interaction, between, residues, 'His435', and, 'Trp457', that, destabilizes, the, 'H11-H12', region, of, the, receptor, and, favors, the, binding, of, corepressors])].
[sujeto(['The', introduction, of, fluorine, atoms, on, the, oxysterol, side, chain, can, favor, both, hydrophobic, interactions, as, well, as, hydrogen, bonds, with, the, fluorine, atoms, and, may, thus]), verbo([induce]), complemento([changes, in, the, receptor, that, may, lead, to, changes, in, the, activity, profile])].
[sujeto(['To', evaluate, these, effects, we]), verbo([have]), complemento([synthesized, two, fluorinated, 27, -, 'nor-steroids,', analogues, of, 27, -, norcholestenoic, 'acid,', the, 25, ',', 25, -, difluoroacid, and, the, corresponding, 26, -, alcohol])].
[sujeto(['Molecular', dynamics, simulation, of, the, 'ligand-receptor', complexes, showed, that, the, difluoroacid, disrupted, the, 'His435-Trp457', interaction, although, the, resulting, conformational, changes, were, different, from, those]), verbo([induced]), complemento([by, the, 'non-fluorinated', analogue])].
[sujeto(['In', the, case, of, the, 'difluoroalcohol,', the, fluorine, atoms, actively]), verbo([participated]), complemento([in, the, interaction, with, several, residues, in, the, ligand, binding, pocket, leading, to, a, stabilization, of, the, active, receptor, conformation])].
[sujeto(['Mutations', in, the, 'PDGFB', gene, are, the, second, most, common]), verbo([cause]), complemento([of, 'PFBC'])].
[sujeto(['A', model, for, 'PDGFB-associated', 'PFBC,', hypomorphic, 'PDGFB', '(', 'ret/ret)', 'mouse,', displays, impaired, 'blood-brain', barrier, '(', 'BBB),', progressive, brain, calcifications, and]), verbo([increased]), complemento([flux, of, the, oxysterol, 24, 'S-hydroxycholesterol', from, the, brain, into, the, circulation])].
[sujeto(['(', 1, ',', 2, ')', 'Only', 8, families, and, 2, sporadic, cases, with, 'PDGFB', mutations]), verbo([have]), complemento([been, identified, so, 'far,', one, of, them, a, 'Swedish-Finnish', family, previously, described, as, 'F13'])].
[sujeto(['Here,', we]), verbo([provide]), complemento([a, comprehensive, 'long-term', 'follow-up', of, the, 'F13', family])].
[sujeto(['Bile', acids, are, signaling, molecules, that, play, a, critical, role, in, regulation, of, hepatic, metabolic, homeostasis, by]), verbo([activating]), complemento([nuclear, farnesoid, 'X', receptor, '(', 'Fxr)', and, membrane, 'G-protein-coupled', receptor, '(', 'Takeda', 'G-protein-coupled', receptor, 5, ;, 'Tgr5)'])].
[sujeto(['The', role, of, 'FXR', in, regulation, of, bile, acid, synthesis, and, hepatic, metabolism]), verbo([has]), complemento([been, studied, extensively])].
[sujeto(['However,', the, role, of, 'TGR5', in, hepatic, metabolism]), verbo([has]), complemento([not, been, explored])].
[sujeto(['We']), verbo([have]), complemento([performed, a, detailed, analysis, of, gallbladder, bile, acid, and, lipid, metabolism, in, 'Tgr5(-/-)', mice, in, both, 'free-fed', and, fasted, conditions])].
[sujeto(['Lipid', profiles, of, 'serum,', liver, and, adipose, 'tissues,', bile, acid, 'composition,', energy, 'metabolism,', and, messenger, 'RNA', and, protein, expression, of, the, genes]), verbo([involved]), complemento([in, lipid, metabolism, were, analyzed])].
[sujeto(['Analysis', of, gallbladder, bile, acid, composition, showed, marked]), verbo([increase]), complemento([of, taurocholic, acid, and, decrease, of, 'tauro-α', and, 'β-muricholic', acid, in, 'Tgr5(-/-)', mice])].
[sujeto(['Tgr5(-/-)', mice, had]), verbo([increased]), complemento([hepatic, fatty, acid, oxidation, rate, and, decreased, hepatic, fatty, acid, uptake])].
[sujeto(['In', 'addition,', fasted, 'Tgr5(-/-)', mice, had]), verbo([increased]), complemento([activation, of, hepatic, growth, 'hormone-signal', transducer, and, activator, of, transcription, 5, '(', 'GH-Stat5)', signaling, compared, to, 'wild-type', mice])].
[sujeto(['This', study]), verbo([suggests]), complemento([that, 'TGR5', may, play, a, role, in, determining, bile, acid, composition, and, in, 'fasting-induced', hepatic, steatosis, through, a, novel, mechanism, involving, activation, of, the, 'GH-Stat5', signaling, pathway])].
[sujeto(['It']), verbo([caused]), complemento([the, 'sn-2', acyl, chains, of, phospholipid, hydroperoxides, to, bend, and, the, whole, sterol, backbone, of, cholesterol, hydroperoxides, to, tilt])].
[sujeto(['When', phospholipids, were, kept, 'intact,', peroxidation, of, the, sterol, backbone]), verbo([led]), complemento([to, a, partial, degradation, of, its, condensing, and, ordering, 'properties,', independently, of, the, position, and, isomerism, of, the, 'OOH', substitution])].
[sujeto(['Cholesterol', peroxyl, radicals, were, also, investigated, and, we]), verbo([found]), complemento([that, the, 'OO', groups, did, not, migrate, to, the, headgroups, region])].
[sujeto(['Accumulating', evidence, indicates, that, cholesterol, oxygenation, 'products,', also, known, as, oxysterols, '(', 'OS),', are]), verbo([involved]), complemento([in, breast, cancer, '(', 'BC)', promotion])].
[sujeto(['Interestingly', 5, ',', 6, 'β-epoxycholesterol', relative, concentrations, significantly]), verbo([increased]), complemento([in, the, entire, population, '(', 'p=0'])].
[sujeto([109, ')', ',', while, no]), verbo([increase]), complemento([in, 'Cholestane-triol', '(', 'CT)', levels, was, measured])].
[sujeto(['Interestingly,', we]), verbo([found]), complemento(['that,', in, contrast, to, 'AI,', 'Tam', therapy, significantly, decreased, blood, levels, of, 24, -, hydroxycholesterol, '(', 24, -, 'HC),', 7, 'α-HC', and, 25, -, 'HC', '(', a, tumor, 'promoter)', '(', 'p=0'])].
[sujeto([231, ',', 'respectively),', whereas, 4, 'β-HC', levels]), verbo([increased]), complemento(['(', 'p=0'])].
[sujeto(['Interestingly,', levels, of, 27, -, 'HC', '(', a, tumor, 'promoter)', significantly]), verbo([increased]), complemento([in, response, to, 'AI', '(', 'p=0'])].
[sujeto(['Oxysterols', are, oxidised, derivatives, of, 'cholesterol,', formed, by, the, enzymatic, activity, of, several, cytochrome, 'P450', enzymes, and, 'tumour-derived', oxysterols]), verbo([have]), complemento([been, implicated, in, tumour, growth, and, survival])].
[sujeto(['Immunohistochemistry', was, performed, on, a, colorectal, cancer, tissue, microarray, containing, 650, primary, colorectal, cancers, using, monoclonal, antibodies, to, 'CYP2R1,', 'CYP7B1,', 'CYP8B1,', 'CYP27A1,', 'CYP39A1,', 'CYP46A1', and, 'CYP51A1,', which, we]), verbo([have]), complemento([developed])].
[sujeto(['Unsupervised', hierarchical, cluster, analysis, was, used, to, examine, the, overall, relationship, of, oxysterol, metabolising, enzyme, expression, with, outcome, and, based, on, this, identify, an, oxysterol, metabolising, enzyme, signature]), verbo([associated]), complemento([with, prognosis])].
[sujeto(['Individual', oxysterol, metabolising, enzymes, are, overexpressed, in, colorectal, cancer, and, an, oxysterol, metabolising, enzyme, expression, profile]), verbo([associated]), complemento([with, prognosis, has, been, identified, in, the, whole, patient, cohort, and, in, mismatch, repair, proficient, colorectal, cancers])].
[sujeto(['Oxysterol', like, 27, -, hydroxycholesterol, '(', 27, 'OHChol)']), verbo([has]), complemento([been, reported, to, induce, differentiation, of, monocytic, cells, into, a, mature, dendritic, cell, phenotype])].
[sujeto(['Treatment', of, monocytic, cells, with, 'Dx', resulted, in, almost, complete, inhibition, of, transcription, and, surface, expression, of, 'CD80,', 'CD83,', and, 'CD88']), verbo([induced]), complemento([by, 27, 'OHChol'])].
[sujeto(['Elevated', surface, levels, of, 'MHC', class, 'I', and, 'II', molecules]), verbo([induced]), complemento([by, 27, 'OHChol', were, reduced, to, basal, levels, by, treatment, with, 'Dx'])].
[sujeto(['A']), verbo([decreased]), complemento([endocytosis, ability, caused, by, 27, 'OHChol', was, recovered, by, 'Dx'])].
[sujeto(['We', also, examined, effects, of, 'Dx', on, expression, of, 'CD', molecules]), verbo([involved]), complemento([in, atherosclerosis])].
[sujeto(['Increased', levels, of, surface, protein, and, transcription, of, 'CD105,', 'CD137,', and, 'CD166', by, treatment, with, 27, 'OHChol', were, significantly]), verbo([inhibited]), complemento([by, cotreatment, with, 'Dx'])].
[sujeto(['These', results, indicate, that, 'Dx']), verbo([inhibits]), complemento([27, 'OHChol-induced', differentiation, of, monocytic, cells, into, a, mature, dendritic, cell, phenotype, and, expression, of, 'CD', molecules, whose, levels, are, associated, with, atherosclerosis])].
[sujeto(['In', 'addition,', we, examined, phosphorylation, of, 'AKT']), verbo([induced]), complemento([by, 27, 'OHChol', and, effect, of, 'Dx,', where, cotreatment, with, 'Dx', inhibited, the, phosphorylation, of, 'AKT'])].
[sujeto(['The', current, study]), verbo([reports]), complemento([that, 'Dx', regulates, 'oxysterol-mediated', dendritic, cell, differentiation, of, monocytic, cells])].
[sujeto(['Niemann-Pick', disease, type, 'C', '(', 'NP-C)', is, a, neurovisceral, lysosomal, cholesterol, trafficking, and, lipid, storage, disorder]), verbo([caused]), complemento([by, mutations, in, one, of, the, two, 'genes,', 'NPC1', or, 'NPC2'])].
[sujeto(['Diagnosis']), verbo([has]), complemento([often, been, a, difficult, 'task,', due, to, the, wide, range, in, age, of, onset, of, 'NP-C', and, clinical, presentation, of, the, 'disease,', combined, with, the, complexity, of, the, cell, biology, '(', 'filipin)', laboratory, 'testing,', even, in, combination, with, genetic, testing])].
[sujeto(['This']), verbo([has]), complemento([led, to, substantial, delays, in, 'diagnosis,', largely, depending, on, the, access, to, specialist, centres, and, the, level, of, knowledge, about, 'NP-C', of, the, physician, in, the, area])].
[sujeto(['In', recent, 'years,', advances, in, mass, spectrometry]), verbo([has]), complemento([allowed, identification, of, several, sensitive, plasma, biomarkers, elevated, in, 'NP-C', '(', e])].
[sujeto(['cholestane-3β,5α,6β-triol,', lysosphingomyelin, isoforms, and, bile, acid, 'metabolites),', 'which,', together, with, the, concomitant, progress, in, molecular, genetic, 'technology,']), verbo([have]), complemento([greatly, impacted, the, strategy, of, laboratory, testing])].
[sujeto(['Specificity', of, the, biomarkers, is, currently, under, investigation, and, other, pathologies, are, being]), verbo([found]), complemento([to, also, result, in, elevations])].
[sujeto(['Molecular', genetic, testing, also]), verbo([has]), complemento([its, 'limitations,', notably, with, unidentified, mutations, and, the, classification, of, new, variants])].
[sujeto(['This', review, is, intended, to]), verbo([increase]), complemento([awareness, on, the, currently, available, approaches, to, laboratory, diagnosis, of, 'NP-C,', to, provide, an, up, to, 'date,', comprehensive, and, critical, evaluation, of, the, various, techniques, '(', cell, 'biology,', biochemical, biomarkers, and, molecular, 'genetics),', and, to, briefly, discuss, 'ongoing/future', developments])].
[sujeto(['However,', even, with, recent, 'progress,', definitive, diagnosis, remains, challenging, in, some, 'patients,', for, whom, combined, 'genetic/biochemical/cytochemical', markers, do, not]), verbo([provide]), complemento([a, clear, answer])].
[sujeto(['Expertise', and, reference, laboratories, thus, remain, 'essential,', and, further, work, is, still]), verbo([required]), complemento([to, fulfill, unmet, needs])].
[sujeto(['By', 1, y, of, 'age,', most, of, these, mice]), verbo([have]), complemento([to, be, euthanized, because, of, severe, dyspnea])].
[sujeto(['RNA', sequencing, analysis, at, 12, mo, confirmed, a, massive]), verbo([increase]), complemento([in, markers, of, 'M1', macrophages, and, lymphocytes])].
[sujeto(['The', data]), verbo([suggest]), complemento([a, previously, unidentified, etiology, of, 'PSCCa:', cholesterol, dysregulation, and, 'M1', 'macrophage-predominant', lung, inflammation, combined, with, damage, 'to,', and, aberrant, repair, 'of,', lung, 'tissue,', particularly, the, peripheral, parenchyma])].
[sujeto(['The', results, raise, the, possibility, that, components, of, the, 'LXR', signaling, may, be, useful]), verbo([targets]), complemento([in, the, treatment, of, 'PSCCa'])].
[sujeto(['Agonists', of, the]), verbo([nuclear]), complemento([receptors, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)', 'gamma,', 'PPARalpha,', and, liver, 'X', receptors, '(', 'LXRs)', reduce, blood, glucose, in, type, 2, diabetic, patients, and, comparable, mouse, models])].
[sujeto(['The', 10, -, day, treatment, period, of, 'db/db', mice, with, 'Rosi,', 'Wy,', and, 'T09', altered, expression, of, 300, ',', 620, ',', and, 735, genes, including, 'agonist-specific']), verbo([target]), complemento(['genes,', respectively])].
[sujeto(['However,', from, the, 337, genes, differentially]), verbo([regulated]), complemento([in, untreated, 'db/+', versus, 'db/db', 'animals,', only, 34, '(', 10, '%', ')', ',', 51, '(', 15, '%', ')', ',', and, 82, '(', 24, '%', ')', were, regulated, in, the, direction, of, the, 'db/+', group, by, 'Rosi,', 'Wy,', and, 'T09,', respectively])].
[sujeto(['Gene', expression, normalization, by, drug, treatment]), verbo([involved]), complemento([glucose, 'homeostasis,', lipid, 'homeostasis,', and, local, glucocorticoid, activation])].
[sujeto(['In', 'addition,', our, data, pointed, to, hitherto, unknown, interference, of, these]), verbo([nuclear]), complemento([receptors, with, growth, hormone, receptor, gene, expression, and, endoplasmic, reticulum, stress])].
[sujeto(['However,', many, 'diabetes-associated', gene, alterations, remained, unaffected, or, were, even, aggravated, by]), verbo([nuclear]), complemento([receptor, agonist, treatment])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'diabetes-induced', gene, expression, is, minimally, reversed, by, potent, blood, 'glucose-lowering', nuclear, receptor, agonists])].
[sujeto(['Liver', 'X', receptors, '(', 'LXRs)', are, master, transcription, factors]), verbo([regulating]), complemento([cholesterol, and, fatty, acid, metabolism])].
[sujeto(['Peroxisome', 'proliferator-activated', 'receptor-alpha', '(', 'PPARalpha)', agonists, are, known, to]), verbo([induce]), complemento([peroxisomal, fatty, acid, 'beta-oxidation', and, also, mediate, 'HDL', cholesterol, metabolism])].
[sujeto(['We']), verbo([have]), complemento([explored, the, hypothesis, that, simultaneous, activation, of, 'PPARalpha', and, 'LXR', may, lead, to, additive, effects, on, 'HDL', cholesterol, elevation, as, well, as, attenuation, of, triglyceride, accumulation])].
[sujeto(['Coadministration', of, 'T0901317', and, the, specific, 'PPARalpha', agonist, '[', 4, -, 'chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic', acid, '(', 'Wy14643)]', in, mice]), verbo([led]), complemento([to, synergistic, elevation, of, 'HDL', cholesterol, that, was, primarily, associated, with, enlarged, 'HDL', particles, enriched, with, apoE, and, apoAI])].
[sujeto(['Liver', phospholipid, transfer, protein, '(', 'PLTP)', mRNA, and, plasma, 'PLTP', activity, were, additively, 'elevated,']), verbo([suggesting]), complemento([a, role, of, 'PLTP', in, the, observed, 'HDL', cholesterol, elevation])].
[sujeto(['Moderate']), verbo([increases]), complemento([in, plasma, triglyceride, levels, induced, by, 'LXR', activation, was, 'reduced,', whereas, the, accumulation, of, triglyceride, in, the, liver, was, not, altered, upon, coadministration, of, the, 'PPARalpha', agonist])].
[sujeto(['Interestingly,', activation, of, 'LXRs', via, 'T0901317', also]), verbo([led]), complemento([to, a, significant, increase, in, peroxisomal, fatty, acid, 'beta-oxidation'])].
[sujeto(['Sterol', regulatory, element]), verbo([binding]), complemento([protein, 1, c, expression, was, dramatically, 'up-regulated', by, the, 'LXR', agonist, but, was, not, changed, with, 'PPARalpha', agonist, treatment])].
[sujeto(['Liver', lipoprotein, lipase, expression, was, additively]), verbo([increased]), complemento([upon, 'LXR', agonist, and, 'PPARalpha', agonist, coadministration])].
[sujeto(['Our', studies, mark, the, first, exploration, of]), verbo([nuclear]), complemento([receptor, interplay, on, lipid, homeostasis, in, vivo])].
[sujeto(['Treatment', of, rat, hepatocyte, cultures, with, either, 25, -, hydroxycholesterol, or, 24, '(', 'S),25-epoxycholesterol', '(', 10, '(', -, 5, ')', to, 5, x, 10, '(', -, 5, ')', 'M)', produced, 'concentration-dependent', elevations, in, 'CYP3A', mRNA, and, immunoreactive, protein, levels, but, did, not]), verbo([increase]), complemento([the, amounts, of, 'CYP1A1,', 'CYP2B,', or, 'CYP4A', gene, products])].
[sujeto(['The', effects, of, 24, '(', 'S),25-epoxycholesterol', on, 'CYP3A', content, were, much, greater, than, were, those, of, 25, -, 'hydroxycholesterol,', consistent, with, the, relative, abilities, of, these, sterols, to]), verbo([bind]), complemento([and, activate, 'LXR'])].
[sujeto(['CYP3A', mRNA, levels, were]), verbo([increased]), complemento([after, treatment, with, 24, '(', 'S),25-epoxycholesterol', in, both, 'wild-type', and, 'LXR-null', mouse, hepatocytes])].
[sujeto(['In', 'contrast,', neither, 24, '(', 'S),25-epoxycholesterol', nor, either, of, two, additional, potent, 'LXR', 'ligands,', 22, '(', 'R)-hydroxycholesterol', and, 'N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)ethyl-]phenyl]-benzenesulfonamide', '(', 'T0901317),', altered, 'CYP3A', mRNA, levels, in, hepatocytes, prepared, from, 'PXR-null', 'mice,', although, these, agents]), verbo([induced]), complemento(['CYP3A', mRNA, content, in, 'wild-type', cultures])].
[sujeto(['As', evidence, that, the, 'LXR', ligands, also]), verbo([activated]), complemento(['PXR', in, rat, 'hepatocytes,', cotransfection, of, primary, cultures, with, a, dominant, negative, 'PXR', abolished, reporter, gene, induction, after, treatment, with, any, of, the, test, agents])].
[sujeto(['These', results, indicate, that, selected, 'LXR', ligands, are, capable, of]), verbo([activating]), complemento(['PXR,', probably, as, a, defensive, measure, to, prevent, the, accumulation, of, these, potentially, toxic, endogenous, molecules])].
[sujeto(['APOE', expression, is, transcriptionally]), verbo([regulated]), complemento([through, the, action, of, a, family, of, nuclear, receptors, including, the, peroxisome, 'proliferator-activated', receptor, gamma, and, liver, 'X', receptors, '(', 'LXRs)', in, coordination, with, retinoid, 'X', receptors, '(', 'RXRs)'])].
[sujeto(['It']), verbo([has]), complemento([been, previously, reported, that, various, agonists, of, this, receptor, family, can, influence, brain, 'Aβ', levels, in, rodents])].
[sujeto(['Nuclear', hormone, receptors, are, transcription, factors, that, can, be]), verbo([activated]), complemento([by, 'nutrition-derived', ligands, and, alter, the, expression, of, various, specific, target, genes])].
[sujeto(['We', examined, how, synthetic, selective, ligands, of]), verbo([nuclear]), complemento([hormone, receptors, alter, the, gene, expression, of, hepatic, enzymes, in, mice])].
[sujeto(['SCD1', and, 'ELOVL6', expression]), verbo([increased]), complemento([after, the, gavage, of, 'LXR', and, 'RXR', ligands])].
[sujeto(['The', analysis, of, fatty, acid, composition, of, total, phospholipids, in, plasma, and, liver, showed]), verbo([increased]), complemento([percentage, contributions, of, the, 'SCD1', and, 'ELOVL6', products, 18, :, 1, 'n-9,', 18, :, 1, 'n-7', and, 20, :, 1, 'n-9', after, 'LXR', and, 'RXR', ligand, application])].
[sujeto(['Analysis', of, total, phospholipids, from, plasma, and, liver, revealed, a, significant]), verbo([increase]), complemento([in, monounsaturated, fatty, acids, bound, in, phosphatidylcholine, '(', 'PtdCho)', and, lysophosphatidylcholine, '(', 'PtdEtn)', after, 'LXR', and, 'RXR', ligand, administration])].
[sujeto(['Increased', hepatic, gene, expression, of, 'SCD1', and, 'ELOVL6', after, gavage, of, selective, 'RXR', or, 'LXR', ligands, to, mice, resulted, in]), verbo([increased]), complemento([concentrations, of, their, metabolic, products, in, phospholipids, of, liver, and, plasma])].
[sujeto(['ABCG1,', a, member, of, the, 'ATP']), verbo([binding]), complemento([cassette, 'superfamily,', facilitates, the, efflux, of, cholesterol, from, cells, to, 'HDL'])].
[sujeto(['In', this, 'study,', we, demonstrate, that, 'ABCG1', is]), verbo([expressed]), complemento([in, cultured, human, keratinocytes, and, murine, 'epidermis,', and, induced, during, keratinocyte, 'differentiation,', with, increased, levels, in, the, outer, epidermis])].
[sujeto(['ABCG1', is]), verbo([regulated]), complemento([by, liver, 'X', receptor, '(', 'LXR)', and, peroxisome, 'proliferator-activated', 'receptor-δ', '(', 'PPAR-δ)', 'activators,', cellular, sterol, 'levels,', and, acute, barrier, disruption])].
[sujeto(['Both', 'LXR', and, 'PPAR-δ', activators, markedly]), verbo([stimulate]), complemento(['ABCG1', expression, in, a, 'dose-', and, 'time-dependent', fashion])].
[sujeto(['PPAR-γ', activators, also]), verbo([increase]), complemento(['ABCG1', 'expression,', but, to, a, lesser, degree])].
[sujeto(['In', response, to]), verbo([increased]), complemento([intracellular, sterol, 'levels,', 'ABCG1', expression, 'increases,', whereas, inhibition, of, cholesterol, biosynthesis, decreases, 'ABCG1', expression])].
[sujeto(['In', 'vivo,', 'ABCG1', is]), verbo([stimulated]), complemento([3, -, 6, h, after, acute, barrier, disruption, by, either, tape, stripping, or, acetone, 'treatment,', an, increase, that, can, be, inhibited, by, 'occlusion,', suggesting, a, potential, role, of, 'ABCG1', in, permeability, barrier, homeostasis])].
[sujeto(['Although', 'Abcg1-null', mice, display, normal, epidermal, permeability, barrier, function, and, gross, 'morphology,', abnormal, lamellar, body, '(', 'LB)', contents, and, secretion]), verbo([leading]), complemento([to, impaired, lamellar, bilayer, formation, could, be, demonstrated, by, electron, 'microscopy,', indicating, a, potential, role, of, 'ABCG1', in, normal, 'LB', formation, and, secretion])].
[sujeto(['The', 'Taqman', 'Array', results, show, that, '(', 1, ')', stimulation, with, the, 'liver-X-receptor', and, 'retinoid-X-receptor', ligands, 'T0901317', and, 9, -, cis, retinoic, acid]), verbo([induces]), complemento([several, genes, of, lipid, 'metabolism,', '(', 2, ')', lipopolysaccharide, '(', 'LPS)', and, 'interferon-g', '(', 'Ifn-g)', strongly, repress, 'lipid-related', 'genes,', and, '(', 3, ')', coincubation, with, docosahexaenoic, acid, dampens, the, repressing, effect, of, 'LPS'])].
[sujeto(['Both', the, 'LXR', agonist, 'T0901317', and, the, natural, 'RXR/LXR', agonists, 22, -, hydroxycholesterol, and, 9, -, cis, retinoic, acid]), verbo([enhanced]), complemento([the, basolateral, efflux, of, 'beta-sitosterol', without, altering, apical, efflux])].
[sujeto(['LXR-mediated']), verbo([enhanced]), complemento(['beta-sitosterol', efflux, occurred, between, 6, h, and, 12, h, after, 'activation,', suggesting, that, 'transcription,', protein, 'synthesis,', and, trafficking, was, likely, necessary, prior, to, facilitating, efflux])].
[sujeto(['The', transcription, inhibitor, actinomycin, 'D']), verbo([prevented]), complemento([the, increase, in, 'beta-sitosterol', efflux, by, 'T0901317'])].
[sujeto(['Glybenclamide,', an, inhibitor, of, 'ABCA1', 'activity,', and, arachidonic, 'acid,', a, fatty, acid, that, interferes, with, 'LXR', 'activation,', also]), verbo([prevented]), complemento(['beta-sitosterol', efflux, in, response, to, the, 'LXR', ligand, activation])].
[sujeto(['Similar', to, results, observed, with, intestinal, 'ABCA1-facilitated', cholesterol, 'efflux,', 'LXR/RXR', ligand, activation]), verbo([enhanced]), complemento([the, basolateral, efflux, of, 'beta-sitosterol', without, affecting, apical, efflux])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, 'ABCA1', does, not, differentiate, between, cholesterol, and, 'beta-sitosterol', and, thus, is, not, responsible, for, the, selectivity, of, sterol, absorption, by, the, intestine])].
[sujeto(['Liver', 'X', receptors, '(', 'LXRs)', and, peroxisome, 'proliferator-activated', receptors, '(', 'PPARs)', are, members, of]), verbo([nuclear]), complemento([receptors, that, form, obligate, heterodimers, with, retinoid, 'X', receptors, '(', 'RXRs)'])].
[sujeto(['These']), verbo([nuclear]), complemento([receptors, play, crucial, roles, in, the, regulation, of, fatty, acid, 'metabolism:', 'LXRs', activate, expression, of, sterol, regulatory, 'element-binding', protein, 1, c, '(', 'SREBP-1c),', a, dominant, lipogenic, gene, 'regulator,', whereas, 'PPARalpha', promotes, fatty, acid, 'beta-oxidation', genes])].
[sujeto(['Luciferase', assays, in, human, embryonic, kidney, 293, cells, showed, that, overexpression, of, 'PPARalpha', and, gamma, 'dose-dependently']), verbo([inhibited]), complemento(['SREBP-1c', promoter, activity, induced, by, 'LXR'])].
[sujeto(['Gel', shift, assays, indicated, that, 'PPARs', reduce]), verbo([binding]), complemento([of, 'LXR/RXR', to, 'LXRE'])].
[sujeto(['PPARalpha-selective', agonist]), verbo([enhanced]), complemento([these, inhibitory, effects])].
[sujeto(['Competition', of, 'PPARalpha', ligand, with, 'LXR', ligand, was, observed, in, 'LXR/RXR']), verbo([binding]), complemento([to, 'LXRE', in, gel, shift, 'assay,', in, 'LXR/RXR', formation, in, nuclear, extracts, by, 'coimmunoprecipitation,', and, in, gene, expression, of, 'SREBP-1c', by, 'Northern', blot, analysis, of, rat, primary, hepatocytes, and, mouse, liver, 'RNA'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'PPARalpha', activation, can, suppress, 'LXR-SREBP-1c', pathway, through, reduction, of, 'LXR/RXR', 'formation,', proposing, a, novel, transcription, factor, 'cross-talk', between, 'LXR', and, 'PPARalpha', in, hepatic, lipid, homeostasis])].
[sujeto(['One', described, mechanism]), verbo([leading]), complemento([to, the, impaired, clearance, of, these, cells, from, the, lung, is, the, delay, in, their, programmed, cell, death, '(', 'apoptosis)'])].
[sujeto(['β(2)-Adrenoceptor', agonists]), verbo([have]), complemento([been, shown, to, prolong, survival, and, delay, apoptosis, of, eosinophils])].
[sujeto(['Salbutamol', prolonged, survival, of, human, eosinophils, and, it, was]), verbo([inhibited]), complemento([by, a, 'β-receptor', antagonist, propranolol, and, mimicked, by, 'cell-permeant', cAMP, analogues, 'dibutyryl-', and, 8, -, 'bromo-cAMP'])].
[sujeto(['Taken', 'together,', the, present, results]), verbo([suggest]), complemento([that, salbutamol, at, clinically, relevant, concentrations, decreases, apoptosis, in, human, eosinophils, by, activating, the, cannonical, 'β(2)-receptor-adenylyl', 'cyclase-cAMP-protein', kinase, 'A', pathway])].
[sujeto(['This', group, of, compounds, is, best, known, for, their, neurotoxic, effects, in, 'mammals,']), verbo([causing]), complemento([syndromes, such, as, '\'', ryegrass, 'staggers\'', in, sheep, and, cattle])].
[sujeto(['Because', many, of, the, fungi, that, synthesise, these, compounds, form, symbiotic, relationships, with, 'plants,', 'insects,', and, other, 'fungi,', the, synthesis, of, these, compounds, may]), verbo([confer]), complemento([an, ecological, advantage, to, these, associations])].
[sujeto(['Considerable', recent, progress]), verbo([has]), complemento([been, made, on, understanding, 'indole-diterpene', biosynthesis, in, filamentous, 'fungi,', principally, through, the, cloning, and, characterisation, of, the, genes, and, gene, products, for, paxilline, biosynthesis, in, 'Penicillium', paxilli])].
[sujeto(['Important', insights, into, how, the, 'indole-diterpene', backbone, is, synthesised, and, decorated]), verbo([have]), complemento([been, obtained, using, 'P'])].
[sujeto(['This', review]), verbo([provides]), complemento([an, overview, of, these, recent, developments])].
[sujeto(['The', gene, cluster]), verbo([required]), complemento([for, paxilline, biosynthesis, in, 'Penicillium', paxilli, contains, two, cytochrome, 'P450', monooxygenase, 'genes,', paxP, and, paxQ])].
[sujeto(['The', primary, sequences, of, both, proteins, are, very, similar, to, those, of, proposed, cytochrome, 'P450', monooxygenases, from, other, filamentous, 'fungi,', and, contain, several]), verbo([conserved]), complemento(['motifs,', including, that, for, a, 'haem-binding', site])].
[sujeto(['Paspaline', is, essentially, inactive, as, a, channel, 'blocker,']), verbo([causing]), complemento([only, slight, inhibition, at, concentrations, up, to, 1, microM])].
[sujeto(['Increasing', evidence]), verbo([has]), complemento([recently, demonstrated, that, soluble, heparan, sulfate, '(', 'HS),', a, degradation, product, of, extracellular, matrix, produced, by, 'elastase,', plays, a, key, role, in, the, aggravation, of, acute, pancreatitis, '(', 'AP)', and, associated, lung, injury])].
[sujeto(['Our', previous, work]), verbo([has]), complemento([provided, a, valuable, clue, that, a, 'large-conductance', 'K(+)', channel, '(', 'MaxiK)', was, involved, in, the, 'HS-stimulated', activation, of, murine, macrophages])].
[sujeto(['The', protective, effects, of, 'paxilline,', a, specific, blocker, of, 'MaxiK,', on, rats, against, sodium, taurocholate]), verbo([induced]), complemento(['AP', were, evaluated])].
[sujeto(['Our', data, showed, that, paxilline, substantially, attenuated, 'AP', and, resultant, lung, 'injury,', mainly, by, limiting, the, burst, of, inflammatory, 'responses,', as, proven, by]), verbo([decreased]), complemento([plasma, concentrations, of, tumor, necrosis, 'factor-α', and, macrophage, inflammatory, 'protein-2,', together, with, unimpaired, pancreatic, enzyme, activities, in, rats, suffering, from, 'AP'])].
[sujeto(['Taken', 'together,', our, study]), verbo([provides]), complemento([evidence, that, 'MaxiK', is, involved, in, the, spread, of, inflammatory, responses, and, the, following, lung, injury, during, the, attack, of, 'AP,', indicating, that, this, ion, channel, is, a, promising, candidate, as, a, therapeutic, target, for, 'AP'])].
[sujeto(['Increasing', evidence]), verbo([has]), complemento([demonstrated, that, 'Toll-like', receptor, 4, '(', 'TLR4)', -, mediated, systemic, inflammatory, response, syndrome, accompanied, by, multiple, organ, 'failure,', is, one, of, the, most, common, causes, of, death, in, patients, with, severe, acute, pancreatitis])].
[sujeto(['Recent']), verbo([reports]), complemento([have, revealed, that, heparan, sulphate, '(', 'HS)', 'proteoglycan,', a, component, of, extracellular, 'matrices,', potentiates, the, activation, of, intracellular, 'pro-inflammatory', responses, via, 'TLR4,', contributing, to, the, aggravation, of, acute, pancreatitis])].
[sujeto(['Our', previous, work]), verbo([provided]), complemento([a, clue, that, a, membrane, potassium, channel, '(', 'MaxiK)', is, responsible, for, 'HS-induced', production, of, inflammatory, cytokines])].
[sujeto(['Therefore,', in, this]), verbo([report]), complemento([we, attempted, to, reveal, the, roles, of, 'MaxiK', in, the, activation, of, macrophages, stimulated, by, 'HS'])].
[sujeto(['HS', could, also]), verbo([activate]), complemento(['MaxiK', channels, to, promote, the, efflux, of, potassium, ions, from, 'cells,', as, measured, by, the, elevated, activity, of, 'caspase-1,', whereas, this, was, significantly, abolished, by, treatment, with, 'paxilline,', a, specific, blocker, of, the, 'MaxiK', channel])].
[sujeto(['Moreover,', it, was]), verbo([found]), complemento([that, paxilline, substantially, inhibited, 'HS-induced', activation, of, several, different, transcription, factors, in, 'macrophages,', including, nuclear, 'factor-κB,', p38, and, interferon, regulatory, 'factor-3,', followed, by, decreased, production, of, tumour, necrosis, 'factor-α', and, 'interferon-β'])].
[sujeto(['Taken', 'together,', our, investigation]), verbo([provides]), complemento([evidence, that, the, 'HS/TLR4-mediated', intracellular, inflammatory, cascade, depends, on, the, activation, of, 'MaxiK,', which, may, offer, an, important, opportunity, for, a, new, approach, in, therapeutic, strategies, of, severe, acute, pancreatitis])].
[sujeto(['In', addition, to, improving, sexual, 'function,', testosterone]), verbo([has]), complemento([been, reported, to, have, beneficial, effects, in, ameliorating, lower, urinary, tract, symptoms, by, increasing, bladder, capacity, and, 'compliance,', while, decreasing, bladder, pressure])].
[sujeto(['However,', the, cellular, mechanisms, by, which, testosterone]), verbo([regulates]), complemento([detrusor, smooth, muscle, '(', 'DSM)', excitability, have, not, been, elucidated])].
[sujeto(['Testosterone', '(', 100, 'nM)', significantly]), verbo([increased]), complemento([the, 'depolarization-induced', whole, cell, outward, currents, in, 'DSM', cells])].
[sujeto(['The', selective, pharmacological, inhibition, of, the, large, conductance, 'voltage-', and, 'Ca2+-activated', 'K+', '(', 'BK)', channels, with, paxilline, '(', 1, 'µM)', completely, abolished, this, stimulatory, effect, of, 'testosterone,']), verbo([suggesting]), complemento([a, mechanism, involving, 'BK', channels])].
[sujeto(['Testosterone', '(', 100, 'nM)', significantly]), verbo([increased]), complemento(['TBKC', activity, in, 'DSM', cells])].
[sujeto(['In', 'current-clamp', 'mode,', testosterone, '(', 100, 'nM)', significantly, hyperpolarized, the, 'DSM', cell, resting, membrane, potential, and]), verbo([increased]), complemento([spontaneous, transient, hyperpolarizations])].
[sujeto(['Testosterone', '(', 100, 'nM)', rapidly]), verbo([increased]), complemento([the, single, 'BK', channel, open, probability, in, 'inside-out', excised, membrane, patches, from, 'DSM', 'cells,', clearly, suggesting, a, direct, 'BK', channel, activation, via, a, 'non-genomic', mechanism])].
[sujeto(['Live-cell', 'Ca2+', imaging, showed, that, testosterone, '(', 100, 'nM)']), verbo([caused]), complemento([a, decrease, in, global, intracellular, 'Ca2+', 'concentration,', consistent, with, 'testosterone-induced', membrane, hyperpolarization])].
[sujeto(['In', 'conclusion,', the, data]), verbo([provide]), complemento([compelling, mechanistic, evidence, that, under, physiological, 'conditions,', testosterone, at, nanomolar, concentrations, directly, activates, 'BK', channels, in, 'DSM', 'cells,', independent, fromgenomic, testosterone, 'receptors,', and, thus, regulates, 'DSM', excitability])].
[sujeto(['A', major]), verbo([finding]), complemento([of, our, study, indicates, that, 'short-term', application, of, 'Hcy', increased, the, open, probability, of, oxidized, 'BK', channels, in, 'inside-out', recordings])].
[sujeto(['Furthermore,', 'Hcy']), verbo([decreased]), complemento([the, exocytosis, of, secretory, granules])].
[sujeto(['This']), verbo([decrease]), complemento([was, partially, prevented, by, the, 'BK', channel, inhibitor, paxilline, and, fully, prevented, by, 'N-acetylcysteine,', a, reactive, oxygen, species, scavenger])].
[sujeto(['Taken', 'together,', our, data, show, that, elevation, of, cellular, 'Hcy', level]), verbo([induces]), complemento([oxidative, 'stress,', increases, 'BK', channel, 'activity,', and, decreases, exocytosis, of, secretory, granules])].
[sujeto(['These', findings, may]), verbo([provide]), complemento([insight, into, some, of, the, developmental, impairments, and, neurotoxicity, associated, with, 'Hyperhomocysteinemia', '(', 'HHcy),', a, disease, arising, due, to, abnormally, elevated, levels, of, 'Hcy', in, the, plasma])].
[sujeto(['We', investigated, the, role, of, 'TRPV4', channels, '(', 'TRPV4)', in]), verbo([regulating]), complemento([the, contractility, of, detrusor, smooth, muscle, '(', 'DSM)', and, muscularis, mucosae, '(', 'MM)', of, the, urinary, bladder])].
[sujeto(['DSM', and, 'MM']), verbo([expressed]), complemento(['TRPV4', immunoreactivity])].
[sujeto(['GSK1016790A', '(', 'GSK,', 1, &, 'nbsp;nM),', a, 'TRPV4', 'agonist,', evoked, a, sustained, contraction, in, both, 'DSM', and, 'MM']), verbo([associated]), complemento([with, a, cessation, of, spontaneous, phasic, contractions, in, a, manner, sensitive, to, 'HC-067047', '(', 10, &, 'nbsp;μM),', a, 'TRPV4', antagonist])].
[sujeto(['GSK', '(', 1, &, 'nbsp;nM)', abolished, spontaneous, 'Ca(2+)', 'transients,']), verbo([increased]), complemento([basal, 'Ca(2+)', levels, and, also, prevented, spontaneous, action, potential, discharge, associated, with, 'DSM', membrane, hyperpolarization])].
[sujeto(['In', 'conclusion,', 'Ca(2+)', influx, through, 'TRPV4', appears, to]), verbo([activate]), complemento(['BK', channels, to, suppress, spontaneous, contractions, and, thus, a, functional, coupling, of, 'TRPV4', with, 'BK', channels, may, act, as, a, 'self-limiting', mechanism, for, bladder, contractility, during, its, storage, phase])].
[sujeto(['The', channel, expression, was, demonstrated, as, a, significant]), verbo([increase]), complemento([in, the, 'voltage-independent', current, by, 'NS309,', a, 'KCa', 3.1, /, 'KCa', 2, 'activator,', followed, by, full, inhibition, upon, 'co-application', with, 'NS6180,', a, highly, selective, 'KCa', 3.1, inhibitor])].
[sujeto(['A', major, fraction, '(', 79, '%', ')', of, unstimulated, human, microglia]), verbo([expressed]), complemento(['KCa', 3.1, ',', and, the, difference, in, current, between, full, activation, and, inhibition, '(', 'ΔKCa', 3.1, ')', was, estimated, at, 292, ±, 48, pA, at, -, 40, mV, '(', n, =, 75, ')', ',', which, equals, at, least, 585, channels, per, cell])].
[sujeto(['The', isolated, human, microglia, were, potently]), verbo([activated]), complemento([by, lipopolysaccharide, '(', 'LPS)', shown, as, a, prominent, increase, in, 'TNF-α', production])].
[sujeto(['However,', incubation, with, 'LPS', neither, changed, the, 'KCa', 3.1, current, nor, the, fraction, of, 'KCa', 3.1]), verbo([expressing]), complemento([cells])].
[sujeto(['In', 'contrast,', the, 'anti-inflammatory', cytokine, 'IL-4', slightly]), verbo([increased]), complemento([the, 'KCa', 3.1, current, per, 'cell,', but, as, the, membrane, area, also, 'increased,', there, was, no, significant, change, in, channel, density])].
[sujeto(['A', large, fraction, of, the, microglia, also]), verbo([expressed]), complemento([a, 'voltage-dependent', current, sensitive, to, the, 'KCa', 1.1, modulators, 'NS1619', and, 'Paxilline', and, an, 'inward-rectifying', current, with, the, characteristics, of, a, 'Kir', channel])].
[sujeto(['Repaglinide']), verbo([induced]), complemento([vasorelaxation, in, a, 'concentration-dependent', manner])].
[sujeto(['Also,', pretreatment, with, a, guanylyl, cyclase, inhibitor, '(', 'ODQ)', or, a, 'PKG', inhibitor, '(', 'KT', 5823, ')']), verbo([inhibited]), complemento(['repaglinide-induced', vasorelaxation])].
[sujeto(['Based', on, these, 'results,', we, conclude, that, repaglinide]), verbo([induces]), complemento([vasorelaxation, via, activation, of, adenylyl, 'cyclase/PKA', and, guanylyl, 'cyclase/PKG', signaling, pathways, independently, of, the, 'endothelium,', 'K(+)', 'channels,', 'Ca(2+)', 'channels,', and, intracellular, 'Ca(2+)', '(', '[', 'Ca(2+)]i)'])].
[sujeto(['To', 'date,', we, are, one, of, the]), verbo([leading]), complemento([laboratory, that, compared, microRNA, expression, profiles, in, 'MPM', and, normal, mesothelium, samples, in, order, to, identify, dysregulated, microRNAs, with, functional, roles, in, mesothelioma])].
[sujeto(['Utilizing', 'mRNA-microRNA', correlations, based, on, differential, gene, expression, using, 'Gene', 'Set', 'Enrichment', 'Analysis', '(', 'GSEA),', we, systematically, combined, publicly, available, gene, expression, datasets, with, our, own, 'MPM', data, in, order, to, identify, candidate]), verbo([targets]), complemento([for, 'MPM', therapy])].
[sujeto(['We', identified, enrichment, of]), verbo([target]), complemento([binding, sites, for, the, 'miR-17', and, 'miR-30', families, in, both, 'MPM', tumors, and, cell, lines])].
[sujeto(['Interestingly,', lower, expression, of, 'miR-17-5p', '(', 'P', =, 0.022, ')', and, 'miR-20a-5p', '(', 'P', =, 0.026, ')', was, clearly]), verbo([associated]), complemento([with, epithelioid, histology])].
[sujeto(['We', interrogated, the, predicted]), verbo([targets]), complemento([of, these, differentially, expressed, microRNA, families, in, 'MPM', cell, 'lines,', and, identified, 'KCa1'])].
[sujeto([1, ',', a, 'calcium-activated', potassium, channel, subunit, alpha, 1, encoded, by, the, 'KCNMA1', 'gene,', as, a]), verbo([target]), complemento([of, 'miR-17-5p'])].
[sujeto([1, and]), verbo([inhibited]), complemento(['MPM', cell, migration])].
[sujeto([1, ')', are, important, in]), verbo([regulating]), complemento([physiologic, responses, in, many, types, of, tissues, 'and,', as, 'such,', present, opportunities, for, development, of, new, therapeutic, agents])].
[sujeto(['Both', channel, agonists, and, inhibitors, could]), verbo([have]), complemento([therapeutic, 'utility,', depending, on, medical, application, under, consideration])].
[sujeto(['However,', characterization, of, molecular, pharmacology, of, 'BK', channels, is, incomplete, and]), verbo([has]), complemento([been, difficult, to, accomplish, because, of, paucity, of, chemical, leads, that, are, acceptable, templates, for, 'Medicinal', 'Chemistry', investigation])].
[sujeto(['Resveratrol,', a, phytoalexin]), verbo([found]), complemento([in, grapes, and, red, 'wine,', exhibits, diverse, pharmacological, activities])].
[sujeto(['However,', relatively, little, is, known, about, whether, resveratrol]), verbo([modulates]), complemento([the, ion, channels, in, cortical, neurons])].
[sujeto(['The', 'large-conductance', 'calcium-activated', potassium, channels, '(', 'BKCa)', and, 'voltage-gated', sodium, channels, were]), verbo([expressed]), complemento([in, cortical, neurons, and, play, important, roles, in, regulation, of, neuronal, excitability])].
[sujeto(['Resveratrol', 'concentration-dependently']), verbo([increased]), complemento([the, current, amplitude, and, the, opening, activity, of, 'BKCa', 'channels,', but, suppressed, the, amplitude, of, 'voltage-gated', sodium, currents])].
[sujeto(['Similar', to, the, 'BKCa', channel, opener, 'NS1619,', resveratrol]), verbo([decreased]), complemento([the, firing, rate, of, action, potentials])].
[sujeto(['In', 'addition,', the]), verbo([enhancing]), complemento([effects, of, 'BKCa', channel, blockers, tetraethylammonium, '(', 'TEA)', and, paxilline, on, action, potential, firing, were, sensitive, to, resveratrol])].
[sujeto(['Our', results, indicated, that, the, attenuation, of, action, potential, firing, rate, by, resveratrol, might, be]), verbo([mediated]), complemento([through, opening, the, 'BKCa', channels, and, closing, the, 'voltage-gated', sodium, channels])].
[sujeto(['As', 'BKCa', channels, and, sodium, channels, are, critical, molecular, determinants, for, seizure, 'generation,', our, findings]), verbo([suggest]), complemento([that, regulation, of, these, two, channels, in, cortical, neurons, probably, makes, a, considerable, contribution, to, the, antiseizure, activity, of, resveratrol])].
[sujeto(['Mitochondria']), verbo([have]), complemento([been, suggested, as, a, potential, target, for, cytoprotective, strategies])].
[sujeto(['It']), verbo([has]), complemento([been, shown, that, increased, 'K+', uptake, mediate, by, mitochondrial, 'ATP-regulated', potassium, channels, '(', mitoKATP, 'channel)', or, 'large-conductance', 'Ca2+-activated', potassium, channels, '(', mitoBKCa, 'channel)', may, provide, protection, in, different, models, of, cell, death])].
[sujeto(['Using', organotypic, hippocampal, slice, cultures, exposed, to, 'glutamate,', we, demonstrated, that, preincubation, of, the, slices, with, the, 'BKCa', channel, opener, 'NS1619', resulted, in]), verbo([decreased]), complemento([neuronal, cell, death, measured, as, reduced, uptake, of, propidium, iodide])].
[sujeto(['Moreover,', mitochondrial, respiration, measurements, revealed, that, 'NS1619']), verbo([induced]), complemento([an, 'IbTx-sensitive', increase, in, state, 2, respiration, of, isolated, brain, mitochondria])].
[sujeto(['Taken', 'together,', our, results, confirm, presence, of, 'BKCa', channel, in, rat, hippocampal, neurons, mitochondria, and]), verbo([suggest]), complemento([putative, role, for, mitoBKCa, in, neuroprotection])].
[sujeto(['Progression', of, hypoxic, pulmonary, hypertension, is, thought, to, be, 'due,', in, 'part,', to, suppression, of, 'voltage-gated', potassium, channels, '(', 'Kv', ')', in, pulmonary, arterial, smooth, muscle, by, 'hypoxia,', although, the, precise, molecular, mechanisms]), verbo([have]), complemento([been, unclear])].
[sujeto(['AMP-activated', protein, kinase, '(', 'AMPK)']), verbo([has]), complemento([been, proposed, to, couple, inhibition, of, mitochondrial, metabolism, by, hypoxia, to, acute, hypoxic, pulmonary, vasoconstriction, and, progression, of, pulmonary, hypertension])].
[sujeto(['Inhibition', of, complex, 'I', of, the, mitochondrial, electron, transport, chain]), verbo([activated]), complemento(['AMPK', and, inhibited, 'Kv', 1.5, channels, in, pulmonary, arterial, myocytes])].
[sujeto(['Recombinant', 'AMPK']), verbo([phosphorylated]), complemento([recombinant, human, 'Kv', 1.5, channels, in, 'cell-free', 'assays,', and, inhibited, 'K(+)', currents, when, introduced, into, 'HEK', 293, cells, stably, expressing, 'Kv', 1.5])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'AMPK', is, the, primary, mediator, of, reductions, in, 'Kv', 1.5, channels, following, inhibition, of, mitochondrial, oxidative, phosphorylation, during, hypoxia, and, by, mitochondrial, poisons])].
[sujeto(['Progression', of, hypoxic, pulmonary, hypertension, is, thought, to, be, 'due,', in, 'part,', to, suppression, of, 'voltage-gated', potassium, channels, '(', 'Kv', ')', in, pulmonary, arterial, smooth, muscle, cells, that, is]), verbo([mediated]), complemento([by, the, inhibition, of, mitochondrial, oxidative, phosphorylation])].
[sujeto(['We', sought, to, determine, the, role, in, this, process, of, the, 'AMP-activated', protein, kinase, '(', 'AMPK),', which, is, intimately, coupled, to, mitochondrial, function, due, to, its, activation, by, 'LKB1-dependent', phosphorylation, in, response, to]), verbo([increases]), complemento([in, the, cellular, 'AMP:ATP', 'and/or', 'ADP:ATP', ratios])].
[sujeto(['Inhibition', of, complex, 'I', of, the, mitochondrial, electron, transport, chain, using, phenformin]), verbo([activated]), complemento(['AMPK', and, inhibited, 'Kv', currents, in, pulmonary, arterial, 'myocytes,', consistent, with, previously, reported, effects, of, mitochondrial, inhibitors])].
[sujeto(['Myocyte', 'Kv', currents, were, also, markedly]), verbo([inhibited]), complemento([upon, 'AMPK', activation, by, 'A769662,', 5, -, 'aminoimidazole-4-carboxamide', riboside, and, 'C13', and, by, intracellular, dialysis, from, a, 'patch-pipette', of, activated, '(', 'thiophosphorylated)', recombinant, 'AMPK', heterotrimers, '(', α2β2γ1, or, 'α1β1γ1)'])].
[sujeto(['Moreover,', recombinant, human, 'Kv', 1.5, channels, were]), verbo([phosphorylated]), complemento([by, 'AMPK', in, 'cell-free', 'assays,', and, 'K(+)', currents, carried, by, 'Kv', 1.5, stably, expressed, in, 'HEK', 293, cells, were, inhibited, by, intracellular, dialysis, of, 'AMPK', heterotrimers, and, by, 'A769662,', the, effects, of, which, were, blocked, by, compound, 'C'])].
[sujeto(['We', conclude, that, 'AMPK']), verbo([mediates]), complemento(['Kv', channel, inhibition, by, hypoxia, in, pulmonary, arterial, 'myocytes,', at, least, in, 'part,', through, phosphorylation, of, 'Kv', 1.5, 'and/or', an, associated, protein])].
[sujeto(['The', 'large-conductance,', 'voltage-gated,', calcium, '(', 'Ca(2+))-activated', potassium, channel, '(', 'BKCa)', plays, an, important, role, in]), verbo([regulating]), complemento(['Ca(2+)signaling', and, is, implicated, in, the, maintenance, of, uterine, quiescence, during, pregnancy])].
[sujeto(['We', used, immunopurification, and, mass, spectrometry, to, identify, proteins, that]), verbo([interact]), complemento([with, 'BKCain', myometrium, samples, from, term, pregnant, '(', '≥37', wk, 'gestation)', women])].
[sujeto(['Single-channel', electrophysiological, recordings, in, the, 'cell-attached', configuration, demonstrated, that]), verbo([activated]), complemento([α2M, '(', 'α2M*)', increased, the, open, probability, of, 'BKCain', an, oscillatory, pattern, in, hMSMCs])].
[sujeto(['Furthermore,', 'α2M*']), verbo([caused]), complemento([intracellular, levels, of, 'Ca(2+)to', oscillate, in, 'oxytocin-primed', hMSMCs])].
[sujeto(['The', initiation, of, oscillations]), verbo([required]), complemento([an, interaction, between, 'α2M*', and, 'LRP1'])].
[sujeto(['By', using, 'Ca(2+)-free', medium, and, inhibitors, of, various, 'Ca(2+)signaling', 'pathways,', we, demonstrated, that, the, oscillations]), verbo([required]), complemento([entry, of, extracellular, 'Ca(2+)through', 'store-operated', 'Ca(2+)channels'])].
[sujeto(['Finally,', we]), verbo([found]), complemento([that, the, specific, 'BKCablocker', paxilline, inhibited, the, 'oscillations,', whereas, the, channel, opener, 'NS11021', increased, the, rate, of, these, oscillations])].
[sujeto(['These', data, demonstrate, that, 'α2M*', and, 'LRP1']), verbo([modulate]), complemento([the, 'BKCachannel', in, human, myometrium, and, that, 'BKCaand', its, immunomodulatory, interacting, partners, regulate, 'Ca(2+)dynamics', in, hMSMCs, during, pregnancy])].
[sujeto(['Outward', 'K(+)', current, in, smooth, muscle, cells, of, cerebral, basilar, 'artery,', 'large-conductance', 'Ca(2+)-activated', 'K(+)', '(', 'BK)', channel, current, in, 'BK-HEK', 293, cells, stably]), verbo([expressing]), complemento([both, human, α, '(', 'hSlo)-', and, 'β1-subunits,', and, hSlo, channel, current, in, 'hSlo-HEK', 293, cells, expressing, only, the, 'α-subunit', of, 'BK', channels, were, recorded, with, whole, cell, 'patch-clamp', technique])].
[sujeto(['The', results, showed, that, equol, significantly]), verbo([increased]), complemento([regional, cerebral, blood, flow, in, 'rats,', and, produced, a, 'concentration-dependent', but, 'endothelium-independent', relaxation, in, rat, cerebral, basilar, arteries])].
[sujeto(['Both', paxilline, and, 'iberiotoxin,', two, selective, 'BK', channel, 'blockers,', significantly]), verbo([inhibited]), complemento(['equol-induced', vasodilation, in, cerebral, arteries])].
[sujeto(['Outward', 'K(+)', currents, in, smooth, muscle, cells, of, cerebral, basilar, artery, were]), verbo([increased]), complemento([by, equol, and, fully, reversed, by, washout, or, blockade, of, 'BK', channels, with, iberiotoxin])].
[sujeto(['Equol', remarkably]), verbo([enhanced]), complemento([human, 'BK', current, in, 'BK-HEK', 293, 'cells,', but, not, hSlo, current, in, 'hSlo-HEK', 293, 'cells,', and, the, increase, was, completely, abolished, by, 'co-application', of, paxilline])].
[sujeto(['Our', findings]), verbo([provide]), complemento([the, first, information, that, equol, selectively, stimulates, 'BK', channel, current, by, acting, on, its, β1, 'subunit,', which, may, in, turn, contribute, to, the, 'equol-mediated', vasodilation, and, cerebral, blood, flow, increase])].
[sujeto(['Infiltration', of, the, brain, by, glioblastoma, cells, reportedly]), verbo([requires]), complemento(['Ca2+', signals, and, 'BK', 'K+', channels, that, program, and, drive, glioblastoma, cell, 'migration,', respectively])].
[sujeto(['Ionizing', radiation, '(', 'IR)']), verbo([has]), complemento([been, shown, to, induce, expression, of, the, chemokine, 'SDF-1,', to, alter, the, 'Ca2+', 'signaling,', and, to, stimulate, cell, migration, of, glioblastoma, cells])].
[sujeto(['In', 'addition,', 'U-87MG-Katushka', cells, were, grown, to, solid, glioblastomas, in, the, right, hemispheres, of, immunocompromised, 'mice,', fractionated, irradiated, '(', 6, 'MV', 'photons)', with, 5, ×, 0, or, 5, ×, 2, 'Gy,', and, 'SDF-1,', 'CXCR4,', and, 'BK', protein, expression, by, the, tumor, as, well, as, glioblastoma, brain, infiltration, was, analyzed, in, dependence, on, 'BK', channel]), verbo([targeting]), complemento([by, systemic, paxilline, application, concomitant, to, 'IR'])].
[sujeto(['As', a, 'result,', 'IR']), verbo([stimulated]), complemento(['SDF-1', signaling, and, induced, migration, of, glioblastoma, cells, in, vitro, and, in, vivo])].
[sujeto(['Collectively,', our, data, demonstrate, that, fractionated, 'IR', of, glioblastoma]), verbo([stimulates]), complemento([and, 'BK', 'K+', channel, targeting, mitigates, migration, and, brain, infiltration, of, glioblastoma, cells, in, vivo])].
[sujeto(['This']), verbo([suggests]), complemento([that, 'BK', channel, targeting, might, represent, a, novel, approach, to, overcome, 'radiation-induced', spreading, of, malignant, brain, tumors, during, radiotherapy])].
[sujeto(['The', pineal, glands]), verbo([regulate]), complemento([circadian, rhythm, through, the, synthesis, and, secretion, of, melatonin])].
[sujeto(['The', stimulation, of, nicotinic, acetylcholine, receptor, due, to, parasympathetic, nerve, activity]), verbo([causes]), complemento([an, increase, in, intracellular, 'Ca(2+)', concentration, and, eventually, downregulates, melatonin, production])].
[sujeto(['Our', previous]), verbo([report]), complemento([shows, that, rat, pinealocytes, have, spontaneous, and, 'nicotine-induced', 'Ca(2+)', oscillations, that, are, evoked, by, membrane, depolarization, followed, by, 'Ca(2+)', influx, through, 'voltage-dependent', 'Ca(2+)', channels, '(', 'VDCCs)'])].
[sujeto(['Spontaneous', 'Ca(2+)', oscillations, were, markedly]), verbo([enhanced]), complemento([by, 'BKCa', channel, blockers, '(', 1, μM, paxilline, or, 100, nM, 'iberiotoxin)'])].
[sujeto(['Under', whole, cell, 'voltage-clamp', 'configurations,', 'depolarization-elicited', outward, currents, were, significantly]), verbo([activated]), complemento([by, 'diCl-DHAA', and, blocked, by, paxilline])].
[sujeto(['Expression', analyses, revealed, that, the, α, and, β3, subunits, of, 'BKCa', channel, were, highly]), verbo([expressed]), complemento([in, rat, pinealocytes])].
[sujeto(['Importantly,', the, activity, of, 'BKCa', channels]), verbo([modulated]), complemento([melatonin, secretion, from, whole, pineal, gland, of, the, rat])].
[sujeto(['Studying', mouse, substantia, nigra, pars, compacta, dopaminergic, neurons, both, in, brain, slice, and, after, acute, 'dissociation,', we]), verbo([found]), complemento([that, 'BK', 'calcium-activated', potassium, channels, and, 'Kv2', channels, both, make, major, contributions, to, the, 'depolarization-activated', potassium, current])].
[sujeto(['Inhibiting', 'Kv2', channels]), verbo([increased]), complemento([spike, width, and, decreased, the, 'afterhyperpolarization,', as, expected, for, loss, of, an, action, 'potential-activated', potassium, conductance])].
[sujeto(['BK', inhibition, also]), verbo([increased]), complemento([spike, width, but, paradoxically, increased, the, afterhyperpolarization])].
[sujeto(['Kv2', channel, inhibition, steeply]), verbo([increased]), complemento([the, slope, of, the, 'frequency-current', '(', 'f-I)', 'relationship,', whereas, 'BK', channel, inhibition, had, little, effect, on, the, 'f-I', slope, or, decreased, 'it,', sometimes, resulting, in, slowed, firing])].
[sujeto(['Action', potential, clamp, experiments, showed, that, both, 'BK', and, 'Kv2', current, flow, during, spike, repolarization, but, with, very, different, 'kinetics,', with, 'Kv2', current]), verbo([activating]), complemento([later, and, deactivating, more, slowly])].
[sujeto(['Further', experiments, revealed, that]), verbo([inhibiting]), complemento([either, 'BK', or, 'Kv2', alone, leads, to, recruitment, of, additional, current, through, the, other, channel, type, during, the, action, potential, as, a, consequence, of, changes, in, spike, shape])].
[sujeto(['Enhancement', of, slowly, deactivating, 'Kv2', current, can, account, for, the]), verbo([increased]), complemento([afterhyperpolarization, produced, by, 'BK', inhibition, and, likely, underlies, the, very, different, effects, on, the, 'f-I', relationship])].
[sujeto(['This', work, shows, that, 'BK', 'calcium-activated', potassium, channels, and, 'Kv2', 'voltage-activated', potassium, channels, both]), verbo([regulate]), complemento([action, potentials, in, dopamine, neurons, of, the, substantia, nigra, pars, compacta])].
[sujeto(['Although', both, channel, types]), verbo([participate]), complemento([in, action, potential, repolarization, about, 'equally,', they, have, contrasting, and, partially, opposite, effects, in, regulating, neuronal, firing, at, frequencies, typical, of, bursting])].
[sujeto(['Large', conductance, 'Ca2+-activated', potassium, channels, '(', 'BK)', are]), verbo([targets]), complemento([for, research, that, explores, therapeutic, means, to, various, 'diseases,', owing, to, the, roles, of, the, channels, in, mediating, multiple, physiological, processes, in, various, cells, and, tissues])].
[sujeto(['As', recorded, by, 'whole-cell', 'patch-clamp,', curcumin]), verbo([increased]), complemento(['BK', '(', 'α)', and, 'BK', '(', 'α+β1)', currents, in, transfected, 'HEK293', cells, as, well, as, the, current, density, of, 'BK', in, 'A7r5', smooth, muscle, cells, in, a, 'dose-dependent', manner])].
[sujeto(['By', incubating, with, curcumin, for, 24, 'hours,', the, current, density, of, exogenous, 'BK', '(', 'α)', in, 'HEK293', cells, and, the, endogenous, 'BK', in, 'A7r5', cells, were, both]), verbo([enhanced]), complemento(['notably,', though, the, 'steady-state', activation, of, the, channels, did, not, shift, 'significantly,', except, for, 'BK', '(', 'α+β1)'])].
[sujeto(['The', surface, expression, and, the, 'half-life', of, 'BK', channels, were, also]), verbo([increased]), complemento([by, curcumin, in, 'HEK293', cells])].
[sujeto(['Curcumin', also]), verbo([increased]), complemento(['ERK', 1, /, 2, 'phosphorylation,', while, inhibiting, 'ERK', by, 'U0126', attenuated, the, 'curcumin-induced', 'up-regulation', of, 'BK', protein, expression])].
[sujeto(['These', results, show, that, curcumin]), verbo([enhances]), complemento([the, activity, of, the, 'BK', channels, by, interacting, with, 'BK', directly, as, well, as, enhancing, 'BK', protein, expression, through, inhibiting, proteasomal, degradation, and, activating, 'ERK', signaling, pathway])].
[sujeto(['The', findings]), verbo([suggest]), complemento([that, curcumin, is, a, potential, 'BK', channel, activator, and, provide, novel, insight, into, its, complicated, pharmacological, effects, and, the, underlying, mechanisms])].
[sujeto(['Mitochondrial', 'large-conductance', 'Ca2+-sensitive', potassium, '(', 'mBKCa)', channels, are]), verbo([involved]), complemento([in, myocardial, ischemic, preconditioning])].
[sujeto(['We', investigated, whether, 'sildenafil-induced', acute, cardioprotection, is]), verbo([mediated]), complemento([by, activation, of, mBKCa, channels, in, the, rat, heart, in, vitro])].
[sujeto(['Sildenafil']), verbo([increased]), complemento([cGMP, concentration, and, reduced, infarct, size, to, 35, '±6%', '(', 'P<0'])].
[sujeto(['ATP-producing', cell, 'organelles,', 'mitochondria,', are, the, primary]), verbo([target]), complemento([for, heavy, metals, which, are, major, environmental, pollutants, and, cause, various, pathological, conditions, and, diseases])].
[sujeto(['It']), verbo([has]), complemento([been, established, that, the, mechanism, of, toxic, action, of, heavy, 'metals,', includes, changes, in, the, intracellular, production, of, reactive, oxygen, species, and, mitochondrial, dysfunction, mediated, by, disturbances, of, the, respiratory, chain, and, by, activation, of, 'Ca2+-dependent', nonselective, pore, of, the, inner, mitochondrial, membrane])].
[sujeto(['The', role, of, other, ion, 'channels,', in, particular, such, selective, potassium, channels, as, 'Ca2+']), verbo([activated]), complemento(['large-conductance', potassium, 'channels,', 'BK(Ca),', considered, to, be, &, 'lt;protective>', for, a, 'cell,', is, practically, not, investigated])].
[sujeto(['After', 24, 'h-incubation', of, 'AS-30D', cells, with, 10, µM, of, either, 'NS', 1619, or, 'N5004,', the, number, of, apoptotic, cells, was]), verbo([found]), complemento([to, increase, compared, with, control])].
[sujeto(['The', same, concentration, of, 'N51619', and, 'N5004', did, not, affect, significantly, respiration, 'ofAS-30D', cells, after, 3, ',', 24, and, 48, h, of, incubation, but, produced, a, substantial]), verbo([increase]), complemento([in, intracellular, production, of, reactive, oxygen, species, after, 3, h, of, the, treatment])].
[sujeto(['In', experiments, on, isolated, rat, liver, mitochondria, 'NS1619', and, 'N5004,', added, at, the, same, concentration, to, the, 'KCI-containing', 'medium,', had, no, effect, on, the, respiratory, rate, at, state, 3, by, 'Chance', and, on, the, maximally, uncoupled, respiration, rate, '(', both, in, the, presence, and, absence, of, 'Cd2+);', at, the, same, time, they]), verbo([induced]), complemento([a, weak, uncoupling, action, by, accelerating, the, basal, respiration, and, the, resting, state, respiration, '(', at, state, 4, by, 'Chance)', as, well, as, they, enlarged, the, 'high-amplitude', mitochondrial, swelling, induced, by, 'Cd2+', in, this, medium])].
[sujeto(['It', was, shown, that, 'paxilline,', at, concentration, of, 1, 'µM,']), verbo([decreased]), complemento([the, mortality, of, 'AS-30D', cells, after, 3, ',', 24, and, 48, h, of, incubation, in, the, presence, of, 'Cd2+', and, enhanced, intracellular, production, of, reactive, oxygen, species, in, control, cells, after, 3, and, 24, h, of, incubation])].
[sujeto(['At', concentration, producing, a, 'long-term', protective, 'effeet,', paxilline, did, not, influence, the, respiration, of, 'AS-30D', cells, and, isolated, rat, liver, mitochondria, '(', both, in, the, presence, and, absence, of, 'Cd2+)', and, did, not]), verbo([decrease]), complemento([mitochondrial, swelling, observed, in, the, presence, of, 'Cd2+', and, the, 'BK(Ca)', activators])].
[sujeto(['Estrogen', replacement, therapies]), verbo([have]), complemento([been, suggested, to, be, beneficial, in, alleviating, symptoms, of, overactive, bladder])].
[sujeto(['Large', conductance, 'voltage-', and, 'Ca2+-activated', 'K+', '(', 'BK)', 'channels,', which, are, key, regulators, of, 'UBSM', 'function,', are]), verbo([suggested]), complemento([to, be, 'non-genomic', targets, of, estrogens])].
[sujeto(['This', study]), verbo([provides]), complemento([an, electrophysiological, investigation, into, the, role, of, 'UBSM', 'BK', channels, as, direct, targets, for, 17, 'β-estradiol,', the, principle, estrogen, in, human, circulation])].
[sujeto([17, 'β-Estradiol', '(', 100, 'nM)', significantly]), verbo([increased]), complemento([the, amplitude, of, 'depolarization-induced', whole, cell, 'steady-state', 'BK', currents, and, the, frequency, of, spontaneous, transient, 'BK', currents, in, 'freshly-isolated', 'UBSM', cells])].
[sujeto(['The']), verbo([increase]), complemento([in, whole, cell, 'BK', currents, by, 17, 'β-estradiol', was, eliminated, upon, blocking, 'BK', channels, with, paxilline])].
[sujeto([17, 'β-Estradiol', '(', 100, 'nM)', significantly]), verbo([increased]), complemento(['(', '~3-fold)', the, single, 'BK', channel, open, 'probability,', indicating, direct, 17, 'β-estradiol-BK', channel, interactions])].
[sujeto([17, 'β-Estradiol', '(', 100, 'nM)']), verbo([caused]), complemento([a, significant, hyperpolarization, of, the, membrane, potential, of, 'UBSM', 'cells,', and, this, hyperpolarization, was, reversed, by, blocking, the, 'BK', channels, with, paxilline])].
[sujeto(['This', study]), verbo([reveals]), complemento([a, new, regulatory, mechanism, in, the, urinary, bladder, whereby, 'BK', channels, are, directly, activated, by, 17, 'β-estradiol', to, reduce, 'UBSM', cell, excitability])].
[sujeto(['In', sensory, 'neurons,']), verbo([increases]), complemento([in, 'NGF', augment, neuronal, sensitivity, '(', 'sensitization)', to, noxious, stimuli])].
[sujeto(['The', 'NGF', 'effect,', which]), verbo([requires]), complemento([trkA, 'receptors,', takes, hours, to, develop, and, days, to, reverse])].
[sujeto(['We']), verbo([found]), complemento([that, 'NGF', reduces, 'Maxi-K', channel, opening, by, decreasing, the, activity, of, 'nifedipine-sensitive', calcium, channels])].
[sujeto(['Myogenic', 'tone,', an, important, regulator, of, vascular, 'resistance,', is, dependent, on, vascular, smooth, muscle, '(', 'VSM)', 'depolarization,', can, be]), verbo([modulated]), complemento([by, endothelial, 'factors,', and, is, increased, in, several, models, of, hypertension])].
[sujeto(['Intermittent', hypoxia, '(', 'IH)', elevates, blood, pressure, and]), verbo([causes]), complemento([endothelial, dysfunction])].
[sujeto(['Hydrogen', sulfide, '(', 'H(2)S),', a, recently, described, 'endothelium-derived', 'vasodilator,', is, produced, by, the, enzyme, cystathionine, 'γ-lyase', '(', 'CSE)', and]), verbo([acts]), complemento([by, hyperpolarizing, 'VSM'])].
[sujeto(['Determine', whether, 'IH']), verbo([decreases]), complemento([endothelial, 'H(2)S', production, to, increase, myogenic, tone, in, small, mesenteric, arteries])].
[sujeto(['Endothelium', inactivation, or, scavenging, of, 'H(2)S']), verbo([enhanced]), complemento([myogenic, tone, in, sham, arteries, to, the, level, of, 'IH'])].
[sujeto(['Inhibiting', 'CSE', also]), verbo([enhanced]), complemento([myogenic, tone, and, depolarized, 'VSM', in, sham, but, not, 'IH', arteries])].
[sujeto(['Iberiotoxin']), verbo([enhanced]), complemento([myogenic, tone, in, both, groups, but, more, in, sham, than, 'IH'])].
[sujeto(['IH', appears, to]), verbo([decrease]), complemento([endothelial, 'CSE', expression, to, reduce, 'H(2)S', 'production,', depolarize, 'VSM,', and, enhance, myogenic, tone])].
[sujeto(['H(2)S', dilatation, and, hyperpolarization, of, 'VSM', in, small, mesenteric, arteries]), verbo([requires]), complemento(['BK(Ca)', channels])].
[sujeto(['Disruption', of, rafts, by, selective, depletion, of, cholesterol]), verbo([released]), complemento(['BK(Ca)', channels, from, these, domains, with, a, consequent, increase, in, their, activity])].
[sujeto(['Consistently,', cholesterol, enrichment, of, the, cells]), verbo([increased]), complemento([the, proportion, of, 'BK(Ca)', channels, in, rafts, and, decreased, their, activity])].
[sujeto(['Immunocytochemical', analysis, showed, that, 'BK(Ca)', channels, 'co-localize', with, 'Na(+)/K(+)-ATPase', in, a, 'cholesterol-dependent', 'manner,', thus]), verbo([suggesting]), complemento([their, 'co-presence', in, rafts])].
[sujeto(['Supporting', 'this,', 'ouabain,', a, specific, blocker, of, 'Na(+)/K(+)-ATPase,']), verbo([inhibited]), complemento(['BK(Ca)', 'whole-cell', current, markedly, in, control, cells, but, not, in, 'cholesterol-depleted', ones])].
[sujeto(['This', inhibition]), verbo([required]), complemento([the, presence, of, external, 'Na(+)'])].
[sujeto(['Collectively,', these, data, indicate, that, the, presence, of, 'Na(+)/K(+)-ATPase', in, rafts, is, essential, for, efficient, functioning, of, 'BK(Ca)', 'channels,', presumably, because, the, pump]), verbo([maintains]), complemento([a, low, intracellular, 'Na(+)', proximal, to, the, 'BK(Ca)', channel])].
[sujeto(['In', 'conclusion,', cholesterol, could, play, an, important, role, in, cellular, ion, homeostasis, and, thus]), verbo([modulate]), complemento([many, cellular, functions, and, cell, proliferation])].
[sujeto(['Paxilline,', an, inhibitor, of, 'BK(Ca)', 'channels,']), verbo([decreased]), complemento([outward, 'K(+)', current, density])].
[sujeto(['Outward', currents, in, smooth, muscle, cells, obtained, from, irradiated, animals, 9, and, 30, days, following, radiation, exposure, demonstrated, a, significant]), verbo([decrease]), complemento([in, 'K(+)', current, density])].
[sujeto(['Paxilline']), verbo([decreased]), complemento(['K(+)', current, in, cells, obtained, 9, 'days,', but, was, without, effect, 30, days, after, irradiation, suggesting, the, absence, of, 'BK(Ca)', channels])].
[sujeto(['Aortic', tissue, from, irradiated, animals, showed, progressively]), verbo([enhanced]), complemento([contractile, responses, to, phenylephrine, in, the, 'post-irradiation', period, of, 9, and, 30, days])].
[sujeto(['The', concomitant, 'Ca(2+)', transients, were, significantly, 'smaller,', as, compared, to, tissues, from, control, 'animals,', 9, days, following, irradiation, but, were]), verbo([increased]), complemento([above, control, levels, 30, days, following, irradiation])].
[sujeto(['Irradiation', produced, a]), verbo([decrease]), complemento([in, 'BK(Ca)', 'alpha-', and, 'beta(1)-subunit', mRNA, levels, in, aortic, smooth, muscle, cells, suggesting, that, the, vasorelaxant, effect, of, these, channels, may, be, diminished])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, enhanced, contractility, of, vascular, tissue, from, animals, exposed, to, radiation, may, result, from, an, increase, in, myofilament, 'Ca(2+)', sensitivity, in, the, early, 'post-irradiation', period, and, a, decrease, in, 'BK(Ca)', channel, expression, in, the, late, 'post-irradiation', period])].
[sujeto(['The', stimulation, of, control, 'SMCs', by, increasingly, depolarized, voltage, steps, showed, clearly]), verbo([expressed]), complemento([outward, 'K+', currents, in, control, 'SMCs'])].
[sujeto(['Outward', currents, in, 'SMCs', obtained, from, irradiated, animals, on, the, 9, th, and, 30, th, days, 'post-irradiation', demonstrated, a, significant]), verbo([decrease]), complemento([of, 'K', current, density, amplitudes])].
[sujeto(['In', 'conclusion,', the, data, obtained, clearly, demonstrate, that]), verbo([decreased]), complemento([of, the, 'BK(Ca)', channels, 'alpha-', and, 'beta1-subunit', expression, in, 'SMCs', is, a, key, factor, of, abnormality, in, 'BK(Ca)', channels, activity])].
[sujeto(['Cardiac', fibroblasts, are]), verbo([involved]), complemento([in, the, maintenance, of, myocardial, tissue, structure])].
[sujeto(['It']), verbo([has]), complemento([been, recently, reported, that, cardiac, fibroblasts, can, interact, electrically, with, cardiomyocytes, through, gap, junctions])].
[sujeto(['In', 'whole-cell', 'configuration,', depolarizing, pulses, evoked, 'I', '(', 'K(Ca))', in, an, outward, rectification, in, these, 'cells,', the, amplitude, of, which, was]), verbo([suppressed]), complemento([by, paxilline, '(', 1, 'microM:', ')', or, iberiotoxin, '(', 200, 'nM:', ')'])].
[sujeto(['This', study, demonstrates, that, a, 'BK(Ca)', channel, is, functionally]), verbo([expressed]), complemento([in, human, cardiac, fibroblasts])].
[sujeto(['It']), verbo([has]), complemento([been, shown, that, outward, potassium, currents, in, endothelial, cells, 9, days, after, irradiation, appear, to, be, suppressed, or, even, totally, abolished])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, 'non-fatal,', 'whole-body', 'gamma-irradiation', suppresses, large, 'conductance,', 'calcium-activated', potassium, 'channels,', which, control, the, driving, force, for, 'Ca2+', entry, and, therefore, 'Ca2+', dependent, nitric, oxide, '(', 'NO)', synthesis, in, endothelial, cells])].
[sujeto(['This', may, 'contribute,', in, 'part,', to, 'radiation-induced', endothelium, dysfunction, and, an]), verbo([increase]), complemento([in, arterial, blood, pressure])].
[sujeto(['The', resulting, system, of, transfected, cells, with, a]), verbo([modulated]), complemento([metastatic, potential, provide, a, convenient, model, to, study, the, molecular, mechanisms, of, tumor, progression, at, various, steps])].
[sujeto(['In', the, 'whole-cell', 'configuration,', resveratrol, reversibly]), verbo([increased]), complemento([the, amplitude, of, 'K+', outward, currents])].
[sujeto(['The']), verbo([increase]), complemento([in, outward, current, caused, by, resveratrol, was, greatly, inhibited, by, iberiotoxin, '(', 200, 'nM)', or, paxilline, '(', 1, 'microM),', but, not, by, glibenclamide, '(', 10, 'microM),', tamoxifen, '(', 10, 'microM),', or, 'beta-bungarotoxin', '(', 200, 'nM)'])].
[sujeto(['In', the, 'inside-out', 'configuration,', bath, application, of, resveratrol, '(', 30, 'microM)']), verbo([caused]), complemento([no, change, in, the, 'single-channel', 'conductance,', but, increased, the, activity, of, 'large-conductance', 'Ca(2+)-activated', 'K+', '(', 'BKCa)', channels])].
[sujeto(['Resveratrol']), verbo([enhanced]), complemento([the, channel, activity, in, a, 'concentration-dependent', manner])].
[sujeto(['The', 'resveratrol-stimulated']), verbo([increase]), complemento([in, the, channel, activity, was, independent, of, internal, 'Ca2+'])].
[sujeto(['The', change, in, the, kinetic, behavior, of, 'BKCa', channels]), verbo([caused]), complemento([by, resveratrol, in, these, cells, in, due, to, an, increase, in, mean, open, time, and, a, decrease, in, mean, closed, time])].
[sujeto(['In', a, pancreatic, islet, endothelial, cell, line, '(', 'MS1),', resveratrol, '(', 30, 'microM)', also]), verbo([increased]), complemento([the, activity, of, 'intermediate-conductance', 'KCa', channels])].
[sujeto(['These', results]), verbo([provide]), complemento([evidence, that, in, addition, to, the, presence, of, antioxidative, 'activity,', resveratrol, can, also, stimulate, 'KCa', channels, in, endothelial, cells])].
[sujeto(['Using', the, 'patch-clamp', 'technique,', we]), verbo([have]), complemento([characterized, membrane, currents, in, single, detrusor, smooth, muscle, cells, from, rat, and, human, urinary, bladder])].
[sujeto(['From', the, 'voltage-', and, 'Ca(2+)-dependence', of, the, current, as, well, as, the, single, channel, conductance, we, conclude, that, rat, and, human, urinary, bladder, smooth, muscle, cells]), verbo([express]), complemento(['MaxiK', channels])].
[sujeto(['Application', of, 10, microm, 'NS1608']), verbo([increased]), complemento([the, amplitude, of, the, current, and, this, increase, could, be, explained, by, a, shift, in, the, activation, voltage, of, the, 'MaxiK', channels, approximately, 100, mV, towards, more, negative, potentials])].
[sujeto(['We', conclude, that, application, of, 'NS1608', results, in, the, opening, of, 'MaxiK', channels, under, physiological, conditions, that]), verbo([leads]), complemento([to, a, hyperpolarization, of, the, cells])].
[sujeto(['MaxiK', channels, in, these, cells, could, therefore, play, a, role, in, directly, controlling, muscle, tone, by]), verbo([regulating]), complemento([the, membrane, potential])].
[sujeto(['This', opens, up, the, possibility, of, 'MaxiK', channels, being]), verbo([targets]), complemento([for, the, treatment, of, urge, incontinence])].
[sujeto(['mRNA-profiling,']), verbo([has]), complemento([been, proven, successful, in, improving, the, prediction, of, genotoxicity, in, vivo, and, the, understanding, of, underlying, mechanisms])].
[sujeto(['Recently,', microRNAs]), verbo([have]), complemento([been, discovered, as, 'post-transcriptional', regulators, of, mRNAs])].
[sujeto(['Growth']), verbo([arrest]), complemento([and, 'DNA', 'damage-inducible', beta, '(', 'GADD45b)', plays, a, pivotal, role, in, many, intracellular, events, in, both, cell, 'survival-', and, cell, 'death-related', signaling])].
[sujeto(['To', 'date,', the, study, of, 'GADD35b']), verbo([has]), complemento([mainly, focused, on, investigation, of, its, 'function,', as, well, as, interacting, molecules])].
[sujeto(['Since', 'Gadd45b', mRNA, is, highly]), verbo([induced]), complemento([by, the, 'PPARα', agonist, 'Wy-14,643', in, the, mouse, 'liver,', we, analyzed, the, 'Gadd45b', promoter, using, an, 'in vivo', reporter, assay])].
[sujeto(['Interestingly,', the, naked, 'Gadd45b-luciferase', construct, strongly]), verbo([induced]), complemento([luciferase, activity, without, any, stimulant, in, our, 'in vivo', system])].
[sujeto(['Gene', duplication, is, thought, to, facilitate]), verbo([increasing]), complemento([complexity, in, the, evolution, of, life])].
[sujeto(['According', to, the, 'duplication-degeneration-complementation', '(', 'DDC)', 'model,', duplicated, genes, are]), verbo([retained]), complemento([by, 'subfunctionalization,', where, the, functions, of, the, ancestral, gene, are, 'sub-divided', between, duplicate, 'genes,', or, by, 'neofunctionalization,', where, one, of, the, duplicates, acquires, a, new, function])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, differential, regulation, of, the, zebrafish, tandemly, duplicated, fatty, 'acid-binding', protein, 'genes,', fabp1b])].
[sujeto([1, mRNA, levels, were]), verbo([induced]), complemento([in, tissue, explants, of, 'liver,', but, not, 'intestine,', by, 'PPAR', agonists])].
[sujeto([1, promoter, activity, was]), verbo([induced]), complemento([to, a, greater, extent, by, rosiglitazone, '(', 'PPARγ-selective', 'agonist)', compared, to, 'WY', 14, ',', 643, '(', 'PPARα-selective', 'agonist)', in, 'HEK293A', cells])].
[sujeto(['Differential', regulation, of, the, duplicated, fabp1b, promoters, may, be, the, result, of, 'PPRE']), verbo([loss]), complemento([in, fabp1b])].
[sujeto([2]), verbo([suggests]), complemento([unique, regulation, and, function, of, the, fabp1b, duplicates])].
[sujeto(['Numerous', clinical, and, population, studies]), verbo([have]), complemento([demonstrated, that, increased, serum, bilirubin, levels, protect, against, cardiovascular, and, metabolic, diseases, such, as, obesity, and, diabetes])].
[sujeto(['Bilirubin', is, a, potent, 'antioxidant,', and, the, beneficial, actions, of, moderate]), verbo([increases]), complemento([in, plasma, bilirubin, have, been, thought, to, be, due, to, the, antioxidant, effects, of, this, bile, pigment])].
[sujeto(['In', the, present, 'study,', we]), verbo([found]), complemento([that, bilirubin, has, a, new, function, as, a, ligand, for, 'PPARα'])].
[sujeto(['We', show, that, bilirubin, can]), verbo([bind]), complemento([directly, to, 'PPARα', and, increase, transcriptional, activity])].
[sujeto(['When', we, compared, 'biliverdin,', the, precursor, to, 'bilirubin,', on, 'PPARα', transcriptional, activation, to, known, 'PPARα', 'ligands,', 'WY', 14, ',', 643, and, 'fenofibrate,', it, showed, that, fenofibrate, and, biliverdin]), verbo([have]), complemento([similar, activation, properties])].
[sujeto(['Treatment', of, 3, 'T3-L1', adipocytes, with, biliverdin]), verbo([suppressed]), complemento([lipid, accumulation, and, upregulated, 'PPARα', target, genes])].
[sujeto(['We', treated, 'wild-type', and, 'PPARα', 'KO', mice, on, a, high, fat, diet, with, fenofibrate, or, bilirubin, for, seven, days, and]), verbo([found]), complemento([that, both, signal, through, 'PPARα', dependent, mechanisms])].
[sujeto(['These', data, demonstrate, a, new, function, for, bilirubin, as, an, agonist, of, 'PPARα,', which]), verbo([mediates]), complemento([the, protection, from, adiposity, afforded, by, moderate, increases, in, bilirubin])].
[sujeto(['Chemical', carcinogenesis, can, be]), verbo([induced]), complemento([by, genotoxic, '(', 'GTX)', or, 'non-genotoxic', '(', 'NGTX)', carcinogens])].
[sujeto(['GTX', carcinogens]), verbo([have]), complemento([a, 'well-described', mode, of, action])].
[sujeto(['However,', the, complex, mechanisms, by, which, 'NGTX', carcinogens]), verbo([act]), complemento([are, less, clear, and, may, result, in, conflicting, results, between, species, '[', e])].
[sujeto(['From', the, three, discriminative, microRNAs]), verbo([found]), complemento([following, 48, h, of, 'exposure,', 'mmu-miR-503-5p', revealed, to, have, an, interaction, with, mRNA, target, gene, cyclin, 'D2', '(', 'Ccnd2', -, 12444, ')', which, was, involved, in, the, discriminative, process, of, p53, signalling, and, metabolism])].
[sujeto(['Following', exposure, to, 'NGTX', carcinogens, 'Mmu-miR-503-5p', may]), verbo([have]), complemento([an, oncogenic, function, by, stimulating, 'Ccnd2', possibly, leading, to, a, tumourigenic, cell, cycle, progression])].
[sujeto(['By', 'contrast,', after, 'GTX', carcinogen, exposure, it, may]), verbo([have]), complemento([a, 'tumour-suppressive', function, '(', repressing, 'Ccnd2)', leading, to, cell, cycle, arrest, and, to, increased, 'DNA', repair, activities])].
[sujeto(['In', 'addition,', 'compound-specific', 'microRNA-mRNA', interactions, '[', 'mmu-miR-301b-3p-Papss2', '(', for, 'AFB1),', as, well, as, 'mmu-miR-29b-3p-Col4a2', and, 'mmu-miR-24-3p-Flna', '(', for, 'BaP)]', were]), verbo([found]), complemento([to, contribute, to, a, better, understanding, of, microRNAs, in, cell, cycle, arrest, and, the, impairment, of, the, 'DNA', damage, 'repair,', an, important, hallmark, of, 'GTX-induced', carcinogenesis])].
[sujeto(['In', order, to, get, mechanistic, 'insights,', alterations, of, plasma, lipids, '(', free, 'cholesterol,', 'FC;', 'HDL']), verbo([associated]), complemento(['cholesterol,', 'C-HDL;', 'triglycerides,', 'TG;', 'non-esterified', fatty, 'acids,', 'NEFA)', and, hepatic, mRNA, expression, of, 17, genes, involved, in, fatty, acid, and, lipid, metabolism, were, studied])].
[sujeto(['Microsomal', triglyceride, transfer, protein, and, apolipoprotein, 'E', mRNA, expression, were, higher, in, 'hi-WY,', and, indicated, an]), verbo([increased]), complemento([formation, of, 'VLDL', particles, and, energy, mobilization, from, liver])].
[sujeto(['The', pervasive, nature, of, plastics]), verbo([has]), complemento([raised, concerns, about, the, impact, of, continuous, exposure, to, plastic, additives, on, human, health])].
[sujeto(['Recent', epidemiological, studies]), verbo([have]), complemento([reported, correlations, between, urinary, phthalate, concentrations, and, cardiovascular, 'disease,', including, an, increased, risk, of, high, blood, pressure, and, coronary, risk])].
[sujeto(['DEHP', exposure, '(', 24, -, 72, 'hr)', had, a, negative, chronotropic, and, inotropic, effect, on, 'cardiomyocytes,']), verbo([increased]), complemento([the, minimum, threshold, voltage, required, for, external, 'pacing,', and, modified, 'connexin-43', expression])].
[sujeto(['Obesity', poses, an]), verbo([increased]), complemento([risk, of, developing, metabolic, syndrome, and, closely, associated, nonalcoholic, fatty, liver, 'disease,', including, liver, cancer])].
[sujeto(['Sustained', activation, of, peroxisome, 'proliferator-activated', receptor, α, '(', 'PPARα)', in, 'ob/ob', mouse, liver]), verbo([increases]), complemento([fatty, acid, oxidation, '(', 'FAO),', which, contributes, to, attenuation, of, obesity, but, enhances, liver, cancer, risk])].
[sujeto(['These', mice, become, strikingly, more, obese, compared, to, 'ob/ob', 'littermates,', with]), verbo([increased]), complemento([white, and, brown, adipose, tissue, content, and, severe, hepatic, steatosis])].
[sujeto(['PPARα(Δ)ob/ob', mice, also, do, not]), verbo([respond]), complemento([to, peroxisome, proliferative, and, mitogenic, effects, of, 'PPARα', agonist, 'Wy-14,643'])].
[sujeto(['Although', 'PPARα(Δ)ob/ob', mice, are, severely, 'obese,', there, was, no, significant]), verbo([increase]), complemento([in, liver, tumor, 'incidence,', even, when, maintained, on, a, diet, containing, 'Wy-14,643'])].
[sujeto(['We', conclude, that, sustained, 'PPARα', 'activation-related']), verbo([increase]), complemento([in, 'FAO', in, fatty, livers, of, obese, 'ob/ob', mice, increases, liver, cancer, 'risk,', whereas, deletion, of, 'PPARα', in, 'ob/ob', mice, aggravates, obesity, and, hepatic, steatosis])].
[sujeto(['However,', it, does, not]), verbo([lead]), complemento([to, liver, tumor, development, because, of, reduction, in, 'FAO', and, energy, burning])].
[sujeto(['The']), verbo([nuclear]), complemento([receptor, family, member, peroxisome, 'proliferator-activated', receptor, α, '(', 'PPARα)', is, activated, by, therapeutic, hypolipidemic, drugs, and, 'environmentally-relevant', chemicals, to, regulate, genes, involved, in, lipid, transport, and, catabolism])].
[sujeto(['Chronic', activation, of, 'PPARα', in, rodents]), verbo([increases]), complemento([liver, cancer, 'incidence,', whereas, suppression, of, 'PPARα', activity, leads, to, hepatocellular, steatosis])].
[sujeto(['The', signature, was, then, used, to, identify, factors, that]), verbo([activate]), complemento([or, suppress, 'PPARα', in, an, annotated, mouse, 'liver/primary', hepatocyte, gene, expression, compendium, of, '~1850', biosets])].
[sujeto(['In', addition, to, the, expected, activation, of, 'PPARα', by, fibrate, 'drugs,', 'di(2-ethylhexyl)', 'phthalate,', and, perfluorinated, 'compounds,', 'PPARα', was]), verbo([activated]), complemento([by, 'benzofuran,', 'galactosamine,', and, 'TCDD', and, suppressed, by, hepatotoxins, 'acetaminophen,', 'lipopolysaccharide,', silicon, dioxide, 'nanoparticles,', and, trovafloxacin])].
[sujeto(['Additional', factors, that]), verbo([activate]), complemento(['(', 'fasting,', caloric, 'restriction)', or, suppress, '(', 'infections)', 'PPARα', were, also, identified])].
[sujeto(['This', study, 1, ')', developed, methods, useful, for, future, screening, of, environmental, 'chemicals,', 2, ')', identified, chemicals, that]), verbo([activate]), complemento([or, suppress, 'PPARα,', and, 3, ')', identified, factors, including, diets, and, infections, that, modulate, 'PPARα', activity, and, would, be, hypothesized, to, affect, 'chemical-induced', 'PPARα', activity])].
[sujeto(['The', current, study, extends, previously]), verbo([reported]), complemento(['PPARα', agonist, 'WY', 14, ',', 643, '(', 30, 'µmol/kg/day', for, 4, 'weeks)', effects, on, circulating, amino, acid, concentrations, in, rats, fed, a, 48, '%', saturated, fat, diet])].
[sujeto(['WY', 14, ',', 643, treated, animals, demonstrated, reduced, efficiency, to, convert, food, consumed, to, body, weight]), verbo([gain]), complemento([while, liver, weight, was, increased, compared, to, controls])].
[sujeto(['Arginine', was, substantially]), verbo([decreased]), complemento(['(', -, 62, '%', ')', in, plasma, with, estimated, 'Ra', reduced, from, 3.1, ±, 0.3, to, 1.2, ±, 0.2, 'µmol/kg/min', in, control, versus, 'WY', 14, ',', 643])].
[sujeto(['Hepatic', arginase, activity, was, substantially]), verbo([decreased]), complemento([by, 'WY', 14, ',', 643, treatment])].
[sujeto(['This']), verbo([suggests]), complemento([that, 'PPARα', has, an, important, role, in, modulating, 'serine,', glycine, and, arginine, de, novo, synthesis])].
[sujeto(['The', 3, 'T3-L1', preadipocyte, culture, system]), verbo([has]), complemento([been, used, to, examine, numerous, compounds, that, influence, adipocyte, differentiation, or, function])].
[sujeto(['Cells', were, treated, with, perfluorooctanoic, acid, '(', 'PFOA)', '(', 5, -, 100, 'µM),', perfluorononanoic, acid, '(', 'PFNA)', '(', 5, -, 100, 'µM),', perfluorooctane, sulfonate, '(', 'PFOS)', '(', 50, -, 300, 'µM),', perfluorohexane, sulfonate, '(', 'PFHxS)', '(', 40, -, 250, 'µM),', the, peroxisome, proliferator]), verbo([activated]), complemento([receptor, '(', 'PPAR)', 'PPARα', agonist, 'Wyeth-14,643', '(', 'WY-14,643),', and, the, 'PPARγ', agonist, rosiglitazone])].
[sujeto(['There', was, a, significant, 'concentration-related']), verbo([increase]), complemento([in, cell, number, and, decreased, cell, size, after, exposure, to, 'PFOA,', 'PFHxS,', 'PFOS,', and, 'PFNA'])].
[sujeto(['All', four, 'PFAA', treatments, produced, a, 'concentration-related']), verbo([decrease]), complemento([in, the, calculated, average, area, occupied, by, lipid, per, cell])].
[sujeto(['However,', total, triglyceride, levels, per, well]), verbo([increased]), complemento([with, a, 'concentration-related', trend, for, all, 'compounds,', likely, due, to, the, increased, cell, number])].
[sujeto(['In', 'summary,', all, perfluorinated, compounds]), verbo([increased]), complemento([cell, 'number,', decreased, cell, 'size,', increased, total, 'triglyceride,', and, altered, expression, of, genes, associated, with, adipocyte, differentiation, and, lipid, metabolism])].
[sujeto(['In', the, intact, rumen, 'epithelium,', isoforms, 1, and, 4, of, the, monocarboxylate, transporter, '(', 'MCT1', and, 'MCT4)', are, thought, to, play, key, roles, in]), verbo([mediating]), complemento([transcellular, and, intracellular, permeation, of, 'short-chain', fatty, acids, and, their, metabolites, and, in, maintaining, intracellular, pH])].
[sujeto(['We', examined, whether, both, 'MCT1', and, 'MCT4', are]), verbo([expressed]), complemento([at, mRNA, and, protein, levels, in, ovine, ruminal, epithelial, cells, '(', 'REC)', maintained, in, primary, culture, and, whether, they, are, regulated, by, peroxisome, 'proliferator-activated', 'receptor-α', '(', 'PPARα)'])].
[sujeto(['Because', both, transporters]), verbo([have]), complemento([been, characterized, to, function, coupled, to, 'protons,', the, influence, of, 'PPARα', on, the, recovery, of, intracellular, pH, after, 'l-lactate', exposure, was, evaluated, by, spectrofluorometry])].
[sujeto(['The', subsequent, qPCR, analysis, resulted, in, a, 'dose-dependent', upregulation, of, 'MCT1', and, 'PPARα']), verbo([target]), complemento(['genes,', whereas, response, of, 'MCT4', was, not, uniform])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'PPARα', is, particularly, regulating, 'MCT1', but, not, 'MCT4', expression])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, α, '(', 'PPARα)']), verbo([has]), complemento([been, reported, to, induce, a, potent, 'anti-inflammatory', response])].
[sujeto(['Autophagy', is, a, recently]), verbo([recognized]), complemento([rudimentary, cellular, response, to, inflammation, and, injury])].
[sujeto(['The', aim, of, the, present, study, was, to, test, the, hypothesis, that, 'PPARα', activation]), verbo([mediates]), complemento([autophagy, to, inhibit, liver, inflammation, and, protect, against, acute, liver, failure, '(', 'ALF)'])].
[sujeto(['Autophagy', was]), verbo([inhibited]), complemento([by, 3, -, methyladenine, or, small, interfering, 'RNA', '(', 'siRNA)', against, 'Atg7'])].
[sujeto(['This', hypothesis, is, supported, by, the, following, 'evidence:', 'first,', 'PPARα', activation]), verbo([suppressed]), complemento([proinflammatory, responses, and, inhibited, phosphorylated, 'NF-κBp65,', phosphorylated, 'JNK', and, phosphorylated, 'ERK', pathways, in, vivo])].
[sujeto(['Third,', 'PPARα', activation, directly]), verbo([induced]), complemento([autophagy, in, primary, macrophages, in, 'vitro,', which, protected, cells, from, a, 'lipopolysaccharide-induced', proinflammatory, response])].
[sujeto(['Here,', for, the, first, 'time,', we]), verbo([have]), complemento([demonstrated, that, 'PPARα-mediated', induction, of, autophagy, ameliorated, liver, injury, in, cases, of, 'ALF', by, attenuating, inflammatory, 'responses,', indicating, a, potential, therapeutic, application, for, 'ALF', treatment])].
[sujeto(['Excess', dietary, lipid, generally]), verbo([leads]), complemento([to, fat, deposition, and, impaired, glucose, 'homeostasis,', but, consumption, of, fish, oil, '(', 'FO)', alleviates, many, of, these, detrimental, effects])].
[sujeto(['The', beneficial, effects, of, 'FO', are, thought, to, be]), verbo([mediated]), complemento([largely, via, activation, of, the, nuclear, receptor, 'peroxisomal-proliferator-activated', receptor, α, '(', 'PPARα)', by, 'omega-3', polyunsaturated, fatty, acids, and, the, resulting, upregulation, of, lipid, catabolism])].
[sujeto(['However,', pharmacological, and, genetic, 'PPARα', manipulations]), verbo([have]), complemento([yielded, variable, results])].
[sujeto(['We']), verbo([have]), complemento([compared, the, metabolic, effects, of, 'FO', supplementation, and, the, synthetic, 'PPARα', agonist, 'Wy-14,643', '(', 'WY)', in, mice, fed, a, 'lard-based', 'high-fat', diet])].
[sujeto(['These', differences, were, likely, due, to, differential, effects, on, hepatic, lipid, 'synthesis,', with, 'FO']), verbo([decreasing]), complemento([and, 'WY', amplifying, hepatic, lipid, accumulation])].
[sujeto(['Our', results, highlight, that, the, beneficial, metabolic, effects, of, 'FO', are, likely]), verbo([mediated]), complemento([through, multiple, independent, pathways])].
[sujeto(['Endoplasmic', reticulum, '(', 'ER)', stress]), verbo([has]), complemento([been, linked, to, several, cardiovascular, 'diseases,', such, as, 'atherosclerosis,', heart, failure, and, cardiac, hypertrophy])].
[sujeto(['Since', several, studies]), verbo([have]), complemento([reported, that, 'PPARα', may, inhibit, 'ER', 'stress,', the, main, aim, of, this, study, consisted, in, investigating, whether, activation, of, this, nuclear, receptor, is, able, to, prevent, 'lipid-induced', 'ER', stress, in, cardiac, 'cells,', as, well, as, studying, the, mechanisms, involved])].
[sujeto(['The', results, demonstrate, that, both, palmitate, and, the, 'HFD']), verbo([induced]), complemento(['ER', stress, in, cardiac, 'cells,', since, they, upregulated, the, expression, '(', 'ATF3,', 'BiP/GRP78', and, 'CHOP),', splicing, '(', 'sXBP1),', and, phosphorylation, '(', 'IRE-1α', and, 'eIF2α)', of, several, 'ER', stress, markers])].
[sujeto(['Interestingly,', treatment, with, the, 'PPARα', agonist, 'Wy-14,643']), verbo([prevented]), complemento([an, increase, in, the, majority, of, these, 'ER', stress, markers, in, human, cardiac, cells, by, means, of, 'AMPK', activation])].
[sujeto(['These', data, indicate, that, 'PPARα', activation, by, 'Wy-14,643', might, be, useful, to]), verbo([prevent]), complemento([the, harmful, effects, of, 'ER', stress, and, associated, cardiovascular, diseases, in, obese, 'patients,', and, even, during, diabetic, 'cardiomyopathy,', by, enhancing, 'AMPK', activity])].
[sujeto(['The', results, show, that, 'WY-14,643']), verbo([increases]), complemento([mRNA, and, protein, levels, of, 'OCTN2,', whereas, 'co-treatment', of, 'MDBK', cells, with, 'WY-14,643', and, the, 'PPARα', antagonist, 'GW6471', blocks, the, 'WY-14,643-induced', increase, in, mRNA, and, protein, levels, of, 'OCTN2', in, bovine, cells])].
[sujeto(['In', 'addition,', treatment, of, 'MDBK', cells, with, 'WY-14,643']), verbo([stimulates]), complemento([specifically, 'Na(+)-dependent', carnitine, uptake, in, 'MDBK', 'cells,', which, is, likely, the, consequence, of, the, increased, carnitine, transport, capacity, of, cells, due, to, the, elevated, expression, of, 'OCTN2'])].
[sujeto(['In', 'conclusion,', our, results, indicate, that, 'OCTN2', expression, and, carnitine, transport, in, 'cattle,', as, in, 'rodents,', are]), verbo([regulated]), complemento([by, 'PPARα'])].
[sujeto(['Myc', is]), verbo([involved]), complemento([in, cell, 'growth,', 'proliferation,', 'apoptosis,', energy, 'metabolism,', and, differentiation])].
[sujeto(['Tamoxifen', administration]), verbo([induced]), complemento([recombination, of, 'Myc', specifically, in, hepatocytes, of, 'Myc(fl/fl,ERT2-Cre)', mice])].
[sujeto(['When', treated, with, a, known, hepatocellular, proliferative, stimulus, 'Wy-14,643,', 'Myc(fl/fl,ERT2-Cre)', mice, showed, a, lower, 'liver/body', weight, ratio, and]), verbo([suppressed]), complemento([hepatocyte, proliferation, as, compared, to, 'Myc(fl/fl)', mice])].
[sujeto(['Hepatic', expression, of, cell, cycle, control, 'genes,', 'DNA', repair, 'genes,', and, 'Myc']), verbo([target]), complemento([gene, miRNAs, were, upregulated, in, 'Wy-14,643-treated', 'Myc(fl/fl)', mouse, 'livers,', but, not, in, 'Wy-14,643-treated', 'Myc(fl/fl,ERT2-Cre)', livers])].
[sujeto(['However,', no, differences, were, observed, in, the, 'lipid-lowering', effect, of, 'Wy-14,643', between, 'Myc(fl/fl,ERT2-Cre)', and, 'Myc(fl/fl)', 'mice,', consistent, with, no, differences, in, the, expression, of, several, 'PPARα']), verbo([target]), complemento([genes, involved, in, fatty, acid, 'β-oxidation'])].
[sujeto(['In', the, 'liver,', the, key, subunit, of, the, 'Mediator', 'complex,', 'Med1,']), verbo([interacts]), complemento([with, several, nuclear, receptors, and, transcription, factors, to, direct, 'gene-specific', transcription])].
[sujeto(['Conditional', 'knock-out', of, 'Med1', in, the, liver, showed, that, hepatocytes, lacking, 'Med1', did, not, regenerate, following, either, partial, hepatectomy, or, treatment, with, certain]), verbo([nuclear]), complemento([receptor, activators, and, failed, to, give, rise, to, tumors, when, challenged, with, carcinogens])].
[sujeto(['We', now]), verbo([report]), complemento([that, the, adenovirally, driven, overexpression, of, 'Med1', in, mouse, liver, stimulates, hepatocyte, 'DNA', synthesis, with, enhanced, expression, of, 'DNA', 'replication,', cell, cycle, 'control,', and, 'liver-specific', 'genes,', indicating, that, 'Med1', alone, is, necessary, and, sufficient, for, liver, cell, proliferation])].
[sujeto(['Importantly,', we, demonstrate, that, 'AMP-activated', protein, kinase, '(', 'AMPK),', an, important, cellular, energy, 'sensor,']), verbo([interacts]), complemento(['with,', and, directly, 'phosphorylates,', 'Med1', in, vitro, at, serine, 656, ',', serine, 756, ',', and, serine, 796])].
[sujeto(['AMPK', also]), verbo([phosphorylates]), complemento(['Med1', in, vivo, in, mouse, liver, and, in, cultured, primary, hepatocytes, and, 'HEK293', and, 'HeLa', cells])].
[sujeto(['In', 'addition,', we, demonstrate, that, 'PPARα', activators]), verbo([increase]), complemento(['AMPK-mediated', 'Med1', phosphorylation, in, vivo])].
[sujeto(['Inhibition', of, 'AMPK', by, compound, 'C']), verbo([decreased]), complemento([hepatocyte, proliferation, induced, by, 'Med1', and, also, by, the, 'PPARα', activators, fenofibrate, and, 'Wy-14,643'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'Med1', phosphorylation, by, its, association, with, 'AMPK', regulates, liver, cell, proliferation, and, fatty, acid, 'oxidation,', most, likely, as, a, downstream, effector, of, 'PPARα', and, 'AMPK'])].
[sujeto(['Perfluorooctanoic', acid, '(', 'PFOA)', is, an, environmental, contaminant, known, to]), verbo([induce]), complemento([developmental, toxicity, in, animal, models, through, activation, of, the, peroxisome, 'proliferator-activated', receptor, α, '(', 'PPARα)'])].
[sujeto(['Previously,', it, was, demonstrated, that, in, ovo, exposure, to, 'PFOA']), verbo([induced]), complemento([cardiotoxicity, in, chicken, embryos, and, hatchlings])].
[sujeto(['Histologically,', unlike, 'PFOA,', 'WY', 14, ',', 643, did, not]), verbo([induce]), complemento([thinning, of, the, right, ventricular, wall])].
[sujeto(['Via', 'echocardiography,', 'however,', 'WY', 14, ',', 643]), verbo([induced]), complemento([effects, similar, to, those, of, 'PFOA,', including, increased, left, ventricular, wall, thickness, and, 'mass,', elevated, heart, 'rate,', ejection, 'fraction,', fractional, 'shortening,', and, decreased, stroke, volume])].
[sujeto(['Additionally,', to, investigate, mechanisms]), verbo([associated]), complemento([with, early, heart, 'development,', a, separate, group, of, fertile, chicken, eggs, was, injected, prior, to, incubation, with, 'PFOA', or, 'WY', 14, ',', 643, and, in, 'early-stage', 'embryos,', gene, expression, and, protein, concentration, associated, with, the, bone, morphogenic, protein, '(', 'BMP2)', pathway, were, determined])].
[sujeto([5, ',', and, 'GATA4', mRNA, in, early, embryos, was, altered, by, 'PFOA', 'exposure;', 'however,', protein, concentrations, of, these]), verbo([targets]), complemento([were, not, markedly, altered, by, either, 'PFOA', or, 'WY', 14, ',', 643])].
[sujeto(['Protein', levels, of, 'pSMAD1/5,', a, transcriptional, regulator]), verbo([stimulated]), complemento([by, 'BMPs,', were, altered, by, both, 'PFOA', and, 'WY', 14, ',', 643, ',', but, in, different, 'directions;', 'PFOA', reduced, cytoplasmic, 'pSMAD1/5,', whereas, 'WY', 14, ',', 643, decreased, nuclear, 'pSMAD1/5'])].
[sujeto(['Taken', 'together,', these, data]), verbo([suggest]), complemento([that, developmental, cardiotoxicity, induced, by, 'PFOA', likely, involves, both, 'PPARα', and, 'BMP2', pathways])].
[sujeto(['Growth']), verbo([arrest]), complemento([and, 'DNA', 'damage-inducible', beta, '(', 'GADD45b)', plays, an, important, role, in, many, intracellular, 'events,', such, as, cell, cycle, 'arrest,', 'DNA', 'repair,', cell, 'survival,', 'apoptosis,', and, senescence])].
[sujeto(['Gadd45b', messenger, 'RNA', '(', 'mRNA)', was, markedly]), verbo([induced]), complemento([by, the, 'PPARα', agonist, 'Wy-14,643', in, 'wild-type', mice, but, not, in, 'Ppara-null', mice])].
[sujeto(['Signal', transducer, and, activator, of, transcription, 3, '(', 'STAT3)', was]), verbo([found]), complemento([to, be, a, repressor, of, the, 'Gadd45b', gene, through, binding, to, upstream, regulatory, elements])].
[sujeto(['Wy-14,643', treatment]), verbo([stimulated]), complemento(['STAT3', ubiquitination, leading, to, activation, of, the, 'Gadd45b', gene, as, a, result, of, loss, of, 'Gadd45b', repression, by, 'STAT3'])].
[sujeto(['STAT3', degradation, was]), verbo([induced]), complemento([by, forced, overexpression, of, the, 'PPARα', target, 'gene-encoded', enzyme, 'ACOX1,', which, produces, increased, 'H(2)O(2)', as, a, byproduct, of, fatty, acid, 'β-oxidation'])].
[sujeto(['H(2)O(2)', also]), verbo([stimulated]), complemento([expression, of, 'Gadd45b', in, cultured, cells])].
[sujeto(['PPARα', indirectly]), verbo([induces]), complemento([the, 'Gadd45b', gene, in, liver, through, promoting, degradation, of, the, repressor, 'STAT3', as, a, result, of, elevated, oxidative, stress])].
[sujeto(['Although', mammalian, 'TRPM7', is, well, characterized, biophysically, and, its, pivotal, role, in, 'cancer,', ischemia, and, cardiovascular, disease, is, becoming, increasingly, 'evident,', the, study, of, 'TRPM7', in, mouse, models]), verbo([has]), complemento([been, hampered, by, embryonic, lethality, of, transgenic, ablations])].
[sujeto(['In', 'zebrafish,', functional]), verbo([loss]), complemento([of, 'TRPM7', '(', 'drTRPM7)', manifests, itself, in, an, array, of, 'non-lethal', physiological, malfunctions])].
[sujeto(['We']), verbo([find]), complemento([that, the, biophysical, properties, of, drTRPM7, are, very, similar, to, mammalian, 'TRPM7'])].
[sujeto(['However,', pharmacological, profiling]), verbo([reveals]), complemento([that, drTRPM7, is, facilitated, rather, than, inhibited, by, 2, -, 'APB,', and, that, the, 'TRPM7', inhibitor, waixenicin, 'A', has, no, effect])].
[sujeto(['Furthermore,', using, truncation, 'mutations,', we, show, that, the, 'coiled-coil', domain, of, drTRPM7, is]), verbo([involved]), complemento([in, the, 'channel\'s', regulation, by, magnesium, '(', 'Mg)', and, 'Mg·adenosine', triphosphate, '(', 'Mg·ATP)'])].
[sujeto(['We', propose, that, drTRPM7]), verbo([has]), complemento([two, protein, domains, that, regulate, inhibition, by, intracellular, magnesium, and, 'nucleotides,', and, one, domain, that, is, concerned, with, sensing, magnesium, only])].
[sujeto(['A', marked]), verbo([decrease]), complemento([in, blood, magnesium, in, the, group, of, patients, with, hypocalcemia, was, observed, when, compared, to, those, with, normal, calcemia, on, the, first, postoperative, day, '(', mean, variation, 'respectively,', 0.125, &, 'nbsp;± 0'])].
[sujeto(['Hypomagnesemia', is, significantly]), verbo([associated]), complemento([with, early, hypocalcemia, following, thyroidectomy])].
[sujeto(['Magnesium', is, an, important, micronutrient, essential, for, various, biological, processes, and, its, deficiency]), verbo([has]), complemento([been, linked, to, several, inflammatory, disorders, in, humans])].
[sujeto(['Some', anecdotal, evidence, and, a, few, published]), verbo([reports]), complemento([have, attributed, amelioration, of, inflammatory, skin, conditions, to, the, topical, application, of, magnesium])].
[sujeto(['Upon', topical, application, of, magnesium, 'solution,', we]), verbo([found]), complemento([that, magnesium, penetrates, through, human, stratum, corneum, and, it, depends, on, concentration, and, time, of, exposure])].
[sujeto(['We', also]), verbo([found]), complemento([that, hair, follicles, make, a, significant, contribution, to, magnesium, penetration])].
[sujeto(['The', crystal, structure]), verbo([has]), complemento([been, determined, of, the, 'F1-catalytic', domain, of, the, 'F-ATPase', from, 'Caldalkalibacillus', 'thermarum,', which, hydrolyzes, adenosine, triphosphate, '(', 'ATP)', poorly])].
[sujeto(['When', 'ATP', is, 'plentiful,', the, 'ε-subunit', assumes, a, &, 'quot;down"', 'state,', with, an, 'ATP', molecule]), verbo([bound]), complemento([to, its, two, 'C-terminal', 'α-helices;', when, 'ATP', is, 'scarce,', the, 'α-helices', are, proposed, to, inhibit, 'ATP', hydrolysis, by, assuming, an, &, 'quot;up"', 'state,', where, the, 'α-helices,', devoid, of, 'ATP,', enter, the, 'α3β3-catalytic', region])].
[sujeto(['However,', in, the, 'Escherichia', coli, 'enzyme,', there, is, no, evidence, that, such, 'ATP']), verbo([binding]), complemento([to, the, 'ε-subunit', is, mechanistically, important, for, modulating, the, 'enzyme\'s', hydrolytic, activity])].
[sujeto(['thermarum,', 'ATP', and, a, magnesium, ion, are]), verbo([bound]), complemento([to, the, 'α-helices', in, the, down, state])].
[sujeto(['In', a, form, with, a, mutated, 'ε-subunit', unable, to]), verbo([bind]), complemento(['ATP,', the, enzyme, remains, inactive, and, the, 'ε-subunit', is, down])].
[sujeto(['Therefore,', neither, the, 'γ-subunit', nor, the, regulatory, 'ATP']), verbo([bound]), complemento([to, the, 'ε-subunit', is, involved, in, the, inhibitory, mechanism, of, this, particular, enzyme])].
[sujeto(['These']), verbo([bound]), complemento([hydrolytic, products, are, likely, to, be, the, basis, of, inhibition, of, 'ATP', hydrolysis])].
[sujeto(['In', typical, nonlinear, plasma, protein]), verbo([binding]), complemento(['(', 'PPB)', 'behavior,', the, free, fraction, increases, with, increasing, total, concentrations])].
[sujeto(['In', 'contrast,', when, a, drug, exhibits, atypical, nonlinear, 'PPB', 'behavior,', the, free, fraction]), verbo([decreases]), complemento([with, increasing, total, concentrations])].
[sujeto(['The', saturation, of, ethylenediaminetetraacetic, acid, 'chelation,', by, addition, of, excessive, divalent, metal, 'ions,', such, as, calcium, and, 'magnesium,']), verbo([led]), complemento([to, the, return, of, the, atypical, nonlinear, 'PPB', behavior])].
[sujeto(['The', role, of, the, zinc, ion, in, 'HhoA', was, tested, in, an, in, vitro, proteolytic, assay, against, the, 'non-specific', substrate, 'β-casein', and, was]), verbo([found]), complemento([to, be, inhibitory])].
[sujeto(['Our', findings]), verbo([provide]), complemento([insights, into, the, regulation, of, 'HhoA', by, a, 'redox-related', mechanism, involving, methionine, residues, and, by, zinc, 'ion-binding', within, the, central, channel])].
[sujeto(['Magnesium', '(', 'Mg)']), verbo([has]), complemento([recently, received, increasing, attention, due, to, its, unique, biological, 'performance,', including, 'cytocompatibility,', antibacterial, and, biodegradable, properties])].
[sujeto(['The', electrochemical, 'test,', pH, 'value,', and, 'Mg', ion, concentration, data, show, that, the, corrosion, resistance, of, 'Mg', samples, is]), verbo([enhanced]), complemento([appreciably, after, surface, treatment])].
[sujeto(['Significantly']), verbo([increased]), complemento([cell, adhesion, and, viability, are, observed, from, the, coated, 'Mg', 'samples,', and, the, amounts, of, adherent, bacteria, on, the, treated, 'Mg', surfaces, diminish, remarkably, compared, to, the, bare, 'Mg'])].
[sujeto(['The', above, results]), verbo([suggested]), complemento([that, our, 'coatings,', which, effectively, enhance, the, 'biocompatibility,', antimicrobial, 'properties,', and, corrosion, resistance, of, 'Mg', 'substrate,', provide, a, simple, and, practical, strategy, to, expedite, clinical, acceptance, of, biodegradableMg, and, its, alloys])].
[sujeto(['Biomedical', 'Mg', metals]), verbo([have]), complemento([been, considered, as, promising, biodegradable, implants, because, of, their, intended, 'functions,', such, as, 'cytocompatibility,', 'antibacterial,', and, biodegradable, properties])].
[sujeto(['Alloying', and, surface, coatings]), verbo([have]), complemento([been, used, to, reduce, the, degradation, rate])].
[sujeto(['It']), verbo([suggested]), complemento([that, the, coating, materials, effectively, improved, the, 'biocompatibility,', antimicrobial, 'behavior,', and, corrosion, resistance, of, biomedical, 'Mg'])].
[sujeto(['As', the, content, of, 'PG']), verbo([increased]), complemento([from, 0, wt])].
[sujeto(['%', ',', the, compressive, strength, of, 'PG-BCP']), verbo([increased]), complemento([from, 0.02, 'MP', to, 0.28, 'MPa'])].
[sujeto(['%', ',', the, compressive, strength, of, 'PG-BCP', dramatically]), verbo([increased]), complemento([to, 5.66, 'MPa'])].
[sujeto(['Magnesium', '(', 'Mg)-based', alloys]), verbo([have]), complemento([been, extensively, considered, as, biodegradable, implant, materials, for, orthopedic, surgery])].
[sujeto(['Mg', and, its, alloys, are, metallic, biomaterials, that, can, degrade, in, the, body, and]), verbo([promote]), complemento([new, bone, formation])].
[sujeto(['After', 72, 'h,', cell, viability, and, proliferation]), verbo([increased]), complemento([in, the, cells, exposed, to, pure, 'Mg', and, 'Mg-2Zn-1Ca', extracts])].
[sujeto(['The']), verbo([release]), complemento([of, 'Mg,', 'Zn', and, 'Ca', ions, in, culture, media, had, no, toxic, impacts, on, 'ASCs', viability, and, proliferation])].
[sujeto(['Mg-2Zn-1Ca', alloy, can, be]), verbo([suggested]), complemento([as, a, good, candidate, to, be, used, in, biomedical, applications])].
[sujeto(['Advancing', the, use, of, therapeutic, nucleic, acids]), verbo([requires]), complemento([understanding, the, 'chem-', ical, and, structural, properties, which, allow, these, polymers, to, promote, the, death, of, malignant, cells])].
[sujeto(['Here', we, explore, 'Zn2+', complexation, by, the, fluoropyrimidine, polymer, 'F10,', which]), verbo([has]), complemento([strong, activities, in, multiple, 'pre-clinical', models, of, cancer])].
[sujeto(['Delivery', of, fluoropyrimidine, 'FdUMP', in, the, 10, -, residue, polymer, 'F10', rather, than, the, nucleobase, '(', 5, -, 'fluorouracil)', allows, consideration, of, metal, ion]), verbo([binding]), complemento([effects, on, drug, delivery])].
[sujeto(['Microsecond', 'time-scale,', 'all-atom,', simulations, of, 'F10', predict, that, zinc, selectively, stabilizes, 'F10', via, interactions, with, 'back-', bone, phosphate, groups, and]), verbo([suggests]), complemento([a, mechanism, of, complexation, for, the, 'zinc-base', interactions, shown, in, previous, experimental, work])].
[sujeto(['Once', the, 'Zn2+', ions, are, near, 'F10,', they]), verbo([cause]), complemento([the, 'base\'s', 'N3', nitrogen, to, deprotonate])].
[sujeto(['Subsequently,', magnesium, atoms, displace, zinc, from, their, interactions, with, 'phosphate,', freeing, the, zinc, ions, to]), verbo([interact]), complemento([with, the, 'FdU', bases, by, forming, weak, interactions, with, the, 'base\'s', 'O4', oxygen, and, the, fluorine, attached, to, 'C5'])].
[sujeto(['These', interactions, of, magnesium, with, phosphate, groups, and, zinc, with, nucleobases, agree, with, previous, experimental, result, and, are, seen, in, 'MD', simulations, only, when, magnesium, is, introduced, after, 'N3', deprotonation, -, indicating, a, specific, order, of, metal]), verbo([binding]), complemento([events])].
[sujeto(['By', comparison, to, 10, mers, of, polyU, and, 'polydT,', we, also, predict, that, the, presence, of, fluorine]), verbo([increases]), complemento([the, binding, affinity, of, zinc, to, 'F10', relative, to, analogous, strands, of, 'RNA', and, 'DNA', consisting, of, only, native, nucleotides])].
[sujeto(['Biodegradable', 'magnesium-based', alloys]), verbo([have]), complemento([shown, great, potential, for, medical, applications, due, to, their, superior, biological, performances, and, mechanical, properties])].
[sujeto(['However,', on, one, 'hand,', some, side, effects, including, inferior, 'biocompatibility,', a, local, 'high-alkaline', environment, and, gas, cavities]), verbo([caused]), complemento([by, a, rapid, corrosion, 'rate,', hinder, their, clinical, application])].
[sujeto(['A', modified, layer, with, a, thickness, of, approximately, 80, nm, is, formed, on, the, surface, of, 'AZ91', 'Mg', 'alloys,', and, the, hydrophobicity, and, roughness, of, these, 'AZ91', 'Mg', alloys, obviously]), verbo([increase]), complemento([after, 'Zr', and, 'N', implantation])].
[sujeto(['The', in, vitro, evaluations, including, corrosion, resistance, 'tests,', antimicrobial, tests, and, cytocompatibility, and, alkaline, phosphatase, '(', 'ALP)', activity, 'tests,', revealed, that, the, dual, ions, implantation, of, 'Zr', and, 'N', not, only]), verbo([enhanced]), complemento([the, corrosion, resistance, of, the, 'AZ91', 'Mg', alloy, but, also, provided, better, antimicrobial, properties, in, vitro])].
[sujeto(['Furthermore,', the, formation, of, biocompatible, metal, nitrides, and, metal, oxides, layer, in, the, near, surface, of, the, 'Zr-N-implanted', 'AZ91', 'Mg', alloy]), verbo([provided]), complemento([a, favorable, implantation, surface, for, cell, adhesion, and, 'growth,', which, in, return, further, promoted, the, bone, formation, in, vivo])].
[sujeto(['These', promising, results]), verbo([suggest]), complemento([that, the, 'Zr-N-implanted', 'AZ91', 'Mg', alloy, shows, potential, for, future, application, in, the, orthopedic, field])].
[sujeto(['The']), verbo([increase]), complemento([in, antibiotic, resistance, in, the, presence, of, the, ion, '(', 25, ')', 'Mg(2+)', was, discovered, in, 'E'])].
[sujeto([coli, cells, incubated, with, 'quinolones/fluoroquinolones,', indicating, the]), verbo([inhibiting]), complemento([effect, of, the, magnetic, moments, of, nuclei, '(', 25, ')', 'Mg', on, 'DNA', synthesis])].
[sujeto(['While', much, of, the, interest, and, application, of, 'beta-diketonate', complexes]), verbo([has]), complemento([focused, predominately, on, the, condensed, 'phases,', we, report, on, the, prevalence, of, 'gas-', phase, ligand, exchange, reactions, leading, to, the, formation, of, novel, species])].
[sujeto(['The', collision, cell, of, the, triple, quadrupole, mass, spectrometer, was, also, employed, to, examine, the, 'gas-phase', reactions, between, 'mass-selected', ions, and, specific, neutral]), verbo([target]), complemento([compounds])].
[sujeto(['The', 'gas-phase', mixed, ligand, products, of, '[', 'Mg(acac)(eeac)](+)', ',', '[', 'Cu(acac)(eeac)](+)', ',', '[', 'Mg(eeac)(tftm)](+)', ',', '[', 'Cu(eeac)(tftm)](+)', ',', '[', 'Mg(acac)(tftm)](+)', ',', and, '[', 'Mg(dbm)(tftm)](+)', were, formed, following, the, 'co-sublimation', of, 'hetero-metal', precursors, and, are]), verbo([reported]), complemento([herein, for, the, first, time])].
[sujeto(['Several', 'gas-phase', ligand, exchange, reactions, were, observed]), verbo([leading]), complemento([to, the, formation, of, both, mixed, and, complete, ligand, exchange, products])].
[sujeto(['An', improved, form, of, cold, cathode, ion, source]), verbo([has]), complemento([been, designed, and, constructed])].
[sujeto(['The', electrical, discharge, and, output, characteristics]), verbo([have]), complemento([been, measured, at, different, pressures, using, 'argon,', 'nitrogen,', and, oxygen, gases])].
[sujeto(['The', stable, discharge, current, and, maximum, output, ion, beam, current]), verbo([have]), complemento([been, obtained, using, grid, exit, aperture])].
[sujeto(['It', was]), verbo([found]), complemento([that, the, optimum, distance, between, ion, collector, plate, and, ion, exit, aperture, is, equal, to, 6.25, cm])].
[sujeto(['Dietary', calorie, restriction, is, a, broadly]), verbo([acting]), complemento([intervention, that, extends, the, lifespan, of, various, organisms, from, yeast, to, mammals])].
[sujeto(['Here,', we, show, that, 'Mg(2+),']), verbo([acting]), complemento([alone, or, in, response, to, dietary, calorie, 'restriction,', allows, eukaryotic, cells, to, combat, 'genome-destabilizing', and, 'lifespan-shortening', accumulations, of, 'RNA-DNA', 'hybrids,', or, 'R-loops'])].
[sujeto(['In', an, 'R-loop', accumulation, model, of, 'Pbp1-deficient', 'Saccharomyces', 'cerevisiae,', magnesium, ions, guided, by, cell, membrane, 'Mg(2+)', transporters, 'Alr1/2']), verbo([act]), complemento([via, 'Mg(2+)-sensitive', 'R-loop', suppressors, 'Rnh1/201', and, 'Pif1', to, restore, 'R-loop', 'suppression,', ribosomal, 'DNA', stability, and, cellular, lifespan])].
[sujeto(['Similarly,', human, cells, deficient, in, 'ATXN2,', the, human, ortholog, of, 'Pbp1,', exhibit]), verbo([nuclear]), complemento(['R-loop', accumulations, repressible, by, 'Mg(2+)', in, a, process, that, is, dependent, on, the, 'TRPM7', 'Mg(2+)', transporter, and, the, 'RNaseH1', 'R-loop', suppressor])].
[sujeto(['Thus,', we, identify, 'Mg(2+)', as, a, biochemical, signal, of, beneficial, calorie, 'restriction,']), verbo([reveal]), complemento([an, 'R-loop', suppressing, function, for, human, 'ATXN2', and, propose, that, practical, magnesium, supplementation, regimens, can, be, used, to, combat, 'R-loop', accumulation, linked, to, the, dysfunction, of, 'disease-linked', human, genes])].
[sujeto(['To', discriminate, against, abundant, 'competitors,', the, 'Nramp', 'metal-binding', site, should, favor, softer, transition, 'metals,', which]), verbo([interact]), complemento([either, covalently, or, ionically, with, coordinating, 'molecules,', over, hard, calcium, and, 'magnesium,', which, interact, mainly, ionically])].
[sujeto(['The', 'metal-binding', site, contains, an, 'unusual,', but, 'conserved,', 'methionine,', and, its, sulfur, coordinates, transition, metal, 'substrates,']), verbo([suggesting]), complemento([a, vital, role, in, their, transport])].
[sujeto(['Using', a, bacterial, 'Nramp', model, 'system,', we, show, 'that,', 'surprisingly,', this]), verbo([conserved]), complemento([methionine, is, dispensable, for, transport, of, the, physiological, manganese, substrate, and, similar, divalents, iron, and, 'cobalt,', with, several, small, amino, acid, replacements, still, enabling, robust, uptake])].
[sujeto(['Thus,', the, putative, evolutionary, pressure, to]), verbo([maintain]), complemento([the, 'Nramp', 'metal-binding', methionine, likely, exists, because, 'it-more', effectively, than, any, other, amino, 'acid-increases', selectivity, for, 'low-abundance', transition, metal, transport, in, the, presence, of, 'high-abundance', divalents, like, calcium, and, magnesium])].
[sujeto(['Treatment', of, chronic, osteomyelitis, '(', bone, 'infection)', remains, a, clinical, 'challenge;', in, 'particular,', it]), verbo([requires]), complemento([an, implantable, material, with, improved, antibacterial, activity])].
[sujeto(['We', evaluated, the, 'microstructures,', mechanical, 'properties,', corrosion, 'behavior,', and, ion]), verbo([release]), complemento([of, the, alloys, 'in vitro,', and, their, biocompatibility, and, antibacterial, activity, 'in vitro', and, 'in vivo'])].
[sujeto(['The', antibacterial, activity, of, the, 'Mg-Cu', alloys, 'in vitro', was, demonstrated, by, microbiological, counting, 'assays,', bacterial, viability, 'assays,', biofilm, formation, 'observations,', and, the, expression, of, 'biofilm,', 'virulence,', and, 'antibiotic-resistance']), verbo([associated]), complemento([genes])].
[sujeto(['RNA-dependent', 'RNA', polymerases, '(', 'RdRps)', are, used, by, 'RNA', viruses, to, replicate, and]), verbo([transcribe]), complemento([their, 'RNA', 'genomes(1)'])].
[sujeto(['They', adopt, a, 'closed,', 'right-handed', fold, with]), verbo([conserved]), complemento([subdomains, called, 'palm,', fingers, and, 'thumb(1,2)'])].
[sujeto(['Orthopedic', implants, containing, biodegradable, magnesium]), verbo([have]), complemento([been, used, for, fracture, repair, with, considerable, 'efficacy;', 'however,', the, underlying, mechanisms, by, which, these, implants, improve, fracture, healing, remain, elusive])].
[sujeto(['This', response, was, accompanied, by, substantial]), verbo([increases]), complemento([of, neuronal, calcitonin, 'gene-related', 'polypeptide-α', '(', 'CGRP)', in, both, the, peripheral, cortex, of, the, femur, and, the, ipsilateral, dorsal, root, ganglia, '(', 'DRG)'])].
[sujeto(['Overexpression', of, these, 'genes,', 'however,']), verbo([enhanced]), complemento(['magnesium-induced', osteogenesis])].
[sujeto(['We', further]), verbo([found]), complemento([that, an, elevation, of, extracellular, magnesium, induces, magnesium, transporter, 1, '(', 'MAGT1)-dependent', and, transient, receptor, potential, cation, 'channel,', subfamily, 'M,', member, 7, '(', 'TRPM7)-dependent', magnesium, 'entry,', as, well, as, an, increase, in, intracellular, adenosine, triphosphate, '(', 'ATP)', and, the, accumulation, of, terminal, synaptic, vesicles, in, isolated, rat, 'DRG', neurons])].
[sujeto(['In', isolated, rat, 'periosteum-derived', stem, 'cells,', 'CGRP']), verbo([induces]), complemento(['CALCRL-', and, 'RAMP1-dependent', activation, of, 'cAMP-responsive', element, binding, protein, 1, '(', 'CREB1)', and, 'SP7', '(', also, known, as, 'osterix),', and, thus, enhances, osteogenic, differentiation, of, these, stem, cells])].
[sujeto(['Furthermore,', we]), verbo([have]), complemento([developed, an, 'innovative,', 'magnesium-containing', intramedullary, nail, that, facilitates, femur, fracture, repair, in, rats, with, 'ovariectomy-induced', osteoporosis])].
[sujeto(['Taken', 'together,', these, findings]), verbo([reveal]), complemento([a, previously, undefined, role, of, magnesium, in, promoting, 'CGRP-mediated', osteogenic, 'differentiation,', which, suggests, the, therapeutic, potential, of, this, ion, in, orthopedics])].
[sujeto(['Magnesium', alloys]), verbo([have]), complemento([been, investigated, by, many, researchers, as, a, new, absorbable, biomaterial, owing, to, their, excellent, degradability, with, 'non-maleficence', or, 'low-maleficence', in, living, tissues])].
[sujeto(['To', clarify, the, factors]), verbo([causing]), complemento([the, negative, 'effects,', the, amount, of, eluted, metal, ions, and, pH, changes, in, the, medium, because, of, the, erosion, of, the, 'Magnesium', samples, were, 'investigated,', together, with, the, cytotoxicity, of, sole, metal, ions, corresponding, to, the, composition, of, the, metals])].
[sujeto(['It', was]), verbo([found]), complemento([that, 'Mg(2+),', 'Zn(2+),', and, 'Al(3+)', ions, were, less, toxic, at, the, investigated, 'concentrations,', and, that, these, factors, will, not, produce, negative, effects, on, cells])].
[sujeto(['Ethylation', of, kanamycin, 'B', at, the, 4, '″-position', entails, little]), verbo([loss]), complemento([of, antiribosomal, and, antibacterial, 'activity,', but, no, increase, of, ribosomal, selectivity])].
[sujeto(['These', results, are, contrasted, with, those, for, the, 4, ',', 5, -, 'aminoglycosides,', where, 4, '\'', -, 'O-alkylation', of, paromomycin]), verbo([causes]), complemento([only, a, minimal, loss, of, activity, but, results, in, a, significant, increase, in, selectivity, with, a, concomitant, loss, of, ototoxicity])].
[sujeto(['These', enzymes, are]), verbo([involved]), complemento([in, the, construction, of, the, characteristic, structural, motif, that, is, not, modified, by, 3, '\'', -, phosphotransferase, in, 'aminoglycoside-resistant', bacterial, strains])].
[sujeto(['In', the, present, 'study,', the, substrate, specificity, of, this, unique, combination, of, enzymes]), verbo([has]), complemento([been, investigated])].
[sujeto(['AprD4', was]), verbo([found]), complemento([to, recognize, 'paromamine,', 'neamine,', kanamycin, 'C,', and, kanamycin, 'B', to, afford, 5, '\'', -, deoxyadenosine, as, one, of, products, during, the, 'C3\'-dehydration', of, 'aminoglycosides,', but, not, 2, '\'', -, 'N-acetylparomamine', and, paromomycin])].
[sujeto(['AprD3']), verbo([recognizes]), complemento([the, 4, '\'', -, oxolividamine, 'moiety,', including, the, pseudotrisaccharide, kanamycin, 'C,', and, seems, to, reject, the, amino, group, at, 'C6\'', of, neamine, and, kanamycin, 'B'])].
[sujeto(['It', is, challenging, to]), verbo([find]), complemento(['safe,', nonscarring, and, noninvasive, treatment, of, facial, cutaneous, leishmaniasis, '(', 'CL)', in, children])].
[sujeto(['Herein,', we]), verbo([report]), complemento([a, child, with, 'CL', from, a, region, endemic, for, 'Leishmania', 'tropica,', whose, lesion, persisted, after, treatment, with, oral, fluconazole, but, responded, to, topical, paromomycin])].
[sujeto(['Fexinidazole', and, 'PA-824', are, new, promising, drugs, which]), verbo([have]), complemento([shown, encouraging, results, in, preclinical, studies])].
[sujeto(['In', this, 'study,', we, developed, a, simple, colorimetric, 'paper-based', biosensor, based, on, a, novel, principle, for, the, detection, of, antibiotics]), verbo([inhibiting]), complemento([bacterial, protein, 'synthesis,', including, 'aminoglycosides,', 'tetracycline,', 'chloramphenicol,', and, macrolides])].
[sujeto(['This', biosensor, is, based, on, the, detection, of, a, color, change]), verbo([induced]), complemento([by, 'β-galactosidase,', which, is, synthesized, on, 'freeze-dried', paper, discs, containing, an, 'in vitro', 'transcription/translation', system])].
[sujeto(['Globally,', mRNA, transfection, profile, was, well, corroborative, with, cytoplasmic, transfection, of, 'pT7-pDNA', as, well, as, with]), verbo([nuclear]), complemento([transfection, of, 'pCMV-DNA'])].
[sujeto(['Furthermore,', a, significant, enhancement, in, the, 'TE', in, the, presence, of, an, excess, of, 'His-lPEI', was, observed, indicating, that, this, polymer]), verbo([promotes]), complemento([cytosolic, delivery])].
[sujeto(['This', study, gives, an, insight, 'that,', whether, with, mRNA, or, 'pDNA,']), verbo([enhancing]), complemento([nanoplex, unpacking, in, the, endosomes, and, cytosol, would, improve, the, delivery, of, nucleic, acid, in, the, cytosol, and, particularly, in, the, case, of, pDNA, where, a, sufficient, available, amount, of, pDNA, in, the, cytoplasm, would, definitely, improve, its, transport, toward, the, nucleus])].
[sujeto(['The', development, of, effective, drug, carriers, can]), verbo([lead]), complemento([to, improved, outcomes, in, a, variety, of, disease, conditions])].
[sujeto(['Aminoglycosides']), verbo([have]), complemento([been, used, as, antibacterial, 'therapeutics,', and, are, attractive, as, monomers, for, the, development, of, polymeric, materials, in, various, applications])].
[sujeto(['The', aminoglycoside, paromomycin, was, first, 'cross-linked', with, resorcinol, diglycidyl, ether]), verbo([leading]), complemento([to, the, formation, of, a, poly, '(', amino, 'ether),', 'PAE'])].
[sujeto(['Cell-based', studies, indicated, that, 'mPEG-PAE', 'nanoparticles,', loaded, with, 'doxorubicin,', were, able, to]), verbo([induce]), complemento([significant, loss, in, viabilities, of, 'PC3', human, prostate, 'cancer,', 'MDA-MB-231', human, breast, 'cancer,', and, 'MB49', murine, bladder, cancer, 'cells;', empty, nanoparticles, resulted, in, negligible, losses, of, cell, viability, under, the, conditions, investigated])].
[sujeto(['The']), verbo([binding]), complemento([of, neomycin, sulfate, '(', 'NS)/paromomycin', sulfate, '(', 'PS)', with, 'DNA', was, investigated, by, fluorescence, quenching, using, acridine, orange, '(', 'AO)', as, a, fluorescence, probe])].
[sujeto(['Fluorescence', 'lifetime,', 'FT-IR,', circular, dichroism, '(', 'CD),', relative, 'viscosity,', ionic, 'strength,', 'DNA', melting, 'temperature,', and, molecular, docking, were, performed, to, explore, the]), verbo([binding]), complemento([mechanism])].
[sujeto(['The']), verbo([binding]), complemento([constant, of, 'NS/PS', and, 'DNA', was, 6.7, &, 'nbsp;× 10(3)/1'])].
[sujeto(['The', values, of, 'ΔH(θ),', 'ΔS(θ),', and, 'ΔG(θ)']), verbo([suggested]), complemento([that, van, der, 'Waals', force, or, hydrogen, bond, might, be, the, main, binding, force, between, 'NS/PS', and, 'DNA'])].
[sujeto(['The', fluorescence, intensity, of, 'NS/PS-DNA-AO', was]), verbo([decreased]), complemento([with, the, increase, in, the, ionic, strength])].
[sujeto(['For', 'CD', spectra, of, 'DNA,', the, intensity, of, positive, band, at, nearly, 275, &, 'nbsp;nm', was]), verbo([decreased]), complemento([and, that, of, negative, band, at, nearly, 245, &, 'nbsp;nm', was, increased, with, the, increase, in, the, concentration, of, 'NS/PS'])].
[sujeto(['The']), verbo([binding]), complemento([constant, of, 'NS/PS', with, 'double-stranded', 'DNA', '(', 'dsDNA)', was, larger, than, that, of, 'NS/PS', with, 'single-stranded', 'DNA', '(', 'ssDNA)'])].
[sujeto(['From', these, 'studies,', the]), verbo([binding]), complemento([mode, of, 'NS/PS', with, 'DNA', was, evaluated, to, be, groove, binding])].
[sujeto(['This', pathogen, is]), verbo([associated]), complemento([with, gastrointestinal, illness, in, humans, and, animals])].
[sujeto(['Microparticle', formulations, were, characterized, in, terms, of, 'size,', surface, 'charge,', drug]), verbo([release]), complemento([and, morphology])].
[sujeto(['This']), verbo([finding]), complemento([was, crucial, taking, use, of, the, fact, that, the, parasite, multiplication, occurs, between, 16, and, 20, h, 'post-infection'])].
[sujeto(['Ultrastructural', observations, by, 'TEM', bring, to, light, the, uptake, of, smallest, particles, by, enterocytes]), verbo([associated]), complemento([with, conspicuous, changes, in, enterocytic, cells])].
[sujeto(['The', distinctive, features, of, neonatal, mice]), verbo([requires]), complemento([further, work, to, determine, the, suppressive, effect, of, this, particulate, delivery, system, on, 'C'])].
[sujeto(['Visceral', leishmaniasis, '(', 'VL)']), verbo([caused]), complemento([by, the, protozoan, parasite, 'Leishmania', 'infantum,', is, one, of, the, most, important, zoonotic, diseases, affecting, dogs, and, humans, in, the, 'Mediterranean', area])].
[sujeto(['We']), verbo([have]), complemento([studied, the, susceptibility, profile, to, antimony, and, other, 'anti-leishmania', drugs, '(', amphotericin, 'B,', 'miltefosine,', 'paromomycin)', in, 'Leishmania', infantum, isolates, extracted, from, a, dog, before, and, after, two, therapeutic, interventions, with, meglumine, antimoniate, '(', subcutaneous, 'Glucantime(®),', 100, &, 'nbsp;mg/kg/day', for, 28, 'days)'])].
[sujeto([infantum, line, is, related, to, a]), verbo([decreased]), complemento([antimony, uptake, due, to, lower, 'aquaglyceroporin-1', expression, levels])].
[sujeto(['Additionally,', other, mechanisms, including, an]), verbo([increase]), complemento([in, thiols, and, overexpression, of, enzymes, involved, in, thiol, 'metabolism,', such, as, ornithine, 'decarboxylase,', trypanothione, 'reductase,', mitochondrial, tryparedoxin, and, mitochondrial, tryparedoxin, 'peroxidase,', could, contribute, to, the, resistance, as, antimony, detoxification, mechanisms])].
[sujeto([infantum, isolate, is, to]), verbo([find]), complemento([an, 'antimony-resistant', mechanism, similar, to, that, previously, described, in, other, human, clinical, isolates])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([that, 'paromomycin,', an, antibiotic, derived, from, the, 'Streptomyces', sp])].
[sujeto(['AG-P', 1441, '(', 'AG-P', 1441, ')', controlled, 'Phytophthora', blight, and, soft, rot, diseases]), verbo([caused]), complemento([by, 'Phytophthora', capsici, and, 'Pectobacterium', 'carotovorum,', 'respectively,', in, chili, pepper, '(', 'Capsicum', annum, 'L'])].
[sujeto(['Furthermore,', the, treatment, slightly]), verbo([promoted]), complemento(['growth;', this, growth, was, supported, by, increased, chlorophyll, content, in, 'paromomycin-treated', chili, pepper, plants])].
[sujeto(['Additionally,', paromomycin, likely]), verbo([induced]), complemento([resistance, as, confirmed, by, the, expression, of, 'pathogenesis-related', '(', 'PR)', 'genes:', 'PR-1,', 'β-1,3-glucanase,', 'chitinase,', 'PR4,', 'peroxidase,', and, 'PR-10,', which, enhanced, plant, defense, against, 'P'])].
[sujeto(['This']), verbo([finding]), complemento([indicates, that, 'AG-P', 1441, plays, a, role, in, pathogen, resistance, upon, the, activation, of, defense, 'genes,', by, secretion, of, the, plant, resistance, 'elicitor,', paromomycin])].
[sujeto(['Agrobacterium-mediated', transformation, of, 'Brachypodium']), verbo([has]), complemento([relied, mainly, on, 'Agrobacterium', tumefaciens, strain, 'AGL1'])].
[sujeto(['Currently', the, antibiotic, hygromycin, 'B']), verbo([has]), complemento([been, the, selective, agent, of, choice, for, robust, identification, of, transgenic, calli, in, 'Brachypodium', distachyon, and, 'Brachypodium', sylvaticum, but, few, other, chemicals, have, been, shown, to, work, as, well, for, selection, of, transgenic, 'Brachypodium', cells, in, tissue, culture])].
[sujeto([distachyon, which, were, created, using, hygromycin, 'selection,', as, well, as, aid, the, implementation, of, more, complex, genome, manipulation, strategies, which]), verbo([require]), complemento([multiple, rounds, of, transformation])].
[sujeto(['In', 2015, ',', four, newly, developed, active, pharmaceutical, ingredients, for, horses, and, 'food-producing', animals, were]), verbo([released]), complemento([on, the, 'German', market, for, veterinary, drug, products])].
[sujeto(['Furthermore,', three, veterinary, drugs, with, a, new, formulation, as, well, as, one, product, with, a, new, strength, and, two, products, with, a, new, combination, of, active, pharmaceutical, ingredients]), verbo([have]), complemento([been, launched])].
[sujeto(['Leishmaniasis']), verbo([caused]), complemento([by, protozoan, parasites, of, the, genus, 'Leishmania'])].
[sujeto(['Moreover,', most, of, the, current, drugs, are, confined, to, some, toxic, 'compounds,', and, there, are]), verbo([increasing]), complemento([incidences, of, development, of, drug, resistance])].
[sujeto(['Innovative', strategies, are, needed, to, accelerate, the, identification, of, antimicrobial, drug]), verbo([targets]), complemento([and, resistance, mechanisms])].
[sujeto(['Functional', validation, highlighted, both, known, and, previously, unidentified, drug]), verbo([targets]), complemento([and, resistance, 'genes,', including, novel, roles, for, phosphatases, in, resistance, to, methotrexate, and, 'antimony,', for, ergosterol, and, phospholipid, metabolism, genes, in, resistance, to, 'miltefosine,', and, for, hypothetical, proteins, in, resistance, to, 'paromomycin,', amphothericin, 'B,', and, pentamidine])].
[sujeto(['Several', 'genes/loci', were, also]), verbo([found]), complemento([to, confer, resistance, to, two, or, more, antileishmanials])].
[sujeto(['This', screening, method, will, expedite, the, discovery, of, drug]), verbo([targets]), complemento([and, resistance, mechanisms, and, is, easily, adaptable, to, other, microorganisms])].
[sujeto(['Although', miltefosine, and, paromomycin, were, only, recently, introduced, to, treat, visceral, 'leishmaniasis,']), verbo([increasing]), complemento([numbers, of, miltefosine, treatment, failures, and, occasional, primary, resistance, to, both, drugs, have, been, reported])].
[sujeto(['Understanding', alterations, in, parasite, behaviour, linked, to, drug, resistance, is, essential, to, assess, the, propensity, for, emergence, and, spread, of, resistant, 'strains,', particularly, since, a, positive, effect, on, fitness]), verbo([has]), complemento([been, reported, for, 'antimony-resistant', parasites])].
[sujeto(['No', significant, differences, in, promastigote, fitness, were, noted, between, the, 'WT', and, 'paromomycin-resistant', 'strain,', while, clear, benefits, could, be, demonstrated, for, 'paromomycin-resistant', amastigotes, in, terms, of]), verbo([enhanced]), complemento([in, vitro, and, in, vivo, growth, potential, and, intracellular, stress, response])].
[sujeto(['The', 'miltefosine-resistant', phenotype, showed, incomplete, promastigote, 'metacyclogenesis,']), verbo([decreased]), complemento([intracellular, growth, and, weakened, stress, 'response,', revealing, a, reduced, fitness, compared, with, 'WT', parent, parasites])].
[sujeto(['Although', a, reduced, fitness, of, 'miltefosine-resistant', strains, may, explain, the, difficulty, of, miltefosine, resistance, selection, in, 'vitro,', the, growing, number, of, miltefosine, treatment, failures, in, the, field, still]), verbo([requires]), complemento([further, exploratory, research])].
[sujeto(['Potentiation', was, absent, in, a, mutant, lacking, the, 'AmgRS', envelope, stress, response, 'two-component', system, '(', 'TCS),', which, protects, the, organism, from, 'AG-generated', 'membrane-damaging', aberrant, polypeptides, 'and,', 'thus,']), verbo([promotes]), complemento(['AG', 'resistance,', an, indication, that, 'RIF', was, acting, via, this, 'TCS', in, potentiating, 4, ',', 5, -, linked, 'AG', activity])].
[sujeto(['PAR-inducible', expression, of, the, 'AmgRS-dependent', genes, htpX, and, yccA, was, reduced, by, 'RIF,']), verbo([suggesting]), complemento([that, 'AG', activation, of, this, 'TCS', was, compromised, by, this, agent])].
[sujeto(['These', cases, 'were,', in, one, 'instance,', explained, by, an, observed, 'AmgRS-dependent', expression, of, the, 'MexXY', multidrug, efflux, 'system,', which, accommodates, a, range, of, 'AGs,', with, 'RIF']), verbo([targeting]), complemento([of, 'AmgRS', undermining, mexXY, expression, and, its, promotion, of, resistance, to, 4, ',', 5, -, and, 4, ',', 6, -, linked, 'AGs'])].
[sujeto(['Leishmaniasis', is, a, parasitic, disease, transmitted, through, the, bite, of, an, infected, phlebotomine, sand, fly, and]), verbo([caused]), complemento([by, protozoan, parasites, of, the, genus, 'Leishmania'])].
[sujeto(['Most', of, available, drugs, are, confined, to, a, limited, number, of, toxic, chemical, 'compounds,', which, some, parasite, strains]), verbo([have]), complemento([evolved, drug, resistance, against])].
[sujeto(['To', do, 'so,', the]), verbo([increase]), complemento([in, footpad, thickness, was, measured, and, 'real-time', 'PCR', was, performed, to, quantify, the, parasite, load, after, infectious, challenge])].
[sujeto(['Altogether,', the, results, show, that, 'PM', loaded, into, 'SLN', is, significantly, more, effective, than, 'PM', alone, in]), verbo([inhibiting]), complemento([the, parasite, propagation, and, switching, towards, 'Th1', response])].
[sujeto(['Inclusion', of, 'PL', in, 'HPBCD', nanoparticles, resulted, in, 10, -, fold, and, 4, -, 10, -, fold]), verbo([increase]), complemento([in, selectivity, indexes, '(', 'CC50/IC50)', for, 'wild-type', and, drug, resistant, 'strains,', respectively])].
[sujeto(['Leishmania', aethiopica, is, the, etiological, agent, of, cutaneous, leishmaniasis, '(', 'CL)', in, 'Ethiopia', and, can]), verbo([cause]), complemento([severe, and, complicated, cases, such, as, diffuse, 'CL', '(', 'DCL),', mucocutaneous, leishmaniasis, or, extensive, 'CL,', requiring, systemic, treatment])].
[sujeto(['We', conducted, a, systematic, review, of, clinical, studies]), verbo([reporting]), complemento([on, treatment, outcomes, of, 'CL', due, to, 'L', aethiopica, in, order, to, help, identify, potentially, efficacious, medications, on, 'CL', that, can, be, taken, forward, for, clinical, trials])].
[sujeto(['We', identified, a, total, of, 24, records]), verbo([reporting]), complemento([on, 506, treatment, episodes, of, 'CL', presumably, due, to, 'L', aethiopica])].
[sujeto(['There', were, two, prospective, 'non-randomized', studies]), verbo([reporting]), complemento([on, 'cryotherapy,', antimonials, and, pentamidine])].
[sujeto(['The', only, potentially, effective, treatment, options, for, 'DCL', seem, to, be, antimonials, with, paromomycin, in, combination, or, 'pentamidine,', but, none]), verbo([have]), complemento([been, properly, evaluated])].
[sujeto(['Increasing', the, steric, bulk, in, 'RZn(+)', to, 'R=CH2', 'CMe3', ',', 'CH2', 'SiMe3', ',', or, 'Cp*,', thus, attempting, to]), verbo([induce]), complemento(['ionization,', failed, and, led, only, to, reaction, mixtures, including, anion, decomposition])].
[sujeto(['These', stable, materials]), verbo([have]), complemento([further, applications, 'as,', for, 'example,', initiators, of, isobutene, polymerization])].
[sujeto(['Here', we]), verbo([report]), complemento([the, application, of, nonstoichiometric, 'ZnMn2O4/carbon', composite, as, a, new, 'Zn-insertion', cathode, material, in, aqueous, 'Zn(CF3SO3)2', electrolyte])].
[sujeto(['In', 3, 'M', 'Zn(CF3SO3)2', solution, that, enables, '~100%', 'Zn', 'plating/stripping', efficiency, with, 'long-term', stability, and]), verbo([suppresses]), complemento(['Mn', 'dissolution,', the, 'spinel/carbon', hybrid, exhibits, a, reversible, capacity, of, 150, mAh, 'g-1', and, a, capacity, retention, of, 94, '%', over, 500, cycles, at, a, high, rate, of, 500, mA, 'g-1'])].
[sujeto(['The', results, would, enlighten, and]), verbo([promote]), complemento([the, use, of, 'cation-defective', spinel, compounds, and, trifluoromethanesulfonic, electrolyte, to, develop, 'high-performance', rechargeable, zinc, batteries])].
[sujeto(['We']), verbo([report]), complemento([a, study, of, a, series, of, isoquinoline, 'derivatives,', including, their, 'synthesis,', in, vitro, microsomal, leucine, aminopeptidase, '(', 'LAP)', inhibition, and, antiproliferative, activity, on, cancer, cell, lines])].
[sujeto(['Among', fourteen, tested, 'compounds,', one, '(', compound, 3, 'b)', was, determined, to]), verbo([have]), complemento([good, activity, against, 'LAP', and, significant, antiproliferative, activity, against, 'HL-60', human, promyelocytic, 'leukemia,', 'Burkitt\'s', lymphoma, 'Raji,', camptothecin, resistant, 'CEM/C2', leukemia, cells, with, mutated, catalytic, site, of, topoisomerase, 'I,', its, parental, cell, line, 'CCRF/CEM', and, 'LoVo', colon, cancer])].
[sujeto(['Moreover,', we]), verbo([have]), complemento([confirmed, that, antiproliferative, activity, towards, cancer, cells, is, due, to, 'LAP', inhibition])].
[sujeto(['Docking', simulation, based, on, positioning, compound, 3, b, into, the, 'LAP', active, site, was, performed, to, explore, the, possible]), verbo([binding]), complemento([mode])].
[sujeto(['The', compound, was, able, to, form, hydrogen, bonds, with, 'Gly362', and, coordinate, zinc, 'ions,', which, was, previously]), verbo([suggested]), complemento([to, be, essential, for, inhibitory, activity])].
[sujeto(['Toxicological', studies]), verbo([involving]), complemento([examination, of, skin, 'sensitization,', acute, skin, 'irritation/corrosion,', acute, dermal, 'toxicity,', acute, oral, toxicity, and, acute, eye, 'irritation/corrosion', established, that, compound, 3, b, is, safe, for, use])].
[sujeto(['Titanium', implant, surfaces]), verbo([have]), complemento([been, modified, to, improve, 'osseointegration;', 'however,', the, evidence, for, incorporating, zinc, into, titanium, implants, to, improve, new, bone, formation, and, osseointegration, is, not, clear])].
[sujeto(['The', results, from, all, studies, showed, that, incorporating, zinc, into, titanium, implants]), verbo([enhanced]), complemento([new, bone, formation, 'and/or', 'bone-to-implant', contact, around, implants])].
[sujeto(['One', study]), verbo([reported]), complemento([that, zinc, enhanced, the, removal, torque, on, implants])].
[sujeto(['The', current, available, evidence, on, adding, zinc, to, titanium, implants, surfaces, to]), verbo([enhance]), complemento([osseointegration, remains, unclear])].
[sujeto(['Phosphate-based', glasses]), verbo([have]), complemento([been, examined, in, many, studies, as, a, potential, biomaterial, for, bone, repair, because, of, its, degradation, 'properties,', which, can, be, controlled, and, allow, the, release, of, various, elements, to, promote, osteogenic, tissue, growth])].
[sujeto(['This', study, investigated, a, qinternary, system, that, included, titanium, dioxide, for, degradation, rate, control, and, zinc, that, is, considered, to]), verbo([have]), complemento([a, role, in, bone, formation])].
[sujeto(['The', results, showed, that, the, glass, was, amorphous, and, that, the, all, thermal, variables]), verbo([decreased]), complemento([as, zinc, oxide, amount, 'raised,', mass, loss, as, well, as, ion, release, increased, as, zinc, oxide, 'increased,', and, the, maximum, rise, was, with, 'ZnO15'])].
[sujeto(['In', 'conclusion,', replacing, calcium, oxide, with, zinc, oxide, in, proportion, less, than, 10, '%', can]), verbo([have]), complemento([a, positive, effect, on, bone, forming, cells])].
[sujeto(['Phenanthroline', '(', 'PhN)', is, an, 'inexpensive,', 'broad-spectrum', inhibitor, of, metalloproteinases, that, functions, by, chelating, the, catalytic, zinc, 'ion,', however, its, use, in, vivo]), verbo([has]), complemento([been, limited, due, to, suspected, 'off-target', effects])].
[sujeto(['PhN', is, very, similar, in, structure, to, phenanthrene, '(', 'PhE),', a, 'well-studied', poly, aromatic, hydrocarbon, '(', 'PAH)', known, to]), verbo([cause]), complemento([toxicity, in, aquatic, animals, by, activating, the, aryl, hydrocarbon, receptor, '(', 'AhR)'])].
[sujeto(['We', show, that, zebrafish, are, more, sensitive, to, 'PhN', than, 'PhE,', and, that, 'PhN']), verbo([causes]), complemento([a, superset, of, the, effects, caused, by, 'PhE'])].
[sujeto(['Morpholino', 'knock-down', of, the, 'AhR', rescues, the, effects, of, 'PhN', that, are, shared, with, 'PhE,']), verbo([suggesting]), complemento([these, are, due, to, 'PAH', toxicity])].
[sujeto(['The', effects, of, 'PhN', that, are, not, shared, with, 'PhE', '(', specifically, disruption, of, neural, crest, development, and, 'angiogenesis)']), verbo([involve]), complemento([processes, known, to, depend, on, metalloproteinase, activity])].
[sujeto(['Furthermore', these, 'PhN-specific', effects, are, not, rescued, by, 'AhR', 'knock-down,']), verbo([suggesting]), complemento([that, these, are, bona, fide, effects, of, metalloproteinase, 'inhibition,', and, that, 'PhN', can, be, used, as, a, broad, spectrum, metalloproteinase, inhibitor, for, studies, with, zebrafish, in, vivo])].
[sujeto(['We', developed, a, '\'', conditional, 'proteomics\'', approach, to, identify, proteins]), verbo([involved]), complemento([in, zinc, homeostasis, based, on, a, chemical, proteomic, strategy, that, utilizes, designer, 'zinc-responsive', labeling, reagents, to, tag, such, proteins, and, quantitative, mass, spectrometry, for, their, identification])].
[sujeto(['We', used, this, method, to, elucidate, zinc, dyshomeostasis]), verbo([induced]), complemento([by, 'nitric-oxide-triggered', oxidative, stress, in, glioma, 'cells,', and, we, unveiled, dynamic, changes, of, the, 'zinc-related', proteomes])].
[sujeto(['Amyloid-associated', metal, 'ions,', particularly, zinc, and, copper, 'ions,']), verbo([have]), complemento([been, implicated, in, disease, pathogenesis])].
[sujeto(['Despite', the, importance, of, such, 'ions,', the]), verbo([binding]), complemento([sites, on, the, 'β-amyloid', peptide, remain, poorly, understood])].
[sujeto(['In', this, 'study,', we, use, scanning, tunneling, 'microscopy,', circular, 'dichroism,', and, 'surface-enhanced', 'Raman', spectroscopy, to, probe, the, interactions, between, 'Cu2+', ions, and, a, key, 'β-amyloid', peptide, 'fragment,', consisting, of, the, first, 16, amino, 'acids,', and, define, the, 'copper-peptide']), verbo([binding]), complemento([site])].
[sujeto(['By', imaging, with, scanning, tunneling, 'microscopy,', we, are, able, to, identify, the]), verbo([binding]), complemento(['site,', which, involves, two, histidine, 'residues,', 'His13', and, 'His14'])].
[sujeto(['We', conclude, that, the]), verbo([binding]), complemento([of, copper, to, these, residues, creates, an, 'inter-strand', histidine, 'brace,', which, enables, the, formation, of, 'β-sheets'])].
[sujeto(['Exfoliation', of, sepiolite, nanofibers]), verbo([led]), complemento([to, the, homogeneous, dispersion, of, 'Zinc', in, the, form, of, 'Zn(OH)2', in, chitosan, matrix])].
[sujeto(['Through', zone, of, 'inhibition,', the, silica, nanocomposite, was, discovered, to]), verbo([have]), complemento([antibacterial, activity])].
[sujeto(['We', thus, hypothesize, that, 'HO', 'radicals,', formed, during, ultrasonic, irradiation]), verbo([trigger]), complemento([the, formation, of, a, silicate, ion, '(', 'SiO3(2-))', and, formation, of, 'ZnO', and, 'Zn2SiO3(OH)2', species, in, 'chitosan/silica/ZnO', 'bio-nanocomposite,', which, causes, to, exhibit, these, antibacterial, properties, against, 'Gram-negative', 'E'])].
[sujeto(['In', this, 'study,', we, investigated, the, interactions, among, 'ZnO', 'NPs,']), verbo([released]), complemento([chemicals, '(', 'Zn(2+)', and, 'Reactive', 'Oxygen', 'Species,', 'ROS)', and, 'Escherichia', coli, '(', 'E'])].
[sujeto(['The', results, of, the, leakage, of, intracellular, 'K(+)', and, integrity, of, carboxyfluoresce, 'in-filled', liposomes, showed, that, 'ZnO', 'NPs']), verbo([have]), complemento([antimicrobial, activity, against, 'E'])].
[sujeto(['Traces', of, zinc, ions, '(', 1.25, 'mg/L)', and, hydrogen, peroxide, '(', from, 1.25, to, 4.5, 'μM/L)', were, detected, in, 'ZnO', 'NPs', 'suspensions,', but, was, insufficient, to]), verbo([cause]), complemento([the, antibacterial, effect])].
[sujeto(['However,', the, addition, of, radical, scavengers]), verbo([suppressed]), complemento([the, bactericidal, effect, of, 'ZnO', coated, films, against, 'E'])].
[sujeto(['The', ionic, liquid]), verbo([induced]), complemento([copolymer, was, coated, on, a, commercially, available, 'PP', membrane, '(', 'Celguard', 5550, ')'])].
[sujeto(['In', our, 'charge/discharge', 'setup,', the, constructed, cell, with, the, ionic, liquid]), verbo([induced]), complemento([copolymer, casted, separator, exhibited, drastically, improved, durability, as, the, battery, life, increased, more, than, 281, '%', compared, to, the, pure, commercial, 'PP', membrane])].
[sujeto(['Achieving', structurally, 'well-defined', catalytic, species]), verbo([requires]), complemento([fundamental, understanding, of, surface, chemistry])].
[sujeto(['Detailed,', structural, characterization, of, the, catalyst]), verbo([binding]), complemento([sites, in, 'situ,', such, as, single, site, catalysts, on, silica, 'supports,', is, technically, challenging, or, even, unattainable])].
[sujeto(['Octadecyltrioxysilane', '(', 'OTOS)', monolayers, formed, from, octadecyltrimethoxysilane, '(', 'OTMS)', at, the, 'air-liquid', interface, after, hydrolysis, and, condensation, at, low, 'pH,', were, chosen, as, a, model, system, of, surface]), verbo([binding]), complemento([sites, in, silica, supported, 'Zn(2+)', catalysts])].
[sujeto(['We']), verbo([suggest]), complemento([an, alternative, mechanism, of, 'hydrolysis/condensation', in, 'OTMS', leading, to, formation, of, structurally, allowed, cyclic, trimers, with, the, 'six-membered', siloxane, 'rings,', which, explain, well, both, 'X-ray', and, infrared, results])].
[sujeto(['XR', and, 'XFS', consistently, demonstrate, that, tetrahedral, '[', 'Zn(NH3)4](2+)', ions]), verbo([bind]), complemento([to, hydroxyl, groups, of, the, film, at, a, stoichiometric, ratio, of, 'OTOS', :, 'Zn', ~, 2, :, 1])].
[sujeto(['The', high]), verbo([binding]), complemento([affinity, of, zinc, ions, to, 'OTOS', trimers, suggests, that, the, 'six-membered', siloxane, rings, are, binding, locations, for, single, site, 'Zn/SiO2', catalysts])].
[sujeto(['Furthermore,', the, amindoximes]), verbo([arrested]), complemento(['HCT116', and, 'A549', cells, in, 'G2/M', phase, and, showed, good, efficacy, in, inducing, cells, death])].
[sujeto(['We']), verbo([provided]), complemento([a, 'proof-of-concept', that, amindoximes, could, be, used, as, 'HDACs', inhibitors, and, hold, great, promise, as, epigenetic, drugs])].
[sujeto(['We']), verbo([report]), complemento([a, new, polydiacetylene, '(', 'PDA)', sensor, strip, for, simple, visual, detection, of, zinc, ions, in, aqueous, solution])].
[sujeto(['The', 'IM-MS', analyses, of, a, pH, titration, of, molar, equivalents, of, 'Zn(II):amb5', showed, that, both, 'negatively-', and, 'positively-charged', complexes, formed, and, coordination, of, 'Zn(II)']), verbo([increased]), complemento([as, the, 'His', and, 'Cys', deprotonated, near, their, pKa, values])].
[sujeto(['The', 'LJ', method]), verbo([provided]), complemento(['CCS', that, agreed, with, five, of, the, alternative, distorted, tetrahedral, and, trigonal, bipyramidal, coordinations, for, the, 'doubly-charged', 'complexes,', but, provided, 'CCS', that, were, 15, 'Å(2)', to, 31, 'Å(2)', larger, than, those, measured, by, 'IM-MS', for, the, 'singly-charged', complexes])].
[sujeto(['Collision-induced', dissociation, of, the, 'Zn(II)', complexes, and, a, further, pH, titration, study, of, amb5B, ',', which, included, amidation, of, the, 'C-terminus,']), verbo([suggested]), complemento([that, the, 2, 'His-2Cys', coordination, was, more, significant, than, coordinations, that, included, the, 'C-terminus'])].
[sujeto(['Therefore,', 'Zn(2+)', ions, can, be, excluded, from, possible]), verbo([causes]), complemento([of, structural, abnormalities, in, microtubules, during, 'Alzheimer\'s', disease])].
[sujeto(['Al(3+)', ions, are, the, most, probable, etiological]), verbo([cause]), complemento([of, 'Alzheimer\'s', disease])].
[sujeto(['The', concentration, of, 'Al(3+)', ions, affecting, the, structure, of, microtubules, is, one, order, of, magnitude, lower, than, that, of, 'Fe(3+)', ions, '(', 10, and, 100, 'μM,', 'respectively),', which, corresponds, to, their, brain, concentration]), verbo([reported]), complemento([in, 'Alzheimer\'s', disease])].
[sujeto(['N-terminal', amino, group, acetylation, '(', 'Ac-Semax)']), verbo([modulates]), complemento([the, chemical, and, biological, properties, of, parental, 'peptide,', modifying, the, ability, of, 'Semax', to, form, complex, species, with, 'Cu(II)', ion])].
[sujeto(['Semax', acetylation, did, not, protect, from, 'Cu(II)']), verbo([induced]), complemento([toxicity, on, a, 'SH-SY5Y', neuroblastoma, cell, 'line,', thus, demonstrating, the, crucial, role, played, by, the, free, 'NH2', terminus, in, the, cell, protection])].
[sujeto(['Since', several, brain, diseases, are]), verbo([associated]), complemento([either, to, 'Cu(II)', or, 'Zn(II)', 'dyshomeostasis,', here, we, characterized, also, the, complex, species, formed, by, 'Zn(II)', with, 'Semax', and, 'Ac-Semax'])].
[sujeto(['Moreover,', a, punctuate, distribution, of, 'Zn(II)', within, the, cells]), verbo([suggests]), complemento([a, preferred, subcellular, localization, that, might, explain, the, zinc, toxic, effect])].
[sujeto(['HaCuZnSOD', had, a, predicted, molecular, mass, of, 15.94, &, 'nbsp;kDa', and, a, theoretical, pI, value, of, 5.73, ',', which, is, favorable, for, copper]), verbo([binding]), complemento([activity])].
[sujeto(['In', silico, analysis, revealed, that, 'HaCuZnSOD', had, a, prominent, 'Cu-Zn_superoxide_dismutase', 'domain,', two, 'Cu/Zn', signature, 'sequences,', a, putative, 'N-glycosylation', 'site,', and, several, active, sites, including, 'Cu(2+)', and, 'Zn(2+)']), verbo([binding]), complemento([sites])].
[sujeto(['Multiple', alignment, analyses, revealed, many]), verbo([conserved]), complemento([regions, and, active, sites, among, its, orthologs])].
[sujeto(['The', highest, amino, acid, identity, to, 'HaCuZnSOD', was]), verbo([found]), complemento([in, 'Siniperca', chuatsi, '(', 87.4, '%', ')', ',', while, 'Maylandia', zebra, shared, a, close, relationship, in, the, phylogenetic, analysis])].
[sujeto(['In', all, the, functional, 'assays,', the, level, of, antioxidant, activity, of, rHaCuZnSOD, was, concentration, 'dependent;', metal, ion, supplementation, also]), verbo([increased]), complemento([its, activity])].
[sujeto(['The', highest, mRNA, expressional, level, of, 'HaCuZnSOD', was]), verbo([found]), complemento([in, blood])].
[sujeto(['Our', findings, demonstrated, that, 'HaCuZnSOD', is, an, important, 'antioxidant,', which, might, be]), verbo([involved]), complemento([in, the, host, antioxidant, defense, mechanism, against, oxidative, stress])].
[sujeto(['The', structure]), verbo([reveals]), complemento([the, intersubunit, contacts, in, the, 55, 'S', 'mitoribosome,', the, molecular, architecture, of, the, mitoribosomal, messenger, 'RNA', '(', 'mRNA)', binding, channel, and, its, interaction, with, transfer, 'RNAs,', and, provides, insight, into, the, highly, specialized, mechanism, of, mRNA, recruitment, to, the, 28, 'S', subunit])].
[sujeto(['The', barcode, sequences, of, 'Thai', species, of, 'Epinephelus', were, aligned, to, the, same, species]), verbo([found]), complemento([in, 'GenBank'])].
[sujeto(['It']), verbo([has]), complemento([been, suggested, that, mitochondrial, dysfunction, plays, a, role, in, the, pathogenesis, of, asthma])].
[sujeto(['Most', of, the, significant, locations]), verbo([found]), complemento([in, boys, are, within, the, 'CYB', gene, and, the, 'non-coding', region])].
[sujeto(['The', variants]), verbo([reported]), complemento([here, have, not, previously, been, described, in, connection, with, asthma])].
[sujeto(['Mitochondrial', ribosomal, 'RNAs', '(', 'mtrRNAs)']), verbo([have]), complemento([been, reported, to, translocate, 'extra-mitochondrially', and, localize, to, the, germ, cell, determinant, of, oocytes, and, zygotes, in, some, metazoa, except, mammals])].
[sujeto(['The', amount, of, mtrRNAs]), verbo([decreased]), complemento([around, first, 'cleavage,', remained, low, during, second, cleavage, and, increased, after, third, cleavage])].
[sujeto(['Similar', distribution, dynamics, of, the, 16, 'S', rRNA, was, observed, in, 'strontium-activated', haploid, 'parthenotes,']), verbo([suggesting]), complemento([the, distribution, rearrangement, does, not, require, a, component, from, sperm])].
[sujeto(['The', distribution, of, 16, 'S', rRNAs, did, not, coincide, with, that, of, 'mitochondrion-specific', heat, shock, protein, 70, ',']), verbo([suggesting]), complemento([that, the, mtrRNA, is, translocated, from, mitochondria])].
[sujeto(['Two-third', of, the, 'CP-treated', zygotes]), verbo([arrested]), complemento([at, either, 2, -, cell, or, 3, -, cell, stage, even, after, the, 'CP', was, washed, out])].
[sujeto(['However,', the, 16, 'S', rRNA, gene, harboured, a, larger, number, of, 'species-specific', mutation, sites, compared, with, the, cytochrome, b, 'gene,']), verbo([suggesting]), complemento([that, it, could, be, useful, for, species, identification])].
[sujeto(['Although', the, single, most, parsimonious, tree, was, not, statistically, different, from, the, two, second, parsimonious, 'trees,', independent, morphological, evidence, from, the, anal, fin, pterygiophore, configuration, and]), verbo([associated]), complemento([structures, strongly, supported, the, former, as, the, preferred, hypothesis])].
[sujeto(['Mapping', of, the, contemporary, geographic, distribution, patterns, of, the, four, species, onto, the, tree]), verbo([suggested]), complemento([that, there, was, a, common, ancestor, of, 'Sternoptyx', with, a, circumglobal, 'distribution,', which, had, been, subdivided, into, southern, and, northern, ancestral, populations, along, 30, degrees, 'S,', possibly, through, some, 'large-scale', oceanographic, event])].
[sujeto(['There']), verbo([has]), complemento([been, no, discernible, speciation, event, in, the, southern, 'population,', though, the, northern, population, has, subsequently, speciated, into, three, contemporary, species, with, largely, 'allopatric/microallopatric', distributions])].
[sujeto(['Ticks', of, the, genus, 'Ixodes']), verbo([have]), complemento([recently, assumed, prominence, because, they, frequently, serve, as, vectors, of, important, 'zoonoses,', including, 'Lyme', disease, and, babesiosis])].
[sujeto(['The', morphological, characteristics, that]), verbo([have]), complemento([been, used, in, their, identification, often, are, ambiguous, and, are, useful, solely, at, a, particular, stage, of, development])].
[sujeto(['Here', we]), verbo([report]), complemento([the, 'DNA', sequence, of, the, mitochondrially, encoded, 16, 'S', rRNA, gene, of, nine, different, 'Ixodes', ticks, and, an, outgroup, from, another, 'genus,', 'Dermacentor'])].
[sujeto(['Improvements', in, endurance, capacity, by, training, are]), verbo([associated]), complemento([with, structural, and, biochemical, adaptations, of, working, muscles, that, affect, the, mitochondrial, compartment])].
[sujeto(['We']), verbo([found]), complemento([that, mitochondrially, encoded, 'RNAs', '(', 'cytochrome-c', oxidase, subunit, 'I,', 'NADH', reductase, subunit, 6, ',', 16, 'S', 'rRNA),', as, well, as, 'nuclear-encoded', 'RNAs', '(', 'cytochrome-c', oxidase, subunit, 'IV,', succinate, 'dehydrogenase,', 'fumarase)', are, all, increased, coordinately, in, the, athletes, '(', 1.54, -, to, 1.94, -, 'fold)'])].
[sujeto(['Results']), verbo([suggested]), complemento([that, at, least, two, major, clades, existed, in, the, 'S'])].
[sujeto(['This', high, posterior, accumulation]), verbo([decreases]), complemento([sharply, during, the, first, hour, of, embryogenesis, and, reaches, the, uniform, level, found, throughout, the, remainder, of, the, embryo, by, the, time, pole, cells, form, 1.5, hr, after, fertilization])].
[sujeto(['In', 'contrast,', 'NADH', dehydrogenase, subunit, 1, 'RNA,', which, is]), verbo([transcribed]), complemento([from, the, same, strand, of, the, mitochondrial, genome, just, downstream, of, the, 12, 'S', and, 16, 'S', 'genes,', does, not, exhibit, a, high, posterior, concentration, but, is, uniformly, distributed, throughout, early, embryos])].
[sujeto(['This']), verbo([leads]), complemento([to, the, conclusion, 'that,', although, the, 16, 'S', and, 12, 'S', 'RNAs', are, concentrated, in, the, posterior, polar, plasm, during, normal, 'development,', functional, pole, cells, can, form, in, the, absence, of, high, levels, of, these, 'RNAs'])].
[sujeto(['The', abundance, of, the, mitochondrially, encoded, mRNA, for, subunit, 'II', of, cytochrome, c, oxidase, '(', 'COII', 'mRNA)']), verbo([increases]), complemento([in, the, liver, of, rats, exposed, to, environmental, cold, stress, '(', 4, degrees, 'C', ambient, 'temperature)'])].
[sujeto(['Only', transient]), verbo([increases]), complemento([or, no, changes, in, 'COII', mRNA, levels, were, observed, in, brown, fat, and, soleus, muscle, respectively])].
[sujeto(['The', time, course, of, the, liver, 'COII', mRNA]), verbo([increase]), complemento([was, compared, with, the, effects, of, cold, stress, on, mitochondrial, 16, 'S', ribosomal, 'RNA', expression, and, indicated, that, cold, induces, a, rapid, '(', few, 'hours)', increase, in, the, liver, mitochondrial, mRNA, levels, and, high, levels, of, both, messenger, and, ribosomal, 'RNA', mitochondrial, transcripts, are, present, after, a, few, days, of, cold, exposure])].
[sujeto(['It', is, concluded, that, mitochondrial, genome, expression, is, specifically]), verbo([increased]), complemento([in, the, liver, of, 'cold-exposed', rats, through, different, 'mechanisms,', independent, of, changes, in, mitochondrial, genome, abundance])].
[sujeto(['Transcripts', for, the, 'liver-type', form, and, for, the, 'heart-type', form, of, subunit, 'VIIa', of, cytochrome, c, oxidase, were, detected, in, all, myogenic, 'cultures;', the, levels, of, the, 'heart-type', form, progressively]), verbo([increased]), complemento([during, the, course, of, differentiation])].
[sujeto(['The', results]), verbo([suggest]), complemento([subunit, switching, of, subunit, 'VIa', and, 'co-expression', of, subunit, 'VIIa', isoforms, during, myogenesis])].
[sujeto(['The']), verbo([nuclear]), complemento([genome, is, the, primary, locus, of, activity, for, thyroid, hormone, and, 'dexamethasone;', 'however,', one, well, described, secondary, effect, of, treatment, with, these, hormones, is, increased, mitochondrial, respiratory, activity])].
[sujeto(['To', examine, the, mechanism, of, the]), verbo([increase]), complemento([in, 'respiration,', we, have, treated, a, rat, hepatoma, cell, 'line,', 'HTC', 'cells,', with, thyroid, hormone, and, dexamethasone, and, measured, their, effects, on, the, activity, of, a, respiratory, chain, enzyme, and, on, mitochondrial, '(', 'mt)', 'RNA', and, mtDNA, levels])].
[sujeto(['Thyroid', 'hormone,', but, not, 'dexamethasone,']), verbo([increased]), complemento([cytochrome, c, oxidase, activity, in, 'HTC', 'cells;', the, increase, in, activity, was, nearly, 2, -, fold, over, control, values])].
[sujeto(['To', determine, whether, this]), verbo([increased]), complemento([activity, was, the, result, of, coordinate, increases, in, expression, of, nuclear, and, cytoplasmic, genes, for, this, 'enzyme,', we, measured, changes, in, the, levels, of, messenger, 'RNAs', for, both, nuclear, and, mitochondrially, encoded, cytochrome, oxidase, subunits])].
[sujeto(['Treatment', of, 'HTC', cells, with, thyroid, hormone, 'and/or', dexamethasone, resulted, in, 3, -, to, 4, -, fold]), verbo([increases]), complemento([in, the, levels, of, several, 'RNAs', encoded, in, the, mt, 'genome,', including, subunit, 'II', of, cytochrome, c, oxidase])].
[sujeto(['In', 'contrast,', this, treatment, had, no, effect, on, the, messenger, 'RNA', encoding, a]), verbo([nuclear]), complemento([subunit, of, this, same, enzyme])].
[sujeto(['Dose', response, and, time, course, of, thyroid, hormone, and, dexamethasone, administration, on, mtRNA, levels, were, consistent, with, these, hormones]), verbo([acting]), complemento([through, their, nuclear, hormone, receptors])].
[sujeto(['Increased', expression, of, the, mt, genome, by, alteration, of, transcription, or, 'RNA', stability, is, a, likely, candidate, for, a, mechanism, by, which, these, hormones, can]), verbo([regulate]), complemento([mitochondrial, activity])].
[sujeto(['A', defect, in, mitochondrial, protein, synthesis]), verbo([has]), complemento([previously, been, identified, in, the, 'respiration-deficient', 'Chinese', hamster, lung, fibroblast, mutant, 'V79-G7'])].
[sujeto(['A', more, sensitive, analysis]), verbo([has]), complemento([shown, that, mutant, mitochondria, synthesize, all, mitochondrially, encoded, 'peptides,', but, in, significantly, reduced, amounts])].
[sujeto(['To', distinguish, between, a, defect, in, the, translational, machinery, and, a, defect, in, the, transcription, of, mitochondrial, 'DNA,', we, investigated, the, synthesis, of, the, 16, 'S', and, 12, 'S', mitochondrial, rRNA, species, and]), verbo([found]), complemento([them, to, be, made, in, normal, amounts, in, 'G7', mitochondria])].
[sujeto(['G7', mitochondria]), verbo([have]), complemento([a, characteristic, ultrastructure, distinguished, by, predominantly, tubular, 'cristae,', but, the, overall, biochemical, composition, of, mitochondrial, membrane, and, matrix, fractions, appears, essentially, unaltered, except, for, the, absence, of, a, few, characteristic, peptides])].
[sujeto(['To', estimate, the, population, frequencies, of, all, common, mitochondrial, variants, and, ancestral, haplogroups, among, 1, ',', 999, subjects]), verbo([recruited]), complemento([for, the, 'Primary', 'Open-Angle', 'African', 'American', 'Glaucoma', 'Genetics', '(', 'POAAGG)', 'Study,', including, 1, ',', 217, primary, 'open-angle', glaucoma, '(', 'POAG)', cases, and, 782, 'controls,', and, to, identify, ancestral, subpopulations, and, mitochondrial, mutations, as, potential, risk, factors, for, 'POAG', susceptibility])].
[sujeto(['However,', the, 'POAG', case, population, was]), verbo([found]), complemento([to, be, enriched, in, 'L1c2', 'haplogroups,', which, are, defined, in, part, by, missense, mutations, m])].
[sujeto(['L2', haplogroups, were, predicted, to, be, overrepresented, in, the, 'POAG', case, population, by, 'Pool-seq,', and, the, difference, was, confirmed, to, be, significant, with, 'Sanger', 'sequencing,', that]), verbo([targeted]), complemento([the, 'L2-associated', variants, m])].
[sujeto([3010, 'G>A', '(', 'rs3928306),', previously, implicated, in, sensitivity, to, the, optic, 'neuropathy-associated', antibiotic, 'linezolid,', and, arising, on, 'D4', and, 'J1', 'lineages,']), verbo([associated]), complemento([with, 'Leber', hereditary, optic, neuropathy, '(', 'LHON)', 'severity,', was, confirmed, to, be, common, '(', &, 'gt;5%)', but, was, not, significantly, enriched, in, the, 'POAG', cases])].
[sujeto(['Approximately', one, in, four, 'African', 'Americans']), verbo([have]), complemento([these, mitochondrial, 'ancestries,', which, may, contribute, to, their, elevated, glaucoma, risk])].
[sujeto(['These', haplogroups, are, defined, in, part, by, ancestral, variants, in, the, 'MT-RNR2', 'and/or', 'MT-CO1', 'genes,', several, of, which]), verbo([have]), complemento([prior, disease, 'associations,', such, as, 'MT-CO1', missense, variants, that, have, been, implicated, in, prostate, cancer])].
[sujeto(['Mitochondrial', 'RNR-2', '(', 'mt-RNR2,', 'humanin)']), verbo([has]), complemento([been, shown, to, play, a, role, in, protecting, several, types, of, cells, and, tissues, from, the, effects, of, oxidative, stress])].
[sujeto(['Addition', of, 'HN', improved, insulin, sensitivity, in, animal, models, of, diabetes, mellitus, but, no, clinical, studies]), verbo([have]), complemento([been, carried, out, to, measure, 'HN', levels, in, humans, associated, with, hyperglycemia])].
[sujeto(['A', significant]), verbo([decrease]), complemento(['(', 'P = 0'])].
[sujeto([91, &, 'nbsp;pg mL(-1))', consistent, with, an, adaptive, cellular, response, by, 'HN', to, a, slight]), verbo([increase]), complemento([in, 'BGL'])].
[sujeto(['Our', data, further, support, the, presence, of, methylation, within, human, mitochondrial, 'DNA', and]), verbo([suggest]), complemento([that, high, levels, of, methylation, of, the, 'MT-RNR1', site, may, reflect, a, condition, of, the, cell, or, of, the, organism, unfavorable, to, survival])].
[sujeto(['In', 'human,', a, systematic, search, for, noncoding, 'RNA', is, mainly, limited, to, the]), verbo([nuclear]), complemento([and, cytosolic, compartments])].
[sujeto(['The', structures, are]), verbo([conserved]), complemento([in, other, five, mammals, including, 'chimp,', 'orangutan,', 'mouse,', 'rat,', and, rhesus, genome])].
[sujeto(['Three', of, them, are]), verbo([expressed]), complemento([less, prominently, in, 'Northern', analysis])].
[sujeto(['The', expression, of, six, novel, 'pre-miRNA', and, miRNA, was, confirmed, by, 'Northern', blot, 'analysis;', 'however,', low, level, of, remaining, miRNA, was]), verbo([found]), complemento([by, sensitive, 'Northern', analysis])].
[sujeto(['The', six, miRNA]), verbo([find]), complemento([their, multiple, targets, throughout, the, human, genome, in, three, different, types, of, software])].
[sujeto(['The', luciferase, assay, was, used, to, confirm, that, 'MT-RNR2', gene, was, the, potential]), verbo([target]), complemento([of, 'hsa-miR-mit3', and, 'hsa-miR-mit4'])].
[sujeto(['Mutations', in, the, two, 'MT-RNR', genes, in, mitochondrial, 'DNA', can]), verbo([cause]), complemento([hearing, impairment, that, presents, with, variable, severity, and, age, of, onset])].
[sujeto(['We', studied, 'children,', who, had, been, born, in, 'Northern', 'Finland', in, 1993, -, 2002, and, who, had, been, ascertained, to]), verbo([have]), complemento([hearing, impairment, by, 31, 'December', 2007])].
[sujeto(['Samples', from, 103, children, were, sequenced, in, order, to]), verbo([find]), complemento([mutations, in, the, 'MT-RNR1', and, 'MT-RNR2', genes])].
[sujeto([1555, 'A', &, 'gt;', 'G', mutation, in, 'MT-RNR1']), verbo([suggesting]), complemento([a, frequency, of, 4.4, /, 100, ',', 0, in, the, 'Finnish', paediatric, population])].
[sujeto(['In', 'addition,', eight, rare, variants, and, 13, polymorphisms, were]), verbo([found]), complemento([in, 'MT-RNR1', and, 'MT-RNR2', genes])].
[sujeto(['Five', of, the, rare, variants, were, deemed, to, be, 'haplogroup-specific', polymorphisms, rather, than, putative, pathogenic, 'mutations,', while, the, remaining, three, variants]), verbo([have]), complemento([been, reported, in, various, haplogroups])].
[sujeto([990, 'T', &, 'gt;', 'C', occurs, at, a]), verbo([conserved]), complemento([site])].
[sujeto([990, 'T', &, 'gt;', 'C', variant, in, various, haplogroups, and, the, rather, high, degree, of, conservation, at, this, site]), verbo([suggest]), complemento([that, this, transition, is, a, pathogenic, rather, than, homoplasic, neutral, variant])].
[sujeto(['Substantial', progress]), verbo([has]), complemento([been, made, in, identifying, susceptibility, variants, for, 'age-related', macular, degeneration, '(', 'AMD)'])].
[sujeto(['The', majority, of, research, to, identify, genetic, variants]), verbo([associated]), complemento([with, 'AMD', has, focused, on, nuclear, genetic, variation])].
[sujeto(['While', there, is, some, evidence, that, mitochondrial, genetic, variation, contributes, to, 'AMD', 'susceptibility,', to, 'date,', these, studies]), verbo([have]), complemento([been, limited, to, populations, of, 'European', descent, resulting, in, a, lack, of, data, in, diverse, populations])].
[sujeto(['We', identified, five, 'SNPs']), verbo([associated]), complemento([with, 'AMD', in, 'Mexican', 'Americans', at, p, &, 'lt;', 0.05, ',', including, three, located, in, the, control, region, '(', 'mt16111,', 'mt16362,', and, 'mt16319),', one, in, 'MT-RNR2', '(', 'mt1736),', and, one, in, 'MT-ND4', '(', 'mt12007)'])].
[sujeto(['No', mitochondrial, variant, or, haplogroup, was, significantly]), verbo([associated]), complemento([in, 'non-Hispanic', blacks, or, 'non-', 'Hispanic', whites, in, the, final, 'meta-analysis'])].
[sujeto(['This', study]), verbo([provides]), complemento([further, evidence, that, mitochondrial, variation, plays, a, role, in, susceptibility, to, 'AMD', and, contributes, to, the, knowledge, of, the, genetic, architecture, of, 'AMD', in, 'Mexican', 'Americans'])].
[sujeto(['Mitochondrial', 'DNA', '(', 'mtDNA)', is, replicated, throughout, life, in, postmitotic, 'cells,', resulting, in, higher, levels, of, somatic, mutation, than, in]), verbo([nuclear]), complemento([genes])].
[sujeto(['We', also, performed, functional, studies, on, a, homoplasmic, nonsense, mutation, in, 'MT-ND1,', previously]), verbo([reported]), complemento([in, 'oncocytomas,', and, show, that, both, 'ATP', generation, and, the, stability, of, oxidative, phosphorylation, complex, 'I', are, disrupted])].
[sujeto(['It']), verbo([has]), complemento([been, reported, that, certain, genetic, factors, involved, in, schizophrenia, could, be, located, in, the, mitochondrial, 'DNA', '(', 'mtDNA)'])].
[sujeto(['This', study, was, performed, in, three, 'steps:', '(', 1, ')', identification, of, pathogenic, mutations, and, variants, in, 14, schizophrenia, patients, with, an, apparent, maternal, inheritance, of, the, disease, by, sequencing, the, entire, 'mtDNA;', '(', 2, ')', 'case-control', association, study, of, 23, variants, identified, in, step, 1, '(', 16, 'missense,', 3, 'rRNA,', and, 4, tRNA, 'variants)', in, 495, patients, and, 615, 'controls,', and, '(', 3, ')', analyses, of, the]), verbo([associated]), complemento([variants, according, to, the, 'clinical,', 'psychopathological,', and, neuropsychological, characteristics, and, according, to, the, oxidative, and, enzymatic, activities, of, the, mitochondrial, respiratory, chain])].
[sujeto(['Two', known, variants, were, nominally]), verbo([associated]), complemento([with, schizophrenia, and, were, further, studied])].
[sujeto(['The', 'MT-RNR2', 1811, 'A', &, 'gt;', 'G', variant, likely, does, not, play, a, major, role, in, 'schizophrenia,', as, it, was, not]), verbo([associated]), complemento([with, 'clinical,', 'psychopathological,', or, neuropsychological, 'variables,', and, the, 'MT-ATP6', 9110, 'T', &, 'gt;', 'C', p])].
[sujeto(['The', variants, nominally]), verbo([associated]), complemento([with, schizophrenia, in, the, present, study, were, not, related, either, to, phenotypic, characteristics, or, to, mitochondrial, function])].
[sujeto(['We', did, not]), verbo([find]), complemento([evidence, pointing, to, a, role, for, mtDNA, sequence, variation, in, schizophrenia])].
[sujeto(['The', objective, of, the, present, study, was, to, develop, an, approach, that, could, assess, the, chromosomal, status, and, the, mitochondrial, 'DNA', '(', 'mtDNA)', content, of, oocytes, and, their, corresponding, polar, bodies, '(', 'PBs)', with, the, goal, of, obtaining, a, comparative, picture, of, the, segregation, process, both, for]), verbo([nuclear]), complemento([and, mtDNA])].
[sujeto(['Despite', their, importance, in, marine, 'biota,', their, deep, phylogenetic, relationships, were, scarcely, investigated, from, a, molecular, 'perspective,', whereas, much, valuable, work]), verbo([has]), complemento([been, done, on, 'taxonomy,', as, well, as, 'phylogeny,', of, lower, taxa])].
[sujeto(['Rigorous', techniques]), verbo([have]), complemento([been, exploited, to, set, up, the, 'dataset,', analyze, phylogenetic, 'signal,', and, infer, a, single, final, tree])].
[sujeto(['Bivalve', morphological, characters, were, traced, onto, the, phylogenetic, trees, obtained, from, the, molecular, 'analysis;', our, analysis]), verbo([suggests]), complemento([that, eulamellibranch, gills, and, heterodont, hinge, are, ancestral, characters, for, all, 'Autobranchia'])].
[sujeto(['Somatic', mutations, of, mitochondrial, 'DNA', '(', 'mtDNA)']), verbo([have]), complemento([been, reported, in, different, types, of, cancers, and, are, suggested, to, play, roles, in, 'metastasis,', cancer, development, and, response, to, anticancer, agents])].
[sujeto(['Four', homoplasmic, and, six, heteroplasmic, alterations, were]), verbo([found]), complemento([to, be, novel])].
[sujeto(['Among', 'them,', homoplasmic, 'G6709A', '(', 'MT-CO1)', and, 'G14804A', '(', 'MT-CYB)', alterations]), verbo([cause]), complemento([amino, acid, changes, in, the, highly, conserved, residues])].
[sujeto(['We']), verbo([provide]), complemento([bioinformatic, and, expression, data, suggesting, the, existence, of, 13, 'MT-RNR2-like', nuclear, loci, predicted, to, maintain, the, open, reading, frames, of, 15, distinct, 'full-length', 'HN-like', peptides])].
[sujeto(['At', least, ten, of, these]), verbo([nuclear]), complemento([genes, are, expressed, in, human, 'tissues,', and, respond, to, staurosporine, '(', 'STS)', and, 'beta-carotene'])].
[sujeto(['Sequence', comparisons, of, the]), verbo([nuclear]), complemento(['HN', isoforms, and, their, homologues, in, other, species, reveal, two, consensus, 'motifs,', encompassing, residues, 5, -, 11, '(', 'GFS/NCLLL),', and, 14, -, 19, '(', 'SEIDLP/S)'])].
[sujeto(['Cytoprotection', against, the, 'STS-induced', apoptosis]), verbo([conferred]), complemento([by, the, polymorphic, 'HN5', 'variant,', in, which, threonine, in, position, 13, is, replaced, with, 'isoleucine,', is, reduced, compared, to, the, wild, type, 'HN5', peptide])].
[sujeto(['Despite', this, 'relevance,', the, mechanisms]), verbo([involved]), complemento([in, the, development, and, progression, of, this, malignancy, remain, unknown])].
[sujeto(['The', involvement, of, polypeptides, of, the, mitochondrial, respiratory, 'chain,', the, 'Krebs', cycle, and, the, glutathione, antioxidant, system, in, this, type, of, cancer]), verbo([has]), complemento([been, previously, 'described,', although, no, publication, has, focused, on, the, expression, of, mitochondrial, genes, in, the, prostate, of, 'PCa', patients])].
[sujeto(['We']), verbo([have]), complemento([determined, by, reverse, 'transcription-quantitative', 'PCR', '(', 'RT-qPCR)', the, relative, amount, of, the, transcripts, of, eight, mitochondrial, genes, '(', 'MT-ND2,', 'MT-ND4,', 'MT-ND6,', 'MT-CYB,', 12, 'S/MT-RNR1,', 16, 'S/MT-RNR2,', 'MT-CO2/COX2,', 'MT-ATP6),', and, four, nuclear, genes, '(', 'COX11,', 'GSR,', 'CS,', 'ACO2),', all, of, them, key, players, in, the, normal, metabolism, of, mitochondria])].
[sujeto(['The', amount, of, mitochondrial, 12, 'S/MT-RNR1,', 'MT-CO2/COX2,', and, 'MT-ATP6', transcripts, is, significantly]), verbo([decreased]), complemento([in, tumor, samples, when, compared, to, their, paired, normal, 'sample,', suggesting, that, mitochondrial, gene, expression, is, altered, in, 'PCa'])].
[sujeto(['During', 'development,', cloned, embryos, often, undergo, embryonic]), verbo([arrest]), complemento([at, any, stage, of, 'embryogenesis,', leading, to, diverse, morphological, abnormalities])].
[sujeto(['The', present, study, carried, out, extensive, gene, expression, analysis, to, screen, a, cluster, of, genes, aberrantly]), verbo([expressed]), complemento([in, embryonic, stem, 'cell-cloned', blastocysts])].
[sujeto(['Differential', screening, of, cDNA, subtraction, libraries, revealed, 224, differentially]), verbo([expressed]), complemento([genes, in, the, cloned, 'blastocysts:', 'eighty-five', were, identified, by, the, 'BLAST', search, as, known, genes, performing, a, wide, range, of, functions])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, an, extraordinarily, high, frequency, of, multiple, functional, disorders, caused, by, the, aberrant, expression, of, various, genes, in, the, blastocyst, stage, is, involved, in, developmental, arrest, and, various, other, disorders, in, cloned, embryos])].
[sujeto(['This', toxicity]), verbo([involves]), complemento([both, the, olfactory, neuroepithelium, and, its, subepithelial, nerves])].
[sujeto(['In', 'addition,', 2, ',', 6, -, dichlorophenyl, methylsulphone]), verbo([induces]), complemento([glial, acidic, fibrillary, protein, expression, '(', 'Gfap,', a, biomarker, for, 'gliosis)', in, the, olfactory, 'bulb,', as, well, as, 'long-lasting', learning, deficits, and, changes, in, spontaneous, behavior, in, mice, and, rats])].
[sujeto(['So', far, the, 2, ',', 5, -, dichlorinated, isomer]), verbo([has]), complemento([not, been, reported, to, cause, toxicity, in, the, olfactory, 'system,', although, it, gives, rise, to, transient, changes, in, spontaneous, behavior])].
[sujeto(['Seven', days, following, a, single, ip, dose, of, 2, ',', 6, -, dichlorophenyl, 'methylsulphone,', 56, genes, were]), verbo([found]), complemento([to, be, differentially, expressed, in, the, olfactory, bulb])].
[sujeto(['The', expression, of, these, genes, was, measured, also, in, mice, dosed, with, 2, ',', 5, -, dichlorophenyl, 'methylsulphone,', and, 'mt-Rnr2', and, 'Olfml3', were]), verbo([found]), complemento([to, be, altered, also, by, this, isomer])].
[sujeto(['Combined', with, previous, 'data,', the, results, support, the, possibility, that, the, persistent, neurotoxicity]), verbo([induced]), complemento([by, 2, ',', 6, -, dichlorophenyl, methylsulphone, in, mice, represents, both, an, indirect, and, a, direct, effect, on, the, brain])].
[sujeto(['Mitochondria', are]), verbo([involved]), complemento([in, essential, cellular, 'pathways,', some, of, which, have, been, associated, with, tumorigenesis])].
[sujeto(['The', 'patients\'', seminal, vesicles, studied, showed, the, same, set, of, variants, as, the, corresponding, 'prostate,']), verbo([suggesting]), complemento([either, that, the, pathogenic, role, of, these, particular, variants, is, minor, or, that, they, participate, in, the, prostatic, carcinogenesis, in, combination, with, other, factors, absent, in, seminal, vesicles])].
[sujeto(['One', affects, a]), verbo([conserved]), complemento([residue, and, three, have, not, been, previously, described])].
[sujeto(['Mitochondrial', dysfunction]), verbo([has]), complemento([been, implicated, in, rare, and, common, forms, of, type, 2, diabetes, '(', 'T2DM)'])].
[sujeto(['Additionally,', rare, mitochondrial, 'DNA', '(', 'mtDNA)', mutations]), verbo([have]), complemento([been, shown, to, be, causal, for, 'T2DM', pathogenesis])].
[sujeto(['So', 'far,', many, studies]), verbo([have]), complemento([investigated, the, possibility, that, mtDNA, variation, might, affect, the, risk, of, 'T2DM,', 'however,', when, 'found,', haplogroup, association, has, been, rarely, 'replicated,', even, in, related, 'populations,', possibly, due, to, an, inadequate, level, of, haplogroup, resolution])].
[sujeto(['Effects', of, mtDNA, variation, on, diabetes, complications]), verbo([have]), complemento([also, been, proposed])].
[sujeto(['In', 'contrast,', our, data, indicate, that, different, mitochondrial, haplogroups, are, significantly]), verbo([associated]), complemento([with, an, increased, risk, of, specific, diabetes, 'complications:', 'H', '(', the, most, frequent, 'European', 'haplogroup)', with, 'retinopathy,', 'H3', with, 'neuropathy,', 'U3', with, 'nephropathy,', and, 'V', with, renal, failure])].
[sujeto(['Our', detailed, understanding, of, the, molecular, processes, that]), verbo([mediate]), complemento([mitochondrial, gene, expression, and, the, 'structure-function', relationships, of, the, 'OXPHOS', components, could, be, greatly, improved, if, we, were, able, to, transfect, mitochondria, and, manipulate, mtDNA, in, vivo])].
[sujeto(['Increasing', our, knowledge, of, this, process, is, not, merely, of, fundamental, 'importance,', as, mutations, of, the, mitochondrial, genome, are, known, to]), verbo([cause]), complemento([a, spectrum, of, clinical, disorders, and, have, been, implicated, in, more, common, neurodegenerative, disease, and, the, ageing, process])].
[sujeto(['In', organellar, or, in, vitro, reconstitution, studies]), verbo([have]), complemento([identified, many, factors, central, to, the, mechanisms, of, mitochondrial, gene, 'expression,', but, being, able, to, investigate, the, molecular, aetiology, of, a, limited, number, of, cell, lines, from, patients, harbouring, mutated, mtDNA, has, been, enormously, beneficial])].
[sujeto(['In', the, absence, of, a, mechanism, for, manipulating, 'mtDNA,', a, much, larger, pool, of, pathogenic, mtDNA, mutations, would]), verbo([increase]), complemento([our, knowledge, of, mitochondrial, gene, expression])].
[sujeto(['Toxic', effects, in, the, uraemic, state, or, during, maintenance, dialysis]), verbo([have]), complemento([been, suggested, to, be, responsible, for, 'DNA', damage, and, tumour, development, in, 'end-stage', renal, disease, '(', 'ESRD)'])].
[sujeto(['Nine', somatic, nucleotide, changes, were]), verbo([found]), complemento([in, seven, of, the, nine, tumours, 'analysed;', four, of, them, were, 'G', to, 'A', transitions])].
[sujeto(['An', 'A', to, 'G', substitution, was, seen, in, the, control, region, at, the, mtTF1]), verbo([binding]), complemento([site])].
[sujeto(['This', study]), verbo([reveals]), complemento([a, high, mutational, rate, of, the, mitochondrial, 'DNA', in, 'tumours,', which, may, correspond, to, the, increased, level, of, reactive, oxidative, species, in, renal, parenchymal, cells, in, 'ESRD'])].
[sujeto(['We']), verbo([found]), complemento([6, somatic, nucleotide, changes, in, 5, out, of, the, 8, chromophobe, 'RCCs'])].
[sujeto(['Although', somatic, mtDNA, mutations, are]), verbo([found]), complemento([in, chromophobe, 'RCCs,', their, role, in, the, maintenance, of, tumor, cell, phenotype, or, in, tumorigenesis, remains, to, be, elucidated])].
[sujeto(['Management', of, burn, injury, is, an, onerous, clinical, task, since, it]), verbo([requires]), complemento([continuous, monitoring, and, extensive, usage, of, specialized, facilities])].
[sujeto(['Excessive']), verbo([loss]), complemento([of, body, 'fluids,', accumulation, of, 'exudate,', and, the, development, of, septic, shock, are, reported, to, be, the, main, reasons, for, morbidity, in, burn, victims])].
[sujeto(['The', blend, subsequently]), verbo([increased]), complemento([the, wettability, '(', 14, '%', ')', and, surface, energy, '(', 24, '%', ')', of, the, novel, dressing])].
[sujeto(['Ultimately,', the, presence, of, hydrophilic, biomolecules, and, high, porosity]), verbo([enhanced]), complemento([the, water, absorption, ability, of, the, 'PU-HN-PA', nanofiber, samples, to, 761.67, '%', from, 285.13, '%', in, 'PU'])].
[sujeto(['In', 'summary,', the, excellent, physicochemical, and, hemocompatible, properties, of, the, developed, 'PU-HN-PA', dressing, exhibit, its, potential, in, reducing, the, clinical, complications]), verbo([associated]), complemento([with, the, treatment, of, burn, injuries])].
[sujeto(['In', this, 'study,', a, 'high-speed', 'counter-current', chromatography, '(', 'HSCCC)', separation, method]), verbo([target]), complemento([guided, by, centrifugal, ultrafiltration, with, 'high-performance', liquid, 'chromatography-mass', spectrometry, '(', 'CU-LC-MS)', was, proposed])].
[sujeto(['The', isolated, two]), verbo([target]), complemento([compounds, '(', with, purities, of, 92.3, '%', and, 94.6, '%', ')', 'were,', 'respectively,', identified, as, 'quercetin-3-O-rhamnoside', '(', 1, ')', and, protocatechuic, acid, '(', 2, ')', based, on, the, 'MS,', 'UV,', and, '¹H-NMR', spectrometry, data])].
[sujeto(['The', impact, of, the, electromagnetic, waves, '(', 'EM)', on, human, neurons, '(', 'HN)']), verbo([has]), complemento([been, under, investigation, for, 'decades,', in, efforts, to, understand, the, impact, of, cell, phones, '(', 'radiation)', on, human, 'health,', or, radiation, absorption, by, 'HN', for, medical, diagnosis, and, treatment])].
[sujeto(['The', minimum, reflected, power, near, the, sample, under, investigation, was]), verbo([found]), complemento([to, be, with, negligible, reflected, field, strengths])].
[sujeto(['The', temperature, profile, resulting, from, the, 'COMSOL', simulation, was]), verbo([found]), complemento([to, be, near, 0.25, 'm°K,', indicating, no, change, in, temperature, on, the, neuro, cells, under, the, 'EM', exposure])].
[sujeto(['It', was]), verbo([found]), complemento([that, 90, '%', '(', 9, /, 10, ')', chickens, died, in, the, intramuscular, injection, group, and, 30, '%', '(', 3, /, 10, ')', birds, died, in, the, oral, route, infection, group, after, challenge])].
[sujeto(['A', tool, for, predicting, the, redox, state, and, secondary, structure, of, cysteine, residues, using, 'multi-dimensional', analyses, of, different, combinations, of]), verbo([nuclear]), complemento([magnetic, resonance, '(', 'NMR)', chemical, shifts, has, been, developed])].
[sujeto(['The', prediction, of, secondary, structure, using, 3, 'D,', 5, 'D,', and, 6, 'D', analyses, had, the, accuracy, of, '~90 %,']), verbo([suggesting]), complemento([that, 'H(N)', and, '[', 'Formula:', see, 'text]', chemical, shifts, may, be, noisy, and, made, the, discrimination, worse])].
[sujeto(['While', chronic, 'HN']), verbo([has]), complemento([been, shown, to, be, a, predictor, of, poor, 'outcome,', 'sodium-increasing', treatments, in, chronic, stable, and, asymptomatic, 'HN', has, not, proven, to, increase, life, expectancy])].
[sujeto(['For', symptomatic, 'HN,', in, 'contrast,', the, necessity, for, urgent, treatment]), verbo([has]), complemento([broadly, been, accepted, to, avoid, the, development, of, fatal, cerebral, oedema])].
[sujeto(['On', the, other, 'hand,', a, too, rapid]), verbo([increase]), complemento([of, serum, sodium, in, chronic, 'HN', may, result, in, cerebral, damage, due, to, osmotic, demyelination])].
[sujeto(['Recently,', administration, of, hypertonic, saline, bolus]), verbo([has]), complemento([been, recommended, as, first, line, treatment, in, patients, with, moderate, to, severe, symptomatic, 'HN'])].
[sujeto(['A', number, of, recommendations, and, guidelines]), verbo([have]), complemento([been, published, on, 'HN'])].
[sujeto(['PET/CT', studies, combining, 'WB', and, 'HN', acquisitions, performed, in, 85, consecutive, patients, were, retrospectively, reviewed, by, two]), verbo([nuclear]), complemento([medicine, physicians])].
[sujeto(['Recombinant', fragments, corresponding, to, both, 'BoNT/A', 'HN', and, 'HC', regions, were, prepared, '(', 'HN519-845', and, 'HC967-1296)', and, their]), verbo([binding]), complemento([to, synaptic, proteins, was, verified])].
[sujeto(['The']), verbo([binding]), complemento([behaviors, of, these, 'heavy-chain', domains, were, analyzed, by, treating, the, 'Neuro', 2, 'a,', a, murine, neuroblastoma, cell, 'line,', with, compounds, known, to, alter, membrane, properties])].
[sujeto(['Cholesterol', depletion, and, lipid, raft, inhibition]), verbo([increased]), complemento([the, binding, of, 'HN519-845', to, 'Neuro', 2, a, cells, without, affecting, 'HC967-1296-cell', interaction])].
[sujeto(['Sphingolipid', depletion]), verbo([decreased]), complemento([the, binding, of, cells, to, both, 'HC967-1296', and, 'HN519-845', 'whereas,', loading, exogenous, 'GD1a,', on, to, the, 'Neuro', 2, a, 'cells,', increased, the, binding, to, both, the, peptides, to, cells])].
[sujeto(['Microtubule', disruption, of, the, 'Neuro', 2, a, cells, by, nocodazole]), verbo([decreased]), complemento([the, binding, of, both, 'HC967-1296', and, 'HN519-845', to, the, treated, cells])].
[sujeto(['Inhibition', of, the, 'clathrin-mediated', endocytosis, using, 'dynasore,', chlorpromazine, or, potassium, '(', 'K(+))', depletion, buffer, lowered, the]), verbo([binding]), complemento([of, both, 'HC967-1296', and, 'HN519-845', to, the, 'cells,', but, seemed, to, exert, a, more, pronounced, effect, on, 'theHC967-1296', binding, than, on, the, 'HN519-845', binding])].
[sujeto(['Results', indicate, that, while, both, the, 'HN', and, 'HC', domains, are]), verbo([involved]), complemento([in, the, binding, of, the, toxin, to, neuronal, cells, there, are, differences, in, their, behavior, which, probably, stem, from, their, respective, amino, acid, composition, and, structural, location, in, the, toxin, 'three-dimensional', structure, along, with, their, intended, role, in, translocation, and, internalization, into, the, cells])].
[sujeto(['The', 'strain,', as, an, efficient, 'As(III)', oxidizer, and, 'As(V)', reducer, in, 'Pseudomonas,']), verbo([has]), complemento([the, potential, to, impact, arsenic, mobility, in, both, anoxic, and, aerobic, 'environments,', and, has, potential, application, in, 'As', remediation, processes])].
[sujeto(['Various', mumps, outbreaks]), verbo([have]), complemento([occurred, in, the, 'Netherlands', since, 2004, ',', particularly, among, persons, who, had, received, 2, doses, of, 'measles,', 'mumps,', and, rubella, '(', 'MMR)', vaccination])].
[sujeto(['Genomic', typing, of, pathogens, can, be, used, to, track, 'outbreaks,', but, the, established, genotyping, of, mumps, virus, based, on, the, small, hydrophobic, '(', 'SH)', gene, sequences, did, not]), verbo([provide]), complemento([sufficient, resolution])].
[sujeto(['The', analyses]), verbo([suggested]), complemento([that, multiple, mumps, virus, introductions, occurred, in, the, 'Netherlands', between, 2004, and, 2015, resulting, in, several, mumps, outbreaks, throughout, this, 'period,', whereas, during, some, local, outbreaks, the, molecular, data, pointed, towards, endemic, circulation])].
[sujeto(['Due', to, changing, global, climatic, 'conditions,', a, lot, of, attention]), verbo([has]), complemento([been, given, to, cyanobacteria, and, their, bioactive, secondary, metabolites])].
[sujeto(['These', conditions, are, expected, to]), verbo([increase]), complemento([the, frequency, of, cyanobacterial, 'blooms,', and, 'consequently,', the, concentrations, of, cyanotoxins, in, aquatic, ecosystems])].
[sujeto(['Under', each, light, 'condition,', exposure, to, 'ATX-A']), verbo([caused]), complemento([a, reduction, in, total, microcystin, '(', 'MC)', content, of, 'M'])].
[sujeto(['Hemoconcentration', '(', 'HC)', is]), verbo([associated]), complemento([with, reduced, 'mortality,', whereas, hyponatremia, '(', 'HN)', has, been, associated, with, an, increased, risk, of, adverse, outcomes, in, patients, with, acute, decompensated, heart, failure, '(', 'ADHF)'])].
[sujeto(['We', defined, 'HC', as, an]), verbo([increased]), complemento([hemoglobin, level, from, admission, to, 'discharge,', and, 'HN', as, sodium, &, 'lt;135mmol/L', at, admission])].
[sujeto(['In', a, multiple, 'Cox', proportional, hazard, 'analysis,', 'HC', without, 'HN']), verbo([conferred]), complemento([a, significant, 'event-free', survival, benefit, '(', hazard, 'ratio:', 0.703, ',', 95, '%', confidence, interval, 0.542, -, 0.912, ',', 'p=0'])].
[sujeto(['Only', 'HC', occurring, in, 'ADHF', without, 'HN', was]), verbo([associated]), complemento([with, improved, clinical, outcomes])].
[sujeto(['These', results]), verbo([provide]), complemento([further, support, for, the, importance, of, 'HN', as, a, challenging, therapeutic, target, in, 'ADHF', patients])].
[sujeto(['A', recent, study]), verbo([reported]), complemento([the, detection, of, a, 'bat-derived', virus, '(', 'BatPV/Epo_spe/AR1/DCR/2009,', 'batMuV)', with, phylogenetic, relatedness, to, human, mumps, viruses, '(', 'hMuV)'])].
[sujeto(['Since', all, efforts, to, isolate, infectious, batMuV]), verbo([have]), complemento([reportedly, 'failed,', we, generated, recombinant, mumps, viruses, '(', 'rMuVs)', in, which, the, open, reading, frames, '(', 'ORFs)', of, the, fusion, '(', 'F)', and, 'hemagglutinin-neuraminidase', '(', 'HN)', glycoproteins, of, a, hMuV, strain, were, replaced, by, the, corresponding, 'ORFs', of, batMuV])].
[sujeto(['The', batMuV, 'F', and, 'HN', proteins, were, successfully, incorporated, into, viral, particles, and, the, resultant, chimeric, virus, was, able, to]), verbo([mediate]), complemento([infection, of, 'Vero', cells])].
[sujeto(['Distinct', differences, were, observed, between, the, fusogenicity, of, rMuVs]), verbo([expressing]), complemento([one, or, both, batMuV, 'glycoproteins:', 'Viruses', expressing, batMuV, 'F', were, highly, 'fusogenic,', regardless, the, origin, of, 'HN'])].
[sujeto(['In', 'contrast,', rMuVs]), verbo([expressing]), complemento([human, 'F', and, 'bat-derived', 'HN', proteins, were, less, fusogenic, compared, to, hMuV])].
[sujeto(['The', growth, kinetics, of, chimeric, 'MuVs']), verbo([expressing]), complemento([batMuV, 'HN', in, combination, with, either, hMuV, or, batMuV, 'F', were, similar, to, the, backbone, 'virus,', whereas, for, rMuVs, harbouring, batMuV, 'F', and, hMuV, 'HN', a, delay, in, virus, replication, was, obtained])].
[sujeto(['Replacement', of, the, hMuV, 'F', and, 'HN', genes, or, the, 'HN', gene, alone, by, the, corresponding, batMuV, genes]), verbo([led]), complemento([to, a, slight, reduction, in, neurovirulence, of, the, highly, neurovirulent, backbone, strain])].
[sujeto(['Neutralizing', antibodies]), verbo([inhibited]), complemento([infection, mediated, by, all, recombinant, viruses, generated])].
[sujeto(['Furthermore,', group, 'IV', 'anti-MuV', antibodies]), verbo([inhibited]), complemento([the, neuraminidase, activity, of, 'bat-derived', 'HN'])].
[sujeto(['Our', study]), verbo([reports]), complemento([the, successful, generation, of, chimeric, 'MuVs', expressing, the, 'F', and, 'HN', proteins, of, 'batMuV,', providing, a, means, for, further, examination, of, this, novel, batMuV])].
[sujeto(['There', was, an, initial]), verbo([increase]), complemento([of, apoptotic, cells, coupled, with, gradual, enhancement, of, reactive, oxygen, series, '(', 'ROS)', generation, at, lower, doses, of, 9, -, 'HPbD'])].
[sujeto(['By', 'contrast,', at, a, higher, dose, of, 9, -, 'HPbD,', there, was, a, clear]), verbo([increase]), complemento([of, necrotic, cells, with, a, gradual, decrease, of, 'ROS', generation])].
[sujeto(['These', results, indicate, that, the, distribution, of, photosensitizer]), verbo([leads]), complemento([to, differences, in, the, generation, of, 'ROS,', which, subsequently, determines, the, type, of, cell, death])].
[sujeto(['Migration', suppression, of, 'HN-3', cells, following, 'PDT', may, be]), verbo([associated]), complemento([with, the, inhibited, expression, of, 'EGFR,', due, to, oxidative, stress])].
[sujeto(['Many', epidemical, and, biological, studies]), verbo([have]), complemento([proposed, that, human, papillomavirus, '(', 'HPV),', primarily, 'high-risk', 'HPV16/18,', is, an, etiological, factor, for, a, subset, of, head, and, neck, '(', 'HN)', cancers])].
[sujeto(['Meta-analyses', were, conducted, to, combine, the, studies, that]), verbo([reported]), complemento([the, association, between, 'HPV', status, and, these, variables, using, 'Rev', 'Man', 5.0])].
[sujeto(['The', pooled, results, showed, that, 'HPV-positive', tumors, were, not, only, poorly, differentiated, '(', 'OR', =, 2.77, ',', 95, '%', 'CI:', 2.3, -, 3.32, ')', and, smaller, '(', 'OR', =, 2.21, ',', 95, '%', 'CI:', 1.75, -, 2.8, ')', but, were, also, strongly]), verbo([associated]), complemento([with, oropharynx, '(', 'OR', =, 5.8, ',', 95, '%', 'CI:', 4.01, -, 8.38, ')', and, node, involvement, '(', 'OR', =, 2.77, ',', 95, '%', 'CI:', 2.3, -, 3.32, ')'])].
[sujeto(['Spinal', motor, neuron, excitability]), verbo([has]), complemento([been, reported, to, increase, in, patients, with, brain, damage])].
[sujeto(['The', excitability, of, the, spinal, motor, neurons, in, patients, with, 'DOC', following, 'TBI', was, reduced, after, acupuncture, 'treatment,']), verbo([suggesting]), complemento([that, it, is, beneficial, for, reducing, spastic, muscle, hypertonia, in, these, patients])].
[sujeto(['Hyposalivation']), verbo([caused]), complemento([this, unsatisfactory, yield, of, valid, saliva, samples])].
[sujeto(['Preliminary', findings]), verbo([suggest]), complemento([that, acupressure, is, effective, in, reducing, both, agitation, and, stress])].
[sujeto(['Radical', hysterectomy, '(', 'RH)', is, an, effective, treatment, for, 'early-stage', cervical, cancer, 'IA2', to, 'IIA1', but, 'RH', is, often]), verbo([associated]), complemento([with, several, significant, complications, such, as, 'urinary,', anorectal, and, sexual, dysfunction, due, to, pelvic, nerve, injuries])].
[sujeto(['We', aimed, to, precise, the, neuroanatomy, of, the, female, pelvis, in, order, to]), verbo([provide]), complemento(['key-points', of, surgical, anatomy, to, improve, 'NSRH', for, cervical, cancer])].
[sujeto(['Anatomical', landmarks, as, middle, rectal, 'artery,', deep, uterine, 'vein,', inferior, vesical, vein, and, ureter, and, the, respect, of, nervous, part, of, uterine, ligament, and, of, parametrium]), verbo([provide]), complemento([to, surgeon, a, safe, preservation, of, pelvic, innervation, without, compromising, oncological, outcomes])].
[sujeto(['The', 'National', 'Cancer', 'Institute\'s', 'Common', 'Terminology', 'Criteria', for, 'Adverse', 'Events', '(', 'CTCAE)', is, the, universal, framework, for, toxicity]), verbo([reporting]), complemento([in, oncology, trials])].
[sujeto(['With', the, development, of, 'DIGEST,', the, 'MBS', rating]), verbo([has]), complemento([been, adapted, to, the, 'CTCAE', nomenclature, of, ordinal, toxicity, grading, used, in, oncology, trials])].
[sujeto(['Benzyl', isothiocyanate, '(', 'BITC)', is, one, of, the, isothiocyanates, that]), verbo([have]), complemento([been, shown, to, induce, human, cancer, cell, apoptosis, and, cell, cycle, arrest])].
[sujeto(['We']), verbo([found]), complemento([that, 'BITC', induced, cell, morphological, 'changes,', decreased, cell, viability, and, the, induction, of, cell, apoptosis, in, 'GBM', 8401, cells, was, 'time-dependent'])].
[sujeto([cDNA, microarray, was, used, to, examine, the, effects, of, 'BITC', on, 'GBM', 8401, cells, and, we]), verbo([found]), complemento([that, numerous, genes, associated, with, cell, death, and, cell, cycle, regulation, in, 'GBM', 8401, cells, were, altered, after, 'BITC', treatment])].
[sujeto(['The', results, show, that, expression, of, 317, genes, was, 'upregulated,', and, two, genes, were]), verbo([associated]), complemento([with, 'DNA', 'damage,', the, 'DNA-damage-inducible', transcript, 3, '(', 'DDIT3)', was, increased, 3.66, -, fold, and, the, growth, arrest, and, 'DNA-damage-inducible', α, '(', 'GADD45A)', was, increased, 2.34, -, fold])].
[sujeto(['We', also]), verbo([found]), complemento([that, expression, of, 182, genes, was, downregulated, and, two, genes, were, associated, with, receptor, for, cell, responses, to, 'stimuli,', the, 'EGF', containing, 'fibulin-like', extracellular, matrix, protein, 1, '(', 'EFEMP1)', was, inhibited, 2.01, -, fold, and, the, 'TNF', 'receptor-associated', protein, 1, '(', 'TRAP1)', was, inhibited, 2.08, -, fold])].
[sujeto(['BITC']), verbo([inhibited]), complemento([seven, mitochondria, ribosomal, 'genes,', the, mitochondrial, ribosomal, 'protein;', tumor, protein, 'D52', '(', 'MRPS28)', was, inhibited, 2.06, -, 'fold,', the, mitochondria, ribosomal, protein, 'S2', '(', 'MRPS2)', decreased, 2.07, -, 'fold,', the, mitochondria, ribosomal, protein, 'L23', '(', 'MRPL23)', decreased, 2.08, -, 'fold,', the, mitochondria, ribosomal, protein, 'S2', '(', 'MRPS2)', decreased, 2.07, -, 'fold,', the, mitochondria, ribosomal, protein, 'S12', '(', 'MRPS12)', decreased, 2.08, -, 'fold,', the, mitochondria, ribosomal, protein, 'L12', '(', 'MRPL12)', decreased, 2.25, -, fold, and, the, mitochondria, ribosomal, protein, 'S34', '(', 'MRPS34)', was, decreased, 2.3, -, fold, in, 'GBM', 8401, cells])].
[sujeto(['These', changes, of, gene, expression, can]), verbo([provide]), complemento([the, effects, of, 'BITC', on, the, genetic, level, and, are, potential, biomarkers, for, glioblastoma, therapy])].
[sujeto(['It']), verbo([has]), complemento([been, proposed, previously, that, only, a, subset, of, the, species, of, 'Clostridium', that, form, a, distinct, cluster, in, the, 16, 'S', rRNA, tree, '(', cluster, 'I)', should, be, regarded, as, the, true, representatives, of, the, genus, 'Clostridium', '(', i])].
[sujeto(['We']), verbo([report]), complemento([here, phylogenomic, and, comparative, analyses, based, on, sequenced, clostridial, genomes, in, an, attempt, to, bridge, this, gap, and, to, clarify, the, evolutionary, relationships, among, species, of, clostridia])].
[sujeto(['In', phylogenetic, trees, for, species, of, clostridia, based, on, concatenated, sequences, for, 37, highly]), verbo([conserved]), complemento(['proteins,', the, species, of, 'Clostridium', cluster, 'I', formed, a, strongly, supported, clade, that, was, separated, from, all, other, clostridia, by, a, long, branch])].
[sujeto(['Our', comparative, genomic, analyses]), verbo([have]), complemento([identified, three, conserved, indels, in, three, highly, conserved, proteins, '(', a, 4, aa, insert, in, 'DNA', gyrase, 'A,', a, 1, aa, deletion, in, 'ATP', synthase, beta, subunit, and, a, 1, aa, insert, in, ribosomal, protein, 'S2)', that, are, unique, to, the, species, of, 'Clostridium', cluster, 'I', and, are, not, found, in, any, other, bacteria])].
[sujeto([blastp, searches, on, various, proteins, in, the, genomes, of, 'Clostridium', tetani, 'E88', and, 'Clostridium', perfringens, 'SM101']), verbo([have]), complemento([also, identified, more, than, 10, proteins, that, are, found, uniquely, in, the, cluster, 'I', species])].
[sujeto(['These', results]), verbo([provide]), complemento([evidence, that, the, species, of, 'Clostridium', cluster, 'I', not, only, are, phylogenetically, distinct, but, also, share, many, unique, molecular, characteristics])].
[sujeto(['These', newly, identified, molecular, markers]), verbo([provide]), complemento([useful, tools, to, define, and, circumscribe, the, genus, 'Clostridium', sensu, stricto, in, more, definitive, terms])].
[sujeto(['We']), verbo([have]), complemento([also, identified, a, 7, -, 9, aa, conserved, insert, in, the, enzyme, phosphoglycerate, dehydrogenase, that, is, uniquely, found, in, the, 'Clostridium', 'thermocellum,', 'Thermoanaerobacter', 'pseudethanolicus,', 'Thermoanaerobacter', tengcogensis, and, 'Caldicellulosiruptor', saccharolyticus, 'homologues,', and, is, absent, from, all, other, bacteria])].
[sujeto(['These', species, form, a, 'well-defined', clade, in, the, phylogenetic, trees, and, this, indel]), verbo([provides]), complemento([a, potential, molecular, marker, for, this, clostridial, cluster])].
[sujeto(['After', 7, -, d, 'exposure,']), verbo([nuclear]), complemento([genes, encoding, mitochondrial, proteins, '(', ribosomal, protein, 'S2,', 'ATP', 'synthase,', 'very-long-chain', specific, 'acyl-CoA', dehydrogenase, '[', 'VLCAD])', were, 'downregulated,', whereas, mitochondrial, phosphoenol, pyruvate, carboxykinase, '(', 'PEP', 'Cbk)', was, upregulated])].
[sujeto(['Taken', 'together,', these, changes]), verbo([suggest]), complemento([a, shift, in, metabolism, toward, gluconeogenesis, and, lipid, export])].
[sujeto(['These', molecular, responses, differ, markedly, from, those]), verbo([induced]), complemento([by, chronic, hypoxia])].
[sujeto(['Demographic', analysis, showed, a, lower, estimated, rate, of, population, growth, in, grass, shrimp, exposed, to, both, continuous, and, 'short-term', cyclic, 'hypoxia,']), verbo([suggesting]), complemento(['population-level', impacts, on, grass, shrimp])].
[sujeto(['Scant', scientific, attention]), verbo([has]), complemento([been, given, to, the, abundance, and, distribution, of, marine, biota, in, the, face, of, the, lower, sea, 'level,', and, steeper, latitudinal, gradient, in, 'climate,', during, the, 'ice-age', conditions, that, have, dominated, the, past, million, years])].
[sujeto(['Although', the, 'LGM', range, of, 'Atlantic', cod, was, much, 'smaller,', and, 'fragmented,', both, the, 'ENMs', agreed, that, populations, should]), verbo([have]), complemento([been, able, to, persist, in, suitable, habitat, on, both, sides, of, the, 'Atlantic'])].
[sujeto(['In', 'contrast,', both, the, 'ENMs', and, the, genetic, data]), verbo([suggest]), complemento([that, the, 'Greenland', 'G'])].
[sujeto(['Confirming', that, in, dicot, plants, the, corresponding, gene]), verbo([has]), complemento([been, transferred, to, the, 'nucleus,', a, corresponding, 'Arabidopsis', thaliana, nuclear, gene, was, identified, that, codes, for, mitochondrial, 'RPS2'])].
[sujeto(['As', several, yeast, and, mammalian, genes, coding, for, mt, ribosomal, 'proteins,', the, 'Arabidopsis', 'RPS2', apparently]), verbo([has]), complemento([no, 'N-terminal', targeting, sequence])].
[sujeto(['These', extensions, are, not]), verbo([conserved]), complemento([in, sequence])].
[sujeto(['Using', specific, antibodies, against, one, of, the, maize, proteins, we]), verbo([found]), complemento([that, a, large, protein, precursor, is, indeed, 'synthesized,', but, it, is, apparently, processed, to, give, the, mature, 'RPS2', protein, which, is, associated, with, the, mitochondrial, ribosome])].
[sujeto(['Using', synchronized, 'Dictyostelium', discoideum, 'Ax-2', cells, and, the, differential, display, 'method,', a, mitochondrial, gene, cluster, '(', referred, to, as, 'differentiation-associated', gene, 3, ;, 'dia3)', was, isolated, as, one, of, the, genes]), verbo([expressed]), complemento([specifically, during, the, transition, of, 'Ax-2', cells, from, growth, to, differentiation])].
[sujeto(['Northern', blot, analysis, using, nonsynchronized, 'Ax-2', cells]), verbo([has]), complemento([shown, that, the, dia3, 'RNA', of, about, 8, kb, is, scarcely, expressed, during, the, vegetative, growth, 'phase,', and, the, maximal, expression, was, attained, at, 2, h, after, starvation])].
[sujeto(['In', this, 'connection,', the, cAMP, receptor, 1, '(', 'car1)', 'expression,', which, is, one, of, the, earliest, markers, of, 'differentiation,', was]), verbo([found]), complemento([to, be, markedly, reduced, in, the, 'rps4-inactivated', cells])].
[sujeto(['The', wheat, gene, is]), verbo([transcribed]), complemento([as, a, single, mRNA, which, is, edited, by, 'C-to-U', conversions, at, seven, 'positions,', all, resulting, in, alteration, of, the, encoded, amino, acid])].
[sujeto(['The', protein, sequence, deduced, from, the, wheat, rps2, gene, sequence]), verbo([has]), complemento([a, long, 'C-terminal', extension, when, compared, to, other, prokaryotic, 'RPS2', sequences])].
[sujeto(['This', extension, presents, no, similarity, with, any, known, sequence, and, is, not]), verbo([conserved]), complemento([in, the, maize, or, rice, mitochondrial, rps2, gene])].
[sujeto(['We']), verbo([have]), complemento([cloned, the, nuclear, gene, 'MRP4', coding, for, a, mitochondrial, ribosomal, protein, of, the, 'yeast,', 'Saccharomyces', cerevisiae])].
[sujeto(['The', nucleotide, sequence, of, 'MRP4', revealed, that, it]), verbo([has]), complemento([sequence, similarity, with, 'Escherichia', coli, ribosomal, protein, 'S2', and, related, proteins, of, chloroplast, ribosomes, from, different, plants])].
[sujeto(['Finally,', we, note, that, the, 'MRP4', protein, and, other, members, of, the, 'S2', family, of, ribosomal, proteins]), verbo([have]), complemento([regions, of, sequence, similarity, with, the, mammalian, 68, -, kDa, high, affinity, laminin, receptor])].
[sujeto(['The', nucleotide, sequence, of, 6472, base, pairs, of, an, 8.2, kb, segment, of, 'Saccharomyces', cerevisiae, chromosome, 'XI']), verbo([has]), complemento([been, determined])].
[sujeto(['Transcription', and, 'Southern', analysis, of, the, four, complete, 'ORFs', showed, that, all, are]), verbo([expressed]), complemento([and, are, present, in, single, copy, on, the, haploid, genome])].
[sujeto(['The', average, codon, adaptation, index, of, the, coding, regions, is, approximately, 0.2, ',']), verbo([suggesting]), complemento([that, these, genes, are, lowly, expressed])].
[sujeto(['The', upstream, regions, of, all, four, genes, as, well, as, the, 'YKL1', 'ORF', contain, putative, promoter, elements, previously]), verbo([found]), complemento([to, be, characteristic, of, nuclear, genes, encoding, mitochondrial, proteins])].
[sujeto(['Significant', sequence, similarities, were]), verbo([found]), complemento([between, the, 'YKL3', protein, and, 'Escherichia', coli, ribosomal, protein, 'S2', as, well, as, between, the, 'TGL1', protein, and, triglyceride, lipases, from, rat, salivary, gland, and, human, gastric, tissue])].
[sujeto([',', 1991, ',', 'Gene', 'Expression', 2, ',', 149, -, 167, ')', ',', thereby]), verbo([increasing]), complemento([the, number, of, genes, on, the, 8.2, kb, fragment, to, at, least, five])].
[sujeto(['The', transcripts, of, these, genes, represent, approximately, 83, '%', of, the, 'DNA', 'fragment,', making, it, one, of, the, most, highly]), verbo([transcribed]), complemento([regions, of, the, yeast, chromosome, analysed, to, date])].
[sujeto(['Our', transcriptomic, 'analysis,', which, highlighted, discrepancies, between, controls, and, tumor, 'tissues,', as, well, as, between, various, tumor, 'types,']), verbo([led]), complemento([to, the, identification, of, 13, 'genes,', allowing, discrimination, between, the, thyroid, 'adenomas,', oncocytic, variants, of, follicular, thyroid, 'tumors,', and, papillary, thyroid, 'carcinomas,', whereas, the, tumors, of, uncertain, malignant, potential, were, found, to, overlap, these, classes])].
[sujeto(['Moreover,', it, is, assumed, that, apoptosis, in, the, follicular, cells]), verbo([has]), complemento([a, beneficial, influence, on, the, developmental, competence, of, oocytes])].
[sujeto(['Moreover,', the, analysis, of, apoptosis, showed, a, higher, 'caspase-3', activity, in, the, follicular, cells, and, an]), verbo([increased]), complemento([degree, of, late, apoptotic, events, in, granulosa, cells, in, the, 'BCB+', compared, with, the, 'BCB-', group])].
[sujeto(['Additionally,', the, global, gene, expression, profile, revealed, a, total, of, 34, and, 37, differentially]), verbo([expressed]), complemento([genes, between, 'BCB+', and, 'BCB-', cumulus, cells, and, granulosa, 'cells,', 'respectively,', whereas, 207, genes, showed, an, altered, transcript, abundance, between, 'BCB+', and, 'BCB-', oocytes])].
[sujeto(['The', multidrug, 'resistance-associated', protein1, '(', 'MRP1/ABCC1)', is, a, member, of, the, 'ABCC', transporter, subfamily, that]), verbo([mediates]), complemento([the, efflux, of, 'pharmaceuticals,', xenobiotics, and, steroid, 'hormones,', typically, as, 'glutathione,', glucuronide, or, sulfate, conjugates])].
[sujeto(['Since']), verbo([loss]), complemento([of, one, transporter, can, be, compensated, by, increasing, the, expression, of, other, transporters, and, conjugation, 'enzymes,', we, sought, to, examine, compensatory, changes, in, phase, 'I,', 'II', and, 'III', enzyme, expression, in, extrahepatic, 'tissues,', including, the, 'kidney,', lungs, and, small, intestine, of, intact, or, castrated, 'Mrp1(-/-)', male, mice])].
[sujeto(['In', the, small, 'intestine,', there, were, interactions, between, steroid, hormone, levels, and, 'genotype,', as, the, expression, differences, were, only]), verbo([found]), complemento([in, mice, lacking, 'Mrp1,', and, were, changed, between, intact, and, castrated, animals])].
[sujeto(['These', results, indicate, that, compensatory, responses, owing, to, the]), verbo([loss]), complemento([of, 'Mrp1', vary, 'dramatically,', depending, on, the, particular, tissue])].
[sujeto(['Mutations', in, mitochondrial, small, subunit, ribosomal, proteins, 'MRPS16', or, 'MRPS22']), verbo([cause]), complemento(['severe,', fatal, respiratory, chain, dysfunction, due, to, impaired, translation, of, mitochondrial, mRNAs])].
[sujeto(['The']), verbo([loss]), complemento([of, either, 'MRPS16', or, 'MRPS22', was, accompanied, by, the, loss, of, most, of, another, small, subunit, protein, 'MRPS11'])].
[sujeto(['This', observation]), verbo([suggests]), complemento([that, the, small, ribosomal, subunit, is, only, partially, able, to, assemble, in, these, patients])].
[sujeto(['Two', large, subunit, ribosomal, 'proteins,', 'MRPL13', and, 'MRPL15,', were, present, in, substantial, amounts]), verbo([suggesting]), complemento([that, the, large, ribosomal, subunit, is, still, present, despite, a, 'non-functional', small, subunit])].
[sujeto(['It']), verbo([has]), complemento([multiple, roles, in, translation, and, 'extra-ribosomal', functions, like, apoptosis, and, 'DNA', repair])].
[sujeto(['A', point, mutation, at, this, residue]), verbo([decreased]), complemento([secretion, of, rpS3, in, cancer, cell, lines])].
[sujeto(['Secretion', was, also]), verbo([inhibited]), complemento([by, the, endoplasmic, reticulum, '(', 'ER)-Golgi', transport, inhibitor, 'Brefeldin', 'A', and, by, 'Tunicamycin,', an, inhibitor, of, 'N-linked', glycosylation])].
[sujeto(['RpS3']), verbo([bound]), complemento([to, 'Concanavalin', 'A,', a, carbohydrate, binding, lectin, 'protein,', while, treatment, with, 'peptide-N-glycosidase', 'F', shifted, the, secreted, rpS3, to, a, lower, molecular, weight, band])].
[sujeto(['An', in, vitro]), verbo([binding]), complemento([assay, detected, rpS3, homodimer, formation, via, the, 'N-terminal', region, '(', 'rpS3:1-85)', and, a, middle, region, '(', 'rpS3:95-158)'])].
[sujeto(['An', immunosuppressant, agent, with, negligible, or, acceptable, toxicity, may]), verbo([provide]), complemento([a, better, therapeutic, strategy, for, treatment, of, allergic, contact, dermatitis])].
[sujeto(['We', identified, a, natural, 'cyclopeptide,', roseotoxin, 'B,', that, effectively]), verbo([suppressed]), complemento([cell, proliferation, and, the, production, of, proinflammatory, cytokines, in, activated, 'T', cells, but, exhibited, little, naive, 'T-cell', toxicity, at, concentrations, of, 0.3, -, 1, 'μmol/L'])].
[sujeto(['In', 'addition,', roseotoxin, 'B']), verbo([inhibited]), complemento([the, activation, of, 'AKT', and, signal, transducer, and, activator, of, 'transcription-3,', suppressed, cell, 'cycle-related', 'signaling,', caused, 'G0/G1', phase, 'arrest,', reduced, ribosomal, 'protein-S3', '(', 'RPS3)-dependent', 'NF-κB-mediated', 'IL-2', 'production,', and, increased, autophagy, in, activated, 'T', cells])].
[sujeto(['The', effects, of, roseotoxin, 'B', were]), verbo([inhibited]), complemento([in, 'LC3-knockout', 'mice,', indicating, that, roseotoxin, 'B', acts, in, an, 'autophagy-dependent', manner, in, 'T-cell-mediated', skin, diseases])].
[sujeto(['Overall,', this, study, showed, a, mechanism, for, roseotoxin, 'B-induced', autophagic, cell, death, and]), verbo([provided]), complemento([a, unique, perspective, on, 'autophagy-mediated', 'down-regulation', of, 'NF-κB', signaling, in, activated, 'T', cells])].
[sujeto(['The', unique, 'anti-inflammatory', mechanism, of, roseotoxin, 'B', against]), verbo([activated]), complemento(['T', lymphocytes, in, allergic, contact, dermatitis, suggests, that, it, could, be, a, potential, target, for, the, treatment, of, 'immune-related', skin, diseases])].
[sujeto(['Verticillium', nonalfalfae, is, a, fungal, plant, pathogen, that]), verbo([causes]), complemento([wilt, disease, by, colonizing, the, vascular, tissues, of, host, plants])].
[sujeto(['The', disease]), verbo([induced]), complemento([by, hop, isolates, of, 'V'])].
[sujeto([nonalfalfae, manifests, in, two, different, 'forms,', ranging, from, mild, symptoms, to, complete, plant, 'dieback,']), verbo([caused]), complemento([by, mild, and, lethal, 'pathotypes,', respectively])].
[sujeto(['Pathogenicity', variations, between, the, causal, strains]), verbo([have]), complemento([been, attributed, to, differences, in, genomic, sequences, and, perhaps, also, to, differences, in, their, mitochondrial, genomes])].
[sujeto([lineage, in, the, 'Glomerellales', 'group,', which, is, also, supported, by, previous, phylogenetic, studies, based, on]), verbo([nuclear]), complemento([markers])].
[sujeto(['The', clustering, with, the, closely, related, 'Verticillium', dahliae, mitochondrial, genome, showed, a, very]), verbo([conserved]), complemento([synteny, and, a, high, sequence, similarity])].
[sujeto(['Eukaryotic', ribosomes, assemble, by, association, of, ribosomal, 'RNA', with, ribosomal, proteins, into]), verbo([nuclear]), complemento([precursor, 'particles,', which, undergo, a, complex, maturation, pathway, coordinated, by, 'non-ribosomal', assembly, factors])].
[sujeto(['Here,', we]), verbo([provide]), complemento([functional, insights, into, how, successive, structural, 're-arrangements', in, ribosomal, protein, 'S3', promote, maturation, of, the, 40, 'S', ribosomal, subunit])].
[sujeto(['We', show, that, 'S3']), verbo([dimerizes]), complemento([and, is, imported, into, the, nucleus, with, its, 'N-domain', in, a, rotated, conformation, and, associated, with, the, chaperone, 'Yar1'])].
[sujeto(['Yar1', is, replaced, by, the, assembly, factor, 'Ltv1,', thereby, fixing, the, 'S3', 'N-domain', in, the, rotated, orientation, and]), verbo([preventing]), complemento([its, 40, 'S', association])].
[sujeto(['Finally,', 'Ltv1', 'release,']), verbo([triggered]), complemento([by, 'phosphorylation,', and, flipping, of, the, 'S3', 'N-domain', into, its, final, position, results, in, the, stable, integration, of, 'S3'])].
[sujeto(['Caspase-3-mediated', p65, cleavage, is, believed, to]), verbo([suppress]), complemento([nuclear, 'factor-kappa', 'B', '(', 'NF-κB)-mediated', 'anti-apoptotic', transactivation, in, cells, undergoing, apoptosis])].
[sujeto(['Here', we, show, that, the, 'p65(1-97)', fragment, generated, by, 'Caspase-3', cleavage, interferes, with, ribosomal, protein, 'S3', '(', 'RPS3),', an, 'NF-κB', &, 'quot;specifier"', 'subunit,', and, selectively, retards, the]), verbo([nuclear]), complemento([translocation, of, 'RPS3,', thus, dampening, the, 'RPS3/NF-κB-dependent', 'anti-apoptotic', gene, expression])].
[sujeto(['Our', findings]), verbo([reveal]), complemento([a, novel, cell, fate, determination, mechanism, to, ensure, cells, undergo, programed, cell, death, through, interfering, with, 'RPS3/NF-κB-conferred', 'anti-apoptotic', transcription, by, the, fragment, from, partial, p65, cleavage, by, activated, 'Caspase-3'])].
[sujeto(['Discovery', and, identification, of, novel, therapeutic]), verbo([targets]), complemento([is, urgently, needed])].
[sujeto(['In', this, 'study,', we, demonstrated, that, ribosomal, protein, 'S3', '(', 'RPS3)', was, a, potential]), verbo([target]), complemento([involved, in, melanoma, growth])].
[sujeto(['Knockdown', of, 'RPS3', by, siRNA]), verbo([suppressed]), complemento([cell, growth, and, induced, apoptosis, in, melanoma, cells])].
[sujeto(['Further', mechanism, studies, showed, that, 'RPS3', knockdown, in, melanoma, cells]), verbo([triggered]), complemento([the, release, of, cytochrome, 'C', '(', 'Cyto', 'C)', from, 'mitochondrial,', increased, the, location, of, 'BID', on, mitochondrial, membrane, and, the, cleavage, of, the, 'pro-apoptotic', proteins, '(', 'PARP,', 'caspase-3', and, -, 9, ')', ',', promoted, the, opening, of, mitochondrial, permeability, transition, pore, and, the, flooding, of, calcium, ions, '(', 'Ca(2+))', into, the, 'mitochondrial,', and, decreased, the, expression, of, the, 'Ca(2+)', gatekeeper, 'MICU1', and, its, location, on, the, mitochondrial])].
[sujeto(['We', also]), verbo([found]), complemento([that, knockdown, of, 'RPS3', significantly, inhibited, tumor, growth, in, a, melanoma, xenograft, mouse, model])].
[sujeto(['Furthermore,', we, showed, that, 'RPS3', was, highly]), verbo([expressed]), complemento([in, melanoma, cell, lines, and, melanoma, tumor, 'tissues,', and, overexpression, of, 'RPS3', was, associated, with, the, poor, prognosis, of, melanoma, patients])].
[sujeto(['Our', results, therefore, demonstrate, that, 'RPS3']), verbo([regulates]), complemento([melanoma, growth, through, the, modulation, of, the, 'Cyto', 'C/Ca(2+)/MICU1', dependent, mitochondrial, signaling, and, suggest, that, 'RPS3', is, a, potential, therapeutic, target, for, melanoma, treatment])].
[sujeto(['This', study]), verbo([reports]), complemento([that, the, gene, for, the, ribosomal, protein, 'S3', '(', 'rps3)', is, preserved, and, physically, clustered, to, an, upstream, rps19, and, a, downstream, overlapping, rpl16, locus, in, the, mitochondrial, 'DNA', of, the, true, fern, 'Adiantum', 'capillus-veneris', 'L'])].
[sujeto(['Human', 'Mpv17-like', protein, '(', 'M-LPH)']), verbo([has]), complemento([been, suggested, to, participate, in, mitochondrial, function])].
[sujeto(['In', this, 'study,', we, investigated, the, proteins, that]), verbo([interact]), complemento([with, 'M-LPH,', and, identified, 'four:', 'H2A', histone, 'family,', member, 'X', '(', 'H2AX),', ribosomal, protein, 'S14', '(', 'RPS14),', ribosomal, protein, 'S3', '(', 'RPS3)', and, 'B-cell', 'receptor-associated', protein, 31, '(', 'Bap31)'])].
[sujeto(['RNAi-mediated', knockdown, of, 'M-LPH', resulted, in, an]), verbo([increase]), complemento([of, mtDNA, damage, and, reduced, the, expression, of, 'mtDNA-encoded', genes])].
[sujeto(['A', 'ROS', 'inducer,', antimycin, 'A,']), verbo([caused]), complemento([an, increase, in, both, the, number, and, size, of, the, mitochondrial, 'M-LPH', 'foci,', and, these, foci, were, 'co-localized', with, two, 'enzymes,', 'DNA', polymerase, γ, '(', 'POLG)', and, 'DNA', ligase, 'III', '(', 'LIG3),', both, involved, in, mtDNA, repair])].
[sujeto(['Taken', 'together,', these, observations]), verbo([suggest]), complemento([that, 'M-LPH', is, involved, in, the, maintenance, of, mtDNA, and, protects, cells, from, mitochondrial, dysfunction])].
[sujeto(['Mycobacterium', abscessus, subspecies, classification]), verbo([has]), complemento([important, clinical, implications])].
[sujeto(['We', used, phylogenomic, network, and, amino, acid, analyses, to]), verbo([provide]), complemento([evidence, for, the, separation, of, 'Mycobacterium', bolletii, and, 'Mycobacterium', massiliense, into, two, distinct, subspecies, which, can, potentially, be, differentiated, rapidly, by, their, protein, signatures])].
[sujeto([pannorum, is]), verbo([found]), complemento([within, the, rnl, 'gene,', and, this, 'group-IA', intron, carries, an, intronic, 'ORF', encoding, for, ribosomal, protein, 'S3'])].
[sujeto(['In', this, 'study,', we, aimed, to, investigate, how, macrophage, migration, inhibitory, factor, '(', 'MIF)', which, is]), verbo([expressed]), complemento([at, high, levels, in, metastatic, and, primary, lung, cancer, cells, could, regulate, 'NSCLC', metastasis, in, response, to, ionizing, radiation, '(', 'IR)'])].
[sujeto(['MIF-rpS3', dissociation]), verbo([induced]), complemento([by, 'IR', activated, 'NF-κB', and, made, the, expression, of, target, genes, of, this, factor, transactivated, in, two, 'NSCLC', cell, 'lines,', 'A549,', and, 'NCI-H358'])].
[sujeto(['We', also]), verbo([found]), complemento([that, 'IR-induced', dissociation, of, this, complex, led, to, increased, secretion, of, 'pro-inflammatory', cytokines, and, modulated, the, expression, of, 'epithelial-mesenchymal', transition, marker, proteins])].
[sujeto(['During', animal, 'development,', various, signaling, pathways, converge, to]), verbo([regulate]), complemento([cell, growth])].
[sujeto(['Using', biochemical, 'studies,', we, discovered, that, 'LTV1']), verbo([interacted]), complemento([with, ribosomal, protein, 'S3', and, 'co-purified', with, free, 40, 'S', ribosome, subunits])].
[sujeto(['We', further, demonstrated, that, 'LTV1', is, crucial, for, ribosome, biogenesis, through, 40, 'S', ribosome, subunit, synthesis, and, preribosomal, 'RNA', 'processing,']), verbo([suggesting]), complemento([that, 'LTV1', is, required, for, cell, growth, by, regulating, protein, synthesis])].
[sujeto(['We', also, demonstrated, that, 'Drosophila', 'Myc', '(', 'dMyc)', directly]), verbo([regulates]), complemento(['LTV1', transcription, and, requires, 'LTV1', to, stimulate, ribosome, biogenesis])].
[sujeto(['Importantly,', the]), verbo([loss]), complemento([of, 'LTV1', blocked, the, cell, growth, and, endoreplication, induced, by, dMyc])].
[sujeto(['Combined,', these, results]), verbo([suggest]), complemento([that, 'LTV1', is, a, key, downstream, factor, of, 'dMyc-induced', cell, growth, by, properly, maintaining, ribosome, biogenesis])].
[sujeto(['This', truffle]), verbo([has]), complemento([a, high, value, in, a, global, market, and, is, cultivated, in, many, countries, of, both, hemispheres])].
[sujeto([melanosporum, genome]), verbo([has]), complemento([given, researchers, unique, opportunities, to, learn, more, about, the, biology, of, the, fungus])].
[sujeto(['Upon', 'infection,', a, myriad, of, virulence, proteins, '(', 'effectors)', encoded, by, 'A/E', pathogens, are, injected, through, their]), verbo([conserved]), complemento([type, 'III', secretion, systems, '(', 'T3SS)', into, host, cells, where, they, interfere, with, cell, signaling, 'cascades,', in, particular, the, nuclear, factor, kappaB, '(', 'NF-κB)', signaling, pathway, that, orchestrates, both, innate, and, adaptive, immune, responses, for, host, defense])].
[sujeto(['Among', the, 'T3SS-secreted', 'non-LEE-encoded', '(', 'Nle)', 'effectors,', 'NleC,', a, 'metalloprotease,']), verbo([has]), complemento([been, recently, elucidated, to, modulate, host, 'NF-κB', signaling, by, cleaving, 'NF-κB', 'Rel', subunits])].
[sujeto(['However,', it, remains, elusive, how, 'NleC']), verbo([recognizes]), complemento(['NF-κB', 'Rel', subunits, and, how, the, 'NleC-mediated', cleavage, impacts, on, host, immune, responses, in, infected, cells, and, animals])].
[sujeto(['In', this, 'study,', we, show, that, 'NleC', specifically]), verbo([targets]), complemento(['p65/RelA', through, an, interaction, with, a, unique, 'N-terminal', sequence, in, p65])].
[sujeto(['Moreover,', the, 'NleC-mediated', p65, cleavage, substantially, affects, the, expression, of, a, subset, of, 'NF-κB']), verbo([target]), complemento([genes, encoding, proinflammatory, 'cytokines/chemokines,', immune, cell, infiltration, in, the, 'colon,', and, tissue, injury, in, 'C'])].
[sujeto(['Mechanistically,', the, 'NleC', 'cleavage-generated', 'p65¹⁻³⁸', fragment, interferes, with, the, interaction, between, p65, and, ribosomal, protein, 'S3', '(', 'RPS3),', a, '\'', 'specifier\'', subunit, of, 'NF-κB', that]), verbo([confers]), complemento([a, subset, of, proinflammatory, gene, 'transcription,', which, amplifies, the, effect, of, cleaving, only, a, small, percentage, of, p65, to, modulate, 'NF-κB-mediated', gene, expression])].
[sujeto(['Thus,', our, results]), verbo([reveal]), complemento([a, novel, mechanism, for, 'A/E', pathogens, to, specifically, block, 'NF-κB', signaling, and, inflammatory, responses, by, cleaving, a, small, percentage, of, p65, and, targeting, the, 'p65/RPS3', interaction, in, host, 'cells,', thus, providing, novel, insights, into, the, pathogenic, mechanisms, of, foodborne, diseases])].
[sujeto(['SPOUT', proteins, constitute, one, class, of, 'methyltransferases,', which, so, far, are]), verbo([found]), complemento([to, exert, activity, mainly, towards, 'RNAs'])].
[sujeto(['Here', we]), verbo([report]), complemento([the, crystal, structure, of, 'Sfm1,', which, comprises, of, a, typical, 'SPOUT', domain, and, a, small, 'C-terminal', domain])].
[sujeto(['Our', biochemical, data, show, that, 'Sfm1', exists, as, a, monomer, and]), verbo([has]), complemento([high, activity, towards, ribosomal, protein, 'S3', but, no, activity, towards, 'RNA'])].
[sujeto(['It', can, specifically, catalyze, the, methylation, of, 'Arg146', of, 'S3', and, the, 'C-terminal', domain, is, critical, for, substrate]), verbo([binding]), complemento([and, activity])].
[sujeto(['These', results, together]), verbo([provide]), complemento([the, structural, basis, for, 'Sfm1', functioning, as, a, 'PRMT', for, ribosomal, protein, 'S3'])].
[sujeto(['It']), verbo([has]), complemento([been, reported, that, 'GLI2', promotes, 'proliferation,', 'migration,', and, invasion, of, mesenchymal, stem, cell, and, osteosarcoma, cells])].
[sujeto(['The', gene, encoding, ribosomal, protein, 'S3', '(', 'RPS3)', was, identified, as, a]), verbo([target]), complemento([of, 'GLI2'])].
[sujeto(['Knockdown', of, 'GLI2']), verbo([decreased]), complemento(['RPS3', 'expression,', whereas, forced, expression, of, a, constitutively, active, form, of, 'GLI2', upregulated, the, expression, of, 'RPS3'])].
[sujeto(['RPS3', knockdown, by, siRNA]), verbo([decreased]), complemento([the, migration, and, invasion, of, osteosarcoma, cells])].
[sujeto(['Although', forced, expression, of, constitutively, active, 'GLI2']), verbo([increased]), complemento([the, migration, of, human, mesenchymal, stem, 'cells,', knockdown, of, 'RPS3', reduced, the, 'up-regulated', migration])].
[sujeto(['In', 'contrast,', forced, expression, of, 'RPS3']), verbo([increased]), complemento([migration, and, invasion, of, osteosarcoma, cells])].
[sujeto(['Immunohistochemical', analysis, showed, that, 'RPS3', expression, was]), verbo([increased]), complemento([in, primary, osteosarcoma, lesions, with, lung, metastases, compared, with, those, without])].
[sujeto(['These', findings, indicate, that, 'GLI2-RPS3', signaling, may, be, a, marker, of, invasive, osteosarcoma, and, a, therapeutic]), verbo([target]), complemento([for, patients, with, osteosarcoma])].
[sujeto(['Ribosome', biogenesis]), verbo([has]), complemento([been, studied, extensively, in, the, yeast, 'Saccharomyces', cerevisiae])].
[sujeto(['Yeast', 'Ltv1', is, a]), verbo([conserved]), complemento([40, 'S-associated', biogenesis, factor, that, has, been, proposed, to, function, in, small, subunit, nuclear, export])].
[sujeto(['Here', we, show, that, 'Ltv1']), verbo([has]), complemento([a, canonical, 'leucine-rich', nuclear, export, signal, '(', 'NES)', at, its, extreme, 'C', terminus, that, is, both, necessary, for, 'Crm1', interaction, and, 'Ltv1', export])].
[sujeto(['Overexpression', of, an, 'Ltv1', lacking, its, 'NES', '(', 'Ltv1∆C13)', was, strongly, dominant, negative, and, resulted, in, the]), verbo([nuclear]), complemento([accumulation, of, 'RpS3-GFP;', 'however,', export, of, the, 'pre-40S', was, not, affected])].
[sujeto(['Thus,', if, 'Ltv1', is, a]), verbo([nuclear]), complemento([export, adapter, for, the, 'pre-40S', 'subunit,', its, function, must, be, fully, redundant, with, additional, export, factors])].
[sujeto(['The', dominant, negative, phenotype, of, 'Ltv1∆NES', overexpression, was]), verbo([suppressed]), complemento([by, 'co-overexpressing', 'RpS3', and, its, 'chaperone,', 'Yar1,', or, by, deletion, of, the, 'RpS3-binding', site, in, 'Ltv1∆NES,', suggesting, that, titration, of, 'RpS3', by, 'Ltv1∆NES', is, deleterious, in, yeast])].
[sujeto(['The', 'dominant-negative', phenotype, did, not, correlate, with, a]), verbo([decrease]), complemento([in, 40, 'S', levels, but, rather, with, a, reduction, in, the, 'polysome-to-monosome', 'ratio,', indicating, reduced, rates, of, translation])].
[sujeto(['We']), verbo([suggest]), complemento([that, titration, of, 'RpS3', by, excess, nuclear, 'Ltv1', interferes, with, 40, 'S', function, or, with, a, nonribosomal, function, of, 'RpS3'])].
[sujeto(['The', pentatricopeptide, repeat, '(', 'PPR)', proteins, represent, a, large, family, of, 'RNA-binding', proteins, that]), verbo([have]), complemento([many, roles, in, 'post-transcriptional', 'RNA', processes, within, plant, organelles])].
[sujeto(['Among', the, 'PPR', proteins, that]), verbo([target]), complemento([plant, 'mitochondria,', the, 'restorer-of-fertility', '(', 'Rf)', proteins, are, characterized, by, their, inhibitory, action, on, 'mitochondrion-localized', cytoplasmic, male, sterility, '(', 'CMS)', genes, in, various, crop, species])].
[sujeto(['Close', homologs, to, known, 'Rfs', from, 'radish,', 'petunia,', and, rice, can, be, identified, in, most, higher, plant, species, and, these, proteins, define, the]), verbo([recognized]), complemento([subgroup, of, 'Rf-like', '(', 'RFL)', 'PPR', proteins])].
[sujeto(['In', this, paper, we, describe, the, function, of, the, 'RFL9', gene, from, 'Arabidopsis', 'thaliana,', and, show, that, it, is]), verbo([associated]), complemento([with, ribonucleolytic, cleavages, within, the, coding, sequences, of, 'rps3-rpl16', and, orf240a, mitochondrial, transcripts, in, the, 'Col-0', accession])].
[sujeto(['RFL9', therefore, represents, an, 'Rf-like', 'PPR', gene, that]), verbo([has]), complemento([the, potential, to, compromise, the, function, of, an, essential, mitochondrial, gene, and, whose, function, is, also, associated, with, a, mitochondrial, orf, sharing, significant, homology, with, a, proven, 'CMS-causing', orf])].
[sujeto(['Additionally,', 'RFL9', counts, among, the, 'RFL', genes, that, are, probably, controlled, by, short, regulatory, 'RNAs,', and, our, results]), verbo([provides]), complemento([a, potential, explanation, for, such, 'control,', which, in, the, case, of, 'RFL9', might, have, evolved, to, limit, its, detrimental, effect, on, rps3, expression])].
[sujeto(['We', show, that, in, resting, 'HEK293', 'cells,', 'RPS3']), verbo([interacts]), complemento([with, 'NF-κB', inhibitor, 'IκBα'])].
[sujeto(['In', 'addition,', a, strong, in, vitro, interaction, was, observed, between, 'RPS3', and, 'IκBα,', while]), verbo([binding]), complemento([between, 'RPS3', and, p65, was, very, weak])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'IκBα', sequesters, not, only, p65, but, also, 'RPS3', in, the, cytoplasm])].
[sujeto(['This', would]), verbo([ensure]), complemento([maintenance, of, an, 'RPS3', pool, for, the, 'NF-κB', pathway, as, well, as, equimolar, release, of, 'RPS3', and, p65, upon, stimulation])].
[sujeto(['Cell', 'competition,', the, conditional]), verbo([loss]), complemento([of, viable, genotypes, only, when, surrounded, by, other, 'cells,', is, a, phenomenon, observed, in, certain, genetic, mosaic, conditions])].
[sujeto(['Mutations', were, identified, by, 'whole-genome', 'sequencing,', making, use, of, software, tools, that, greatly, facilitate, the, distinction, between, newly]), verbo([induced]), complemento([mutations, and, other, sources, of, apparent, sequence, 'polymorphism,', thereby, reducing, 'false-positive', and, 'false-negative', identification, rates])].
[sujeto(['The', use, of, stably]), verbo([expressed]), complemento([genes, as, normalizers, has, crucial, role, in, accurate, and, reliable, expression, analysis, estimated, by, quantitative, 'real-time', polymerase, chain, reaction, '(', 'qPCR)'])].
[sujeto(['Recent', studies]), verbo([have]), complemento([shown, 'that,', the, expression, levels, of, common, housekeeping, genes, are, varying, in, different, tissues, and, experimental, conditions])].
[sujeto(['It', is, estimated, that, the, gDNA, contamination, in, gene, expression, analysis]), verbo([lead]), complemento([to, an, overestimation, of, the, 'RNA', transcript, level])].
[sujeto(['The', aim, of, this, study, was, to, validate, the, most, stably]), verbo([expressed]), complemento([reference, genes, in, two, different, tissues, of, 'Aeluropus', 'littoralis-halophyte', grass, at, salt, stress, and, recovery, condition])].
[sujeto(['Ten', candidate, reference, genes]), verbo([participating]), complemento([in, different, biological, processes, were, analyzed, in, four, groups, of, samples, including, root, and, leaf, 'tissues,', salt, stress, and, recovery, condition])].
[sujeto(['To', determine, the, most, stably]), verbo([expressed]), complemento([reference, 'genes,', three, statistical, methods, '(', 'geNorm,', 'NormFinder', and, 'BestKeeper)', were, applied])].
[sujeto(['Additionally,', for, assessing, 'DNA', contamination, in, 'RNA', 'samples,', a, set, of, unique, primers, were, designed, based, on, the]), verbo([conserved]), complemento([region, of, ribosomal, 'DNA', '(', 'rDNA)'])].
[sujeto(['The', 'universality,', specificity, and, sensitivity, of, these]), verbo([primer]), complemento([pairs, were, also, evaluated, in, 'Poaceae'])].
[sujeto(['Nuclear', and, organellar, genomes]), verbo([have]), complemento([been, recently, sequenced, for, several, 'Nannochloropsis', spp])].
[sujeto(['CAUP', 'Q', 202, and, 'Trachydiscus', 'minutus,', and, carried, out, their, comparative, analysis, in, the, context, of, available, data, from, 'Nannochloropsis', and, other, 'stramenopiles,']), verbo([revealed]), complemento([a, number, of, noticeable, findings])].
[sujeto(['First,', mitogenomes, of, most, eustigmatophytes, are, highly, collinear, and, similar, in, the, gene, 'content,', but, extensive, rearrangements, and]), verbo([loss]), complemento([of, three, otherwise, ubiquitous, genes, happened, in, the, 'Vischeria', 'lineage;', this, correlates, with, an, accelerated, evolution, of, mitochondrial, gene, sequences, in, this, lineage])].
[sujeto(['Third,', eustigmatophyte, mitogenomes, uniquely, share, a, truncated, nad11, gene, encoding, only, the, 'C-terminal', part, of, the, 'Nad11', 'protein,', while, the, 'N-terminal', part, is, encoded, by, a, separate, gene, in, the]), verbo([nuclear]), complemento([genome])].
[sujeto(['Fourth,', 'UGA', as, a, termination, codon, and, the, cognate]), verbo([release]), complemento([factor, mRF2, were, lost, from, mitochondria, independently, by, the, 'Nannochloropsis', and, 'T'])].
[sujeto([saksenae, is]), verbo([reported]), complemento([for, the, first, time])].
[sujeto(['The', phylogeny, based, on, 12, 'protein-coding', genes, '(', except, the]), verbo([loss]), complemento([of, other, two, genes, in, 'Acremonium', 'implicatum)', suggests, the, close, phylogenetic, relationship, between, 'L'])].
[sujeto(['Comparative', analysis]), verbo([reveals]), complemento([that, mitogenome, of, 'L'])].
[sujeto(['The', trnC, between, cob, and, cox1, is]), verbo([conserved]), complemento([in, the, mitogenomes, of, three, nematophagous, fungus, of, 'Pochonia', 'chlamydosporia,', 'A'])].
[sujeto(['This', study, may]), verbo([provide]), complemento([valuable, information, for, further, research, on, mitochondrial, evolution, of, nematophagous, fungus, and, 'Lecanicillium', species])].
[sujeto(['Rps11']), verbo([confers]), complemento([excellent, resistance, to, predominant, 'Phytophthora', sojae, isolates, capable, of, defeating, major, 'Rps', genes, deployed, into, soybean, 'production,', representing, a, novel, source, of, resistance, for, soybean, cultivar, enhancement])].
[sujeto(['Phytophthora', root, and, stem, rot, '(', 'PRSR),']), verbo([caused]), complemento([by, the, 'soil-borne', pathogen, 'Phytophthora', 'sojae,', is, a, devastating, disease, of, soybean, '[', 'Glycine', max, '(', 'L'])].
[sujeto(['The', soybean, landrace, 'PI', 594527, was]), verbo([found]), complemento([to, carry, excellent, resistance, to, all, 'P'])].
[sujeto(['A', mapping, population, consisting, of, 58, 'F2', individuals, and, 209, 'F2:3', families, derived, from, a, cross, between, 'PI', 594527, and, the, susceptible]), verbo([cultivar]), complemento(['\'', 'Williams\'', was, used, to, characterize, the, inheritance, pattern, of, the, resistance, to, 'P'])].
[sujeto(['It', was]), verbo([found]), complemento([that, the, resistance, was, conferred, by, a, single, 'Rps', 'gene,', designated, 'Rps11,', which, was, initially, defined, as, an, '~5', 'Mb', genomic, region, at, the, beginning, of, chromosome, 7, by, bulked, segregant, analysis, '(', 'BSA)', with, a, nucleotide, polymorphism, '(', 'SNP)', chip, comprising, 7039, 'SNP', markers])].
[sujeto([',', 'BARCSOYSSR_07_0295)', was]), verbo([found]), complemento([to, tightly, 'co-segregate', with, 'Rps11', in, the, mapping, population, and, can, be, effectively, used, for, 'marker-assisted', selection, of, this, gene, for, development, of, resistant, soybean, cultivars])].
[sujeto(['The', 23, species, of, mycoheterotrophic, or, exoparasitic, land, plants, '(', from, 15, genera, and, 6, 'families)', studied, so, far, all]), verbo([retain]), complemento([a, minimal, set, of, 17, of, the, normally, 116, plastome, genes])].
[sujeto(['Only', 'Rafflesia', 'lagascae,', an, endoparasite, concealed, in, its, host, except, when, 'flowering,']), verbo([has]), complemento([been, reported, as, perhaps, lacking, a, 'plastome,', although, it, still, possesses, 'plastid-like', compartments])].
[sujeto(['A', similar, extent, of, divergence, might]), verbo([have]), complemento([caused, the, plastome, of, 'Rafflesia', to, escape, detection])].
[sujeto(['The', contents, of, 'A,', 'T,', 'C,', and, 'G', in, the, 'NM92', mitogenome, were]), verbo([found]), complemento([to, be, 27.48, '%', ',', 27.41, '%', ',', 22.63, '%', ',', and, 22.48, '%', ',', respectively])].
[sujeto(['This', complete, mitogenome, sequence]), verbo([provides]), complemento([useful, information, to, understand, the, cultivation, of, 'Vigna', radiata, and, other, crops])].
[sujeto(['Phylogenetic', and, divergence, considerations]), verbo([suggest]), complemento([that, a, 544, -, bp, fragment, of, rps3, was, transferred, to, the, nuclear, genome, shortly, after, divergence, of, the, 'A-', and, 'D-', genome, diploid, cottons])].
[sujeto(['Reverse', transcriptase, quantitative, polymerase, chain, reaction, '(', 'RT-qPCR)']), verbo([has]), complemento([become, a, widely, used, technique, to, quantify, gene, expression])].
[sujeto(['This', study, will, potentially]), verbo([provide]), complemento([more, suitable, reference, gene, candidates, for, 'RT-qPCR', analysis, in, 'T'])].
[sujeto(['The', mitogenome, contains, 44, 'genes,', including, 2, ribosomal, 'RNA,', 19, transfer, 'RNA,', 5, ribosomal, 'proteins,', 1, 'ymf,', 2, open, reading, frames, '(', 'ORFs)', and, 16, genes]), verbo([involved]), complemento([in, cellular, respiration])].
[sujeto([rps3, and, rpl16, also]), verbo([have]), complemento([a, 45, bp, overlapped, region])].
[sujeto(['Except', for, open, reading, frames, near, 'stem-loop', 'region,', the, results, show, 'Calliarthron', tuberculosum, mtDNA]), verbo([has]), complemento([a, high, similarity, with, other, 'Florideophyceae', algae, mitogenomes, in, gene, 'synteny,', structure, and, gene, content])].
[sujeto(['The', larvae, of, the, common, green, bottle, fly, 'Lucilia', sericata, '(', 'Diptera:', 'Calliphoridae)']), verbo([have]), complemento([been, used, for, centuries, to, promote, wound, 'healing,', but, the, molecular, basis, of, their, 'antimicrobial,', debridement, and, healing, functions, remains, largely, unknown])].
[sujeto(['The', analysis, of, differential, gene, expression, in, specific, larval, tissues, before, and, after, immune, challenge, could, be, used, to, identify, key, molecular, 'factors,', but, the, most, sensitive, and, reproducible, method, 'qRT-PCR']), verbo([requires]), complemento([validated, reference, genes])].
[sujeto(['Two', widely, applied, algorithms, '(', 'GeNorm', and, 'Normfinder)', were, used, to, analyze, reference, gene, candidates, in, different, larval, tissues]), verbo([associated]), complemento([with, 'secretion,', 'digestion,', and, antimicrobial, activity, '(', 'midgut,', 'hindgut,', salivary, 'glands,', crop, and, fat, 'body)'])].
[sujeto(['The', 'Gram-negative', bacterium, 'Pseudomonas', aeruginosa, was, then, used, to, boost, the, larval, immune, system, and, the, stability, of, reference, gene, expression, was, tested, in, comparison, to, three, immune, genes, '(', 'lucimycin,', 'defensin-1', and, 'attacin-2),', which]), verbo([target]), complemento([different, pathogen, classes])].
[sujeto(['We', observed, no, differential, expression, of, the, antifungal, peptide, 'lucimycin,', whereas, the, representative]), verbo([targeting]), complemento(['Gram-positive', bacteria, '(', 'defensin-1)', was, upregulated, in, salivary, 'glands,', 'crop,', nerve, ganglion, and, reached, its, maximum, in, fat, body, '(', up, to, 300, -, 'fold)'])].
[sujeto(['The', strongest, upregulation, in, all, immune, challenged, tissues, '(', over, 50, ',', 0, -, fold, induction, in, the, fat, 'body)', was, monitored, for, 'attacin-2,', the, representative]), verbo([targeting]), complemento(['Gram-negative', bacteria])].
[sujeto(['Ribosome', synthesis]), verbo([involves]), complemento([all, three, 'RNA', polymerases, which, are, 'co-ordinately', regulated, to, produce, equimolar, amounts, of, rRNAs, and, ribosomal, proteins, '(', 'RPs)'])].
[sujeto(['After', serum, replenishment, the, activity]), verbo([increased]), complemento([to, normal, 'levels,', suggesting, 'post-transcriptional', regulation, of, these, genes])].
[sujeto(['Transcription', of, luciferase, reporter, was, unaffected, in, this, 'mutant,', and, luciferase, activity, did, not, decline, during, serum, 'starvation,', showing, that, this, sequence, is]), verbo([required]), complemento([to, repress, translation, of, 'RPL30', 'mRNA,', and, mutations, in, this, region, relieve, repression])].
[sujeto([histolytica, blocks, ribosome, biogenesis, 'post-transcriptionally', by]), verbo([inhibiting]), complemento(['pre-rRNA', processing, on, the, one, 'hand,', and, the, translation, of, 'RP', mRNAs, on, the, other])].
[sujeto(['Pseudoperonospora', cubensis, is, a, species, of, water, mould, known, for]), verbo([causing]), complemento([downy, mildew, on, cucurbits])].
[sujeto(['It', is, the, first]), verbo([report]), complemento([of, the, complete, mitochondrial, genome, in, the, genus, 'Pseudoperonospora'])].
[sujeto([cubensis]), verbo([has]), complemento([a, close, genetic, relationship, with, genus, 'Phytophthora'])].
[sujeto(['Rearrangements', of, the, filamentous, actin, network]), verbo([involves]), complemento([a, broad, range, of, actin, binding, proteins])].
[sujeto(['However,', analysis, of, data, from, 'TardiBase']), verbo([reveals]), complemento([that, the, gelsolin, of, the, eutardigrade, 'Hypsibius', dujardini, has, only, three, segments, '(', 'S1-S3)'])].
[sujeto(['The', 'Peripatoides', and, 'Hypsibius', gelsolin, revealed, both]), verbo([conserved]), complemento([binding, motifs, for, 'G-actin,', 'F-actin', and, phosphatidylinositol, 4, ',', 5, -, bisphosphate, '(', 'PIP2),', along, with, a, full, set, of, 'type-1', and, 'type-2', 'Ca(2+)-binding', sites, which, could, result, in, the, binding, of, eight, and, four, calcium, 'ions,', respectively])].
[sujeto(['We']), verbo([suggest]), complemento([that, a, gelsolin, with, three, segments, was, present, in, the, last, common, ancestor, of, the, ecdysozoan, clade, 'Panarthropoda', '(', 'Onychophora,', 'Tardigrada,', 'Arthropoda),', primarily, because, the, gelsolin, of, all, 'non-Ecdysozoa', studied, so, far, '(', except, 'Chordata)', reveals, this, number, of, segments])].
[sujeto(['The', 'TCP', hardness]), verbo([has]), complemento([no, effect, on, difference, in, reduction, of, functional, mitral, regurgitation])].
[sujeto(['The', study, shows, that, 'S3', valve, is]), verbo([associated]), complemento([with, reduced, 'PVL', rate, compared, with, 'SXT,', which, is, an, important, clinical, advantage])].
[sujeto(['This', study, manifested, the, effects, of, polysaccharides, from, 'Ganoderma', lucidum, strain, 'S3', '(', 'GLP', 'S3)', on, chronic, pancreatitis, '(', 'CP)', therapy, and, intestinal, microbiota, modulation, in, mice]), verbo([induced]), complemento([by, diethyldithiocarbamate, '(', 'DDC)'])].
[sujeto(['The', 'GLPS3', was, prepared, from, cultured, mycelium, and, markedly, alleviated, the, pancreatitis, in, mice, through]), verbo([decreasing]), complemento(['lipase,', 'AMS,', 'IFN-γ', and, 'TNF-α', level, as, well, as, increasing, 'SOD', and, total, antioxidant, activity])].
[sujeto(['Furthermore,', high, throughput, sequencing, analysis, revealed, that, 'GLPS3', altered, the, composition, and, diversity, of, intestinal, 'microbiota,', 'especially,']), verbo([decreased]), complemento([the, relative, abundance, of, phylum, 'Bacteroidetes', and, increased, that, of, phylum, 'Firmictutes'])].
[sujeto(['At', the, genus, 'level,', supplementation, of, 'GLPS3']), verbo([increased]), complemento([the, relative, abundance, of, the, beneficial, bacteria, such, as, 'Lactobacillales,', 'Roseburia', and, 'Lachnospiraceae'])].
[sujeto(['Large', randomized, controlled, trials, indicate, that, human, papillomavirus, '(', 'HPV)-based', screening, may]), verbo([provide]), complemento([better, protection, against, cervical, cancer, than, cytology, alone, through, improved, detection, of, premalignant, disease, in, the, first, screening, round, prior, to, progression])].
[sujeto(['Offering', devices, for, 'HPV', 'self-sampling']), verbo([has]), complemento([the, potential, to, increase, participation, rates, in, those, women, who, are, at, higher, risk, of, developing, cervical, cancer])].
[sujeto(['Regarding', primary, 'prevention,', the, 9, -, valent, vaccine, may]), verbo([provide]), complemento([protection, against, up, to, 85, '%', of, cervical, intraepithelial, neoplasia, '(', 'CIN)', 3, and, 90, '%', of, cervical, 'cancer,', and, is, available, in, 'Europe', as, a, 2, -, dose, schedule, from, 'May', 2016])].
[sujeto(['Steel', slag]), verbo([has]), complemento([been, widely, used, as, amendment, and, silicon, fertilizer, to, alleviate, the, mobility, and, bioavailability, of, heavy, metals, in, soil])].
[sujeto(['The', results, indicated, that, application, of, slag]), verbo([increased]), complemento([soil, 'pH,', 'plant-available', silicon, concentrations, in, 'soil,', and, decreased, the, bioavailability, of, metals, compared, with, control, 'treatment,', whereas, pulverous, slag, '(', 'S1)', was, more, effective, than, granular, slag, '(', 'S2', and, 'S3)'])].
[sujeto(['The', 'acid-extractable', fraction, of, 'Cd', in, the, spiked, soil, was, significantly]), verbo([decreased]), complemento([with, application, of, 'S1', at, rates, of, 1, and, 3, &, 'nbsp;%,', 'acid-extractable', fractions, of, 'Cu', and, 'Zn', were, decreased, when, treated, at, 3, &, 'nbsp;%'])].
[sujeto(['However,', use, of, pulverous, slag, at, 1, &, 'nbsp;%', significantly]), verbo([promotes]), complemento([rice, 'growth,', restricted, rice, growth, when, treated, at, 3, &, 'nbsp;%'])].
[sujeto(['Significant', changes, for, 'FMP', were]), verbo([found]), complemento([between, 'S1,', 'S2,', and, 'S3', '(', 23.41, '±8'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, body, composition, changes, observed, during, adolescence, are, not, driven, by, changes, in, 'PA'])].
[sujeto(['Moreover,', the, interaction, analysis]), verbo([suggests]), complemento([that, 'PA', behavior, is, affected, by, 'sex,', but, is, not, modified, by, maturation])].
[sujeto(['We', present, results, from, two, example, 'systems,', firstly, an, active, isotropic, fluid, boundary, consisting, of, particles, that, can]), verbo([bind]), complemento([and, unbind, from, the, interface, and, generate, surface, tension, gradients, through, active, contractility])].
[sujeto(['The', areas, and, intensities, of, labelling]), verbo([increased]), complemento([with, 'CW', severity])].
[sujeto(['The', neutral, monosaccharide, compositions, of, the, 'non-cellulosic', polysaccharides, of, these, wood, types, were, determined, on, 'small,', well, defined, 'discs,', and, showed, the, proportion, of, galactose, was, higher, for, 'CWs', and]), verbo([increased]), complemento([with, severity])].
[sujeto(['Firstly', this, geometric, isomerism, plays, a, major, role, in, controlling, the, guest]), verbo([binding]), complemento([properties, of, cages, because, a, fac, 'tris-chelate', arrangement, of, 'pyrazolyl-pyridine', chelates, around, a, metal, ion, vertex, results, in, formation, of, a, convergent, set, of, 'inwardly-directed', 'C-H', protons, in, a, region, of, high, positive, electrostatic, potential, close, to, a, metal, cation])].
[sujeto(['This', collection, of, 'δ+', protons, therefore]), verbo([provides]), complemento([a, 'charge-assisted', 'hydrogen-bond', donor, 'site,', which, interacts, with, the, 'electron-rich', regions, of, guest, molecules, that, are, of, the, correct, size, and, shape, to, occupy, the, cage, 'cavity,', and, the, strength, of, this, 'hydrogen-bonding', interaction, plays, a, major, role, in, guest, recognition, in, 'non-aqueous', solvents])].
[sujeto(['Secondly', the, ability, to, prepare, mononuclear, complexes, with, either, a, fac, or, mer, arrangement, of, ligands]), verbo([provides]), complemento([an, entry, into, the, 'controlled,', stepwise, assembly, of, heterometallic, cages, based, on, a, combination, of, kinetically, inert, and, kinetically, labile, metal, ions, at, different, sites])].
[sujeto(['This']), verbo([has]), complemento([allowed, introduction, of, useful, physical, properties, such, as, redox, activity, or, 'luminescence,', commonly, associated, with, inert, metal, ions, which, are, not, amenable, to, participation, in, thermodynamic, 'self-assembly', 'processes,', to, be, incorporated, in, a, predictable, way, into, the, superstructures, of, coordination, cages, at, specific, sites])].
[sujeto(['For', this, purpose, we]), verbo([have]), complemento([selected, the, 16, -, mer, peptide, 'Bak16BH3', as, model, of, study, and, carried, out, several, samplings, in, explicit, solvent])].
[sujeto(['Moreover,', the, 8, µs, trajectory, was, further, extended, to, 16, µs, to]), verbo([have]), complemento([reference, values, of, the, diverse, properties, measured])].
[sujeto(['Among', the, 'latter,', we]), verbo([have]), complemento([computed, the, number, of, new, conformational, patterns, sampled, with, 'time,', using, strings, defined, from, the, conformations, attained, by, each, of, the, residues, in, the, peptide])].
[sujeto(['Results']), verbo([suggest]), complemento([that, a, few, short, molecular, dynamics, trajectories, may, provide, a, better, sampling, than, one, unique, trajectory])].
[sujeto(['However,', caution, should, be, exercised, since, short, trajectories, need, to, be, long, enough, to, overcome, local, barriers, surrounding, the, starting, point, and, the]), verbo([required]), complemento([sampling, time, depends, on, the, number, of, degrees, of, freedom, of, the, system, under, study])].
[sujeto(['An', effective, way, to, get, insight, into, the, minimum, 'MD', trajectory, length]), verbo([requires]), complemento([monitoring, the, convergence, of, different, structural, features, as, shown, in, the, present, work])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, putative, '[', 'S3](•-)', ligand, is, only, weakly, coordinating, and, can, be, easily, displaced, by, nucleophiles])].
[sujeto(['We']), verbo([found]), complemento([the, proportion, of, cM, decreased, and, intM, increased, significantly, by, early, 'lactation,', whereas, there, was, a, nadir, in, the, proportion, of, ncM, in, late, 'gestation,', two, weeks, prepartum])].
[sujeto(['Monocyte', composition, appears, to, be]), verbo([regulated]), complemento([in, 'pregnancy,', possibly, to, limit, the, proportion, of, highly, inflammatory, monocytes, i])].
[sujeto(['Ultimately,', we]), verbo([found]), complemento([that, moDC, differentiated, from, 'CD14+', monocytes, isolated, in, the, early, dry, period, of, late, gestation, had, impaired, 'E'])].
[sujeto(['These', data]), verbo([suggest]), complemento([monocytes, in, late, 'gestation,', in, contrast, to, other, stages, of, pregnancy, and, 'lactation,', differentiate, and, maturate, into, moDC, less, capable, of, eliciting, strong, 'T', cell, 'activation,', and, have, 'macrophage-like', cytokine, profiles])].
[sujeto(['These', results]), verbo([provide]), complemento([insight, into, maternal, immune, modulation, and, elucidate, potential, immune, changes, necessary, to, facilitate, bovine, pregnancy])].
[sujeto(['Electron', microscopy]), verbo([has]), complemento([been, used, to, study, the, degradation, of, organic, solar, cells, when, exposed, to, humid, air])].
[sujeto(['Devices', with, various, different, combinations, of, commonly, used, organic, solar, cell, hole, transport, layers, and, cathode, materials]), verbo([have]), complemento([been, investigated])].
[sujeto(['In', this, way, the, ingress, of, water, and, the, effect, it]), verbo([has]), complemento([on, devices, could, be, studied])].
[sujeto(['It', was]), verbo([found]), complemento([that, calcium, and, aluminum, in, the, cathode, both, react, with, 'water,', causing, voids, and, delamination, within, the, device])].
[sujeto(['The', use, of, 'poly(3,4-ethylenedioxythiophene)', polystyrene, sulfonate, '(', 'PEDOT:PSS)', was]), verbo([found]), complemento([to, increase, the, degradation, by, easing, water, ingress, into, the, device])].
[sujeto(['Kidney', injury, 'molecule-1', '(', 'Kim-1)']), verbo([has]), complemento([been, validated, as, a, urinary, biomarker, for, acute, and, chronic, renal, damage])].
[sujeto(['The', expression, of, 'Kim-1', mRNA, is, also]), verbo([activated]), complemento([by, acute, kidney, injury, induced, by, cisplatin, in, rodents, and, humans])].
[sujeto(['To', 'date,', the, measurement, of, 'Kim-1', expression]), verbo([has]), complemento([not, fully, allowed, the, detection, of, in, vitro, cisplatin, nephrotoxicity, in, immortalized, culture, cells, such, as, human, 'kidney-2', cells, and, immortalized, proximal, tubular, epithelial, cells])].
[sujeto(['However,', the, 'Kim-1', reporter, gene, failed, to]), verbo([respond]), complemento([to, cisplatin, in, 'A9', fibroblast, cells, that, contained, the, same, reporter, mouse, artificial, 'chromosome,', suggesting, cell, 'type-specificity', for, activation, of, the, reporter])].
[sujeto(['We']), verbo([report]), complemento([the, feasibility, of, measuring, in, vitro, cisplatin, nephrotoxicity, using, a, 'Kim-1', reporter, gene, in, 'S3', cells])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, the, anesthetics, do, not, present, a, considerable, hepatotoxicity])].
[sujeto(['We', determined, whether, the, 'Y-box']), verbo([binding]), complemento(['protein-1', '(', 'YB-1)', and, its, binding, 'partner,', the, 'X-linked', ribosomal, protein, 'S4', '(', 'RPS4X),', are, associated, with, clinical, outcome, in, bladder, cancer])].
[sujeto(['Kaplan-Meier', and, multivariate, 'Cox', regression, analyses, indicated, that, low, expression, of, 'RPS4X', was]), verbo([associated]), complemento([with, a, higher, risk, of, death, or, disease, recurrence])].
[sujeto(['In', 'contrast,', 'YB-1', was, not, significantly]), verbo([associated]), complemento([with, either, 'recurrence-free', or, overall, survival])].
[sujeto(['Low', 'RPS4X', expression, is]), verbo([associated]), complemento([with, poor, 'disease-specific', and, 'recurrence-free', survival, in, bladder, cancer])].
[sujeto(['Hepatitis', 'C', virus, '(', 'HCV)', nonstructural, protein, 5, 'B', '(', 'NS5B)']), verbo([has]), complemento(['RNA-dependent', 'RNA', polymerase, '(', 'RdRp)', activity])].
[sujeto(['Because', 'NS5B']), verbo([recognizes]), complemento([various, 'RNA', motifs, besides, the, 'HCV', 'genome,', 'NS5B', has, the, potential, of, interacting, with, host, 'RNA', molecules])].
[sujeto(['In', this, 'study,', an, 'RNA', pool, enriched, with, the, 3, '\'', -, 'UTR', sequences, was, generated, and, mRNA, molecules, with, high, affinity]), verbo([binding]), complemento([to, 'NS5B', were, selected, by, iterative, selection])].
[sujeto(['Among', the, high]), verbo([binding]), complemento([mRNA, 3, '\'', -, 'UTR', 'segments,', we, analyzed, the, housekeeping, ribosomal, protein, 'S4,', 'X-linked', '[', 'RPS4X]', mRNA, 3, '\'', -, 'UTR', and, the, 3, '\'', -, 'UTR', of, 'galectin-1', '(', 'GAL-1)', 'mRNA,', which, is, known, to, be, one, of, the, genes, upregulated, in, 'HCV-infected', liver, cells, and, to, have, a, wide, spectrum, of, biological, properties])].
[sujeto(['By', means, of, 'IP-RT-PCR,', it, was, demonstrated, that, both, of, the, mRNA, molecules]), verbo([bind]), complemento([to, 'NS5B', in, the, cytoplasm])].
[sujeto(['Interestingly,', 'GAL-1', and, 'RPS4X', mRNA, can, serve, as, templates, for, 'NS5B', 'RdRp,']), verbo([suggesting]), complemento([these, 'RNA', molecules, are, regulated, in, vivo, by, 'NS5B'])].
[sujeto(['The', 'X-linked', ribosomal, protein, 'S4', '(', 'RPS4X),', which, is]), verbo([involved]), complemento([in, cellular, translation, and, 'proliferation,', has, previously, been, identified, as, a, partner, of, the, overexpressed, multifunctional, protein, 'YB-1', in, several, breast, cancer, cells])].
[sujeto(['Immunohistochemistry', studies, indicated, that, high, expression, of, 'RPS4X', was]), verbo([associated]), complemento([with, a, lower, risk, of, death, and, later, disease, progression, '(', 'HR', =, 0.713, ',', 'P', =, 0.001, and, 'HR', =, 0.761, ',', 'P', =, 0.001, ',', 'respectively)', as, compared, to, low, expression, of, 'RPS4X'])].
[sujeto(['In', 'contrast,', 'YB-1', was, not, significantly]), verbo([associated]), complemento([with, either, recurrence, or, survival, time, in, this, cohort])].
[sujeto(['Finally,', the, depletion, of, 'RPS4X', with, different, siRNAs, in, two, different, ovarian, cancer, cell, lines, reduced, their, proliferative, growth, rate, but, more, importantly]), verbo([increased]), complemento([their, resistance, to, cisplatin])].
[sujeto(['Altogether,', these, results]), verbo([suggest]), complemento([that, the, levels, of, 'RPS4X', could, be, a, good, indicator, for, resistance, to, 'platinum-based', therapy, and, a, prognostic, marker, for, ovarian, cancer])].
[sujeto(['Recent', studies]), verbo([have]), complemento([revealed, heterogeneity, in, the, structure, of, eukaryotic, cytoplasmic, 'ribosomes,', including, a, difference, in, protein, composition])].
[sujeto(['It']), verbo([has]), complemento([been, proposed, that, this, 'heterogeneity,', or, the, specialized, 'ribosome,', contributes, to, tissue, development, and, homeostasis, through, selective, mRNA, 'translation,', although, this, remains, largely, unclear])].
[sujeto(['Our', previous, proteomic, survey, of, rodent, ribosomes]), verbo([found]), complemento([the, 'testis-specific', ribosomal, proteins, 'L10-like', and, 'L39-like,', which, are, paralogues, of, the, 'X-linked', ribosomal, proteins, 'L10', and, 'L39,', respectively])].
[sujeto(['We']), verbo([have]), complemento([hypothesized, that, the, rodent, testis, provides, a, good, model, for, examining, the, possible, functional, importance, of, ribosome, heterogeneity])].
[sujeto(['In', the, present, 'study,', a, new, paralogue, of, 'X-linked', ribosomal, protein, 'S4']), verbo([has]), complemento([been, identified, in, the, mouse, testis])].
[sujeto(['The', gene, encoding, this, paralogue, was, 'autosomal,', intronless, and]), verbo([expressed]), complemento([predominantly, in, the, testis])].
[sujeto(['The', 'Y-box']), verbo([binding]), complemento([protein, 1, '(', 'YB-1)', is, a, multifunctional, protein, that, affects, 'transcription,', 'splicing,', and, translation])].
[sujeto(['Overexpression', of, 'YB-1', in, breast, cancers]), verbo([causes]), complemento([cisplatin, resistance])].
[sujeto(['The', exact, mechanism, by, which, 'YB-1']), verbo([confers]), complemento([cisplatin, resistance, is, unknown])].
[sujeto(['The', aim, of, the, present, study, was, to, 'identify,', using, mass, 'spectrometry,', proteins, that]), verbo([interact]), complemento([with, 'YB-1', that, are, important, for, cisplatin, resistance, in, two, breast, cancer, cell, 'lines,', namely, 'MCF7', and, 'MDA-MB-231'])].
[sujeto(['A', tagged, 'YB-1', construct, was, used, to, identify, proteins]), verbo([interacting]), complemento([directly, with, 'YB-1', in, breast, cancer, cells])].
[sujeto(['We', then, focused, on, proteins, that, are, potentially]), verbo([involved]), complemento([in, breast, cancer, progression, based, on, the, 'ONCOMINE', public, microarray, database])].
[sujeto(['From', these, 'analyses,', we, generated, a, list, of, proteins, potentially]), verbo([involved]), complemento([in, cisplatin, resistance])].
[sujeto(['Further', analyses, indicated, that, the, knock, down, of, 'RPS4X']), verbo([decreased]), complemento(['DNA', 'synthesis,', induced, cisplatin, 'resistance,', and, is, equivalent, to, the, overexpression, of, 'YB-1', in, both, 'MCF7', and, 'MDA-MB-231', cells])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, 'RPS4X/YB-1', complex, is, a, significant, potential, target, to, counteract, cisplatin, resistance, in, breast, cancer])].
[sujeto(['We', performed, a, comprehensive, analysis, of, expression, of, 'Y-linked', transcripts, and, their, 'X', homologues, in, several, human, 'tissues,', and, in, biopsies, of, infertile, 'patients,', in, an, attempt, to, identify, new, 'testis-specific', genes]), verbo([involved]), complemento([in, human, spermatogenesis])].
[sujeto(['We', present, evidence, that, one, of, the, 'primate-specific', 'Y-linked', ribosomal, protein, 'genes,', 'RPS4Y2,']), verbo([has]), complemento([restricted, expression, in, testis, and, 'prostate,', in, contrast, with, its, 'X-linked', 'homologue,', which, is, ubiquitously, expressed])].
[sujeto(['Moreover,', we]), verbo([have]), complemento([determined, by, highly, specific, quantitative, real, time, 'PCR', that, 'RPS4Y2', is, more, highly, expressed, in, testis, biopsies, containing, germ, cells])].
[sujeto(['The', in, silico, analysis, of, the, promoter, region, of, 'RPS4Y2', revealed, several, differences, relative, to, 'RPS4Y1,', the, more, widely]), verbo([expressed]), complemento([paralogue, from, which, 'Y2', has, originated, through, duplication])].
[sujeto(['Finally,', through, comparative, modelling, we, obtained, the, three, dimensional, models, of, the, human, 'S4', 'proteins,']), verbo([revealed]), complemento([a, conserved, structure])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, one, of, the, 'Y-linked', copies, of, the, ribosomal, protein, 'S4', is, preferentially, expressed, during, spermatogenesis, and, might, be, important, for, germ, cell, development])].
[sujeto(['Even', though, 'RPS4Y2']), verbo([has]), complemento([accumulated, several, amino, acid, changes, following, its, duplication, from, 'RPS4Y1,', approximately, 35, million, years, 'ago,', the, evolution, of, the, 'Y-encoded', 'RPS4', proteins, is, structurally, constrained])].
[sujeto(['Mammalian', 'X', and, 'Y', chromosomes, evolved, from, an, autosomal, 'pair;', the, 'X']), verbo([retained]), complemento([and, the, 'Y', gradually, lost, most, ancestral, genes])].
[sujeto(['In', 'females,', one, 'X', chromosome, is, silenced, by, 'X', 'inactivation,', a, process, that, is, often, assumed, to]), verbo([have]), complemento([evolved, on, a, broadly, regional, or, chromosomal, basis])].
[sujeto(['ZFX', evidently, escaped, 'X', inactivation, in, 'proto-eutherians,', which, also, possessed, a, very, similar, 'Y-linked', 'gene;', both, characteristics, were]), verbo([retained]), complemento([in, most, extant, 'orders,', but, not, in, myomorph, rodents])].
[sujeto(['We']), verbo([report]), complemento([here, a, 'single-cell', 'RT-PCR', assay, for, 'allele-specific', gene, expression, that, can, be, used, to, probe, for, somatic, variability, within, the, 'CNS'])].
[sujeto(['Allele-specific', expression, was, then, analyzed, by, means, of, the, previously, described, quantitative, 'RT-PCR', single, nucleotide]), verbo([primer]), complemento([extension, '(', 'SNuPE)', assay, '(', 'Singer-Sam', et, al])].
[sujeto(['Individual', neurons, showed, monoallelic, expression, of, the, two, control, 'genes,', 'X-linked', 'Rps4,', and, the, imprinted, gene, 'Snrpn;', in, contrast, expression, of, 'Ncam', and, 'F3cam,', coding, for, neural, cell, adhesion, 'molecules,', was]), verbo([found]), complemento([to, be, biallelic])].
[sujeto(['Insufficient', expression, of, 'S4', may, play, a, role, in, the, development, of, 'Turner', 'syndrome,', the, complex, human, phenotype]), verbo([associated]), complemento([with, monosomy, 'X'])].
[sujeto(['We']), verbo([report]), complemento([here, the, organization, of, the, human, 'RPS4X', and, 'RPS4Y', and, mouse, 'Rps4', genes])].
[sujeto(['Three', of, the, four, substitutions, are, also, present, in, human, 'S4Y,']), verbo([suggesting]), complemento([that, the, chicken, 'S4', gene, may, have, arisen, by, recombination, between, 'S4X-', and, 'S4Y-like', sequences])].
[sujeto(['Only', about, 1, '%', of, human, 'XO', conceptuses, survive, to, birth, and, these, usually]), verbo([have]), complemento([the, characteristics, of, 'Turner\'s', 'syndrome,', with, a, complex, and, variable, phenotype, including, short, 'stature,', gonadal, dysgenesis, and, anatomical, defects])].
[sujeto(['These', genes, would, be, expected, to, be]), verbo([expressed]), complemento([in, females, from, both, active, and, inactive, 'X', chromosomes, to, ensure, correct, dosage, of, gene, product])].
[sujeto(['Two', genes, with, these, properties, are, 'ZFX', and, 'RPS4X,', both, of, which]), verbo([have]), complemento([been, proposed, to, play, a, role, in, 'Turner\'s', syndrome])].
[sujeto(['We']), verbo([have]), complemento([devised, a, system, to, analyse, whether, specific, genes, on, the, mouse, 'X', chromosome, are, 'inactivated,', and, demonstrate, that, both, 'Zfx', and, 'Rps4X', undergo, normal, 'X-inactivation', in, mice])].
[sujeto(['Although', the, mammalian, 'X', and, 'Y', chromosomes, evolved, from, a, single, pair, of, 'autosomes,', they, are, highly, 'differentiated:', the, 'Y', chromosome, is, dramatically, smaller, than, the, 'X', and]), verbo([has]), complemento([lost, most, of, its, genes])].
[sujeto(['Most', mammalian, lineages]), verbo([have]), complemento([experienced, 'delayed,', or, relatively, 'recent,', loss, of, at, least, one, conserved, 'Y-linked', gene])].
[sujeto(['An', extreme, example, of, this, phenomenon, is, in, the, 'Japanese', spiny, 'rat,', where, the, 'Y', chromosome]), verbo([has]), complemento([disappeared, altogether])].
[sujeto(['In', this, 'species,', many, 'Y-linked', genes, were, rescued, by, transposition, to, new, genomic, 'locations,', but, until, our, work, presented, 'here,', this]), verbo([has]), complemento([been, considered, an, isolated, case])].
[sujeto(['We', describe, eight, cases, of, genes, that]), verbo([have]), complemento([relocated, to, autosomes, in, mammalian, lineages, where, the, corresponding, 'Y-linked', gene, has, been, lost])].
[sujeto(['Rescue', of, 'Y-linked', gene]), verbo([loss]), complemento([through, transposition, to, autosomes, has, previously, been, reported, for, a, single, isolated, rodent, species])].
[sujeto(['Thus,', 'Y-linked', gene]), verbo([loss]), complemento([emerges, as, an, additional, driver, of, gene, transposition, from, the, sex, 'chromosomes,', a, phenomenon, thought, to, be, driven, primarily, by, meiotic, sex, chromosome, inactivation])].
[sujeto(['Oncogene-induced', senescence, '(', 'OIS)', is, an, important, tumor, suppression, mechanism]), verbo([preventing]), complemento([uncontrolled, proliferation, in, response, to, aberrant, oncogenic, signaling])].
[sujeto(['The', profound, functional, and, morphological, remodelling, of, the, senescent, cell]), verbo([involves]), complemento([extensive, changes])].
[sujeto(['In', 'particular,', alterations, in, protein, ubiquitination, during, senescence]), verbo([have]), complemento([not, been, systematically, analyzed, previously])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, first, global, ubiquitination, profile, of, primary, human, cells, undergoing, senescence])].
[sujeto(['We', employed, a, 'well-characterized', in, vitro, model, of, 'OIS,', primary, human, fibroblasts]), verbo([expressing]), complemento([oncogenic, 'RAS'])].
[sujeto(['In', 'addition,', we, observed, enriched, ubiquitination, of, 'aminoacyl-tRNA', ligases, '(', 'isoleucyl-,', 'glutamine-,', and, 'tyrosine-tRNA', 'ligase),', which]), verbo([provide]), complemento([the, amino, 'acid-loaded', tRNAs, for, protein, synthesis])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, ubiquitination, affects, key, components, of, the, translation, machinery, to, regulate, protein, synthesis, during, 'OIS'])].
[sujeto(['Mammalian', sex, chromosomes, originated, from, a, pair, of, 'autosomes,', and, homologous, genes, on, the, sex, chromosomes, '(', 'gametologs)', differentiated, through, recombination]), verbo([arrest]), complemento([between, the, chromosomes])].
[sujeto(['However,', this, prediction, relied, solely, on, the, molecular, clock, hypothesis, between, pairs, of, human, 'gametologs,', and, molecular, evolution, of, marsupial, sex, chromosomal, genes]), verbo([has]), complemento([not, yet, been, investigated])].
[sujeto(['Phylogenetic', analyses, and, estimated, divergence, time, of, these, gametologs]), verbo([reveal]), complemento([that, they, all, differentiated, at, the, same, time, in, the, therian, ancestor])].
[sujeto(['We']), verbo([have]), complemento([also, provided, strong, evidence, for, gene, conversion, that, occurred, in, the, 3, '\'', region, of, the, eutherian, stratum, 2, genes, '(', 'SMCX/Y', and, 'UBE1X/Y)'])].
[sujeto(['The', results, of, the, present, study, show, that, '(', 1, ')', there, is, no, compelling, evidence, for, the, second, stratum, in, the, stem, lineage, of, 'Theria;', '(', 2, ')', gene, 'conversion,', which, may]), verbo([have]), complemento([occurred, between, 'SMCX/Y', and, 'UBE1X/Y', in, the, eutherian, 'lineage,', potentially, accounts, for, their, apparently, lower, degree, of, overall, divergence])].
[sujeto(['Diamond-Blackfan', anemia, '(', 'DBA)', is, an, inherited, form, of, pure, red, cell, aplasia, that, usually, presents, in, infancy, or, early, childhood, and, is]), verbo([associated]), complemento([with, congenital, malformations, in, '∼30-50%', of, patients])].
[sujeto(['DBA']), verbo([has]), complemento([been, associated, with, mutations, in, nine, ribosomal, protein, '(', 'RP)', genes, in, about, 53, '%', of, patients])].
[sujeto(['We', identified, a, de, novo, 'two-nucleotide', deletion, in, 'RPL26', in, one, proband]), verbo([associated]), complemento([with, multiple, severe, physical, abnormalities])].
[sujeto(['We', also]), verbo([found]), complemento([a, deletion, in, 'RPL19', and, missense, mutations, in, 'RPL3', and, 'RPL23A,', which, may, be, variants, of, unknown, significance])].
[sujeto(['Together', with, 'RPL5,', 'RPL11,', and, 'RPS7,', 'RPL26', is, the, fourth, 'RP']), verbo([regulating]), complemento([p53, activity, that, is, linked, to, 'DBA'])].
[sujeto(['The', present, study, compared, developmental, 'potential,', telomerase, activity, and, transcript, levels, of, 'X-linked', genes, '(', 'HPRT,', 'MECP2,', 'RPS4X,', 'SLC25A6,', 'XIAP,', 'XIST', and, 'ZFX)', in, bovine, somatic, cell]), verbo([nuclear]), complemento([transfer, '(', 'SCNT)', embryos, reconstructed, with, cells, derived, from, a, freemartin, '(', female, with, a, male, 'co-twin)', or, from, normal, female, cattle, '(', 'control)'])].
[sujeto(['However,', the, transcript, levels, of, 'SLC25A6,', 'XIST', and, 'ZFX', were, significantly]), verbo([decreased]), complemento([in, the, freemartin, 'SCNT', embryos, compared, to, control, 'SCNT', embryos, '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['Taken', 'together,', the, present, study, demonstrates, that, the, transcript, levels, of, several, 'X-linked', 'genes,', especially, 'XIST,', showed, an, aberrant, pattern, in, the, freemartin, 'SCNT', 'embryos,']), verbo([suggesting]), complemento([aberrant, 'X', inactivation, in, freemartin, clones, which, may, affect, embryo, survival])].
[sujeto(['Publicly', available, data, from, 'GenBank', and, 'Oncomine', were, 'meta-analyzed']), verbo([leading]), complemento([to, 34, candidate, marker, genes, of, 'CRC'])].
[sujeto(['We', show, with, high, confidence, that, 9, '(', 'ECT2,', 'ETV4,', 'DDX21,', 'RAN,', 'S100A11,', 'RPS4X,', 'HSPD1,', 'CKS2,', and, 'C9orf140)', of, the, 34, candidate, genes, are]), verbo([expressed]), complemento([at, significantly, elevated, levels, in, 'CRC', tissues, compared, to, normal, tissues])].
[sujeto(['Furthermore,', 'high-level', expression, of, 'RPS4X', was]), verbo([associated]), complemento([with, nonmucinous, cancer, cell, type, and, that, of, 'ECT2', with, lack, of, lymphatic, invasion, while, upregulation, of, 'CKS2', was, correlated, with, early, tumor, stage, and, lack, of, family, history, of, 'CRC'])].
[sujeto(['We', also, demonstrate, that, 'RPS4X', and, 'DDX21', are, regulatory]), verbo([targets]), complemento([of, 'c-Myc', and, 'ETV4', is, downstream, to, 'K-ras', signaling])].
[sujeto(['We']), verbo([have]), complemento([identified, multiple, novel, biomarkers, of, 'CRC'])].
[sujeto(['Further', analyses, of, their, function, and, connection, to, signaling, pathways, may]), verbo([reveal]), complemento([potential, value, of, these, biomarkers, in, 'diagnosis,', 'prognosis,', and, treatment, of, 'CRC'])].
[sujeto(['In', this, 'study,', we, examined, gene, expression, in, order, to, identify, genes, that, are, differentially]), verbo([expressed]), complemento([between, the, hepatocytes, of, 'Sichuan', 'White', geese, and, 'Landes', geese])].
[sujeto(['We', hypothesized, that, such, genes, may, be]), verbo([involved]), complemento([in, the, different, predispositions, between, these, two, species, to, develop, hepatic, steatosis])].
[sujeto(['Of', these, differentially]), verbo([expressed]), complemento(['genes,', 115, sequences, shared, high, homology, with, 46, known, genes, and, 13, sequences, corresponded, to, eight, novel, expressed, sequence, tags, '(', 'ESTs)'])].
[sujeto(['Based', on, functional, 'clustering,', up, and, 'down-regulated', genes, were, mostly, related, to, lipid, 'metabolism,']), verbo([nuclear]), complemento([mRNA, 'splicing,', enzyme, activity, and, transcription, control])].
[sujeto(['DNA', sequence, analysis, of, the, intronic, and, cDNA, regions, of, 'RPS4Y', genes, from, species, covering, the, entire, primate, phylogeny, showed, that, the, duplication, event]), verbo([leading]), complemento([to, the, second, 'Y-linked', copy, occurred, after, the, divergence, of, 'New', 'World', 'monkeys,', about, 35, million, years, ago])].
[sujeto(['Maximum', likelihood, analyses, of, the, synonymous, and, 'non-synonymous', substitutions, revealed, that, positive, selection, was]), verbo([acting]), complemento([on, 'RPS4Y2', gene, in, the, human, 'lineage,', which, represents, the, first, evidence, of, positive, selection, on, a, ribosomal, protein, gene])].
[sujeto(['Putative', positive, amino, acid, replacements, affected, the, three, domains, of, the, 'protein:', one, of, these, changes, is, located, in, the, 'KOW', protein, domain, and, affects, the, unique, invariable, position, of, this, 'motif,', and, might, thus]), verbo([have]), complemento([a, dramatic, effect, on, the, protein, function])].
[sujeto(['The', results, point, that, the, 'RPS4Y1', gene, might, be]), verbo([maintained]), complemento([to, compensate, gene, dosage, between, 'sexes,', while, 'RPS4Y2', might, have, acquired, a, new, 'function,', at, least, in, the, lineage, leading, to, humans])].
[sujeto(['Pools', of, in, 'vivo-derived', morulae, and, blastocysts, were]), verbo([provided]), complemento([by, a, commercial, embryo, transfer, operation])].
[sujeto(['Finally,', the, pattern, of, expression, of, 'XIST', in, bovine, oocytes, and, embryos, was, similar, to, that]), verbo([reported]), complemento([in, humans])].
[sujeto(['Although', common, for, 'mammals,', 'X', inactivation, shows, marked, 'species-specific', differences, in, mechanisms, and, end, 'results,', and]), verbo([provides]), complemento([a, unique, opportunity, to, study, epigenetic, regulation, of, gene, expression])].
[sujeto(['The', changed, expression, pattern, in, 'vitro,', probably, reflecting, modifications, in, the, epigenetic, mechanisms, that]), verbo([regulate]), complemento([transcriptional, activity, and, gene, silencing, in, 'X', 'inactivation,', has, important, implications, for, the, advancement, of, new, biotechnologies, such, as, somatic, cell, nuclear, transfer, and, stem, cell, therapy])].
[sujeto(['This', resulted, in, the, identification, of, 139, genes, that, were, differentially]), verbo([regulated]), complemento([in, 'MS', plaque, tissue, compared, to, normal, tissue])].
[sujeto([73, ',', by, 'Spearman\'s', rho, 'analysis);', while, 70, transcripts, were, uniquely, differentially]), verbo([expressed]), complemento(['(', &, 'gt;', or, =, 1.5, -, 'fold)', in, either, acute, or, chronic, active, tissues])].
[sujeto(['Both', chronic, active, and, acute, plaques, shared, the, majority, of, factors, identified]), verbo([suggesting]), complemento([that, 'quantitative,', rather, than, gross, qualitative, differences, in, gene, expression, pattern, may, define, the, progression, from, acute, to, chronic, active, plaques, in, 'MS'])].
[sujeto(['Molecular', evolutionary, rate, estimation]), verbo([reveals]), complemento([significantly, elevated, rates, of, 'DNA', and, protein, evolution, in, 'RPS4Y', compared, with, its, 'X-chromosome', homologs])].
[sujeto(['The', large, number, of, redundant, sequences, available, in, nucleotide, databases]), verbo([provides]), complemento([a, resource, for, the, identification, of, polymorphisms])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([identified, six, new, 'X-linked', 'single-nucleotide', polymorphisms, and, determined, the, inactivation, status, of, these, genes, by, examination, of, expression, patterns, in, female, cells, previously, demonstrated, to, have, skewed, 'inactivation,', as, well, as, by, analysis, of, somatic, cell, hybrids, retaining, the, inactive, human, 'X', chromosome])].
[sujeto(['Expression', was, seen, from, both, alleles, in, females, heterozygous, for, the, 'RPS4X', 'gene,', confirming, the, previously]), verbo([reported]), complemento([expression, from, the, inactive, 'X', chromosome])].
[sujeto(['Expression', of, only, a, single, allele, was, seen, in, females, heterozygous, for, polymorphisms, in, the, 'BGN,', 'TM4SF2,', 'ATP6S1,', 'VBP1,', and, 'PDHA1', 'genes,']), verbo([suggesting]), complemento([that, these, genes, are, subject, to, 'X-chromosome', inactivation])].
[sujeto(['It']), verbo([has]), complemento([been, postulated, that, haploinsufficiency, of, these, genes, may, contribute, to, 'Turner', syndrome])].
[sujeto(['We', show, here, that, several, animal, species, that, show, the, 'Turner-like', phenotype, on, monosomy, 'X']), verbo([have]), complemento([no, 'Y-linked', 'Rps4', homolog])].
[sujeto(['Ullrich-Turner', syndrome, '(', 'UTS)', is, frequently]), verbo([associated]), complemento([with, monosomy, 'X', but, may, also, occur, with, structural, aberrations, of, the, 'X', and, the, 'Y', chromosomes])].
[sujeto(['It']), verbo([has]), complemento([been, hypothesized, that, the, ribosomal, protein, genes, 'RPS4X', and, 'RPS4Y', play, a, critical, role, in, the, prevention, of, 'UTS'])].
[sujeto(['Since', haploinsufficiency, of, one, or, several, 'gene(s)', is, thought, to]), verbo([cause]), complemento([the, 'UTS', 'phenotype,', direct, assessment, of, 'RPS4X', expression, levels, in, these, patients, should, establish, whether, 'RPS4X', is, involved, in, 'UTS'])].
[sujeto(['We']), verbo([have]), complemento([investigated, fibroblasts, of, four, 46, ',', 'X,i(Xq)', 'UTS', patients, with, typical, symptoms, and, a, 'non-mosaic', chromosome, 'complement,', and, have, found, significantly, increased, 'RPS4X', mRNA, levels, in, all, patients])].
[sujeto(['Based', on, our, 'results,', we, conclude, that, haploinsufficiency, of, 'RPS4X', is, not, the]), verbo([cause]), complemento([of, 'UTS'])].
[sujeto(['In', this, 'study,', we]), verbo([report]), complemento([on, the, relation, between, the, film, thickness, of, 'hydrophobin-coated', solid, surfaces, and, their, wettability])].
[sujeto(['We']), verbo([found]), complemento([that, the, wettability, of, 'protein-coated', surfaces, strictly, depends, on, the, amount, of, adsorbed, 'protein,', as, reflected, in, an, oscillation, of, the, contact, angles, of, 'hydrophobin-coated', silicon, wafers])].
[sujeto(['The', human, gene, complementing, the, tsBN63, mutation, was, cloned, by, 'DNA-mediated', gene, transfer, and, its, cDNA, of, 1.1, kb]), verbo([conferring]), complemento(['ts+', phenotype, on, tsBN63, cells, was, isolated, from, the, cDNA, library, of, 'Raj', '(', 'mer+)', cells, with, a, frequency, of, 10, '(', -, 3, ')'])].
[sujeto(['Autologous', fat, grafting, '(', 'AFG)']), verbo([provides]), complemento([the, possibility, to, reconstruct, a, functional, sliding, layer, underneath, the, scar])].
[sujeto(['To']), verbo([prevent]), complemento([selection, 'bias,', measurements, were, performed, following, a, standardized, algorithm])].
[sujeto(['Purpose', 'To', retrospectively, determine, if, a, modified, clinical, magnetic, resonance, '(', 'MR)', imaging, protocol]), verbo([provides]), complemento([information, on, the, origin, of, juvenile, osteochondritis, dissecans, '(', 'JOCD)', lesions, and, allows, for, staging, on, the, basis, of, the, proposed, natural, history, of, 'JOCD', to, better, guide, clinical, management, of, the, disease])].
[sujeto(['The', inadequate, management, of, such, cases, may]), verbo([lead]), complemento([to, 'complications,', such, as, 'foreign-body', reaction, and, scarring])].
[sujeto(['This']), verbo([report]), complemento([describes, two, cases, with, dental, fragments, embedded, in, the, lower, 'lip,', which, went, unnoticed, until, the, patients, presented, later, for, completely, different, treatments, and, emphasizes, the, importance, of, clinical, and, radiographic, examination, of, soft, 'tissues,', even, in, cases, that, present, late, for, dental, trauma, management])].
[sujeto(['A', 24, -, 'year-old', female, presented, at, 6, months, period, of, gestation, with]), verbo([increased]), complemento([blood, pressure, records])].
[sujeto(['Transplantation', of, somatic, 'cells,', including, bone, marrow, stromal, cells, '(', 'BMSCs),', bone, marrow, mononuclear, cells, '(', 'BMNCs),', and, choroid, plexus, epithelial, cells, '(', 'CPECs),']), verbo([enhances]), complemento([the, outgrowth, of, regenerating, axons, and, promotes, locomotor, improvements])].
[sujeto(['Regenerating', axons]), verbo([have]), complemento([characteristics, of, peripheral, 'nerves:', they, are, associated, with, 'Schwann', 'cells,', and, embedded, in, connective, tissue, matrices])].
[sujeto(['It']), verbo([has]), complemento([been, suggested, that, neurotrophic, factors, secreted, from, 'BMSCs', and, 'CPECs', promote, &, 'quot;intrinsic"', ability, of, the, spinal, cord, to, regenerate])].
[sujeto(['Schwann', cells]), verbo([have]), complemento([been, approved, for, clinical, applications])].
[sujeto(['A', combined, approach, in, spinal, cord, injury, '(', 'SCI)', therapy, is, the, modulation, of, the, cellular, and, molecular, processes]), verbo([involved]), complemento([in, glial, scarring])].
[sujeto(['Aldaynoglial', cells, are, neural, cell, precursors, with, a, high, capacity, to, differentiate, into, 'neurons,']), verbo([promote]), complemento([axonal, 'growth,', wrapping, and, myelination, of, resident, neurons])].
[sujeto(['These', important, characteristics, of, aldaynoglia, can, be, combined, with, specific, inhibition, of, the, 'RhoGTPase', activity, in, astroglia, and, microglia, that]), verbo([cause]), complemento([reduction, of, glial, 'proliferation,', retraction, of, glial, cell, processes, and, myelin, production, by, oligodendrocytes])].
[sujeto(['Previously', we, used, experimental, central, nervous, system, '(', 'CNS)', injury, 'models,', like, spinal, cord, contusion, and, striatal, lacunar, infarction, and, observed, that, administration, of, 'RhoGTPase', glycolipid, inhibitor, or, aldaynoglial, 'cells,', 'respectively,', produced, a, significant]), verbo([gain]), complemento([of, functional, recovery, in, treated, animals])].
[sujeto(['Here', we]), verbo([suggest]), complemento([that, treatment, of, spinal, lesions, with, aldaynoglia, from, neurospheres, plus, local, administration, of, a, 'RhoGTPase', inhibitor, could, have, an, additive, effect, and, promote, recovery, from, 'SCI'])].
[sujeto(['Therefore,', the, structural, derangements, elicited, in, a, chronic, myocardial, infarction, should]), verbo([cause]), complemento([specific, changes, in, the, local, 'systolic-diastolic', myocardial, 'impedance,', but, this, is, not, known])].
[sujeto(['Resistivity', of, normal, myocardium, depicted, phasic, changes, during, the, cardiac, cycle, and, its, amplitude, markedly]), verbo([decreased]), complemento([in, dense, scar, '(', 18, ±, 2, 'Ω·cm', vs])].
[sujeto(['The', mean, phasic, resistivity]), verbo([decreased]), complemento([progressively, from, normal, to, heterogeneous, and, dense, scar, regions, '(', 285, ±, 10, 'Ω·cm,', 225, ±, 25, 'Ω·cm,', and, 162, ±, 6, 'Ω·cm,', at, 41, 'kHz;', 'P', &, 'lt;', 0.001, 'respectively)'])].
[sujeto(['In', 'conclusion,', this, study]), verbo([reveals]), complemento([that, differences, in, the, degree, of, myocardial, fibrosis, can, be, detected, in, vivo, by, local, measurement, of, phasic, 'systolic-diastolic', bioimpedance, spectrum])].
[sujeto(['An', outbreak, of, epidemic, 'VC', can]), verbo([lead]), complemento([to, definitive, sequelae, in, the, tarsal, conjunctiva])].
[sujeto(['The', sequelae, from, 'VC', were, detected, in, 0.007, '%', of, the, schoolchildren, and, were, not]), verbo([associated]), complemento([with, inflammatory, trachoma])].
[sujeto(['The', 'X-ray', assessment, showed, two, cases, of]), verbo([loss]), complemento([of, stability, and, one, case, of, distal, clavicular, osteolysis])].
[sujeto(['Women', who, underwent, primary, or, elective, 'Cesarean', delivery, showed, a, significantly, '(', p, =, 0.03, ',', p, =, 0.02, ',', &, 'quot;as', 'treated")']), verbo([increased]), complemento([median, scar, thickness, after, double, layer, closure, vs])].
[sujeto(['Conclusion:', 'A', double, layer, closure, of, the, hysterotomy, is]), verbo([associated]), complemento([with, a, thicker, myometrium, scar, only, in, primary, or, elective, 'Cesarean', 'delivery patients'])].
[sujeto(['After', stoma, 'closure,', 'PSC', was]), verbo([associated]), complemento([with, a, significantly, lower, incidence, of, wound, infection, and, greater, patient, satisfaction, compared, to, 'LC'])].
[sujeto(['Implant', removal, is, a, common, procedure, in, orthopedic, surgery, which, can, be]), verbo([associated]), complemento([with, many, complications, such, as, scar, 'formation,', 'hematoma,', nerve, 'injury,', 'infection,', and, refracture])].
[sujeto(['Indications', for, orthopedic, implant, removal]), verbo([have]), complemento([declined, in, recent, years])].
[sujeto(['Most', studies]), verbo([have]), complemento([considered, orthopedic, hardware, removal, as, an, unnecessary, procedure, in, the, absence, of, severe, complications, such, as, nonunion])].
[sujeto(['Some', studies]), verbo([have]), complemento([reported, the, complications, of, orthopedic, hardware, removal, to, be, 24, '%', to, 50, '%', dependent, on, their, types, and, locations, as, well, as, on, other, factors, such, as, 'patient\'s', condition, and, the, 'orthopedist\'s', experience])].
[sujeto(['The', present, study, surveyed, possible, mental, and, psychological]), verbo([causes]), complemento([among, patients, who, asked, for, removal, procedures, in, spite, of, orthopedic, 'surgeons\'', advice, and, being, aware, of, complications])].
[sujeto(['Linear', regression, analysis, results, demonstrated, a, significant, correlation, between]), verbo([increased]), complemento(['VAS', scores, in, the, first, group, '(', 'P', =, 0.0, ')', ',', but, it, was, not, significant, in, the, second, group, '(', 'P', =, 0.083, ')'])].
[sujeto(['The', results, also, showed, that]), verbo([increase]), complemento([in, time, of, daily, pain, and, discomfort, had, a, linear, relationship, with, increased, discomfort, score, in, both, groups, '(', 'P', =, 0.0, ')'])].
[sujeto(['It', is]), verbo([associated]), complemento([with, a, high, success, 'rate,', and, is, not, associated, with, an, increase, in, complications])].
[sujeto(['Spinal', cord, injury, usually]), verbo([leads]), complemento([to, permanent, 'disability,', which, could, cause, a, huge, financial, problem, to, the, patient])].
[sujeto(['The', key, of, the, treatment, is, to, enable, the, damage, zone, axonal, regeneration, and, luckily, it, could, go, through, the, damage, 'zone;', last, a, connection, can, be, established, with, the]), verbo([target]), complemento([neurons])].
[sujeto(['This', study, attempts, to, combine, stem, 'cell,', material, science, and, genetic, modification, technology, 'together,', by, preparing, two, genes, modified, 'adipose-derived', stem, cells, and]), verbo([inducing]), complemento([them, into, neuron, 'direction;', then, by, compositing, them, on, the, silk, 'fibroin/chitosan', scaffold, and, implanting, them, into, the, spinal, cord, injury, 'model,', seed, cells, can, have, features, of, neuron, cells])].
[sujeto(['At', the, same, 'time,', it, could, stably]), verbo([express]), complemento([the, 'brain-derived', neurotrophic, factor, and, 'neurotrophin-3,', both, of, which, could, produce, synergistic, 'effects,', which, have, a, positive, effect, on, the, recovery, of, spinal, cord])].
[sujeto(['The', spinal, cord, scaffold, bridges, the, broken, end, of, the, spinal, cord, and, isolates, with, the, surrounding, 'environment,', which, could, avoid, a, scar, effect, on, the, nerve, regeneration, and]), verbo([provide]), complemento(['three-dimensional', space, for, the, seed, cell, 'growth,', and, at, last, we, hope, to, provide, a, new, treatment, for, spinal, cord, injury, with, the, tissue, engineering, technique])].
[sujeto(['However,', the, buried, suture, technique, is]), verbo([associated]), complemento([with, complications, related, to, implantation, of, the, suture, thread])].
[sujeto(['Among', treatment, of, 'pain,', 'hyperhidrosis,', or, aesthetic, 'purposes,', it, is, also, used, to]), verbo([enhance]), complemento([wound, healing, and, prevent, excessive, scar, formation])].
[sujeto(['Regulation', of, 'Scr']), verbo([requires]), complemento([the, action, of, different, enhancer, elements, spread, over, several, kilobases])].
[sujeto(['In', the, present, 'study,', we, attempted, to, characterize, the, regulatory, sequences]), verbo([involved]), complemento([in, the, maintenance, of, the, 'Scr', activation, by, 'DSP1'])].
[sujeto(['We']), verbo([report]), complemento(['here,', using, a, transgenic, line, for, the, 'Scr10'])].
[sujeto(['We', show, by, immunolocalization, that, 'DSP1', is]), verbo([recruited]), complemento([on, polytene, chromosomes, to, the, insertion, site, of, the, transgene])].
[sujeto(['These', results]), verbo([provide]), complemento([strong, evidence, that, the, 'Scr', gene, expression, is, influenced, by, direct, interaction, between, 'DSP1', and, two, 'Scr', regulation, elements])].
[sujeto(['SCR10', identifies, a, 1, -, kb, mRNA]), verbo([transcribed]), complemento([from, the, human, 'X', chromosome, mapping, to, the, region, 'Xq13-q13'])].
[sujeto([3, -, q22, and, is, an, abundantly, and, ubiquitously]), verbo([expressed]), complemento([gene])].
[sujeto(['In', this, 'study,', five, plastid, regions, '(', 'rbcL,', 'matK,', 'trnH-psbA,', 'trnL-F', and, 'rps4-trnS)', and, eight]), verbo([nuclear]), complemento([regions, '(', 'ITS,', 'pgiC,', 'gapC,', 'LEAFY,', 'ITS2,', 'IBR3_2,', 'DET1,', and, 'SQD1_1)', were, screened, and, evaluated, in, the, fern, genus, 'Adiantum', from, 'China', and, neighboring, areas])].
[sujeto(['Due', to, low]), verbo([primer]), complemento([universality, '(', 'matK)', 'and/or', the, existence, of, multiple, copies, '(', 'ITS),', the, commonly, used, barcodes, matK, and, 'ITS', were, not, appropriate, for, 'Adiantum'])].
[sujeto(['The', 'PCR', amplification, rate, was, extremely, low, in, all]), verbo([nuclear]), complemento([genes, except, for, 'IBR3_2'])].
[sujeto(['The']), verbo([nuclear]), complemento(['IBR3_2', showed, 100, '%', 'PCR', amplification, success, rate, in, 'Adiantum,', 'however,', it, seemed, that, only, diploid, species, could, acquire, clean, sequences, without, cloning])].
[sujeto(['Because', hybridization, and, allopolyploidy, are, common, in, 'ferns,', we, argue, for, including, a, selected, group, of]), verbo([nuclear]), complemento([loci, as, 'barcodes,', especially, via, the, 'next-generation', 'sequencing,', as, it, is, much, more, efficient, to, obtain, 'single-copy', nuclear, loci, without, the, cloning, procedure])].
[sujeto(['Although', plastid, genomes, of, flowering, plants, are, typically, highly]), verbo([conserved]), complemento([regarding, their, 'size,', gene, content, and, 'order,', there, are, some, exceptions])].
[sujeto(['Ericaceae,', a, large, and, diverse, family, of, flowering, 'plants,', warrants, special, attention, within, the, context, of, plastid, genome, evolution, because, it, includes, both, 'non-photosynthetic', and, photosynthetic, species, with, rearranged, plastomes, and, putative]), verbo([losses]), complemento([of, &, 'quot;essential"', genes])].
[sujeto([monotropa]), verbo([have]), complemento([small, plastid, genomes, '(', 46, kb, and, 35, 'kb,', 'respectively)', lacking, genes, related, to, 'photosynthesis,', whereas, 'P'])].
[sujeto([rotundifolia]), verbo([has]), complemento([a, larger, genome, '(', 169, 'kb)', with, a, gene, set, similar, to, other, photosynthetic, plants])].
[sujeto(['Comparative', analysis, of, the, expanded, set, of, 'Ericaceae', plastomes]), verbo([suggests]), complemento([that, the, genes, clpP, and, accD, that, are, present, in, the, plastid, genomes, of, almost, all, plants, have, not, been, lost, in, this, family, '(', as, was, previously, 'thought)', but, rather, persist, in, these, genomes, in, unusual, forms])].
[sujeto(['Also', we]), verbo([found]), complemento([a, new, gene, in, 'P'])].
[sujeto(['Phytophthora', root, and, stem, rot, '(', 'PRR)']), verbo([caused]), complemento([by, 'Phytophthora', sojae, is, one, of, the, most, serious, diseases, affecting, soybean, '(', 'Glycine', max, '(', 'L'])].
[sujeto(['The', resistance, reaction, analyses]), verbo([provided]), complemento([an, excellent, database, of, resistant, resources, and, genetic, variations, for, future, breeding, programs])].
[sujeto(['The', 'SNP', markers]), verbo([associated]), complemento([with, resistance, will, facilitate, 'marker-assisted', selection, '(', 'MAS)', in, breeding, programs, for, resistance, to, 'PRR,', and, the, candidate, genes, may, be, useful, for, exploring, the, mechanism, underlying, 'P'])].
[sujeto(['Although', monophyly, was, not]), verbo([found]), complemento([for, 'U'])].
[sujeto(['While', almost, identical, in, number, of, nucleotides, 'sequenced,', mitochondrial, 'DNA', held, substantially, less, phylogenetically, informative, nucleotides, than, the, chloroplast, 'loci,', but, did]), verbo([have]), complemento([important, indel, information, segregating, 'U'])].
[sujeto(['While', the, evolutionary, dynamics, of, plastid, and, nucleomorph, genomes]), verbo([have]), complemento([been, 'investigated,', a, comparative, investigation, of, mitochondrial, genomes, '(', 'mtDNAs)', has, not, been, carried, out])].
[sujeto(['We']), verbo([have]), complemento([sequenced, the, complete, mtDNA, of, 'Lotharella', oceanica, and, compared, it, to, that, of, another, 'chlorarachniophyte,', 'Bigelowiella', natans])].
[sujeto(['The', codons, 'GUG', and, 'UUG', appear, to, be, capable, of]), verbo([acting]), complemento([as, initiation, codons, in, the, chlorarachniophyte, 'mtDNAs,', in, addition, to, 'AUG'])].
[sujeto([oceanica]), verbo([nuclear]), complemento(['genome,', indicating, that, 'mitochondrion-to-host-nucleus', gene, transfer, occurred, after, the, divergence, of, these, two, genera])].
[sujeto([natans, mtDNA, is, 'low,']), verbo([suggesting]), complemento([frequent, rearrangements])].
[sujeto(['Overall,', our, results]), verbo([suggest]), complemento([that, chlorarachniophyte, mtDNAs, are, more, evolutionarily, dynamic, than, their, plastid, counterparts])].
[sujeto(['Neonatal', pigs, are, used, as, a, model, to, study, and, optimize, the, clinical, treatment, of, infants, who, are, unable, to]), verbo([maintain]), complemento([oral, feeding])].
[sujeto(['Using', this, 'model,', we]), verbo([have]), complemento([previously, shown, that, pulsatile, administration, of, leucine, during, continuous, feeding, over, 24, h, via, orogastric, tube, enhanced, protein, synthesis, in, skeletal, muscle, compared, to, continuous, feeding, alone])].
[sujeto(['The', results, show, that, body, and, muscle, weights, and, lean]), verbo([gain]), complemento([were, '~25%', greater, and, fat, gain, was, 48, '%', lower, in, 'CON+LEU', than, 'CON+ALA;', weights, of, other, tissues, were, unaffected, by, treatment])].
[sujeto(['Fractional', protein, synthesis, rates, in, longissimus, 'dorsi,', 'gastrocnemius,', and, soleus, muscles, were, '~30%', higher, in, 'CON+LEU', compared, to, 'CON+ALA', and, were]), verbo([associated]), complemento([with, decreased, 'Deptor', abundance, and, increased, 'mTORC1,', 'mTORC2,', '4EBP1', and, 'S6K1', 'phosphorylation,', 'SNAT2', 'abundance,', and, association, of, eIF4E, with, eIF4G, and, 'RagC', with, mTOR])].
[sujeto(['There', were, no, treatment, effects, on, 'PKB,', 'eIF2α,', 'eEF2,', or, 'PRAS40', 'phosphorylation,', 'Rheb,', 'SLC38A9,', 'v-ATPase,', 'LAMTOR1,', 'LAMTOR2,', 'RagA,', 'RagC,', and, 'LAT1', 'abundance,', the, proportion, of, polysomes, to, 'nonpolysomes,', or, the, proportion, of, mRNAs, encoding, rpS4, or, rpS8]), verbo([associated]), complemento([with, polysomes])].
[sujeto(['Our', results, demonstrate, that, pulsatile, delivery, of, a, leucine, supplement, during, 21, d, of, continuous, enteral, feeding]), verbo([enhances]), complemento([lean, growth, by, stimulating, the, 'mTORC1-dependent', translation, initiation, pathway, leading, to, protein, synthesis, in, skeletal, muscle, of, neonates])].
[sujeto(['What', proteins, are, carried, by, extracellular, vesicles, '(', 'EVs)']), verbo([released]), complemento([from, normal, first, trimester, 'placentae?', 'One', thousand, five, hundred, and, 'eighty-five,', 1656, and, 1476, proteins, were, characterized, in, 'macro-,', 'micro-', and, 'nano-vesicles,', 'respectively,', from, first, trimester, 'placentae,', with, all, 'EV', fractions, being, enriched, for, proteins, involved, in, vesicle, transport, and, inflammation])].
[sujeto(['Placental', 'EVs', are, being, increasingly]), verbo([recognized]), complemento([as, important, mediators, of, both, healthy, and, pathological, pregnancies])].
[sujeto(['However,', current, research]), verbo([has]), complemento([focused, on, detecting, changes, in, specific, proteins, in, particular, fractions, of, vesicles, during, disease])].
[sujeto(['Gene', 'Ontology', pathway, analysis, showed, an, enrichment, of, proteins]), verbo([involved]), complemento([in, vesicle, transport, and, inflammation, in, all, three, fractions, of, 'EVs'])].
[sujeto(['The', expression, levels, of, proteins]), verbo([involved]), complemento([in, internalization, of, vesicles, '(', annexin, 'V,', 'calreticulin,', 'CD31,', 'CD47),', the, complement, pathway, '[', 'C3,', 'decay-accelerating', factor, '(', 'DAF),', membrane, cofactor, protein, '(', 'MCP),', 'protectin]', and, minor, histocompatibility, antigens, '[', 'ATP-dependent', 'RNA', helicase, '(', 'DDX3),', ribosomal, protein, 'S4', '(', 'RPS4)]', were, different, between, 'different-sized', 'EVs'])].
[sujeto(['Our', results, support, the, concept, that, various, 'EV', factions, can]), verbo([interact]), complemento([with, different, maternal, cells, and, have, unique, effects, to, mediate, 'feto-maternal', communication, during, early, pregnancy])].
[sujeto(['This', study, also]), verbo([provides]), complemento([a, list, of, candidate, 'proteins,', which, may, inform, the, identification, of, robust, markers, that, can, be, used, to, isolate, placental, vesicles, from, the, maternal, blood, in, the, future])].
[sujeto(['No', authors]), verbo([have]), complemento([any, conflicts, of, interest, to, disclose])].
[sujeto(['Endocytosis']), verbo([has]), complemento([been, suggested, to, be, important, in, the, cellular, processes, of, plant, immune, responses])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, plant, 'endocytosis,', especially, 'clathrin-coated', vesicle, formation, at, the, plasma, 'membrane,', is, mediated, by, the, adaptor, 'protein-2', '(', 'AP-2)', complex, and, that, loss, of, the, μ, subunit, of, 'AP-2', '(', 'AP2M)', affects, plant, growth, and, floral, organ, development])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, 'AP2M', is, required, for, 'full-strength', 'ETI', mediated, by, the, disease, resistance, '(', 'R)', genes, 'RPM1', and, 'RPS2', in, 'Arabidopsis'])].
[sujeto([tomato, 'DC3000', strains, carrying, the, corresponding, effector, genes, avrRpm1, or, avrRpt2, and, by, hypersensitive, cell, death, response, and, defense, gene, expression]), verbo([triggered]), complemento([by, these, strains])].
[sujeto(['In', 'contrast,', 'RPS4-mediated', 'ETI', and, its]), verbo([associated]), complemento([immune, responses, were, not, affected, by, the, ap2m, mutation])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'AP2M', is, involved, in, 'ETI', mediated, by, plasma, 'membrane-localized', 'R', 'proteins,', possibly, by, mediating, endocytosis, of, the, immune, receptor, complex, components, from, the, plasma, membrane])].
[sujeto(['Arabidopsis', thaliana, 'leucine-rich', 'repeat-containing', '(', 'NLR)', proteins, 'RPS4', and, 'RRS1,', known, as, dual, resistance, 'proteins,']), verbo([confer]), complemento([resistance, to, multiple, pathogen, 'isolates,', such, as, the, bacterial, pathogens, 'Pseudomonas', syringae, and, 'Ralstonia', solanacearum, and, the, fungal, pathogen, 'Colletotrichum', higginsianum])].
[sujeto(['In', this, 'study,', direct, mutagenesis, of, the, 'C-terminal', 'LZ', motif, in, 'RRS1']), verbo([caused]), complemento([an, autoimmune, response, and, stunting, in, the, mutant])].
[sujeto(['Co-immunoprecipitation', analysis, indicated, that, 'full-length', 'RPS4', and, 'RRS1', are, physically]), verbo([associated]), complemento([with, one, another])].
[sujeto(['Furthermore,', 'virus-induced', gene, silencing, experiments, showed, that, 'hypersensitive-like', cell, death]), verbo([triggered]), complemento([by, 'RPS4/LZ', 'motif-mutated', 'RRS1', depends, on, 'EDS1'])].
[sujeto(['In', 'conclusion,', we]), verbo([suggest]), complemento([that, the, 'RRS1-LZ', motif, is, crucial, for, the, regulation, of, the, 'RPS4/RRS1', complex])].
[sujeto(['The']), verbo([loss]), complemento([of, the, peristome, and, forming, of, cleistocarpous, capsules, also, occurs, independently, in, at, least, two, lineages, of, 'Ditrichaceae', s])].
[sujeto(['Total', 80, '%', of, 'protein-coding', genes]), verbo([have]), complemento([usual, 'ATG', start, codon, and, 20, '%', have, alternative, start, codons])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, additional, mitogenome, data, will, provide, useful, information, for, mitochondrial, genome, diversity, and, evolution, of, the, diatoms, and, stramenopiles])].
[sujeto([sojae]), verbo([has]), complemento([become, a, model, for, the, study, of, oomycete, 'genetics,', physiology, and, pathology])].
[sujeto(['The', lack, of, efficient, techniques, for]), verbo([targeted]), complemento([mutagenesis, and, gene, replacement, have, long, hampered, genetic, studies, of, pathogenicity, in, 'Phytophthora', species])].
[sujeto([sojae, was]), verbo([mediated]), complemento([by, 'non-homologous', 'end-joining', '(', 'NHEJ),', primarily, resulting, in, short, indels])].
[sujeto(['Most', mutants, were, 'homozygous,', presumably, as, a, result, of, gene, conversion]), verbo([triggered]), complemento([by, 'Cas9-mediated', cleavage, of, 'non-mutant', alleles])].
[sujeto(['By', testing, the, specific, virulence, of, several, 'NHEJ', mutants, and, 'HDR-mediated', gene, replacements, in, 'soybean,', we]), verbo([have]), complemento([validated, the, contribution, of, 'Avr4/6', to, recognition, by, soybean, 'R', gene, 'loci,', 'Rps4', and, 'Rps6,', but, also, uncovered, additional, contributions, to, resistance, by, these, two, loci])].
[sujeto(['Our', results, establish, a, powerful, tool, for, the, study, of, functional, genomics, in, 'Phytophthora,', which]), verbo([provides]), complemento([new, avenues, for, better, control, of, this, pathogen])].
[sujeto(['Plant', responses, to, low, temperature, are, tightly]), verbo([associated]), complemento([with, defense, responses])].
[sujeto(['Here', we]), verbo([report]), complemento([the, identification, of, a, suppressor, of, 'chs3,', 'ibr5-7', '(', 'indole-3-butyric', acid, response, 5, ')', ',', which, largely, suppresses, 'chilling-activated', defense, responses])].
[sujeto(['The', accumulation, of, 'CHS3', protein, at, chilling, temperatures, is]), verbo([inhibited]), complemento([by, the, 'IBR5', mutation])].
[sujeto(['Moreover,', 'chs3-conferred', defense, phenotypes, were, synergistically]), verbo([suppressed]), complemento([by, mutations, in, 'HSP90', and, 'IBR5'])].
[sujeto(['Further', analysis, showed, that, 'IBR5,', with, holdase, 'activity,', physically]), verbo([associates]), complemento([with, 'CHS3,', 'HSP90', and, 'SGT1b', '(', 'Suppressor', of, the, 'G2', allele, of, 'skp1)', to, form, a, complex, that, protects, 'CHS3'])].
[sujeto(['In', addition, to, the, positive, role, of, 'IBR5', in]), verbo([regulating]), complemento(['CHS3,', 'IBR5', is, also, involved, in, defense, responses, mediated, by, 'R', 'genes,', including, 'SNC1', '(', 'Suppressor', of, 'npr1-1,', 'Constitutive', 1, ')', ',', 'RPS4', '(', 'Resistance', to, 'P'])].
[sujeto(['Thus,', the, results, of, the, present, study]), verbo([reveal]), complemento([a, role, for, 'IBR5', in, the, regulation, of, multiple, 'R', 'protein-mediated', defense, responses])].
[sujeto(['Delimitating', species, boundaries, could, be, of, critical, importance, when, evaluating, the, 'species\'', evolving, process, and]), verbo([providing]), complemento([guidelines, for, conservation, genetics])].
[sujeto(['A', total, of, 137, individuals, from, 15, populations, were, genotyped, by, using, three, chloroplastic, '(', 'psbA-trnH,', 'atpI-atpH,', and, 'trnL-rps4)', and, two, single, copy]), verbo([nuclear]), complemento(['(', 'RPB1', and, 'SmHP)', 'DNA', sequences])].
[sujeto(['The', higher, genetic, diversity, among, populations, and, relative, lower, genetic, diversity, within, 'populations,', as, well, as, obvious, genetic, differentiation, among, populations, inferred, from, chloroplastic, 'DNA', '(', 'cpDNA)']), verbo([suggested]), complemento([a, recent, genetic, loss, within, this, protected, species])].
[sujeto(['Demographical', history, analyses, based, on, combined, cpDNA, and, one]), verbo([nuclear]), complemento(['DNA', '(', 'nDNA)', 'SmHP', both, showed, the, population, size, of, 'C'])].
[sujeto([diannanensis, began, to]), verbo([decrease]), complemento([in, 'Quaternary', glaciation, with, no, subsequent, 'expansion,', while, another, nDNA, 'RPB1', revealed, a, more, recent, sudden, expansion, after, 'long-term', population, size, 'contraction,', suggesting, its, probable, bottleneck, events, in, history])].
[sujeto(['Its', generic, classification, remains, 'controversial,', with, different, authors]), verbo([recognizing]), complemento([from, one, up, to, 32, genera])].
[sujeto(['Phylogenetic', relationships, within, the, family]), verbo([have]), complemento([not, been, exhaustively, 'studied,', but, previous, studies, have, confirmed, the, monophyly, of, the, lineage])].
[sujeto(['Thus', 'far,', sampling]), verbo([has]), complemento([been, inadequate, for, establishing, a, robust, hypothesis, of, infrafamilial, relationships, within, the, family])].
[sujeto(['Our', results, are, consistent, with, the, general, topological, structure]), verbo([found]), complemento([in, previous, 'studies,', including, two, main, lineages, within, the, 'family:', phegopteroid, and, thelypteroid])].
[sujeto(['The', three, mainly, neotropical, segregates, were]), verbo([found]), complemento([to, be, monophyletic, but, nested, in, a, broadly, defined, 'Cyclosorus'])].
[sujeto(['The', fourth, mainly, neotropical, 'segregate,', 'Amauropelta,', was]), verbo([found]), complemento([to, include, species, considered, to, be, part, of, 'Parathelypteris'])].
[sujeto(['In', 'Old', 'World', 'thelypteroids,', which, correspond, to, nearly, half, the, diversity, in, the, 'family,', an]), verbo([increase]), complemento([in, sampling, is, still, needed, to, resolve, relationships, and, circumscription, of, 'genera,', particularly, in, the, christelloid, clade, '(', i])].
[sujeto(['Plants']), verbo([have]), complemento([developed, diverse, mechanisms, to, fine, tune, defence, responses, to, different, types, of, enemy])].
[sujeto([tomato, strain, 'DC3000']), verbo([expressing]), complemento([avrRps4])].
[sujeto(['Interestingly,', 'srfr1-1', plants, showed]), verbo([increased]), complemento([resistance, to, herbivory, by, the, beet, army, worm, 'Spodoptera', exigua, and, to, parasitism, by, the, cyst, nematode, 'Heterodera', schachtii, compared, with, the, corresponding, 'wild-type', 'Arabidopsis', accession, 'RLD'])].
[sujeto(['Using', quantitative, 'real-time', 'PCR', '(', 'qRT-PCR)', to, measure, the, transcript, levels, of, salicylic, acid, '(', 'SA)', and, 'jasmonate/ethylene', '(', 'JA/ET)', pathway, 'genes,', we]), verbo([found]), complemento([that, enhanced, resistance, of, 'srfr1-1', plants, to, 'S'])].
[sujeto(['In', 'contrast,', the, greater, susceptibility, of, 'RLD', was, accompanied, by, simultaneously]), verbo([increased]), complemento([transcript, levels, of, 'SA,', 'JA', and, 'JA/ET', signalling, pathway, genes])].
[sujeto(['Surprisingly,', mutation, of, either, 'SRFR1', or, 'EDS1']), verbo([increased]), complemento([resistance, to, 'H'])].
[sujeto(['schachtii,', indicating, that, the, concurrent, presence, of, both, 'wild-type', genes]), verbo([promotes]), complemento([susceptibility])].
[sujeto(['This']), verbo([finding]), complemento([suggests, a, novel, form, of, resistance, in, 'Arabidopsis', to, the, biotrophic, pathogen, 'H'])].
[sujeto(['RKS1', '(', 'Resistance', related, 'KinaSe1)']), verbo([has]), complemento([been, reported, recently, to, confer, 'QDR', in, 'Arabidopsis', thaliana, to, most, but, not, all, races, of, the, bacterial, pathogen, 'Xanthomonas', campestris, pv])].
[sujeto(['A', nested, 'genome-wide', association, mapping, approach, was, used, to, finely, map, the, genomic, regions]), verbo([associated]), complemento([with, 'QDR', to, 'Xcc12824', '(', race, 2, ')', and, 'XccCFBP6943', '(', race, 6, ')'])].
[sujeto(['We', identified, two, major, 'QTLs', that]), verbo([confer]), complemento([resistance, specifically, to, 'Xcc12824', and, 'XccCFBP6943'])].
[sujeto(['Although', 'QDR', to, 'Xcc12824', is]), verbo([conferred]), complemento([by, 'At5g22540', encoding, for, a, protein, of, unknown, 'function,', 'QDR', to, 'XccCFBP6943', involves, the, 'well-known', immune, receptor, pair, 'RRS1/RPS4'])].
[sujeto(['In', addition, to, 'RKS1,', this, study]), verbo([reveals]), complemento([that, three, genes, are, involved, in, resistance, to, 'Xc', with, strikingly, different, ranges, of, 'specificity,', suggesting, that, 'QDR', to, 'Xc', involves, a, complex, network, integrating, multiple, response, pathways, triggered, by, distinct, pathogen, molecular, determinants])].
[sujeto(['The', 'Arabidopsis', 'RRS1-R', 'NB-LRR', protein, carries, a, 'C-terminal', 'WRKY', 'DNA']), verbo([binding]), complemento([domain, and, forms, a, receptor, complex, with, 'RPS4,', another, 'NB-LRR', protein])].
[sujeto(['This', complex, detects, the, bacterial, effectors, 'AvrRps4', or, 'PopP2', and, then]), verbo([activates]), complemento([defense])].
[sujeto(['Both', bacterial, proteins]), verbo([interact]), complemento([with, the, 'RRS1', 'WRKY', 'domain,', and, 'PopP2', acetylates, lysines, to, block, 'DNA', binding])].
[sujeto(['PopP2', and, 'AvrRps4']), verbo([interact]), complemento([with, other, 'WRKY', 'domain-containing', 'proteins,', suggesting, these, effectors, interfere, with, 'WRKY', transcription, 'factor-dependent', 'defense,', and, 'RPS4/RRS1', has, integrated, a, &, 'quot;decoy"', domain, that, enables, detection, of, effectors, that, target, 'WRKY', proteins])].
[sujeto(['We', propose, that, 'NB-LRR', receptor, 'pairs,', one, member, of, which, carries, an, additional, protein, 'domain,', enable, perception, of, pathogen, effectors, whose, function, is, to]), verbo([target]), complemento([that, domain])].
[sujeto(['The', 'single-span', membrane, protein, 'KCNE3']), verbo([modulates]), complemento([a, variety, of, 'voltage-gated', ion, channels, in, diverse, biological, contexts])].
[sujeto(['In', epithelial, 'cells,', 'KCNE3']), verbo([regulates]), complemento([the, function, of, the, 'KCNQ1', potassium, ion, '(', 'K(+))', channel, to, enable, 'K(+)', recycling, coupled, to, transepithelial, chloride, ion, '(', 'Cl(-))', 'secretion,', a, physiologically, critical, cellular, transport, process, in, various, organs, and, whose, malfunction, causes, 'diseases,', such, as, cystic, fibrosis, '(', 'CF),', 'cholera,', and, pulmonary, edema])].
[sujeto(['Structural,', 'computational,', 'biochemical,', and, electrophysiological, studies]), verbo([lead]), complemento([to, an, atomically, explicit, integrative, structural, model, of, the, 'KCNE3-KCNQ1', complex, that, explains, how, 'KCNE3', induces, the, constitutive, activation, of, 'KCNQ1', channel, 'activity,', a, crucial, component, in, 'K(+)', recycling])].
[sujeto(['These', interactions, appear, to, stabilize, the]), verbo([activated]), complemento([&, 'quot;up"', state, configuration, of, 'S4,', a, prerequisite, for, full, opening, of, the, 'KCNQ1', channel, gate])].
[sujeto(['An', awareness, of, overlap, in, chronic, gut, syndromes]), verbo([has]), complemento([been, clarified, by, the, realization, that, inflammatory, pathways, involved, in, chronic, gut, disease, can, arise, through, variable, gene, expression, that, is, influenced, by, the, environment, in, susceptible, individuals])].
[sujeto(['When', made, aware, of, the, importance, of, these, recent, developments, in, chronic, gut, 'disease,', histopathologists, can, easily]), verbo([recognize]), complemento([colonic, spirochetosis, and, microscopic, colitis])].
[sujeto(['The', role, of, the, microbiome, alongside, interaction, with, the, 'environment,', are, now]), verbo([recognized]), complemento([as, key, players, in, complex, diseases])].
[sujeto(['Throwing', loads, are, known, to, be, closely, related, to, injury, 'risk,', however, for, logistic, 'reasons,', typically, only, pitchers]), verbo([have]), complemento([their, throws, 'counted,', and, then, only, during, innings])].
[sujeto(['A', potential, solution, to, this, is, the, use, of, wearable, microtechnology, to, automatically, 'detect,', 'quantify,', and]), verbo([report]), complemento([pitch, counts, in, baseball])].
[sujeto(['Seventeen', elite, youth, baseball, players, '(', mean, ±, 'SD', age, 16.5, ±, 0.8, 'years;', height, 184.1, ±, 5.5, 'cm;', mass, 78.3, ±, 7.7, 'kg)']), verbo([participated]), complemento([in, this, study])].
[sujeto(['These', findings, demonstrate, that, the, microtechnology, unit, is, sensitive, to, detect, pitching, and, throwing, 'events,', however, further, development, of, the, pitching, algorithm, is]), verbo([required]), complemento([in, order, to, accurately, and, consistently, quantify, throwing, loads, using, microtechnology])].
[sujeto(['The', 'UK', healthcare, system, is, unique, in, that, it]), verbo([has]), complemento([dedicated, oncology, clinical, nurse, specialists])].
[sujeto(['The', analysis]), verbo([found]), complemento([that, more, patients, experienced, nausea, following, their, most, recent, treatment, cycle, than, vomiting])].
[sujeto(['Altogether,', 42, '%', of, patients]), verbo([reported]), complemento([full, adherence, to, their, antiemetic, regimen])].
[sujeto(['Leading', factors, for, 'non-adherence', included, not, having, a, '\'', preventive, 'mindset\',', low, symptom, severity, and, a, reluctance, to]), verbo([increase]), complemento([pill, burden])].
[sujeto(['Advances', in, management, depend, on]), verbo([enhancing]), complemento([health, 'professional-patient', 'communication,', and, reporting, and, understanding, nausea, as, a, distinct, issue])].
[sujeto(['We']), verbo([report]), complemento([the, design, and, synthesis, of, a, series, of, 'non-nucleoside', 'MtbTMPK', inhibitors, '(', 1, -, 14, ')', based, on, the, 'gram-positive', bacterial, 'TMPK', inhibitor, hit, compound, 1])].
[sujeto(['Hydrophobic', interactions, between, the, outer, blocks]), verbo([cause]), complemento([them, to, 'phase-separate', into, larger, hydrophobic, domains, in, 'water,', forming, physical, crosslinks, between, the, polymers])].
[sujeto(['We', describe, a, modified, procedure]), verbo([associating]), complemento([liver, partition, and, portal, vein, ligation, for, staged, hepatectomy, '(', 'ALPPS)', including, portal, pedicle, preservation, during, parenchymal, 'division,', thus, avoiding, necrosis])].
[sujeto(['Although', 'ALPPS', recently]), verbo([has]), complemento([been, advocated, for, treating, advanced, liver, 'tumors,', sepsis, originating, from, the, ischemic, area, produced, by, parenchymal, division, increases, 'mortality,', accounting, for, 'one-third', of, postoperative, deaths])].
[sujeto(['Our', procedure, differs, from, the, original, 'ALPPS', technique, by, sparing, portal, pedicles, at, the, transection, 'plane,', thus]), verbo([maintaining]), complemento([blood, supply])].
[sujeto(['Our', technique]), verbo([stimulates]), complemento([rapid, hypertrophy, and, may, improve, safety, in, 'ALPPS'])].
[sujeto(['The', compression, 'pressure,', which, corresponds, to, the, dosage, of, compression, 'therapy,']), verbo([has]), complemento([been, widely, neglected, up, to, 'now,', not, only, concerning, scientific, 'literature,', but, also, in, clinical, practice])].
[sujeto(['This', article]), verbo([provides]), complemento([an, overview, of, the, recent, literature, on, the, 'SSI,', which, supports, the, recommendations, of, the, 'International', 'Compression', 'Club'])].
[sujeto(['In', 'addition,', it, aims, to]), verbo([provide]), complemento([an, insight, on, the, importance, of, the, 'SSI', in, daily, 'practice,', as, an, educational, tool, as, well, as, in, defining, the, properties, of, applied, compression, therapy, in, clinical, research])].
[sujeto(['We', sought, to, clarify, the, effects, of, early, 'fast-acting', treatment, '(', 'EFT)', strategies, on, the, time, course, for, achieving, the, treatment]), verbo([target]), complemento([in, generalized, myasthenia, gravis, '(', 'MG)'])].
[sujeto(['The', rarity, of, mutations, in, 'PALB2,', 'CHEK2', and, 'ATM', make, it, difficult, to, estimate, precisely]), verbo([associated]), complemento([cancer, risks])].
[sujeto(['Population-based', family, studies]), verbo([have]), complemento([provided, evidence, that, at, least, some, of, these, mutations, are, associated, with, breast, cancer, risk, as, high, as, those, associated, with, rare, 'BRCA2', mutations])].
[sujeto(['We', aimed, to, estimate, the, relative, risks]), verbo([associated]), complemento([with, specific, rare, variants, in, 'PALB2,', 'CHEK2', and, 'ATM', via, a, multicentre, 'case-control', study])].
[sujeto(['We', also]), verbo([found]), complemento([evidence, of, association, with, breast, cancer, risk, for, three, variants, in, 'CHEK2,', c])].
[sujeto(['No', evidence, of, association, with, ovarian, cancer, was]), verbo([found]), complemento([for, any, of, these, variants])].
[sujeto(['This']), verbo([report]), complemento([adds, to, accumulating, evidence, that, at, least, some, variants, in, these, genes, are, associated, with, an, increased, risk, of, breast, cancer, that, is, clinically, important])].
[sujeto(['Because', the, serum, parathyroid, 'hormone-related', protein, '(', 'PTHrP)', and, 'granulocyte-colony']), verbo([stimulating]), complemento([factor, '(', 'G-CSF)', levels, were, significantly, 'elevated,', we, suspected, that, 'PTHrP', and, 'G-CSF', production, occurred, because, of, adenosquamous, cell, carcinoma, in, the, gallbladder])].
[sujeto(['Senescence', is, a, very, complex, process, characterized, by, a, highly]), verbo([regulated]), complemento([series, of, degenerative, events, which, include, changes, in, cell, 'structure,', metabolism, and, gene, expression])].
[sujeto(['In', some, 'cases,', there, were, no, differences, in, telomere, length, during, plant, developmental, stages, while, in, other, cases, both, shortening, and, lengthening]), verbo([have]), complemento([been, observed])].
[sujeto(['Several', genes]), verbo([involved]), complemento([in, telomere, homeostasis, have, been, identified, in, 'plants,', including, some, helicases])].
[sujeto(['Our', results]), verbo([reveal]), complemento([that, both, 'PDH45', and, 'SUV3', transgenic, rice, lines, present, decreased, levels, of, 'necrosis/apoptosis', as, compared, to, wild, type, plants])].
[sujeto(['Additionally,', in, these, 'plants,', some, 'senescence-associated', genes, '(', 'SAGs)', were, downregulated, at, 'S2', and, 'S4', 'stages,', while, genes]), verbo([involved]), complemento([in, the, maintenance, of, genome, stability, and, 'DNA', repair, were, upregulated])].
[sujeto(['This', was]), verbo([associated]), complemento([with, an, increase, '(', 2.5, -, 'fold)', in, telomerase, '(', 'OsTERT)', transcript, level])].
[sujeto(['This', is, an, interesting, result]), verbo([reporting]), complemento([a, possible, involvement, of, 'SUV3', in, telomere, homeostasis, in, plants])].
[sujeto(['The']), verbo([target]), complemento([audience, was, the, international, community, working, to, improve, medical, '(', 'CME),', nursing, '(', 'CNE),', pharmacy, '(', 'CPE),', and, interprofessional, '(', 'CIPE)', continuing, education, '(', 'CE)', and, continuing, professional, development, '(', 'CPD)'])].
[sujeto(['Goals', 'included:', addressing, 'patients\'', concerns, and, 'needs;', advancing, global, medical, and, interprofessional, health, sciences, 'education;', utilizing, learning, to, address, health, 'disparities;', and]), verbo([promoting]), complemento([international, cooperation])].
[sujeto(['Previously,', we, developed, an, 'LVS', 'ΔcapB', mutant, that, is, significantly, safer, than, 'LVS', and]), verbo([provides]), complemento([potent, protective, immunity, against, 'F'])].
[sujeto(['We', show, that, rLVS, 'ΔcapB/bfr-iglA,', 'iglB,', 'iglC,', and, iglABC]), verbo([express]), complemento([more, 'IglA,', 'IglB,', 'IglC', or, 'IglABC', than, parental, 'LVS', 'ΔcapB', in, broth, and, in, human, 'macrophages,', and, stably, express, 'FPI', proteins, in, macrophages, and, mice, absent, antibiotic, selection])].
[sujeto(['Thus,', rLVS, 'ΔcapB/bfr-iglABC', shows, improved, immunogenicity, and, protective, efficacy, compared, with, parental, 'LVS', 'ΔcapB', 'and,', in, contrast, to, 'LVS,']), verbo([has]), complemento([partial, efficacy, as, immediate, 'pre-', and, 'post-exposure', prophylaxis])].
[sujeto(['The', regulation, of, 'caspase-3', enzyme, activity, is, a, vital, process, in, cell, fate, decisions]), verbo([leading]), complemento([to, cell, differentiation, and, tissue, development, or, to, apoptosis])].
[sujeto(['The', 'zebrafish,', 'Danio', 'rerio,']), verbo([has]), complemento([become, an, increasingly, popular, animal, model, to, study, several, human, diseases, because, of, their, transparent, 'embryos,', short, reproductive, 'cycles,', and, ease, of, drug, administration])].
[sujeto(['While', apoptosis, is, an, evolutionarily]), verbo([conserved]), complemento([process, in, 'metazoans,', little, is, known, about, caspases, from, 'zebrafish,', particularly, regarding, substrate, specificity, and, allosteric, regulation, compared, to, the, human, caspases])].
[sujeto(['We', determined, the, structure, of, zebrafish, 'Casp3a', to, 2.28, 'Å', resolution, by, 'X-ray', 'crystallography,', and, when, combined, with, molecular, dynamics, 'simulations,', the, results]), verbo([suggest]), complemento([that, a, limited, number, of, amino, acid, substitutions, near, the, active, site, result, in, plasticity, of, the, 'S4', 'sub-site', by, increasing, flexibility, of, one, active, site, loop, and, by, affecting, 'hydrogen-bonding', with, substrate])].
[sujeto(['The', data, show, that, zebrafish, 'Casp3a', exhibits, a, broader, substrate, 'portfolio,']), verbo([suggesting]), complemento([overlap, with, the, functions, of, 'caspase-6', in, zebrafish, development])].
[sujeto(['For', many, decades, the, capacity, of, the, hair, follicle, '(', 'HF)', to, directly, contribute, to, skin, repair]), verbo([has]), complemento([been, appreciated, '(', 's1-s4),', although, recent, advances, in, transgenic, mouse, technology, have, heralded, an, explosion, of, research, in, this, area, '(', 1, -, 9, ',', 's5-s9)'])].
[sujeto(['The', 'HF', bulge, '(', see, figure, 1, ')', is, an, epithelial, stem, cell, '(', 'SC)', compartment, '(', 1, ',', 9, ',', 's10-s13)', that]), verbo([has]), complemento([been, of, particular, interest, with, regard, to, wound, repair, '(', 2, ',', 8, ',', 9, ',', 's14),', which, is, intriguing, for, a, number, of, reasons, '(', full, discussion, in, supplemental, text, 'T1)'])].
[sujeto(['Longevity', is]), verbo([regulated]), complemento([by, a, network, of, closely, linked, metabolic, systems])].
[sujeto(['MRP', knockdown]), verbo([triggers]), complemento([mitonuclear, protein, 'imbalance,', reducing, mitochondrial, respiration, and, activating, the, mitochondrial, unfolded, protein, response])].
[sujeto(['Specific', antibiotics]), verbo([targeting]), complemento([mitochondrial, translation, and, ethidium, bromide, '(', which, impairs, mitochondrial, 'DNA', 'transcription)', pharmacologically, mimic, mrp, knockdown, and, extend, worm, lifespan, by, inducing, mitonuclear, protein, 'imbalance,', a, stoichiometric, imbalance, between, nuclear, and, mitochondrially, encoded, proteins])].
[sujeto(['This', mechanism, was, also]), verbo([conserved]), complemento([in, mammalian, cells])].
[sujeto(['In', 'addition,', resveratrol, and, 'rapamycin,', longevity, compounds]), verbo([acting]), complemento([on, different, molecular, 'targets,', similarly, induced, mitonuclear, protein, 'imbalance,', the, mitochondrial, unfolded, protein, response, and, lifespan, extension, in, 'C'])].
[sujeto(['Collectively', these, data, demonstrate, that, 'MRPs', represent, an, evolutionarily]), verbo([conserved]), complemento([protein, family, that, ties, the, mitochondrial, ribosome, and, mitonuclear, protein, imbalance, to, the, mitochondrial, unfolded, protein, 'response,', an, overarching, longevity, pathway, across, many, species])].
[sujeto(['We', used, seven]), verbo([nuclear]), complemento([gene, 'fragments,', elongation, factor, 1, alpha, '(', 'EF-1alpha),', wingless, '(', 'wgl),', isocitrate, dehydrogenase, '(', 'IDH),', 'glyceraldehyde-3-phosphate', dehydrogenase, '(', 'GAPDH),', ribosomal, protein, 'S5', '(', 'RpS5)', and, segments, 'D1', and, 'D2', of, the, 28, 'S', rRNA, 'gene,', and, one, mitochondrial, gene, 'fragment,', cytochrome, oxidase, subunit, 'I', '(', 'COI)'])].
[sujeto(['Bistonini', is, thus]), verbo([suggested]), complemento([to, be, subsumed, to, the, tribe, 'Boarmiini', in, the, broad, sense])].
[sujeto(['Indeed,', an, analysis, of, timing, of, divergence]), verbo([suggested]), complemento([that, 'Boarmiini', s])].
[sujeto(['Within', the, 'Ennominae,', seven, independent, origins, of, female, flightlessness, were, revealed, facilitating, phylogenetic, comparative, analyses, to, be, performed, in, search, of]), verbo([causes]), complemento([and, consequences, of, this, phenomenon])].
[sujeto(['The', present, phylogenetic, hypothesis, supports, the, conclusions, of, the, &, 'quot;adaptive', 'story",', a, hypothesis, of, the, sequence, of, evolutionary, events]), verbo([leading]), complemento([to, 'flightlessness,', we, have, presented, earlier, '(', 'Snäll', et, al])].
[sujeto([clearly, represents, a, group, of, geometrids, in, which, female, flightlessness]), verbo([has]), complemento([evolved, more, frequently, than, in, any, other, 'tribes,', suggesting, that, this, clade, has, likely, been, predisposed, to, evolutionary, events, leading, to, the, manifestation, of, female, flightlessness])].
[sujeto(['The', ancestor, of, the, 'wing-reduced', 'Ennominae']), verbo([has]), complemento([likely, been, a, winged, but, slow, flying, forest, moth, feeding, polyphagously, on, deciduous, trees])].
[sujeto(['The', objective, of, this, study, was, to, evaluate, the, effects, of, these, insecticides, on, the, viability, of, in, vitro, cultured, mouse, oocytes, during, the, early, oogenesis, and, to, get, a, further, understanding, of, the, molecular, mechanisms, by, which, 'OP', insecticides]), verbo([act]), complemento([and, affect, germinal, cells])].
[sujeto(['Results', show, a, significant]), verbo([decrease]), complemento([in, oocytes, survival, after, 24, -, h, exposure, to, 250, microM, malathion, or, 900, nM, 'diazinon,', and, the, effect, of, these, insecticides, on, the, regulation, of, genes, encoding, proteins, involved, in, transcription, '(', 'BP75),', translation, '(', ribosomal, protein, 'S5),', and, mitochondrial, function, '(', cytochrome, oxidase, subunits, 'I', and, 'III),', providing, evidence, for, 'OP', insecticides, as, toxicants, for, mammals, oocytes, during, the, early, oogenesis])].
[sujeto(['The', nucleotide, sequence, of, a, large, rRNA, gene, and, its, flanking, regions, in, cloned, fragments, of, mitochondrial, 'DNA', from, a, patulin, 'producer,', 'Penicillium', urticae, 'NRRL2159A,', was, determined, by, dideoxy, 'sequencing,', and, the, 5, '\'', end, and, 'intron-exon', border, of, the, 1, -, rRNA, gene, were, determined, by]), verbo([primer]), complemento([extension, analysis, and, 'RNA', 'sequencing,', respectively])].
[sujeto([urticae, contains, a, structure, similar, to, the, consensus, one, of, the, self, splicing, group, 'IA', intron, and, a, large, open, reading, frame]), verbo([suggested]), complemento([to, be, a, gene, for, ribosomal, protein, 'S5'])].
[sujeto(['A', sequence, similar, to, the, 'I-SceI', recognition, sequence, was]), verbo([found]), complemento([at, the, 'exon-intron', border])].
[sujeto(['In', the, present, 'work,', we, carried, out, further, structural, analysis, of, the, intron, and, constructed, mutant, derivatives, of, it, in, order, to, identify, features, that, are, either]), verbo([required]), complemento([for, splicing, or, prevent, it, from, 'self-splicing'])].
[sujeto(['Further', 'deletions,', which, remove, all, of, 'P2', or, all, or, part, of, 'P4,', 'P6,', 'P7,', or, 'P9,', inactivate, 'splicing,']), verbo([suggesting]), complemento([that, an, intact, group, 'I', intron, core, structure, is, required])].
[sujeto(['Our', findings, indicate, that, the, inability, of, the, mitochondrial, large, rRNA, intron, to, 'self-splice', reflects, deficiency, of, a, structure, or, activity]), verbo([required]), complemento([for, cleavage, at, the, 5, '\'', splice, 'site,', either, in, the, intron, core, itself, or, in, the, interaction, between, the, core, and, the, 'P1', stem])].
[sujeto(['Comparison', with, the, corresponding, intron, of, the, large, rRNA, gene, of, yeast, mitochondria]), verbo([reveals]), complemento([a, single, highly, homologous, 57, nucleotide, long, 'sequence,', including, the, sequence, '(', 'formula;', see, 'text),', which, is, present, in, virtually, all, the, sequenced, introns, of, 'yeast,', 'Aspergillus', nidulans, and, 'Zea', mays, mitochondrial, 'genes,', and, which, may, be, important, for, their, processing])].
[sujeto(['Sequences', closely, related, to, this, consensus, sequence, are, also, present, within, all, four, of, the, introns, of]), verbo([nuclear]), complemento([rRNA, genes, which, have, been, sequenced])].
[sujeto(['The', intron, is, located, within, a, highly]), verbo([conserved]), complemento([region, of, the, large, rRNA, sequence, and, at, exactly, the, same, site, as, in, the, corresponding, introns, in, yeast, mitochondria, and, also, in, 'Physarum', polycephalum, nuclei])].
[sujeto(['We']), verbo([have]), complemento([developed, a, rapid, method, for, the, purification, of, 'S-5', which, takes, advantage, of, its, high, affinity, for, 'carboxymethyl-Sepharose', in, the, presence, of, 6, 'M', urea])].
[sujeto(['Metabolic', reprogramming]), verbo([has]), complemento([been, regarded, as, an, essential, component, of, malignant, transformation])].
[sujeto(['The', aim, of, this, study, was, to, characterize, metabolic, heterogeneity, in, thyroid, cancers, via, the, analysis, of, the, expression, of, mitochondrial, ribosomal, proteins, '(', 'MRPs)', and, genes]), verbo([involved]), complemento([in, oxidative, phosphorylation, '(', 'OxPhos),', and, investigate, potential, prognostic, correlations])].
[sujeto(['Remarkably,', strong, positive, correlations, between, 'MRPL44', expression, and, those, of, 'OxPhos', and, 'MRPs', such, as, reduced, nicotinamide, adenine, dinucleotide, dehydrogenase, '(', 'ubiquinone)', 1, α, 'subcomplex,', 5, ;, succinate, dehydrogenase, 'complex,', subunit, 'D;', cytochrome, 'c,', 'somatic;', adenosine, triphosphate, 'synthase,', 'H+', 'transporting,', mitochondrial, 'Fo', 'complex,', subunit, 'C1', '(', subunit, 9, ')', ;, and, 'MRP', 'S5', '(', 'MRPS5)', '(', 'P', &, 'lt;', 0.0001, ')', were, clearly, 'denoted,']), verbo([suggesting]), complemento([that, 'MRPL44', is, a, representative, marker, of, 'OxPhos', and, 'MRP', expressions])].
[sujeto(['Furthermore,', multivariate, analysis, clearly, indicated, that, expression, of, 'MRPL44', is]), verbo([associated]), complemento([with, an, increased, risk, of, lateral, neck, 'LNM', '(', odds, ratio, 9.267, ',', 95, '%', confidence, interval, 1.852, -, 46.371, ',', 'P', =, 0.007, ')'])].
[sujeto(['Recent', studies]), verbo([have]), complemento([shown, that, tuberous, sclerosis, complex, '(', 'TSC)', 1, and, 'TSC2', genes, are, linked, to, the, mammalian, target, of, rapamycin, '(', 'mTOR)', cell, signaling, pathway])].
[sujeto(['Loss', of, immunoexpression, of, either, hamartin, or, tuberin, was]), verbo([found]), complemento([in, 19, cases, '(', 68, '%', ')'])].
[sujeto(['There', is, a, definite, role, for, 'TSC1', and, 'TSC2', genes, in, the, pathogenesis, of, 'SEGA', as, evidenced, by]), verbo([loss]), complemento([of, protein, expression, and, presence, of, mutations])].
[sujeto(['Strong', expression, of, mTOR, downstream, signaling, proteins, indicates, activation, of, mTOR, pathway, in, these, 'tumors,']), verbo([suggesting]), complemento([that, proteins, in, this, pathway, may, have, the, potential, to, serve, as, therapeutic, targets, in, these, patients])].
[sujeto(['In', obese, 'subjects,', the]), verbo([loss]), complemento([of, fat, mass, during, energy, restriction, is, often, accompanied, by, a, loss, of, muscle, mass])].
[sujeto(['The', hypothesis, that, 'n-3', 'PUFA,', which]), verbo([modulate]), complemento([protein, homoeostasis, via, effects, on, insulin, 'sensitivity,', could, contribute, to, maintain, muscle, mass, during, energy, restriction, was, tested, in, rats, fed, a, 'high-fat', diet, '(', 4, 'weeks)', rich, in, 18, :, 1, 'n-9', '(', oleic, 'acid,', 'OLE-R),', 18, :, 3, 'n-3', '(', 'α-linolenic', 'acid,', 'ALA-R)', or, 'n-3', 'long-chain', '(', 'LC-R)', fatty, acid, and, then, energy, restricted, '(', 8, 'weeks)'])].
[sujeto(['A', control, group, '(', 'OLE-ad', libitum, '(', 'AL))', was]), verbo([maintained]), complemento([with, 'AL', diet, throughout, the, study])].
[sujeto(['The', proteolytic, 'ubiquitin-proteasome', system, was, differentially, affected, by, energy, 'restriction,', with, 'MAFbx', and, muscle, ring, 'finger-1', mRNA, levels, being]), verbo([decreased]), complemento([in, the, 'LC-R', group, '(', -, 30, and, -, 20, '%', ',', 'respectively)'])].
[sujeto(['RAC-α', 'serine/threonine-protein', kinase, and, insulin, receptor, substrate, 1, phosphorylation, levels]), verbo([increased]), complemento([in, the, 'LC-R', group, '(', +, 70, '%', ')', ',', together, with, insulin, receptor, mRNA, '(', +, 50, '%', ')'])].
[sujeto(['In', 'conclusion,', dietary, 'n-3', 'PUFA']), verbo([prevent]), complemento([the, loss, of, muscle, mass, associated, with, energy, 'restriction,', probably, by, an, improvement, in, the, 'insulin-signalling', pathway, 'activation,', in, relation, to, enrichment, of, plasma, membranes, in, 'n-3', 'LC-PUFA'])].
[sujeto(['The', mammalian]), verbo([target]), complemento([of, rapamycin, '(', 'mTOR)', is, essential, for, 'Th', cell, proliferation, and, effector, 'differentiation,', making, the, mTOR, signaling, network, an, attractive, immunomodulatory, target, for, 'autoimmune-related', diseases])].
[sujeto(['Although', direct]), verbo([targeting]), complemento([of, mTOR, 'complex-1', '(', 'mTORC1)', with, rapamycin, can, provide, clinical, 'benefit,', targeting, downstream, enzymes, has, the, potential, to, offer, more, selective, immunosuppression])].
[sujeto(['S6K2', is, a, direct, substrate, of, 'mTORC1,', with, a, potential, role, in, 'Th17', differentiation]), verbo([suggested]), complemento([by, biochemical, studies])].
[sujeto(['Using', a, genetic, approach, with, 'S6K2', knockout, 'mice,', we]), verbo([found]), complemento([that, 'S6K2', loss, reduces, 'Th17', skewing, and, increases, regulatory, 'T', cell, differentiation, in, vitro, when, cultured, in, 'RPMI', 1640, media])].
[sujeto(['In', an, in, vivo, experimental, autoimmune, encephalomyelitis, model, in, which, rapamycin]), verbo([suppresses]), complemento(['disease,', 'S6K2', knockout, mice, did, not, exhibit, differences, in, clinical, score, or, 'Th17', differentiation])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'S6K2', is, dispensable, for, 'Th17-driven', autoimmunity, and, highlight, how, distinct, experimental, conditions, can, produce, significantly, different, results, in, 'T', cell, differentiation])].
[sujeto(['The', overexpression, of, 'HER2', was, previously]), verbo([associated]), complemento([with, a, poor, prognosis, until, the, development, of, the, first, 'anti-HER2', 'therapy,', 'trastuzumab,', which, drastically, improves, the, prognosis, of, 'HER2-overexpressing', breast, cancers])].
[sujeto(['Several', studies]), verbo([have]), complemento([proposed, that, the, behavior, and, mechanism, of, action, of, trastuzumab, may, be, drastically, altered, in, vitro, and, in, vivo])].
[sujeto(['The', present, study, assesses, the, ability, of, trastuzumab, to]), verbo([inhibit]), complemento([the, phosphorylation, of, the, 'key-proteins', of, phosphoinositide, 3, -, kinase, '(', 'PI3K)/protein', kinase, 'B', '(', 'AKT)/mechanistic', target, of, rapamycin, and, 'Ras/Raf/mitogen-activated', protein, kinase, '(', 'MAPK)', signaling, pathways, in, 'vitro,', in, breast, cancer, cell, lines, and, in, tumor, biopsies, obtained, from, patients, treated, with, trastuzumab, preoperative, monotherapy, as, part, of, the, 'Unicancer', 'GEP04', 'RADHER', phase, 'II', clinical, trial])].
[sujeto(['A', total, of, 19, pairs, of]), verbo([associated]), complemento([baseline, and, surgery, tumor, specimens, were, eligible, for, protein, extraction, and, comparative, phosphoprotein, expression, 'analysis,', prior, to, and, subsequent, to, treatment])].
[sujeto(['In', the, 'SKBR3', cell, 'line,', a, statistically, significant]), verbo([decrease]), complemento([of, the, expression, level, of, phosphorylated, '(', 'p-)AKT,', 'p-ribosomal', protein, 'S6', kinase, 'B1,', 'p-extracellular', signal, regulated, kinase, 1, /, 2, and, 'p-mitogen-activated', protein, kinase, kinase, 1, was, observed, after, exposure, to, trastuzumab])].
[sujeto(['The', lack, of, downregulation, of, 'PI3K', and, 'MAPK', pathways, could, probably, be, explained, by, the, implementation, of, a, predominant, immunological, mechanism, of, action, for, 'trastuzumab,', a, type, of, 'antibody-dependent', 'cell-mediated', 'toxicity,', which]), verbo([has]), complemento([previously, been, reported, in, preoperative, monotherapy, settings])].
[sujeto(['The', present, study, confirms, that, trastuzumab]), verbo([involves]), complemento([various, modes, of, action, when, assayed, in, vitro, and, used, clinically])].
[sujeto(['Previous', evidence]), verbo([has]), complemento([revealed, that, 'POCD', may, be, associated, with, the, pathogenesis, of, neurodegenerative, processes])].
[sujeto(['The', mammalian]), verbo([target]), complemento([of, rapamycin, '(', 'mTOR)', signaling, pathway, has, been, reported, to, be, crucial, in, the, pathophysiology, of, neurodegenerative, diseases])].
[sujeto(['In', the, present, 'study,', western, blotting, and, 'enzyme‑linked', immunosorbent, assay, were, used, to, determine, the, expression, of, mTOR, and, any]), verbo([associated]), complemento([downstream, 'targets;', contextual, fear, conditioning, was, used, to, estimate, the, learning, and, memory, ability, of, mice])].
[sujeto(['Using', an, animal, model, of, orthopedic, 'surgery,', it, was]), verbo([found]), complemento([that, surgical, injury, impaired, 'hippocampal‑dependent', memory, and, enhanced, the, levels, of, phosphorylated, mTOR, at, 'Serine‑2448,', phosphorylated, 70, &, #, 8209, ;, kDa, ribosomal, protein, 'S6', kinase, '(', 'p70S6K)', at, 'Threonine‑389', with, accumulation, of, 'β‑amyloid', '(', 'Aβ)', and, hyperphosphorylated, tau, at, 'Serine-396,', compared, with, the, control, group])].
[sujeto(['Pretreatment', with, 'rapamycin,', an, mTOR, 'inhibitor,', restored, the, abnormal, 'mTOR/p70S6K', signaling]), verbo([induced]), complemento([by, 'surgery,', attenuated, the, accumulation, of, 'Aβ', and, reduced, the, phosphorylation, of, tau, protein])].
[sujeto(['The', results, of, the, present, study]), verbo([suggested]), complemento([that, the, surgical, stimulus, activated, 'mTOR/p70S6K', signaling, 'excessively,', and, that, the, inhibition, of, mTOR, signaling, with, rapamycin, may, prevent, postoperative, cognitive, 'deficits,', partly, through, attenuating, the, accumulation, of, 'Aβ', and, hyperphosphorylation, of, tau, protein])].
[sujeto(['Hexavalent', chromium, '(', 'Cr', '(', 'VI))', is, an, environmental, human, carcinogen, which, primarily]), verbo([targets]), complemento([lungs])].
[sujeto(['Among', a, variety, of, toxic, 'mechanisms,', disruption, of, biological, pathways, via, translational, and, 'post-translational', modifications, represents, a, key, mechanism, through, which, 'Cr', '(', 'VI)']), verbo([induces]), complemento([cytotoxicity, and, carcinogenesis])].
[sujeto(['The', proteins, and, fold, changes, observed, in, cells, exposed, to, the, 'non-toxic', dose, of, 'Cr', '(', 'VI)', '(', 0.3, 'μM)', were, not, necessarily, the, same, as, those]), verbo([found]), complemento([in, the, toxic, one, '(', 1.8, 'μM)'])].
[sujeto(['These', proteins, include, regulators, of, 'glycolysis,', glycogen, synthase, kinase, 3, beta, '(', 'GSK3β)', and, phosphoprotein, 70, ribosomal, protein, s6, kinase, '(', 'p70S6K),', a, signaling, protein]), verbo([associated]), complemento([with, oxidative, stress, and, inflammation, 'responses,', 'JNK', and, metal, regulatory, transcription, factor, 1, '(', 'MTF-1),', and, a, source, of, ubiquitin, for, signaling, targeted, protein, 'degradation,', polyubiquitin, 'C', '(', 'UBC)'])].
[sujeto(['Murine', 'Double', 'Minute-2', '(', 'Mdm2)']), verbo([has]), complemento([been, identified, as, an, essential, regulator, of, skeletal, muscle, angiogenesis, and, the, 'pro-angiogenic', activity, of, endothelial, cells])].
[sujeto(['We']), verbo([have]), complemento([recently, demonstrated, that, the, 'pro-angiogenic', 'Vascular', 'Endothelial', 'Growth', 'Factor-A', '(', 'VEGF-A)', is, a, potent, upstream, regulator, of, 'Mdm2', phosphorylation, on, its, 'Serine', 166, '(', 'p-Ser166-Mdm2),', a, protein, modification, leading, to, an, increase, in, endothelial, cell, migration])].
[sujeto(['Here,', we, investigated, the, kinase, signaling, pathways, that, could, be, responsible, for]), verbo([mediating]), complemento(['VEGF-A-dependent', 'Mdm2', phosphorylation])].
[sujeto(['Incubation', of, primary, human, dermal, microvascular, endothelial, cells, with, recombinant, 'VEGF-A', for, 15, &, 'nbsp;min']), verbo([led]), complemento([to, increased, phosphorylation, levels, of, 'VEGF-receptor-2,', 'Mdm2,', 'Akt,', 'Extracellular', 'Signal-Regulated', 'Kinase', 1, /, 2, '(', 'ERK1/2),', and, p90, 'Ribosomal', 'S6', 'Kinase', '(', 'p90RSK)', proteins])].
[sujeto(['In', addition, to, being, linked, to, 'VEGF-A', 'signaling,', 'Akt,', 'ERK1/2', and, p90RSK]), verbo([have]), complemento([been, shown, to, potentially, lead, to, 'Mdm2', phosphorylation])].
[sujeto(['Inhibition', of, 'ERK1/2', phosphorylation, by, 'UO126', entirely, abrogated, the, response, of, 'p-Ser166-Mdm2', to, 'VEGF-A', 'treatment,', while, 'Akt', phosphorylation, inhibition, by, wortmannin]), verbo([led]), complemento([to, further, elevations, in, 'p-Ser166-Mdm2'])].
[sujeto([p90RSK]), verbo([has]), complemento([been, identified, as, a, potential, candidate, downstream, of, 'ERK1/2', that, could, induce, 'Mdm2', 'Ser166', phosphorylation])].
[sujeto(['Two', independent, p90RSK, 'inhibitors,', 'FMK', and, 'BI-D1870,', each]), verbo([led]), complemento([to, an, entire, loss, of, 'p-Ser166-Mdm2', responsiveness, to, 'VEGF-A'])].
[sujeto(['Inositol', hexakisphosphate, kinase, 3, '(', 'IP6K3)', generates, inositol, 'pyrophosphates,', which]), verbo([regulate]), complemento([diverse, cellular, functions])].
[sujeto(['In', human, 'myotubes,', 'IP6K3', was, upregulated, by, dexamethasone, 'treatment,', which, is, known, to]), verbo([inhibit]), complemento([glucose, metabolism])].
[sujeto(['Ip6k3(-/-)', mice, demonstrated, lower, blood, 'glucose,', reduced, circulating, 'insulin,', deceased, fat, 'mass,', lower, body, 'weight,']), verbo([increased]), complemento([plasma, 'lactate,', enhanced, glucose, 'tolerance,', lower, glucose, during, an, insulin, tolerance, 'test,', and, reduced, muscle, 'Pdk4', expression, under, normal, diet, conditions])].
[sujeto(['The', current, observations]), verbo([suggest]), complemento([novel, roles, of, 'IP6K3', in, cellular, 'regulation,', which, impact, metabolic, control, and, lifespan])].
[sujeto(['Previous', study]), verbo([has]), complemento([indicated, that, exposure, to, 'multi-walled', carbon, nanotubes, '(', 'MWCNTs)', dysregulated, the, transcriptional, expression, of, 'mir-259'])].
[sujeto(['In', this, 'study,', we, examined, the, molecular, basis, for, 'mir-259', in]), verbo([regulating]), complemento(['MWCNTs', toxicity, in, nematodes])].
[sujeto(['Mutation', of, 'mir-259']), verbo([induced]), complemento([a, susceptible, property, to, 'MWCNTs', 'toxicity,', and, 'MWCNTs', exposure, induced, a, significant, increase, in, 'mir-259::GFP', in, 'pharyngeal/intestinal', valve, and, reproductive, 'tract,', implying, that, 'mir-259', might, mediate, a, protection, mechanisms, for, nematodes, against, 'MWCNTs', toxicity])].
[sujeto(['RSKS-1,', a, putative, ribosomal, protein, 'S6', 'kinase,']), verbo([acted]), complemento([as, the, target, for, 'mir-259', in, regulating, 'MWCNTs', 'toxicity,', and, mutation, of, 'rsks-1', suppressed, the, susceptible, property, of, 'mir-259', mutant, to, 'MWCNTs', toxicity])].
[sujeto(['Moreover,', 'mir-259', functioned, in, 'pharynx-intestinal', valve, and, 'RSKS-1', functioned, in, pharynx, to]), verbo([regulate]), complemento(['MWCNTs', toxicity])].
[sujeto(['Furthermore,', 'RSKS-1']), verbo([regulated]), complemento(['MWCNTs', toxicity, by, suppressing, the, function, of, 'AAK-2-DAF-16', signaling, cascade])].
[sujeto(['Our', results, will, strengthen, our, understanding, the, microRNAs]), verbo([mediated]), complemento([protection, mechanisms, for, animals, against, the, toxicity, from, certain, nanomaterials])].
[sujeto(['Equivocal', decline, of, tongue, muscle, performance, with, age, is, compatible, with, resistance, of, the, tongue, to, 'sarcopenia,', the]), verbo([loss]), complemento([of, muscle, volume, and, function, that, typically, occurs, with, aging])].
[sujeto(['We', quantified, myosin, heavy, chain, '(', 'MHC),', muscle, fiber, 'MHC', phenotype, and, size, and, total, and]), verbo([phosphorylated]), complemento(['growth-', and, 'atrophy-related', proteins, by, sodium, dodecyl, sulfate, polyacrylamide, gel, electrophoresis, '(', 'SDS-PAGE),', immunoblot, and, immunohistochemistry, '(', 'IHC)', in, the, 'SG', in, 'twenty-four', macaque, monkeys, '(', 'Macaca', 'rhesus,', age, range, 9, months, to, 31, 'years)', categorized, into, 'Young', '(', &, 'lt;8years', of, 'age),', 'Middle-aged', '(', 15, -, 21, years, of, 'age)', and, 'Old', '(', &, 'gt;22years', of, 'age)', groups])].
[sujeto(['For', each, age, 'group,', mean, 'CSA']), verbo([increased]), complemento([across, 'MHC', phenotype, '(', lowest, mean, 'CSA', for, 'MHCI', and, highest, mean, 'CSA', for, 'MHCII)'])].
[sujeto(['Spearman', analysis, demonstrated, 'age-related']), verbo([increases]), complemento([in, total, p70, ribosomal, protein, 'S6', kinase, '(', 'P70),', phosphorylated, 'P70(421/424),', phosphorylated, 'P38', 'mitogen-activated', protein, kinase, and, muscle, atrophy, 'F-Box,', a, trend, to, 'age-related', decrease, in, total, extracellular, 'signal-regulated', kinase, '(', 'ERK),', and, no, 'age-related', change, in, total, protein, kinase, 'B', '(', 'Akt/PKB),', phosphorylated, 'Akt,', phosphorylated, 'ERK,', phosphorylated, 'c-Jun', 'N-terminal', kinase, '(', 'JNK46)', and, phosphorylated, 'P70(389)'])].
[sujeto(['Although', 'MAFbx', expression]), verbo([increases]), complemento([with, 'age,', this, is, not, associated, with, fiber, 'atrophy,', perhaps, reflecting, compensatory, growth, signaling, by, p70])].
[sujeto(['Final', 'BW', and, skeletal, muscle, weight, were]), verbo([decreased]), complemento(['(', 'P', &, 'lt;', 0.01, ')', by, feed, restriction])].
[sujeto(['Insulin-like', growth, factor, 1, '(', 'IGF-1)', messenger, 'RNA', '(', 'mRNA)', content, was]), verbo([decreased]), complemento(['(', 'P', &, 'lt;', 0.05, ')', when, lambs, were, 'underfed,', whereas, no, difference, for, 'IGF-2', mRNA, expression, was, observed, '(', 'P', &, 'gt;', 0.05, ')'])].
[sujeto(['Moreover,', the, mammalian]), verbo([target]), complemento([of, rapamycin, '(', 'mTOR)', pathway, was, inhibited, by, feed, 'restriction,', which, was, associated, with, decreased, 'phosphor-mTOR,', phosphorylated, eukaryotic, initiation, factor, '4E', binding, protein, 1, '(', 'phosphor-4EBP1),', and, phosphorylated, ribosomal, protein, 'S6', kinase, '(', 'phosphor-S6K)'])].
[sujeto(['In', 'addition,', mRNA, expression, of, both, muscle, 'RING', finger, 1, and, muscle, atrophy, 'F-box', was]), verbo([increased]), complemento([when, ewe, lambs, were, underfed])].
[sujeto(['In', 'summary,', feed, restriction, in, young, growing, ewe, lambs, attenuates, skeletal, muscle, hypertrophy, by]), verbo([inhibiting]), complemento([protein, synthesis, and, increasing, protein, 'degradation,', which, may, act, through, the, 'Akt-dependent', pathway])].
[sujeto(['Chronic', inflammation, is, a, risk, factor, for, the, onset, of, cancer, and, the]), verbo([regular]), complemento([use, of, aspirin, reduces, the, risk, of, cancer, development])].
[sujeto(['We']), verbo([found]), complemento([that, therapeutic, dosages, of, aspirin, prevented, 'IL-6', from, inducing, the, 'down-regulation', of, p53, expression, and, the, acquisition, of, the, epithelial, mesenchymal, transition, '(', 'EMT)', phenotypic, changes, in, the, cell, lines])].
[sujeto(['The', same, effects, were, observed, in, livers, from, mice]), verbo([stimulated]), complemento([with, 'IL-6', and, treated, with, aspirin])].
[sujeto(['In', 'conclusion,', these, data, showed, that, therapeutic, dosages, of, aspirin]), verbo([increase]), complemento([the, 'p53-mediated', 'tumor-suppressor', activity, of, the, cells, thus, being, in, this, way, able, to, reduce, the, risk, of, cancer, 'onset,', either, or, not, linked, to, chronic, inflammatory, processes])].
[sujeto(['However,', to, 'date,', no, clinically, relevant, inhibitor, of, this, cascade]), verbo([has]), complemento([been, tested, in, experimental, models, of, 'addiction,', a, necessary, step, toward, clinical, trials])].
[sujeto(['We', designed, two, new, 'cell-penetrating', peptides, -, 'RB1', and, 'RB3', -, that, penetrate, the, brain, 'and,', in, the, micromolar, 'range,']), verbo([inhibit]), complemento([phosphorylation, of, 'ERK,', histone, 'H3', and, 'S6', ribosomal, protein, in, striatal, slices])].
[sujeto(['All', three, compounds]), verbo([have]), complemento([an, inhibitory, effect, on, 'cocaine-induced', 'ERK', activation, and, reward, in, mice])].
[sujeto(['Since', 'years,', research, on, 'SnRK1,', the, major, cellular, energy, sensor, in, 'plants,']), verbo([has]), complemento([tried, to, define, its, role, in, energy, signalling])].
[sujeto(['Therefore,', we, generated, an, inducible, 'amiRNA::SnRK1α2', in, a, snrk1α1, knock, out, background, '(', 'snrk1α1/α2)', to, abolish, 'SnRK1', activity, to, understand, major, systemic, functions, of, 'SnRK1', signalling, under, energy, deprivation]), verbo([triggered]), complemento([by, extended, night, treatment])].
[sujeto(['We', analysed, the, in, vivo, 'phosphoproteome,', proteome, and, metabolome, and]), verbo([found]), complemento([that, activation, of, 'SnRK1', is, essential, for, repression, of, high, energy, demanding, cell, processes, such, as, protein, synthesis])].
[sujeto(['RPS6', is, a, major]), verbo([target]), complemento([of, 'TOR', signalling, and, its, phosphorylation, correlates, with, translation])].
[sujeto(['Signaling', pathways, such, as, extracellular]), verbo([regulated]), complemento(['kinase/mitogen', activated, protein, kinase, '(', 'ERK/MAPK)', have, increased, activity, in, leukemia])].
[sujeto(['Ribosomal', 6, kinase, '(', 'RSK4)', is, a, factor, downstream, of, the, 'MAPK/ERK', pathway, and, an, important, tumor, suppressor, which]), verbo([inhibits]), complemento(['ERK', trafficking])].
[sujeto(['Decrease', in, 'RSK4', expression]), verbo([has]), complemento([been, reported, in, some, 'malignancies,', which, leads, to, an, increase, in, growth, and, proliferation, and, eventually, poor, prognosis])].
[sujeto(['Expression', rate, of, 'RSK4', was, significantly]), verbo([decreased]), complemento([in, the, 'AML', group, in, comparison, with, the, 'non-AML', group, '(', 'P<0'])].
[sujeto(['There', was, also, a, significant]), verbo([decrease]), complemento([in, 'RSK4', expression, in, 'AML', with, 't(15;17)', in, comparison, to, other, translocations, '(', 'P=0'])].
[sujeto(['This', may]), verbo([lead]), complemento([to, an, increase, in, the, activity, of, the, 'ERK/MPAK', pathway, and, exacerbate, leukemogenesis, or, the, prognosis, of, the, patients])].
[sujeto(['The', results, indicated, that, optimal, levels, of, dietary, protein, had, the, following, 'effects:', '(', 1, ')', the, production, of, antibacterial, components, 'increased,', and, 'anti-inflammatory', 'cytokines,', inhibitor, of, 'κBα,']), verbo([target]), complemento([of, rapamycin, and, ribosomal, protein, 'S6', kinases, 1, mRNA, levels, were, 'up-regulated,', whereas, mRNA, levels, of, 'pro-inflammatory', 'cytokines,', nuclear, factor, kappa, 'B', '(', 'NF-κB)', 'P65,', 'NF-κB', 'P52,', 'IκB', kinase, '(', 'IKK)', 'α,', 'IKKβ,', 'IKKγ,', 'eIF4E-binding', proteins, '(', '4E-BP)', 1, and, '4E-BP2', were, 'down-regulated', in, the, gills, of, grass, carp, '(', 'P < 0'])].
[sujeto([5, ')', ',', indicating, that, fish, gill, immune, function, was]), verbo([enhanced]), complemento([at, an, optimal, level, of, dietary, 'protein;', '(', 2, ')', the, activities, and, mRNA, levels, of, antioxidant, enzymes, and, glutathione, content, 'increased,', the, contents, of, reactive, oxygen, 'species,', malondialdehyde, and, protein, carbonyl, '(', 'PC)', 'decreased,', and, 'NF-E2-related', factor, 2, ',', 'B-cell', lymphoma, 'protein-2,', inhibitor, of, apoptosis, 'proteins,', myeloid, cell, 'leukemia-1', and, tight, junction, complexes, mRNA, levels, were, 'up-regulated,', whereas, 'Kelch-like-ECH-associated', protein, '(', 'Keap)', 1, 'a,', 'Keap1b,', cysteinyl, aspartic, 'acid-protease', 3, ',', 8, ',', 9, ',', fatty, acid, synthetase, 'ligand,', apoptotic, protease, activating, 'factor-1,', 'Bcl-2', associated, 'X', 'protein,', 'c-Jun', 'N-terminal', protein, 'kinase,', myosin, light, chain, kinase, and, p38, 'mitogen-activated', protein, kinase, mRNA, levels, were, 'down-regulated', in, the, gills, of, grass, carp, '(', 'P < 0'])].
[sujeto(['Sixty', male, 'Sprague-Dawley', rats, were, divided, into, 'CO', '(', 'Normal', 'diet)', and, 'HF', '(', 'High', 'Fat', 'diet)', groups, in, order, to]), verbo([induce]), complemento([obesity, for, 15, weeks])].
[sujeto(['In', 'addition,', the, protein, levels, of, the, mammalian]), verbo([target]), complemento([of, rapamycin, complex, 1, '(', 'mTORC1)', and, ribosomal, 'S6', protein, kinase, 1, were, significantly, decreased, by, exercise, and, dietary, change, '(', p, &, 'lt;'])].
[sujeto(['However,', mTORC2, and, phosphoinositide, 3, -, kinase, were, significantly]), verbo([increased]), complemento(['(', p, &, 'lt;'])].
[sujeto(['In', 'summary,', despite, the, negative, impact, of, continuous, high, fat, 'intake,']), verbo([regular]), complemento([exercise, and, dietary, change, showed, a, positive, effect, on, insulin, resistance, and, mTOR, signaling, protein, levels])].
[sujeto(['Luteinizing', 'hormone/human', chorionic, gonadotropin]), verbo([stimulates]), complemento([progesterone, biosynthesis, in, the, corpus, luteum, by, activating, cyclic, adenosine, 'monophosphate/protein', kinase, 'A', cascade])].
[sujeto(['Recent', studies]), verbo([have]), complemento([shown, that, cyclic, adenosine, 'monophosphate-mediated', activation, of, protein, kinase, 'A', interacts, with, the, mammalian, target, of, rapamycin, signaling, pathways])].
[sujeto(['Furthermore,', the, use, of, mammalian]), verbo([target]), complemento([of, rapamycin, inhibitors, for, immunosuppression, in, transplant, patients, has, shown, adverse, effects, in, reproductive, functions])].
[sujeto(['This', study, examined, whether, the, mammalian]), verbo([target]), complemento([of, rapamycin, pathway, plays, any, role, in, luteinizing, 'hormone-mediated', regulation, of, progesterone, production])].
[sujeto(['Cells', were, cultured, for, 72, h, and, treated, with, human, chorionic, gonadotropin, '(', 50, 'ng/ml)', for, different, time, periods, with, or, without, pretreatment, with, mammalian]), verbo([target]), complemento([of, rapamycin, complex, 1, 'inhibitor,', 'rapamycin,', '(', 20, 'nM)', for, 1, h])].
[sujeto(['Treatment', with, human, chorionic, gonadotropin]), verbo([increased]), complemento([the, expression, of, downstream, targets, of, mammalian, target, of, rapamycin, complex, 1, ',', as, well, as, cholesterol, side, chain, cleavage, 'enzyme,', 3, 'β-hydroxysteroid', dehydrogenase, type, 1, and, steroidogenic, acute, regulatory, protein, messenger, 'RNAs'])].
[sujeto(['These']), verbo([increases]), complemento([were, inhibited, by, rapamycin, pretreatment])].
[sujeto(['Our', findings, support, a, role, for, mammalian]), verbo([target]), complemento([of, rapamycin, complex, 1, in, regulating, steroidogenesis, in, human, granulosa, lutein, cells])].
[sujeto(['Androgen', receptor, '(', 'AR)', is, a, steroid, hormone, receptor, that, functions, as, a, transcription, factor, for]), verbo([regulating]), complemento([cell, growth, and, survival])].
[sujeto(['Aberrant', 'AR', function, becomes, a, risk, factor, for]), verbo([promoting]), complemento([the, progression, of, prostate, cancer, '(', 'PCa)'])].
[sujeto(['In', this, 'study,', we, examined, the, roles, of, 'proline-rich', tyrosine, kinase, 2, '(', 'PYK2)', and, ribosomal, 'S6', kinase, 1, '(', 'S6K1)', in]), verbo([regulating]), complemento(['AR', expression, and, activity, and, growth, properties, in, 'PCa', cells])].
[sujeto(['Furthermore,', the, expression, levels, of, 'PYK2', and, 'S6K1', were, significantly, correlated, with]), verbo([nuclear]), complemento(['AR', expression, in, 'PCa', tissues])].
[sujeto(['We', further]), verbo([found]), complemento([the, association, between, 'PYK2,', 'S6K1,', and, 'AR', in, their, protein, expression, and, phosphorylation, levels, among, normal, prostate, 'PZ-HPV-7', cells, and, prostate, cancer, 'LNCaP', and, 22, 'Rv1', cells])].
[sujeto(['Overexpression', of, the, 'wild-type', 'PYK2', in, 'PZ-HPV-7', and, 'LNCaP', cells]), verbo([promoted]), complemento(['AR', and, 'S6K1', expression, and, phosphorylation, as, well, as, enhanced, cell, growth])].
[sujeto(['In', 'contrast,', expression, of, the, mutated, 'PYK2', or, knockdown, of, 'PYK2', expression, in, 'LNCaP', or, 22, 'Rv1', cells]), verbo([caused]), complemento([reduced, expression, or, phosphorylation, of, 'AR', and, 'S6K1', as, well, as, retarded, cell, growth])].
[sujeto(['In', 'summary,', our, data]), verbo([suggested]), complemento([that, 'PYK2', via, 'S6K1', activation, modulated, 'AR', function, and, growth, properties, in, 'PCa', cells])].
[sujeto(['Thus,', 'PYK2', and, 'S6K1', may, potentially, serve, as, therapeutic]), verbo([targets]), complemento([for, 'PCa', treatment])].
[sujeto(['The', expression, of, lipogenic, and, lipolytic, gene, and, protein, and, the, phosphorylation, of, 'calcium/calmodulin', -, dependent, kinase, kinase, '(', 'CaMKK),', 'AMP-activated', protein, kinase, '(', 'AMPK),', mechanistic]), verbo([target]), complemento([of, rapamycin, '(', 'mTOR)', and, p70, ribosomal, 'S6', 'Kinase', '(', 'p70S6K)', were, measured, in, vitro, and, vivo])].
[sujeto(['Emodin', 'down-regulated', the, levels, of, sterol, regulatory, element]), verbo([binding]), complemento([protein, 1, '(', 'SREBP1)', and, its, target, enzymes, but, increased, 'lipolysis-related', proteins, and, mRNA])].
[sujeto(['Phosphorylation', of, 'AMPK', was]), verbo([increased]), complemento([',', while, phosphorylation, of, mTOR, and, p70S6K, were, suppressed, by, emodin])].
[sujeto(['The']), verbo([nuclear]), complemento([translocation, of, 'SREBP1', was, inhibited, by, emodin, via, 'AMPK', and, mTOR])].
[sujeto(['Emodin']), verbo([activated]), complemento(['AMPK', by, 'CaMKK', and, reversed, the, reduction, of, 'CaMKK', in, 'HFD-fed', rats])].
[sujeto(['Effect', of, peroxisome, 'proliferator-activated', receptor, alpha, '(', 'PPARalpha)', 'agonists,', 'WY-14,643', '(', 'WY)', 'and/or', 'clofibrate,', on, the, 'leucine-induced', phosphorylation, of, translational]), verbo([targets]), complemento([in, 'C2C12', myoblasts, was, studied])].
[sujeto(['WY', treatment, also]), verbo([increased]), complemento([the, 'leucine-induced', phosphorylation, of, ribosomal, protein, 'S6', and, eukaryotic, initiation, factor, 4, 'B'])].
[sujeto(['In', 'contrast,', eukaryotic, elongation, factor, 2, ',', a, marker, for, peptide, chain, elongation, 'process,', was, significantly]), verbo([activated]), complemento(['(', 'dephosphorylated)', only, in, 'leucine-stimulated', control, cells])].
[sujeto(['Pre-treatment', of, the, cells, with, 'PD98059', '(', 'ERK1/2', kinase, 'inhibitor)']), verbo([prevented]), complemento([the, phosphorylation, of, 'ERK1/2', and, decreased, the, 'leucine-induced', phosphorylation, of, p70S6K])].
[sujeto(['It', is, concluded, that, 'WY']), verbo([increased]), complemento([the, 'leucine-induced', phosphorylation, of, target, proteins, involving, in, translation, initiation, via, 'ERK/p70S6K', 'pathway,', but, impaired, the, signaling, for, elongation, 'process,', suggesting, that, p70S6K, phosphorylation, may, be, 'essential,', but, not, sufficient, for, the, activation, of, entire, targets, for, protein, translation, in, 'WY-treated', cells])].
[sujeto(['The', objective, of, the, present, study, was, to]), verbo([provide]), complemento([genomic, and, transcriptomic, information, that, may, improve, clinical, outcomes, for, locally, advanced, cervical, cancer, '(', 'LACC)', patients, by, searching, for, therapeutic, targets, or, potential, biomarkers, through, the, analysis, of, significantly, altered, signaling, pathways, in, 'LACC'])].
[sujeto(['By', 'KEGG', 'analysis,', we]), verbo([found]), complemento([93, dysregulated, signaling, 'pathways,', including, the, 'JAK-STAT,', 'NOTCH', and, 'mTOR-autophagy', 'pathways,', which, were, significantly, upregulated])].
[sujeto(['Through', comprehensive, genomic, and, transcriptomic, 'analyses,', this, work]), verbo([provides]), complemento([information, regarding, signaling, pathways, with, promising, therapeutic, 'targets,', suggesting, novel, target, therapies, to, be, considered, in, future, clinical, trials, for, 'LACC', patients])].
[sujeto(['Recent', studies, demonstrated, that, resistance, exercise, not, only]), verbo([leads]), complemento([to, muscle, 'hypertrophy,', but, also, improves, mitochondrial, function])].
[sujeto(['Since', it]), verbo([has]), complemento([been, suggested, that, calorie, restriction, '(', 'CR)', induces, mitochondrial, 'biogenesis,', we, examined, the, effects, of, resistance, training, with, or, without, 'CR', on, muscle, weight, and, key, mitochondrial, parameters, in, rat, skeletal, muscle])].
[sujeto(['Four', weeks, of, resistance, training, '(', 'thrice/week)']), verbo([increased]), complemento([gastrocnemius, muscle, weight, in, ad, 'libitum-fed', '(', 'AL)', rats, by, 14, '%'])].
[sujeto(['The', degree, of, 'muscle-weight']), verbo([increase]), complemento([by, resistance, training, was, lower, in, 'CR', rats, '(', 7.4, '%', ')'])].
[sujeto(['CR', showed, no, effect, on, phosphorylation, of, mammalian]), verbo([target]), complemento([of, rapamycin, '(', 'mTOR)', signaling, proteins, rpS6, and, 'ULK1'])].
[sujeto(['Resistance', training, alone, also]), verbo([increased]), complemento(['PGC-1α', levels, in, skeletal, muscle])].
[sujeto(['The', magnitude, of, the]), verbo([increase]), complemento([in, 'PGC-1α', was, similar, in, both, 'CR', and, 'AL', rats])].
[sujeto(['Moreover,', we]), verbo([found]), complemento([that, resistance, training, with, 'CR', elevated, the, levels, of, proteins, involved, in, mitochondrial, 'fusion,', 'Opa1', and, 'Mfn1,', and, oxidative, 'phosphorylation,', whereas, there, was, no, effect, of, 'CR', on, fission, regulatory, proteins, 'Fis1', and, 'Drp1'])].
[sujeto(['These', results, indicate, that, 'CR', attenuates, resistance, 'training-induced', muscle, 'hypertrophy,', but, may]), verbo([enhance]), complemento([mitochondrial, adaptations, in, skeletal, muscle])].
[sujeto(['The', basal, ganglia]), verbo([have]), complemento([a, central, role, in, motor, 'patterning,', 'habits,', motivated, 'behaviors,', and, 'cognition,', as, well, as, in, numerous, neuropsychiatric, disorders])].
[sujeto(['Receptors', for, histamine, '(', 'HA),', especially, the, 'H3', 'receptor,', are, highly]), verbo([expressed]), complemento([in, the, 'striatum,', the, primary, input, nucleus, of, the, basal, 'ganglia,', but, their, effects, on, this, circuitry, have, been, little, explored])].
[sujeto(['H3']), verbo([interacts]), complemento([with, dopamine, '(', 'DA)', receptors, ex, 'vivo;', the, nature, and, functional, importance, of, these, interactions, in, vivo, remain, obscure])].
[sujeto(['We']), verbo([found]), complemento(['H3', activation, with, the, agonist, 'RAMH', to, produce, a, unique, 'time-', and, 'cell-type-dependent', profile, of, molecular, signaling, events, in, the, striatum])].
[sujeto(['In', 'D1-MSNs,', 'H3', agonist, treatment, transiently]), verbo([activated]), complemento(['MAPK', signaling, and, phosphorylation, of, rpS6, and, leads, to, phosphorylation, of, 'GSK3β-S9,', a, novel, effect])].
[sujeto(['H3R', signaling]), verbo([has]), complemento([been, neglected, in, models, of, basal, ganglia, function, and, has, implications, for, a, range, of, pathophysiologies])].
[sujeto(['Caveolin-1', '(', 'CAV1)', is, a, 'well-known']), verbo([target]), complemento([of, 'EWS/FLI1,', the, main, driver, of, 'ES,', with, an, oncogenic, role, in, 'ES'])].
[sujeto(['We']), verbo([have]), complemento([previously, described, how, 'CAV1', is, able, to, induce, metastasis, in, 'ES', via, matrix, 'metalloproteinase-9', '(', 'MMP-9)'])].
[sujeto(['Furthermore,', 'IQGAP1', silenced, cells, showed, a, marked]), verbo([decrease]), complemento([in, their, migratory, and, invasive, capacity])].
[sujeto(['Analysis', of, the, phosphorylation, profile, of, 'CAV1-silenced', cells, showed, a]), verbo([decrease]), complemento([of, 'p-ribosomal', protein, 'S6', '(', 'RPS6)'])].
[sujeto(['RPS6', can, be]), verbo([phosphorylated]), complemento([by, p90, ribosomal, 'S6', kinases, '(', 'RSK)', proteins])].
[sujeto(['CAV1-silenced', cells, showed, reduced, levels, of, 'p-RSK1', and, treatment, with, 'U0126']), verbo([provoked]), complemento([the, same, effect])].
[sujeto(['The', present, work]), verbo([provides]), complemento([new, insights, into, 'CAV1-driven', metastatic, process, in, 'ES', unveiling, novel, key, nodes])].
[sujeto(['Communication', between, oocytes, and, their, companion, somatic, cells]), verbo([promotes]), complemento([the, healthy, development, of, ovarian, 'follicles,', which, is, crucial, for, producing, oocytes, that, can, be, fertilized, and, are, competent, to, support, embryogenesis])].
[sujeto(['However,', how, 'oocyte-derived', signaling]), verbo([regulates]), complemento([these, essential, processes, remains, largely, undefined])].
[sujeto(['Here,', we, demonstrate, that, 'oocyte-derived', paracrine, 'factors,', particularly, 'GDF9', and, 'GDF9-BMP15', 'heterodimer,']), verbo([promote]), complemento([the, development, and, survival, of, 'cumulus-cell-oocyte', complexes, '(', 'COCs),', partly, by, suppressing, the, expression, of, 'Ddit4l,', a, negative, regulator, of, 'MTOR,', and, enabling, the, activation, of, 'MTOR', signaling, in, cumulus, cells])].
[sujeto(['Cumulus', cells]), verbo([expressed]), complemento([less, 'Ddit4l', mRNA, and, protein, than, mural, granulosa, 'cells,', which, is, in, striking, contrast, to, the, expression, of, phosphorylated, 'RPS6', '(', a, major, downstream, effector, of, 'MTOR)'])].
[sujeto(['Knockdown', of, 'Ddit4l']), verbo([activated]), complemento(['MTOR', signaling, in, cumulus, 'cells,', whereas, inhibition, of, 'MTOR', in, 'COCs', compromised, oocyte, developmental, competence, and, cumulus, cell, 'survival,', with, the, latter, likely, to, be, attributable, to, specific, changes, in, a, subset, of, transcripts, in, the, transcriptome, of, 'COCs'])].
[sujeto(['Sarcopenia', was, evident, by, 18, m, and, was, accompanied, by, 'hyper-phosphorylation', of, 'S6K1,', indicating]), verbo([increased]), complemento([mTORC1, signaling])].
[sujeto(['In', the, 1, '%', 'NP40', insoluble, protein, 'fraction,', the, abundance, of, 'MuRF1']), verbo([increased]), complemento([at, 24, 'm,', while, p62, increased, at, 15, 'm,', and, remained, elevated, at, older, ages])].
[sujeto(['In', 'addition,', we, investigated, how, protein, synthesis, and, degradation, pathways, are]), verbo([modulated]), complemento([by, fasting, in, young, '(', 4, 'm)', and, old, '(', 24, 'm)', 'muscles,', and, showed, that, old, mice, respond, to, fasting, less, robustly, compared, with, young])].
[sujeto(['Overnight', fasting, for, 16, h]), verbo([caused]), complemento(['de-phosphorylation', of, 'AKT', and, molecules, downstream, of, mTORC1, '(', 'S6K1,', rpS6, and, '4E-BP1)', in, 'young,', but, not, old, muscles])].
[sujeto(['A', longer, time, of, fasting, '(', 24, 'h)', was]), verbo([required]), complemento([to, reduce, phosphorylation, of, these, molecules, in, old, mice])].
[sujeto(['The', striking, accumulation, of, insoluble, p62, protein, in, muscles, of, all, old, male, mice, '(', fed, or, 'fasted),']), verbo([suggests]), complemento(['age-related', dysregulation, of, autophagy, and, protein, aggregation])].
[sujeto(['These', data]), verbo([provide]), complemento([an, insight, into, the, mechanisms, of, metabolic, responses, that, affect, protein, homeostasis, in, old, skeletal, 'muscles,', with, applications, to, design, of, clinical, interventions, that, target, sarcopenia])].
[sujeto(['In', mammalian, 'ovaries,', follicle, assembly]), verbo([requires]), complemento([proper, germ, cell, cyst, breakdown, and, the, invasion, of, somatic, cells, to, encapsulate, individual, oocytes])].
[sujeto(['Abnormalities', in, this, process]), verbo([lead]), complemento([to, a, number, of, pathologies, such, as, premature, ovarian, failure, and, infertility])].
[sujeto(['As', a]), verbo([conserved]), complemento([pathway, regulating, cell, growth, and, metabolism, in, response, to, growth, factors, and, 'nutrients,', the, roles, of, mTOR, signaling, in, follicular, development, have, been, extensively, studied, in, recent, years])].
[sujeto(['Further', studies, showed, a, significant]), verbo([decrease]), complemento([in, somatic, cell, proliferation, and, the, expression, of, marker, genes, related, to, follicular, development, '(', 'Kitl,', 'Kit,', 'Gdf9,', 'Bmp15,', 'Zp3,', and, 'Amhr2)', in, treated, ovaries])].
[sujeto(['Moreover,', the, addition, of, 'KITL,', a, growth, factor, that, is, mainly, produced, by, pregranulosa, cells, during, germ, cell, nest, 'breakdown,', rescued, the, extension, of, follicle, formation]), verbo([induced]), complemento([by, mTOR, inhibitors])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'KITL', functions, downstream, of, mTOR, in, somatic, cells, to, regulate, their, communication, with, oocytes, during, follicle, formation])].
[sujeto(['Cultured', hippocampal, neurons, treated, with, 'KCl', showed]), verbo([increased]), complemento(['BDNF', in, the, 'soma,', proximal, and, distal, 'dendrites,', even, in, quaternary, branches])].
[sujeto(['This', 'activity-dependent']), verbo([increase]), complemento([of, 'BDNF', was, abolished, by, 'cycloheximide,', suggesting, local, 'translation,', and, required, activation, of, glutamate, and, 'Trk', receptors])].
[sujeto(['Our', data, showed, that, 'BDNF', translation, was]), verbo([regulated]), complemento([by, multiple, signaling, cascades, including, 'RAS-Erk', and, mTOR, 'pathways,', and, 'CaMKII-CPEB1,', 'Aurora-A-CPEB1', and, 'Src-ZBP1', pathways])].
[sujeto(['Neuronal', activity]), verbo([increased]), complemento([the, levels, of, 'Aurora-A,', 'CPEB1', and, 'ZBP1', in, distal, dendrites, whereas, those, of, eiF4E, and, 'S6', were, unaffected])].
[sujeto(['BDNF-6,', the, main, dendritic, 'BDNF', 'transcript,', was]), verbo([translated]), complemento([in, the, same, subcellular, domains, and, in, response, to, the, same, pathways, as, total, 'BDNF'])].
[sujeto(['In', 'conclusion,', we, identified, the, signaling, cascades, controlling, 'BDNF', translation, and, we, describe, how, the, translational, machinery, localization, is]), verbo([modulated]), complemento([in, response, to, electrical, activity])].
[sujeto(['Rapamycin']), verbo([inhibits]), complemento([mechanistic, '(', or, 'mammalian)', target, of, rapamycin, '(', 'mTOR)', that, promotes, protein, production, in, cells, by, facilitating, ribosome, biogenesis, '(', 'RiBi)', and, 'eIF4E-mediated', 5, '\'', cap, mRNA, translation])].
[sujeto(['Here,', we]), verbo([report]), complemento([our, observations, of, chronic, eRapa, treatment, on, mTORC1, signaling, and, 'RiBi', in, mouse, colon, and, visceral, adipose])].
[sujeto(['As', 'expected,', chronic, eRapa, treatment]), verbo([decreased]), complemento([detection, of, phosphorylated, 'mTORC1/S6K', 'substrate,', ribosomal, protein, '(', 'rpS6)', in, colon, and, fat])].
[sujeto(['However,', in, 'colon,', contrary, to, 'expectations,', there, was, an, upregulation, of, 18, 'S', rRNA, and, some, ribosomal, protein, genes, '(', 'RPGs)']), verbo([suggesting]), complemento([increased, 'RiBi'])].
[sujeto(['Among', 'RPGs,', eRapa]), verbo([increases]), complemento([rpl22l1, mRNA, but, not, its, paralog, rpl22])].
[sujeto(['Furthermore,', there, was, an]), verbo([increase]), complemento([in, the, 'cap-binding', 'protein,', eIF4E, relative, to, its, repressor, '4E-BP1', suggesting, increased, translation])].
[sujeto(['By', 'comparison,', in, 'fat,', there, was, a]), verbo([decrease]), complemento([in, the, level, of, 18, 'S', rRNA, '(', opposite, to, 'colon),', while, overall, mRNAs, encoding, ribosomal, protein, genes, appeared, to, 'increase,', including, 'rpl22,', but, not, rpl22l1, '(', opposite, to, 'colon)'])].
[sujeto(['In', 'fat,', there, was, a]), verbo([decrease]), complemento([in, eIF4E, relative, to, actin, '(', opposite, to, 'colon)', but, also, an, increase, in, the, 'eIF4E/4E-BP1', ratio, likely, due, to, reductions, in, '4E-BP1', at, our, lower, eRapa, dose, '(', similar, to, 'colon)'])].
[sujeto(['Thus,', in, contrast, to, predictions, of]), verbo([decreased]), complemento([protein, production, seen, in, 'cell-based', 'studies,', we, provide, evidence, that, colon, from, chronically, treated, mice, exhibited, an, adaptive, '\'', 'pseudo-anabolic\'', 'state,', which, is, only, partially, present, in, 'fat,', which, might, relate, to, differing, tissue, levels, of, 'rapamycin,', 'cell-type-specific', 'responses,', 'and/or', strain, differences])].
[sujeto(['In', mammalian, 'cells,', mTORC1, activity, is]), verbo([regulated]), complemento([by, 'Rag', 'GTPases'])].
[sujeto(['It', is, thought, that, the, 'Ragulator', complex, and, the, 'GATOR', '(', 'GAP', activity, towards, 'Rags)', complex]), verbo([regulate]), complemento(['RagA/B', as, its, 'GDP/GTP', exchange, factor, '(', 'GEF)', and, 'GTPase-activating', protein, '(', 'GAP),', respectively])].
[sujeto(['Using', fission, yeast, as, a, model, 'organism,', here, we]), verbo([found]), complemento([that, the, loss, of, 'Lam2', '(', 'SPBC1778'])].
[sujeto([5, 'c),', a, homolog, of, a, 'Ragulator', component, 'LAMTOR2,', as, well, as, the]), verbo([loss]), complemento([of, 'Gtr1', or, 'Gtr2', phenocopies, the, loss, of, 'Npr2', or, 'Npr3,', homologs, of, 'GATOR', components, 'Nprl2', or, 'Nprl3,', respectively])].
[sujeto(['These', phenotypes, were, rescued, by, 'TORC1', inhibition, using, pharmacological, or, genetic, 'means,', and, the]), verbo([loss]), complemento([of, 'Lam2,', 'Gtr1,', 'Gtr2,', 'Npr2', or, 'Npr3', disinhibited, 'TORC1', activity, under, nitrogen, 'depletion,', as, measured, by, 'Rps6', phosphorylation])].
[sujeto(['Consistently,', overexpression, of, 'GDP-locked', 'Gtr1S20L', or, 'GTP-locked', 'Gtr2Q60L,', which]), verbo([suppress]), complemento(['TORC1', activity, in, budding, 'yeast,', rescued, the, growth, defect, of, 'Δgtr1', cells, or, 'Δgtr2', 'cells,', 'respectively,', and, the, loss, of, 'Lam2,', 'Npr2', or, 'Npr3', similarly, diminished, the, vacuolar, localization, and, the, protein, levels, of, 'Gtr1', and, 'Gtr2'])].
[sujeto(['Furthermore,', 'Lam2', physically]), verbo([interacted]), complemento([with, 'Npr2', and, 'Gtr1'])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'Lam2', and, 'Npr2-Npr3', function, together, as, a, tether, for, 'GDP-bound', 'Gtr1', to, the, vacuolar, 'membrane,', thereby, suppressing, 'TORC1', activity, for, multiple, cellular, functions])].
[sujeto(['Previous', studies]), verbo([have]), complemento([shown, that, induction, of, 'long-term', potentiation, '(', 'LTP)', induces, phosphorylation, of, ribosomal, protein, 'S6', '(', 'rpS6)', in, postsynaptic, 'neurons,', but, the, functional, significance, of, rpS6, phosphorylation, is, poorly, understood])].
[sujeto(['Here,', we, show, that, synaptic, stimulation, that]), verbo([induces]), complemento([perforant, path, 'LTP', triggers, phosphorylation, of, rpS6, '(', 'p-rpS6)', locally, near, active, synapses])].
[sujeto(['Using', antibodies, specific, for, phosphorylation, at, different, sites, '(', 'ser235/236', versus, 'ser240/244),', we, show, that, strong, synaptic, activation]), verbo([led]), complemento([to, dramatic, increases, in, immunostaining, throughout, postsynaptic, neurons, with, selectively, higher, staining, for, 'p-ser235/236', in, the, activated, dendritic, lamina])].
[sujeto(['Following', 'LTP', 'induction,', phosphorylation, at, 'ser235/236', was, detectable, by, 5, 'min,', peaked, at, 30, 'min,', and, was]), verbo([maintained]), complemento([for, hours])].
[sujeto(['Exploration', of, a, novel, environment]), verbo([led]), complemento([to, increases, in, the, number, of, 'p-rpS6-positive', neurons, throughout, the, forebrain, in, a, pattern, reminiscent, of, immediate, early, gene, induction, and, many, individual, neurons, that, were, 'p-rpS6-positive', coexpressed, 'Arc', protein])].
[sujeto(['Our', results, constrain, hypotheses, about, the, possible, role, of, rpS6, phosphorylation, in]), verbo([regulating]), complemento([postsynaptic, protein, synthesis, during, induction, of, synaptic, plasticity])].
[sujeto(['Indeed,', treatment, of, 'CLL', 'B-cells', with, 'Tris-DBA']), verbo([induced]), complemento([apoptosis, in, a, 'dose-dependent', manner, irrespective, of, 'IgVH', mutational, status])].
[sujeto(['Further', analyses]), verbo([suggest]), complemento([that, 'Tris-DBA-induced', apoptosis, involves, reduced, expression, of, the, 'anti-apoptotic', proteins, 'Bcl-xL,', and, 'XIAP', with, an, upregulation, of, the, 'pro-apoptotic', protein, 'BIM', in, 'CLL', 'B-cells'])].
[sujeto(['Our', findings, also, indicate, that, 'Tris-DBA']), verbo([targets]), complemento([the, ribosomal, protein, '(', 'rp)-S6,', an, essential, component, of, the, 'Akt/mTOR', signaling, axis, in, 'CLL', 'B-cells'])].
[sujeto(['In', 'total,', 'Tris-DBA', is, effective, at]), verbo([inducing]), complemento([apoptosis, in, 'CLL', 'B-cells', even, in, the, presence, of, stromal, cells, likely, by, targeting, directly, the, signal, 'mediator,', rpS6])].
[sujeto(['Ribosomal', transcripts, produce, critical, proteins, that, are]), verbo([involved]), complemento([in, most, cellular, production, processes])].
[sujeto(['Targeting', ribosomal, transcripts]), verbo([has]), complemento([produced, mortality, in, mites, and, ticks, but, the, effect, of, ribosomal, transcript, knockdown, has, not, been, thoroughly, examined, in, mosquitoes])].
[sujeto(['We', examine, the, effects, of]), verbo([triggers]), complemento([targeting, four, ribosomal, proteins, '(', 'RP)', transcripts])].
[sujeto(['Triggers']), verbo([targeting]), complemento(['RPS6', and, 'RPL26', effectively, reduced, gene, expression, but, more, 'importantly,', reduced, reproductive, output, by, more, than, 96, '%', and, 91, '%', at, the, first, oviposition, while, triggers, targeting, 'RPL1', and, 'RPS2', did, not, cause, a, reduction, although, gene, expression, was, reduced])].
[sujeto(['The', strong, phenotype, produced, by, dsRPS6, allowed, us, to, examine, the, effects, in, various, tissues, as, well, as, the, dose, 'response,']), verbo([trigger]), complemento(['format,', delivery, method, and, trigger, specificity, in, 'Aedes', aegypti])].
[sujeto(['Similar', bioassays, with, mutated, dsRPS6]), verbo([triggers]), complemento([indicates, that, up, to, three, mismatches, per, possible, siRNA, are, still, effective, in, reducing, fecundity])].
[sujeto(['These', studies, indicate, that, while, active, and, effective]), verbo([triggers]), complemento([can, be, developed, for, vector, 'species,', the, lack, of, an, efficient, delivery, method, is, the, biggest, barrier, to, use, as, a, potential, control, method])].
[sujeto(['This', approach]), verbo([suggested]), complemento([that, metformin, treatment, makes, cancer, cells, more, sensitive, to, apoptotic, stimuli, and, less, sensitive, to, 'pro-growth', stimuli])].
[sujeto(['These', hypotheses, were, tested, 'in vivo;', as, a, 'proof-of-principle,', we, demonstrated, that, metformin]), verbo([inhibits]), complemento([the, 'p70S6K-rpS6', axis, in, a, 'PP2A-phosphatase', dependent, manner])].
[sujeto(['In', 'conclusion,', analysis, of, deep, proteomics]), verbo([reveals]), complemento([both, detailed, and, global, mechanisms, that, contribute, to, the, 'anti-cancer', activity, of, metformin])].
[sujeto(['What', is, the, central, question, of, this, 'study?', 'Does', shorter, rest, between, sets, of, resistance, exercise]), verbo([promote]), complemento([a, superior, circulating, hormonal, and, acute, muscle, anabolic, response, compared, with, longer, rest, 'periods?', 'What', is, the, main, finding, and, its, 'importance?', 'We', demonstrate, that, short, rest, '(', 1, &, 'nbsp;min)', between, sets, of, 'moderate-intensity,', 'high-volume', resistance, exercise, blunts, the, acute, muscle, anabolic, response, compared, with, a, longer, rest, period, '(', 5, &, 'nbsp;min),', despite, a, superior, circulating, hormonal, milieu])].
[sujeto(['These', data]), verbo([have]), complemento([important, implications, for, the, development, of, training, regimens, to, maximize, muscle, hypertrophy])].
[sujeto(['We']), verbo([found]), complemento([that, the, rate, of, myofibrillar, protein, synthesis, increased, above, resting, values, from, 0, to, 4, &, 'nbsp;h', postexercise, with, 1, '(', 76, '%', ;, 'P = 0'])].
[sujeto(['We', compared, the, effects, of, concurrent, 'exercise,', incorporating, either, 'high-intensity', interval, training, '(', 'HIT)', or, 'moderate-intensity', continuous, training, '(', 'MICT),', on, mechanistic]), verbo([target]), complemento([of, rapamycin, complex, 1, '(', 'mTORC1)', signaling, and, microRNA, expression, in, skeletal, 'muscle,', relative, to, resistance, exercise, '(', 'RE)', alone])].
[sujeto(['Prior', 'HIT', and, 'MICT', similarly, reduced, muscle, glycogen, content, and]), verbo([increased]), complemento(['ACC(Ser79)', and, 'p70S6K(Thr389)', phosphorylation, before, subsequent, 'RE', '(', i])].
[sujeto(['Compared', with, 'MICT,', 'HIT']), verbo([induced]), complemento([greater, 'mTOR(Ser2448)', and, 'rps6(Ser235/236)', phosphorylation, at, 'POST'])].
[sujeto(['RE-induced']), verbo([increases]), complemento([in, p70S6K, and, rps6, phosphorylation, were, not, influenced, by, prior, 'HIT', or, 'MICT;', 'however,', mTOR, phosphorylation, was, reduced, at, 'RE', +, 1, h, for, 'MICT', +, 'RE', vs])].
[sujeto(['The', mango, extract, '(', 10, mg, 'GAE/L)']), verbo([suppressed]), complemento([the, protein, expression, of, 'NF-κB,', 'p-NF-κB,', 'PI3K', '(', 'p85β),', 'HIF-1α,', 'p70S6K1,', and, 'RPS6', in, 'LPS-treated', 'CCD-18Co', cells])].
[sujeto(['LPS', reduced, 'miR-126', 'expression,', 'whereas,', the, mango, extract]), verbo([induced]), complemento(['miR-126', expression, in, a, 'dose-dependent', manner])].
[sujeto(['In', 'vivo,', mango, beverage, protected, against, 'DSS-induced', colonic, inflammation, '(', 47, '%', ',', 'P', =, 0.05, ')', and]), verbo([decreased]), complemento([the, 'Ki-67', labeling, index, in, the, central, and, basal, regions, compared, to, the, control])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, mango, polyphenols, attenuated, inflammatory, response, by, modulating, the, 'PI3K/AKT/mTOR', pathway, at, least, in, part, through, upregulation, of, 'miRNA-126', expression, both, in, vitro, and, in, 'vivo;', 'thus,', mango, polyphenolics, might, be, relevant, as, preventive, agents, in, ulcerative, colitis])].
[sujeto(['Lysophosphatidic', acid, '(', 'LPA)', is, a, phospholipid, with, a, variety, of, fatty, acyl, groups, that]), verbo([mediates]), complemento([diverse, biological, effects, on, various, types, of, cells, through, specific, 'G', 'protein-coupled', receptors])].
[sujeto(['Our', previous, study, in, pigs, demonstrated, that, 'LPA', and, the, 'LPA', receptor, system, are, present, at, the, 'maternal-conceptus', interface, and, that, 'LPA']), verbo([increases]), complemento([uterine, endometrial, expression, of, 'prostaglandin-endoperoxide', synthase, 2, '(', 'PTGS2)', through, 'LPA', receptor, 3, '(', 'LPAR3)'])].
[sujeto(['However,', the, role, of, 'LPA', in, conceptuses, during, early, pregnancy]), verbo([has]), complemento([not, been, determined])].
[sujeto(['All', examined, 'LPA', species, with, various, fatty, acid, lengths]), verbo([increased]), complemento([proliferation, and, migration, of, pTr, cells, as, the, dosage, increased])].
[sujeto(['Immunoblot', analyses]), verbo([found]), complemento([that, 'LPA', activated, intracellular, signaling, 'molecules,', extracellular, 'signal-regulated', kinase, 1, /, 2, '(', 'ERK1/2),', ribosomal, protein, 'S6', kinase, 90, kDa, '(', 'P90RSK),', ribosomal, protein, 'S6', '(', 'RPS6),', and, 'P38', in, pTr, cells])].
[sujeto(['Furthermore,', 'LPA']), verbo([increased]), complemento([expression, of, 'PTGS2', and, 'urokinase-type', plasminogen, activator, '(', 'PLAU),', and, the, 'LPA-induced', increases, in, 'PTGS2', and, 'PLAU', expression, were, inhibited, by, 'LPAR3', siRNA])].
[sujeto(['Collectively,', these, results, showed, that, 'LPA']), verbo([promotes]), complemento(['proliferation,', 'migration,', and, differentiation, of, pTr, cells, by, activating, the, 'ERK1/2-P90RSK-RPS6', and, 'P38', 'pathways,', indicating, that, the, 'LPA-LPAR3', system, may, be, involved, in, the, development, of, trophoblast, during, early, pregnancy, in, pigs])].
[sujeto(['Tannin-rich', fruits]), verbo([have]), complemento([been, evaluated, as, alternative, prevention, strategies, for, colorectal, cancer, based, on, their, 'anti-inflammatory', properties])].
[sujeto(['In', 'rats,', mango, and, pomegranate, beverages]), verbo([decreased]), complemento([intestinal, inflammation, and, the, levels, of, 'pro-inflammatory', cytokines, in, mucosa, and, serum])].
[sujeto(['The', mango, beverage]), verbo([suppressed]), complemento([the, ratio, of, 'phosphorylated/total', protein, expression, of, the, 'IGF-1R-AKT/mTOR', axis, and, 'down-regulated', mRNA, expression, of, 'Igf1,', 'Insr,', and, pik3cv])].
[sujeto(['Pomegranate']), verbo([decreased]), complemento([p70S6K, and, 'RPS6,', as, well, as, 'Rps6ka2,', 'Map2k2,', and, 'Mapk1', mRNA])].
[sujeto(['In', silico, modeling, indicated, a, high, 'binding-docked', of, gallic, acid, to, the, catalytic, domain, of, 'IGF-1R,', which, may]), verbo([suppress]), complemento([the, activity, of, the, enzyme])].
[sujeto(['Mango', polyphenols]), verbo([inhibited]), complemento([the, 'IGF-1R-', 'AKT/mTOR', 'axis,', and, pomegranate, polyphenols, downregulate, the, mTOR, downstream, pathway, through, reductions, in, 'ERK1/2'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, extracts, rich, in, 'gallo-', and, ellagitannins, act, on, different, molecular, targets, in, the, protection, against, ulcerative, colitis])].
[sujeto(['Malignant', pleural, mesothelioma, '(', 'MPM)', is, an, aggressive, cancer, that, is, commonly]), verbo([associated]), complemento([with, prior, asbestos, exposure])].
[sujeto(['Receptor', tyrosine, kinases, '(', 'RTKs)', such, as, 'MET', and, its, downstream]), verbo([target]), complemento(['PI3K', are, overexpressed, and, activated, in, a, majority, of, 'MPMs'])].
[sujeto(['Cell', viability, results, showed, that, 'MPM', cells, were, highly, sensitive, to, 'crizotinib,', 'BKM120', and, 'GDC-0980', when, used, individually, and, their, combination, was, more, effective, in]), verbo([suppressing]), complemento([growth])].
[sujeto(['Treatment', of, 'MPM', cells, with, these, inhibitors, also, significantly]), verbo([decreased]), complemento([cell, 'migration,', and, the, combination, of, them, was, synergistic])].
[sujeto(['Treatment', with, 'BKM120', alone, or, in, combination, with, crizotinib]), verbo([induced]), complemento(['G2-M', arrest, and, apoptosis])].
[sujeto(['Both', crizotinib, and, 'BKM120', strongly]), verbo([inhibited]), complemento([the, activity, of, 'MET', and, 'PI3K', as, evidenced, by, the, decreased, phosphorylation, of, 'MET,', 'AKT', and, ribosomal, 'S6', kinase])].
[sujeto(['Using', a, 'PDX', mouse, 'model,', we, showed, that, a, combination, of, crizotinib, with, 'BKM120', was, highly, synergetic, in]), verbo([inhibiting]), complemento(['MPM', tumor, growth])].
[sujeto(['In', conclusion, our, findings]), verbo([suggest]), complemento([that, dual, inhibition, of, 'PI3K', and, 'MET', pathway, is, an, effective, strategy, in, treating, 'MPM', as, compared, to, a, single, agent])].
[sujeto(['The', geoaccumulation, indices, '(', 'Igeo)', of, trace, metals]), verbo([decreased]), complemento([in, the, order, 'Cd>Zn>Ni>Cu>Co>Cr>Pb>As>V'])].
[sujeto(['HACA', based, on, the, 'Igeo', showed, that, 'Cd', was]), verbo([associated]), complemento([mainly, with, 'fertilizers,', and, the, origins, of, 'Cr,', 'Ni,', 'Cu', and, 'Zn', were, probably, industrial, 'effluents,', whereas, 'Co', and, 'Pb', were, related, to, traffic, activities])].
[sujeto(['HACA', of, sediment, cores]), verbo([suggested]), complemento([that, 'Dongguan', and, 'Shenzhen', cities, contribute, large, quantities, of, metals, to, the, riverine, 'sediment,', whereas, few, metals, were, discharged, from, 'Huizhou', 'City'])].
[sujeto(['Colonic', diverticular, disease, is, a, frequent]), verbo([finding]), complemento([in, daily, clinical, practice])].
[sujeto(['This', condition, is, likely, the, result, of, several, concomitant, factors, occurring, together, to]), verbo([cause]), complemento([anatomic, and, functional, 'abnormalities,', leading, as, a, result, to, the, outpouching, of, the, colonic, mucosa])].
[sujeto(['The', latter, might, be, responsible, for, the, development, of, visceral, 'hypersensitivity,', often]), verbo([causing]), complemento([abdominal, pain, in, a, subset, of, these, patients])].
[sujeto(['Our', results, showed, that, 'E/E-SBGS,', not, 'E/A-SBGS,']), verbo([inhibited]), complemento([the, survival, and, migration, of, lung, cancer, cells, in, a, 'dose-dependent', manner])].
[sujeto(['E/E-SBGS']), verbo([arrested]), complemento([cell, cycle, at, 'G2/M', phase, and, triggered, apoptosis, by, decreasing, the, expression, and, activity, of, cell, cycle, 'regulators,', cyclin, 'B1', and, 'cdc2,', as, well, as, 'anti-apoptotic', 'proteins,', 'Bcl-2', and, 'Bcl-xl'])].
[sujeto(['Oral', administration, of, both, 'E/E-SBGS', and, 'SBGS', significantly]), verbo([suppressed]), complemento([tumor, volume, and, tumor, weight, without, gross, toxicity, in, mice])].
[sujeto(['Mechanism', study, showed, that, 'E/E-SBGS', 'dose-dependently']), verbo([suppressed]), complemento([the, activation, of, 'Akt,', the, mammalian, target, of, rapamycin, '(', 'mTOR)', and, their, downstream, molecules, 'S6', kinase, and, '4E-BP1', in, treated, tumor, cells])].
[sujeto([lucidum]), verbo([suppresses]), complemento([the, growth, of, human, lung, 'cancer,', at, least, in, 'part,', through, inhibition, of, the, 'Akt/mTOR', signaling, 'pathway,', suggesting, its, potential, role, in, cancer, treatments])].
[sujeto(['A', safe, and, effective, direct]), verbo([acting]), complemento(['anti-hepatitis', 'C', virus, '(', 'HCV)', agent, is, still, needed])].
[sujeto(['In', this, 'study,', human, single, chain, variable, fragments, of, antibody, '(', 'scFvs)', that]), verbo([bound]), complemento([to, 'HCV', 'NS3/4A', protein, were, produced, by, phage, display, technology])].
[sujeto(['Computerized', homology, modeling, and, intermolecular, docking, predicted, that, the, effective, transbodies]), verbo([interacted]), complemento([with, several, critical, residues, of, the, 'NS3/4A', 'protease,', including, those, that, form, catalytic, 'triads,', oxyanion, 'loop,', and, 'S1', and, 'S6', 'pockets,', as, well, as, a, 'zinc-binding', site])].
[sujeto(['Although', insight, into, molecular, mechanisms, of, the, transbodies, need, further, laboratory, 'investigation,', it, can, be, deduced, from, the, current, data, that, the, transbodies, blocked, the, 'HCV', 'NS3/4A', protease, 'activities,']), verbo([leading]), complemento([to, the, 'HCV', replication, inhibition, and, restoration, of, the, virally, suppressed, host, innate, immunity])].
[sujeto(['It', contained, 'phosphatidylglycerol,', 'diphosphatidylglycerol,', phosphatidylethanolamine, and, phospholipid, as, major, polar, lipids, and, 'C10:0,', 'C12:0', 3, 'OH,', 'C16:0,', 'C18:1', 'ɷ9c,', 'C17:1', ɷ8c, and, 'C16:1', ɷ7c, were]), verbo([found]), complemento([as, predominant, fatty, acids])].
[sujeto(['Patients', recover, faster, from, restrictive, respiratory, 'disorders,']), verbo([have]), complemento([less, pain, and, return, to, the, workplace, earlier, after, an, operation, compared, with, those, that, receive, conservative, treatment])].
[sujeto(['Prostate', cancer, is, the, most, common, cancer, in, men, and, the, second, most, common]), verbo([cause]), complemento([of, 'cancer-related', deaths, in, men])].
[sujeto(['Although', various, drugs]), verbo([targeting]), complemento([the, androgen, receptor, are, normally, 'used,', the, patients, frequently, undergo, recurrence, of, the, disease])].
[sujeto(['To', overcome, these, 'limitations,', natural, compounds]), verbo([have]), complemento([been, researched, for, evidence, that, they, suppress, progression, and, metastasis, of, various, cancer, cells])].
[sujeto(['Results', of, present, study, with, 'PC3', and, 'LNCaP', cells, revealed, that, naringenin]), verbo([inhibited]), complemento([proliferation, and, 'migration,', while, inducing, apoptosis, and, 'ROS', production, by, those, cells])].
[sujeto(['In', 'addition,', 'naringenin-induced']), verbo([loss]), complemento([of, mitochondrial, membrane, potential, and, increased, 'Bax', and, decreased, 'Bcl-2', proteins, in, 'PC3', 'cells,', but, not, 'LNCaP', cells])].
[sujeto(['In', a, 'dose-dependent', 'manner,', naringenin]), verbo([decreased]), complemento([phosphorylation, of, 'ERK1/2,', 'P70S6K,', 'S6', and, 'P38', in, 'PC3', 'cells,', and, reduced, phosphorylation, of, 'ERK1/2,', 'P53,', 'P38', and, 'JNK', proteins, in, 'LNCaP', cells])].
[sujeto(['However,', naringenin]), verbo([activated]), complemento([phosphorylation, of, 'AKT', in, both, 'PC3', and, 'LNCaP', cells])].
[sujeto(['Then,']), verbo([targeted]), complemento([signaling, proteins, associated, with, viability, of, 'PC3', and, 'LNCaP', cells, were, analyzed, using, pharmacological, inhibitors, of, 'AKT', and, 'ERK1/2', cell, signaling, pathways])].
[sujeto(['Moreover,', we, compared, the, apoptotic, effects, of, naringenin, and, paclitaxel, alone, and, in, combination, to]), verbo([find]), complemento([that, naringenin, enhanced, the, efficiency, of, paclitaxel, to, suppress, progression, of, prostate, cancer, cell, lines])].
[sujeto(['Recently,', 'BRAF', 'V600E', 'mutation,', and, activation, of, mTOR, and, 'MAPK', pathways]), verbo([have]), complemento([been, identified, in, various, 'glial/glioneuronal', tumors])].
[sujeto(['Dysembryoplastic', neuroepithelial, tumors, '(', 'DNTs)', are, 'epilepsy-associated', glioneuronal, neoplasms, which]), verbo([have]), complemento([not, been, analyzed, extensively, in, this, respect])].
[sujeto(['BRAF', 'V600E', mutation, was, identified, in, 3.7, '%', of, 'DNTs,', while, 'BRAF', copy, number]), verbo([gain]), complemento([was, observed, in, 33.3, '%'])].
[sujeto(['BRAF', alterations, are, frequent, in, 'DNTs,', particularly, 'BRAF', copy, number]), verbo([gain]), complemento([which, is, being, reported, for, the, first, time, in, these, tumors])].
[sujeto(['Evidence', of, activation, of, mTOR, and, 'MAPK', pathways]), verbo([suggests]), complemento([a, role, for, altered, signalling, in, 'DNT', 'pathogenesis,', and, will, pave, the, way, for, development, of, targeted, 'therapies,', particularly, relevant, for, patients, having, persistent, seizures, after, incomplete, resection])].
[sujeto(['A', partnership, working, initiative, between, 'Greenwich', 'CCG', 'Medicines', management, '(', 'commissioner),', 'Oxleas', 'NHS', 'Foundation', 'Trust', '(', 'provider)', and, 'ConvaTec', '(', commercial, 'partner)', was, set, up, to]), verbo([provide]), complemento(['wound-care', dressings, and, products, to, patients, via, the, community, services])].
[sujeto(['It']), verbo([lead]), complemento([to, improved, 'access,', greater, patient, 'benefits,', a, reduction, in, dressings, 'waste,', and, an, increase, in, clinical, confidence, to, make, 'cost-effective,', 'evidence-based', prescribing, decisions])].
[sujeto(['Pentatricopeptide', repeat, '(', 'PPR)', 336, was, identified, as, the, candidate, gene, for, 'Paternal', 'Sorting', of, 'Mitochondria', '(', 'Psm', ')', ',', a]), verbo([nuclear]), complemento([locus, that, affects, the, predominant, mitochondria, transmitted, to, progenies])].
[sujeto(['The', mitochondrial, 'DNA', '(', 'mtDNA)', of, cucumber, is, relatively, large, due, in, part, to, accumulation, of, repetitive, 'DNAs', and, recombination, among, these, repetitive, regions, produces, structurally, polymorphic, mtDNAs]), verbo([associated]), complemento([with, paternally, transmitted, mosaic, '(', 'MSC)', phenotypes])].
[sujeto(['A']), verbo([nuclear]), complemento(['locus,', 'Paternal', 'Sorting', of, 'Mitochondria', '(', 'Psm),', affects, the, predominant, mitochondria, transmitted, to, progenies, generated, from, crosses, with, 'MSC16', as, the, male, parent])].
[sujeto(['PPR336', stabilizes, mitochondrial, ribosomes, in, 'Arabidopsis', thaliana, and, because, 'MSC16', shows, reduced, transcription, of, 'rps7,', the, cucumber, homolog, of, 'PPR336', '(', 'CsPPR336)', as, the, candidate, for, 'Psm', is, consistent, with, a]), verbo([nuclear]), complemento([effect, on, ribosome, assembly, or, stability, in, the, mitochondrion])].
[sujeto(['This', research, illustrates, the, usefulness, of, the, 'MSC', mutants, of, cucumber, to]), verbo([reveal]), complemento([and, study, unique, interactions, between, the, mitochondrion, and, nucleus])].
[sujeto(['The', nucleotide, sequences, of, two, mitochondrial, genes, '(', cytochrome, c, oxidase, subunit, 'I,', 'COI,', and, cytochrome, 'b,', cyt, 'b)', and, four]), verbo([nuclear]), complemento([genes, '(', growth, hormone, gene, 'GH1,', ribosomal, protein, 'S7', gene, 'RP1,', recombination, activating, gene, 'RAG1,', and, rhodopsin, gene, 'RH)', from, the, 'Far', 'Eastern', redfins, of, the, genus, 'Tribolodon', were, examined, to, clarify, the, status, of, the, southern, form, of, 'T'])].
[sujeto(['Analysis', of, the]), verbo([nuclear]), complemento([genes, showed, that, 'Tribolodon', sp])].
[sujeto(['hakonensis)']), verbo([has]), complemento([a, mosaic, of, nuclear, genes, received, from, the, 'Pacific', redfin, 'T'])].
[sujeto(['It', is]), verbo([suggested]), complemento([that, the, new, species, could, have, formed, as, a, result, of, homoploid, hybridization, between, the, true, 'T'])].
[sujeto(['Functional', defects, of, the, mitochondrial, translation, 'machinery,', as, a, result, of, mutations, in, 'nuclear-encoded', 'genes,']), verbo([have]), complemento([been, associated, with, combined, oxidative, phosphorylation, '(', 'OXPHOS)', deficiencies])].
[sujeto(['We']), verbo([report]), complemento([siblings, with, congenital, sensorineural, deafness, and, lactic, acidemia, in, association, with, combined, respiratory, chain, '(', 'RC)', deficiencies, of, complexes, 'I,', 'III', and, 'IV', observed, in, fibroblasts, and, liver])].
[sujeto([550, 'A>G', transition, that, encodes, a, substitution, of, valine, for, a, highly]), verbo([conserved]), complemento([methionine, '(', p])].
[sujeto(['MRPS7', is, a, 12, 'S', ribosomal, 'RNA-binding', subunit, of, the, small, mitochondrial, ribosomal, 'subunit,', and, is]), verbo([required]), complemento([for, the, assembly, of, the, small, ribosomal, subunit])].
[sujeto(['Our', data, demonstrate, the, pathogenicity, of, the, identified, 'MRPS7', mutation, as, a, novel]), verbo([cause]), complemento([of, mitochondrial, 'RC', 'dysfunction,', congenital, sensorineural, deafness, and, progressive, hepatic, and, renal, failure])].
[sujeto(['Overexploitation', of, wild, populations, due, to, the, high, economic, value, of, caviar]), verbo([has]), complemento([driven, sturgeons, to, near, extinction])].
[sujeto(['The', high, prices, commanded, by, caviar, on, world, markets]), verbo([have]), complemento([made, it, a, magnet, for, illegal, and, fraudulent, caviar, 'trade,', often, involving, 'low-value', farmed, caviar, being, sold, as, 'top-quality', caviar])].
[sujeto(['Test', validations, performed, in, 702, specimens, of]), verbo([target]), complemento([and, nontarget, sturgeon, species, demonstrated, a, 100, '%', identification, success, for, 'Acipenser', 'naccarii,', 'A'])].
[sujeto(['Moreover,', the, approach]), verbo([has]), complemento([the, potential, to, identify, many, other, existing, sturgeon, hybrids])].
[sujeto(['The', development, of, a, standardized, sturgeon, identification, tool, will, directly, benefit, trade, law, 'enforcement,']), verbo([providing]), complemento([the, tools, to, monitor, and, regulate, the, legal, trade, of, caviar, and, protect, sturgeon, stocks, from, illicit, producers, and, 'traders,', hence, contributing, to, safeguarding, this, group, of, heavily, threatened, species])].
[sujeto(['Moreover,', combined, analysis, of, mitochondrial, and]), verbo([nuclear]), complemento([gene, sequence, data, '(', c])].
[sujeto(['affinis,', with, levels, of, genetic, divergence]), verbo([suggesting]), complemento([the, two, species, diverged, from, one, another, over, a, million, years, ago])].
[sujeto([quadruncus, may, reflect, a, vicariant, event]), verbo([associated]), complemento([with, 'Pliocene', orogenesis, in, the, 'Tamaulipas', 'Arch', and, a, frontal, section, of, the, 'Sierra', 'Madre', 'Oriental', '(', 'Lleran', 'Mesas)'])].
[sujeto(['The', longest, detectable, precursor, 'RNA', maps, precisely, to, the, 3, '\'', end, of, a, 'chloroplast-origin', 'tRNA-Phe', 'gene,', consistent, with, it]), verbo([providing]), complemento([signals, for, endonucleolytic, cleavage])].
[sujeto(['Several', ecotypes, exist, and, this]), verbo([provides]), complemento([a, useful, model, for, the, study, of, comparative, diversity, between, molecular, markers])].
[sujeto(['Here', we, analyze, and, compare, the, nucleotide, sequences, between, 'single-copy', ribosomal, protein, 'S7', gene, intron, 1, '(', 'rpS7)', and, 'multiple-copy', ribosomal, internal]), verbo([transcribed]), complemento([spacer, 1, '(', 'ITS1)', in, this, species, to, compare, the, phylogenetic, signal, of, the, two, nuclear, genes])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, rpS7, is, more, suitable, than, 'ITS1', as, a, marker, for, genetic, divergence, of, this, group])].
[sujeto([nasus, from, the, phylogeny, of, this, species, based, on, 'rpS7,', showing, that, rpS7]), verbo([has]), complemento([more, evolutionary, characteristics, for, understanding, the, processes, of, genomic, evolution, at, the, intraspecific, level])].
[sujeto(['Our', phylogenetic, data, set, comprises, a, single, mitochondrial, 'DNA', '(', 'mtDNA)', gene, and, two]), verbo([nuclear]), complemento([genes, sampled, from, 245, of, the, 248, darter, species])].
[sujeto(['This', dense, sampling, allows, us, to, determine, if, a, modest, amount, of]), verbo([nuclear]), complemento(['DNA', sequence, data, can, resolve, relationships, among, closely, related, animal, species])].
[sujeto(['Darters', lack, a, fossil, record, to]), verbo([provide]), complemento([age, calibration, priors, in, 'relaxed-clock', analyses])].
[sujeto(['Therefore,', we, use, a, 'near-complete', 'species-sampled', phylogeny, of, the, perciform, clade, 'Centrarchidae,', which]), verbo([has]), complemento([a, rich, fossil, 'record,', to, assess, two, distinct, strategies, of, external, calibration, in, 'relaxed-clock', divergence, time, estimates, of, 'darters:', using, ages, inferred, from, the, fossil, record, and, molecular, evolutionary, rate, estimates])].
[sujeto(['Comparison', of, 'Bayesian', phylogenies, inferred, from, mtDNA, and]), verbo([nuclear]), complemento([genes, reveals, that, heterospecific, mtDNA, is, present, in, approximately, 12.5, '%', of, all, darter, species])].
[sujeto(['We', identify, three, patterns, of, mtDNA, introgression, in, 'darters:', proximal, mtDNA, 'transfer,', which]), verbo([involves]), complemento([the, transfer, of, mtDNA, among, extant, and, sympatric, darter, 'species,', indeterminate, 'introgression,', which, involves, the, transfer, of, mtDNA, from, a, lineage, that, cannot, be, confidently, identified, because, the, introgressed, haplotypes, are, not, clearly, referable, to, mtDNA, haplotypes, in, any, recognized, 'species,', and, deep, 'introgression,', which, is, characterized, by, species, diversification, within, a, recipient, clade, subsequent, to, the, transfer, of, heterospecific, mtDNA])].
[sujeto(['The', results, of, our, analyses, indicate, that, 'DNA', sequences, sampled, from, 'single-copy']), verbo([nuclear]), complemento([genes, can, provide, appreciable, phylogenetic, resolution, for, closely, related, animal, species])].
[sujeto(['A', 'well-resolved', 'near-complete', 'species-sampled', phylogeny, of, darters, was, estimated, with, 'Bayesian', methods, using, a, concatenated, mtDNA, and]), verbo([nuclear]), complemento([gene, data, set, with, all, identified, heterospecific, mtDNA, haplotypes, treated, as, missing, data])].
[sujeto(['In', 'addition,', an, informative, 'rank-free', 'clade-based', classification, of, darters, that, preserves, the, rich, history, of, nomenclature, in, the, group, and]), verbo([provides]), complemento([formal, taxonomic, communication, of, darter, clades, was, constructed, using, the, mtDNA, and, nuclear, gene, phylogeny])].
[sujeto(['On', the, 'whole,', the, appeal, of, mtDNA, for, phylogeny, inference, among, closely, related, animal, species, is, diminished, by, the, observations, of, extensive, mtDNA, introgression, and, by]), verbo([finding]), complemento([appreciable, phylogenetic, signal, in, a, modest, sampling, of, nuclear, genes, in, our, phylogenetic, analyses, of, darters])].
[sujeto([bureschi, from, 17, 'sites,', covering, the, entire, distribution, of, the, 'species,', including, the, 'Rivers', 'Vardar', '(', =, 'Axios),', 'Struma', '(', =, 'Strymon),', 'Mesta', '(', =, 'Nestos)', and, 'Danube,', were, performed, using, one, mitochondrial, and, one]), verbo([nuclear]), complemento([marker])].
[sujeto(['In', 'contrast,', the, results]), verbo([suggest]), complemento([that, populations, in, the, 'Vardar', 'River,', as, well, as, those, in, the, 'Danube', 'River,', are, of, recent, 'origin,', and, a, 'human-mediated', introduction, cannot, be, excluded])].
[sujeto(['Demographic', analyses]), verbo([suggest]), complemento([a, recent, population, expansion, for, 'O'])].
[sujeto(['The', mitochondrial, genomes, of, flowering, plants, are, highly, recombinogenic, and, this, can]), verbo([lead]), complemento([to, altered, transcriptional, 'units,', even, between, closely, related, species])].
[sujeto(['We', are, interested, in, the, effects, that, 'DNA', rearrangements]), verbo([have]), complemento([on, the, generation, of, mature, 'mRNAs,', and, to, this, end, we, have, determined, the, termini, of, mitochondrial, 'S7', ribosomal, protein, '(', 'rps7)', mRNAs, from, selected, 'grasses,', using, 'circularized-RT-PCR'])].
[sujeto(['Although', the, rps7, mRNAs, show, a, similar, size, of, about, 750, nt, by, northern, hybridization, analysis, and]), verbo([have]), complemento([virtually, identical, 3, '\'', 'UTRs,', their, 5, '\'', terminal, extremities, differ, among, plant, 'species,', and, this, is, attributable, to, genome, rearrangements, in, some, but, not, all, cases])].
[sujeto(['In', 'contrast,', the, 'rye,', brome, and, 'Lolium', 5, '\'', ends, are, quite, heterogeneous, in, length, even, though, they, are, located, within]), verbo([conserved]), complemento([genomic, regions])].
[sujeto(['Comparative', sequence, analysis]), verbo([suggests]), complemento([that, certain, grass, lineages, have, retained, an, ancestral, organization, upstream, of, rps7, that, includes, a, 170, -, bp, block, homologous, to, sequences, preceding, several, other, mitochondrial, 'genes,', whereas, others, have, undergone, independent, rearrangements, at, a, 'recombination-prone', site])].
[sujeto(['Our', analysis, of, mature, rps7, transcripts, revealed, two, 'non-silent', 'RNA', edits, within, the, coding, 'sequences,', and, also, editing, at, several, sites, within, the]), verbo([conserved]), complemento([5, '\'', and, 3, '\'', 'UTR', regions, in, these, 'plants,', raising, the, possibility, of, their, role, in, rps7, expression, at, the, 'post-transcriptional', level])].
[sujeto(['Despite', the, small, number, of, 'species,', this, genus]), verbo([has]), complemento([had, an, unsettled, taxonomic, history, due, to, high, levels, of, intraspecific, morphological, variation])].
[sujeto(['Moreover,', several, phylogenetic, hypotheses, among, congeners]), verbo([have]), complemento([been, proposed, but, have, had, the, following, 'shortcomings:', the, use, of, homoplasious, morphological, 'characters,', the, use, of, character, codification, and, polarisation, methods, that, lacked, 'objectivity,', and, incomplete, taxonomic, sampling])].
[sujeto(['Congruence']), verbo([found]), complemento([between, the, available, geological, and, climatic, history, and, the, divergence, times, made, it, possible, to, infer, the, biogeographical, history, of, 'Algansea,', which, suggested, that, vicariance, events, were, responsible, for, the, evolutionary, history, of, the, genus])].
[sujeto(['Mitochondrial', 'DNA', analyses, recovered, significant, genetic, differentiation, between, fish, populations, from, the, east, coast, and, other, sampling, 'locations,', with, a, second, break]), verbo([found]), complemento([between, 'Gansbaai', and, 'Cape', 'Agulhas', on, the, south, coast])].
[sujeto(['Coalescent', analyses]), verbo([suggested]), complemento([remarkably, asymmetrical, gene, flow, between, sampling, 'locations,', suggesting, that, the, cold, 'Atlantic', 'Benguela', 'Current', and, 'Indian', 'Ocean', 'Agulhas', 'counter-current', play, important, roles, in, facilitating, dispersal])].
[sujeto(['There', was, no, gene, flow, between, the, east, coast, and, the, other, 'sites,']), verbo([suggesting]), complemento([that, these, populations, are, effectively, isolated])].
[sujeto(['Neutrality', tests, and, mismatch, distributions]), verbo([suggest]), complemento([recent, population, 'expansions,', with, the, exception, of, peripheral, western, and, eastern, populations, '(', possibly, a, consequence, of, environmental, extremes, at, the, edge, of, the, species, 'distribution)'])].
[sujeto(['Analyses', of, the, current, 'South', 'African', marine, protected, areas, network, show, that, it, is, not, connected, and, that, 'De', 'Hoop,', one, of, 'South', 'Africa\'s', largest, marine, 'reserves,', appears, to, be, an, important, source, population, of]), verbo([recruits]), complemento([to, both, the, south, and, southwest, coasts])].
[sujeto(['In', this, 'study,', the, phylogenetic, relationships, for, all, described, species, were, examined, based, on, one, mitochondrial, gene, '(', cytochrome, 'b)', and, one]), verbo([nuclear]), complemento([marker, '(', the, first, intron, of, the, ribosomal, protein, 'S7)'])].
[sujeto(['Two', 'sweetlips,', genus, 'Plectorhinchus,', which, belong, to, the]), verbo([recognized]), complemento([sister, subfamily, 'Plectorhynchinae,', were, used, as, outgroups])].
[sujeto(['Two', species, pairs, in, the, ingroup, genus, 'Anisotremus', are, geminate, 'species,', which, presumably, diverged, after, the, rise, of, the, 'Isthmus', of, 'Panama,', thus]), verbo([providing]), complemento([an, internal, molecular, clock, calibration])].
[sujeto(['As', proposed, for, other, coral, reef, 'species,', 'Anisotremus', seems, to]), verbo([have]), complemento([colonized, coral, reefs, from, 'non-coral', reef, habitats])].
[sujeto(['In', 'addition,', ancestral, species, seem, to]), verbo([have]), complemento([been, 'widespread,', since, species, that, are, currently, found, in, 'Brazilian', and, 'Pacific', waters, are, basal, on, the, phylogenetic, tree])].
[sujeto(['The', 'Black', and, 'Caspian', 'Seas']), verbo([have]), complemento([experienced, alternating, periods, of, isolation, and, interconnection, over, many, 'Milankovitch', climate, oscillations, and, most, recently, became, separated, when, the, meltwater, overflow, from, the, 'Caspian', 'Sea', ceased, at, the, end, of, the, last, glaciation])].
[sujeto(['Climate-induced', habitat, changes]), verbo([have]), complemento([indisputably, had, profound, impacts, on, distribution, and, demography, of, aquatic, 'species,', yet, uncertainties, remain, about, the, relative, roles, of, isolation, and, dispersal, in, the, response, of, species, shared, between, the, 'Black', and, 'Caspian', 'Sea', basins])].
[sujeto(['Bayesian', coalescence, analyses, of, sequence, variation, at, two]), verbo([nuclear]), complemento([and, one, mitochondrial, genes, suggest, that, the, 'Black', and, 'Caspian', 'Seas', supported, separate, populations, of, 'R'])].
[sujeto(['These', analyses, also]), verbo([suggested]), complemento([that, majority, of, migrations, occurred, during, the, 'Pleistocene,', showing, that, the, variation, shared, between, the, 'Black', and, 'Caspian', 'Seas', is, the, result, of, ancient, dispersal, along, the, temporary, natural, connections, between, the, 'basins,', rather, than, of, incomplete, lineage, sorting, or, recent, 'human-mediated', dispersal])].
[sujeto(['Gene', flow, between, the, refugial, populations, was, therefore, an, important, source, of, genetic, 'variation,', and, we]), verbo([suggest]), complemento([that, it, facilitated, the, evolutionary, response, of, the, populations, to, changing, climate])].
[sujeto(['The', phylogenetic, relationships, of, major, clades, within, this, family, are, simply, poorly, 'understood,', largely, because, of, the, overwhelming, diversity, of, the, 'group;', 'however,', several, investigators]), verbo([have]), complemento([advanced, different, hypotheses, of, relationships, that, 'pre-', and, 'post-date', the, use, of, 'shared-derived', characters, as, advocated, through, phylogenetic, systematics])].
[sujeto(['Recently,', mitochondrial, 'DNA', '(', 'mtDNA)', sequences, and, combined, morphological, and, mtDNA, investigations]), verbo([have]), complemento([been, used, to, explore, and, advance, our, understanding, of, species, relationships, and, test, monophyletic, groupings])].
[sujeto(['The', present, study, is, the, first, endeavor, to, recover, the, phylogenetic, relationships, of, the, 12, previously]), verbo([recognized]), complemento([monophyletic, subfamilies, within, the, 'Cyprinidae', using, newly, sequenced, nuclear, 'DNA', '(', 'nDNA)', for, over, 50, species, representing, members, of, the, different, previously, hypothesized, subfamily, and, family, groupings, within, the, 'Cyprinidae', and, from, other, cypriniform, families, as, outgroup, taxa])].
[sujeto(['To', 'date,', little, is, known, about, the, significance, of, the, specific, 'protein(s)']), verbo([express]), complemento([in, the, dermal, papilla, cells, '(', 'DPC)', with, regard, to, their, aggregative, behaviour])].
[sujeto(['To', identify, proteins]), verbo([involved]), complemento([in, aggregative, behaviour, of, 'DPC,', we, comparatively, analyzed, the, proteome, of, cells, with, and, without, aggregative, behaviour])].
[sujeto(['A', series, of, methods, were, 'used,', including, 'two-dimensional', gel, electrophoresis, '(', 2, -, 'DE),', 'PDQuest', software, analysis, of, 2, -, 'DE', 'gels,', peptide, mass, fingerprinting, based, on, 'matrix-assisted', laser, 'desorption/ionisation-time', of, 'flight-mass', spectrometry, '(', 'MALDI-TOF-MS),', and, 'NCBInr', database, 'searching,', to, separate, and, identify, differentially]), verbo([expressed]), complemento([proteins])].
[sujeto(['Western', blotting, and, reverse, transcriptase, polymerase, chain, reaction, '(', 'RT-PCR)', were, used, to, validate, the, differentially]), verbo([expressed]), complemento([proteins])].
[sujeto(['Over-expression', of, mitochondrial, ribosomal, protein, 'S7', was, confirmed, by, 'RT-PCR,', indicating, that, they, are]), verbo([involved]), complemento([in, aggregation, of, 'DPC', through, some, signaling, pathway])].
[sujeto(['The', clues]), verbo([provided]), complemento([by, the, comparative, proteome, strategy, utilized, here, will, shed, light, on, molecular, mechanisms, of, 'DPC', in, aggregative, behaviour])].
[sujeto(['The', importance, of, vicariance, events, on, the, establishment, of, phylogeographic, patterns, in, the, marine, environment, is, well, 'documented,', and, generally, accepted, as, an, important]), verbo([cause]), complemento([of, cladogenesis])].
[sujeto(['long-distance', dispersal, followed, by, founder, effect, 'speciation)', is, also, frequently, invoked, as, a]), verbo([cause]), complemento([of, genetic, divergence, among, 'lineages,', but, its, role, has, long, been, challenged, by, vicariance, biogeographers])].
[sujeto(['In', the, present, 'study,', the, relative, importance, of, vicariance, and, founder, dispersal, as]), verbo([causes]), complemento([of, cladogenesis, in, a, circumglobally, distributed, seahorse, lineage, was, investigated, using, molecular, dating])].
[sujeto(['A', phylogeny, was, reconstructed, using, sequence, data, from, mitochondrial, and]), verbo([nuclear]), complemento(['markers,', and, the, 'well-documented', closure, of, the, 'Central', 'American', seaway, was, used, as, a, primary, calibration, point, to, test, whether, other, bifurcations, in, the, phylogeny, could, also, have, been, the, result, of, vicariance, events])].
[sujeto(['The', feasibility, of, three, other, vicariance, events, was, 'explored:', 'a)', the, closure, of, the, 'Indonesian', 'Seaway,', resulting, in, sister, lineages]), verbo([associated]), complemento([with, the, 'Indian', 'Ocean', and, 'West', 'Pacific,', 'respectively;', 'b)', the, closure, of, the, 'Tethyan', 'Seaway,', resulting, in, sister, lineages, associated, with, the, 'Indo-Pacific', and, 'Atlantic', 'Ocean,', 'respectively,', and, 'c)', continental, 'break-up', during, the, 'Mesozoic', followed, by, spreading, of, the, 'Atlantic', 'Ocean,', resulting, in, pairs, of, lineages, with, 'amphi-Atlantic', distribution, patterns])].
[sujeto(['Comparisons', of, pairwise, genetic, distances, among, the, seahorse, species, hypothesized, to]), verbo([have]), complemento([diverged, as, a, result, of, the, closure, of, the, 'Central', 'American', 'Seaway', with, those, of, published, teleost, sequences, having, the, same, distribution, patterns, show, that, the, seahorses, were, among, the, last, to, diverge])].
[sujeto(['This']), verbo([suggests]), complemento([that, their, cladogenesis, was, associated, with, the, final, closure, of, this, seaway])].
[sujeto(['Although', two, other, divergence, events, in, the, phylogeny, could, potentially]), verbo([have]), complemento([arisen, as, a, result, of, the, closures, of, the, 'Indonesian', and, 'Tethyan', 'seaways,', 'respectively,', the, timing, of, the, majority, of, bifurcations, in, the, phylogeny, differed, significantly, from, the, dates, of, vicariance, events, suggested, in, the, literature])].
[sujeto(['We', conclude, that, the, evolution, of, the, circumglobally, distributed, seahorse, lineage, was, strongly, influenced, by, founder, 'dispersal,', and]), verbo([suggest]), complemento([that, this, mode, of, speciation, may, be, particularly, important, in, marine, organisms, that, lack, a, pelagic, dispersal, phase, and, instead, disperse, by, means, of, rafting])].
[sujeto(['The', comparison, of, different, samples]), verbo([requires]), complemento([the, transformation, of, data, through, a, process, called, normalisation])].
[sujeto(['At', 'present,', no, reference, gene]), verbo([has]), complemento([been, identified, for, any, organism, which, is, universally, optimal, for, use, across, different, tissue, types, or, disease, situations])].
[sujeto(['One', gene, '(', mitochondrial, ribosomal, protein, 'S7', '[', 'MRPS7])', was, stably]), verbo([expressed]), complemento([in, all, five, of, the, articular, tissues, evaluated])].
[sujeto(['One', gene, 'HIRA']), verbo([interacting]), complemento([protein, 5, isoform, 2, '[', 'HIRP5])', was, stably, expressed, in, four, of, the, tissues, evaluated])].
[sujeto(['A', commonly, used, reference, gene, 'glyceraldehyde-3-phosphate', dehydrogenase, '(', 'GAPDH)', was, not, stably]), verbo([expressed]), complemento([in, any, of, the, tissues, evaluated])].
[sujeto(['Most', consistent, agreement, between, rank, ordering, of, reference, genes, was, observed, between, 'Bestkeeper(c)', and, 'geNorm,', although, each, method, tended, to, agree, on, the, identity, of, the, most, stably]), verbo([expressed]), complemento([genes, and, the, least, stably, expressed, genes, for, each, tissue])].
[sujeto(['Different', methods, of, reference, gene, stability, assessment, will, generally, agree, on, the, most, and, least, stably]), verbo([expressed]), complemento(['genes,', when, 'co-regulation', is, not, present])].
[sujeto(['While', studies]), verbo([have]), complemento([been, performed, with, complete, sampling, of, a, single, 'subgenus,', none, have, included, representatives, of, all, remaining, subgenera])].
[sujeto(['The', subgenus, 'Oligocephalus', is, the, 'largest,', consisting, of, 25, -, 27, species, in, four, species, 'groups,', and, its, monophyly]), verbo([has]), complemento([never, been, clearly, demonstrated])].
[sujeto(['Using', sequences, of, the, mitochondrial, 'NADH', dehydrogenase, subunit, 2, gene, '(', 'ND2,', 1047, 'bp)', and, a, segment, of, the, 'non-coding', mitochondrial, control, 'region,', as, well, as]), verbo([nuclear]), complemento([sequences, including, two, introns, from, the, 'S7', ribosomal, protein, and, the, loci, 'TmoM25,', 'TmoM27,', and, 'UME002,', we, explore, the, phylogenetic, relationships, of, 'Lepidiolamprologus,', one, of, seven, lamprologine, cichlid, genera, in, 'Lake', 'Tanganyika,', 'East', 'Africa'])].
[sujeto(['Lepidiolamprologus', 'nkambae,', in, marked, conflict, with, morphological, and]), verbo([nuclear]), complemento(['DNA', 'evidence,', nested, outside, of, the, 'two-pore', 'Lepidiolamprologus', 'clade,', suggesting, that, the, mtDNA, signal, has, been, convoluted, by, introgressive, hybridization])].
[sujeto(['First,', 're-analysis', of, 'genome-wide', transcriptional, profiling, data, revealed, that, &, 'gt;', 95, gene, transcripts]), verbo([associated]), complemento([with, mitochondrial, biogenesis, 'and/or', mitochondrial, translation, were, significantly, elevated, in, human, breast, cancer, 'cells,', as, compared, with, adjacent, stromal, tissue])].
[sujeto(['Remarkably,', nearly, 40, of, these, upregulated, gene, transcripts, were, mitochondrial, ribosomal, proteins, '(', 'MRPs),', functionally]), verbo([associated]), complemento([with, mitochondrial, translation, of, protein, components, of, the, 'OXPHOS', complex])].
[sujeto(['Finally,', markers, of, mitochondrial, lipid, synthesis, '(', 'GOLPH3)', and, mitochondrial, translation, '(', 'POLRMT)', were]), verbo([associated]), complemento([with, poor, clinical, outcome, in, human, breast, cancer, patients])].
[sujeto(['New', anticancer, therapies, should, be, developed, to]), verbo([target]), complemento([mitochondrial, biogenesis, 'and/or', mitochondrial, translation, in, human, cancer, cells])].
[sujeto(['Directional', tag, 'PCR', subtractive, hybridization, was, applied, to, construct, a, cDNA, library, generated, from, three, different, human, osteosarcoma, '(', 'OS)']), verbo([target]), complemento([cell, lines, '(', 'OHS,', 'SaOS-2', and, 'KPDXM)', from, which, normal, osteoblast, '(', 'NO)', sequences, were, subtracted])].
[sujeto(['After', two, consecutive, subtractive, steps, more, than, 98, '%', of, the, common, mRNAs, species, were, 'depleted,']), verbo([leading]), complemento([to, effective, enrichment, of, the, remaining, target, sequences])].
[sujeto(['Seven', cDNAs, highly]), verbo([expressed]), complemento([in, 'Northern', blot, analysis, were, tested])].
[sujeto(['In', the, xenograft, made, from, one, of, the]), verbo([target]), complemento([cell, lines, '(', 'OHS),', a, fair, to, strong, representation, of, 3, cloned, mRNAs, was, observed, while, collagen, 'I', mRNA, was, not, detectable])].
[sujeto(['These', results, ought, to]), verbo([have]), complemento([implications, for, future, work, to, describe, phenotypic, subtypes, with, the, aim, of, improving, the, diagnosis, of, human, osteosarcomas])].
[sujeto(['Electrospray', tandem, mass, spectrometry, was, used, to]), verbo([provide]), complemento([sequence, information, on, some, of, the, peptide, products])].
[sujeto(['Efflux', transport, of, rebamipide, was]), verbo([inhibited]), complemento([by, cyclosporine, 'A,', a, 'P-gp', 'inhibitor,', and, 'probenecid,', which, is, a, general, 'MRP', 'inhibitor,', but, not, by, 'Ko143,', a, 'BCRP', inhibitor])].
[sujeto(['By', the, addition, of, 'IL-6,', mannitol, transport, was, slightly]), verbo([increased]), complemento([in, a, 'concentration-dependent', manner, in, both, directions, of, absorption, and, efflux])].
[sujeto(['The', addition, of, 'IL-6', did, not, change, efflux, transport, of, rebamipide, even, though, efflux, transport, of, 'digoxin,', a, typical, substrate, of, 'P-gp,', was, significantly]), verbo([decreased]), complemento([by, the, addition, of, 'IL-6,', indicating, decrease, of, the, function, of, 'P-gp'])].
[sujeto(['Therefore,', it, was]), verbo([suggested]), complemento([that, increase, of, 'MRP(s)-mediated', transport, compensates, for, the, decrease, of, 'P-gp', mediated, transport, of, rebamipide])].
[sujeto(['These', findings]), verbo([suggested]), complemento([that, rebamipide, absorption, is, unlikely, to, be, changed, in, 'IBD', patients])].
[sujeto(['The', global, need, to, develop, 'clinician-scientists', capable, of, using, research, in, clinical, 'practice,']), verbo([translating]), complemento([research, knowledge, into, 'practice,', and, carrying, out, research, that, affects, the, 'quality,', 'efficacy,', and, efficiency, of, health, care, is, well, documented])].
[sujeto(['Half', of, the]), verbo([participating]), complemento([doctor, of, chiropractic, '(', 'DC)', students, continued, on, to, 'PhD', 'programs,', and, half, established, integrative, 'medicine,', primary, care, clinical, careers])].
[sujeto(['Establishing', rigorous, criteria, for, mentors, and, 'mentees,', communicating, 'expectations,', developing, solid, relationships, between, the, 'mentor,', 'mentee,', and, home, school, 'advisor,']), verbo([responding]), complemento([quickly, to, 'impediments,', and, providing, adequate, support, from, 'CAM', and, 'TRI', investigators, were, key, to, the, 'MRP\'s', success])].
[sujeto(['Efflux', transporters, of, the, 'ATP-binding', cassette, superfamily, including, breast, cancer, resistance, protein, '(', 'Bcrp/Abcg2),', 'P-glycoprotein', '(', 'P-gp/Abcb1)', and, multidrug, 'resistance-associated', proteins, '(', 'Mrp\'s/Abcc\'s)', are]), verbo([expressed]), complemento([in, the, 'blood-brain', barrier, '(', 'BBB)'])].
[sujeto(['The', findings, indicate, that, 'P-gp,', 'Bcrp', and, at, least, one, isoform, of, 'Mrp', are, functionally]), verbo([expressed]), complemento([in, our, 'bovine/rat', 'co-culture', model, and, that, the, model, is, suitable, for, investigations, of, small, molecule, transport])].
[sujeto(['Endocrine-disrupting', chemicals, '(', 'EDCs)', are, considered, to]), verbo([cause]), complemento([testicular, toxicity, primarily, via, interference, with, steroid, hormone, function])].
[sujeto(['Alternatively,', 'EDCs', could, possibly, exert, their, effects, by, interaction, with, 'ATP-binding', cassette, '(', 'ABC)', transporters, that, are]), verbo([expressed]), complemento([in, the, 'blood-testis', barrier])].
[sujeto(['BPA', solely]), verbo([inhibited]), complemento(['BCRP', 'activity,', whereas, 'TBBPA,', 'PFOA,', and, 'PFOS', inhibited, all, transporters, tested])].
[sujeto(['Only', 'BPA', and, 'TBBPA', concentration, dependently]), verbo([increased]), complemento([testosterone, secretion, by, 'MA-10', cells, to, 6, -, and, 46, -, fold, of, control, 'levels,', respectively])].
[sujeto(['Therefore,', we, hypothesize, that, 'transporter-mediated', efflux, of, testosterone, precursors, out, of, 'MA-10', cells, is]), verbo([inhibited]), complemento([by, 'TBBPA', resulting, in, higher, availability, for, testosterone, production])].
[sujeto(['They']), verbo([provide]), complemento([resistance, of, aquatic, organisms, by, binding, xenobiotics, and, extruding, them, from, cells, in, an, 'energy-dependent', manner])].
[sujeto(['Since', 'Cyprinid', fish, species, are, common]), verbo([target]), complemento([in, freshwater, biomonitoring, 'programs,', we, have, studied, the, presence, of, two, main, 'MDR/MXR', efflux, transporters, 'P-glycoprotein', '(', 'Pgp,', 'Abcb1)', and, 'MRP-like', 'protein(s)', '(', 'Abcc)', in, the, liver, of, five, 'Cyprinid', 'species:', common, 'carp,', 'European', 'chub,', 'sneep,', 'barbel,', and, silver, prussian, carp])].
[sujeto(['Transcripts', of, both, key, types, of, 'MXR', transporters, were, identified, in, all, species, examined, and, here, we]), verbo([provide]), complemento([the, phylogenetic, analysis, of, new, partial, sequences])].
[sujeto(['Immunochemical', determinations, with, mammalian, antibodies, failed, to, identify, the, presence, of, 'MRP(s),', but, 'Pgp', expression, was]), verbo([found]), complemento([in, all, five, 'Cyprinid', species])].
[sujeto(['These', results, support, that, 'MXR', is, a, defence, system]), verbo([mediated]), complemento([by, both, 'Pgp', and, 'MRP', types, of, 'ABC', transport, proteins])].
[sujeto(['Scholars']), verbo([have]), complemento([recently, become, increasingly, interested, in, the, role, religion, plays, in, the, responses, to, the, 'HIV/AIDS', epidemic, in, 'sub-Saharan', 'Africa'])].
[sujeto(['Here,', we, present, the, 'Malawi', 'Religion', 'Project', '(', 'MRP),', which]), verbo([provides]), complemento([data, to, examine, the, relationship, between, religion, and, 'HIV/AIDS', through, surveys, and, 'in-depth', interviews, with, denominational, 'leaders,', congregational, 'leaders,', and, congregation, members, in, three, districts, of, rural, 'Malawi'])].
[sujeto(['In', the, 'paper,', we, outline, existing, perspectives, on, the, 'religion-HIV/AIDS', 'link,', describe, the, 'MRP\'s', 'design,', 'implementation,', and, subsequent, 'data;']), verbo([provide]), complemento([initial, evidence, for, a, series, of, general, research, 'hypotheses;', and, describe, how, these, data, can, be, used, both, to, extend, explorations, of, these, relationships, further, and, as, a, model, for, gathering, similar, data, in, other, contexts])].
[sujeto(['In', particular, we, highlight, the, unique, possibilities, this, project]), verbo([provides]), complemento([for, analyses, that, link, 'MRP', data, to, the, 'Malawi', 'Diffusion', and, 'Ideational', 'Change', 'Project'])].
[sujeto(['Taking', into, account, both, children, and, 'adults,', it, seems, that, age, is, adversely, related, to, therapy, outcome, in, 'AML,', and, the, percentage, of, patients, with, favorable, cytogenetics]), verbo([decreases]), complemento([with, 'age;', 'however,', age, is, positively, correlated, with, 'multi-drug', resistance, and, the, proportion, of, patients, with, unfavorable, cytogenetics])].
[sujeto(['BCRP,', 'PGP', and, 'MRP\'s', are, preferentially]), verbo([expressed]), complemento([in, leukemic, stem, 'cells,', making, this, disease, drug, resistant])].
[sujeto(['In', contrast, to, 'ALL,', the, prognostic, value, of, in, vitro, drug, resistance, in, childhood, 'AML']), verbo([has]), complemento([not, been, well, documented, yet])].
[sujeto(['Rapid', and, timely, information, about, manure, nutrient, content, are, needed, to, minimize, the, risks, of, phosphorus, '(', 'P)', 'over-application', and]), verbo([losses]), complemento([of, dissolved, 'P', '(', 'DP)', in, runoff, from, fields, treated, with, manure])].
[sujeto(['The', 'DP', quick, test, can]), verbo([provide]), complemento([near, 'real-time', information, on, soluble, manure, nutrient, content, across, a, wide, range, of, handling, and, storage, conditions, on, dairy, farms, and, quick, estimates, of, potential, soluble, 'P', losses, in, runoff, following, land, applications, of, manure])].
[sujeto(['The', basis, for, low, brain, permeability, of, valproic, acid, '(', 'VPA)', appears, to, be, the, result, of, efflux, transport, at, the, 'blood-brain', barrier, '(', 'BBB);', 'however,', the, identity, of, the, putative, efflux, transporter]), verbo([has]), complemento([not, been, investigated])].
[sujeto(['The', objective, of, our, studies, was, to, determine, whether, the, multidrug, 'resistance-associated', protein, '(', 'MRP)', might, be]), verbo([involved]), complemento([in, efflux, transport, of, 'VPA'])].
[sujeto(['The', biphasic, pattern, of, 'VPA', uptake]), verbo([suggested]), complemento([concurrent, inhibition, of, uptake, and, efflux, transporters, by, the, inhibitor, with, differing, 'sensitivities,', i])].
[sujeto(['Overall,', the, results]), verbo([suggest]), complemento([that, 'MRP(s)', 'is(are)', involved, in, the, efflux, transport, of, 'VPA,', but, do, not, preclude, the, possible, 'contribution(s)', of, other, organic, anion, transporters])].
[sujeto(['The', 190, kDa, multidrug, resistance, protein, 'MRP1', is, likely, to, be]), verbo([involved]), complemento([in, the, multidrug, resistance, phenotype, of, human, gliomas])].
[sujeto(['In', 'addition,', the, impact, of, the, 'MRP\'s', 'inhibitor,', 'indomethacin,', on, the, chemosensitivity, to, etoposide, '(', 'VP16)', and, vincristine, '(', 'VCR)', of, two, glioblastoma, cell, lines]), verbo([expressing]), complemento(['MRP1', '(', 'GL15', and, 8, 'MG)', was, investigated])].
[sujeto(['MRP1', was, also, strongly]), verbo([expressed]), complemento([at, the, membrane, of, the, vascular, endothelial, cells, in, the, same, 14, tumor, 'samples,', suggesting, that, the, permeability, to, anticancer, drugs, could, be, also, limited, across, brain, tumor, vessels])].
[sujeto(['At', concentrations, comprised, between, 5, and, 50, 'microM,', indomethacin, significantly]), verbo([increased]), complemento([the, cytotoxic, effect, of, etoposide, in, both, cell, lines, but, it, was, more, efficient, in, increasing, the, cytotoxicity, of, 'VCR', on, 'GL15', 'cells,', as, compared, with, 8, 'MG', cells])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, association, of, indomethacin, to, 'VCR', or, etoposide, could, be, of, interest, in, the, clinical, management, of, gliomas])].
[sujeto(['The', visibility, of, the, pancreatic, duct, could, be]), verbo([increased]), complemento([significantly, after, secretin, injection, in, all, subgroups, '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['However,', this]), verbo([finding]), complemento([alone, did, not, suffice, in, differentiating, between, both, groups, '(', sensitivity, 0.68, and, specificity, 0.59, ',', 'respectively)'])].
[sujeto([injection, of, secretin, improves, the, ability, of, 'MRP', to, evaluate, the, pancreas, by]), verbo([increasing]), complemento([the, visibility, of, the, pancreatic, duct, structures, and, provides, a, method, to, assess, the, excretion, rate, of, the, gland])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, a, strong, correlation, between, poor, prognosis, in, childhood, neuroblastoma, '(', 'NB)', patients, and, 'high-level', expression, of, the, transmembrane, efflux, 'pump,', 'Multidrug', 'Resistance-associated', 'Protein', '(', 'MRP1),', in, 'NB', tumour, tissue])].
[sujeto(['In', this, 'study,', we]), verbo([inhibited]), complemento([the, endogenous, expression, of, 'MRP1', in, 2, different, 'NB', tumour, cell, lines, by, stably, transfecting, an, 'MRP1', antisense, expression, vector, '(', 'MRP-AS)'])].
[sujeto(['Compared', with, control, 'cells,', 'MRP-AS', transfectant, cells, demonstrated, a, higher, proportion, of, dead, and, morphologically, apoptotic, 'cells,', spontaneous, 'neuritogenesis,', 'and,']), verbo([increased]), complemento([synaptophysin, and, neurofilament, expression])].
[sujeto(['Conversely,', we]), verbo([found]), complemento([that, the, same, 'NB', tumour, cell, line, overexpressing, the, 'full-length', 'MRP1', cDNA, in, sense, orientation, '(', 'MRP-S)', demonstrated, resistance, to, the, neuritogenic, effect, of, the, differentiating, 'agent,', 'all-trans-retinoic', acid])].
[sujeto(['Taken', 'together,', the, results]), verbo([suggest]), complemento([that, the, level, of, 'MRP1', expression, in, 'NB', tumour, cells, may, influence, the, capacity, of, 'NB', cells, for, spontaneous, regression, in, vivo, through, cell, differentiation, and, death])].
[sujeto(['Organic', anion, 'transport,']), verbo([mediated]), complemento([by, the, canalicular, multispecific, organic, anion, transporter, '(', 'cmoat),', has, been, extensively, studied])].
[sujeto(['The', regulation, of, intracellular, vesicular, sorting, of, cmoat, by, protein, kinase, 'C', and, protein, kinase, 'A,', and, the, regulation, of, 'cmoat-mediated', transport, in, endotoxemic, liver, 'disease,']), verbo([have]), complemento([been, examined])].
[sujeto(['The', discovery, that, the, multidrug, resistance, protein, '(', 'MRP),', responsible, for, multidrug, resistance, in, 'cancers,', transports, similar, substrates, as, cmoat]), verbo([led]), complemento([to, the, cloning, of, a, 'MRP', homologue, from, rat, 'liver,', named, mrp2])].
[sujeto(['The', expression, of, mrp1, and, mrp2, in, hepatocytes, appears, to, be, 'cell-cycle-dependent', and]), verbo([regulated]), complemento([in, a, reciprocal, fashion])].
[sujeto(['We']), verbo([found]), complemento([that, the, 'over-expression', of, 'BGL1,', 'BGL4,', or, 'BGL5', significantly, enhanced, both, 'β-glucosidase', activity, and, hydrolysis, efficiency, of, the, enzyme, system, on, filter, paper])].
[sujeto(['We']), verbo([found]), complemento([that, all, mutants, show, significantly, enhanced, levels, of, 'β-glucosidase', at, 'transcriptional,', 'protein,', and, activity, levels])].
[sujeto(['Surprisingly,', this]), verbo([induced]), complemento([expression, strategy, enables, significantly, improved, expression, efficiency])].
[sujeto([oxalicum, to, significantly, improve, 'β-glucosidase', activity, is, a, potent, strategy, to, substantially, boost, the, hydrolytic, efficiency, of, the, cellulase, 'cocktail,', which, will, ultimately]), verbo([lead]), complemento([to, a, considerable, reduction, of, cost, for, 'biomass-based', biofuel])].
[sujeto(['We']), verbo([have]), complemento([developed, an, affinity, purification, strategy, based, on, an, 'RNA', affinity, tag, that, allows, 'large-scale', preparation, of, native, viral, 'RNA-binding', proteins, '(', 'RBPs)'])].
[sujeto(['The', 'streptavidin-binding', aptamer, 'S1', sequence, was, inserted, into, the, 3, '\'', end, of, dengue, virus, '(', 'DENV)', 5, '\'', -, 3, '\'', 'UTR', 'RNA,', and, the, 'DENV', 'RNA', 'UTR', fused, to, the, 'S1', 'RNA', aptamer, was]), verbo([expressed]), complemento([in, living, mammalian, cells])].
[sujeto(['This', allowed, endogenous, viral, ribonucleoprotein, '(', 'RNP)', assembly, and, isolation, of, 'RNPs', from, whole, cell, 'extract,', through]), verbo([binding]), complemento([the, 'S1', aptamer, to, streptavidin, magnetic, beads])].
[sujeto(['Bovine', babesiosis, and, theileriosis, is, an, important, hemoprotozoal, disease, in, cattles, and, yaks, in, tropical, and, subtropical, regions]), verbo([leading]), complemento([to, significant, economic, losses])].
[sujeto(['To', standardize, gene, expression, studies, and, obtain, more, accurate, 'qRT-PCR', 'analysis,', normalization, relative, to, consistently]), verbo([expressed]), complemento([housekeeping, genes, '(', 'HKGs)', is, required])].
[sujeto(['Better', understanding, the, molecular, characteristics, of, the, pancreatic, adenocarcinomas, from, these, 'very-long-term', survivors, '(', 'VLTS)', may]), verbo([provide]), complemento([clues, for, personalized, medicine, and, improve, current, pancreatic, cancer, treatment])].
[sujeto(['With', a, given, analytical, 'sensitivity,', the, protein, profile, of, each, pancreatic, tumor, tissue, was, compared, to]), verbo([reveal]), complemento([the, proteome, alterations, that, may, be, associated, with, pancreatic, cancer, survival])].
[sujeto(['Pathway', analysis, of, the, differential, proteins, identified]), verbo([suggested]), complemento([that, 'MYC,', 'IGF1R', and, p53, were, the, top, three, upstream, regulators, for, the, 'STS-associated', 'proteins,', and, 'VEGFA,', 'APOE', and, 'TGFβ-1', were, the, top, three, upstream, regulators, for, the, 'VLTS-associated', proteins])].
[sujeto(['Multivariate', 'Cox', analysis, indicated, that, '\'', 'High-RPS8', and, 'Low-PRELP\'', was, significantly]), verbo([associated]), complemento([with, shorter, survival, time, '(', 'HR=2'])].
[sujeto(['In', 'addition,', 'galectin-1,', a, previously, identified, protein, with, its, abundance, aversely]), verbo([associated]), complemento([with, pancreatic, cancer, 'survival,', was, further, evaluated, for, its, significance, in, 'cancer-associated', fibroblasts])].
[sujeto(['The', results, from, our, study]), verbo([suggested]), complemento([that, 'PRELP,', 'LGALS1', and, 'RPS8', might, be, significant, prognostic, 'factors,', and, 'RPS8', and, 'LGALS1', could, be, potential, therapeutic, targets, to, improve, pancreatic, cancer, survival, if, further, validated])].
[sujeto(['Blood', progenitors, within, the, lymph, 'gland,', a, larval, organ, that, supports, hematopoiesis, in, 'Drosophila', 'melanogaster,', are]), verbo([maintained]), complemento([by, integrating, signals, emanating, from, 'niche-like', cells, and, those, from, differentiating, blood, cells])].
[sujeto(['To', identify, new, genes]), verbo([involved]), complemento([in, lymph, gland, blood, progenitor, 'maintenance,', particularly, those, involved, in, equilibrium, 'signaling,', we, performed, a, genetic, screen, that, identified, bip1, '(', bric, à, brac, interacting, protein, 1, ')', and, 'Nucleoporin', 98, '(', 'Nup98)', as, additional, regulators, of, the, equilibrium, signal])].
[sujeto(['We', show, that, the, products, of, these, genes, along, with, the, 'Bip1-interacting', protein, 'RpS8', '(', 'Ribosomal', protein, 'S8)', are]), verbo([required]), complemento([for, the, proper, expression, of, 'Pvr'])].
[sujeto(['Several', 'protein-targeted', 'RNA', aptamers]), verbo([have]), complemento([been, identified, for, a, variety, of, applications, and, although, the, affinities, of, numerous, 'protein-aptamer', complexes, have, been, 'determined,', the, structural, details, of, these, complexes, have, not, been, widely, explored])].
[sujeto(['We', examined, the, structural, accommodation, of, an, 'RNA', aptamer, that]), verbo([binds]), complemento([bacterial, 'r-protein', 'S8'])].
[sujeto(['The', core, of, the, primary]), verbo([binding]), complemento([site, for, 'S8', on, helix, 21, of, 16, 'S', rRNA, contains, a, pair, of, conserved, base, triples, that, mold, the, 'sugar-phosphate', backbone, to, 'S8'])].
[sujeto(['The', 'aptamer,', which, does, not, contain, the]), verbo([conserved]), complemento([sequence, 'motif,', is, specific, for, the, rRNA, binding, site, of, 'S8'])].
[sujeto(['Surprisingly,']), verbo([binding]), complemento([of, 'S8', leads, to, a, dramatic, change, in, the, 'RNA', conformation, that, restores, the, signature, 'S8', recognition, fold, through, a, novel, combination, of, nucleobase, interactions])].
[sujeto(['The', differentially]), verbo([expressed]), complemento([genes, in, 'SHED', and, 'DPSCs', were, identified, using, the, 'GeneFishing™', technique])].
[sujeto(['Two', bands, were, highly]), verbo([expressed]), complemento([in, 'SHED', and, three, bands, in, 'DPSCs'])].
[sujeto(['TIMP1', is]), verbo([involved]), complemento([in, degradation, of, the, extracellular, 'matrix,', cell, proliferation, and, 'anti-apoptotic', function, and, 'RPS8', is, involved, as, a, 'rate-limiting', factor, in, translational, 'regulation;', 'COL1A1', is, involved, in, the, resistance, and, elasticity, of, the, 'tissues;', 'FSTL1', is, an, autoantigen, associated, with, rheumatoid, 'arthritis;', 'LGALS1', is, involved, in, cell, 'growth,', 'differentiation,', 'adhesion,', 'RNA', 'processing,', apoptosis, and, malignant, transformation])].
[sujeto(['Similar', to, 18, 'S', 'rDNA,', the, 40, 'S', ribosomal, protein, 'S8', 'gene,', 'RPS8,', including, both, coding, and, 'non-coding', regions, is, a, useful, and, novel, genetic, marker, for, defining, species, boundaries, and, for, inferring, phylogenies, because, it, tends, to]), verbo([have]), complemento([little, 'intra-specific', variation, but, considerable, 'inter-specific', difference])].
[sujeto(['Ovine', babesiosis, and, theileriosis, are, important, hemoprotozoal, diseases, of, sheep, and, goats, in, tropical, and, subtropical, regions, that]), verbo([lead]), complemento([to, economic, losses, in, these, animals])].
[sujeto(['In', order, to, identify, the, optimal, internal, control, for, relative, 'real-time', 'PCR', when, studying]), verbo([target]), complemento([gene, expression, in, the, red, alga, 'Porphyra', 'yezoensis,', we, quantified, the, expression, of, seven, housekeeping, genes, '(', 18, 'S', ribosomal, 'RNA,', 30, 'S', ribosomal, protein, 'S8,', 'Polyubiquitin-2,', 'Glyceraldehyde-3-phosphate', 'dehydrogenase,', 'Elongation', factor, 1, -, 'alpha,', 'Beta-tubulin', and, 'Actin', 3, ')', at, different, 'life-history', stages])].
[sujeto(['We']), verbo([found]), complemento(['GAPDH', had, the, best, stability, in, all, cases, and, we, recommend, that, 'GAPDH', be, considered, as, a, potential, internal, control, for, gene, expression, studies, at, different, 'life-history', stages, in, 'P'])].
[sujeto(['Serum', calcitonin, '(', 'sCT)', is, the, main, tumor, marker, for, medullary, thyroid, cancer, '(', 'MTC),', but, it]), verbo([has]), complemento([certain, limitations])].
[sujeto(['Various', sCT, assays, may]), verbo([have]), complemento([important, 'intra-assay', or, interassay, variation, and, may, yield, different, and, sometimes, conflicting, results])].
[sujeto(['Alternatively,', or, in, the, absence, of, the, stimulation, 'test,', mRNA, detection, offers, the, advantages, of, being, more, comfortable, and, less, 'invasive;', it, only]), verbo([requires]), complemento([blood, collection, and, has, no, side, effects])].
[sujeto(['Quantitative', 'real-time', polymerase, chain, reaction, '(', 'RT-qPCR)', was, performed, with, 'SYBR', 'Green', and, 200, nM, of, each]), verbo([primer]), complemento([for, the, two, specific, mRNA, targets, '(', 'CT-CALCA', or, 'CGRP-CALCA)', and, normalized, with, the, ribosomal, protein, 'S8', as, the, reference, gene])].
[sujeto(['Duffy', or, 'DARC', '(', 'Duffy', 'Antigen', 'Receptor', for, 'Chemokines)', is, a, glycosylated, membrane, protein, that, selectively]), verbo([binds]), complemento([angiogenic, chemokines])].
[sujeto(['Previous', in, vivo, and, in, vitro, studies, of, 'DARC', function, in, cancer]), verbo([have]), complemento([associated, 'DARC', over, expression, with, better, 'prognosis,', decreased, metastatic, 'potential,', and, inhibition, of, 'tumor-associated', neovascularization])].
[sujeto(['Another', 'carcinogenesis-associated', antigen, is, 'Lutheran', or, 'BCAM', '(', basal, cell, adhesion, 'molecule),', a, surface, glycoprotein, that]), verbo([acts]), complemento([as, a, receptor, for, the, extracellular, matrix, 'protein,', laminin])].
[sujeto(['BCAM', is, a, protein, related, to, tumor, 'progression;', 'and,', its, over, expression, is]), verbo([associated]), complemento([with, 'skin,', ovarian, and, pancreatic, cancers])].
[sujeto(['RNA', was, 'isolated,', reverse]), verbo([transcribed]), complemento([to, 'cDNA,', and, used, in, qPCR, reactions, containing, 'SYBR', 'Green'])].
[sujeto(['When', we, compared, benign, '(', 'NT', and, 'FTA)', versus, malignant, samples, '(', 'FTC,', 'CVPTC', and, 'FVPTC)', we, observed, a, significant]), verbo([decrease]), complemento([of, 'DARC', and, 'BCAM', relative, expression, in, malignant, cases])].
[sujeto(['We']), verbo([found]), complemento([a, diminished, expression, of, 'DARC', in, 'PTC', 'samples,', which, was, correlated, with, tumor, size, and, presence, of, a, lymphocyte, infiltrate])].
[sujeto(['We,', 'also,']), verbo([found]), complemento([a, correlation, between, decreased, 'BCAM', expression, and, tumor, size, or, presence, of, metastasis])].
[sujeto(['DARC', and, 'BCAM', expression, was]), verbo([associated]), complemento([with, pathogenesis, of, thyroid, carcinoma, and, correlated, with, 'clinical-pathological', features])].
[sujeto(['The', assembly, of, ribonucleoprotein, complexes, occurs, under, a, broad, range, of, 'conditions,', but, the, principles, that]), verbo([promote]), complemento([assembly, and, allow, function, at, high, temperature, are, poorly, understood])].
[sujeto(['Deletion', analysis, demonstrated, that]), verbo([binding]), complemento([to, the, minimal, site, on, helix, 21, occurred, at, the, same, nanomolar, affinity, found, for, other, bacterial, species])].
[sujeto(['The', additional, affinity]), verbo([required]), complemento([the, presence, of, a, 'three-helix', junction, between, helices, 20, ',', 21, ',', and, 22])].
[sujeto(['The', crystal, structure, of, 'AS8', was, 'solved,']), verbo([revealed]), complemento([the, 'helix-loop-helix', geometry, of, the, unique, 'AS8', insertion, 'region,', while, the, core, of, the, molecule, is, conserved, with, known, 'S8', structures])].
[sujeto(['coli,']), verbo([suggesting]), complemento([the, possibility, that, the, unique, subdomain, provides, additional, backbone, and, 'side-chain', contacts, between, the, protein, and, an, unpaired, base, within, the, 'three-way', junction, of, helices, 20, ',', 21, ',', and, 22])].
[sujeto(['Point', mutations, in, the, protein, insertion, subdomain, resulted, in, a, significantly, reduced, 'RNA']), verbo([binding]), complemento([affinity, with, respect, to, 'wild-type', 'AS8'])].
[sujeto(['These', results, indicate, that, the, 'AS8-specific', subdomain]), verbo([provides]), complemento([additional, interactions, with, the, 'three-way', junction, that, contribute, to, the, extremely, tight, binding, to, ribosomal, 'RNA'])].
[sujeto(['By', using, 'His', 'pull-down', and, mass, spectrometry, 'analysis,', we, identified, the, ribosomal, protein, 'S8', '(', 'RPS8),', a, member, of, the, small, subunit, 'ribosome,', as, an]), verbo([interacting]), complemento([partner, of, 'CDK11p46'])].
[sujeto(['Moreover,', 'RPS8', and, 'CDK11p46', synergize, to]), verbo([inhibit]), complemento([the, translation, process, both, in, 'cap-', and, internal, ribosomal, entry, site, '(', 'IRES)-dependent', 'way,', and, sensitize, cells, to, 'Fas', 'ligand-induced', apoptosis])].
[sujeto(['Taken', 'together,', our, results]), verbo([provide]), complemento([evidence, for, the, novel, role, of, 'CDK11p46', in, the, regulation, of, translation, and, cell, apoptosis])].
[sujeto(['We', examined, 16, 'S', rRNA, conformational, changes, during, in, vitro, assembly, using, directed, hydroxyl, radical, probing]), verbo([mediated]), complemento([by, 'Fe(II)-derivatized', ribosomal, protein, '(', 'r-protein)', 'S8'])].
[sujeto(['R-protein', 'S8']), verbo([binds]), complemento([the, central, domain, of, 16, 'S', rRNA, directly, and, independently, and, its, iron, derivatized, substituents, have, been, shown, to, mediate, cleavage, in, three, domains, of, 16, 'S', 'rRNA,', thus, making, it, an, ideal, probe, to, monitor, multidomain, orientation, during, assembly])].
[sujeto(['The', minimal]), verbo([binding]), complemento([site, of, 'S8', at, helix, 21, exists, in, a, structure, similar, to, that, observed, in, the, mature, 'subunit,', in, the, absence, of, other, 'r-proteins'])].
[sujeto(['However,', the]), verbo([binding]), complemento([site, of, 'S8', at, the, junction, of, helices, 25, -, 26, 'a,', which, is, transcribed, after, helix, 21, ',', is, cleaved, with, differing, intensities, in, the, presence, and, absence, of, other, 'r-proteins'])].
[sujeto(['Thus,', a, complex, interrelationship, is, observed, between, assembly, events, of, independent, domains, and, the, incorporation, of, primary]), verbo([binding]), complemento([proteins, during, 30, 'S', subunit, formation])].
[sujeto(['By', taking, advantage, of, the, zonation, of, this, 'organ,', we]), verbo([have]), complemento([used, suppressive, subtractive, libraries, 'construction,', 'real-time', 'PCR,', and, in, situ, hybridization, to, identify, 32, dogfish, genes, showing, differential, expressions, during, spermatogenesis])].
[sujeto(['These', include, homologs, of, genes, already, known, to, be]), verbo([expressed]), complemento([in, the, vertebrate, 'testis,', but, found, here, to, be, specifically, expressed, either, in, 'pre-meiotic', 'and/or', meiotic, zones, '(', ribosomal, protein, 'S8,', 'high-mobility', group, box, 3, ',', ubiquitin, 'carboxyl-terminal', esterase, 'L3,', 20, 'beta-hydroxysteroid', 'dehydrogenase,', or, cyclophilin, 'B)', or, in, 'post-meiotic', zone, '(', 'speriolin,', 'Soggy,', zinc, finger, protein, 474, ',', 'calreticulin,', or, phospholipase, 'c-zeta)'])].
[sujeto(['This', study]), verbo([provides]), complemento([the, first, molecular, characterization, of, spermatogenesis, in, a, 'chondrichthyan,', a, key, species, to, gain, insight, into, the, evolution, of, this, process, in, gnathostomes])].
[sujeto([described, a, set, of, ribosomal, protein, '(', 'RP)', genes, extracted, from, a, collection, of]), verbo([expressed]), complemento([sequence, tags, '(', 'ESTs)', of, the, chaetognath, '(', arrow, 'worm)', 'Spadella', cephaloptera])].
[sujeto(['First,', the, authors, stated, that, 'RP', genes, present, paralogous, 'copies,', which]), verbo([have]), complemento([arisen, through, allopolyploidization])].
[sujeto(['Second,', they]), verbo([reported]), complemento([two, alternate, nucleotide, stretches, conserved, within, the, 5, '\'', untranslated, regions, '(', 'UTR)', of, multiple, ribosomal, cDNAs, and, they, suggested, that, these, motifs, are, involved, in, the, differential, transcriptional, regulation, of, paralogous, 'RP', genes])].
[sujeto(['We']), verbo([find]), complemento([that, their, evidence, for, paralogous, copies, relies, on, faulty, 'PCR', experiments, since, they, attempted, to, amplify, 'DNA', fragments, absent, from, the, genomic, template])].
[sujeto(['Our', 'PCR', experiments, proved, that, the]), verbo([conserved]), complemento([motifs, in, 5, '\'', 'UTRs', that, they, targeted, in, their, amplifications, are, added, 'post-transcriptionally', by, a, 'trans-splicing', mechanism])].
[sujeto(['The', 'AMP-activated', protein, kinase, '(', 'AMPK)']), verbo([represses]), complemento([signaling, through, the, mammalian, target, of, rapamycin, complex, 1, '(', 'mTORC1)'])].
[sujeto(['In', 'muscle,', repression, of, mTORC1]), verbo([leads]), complemento([to, a, reduction, in, global, protein, synthesis])].
[sujeto(['In', 'contrast,', repression, of, mTORC1, in, the, liver]), verbo([has]), complemento([no, immediate, effect, on, global, protein, synthesis])].
[sujeto(['Activation', of, 'AMPK']), verbo([repressed]), complemento([translation, of, the, 'TOP', mRNAs, encoding, 'rpS6,', 'rpS8,', and, eEF1alpha])].
[sujeto(['Basal', phosphorylation, of, the, mTORC1]), verbo([target]), complemento(['4E-BP1,', but, not, 'S6K1', or, 'rpS6,', was, reduced, following, activation, of, 'AMPK'])].
[sujeto(['Thus,', in, 'liver,', 'AMPK', activation]), verbo([repressed]), complemento([translation, of, 'TOP', mRNAs, through, a, mechanism, distinct, from, downregulated, phosphorylation, of, 'S6K1', or, rpS6])].
[sujeto(['The', molecular, signalling, pathways]), verbo([mediating]), complemento([sexual, dimorphism, have, principally, been, investigated, in, the, 'gonads,', and, to, a, lesser, extent, in, other, organs])].
[sujeto([42, genes, were, differentially]), verbo([expressed]), complemento([between, the, 'sexes,', from, which, 18, genes, were, 'over-expressed', in, males, and, 24, genes, were, 'over-expressed', in, females])].
[sujeto(['In', 'males,', these, included, 'deiodinase,', 'iodothyronine,', type, 'II', and, ribosomal, protein, 'S8,', and, in, 'females,', superoxide, dismutase, '[', 'Cu-Zn],', 'sprouty-4,', frizzled, 10, and, testis]), verbo([enhanced]), complemento([gene, transcript])].
[sujeto(['Estrogen', responsive, elements, were]), verbo([found]), complemento([in, the, regulatory, regions, for, 3, genes, 'over-expressed', in, males, and, 7, genes, 'over-expressed', in, females])].
[sujeto(['We']), verbo([have]), complemento([demonstrated, the, existence, of, dimorphic, patterns, of, gene, expression, in, the, brain, of, a, sexually, 'mature,', 'non-mammalian,', vertebrate, 'model,', with, implications, for, studies, into, reproduction, and, chemical, disruption, of, brain, function])].
[sujeto(['In', this, 'study,', we]), verbo([reported]), complemento([the, complete, chloroplast, genome, sequence, of, 'Primula', sinensis, and, compared, it, with, other, related, species])].
[sujeto(['Among', 'them,', seven, coding, 'genes,', seven, tRNA, genes, and, four, rRNA, genes]), verbo([have]), complemento([two, copies, due, to, their, locations, in, the, 'IR', regions])].
[sujeto(['A', transcript]), verbo([found]), complemento([from, 'P'])].
[sujeto(['The', result, strongly]), verbo([suggested]), complemento([that, plastid, accD, has, been, functionally, transferred, to, the, nucleus, in, 'P'])].
[sujeto(['The', yak, is, primarily]), verbo([found]), complemento([throughout, the, 'Tibetan', high, plateau, and, the, surrounding, mountainous, area, of, south, central, 'Asia;', among, its, others, 'attributes,', its, milk, is, very, important, for, the, local, population])].
[sujeto(['We', compared, the, results, of, 3]), verbo([target]), complemento([genes, '(', 'CSN1S1,', 'ESR1,', and, 'MYC)', normalized, using, 6, ',', 3, ',', or, 1, of, the, best, 'ICGs'])].
[sujeto(['A', dilution, effect, of, the, 'ICGs', due, to, a, large]), verbo([increase]), complemento([in, the, mRNA, of, abundantly, expressed, genes, in, bovine, and, porcine, mammary, tissue, during, the, lactation, cycle, was, previously, observed])].
[sujeto(['To', test, for, the, presence, of, a, dilution, effect, in, our, 'study,', we, evaluated, the, pattern, of, 'non-normalized', 'RT-qPCR', data, of, 'ICGs', from, pregnancy, to, lactation, and, compared, them, with, the, total, 'RNA', 'concentration,', milk, 'yield,', and, 'non-normalized', 'RT-qPCR', data, of, 3]), verbo([target]), complemento([genes])].
[sujeto(['With', a, few, 'exceptions,', the, 'non-', normalized, 'RT-qPCR', data, for, the, tested, 'ICGs', was, significantly]), verbo([increased]), complemento([by, lactation, and, had, a, positive, correlation, with, total, 'RNA', and, the, 'non-normalized', 'RT-qPCR', data, of, 'CSN1S1'])].
[sujeto(['Patients', treated, with, standard, chemotherapy, for, metastatic, or, relapsed, cervical, cancer]), verbo([respond]), complemento([poorly, to, conventional, chemotherapy, '(', response, achieved, in, 20, -, 30, '%', of, 'patients)', with, an, overall, survival, of, less, than, 1, year])].
[sujeto(['This', trial, is, registered, with, the, 'ISCRTN', 'registry,', number, 'ISRCTN23516549,', and]), verbo([has]), complemento([been, completed])].
[sujeto(['Cediranib']), verbo([has]), complemento([significant, efficacy, when, added, to, carboplatin, and, paclitaxel, in, the, treatment, of, metastatic, or, recurrent, cervical, cancer])].
[sujeto(['This']), verbo([finding]), complemento([was, accompanied, by, an, increase, in, toxic, effects, '(', mainly, 'diarrhoea,', 'hypertension,', and, febrile, 'neutropenia)'])].
[sujeto(['The', psoriasis, lesional, skin, transcriptome]), verbo([has]), complemento([been, extensively, 'investigated,', but, mRNA, levels, do, not, necessarily, reflect, protein, abundance])].
[sujeto(['We', identified, 4122, differentially]), verbo([expressed]), complemento([genes, '(', 'DEGs)', along, with, 748, differentially, expressed, proteins, '(', 'DEPs)'])].
[sujeto(['We', identified, similar, numbers, of]), verbo([increased]), complemento([and, decreased, 'DEGs,', but, 4, -, fold, more, increased, than, decreased, 'DEPs'])].
[sujeto(['We', identified, 209, differentially]), verbo([expressed]), complemento(['genes/proteins', '(', 'DEGPs)', with, corresponding, trends, at, the, transcriptome, and, proteome, levels])].
[sujeto(['Our', findings]), verbo([reveal]), complemento([global, imbalance, between, the, number, of, increased, and, decreased, proteins, in, psoriasis, 'lesions,', consistent, with, heightened, translation])].
[sujeto(['This', effect, could, not]), verbo([have]), complemento([been, discerned, from, mRNA, profiling, data, alone])].
[sujeto(['By', distinguishing, between, 'psoriasis-specific', and, 'non-specific', 'DEGPs,', our, analysis, uncovered, new, functional, insights, that, would, otherwise]), verbo([have]), complemento([been, overlooked])].
[sujeto([ocellatus, were, surveyed, for, variation, at, two, mitochondrial, genes, '(', 'ND2,', 'ND4),', and, two]), verbo([nuclear]), complemento([genes, '(', 'β-globin,', 'RPS8)'])].
[sujeto(['There', was, a, high, degree, of, mitochondrial, haplotype, diversity, '(', 96, unique, 'haplotypes)', and, phylogeographic, 'structure,', where, spatially, distinct, groups, were]), verbo([associated]), complemento([with, 'Tasmania\'s', 'Northeast', and, a, large, area, covering, 'Southeast', and, 'Central', 'Tasmania'])].
[sujeto(['In', 'contrast,']), verbo([nuclear]), complemento(['DNA', had, low, levels, of, variation, and, a, lack, of, phylogeographic, 'structure,', and, further, loci, should, be, surveyed, to, corroborate, the, mitochondrial, inferences])].
[sujeto(['Expansion', in, 'Central', and, 'Southeastern', areas, appears, to]), verbo([have]), complemento([been, more, recent, in, both, demographic, and, spatial, 'contexts,', than, in, 'Northeast', 'Tasmania,', which, is, consistent, with, inferences, for, other, taxa, of, greater, stability, and, persistence, in, 'Northeast', 'Tasmania', during, the, 'Last', 'Glacial', 'Maximum'])].
[sujeto(['qRT-PCR']), verbo([requires]), complemento([the, selection, of, one, or, several, suitable, reference, 'genes,', whose, expression, profiles, remain, stable, across, 'conditions,', to, normalize, the, 'qRT-PCR', expression, profiles, of, candidate, genes])].
[sujeto(['Although', several, butterfly, species, '(', 'Lepidoptera)']), verbo([have]), complemento([become, important, models, in, molecular, evolutionary, 'ecology,', so, far, no, study, aimed, at, identifying, reference, genes, for, accurate, data, normalization, for, any, butterfly, is, available])].
[sujeto(['The', 'African', bush, brown, butterfly, 'Bicyclus', anynana]), verbo([has]), complemento([drawn, considerable, attention, owing, to, its, suitability, as, a, model, for, evolutionary, 'ecology,', and, we, here, provide, a, maiden, extensive, study, to, identify, suitable, reference, gene, in, this, species])].
[sujeto(['Finally,', we, tested, the, effect, of, choosing, reference, genes, with, different, stability, on, the, normalization, of, the, transcript, abundance, of, a, candidate, gene]), verbo([involved]), complemento([in, olfactory, communication, in, 'B'])].
[sujeto(['anynana,', the, 'Fatty', 'Acyl', 'Reductase', 2, ',', and, we, confirmed, that, using, an, unstable, reference, gene, can, drastically, alter, the, expression, profile, of, the]), verbo([target]), complemento([candidate, genes])].
[sujeto(['Most', of, the, 'protein-coding', '(', 27, ')', genes]), verbo([have]), complemento([usual, 'ATG', start, 'codon,', except, 9, genes, such, as, 'ATA', for, 'rps8;', 'ATC', for, 'rps14;', 'ATT', for, rps12, and, 'orf51;', 'GTG', for, 'nad5;', 'TTA', for, 'cox3,', nad4, and, 'orf147;', and, 'TTG', for, cob])].
[sujeto(['A', new, mitogenome, will]), verbo([provide]), complemento([useful, information, for, mitochondrial, genome, diversity, and, evolution, of, the, diatoms])].
[sujeto(['pagenstecheri,', we, sequenced, one, mitochondrial, locus, '(', 'ND4)', and, five]), verbo([nuclear]), complemento([loci, '(', 'β-globin,', 'LGMN,', 'PRLR,', 'Rhodopsin,', 'RPS8)'])].
[sujeto(['While', we]), verbo([find]), complemento([strong, support, for, the, monophyly, of, the, 'P'])].
[sujeto([entrecasteauxii, 'complex,', there, exists, marked, incongruence, between, the, mitochondrial, and]), verbo([nuclear]), complemento(['markers,', particularly, in, regards, to, the, high, altitude, 'specialist,', 'P'])].
[sujeto(['Our', study]), verbo([reveals]), complemento([a, more, complex, evolutionary, history, of, the, genus, 'Pseudemoia', than, previously, appreciated, and, contributes, to, our, understanding, of, the, biogeography, and, evolution, of, 'Australian', mesic, zone, fauna])].
[sujeto(['Plastid-to-nucleus', 'DNA', transfer]), verbo([provides]), complemento([a, rich, genetic, resource, to, the, complexity, of, plant, nuclear, genome, architecture])].
[sujeto(['To', 'date,', the, evolutionary, route, of]), verbo([nuclear]), complemento([plastid, 'DNA', '(', 'nupt)', remain, unknown, in, conifers])].
[sujeto(['We']), verbo([have]), complemento([sequenced, the, complete, plastomes, of, two, 'yews,', 'Amentotaxus', formosana, and, 'Taxus', mairei, '(', 'Taxaceae', of, 'coniferales)'])].
[sujeto(['These', nupts]), verbo([have]), complemento([significantly, accumulated, 'GC-to-AT', 'mutations,', reflecting, a, nuclear, mutational, environment, shaped, by, spontaneous, deamination, of, 5, -, methylcytosin])].
[sujeto(['The', ancestral, initial, codon, of, rps8, is]), verbo([retained]), complemento([in, the, 'T'])].
[sujeto(['nupts,', but, its, corresponding, extant, codon, is, mutated, and]), verbo([requires]), complemento(['C-to-U', 'RNA-editing'])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, nupts, can, help, recover, scenarios, of, the, nucleotide, mutation, process])].
[sujeto(['We', show, that, the, 'Taxaceae', nupts, we, retrieved, may]), verbo([have]), complemento([been, retained, because, the, 'Cretaceous', and, they, carry, information, of, both, ancestral, genomic, organization, and, nucleotide, 'composition,', which, offer, clues, for, understanding, the, plastome, evolution, in, conifers])].
[sujeto(['Using', 'RNAi', 'approach,', we, demonstrate, that, 'GmSGT1', is, an, essential, component, in, soybean, against, 'Phytophthora', 'sojae,', but, not]), verbo([required]), complemento([for, 'Rps', 2, or, 'Rps', 3, 'a-mediated', resistance])].
[sujeto(['Utilization', of, disease, resistance, in, soybean, is, a, major, approach, to, combat, root, and, stem, rot, 'disease,', which, is]), verbo([caused]), complemento([by, 'Phytophthora', sojae, and, poses, a, growing, threat, to, soybean, safety, production])].
[sujeto(['Transcriptional', levels, of, all, the, tested, genes, were, highly]), verbo([induced]), complemento([upon, 'P'])].
[sujeto([sojae, infection, in, four, soybean, cultivars, that]), verbo([confer]), complemento([different, resistant, levels])].
[sujeto(['In', 'contrast,', the, resistance]), verbo([mediated]), complemento([by, 'Rps2', or, 'Rps3a', was, not, affected])].
[sujeto(['We', further, showed, that, transient, overexpression, of, 'GmSGT1-1', in, 'Nicotiana', benthamiana, could]), verbo([enhance]), complemento([the, resistance, to, 'P'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'GmSGT1', is, an, essential, component, for, soybean, in, resisting, the, pathogen, and, pathways, of, 'Rps-mediated', disease, resistance, are, diverse, in, soybean])].
[sujeto(['We', evaluated, nine, plastid, '(', 'matK,', 'rbcL,', 'rpoC1,', 'rpoB,', 'rpl36-rps8,', 'ndhJ,', 'trnL-F,', 'trnH-psbA,', 'accD)', and, two]), verbo([nuclear]), complemento(['(', 'ITS', and, 'ITS2)', barcode, loci, in, family, 'Zingiberaceae', by, analyzing, 60, accessions, of, 20, species, belonging, to, seven, genera, from, 'India'])].
[sujeto(['To', be, economically, 'competitive,', producer, strains, need, to, be, established, that, synthesize, the]), verbo([targeted]), complemento([product, at, high, yield, and, over, a, long, time])].
[sujeto(['Therefore,', 'in-depth', characterization, of, the, cellular, response, upon, 'long-term', production, is, of, high, interest, for, the]), verbo([targeted]), complemento([improvement, of, a, desired, strain])].
[sujeto(['Ethanol', production]), verbo([caused]), complemento([a, significant, '(', '~40%)', delay, in, biomass, 'accumulation,', the, development, of, a, bleaching, phenotype, and, a, 'down-regulation', of, light, harvesting, capacity])].
[sujeto(['In', addition, to, the, overexpressed, adhA, '(', 'slr1192)', 'gene,', this, was, an, approximately, 4, fold, reduction, in, cpcB, '(', 'sll1577)', and, 3, to, 6, fold]), verbo([increase]), complemento([in, rps8, '(', 'sll1809)', mRNA, levels])].
[sujeto(['Much', weaker, modifications, of, expression, level, or, modifications, restricted, to, day, 18, of, the, experiment, were, observed, for, genes]), verbo([involved]), complemento([in, carbon, assimilation, '(', 'Ribulose', bisphosphate, carboxylase, and, 'Glutamate', 'decarboxylase)'])].
[sujeto(['Moreover,', western, blots, and, 'zinc-enhanced', bilin, fluorescence, blots, confirmed, a, severe, reduction, in, the, amounts, of, both, phycocyanin, 'subunits,', explaining, the]), verbo([cause]), complemento([of, the, bleaching, phenotype])].
[sujeto(['In', 'particular,', we, did, not, observe, a, comprehensive, stress, response, as, might]), verbo([have]), complemento([been, expected])].
[sujeto(['Several', key, developmental, or, signaling, pathways]), verbo([have]), complemento([been, shown, to, play, essential, roles, in, this, regulatory, capacity])].
[sujeto(['Specifically,', the, 'Janus-activated', 'kinase/signal', transducer, and, activator, of, 'transcription,', 'Hedgehog,', 'Wnt,', 'Notch,', phosphatidylinositol, 3, -, 'kinase/phosphatase', and, tensin, 'homolog,', and]), verbo([nuclear]), complemento(['factor-κB', signaling, pathways, have, all, been, shown, experimentally, to, mediate, various, stem, cell, 'properties,', such, as, 'self-renewal,', cell, fate, 'decisions,', 'survival,', 'proliferation,', and, differentiation])].
[sujeto(['Growing', evidence]), verbo([suggests]), complemento([that, overactive, or, abnormal, signaling, within, and, among, these, pathways, may, contribute, to, the, survival, of, cancer, stem, cells, '(', 'CSCs)'])].
[sujeto(['Nivolumab,', an, immune, checkpoint, 'inhibitor,', is, recently, clinically, applied, to, 'non-small', cell, lung, cancer, '(', 'NSCLC)', 'treatment,', and, this]), verbo([causes]), complemento(['T', cell, activation, and, 'T', cell, infiltration, to, tumor, tissue, through, the, blockade, of, the, interaction, between, programmed, cell, death, 1, '(', 'PD-1)', and, programmed, cell, death, ligand, 1, '(', 'PD-L1)'])].
[sujeto(['To', 'date,', there, is, only, one]), verbo([report]), complemento([except, our, 'case,', which, described, the, correlation, between, 'FDG-PET', and, nivolumab])].
[sujeto(['We']), verbo([report]), complemento([on, a, 75, -, 'year-old', man, on, nivolumab, treatment, for, metastatic, 'non-small', cell, lung, cancer])].
[sujeto(['He', underwent, chemotherapy, with, a, combination, of, cisplatin, and, pemetrexed, for, four, cycles, but, developed, progressive, disease]), verbo([involving]), complemento([the, right, 'hemithorax,', multiple, lymph, 'nodes,', and, multiple, osseous, sites])].
[sujeto(['After', six, courses, of, this, 'immunotherapy,', 'FDG-PET', scan, showed]), verbo([decreased]), complemento(['FDG', uptake, in, each, recurrent, lesion, despite, 'T', lymphocyte, activation, by, nivolumab])].
[sujeto(['The', issue, addressed, in, this, chapter, of, recommendations, 'is:', 'What', is, the, clinical, and, 'para-clinical', assessment, to, achieve, in, women, with, genital, prolapse, and, for, whom, surgical, treatment]), verbo([has]), complemento([been, decided])].
[sujeto(['Its', implementation]), verbo([has]), complemento([followed, the, methodology, of, the, 'HAS', on, the, recommendations, for, clinical, 'practice,', with, a, scientific, argument, '(', with, the, level, of, 'evidence,', 'NP)', and, a, recommendation, grade, '(', 'A,', 'B,', 'C,', and, professional, agreement, '[', 'AP])'])].
[sujeto(['It', suits, first, of, all, to, describe, 'prolapse,', by, clinical, 'examination,', 'helped,', if, 'needed,', by, a, supplement, of, imagery, if, clinical, examination, data, are, insufficient, or, in, case, of, discrepancy, between, the, functional, signs, and, clinical, anomalies, 'found,', or, in, case, of, doubt, in]), verbo([associated]), complemento([pathology])].
[sujeto(['Urinary', functional, disorders]), verbo([associated]), complemento([with, prolapse, '(', urinary, 'incontinence,', overactive, 'bladder,', 'dysuria,', urinary, tract, 'infection,', upper, urinary, tract, 'impact)', will, be, search, and, evaluated, by, interview, and, clinical, examination, and, by, a, flowmeter, with, measurement, of, the, post, voiding, 'residue,', a, 'urinalysis,', and, 'renal-bladder', ultrasound])].
[sujeto(['Anorectal', symptoms]), verbo([associated]), complemento([with, prolapse, '(', irritable, bowel, 'syndrome,', obstruction, of, 'defecation,', fecal, 'incontinence)', should, be, search, and, evaluated])].
[sujeto(['Before', proposing, a, surgical, cure, of, genital, prolapse, of, 'women,', it, suits, to, achieve, a, clinical, and, paraclinical, assessment, to, describe, prolapse, '(', anatomical, structures, 'involved,', 'grade),', to, look, for, 'recurrence,', difficulties, approach, and, postoperative, complications, risk, 'factors,', and, to, appreciate, the, impact, or, the, symptoms]), verbo([associated]), complemento([with, prolapse, '(', 'urinary,', 'anorectal,', 'gynecological,', 'pelvic-perineal', 'pain)', to, guide, their, evaluation, and, their, treatment])].
[sujeto(['Micro-environmental', factors, '(', specific, features, within, a, 'streetscape),', instead, of, 'macro-environmental', factors, '(', urban, planning, 'features),', are, more, feasible, to, modify, in, existing, neighborhoods, and, thus, more, practical, to]), verbo([target]), complemento([for, environmental, interventions])].
[sujeto(['Because', it, is, often, not, possible, to, change, the, whole, 'micro-environment', at, 'once,', the, current, study, aims, to, determine, which, 'micro-environmental', factors, should, get, the, priority, to]), verbo([target]), complemento([in, physical, environmental, interventions, increasing, bicycle, transport])].
[sujeto(['Providing', streets, with, a, cycle, path, separated, from, motorized, traffic, seems, to, be, the, best, strategy, to]), verbo([increase]), complemento([the, 'street\'s', appeal, for, 'adults\'', bicycle, transport])].
[sujeto([speed, 'limit,', traffic, 'density)', may, be, more, effective, in]), verbo([promoting]), complemento([bicycle, transport, than, 'micro-environmental', factors, related, to, comfort, '(', i])].
[sujeto(['Findings', obtained, from, this, research, could]), verbo([provide]), complemento([advice, to, physical, environmental, interventions, about, which, environmental, factors, should, get, priority, to, modify, in, different, environmental, situations])].
[sujeto(['The', critical, role, of, continuing, professional, development, '(', 'CPD)', in, supporting, delivery, of, patient, care, of, the, highest, quality, and, safety, is, receiving, significant, attention, in, the, current]), verbo([era]), complemento([of, monumental, change])].
[sujeto(['CPD', is, essential, in, efforts, to]), verbo([ensure]), complemento([effectiveness, of, new, models, of, health, care, 'delivery,', improve, outcomes, and, value, in, health, 'care,', address, external, 'regulations,', and, foster, patient, engagement])].
[sujeto(['The', unique, features, of, 'CPD;', the, use, of, special, 'mastery-based', 'teaching,', 'learning,', and, assessment, 'methods,', and, other, special, interventions, to]), verbo([promote]), complemento(['excellence;', and, direct, involvement, of, a, variety, of, key, stakeholders, differentiate, 'CPD', from, undergraduate, medical, education, and, graduate, medical, education])].
[sujeto(['The', needs, of, procedural, specialties, relating, to, 'CPD', are, different, from, those, of, primary, care, disciplines, and]), verbo([require]), complemento([special, attention, for, the, greatest, impact])].
[sujeto(['Simulation-based', education, and, training, can, be, very, useful, in, 'CPD', aimed, at, improving, outcomes, and]), verbo([promoting]), complemento([patient, safety])].
[sujeto(['This', change, is, a, normal, physiological, adaptation, to, better, accommodate, the, foetal, growth, and]), verbo([provides]), complemento([adequate, 'blood,', nutrition, and, oxygen])].
[sujeto(['Early', gestational, period, is, considered, as, an, anabolic, 'phase,', in, which, female, body, stores, 'nutrients,']), verbo([enhance]), complemento([insulin, sensitivity, to, encounter, the, maternal, and, 'feto-placental', demands, of, late, gestation, and, lactation])].
[sujeto(['However,', if, the, maternal, metabolic, physiology, during, pregnancy, is, 'disturbed,', it, can]), verbo([cause]), complemento([hormonal, 'imbalance,', fat, 'accumulation,', decreased, insulin, 'sensitivity,', increased, insulin, resistance, and, even, gestational, diabetes, mellitus])].
[sujeto(['Sequence', analyses, of, the, 'D1/D2', domains, of, the, large, subunit, '(', 'LSU)', rRNA, gene, and, internal]), verbo([transcribed]), complemento([spacer, '(', 'ITS)', region, indicated, that, the, novel, species, belongs, to, the, recently, resurrected, genus, 'Apiotrichum,', and, is, most, closely, related, to, 'Apiotrichum', 'scarabaeorum,', a, 'beetle-associated', species, first, found, in, 'South', 'Africa'])].
[sujeto([s, 'No', statistical, significance, was]), verbo([found]), complemento([in, the, synovial, thickness, of, the, wrist, 'joints,', 'MCP', joints, and, 'PIP', joints, between, the, left, and, right, 'hands,', between, young, '(', &, 'lt;40', 'years)', and, 'middle-aged', '(', '≥40', 'years)', 'subjects,', or, between, the, flexor, surface, and, the, extensor, surface])].
[sujeto(['We']), verbo([report]), complemento([a, case, of, 'MEN1', concomitant, with, pheochromocytoma])].
[sujeto(['Although', a, newly, formed, liver, metastasis, was]), verbo([found]), complemento([19, &, 'nbsp;months', after, the, 'hepatectomy,', he, is, still, alive, 4, &, 'nbsp;years', and, 4, &, 'nbsp;months', after, the, initial, surgery])].
[sujeto(['We']), verbo([reported]), complemento([an, extremely, rare, case, of, giant, insulinoma, and, simultaneous, occurrence, of, pheochromocytoma, and, adrenal, cortical, adenoma, in, the, ipsilateral, adrenal, gland, in, a, patient, clinically, and, genetically, diagnosed, as, having, 'MEN1'])].
[sujeto(['UAS', therapy, results, in, surgical, success, '(', 'AHI']), verbo([decrease]), complemento([of, &, 'gt;50%', and, overall, 'AHI', &, 'lt;=', 20, ')', in, 66, '%', of, implanted, subjects])].
[sujeto(['Rice', ragged, stunt, disease]), verbo([caused]), complemento([leads, to, severe, loss, of, rice, yield])].
[sujeto(['Recently,', rice, ragged, stunt, virus, '(', 'RRSV)', were]), verbo([found]), complemento([to, be, increasingly, common, in, 'rice-growing', regions, of, 'China', and, 'Vietnam'])].
[sujeto(['RRSV', may]), verbo([cause]), complemento([problem, by, interacting, with, microRNAs, '(', 'miRNAs)', of, host, cells, and, the, mechanism, is, not, clear, yet])].
[sujeto(['In', this, study, we, identified, 11, miRNAs, in, response, to, 'RRSV', infection, and, predicted, their, possible]), verbo([targets]), complemento([to, viral, 'RNA', segments, '(', 'S1-S10)', through, the, bioinformatics, analysis])].
[sujeto(['Interestingly,', we]), verbo([found]), complemento([that, 'Osa-miR-168b', might, bind, to, both, the, 'CDS', region, and, 3, '\'', 'UTR', of, 'S5', and, 'S8', and, target, 'eEF-1A', to, inhibit, the, activity, of, host, cells, to, facilitate, 'RRSV', replication])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, miRNAs, may, be, a, potential, target, for, developing, rice, against, 'RRSV', infection])].
[sujeto(['Using', stable, isotope, 'analysis,', we, investigated, trophic, interactions, between, indigenous, benthic, taxa, and, the, 'non-indigenous', species, '(', 'NIS):', the, green, alga, 'Caulerpa', 'cylindracea,', the, red, alga, 'Asparagopsis', 'taxiformis,', the, crab, 'Percnon', gibbesi, and, the]), verbo([sea]), complemento([hare, 'Aplysia', dactylomela])].
[sujeto(['Caulerpa', cylindracea]), verbo([provided]), complemento([the, largest, contribution, to, the, diet, of, 'P'])].
[sujeto([&, 'nbsp;cylindracea', is]), verbo([increasing]), complemento([the, diversity, of, available, prey, and, might, facilitate, the, expansion, of, other, 'NIS'])].
[sujeto(['Adolescent', 'pregnancy,', particularly, unintended, 'pregnancy,', can]), verbo([have]), complemento([lasting, 'social,', 'economic,', and, health, outcomes])].
[sujeto(['The', objective, of, this, review, is, to, identify, 'high-quality', interventions, and, evaluations, to]), verbo([decrease]), complemento([unintended, and, repeat, pregnancy, among, young, people, in, 'low-', and, 'middle-income', countries])].
[sujeto(['Nine']), verbo([reported]), complemento([statistically, significant, declines, in, pregnancy, rates, '(', five, cash, transfer, 'programs,', one, education, 'curriculum,', two, 'life-skills', 'curricula,', and, a, provision, of, contraception, 'intervention),', seven, reported, increases, in, contraceptive, use, '(', three, provision, of, contraception, 'interventions,', two, 'life-skills', 'curricula,', a, peer, education, 'program,', and, a, mass, media, 'campaign),', two, reported, decreases, in, sexual, activity, '(', a, cash, transfer, program, and, an, education, and, 'life-skills', 'curriculum),', and, two, reported, an, increase, in, age, of, sexual, debut, '(', both, cash, transfer, 'programs)'])].
[sujeto(['The', selected, high, 'quality,', effective, interventions, included, in, this, review, can, inform, 'researchers,', 'donors,', and, policy, makers, about, where, to, make, strategic, investments, to]), verbo([decrease]), complemento([unintended, pregnancy, during, young, adulthood])].
[sujeto(['The', diversity, of, successful, 'high-quality', 'interventions,', implemented, in, a, range, of, 'venues,', with, a, diversity, of, young, 'people,']), verbo([suggests]), complemento([that, there, are, multiple, strategies, that, can, work, to, prevent, unintended, pregnancy])].
[sujeto(['The', rice, blast, fungus]), verbo([causes]), complemento([significant, annual, harvest, losses])].
[sujeto(['Whilst', pathogenicity, determinants]), verbo([have]), complemento([been, unmasked, and, changes, in, global, gene, expression, 'described,', we, know, little, about, 'Magnaporthe', oryzae, cell, wall, remodelling])].
[sujeto(['Our', 'interests,', in, wall, remodelling, genes]), verbo([expressed]), complemento([during, 'infection,', vegetative, growth, and, under, exogenous, wall, 'stress,', demand, robust, choice, of, reference, genes, for, quantitative, 'Real', 'Time-PCR', '(', 'qRT-PCR)', data, normalisation])].
[sujeto(['Our', 'Minimum', 'Information', for, 'Publication', of, 'qRT-PCR', 'Experiments', '(', 'MIQE)', compliant, analysis]), verbo([reveals]), complemento([a, set, of, robust, reference, genes, used, to, track, changes, in, the, expression, of, the, cell, wall, remodelling, gene, 'MGG_Crh2', '(', 'MGG_00592)'])].
[sujeto(['We', ranked, nine, candidate, reference, genes, by, their, expression, stability, '(', 'M)', and]), verbo([report]), complemento([the, best, gene, combination, needed, for, reliable, gene, expression, 'normalisation,', when, assayed, in, three, tissue, groups, '(', 'Infective,', 'Vegetative,', and, 'Global)', frequently, used, in, 'M'])].
[sujeto(['We']), verbo([found]), complemento([that, 'MGG_Actin', '(', 'MGG_03982)', and, the, 40, 'S', 27, a, ribosomal, subunit, 'MGG_40s', '(', 'MGG_02872)', proved, to, be, robust, reference, genes, for, the, 'Infection', group, and, 'MGG_40s', and, 'MGG_Ef1', '(', 'Elongation', 'Factor1-α)', for, both, 'Vegetative', and, 'Global', groups])].
[sujeto([oryzae, 'MGG_Crh2', expression, was]), verbo([found]), complemento([to, be, significantly, '(', 'p<0'])].
[sujeto(['By', 'contrast,', metabolic, pathway, genes, 'MGG_Fad', '(', 'FAD']), verbo([binding]), complemento(['domain-containing', 'protein)', and, 'MGG_Gapdh', '(', 'Glyceraldehyde-3-phosphate', 'dehydrogenase)', performed, 'poorly,', due, to, their, lack, of, expression, stability, across, samples])].
[sujeto(['With', the, 'American', 'Ophthalmological', 'Society', and, the, 'American', 'Academy', of, 'Ophthalmology', and, 'Otolaryngology,', the, 'AMA\'s', contributions, to, the, formation, of, the, 'American', 'Board', of, 'Ophthalmology']), verbo([led]), complemento(['to the', establishment, of, sound, educational, standards, for, practicing, ophthalmologists, and, helped, to, advance, 'the culture', of, medical, excellence, within, the, profession, that, is, synonymous, with, board, certification, today])].
[sujeto(['Carbon', capture, and, storage, is]), verbo([promoted]), complemento([as, a, mitigation, method, counteracting, the, increase, of, atmospheric, 'CO2', levels])].
[sujeto([edule, was, significantly]), verbo([increased]), complemento([in, the, highest, treatment, '(', 24, ',', 400, 'μatm)', and, exceeded, 50, '%'])].
[sujeto(['Furthermore,', mortality, of, small, size, classes, '(', 0, -, 1, 'cm)', was, significantly]), verbo([increased]), complemento([in, treatment, levels, '≥6,600', μatm])].
[sujeto([edule, body, condition]), verbo([decreased]), complemento([significantly, at, all, treatment, levels, '(', 1, ',', 500, -, 24, ',', 400, 'μatm)'])].
[sujeto(['Gastropoda', and, 'Ostracoda)']), verbo([decreased]), complemento([in, high, 'CO2', treatments, '(', &, 'gt;6,600', 'μatm),', while, the, non, -, calcifying, 'Gastrotricha', significantly, increased, in, abundance, at, 24, ',', 400, μatm])].
[sujeto(['The', taxonomy, of, the, 'Cladophoraceae,', a, large, family, of, filamentous, green, 'algae,']), verbo([has]), complemento([been, problematic, for, a, long, time, due, to, morphological, 'simplicity,', parallel, 'evolution,', phenotypic, plasticity, and, unknown, distribution, ranges])].
[sujeto(['There']), verbo([have]), complemento([been, at, least, three, independent, switches, between, branched, and, unbranched, morphologies, within, the, 'Cladophoraceae'])].
[sujeto(['Freshwater', environments]), verbo([have]), complemento([been, colonised, twice, 'independently,', namely, by, the, freshwater, 'Cladophora', species, as, well, as, by, several, lineages, of, the, 'Rhizoclonium', riparium, clade])].
[sujeto(['Individuals', were, initially, identified, to, species, and, genotyped, using, the, ribosomal, 'DNA', second, internal]), verbo([transcribed]), complemento([spacer])].
[sujeto(['DNA', sequencing, of, a, single, copy]), verbo([nuclear]), complemento([ribosomal, protein, 'S9', and, the, mitochondrial, cytochrome, oxidase, 'I', loci, were, then, investigated, and, 12, nuclear, microsatellite, markers, were, developed, and, analysed])].
[sujeto(['Genetic', differentiation, within, 'Papua', 'New', 'Guinea', was, much, lower, than, that]), verbo([found]), complemento([in, studies, of, other, closely, related, species, in, the, region])].
[sujeto(['The', data, does]), verbo([suggest]), complemento([that, 'A'])].
[sujeto([punctulatus]), verbo([has]), complemento([undergone, a, population, bottleneck, followed, by, a, recent, population, and, range, expansion, in, 'Papua', 'New', 'Guinea'])].
[sujeto(['We', therefore, anticipate, extensive, movement, of, this, species, through, 'New', 'Guinea--particularly', into, the, 'highlands,', with, a, potential]), verbo([increase]), complemento([in, malaria, frequency, in, a, warming, 'climate--as', well, as, relatively, unrestricted, gene, flow, of, advantageous, alleles, that, may, confound, vector, control, efforts])].
[sujeto(['Australia', and, 'New', 'Guinea', contain, high, levels, of, endemism, and, 'biodiversity,', yet, there]), verbo([have]), complemento([been, few, evaluations, of, 'population-level', genetic, diversity, in, fauna, occurring, throughout, the, 'Australo-Papuan', region])].
[sujeto([&, 'nbsp;irenicus', throughout, their, ranges, in, the, southwest, 'Pacific', using, mitochondrial, '(', mtDNA, 'COI)', and]), verbo([nuclear]), complemento(['(', ribosomal, protein, 'S9', and, ribosomal, 'DNA', 'ITS2)', loci])].
[sujeto(['Phylogenetic', analyses]), verbo([suggest]), complemento([that, the, ability, to, utilize, humans, as, hosts, has, been, lost, 'repeatedly,', coincident, with, independent, colonizations, of, the, 'Solomon', 'Islands'])].
[sujeto(['Maximum', likelihood, and, 'Bayesian', phylogenetic, analyses, of]), verbo([nuclear]), complemento([loci, also, showed, that, the, three, species, are, monophyletic])].
[sujeto([&, 'nbsp;hinesorum', mtDNA, onto, a]), verbo([nuclear]), complemento([background, of, 'An'])].
[sujeto(['Atovaquone,', a, 'hydroxynaphthoquinone,', is, an, 'anti-parasite', 'drug,', selectively]), verbo([targeting]), complemento([the, mitochondrial, respiratory, chain, of, malaria, parasite])].
[sujeto(['Although', atovaquone]), verbo([has]), complemento([not, often, been, associated, with, severe, adverse, reactions, in, the, recommended, dosages, and, has, a, relatively, favorable, side, effect, 'profile,', the, present, study, was, undertaken, to, evaluate, its, cytogenotoxic, potential, towards, human, peripheral, blood, lymphocytes])].
[sujeto(['Two', different, concentrations, of, atovaquone]), verbo([found]), complemento([in, plasma, when, used, in, 'fixed-dose', combination, with, proguanile, hydrochloride, were, used, with, and, without, 'S9', metabolic, 'activation:', 2950, ng, 'ml(-1)', used, for, prophylactic, treatment, and, 11, 800, ng, 'ml(-1)', used, in, treatment, of, malaria])].
[sujeto(['The', results, showed, that, lymphocyte, viability, was, not, affected, after, the, 'treatment,']), verbo([suggesting]), complemento([that, atovaquone, was, not, cytotoxic, in, the, given, concentrations])].
[sujeto(['There', were, no, differences, in, tested, parameters, with, the, addition, of, 'S9', metabolic, 'activation,', indicating, that, atovaquone, either]), verbo([has]), complemento([no, metabolite, or, it, is, not, toxic, in, the, given, concentrations])].
[sujeto(['Benzo(a)pyrene', '(', 'BaP)']), verbo([has]), complemento([been, shown, to, be, an, inducer, of, apoptosis])].
[sujeto(['However,', mechanisms]), verbo([involved]), complemento([in, 'BaP-induced', mitochondrial, dysfunction, are, not, 'well-known'])].
[sujeto(['Cell', 'viability,', intracellular, level, of, reactive, oxygen, species, '(', 'ROS),', total, antioxidant, capacity, '(', 'T-AOC),', mitochondrial, membrane, potential, '(', 'ΔΨ(m))', and, cytochrome, c]), verbo([release]), complemento([were, determined])].
[sujeto(['At', time, point, of, 4, 'h,', 'BaP']), verbo([induced]), complemento([the, intracellular, 'ROS', generation, in, 64, '(', p, &, 'lt;'])].
[sujeto([1, ')', but]), verbo([decreased]), complemento([the, 'T-AOC', activities, in, 32, ',', 64, '(', p, &, 'lt;'])].
[sujeto(['At', time, point, of, 12, 'h,', 'ΔΨ(m)', significantly]), verbo([decreased]), complemento([in, '≥32', μM, 'BaP', groups, '(', p, &, 'lt;'])].
[sujeto(['Amount', of, mitochondrial, cytochrome, c, significantly]), verbo([increased]), complemento([in, 128, μM, 'BaP', group, '(', p, &, 'lt;'])].
[sujeto(['The', results, indicate, that, in, the, earlier, period, 'BaP']), verbo([promoted]), complemento([the, generation, of, excessive, 'ROS', and, subsequently, the, mitochondrial, 'depolarization,', whereas, transactivations, of, the, 'p53-dependent', apoptotic, genes, were, significantly, induced, at, the, later, period])].
[sujeto(['Heat', stress, perturbs, prolactin, '(', 'PRL)']), verbo([release]), complemento([and, affects, dairy, cow, lactational, performance, and, immune, cell, function])].
[sujeto(['We', hypothesized, that, greater, 'PRL', concentration, in, plasma, of, 'heat-stressed', cows, relative, to, cooled, cows, would]), verbo([decrease]), complemento([expression, of, prolactin, receptor, '(', 'PRL-R)', mRNA, and, increase, mRNA, expression, of, suppressors, of, cytokine, signaling, '(', 'SOCS)', in, 'lymphocytes,', altering, their, cytokine, production])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, changes, in, 'PRL-signaling', pathway, genes, during, heat, stress, are, associated, with, differential, cytokine, secretion, by, lymphocytes, and, may, regulate, lymphocyte, proliferation, in, dairy, cows])].
[sujeto([gondii, apicoplast, proteins, often]), verbo([have]), complemento([a, long, 'N-terminal', extension, that, directs, the, protein, to, the, apicoplast])].
[sujeto(['It', can, be, modeled, as, a, bipartite]), verbo([targeting]), complemento([sequence, that, contains, a, signal, sequence, and, a, plastid, transit, peptide])].
[sujeto(['We', identified, two, nuclearly, encoded, predicted, plastid, proteins, and, made, fusions, with, green, fluorescent, protein, to, study, protein, domains]), verbo([required]), complemento([for, apicoplast, targeting])].
[sujeto(['The', 'N-terminal', 42, amino, acids, of, the, apicoplast, ribosomal, protein, 'S9', directs, secretion, of, green, fluorescent, 'protein,', indicating, that]), verbo([targeting]), complemento([to, the, apicoplast, proceeds, through, the, secretory, system])].
[sujeto(['The', predicted, transit, peptide, domain, of, the, 'S9']), verbo([targeting]), complemento([sequence, directs, protein, to, the, mitochondrion, in, vivo])].
[sujeto(['These', data, substantiate, the, model, that, protein]), verbo([targeting]), complemento([to, the, apicoplast, involves, two, distinct, 'mechanisms:', the, first, involving, the, secretory, system, and, the, second, sharing, features, with, typical, chloroplast, protein, import])].
[sujeto(['A', 'Candida', albicans, mitochondrial, ribosomal, protein, 'S9', '(', 'MRPS9)', cDNA, was, identified, in, a, screen, for, sequences, whose, expression]), verbo([induce]), complemento([galactose, lethality, in, 'Saccharomyces', cerevisiae])].
[sujeto(['MRPS9', appears, to, encode, a, protein, of, 346, amino, acids, with, an, 'N-terminal', mitochondrial]), verbo([targeting]), complemento([sequence, and, an, internal, 'S9', signature, that, is, conserved, amongst, eukaryotic, mitochondrial, and, prokaryotic, ribosomal, protein, 'S9', sequences])].
[sujeto([cerevisiae]), verbo([caused]), complemento([the, slow, development, of, a, 'galactose-negative', phenotype, upon, repeated, 'subculturing,', and, this, correlated, with, an, increased, frequency, of, petite, mutant, formation])].
[sujeto(['The', 'Saccharomyces', cerevisiae]), verbo([nuclear]), complemento([gene, 'MRP-S9', was, identified, as, part, of, the, 'European', effort, in, sequencing, chromosome, 'II'])].
[sujeto(['Cells', disrupted, in, the, chromosomal, copy, of, 'MRP-S9', were, unable, to, respire, and, displayed, a, characteristic, phenotype, of, mutants, with, defects, in, mitochondrial, protein, synthesis, as, indicated, by, a]), verbo([loss]), complemento([of, cytochrome, c, oxidase, activity])].
[sujeto(['The', 'respiration-deficient', phenotype, could, not, be, restored, by, transformation, of, the, disruption, strain, with, a, 'wild-type', copy, of, 'MRP-S9,', indicating, that, 'MRP-S9', disruption]), verbo([led]), complemento([to, 'rho-', or, rho0, cells])].
[sujeto(['The', deletion, results, in, a]), verbo([loss]), complemento([of, the, 'POU3F3', and, 'MRPS9', genes])].
[sujeto(['We']), verbo([report]), complemento([here, the, characterization, of, 'Kluyveromyces', marxianus, 'ADH2', and, the, five, genes, found, in, its, immediate, downstream, 'region,', 'MRPS9,', 'YOL087C,', 'RPB5,', 'RIB7', and, 'SPP381'])].
[sujeto(['On', the, one, 'hand,', the, two, genes]), verbo([found]), complemento([immediately, downstream, of, 'KmADH2', are, 'located,', for, the, 'first,', downstream, 'ADH5', 'and,', for, the, 'second,', downstream, 'ADH1', in, 'S'])].
[sujeto([cerevisiae]), verbo([suggests]), complemento([that, two, of, them, have, been, inverted, within, one, block, after, its, 'formation,', and, that, inversion, is, confirmed, by, the, gene, order, observed, in, 'K'])].
[sujeto(['Here,', we]), verbo([provide]), complemento([evidence, for, differential, translation, of, mitochondrial, transcripts, in, 'Arabidopsis', thaliana])].
[sujeto(['We']), verbo([found]), complemento([that, silencing, of, the, nuclear, 'RPS10', gene, encoding, mitochondrial, ribosomal, protein, 'S10', disturbs, the, ratio, between, the, small, and, large, subunits, of, 'mitoribosomes,', with, an, excess, of, the, latter])].
[sujeto([rps10, cells, also]), verbo([have]), complemento([an, increased, mitochondrial, 'DNA', copy, number, per, 'cell,', causing, an, upregulation, of, all, mitochondrial, transcripts])].
[sujeto(['The', ultimate, coordination, of, expression, of, the]), verbo([nuclear]), complemento([and, mitochondrial, genomes, occurs, at, the, complex, assembly, level])].
[sujeto(['These', findings, indicate, that, mitoribosomes, can]), verbo([regulate]), complemento([gene, expression, by, varying, the, efficiency, of, translation, of, mRNAs, for, 'OXPHOS', and, ribosomal, proteins])].
[sujeto(['However,', some, 'RNA', editing, events, are]), verbo([found]), complemento([in, 'non-coding', regions, at, critical, positions, in, the, predicted, secondary, and, tertiary, structures, of, 'introns,', suggesting, that, 'RNA', editing, could, be, important, for, splicing])].
[sujeto(['Here,', we, studied, the, relationships, between, editing, and, splicing, of, the, mRNA, encoding, the, ribosomal, protein, 'S10', '(', 'rps10),', which]), verbo([has]), complemento([a, group, 'II', intron, and, five, editing, sites])].
[sujeto(['While', mutations, of, 'C2']), verbo([involved]), complemento([in, 'EBS2/IBS2', interactions, did, not, affect, 'splicing,', probably, by, the, presence, of, an, alternative, 'EBS2\'', region, in, domain, 'I', of, the, 'intron,', the, edition, of, site, 'C3', turned, out, to, be, critical, for, rps10, mRNA, 'splicing;', only, the, edited, '(', 'U)', form, of, the, transcript, was, processed])].
[sujeto(['Interestingly,', 'RNA', editing, was, strongly, reduced, in, transcripts, from, two, different, intronless, 'genes,', rps10, from, potato, and, cox2, from, 'wheat,']), verbo([suggesting]), complemento([that, efficient, 'RNA', processing, may, require, a, close, interaction, of, factors, engaged, in, different, maturation, processes])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([linking, editing, and, splicing, in, conditions, close, to, the, in, vivo, situation])].
[sujeto(['Ribosomal', protein, 10, of, the, small, subunit, is, encoded, in, the, mitochondrion, in, soybean, and, many, other, 'angiosperms,', whereas, in, several, other, species, it, is]), verbo([nuclear]), complemento([encoded, and, thus, must, be, imported, into, the, mitochondrial, matrix, to, function])].
[sujeto(['When', encoded, by, the]), verbo([nuclear]), complemento(['genome,', it, has, adopted, different, strategies, for, mitochondrial, targeting, and, import])].
[sujeto(['In', maize, '(', 'Zea', 'mays),', 'Rps10']), verbo([has]), complemento([not, acquired, an, extension, upon, transfer, but, can, be, readily, imported, into, mitochondria])].
[sujeto(['Deletion', analysis, located, the, mitochondrial]), verbo([targeting]), complemento([region, to, the, first, 20, amino, acids])].
[sujeto(['Using', site, directed, 'mutagenesis,', we, changed, residues, in, the, first, 20, amino, acids, of, the, mitochondrial, encoded, soybean, '(', 'Glycine', 'max)', rps10, to, the, corresponding, amino, acids, in, the]), verbo([nuclear]), complemento([encoded, maize, 'Rps10', until, import, was, achieved])].
[sujeto(['Changes', were]), verbo([required]), complemento([that, altered, 'charge,', 'hydrophobicity,', predicted, ability, to, form, an, amphipathic, 'alpha-helix,', and, generation, of, a, binding, motif, for, the, outer, mitochondrial, membrane, 'receptor,', translocase, of, the, outer, membrane, 20])].
[sujeto(['In', addition, to, defining, the, changes]), verbo([required]), complemento([to, achieve, mitochondrial, 'localization,', the, results, demonstrate, that, even, proteins, that, do, not, present, barriers, to, import, can, require, substantial, changes, to, acquire, a, mitochondrial, targeting, signal])].
[sujeto(['Most', of, this, transfer, occurred, early, in, mitochondrial, 'evolution;', functional, transfer, of, mitochondrial, genes]), verbo([has]), complemento([ceased, in, animals])].
[sujeto(['Although', mitochondrial, gene, transfer, continues, to, occur, in, 'plants,', no, comprehensive, study, of, the, frequency, and, timing, of, transfers, during, plant, evolution]), verbo([has]), complemento([been, conducted])].
[sujeto(['Here', we]), verbo([report]), complemento([frequent, loss, '(', 26, 'times)', and, transfer, to, the, nucleus, of, the, mitochondrial, gene, rps10, among, 277, diverse, angiosperms])].
[sujeto(['Characterization', of]), verbo([nuclear]), complemento([rps10, genes, from, 16, out, of, 26, loss, lineages, implies, that, many, 'independent,', 'RNA-mediated', rps10, transfers, occurred, during, recent, angiosperm, 'evolution;', each, of, the, genes, may, represent, a, separate, functional, gene, transfer])].
[sujeto(['Thus,', rps10]), verbo([has]), complemento([been, transferred, to, the, nucleus, at, a, surprisingly, high, rate, during, angiosperm, evolution])].
[sujeto(['The', structures, of, several]), verbo([nuclear]), complemento([rps10, genes, reveal, diverse, mechanisms, by, which, transferred, genes, become, 'activated,', including, parasitism, of, 'pre-existing', nuclear, genes, for, mitochondrial, or, cytoplasmic, 'proteins,', and, activation, without, gain, of, a, mitochondrial, targeting, sequence])].
[sujeto(['Here', we, show, that, the, rps10, gene, is, absent, from, the, mitochondrial, genome, of, rice, and]), verbo([has]), complemento([been, transferred, to, the, nucleus])].
[sujeto(['Cloning', and, transcriptional, analysis, show, that, there, are, two, rps10, genes, in, the, rice]), verbo([nuclear]), complemento([genome, and, that, their, transcripts, differ, in, abundance])].
[sujeto(['Western', analysis, detected, the, 'RPS10', protein, in, the, soluble, fraction, of, rice, 'mitochondria,', although, neither, 'RPS10']), verbo([has]), complemento([any, obvious, 'N-terminal', presequence, for, targeting, to, mitochondria])].
[sujeto(['This', result]), verbo([suggests]), complemento([that, targeting, information, is, present, in, the, internal, region, of, rice, 'RPS10'])].
[sujeto(['Genomic', sequence, analysis, indicated, that, each, rps10, gene]), verbo([has]), complemento([an, intron, in, the, 5, '\'', untranslated, region, '(', 5, '\'', 'UTR)', and, that, these, intron, sequences, are, homologous, to, each, other])].
[sujeto(['This', result, strongly]), verbo([suggests]), complemento([that, a, duplication, event, occurred, after, transfer, of, the, rps10, gene, to, the, nucleus])].
[sujeto(['The', duplicated, rps10, genes]), verbo([have]), complemento([since, been, translocated, to, different, 'chromosomes,', because, the, two, rps10, genes, were, mapped, on, chromosomes, 6, and, 12, by, 'RFLP', analysis])].
[sujeto(['Interestingly,', the, 5, '\'', 'UTR', and, the, intron, of, the, rice, rps10, genes, are, homologous, to, sequences]), verbo([found]), complemento([in, several, rice, genes, with, various, 'functions,', such, as, 'osk4,', 'EF-1beta2', and, 'RAG1,', suggesting, a, common, origin, and, a, functional, role, for, the, 5, '\'', 'UTR'])].
[sujeto(['Acquisition', of, the, 5, '\'', flanking, region, might]), verbo([have]), complemento([accelerated, the, activation, of, the, mitochondrial, rps10, gene, which, was, transferred, to, the, nuclear, genome])].
[sujeto(['An', approach, towards, the, identification, at, the, protein, level, of, the, ribosomal, proteins, encoded, by, the, mitochondrial, genome, of, broad, bean, '(', 'Vicia', 'faba)']), verbo([has]), complemento([been, developed])].
[sujeto(['Rps10,', a, gene, coding, for, ribosomal, protein, 'S10', of, 'Arabidopsis', mitochondria]), verbo([has]), complemento([been, transferred, to, the, nuclear, 'compartment,', while, in, pea, and, potato, the, active, rps10, is, mitochondrially, located])].
[sujeto(['The']), verbo([nuclear]), complemento([rps10, gene, contains, an, intron, at, the, junction, of, the, target, signal, sequence, and, the, 'mitochondrial-derived', 'sequence,', indicating, that, exon, shuffling, may, have, been, involved, in, the, addition, of, the, transit, peptide, signal])].
[sujeto(['This']), verbo([finding]), complemento([corroborates, 'RNA', as, an, intermediate, of, a, functional, gene, transfer, between, mitochondria, and, the, nucleus])].
[sujeto(['The', structure, and, expression, of, the, potato, mitochondrial, gene, 'rps10,', encoding, ribosomal, protein, 'S10,']), verbo([has]), complemento([been, characterized])].
[sujeto(['All', these, changes]), verbo([increase]), complemento([the, similarity, between, the, potato, and, liverwort, polypeptides])].
[sujeto(['One', additional, 'C-to-U', 'RNA', editing, 'event,', observed, in, the, intron, sequence, of, unspliced, 'cDNAs,', improves, the, stability, of, the, secondary, structure, in, stem, 'I', '(', 'i)', of, domain, 'I', and, may, thus, be]), verbo([required]), complemento([for, the, splicing, reaction])].
[sujeto(['All', spliced, 'cDNAs,', and, most, unspliced, 'cDNAs,', were, completely, 'edited,']), verbo([suggesting]), complemento([that, editing, is, an, early, step, of, rps10, mRNA, processing, and, precedes, splicing])].
[sujeto(['A', novel, group, 'II', intron]), verbo([has]), complemento([been, identified, in, the, pea, '(', 'Pisum', 'sativum)', mitochondrial, genome])].
[sujeto(['The', rps10, gene, is]), verbo([transcribed]), complemento([in, 'pea,', the, intron, is, 'removed,', and, 'RNA', editing, in, the, rps10, reading, frame, increases, similarity, to, its, homologue, in, the, 'M'])].
[sujeto(['The', 'S10', ribosomal, protein, gene, '(', 'rps10),', which]), verbo([has]), complemento([not, been, previously, reported, in, any, angiosperm, mitochondrial, 'genome,', was, identified, by, sequence, analysis, in, the, potato, mitochondrial, 'DNA'])].
[sujeto(['This', gene, is]), verbo([found]), complemento([downstream, of, a, truncated, 'non-functional', apocytochrome, b, '(', 'cob)', 'pseudogene,', and, is, expressed, as, multiple, transcripts, ranging, in, size, from, 0.8, to, 5.0, kb])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, functional, genes, coding, for, wheat, and, pea, mitochondrial, 'RPS10', polypeptides, have, been, translocated, to, the, nucleus])].
[sujeto(['Few']), verbo([reports]), complemento([have, shown, the, influence, of, individual, variability, in, identifying, the, genes, associated, with, 'depressive-like', behaviors])].
[sujeto(['In', this, 'study,', we, conducted, microarray, analysis, to, identify, genes, differentially]), verbo([expressed]), complemento([in, the, prefrontal, cortex, '(', 'PFC)', and, cerebellum, of, rats, stratified, by, 'FST', immobility, ratio, '(', '%', immobility, in, 5, 'min)', into, a, control, group, '[', immobility, 'ratio:', -, 1, to, +, 1, standard, deviation, '(', 'SD)', from, the, 'mean]', and, a, depressive, group, '(', immobility, 'ratio:', +, 1, to, +, 2, 'SDs', above, the, 'mean)'])].
[sujeto(['Genes', differentially]), verbo([expressed]), complemento([in, both, the, cerebellum, and, 'PFC', of, the, depressive, group, were, 'Alas2,', 'Gh1,', 'Hba-a2,', 'Hbb,', 'Hbb-b1,', 'Hbe2,', 'LOC689064,', 'Mrps10,', 'Mybpc,', 'Olf6415,', and, 'Pfkb1'])].
[sujeto(['Ingenuity', 'Pathway', 'Analysis', identified, 'Gh1', as, a, hub, gene, in, the, networks, of, differentially]), verbo([expressed]), complemento([genes, in, both, brain, regions])].
[sujeto(['This', study, indicates, that, the, 'depressive-like', behavior, may, be, related, to, the]), verbo([decrease]), complemento([of, 'Gh1', expression, in, the, cerebellum, and, 'PFC'])].
[sujeto(['Elucidating', genes, that, affect, life, span, or, that, can, be, used, as, biomarkers, for, ageing]), verbo([has]), complemento([received, attention, in, diverse, studies, in, recent, years])].
[sujeto(['Using', model, organisms, and, various, approaches, several, genes]), verbo([have]), complemento([been, linked, to, the, longevity, phenotype])].
[sujeto(['For', 'Drosophila', melanogaster, those, studies]), verbo([have]), complemento([usually, focussed, on, one, sex, and, on, flies, originating, from, one, genetic, 'background,', and, results, from, different, studies, often, do, not, overlap])].
[sujeto([melanogaster, selected, for]), verbo([increased]), complemento([longevity, we, aimed, to, find, robust, longevity, related, genes, by, examining, gene, expression, in, both, sexes, of, flies, originating, from, different, genetic, backgrounds])].
[sujeto(['We']), verbo([found]), complemento([one, robust, candidate, gene, for, 'longevity,', 'CG32638'])].
[sujeto(['Three', other, 'genes,', 'CG8934,', mRpS10, and, 'Spn43Ad,', showed, a, tendency, to, be]), verbo([involved]), complemento([in, life, span, determination, in, both, backgrounds, tested])].
[sujeto(['Genome-wide', pharmacogenomic, screening, in, a, canine, model, of, 'HF']), verbo([suggests]), complemento([3, novel, 'BB', response, candidate, loci])].
[sujeto(['Multidrug', resistant, genes, are, highly]), verbo([expressed]), complemento([in, hepatocellular, carcinoma, that, seriousty, affects, the, effect, of, chemotherapy])].
[sujeto(['The', survival, 'cells,', stably, integrated, 'helper-free', retroviral, 'libraries,', were, recovered, rapidly, after, transfection, with, plasmids]), verbo([expressing]), complemento([retroviral, 'gag-pol', and, env, genes])].
[sujeto(['Recovered', retroviral, supernatant, was, then, used, to, reinfect, fresh]), verbo([target]), complemento([cells])].
[sujeto(['When', performed, in, concert, with, selection, using, functional, 'assays,', cDNAs]), verbo([regulating]), complemento([functional, responses, could, be, identified, by, enrichment, through, multiple, rounds, of, retroviral, library, recovery, and, retransmission])].
[sujeto(['After', a, preliminary, 'detection,', we]), verbo([found]), complemento(['Ribosomal', protein, 'S11', '(', 'RPS11),', 'Ribosomal', protein, 'L6', '(', 'RPL6),', 'Ribosomal', protein, 'L11', '(', 'RPL11),', 'Ribosomal', protein, 'L24', '(', 'RPL24)', possibly, had, drug, resistant, function])].
[sujeto(['We']), verbo([have]), complemento([previously, characterized, 'patient-derived,', 'treatment-resistant', 'GSC', clones, '(', 'TRGC)', that, survived, radiochemotherapy])].
[sujeto(['Using', comparative, 'genome-wide', transcriptome, 'analysis,', a, series, of, defense, signatures]), verbo([associated]), complemento([with, 'TRGC', survival, were, identified, and, verified, by, 'siRNA-based', gene, knockdown, experiments, that, led, to, loss, of, cell, integrity])].
[sujeto(['Moreover,', tumors, that, exhibited, unmethylated, 'O-6-methylguanine-DNA', methyltransferase, '(', 'MGMT)', or, 'wild-type', isocitrate, dehydrogenase, 1, '(', 'IDH1)', were]), verbo([associated]), complemento([with, higher, 'RPS11', expression, levels, '[', corr, '(', 'IDH1,', 'RPS11)', =, 0.64, ',', p, =, 0.03, ')', ;, '[', corr, '(', 'MGMT,', 'RPS11)', =, 0.52, ',', p, =, 0.04, ']'])].
[sujeto(['These', data, indicate, that]), verbo([increased]), complemento([expression, of, 'RPS11', and, 'RPS20', predicts, shorter, patient, survival])].
[sujeto(['The', study, also]), verbo([suggests]), complemento([that, 'TRGC', are, clinically, relevant, cells, that, represent, resistant, tumorigenic, clones, from, patient, tumors, and, that, their, 'properties,', at, least, in, 'part,', are, reflected, in, 'poor-prognosis', 'GBM'])].
[sujeto(['The', purpose, of, this, study, was, to, identify, differentially]), verbo([expressed]), complemento(['(', 'DE)', genes, and, biological, processes, associated, with, changes, in, gene, expression, in, ankylosing, spondylitis, '(', 'AS)'])].
[sujeto(['The', upregulated, gene, with, the, largest, effect, size, '(', 'ES;', -, 1.2628, ',', 'P', =, 0.020951, ')', was, integral, membrane, protein, 2, 'A', '(', 'ITM2A),', which, is]), verbo([expressed]), complemento([by, 'CD4+', 'T', cells, and, plays, a, role, in, activation, of, 'T', cells])].
[sujeto(['Therefore,', our, 'meta-analysis', identified, genes, that, were, consistently, 'DE', as, well, as, biological, pathways]), verbo([associated]), complemento([with, gene, expression, changes, in, 'AS'])].
[sujeto(['NuA4', '(', nucleosome, acetyltransferase, of, 'H4)']), verbo([promotes]), complemento([transcriptional, initiation, of, 'TFIID', '(', a, complex, of, 'TBP', and, 'TBP-associated', factors, '[', 'TAFs])-dependent', ribosomal, protein, genes, involved, in, ribosome, biogenesis])].
[sujeto(['However,', it, is, not, clearly, understood, how, 'NuA4']), verbo([regulates]), complemento([the, transcription, of, ribosomal, protein, genes])].
[sujeto(['Here,', we, show, that, 'NuA4', is]), verbo([recruited]), complemento([to, the, promoters, of, ribosomal, protein, 'genes,', such, as, 'RPS5,', 'RPL2B,', and, 'RPS11B,', for, 'TFIID', recruitment, to, initiate, 'transcription,', and, the, recruitment, of, 'NuA4', to, these, promoters, is, impaired, in, the, absence, of, its, 'Eaf1p', component])].
[sujeto(['However,', in, the, absence, of, 'NuA4,', 'SAGA', '(', 'Spt-Ada-Gcn5-acetyltransferase)', is]), verbo([involved]), complemento([in, targeting, the, 'TAF-independent', form, of, 'TBP', to, the, promoters, of, ribosomal, protein, genes, for, transcriptional, initiation])].
[sujeto(['Thus,', 'NuA4', plays, an, important, role, in]), verbo([targeting]), complemento(['TFIID', to, the, promoters, of, ribosomal, protein, genes, for, transcriptional, initiation, in, vivo])].
[sujeto(['Such', a, function, is]), verbo([mediated]), complemento([via, its, targeted, histone, acetyltransferase, activity])].
[sujeto(['Collectively,', these, results]), verbo([provide]), complemento([significant, insights, into, the, regulation, of, ribosomal, protein, gene, expression, 'and,', 'hence,', ribosome, biogenesis, and, functions])].
[sujeto(['The', two, major, operons, for, biofilm, 'formation,', 'tapA-sipW-tasA', and, 'epsA-O,', were, strongly]), verbo([expressed]), complemento([in, the, rpsU, 'mutant,', whereas, the, 'flagellin-encoding', hag, gene, and, other, 'SigD-dependent', motility, regulons, were, not])].
[sujeto(['Our', studies, demonstrate, that, 'S11', and, 'S21']), verbo([participate]), complemento([in, the, regulation, of, bistability, via, the, 'RemA/RemB', pathway])].
[sujeto(['Abundant', genetic, studies, on, 'BPH']), verbo([have]), complemento([been, conducted, using, 'reverse-transcription', quantitative, 'real-time', 'PCR', '(', 'qRT-PCR)'])].
[sujeto(['Using', 'qRT-PCR,', the, expression, levels, of]), verbo([target]), complemento([genes, are, calculated, on, the, basis, of, endogenous, controls])].
[sujeto(['These', genes, need, to, be, appropriately, selected, by, experimentally, assessing, whether, they, are, stably]), verbo([expressed]), complemento([under, different, conditions])].
[sujeto(['Based', on, the, results, of, 'RefFinder,', which, integrates, four, currently, available, major, software, programs, to, compare, and, rank, the, tested, candidate, reference, 'genes,', 'RPS15,', 'RPS11,', and, 'TUB', were]), verbo([found]), complemento([to, be, the, most, suitable, reference, genes, in, different, developmental, 'stages,', body, 'parts,', and, geographic, 'populations,', respectively])].
[sujeto(['RPS14', is, a, component, of, the, 40, 'S', ribosomal, subunit, encoded, by, the, 'RPS14', gene, and, is]), verbo([required]), complemento([for, its, maturation])].
[sujeto(['This', degree, of, conservation, of, 'RPS14']), verbo([suggests]), complemento([evolutionary, selection])].
[sujeto(['The', 'RPS14', gene, can, be, readily]), verbo([expressed]), complemento([in, 'Escherichia', coli])].
[sujeto(['A', description, of, the, site, of, interaction, of, 'YS11,', the, yeast, homolog, of, eubacterial, 'S17,', with, 18, 'S', rRNA, was, obtained, by, assessing, the]), verbo([binding]), complemento([of, the, ribosomal, 'protein,', in, a, filter, retention, 'assay,', to, oligoribonucleotides, that, reproduce, regions, of, 18, 'S', rRNA])].
[sujeto(['YS11']), verbo([binds]), complemento([predominantly, to, domain, 'I;', the, 'Kd', value, is, 113, nM])].
[sujeto(['The', dimensions, of, the, 'YS11']), verbo([binding]), complemento([site, were, 'refined,', guided, by, chemical, protection, data, and, by, the, atomic, structure, of, the, 'Thermus', thermophilus, 30, 'S', 'subunit,', which, has, the, 'S17', recognition, site, in, 16, 'S', rRNA])].
[sujeto(['An', oligoribonucleotide, that, mimics, helix, 11, ',', a, phylogenetically]), verbo([conserved]), complemento([region, in, domain, 'I,', binds, 'YS11', with, a, 'Kd', value, of, 230, 'nM;', a, second, oligoribonucleotide, that, contains, only, the, 'kink-turn', motif, in, helix, 11, binds, 'YS11', with, a, 'Kd', value, of, 528, nM])].
[sujeto(['Thus,', helix, 11]), verbo([has]), complemento([most, of, the, nucleotides, required, for, the, recognition, of, 'YS11'])].
[sujeto(['To', identify, those, nucleotides, a, set, of, 27, transversion, mutations, in, 'H11', was, constructed, and, their, contribution, to, the]), verbo([binding]), complemento([of, 'YS11', determined])].
[sujeto(['Mutations', of, nine, nucleotides, '(', 'U313,', 'C314,', 'A316,', 'G337,', 'C338,', 'G347,', 'U348,', 'U350,', and, 'C351)']), verbo([increased]), complemento([the, 'Kd', value, for, 'YS11', binding, by, at, least, 'eightfold;', 'G325U', and, 'U349A', mutations, increased, the, 'Kd', value, fivefold])].
[sujeto(['The', effect, of, the, other, nucleotides, that]), verbo([decrease]), complemento([binding, is, probably, 'indirect,', presumably, they, affect, the, conformation, of, the, binding, site, but, do, not, have, contacts, to, 'YS11', amino, acid, residues])].
[sujeto(['The', eight, identity, element, nucleotides, are, in, regions, of, 'H11', that, deviate, from, 'A-form', geometry, and, the, contacts, are, 'predominantly,', if, not, 'exclusively,', to, backbone, phosphate, and, sugar, oxygen, 'atoms,', indicating, that, 'YS11']), verbo([recognizes]), complemento([the, shape, of, the, rRNA, binding, site, rather, than, reading, the, sequence, of, nucleotides])].
[sujeto(['The', in, vitro, reconstitution, of, the, small, subunit, of, the, bacterial, ribosome]), verbo([provides]), complemento([a, tractable, system, for, the, detailed, study, of, ordered, assembly])].
[sujeto(['We', present, a, quantitative, thermodynamic, description, of, the, hierarchical]), verbo([binding]), complemento([of, ribosomal, proteins, to, 16, 'S', rRNA, during, assembly, of, the, platform, of, the, 30, 'S', ribosomal, subunit])].
[sujeto(['The']), verbo([binding]), complemento([of, 'S8,', 'S11,', 'S15,', and, the, 'S6:S18', heterodimer, to, the, central, domain, of, 16, 'S', rRNA, has, been, measured, both, individually, and, in, combination, using, isothermal, titration, calorimetry, and, gel, mobility, shift, assays])].
[sujeto(['Both', enthalpy, and, free, energy, measurements, demonstrate, the, cooperative]), verbo([binding]), complemento([of, 'S15', and, the, 'S6:S18', 'heterodimer,', but, no, cooperativity, is, observed, for, either, 'S8', or, 'S11'])].
[sujeto(['We']), verbo([have]), complemento([identified, a, 'cisplatin-inducible', 'gene,', the, mitochondrial, ribosomal, protein, 'S11', '(', 'MRP', 'S11)', 'gene,', by, means, of, mRNA, differential, display])].
[sujeto(['Functional', analysis, of, the, 'MRP', 'S11', promoter, showed, that, a, 'Staf']), verbo([binding]), complemento([site, in, the, promoter, is, required, for, both, basal, promoter, activity, and, 'cisplatin-inducible', activity])].
[sujeto(['We', also]), verbo([found]), complemento([that, 'Staf', binding, activity, is, significantly, increased, in, nuclear, extracts, from, cells, treated, with, cisplatin])].
[sujeto(['ZNF', 143, expression, is]), verbo([induced]), complemento([by, cisplatin, but, 'ZNF', 76, expression, is, not])].
[sujeto(['However,', 'ZNF', 143, expression, is, not]), verbo([induced]), complemento([by, 'transplatin,', which, is, clinically, ineffective])].
[sujeto(['ZNF', 143, also]), verbo([binds]), complemento([preferentially, to, 'cisplatin-modified', 'DNA'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'ZNF', 143, participates, in, cellular, responses, to, 'DNA', damage])].
[sujeto(['Ribosomal', protein, 'S15']), verbo([binds]), complemento([specifically, to, the, central, domain, of, 16, 'S', ribosomal, 'RNA', '(', 16, 'S', 'rRNA)', and, directs, the, assembly, of, four, additional, proteins, to, this, domain])].
[sujeto(['Here,', this, same, approach, was, used, to, understand, the, 16, 'S', rRNA, environment, of, 'Fe(II)-S15', in, 30, 'S', subunits, and, to, determine, the, ribosomal, proteins, that, are]), verbo([involved]), complemento([in, forming, the, mature, 'S15-16', 'S', rRNA, environment])].
[sujeto(['We']), verbo([have]), complemento([identified, additional, sites, of, 'Fe(II)-S15-directed', cleavage, in, 30, 'S', subunits, compared, to, the, binary, complex, of, 'Fe(II)-S15/16', 'S', rRNA])].
[sujeto(['Along', with, novel]), verbo([targets]), complemento([in, the, central, 'domain,', sites, within, the, 5, '\'', and, 3, '\'', minor, domains, are, also, cleaved])].
[sujeto(['This']), verbo([suggests]), complemento([that, during, the, course, of, 30, 'S', subunit, assembly, these, elements, are, positioned, in, the, vicinity, of, 'S15'])].
[sujeto(['These', studies]), verbo([reveal]), complemento([that, ribosomal, proteins, can, alter, the, assembly, of, regions, of, the, 30, 'S', subunit, from, a, considerable, distance, and, influence, the, overall, conformation, of, this, ribonucleoprotein, particle])].
[sujeto(['Yeast', ribosomal, protein, 'S14', '(', 'rpS14)']), verbo([binds]), complemento([to, two, different, 'RNA', 'molecules:', '(', 1, ')'])].
[sujeto([a, 'stem-loop', structure, in, 'RPS14B', 'pre-mRNA', to]), verbo([repress]), complemento([expression, of, the, 'RPS14B', gene])].
[sujeto(['S11', contains, an, extended, 'carboxy-terminal', domain, rich, in, basic, amino, 'acids,', which]), verbo([interacts]), complemento([with, rRNA])].
[sujeto(['We', systematically, evaluated, the, importance, of, each, of, the, last, ten, amino, acid, residues, in, the, 'basic,', 'carboxy-terminal', tail, of, yeast, rpS14, for]), verbo([binding]), complemento([to, 'RNA,', by, mutating, each, to, alanine])].
[sujeto(['Mutations', in, nine, of, these, residues]), verbo([decreased]), complemento([binding, of, rpS14, to, one, or, both, of, its, 'RNA', ligands])].
[sujeto(['In', 'addition,', we, examined, the, importance, of, four, structural, motifs, in, helix, 23, of, 18, 'S', rRNA, for]), verbo([binding]), complemento([to, rpS14])].
[sujeto(['Mutations', that, altered, either, the, terminal, 'loop,', the, 'G-U', 'base-pair', closing, the, terminal, 'loop,', or, the, internal, loop, affected]), verbo([binding]), complemento([of, rpS14, to, helix, 23])].
[sujeto(['This', 'interaction,', which, is, located, in, the, 'E', 'site,', connects, the, head, of, the, 30, 'S', subunit, to, the, platform, and, is]), verbo([involved]), complemento([in, the, formation, of, the, exit, channel, through, which, passes, the, 30, 'S-bound', messenger, 'RNA'])].
[sujeto(['Neither', mutations, in, 'S7', nor, mutations, in, 'S11']), verbo([prevented]), complemento([the, incorporation, of, the, proteins, into, the, 30, 'S', subunits, but, they, perturbed, the, function, of, the, ribosome])].
[sujeto(['In', vivo, assays, showed, that, ribosomes, with, either, mutated, 'S7', or, 'S11', were, altered, in, the, control, of, translational, 'fidelity,', having, an]), verbo([increased]), complemento([capacity, for, 'frameshifting,', readthrough, of, a, nonsense, codon, and, codon, misreading])].
[sujeto(['Toeprinting', and, 'filter-binding', assays, showed, that, 30, 'S', subunits, with, either, mutated, 'S7', or, 'S11']), verbo([have]), complemento([an, enhanced, capacity, to, bind, mRNA])].
[sujeto(['The', effects, of, the, 'S7', and, 'S11', mutations, can, be, related, to, an]), verbo([increased]), complemento([flexibility, of, the, head, of, the, 30, 'S,', to, an, opening, of, the, mRNA, exit, channel, and, to, a, perturbation, of, the, proposed, allosteric, coupling, between, the, 'A', and, 'E', sites])].
[sujeto(['Altogether,', our, results, demonstrate, that, 'S7', and, 'S11']), verbo([interact]), complemento([in, a, functional, manner, and, support, the, notion, that, 'protein-protein', interactions, contribute, to, the, dynamics, of, the, ribosome])].
[sujeto(['Phosphorylation', of, ribosomal, protein, 'S6']), verbo([leads]), complemento([to, the, stabilization, of, 'pre-spore', specific, mRNAs, during, development, of, 'Dictyostelium', discoideum])].
[sujeto(['The', purification, of, 'S6', kinase]), verbo([has]), complemento([allowed, the, identification, of, protein, 'S11', as, the, mRNase, specific, for, 'pre-spore', mRNAs])].
[sujeto(['Methylation', of, ribosomal, protein, 'S31']), verbo([leads]), complemento([to, the, destabilization, of, ribosomal, protein, mRNAs])].
[sujeto(['The', purification, of, 'S31', methyltransferase]), verbo([has]), complemento([allowed, the, identification, of, protein, 'S29', as, the, mRNAse, specific, for, ribosomal, protein, mRNAs])].
[sujeto(['Programmed', cell, death, 4, '(', 'PDCD4)']), verbo([has]), complemento([a, common, 'MI', domain, sharing, with, death, associated, protein, 5, '(', 'DAP5)', and, a, component, of, eukaryotic, translation, initiation, factor, '(', 'eIF4G)', complex, and, it, might, also, work, as, a, tumor, suppressor])].
[sujeto(['We', could]), verbo([find]), complemento([that, the, message, and, product, of, 'Pdcd4', gene, were, 'up-regulated', in, senescent, human, diploid, fibroblasts])].
[sujeto(['In', yeast, two, hybrid, 'analysis,', the, 'C-terminal', region, of, 'PDCD4']), verbo([interacted]), complemento([with, ribosomal, protein, 'S13', '(', 'RPS13),', ribosomal, protein, 'L5', '(', 'RPL5),', and, 'TI-227H'])].
[sujeto(['In', in, vitro]), verbo([binding]), complemento(['assay,', 'RPS13,', a, component, of, 40, 'S', ribosome, was, stably, bound, to, 'PDCD4'])].
[sujeto(['We', also]), verbo([found]), complemento([that, 'PDCD4', was, localized, to, polysome, fractions])].
[sujeto(['We', could, pull, out, eIF4G, with, 'GST-PDCD4,', but, eIF4E, did, not]), verbo([interact]), complemento([with, 'PDCD4'])].
[sujeto(['From', these, 'results,', we, could, assume, that, 'PDCD4', might]), verbo([regulate]), complemento([the, 'eIF4G-dependent', translation, through, direct, interactions, with, eIF4G, and, 'RPS13', in, senescent, fibroblasts])].
[sujeto(['Stimulation', of, death, receptors, '(', 'Fas', on, human, 'T-cell', leukemia, 'Jurkat', cells, and, tumor, necrosis, factor, 'receptor-1', on, human, monoblastic, leukemia, 'U937', 'cells)']), verbo([triggers]), complemento([the, specific, degradation, of, 28, 'S', ribosomal, 'RNA,', and, this, process, may, contribute, to, cell, death, through, the, inhibition, of, protein, synthesis])].
[sujeto(['We']), verbo([have]), complemento([developed, an, analytical, method, using, a, 'polyacrylamide-agarose', composite, gel, to, evaluate, ribosomal, subunits, in, apoptotic, cells, '(', human, breast, carcinoma, 'MCF-7', cells, treated, with, staurosporine, and, human, 293, 'T', cells, irradiated, with, ultraviolet, light, were, used, in, addition, to, the, two, apoptosis, systems, described, 'above)'])].
[sujeto(['No', alterations, were, detected, by, this, 'method,']), verbo([suggesting]), complemento([that, 'apoptosis,', including, the, process, of, ribosomal, 'RNA', 'degradation,', does, not, cause, fragmentation, or, extensive, conformational, changes, in, the, ribosome])].
[sujeto(['Previous', studies]), verbo([have]), complemento([shown, that, 'S11', is, heterogeneously, expressed, in, cancer, cells])].
[sujeto(['Taken', 'together,', it, appears, that, particular, intracellular, environments]), verbo([regulate]), complemento([the, expression, of, 'S11', protein])].
[sujeto(['However,', the, mechanism, by, which, this, process, is]), verbo([modulated]), complemento([is, as, yet, unknown])].
[sujeto(['Furthermore,', we]), verbo([have]), complemento([demonstrated, that, our, composite, gel, electrophoresis, system, can, efficiently, detect, ubiquitination, of, ribosomal, subunits])].
[sujeto(['Mutants', of, model, eukaryotic, organisms]), verbo([have]), complemento([revealed, that, most, ribosomal, proteins, are, essential, for, cell, viability])].
[sujeto(['Recent']), verbo([reports]), complemento([on, the, involvement, of, ribosomal, proteins, in, various, genetic, diseases, and, studies, on, the, extraribosomal, functions, of, these, proteins, have, cast, some, light, on, their, localization, and, functions])].
[sujeto(['Here', we, prepared, rabbit, polyclonal, antibodies, against, 26, human, ribosomal, 'proteins;', each, of, these, reagents]), verbo([recognized]), complemento([a, single, band, in, immunoblots, of, the, purified, ribosome])].
[sujeto(['To', identify, genes, that]), verbo([regulate]), complemento([this, process, we, performed, a, complementary, 'DNA', '(', 'cDNA)', subtractive, hybridization, of, fetal, bovine, proliferative, chondrocyte, cDNA, from, epiphyseal, cartilage, cDNA])].
[sujeto([&, 'quot;', 'Northern', and, western, blot, analysis, confirmed, that, 'QM', was, highly]), verbo([expressed]), complemento([by, cells, isolated, from, epiphyseal, cartilage, as, opposed, to, proliferative, chondrocytes])].
[sujeto(['Immunohistochemical', analysis, of, fetal, bovine, limb, sections, revealed, that, 'QM', was, not]), verbo([expressed]), complemento([by, the, majority, of, the, epiphyseal, chondrocytes, but, only, by, chondrocytes, in, close, proximity, to, capillaries, that, had, invaded, the, epiphyseal, cartilage])].
[sujeto(['The', in, vivo, and, in, vitro, expression, pattern, of, 'QM']), verbo([suggests]), complemento([that, this, protein, may, have, a, role, in, cell, differentiation, before, mineralization])].
[sujeto([coli, cells]), verbo([expressing]), complemento([rat, 'PIMT', had, significantly, lower, isoaspartate, levels, than, control, 'cells,', especially, in, stationary, phase])].
[sujeto(['The', near, stoichiometric, levels, of, isoaspartate, in, 'S11,', estimated, at, 0.5, mol, of, isoaspartate, per, mol, of, 'S11,']), verbo([suggests]), complemento([that, this, unusual, modification, may, be, important, for, 'S11', function])].
[sujeto(['Although', plastid, transcriptomes]), verbo([have]), complemento([been, characterised, for, many, plant, 'species,', less, is, known, about, the, transcripts, produced, in, other, plastid, lineages])].
[sujeto(['This', plastid, 'lineage,', acquired, through, tertiary, 'endosymbiosis,', utilises, transcript, processing, pathways, that, are, very, different, from, those]), verbo([found]), complemento([in, plants, and, green, 'algae,', including, 3, '\'', 'poly(U)', tail, 'addition,', and, extensive, substitutional, editing, of, transcript, sequences])].
[sujeto(['We']), verbo([have]), complemento([sequenced, the, plastid, transcriptome, of, 'K'])].
[sujeto(['mikimotoi,', and]), verbo([have]), complemento([detected, evidence, for, divergent, evolution, of, fucoxanthin, plastid, genomes])].
[sujeto(['We']), verbo([have]), complemento([additionally, characterised, polycistronic, and, monocistronic, transcripts, from, two, plastid, 'loci,', 'psbD-tRNA', '(', 'Met)-ycf4', and, 'rpl36-rps13-rps11'])].
[sujeto(['We']), verbo([find]), complemento([evidence, for, a, range, of, transcripts, produced, from, each, locus, that, differ, in, terms, of, editing, 'state,', 5, '\'', end, cleavage, 'position,', and, 'poly(U)', tail, addition])].
[sujeto(['Overall,', our, study]), verbo([provides]), complemento([insights, into, the, diversity, of, transcripts, and, processing, intermediates, found, in, plastid, lineages, across, the, eukaryotes])].
[sujeto(['It', was, believed, earlier, that, spermatozoa]), verbo([have]), complemento([no, traces, of, 'RNA', because, of, loss, of, most, of, the, cytoplasm])].
[sujeto(['Recent', studies]), verbo([have]), complemento([revealed, the, presence, of, about, 3000, different, kinds, of, mRNAs, in, ejaculated, spermatozoa])].
[sujeto(['A', number, of, differentially]), verbo([expressed]), complemento([transcripts, in, spermatozoa, were, related, to, reproduction, '(', n, =, 58, ')', and, development, '(', 'n=', 210, ')'])].
[sujeto(['A', number, of, transcripts, that]), verbo([participate]), complemento([in, a, host, of, cellular, 'processes,', including, reproduction, and, development, were, differentially, expressed, between, fertile, and, infertile, individuals])].
[sujeto(['Differences', between, comparison, groups]), verbo([suggest]), complemento([that, sperm, 'RNA', has, strong, potential, of, acting, as, markers, for, fertility, evaluation])].
[sujeto(['Rafflesia', is, a, genus, of, holoparasitic, plants, endemic, to, 'Southeast', 'Asia', that]), verbo([has]), complemento([lost, the, ability, to, undertake, photosynthesis])].
[sujeto(['Phylogenetic', analysis]), verbo([suggests]), complemento([that, '∼33%', of, these, remnant, plastid, genes, may, have, been, horizontally, transferred, from, the, host, plant, genus, 'Tetrastigma', with, the, rest, having, ambiguous, phylogenetic, positions, '(', &, 'lt;50%', bootstrap, 'support),', except, for, psaB, that, was, strongly, allied, with, the, plastid, homolog, in, 'Nicotiana'])].
[sujeto([lagascae, using, multiple, 'approaches--despite', success, in, identifying, and, developing, a, draft, assembly, of, the, much, larger, mitochondrial, 'genome--suggests', that, the, parasitic, plant, genus, 'Rafflesia', may, be, the, first, plant, group, for, which, there, is, no, recognizable, plastid, 'genome,', or, if, present, is]), verbo([found]), complemento([in, cryptic, form, at, very, low, levels])].
[sujeto(['Although', the, accuracy, of, quantitative, 'real-time', polymerase, chain, reaction, '(', 'qRT-PCR)', is, highly, dependent, on, the, reliable, reference, 'genes,', many, commonly, used, reference, genes, are, not, stably]), verbo([expressed]), complemento([and, as, such, are, not, suitable, for, quantification, and, normalization, of, 'qRT-PCR', data])].
[sujeto(['In', 'contrast,', 1, of, the, 15, common, reference, genes, '(', 'ACTB)', and, the, 5, additional, candidate, reference, genes, '(', 'EEF1A1,', 'FAU,', 'RPS9,', 'RPS11,', and, 'RPS14)', were, stably, and, constitutively]), verbo([expressed]), complemento([at, high, levels, in, all, the, samples, tested])].
[sujeto(['Cellular', viability, of, 'ETV6-RUNX1-positive', 'Reh', cells, significantly]), verbo([increased]), complemento([in, presence, of, 9, 'ng/mL', vincristine, upon, 'co-expression', of, 'miR-125b/miR-99a', '(', 91, ±, 4, '%', ')', ',', 'miR-125b/miR-100', '(', 93, ±, 5, '%', ')', or, 'miR-125b/miR-99a/miR-100', '(', 82, ±, 17, '%', ')', compared, with, 'miR-125b-transduced', cells, '(', 38, ±, 13, '%', ',', 'P<0'])].
[sujeto(['Similarly,', 7, out, of, these, genes, are, lower]), verbo([expressed]), complemento([in, 'vincristine-resistant', 'ALL', cells, of, children, '(', 'p<0'])].
[sujeto(['Microalgae', are, promising, feedstock, for, production, of, 'lipids,', 'sugars,', bioactive, compounds, and, in, particular, 'biofuels,', yet, development, of, sensitive, and, reliable, phylotyping, strategies, for, microalgae]), verbo([has]), complemento([been, hindered, by, the, paucity, of, phylogenetically, 'closely-related', finished, genomes])].
[sujeto(['Genes', on, the, pt, and, mt, genomes]), verbo([have]), complemento([been, highly, conserved, in, 'content,', size, and, 'order,', strongly, negatively, selected, and, evolving, at, a, rate, 33, '%', and, 66, '%', of, nuclear, genomes, respectively])].
[sujeto(['Pt', genome, diversification, was, driven, by, asymmetric, evolution, of, two, inverted, repeats, '(', 'IRa', and, 'IRb):', psbV, and, clpC, in, 'IRb', are, highly]), verbo([conserved]), complemento([whereas, their, counterparts, in, 'IRa', exhibit, three, 'lineage-associated', types, of, structural, polymorphism, via, duplication, or, disruption, of, whole, or, partial, genes])].
[sujeto([',', 'cox1,', 'cox2,', 'psbA,', rbcL, and, 'rrn16_mt)', and]), verbo([nuclear]), complemento([markers, '(', e])].
[sujeto(['We']), verbo([have]), complemento([sequenced, the, complete, nucleotide, sequence, of, the, chloroplast, '(', 'cp)', genome, of, 'M'])].
[sujeto([bealei, is, 164, ',', 792, bp, in, 'length,', and]), verbo([has]), complemento([a, typical, structure, with, large, '(', 'LSC', 73, ',', 52, 'bp)', and, small, '(', 'SSC', 18, ',', 591, 'bp)', 'single-copy', regions, separated, by, a, pair, of, inverted, repeats, '(', 'IRs', 36, ',', 501, 'bp)', of, large, size])].
[sujeto(['A', large, 'IR', expansion, of, over, 12, kb]), verbo([has]), complemento([occurred, in, 'M'])].
[sujeto(['bealei,', 15, genes, '(', 'rps19,', 'rpl22,', 'rps3,', 'rpl16,', 'rpl14,', 'rps8,', 'infA,', 'rpl36,', 'rps11,', 'petD,', 'petB,', 'psbH,', 'psbN,', psbT, and, 'psbB)']), verbo([have]), complemento([expanded, to, have, an, additional, copy, in, the, 'IRs'])].
[sujeto(['Comparison', of, 'protein-coding', sequences, with, 'ESTs']), verbo([reveals]), complemento([9, putative, 'RNA', edits, and, 5, of, them, resulted, in, 'non-synonymous', modifications, in, 'rpoC1,', 'rps2,', rps19, and, ycf1])].
[sujeto(['Phylogenetic', analysis, using, maximum, parsimony, '(', 'MP)', and, maximum, likelihood, '(', 'ML)', was, performed, on, a, dataset, composed, of, 65, 'protein-coding', genes, from, 25, 'taxa,', which, yields, an, identical, tree, topology, as, previous, 'plastid-based', 'trees,', and]), verbo([provides]), complemento([strong, support, for, the, sister, relationship, between, 'Ranunculaceae', and, 'Berberidaceae'])].
[sujeto(['Molecular', dating, analyses]), verbo([suggest]), complemento([that, 'Ranunculaceae', and, 'Berberidaceae', diverged, between, 90, and, 84, 'mya,', which, is, congruent, with, the, fossil, records, and, with, recent, estimates, of, the, divergence, time, of, these, two, taxa])].
[sujeto(['However,', a, number, of, 'RPs', appear, to]), verbo([have]), complemento(['non-ribosomal', 'functions,', which, involve, direct, association, with, 'pre-mRNA', and, transcription, factors, at, transcription, sites])].
[sujeto(['The', consensus, is, that, the, 'RPs']), verbo([found]), complemento([at, these, sites, are, off, ribosomal, 'subunits,', but, observation, that, different, 'RPs', are, usually, found, together, suggests, that, ribosomal, or, 'ribosomal-like', subunits, might, be, present])].
[sujeto(['Notably,', it]), verbo([has]), complemento([previously, been, reported, that, antibodies, against, 20, different, 'RPs', stain, the, same, 'Pol', 'II', transcription, sites, in, 'Drosophila', polytene, chromosomes])].
[sujeto(['To', investigate, further, whether, 'RPs', are, present, at, transcription, sites, in, 'Drosophila,', we]), verbo([have]), complemento([generated, several, transgenic, flies, expressing, 'RPs', '(', 'RpS2,', 'RpS5a,', 'RpS9,', 'RpS11,', 'RpS13,', 'RpS18,', 'RpL8,', 'RpL11,', 'RpL32,', and, 'RpL36)', tagged, with, either, green, or, red, fluorescent, protein])].
[sujeto(['Indeed,', polytene, chromosome, immunostaining, of, a, representative, subset, of, tagged, 'RPs', confirms, the, association, with]), verbo([transcribed]), complemento([loci])].
[sujeto(['Furthermore,', characterization, of, a, strain]), verbo([expressing]), complemento(['RpL41', functionally, tagged, at, its, native, genomic, locus, with, 'YFP,', also, showed, apparent, nuclear, accumulation, and, chromosomal, 'association,', suggesting, that, such, a, nuclear, localization, pattern, might, be, a, shared, feature, of, 'RPs', and, is, biologically, important])].
[sujeto(['We', anticipate, that, the, transgenes, described, here, should]), verbo([provide]), complemento([a, useful, research, tool, to, visualize, ribosomal, subunits, in, 'Drosophila', tissues, and, to, study, the, 'non-ribosomal', functions, of, 'RPs'])].
[sujeto(['Many', disorders, are]), verbo([associated]), complemento([with, altered, serum, protein, 'concentrations,', including, 'malnutrition,', 'cancer,', and, 'cardiovascular,', 'kidney,', and, inflammatory, diseases])].
[sujeto(['We', demonstrated, a, functional, role, for, the, most, strongly]), verbo([associated]), complemento([serum, albumin, 'locus,', 'HPN,', for, which, 'Hpn', knockout, mice, manifest, low, plasma, albumin, concentrations])].
[sujeto(['Other', loci]), verbo([associated]), complemento([with, serum, albumin, harbor, genes, related, to, ribosome, 'function,', protein, 'translation,', and, proteasomal, 'degradation,', whereas, those, associated, with, serum, total, protein, include, genes, related, to, immune, function])].
[sujeto(['Our', results, highlight, the, advantages, of, transethnic, 'meta-analysis', for, the, discovery, and, fine, mapping, of, complex, trait, loci, and]), verbo([have]), complemento([provided, initial, insights, into, the, underlying, genetic, architecture, of, serum, protein, concentrations, and, their, association, with, human, disease])].
[sujeto(['We', identified, ten, 'genome-wide', significant, signals, newly]), verbo([associated]), complemento([with, traits, from, an, overall, 'meta-analysis'])].
[sujeto(['The', most, compelling, associations]), verbo([involved]), complemento([12, q24])].
[sujeto(['Of', 14, ',', 564, 'genes,', only, 3, '(', 'PAP,', 'REG1A,', and, 'DPEP1)', were, selectable, as, final, candidates, which, were]), verbo([expressed]), complemento([frequently, at, any, stage, of, this, cancer, and, were, suppressed, in, 'non-cancerous', tissues, and, also, in, the, peripheral, blood, and, colonocytes, of, healthy, volunteers])].
[sujeto(['Next,', we, directly, compared, fecal, 'RNA-expression', profiles, between, colorectal, cancer, patients, and, healthy, 'volunteers,', and]), verbo([found]), complemento([that, most, of, the, genes, '(', 92, '%', ')', expressed, in, the, colonocytes, of, the, cancer, patients, were, not, expressed, in, those, of, the, healthy, volunteers])].
[sujeto(['Our', extensive, gene, list]), verbo([provides]), complemento([other, markers, for, fecal, 'RNA-based', colorectal, cancer, screening])].
[sujeto(['We']), verbo([have]), complemento([determined, the, organization, and, sequence, of, the, region, containing, two, ribosomal, protein, '(', 'rp)', genes, in, the, human, and, mouse, genomes])].
[sujeto(['The', human, 'RPL13A', and, 'RPS11', are, 4236, bp, and, 3254, bp, in, length, and, comprise, eight, and, five, exons, 'respectively,', whereas, the, mouse, 'Rps11', is, 1951, bp, long, and]), verbo([has]), complemento([five, exons])].
[sujeto(['Structural', comparison, of, these, 'genes,', including, previously]), verbo([reported]), complemento([mouse, 'Rpl13a,', revealed, a, significant, conservation, of, sequences, in, the, promoter, regions])].
[sujeto(['Although', most, rp, genes, are, dispersed, throughout, the, human, 'genome,', the]), verbo([conserved]), complemento([features, and, adjacent, localization, indicate, possible, coordinate, transcription, of, the, two, genes])].
[sujeto(['Furthermore,', we]), verbo([have]), complemento([found, that, four, small, nucleolar, 'RNA', '(', 'snoRNA)', genes, are, located, in, the, introns, of, the, two, rp, 'genes,', both, human, and, mouse])].
[sujeto(['Research']), verbo([has]), complemento([shown, that, biofilm, is, the, preferred, microbial, phenotype, in, health, and, disease, and, is, present, in, a, majority, of, chronic, wounds])].
[sujeto(['Biofilm']), verbo([has]), complemento([been, linked, to, chronic, wound, 'inflammation,', impairment, in, granulation, tissue, and, epithelial, 'migration,', yet, there, lacks, the, ability, to, confirm, the, clinical, presence, of, biofilm])].
[sujeto(['Wounds']), verbo([found]), complemento([to, contain, biofilm, were, not, all, acutely, infected, but, biofilm, was, present, when, infection, was, noted])].
[sujeto(['The', clinical, histories]), verbo([associated]), complemento([with, positive, samples, were, consistent, with, ideas, presented, in, the, algorithm, used, to, guide, sample, selection])].
[sujeto(['This', suspicion, can, be, further]), verbo([enhanced]), complemento([with, the, use, of, a, clinical, algorithm])].
[sujeto(['Gestational', diabetes, mellitus, '(', 'GDM)']), verbo([has]), complemento([now, become, a, major, public, health, problem, because, of, its, prevalence, and, its, associated, complications, during, pregnancy])].
[sujeto(['Earlier', studies]), verbo([have]), complemento([suggested, that, type, 2, diabetes, mellitus, '(', 'T2DM)', and, 'GDM', might, have, similar, 'pathophysiology,', such, as, increased, insulin, 'resistance,', decreased, insulin, secretion, resulting, in, hyperglycaemia])].
[sujeto(['Evidence', for, a, genetic, basis, of, 'GDM']), verbo([has]), complemento([been, poorly, understood])].
[sujeto(['To', some, 'extent,', the, current, advancement, in, genomic, techniques]), verbo([has]), complemento([thrown, better, light, on, the, genetics, of, 'GDM'])].
[sujeto(['Based', on, the, candidate, gene, approach, and, genome, wide, association, 'studies,', genetic, loci, in, several, genes, that, are, responsible, for, insulin, 'secretion,', insulin, 'resistance,', lipid, and, glucose, metabolism, and, other, pathways]), verbo([have]), complemento([shown, association, with, the, 'GDM', susceptibility])].
[sujeto(['Understanding', the, possible, underlying, genetic, factors, of, 'GDM', would, help, us, in]), verbo([gained]), complemento([knowledge, on, the, pathophysiologic, mechanism, of, the, disease])].
[sujeto(['It', is, indicated, for, patients, who, are, intolerant, to, traditional, forms, of, therapy, such, as, 'CPAP,', and, who]), verbo([have]), complemento([moderate, to, severe, disease])].
[sujeto(['T2DM', prevalence]), verbo([has]), complemento([risen, dramatically, from, around, 1, &, 'nbsp;%', in, the, 1980, s, to, now, over, 10, &, 'nbsp;%', and, is, expected, to, continue, rising])].
[sujeto(['Despite', the, growing, disease, 'burden,', few, people, with, 'T2DM', are, achieving, adequate, management]), verbo([targets]), complemento([to, prevent, complications])].
[sujeto(['We', hypothesise, that, an, interactive, mobile, health, management, system, can, support, lay, family, health, promoters, '(', 'FHP)', and, healthcare, staff, to, improve, clinical, outcomes, for, family, members, with, 'T2DM', through, medical, 'assessment,']), verbo([regular]), complemento(['monitoring,', lifestyle, advice, and, the, prescribing, of, guidelines, recommended, medications])].
[sujeto(['This', intervention, will, be, implemented, as, a, cluster, randomised, controlled, trial]), verbo([involving]), complemento([80, communities, '(', 40, communities, in, 'Beijing', and, 40, rural, villages, in, 'Hebei', 'province)', and, 2000, people, with, 'T2DM'])].
[sujeto(['The', 'Chinese', government]), verbo([has]), complemento([prioritised, prevention, and, treatment, of, diabetes, as, 1, of, 11, 'National', 'Basic', 'Public', 'Health', 'Services'])].
[sujeto(['Recent', studies]), verbo([have]), complemento([shown, that, its, prevalence, is, rising])].
[sujeto(['The', mean, difference, of, pain, severity]), verbo([decrease]), complemento([in, both, groups, was, meaningful, '(', 'P=0/007)'])].
[sujeto(['The', mean, difference, of, disability]), verbo([decrease]), complemento([in, both, groups, was, meaningful, '(', 'P=0/003)'])].
[sujeto(['However,', the, mean, difference, of, quality, of, life]), verbo([increase]), complemento([in, both, groups, was, not, meaningful])].
[sujeto(['Iranian', traditional, massage, may, be, useful, for, the, treatment, of, 'non-acute', 'sciatica,', but, more, studies, are]), verbo([required]), complemento([to, confirm, and, clarify, the, protocols])].
[sujeto(['Coastal', water, quality, and, trophic, status, are, subject, to, intensive, environmental, stress]), verbo([induced]), complemento([by, human, activities, and, climate, change])].
[sujeto(['Although', 'matrix-assisted', laser, desorption, 'ionization-time', of, flight, mass, spectrometry, '(', 'MALDI-TOF', 'MS)']), verbo([has]), complemento([become, a, prevailing, tool, for, rapid, and, reliable, microbial, 'identification,', the, precise, discrimination, of, 'Listeria', species, and, lineages, remains, a, crucial, issue, in, clinical, settings, and, for, food, safety])].
[sujeto([monocytogenes, and, the, different, species, of, 'Listeria,', and]), verbo([led]), complemento([to, the, construction, of, a, 'MS', database, that, was, successful, in, discriminating, between, these, organisms, in, 'MALDI-TOF', 'MS', fingerprinting, analysis, followed, by, advanced, proteotyping, software, 'Strain', 'Solution', analysis])].
[sujeto(['The', traditional, utilitarian, approach, to, the, 'shoulder,', the, 'deltopectoral,']), verbo([has]), complemento([distinct, disadvantages, when, performing, fracture, reduction, and, locked, plating])].
[sujeto(['The', cancellous, surface, of, the, humeral, head, fragment]), verbo([provides]), complemento([an, excellent, surface, for, direct, manipulation, without, further, endangering, the, extraosseous, soft, tissue, attachments])].
[sujeto(['The', absolute, energy, cost, of, activities, in, children]), verbo([increase]), complemento([with, age, due, to, greater, muscle, mass, and, physical, capability, associated, with, growth, and, developmental, 'maturation;', 'however,', there, is, a, paucity, of, data, in, 'preschool-aged', children])].
[sujeto(['Suitable', tools, for, 'live-cell', imaging, of, enterovirus, 'ROs', are, currently, 'unavailable,', as, recombinant, enteroviruses, that, carry, genes, that, encode, 'RO-anchored', viral, proteins, tagged, with, fluorescent, reporters]), verbo([have]), complemento([not, been, reported, thus, far])].
[sujeto(['The', introduction, of, 'GFP(S11)', did, not, affect, the, known, functions, of, 3, 'A', when]), verbo([expressed]), complemento([in, isolation])].
[sujeto(['It', is, well, established, that, enterovirus, infection]), verbo([leads]), complemento([to, 'Golgi', disintegration])].
[sujeto(['Through', 'live-cell', imaging, of, infected, cells]), verbo([expressing]), complemento([an, 'mCherry-tagged', 'Golgi', 'marker,', we, monitored, 'RO', development, and, revealed, the, dynamics, of, 'Golgi', disassembly, in, real, time])].
[sujeto(['Having', demonstrated, the, suitability, of, this, virus, for, imaging, 'ROs,', we, constructed, a, 'CVB3', encoding, 'GFP(S1-10)', and, 'GFP(S11)-tagged', 3, 'A', to, bypass, the, need, to]), verbo([express]), complemento(['GFP(S1-10)', prior, to, infection])].
[sujeto(['These', tools, will]), verbo([have]), complemento([multiple, applications, in, future, studies, on, the, 'origin,', 'location,', and, function, of, enterovirus, 'ROs'])].
[sujeto(['IMPORTANCE', 'Enteroviruses']), verbo([induce]), complemento([the, formation, of, membranous, structures, '(', replication, organelles, '[', 'ROs])', with, a, unique, protein, and, lipid, composition, specialized, for, genome, replication])].
[sujeto(['Electron', microscopy]), verbo([has]), complemento([revealed, the, morphology, of, enterovirus, 'ROs,', and, immunofluorescence, studies, have, been, conducted, to, investigate, their, origin, and, formation])].
[sujeto(['While', 'live-cell', imaging, of, 'ROs', would, be, 'preferred,', enteroviruses, encoding, a, 'membrane-anchored', viral, protein, fused, to, a, large, fluorescent, reporter]), verbo([have]), complemento([thus, far, not, been, described])].
[sujeto(['Regulatory', agencies, including, the, 'US', 'Food', and, 'Drug', 'Administration,', 'European', 'Medicines', 'Agency,', and, 'Japan', 'Pharmaceuticals', and, 'Medical', 'Devices', 'Agency']), verbo([have]), complemento([issued, guidance, for, industry, on, drug, interaction, 'studies,', which, contain, comprehensive, recommendations, on, in, vitro, and, in, vivo, study, tools, and, cutoff, values, to, evaluate, the, 'DDI', potential, of, new, molecular, entities, mediated, by, hepatic, drug, transporters])].
[sujeto(['In', this]), verbo([report]), complemento([we, summarize, the, latest, regulatory, and, scientific, progress, of, hepatic, drug, transporters, in, clinical, 'DDIs,', 'pharmacogenetics,', 'drug-induced', liver, injury, '(', 'DILI),', as, well, as, methods, for, predicting, 'transporter-mediated', pharmacokinetics, and, 'DDIs'])].
[sujeto(['The', purpose, of, this, review, is, to, present, an, overview, on, the, potential, role, of, gut, microbiota, as]), verbo([target]), complemento([of, intervention, against, food, allergy])].
[sujeto(['Many', studies]), verbo([suggest]), complemento([a, key, pathogenetic, role, for, gut, microbiota, modifications, '(', 'dysbiosis)', in, food, allergy, development])].
[sujeto(['Several', factors, responsible, for, dysbiosis]), verbo([have]), complemento([been, associated, with, the, occurrence, of, food, 'allergy,', such, as, caesarean, 'delivery,', lack, of, breast, 'milk,', drugs, use, '(', mainly, antibiotics, and, gastric, acidity, 'inhibitors),', antiseptic, agents, 'use,', and, low, 'fibers/hight', fat, diet])].
[sujeto(['No', specific, bacterial, taxa]), verbo([have]), complemento([been, consistently, associated, with, food, 'allergy,', but, evidence, suggests, that, gut, dysbiosis, occurs, even, before, food, allergy, signs, and, symptoms, presentation])].
[sujeto(['Retail', distributors, and, consumers, are, putting, even, more, pressure, on, the, animal, industry, to]), verbo([find]), complemento([new, ways, to, produce, meat, without, antibiotics, and, chemicals])].
[sujeto(['In', 'addition,', federal, funding, agencies, are, increasingly, pressuring, researchers, to, conduct, science, that]), verbo([has]), complemento([application])].
[sujeto(['In', the, review, that, 'follows,', we, outline, our, approach, to]), verbo([finding]), complemento([novel, ways, to, improve, animal, performance, and, health])].
[sujeto(['We', use, a, strict, set, of, guidelines, in, our, applied, research, as, 'follows:', '(', 1, ')', 'Does', the, work]), verbo([have]), complemento([value, to, 'society?', '(', 2, ')', 'Does', our, team, have, the, skills, to, innovate, in, the, 'field?', '(', 3, ')', 'Is', the, product, we, produce, commercially, 'cost-effective?', '(', 4, ')', 'Are', there, any, reasons, why, the, general, consumer, will, reject, the, 'technology?', '(', 5, ')', 'Is', it, safe, for, the, 'animal,', 'consumer,', and, the, 'environment?', 'Within', this, 'framework,', we, describe, 4, areas, of, research, that, have, produced, useful, 'products,', areas, that, we, hope, other, scientists, will, likewise, explore, and, innovate, such, as, '(', 1, ')', methods, to, detect, infection, in, herds, and, 'flocks,', '(', 2, ')', methods, to, control, systemic, and, mucosal, 'inflammation,', '(', 3, ')', improvements, to, intestinal, barrier, 'function,', and, '(', 4, ')', methods, to, strategically, potentiate, immune, defense])].
[sujeto(['We']), verbo([recognize]), complemento([that, others, are, working, in, these, 'areas,', using, different, 'strategies,', but, believe, our, examples, will, illustrate, the, vast, opportunity, for, research, and, innovation, in, a, world, without, antibiotics])].
[sujeto(['Animal', scientists]), verbo([have]), complemento([been, given, a, new, challenge, that, may, help, shape, the, future, of, both, animal, and, human, medicine])].
[sujeto(['In', this, 3, 'D', 'model,', the, heat, flux, density]), verbo([decreases]), complemento([from, the, upper, surface, to, the, lower, surface, of, the, 'GaAs', substrate, while, it, was, supposed, to, be, a, constant, in, the, 2, 'D', model])].
[sujeto(['The', power, response, experiment, demonstrates, that, the, output, voltage]), verbo([increases]), complemento([from, 0, mV, to, 27, 'mV,', while, the, incident, power, varies, from, 1, mW, to, 100, mW])].
[sujeto(['The', relative, error]), verbo([has]), complemento([been, reduced, from, 7.5, '%', of, the, 2, 'D', model, to, 3.7, '%', of, the, 3, 'D', model])].
[sujeto(['For', each, of, these, 'factors,', the, changes, seen, with, osteoporosis, and, ageing, will, be, described, and, how, they, can, compromise, strength, and, eventually]), verbo([lead]), complemento([to, bone, fragility])].
[sujeto(['Historically,', pharmaceutical, industry, regulatory, guidelines]), verbo([have]), complemento([assigned, certain, active, pharmaceutical, ingredients, '(', 'APIs)', to, various, categories, of, 'concern,', such, as, &, 'quot;cytotoxic",', &, 'quot;hormones",', and, &, 'quot;steroids"'])].
[sujeto(['These', categories]), verbo([have]), complemento([been, used, to, identify, 'APIs', requiring, segregation, or, dedication, in, order, to, prevent, 'cross-contamination', and, protect, the, quality, and, safety, of, drug, products])].
[sujeto(['Since', these, terms, were, never, defined, by, regulatory, 'authorities,', and, many, novel, pharmacological, mechanisms, challenge, these, 'categories,', there, is, a]), verbo([recognized]), complemento([need, to, modify, the, historical, use, of, these, terms])].
[sujeto(['The', toxicological, and, pharmacological, characteristics, of, these, categories, are, discussed, to, help, identify, and, prioritize, compounds]), verbo([requiring]), complemento([special, attention])].
[sujeto(['Controlling', airborne, concentrations, and, the, contamination, of, product, contact, surfaces, in, accordance, with, values, derived, from, quantitative, risk, assessments, can]), verbo([prevent]), complemento([adverse, effects, in, workers, and, 'patients,', regardless, of, specific, categorical, designations, to, which, these, 'APIs', have, been, assigned])].
[sujeto(['Based', on, the, results, of, a, risk, 'assessment,', segregation, and, dedication, may, also, be]), verbo([required]), complemento([for, some, compounds, to, prevent, cross, contamination, during, manufacture, of, 'APIs'])].
[sujeto(['This', prototype]), verbo([enhances]), complemento([the, actual, capability, of, the, instrument, for, a, 'sub-surface', imaging, at, the, nanoscale])].
[sujeto(['The', aim, of, the, present, study, was, to, screen, differentially, 'co-expressed', genes, and, the]), verbo([involved]), complemento([transcription, factors, '(', 'TFs)', and, microRNAs, '(', 'miRNAs)', in, venous, thromboembolism, '(', 'VTE)'])].
[sujeto([adenylate, cyclase, 7, and, 'single-stranded', 'DNA']), verbo([binding]), complemento([protein, 2, ')', were, 'identified,', which, were, further, mined, to, obtain, 17, and, eight, modules, separately])].
[sujeto(['Functional', annotation, revealed, that, the, largest, upregulated, module, was, primarily]), verbo([associated]), complemento([with, acetylation, and, the, largest, downregulated, module, was, mainly, involved, in, mitochondrion])].
[sujeto(['Moreover,', 48, 'TFs', and, 62, miRNA, families, were, screened, for, the, 17, upregulated, 'modules,', such, as, 'E2F', transcription, factor, 4, ',', 'miR-30', and, 'miR-135']), verbo([regulating]), complemento([the, largest, module])].
[sujeto(['Conversely,', 35, 'TFs', and, 18, miRNA, families, were, identified, for, the, 8, downregulated, 'modules,', including, mitochondrial, ribosomal, protein, 'S12', and, 'miR-23']), verbo([regulating]), complemento([the, largest, module])].
[sujeto(['Differentially', 'co-expressed', genes]), verbo([regulated]), complemento([by, 'TFs', and, miRNAs, may, jointly, contribute, to, the, abnormal, acetylation, and, mitochondrion, presentation, in, the, progression, of, 'VTE'])].
[sujeto(['Several', homoplasmic, pathologic, mutations, in, mitochondrial, 'DNA,', such, as, those]), verbo([causing]), complemento(['Leber', hereditary, optic, neuropathy, or, 'non-syndromic', hearing, 'loss,', show, incomplete, penetrance])].
[sujeto(['Here,', we]), verbo([have]), complemento([taken, an, evolutionary, approach, to, unmask, putative, modifying, factors, for, a, particular, homoplasmic, pathologic, mutation, causing, 'aminoglycoside-induced', and, 'non-syndromic', hearing, 'loss,', the, m])].
[sujeto(['These', mutations, are, called, compensated, pathogenic, deviations, because, an, organism, carrying, one, must, also]), verbo([have]), complemento([another, that, suppresses, the, deleterious, effect, of, the, first])].
[sujeto(['We']), verbo([found]), complemento([that, species, from, the, primate, family, 'Cercopithecidae', '(', old, world, 'monkeys)', harbor, the, m])].
[sujeto([1494, 'T', allele]), verbo([increases]), complemento([the, susceptibility, to, aminoglycosides])].
[sujeto(['Because', several, mutations, in, this, human, protein]), verbo([have]), complemento([been, 'described,', they, may, possibly, explain, the, absence, of, pathologic, phenotype, in, some, pedigree, members, with, the, most, frequent, pathologic, mutations, in, mitochondrial, ribosomal, 'RNA'])].
[sujeto(['tko(25t)']), verbo([has]), complemento([been, intensively, studied, as, an, animal, model, for, human, mitochondrial, diseases, associated, with, deficiency, of, mitochondrial, protein, synthesis, and, consequent, multiple, respiratory, chain, defects])].
[sujeto(['Transgenic', expression, in, 'Drosophila', of, the, alternative, oxidase, '(', 'AOX)', derived, from, 'Ciona', intestinalis]), verbo([has]), complemento([previously, been, shown, to, mitigate, the, toxicity, of, respiratory, chain, inhibitors, and, to, rescue, mutant, and, knockdown, phenotypes, associated, with, cytochrome, oxidase, deficiency])].
[sujeto(['We', therefore, tested, whether, 'AOX', expression, could, compensate, the, mutant, phenotype, of, 'tko(25t)', using, the, 'GeneSwitch', system, to]), verbo([activate]), complemento([expression, at, different, times, in, development])].
[sujeto(['However,', the, role, of, 'RPS12', in, gastric, cancer, is, not, 'clear,', which]), verbo([led]), complemento([us, to, conduct, the, current, study, to, further, investigate, the, effects, of, 'RPS12', on, the, proliferation, and, migration, of, gastric, cancer, 'cells,', and, also, to, explore, the, underlying, molecular, mechanisms])].
[sujeto(['RNA', interference, was, used, to]), verbo([inhibit]), complemento([the, expression, of, 'RPS12'])].
[sujeto(['We']), verbo([found]), complemento([that, 'RNAi‑mediated', 'RPS12', downregulation, led, to, reduced, proliferation, and, migration, of, 'BGC823', and, 'SGC7901', gastric, cancer, cells])].
[sujeto(['Further', results, showed, that, 'RPS12', inhibition]), verbo([led]), complemento([to, reduced, 'S100A4', expression, and, decreased, promoter, activity, of, 'S100A4', in, 'BGC823', cells])].
[sujeto(['Our', findings]), verbo([provide]), complemento([the, first, demonstration, that, 'RPS12', plays, important, roles, in, regulating, the, proliferation, and, migration, of, gastric, cancer, cells])].
[sujeto(['S100A4', can]), verbo([mediate]), complemento([the, effects, of, 'RPS12', as, a, downstream, effector])].
[sujeto(['However,', this, process, frequently]), verbo([causes]), complemento([hearing, damage])].
[sujeto(['Aminoglycosides,']), verbo([interacting]), complemento([with, mitochondrial, 'rRNAs,', alter, mitochondrial, protein, synthesis, and, the, oxidative, phosphorylation, 'system,', which, provide, most, of, the, energy, in, sensory, hair, cells])].
[sujeto(['For', this, 'reason,', we, hypothesized, that, genetic, variation, in, mitochondrial, rRNA, genes, and, in, two]), verbo([nuclear]), complemento([genes, coding, for, proteins, that, also, modify, the, susceptibility, to, aminoglycosides, might, affect, the, risk, of, hearing, loss, in, 'Ménière\'s', disease, patients, suffering, chemical, labyrinthectomy])].
[sujeto(['This', is, only, a, pilot, study, and, larger, studies, are]), verbo([required]), complemento([to, use, this, therapeutic, approach, in, a, rational, way, and, decrease, the, risk, of, hearing, damage])].
[sujeto(['An', efficient, and, simple, mechanism, for, neutralizing, deleterious, mitochondrial, 'DNA', '(', 'mtDNA)', alterations]), verbo([has]), complemento([unfortunately, remained, elusive])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, a, 20, -, ribonucleotide, 'stem-loop', sequence, from, the, 'H1', 'RNA,', the, 'RNA', component, of, the, human, 'RNase', 'P', 'enzyme,', appended, to, a, nonimported, 'RNA', directs, the, import, of, the, resultant, 'RNA', fusion, transcript, into, human, mitochondria])].
[sujeto(['In', 'addition,', 'nucleus-encoded', mRNAs, for, mitochondrial, 'proteins,', such, as, the, mRNA, of, human, mitochondrial, ribosomal, protein, 'S12', '(', 'MRPS12),', contain, regulatory, sequences, in, their, 3, '\'', -, untranslated, region, '(', 'UTR)', that]), verbo([confers]), complemento([localization, to, the, mitochondrial, outer, 'membrane,', which, is, postulated, to, aid, in, protein, translocation, after, translation])].
[sujeto(['We', show, that, for, some, 'mitochondrial-encoded', 'transcripts,', such, as, 'COX2,', a, 3, '\'', -, 'UTR', localization, sequence, is, not]), verbo([required]), complemento([for, mRNA, 'import,', whereas, for, corrective, 'mitochondrial-encoded', 'tRNAs,', appending, the, 3, '\'', -, 'UTR', localization, sequence, was, essential, for, efficient, 'fusion-transcript', translocation, into, mitochondria])].
[sujeto(['Thus,', this, study, indicates, that, a, wide, range, of, 'RNAs', can, be]), verbo([targeted]), complemento([to, mitochondria, by, appending, a, targeting, sequence, that, interacts, with, 'PNPASE,', with, or, without, a, mitochondrial, localization, 'sequence,', providing, an, 'exciting,', general, approach, for, overcoming, mitochondrial, genetic, disorders])].
[sujeto(['Unexpectedly,', we]), verbo([find]), complemento([in, the, small, teleost, fish, medaka, '(', 'Oryzias', 'latipes)', that, at, very, early, 'stages,', well, before, 'midblastula,', cell, division, becomes, asynchronous, and, cell, volumes, diverge])].
[sujeto(['Furthermore,', zygotic, transcription, is, extensively]), verbo([activated]), complemento([already, after, the, 64, -, cell, stage])].
[sujeto(['Ectopic,']), verbo([expressed]), complemento([copies, of, 'tko(25t)', and, mRpL14, conferred, no, phenotypic, suppression])].
[sujeto(['When', placed, over, a, null, allele, of, 'tko,', 'Weeble']), verbo([retained]), complemento([the, mutant, 'phenotype,', even, in, the, presence, of, additional, transgenic, copies, of, 'tko(25t)'])].
[sujeto(['In', 'mouse,', these, elements, were, shown, previously, to]), verbo([interact]), complemento([with, transcription, factor, 'NF-Y', and, to, be, required, for, efficient, transcription])].
[sujeto(['Here', we, show, that, the, 'CCAAT', boxes, of, the, human, promoter, also, influence, relative, transcriptional, activities, in, the, two, 'directions,', although, they, are, not, absolutely]), verbo([required]), complemento([for, transcription])].
[sujeto(['EMSA', indicated, that, 'NF-Y']), verbo([interacts]), complemento([with, the, array, in, two, alternate, ways, related, to, the, directional, selectivity, of, transcription])].
[sujeto(['Over-expression', of, 'wild-type', or, 'dominant-negative', 'NF-Y', affected, transcription, in, the, 'Sarsm', direction, 'only,', but, in, human, 'cells,', concomitant, expression, of, 'dominant-negative', constructs, for, other, factors, was, needed, to]), verbo([reveal]), complemento([such, effects])].
[sujeto(['We', propose, that, the, array, of, 'NF-Y', type, 'CCAAT', boxes]), verbo([maintains]), complemento([bidirectional, transcription, with, an, appropriate, directional, selectivity])].
[sujeto(['Computational', analysis, confirmed, that, 'NF-Y', type, 'CCAAT', boxes, are]), verbo([found]), complemento([preferentially, in, bidirectional, 'promoters,', but, many, such, promoters, lack, them, and, must, be, regulated, in, another, way])].
[sujeto([mRNA, localization, is, a]), verbo([conserved]), complemento(['post-transcriptional', process, crucial, for, a, variety, of, systems])].
[sujeto(['Although', several, mechanisms]), verbo([have]), complemento([been, 'identified,', emerging, evidence, suggests, that, most, transcripts, reach, the, protein, functional, site, by, moving, along, cytoskeleton, elements])].
[sujeto(['We', demonstrated, previously, that, mRNA, for, mitochondrial, ribosomal, proteins, are, asymmetrically, distributed, in, the, 'cytoplasm,', and, that, localization, in, the, proximity, of, mitochondria, is]), verbo([mediated]), complemento([by, the, 3, '\'', -, 'UTR'])].
[sujeto(['Here', we, show, by, biochemical, analysis, that, these, mRNA, transcripts, are]), verbo([associated]), complemento([with, the, cytoskeleton, through, the, microtubule, network])].
[sujeto(['Cytoskeleton', association, is, functional, for, their, intracellular, localization, near, the, 'mitochondrion,', and, the, 3, '\'', -, 'UTR', is]), verbo([involved]), complemento([in, this, 'cytoskeleton-dependent', localization])].
[sujeto(['To', identify, the, minimal, elements]), verbo([required]), complemento([for, 'localization,', we, generated, 'DNA', constructs, 'containing,', downstream, from, the, 'GFP', 'gene,', deletion, mutants, of, mitochondrial, ribosomal, protein, 'S12', 3, '\'', -, 'UTR,', and, expressed, them, in, 'HeLa', cells])].
[sujeto(['RNA', 'pull-down', 'assays,', mass, 'spectrometry,', and, 'RNP', immunoprecipitation, assay, 'experiments,', demonstrated, that, mitochondrial, ribosomal, protein, 'S12', 3, '\'', -, 'UTR']), verbo([interacts]), complemento([specifically, with, 'TRAP1', '(', tumor, necrosis, factor, 'receptor-associated', 'protein1),', hnRNPM4, '(', heterogeneous, nuclear, ribonucleoprotein, 'M4),', 'Hsp70', and, 'Hsp60', '(', heat, shock, proteins, 70, and, 60, ')', ',', and, 'alpha-tubulin', in, vitro, and, in, vivo])].
[sujeto(['Transcription', from, the, bidirectional, promoter, of, two, mouse, genes, encoding, components, of, the, mitochondrial, translational, 'apparatus,', mitoribosomal, protein, 'S12', '(', 'Mrps12)', and, mitochondrial, 'seryl-tRNA', ligase, '(', 'Sarsm),', was, shown, previously, to, be, dependent, upon, an, array, of, four, 'CCAAT', 'boxes,']), verbo([interacting]), complemento([with, the, transcription, factor, 'NF-Y'])].
[sujeto(['Here', we]), verbo([report]), complemento([that, the, homologous, human, promoter, is, governed, by, a, 'CCAAT', box, array, acting, in, an, essentially, similar, manner])].
[sujeto(['Analysis', of, the, transcriptional, response, of, both, the, human, and, mouse, promoters, to, various, mitochondrially]), verbo([acting]), complemento(['toxins,', including, inhibitors, of, mitochondrial, protein, 'synthesis,', and, agents, that, bring, about, uncoupling, or, respiratory, chain, 'inhibition,', produced, either, of, two, distinct, 'outcomes,', depending, on, the, cell, type, and, the, conditions, used])].
[sujeto(['Reporter', studies, using, mutated, variants, of, the, mouse, promoter, construct, indicated, that, the, stimulation, of, promoter, activity, in, response, to, mitochondrial, 'OXPHOS', stress, in, 3, 'T3', cells, was, independent, of, the, 'CCAAT', box, array, and, of, putative]), verbo([binding]), complemento([sites, for, 'NRF-2,', 'AP-1', and, other, transcription, 'factors,', whereas, transcriptional, downregulation, under, prolonged, mitochondrial, stress, was, 'CCAAT', 'box-dependent'])].
[sujeto(['Unravelling', gene, regulatory, mechanisms, in, human, filarial, parasites, will]), verbo([require]), complemento([an, understanding, of, their, basic, promoter, structure])].
[sujeto(['Only', a, single, promoter, from, a, human, filarial, parasite]), verbo([has]), complemento([been, characterised, in, 'detail,', the, 70, kDa, heat, shock, promoter, of, 'Brugia', malayi, '(', 'BmHSP70)'])].
[sujeto(['This', promoter, was]), verbo([found]), complemento([to, lack, features, found, in, a, typical, eukaryotic, promoter])].
[sujeto(['Deletion', of, these, repeats, resulted, in, the]), verbo([loss]), complemento([of, 80, '%', of, promoter, activity])].
[sujeto(['No', predicted]), verbo([binding]), complemento([sites, for, proteins, that, normally, associate, with, the, typical, eukaryotic, core, promoter, domains, were, found, in, the, essential, domains, or, the, repeat, region])].
[sujeto(['However,', the, repeat, region, contained, many, putative]), verbo([binding]), complemento([sites, for, 'GATAA', transcription, factor, family, proteins])].
[sujeto(['Of', 20, upstream, domains, of, other, ribosomal, protein, 'genes,', one, contained, a, repeat, structure, similar, to, that]), verbo([found]), complemento([in, the, 'BmRPS12', 'promoter,', and, the, majority, encoded, putative, 'GATAA', transcription, factor, binding, sites])].
[sujeto(['The', genes, for, mitoribosomal, protein, 'S12', '(', 'Mrps12)', and, mitochondrial, 'seryl-tRNA', ligase, '(', 'Sarsm', and, 'Sars2)', are, oppositely]), verbo([transcribed]), complemento([from, a, conserved, promoter, region, of, &, 'lt;200', bp, in, both, human, and, mouse])].
[sujeto(['Using', a, dual, reporter, vector, we, identified, an, array, of, 4, 'CCAAT', box, elements]), verbo([required]), complemento([for, efficient, transcription, of, the, two, genes, in, cultured, mouse, 3, 'T3', 'cells,', and, for, enforcing, directionality, in, favour, of, 'Mrps12'])].
[sujeto(['Electrophoretic', mobility, shift, assay, '(', 'EMSA)', and, in, vivo, footprinting, confirmed, the, importance, of, these, promoter, elements, as, sites, of, 'protein-binding,', and, 'EMSA', supershift, and, chromatin, immunoprecipitation, '(', 'ChIP)', assays, identified, 'NF-Y', as, the, key, transcription, factor, 'involved,']), verbo([revealed]), complemento([a, common, pattern, of, 'protein-DNA', interactions, in, all, tissues, tested, '(', 'liver,', 'brain,', 'heart,', kidney, and, 3, 'T3', 'cells)'])].
[sujeto([mRNA, localization, is, a]), verbo([conserved]), complemento(['post-transcriptional', process, crucial, for, a, variety, of, systems])].
[sujeto(['We']), verbo([have]), complemento([analyzed, the, subcellular, distribution, of, mRNAs, encoding, human, cytosolic, and, mitochondrial, ribosomal, proteins])].
[sujeto(['Biochemical', fractionation, experiments, showed, that, the, transcripts, for, cytosolic, ribosomal, proteins]), verbo([associate]), complemento([preferentially, with, the, cytoskeleton, via, actin, microfilaments])].
[sujeto(['Using', confocal, analysis, we, demonstrate, that, the, chimeric, transcript, is, specifically]), verbo([associated]), complemento([with, the, perinuclear, cytoskeleton])].
[sujeto(['We', previously, showed, that, polyadenylation]), verbo([stimulates]), complemento([turnover, of, unedited, 'RNAs'])].
[sujeto(['The', same, minimal, edited, sequence, that]), verbo([stimulates]), complemento([decay, of, nonadenylated, 'RNA', is, sufficient, to, switch, the, 'poly(A)', tail, from, a, destabilizing, to, a, stabilizing, element])].
[sujeto(['Titration', of, 'poly(A)', into, 'RNA', degradation, reactions]), verbo([has]), complemento([no, effect, on, turnover, of, polyadenylated, edited, 'RNA'])].
[sujeto(['These', results]), verbo([suggest]), complemento([the, presence, of, a, protective, 'protein(s)', that, simultaneously, recognizes, the, 'poly(A)', tail, and, small, edited, element, and, which, blocks, the, action, of, a, 3, '\'', -, 5, '\'', exonuclease])].
[sujeto(['This', study]), verbo([provides]), complemento([the, first, evidence, for, opposing, effects, of, polyadenylation, on, 'RNA', stability, within, a, single, organelle, and, suggests, a, novel, and, unique, regulation, of, 'RNA', turnover, in, this, system])].
[sujeto([parasuis, so, 'far,', in, vivo, studies, about, the, role, of, its, genes]), verbo([involved]), complemento([in, virulence, are, unfeasible])].
[sujeto([parasuis]), verbo([has]), complemento([a, cyclic, 'AMP', '(', 'cAMP)-dependent', natural, transformation, system, that, enables, the, uptake, of, 'DNA', in, which, the, 'ACCGAACTC', sequence, signal, must, be, present])].
[sujeto([parasuis, defective, in, the, thy, 'gene,', encoding, the, thymidylate, synthase, 'enzyme,']), verbo([has]), complemento([been, constructed])].
[sujeto(['Data', presented, in, this, work, open, the, possibility, for, the, functional, analysis, of, genes]), verbo([involved]), complemento([in, the, infectious, process, of, this, animal, pathogen])].
[sujeto(['To', identify, esophageal, cancer, related, gene2, '(', 'ECRG2)']), verbo([associated]), complemento([proteins, and, their, possible, interactions, with, 'ECRG2', gene])].
[sujeto(['We']), verbo([found]), complemento([the, following, 9, putatively, associated, proteins])].
[sujeto([2, ',', mitochondrial, ribosomal, protein, 'S12,', hypothetical, protein, 'FLJ10101,', and, a, novel, gene, whose, cDNA, was]), verbo([found]), complemento([to, have, no, strong, homology, to, any, other, previously, characterized, gene, whose, 'DDBJ/EMBL/GenBank', accession, number, is, 'AF422192', mapped, to, human, chromosome, 14, q31])].
[sujeto(['MT,', a, potential, interaction, partner, for, 'ECRG2,', might, be]), verbo([involved]), complemento([in, the, regulation, of, cell, proliferation, and, 'apoptosis,', and, in, various, physiological, processes])].
[sujeto(['scabiei,', which]), verbo([has]), complemento([been, blamed, for, the, extinction, of, populations, of, wombats, in, 'Australia,', may, be, a, parasitic, mite, that, was, introduced, to, 'Australia', with, people, 'and/or', their, dogs])].
[sujeto(['Mutations', in, 'mtDNA-encoded', components, of, the, mitochondrial, translational, apparatus, are]), verbo([associated]), complemento([with, diverse, pathological, states, in, 'humans,', notably, sensorineural, deafness])].
[sujeto(['To', develop, animal, models, of, such, 'disorders,', we]), verbo([have]), complemento([manipulated, the, nuclear, gene, for, mitochondrial, ribosomal, protein, 'S12', in, 'Drosophila', '(', technical, 'knockout,', 'tko)'])].
[sujeto(['On', the, basis, of, a, transgenic, reversion, 'test,', these, phenotypes, are, attributable, to, a, single, substitution, '(', 'L85H)', at, a]), verbo([conserved]), complemento([residue, of, the, tko, protein])].
[sujeto(['The', mutant, is, hypersensitive, to, 'doxycyclin,', an, antibiotic, that, selectively]), verbo([inhibits]), complemento([mitochondrial, protein, 'synthesis,', and, mutant, larvae, have, greatly, diminished, activities, of, mitochondrial, redox, enzymes, and, decreased, levels, of, mitochondrial, 'small-subunit', rRNA])].
[sujeto(['We', infer, that, the, 'tko(25t)', mutant]), verbo([provides]), complemento([a, model, of, mitochondrial, hearing, impairment, resulting, from, a, quantitative, deficiency, of, mitochondrial, translational, capacity])].
[sujeto(['Both', genes, are, plausible, candidates, for, 'DFNA4,', based, on, the, fact, that, deafness, mutations, in, mtDNA]), verbo([have]), complemento([been, mapped, both, to, 'tRNA-ser(UCN)', and, to, the, accuracy, domain, of, the, small, subunit, rRNA])].
[sujeto(['We']), verbo([have]), complemento([sequenced, the, coding, 'regions,', proximal, 'promoters,', 5, '\'', and, 3, '\'', 'UTR', and, splice, junctional, regions, of, both, genes, in, two, families, with, 'DFNA4-linked', deafness, and, in, controls])].
[sujeto(['Novel', polymorphisms, 84425, 'C>T,', 83907, 'A>G,', 79485, 'T>G,', 79406, 'C>T,', 71755, 'A>C', and, 68686, 'C>G', '(', numbered, as, in, 'GenBank', 'AC011455)', were]), verbo([found]), complemento([in, one, or, both, 'families,', but, none, is, a, plausible, 'disease-causing', mutation])].
[sujeto(['Although', regulatory, mutations, affecting, either, gene, could, still, be]), verbo([involved]), complemento([in, the, 'phenotype,', structural, gene, mutations, affecting, 'SARSM', or, 'RPMS12', can, be, excluded, from, consideration, as, the, cause, of, 'DFNA4-linked', 'deafness,', at, least, in, the, families, identified, thus, far])].
[sujeto(['The', full, 5, '\'', -, 'UTR', contains, two, types, of, sequence, element, implicated, elsewhere, in, translational, regulation, as, 'follows:', a, short, upstream, open, reading, frame, and, an, oligopyrimidine, tract, similar, to, that]), verbo([found]), complemento([at, the, 5, '\'', end, of, mRNAs, encoding, other, 'growth-regulated', 'proteins,', including, those, of, cytosolic, ribosomes])].
[sujeto(['By', 'contrast,', other, splice, variants, containing, one, or, both, of, these, elements, are, not, translationally]), verbo([regulated]), complemento([by, growth, status, but, are, translated, poorly, in, both, growing, and, 'non-growing', cells])].
[sujeto(['These', findings, indicate, a, 'complex,', multilevel, regulation, of, 'RPMS12', gene, expression, in, response, to, signals]), verbo([mediating]), complemento(['growth,', tissue, 'specialization,', and, probably, metabolic, needs])].
[sujeto(['The', ribosomal, 'RNA', components, of, the, mitochondrial, ribosomes, are, coded, for, by, mitochondrial, 'DNA,', while, all, the, protein, subunits, are, coded, for, by]), verbo([nuclear]), complemento([chromosomes])].
[sujeto(['We']), verbo([have]), complemento([now, cloned, the, gene, for, the, human, mitochondrial, ribosomal, protein, 'S12,', termed, 'RPMS12,', based, on, its, homology, to, the, 'Drosophila', tko, gene])].
[sujeto(['The', mRNA, is, predicted, to, be]), verbo([translated]), complemento([to, a, prepeptide, of, 138, amino, acids, in, length, and, processed, to, a, peptide, of, 112, aa, and, a, molecular, mass, of, 12.3, kDa])].
[sujeto(['The', protein, is, very, 'basic,', with, a, predicted, pI, of, 10.3, ',', and, is, highly]), verbo([conserved]), complemento([through, evolution])].
[sujeto(['We']), verbo([have]), complemento([mapped, the, chromosomal, locations, of, three, human, nuclear, genes, for, putative, components, of, the, apparatus, of, mitochondrial, gene, 'expression,', using, a, combination, of, in, situ, hybridization, and, interspecies, hybrid, mapping])].
[sujeto(['The', genes, 'RPMS12', '(', mitoribosomal, protein, 'S12,', a]), verbo([conserved]), complemento([protein, component, of, the, mitoribosomal, accuracy, 'center),', 'TUFM', '(', mitochondrial, elongation, factor, 'EF-Tu),', and, 'AFG3L1', '(', similar, to, the, yeast, genes, 'Afg3', and, 'Rca1', involved, in, the, turnover, of, mistranslated, or, misfolded, 'mtDNA-encoded', 'polypeptides)', were, initially, characterized, by, a, combination, of, database, sequence, 'analysis,', 'PCR,', 'cloning,', and, 'DNA', sequencing])].
[sujeto([1, ',', close, to, the, previously, mapped, gene, for, autosomal, dominant, hearing]), verbo([loss]), complemento(['DFNA4'])].
[sujeto(['To', explore, the, phylogenetic, relationships, within, 'Chinese', 'Rubus,', inferences, upon, three, chloroplast, 'DNA', '(', 'rbcL,', 'rpl20-rps12,', and, 'trnG-trnS),']), verbo([nuclear]), complemento([ribosomal, 'ITS,', and, two, 'low-copy', nuclear, markers, '(', 'GBSSI-2', and, 'PEPC)', were, deduced, in, 142, 'Rubus', taxa, from, 17, subsections, in, 6, sections])].
[sujeto(['Phylogenetic', relationships, within, 'Rubus', were, 'well-resolved', by, combined]), verbo([nuclear]), complemento([datasets, rather, than, chloroplast, markers])].
[sujeto(['This']), verbo([suggests]), complemento([that, some, polyploids, of, 'Malachobatus', might, originate, from, common, 'ancestors,', via, polyploidization, of, hybrids, between, 'R'])].
[sujeto(['Section', 'Dalibardastrum', species]), verbo([have]), complemento([potential, parental, lineages, from, subsects])].
[sujeto(['Based', on, molecular, 'phylogenies,', we, also]), verbo([provided]), complemento([recommendations, for, the, taxonomic, treatments, of, four, taxa])].
[sujeto(['In', 'addition,', our, results, showed, certain, incongruence, between, chloroplast, and]), verbo([nuclear]), complemento(['markers,', which, might, be, due, to, hybridization, and, introgression])].
[sujeto(['In', 'addition,', the, organization, and, structure, of, plastomes, is, 'fluid,', and, rearrangements, through, time]), verbo([have]), complemento([repeatedly, shuffled, genes, into, and, out, of, the, 'IR,', providing, recurrent, natural, experiments, on, how, chloroplast, genome, structure, can, impact, rates, and, patterns, of, molecular, evolution])].
[sujeto(['Taken', 'together,', our, results]), verbo([suggest]), complemento([that, the, 'IR', region, not, only, reduces, substitution, 'rates,', but, also, impacts, nucleotide, composition])].
[sujeto(['This']), verbo([finding]), complemento([highlights, a, potential, vulnerability, of, correlating, substitution, rate, heterogeneity, with, organismal, life, history, traits, without, knowledge, of, the, underlying, genome, structure])].
[sujeto(['Complex', geological, movements, more, or, less, affected, or, changed, floristic, 'structures,', while, the, alternation, of, glacials, and, interglacials, is, presumed, to]), verbo([have]), complemento([further, shaped, the, present, discontinuous, genetic, pattern, of, temperate, plants])].
[sujeto(['Here', we, consider, 'Capparis', 'spinosa,', a, xeromorphic, 'Tethyan', 'relict,', to, discuss, its, divergence, pattern, and, explore, how, it]), verbo([responded]), complemento([in, a, stepwise, fashion, to, 'Pleistocene', geologic, and, climatic, changes])].
[sujeto(['AMOVA']), verbo([suggests]), complemento([that, gene, flow, between, them, might, be, restricted, by, vicariance])].
[sujeto(['Species', distribution, modeling]), verbo([suggests]), complemento([range, reduction, in, the, high, mountains, during, the, 'Last', 'Glacial', 'Maximum', '(', 'LGM)', as, a, result, of, cold, climates, when, glacier, 'advanced,', while, gorges, at, midelevations, in, 'Tianshan', appear, to, have, served, as, refugia])].
[sujeto([genes]), verbo([regulated]), complemento([by, hypoxia, in, eight, cervical, cancer, cell, lines, or, correlating, with, the, 'hypoxia-associated', dynamic, 'contrast-enhanced', magnetic, resonance, imaging, parameter, 'ABrix', in, 42, 'patients,', were, excluded])].
[sujeto(['Among', the, 182, 'genes,', nine, candidates, '(', 'CHCHD1,', 'GNB2L1,', 'IPO8,', 'LASP1,', 'RPL27A,', 'RPS12,', 'SOD1,', 'SRSF9,', 'TMBIM6)', that, were, not]), verbo([associated]), complemento([with, tumor, 'volume,', 'stage,', lymph, node, involvement, or, disease, progression, in, array, data, of, 150, 'patients,', were, selected, for, further, testing, by, 'RT-qPCR'])].
[sujeto([5, ',', n, =, 32, ')', ',', and, the, 'STC2', data, were]), verbo([associated]), complemento([with, clinical, 'outcome,', in, accordance, with, the, 'Illumina', data])].
[sujeto(['We', sequence, the]), verbo([nuclear]), complemento([ribosomal, internal, transcribed, spacer, '(', 'ITS)', 'regions,', 'matK,', 'rbcL,', 'rpoC1,', trnL, '(', 'UAA),', 'psbA-trnH,', 'atpB-rbcL,', 'trnS(', 'GCU)-trnG(UCC),', 'rpl20-rps12,', 'trnL(UAA)-trnF(', 'GAA)', fragments, of, cp, 'DNA', in, both, 'G'])].
[sujeto(['With', 'Halenia', elliptica, as, the, 'outgroup,', molecular, systematic, analysis]), verbo([reveals]), complemento([that, 'G'])].
[sujeto(['Our', studies, may]), verbo([provide]), complemento([valuable, reference, for, the, species, identifications, of, medicinal, plants, with, complex, genetic, backgrounds])].
[sujeto(['Cytoplasmic', 'male-sterility', '(', 'CMS)']), verbo([conferred]), complemento([by, the, 'CMS-S', cytoplasm, has, been, most, commonly, used, for, onion, '(', 'Allium', cepa, 'L'])].
[sujeto(['We', first]), verbo([report]), complemento([the, complete, mitochondrial, genome, sequence, containing, 'CMS-S', cytoplasm, in, this, study])].
[sujeto(['Unusual', 'trans-splicing', of, the, cox2, gene, was, 'verified,', and, the, cox1, gene, was, identified, as, part, of, the, chimeric, orf725, 'gene,', which, is, a, candidate, gene, responsible, for]), verbo([inducing]), complemento(['CMS'])].
[sujeto(['The', complete, onion, mitochondrial, genome, sequence]), verbo([reported]), complemento([in, this, study, would, be, fundamental, information, for, elucidation, of, onion, 'CMS', evolution])].
[sujeto(['Our', studies, may]), verbo([provide]), complemento([reference, for, the, genetic, diversity, analysis, and, molecular, identification, of, the, three, 'Tibetan', herbs])].
[sujeto(['The', toxic, effects, of, 'MCLR', on, the, expression, of, some, organelles, genes, '(', 'mitochondrion,', endoplasmic, 'reticulum,', and, cytoskeleton, 'etc)']), verbo([have]), complemento([been, widely, 'investigated,', but, little, is, known, how, it, impacts, on, the, expression, of, ribosomal, genes])].
[sujeto(['In', this, study, we, identified, seven, ribosomal, protein, genes, 'RPS6,', 'RPS12,', 'RPS24,', 'RPS27a,', 'RPL12,', 'RPL27', and, 'RPL29', in, bighead, carp, '(', 'Aristichthys', 'nobilis),', whose, expression, was]), verbo([regulated]), complemento([by, 'MCLR'])].
[sujeto(['The', amino, acid, sequences, of, those, 7, genes, shared, more, than, 90, '%', identity, with, corresponding, sequences, from, 'zebrafish,', and, were, well]), verbo([conserved]), complemento([throughout, evolution])].
[sujeto(['Recent', research]), verbo([has]), complemento([convincingly, documented, cases, of, mitochondrial, heteroplasmy, in, a, small, set, of, wild, and, cultivated, plant, species])].
[sujeto(['The', role, of, mitochondrial, heteroplasmy, is, of, particular, interest, in, plants, as, cytoplasmic, male, sterility, is, controlled, by, mitochondrial, 'genotypes,', sometimes]), verbo([leading]), complemento([to, 'co-occurring', female, and, hermaphroditic, individuals, '(', 'gynodioecy)'])].
[sujeto(['We', conducted, a, genetic, survey, of, the, gynodioecious, plant, 'Plantago', 'lanceolata,', in, which, heteroplasmy]), verbo([has]), complemento([not, previously, been, 'reported,', and, estimated, the, frequencies, of, mitochondrial, genotypes, and, heteroplasmy])].
[sujeto(['These', were, distributed, among, 6, of, the, 10, populations, that, had, polymorphisms, in, the]), verbo([target]), complemento([loci, and, represented, 8, '%', of, all, sampled, individuals, and, 15, '%', of, the, individuals, in, those, 6, populations])].
[sujeto(['Our', results, are, consistent, with, geographic, differences, in, the, incidence, of, paternal, leakage, 'and/or', the, rates, of]), verbo([nuclear]), complemento([restoration, of, male, fertility])].
[sujeto(['This', complex, process]), verbo([requires]), complemento([the, coordinated, use, of, several, multiprotein, complexes, as, well, as, the, sequential, use, of, noncoding, template, 'RNAs', called, guide, 'RNAs'])].
[sujeto(['Here,', we]), verbo([report]), complemento([a, novel, method, for, sequencing, entire, populations, of, 'pre-edited', partially, 'edited,', and, fully, edited, 'RNAs', and, analyzing, editing, characteristics, across, populations, using, a, new, bioinformatics, 'tool,', the, 'Trypanosome', 'RNA', 'Editing', 'Alignment', 'Tool', '(', 'TREAT)'])].
[sujeto(['Using', 'TREAT,', we, examined, populations, of, two, 'transcripts,', 'RPS12', and, 'ND7-5\',', in, 'wild-typeTrypanosoma', brucei, 'We']), verbo([provide]), complemento([evidence, that, the, majority, of, partially, edited, sequences, contain, 'junctions,', that, intrinsic, pause, sites, arise, during, the, progression, of, 'editing,', and, that, the, mechanisms, that, mediate, pausing, in, the, generation, of, canonical, fully, edited, sequences, are, distinct, from, those, that, mediate, the, ends, of, junction, regions])].
[sujeto(['Plastid', genomes, of, photosynthetic, flowering, plants, are, usually, highly]), verbo([conserved]), complemento([in, both, structure, and, gene, content])].
[sujeto(['However,', the, plastomes, of, parasitic, and, mycoheterotrophic, plants, may, be]), verbo([released]), complemento([from, selective, constraint, due, to, the, reduction, or, loss, of, photosynthetic, ability])].
[sujeto(['The', inverted, repeat, and, the, small, single, copy, region, are, only, approximately, 1.5, 'kb,', and, intergenic, regions]), verbo([have]), complemento([been, drastically, reduced])].
[sujeto(['Gene', sequences, in, 'Hydnora', are, highly, divergent, and, several, complementary, approaches, using, the, highest, possible, sensitivity, were]), verbo([required]), complemento([for, identification, and, annotation, of, this, plastome])].
[sujeto(['The', 'whole-genome', shotgun, read, depth, is, 1, ',', 400, ×, coverage, for, the, 'plastome,', whereas, the, mitochondrial, genome, is, covered, at, 40, ×, and, the]), verbo([nuclear]), complemento([genome, at, 2, ×])].
[sujeto(['Despite', the, extreme, reduction, of, the, genome, and, high, sequence, 'divergence,', the, presence, of, 'syntenic,', long, transcriptionally, active, 'open-reading', frames, with, distant, similarity, to, other, plastid, genomes, and, a, high, plastome, stoichiometry, relative, to, the, mitochondrial, and]), verbo([nuclear]), complemento([genomes, suggests, that, the, plastome, remains, functional, in, 'H'])].
[sujeto(['A', maximum, likelihood, phylogenetic, analysis, showed, that, this, newly, characterized, 'Cunninghamia', lanceolata, chloroplast, genome, will]), verbo([provide]), complemento([essential, data, for, further, study, on, phylogenetic, 'resolution,', biodiversity, for, the, genus, 'Cunninghamia', and, 'Taxodiacea'])].
[sujeto(['The', haemoflagellate, 'Trypanosoma', lewisi, is, a, kinetoplastid, parasite, 'which,', as, it]), verbo([has]), complemento([been, recently, reported, to, cause, human, 'disease,', deserves, increased, attention])].
[sujeto(['We']), verbo([have]), complemento([sequenced, and, comprehensively, annotated, the, kinetoplast, maxicircle, of, 'T'])].
[sujeto(['Our', analysis]), verbo([reveals]), complemento([that, 'T'])].
[sujeto(['These', findings]), verbo([provide]), complemento([novel, insight, into, the, biological, features, of, this, emerging, human, pathogen])].
[sujeto(['The', two, chloroplast, genomes]), verbo([have]), complemento([an, identical, composition, with, each, other, as, a, circular, molecule, of, 150, 931, bp, in, 'length,', with, an, overall, 'GC', content, of, 36.4, '%'])].
[sujeto(['The', two, newly, sequenced, chloroplast, genomes]), verbo([provide]), complemento([valuable, information, for, detecting, polymorphisms, within, species, and, between, sexes])].
[sujeto(['We']), verbo([have]), complemento([sequenced, the, highly, reduced, mitochondrial, genome, of, 'Perkinsela,', which, possesses, only, six, 'protein-coding', genes, '(', 'cox1,', 'cox2,', 'cox3,', 'cob,', 'atp6,', and, 'rps12),', despite, the, fact, that, the, organelle, itself, contains, more, 'DNA', than, is, present, in, either, the, host, or, endosymbiont, nuclear, genomes])].
[sujeto(['We']), verbo([have]), complemento([developed, software, tools, for, accurate, and, exhaustive, mapping, of, transcriptome, sequencing, '(', 'RNA-seq)', reads, with, extensive, 'U-insertions/deletions,', which, allows, detailed, investigation, of, 'RNA', editing, via, deep, sequencing])].
[sujeto(['Uridine', 'insertion/deletion-type', 'RNA', 'editing,', which, occurs, in, the, mitochondrion, of, kinetoplastid, 'protists,']), verbo([has]), complemento([been, 'well-studied', in, the, model, parasite, genera, 'Trypanosoma,', 'Leishmania,', and, 'Crithidia'])].
[sujeto(['Perkinsela']), verbo([provides]), complemento([a, unique, opportunity, to, broaden, our, knowledge, of, 'RNA', editing, machinery, from, an, evolutionary, 'perspective,', as, it, represents, the, earliest, kinetoplastid, branch, and, is, an, obligatory, endosymbiont, with, extensive, reductive, trends])].
[sujeto(['Platycodin', 'D', '(', 'PD),', a, triterpenoid, saponin, isolated, from, 'Platycodonis', 'Radix,', is, a, famous, 'Chinese', herbal, medicine, that]), verbo([has]), complemento([been, shown, to, have, 'anti-proliferative', effects, in, several, cancer, cell, lines])].
[sujeto(['Our', results, showed, that, 'PD']), verbo([inhibited]), complemento([the, proliferation, of, 'HepG2', cells, in, 'concentration-', and, 'time-dependent', manners])].
[sujeto([',', 'RPS12,', 'EMG1,', and, 'KRT1)']), verbo([decreased]), complemento([in, 'HepG2', cells, after, treatment, with, 'PD'])].
[sujeto(['The', complete, chloroplast, '(', 'cp)', genome, sequence, of, the, 'Euonymus', 'japonicus,', the, first, sequenced, of, the, genus, 'Euonymus,', was]), verbo([reported]), complemento([in, this, study])].
[sujeto(['Persistent', 'HIV', reservoirs, and, the, absolute, quantification, of, viral, 'RNA', copies, in, tissues]), verbo([have]), complemento([become, a, prominent, focus, of, multiple, areas, 'ofHIV/SIV', research])].
[sujeto(['Among', the, 'mutants,', 'S13', displayed, the, greatest]), verbo([increase]), complemento([in, the, yield, of, 'butenyl-spinosyns,', which, was, 1.79, fold, higher, than, that, in, the, parent, strain])].
[sujeto(['Further', analysis, of, the, metabolite, profile, of, 'S13', by, mass, spectrometry]), verbo([lead]), complemento([to, the, discovery, of, 'Spinosyn', 'α1,', which, was, absent, from, the, parent, strain])].
[sujeto(['DNA', sequencing, showed, that, there, existed, two, point, mutations, in, the]), verbo([conserved]), complemento([regions, of, rpsL, gene, which, encodes, ribosomal, protein, 'S12', in, 'S13'])].
[sujeto(['Translocation', of, mRNA, and, tRNA, through, the, ribosome, is]), verbo([associated]), complemento([with, 'large-scale', rearrangements, of, the, head, domain, in, the, 30, 'S', ribosomal, subunit])].
[sujeto(['Here', we]), verbo([provide]), complemento([a, statistical, analysis, of, 250, spontaneous, transitions, between, the, 'A/P-P/E', and, 'P/P-E/E', ensembles])].
[sujeto(['The', accuracy, of, the, determination, of, a]), verbo([target]), complemento([gene, expression, level, by, 'RT-qPCR', demands, the, use, of, appropriate, reference, genes, to, normalize, the, mRNA, levels, among, different, samples])].
[sujeto(['However,', suitable, reference, genes, for, 'RT-qPCR']), verbo([have]), complemento([not, been, identified, in, 'Sacha', inchi, '(', 'Plukenetia', 'volubilis),', a, promising, oilseed, crop, known, for, its, polyunsaturated, fatty, acid, '(', 'PUFA)-rich', seeds])].
[sujeto(['Our', results]), verbo([provide]), complemento([useful, guidelines, for, the, selection, of, reliable, reference, genes, for, the, normalization, of, 'RT-qPCR', data, for, seedlings, and, adult, 'plants,', for, reproductive, 'organs,', and, for, the, entire, growth, cycle, of, 'Sacha', inchi])].
[sujeto(['The', pink, stem, 'borer,', 'Sesamia', 'inferens,', which, is, endemic, in, 'China', and, other, parts, of, 'Asia,', is, a, major, pest, of, rice, and]), verbo([causes]), complemento([significant, yield, loss, in, this, host, plant])].
[sujeto(['Very', few, studies]), verbo([have]), complemento([addressed, gene, expression, in, 'S'])].
[sujeto(['To', validate, this, 'recommendation,', the, expression, profile, of, a]), verbo([target]), complemento([gene, heat, shock, protein, 83, gene, '(', 'hsp83)', was, 'investigated,', and, results, showed, the, selection, was, necessary, and, effective])].
[sujeto(['Specifically,', this, method, is, based, on, 'next-generation', 'sequencing,', which, theoretically, can]), verbo([provide]), complemento([footprint, counts, that, correspond, to, the, probability, of, observing, a, ribosome, in, this, position, for, each, nucleotide, in, each, transcript])].
[sujeto(['In', this, 'study,', we]), verbo([report]), complemento([for, the, first, time, various, novel, properties, of, the, distribution, of, codon, footprint, counts, in, five, 'organisms,', based, on, 'large-scale', analysis, of, ribosomal, profiling, data])].
[sujeto(['We', show, that, codons]), verbo([have]), complemento([distinctive, footprint, count, distributions])].
[sujeto(['These', tend, to, be, preserved, along, the, inner, part, of, the, 'ORF,', but, differ, at, the, 5, '\'', and, 3, '\'', ends, of, the, 'ORF,']), verbo([suggesting]), complemento([that, the, 'translation-elongation', stage, actually, includes, three, biophysical, 'sub-steps'])].
[sujeto(['In', 'addition,', we, study, various, basic, properties, of, the, codon, footprint, count, distributions, and, show, that, some, of, them, correlate, with, the, abundance, of, the, tRNA, molecule, types]), verbo([recognizing]), complemento([them])].
[sujeto(['Previous', evidence, indicates, that, a, number, of, proteins, are, able, to]), verbo([interact]), complemento([with, cognate, mRNAs])].
[sujeto(['Using', the, catRAPID, approach, to, predict, the, propensity, of, proteins, to]), verbo([bind]), complemento([to, 'RNA,', we, investigated, the, occurrence, of, autogenous, associations, in, the, human, proteome])].
[sujeto(['Our', algorithm, correctly, identified]), verbo([binding]), complemento([sites, in, 'well-known', cases, such, as, thymidylate, 'synthase,', tumor, suppressor, 'P53,', 'synaptotagmin-1,', 'serine/ariginine-rich', splicing, factor, 2, ',', heat, shock, 70, 'kDa,', ribonucleic, 'particle-specific', 'U1A', and, ribosomal, protein, 'S13'])].
[sujeto(['In', 'addition,', we]), verbo([found]), complemento([that, several, other, proteins, are, able, to, bind, to, their, own, mRNAs])].
[sujeto(['A', 'large-scale', analysis, of, biological, pathways, revealed, that, 'aggregation-prone', and, structurally, disordered, proteins]), verbo([have]), complemento([the, highest, propensity, to, interact, with, cognate, 'RNAs'])].
[sujeto(['Among', the, amyloidogenic, 'proteins,', we, predicted, that, 'Parkinson\'s', 'disease-related', 'α-synuclein', is, highly, prone, to]), verbo([interact]), complemento([with, cognate, 'transcripts,', which, suggests, the, existence, of, 'RNA-dependent', factors, in, its, function, and, dysfunction])].
[sujeto([lycopersicum]), verbo([has]), complemento([been, sequenced])].
[sujeto(['Parallel', with, the, development, of, contemporary, genetics, and, the, constant]), verbo([increase]), complemento([in, sequencing, 'data,', progress, has, to, be, aligned, with, improvement, of, experimental, methods, used, for, studying, genes, functions, and, gene, expression, 'levels,', of, which, the, quantitative, polymerase, chain, reaction, '(', 'qPCR)', is, still, the, most, reliable])].
[sujeto(['As', well, as, with, other, nucleic, 'acid-based', methods, used, for, comparison, of, the, abundance, of, specific, 'RNAs,', the, 'RT-qPCR', data]), verbo([have]), complemento([to, be, normalised, to, the, levels, of, 'RNAs', represented, stably, in, a, cell])].
[sujeto([',', 'RNAs', 'encoding,', for, 'instance,', proteins, playing, an, important, role, in, the, cell, metabolism, or, structure, 'maintenance),', are, used, for, normalisation, of, the]), verbo([target]), complemento([gene, expression, data])].
[sujeto(['However,', a, number, of, studies]), verbo([have]), complemento([indicated, the, transcriptional, instability, of, commonly, used, reference, genes, analysed, in, different, situations, or, 'conditions;', for, 'instance,', the, origin, of, 'cells,', tissue, 'types,', or, environmental, or, other, experimental, conditions])].
[sujeto(['Changes', in, the, expression, levels, of, the, genes, were, estimated, by, comparison, of, the, 'non-inoculated', tomato, plants, with, those, infected, with, commonly, known, tomato, viral, 'pathogens,', 'Tomato', torrado, 'virus,', 'Cucumber', mosaic, 'virus,', 'Tobacco', mosaic, virus, and, 'Pepino', mosaic, 'virus,']), verbo([inducing]), complemento([a, diverse, range, of, disease, symptoms, on, the, common, 'host,', ranging, from, mild, leaves, chlorosis, to, very, severe, stem, necrosis])].
[sujeto(['In', protein, 'synthesis,', elongation, factor, 'G', '(', 'EF-G)', facilitates, movement, of, 'tRNA-mRNA', by, one, 'codon,', which, is, coupled, to, the, 'ratchet-like', rotation, of, the, ribosome, complex, and, is]), verbo([triggered]), complemento([by, 'EF-G-mediated', 'GTP', hydrolysis])].
[sujeto(['Here', we]), verbo([report]), complemento([the, structure, of, a, pretranslocational, ribosome, bound, to, 'Thermus', thermophilus, 'EF-G', trapped, with, a, 'GTP', analog])].
[sujeto(['The', positioning, of, the, catalytic, 'His87', into, the, active, site, coupled, to, 'hydrophobic-gate', opening]), verbo([involves]), complemento([the, 23, 'S', rRNA, 'sarcin-ricin', loop, and, domain, 'III', of, 'EF-G', and, provides, a, structural, basis, for, the, 'GTPase', activation, of, 'EF-G'])].
[sujeto(['It', is, known, that, 'Mg2+', ions, at, high, concentrations, stabilize, the, structure, of, the, 16, 'S', rRNA, in, a, conformation, favorable, for]), verbo([binding]), complemento([to, the, ribosomal, proteins, in, the, course, of, the, eubacterial, 30, 'S', ribosomal, subunits, assembly, in, vitro])].
[sujeto(['In', this, 'paper,', we, show, that, the, sequentional]), verbo([increase]), complemento([of, the, 'Mg2+', concentration, from, 0.5, mM, to, 20, mM, leads, to, a, significant, decrease, of, the, affinity, of, recombinant, human, ribosomal, protein, 'S13', '(', 'rpS13e)', to, a, 'RNA', transcript, corresponding, to, the, central, domain, fragment, of, the, 18, 'S', rRNA, '(', 18, 'SCD)'])].
[sujeto(['The', regions, near, the, rpS13e]), verbo([binding]), complemento([site, in, 18, 'SCD', '(', including, the, nucleotides, of, helices, 'H20', and, 'H22),', whose, availabilities, to, hydroxyl, radicals, were, dependent, on, the, 'Mg2+', 'concentration,', were, determined])].
[sujeto(['It', was]), verbo([found]), complemento([that, increase, of, the, concentrations, of, 'Mg2+', results, in, the, enhanced, accessibilities, of, nucleotides, 'G933-C937', and, 'C1006-A1009', in, helix, 'H22', and, reduces, those, of, nucleotides, 'A1023,', 'A1024,', and, 'A1028-S1026', in, the, helix, 'H20'])].
[sujeto(['Comparison', of, the, results, obtained, with, the, crystallographic, data, on, the, structure, of, the, central, domain, of, 18, 'S', rRNA, in, the, 40, 'S', ribosomal, subunit]), verbo([led]), complemento([to, conclusion, that, increase, of, 'Mg2+', concentrations, results, in, the, reorientation, of, helices, 'H20', and, 'H24', relatively, helices, 'H22', and, 'H23', to, form, a, 'structure,', in, which, these, helices, are, positioned, the, same, way, as, in, 40, 'S', subunits])].
[sujeto(['Hence,', saturation, of, the, central, domain, of, 18, 'S', rRNA, with, coordinated, 'Mg2+', ions]), verbo([causes]), complemento([the, same, changes, in, its, structure, as, rpS13e, binding, 'does,', and, leads, to, decreasing, of, this, domain, affinity, to, the, protein])].
[sujeto(['We', here, present, the, first, structure, of, a, cognate, tRNA]), verbo([bound]), complemento([to, the, ribosomal, 'E', site, resulting, from, translocation, by, 'EF-G,', in, which, an, entire, 'L1', stalk, '(', 'L1', protein, and, 'L1', 'rRNA)', interacts, with, 'E-site', tRNA, '(', 'E-tRNA),', representing, an, authentic, ribosome, elongation, complex])].
[sujeto(['Analysis', of, the, observed, conformations, of, mRNA, and, 'E-tRNA']), verbo([suggests]), complemento([that, the, ribosome, intrinsically, has, the, potential, to, form, 'codon-anticodon', interaction, in, the, 'E', 'site,', independently, of, the, mRNA, configuration])].
[sujeto(['We', also, present, a, detailed, description, of, the, biologically, relevant, position, of, the, entire, 'L1', stalk, and, its]), verbo([interacting]), complemento([cognate, 'E-tRNA,', which, provides, a, better, understanding, of, the, structural, basis, for, translation, elongation])].
[sujeto(['Furthermore,', to]), verbo([gain]), complemento([insight, into, 'translocation,', we, report, the, positioning, of, protein, 'L6', contacting, 'EF-G,', as, well, as, the, conformational, change, of, the, 'C-terminal', tail, of, protein, 'S13', in, the, decoding, center])].
[sujeto(['Myasthenia', gravis, is, a, disorder, of, neuromuscular, transmission]), verbo([associated]), complemento([with, autoantibodies, against, the, nicotinic, acetylcholine, receptor])].
[sujeto(['We']), verbo([have]), complemento([previously, developed, a, customized, protein, macroarray, comprising, 1827, potential, human, 'autoantigens,', which, permitted, to, discriminate, sera, of, patients, with, different, cancers, from, sera, of, healthy, 'controls,', but, has, not, yet, been, evaluated, in, 'antibody-mediated', autoimmune, diseases])].
[sujeto(['Intensity', values, of, one, antigen, '(', poly, 'A']), verbo([binding]), complemento([protein, cytoplasmic, 1, ',', p, =, 0.0045, ')', were, higher, in, patients, with, myasthenia, 'gravis,', but, the, relevance, of, this, and, two, further, 'antigens,', 40, 'S', ribosomal, protein, 'S13', '(', 20.8, '%', vs])].
[sujeto(['GE82832', and, dityromycin, were, shown, to, interfere, with, both, 'aminoacyl-tRNA', and, mRNA, movement, and, with, the, 'Pi']), verbo([release]), complemento([occurring, after, 'ribosome-', and, 'EF-G-dependent', 'GTP', hydrolysis])].
[sujeto(['These', findings, and, the, unusual, ribosomal, localization, of, 'GE82832/dityromycin', near, protein, 'S13']), verbo([suggest]), complemento([that, the, mechanism, of, inhibition, entails, an, interference, with, the, rotation, of, the, 30, 'S', subunit, &, 'quot;head"', which, accompanies, the, 'ribosome-unlocking', step, of, translocation])].
[sujeto(['Transcript', mapping, via, reverse, transcription, polymerase, chain, reaction, demonstrates, that, 'IF1,', 'S13,', 'S11,', 'S4,', α, and, 'L17', are]), verbo([transcribed]), complemento([as, a, polycistronic, transcript, from, two, tandem, promoters, preceding, the, 'IF-1', gene])].
[sujeto(['The', regions, that]), verbo([mediate]), complemento([interactions, with, β, and, 'β\'', subunits, and, the, residues, that, participate, in, the, recognition, of, the, 'UP', element, are, conserved, in, the, 'C'])].
[sujeto([coli, α, subunits, in, the, residues, assigned, to, the, dimerization, domain, and, the, amino, acids, adjacent, to]), verbo([conserved]), complemento([residues, that, mediate, 'UP', element, recognition])].
[sujeto([ammoniagenes, rpoA, gene]), verbo([expressed]), complemento([in, 'E'])].
[sujeto(['In', the, present, 'study,', we, investigated]), verbo([binding]), complemento([of, recombinant, ribosomal, protein, 'S13', and, its, mutants, containing, deletions, or, substitutions, of, amino, acid, residues, in, different, regions, with, an, 'RNA', transcript, corresponding, to, a, fragment, of, the, central, domain, of, 18, 'S', rRNA])].
[sujeto(['We']), verbo([found]), complemento([that, replacement, of, 'ultra-conservative', residues, 'H101', and, 'D108', as, well, as, deletions, of, either, 29, 'C-terminal', or, 27, 'N-terminal', residues, substantially, reduced, affinity, of, the, protein, to, the, 'RNA', transcript])].
[sujeto(['Deletion', of, 54, 'C-terminal', or, 80, 'N-terminal', residues, completely, deprived, the, protein, of]), verbo([binding]), complemento([capacity])].
[sujeto(['Using', a, footprinting, 'assay,', we, identified, sites, in, the, 'RNA', transcript, changing, their, accessibilities, to, action, of, hydroxyl, radicals, under]), verbo([binding]), complemento([of, either, 'full-length', protein, 'S13', or, its, mutant, lacking, 27, 'N-terminal', residues])].
[sujeto(['It', is, shown, that, these, sites, are, located, mainly, in, helix, 'H22', of, the, 18, 'S', rRNA, and, in, the, region, of, its, junction, with, helix, 'H20', and, are, consistent, predominantly, with, contacts, of, the, rRNA, with, the]), verbo([conserved]), complemento([part, of, the, protein])].
[sujeto(['We', concluded, that]), verbo([binding]), complemento([of, ribosomal, protein, 'S13', to, 18, 'S', rRNA, is, provided, mainly, by, conserved, motifs, of, the, protein, corresponding, to, those, motifs, in, its, eubacterial, homologue, that, are, involved, in, the, interaction, with, 16, 'S', rRNA, in, the, 30, 'S', subunit])].
[sujeto(['Role', of, the, 'N-terminal', region, of, the, protein, in, its]), verbo([binding]), complemento([to, the, central, domain, of, 18, 'S', rRNA, is, discussed])].
[sujeto(['Twenty-eight']), verbo([expressed]), complemento([sequence, tags, '(', 'ESTs)', were, isolated, from, a, 'Nile', tilapia, '(', 'Oreochromis', 'niloticus)', vaccinated, vs, 'non-vaccinated', subtractive, library, at, 12, -, h, post, injection, of, a, formalin, killed, 'Streptococcus', iniae, 'ARS-98-60', vaccine])].
[sujeto(['Of', the, remaining, half, 'ESTs,', 17, '%']), verbo([have]), complemento([putative, functions, in, protein, biosynthesis, and, 11, '%', have, putative, functions, in, 'immunity,', energy, 'production,', and, signal, 'transduction,', respectively])].
[sujeto(['The', upregulation, of, these, genes]), verbo([induced]), complemento([by, killed, 'S'])].
[sujeto([iniae, vaccines]), verbo([suggest]), complemento([that, they, might, play, important, role, in, 'Nile', tilapia, defense, against, 'S'])].
[sujeto(['The', 'RPS13', gene, can, be]), verbo([expressed]), complemento([in, 'E'])].
[sujeto(['The', occurrence, of]), verbo([phosphorylated]), complemento([proteins, in, ribosomes, of, 'Streptomyces', coelicolor, was, investigated])].
[sujeto(['A', protein, kinase]), verbo([associated]), complemento([with, ribosomes, phosphorylated, six, ribosomal, proteins, of, the, small, subunit, '(', 'S3,', 'S4,', 'S12,', 'S13,', 'S14', and, 'S18)', and, seven, ribosomal, proteins, of, the, large, subunit, '(', 'L2,', 'L3,', 'L7/L12,', 'L16,', 'L17,', 'L23', and, 'L27)'])].
[sujeto(['The', ribosomal, proteins, were]), verbo([phosphorylated]), complemento([mainly, on, the, 'Ser/Thr', residues])].
[sujeto(['Ribosomes', with]), verbo([phosphorylated]), complemento([proteins, were, used, to, examine, poly, '(', 'U)', translation, activity])].
[sujeto(['Phosphorylation']), verbo([induced]), complemento([about, 50, '%', decrease, in, polyphenylalanine, synthesis])].
[sujeto(['Small', differences, were, observed, between]), verbo([phosphorylated]), complemento([and, unphosphorylated, ribosomes, in, the, kinetic, parameters, of, the, binding, of, 'Phe-tRNA', to, the, 'A-site', of, poly, '(', 'U)', programmed, 'ribosomes,', suggesting, that, the, initial, binding, of, 'Phe-tRNA', is, not, significantly, affected, by, phosphorylation])].
[sujeto(['We', observe, that, ribosomal, proteins, 'S13,', 'S19,', 'L16,', 'L25,', 'L27', and, 'L31', are, actively]), verbo([involved]), complemento([in, the, proofreading, of, tRNA])].
[sujeto(['We']), verbo([suggest]), complemento([that, proofreading, begins, with, the, monitoring, of, the, entire, anticodon, loop, of, tRNA, by, nucleotides, from, 16, 'S', rRNA, '(', helices, 18, and, 44, ')', of, the, small, subunit, and, 23, 'S', rRNA, '(', helix, 69, ')', of, the, large, subunit, with, involvement, of, magnesium, ions])].
[sujeto(['The', ribosomal, intersubunit, bridges]), verbo([maintain]), complemento([the, overall, architecture, of, the, ribosome, and, thereby, play, a, pivotal, role, in, the, dynamics, of, translation])].
[sujeto(['Our', results, in, this, study, of, b1b, in, the, 'Escherichia', coli, 70, 'S', ribosome]), verbo([suggest]), complemento([that, the, intrinsic, molecular, features, of, the, bridging, proteins, allow, the, bridge, to, modulate, the, 'ratchet-like', motion, in, a, controlled, manner])].
[sujeto(['Additionally,', another, large, subunit, 'protein,', 'L31,', seems, to]), verbo([participate]), complemento([with, 'S13', and, 'L5', in, the, 'formation,', 'dynamics,', and, stabilization, of, this, bridge])].
[sujeto(['The', soil, insect, 'Bradysia', odoriphaga, '(', 'Diptera:', 'Sciaridae)']), verbo([causes]), complemento([substantial, damage, to, 'Chinese', chive])].
[sujeto([odoriphaga, '(', 'Bradysia', 'odoriphaga)']), verbo([have]), complemento([yet, to, be, identified, for, normalizing, target, gene, expression, among, samples, by, quantitative, 'real-time', 'PCR', '(', 'qRT-PCR)'])].
[sujeto(['The', use, of, the, most, suitable, reference, genes, versus, an, arbitrarily, selected, reference, gene, resulted, in, significant, differences, in, the, analysis, of, a]), verbo([target]), complemento([gene, expression])].
[sujeto([odoriphaga, was]), verbo([found]), complemento([to, be, 'up-regulated', under, low, temperatures])].
[sujeto(['Primers', were, designed, for, the, genes, 'MUC2,', 'TFF2,', 'RPS13', and, 'TBP', using, a, degenerative]), verbo([primer]), complemento([design, method, based, on, the, available, 'Gallus', gallus, sequences])].
[sujeto(['All']), verbo([primer]), complemento(['sets,', which, produced, a, single, 'PCR', amplicon, of, the, expected, 'sizes,', were, cloned, into, the, 'TOPO(®)', vector, and, then, transformed, into, 'TOP', 10, '(', '®)', competent, cells])].
[sujeto(['The', sequences, were, used, to, design, new, 100, '%', homologous]), verbo([primer]), complemento([sets, for, the, genes, of, interest])].
[sujeto(['The', advent, of, 'fluorescence-based', quantitative, 'real-time', 'PCR', '(', 'qPCR)']), verbo([has]), complemento([revolutionized, the, quantification, of, gene, expression, analysis, in, many, 'fields,', including, life, 'sciences,', 'agriculture,', forensic, 'science,', molecular, 'diagnostics,', and, medicine])].
[sujeto(['Using', the, same, cDNA, 'templates,', we]), verbo([find]), complemento([that, 'TqPCR', can, reduce, the, average, 'Cq', values, for, 'Gapdh,', 'Rps13,', and, 'Hprt1', reference, genes, by, 4.45, ',', 5.47, ',', and, 4.94, 'cycles,', 'respectively,', when, compared, with, conventional, 'qPCR;', the, overall, average, 'Cq', value, reduction, for, the, three, reference, genes, together, is, 4.95])].
[sujeto(['We', further]), verbo([find]), complemento([that, 'TqPCR', can, improve, 'PCR', amplification, efficiency, and, thus, increase, detection, sensitivity])].
[sujeto(['When', the, quantification, of, 'Wnt3A-induced']), verbo([target]), complemento([gene, expression, in, mesenchymal, stem, cells, is, 'analyzed,', we, find, 'that,', while, both, conventional, qPCR, and, 'TqPCR', can, detect, the, 'up-regulation', of, the, relatively, abundant, target, 'Axin2,', only, 'TqPCR', can, detect, the, 'up-regulation', of, the, 'lowly-expressed', targets, 'Oct4', and, 'Gbx2'])].
[sujeto(['Finally,', we, demonstrate, that, the, 'MRQ2', and, 'MRQ3']), verbo([primer]), complemento([pairs, derived, from, mouse, reference, gene, 'Tbp', can, be, used, to, validate, the, 'RNA/cDNA', integrity, of, qPCR, samples])].
[sujeto(['Taken', 'together,', our, results, strongly]), verbo([suggest]), complemento([that, 'TqPCR', may, increase, detection, sensitivity, and, 'PCR', amplification, efficiency])].
[sujeto(['We']), verbo([report]), complemento([the, results, of, a, 'large-scale', lentiviral, 'loss-of-function', 'RNA', interference, '(', 'RNAi)', screen, in, primary, leukemic, cells])].
[sujeto(['Dependence', on, these, genes, was, not]), verbo([caused]), complemento([by, mutation, or, 'overexpression,', and, although, some, of, the, candidates, seemed, to, be, rather, patient, 'specific,', others, were, essential, in, cells, isolated, from, other, 'AML', patients])].
[sujeto(['In', addition, to, the, phenotype, observed, after, 'ROCK1', 'knockdown,', treatment, with, the, approved, 'ROCK', inhibitor, fasudil, resulted, in]), verbo([increased]), complemento([apoptosis, and, decreased, viability, of, primary, 'AML', cells])].
[sujeto(['YBX3/ZONAB/CSDA', is, an, 'epithelial-specific', transcription, factor]), verbo([acting]), complemento([in, the, 'density-based', switch, between, proliferation, and, differentiation])].
[sujeto(['Our', laboratory]), verbo([reported]), complemento([overexpression, of, 'YBX3', in, clear, cell, renal, cell, arcinoma, '(', 'ccRCC),', as, part, of, a, wide, study, of, 'YBX3', regulation, in, vitro, and, in, vivo])].
[sujeto(['We', thus, decided, to, 're-evaluate', 'YBX3', expression, by, 'real-time-PCR', in, a, larger, panel, of, ccRCC, 'samples,', and, their, paired, healthy, 'tissue,', with, special, attention, on, experimental, biases, such, as, 'inter-individual', 'variations,']), verbo([primer]), complemento(['specificity,', and, reference, gene, for, normalization])].
[sujeto(['Using', this, pair, as, 'reference,', 'YBX3', expression, level, among, a, collection, of, 16, ccRCC, tumors, was, not, significantly]), verbo([increased]), complemento([as, compared, to, normal, adjacent, tissues])].
[sujeto(['Immunoperoxidase', confirmed, homogeneous]), verbo([nuclear]), complemento([staining, for, 'YBX3', in, 'low-grade', but, revealed, nuclear, heterogeneity, in, 'high-grade', tumors])].
[sujeto(['Furthermore,', we]), verbo([found]), complemento([that, global, 'YBX3/ZONAB/CSDA', mRNA, expression, level, may, be, considered, within, a, &, 'quot;signature"', of, 'RCC', grading])].
[sujeto(['Neospora', caninum, belongs, to, the, phylum, 'Apicomplexa,', the, causative, agent, of, 'neosporosis,', which]), verbo([leads]), complemento([to, economic, impacts, on, cattle, production])].
[sujeto(['This', work]), verbo([involved]), complemento([the, development, of, a, new, cell, culture, 'ELISA', and, transient, 'β-galactosidase', activity, applied, to, the, 'semi-quantitative', detection, of, 'N'])].
[sujeto([qPCR, efficiency, was, given, in, 68.4, '%', of, all, 'publications,', but, only, 28.9, '%', of, all, studies]), verbo([provided]), complemento(['RNA/cDNA', amount, and, standard, curves])].
[sujeto(['In', our, selection, of, 25, cancer, cell, 'lines,', we, identified, 'HSPCB,', 'RRN18S,', and, 'RPS13', as, the, most, stable]), verbo([expressed]), complemento([reference, genes])].
[sujeto(['In', 'angiosperms,', 'mitochondrial-encoded', genes, can]), verbo([cause]), complemento([cytoplasmic, male, sterility, '(', 'CMS),', resulting, in, the, coexistence, of, female, and, hermaphroditic, individuals, '(', 'gynodioecy)'])].
[sujeto(['We', compared, four, complete, mitochondrial, genomes, from, the, gynodioecious, species, 'Silene', vulgaris, and]), verbo([found]), complemento([unprecedented, amounts, of, intraspecific, diversity, for, plant, mitochondrial, 'DNA', '(', 'mtDNA)'])].
[sujeto(['The', genomes, also, contain, a, variable, number, of, small, autonomously, mapping, 'chromosomes,', which]), verbo([have]), complemento([only, recently, been, identified, in, angiosperm, mtDNA])].
[sujeto(['Molecular', pathways]), verbo([regulating]), complemento([rapid, proliferation, and, persistence, are, fundamental, for, pathogens, but, are, not, elucidated, fully, in, 'Toxoplasma', gondii])].
[sujeto(['One', 'RP', promoter, 'domain,', known, to]), verbo([bind]), complemento([an, 'Apetela', 2, ',', bound, to, nuclear, extract, proteins])].
[sujeto(['Promoter', domains, appeared, to]), verbo([associate]), complemento([with, histone, acetyl, transferases])].
[sujeto(['This', permitted, conditional, knockdown, of, rps13, expression, in, a, tightly]), verbo([regulated]), complemento([manner])].
[sujeto(['Study', of, 'Δrps13']), verbo([expressing]), complemento(['Myc-tagged', 'RPL22,', -, 'ATc,', showed, 'RPL22', diminished, but, at, a, slower, rate])].
[sujeto(['Depletion', of, 'RPS13']), verbo([caused]), complemento([arrest, of, parasites, in, the, 'G1', cell, cycle, 'phase,', thereby, stopping, parasite, proliferation])].
[sujeto(['Our', results, demonstrate, that, 'G1']), verbo([arrest]), complemento([by, ribosomal, protein, depletion, is, associated, with, persistence, of, 'T'])].
[sujeto(['Colonic', diverticula, are, one, of, the, most, frequent, conditions]), verbo([found]), complemento([during, the, endoscopic, examination, of, the, lower, digestive, 'tract,', interestingly, in, &, 'gt;70%', of, people, after, 80, years, old])].
[sujeto(['Venous', leg, ulceration, '(', 'VLU)', is, a, chronic, condition]), verbo([associated]), complemento([with, chronic, venous, insufficiency, '(', 'CVI),', where, the, most, frequent, complication, is, recurrence, of, ulceration, after, healing])].
[sujeto(['Traditionally,', graduated, compression, therapy]), verbo([has]), complemento([been, shown, to, increase, healing, rates, and, also, to, reduce, recurrence, of, 'VLU'])].
[sujeto(['Recently,', the, view, that, compression, therapy, must]), verbo([provide]), complemento([a, graduated, pressure, gradient, has, been, challenged])].
[sujeto(['However,', few, studies, so, far]), verbo([have]), complemento([focused, on, the, potential, benefits, of, progressive, compression, where, the, pressure, profile, is, inverted])].
[sujeto(['Lifestyle', modification, is, not, a, 'short-term', 'endeavor,', and]), verbo([maintaining]), complemento([a, healthy, weight, requires, sustained, changes, in, dietary, and, physical, activity])].
[sujeto(['Intensive', behavioral, intervention, can, help, modify, 'deep-rooted', behaviors, and]), verbo([provide]), complemento([the, support, required, to, both, initiate, and, maintain, the, behavioral, changes, that, are, needed, to, achieve, weight, loss, goals])].
[sujeto(['PNs', that]), verbo([cause]), complemento([airway, compromise, or, pulmonary, dysfunction, are, uncommon, but, clinically, important])].
[sujeto(['Because', improvement, in, sleep, quality, or, airway, function, represents, direct, clinical, 'benefit,', measures, of, sleep, and, pulmonary, function, may, be, more, meaningful, than, tumor, size, as, endpoints, in, therapeutic, clinical, trials]), verbo([targeting]), complemento([airway, 'PN'])].
[sujeto(['For', patients, with, airway, 'PNs,', 'polysomnography,', impulse, 'oscillometry,', and, spirometry, should, be, performed, to, identify, abnormal, function, that, will, be]), verbo([targeted]), complemento([by, the, agent, under, clinical, investigation])].
[sujeto(['These', recommended, sleep, and, pulmonary, evaluations, are, intended, to]), verbo([provide]), complemento([researchers, with, a, standardized, set, of, clinically, meaningful, endpoints, for, response, evaluation, in, trials, of, 'NF1-related', airway, 'PNs'])].
[sujeto(['As', early, as, 1942, ',', 'Epstein']), verbo([suggested]), complemento([a, photoallergic, concept, for, photodermatoses, '[', 's1]'])].
[sujeto(['Since', then, much, progress]), verbo([has]), complemento([been, made, in, understanding, the, pathophysiology, of, photodermatoses, and, their, most, common, 'form,', polymorphic, light, eruption, '(', 'PLE)', '(', 1, ')', '(', 's2-s13)'])].
[sujeto(['However,', specific, photoantigens, that, initiate, 'PLE']), verbo([have]), complemento([not, yet, been, identified])].
[sujeto(['We', hypothesize, that, 'PLE', may, be, initiated, by, elements, resulting, from, 'UV-induced', damage, to, microbial, communities, of, the, 'skin,']), verbo([leading]), complemento([to, a, cascade, of, events, eventually, resulting, in, the, skin, rash, of, the, disease])].
[sujeto(['Findings', from, multiple, lines, of, research]), verbo([provide]), complemento([evidence, of, aberrant, functional, brain, connectivity, in, schizophrenia])].
[sujeto(['However,', there]), verbo([has]), complemento([not, been, a, systematic, investigation, of, functional, brain, network, changes, in, schizophrenia, to, test, the, consistency, of, these, changes, across, multiple, studies])].
[sujeto(['The', results, of, a, total, of, n, =, 13, functional, neuroimaging, studies, indicated, that, brain, networks, in, patients, with, schizophrenia, exhibit, significant]), verbo([decreases]), complemento([in, measures, of, local, organization, '(', g, =, -, 0.56, ',', 'P', =])].
[sujeto([2, ')', and, significant]), verbo([decreases]), complemento([in, 'small-worldness', '(', g, =, -, 0.65, ',', 'P', =])].
[sujeto(['The', present, 'meta-', analysis, demonstrates, significant, changes, in, whole, brain, network, architecture]), verbo([associated]), complemento([with, schizophrenia, across, studies])].
[sujeto(['In', 'glioblastoma,', invasion, and, proliferation, are, presumed, to, be, mutually, exclusive, 'events;', 'however,', the, molecular, mechanisms, that]), verbo([mediate]), complemento([this, 'switch at', the, cellular, level, remain, elusive])].
[sujeto(['Previously,', we]), verbo([have]), complemento([shown, that, 'phospho-OLIG2,', a, 'central-nervous-system-specific', transcription, 'factor,', is, essential, for, tumor, growth, and, proliferation])].
[sujeto(['Here,', we, show, that, the, modulation, of, 'OLIG2', phosphorylation, can]), verbo([trigger]), complemento([a, switch, between, proliferation, 'and invasion'])].
[sujeto(['Mechanistically,', unphosphorylated, 'OLIG2']), verbo([induces]), complemento(['TGF-β2', expression, and, promotes, invasive, mesenchymal, properties, in, glioma, cells])].
[sujeto(['Our', results, not, only]), verbo([provide]), complemento([a, mechanistic, insight, into, how, cells, switch, from, proliferation, to, invasion, but, also, offer, therapeutic, opportunities, for, inhibiting, dissemination, of, gliomas])].
[sujeto(['We']), verbo([report]), complemento([a, case, of, a, 61, -, year, woman, presenting, with, hilar, cholangiocarcinoma])].
[sujeto(['The', common, hepatic, 'duct,', biliary, 'confluence,', right, anterior, segmental, 'duct,', and, right, anterior, branch, of, portal, vein, were]), verbo([involved]), complemento([by, the, tumor, '(', 'Bismuth', 'IIIa)'])].
[sujeto(['Ar-BVMO', was]), verbo([found]), complemento([to, oxidize, ethionamide, as, well, as, linear, ketones])].
[sujeto(['The', active, site, 'Arginine', 292, is]), verbo([required]), complemento([for, its, 'Baeyer-Villiger', activity, but, not, for, heteroatom, oxidation])].
[sujeto(['Studies']), verbo([have]), complemento([demonstrated, advantages, of, the, 'ShangRing', device, over, conventional, circumcision])].
[sujeto(['Immune', thrombocytopenia, '(', 'ITP)', is, an, acquired, autoimmune, bleeding, disease, characterized, by, both]), verbo([increased]), complemento([platelet, destruction, and, reduced, platelet, production])].
[sujeto(['ITP']), verbo([involves]), complemento([complicated, upstream, immune, dysregulations, in, which, 'T-cell', subsets, are, supposed, to, take, the, center, stage])].
[sujeto(['T-follicular', helper, cells, '(', 'TFH)', are, recently]), verbo([found]), complemento([to, regulate, 'antiplatelet-antibody', production, in, 'ITP'])].
[sujeto(['Autoreactive', 'CD8(+)', 'T', cells]), verbo([mediate]), complemento([direct, lysis, of, platelets, and, according, to, our, latest, 'study,', participate, in, desialylation, and, hepatic, clearance, of, platelets])].
[sujeto(['Future', studies, need, to, identify, definite]), verbo([targets]), complemento([for, management, of, 'ITP'])].
[sujeto(['Targeted', disruption, of, 'RPS14']), verbo([causes]), complemento([an, increase, in, p53, activity, and, 'p53-mediated', 'apoptosis,', similar, to, what, is, observed, with, other, ribosomal, proteins])].
[sujeto(['However,', due, to, the, higher, risk, for, cancer, development, in, patients, with, ribosome, 'deficiency,']), verbo([targeting]), complemento([the, p53, pathway, is, not, a, viable, treatment, option])].
[sujeto(['Impaired', erythropoiesis, in, the, deletion, 5, q, '(', 'del(5q))', subtype, of, myelodysplastic, syndrome, '(', 'MDS)']), verbo([has]), complemento([been, linked, to, heterozygous, deletion, of, 'RPS14,', which, encodes, the, ribosomal, protein, small, subunit, 14])].
[sujeto(['This', defect, resulted, in, 'age-dependent', progressive, 'anemia,', megakaryocyte, dysplasia, and]), verbo([loss]), complemento([of, hematopoietic, stem, cell, '(', 'HSC)', quiescence])].
[sujeto(['As', assessed, by, quantitative, 'proteomics,', mutant, erythroblasts]), verbo([expressed]), complemento([higher, levels, of, proteins, involved, in, innate, immune, 'signaling,', notably, the, heterodimeric, 'S100', 'calcium-binding', proteins, 'S100a8', and, 'S100a9'])].
[sujeto(['S100a8--whose', expression, was]), verbo([increased]), complemento([in, mutant, 'erythroblasts,', monocytes, and, 'macrophages--is', functionally, involved, in, the, erythroid, defect, caused, by, the, 'Rps14', 'deletion,', as, addition, of, recombinant, 'S100a8', was, sufficient, to, induce, a, differentiation, defect, in, 'wild-type', erythroid, 'cells,', and, genetic, inactivation, of, 'S100a8', expression, rescued, the, erythroid, differentiation, defect, of, 'Rps14-haploinsufficient', 'HSCs'])].
[sujeto(['Our', data, link, 'Rps14', haploinsufficiency, in, 'del(5q)', 'MDS', to, activation, of, the, innate, immune, system, and, induction, of, 'S100A8-S100A9', 'expression,']), verbo([leading]), complemento([to, a, 'p53-dependent', erythroid, differentiation, defect])].
[sujeto(['The', 'seedling-lethal', 'Arabidopsis', thaliana, high, chlorophyll, fluorescence145, '(', 'hcf145)', mutation]), verbo([leads]), complemento([to, reduced, stability, of, the, plastid, tricistronic, 'psaA-psaB-rps14', mRNA, and, photosystem, 'I', '(', 'PSI)', deficiency])].
[sujeto(['Here,', we, genetically, mapped, the, 'HCF145', 'gene,', which, encodes, a, 'plant-specific,', 'chloroplast-localized,']), verbo([modular]), complemento([protein, containing, two, homologous, domains, related, to, the, polyketide, cyclase, family, comprising, 37, annotated, 'Arabidopsis', proteins, of, unknown, function])].
[sujeto(['Two', further, highly]), verbo([conserved]), complemento([and, previously, uncharacterized, tandem, repeat, motifs, at, the, 'C', 'terminus,', herein, designated, the, transcript, binding, motif, repeat, '(', 'TMR)', 'domains,', confer, 'sequence-specific', 'RNA', binding, capability, to, 'HCF145'])].
[sujeto(['Homologous', 'TMR', motifs, are, often]), verbo([found]), complemento([as, multiple, repeats, in, quite, diverse, proteins, of, green, and, red, algae, and, in, the, cyanobacterium, 'Microcoleus', sp, 'PCC', 7113, with, unknown, function])].
[sujeto(['HCF145', represents, the, only, 'TMR', protein]), verbo([found]), complemento([in, vascular, plants])].
[sujeto(['Detailed', analysis, of, hcf145, mutants, in, 'Arabidopsis', and, 'Physcomitrella', patens, as, well, as, in, vivo, and, in, vitro, 'RNA']), verbo([binding]), complemento([assays, indicate, that, 'HCF145', has, been, recruited, in, embryophyta, for, the, stabilization, of, the, 'psaA-psaB-rps14', mRNA, via, specific, binding, to, its, 5, '\'', untranslated, region])].
[sujeto(['Several', genes, related, to, the, mechanism, of, 'BC']), verbo([have]), complemento([been, studied, in, recent, 'years,', but, the, current, understanding, of, 'BC', is, still, rather, limited])].
[sujeto(['This', study, aimed, to]), verbo([find]), complemento([new, differentially, expressed, genes, '(', 'DEGs)', associated, with, the, occurrence, and, development, of, 'BC'])].
[sujeto(['A', total, of, 2, ',', 68, 'DEGs', were]), verbo([found]), complemento([between, 'BC', and, normal, tissues])].
[sujeto(['These', genes, were]), verbo([involved]), complemento([in, 49, functional, clusters])].
[sujeto(['Interestingly,', the, 3, '\'', 'UTR', of, 'Cry1', mRNA]), verbo([decreased]), complemento([its, mRNA, levels, but, increased, protein, amounts])].
[sujeto(['The', 3, '\'', 'UTR', also]), verbo([provides]), complemento([a, binding, site, for, microRNA, and, mainly, suppresses, translation, of, target, mRNAs])].
[sujeto(['We']), verbo([found]), complemento([that, 'AU-rich', element, 'RNA', binding, protein, 1, '(', 'AUF1)', directly, binds, to, the, 'Cry1', 3, '\'', 'UTR', and, regulates, translation, of, 'Cry1', mRNA])].
[sujeto(['AUF1']), verbo([interacted]), complemento([with, eukaryotic, translation, initiation, factor, 3, subunit, 'B', and, also, directly, associated, with, ribosomal, protein, 'S3', or, ribosomal, protein, 'S14,', resulting, in, translation, of, 'Cry1', mRNA, in, a, 3, '\'', 'UTR-dependent', manner])].
[sujeto(['Expression', of, cytoplasmic, 'AUF1', and]), verbo([binding]), complemento([of, 'AUF1', to, the, 'Cry1', 3, '\'', 'UTR', were, parallel, to, the, circadian, 'CRY1', protein, profile])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, the, 3, '\'', 'UTR', of, 'Cry1', is, important, for, its, rhythmic, 'translation,', and, 'AUF1', bound, to, the, 3, '\'', 'UTR', facilitates, interaction, with, the, 5, '\'', end, of, mRNA, by, interacting, with, translation, initiation, factors, and, recruiting, the, 40, 'S', ribosomal, subunit, to, initiate, translation, of, 'Cry1', mRNA])].
[sujeto(['Ribosomal', protein, 'S14', '(', 'RPS14)', plays, a, key, role, in, erythropoiesis, and]), verbo([causes]), complemento([p53, activation, in, 5, 'q-', syndrome])].
[sujeto(['Transfection', also]), verbo([arrested]), complemento([cells, in, 'G0/G1', phase, and, induced, 'apoptosis,', indicating, that, 'RPS14', is, involved, in, the, pathophysiology, of, 'MDS/AML'])].
[sujeto(['These', findings, indicate, that, partial, silencing, of, 'RPS14']), verbo([inhibits]), complemento([the, proliferation, of, 'MDS/AML', 'cells,', and, 'RPS14', may, negatively, regulate, p53, activation, in, 'MDS/AML', cells])].
[sujeto(['The', ribosomal, gene, 'RPS14', is]), verbo([associated]), complemento([with, the, 'cancer-prone', 5, 'q-syndrome,', which, is, caused, by, an, interstitial, deletion, of, the, long, arm, of, human, chromosome, 5])].
[sujeto(['Previously,', we]), verbo([found]), complemento([that, ribosomal, protein, 'S14', '(', 'RPS14)', binds, to, and, inactivates, 'MDM2,', consequently, leading, to, 'p53-dependent', 'cell-cycle', arrest, and, growth, inhibition])].
[sujeto(['However,', it, remains, elusive, whether, 'RPS14']), verbo([regulates]), complemento([cell, proliferation, in, a, 'p53-independent', manner])].
[sujeto(['Here,', we, show, that, 'RPS14']), verbo([interacts]), complemento([with, the, 'Myc', homology, box, 'II', '(', 'MBII)', and, the, 'C-terminal', basic, 'helix-loop-helix', leucine, zipper, '(', 'bHLH-LZ)', domains, of, the, oncoprotein, 'c-Myc'])].
[sujeto(['Further,', 'RPS14']), verbo([inhibited]), complemento(['c-Myc', transcriptional, activity, by, preventing, the, recruitment, of, 'c-Myc', and, its, 'cofactor,', 'TRRAP,', to, the, target, gene, 'promoters,', as, thus, suppressing, 'c-Myc-induced', cell, proliferation])].
[sujeto(['Also,', 'siRNA-mediated', 'RPS14', depletion, elevated, 'c-Myc', transcriptional, activity, determined, by, its]), verbo([target]), complemento(['gene,', 'Nucleolin,', expression])].
[sujeto(['Consistent', with, 'this,', 'RPS14']), verbo([promoted]), complemento(['c-Myc', mRNA, turnover, through, an, 'Argonaute', 2, '(', 'Ago2)-', and, 'microRNA-mediated', pathway])].
[sujeto(['Taken', 'together,', our, study, demonstrates, that, 'RPS14', negates, 'c-Myc', functions, by, directly]), verbo([inhibiting]), complemento([its, transcriptional, activity, and, mediating, its, mRNA, degradation, via, miRNA])].
[sujeto(['Haploinsufficiency', of, the, ribosomal, protein, 'S14', '(', 'RPS14)']), verbo([has]), complemento([been, identified, as, a, causal, factor, in, myelodysplastic, syndrome, '(', 'MDS)', with, isolated, del, '(', 5, 'q)'])].
[sujeto(['This', study, was, carried, out, to, investigate, 'RPS14', expression, in, 'MDS', without, 5, q, deletion, and, the, role, of, lower]), verbo([expressed]), complemento(['RPS14', plays, in, pathogenesis, and, the, prognosis, and, 'lenalidomide-response', predicting, of, 'non-5q-MDS'])].
[sujeto(['The', lower, 'RPS14', expression, status, was, inversely, correlated, with]), verbo([increased]), complemento([apoptosis, ratio, in, nucleated, erythrocytes, from, 'BM', '(', r, =, -, 0.54, ',', 'P', =, 0.013, ')'])].
[sujeto(['Patients', with, lower, 'RPS14', expression]), verbo([have]), complemento([a, higher, 2, -, yr, survival, probability, than, normal, 'RPS14', cases, in, the, international, prognosis, scoring, system, '(', 'IPSS)', lower, risk, group, '(', 90.8, '%', vs])].
[sujeto(['Lower', 'RPS14', expression, in, 'MDS', patients, without, 5, q, deletion, is]), verbo([associated]), complemento([with, increased, apoptosis, of, nucleated, erythrocytes, in, lower, risk, 'MDS'])].
[sujeto(['The', 'tumor-suppressor', p53]), verbo([provides]), complemento([a, critical, brake, on, tumor, development])].
[sujeto(['Mounting', evidence]), verbo([has]), complemento([suggested, that, ribosomal, proteins, '(', 'RPs)', modulate, 'HDM2-p53', as, a, novel, pathway, for, regulating, p53, signaling])].
[sujeto(['However,', the, upstream, regulators, that]), verbo([mediate]), complemento(['RP-HDM2-p53', circuits, remain, poorly, understood])].
[sujeto(['Here', we, identify, human, 'coilin-interacting']), verbo([nuclear]), complemento(['ATPase', protein, '(', 'hCINAP)', as, an, interacting, partner, of, ribosomal, protein, 'S14', '(', 'RPS14)'])].
[sujeto(['RPS14', stabilized, and]), verbo([activated]), complemento([p53, by, inhibiting, 'HDM2-mediated', p53, polyubiquitination, and, degradation])].
[sujeto(['More', 'importantly,', 'RPS14', was, specifically, modified, with, 'NEDD8', and, hCINAP]), verbo([inhibited]), complemento(['RPS14', 'NEDDylation', by, recruiting, 'NEDD8-specific', protease, 1])].
[sujeto(['The']), verbo([decrease]), complemento([in, 'RPS14', 'NEDDylation', led, to, reduced, stability, and, incorrect, localization, of, 'RPS14,', thereby, attenuating, the, interaction, between, 'RPS14', and, 'HDM2'])].
[sujeto(['Free', 'HDM2']), verbo([stimulated]), complemento([p53, polyubiquitination, and, degradation])].
[sujeto(['In', 'conclusion,', we, demonstrate, that, hCINAP]), verbo([acts]), complemento([as, a, novel, regulator, of, 'RPS14-HDM2-p53', by, regulating, the, interaction, between, 'RPS14', and, 'HDM2', through, the, control, of, 'RPS14', 'NEDDylation'])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, hCINAP, is, an, important, regulator, of, 'RP-HDM2-p53', pathway, and, a, potential, anticancer, drug, target])].
[sujeto(['The', mechanism, of, erythroid, failure, appears, to]), verbo([involve]), complemento([the, decreased, expression, of, the, ribosomal, protein, 'S14', '(', 'RPS14)', gene, and, the, upregulation, of, the, p53, pathway, by, ribosomal, stress])].
[sujeto(['Friend', leukemia, virus, integration, 1, '(', 'Fli1)', is, one, of, the]), verbo([target]), complemento([genes, of, miR145])].
[sujeto(['Haploinsufficiency', of, ribosomal, proteins, '(', 'RPs)']), verbo([has]), complemento([been, proposed, to, be, the, common, basis, for, the, anemia, observed, in, 'Diamond-Blackfan', anemia, '(', 'DBA)', and, myelodysplastic, syndrome, with, loss, of, chromosome, 5, q, '[', 'del(5q)', 'MDS]'])].
[sujeto(['We']), verbo([have]), complemento([modeled, 'DBA', and, 'del(5q)', 'MDS', in, zebrafish, using, antisense, morpholinos, to, rps19, and, 'rps14,', 'respectively,', and, have, demonstrated, 'that,', as, in, 'humans,', haploinsufficient, levels, of, these, proteins, lead, to, a, profound, anemia])].
[sujeto(['To', address, the, hypothesis, that, 'RP']), verbo([loss]), complemento([results, in, impaired, mRNA, 'translation,', we, treated, 'Rps19', and, 'Rps14-deficient', embryos, with, the, amino, acid, 'L-leucine,', a, known, activator, of, mRNA, translation])].
[sujeto(['This', resulted, in, a, striking, improvement, of, the, anemia]), verbo([associated]), complemento([with, 'RP', loss])].
[sujeto(['Furthermore,', we, showed, that]), verbo([loss]), complemento([of, 'Rps19', or, 'Rps14', activates, the, mTOR, 'pathway,', and, this, is, accentuated, by, 'L-leucine', in, both, 'Rps19', and, 'Rps14', morphants])].
[sujeto(['This', effect, could, be, abrogated, by, rapamycin]), verbo([suggesting]), complemento([that, mTOR, signaling, may, be, responsible, for, the, improvement, in, anemia, associated, with, 'L-leucine'])].
[sujeto(['The', 'MDM2-p53', feedback, loop, is, crucially, important, for, restricting, p53, level, and, activity, during, normal, cell, growth, and, 'proliferation,', and, is, thus, subjected, to, dynamic, regulation, in, order, for, cells, to]), verbo([activate]), complemento([p53, upon, various, stress, signals])].
[sujeto(['Several', ribosomal, 'proteins,', such, as, 'RPL11,', 'RPL5,', 'RPL23,', 'RPL26', or, 'RPS7,']), verbo([have]), complemento([been, shown, to, have, a, role, in, regulation, of, this, feedback, loop, in, response, to, ribosomal, stress])].
[sujeto(['Here,', we, identify, another, ribosomal, protein, 'S14,', which, is, highly]), verbo([associated]), complemento([with, 5, 'q-syndrome,', as, a, novel, activator, of, p53, by, inhibiting, 'MDM2', activity])].
[sujeto(['We']), verbo([found]), complemento([that, 'RPS14,', but, not, 'RPS19,', binds, to, the, central, acidic, domain, of, 'MDM2,', similar, to, 'RPL5', and, 'RPL23,', and, inhibits, its, 'E3', ubiquitin, ligase, activity, toward, p53])].
[sujeto(['This', 'RPS14-MDM2']), verbo([binding]), complemento([was, induced, upon, ribosomal, stress, caused, by, actinomycin, 'D', or, mycophenolic, acid])].
[sujeto(['Overexpression', of, 'RPS14,', but, not, 'RPS19,', elevated, p53, level, and, 'activity,']), verbo([leading]), complemento([to, 'G1', or, 'G2', arrest])].
[sujeto(['Interestingly,', knockdown, of, either, 'RPS14', or, 'RPS19']), verbo([caused]), complemento([a, ribosomal, stress, that, led, to, p53, 'activation,', which, was, impaired, by, further, knocking, down, the, level, of, 'RPL11', or, 'RPL5'])].
[sujeto(['Together,', our, results, demonstrate, that, 'RPS14', and, 'RPS19']), verbo([have]), complemento([distinct, roles, in, regulating, the, 'MDM2-p53', feedback, loop, in, response, to, ribosomal, stress])].
[sujeto(['Although', these, abnormalities]), verbo([lead]), complemento([to, defective, ribosome, 'biogenesis,', why, ribosomal, protein, hemizygosity, results, in, anemia, is, not, certain])].
[sujeto(['The', mice]), verbo([have]), complemento([an, erythroid, phenotype, similar, to, both, 'Diamond-Blackfan', anemia, and, the, 5, 'q-', syndrome, and, lenalidomide, therapy, improves, their, anemia])].
[sujeto(['Haploinsufficiency', for, ribosomal, protein, genes]), verbo([has]), complemento([been, implicated, in, the, pathophysiology, of, 'Diamond-Blackfan', anemia, '(', 'DBA)', and, the, 5, 'q-syndrome,', a, subtype, of, myelodysplastic, syndrome])].
[sujeto(['The', p53, pathway, is]), verbo([activated]), complemento([by, ribosome, 'dysfunction,', but, the, molecular, basis, for, selective, impairment, of, the, erythroid, lineage, in, disorders, of, ribosome, function, has, not, been, determined])].
[sujeto(['We']), verbo([found]), complemento([that, p53, accumulates, selectively, in, the, erythroid, lineage, in, primary, human, hematopoietic, progenitor, cells, after, expression, of, shRNAs, targeting, 'RPS14,', the, ribosomal, protein, gene, deleted, in, the, 5, 'q-syndrome,', or, 'RPS19,', the, most, commonly, mutated, gene, in, 'DBA'])].
[sujeto(['Induction', of, p53]), verbo([led]), complemento([to, 'lineage-specific', accumulation, of, p21, and, consequent, cell, cycle, arrest, in, erythroid, progenitor, cells])].
[sujeto(['Pharmacologic', inhibition, of, p53, rescued, the, erythroid, 'defect,', whereas, 'nutlin-3,', a, compound, that]), verbo([activates]), complemento([p53, through, inhibition, of, 'HDM2,', selectively, impaired, erythropoiesis])].
[sujeto(['In', bone, marrow, biopsies, from, patients, with, 'DBA', or, 'del(5q)', myelodysplastic, 'syndrome,', we]), verbo([found]), complemento([an, accumulation, of, nuclear, p53, staining, in, erythroid, progenitor, cells, that, was, not, present, in, control, samples])].
[sujeto(['Our', findings, indicate, that, the, erythroid, lineage]), verbo([has]), complemento([a, low, threshold, for, the, induction, of, 'p53,', providing, a, basis, for, the, failure, of, erythropoiesis, in, the, 5, 'q-syndrome,', 'DBA,', and, perhaps, other, bone, marrow, failure, syndromes])].
[sujeto(['After', 12, wk, of, lenalidomide, 'treatment,', erythroid, responses, were, observed, in, all, cases, with, an]), verbo([increase]), complemento([in, hemoglobin, levels, of, 2.7, +, /, -, 2.5, 'g/dL', '(', up, to, a, mean, 11.8, +, /, -, 1.9, 'g/dL;', 'P', =, 0.001, ')'])].
[sujeto(['There', was, a, significant]), verbo([increase]), complemento([in, median, 'RPS14', expression, from, baseline, 0.01, '(', 'IQR', 0.05, -, 0.31, ')', to, 12, wk, 204.71, -, fold, '(', 2.86, -, 446.32, ;, 'P', &, 'lt;', 0.0001, ')'])].
[sujeto(['Diamond-Blackfan', anemia, is, a, 'rare,', clinically, 'heterogeneous,', congenital, red, cell, 'aplasia:', 40, '%', of, patients]), verbo([have]), complemento([congenital, abnormalities])].
[sujeto(['Recent', studies]), verbo([have]), complemento([shown, that, in, western, 'countries,', the, disease, is, associated, with, heterozygous, mutations, in, the, ribosomal, protein, '(', 'RP)', genes, in, about, 50, '%', of, patients])].
[sujeto(['There']), verbo([have]), complemento([been, no, studies, to, determine, the, incidence, of, these, mutations, in, 'Asian', patients, with, 'Diamond-Blackfan', anemia])].
[sujeto(['We', screened, 49, 'Japanese', patients, with, 'Diamond-Blackfan', anemia, '(', 45, 'probands)', for, mutations, in, the, six, known, genes]), verbo([associated]), complemento([with, 'Diamond-Blackfan', 'anemia:', 'RPS19,', 'RPS24,', 'RPS17,', 'RPL5,', 'RPL11,', and, 'RPL35A'])].
[sujeto(['We', observed, a, slightly, lower, frequency, of, mutations, in, the, ribosomal, protein, genes, in, patients, with, 'Diamond-Blackfan', anemia, compared, to, the, frequency]), verbo([reported]), complemento([in, western, countries])].
[sujeto(['Genotype-phenotype', data]), verbo([suggest]), complemento([an, association, between, anomalies, and, 'RPS19', 'mutations,', and, a, negative, association, between, 'small-for-date', phenotype, and, 'RPL5', mutations])].
[sujeto(['The', identification, of, the, genes]), verbo([associated]), complemento([with, chromosomal, translocation, breakpoints, has, fundamentally, changed, understanding, of, the, molecular, basis, of, hematological, malignancies])].
[sujeto(['By', 'contrast,', the, study, of, chromosomal, deletions]), verbo([has]), complemento([been, hampered, by, the, large, number, of, genes, deleted, and, the, complexity, of, their, analysis])].
[sujeto(['We']), verbo([report]), complemento([the, generation, of, a, mouse, model, for, human, 5, 'q-', syndrome, using, 'large-scale', chromosomal, engineering])].
[sujeto(['Haploinsufficiency', of, the, 'Cd74-Nid67', interval, '(', containing, 'Rps14,', encoding, the, ribosomal, protein, 'S14)']), verbo([caused]), complemento([macrocytic, 'anemia,', prominent, erythroid, dysplasia, and, monolobulated, megakaryocytes, in, the, bone, marrow])].
[sujeto(['These', effects, were]), verbo([associated]), complemento([with, defective, bone, marrow, progenitor, 'development,', the, appearance, of, bone, marrow, cells, expressing, high, amounts, of, the, tumor, suppressor, p53, and, increased, bone, marrow, cell, apoptosis])].
[sujeto(['This', mouse, model]), verbo([suggests]), complemento([that, a, 'p53-dependent', mechanism, underlies, the, pathophysiology, of, the, 5, 'q-', syndrome])].
[sujeto(['The', drop, in, red, blood, cell, production, was, secondary, to, the]), verbo([decrease]), complemento([in, the, erythroid, progenitor, cell, pool, and, to, impaired, proliferative, capacity])].
[sujeto(['Previous', studies]), verbo([suggested]), complemento([that, in, some, 'Zn/Cd', 'hyperaccumulators,', many, steps, in, photosynthesis, may, be, 'Cd', tolerant, or, even, 'Cd', stimulated])].
[sujeto(['Using', 'RNA-seq', 'data,', we]), verbo([found]), complemento([not, only, that, 'Cd', and, 'Zn', both, 'up-regulated', the, 'CA1', 'gene,', which, encodes, a, β, class, carbonic, anhydrase, '(', 'CA)', in, 'chloroplasts,', but, that, a, large, number, of, other, 'Zn', 'up-regulated', genes, in, the, photosynthetic, pathway, were, also, significantly, 'up-regulated', by, 'Cd', in, leaves, of, the, 'Zn/Cd', hyperaccumulator, 'Sedum', alfredii])].
[sujeto(['These', genes, also, include, chloroplast, genes]), verbo([involved]), complemento([in, transcription, and, translation, '(', rps18, and, 'rps14),', electron, transport, and, 'ATP', synthesis, '(', atpF, and, 'ccsA),', 'Photosystem', 'II', '(', 'PSBI,', 'PSBM,', 'PSBK,', 'PSBZ/YCF9,', 'PSBO-1,', 'PSBQ,', 'LHCB1'])].
[sujeto(['Cadmium', and, 'Zn', also, 'up-regulated', the, 'VAR1', 'gene,', which, encodes, the, 'ATP-dependent', zinc, metalloprotease, 'FTSH', 5, '(', a, member, of, the, 'FtsH', 'family),', and, the, 'DAG', 'gene,', which, influences, chloroplast, differentiation, and, plastid, 'development,', and, the, 'CP29', 'gene,', which, supports, 'RNA', processing, in, chloroplasts, and]), verbo([has]), complemento([a, potential, role, in, 'signal-dependent', 'co-regulation', of, chloroplast, genes])].
[sujeto([&, 'nbsp;alfredii']), verbo([responded]), complemento([to, 'Cd', much, as, it, did, to, 'Zn,', which, will, contribute, to, our, understanding, of, the, positive, effects, of, 'Zn', and, 'Cd', on, growth, of, this, plant])].
[sujeto(['HCMV', inhibition, occurred, after, virus, 'entry,', but, before, 'DNA', 'replication,', and, resulted, in]), verbo([decreased]), complemento([expression, of, viral, proteins])].
[sujeto(['In', a, mouse, 'CMV', '(', 'MCMV)', 'model,', emetine, was, 'well-tolerated,', displayed, long, 'half-life,', preferential, distribution, to, tissues, over, 'plasma,', and, effectively]), verbo([suppressed]), complemento(['MCMV'])].
[sujeto(['Since', the, in, vitro, 'anti-HCMV', activity, of, emetine]), verbo([decreased]), complemento([significantly, in, 'low-density', 'cells,', a, mechanism, involving, cell, cycle, regulation, was, suspected])].
[sujeto(['HCMV', inhibition, by, emetine, depended, on, ribosomal, processing, 'S14', '(', 'RPS14)']), verbo([binding]), complemento([to, 'MDM2,', leading, to, disruption, of, 'HCMV-induced', 'MDM2-p53', and, 'MDM2-IE2', interactions])].
[sujeto(['Irrespective', of, cell, 'density,', emetine]), verbo([induced]), complemento(['RPS14', translocation, into, the, nucleus, during, infection])].
[sujeto(['However,', in, 'low-density', cells, the, 'pre-existing', interaction, of, 'MDM2-p53', could, not, be, 'disrupted,', and, 'RPS14', could, not]), verbo([interact]), complemento([with, 'MDM2'])].
[sujeto(['In', 'infected-only', or, in, 'non-infected', 'emetine-treated', 'cells,', 'RPS14', failed, to, translocate, into, the, 'nucleus,', hence, could, not]), verbo([interact]), complemento([with, 'MDM2,', and, was, not, ubiquitinated])].
[sujeto(['HCMV', replicated, similarly, in, 'RPS14', knockdown, or, control, 'cells,', but, emetine, did, not]), verbo([inhibit]), complemento([virus, replication, in, the, former, cell, line])].
[sujeto(['The', interaction, of, 'MDM2-p53', was]), verbo([maintained]), complemento([in, infected, 'RPS14', knockdown, cells, despite, emetine, 'treatment,', confirming, a, unique, mechanism, by, which, emetine, exploits, 'RPS14', to, disrupt, 'MDM2-p53', interaction])].
[sujeto(['Myelodysplastic', syndromes, '(', 'MDS)', are, difficult, to, culture, 'long-term', showing, the, need, of, a, model, to, study, the, fate, of, cells, with, 'MDS-abnormalities']), verbo([associated]), complemento([with, chromosomal, instability, '(', 'CIN)'])].
[sujeto(['As', the, establishment, of, appropriate, xenograft, models, is]), verbo([increasing]), complemento([worldwide, we, aim, to, share, our, experiences, to, contribute, toward, minimizing, loss, of, mice, and, following, the, &, 'quot;right"', approach])].
[sujeto(['However,', the, analysis, of, modified, 'HSCs', is, limited, and, further, experiments, are]), verbo([required]), complemento([to, improve, this, model])].
[sujeto(['Angiosperm', mitochondrial, genes, appear, to]), verbo([have]), complemento([very, low, mutation, 'rates,', while, 'non-gene', regions, 'expand,', 'diverge,', and, rearrange, quickly])].
[sujeto(['Rps14', is, 'co-transcribed', with, cob, and, rpl5, in, most, plant, mitochondrial, 'genomes,', but, in, some, 'genomes,', rps14]), verbo([has]), complemento([been, duplicated, to, the, nucleus, leaving, a, pseudogene, in, the, mitochondria])].
[sujeto(['This']), verbo([provides]), complemento([an, opportunity, to, compare, neutral, substitution, rates, in, pseudogenes, with, synonymous, substitution, rates, in, the, orthologs])].
[sujeto(['Genes', and, pseudogenes, of, rps14]), verbo([have]), complemento([been, aligned, among, different, species, and, the, mutation, rates, have, been, calculated])].
[sujeto(['Neutral', substitution, rates, in, pseudogenes, and, synonymous, substitution, rates, in, genes, are, significantly, 'different,']), verbo([providing]), complemento([evidence, that, synonymous, substitutions, in, plant, mitochondrial, genes, are, not, completely, neutral])].
[sujeto(['Aberrations', of, ribosomal, biogenesis]), verbo([have]), complemento([been, implicated, in, several, congenital, bone, marrow, failure, 'syndromes,', such, as, 'Diamond-Blackfan', 'anaemia,', 'Shwachman-Diamond', syndrome, and, 'Dyskeratosis', 'Congenita'])].
[sujeto(['Recent', studies]), verbo([have]), complemento([identified, haploinsufficiency, of, 'RPS14', in, the, acquired, bone, marrow, disease, isolated, 5, q, minus, 'syndrome,', a, subtype, of, myelodysplastic, syndromes, '(', 'MDS)'])].
[sujeto(['However,', the, expression, of, various, proteins, comprising, the, ribosomal, subunits, and, other, proteins, enzymatically]), verbo([involved]), complemento([in, the, synthesis, of, the, ribosome, has, not, been, explored, in, 'non-5q', minus, 'MDS'])].
[sujeto(['Furthermore,', differences, in, the, effects, of, these, expression, alterations, among, 'myeloid,', erythroid, and, megakaryocyte, lineages]), verbo([have]), complemento([not, been, well, elucidated])].
[sujeto(['Specifically,', we]), verbo([found]), complemento([that, there, is, overexpression, of, 'RPS24,', 'DKC1', and, 'SBDS', in, 'MDS'])].
[sujeto(['Use', of, 'Host', 'Induced', 'Gene', 'Silencing', '(', 'HIGS)', and, the, study, of, effector, proteins, could]), verbo([provide]), complemento([novel, strategies, for, pathogen, control])].
[sujeto(['Gene', expression, during, in, vitro, stages, and, over, the, whole, infection, process, was]), verbo([found]), complemento([to, be, highly, unstable])].
[sujeto(['Alternatively', 'CytB', that]), verbo([has]), complemento([the, smallest, 'Cq', range, '(', 'Cq:', quantification, 'cycle)', could, be, used])].
[sujeto(['The', 5, 'q-', syndrome, is, the, most, distinct, of, the, myelodysplastic, syndromes, '(', 'MDS)', and, patients, with, this, disorder]), verbo([have]), complemento([a, deletion, of, chromosome, 5, q, '[', 'del(5q)]', as, the, sole, karyotypic, abnormality])].
[sujeto(['Several', genes, mapping, to, the, commonly, deleted, region, of, the, 5, 'q-', syndrome]), verbo([have]), complemento([been, implicated, in, disease, pathogenesis, in, recent, years])].
[sujeto(['Haploinsufficiency', of, the, ribosomal, gene, 'RPS14']), verbo([has]), complemento([been, shown, to, cause, the, erythroid, defect, in, the, 5, 'q-', syndrome])].
[sujeto(['Loss', of, the, microRNA, genes, 'miR-145', and, 'miR-146a']), verbo([has]), complemento([been, associated, with, the, thrombocytosis, observed, in, 5, 'q-', syndrome, patients])].
[sujeto(['Haploinsufficiency', of, 'CSNK1A1']), verbo([leads]), complemento([to, hematopoietic, stem, cell, expansion, in, mice, and, may, play, a, role, in, the, initial, clonal, expansion, in, patients, with, 5, 'q-', syndrome])].
[sujeto(['Importantly,', activation, of, p53]), verbo([has]), complemento([been, demonstrated, in, the, human, 5, 'q-', syndrome])].
[sujeto(['Recurrent', 'TP53', mutations]), verbo([have]), complemento([been, associated, with, an, increased, risk, of, disease, evolution, and, with, decreased, response, to, the, drug, lenalidomide, in, 'del(5q)', 'MDS', patients])].
[sujeto([ornata, was, determined, and, compared, with, other]), verbo([reported]), complemento([brown, algal, mtDNAs])].
[sujeto(['The', total, spacer, size]), verbo([has]), complemento([positive, correlation, with, the, brown, algal, mitogenome, size, with, the, correlation, coefficient, of, 0.7972])].
[sujeto(['Several', regions, displaying, greater, inconsistency, '(', 'rnl-trnK', 'spacer,', cox2, 'gene,', 'cox3-atp6', 'spacer,', 'rps14-rns', middle, region, and, 'trnP-rnl', 'spacer)']), verbo([have]), complemento([been, identified, in, brown, algal, mtDNAs])].
[sujeto(['The', observed, uncertainty, regarding, the, position, and, support, values, of, some, branches, might, be, closely]), verbo([associated]), complemento([with, the, heterogeneity, of, evolutionary, rate])].
[sujeto(['In', a, functional, genomics, screen, of, mouse, embryonic, stem, cells, '(', 'ESCs)', with, nested, hemizygous, chromosomal, 'deletions,', we]), verbo([reveal]), complemento([that, ribosomal, protein, '(', 'RP)', genes, are, the, most, significant, haploinsufficient, determinants, for, embryoid, body, '(', 'EB)', formation])].
[sujeto(['Hemizygocity', for, three, 'RP', genes, '(', 'Rps5,', 'Rps14,', or, 'Rps28),', distinguished, by, the, proximity, of, their, corresponding, protein, to, the, 'ribosome\'s', mRNA, exit, 'site,', is]), verbo([associated]), complemento([with, the, most, profound, phenotype])].
[sujeto(['Together,', these, results]), verbo([reveal]), complemento([that, 'RP', gene, dosage, limits, the, 'differentiation,', not, the, 'self-renewal,', of, mouse, 'ESCs'])].
[sujeto(['Recent', studies]), verbo([have]), complemento([greatly, illuminated, the, genomic, landscape, of, the, myelodysplastic, syndromes, '(', 'MDS),', and, the, pace, of, discovery, is, accelerating])].
[sujeto(['The', most, common, mutations]), verbo([found]), complemento([in, 'MDS', occur, in, genes, involved, in, 'RNA', splicing, '(', including, 'SF3B1,', 'SRSF2,', 'U2AF1,', and, 'ZRSR2)', and, epigenetic, modification, '(', including, 'TET2,', 'ASXL1,', and, 'DNMT3A)'])].
[sujeto(['The', identification, of, spliceosome, mutations, in, approximately, half, of, all, patients, with, 'MDS', implicates, abnormalities, of, 'RNA', 'splicing,', a, pathway, not, previously, known, as, a]), verbo([target]), complemento([for, 'mutation,', in, the, 'MDS', pathogenesis])].
[sujeto(['The', complex, patterns, of, associations, between, gene, mutations, identified]), verbo([have]), complemento([revealed, epistatic, interactions, between, spliceosome, components, and, epigenetic, modifiers, in, 'MDS'])].
[sujeto(['The', cytogenetic, abnormalities]), verbo([found]), complemento([in, 'MDS', are, characterized, by, the, loss, of, genetic, 'material,', whereas, translocations, are, rare])].
[sujeto([',', 5, 'q-,', 7, 'q-,', 20, 'q-)']), verbo([provide]), complemento([us, with, circumstantial, evidence, for, the, presence, of, tumor, suppressor, genes])].
[sujeto(['It', is, now]), verbo([recognized]), complemento([that, haploinsufficiency, '(', a, gene, dosage, 'effect)', resulting, from, gene, deletions, or, inactivating, mutations, is, an, important, disease, mechanism, in, 'MDS'])].
[sujeto(['Haploinsufficiency', of, the, ribosomal, protein, gene, 'RPS14', plays, a, critical, role, in, the, development, of, anemia, in, the, 5, 'q-', 'syndrome,', and, haploinsufficiency, of, 'CUX1', is, important, in, some, patients, with, 'MDS', and, 'AML', with, complete, or, partial]), verbo([loss]), complemento([of, chromosome, 7])].
[sujeto(['Gene', expression, profiling]), verbo([has]), complemento([identified, key, deregulated, genes, and, pathways, and, new, prognostic, gene, signatures, in, 'MDS'])].
[sujeto(['Recent', advances, in, the, molecular, pathogenesis, of, 'MDS', are]), verbo([leading]), complemento([to, new, 'biological,', 'clinical,', and, therapeutic, insights])].
[sujeto(['Ineffective', erythropoiesis, in, 'del(5q)', 'MDS', arises, from, allelic, deletion, of, the, ribosomal, processing, 'S-14', '(', 'RPS14)', 'gene,', which]), verbo([leads]), complemento([to, 'MDM2', sequestration, with, consequent, p53, activation, and, erythroid, cell, death])].
[sujeto(['Since', its, approval, in, 2005, ',', lenalidomide]), verbo([has]), complemento([changed, the, natural, course, of, the, disease])].
[sujeto(['Patients', who, achieve, transfusion, independence, 'and/or', a, cytogenetic, response, with, lenalidomide]), verbo([have]), complemento([a, decreased, risk, of, progression, to, acute, myeloid, leukemia, and, an, improved, overall, survival, compared, to, 'non-responders'])].
[sujeto(['Elucidation', of, the, mechanisms, of, action, of, lenalidomide, in, 'del(5q)', 'MDS']), verbo([has]), complemento([advanced, therapeutic, strategies, for, this, disease])].
[sujeto(['Inhibition', of, 'PP2Acα', results, in, 'cell-cycle']), verbo([arrest]), complemento([and, apoptosis, in, 'del(5q)', cells])].
[sujeto(['Through', its, inhibitory, effect, on, 'PP2A,', lenalidomide, stabilizes, 'MDM2', to, restore, p53, degradation, in, erythroid, 'precursors,', with, subsequent]), verbo([arrest]), complemento([in, 'G2/M'])].
[sujeto(['Unfortunately,', the, majority, of, patients, with, 'del(5q)', 'MDS', develop, resistance, to, lenalidomide, over, time]), verbo([associated]), complemento([with, 'PP2Acα', 'over-expression'])].
[sujeto(['Targeted', inhibition, of, 'PP2A', with, a, more, potent, inhibitor]), verbo([has]), complemento([emerged, as, an, attractive, therapeutic, approach, for, patients, with, 'del(5q)', 'MDS'])].
[sujeto(['The', moss, 'Physcomitrella', patens]), verbo([has]), complemento([two, 'RNA', editing, sites, in, the, chloroplasts])].
[sujeto(['Knockdown', of, the, 'PpPPR_45', gene, reduced, the, extent, of, 'RNA', editing, at, the, chloroplast, 'rps14-C2', 'site,', whereas, 'over-expression', of, 'PpPPR_45']), verbo([increased]), complemento([the, levels, of, 'RNA', editing, at, both, the, 'rps14-C2', site, and, its, neighboring, 'C', site])].
[sujeto(['Haploinsufficiency', of, ribosomal, proteins, '(', 'RPs)', and, upregulation, of, the, tumour, suppressor, 'TP53']), verbo([have]), complemento([been, shown, to, be, the, common, basis, for, the, anaemia, observed, in, 'Diamond', 'Blackfan', anaemia, and, 5, 'q-', myelodysplastic, syndrome])].
[sujeto(['To', determine, if, the, 'L-Leucine', effect, was, 'Tp53-dependent,', we, used, antisense, 'MOs', to, rps19, and, rps14, in, 'zebrafish;', expression, of, tp53, and, its, downstream]), verbo([target]), complemento([cdkn1a, remained, elevated, following, 'L-leucine', treatment])].
[sujeto(['Flow', cytometry]), verbo([has]), complemento([also, been, proposed, as, a, tool, to, improve, the, evaluation, of, marrow, 'dysplasia,', because, immunophenotyping, is, an, accurate, method, for, quantitative, and, qualitative, evaluations, of, hematopoietic, 'cells,', and, 'MDS', specimens, have, been, found, to, exhibit, abnormal, expressions, of, several, cellular, antigens])].
[sujeto(['In', 'addition,', the, molecular, classification, of, 'MDS']), verbo([has]), complemento([received, marked, attention, in, recent, years])].
[sujeto(['New', molecular, markers, including, 'RPS14,', 'TET2,', 'IDH1/2,', 'SF3B1,', 'ASXL1,', 'RUNX1,', 'TP53,', 'EZH2,', 'JAK2,', and, 'WT1']), verbo([have]), complemento([been, revealed, to, be, important, for, the, 'prognosis,', as, well, as, diagnosis, and, classification])].
[sujeto(['Cortical', porosity, is, increasingly]), verbo([recognized]), complemento([as, an, important, risk, for, fracture, in, 'DM', patients])].
[sujeto(['The', present, study, demonstrated, that]), verbo([decreased]), complemento([cortical, 'thickness,', assessed, using, a, newly, developed, quantitative, ultrasonic, bone, 'densitometry,', is, a, significant, risk, factor, for, vertebral, fractures, in, type, 2, diabetes, mellitus, patients, with, stage, 3, or, higher, chronic, kidney, 'disease,', but, not, in, those, without])].
[sujeto(['Cortical', porosity, is, increasingly]), verbo([recognized]), complemento([as, an, important, risk, factor, for, fracture, in, type, 2, diabetes, mellitus, '(', 'T2DM)', patients, as, well, as, in, stage, 3, chronic, kidney, disease, '(', 'CKD)', patients, in, whom, serum, parathyroid, hormone, '(', 'PTH)', starts, to, increase])].
[sujeto(['The', present, study, aimed, to, clarify, whether, the, coexistence, of, 'CKD', might, affect, the, relationship, of]), verbo([decreased]), complemento([cortical, thickness, '(', 'CoTh)', in, the, development, of, vertebral, fractures, '(', 'VF)', in, 'T2DM', patients])].
[sujeto(['In', a, multivariate, logistic, regression, 'analysis,', 'EMTb', was, independently, and, significantly]), verbo([associated]), complemento([with, 'VF', in, 'T2DM', patients, with, a, high, 'eGFR,', in, contrast, to, those, with, only, 'CoTh', with, 'VF', in, 'T2DM', with, low, eGFR])].
[sujeto(['This', study, demonstrated, 'CoTh', as, a, factor, independently]), verbo([associated]), complemento([with, 'VF', in, 'T2DM', patients, with, low, eGFR, and, increasing, serum, 'PTH', levels])].
[sujeto(['In', the, fundamental, process, of, neuronal, 'path-finding,', a, growth, cone, at, the, tip, of, every, neurite, detects, and, follows, multiple, guidance, cues]), verbo([regulating]), complemento([outgrowth, and, initiating, directional, changes])].
[sujeto(['Using', fluorescence, time, lapse, microscopy, we, could, identify, two, distinct, modes, of, growth, cone, collapse]), verbo([leading]), complemento([either, to, neurite, retraction, or, to, a, controlled, halt, of, neurite, extension])].
[sujeto(['We', term, this, previously, unreported, second, type, fold, collapse, and]), verbo([suggest]), complemento([that, it, marks, an, 'intermediate-term', mode, of, growth, regulation, closing, the, gap, between, full, retraction, and, small, scale, fluctuations])].
[sujeto(['The', large, and, transparent, cells, of, 'cleavage-stage', zebrafish, embryos]), verbo([provide]), complemento([unique, opportunities, to, study, cell, division, and, cytoskeletal, dynamics, in, very, large, animal, cells])].
[sujeto(['First,', we, present, simple, protocols, for, extending, the, breeding, competence, of, zebrafish, mating, ensembles, throughout, the, 'day,', which]), verbo([ensures]), complemento([a, steady, supply, of, embryos, in, early, 'cleavage,', and, for, mounting, these, embryos, for, imaging])].
[sujeto(['Second,', we, describe, a, transgenic, zebrafish, line, '[', 'Tg(bactin2:HsENSCONSIN17-282-3xEGFP)hm1]', that]), verbo([expresses]), complemento([the, green, fluorescent, protein, '(', 'GFP)-labeled', 'microtubule-binding', part, of, ensconsin, '(', 'EMTB-3GFP)'])].
[sujeto(['Microtubules', are, much, more, easily, visualized, using, this, tagged]), verbo([binding]), complemento([protein, rather, than, directly, labeled, tubulin, '(', injected, 'Alexa-647-labeled', 'tubulin),', presumably, due, to, lower, background, from, probe, molecules, not, attached, to, microtubules])].
[sujeto(['Highly', significant, correlations, between, the, 'LD-100', and, pQCT, systems, were]), verbo([found]), complemento([in, 'TBD', '(', r, =, 0.877, ',', p, &, 'lt;', 0.001, ')', and, 'CoTh', '(', r, =, 0.723, ',', p, &, 'lt;', 0.001, ')'])].
[sujeto(['The', 'TBD', fell, significantly, '(', p, &, 'lt;', 0.05, ')', beginning, at, 55, -, 59, years, in, both, 'sexes,', with, a, relatively, rapid]), verbo([decrease]), complemento([in, women])].
[sujeto(['The', 'CoTh', showed, a, significant]), verbo([decrease]), complemento([beginning, at, 40, -, 44, years, in, men, and, 50, -, 54, years, in, women])].
[sujeto(['The', 'EMTb', showed, a, significant]), verbo([decrease]), complemento([beginning, at, 40, -, 44, years, in, men, and, 55, -, 59, years, in, women])].
[sujeto(['The', 'LD-100', system, is, a, useful, bone, densitometry, device, and, the, database, of, 'age-related', changes, in, 'TBD,', 'CoTh,', and, 'EMTb', established, in, this, study, will]), verbo([provide]), complemento([fundamental, data, for, future, studies, related, to, bone, status])].
[sujeto(['This', patient, was]), verbo([provided]), complemento([excellent, care, in, the, prehospital, setting, because, the, paramedic, and, his, 'EMT-B', partner, worked, together, effectively, as, a, team])].
[sujeto(['This']), verbo([involves]), complemento([preparing, 'IV', equipment, and, 'supplies,', applying, the, cardiac, 'monitor,', and, recognizing, and, handling, the, various, paramedic, medications])].
[sujeto(['This']), verbo([enhanced]), complemento([role, of, the, 'EMT-B', allows, the, paramedic, to, perform, a, more, focused, and, careful, patient, assessment])].
[sujeto(['We']), verbo([expressed]), complemento([chimeras, of, green, fluorescent, protein, '(', 'GFP)', conjugated, to, 'ensconsin\'s', 'N-terminal', 'MT-binding', domain, '(', 'EMTB),', to, study, 'distribution,', 'dynamics,', and, function, of, the, 'MAP', in, living, cells])].
[sujeto(['We', tested, the, hypothesis, that, behavior, of]), verbo([expressed]), complemento(['GFP-EMTB', accurately, matched, behavior, of, endogenous, ensconsin])].
[sujeto(['Like', endogenous, 'MAP,', 'GFP-EMTB', was]), verbo([associated]), complemento([with, microtubules, in, living, or, fixed, 'cells,', and, microtubule, association, of, either, molecule, was, impervious, to, extraction, with, nonionic, detergents])].
[sujeto(['In', cell, lysates, both, 'GFP-EMTB', and, endogenous, ensconsin, were, dissociated, from, microtubules, by, identical, salt, extraction, 'conditions,', and, both, molecules, remained]), verbo([bound]), complemento([to, a, 'calcium-stable', subset, of, 'Taxol-stabilized', microtubules])].
[sujeto(['We', took, advantage, of, this]), verbo([finding]), complemento([to, generate, constructs, in, which, additional, 'GFP', moieties, were, attached, to, 'EMTB,', to, obtain, a, more, intensely, fluorescent, reporter, of, in, vivo, 'MAP', binding])].
[sujeto(['Thus,', we]), verbo([have]), complemento([demonstrated, the, utility, of, chimeric, proteins, containing, 'GFP', multimers, as, authentic, reporters, of, ensconsin, distribution, and, 'dynamics;', expression, of, these, 'GFP-EMTB', chimeric, molecules, also, provides, a, 'non-perturbing', label, of, the, microtubule, system, in, living, cells])].
[sujeto(['Microtubule-associated', proteins, '(', 'MAPs)', are, proteins, that, reversibly]), verbo([bind]), complemento([to, and, regulate, microtubule, dynamics, and, functions, in, vivo])].
[sujeto(['We', examined, the, dynamics, of]), verbo([binding]), complemento([of, a, 'MAP', called, ensconsin, '(', 'E-MAP-115)', to, microtubules, in, vivo])].
[sujeto(['We', also, used, fluorescence, recovery, after, photobleaching, '(', 'FRAP)', to, quantify, the, 'half-time', of]), verbo([binding]), complemento([and, dissociation, of, the, 5, 'xGFP-EMTB', chimera, and, to, compare, this, 'half-time', to, that, of, the, 'full-length', 'MAP', molecule])].
[sujeto(['In', untreated, 'cells,', the, 't(g)', of, either, 5, 'xGFP-EMTB', or, 'full-length', 'GFP-ensconsin', was, similarly, rapid, '(', approximately, 4, 'seconds),', while, in, 'ATP-reduced', and, 'Taxol-treated', 'cells,', 't(g)', was]), verbo([increased]), complemento([to, 210, seconds, and, 40, 'seconds,', respectively])].
[sujeto(['However,', 'K(D,app)', was, not, significantly, changed, in, the, presence, of, azide, and, was]), verbo([increased]), complemento([to, 110, microM, in, the, presence, of, 'Taxol'])].
[sujeto(['We', used, human, 'MCF-7', or, 'HeLa', 'cells,', which, are, sensitive, to, low, 'Taxol', concentrations, '(', 'LD(50)', of, 30, -, 35, and, 3.5, 'nM,', 'respectively)', to, prepare, stably, transfected, populations, of, cells]), verbo([expressing]), complemento([heterogeneous, levels, of, ensconsin, 'chimeras,', either, green, fluorescent, protein, '(', 'GFP)', conjugated, to, 'full-length', ensconsin, '(', 'GFP-Ensc)', or, to, 'ensconsin\'s', 'microtubule-binding', domain, '(', 'GFP-EMTB)'])].
[sujeto([',', measuring, level, of, 'GFP-ensconsin', chimera, in, cells, surviving, treatment, with, 'Taxol,', showed, that, cells]), verbo([expressing]), complemento([higher, levels, of, 'GFP-ensconsin', chimera, were, killed, more, readily, by, 'Taxol', concentrations, approaching, the, 'LD(50)'])].
[sujeto(['In', 'contrast,', in, 'TC-7', 'cells,', which, are, relatively, insensitive, to, 'Taxol', '(', 'LD(50)', &, 'gt;', 600, 'nM),', 'high-level', expression, of, 'GFP-EMTB']), verbo([conferred]), complemento([no, significant, susceptibility, to, killing, by, 'Taxol'])].
[sujeto(['However,', heightening, the, 'Taxol', sensitivity, of, 'GFP-EMTB-TC-7', cells, by, 'pre-incubating', cells, with, the, 'p-glycoprotein', 'inhibitor,', 'verapamil,', did, result, in, selective, killing, of, cells, highly]), verbo([expressing]), complemento(['GFP-EMTB'])].
[sujeto(['Taken', 'together,', results, obtained, in, 'MCF-7,', 'HeLa,', and, 'TC-7', cells]), verbo([suggest]), complemento([that, elevated, ensconsin, level, bestowed, a, selective, disadvantage, upon, 'Taxol-sensitive', cells])].
[sujeto(['In', vivo, 'Taxol', treatment, significantly, tightened, 'microtubule-binding', of, 'ensconsin,']), verbo([suggesting]), complemento([that, 'Taxol', alters, 'ensconsin\'s', 'microtubule-binding', properties, and, 'may,', in, 'turn,', alter, the, 'Taxol', response, of, the, microtubules])].
[sujeto(['Microtubule-associated', proteins, '(', 'MAPs)']), verbo([have]), complemento([been, hypothesized, to, regulate, microtubule, dynamics, 'and/or', functions])].
[sujeto(['To', test, hypotheses, concerning, 'E-MAP-115', '(', 'ensconsin)', 'function,', we, prepared, stable, cell, lines]), verbo([expressing]), complemento([conjugates, in, which, the, 'full-length', 'MAP', '(', 'Ensc)', or, its, 'microtubule-binding', domain, '(', 'EMTB)', was, conjugated, to, one, or, more, green, fluorescent, protein, '(', 'GFP)', molecules])].
[sujeto(['Dual', wavelength, 'time-lapse', fluorescence, imaging, of, 2, 'xGFP-EMTB', in, cells, microinjected, with, labeled, tubulin, revealed, that, this, 'GFP-MAP', chimera]), verbo([associated]), complemento([with, the, lattice, of, all, microtubules, immediately, upon, polymerization, and, dissociated, concomitant, with, 'depolymerization,', suggesting, that, dynamics, of, 'MAP:microtubule', interactions, were, at, least, as, rapid, as, 'tubulin:microtubule', dynamics, in, the, polymerization, reaction])].
[sujeto(['Presence', of, both, 'GFP-EMTB', chimeras, and, endogenous, 'E-MAP-115', '(', 'ensconsin)', along, apparently, all, cellular, microtubules, at, all, cell, cycle, stages]), verbo([suggested]), complemento([that, the, 'MAP', might, function, in, modulating, stability, or, dynamics, of, 'microtubules,', a, capability, shown, previously, in, transiently, transfected, cells])].
[sujeto(['Although', cells, with, extremely, high, expression, levels, of, 'GFP-EMTB', chimera, exhibited, stabilized, 'microtubules,', cells]), verbo([expressing]), complemento([four, to, ten, times, the, physiological, level, of, endogenous, 'MAP', exhibited, microtubule, dynamics, indistinguishable, from, those, of, untransfected, cells])].
[sujeto(['Instead,', this, 'MAP', most, likely, serves, to]), verbo([modulate]), complemento([microtubule, functions, or, interactions, with, other, cytoskeletal, elements])].
[sujeto(['In', previous, studies, at, these, loci, we]), verbo([have]), complemento([determined, that, segregation, of, the, recessive, phenotype, occurs, primarily, by, '(', 1, ')', the, loss, of, the, chromosome, 2, carrying, the, 'wild-type,', 'drug-sensitive,', 'allele,', '(', 2, ')', deletion, of, the, long, arm, of, chromosome, 2, ',', or, '(', 3, ')', loss, of, one, chromosome, 2, followed, by, duplication, of, the, remaining, homologue])].
[sujeto(['However,', a, small, proportion, of, segregants]), verbo([have]), complemento([also, been, detected, which, may, have, arisen, by, the, mechanisms, of, de, novo, gene, inactivation, or, mutation])].
[sujeto(['We', also, demonstrate, a, dramatic]), verbo([increase]), complemento([in, the, proportion, of, segregants, occurring, by, gene, inactivation, in, two, of, these, hybrids, as, compared, with, those, previously, 'reported,', indicating, that, this, mechanism, may, be, an, important, mode, of, phenotype, segregation, in, diploid, cells, 'and,', 'therefore,', in, the, development, of, 'cancers--such', as, the, childhood, tumors, retinoblastoma, and, 'Wilms', 'tumor--resulting', from, recessive, alleles, 'In', 'Chinese', hamster, ovary, 'cells,', mutations, in, the, 'RPS14', gene, '(', which, was, previously, designated, 'emtB)', render, cells, resistant, to, normally, cytotoxic, concentrations, of, the, protein, synthesis, 'inhibitor,', emetine])].
[sujeto(['Several', lines, of, evidence, indicate, the, 'RPS14', gene, in, 'Chinese', hamster, is, the, structural, gene, for, ribosomal, protein, 'S14,', including, the]), verbo([finding]), complemento([that, mutants, with, alterations, in, this, gene, produce, an, electrophoretically, altered, form, of, this, protein])].
[sujeto(['A', human, gene, which, complements, the, defect, in, 'CHO', 'RPS14', mutants, and, renders, them, sensitive, to, emetine]), verbo([has]), complemento([previously, been, assigned, to, the, long, arm, of, chromosome, 5])].
[sujeto(['The', 'Chinese', hamster, ovary, '(', 'CHO)', cell, 40, 'S', ribosomal, subunit, protein, 'S14']), verbo([provides]), complemento([a, unique, opportunity, to, investigate, an, important, mammalian, housekeeping, gene, and, its, mRNA, and, protein, products])].
[sujeto(['The', 'S14', gene, appears, to, be, single, 'copy,', and, 'CHO', cell, 'S14', mutants]), verbo([have]), complemento([been, isolated, as, 'emetine-resistant', '(', 'emtB)', clones, in, tissue, culture])].
[sujeto(['We']), verbo([report]), complemento([both, mRNA, and, polypeptide, sequences, of, the, 'wild-type', and, mutant, ribosomal, protein, transcripts])].
[sujeto(['This']), verbo([provides]), complemento([a, convenient, cytogenetic, and, biochemical, means, to, distinguish, the, chromosome, 2, s, from, the, different, parents])].
[sujeto(['One', rare, class, of, segregants, loses, the, 'wild-type', leuS, and, emtB, gene, functions, on, the, long, arm, of, the, hsr, chromosome, 2, '(', 'H-2)', but]), verbo([retains]), complemento([the, amplified, dhfr, genes, on, the, opposite, arm])].
[sujeto(['Detailed', genetic, analysis, of, two, such, segregants, that, did, not, arise, by, chromosome]), verbo([loss]), complemento([or, deletion, revealed, that, new, gene, linkage, relationships, had, been, established, on, the, 'H-2', chromosome, in, 'each,', demonstrating, that, the, segregation, events, in, these, cell, lines, involved, mitotic, recombination])].
[sujeto(['Starting', with, hybrid, cell, lines, between, a, 'Chinese', hamster, cell, 'EmtA', mutant, and, a, 'Chinese', hamster, cell, 'EmtB', 'mutant,', we]), verbo([have]), complemento([constructed, cell, lines, that, are, homozygous, for, mutant, alleles, at, both, the, emtA, locus, and, the, emtB, 'locus,', by, using, a, 'two-step', segregation, protocol])].
[sujeto(['Having', both, the, 'EmtA', mutation, and, the, 'EmtB', mutation]), verbo([expressed]), complemento([in, the, same, cell, also, results, in, a, level, of, resistance, to, cryptopleurine, that, is, significantly, higher, than, a, simple, additive, effect, of, the, two, mutations, alone])].
[sujeto(['Analysis', of, ribosomal, proteins, by, 'two-dimensional', polyacrylamide, gel, electrophoresis, demonstrated, that, a, parental, hybrid, and, a, 'first-step', 'segregant,', which]), verbo([has]), complemento([lost, the, 'wild-type', emtA, 'allele,', synthesize, both, a, normal, and, an, altered, form, of, ribosomal, protein, 'S14,', whereas, an, 'EmtA', 'EmtB', double, mutant, synthesizes, only, the, altered, form, of, this, ribosomal, protein])].
[sujeto(['Our', results, also]), verbo([suggest]), complemento([that, the, products, of, the, emtA, and, emtB, loci, interact, 'directly,', indicating, that, the, emtA, 'locus,', like, the, emtB, 'locus,', encodes, a, component, of, the, ribosome])].
[sujeto(['Genetic', and, biochemical, experiments]), verbo([have]), complemento([enabled, us, to, more, clearly, distinguish, three, genetic, 'loci,', 'emtA,', 'emtB,', and, 'emtC,', all, of, which, can, be, altered, to, give, rise, to, resistance, to, the, protein, synthesis, 'inhibitor,', 'emetine,', in, cultured, 'Chinese', hamster, cells])].
[sujeto(['Genetic', experiments]), verbo([have]), complemento([demonstrated, 'that,', unlike, the, emtB, 'locus,', neither, the, emtA, locus, nor, the, emtC, locus, is, linked, to, chromosome, 2, in, 'Chinese', hamster, 'cells,', clearly, distinguishing, the, latter, two, genes, from, emtB])].
[sujeto(['Two', of, the, 'genes,', emtA, and, 'emtB,']), verbo([recognized]), complemento([in, 'Chinese', hamster, lung, and, ovary, cell, 'lines,', 'respectively,', are, known, to, affect, the, ribosomes, of, the, cells, directly])].
[sujeto(['To', seek, unambiguous, genetic, evidence, for, a]), verbo([cause]), complemento([and, effect, relationship, between, 'CHO', cell, emetine, resistance, and, mutations, in, the, 'S14', 'gene,', we, mutagenized, a, 'one-step', 'CHO', cell, mutant, and, isolated, 'second-step', mutant, clones, resistant, to, 10, -, 'fold-higher', concentrations, of, emetine])].
[sujeto(['Chinese', 'hamster-human', interspecific, hybrid, 'cells,', which, contain, human, chromosome, 5, and]), verbo([express]), complemento([four, genes, linked, on, that, 'chromosome,', were, subjected, to, selective, conditions, requiring, them, to, retain, one, of, the, four, linked, 'genes,', leuS, '(', encoding, 'leucyl-tRNA', 'synthetase),', but, lose, 'another,', either, emtB, '(', encoding, ribosomal, protein, 'S14)', or, chr])].
[sujeto(['Cytogenetic', and, biochemical, analyses, of, spontaneous, segregants, isolated, by, using, these, unique, selective, pressures]), verbo([have]), complemento([enabled, us, to, determine, the, order, and, regional, location, of, the, 'leuS,', 'hexB,', 'emtB,', and, chr, genes, on, human, chromosome, 5])].
[sujeto(['In', 'addition,', these, hybrids, and, selective, conditions]), verbo([provide]), complemento([a, very, simple, and, quantitative, means, to, assess, the, potency, of, various, agents, suspected, of, inducing, gross, chromosomal, damage])].
[sujeto(['We', isolated, interspecific, hybrids, between, normal, human, leukocytes, and, a, 'Chinese', hamster, ovary, cell, line, that]), verbo([has]), complemento([mutations, in, three, 'genes,', 'leuS,', 'emtB,', and, 'chr,', all, of, which, are, linked, to, chromosome, 2])].
[sujeto(['The', interspecific, hybrids, were, selected, at, 39, degrees, 'C', so, that, they, were]), verbo([required]), complemento([to, retain, and, express, the, human, leuS, gene])].
[sujeto(['Ten', out, of, ten, such, 'heat-resistant', hybrids, also]), verbo([expressed]), complemento([the, human, emtB, and, chr, genes])].
[sujeto(['The', linkage, relationship, between, these, three, genes]), verbo([has]), complemento([thus, been, conserved, during, the, evolution, of, the, human, and, 'Chinese', hamster, genomes])].
[sujeto(['Bacteria']), verbo([respond]), complemento([dynamically, to, the, changes, in, zinc, availability])].
[sujeto(['Repression', by, the, 'Bacillus', subtilis, transcription, factor, 'Zur']), verbo([requires]), complemento(['Zn(II),', which, binds, with, negative, cooperativity, to, two, regulatory, sites, per, dimer, to, 'form,', 'sequentially,', 'Zur2:Zn3', and, 'Zur2:Zn4', forms, of, the, repressor])].
[sujeto(['Here', we, show, 'that,', as, cells, transition, from, zinc, sufficiency, to, 'deficiency,', operons]), verbo([regulated]), complemento([by, 'Zur', are, derepressed, in, three, distinct, waves])].
[sujeto(['Finally,', as, zinc, levels]), verbo([decrease]), complemento(['further,', the, 'Zur2:Zn3', form, loses, 'Zn(II)', leading, to, derepression, of, 'RpsNB(S14*)', and, 'FolE2,', which, allow, continued, ribosome, assembly, and, folate, 'synthesis,', respectively])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, inhibitors, of, this, enzyme, are, potent, neuroprotective, and, 'anti-inflammatory', agents])].
[sujeto(['In', addition, we, also, demonstrated, that, 'PDE7', inhibition]), verbo([induces]), complemento([endogenous, neuroregenerative, processes, towards, a, dopaminergic, phenotype])].
[sujeto(['Neurospheres', cultures, obtained, from, 'SGZ', and, 'SVZ', of, adult, rats, treated, with, 'PDE7', inhibitors, presented, an]), verbo([increased]), complemento([proliferation, and, neuronal, differentiation, compared, to, control, cultures])].
[sujeto(['PDE7', inhibitors, treatment, of, neurospheres, cultures, also, resulted, in, an]), verbo([increase]), complemento([of, the, levels, of, phosphorylated, 'CREB,', suggesting, that, their, effects, were, indeed, mediated, through, the, activation, of, the, 'cAMP/PKA', signaling, pathway])].
[sujeto(['Moreover,', 'long-term', treatment, with, this, 'PDE7', inhibitor, shows, a, significant]), verbo([increase]), complemento([in, newly, generated, neurons, in, the, olfactory, bulb, and, the, hippocampus])].
[sujeto(['Also', a, better, performance, in, memory, tests, was, observed, in, 'S14', treated, 'rats,']), verbo([suggesting]), complemento([a, functional, relevance, for, the, 'S14-induced', increase, in, 'SGZ', neurogenesis])].
[sujeto(['Taken', 'together,', our, results, indicate, for, the, first, time, that, inhibition, of, 'PDE7', directly]), verbo([regulates]), complemento(['proliferation,', migration, and, differentiation, of, neural, stem, 'cells,', improving, spatial, learning, and, memory, tasks])].
[sujeto(['This', article, describes, how, an, interprofessional, project, in, a, 'London', 'NHS', 'Foundation', 'Trust', was, undertaken, to, develop, an, 'intranet-based', medical, 'device-related', pressure, ulcer, prevention, and, management, pathway, for, clinical, staff, working, across, an, adult, critical, care, 'directorate,', where, 'life-threatening', events]), verbo([require]), complemento([interventions, using, medical, devices])].
[sujeto(['The', aim, of, this, project, was, to, improve, working, policies, and, processes, to, define, key, prevention, strategies, and]), verbo([provide]), complemento([clinicians, with, a, 'clear,', standardised, approach, to, risk, and, skin, 'assessment,', equipment, 'use,', documentation, and, reporting, clinical, data, using, the, 'Trust\'s', 'CareVue', '(', electronic, medical, 'records),', 'Datix', '(', incident, reporting, and, 'risk-management', 'tool)', and, eTRACE, '(', online, clinical, protocol, 'ordering)', systems])].
[sujeto(['Cholesterol', is, essential, for, 'survival,', but, too, much, or, too, little, can]), verbo([cause]), complemento([disease])].
[sujeto(['Largely,', 'DHCR7', research, is]), verbo([associated]), complemento([with, the, developmental, disease, 'Smith-Lemli-Opitz', 'syndrome,', which, is, caused, by, mutations, in, the, 'DHCR7', gene])].
[sujeto(['However,', little, is, known, about, what]), verbo([regulates]), complemento(['DHCR7', activity])].
[sujeto(['Here', we]), verbo([provide]), complemento([evidence, that, phosphorylation, plays, a, role, in, controlling, 'DHCR7', 'activity,', which, may, provide, a, means, to, divert, flux, from, cholesterol, synthesis, to, vitamin, 'D', production])].
[sujeto(['DHCR7', activity, was, significantly]), verbo([decreased]), complemento([when, we, used, pharmacological, inhibitors, against, two, important, 'kinases,', 'AMP-activated', protein, kinase, and, protein, kinase, 'A'])].
[sujeto(['Moreover,', mutating, a, known]), verbo([phosphorylated]), complemento(['residue,', 'S14,', also, decreased, 'DHCR7', activity])].
[sujeto(['Thus,', we, demonstrate, that, phosphorylation]), verbo([modulates]), complemento(['DHCR7', activity, in, 'cells,', and, contributes, to, the, overall, synthesis, of, 'cholesterol,', and, probably, vitamin, 'D'])].
[sujeto(['The', results, of, this, study, confirm, that, obese, people, are, cold, and, wet, or]), verbo([have]), complemento([phlegmatic, temperament, whereas, in, comparison, thin, people, are, drier])].
[sujeto(['Practitioners', and, patients, alike, widely]), verbo([recognize]), complemento([the, limitations, of, current, therapeutic, approaches, to, the, treatment, of, bacterial, vaginosis, '(', 'BV)'])].
[sujeto(['Options', remain, extremely, 'limited,', and, our, inability, to]), verbo([prevent]), complemento([the, 'frequently,', often, relentless, symptomatic, recurrences, of, 'BV', and, to, reduce, serious, sequelae, such, as, preterm, 'delivery,', remains, an, acknowledged, but, unresolved, shortcoming])].
[sujeto(['Our', incomplete, understanding, of, the, pathophysiology, of, this, unique, form, of, vaginal, dysbiosis]), verbo([has]), complemento([been, a, significant, impediment, to, developing, optimal, treatment, and, prevention, approaches])].
[sujeto(['New', drugs]), verbo([have]), complemento([not, been, forthcoming, and, are, not, likely, to, be, available, in, the, immediate, 'future;', 'hence,', reliance, on, the, optimal, use, of, available, agents, has, become, essential, as, improvised, often, unproven, regimens, are, implemented])].
[sujeto(['In', this, 'review,', we, will, explore, the, limitations, of, currently, recommended, 'therapies,', with, a, particular, focus, on, the, contribution, of, reinfection, and, pathogen, persistence, to, 'BV', 'recurrence,', and, the, development, of, interventions, that]), verbo([target]), complemento([these, mechanisms])].
[sujeto(['Tumour', cells, with, highest, adaptive, potential]), verbo([have]), complemento([a, selective, advantage, over, less, fit, cells])].
[sujeto(['Naturally', occurring, transmissible, cancers]), verbo([provide]), complemento([an, ideal, model, system, for, investigating, the, evolutionary, arms, race, between, cancer, cells, and, their, surrounding, 'micro-environment', and, 'macro-environment'])].
[sujeto(['However,', the, evolutionary, landscapes, in, which, contagious, cancers, reside]), verbo([have]), complemento([not, been, subjected, to, comprehensive, investigation])].
[sujeto(['Here,', we]), verbo([provide]), complemento([a, multifocal, analysis, of, transmissible, tumour, progression, and, discuss, the, selection, forces, that, shape, it])].
[sujeto(['While', all, three, contagious, cancers, carry, the, signature, of, ongoing, and, fairly, recent, adaptations, to, selective, 'forces,', 'CTVT', appears, to]), verbo([have]), complemento([reached, an, evolutionary, stalemate, with, its, 'host,', while, 'DFTD', and, the, clam, leukaemia, appear, to, be, still, at, a, more, dynamic, phase, of, their, evolution])].
[sujeto(['A', greater, understanding, of, transmissible, cancers, from, an, evolutionary, ecology, perspective, will]), verbo([provide]), complemento([novel, avenues, for, the, prevention, and, treatment, of, both, contagious, and, 'non-communicable', cancers])].
[sujeto(['Malnutrition', is, both, a]), verbo([cause]), complemento([and, consequence, of, disease, and, can, lead, to, increased, mortality, and, 'morbidity,', delayed, recovery, from, illness, and, impaired, body, function, which, can, make, carrying, out, activities, of, daily, living, difficult])].
[sujeto(['Managing', malnutrition, in, the, community]), verbo([involves]), complemento([identifying, malnutrition, using, a, universally, validated, screening, tool, and, implementing, appropriate, care, plans, according, to, the, degree, of, malnutrition])].
[sujeto(['Elaborating', on, this, theoretical, 'basis,', studies, did, assess, the, possibilities, to]), verbo([prevent]), complemento([allergic, diseases, in, infancy, through, manipulation, of, the, intestinal, microbiota])].
[sujeto([interventional, studies]), verbo([led]), complemento([to, conflicting, conclusions, on, the, possible, role, of, probiotics, and, prebiotics, in, allergy, prevention])].
[sujeto(['Guidelines']), verbo([have]), complemento([been, predicated, on, such, studies, using, the, 'GRADE', methodology])].
[sujeto([the, guidelines, for, allergy, prevention]), verbo([suggest]), complemento([for, the, first, time, the, use, of, probiotics, and, prebiotics])].
[sujeto(['This', was, the, first, cohort, to, undergo, the, new, training, programme, and]), verbo([has]), complemento([shown, promising, initial, 'results;', 'however,', it, also, demonstrates, that, the, training, 'content,', while, leading, to, positive, 'changes,', does, in, some, areas, need, to, be, further, developed, and, then, disseminated, across, the, hospital, to, all, nurses, who, provide, direct, wound, care, for, patients])].
[sujeto(['There', are, several, natural, examples, of, distinct, 'RNA', structures, that]), verbo([interact]), complemento([with, the, same, ligand, to, regulate, the, expression, of, homologous, genes, in, different, organisms])].
[sujeto(['Are', the, 'RNAs', derived, from, some, common, ancestor, and, diverged, to, the, point, where, we, cannot, identify, the, 'similarity,', or]), verbo([have]), complemento([multiple, solutions, to, the, same, biological, problem, arisen, 'independently?', 'A', key, variable, in, assessing, these, alternatives, is, how, frequently, such, regulators, arise, within, sequence, space])].
[sujeto(['Ribosomal', protein, 'S15', is, autogenously]), verbo([regulated]), complemento([via, an, 'RNA', regulator, in, many, bacterial, 'species;', four, apparently, distinct, regulators, have, been, functionally, validated, in, different, bacterial, phyla])].
[sujeto(['We']), verbo([find]), complemento([many, 'RNAs', that, interact, specifically, with, ribosomal, protein, 'S15', from, 'Geobacillus', kaustophilus, with, biologically, relevant, dissociation, constants])].
[sujeto(['Subsequent', footprinting, and, mutagenesis, analysis, indicates, that, protein]), verbo([binding]), complemento([proximal, to, regulatory, features, such, as, the, 'Shine-Dalgarno', sequence, is, sufficient, to, enable, 'regulation,', suggesting, that, regulation, in, response, to, 'S15', is, relatively, easily, acquired])].
[sujeto(['Quantification', of, gene, expression, by, quantitative, reverse, transcription, polymerase, chain, reaction, '(', 'qRT-PCR)', with, stably]), verbo([expressed]), complemento([reference, genes, for, normalization, can, effectively, elucidate, the, biological, functions, of, genes, that, regulate, fruit, development])].
[sujeto(['However,', the, reference, genes, for, data, normalization, in, melon, fruits]), verbo([have]), complemento([not, yet, been, systematically, validated])].
[sujeto(['GeNorm', identified, ribosomal, protein, 'L', '(', 'CmRPL)', and, cytosolic, ribosomal, protein, 'S15', '(', 'CmRPS15)', as, the, best, pair, of, reference, 'genes,', and, as, many, as, five, genes, including, 'CmRPL,', 'CmRPS15,', 'TIP41-like', family, protein, '(', 'CmTIP41),', cyclophilin, 'ROC7', '(', 'CmCYP7),', and, 'ADP', ribosylation, factor, 1, '(', 'CmADP)', were]), verbo([required]), complemento([for, more, reliable, normalization])].
[sujeto(['NormFinder', ranked, 'CmRPS15', as, the, best, single, reference, 'gene,', and, 'RAN', 'GTPase', gene, family, '(', 'CmRAN)', and, 'TATA-box']), verbo([binding]), complemento([protein, '(', 'CmTBP2)', as, the, best, combination, of, reference, genes, in, melon, fruits])].
[sujeto(['The', 'rpsO-pnp', operon, encodes, ribosomal, protein, 'S15', and, polynucleotide, 'phosphorylase,', a, major, 3, '\'', -, 5, '\'', exoribonuclease]), verbo([involved]), complemento([in, mRNA, decay, in, 'Escherichia', coli, 'The', gene, for, the, 'SraG', small, 'RNA', is, located, between, the, coding, regions, of, the, rpsO, and, pnp, 'genes,', and, it, is, transcribed, in, the, opposite, direction, relative, to, the, two, genes])].
[sujeto(['No', function]), verbo([has]), complemento([been, assigned, to, 'SraG'])].
[sujeto(['Multiple', levels, of, 'post-transcriptional', regulation]), verbo([have]), complemento([been, demonstrated, for, the, 'rpsO-pnp', operon])].
[sujeto(['Furthermore,', in, vitro, experiments, indicate, that, 'SraG']), verbo([inhibits]), complemento([translation, initiation, of, pnp, 'Together,', these, observations, demonstrate, that, 'SraG', participates, in, the, 'post-transcriptional', control, of, pnp, by, a, direct, antisense, interaction, between, 'SraG', and, 'PNPase', 'RNAs'])].
[sujeto(['Our', data]), verbo([reveal]), complemento([a, new, level, of, regulation, in, the, expression, of, this, major, exoribonuclease])].
[sujeto(['Although', recent, 'high-throughput', studies]), verbo([have]), complemento([identified, novel, recurrent, genetic, lesions, in, adverse, prognostic, 'CLL,', the, mechanisms, leading, to, relapse, after, 'FCR', therapy, are, not, completely, understood])].
[sujeto(['To']), verbo([gain]), complemento([insight, into, this, 'issue,', we, performed, 'whole-exome', sequencing, of, sequential, samples, from, 41, 'CLL', patients, who, were, uniformly, treated, with, 'FCR', but, relapsed, after, a, median, of, 2, years])].
[sujeto(['Notably,', all, 'RPS15', mutations, represented, somatic, missense, variants, and, resided, within, a, 7, 'amino-acid,', evolutionarily]), verbo([conserved]), complemento([region])].
[sujeto(['In', 'summary,', we]), verbo([provide]), complemento([novel, insights, into, the, heterogeneous, genetic, landscape, of, 'CLL', relapsing, after, 'FCR', treatment, and, highlight, a, novel, mechanism, underlying, clinical, aggressiveness, involving, a, mutated, ribosomal, 'protein,', potentially, representing, an, early, genetic, lesion, in, 'CLL', pathobiology])].
[sujeto(['Ribosomal', protein, 'S15']), verbo([has]), complemento([two, 'RNA', binding, functions])].
[sujeto(['Second,', in, many, bacterial, species, 'S15', also]), verbo([interacts]), complemento([with, a, structured, portion, of, its, own, transcript, to, negatively, regulate, gene, expression])].
[sujeto(['While', the, first, interaction, is]), verbo([conserved]), complemento([in, most, 'bacteria,', the, second, is, not])].
[sujeto(['Four', distinct, mRNA, structures]), verbo([interact]), complemento([with, 'S15', to, enable, 'regulation,', each, of, which, appears, to, be, independently, derived, in, different, groups, of, bacteria])].
[sujeto(['With', the, goal, of, understanding, how, 'protein-binding', specificity, may, influence, the, evolution, of, such, 'RNA', regulatory, 'structures,', we, examine, whether, examples, of, these, mRNA, structures, are, able, to]), verbo([interact]), complemento(['with,', and, regulate, in, response, 'to,', 'S15', homologs, from, organisms, containing, distinct, mRNA, structures])].
[sujeto(['We']), verbo([find]), complemento([that, despite, their, shared, 'RNA', binding, function, in, the, 'rRNA,', 'S15', homologs, have, distinct, 'RNA', recognition, profiles])].
[sujeto(['After', analyzing, the, patterns, of, conservation, for, the, 'S15', protein, coding, 'sequences,', we, also, identified, amino, acid, changes, that, alter, the]), verbo([binding]), complemento([specificity, of, an, 'S15', homolog])].
[sujeto(['In', this, work, we, demonstrate, that, homologous, 'RNA-binding', proteins]), verbo([have]), complemento([different, specificity, 'profiles,', and, minor, changes, to, amino, acid, 'sequences,', or, to, 'RNA', structural, 'motifs,', can, have, large, impacts, on, 'RNA-protein', recognition])].
[sujeto(['Ribosomes', and, functional, complexes, of, them]), verbo([have]), complemento([been, analyzed, at, the, atomic, level])].
[sujeto(['Using', genetic, and, chemical, perturbations, by, depleting, genes, encoding, the, ribosomal, proteins, 'L3', and, 'S17,', 'respectively,', or, using, 'ribosome-targeting', 'antibiotics,', we]), verbo([provoked]), complemento([ribosomal, subunit, assembly, defects])].
[sujeto(['This', strategy, is, useful, to, monitor, and, characterize, subunit, specific, assembly, defects]), verbo([caused]), complemento([by, 'ribosome-targeting', drugs, that, are, currently, used, and, to, characterize, new, molecules, that, affect, ribosome, assembly, and, thereby, constitute, new, classes, of, antibacterial, agents])].
[sujeto(['LRRK2', mutations, are, a, frequent]), verbo([cause]), complemento([of, familial, 'Parkinson', disease, '(', 'PD)', and, are, also, found, in, a, number, of, sporadic, 'PD', cases])].
[sujeto(['PD-linked', 'G2019S', and, 'I2020T', mutations, in, the, kinase, domain, of, 'LRRK2', result, in, elevated, kinase, 'activity,', which, is]), verbo([required]), complemento([for, the, toxicity, of, these, pathogenic, variants, in, cell, and, animal, models, of, 'PD'])].
[sujeto(['We', recently]), verbo([reported]), complemento([that, 'LRRK2', interacts, with, and, phosphorylates, a, number, of, mammalian, ribosomal, 'proteins,', several, of, which, exhibit, increased, phosphorylation, via, both, 'G2019S', and, 'I2020T', 'LRRK2'])].
[sujeto(['Blocking', the, phosphorylation, of, ribosomal, protein, s15, through, expression, of, 'phospho-deficient', 'T136A', s15]), verbo([prevents]), complemento(['age-associated', locomotor, deficits, and, dopamine, neuron, loss, caused, by, 'G2019S', 'LRRK2', expression, in, 'Drosophila', indicating, that, s15, is, a, pathogenic, 'LRRK2', substrate])].
[sujeto(['We', previously, described, that, 'G2019S', 'LRRK2']), verbo([causes]), complemento([an, induction, of, bulk, mRNA, translation, that, is, blocked, by, 'T136A', s15, or, the, protein, synthesis, inhibitor, anisomycin])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, protective, effects, of, the, 'eIF4E/eIF4G', interaction, inhibitor, '4EGI-1,', in, preventing, neurodegenerative, phenotypes, in, 'G2019S', 'LRRK2', 'flies,', and, discuss, how, our, findings, and, those, of, other, groups, provide, a, framework, to, begin, investigating, the, mechanistic, impact, of, 'LRRK2', on, translation])].
[sujeto(['Autogenous', 'cis-regulators', of, ribosomal, protein, synthesis, play, a, critical, role, in]), verbo([maintaining]), complemento([the, stoichiometry, of, ribosome, components])].
[sujeto(['Structured', portions, within, an, mRNA, transcript, typically]), verbo([interact]), complemento([with, specific, ribosomal, proteins, to, prevent, expression, of, the, entire, 'operon,', thus, balancing, levels, of, ribosomal, proteins, across, transcriptional, units])].
[sujeto(['Three', distinct, 'RNA', structures, from, different, bacterial, phyla]), verbo([have]), complemento([demonstrated, interactions, with, 'S15', to, regulate, gene, 'expression;', 'however,', these, 'RNAs', are, distributed, across, a, small, fraction, of, bacterial, diversity])].
[sujeto(['We', used, comparative, genomics, in, combination, with, analysis, of, existing, transcriptomic, data, to, identify, three, novel, putative, 'RNA', structures]), verbo([associated]), complemento([with, the, 'S15', coding, region, in, microbial, genomes])].
[sujeto(['To', validate, the, biological, relevance, of, our, 'findings,', we, demonstrate, that, an, example, of, the, 'Alphaproteobacterial', 'RNA', from, 'Rhizobium', radiobacter, specifically]), verbo([interacts]), complemento([with, 'S15', in, 'vitro,', and, allows, in, vivo, regulation, of, gene, expression, in, an, 'E'])].
[sujeto(['In', 'addition,', structural, probing, and, nuclease, protection, assays, confirm, the, predicted, secondary, structure, and, indicate, nucleotides]), verbo([required]), complemento([for, protein, interaction])].
[sujeto(['This', work, illustrates, the, importance, of, integrating, comparative, genomic, and, transcriptomic, approaches, during, de, novo, ncRNA, identification, and]), verbo([reveals]), complemento([a, diversity, of, distinct, natural, 'RNA', regulators, that, support, analogous, biological, functions])].
[sujeto(['Mutations', in, 'leucine-rich', repeat, kinase, 2, '(', 'LRRK2)', are, a, common]), verbo([cause]), complemento([of, familial, and, sporadic, 'Parkinson\'s', disease, '(', 'PD)'])].
[sujeto(['Phosphodeficient', s15, carrying, a, threonine, 136, to, alanine, substitution, rescues, dopamine, neuron, degeneration, and, 'age-related', locomotor, deficits, in, 'G2019S', 'LRRK2', transgenic, 'Drosophila', and, substantially, reduces, 'G2019S', 'LRRK2-mediated', neurite]), verbo([loss]), complemento([and, cell, death, in, human, dopamine, and, cortical, neurons])].
[sujeto(['Remarkably,', pathogenic, 'LRRK2']), verbo([stimulates]), complemento([both, 'cap-dependent', and, 'cap-independent', mRNA, translation, and, induces, a, bulk, increase, in, protein, synthesis, in, 'Drosophila,', which, can, be, prevented, by, phosphodeficient, 'T136A', s15])].
[sujeto(['These', results]), verbo([reveal]), complemento([a, novel, mechanism, of, 'PD', pathogenesis, linked, to, elevated, 'LRRK2', kinase, activity, and, aberrant, protein, synthesis, in, vivo])].
[sujeto([link, 'PD', protein, 'leucine-rich', repeat, kinase, 2, '(', 'LRRK2)', to, abnormalities, of, translational, 'control,', a, pathogenic, mechanism, implicated, in, an]), verbo([increasing]), complemento([number, of, 'CNS', neurodegenerative, 'diseases,', as, well, as, in, normal, aging])].
[sujeto(['Primer', extension, with, 'RNA', from, an, 'RNase', 'III', null, mutant, of, 'Streptomyces', coelicolor, 'M145', and, a]), verbo([primer]), complemento([complementary, to, the, polynucleotide, phosphorylase, gene, revealed, two, major, extension, products])].
[sujeto(['Two', different, extension, products, were, observed, using, 'RNA', from, either, wild, type, 'M145', or, the, null, mutant, with, a]), verbo([primer]), complemento([complementary, to, rpsO])].
[sujeto([coelicolor, and, the, activity, of, the, 'rpsO-pnp', promoters]), verbo([increased]), complemento([during, cold, shock, at, 10, °, ',', resulting, in, a, 'two-fold', increase, in, 'PNPase', 'activity,', compared, with, the, activity, at, 30, °])].
[sujeto(['Differential', expression, proteins, were, mainly]), verbo([associated]), complemento([with, metabolism, '(', involved, in, intermediary, 'metabolism,', 'respiration,', and, lipid, 'metabolism)', and, took, part, in, catalysis, and, binding, function])].
[sujeto(['Differential', expression, proteins, were]), verbo([found]), complemento([in, 'SMr', strain, compared, with, both, 'SM-sensitive', strain, and, 'H37Rv'])].
[sujeto(['With', 'hindsight,', this, spurious, interaction, not, only, yielded, 'diffraction-quality', crystals, but, would, also]), verbo([have]), complemento([allowed, structure, determination, by, molecular, replacement, using, 'S15', as, a, search, model, and, subsequent, automatic, rebuilding, of, the, asymmetric, unit])].
[sujeto(['Excess', polyamines, 'post-transcriptionally']), verbo([induce]), complemento([the, synthesis, of, a, unique, 'non-competitive', protein, inhibitor, of, 'ODC,', termed, antizyme])].
[sujeto(['No', homologue, of, 'ODC', antizyme]), verbo([has]), complemento([been, detected, in, plant, genomes, but, several, biochemical, studies, have, reported, plant, 'ODC', antizyme, proteins, of, 9, and, 16, kDa])].
[sujeto(['The', 'Arabidopsis', rpS15, polypeptide]), verbo([interacted]), complemento([specifically, with, plant, 'ODC', but, not, with, human, or, 'Saccharomyces', cerevisiae, 'ODCs'])].
[sujeto(['Only', the, full, length, mRNA, encoding, rpS15, was, detected, in, 'Arabidopsis', 'cells,']), verbo([suggesting]), complemento([that, the, 'C-terminal', rpS15, polypeptide, is, encoded, by, a, low, abundance, mRNA, or, the, polypeptide, is, not, physiologically, relevant, in, plants])].
[sujeto(['The', results]), verbo([provided]), complemento([strong, evidence, that, endonuclease, cleavage, in, the, body, of, the, 'message,', rather, than, degradation, from, the, native, 3, '\'', 'end,', is, the, 'rate-determining', step, for, mRNA, decay])].
[sujeto(['The', rpsO, mRNA, 'half-life', was, unchanged, in, a, strain, that, had]), verbo([decreased]), complemento(['RNase', 'J1', activity, and, no, 'RNase', 'J2', 'activity,', but, it, was, 2.3, -, fold, higher, in, a, strain, with, decreased, activity, of, 'RNase', 'Y,', a, recently, discovered, 'RNase', of, 'B'])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([of, a, specific, mRNA, whose, stability, is, determined, by, 'RNase', 'Y'])].
[sujeto(['The', eukaryotic, ribosomal, protein, 'S15', is, a, key, component, of, the, decoding, site, in, contrast, to, its, prokaryotic, 'counterpart,', 'S19p,', which, is, located, away, from, the, mRNA]), verbo([binding]), complemento([track, on, the, ribosome])].
[sujeto(['Here,', we, determined, the, oligopeptide, of, 'S15', neighboring, the, 'A', site, mRNA, codon, on, the, human, 80, 'S', ribosome, with, the, use, of, mRNA, analogues, bearing, perfluorophenyl, 'azide-modified', nucleotides, in, the, sense, or, stop, codon]), verbo([targeted]), complemento([to, the, 80, 'S', ribosomal, 'A', site])].
[sujeto(['The', position, of, 'cross-linking', site, on, the, 'S15', protein, did, not, depend, on, the, nature, of, the, 'A', 'site-bound', codon, '(', sense, or, stop, 'codon)', and, on, the, presence, of, polypeptide, chain]), verbo([release]), complemento([factor, eRF1, in, the, ribosomal, complexes, with, mRNA, analogues, bearing, a, stop, codon])].
[sujeto(['Alignment', of, amino, acid, sequences, of, eukaryotic, 'S15', and, its, prokaryotic, 'counterpart,', 'S19p', from, eubacteria, and, 'archaea,', revealed, that, decapeptide, 'PGIGATHSSR', in, positions, 131, -, 140, is, strongly]), verbo([conserved]), complemento([in, eukaryotes, and, has, minor, variations, in, archaea, but, has, no, homology, with, any, sequence, in, 'C-terminal', part, of, eubacterial, 'S19p,', which, suggests, involvement, of, the, decapeptide, in, the, translation, process, in, a, 'eukaryote-specific', manner])].
[sujeto(['Here,', we, used, inducibly]), verbo([expressed]), complemento([derivatives, of, 'rpsO,', encoding, smaller, 'RNAs', that, had, the, complex, 5, '\'', region, 'deleted,', to, study, aspects, of, mRNA, processing, in, 'B'])].
[sujeto(['Interestingly,', this, stability, depended, also, on, ribosome]), verbo([binding]), complemento([to, a, nearby, 'Shine-Dalgarno', sequence, but, was, independent, of, downstream, translation])].
[sujeto(['Analysis', of, processing, of, an, untranslated, 'lac-rpsO', 'RNA', in, the, pnpA, strain, shortly, after, induction, of, transcription]), verbo([suggested]), complemento([that, endonuclease, cleavage, at, 3, '\'', -, proximal, sites, was, an, early, step, in, turnover, of, mRNA])].
[sujeto(['In', this]), verbo([report]), complemento([we, demonstrate, for, the, first, time, that, 'RNase', 'R', has, in, vivo, affinity, for, polyadenylated, 'RNA', and, can, be, a, key, enzyme, involved, in, 'poly(A)', metabolism])].
[sujeto(['Moreover,', we]), verbo([have]), complemento([found, that, the, 'RNase', 'R', inactivation, counteracts, the, extended, degradation, of, this, transcript, observed, in, 'RNase', 'II-deficient', cells])].
[sujeto(['Elongated', rpsO, transcripts, harboring]), verbo([increasing]), complemento(['poly(A)', tails, are, specifically, recognized, by, 'RNase', 'R', and, strongly, accumulate, in, the, absence, of, this, exonuclease])].
[sujeto(['The', 3, '\'', 'oligo(A)', extension, may]), verbo([stimulate]), complemento([the, binding, of, 'RNase', 'R,', allowing, the, complete, degradation, of, the, 'mRNA,', as, 'RNase', 'R', is, not, susceptible, to, 'RNA', secondary, structures])].
[sujeto(['This']), verbo([report]), complemento([shows, that, polyadenylation, favors, in, vivo, the, 'RNase', 'R-mediated', pathways, of, 'RNA', degradation])].
[sujeto(['However,', some, 'del(17p)', patients, do, not, progress, for, 'years,']), verbo([suggesting]), complemento([that, 'del(17p)', is, not, the, only, driving, event, in, 'CLL', progression])].
[sujeto(['Results', 'We']), verbo([found]), complemento([that, increased, somatic, mutation, number, associates, with, poor, overall, survival, independent, of, 17, p, deletion, '(', 'p=0'])].
[sujeto(['Del(17p)', 'CLL']), verbo([has]), complemento([a, unique, driver, mutation, 'profile,', including, 'NOTCH1', '(', 15, '%', ')', ',', 'RPS15', '(', 12, '%', ')', ',', 'DDX3X', '(', 8, '%', ')', and, 'GPS2', '(', 6, '%', ')'])].
[sujeto(['We']), verbo([found]), complemento([that, about, half, of, 'del(17p)', 'CLL', cases, have, recurrent, deletions, at, 3, 'p,', 4, 'p,', or, 9, p, and, that, any, of, these, deletions, significantly, predicts, shorter, overall, survival])].
[sujeto(['Conclusions', 'We', conclude, that, 'del(17p)']), verbo([has]), complemento([a, unique, genomic, profile, and, that, clonal, 'TP53', 'mutations,', 3, 'p,', 4, p, or, 9, p, 'deletions,', and, genomic, complexity, are, associated, with, shorter, overall, survival])].
[sujeto(['Polyomavirus', nephropathy, '(', 'PVAN)', is, a, common]), verbo([cause]), complemento([of, kidney, allograft, dysfunction, and, loss])].
[sujeto(['Although', 'TCMR-specific', genes, were, overwhelmingly]), verbo([involved]), complemento([in, immune, response, costimulation, and, 'TCR', 'signaling,', 'PVAN-specific', genes, were, mainly, related, to, 'DNA', replication, 'process,', 'RNA', polymerase, 'assembly,', and, pathogen, recognition, receptors])].
[sujeto(['Validation', of, 4, 'PVAN-specific', genes, '(', 'RPS15,', complement, factor, 'D,', 'lactotransferrin,', and, nitric, oxide, synthase]), verbo([interacting]), complemento(['protein)', by, quantitative, polymerase, chain, reaction, and, confirmation, by, immunohistochemistry, of, 2, 'PVAN-specific', proteins, with, antiviral, function, '(', lactotransferrin, and, 'IFN-inducible', transmembrane, 1, ')', was, done])].
[sujeto(['In', 'conclusion,', even, though, 'PVAN', and, 'TCMR', kidney, allografts, share, great, similarities, on, gene, 'perturbation,', 'PVAN-specific', genes, were, identified, with, 'well-known', antiviral, properties, that]), verbo([provide]), complemento([tools, for, discerning, 'PVAN', and, 'AR', as, well, as, attractive, targets, for, rational, drug, design])].
[sujeto(['MIQE', guidelines]), verbo([ensure]), complemento([that, the, choice, and, appropriateness, of, 'IRG', should, be, validated, for, particular, tissues, or, cell, types, and, specific, experimental, designs])].
[sujeto(['The', 'NormFinder', analysis, also, identified, the, same, set, of, stably]), verbo([expressed]), complemento([genes, '(', 'UXT,', 'RPL4,', 'RPS23', and, 'HPRT);', 'however,', the, rank, order, was, little, different])].
[sujeto(['The', 'D', genome, is, also]), verbo([found]), complemento([in, tetraploid, 'Ae'])].
[sujeto(['Recently,', a, series, of, studies, applying, 'whole-exome', or, 'whole-genome', sequencing, techniques]), verbo([have]), complemento([led, to, the, discovery, of, ribosomal, protein, gene, mutations, in, different, cancer, types])].
[sujeto(['Mutations', in, ribosomal, protein, genes]), verbo([have]), complemento([for, example, been, found, in, endometrial, cancer, '(', 'RPL22),', 'T-cell', acute, lymphoblastic, leukemia, '(', 'RPL10,', 'RPL5', and, 'RPL11),', chronic, lymphocytic, leukemia, '(', 'RPS15),', colorectal, cancer, '(', 'RPS20),', and, glioma, '(', 'RPL5)'])].
[sujeto(['Moreover,', patients, suffering, from, 'Diamond-Blackfan', 'anemia,', a, bone, marrow, failure, syndrome]), verbo([caused]), complemento([by, mutant, ribosomal, proteins, are, also, at, higher, risk, for, developing, 'leukemia,', or, solid, tumors])].
[sujeto(['The', field, of, chronic, lymphocytic, leukemia, '(', 'CLL)']), verbo([has]), complemento([witnessed, considerable, change, since, the, time, clinical, staging, was, introduced, in, clinical, practice, in, 1975])].
[sujeto(['Over', the, 'years,', the, prognostication, in, 'CLL']), verbo([has]), complemento([expanded, with, the, addition, in, late, 90, s, of, mutational, status, of, variable, region, of, immunoglobulin, heavy, chain, '(', 'IGHV),', and, chromosomal, analyses, using, fluorescent, in, situ, hybridization, '(', 'FISH)'])].
[sujeto(['In', 'therapy,', the, field, of, 'CLL']), verbo([has]), complemento([seen, major, changes, from, oral, chlorambucil, and, steroids, prior, to, 1980, 's,', to, 'chemo-immunotherapy', '(', 'CIT)', with, 'fludarabine,', 'cyclophosphamide,', rituximab, '(', 'FCR)', to, the, orally, administered, targeted, therapeutic, agents, inhibiting, kinases, in, the, 'B', cell, receptor, '(', 'BCR)', signaling, pathway, such, as, 'Ibrutinib', '(', 'BTK', 'inhibitor)', and, 'Idelalisib', '(', p110, 'PI3Kδ', 'inhibitor)', and, novel, 'anti-CD20', 'mAb\'s', '(', monoclonal, 'antibodies)', such, as, obinutuzumab])].
[sujeto(['This', progress, is, continuing, and, other]), verbo([targeted]), complemento([therapeutics, such, as, 'Bcl2', antagonists, '(', 'Venetoclax', or, 'ABT-199)', and, finally, chimeric, antigen, receptor, against, 'T', cells, '(', 'CART)', are, in, the, process, of, being, developed])].
[sujeto(['The', topic, allocated, to, us, by, 'Dr', 'Ayalew', 'Tefferi', and, 'Dr', 'Carlo', 'Brugnara', is, very, appropriate, to, reminisce, what, our, understanding, of, chronic, lymphocytic, leukemia, '(', 'CLL)', was, in, 1976, and, how, rapidly]), verbo([have]), complemento([the, advances, occurring, in, this, field, affected, the, patients, with, 'CLL'])].
[sujeto(['But', until, 'now,', just, fewer, genes]), verbo([have]), complemento([been, found, linked, with, flower, development])].
[sujeto(['So', we, need, to, discriminate, even, more, genes]), verbo([involving]), complemento([in, the, flower, development])].
[sujeto(['We']), verbo([found]), complemento([that, the, most, possible, potential, new, genes, underlining, the, floral, pattern, formation, in, 'A'])].
[sujeto([thaliana, were, 'FY,', 'CBL2,', 'ZFN3,', and, 'AT1G77370;', among, 'them,', 'FY,', 'CBL2']), verbo([acted]), complemento([as, an, upstream, regulator, of, 'AP2;', 'ZFN3', activated, the, flower, primordial, determining, gene, 'AP1', and, 'AP2', by, 'HY5/HYH', gene, via, photo, induction, possibly])].
[sujeto(['It', possibly, formed, a, complex, between, 'RFC3', and, 'RPS15', in, 'cytoplasm,', which]), verbo([regulated]), complemento(['TSO1', and, 'CPSF160', in, the, 'nucleus,', to, control, the, floral, organ, morphogenesis])].
[sujeto(['These', include, previously, unrecognized, putative, cancer, drivers, '(', 'RPS15,', 'IKZF3),', and, collectively, identify, 'RNA', processing, and, 'export,', 'MYC', 'activity,', and, 'MAPK', signalling, as, central, pathways]), verbo([involved]), complemento([in, 'CLL'])].
[sujeto(['Thus,', large, sequencing, data, sets, of, clinically, informative, samples, enable, the, discovery, of, novel, genes]), verbo([associated]), complemento([with, 'cancer,', the, network, of, relationships, between, the, driver, 'events,', and, their, impact, on, disease, relapse, and, clinical, outcome])].
[sujeto(['As', invasive, species]), verbo([have]), complemento([successfully, colonized, a, wide, range, of, dramatically, different, local, 'environments,', they, offer, a, good, opportunity, to, study, interactions, between, species, and, rapidly, changing, environments])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, the, necessity, of, selection, and, test, of, reference, genes, for, different, tissues, under, varying, environmental, stresses])].
[sujeto(['The', results, obtained, here, are, expected, to]), verbo([reveal]), complemento([mechanisms, of, gene, 'expression-mediated', invasion, success, using, 'C'])].
[sujeto([spathulifolius, showed, the, closest, relationship, with, 'Jacobaea', 'vulgaris,', and, its, atpB, gene, was]), verbo([found]), complemento([to, be, a, 'pseudogene,', unlike, 'J'])].
[sujeto(['These', findings, revealed, that, substitution]), verbo([has]), complemento([occurred, at, similar, rates, in, most, 'genes,', and, the, substitution, rates, suggested, that, most, genes, is, a, purified, selection])].
[sujeto(['Four', 'Erythronium', species]), verbo([have]), complemento([been, traditionally, recognised, within, 'Eurasia', based, on, their, disjunct, distributions, and, the, slight, morphological, divergence, between, 'them:', 'E'])].
[sujeto(['sulevii),', this, species]), verbo([has]), complemento([never, been, tested, for, genetic, subdivisions])].
[sujeto(['We', here, used, nucleotide, sequence, variation, in, one]), verbo([nuclear]), complemento(['(', internal, transcribed, 'spacer)', and, two, plastid, '(', 'rpl32-trnL,', 'rps15-ycf1)', regions, to, test, for, genetic, divisions, within, 'Siberian', 'Erythronium', 'and,', in, 'particular,', to, examine, the, phylogenetic, position, of, 'E'])].
[sujeto(['The']), verbo([nuclear]), complemento([topology, agrees, with, the, plastid, one, in, recovering, 'E'])].
[sujeto(['Topological', incongruences, exist, between, the, plastid, and]), verbo([nuclear]), complemento([phylogenies, but, these, do, not, affect, the, taxonomic, recognition, of, 'E'])].
[sujeto(['Whereas']), verbo([nuclear]), complemento([phylogeny, failed, to, resolve, any, genetic, grouping, within, 'E'])].
[sujeto(['Recent', studies]), verbo([have]), complemento([focused, on, determining, functional, genes, and, microRNAs, in, the, pest, 'Helicoverpa', armigera, '(', 'Lepidoptera:', 'Noctuidae)'])].
[sujeto(['Two']), verbo([target]), complemento(['genes,', thioredoxin, '(', 'TRX)', and, 'Cu/Zn', superoxide, dismutase, '(', 'SOD),', were, used, to, validate, the, selection, of, reference, genes])].
[sujeto(['Results', showed, that, the, most, suitable, candidate, combinations, of, reference, genes, were, as, 'follows:', 28, 'S', and, 'RPS15', for, developmental, 'stages;', 'RPS15', and, 'RPL13', for, larvae, 'tissues;', 'EF', and, 'RPL27', for, adult, 'tissues;', 'GAPDH,', 'RPL27,', and, 'β-TUB', for]), verbo([nuclear]), complemento([polyhedrosis, virus, 'infection;', 'RPS15', and, 'RPL32', for, insecticide, 'treatment;', 'RPS15', and, 'RPL27', for, temperature, 'treatment;', and, 'RPL32,', 'RPS15,', and, 'RPL27', for, all, samples])].
[sujeto(['These', chloroplast, 'DNAs', '(', 'cpDNAs)', were, compared, with, those, of, the, six, previously, sampled, prasinophytes, '(', clades, 'I,', 'II,', 'III', and, 'V)', in, order, to]), verbo([gain]), complemento([information, both, on, the, relationships, among, prasinophyte, lineages, and, on, chloroplast, genome, evolution])].
[sujeto(['Varying', from, 64.3, to, 85.6, kb, in, size, and, encoding, 100, to, 115]), verbo([conserved]), complemento(['genes,', the, cpDNAs, of, the, newly, investigated, picoplanktonic, species, are, substantially, smaller, than, those, observed, for, 'larger-size', 'prasinophytes,', are, economically, packed, and, contain, a, reduced, gene, content])].
[sujeto(['Unexpectedly,', we]), verbo([found]), complemento([that, all, three, species, from, clade, 'VI', '(', 'Prasinococcales)', harbor, chloroplast, genes, not, previously, documented, for, chlorophytes, '(', 'ndhJ,', 'rbcR,', 'rpl21,', 'rps15,', rps16, and, 'ycf66)', and, that, 'Picocystis', contains, a, 'trans-spliced', group, 'II', intron])].
[sujeto(['Our', results, underscore, the, high, variability, in, genome, architecture, among, prasinophyte, 'lineages,', highlighting, the, strong, pressure, to]), verbo([maintain]), complemento([a, small, and, compact, chloroplast, genome, in, picoplanktonic, species])].
[sujeto(['The', unique, set, of, six, chloroplast, genes]), verbo([found]), complemento([in, the, 'Prasinococcales', supports, the, ancestral, status, of, this, lineage, within, the, prasinophytes])].
[sujeto(['Mutations', in, the, catalytic, 'Roc-COR', and, kinase, domains, of, 'leucine-rich', repeat, kinase, 2, '(', 'LRRK2)', are, a, common]), verbo([cause]), complemento([of, familial, 'Parkinson\'s', disease, '(', 'PD)'])].
[sujeto(['LRRK2', mutations]), verbo([cause]), complemento(['PD', with, 'age-related', penetrance, and, clinical, features, identical, to, 'late-onset', sporadic, 'PD'])].
[sujeto(['Biochemical', studies, support, an]), verbo([increase]), complemento([in, 'LRRK2', kinase, activity, and, a, decrease, in, 'GTPase', activity, for, kinase, domain, and, 'Roc-COR', 'mutations,', respectively])].
[sujeto(['Strong', evidence, exists, that, 'LRRK2', toxicity, is, kinase, dependent]), verbo([leading]), complemento([to, extensive, efforts, to, identify, selective, and, 'brain-permeable', 'LRRK2', kinase, inhibitors, for, clinical, development])].
[sujeto(['Here,', we, summarize, biochemical, and, functional, studies, of, 'LRRK2', and, its, mutations, and, focus, on, aberrant, vesicular, trafficking, and, protein, synthesis, as, two]), verbo([leading]), complemento([mechanisms, underlying, 'LRRK2-linked', disease])].
[sujeto(['UVI3003']), verbo([induced]), complemento([multiple, malformations, at, the, concentrations, of, 200, -, 1000, 'μg/L', after, 48, h, exposure])].
[sujeto(['UVI3003', also]), verbo([induced]), complemento([variable, and, divergent, malformations, at, 250, -, 1500, 'μg/L', after, 0, -, 24, and, 24, -, 48, h, exposure])].
[sujeto(['Microarray', analysis, showed, that, seven, genes, '(', 'rps15,', 'serp2,', 'fmr1,', 'cyp2e1,', 'lrrc9,', ugtla6, and, 'LOC100490188)', were, differentially]), verbo([regulated]), complemento([in, all, three, treatment, groups, after, 0, -, 24, h, exposure])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, 'UVI3003', is, teratogenic, in, amphibian, embryos])].
[sujeto(['Differential', gene, expression]), verbo([suggests]), complemento([that, galactose, metabolism, and, 'PPAR', signaling, pathways, may, provide, underlying, mechanistic, detail, accounting, for, the, observed, malformations])].
[sujeto(['Although', advances]), verbo([have]), complemento([been, made, in, elucidating, phylogenetic, relationships, within, 'Ptychospermatinae,', some, relationships, among, and, within, genera, still, remain, to, be, clarified])].
[sujeto(['Here', we, used, a, combination, of, five]), verbo([nuclear]), complemento([markers, '(', 'nrITS2,', the, conserved, nuclear, intron, 'BRSC10', and, three, low, copy, 'genes,', 'PRK,', 'RPB2', and, 'AGAMOUS)', and, three, chloroplast, markers, '(', 'matK,', ndhA, and, 'rps15-ycf1)', to, propose, a, new, phylogenetic, hypothesis, for, the, subtribe])].
[sujeto(['The', plastid, genomes, of, seed, plants, contain, a]), verbo([conserved]), complemento([set, of, ribosomal, protein, genes])].
[sujeto(['Three', of, these]), verbo([have]), complemento([proven, to, be, nonessential, for, translation, 'and,', 'thus,', for, cellular, 'viability:', 'rps15,', 'rpl33,', and, rpl36])].
[sujeto(['We']), verbo([find]), complemento(['that,', although, 'S15', and, 'L33', function, in, different, ribosomal, particles, '(', 30, 'S', and, 50, 'S,', 'respectively),', their, combined, deletion, from, the, plastid, genome, results, in, synthetic, lethality, under, autotrophic, conditions])].
[sujeto(['Our', results]), verbo([reveal]), complemento([functional, interactions, between, protein, and, 'RNA', components, of, the, 70, 'S', ribosome, and, uncover, the, interdependence, of, the, biogenesis, of, the, two, ribosomal, subunits])].
[sujeto(['In', 'addition,', our, findings]), verbo([suggest]), complemento([that, defining, a, minimal, set, of, plastid, genes, may, prove, more, complex, than, generally, believed])].
[sujeto(['The', 'ALL', resection, determined, a, significant]), verbo([increase]), complemento([in, terms, of, internal, rotation, '(', 'INT30', 'P = 0'])].
[sujeto(['ALL', resection, produced, a, significant]), verbo([increase]), complemento([in, terms, of, acceleration, during, 'PS', test, '(', 'P < 0'])].
[sujeto(['A', trend, was, seen, for, the, internal, rotation, during, the, 'pivot-shift', test, to]), verbo([increase]), complemento([after, 'ALL', resection, was, higher, when, compared, to, the, intact, and, isolated, 'ACL', lesion, 'states;', 'however,', the, differences, were, not, significant])].
[sujeto(['MAVS', then]), verbo([recruits]), complemento([the, 'adaptor\'s', tumor, necrosis, factor, 'receptor-associated', factor, '(', 'TRAF)', 3, and, 'TRAF6,', which, in, turn, activate, 'IRF3', and, 'NF-κB,', 'respectively,', to, induce, interferons, '(', 'IFNs)', and, inflammatory, responses])].
[sujeto(['Here', we, show, that, the, 'biotin-containing', enzyme, 'methylcrotonoyl-CoA', carboxylase, 1, '(', 'MCCC1)']), verbo([enhances]), complemento(['virus-induced,', 'MAVS-mediated', 'IFN', and, inflammatory, cytokine, expression, through, the, 'NF-κB', signaling, pathway])].
[sujeto(['MCCC1', knockdown, strongly]), verbo([inhibits]), complemento([induction, of, 'IFNs', and, inflammatory, cytokines])].
[sujeto(['Here,', we]), verbo([have]), complemento([elucidated, the, mechanism, underlying, 'MCCC1-mediated', inhibition, of, viral, replication])].
[sujeto(['MCCC1']), verbo([interacts]), complemento([with, 'MAVS', and, components, of, the, 'MAVS', signalosome, and, contributes, to, enhanced, production, of, type, 'I', 'IFNs', and, 'pro-inflammatory', cytokines, by, promoting, phosphorylation, of, the, 'IκB', kinase, '(', 'IKK)', complex, and, 'NF-κB', 'inhibitor-α', '(', 'IκBα),', as, well, as, 'NF-κB', nuclear, translocation])].
[sujeto(['This', process]), verbo([leads]), complemento([to, activation, of, 'IFNs', and, cytokine, expression, and, subsequent, activation, of, 'IFN-stimulated', 'genes,', including, 'double-stranded', 'RNA-dependent', protein, kinase, 'PKR', and, myxovirus, resistance, protein, 1])].
[sujeto(['RIG-I', is, an, innate, immune, receptor, that, detects, and]), verbo([responds]), complemento([to, infection, by, deadly, 'RNA', viruses, such, as, 'influenza,', and, 'Hepatitis', 'C'])].
[sujeto(['It']), verbo([has]), complemento([been, suggested, that, 'RIG-I', has, a, '\'', 'proof-reading\'', mechanism, for, rejecting, host, 'RNA', 'targets,', and, that, disruptions, of, this, selectivity, filter, give, rise, to, autoimmune, diseases])].
[sujeto(['Here,', we, directly, monitor, 'RNA', 'proof-reading', by, 'RIG-I', and, we, show, that, it, is, controlled, by, a, set, of]), verbo([conserved]), complemento([amino, acids, that, couple, 'RNA', and, 'ATP', binding, to, the, protein, '(', 'Motif', 'III)'])].
[sujeto(['Mutations', of, this, motif, directly]), verbo([modulate]), complemento(['proof-reading', by, eliminating, or, enhancing, selectivity, for, viral, 'RNA,', with, major, implications, for, autoimmune, disease, and, cancer])].
[sujeto(['More', 'broadly,', the, results]), verbo([provide]), complemento([a, physical, explanation, for, the, 'ATP-gated', behavior, of, 'SF2', 'RNA', helicases, and, receptor, proteins])].
[sujeto(['The', function, of, the, 'RIG-I-like', receptors, '(', 'RLRs;', including, 'RIG-I,', 'MDA5,', and, 'LGP2)', as, key, cytoplasmic, sensors, of, viral, 'pathogen-associated', molecular, patterns, '(', 'PAMPs)']), verbo([has]), complemento([been, subjected, to, numerous, pathogenic, challenges, and, has, undergone, a, dynamic, evolution])].
[sujeto(['We']), verbo([found]), complemento([evolutionary, evidence, that, 'RIG-I', was, lost, in, the, 'Chinese', tree, shrew, lineage])].
[sujeto(['Along', with, the]), verbo([loss]), complemento([of, 'RIG-I,', both, 'MDA5', '(', 'tMDA5)', and, 'LGP2', '(', 'tLGP2)', have, undergone, strong, positive, selection, in, the, tree, shrew])].
[sujeto([tMDA5, or, 'tMDA5/tLGP2', could, sense, 'Sendai', virus, '(', an, 'RNA', virus, posed, as, a, 'RIG-I', 'agonist)', for]), verbo([inducing]), complemento([type, 'I', 'IFN,', although, conventional, 'RIG-I', and, 'MDA5', were, thought, to, recognize, distinct, 'RNA', structures, and, viruses])].
[sujeto([tMDA5]), verbo([interacted]), complemento([with, adaptor, tMITA, '(', 'STINGTMEM173/ERIS),', which, was, reported, to, bind, only, with, 'RIG-I'])].
[sujeto(['These', findings]), verbo([provided]), complemento([insights, into, the, adaptation, and, functional, diversity, of, innate, antiviral, activity, in, vertebrates])].
[sujeto(['T2DM', is, known, to, potentiate, 'CAD', which, had]), verbo([led]), complemento([to, the, coining, of, a, new, clinical, entity, named, diabetic, 'CAD', '(', 'DM-CAD),', leading, to, excessive, morbidity, and, mortality])].
[sujeto(['Those', are, 'enveloped,', 'single-stranded', positive, sense, 'RNA', 'viruses,', which, replicate, mostly, in, intracellular, compartments]), verbo([associated]), complemento([to, endoplasmic, reticulum, '(', 'ER)', and, 'Golgi', complex])].
[sujeto(['Virus', replication, results, in, abundant, viral, 'RNAs', and, 'proteins,', which, are]), verbo([recognized]), complemento([by, cellular, mechanisms, evolved, to, prevent, virus, 'infection,', resulting, in, inflammation, and, stress, responses])].
[sujeto(['Virus', 'RNA', molecules, are, sensed, by, 'Toll-like', receptors, '(', 'TLRs),', 'RIG-I-like', receptors, '(', 'RIG-I', and, 'MDA5)', and, 'RNA-dependent', protein, kinases, '(', 'PKR),']), verbo([inducing]), complemento([the, production, of, inflammatory, mediators, and, interferons])].
[sujeto(['Simultaneously,', the, synthesis, of, virus, 'RNA', and, proteins, are, distinguished, in, different, compartments, such, as, 'mitochondria,', 'ER', and, cytoplasmic, 'granules,']), verbo([triggering]), complemento([intracellular, stress, 'pathways,', including, oxidative, 'stress,', unfolded, protein, response, 'pathway,', and, stress, granules, assembly])].
[sujeto(['Cigarette', smoking, '(', 'CS)', is, the, main, risk, factor, for, the, development, of, chronic, obstructive, pulmonary, disease, '(', 'COPD)', and, most, 'COPD', exacerbations, are]), verbo([caused]), complemento([by, respiratory, infections, including, influenza])].
[sujeto(['The', mechanism, of, the]), verbo([increased]), complemento([risk, and, severity, of, infections, in, smokers, is, likely, 'multifactorial,', but, certainly, includes, changes, in, immunologic, host, defenses])].
[sujeto(['IAV', exposure]), verbo([induced]), complemento([a, vigorous, 'IFN-β,', 'IFN-λ', 1, and, 'IFN-λ', 2, /, 3, antiviral, response, in, 'HBEC', from, nonsmokers, and, significant, induction, of, 'RIG-I', and, 'TLR3'])].
[sujeto(['CS', exposure, history, was]), verbo([associated]), complemento([with, inhibition, of, viral, induction, of, the, 'IFN-β,', 'IFN-λ1', and, 'IFN-λ', 2, /, 3, mRNA, response, by, 85, ',', 96, and, 95, &, 'nbsp;%,', 'respectively,', from, that, seen, in, 'HBEC', from, nonsmokers])].
[sujeto(['IFN-β', induction, of, 'RIG-I', and, 'TLR3', was, also]), verbo([suppressed]), complemento([in, the, cells, from, smokers])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, active, smoking, reduces, expression, of, antiviral, cytokines, in, primary, 'HBEC', cells])].
[sujeto(['Reduction', in, lung, epithelial, cell, 'RIG-I', and, 'TLR3', responses, may, be, a, major, mechanism, contributing, to, the]), verbo([increased]), complemento([risk, and, severity, of, viral, respiratory, infections, in, smokers, and, to, 'viral-mediated', acute, exacerbations, of, 'COPD'])].
[sujeto(['Here,', we]), verbo([found]), complemento([that, ectopic, expression, of, 'Rig-G', can, lead, to, a, significant, decrease, in, proliferation, of, lung, cancer, 'cells,', resulting, in, an, inhibition, of, tumor, growth])].
[sujeto(['Rig-G', knockdown, results, in, a, modest]), verbo([increase]), complemento([in, cell, 'proliferation,', as, well, as, confers, an, increase, in, colony, formation])].
[sujeto(['Rig-G']), verbo([inhibits]), complemento(['NF-κB', activity, by, suppressing, 'STAT3', in, lung, cancer, cells])].
[sujeto(['The', downregulation, of, miR21, and, 'miR181b-1', and, subsequent, activation, of, 'PTEN/Akt', and, 'CYLD/IκB', signaling, axis]), verbo([leading]), complemento([to, decreased, 'NF-κB', activity, required, to, maintain, the, 'tumor-inhibiting', effect, of, 'Rig-G'])].
[sujeto(['After', the, 'April', 2010, explosion, on, the, 'Deepwater', 'Horizon', oil, 'rig,', and, subsequent]), verbo([release]), complemento([of, millions, of, barrels, of, 'oil,', two, 'Corexit', oil, dispersant, formulations, were, used, in, unprecedented, quantities, both, on, the, surface, and, 'sub-surface', of, the, 'Gulf', of, 'Mexico'])].
[sujeto(['Factors', affecting, the, integrity, of, environmental, and, laboratory, samples, for, 'Corexit', analysis]), verbo([have]), complemento([not, been, systematically, investigated])].
[sujeto(['Best', practices, are]), verbo([provided]), complemento([to, ensure, sample, integrity, and, data, quality, for, environmental, monitoring, studies, and, laboratory, that, require, the, detection, and, quantification, of, 'Corexit-based', surfactants, in, seawater])].
[sujeto(['Innate', immune, responses, to, dsRNA, result, in, signaling, through, the, 'TLR3', pathway, 'and/or', the, 'RIG-I/MDA-5/MAVS', pathway, which, can]), verbo([activate]), complemento([type, 'I', 'IFN,', proinflammatory, cytokines, and, apoptosis])].
[sujeto(['Using', a, model, of, epithelial, cells, that]), verbo([express]), complemento([a, functional, 'TLR3', signaling, 'pathway,', we, found, that, 'TLR3-dependent', responses, to, extracellular, dsRNA, are, negatively, regulated, by, 'MAVS,', precisely, &, 'quot;miniMAVS",', a, recently, described, 50, kDa, isoform, of, 'MAVS'])].
[sujeto(['This', regulation, of, 'TLR3', by, a, 'MAVS', isoform, constitutes, an, endogenous, regulatory, mechanism, in, epithelial, cells, that, could, help]), verbo([prevent]), complemento([a, potentially, damaging, excessive, inflammatory, response])].
[sujeto(['Therefore,', there, is, an, urgent, need, to]), verbo([find]), complemento([a, potent, antiviral, agent, against, dengue, virus, '(', 'DENV)'])].
[sujeto(['Its', underlying, mechanism]), verbo([involved]), complemento([in, antiviral, action, was, determined, by, evaluating, expression, of, host, innate, immune, factors, including, 'RIG-I,', 'IRF-3,', 'IRF-7,', 'PKR,', 'P-eIF2α', and, 'NF-κB'])].
[sujeto(['Salidroside', potently]), verbo([inhibited]), complemento(['DENV', infection, by, decreasing, 'DENV', envelope, protein, expression, more, than, tenfold])].
[sujeto(['Salidroside', exerts, its, antiviral, activity, by]), verbo([increasing]), complemento([expression, of, 'RNA', helicases, such, as, 'RIG-I,', thereby, initiating, a, downstream, signaling, cascade, that, induces, upregulation, of, 'IRF-3', and, 'IRF-7'])].
[sujeto(['It']), verbo([prevents]), complemento([viral, protein, synthesis, by, increasing, the, expression, of, 'PKR', and, 'P-eIF2α', while, decreasing, 'NF-κB', expression])].
[sujeto(['It', was, also]), verbo([found]), complemento([to, induce, the, expression, of, 'IFN-α'])].
[sujeto(['In', 'addition,', the, number, of, 'NK', cells, and, 'CD8(+)', 'T', cells, were, also]), verbo([found]), complemento([to, be, increased, by, salidroside, treatment, in, human, 'PBMCs,', which, are, important, in, limiting, 'DENV', replication, during, early, stages, of, infection])].
[sujeto(['The', findings, presented, here]), verbo([suggest]), complemento([that, salidroside, exhibits, antiviral, activity, against, 'DENV', by, inhibiting, viral, protein, synthesis, and, boosting, host, immunity, by, increasing, the, expression, of, host, innate, immune, factors, and, hence, could, be, considered, for, the, development, of, an, effective, therapeutic, agent, against, 'DENV', infection])].
[sujeto(['Interferon', '(', 'IFN)', regulatory, factors, '(', 'IRF)', are, the, crucial, transcription, factors, for, 'IFN', 'expression,']), verbo([leading]), complemento([host, cell, response, to, viral, infection])].
[sujeto(['In', this, 'study,', we, identified, that, zebrafish, 'IRF6', was, a, positive, regulator, of, 'IFN', transcription, and, could, be]), verbo([phosphorylated]), complemento([by, both, 'MyD88', and, 'TBK1'])].
[sujeto(['First,', the, transcript, level, of, cellular, irf6, was, upregulated, by, treatment, with, poly, 'I:C', '(', a, mimic, of, viral, 'RNAs),', indicating, 'IRF6', might, be]), verbo([involved]), complemento([in, the, process, of, host, cell, response, to, viruses])].
[sujeto(['Subsequently,', at, the, protein, regulation, level, and, in, the, interaction, 'relationship,', 'IRF6', was]), verbo([phosphorylated]), complemento([by, and, associated, with, both, 'MyD88', and, 'TBK1'])].
[sujeto(['In', 'addition,', overexpression, of, 'IRF6']), verbo([activated]), complemento([the, transcription, of, 'isg15,', 'rig-i', and, mavs, of, host, 'cells;', 'meanwhile,', the, transcripts, of, 'p,', m, and, n, genes, of, 'SVCV', were, significantly, declined, in, 'IRF6-overexpressing', cells])].
[sujeto(['Taken', 'together,', our, data, demonstrate, that, fish, 'IRF6', is, distinguished, from, the, homolog, of, mammals, by, being, a, positive, regulator, of, 'IFN', transcription, and]), verbo([phosphorylated]), complemento([by, 'MyD88', and, 'TBK1,', suggesting, that, differences, in, the, 'IRF6', regulation, pattern, exist, between, lower, and, higher, vertebrates])].
[sujeto(['Exogenous', nucleic, acids]), verbo([induce]), complemento([an, innate, immune, response, in, mammalian, host, cells, through, activation, of, the, retinoic, 'acid-inducible', gene, 'I', '(', 'RIG-I)'])].
[sujeto(['We', evaluated, 'RIG-I', protein, for, 'RNA']), verbo([binding]), complemento([and, 'ATPase', stimulation, with, 'RNA', ligands, to, investigate, the, correlation, with, the, extent, of, immune, response, through, 'RIG-I', activation, in, cells])].
[sujeto(['Moreover,', the, presence, of, the, 5, '\'', -, triphosphate, '(', 5, '\'', -, 'ppp)', moiety, in, dsRNA, further]), verbo([enhanced]), complemento([binding, affinity, to, 'RIG-I'])].
[sujeto(['Two', structural, motifs, in, 'RNA,', blunt, ends, in, dsRNA, and, 5, '\'', -, 'ppp,']), verbo([stimulated]), complemento([the, 'ATP', hydrolysis, activity, of, 'RIG-I'])].
[sujeto(['These', structural, motifs, also, strongly]), verbo([induced]), complemento(['IFN', expression, as, an, innate, immune, response, in, cells])].
[sujeto(['Therefore,', we]), verbo([suggest]), complemento([that, 'IFN', induction, through, 'RIG-I', activation, is, mainly, determined, by, structural, motifs, in, dsRNA, that, increase, its, affinity, for, 'RIG-I', protein, and, stimulate, 'ATPase', activity, in, 'RIG-I'])].
[sujeto(['After']), verbo([releasing]), complemento([from, the, balloon, and, a, stabilized, 'freefall,', the, pilot, safely, landed, using, a, parachute, system, based, on, a, modified, tandem, parachute, rig])].
[sujeto(['A', custom, spacesuit]), verbo([provided]), complemento([life, support, using, a, similar, system, to, 'NASA\'s', '(', 'National', 'Aeronautics', and, 'Space', 'Administration;', 'Washington,', 'DC', 'USA)', 'Extravehicular', 'Mobility', 'Unit'])].
[sujeto(['It', also]), verbo([provided]), complemento(['tracking,', 'communications,', and, connection, to, the, parachute, system])].
[sujeto(['A', recovery, support, 'team,', including, at, least, two, medical, personnel, and, two, spacesuit, 'technicians,', was, charged, with, reaching, the, pilot, within, five, minutes, of, touchdown, to, extract, him, from, the, suit, and]), verbo([provide]), complemento([treatment, for, any, injuries])].
[sujeto(['The', team, had, to, track, the, flight, at, all, 'times,', be, prepared, to]), verbo([respond]), complemento([in, case, of, premature, 'release,', and, to, operate, in, any, terrain])].
[sujeto(['An', extensive, period, of, testing, and, practice, culminated, in, three, manned, flights]), verbo([leading]), complemento([to, a, successful, mission, and, setting, the, record, for, exit, 'altitude,', distance, of, fall, with, stabilizing, 'device,', and, vertical, speed, with, a, stabilizing, device])].
[sujeto(['During', this, 'mission,', recovery, teams, reached, the, landing, spot, within, one, 'minute,', extracted, the, 'pilot,', and, confirmed, that]), verbo([he]), complemento([was, not, injured])].
[sujeto(['RIG-I', is, a, cytosolic, receptor]), verbo([recognizing]), complemento(['virus-specific', 'RNA', structures, and, initiates, an, antiviral, signaling, that, induces, the, production, of, interferons, and, proinflammatory, cytokines])].
[sujeto(['Because', inappropriate, 'RIG-I', signaling, affects, either, viral, clearance, or, immune, 'toxicity,', multiple, regulations, of, 'RIG-I']), verbo([have]), complemento([been, investigated, since, its, discovery, as, the, viral, 'RNA', detector])].
[sujeto(['Specifically,', we, focus, on, the, mechanism, that]), verbo([modulates]), complemento(['RIG-I-dependent', antiviral, response, through, 'post-translational', modifications, of, or, 'protein-protein', interactions, with, 'RIG-I'])].
[sujeto(['Spiral', laminar, flow, was]), verbo([suggested]), complemento([as, potentially, the, predominant, arterial, blood, flow, pattern, many, years, ago])].
[sujeto(['Computational', fluid, dynamics, and, flow, rig, testing]), verbo([have]), complemento([suggested, there, are, advantages, to, spiral, laminar, flow])].
[sujeto(['This', observation, raises, questions, and]), verbo([suggests]), complemento([a, need, for, further, studies, concerning, the, form, and, function, of, the, left, 'ventricle,', the, geometry, of, the, arterial, 'system,', and, the, function, of, the, arterial, wall])].
[sujeto(['Residual', feed, intake, '(', 'RFI),', residual]), verbo([gain]), complemento(['(', 'RG)', and, residual, intake, and, gain, '(', 'RIG)', were, used, as, measures, of, feed, efficiency])].
[sujeto(['The', overall, mean, performance, for, daily]), verbo([gain]), complemento(['(', 'ADG),', daily, feed, intake, '(', 'ADFI),', weekly, metabolic, body, weight, '(', 'MBW),', 'RFI,', 'RG', and, 'RIG', was, 10.38, &, 'nbsp;g/day,', 133.01, &, 'nbsp;g/day,', 164.12, &, 'nbsp;g/day,', 0.0, '(', '±14'])].
[sujeto(['Stress', granules, '(', 'SGs)', are, cytoplasmic, granular, aggregations, that, are]), verbo([induced]), complemento([by, cellular, 'stress,', including, viral, infection])].
[sujeto(['SGs']), verbo([have]), complemento([opposing, antiviral, and, proviral, 'roles,', which, depend, on, virus, species])].
[sujeto(['Here,', we, showed, that, mumps, virus, '(', 'MuV)']), verbo([induced]), complemento(['SGs', depending, on, activation, of, protein, kinase, 'R', '(', 'PKR)'])].
[sujeto(['MuV', infection, strongly]), verbo([induced]), complemento([interferon, '(', 'IFN)-λ1,', 2, and, 3, ',', and, 'IFN-β', through, activation, of, 'IFN', regulatory, factor, 3, '(', 'IRF3)', via, retinoic, acid, inducible, 'gene-I', '(', 'RIG-I)', and, the, mitochondrial, antiviral, signaling, '(', 'MAVS)', pathway])].
[sujeto(['MuV-induced', 'SG', formation, was]), verbo([suppressed]), complemento([by, knockdown, of, 'PKR', and, 'SG', marker, 'proteins,', 'Ras-GTPase-activating', protein, 'SH3-domain-binding', protein, 1, and, 'T-cell-restricted', intracellular, 'antigen-1,', and, significantly, increased, the, levels, of, 'MuV-induced', 'IFN-λ1'])].
[sujeto(['PKR', was]), verbo([required]), complemento([for, induction, of, 'SGs', by, 'MuV', infection, and, regulated, type, 'III', 'IFN', '(', 'IFN-λ1)', mRNA, stability])].
[sujeto(['MuV-induced', 'SGs', partly]), verbo([suppressed]), complemento([type, 'III', 'IFN', production, by, 'MuV;', 'however,', the, limited, suppression, was, not, sufficient, to, inhibit, 'MuV', replication, in, cell, culture])].
[sujeto(['Our', results]), verbo([provide]), complemento([insight, into, the, relationship, between, 'SGs', and, 'IFN', production, induced, by, 'MuV', infection])].
[sujeto(['Prion', is, a, unique, nucleic, 'acid-free', pathogen, that]), verbo([causes]), complemento([human, and, animal, fatal, neurodegenerative, diseases])].
[sujeto(['There', are, two, distinct, classes, of, glycosylated, 'receptors,', neurotrophin, receptor, p75, '(', 'p75NTR)', and, 'tropomyosin-related', kinase, '(', 'Trk),', that, can]), verbo([bind]), complemento([to, 'BDNF'])].
[sujeto(['Double-stained', immunofluorescent, assay, '(', 'IFA)', demonstrated, that, 'BDNF', and, 'phospho-TrkB', predominately]), verbo([expressed]), complemento([in, neurons])].
[sujeto(['Dynamic', analyses, of, the, brain, samples, collected, at, the, different, 'time-points', during, the, incubation, period, illustrated, continuous]), verbo([decreases]), complemento([of, 'BDNF,', 'TrkB,', 'phospho-TrkB,', 'GRB2', and, 'p75NTR,', which, correlated, well, with, neuron, loss])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, the, 'BDNF', signaling, pathway, is, severely, hindered, in, the, brains, of, prion, 'disease,', which, may, 'contribute,', at, least, 'partially,', to, the, neuron, death])].
[sujeto(['The', prevalence, of, 'Diabetes', 'Mellitus', is]), verbo([increasing]), complemento([worldwide])].
[sujeto(['Thus', in, developing, countries]), verbo([increased]), complemento([number, of, pregnancies, are, complicated, by, diabetes])].
[sujeto(['Uncontrolled', diabetes, in, pregnancy, is]), verbo([associated]), complemento([with, increased, risk, for, both, mother, and, foetus])].
[sujeto(['Detailed', management]), verbo([involves]), complemento([general, advice, of, lifestyle, modification, followed, by, specific, details, of, screening, for, complications, of, diabetes])].
[sujeto(['The', recommended, insulin, regimen, in, the, preconception, period, and, monitoring, of, glycaemic, control, by, 'self-monitoring', of, blood, glucose, '(', 'SMBG)', and, 'HbA1C']), verbo([has]), complemento([also, been, highlighted])].
[sujeto(['We', examined, whether]), verbo([decreasing]), complemento([salinity, from, 30, to, 15, &, 'nbsp;ppt', during, acclimation, of, groupers, could, affect, survival, with, 'NNV', infection, and, the, associated, factors])].
[sujeto(['Although', 'NNV', infection]), verbo([decreased]), complemento([muscle, 'moisture,', 'up-regulated', the, gene, expression, of, 'Na(+)-K(+)-2Cl(-)', cotransporter, isoform, 2, ',', and, elevated, plasma, cortisol, level, in, 'groupers,', these, factors, were, not, related, to, the, higher, mortality, of, groupers, reared, at, 30, -, ppt, salinity, '(', 'S30-groupers),', compared, to, 15, -, ppt, reared, groupers, '(', 'S15-groupers)'])].
[sujeto(['Since', the, inception, of, board, certification, in, ophthalmology, in, 1916, ',', a, written, assessment, of, 'candidates\'', knowledge, base]), verbo([has]), complemento([been, an, integral, part, of, the, certification, process])].
[sujeto(['Although', the, committee, structure, and, technique, for, writing, examination, questions]), verbo([has]), complemento([evolved, over, the, past, 100, 'years,', the, written, qualifying, examination, remains, an, essential, tool, for, assessing, the, competency, of, physicians, entering, the, workforce])].
[sujeto(['Our', results, show, that, the, 'plant-derived', steroid, solasodine]), verbo([decreased]), complemento(['PC12', 'glutamate-induced', 'excitotoxicity,', but, not, the, cell, death, induced, by, mitochondrial, damage, and, glucose, deprivation])].
[sujeto(['Among', the, two, synthetic, spirosteroid, 'analogues,', only, the, '(', 25, 'R)-5α-spirostan-3,6-one', '(', 'S15)', protected, 'PC12', against, 'ischemia-related', in, vitro, models, and]), verbo([inhibited]), complemento(['NO', 'production,', as, well, as, the, release, of, 'IL-1β', by, stimulated, primary, microglia])].
[sujeto(['These', findings]), verbo([provide]), complemento([further, insights, into, the, role, of, specific, modifications, of, the, 'A', and, 'B', rings, of, sapogenins, for, their, neuroprotective, potential])].
[sujeto(['The', 'SN', 1, alkylating, agents]), verbo([activate]), complemento([the, mismatch, repair, system, leading, to, delayed, 'G2', /, 'M', cell, cycle, arrest, and, 'DNA', repair, with, subsequent, survival, or, cell, death])].
[sujeto(['We', studied, whether, 'STAT1', may]), verbo([modulate]), complemento([cell, fate, following, activation, of, the, mismatch, repair, system, upon, exposure, to, the, alkylating, agent, 'N-methyl-N\'-nitro-N-nitrosoguanidine', '(', 'MNNG)'])].
[sujeto(['Using', 'STAT1-proficient', or, -, deficient, cell, 'lines,', we]), verbo([found]), complemento([that, 'STAT1', is, required, 'for:', '(', 'i)', reduction, in, the, extent, of, 'DNA', 'lesions,', '(', 'ii)', rapid, phosphorylation, of, 'T68-CHK2', and, of, 'S15-p53,', '(', 'iii)', progression, through, the, 'G2', /, 'M', checkpoint, and, '(', 'iv)', 'long-term', survival, following, treatment, with, 'MNNG'])].
[sujeto(['Thus,', our, data, highlight, the, important, modulatory, role, of, 'STAT1', in, the, signalling, pathway]), verbo([activated]), complemento([by, the, mismatch, repair, system])].
[sujeto(['This', ability, of, 'STAT1', to, favour, resistance, to, 'MNNG', indicates, the]), verbo([targeting]), complemento([of, 'STAT1', pathway, as, a, therapeutic, option, for, enhancing, the, efficacy, of, 'SN1', alkylating, 'agent-based', chemotherapy])].
[sujeto(['A', patient, with, a, 'comminuted,', 'intra-articular', distal, humerus, fracture]), verbo([requiring]), complemento(['ORIF', is, presented, in, this, video, demonstration, of, the, surgical, technique, of, an, olecranon, osteotomy])].
[sujeto(['Once', the, osteotomy]), verbo([has]), complemento([been, 'completed,', the, proximal, ulna, is, reflected, proximally, to, allow, access, to, the, distal, humerus])].
[sujeto(['A', figure, 8, ',', 18, -, gauge, cerclage, wire, is, twisted, to, compress, the, osteotomy, site, at, the, end, of, the, procedure, to]), verbo([promote]), complemento([stability, and, healing])].
[sujeto(['Various', techniques, of, olecranon, osteotomy]), verbo([have]), complemento([been, described])].
[sujeto(['A', total, of, 13, normally, calved, 'Surti', and, 'Mehsani', buffaloes, each]), verbo([maintained]), complemento([at, 'Livestock', 'Research', 'Stations', of, 'Navsari', and, 'Sardarkrushinagar', 'Dantiwada', 'Agricultural', 'Universities,', 'respectively,', were, selected, for, the, study])].
[sujeto([5, ')']), verbo([increase]), complemento([in, mean, test, day, milk, yield, '(', 'TDMY)', of, 'S60', and, 'M60', as, compared, to, 'S15', and, 'M15', 'groups,', respectively])].
[sujeto(['The', mean, fat, and, protein, corrected, test, day, milk, yield, '(', 'FPCTDMY)', of, all, the, groups, was]), verbo([found]), complemento([to, be, significantly, different, '(', 'p≤0'])].
[sujeto([5, ')']), verbo([increase]), complemento([of, 1.94, and, 3.45, kg, in, mean, 'FPCTDMY', with, the, progression, of, lactation, between, day, 15, and, 60, pp, in, 'Surti', and, 'Mehsani', 'buffaloes,', respectively])].
[sujeto(['Major', consistent]), verbo([finding]), complemento([of, the, present, study, reveals, that, milk, yield, and, 'protein%', of, 'Mehsani', buffalo, was, significantly, higher, than, 'Surti', buffalo, at, day, 15, and, 60, pp])].
[sujeto(['This', article]), verbo([provides]), complemento([reflections, based, on, decades, of, observation, and, study, and, confirms, that, knowing, something, and, doing, something, are, not, the, same])].
[sujeto(['Polo-like', kinase, 3, '(', 'PLK3)', is, the, main]), verbo([cause]), complemento([of, cell, cycle, 'reentry-related', neuronal, apoptosis, which, has, been, implicated, in, the, pathogenesis, of, prion, diseases])].
[sujeto(['In', this, 'study,', we, identified, that, the, overexpression, of, 'PLK3-mediated', degradation, of, 'PrP', mutant, and, 'PrP(Sc)', was]), verbo([repressed]), complemento([by, lysosome, rather, than, by, proteasomal, and, macroautophagy, inhibitors])].
[sujeto(['Core', components, of, 'chaperone-mediated', autophagy, '(', 'CMA)', 'effectors,', 'lysosome-associated', membrane, protein, type, 2, 'A', '(', 'LAMP2a),', and, heat, shock, cognate, protein, 70, '(', 'Hsc70)', are, markedly]), verbo([decreased]), complemento([in, the, 'HEK293T', cells, expressing, 'PrP', mutant, and, 'scrapie-infected', cell, line, 'SMB-S15'])].
[sujeto(['Meanwhile,', 'PrP', mutant, showed, ability, to]), verbo([interact]), complemento([with, 'LAMP2a', and, 'Hsc70'])].
[sujeto(['Overexpression', of, 'PLK3', sufficiently]), verbo([increased]), complemento([the, cellular, levels, of, 'LAMP2a', and, 'Hsc70,', accompanying, with, declining, the, accumulations, of, 'PrP', mutant, and, 'PrP(Sc)'])].
[sujeto(['Knockdown', of, endogenous, 'PLK3']), verbo([enhanced]), complemento([the, activity, of, macroautophagy, in, the, cultured, cells])].
[sujeto(['In', the, past, 3, 'decades,', a, better, understanding, of, the, pathophysiology, of, cardiovascular, disease]), verbo([has]), complemento([resulted, in, innovations, in, the, treatment, and, prevention, of, its, clinical, manifestations, such, as, 'death,', myocardial, 'infarction,', or, stroke])].
[sujeto(['This']), verbo([leads]), complemento([to, opportunities, to, initiate, strategies, to, reduce, complications, resulting, from, myocardial, injury, '(', cardiac, 'protection)', and, to, prevent, recurrent, acute, coronary, events, '(', vascular, 'protection)'])].
[sujeto(['Moreover,', many, others, do, not, receive, treatment, that, follows, the, strategy, proven, in, the, clinical, trial, and, this, is]), verbo([associated]), complemento([with, a, significant, loss, of, opportunities, to, improve, outcomes])].
[sujeto(['The', 'Canadian', 'Heart', 'Research', 'Centre']), verbo([has]), complemento([therefore, assembled, a, panel, of, experts, to, provide, a, review, of, available, data, and, distill, it, to, specific, 'evidence-based', recommendations, that, can, be, used, by, specialists, and, primary, care, physicians, as, a, platform, for, secondary, prevention])].
[sujeto(['A', study, was, conducted, to, determine, the, effects, of, feeding, sorghum, 'distiller\'s', dried, grains, with, solubles, '(', 'SDDGS)', on, carcasses, characteristics, '(', live, 'weight,', whole, net, carcass, 'rate,', breast, muscle, 'percentage,', thigh, muscle, 'percentage),', muscle, quality, '(', meat, 'color,', shear, 'stress,', cooking]), verbo([loss]), complemento(['rate,', cooked, meat, 'percentage),', and, meat, composition, of, 'China', 'Micro', 'Duck', '(', 'CMD)', drakes, aged, from, 4, to, 8, wk])].
[sujeto(['The', results, showed, that, 'S5,', 'S10,', and, 'S15', could]), verbo([decrease]), complemento([the, thigh, muscle, percentage, linearly, '(', 'P', &, 'lt; 0'])].
[sujeto([5, ')', effect, on, other, carcass, characteristic, and, muscle, quality, indexes, of, live, body, weight, '(', 'BW),', whole, net, carcass, yield, '(', 'WNCY),', breast, muscle, percentage, '(', 'BMP),', breast, muscle, color, '(', 'BMC),', thigh, muscle, color, '(', 'TMC),', breast, shear, strength, '(', 'BSS),', cooking]), verbo([loss]), complemento(['(', 'CL),', or, cooked, meat, percentage, '(', 'CMP)'])].
[sujeto(['For', meat, 'composition,', the]), verbo([increasing]), complemento([level, of, 'SDDGS', caused, a, linear, and, quadratic, decrease, '(', 'P', &, 'lt; 0'])].
[sujeto([1, ')']), verbo([increase]), complemento([of, crude, fat, of, thigh, and, breast, 'muscle,', while, breast, muscle, ash, was, not, significantly, affected, '(', 'P', &, 'gt; 0'])].
[sujeto(['Fisetin', '(', 25, -, 100, 'µM)']), verbo([caused]), complemento([significant, decrease, in, the, levels, of, 'G1', phase, cyclins, and, 'CDKs,', and, increased, the, levels, of, p53, and, its, 'S15', phosphorylation, in, gastric, cancer, cells])].
[sujeto(['Fisetin', strongly]), verbo([increased]), complemento([apoptotic, cells, and, showed, mitochondrial, membrane, depolarization, in, gastric, cancer, cells])].
[sujeto(['DCFDA', and, 'MitoSOX', analyses, showed, an]), verbo([increase]), complemento([in, mitochondrial, 'ROS', generation, in, 'time-', and, 'dose-dependent', fashion])].
[sujeto(['It', also]), verbo([increased]), complemento([cellular, nitrite, and, superoxide, generation])].
[sujeto(['Pre-treatment', with, 'N-acetyl', cysteine, '(', 'NAC)']), verbo([inhibited]), complemento(['ROS', generation, and, also, caused, protection, from, 'fisetin-induced', 'DNA', damage])].
[sujeto(['Further', investigation, of, the, source, of, 'ROS,', using, mitochondrial, respiratory, chain, '(', 'MRC)', complex, 'inhibitors,']), verbo([suggested]), complemento([that, fisetin, caused, 'ROS', generation, specifically, through, complex, 'I'])].
[sujeto(['Collectively,', these, results, for, the, first, time, demonstrated, that, fisetin, possesses, anticancer, potential, through, 'ROS', production, most, likely, via, 'MRC', complex, 'I']), verbo([leading]), complemento([to, apoptosis, in, human, gastric, carcinoma, cells])].
[sujeto(['This', article, aims, to, demonstrate, that, children, with, asymmetric, hearing]), verbo([loss]), complemento(['(', 'AHL),', specifically, those, with, single, side, deafness, '(', 'SSD', 'condition)', and, pure, 'SSD,', with, substantial, hearing, '(', &, 'gt;70%', normal, speech, 'discrimination)', in, the, ear, with, hearing, aid, '(', 'HA),', obtain, clinically, relevant, speech, perception, benefit, after, cochlear, implantation, in, the, contralateral, side])].
[sujeto(['Tissue', clearing, techniques]), verbo([have]), complemento([become, a, powerful, approach, to, understand, further, the, structural, information, of, intact, biological, tissues])].
[sujeto(['Here,', we, described, an, overview, of, various, 'tissue-clearing', 'techniques,', with, focus, on, the, 'tissue-hydrogel']), verbo([mediated]), complemento([clearing, 'methods,', and, discussed, the, main, advantages, and, limitations, of, transparent, tissue, for, clinical, diagnosis])].
[sujeto(['Ages', of, the, plant, lineages, and, the, timing, of, their, radiations]), verbo([have]), complemento([frequently, been, debated, but, remain, contentious, as, there, are, few, estimates, based, on, explicit, models, and, 'fossil-calibrated', molecular, clocks])].
[sujeto(['We', used, the, plastid, region, maturaseK, '(', 'matK)', and, a, 'Caryophylloflora', paleogenica, fossil, to, infer, the, age, of, the, genus, 'Lychnis,', and, constructed, a, data, set, of, three, plastid, '(', 'matK;', a, ribosomal, protein, 'S16', '(', 'rps16);', and, an, intergenic, spacer, '(', 'psbE-petL))', and, two]), verbo([nuclear]), complemento(['(', internal, transcribed, spacer, '(', 'ITS)', and, a, region, spanning, exon, 18, -, 24, in, the, second, largest, subunit, of, 'RNA', polymerase, 'II', '(', 'RPB2))', loci, for, joint, estimation, of, the, species, tree, and, divergence, time, of, the, 'African', representatives])].
[sujeto(['We']), verbo([provide]), complemento([further, support, for, a, 'Eurasian', origin, of, the, 'African', '\'', sky, 'islands\'', floral, 'elements,', which, seem, to, have, been, recruited, via, dispersals, at, different, 'times:', some, 'old,', as, in, 'Lychnis,', and, others, very, recent])].
[sujeto(['As', expected, for, an, 'excluded-volume', 'effect,', the, resistance, of, the, mesophilic, protein, to, 'heat-induced', unfolding]), verbo([increased]), complemento([in, the, presence, of, dextran, 20, ',', and, chemical, denaturation, experiments, at, different, fixed, temperatures, showed, the, macromolecular, crowding, effect, to, be, 'temperature-independent'])].
[sujeto(['All', 'S16Meso', variants, exhibited, a]), verbo([decrease]), complemento([in, the, average, 'Trp-BODIPY', distance, at, up, to, 100, &, 'nbsp;mg/mL', dextran, 20, ',', whereas, the, changes, in, distance, became, anisotropic, '(', one, distance, 'increased,', two, distances, 'decreased)', at, higher, dextran, concentrations])].
[sujeto(['In', 'contrast,', the, two, 'S16Thermo', mutants, did, not, show, any, changes, in, 'Trp-BODIPY', distances, upon]), verbo([increase]), complemento([of, dextran, 20, concentrations])].
[sujeto(['It', should, be, noted, that, the, fluorescence, quantum, yields, and, lifetimes, of, 'BODIPY', attached, to, the, two, 'S16', homologs]), verbo([decreased]), complemento([gradually, in, the, presence, of, dextran, 20])].
[sujeto(['The', experiments, revealed, distinct, tyrosine, quenching, behaviors, of, 'BODIPY', in, the, three, 'variants,']), verbo([suggesting]), complemento([a, dynamic, local, interaction, between, dextran, and, one, particular, 'S16', variant])].
[sujeto(['Nucleotide', sequences, of, the, 'self-splicing', 'group-II', intron, of, rps16]), verbo([have]), complemento([first, been, determined, in, nine, species, of, the, 'Solanum', genus])].
[sujeto(['It', was]), verbo([found]), complemento([that, the, observed, variations, in, the, intron, length, '(', 855, -, 864, 'bp)', was, associated, with, indels, of, 1, to, 9, b])].
[sujeto(['Increasing', evidence]), verbo([has]), complemento([shown, the, complex, and, dynamic, nature, of, polyploids])].
[sujeto(['Two', single, copy]), verbo([nuclear]), complemento([genes, were, used, to, explore, genome, evolutionary, dynamics, and, the, origin, of, tetraploid, 'E'])].
[sujeto([ciliairs]), verbo([has]), complemento([multiple, 'origins,', and, originated, from, the, 'Pseudorogneria', '(', 'St)', and, unknown, donor, '(', 'Y)', diploids])].
[sujeto([ciliaris, species]), verbo([has]), complemento([a, complex, evolutionary, history])].
[sujeto(['Both', 'RPB2', and, 'PGK1', data]), verbo([suggested]), complemento([the, absence, of, 'St', genome, in, accession, 'PI', 377532, of, 'E'])].
[sujeto(['Results']), verbo([suggest]), complemento([that, there, are, two, lineages, of, 'St', genome, present, in, 'E'])].
[sujeto(['The', 'Japanese', accession, 'PI', 377532, might]), verbo([have]), complemento([introgression, either, from, 'HordeumH', genome, species, or, from, 'ElymusStH', genome, species, with, replacement, of, at, least, some, nuclear, 'St-loci', by, 'H-loci'])].
[sujeto(['As', 'expected,', we]), verbo([found]), complemento([that, dextran, 20, '(', 200, 'mg/ml)', stabilized, the, variants, against, 'urea-induced', unfolding])].
[sujeto(['At', conditions, where, the, protein, is, 'unfolded,', 'Förster', resonance, energy, transfer, measurements]), verbo([reveal]), complemento([that, in, the, presence, of, 'dextran,', the, unfolded, ensemble, is, more, compact, and, there, is, residual, structure, left, as, probed, by, 'far-ultraviolet', circular, dichroism])].
[sujeto(['Our', study]), verbo([provides]), complemento([direct, evidence, for, protein, 'unfolded-state', compaction, in, the, presence, of, macromolecular, crowding, along, with, its, energetic, and, kinetic, consequences])].
[sujeto(['However,', it]), verbo([has]), complemento([been, reported, that, 'chloroplast-encoded', 'RPS16', in, 'mono-', and, dicotyledonous, plants, has, been, substituted, by, the, product, of, 'nuclear-encoded', 'rps16,', which, was, transferred, from, the, mitochondria, to, the, nucleus, before, the, early, divergence, of, angiosperms])].
[sujeto(['Current', databases, show, that, the, 'chloroplast-encoded', rps16]), verbo([has]), complemento([become, a, pseudogene, in, four, species, of, the, 'Brassicaceae', '(', 'Aethionema', 'grandiflorum,', 'Arabis', 'hirsuta,', 'Draba', 'nemorosa,', and, 'Lobularia', 'maritima)'])].
[sujeto(['Further', analysis, of, 'Arabidopsis', thaliana, and, its, close, relatives]), verbo([has]), complemento([shown, that, pseudogenization, has, also, occurred, via, the, loss, of, its, splicing, capacity, '(', 'Arabidopsis', thaliana, and, 'Olimarabidopsis', 'pumila)'])].
[sujeto(['Our', results, strongly]), verbo([suggest]), complemento([that, 'nuclear-', and, 'chloroplast-encoded', rps16, genes, coexisted, for, at, least, 126, million, years])].
[sujeto(['We', raise, the, possibility, of, the, widespread, pseudogenization, of, rps16, in, the, angiosperm, chloroplast, genomes, via, the]), verbo([loss]), complemento([of, its, splicing, 'capacity,', even, when, the, rps16, encoded, in, the, chloroplast, genome, is, transcriptionally, active])].
[sujeto(['Recombinant', human, ribosomal, protein, 'S16', '(', 'rpS16)', is, shown, to]), verbo([bind]), complemento([specifically, to, a, fragment, of, its, own, 'pre-mRNA', that, includes, exons, 1, and, 2, ',', intron, 1, ',', and, part, of, intron, 2, ',', and, to, inhibit, the, splicing, of, the, fragment, in, vitro])].
[sujeto(['The', weaker]), verbo([binding]), complemento([of, other, recombinant, human, ribosomal, 'proteins,', 'S10', and, 'S13,', to, this, 'pre-mRNA', fragment, indicated, that, the, binding, of, rpS16, was, specific])].
[sujeto(['Besides,', 'poly(AU)', and, rpS16, mRNA, fragment, affected, poorly, the]), verbo([binding]), complemento([of, rpS16, to, its, 'pre-mRNA,', providing, another, evidence, that, the, interaction, was, specific])].
[sujeto(['RpS16', specifically]), verbo([inhibited]), complemento([the, 'pre-mRNA', fragment, splicing, whereas, recombinant, rpS10, and, rpS16, did, not, affect, excision, of, intron, from, this, 'pre-mRNA', fragment, in, contrast, to, rpS16])].
[sujeto(['Those', positions, in, rpS16, 'pre-mRNA', fragment, that, were, protected, by, rpS16, against, cleavage, by, 'RNases', 'T1,', 'T2', and, 'V1', were]), verbo([found]), complemento([to, be, located, closely, to, the, branch, point, and, 3, '\'', splice, site, in, the, 'pre-mRNA'])].
[sujeto(['We']), verbo([have]), complemento([developed, an, affinity, purification, of, the, large, ribosomal, subunit, from, 'Deinococcus', radiodurans, that, exploits, its, association, with, 'FLAG-tagged', 30, 'S', subunits])].
[sujeto(['Thus,', capture, is, indirect, so, that, no, modification, of, the, 50, 'S', is]), verbo([required]), complemento([and, elution, is, achieved, under, mild, conditions, '(', low, 'magnesium)', that, disrupt, the, 'association,', avoiding, the, addition, of, competitor, ligands, or, coelution, of, common, contaminants])].
[sujeto(['We', used, hydroxyl, radical, footprinting, to, measure, how, much, the, proteins, stabilize, individual, ribosomal, 'RNA', tertiary, 'interactions,']), verbo([revealed]), complemento([the, 'free-energy', landscape, for, assembly, of, the, 16, 'S', 5, '\'', domain])].
[sujeto(['When', ribosomal, proteins, 'S4,', 'S17', and, 'S20']), verbo([bind]), complemento([the, 5, '\'', domain, 'RNA,', a, native, and, a, 'non-native', assembly, intermediate, are, equally, populated])].
[sujeto(['The', secondary, assembly, protein, 'S16']), verbo([suppresses]), complemento([the, 'non-native', 'intermediate,', smoothing, the, path, to, the, native, complex])].
[sujeto(['Long-range', communication, between, the, 'S16']), verbo([binding]), complemento([site, and, the, decoding, center, helps, to, explain, the, crucial, role, of, 'S16', in, 30, 'S', assembly])].
[sujeto(['In', an, effort, to, identify, such, 'mechanisms,', we]), verbo([have]), complemento([performed, a, detailed, comparative, study, of, the, folding, thermodynamics, and, kinetics, of, the, ribosomal, protein, 'S16', isolated, from, a, mesophilic, '(', 'S16(meso))', and, hyperthermophilic, '(', 'S16(thermo))', bacterium, by, using, a, variety, of, biophysical, methods])].
[sujeto(['Thermal', unfolding, experiments, yielded, midpoints, of, 59, and, 111, degrees, 'C', with]), verbo([associated]), complemento([changes, in, heat, capacity, upon, unfolding, '(', 'DeltaC(p)(0))', of, 6.4, and, 3.3, kJ, 'mol(-1)', 'K(-1),', respectively])].
[sujeto(['A', strong, linear, correlation, between, 'DeltaC(p)(0)', and, melting, temperature, '(', 'T(m))', was, observed, for, the, 'wild-type', proteins, and, mutated, 'variants,']), verbo([suggesting]), complemento([that, these, variables, are, intimately, connected])].
[sujeto(['Taken', 'together,', our, results]), verbo([suggest]), complemento([the, presence, of, residual, structure, in, the, denatured, state, ensemble, of, 'S16(thermo)', that, appears, to, account, for, the, large, difference, in, quantified, 'DeltaC(p)(0)', values, 'and,', in, 'turn,', parts, of, the, observed, extreme, thermal, stability, of, 'S16(thermo)'])].
[sujeto(['Gene']), verbo([loss]), complemento([is, an, ongoing, process, in, the, mitochondria, and, chloroplasts, of, higher, plants])].
[sujeto(['Here,', we, show, that, these, 2, species]), verbo([have]), complemento([compensated, for, loss, of, the, rps16, from, the, chloroplast, genome, by, having, a, mitochondrial, rps16, that, can, target, the, chloroplasts, as, well, as, mitochondria])].
[sujeto(['Furthermore,', in, 'Arabidopsis', 'thaliana,', 'Lycopersicon', 'esculentum,', and, 'Oryza', 'sativa,', whose, chloroplast, genomes, encode, the, 'rps16,', we, show, that, the, product, of, the, mitochondrial, rps16]), verbo([has]), complemento([dual, targeting, ability])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, dual, targeting, of, 'RPS16', to, the, mitochondria, and, chloroplasts, emerged, before, the, divergence, of, monocots, and, dicots, '(', 140, -, 150, 'MYA)'])].
[sujeto(['The', gene, substitution, of, the, chloroplast, rps16, by, the, 'nuclear-encoded', rps16, in, higher, plants, is, the, first]), verbo([report]), complemento([about, ongoing, gene, substitution, by, dual, targeting, and, provides, evidence, for, an, intermediate, stage, in, the, formation, of, this, heterogeneous, organelle])].
[sujeto(['In', the, present, 'work,', we]), verbo([report]), complemento([studying, interaction, of, human, recombinant, rpS16, with, a, 'RNA', transcript, corresponding, to, the, region, 1203, -, 1236, /, 1521, -, 1698, '(', helices, 'H28-30', and, 'H41-43)', of, human, 18, 'S', 'rRNA,', which, is, homologous, to, the, 16, 'S', rRNA, region, known, to, bind, rpS9])].
[sujeto(['RpS16', was, shown, to, specifically]), verbo([bind]), complemento([to, the, transcript, forming, a, stable, complex, with, the, apparent, dissociation, constant, of, '(', 1.3, +, /, -, 0.1, ')', x, 10, '(', -, 8, ')', 'M', at, 20, degrees, 'C'])].
[sujeto(['Nucleotide', residues, of, the, transcript, that, change, their, accessibility, to, 'RNases', and, modifying, chemical, probes, upon, the, rpS16]), verbo([binding]), complemento([were, determined, by, enzymatic, and, chemical, footprinting])].
[sujeto(['It', was, shown, that, rpS16]), verbo([causes]), complemento([significant, enhancement, of, reactivities, of, nucleotides, 'C1544', '(', internal, loop, of, helix, 'H41),', 'C1618-U1622', and, 'C1629-A1634', '(', helix, 'H42),', 'C1521-C1523,', 'U1530,', 'C1532', '(', helix, 'H30)', and, 'C1645,', 'C1646,', 'G1648', '(', helix, 'H43)', and, protection, of, nucleotides, 'C1670-A1675', '(', helix, 'H43)'])].
[sujeto(['To']), verbo([provide]), complemento([evidence, that, the, production, of, bacteriocin, by, lactic, acid, bacteria, can, be, enhanced, by, the, presence, of, a, 'bacteriocin-sensitive', strain, and, identify, the, agent, that, is, responsible, for, enhancing, bacteriocin, production])].
[sujeto(['The', isolate, produced, a, 'heat-', and, 'pH-stable', bacteriocin, '(', kimchicin, 'GJ7),', which]), verbo([has]), complemento([antagonistic, activity, against, a, broad, spectrum, of, 'micro-organisms'])].
[sujeto([citreum, 'GJ7', in, the, presence, of, thermally, inactivated, kimchicin, 'GJ7-sensitive', 'strains,', 'Lactobacillus', plantarum, 'KFRI', 464, ',', 'Lactobacillus', delbrueckii, 'KFRI', 347, ',', or, 'Leuconostoc', mesenteroides, 'KCTC', 1628, ',']), verbo([increased]), complemento([bacteriocin, production])].
[sujeto(['This']), verbo([inducing]), complemento([factor, was, characterized, and, purified, from, 'Lact'])].
[sujeto(['The']), verbo([inducing]), complemento([factor, was, purified, using, a, 'DEAE', '(', diethyl, 'aminoethyl)-Sephacel', column, and, 'high-performance', liquid, 'chromatography,', and, yielded, a, single, band, of, c])].
[sujeto(['N-terminal', sequencing, of, the]), verbo([inducing]), complemento([factor, identified, 16, amino, acids])].
[sujeto(['The', 'N-terminal', sequence, of, the]), verbo([inducing]), complemento([factor, was, synthesized, and, examined, for, the, induction, of, kimchicin, 'GJ7', 'activity,', and, was, found, to, induce, 'activity,', but, at, a, level, about, 10, '%', lower, than, that, of, the, entire, molecule])].
[sujeto([plantarum, 'KFRI', 464, ',']), verbo([acts]), complemento([as, an, environmental, stimulus, to, activate, the, production, of, kimchicin, 'GJ7', by, 'Leuc'])].
[sujeto(['The']), verbo([inducing]), complemento([factor, from, 'Lact'])].
[sujeto(['The', 'N-terminal', sequence, of, the]), verbo([inducing]), complemento([factor, examined, in, this, study, is, a, very, important, sequence, related, to, the, inducing, activity])].
[sujeto(['Nevertheless,', the]), verbo([inducing]), complemento([factor, may, not, be, part, of, the, ribosomal, protein, 'S16', itself])].
[sujeto(['Eukaryotic', ribosomal, 'proteins,', which]), verbo([participate]), complemento([in, the, structure, and, function, of, the, translational, 'machinery,', are, generally, well, conserved])].
[sujeto(['Although', analysis, of, 'RpS6', protein, was, consistent, with, analyses, based, on, ribosomal, 'DNA,']), verbo([suggesting]), complemento([that, 'Chironomidae', is, the, sister, group, to, the, remaining, families, in, the, 'Culicomorpha,', trees, generated, from, 'RpS6', amino, acid, sequences, were, largely, congruent, with, accepted, phylogenies, based, on, morphological, characters])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, a, 'C-terminal,', lysinerich, extension, on, 'RpS6', is, a, potential, molecular, synapomorphy, for, the, 'Culicomorpha'])].
[sujeto(['We']), verbo([have]), complemento([identified, several, protein, biomarkers, of, three, 'Campylobacter', jejuni, strains, '(', 'RM1221,', 'RM1859,', and, 'RM3782)', by, proteomic, techniques])].
[sujeto(['The', protein, biomarkers, identified, 'were:', 'DNA-binding', protein, 'HU,', translation, initiation, factor, 'IF-1,', cytochrome, 'c553,', a, 'transthyretin-like', periplasmic, 'protein,', chaperonin, 'GroES,', thioredoxin, 'Trx,', and, ribosomal, 'proteins:', 'L7/L12', '(', 50, 'S),', 'L24', '(', 50, 'S),', 'S16', '(', 30, 'S),', 'L29', '(', 50, 'S),', and, 'S15', '(', 30, 'S),', and]), verbo([conserved]), complemento([proteins, similar, to, strain, 'NCTC', 11168, proteins, 'Cj1164', and, 'Cj1225'])].
[sujeto(['Two', protein, biomarkers, '(', 'HU', and, 30, 'S', ribosomal, protein, 'S16)', that]), verbo([have]), complemento([a, penultimate, threonine, residue, do, not, show, 'N-Met', cleavage])].
[sujeto(['This', exception, to, the, 'N-Met', cleavage, rule]), verbo([has]), complemento([implications, for, the, development, of, bioinformatics, algorithms, for, 'protein/pathogen', identification])].
[sujeto(['As', the, mass, shifts, were, due, to, the, frequency, of, amino, acid, substitutions, '(', and, thus, underlying, genetic, 'variations),', this]), verbo([suggested]), complemento([that, strains, 'RM1221', and, 'RM1859', were, phylogenetically, closer, to, one, another, than, to, strain, 'RM3782', '(', in, 'addition,', a, protein, biomarker, prominent, in, the, spectra, of, 'RM1221', and, 'RM1859', was, absent, from, the, 'RM3782', spectrum, due, to, a, nonsense, mutation, in, the, gene, of, the, 'biomarker)'])].
[sujeto(['This', result]), verbo([suggests]), complemento([that, 'detection/identification', of, protein, biomarkers, by, pattern, recognition, 'and/or', bioinformatics, algorithms, may, easily, subspeciate, bacterial, microorganisms])].
[sujeto(['(', 6, ')', 'Finally,', the, number, and, variation, of, 'PTMs', detected, in, this, relatively, small, number, of, protein, biomarkers]), verbo([suggest]), complemento([that, bioinformatics, algorithms, for, pathogen, identification, may, need, to, incorporate, many, more, possible, 'PTMs', than, suggested, previously, in, the, literature])].
[sujeto(['The', methodology, was, then, used, on, algal, mats, from, geothermal, hot, springs, in, 'Tengchong', 'county,', 'Yunnan', 'Province,', 'People\'s', 'Republic', of, 'China,', and]), verbo([activated]), complemento([sludge, from, a, sewage, treatment, plant, in, 'Leicestershire,', 'United', 'Kingdom'])].
[sujeto(['In', 'contrast,', many, clones, from, the]), verbo([activated]), complemento([sludge, library, had, significant, similarity, to, eukaryote, 'mRNA-encoded', protein, sequences])].
[sujeto(['A', library, was, also, made, using, polyadenylated, 'RNA', isolated, from, total, 'RNA', from]), verbo([activated]), complemento(['sludge;', many, more, clones, in, this, library, were, related, to, eukaryotic, mRNA, sequences, and, proteins])].
[sujeto(['It']), verbo([has]), complemento([many, 'uses,', including, the, identification, of, novel, eukaryotic, 'ORFs', encoding, proteins, and, enzymes])].
[sujeto(['Bacterial', 30, 'S', subunit, crystal, structures, depicting, 'Mg(2+)']), verbo([binding]), complemento([sites, resolve, two, magnesium, ions, within, the, vicinity, of, 'H27:', one, in, the, major, groove, of, the, 'G886-U911', wobble, 'pair,', and, one, within, the, 'GCAA', tetraloop])].
[sujeto(['To', ask, how, metal, 'ion-RNA', interactions, in, crystals, compare, with, those, in, 'solution,', we]), verbo([have]), complemento(['characterized,', using, solution, 'NMR', 'spectroscopy,', 'Tb(3+)', footprinting, and, 'time-resolved', fluorescence, resonance, energy, transfer, '(', 'tr-FRET),', 'location,', and, modes, of, metal, ion, binding, in, an, isolated, 'H27'])].
[sujeto(['NMR', and, 'Tb(3+)', footprinting, data, indicate, that, solution, secondary, structure, and, 'Mg(2+)']), verbo([binding]), complemento([are, generally, consistent, with, the, ribosomal, crystal, structures])].
[sujeto(['However,', our, analyses, also]), verbo([suggest]), complemento([that, 'H27', is, dynamic, in, solution, and, that, metal, ions, localize, within, the, narrow, major, groove, formed, by, the, juxtaposition, of, the, loop, 'E', motif, with, the, tandem, 'G894-U905', and, 'G895-U904', wobble, pairs])].
[sujeto(['In', 'addition,', 'tr-FRET', studies]), verbo([provide]), complemento([evidence, that, 'Mg(2+)', uptake, by, the, 'H27', construct, results, in, a, global, lengthening, of, the, helix])].
[sujeto(['We', propose, that, only, a, subset, of, 'H27-metal', ion, interactions]), verbo([has]), complemento([been, captured, in, the, crystal, structures, of, the, 30, 'S', ribosomal, 'subunit,', and, that, 'small-scale', structural, dynamics, afforded, by, solution, conditions, may, contribute, to, these, differences])].
[sujeto(['It', was]), verbo([found]), complemento([that, 21, +, /, -, 4, '%', of, the, amino, acid, sequence, of, the, protein, forms, 'alpha-helices', and, 24, +, /, -, 3, '%', is, in, 'beta-strands'])].
[sujeto(['The', protein, is, quickly, denatured, at, pH, above, 8.0, ',', whereas]), verbo([increasing]), complemento([of, urea, concentration, causes, slow, unfolding, of, the, protein])].
[sujeto(['The', original, interpretation, of, a, series, of, genetic, studies]), verbo([suggested]), complemento([that, the, highly, conserved, 'Escherichia', coli, 16, 'S', ribosomal, 'RNA', helix, 27, '(', 'H27)', adopts, two, alternative, secondary, structure, 'motifs,', the, 885, and, 888, 'conformations,', during, each, cycle, of, amino, acid, incorporation])].
[sujeto(['Recent', crystallographic, and, genetic, evidence]), verbo([has]), complemento([called, this, hypothesis, into, question])].
[sujeto(['To', ask, whether, a, slippery, sequence, such, as, that, of, 'H27', may, harbor, inherent, conformational, 'dynamics,', we]), verbo([have]), complemento([designed, a, series, of, model, 'RNAs', based, on, 'E'])].
[sujeto(['UV', irradiation, assays, conducted, under, conditions, analogous, to, those, used, for, assays, of, ribosomal, function, '(', pH, 7.5, and, 20, mM, 'MgCl(2))']), verbo([suggest]), complemento([that, nucleotides, 892, and, 905, ',', which, are, too, far, apart, in, the, known, 885, crystal, 'structures,', can, approach, each, other, closely, enough, to, form, an, efficient, 'cross-link'])].
[sujeto(['The', use, of, a, fluorescence, resonance, energy, transfer, '(', 'FRET)-labeled', 'RNA', together, with, a, partially, complementary, 'DNA', oligonucleotide, that]), verbo([induces]), complemento([a, shift, to, the, 888, conformation, shows, that, 'H27', interchanges, between, the, 885, and, 888, conformations, on, the, millisecond, time, 'scale,', with, an, equilibrium, constant, of, 0.33, +, /, -, 0.12])].
[sujeto(['FRET', assays, also, show, that, tetracycline, interferes, with, the]), verbo([induced]), complemento([shift, to, the, 888, 'conformation,', a, finding, that, is, consistent, with, crystallographic, localization, of, tetracycline, bound, to, the, 885, conformation, of, 'H27', in, the, 30, 'S', ribosomal, subunit])].
[sujeto(['This', begs, the, question, of, how, these, inherent, structural, dynamics, are]), verbo([suppressed]), complemento([within, the, context, of, the, ribosome])].
[sujeto(['Ebp2p,', the, yeast, homolog, of, human, 'Epstein-Barr', virus]), verbo([nuclear]), complemento([antigen, 1, -, binding, protein, 2, ',', is, essential, for, biogenesis, of, the, 60, 'S', ribosomal, subunit])].
[sujeto(['Two-hybrid', screening, exhibited, 'that,', in, addition, to, factors, necessary, for, assembly, of, the, 60, 'S', 'subunit,', 'Ebp2p']), verbo([interacts]), complemento([with, 'Rps16p,', ribosomal, protein, 'S16,', and, the, 40, 'S', ribosomal, subunit, assembly, 'factor,', 'Utp11p,', as, well, as, 'Yil019w,', the, function, of, which, was, previously, uncharacterized])].
[sujeto([35, 'S', 'pre-rRNA', and, aberrant, 23, 'S', 'RNA', 'accumulated,', indicating, that, 'pre-rRNA', processing, at, sites, 'A(0)-A(2)', is]), verbo([inhibited]), complemento([when, 'Yil019w', is, depleted])].
[sujeto(['Its', morphology, and, distributional, range]), verbo([suggest]), complemento([that, it, is, allied, to, 'P'])].
[sujeto(['We', sequenced, four, chloroplast, '(', 'cp)', 'DNA', fragments, '(', 'trnH-psbA,', 'trnL-trnF,', 'rps16,', and, 'trnG)', and, the]), verbo([nuclear]), complemento([internal, transcribed, spacer, '(', 'ITS)', region, for, all, samples])].
[sujeto(['Moreover,', our, phylogenetic, 'analyses-based', 'ITS', sequence, variations]), verbo([suggested]), complemento([that, 'O'])].
[sujeto(['Because', polyploids, are]), verbo([suggested]), complemento([to, have, better, colonization, abilities, and, are, abundant, in, 'Deparia,', we, also, examined, whether, polyploidy, could, be, correlated, to, 'long-distance', dispersal, events, and, whether, polyploidy, could, play, a, role, in, these, 'dispersals/establishment', and, range, expansion])].
[sujeto(['We']), verbo([found]), complemento([that, 'Deparia', originated, around, 27.7, 'Ma', in, continental, 'Asia/East', 'Asia'])].
[sujeto(['In', 'particular,', the, 'long-distance', dispersal, to, the, 'Hawaiian', 'Islands', was]), verbo([associated]), complemento([with, 'polyploidization,', and, the, dispersal, rate, was, slightly, higher, in, the, polyploids, than, in, diploids])].
[sujeto(['Moreover,', we]), verbo([found]), complemento([five, species, showing, recent, infraspecific, range, 'expansions,', all, of, which, took, place, concurrently, with, polyploidization])].
[sujeto(['In', 'conclusion,', our, study]), verbo([provides]), complemento([the, first, investigation, using, phylogenetic, and, biogeographic, analyses, trying, to, explore, the, link, between, historical, biogeography, and, ploidy, evolution, in, a, fern, genus, and, our, results, imply, that, polyploids, might, be, better, colonizers, than, diploids])].
[sujeto([',', which]), verbo([has]), complemento([traditionally, been, an, important, food, resource, in, 'China,', 'Korea,', and, 'Japan'])].
[sujeto(['This', is, the, first, cp, genome]), verbo([reported]), complemento([in, 'Ebenaceae'])].
[sujeto(['Both', maximum, parsimony, and, likelihood, analyses, for, 19, taxa, indicated, the, basal, position, of, 'Ericales', in, asterids, and]), verbo([suggested]), complemento([that, 'Ebenaceae', is, monophyletic, in, 'Ericales'])].
[sujeto(['Also,', the, genomic, analyses, could]), verbo([provide]), complemento([important, information])].
[sujeto(['As', the, second, and, third, sequenced, members, within, 'Gentianaceae,', we]), verbo([report]), complemento([the, construction, of, complete, cp, sequences, of, 'Gentiana', robusta, 'King', ex, 'Hook'])].
[sujeto(['These', cp, genomes, are, highly]), verbo([conserved]), complemento([in, gene, 'size,', gene, 'content,', and, gene, order, and, the, rps16, pseudogene, with, exon2, missing, was, found, common])].
[sujeto(['Sixteen', genome, divergent, hotspot, regions, were, identified, across, these, cp, genomes, that, could]), verbo([provide]), complemento([potential, molecular, markers, for, further, phylogenetic, studies, in, 'Gentiana'])].
[sujeto(['This', study]), verbo([provides]), complemento([a, platform, for, further, research, into, the, molecular, phylogenetics, of, species, in, the, order, 'Gentianales', '(', family, 'Gentianaceae)', notably, in, respect, of, speciation, and, species, identification])].
[sujeto(['A', primary, aim, of, historical, biogeography, is, to, identify, the, causal, factors, or, processes, that]), verbo([have]), complemento([shaped, the, composition, and, distribution, of, biotas, over, time])].
[sujeto(['To', this, 'end,', historical, biogeography, addresses, important, questions, such, 'as:', 'Where', were, ancestors, 'distributed?', 'Where', did, lineages, 'originate?', 'Which', processes]), verbo([cause]), complemento([geographic, ranges, to, evolve, through, 'time?', 'Allium', subgenus, 'Anguinum', comprises, approximately, twelve, taxa, with, a, disjunct, distribution, in, the, high, mountains, from, 'south-western', 'Europe', to, eastern, 'Asia', and, in, northeastern, 'North', 'America'])].
[sujeto(['Although', both, the, systematic, position, and, the, geographical, limits, of, 'Anguinum']), verbo([have]), complemento([been, 'identified,', to, date, no, molecular, systematic, study, has, been, performed, utilizing, a, comprehensive, sampling, of, these, species])].
[sujeto(['Anguinum', 'RbcL', sequences, were, used, to, estimate, divergences, time, for, 'Allium,', and, sequences, of, 'ITS', were, used, to, estimate, the, divergence, times, for, 'Anguinum', and, its, main, lineages, and, to]), verbo([provide]), complemento([implications, for, the, evolutionary, history, of, the, subgenus])].
[sujeto(['In', the, eastern, 'Asian', geographical, 'group,', incongruence, between, gene, trees, and, 'morphology-based', taxonomies, was, recovered, as, was, incongruence, between, data, from, plastid, and]), verbo([nuclear]), complemento([sequences])].
[sujeto(['Divergence', time, estimates]), verbo([suggest]), complemento([that, the, crown, group, of, 'Anguinum', originated, during, the, late, 'Miocene', '(', ca])].
[sujeto(['This', 'amphi-Atlantic', 'disjunction,', frequently, displayed, by, pantropical, 'taxa,']), verbo([has]), complemento([been, traditionally, explained, with, vicariance, or, geodispersal, hypotheses, and, increasingly, with, 'long-distance', dispersal])].
[sujeto(['A', molecular, phylogeographic, study, based, on, the]), verbo([nuclear]), complemento([ribosomal, 'ITS', region, and, plastid, 'trnL-F,', 'rps16,', and, 'trnS-G', sequences, was, done, to, clarify, the, origin, of, this, tropical, intercontinental, disjunction])].
[sujeto(['Our', data]), verbo([suggest]), complemento([ancient, 'long-distance', dispersal, from, the, 'Old', to, the, 'New', 'World', probably, during, the, 'Pliocene', or, 'Upper', 'Miocene'])].
[sujeto([and, other, related, 'Anacardiaceae,', as, well, as, the, 'PCR', protocols, for, 'DNA', amplification, of, the, chloroplast, 'trnL-F,', rps16, and, ndhF, and]), verbo([nuclear]), complemento(['ITS-ETS', fragments])].
[sujeto(['The', vast, 'Australian', arid, zone, formed, over, the, last, 15, million, 'years,', and, gradual, aridification, as, well, as, more, extreme, 'Pliocene', and, 'Pleistocene', climate, shifts]), verbo([have]), complemento([impacted, the, evolution, of, its, biota])].
[sujeto(['Understanding', the, evolutionary, history, of, groups, of, organisms, or, regional, biotas, such, as, the, 'Australian', arid, biota]), verbo([requires]), complemento([clear, delimitation, of, the, units, of, biodiversity, '(', 'taxa)'])].
[sujeto(['Here', we, integrate, evidence, from]), verbo([nuclear]), complemento(['(', 'ETS', and, 'ITS)', and, chloroplast, '(', 'rps16-trnK', 'spacer)', regions, and, morphology, to, clarify, taxonomic, boundaries, in, a, species, complex, of, 'Australian', hummock, grasses, '(', 'Triodia)', to, better, understand, the, evolution, of, 'Australian', arid, zone, plants, and, to, evaluate, congruence, in, distribution, patterns, with, 'co-occurring', organisms])].
[sujeto(['We']), verbo([find]), complemento([evidence, for, multiple, new, taxa, in, the, 'T'])].
[sujeto(['We']), verbo([find]), complemento([that, the, 'T'])].
[sujeto([basedowii, complex]), verbo([has]), complemento([high, lineage, diversity, and, endemism, in, the, biologically, important, 'Pilbara', region, of, 'Western', 'Australia,', consistent, with, the, region, acting, as, a, refugium])].
[sujeto(['Taxa', show, strong, geographic, structure, in, the, 'Pilbara,', congruent, with, recent, work, on, 'co-occurring', animals, and]), verbo([suggesting]), complemento([common, evolutionary, drivers, across, the, biota])].
[sujeto(['Our', findings, confirm, recognition, of, the, 'Pilbara', as, an, important, centre, of, biodiversity, in, the, 'Australian', arid, 'zone,', and]), verbo([provide]), complemento([a, basis, for, future, taxonomic, revision, of, the, 'T'])].
[sujeto(['The', infrageneric, taxonomy, of, the, genus]), verbo([has]), complemento([historically, been, troublesome, due, to, morphological, variability, and, putative, convergent, evolution, within, the, genus])].
[sujeto(['Phylogenetic', analyses, using, the]), verbo([nuclear]), complemento([ribosomal, internal, transcribed, spacer, '(', 'ITS)', and, five, plastid, regions, '(', 'matK,', 'rbcL,', 'rps16,', 'trnH-psbA,', 'trnL-F),', confirmed, the, monophyly, of, 'Pogostemon', and, its, sister, relationship, with, the, genus, 'Anisomeles'])].
[sujeto(['Molecular', dating, and, biogeographic, diversification, analyses]), verbo([suggest]), complemento([that, 'Pogostemon', split, from, its, sister, genus, in, southern, and, southeast, 'Asia', in, the, early, 'Miocene'])].
[sujeto(['The', early, strengthening, of, the, 'Asia', monsoon, system, that, was]), verbo([triggered]), complemento([by, the, uplifting, of, the, 'Qinghai-Tibetan', 'Plateau', may, have, played, an, important, role, in, the, subsequent, diversification, of, the, genus])].
[sujeto(['In', 'addition,', our, results]), verbo([suggest]), complemento([that, transoceanic, 'long-distance', dispersal, of, 'Pogostemon', from, 'Asia', to, 'Africa', occurred, at, least, 'twice,', once, in, the, late, 'Miocene', and, again, during, the, 'late-Miocene/early-Pliocene'])].
[sujeto(['The', barley, chloroplast, mutator, '(', 'cpm)', is, an, allele, of, a]), verbo([nuclear]), complemento([gene, that, when, homozygous, induces, several, types, of, cytoplasmically, inherited, chlorophyll, deficiencies])].
[sujeto(['Besides,', 4, large, indels, that]), verbo([have]), complemento([direct, repeats, at, both, ends, were, also, 'observed,', which, appear, to, be, originated, from, recombinational, events])].
[sujeto(['The', cpm, mutation, spectrum]), verbo([suggests]), complemento([that, the, 'CPM', gene, product, is, probably, involved, in, plastome, mismatch, repair])].
[sujeto(['Moreover,', the, cpm, mutant, appears, to, be, an, interesting, experimental, material, for, investigating, the, mechanisms, responsible, for]), verbo([maintaining]), complemento([the, stability, of, plant, organelle, 'DNA'])].
[sujeto(['Previous', studies]), verbo([have]), complemento([shown, that, species, delimitation, in, the, genus, is, 'problematic,', but, have, not, yet, explored, the, evolutionary, history, of, the, genus])].
[sujeto(['Premating', reproductive, barriers, between, 'European', species, appear, to, be, 'weak,', as, several, species]), verbo([have]), complemento([strongly, overlapping, distribution, 'areas,', flower, at, the, same, time, and, share, the, same, 'pollinators,', suggesting, that, hybridization, may, have, contributed, to, the, evolutionary, history, of, 'Pulmonaria'])].
[sujeto(['To', test, this, 'hypothesis,', phylogenetic, analyses, of]), verbo([nuclear]), complemento(['ITS', and, plastid, data, '(', 'rps16,', 'trnH-psbA,', 'rpl16)', from, 48, allopatric, and, four, sympatric, populations, were, performed, to, '(', 1, ')', provide, a, molecular, phylogeny, for, nine, of, the, most, common, 'Pulmonaria', species, in, 'Europe,', '(', 2, ')', detect, current, and, ancient, hybridization, 'events,', and, '(', 3, ')', assess, the, contribution, of, hybridization, versus, incomplete, lineage, sorting, to, the, inferred, phylogenetic, patterns])].
[sujeto(['Our', results, showed, that, gene, trees, displayed, 'widespread,', strongly, supported, incongruence]), verbo([associated]), complemento([with, the, conflicting, position, of, hybrid, samples, rather, than, incomplete, lineage, sorting])].
[sujeto(['Evidence', was]), verbo([found]), complemento([of, different, degrees, of, 'hybridization,', ranging, from, current, interspecific, gene, flow, at, secondary, contact, zones, to, introgression, at, the, population, level, and, at, least, one, event, of, hybrid, speciation])].
[sujeto(['Overall,', these, results]), verbo([suggest]), complemento([that, hybridization, and, introgression, were, -, and, could, still, be, -, important, processes, affecting, speciation, in, the, genus, 'Pulmonaria'])].
[sujeto([involucrata]), verbo([provides]), complemento([essential, and, important, 'DNA', molecular, data, for, further, phylogenetic, and, evolutionary, analysis, for, 'Asteraceae'])].
[sujeto(['Here', we]), verbo([report]), complemento([the, complete, chloroplast, '(', 'cp)', genome, sequence, of, 'G'])].
[sujeto(['The', rps16, gene, lacks, exon2, between, 'trnK-UUU', and, 'trnQ-UUG,', which, is, the, first, rps16, pseudogene]), verbo([found]), complemento([in, the, nonparasitic, plants, of, 'Asterids', clade])].
[sujeto(['The', complete, chloroplast, genome, sequence, will]), verbo([provide]), complemento([intragenic, information, for, its, conservation, and, contribute, to, research, on, the, genetic, and, phylogenetic, analyses, of, 'Gentianales', and, 'Asterids'])].
[sujeto(['Here', we, conduct, phylogenetic, analysis, with, the]), verbo([nuclear]), complemento([marker, 'ITS', and, three, different, chloroplast, markers, '(', rps16, 'intron,', 'rbcL-atpB', 'spacer,', 'rpl32-trnL', 'spacer)'])].
[sujeto(['They']), verbo([have]), complemento([their, origins, in, the, mid, 'Miocene', in, 'East', 'Asia', and, were, highly, influenced, by, the, climate, fluctuations, in, the, 'Pliocene/Pleistocene', period])].
[sujeto(['Conflicting', tree, topologies, between]), verbo([nuclear]), complemento([and, cpDNA, markers, of, 'Allium', tricoccum, 'Solander', indicate, that, the, species, is, of, hybridogenous, origin])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, 'Allium', victorialis, 'L'])].
[sujeto(['In', the, analysis, of, the, molecular, markers, we]), verbo([found]), complemento([two, distinct, types, of, 'Allium', ochotense, 'Prokh'])].
[sujeto([and, we]), verbo([suggest]), complemento([splitting, the, species, based, on, 'Prokhanov\'s', '(', 1930, ')', proposal])].
[sujeto(['Diverticular', inflammation, and, complication, assessment, '(', 'DICA)', endoscopic, classification]), verbo([has]), complemento([been, recently, developed, for, patients, suffering, from, diverticulosis, and, diverticular, disease])].
[sujeto(['For', each, 'patient,', the, following, parameters, were, 'recorded:', 'age,', severity, of, 'DICA,', presence, of, abdominal, 'pain,', 'C-reactive', 'protein,', fecal, calprotectin, test, '(', if, 'available)', at, the, time, of, 'diagnosis,', months, of, 'follow-up,', therapy, taken, during, the, 'follow-up', to]), verbo([maintain]), complemento([remission, '(', if, 'any),', 'occurrence/recurrence', of, 'diverticulitis,', and, need, of, surgery])].
[sujeto(['DICA', was, the, only, factor, significantly]), verbo([associated]), complemento([with, the, 'occurrence/recurrence', of, diverticulitis, and, surgery, either, at, univariate, '(', 'χ=405'])].
[sujeto(['Structured', 'frameworks,', such, as, the, 'Standards', for, 'Quality', 'Improvement', 'Reporting', 'Excellence', '(', 'SQUIRE)', 'guidelines,']), verbo([provide]), complemento([guidance, in, the, 'design,', 'planning,', and, dissemination, of, interventions, designed, to, improve, care, through, 'co-production', and, 'co-learning', strategies])].
[sujeto(['Most', 'gynecologists,', whether, or, not, they, are, 'objectors,', proved, to]), verbo([have]), complemento([a, &, 'quot;loyalty', to, 'duty,"', fulfilling, their, primary, obligation, to, abide, by, the, ethical, duty, to, give, treatment, to, the, persons, who, need, it])].
[sujeto(['Selective', upper, airway, stimulation]), verbo([has]), complemento([been, established, as, an, additional, treatment, for, obstructive, sleep, apnea, '(', 'OSA)'])].
[sujeto(['A', direct, approach, to, the, distal, hypoglossal, nerve]), verbo([has]), complemento([been, established, to, achieve, this, goal])].
[sujeto(['Another', decisive, step, is, the, placement, of, the, sensing]), verbo([lead]), complemento([between, the, intercostal, muscles])].
[sujeto(['The', aim, of, this, article, is, to]), verbo([provide]), complemento([the, latest, knowledge, on, the, neuroanatomy, of, the, hypoglossal, nerve, and, to, give, surgeons, a, 'step-by-step', guide, on, the, current, operative, technique])].
[sujeto(['The', recent, approval, of, 'liraglutide,', 'lorcaserin,', 'naltrexone/bupropion', 'extended-release,', and, 'phentermine/topiramate', 'extended-release,', brings, the, number, of, medications, for, 'long-term', weight]), verbo([loss]), complemento([to, 5, '(', including, 'orlistat)'])].
[sujeto(['Indicated', for, the, treatment, of, patients, with, overweight, '(', body, mass, index, '[', 'BMI]', '≥27', 'kg/m2', with, '≥1', 'weight-related', 'comorbidity)', or, obesity, '(', 'BMI', '≥30', 'kg/m2),', these, medications]), verbo([provide]), complemento([new, opportunities, to, address, this, burgeoning, health, problem])].
[sujeto(['Child', 'marriage,', defined, as, marriage, before, the, age, of, 18, 'years,', is, a, human, rights, violation, that, can]), verbo([have]), complemento([lasting, adverse, educational, and, economic, impacts])].
[sujeto(['Six']), verbo([found]), complemento([positive, results, in, decreasing, the, proportion, married, or, increasing, age, at, 'marriage,', one, had, both, positive, and, negative, 'findings,', and, four, had, no, statistical, impact, on, the, proportion, married, or, age, at, marriage])].
[sujeto(['There', is, wide, range, of, 'high-quality,', impactful, interventions, included, in, this, review, which, can, inform, 'researchers,', 'donors,', and, policy, makers, about, where, to, make, strategic, investments, to, eradicate, 'marriage,', a, current]), verbo([target]), complemento([of, the, 'Sustainable', 'Development', 'Goals'])].
[sujeto(['Despite', the, cultural, factors, that]), verbo([promote]), complemento([child, 'marriage,', the, diversity, of, interventions, can, allow, decision, makers, to, tailor, interventions, to, the, cultural, context, of, the, target, population])].
[sujeto(['While', aberrant, 'JAK/STAT', signaling, is, crucial, to, the, development, of, gastric, cancer, '(', 'GC),', its, effects, on, epigenetic, alterations, of, its, transcriptional]), verbo([targets]), complemento([remains, unclear])].
[sujeto(['In', this, 'study,', by, expression, microarrays, coupled, with, bioinformatic, 'analyses,', we, identified, a, putative, 'STAT3']), verbo([target]), complemento(['gene,', 'NR4A3', that, was, downregulated, in, 'MKN28', 'GC', daughter, cells, overexpressing, a, constitutively, activated, 'STAT3', mutant, '(', 'S16),', as, compared, to, an, empty, vector, control, '(', 'C9)'])].
[sujeto(['Subsequent', experiments, revealed, that, 'NR4A3', promoter]), verbo([binding]), complemento([by, 'STAT3', might, repress, its, transcription])].
[sujeto(['NR4A3', 're-expression', in, 'GC', cell, lines, sensitized, the, cells, to, 'cisplatin,', and]), verbo([inhibited]), complemento([tumor, growth, in, vitro, and, in, 'vivo,', in, an, animal, model])].
[sujeto(['Intriguingly,', 'STAT3', activation, significantly]), verbo([associated]), complemento([only, with, 'NR4A3', methylation, in, 'low-stage', patient, samples])].
[sujeto(['For', a, long, 'time,', shallots]), verbo([have]), complemento([been, used, as, a, source, of, food, and, medicine, in, 'Iran'])].
[sujeto(['Subsequently,', the, findings, were, 'reviewed,', 'classified,', and]), verbo([reported]), complemento([in, a, tabular, format])].
[sujeto(['Depending', on, its, natural, 'habitats,', shallots]), verbo([have]), complemento([different, pharmacological, effects, for, which, many, usages, are, mentioned, in, traditional, medicine])].
[sujeto(['Some', of, these, effects]), verbo([have]), complemento([been, investigated, in, modern, 'medicine;', 'however,', further, evaluation, of, its, safety, and, dosages, for, clinical, use, is, necessary])].
[sujeto(['Furthermore,', some, cases]), verbo([have]), complemento([not, been, studied, in, modern, 'medicine,', which, could, be, the, basis, for, future, research])].
[sujeto(['These', are, clonal, diseases, resulting, from, the, transformation, of, an, hematopoietic, stem, cell, and]), verbo([leading]), complemento([to, an, abnormal, production, of, myeloid, cells])].
[sujeto(['Among', 'them,', 'JAK2,', the, thrombopoietin, receptor, '(', 'MPL)', and, calreticulin, '(', 'CALR)', mutations, are]), verbo([found]), complemento([in, around, 90, '%', of, the, cases])].
[sujeto(['These', driver, 'MPN', mutations, can, be]), verbo([associated]), complemento([with, other, driver, mutations, also, found, in, other, hematological, 'malignancies,', especially, in, 'PMFs'])].
[sujeto(['Most', recent, therapeutic]), verbo([have]), complemento([focused, on, targeting, the, 'JAK2', signaling, pathway, directly, by, inhibitors, of, 'JAK2', or, indirectly])].
[sujeto(['We', used, 'WGS', to, characterize, the, chromosomal, and, plasmid, molecular, epidemiology, of, 'NDM', transmission]), verbo([involving]), complemento([four, institutions, in, 'Singapore'])].
[sujeto(['In', six, '(', 18, '%', ')', 'isolates,', a, novel, 'blaNDM-positive', 'plasmid,', 'pSg1-NDM,', was]), verbo([found]), complemento([only, in, 'K'])].
[sujeto(['The', largest, 'inter-institution', cluster]), verbo([involved]), complemento([six, 'K'])].
[sujeto(['Fifteen', patients, were]), verbo([involved]), complemento([in, transmission, 'clusters,', of, which, four, had, ward, 'contact,', six, had, hospital, contact, and, five, had, an, unknown, transmission, link])].
[sujeto(['The', 4, th, 'Global', 'Forum', on, 'TB', 'Vaccines,', convened, in, 'Shanghai,', 'China,', from, 21, -, 24, 'April', 2015, ',', brought, together, a, wide, and, diverse, community]), verbo([involved]), complemento([in, tuberculosis, vaccine, research, and, development, to, discuss, the, current, status, 'of,', and, future, directions, for, this, critical, effort])].
[sujeto(['Since', the, introduction, of, sutureless, securement, products, for, vascular, access, devices, '(', 'VADs),', there]), verbo([has]), complemento([been, a, great, deal, of, discussion, of, their, advantages, and, disadvantages, in, comparison, with, sutures])].
[sujeto(['Evaluation', forms]), verbo([have]), complemento([been, provided, and, filled, in, by, the, practitioners])].
[sujeto(['The', results, showed, that, the, trialled, product, is, perceived, as, 'user-and', 'patient-friendly,', resulting, in]), verbo([increased]), complemento([security, of, 'VAD', and, easier, handling, compared, to, the, current, devices])].
[sujeto(['Overall,', 70, '%', of, the, evaluators, stated, that, the, trialled, product]), verbo([has]), complemento([better, or, much, better, overall, performance])].
[sujeto(['Schwann', cells, are, the, myelinating, glia, of, the, peripheral, nervous, system, and, dysfunction, of, these, cells]), verbo([causes]), complemento([motor, and, sensory, peripheral, neuropathy])].
[sujeto(['The', transcription, factor, 'SOX10', is, critical, for, 'Schwann', cell, development, and, 'maintenance,', and, many, 'SOX10']), verbo([target]), complemento([genes, encode, proteins, required, for, 'Schwann', cell, function])].
[sujeto(['Loss-of-function', mutations, in, the, gene, encoding, myotubularin, related, protein, 2, '(', 'MTMR2)']), verbo([cause]), complemento(['Charcot-Marie-Tooth', disease, type, 4, 'B1', '(', 'CMT4B1),', a, severe, demyelinating, peripheral, neuropathy, characterized, by, myelin, outfoldings, along, peripheral, nerves])].
[sujeto(['Previous']), verbo([reports]), complemento([indicate, that, 'MTMR2', is, ubiquitously, expressed, making, it, unclear, how, loss, of, this, gene, causes, a, 'Schwann', 'cell-specific', phenotype])].
[sujeto(['The', expression, of, the, endogenous, transcript, is]), verbo([induced]), complemento([in, a, heterologous, cell, line, by, ectopically, expressing, 'SOX10,', and, is, nearly, ablated, in, 'Schwann', cells, by, impairing, 'SOX10', function])].
[sujeto(['Intriguingly,', overexpressing, the, two, 'MTMR2', protein, isoforms, in, 'HeLa', cells, revealed, that, both, localize, to]), verbo([nuclear]), complemento([puncta, and, the, shorter, isoform, displays, higher, nuclear, localization, compared, to, the, longer, isoform])].
[sujeto(['Tumor']), verbo([associated]), complemento([macrophages, '(', 'TAMs)', are, a, major, stromal, component, of, the, tumor, microenvironment, in, several, cancers])].
[sujeto(['TAMs', are, a, potential]), verbo([target]), complemento([for, adjuvant, cancer, therapies, due, to, their, established, roles, in, promoting, proliferation, of, cancer, 'cells,', 'angiogenesis,', and, metastasis])].
[sujeto(['We', previously, discovered, an, 'M2', 'macrophage-targeting', peptide, '(', 'M2pep)', which, was, successfully, used, to]), verbo([target]), complemento([and, deliver, a, 'pro-apoptotic', 'KLA', peptide, to, 'M2-like', 'TAMs', in, a, 'CT-26', colon, carcinoma, model])].
[sujeto(['However,', the, effectiveness, of, in, vivo, 'TAM-targeting', using, 'M2pep', is, limited, by, its, poor, serum, stability, and, low]), verbo([binding]), complemento([affinity])].
[sujeto(['In', this, 'study,', we, synthesized, 'M2pep', derivatives, with, the, goals, of]), verbo([increasing]), complemento([serum, stability, and, binding, affinity])].
[sujeto(['However,', no, tested, amino, acid, changes, at, the, 'W10', position, resulted, in, both, protease, resistance, at, that, site, and, retention, of]), verbo([binding]), complemento([activity])].
[sujeto(['Cyclized', 'M2pep', better, resisted, serum, degradation, without, compromising]), verbo([binding]), complemento([activity, to, 'M2', macrophages])].
[sujeto(['During', the, serum, stability, optimization, 'process,', we, also, discovered, that, 'K9R', and, 'W10Y', substitutions, significantly]), verbo([enhanced]), complemento([binding, affinity, of, 'M2pep'])].
[sujeto(['In', an, in, vitro]), verbo([binding]), complemento([study, of, different, 'M2pep', analogs, 'pre-incubated', in, mouse, 'serum,', cyclic, 'M2pep', with, 'K9R', and, 'W10Y', modifications, '(', cyclic, 'M2pep(RY))', retained, the, highest, binding, activity, to, 'M2', macrophages, over, time, due, to, its, improved, serum, stability])].
[sujeto(['In', 'conclusion,', we]), verbo([report]), complemento([cyclic, 'M2pep(RY)', as, our, lead, 'M2pep', analog, with, improved, serum, stability, and, 'M2', 'macrophage-binding', activity])].
[sujeto(['Its']), verbo([enhanced]), complemento([utility, as, an, in, vivo, 'M2-like-TAM-targeting', agent, was, demonstrated, in, two, tumor, 'models,', and, is, expected, to, be, applicable, for, other, tumor, models, or, in, models, of, 'M2', 'macrophage-related', diseases])].
[sujeto(['We', used, patterns, of, variation, in, 30]), verbo([nuclear]), complemento([and, two, mitochondrial, 'SNPs', to, examine, the, factors, that, could, be, involved, in, stabilizing, clines, across, a, hybrid, zone, between, two, subspecies, of, the, 'Atlantic', 'killifish,', 'Fundulus', heteroclitus])].
[sujeto(['Increased', heterozygote, deficit, and, cytonuclear, disequilibrium, in, populations, near, the, center, of, the, mtDNA, cline]), verbo([suggest]), complemento([that, some, form, of, reproductive, isolation, such, as, assortative, mating, or, selection, against, hybrids, may, be, acting, in, this, hybrid, zone])].
[sujeto(['However,', only, a, small, number, of, loci, exhibited, these, 'signatures,']), verbo([suggesting]), complemento(['locus-specific,', rather, than, 'genomewide,', factors])].
[sujeto(['Seven', of, the, 12, putatively, 'non-neutral']), verbo([nuclear]), complemento([clines, were, for, 'SNPs', in, genes, related, to, oxidative, metabolism])].
[sujeto(['Among', these, putatively, 'non-neutral']), verbo([nuclear]), complemento(['clines,', 'SNPs', in, two, 'nuclear-encoded', mitochondrial, genes, '(', 'SLC25A3', and, 'HDDC2),', as, well, as, 'SNPs', in, the, 'myoglobin,', 40, 'S', ribosomal, protein, 'S17,', and, 'actin-binding', 'LIM', protein, 'genes,', had, clines, that, were, coincident, and, concordant, with, the, mitochondrial, clines])].
[sujeto(['When', hybrid, index, was, calculated, using, this, subset, of, 'loci,', the, frequency, distribution, of, hybrid, indices, for, a, population, located, at, the, mtDNA, cline, center, was, 'non-unimodal,']), verbo([suggesting]), complemento([selection, against, 'advanced-generation', 'hybrids,', possibly, due, to, effects, on, processes, involved, in, oxidative, metabolism])].
[sujeto(['The', mitochondrial, 45, 'S', 'SSU*', complex, in, 'Trypanosoma', brucei, contains, the, 9, 'S', 'SSU', ribosomal, 'RNA,', a, set, of, 'SSU', ribosomal, 'proteins,', several, pentatricopeptide, repeat, '(', 'PPR)', 'proteins,', and, proteins, not, typically]), verbo([found]), complemento([in, 'ribosomes,', including, rhodanese, domain, protein, '(', 'Rhod)', and, a, 200, -, kDa, 'coiled-coil', protein])].
[sujeto(['On', the, 'contrary,', the, 'down-regulation', of, mitochondrial, ribosomal, protein, 'L3', drastically, reduced, the, amount, of, the, large, subunit, and, indiscriminately]), verbo([inhibited]), complemento([mitochondrial, translation])].
[sujeto(['We', propose, that, the, 45, 'S', 'SSU*', complex, represents, a, factor]), verbo([required]), complemento([for, normal, mitochondrial, translation, that, may, have, selective, effects, on, different, mRNAs])].
[sujeto(['We']), verbo([report]), complemento([on, a, 27, &, 'nbsp;month', old, boy, presenting, with, psychomotor, delay, and, dysmorphic, 'features,', mainly, mild, facial, 'asymmetry,', prominent, 'cup-shaped', 'ears,', long, 'eyelashes,', open, mouth, appearance, and, slight, abnormalities, of, the, hands, and, feet])].
[sujeto(['Based', on, current, knowledge, and, the, de, novo, occurrence, of, this]), verbo([finding]), complemento([in, our, proband, we, presume, that, the, aberration, is, likely, to, be, pathogenic, in, our, case])].
[sujeto(['Further', elucidation, of, the, properties, of, this, chromosomal, 'region,', as, well, as, of, the, role, of, the, genes]), verbo([involved]), complemento([will, be, needed, in, order, to, draw, safe, conclusions, regarding, the, association, of, the, chromosomal, deletion, with, the, 'patient\'s', features])].
[sujeto(['Sporulation', in, the, yeast, 'Saccharomyces', cerevisiae, is, a, complex, and, tightly]), verbo([regulated]), complemento([pathway, that, involves, the, induction, of, a, large, number, of, genes])].
[sujeto(['We']), verbo([have]), complemento([identified, 'MRPS17', in, a, cDNA, library, enriched, for, 'sporulation-specific', genes])].
[sujeto(['Homology', searches, show, that, the, first, 'one-third', of, 'Mrps17']), verbo([has]), complemento([strong, sequence, similarity, to, bacterial, 'S17', 'proteins,', suggesting, that, 'Mrps17', is, a, potential, mitochondrial, ribosomal, protein])].
[sujeto(['We']), verbo([have]), complemento([confirmed, by, 'Northern', blot, analysis, that, both, 'MRPS17', and, 'MRPL37', are, strongly, induced, during, the, middle, stages, of, sporulation, and, that, this, induction, is, dependent, on, the, presence, of, a, middle, sporulation, element, '(', 'MSE)', in, the, promoters, of, these, genes])].
[sujeto(['Interestingly,', we]), verbo([found]), complemento([that, 'Mrps17', and, 'Mrpl37,', but, not, other, mitochondrial, ribosomal, 'proteins,', accumulate, during, the, middle, stages, of, sporulation])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'Mrps17', and, 'Mrpl37', may, have, additional, 'meiosis-specific', roles])].
[sujeto(['Mitochondrial', ribosomal, proteins, '(', 'mrps)', of, the, budding, 'yeast,', 'Saccharomyces', 'cerevisiae,']), verbo([have]), complemento([been, extensively, characterized, genetically, and, biochemically])].
[sujeto(['We']), verbo([have]), complemento([constructed, a, yeast, strain, in, which, one, of, the, small, subunit, 'proteins,', termed, 'Mrp4,', was, tagged, with, 'S-peptide', and, used, for, affinity, purification, of, mitochondrial, ribosome])].
[sujeto(['Thus,', we]), verbo([have]), complemento([newly, established, 'Ymr158w', '(', 'MrpS8),', 'Ypl013c', '(', 'MrpS16),', 'Ymr188c', '(', 'MrpS17)', and, 'Ygr165w', '(', 'MrpS35)', as, small, subunit, mrps, and, 'Img1,', 'Img2,', 'Ydr116c', '(', 'MrpL1),', 'Ynl177c', '(', 'MrpL22),', 'Ynr022c', '(', 'MrpL50)', and, 'Ypr100w', '(', 'MrpL51)', as, large, subunit, mrps])].
[sujeto(['With', the]), verbo([increasing]), complemento([number, of, 'genome-wide', 'studies,', accurate, analyses, of, quantitative, gene, expression, during, development, are, impeded, by, the, lack, of, validated, reference, genes])].
[sujeto(['To', improve, the, 'situation,', in, this, 'study,', we, analyzed, the, expression, stability, of, seven, candidate, housekeeping, genes, during, early, development, of, the, 'Pacific', oyster, 'Crassostrea', 'gigas:', 'actin,', 'glyceraldehyde-3', 'phosphate-dehydrogenase', '(', 'gapdh),', α, subunit, of, elongation, factor, 1, '(', 'elf1α),', 'adp-ribosylation', factor, 1, '(', 'arf1),', heterogeneous]), verbo([nuclear]), complemento([ribonucleoprotein, 'q,', 'ubiquitin-conjugating', enzyme, e2d2, and, ribosomal, protein, s18])].
[sujeto(['Endometrial', cancer, '(', 'EC)', is, one, of, the, most, frequent]), verbo([causes]), complemento([of, cancer, death, among, women, in, developed, countries])].
[sujeto(['In', the, present, paper, we, showed, that, the, level, of, mitochondrial, ribosomal, protein, 'MRPS18-2', '(', 'S18-2)']), verbo([increased]), complemento([in, 'EC', compared, with, the, normal, endometrium, and, 'hyperplasia,', based, on, a, study, of, 42, patient, biopsies])].
[sujeto(['The', 'EC', cell, line, 'HEC-1-A,', which, overexpresses, 'S18-2', 'constitutively,', showed, an]), verbo([increased]), complemento([proliferation, capacity, in, vitro, and, in, vivo, '(', in, 'SCID', 'mice)'])].
[sujeto(['This', may, be]), verbo([associated]), complemento([with, 'epithelial-mesenchymal', cell, transition, '(', 'EMT)'])].
[sujeto(['For', a, better, control, 'strategy,', various, genetic, studies]), verbo([have]), complemento([been, conducted, using, 'reverse-transcription', quantitative, 'real-time', polymerase, chain, reaction, '(', 'qRT-PCR)'])].
[sujeto(['The', appropriate, application, of, 'qRT-PCR']), verbo([requires]), complemento([reliable, endogenous, 'controls;', 'however,', studies, on, this, aspect, of, the, 'white-backed', planthopper, are, lacking])].
[sujeto(['These', results, will]), verbo([provide]), complemento([a, solid, foundation, for, future, gene, expression, study, on, the, 'white-backed', 'planthopper,', and, also, will, give, aids, in, establishing, a, standardized, 'qRT-PCR', procedure, for, other, related, insects])].
[sujeto(['More', than, half, of, the, ribosomal, protein, operons, in, 'Escherichia', coli, are]), verbo([regulated]), complemento([by, structures, within, the, mRNA, transcripts, that, interact, with, specific, ribosomal, proteins, to, inhibit, further, protein, expression])].
[sujeto(['This', regulation, is, accomplished, using, a, variety, of, mechanisms, and, the, 'RNA', structures, responsible, for, regulation, are, often, not]), verbo([conserved]), complemento([across, bacterial, phyla])].
[sujeto(['A', widely]), verbo([conserved]), complemento([mRNA, structure, preceding, the, ribosomal, protein, operon, containing, rpsF, and, rpsR, '(', encoding, 'S6', and, 'S18)', was, recently, identified, through, comparative, genomics])].
[sujeto([coli, and, 'Bacillus', subtilis, were, shown, to]), verbo([interact]), complemento([in, vitro, with, an, 'S6:S18', complex])].
[sujeto(['coli,', this, 'RNA', structure]), verbo([regulates]), complemento([gene, expression, in, response, to, the, 'S6:S18', complex])].
[sujeto(['Measurement', of, transcript, levels, shows, that, although, reporter, levels, do, not, change, upon, protein, 'overexpression,', levels, of, the, native, transcript, are, reduced, 'fourfold,']), verbo([suggesting]), complemento([that, the, mRNA, regulator, prevents, translation, and, this, effect, is, amplified, on, the, native, transcript, by, other, mechanisms])].
[sujeto(['We']), verbo([have]), complemento([shown, earlier, that, overexpression, of, the, human, mitochondrial, ribosomal, protein, 'MRPS18-2', '(', 'S18-2)', led, to, immortalization, of, primary, rat, embryonic, fibroblasts])].
[sujeto(['The', derived, cells]), verbo([expressed]), complemento([the, embryonic, stem, cell, 'markers,', and, cellular, pathways, that, control, cell, 'proliferation,', oxidative, 'phosphorylation,', cellular, 'respiration,', and, other, redox, reactions, were, activated, in, the, immortalized, cells])].
[sujeto(['Here', we]), verbo([report]), complemento(['that,', upon, overexpression, of, 'S18-2', 'protein,', primary, rat, skin, fibroblasts, underwent, cell, transformation])].
[sujeto(['Transformed', cells, showed, 'anchorage-independent', growth, and]), verbo([loss]), complemento([of, contact, 'inhibition;', they, expressed, epithelial, 'markers,', such, as, 'E-cadherin', and, 'β-catenin'])].
[sujeto(['Transformed', cells, showed]), verbo([increased]), complemento([telomerase, 'activity,', disturbance, of, the, cell, 'cycle,', and, chromosomal, instability])].
[sujeto(['Taken', 'together,', our, data]), verbo([suggest]), complemento([that, 'S18-2', is, a, newly, identified, oncoprotein, that, may, be, involved, in, cancerogenesis])].
[sujeto(['The', 'Mycobacterium', tuberculosis, genome, encodes, five, putative, '\'', 'alternative\'', ribosomal, proteins, whose, expression, is]), verbo([repressed]), complemento([at, high, 'Zn(2+)', concentration])].
[sujeto(['Each', alternative, protein]), verbo([has]), complemento([a, primary, homologue, that, is, predicted, to, bind, 'Zn(2+)'])].
[sujeto(['We', hypothesized, that, zinc]), verbo([triggers]), complemento([a, switch, between, these, paired, homologous, proteins, and, therefore, chose, one, of, these, 'pairs,', 'S18-1/S18-2,', to, study, mechanisms, of, the, predicted, competition, for, their, incorporation, into, ribosomes])].
[sujeto(['Our', data, show, that, 'Zn(2+)-depletion']), verbo([causes]), complemento([accumulation, of, both, 'S18-2', mRNA, and, protein])].
[sujeto(['We', further, demonstrate, that, both, 'S18', proteins]), verbo([interact]), complemento([with, ribosomal, protein, 'S6,', a, committed, step, in, ribosome, biogenesis])].
[sujeto(['Zn(2+)', is, absolutely]), verbo([required]), complemento([for, the, 'S18-1/S6', interaction, while, it, is, dispensable, for, 'S18-2/S6', dimer, formation])].
[sujeto(['These', data]), verbo([suggest]), complemento([a, model, in, which, 'S18-1', is, the, dominant, ribosome, constituent, in, high, zinc, 'conditions,', e])].
[sujeto([tuberculosis, is]), verbo([released]), complemento([from, 'macrophages,', to, allow, survival, in, the, extracellular, environment])].
[sujeto(['We', explored, the]), verbo([cause]), complemento([of, cell, growth, inhibition, by, antisense, 'RNA', mediated, nonessential, gene, silencing, of, rpsF, gene, in, 'Escherichia', coli])].
[sujeto(['Antisense', 'RNA', expression, was]), verbo([induced]), complemento([by, 'isopropyl-beta-D-thiogalactopyranoside', '(', 'IPTG),', the, difference, of, liquid, growth, phenotype, was, identified, between, 'E'])].
[sujeto(['We', obtained, one, antisense, 'RNA', strain]), verbo([targeted]), complemento([rpsF])].
[sujeto(['We']), verbo([found]), complemento([that, the, reduced, growth, rate, of, this, strain, was, positively, related, to, the, 'IPTG', concentration])].
[sujeto(['When', 'IPTG', was, 100, 'micromol/L,', the, cell, growth, was, not]), verbo([inhibited]), complemento([whereas, the, mRNA, amount, of, rpsF, had, decreased, by, 36, '%', ',', and, mRNA, of, essential, gene, rpsR, in, the, same, operon, did, not, decayed])].
[sujeto(['However,', when, 'IPTG', reached, 200, 'micromol/L,', the, cell, growth, was, obviously]), verbo([inhibited]), complemento([and, rpsR, mRNA, was, reduced, by, 12, '%'])].
[sujeto(['The', essential, gene, transcription, level, of, rpsR]), verbo([decreases]), complemento([with, the, nonessential, gene, silencing, of, rpsF, in, the, same, 'operon,', and, leads, to, the, growth, inhibition, of, 'E'])].
[sujeto(['Approximately', half, the, transcripts, encoding, ribosomal, proteins, in, 'Escherichia', coli, include, a, structured, 'RNA', motif, that]), verbo([interacts]), complemento([with, a, specific, ribosomal, protein, to, inhibit, gene, 'expression,', thus, allowing, stoichiometric, production, of, ribosome, components])].
[sujeto(['It', is, increasingly, common, for, 'RNA', motifs]), verbo([associated]), complemento([with, ribosomal, protein, genes, to, be, identified, using, comparative, genomic, 'methods,', yet, these, are, rarely, experimentally, validated])].
[sujeto([subtilis, and, an, 'S6:S18', complex, using, in, vitro]), verbo([binding]), complemento(['assays,', verify, our, predicted, secondary, 'structure,', and, identify, a, putative, 'protein-binding', site])].
[sujeto(['The', proposed]), verbo([binding]), complemento([site, bears, a, strong, resemblance, to, the, 'S18', binding, site, within, the, 16, 'S', 'rRNA,', suggesting, molecular, mimicry])].
[sujeto(['This', work, shows, how, experimental, verification]), verbo([translates]), complemento([computational, results, into, concrete, knowledge, of, biological, systems])].
[sujeto(['Cold', exposure, and, 'β3-adrenergic', receptor, agonist, '(', 'CL316,243)', treatment]), verbo([induce]), complemento([the, production, of, beige, 'cells,', which, express, brown, 'adipocytes(BA)-specific', 'UCP1', 'protein,', in, white, adipose, tissue, '(', 'WAT)'])].
[sujeto(['It', remains, unclear, whether, the, beige, 'cells,', which]), verbo([have]), complemento([different, gene, expression, patterns, from, 'BA,', express, 'BA-characteristic', fatty, acid, oxidation, '(', 'FAO)', proteins])].
[sujeto(['Here', we]), verbo([found]), complemento([that, 5, day, cold, exposure, and, 'CL316,243', treatment, of, 'WAT,', but, not, 'CL316,243', treatment, of, primary, adipocytes, of, 'C57BL/6J', 'mice,', increased, mRNA, levels, of, 'BA-characteristic', 'FAO', proteins])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'BA-characteristic', 'FAO', proteins, are, induced, in, beige, cells, in, a, different, pathway, from, 'UCP1'])].
[sujeto(['The', 'HepaRG', cell, line, is, widely, used, as, an, alternative, for, primary, human, hepatocytes, for, numerous, 'applications,', including, drug, 'screening,', and, is, progressively]), verbo([gained]), complemento([importance, as, a, 'human-relevant', cell, source])].
[sujeto(['Consequently,']), verbo([increasing]), complemento([numbers, of, experiments, are, being, performed, with, this, cell, 'line,', including, 'real-time', quantitative, 'PCR', '(', 'RT-qPCR)', experiments, for, gene, expression, studies])].
[sujeto(['This', study, additionally]), verbo([provided]), complemento([clear, evidence, that, the, use, of, a, single, reference, gene, '[', 'glyceraldehyde-3-phosphate', dehydrogenase, '(', 'GAPDH),', ribosomal, protein, 'S18', '(', 'RPS18),', or, 'actin,', beta, '(', 'ACTB)]', was, insufficient, for, normalization, in, 'HepaRG', cells])].
[sujeto(['Our', screening, of, relevant, studies, published, after, our, study]), verbo([suggested]), complemento([that, the, findings, of, our, study, were, completely, ignored])].
[sujeto(['Only', 1, reference, gene, was, included, for, normalization, in, 21, out, of, the, 24]), verbo([reported]), complemento([studies, we, 'screened,', with, 'RPS18', and, 'GAPDH', used, most, 'frequently,', followed, by, hypoxanthine, phosphoribosyltransferase, 1, '(', 'HPRT1),', glutathione, synthetase, '(', 'GSS)', '(', 'hGus),', 'β-2', microglobin, '(', 'B2M),', and, acidic, ribosomal, phosphoprotein, 'P0', '(', 36, 'B4)'])].
[sujeto(['Prokaryotic', ribosomal, protein, genes, are, typically, grouped, within, highly]), verbo([conserved]), complemento([operons])].
[sujeto(['In', many, 'cases,', one, or, more, of, the, encoded, proteins, not, only]), verbo([bind]), complemento([to, a, specific, site, in, the, ribosomal, 'RNA,', but, also, to, a, motif, localized, within, their, own, 'mRNA,', and, thereby, regulate, expression, of, the, operon])].
[sujeto(['We', demonstrated, that, the, 'S6:S18', complex]), verbo([binds]), complemento([to, this, 'motif,', which, we, hereafter, refer, to, as, the, 'S6:S18', 'complex-binding', motif, '(', 'S6S18CBM)'])].
[sujeto(['This', motif, is, a]), verbo([conserved]), complemento(['CCG', sequence, presented, in, a, bulge, flanked, by, a, stem, and, a, hairpin, structure])].
[sujeto(['A', similar, structure, containing, a, 'CCG', trinucleotide, forms, the, 'S6:S18', complex]), verbo([binding]), complemento([site, in, 16, 'S', ribosomal, 'RNA'])].
[sujeto(['We']), verbo([have]), complemento([constructed, a, 3, 'D', structural, model, of, a, 'S6:S18', complex, with, 'S6S18CBM,', which, suggests, that, the, 'CCG', trinucleotide, in, a, specific, structural, context, may, be, specifically, recognized, by, the, 'S18', protein])].
[sujeto(['These', results]), verbo([provide]), complemento([a, molecular, basis, for, understanding, 'protein-RNA', recognition, and, suggest, that, the, 'S6S18CBM', is, involved, in, an, 'auto-regulatory', mechanism])].
[sujeto(['Androgens', can]), verbo([induce]), complemento([complete, spermatogenesis, in, immature, or, prepubertal, teleost, 'fish;', 'however,', many, aspects, of, the, role, of, androgens, in, adult, teleost, spermatogenesis, remain, elusive])].
[sujeto(['The', effect, of, 'T-ISM', was, evaluated, on, '(', 'i)', de, novo, synthesis, and, metabolism, of, 'T', in, the, gonad, and, liver, by, measuring, the, gene, expression, levels, of, the, main, steroidogenic, proteins, 'involved,', '(', 'ii)', the, progress, of, 'spermatogenesis,', '(', 'iii)', the, presence, of, different, leukocyte, cell, types, in, the, 'gonad,', and, '(', 'iv)', the, mRNA, expression, of, some, genes]), verbo([involved]), complemento([in, the, leukocyte, migratory, influx, into, the, gonad, and, of, some, 'immune-relevant', molecules])].
[sujeto(['T-ISM', implants]), verbo([promote]), complemento([an, increase, of, 'T', up, to, 'supra-physiological', levels, which, induce, a, depletion, of, 'E2', levels, and, maintain, the, 11, 'KT', levels, at, physiological, concentrations])].
[sujeto(['Moreover,', androgens, may, also, be]), verbo([involved]), complemento([in, the, leukocyte, migratory, 'influx,', which, occurred, even, when, 'cytokine,', chemokine, and, cell, adhesion, molecule, gene, expressions, were, 'down-regulated'])].
[sujeto(['Moreover,', 'T-ISM', implants, block, germ, cell, 'proliferation,', although]), verbo([increased]), complemento([dmrt1, gene, expression, may, prevent, the, complete, depletion, of, germ, cells, in, the, gonad])].
[sujeto(['Furthermore,', 'T', 'down-regulated', the, expression, of, several, tlr, 'genes,', which, may, result, in, the, inhibition, of, the, immune, response, in, the, gonad, through, the, impaired, ability, to]), verbo([recognize]), complemento([and, respond, to, pathogens])].
[sujeto(['Obesity']), verbo([has]), complemento([a, complicated, metabolic, 'pathology,', and, defining, the, underlying, mechanisms, of, obesity, requires, integrative, studies, with, molecular, end, points])].
[sujeto(['Real-time', quantitative, 'PCR', '(', 'RT-qPCR)', is, a, powerful, tool, that]), verbo([has]), complemento([been, widely, utilized])].
[sujeto(['However,', the, importance, of, using, carefully, validated, reference, genes, in, 'RT-qPCR', seems, to]), verbo([have]), complemento([been, overlooked, in, 'obesity-related', research])].
[sujeto(['Using', geNorm, 'analysis,', we]), verbo([found]), complemento([that, it, was, sufficient, to, use, the, two, most, stably, expressed, genes, as, references, in, 'RT-qPCR', analyses, for, each, tissue, under, specific, experimental, conditions])].
[sujeto(['These', findings, underline, the, importance, of, using, reference, genes, that, are, stable, in, expression, across, experimental, conditions, when, studying, the, rat, hypothalamus, and, 'intestine,', because, these, tissues]), verbo([have]), complemento([an, integral, role, in, the, regulation, of, energy, homeostasis])].
[sujeto(['We', discovered, that, overexpression, of, the, 'S18-2', protein]), verbo([led]), complemento([to, immortalization, and, 'de-differentiation', of, primary, rat, embryonic, fibroblasts])].
[sujeto(['It', is, possible, that, the, 'S18-2', overexpression]), verbo([induced]), complemento([disturbance, in, cell, cycle, regulation])].
[sujeto(['We']), verbo([found]), complemento([that, overexpression, of, 'S18-2', protein, in, human, cancer, cell, lines, led, to, an, appearance, of, multinucleated, cells, in, the, selected, clones])].
[sujeto(['Hatchery-reared', larvae, of, the, 'Pacific', oyster, '(', 'Crassostrea', 'gigas)', often, suffer, from, massive, mortality]), verbo([induced]), complemento([by, 'Ostreid', herpesvirus, 1, '(', 'OsHV-1)', 'infection,', indicating, the, importance, of, better, understanding, of, oyster, immune, defense, systems])].
[sujeto(['The', accuracy, of, measurements, of, gene, expression, levels, based, on, quantitative, 'real-time', 'PCR', assays, relies, on, the, use, of, housekeeping, genes, as, internal, 'controls;', 'however,', few, studies]), verbo([have]), complemento([focused, on, the, selection, of, such, internal, controls])].
[sujeto(['After', combining, the, expression, profiles, and, oyster, housekeeping, gene, 'dataset,', 14, candidate, internal, controls, were, selected, for, further, 'investigation:', 'Elongation', 'factor-1α', '(', 'EF-1α),', 18, 'S', rRNA, '(', 18, 'S),', 28, 'S', rRNA, '(', 28, 'S),', 'Glyceraldehyde', 3, -, phosphate, dehydrogenase, '(', 'GAPDH),', 'β-actin', '(', 'ACT),', 'Ribosomal', protein, 'L7', '(', 'RL7),', 'Ribosomal', protein, 'L27', '(', 'RL27),', 'Ribosomal', protein, 'L36', '(', 'RL36),', 'Ribosomal', protein, 'S18', '(', 'RS18),', 'Heterogeneous']), verbo([nuclear]), complemento([ribonucleoprotein, 'A2/B1', '(', 'RO21),', 'Eukaryotic', translation, elongation, factor, 2, '(', 'EF2),', 'Ubiquitin-conjugating', enzyme, 'E2D2', '(', 'UBCD1),', 'S-phase', 'kinase-associated', protein, 1, '(', 'SKP1)', and, 'Heterogeneous', nuclear, ribonucleoprotein, 'Q', '(', 'HNRPQ)'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'RL7', and, 'RS18', could, be, used, as, internal, controls, for, studying, gene, expression, in, normal, growing, oyster, larvae, and, in, 'OsHV-1', infected, larvae])].
[sujeto(['Total', 'RNA', of, the, liver, tissue, was, extracted, and, reversely]), verbo([transcribed]), complemento([into, cDNA])].
[sujeto(['In', 'vitro,', immunohistochemistry, study, revealed, that, 'Sema3A', and, 'Nrp-1', were, constitutively]), verbo([expressed]), complemento([in, hepatocytes, and, 'SECs,', 'respectively,', in, normal, rat, liver, tissues])].
[sujeto(['Compared', with, the, baseline, '(', 5.2, '%', ±, 0.1, '%', ')', ',', 'Nrp-1', expression, in, 'SECs', significantly]), verbo([increased]), complemento([at, 24, h, '(', 17.3, '%', ±, 0.7, '%', ',', 'P', &, 'lt;', 0.05, ')', ',', 48, h, '(', 39.1, '%', ±, 0.6, '%', ',', 'P', &, 'lt;', 0.01, ')', ',', 72, h, '(', 46.9, '%', ±, 4.5, '%', ',', 'P', &, 'lt;', 0.01, ')', and, 96, h, '(', 29.9, '%', ±, 3.8, '%', ',', 'P', &, 'lt;', 0.01, ')', after, 'PHx,', then, returned, to, the, basal, level, at, termination, of, liver, regeneration])].
[sujeto(['Interestingly,', the, expression, of, 'Sema3A', was, inversely]), verbo([associated]), complemento([with, that, of, 'Nrp-1', in, liver, after, 'PHx'])].
[sujeto(['In', 'vitro,', 'SECs', isolated, from, rats, after, 'PHx', '(', 'PHx-SECs)', were, observed, to, migrate, to, the, lower, chamber, of, the, cell, transwell, system, after, incubation, for, 24, 'h,', but, not, cells, from, normal, rats, '(', 'CONT-SECs),', indicating, that, mobility, of, 'PHx-SECs']), verbo([increases]), complemento([as, compared, with, that, of, 'CONT-SECs'])].
[sujeto(['Compared', with, 'CONT-SECs,', the, apoptotic, rate, of, 'PHx-SECs']), verbo([decreased]), complemento([by, 78.3, '%', '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['However,', in, 'PHx-SECs,', apoptosis, was]), verbo([induced]), complemento([by, the, presence, of, 5, nmol, 'Sema3A', for, 24, h, '(', 'vehicle-treated', 21.7, '%', ±, 7.6, '%', vs, 'Sema3A-treated', 104.3, '%', ±, 8.9, '%', ',', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['In', 'addition,', immunohistochemistry, confirmed, the]), verbo([increased]), complemento([expression, of, 'Nrp-1', in, 'PHx-SECs,', while, it, was, noted, to, a, lesser, extent, in, 'CONT-SECs'])].
[sujeto(['The', interplay, of, 'Nrp-1', and, 'Sema3A', shown, in, our, results, may]), verbo([lead]), complemento([to, a, better, understanding, of, interaction, between, sinusoidal, remodeling, and, 'SECs', during, liver, regeneration])].
[sujeto(['However,', there, are, many, conflicting]), verbo([reports]), complemento([about, the, same, gene, or, sets, of, gene, expression])].
[sujeto(['A', common, method, is, to]), verbo([report]), complemento([the, interest, gene, expression, relative, to, an, internal, 'control,', usually, a, housekeeping, gene, '(', 'HKG),', which, should, be, constant, in, cells, independently, of, experimental, conditions])].
[sujeto(['In', this, 'study,', the, expression, stability, of, ten, 'HKGs', was, considered, in, parallel, in, two, cell, systems, '(', endothelial, and, osteosarcoma, 'cells):', beta, actin, '(', 'ACTB),', 'glyceraldehyde-3-phosphate', dehydrogenase, '(', 'GAPDH),', 'TATA', box]), verbo([binding]), complemento([protein, '(', 'TBP),', hypoxanthine, 'phosphoribosyl-transferase', 1, '(', 'HPRT1),', 'Cyclophilin', 'A', '(', 'PPIA),', 'beta-2-microglobulin', '(', 'B2M),', glucuronidase, beta, '(', 'GUSB),', eukaryotic, translation, elongation, factor, 1, alpha1, '(', 'EEF1A1),', transferrin, receptor, '(', 'TFRC),', ribosomal, protein, 'S18', '(', 'RPS18)'])].
[sujeto(['In', order, to, study, the, stability, of, candidate, reference, 'genes,', data]), verbo([have]), complemento([been, also, analyzed, by, several, algorithms, '(', 'geNorm,', 'NormFinder,', 'BestKeeper', and, 'delta-Ct', 'method)'])].
[sujeto(['This', study, aimed, to, identify, sites, of, lysine, methylation, in, 'Saccharomyces', cerevisiae, and, the]), verbo([associated]), complemento([methyltransferases])].
[sujeto(['Lysine', methylation, was]), verbo([found]), complemento([on, the, proteins, elongation, factor, '(', 'EF)', 1, -, 'α,', 2, ',', and, 3, 'A,', as, well, as, ribosomal, proteins, 40, 'S', 'S18-A/B,', 60, 'S', 'L11-A/B,', 'L18-A/B,', and, 'L42-A/B'])].
[sujeto(['Methyltransferase', 'Rkm1', was]), verbo([found]), complemento([to, monomethylate, 40, 'S', ribosomal, protein, 'S18-A/B', at, lysine, 48])].
[sujeto(['This', methyltransferase, shows, strong, interspecies, conservation, and, a, 'tryptophan-containing', motif]), verbo([associated]), complemento([with, its, active, site])].
[sujeto(['We']), verbo([suggest]), complemento([that, enzyme, 'YBR271W', is, named, 'EF', methyltransferase, 2, '(', 'Efm2),', in, line, with, the, recent, naming, of, 'YHL039W', as, 'Efm1'])].
[sujeto(['Recently,', it]), verbo([has]), complemento([been, suggested, that, cellular, senescence, is, associated, with, stem, cell, 'exhaustion,', which, reduces, the, regenerative, potential, of, tissues, and, contributes, to, aging, and, 'age-related', diseases])].
[sujeto(['It', is, important, to, quantitatively, evaluate, senescence, markers, to, both, identify, and, study, the, mechanisms]), verbo([involved]), complemento([in, 'MSC', senescence])].
[sujeto(['However,', no]), verbo([report]), complemento([has, demonstrated, the, optimal, reference, genes, that, should, be, used, to, normalize, 'RT-qPCR', in, senescence, studies, of, 'MSCs'])].
[sujeto(['We', also, confirmed, that, different, reference, genes]), verbo([lead]), complemento([to, different, evaluations, of, senescence, markers])].
[sujeto(['Our', work]), verbo([ensures]), complemento([that, results, obtained, from, senescence, studies, of, 'hAD-MSCs', will, be, appropriately, evaluated, in, both, basic, research, and, clinical, trials])].
[sujeto(['Tremendous', economic, significance]), verbo([has]), complemento([led, to, substantial, basic, research, involving, 'gene-expression', studies, in, this, insect, species])].
[sujeto(['Unlike', other, 'studies,', we, validated, true, effects, of, the, treatments, on, the, samples, either, by, 'gene-expression', study, of, an]), verbo([associated]), complemento([marker, gene, or, by, biochemical, tests])].
[sujeto(['This', study]), verbo([provides]), complemento([for, the, first, time, a, comprehensive, list, of, suitable, reference, genes, for, mustard, aphid, and, demonstrates, the, advantage, of, using, more, than, one, reference, gene, in, combination, for, certain, experimental, conditions])].
[sujeto(['To', elucidate, the, 'mechanism(s)', by, which, 'S-adenosyl-L-methionine', '(', 'SAM)']), verbo([decreases]), complemento([hepatitis, 'C', virus, '(', 'HCV)', expression])].
[sujeto(['SAM', exposition]), verbo([decreased]), complemento(['HCV-RNA', levels, 50, '%', -, 70, '%', compared, to, 'non-treated', controls, '(', 24, -, 72, 'h)'])].
[sujeto(['SAM']), verbo([induced]), complemento([a, synergic, antiviral, effect, with, standard, 'IFN', treatment, but, it, was, independent, of, 'IFN', signaling])].
[sujeto(['In', 'addition,', 1, 'mmol/L', 'SAM', exposition, did, not, modify, viral, 'RNA', 'stability,', but, it, needs, cellular, translation, machinery, in, order, to]), verbo([decrease]), complemento(['HCV', expression])].
[sujeto(['Total', glutathione, levels]), verbo([increased]), complemento([upon, 'SAM', treatment, in, 'HCV-replicon', cells])].
[sujeto(['Transcriptional', antioxidant, enzyme, expression, '(', 'SOD-1,', 'SOD-2', and, 'thioredoxin-1)', was]), verbo([increased]), complemento([at, different, times, but, 'interestingly,', there, was, no, significant, change, in, 'ROS', levels, upon, 'SAM', 'treatment,', contrary, to, what, was, detected, with, 'PDTC', 'treatment,', where, an, average, 40, '%', reduction, was, observed, in, exposed, cells])].
[sujeto(['There', was, a, turnover, from, 'MAT1A/MAT2A,', since, 'MAT1A', expression, was]), verbo([increased]), complemento(['(', 2.5, 'fold-times', at, 48, 'h)', and, 'MAT2A', was, diminished, '(', from, 24, 'h)', upon, 'SAM', treatment, at, both, the, transcriptional, and, translational, level])].
[sujeto(['A', likely, 'mechanism(s)', by, which, 'SAM', diminish, 'HCV', expression, could]), verbo([involve]), complemento([modulating, antioxidant, 'enzymes,', restoring, biosynthesis, of, glutathione, and, switching, 'MAT1/MAT2', turnover, in, 'HCV', expressing, cells])].
[sujeto(['The', purpose, of, this, study, is, to, determine, stably]), verbo([expressed]), complemento(['HKGs', in, blood, of, beluga, whales, '(', 'Delphinapterus', 'leucas)', that, can, be, the, appropriate, reference, genes, in, relative, quantification, in, gene, expression, research])].
[sujeto(['This', research]), verbo([provides]), complemento([recommendation, of, reference, gene, 'selection,', which, may, contribute, to, further, mRNA, relative, quantification, research, in, the, peripheral, blood, leukocytes, in, captive, cetaceans])].
[sujeto(['The', gene, expression, assessment, of, the, immune, components, in, blood]), verbo([have]), complemento([the, potential, to, serve, as, an, important, approach, to, evaluating, cetacean, health, influenced, by, environmental, insults])].
[sujeto(['The']), verbo([increasing]), complemento([demand, for, a, sustainable, larviculture, has, promoted, research, regarding, environmental, 'parameters,', diseases, and, 'nutrition,', intersecting, at, the, mucosal, surface, of, the, gastrointestinal, tract, of, fish, larvae])].
[sujeto(['This', study, aimed, at, optimizing, an, 'LCM', protocol, for, intestinal, tissue, of]), verbo([sea]), complemento([bass, larvae])].
[sujeto(['Furthermore,', reliable, reference, genes, for, performing, qPCR, in, larval]), verbo([sea]), complemento([bass, gene, expression, studies, were, 'identified,', as, data, normalization, is, critical, in, gene, expression, experiments, using, 'RT-qPCR'])].
[sujeto(['According', to, the, geNorm, and, 'Normfinder', 'algorithms,', 'ef1a,', 'rpl13a,', rps18, and, faua, were, the, most, stable, genes, to, be, implemented, as, reference, genes, for, an, appropriate, normalization, of, intestinal, tissue, from]), verbo([sea]), complemento([bass, across, a, range, of, experimental, settings])].
[sujeto(['Quantitative', 'real-time', 'PCR', '(', 'qPCR)', is, often, used, to, screen, the, differentially]), verbo([expressed]), complemento([genes, during, differentiation, of, 'MSVCs,', where, proper, reference, genes, are, essential])].
[sujeto(['In', this, 'study,', we, assessed, 31, of, previously]), verbo([reported]), complemento([reference, genes, for, their, expression, suitability, in, porcine, 'MSVCs', derived, form, longissimus, dorsi, with, qPCR])].
[sujeto(['GAPDH', was]), verbo([found]), complemento([to, be, the, least, stable, gene, by, all, of, the, three, software, 'packages,', indicating, it, is, not, an, appropriate, reference, gene, in, qPCR, assay])].
[sujeto(['Utilization', of, 'RefFinder,', which, combined, all, 4, 'algorithms,']), verbo([suggested]), complemento([that, 'PGK1,', 'HPRT1', and, 'RPL4', were, the, most, stable, 'HKGs', in, bottlenose, dolphin, blood])].
[sujeto(['In', biological, research, the, analysis, of, gene, expression, levels, in, cells, and, tissues, can, be, a, powerful, tool, to]), verbo([gain]), complemento([insights, into, biological, processes])].
[sujeto(['For', 'this,', quantitative, 'RT-PCR', '(', 'RT-qPCR)', is, a, popular, method, that, often]), verbo([involve]), complemento([the, use, of, constitutively, expressed, endogenous, reference, '(', or, '\'', 'housekeeping\')', gene, for, normalization, of, data])].
[sujeto(['Thus,', it, is, essential, to, use, reference, genes, that]), verbo([have]), complemento([been, verified, to, be, stably, expressed, within, the, specific, experimental, setting])].
[sujeto(['Here,', we]), verbo([have]), complemento([analysed, the, expression, stability, of, 12, commonly, used, reference, genes, '(', 'Actb,', 'B2m,', 'Gapdh,', 'Hprt,', 'Pgk1,', 'Rn18s,', 'Rpl13a,', 'Rps18,', 'Rps29,', 'Sdha,', 'Tbp', and, 'Ubc)', across, several, juvenile, and, adult, rat, tissues, '(', 'liver,', 'adrenal,', 'prostate,', fat, 'pad,', testis, and, 'ovaries),', both, under, normal, conditions, and, following, exposure, to, various, chemicals, during, development])].
[sujeto(['Employing', 'NormFinder', and, 'BestKeeper', 'softwares,', we]), verbo([found]), complemento(['Hprt', and, 'Sdha', to, be, amongst, the, most, stable, genes, across, normal, and, manipulated, 'tissues,', with, several, others, also, being, suitable, for, most, tissues])].
[sujeto(['Spinocerebellar', ataxia, type, 2, '(', 'SCA2)', and, amyotrophic, lateral, sclerosis, '(', 'ALS)', are, neurodegenerative, 'disorders,']), verbo([caused]), complemento([or, modified, by, an, unstable, 'CAG-repeat', expansion, in, the, 'SCA2', 'gene,', which, encodes, a, polyglutamine, '(', 'polyQ)', domain, expansion, in, 'ataxin-2', '(', 'ATXN2)'])].
[sujeto(['ATXN2', is, an, 'RNA-binding', protein, and]), verbo([interacts]), complemento([with, the, 'poly(A)-binding', protein, 'PABPC1,', localizing, to, ribosomes, at, the, rough, endoplasmic, reticulum])].
[sujeto(['It', is, unknown, whether, 'ATXN2']), verbo([associates]), complemento([preferentially, with, specific, mRNAs, or, how, it, modulates, 'RNA', processing])].
[sujeto(['Prominent']), verbo([increases]), complemento([were, observed, for, 'Lsm12/Paip1', '(', &, 'gt;2-fold),', translation, modulators, known, as, protein, 'interactor/competitor', of, 'ATXN2', and, for, 'Plin3/Mttp', '(', &, 'gt;1'])].
[sujeto(['Quantitative', immunoblots, substantiated, the]), verbo([increased]), complemento([abundance, of, 'NOP10,', 'RPS3,', 'RPS6,', 'RPS10,', 'RPS18,', 'GNB2L1', in, 'SDS', protein, 'fractions,', and, of, 'PABPC1'])].
[sujeto(['In', mouse, embryonal, 'fibroblasts,', 'ATXN2', absence, also]), verbo([enhanced]), complemento([phosphorylation, of, the, ribosomal, protein, 'S6', during, growth, 'stimulation,', while, impairing, the, rate, of, overall, protein, synthesis, 'rates,', suggesting, a, block, between, the, enhanced, translation, drive, and, the, impaired, execution])].
[sujeto(['Taken', 'together,', our, data, could, help, to, select, reliable, reference, genes, for, the, normalization, of, expression, levels, of, various]), verbo([target]), complemento([genes, in, pigs])].
[sujeto(['Folliculogenesis', and, luteinization, are]), verbo([associated]), complemento([with, increasing, density, of, cells, and, local, hypoxic, conditions])].
[sujeto(['During', the, current, experiments, cells, were, subjected, to, different, biological, and, physical, 'stimuli,', follicle]), verbo([stimulating]), complemento(['hormone,', different, initial, cell, plating, density, and, hypoxia])].
[sujeto(['Three', of, the, 'genes,', 'GAPDH,', 'HMBS,', and, 'HPRT1', were]), verbo([found]), complemento([to, be, regulated, by, initial, cell, plating, 'density,', five, of, 'them,', 'GAPDH,', 'HMBS,', 'HPRT1,', 'RPLP0', and, 'RPS18', under, hypoxic, 'conditions,', but, none, of, them, after, 'FSH', stimulation])].
[sujeto(['In', 'detail,', 'GAPDH', was, up, 'regulated,', but, 'HPRT1', and, 'HMBS', were, down]), verbo([regulated]), complemento([at, high, density, and, under, hypoxia])].
[sujeto(['In', 'contrast,', 'TBP', and, 'B2M', genes, were, neither]), verbo([regulated]), complemento([under, different, plating, density, conditions, nor, by, hypoxia, as, they, showed, similar, expression, levels, under, all, conditions, analyzed])].
[sujeto(['The', most, stably]), verbo([expressed]), complemento([genes, according, to, 'genorm,', normfinder, and, bestkeeper, approaches, contained, the, candidates, 'H3F3B,', 'RPS9,', 'YWHAZ,', 'RPS18,', 'POLR2C', and, 'UBA52'])].
[sujeto(['We']), verbo([have]), complemento([sequenced, the, complete, nucleotide, sequence, of, the, chloroplast, '(', 'cp)', genome, of, 'T'])].
[sujeto([mairei, cp, genome]), verbo([has]), complemento([lost, one, of, the, large, inverted, repeats, '(', 'IRs)', found, in, 'angiosperms,', 'fern,', 'liverwort,', and, gymnosperm, such, as, 'Cycas', revoluta, and, 'Ginkgo', biloba, 'L'])].
[sujeto([mairei]), verbo([has]), complemento([a, large, inversion, of, '~110kb', including, 91, genes, '(', from, rps18, to, 'accD)', with, gene, contents, unarranged])].
[sujeto(['Repeated', short, segments, were]), verbo([found]), complemento([in, genes, 'rps18,', rps19, and, clpP])].
[sujeto(['DHT', significantly]), verbo([decreased]), complemento([ex, vivo, 11, -, ketotestosterone, '(', 11, 'KT)', production, in, males, exposed, to, 50, 'μg/L', 'DHT', but, not, 5, 'μg/L', 'DHT,', and, 'DHT', exposure, did, not, affect, ex, vivo, testosterone, production])].
[sujeto(['Histological', examination, revealed, that, the, amount, of, interlobular, and, connective, tissue, present, in, the, testes, was]), verbo([increased]), complemento([in, the, 50, 'μg/L', 'DHT', treatment])].
[sujeto(['Despite', reductions, in, the, production, of, 11, 'KT,', 'DHT', did, not, affect, the, expression, of]), verbo([targeted]), complemento([genes, in, the, steroidogenic, pathway, such, as, steroidogenic, acute, regulatory, protein, '(', 'star),', 'P450', side, chain, cleavage, '(', 'cyp11a1)', and, 11, 'β-hydroxysteroid', dehydrogenase, '(', 'hsd11b3)'])].
[sujeto(['Microarray', analysis, in, the, testes, of, individuals, from, control, and, 50, 'μg/L', 'DHT', revealed, that, males, exposed, to, 50, 'μg/L', 'DHT', showed]), verbo([regulated]), complemento([transcriptional, 'sub-networks', that, were, related, to, 'immunity,', regulation, of, blood, 'flow,', lipids, and, xenobiotic, 'clearance,', suggesting, that, 'DHT', may, be, involved, in, the, physiological, regulation, of, these, processes, in, the, fish, testes])].
[sujeto(['There', was, no, significant, difference, in, 'RNA', quality, between, the, two, time, 'points,', indicating, 'RNA', integrity, can, remain, intact, for, at, least, 18, h, in, ex, vivo, 'assays,', thereby]), verbo([providing]), complemento([a, viable, option, for, researchers, assessing, 'multi-level', biological, reproductive, endpoints, when, limited, tissue, is, available])].
[sujeto(['This', study, improves, our, understanding, of, 'DHT', action, in, the, teleostean, testis, and, generates, new, hypotheses, regarding, cell, processes, that, are]), verbo([regulated]), complemento([by, this, underexplored, and, potent, androgen])].
[sujeto(['Since', the, underlying, assumption, of, reference, genes, is, that]), verbo([expressed]), complemento([at, the, exact, same, level, in, all, sample, 'types,', in, this, 'study,', we, evaluated, the, expression, stability, of, nine, most, commonly, used, endogenous, controls, '(', 'GAPDH,', 'ACTB,', 18, 'S', 'rRNA,', 'RPS18,', 'HSP-90,', 'ALAS,', 'HMBS,', 'ACAC,', and, 'B2M)', in, four, different, tissues, of, the, domestic, 'goat,', 'Capra', 'hircus,', including, 'liver,', 'visceral,', subcutaneous, fat, and, longissimus, 'muscles,', across, different, experimental, treatments, '(', a, standard, diet, prepared, using, the, 'NRC', computer, software, as, control, and, the, same, diet, plus, one, mg, 'chromium/day)'])].
[sujeto(['We', used, six, different, software, programs, for, ranking, of, reference, genes, and]), verbo([found]), complemento([that, individual, rankings, of, the, genes, differed, among, them])].
[sujeto(['In', this, 'review,', we]), verbo([provide]), complemento([an, update, on, the, available, computational, tools, and, 'animal-free', test, methods, for, the, prediction, of, skin, sensitization, hazard])].
[sujeto(['The', adverse, outcome, pathway, '(', 'AOP)', for, skin, sensitization, describes, the, key, events, '(', 'KEs)', that]), verbo([lead]), complemento([to, skin, sensitization])].
[sujeto(['In', our, 'review,', we]), verbo([have]), complemento([clustered, the, available, test, methods, according, to, the, 'KE', they, 'inform:', the, molecular, initiating, event, '(', 'MIE/KE1)-protein', 'binding,', 'KE2-keratinocyte', 'activation,', 'KE3-dendritic', cell, activation, and, 'KE4-T', cell, activation, and, proliferation])].
[sujeto(['In', recent, 'years,', most, progress]), verbo([has]), complemento([been, made, in, the, development, and, validation, of, in, vitro, assays, that, address, 'KE2', and, 'KE3'])].
[sujeto(['Three', 'non-animal', test, 'methods,', addressing, either, the, 'MIE,', 'KE2', or, 'KE3,', are, accepted, as, 'OECD', test, 'guidelines,', and, this]), verbo([has]), complemento([accelerated, the, development, of, integrated, or, defined, approaches, for, testing, and, assessment, '(', e])].
[sujeto(['Until', 'now,', eleven, different, testing, strategies]), verbo([have]), complemento([been, 'published,', the, majority, using, the, same, individual, information, sources])].
[sujeto(['A', few, defined, approaches, are, developed, to]), verbo([provide]), complemento([an, estimate, of, the, potency, 'sub-category', of, a, skin, sensitizer, as, 'well,', but, these, approaches, need, further, independent, evaluation, with, a, new, dataset, of, chemicals])].
[sujeto(['To', 'conclude,', this, update, shows, that, the, field, of, 'non-animal', approaches, for, skin, sensitization]), verbo([has]), complemento([evolved, greatly, in, recent, years, and, that, it, is, possible, to, predict, skin, sensitization, hazard, without, animal, testing])].
[sujeto(['Tropolone,', a, phytotoxin, produced, by, 'Burkholderia', 'plantarii,']), verbo([causes]), complemento([rice, seedling, blight])].
[sujeto(['To', identify, genes]), verbo([involved]), complemento([in, tropolone, 'synthesis,', we, systematically, constructed, mutations, in, the, genes, encoding, 55, histidine, kinases, and, 72, response, regulators])].
[sujeto(['The', mutant, strains, did, not]), verbo([cause]), complemento([rice, seedling, 'blight,', and, complementation, experiments, indicated, that, 'TroR1,', 'TroK,', and, 'TroR2', were, involved, in, the, synthesis, of, tropolone, in, 'B'])].
[sujeto([plantarii, 'However,', tropolone, synthesis, was]), verbo([repressed]), complemento([in, the, 'TroR1', 'D52A,', 'TroK', 'H253A,', and, 'TroR2', 'D46A', 'site-directed', mutants])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, putative, sensor, kinase, '(', 'TroK)', and, two, response, regulators, '(', 'TroR1', and, 'TroR2)', control, the, production, of, tropolone, in, 'B'])].
[sujeto(['In', this, 'study,', 'HK', '(', 'TroK)', and, two, 'RRs', '(', 'TroR1', and, 'TroR2)', were]), verbo([found]), complemento([to, be, involved, in, controlling, tropolone, production, in, 'B'])].
[sujeto(['Such', networks, are, thought, to, exist, in, other, bacteria, to]), verbo([regulate]), complemento([phytotoxin, 'production,', as, well, as, environmental, adaptation, and, signal, transduction])].
[sujeto(['To', identify, novel, antibiotics, against, 'Mycobacterium', 'tuberculosis,', we, performed, a, hierarchical, 'structure-based', drug, screening, '(', 'SBDS)']), verbo([targeting]), complemento([the, 'enoyl-acyl', carrier, protein, reductase, '(', 'InhA)', with, a, compound, library, of, 154, ',', 118, chemicals])].
[sujeto(['Based', on, the, predicted]), verbo([binding]), complemento(['modes,', we, probed, the, 'structure-activity', relationships, of, 'KE4', and, its, analogs, and, found, a, correlative, relationship, between, the, 'IC50', values, and, the, interaction, 'residues/LogP', values])].
[sujeto(['The', most, potent, 'inhibitor,', compound, 'KES4,', strongly, and, stably]), verbo([inhibited]), complemento([the, 'long-term', growth, of, the, model, bacteria, and, showed, higher, inhibitory, effects, '(', 'IC50', =, 4.8, 'μM)', than, isoniazid, '(', 'IC50', =, 5.4, 'μM),', which, is, a, 'first-line', drug, for, tuberculosis, therapy])].
[sujeto(['In', simulated, counseling, 'sessions,', a, trained, actor, portrayed, a, 'parent,', and, ten, graduate, audiology, students, 'role-played', counseling, sessions, as, audiologists, informing, the, &, 'quot;parent"', that, her, infant]), verbo([has]), complemento([a, hearing, loss])].
[sujeto(['The', 'ACE', was]), verbo([found]), complemento([to, have, excellent, internal, reliability, '(', alpha, =])].
[sujeto(['This', instrument, can, be, used, by, audiology, faculty, and, clinical, instructors, to, help, students, improve, their, counseling, skills, before]), verbo([interacting]), complemento([with, parents])].
[sujeto(['In', our, previous, 'study,', the, proliferation, rate, of, esophageal, squamous, cell, carcinoma, cell, 'lines,', which, poorly]), verbo([expressed]), complemento(['p21Waf1,', was, found, to, be, regulated, by, p21Waf1, gene, transfection, using, adenovirus, vector])].
[sujeto([p21Waf1, transfection, to, 'KE3', and, 'YES2', cells, '(', weakly]), verbo([expressed]), complemento([p21Waf1, protein, 'cells)', showed, a, high, expression, of, p21Waf1, protein, after, applying, this, gene, gun, technique])].
[sujeto(['In', in, vivo, transfection, 'experiments,', on, day, 14, ',', the, estimated, volume, of, 'KE3', tumors, subjected, to, p21Waf1, gene, transfection, was, 95, '%', in, comparison, with, the, pretreatment, volume, on, day, 0, ',', while, the, volume, of, 'KE3', tumors, subjected, to, 'LacZ', gene, therapy]), verbo([increased]), complemento([to, 268, '%'])].
[sujeto(['On', day, 14, ',', the, estimated, volume, of, 'YES2', tumors, subjected, to, either, p21Waf1, or, 'LacZ', gene, therapy]), verbo([increased]), complemento([to, 474, and, 686, '%', ',', respectively])].
[sujeto(['In', 'conclusion,', p21Waf1, gene, therapy, using, the, gene, gun, technique, significantly]), verbo([inhibited]), complemento([the, low, basal, p21Waf1, expressed, esophageal, cancer, cell, growth, in, vitro, and, in, vivo])].
[sujeto(['Furthermore,', p21Waf1, transfection, strongly]), verbo([enhanced]), complemento([the, effect, of, 5, 'Fu', suggesting, that, p21Waf1, may, prove, beneficial, in, chemotherapy, combined, with, gene, therapy, using, gene, gun, technology, in, patients, with, esophageal, cancer, who, have, a, low, level, of, p21Waf1, expressed, tumor])].
[sujeto(['Vascular', endothelial, growth, factor, '(', 'VEGF)', plays, an, essential, role, in, angiogenesis, in, the, growth, plate, and, ultimately, in]), verbo([regulating]), complemento([endochondral, ossification])].
[sujeto(['Dexamethasone', '(', 100, 'nM)']), verbo([inhibited]), complemento([both, protein, and, mRNA, expression, by, approximately, 45, '%'])].
[sujeto(['Hydrocortisone', '(', 'cortisol)', and, prednisolone, also]), verbo([inhibited]), complemento(['VEGF', 'secretion,', but, they, were, less, active, than, dexamethasone])].
[sujeto(['The', inhibitory, actions, of, dexamethasone, were, almost, completely, blocked, by, the, 'GR', antagonist, 'Org34116,', indicating, that, the, 'GR']), verbo([mediates]), complemento([these, actions])].
[sujeto(['Downregulation', of, this, important, growth, factor, could]), verbo([lead]), complemento([to, disruption, of, the, normal, invasion, of, blood, vessels, in, the, growth, 'plate,', which, could, contribute, to, disturbed, endochondral, ossification, and, growth])].
[sujeto(['p21/WAF1', '(', 'p21)']), verbo([inhibits]), complemento([the, activity, of, the, 'cyclin/cdk', complex, and, controls, the, 'G1', to, 'S', cell, phase, transition])].
[sujeto(['The', levels, of, 'involucrin,', which, is, a, marker, of, squamous, epithelium, 'differentiation,', markedly]), verbo([increased]), complemento([at, 48, h, and, 72, h, after, p21, 'AdV', infection, in, 'TE9', cells])].
[sujeto(['Overexpression', of, the, p21, gene, can]), verbo([inhibit]), complemento([cell, growth, and, induce, differentiation, in, esophageal, cancer, cells])].
[sujeto(['To', determine, the, crucial, abnormality, in, the, cell, cycle, regulatory, proteins, in, human, squamous, cell, carcinoma, of, the, 'esophagus,', we, examined, the, cell, growth, ratio, '(', 'CGR)', and, basal, expression, levels, of, 'G1', cyclins, '(', cyclin, 'D1,', cyclin, 'E),', 'cyclin-dependent', kinase, '(', 'cdk)', 2, ',', 'cdk4,', proliferating, cell]), verbo([nuclear]), complemento([antigen, '(', 'PCNA),', and, 'p21Waf-1', using, 9, cell, lines, '(', 'KE3,', 'KE4,', 'TE8,', 'TE9,', 'TE10,', 'TE11,', 'YES1,', 'YES2,', and, 'YES6)'])].
[sujeto(['Next,', when, the, cells, were]), verbo([stimulated]), complemento([with, serum, 48, h, after, the, 'starvation,', stimulated, levels, of, the, above, 'G1', cell, cycle, markers, were, variously, observed, among, cell, lines, irrespective, of, 'CGR'])].
[sujeto(['Serum', stimulation, markedly]), verbo([induced]), complemento([phosphorylated, 'Rb', in, 'TE9', '(', a, high, 'CGR', cell, 'line,', 'CGR>2'])].
[sujeto(['p21Waf-1-mediated', growth, suppression, was]), verbo([associated]), complemento([with, the, induction, of, 'involucrin,', a, marker, of, squamous, cell, differentiation])].
[sujeto(['Our', data]), verbo([suggested]), complemento([that, the, basal, 'level,', but, not, the, stimulated, 'level,', of, 'p21Waf-1', expression, play, a, pivotal, role, in, abnormal, growth, in, human, squamous, cell, carcinoma, of, the, esophagus])].
[sujeto(['Physical', linkage, of, genes, whose, products, are]), verbo([involved]), complemento([in, similar, physiological, pathways, may, have, functional, significance])].
[sujeto(['The', identification, of]), verbo([conserved]), complemento([gene, linkage, in, distantly, related, organisms, can, therefore, strengthen, the, hypothesis, of, selection, acting, towards, keeping, genes, on, a, chromosome])].
[sujeto(['We']), verbo([found]), complemento([six, new, genes, '(', 'BING1,', 'DAXX,', 'TAPBP,', 'KNSL2,', 'TAP2B', and, 'KE6)', whose, orthologues, are, known, to, be, linked, to, the, 'Mhc', class, 'II', region, in, humans, and, mice])].
[sujeto(['Our', data, showed, that, the, concentration, of, nisin]), verbo([required]), complemento([for, effective, control, of, 'food-borne', pathogenic, bacteria, could, be, considerably, lowered, by, the, use, of, thymol, in, combination])].
[sujeto(['The', use, of, low, concentrations, of, nisin, could]), verbo([lead]), complemento([to, a, less, favourable, condition, for, the, occurrence, of, 'nisin-resistant', bacterial, 'sub-populations'])].
[sujeto(['Taking', advantage, of, five, mouse, genomic, or, cDNA, probes, '[', 'KE5(probe', 14, ')', ',', 'KE4', '(', probe, 11, ')', ',', 'KE3', '(', probe, 7, ')', ',', 'KE2', '(', probe, 5, ')', ',', and, 'SET]', mapped, on, the, 'H-2K', region, in, 'mouse,', we]), verbo([have]), complemento([identified, and, localized, homologues, of, these, five, genes, in, the, human, major, histocompatibility, complex, region, '(', 'HKE5,', 'HKE4,', 'HKE3,', 'HKE2,', and, 'HSET,', 'respectively)'])].
[sujeto(['S18']), verbo([has]), complemento([152, amino, acids, and, has, a, molecular, weight, of, 17, ',', 707])].
[sujeto(['Hybridization', of, the, cDNA, to, digests, of]), verbo([nuclear]), complemento(['DNA', suggests, that, there, are, 10, -, 13, copies, of, the, 'S18', gene])].
[sujeto(['To', examine, the, degree, of, conservation, of, gene, organization, in, and, around, the, class, 'II', regions, of, the, major, histocompatibility, complexes, of, mouse, and, 'human,', we]), verbo([have]), complemento([established, the, positions, of, sequences, homologous, to, five, human, 'non-class', 'II', genes, '(', 'RING1-5)', in, 'mouse,', and, the, positions, of, sequences, homologous, to, three, mouse, 'non-class', 'II', genes, '(', 'KE3-5)', in, human])].
[sujeto(['The', resulting, comparative, map]), verbo([reveals]), complemento([that, the, organization, of, genes, in, the, entire, proximal, region, of, the, 'MHCs', of, mouse, and, human, is, remarkably, 'conserved,', apart, from, the, 'H-2K', gene, pair, in, 'mouse,', which, can, be, accounted, for, by, a, 60, kilobase, '(', 'kb)', insertion])].
[sujeto(['Partial', nucleotide, sequencing, of, a, 'RING5', cDNA, clone]), verbo([reveals]), complemento([that, it, is, the, human, homolog, of, the, mouse, 'KE4', gene])].
[sujeto(['We', describe, the, purification, to, near, homogeneity, of, proteins]), verbo([binding]), complemento([to, site, 'C2', '(', 'muE3)', in, the, immunoglobulin, 'heavy-chain', enhancer])].
[sujeto(['Proteins']), verbo([binding]), complemento([to, this, site, produce, four, 'protein-DNA', complexes, which, are, distinguished, by, their, mobility, in, gel, retardation, assays, and, their, elution, properties, in, an, anion, exchange, column])].
[sujeto(['UV', crosslinking, of, protein, to, enhancer, 'DNA', demonstrated, that, site, 'C2-binding', activities, in, the, three, different, pools]), verbo([bound]), complemento(['DNA', through, proteins, of, similar, sizes, '(', about, 45, 'kDa),', even, though, the, 'protein-DNA', complexes, formed, by, these, binding, activities, were, quite, distinct])].
[sujeto(['Gel', exclusion, chromatography, and, equilibrium]), verbo([binding]), complemento([analyses, indicated, that, the, distinct, 'protein-DNA', complexes, were, due, to, different, oligomeric, forms, of, the, individual, subunits, and, that, a, larger, multimeric, form, bound, with, high, affinity, to, the, 'heavy-chain', enhancer, site, 'C2,', while, a, smaller, species, had, a, much, lower, affinity, for, 'heavy-chain', enhancer, sequences])].
[sujeto(['Purified', protein]), verbo([has]), complemento([been, used, to, map, 'high-affinity', binding, sites, for, site, 'C2-binding', proteins, within, an, immunoglobulin, 'heavy-chain', promoter, and, at, site, 'KE3', in, the, kappa, 'light-chain', enhancer])].
[sujeto(['Measurement', of, intracardiac, kinetic, energy, '(', 'KE)']), verbo([provides]), complemento([new, insights, into, cardiac, hemodynamics, and, may, improve, assessment, and, understanding, of, heart, failure])].
[sujeto(['Patients', with, heart, failure, exhibit, higher, systolic, average, 'KE', compared, to, 'controls,']), verbo([suggesting]), complemento([altered, intracardiac, blood, flow])].
[sujeto(['Recent', evidence]), verbo([suggests]), complemento([that, exercising, the, antagonist, musculature, acutely, enhances, subsequent, performance, for, the, agonist, musculature])].
[sujeto(['The', purpose, of, the, current, study, was, to, examine, the, effects, of, different, rest, intervals, between, sets, for, exercises, that]), verbo([involve]), complemento([antagonistic, muscle, 'groups;', a, technique, referred, to, as, antagonist, paired, sets, '(', 'APS)'])].
[sujeto(['Oesophageal', cancer, is, an, aggressive, tumour, which]), verbo([responds]), complemento([poorly, to, both, chemotherapy, and, radiation, therapy, and, has, a, poor, prognosis])].
[sujeto(['Among', these]), verbo([targets]), complemento([p38, 'MAPK', isoforms, are, becoming, increasingly, important, for, a, variety, of, cellular, functions])].
[sujeto(['OESCC', cell, lines, which, are, 'p38δ-negative', '(', 'KE-3', and, -, 8, ')', grew, more, quickly, than, cell, lines, '(', 'KE-6', and, -, 10, ')', which]), verbo([express]), complemento([endogenous, p38δ])].
[sujeto(['Re-introduction', of, p38δ, resulted, in, a, 'time-dependent']), verbo([decrease]), complemento([in, 'OESCC', cell, proliferation, which, was, exacerbated, with, 'p-p38δ'])].
[sujeto(['In', 'addition,', we, observed, that, p38δ, and, 'p-p38δ', negatively]), verbo([regulated]), complemento(['OESCC', cell, migration, in, vitro])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, p38δ, and, 'p-p38δ', have, a, role, in, the, suppression, of, 'OESCC'])].
[sujeto(['Our', research, may]), verbo([provide]), complemento([a, new, potential, target, for, the, treatment, of, oesophageal, cancer])].
[sujeto(['Four-glass', test, is, uncomfortable, both, for, patients, and, 'doctors,', and]), verbo([leads]), complemento([to, contamination, of, urine, with, prostatic, secretion])].
[sujeto(['Three-glass', test, as, screening, test, with, the, option, of, an, additional, 'EPS', investigation, in, those, patients, the, final, diagnosis, of, chronic, prostatitis]), verbo([has]), complemento([to, be, confirmed, is, more, convenient, for, patients, and, doctors, than, the, standard, 'M&S', 4, -, glass, test, and, &, 'quot;false-positive"', '(', contaminated, with, 'EPS)', midstream, urine, results, are, avoided, thus, improving, discrimination, of, 'urethritis,', cystitis, and, prostatitis])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, a, novel, promoter, enhancer, element, &, 'quot;human', tissue, inhibitors, of, metalloproteinases, 1, '(', 'TIMP-1)', 'enhancer"', '(', 'HTE)', and, a, novel, transacting, protein, &, 'quot;cysteine', rich, transcription, 'factor"', '(', 'CRTF)', induced, 'TIMP-1', synthesis, in, prostate, cancer, cells, 2, xN])].
[sujeto(['In', the, present, 'study,', to, clarify, the, significance, of, 'CRTF', in, gastrointestinal, cancers, we, measured, the]), verbo([binding]), complemento([activity, of, 'CRTF', to, 'HTE', using, an, electrophoretic, mobility, shift, assay, '(', 'EMSA),', and, the, 'TIMP-1', concentration, by, 'ELISA', after, various, stimulation, of, six, cancer, cell, lines, '(', 'KE-3,', 'TE-9,', 'MKN-28,', 'MKN-45,', 'KM12SM,', 'SW620)'])].
[sujeto(['In', three, cell, lines, '(', 'KE-3,', 'MKN-45,', 'SW620),', both, the]), verbo([binding]), complemento([activity, of, 'CRTF', and, 'TIMP-1', concentration, significantly, increased, after, 'IL-10', stimulation])].
[sujeto(['Fetal', bovine, serum, '(', 'FBS)', did, not, affect, the]), verbo([binding]), complemento([activity, of, 'CRTF,', whereas, 'FBS', induced, 'TIMP-1', synthesis, in, all, cell, lines])].
[sujeto(['In', 'KE-3', esophageal, cancer, cells, and, 'SW620', colon, cancer, 'cells,', both, the]), verbo([binding]), complemento([activity, of, 'CRTF', and, 'TIMP-1', concentration, increased, in, the, presence, of, a, conditioned, medium, '(', 'CM)', of, fibroblasts, which, was, isolated, from, human, colon, cancer, 'tissues,', but, did, not, increase, in, 'MKN-45', cells])].
[sujeto(['Moreover,', in, the, 'fibroblasts,', both, the]), verbo([binding]), complemento([activity, of, 'CRTF', and, the, 'TIMP-1', concentration, increased, in, the, presence, of, 'CM', from, 'KM12SM,', 'SW620,', and, 'TE-9', cancer, cell, lines])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, 'IL-I0,', and, unknown, factors, in, addition, to, 'IL-10,', induced, 'TIMP-1', synthesis, via, an, increase, in, the, binding, activity, of, 'CRTF', in, gastrointestinal, 'cancers,', and, that, interaction, between, cancer, cells, and, fibroblasts, may, play, an, important, role, in, 'TIMP-1', synthesis, through, a, signal, transduction, pathway, consisting, of, 'CRTF', phosphorylation, and, 'HTE', activation])].
[sujeto(['The', tumor, bearing, mice, were]), verbo([maintained]), complemento([on, either, a, standard, or, 'methionine-free', diet, '(', 'MFD)', and, treated, with, 'PBS,', 'MMC,', or, 'M-M', conj])].
[sujeto(['The', lowest, tumor, cell, survival, rate, was]), verbo([found]), complemento([with, the, 'M-M', conj, plus, 'methionine-free', media, at, every, dose, tested, '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['Methionine']), verbo([targets]), complemento(['MMC', to, tumor, during, administration, of, 'MFD'])].
[sujeto(['Using', 'FIB', with, 'MMC,', we, expected, to]), verbo([enhance]), complemento([the, efficiency, of, 'MMC', by, sustained, release, of, 'MMC'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'MMC-FIB', is, an, effective, treatment, as, a, local, chemotherapy, for, postoperative, residual, cancer])].
[sujeto(['These', peptides]), verbo([have]), complemento([the, potential, of, assuming, a, cis, 'Tyr1-Xaa2', peptide, bond])].
[sujeto(['Their', in, vitro, opioid, activity, profiles, were, determined, in, 'mu-', and, 'delta-receptor-representative']), verbo([binding]), complemento([assays, and, bioassays])].
[sujeto(['Whereas', most, compounds, were]), verbo([found]), complemento([to, be, full, 'mu-agonists', in, the, guinea, pig, ileum, '(', 'GPI)', 'assay,', '[', 'Tic2]dermorphin', '(', compound, 7, ')', was, a, partial, 'mu-agonist'])].
[sujeto(['Compound', 3, ',', containing, 'L-Pro', in, the, 2, -, 'position,', turned, out, to, be, one, of, the, most, 'mu-receptor-selective', linear, dermorphin, analogues]), verbo([reported]), complemento([to, date])].
[sujeto(['(', 'ABSTRACT', 'TRUNCATED', 'AT', 250, 'WORDS)', 'Four', different, opioid, receptor]), verbo([binding]), complemento([assays, and, three, different, isolated, tissue, studies, were, used, to, screen, for, delta, 'receptor-selective', nonpeptidic, compounds])].
[sujeto(['(', +, /, -, ')', -, 4, -, '(', '(', 'alpha-R*)-alpha-((2S*,5R*)-4-Allyl-2,5-', 'dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide', '(', 'BW373U86)', was, a, potent, delta, 'receptor-selective', ligand, in, receptor]), verbo([binding]), complemento([assays])].
[sujeto(['The', 'Ki', values, were, 1.8, +, /, -, 0.4, ',', 15, +, /, -, 3, ',', 85, +, /, -, 4, and, 34, +, /, -, 3, nM, for, 'delta,', 'mu,', epsilon, and, kappa, receptor]), verbo([binding]), complemento(['sites,', respectively])].
[sujeto(['BW373U86']), verbo([inhibited]), complemento([electrically, evoked, muscle, contraction, of, mouse, vas, deferens, with, an, 'ED50', value, of, 0.2, +, /, -, 0.06, nM])].
[sujeto(['BW373U86', did, not]), verbo([interact]), complemento([significantly, with, other, receptors])].
[sujeto(['BW373U86']), verbo([inhibited]), complemento([the, acoustic, startle, reflex, after, subcutaneous, administration, from, 0.2, -, to, 2, -, 'mg/kg', doses, in, 'rats,', and, this, inhibition, was, blocked, by, naltrindole])].
[sujeto(['BW373U86', also]), verbo([induced]), complemento([a, 'dose-dependent', increase, of, locomotor, activity, in, rats, at, similar, doses])].
[sujeto(['This', effect, was]), verbo([inhibited]), complemento([by, naltrindole])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'BW373U86', is, a, potent, and, selective, nonpeptidic, delta, 'agonist,', and, it, elicits, distinct, in, vivo, pharmacological, activities])].
[sujeto(['Further', conformational, restriction, at, position, 2, in, the, 'sequence,', as, achieved, through, substitution, of, 'D-', or, 'L-tetrahydro-3-isoquinoline', carboxylic, acid, '(', 'Tic),', produced, a, 'configuration-dependent', differential, effect, on, receptor, selectivity, and, intrinsic, 'activity,']), verbo([leading]), complemento([to, a, potent, 'mu-selective', mu, agonist, '(', the, 'D-Tic2', 'analog)', with, increased, intrinsic, activity, in, the, mouse, vas, deferens, assay, and, to, a, potent, 'delta-selective', delta, antagonist, '(', the, 'L-Tic2', 'analog)'])].
[sujeto(['These', results, demonstrate, that, imposition, of, conformational, constraints, in, a, peptide, not, only, may, alter, receptor, selectivity, but, also, may, 'decrease,', totally, 'abolish,', or, even]), verbo([enhance]), complemento([intrinsic, activity])].
[sujeto(['We']), verbo([have]), complemento([screened, overlapping, cosmid, clones, covering, 170, kb, of, the, 'H-2K', region, for, genes, expressed, in, embryonal, carcinoma, '(', 'EC)', cells])].
[sujeto([1988, ')']), verbo([found]), complemento([in, this, region, was, further, studied, by, 'Southern,', 'Northern,', and, sequence, analysis])].
[sujeto(['This', is, the, first, 'non-organelle', 'S13', homolog, identified, in, 'metazoans,', and, its, genomic, location]), verbo([has]), complemento([been, determined, precisely])].
[sujeto([coli, 'strains,', which, were, unable, to, transfer, their, antibiotic, resistance, by, 'conjugation,', were]), verbo([found]), complemento([to, harbour, plasmids])].
[sujeto(['To', examine, the, cytotoxic, activity, of, congeners, of, 3, -, 'amino-isoquinoline,', we, performed, the, phenotypic, screening, using, panel, of, 60, cell, lines, and]), verbo([found]), complemento([that, '(', 'N-(6,7-dimethoxy-1-methyl-isoquinolin-3-yl)-4-{[(1-ethyl-4-methyl-1H-pyrazol-3-yl)methyl]amino}benzamide', '(', 4, 'd))', exhibited, the, significant, effect, against, different, tumor, cell, lines, while, showing, the, high, activity, toward, human, colorectal, cancer, 'HCT-116', cells, '(', 'IC50', =, 18, 'μm)', and, human, breast, cancer, 'T-47D', cells, '(', 'GI50', =, 1.9, 'μm)'])].
[sujeto(['Virtual', screening, indicated, that, these, compounds]), verbo([target]), complemento([protein, kinases, and, phosphodiesterases, '(', 'PDE)'])].
[sujeto(['By', 'contrast,', 50, μm, of, 4, c, and, 4, d]), verbo([inhibited]), complemento([the, growth, of, 'HKe3-mtKRAS', spheroids, in, the, 3, 'D', floating, '(', 3, 'DF)', culture, suggesting, that, 4, c, and, 4, d, target, 'PDE4B', which, is, selectively, upregulated, by, mtKRAS, in, 3, 'DF', culture])].
[sujeto(['Oncogenic', mutations, in, the, 'KRAS', gene, are, critically]), verbo([involved]), complemento([in, many, human, tumors, but, drugs, targeting, oncogenic, 'KRAS', have, not, yet, been, clinically, developed])].
[sujeto(['Herein,', we, established, a, 'three-dimensional', floating, '(', 3, 'DF)', culture, system, for, screening, drugs, that]), verbo([target]), complemento(['KRAS-mediated', signaling, molecules])].
[sujeto(['HKe3', 'cells,', derived, from, colorectal, cancer, 'HCT116', cells, and, disrupted, at, mutated, '(', 'mt)', 'KRAS', 'gene,', were, infected, with, a, retrovirus]), verbo([expressing]), complemento(['wild-type', '(', 'wt)', 'KRAS', or, mtKRAS, to, establish, 'HKe3-derived', cells, expressing, wtKRAS, or, mtKRAS])].
[sujeto(['Furthermore,', mtKRAS, but, not, wtKRAS, expression]), verbo([inhibited]), complemento([luminal, apoptosis, in, spheroids, indicating, that, the, 3, 'DF', culture, was, compatible, with, the, 3, 'D', matrigel, culture])].
[sujeto(['This', 3, 'DF', culture, system, could, be, useful, for, screening, drugs, that]), verbo([target]), complemento(['KRAS-mediated', signaling, molecules])].
[sujeto(['Reovirus', preferentially]), verbo([induced]), complemento([apoptosis, in, 'KRAS', mutant, 'HCT116', cells, compared, to, its, isogenic, 'KRAS', 'WT', 'derivative,', and, in, 'KRAS', mutant, 'IEC', cells])].
[sujeto(['Reovirus', synergistically]), verbo([induced]), complemento([growth, inhibition, when, combined, with, irinotecan])].
[sujeto(['Reovirus', preferentially]), verbo([induces]), complemento([apoptosis, in, 'KRAS', mutant, colon, cancer, cells])].
[sujeto(['Among', the, genes, that, were, upregulated, by, oncogenic, 'KRAS', in, this, 'model,', we, focused, on, the, phosphodiesterase, 4, 'B', '(', 'PDE4B)', of, which, expression, levels, were]), verbo([found]), complemento([to, be, higher, in, clinical, tumor, samples, from, 'CRC', patients, in, comparison, to, those, from, healthy, control, in, the, public, datasets, of, gene, expression, analysis])].
[sujeto(['Furthermore,', the, inhibition, of, 'PDE4', catalytic, activity, using, rolipram, reverted, the, disorganization, of, 'HCT116', cells, into, the, normal, physiologic, state, of, the, epithelial, cell, polarity, by]), verbo([inducing]), complemento([the, apical, assembly, of, 'ZO-1', '(', a, tight, junction, 'marker)', and, 'E-cadherin', '(', an, adherens, junction, 'marker)', and, by, increasing, the, activity, of, 'caspase-3', '(', an, apoptosis, 'marker)', in, luminal, cavities])].
[sujeto(['Notably,', rolipram, reduced, the, 'AKT', 'phosphorylation,', which, is, known, to, be]), verbo([associated]), complemento([with, the, disruption, of, luminal, cavity, formation, and, 'CRC', development])].
[sujeto(['In', 'addition,']), verbo([increased]), complemento([expression, of, 'PDE4B', mRNA, was, found, to, be, correlated, with, relapsed, 'CRC', in, a, public, datasets, of, gene, expression, analysis])].
[sujeto(['These', results, collectively]), verbo([suggested]), complemento([that, 'PDE4B', is, upregulated, by, oncogenic, 'KRAS,', and, also, that, the, inhibition, of, 'PDE4', catalytic, activity, can, induce, both, epithelial, cell, polarity, and, luminal, apoptosis, in, 'CRC,', thus, highlighting, the, utility, of, our, 3, -, 'D', culture, '(', 3, 'DC)', model, for, the, 'KRAS-induced', development, of, 'CRC', in, 3, -, 'D', microenvironment])].
[sujeto(['Indeed,', using, this, 'model,', we]), verbo([found]), complemento([that, 'PDE4B', is, a, promising, candidate, for, a, therapeutic, target, as, well, as, prognostic, molecular, marker, in, 'CRC'])].
[sujeto(['Further', elucidation, of, the, signaling, network, of, 'PDE4B2', in, 3, 'DC', would]), verbo([provide]), complemento([a, better, understanding, of, 'CRC', in, vivo])].
[sujeto(['In', 'HKe3', cells, grown, in, 3, 'D', 'culture,', 'ALPK2', siRNA]), verbo([inhibited]), complemento([luminal, apoptosis, and, reduced, the, expression, of, cleaved, 'caspase-3'])].
[sujeto(['Reduced', expression, of, 'ALPK2', mRNA, was]), verbo([found]), complemento([to, be, correlated, with, clinical, colorectal, adenomas, in, a, public, dataset, of, gene, expression, analyses])].
[sujeto(['We', previously, investigated, the, mRNA, expression, of, colorectal, cancer, cell, lines, via, a, microarray, analysis, and]), verbo([found]), complemento([several, genes, that, were, significantly, 'up-regulated', by, oncogenic, 'KRAS', under, 'serum-starved', conditions])].
[sujeto(['Of', these, 'genes,', we, focused, on, ribonucleotide, reductase, 'M2', '(', 'RRM2),', which, was]), verbo([reported]), complemento([to, be, associated, with, 'DNA', synthesis])].
[sujeto(['Under', 'serum-starved', 'conditions,', the, expression, level, of, 'RRM2', protein]), verbo([increased]), complemento([in, 'HCT116', cells, compared, to, 'HKe3', cells, '(', 'HCT116', cells, with, a, disruption, in, oncogenic, 'KRAS),', and, the, 're-expression', of, 'KRAS', in, 'HKe3', cells, induced, the, expression, of, 'RRM2'])].
[sujeto(['However,', miRNA, expression]), verbo([regulated]), complemento([by, oncogenic, 'KRAS', in, this, model, is, still, elusive])].
[sujeto(['The']), verbo([increased]), complemento([expression, of, 'miR-200c,', 'miR-221', and, 'miR-222', were, observed, exclusively, in, 3, 'D', 'culture,', but, not, in, the, 'two-dimensional', culture])].
[sujeto(['These', microRNAs, were]), verbo([regulated]), complemento([by, oncogenic, 'KRAS', and, were, significantly, overexpressed, in, human, colorectal, tumor, specimens])].
[sujeto(['Of', 'note,', the, protein, expression, level, of, 'Phosphatase', and, tensin, homolog, '(', 'PTEN),', a, putative]), verbo([target]), complemento([of, 'miR-221/222', 'cluster,', was, reduced, under, the, control, of, oncogenic, 'KRAS', in, a, 3, 'D-specific', manner])].
[sujeto(['Oncogenic', 'KRAS']), verbo([regulates]), complemento([3, 'D-specific', 'molecules,', possibly, being, associated, with, colorectal, tumor, development, in, vivo])].
[sujeto(['Growth', and, differentiation, of, colonic, epithelium, are]), verbo([regulated]), complemento([in, the, 'three-dimensional', '(', 3, 'D)', physiological, 'architecture,', colonic, 'crypt,', and, deregulation, of, 3, 'D', interactions, is, involved, in, tumorigenesis])].
[sujeto(['Cell-based', 3, 'D', culture, systems]), verbo([provide]), complemento([a, suitable, approach, bridging, the, gap, between, 'two-dimensional', '(', 2, 'D)', culture, and, animal, models])].
[sujeto(['KRAS', mutations, are]), verbo([found]), complemento([at, high, frequencies, in, human, colorectal, cancer, '(', 'CRC);', 'however,', 'KRAS-targeted', cancer, therapy, has, not, been, developed])].
[sujeto(['Here,', we]), verbo([have]), complemento([established, a, 3, 'D', cell, culture, model, resembling, the, colonic, crypt, by, use, of, 'HKe3', 'cells,', human, 'CRC', 'HCT116', cells, disrupted, at, activated, 'KRAS'])].
[sujeto(['On', the, basis, of, the, features, of, 'HCT116', 'cells,']), verbo([activated]), complemento(['KRAS', inhibited, normal, cell, polarity, and, apoptosis, in, 3, 'D', culture])].
[sujeto(['The', expression, of, 'DNA', 'repair-related', tumor, suppressor, genes, including, 'TP53,', 'BRCA1,', 'BRCA2,', and, 'EXO-1', was, markedly]), verbo([suppressed]), complemento([by, activated, 'KRAS', in, 3, 'D', culture, but, not, in, 2, 'D', culture])].
[sujeto(['These', results, together]), verbo([suggest]), complemento([that, activated, 'KRAS', plays, critical, roles, in, the, accumulation, of, genetic, alterations, through, inhibition, of, 'DNA', repair, genes, and, apoptosis, and, that, this, 3, 'D', culture, model, will, provide, a, useful, tool, for, investigating, the, molecular, mechanisms, of, 'CRC', development])].
[sujeto(['Their', effects, are, selective, for, transformed, 'cells,', and, we, recently, demonstrated, that, transformation, of, epithelial, cells, with, 'k-Ras', sensitizes, cells, to, 'HDACi']), verbo([induced]), complemento([apoptosis])].
[sujeto(['The', aim, of, this, study, was, to, determine, whether, the, ability, of, 'HDACi', to]), verbo([modulate]), complemento([signaling, by, a, major, 'pro-inflammatory', 'cytokine,', 'TNFalpha,', is, also, restricted, to, cells, that, harbor, mutant, 'k-Ras'])].
[sujeto(['Treatment', of, cells, with, 'TNFalpha', alone, did, not]), verbo([induce]), complemento(['apoptosis;', however, 'HDACi', potentiated, 'TNFalpha-induced', apoptosis, in, both, 'HCT116', and, 'Hke3', cells])].
[sujeto(['We', demonstrated, that, 'HDACi']), verbo([inhibited]), complemento(['TNFalpha-induced', 'NF-kappaB', transcriptional, and, 'DNA', binding, activity, in, both, cell, 'lines,', underlying, the, increased, apoptosis, in, cells, treated, with, both, agents])].
[sujeto(['We', showed, that, overexpression, of, 'HDAC2']), verbo([enhanced]), complemento(['TNFalpha-induced', 'NF-kappaB', activity, and, that, silencing, of, 'HDAC2', decreased, 'NF-kappaB', activity])].
[sujeto(['Suppression', of, 'PKC', activity, can, selectively]), verbo([induce]), complemento([apoptosis, in, cells, expressing, a, constitutively, activated, p21Ras, protein])].
[sujeto(['We', demonstrate, that, continued, expression, of, p21Ras, activity, is]), verbo([required]), complemento([in, 'PKC-mediated', apoptosis, because, farnesyltransferase, inhibitors, abrogated, the, loss, of, viability, in, 'p21Ras-transformed', cells, occurring, following, 'PKC', inhibition])].
[sujeto(['Studies', utilizing, gene, transfer, or, viral, vectors, demonstrate, that, transient, expression, of, oncogenic, p21Ras, activity, is, sufficient, for, induction, of, apoptosis, by, 'PKC', 'inhibition,', whereas, physiologic, activation, of, p21Ras, by, growth, factor, is, not, sufficient, to]), verbo([induce]), complemento([apoptosis])].
[sujeto(['Mechanistically,', the, 'p21Ras-mediated', apoptosis]), verbo([induced]), complemento([by, 'PKC', inhibition, is, dependent, upon, mitochondrial, 'dysregulation,', with, a, concurrent, loss, of, mitochondrial, membrane, potential, '(', 'psim)'])].
[sujeto(['Cyclosporine', 'A,', which]), verbo([prevented]), complemento([the, loss, of, 'psim,', also, inhibited, 'HMG-induced', 'DNA', fragmentation, in, cells, expressing, an, activated, p21Ras])].
[sujeto(['Inhibition', of, 'PKC']), verbo([caused]), complemento([increased, apoptosis, in, 'MIA-PaCa-2,', a, human, pancreatic, tumor, line, containing, a, mutated, 'Ki-ras', 'allele,', when, compared, to, 'HS766T,', a, human, pancreatic, tumor, line, with, normal, 'Ki-ras', alleles])].
[sujeto(['Furthermore,', 'PKC', inhibition]), verbo([induced]), complemento([apoptosis, in, 'HCT116,', a, human, colorectal, tumor, line, containing, an, oncogenic, 'Ki-ras', allele, but, not, in, a, subline, '(', 'Hke3)', in, which, the, mutated, 'Ki-ras', allele, had, been, disrupted])].
[sujeto(['Collectively', these, studies]), verbo([suggest]), complemento([the, therapeutic, feasibility, of, targeting, 'PKC', activity, in, tumors, expressing, an, activated, p21Ras, oncoprotein])].
[sujeto(['To', identify, the, genes, located, downstream, of, the]), verbo([activated]), complemento(['Ki-Ras', signaling, pathways, in, human, colon, cancer, 'cells,', a, 'PCR-based', cDNA, subtraction, library, was, constructed, between, 'HCT116', cells, and, 'HCT116-derived', activated, 'Ki-ras-disrupted', cells, '(', 'HKe3)'])].
[sujeto(['One', of, the, genes, in, 'HCT116', that, was, evidently, 'up-regulated', was, 'epiregulin,', a, member, of, the, epidermal, growth, factor, family, that, is]), verbo([expressed]), complemento([in, many, kinds, of, human, cancer, cells])].
[sujeto(['HKe3-stable', transfectants]), verbo([expressing]), complemento([activated, 'Ki-Ras', regained, 'over-expression', of, epiregulin])].
[sujeto(['To', further, elucidate, the, biochemical, structure, and, significance, of, epiregulin, expression, in, 'tumorigenesis,', 'HKe3-stable', transfectants]), verbo([expressing]), complemento([epiregulin, '(', 'e3-pSE', 'cells)', were, established])].
[sujeto(['Epiregulin', existed, as, highly, glycosylated, 'membrane-bound', 'forms,', and, 'TPA', rapidly]), verbo([induced]), complemento([ectodomain, shedding, of, epiregulin])].
[sujeto(['Furthermore,', the, conditioned, medium, of, 'e3-pSE', cells, showed, more, 'DNA', synthesis, for, 32, 'D', cells]), verbo([expressing]), complemento([epidermal, growth, factor, receptor, '(', 'DER)', cells, than, that, of, 'HKe3'])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, activated, 'Ki-Ras', will, be, one, of, the, factors, contributing, to, the, overexpression, of, epiregulin, in, human, colon, cancer, 'cells,', and, that, epiregulin, will, play, a, critical, role, in, human, tumorigenesis, in, vivo])].
[sujeto(['The', previously]), verbo([reported]), complemento(['RING2', gene, was, revealed, to, be, identical, to, 'HKE6'])].
[sujeto(['Those', of, 'HKE6', were]), verbo([found]), complemento([in, the, liver, and, pancreas])].
[sujeto(['The', 25, -, kb, region, proximal, to, the, 'RING1', gene, includes, an, extensive, dense, cluster, of, 'Alu', repeats, '(', about, 1.2, 'Alu', per, 'kb),', and, no, gene]), verbo([has]), complemento([been, identified, in, this, so, far])].
[sujeto(['This', article, gives, a, comprehensive, overview, of, multiple, myeloma, '(', 'MM),', a, complex, blood, cancer]), verbo([involving]), complemento([overproduction, of, plasma, cells])].
[sujeto(['Chronic', disease]), verbo([leads]), complemento([to, fibrin, deposits, on, both, pleural, surfaces, '(', stage, 'II),', followed, by, a, thickened, pleura, peel, '(', stage, 'III)'])].
[sujeto(['A', trapped, or, compressed, lung, can, only, be]), verbo([released]), complemento([by, surgical, 'decortication,', which, may, be, performed, with, a, 'minimally-invasive', approach, '(', 'video-assisted', 'thoracoscopy)', or, an, open, technique, '(', 'thoracotomy)'])].
[sujeto(['Decortication', in, chronic, 'PE', significantly]), verbo([enhanced]), complemento([spirometric, parameters, '(', 'FEV1,', 'VC/FVC)', in, all, analysed, studies])].
[sujeto(['Statistical', comparison, revealed, a, significant]), verbo([decrease]), complemento([in, thoracic, asymmetry])].
[sujeto(['Surgical', decortication, in, chronic, pleural, empyema, improves, lung, function, and]), verbo([increases]), complemento([perfusion])].
[sujeto(['Besides', a, significant, enhancement, of, spirometric, 'parameters,', 're-expansion', of, the, diseased, lung]), verbo([leads]), complemento([to, equalisation, of, thoracic, asymmetry, and, may, even, prevent, loss, of, volume, in, the, affected, lung])].
[sujeto(['Computational', models]), verbo([have]), complemento([been, used, to, calculate, plaque, stress, and, strain, for, plaque, progression, and, rupture, investigations])].
[sujeto(['Dropping', axial, and, circumferential, shrink, consideration]), verbo([led]), complemento([to, stress, and, strain, 'over-estimations'])].
[sujeto(['Material', stiffness, variations, may]), verbo([cause]), complemento([50, -, 75, &, 'nbsp;%', stress, and, 150, -, 180, &, 'nbsp;%', strain, variations])].
[sujeto(['WILL', 'study,', is]), verbo([provided]), complemento([here])].
[sujeto(['A', recently, published, prospective, observational, cohort, study, in, women, with, and, without, 'VWD', during, the, postpartum, period]), verbo([provides]), complemento([important, data, that, should, allow, the, improvement, of, postpartum, treatment, protocols])].
[sujeto(['Multiple', sclerosis, '(', 'MS)', is, a, chronic, inflammatory, disease, of, central, nervous, system, '(', 'CNS)', and, is, the, most, common]), verbo([cause]), complemento([of, neurologic, disability, in, young, adults, '(', 20, -, 40, years, 'old)'])].
[sujeto(['Although', we, did, not]), verbo([find]), complemento(['MS', in, our, 'search;', 'however,', there, are, some, ailments, with, similar, signs, and, symptoms, in, 'TPM', literature])].
[sujeto(['A', list, of, various, herbal, medicaments]), verbo([has]), complemento([been, introduced, for, these, 'ailments,', which, should, be, evaluated, critically, during, precise, experimental, and, clinical, studies])].
[sujeto(['Earlier,', we]), verbo([found]), complemento([that, overexpression, of, 'S18-2', protein, resulted, in, immortalization, and, eventual, transformation, of, primary, rat, fibroblasts])].
[sujeto(['The', 'S18-1', and, -, 3]), verbo([have]), complemento([not, exhibited, such, abilities])].
[sujeto(['However,', the, most]), verbo([conserved]), complemento([metazoan, 'S18', homolog, is, the, 'S18-1;', it, shares, the, most, sequence, similarity, with, 'S18', proteins, of, bacteria, and, of, other, eukaryotic, clades])].
[sujeto(['Evolutionarily']), verbo([conserved]), complemento([residues, of, 'S18', proteins, were, analyzed, in, various, cancers])].
[sujeto(['Moreover,', the, evolutionarily]), verbo([conserved]), complemento(['residue,', 'Gly132', of, 'S18-2,', shows, genetic, polymorphism, in, colon, adenocarcinomas, that, was, confirmed, by, direct, 'DNA', sequencing])].
[sujeto(['Some', of, the, men, and, women, were, parents, of, the, adolescents, who]), verbo([participated]), complemento([in, the, focus, group, discussions])].
[sujeto(['In', the, 'French-speaking', 'areas,', the, focus, group, discussions, were, conducted, in, 'French', through, an, accredited, 'translator,', audio, 'recorded,', and]), verbo([transcribed]), complemento([into, 'English'])].
[sujeto(['Neither', country]), verbo([has]), complemento(['policies,', 'guidelines,', or, strategies, for, 'EIMC'])].
[sujeto(['There', are, no, key, messages, on, 'EIMC', for, 'families;', the]), verbo([increasing]), complemento([demand, for, 'EIMC', is, led, by, the, community])].
[sujeto(['Improving', circumcision, services, will]), verbo([require]), complemento([guidelines, for, 'EIMC', and, improvements, in, 'training,', 'equipment,', supply, 'chains,', 'recordkeeping,', and, demand, creation])].
[sujeto(['Those', subjects, whose, 'DFUs']), verbo([decreased]), complemento([in, size, by, '≤30%', or, increased, by, '≤50%', during, the, standard, of, care, '(', 'SOC)', phase, were, randomised, into, the, treatment, phase, of, the, study])].
[sujeto(['Standard', adjunctive, 'therapy,', including, 'debridement,', saline, irrigation, and, foot, 'off-loading,', was]), verbo([provided]), complemento([to, both, arms, during, the, 'four-week', screening, 'period,', after, which, eligible, subjects, were, randomised, in, a, 1, :, 1, 'ratio,', to, either, the, 'MatriStem', '(', 'MS)', or, 'DG', treatment, arm])].
[sujeto(['However,', there, was, not, a, statistically, significant, difference]), verbo([found]), complemento([during, the, analysis, of, the, interim, data, between, the, two, study, groups, for, rate, of, wound, healing, or, number, of, subjects, with, complete, wound, closure])].
[sujeto(['The', data, from, this, interim, analysis, show, that, 'MSMM', and, 'MSWM']), verbo([provide]), complemento([results, for, healing, 'DFUs', that, are, similar, to, the, results, obtained, for, 'DG', at, a, significant, quality, of, life, and, economic, advantage])].
[sujeto(['Lesbian', and, bisexual, women, are, more, likely, to, be, overweight, or, obese, than, heterosexual, 'women,']), verbo([leading]), complemento([to, increased, 'weight-related', health, risks])].
[sujeto(['Overweight', women, aged, 40, or, older, who, 'self-identified', as, 'lesbian,', 'bisexual,', or, &, 'quot;something', 'else"']), verbo([participated]), complemento([in, five, pilot, interventions, of, 12, or, 16, &, 'nbsp;weeks\'', duration])].
[sujeto(['Participants', in, the, pedometer, '(', 'n = 43)', and, mindfulness, '(', 'n = 160)', programs, were, more, likely, to]), verbo([increase]), complemento([total, physical, activity, minutes, '(', relative, risk, '[', 'RR],', 1.67, ;, 95, '%', confidence, interval, '[', 'CI],', 1.18, -, 2.36, ;, 'p = '])].
[sujeto([42, ',', 'respectively)', and, those, in, the, gym, program, '(', 'n = 63)', were, more, likely, to]), verbo([decrease]), complemento([their, 'waist-to-height', ratio, '(', 'RR,', 1.89, ;, 95, '%', 'CI,', 0.97, -, 3.68, ',', 'p = '])].
[sujeto(['Overweight', and, obesity, prevalence, globally]), verbo([has]), complemento([increased, at, an, alarming, rate])].
[sujeto(['Cytotoxic', experiments, in, vitro, indicated, that, the, antitumor, activities, were]), verbo([increased]), complemento([by, 5, -, fold, when, its, 'Pt(iv)', derivative, was, conjugated, to, 'S18', '(', 'IC50', =, 4.82, ±, 0.45, 'μM)', and, by, 12, -, fold, when, conjugated, to, 'S21', '(', 'IC50', =, 1.9, ±, 0.67, 'μM)'])].
[sujeto(['ESI-MS', analysis, of, 'A5']), verbo([binding]), complemento([to, 5, '\'', -, dGMP, revealed, that, bifunctional, 'DNA', lesions, were, formed])].
[sujeto(['Data', on]), verbo([triggers]), complemento([for, early, resumption, of, sex, may, be, useful, as, 'scale-up', of, 'VMMC', for, 'HIV', prevention, continues, in, 'sub-Saharan', 'Africa'])].
[sujeto(['Data', on, understanding, of, 'post-VMMC', abstinence, 'recommendations,', resumption, of, 'sex,', condom, 'use,', and]), verbo([triggers]), complemento([for, resuming, sex, were, collected, from, participants, during, a, 'follow-up', interview, 35, -, 42, days, after, 'ShangRing', circumcision, in, 'Kenya', and, 'Zambia'])].
[sujeto(['Nearly', all, '(', 99.2, '%', ')']), verbo([reported]), complemento([being, counseled, to, abstain, from, sex, 'post-VMMC;', among, 'those,', most, '(', 92.2, '%', ')', recalled, the, recommended, abstinence, period, was, 6, weeks])].
[sujeto(['Most', men, '(', 94.1, '%', ')']), verbo([reported]), complemento([that, the, counselor, gave, reasons, for, 'post-VMMC', abstinence, and, recalled, appropriate, reasons])].
[sujeto(['Few', '(', 13.4, '%', ')', men]), verbo([reported]), complemento([resuming, sex, at, 35, -, 42, 'days\'', 'follow-up'])].
[sujeto(['Among', 'those,', 54.8, '%']), verbo([reported]), complemento([never, using, a, condom, 'post-VMMC'])].
[sujeto(['Younger', participants, '(', odds, ratio, 0.3, ',', 95, '%', confidence, 'interval:', 0.2, to, 0.5, ',', 'P', &, 'lt;', 0.0001, ')', and, those]), verbo([reporting]), complemento([at, least, some, condom, use, at, baseline, '(', odds, ratio, 0.5, ',', 95, '%', confidence, 'interval:', 0.3, to, 0.7, ',', 'P', =, 0.0003, ')', were, less, likely, to, report, resuming, sex])].
[sujeto(['Among', men, who]), verbo([reported]), complemento([some, condom, 'use,', most, '(', 71.5, '%', ')', said, condoms, were, much, easier, or, easier, to, use, after, circumcision])].
[sujeto(['Men']), verbo([reported]), complemento([various, reasons, for, early, resumption, of, 'sex,', primarily, strong, sexual, desire, '(', 76.4, '%', ')'])].
[sujeto(['Most', men]), verbo([reported]), complemento([awareness, of, and, adherence, to, the, counseling, recommendations, for, 'post-VMMC', abstinence])].
[sujeto(['A', minority]), verbo([reported]), complemento([early, resumption, of, 'sex,', 'and,', among, 'those,', condom, use, was, low])].
[sujeto(['Dogs', trained, to, search, for, contraband, perform, a, chain, of, behavior, in, which, they, first, search, for, a]), verbo([target]), complemento([and, then, make, a, separate, response, that, indicates, to, the, trainer, that, they, have, found, one])].
[sujeto(['The', dogs, often, conduct, multiple, searches, without, encountering, a]), verbo([target]), complemento([and, receiving, the, reinforcer, '(', i])].
[sujeto([',', the, decline, in, work, rate, when, reinforcers, are, no, longer, 'encountered)', may, assist, in, training, dogs, to, work, in, conditions, where]), verbo([targets]), complemento([are, rare])].
[sujeto([',', chain, 'pull)']), verbo([led]), complemento([to, a, second, stimulus, that, set, the, occasion, for, a, target, response, '(', e])].
[sujeto([some, trials, had, no]), verbo([target]), complemento(['present)', both, led, to, more, persistent, search, responding, in, extinction])].
[sujeto(['The']), verbo([loss]), complemento([of, search, behavior, in, extinction, was, primarily, dependent, on, the, number, of, 'non-reinforced', searches, rather, than, time, searching, without, reinforcement])].
[sujeto(['In', 'Experiments', 2, and, 3, ',', delivery, of, 'non-contingent', reinforcers, during, extinction]), verbo([increased]), complemento([search, persistence, provided, they, had, also, been, presented, during, training])].
[sujeto(['Thus,', results, with, rats]), verbo([suggest]), complemento([that, the, persistence, of, working, dog, performance, '(', or, chained, behavior, 'generally)', may, be, improved, by, training, with, partial, reinforcement, of, searching, and, 'non-contingent', reinforcement, during, both, training, and, work, '(', 'extinction)'])].
[sujeto(['More', than, 80, '%', of, patients, with, 'PD', develop, dysphagia, during, the, course, of, their, disease]), verbo([leading]), complemento([to, a, reduced, quality, of, 'life,', complicated, medication, 'intake,', malnutrition, and, aspiration, 'pneumonia,', which, is, a, major, cause, of, death, 'in PD'])].
[sujeto(['Impaired', dopaminergic, and, 'non-dopaminergic', mechanisms, of, the, cortical, swallowing, network, as, well, as, peripheral, neuromuscular, involvement]), verbo([have]), complemento([been, suggested, to, contribute, to, its, multifactorial, genesis])].
[sujeto(['Deep', brain, stimulation, does, not, seem, to]), verbo([have]), complemento([a, clinically, relevant, effect, on, swallowing, function, in, 'PD'])].
[sujeto(['The', activation, of, 'PPARalpha']), verbo([leads]), complemento([to, a, cascade, of, events, that, result, in, the, pharmacological, '(', 'hypolipidemic)', and, adverse, '(', 'carcinogenic)', effects, in, rodent, liver])].
[sujeto(['Among', differentially]), verbo([expressed]), complemento([genes, '(', 'DEGs),', there, were, 4, ',', 8, ',', and, 21, genes, commonly, regulated, by, 'bezafibrate,', 'fenofibrate,', and, 'WY-14,643', treatments, across, 3, 'doses,', 'respectively,', in, a, 'dose-dependent', manner])].
[sujeto(['Among', 'them,', 121, genes, were, commonly]), verbo([regulated]), complemento([by, at, least, two, drugs])].
[sujeto(['Many', genes, are]), verbo([involved]), complemento([in, fatty, acid, metabolism, including, oxidative, reaction])].
[sujeto(['Some', of, the, gene, changes, were]), verbo([associated]), complemento([with, production, of, reactive, oxygen, 'species,', cell, proliferation, of, 'peroxisomes,', and, hepatic, disorders])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, treatment, of, 'PPARalpha', agonists, results, in, the, production, of, oxidative, stress, and, increased, peroxisome, 'proliferation,', thus, providing, a, better, understanding, of, mechanisms, underlying, 'PPARalpha', 'agonist-induced', hepatic, disorders, and, hepatocarcinomas])].
[sujeto(['Most', affected, patients]), verbo([have]), complemento([heterozygous, loss, of, function, mutations, in, ribosomal, protein, genes, but, the, pathogenic, mechanism, is, still, unknown])].
[sujeto(['We', generated]), verbo([induced]), complemento([pluripotent, stem, cells, from, 'DBA', patients, carrying, 'RPS19', or, 'RPL5', mutations])].
[sujeto(['Expression', of, 'TGFβ']), verbo([target]), complemento(['genes,', such, as, 'TGFBI,', 'BAMBI,', 'COL3A1', and, 'SERPINE1', was, significantly, increased, in, the, 'DBA', iPSCs])].
[sujeto(['We', quantified, intermediates, in, canonical, and, 'non-canonical', 'TGFβ', pathways, and, observed, a, significant]), verbo([increase]), complemento([in, the, levels, of, the, 'non-canonical', pathway, mediator, 'p-JNK', in, the, 'DBA', iPSCs])].
[sujeto(['Surprisingly,']), verbo([nuclear]), complemento([levels, of, 'SMAD4,', a, mediator, of, canonical, 'TGFβ', 'signaling,', were, decreased, in, 'DBA', cells, due, to, increased, proteolytic, turnover])].
[sujeto(['We', also, observed, the, 'up-regulation', of, 'TGFβ1R,', 'TGFβ2,', 'CDKN1A', and, 'SERPINE1', 'mRNA,', and, the, significant]), verbo([decrease]), complemento([of, 'GATA1', mRNA, in, the, primitive, multilineage, progenitors])].
[sujeto(['N']), verbo([binds]), complemento([to, both, the, mRNA, 5, '\'', cap, and, 40, 'S', ribosomal, subunit, via, 'RPS19', '(', ribosomal, protein, 'S19)'])].
[sujeto(['The', 'N', variant, lacking, the, 'RPS19-binding', region, was, able, to]), verbo([bind]), complemento([both, the, mRNA, 5, '\'', cap, and, 'panhandle-like', 'structure,', formed, by, the, termini, of, viral, genomic, 'RNA'])].
[sujeto(['Use', of, this, variant, in, multiple, experiments]), verbo([provided]), complemento([insights, into, the, mechanism, of, ribosome, loading, during, 'N-mediated', translation, strategy])].
[sujeto(['The', present, study]), verbo([suggests]), complemento([that, 'N', molecules, individually, associated, with, the, mRNA, 5, '\'', cap, and, 'RPS19', of, the, 40, 'S', ribosomal, subunit, undergo, 'N-N', interaction, to, facilitate, the, engagement, of, 'N-associated', ribosomes, at, the, mRNA, 5, '\'', cap])].
[sujeto(['This']), verbo([has]), complemento([revealed, new, targets, for, therapeutic, intervention, of, hantavirus, infection])].
[sujeto(['Yet,', how, mutations, in, genes, encoding, ubiquitously]), verbo([expressed]), complemento([proteins, such, as, these, result, in, 'cell-type-', and, 'tissue-specific', defects, remains, unknown])].
[sujeto(['Here,', we, identify, mutations, in, 'GATA1,', encoding, the, critical, hematopoietic, transcription, factor, 'GATA-binding', 'protein-1,', that, reduce, levels, of, 'full-length', 'GATA1', protein, and]), verbo([cause]), complemento(['DBA', in, rare, instances])].
[sujeto(['We', show, that, ribosomal, protein, 'haploinsufficiency,', the, more, common]), verbo([cause]), complemento([of, 'DBA,', can, lead, to, decreased, 'GATA1', mRNA, 'translation,', possibly, resulting, from, a, higher, threshold, for, initiation, of, translation, of, this, mRNA, in, comparison, with, other, mRNAs])].
[sujeto(['In', primary, hematopoietic, cells, from, patients, with, mutations, in, 'RPS19,', encoding, ribosomal, protein, 'S19,', the, amplitude, of, a, transcriptional, signature, of, 'GATA1']), verbo([target]), complemento([genes, was, globally, and, specifically, 'reduced,', indicating, that, the, 'activity,', but, not, the, mRNA, 'level,', of, 'GATA1', is, decreased, in, patients, with, 'DBA', associated, with, mutations, affecting, ribosomal, proteins])].
[sujeto(['Moreover,', the, defective, hematopoiesis, observed, in, patients, with, 'DBA']), verbo([associated]), complemento([with, ribosomal, protein, haploinsufficiency, could, be, partially, overcome, by, increasing, 'GATA1', protein, levels])].
[sujeto(['Our', results]), verbo([provide]), complemento([a, paradigm, by, which, selective, defects, in, translation, due, to, mutations, affecting, ubiquitous, ribosomal, proteins, can, result, in, human, disease])].
[sujeto(['The', transcriptional]), verbo([nuclear]), complemento([factor, binding, to, the, 'Y', box, of, human, leukocyte, antigen, genes, '(', 'NF-Y)', for, the, 'C5a', receptor, '(', 'C5aR)', gene, is, active, in, erythroblasts])].
[sujeto(['We']), verbo([have]), complemento([previously, demonstrated, that, apoptotic, 'cell-derived', ribosomal, protein, 'S19', '(', 'RP', 'S19)', oligomers, exhibit, extraribosomal, functions, in, promoting, monocyte, chemotaxis, and, proapoptosis, via, the, 'C5aR', without, receptor, internalisation])].
[sujeto(['In', contrast, to, the, extraribosomal, functions, of, the, 'RP', 'S19,', a, proapoptotic, signal, in, 'pro-EBs,', which, is]), verbo([caused]), complemento([by, mutations, in, the, 'RP', 'S19', 'gene,', is, associated, with, the, inherited, 'erythroblastopenia,', 'Diamond-Blackfan', anaemia])].
[sujeto(['Under', monocell, culture, 'conditions,', the, differentiation, into, 'K562', 'erythrocyte-like', cells, was]), verbo([enhanced]), complemento([following, the, overexpression, of, 'Wild-type', 'RP', 'S19'])].
[sujeto(['Conversely,', the, differentiation, was]), verbo([repressed]), complemento([following, the, overexpression, of, mutant, 'RP', 'S19'])].
[sujeto(['When']), verbo([bound]), complemento([to, 'RP', 'S19', 'oligomers,', the, 'C5aR', may, exhibit, dual, functions, as, a, connector, for, the, 'EB-macrophage', island, and, as, a, sensor, for, 'EB', differentiation, in, the, bone, marrow])].
[sujeto(['Diamond-Blackfan', anemia, '(', 'DBA)', is]), verbo([associated]), complemento([with, developmental, defects, and, profound, anemia])].
[sujeto([',', 'RPL11)', ribosomal, subunit, are]), verbo([found]), complemento([in, more, than, half, of, these, patients])].
[sujeto(['The', mutations]), verbo([cause]), complemento([ribosomal, 'haploinsufficiency,', which, reduces, overall, translation, efficiency, of, cellular, mRNAs])].
[sujeto(['Among', these, were, 'Bag1,', encoding, a, 'Hsp70', 'cochaperone,', and, 'Csde1,', encoding, an, 'RNA-binding', 'protein,', and, both, were]), verbo([expressed]), complemento([at, increased, levels, in, erythroblasts])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, impaired, internal, ribosomal, entry, 'site-mediated', translation, of, mRNAs, expressed, at, increased, levels, in, erythroblasts, contributes, to, the, erythroid, phenotype, of, 'DBA'])].
[sujeto(['Ribosomal', protein, 'S19', '(', 'RP', 'S19)', oligomers]), verbo([have]), complemento([been, discovered, as, the, first, chemoattractant, of, migrating, 'monocytes/macrophages', to, apoptotic, cells, via, the, 'C5a', receptor, '(', 'C5aR)'])].
[sujeto(['We', recently, discovered, a]), verbo([gain]), complemento([of, binding, affinity, when, the, 'I(134)-H(145)', inhibited, the, activation, of, neutrophil, 'C5aR-mediated', chemotactic, pathways])].
[sujeto(['In', this, 'study,', a]), verbo([loss]), complemento([of, this, additional, binding, affinity, appeared, to, cause, the, monocyte, 'C5aR', to, activate, an, alternative, signalling, pathway])].
[sujeto(['C5aR', internalization, was, not]), verbo([involved]), complemento([in, the, alternative, chemotactic, pathway])].
[sujeto(['We', propose, a, model, of, activation]), verbo([involving]), complemento([a, 'C5aR', 'co-molecule', that, interferes, with, the, 'C5aR-Gi', protein, interaction, upon, binding, to, the, 'I(134)-H(145)', in, 'neutrophils;', 'however,', a, free, 'I(134)-H(145)', from, the, 'C5aR', 'co-molecule', can, guide, the, alternative, activation, of, the, chemotactic, p38MAPK, pathway, in, 'monocytes/macrophages'])].
[sujeto(['Hantaviruses,', members, of, the, 'Bunyaviridae', 'family,', are, 'negative-stranded', emerging, 'RNA', viruses, and, category, 'A', pathogens, that]), verbo([cause]), complemento([serious, illness, when, transmitted, to, humans, through, aerosolized, excreta, of, infected, rodent, hosts])].
[sujeto(['Hantaviruses']), verbo([have]), complemento([evolved, a, novel, translation, initiation, 'mechanism,', operated, by, nucleocapsid, protein, '(', 'N),', which, preferentially, facilitates, the, translation, of, viral, mRNAs])].
[sujeto(['N']), verbo([binds]), complemento([to, the, ribosomal, protein, 'S19', '(', 'RPS19),', a, structural, component, of, the, 40, 'S', ribosomal, subunit])].
[sujeto(['In', 'addition,', 'N', also]), verbo([binds]), complemento([to, both, the, viral, mRNA, 5, '\'', cap, and, a, highly, conserved, triplet, repeat, sequence, of, the, viral, mRNA, 5, '\'', 'UTR'])].
[sujeto(['The', simultaneous]), verbo([binding]), complemento([of, 'N', at, both, the, terminal, cap, and, the, 5, '\'', 'UTR', favors, ribosome, loading, on, viral, transcripts, during, translation, initiation])].
[sujeto(['We', characterized, the]), verbo([binding]), complemento([between, 'N', and, 'RPS19', and, demonstrate, the, role, of, the, 'N-RPS19', interaction, in, 'N-mediated', translation, initiation, mechanism])].
[sujeto(['We', show, that, 'N', specifically]), verbo([binds]), complemento([to, 'RPS19', with, high, affinity, and, a, binding, stoichiometry, of, 1, :, 1])].
[sujeto(['RPS19', undergoes, a, conformational, change, after]), verbo([binding]), complemento([to, 'N'])].
[sujeto(['We']), verbo([suggest]), complemento([that, the, 'N-RPS19', interaction, is, a, novel, target, to, shut, down, the, 'N-mediated', translation, strategy, and, hence, virus, replication, in, cells])].
[sujeto(['There', are, protein, 'trans-acting', factors, predicted, to]), verbo([participate]), complemento([in, ribosome, biogenesis, that, have, not, been, so, far, characterized])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, functional, analysis, of, the, 'Nucleolar', protein, 6, '(', 'Nop6)', in, ribosome, biogenesis])].
[sujeto(['Deletion', of, 'NOP6']), verbo([leads]), complemento([to, an, appropriate, 20, '%', reduction, in, 18, 'S', rRNA, levels, and, therefore, in, 40, 'S', ribosomal, subunits])].
[sujeto([rDNA, chromatin, immunoprecipitation, experiments, and, analysis, of, the, intracellular, localisation, of, 'Nop6-eGFP', after, in, vivo, shut, down, of, 'pre-rRNA', transcription, strongly]), verbo([suggest]), complemento([that, 'Nop6', binds, to, the, 'pre-rRNA', early, during, transcription])].
[sujeto(['Genetic', data]), verbo([suggest]), complemento([that, 'Nop6', and, the, snoRNA, snR57, both, interact, similarly, with, the, protein, 'trans-acting', factor, 'Nep1'])].
[sujeto(['It']), verbo([has]), complemento([been, proposed, that, snR57, and, 'Nep1', participate, in, a, 'pre-rRNA', conformational, switch, that, allows, the, proper, assembly, of, 40, 'S', ribosomal, protein, 'S19'])].
[sujeto(['Our', results, strongly]), verbo([suggest]), complemento([that, the, role, 'Nop6', might, have, in, this, conformational, switch, is, independent, of, snR57])].
[sujeto(['We']), verbo([have]), complemento([demonstrated, that, an, alternative, 'C5a', receptor, '(', 'C5aR)', 'ligand,', the, homodimer, of, ribosomal, protein, 'S19', '(', 'RP', 'S19),', contains, a, unique, 'C-terminus', '(', 'I(134)-H(145))', that, is, distinct, from, the, moieties, involved, in, the, 'C5a-C5aR', interaction])].
[sujeto(['To', examine, the, role, of, 'I(134)-H(145)', in, the, 'ligand-C5aR', 'interaction,', we, connected, this, peptide, to, the, 'C-terminus', of, 'C5a', '(', 'C5a/RP', 'S19)', and]), verbo([found]), complemento([that, it, endowed, the, second, binding, moiety, of, 'RP', 'S19', '(', 'L(131)DR)', with, a, relatively, higher, binding, affinity, to, the, 'C5aR', on, a, human, mast, cell, 'line,', 'HMC-1'])].
[sujeto(['As', a, 'result,', the, 'mitogen-activated', protein, kinase, '(', 'MAPK)', downstream, of, the, 'Gi', protein, exchanged, 'extracellular-signal']), verbo([regulated]), complemento([kinase, for, p38MAPK])].
[sujeto(['This', alternative, p38MAPK, activation, could, be, pharmacologically]), verbo([suppressed]), complemento([not, only, by, the, downregulation, of, phosphoinositide, 3, -, kinase, '(', 'PI3K)', by, 'LY294002,', but, also, by, the, 'over-activation', of, protein, kinase, 'C', by, phorbol, 12, -, myristate, 13, -, acetate])].
[sujeto(['Moreover,', p38MAPK, phosphorylation, upstream, of, the, pertussis, 'toxin-dependent', extracellular, 'Ca(2+)', entry, was, also]), verbo([suppressed]), complemento([by, high, concentrations, of, 'MgCl(2),', which, blocks, 'melastatin-type', transient, receptor, potential, 'Ca(2+)', channels, '(', 'TRPMs)'])].
[sujeto(['Heterozygous', mutations, in, the, ribosomal, protein, 'S19', '(', 'RPS19)', gene, are]), verbo([associated]), complemento([with, 'Diamond-Blackfan', anemia, '(', 'DBA)'])].
[sujeto(['The', mechanism, by, which, 'RPS19']), verbo([mediates]), complemento([anemia, are, still, 'unclear,', as, well, as, the, regulation, of, 'RPS19', expression])].
[sujeto(['We', show, herein, that, 'RPS19']), verbo([binds]), complemento([specifically, to, the, 5, '\'', untranslated, region, of, its, own, mRNA, with, an, equilibrium, binding, constant, '(', 'K(D))', of, 4.1, +, /, -, 1.9, nM])].
[sujeto(['We', investigated, the, mRNA]), verbo([binding]), complemento([properties, of, two, mutant, 'RPS19', proteins, '(', 'W52R', and, 'R62W)', identified, in, 'DBA', patients])].
[sujeto(['We', observed, a, significant]), verbo([increase]), complemento([in, 'K(D)', for, both, proteins, '(', 16.1, +, /, -, 2.1, and, 14.5, +, /, -, 4.9, 'nM,', 'respectively),', indicating, a, reduced, 'RNA', binding, capability, '(', 'p<0'])].
[sujeto(['We']), verbo([suggest]), complemento([that, the, binding, of, 'RPS19', to, its, mRNA, has, a, regulatory, function, and, hypothesize, that, the, weaker, 'RNA', binding, of, mutant, rRPS19, may, have, implications, for, the, pathophysiological, mechanisms, in, 'DBA'])].
[sujeto(['This', chemotactic, factor, attracts, monocytes, as, a, ligand, of, the, 'C5a', 'receptor;', 'however,', it]), verbo([inhibits]), complemento(['C5a-induced', neutrophil, chemotaxis, as, an, apparent, receptor, antagonist])].
[sujeto(['Coagulation', factor, 'XIIIa,', plasma, 'transglutaminase,', and, membrane, phosphatidylserine, on, the]), verbo([activated]), complemento([platelets, were, required, for, conversion, of, the, precursor, to, the, active, form])].
[sujeto(['The', 'Ribosomal', protein, 'S19', gene, locus, '(', 'RPS19)']), verbo([has]), complemento([been, linked, to, two, kinds, of, red, cell, 'aplasia,', 'Diamond-Blackfan', 'Anemia', '(', 'DBA)', and, 'Transient', 'Erythroblastopenia', in, 'Childhood', '(', 'TEC)'])].
[sujeto(['Mutations', in, 'RPS19', coding, sequences]), verbo([have]), complemento([been, found, in, 25, '%', of, 'DBA', 'patients,', but, not, in, 'TEC', patients])].
[sujeto(['It']), verbo([has]), complemento([been, suggested, that, 'non-coding', 'RPS19', sequence, variants, contribute, to, the, considerable, clinical, variability, in, red, cell, aplasia])].
[sujeto(['We', therefore, aimed, at, identifying, 'non-coding', variations]), verbo([associated]), complemento([with, 'DBA', or, 'TEC', phenotypes])].
[sujeto(['We']), verbo([targeted]), complemento([a, region, of, 19, '\'', 980, bp, encompassing, the, 'RPS19', gene, in, a, cohort, of, 89, 'DBA', and, 'TEC', patients, for, resequencing])].
[sujeto(['We']), verbo([provide]), complemento([here, a, catalog, of, the, 'considerable,', previously, unrecognized, degree, of, variation, in, this, region])].
[sujeto(['We', hypothesize, that, specific, alleles, in, 'non-coding', regions, of, 'RPS19', could, alter, the]), verbo([binding]), complemento([of, regulatory, proteins, or, transcription, factors])].
[sujeto(['Therefore,', we, carried, out, an, extensive, analysis, to, identify, transcription, factor]), verbo([binding]), complemento([sites, '(', 'TFBS)'])].
[sujeto(['We']), verbo([suggest]), complemento([that, the, detected, interactions, are, of, importance, for, hematopoiesis, and, could, provide, new, insights, into, individual, response, to, treatment])].
[sujeto(['The', 'ligand-receptor', 'interaction,', in, an, 'autocrine/paracrine', 'fashion,']), verbo([promotes]), complemento(['apoptosis,', which, can, be, bypassed, by, exogenous, administration, of, 'C5a,', another, ligand])].
[sujeto(['The', 'RP', 'S19', dimer, or, 'C5a/RPS19', and, 'C5a', inversely]), verbo([regulate]), complemento([the, expression, of, 'Regulator', of, 'G', protein, 'Signaling', 3, '(', 'RGS3)', gene, in, the, 'apoptosis-initiated', cells])].
[sujeto(['Transformation', of, 'HL-60', cells, to, overexpress, 'RGS3']), verbo([promotes]), complemento([apoptosis, in, association, with, the, downregulation, of, the, 'Extracellular', 'signal-Regulated', 'Kinase', '(', 'ERK)', 'signal,', and, vice, versa, in, the, 'RGS3', 'knocked-down', cells])].
[sujeto(['Consistent', with, this, 'result,', an, inhibitor, of, 'ERK', phosphorylation, effectively]), verbo([enhances]), complemento([the, apoptotic, rate, in, 'wild-type', 'HL-60', cells])].
[sujeto(['We']), verbo([found]), complemento([that, 'CaM', kinase, 'Ialpha,', but, not, 'CaM', kinase, 'Ibeta1,', 'Ibeta2,', 'II,', or, 'IV,', robustly, phosphorylated, 'RPS19'])].
[sujeto(['From', the, consensus, phosphorylation, site, 'sequence,', 'Ser59,', 'Ser90,', and, 'Thr124', were, likely, to, be, 'phosphorylated;', 'therefore,', we, mutated, each, amino, acid, to, alanine, and]), verbo([found]), complemento([that, the, mutation, of, 'Ser59', to, alanine, strongly, attenuated, phosphorylation, by, 'CaM', kinase, 'Ialpha,', suggesting, that, 'Ser59', was, a, major, phosphorylation, site])].
[sujeto(['Furthermore,', we, produced, a, specific, antibody, against, 'RPS19']), verbo([phosphorylated]), complemento([at, 'Ser59,', and, found, that, 'Ser59', was, phosphorylated, both, in, 'GT1-7', cells, and, rat, brain])].
[sujeto(['Phosphorylation', of, 'RPS19', in, 'GT1-7', cells, was]), verbo([inhibited]), complemento([by, 'KN93,', an, inhibitor, of, 'CaM', kinases])].
[sujeto(['Immunoblot', analysis, after, subcellular, fractionation, of, rat, brain, demonstrated, that]), verbo([phosphorylated]), complemento(['RPS19', was, present, in, 80, 'S', ribosomes])].
[sujeto(['Phosphorylation', of, 'RPS19', by, 'CaM', kinase, 'Ialpha', augmented, the, interaction, of, 'RPS19', with, the, previously, identified, 'S19']), verbo([binding]), complemento([protein])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'CaM', kinase, 'Ialpha', regulates, the, functions, of, 'RPS19', through, phosphorylation, of, 'Ser59'])].
[sujeto(['Macrophage', migration, inhibitory, factor, '(', 'MIF)', is, a, pleiotropic, cytokine, that]), verbo([has]), complemento([been, implicated, in, the, pathogenesis, of, inflammatory, disorders, such, as, 'infection,', 'sepsis,', and, autoimmune, disease])].
[sujeto(['Using', in, vivo, 'biotin-tagging', and, endogenous, 'co-immunoprecipitation,', the, ribosomal, protein, 'S19', '(', 'RPS19)', was, identified, as, a, novel, 'MIF']), verbo([binding]), complemento([partner])].
[sujeto(['As', 'RPS19', is]), verbo([released]), complemento([in, inflammatory, lesions, by, apoptotic, 'cells,', we, explored, whether, it, affects, 'MIF', function, and, inhibits, its, binding, to, receptors, 'CD74', and, 'CXCR2'])].
[sujeto(['Low', doses, of, 'RPS19', were]), verbo([found]), complemento([to, strongly, inhibit, 'MIF-CD74', interaction])].
[sujeto(['We,', 'therefore,', propose, that, 'RPS19']), verbo([acts]), complemento([as, an, extracellular, negative, regulator, of, 'MIF'])].
[sujeto(['We']), verbo([have]), complemento([developed, a, novel, automated, system, to, analyze, protein, complexes, by, integrating, a, surface, plasmon, resonance, '(', 'SPR)', biosensor, with, highly, sensitive, nanoflow, liquid, 'chromatography-tandem', mass, spectrometry, '(', 'LC-MS/MS)'])].
[sujeto(['A', 'His-tagged', 'protein,', which, is, also, tagged, with, 'FLAG', and, biotinylated, 'sequences,', was]), verbo([expressed]), complemento([in, mammalian, cells])].
[sujeto(['Diamond-Blackfan', anemia, '(', 'DBA)', is, a, congenital, 'red-cell', aplasia, in, which, 25, '%', of, the, patients]), verbo([have]), complemento([a, mutation, in, the, ribosomal, protein, '(', 'RP)', 'S19', gene])].
[sujeto(['We', did, not]), verbo([find]), complemento([any, abnormality, in, 'EPO-induced', signal, transduction])].
[sujeto(['However,', 'RPS19-deficient', 'TF-1', cells, showed, 'G0/G1']), verbo([arrest]), complemento(['(', 82, '%', vs])].
[sujeto(['The', fraction, of, apoptotic, cells, detected, by, 'Annexin', 'V', analysis, also]), verbo([increased]), complemento([compared, with, control, cells, '(', 13, '%', vs])].
[sujeto(['Western', blot, analysis, of, 'apoptosis-related', proteins, showed, that, the, level, of, 'bcl-2', and, 'Bad', was]), verbo([decreased]), complemento([and, 'Bax', was, increased, in, 'RPS19-deficient', 'TF-1', cells])].
[sujeto(['Finally,', we, show, that, although, 'RPS19', silencing, reduces, 'EPO-induced', development, of, erythroid, progenitors]), verbo([expressing]), complemento([glycophorin, 'A', '(', 'GPA),', 'RPS19', silencing, in, cells, already, expressing, 'GPA', does, not, affect, 'GPA', expression])].
[sujeto(['These', findings, indicate, that, 'RPS19', deficiency]), verbo([causes]), complemento([apoptosis, and, accelerated, loss, of, erythroid, progenitors, in, 'RPS19-deficient', 'DBA'])].
[sujeto(['The', 'RimM', protein]), verbo([has]), complemento([been, implicated, in, the, maturation, of, the, 30, 'S', ribosomal, subunit])].
[sujeto(['It']), verbo([binds]), complemento([to, ribosomal, protein, 'S19,', located, in, the, head, domain, of, the, 30, 'S', subunit])].
[sujeto(['In', the, present, 'study,', we]), verbo([have]), complemento([produced, 'Thermus', thermophilus, 'RimM', in, both, the, 'full-length', form, '(', 162, 'residues)', and, its, 'N-terminal', 'fragment,', spanning, residues, 1, to, 85, ',', as, soluble, proteins, in, 'Escherichia', coli, and, have, performed, structural, analyses, by, nuclear, magnetic, resonance, spectroscopy])].
[sujeto(['Ribosomal', protein, 'S19', '(', 'RPS19)', is, a, 16, -, kDa, protein]), verbo([found]), complemento([mainly, as, a, component, of, the, ribosomal, 40, 'S', subunit])].
[sujeto(['Dysregulation', of, 'RPS19']), verbo([has]), complemento([therefore, been, implicated, in, this, defective, 'erythropoiesis,', although, the, link, between, them, is, still, unclear])].
[sujeto(['Two', not, mutually, exclusive, hypotheses]), verbo([have]), complemento([been, 'proposed:', altered, protein, synthesis, and, loss, of, unknown, functions, not, directly, connected, with, the, structural, role, of, 'RPS19', in, the, ribosome])].
[sujeto(['A', role, in, rRNA, processing]), verbo([has]), complemento([been, surmised, for, the, yeast, 'ortholog,', whereas, the, extracellular, 'RPS19', dimer, has, a, monocyte, chemotactic, activity])].
[sujeto(['Three', proteins, are, known, to]), verbo([interact]), complemento([with, 'RPS19:', 'FGF2,', complement, component, 5, receptor, 1, ',', and, a, nucleolar, protein, called, 'RPS19-binding', protein])].
[sujeto(['We']), verbo([have]), complemento([used, a, yeast, 'two-hybrid', approach, to, identify, a, fourth, 'protein:', the, 'serine-threonine', kinase, 'PIM1'])].
[sujeto(['The', present, study, describes, our, use, of, proteomics, strategies, to, look, for, proteins]), verbo([interacting]), complemento([with, 'RPS19', to, determine, its, functions])].
[sujeto(['Many', interactors, are, nucleolar, proteins, and, thus, are, expected, to, take, part, in, the, 'RPS19', 'interactome;', 'however,', some, proteins]), verbo([suggest]), complemento([additional, functional, roles, for, 'RPS19'])].
[sujeto(['DBA', patients]), verbo([have]), complemento([a, variety, of, clinical, 'characteristics,', and, the, role, of, the, 'RPS19', gene, in, the, pathogenesis, of, the, disease, is, presently, unknown])].
[sujeto(['To', investigate, a, possible, role, for, 'RPS19', in, 'erythropoiesis,', we, looked, for, proteins]), verbo([associated]), complemento([with, mouse, 'RPS19', using, a, yeast, 'two-hybrid', system, and, identified, a, novel, 'protein,', which, we, named, 'S19', binding, protein, '(', 'S19BP)'])].
[sujeto(['No', known, functional, motifs, were]), verbo([found]), complemento([in, 'S19BP', except, a, short, polylysine, tract, embedded, in, a, putative, nucleolar, localization, signal])].
[sujeto(['S19BP', was]), verbo([expressed]), complemento([ubiquitously, at, a, basal, level, but, a, significantly, high, level, of, expression, was, observed, in, some, tissues])].
[sujeto(['Despite', a, low, risk, of, liver, failure, and, preserved, liver, 'function,', 'non-cirrhotic', hepatocellular, carcinoma, '(', 'HCC)']), verbo([has]), complemento([a, poor, prognosis])].
[sujeto(['High', mRNA, levels, of, 'AROS', were, statistically, significantly]), verbo([associated]), complemento([with, tumor, stage, '(', 'P', &, 'lt;', 0.001, ')', ',', 'BCLC', stage, '(', 'P', =, 0.007, ')', ',', alpha, fetoprotein, '(', 'AFP)', level, '(', 'P', =, 0.013, ')', ',', microvascular, invasion, '(', 'P', =, 0.001, ')', ',', tumor, size, '(', 'P', =, 0.036, ')', ',', and, portal, vein, invasion, '(', 'P', =, 0.005, ')'])].
[sujeto(['The', modulation, of, protein, deacetylase, 'SIRT1']), verbo([has]), complemento([a, vast, therapeutic, potential, in, treatment, of, several, 'aging-associated', diseases])].
[sujeto(['Active', regulator, of, 'SIRT1', '(', 'AROS)', is, a, small, endogenous, protein, which, was, originally]), verbo([reported]), complemento([to, activate, 'SIRT1', through, a, direct, interaction, in, cancer, cells])].
[sujeto(['The', 'NAD(+)-dependent', deacetylase, 'SIRT1', is]), verbo([involved]), complemento([in, diverse, cellular, 'processes,', and, has, also, been, linked, with, multiple, disease, states])].
[sujeto(['Active', regulator, of, 'SIRT1', '(', 'AROS)', was, the, first]), verbo([reported]), complemento(['post-transcriptional', regulator, of, 'SIRT1', 'activity,', enhancing, 'SIRT1-mediated', deacetylation, and, downregulation, of, the, 'SIRT1', target, p53])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, cellular, and, molecular, effects, of, 'RNAi-mediated', 'AROS', 'suppression,', comparing, this, with, the, role, of, 'SIRT1', in, a, panel, of, human, cell, lines, of, both, cancerous, and, 'non-cancerous', origins])].
[sujeto(['Unexpectedly,', 'AROS', is]), verbo([found]), complemento([to, vary, in, its, modulation, of, p53, acetylation, according, to, cell, context])].
[sujeto(['AROS']), verbo([suppresses]), complemento([p53, acetylation, only, following, the, application, of, cell, damaging, 'stress,', whereas, 'SIRT1', suppresses, p53, under, all, conditions, analysed])].
[sujeto(['We', also, demonstrate, that, knockdown, of, 'AROS']), verbo([induces]), complemento([apoptosis, in, three, cancer, cell, 'lines,', independent, of, p53, activation])].
[sujeto(['Importantly,', 'AROS', is, not]), verbo([required]), complemento([for, the, viability, of, three, 'non-cancer', cell, lines, indicating, a, putative, role, for, 'AROS', in, specifically, promoting, cancer, cell, survival])].
[sujeto(['Sirtuins', are, 'NAD+-dependent', protein, deacetylases]), verbo([regulating]), complemento(['metabolism,', stress, responses, and, ageing, processes])].
[sujeto(['It']), verbo([regulates]), complemento([nuclear, functions, such, as, chromatin, remodelling, and, gene, 'transcription,', and, it, appears, to, mediate, beneficial, effects, of, a, low, calorie, diet, which, can, partly, be, mimicked, by, the, 'Sirt1', activating, polyphenol, resveratrol])].
[sujeto(['It']), verbo([has]), complemento([a, unique, 'N-terminal', domain, and, 'CTD', '(', 'C-terminal', 'domain)', flanking, a, conserved, 'Sirtuin', catalytic, core, and, these, extensions, are, assumed, to, mediate, 'Sirt1-specific', features, such, as, 'homo-oligomerization', and, activation, by, resveratrol])].
[sujeto(['We']), verbo([find]), complemento([that, 'Sirt1', is, monomeric, and, has, extended, conformations, in, its, flanking, 'domains,', likely, disordered, especially, in, the, 'N-terminus,', resulting, in, an, increased, hydrodynamic, radius])].
[sujeto(['Nevertheless,', both, termini]), verbo([increase]), complemento(['Sirt1', deacetylase, 'activity,', indicating, a, regulatory, function])].
[sujeto(['We', also]), verbo([find]), complemento([an, unusual, but, defined, conformation, for, 'AROS', 'protein,', which, 'fails,', 'however,', to, stimulate, 'Sirt1'])].
[sujeto(['Resveratrol,', in, 'contrast,']), verbo([activates]), complemento([the, 'Sirt1', catalytic, core, independent, of, the, terminal, 'domains,', indicating, a, binding, site, within, the, catalytic, core, and, suggesting, that, small, molecule, activators, for, other, isoforms, might, also, exist])].
[sujeto(['Active', regulator, of, 'SIRT1', '(', 'AROS)']), verbo([binds]), complemento([and, upregulates, 'SIRT1,', an, 'NAD(+)-dependent', deacetylase])].
[sujeto(['In', 'addition,', 'AROS']), verbo([binds]), complemento(['RPS19,', a, structural, ribosomal, 'protein,', which, also, functions, in, ribosome, biogenesis, and, is, implicated, in, multiple, disease, states])].
[sujeto(['AROS', association, with, cytoplasmic, ribosomes, was, analysed, by, sucrose, density, fractionation, and, 'immunoprecipitation,']), verbo([revealed]), complemento([that, 'AROS', selectively, associates, with, 40, 'S', ribosomal, subunits, and, also, with, polysomes])].
[sujeto(['RNAi-mediated', depletion, of, 'AROS']), verbo([leads]), complemento([to, deficient, ribosome, biogenesis, with, aberrant, precursor, ribosomal, 'RNA', 'processing,', reduced, 40, 'S', subunit, ribosomal, 'RNA', and, 40, 'S', ribosomal, proteins, '(', including, 'RPS19)'])].
[sujeto(['Together,', this, results, in, a, reduction, in, 40, 'S', subunits, and]), verbo([translating]), complemento(['polysomes,', correlating, with, reduced, overall, cellular, protein, synthesis])].
[sujeto(['Interestingly,', knockdown, of, 'AROS', also, results, in, a, functionally, significant]), verbo([increase]), complemento([in, eIF2α, phosphorylation])].
[sujeto(['The', heat, shock, 'response,', the, cellular, response, to, protein, damaging, 'stress,', is, critical, in]), verbo([maintaining]), complemento([proteostasis])].
[sujeto(['The', heat, shock, response, is]), verbo([regulated]), complemento([by, the, transcription, factor, 'HSF1,', which, is, activated, upon, heat, shock, and, other, stresses, to, induce, the, expression, of, molecular, chaperones])].
[sujeto(['SIRT1']), verbo([has]), complemento([previously, been, shown, to, activate, 'HSF1', by, deacetylating, 'it,', leading, to, increased, 'DNA', binding, ability])].
[sujeto(['We']), verbo([have]), complemento([investigated, how, the, heat, shock, response, may, be, controlled, by, factors, influencing, 'SIRT1', activity])].
[sujeto(['We']), verbo([found]), complemento([that, heat, shock, results, in, an, increase, in, the, cellular, 'NAD(+)/NADH', ratio, and, an, increase, in, recruitment, of, 'SIRT1', to, the, hsp70, promoter])].
[sujeto(['Furthermore,', we]), verbo([found]), complemento([that, the, 'SIRT1', modulators, 'AROS', and, 'DBC1', have, an, impact, on, hsp70, 'transcription,', 'HSF1', acetylation, 'status,', and, 'HSF1', recruitment, to, the, hsp70, promoter])].
[sujeto(['Therefore,', 'AROS', and, 'DBC1', are, now, two, new]), verbo([targets]), complemento([available, for, therapeutic, regulation, of, the, heat, shock, response])].
[sujeto(['Reversible', acetylation]), verbo([has]), complemento([emerged, as, a, key, 'post-translational', modification, of, proteins])].
[sujeto(['Recently,', a, regulatory, network]), verbo([has]), complemento([emerged, that, controls, the, expression, and, activity, of, 'SIRT1,', a, mammalian, 'class-III', protein, deacetylase])].
[sujeto(['These', connections]), verbo([provide]), complemento([important, clues, about, how, protein, acetylation, and, deacetylation, mediate, cellular, adaptations, to, extrinsic, stress])].
[sujeto(['Sirt-1', is, a, 'NAD+-dependent']), verbo([nuclear]), complemento([deacetylase, of, 747, residues, that, in, mammals, is, involved, in, various, important, metabolic, 'pathways,', such, as, glucose, metabolism, and, insulin, 'secretion,', and, often, works, on, many, different, metabolic, substrates, as, a, multifunctional, protein])].
[sujeto(['Sirt-1', 'down-regulates', p53, 'activity,', rising, 'lifespan,', and, cell, 'survival;', it, also, deacetylases, peroxisome, 'proliferator-activated', 'receptor-gamma', '(', 'PPAR-gamma)', and, its, coactivator, 1, alpha, '(', 'PGC-1alpha),']), verbo([promoting]), complemento([lipid, 'mobilization,', positively, regulating, insulin, 'secretion,', and, increasing, mitochondrial, dimension, and, number])].
[sujeto(['Therefore,', it]), verbo([has]), complemento([been, implicated, in, diseases, such, as, diabetes, and, the, metabolic, syndrome, 'and,', 'also,', in, the, mechanisms, of, longevity, induced, by, calorie, restriction])].
[sujeto(['Its', whole, structure, is, not, yet, experimentally, determined, and, the, structural, features, of, its, allosteric, site, are, 'unknown,', and, no, information, is, known, about, the, structural, changes, determined, by, the]), verbo([binding]), complemento([of, its, allosteric, effectors])].
[sujeto(['In', this, 'study,', we, modelled, the, whole, 'three-dimensional', structure, of, 'Sirt-1', and, that, of, its, endogenous, 'activator,', the]), verbo([nuclear]), complemento([protein, 'AROS'])].
[sujeto(['Moreover,', we]), verbo([have]), complemento([found, on, 'Sirt-1', a, conserved, pharmacophore, pocket, of, which, we, have, discussed, the, implication])].
[sujeto(['SIRT1', is, a, protein, deacetylase, that]), verbo([regulates]), complemento([cellular, responses, to, a, variety, of, stresses])].
[sujeto(['(', 2007, ')']), verbo([report]), complemento([the, identification, of, a, cellular, 'protein,', 'AROS,', that, activates, the, 'SIRT1-mediated', deacetylation, of, p53])].
[sujeto(['While', its, 'substrates,', including, 'p53,']), verbo([have]), complemento([been, well, 'characterized,', no, direct, regulators, are, known])].
[sujeto(['We', describe, here, a]), verbo([nuclear]), complemento(['protein,', active, regulator, of, 'SIRT1', '(', 'AROS),', which, directly, regulates, 'SIRT1', function])].
[sujeto(['AROS']), verbo([enhanced]), complemento(['SIRT1-mediated', deacetylation, of, p53, both, in, vitro, and, in, 'vivo,', and, it, inhibited, 'p53-mediated', transcriptional, activity])].
[sujeto(['Finally,', knockdown, of, endogenous, 'AROS', using, an, antisense, expression, vector]), verbo([enhanced]), complemento([p21WAF1, expression, and, increased, both, the, 'G0/G1', population, and, apoptosis, in, response, to, 'DNA', 'damage,', while, 'AROS', overexpression, improved, cell, survival])].
[sujeto(['To', our, 'knowledge,', 'AROS', is, the, first, direct, 'SIRT1', regulator, to, be, identified, that]), verbo([modulates]), complemento(['p53-mediated', growth, regulation])].
[sujeto(['Repetitive', proteins, are, thought, to]), verbo([have]), complemento([arisen, through, the, amplification, of, 'subdomain-sized', peptides])].
[sujeto(['Many', of, these, originated, in, a, 'non-repetitive', context, as, cofactors, of, 'RNA-based', replication, and, 'catalysis,', and]), verbo([required]), complemento([the, 'RNA', to, assume, their, active, conformation])].
[sujeto(['The', mutations, were, neutral, in, the, parent, 'organism,']), verbo([suggesting]), complemento([that, they, could, have, been, sampled, in, the, course, of, evolution])].
[sujeto(['TPRs', could, thus]), verbo([have]), complemento([plausibly, arisen, by, amplification, from, an, ancestral, helical, hairpin])].
[sujeto(['In', an, adaptive, evolution, 'experiment,', these, fitness, impairments, could, be, compensated, by, mutations, that, either]), verbo([caused]), complemento(['up-regulation', of, 'S20', through, increased, gene, dosage, '(', due, to, 'duplications),', increased, transcription, of, the, rpsT, gene, '(', due, to, an, rpoD, mutation, or, mutations, in, 'rpsT),', or, increased, translation, from, the, rpsT, transcript, '(', due, to, rpsT, 'mutations)'])].
[sujeto(['We']), verbo([suggest]), complemento([that, the, reduced, levels, of, 'S20', in, the, synonymous, mutants, result, in, production, of, a, defective, subpopulation, of, 30, 'S', subunits, lacking, 'S20', that, reduce, protein, synthesis, and, bacterial, growth, and, that, the, compensatory, mutations, restore, 'S20', levels, and, the, number, of, functional, ribosomes])].
[sujeto(['Our', results, demonstrate, how, specific, synonymous, mutations, can]), verbo([cause]), complemento([substantial, fitness, reductions, and, that, many, different, types, of, 'intra-', and, extragenic, compensatory, mutations, can, efficiently, restore, fitness])].
[sujeto(['Furthermore,', this, study, highlights, that, also, synonymous, sites, can, be, under, strong, 'selection,', which, may]), verbo([have]), complemento([implications, for, the, use, of, 'dN/dS', ratios, as, signature, for, selection])].
[sujeto(['Grass', carp, reovirus, '(', 'GCRV)']), verbo([has]), complemento([caused, serious, economic, losses, for, several, decades, in, 'China'])].
[sujeto(['This', study]), verbo([suggested]), complemento([that, the, protein, 'VP7', played, the, role, in, viral, replication, and, most, likely, interacted, with, host, proteins, by, 'RPS20', and, eIF3b])].
[sujeto(['The', protein, 'VP7', and, its, untranslated, region, may]), verbo([have]), complemento([the, unknown, special, function])].
[sujeto(['DNA', sequencing, exposed]), verbo([transcribed]), complemento([paralogous, 'EEF1A1A', and, 'EEF1A1B', genes, differing, in, their, putative, protein, structure])].
[sujeto(['This', is, the, first, study, that]), verbo([provides]), complemento([a, subset, of, seven, de, novo, sequenced, housekeeping, genes, usable, as, reference, genes, in, studies, of, stress, response, in, maraena, whitefish])].
[sujeto(['Genetic', linkage, 'analysis,', exome, 'sequencing,', tumor, 'studies,', and, functional, investigations, of, 4, generations, of, a, 'FCCX', family]), verbo([led]), complemento([to, the, identification, of, a, truncating, germline, mutation, in, 'RPS20,', which, encodes, a, component, '(', 'S20)', of, the, small, ribosomal, subunit, and, is, a, new, colon, cancer, predisposition, gene])].
[sujeto(['The', mutation, was]), verbo([associated]), complemento([with, a, defect, in, 'pre-ribosomal', 'RNA', maturation])].
[sujeto(['For', quantitative, '(', or, 'real-time)', 'RT-PCR', 'assays,', the, method, of, choice, is, often, to, normalize, gene, expression, data, to, an, endogenous, gene, that, is, stably]), verbo([expressed]), complemento([across, the, samples, 'analysed:', a, 'so-called', normalizing, or, housekeeping, gene])].
[sujeto(['Although', this, is, a, valid, 'strategy,', the, identification, of, stable, normalizing, genes]), verbo([has]), complemento([proved, challenging, and, a, gene, showing, stable, expression, across, all, cells, or, tissues, is, unlikely, to, exist])].
[sujeto(['Here,', we]), verbo([report]), complemento([on, the, performance, of, a, panel, of, nine, commonly, employed, normalizing, genes, in, adult, human, testis, and, testicular, pathologies])].
[sujeto(['Based', on, our, 'results,', we, recommend, using, 'RPS20,', 'RPS29', or, 'SRSF4', when, analysing, relative, gene, expression, levels, in, human, testis, and]), verbo([associated]), complemento([testicular, pathologies])].
[sujeto(['Using', 'immuno-fluorescent', probing, and, 'Western', blotting, 'analysis,', we]), verbo([reveal]), complemento([the, exclusive, cytoplasm, nature, of, the, small, subunit, ribosomal, protein, 'S20'])].
[sujeto(['To', illustrate, the, importance, of, the, cellular, compartmentation, of, 'S20', to, the, function, of, small, subunit, 40, 'S,', we, created, a]), verbo([nuclear]), complemento([resident, 'S20NLS', mutant, gene, and, examined, polysome, profile, of, cells, that, had, been, transfected, with, the, 'S20NLS', gene])].
[sujeto(['As', a, 'result,', we, observed, the, formation, of, recombinant, 40, 'S', carried, 'S20NLS', but, this, recombinant, 40, 'S', was, never]), verbo([found]), complemento([in, the, 'polysome,', suggesting, such, a, recombinant, 40, 'S', was, translation, incompetent])].
[sujeto(['This', albino, phenotype, was]), verbo([associated]), complemento([with, altered, chlorophyll, '(', 'Chl)', content, and, chloroplast, development])].
[sujeto(['ASL1', showed, 'tissue-specific', 'expression,', as, it, was, highly]), verbo([expressed]), complemento([in, plumule, and, young, seedlings, but, expressed, at, much, lower, levels, in, other, tissues])].
[sujeto(['In', 'addition,', 'ASL1', expression, was]), verbo([regulated]), complemento([by, light])].
[sujeto(['The', transcript, levels, of]), verbo([nuclear]), complemento([genes, for, 'Chl', biosynthesis, and, chloroplast, development, were, strongly, affected, in, asl1, 'mutants;', transcripts, of, some, plastid, genes, for, photosynthesis, were, undetectable])].
[sujeto(['Changes', to, the, 'nucleolus,', the, site, of, ribosome, 'production,']), verbo([have]), complemento([long, been, linked, to, 'cancer,', and, mutations, in, several, ribosomal, proteins, '(', 'RPs)', have, been, associated, with, an, increased, risk, for, cancer, in, human, diseases])].
[sujeto(['Relevantly,', a, number, of, 'RPs']), verbo([have]), complemento([been, shown, to, bind, to, 'MDM2', and, inhibit, 'MDM2', 'E3', ligase, 'activity,', leading, to, p53, stabilization, and, cell, cycle, 'arrest,', thus, revealing, a, 'RP-Mdm2-p53', signaling, pathway, that, is, critical, for, ribosome, biogenesis, surveillance])].
[sujeto(['Here,', we]), verbo([have]), complemento([identified, 'RPL37,', 'RPS15,', and, 'RPS20', as, 'RPs', that, can, also, bind, 'Mdm2', and, activate, p53])].
[sujeto(['We']), verbo([found]), complemento([that, each, of, the, aforementioned, 'RPs,', when, ectopically, 'expressed,', can, stabilize, both, 'co-expressed', 'Flag-tagged', 'Mdm2', and, 'HA-tagged', p53, in, 'p53-null', cells, as, well, as, endogenous, p53, in, a, 'p53-containing', cell, line])].
[sujeto(['For', each, 'RP,', the, mechanism, of, 'Mdm2', and, p53, stabilization, appears, to, be, through]), verbo([inhibiting]), complemento([the, 'E3', ubiquitin, ligase, activity, of, 'Mdm2'])].
[sujeto(['Interestingly,', although, they, are, each, capable, of]), verbo([inducing]), complemento([cell, death, and, cell, cycle, 'arrest,', these, 'RPs', differ, in, the, p53, target, genes, that, are, regulated, upon, their, respective, introduction, into, cells])].
[sujeto(['Thus,', 'RPL37,', 'RPS15', and, 'RPS20']), verbo([regulate]), complemento([the, 'Mdm2-p53-MdmX', network, but, employ, different, mechanisms, to, do, so])].
[sujeto(['The', basis, for, this, property]), verbo([has]), complemento([been, explored, in, vitro])].
[sujeto(['At', limiting, 'substrate,', cleavage, of, the, rpsT, mRNA, by, 'RNase', 'E', '(', residues, 1, -, 529, ')', is, 'inefficient,']), verbo([requiring]), complemento([excess, enzyme])].
[sujeto(['Generation', of, the, 147, nt, 3, '\'', -, limit, product]), verbo([requires]), complemento([sequential, cleavages, that, generate, 5, '\'', -, monophosphorylated, termini, on, 'intermediates,', and, the, 5, '\'', -, sensor, domain, of, 'RNase', 'E'])].
[sujeto(['Alternatively,', this, specific, cleavage, can, be]), verbo([activated]), complemento([substantially, by, a, 5, '\'', -, phosphorylated, oligonucleotide, annealed, 5, '\'', to, the, cleavage, site])].
[sujeto(['This']), verbo([finding]), complemento([suggests, that, monophosphorylated, small, 'RNAs', may, destabilize, their, mRNA, targets, by, recruiting, the, 5, -, sensor, domain, of, 'RNase', 'E', '\'', in, 'trans\''])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, the, distribution, of, fitness, effects, for, 'non-synonymous', and, synonymous, mutations, in, 'Salmonella', typhimurium, ribosomal, proteins, 'S20', and, 'L1', are, 'similar,', suggesting, that, fitness, constraints, are, present, at, the, level, of, mRNA])].
[sujeto(['Here', we, explore, the, hypothesis, that, synonymous, mutations]), verbo([confer]), complemento([their, 'fitness-reducing', effect, by, alterating, the, secondary, structure, of, the, mRNA])].
[sujeto(['Our', results, show, that, for, 3, /, 9, cases, 'tested,', the, reduced, fitness]), verbo([conferred]), complemento([by, a, synonymous, mutation, could, be, fully, or, partly, restored, by, introducing, a, second, synonymous, substitution, that, restore, base, pairing, in, a, mRNA, stem])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, for, ribosomal, protein, 'S20,', the, deleterious, effects, of, synonymous, mutations, are, not, generally, due, to, codon, usage, 'effects,', but, that, mRNA, secondary, structure, is, a, major, fitness, constraint])].
[sujeto(['In', 'Escherichia', 'coli,', 12, distinct, 'RNA', structures, within, the, transcripts, encoding, ribosomal, proteins]), verbo([interact]), complemento([with, specific, ribosomal, proteins, to, allow, autogenous, regulation, of, expression, from, large, 'multi-gene', 'operons,', thus, coordinating, ribosomal, protein, biosynthesis, across, multiple, operons])].
[sujeto(['To', investigate, the, extent, to, which, these, 'RNA', structures, are]), verbo([conserved]), complemento([across, eubacterial, 'phyla,', we, created, multiple, sequence, alignments, representing, 10, of, these, messenger, 'RNA', '(', 'mRNA)', structures, in, 'E'])].
[sujeto(['We']), verbo([find]), complemento([that, while, three, 'RNA', structures, are, widely, distributed, across, many, phyla, of, 'bacteria,', seven, of, the, 'RNAs', are, narrowly, distributed, to, a, few, orders, of, 'Gammaproteobacteria'])].
[sujeto(['This', work]), verbo([reveals]), complemento([that, 'RNA-based', regulation, of, ribosomal, protein, biosynthesis, is, used, in, nearly, all, eubacterial, 'phyla,', but, the, specific, 'RNA', structures, that, regulate, ribosomal, protein, biosynthesis, in, 'E'])].
[sujeto(['coli,', and, the, potential, for, alternative, 'RNA', structures, responsible, for]), verbo([regulating]), complemento([ribosomal, proteins, in, other, eubacteria])].
[sujeto(['To', study, the, effects, of, yiqi, huoxue, recipe, and, 'Coxsackie', 'B', virus, type, 3, '(', 'CVB3)', on, the, expression, of, ribosomal, protein, 'S20', in, rat, cardiac, 'myocytes,', to, explore, the, pathogenesis, of, myocarditis]), verbo([induced]), complemento([by, 'CVB3', and, the, mechanism, of, yiqi, huoxue, recipe, on, gene, 'level,', and, to, further, investigate, whether, yiqi, huoxue, recipe, is, an, effective, prescription, for, 'CVB3', myocarditis])].
[sujeto(['A', modified, suppression, subtractive, hybridization, '(', 'SSH)', was, used, to, isolate, differentially]), verbo([expressed]), complemento([genes, between, the, 'CVB3', infection, group, and, the, treatment, group, with, yiqi, huoxue, recipe])].
[sujeto(['Down-regulation', of, ribosomal, protein, 'S20', mRNA, expression, might, be, one, of, the, mechanisms, in, 'CVB3', 'myocarditis,', and, yiqi, huoxue, recipe, could, achieve, the, treatment, of, viral, myocarditis, by]), verbo([regulating]), complemento([the, expression, of, ribosomal, protein, 'S20'])].
[sujeto(['Selecting', genes, that]), verbo([have]), complemento([stable, expression, levels, as, the, internal, standards, in, a, comparative, study, is, essential, for, identifying, real, 'gene-specific', variation, by, quantitative, 'RT-PCR', '(', 'qRT-PCR)'])].
[sujeto(['Five', genes]), verbo([expressed]), complemento([in, sow, endometria, on, 'GD12', were, evaluated, for, their, suitability, as, internal, control, for, relative, quantification, by, 'qRT-PCR'])].
[sujeto(['The', two, most, significantly]), verbo([associated]), complemento(['SNPs', explain, 10, '%', of, the, 'EBV', variation])].
[sujeto(['Since', marker, alleles, with, negative, effect, on, pCE]), verbo([have]), complemento([positive, effects, on, 'growth-related', 'traits,', the, 'QTL', may, exert, their, effects, on, the, birthing, process, through, fetal, growth, traits])].
[sujeto(['The', 'QTL', region, on, 'BTA14', corresponds, to, a, human, chromosome, '(', 'HSA)', region, that, is]), verbo([associated]), complemento([with, growth, characteristics])].
[sujeto(['The', 'HSA', region, corresponding, to, the, 'BTA21', pCE, 'QTL', is, maternally, imprinted, and]), verbo([involved]), complemento([in, the, 'Prader-Willi', and, 'Angelman', syndromes])].
[sujeto(['Resequencing', of, positional, candidate, genes, on, 'BTA14', revealed, a, highly, significantly, '(', 'P', =, 1.96, ×, 10, '(', -, 14, ')', ')']), verbo([associated]), complemento([polymorphism, ablating, a, polyadenylation, signal, of, the, gene, encoding, ribosomal, protein, 'S20', '(', 'RPS20)'])].
[sujeto(['The', distribution, of, fitness, effects, '(', 'DFE)', of, mutations, is, of, fundamental, importance, for, understanding, evolutionary, dynamics, and, complex, diseases, and, for]), verbo([conserving]), complemento([threatened, species])].
[sujeto(['DFEs', estimated, from, 'DNA', sequences]), verbo([have]), complemento([rarely, been, subject, to, direct, experimental, tests])].
[sujeto(['The', 'DFEs', for, synonymous, and, nonsynonymous, substitutions, are, 'similar,']), verbo([suggesting]), complemento([that, in, some, 'genes,', strong, fitness, constraints, are, present, at, the, level, of, the, messenger, 'RNA'])].
[sujeto(['Ribosomal', protein, 'S20', is, a, primary]), verbo([binding]), complemento([protein, that, bridges, the, 5, '\'', domain, and, the, 3, '\'', minor, domain, of, the, 16, 'S', ribosomal, 'RNA', '(', 'rRNA)', in, the, 30, 'S', ribosomal, subunit])].
[sujeto(['Using', 'time-dependent', dimethyl, sulfate, 'modification,', we]), verbo([have]), complemento([determined, that, as, it, is, bound, to, 16, 'S', 'rRNA,', protein, 'S20', causes, rapid, protection, of, bases, 'A246,', 'A274,', 'A279,', and, 'A282', in, the, stem, region, of, helix, 11, in, the, 5, '\'', domain, and, moderately, fast, modifications, of, helix, 44, bases, 'A1433', and, 'A1434', in, the, 3, '\'', minor, domain])].
[sujeto(['The', modifications, that, occur, in, the, stem, region, of, helix, 11, are, distant, from, the]), verbo([binding]), complemento([site, of, protein, 'S20,', as, determined, from, the, crystal, structure])].
[sujeto(['Simultaneous', addition, of, protein, 'S17', with, 'S20', to, the, complex, significantly, alters, the, modifications]), verbo([caused]), complemento([by, protein, 'S20', in, the, stem, region, of, helix, 11, but, does, not, alter, the, remaining, modifications])].
[sujeto(['Our', results, indicate, that, protein, 'S20', is]), verbo([binding]), complemento([to, at, least, two, alternate, 16, 'S', rRNA, sites, during, the, early, assembly, process])].
[sujeto(['Quantitative', 'real-time', reverse, transcription, 'PCR', '(', 'qRT-PCR)']), verbo([has]), complemento([become, a, widely, used, method, for, gene, expression, 'analysis;', 'however,', its, data, interpretation, largely, depends, on, the, stability, of, reference, genes])].
[sujeto(['Although', the, best, reference, genes, were]), verbo([found]), complemento([to, vary, across, different, 'samples,', 'CYP', and, 'EF-1α', were, the, most, stable, genes, amongst, all, samples])].
[sujeto(['CYP/60S', 'RPL13,', 'CYP/eIF-5A,', 'aTUB/V-ATP,', 'eIF-5A/SAR1,', and, 'aTUB/pol', 'IIa', were, the, most, stably]), verbo([expressed]), complemento([combinations, in, each, of, the, five, developmental, stages])].
[sujeto(['Efficient', use, of, feed, resources]), verbo([has]), complemento([become, a, clear, challenge, for, the, 'U'])].
[sujeto(['The', availability, of, the, 'Illumina', 'Porcine60K', 'BeadChip']), verbo([has]), complemento([greatly, facilitated, 'whole-genome', association, studies, to, identify, chromosomal, regions, harboring, genes, influencing, those, traits])].
[sujeto(['The', current, study, aimed, at, identifying, genomic, regions]), verbo([associated]), complemento([with, variation, in, feed, efficiency, and, several, production, traits, in, a, 'Duroc', terminal, sire, 'population,', including, 'ADFI,', 'ADG,', feed, conversion, 'ratio,', residual, feed, intake, '(', 'RFI),', 'real-time', ultrasound, back, fat, thickness, '(', 'BF),', ultrasound, muscle, 'depth,', intramuscular, fat, content, '(', 'IMF),', birth, weight, '(', 'BW', at, 'birth),', and, weaning, weight, '(', 'BW', at, 'weaning)'])].
[sujeto(['A', region, ranging, from166, to, 140, 'Mb', '(', 4, -, 'Mb', 'length)', on, 'SSC', 1, ',', approximately, 8, 'Mb', upstream, of, the, 'MC4R', 'gene,', was, significantly]), verbo([associated]), complemento([with, 'ADFI,', 'ADG,', and, 'BF,', where, 'SOCS6', and, 'DOK6', are, proposed, as, the, most, likely, candidate, genes])].
[sujeto(['Another', region, affecting, 'BW', at, weaning, was, identified, on, 'SSC', 4, '(', 84, -, 85, 'Mb),', harboring, genes, previously]), verbo([found]), complemento([to, influence, both, human, and, cattle, 'height:', 'PLAG1,', 'CHCHD7,', 'RDHE2', '(', or, 'SDR16C5),', 'MOS,', 'RPS20,', 'LYN,', and, 'PENK'])].
[sujeto(['In', 'conclusion,', we]), verbo([have]), complemento([identified, several, genomic, regions, associated, with, traits, affecting, nutrient, utilization, that, could, be, considered, for, future, genomic, prediction, to, improve, feed, utilization])].
[sujeto(['Compared', with, the, 'WT,', 1529, and, 405]), verbo([expressed]), complemento([sequence, tags, were, significantly, 'up-', or, downregulated, on, days, 119, and, 147, ',', respectively])].
[sujeto(['The', differentially]), verbo([expressed]), complemento([genes, '(', 'DEGs)', are, involved, in, metabolic, 'regulation,', cell, division, and, 'differentiation,', material, synthesis, and, 'transport,', signal, 'transduction,', and, protein, synthesis, and, degradation])].
[sujeto(['Candidate', genes, that, may]), verbo([increase]), complemento([cell, 'density,', thicken, cell, 'walls,', promote, secondary, metabolite, 'synthesis,', and, mediate, plant, 'hormone-induced', resistance, responses, were, used, to, identify, the, 'ChIFN-γ-mediated', 'insect-resistance', mechanisms])].
[sujeto(['The', 'insect-resistance', of, transgenic, 'ChIFN-γ', tobacco, possibly]), verbo([involves]), complemento([unknown, signaling, 'pathways,', which, may, directly, or, indirectly, affect, 'DEG', 'expression-mediating', genes])].
[sujeto(['The', degree, of, pest, resistance]), verbo([increased]), complemento([as, the, plants, grew])].
[sujeto(['The', mechanism, of, transgenic, 'ChIFN-γ', tobacco, resistance, also]), verbo([involves]), complemento(['RPS20', and, other, genes, that, induce, 'microRNA-based', gene, regulation])].
[sujeto(['The', 'ChIFN-γ-mediated', 'DGEs', contribute, to, 'insect-resistance', in, transgenic, 'ChIFN-γ', 'tobacco,', which]), verbo([provides]), complemento([new, insight, into, the, role, of, 'ChIFN-γ'])].
[sujeto(['Birth', weight, '(', 'BW)', is, an, economically, important, trait, in, beef, 'cattle,', and, is]), verbo([associated]), complemento([with, 'growth-', and, 'stature-related', traits, and, calving, difficulty])].
[sujeto(['One', region, of, the, cattle, 'genome,', located, on, 'Bos', primigenius, taurus, chromosome, 14, '(', 'BTA14),']), verbo([has]), complemento([been, previously, shown, to, be, associated, with, stature, by, multiple, independent, 'studies,', and, contains, orthologous, genes, affecting, human, height])].
[sujeto(['The', region, also, overlapped, 28, quantitative, trait, loci, '(', 'QTLs)', previously]), verbo([reported]), complemento([in, literature, by, linkage, mapping, studies, in, 'cattle,', including, 'QTLs', for, birth, 'weight,', mature, 'height,', carcass, 'weight,', 'stature,', 'pre-weaning', average, daily, 'gain,', calving, 'ease,', and, gestation, length])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, 'QTLs', on, 'BTA14', associated, with, body, size, in, taurine, cattle, '(', 'Bos', primigenius, 'taurus)', also, affect, birth, weight, and, size, in, zebu, cattle, '(', 'Bos', primigenius, 'indicus)'])].
[sujeto(['Eukaryotic', translation, initiation, factor, '(', 'eIF)4B']), verbo([stimulates]), complemento([recruitment, of, mRNA, to, the, 43, 'S', ribosomal, 'pre-initiation', complex, '(', 'PIC)'])].
[sujeto(['Yeast', eIF4B, '(', 'yeIF4B),', shown, previously, to]), verbo([bind]), complemento(['single-stranded', '(', 'ss)', 'RNA,', consists, of, an, 'N-terminal', domain, '(', 'NTD),', predicted, to, be, unstructured, in, 'solution;', an, 'RNA-recognition', motif, '(', 'RRM);', an, unusual, domain, comprised, of, seven, imperfect, repeats, of, 26, amino, 'acids;', and, a, 'C-terminal', domain])].
[sujeto(['Although', the, mechanism, of, yeIF4B, action]), verbo([has]), complemento([remained, 'obscure,', most, models, have, suggested, central, roles, for, its, 'RRM', and, 'ssRNA-binding', activity])].
[sujeto(['We']), verbo([have]), complemento([dissected, the, functions, of, 'yeIF4B\'s', domains, and, show, that, the, 'RRM', and, its, 'ssRNA-binding', activity, are, dispensable, in, vitro, and, in, vivo])].
[sujeto(['Instead,', our, data, indicate, that, the, 7, -, repeats, and, 'NTD', are, the, most, critical, 'domains,', which]), verbo([mediate]), complemento([binding, of, yeIF4B, to, the, head, of, the, 40, 'S', ribosomal, subunit, via, interaction, with, 'Rps20'])].
[sujeto(['This', interaction]), verbo([induces]), complemento([structural, changes, in, the, 'ribosome\'s', mRNA, entry, channel, that, could, facilitate, mRNA, loading])].
[sujeto(['We', also, show, that, yeIF4B, strongly]), verbo([promotes]), complemento([productive, interaction, of, eIF4A, with, the, 43, 'S•mRNA', 'PIC', in, a, manner, required, for, efficient, mRNA, recruitment])].
[sujeto(['Glioblastoma', is, a, complex, multifactorial, disorder, that]), verbo([has]), complemento([swift, and, devastating, consequences])].
[sujeto(['Few', genes]), verbo([have]), complemento([been, consistently, identified, as, prognostic, biomarkers, of, glioblastoma, survival])].
[sujeto(['A', total, of, 61, ',', 47, and, 60, gene, expression, profiles, were, significantly]), verbo([associated]), complemento([with, 'lifetime,', 'overall,', and, 'progression-free', 'survival,', respectively])].
[sujeto(['The', vast, majority, of, these, genes]), verbo([have]), complemento([been, previously, reported, to, be, associated, with, glioblastoma, '(', 35, ',', 24, ',', and, 35, 'genes,', 'respectively)', or, with, other, cancers, '(', 10, ',', 19, ',', and, 15, 'genes,', 'respectively)', and, the, rest, '(', 16, ',', 4, ',', and, 10, 'genes,', 'respectively)', are, novel, associations])].
[sujeto(['Pik3r1,', 'E2f3,', 'Akr1c3,', 'Csf1,', 'Jag2,', 'Plcg1,', 'Rpl37a,', 'Sod2,', 'Topors,', 'Hras,', 'Mdm2,', 'Camk2g,', 'Fstl1,', 'Il13ra1,', 'Mtap', and, 'Tp53', were]), verbo([associated]), complemento([with, multiple, survival, events])].
[sujeto(['Most', genes, '(', from, 90, to, 96, '%', ')', were]), verbo([associated]), complemento([with, survival, in, a, general, or, 'cohort-independent', manner, and, thus, the, same, trend, is, observed, across, all, clinical, levels, studied])].
[sujeto(['Several', genes, were]), verbo([found]), complemento([to, have, a, 'cohort-dependent', association, with, survival, and, these, associations, are, the, basis, for, individualized, prognostic, and, 'gene-based', therapies])].
[sujeto(['Biological', processes]), verbo([associated]), complemento([glioblastoma, survival, included, 'morphogenesis,', cell, 'cycle,', 'aging,', response, to, 'stimuli,', and, programmed, cell, death])].
[sujeto(['In', 'RT-qPCR,', the, expression, levels, of]), verbo([target]), complemento([genes, are, estimated, on, the, basis, of, endogenous, controls])].
[sujeto(['Although', determination, of, suitable, reference, genes, is, essential, to, 'RT-qPCR', 'studies,']), verbo([reports]), complemento([on, the, evaluation, of, reference, genes, in, 'D'])].
[sujeto(['The', differences, between, the, experimental, treatments]), verbo([suggest]), complemento([that, assessing, the, stability, of, reference, gene, expression, 'patterns,', determining, candidates, and, testing, their, suitability, is, required, for, each, experimental, investigation])].
[sujeto(['Recent']), verbo([reports]), complemento([have, begun, unraveling, the, details, of, various, roles, of, individual, eukaryotic, translation, initiation, factor, 3, '(', 'eIF3)', subunits, in, translation, initiation])].
[sujeto(['Here', we, describe, functional, characterization, of, two, essential, 'Saccharomyces', cerevisiae, eIF3, 'subunits,', 'g/Tif35', and, 'i/Tif34,', previously]), verbo([suggested]), complemento([to, be, dispensable, for, formation, of, the, 48, 'S', preinitiation, complexes, '(', 'PICs)', in, vitro])].
[sujeto(['A', 'triple-Ala', substitution, of]), verbo([conserved]), complemento([residues, in, the, 'RRM', of, 'g/Tif35', '(', 'g/tif35-KLF)', or, a, 'single-point', mutation, in, the, 'WD40', repeat, 6, of, 'i/Tif34', '(', 'i/tif34-Q258R)', produces, severe, growth, defects, and, decreases, the, rate, of, translation, initiation, in, vivo, without, affecting, the, integrity, of, eIF3, and, formation, of, the, 43, 'S', 'PICs', in, vivo])].
[sujeto(['Whereas', 'g/tif35-KLF', impedes, resumption, of, scanning, for, downstream, reinitiation, by, 40, 'S', ribosomes, terminating, at, upstream, open, reading, frame, 1, '(', 'uORF1)', in, the, 'GCN4', mRNA, 'leader,', 'i/tif34-Q258R']), verbo([prevents]), complemento([full, 'GCN4', derepression, by, impairing, the, rate, of, scanning, of, posttermination, 40, 'S', ribosomes, moving, downstream, from, uORF1])].
[sujeto(['In', 'addition,', 'g/tif35-KLF', reduces, processivity, of, scanning, through, stable, secondary, 'structures,', and, 'g/Tif35', specifically]), verbo([interacts]), complemento([with, 'Rps3', and, 'Rps20', located, near, the, ribosomal, mRNA, entry, channel])].
[sujeto(['Diverticula', of, the, colon, and, their, symptomatic, 'manifestations,', including, acute, diverticulitis, '(', 'AD),', are, frequent, complaints, and, the]), verbo([cause]), complemento([of, an, increasing, burden, of, ambulatory, 'visits,', diagnostic, 'procedures,', and, hospital, admissions])].
[sujeto(['Endoscopic', and, radiologic, diagnostic, procedures]), verbo([have]), complemento([a, 'well-known', role, in, the, diagnosis, and, management, of, the, 'disease,', but, recently, intestinal, ultrasonography, has, been, proposed, as, a, complementary, tool, in, the, diagnosis, and, 'follow-up', of, diverticular, disease])].
[sujeto(['This', review, shows, the, main, sonographic, features, of, diverticula, and, discusses, the, potential, role, of, ultrasound, in]), verbo([suggesting]), complemento([the, presence, of, symptomatic, uncomplicated, diverticular, disease, of, the, colon])].
[sujeto(['Owing', to, its, high, sensitivity, and, high, positive, predictive, value, in, assessing, 'AD,', intestinal, ultrasound, is, currently]), verbo([suggested]), complemento([by, some, 'European', national, consensus, guidelines, as, the, 'first-line', examination, in, this, setting])].
[sujeto(['Cancer', stem, cells, '(', 'CSCs)', are, a, class, of, pluripotent, cells, that]), verbo([have]), complemento([been, observed, in, most, types, of, solid, and, hematologic, cancers])].
[sujeto(['CSCs']), verbo([have]), complemento([been, shown, in, numerous, cancer, models, to, be, involved, in, tumor, 'development,', cell, 'proliferation,', and, metastatic, 'dissemination,', while, possessing, a, capacity, for, sustained, 'self-renewal'])].
[sujeto(['Indeed,', exposure, to, these, treatments, may]), verbo([promote]), complemento([&, 'quot;stemness"', in, nonstem, cancer, 'cells,', which, may, explain, why, successful, therapeutic, reduction, of, tumor, bulk, will, often, fail, to, produce, clinical, improvement])].
[sujeto(['Acquisition', of, stemness]), verbo([involves]), complemento(['epithelial-mesenchymal', transition, '(', 'EMT),', in, which, epithelial, cells, are, transformed, into, a, mesenchymal, phenotype, characterized, by, increased, capacities, for, 'migration,', 'invasiveness,', and, resistance, to, apoptosis])].
[sujeto(['These', include, agents]), verbo([targeting]), complemento([tumorigenic, 'pathways,', such, as, 'JAK2/STAT3', and, 'PI3K/mTOR,', and, 'immunotherapies,', including, vaccines, and, natural, killer, cells, employed, to, induce, a, 'T', cell, response])].
[sujeto(['The', swiftness, of, the]), verbo([decrease]), complemento([in, maternal, mortality, per, 'five-year', 'period,', the, variation, in, the, percentage, of, 'abortion-related', 'deaths,', and, the, correlation, with, 'HDI', indicators, were, evaluated])].
[sujeto(['Maternal', mortality]), verbo([decreased]), complemento(['significantly,', basically, due, to, a, reduction, in, the, number, of, deaths, from, unsafe, 'abortion,', which, was, the, principal, cause, of, maternal, mortality, in, the, 1990, s])].
[sujeto(['This', coincided, with, the, application, of, a, model, for, reducing, the, risk, and, harm, of, unsafe, 'abortions,', which, finally]), verbo([led]), complemento([to, the, decriminalization, of, abortion])].
[sujeto(['The', disease, in, adults]), verbo([has]), complemento([a, complex, genetic, and, environmental, inheritability])].
[sujeto(['One', of, the, main, risk, 'factors,', also, confirmed, in, pediatric, 'MS,', is, 'HLA', 'DRB1*1501', 'In', addition, to, genetic, 'factors,', a, large, part, of, disease, susceptibility, in, adults, is]), verbo([conferred]), complemento([by, environmental, risk, factors, such, as, low, vitamin, 'D', 'status,', exposure, to, cigarette, 'smoking,', and, remote, 'Epstein-Barr', virus, '(', 'EBV)', infection])].
[sujeto(['In', 'children,', both, exposure, to, cigarette, smoking, and, prior, 'EBV', infection]), verbo([have]), complemento([been, reported, consistently, as, risk, factors, for, 'MS'])].
[sujeto(['Finally,', although, very, likely, critical, in, disease, 'processes,', few, 'gene-environment', interactions, and, epigenetic, changes]), verbo([have]), complemento([been, reported, for, adult, and, pediatric, 'MS', susceptibility])].
[sujeto(['Of', 'interest,', some, of, the, risk, factors, for, 'MS']), verbo([have]), complemento([also, been, associated, with, disease, course, 'modification,', such, as, low, 25, '(', 'OH)', vitamin, 'D', serum, levels, in, pediatric, and, adult, 'MS'])].
[sujeto(['Finally,', although, much]), verbo([has]), complemento([yet, to, be, unraveled, regarding, molecular, processes, at, play, in, 'MS,', there, is, a, larger, gap, in, our, knowledge, of, genetic, and, environmental, risk, factors, for, pediatric, neuromyelitis, optica, spectrum, disorders, and, acute, disseminated, encephalomyelitis, and, only, collaborative, studies, will, answer, those, questions])].
[sujeto(['The', oral, examination]), verbo([has]), complemento([been, an, integral, part, of, certification, by, the, 'American', 'Board', of, 'Ophthalmology', '(', 'ABO)', since, its, founding, in, 1916])].
[sujeto(['An', overview, is]), verbo([provided]), complemento([regarding, the, 'history,', 'evolution,', and, application, of, new, technology, for, the, oral, examination])].
[sujeto(['Quality', and, safety, management]), verbo([have]), complemento([been, implemented, for, many, years, in, healthcare, structures, '(', hospitals, treating, 'cancer,', private, radiotherapy, 'centres)'])].
[sujeto(['Their', structure, and, formalization]), verbo([have]), complemento([improved, progressively, over, time])].
[sujeto(['The', third, category, is, on, 'Materia', 'Medica', covering, the, aspect, of, 'Unani', 'medicine,', from, which, only, 28, volumes, of, the, comprehensive, book, on, the, traditional, medicine]), verbo([have]), complemento([been, found, so, far])].
[sujeto(['Hypoglossal', nerve, stimulation, with, an]), verbo([activated]), complemento([implanted, device, does, not, awaken, individuals, from, sleep, once, they, have, acclimated, to, the, new, sensation, of, the, resulting, tongue, movement])].
[sujeto(['This', case]), verbo([report]), complemento([illustrates, the, importance, of, an, acclimation, 'period,', allowing, a, patient, to, become, accustomed, to, stimulation, settings, below, the, level, at, which, there, is, gross, tongue, movement])].
[sujeto(['For', pure, monomer, d, 'solution,', 'SDS']), verbo([promotes]), complemento([the, dimerization, of, subunit, 'd,', and, the, monomeric, and, dimeric, forms, have, sedimentation, coefficient, 'values,', 's20,w,', around, 2.1, -, 2.4, 'S', and, 2.9, -, 3.2, 'S,', respectively])].
[sujeto(['Analytical', ultracentrifugation, '(', 'AUC)', and, isothermal, titration, calorimetry, '(', 'ITC)', data]), verbo([suggest]), complemento([that, up, to, 26, 'DS(-)', anions, are, bound, to, the, monomer])].
[sujeto(['For', the, 'oxy-HbGp,', 'SDS']), verbo([induces]), complemento([the, dissociation, into, smaller, 'subunits,', such, 'as,', monomer, 'd,', trimer, 'abc,', and, tetramer, 'abcd,', and, unfolding, without, promoting, the, protein, aggregation])].
[sujeto(['On', the, other, 'hand,', lower, 'CTAC', concentration]), verbo([promotes]), complemento([protein, 'aggregation,', mainly, of, 'trimer,', while, higher, concentration, induces, the, unfolding, of, dissociated, species])].
[sujeto(['Our', study]), verbo([provides]), complemento([strong, evidence, that, surfactant, effects, upon, the, 'HbGp-subunits', are, 'different,', and, depend, on, the, 'surfactant:', protein, concentration, ratio, and, the, charges, of, surfactant, headgroups])].
[sujeto([citri, in, a, 'persistent-circulative', 'manner,', but, the, question, of, replication, of, this, bacterium, in, its, psyllid, vector]), verbo([has]), complemento([not, been, resolved])].
[sujeto(['Q-PCR', analysis, also, indicated, that, 'Las', titer, in, the, 'Las-exposed', psyllids, '(', relative, to, that, of, the, psyllid, 'S20', ribosomal, protein, 'gene)', 'was:', 1, ')', significantly, 'higher,', and]), verbo([increasing]), complemento([at, a, faster, 'rate,', following, 'Las', acquisition, as, nymphs, compared, to, that, following, 'Las', acquisition, as, 'adults;', 2, ')', higher, as, 'post-acquisition', time, of, psyllids, on, healthy, plants, increased, reaching, a, peak, at, 14, -, 28, days, padp, for, nymphs, and, 21, -, 35, days, padp, for, 'adults,', with, 'Las', titer, decreasing, or, fluctuating, after, 'that;', 3, ')', higher, with, longer, 'AAP', on, infected, 'plants,', especially, with, acquisition, as, adults])].
[sujeto(['Our', results, strongly]), verbo([suggest]), complemento([that, 'Las', multiplies, in, both, nymphs, and, adults, of, 'D'])].
[sujeto([citri, but, attains, much, higher, levels, in, a, shorter, period, of, time, 'post-acquisition', when, acquired, by, nymphs, than, when, acquired, by, 'adults,', and, that, adults, may]), verbo([require]), complemento([longer, access, to, infected, plants, compared, to, nymphs, for, 'Las', to, reach, higher, levels, in, the, vector])].
[sujeto(['The', higher, probability, of, 'Las', inoculation, into, citrus, by, psyllids, when, they]), verbo([have]), complemento([acquired, this, bacterium, from, infected, plants, during, the, nymphal, rather, than, the, adult, 'stage,', as, reported, by, us, and, 'others,', has, significant, implications, in, the, epidemiology, and, control, of, this, economically, important, citrus, disease])].
[sujeto(['The', association, between, income, inequality, and, societal, performance]), verbo([has]), complemento([been, intensely, debated, in, recent, decades])].
[sujeto(['This', paper]), verbo([reports]), complemento([how, unmet, need, for, medical, care, has, changed, in, 'Europe', during, 'The', 'Great', 'Recession,', and, investigates, whether, countries, with, smaller, income, differences, have, been, more, successful, than, inegalitarian, countries, in, protecting, access, to, medical, care, during, an, economic, crisis])].
[sujeto(['Foregone', medical, care]), verbo([increased]), complemento([2008, -, 2013, in, the, majority, of, the, 30, 'countries,', especially, among, the, disadvantaged, parts, of, the, population])].
[sujeto(['During', 'The', 'Great', 'Recession,', unmet, need, for, medical, care]), verbo([increased]), complemento([in, 'Europe,', and, social, inequalities, in, foregone, medical, care, widened])].
[sujeto(['Overall,', countries, with, a, more, egalitarian, income, distribution]), verbo([have]), complemento([been, more, able, to, protect, their, 'populations,', and, especially, disadvantaged, 'groups,', against, deteriorated, access, to, medical, care, when, the, country, is, confronted, with, an, economic, crisis])].
[sujeto(['These', cations, can]), verbo([interact]), complemento([with, the, phosphate, groups, of, the, 'DNA', segment, 'and/or', with, the, 'O6', oxygen, atom, of, 'guanines,', which, are, called, 'non-specific', interactions, and, specific, 'interactions,', respectively])].
[sujeto(['However,', until, now, how, these, two, interactions, affect, the, structure, of, 'HT-DNA']), verbo([has]), complemento([not, been, well, understood])].
[sujeto(['The', results, showed, that, the, standard, sedimentation, coefficient, '(', 's20,w)', of, 'HT-DNA', starts, to]), verbo([increase]), complemento([when, the, concentration, of, potassium, ions, '(', 'CK(+))', is, higher, than, 10.0, µM, due, to, the, formation, of, a, 'G-quadruplex', through, specific, interactions])].
[sujeto(['Whereas,', for, a, control, 'DNA,', a, higher, 'CK(+)', value, of, 1.0, mM, was, needed, for]), verbo([increasing]), complemento(['s20,w', due, to, 'non-specific', interactions])].
[sujeto(['Moreover,', potassium, ions, could]), verbo([promote]), complemento([the, formation, of, the, 'G-quadruplex', much, more, easily, than, 'lithium,', sodium, and, cesium, 'ions,', presumably, due, to, its, appropriate, size, in, the, dehydrated, state, and, easier, dehydration])].
[sujeto(['One', of, the, most, successful, treatments, for, 'ITP', is, intravenous, immunoglobulin, '(', 'IVIg),', and, while, it]), verbo([has]), complemento([been, used, in, 'ITP', for, over, 30, 'years,', its, 'mechanism(s)', of, action, still, remain, unclear])].
[sujeto(['Animal', models, of, 'ITP']), verbo([have]), complemento([proven, useful, in, understanding, 'IVIg\'s', immunomodulatory, 'properties,', providing, a, valuable, tool, to, test, new, mechanistic, theories, as, well, as, further, explore, the, soundness, of, older, ones])].
[sujeto(['This', model]), verbo([has]), complemento([also, provided, the, key, evidence, that, 'IVIg', exerts, its, effects, via, activating, receptors, for, 'IgG', 'Fc,', specifically, 'FcγRIII,', via, formation, of, 'IgG', dimers, or, immune, complexes])].
[sujeto(['Here,', we, discuss, the, validity, of, one, prominent, theory, of, 'IVIg', 'function,', 'anti-inflammatory', activity]), verbo([mediated]), complemento([through, the, inhibitory, 'Fcγ', receptor, 'FcγRIIB,', and, review, evidence, to, suggest, that, this, theory, is, not, likely, valid, in, the, practical, sense])].
[sujeto(['At', 'first,', we, show, that, 'Slovakia']), verbo([has]), complemento([the, worst, values, of, standardised, mortality, rates, for, ischemic, heart, diseases, in, 'EU', countries])].
[sujeto(['Very', few, investigations]), verbo([have]), complemento([been, carried, out, to, ascertain, the, structural, changes, that, occur, in, the, groin, affected, by, this, clinical, condition])].
[sujeto(['In', the, same, patient, 'cohort,', double, inguinal, hernia, further]), verbo([involves]), complemento([22, '%', of, elderly, subjects])].
[sujeto(['The', results, seem, to, confirm, that, inguinal, hernia, is, an, unremitting, progressive, disease]), verbo([caused]), complemento([by, chronic, compressive, structural, damage])].
[sujeto(['Among', preterm, infants, with, late, 'HRF,', the, pulmonary, vascular, abnormalities]), verbo([associated]), complemento([with, bronchopulmonary, dysplasia, '(', 'BPD)', represent, a, therapeutic, challenge, for, clinicians])].
[sujeto(['Surfactant,', inhaled, nitric, oxide, '(', 'iNO),', 'sildenafil,', prostacyclin, and, endothelin, receptor, blockers]), verbo([have]), complemento([been, used, to, manage, infants, with, both, early, and, late, 'HRF'])].
[sujeto(['Chronic', oral, sildenafil, therapy, for, 'BPD-associated', 'PH']), verbo([has]), complemento([demonstrated, some, preliminary, efficacy])].
[sujeto(['A', favorable, response, to, iNO]), verbo([has]), complemento([been, documented, in, some, preterm, infants, with, early, 'PH', following, premature, prolonged, rupture, of, membranes, and, oligohydramnios])].
[sujeto(['Management', is, complicated, by, a, lack, of, clear, demarcation, between, interventions, designed, to, manage, respiratory, distress, 'syndrome,']), verbo([prevent]), complemento(['BPD', and, treat, 'HRF'])].
[sujeto(['Greater', insight, into, the, spectrum, of, disease, phenotypes, represented, by, 'BPD', can, optimize, existing, therapies, and]), verbo([promote]), complemento([development, of, new, treatments])].
[sujeto(['In', 'addition,', better, understanding, of, an, 'individual\'s', 'phenotype,', genotype, and, biomarkers, may]), verbo([suggest]), complemento([targeted, personalized, interventions])].
[sujeto(['Initiatives', such, as, the, 'Prematurity', and, 'Respiratory', 'Outcomes', 'Program']), verbo([provide]), complemento([a, framework, to, address, these, challenges, using, 'genetic,', 'environmental,', physiological, and, clinical, data, as, well, as, large, repositories, of, patient, samples])].
[sujeto(['Compared', with, that, of, the, control, 'group,', the, protein, expression, of, 'C3', and, 'AC2']), verbo([increased]), complemento([significantly, in, the, 'NIPPV', group, '(', 'P', &, 'lt;', 0.01, ')'])].
[sujeto(['There', is, growing, evidence, in, support, of, mitochondrial, translation, in, trypanosomes, but, mitoribosomes]), verbo([have]), complemento([never, been, characterized, or, localized, in, these, parasites])].
[sujeto(['On', 'RNA-protein', blots, we, identified, several, proteins, from, the, trypanosomatid, 'Crithidia', fasciculata, which]), verbo([bound]), complemento([the, 'parasite\'s', 12, 'S', and, 9, 'S', mitochondrial, ribosomal, 'RNAs'])].
[sujeto(['The', proteins, were, immunologically, related, to, two, cytosolic, riboproteins, which, were, also, of, identical, 'size,']), verbo([suggesting]), complemento([the, interesting, possibility, that, the, same, set, of, riboproteins, is, shared, between, the, cytosol, and, the, mitochondrion, in, this, parasite])].
[sujeto(['Translation', of, mitochondrial, mRNAs, in, 'Saccharomyces', cerevisiae, depends, on, 'mRNA-specific', translational, activators, that]), verbo([recognize]), complemento([the, 5, '\'', untranslated, leaders, '(', 5, '\'', -, 'UTLs)', of, their, target, mRNAs])].
[sujeto(['We']), verbo([have]), complemento([identified, mutations, in, two, new, nuclear, genes, that, suppress, translation, defects, due, to, certain, alterations, in, the, 5, '\'', -, 'UTLs', of, both, the, 'COX2', and, 'COX3', 'mRNAs,', indicating, a, general, function, in, translational, activation])].
[sujeto([coli, 'S21,', which, is, known, to]), verbo([interact]), complemento([with, mRNAs])].
[sujeto(['Interactions', of, the, suppressor, mutations, with, leaky, mitochondrial, initiation, codon, mutations, strongly]), verbo([suggest]), complemento([that, the, suppressors, do, not, generally, increase, translational, 'efficiency,', since, some, alleles, that, strongly, suppress, 5, '\'', -, 'UTL', mutations, fail, to, suppress, initiation, codon, mutations])].
[sujeto(['We', propose, that, mitochondrial, ribosomes, themselves]), verbo([recognize]), complemento([a, common, feature, of, mRNA, 5, '\'', -, 'UTLs', 'which,', in, conjunction, with, 'mRNA-specific', translational, 'activation,', is, required, for, organellar, translation, initiation])].
[sujeto(['The', 'RPL44\'', gene, from, 'Saccharomyces', cerevisiae, encoding, the, ribosomal, protein, 'YP1', 'beta(L44\')']), verbo([has]), complemento([been, found, to, be, linked, to, the, 'STF1', 'gene,', encoding, a, stabilizing, factor, of, the, 'F1F0-ATPase', inhibitor, protein, from, mitochondria])].
[sujeto(['Similarly,', a, data, bank, search]), verbo([has]), complemento([shown, that, 'RPL44,', encoding, ribosomal, protein, 'YP2', alpha, '(', 'L44)', is, linked, to, the, rig, gene, that, encodes, ribosomal, protein, 'S21'])].
[sujeto(['Digital', gene, expression, profiling, was, used, to, characterize, the, assembly, of, genes]), verbo([expressed]), complemento([in, equine, skeletal, muscle, and, to, identify, the, subset, of, genes, that, were, differentially, expressed, following, a, 'ten-month', period, of, exercise, training])].
[sujeto(['The', most, abundant, mRNA, transcripts, in, the, muscle, transcriptome, were, those]), verbo([involved]), complemento([in, muscle, 'contraction,', aerobic, respiration, and, mitochondrial, function])].
[sujeto(['Following', training, 92, tags, were, differentially]), verbo([expressed]), complemento([of, which, 74, were, annotated])].
[sujeto(['Sixteen', genes, showed]), verbo([increased]), complemento(['expression,', including, the, mitochondrial, genes, 'ACADVL,', 'MRPS21', and, 'SLC25A29', encoded, by, the, nuclear, genome])].
[sujeto(['Among', the, 58, genes, with]), verbo([decreased]), complemento(['expression,', 'MSTN,', a, negative, regulator, of, muscle, 'growth,', had, the, greatest, decrease])].
[sujeto(['Functional', analysis, of, all]), verbo([expressed]), complemento([genes, using, 'FatiScan', revealed, an, asymmetric, distribution, of, 482, 'Gene', 'Ontology', '(', 'GO)', groups, and, 18, 'KEGG', pathways])].
[sujeto(['Functional', groups, displaying, highly, significant, '(', 'P', &, 'lt;', 0.0001, ')']), verbo([increased]), complemento([expression, included, 'mitochondrion,', oxidative, phosphorylation, and, fatty, acid, metabolism, while, functional, groups, with, decreased, expression, were, mainly, associated, with, structural, genes, and, included, the, 'sarcoplasm,', laminin, complex, and, cytoskeleton])].
[sujeto(['Mitochondrial', disorders, are, clinically, and, genetically, 'diverse,', with, mutations, in, mitochondrial, or]), verbo([nuclear]), complemento([genes, able, to, cause, defects, in, mitochondrial, gene, expression])].
[sujeto(['Recently,', mutations, in, several, genes, encoding, factors]), verbo([involved]), complemento([in, 'mt-tRNA', processing, have, been, identified, to, cause, mitochondrial, disease])].
[sujeto(['Additionally,', a, stable, complex, of, 'MRPP1', and, 'MRPP2']), verbo([has]), complemento(['m(1)R9', methyltransferase, 'activity,', which, methylates, 'mt-tRNAs', at, position, 9, and, is, vital, for, folding, 'mt-tRNAs', into, their, correct, tertiary, structures])].
[sujeto(['Analyses', of, fibroblasts, from, affected, individuals, harboring, 'TRMT10C', missense, variants, revealed]), verbo([decreased]), complemento([protein, levels, of, 'MRPP1', and, an, increase, in, 'mt-RNA', precursors, indicative, of, impaired, 'mt-RNA', processing, and, defective, mitochondrial, protein, synthesis])].
[sujeto(['Our', study]), verbo([suggests]), complemento([that, these, variants, affect, 'MRPP1', protein, stability, and, 'mt-tRNA', processing, without, affecting, 'm(1)R9', methyltransferase, 'activity,', identifying, mutations, in, 'TRMT10C', as, a, cause, of, mitochondrial, disease, and, highlighting, the, importance, of, 'RNA', processing, for, correct, mitochondrial, function])].
[sujeto(['We']), verbo([report]), complemento([a, 'Caucasian', boy, with, intractable, epilepsy, and, global, developmental, delay])].
[sujeto(['Mutations', in, 'HSD17B10']), verbo([cause]), complemento([the, 'HSD10', 'disease,', traditionally, classified, as, a, metabolic, disorder, due, to, the, role, of, 'SDR5C1', in, fatty, and, amino, acid, metabolism])].
[sujeto(['K212E', mutation, impairs, the, 'SDR5C1-dependent', mitochondrial, 'RNase', 'P', 'activities,', and]), verbo([suggest]), complemento([that, the, pathogenicity, of, p])].
[sujeto(['K212E', is, due, to, a, general, mitochondrial, dysfunction]), verbo([caused]), complemento([by, reduction, in, 'SDR5C1-dependent', maturation, of, mitochondrial, tRNAs])].
[sujeto(['Moreover,', a, subcomplex, of, mitochondrial, 'RNase', 'P', catalyzes, the, 'N(1)-methylation', of, purines, at, position, 9, ',', a, modification]), verbo([found]), complemento([in, most, mitochondrial, tRNAs, and, thought, to, stabilize, their, structure])].
[sujeto(['Missense', mutations, in, 'SDR5C1']), verbo([cause]), complemento([a, disease, characterized, by, progressive, neurodegeneration, and, 'cardiomyopathy,', called, 'HSD10', disease])].
[sujeto(['We']), verbo([have]), complemento([investigated, the, effect, of, selected, mutations, on, 'SDR5C1\'s', functions])].
[sujeto(['We', propose, that, the, structural, and, functional, alterations, of, 'SDR5C1', impair, mitochondrial, 'RNA', processing, and, 'modification,']), verbo([leading]), complemento([to, the, mitochondrial, dysfunction, observed, in, 'HSD10', patients])].
[sujeto(['Mutations', in, this, gene]), verbo([cause]), complemento(['HSD10', disease, characterized, by, progressive, neurological, abnormalities, and, cardiomyopathy])].
[sujeto(['Recently,', it, was, shown, that, 'HSD10', is, an, essential, component, of, mitochondrial, 'Ribonuclease', 'P', '(', 'RNase', 'P),', an, enzyme]), verbo([required]), complemento([for, mitochondrial, tRNA, 'processing,', but, little, is, known, about, the, role, of, 'HSD10', in, 'RNase', 'P', function])].
[sujeto(['Our', findings, indicate, that, 'HSD10', is, important, for, the, maintenance, of, the, 'MRPP1-HSD10', subcomplex, of, 'RNase', 'P', and, that]), verbo([loss]), complemento([of, 'HSD10', causes, impaired, mitochondrial, precursor, transcript, processing, which, may, explain, mitochondrial, dysfunction, observed, in, 'HSD10', disease])].
[sujeto(['The', 'amyloid-β', peptide, '(', 'Aβ)', is]), verbo([suggested]), complemento([to, cause, mitochondrial, dysfunction, in, 'Alzheimer\'s', disease])].
[sujeto(['The', mitochondrial, dehydrogenase, 'SDR5C1', '(', also, known, as, 'ABAD)', was, shown, to]), verbo([bind]), complemento(['Aβ', and, was, proposed, to, thereby, mediate, mitochondrial, 'toxicity,', but, the, molecular, mechanism, has, not, been, clarified])].
[sujeto(['We', recently, identified, 'SDR5C1', as, an, essential, component, of, human, mitochondrial, 'RNase', 'P', and, its]), verbo([associated]), complemento(['tRNA:m¹R9', 'methyltransferase,', the, enzymes, responsible, for, tRNA, 5, '\'', -, end, processing, and, methylation, of, purines, at, tRNA, position, 9, ',', respectively])].
[sujeto(['Micromolar', concentrations, of, monomeric, or, oligomerized, 'Aβ', were]), verbo([required]), complemento([to, inhibit, tRNA, 5, '\'', -, end, processing, and, position, 9, methylation, catalyzed, by, the, 'SDR5C1-containing', 'enzymes,', yet, similar, concentrations, of, 'Aβ', also, inhibited, related, 'RNase', 'P', and, methyltransferase, 'activities,', which, do, not, contain, an, 'SDR5C1', homolog])].
[sujeto(['In', contrast, to, all, the, related, 'methyltransferases,', the, human, mitochondrial, 'enzyme,', 'moreover,']), verbo([requires]), complemento([a, 'short-chain', dehydrogenase, as, a, partner, protein])].
[sujeto(['Proteins', encoded, by, mitochondrial, 'DNA', are]), verbo([translated]), complemento([using, mitochondrially, encoded, tRNAs, and, rRNAs])].
[sujeto(['As', with]), verbo([nuclear]), complemento([encoded, 'tRNAs,', mitochondrial, tRNAs, must, be, processed, to, become, fully, functional])].
[sujeto(['Using', homology, 'searches,', we]), verbo([have]), complemento([identified, the, three, proteins, composing, 'Drosophila', 'mt:RNase', 'P:', 'Mulder', '(', 'PRORP),', 'Scully', '(', 'MRPP2)', and, 'Roswell', '(', 'MRPP1)'])].
[sujeto(['Furthermore,', reducing, levels, of, each]), verbo([causes]), complemento([mitochondrial, 'deficits,', which, appear, to, be, due, at, least, in, part, to, defective, mitochondrial, tRNA, processing])].
[sujeto(['Overexpressing', two, members, of, the, 'complex,', 'Mulder', and, 'Roswell,', is, also, 'lethal,', and, in, the, case, of, 'Mulder,']), verbo([causes]), complemento([abnormal, mitochondrial, morphology])].
[sujeto(['These', data, are, the, first, evidence, that, defective, 'mt:RNase', 'P']), verbo([causes]), complemento([mitochondrial, 'dysfunction,', lethality, and, aberrant, mitochondrial, tRNA, processing, in, 'vivo,', underscoring, its, physiological, importance])].
[sujeto(['This', in, vivo, 'mt:RNase', 'P', model, will, advance, our, understanding, of, how]), verbo([loss]), complemento([of, mitochondrial, tRNA, processing, causes, tissue, 'failure,', an, important, aspect, of, human, mitochondrial, disease])].
[sujeto(['Synthesis', of, proteins, coded, by, mitochondrial, 'DNA', '(', 'mtDNA)']), verbo([requires]), complemento([the, correct, processing, of, long, polycistronic, precursor, 'RNA', molecules])].
[sujeto(['High', 'HSD10', expression, was]), verbo([found]), complemento([in, 28, '%', ;, high, 'MRPP1', expression, in, 40, '%', of, colorectal, 'cancers,', respectively])].
[sujeto(['Expression', of, both, proteins, was, not, significantly]), verbo([associated]), complemento([with, clinicopathological, parameters])].
[sujeto(['Survival', analysis, revealed, that]), verbo([loss]), complemento([of, 'HSD10', expression, is, associated, with, poor, prognosis])].
[sujeto(['High', 'HSD10', expression, was, significantly]), verbo([associated]), complemento([with, high, mtDNA, content, in, tumor, tissue])].
[sujeto(['A', causal, effect, of, 'HSD10', overexpression, or, knock, down, with]), verbo([increased]), complemento([or, reduced, mtDNA, 'levels,', 'respectively,', was, confirmed, in, tumor, cell, lines])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, 'HSD10', plays, a, role, in, alterations, of, energy, metabolism, by, regulating, mtDNA, content, in, colorectal, 'carcinomas,', and, 'HSD10', protein, analysis, may, be, of, prognostic, value])].
[sujeto(['The', reason, for, this, discrepancy]), verbo([has]), complemento([so, far, remained, obscure])].
[sujeto(['We']), verbo([suggest]), complemento([a, mechanism, in, which, 'MRPP1', and, 'MRPP2', both, deliver, the, 'pre-tRNA', substrate, and, activate, 'MRPP3', through, an, 'induced-fit', process])].
[sujeto(['Mammalian', 'RNase', 'H1']), verbo([has]), complemento([been, implicated, in, mitochondrial, 'DNA', replication, and, 'RNA', processing, and, is, required, for, embryonic, development])].
[sujeto(['We', identified, the, mitochondrial, protein, 'P32', that]), verbo([binds]), complemento([specifically, to, human, 'RNase', 'H1,', but, not, human, 'RNase', 'H2'])].
[sujeto(['P32']), verbo([binds]), complemento([human, 'RNase', 'H1', via, the, 'hybrid-binding', domain, of, the, enzyme, at, an, approximately, 1, '∶1', ratio])].
[sujeto(['P32']), verbo([enhanced]), complemento([the, cleavage, activity, of, 'RNase', 'H1', by, reducing, the, affinity, of, the, enzyme, for, the, heteroduplex, substrate, and, enhancing, 'turnover,', but, had, no, effect, on, the, cleavage, pattern])].
[sujeto(['P32', also, 'co-immunoprecipitated', with, 'MRPP1,', a, mitochondrial, 'RNase', 'P', protein]), verbo([required]), complemento([for, mitochondrial, 'pre-rRNA', processing])].
[sujeto(['The', 'P32-RNase', 'H1', complex, was, shown, to, physically]), verbo([interact]), complemento([with, mitochondrial, 'DNA', and, 'pre-rRNA'])].
[sujeto(['Further,', the, results, identify, 'P32', as, a, member, of, the, '\'', 'RNase', 'H1', 'degradosome\'', and, the, key, 'P32']), verbo([enhances]), complemento([the, enzymatic, efficiency, of, human, 'RNase', 'H1'])].
[sujeto(['Human', mitochondrial, long, noncoding, 'RNAs', '(', 'lncRNAs)']), verbo([have]), complemento([not, been, described, to, date])].
[sujeto(['By', analysis, of, 'deep-sequencing', data, we]), verbo([have]), complemento([identified, three, lncRNAs, generated, from, the, mitochondrial, genome, and, confirmed, their, expression, by, 'Northern', blotting, and, 'strand-specific', 'qRT-PCR'])].
[sujeto(['We', show, that, the, abundance, of, these, lncRNAs, is, comparable, to, their, complementary, mRNAs, and, that, 'nuclear-encoded', mitochondrial, proteins]), verbo([involved]), complemento([in, 'RNA', processing, regulate, their, expression])].
[sujeto(['Finally,', we, show, that, mitochondrial, lncRNAs, form, intermolecular, duplexes, and, that, their, abundance, is, 'cell-', and, 'tissue-specific,']), verbo([suggesting]), complemento([a, functional, role, in, the, regulation, of, mitochondrial, gene, expression])].
[sujeto(['Mammalian', mitochondrial, 'DNA', is]), verbo([transcribed]), complemento([as, precursor, polycistronic, transcripts, containing, 13, 'mRNAs,', 2, 'rRNAs,', punctuated, by, 22, tRNAs])].
[sujeto(['The', mechanisms]), verbo([involved]), complemento([in, the, excision, of, mitochondrial, tRNAs, from, these, polycistronic, transcripts, have, remained, largely, unknown])].
[sujeto(['We']), verbo([have]), complemento([investigated, the, roles, of, 'ELAC2,', mitochondrial, 'RNase', 'P', proteins, 1, and, 3, ',', and, pentatricopeptide, repeat, domain, protein, 1, in, the, processing, of, mitochondrial, polycistronic, transcripts])].
[sujeto(['We', used, a, deep, sequencing, approach, to, characterize, the, 5, '\'', and, 3, '\'', ends, of, processed, mitochondrial, transcripts, and]), verbo([provide]), complemento([a, detailed, map, of, mitochondrial, tRNA, processing, sites, affected, by, these, proteins])].
[sujeto(['By', 'contrast,', we]), verbo([find]), complemento([that, 'ELAC2', and, 'PTCD1', affect, the, 3, '\'', end, processing, of, tRNAs])].
[sujeto(['Finally,', we]), verbo([found]), complemento([that, 'MRPP1', is, essential, for, transcript, 'processing,', 'RNA', 'modification,', translation, and, mitochondrial, respiration])].
[sujeto(['Accurate', tRNA, processing, is, crucial, for, human, mitochondrial, genome, 'expression,', but, the, mechanisms, of, 'mt-tRNA', cleavage, and, the, key, enzymes]), verbo([involved]), complemento([in, this, process, are, poorly, characterized])].
[sujeto(['At', least, two, activities, are]), verbo([required]), complemento([for, proper, 'mt-tRNA', 'maturation:', 'RNase', 'P', cleaving, precursor, molecules, at, the, 5, '\'', end, and, tRNase, 'Z', at, the, 3, '\'', end])].
[sujeto(['In', human, mitochondria, only, 'RNase', 'P']), verbo([has]), complemento([been, identified, so, far])].
[sujeto(['Using', 'RT-PCR', and, northern, blot, analyses, we]), verbo([found]), complemento([that, silencing, of, the, human, 'ELAC2', gene, results, in, impaired, 3, '\'', end, of, 'mt-tRNAs'])].
[sujeto(['Our', results, indicate, that, 'ELAC2', functions, as, a, tRNase, 'Z', in, human, mitochondria, and]), verbo([suggest]), complemento([that, 'mt-tRNase', 'Z', preferentially, cleaves, molecules, already, processed, by, the, proteinaceous, mtRNase, 'P'])].
[sujeto(['Nitric', oxide, '(', 'NO)', overproduction, via, induction, of, inducible, nitric, oxide, synthase, '(', 'iNOS)', is, implicated, in, vasodilatory, shock, in, 'sepsis,']), verbo([leading]), complemento([to, septic, encephalopathy, and, accelerating, cerebral, ischemic, injury])].
[sujeto(['An', abbreviated, 'urea-cycle', '(', 'l-citrulline-l-arginine-NO', 'cycle)']), verbo([has]), complemento([been, demonstrated, in, cerebral, perivascular, nitrergic, nerves, and, endothelial, cells, but, not, in, normal, cerebral, vascular, smooth, muscle, cell, '(', 'CVSMC)'])].
[sujeto(['The', possibility, that, 'ASS', enzyme, in, this, cycle, was]), verbo([induced]), complemento([in, the, 'CVSMC', in, sepsis, was, examined])].
[sujeto(['l-cit', and, 'l-arg,', which, did, not, relax, 'endothelium-denuded', normal, basilar, arteries, precontracted, by, 'U-46619,']), verbo([induced]), complemento([significant, vasorelaxation, with, increased, 'NO', production, in, these, arteries, and, the, 'CVSMCs', following, 6, -, hour, exposure, to, 20, 'μg/ml', lipopolysaccharide, '(', 'LPS)', or, lipoteichoic, acid, '(', 'LTA)'])].
[sujeto(['Furthermore,', immunohistochemical, and, immunoblotting, studies, demonstrated, that, expression, of, basal, iNOS, and, 'ASS', in, the, smooth, muscle, cell, of, arterial, segments, denuded, of, endothelium, and, the, cultured, 'CVSMCs', was, significantly]), verbo([increased]), complemento([following, 6, -, hour, incubation, with, 'LPS', or, 'LTA'])].
[sujeto(['This']), verbo([increased]), complemento(['iNOS-', and, 'ASS-proteins', expression, in, both, preparations, was, inhibited, by, 'SAL,', but, was, further, increased, by, 'AG'])].
[sujeto(['These', results, indicate, that, 'LPS', and, 'LTA']), verbo([induce]), complemento([the, 'l-cit-l-arg-NO', cycle, via, induction, of, iNOS, and, 'ASS', in, the, 'CVSMCs,', accounting, for, massively, increased, 'NO-production', and, cerebral, vasodilation, in, septic, shock])].
[sujeto(['Simultaneous', inhibition, of, both, pathways, and, 'NFκB-activation', may, be, necessary, to, efficiently]), verbo([decrease]), complemento([or, normalize, 'NO', production, in, the, 'CVSMCs', in, this, disease, 'condition,', 'and/or', prevention, and, treatment, of, cerebral, 'vessel-related', brain, dysfunctions])].
[sujeto(['Our', results, further]), verbo([suggest]), complemento([to, avoid, using, iNOS, inhibitors, alone, which, may, cause, upregulation, of, iNOS, and, 'ASS', resulted, from, 'feedback-inhibition', of, iNOS, activity])].
[sujeto(['Accordingly,', combined, treatments, with, specific, 'iNOS-activity', inhibitor, and, inhibitor, for, iNOS, genomic, expression, may]), verbo([provide]), complemento([a, strategy, in, optimally, managing, brain, sepsis, and, related, encephalopathy, associated, with, enhanced, iNOS, expression, and, 'NO', overproduction])].
[sujeto(['The', global, 'regulator,', 'sarA,']), verbo([modulates]), complemento([virulence, of, 'MRSA', via, regulation, of, principal, virulence, factors, '(', e])].
[sujeto(['Moreover,', 'RNA-seq', analyses, showed, that, sarA, mutant, exhibited, significantly]), verbo([increased]), complemento([levels, of, primary, extracellular, 'proteases,', and, suppressed, pyrimidine, biosynthetic, 'pathway,', argininosuccinate, 'lyase-encoding', and, 'ABC', 'transporter-related', genes, as, compared, to, the, parental, strain])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, sarA, regulates, oxacillin, resistance, in, 'mecA-positive', 'MRSA'])].
[sujeto(['Thus,', abrogation, of, this, regulator, represents, an, attractive, and, novel, drug]), verbo([target]), complemento([to, potentiate, efficacy, of, existing, antibiotic, for, 'MRSA', therapy])].
[sujeto(['This', result, is, further, confirmed, by, a, separate, analysis, of, the, three, 'Sericomyrmex', 'species,', which]), verbo([reveals]), complemento([that, 92.71, '%', of, orthologs, have, 99, '%', -, 100, '%', 'pairwise-identical', nucleotide, sequences])].
[sujeto(['We', searched, the, transcriptomes, for, genes, of, 'interest,', most, importantly, argininosuccinate, synthase, and, argininosuccinate, 'lyase,', which, are, functional, in, other, ants, but, which, are, known, to]), verbo([have]), complemento([been, lost, in, seven, previously, studied, attine, ant, species])].
[sujeto(['Loss', of, the, ability, to, produce, the, amino, acid, arginine]), verbo([has]), complemento([been, hypothesized, to, contribute, to, the, obligate, dependence, of, attine, ants, upon, their, cultivated, 'fungi,', but, the, point, in, 'fungus-farming', ant, evolution, at, which, these, losses, occurred, has, remained, unknown])].
[sujeto(['We', did, not]), verbo([find]), complemento([these, genes, in, any, of, the, sequenced, transcriptomes])].
[sujeto(['Although', expected, for, 'Sericomyrmex', 'species,', the, absence, of, arginine, anabolic, genes, in, the, 'lower-attine', ant, 'Apterostigma', megacephala, strongly]), verbo([suggests]), complemento([that, the, loss, coincided, with, the, origin, of, attine, ants])].
[sujeto(['The', 'Urea', 'Cycle', 'Disorders', 'Consortium', '(', 'UCDC)']), verbo([has]), complemento(['conducted,', beginning, in, 2006, ',', a, longitudinal, study, '(', 'LS)', of, eight, enzyme, 'deficiencies/transporter', defects, associated, with, the, urea, cycle])].
[sujeto(['Neuroimaging', studies, in, late, onset, 'OTCD', offered, evidence, that, brain, injury]), verbo([caused]), complemento([by, biochemical, dysregulation, may, impact, functional, neuroanatomy, serving, working, memory, 'processes,', an, important, component, of, executive, function, and, regulation])].
[sujeto(['Further', longitudinal, 'follow-up', will]), verbo([reveal]), complemento([whether, this, is, due, to, declines, throughout, life, or, to, improvements, in, diagnostics, '(', especially, newborn, 'screening)', and, treatments, in, the, younger, generation, of, patients])].
[sujeto(['Patients', with, urea, cycle, disorders, '(', 'UCDs)']), verbo([have]), complemento([an, increased, risk, of, neurological, disease, manifestation])].
[sujeto(['Evaluation', of, 'baseline,']), verbo([regular]), complemento(['follow-up', and, emergency, visits, of, 456, 'UCD', patients, prospectively, followed, between, 2011, and, 2015, by, the, 'E-IMD', patient, registry])].
[sujeto([the, median, age, at, diagnosis, of, patients, identified, by, newborn, screening, '(', 'NBS)]']), verbo([suggesting]), complemento([a, potential, benefit, of, 'NBS'])].
[sujeto(['In', 'fact,', 'NBS', lowered, the, age, at, diagnosis, in, patients, with, late, onset, of, symptoms, '(', &, 'gt;28', 'days),', and, a, trend, towards, improved, 'long-term', neurological, outcome, was]), verbo([found]), complemento([for, patients, with, argininosuccinate, synthetase, and, lyase, deficiency, as, well, as, argininemia, identified, by, 'NBS'])].
[sujeto(['Promising', results, of, 'NBS', for, late, onset, 'UCD', patients, are]), verbo([reported]), complemento([and, should, be, 're-evaluated', in, a, larger, and, more, advanced, age, group])].
[sujeto(['Available', 'evidence-based', guideline, recommendations, are, currently, heterogeneously, implemented, into, 'practice,']), verbo([leading]), complemento([to, a, high, variability, of, drug, combinations, that, hamper, our, understanding, of, optimised, 'long-term', and, emergency, treatment])].
[sujeto(['Alterations', of, enzymes, linked, to, arginine, metabolism]), verbo([have]), complemento([been, recently, implicated, in, 'Alzheimer's', disease, '(', 'AD)'])].
[sujeto(['Real-time', 'PCR', analysis, revealed, in, 'APPwt', cells, significant]), verbo([decreases]), complemento([of, 'ARG1', and, 'ARG2', which, are, responsible, for, lysing, arginine, into, ornithine, and, 'urea;', this, reduction, was, followed, by, significantly, lower, enzyme, activity])].
[sujeto(['Elevated', 'miRNA-9', and, 'miRNA-128a']), verbo([found]), complemento([in, 'AD', brain, tissues, might, modulate, the, expression, of, 'ASS', and, 'NOS,', respectively])].
[sujeto(['Our', results, indicate, that, 'Aβ', affects, arginine, metabolism, and, this, influence, might]), verbo([have]), complemento([important, role, in, the, pathomechanism, of, 'AD'])].
[sujeto(['However,', 'Leishmania,', an, intracellular, 'pathogen,']), verbo([has]), complemento([evolved, mechanisms, to, survive, by, counterbalancing, the, toxic, oxygen, metabolites, produced, during, infection])].
[sujeto(['Argininosuccinate', synthase, '(', 'ASS)', plays, an, important, role, as, the, 'rate-limiting', step]), verbo([required]), complemento([for, converting, 'L-citrulline', to, argininosuccinate, to, provide, arginine, for, an, assortment, of, metabolic, processes])].
[sujeto(['Leishmania', produce, an, active, 'ASS', 'enzyme,', yet, it]), verbo([has]), complemento([an, incomplete, urea, cycle, as, it, lacks, an, argininosuccinate, lyase, '(', 'ASL)'])].
[sujeto(['There', is, no, evidence, for, endogenous, synthesis, of, 'L-arginine', in, 'Leishmania,', which]), verbo([suggests]), complemento([that, these, parasites, salvage, 'L-arginine', from, extracellular, milieu, and, makes, the, biological, function, of, 'ASS', and, the, production, of, argininosuccinate, in, 'Leishmania', unclear])].
[sujeto(['Our', previous, quantitative, proteomic, analysis, of, 'Leishmania', promastigotes, treated, with, 'sub-lethal', doses, of, 'ROS,', 'RNS,', or, a, combination, of, 'both,']), verbo([led]), complemento([to, the, identification, of, several, differentially, expressed, proteins, which, included, 'ASS'])].
[sujeto(['Interestingly,', 'LdASS', is, encoded, by, three, copies, of, 'allele,', but, 'Western', blot, analysis, showed, the, third, allele, did, not, appear, to]), verbo([express]), complemento(['ASS'])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'ASS', is, important, for, 'Leishmania', donovani, to, counterbalance, the, stressed, environments, encountered, during, infection, and, can, be, targeted, for, chemotherapeutic, purpose, to, treat, visceral, leishmaniasis])].
[sujeto(['The', patient]), verbo([required]), complemento(['IV', supportive, care, and, supplementation, with, 'potassium,', magnesium, and, calcium])].
[sujeto(['Argininosuccinic', aciduria, '(', 'ASAuria;', 'OMIM', 207900, ')', is, a, rare, autosomal, recessive, heterogeneous, urea, cycle, 'disorder,', which]), verbo([leads]), complemento([to, the, accumulation, of, argininosuccinic, acid, in, the, blood, and, urine])].
[sujeto(['(', 'R456W))', mutation, had, been, previously]), verbo([reported]), complemento([in, an, 'Italian', patient])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([of, a, missense, mutation, driving, alternative, splicing, which, results, in, the, loss, of, exon, 5, in, 'ASAuria'])].
[sujeto(['Argininosuccinic', aciduria, is, a, urea, cycle, disorder]), verbo([caused]), complemento([by, an, argininosuccinate, lyase, enzyme, deficiency, that, ends, with, nitrogen, accumulation, as, ammonia])].
[sujeto(['Liver', transplant, should, be, an, option, for, argininosuccinic, aciduria, patients, to]), verbo([prevent]), complemento([further, neurologic, deterioration, and, improve, the, 'patient\'s', quality, of, life])].
[sujeto(['However,', incubation, of, transfected, cells, with, 0.05, mM, cysteamine, immediately, before, the, enzyme, assay, resulted, in]), verbo([increased]), complemento(['ASL', activity, of, p])].
[sujeto(['Arg385Lys,']), verbo([providing]), complemento([circumstantial, evidence, for, the, assumed, 'cysteamine-induced', change, of, a, cysteine, to, a, lysine, analogue])].
[sujeto(['Lys-315', is, the, only, residue, which, is, arranged, symmetrically, at, the, diagonal, subunit, interfaces, to]), verbo([interact]), complemento([with, each, other])].
[sujeto(['This', study]), verbo([found]), complemento([that, 'wild-type', protein, had, both, dimers, and, monomers, present, in, 2, -, 4, 'M', urea, whilst, only, monomers, of, the, 'K315A', mutant, were, observed, under, the, same, 'conditions,', as, judged, by, sedimentation, velocity, analysis])].
[sujeto(['These', results]), verbo([suggest]), complemento([the, critical, role, of, 'Lys-315', in, stabilization, of, the, diagonal, dimer, structure])].
[sujeto(['The', formation, of, aggregates, was, not]), verbo([prevented]), complemento([by, the, addition, of, 'α-crystallin'])].
[sujeto(['Urea', cycle, defects, are, a, group, of, metabolic, disorders]), verbo([caused]), complemento([by, enzymatic, disruption, of, the, urea, cycle, 'pathway,', transforming, nitrogen, to, urea, for, excretion, from, the, body])].
[sujeto(['Liver', transplant, is, an, alternative, treatment, 'option,']), verbo([providing]), complemento([sufficient, enzymatic, activity, and, decreasing, the, risk, of, metabolic, decompensation])].
[sujeto(['A', major, improvement, could, not, be, 'achieved,', and]), verbo([he]), complemento([is, wheelchair, dependent, at, the, age, of, 6, years])].
[sujeto(['The', other, 2, patients, had, normal, motor, and, mental, skills, before, 'transplant,', which]), verbo([have]), complemento([continued, 12, and, 14, months, after, transplant])].
[sujeto(['Proper', timing, for, transplant, is, important, because, high, ammonia, levels, may, result, in, permanent, neurologic, 'damage;', 'however,', transplant, at, younger, ages, also, may]), verbo([increase]), complemento([morbidity])].
[sujeto(['Medline', search, for]), verbo([reports]), complemento([published, between, 1978, and, 'Dec', 22, ',', 2014, was, completed, by, hand, search])].
[sujeto(['Twenty-four', publications]), verbo([report]), complemento([onset, time, '(', n, =, 1542, 'patients),', survival, of, 'EO', '(', n, =, 665, 'patients)', and, outcome, at, one, year, of, life, '(', n, =, 172, 'patients)'])].
[sujeto(['UCDs,', except, for, 'OTCDf,']), verbo([have]), complemento([high, risks, of, 'EO', disease, manifestation, 'and,', except, for, 'ASLD,', of, neonatal, death])].
[sujeto(['Arginine', is, a, 'non-essential', amino, acid, that]), verbo([modulates]), complemento([nitric, oxide, production, and, cancer, homeostasis])].
[sujeto(['However,', the, role, of, 'ASL', in, human, breast, cancer]), verbo([has]), complemento([been, studied, to, a, lesser, degree])].
[sujeto(['In', the, present, 'study,', we, investigated, the, effect, of]), verbo([targeting]), complemento(['ASL', in, breast, cancer])].
[sujeto(['We']), verbo([found]), complemento([that, 'ASL', was, induced, by, 'ER', stress, and, was, significantly, upregulated, in, breast, cancer, tissues, compared, to, that, in, the, corresponding, normal, tissues])].
[sujeto(['Downregulation', of, 'ASL']), verbo([inhibited]), complemento([the, growth, of, breast, cancer, in, vitro, and, in, vivo])].
[sujeto(['Furthermore,', autophagy, was, observed, in, the, cells]), verbo([expressing]), complemento(['ASL', 'shRNA,', and, inhibition, of, autophagy, reduced, cell, 'growth,', indicating, that, autophagy, played, a, cell, survival, role, in, the, 'ASL', knockdown, cells])].
[sujeto(['Thus,', the, mechanism]), verbo([induced]), complemento([by, 'ASL', shRNA, which, occurred, in, human, breast, cancer, may, be, attributed, to, a, decrease, in, cyclin, 'A2', and, 'NO'])].
[sujeto([lentis, likely, secretes, numerous, effector, 'proteins,', including, toxins, to, alter, the, 'plant\'s', innate, 'immunity,', thereby]), verbo([gained]), complemento([access, to, the, host, tissues, for, nutrition, and, reproduction])].
[sujeto(['The', 'knock-down', of, 'ClToxB', transcripts, by, 'RNAi', resulted, in, reduced, 'virulence,']), verbo([suggesting]), complemento([that, 'ClToxB', is, a, virulence, factor])].
[sujeto(['EST', mining, and, expression, profiling, revealed, a, set, of, in, planta]), verbo([expressed]), complemento([candidate, effectors])].
[sujeto(['We', recently, showed, that, 'CIT']), verbo([stimulated]), complemento(['β-oxidation', in, rat, 'WAT', explants, from, young, '(', 2, -, 4, 'months)', but, not, old, '(', 25, 'months)', rats])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'CIT', induces, a, new, metabolic, status, in, 'WAT,', with, increased, 'β-oxidation', and, uncoupling, of, respiratory, 'chain,', resulting, in, energy, expenditure, that, favors, fat, mass, reduction])].
[sujeto(['Acquired', microcephaly, and, movement, disorders, were, common, in, 'OAD', and, 'UCD', highlighting, that, the, brain, is, the, major, organ]), verbo([involved]), complemento([in, these, diseases])].
[sujeto(['Cardiomyopathy', '[', methylmalonic, '(', 'MMA)', and, propionic, aciduria, '(', 'PA)],', prolonged, 'QTc', interval, '(', 'PA),', optic, nerve, atrophy, '[', 'MMA,', isovaleric, aciduria, '(', 'IVA)],', pancytopenia, '(', 'PA),', and, macrocephaly, '[', glutaric, aciduria, type, 1, '(', 'GA1)]', were, exclusively]), verbo([found]), complemento([in, 'OAD', 'patients,', whereas, hepatic, involvement, was, more, frequent, in, 'UCD', 'patients,', in, particular, in, argininosuccinate, lyase, '(', 'ASL)', deficiency])].
[sujeto(['Chronic', renal, failure, was, often]), verbo([found]), complemento([in, 'MMA,', with, highest, frequency, in, 'mut(0)', patients])].
[sujeto(['It', had, a, similar, frequency, in, patients, with, or, without, a, movement, disorder]), verbo([suggesting]), complemento([different, pathophysiology])].
[sujeto(['Loss', of, function, of, the, urea, cycle, enzyme, argininosuccinate, lyase, '(', 'ASL)', is]), verbo([caused]), complemento([by, mutations, in, the, 'ASL', gene, leading, to, 'ASL', deficiency, '(', 'ASLD)'])].
[sujeto(['ASLD']), verbo([has]), complemento([a, broad, clinical, spectrum, ranging, from, 'life-threatening', severe, neonatal, to, asymptomatic, forms])].
[sujeto(['We']), verbo([found]), complemento([residual, activities, &, 'gt;3%', of, 'ASL', wild, type, '(', 'WT)', in, nine, of, 11, 'ASL', mutations])].
[sujeto(['Computational', structural, analysis, supported, the, biochemical, findings, by]), verbo([revealed]), complemento([multiple, effects, including, protein, 'instability,', disruption, of, ionic, interactions, and, hydrogen, bonds, between, residues, in, the, monomeric, form, of, the, 'protein,', and, disruption, of, contacts, between, adjacent, monomeric, units, in, the, 'ASL', tetramer])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, clinical, and, biochemical, course, in, variant, forms, of, 'ASLD', is, associated, with, relevant, residual, levels, of, 'ASL', activity, as, well, as, instability, of, mutant, 'ASL', proteins])].
[sujeto(['Half', of, the, 'GBM', cell, lines, tested]), verbo([responded]), complemento([well, toward, 'ADI', monotherapy])].
[sujeto(['In', those, cell, 'lines,', viability]), verbo([decreased]), complemento([significantly, '(', up, to, 50, '%', ')'])].
[sujeto(['Apoptosis,', as, well, as, cell, cycle, dysregulation, were]), verbo([found]), complemento([to, play, a, minor, role])].
[sujeto(['In', 'vivo,', 'ADI', as, well, as, the, combination, of, 'ADI', and, 'SAHA', efficiently, controlled, 'HROG05', xenograft, 'growth,', whereas, adding, 'Palomid', 529, to, 'ADI', did, not, further]), verbo([increase]), complemento([the, strong, antitumoral, effect, of, 'ADI'])].
[sujeto([1, ',', 11, 'MS', patients]), verbo([participated]), complemento([in, the, study])].
[sujeto(['Abnormal', reductions, in, cortical, cerebral, blood, flow, '(', 'CBF)']), verbo([have]), complemento([been, identified, in, subcortical, vascular, cognitive, impairment, '(', 'SVCI)'])].
[sujeto(['Compared', with, the, control, 'subjects,', 'SVCI', group, demonstrated, diffuse]), verbo([decreased]), complemento(['CBF', in, the, brain])].
[sujeto(['Thus,', our, results]), verbo([provide]), complemento([further, evidence, for, the, mechanisms, underlying, the, cognitive, deficit, in, patients, with, 'SVCI'])].
[sujeto(['Borderline', resectable, pancreatic, cancer, is, now]), verbo([recognized]), complemento([as, a, distinct, clinical, entity])].
[sujeto(['However,', the, enormous, difficulties, in, achieving, a, consensus, and, the, variability, in, therapeutic, algorithms]), verbo([have]), complemento([delayed, progress, in, establishing, strong, 'evidence-based', practices, for, diagnosis, and, treatment])].
[sujeto(['In', 'addition,', advantages, and, limitations, resulting, from, the, use, of, vasopressin, receptor, 'antagonists,', drugs, that]), verbo([have]), complemento([recently, emerged, as, the, best, available, resource, against, 'hyponatremia,', are, highlighted])].
[sujeto(['Familial', forms, can, be]), verbo([caused]), complemento([by, genetic, defects, in, 'microtubule-associated', protein, tau, '(', 'MAPT),', progranulin, '(', 'GRN),', and, 'C9orf72'])].
[sujeto(['GRN', mutation, carriers, showed, significant, frontoparietal, hypoperfusion, compared, with, controls, at, 'follow-up,', whereas, we]), verbo([found]), complemento([no, 'cross-sectional', group, differences, in, the, total, study, group, or, the, 'MAPT', subgroup])].
[sujeto(['Longitudinal', analyses, revealed, a, significantly, stronger]), verbo([decrease]), complemento([in, 'CBF', in, 'frontal,', 'temporal,', 'parietal,', and, subcortical, areas, in, the, total, group, of, mutation, carriers, and, the, 'GRN', 'subgroup,', with, the, strongest, decrease, in, two, mutation, carriers, who, converted, to, clinical, 'FTD', during, 'follow-up'])].
[sujeto(['We', demonstrated, longitudinal, alterations, in, 'CBF', in, presymptomatic, 'FTD', independent, of, grey, matter, 'atrophy,', with, the, strongest]), verbo([decrease]), complemento([in, individuals, that, developed, symptoms, during, 'follow-up'])].
[sujeto(['Therefore,', 'ASL', could]), verbo([have]), complemento([the, potential, to, serve, as, a, sensitive, biomarker, of, disease, progression, in, the, presymptomatic, stage, of, 'FTD', in, future, clinical, trials])].
[sujeto(['The', active, immunization, status, against, influenza, was]), verbo([found]), complemento([the, most, clearly, associated, with, difference, levels, in, three, psychometric, 'variables:', personal, 'responsibility,', beliefs, on, usefulness, and, beliefs, on, risk, of, vaccination])].
[sujeto(['A', mediation, mechanism, was, analysed, between, these, 'constructs,', and, an, interesting, indirect, effect, was, highlighted, for, beliefs, that, could]), verbo([enhance]), complemento([the, advantage, of, increased, responsibility, for, 'HCWs'])].
[sujeto(['Rifaximin,', 'probiotics,', and, mesalazine, were, the, most, frequent, prescribed, drugs, both, in, symptomatic, patients, '(', 28.1, ',', 14.9, '%', ',', and, 11.4, '%', ',', 'respectively)', and, to]), verbo([prevent]), complemento([recurrence, of, the, disease, '(', 42.5, '%', ',', 12.4, '%', ',', and, 28.2, '%', ',', 'respectively)'])].
[sujeto(['Rifaximin,', 'probiotics,', and, mesalazine, were, the, most, frequent, prescribed, drugs, to]), verbo([prevent]), complemento([recurrence, of, the, disease, '(', 32.2, '%', ',', 13.2, '%', ',', and, 11.4, '%', ',', 'respectively),', whereas, 25.4, '%', of, participants, did, not, prescribe, any, drugs])].
[sujeto(['Finally,', no, differences, were]), verbo([found]), complemento([among, 'gastroenterologists,', 'surgeons,', and, general, practitioners, in, managing, this, disease])].
[sujeto(['Real-time', polymerase, chain, reaction, was, used, to, quantify]), verbo([targeted]), complemento([microorganisms])].
[sujeto(['High-resolution', proton]), verbo([nuclear]), complemento([magnetic, resonance, spectroscopy, associated, with, multivariate, analysis, with, partial, 'least-square', discriminant, analysis, '(', 'PLS-DA)', was, applied, on, the, metabolite, data, set])].
[sujeto(['PLS-DA', analysis, of]), verbo([nuclear]), complemento([magnetic, resonance, -, based, metabolomics, associated, with, microbiological, data, showed, significant, discrimination, between, 'HCs', and, 'AD', patients, '(', 'R=0'])].
[sujeto(['PLS', analysis, showed, lower, 'N-acetyl', compound, and, isovalerate, levels, in, 'AD,']), verbo([associated]), complemento([with, higher, levels, of, 'A'])].
[sujeto(['Moreover,']), verbo([increasing]), complemento([expression, of, some, metabolites, as, expression, of, different, 'AD', and, 'SUDD', metabolic, activity, was, found])].
[sujeto(['Some', studies]), verbo([have]), complemento([shown, the, presence, of, bacterial, overgrowth, in, subgroups, of, patients, with, diverticular, disease, and, recent, 'studies,', using, molecular, biology, 'techniques,', found, an, increase, of, proteobacteria, and, actinobacteria, in, patients, with, symptomatic, uncomplicated, diverticular, disease, '(', 'SUDD),', compared, with, healthy, controls])].
[sujeto(['The', use, of, probiotics, to]), verbo([modulate]), complemento([intestinal, microecology, in, 'SUDD', appears, therefore, rational])].
[sujeto(['Although', several, investigations, evaluating, the, clinical, efficacy, of, probiotics]), verbo([have]), complemento([been, 'performed,', no, definitive, results, have, yet, been, 'achieved,', mainly, due, to, the, heterogeneity, of, the, available, studies])].
[sujeto(['The', analysis, of, the, available, evidence]), verbo([reveals]), complemento([a, poor, quality, of, the, published, 'studies,', whose, design, was, 'heterogeneous,', with, only, 2, out, of, 11, trials, being, 'double-blind', and, randomized])].
[sujeto(['Therefore,', available, data, can, only]), verbo([suggest]), complemento([a, benefit, of, probiotics, in, 'SUDD,', but, do, not, allow, any, 'evidence-based', definite, conclusion])].
[sujeto(['To', assess, the, effectiveness, of, mesalazine, in, improving, symptoms, '(', namely, abdominal, 'pain)', and, in]), verbo([preventing]), complemento([diverticulitis, occurrence, in, patients, with, 'SUDD'])].
[sujeto(['The', segmental, colitis]), verbo([associated]), complemento([with, 'diverticulosis,"', better, known, by, its, acronym, &, 'quot;SCAD,"', is, a, chronic, inflammatory, process, localized, in, the, colonic, area, presenting, 'diverticulosis,', and, therefore, mainly, in, the, sigmoid, colon])].
[sujeto(['Recent', data]), verbo([have]), complemento([hypothesized, that, 'SCAD', may, be, an, independent, clinical, entity, within, the, inflammatory, bowel, disease, set, of, diseases])].
[sujeto(['Compared', with, inflammatory, bowel, 'disease,', 'SCAD', seems, to]), verbo([have]), complemento([a, more, benign, 'outcome,', with, low, rate, of, complications])].
[sujeto(['Sigma', and, left, colon, was, mainly]), verbo([involved]), complemento([in, group, 'A', than, group, 'B', '(', 97.6, '%', vs])].
[sujeto([1, ')', ',', whereas, in, group, 'B', the, right, colon, was, mainly]), verbo([involved]), complemento([in, group, 'B', versus, group, 'A', '(', 22.2, '%', vs])].
[sujeto(['We']), verbo([have]), complemento([evaluated, the, 'sensitivity,', 'accuracy,', positive, predictive, value, '(', 'PPV)', and, negative, predictive, value, '(', 'NPV)', of, the, 'c-TBNA', performed, during, the, 2005, -, 2015, period, for, suspicious, lung, neoplasia, 'and/or', hilar, and, mediastinal, lymphadenopathy, at, the, 'Thoracic', endoscopy, of, the, 'Thoracic', 'Surgery', 'Department', of, the, 'Regina', 'Elena', 'National', 'Cancer', 'Institute,', 'Rome'])].
[sujeto(['Endoscopist\'s', skill, and, technical, 'development,']), verbo([associated]), complemento([to, 'thin-prep', cytology, and, to, a, rapid, on, site, examination, '(', 'ROSE),', were, able, to, provide, by, 'c-TBNA', a, high, diagnostic, yield, and, molecular, predictive, data, in, advanced, lung, carcinomas])].
[sujeto(['In', 'Italy,', prostate, cancer, mortality]), verbo([has]), complemento([been, dropping, since, 2000, ',', but, it, is, difficult, to, understand, whether, 'PSA', testing, is, the, main, 'reason,', considering, the, role, of, treatment, in, prognosis])].
[sujeto(['In', patients, younger, than, 75, 'years,', there, was, an]), verbo([increase]), complemento([in, radical, prostatectomy, but, not, 'radiotherapy;', patients, older, than, 75, years, rarely, had, treatment, with, radical, intent])].
[sujeto(['These', findings, raise, several, 'questions:', the, possible, overtreatment, of, 'low-risk', patients, undergoing, radical, 'treatment;', the, utility, of, more, aggressive, treatment, for, elderly, patients, with, 'high-risk', 'disease;', and, the, importance, of, a, multidisciplinary, clinical, approach, to]), verbo([ensure]), complemento([multiple, and, alternative, treatment, options])].
[sujeto(['The']), verbo([increase]), complemento([in, 'survival,', with, the, decrease, in, 'mortality,', suggests, an, effect, of, radical, treatments, on, prognosis])].
[sujeto(['Although', the, relationship, between, neuronavigated, transcranial, magnetic, stimulation, '(', 'nTMS)', and, functional, magnetic, resonance, imaging, '(', 'fMRI)']), verbo([has]), complemento([been, widely, studied, in, motor, 'mapping,', it, is, unknown, how, the, motor, response, type, or, the, choice, of, motor, task, affect, this, relationship])].
[sujeto(['The', relationship, between, fMRI, and, nTMS, mapped, excitatory, '(', 'MEP)', and, inhibitory, '(', 'SP)', 'responses,', and, whether, the, choice, of, motor, task, affects, this, 'relationship,']), verbo([have]), complemento([not, been, studied, before])].
[sujeto(['Telemedicine']), verbo([has]), complemento([demonstrated, to, improve, access, and, quality, of, health, services, in, underserved, 'area,', curtailing, the, 'costs,', therefore, its, application, to, the, delivery, of, health, care, in, prison, would, be, desirable])].
[sujeto(['A', 'top-down', approach, was, used, to, collect, information, from, persons]), verbo([involved]), complemento([in, prison, administration, or, project, leaders, at, national, level])].
[sujeto(['We']), verbo([have]), complemento([found, that, 'telemedicine,', as, additional, healthcare, delivery, 'model,', is, used, only, in, 11, 'countries,', especially, among, members, of, 'Northern', and, 'Western', 'Europe'])].
[sujeto(['Only', 'Romania', showed, to]), verbo([have]), complemento([a, pilot, project, for, a, nationwide, program, of, telemedicine])].
[sujeto(['To', investigate, the, role, of, 'Tal1', 'gene,', which, is, aberrantly]), verbo([expressed]), complemento([in, 40, '%', -, 60, '%', of, patients, with, 'T', lymphocytic, leukemia, '(', 'T-ALL),', in, the, proliferation, of, 'T-ALL', cells])].
[sujeto(['In', 'Jurkat-T1', 'cells,', 'G0/G1', phase, cells, were]), verbo([decreased]), complemento([and, 'S', phase, cells, increased, compared, with, 'Jurkat-mock2', 'cells,', and, 'Jurkat-siTal1', cells, showed, increased, 'G0/G1', phase, cells, and, decreased, 'S', phase, cells, compared, with, 'Jurkat-mock1', cells])].
[sujeto(['Real-time', 'RT-PCR', and, 'Western', blotting, showed, that, 'Tal1']), verbo([inhibited]), complemento([the, cellular, expression, of, 'CDKN2A', and, 'CDKN2B', at, both, mRNA, and, protein, levels])].
[sujeto(['Tal1']), verbo([promotes]), complemento([the, growth, and, the, transition, from, 'G0/G1', phase, to, 'S', phase, in, 'T-ALL', cells, 'Jurkat', by, inhibiting, the, expressions, of, 'G0/G1', and, 'S', phase, negative, regulatory, proteins, 'CDKN2A', and, 'CDKN2B'])].
[sujeto(['A', total, of, 498, lung, cancer, patients, and, 213, healthy, controls, were]), verbo([recruited]), complemento([in, the, study])].
[sujeto(['Thirteen', polymorphisms, in, 'HOXA', distal, transcript, antisense, 'RNA', '(', 'HOTTIP),', 'HOX', transcript, antisense, intergenic, 'RNA', '(', 'HOTAIR),', 'H19,', 'CDKN2B', antisense, 'RNA', 1, '(', 'ANRIL),', colon, 'cancer-associated', transcript, 2, '(', 'CCAT2),', 'metastasis-associated', lung, adenocarcinoma, transcript, 1, '(', 'MALAT1),', and, maternally]), verbo([expressed]), complemento([gene, 3, '(', 'MEG3)', genes, were, genotyped, by, 'allele-specific', 'MALDI-TOF', mass, spectrometry])].
[sujeto(['We']), verbo([found]), complemento([that, patients, with, 'HOTTIP', rs5883064, 'C', allele, or, rs1859168, 'A', allele, had, increased, lung, cancer, risk, '(', 'P', =, 0.01, ',', 'P', =, 0.01, ',', 'respectively)'])].
[sujeto(['CCAT2', 'rs6983267,', 'H19', 'rs2839698,', 'MALAT1', 'rs619586,', and, 'HOTAIR', rs7958904, were]), verbo([associated]), complemento([with, 'platinum-based', chemotherapy, response, in, dominant, model, '(', '(', 'P', =, 0.02, ',', 'P', =, 0.04, ',', 'P', =, 0.04, ',', 'P', =, 0.01, ',', 'respectively)'])].
[sujeto(['ANRIL', rs10120688, '(', 'P', =, 0.02, ',', 'adenocarcinoma)', and, rs1333049, '(', 'P', =, 0.04, ',', 'small-cell', lung, 'cancer),', 'H19', rs2107425, '(', 'P', =, 0.02, ',', 'small-cell', lung, 'cancer)', and, 'HOTAIR', rs1899663, '(', 'P', =, 0.03, ',', 'male;', 'P', =, 0.03, ',', 'smoker)', were]), verbo([associated]), complemento([with, response, to, 'platinum-based', chemotherapy])].
[sujeto(['HOTTIP,', 'CCAT2,', 'H19,', 'HOTAIR,', 'MALATI,', 'ANRIL', genetic, polymorphisms, were, significantly]), verbo([associated]), complemento([with, lung, cancer, susceptibility, or, 'platinum-based', chemotherapy, response])].
[sujeto(['To', predict, the]), verbo([regulating]), complemento([network, of, innate, immunity, signaling, molecule, 'hsa-miR-181a', in, stroke, based, on, the, methods, of, bioinformatics])].
[sujeto(['The', 'UCSC', genome, 'browser,', the, human, miRNA, disease, database, '(', 'HMDD),', the, transcription, 'factor-miRNA', regulation, database, '(', 'TransmiR),', the, database, on, predicted, and, validated, miRNA]), verbo([targets]), complemento(['(', 'miRwalk),', the, 'Genecards,', the, long, 'non-coding', 'RNA', '(', 'LncRNA)', disease, 'database,', the, 'DIANA', 'LAB-LncBase', and, the, 'ConSite', were, employed, to, study, the, upstream, transcription, 'factor,', downstream, target, genes, and, the, interactive, 'LncRNA', of, 'hsa-miR-181a', and, to, draw, the, core, regulating, network, of, 'hsa-miR-181a'])].
[sujeto(['To', verify, the, 'hsa-miR-181a']), verbo([regulating]), complemento(['network,', we, used, lipopolysaccharide, '(', 'LPS)', to, stimulate, the, 'BV2', cells, transfected, by, lentivirus, and, 'real-time', quantitative, 'PCR', to, detect, the, changes, of, 'Toll-like', receptor, 4, '(', 'TLR4),', tumor, protein, 63, '(', 'p63),', 'miR-181a', and, nuclear, factor, κB, '(', 'NF-κB)', p65])].
[sujeto(['Bioinformatics', analysis, indicated, that, 'hsa-miR-181a', was]), verbo([regulated]), complemento([by, the, transcription, factors, 'p63,', and, at, the, same, 'time,', it, could, regulate, 58, target, genes, such, as, 'brain-derived', neurotrophic, factor, '(', 'BDNF),', 'TLR4', etc])].
[sujeto(['IncRNA', 'CDKN2B-AS1', and, its, transcription, factors, 'Snail', and, 'n-MYC', might, also]), verbo([interact]), complemento([with, 'hsa-miR-181a'])].
[sujeto(['In', 'LPS-stimulated', 'BV2', 'cells,', the, expression, levels, of, 'TLR4,', 'p63,', 'miR-181a', were, 'up-regulated;', while, the, levels, of, 'p63,', 'miR-181a', and, 'NF-κB', p65]), verbo([decreased]), complemento([in, the, 'lentivirus-infected', 'BV2', 'cells,', indicating, that, p63, was, the, key, signaling, molecule, in, the, process, of, 'TLR4', regulating, 'miR-181a'])].
[sujeto(['The', bioinformatics, analysis, and, preliminary, experimental, verification, predicted, and, demonstrated, the]), verbo([regulating]), complemento([network, of, 'hsa-miR-181a', in, stroke])].
[sujeto(['Oxidative', stress, '(', 'OS)', is, the, root]), verbo([cause]), complemento([of, 'CAFs', abnormal, proliferation])].
[sujeto(['ATM', '(', 'ataxia-telangiectasia', mutated, protein, 'kinase),', an, important, redox, 'sensor,', is]), verbo([involved]), complemento([in, 'DNA', damage, response, and, cellular, homeostasis])].
[sujeto(['Whether', and, how, oxidized, 'ATM']), verbo([regulating]), complemento(['CAFs', proliferation, remains, unclear])].
[sujeto(['The', effect, of, oxidized, 'ATM', on, 'CAFs', proliferation, is]), verbo([mediated]), complemento([by, its, regulation, of, cellular, redox, balance, and, the, activity, of, the, 'ERK,', 'PI3K-AKT,', and, 'Wnt', signaling, pathways])].
[sujeto(['Treating', cells, with, antioxidant, 'N-acetyl-cysteine', '(', 'NAC)', partially, rescues, the, proliferation, defect, of, the, breast, 'CAFs']), verbo([caused]), complemento([by, 'ATM', deficiency])].
[sujeto(['This', is, mainly, ascribed, to, the, 'β-catenin', suppression, and, 'down-regulation', of, 'c-Myc,', thus, further]), verbo([leading]), complemento([to, the, decreased, 'cyclinD1,', 'cyclinE,', and, 'E2F1', expression, and, the, enhanced, 'p21(Cip1)', level])].
[sujeto(['Our', results]), verbo([reveal]), complemento([an, important, role, of, oxidized, 'ATM', in, the, regulation, of, the, abnormal, proliferation, of, breast, 'CAFs'])].
[sujeto(['Oxidized', 'ATM', could, serve, as, a, potential]), verbo([target]), complemento([for, treating, breast, cancer])].
[sujeto(['Although', various, genes, that]), verbo([confer]), complemento([susceptibility, to, myocardial, infarction, '(', 'MI)', have, been, identified, for, 'Caucasian', populations, in, 'genome-wide', association, studies, '(', 'GWAS),', genetic, variants, related, to, this, condition, in, 'Japanese', individuals, have, not, been, identified, definitively])].
[sujeto([300, ')', were, significantly]), verbo([associated]), complemento([with, 'MI'])].
[sujeto([5, ')']), verbo([associated]), complemento([with, 'MI'])].
[sujeto(['Hepatocellular', carcinoma, '(', 'HCC)', is, one, of, the]), verbo([leading]), complemento([causes, of, 'cancer-related', 'death,', especially, in, 'China'])].
[sujeto(['Growing', evidence, indicates, that, long, 'non-coding', 'RNAs', '(', 'lncRNAs)', are]), verbo([found]), complemento([to, be, dysregulated, in, many, 'cancers,', including, 'HCC'])].
[sujeto(['CDKN2B', antisense, 'RNA1', '(', 'ANRIL),', a, 'lncRNA,', coclustered, mainly, with, 'p14/ARF']), verbo([has]), complemento([been, reported, to, be, dysregulated, in, gastric, 'cancer,', esophageal, squamous, cell, 'carcinoma,', and, lung, cancer])].
[sujeto(['Moreover,', taking, advantage, of]), verbo([loss]), complemento([of, function, experiments, in, 'HCC', 'cells,', we, found, that, knockdown, of, 'ANRIL', expression, could, impair, cell, proliferation, and, invasion, and, induce, cell, apoptosis, both, in, vitro, and, in, vivo])].
[sujeto(['We', also]), verbo([found]), complemento([that, 'ANRIL', could, epigenetically, repress, 'KLF2', transcription, in, 'HCC', cells, by, binding, with, 'PRC2', and, recruiting, it, to, 'KLF2', promoter, region])].
[sujeto(['We', also]), verbo([found]), complemento([that, 'Sp1', could, regulate, the, expression, of, 'ANRIL'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, lncRNA, 'ANRIL,', as, a, growth, 'regulator,', may, serve, as, a, new, biomarker, and, target, for, therapy, in, 'HCC'])].
[sujeto([1, -, 'K562', 'cells,', the, growth, rate, was, slower, than, that, of, the, control, 'K562', 'cells,', 'G0/G1-phase', was]), verbo([increased]), complemento([and, 'S-phase', was, decreased, significantly])].
[sujeto(['In', the, siRNA, 'group,', 'bcr-abl', fusion, gene, expression, was, significantly]), verbo([decreased]), complemento([in, 'K562', cells, accompanied, by, the, downregulation, of, 'BCL-xL', protein, expression, and, 'G1-phase', arrest])].
[sujeto(['Cell', survival, rate, was, significantly]), verbo([decreased]), complemento([compared, with, the, sole, 'p15-K562', cell, group, and, the, sole, 'RNA', 'interference-K562', cell, group])].
[sujeto([1, -, 'K562', cells, with, 'STI571,', the, proportion, of, apoptosis, was, significantly]), verbo([increased]), complemento([and, the, cell, survival, rate, was, significantly, decreased, compared, with, the, 'p15-K562', cell, group, and, 'STI571-K562', cell, group])].
[sujeto([siRNA, at, 30, pM, combined, with, 0.5, μM, 'STI571']), verbo([promoted]), complemento([apoptosis, compared, with, sole, application])].
[sujeto(['Exogenous', p15, protein, expression, combined, with, 'STI571', appeared, to]), verbo([have]), complemento([a, synergistic, effect, on, proliferation, inhibition, and, apoptosis, induction, in, 'K562', cells])].
[sujeto(['The', combination, of, 'low-dose', 'RNA', interference, with, 'STI571', showed, a, synergistic, effect, in]), verbo([inducing]), complemento([apoptosis])].
[sujeto(['With', the, development, of, whole, genome, and, transcriptome, sequencing, 'technologies,', long, noncoding, 'RNAs', '(', 'lncRNAs)']), verbo([have]), complemento([received, increased, attention])].
[sujeto(['Multiple', studies, indicate, that, lncRNAs]), verbo([act]), complemento([not, only, as, the, intermediary, between, 'DNA', and, protein, but, also, as, important, protagonists, of, cellular, functions])].
[sujeto(['LncRNAs', can]), verbo([regulate]), complemento([gene, expression, in, many, 'ways,', including, chromosome, 'remodeling,', transcription, and, 'post-transcriptional', processing])].
[sujeto(['Moreover,', the, dysregulation, of, lncRNAs]), verbo([has]), complemento([increasingly, been, linked, to, many, human, 'diseases,', especially, in, cancers])].
[sujeto(['Id1']), verbo([regulates]), complemento([prostate, cancer, '(', 'PCa)', cell, 'proliferation,', 'apoptosis,', and, androgen, 'independence,', but, its, clinical, significance, in, 'PCa', remains, controversial])].
[sujeto(['We', show, that]), verbo([increased]), complemento(['Id1', and, 'Id3', protein, expression, is, strongly, associated, with, increasing, grade, of, 'PCa'])].
[sujeto(['At', the, molecular, 'level,', we]), verbo([report]), complemento([that, silencing, either, 'Id1', or, 'Id3', attenuates, cell, cycle])].
[sujeto(['We', propose, that]), verbo([increased]), complemento(['Id1', and, 'Id3', expression, attenuates, all, three, 'cyclin-dependent', kinase, inhibitors, '(', 'CDKN2B,', -, 1, 'A,', and, -, 1, 'B)', resulting, in, a, more, aggressive, 'PCa', phenotype])].
[sujeto(['We', searched, 'ERα', cistromes, of, 'MCF-7', breast, cancer, cells, for, previously, unrecognized, 'ERα']), verbo([targets]), complemento([and, identified, 'proto-oncogene', 'PIM-1', as, a, novel, potential, target, gene])].
[sujeto(['We', show, that, the, expression, of, 'PIM-1', is]), verbo([induced]), complemento([in, response, to, estradiol, in, 'MCF-7', cells, and, that, the, induction, is, mediated, by, 'ERα-regulated', enhancers, located, distally, upstream, from, the, gene])].
[sujeto(['Analysis', of, 'PIM-1', expression, between, invasive, breast, tumors, and, benign, breast, tissue, samples, showed, that, elevated, 'PIM-1', expression, is]), verbo([associated]), complemento([with, malignancy, and, a, higher, tumor, grade])].
[sujeto(['In', 'sum,', identification, of, 'PIM-1', as, an, 'ERα']), verbo([target]), complemento([gene, adds, a, novel, potential, mechanism, by, which, estrogens, can, contribute, to, breast, cancer, cell, proliferation, and, carcinogenesis])].
[sujeto(['For', 9, of, the, 10, protective, 'CDKN2B-AS1', 'SNPs', with, minor, alleles]), verbo([associated]), complemento([with, reduced, disease, risk, '(', 'eg,', the, 'G', allele, at, 'rs2157719),', 'POAG', patients, carrying, these, minor, alleles, had, smaller, 'cup-to-disc', ratio, '(', 0.05, units, smaller, per, 'G', allele, at, 'diagnosis;', 95, '%', 'CI:', -, 0.08, ',', -, 0.03, ;, 'P =', 6.23e-5, ')', despite, having, higher, intraocular, pressure, '(', 'IOP)', '(', 0.7, &, 'nbsp;mm', 'Hg', higher, per, 'G', allele, at, 'DNA', 'collection;', 95, '%', 'CI:', 0.4, ',', 1.0, ;, 'P =', 5.45e-6, ')'])].
[sujeto(['For', the, 1, adverse, rs3217992, 'SNP', with, minor, allele, 'A']), verbo([associated]), complemento([with, increased, disease, 'risk,', 'POAG', patients, with, 'A', alleles, had, larger, 'cup-to-disc', ratio, '(', 0.05, units, larger, per, 'A', allele, at, 'diagnosis;', 95, '%', 'CI:', 0.02, ',', 0.07, ;, 'P =', 0.000474, ')', despite, having, lower, 'IOP', '(', -, 0.57, &, 'nbsp;mm', 'Hg', per, 'A', allele, at, 'DNA', 'collection;', 95, '%', 'CI:', -, 0.84, ',', -, 0.29, ;, 'P =', 6.55e-5, ')'])].
[sujeto(['Alleles', of, 'CDKN2B-AS1', 'SNPs,', which, influence, risk, of, developing, 'POAG,', also]), verbo([modulate]), complemento(['optic nerve', degeneration, among, 'POAG', 'patients,', underscoring, the, role, of, 'CDKN2B-AS1', in, 'POAG'])].
[sujeto(['Genetic', factors, unrelated, to, the, 'NF1', locus, are, thought, to, influence, the, number, of, plexiform, neurofibromas, '(', 'PNFs)', in, patients, with, 'NF1,', but, no, factors]), verbo([have]), complemento([been, identified, to, date])].
[sujeto(['We', used, 'high-resolution', array, comparative, genomic, hybridization, of, tissue, from, 22, 'PNFs', obtained, from, 18, 'NF1', patients, to, identify, modifier, genes]), verbo([involved]), complemento([in, 'PNF', development])].
[sujeto([3, deletions, '(', including, the, 'CDKN2A/B-ANRIL', 'locus)', were]), verbo([found]), complemento([as, the, only, recurrent, somatic, alterations])].
[sujeto(['Single-nucleotide', polymorphism, rs2151280, '(', located, in, 'ANRIL)', was, statistically, significantly]), verbo([associated]), complemento([with, the, number, of, 'PNFs', '(', 'P', &, 'lt;'])].
[sujeto(['In', 'addition,', allele, 'T', of, rs2151280, was, statistically, significantly]), verbo([associated]), complemento([with, reduced, 'ANRIL', transcript, levels, '(', 'P', &, 'lt;'])].
[sujeto([1, ')', ',']), verbo([suggesting]), complemento([that, modulation, of, 'ANRIL', expression, mediates, 'PNF', susceptibility])].
[sujeto(['Pancreatic', cancer, '(', 'PaCa)', is, the, fourth]), verbo([leading]), complemento([cause, of, cancer, deaths, in, 'Western', 'societies,', with, pancreatic, ductal, adenocarcinomas, '(', 'PDACs)', accounting, for, &, 'gt;90%', of, such, cases])].
[sujeto(['The', biological, function, of, 'Dkk-3', in, this, subset, was, studied, using, the, 'Dkk-3']), verbo([expressing]), complemento(['PANC-1', cell, line, as, a, model, for, 'PDACs'])].
[sujeto(['Confocal', microscopy, showed, that, 'Dkk-3', was]), verbo([expressed]), complemento([in, a, fraction, of, 'PANC-1', cells])].
[sujeto(['Thus,', we, conclude, that, 'Dkk-3', is]), verbo([required]), complemento([to, maintain, a, highly, dedifferentiated, and, consequently, proliferative, state, in, 'PANC-1,', indicating, a, similar, function, in, the, 'Dkk-3', overexpressing, subset, of, 'PDACs'])].
[sujeto(['Therefore,', 'Dkk-3', represents, a, potential]), verbo([target]), complemento([for, the, treatment, of, 'Dkk-3-positive', subtypes, of, 'PaCa', to, drive, cells, into, cell, cycle, arrest, and, differentiation])].
[sujeto(['The', important, role, of, 'PcG', in]), verbo([mediating]), complemento([repression, of, the, 'INK4b-ARF-INK4a', 'locus,', by, directly, binding, to, the, long, noncoding, 'RNA', '(', 'lncRNA)', transcript, antisense, noncoding, 'RNA', in, the, 'INK4', locus, '(', 'ANRIL),', was, recently, shown])].
[sujeto(['ANRIL', gene, is]), verbo([transcribed]), complemento([in, the, antisense, orientation, of, the, 'INK4b-ARF-INK4a', gene, 'cluster,', and, different, 'single-nucleotide', polymorphisms, are, associated, with, increased, susceptibility, to, several, diseases])].
[sujeto(['Although', 'lncRNA-mediated', regulation, of, 'INK4b-ARF-INK4a', gene, is, not, restricted, to, 'ANRIL,', both, polycomb, repressive, 'complex-1', '(', 'PRC1)', and, -, 2, '(', 'PRC2)']), verbo([interact]), complemento([with, 'ANRIL', to, form, heterochromatin, surrounding, the, 'INK4b-ARF-INK4a', 'locus,', leading, to, its, repression])].
[sujeto(['This', mechanism, would]), verbo([provide]), complemento([an, increased, advantage, for, bypassing, 'senescence,', sustaining, the, requirements, for, the, proliferation, of, stem, 'and/or', progenitor, cell, populations, or, inappropriately, leading, to, oncogenesis, through, the, aberrant, saturation, of, the, 'INK4b-ARF-INK4a', locus, by, 'PcG', complexes])].
[sujeto([3, ',', which, encode, 'CDKN2A/CDKN2B', tumor, suppressor, 'genes,']), verbo([have]), complemento([been, isolatedly, reported, to, be, associated, with, 'GBM', risk, and, prognosis])].
[sujeto([3]), verbo([loss]), complemento([and, low, 'CDKN2B', expression, were, associated, with, worse, prognosis, for, both, tumor, 'progression/recurrence-free', survival, '(', 'P', =])].
[sujeto(['Representing', one, of, the, first, attempts, to, systematically, integrate, various, levels, of, alterations]), verbo([associated]), complemento([with, the, often, complex, cancer, genomes, and, 'phenotypes,', our, study, provided, a, holistic, view, and, a, mechanistic, explanation, over, the, functional, connections, of, multiple, 9, p21])].
[sujeto(['Epidemiological', studies]), verbo([have]), complemento([indicated, a, relationship, between, coronary, heart, disease, '(', 'CHD)', and, periodontitis])].
[sujeto(['Recently,', 'CDKN2BAS', was]), verbo([reported]), complemento([as, a, shared, genetic, risk, factor, of, 'CHD', and, aggressive, periodontitis, '(', 'AgP),', but, the, causative, variant, has, remained, unknown])].
[sujeto(['After', 24, h, of, stimulation, with, 'Porphyromonas', gingivalis, in, 'Streptococcus', gordonii, 'pre-treated', gingival, fibroblast, '(', 'HGF)', and, cultured, gingival, epithelial, cells, '(', 'GECs),', we, observed, a, 25, -, fold, and, fourfold]), verbo([increase]), complemento([of, 'CDKN2BAS', gene, expression, in, 'HGFs', '(', 'p=0'])].
[sujeto(['Although', the, pathogenesis, of, endometriosis, is, not, well, 'understood,', genetic, factors]), verbo([have]), complemento([been, considered, to, have, critical, roles, in, its, etiology])].
[sujeto(['By', fine, 'mapping,', the, 'SNP', showing, the, strongest, association, was, located, in, intron, 16, of, 'CDKN2BAS', and, was, implicated, in]), verbo([regulating]), complemento([the, expression, of, 'p15,', p16, and, p14])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, these, regions, are, new, susceptibility, loci, for, endometriosis])].
[sujeto(['Single', nucleotide, polymorphisms, '(', 'SNPs)', on, chromosome, 9, p21, are]), verbo([associated]), complemento([with, coronary, artery, 'disease,', 'diabetes,', and, multiple, cancers])].
[sujeto(['Risk', 'SNPs', are, mainly, 'non-coding,']), verbo([suggesting]), complemento([that, they, influence, expression, and, may, act, in, cis])].
[sujeto([5, ')', ',']), verbo([suggesting]), complemento([that, they, are, 'co-regulated'])].
[sujeto(['Multiple', 'SNPs', were, independently]), verbo([associated]), complemento([with, expression, of, each, gene, '(', 'P<0'])].
[sujeto([5, after, correction, for, multiple, 'testing),']), verbo([suggesting]), complemento([that, several, sites, may, modulate, disease, susceptibility])].
[sujeto(['Risk', 'SNPs', for, coronary, 'disease,', 'stroke,', 'diabetes,', 'melanoma,', and, glioma, were, all]), verbo([associated]), complemento([with, allelic, expression, of, 'ANRIL', '(', all, 'P<0'])].
[sujeto(['Our', study]), verbo([suggests]), complemento([that, modulation, of, 'ANRIL', expression, mediates, susceptibility, to, several, important, human, diseases])].
[sujeto(['We', tested, the, hypothesis, that, expression, of, transcripts, adjacent, to, the, chromosome, 9, p21, '(', 'Chr9p21)', locus, of, coronary, artery, disease, was, affected, by, the, genotype, at, this, locus, and]), verbo([associated]), complemento([with, atherosclerosis, risk])].
[sujeto(['Expression', analysis, in, peripheral, blood, mononuclear, cells, '(', 'n=1098)', revealed, that, transcripts, 'EU741058', and, 'NR_003529', of, antisense, noncoding, 'RNA', in, the, 'INK4', locus, '(', 'ANRIL)', were, significantly]), verbo([increased]), complemento([in, carriers, of, the, risk, haplotype, '(', 'P=2'])].
[sujeto(['In', 'contrast,', transcript, 'DQ485454', remained, 'unaffected,']), verbo([suggesting]), complemento([differential, expression, of, 'ANRIL', transcripts, at, 'Chr9p21'])].
[sujeto(['No', consistent, association, of, 'Chr9p21', or, atherosclerosis, was]), verbo([found]), complemento([with, expression, of, other, genes, such, as, 'CDKN2A,', 'CDKN2B,', 'C9orf53,', and, 'MTAP'])].
[sujeto(['Our', data]), verbo([provide]), complemento([robust, evidence, for, an, association, of, 'ANRIL', but, not, 'CDKN2A,', 'CDKN2B,', 'C9orf53,', and, 'MTAP,', with, atherosclerosis, and, 'Chr9p21', genotype, in, a, large, cohort])].
[sujeto(['RhoA,', a, member, of, the, 'Rho', 'GTPase', 'family,']), verbo([has]), complemento([been, extensively, studied, in, the, regulation, of, cytoskeletal, 'dynamics,', gene, 'transcription,', cell, cycle, 'progression,', and, cell, transformation])].
[sujeto(['Overexpression', of, 'RhoA', is]), verbo([found]), complemento([in, many, malignancies, and, elevated, 'RhoA', activity, is, associated, with, proliferation, phenotypes, of, cancer, cells])].
[sujeto(['We']), verbo([reported]), complemento([previously, that, 'RhoA', was, hyperactivated, in, gastric, cancer, tissues, and, suppression, of, 'RhoA', activity, could, partially, reverse, the, proliferation, phenotype, of, gastric, cancer, 'cells,', but, the, underlying, mechanism, has, yet, to, be, elucidated])].
[sujeto(['It']), verbo([has]), complemento([been, reported, that, 'RhoA', activation, is, crucial, for, the, cell, cycle, 'G(1)-S', procession, through, the, regulation, of, 'Cip/Kip', family, tumor, suppressors, in, benign, cell, lines])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, selective, suppression, of, 'RhoA', or, its, effectors, mammalian, 'Diaphanous', 1, and, 'Rho', kinase, '(', 'ROCK)', by, small, interfering, 'RNA', and, a, pharmacologic, inhibitor, effectively, inhibited, proliferation, and, cell, cycle, 'G(1)-S', transition, in, gastric, cancer, lines])].
[sujeto(['Down-regulation', of, 'RhoA-mammalian', 'Diaphanous', 1, 'pathway,', but, not, 'RhoA-ROCK', 'pathway,']), verbo([caused]), complemento([an, increase, in, the, expression, of, 'p21(Waf1/Cip1)', and, 'p27(Kip1),', which, are, coupled, with, reduced, expression, and, activity, of, 'CDK2', and, a, cytoplasmic, mislocalization, of, 'p27(Kip1)'])].
[sujeto(['Suppression', of, 'RhoA-ROCK', 'pathway,', on, the, other, 'hand,', resulted, in, an, accumulation, of, 'p15(INK4b),', 'p16(INK4a),', 'p18(INK4c),', and, 'p19(INK4d),']), verbo([leading]), complemento([to, reduced, expression, and, activities, of, 'CDK4', and, 'CDK6'])].
[sujeto(['Thus,', 'RhoA', may, use, two, distinct, effector, pathways, in]), verbo([regulating]), complemento([the, 'G(1)-S', progression, of, gastric, cancer, cells])].
[sujeto(['Many', 'genome-wide', association, studies]), verbo([have]), complemento([identified, common, single, nucleotide, polymorphisms, '(', 'SNPs)', at, the, 9, p21, glaucoma, locus, '(', 'CDKN2B/CDKN2B-AS1)', to, be, significantly, associated, with, primary, 'open-angle', glaucoma, '(', 'POAG),', with, association, being, stronger, in, normal, tension, glaucoma, '(', 'NTG)', and, advanced, glaucoma])].
[sujeto(['In', all, 'POAG', 'cases,', the, strongest]), verbo([associated]), complemento(['SNP', at, 9, p21, was, rs1063192, '(', 'OR,', 1.43, ;, 'P', =, 4, ×, 10, -, 18, ')'])].
[sujeto(['Long', noncoding, 'RNAs', '(', 'lncRNAs)', are, 'non-protein', coding, transcripts]), verbo([regulating]), complemento([a, variety, of, physiological, and, pathological, functions])].
[sujeto(['Fourteen', lncRNAs, were, significantly]), verbo([modulated]), complemento([in, non, 'end-stage', heart, failure, 'patients,', identifying, a, heart, failure, lncRNA, signature])].
[sujeto(['Intriguingly,', among, the]), verbo([conserved]), complemento(['lncRNAs,', 'h19,', rmrp, and, hotair, were, also, induced, in, a, mouse, model, of, heart, hypertrophy])].
[sujeto(['CDKN2B-AS1/ANRIL,', 'HOTAIR', and, 'LOC285194/TUSC7', showed, similar, modulation, in, peripheral, blood, mononuclear, cells, and, heart, 'tissue,']), verbo([suggesting]), complemento([a, potential, role, as, disease, biomarkers])].
[sujeto(['Interestingly,', 'RMRP', displayed, a, ubiquitous]), verbo([nuclear]), complemento(['distribution,', while, 'H19', 'RNA', was, more, abundant, in, blood, vessels, and, was, both, cytoplasmic, and, nuclear])].
[sujeto(['Gene', ontology, analysis, of, the, mRNAs, displaying, a, significant, correlation, in, expression, with, heart, failure, lncRNAs, identified, numerous, pathways, and, functions]), verbo([involved]), complemento([in, heart, failure, progression])].
[sujeto(['These', data, strongly]), verbo([suggest]), complemento([lncRNA, implication, in, the, molecular, mechanisms, underpinning, 'HF'])].
[sujeto(['We', identified, a, novel, pleiotropic, association, at, 1, q22]), verbo([involving]), complemento([breast, and, lung, squamous, cell, 'carcinoma,', with, eQTL, analysis, showing, an, association, with, 'ADAM15/THBS3', gene, expression, in, lung])].
[sujeto(['We', also, identified, a, known, breast, cancer, locus, 'CASP8/ALS2CR12']), verbo([associated]), complemento([with, prostate, 'cancer,', a, known, cancer, locus, at, 'CDKN2B-AS1', with, different, variants, associated, with, lung, adenocarcinoma, and, prostate, 'cancer,', and, confirmed, the, associations, of, a, breast, 'BRCA2', locus, with, lung, and, serous, ovarian, cancer])].
[sujeto(['The', objective, of, this, study, was, to, investigate, the, association, between, mRNA, expression, and, single, nucleotide, polymorphisms, '(', 'SNPs)', of, the, 'ATP-binding', cassette, transporter, '(', 'ABCA1)', 'gene,', apolipoprotein, 'A1', '(', 'APOA1)', 'gene,', 'low-density', lipoprotein, '(', 'LDLR)', gene, and, 'RNA', gene, located, in, the, 'CDKN2B-CDKN2A', cluster, '(', 'CDKN2B-AS1)']), verbo([involved]), complemento([in, lipid, metabolism, and, the, occurrence, of, intracranial, aneurysm, '(', 'IA)'])].
[sujeto([-, 113, 'G>A', polymorphism, of, the, 'APOA1', gene, were]), verbo([associated]), complemento([with, increased, occurrence, of, 'IA', '(', 'ORs', 12.36, and, 14.14, ',', 'respectively),', while, the, 'G/G', genotype, and, 'G', allele, showed, the, opposite, tendency, '(', 'ORs', 0.06, and, 0.07, ',', 'respectively)'])].
[sujeto([46859, 'A>G', -, 'LDLR', 'SNPs', was]), verbo([associated]), complemento([with, a, decreased, occurrence, of, 'IA'])].
[sujeto([-, 113, 'G>A', -, 'APOA1', was]), verbo([associated]), complemento([with, a, decreased, occurrence, of, 'IA'])].
[sujeto(['The', results, of, our, study]), verbo([suggest]), complemento([the, association, between, expression, and, variability, of, lipid, metabolism, genes, and, occurrence, of, 'IA'])].
[sujeto([3]), verbo([conferring]), complemento([the, risk, for, 'CAD', '(', coronary, artery, 'disease)', in, individuals, of, 'Caucasian', ancestry])].
[sujeto(['Controls', with, evidenced, lack, of, 'CAD']), verbo([provided]), complemento([90, '%', of, statistical, power, at, the, type, 'I', error, rate, of, 0.05])].
[sujeto(['This', study, is, in, line, with, others, that, indicated, that, the, 'SNPs', located, in, the, intronic, region, of, the, 'CDKN2B-AS1', gene, are]), verbo([associated]), complemento([with, 'CAD'])].
[sujeto(['Recent', 'genome-wide', association, studies]), verbo([have]), complemento([identified, a, major, risk, locus, for, atherosclerosis, on, chromosome, 9, p21])].
[sujeto([47, ')', ',', while, weight]), verbo([gain]), complemento([and, increased, fasting, glucose, levels, were, significantly, associated, with, rs2383207, 'AA', genotype, '(', 'p=0'])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, 'SNPs', 'rs10757274,', 'rs2383207,', 'rs10757278,', and, 'rs1333049,', particularly, those, within, the, 'CDKN2B-AS1', 'gene,', and, related, haplotypes, may, confer, increased, susceptibility, to, 'HT', development])].
[sujeto(['Long', noncoding, 'RNAs', '(', 'lncRNAs)', were, recently]), verbo([found]), complemento([to, be, key, regulators, of, biological, functions, and, associated, with, human, diseases])].
[sujeto(['We', aimed, to, determine, whether, lncRNAs, are]), verbo([associated]), complemento([with, 'IBD', and, regulate, epithelial, cell, physiology])].
[sujeto(['We', identified, 329, lncRNAs, with]), verbo([increased]), complemento([and, 126, lncRNAs, with, decreased, expression, in, active, 'UC', tissues, compared, with, normal, control, 'tissues,', including, the, most, significantly, upregulated, '(', 'BC012900,', 'AK001903,', and, 'AK023330)', and, downregulated, '(', 'BC029135,', 'CDKN2B-AS1,', and, 'BC062296)', transcripts])].
[sujeto(['We']), verbo([found]), complemento([that, most, of, the, lncRNAs, are, localized, to, the, nucleus])].
[sujeto(['In', 'particular,', 'BC012900', expression, was, significantly]), verbo([increased]), complemento([in, active, 'UC', and, stimulated, by, cytokines, and, pathogenic, molecules])].
[sujeto(['Furthermore,', 'BC012900', overexpression, in, epithelial, cells, results, in, a, significant, inhibition, of, cell, proliferation, and, an]), verbo([increased]), complemento([susceptibility, to, 'apoptosis,', which, differ, from, its, adjacent, gene, 'DUSP4'])].
[sujeto(['Multiple', lncRNAs, are, differentially]), verbo([expressed]), complemento([in, 'IBD', and, play, a, role, in, regulating, cellular, physiology])].
[sujeto(['Our', results, indicate, that, lncRNAs, may, be, integral, modulators, of, intestinal, inflammation]), verbo([associated]), complemento([with, 'IBD', and, represent, novel, targets, for, future, therapeutics, and, diagnostic, marker, development])].
[sujeto(['Epidemiological', studies]), verbo([suggest]), complemento([that, by, 2020, the, prevalence, of, primary, open, angle, glaucoma, '(', 'POAG)', is, estimated, to, increase, to, 76.0, 'million,', and, to, 111.8, million, by, 2040, globally, due, to, the, population, aging])].
[sujeto(['Less', than, 10, '%', of, 'POAG', cases, in, the, general, population, are]), verbo([caused]), complemento([by, specific, gene, mutations, and, the, remaining, cases, are, polygenic])].
[sujeto(['Recent', 'genome-wide', association, studies, '(', 'GWAS)']), verbo([have]), complemento([identified, several, single, nucleotide, polymorphisms, '(', 'SNPs)', at, different, loci, including, 'CAV1/CAV2,', 'TMCO1,', 'CDKN2B-AS1,', 'CDC7-TGFBR3,', 'SIX1/SIX6,', 'GAS7', and, 'ATOH7', to, be, associated, with, 'POAG', and, its, related, quantitative, traits, '(', 'endophenotypes)'])].
[sujeto(['The', chapter]), verbo([provides]), complemento([a, brief, overview, on, the, different, 'GWAS', and, 'SNP', association, studies, and, their, correlation, with, various, clinical, parameters, important, for, 'POAG', in, the, population, 'worldwide,', including, the, 'Middle', 'East'])].
[sujeto(['To', investigate, whether, known, genetic, loci, for, primary, 'open-angle', glaucoma, '(', 'POAG)', are]), verbo([associated]), complemento([with, visual, field, '(', 'VF)', progression, in, patients, from, a, 'Singaporean', 'Chinese', population])].
[sujeto(['Univariate', analysis, revealed, that]), verbo([increased]), complemento(['VCDR', '(', 'P =', 0.003, ')', ',', reduced, 'CCT', '(', 'P =', 0.045, ')', ',', and, reduced, superior, and, inferior, retinal, nerve, fiber, layer, thickness, '(', 'P =', 0.01, ',', 'respectively)', were, associated, with, 'VF', progression])].
[sujeto(['No', clinical, or, structural, features, were]), verbo([associated]), complemento([significantly, with, 'VF', progression, on, multivariate, analysis])].
[sujeto(['The', rs1192415, index, 'SNP', in, 'TGFBR3-CDC7', '(', 'P =', 0.002, ;, odds, 'ratio,', 6.71, per, risk, 'allele)', was, the, only, 'SNP']), verbo([associated]), complemento([with, 'VF', progression])].
[sujeto(['The', presence, of, the, index, 'SNP', rs1192415, '(', 'TGFBR3-CDC7)', was]), verbo([associated]), complemento([with, 'VF', progression, in, 'POAG', patients])].
[sujeto(['Genome-wide', and, 'candidate-gene', association, studies, for, endometriosis]), verbo([have]), complemento([identified, 10, independent, risk, 'loci,', and, of, 'these,', nine, '(', 'rs7521902,', 'rs13394619,', 'rs4141819,', 'rs6542095,', 'rs1519761,', 'rs7739264,', 'rs12700667,', 'rs1537377,', and, 'rs10859871)', are, polymorphic, in, 'European', populations])].
[sujeto(['Overall,', this, study]), verbo([provides]), complemento([important, replication, in, a, uniquely, characterized, independent, 'population,', and, indicates, that, the, majority, of, the, original, 'genome-wide', association, findings, are, not, due, to, chance, alone])].
[sujeto(['The', long, 'non-coding', 'RNA', 'CDKN2B-AS1,', commonly, referred, to, as, the, 'A', ntisense, 'N', 'on-coding', 'R', 'NA', in, the, 'I', 'NK4', 'L', ocus, '(', 'ANRIL),', is, a, 3.8, -, 'kb-long', 'RNA']), verbo([transcribed]), complemento([from, the, short, arm, of, human, chromosome, 9, on, p21])].
[sujeto(['Genome-wide', association, studies]), verbo([have]), complemento([identified, this, region, with, a, remarkable, and, growing, number, of, 'disease-associated', 'DNA', alterations, and, single, nucleotide, 'polymorphisms,', which, corresponds, to, increased, susceptibility, to, human, disease])].
[sujeto(['Recent', attention]), verbo([has]), complemento([been, devoted, on, whether, these, alterations, in, the, 'ANRIL', sequence, affect, its, expression, levels, 'and/or', its, splicing, transcript, 'variation,', and, in, 'consequence,', global, cellular, homeostasis])].
[sujeto(['Moreover,', recent, evidence, postulates, that, 'ANRIL', not, only, can]), verbo([regulate]), complemento([their, immediate, genomic, neighbors, in, 'cis,', but, also, has, the, capacity, to, regulate, additional, loci, in, trans])].
[sujeto(['This', action, would, further]), verbo([increase]), complemento([the, complexity, for, mechanisms, imposed, through, 'ANRIL', and, furthering, the, scope, of, this, lncRNA, in, disease, pathogenesis])].
[sujeto(['In', this, 'chapter,', we, summarize, the, most, recent, findings, on, the, investigation, of, 'ANRIL', and]), verbo([provide]), complemento([a, perspective, on, the, biological, and, clinical, significance, of, 'ANRIL', as, a, putative, 'biomarker,', 'specifically,', its, potential, role, in, directing, cellular, fates, leading, to, cancer, and, cardiovascular, disease])].
[sujeto(['The', identification, of, the, breast, cancer, susceptibility, genes, 'BRCA1', and, 'BRCA2']), verbo([enhanced]), complemento(['clinicians\'', ability, to, select, 'high-risk', individuals, for, aggressive, surveillance, and, 'prevention,', and, led, to, the, development, of, targeted, therapies])].
[sujeto(['To', systematically, identify, 'rare,', probably, pathogenic, variants, in, familial, cases, of, breast, cancer, without, 'BRCA1/2', 'mutations,', we, developed, a, list, of, 312, 'genes,', and, performed]), verbo([targeted]), complemento(['DNA', enrichment, coupled, to, multiplex, 'next-generation', sequencing, on, 104, '\'', 'BRCAx\'', patients, and, 101, geographically, matched, controls, in, 'Ireland'])].
[sujeto(['Primary', open, angle, glaucoma, '(', 'POAG),', a, major]), verbo([cause]), complemento([of, blindness, 'worldwide,', is, a, complex, disease, with, a, significant, genetic, contribution])].
[sujeto(['This', particular, 'SNP']), verbo([has]), complemento([previously, been, shown, to, be, strongly, associated, with, optic, disc, area, and, vertical, 'cup-to-disc', 'ratio,', which, are, regarded, as, 'glaucoma-related', quantitative, traits])].
[sujeto(['Four', large, 'genome-wide', association, studies, '(', 'GWAS)']), verbo([have]), complemento([linked, common, genetic, variants, with, an, increased, glioma, risk])].
[sujeto(['However,', to, 'date,', these, studies, are, based, largely, on, a, 'case-control', 'design,', where, cases]), verbo([have]), complemento([been, recruited, at, the, time, of, or, after, diagnosis])].
[sujeto(['To', confirm, glioma, risk, variants, in, a, prospective, 'setting,', we]), verbo([have]), complemento([analyzed, 11, previously, identified, risk, variants, in, a, set, of, prediagnostic, serum, samples, with, 598, cases, and, 595, matched, controls])].
[sujeto(['Our', results, indicate, that, the, risk, variants, that, were, confirmed, by, this, study, are, truly]), verbo([associated]), complemento([with, glioma, risk, and, 'may,', 'consequently,', affect, gliomagenesis])].
[sujeto(['We']), verbo([recruited]), complemento([1157, 'POAG', 'cases,', including, 860, 'HTG', and, 297, 'NTG,', and, 934, normal, controls])].
[sujeto(['A', total, of, 13, previously]), verbo([reported]), complemento([single, nucleotide, polymorphisms, '(', 'SNPs)', located, at, four, gene, regions, '(', 'TMCO1,', 'CDKN2B-AS1,', 'ATOH7,', and, 'SIX1/SIX6)', was, genotyped])].
[sujeto(['The', 'SNPs', rs523096, and, rs2157719, at, 'CDKN2B-AS1', as, well, as, rs33912345, and, rs10483727, at, 'SIX1/SIX6', were]), verbo([found]), complemento([to, be, associated, with, 'IOP', where, the, minor, alleles, were, associated, with, an, increase, in, 'IOP'])].
[sujeto(['Genetic', variants, in, 'CDKN2B-AS1,', 'SIX1/SIX6,', and, 'TMCO1', were]), verbo([associated]), complemento([with, 'POAG', in, a, 'Han', 'Chinese', population])].
[sujeto(['Is', it, possible, to, replicate, the, genetic, association, of, single, nucleotide, polymorphisms, '(', 'SNPs)', 'rs13394619,', 'rs4141819,', 'rs7739264,', rs17694933, and, rs10859871, in, five, genetic, loci, previously, identified, as]), verbo([associated]), complemento([with, endometriosis, in, an, 'Italian', 'Caucasian', 'population?', 'SNP', rs10859871, near, the, vezatin, '(', 'VEZT)', gene, was, found, to, be, significantly, associated, with, endometriosis, in, general, while, 'SNPs', rs17694933, and, rs4141819, were, associated, with, 'Stage', 'III/IV', and, ovarian, 'disease,', respectively])].
[sujeto(['Recent', 'genome-wide', association, studies, '(', 'GWASs)']), verbo([have]), complemento([allowed, to, identify, some, 'SNPs', associated, with, the, predisposition, to, the, disease])].
[sujeto(['A', 'meta-analysis', published, in, 2014, combined, results, from, 'GWAS', and, replication, studies, showing, that, of, the, nine, loci]), verbo([found]), complemento([to, be, associated, with, the, disease, in, at, least, one, of, the, 'studies,', six, '(', 'rs7521902,', 'rs1270667,', 'rs13394619,', 'rs7739264,', rs1537377, and, 'rs10859871)', remained, 'genome-wide', significant, while, two, others, '(', rs1250248, and, 'rs4141819)', showed, borderline, 'genome-wide', significant, association, with, more, severe, disease])].
[sujeto(['A', statistically, significant, association, with, endometriosis, was]), verbo([found]), complemento([for, 'SNP', 'rs10859871,', close, to, the, 'VEZT', 'gene,', compared, with, both, general, population, '[', odds, ratio, '(', 'OR)', =, 1.43, ',', 95, '%', confidence, interval, '(', 'CI):', 1.2, -, 1.71, ',', 'P', =, 6.9, ×, 10, '(', -, 5, ')', ']', and, laparoscopic, controls, '(', 'OR', =, 1.58, ',', 95, '%', 'CI:', 1.24, -, 2.02, ',', 'P', =, 2.1, ×, 10, '(', -, 4, ')', ')'])].
[sujeto(['The', associations, with, the, 'SNPs', identified, so, far]), verbo([have]), complemento([been, obtained, with, a, relatively, small, sample, size, supporting, a, limited, heterogeneity, across, the, various, datasets])].
[sujeto(['The', authors]), verbo([have]), complemento([no, competing, financial, interests, in, relation, to, the, content, of, this, research, paper])].
[sujeto(['Western', blot, was, used, to, detect, the, hTERT, level, after, the, differentially]), verbo([expressed]), complemento([lncRNAs, in, 'ECA-109', cells, were, interfered, with, small, interfering, 'RNA', '(', 'siRNA)'])].
[sujeto(['A', specific, siRNA, '(', 'si-CDKN2B-AS1)', that]), verbo([targets]), complemento([the, 'β-elemene-mediated', lncRNA, 'CDKN2B-AS1', was, 'designed,', 'synthesized,', and, applied, to, treat, 'ECA-109', cells])].
[sujeto(['When', 'ECA-109', cells, were, transfected, with, the, 'siRNA,', the, hTERT, level, was]), verbo([increased]), complemento([by, 84.7, '%'])].
[sujeto(['The', 'CCK-8', assay, showed, that, the, proliferation, of, 'ECA-109', cells, treated, with, 'β-elemene', was, significantly]), verbo([promoted]), complemento([after, siRNA, transfection, '(', 'P<0'])].
[sujeto(['It', was, also, shown, by, flow, cytometry, 'that,', compared, with, the, 'scramble-treated', group, '(', negative, 'control),', the, proliferation, index, value, of, 'ECA-109', cells, in, the, 'si-CDKN2B-AS1', treatment, group, was, notably]), verbo([increased]), complemento(['(', 25.7, vs])].
[sujeto([51.7, '%', ')', and, the, 'TERT', protein, level, was]), verbo([increased]), complemento([by, 67.25, '%', after, the, cells, were, treated, with, 'si-CDKN2B-AS1'])].
[sujeto(['The', chemotherapeutic, drug, 'β-elemene']), verbo([suppressed]), complemento([the, proliferation, of, esophageal, carcinoma, 'ECA-109', cells, by, regulating, the, inhibition, of, hTERT, expression, by, lncRNA, 'CDKN2B-AS1'])].
[sujeto(['Antisense', 'non-coding', 'RNA', in, the, 'INK4', locus, '(', 'ANRIL)', fixed, genetic, variants]), verbo([have]), complemento([consistently, been, linked, with, coronary, heart, disease, '(', 'CHD)', risk])].
[sujeto(['Increasing', evidence]), verbo([suggests]), complemento([that, the, early, life, environment, may, act, through, epigenetic, processes, to, influence, later, 'CHD', risk, markers, such, as, increased, arterial, pulse, wave, velocity, '(', 'PWV,', a, measure, of, arterial, 'stiffness)', blood, pressure, or, heart, rate])].
[sujeto(['Perinatal', methylation, was, not]), verbo([associated]), complemento([with, 'child\'s', later, blood, 'pressure,', but, higher, methylation, at, 'CpG5', was, associated, with, increased, childhood, 'PWV', '(', β, =, 0.066, &, 'nbsp;m/s/10 %', methylation, increase, '[', 95, &, 'nbsp;%', 'CI,', 0.004, to, 0.128, ']', ',', p, =, 0.037, ')', ;, 10, &, 'nbsp;%', decreases, in, methylation, at, 'CpG1', and, 'CpG2', were, associated, with, increased, heart, rate, '(', 'CpG1', β, =, 1.93, '[', 0.07, to, 3.8, ']', 'beats/min,', p, =, 0.041, ;, 'CpG2', β, =, 2.3, '[', 0.18, to, 4.41, ']', 'beats/min,', p, =, 0.033, ',', accounting, for, potential, confounding, 'variables)'])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([developmental, epigenetic, regulation, of, 'ANRIL', promoter, methylation, as, a, factor, in, later, 'CHD', risk, in, children])].
[sujeto(['In', this, 'study,', we]), verbo([report]), complemento([that, 'LncRNA', 'ANRIL,', which, encodes, a, 3834, -, nt, 'RNA', that, contains, 19, exons, at, the, antisense, orientation, of, the, 'INK4B-ARF-INK4A', gene, 'cluster,', generally, 'up-regulated', in, nasopharyngeal, carcinoma, '[', 1, ']'])].
[sujeto(['In', a, cohort, of, 88, 'NPC', 'patients,', 'ANRIL', was, highly]), verbo([expressed]), complemento([in, 'advanced-stage', cancer])].
[sujeto(['Further', investigation, showed, that, knockdown, of, 'ANRIL', significantly]), verbo([repressed]), complemento(['NPC', cell, proliferation, and, transformation])].
[sujeto(['We', also]), verbo([found]), complemento([that, 'ANRIL', could, induce, the, percentage, of, side, population, cells, '(', 'SP', 'cells)', in, 'NPC'])].
[sujeto(['To', meet, the, urgent, needs, of, energy, 'provision,', 'ANRIL', can, also, reprogram, glucose, metabolism, via]), verbo([increasing]), complemento([glucose, uptake, for, 'glycolysis,', which, was, regulated, by, the, mTOR, signal, pathway, to, affect, the, expression, of, essential, genes, in, glycolysis])].
[sujeto(['We', concluded, that, 'ANRIL', could]), verbo([promote]), complemento(['NPC', progression, via, increasing, cell, 'proliferation,', reprograming, cell, glucose, metabolism, and, inducing, 'side-population', 'stem-like', cancer, cells])].
[sujeto(['Our', results, also]), verbo([suggested]), complemento([that, 'ANRIL', may, serve, as, a, novel, diagnostic, or, prognostic, biomarker, and, a, candidate, target, for, new, therapies, in, 'NPC'])].
[sujeto(['Circular', 'RNAs', '(', 'circRNAs)', are, broadly]), verbo([expressed]), complemento([in, eukaryotic, 'cells,', but, their, molecular, mechanism, in, human, disease, remains, obscure])].
[sujeto(['Here', we, show, that, circular, antisense, 'non-coding', 'RNA', in, the, 'INK4', locus, '(', 'circANRIL),', which, is]), verbo([transcribed]), complemento([at, a, locus, of, atherosclerotic, cardiovascular, disease, on, chromosome, 9, 'p21,', confers, atheroprotection, by, controlling, ribosomal, 'RNA', '(', 'rRNA)', maturation, and, modulating, pathways, of, atherogenesis])].
[sujeto(['CircANRIL']), verbo([binds]), complemento([to, pescadillo, homologue, 1, '(', 'PES1),', an, essential, 60, 'S-preribosomal', assembly, 'factor,', thereby, impairing, 'exonuclease-mediated', 'pre-rRNA', processing, and, ribosome, biogenesis, in, vascular, smooth, muscle, cells, and, macrophages])].
[sujeto(['As', a, 'consequence,', circANRIL]), verbo([induces]), complemento([nucleolar, stress, and, p53, 'activation,', resulting, in, the, induction, of, apoptosis, and, inhibition, of, 'proliferation,', which, are, key, cell, functions, in, atherosclerosis])].
[sujeto(['Collectively,', these, findings, identify, circANRIL, as, a, prototype, of, a, circRNA]), verbo([regulating]), complemento([ribosome, biogenesis, and, conferring, 'atheroprotection,', thereby, showing, that, circularization, of, long, 'non-coding', 'RNAs', may, alter, 'RNA', function, and, protect, from, human, disease])].
[sujeto(['The', 'siRNA-mediated', 'ANRIL', silencing]), verbo([inhibits]), complemento(['proliferation,', 'invasion,', and, metastasis, of, 'TPC-1', and, 'SW579', 'cells,', and, lung, 'metastasis,', which, can, be, reversed, by, 'TGF-β1', siRNA])].
[sujeto(['The', mRNA, levels, of, 'p15INK4b,', p14ARF, and, p16INK4a, in, 'TPC-1', and, 'SW579', cells]), verbo([increased]), complemento([significantly, after, silencing, 'ANRIL', '(', all, 'P', &, 'lt;', 0.001, ')', ',', and, 'TGF-β1', siRNA, could, reverse, the, 'ANRIL', siRNA, induced, increase, of, 'p15INK4b;', expressions, of, 'TGF-β1', and, 'p-Smad2/3', were, increased, after, silencing, 'ANRIL', '(', both, 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['ANRIL', may, reduce, p15INK4B, expression, through]), verbo([inhibiting]), complemento(['TGF-β/Smad', signaling, 'pathway,', promoting, invasion, and, metastasis, of, 'TC', 'cells,', and, the, silencing, of, 'ANRIL', inhibits, the, invasion, and, metastasis, of, 'TPC-1', cells])].
[sujeto(['Simultaneous', correction, of, multiple, 'tumor-specific', gene, abnormalities]), verbo([has]), complemento([become, an, attractive, approach, for, developing, therapeutics, to, treat, melanoma])].
[sujeto(['To', potentiate, 'anti-melanoma', 'activity,', we, tested, a, &, 'quot;domino', 'effect-like"', therapeutic, approach, by, uniquely]), verbo([targeting]), complemento([one, defect, and, automatically, triggering, the, endogenous, corrections, of, other, defects])].
[sujeto(['Using', this, 'strategy,', in, a, suspicious, 'INK4b-ARF-INK4a', gene, cluster, at, chromosome, 9, 'p21,', aberrant, 'INK4a', and, 'INK4b', defects, were, simultaneously, endogenously, 'auto-corrected', after]), verbo([targeting]), complemento([the, suppression, of, abnormal, 'ANRIL', lncRNA])].
[sujeto(['In', animals, harboring, tumor, 'xenografts,', this, therapeutic, approach, significantly]), verbo([inhibited]), complemento([tumor, growth, and, reduced, the, tumor, weight])].
[sujeto(['Our', results]), verbo([reveal]), complemento([a, novel, therapeutic, strategy, that, significantly, potentiates, 'anti-melanoma', efficiency, by, reprogramming, the, aberrant, 'INK4-hub'])].
[sujeto(['Cardiovascular', disease, '(', 'CVD)', is, the]), verbo([leading]), complemento([cause, of, global, mortality])].
[sujeto(['Although', extensive, efforts]), verbo([have]), complemento([been, made, to, identify, valid, biomarkers, for, 'CVD', 'risk,', relatively, '¬¬¬few', are, of, proven, clinical, utility])].
[sujeto(['It', is]), verbo([recognized]), complemento([that, genetic, factors, play, a, major, role, in, determining, the, susceptibility, to, 'CVD'])].
[sujeto(['Recent', 'genome-wide-association-studies']), verbo([have]), complemento([demonstrated, common, genetic, variants, in, a, region, on, chromosome, 9, p21, associated, with, an, increased, risk, of, 'CVD'])].
[sujeto(['Several', 'genetic-polymorphisms']), verbo([have]), complemento([been, identified, in, this, region, that, are, highly, associated, with, 'CVD,', and, these, are, clustered, around, the, gene, loci, for, 'CDKN2B', '(', coding, for, 'p15ink4b),', 'CDKN2A', '(', coding, for, p16ink4a, and, 'p14ARF)', and, the, 3, '\'', end, of, 'CDKN2BAS,', which, has, been, termed, antisense, noncoding, 'RNA', in, the, 'INK4', locus, '(', 'ANRIL)'])].
[sujeto(['Targeted', deletion, of, the, 9, p21, locus, reduces, the, cardiac, expression, of, 'CDKN2A/B', and, is, the, most, frequent, mechanism, for, methylthioadenosine, phosphorylase, 'inactivation,']), verbo([leading]), complemento([to, a, less, stable, plaque, phenotype, in, the, artery])].
[sujeto(['The', aim, of, the, current, review, was, to]), verbo([provide]), complemento([an, overview, of, the, possible, molecular, mechanisms, by, which, the, chromosome, 9, p21, locus, may, confer, 'CVD', 'risk,', and, the, consequential, clinical, implications, with, particular, emphasis, on, 'preclinical/clinical', trials, on, genetic, changes, of, this, locus, and, 'CVD', risk])].
[sujeto(['The', chromobox, 7, '(', 'CBX7)', protein, of, the, polycomb, repressive, complex, 1, '(', 'PRC1)', functions, to]), verbo([repress]), complemento([transcription, of, tumor, suppressor, p16, '(', 'INK4a)', through, long, noncoding, 'RNA,', 'ANRIL', '(', antisense, noncoding, 'RNA', in, the, 'INK4', 'locus)', directed, chromodomain, '(', 'ChD)', binding, to, trimethylated, lysine, 27, of, histone, 'H3', '(', 'H3K27me3),', resulting, in, chromatin, compaction, at, the, 'INK4a/ARF', locus])].
[sujeto(['In', this, 'study,', we]), verbo([report]), complemento(['structure-guided', discovery, of, two, distinct, classes, of, 'small-molecule', antagonists, for, the, 'CBX7ChD'])].
[sujeto(['Our', 'Class', 'A', 'compounds,', a, series, including, analogues, of, the, previously]), verbo([reported]), complemento(['MS452,', inhibit, 'CBX7ChD/methyl-lysine', binding, by, occupying, the, 'H3K27me3', peptide, binding, 'site,', whereas, our, 'Class', 'B', 'compound,', the, newly, discovered, 'MS351,', appears, to, inhibit, 'H3K27me3', binding, when, 'CBX7ChD', is, bound, to, 'RNA'])].
[sujeto(['Our', crystal, structure, of, the, 'CBX7ChD/MS351', complex]), verbo([reveals]), complemento([the, molecular, details, of, ligand, recognition, by, the, aromatic, cage, residues, that, typically, engage, in, 'methyl-lysine', binding])].
[sujeto(['We', further, demonstrate, that, 'MS351', effectively]), verbo([induces]), complemento([transcriptional, derepression, of, 'CBX7', target, 'genes,', including, p16, '(', 'INK4a)', in, mouse, embryonic, stem, cells, and, human, prostate, cancer, 'PC3', cells])].
[sujeto(['Thus,', 'MS351', represents, a, new, class, of, 'ChD', antagonists, that, selectively]), verbo([targets]), complemento([the, biologically, active, form, of, 'CBX7', of, the, 'PRC1', in, long, noncoding, 'RNA-', and, 'H3K27me3-directed', gene, transcriptional, repression])].
[sujeto(['Antisense', noncoding, 'RNA', in, the, 'INK4', locus, '(', 'ANRIL)']), verbo([has]), complemento([been, reported, to, be, upregulated, in, various, types, of, human, 'cancer,', and, is, also, highly, expressed, in, normal, human, tissue])].
[sujeto(['The', aim, of, the, present, study, was, to, identify, whether, 'ANRIL', may, be, a, possible]), verbo([target]), complemento([for, colorectal, cancer, '(', 'CRC)', therapy])].
[sujeto(['The', 'CRC', tissues, were, revealed, to]), verbo([express]), complemento([higher, levels, of, 'ANRIL', lncRNA, compared, with, the, adjacent, 'non‑neoplastic', tissues, '(', 'P<0'])].
[sujeto(['Furthermore,', high, 'ANRIL', expression, was, significantly]), verbo([associated]), complemento([with, reduced, survival, rate, '(', 'P<0'])].
[sujeto(['ANRIL', knockdown]), verbo([decreased]), complemento(['proliferation,', inhibited, migration, and, 'invasion,', and, reduced, the, 'colony‑forming', ability, of, the, cells])].
[sujeto(['These', data, indicated, that, the, lncRNA, 'ANRIL', is, upregulated, in, 'CRC', 'tissues,', and, is]), verbo([associated]), complemento([with, 'CRC', cell, pathogenesis])].
[sujeto(['In', recent, 'years,', long, noncoding, 'RNAs', '(', 'lncRNAs)']), verbo([have]), complemento([been, demonstrated, to, play, important, roles, in, the, development, of, human, cancer])].
[sujeto(['ANRIL', silencing, significantly]), verbo([inhibited]), complemento(['NSCLC', cell, proliferation])].
[sujeto(['Together,', we, showed, that, 'ANRIL', is]), verbo([involved]), complemento([in, the, oncogenesis, of, 'NSCLC,', and, 'ANRIL', may, be, a, potential, therapeutic, target, for, patients, with, 'NSCLC'])].
[sujeto(['normal)', and, cell, lines, '(', 'HCoEpic,', 'SW480,', 'HT29,', 'LoVo', and, 'HCT116),']), verbo([finding]), complemento([that, 'ANRIL', was, overexpressed, in, colorectal, cancer])].
[sujeto(['By', statistical, 'analysis,']), verbo([increased]), complemento(['ANRIL', was, found, to, be, in, close, association, with, 'TNM', 'staging,', 'Duke', staging, and, lymphatic, metastasis, and, poor, prognosis])].
[sujeto(['We', 'down-regulated', the, high, 'ANRIL', expression, in, 'LoVo', and, 'HCT116', with, lentivirus, 'transfection,', and]), verbo([found]), complemento([that, the, activity, of, cell, mobility, and, invasion, was, remarkably, reduced])].
[sujeto(['And', also, we, also, identified, that, 'ANRIL', 'down-regulation', could]), verbo([suppress]), complemento(['in-vitro', tube, formation, 'HLECs', invasion])].
[sujeto(['In', the, mouse, 'model,', we, 'recorded,', after, 'ANRIL', 'downregulation,']), verbo([decreased]), complemento([tumor, growth, rates, and, tumor, size, and, reduced, lymphatic, metastasis, rate, and, frequency, of, transferred, lymph, 'nodes,', 'LMVD', and, expressions, of, 'VEFG-C,', 'VEGFR-3', and, 'LYVE-1'])].
[sujeto(['Based', on, these, 'findings,', we, concluded, that]), verbo([increased]), complemento(['ANRIL', is, promoter, in, the, development, of, colorectal, cancer])].
[sujeto(['Through', 'down-regulation', of, the, overexpressed, 'ANRIL,', lymphangiogenesis, may, be]), verbo([suppressed]), complemento([and, therefore, lymphatic, metastasis, may, be, inhibited])].
[sujeto(['On', this, 'ground,', we]), verbo([suggest]), complemento([that, 'ANRIL', may, be, a, therapeutic, target, for, colorectal, cancer])].
[sujeto(['Numerous', researches]), verbo([have]), complemento([showed, that, the, dysregulation, of, lncRNA, 'ANRIL', play, a, significant, role, in, cancer, 'progression,', and, high, expression, of, 'ANRIL', may, have, important, clinical, value])].
[sujeto(['The', results, showed, that, cancer, patients, with, high, 'ANRIL', expression, may]), verbo([have]), complemento([a, poorer, 'OS', '(', 'HR=1'])].
[sujeto(['High', expression, of, 'ANRIL', is]), verbo([associated]), complemento([with, poor, clinical, outcome])].
[sujeto(['ANRIL', might, be]), verbo([act]), complemento([as, a, novel, potential, prognostic, biomarker, in, various, cancers])].
[sujeto(['Type', 2, 'diabetes,', fuelled, by, the, obesity, 'epidemic,', is, an, escalating, worldwide]), verbo([cause]), complemento([of, personal, hardship, and, public, cost])].
[sujeto(['Diabetes', incidence]), verbo([increases]), complemento([with, 'age,', and, many, studies, link, the, classic, senescence, and, ageing, protein, 'p16(INK4A)', to, diabetes, pathophysiology, via, pancreatic, islet, biology])].
[sujeto(['Genome-wide', association, studies, '(', 'GWASs)']), verbo([have]), complemento([unequivocally, linked, the, 'CDKN2A/B', 'locus,', which, encodes, p16, inhibitor, of, 'cyclin-dependent', kinase, '(', 'p16(INK4A))', and, three, other, gene, 'products,', p14, alternate, reading, frame, '(', 'p14(ARF)),', 'p15(INK4B)', and, antisense, 'non-coding', 'RNA', in, the, 'INK4', locus, '(', 'ANRIL),', with, human, diabetes, risk])].
[sujeto(['The', development, of, multidrug, resistance, '(', 'MDR)', is, a, crucial]), verbo([cause]), complemento([of, therapy, failure, in, gastric, 'cancer,', which, results, in, disease, recurrence, and, metastasis])].
[sujeto(['Long', 'non-coding', 'RNAs', '(', 'lncRNAs)']), verbo([have]), complemento([been, proven, to, be, critical, in, carcinogenesis, and, metastasis, of, gastric, cancer])].
[sujeto(['In', our, 'results,', 'ANRIL', was, highly]), verbo([expressed]), complemento([in, gastric, cancer, tissues, of, 'cisplatin-resistant', and, 5, -, fluorouracil, '(', 5, -, 'FU)-resistant', 'patients,', and, the, same, upregulation, trends, were, observed, in, 'cisplatin-resistant', cells, '(', 'BGC823/DDP)', and, 5, -, 'FU-resistant', cells, '(', 'BGC823/5-FU)'])].
[sujeto(['In', 'addition,', 'BGC823/DDP', and, 'BGC823/5-FU', cells, transfected, with, 'ANRIL', siRNA, and, treated, with, cisplatin, or, 5, -, 'FU,', 'respectively,', exhibited, significant, lower, survival, 'rate,']), verbo([decreased]), complemento([invasion, 'capability,', and, high, percentage, of, apoptotic, tumor, cells])].
[sujeto(['The', influence, of, 'ANRIL', knockdown, on, 'MDR', was, assessed, by, measuring, 'IC50', of, 'BGC823/DDP', and, 'BGC823/5-FU', cells, to, cisplatin, and, 5, -, 'FU,', the, result, showed, that, silencing, 'ANRIL']), verbo([decreased]), complemento([the, 'IC50', values, in, gastric, cancer, cells])].
[sujeto(['Moreover,', 'qRT-PCR', and, western, blotting, revealed, that, 'ANRIL', knockdown]), verbo([decreased]), complemento([the, expression, of, 'MDR1', and, 'MRP1,', both, of, which, are, 'MDR', related, 'genes;', regression, analysis, showed, that, the, expression, of, 'ANRIL', positively, correlated, with, the, expression, of, 'MDR1', and, 'MRP1,', resprectively, 'In', 'summary,', knockdown, of, lncRNA, 'ANRIL', in, gastric, cancer, cells, inhibits, the, development, of, 'MDR,', suggesting, an, efficacious, target, for, reversing, 'MDR', in, gastric, cancer, therapy])].
[sujeto(['ANRIL,', a, long, noncoding, 'RNA', '(', 'lncRNA),']), verbo([has]), complemento([recently, been, reported, to, have, a, direct, role, in, recruiting, polycomb, repressive, complexes, 'PRC2', and, 'PRC1', to, regulate, the, expression, of, the, 'p15/CDKN2B-p16/CDKN2A-p14/ARF', gene, cluster])].
[sujeto(['In', 'addition,', several, miRNAs, negatively]), verbo([associated]), complemento([with, 'CBX7', underexpression, and, 'EZH2', overexpression])].
[sujeto(['These', data, demonstrate, a, complex, pattern, of, interactions, between, lncRNA, 'ANRIL,', several, 'miRNAs,', 'PRC2/PRC1', 'subunits,', and, 'p15/CDKN2B-p16/CDKN2A-p14/ARF', locus, and]), verbo([suggest]), complemento([that, their, expression, should, be, considered, together, to, evaluate, antitumoral, 'drugs,', in, particular, the, 'BET', bromodomain, inhibitors])].
[sujeto(['This', study]), verbo([suggests]), complemento([that, the, global, pattern, of, expression, rather, than, expression, of, individual, family, members, should, be, taken, into, account, when, defining, functionality, of, repressive, 'Polycomb', complexes, and, therapeutic, targeting, potential])].
[sujeto(['Refined', genetic, analyses, revealed, unique, haplotype, blocks]), verbo([conferring]), complemento([susceptibility, to, atherosclerosis, per, se, versus, risk, for, acute, complications, in, the, presence, of, underlying, coronary, artery, disease])].
[sujeto(['The', cell, proliferation, inhibitor, 'locus,', 'CDKN2A,', maps, just, upstream, of, the, myocardial, infarction, risk, 'block,', is, at, least, partly]), verbo([regulated]), complemento([by, the, noncoding, 'RNA,', 'ANRIL,', overlapping, the, risk, 'block,', and, has, been, associated, with, platelet, counts, in, humans])].
[sujeto(['Thus,', we, tested, the, hypothesis, that, 'CDKN2A', deficiency, predisposes, to]), verbo([increased]), complemento([platelet, 'production,', leading, to, increased, platelet, activation, in, the, setting, of, hypercholesterolemia])].
[sujeto(['The', strains, exhibit]), verbo([decreased]), complemento([expression, of, 'CDKN2A', '(', both, 'p16(INK4a)', and, 'p19(ARF))', but, not, 'CDKN2B', '(', 'p15(INK4b))'])].
[sujeto(['Compared', with, 'B6-Ldlr(-/-)', 'controls,', both, 'Cdkn2a-deficient', strains, exhibited]), verbo([increased]), complemento([platelet, counts, and, bone, marrow, megakaryopoiesis])].
[sujeto(['Western', diet, feeding, resulted, in]), verbo([increased]), complemento([platelet, 'activation,', increased, 'thrombin/antithrombin', 'complex,', and, decreased, bleeding, times, in, 'Cdkn2a-deficient', mice, compared, with, controls])].
[sujeto(['Together,', the, data]), verbo([suggest]), complemento([that, one, or, more, 'Cdkn2a', transcripts, modulate, platelet, production, and, activity, in, the, setting, of, 'hypercholesterolemia,', amenable, to, pharmaceutical, intervention])].
[sujeto(['Enhanced', platelet, production, and, activation, may, predispose, to, arterial, 'thrombosis,']), verbo([suggesting]), complemento([an, 'explanation,', at, least, in, 'part,', for, the, association, of, 9, p21])].
[sujeto(['Antisense', 'non-coding', 'RNA', in, the, 'INK4', locus, '(', 'ANRIL)']), verbo([has]), complemento([been, implicated, in, a, variety, of, cancers])].
[sujeto(['Gain-', and, 'loss-of-function', experiments, demonstrated, that, 'ANRIL']), verbo([promotes]), complemento(['EOC', cell, proliferation, both, in, vitro, and, in, vivo])].
[sujeto(['This', study, is, the, first, to, establish, that, 'ANRIL']), verbo([promotes]), complemento(['EOC', progression, and, is, a, potential, prognostic, biomarker])].
[sujeto(['Genome-wide', association, studies, '(', 'GWASs)']), verbo([have]), complemento([discovered, numerous, single, nucleotide, polymorphisms, '(', 'SNPs)', associated, with, human, complex, disorders])].
[sujeto(['Here', we, explored, regulatory, mechanism, of, a, 'SNP', on, chromosome, 9, p21]), verbo([associated]), complemento([with, endometriosis, by, leveraging, &, 'quot;allele-specific"', functional, genomic, approaches])].
[sujeto(['We', demonstrated, that, the, protective, allele, exhibited, preferential]), verbo([binding]), complemento([affinities, to, 'TCF7L2', and, 'EP300', by, bioinformatics, and, chromatin, immunoprecipitation, '(', 'ChIP)', analyses])].
[sujeto(['The', allele, specific, expression, analysis, for, eutopic, endometrial, tissues, and, endometrial, carcinoma, cell, lines, showed, that, rs17761446, was, a, 'cis-regulatory', variant, where, 'G', allele, was]), verbo([associated]), complemento([with, increased, 'ANRIL', expression])].
[sujeto(['Our', work, illuminates, the, allelic, imbalances, in, a, series, of, transcriptional, regulation, from, factor]), verbo([binding]), complemento([to, gene, expression, mediated, by, chromatin, interaction, underlie, the, molecular, mechanism, of, 9, p21, endometriosis, risk, locus])].
[sujeto(['With', the, rising, interest, in, the, regulatory, functions, of, long, 'non-coding', 'RNAs', '(', 'lncRNAs)', in, complex, human, diseases, such, as, cardiovascular, 'diseases,', there, is, an]), verbo([increasing]), complemento([need, in, public, databases, offering, comprehensive, and, integrative, data, for, all, aspects, of, these, versatile, molecules])].
[sujeto(['Recently,', a, variety, of, public, data, repositories, that, specialized, in, lncRNAs]), verbo([have]), complemento([been, 'developed,', which, make, use, of, huge, 'high-throughput', data, particularly, from, 'next-generation', sequencing, '(', 'NGS)', approaches])].
[sujeto(['Here,', we]), verbo([provide]), complemento([an, overview, of, current, lncRNA, databases, covering, basic, and, functional, 'annotation,', lncRNA, expression, and, 'regulation,', interactions, with, other, 'biomolecules,', and, genomic, variants, influencing, the, structure, and, function, of, lncRNAs])].
[sujeto(['The', prominent, lncRNA, antisense, noncoding, 'RNA', in, the, 'INK4', locus, '(', 'ANRIL),', which]), verbo([has]), complemento([been, unequivocally, associated, with, coronary, artery, disease, through, 'genome-wide', association, studies, '(', 'GWAS),', serves, as, an, example, to, demonstrate, the, features, of, each, individual, database])].
[sujeto(['A', 'case-control', study, consisting, of, 5338, 'T2D', patients, and, 4663, normal, glycemic, controls, of, 'Chinese', 'Han']), verbo([recruited]), complemento([in, the, 'Chinese', 'National', 'Diabetes', and, 'Metabolic', 'Disorders', 'Study', was, conducted])].
[sujeto(['After', adjusting, for, multiple, 'covariates,', 'SNPs', in, or, near, 'CDKAL1,', 'CDKN2BAS,', 'KCNQ1,', 'TCF7L2,', 'CDC123/CAMK1D,', 'HHEX,', and, 'TCF2', were]), verbo([associated]), complemento([with, the, risk, for, lean, 'T2D,', and, 'SNPs', in, or, near, 'KCNQ1', and, 'FTO', were, associated, with, the, risk, for, obese, 'T2D'])].
[sujeto(['The', results, showed, that, the, 'GRS', for, 25, 'T2D-related', 'SNPs', was, more, strongly]), verbo([associated]), complemento([with, the, risk, for, lean, 'T2D', '(', 'Ptrend', =, 2.66, ×, 10, ')', than, for, obese, 'T2D', '(', 'Ptrend', =, 2.91, ×, 10, ')', in, our, study, population])].
[sujeto(['Notably,', the, 'T2D', 'GRS', contributed, to, lower, 'obesity-related', measurements, and, greater, 'β-cell', 'dysfunction,', including, lower, insulin, levels, in, oral, glucose, tolerance, 'test,']), verbo([decreased]), complemento([insulinogenic, 'index,', and, 'Homeostasis', 'Model', 'Assessment', for, 'β-cell', 'Function'])].
[sujeto(['Endometriosis', is, a, common, multifactorial, disease]), verbo([caused]), complemento([by, an, interaction, between, multiple, gene, loci, and, environment])].
[sujeto(['Four', 'genome-wide', association, studies, '(', 'GWASs)', of, endometriosis]), verbo([have]), complemento([identified, several, 'single-nucleotide', polymorphisms, '(', 'SNPs)', associated, with, endometriosis])].
[sujeto(['The', results, show, that, the, 'G/A', genotype, of, rs12700667, can, significantly]), verbo([increase]), complemento([the, risk, of, developing, ovarian, endometriosis, when, compared, with, the, 'G/G', genotype, '(', odds, ratio, '[', 'OR]', =, 1.57, ',', 95, '%', confidence, interval, '[', 'CI]', =, 1.23, -, 2.0, ')'])].
[sujeto(['The', study]), verbo([suggests]), complemento([that, the, 'endometriosis-associated', genetic, polymorphisms, '(', 'rs12700667)', from, 'GWAS', be, associated, with, the, risk, of, developing, ovarian, endometriosis, in, 'North', 'Chinese', women])].
[sujeto(['The', comorbidity, of, 'MetS', and, 'T2D']), verbo([increases]), complemento([the, risk, of, cardiovascular, complications])].
[sujeto(['We', successfully, genotyped, 25, genome, wide, association, study, validated, 'T2D-related', single, nucleotide, polymorphisms, '(', 'SNPs)', among, 5, ',', 169, 'T2D', individuals, and, 4, ',', 560, normal, glycemic, controls]), verbo([recruited]), complemento([from, the, 'Chinese', 'National', 'Diabetes', and, 'Metabolic', 'Disorders', 'Study', '(', 'DMS)'])].
[sujeto(['The', 'T2D', risk, alleles, of, rs972283, near, 'KLF14', and, rs11634397, near, 'ZFAND6', were]), verbo([associated]), complemento([with, a, higher, risk, for, elevated, triglycerides, '(', 'rs972283:', 1.11, '(', 1.02, ',', 1.24, ')', ',', 'P', =, 1.46, ×, 10, -, 2, ;, 'rs11634397:', 1.14, '(', 1.0, ',', 1.29, ')', ',', 'P', =, 4.66, ×, 10, -, 2, ')', ',', while, the, 'T2D', risk, alleles, of, rs780094, in, 'GCKR', and, rs7903146, in, 'TCF7L2', were, related, to, a, lower, risk, of, elevated, triglycerides, '(', 'rs780094:', 0.86, '(', 0.8, ',', 0.93, ')', ',', 'P', =, 1.35, ×, 10, -, 4, ;, 'rs7903146:', 0.82, '(', 0.69, ',', 0.98, ')', ',', 'P', =, 3.18, ×, 10, -, 2, ')'])].
[sujeto(['Genetic', variants, of, 'WFS1,', 'CDKAL1,', 'CDKN2BAS,', 'TCF7L2,', 'HHEX,', 'KCNQ1,', 'TSPAN8/LGR5,', 'FTO,', and, 'TCF2', were]), verbo([associated]), complemento([with, the, risk, for, 'T2D', with, 'MetS,', as, well, as, the, risk, for, development, of, 'T2D', with, at, least, one, of, the, 'MetS', components, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['The', study, also]), verbo([provides]), complemento([insight, into, the, pleotropic, effects, of, 'genome-wide', association, loci, of, diabetes, on, metabolic, regulation])].
[sujeto(['Glaucoma', is, presumed, to, be, a, complex, progressive, neurodegenerative, disorder]), verbo([caused]), complemento([by, genetic, and, environmental, 'factors,', and, it, is, also, one, of, the, leading, causes, of, irreversible, blindness, worldwide])].
[sujeto(['Familial', linkage, studies, for, 'POAG']), verbo([have]), complemento([been, performed, and, identified, causative, 'POAG', disease, genes, '(', e])].
[sujeto(['Recent', 'genome-wide', association, studies, revealed, a, large, number, of, susceptibility, gene, variants]), verbo([associated]), complemento([with, both, 'POAG', '(', e])].
[sujeto(['In', 'POAG,', these, genes, were]), verbo([expressed]), complemento([in, ocular, tissues, including, retinal, ganglion, 'cells,', ciliary, 'body,', trabecular, 'meshwork,', and, the, optic, nerve, head])].
[sujeto(['A', further, functional, analysis, of, these, genes, would]), verbo([provide]), complemento([the, precise, mechanism, underlying, 'glaucoma,', including, 'POAG', and, 'PACG'])].
[sujeto(['Many', associations, between, abdominal, aortic, aneurysm, '(', 'AAA)', and, genetic, polymorphisms]), verbo([have]), complemento([been, reported])].
[sujeto(['It', is, unclear, which, are, genuine, and, which, may, be]), verbo([caused]), complemento([by, type, 1, 'errors,', 'biases,', and, flexible, study, design])].
[sujeto(['The', objectives, of, the, study, were, to, identify, associations, supported, by, current, evidence, and, to, investigate, the, effect, of, study, design, on]), verbo([reporting]), complemento([associations])].
[sujeto(['Study', characteristics, and, data, were, extracted, using, an, agreed, tool, and]), verbo([reports]), complemento([assessed, for, quality])].
[sujeto(['Heterogeneity', was, assessed, using, 'I(2)', and, 'fixed-', and, 'random-effects', 'meta-analyses', were, conducted, for, variants, that, were]), verbo([reported]), complemento([at, least, 'twice,', if, any, had, reported, an, association])].
[sujeto(['Of', 97, 'studies,', 63]), verbo([reported]), complemento([at, least, one, association])].
[sujeto(['In', 'total,', 263, genes, were, 'investigated,', and, associations, were]), verbo([reported]), complemento([in, polymorphisms, in, 87, genes])].
[sujeto(['To', evaluate, the, association, of, 'BC', susceptibility, loci, with, 'BCIS', 'risk,', we, genotyped, 39, single, nucleotide, polymorphisms, '(', 'SNPs),']), verbo([associated]), complemento([with, risk, of, invasive, 'BC,', in, 1317, 'BCIS', 'cases,', 10, ',', 645, invasive, 'BC', 'cases,', and, 14, ',', 6, healthy, controls, in, the, 'National', 'Cancer', 'Institute\'s', 'Breast', and, 'Prostate', 'Cancer', 'Cohort', 'Consortium', '(', 'BPC3)'])].
[sujeto(['We']), verbo([found]), complemento([that, five, 'SNPs', '(', 'CDKN2BAS-rs1011970,', 'FGFR2-rs3750817,', 'FGFR2-rs2981582,', 'TNRC9-rs3803662,', 5, 'p12-rs10941679)', were, significantly, associated, with, 'BCIS', risk, '(', 'P', value, adjusted, for, multiple, comparisons, &, 'lt;0'])].
[sujeto(['Subgroup', analyses, investigating, associations, with, ductal, carcinoma, in, situ, '(', 'DCIS)']), verbo([found]), complemento([similar, 'associations,', albeit, less, significant, '(', 'OR', =, 1.25, ',', 95, '%', 'CI:', 1.09, -, 1.42, ',', 'P', =, 1.07, x, 10, '(', -, 3, ')', ')'])].
[sujeto(['Additional', risk, analyses, showed, significant, associations, with, invasive, disease, at, the, 0.05, level, for, 28, of, the, alleles, and, the, 'OR', estimates, were, consistent, with, those]), verbo([reported]), complemento([by, other, studies])].
[sujeto(['We', hypothesized, that, single, nucleotide, polymorphisms, '(', 'SNPs)', identified, in, 'genome-wide', association, studies, '(', 'GWAS)', on, adult, glioma, would, also, be]), verbo([associated]), complemento([with, 'PBT', risk])].
[sujeto(['Saliva', 'DNA', from, 245, cases, and, 489, 'controls,', aged, 7, -, 19, years, at, 'diagnosis/reference', 'date,', was, extracted, and, genotyped, for, 29, 'SNPs']), verbo([reported]), complemento([by, 'GWAS', to, be, significantly, associated, with, risk, of, adult, glioma])].
[sujeto(['The', results, indicated, that, four, 'SNPs,', 'CDKN2BAS', rs4977756, '(', p, =, 0.036, ')', ',', rs1412829, '(', p, =, 0.037, ')', ',', rs2157719, '(', p, =, 0.018, ')', and, rs1063192, '(', p, =, 0.021, ')', ',', were]), verbo([associated]), complemento([with, an, increased, susceptibility, to, 'PBTs,', whereas, the, 'TERT', rs2736100, was, associated, with, a, decreased, risk, '(', p, =, 0.018, ')'])].
[sujeto(['Moreover,', the, stratified, analyses, showed, a]), verbo([decreased]), complemento([risk, of, astrocytoma, associated, with, 'RTEL1', 'rs6089953,', rs6010620, and, rs2297440, '(', p, trend, =, 0.022, ',', p, trend, =, 0.042, ',', p, trend, =, 0.029, ',', 'respectively)', as, well, as, an, increased, risk, of, this, subtype, associated, with, 'RTEL1', rs4809324, '(', p, trend, =, 0.033, ')'])].
[sujeto(['In', 'addition,', 'SNPs', rs10464870, and, rs891835, in, 'CCDC26', were]), verbo([associated]), complemento([with, an, increased, risk, of, 'non-astrocytoma', tumor, subtypes, '(', p, trend, =, 0.009, ',', p, trend, =, 0.007, ',', 'respectively)'])].
[sujeto(['Our', findings, indicate, that, 'SNPs', in, 'CDKN2BAS,', 'TERT,', 'RTEL1', and, 'CCDC26', may, be]), verbo([associated]), complemento([with, the, risk, of, 'PBTs'])].
[sujeto(['Therefore,', we]), verbo([suggest]), complemento([that, pediatric, and, adult, brain, tumors, might, share, common, genetic, risk, factors, and, similar, etiological, pathways])].
[sujeto(['Multiple', loci]), verbo([have]), complemento([been, associated, with, either, primary, open, angle, glaucoma, '(', 'POAG)', or, heritable, ocular, quantitative, traits, associated, with, this, condition])].
[sujeto(['However,', 'SNP', rs12522383, in, 'WDR36', was]), verbo([associated]), complemento([with, diabetes, mellitus, '(', p, =, 8.0e-5, ')'])].
[sujeto(['This', first, 'POAG', genetic, association, study, in, black, 'South', 'Africans']), verbo([has]), complemento([therefore, identified, associations, that, require, additional, investigation, in, this, and, other, populations, to, determine, their, significance])].
[sujeto(['This', highlights, the, need, for, larger, studies, in, this, population, if, we, are, to, achieve, the, goal, of, facilitating, early, 'POAG', detection, and, ultimately]), verbo([preventing]), complemento([irreversible, blindness, from, this, condition])].
[sujeto(['Metabolic', disorders, including, type, 2, 'diabetes,', obesity, and, hypertension]), verbo([have]), complemento([growing, prevalence, globally, every, year])].
[sujeto(['Genome-wide', association, studies]), verbo([have]), complemento([successfully, identified, many, genetic, markers, associated, to, these, 'diseases,', but, few, studied, their, interaction, effects])].
[sujeto(['It', is]), verbo([found]), complemento([out, that, the, main, effects, of, the, markers, are, weak, but, the, interactions, among, the, candidates, showed, a, significant, association, to, diseases])].
[sujeto(['SNPs', from, genes, 'CDKN2BAS', and, 'KCNJ11', are, significantly]), verbo([associated]), complemento([to, risk, for, developing, 'diabetes,', and, 'SNPs', from, 'FTO', and, 'APOA5', might, interact, to, play, an, important, role, for, the, onset, of, hypertension])].
[sujeto(['A', total, of, 590, 'CHD', cases, and, 482, 'non-CHD', controls, were]), verbo([involved]), complemento([in, the, present, association, study])].
[sujeto(['A', breakdown, analysis, by, age, had, shown, that, there, was, an, 87, '%']), verbo([increased]), complemento([risk, of, 'CHD', for, females, younger, than, 65, years, '(', 'genotype:', 'χ2=14'])].
[sujeto(['Similar', observation, was, also]), verbo([found]), complemento([in, males, younger, than, 65, years, '(', 'genotype:', 'χ2=8'])].
[sujeto(['Common', variants]), verbo([have]), complemento([been, identified, using, 'genome-wide', association, studies, which, contribute, to, intracranial, aneurysms, '(', 'IA)', susceptibility])].
[sujeto([0, '×10(-11)),', in, a, gene, previously]), verbo([associated]), complemento([with, 'IA'])].
[sujeto(['A', novel, region, on, chromosome, 7, ',', near, 'HDAC9,', was]), verbo([associated]), complemento([with, 'IA', '(', 'rs10230207;', 'P=4'])].
[sujeto(['We', detected, a, novel, region]), verbo([associated]), complemento([with, 'IA', susceptibility, that, was, replicated, in, an, independent, 'Dutch', sample])].
[sujeto(['This', region, on, chromosome, 7]), verbo([has]), complemento([been, previously, associated, with, ischemic, stroke, and, the, large, vessel, stroke, occlusive, subtype, '(', including, 'HDAC9),', suggesting, a, possible, genetic, link, between, this, stroke, subtype, and, 'IA'])].
[sujeto([3, locus, was, the, first, to, yield, to, 'genome-wide', association, studies, '(', 'GWAS)', seeking, common, genetic, variants, predisposing, to]), verbo([increased]), complemento([risk, of, coronary, artery, atherosclerotic, disease, '(', 'CAD)'])].
[sujeto(['This', region, also, covers, the, 3, '\'', end, of, a, long, noncoding, 'RNA']), verbo([transcribed]), complemento([antisense, to, 'CDKN2B', '(', 'CDKN2BAS,', aka, 'ANRIL', for, antisense, noncoding, 'RNA', at, the, ink4, 'locus)', whose, expression, has, been, linked, to, chromatin, remodeling, at, the, locus])].
[sujeto(['Other', variants, at, this, locus]), verbo([have]), complemento([been, associated, with, 'glaucoma,', 'glioma,', and, type, 2, diabetes, 'mellitus,', diseases, that, implicate, 'tissue-resident', macrophages])].
[sujeto(['Association', of, 'melanoma,', neural, system, tumors, and, germ, line, mutations, at, the, 9, p21, region, in, the, 'CDKN2A,', 'CDKN2B', and, 'CDKN2BAS', genes]), verbo([has]), complemento([been, reported, in, a, small, number, of, families, worldwide, and, described, as, a, discrete, syndrome, in, melanoma, families, registered, as, a, rare, 'disease,', the, 'melanoma-astrocytoma', syndrome])].
[sujeto(['We', here, studied, two, young, patients, developing, melanoma, after, radiotherapy, for, 'astrocytoma,', both]), verbo([reporting]), complemento([lack, of, family, history, for, melanoma, or, neural, system, tumors, at, genetic, counselling])].
[sujeto(['Patient', 'A', is, a, girl, treated, for, anaplastic, astrocytoma, at, 10, years, and, for, multiple, melanomas, on, the, scalp]), verbo([associated]), complemento([to, dysplastic, nevi, two, years, later])].
[sujeto([3, and, occurring, de, novo, after, the]), verbo([loss]), complemento([of, one, paternal, allele])].
[sujeto(['Patient', 'B', is, a, boy, of, 7, years, when, treated, for, astrocytoma, then, developing, melanoma]), verbo([associated]), complemento([to, congenital, nevi, on, the, head, 10, years, 'later:', sequencing, and, multiplex, 'ligation-dependent', probe, amplification, revealed, a, normal, profile, of, the, 'CDKN2A/CDKN2B/CDKN2BAS', region])].
[sujeto([3, and, failed, to]), verbo([reveal]), complemento([known, pathogenic, copy, number, variations])].
[sujeto(['By', comparison, with, the, other, germ, line, deletions, at, the, 'CDKN2A,', 'CDKN2B', and, 'CDKN2BAS', gene, cluster]), verbo([reported]), complemento([in, melanoma, susceptible, 'families,', the, deletion, detected, in, the, two, sisters, is, peculiar, for, its, de, novo, origin, and, for, its, 'extension,', as, it, represents, the, largest, constitutive, deletion, at, 9, p21])].
[sujeto(['Genome-wide', association, studies, '(', 'GWAS)', of, chronic, periodontitis, '(', 'CP)', identified, no, significant, 'variants,', but, 'CDKN2BAS', variants, on, chromosome, 9, were, significantly]), verbo([associated]), complemento([with, aggressive, periodontitis])].
[sujeto(['Trials', of, molecularly]), verbo([targeted]), complemento([therapies, are, in, progress, for, 'oral,', 'head,', and, neck, squamous, cell, carcinomas, '(', 'OHNSCC)', and, results, have, been, promising, but, limited, in, their, effectiveness])].
[sujeto(['Current', opportunities, and, challenges, for, molecular]), verbo([targeting]), complemento([for, 'OHNSCC', are, discussed])].
[sujeto(['Nevertheless,', the, genetics, of, endometriosis, remains, complex, and, in, part, 'unsolved,', but, 'recently,', based, on, the, results, of, few, 'genome-wide', association, 'studies,', some, genetic, susceptibility, loci]), verbo([have]), complemento([been, identified, as, associated, robustly, with, the, 'disease,', providing, new, insights, into, potential, pathways, leading, to, endometriosis])].
[sujeto(['Very', severe, gynecological, and, obstetric, complications]), verbo([caused]), complemento([by, the, invasiveness, of, the, disease, have, been, observed, in, all, members, of, the, single, family])].
[sujeto(['The', entire, family]), verbo([has]), complemento([been, genotyped, for, 3, 'single-nucleotide', polymorphisms, identified, as, associated, with, endometriosis])].
[sujeto(['The', 'INK4/ARF', transcript, 'p16(INK4a)']), verbo([inhibits]), complemento([the, activity, of, the, 'cyclin-dependent', kinases, 'CDK4/CDK6', and, arrests, 'cell-cycle', progression])].
[sujeto(['CDK', inhibitors, also]), verbo([regulate]), complemento(['G1/S', phase, progression, in, vascular, smooth, muscle, 'cells(VSMCs)', and, may, modulate, the, early, stages, of, atherosclerosis])].
[sujeto(['All', tissue, sections, were, also, analyzed, for, the, 'p16(INK4a)', and, proliferating, cell]), verbo([nuclear]), complemento(['antigen(PCNA)', protein, expression, using, 'immunohistochemistry(IHC)'])].
[sujeto([50, ')', ;, this]), verbo([finding]), complemento([was, also, associated, with, the, severity, of, internal, carotid, 'artery(ICA)', 'stenosis(p=0'])].
[sujeto(['An']), verbo([increased]), complemento(['CDKN2A', gene, expression, in, carotid, plaques, may, increase, the, severity, of, 'ICA', 'stenosis,', thus, raising, the, risk, of, atherosclerosis, and, contributing, to, the, development, of, symptoms])].
[sujeto(['In', 'addition,', the, 'p16(INK4a)', expression, is]), verbo([associated]), complemento([with, carotid, atherosclerosis, in, various, patient, subgroups])].
[sujeto(['Studies', to, elucidate, the, role, of, genetics, as, a, risk, factor, for, periodontal, disease]), verbo([have]), complemento([gone, through, various, phases])].
[sujeto(['In', the, majority, of, 'cases,', the, initial, '\'', 'hypothesis-dependent\'', 'candidate-gene', polymorphism, studies, did, not]), verbo([report]), complemento([valid, genetic, risk, loci])].
[sujeto(['Following', a, 'large-scale', replication, 'study,', these, initially, positive, results, are, believed, to, be]), verbo([caused]), complemento([by, type, 1, errors])].
[sujeto(['However,', susceptibility, 'genes,', such, as, 'CDKN2BAS', '(', 'Cyclin', 'Dependend', 'KiNase', 2, 'B', 'AntiSense', 'RNA;', alias, 'ANRIL', '[', 'ANtisense', 'Rna', 'In', the, 'Ink', 'locus]),', glycosyltransferase, 6, domain, containing, 1, '(', 'GLT6D1)', and, cyclooxygenase, 2, '(', 'COX2),']), verbo([have]), complemento([been, reported, as, conclusive, risk, loci, of, periodontitis])].
[sujeto(['However,', despite, many, different, 'GWAS', being, performed, for, almost, all, human, 'diseases,', only, three, 'GWAS', on, periodontitis]), verbo([have]), complemento([been, published, -, one, reported, 'genome-wide', association, of, 'GLT6D1', with, aggressive, periodontitis, '(', a, severe, phenotype, of, 'periodontitis),', whereas, the, remaining, 'two,', which, were, performed, on, patients, with, chronic, 'periodontitis,', were, not, able, to, find, significant, associations])].
[sujeto(['Candidate', gene, and, 'genome-wide', association, studies]), verbo([have]), complemento([identified, '∼60', susceptibility, loci, for, type, 2, diabetes])].
[sujeto(['A', majority, of, these, loci]), verbo([have]), complemento([been, discovered, and, tested, only, in, 'European', populations])].
[sujeto(['We']), verbo([found]), complemento([that, 14, loci, significantly, transferred, to, the, 'Chinese', 'population,', with, two, loci, '(', p, =, 5.7, ×, 10, '(', -, 12, ')', for, 'KCNQ1;', p, =, 5.0, ×, 10, '(', -, 8, ')', for, 'CDKN2A/B-CDKN2BAS)', reaching, independent, 'genome-wide', statistical, significance])].
[sujeto(['Five', of, these, 14, loci, had, similar]), verbo([lead]), complemento(['single-nucleotide', polymorphisms, '(', 'SNPs)', as, were, found, in, the, 'European', studies, while, the, other, nine, were, different])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, many, loci, associated, with, type, 2, diabetes, are, commonly, shared, between, 'European', and, 'Chinese', populations])].
[sujeto(['Identification', of, 'population-specific', 'SNPs', may]), verbo([increase]), complemento([our, understanding, of, the, genetic, architecture, underlying, type, 2, diabetes, in, different, ethnic, populations])].
[sujeto([3, region]), verbo([has]), complemento([been, implicated, in, the, pathogenesis, of, multiple, cancers])].
[sujeto(['Rs3731239', in, 'cyclin-dependent', kinase, inhibitors, 2, 'A', '(', 'CDKN2A)', was, significantly]), verbo([associated]), complemento([with, 'ESCC', '(', 'P=7', ×, 10, '(', -, 6, ')', ')'])].
[sujeto(['One', 'SNP', in, 'MTAP', '(', methylthioadenosine, 'phosphorylase)', '(', 'rs7023329)', that, was, previously]), verbo([associated]), complemento([with, melanoma, and, nevi, in, multiple, 'genome-wide', association, studies, was, associated, with, 'CRC,', 'CA', and, 'OS', by, 'ASSET', '(', 'P=0'])].
[sujeto(['Our', data, indicate, that, genetic, variants, in, 'CDKN2A,', and, possibly, nearby, 'genes,', may, be]), verbo([associated]), complemento([with, 'ESCC', and, several, other, 'tumours,', further, highlighting, the, importance, of, 9, p21])].
[sujeto([p15AS, and, p15, mRNA, in, two, leukemia, cell, lines, was, detected, with, 'strand-specific']), verbo([primer]), complemento(['RT-qPCR'])].
[sujeto(['The', expression, level, of, p15AS, in, bone, marrow, cells, derived, from, the, patients, and, the, controls, were, determined, by, 'strand-specific']), verbo([primer]), complemento(['RT-qPCR,', and, its, relationship, with, clinical, features, was, analyzed])].
[sujeto(['Samples', derived, from, the, 'AML', patients, showed, relatively]), verbo([increased]), complemento([expression, of, p15AS, and, 'down-regulated', p15, expression, in, their, bone, cells])].
[sujeto(['High', expression, of, p15, antisense, 'RNA', was, frequently]), verbo([found]), complemento([among, 'AML', 'patients,', and, may, play, an, important, role, in, epigenetic, silencing, of, p15])].
[sujeto(['Tumour', suppressor, genes, '(', 'TSGs)']), verbo([inhibiting]), complemento([normal, cellular, growth, are, frequently, silenced, epigenetically, in, cancer])].
[sujeto(['DNA', methylation, is, commonly]), verbo([associated]), complemento([with, 'TSG', 'silencing,', yet, mutations, in, the, 'DNA', methylation, initiation, and, recognition, machinery, in, carcinogenesis, are, unknown])].
[sujeto(['An', intriguing, possible, mechanism, for, gene, regulation]), verbo([involves]), complemento([widespread, 'non-coding', 'RNAs', such, as, 'microRNA,', 'Piwi-interacting', 'RNA', and, antisense, 'RNAs'])].
[sujeto(['Widespread', 'sense-antisense', transcripts]), verbo([have]), complemento([been, systematically, identified, in, mammalian, 'cells,', and, global, transcriptome, analysis, shows, that, up, to, 70, '%', of, transcripts, have, antisense, partners, and, that, perturbation, of, antisense, 'RNA', can, alter, the, expression, of, the, sense, gene])].
[sujeto(['For', 'example,', it]), verbo([has]), complemento([been, shown, that, an, antisense, transcript, not, naturally, occurring, but, induced, by, genetic, mutation, leads, to, gene, silencing, and, 'DNA', 'methylation,', causing, thalassaemia, in, a, patient])].
[sujeto(['Here', we, show, that, many, 'TSGs']), verbo([have]), complemento([nearby, antisense, 'RNAs,', and, we, focus, on, the, role, of, one, 'RNA', in, silencing, 'p15,', a, 'cyclin-dependent', kinase, inhibitor, implicated, in, leukaemia])].
[sujeto(['We']), verbo([found]), complemento([an, inverse, relation, between, p15, antisense, '(', 'p15AS)', and, p15, sense, expression, in, leukaemia])].
[sujeto(['A', p15AS, expression, construct]), verbo([induced]), complemento([p15, silencing, in, cis, and, in, trans, through, heterochromatin, formation, but, not, 'DNA', 'methylation;', the, silencing, persisted, after, p15AS, was, turned, 'off,', although, methylation, and, heterochromatin, inhibitors, reversed, this, process])].
[sujeto(['Expression', of, exogenous, p15AS, in, mouse, embryonic, stem, cells]), verbo([caused]), complemento([p15, silencing, and, increased, 'growth,', through, heterochromatin, 'formation,', as, well, as, 'DNA', methylation, after, differentiation, of, the, embryonic, stem, cells])].
[sujeto(['Thus,', natural, antisense, 'RNA', may, be, a]), verbo([trigger]), complemento([for, heterochromatin, formation, and, 'DNA', methylation, in, 'TSG', silencing, in, tumorigenesis])].
[sujeto(['A', genomic, region, located, on, chromosome, 9, p21, is]), verbo([associated]), complemento([with, primary, 'open-angle', glaucoma, and, normal, tension, glaucoma, in, 'genome-wide', association, studies])].
[sujeto(['We', used, a, transgenic, mouse, model, in, which, 70, kb, of, murine, chromosome, 4, ',', syntenic, to, human, chromosome, 9, 'p21,', are, deleted, to, study, whether, this, deletion]), verbo([leads]), complemento([to, a, discernible, phenotype, in, ocular, structures, implicated, in, glaucoma])].
[sujeto(['Homozygous', mice, of, this, strain, were, previously]), verbo([reported]), complemento([to, show, persistent, hyperplastic, primary, vitreous])].
[sujeto(['Fundus', photography, and, optical, coherence, tomography, confirmed, that]), verbo([finding]), complemento([but, showed, no, abnormalities, for, heterozygous, mice])].
[sujeto(['Optokinetic', 'response,', 'eletroretinogram,', and, histology, indicated, that, the, heterozygous, and, mutant, retinas, were, normal, functionally, and, 'morphologically,', whereas, glial, cells, were]), verbo([activated]), complemento([in, the, retina, and, optic, nerve, head, of, mutant, eyes])].
[sujeto(['In', quantitative, 'PCR,', 'CDKN2B', expression, was, reduced, by, approximately, 50, '%', in, the, heterozygous, mice, and, by, 90, '%', in, the, homozygous, 'mice,', which]), verbo([suggested]), complemento([that, the, 'CDKN2B', knock, down, had, no, deleterious, consequences, for, the, retina, under, normal, conditions])].
[sujeto(['However,', compared, with, 'wild-type', and, heterozygous, 'animals,', the, homozygous, mice, are, more, vulnerable, to, retinal, ganglion, cell]), verbo([loss]), complemento([in, response, to, elevated, intraocular, pressure])].
[sujeto(['To', investigate, whether, specific, genetic, polymorphisms, in, the, 'cyclin-dependent', kinase, inhibitor, 2, 'B', antisense, 'RNA', '(', 'CDKN2B-AS)', gene, and, near, the, 'wingless-type', 'MMTV', integration, site, family, member, 4, '(', 'WNT4)', gene, are]), verbo([associated]), complemento([with, endometriosis, in, a, 'Korean', population])].
[sujeto(['Significant', differences, were]), verbo([found]), complemento([in, the, allele, distributions, of, the, 'CC', genotype, of, the, rs10965235, 'single-nucleotide', polymorphism, '(', 'SNP)', of, the, 'CDKN2B-AS', gene, and, the, 'GG', genotype, of, the, rs16826658, 'SNP', on, chromosome, 1, p36, between, the, endometriosis, cases, and, the, controls, '(', 'rs10965235:', 69.7, '%', 'CC,', 26.9, '%', 'CA,', and, 3.4, '%', 'AA', vs])].
[sujeto(['A', significant, interaction, was, not]), verbo([found]), complemento([between, the, 'CC', genotype, of, the, rs10965235, 'SNP', and, the, 'GG', genotype, of, the, rs16826658, 'SNP', after, 'Bonferroni', correction, '(', 32.8, '%', of, 'CC+GG', and, 67.2, '%', of, 'CC+non-GG', in, the, endometriosis, cases, vs])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, the, rs10965235, 'SNP', in, the, 'CDKN2B-AS', gene, and, the, rs16826658, 'SNP', near, the, 'WNT4', gene, were, significantly, associated, with, endometriosis, in, this, 'Korean', population])].
[sujeto(['The', ability, of, 'Miz-1', and, 'Arnt', to]), verbo([interact]), complemento([was, identified, in, a, yeast, 'two-hybrid', screen])].
[sujeto(['In', the, present, study, we, demonstrate, that, the, aryl, hydrocarbon, receptor]), verbo([nuclear]), complemento([translocator, '(', 'Arnt),', which, is, central, in, 'hypoxia-induced', 'signaling,', forms, a, complex, with, 'Miz-1,', an, important, transcriptional, regulator, in, 'Myc-mediated', transcriptional, repression])].
[sujeto(['Overexpression', of, 'Arnt']), verbo([induced]), complemento([reporter, gene, activity, driven, by, the, proximal, promoter, of, the, 'cyclin-dependent', kinase, inhibitor, 2, 'B', gene, '(', 'CDKN2B),', which, is, an, established, target, for, the, 'Myc/Miz-1', complex])].
[sujeto(['In', 'contrast,', mutated, forms, of, 'Arnt,', that, were, unable, to]), verbo([interact]), complemento([with, 'Miz-1,', had, reduced, capability, to, activate, transcription])].
[sujeto(['Moreover,', repression, of, 'Arnt', reduced, endogenous, 'CDKN2B', 'expression,', and, chromatin, immunoprecipitation, demonstrated, that, 'Arnt']), verbo([interacts]), complemento([with, the, 'CDKN2B', promoter])].
[sujeto(['The', transcriptional, activity, of, 'Arnt', was, counteracted, by, 'Myc,', but, not, by, a, mutated, variant, of, 'Myc', that, is, unable, to]), verbo([interact]), complemento([with, 'Miz-1,', suggesting, mutually, exclusive, interaction, of, 'Arnt', and, 'Myc', with, 'Miz-1'])].
[sujeto(['Our', results, also, establish, 'CDKN2B', as, a, hypoxia]), verbo([regulated]), complemento(['gene,', as, endogenous, 'CDKN2B', mRNA, and, protein, levels, were, reduced, by, hypoxic, treatment, of, 'U2OS', cells])].
[sujeto(['Our', data]), verbo([reveal]), complemento([a, novel, mode, of, regulation, by, 'protein-protein', interaction, that, directly, ties, 'together,', at, the, transcriptional, 'level,', the, 'Myc-', and, 'hypoxia-dependent', signaling, pathways, and, expands, our, understanding, of, the, roles, of, hypoxia, and, cell, cycle, alterations, during, tumorigenesis])].
[sujeto(['Many', long, 'non-coding', 'RNA', '(', 'lncRNA)', genes, identified, in, mammals]), verbo([have]), complemento([multiple, exons, and, functional, 'domains,', allowing, them, to, bind, to, polycomb, 'proteins,', 'DNA', 'methyltransferases,', and, specific, 'DNA', sequences, to, regulate, genome, methylation])].
[sujeto(['ANRIL/CDKN2B-AS', consists, of, 19, exons, on, human, chromosome, 9, p21, and]), verbo([regulates]), complemento([the, expression, of, three, 'cyclin-dependent', kinase, inhibitors, '(', 'CDKN2A/ARF/CDKN2B)'])].
[sujeto(['A', further, survey]), verbo([reveals]), complemento([that, multiple, transposons, exist, in, many, lncRNAs])].
[sujeto(['Human', cells]), verbo([have]), complemento([evolved, prompt, and, efficient, 'DNA', damage, response, to, eliminate, the, detrimental, effects, of, 'DNA', lesions])].
[sujeto(['The', 'DNA', damage, response]), verbo([involves]), complemento([a, complex, network, of, processes, that, detect, and, repair, 'DNA', 'damage,', in, which, long, 'non-coding', 'RNAs', '(', 'lncRNAs),', a, new, class, of, regulatory, 'RNAs,', may, play, important, roles])].
[sujeto(['Recent', studies]), verbo([have]), complemento([identified, a, large, number, of, lncRNAs, in, mammalian, transcriptomes])].
[sujeto(['In', the, present, 'study,', we, demonstrate, that, one, specific, 'lncRNA,', 'ANRIL,', is, transcriptionally, 'up-regulated', by, the, transcription, factor, 'E2F1', in, an, 'ATM-dependent', manner, following, 'DNA', 'damage,', and, elevated, levels, of, 'ANRIL']), verbo([suppress]), complemento([the, expression, of, 'INK4a,', 'INK4b', and, 'ARF', at, the, 'late-stage', of, 'DNA', damage, 'response,', allowing, the, cell, to, return, to, normal, at, the, completion, of, the, 'DNA', repair])].
[sujeto(['To', ascertain, if, single, nucleotide, polymorphisms, '(', 'SNPs)']), verbo([involved]), complemento([in, the, determination, of, central, corneal, 'thickness,', optic, disc, 'area,', and, vertical, 'cup-to-disc', ratio, '(', 'VCDR)', also, are, associated, with, 'open-angle', glaucoma, '(', 'OAG)'])].
[sujeto(['A', total, of, 16, 'SNPs']), verbo([associated]), complemento([with, central, corneal, 'thickness,', optic, disc, 'area,', and, 'VCDR', were, genotyped, in, 876, 'OAG', cases, and, 883, normal, controls])].
[sujeto(['Both', the, cases, and, controls, were, of, 'European', descent, and, were]), verbo([recruited]), complemento([from, within, 'Australia'])].
[sujeto(['Two', 'VCDR', 'SNPs', were]), verbo([found]), complemento([to, be, significantly, associated, with, 'OAG', after, correction, for, multiple, testing])].
[sujeto(['The', 2, 'SNPs', were, 'rs10483727,']), verbo([found]), complemento([adjacent, to, the, 'SIX1', gene, '(', 'P', =, 6.2, ×, 10, '(', -, 6, ')', ;, odds, 'ratio,', 1.38, ;, 95, '%', confidence, 'interval,', 1.2, to, 1.59, ')', ',', and, 'rs1063192,', found, within, the, 'CDKN2B', gene, '(', 'P', =, 2.2, ×, 10, '(', -, 5, ')', ;, odds, 'ratio,', 0.74, ;, 95, '%', confidence, 'interval,', 0.64, to, 0.85, ')'])].
[sujeto(['The', 'CDKN2B', variant, rs1063192, also, was]), verbo([found]), complemento([to, be, associated, more, strongly, with, advanced, 'OAG'])].
[sujeto(['The', identification, of, 'SIX1', and, 'CDKN2B', as, susceptibility, loci, will, assist, in, understanding, the, pathologic, mechanisms]), verbo([involved]), complemento([in, the, development, of, 'OAG'])].
[sujeto(['Recent', insights, into, the, role, of, the, 'von-Hippel', 'Lindau', '(', 'VHL)', tumor, suppressor, gene, in, hereditary, and, sporadic, 'clear-cell', renal, cell, carcinoma, '(', 'ccRCC)']), verbo([have]), complemento([led, to, new, treatments, for, patients, with, metastatic, 'ccRCC,', although, virtually, all, patients, eventually, succumb, to, the, disease])].
[sujeto(['We', performed, an, 'integrated,', 'genome-wide', analysis, of, 'copy-number', changes, and, gene, expression, profiles, in, 90, 'tumors,', including, both, sporadic, and, 'VHL', 'disease-associated', 'tumors,', in, hopes, of, identifying, new, therapeutic]), verbo([targets]), complemento([in, ccRCC])].
[sujeto(['An', integrated, analysis, to, identify, genes, in, amplification, peaks, that, are, consistently, overexpressed, among, amplified, samples, confirmed, 'MYC', as, a, potential]), verbo([target]), complemento([of, 8, q, amplification, and, identified, candidate, oncogenes, in, the, other, regions])].
[sujeto(['Pathogenic', and, 'non-pathogenic', fungi, synthesize, 'glycosphingolipids,', which]), verbo([have]), complemento([a, crucial, role, in, growth, and, viability])].
[sujeto(['Through', its, lipid, and, glycan, 'moieties,', 'PLM', contributes, to, the, initial, recognition, of, the, 'yeast,']), verbo([causing]), complemento([immune, system, disorder, and, persistent, fungal, disease, through, activation, of, host, signaling, pathways])].
[sujeto(['The', lipid, moiety, of, 'PLM']), verbo([activates]), complemento([the, deregulation, signaling, pathway, involved, in, yeast, phagocytosis, whereas, its, glycan, 'moiety,', composed, of, 'β-1,2', mannosides, '(', 'β-Mans),', participates, to, inflammatory, processes, through, a, mechanism, involving, 'Galectin-3'])].
[sujeto(['Biosynthesis', of, 'PLM', 'β-Mans']), verbo([involves]), complemento([two, 'β-1,2', mannosyltransferases, '(', 'Bmts)', that, initiate, '(', 'Bmt5)', and, elongate, '(', 'Bmt6)', the, glycan, chains])].
[sujeto(['After', generation, of, double, bmtsΔ, 'mutants,', we, show, that, 'Bmt5']), verbo([has]), complemento([redundant, activity, with, 'Bmt2,', which, can, replace, 'Bmt5', in, bmt5Δ, mutant])].
[sujeto(['We', also]), verbo([report]), complemento([that, 'PLM', is, located, in, the, inner, layer, of, the, yeast, cell, wall])].
[sujeto(['However,', defect, of, 'PLM', 'β-mannosylation']), verbo([increases]), complemento([resistance, of, 'C'])].
[sujeto(['Recently,', we, identified, 'Rrp8', as, a, methyltransferase]), verbo([involved]), complemento([in, 'm(1)A645', modification, of, 25, 'S', rRNA])].
[sujeto(['Intriguingly,', the]), verbo([loss]), complemento([of, 'm(1)A2142', modification, confers, anisomycin, and, peroxide, sensitivity, to, the, cells])].
[sujeto(['BMT2', in, baboons, is, an, integrated, part, of, the, natural, phenomenon, of, mucosal, adaptation, to, daily, regurgitation, of, gastric, acid, into, the, distal, esophagus, '(', natural, 'GER),', whereas, 'BMT2', in, humans, might, reflect, an, evolutionary, atavism, in, the, 'esophagus,']), verbo([triggered]), complemento([by, a, 'non-physiological', disorder, '(', pathological, 'GER)'])].
[sujeto(['Candida', 'glabrata,', like, 'Candida', 'albicans,', is, an, opportunistic, yeast, pathogen, that]), verbo([has]), complemento([adapted, to, colonize, all, segments, of, the, human, gastrointestinal, tract, and, vagina])].
[sujeto([albicans, cell, wall]), verbo([expresses]), complemento(['β-1,2-linked', mannosides, '(', 'β-Mans),', promoting, its, adherence, to, host, cells, and, tissues])].
[sujeto([glabrata, 'wild-type', strain, in, mice, with, 'DSS-induced', colitis]), verbo([caused]), complemento([a, loss, of, body, 'weight,', colonic, 'inflammation,', and, mortality])].
[sujeto(['Histopathologic', examination, revealed, that, the, 'wild-type', strain, had, a, greater, ability, to, colonize, tissue, and]), verbo([cause]), complemento([tissue, damage])].
[sujeto([glabrata]), verbo([has]), complemento([a, high, pathogenic, potential, in, 'DSS-induced', 'colitis,', where, 'β-Mans', contribute, to, colonization, and, virulence])].
[sujeto(['However,', the, presence, of, 'fungal-like', 'glycans,', such, as, those, containing, 'β-mannose', '(', 'Man)', 'linkages,', can, elicit, an, immune, response, or]), verbo([bind]), complemento([to, 'Man', 'receptors,', thus, reducing, their, efficacy])].
[sujeto(['Recent', studies]), verbo([have]), complemento([confirmed, that, 'P'])].
[sujeto([pastoris]), verbo([has]), complemento([four, genes, from, the, 'β-mannosyl', transferase, '(', 'BMT)', family, and, that, 'Bmt2p', is, responsible, for, the, majority, of, 'β-Man', linkages, on, glycans])].
[sujeto(['While']), verbo([expressing]), complemento([recombinant, human, erythropoietin, '(', 'rhEPO)', in, a, developmental, glycoengineered, strain, devoid, of, 'BMT2', gene, 'expression,', 'cross-reactivity', was, observed, with, an, antibody, raised, against, host, cell, antigens])].
[sujeto(['Treatment', of, the, rhEPO, with, protein, 'N-glycosidase', 'F', eliminated, 'cross-reactivity,', indicating, that, the, antigen, was]), verbo([associated]), complemento([with, the, glycan])].
[sujeto(['Data', presented, here, conclude, that, the, additive, elimination, of, 'Bmt2p,', 'Bmt3p', and, 'Bmt1p', activities, are]), verbo([required]), complemento([for, total, abolition, of, 'β-Man-associated', glycans, and, their, related, antigenicity])].
[sujeto(['Significant', organ, toxicity]), verbo([leading]), complemento([to, procedure, related, death, in, 13, patients, '(', 30, '%', ')', was, observed, after, 'BMT2'])].
[sujeto(['This', single, institution, study]), verbo([suggests]), complemento([that, second, allogeneic, 'BMT', after, myeloblative, conditioning, has, an, acceptable, treatment, related, 'morbidity/mortality', and, favorable, outcome, if, performed, at, age, &, 'lt;', or, =, 10, years, and, with, an, interval, of, &, 'gt;', or, =, 6, months, after, the, first, 'BMT'])].
[sujeto(['All', but, six, patients, are, currently, on, no, medication, and]), verbo([have]), complemento([resumed, all, activities, without, any, limitation])].
[sujeto(['Severe', aplastic, anemia, '(', 'sAA)', is, a, bone, marrow, failure, disorder, which, is, mostly, a, consequence, of, immunologically]), verbo([mediated]), complemento([stem, cell, destruction])].
[sujeto(['Allogeneic', bone, marrow, transplantation, '(', 'BMT)', from, a, compatible, donor]), verbo([provides]), complemento(['long-term', survival, in, 60, to, 80, '%', of, sAA, patients])].
[sujeto(['We', conclude, that, early, detection, of, primary, graft, failure, '(', 'PGF),', followed, by, measures, attempting, to]), verbo([promote]), complemento([hematopoietic, recovery, '(', eg, use, of, growth, 'factors,', further, infusion, of, stem, 'cells)', may, decrease, mortality])].
[sujeto(['The', second, group, of, patients, appeared, to]), verbo([have]), complemento([less, graft, failure, compared, with, the, first, group, '(', 30, '%', vs, 63, '%', ;, 'P', =, 0.1, ')'])].
[sujeto(['Forty-one', patients]), verbo([have]), complemento(['died,', 27, of, 'lymphoma,', evenly, distributed, in, the, cohorts])].
[sujeto(['Earlier', deaths, were, observed, in, those, who, received, 'BMT2', within, 12, months, after, 'BMT1,', mostly]), verbo([caused]), complemento([by, 'regimen-related', toxicity, and, infections])].
[sujeto(['Six', patients, 'engrafted,', one, of, whom, had, an, uneventful, 'BMT2,', but]), verbo([he]), complemento([relapsed, 6, months, later])].
[sujeto(['The', other, five, developed, severe, acute, 'GVHD', '(', grades, 'III-IV),', with, a, fatal, outcome, in, three, 'cases,', while, two]), verbo([responded]), complemento([to, treatment, and, are, currently, alive, in, continuous, 'CR', at, 12, and, 36, months])].
[sujeto(['We', identified, 1, ',', 102, known, genes, differentially]), verbo([expressed]), complemento([to, a, significant, degree, '(', 'p<0'])].
[sujeto(['These', genes, are, 'RNA-binding', 'motif,', 'single-stranded']), verbo([interacting]), complemento([protein, 1, '(', 'RBMS1),', ribosomal, protein, 'L29', '(', 'RPL29),', glutathione, 'S-transferase', mu, 2, '(', 'GSTM2),', 'C15orf32,', 'Akt3,', 'B', cell, translocation, gene, 1, '(', 'BTG1),', 'C6orf62,', 'C7orf60,', 'kinesin-associated', protein, 3, '(', 'KIFAP3),', 'FBXO11,', 'AT-rich', interactive, domain, 4, 'A', '(', 'ARID4A),', 'COPS2,', 'TBPL1|SLC2A12,', 'TMEM59,', 'SNORD46,', glioma, tumor, suppressor, candidate, region, gene, 2, '(', 'GLTSCR2),', and, 'LRRFIP'])].
[sujeto(['The', extent, of, changes, in, genes, is, related, to, and]), verbo([involved]), complemento([significantly, in, gap, junction, 'signaling,', amyloid, 'processing,', cell, cycle, regulation, by, 'BTG', family, 'proteins,', and, breast, cancer, regulation, by, stathmin1, that, play, major, roles])].
[sujeto(['We']), verbo([have]), complemento([identified, a, novel, gene, '(', 'WBSCR9)', within, the, common, 'Williams-Beuren', syndrome, '(', 'WBS)', deletion, by, interspecies, sequence, conservation])].
[sujeto(['The', transcript, is]), verbo([expressed]), complemento([ubiquitously, throughout, development, and, is, subject, to, alternative, splicing])].
[sujeto(['Functional', motifs, identified, by, sequence, homology, searches, include, a, 'bromodomain;', a, 'PHD,', or, 'C4HC3,', 'finger;', several, putative]), verbo([nuclear]), complemento([localization, 'signals;', four, nuclear, receptor, binding, 'motifs;', a, polyglutamate, stretch, and, two, 'PEST', sequences])].
[sujeto(['Bromodomains,', 'PHD', motifs, and]), verbo([nuclear]), complemento([receptor, binding, motifs, are, cardinal, features, of, proteins, that, are, involved, in, chromatin, remodeling, and, modulation, of, transcription])].
[sujeto(['Haploinsufficiency', for, 'WBSCR9', gene, products, may, contribute, to, the, complex, phenotype, of, 'WBS', by]), verbo([interacting]), complemento([with, 'tissue-specific', regulatory, factors, during, development])].
[sujeto(['We']), verbo([report]), complemento([on, the, analysis, of, a, human, gene, homologous, to, the, rat, ventral, prostate])].
[sujeto([1, ')', ',', which, is, transcriptionally]), verbo([induced]), complemento([in, the, regressing, rat, prostate, after, castration])].
[sujeto(['EST', database, searching, and, 'Northern', blotting]), verbo([reveal]), complemento([that, this, is, one, of, at, least, four, different, members, of, a, gene, family, in, the, human, genome, that, produce, transcripts, of, 3.4, ',', 2.4, ',', 1.9, ',', and, 1.2, 'kb,', expressed, in, a, wide, range, of, tissues])].
[sujeto(['Three', other, members, of, this, gene, family]), verbo([have]), complemento([already, been, mapped, to, chromosomes, 7, 'q,', 17, 'p,', and, 22, q, and, reported, either, as, anonymous, 'ESTs', or, as, 'full-length', clones])].
[sujeto(['We']), verbo([have]), complemento([now, characterized, a, fourth, member, '(', assigned, the, gene, now, characterized, a, fourth, member, '(', assigned, the, gene, name, 'C7orf1', by, 'GDB)', and, localized, it, also, to, chromosome, 7, q])].
[sujeto(['C7orf1', is, almost, identical, over, much, of, its, length, to, the]), verbo([reported]), complemento(['ORF', of, 'RVP'])].
[sujeto(['The', genomic, sequence, of, 'C7orf1', is, 'intron-less,', is, spanned, by, a, 'CpG', 'low-methylation', 'island,', and]), verbo([has]), complemento([two, 'noncoding,', nonpolymorphic, 'STR', regions, immediately, adjacent, to, the, open, reading, 'frame,', one, 5, '\'', and, one, 3, '\''])].
[sujeto([1, ',', it]), verbo([has]), complemento([four, hydrophobic, potential, 'membrane-spanning', 'regions,', but, it, lacks, 60, amino, acid, residues, at, its, carboxyl, terminus, relative, to, rat, 'RVP'])].
[sujeto(['During', the, course, of, systematic, sequence, tag, analysis, of, clones, isolated, from, an, adult, testis, cDNA, 'library,', clones, 296, and, 576, were]), verbo([found]), complemento([to, detect, 71, -, 74, '%', sequence, identity, to, the, guinea, pig, sperm, surface, protein, 'PH-20'])].
[sujeto(['This', surface, protein, is]), verbo([involved]), complemento([in, 'sperm-egg', adhesion, in, the, guinea, pig])].
[sujeto(['Fluorescence', in, situ, hybridization, with, yeast, artificial, chromosome, '(', 'YAC)', clones, isolated, from, the, 'CEPH', megaYAC, library]), verbo([has]), complemento([refined, this, localization, to, 7, q31])].
[sujeto(['PCR', analysis, of, genomic, 'DNA', and, 'YAC', clone, 'DNA']), verbo([has]), complemento([shown, that, the, 1919, bp, of, the, gene, that, has, been, cloned, covers, approximately, 11, kb, of, genomic, 'DNA', and, is, encoded, by, at, least, 4, exons])].
[sujeto(['Northern', analysis, of, 'poly(A)+', mRNA, from, a, range, of, 16, human, tissues]), verbo([has]), complemento([demonstrated, that, expression, of, the, gene, as, a, single, 2.4, -, kb, transcript, is, strictly, limited, to, the, testis])].
[sujeto(['Gene', transfer, events, from, organelles, to, the, nucleus]), verbo([have]), complemento([occurred, over, evolutionary, time])].
[sujeto(['In', the, case, that, a, transferred, gene, in, the, nucleus, needs, to, go, back, to, the, original, 'organelle,', it, must, obtain]), verbo([targeting]), complemento([information, for, sorting, its, protein, to, that, organelle])].
[sujeto(['Here,', we]), verbo([reveal]), complemento([that, the, genes, for, the, ribosomal, proteins, 'L2', and, 'S4', in, the, 'Arabidopsis', thaliana, mitochondrial, '(', 'mt)', genome, contain, information, for, protein, targeting, into, the, mitochondria])].
[sujeto(['Similarly,', the, genes, for, the, ribosomal, proteins, 'L2', and, 'S19', in, the, 'Oryza', sativa, mt, genome, contain, information, for, protein]), verbo([targeting]), complemento([into, mitochondria])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, targeting, information, already, existed, in, each, gene, in, the, plant, mt, genome, before, the, transfer, event, to, the, nucleus, occurred])].
[sujeto(['We']), verbo([provide]), complemento([new, insights, into, the, timing, of, the, appearance, of, targeting, signals, in, evolution])].
[sujeto(['The', 'L2', ribosomal, protein, is, typically, one, of, the, most]), verbo([conserved]), complemento([proteins, in, the, ribosome, and, is, universally, present, in, 'bacterial,', 'archaeal,', and, eukaryotic, cytosolic, and, organellar, ribosomes])].
[sujeto(['It', is, usually, 260, -, 270, amino, acids, long, and, its]), verbo([binding]), complemento([to, the, 'large-subunit', ribosomal, 'RNA', near, the, peptidyl, transferase, center, is, mediated, by, a, 'beta-barrel', 'RNA-binding', domain, with, 10, beta, strands])].
[sujeto(['We']), verbo([have]), complemento([determined, 'that,', in, 'wheat,', the, functional, rpl2, gene, has, been, transferred, to, the, nucleus, and, much, of, the, 'plant-specific', internal, insert, has, been, deleted])].
[sujeto(['Its', mRNA, is, only, 1.2, 'kb,', and, two]), verbo([expressed]), complemento([copies, in, wheat, encode, proteins, of, 318, and, 319, amino, 'acids,', so, they, are, considerably, shorter, than, the, maize, 'nuclear-located', rpl2, gene, of, 448, codons])].
[sujeto(['Comparative', sequence, analysis, of, cereal, mitochondrial, 'L2', ribosomal, proteins, indicates, that, the, mid, region]), verbo([has]), complemento([undergone, unexpectedly, rapid, evolution, during, the, last, 60, million, years])].
[sujeto(['To', search, for, novel, transcriptional, pathways, that, are]), verbo([activated]), complemento([in, skeletal, muscle, after, endurance, 'exercise,', we, used, cDNA, microarrays, to, measure, global, mRNA, expression, after, an, exhaustive, bout, of, 'high-intensity', cycling, '(', approximately, 75, 'min)'])].
[sujeto(['In', 'total,', the, expression, of, 118, genes, significantly]), verbo([increased]), complemento([3, h, postcycling, and, 8, decreased])].
[sujeto(['At', 48, 'h,', the, expression, of, 29, genes, significantly]), verbo([increased]), complemento([and, 5, decreased])].
[sujeto(['Many', of, these, are, potentially, important, novel, genes]), verbo([involved]), complemento([in, exercise, recovery, and, 'adaptation,', including, several, involved, in, 1, ')', metabolism, and, mitochondrial, biogenesis, '(', 'FOXO1,', 'PPARdelta,', 'PPARgamma,', nuclear, receptor, binding, protein, 2, ',', 'IL-6', 'receptor,', ribosomal, protein, 'L2,', aminolevulinate, 'delta-synthase', 2, ')', ;, 2, ')', the, oxidant, stress, response, '(', metalothioneins, 1, 'B,', 1, 'F,', 1, 'G,', 1, 'H,', 1, 'L,', 2, 'A,', 3, ',', interferon, regulatory, factor, 1, ')', ;, and, 3, ')', electrolyte, transport, across, membranes, '[', 'Na+-K+-ATPase', '(', 'beta3),', 'SERCA3,', chloride, channel, 4, ']'])].
[sujeto(['Others', include, genes]), verbo([involved]), complemento([in, cell, 'stress,', 'proteolysis,', 'apoptosis,', 'growth,', 'differentiation,', and, transcriptional, 'activation,', as, well, as, all, three, nuclear, receptor, subfamily, 4, 'A', family, members, '(', 'Nur77,', 'Nurr1,', and, 'Nor1)'])].
[sujeto(['This', study, is, the, first, to, characterize, global, mRNA, expression, during, recovery, from, endurance, 'exercise,', and, the, results]), verbo([provide]), complemento([potential, insight, into, 1, ')', the, transcriptional, contributions, to, homeostatic, recovery, in, human, skeletal, muscle, after, endurance, 'exercise,', and, 2, ')', the, transcriptional, contributions, from, a, single, bout, of, endurance, exercise, to, the, adaptive, processes, that, occur, after, a, period, of, endurance, exercise, training])].
[sujeto(['Can', sequence, segments, coding, for, subcellular]), verbo([targeting]), complemento([or, for, posttranslational, modifications, occur, in, proteins, that, are, not, substrates, in, either, of, these, 'processes?', 'Although', considerable, effort, has, been, invested, in, achieving, low, 'false-positive', prediction, 'rates,', even, accurate, 'sequence-analysis', tools, for, the, recognition, of, these, motifs, generate, a, small, but, noticeable, number, of, protein, hits, that, lack, the, appropriate, biological, context, but, cannot, be, rationalized, as, false, positives])].
[sujeto(['We', show, that, the, carboxyl, termini, of, a, set, of, definitely, 'non-peroxisomal', proteins, with, predicted, peroxisomal]), verbo([targeting]), complemento([signals, interact, with, the, peroxisomal, matrix, protein, receptor, peroxin, 5, '(', 'PEX5)', in, a, yeast, 'two-hybrid', test])].
[sujeto(['We', also, show, that, even, prokaryotic, proteins, can, contain, peroxisomal]), verbo([targeting]), complemento([sequences])].
[sujeto(['Thus,', functional, localization, signals, can, evolve, in, unrelated, protein, sequences, as, a, result, of, neutral, 'mutations,', and, subcellular]), verbo([targeting]), complemento([is, hierarchically, 'organized,', with, signal, accessibility, playing, a, decisive, role])].
[sujeto(['Silent', functional, signals]), verbo([have]), complemento([the, potential, to, acquire, importance, in, future, evolutionary, scenarios, and, in, pathological, conditions])].
[sujeto(['Mitochondrial', genes, are, usually]), verbo([conserved]), complemento([in, size, in, angiosperms])].
[sujeto(['The', sequence, corresponding, to, the, 3, '\'', end, of, rice, rpl2, '(', termed, 3, '\'', 'rpl2)']), verbo([has]), complemento([been, lost, much, more, pervasively, among, the, mitochondrial, 'DNAs', of, core, eudicots, than, has, 5, '\'', rpl2])].
[sujeto(['An', intact, and]), verbo([expressed]), complemento([3, '\'', rpl2, gene, was, discovered, in, the, nucleus, of, five, diverse, eudicots, '(', 'tomato,', 'cotton,', 'Arabidopsis,', 'soybean,', and, 'Medicago)'])].
[sujeto(['The', 'full-length', rpl2, gene]), verbo([has]), complemento([been, transferred, intact, to, the, nucleus, in, maize])].
[sujeto(['This', complex, history, of, gene, fission, and, gene, transfer]), verbo([has]), complemento([created, four, distinct, types, of, rpl2, structures, or, compartmentalizations, in, 'angiosperms:', '(', 1, ')', intact, rpl2, gene, in, the, 'mitochondrion,', '(', 2, ')', intact, gene, in, the, 'nucleus,', '(', 3, ')', split, 'gene,', 5, '\'', in, the, mitochondrion, and, 3, '\'', in, the, 'nucleus,', and, '(', 4, ')', split, 'gene,', both, parts, in, the, nucleus])].
[sujeto(['These', 'cells,', denoted, 'rml2(fat21),']), verbo([have]), complemento([an, apparent, inability, to, induce, peroxisomal, 'function,', as, evidenced, by, a, deficiency, in, oleic, acid, induction, of, 'beta-oxidation'])].
[sujeto(['Several', assays, of, mitochondria, from, 'rml2(fat21)', strains]), verbo([suggest]), complemento([normal, mitochondrial, function])].
[sujeto(['The', wheat, mitochondrial, genome, contains, only, partial, coding, sequences, for, the, 'L2', and, 'S19', ribosomal, 'proteins,', unlike, in, rice, or, liverwort, 'mitochondria,', where, these, genes, are, functional, and]), verbo([have]), complemento([a, 'bacterial-type', linkage])].
[sujeto(['This']), verbo([finding]), complemento([suggests, that, mammalian, mitochondrial, ribosomes, contain, several, novel, proteins])].
[sujeto(['In', an, attempt, to, identify, essential, mediators, of, these, 'processes,', we]), verbo([have]), complemento([isolated, mutant, strains, of, the, yeast, 'Saccharomyces', cerevisiae, unable, to, utilize, oleic, acid, as, sole, carbon, 'source,', while, retaining, the, ability, to, utilize, acetate])].
[sujeto(['Oxidation', of, acetate, after, growth, in, acetate, medium, is]), verbo([increased]), complemento([similarly, in, the, mutant, and, parent, strains])].
[sujeto(['The', fat21, mutant, allele, displays, conditional, synthetic, lethality, in, combination, with, a, null, allele, of, the, 'OLE1', 'gene,', which, encodes, 'Delta9-desaturase', and, is]), verbo([required]), complemento([for, proper, mitochondrial, segregation])].
[sujeto(['These', observations, of, a, defect, in, a, mitochondrial, protein, differentially, affecting, the, adaptation, to, oleic, acid, and, acetate, as, carbon, sources]), verbo([suggest]), complemento([that, the, phenotype, of, fat21, is, associated, with, a, novel, pathway, of, 'mitochondrial-nuclear-peroxisomal', communication])].
[sujeto(['The', yeast]), verbo([nuclear]), complemento([gene, 'RML2,', identified, through, genomic, sequencing, of, 'Saccharomyces', cerevisiae, chromosome, 'V,', was, shown, to, encode, a, mitochondrial, homologue, of, the, bacterial, ribosomal, protein, 'L2'])].
[sujeto(['RML2', is]), verbo([regulated]), complemento([transcriptionally, in, response, to, carbon, source, and, the, accumulation, of, 'Rml2p', is, dependent, on, the, presence, of, the, 21, 'S', large, rRNA])].
[sujeto(['Site-directed', mutagenesis, showed, that, a, highly]), verbo([conserved]), complemento([7, -, amino, acid, sequence, '(', 'Val336', to, 'Asp342)', of, 'Rml2p', is, essential, for, function])].
[sujeto(['Substitution', of, 'Gln', for, 'His-343,', the, most, highly]), verbo([conserved]), complemento([histidine, in, the, 'L2', protein, 'family,', caused, 'cold-sensitive', respiratory, growth, but, did, not, affect, the, assembly, of, 54, 'S', ribosomal, subunits])].
[sujeto(['His343', corresponds, to, 'His229', in, 'Escherichia', coli, 'L2,', which]), verbo([has]), complemento([been, implicated, in, a, direct, involvement, in, peptidyl, transferase, activity])].
[sujeto(['The', mitochondrial, rpl2, sequence, is, absent, from, the, pea, mitochondrial, genome, and, we, consequently, propose, that, the, mitochondrial, 'RPL2', protein, is, encoded, by, a]), verbo([nuclear]), complemento([gene, in, pea])].
[sujeto(['Based', on, 'DNA', and, amino, acid, comparisons, with, known, genes, and, their, 'products,', a, region, of, the, 'Paramecium', aurelia, mitochondrial, '(', 'mt)', genome]), verbo([has]), complemento([been, found, to, encode, the, following, gene, 'products:', '(', 1, ')', photosystem, 'II', protein, 'G', '(', 'psbG);', '(', 2, ')', a, large, open, reading, frame, '(', 'ORF400)', which, is, also, found, encoded, in, the, chloroplast, '(', 'cp)', 'DNA', of, tobacco, '(', as, 'ORF393)', and, liverwort, '(', as, 'ORF392),', and, in, the, kinetoplast, maxicircle, 'DNA', of, 'Leishmania', tarentolae, '(', as, 'ORFs', 3, and, 4, ')', ;, '(', 3, ')', ribosomal, protein, 'L2', '(', 'rpl2);', '(', 4, ')', ribosomal, protein, 'S12', '(', 'rps12);', '(', 5, ')', ribosomal, protein, 'S14', '(', 'rps14);', and, '(', 6, ')', 'NADH', dehydrogenase, subunit, 2, '(', 'ndh2)'])].
[sujeto(['All', of, these, genes]), verbo([have]), complemento([been, found, in, cp, 'DNA,', but, the, psbG, gene, has, never, been, identified, in, a, mt, 'genome,', and, ribosomal, protein, genes, have, never, been, located, in, an, animal, or, protozoan, mitochondrion])].
[sujeto(['The', ndh2, gene]), verbo([has]), complemento([been, found, in, both, mitochondria, and, plastids])].
[sujeto(['It', is, not, yet, known, whether, these, genes, are]), verbo([transcribed]), complemento([or, have, functional, gene, products])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, the, isolation, and, partial, sequence, analysis, of, a, rice, mitochondrial, 'DNA', fragment, '(', 6.9, 'kb)', which, contains, a, transferred, copy, of, a, chloroplast, gene, cluster, coding, for, the, large, subunit, of, 'ribulose-1,5-bisphosphate', carboxylase, '(', 'rbcL),', beta, and, epsilon, subunits, of, 'ATPase', '(', atpB, and, 'atpE),', methionine, tRNA, '(', 'trnM)', and, valine, tRNA, '(', 'trnV)'])].
[sujeto(['We']), verbo([have]), complemento([now, completely, sequenced, this, 6.9, kb, fragment, and, found, it, to, also, contain, a, sequence, homologous, to, the, chloroplast, gene, coding, for, the, ribosomal, protein, 'L2', '(', 'rpl2),', beginning, at, a, site, 430, bp, downstream, from, the, termination, codon, of, rbcL])].
[sujeto(['We']), verbo([have]), complemento([sequenced, these, two, copies, of, rice, chloroplast, rpl2, and, found, their, sequences, to, be, identical])].
[sujeto(['In', 'addition,', a, 151, bp, sequence, located, upstream, of, the, chloroplast, rpl2, coding, region, is, also]), verbo([found]), complemento([in, the, 3, '\'', noncoding, region, of, chloroplast, rbcL, and, other, as, yet, undefined, locations, in, the, rice, chloroplast, genome])].
[sujeto(['Hybridization', analysis, revealed, that, this, 151, bp, repeat, sequence, identified, in, rice, is, also, present, in, several, copies, in, 11, other, plant, species, we]), verbo([have]), complemento([examined])].
[sujeto(['Findings', from, these, studies]), verbo([suggest]), complemento([that, the, translocation, of, rpl2, to, the, rbcL, gene, cluster, found, in, the, rice, mitochondrial, genome, might, have, occurred, through, homologous, recombination, between, the, 151, bp, repeat, sequence, present, in, both, rpl2, and, rbcL])].
[sujeto(['Mammalian', mitochondria, harbor, a, dedicated, translation, apparatus, that, is]), verbo([required]), complemento([for, the, synthesis, of, 13, mitochondrial, 'DNA', '(', 'mtDNA)-encoded', 'polypeptides,', all, of, which, are, essential, components, of, the, oxidative, phosphorylation, '(', 'OXPHOS)', complexes])].
[sujeto(['Here', we, show, that, 'C7orf30,', a, member, of, the, large, family, of, 'DUF143', 'proteins,']), verbo([associates]), complemento([with, the, mitochondrial, large, ribosomal, subunit, '(', 'mt-LSU)'])].
[sujeto(['Knockdown', of, 'C7orf30', by, short, hairpin, 'RNA', '(', 'shRNA)', does, not, alter, the, sedimentation, profile, of, the, 'mt-LSU,', but, results, in, the, depletion, of, several, 'mt-LSU', proteins, and]), verbo([decreased]), complemento([monosome, formation])].
[sujeto(['This']), verbo([leads]), complemento([to, a, mitochondrial, translation, 'defect,', involving, the, majority, of, mitochondrial, 'polypeptides,', and, a, severe, 'OXPHOS', assembly, defect])].
[sujeto(['Immunoprecipitation', and, mass, spectrometry, analyses, identified, mitochondrial, ribosomal, protein, '(', 'MRP)L14', as, the, specific]), verbo([interacting]), complemento([protein, partner, of, 'C7orf30', in, the, 'mt-LSU'])].
[sujeto(['Members', of, the, 'DUF143', family]), verbo([have]), complemento([been, suggested, to, be, universally, conserved, ribosomal, silencing, 'factors,', acting, by, sterically, inhibiting, the, association, of, the, small, and, large, ribosomal, subunits])].
[sujeto(['Our', results, demonstrate, 'that,', although, the, interaction, between, 'C7orf30', and, 'MRPL14']), verbo([has]), complemento([been, evolutionarily, 'conserved,', human, 'C7orf30', 'is,', on, the, 'contrary,', essential, for, mitochondrial, ribosome, biogenesis, and, mitochondrial, translation])].
[sujeto(['Peptide', sequences, obtained, were, used, to, virtually, screen]), verbo([expressed]), complemento([sequence, tag, data, bases, from, 'human,', 'mouse,', and, rat])].
[sujeto(['Consensus', cDNAs, were, assembled, in, silico, from, various]), verbo([expressed]), complemento([sequence, tag, sequences, identified])].
[sujeto([coli, 'EcoL2', ribosomal, protein, '(', 'MRP-L14),', that, do, not]), verbo([conserve]), complemento([the, specific, and, functional, highly, important, 'His(229)', residue, of, 'E'])].
[sujeto(['Recent', findings, revealed, in, cancer, cells, novel, stress, response, 'pathways,', which, in, response, to, many, chemotherapeutic, drugs]), verbo([causing]), complemento([nucleolar, 'stress,', will, function, independently, from, tumor, protein, p53, '(', 'p53)', and, still, lead, to, cell, cycle, arrest, 'and/or', apoptosis])].
[sujeto(['Here,', we, demonstrate, that, nucleolar, stress]), verbo([induced]), complemento([by, 5, -, fluorouracil, '(', 5, -, 'FU)', in, colon, cancer, cells, devoid, of, p53, leads, to, the, activation, of, ribosomal, protein, 'L3', '(', 'rpL3)', as, proapoptotic, factor])].
[sujeto(['rpL3,', as, 'ribosome-free', 'form,', is, a, negative, regulator, of, 'cystathionine-β-synthase', '(', 'CBS)', expression, at, transcriptional, level, through, a, molecular, mechanism]), verbo([involving]), complemento(['Sp1'])].
[sujeto(['The', 'rpL3-CBS', association, affects, 'CBS', stability, 'and,', in, 'addition,', can]), verbo([trigger]), complemento(['CBS', translocation, into, mitochondria])].
[sujeto(['Consequently', apoptosis, will, be]), verbo([induced]), complemento([through, the, mitochondrial, apoptotic, cell, death, pathway, characterized, by, an, increased, ratio, of, 'Bax', to, 'Bcl-2,', cytochrome, c, release, and, subsequent, caspase, activation])].
[sujeto(['It', is, noteworthy, that, silencing, of, 'CBS', is]), verbo([associated]), complemento([to, a, strong, increase, of, 5, -, 'FU-mediated', inhibition, of, cell, migration, and, proliferation])].
[sujeto(['These', data]), verbo([reveal]), complemento([a, novel, mechanism, to, accomplish, 'p53-independent', apoptosis, and, suggest, a, potential, therapeutic, approach, aimed, at, upregulating, rpL3, for, treating, cancers, lacking, p53])].
[sujeto(['Many', evidences, show, that, a, subset, of, ribosomal, proteins, are]), verbo([involved]), complemento([in, the, regulation, of, the, cell, cycle, and, apoptosis, through, modulation, of, p53, activity])].
[sujeto(['In', 'addition,', 'p53-independent', mechanisms, of, cell, cycle]), verbo([arrest]), complemento([in, response, to, alterations, of, ribosomal, proteins, availability, have, been, described])].
[sujeto(['We', demonstrate, that, the, 'rpL3-mediated', p21, upregulation]), verbo([requires]), complemento([the, specific, interaction, between, rpL3, and, 'Sp1'])].
[sujeto(['Furthermore,', in, our, experimental, 'system,', p21, overexpression]), verbo([leads]), complemento([to, a, dual, 'outcome,', activating, the, 'G₁/S', arrest, of, the, cell, cycle, or, the, apoptotic, pathway, through, 'mitochondria,', depending, on, its, intracellular, levels])].
[sujeto(['Taken', 'together,', our, findings, unravel, a, novel, extraribosomal, function, of, rpL3, and, reinforce, the, proapoptotic, role, of, p21, in, addition, to, its, widely]), verbo([reported]), complemento([ability, as, an, inhibitor, of, cell, proliferation])].
[sujeto(['Tourette', 'syndrome/chronic', tic, phenotype, '(', 'TS-CTD)', is, a, neurological, disorder, manifested, particularly, by, motor, and, vocal, tics, and]), verbo([associated]), complemento([with, a, variety, of, behavioral, abnormalities])].
[sujeto([-, 5, 'A>G', variants, are]), verbo([reported]), complemento([to, be, associated, with, 'Tourette', 'syndrome/chronic', tic, phenotype, '(', 'TS-CTD)', in, patients, of, 'European', ancestry])].
[sujeto(['To', evaluate, whether, these, variants, are]), verbo([associated]), complemento([with, 'TS-CTD', in, 'Chinese', 'Han', 'patients,', we, screened, 132, 'Chinese', 'Han', patients, from, 'Mainland', 'China'])].
[sujeto([-, 5, 'A>G', 'variants,', and, these, variants, probably, are, a, rare]), verbo([cause]), complemento([of, 'TS-CTD', in, a, 'Chinese', 'Han', ethnic, group])].
[sujeto(['Genetic', heterogeneity, of, 'TS', should, be, considered, and, tests, designed, to, detect, these, variants, in, 'Chinese', 'Han', ethnic, group, probably, will, not]), verbo([have]), complemento([a, diagnostic, utility, in, clinical, practice])].
[sujeto(['This', study, is, the, first, comparative, proteomic, analysis, of, basic, proteins, between, the, 'DLD-1', human, colon, cancer, cell, line, and, 'DLD-1/5-FU', its, 5, -, 'FU', resistant, 'sub-line', using, the, 'radical-free', and, highly, reducing, method, of, 'two-dimensional', polyacrylamide, gel, 'electrophoresis,', which]), verbo([has]), complemento([a, superior, ability, in, the, separation, of, basic, proteins, and, the, quantification, of, 'post-translational', modification])].
[sujeto(['A', densitometric, analysis, was, performed, to, quantify, the]), verbo([modulated]), complemento(['proteins,', and, protein, spots, showing, significant, changes, were, identified, by, 'matrix-assisted', laser, 'desorption/ionization', 'time-of-flight/time-of-flight', mass, spectrometry])].
[sujeto(['Six', basic, proteins, significantly]), verbo([modulated]), complemento([between, 'DLD-1', and, 'DLD-1/5-FU', were, identified])].
[sujeto(['The', six, identified, 'spots,', corresponding, to, five, different, proteins, included, heterogeneous]), verbo([nuclear]), complemento([ribonucleoprotein, 'G,', mitochondrial, transcription, factor, 'A,', histone, 'H2B,', histone, 'H4', and, ribosomal, protein, 'L3'])].
[sujeto(['From', about, 9, ',', 0, cDNAs, 'displayed,', we]), verbo([found]), complemento([12, differentially, expressed, in, 'ob/ob', mice, skeletal, muscle, that, could, be, recovered, from, the, differential, display, gels, and, confirmed, by, 'Northern', blot, analysis, and, sequenced])].
[sujeto(['The', level, of, overexpression, of, these, mRNAs, in, skeletal, muscle, varied, from, a, 500, '%']), verbo([increase]), complemento([to, as, little, as, a, 25, '%', increase])].
[sujeto(['The']), verbo([nuclear]), complemento([gene, for, mitochondrial, ribosomal, protein, 'YmL9', '(', 'MRP-L9)', of, yeast, has, been, cloned, and, sequenced])].
[sujeto(['Survival', analyses, were, performed, on, the, individual]), verbo([target]), complemento(['level,', as, well, as, on, the, combined, multimarker, signature])].
[sujeto(['OBJECTIVE', 'To', determine, the, genetic]), verbo([cause]), complemento([of, a, child, with, 'blepharophimosis,', 'ptosis,', and, epicanthus, inverses, syndrome, and, tetralogy, of, 'Fallot,', and, to, correlate, the, phenotype, with, the, genotype])].
[sujeto(['METHODS', 'Routine', 'G-banding']), verbo([has]), complemento([been, previously, performed, on, the, patient, and, her, parents])].
[sujeto(['RESULTS', 'Chromosomal', analysis]), verbo([has]), complemento([suggested, normal, karyotypes, for, the, child, and, her, parents])].
[sujeto(['The', deleted, region]), verbo([has]), complemento([encompassed, 74, genes, including, 41, 'disease-related', 'genes,', and, this, is, also, the, most, frequent, region, involved, in, interstitial, 3, q, deletion])].
[sujeto(['Patients', with, deletion, of, this, region, often]), verbo([have]), complemento([a, common, feature, of, dysplasia, of, 'eyelids,', as, well, as, a, spectrum, of, other, anomalies, according, to, different, 'breakpoints,', including, 'microcephaly,', skeletal, 'anomalies,', congenital, heart, 'defects,', cranial, 'anomalies,', intellectual, disability, and, developmental, delay])].
[sujeto(['CMA', can]), verbo([provide]), complemento([more, detailed, information, and, allow, further, investigation, of, the, 'genotype-phenotype', correlation])].
[sujeto(['Loss', of, heterozygosity, was, examined, in, all, respective, cancer, 'samples,', and, was, detected, in, seven, occasions]), verbo([involving]), complemento([four, of, the, candidate, genes])].
[sujeto(['In', all, seven, occasions, the, 'wild-type', allele, was, lost, '(', 'P', =, 0.0078, ')']), verbo([providing]), complemento([additional, evidence, that, these, eleven, genes, are, likely, to, include, true, culprits])].
[sujeto(['The', study]), verbo([provides]), complemento([a, set, of, candidate, predisposition, genes, which, may, explain, a, subset, of, common, familial, 'CRC'])].
[sujeto(['Additional', genetic, validation, in, other, populations, is]), verbo([required]), complemento([to, provide, firm, evidence, for, 'causality,', as, well, as, to, characterize, the, natural, history, of, the, respective, phenotypes])].
[sujeto(['Lung', cancer, is, a]), verbo([leading]), complemento([cause, of, cancer, death, worldwide])].
[sujeto(['Several', alterations, in, 'RNA', metabolism]), verbo([have]), complemento([been, found, in, lung, cancer, 'cells;', this, suggests, that, 'RNA', 'metabolism-related', molecules, are, involved, in, the, development, of, this, pathology])].
[sujeto(['We', identified, eight, genes, differentially]), verbo([expressed]), complemento([in, lung, adenocarcinoma, microarray, datasets])].
[sujeto(['Interestingly,', most, of, these, genes, had, not, previously, been]), verbo([associated]), complemento([with, lung, cancer])].
[sujeto(['These', genes, play, diverse, roles, in, mRNA, 'metabolism:', three, are]), verbo([associated]), complemento([with, the, spliceosome, '(', 'ASCL3L1,', 'SNRPB', and, 'SNRPE),', whereas, others, participate, in, 'RNA-related', processes, such, as, translation, '(', 'MARS', and, 'MRPL3),', mRNA, stability, '(', 'PCBPC1),', mRNA, transport, '(', 'RAE),', or, mRNA, editing, '(', 'ADAR2,', also, known, as, 'ADARB1)'])].
[sujeto(['Moreover,', we]), verbo([found]), complemento([a, high, incidence, of, loss, of, heterozygosity, at, chromosome, 21, q22])].
[sujeto([3, ',', where, the, 'ADAR2', locus, is, 'located,', in, 'NSCLC', cell, lines, and, primary, 'tissues,']), verbo([suggesting]), complemento([that, the, downregulation, of, 'ADAR2', in, lung, cancer, is, associated, with, specific, genetic, losses])].
[sujeto(['Taken', 'together,', these, results, support, the, hypothesis, that, changes, in, 'RNA', metabolism, are]), verbo([involved]), complemento([in, the, pathogenesis, of, lung, 'cancer,', and, identify, new, potential, targets, for, the, treatment, of, this, disease])].
[sujeto(['By', combining, exome, sequencing, in, conjunction, with, genetic, 'mapping,', we]), verbo([have]), complemento([identified, the, first, mutation, in, large, mitochondrial, ribosomal, protein, 'MRPL3', in, a, family, of, four, sibs, with, hypertrophic, 'cardiomyopathy,', psychomotor, 'retardation,', and, multiple, respiratory, chain, deficiency])].
[sujeto(['These', mutations, were, shown, to, alter, ribosome, assembly, and]), verbo([cause]), complemento([a, mitochondrial, translation, deficiency, in, cultured, skin, fibroblasts, resulting, in, an, abnormal, assembly, of, several, complexes, of, the, respiratory, chain])].
[sujeto(['A', novel, variant, in, the, 5, '\'', untranslated, region, of, the, 'OFCC1', gene, was]), verbo([found]), complemento([in, 2, 'TS-CTD', patients, from, a, different, pedigree])].
[sujeto(['A', variety, of, small, 'RNAs,', including, the, 'Dicer-dependent', miRNAs, and, the, 'Dicer-independent', 'Piwi-interacting', 'RNAs,']), verbo([associate]), complemento([with, 'Argonaute', family, proteins, to, regulate, gene, expression, in, diverse, cellular, processes])].
[sujeto(['These', two, species, of, small, 'RNA']), verbo([have]), complemento([not, been, found, in, fungi])].
[sujeto(['Here,', by, analyzing, small, 'RNAs']), verbo([associated]), complemento([with, the, 'Neurospora', 'Argonaute', protein, 'QDE-2,', we, show, that, diverse, pathways, generate, 'miRNA-like', small, 'RNAs', '(', 'milRNAs)', and, 'Dicer-independent', small, interfering, 'RNAs', '(', 'disiRNAs)', in, this, filamentous, fungus])].
[sujeto(['In', 'contrast,', disiRNAs, originate, from, loci, producing, overlapping, sense, and, antisense, 'transcripts,', and, do, not]), verbo([require]), complemento([the, known, 'RNAi', components, for, their, production])].
[sujeto(['Oxidative', phosphorylation, in, mitochondria]), verbo([requires]), complemento([the, synthesis, of, proteins, encoded, in, the, mitochondrial, 'DNA'])].
[sujeto(['Many', biogenesis, factors]), verbo([interact]), complemento([with, the, tunnel, exit, of, 'pro-', and, eukaryotic, ribosomes, to, help, the, newly, synthesized, proteins, to, mature])].
[sujeto(['Our', analysis, revealed, a, complex, network, of]), verbo([interacting]), complemento([proteins, including, proteins, and, protein, domains, specific, to, mitochondrial, ribosomes])].
[sujeto(['This', network, includes, 'Mba1,', the, 'membrane-bound', ribosome, receptor, of, the, inner, 'membrane,', as, well, as, 'Mrpl3,', 'Mrpl13,', and, 'Mrpl27,', which, constitute, ribosomal, proteins, exclusively]), verbo([found]), complemento([in, mitochondria])].
[sujeto(['Application', of, insecticides, in, modern, agriculture, in, order, to]), verbo([enhance]), complemento([legume, production, has, led, to, their, accumulation, in, soils, to, levels, that, adversely, affect, soil, microflora, such, as, rhizobia, and, exert, a, negative, impact, on, the, physiological, activities, associated, with, them])].
[sujeto(['This', study, was, therefore, designed, to, identify, rhizobial, strains]), verbo([expressing]), complemento([higher, tolerance, to, insecticides, fipronil, and, pyriproxyfen, and, synthesising, plant, growth, regulators, even, amid, insecticide, stress])].
[sujeto([strain, 'MRL3', significantly]), verbo([increased]), complemento([the, measured, parameters, compared, with, plants, grown, in, soils, treated, solely, with, the, same, concentration, of, each, insecticide, but, without, inoculant])].
[sujeto(['This', study]), verbo([suggests]), complemento([that, 'Rhizobium', strain, 'MRL3', may, be, exploited, as, a, bioinoculant, to, augment, the, efficiency, of, lentil, exposed, to, 'insecticide-stressed', soils])].
[sujeto(['This', study, was, designed, to, evaluate, the, effect, of, the, selected, pesticides, '[', herbicides, '(', metribuzin, and, 'glyphosate),', insecticides, '(', imidacloprid, and, 'thiamethoxam)', and, fungicides, '(', 'hexaconazole,', metalaxyl, and, 'kitazin)]', at, the, recommended, and, the, higher, dose, rates, on, plant, growth]), verbo([promoting]), complemento([traits, of, 'Rhizobium', sp])].
[sujeto(['A', trend, of, 'pesticide-concentration', dependent, 'progressive-decline', for, plant, growth]), verbo([promoting]), complemento([properties, of, 'Rhizobium', sp])].
[sujeto(['Commonly,', the, maximum, toxicity, to, plant, growth]), verbo([promoting]), complemento([traits, of, 'Rhizobium', was, shown, by, 'glyphosate,', imidacloprid, and, hexaconazole, at, three, times, the, recommended, rate, among, 'herbicides,', insecticides, and, 'fungicides,', respectively])].
[sujeto(['Hepatocellular', carcinoma, is, strongly]), verbo([associated]), complemento([with, hepatitis, 'B', virus, carrier, patients, who, usually, have, 'HBV', sequences, integrated, in, the, chromosomal, 'DNA', of, liver, cells])].
[sujeto([',', the, 'enhancer)', on, expression, of, neighboring, host, genes, we]), verbo([have]), complemento([screened, for, cellular, genes, that, are, both, overexpressed, and, adjacent, to, integrated, 'HBV', sequences, in, hepatocellular, carcinoma, cells])].
[sujeto([coli, 'L-3', ribosomal, protein, which, is, thought, to, play, a, role, in, mRNA]), verbo([binding]), complemento([to, the, ribosome])].
[sujeto(['The', protein, encoded, by, the, cDNA, localizes, to, the, nucleolus, and, is, also]), verbo([found]), complemento([in, 'ribosomes;', possibly, it, is, the, mammalian, homologue, of, 'L-3', '(', 'MRL3)'])].
[sujeto(['Acquired', genes, encoding, efflux, 'pumps,', most, predominantly, 'mef(A)', +, 'msr(D)', in, 'pneumococci/streptococci', and, 'msr(A/B)', in, 'staphylococci,', also]), verbo([mediate]), complemento([resistance])].
[sujeto(['Drug-inactivating', mechanisms, include, phosphorylation, of, the, 2, '\'', -, hydroxyl, of, the, amino, sugar]), verbo([found]), complemento([at, position, 'C5', by, phosphotransferases, and, hydrolysis, of, the, macrocyclic, lactone, by, esterases])].
[sujeto(['These', acquired, genes, are]), verbo([regulated]), complemento([by, either, translation, or, transcription, 'attenuation,', largely, because, cells, are, less, fit, when, these, 'genes,', especially, the, rRNA, 'methyltransferases,', are, highly, induced, or, constitutively, expressed])].
[sujeto(['The', induction, of, gene, expression, is, cleverly, tied, to, the, mechanism, of, action, of, 'macrolides,', relying, on, 'antibiotic-bound', ribosomes, stalled, at, specific, sequences, of, nascent, polypeptides, to]), verbo([promote]), complemento([transcription, or, translation, of, downstream, sequences])].
[sujeto(['A', number, of, ribosomal, proteins, '(', 'RPs)']), verbo([have]), complemento([been, shown, to, play, a, critical, role, in, coordinating, ribosome, biogenesis, with, cell, growth, and, proliferation, by, suppressing, 'MDM2', to, induce, p53, activation])].
[sujeto(['While', how, the, 'MDM2-p53', pathway, is]), verbo([regulated]), complemento([by, multiple, 'RPs', is, 'unclear,', it, remains, to, be, interesting, to, identify, additional, 'RPs', that, can, regulate, this, pathway])].
[sujeto(['Here', we]), verbo([report]), complemento([that, ribosomal, protein, 'L4', '(', 'RPL4)', directly, interacts, with, 'MDM2', at, the, central, acidic, domain, and, suppresses, 'MDM2-mediated', p53, ubiquitination, and, 'degradation,', leading, to, p53, stabilization, and, activation])].
[sujeto(['Interestingly,', overexpression, of, 'RPL4']), verbo([promotes]), complemento([the, binding, of, 'MDM2', to, 'RPL5', and, 'RPL11', and, forms, a, complex, with, 'RPL5,', 'RPL11', and, 'MDM2', in, cells])].
[sujeto(['Conversely,', knockdown, of, 'RPL4', also]), verbo([induces]), complemento([p53, levels, and, 'p53-dependent', cell, cycle, arrest])].
[sujeto(['This', 'p53-dependent', effect]), verbo([requires]), complemento([both, 'RPL5', and, 'RPL11,', suggesting, that, depletion, of, 'RPL4', triggers, ribosomal, stress])].
[sujeto(['Together,', our, results]), verbo([reveal]), complemento([that, balanced, levels, of, 'RPL4', are, critical, for, normal, cell, growth, and, proliferation, via, regulating, the, 'MDM2-p53', loop])].
[sujeto(['We']), verbo([have]), complemento([now, found, that, 'EBNA1', binds, to, 'Ribosome', 'Protein', 'L4', '(', 'RPL4)'])].
[sujeto(['RPL4', shRNA, knockdown]), verbo([decreased]), complemento(['EBNA1', activation, of, an, oriP, luciferase, 'reporter,', 'EBNA1', 'DNA', binding, in, lymphoblastoid, cell, 'lines,', and, 'EBV', genome, number, per, lymphoblastoid, cell, line])].
[sujeto(['EBV', infection]), verbo([increased]), complemento(['RPL4', expression, and, redistributed, 'RPL4', to, cell, nuclei])].
[sujeto(['The', 'RPL4', 'N', terminus, cooperated, with, 'NCL-K429', to, support, 'EBNA1', and, 'oriP-mediated', episome]), verbo([binding]), complemento([and, 'maintenance,', whereas, the, 'NCL', 'C-terminal', 'K380', and, 'K393', induced, oriP, 'DNA', 'H3K4me2', modification, and, promoted, 'EBNA1', activation, of, 'oriP-dependent', transcription])].
[sujeto(['These', observations]), verbo([provide]), complemento([new, insights, into, the, mechanisms, by, which, 'EBV', uses, 'NCL', and, 'RPL4', to, establish, persistent, 'B-lymphoblastoid', cell, infection])].
[sujeto(['The', main, principles, underlying, the, making, of, ribosomes, are]), verbo([conserved]), complemento([across, eukaryotic, organisms, and, this, process, has, been, studied, in, most, detail, in, the, yeast, 'Saccharomyces', cerevisiae])].
[sujeto(['Due', to, the, high, abundance, and, difficult, physicochemical, properties, of, 'r-proteins,', their, correct, folding, and, 'fail-safe']), verbo([targeting]), complemento([to, the, assembly, site, depends, largely, on, 'general,', as, well, as, highly, 'specialized,', chaperone, and, transport, systems])].
[sujeto(['Many', 'r-proteins', contain, universally]), verbo([conserved]), complemento([or, 'eukaryote-specific', internal, loops, 'and/or', terminal, 'extensions,', which, were, shown, to, mediate, their, nuclear, targeting, and, association, with, dedicated, chaperones, in, a, growing, number, of, cases])].
[sujeto(['The', 60, 'S', 'r-protein', 'Rpl4', is, particularly, interesting, since, it, harbours, a]), verbo([conserved]), complemento([long, internal, loop, and, a, prominent, 'C-terminal', 'eukaryote-specific', extension])].
[sujeto(['Here', we, show, that, both, the, long, internal, loop, and, the, 'C-terminal', 'eukaryote-specific', extension, are, strictly]), verbo([required]), complemento([for, the, functionality, of, 'Rpl4'])].
[sujeto(['While', 'Rpl4', contains, at, least, five, distinct]), verbo([nuclear]), complemento([localization, signals, '(', 'NLS),', the, 'C-terminal', part, of, the, long, internal, loop, associates, with, a, specific, binding, 'partner,', termed, 'Acl4'])].
[sujeto(['Absence', of, 'Acl4']), verbo([confers]), complemento([a, severe, 'slow-growth', phenotype, and, a, deficiency, in, the, production, of, 60, 'S', subunits])].
[sujeto(['Notably,', 'Acl4', localizes, to, both, the, cytoplasm, and, nucleus, and, it]), verbo([has]), complemento([the, capacity, to, capture, nascent, 'Rpl4', in, a, 'co-translational', manner])].
[sujeto(['To', explore, the, potential, roles, of, 'VP3', in, the, interplay, of, 'IBDV', with, the, host, 'cell,', an, immunoprecipitation, '(', 'IP)-coupled', mass, spectra, '(', 'MS)', screening, was, performed, and, the, host, cellular, ribosomal, protein, 'L4', '(', 'RPL4)', was, identified, as, a, putative]), verbo([interacting]), complemento([partner, of, 'VP3', protein])].
[sujeto(['In', 'addition,', knockdown, of, 'RPL4', in, 'DF1', cells, resulted, in, reductions, of, the, viral, protein, pVP2, expression, and, the, virus, 'titers,', which]), verbo([reveals]), complemento([a, significant, role, of, 'RPL4', in, 'IBDV', replication])].
[sujeto(['Taken', 'together,', we, indicated, for, the, first, time, that, ribosomal, protein, 'L4', '(', 'RPL4)', was, an]), verbo([interacting]), complemento([partner, of, 'VP3', and, involved, in, the, modulation, of, 'IBDV', replication])].
[sujeto(['To']), verbo([ensure]), complemento([the, correct, interpretation, of, the, results, of, quantitative, 'real-time', reverse, 'transcription-polymerase', chain, reaction, '(', 'qRT-PCR)', from, ovarian, tissue, cryopreserved, by, 'vitrification,', it, is, critical, to, normalize, expression, levels, to, a, reference, gene, with, stable, messenger, 'RNA', '(', 'mRNA)', expression, in, the, 'vitrified/warmed', ovarian, tissue])].
[sujeto(['Eukaryotic', ribosome, biogenesis]), verbo([requires]), complemento([nuclear, import, and, hierarchical, incorporation, of, '∼80', ribosomal, proteins, '(', 'RPs)', into, the, ribosomal, 'RNA', core])].
[sujeto(['Here,', we, identify, assembly, chaperone, 'Acl4', that, initially]), verbo([binds]), complemento([the, universally, conserved, internal, loop, of, newly, synthesized, 'RpL4', via, its, superhelical, 'TPR', 'domain,', thereby, restricting, 'RpL4', loop, insertion, at, its, cognate, nascent, rRNA, site])].
[sujeto(['RpL4']), verbo([release]), complemento([from, 'Acl4', is, orchestrated, with, 'pre-ribosome', 'assembly,', during, which, the, 'eukaryote-specific', 'RpL4', extension, makes, several, distinct, interactions, with, the, 60, 'S', 'surface,', including, a, 'co-evolved', site, on, neighboring, 'RpL18'])].
[sujeto(['Dual', luciferase, reporter, systems, are, valuable, tools, for, functional, genomic, 'studies,', but]), verbo([have]), complemento([not, previously, been, developed, for, use, in, tick, cell, culture])].
[sujeto(['The', aim, of, the, study, was, to, develop, a, multiplex, 'real-time', 'PCR', method, to, identify, 'Campylobacter', jejuni, containing, mutations, commonly]), verbo([associated]), complemento([with, macrolide, resistance])].
[sujeto([jejuni, and, detect, the, gene, mutations]), verbo([associated]), complemento([with, macrolide, resistance])].
[sujeto(['This', method]), verbo([has]), complemento([a, potential, for, application, in, different, research, areas, and, molecular, surveillance])].
[sujeto(['Thermospermine']), verbo([acts]), complemento([in, negative, regulation, of, xylem, differentiation, and, its, deficient, mutant, of, 'Arabidopsis', 'thaliana,', acaulis5, '(', 'acl5),', shows, excessive, xylem, formation, and, severe, dwarfism])].
[sujeto(['Studies', of, two, dominant, suppressors, of, 'acl5,', 'sac51-d', and, 'sac52-d,']), verbo([have]), complemento([revealed, that, 'SAC51', and, 'SAC52', encode, a, transcription, factor, and, a, ribosomal, protein, 'L10', '(', 'RPL10),', 'respectively,', and, these, mutations, enhance, translation, of, the, 'SAC51', 'mRNA,', which, contains, conserved, upstream, open, reading, frames, in, the, 5, '\'', leader])].
[sujeto(['Here', we]), verbo([report]), complemento([identification, of, 'SAC53', and, 'SAC56', responsible, for, additional, suppressors, of, acl5])].
[sujeto(['sac53-d', is, a, 'semi-dominant', allele, of, the, gene, encoding, a, receptor, for]), verbo([activated]), complemento(['C', kinase, 1, '(', 'RACK1)', 'homolog,', a, component, of, the, 40, 'S', ribosomal, subunit])].
[sujeto(['Furthermore,', the, 'SAC51', 'mRNA,', which, may, be, a]), verbo([target]), complemento([of, 'nonsense-mediated', mRNA, 'decay,', was, found, to, be, stabilized, in, these, ribosomal, mutants, and, by, thermospermine])].
[sujeto(['These', ribosomal, proteins, are]), verbo([suggested]), complemento([to, act, in, the, control, of, 'uORF-mediated', translation, repression, of, 'SAC51,', which, is, derepressed, by, thermospermine])].
[sujeto(['Numerous', ribosomal, proteins]), verbo([have]), complemento([a, striking, bipartite, 'architecture:', a, globular, body, positioned, on, the, ribosomal, exterior, and, an, internal, loop, buried, deep, into, the, rRNA, core])].
[sujeto(['In', 'eukaryotes,', a, significant, number, of]), verbo([conserved]), complemento(['r-proteins', have, evolved, extra, 'amino-', or, 'carboxy-terminal', tail, 'sequences,', which, thread, across, the, 'solvent-exposed', surface])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([investigated, the, universally, conserved, internal, loop, and, the, 'eukaryote-specific', extensions, of, yeast, 'L4'])].
[sujeto(['We', show, that, in, contrast, to, findings, with, bacterial, 'L4,', deleting, the, internal, loop, of, yeast, 'L4']), verbo([causes]), complemento([severely, impaired, growth, and, reduced, levels, of, large, ribosomal, subunits])].
[sujeto(['We', further]), verbo([report]), complemento([that, while, depleting, the, entire, 'L4', protein, blocks, early, assembly, steps, in, 'yeast,', deletion, of, only, its, extended, internal, loop, affects, later, steps, in, 'assembly,', revealing, a, second, role, for, 'L4', during, ribosome, biogenesis])].
[sujeto(['Surprisingly,', deletion, of, the, entire, 'eukaryote-specific', 'carboxy-terminal', tail, of, 'L4']), verbo([has]), complemento([no, effect, on, 'viability,', production, of, 60, 'S', 'subunits,', or, translation])].
[sujeto(['These', unexpected, observations]), verbo([provide]), complemento([impetus, to, further, investigate, the, functions, of, ribosomal, protein, 'extensions,', especially, 'eukaryote-specific', 'examples,', in, ribosome, assembly, and, function])].
[sujeto(['Although', it]), verbo([has]), complemento([been, suggested, that, the, exit, tunnel, is, simply, a, convenient, route, of, egress, for, the, nascent, 'chain,', specific, protein, sequences, serve, to, slow, the, rate, of, 'translation,', suggesting, some, degree, of, interaction, between, the, nascent, peptide, chain, and, the, exit, tunnel])].
[sujeto(['To', understand, how, the, ribosome]), verbo([interacts]), complemento([with, nascent, peptide, 'sequences,', we, synthesized, and, characterized, a, novel, class, of, probe, molecules])].
[sujeto(['Biochemical', and, 'X-ray', structural, analyses, of, the, interactions, between, these, probes, and, the, ribosome]), verbo([reveal]), complemento([interesting, insights, about, the, exit, tunnel])].
[sujeto(['Using', translation, inhibition, and, 'RNA', structure, probing, 'assays,', we]), verbo([find]), complemento([the, exit, tunnel, has, a, relaxed, preference, for, the, directionality, '(', 'N', '→', 'C', or, 'C', '→', 'N', 'orientation)', of, the, nascent, peptides])].
[sujeto(['Moreover,', the, 'X-ray', crystal, structure, of, one, peptolide, derived, from, a, positively, 'charged,', reverse, 'Nuclear', 'Localization', 'Sequence', 'peptide,']), verbo([bound]), complemento([to, the, 70, 'S', bacterial, 'ribosome,', reveals, that, the, macrolide, ring, of, the, peptolide, binds, in, the, same, position, as, other, macrolides])].
[sujeto(['However,', the, peptide, tail, folds, over, the, macrolide, 'ring,', oriented, toward, the, peptidyl, transferase, center, and]), verbo([interacting]), complemento([in, a, novel, manner, with, 23, 'S', rRNA, residue, 'C2442', and, 'His69', of, ribosomal, protein, 'L4'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, these, peptolides, are, viable, probes, for, interrogating, nascent, 'peptide-exit', tunnel, interaction])].
[sujeto(['Genome-wide', ribosome, profiling, in, mammalian, cells]), verbo([reveals]), complemento([elevated, ribosome, density, at, the, start, codon, and, surprisingly, the, downstream, 5, th, codon, position, as, well])].
[sujeto(['We']), verbo([found]), complemento([that, the, highly, focused, ribosomal, pausing, shortly, after, initiation, is, attributed, to, the, geometry, of, the, exit, 'tunnel,', as, deletion, of, the, loop, region, from, ribosome, protein, 'L4', diminishes, translational, pausing, at, the, 5, th, codon, position])].
[sujeto(['Unexpectedly,', the, ribosome, variant, undergoes, translational, abandonment, shortly, after, 'initiation,']), verbo([suggesting]), complemento([that, there, exists, an, obligatory, step, between, initiation, and, elongation, commitment])].
[sujeto(['We', propose, that, the, 'post-initiation', pausing, of, ribosomes, represents, an, inherent, signature, of, the, translation, machinery, to]), verbo([ensure]), complemento([productive, translation])].
[sujeto(['Linezolid,', approved, for, clinical, use, since, 2000, ',']), verbo([has]), complemento([become, an, important, addition, to, the, 'anti-Gram-positive', infection, armamentarium])].
[sujeto(['This', oxazolidinone, drug]), verbo([has]), complemento([in, vitro, and, in, vivo, activity, against, essentially, all, 'Gram-positive', 'organisms,', including, 'methicillin-resistant', 'Staphylococcus', aureus, '(', 'MRSA)', and, 'vancomycin-resistant', enterococci, '(', 'VRE)'])].
[sujeto(['Emergence', of, resistance]), verbo([has]), complemento([been, limited, and, associated, with, invasive, 'procedures,', deep, organ, 'involvement,', presence, of, foreign, material, and, mainly, prolonged, therapy])].
[sujeto(['Non-susceptible', organisms, usually, demonstrate, alterations, in, the, 23, 'S', rRNA, 'target,', which, remain, the, main, resistance, mechanism, observed, in, 'enterococci;', although, a, few]), verbo([reports]), complemento([have, described, the, detection, of, 'cfr-mediated', resistance, in, 'Enterococcus', faecalis])].
[sujeto(['Most', isolates, harbour, 23, 'S', rRNA, 'mutations;', 'however,', 'cfr-carrying', 'MRSA', isolates]), verbo([have]), complemento([been, observed, in, the, 'United', 'States', and, elsewhere])].
[sujeto(['Surveillance', data]), verbo([have]), complemento([indicated, that, 'CoNS', 'isolates,', mainly, 'Staphylococcus', 'epidermidis,', currently, account, for, the, majority, of, 'Gram-positive', organisms, displaying, elevated, 'MIC', results, to, linezolid])].
[sujeto(['The', knowledge, acquired, during, the, past, decades, on, this, initially, used, oxazolidinone]), verbo([has]), complemento([been, utilized, for, developing, new, candidate, 'agents,', such, as, tedizolid, and, 'radezolid,', and, as, linezolid, patents, soon, begin, to, 'expire,', generic, brands, will, certainly, become, available])].
[sujeto(['In', 'addition,', all, the, mutants, selected, by, chloramphenicol, also, exhibited, the, 'G74D', modification, in, ribosomal, protein, 'L4,', which, was, previously, shown, to]), verbo([confer]), complemento([a, 'low-level', erythromycin, resistance, in, 'Campylobacter', species])].
[sujeto(['The', mutants, selected, by, florfenicol, did, not]), verbo([have]), complemento([the, 'G74D', mutation, in, 'L4'])].
[sujeto(['Notably,', the, 'amphenicol-resistant', mutants, also, exhibited, reduced, susceptibility, to, 'erythromycin,']), verbo([suggesting]), complemento([that, the, selection, resulted, in, cross, resistance, to, macrolides])].
[sujeto(['Streptococcus', pneumoniae, is, an, important]), verbo([cause]), complemento([of, bacterial, meningitis, and, pneumonia, but, usually, colonizes, the, human, nasopharynx, harmlessly])].
[sujeto(['pneumoniae,', 'AliB-like', 'ORF', 1, and, 'ORF', 2, ',']), verbo([bind]), complemento([specifically, to, peptides, matching, other, species, resulting, in, changes, in, the, pneumococci])].
[sujeto(['AliB-like', 'ORF', 1]), verbo([binds]), complemento([specifically, peptide, 'SETTFGRDFN,', matching, 50, 'S', ribosomal, subunit, protein, 'L4', of, 'Enterobacteriaceae,', and, facilitates, upregulation, of, competence, for, genetic, transformation])].
[sujeto(['AliB-like', 'ORF', 2]), verbo([binds]), complemento([specifically, peptides, containing, sequence, 'FPPQS,', matching, proteins, of, 'Prevotella', species, common, in, healthy, human, nasopharyngeal, microbiota])].
[sujeto(['We']), verbo([found]), complemento([that, 'AliB-like', 'ORF', 2, mediates, the, early, phase, of, nasopharyngeal, colonization, in, vivo])].
[sujeto([pneumoniae, to]), verbo([bind]), complemento([and, respond, to, peptides, of, other, bacterial, species, occupying, the, same, host, niche, may, play, a, key, role, in, adaptation, to, its, environment, and, in, interspecies, communication])].
[sujeto(['These', findings]), verbo([reveal]), complemento([a, completely, new, concept, of, pneumococcal, interspecies, communication, which, may, have, implications, for, communication, between, other, bacterial, species, and, for, future, interventional, therapeutics])].
[sujeto(['Quantitative', 'RT-PCR', analysis, indicated, their, expression, during, the, mid, to, late, 'G1', 'phase,', whereas, the, rRNA, genes, were]), verbo([expressed]), complemento([during, the, early, 'G1', phase, of, the, cell, cycle])].
[sujeto(['The', promoter, reporter, analysis, of, the, 'RPS27a', gene, revealed, that, it, could, be, synergistically]), verbo([stimulated]), complemento([by, the, transcription, factors, specificity, protein, 1, '(', 'Sp1)', and, cAMP, response, 'element-binding', protein, '(', 'CREB)'])].
[sujeto(['However,', 'E2F', transcription, factor, 1, '(', 'E2F1)', appeared, to, negatively]), verbo([regulate]), complemento([gene, expression])].
[sujeto(['Although', 'Sp1', and, 'CREB']), verbo([binding]), complemento([enhanced, the, promoter, occupancy, of, histone, acetyltransferases, 'PCAF,', p300, and, 'CREB', binding, 'protein,', 'E2F1', facilitated, the, recruitment, of, histone, deacetylases])].
[sujeto(['Both', acetylation, '(', histone, 'H4', 'pan-acetyl,', histone, 'H3', acetyl, 'Lys', 14, ')', and, methylation, '(', histone, 'H3', trimethyl, 'Lys', 9, ')', marks, were, observed, in, the, 'RPS27a', promoter, 'region,']), verbo([suggesting]), complemento([their, important, regulatory, role, in, gene, expression])].
[sujeto(['Domains', 'II', and, 'V', of, the, 23, 'S', rRNA, gene, and, the, ribosomal, protein, 'L4', and, 'L22', 'genes,', both, of, which, are, considered, to, be]), verbo([associated]), complemento([with, macrolide, 'resistance,', were, sequenced, and, the, sequences, were, compared, with, the, corresponding, sequences, in, 'M129', registered, with, 'NCBI', and, the, 'FH', strain])].
[sujeto(['Site', mutations, of, 'L4', or, 'L22', can, be, observed, in, either, resistant, or, sensitive, 'strains,', although, it, is, not, known, whether, this, is]), verbo([associated]), complemento([with, drug, resistance])].
[sujeto(['In', this, 'work,', we]), verbo([have]), complemento([investigated, regulatory, functions, of, ribosomal, protein, 'L4', of, the, thermophilic, archaea, 'Methanococcus', jannaschii])].
[sujeto(['We']), verbo([have]), complemento([shown, that, 'MjaL4', and, its, mutant, form, lacking, an, elongated, loop, specifically, inhibit, expression, of, the, first, gene, of, the, 'S10-like', operon, from, the, same, organism, in, a, coupled, 'transcription-translation', system, in, vitro])].
[sujeto(['By', deletion, 'analysis,', an, 'L4-binding', regulatory, site]), verbo([has]), complemento([been, found, on, 'MjaL3', 'mRNA,', and, a, fragment, of, mRNA, with, length, of, 40, nucleotides, has, been, prepared, that, is, necessary, and, sufficient, for, the, specific, interaction, with, the, 'MjaL4', protein])].
[sujeto(['Linezolid']), verbo([binds]), complemento([ribosomal, proteins, where, structural, changes, within, its, target, site, may, confer, resistance])].
[sujeto(['Our', study, identified, mutations, and, deletions, near, the, linezolid]), verbo([binding]), complemento([pocket, of, two, of, these, strains, within, the, rplD, 'gene,', which, encodes, ribosomal, protein, 'L4'])].
[sujeto(['Human', babesiosis]), verbo([caused]), complemento([by, 'Babesia', microti, is, an, emerging, 'tick-borne', zoonosis, of, increasing, importance, due, to, its, rising, incidence, and, expanding, geographic, 'range(1)'])].
[sujeto(['Infection', with, this, 'organism,', an, intraerythrocytic, parasite, of, the, phylum, 'Apicomplexa,']), verbo([causes]), complemento([a, febrile, syndrome, similar, to, 'malaria(2)'])].
[sujeto(['Relapsing', disease, is, common, among, immunocompromised, and, asplenic, 'individuals(3,4)', and, drug, resistance]), verbo([has]), complemento([recently, been, 'reported(5)'])].
[sujeto(['We', identify, parasite, variants, that]), verbo([associate]), complemento([with, relapsing, 'disease,', including, amino, acid, substitutions, in, the, 'atovaquone-binding', regions, of, cytochrome, b, '(', 'cytb)', and, the, 'azithromycin-binding', region, of, ribosomal, protein, subunit, 'L4', '(', 'rpl4)'])].
[sujeto(['microti,']), verbo([suggest]), complemento([possible, mechanisms, for, clinical, 'relapse,', and, create, the, foundation, for, further, research, on, this, emerging, pathogen])].
[sujeto(['The', present, analysis]), verbo([has]), complemento([provided, evidence, that, 'RPL4,', 'EEF1A1,', 'GAPDH', and, 'ACTB', could, probably, act, as, most, suitable, genes, for, normalizing, the, transcriptional, data, of, 'milk-derived', mammary, epithelial, cells, of, 'Indian', cows])].
[sujeto(['Duplicate', genes, within, a, family, are, often, necessary, to]), verbo([provide]), complemento([a, threshold, dose, of, a, ribosomal, protein, but, in, some, instances, appear, to, have, 'non-redundant', functions])].
[sujeto(['Here,', we, addressed, whether, divergent, members, of, the, 'RPL9', gene, family, are, dosage, sensitive, or, whether, these, genes]), verbo([have]), complemento(['non-overlapping', functions])].
[sujeto(['Mutations', in, 'RPL9C', and, 'RPL9D', genes]), verbo([lead]), complemento([to, delayed, growth, early, in, 'development,', and, loss, of, both, genes, is, embryo, 'lethal,', indicating, that, these, are, 'dosage-sensitive', and, redundant, genes])].
[sujeto(['Phylogenetic', analysis, of, 'RPL9', as, well, as, 'RPL4,', 'RPL5,', 'RPL27a,', 'RPL36a,', and, 'RPS6', family, genes, in, the, 'Brassicaceae', indicated, that, multicopy, ribosomal, protein, genes]), verbo([have]), complemento([been, largely, retained, following, whole, genome, duplication])].
[sujeto(['Furthermore,', phylogenetic, analysis, of, 'RPL9', genes, in, angiosperm, species, showed, that, genes, within, a, species, are, more, closely, related, to, each, other, than, to, 'RPL9', genes, in, other, 'species,']), verbo([suggesting]), complemento([ribosomal, protein, genes, undergo, convergent, evolution])].
[sujeto(['Identification', of, genes, differentially]), verbo([expressed]), complemento([in, 'mechano-biological', pathways, in, articular, cartilage, provides, insight, into, the, molecular, mechanisms, behind, initiation, 'and/or', progression, of, osteoarthritis, '(', 'OA)'])].
[sujeto(['Butyl', benzyl, phthalate, '(', 'BBP)', is, a, ubiquitous, contaminant, whose, presence, in, the, environment, is, expected, for, 'decades,', since, it]), verbo([has]), complemento([been, extensively, used, worldwide, as, a, plasticizer, in, the, polyvinyl, chloride, '(', 'PVC)', industry, and, the, manufacturing, of, many, other, products])].
[sujeto(['In', the, present, 'study,', the, interaction, of, 'BBP', with, the, ribosome, biogenesis, pathway, and, the, general, transcriptional, profile, of, 'Chironomus', riparius, aquatic, larvae, were, investigated, by, means, of, changes, in, the, rDNA, activity, '(', through, the, study, of, the, internal]), verbo([transcribed]), complemento([spacer, 2, ',', 'ITS2)', and, variations, in, the, expression, profile, of, ribosomal, protein, genes, '(', 'rpL4,', 'rpL11,', and, 'rpL13)', after, acute, 24, -, h, and, 48, -, h, exposures, to, a, wide, range, of, 'BBP', doses])].
[sujeto(['BBP']), verbo([caused]), complemento([a, dose, and, 'time-dependent', toxicity, in, most, of, the, selected, 'biomarkers,', with, a, general, depletion, in, the, gene, expression, levels, and, the, activity, of, 'BR2', after, 48, -, h, treatments])].
[sujeto(['These', data]), verbo([provide]), complemento([the, first, evidence, on, the, interaction, of, 'BBP', with, the, ribosome, synthesis, 'pathways,', which, results, in, a, significant, impairment, of, the, functional, activity, of, ribosomal, protein, genes])].
[sujeto(['These', findings, may]), verbo([have]), complemento([important, implications, for, understanding, the, adverse, biological, effects, of, 'BBP', in, 'C'])].
[sujeto([&, 'nbsp;riparius,', since, they]), verbo([provide]), complemento([new, sensitive, biomarkers, of, 'BBP', exposure, and, highlight, the, suitability, of, this, organism, for, ecotoxicological, risk, 'assessment,', especially, in, aquatic, ecosystems])].
[sujeto(['To', study, gene, expression, and, to, determine, distinctive, characteristics, of, embryos, produced, by, different, 'methods,', normalisation, of, the, 'gene(s)', of, interest, against, reference, 'gene(s)']), verbo([has]), complemento([commonly, been, employed])].
[sujeto(['Therefore,', the, present, study, aimed, to, assess, which, reference, genes, tend, to]), verbo([express]), complemento([more, stably, in, single, porcine, blastocysts, produced, in, vivo, '(', 'IVO)', or, by, parthenogenetic, activation, '(', 'PA),', in, vitro, fertilisation, '(', 'IVF)', and, somatic, cell, nuclear, transfer, '(', 'SCNT)', using, different, analysis, 'programs,', namely, 'geNorm,', 'Normfinder', and, 'Bestkeeper'])].
[sujeto(['In', 'conclusion,', 'SDHA', and, 'H2A', were, determined, as, the, most, appropriate, reference, genes, for, reliable, normalisation, in, order, to]), verbo([find]), complemento([the, comparative, gene, expression, in, porcine, blastocysts, produced, by, different, 'methods,', whereas, 18, 'S', was, regarded, as, a, 'less-stable', reference, gene])].
[sujeto(['The', present, study]), verbo([has]), complemento([evaluated, the, stability, of, commonly, used, reference, genes, for, accurate, normalisation, in, porcine, embryos, to, obtain, reliable, results])].
[sujeto(['The', bovine, viral, diarrhea, virus, '(', 'BVDV)']), verbo([causes]), complemento([significant, economic, losses, to, the, dairy, industry, 'worldwide,', and, understanding, its, infection, mechanisms, would, be, extremely, useful, in, designing, new, and, efficient, treatments])].
[sujeto(['qRT-PCR']), verbo([provides]), complemento([a, sensitive, platform, to, conduct, such, gene, expression, 'analyses,', but, suitable, housekeeping, genes, are, needed, for, accurate, transcript, normalization])].
[sujeto([8, are, both]), verbo([involved]), complemento([in, bone, cancer, 'pain,', the, present, study, was, designed, to, investigate, whether, crosstalk, between, the, 'LPA', receptor, 'LPA1', '(', also, known, as, 'EDG2)', and, 'Nav1'])].
[sujeto(['We', showed, that, the, 'EDG2', antagonist, 'Ki16198', blocked, the, mechanical, allodynia]), verbo([induced]), complemento([by, intrathecal, 'LPA', in, naïve, rats, and, attenuated, mechanical, allodynia, in, a, rat, model, of, bone, cancer])].
[sujeto([8, expression, in, ipsilateral, 'L4-6', 'DRGs']), verbo([increased]), complemento([with, the, development, of, bone, cancer])].
[sujeto([8, and, 'LPA', remarkably]), verbo([enhanced]), complemento(['Nav1'])].
[sujeto(['Conquering', postoperative, pain, which]), verbo([has]), complemento([significant, impact, on, the, surgery, outcome, can, be, challenging, for, the, clinicians])].
[sujeto(['Rescue', analgesia, was]), verbo([provided]), complemento([with, using, 'Inj'])].
[sujeto(['Time', for, rescue, analgesia, '(', 'VAS', score, &, 'gt;3)', was, significantly]), verbo([increased]), complemento([in, 'Group', 'P', than, in, 'Group', 'C'])].
[sujeto(['The', total, dose, of, diclofenac]), verbo([required]), complemento([in, the, 24, hour, postoperative, period, was, significantly, lower, in, 'Group', 'P', than, in, 'Group', 'C'])].
[sujeto(['This', paper, presents, a, highly, challenging, technique]), verbo([involving]), complemento([posterior, double, vertebral, column, resections, '(', 'VCRs)', and, satellite, rods, placement])].
[sujeto(['In', 'conclusion,', double, 'VCRs', are, effective, to, correct, severe, angular, 'kyphosis,', and, addition, of, satellite, rods, may, be, imperative, to]), verbo([enhance]), complemento([instrumentation, strength, and, thus, prevent, correction, loss])].
[sujeto(['Detailed', understanding, of, encapsulation, events, is]), verbo([required]), complemento([to, facilitate, functional, molecular, encapsulation])].
[sujeto(['The', individual, guests, are, not, 'encapsulated,']), verbo([suggesting]), complemento([that, only, the, pair, of, guests, can, fill, the, void, of, the, cage])].
[sujeto(['This', principle, is, demonstrated, by, 'co-encapsulation', of, a, variety, of, combinations, of, metal, complexes, and, aromatic, 'guests,']), verbo([leading]), complemento([to, several, ternary, complexes])].
[sujeto(['Moreover,', selective, exchange, of, the, components, is, 'possible,']), verbo([leading]), complemento([to, formation, of, the, most, favorable, complex])].
[sujeto(['A', change, in, the, oxidation, potential, of, the, encapsulated, electron, donor, also]), verbo([leads]), complemento([to, a, shift, in, the, 'charge-transfer', energy, bands])].
[sujeto(['These', subtle, energy, differences, may, potentially, be, used, to, control, the]), verbo([binding]), complemento([and, reactivity, of, the, complexes, bound, in, a, confined, space])].
[sujeto(['Multivariate', analysis, revealed, that, the, 'PS', 'MCSA', at, 'L4-L5', was, an, independent, factor, for]), verbo([decreased]), complemento([possibility, of, nonfusion, status, in, both, segments, '(', 'OR=0'])].
[sujeto(['Between', 2011, and, 2014, ',', a, total, of, 84, subjects, with, 'L5-DS', were, enrolled, in, the, 'DLS', 'group,', and, 56, healthy, volunteers, were]), verbo([recruited]), complemento([to, the, control, group])].
[sujeto([22, ')', were, identified, as, being]), verbo([associated]), complemento([with, the, 'DLS', group, by, multiple, logistic, regression, analysis])].
[sujeto(['In', this, 'study,', 'SS,', 'LL,', 'PI,', and, a, more, sagittal, 'FJA', were, proven, to, be, risk, factors, for, 'L5-DS,', whereas, 'L5-VS', was]), verbo([found]), complemento([to, be, a, likely, protective, factor, against, 'L5-DS'])].
[sujeto(['This', demonstrates, that, sarcopenia, as, measured, by, psoas, muscle, area, is]), verbo([associated]), complemento([with, increased, composite, length, of, stay, and, mortality, after, 'LVAD', implantation, and, may, serve, as, correlate, for, frailty])].
[sujeto(['In', 'addition,', few, studies]), verbo([have]), complemento([reported, the, outcome, of, surgeries, for, plantar, hyperhidrosis])].
[sujeto(['Limited', 'video-assisted', 'LSB', using, clip]), verbo([provided]), complemento([good, results, with, minimal, complications, and, low, compensatory, 'hidrosis,', contrary, to, the, prejudice, toward, it])].
[sujeto(['We']), verbo([reveal]), complemento([here, by, electron, microscopy, that, the, architecture, of, 'CNTNAP2', is, composed, of, a, 'large,', 'medium,', and, small, lobe, that, flex, with, respect, to, each, other])].
[sujeto(['Our', data]), verbo([reveal]), complemento([that, 'CNTNAP2', has, a, very, different, architecture, compared, to, neurexin, 1, 'alpha,', a, fellow, member, of, the, neurexin, superfamily, and, a, 'prototype,', suggesting, that, 'CNTNAP2', uses, a, different, strategy, to, integrate, into, the, synaptic, protein, network])].
[sujeto(['We', show, that, the, ectodomains, of, 'CNTNAP2', and, contactin, 2, '(', 'CNTN2)']), verbo([bind]), complemento([directly, and, 'specifically,', with, low, nanomolar, affinity])].
[sujeto(['Within', this, 'period,', 'whisker-evoked', activity, of, neurons, displayed, a, general]), verbo([decrease]), complemento([in, layer, 2, /, 3, '(', 'L2/3)', and, 'L4,', but, increased, in, 'L5', and, 'L6'])].
[sujeto(['For', superficial, layers, we, confirmed, this]), verbo([finding]), complemento([using, calcium, imaging, of, 'L2/3', 'neurons,', which, also, exhibited, emergence, of, response, selectivity, as, well, as, progressive, sparsification, and, decorrelation, of, evoked, responses, around, 'P14'])].
[sujeto(['This', results]), verbo([suggests]), complemento([that, the, 'VR-VI', response, rate, difference, is, not, an, indication, of, a, difference, in, the, overall, tendency, to, respond, but, it, is, rather, a, difference, in, terms, of, what, types, of, response, patterns, are, engendered, between, the, two, schedules])].
[sujeto(['This', study]), verbo([involved]), complemento([an, extensive, analysis, of, published, research, on, the, morphology, of, the, temporalis, muscle, in, order, to, provide, an, anatomical, guideline, on, how, to, distinguish, the, temporalis, muscle, and, temporalis, tendon, by, observing, the, surface, of, the, 'patient\'s', face])].
[sujeto(['This', will]), verbo([ensure]), complemento([that, the, muscle, region, is, targeted, and, so, produce, the, greatest, clinical, effect, with, the, minimum, concentration, of, 'BoNT-A'])].
[sujeto(['Synovial', cysts, are, a]), verbo([cause]), complemento([of, 'radiculopathy/neurogenic', claudication])].
[sujeto(['Spinal', cysts, are, commonly]), verbo([found]), complemento([at, the, 'L4-L5', level])].
[sujeto(['The', results, showed, that, the, correlation, between, 'APF', and, 'BMD', was, better, than, the, correlation, among, 'PF,', 'FB', and, 'BMD,', and, 'APF']), verbo([have]), complemento([a, significant, correlation, with, 'BMD'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, ultrasonic, power, spectrum, may, contain, substantial, information, not, already, contained, in, 'BUA', and, 'SOS'])].
[sujeto(['Sarcopenia', is]), verbo([associated]), complemento([with, a, poor, prognosis, in, the, 'ICU'])].
[sujeto(['Using', 'Pearson\'s', correlation, 'coefficient,', serum, 'creatinine-to-serum', cystatin, 'C', ratio, was]), verbo([found]), complemento([to, be, the, best, performer, in, the, estimation, of, muscle, mass])].
[sujeto(['The', sarcopenia, index, is, a, fair, measure, for, muscle, mass, estimation, among, 'ICU', patients, and, can, modestly, predict, hospital, and, 90, -, day, mortality, among, patients, who, do, not]), verbo([have]), complemento([acute, kidney, injury, at, the, time, of, measurement])].
[sujeto(['The', steppe, climate]), verbo([has]), complemento([cold, winters, and, hot, and, dry, summers])].
[sujeto(['The', dynamics, of, infection, observed, here, '(', highest, faecal, egg, count, in, 'August)', and, the, stage, composition, of, worm, burden, '(', highest, percentage, of, 'L4', in, 'June)']), verbo([provide]), complemento([strong, evidence, that, arrested, development, had, occurred])].
[sujeto(['The', patient, was, hit, by, a, 'car;']), verbo([he]), complemento([suffered, a, fracture, of, the, iliac, ala, with, a, complete, traumatic, damage, to, the, 'L4-L5', nerve, roots])].
[sujeto(['Impairment', of, the, fibrinolytic, 'system,', mostly, due, to, elevated, plasma, levels, of, plasminogen, activator, inhibitor, 1, '(', 'PAI-1),', is, often]), verbo([associated]), complemento([with, metabolic, disorders, such, as, diabetes, mellitus, and, 'insulin-resistance', syndrome])].
[sujeto(['Moreover,', 'insulin,', as, we]), verbo([have]), complemento([previously, 'shown,', directly, stimulates, 'PAI-1', production, with, a, mechanism, underlying, a, complex, signaling, network, which, ultimately, leads, to, 'ERK', activation])].
[sujeto(['In', this, study, we]), verbo([have]), complemento([analyzed, the, effects, of, agonists, of, the, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)', alpha, and, gamma, on, 'PAI-1', biosynthesis, in, 'HepG2', cells, in, the, presence, or, absence, of, insulin])].
[sujeto(['The', high, affinity, 'PPARalpha', 'agonist,', 'Wy-14,643,']), verbo([increased]), complemento([basal, and, 'insulin-stimulated', 'PAI-1', antigen, release, with, a, mechanism, involving, gene, transcription])].
[sujeto(['Wy-L4,643']), verbo([increases]), complemento([phosphorylation, of, 'ERK', and, p38, in, a, 'time-dependent', manner, without, affecting, that, of, 'SAPK/JNK', or, 'ERK5'])].
[sujeto(['Moreover,', the, 'MEK', '(', 'ERK', 'kinase)', 'inhibitors,', 'PD98059', and, 'UO126,', completely]), verbo([prevented]), complemento(['PAI-1', induction, by, 'Wy-14,643', without, inhibiting, the, activation, of, a, reporter, gene, carrying, the, 'PPRE', element])].
[sujeto(['Interestingly,', the, addition, of, p38, inhibitor, followed, by, insulin, and, 'Wy-14,643', resulted, in, a, greater, than, additive, stimulation, of, 'PAI-1', secretion]), verbo([acting]), complemento([through, 'ERK1/2', phosphorylation])].
[sujeto(['In', 'contrast,', the, synthetic, 'PPARgamma', 'agonist,', 'rosiglitazone,', did, not, change, 'PAI-1', 'level,', although, this, compound]), verbo([induced]), complemento([transcription, from, the, 'PPRE-driven', luciferase, reporter, construct])].
[sujeto(['In', 'conclusion,', 'Wy-14,643']), verbo([induces]), complemento(['PAI-1', gene, 'expression,', in, the, presence, or, absence, of, 'insulin,', with, a, mechanism, which, is, independent, on, 'PPARalpha', activation, and, requires, signaling, through, the, 'ERK1/2', signaling, pathway])].
[sujeto(['Severe', outbreaks, of, 'Phytophthora', fruit, rot, on, 'brinjal,', ridge, gourd, and, tomato]), verbo([have]), complemento([been, observed, since, 2011, in, 'Andhra', 'Pradesh,', 'Karnataka,', 'Telangana', and, 'Tamil', 'Nadu', states, of, 'India'])].
[sujeto(['In', 'addition,', isolates, were, genotyped, for, three, mitochondrial, '[', ribosomal, protein, 'L5', -, small, subunit, ribosomal, 'RNA', '(', 'rpl5-rns),', small, subunit, ribosomal, 'RNA', -, cytochrome, c, oxidase, subunit, 2, '(', 'rns-cox2)', and, 'cox2+spacer]', and, three]), verbo([nuclear]), complemento([loci, '[', hypothetical, protein, '(', 'hyp),', 'scp-like', extracellular, protein, '(', 'scp)', and, 'beta-tubulin', '(', 'β-tub)]'])].
[sujeto(['All', regions, were, polymorphic, but]), verbo([nuclear]), complemento([regions, were, more, variable, than, mitochondrial, regions])].
[sujeto(['The', network, analysis, of, genotypes, using, the, combined, dataset, of, three]), verbo([nuclear]), complemento([regions, revealed, a, host, specific, association])].
[sujeto(['nicotianae,']), verbo([leading]), complemento([to, identification, of, host, specific, lineages, responsible, for, severe, outbreaks, on, 'brinjal,', ridge, gourd, and, tomato])].
[sujeto(['Two-dimensional', differential, gel, electrophoresis, was, applied, to, identify, proteins, that, were, differentially]), verbo([expressed]), complemento([in, 'fluconazole-susceptible', and, 'fluconazole-resistant', isolates, of, 'C'])].
[sujeto(['Eight', proteins, including, 'aspartyl-tRNA', 'synthetase,', translation, elongation, factor, 3, ',', 3, -, phosphoglycerate, 'kinase,', ribosomal, protein, 'L5,', coproporphyrinogen, 'III', 'oxidase,', pyruvate, 'kinase,', 'G-beta', like, 'protein,', and, 'F1F0-ATPase', alpha, subunit, were]), verbo([found]), complemento([to, be, more, abundantly, 'represented,', while, four, proteins, including, vitamin, 'B12-(cobalamin)-independent', isozyme, of, methionine, 'synthase,', 'microtubule-associated', 'protein,', adenylosuccinate, 'synthetase,', and, aldose, reductase, were, found, to, be, less, abundantly, represented, in, 'fluconazole-resistant', strains, versus, those, with, 'fluconazole-susceptible', ones])].
[sujeto(['These', differentially]), verbo([expressed]), complemento([proteins, were, primarily, associated, with, energy, 'metabolism,', stress, 'response,', and, macromolecule, synthesis])].
[sujeto(['Proteins']), verbo([associated]), complemento([with, energy, 'metabolism,', stress, 'response,', and, macromolecule, synthesis, may, play, a, role, in, the, development, of, fluconazole, resistance, in, the, clinical, isolates, of, 'C'])].
[sujeto(['Multiple', different, mechanisms, are]), verbo([involved]), complemento([in, the, development, of, fluconazole, resistance, in, 'C'])].
[sujeto(['These', findings]), verbo([provide]), complemento([a, scientific, basis, for, discovering, new, genes, and, mechanisms, associated, with, fluconazole, resistance, in, 'C'])].
[sujeto(['Here,', we, show, that, the, 5, 'S', 'RNP', contributes, to, p53, activation, and]), verbo([promotes]), complemento([cellular, senescence, in, response, to, oncogenic, or, replicative, stress])].
[sujeto(['Oncogenic', stress, accelerates, rRNA, transcription, and, replicative, stress, delays, rRNA, 'processing,', resulting, in, 'RPL11', and, 'RPL5', accumulation, in, the, 'ribosome-free', 'fraction,', where, they]), verbo([bind]), complemento(['MDM2'])].
[sujeto(['Experimental', upregulation, of, rRNA, transcription, or, downregulation, of, rRNA, 'processing,', mimicking, the, nucleolus, under, oncogenic, or, replicative, 'stress,', 'respectively,', also]), verbo([induces]), complemento(['RPL11-mediated', p53, activation, and, cellular, senescence])].
[sujeto(['We', demonstrate, that, exogenous, expression, of, certain, 'rRNA-processing', factors, rescues, the, processing, 'defect,', attenuates, p53, 'accumulation,', and]), verbo([increases]), complemento([replicative, lifespan])].
[sujeto(['It', significantly, ameliorates, clinical, manifestations, in, autoimmune, patients, with, systemic, lupus, erythematosus, and]), verbo([enhances]), complemento([survival, in, 'MRL/lpr', 'lupus-prone', mice])].
[sujeto(['We', now, identify, 'chaperone-mediated', autophagy, '(', 'CMA)', as, a]), verbo([target]), complemento([of, 'P140', and, demonstrate, that, its, inhibitory, effect, on, 'CMA', is, likely, tied, to, its, ability, to, alter, the, composition, of, 'HSPA8/HSC70', heterocomplexes])].
[sujeto(['As', in, the, case, of, 'HSPA8,', expression, of, the, limiting, 'CMA', component, 'LAMP2A,', which, is]), verbo([increased]), complemento([in, 'MRL/lpr', 'B', 'cells,', is, downregulated, after, 'P140', treatment])].
[sujeto(['This', dual, effect, may, interfere, with, the, endogenous, autoantigen, processing, and, loading, to, major, histocompatibility, complex, class, 'II', molecules, and, as, a, 'consequence,']), verbo([lead]), complemento([to, lower, activation, of, autoreactive, 'T', cells])].
[sujeto(['These', results, shed, light, on, mechanisms, by, which, 'P140', can]), verbo([modulate]), complemento([lupus, disease, and, exert, its, tolerogenic, activity, in, patients])].
[sujeto(['Previously,', we, showed, that, inauhzin, '(', 'INZ)']), verbo([activates]), complemento([p53, and, inhibits, tumor, growth])].
[sujeto(['However,', whether, 'INZ', could]), verbo([suppress]), complemento([cancer, cell, growth, independently, of, p53, activity, is, still, elusive])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, 'INZ(c),', a, second, generation, of, 'INZ,', suppresses, 'c-Myc', activity, and, thus, inhibits, growth, of, human, lymphoma, cells, in, a, 'p53-independent', manner])].
[sujeto(['INZ(c)', treatment]), verbo([decreased]), complemento(['c-Myc', expression, at, both, mRNA, and, protein, 'level,', and, suppressed, 'c-Myc', transcriptional, activity, in, human, 'Burkitt\'s', lymphoma, 'Raji', cells, with, mutant, p53])].
[sujeto(['Also,', we, showed, that, overexpressing, ectopic, 'c-Myc', rescues, the, inhibition, of, cell, proliferation, by, 'INZ(c)', in, 'Raji', 'cells,', implicating, 'c-Myc', activity, is]), verbo([targeted]), complemento([by, 'INZ(c)'])].
[sujeto(['Interestingly,', the, effect, of, 'INZ(c)', on, 'c-Myc', expression, was, impaired, by, disrupting, the]), verbo([targeting]), complemento([of, 'c-Myc', mRNA, by, miRNAs, via, knockdown, of, ribosomal, protein, '(', 'RP)', 'L5,', 'RPL11,', or, 'Ago2,', a, subunit, of, 'RISC', 'complex,', indicating, that, 'INZ(c)', targets, 'c-Myc', via, miRNA, pathways])].
[sujeto(['These', results]), verbo([reveal]), complemento([a, new, mechanism, that, 'INZ', 'The', '\'', ribosomal, stress, '(', 'RS)-p53', 'pathway\'', is, triggered, by, any, stressor, or, genetic, alteration, that, disrupts, ribosomal, 'biogenesis,', and, mediated, by, several, ribosomal, proteins, '(', 'RPs),', such, as, 'RPL11', and, 'RPL5,', which, inhibit, 'MDM2', and, activate, p53])].
[sujeto(['Inosine', monophosphate, '(', 'IMP)', dehydrogenase, 2, '(', 'IMPDH2)', is, a, 'rate-limiting', enzyme, in, de, novo, guanine, nucleotide, biosynthesis, and, crucial, for]), verbo([maintaining]), complemento([cellular, guanine, 'deoxy-', and, ribonucleotide, pools, needed, for, 'DNA', and, 'RNA', synthesis])].
[sujeto(['It', is, highly]), verbo([expressed]), complemento([in, many, malignancies])].
[sujeto(['We', previously, showed, that, inhibition, of, 'IMPDH2']), verbo([leads]), complemento([to, p53, activation, by, causing, 'RS'])].
[sujeto(['Surprisingly,', our, current, study]), verbo([reveals]), complemento([that, 'Inauzhin', '(', 'INZ),', a, novel, 'non-genotoxic', p53, activator, by, inhibiting, 'SIRT1,', can, also, inhibit, cellular, 'IMPDH2', 'activity,', and, reduce, the, levels, of, cellular, 'GTP', and, 'GTP-binding', nucleostemin, that, is, essential, for, rRNA, processing])].
[sujeto(['Consequently,', 'INZ']), verbo([induces]), complemento(['RS', and, the, 'RPL11/RPL5-MDM2', 'interaction,', activating, p53])].
[sujeto(['These', results, support, the, new, notion, that, 'INZ']), verbo([suppresses]), complemento([cancer, cell, growth, by, dually, targeting, 'SIRT1', and, 'IMPDH2'])].
[sujeto(['Diamond', 'Blackfan', 'Anemia', '(', 'DBA)', is, a, rare, 'congenital,', bone, marrow, failure, syndrome, characterized, by, normochromic, macrocytic, 'anemia,', reticulocytopenia, and, absence, or, insufficiency, of, erythroid, precursors, in, normocellular, bone, 'marrow,', frequently]), verbo([associated]), complemento([with, somatic, malformations])].
[sujeto(['Six', patients, '(', 35.2, '%', ')', were]), verbo([found]), complemento([to, carry, mutations, on, either, the, 'RPS19', gene, '(', three, 'patients,)', or, the, 'RPL5', gene, '(', three, 'patients)'])].
[sujeto(['The', occurrence, of, thyroid, carcinoma, in, an, adult, patient, with, 'DBA', is, the, first, to, be]), verbo([reported]), complemento([in, 'DBA'])].
[sujeto(['Ribosome', biogenesis, can]), verbo([modulate]), complemento([protein, 'synthesis,', a, process, heavily, relied, upon, for, cancer, cell, proliferation])].
[sujeto(['In', this, 'study,', involvement, of, large, subunit, ribosomal, proteins, '(', 'RPLs)', in, melanoma]), verbo([has]), complemento([been, dissected, and, 'RPLs', categorized, based, on, modulation, of, cell, proliferation, and, therapeutic, targeting, potential])].
[sujeto(['Based', on, these, 'results,', two, categories, of, 'RPLs', were, 'identified:', the, first]), verbo([causing]), complemento([negligible, effects, on, cell, 'viability,', p53, 'expression,', and, protein, 'translation,', while, the, second, category, decreased, cell, viability, and, inhibited, protein, synthesis, mediated, with, or, without, p53, protein, stabilization])].
[sujeto(['RPL13', represents, the, second, 'category,', where, 'siRNA-mediated']), verbo([targeting]), complemento([inhibited, tumor, development, through, decreased, cellular, proliferation])].
[sujeto(['Mechanistically,']), verbo([decreased]), complemento(['RPL13', levels, increased, p53, stability, mediated, by, 'RPL5', and, 'RPL11', binding, to, and, preventing, 'MDM2', from, targeting, p53, for, degradation])].
[sujeto(['The', consequence, was, 'p53-dependent', cell, cycle]), verbo([arrest]), complemento([and, decreased, protein, translation])].
[sujeto(['Thus,']), verbo([targeting]), complemento([certain, category, 2, 'RPL', proteins, can, inhibit, melanoma, tumor, development, mediated, through, the, 'MDM2-p53', pathway])].
[sujeto(['Fragile', 'X', syndrome, '(', 'FXS)', is, the, most, common, form, of, inherited, mental, 'retardation,', and, it, is]), verbo([caused]), complemento([by, loss, of, function, of, the, fragile, 'X', mental, retardation, protein, '(', 'FMRP)'])].
[sujeto(['FMRP', is, an, 'RNA-binding', protein, that, is]), verbo([involved]), complemento([in, the, translational, regulation, of, several, neuronal, mRNAs])].
[sujeto(['Here,', we, show, that, 'FMRP']), verbo([inhibits]), complemento([translation, by, binding, directly, to, the, 'L5', protein, on, the, 80, 'S', ribosome])].
[sujeto(['Furthermore,', cryoelectron, microscopic, reconstruction, of, the, 80, 'S', 'ribosome⋅FMRP', complex, shows, that, 'FMRP']), verbo([binds]), complemento([within, the, intersubunit, space, of, the, ribosome, such, that, it, would, preclude, the, binding, of, tRNA, and, translation, elongation, factors, on, the, ribosome])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'FMRP', inhibits, translation, by, blocking, the, essential, components, of, the, translational, machinery, from, binding, to, the, ribosome])].
[sujeto(['In', 'Trypanosoma', 'brucei,', in, addition, to, 'L5,', 'trypanosome-specific', proteins, 'P34', and, 'P37', also]), verbo([participate]), complemento([in, this, process])].
[sujeto(['We']), verbo([have]), complemento([generated, a, procyclic, 'L5', 'RNA', interference, cell, line, and, found, that, 'L5', itself, is, a, protein, essential, for, trypanosome, 'growth,', despite, the, presence, of, other, 5, 'S', rRNA, binding, proteins])].
[sujeto(['Loss', of, 'L5']), verbo([decreases]), complemento([the, levels, of, all, 'large-subunit', 'rRNAs,', 25, /, 28, 'S,', 5.8, 'S,', and, 5, 'S', 'rRNAs,', but, does, not, alter, 'small-subunit', 18, 'S', rRNA])].
[sujeto(['L5-knockdown', cells, showed, an]), verbo([increase]), complemento([in, the, 40, 'S', ribosomal, subunit, and, a, loss, of, the, 60, 'S', ribosomal, 'subunits,', 80, 'S', 'monosomes,', and, polysomes])].
[sujeto(['In', 'addition,', 'L5', was]), verbo([involved]), complemento([in, the, processing, and, maturation, of, precursor, rRNAs])].
[sujeto(['Although', we, previously]), verbo([found]), complemento([that, the, loss, of, 'P34', and, 'P37', does, not, result, in, a, change, in, the, levels, of, 'L5,', the, loss, of, 'L5', resulted, in, an, increase, of, 'P34', and, 'P37', 'proteins,', suggesting, the, presence, of, a, compensatory, feedback, loop])].
[sujeto(['This', study, demonstrates, that, ribosomal, protein, 'L5']), verbo([has]), complemento([conserved, 'functions,', in, addition, to, nonconserved, 'trypanosome-specific', 'features,', which, could, be, targeted, for, drug, intervention])].
[sujeto(['Diamond', 'Blackfan', anemia, '(', 'DBA)', is, a, rare, inherited, bone, marrow, failure, syndrome]), verbo([caused]), complemento([by, ribosomal, protein, haploinsufficiency])].
[sujeto(['The', p53, 'pathway,']), verbo([activated]), complemento([by, abortive, ribosome, 'assembly,', is, hypothesized, to, contribute, to, the, erythroid, failure, of, 'DBA'])].
[sujeto(['Rps19', mutant, 'ES', cells, showed, significant]), verbo([increase]), complemento([in, p53, protein, 'expression,', 'however,', there, was, no, similar, increase, in, the, 'Rpl5', mutant, cells])].
[sujeto(['We', conclude, that, the, defects, in, our, 'RPS19', and, 'RPL5', haploinsufficient, mouse, 'ES', cells, are, not, adequately, explained, by, p53, 'stabilization,', as, p53, knockdown, appears, to]), verbo([increase]), complemento([the, growth, and, differentiation, potential, of, both, parental, and, mutant, cells])].
[sujeto(['Two', 'Leishmania', major, ribosomal, proteins, 'L3', '(', 'LmL3)', and, 'L5', '(', 'LmL5)']), verbo([have]), complemento([been, described, as, protective, molecules, against, cutaneous, leishmaniasis, due, to, infection, with, 'L'])].
[sujeto(['The', size, of, the, cutaneous, lesions]), verbo([caused]), complemento([by, the, infection, with, the, first, 'species,', the, parasite, loads, and, the, immune, response, in, both, infection, models, were, analyzed, nine, weeks, after, challenge])].
[sujeto(['Oncogene', 'MYC', is, highly]), verbo([expressed]), complemento([in, many, human, cancers, and, functions, as, a, global, regulator, of, ribosome, biogenesis])].
[sujeto(['Previously,', we]), verbo([reported]), complemento([that, ribosomal, protein, '(', 'RP)', 'L11', binds, to, 'c-Myc', and, inhibits, its, transcriptional, activity, in, response, to, ribosomal, stress])].
[sujeto(['Here,', we, show, that, 'RPL5,', 'co-operatively', with, 'RPL11,', guides, the, 'RNA-induced', silencing, complex, '(', 'RISC)', to, 'c-Myc', mRNA, and]), verbo([mediates]), complemento([the, degradation, of, the, 'mRNA,', consequently, leading, to, inhibition, of, 'c-Myc', activity])].
[sujeto(['Knocking', down, of, 'RPL5']), verbo([induced]), complemento(['c-Myc', expression, at, both, mRNA, and, protein, 'levels,', whereas, overexpression, of, 'RPL5', suppressed, 'c-Myc', expression, and, activity])].
[sujeto(['Immunoprecipitation', revealed, that, 'RPL5']), verbo([binds]), complemento([to, 3, '\'', 'UTR', of, 'c-Myc', mRNA, and, two, subunits, of, 'RISC,', 'TRBP', '(', 'HIV-1', 'TAR', 'RNA-binding', 'protein)', and, 'Ago2,', mediating, the, targeting, of, 'c-Myc', mRNA, by, miRNAs])].
[sujeto(['Interestingly,', 'RPL5', and, 'RPL11', 'co-resided', on, 'c-Myc', mRNA, and]), verbo([suppressed]), complemento(['c-Myc', expression, 'co-operatively'])].
[sujeto(['These', findings, uncover, a, mechanism, by, which, these, two, 'RPs', can, 'co-operatively']), verbo([suppress]), complemento(['c-Myc', 'expression,', allowing, a, tightly, controlled, ribosome, biogenesis, in, cells])].
[sujeto(['Humans']), verbo([have]), complemento([evolved, elaborate, mechanisms, to, activate, p53, in, response, to, insults, that, lead, to, 'cancer,', including, the, binding, and, inhibition, of, 'Hdm2', by, the, 60, 'S', ribosomal, proteins, '(', 'RPs)', 'RPL5', and, 'RPL11'])].
[sujeto(['This', same, mechanism, appears, to, be]), verbo([activated]), complemento([upon, impaired, ribosome, 'biogenesis,', a, risk, factor, for, cancer, initiation])].
[sujeto(['As']), verbo([loss]), complemento([of, 'RPL5/RPL11', abrogates, ribosome, biogenesis, and, protein, synthesis, to, the, same, extent, as, loss, of, other, essential, 60, 'S', 'RPs,', we, reasoned, the, loss, of, 'RPL5', and, 'RPL11', would, induce, a, 'p53-independent', cell, cycle, checkpoint])].
[sujeto(['Unexpectedly,', we]), verbo([found]), complemento([that, their, depletion, in, primary, human, lung, fibroblasts, failed, to, induce, cell, cycle, arrest, but, strongly, suppressed, cell, cycle, progression])].
[sujeto(['We', show, that, the, effects, on, cell, cycle, progression, stemmed, from, reduced, ribosome, content, and, translational, 'capacity,', which]), verbo([suppressed]), complemento([the, accumulation, of, cyclins, at, the, translational, level])].
[sujeto(['Thus,', unlike, other, tumor, 'suppressors,', 'RPL5/RPL11', play, an, essential, role, in, normal, cell, 'proliferation,', a, function, cells]), verbo([have]), complemento([evolved, to, rely, on, in, lieu, of, a, cell, cycle, checkpoint])].
[sujeto(['Cell', cycle, regulation, is, a, very, accurate, process, that]), verbo([ensures]), complemento([cell, viability, and, the, genomic, integrity, of, daughter, cells])].
[sujeto(['A', fundamental, part, of, this, regulation, consists, in, the]), verbo([arrest]), complemento([of, the, cycle, at, particular, points, to, ensure, the, completion, of, a, previous, 'event,', to, repair, cellular, 'damage,', or, to, avoid, progression, in, potentially, risky, situations])].
[sujeto(['This', delay, is, concomitant, with, an, imbalance, between, ribosomal, 'RNAs', and, proteins, 'which,', among, 'others,']), verbo([provokes]), complemento([an, accumulation, of, free, ribosomal, protein, 'L5'])].
[sujeto(['Consistently', with, a, direct, impact, of, free, 'L5', on, the, 'G1/S', 'transition,', rrs1, 'mutants,', which, weaken, the, assembly, of, 'L5', and, 'L11', on, 'pre-60S', ribosomal, 'particles,']), verbo([enhance]), complemento([both, the, 'G1/S', delay, and, the, accumulation, of, free, ribosomal, protein, 'L5'])].
[sujeto(['Recently,', we, demonstrated, that, 'RPL5', and, 'RPL11']), verbo([act]), complemento([in, a, mutually, dependent, manner, to, inhibit, 'Hdm2', and, stabilize, p53, following, impaired, ribosome, biogenesis])].
[sujeto(['Given', that, 'RPL5', and, 'RPL11', form, a, preribosomal, complex, with, noncoding, 5, 'S', ribosomal, 'RNA', '(', 'rRNA)', and, the, three]), verbo([have]), complemento([been, implicated, in, the, p53, 'response,', we, reasoned, they, may, be, part, of, an, 'Hdm2-inhibitory', complex])].
[sujeto(['Here,', we, show, that, small, interfering, 'RNAs', directed, against, 5, 'S', rRNA]), verbo([have]), complemento([no, effect, on, total, or, nascent, levels, of, the, noncoding, 'rRNA,', though, they, prevent, the, reported, 'Hdm4', inhibition, of, p53])].
[sujeto(['To', achieve, efficient, inhibition, of, 5, 'S', rRNA, 'synthesis,', we]), verbo([targeted]), complemento(['TFIIIA,', a, specific, 'RNA', polymerase, 'III', 'cofactor,', 'which,', like, depletion, of, either, 'RPL5', or, 'RPL11,', did, not, induce, p53])].
[sujeto(['Instead,', 5, 'S', rRNA]), verbo([acts]), complemento([in, a, dependent, manner, with, 'RPL5', and, 'RPL11', to, inhibit, 'Hdm2', and, stabilize, p53])].
[sujeto(['Moreover,', depletion, of, any, one, of, the, three, components, abolished, the]), verbo([binding]), complemento([of, the, other, two, to, 'Hdm2,', explaining, their, common, dependence])].
[sujeto(['Thus,', the, activation, of, the, 'Hdm2-inhibitory', complex, is, not, a, passive, but, a]), verbo([regulated]), complemento(['event,', whose, potential, role, in, tumor, suppression, has, been, recently, noted])].
[sujeto(['Cisplatin\'s', selectivity, in, killing, rapidly, proliferating, cancer, cells, is, largely, dependent, on, covalent]), verbo([binding]), complemento([to, 'DNA', via, 'cisplatin\'s', chloride, sites, that, had, been, aquated])].
[sujeto(['To', identify, proteins, that]), verbo([bind]), complemento([to, 'cisplatin,', we, synthesized, two, different, 'platinum-agarose', 'conjugates,', one, with, two, amino, groups, and, another, with, two, chlorides, attached, to, platinum, that, are, available, for, protein, 'binding,', and, conducted, 'pull-down', assays, using, cochlear, and, kidney, cells])].
[sujeto(['Future', studies, on, the, interaction, of, these, proteins, with, cisplatin, will, elucidate, whether, these, 'drug-protein', interactions, are]), verbo([involved]), complemento([in, ototoxicity, and, 'nephrotoxicity,', or, contribute, to, tumor, sensitivity, or, resistance, to, cisplatin, treatment])].
[sujeto(['Most', 'DBA', cases, are]), verbo([caused]), complemento([by, heterozygous, null, mutations, in, genes, encoding, ribosomal, proteins])].
[sujeto(['Understanding', how, haploinsufficiency, of, these, ubiquitous, proteins]), verbo([causes]), complemento(['DBA', is, hampered, by, limited, availability, of, tissues, from, affected, patients])].
[sujeto(['We', generated]), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'iPSCs)', from, fibroblasts, of, 'DBA', patients, carrying, mutations, in, 'RPS19', and, 'RPL5'])].
[sujeto(['Upon']), verbo([induced]), complemento(['differentiation,', the, mutant, clone, exhibited, globally, impaired, 'hematopoiesis,', with, the, 'Ery', lineage, affected, most, profoundly])].
[sujeto(['Our', studies, show, that, pathological, features, of, 'DBA', are, recapitulated, by, 'iPSCs,']), verbo([provide]), complemento([a, renewable, source, of, cells, to, model, various, tissue, 'defects,', and, demonstrate, proof, of, principle, for, genetic, correction, strategies, in, patient, stem, cells])].
[sujeto(['Thus', it, is, understandable, that, cells]), verbo([have]), complemento([developed, a, surveillance, system, to, monitor, the, status, of, the, translational, machinery])].
[sujeto(['Recent', discoveries, of, causative, mutations, and, deletions, in, genes, linked, to, ribosome, biogenesis]), verbo([have]), complemento([defined, a, group, of, similar, pathologies, termed, ribosomopathies])].
[sujeto(['Over', the, past, 'decade,', much]), verbo([has]), complemento([been, learned, regarding, the, relationship, between, growth, control, and, ribosome, biogenesis])].
[sujeto(['The', discovery, of, 'extra-ribosomal', functions, of, several, ribosome, proteins, and, their, regulation, of, p53, levels]), verbo([has]), complemento([provided, a, link, from, ribosome, impairment, to, cell, cycle, regulation])].
[sujeto(['Yet,', evidence]), verbo([suggesting]), complemento([p53, 'and/or', 'Hdm2', independent, pathways, also, exists])].
[sujeto(['Inactivation', of, the, adenomatous, polyposis, coli, '(', 'APC)', tumor, suppressor, is, frequently]), verbo([found]), complemento([in, colorectal, cancer])].
[sujeto(['Loss', of, 'APC', function, results, in, deregulation, of, the, 'Wnt/β-catenin', signaling, pathway]), verbo([causing]), complemento([overexpression, of, the, 'c-MYC', oncogene])].
[sujeto(['In', 'lymphoma,', both, p19ARF, and, ribosomal, proteins, 'RPL11', and, 'RPL5']), verbo([respond]), complemento([to, 'c-MYC', activation, to, induce, p53])].
[sujeto(['Interestingly,']), verbo([loss]), complemento([of, 'RP-MDM2', binding, significantly, accelerated, colorectal, tumor, formation, while, having, no, discernable, effect, on, small, intestinal, tumor, formation])].
[sujeto(['Mechanistically,', 'APC']), verbo([loss]), complemento([leads, to, overexpression, of, 'c-MYC,', 'RPL11', and, 'RPL5', in, mouse, colonic, tumor, cells, irrespective, of, 'MDM2(C305F)', mutation])].
[sujeto(['Although', the, employed, algorithms, returned, different, 'rankings,', the, most, frequently, 'top-ranked', genes, 'were:', 'B2m', 'and/or', 'Ppia', for, all, 28, day, treatments, '(', 'ALL28);', 'Ppia', and, 'Hprt1', '(', adipogenic, 'differentiation;', 'A28),', 'B2m', '(', chondrogenic, 'differentiation;', 'C28),', 'Rpl5', '(', controls]), verbo([maintained]), complemento([in, complete, culture, 'medium;', 'CCM),', 'Rplp0', '(', osteogenic, differentiation, for, 3, 'days;', 'O3),', 'Rpl13a', and, 'Actb', '(', osteogenic, differentiation, for, 7, 'days;', 'O7),', 'Rplp0', and, 'Ppia', '(', osteogenic, differentiation, for, 14, 'days;', 'O14),', 'Hprt1', and, 'Ppia', '(', osteogenic, differentiation, for, 28, 'days;', 'O28),', as, well, as, 'Actb', '(', all, osteogenesis, time, points, 'combined;', 'ALLOSTEO)'])].
[sujeto(['The', obtained, results, indicate, that, the, performance, of, reference, genes, depends, on, the, differentiation, protocol, and, on, the, analysis, 'time,', thus]), verbo([providing]), complemento([valuable, information, for, the, design, of, 'RT-PCR', experiments])].
[sujeto(['The', production, of, ribosomes, is, an, extremely, energetically, expensive, cellular, process, that]), verbo([has]), complemento([long, been, linked, to, human, health, and, disease])].
[sujeto(['More', 'recently,', it]), verbo([has]), complemento([been, shown, that, ribosome, biogenesis, is, intimately, linked, to, multiple, cellular, signalling, pathways, and, that, defects, in, ribosome, production, can, lead, to, a, wide, variety, of, human, diseases])].
[sujeto(['Furthermore,', changes, in, ribosome, production, in, response, to, nutrient, levels, in, the, diet]), verbo([lead]), complemento([to, metabolic, 're-programming', of, the, liver])].
[sujeto(['Reduced', or, abnormal, ribosome, production, in, response, to, cellular, stress, or, mutations, in, genes, encoding, factors, critical, for, ribosome, biogenesis]), verbo([causes]), complemento([the, activation, of, the, tumour, suppressor, 'p53,', which, leads, to, 're-programming', of, cellular, transcription])].
[sujeto(['The', excess, 5, 'S', 'RNP']), verbo([binds]), complemento([to, murine, double, minute, 2, '(', 'MDM2),', the, main, 'p53-suppressor', in, the, 'cell,', inhibiting, its, function, and, leading, to, p53, activation])].
[sujeto(['We', show, in, breast, '(', 'MCF-7)', and, lung, '(', 'H1944)', cancer, cells, that, 'U3', and, 'U8', are]), verbo([required]), complemento([for, 'pre-rRNA', processing, reactions, 'leading,', 'respectively,', to, synthesis, of, the, small, and, large, ribosomal, subunits])].
[sujeto(['U3', or, 'U8', depletion]), verbo([triggers]), complemento([a, remarkably, potent, 'p53-dependent', 'anti-tumor', stress, response, involving, the, ribosomal, proteins, uL5, '(', 'RPL11)', and, uL18, '(', 'RPL5)'])].
[sujeto(['We']), verbo([reveal]), complemento([in, a, mouse, xenograft, model, that, the, tumorigenic, potential, of, cancer, cells, is, reduced, in, the, case, of, 'U3', suppression, and, totally, abolished, upon, 'U8', depletion])].
[sujeto(['For', samples, in, each, 'group,', 'RNA-sequencing', was, performed, on, 'Illumina', platform, and, differentially]), verbo([expressed]), complemento([genes, '(', 'DEGs)', between, any, two, of, the, three, groups, were, selected, using, 'NOISeq', package])].
[sujeto(['Drugs']), verbo([associating]), complemento([with, these, genes, were, selected, by, 'WebGestalt'])].
[sujeto(['In', 'addition,', 'KHSRP', and, 'TUBB2A', were, significantly]), verbo([associated]), complemento([with, several, drugs, such, as, 'cefotaxime,', cefacetrile, and, netilmicin])].
[sujeto(['These', genes, might, also]), verbo([involve]), complemento([in, the, regulation, of, metabolism, related, functions, and, pathways])].
[sujeto(['KHSRP', and, 'TUBB2A', might, be, novel]), verbo([targets]), complemento([of, three, 'drugs,', 'cefotaxime,', cefacetrile, and, netilmicin])].
[sujeto(['The', nucleolus, is, a, potent, disease, biomarker, and, a]), verbo([target]), complemento([in, cancer, therapy])].
[sujeto(['Remarkably,', we]), verbo([find]), complemento([that, uL5, '(', formerly, 'RPL11)', and, uL18, '(', 'RPL5)', are, the, strongest, contributors, to, nucleolar, integrity])].
[sujeto(['Together', with, the, 5, 'S', 'rRNA,', they, form, the, 'late-assembling', central, protuberance, on, mature, 60, 'S', 'subunits,', and]), verbo([act]), complemento([as, an, 'Hdm2', trap, and, p53, stabilizer])].
[sujeto(['The', identification, of, the, 'r-proteins', that, specifically, contribute, to]), verbo([maintaining]), complemento([nucleolar, structure, and, p53, 'steady-state', level, provides, insights, into, fundamental, aspects, of, cell, and, cancer, biology])].
[sujeto(['In', turn, the, 'Mdm2', gene, is, a, transcriptional]), verbo([target]), complemento([of, 'p53,', forming, a, negative, feedback, loop, that, is, important, in, cell, cycle, control])].
[sujeto(['It']), verbo([has]), complemento([recently, become, apparent, that, the, ubiquitination, of, p53, by, 'MDM2', can, be, inhibited, when, certain, ribosomal, 'proteins,', including, 'RPL5', and, 'RPL11,', bind, to, 'MDM2'])].
[sujeto(['This', 'inhibition,', and, the, resulting]), verbo([increase]), complemento([in, p53, levels, has, been, proposed, to, be, responsible, for, the, red, cell, aplasia, seen, in, 'Diamond-Blackfan', anemia, '(', 'DBA)', and, in, 5, 'q-', myelodysplastic, syndrome, '(', 'MDS)'])].
[sujeto(['DBA', and, 5, 'q-', 'MDS', are]), verbo([associated]), complemento([with, inherited, '(', 'DBA)', or, acquired, '(', 5, 'q-', 'MDS)', haploinsufficiency, of, ribosomal, proteins])].
[sujeto(['A', mutation, in, 'Mdm2']), verbo([causing]), complemento([a, 'C305F', amino, acid, substitution, blocks, the, binding, of, ribosomal, proteins])].
[sujeto(['Mice', harboring, this, mutation, '(', 'Mdm2C305F),']), verbo([retain]), complemento([a, normal, p53, response, to, 'DNA', 'damage,', but, lack, the, p53, response, to, perturbations, in, ribosome, biogenesis])].
[sujeto(['In', the, bone, marrow, '(', 'BM),', these, mice, showed, a, significant]), verbo([decrease]), complemento([in, 'Ter119hi', cells, compared, to, wild, type, '(', 'WT)', 'littermates,', while, no, decrease, in, the, number, of, mature, erythroid, cells, '(', 'Ter119hiCD71low)', was, found, in, the, 'spleen,', which, showed, compensated, bone, marrow, hematopoiesis])].
[sujeto(['Further', investigation, revealed, that, in, 'Mdm2C305F', 'animals,', there, was, a]), verbo([decrease]), complemento([in, 'Lin-Sca-1+c-Kit+', '(', 'LSK)', 'cells,', accompanied, by, significant, decreases, in, multipotent, progenitor, '(', 'MPP)', cells, '(', p, &, 'lt;', 0.01, ')'])].
[sujeto(['Competitive', 'BM', repopulation, experiments, showed, that, donor, 'BM', harboring, the, 'Mdm2C305F', mutation, possessed]), verbo([decreased]), complemento([repopulation, capacity, compared, to, 'WT', 'BM,', suggesting, a, functional, stem, cell, deficit])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, there, is, a, fine, tuned, balance, in, the, interaction, of, ribosomal, proteins, with, the, 'MDM2/p53', axis, which, is, important, in, normal, hematopoiesis])].
[sujeto(['Diamond-Blackfan', anemia, '(', 'DBA)', was, the, first, ribosomopathy]), verbo([associated]), complemento([with, mutations, in, ribosome, protein, '(', 'RP)', genes])].
[sujeto(['Mutations', in, 'RPL5', are]), verbo([reported]), complemento([in, approximately, 9, ~, 21, '%', of, 'DBA', 'patients,', which, represents, the, most, common, pathological, condition, related, to, a, 'large-subunit', ribosomal, protein])].
[sujeto(['We', demonstrated, that, 'RPL5', is]), verbo([required]), complemento([for, both, primitive, and, definitive, hematopoiesis, processes])].
[sujeto(['By', comparing, with, other, 'DBA', zebrafish, models, and, processing, functional, coupling, 'network,', we, identified, some, common]), verbo([regulated]), complemento(['genes,', lncRNAs, and, 'miRNAs,', that, might, play, important, roles, in, development, and, hematopoiesis])].
[sujeto(['Our', results, therefore]), verbo([provide]), complemento([a, comprehensive, basis, for, the, study, of, molecular, pathogenesis, of, 'RPL5-mediated', 'DBA', and, other, ribosomopathies])].
[sujeto(['Nonmuscle', myosin, 'type II', '(', 'Myo1p)', is]), verbo([required]), complemento([for, cytokinesis, in, the, budding, yeast, 'Saccharomyces', cerevisiae, 'Loss', of, 'Myo1p', activity, has, been, associated, with, growth, abnormalities, and, enhanced, sensitivity, to, osmotic, 'stress,', making, it, an, appealing, antifungal, therapeutic, target])].
[sujeto(['The', 'Myo1p', 'tail-only', domain, was, previously]), verbo([reported]), complemento([to, have, functional, activity, equivalent, to, the, 'full-length', 'Myo1p', whereas, the, 'head-only', domain, did, not])].
[sujeto(['Since', 'Myo1p', 'tail-only', constructs, are, biologically, 'active,', the, tail, domain, must]), verbo([have]), complemento([additional, functions, beyond, its, previously, described, role, in, myosin, dimerization, or, trimerization])].
[sujeto(['To', identify, novel, 'Myo1p-interacting', 'proteins,', and, determine, if, 'Myo1p', can, serve, as, a, scaffold, to]), verbo([recruit]), complemento([proteins, to, the, bud, neck, during, 'cytokinesis,', we, used, the, integrated, 'split-ubiquitin', membrane, yeast, 'two-hybrid', '(', 'iMYTH)', system])].
[sujeto(['Myo1p', was, 'iMYTH-tagged', at, its, 'C-terminus,', and, screened, against, both, cDNA, and, genomic, prey, libraries, to, identify]), verbo([interacting]), complemento([proteins])].
[sujeto(['For', 'in vitro', 'data,', 'TEST', treatment]), verbo([increased]), complemento(['c-Myc', mRNA, expression, by, 38, '%', '(', 'P = 0'])].
[sujeto(['For', 'in vivo', 'data,', 'ORX']), verbo([decreased]), complemento([levator, 'ani/bulbocavernosus', '(', 'LABC)', myofibril, protein, versus, 'Sham', '(', 'P = 0'])].
[sujeto(['ORX', also]), verbo([decreased]), complemento([muscle, ribosome, content, '(', total, 'RNA)', compared, to, 'Sham', '(', 'P = 0'])].
[sujeto(['However,', other, markers, of, ribosome, biogenesis, including, 'c-Myc', 'mRNA,', 'Nop56', 'mRNA,', 'Bop1', 'mRNA,', 'Ncl', mRNA]), verbo([decreased]), complemento([with, 'ORX', independently, of, 'TEST', treatments, '(', 'P < 0'])].
[sujeto(['Finally,', lower, 'phospho-(Ser235/236)-to-total', rps6, protein, and, lower, rpl5, protein, levels, existed, in, 'ORX+TEST', rats, versus, other, 'treatments,']), verbo([suggesting]), complemento([that, chronic, 'TEST', treatment, may, lower, translational, capacity])].
[sujeto(['Diamond-Blackfan', anemia, '(', 'DBA)', is, an, inherited, bone, marrow, failure, syndrome]), verbo([associated]), complemento([with, ribosomal, protein, '(', 'RP)', gene, mutations])].
[sujeto(['Recent', studies]), verbo([have]), complemento([also, demonstrated, an, increased, risk, of, cancer, predisposition, among, 'DBA', patients])].
[sujeto(['In', this, 'study,', we]), verbo([report]), complemento([the, formation, of, soft, tissue, sarcoma, in, the, 'Rpl5', and, 'Rps24', heterozygous, mice])].
[sujeto(['Our', observation]), verbo([suggests]), complemento([that, even, though, one, 'wild-type', allele, of, the, 'Rpl5', or, 'Rps24', gene, prevents, anemia, in, these, 'mice,', it, still, predisposes, them, to, cancer, development])].
[sujeto(['Here,', we, demonstrate, that, coordinated]), verbo([targeting]), complemento([of, rDNA, transcription, and, 'PI3K-AKT-mTORC1-dependent', ribosome, biogenesis, and, protein, synthesis, provides, a, remarkable, improvement, in, survival, in, 'MYC-driven', 'B', lymphoma])].
[sujeto(['The', ability, of, each, agent, to]), verbo([trigger]), complemento([tumor, cell, death, via, independent, pathways, was, central, to, their, synergistic, efficacy])].
[sujeto(['CX-5461']), verbo([induced]), complemento([nucleolar, stress, and, p53, pathway, 'activation,', whereas, everolimus, induced, expression, of, the, proapoptotic, protein, 'BMF', that, was, independent, of, p53, and, reduced, expression, of, 'RPL11', and, 'RPL5'])].
[sujeto(['Thus,']), verbo([targeting]), complemento([the, network, controlling, the, synthesis, and, function, of, ribosomes, at, multiple, points, provides, a, potential, new, strategy, to, treat, 'MYC-driven', malignancies])].
[sujeto(['We', demonstrate, that, combining, pharmacologic]), verbo([targeting]), complemento([of, ribosome, biogenesis, and, 'mTORC1-dependent', translation, provides, a, remarkable, therapeutic, benefit, to, 'Eμ-Myc', 'lymphoma-bearing', mice])].
[sujeto(['These', results, establish, a, rationale, for]), verbo([targeting]), complemento([ribosome, biogenesis, and, function, to, treat, 'MYC-driven', cancer])].
[sujeto(['DBA', is]), verbo([associated]), complemento([with, 'single,', 'monoallelic,', inactivating, mutations, in, ribosomal, protein, '(', 'RP)', genes])].
[sujeto(['These', mutations]), verbo([have]), complemento([been, reported, in, up, to, 60, '%', of, 'DBA', patients])].
[sujeto(['To', 'date,', no, known, pathogenic, mutations]), verbo([have]), complemento([been, found, in, the, remaining, patients])].
[sujeto(['Dynorphin', 'A', '(', 'Dyn', 'A)', is, a, unique, endogenous, ligand, that, possesses, 'well-known', neuroinhibitory, effects, via, opioid, receptors, with, preference, at, the, kappa, receptor, but, also, neuroexcitatory, 'effects,', which]), verbo([cause]), complemento([hyperalgesia])].
[sujeto(['We']), verbo([have]), complemento([shown, that, the, neuroexcitatory, effects, are, mediated, through, bradykinin, receptors, '(', 'BK', 'receptors)', and, that, intrathecal, '(', i])].
[sujeto([')', administration, of, our]), verbo([lead]), complemento([ligand, 1, ',', '[', 'Des-Arg7]-Dyn', 'A-(4-11),', which, shows, good, binding, affinity, '(', 'IC50', =, 150, 'nM)', at, the, 'BK', 'receptors,', blocks, 'Dyn', 'A-induced', hyperalgesia, in, naïve, animals, and, reverses, thermal, and, tactile, hypersensitivities, in, a, 'dose-dependent', manner, in, nerve, injured, animals])].
[sujeto(['However,', 1]), verbo([has]), complemento([a, serious, drawback, as, a, potential, drug, candidate, for, the, treatment, of, neuropathic, pain, due, to, its, susceptibility, to, enzymatic, degradation])].
[sujeto(['In', an, effort, to]), verbo([increase]), complemento([the, 'stability,', we, modified, ligand, 1, using, 'non-natural', amino, acids, and, found, that, analogues, substituted, at, or, near, the, 'N-terminus', with, a, 'D-isomer', retain, binding, at, the, receptor, as, well, as, provide, a, large, increase, in, stability])].
[sujeto(['In', particular, when, 'Leu5', was, 'modified,', by, either, the, 'D-isomer', or, 'N-methylation,', there, was, a, large]), verbo([increase]), complemento([in, stability, '(', 't1/2=', 0.7, h, to, 160, h, in, rat, 'plasma)', observed])].
[sujeto(['From', these, 'studies,', we]), verbo([have]), complemento([developed, a, very, stable, 'Dyn', 'A', analogue, 16, ',', '[', 'DLeu5,', 'des-Arg7]-Dyn', 'A-(4-11),', that, binds, to, 'BK', receptors, '(', 'IC50', =, 130, 'nM)', in, the, same, range, as, ligand, 1, and, shows, good, 'anti-hyperalgesic', effects, both, in, naïve, rats, and, 'L5/L6', spinal, nerve, ligation, '(', 'SNL)', rats])].
[sujeto(['The', most, common]), verbo([cause]), complemento([of, foot, drop, is, a, neuropathy, of, the, common, peroneal, nerve, '(', 'CPN)'])].
[sujeto(['However,', similar, symptoms, can, be]), verbo([caused]), complemento([by, proximal, lesions, of, the, sciatic, 'nerve,', lumbar, plexus, or, 'L5', nerve, root])].
[sujeto(['Although', the, initial, concern, was, a, postoperative, lesion, at, 'L5,', the]), verbo([cause]), complemento([for, this, delayed, presentation, was, extrinsic, compression, of, the, 'CPN', at, the, level, of, the, fibular, head, by, a, 'tight-fitting', 'below-knee', thromboembolic, deterrent, stocking])].
[sujeto(['It', is, important, to]), verbo([recognize]), complemento([this, potential, cause, of, progressive, foot, drop, early, as, it, is, preventable, by, simple, 'measures,', which, can, significantly, reduce, morbidity])].
[sujeto(['As', we, are, likely, to, encounter]), verbo([increasing]), complemento([numbers, of, veterans, treated, for, 'PTSD', who, require, multiple, surgical, procedures, to, treat, their, 'service-related', 'injuries,', health, care, providers, need, to, be, familiar, with, 'prevention,', 'recognition,', and, the, clinical, challenges, in, the, management, of, 'SS', in, the, postoperative, period])].
[sujeto(['Previous', biomechanical, studies, indicate, that]), verbo([providing]), complemento([less, rigid, fixation, at, the, cranial, aspect, of, a, long, posterior, instrumented, 'construct,', via, transition, rods, or, hooks, at, the, upper, instrumented, vertebra, '(', 'UIV),', may, provide, a, gradual, transition, to, normal, motion, and, prevent, 'PJK'])].
[sujeto(['RESULTS', 'Proximal-segment', range, of, motion, '(', 'ROM)', for, the, 'PS', construct]), verbo([increased]), complemento([from, 16, '%', at, 'UIV-1', to, 91, '%', at, 'UIV'])].
[sujeto(['Proximal-segment', 'ROM', for, the, 'TPH', construct]), verbo([increased]), complemento([from, 27, '%', at, 'UIV-1', to, 92, '%', at, 'UIV'])].
[sujeto(['Proximal', segment, intradiscal, 'pressures,', pedicle, screw, 'loads,', and, ligament, forces, in, the, posterior, ligament, complex, were, progressively, reduced, with]), verbo([increasing]), complemento([number, of, posterior, tethers, used])].
[sujeto(['Dopamine', can, influence, 'NMDA', receptor, function, and]), verbo([regulate]), complemento(['glutamate-triggered', 'long-term', changes, in, synaptic, strength, in, several, regions, of, the, 'CNS'])].
[sujeto(['In', the, current, 'study,', we]), verbo([increased]), complemento([endogenous, dopamine, levels, in, the, dorsal, horn, by, using, 're-uptake', inhibitor, 'GBR', 12935])].
[sujeto(['During', the, 'so-induced', hyperdopaminergic, 'transmission,', conditioning, 'low-frequency', '(', 1, 'Hz)', stimulation, '(', 'LFS)', to, the, sciatic, nerve]), verbo([induced]), complemento(['long-term', potentiation, '(', 'LTP)', of, 'C-fiber-evoked', potentials, in, dorsal, horn, neurons])].
[sujeto(['Conditioning', 'LFS', during, 'GBR', 12935, administration]), verbo([increased]), complemento([phosphorylation, of, 'dopamine-', and, 'cAMP-regulated', phosphoprotein, of, 'Mr', 32, kDa, '(', 'DARPP-32)', at, threonine, 34, residue, in, synaptosomal, '(', 'P3)', fraction, of, dorsal, horn, 'homogenates,', as, assessed, by, 'Western', blot, 'analysis,', which, was, partially, prevented, by, 'NR2B', blockade, prior, to, conditioning, stimulation])].
[sujeto(['Conditioning', 'LFS', also, was, followed, by, higher, 'co-localization', of]), verbo([phosphorylated]), complemento([form, of, 'NR2B', at, tyrosine, 1472, and, 'pDARPP-32Thr34-', with, postsynaptic, marker, 'PSD-95', in, transverse, 'L5', dorsal, horn, sections])].
[sujeto(['Such']), verbo([increase]), complemento([could, be, significantly, attenuated, by, 'D1LR', blockade, with, 'SCH', 23390])].
[sujeto(['The', current, results, support, that, coincidental, endogenous, recruitment, of, 'D1LRs', and, 'NR2B', in, dorsal, horn, synapses, plays, a, role, in]), verbo([regulating]), complemento(['afferent-induced', nociceptive, plasticity])].
[sujeto(['Parallel']), verbo([increases]), complemento([in, 'DARPP-32', phosphorylation, upon, 'LTP', induction, suggests, a, role, for, this, phosphoprotein, as, intracellular, detector, of, convergent, 'D1L-', and, 'NMDA', receptor, activation])].
[sujeto(['Identification', of, specific, aspects, of, spine, dynamics, that, can, be, unmasked, in, adulthood, and, its, regulatory, molecular, mechanisms, could]), verbo([provide]), complemento([novel, therapeutic, targets, for, inducing, plasticity, at, both, the, functional, and, structural, levels, for, robust, recovery, from, brain, disorders, and, injuries, in, adults])].
[sujeto(['Lynx1,', an, endogenous, inhibitor, of, nicotinic, acetylcholine, 'receptors,', was, previously, shown, to]), verbo([increase]), complemento([its, expression, in, adulthood, and, thus, to, limit, functional, ocular, dominance, plasticity, in, adult, primary, visual, cortex, '(', 'V1)'])].
[sujeto(['We']), verbo([found]), complemento([that, the, deletion, of, 'Lynx1', doubled, the, baseline, spine, turnover, 'rate,', suggesting, that, the, spine, dynamics, in, the, adult, cortex, is, actively, limited, by, the, presence, of, 'Lynx1'])].
[sujeto(['After', 'MD,', adult, 'Lynx1-KO', mice, selectively, exhibit, higher, rate, of, spine]), verbo([loss]), complemento([with, no, difference, in, gain, rate, in, 'L5', neurons, compared, with, control, 'wild-type', 'counterparts,', revealing, a, key, signature, of, spine, dynamics, associated, with, robust, functional, plasticity, in, adult, 'V1'])].
[sujeto(['Overall,', 'Lynx1', could, be, a, promising, therapeutic]), verbo([target]), complemento([to, induce, not, only, 'functional,', but, also, structural, plasticity, at, the, level, of, spine, dynamics, in, the, adult, brain])].
[sujeto(['In', mouse, visual, 'cortex,', a, premier, model, of, 'experience-dependent', 'plasticity,', we]), verbo([found]), complemento([that, the, deletion, of, 'Lynx1,', a, nicotinic, &, 'quot;brake"', for, functional, 'plasticity,', doubled, the, baseline, spine, turnover, in, 'adulthood,', suggesting, that, the, spine, dynamics, in, the, adult, cortex, is, actively, limited, by, 'Lynx1'])].
[sujeto(['After', visual, 'deprivation,', spine, 'loss,', but, not]), verbo([gain]), complemento(['rate,', remains, higher, in, adult, 'Lynx1', 'knock-out', mice, than, in, control, 'wild-type', 'mice,', revealing, a, key, signature, of, spine, dynamics, associated, with, robust, functional, plasticity])].
[sujeto(['Lynx1', would, be, a, promising]), verbo([target]), complemento([to, induce, not, only, 'functional,', but, also, structural, plasticity, at, the, level, of, spine, dynamics, in, adulthood])].
[sujeto(['We', also]), verbo([provide]), complemento([mutational, evidence, that, an, 'L9-P1', tertiary, 'contact,', as, found, in, some, 'Mycoplasma', type, 'B', 'RNAs,', is, not, formed, in, canonical, type, 'B', 'RNAs', as, represented, by, 'B'])].
[sujeto([1, and, 'P15', 'stem-loop', structures, as]), verbo([targets]), complemento([for, 'LNA-modified', antisense, oligonucleotides])].
[sujeto(['Oligonucleotides']), verbo([targeting]), complemento(['P15,', but, not, those, directed, against, 'P5'])].
[sujeto([1, ',', were]), verbo([found]), complemento([to, efficiently, anneal, to, 'P', 'RNA', and, to, inhibit, activity, '(', 'IC50', of, '∼2', 'nM)', when, incubated, with, preassembled, 'B'])].
[sujeto(['Here,', we, show, that, ubiquitin, 'carboxyl-terminal', 'hydrolase-L5', '(', 'UCHL5', or, 'UCH37)', 'de-ubiquitinates', both, 'Smad2', and, 'Smad3,', 'up-regulates', their, 'stability,', and]), verbo([promotes]), complemento(['TGFβ-1-induced', expression, of, profibrotic, 'proteins,', such, as, fibronectin, '(', 'FN)', and, 'α-smooth', muscle, actin, '(', 'α-SMA)'])].
[sujeto(['We', demonstrate, that, 'Smad2', and, 'Smad3', ubiquitination, was, diminished, by, 'over-expression', of, 'UCHL5,', while, it, was]), verbo([enhanced]), complemento([by, inhibition, or, 'down-regulation', of, 'UCHL5'])].
[sujeto(['UCHL5', is, highly]), verbo([expressed]), complemento([in, 'IPF', lungs])].
[sujeto(['UCHL5,', 'Smad2,', and, 'Smad3', levels, were]), verbo([increased]), complemento([in, 'bleomycin-injured', lungs])].
[sujeto(['Our', studies]), verbo([provide]), complemento([a, molecular, mechanism, by, which, 'UCHL5', mitigates, 'TGFβ-1', signaling, by, stabilizing, 'Smad2/Smad3'])].
[sujeto(['A', statistically, significant]), verbo([increase]), complemento([in, 'L3-4', and, 'L4-5', lumbar, facet, joint, loads, of, 30.81, '%', was, found, in, the, 'IFI', state, as, compared, with, the, native, state, during, terminal, hip, extension])].
[sujeto(['Limited', terminal, hip, extension, due, to, simulated, 'IFI', significantly]), verbo([increases]), complemento(['L3-4', and, 'L4-5', lumbar, facet, joint, load, when, compared, with, 'non-IFI', native, hips])].
[sujeto(['This', biomechanical, study, directly, links, 'IFI', to]), verbo([increased]), complemento([lumbar, facet, loads, and, supports, the, clinical, findings, of, 'IFI', causing, lumbar, pathology])].
[sujeto(['Assessing', and, treating, '(', open, or, 'endoscopic)', hip, disorders, that, limit, extension, could]), verbo([have]), complemento([benefit, in, patients, with, concomitant, lower, back, symptoms])].
[sujeto(['The', inferred, angles, were, compared, to, optimal, angles]), verbo([leading]), complemento([to, the, central, dorsal, part, of, the, dural, sac, from, 1, -, 2, cm, 'paramedian,', measured, by, 'MRI', in, seven, cases, and, in, a, short, stature, volunteer, '(', 1.58, 'm,', 'BMI', 23.2, ')', ',', to, study, supine, and, fetal, positions, using, both, closed, 'MR', and, ultrasound])].
[sujeto([3, cm, '(', 'T11-T12)]', while, the, mean, optimal, incidence, angles]), verbo([increased]), complemento(['[', 8.3, º, -, 16.5, º, '(', 'L4-L5)', to, 12.7, º, -, 24.1, º, '(', 'T11-T12)', at, 1, -, 2, cm, 'paramedian,', 'respectively]', and, coincided, with, the, estimated, angles, with, a, correlation, 'coefficient=0'])].
[sujeto(['In', the, 'volunteer,', the, optimal, 'latero-medial', angles]), verbo([increased]), complemento([from, 14.4, º, -, 26.7, º, '(', 'L3-L4)', to, 17.1, º, -, 30.3, º, '(', 'T11-T12)', for, a, '(', 'd)=3'])].
[sujeto([1, cm, '(', 'T11-T12)', and]), verbo([increased]), complemento(['≤3'])].
[sujeto(['The', classically, recommended, angles, of, 10, -, 15, º, differ, from, the, optimal, 'angles,', particularly, in, small, 'patients,']), verbo([suggesting]), complemento([the, need, for, ultrasound, guidance, or, for, inferring, angles, prior, to, spinal, anesthesia])].
[sujeto(['The', prognostic, index, that, incorporated, these, measures, with, the, 'CCI', was]), verbo([associated]), complemento([with, improved, accuracy, for, prediction, of, noncancer, death])].
[sujeto(['Ribosomal', protein, 'L6,', an, essential, component, of, the, large, '(', 50, 'S)', 'subunit,', primarily]), verbo([binds]), complemento([to, helix, 97, of, 23, 'S', rRNA, and, locates, near, the, 'sarcin/ricin', loop, of, helix, 95, that, directly, interacts, with, 'GTPase', translation, factors])].
[sujeto(['Although', 'L6', is, believed, to, play, important, roles, in, 'factor-dependent', ribosomal, 'function,', crucial, biochemical, evidence, for, this, hypothesis]), verbo([has]), complemento([not, been, obtained])].
[sujeto(['RbgA', is, an, essential, 'GTPase', that]), verbo([participates]), complemento([in, the, assembly, of, the, large, ribosomal, subunit, in, 'Bacillus', subtilis, and, its, homologs, are, implicated, in, mitochondrial, and, eukaryotic, large, subunit, assembly])].
[sujeto(['To']), verbo([gain]), complemento([insight, into, the, function, of, 'RbgA', we, isolated, suppressor, mutations, that, partially, restored, the, growth, of, an, 'RbgA', mutation, '(', 'RbgA-F6A)', that, caused, a, severe, growth, defect])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'RbgA', functions, to, properly, position, 'L6', on, the, 'ribosome,', prior, to, the, incorporation, of, 'L16', and, other, late, assembly, proteins])].
[sujeto([aureus, small, colony, variants, '(', 'SCVs)', are, linked, to, 'chronic,', 'recurrent,', and, 'antibiotic-resistant', 'infections,', and, the, study, of, 'SCVs']), verbo([has]), complemento([contributed, significantly, to, understanding, of, persistence])].
[sujeto(['Since', 2006, ',', it]), verbo([has]), complemento([been, found, that, persistent, organisms, including, 'SCVs', are, part, of, the, normal, life, cycle, of, 'bacteria,', and, often, they, arise, in, response, to, harsh, 'conditions,', e])].
[sujeto(['Many', of, the, changes]), verbo([found]), complemento([in, these, early, 'SCVs', have, provided, a, map, for, the, discovery, mechanisms, '(', 'pathways)', for, the, development, of, persistent, organisms])].
[sujeto(['For', 'example,', changes, in, 'RNA', 'processing,', stringent, 'response,', 'toxin-antitoxin,', ribosome, protein, 'L6', '(', 'RplF),', and, cold, shock, protein, 'B', '(', 'CspB)']), verbo([found]), complemento([in, 'SCVs', are, also, found, in, other, persisters])].
[sujeto([aureus, 'USA300']), verbo([has]), complemento([elucidated, the, impact, of, aerobic, expression, of, arginine, deiminase, genes, on, its, ability, to, chronically, colonize, the, skin, and, survive, in, abscesses])].
[sujeto([aureus, 'SCVs', also]), verbo([express]), complemento([arginine, deiminase, genes, aerobically, as, well])].
[sujeto(['Thus,', many, pathways]), verbo([found]), complemento([activated, in, electron, transport, type, of, 'SCVs', are, also, increased, in, persisters, that, have, intact, electron, transport])].
[sujeto(['Another', common, theme, is, that, slow, growth, is, also]), verbo([associated]), complemento([with, reduced, expression, of, virulence, factors, and, enhanced, 'uptake/survival', within, host, cells])].
[sujeto(['These', adaptations, to, survive, within, the, host, are, rooted, in, responses, that, were]), verbo([required]), complemento([for, organisms, to, survive, in, a, harsh, environment, long, before, they, were, mammals, on, the, earth])].
[sujeto(['This', is, a, problem, in, clinical, situations, in, those, 'genera,', such, as, 'Neisseria,', where, some, species, are]), verbo([associated]), complemento([with, disease, while, others, are, not])].
[sujeto(['Here,', we, identified, and, validated, an, alternative, genetic]), verbo([target]), complemento([common, to, all, 'Neisseria', species, which, can, be, readily, sequenced, to, provide, an, assay, that, rapidly, and, accurately, discriminates, among, members, of, the, genus])].
[sujeto(['Ribosomal', multilocus, sequence, typing, '(', 'rMLST)', using, ribosomal, protein, genes]), verbo([has]), complemento([been, shown, to, unambiguously, identify, these, bacteria])].
[sujeto(['Allele', sequences, were, defined, for, the, gene, 'fragment,']), verbo([associated]), complemento([with, particular, species, 'names,', and, stored, on, the, 'PubMLST', 'Neisseria', 'database,', providing, a, curated, electronic, resource])].
[sujeto(['This', approach]), verbo([provides]), complemento([an, alternative, to, 16, 'S', rRNA, gene, 'sequencing,', which, can, be, readily, replicated, for, other, organisms, for, which, more, resolution, is, 'required,', and, it, has, potential, applications, in, 'high-resolution', metagenomic, studies])].
[sujeto(['Therefore,', identification, of, novel, molecules]), verbo([involved]), complemento([in, this, regulatory, loop, is, necessary, for, understanding, the, dynamic, regulation, of, p53, and, treatment, of, human, diseases])].
[sujeto(['Here,', we, characterized, that, the, ribosomal, protein, 'L6']), verbo([binds]), complemento([to, and, suppresses, the, 'E3', ubiquitin, ligase, activity, of, 'HDM2,', and, subsequently, attenuates, 'HDM2-mediated', p53, polyubiquitination, and, degradation])].
[sujeto(['The']), verbo([enhanced]), complemento([p53, activity, further, slows, down, cell, cycle, progression, and, leads, to, cell, growth, inhibition])].
[sujeto(['Conversely,', the, level, of, p53, is, dramatically]), verbo([decreased]), complemento([upon, the, depletion, of, 'RPL6,', indicating, that, 'RPL6', is, essential, for, p53, stabilization])].
[sujeto(['We', also]), verbo([found]), complemento([that, 'RPL6', translocalizes, from, the, nucleolus, to, nucleoplasm, under, ribosomal, 'stress,', which, facilitates, its, binding, with, 'HDM2'])].
[sujeto(['Longer', treatment, of, actinomycin, 'D']), verbo([increases]), complemento(['RPL6', ubiquitination, and, destabilizes, 'RPL6,', and, thereby, putatively, attenuates, p53, response, until, the, level, of, 'L6', subsides])].
[sujeto(['Together,', our, study, identifies, the, crucial, function, of, 'RPL6', in]), verbo([regulating]), complemento(['HDM2-p53', 'pathway,', which, highlights, the, importance, of, 'RPL6', in, human, genetic, diseases, and, cancers])].
[sujeto(['Colorectal', cancer, '(', 'CRC)', is, the, fourth, most, common]), verbo([cause]), complemento([of, 'cancer-related', death, worldwide])].
[sujeto(['Accurate', 'non-invasive', screening, for, 'CRC', would, greatly]), verbo([enhance]), complemento([a, 'population\'s', health])].
[sujeto(['Adenomatous', polyposis, coli, '(', 'Apc)', gene, mutations, commonly, occur, in, human, colorectal, adenomas, and, 'carcinomas,']), verbo([leading]), complemento([to, 'Wnt', signalling, pathway, activation])].
[sujeto(['Acute', conditional, transgenic, deletion, of, 'Apc', in, murine, intestinal, epithelium, '(', 'AhCre(+)Apc(fl)(/)(fl))']), verbo([causes]), complemento([phenotypic, changes, similar, to, those, found, during, colorectal, tumourigenesis])].
[sujeto(['Eighty-one', proteins, showed, significantly]), verbo([increased]), complemento([expression, following, iTRAQ, 'analysis,', and, validation, of, nine, of, these, by, 'Ingenuity', 'Pathaway', 'Analysis', showed, they, could, be, detected, in, blood, or, serum])].
[sujeto(['Expression', was, assessed, in, 'AhCre(+)Apc(fl)(/)(fl)', small, intestinal, epithelium, by, 'immunohistochemistry,', western, blot, and, quantitative, 'real-time', 'PCR;']), verbo([increased]), complemento([nucelolin, concentrations, were, also, detected, in, the, serum, of, 'AhCre(+)Apc(fl)(/)(fl)', and, 'Apc(Min)(/)(+)', mice, by, 'ELISA'])].
[sujeto(['In', 'conclusion,', several, novel, candidate, biomarkers]), verbo([have]), complemento([been, identified, from, analysis, of, transgenic, mice, in, which, the, 'Apc', gene, was, deleted, in, the, intestinal, epithelium, that, also, showed, increased, expression, in, human, 'CRC'])].
[sujeto(['The', gene, candidates, isolated, in, this, study, were, differentially]), verbo([expressed]), complemento([and, therefore, have, potential, as, molecular, biomarkers, for, understanding, coral, responses, to, environmental, stressors])].
[sujeto(['Our', results, showed, that, the, mRNA, expression, levels, of, both, 'igf-I', and, ghrl, were, low, during, early, larval, development, and, then]), verbo([increased]), complemento([significantly, to, the, late, larval, 'time-points', when, larvae, started, exogenous, feeding])].
[sujeto(['In', both, 'Beluga', and, 'Persian', 'sturgeon,', after, a, low, mRNA, expression, during, the, embryonic, 'stage,', the, transcript, levels, of, vegf, displayed, an]), verbo([increasing]), complemento([trend, during, 'yolk-sac', 'fry,', consistent, with, organogenesis])].
[sujeto(['In', 'Persian', 'sturgeon,', the, gh, transcript, started, to]), verbo([decrease]), complemento([to, the, rest, of, the, developmental, 'time-points,', whereas, in, 'Beluga', gh, transcript, had, a, marked, second, increase, from, the, time, of, exogenous, feeding, '(', 20, -, 'dph)'])].
[sujeto(['This', 'Beluga', specific]), verbo([increase]), complemento([in, gh, transcription, may, be, associated, with, the, marked, growth, rate, and, extraordinary, size, of, this, fish, species])].
[sujeto(['All', 'FusE', 'SCVs']), verbo([have]), complemento([mutations, in, 'rplF,', encoding, ribosomal, protein, 'L6'])].
[sujeto(['However,', individual, 'FusE', mutants, including, some, with, the, same, mutation, in, rplF, display, auxotrophy, for, either, hemin, or, 'menadione,']), verbo([suggesting]), complemento([that, additional, mutations, are, involved])].
[sujeto(['Here', we, show, that, 'FusE', 'SCVs', can, be, divided, into, three, genetic, 'sub-groups', and, that, some, carry, an, additional, 'mutation,', in, one, of, the, genes]), verbo([required]), complemento([for, hemin, 'biosynthesis,', or, in, one, of, the, genes, required, for, menadione, biosynthesis])].
[sujeto(['It', was, further, demonstrated, that, 'up-regulation', of, 'RPL6', accelerated, growth, and]), verbo([enhanced]), complemento([in, vitro, colony, forming, ability, of, 'GES', cells, while, 'down-regulation', of, 'RPL6', exhibited, the, opposite, results])].
[sujeto(['It', was]), verbo([found]), complemento([that, 'RPL6', and, cyclin, 'E', were, expressed, at, a, higher, level, in, gastric, cancer, tissues, than, that, in, normal, gastric, mucosa, and, the, two, were, correlative, in, gastric, cancer])].
[sujeto(['Survival', time, of, postoperative, patients, was, analyzed, by, 'Kaplan-', 'Meier', analysis, and, it, was]), verbo([found]), complemento([that, patients, with, 'RPL6', positive, expression, showed, shorter, survival, time, than, patients, that, with, 'RPL6', negative, expression])].
[sujeto(['Moreover,', 'down-regulation', of, 'RPL6', could]), verbo([suppress]), complemento(['G1', to, 'S', phase, transition, in, these, cells])].
[sujeto(['Taken', 'together,', these, data]), verbo([suggested]), complemento([that, 'RPL6', was, 'over-expressed', in, human, gastric, tissues, and, caused, poor, prognosis])].
[sujeto(['Down-regulation', of, 'RPL6', could]), verbo([suppress]), complemento([cell, growth, and, cell, cycle, progression, at, least, through, 'down-regulating', cyclin, 'E', and, which, might, be, used, as, a, novel, approach, to, gastric, cancer, therapy])].
[sujeto(['The', differentially]), verbo([expressed]), complemento([genes, 'CAMKK2,', 'CRHBP,', 'EPHX2,', 'HOMER3,', 'NDN,', 'PRL', and, 'RPL6', were, selected, for, microarray, validation, using, 'qRT-PCR'])].
[sujeto(['The', ribosomal, protein, 'L9', '(', 'RPL9),', a, component, of, the, large, subunit, of, the, 'ribosome,']), verbo([has]), complemento([an, unusual, 'structure,', comprising, two, compact, globular, domains, connected, by, an, 'α-helix;', it, interacts, with, 23, 'S', rRNA])].
[sujeto(['Based', on, alignment, 'analysis,', rpL9]), verbo([has]), complemento([high, similarity, among, 'species;', we, found, 85, '%', agreement, of, 'DNA', and, amino, acid, sequences, with, the, other, species, that, have, been, analyzed])].
[sujeto(['The', rpL9, gene, can, be, readily]), verbo([expressed]), complemento([in, 'E'])].
[sujeto(['Elasmobranch', fishes, are, an, ancient, group, of, vertebrates, which]), verbo([have]), complemento([high, potential, as, model, species, for, research, into, evolutionary, physiology, and, genomics])].
[sujeto(['However,', no, comparative, studies]), verbo([have]), complemento([established, suitable, reference, genes, for, quantitative, 'PCR', '(', 'qPCR)', in, elasmobranchs, for, any, physiological, conditions])].
[sujeto(['Oxygen', availability]), verbo([has]), complemento([been, a, major, force, shaping, the, physiological, evolution, of, 'vertebrates,', especially, fishes])].
[sujeto(['It', was]), verbo([found]), complemento(['RPL6', was, expressed, at, a, higher, level, in, gastric, cancer, tissues, than, that, in, normal, gastric, mucosa])].
[sujeto(['It', was, demonstrated, that, upregulation, of, 'RPL6', accelerated, the, growth, and]), verbo([enhanced]), complemento([in, vitro, colony, forming, ability, of, 'GES', cells, whereas, downregulation, of, 'RPL6', showed, adverse, effects])].
[sujeto(['Moreover,', 'over-expression', of, 'RPL6', could]), verbo([promote]), complemento(['G1', to, 'S', phase, transition, of, 'GES', cells])].
[sujeto(['It', was, further, evidenced, that, upregulation, of, 'RPL6', resulted, in, elevated, cyclin, 'E', expression, while, downregulation, of, 'RPL6']), verbo([caused]), complemento([decreased, cyclin, 'E', expression, in, 'GES', cells])].
[sujeto(['Taken', 'together,', these, data, indicated, that, 'RPL6', was, overexpressed, in, human, gastric, cancer, and, its, 'over-expression', could]), verbo([promote]), complemento([cell, growth, and, cell, cycle, progression, at, least, through, upregulating, cyclin, 'E', expression])].
[sujeto(['The', mitochondria, of, contemporary, organisms, contain, fewer, genes, than, the, ancestral, bacteria, are, predicted, to]), verbo([have]), complemento([contained])].
[sujeto(['Because', most, of, the, mitochondrial, proteins, are, encoded, in, the, 'nucleus,', the, genes, would]), verbo([have]), complemento([been, transferred, from, the, mitochondrion, to, the, nucleus, at, some, stage, of, evolution, and, they, must, have, acquired, 'cis-regulatory', elements, compatible, with, eukaryotic, gene, expression])].
[sujeto(['The', ribosomal, protein, 'L6', gene, '(', 'rpl6)']), verbo([has]), complemento([been, lost, in, 'presently-known', angiosperm, mitochondrial, genomes])].
[sujeto(['We']), verbo([found]), complemento([that, each, of, the, two, rice, rpl6, genes, '(', 'OsRpl6-1', and, 'OsRpl6-2)', has, an, intron, in, an, identical, position, within, the, 5, '\'', -, untranslated, region, '(', 'UTR),', which, suggests, a, duplication, of, the, rpl6, gene, after, its, transfer, to, the, nucleus])].
[sujeto(['Each', of, the, predicted, 'RPL6', proteins, lacks, an, 'N-terminal', extension, as, a, mitochondrial]), verbo([targeting]), complemento([signal])].
[sujeto(['Transient', assays, using, green, fluorescent, protein, indicated, that, their, mature, 'N-terminal', coding, regions, contain, the, mitochondrial]), verbo([targeting]), complemento([information])].
[sujeto(['Reverse', 'transcription-PCR', analysis, showed, that, 'OsRpl6-2']), verbo([expresses]), complemento([considerably, fewer, transcripts, than, 'OsRpl6-1'])].
[sujeto(['These', sequences]), verbo([have]), complemento([characteristics, similar, to, those, of, the, transposable, elements, '(', 'TE)', belonging, to, the, 'PIF/Harbinger', superfamily])].
[sujeto(['The', above, evidences]), verbo([suggest]), complemento([a, novel, mechanism, in, which, the, 5, '\'', -, 'UTR', of, the, transferred, mitochondrial, gene, was, acquired, via, a, 'TE'])].
[sujeto(['Since', the, 5, '\'', -, 'UTRs', and, introns, within, the, 5, '\'', -, 'UTRs', often, contain, transcriptional, and, posttranscriptional, 'cis-elements,', the, transferred, rice, mitochondrial, rpl6, gene, may]), verbo([have]), complemento([acquired, its, 'cis-element', from, a, 'TE'])].
[sujeto(['Most', attention]), verbo([has]), complemento([been, dedicated, to, the, 'smallest,', 18, kDa, 'FGF2', variant, that, is, released, by, cells, and, acts, through, activation, of, 'cell-surface', 'FGF-receptor', tyrosine, kinases])].
[sujeto(['There', 'are,', 'however,', several, higher, molecular, weight, '(', 'HMW)', variants, of, 'FGF2', that, rarely, leave, their, producing, 'cells,', are]), verbo([retained]), complemento([in, the, nucleus, and, act, independently, of, 'FGF-receptors', '(', 'FGFR)'])].
[sujeto(['Small-colony', variants, '(', 'SCVs)', of, 'Staphylococcus', aureus, are, a, 'slow-growing', subpopulation, whose, phenotypes, can, include, resistance, to, 'aminoglycosides,', defects, in, electron, 'transport,', and]), verbo([enhanced]), complemento([persistence, in, mammalian, cells])].
[sujeto(['Mutation', analysis]), verbo([reveals]), complemento([different, genetic, classes, of, 'FA-resistant', 'SCVs'])].
[sujeto(['One', 'class,', 'FusA-SCVs,']), verbo([have]), complemento([amino, acid, substitution, mutations, in, the, ribosomal, translocase, 'EF-G', different, from, those, found, in, classic, 'FusA', mutants])].
[sujeto(['Accordingly,', we]), verbo([have]), complemento([identified, new, genetic, and, phenotypic, classes, of, 'FA-resistant', mutants, and, clarified, the, genetic, basis, of, a, subset, of, 'S'])].
[sujeto(['The', results, indicated, that, expression, of, 'RPL6', in, 'K562/A02', was, higher, than, that, in, 'K562;', resistance, of, 'sense-transfected', 'K562', cells, to, doxorubicin, was, 325, '%', of, control, 'cells,', apoptosis, and, 'caspase-3', activity]), verbo([decreased]), complemento(['(', 'P<0'])].
[sujeto([5, ')', ;, whereas, resistance, of, 'antisense-transfected', 'K562/A02', cells, to, adriamycin, was, 38, '%', of, control, 'cells,', apoptosis, and, 'caspase-3', activity, significantly]), verbo([increased]), complemento(['(', 'P<0'])].
[sujeto(['The', 'three-dimensional', structures, of, the, 'alpha-sarcin', ribotoxin, and, its, 'delta(7-22)', deletion, 'mutant,', both, complexed, with, a, 20, -, mer, oligonucleotide, mimicking, the, 'sarcin/ricin', loop, '(', 'SRL)', of, the, 'ribosome,']), verbo([have]), complemento([been, docked, into, the, structure, of, the, 'Halobacterium', marismortui, ribosome, by, fitting, the, nucleotide, atomic, coordinates, into, those, of, the, ribosomal, 'SRL'])].
[sujeto(['This', study]), verbo([has]), complemento([revealed, that, two, regions, of, the, 'ribotoxin,', residues, 11, -, 16, and, 84, -, 85, ',', contact, the, ribosomal, proteins, 'L14', '(', residues, 99, -, 105, ')', and, 'L6', '(', residues, 88, -, 92, ')', ',', respectively])].
[sujeto(['We']), verbo([have]), complemento([generated, 3900, 'enhancer-based', 'activation-tagged', 'plants,', in, addition, to, 1030, stable, 'Dissociator-enhancer', plants, in, a, widely, cultivated, indica, rice, 'variety,', 'BPT-5204'])].
[sujeto(['We']), verbo([have]), complemento([further, selected, five, plants, with, low, 'Δ(13)', 'C,', high, quantum, efficiency, and, increased, plant, yield, compared, with, wild, type, for, a, detailed, investigation])].
[sujeto(['Two', genes, coding, for, proteins]), verbo([involved]), complemento([in, 60, 'S', ribosomal, 'assembly,', 'RPL6', and, 'RPL23A,', were, among, those, that, became, activated, by, enhancers])].
[sujeto(['The', high, 'up-regulation', of, 'RPL6', and, 'RPL23A', in, various, stress, treatments, and, the, presence, of, significant, 'cis-regulatory', elements, in, their, promoter, regions, along, with, the, high, 'up-regulation', of, several, of, 'RPL', genes, in, various, stress, treatments, indicate, that, they, are, potential]), verbo([targets]), complemento([for, manipulating, 'WUE/abiotic', stress, tolerance])].
[sujeto(['Herein', we, present, evidence, that, 'VHLs']), verbo([associates]), complemento([with, ribosome, complex, via, interaction, with, the, large, subunit, 6, '(', 'RPL6)'])].
[sujeto(['VHLs', deficiency]), verbo([leads]), complemento([to, remarkable, sensitivity, to, drug, treatments, eliciting, nascent, protein, 'mis-folding', and, translational, errors])].
[sujeto(['The', ubiquitination, of, nascent, peptides, are, dramatically]), verbo([increased]), complemento([upon, the, ectopic, 'over-expression', of, 'VHLs,', which, simultaneously, 'co-localizes', with, proteasome, and, thus, may, facilitate, the, 'ubiquitin-proteasome', mediated, degradation])].
[sujeto(['In', 'summary,', 'VHLs', contributes, to, protein, quality, control, in, addition, to, its, canonical, function, in]), verbo([maintaining]), complemento([homeostasis, of, 'hypoxia-induced', factors, alpha, subunit, '(', 'HIFα)', in, response, to, environmental, oxygen, supply])].
[sujeto(['The', objective, of, this, study, was, to, identify, hub, genes, and, pathways]), verbo([associated]), complemento([with, acute, respiratory, infection, '(', 'ARI)', in, infants, based, on, gene, expression, profiles])].
[sujeto(['Differentially']), verbo([expressed]), complemento([genes, '(', 'DEGs)', between, 'ARI', and, normal, '(', 'controls)', infants, were, identified, based, on, linear, modeling, of, the, microarray, data, using, 'Limma', package])].
[sujeto(['In', 'summary,', this, study]), verbo([suggests]), complemento(['RPL6,', 'RPL3,', and, 'RPL15', as, hub, genes, and, the, ribosome, pathway, to, be, significantly, associated, with, viral, 'ARI', in, 'infants,', which, might, also, be, used, as, potential, markers, for, the, viral, etiology])].
[sujeto(['The', disease]), verbo([has]), complemento([been, associated, with, mutations, or, large, deletions, in, 11, ribosomal, protein, genes, including, 'RPS7,', 'RPS10,', 'RPS17,', 'RPS19,', 'RPS24,', 'RPS26,', 'RPS29,', 'RPL5,', 'RPL11,', 'RPL26', and, 'RPL35A', as, well, as, 'GATA1', in, more, than, 50, '%', of, patients])].
[sujeto(['To', identify, new, mutations, responsible, for, 'Diamond-Blackfan', 'anaemia,', we, performed, 'whole-exome', sequencing, analysis, of, 48, patients, with, no, documented, 'mutations/deletions']), verbo([involving]), complemento([known, 'Diamond-Blackfan', anaemia, genes, except, for, 'RPS7,', 'RPL26,', 'RPS29', and, 'GATA1'])].
[sujeto(['Additional', novel, mutations, were]), verbo([found]), complemento([in, eight, 'patients,', including, 'RPL3L,', 'RPL6,', 'RPL7L1T,', 'RPL8,', 'RPL13,', 'RPL14,', 'RPL18A', and, 'RPL31'])].
[sujeto(['In', 'conclusion,', we, identified, novel, germline, mutations, of, two, ribosomal, protein, genes, responsible, for, 'Diamond-Blackfan', 'anaemia,', further, confirming, the, concept, that, mutations, in, ribosomal, protein, genes]), verbo([lead]), complemento([to, 'Diamond-Blackfan', anaemia])].
[sujeto(['Ribosomes', are, the, molecular, machines, that]), verbo([translate]), complemento([mRNAs, into, proteins])].
[sujeto(['The', synthesis, of, ribosomes, is, therefore, a, fundamental, cellular, process, and, consists, in, the, ordered, assembly, of, 79, ribosomal, proteins, '(', 'r-proteins)', and, four, ribosomal, 'RNAs', '(', 'rRNAs)', into, a, small, 40, 'S', and, a, large, 60, 'S', ribosomal, subunit, that, form, the]), verbo([translating]), complemento([80, 'S', ribosomes])].
[sujeto(['Most', of, our, knowledge, concerning, this, dynamic, 'multi-step', process, comes, from, studies, with, the, yeast, 'Saccharomyces', 'cerevisiae,', which]), verbo([have]), complemento([shown, that, assembly, and, maturation, of, 'pre-ribosomal', 'particles,', as, they, travel, from, the, nucleolus, to, the, 'cytoplasm,', relies, on, a, multitude, '(', &, 'gt;200)', of, biogenesis, factors])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, the, 'AAA-ATPase', 'Rix7', promotes, the, release, of, the, essential, biogenesis, factor, 'Nsa1', from, late, nucleolar, 'pre-60S', particles])].
[sujeto(['Interestingly,', 'dominant-negative', alleles, of, 'RIX7']), verbo([retain]), complemento([their, phenotype, in, the, absence, of, 'Nsa1,', suggesting, that, 'Rix7', may, have, additional, nuclear, substrates, besides, 'Nsa1'])].
[sujeto(['Mak5', is]), verbo([associated]), complemento([with, the, 'Nsa1', 'pre-60S', particle, and, synthetic, lethal, screens, with, mak5, alleles, identified, the, 'r-protein', 'Rpl14', and, the, 60, 'S', biogenesis, factors, 'Ebp2,', 'Nop16', and, 'Rpf1,', which, are, genetically, linked, amongst, each, other])].
[sujeto(['Finally,', 'over-expression', of, 'Rix7', negatively, affects, growth, of, mak5, and, ebp2, mutant, cells, both, in, the, absence, and, presence, of, 'Nsa1,']), verbo([suggesting]), complemento([that, 'Rix7,', at, least, when, excessively, 'abundant,', may, act, on, structurally, defective, 'pre-60S', subunits, and, may, subject, these, to, degradation])].
[sujeto(['We']), verbo([have]), complemento([identified, a, common, expression, pattern, for, rpl, genes, in, developing, zebrafish, larvae])].
[sujeto(['With', respect, to, the, 'pancreas,', rpl, genes, are, highly]), verbo([expressed]), complemento([in, 'ptf1a-expressing', pancreatic, progenitors, at, 48, 'hpf,', suggesting, possible, functional, roles, in, pancreatic, morphogenesis, 'and/or', differentiation])].
[sujeto(['Utilizing', two, available, mutant, 'lines,', 'rpl23a(hi2582)', and, 'rpl6(hi3655b),', we]), verbo([found]), complemento([that, 'ptf1a-expressing', pancreatic, progenitors, fail, to, properly, expand, in, embryos, homozygous, for, either, of, these, genes])].
[sujeto(['However,', concomitant, p53, knockdown, was, unable, to, rescue, normal, pancreatic, progenitor, expansion, in, either, 'rpl23a(hi2582)', or, 'rpl6(hi3655b)', mutant, 'embryos,']), verbo([suggesting]), complemento([required, and, 'p53-independent', roles, for, rpl23a, and, rpl6, in, pancreas, development])].
[sujeto(['Penile', cancer, is]), verbo([associated]), complemento([with, a, number, of, established, risk, factors, and, associated, diseases, including, phimosis, with, chronic, 'inflammation,', human, papillomavirus, '(', 'HPV)', 'infection,', poor, hygiene, and, smoking])].
[sujeto(['ANXA1', and, p16, proteins, were, significantly, more]), verbo([expressed]), complemento([in, the, cells, from, 'high-risk', 'HPV-positive', penile, carcinoma, as, compared, to, 'HPV-negative', tumors, '(', 'p<0'])].
[sujeto(['Overexpression', of, 'ANXA1', might, be]), verbo([mediated]), complemento([by, 'HPV', 'E6', in, penile, squamous, cell, carcinoma, of, patients, with, 'high-risk', 'HPVs,', suggesting, that, this, gene, plays, an, important, role, in, penile, cancer])].
[sujeto([3, 'T3-L1', preadipocytes, were, cultured, to, confluency, and, adipogenesis, was]), verbo([induced]), complemento([by, standard, protocols, using, a, hormonal, cocktail])].
[sujeto(['Interestingly,', we]), verbo([found]), complemento(['Ghrelin', to, be, 'down-regulated'])].
[sujeto(['Up-regulated', genes, comprise, factors, that, are, nucleic, acid]), verbo([binding]), complemento(['(', 'eIF4B,', 'HSF1,', 'IRF6,', 'MYC,', 'POLR2a,', 'RPL18,', 'RPL27a,', 'RPL6,', 'RPL7a,', 'RPS18,', 'RPSa,', 'TSC22d3),', form, part, of, ribosomes, '(', 'RPL18,', 'RPL27a,', 'RPL6,', 'RPL7a,', 'RPS18,', 'RPSa),', act, on, the, regulation, of, translation, '(', 'eIF4B)', or, transcription, '(', 'HSF1,', 'IRF6,', 'MYC,', 'TSC22d3)'])].
[sujeto(['Others']), verbo([act]), complemento([as, chaperones, '(', 'BAG3,', 'HSPA8,', 'HSP90ab1)', or, in, other, metabolic, or, signals, transducing, processes])].
[sujeto(['First,', because, there, are, no, comparative, studies, that]), verbo([have]), complemento([established, suitable, quantitative, 'real-time', 'PCR', reference, genes, in, sturgeons, for, any, physiological, 'conditions,', we, evaluated, six, candidate, reference, genes, '(', 'ACTB,', 'RPL13,', 'UBQ,', 'RPL6,', 'GAPDH', and, 'EF1A)', during, the, early, development, of, 'Persian', sturgeon])].
[sujeto(['This']), verbo([suggests]), complemento([that, the, vitamin, 'C', requirements, are, highest, during, early, life, 'stages,', and, it, is, likely, that, the, changes, in, 'GULO', mRNA, expression, are, associated, with, changes, in, 'GULO', enzyme, activity])].
[sujeto(['Among', the, genes, identified, by, this, approach, were, genes, from, diverse, functional, groups, such, as, structural, constituents, of, ribosomes, '(', 'RPL6,', 'RPL7,', 'RPS12,', 'RPS15A),', kinases, '(', 'CABC1,', 'CCT2,', 'RPL41),', transcriptional, and, translational, regulators, '(', 'SFRS2,', 'TUFM,', 'ZBTB4),', signal, transducers, '(', 'FLNA),', control, of, cell, growth, and, proliferation, '(', 'RPS6),', angiogenesis]), verbo([promoting]), complemento([factors, '(', 'ITGB1),', and, others, '(', 'SLC25A19,', 'NCKAP1,', 'BST1,', 'DBH,', 'FZD7,', 'NACA,', 'MTHFD2)'])].
[sujeto(['By', using, transfected, or, knockout, cell, models, we]), verbo([found]), complemento([that, the, tumor, suppressor, 'p16(INK4A)', and, the, 'anti-oxidant', 'protein,', 'catalase,', conferred, resistance, towards, 'ART,', while, the, oncogene, 'HPV-E6', conferred, sensitivity, towards, 'ART'])].
[sujeto(['In', 'conclusion,', our, pharmacogenomic, approach, revealed, that, response, of, tumor, cells, towards, 'ART', is, 'multi-factorial', and, is, determined, by, gene, expression]), verbo([associated]), complemento([with, either, 'ART', sensitivity, or, resistance])].
[sujeto([angiogenesis]), verbo([promoting]), complemento(['factors,', cell, growth, and, 'proliferation-associated', genes, signal, transducers, and, 'kinases)', are, also, implicated, in, clinical, responsiveness, of, tumors, towards, chemotherapy])].
[sujeto(['Diamond-Blackfan', anemia, '(', 'DBA),', an, inherited, bone, marrow, failure, syndrome, characterized, by, anemia, that, usually, presents, before, the, first, birthday, or, in, early, 'childhood,', is]), verbo([associated]), complemento([with, birth, defects, and, an, increased, risk, of, cancer])].
[sujeto(['DBA']), verbo([has]), complemento([been, associated, with, mutations, in, seven, ribosomal, protein, '(', 'RP)', 'genes,', 'RPS19,', 'RPS24,', 'RPS17,', 'RPL35A,', 'RPL5,', 'RPL11,', and, 'RPS7,', in, about, 43, '%', of, patients])].
[sujeto(['Mammary', gland, development, and, differentiation, is]), verbo([regulated]), complemento([by, a, number, of, growth, factors, and, hormones])].
[sujeto(['To', 'date,', few, '\'', 'early-response\'', genes, transcriptionally]), verbo([activated]), complemento([by, lactogenic, hormones, have, been, described])].
[sujeto(['We']), verbo([have]), complemento([used, representational, difference, analysis, '(', 'RDA)', to, search, for, 'lactogenic-responsive', genes, in, 'SCp2', mouse, mammary, epithelial, cells])].
[sujeto(['One', of, the, cDNAs, identified, encoded, the, 'DNA-binding', protein, 'Taxreb107,', originally, identified, as, a, 'HTLV-I', 'Tax', responsive, element]), verbo([binding]), complemento([protein])].
[sujeto(['Taxreb107', 'RNA', levels, were, developmentally]), verbo([regulated]), complemento([in, the, mouse, mammary, 'gland,', where, levels, increased, substantially, during, 'mid-', and, late, pregnancy, and, persisted, during, lactation])].
[sujeto(['Ribosomal', protein, '(', 'Rp)', 'L6', is, also, defined, as, 'Taxreb107', '(', 'Tax', responsive, element]), verbo([binding]), complemento([protein, 107, ')', for, its, binding, activity, to, the, long, terminal, repeats, of, human, 'T', cell, leukemia, virus, '(', 'HTLV)-I'])].
[sujeto(['The', promoter, of, 'RpL6/Taxreb107', contains, recognition, sites, for, multiple, transcription, factors, including]), verbo([nuclear]), complemento([factor, '(', 'NF)-kappa', 'B'])].
[sujeto(['Luciferase', reporter, assay, showed, that, the, 'RpL6/Taxreb107', promoter]), verbo([has]), complemento([a, constitutive, activity, in, transfected, 'cells,', and, the, constitutive, activity, depends, on, the, intact, promoter])].
[sujeto(['Expression', of, 'HTLV-I', viral, protein, 'Tax', mildly, but, reproducibly]), verbo([induced]), complemento(['RpL6/Taxreb107', mRNA, and, promoter, activity])].
[sujeto(['We']), verbo([provide]), complemento([evidence, suggesting, that, induction, of, 'RpL6/Taxreb107', by, 'Tax', is, at, least, partially, mediated, by, the, 'NF-kappa', 'B', site, in, the, promoter, of, 'RpL6/Taxreb107'])].
[sujeto(['Taken', 'together,', 'Tax', 'up-regulates', 'RpL6/Taxreb107', and, this, may]), verbo([provide]), complemento([a, feedback, mechanism, to, facilitate, proliferation, of, 'HTLV-I-infected', cells, and, production, of, viral, particles])].
[sujeto(['Ribosomal', protein, 'L6', was, also, defined, as, 'Taxreb107', '(', 'Tax', responsible, element]), verbo([binding]), complemento([protein, 107, ')', for, its, activity, of, binding, to, the, long, terminal, repeats, of, 'HTLV-1'])].
[sujeto(['Results']), verbo([suggest]), complemento([that, 'Tax', can, interact, with, 'Taxreb107/RpL6', directly, and, 'Taxreb107/RpL6', may, regulate, the, function, of, 'Tax', in, 'HTLV-1', proliferation])].
[sujeto(['In', 'PNH,', as, well, as, in, 'AA', and, 'MDS,', genetic, instability, and]), verbo([increased]), complemento([mutation, frequency, have, been, detected])].
[sujeto(['Therefore,', a, second, event, is, very, 'likely,', such, as, additional, 'mutations,']), verbo([leading]), complemento([to, clonal, expansion, of, 'GPI-deficient', bone, marrow, stem, cell, in, 'PNH'])].
[sujeto(['In', order, to, elucidate, the, molecular, basis, of, clonal, expansion, in, 'PNH,', we, identified, several, genes, differentially]), verbo([expressed]), complemento([in, normal, and, 'GPI-deficient', cells, of, 'PNH', patients, by, combination, of, 'RNA', fingerprinting, and, cDNA, array, hybridization])].
[sujeto(['Expression', of, two, of, these, 'genes,', 'EGR-1', and, 'TAXREB107,']), verbo([has]), complemento([been, further, investigated])].
[sujeto(['Moreover,', similar, levels, of, expression, in, cases, of, other, clonal, 'diseases,', such, as, 'MPS', and, 'MDS,']), verbo([has]), complemento([been, identified])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, additional, genetic, alterations, apart, from, 'PIG-A', mutations, could, be, present, in, 'PNH', granulocytes])].
[sujeto(['Myogenic', regulatory, factors, '(', 'MRFs)', are, vital, transcription, factors, that]), verbo([act]), complemento([at, multiple, points, during, development, to, establish, the, skeletal, muscle, phenotype])].
[sujeto(['This', class, of, 'muscle-restricted,', basic, 'helix-loop-helix', '(', 'bHLH)', proteins]), verbo([acts]), complemento([in, concert, with, additional, transcriptional, modulators, to, precisely, control, muscle, gene, expression])].
[sujeto(['We']), verbo([have]), complemento([isolated, the, chicken, homologue, of, 'Tax', responsive, element, binding, protein, 107, '(', 'TaxREB107)'])].
[sujeto(['Northern', analysis, demonstrated, that, the, gene, is]), verbo([expressed]), complemento([in, multiple, tissues, including, skeletal, muscle])].
[sujeto(['Immunofluorescent', staining, revealed, that, the, cTaxREB107, protein, is, located, in, both, the]), verbo([nuclear]), complemento([and, cytoplasmic, compartments])].
[sujeto([cTaxREB107]), verbo([increased]), complemento([troponin, 'I', reporter, gene, activity, as, well, as, 'MRF-directed', transcription, from, a, multimerized, skeletal, muscle, 'E-box', reporter, gene, '(', 4, 'Rtk-luc)'])].
[sujeto(['However,', cotransfection, of, expression, plasmids, coding, for, 'MyoD', and, cTaxREB107, did, not, produce, an]), verbo([increase]), complemento([in, 4, 'Rtk-luc', suggesting, that, cTaxREB107, enhances, myogenic, gene, transcription, through, a, means, independent, of, a, physical, association, with, 'MyoD'])].
[sujeto(['Using', a, subtractive, hybridization, 'strategy,', we]), verbo([have]), complemento([identified, the, murine, homolog, of, the, 'TAX', response, 'element-binding', protein, 'TAXREB107', as, an, 'Epo', early, response, gene, in, 'Rauscher', murine, erythroleukemia, cells])].
[sujeto(['This', was, confirmed, by, 'Northern', blot, 'analyses,', which, showed, a, fourfold]), verbo([increase]), complemento([in, 'TAXREB107', mRNA, after, 1, hr, of, erythropoietin, treatment])].
[sujeto(['After', 3, hr, the, transcript, had]), verbo([decreased]), complemento([to, approximately, twofold, above, control, levels])].
[sujeto(['Inhibition', of, this, induction, with, antisense, oligodeoxynucleotides]), verbo([increased]), complemento(['Epo-induced', hemoglobinization, 2.5, -, fold])].
[sujeto(['The', results, implicate, 'TAXREB107', in, erythropoiesis, and, support, the, hypothesis, that, the, 'TAXREB', proteins]), verbo([have]), complemento([functions, outside, the, context, of, 'HTLV-I', infection])].
[sujeto(['L6/TAXREB107', also]), verbo([mediates]), complemento([the, 'DNA', binding, of, the, 'HTLV-1', transactivator, 'Tax'])].
[sujeto(['In', vitro]), verbo([binding]), complemento([experiments, indicated, that, both, the, 'high-molecular-weight', forms, '(', 'HMW)', and, the, 18, -, kDa, form, of, 'FGF-2', bind, to, 'L6/TAXREB107'])].
[sujeto(['Deletion', analysis]), verbo([suggested]), complemento([that, 'L6/TAXREB107', has, two, binding, sites, for, 'HMW', 'FGF-2', and, one, binding, site, for, 18, -, kDa, 'FGF-2,', implying, that, the, unique, 'N-terminal', extension, of, the, 'HMW', 'FGF-2', is, one, of, the, binding, domains, for, 'L6/TAXREB107'])].
[sujeto(['Transfection', assays, showed, that, high, expression, of, either, 'HMW', or, 18, kDa, 'FGF-2']), verbo([stimulates]), complemento(['Tax-mediated', transactivation, in, 'NIH', 3, 'T3', cells])].
[sujeto(['This', result]), verbo([suggests]), complemento([a, possible, role, of, 'FGF-2', in, 'Tax-mediated', 'HTLV-1', transformation, as, well, as, 'FGF-2', binding, to, ribosomes, 'and/or', their, precursors])].
[sujeto(['Rel/NF-kappa', 'B', is, a, ubiquitous, transcription, factor, that, consists, of, multiple, polypeptide, 'subunits,', and, is, subject, to, complex, regulatory, mechanisms, that]), verbo([involve]), complemento(['protein-protein', 'interactions,', 'phosphorylation,', 'ubiquitination,', proteolytic, 'degradation,', and, nucleocytoplasmic, translocation])].
[sujeto(['The', sophisticated, control, of, 'Rel/NF-kappa', 'B', activity, is, not, surprising, since, this, transcription, factor, is]), verbo([involved]), complemento([in, a, wide, array, of, cellular, responses, to, extracellular, 'cues,', associated, with, 'growth,', 'development,', 'apoptosis,', and, pathogen, invasion])].
[sujeto(['Thus,', it, is, not, unexpected, that, this, versatile, cellular, homeostatic, switch, would, be, affected, by, a, variety, of, viral, 'pathogens,', which]), verbo([have]), complemento([evolved, mechanisms, to, utilize, various, aspects, of, 'Rel/NF-kappa', 'B', activity, to, facilitate, their, 'replication,', cell, survival, and, possibly, evasion, of, immune, responses])].
[sujeto(['We']), verbo([report]), complemento([the, cDNA, sequence, of, a, mouse, gene, homologous, to, the, 'HTLV-I', tax, responsive, element, binding, protein, 'TAXREB107', '(', 'M-TAXREB107)'])].
[sujeto(['This', gene, is, constitutively, and, ubiquitously]), verbo([expressed]), complemento([indicating, a, conserved, biological, function])].
[sujeto(['Five', cDNA, clones, for, 'TAXREB', proteins, that]), verbo([bind]), complemento([to, the, 'tax-responsive', enhancer, element, of, human, 'T-cell', leukemia, virus, type, 'I', '(', 'HTLV-I)', were, isolated, from, a, 'Jurkat', cell, cDNA, library])].
[sujeto(['The', 'beta-galactosidase', fusion, proteins, of, three, of, these, clones, specifically]), verbo([recognized]), complemento([the, domain, 'C', within, the, enhancer])].
[sujeto(['RNA', blot, analysis, showed, that, the, level, of, mRNA, for, 'TAXREB107']), verbo([increased]), complemento([transiently, in, 'Jurkat', cells, on, treatment, with, 'TPA'])].
[sujeto(['Immunoblot', analysis, showed, that, polyclonal, antibody, against, 'TAXREB107', specifically]), verbo([recognized]), complemento([a, 34, -, kD, protein, in, 'Jurkat', cells])].
[sujeto(['TAXREB107', may]), verbo([participate]), complemento([in, 'tax-mediated', 'trans-activation', of, transcription])].
[sujeto(['We']), verbo([have]), complemento([previously, observed, the, reversal, of, lipid, droplet, deposition, in, skeletal, muscle, of, morbidly, obese, patients, following, bariatric, surgery])].
[sujeto(['Inhibition', of, autophagy, by, bafilomycin]), verbo([increased]), complemento(['TG', accumulation, and, also, increased, 'lipid-mediated', cell, death])].
[sujeto(['Unexpectedly,', treatment, with, both, drugs, added, simultaneously, resulted, in]), verbo([decreased]), complemento([lipid, accumulation])].
[sujeto(['Thus', the, association, of, p62, with, lipid, droplet, turnover]), verbo([suggests]), complemento([a, novel, pathway, for, the, breakdown, of, lipid, droplets, in, muscle, cells])].
[sujeto(['In', 'addition,', treatment, with, rapamycin, and, bafilomycin, together, also]), verbo([suggested]), complemento([the, export, of, 'TG', into, the, extracellular, space])].
[sujeto(['We', conclude, that, lipophagy]), verbo([promotes]), complemento([the, clearance, of, lipids, from, myocytes, and, switches, to, an, 'alternative,', 'p62-mediated,', 'lysosomal-independent', pathway, in, the, context, of, chronic, lipid, overload, '(', *, 'P<0'])].
[sujeto(['Following', intraperitoneal, administration, of, 'Vehicle', or, 'Milnacipran', '(', 30, 'mg/kg),', which, is, one, of, 'serotonin-noradrenaline', reuptake, inhibitors, '(', 'SNRI),', 0.1, '%', 'AA', was, infused, into, the, bladder, in, normal, '(', n, =, 4, ',', 'each)', and, spinal, cord, injury, '(', 'SCI)', '(', n, =, 4, ',', 'each)', rats, for, 2, h, on, 'consciousness,', and, 'c-Fos,', 5, -, 'HT', and, 'DβH', were, stained, using, immunohistochemistry, at, the, 'L6', spinal, cord, as, spinal, areas]), verbo([associated]), complemento([with, 'LUT'])].
[sujeto(['The', total, number, of, 'c-Fos-positive', cells, was, significantly]), verbo([increased]), complemento([in, 'SCI', rats, compared, to, 'Normal', rats, '(', 209.4, ±, 7.1, in, 'Normal,', 336.4, ±, 28.9, in, 'SCI,', 'P', &, 'lt;', 0.05, ')', ',', which, indicated, that, interruption, of, supraspinal, modulation, enhances, nocieptive, transmission, in, the, 'LUT'])].
[sujeto(['Regarding', the, effect, of, 'Milnacipran', 'administration,', the, number, of, 'c-Fos-positive', cells, was, significantly]), verbo([decreased]), complemento([at, all, region, of, the, 'L6', spinal, cord, in, normal, rats, '(', 'P', &, 'lt;', 0.05, ')', ',', while, this, reduction, was, not, observed, in, 'SCI', rats])].
[sujeto(['Supraspinal', projections, of, descending, serotonergic, and, noradrenergic, pathways, to, the, lower, lumbar, spinal, cord]), verbo([modulate]), complemento([nocieptive, transmission, in, the, 'LUT'])].
[sujeto(['Administration', of, 'SNRI', attenuates, nocieptive, transmission, in, the, 'LUT,', which, could, result, from, enhancement, of]), verbo([modulating]), complemento([descending, serotonergic, and, noradrenergic, pathways])].
[sujeto(['Dietary', administration, of, the, histone, deacetylase, '(', 'HDAC)', inhibitor, butyric, acid, -, a, short, chain, fatty, acid, present, in, milk, products, and, also, bacterially, produced, in, the, intestine, -]), verbo([has]), complemento([been, shown, to, increase, energy, expenditure, and, favour, insulin, sensitivity, in, mice, through, induction, of, 'PGC1α', '(', peroxisome, 'proliferator-activated', receptor, gamma, 'co-activator', 1, 'α)', and, 'AMPK', '(', 'AMP-activated', protein, 'kinase)', in, skeletal, 'muscle,', and, a, consequential, increase, of, mitochondrial, fatty, acid, oxidation])].
[sujeto(['Here,', we, investigate, whether, such, physiological, improvements, are]), verbo([associated]), complemento([to, epigenetic, effects, dependent, on, increased, histone, acetylation, and, whether, butyrate, exerts, a, direct, action, on, skeletal, muscle, insulin, signalling])].
[sujeto(['We', show, that, sodium, butyrate, '(', 'NaBut)', ameliorates, the, 'insulin-resistant', 'phenotype,']), verbo([induced]), complemento([in, 'L6', myotubes, by, prolonged, exposure, to, 'palmitate,', by, 'i)', increasing, the, 'insulin-induced', phosphorylation, of, both, 'PKB', '(', protein, kinase, 'B)', and, 'MAPK', '(', mitogen, activated, protein, 'kinase),', the, two, branches, of, insulin, signalling, and, 'ii)', increasing, histone, 'H3', acetylation, -, even, in, the, presence, of, palmitate, -, on, chromatin, in, proximity, of, the, 'Irs1', '(', insulin, receptor, substrate, 1, ')', transcriptional, start, site])].
[sujeto(['Consequently,', 'NaBut']), verbo([induced]), complemento(['Irs1', mRNA, and, protein, 'overexpression,', which, in, turn, relayed, higher, 'insulin-stimulated', 'IRS1', tyrosine, phosphorylation, and, 'PI', 3, -, kinase, '(', phosphoinositide, 3, -, 'kinase)', 'association,', suggesting, that, the, increased, 'IRS1', expression, may, mediate, the, 'insulin-sensitizing', effects, of, 'NaBut'])].
[sujeto(['Furthermore,', downstream, of, 'PKB,', 'NaBut']), verbo([induced]), complemento(['GSK3β', gene, upregulation])].
[sujeto(['Our', observations, indicate, that, 'NaBut', -, through, its, action, as, 'HDAC', inhibitor, -, can]), verbo([promote]), complemento([insulin, responsiveness, in, 'L6', myotubes, under, conditions, of, 'lipid-induced', insulin, resistance])].
[sujeto(['In-depth', proteomic, and, biochemical, studies, on, 'CVF']), verbo([have]), complemento([revealed, that, it, contains, large, amounts, of, endogenous, proteases, and, protease, 'inhibitors,', including, an, abundance, of, several, members, of, the, tissue, 'kallikrein-related', peptidase, '(', 'KLK)', family])].
[sujeto(['KLKs']), verbo([have]), complemento([been, postulated, to, have, roles, in, physiological, functions, related, to, antimicrobial, 'processes,', vaginal, and, cervical, epithelial, 'desquamation,', sperm, 'transport,', and, the, processing, of, fetal, membranes, as, observed, in, preterm, premature, rupture, of, membranes])].
[sujeto(['Increased', understanding, of, the, functional, roles, of, 'KLKs', in, the, lower, female, reproductive, system, could]), verbo([lead]), complemento([to, new, diagnostic, and, therapeutic, modalities, for, conditions, such, as, vaginal, infections, and, vaginal, atrophy])].
[sujeto(['Contraction', of, the, sheath, propels, the, inner, tube, capped, by, the, 'VgrG', spike, protein, towards, the]), verbo([target]), complemento([cell])].
[sujeto(['During', the, assembly, 'process,', the, baseplate, is]), verbo([recruited]), complemento([to, a, 'trans-envelope', complex, comprising, the, 'TssJ', outer, membrane, lipoprotein, and, the, 'TssL', and, 'TssM', inner, membrane, proteins])].
[sujeto(['The', baseplate, is]), verbo([recruited]), complemento([to, the, membrane, complex, through, multiple, contacts, including, interactions, of, 'TssG', and, 'TssK', with, the, cytoplasmic, loop, of, 'TssM,', and, 'TssK', interaction, with, the, cytoplasmic, domain, of, 'TssL,', 'TssLCyto'])].
[sujeto(['Here,', we, show, that, 'TssLCyto']), verbo([interacts]), complemento([also, with, the, 'TssE', baseplate, subunit])].
[sujeto(['Based', on, the, available, 'TssLCyto', 'structures,', we]), verbo([targeted]), complemento([conserved, regions, and, specific, features, of, 'TssLCyto', in, enteroaggregative, 'Escherichia', coli, '(', 'EAEC)'])].
[sujeto(['By', using, bacterial, 'two-hybrid', and, 'co-immunoprecipitation,', we, further, show, that, the, disordered, 'L3-L4', loop, is, necessary, to]), verbo([interact]), complemento([with, 'TssK,', that, the, 'L6-L7', loop, mediates, the, interaction, with, 'TssE,', whereas, the, 'TssM', cytoplasmic, loop, binds, the, conserved, groove, of, 'TssLCyto'])].
[sujeto(['Comparison', of, control, and, experimental, groups, resulted, with, an]), verbo([increase]), complemento([in, resistance, in, all, activities, in, biomechanical, tests, '(', p, 0.01, ')'])].
[sujeto(['Our', study, revealed, that, xenograft, plate, screw, and, metal, plate, screws]), verbo([provided]), complemento([equivalent, fusion, and, stabilization, in, anterior, lumbar, stabilization])].
[sujeto([2.2, ']', nonanes, are, already]), verbo([reported]), complemento([as, antiprotozoal, agents])].
[sujeto(['Our', previous, study, demonstrated, that, electrical, stimulation, at, the, dorsal, root, ganglion, '(', 'DRG)', with, an, implantable, 'micro-electrical', stimulation, system, '(', 'IMESS)', could]), verbo([trigger]), complemento([secretion, of, bone, anabolic, calcitonin, 'gene-related', peptide, '(', 'CGRP)', and, prevent, bone, loss, in, a, 'short-term', hindlimb, unloading, rat, model])].
[sujeto(['This', study, was, designed, to, further, investigate, whether, electrical, stimulation, to, the, 'DRG', could]), verbo([prevent]), complemento([bone, loss, due, to, prolonged, unloading])].
[sujeto(['Following', unloading, for, 6, 'weeks,', proximal, tibia, metaphysis, was, shown, 64.0, '%']), verbo([decrease]), complemento([in, bone, mineral, content, '(', 'BMC)', and, 47.0, '%', decrease, in, bone, mineral, density, '(', 'BMD)', in, 'HU', group, while, significant, reduced, bone, lose, with, 2.7, '%', increase, in, total, 'BMC', and, only, 9.2, '%', decrease, in, total, 'BMD', in, 'HUES', group])].
[sujeto(['Diaphyseal', 'BMD']), verbo([decreased]), complemento([significantly, in, both, 'HU', and, 'HUES', group, as, compared, with, 'CC', group])].
[sujeto(['This', experimental, study, proved, the, proposed, concept, using, electrical, stimulation, at, the, 'DRG', for, prevention, of, 'disuse-induced', bone]), verbo([loss]), complemento([in, a, rat, hindlimb, suspension, model])].
[sujeto(['Sudden', onset, of, an, unexpected, and, severe, illness, is]), verbo([associated]), complemento([with, an, increased, stress, experience, of, family, members])].
[sujeto(['Only', one, study, to, date]), verbo([has]), complemento([explored, the, experience, of, family, members, of, patients, that, are, at, high, risk, of, dying, and, treated, with, 'ECMO'])].
[sujeto([&, 'nbsp;A', total, of, 10, family, members, of, patients, treated, with, 'ECMO', were]), verbo([recruited]), complemento([through, a, convenient, sampling, approach])].
[sujeto(['Nurses', and, other, staff]), verbo([involved]), complemento([in, the, care, of, 'ECMO', patients, must, pay, attention, to, individual, needs, of, the, family, and, activate, all, available, support, systems, to, help, them, cope, with, stress, and, strain])].
[sujeto(['Impaired', insulin, signaling, in, skeletal, muscle, cells]), verbo([causes]), complemento([insulin, resistance, associated, with, the, onset, of, type, 2, diabetes])].
[sujeto(['Although', interleukin, '(', 'IL)-1β']), verbo([has]), complemento([been, considered, to, be, implicated, in, the, pathogenesis, of, type, 2, 'diabetes,', the, action, of, prolonged, stimulation, with, 'IL-1β', on, the, insulin, signaling, pathway, in, skeletal, muscle, cells, remains, poorly, understood])].
[sujeto(['In', 'L6-GLUT4myc', 'cells,', stimulation, with, 'IL-1β', for, 24, h]), verbo([promoted]), complemento(['GLUT4', translocation, to, the, plasma, membrane, and, increased, glucose, uptake, in, a, 'concentration-dependent', 'manner,', whereas, 'short-term', stimulation, with, 'IL-1', for, up, to, 6, h, did, not, affect, that])].
[sujeto(['In', 'addition,', stimulation, with, 'IL-1β', for, 24, h, further]), verbo([increased]), complemento(['insulin-stimulated', 'GLUT4', translocation])].
[sujeto(['Interestingly,', stimulation, with, 'IL-1β', for, 24, h, did, not]), verbo([cause]), complemento([any, change, in, the, phosphorylation, of, insulin, signal, molecules, 'IR,', insulin, receptor, substrate, '(', 'IRS)-1,', 'Akt,', and, 'p21-activated', kinase, '(', 'PAK1)'])].
[sujeto(['Stimulation', with, 'IL-1β', for, 24, h, significantly]), verbo([increased]), complemento(['AMP-activated', protein, kinase, '(', 'AMPK)', phosphorylation, and, 'GLUT4', protein, expression])].
[sujeto(['Small', interfering, 'RNA', '(', 'siRNA)']), verbo([targeting]), complemento(['AMPK1/2', significantly, inhibited, 'IL-1β-stimulated', 'GLUT4', translocation])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, prolonged, stimulation, with, 'IL-1β', positively, regulates, 'GLUT4', translocation, in, skeletal, muscle, cells])].
[sujeto(['IL-1β', may]), verbo([have]), complemento([a, beneficial, effect, on, maintaining, glucose, homeostasis, in, skeletal, muscle, cells, in, patients, with, type, 2, diabetes])].
[sujeto(['The', 'pain-related', peptide, expression, was]), verbo([suppressed]), complemento([in, the, etanercept, '(', 100, µg, and, 1, ',', 0, 'µg)-administered', groups, in, a, 'dose-dependent', manner])].
[sujeto(['However,', a, significant]), verbo([decrease]), complemento([in, the, percentage, of, 'FG', and, 'CGRP', 'double-positive', cells, in, 'FG-positive', cells, was, observed, in, the, etanercept, '(', 100, µg, and, 1, ',', 0, 'µg)-administered', groups, in, a, 'dose-dependent', manner, '(', p, &, 'lt;0'])].
[sujeto(['However,', when, a, higher, dose, of, etanercept, '(', 100, µg, and, 1, ',', 0, 'µg)', was, 'administered,', the, 'pain-related', peptide, expression, was]), verbo([suppressed]), complemento([in, a, 'dose-dependent', manner])].
[sujeto(['The', stable, formation, of, remote, fear, memories, is, thought, to]), verbo([require]), complemento([neuronal, gene, induction, in, cortical, ensembles, that, are, activated, during, learning])].
[sujeto(['However,', the, set, of, genes]), verbo([expressed]), complemento([specifically, in, these, activated, ensembles, is, not, 'known;', knowledge, of, such, transcriptional, profiles, may, offer, insights, into, the, molecular, program, underlying, stable, memory, formation])].
[sujeto(['Here', we, use, 'RNA-Seq', to, identify, genes, whose, expression, is, enriched, in]), verbo([activated]), complemento([cortical, ensembles, labeled, during, associative, fear, learning])].
[sujeto(['We', first, establish, that, mouse, temporal, association, cortex, '(', 'TeA)', is]), verbo([required]), complemento([for, remote, recall, of, auditory, fear, memories])].
[sujeto(['Cross', comparisons, to, other, transcriptional, profiles, show, that, 125, of, the, enriched, genes, are, also, 'activity-regulated', in, vitro, or]), verbo([induced]), complemento([by, visual, stimulus, in, the, visual, 'cortex,', suggesting, that, they, may, be, induced, generally, in, the, cortex, in, an, 'experience-dependent', fashion])].
[sujeto(['Prominent', among, the, enriched, genes, are, those, encoding, potassium, channels, that, 'down-regulate', neuronal, 'activity,']), verbo([suggesting]), complemento([the, possibility, that, part, of, the, molecular, program, induced, by, fear, conditioning, may, initiate, homeostatic, plasticity])].
[sujeto(['Electrospun', nanofibres]), verbo([have]), complemento([been, shown, to, exhibit, extracellular, matrix, '(', 'ECM)-like', characteristics, required, for, tissue, engineering, in, terms, of, 'porosity,', 'flexibility,', fibre, organization, and, strength])].
[sujeto([3, -, 'D', primary, chondrocyte, and, neuronal, cultures, were, established, on, the, scaffolds, and]), verbo([maintained]), complemento([for, a, period, of, 10, days])].
[sujeto(['Sciatic', nerve, irritation, is, often]), verbo([associated]), complemento([with, disturbed, 'Ca(2+)', homeostasis, in, related, neurons, of, the, spinal, cord])].
[sujeto(['The', intensity, of, 'MT-Red', staining, was]), verbo([enhanced]), complemento([exclusively, at, the, ipsilateral, 'side,', indicating, increased, mitochondrial, activity])].
[sujeto(['CCI', of, the, sciatic, nerve]), verbo([caused]), complemento([massive, changes, in, the, composition, of, cardiolipin, reflecting, mitochondrial, impairment, in, the, early, phase, followed, by, regeneration, processes, as, late, response])].
[sujeto(['Sciatic', nerve, 'CCI']), verbo([caused]), complemento([decrease, in, the, capacity, of, mitochondrial, 'ATP', production, that, recovered, within, 14, &, 'nbsp;days', after, treatment])].
[sujeto(['In', 'conclusion,', we]), verbo([provide]), complemento([evidence, that, clustering, of, 'mitochondria,', already, verified, for, the, spinal, cord, sensory, neurons, after, 'CCI,', also, occurs, in, the, respective, motor, neurons])].
[sujeto(['Further', we]), verbo([have]), complemento([demonstrated, transient, impairment, of, the, capacity, of, mitochondrial, 'ATP', production, in, tissue, samples])].
[sujeto(['The', combination, of, 45, 'S5', bioactive, glass, and, biphasic, 'HA/βTCP', granules, of, 'Signafuse', appear, to]), verbo([provide]), complemento([greater, bone, healing, capability, in, comparison, to, the, 0.8, '%', 'silicate-substituted', hydroxyapatite, material, of, 'Actifuse', 'ABX'])].
[sujeto(['The', petroleum, '(', 'PE)', extract, of, the, plant, showed, a, significant]), verbo([increase]), complemento([in, insulin, stimulated, glucose, uptake, by, 'L6', myotubes])].
[sujeto(['The', compound]), verbo([induced]), complemento([a, dose, dependent, increase, in, insulin, stimulated, glucose, uptake, in, 'L6', myotubes, with, an, 'EC50', of, 22.96, μM])].
[sujeto(['OEA', also]), verbo([increased]), complemento([the, phosphorylation, of, 'IRS-1,', 'Akt', and, 'AS160', leading, to, increased, 'GLUT4', translocation, to, the, plasma, membrane, indicating, that, it, promotes, insulin, stimulated, glucose, uptake, in, 'L6', myotubes, by, activating, the, 'PI3K', pathway])].
[sujeto(['The']), verbo([enhanced]), complemento([disposal, of, glucose, by, the, peripheral, tissue, is, an, important, mechanism, to, regulate, hyperglycemia])].
[sujeto(['In', 'L6', 'myotubes,', 'Arnebin-1']), verbo([stimulated]), complemento([glucose, 'uptake,', mediated, through, the, enhanced, translocation, of, the, glucose, 'transporter-4', '(', 'GLUT4)', to, plasma, 'membrane,', without, changing, the, amount, of, 'GLUT4', or, 'GLUT1'])].
[sujeto(['The', effect, of, 'Arnebin-1', on, glucose, uptake, was, abolished, in, presence, of, 'wortmannin,', and, 'Arnebin-1', significantly]), verbo([stimulated]), complemento([the, phosphorylation, of, 'Akt', and, downstream, marker, 'GSK-3β'])].
[sujeto(['Moreover,', treatment, with, 'Arnebin-1', lowered, postprandial, blood, glucose, levels, in, 'streptozotocin-induced', diabetic, 'rats,', and, improved, glucose, tolerance, and]), verbo([suppressed]), complemento([the, rises, in, the, fasting, blood, 'glucose,', serum, 'insulin,', 'triglycerides,', and, total, cholesterol, in, 'db/db', 'mice,', associated, with, enhanced, expression, of, the, major, marker, of, the, 'PI-3-Kinase-mediated', signaling, cascade, in, skeletal, muscle])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'Arnebin-1', exert, antihyperglycemic, activity, through, stimulating, glucose, disposal, in, peripheral, tissues, via, 'PI-3-Kinase-dependent', pathway])].
[sujeto(['The', present, results, show, the, existence, of, resiniferatoxin, 'desensitization-resistant', mechanosensitive, 'Aδ-', and, 'C-fibers', in, rat, primary, bladder, afferent, 'nerves,']), verbo([suggesting]), complemento([that, systemic, resiniferatoxin, treatment, might, induce, 'non-specific', partial, desensitization, or, denervation, of, mechanosensitive, 'capsaicin-insensitive', 'Aδ-', and, 'C-fibers', of, the, rat, bladder])].
[sujeto(['Uncoupling', protein, 3, '(', 'UCP3),', which, uncouples, electron, transport, from, 'ATP', 'synthesis,', is]), verbo([expressed]), complemento([at, high, levels, in, the, skeletal, 'muscle,', an, important, organ, in, glucose, and, lipid, metabolism])].
[sujeto(['Because', several]), verbo([reports]), complemento([proposed, that, fatty, acids, induced, 'UCP3', gene, expression, in, skeletal, muscle, in, 'vivo,', in, the, present, study, we, examined, the, regulation, of, 'UCP3', gene, expression, by, various, fatty, acids, using, 'L6', myotubes])].
[sujeto(['UCP3', gene, expression, was]), verbo([increased]), complemento([in, 'L6', myotubes, by, various, fatty, acids, or, by, 'alpha-bromopalmitate,', a, nonmetabolized, derivative, of, palmitic, acid])].
[sujeto(['L-165041,', a, 'PPAR', delta, 'agonist,']), verbo([increased]), complemento(['UCP3', gene, expression, in, 'L6', 'myotubes,', whereas, neither, 'Wy', 14, ',', 643, ',', a, 'PPAR', alpha, 'agonist,', nor, 'Pioglitazone,', a, 'PPAR', gamma, 'agonist,', increased, it])].
[sujeto(['Therefore,', we, conclude, that, 'UCP3', gene, expression, is]), verbo([increased]), complemento([by, the, activation, of, 'PPAR', delta, in, 'L6', myotubes, and, postulate, that, 'PPAR', delta, mediates, at, least, some, part, of, the, increased, 'UCP3', gene, expression, by, fatty, acids, in, skeletal, muscle, in, vivo])].
[sujeto(['Uncoupling', protein, 3, '(', 'UCP3),']), verbo([expressed]), complemento([abundantly, in, the, skeletal, 'muscle,', is, one, of, the, carrier, proteins, dissipating, the, transmitochondrial, electrochemical, gradient, as, 'heat,', and, thereby, has, been, implicated, in, the, regulation, of, energy, metabolism])].
[sujeto(['We']), verbo([have]), complemento([investigated, 'UCP3', mRNA, expression, in, the, widely, used, 'L6', myocyte, cell, line, by, 'Northern', blot, analysis])].
[sujeto(['The', 'UCP3', mRNA, level, was]), verbo([increased]), complemento([when, 'L6', myotubes, were, treated, with, increasing, concentrations, of, triiodothyronine, '(', 'T3),', oleic, 'acid,', 'alpha-bromopalmitate', and, 'carbacyclin,', a, 'non-selective', ligand, of, peroxisome, 'proliferator-activated', receptors, '(', 'PPARs),', whereas, it, was, not, influenced, when, treated, with, selective, ligands, of, 'PPARalpha', '(', 'WY', 14, ¿, 'omitted¿643)', and, 'PPARgamma', '(', 'troglitazone)'])].
[sujeto(['A', ligand, of, retinoid, 'X', receptor, '(', 'RXR),', 9, -, cis, retinoic, 'acid,', was, also, effective, by, itself, and, in, combination, with, carbacyclin, in]), verbo([stimulating]), complemento(['UCP3', mRNA, expression])].
[sujeto(['The', mRNA, analysis, of, individual, 'PPAR', isoforms, revealed, that, 'L6', cell]), verbo([expressed]), complemento([a, significant, level, of, 'PPARdelta', but, undetectable, levels, of, 'PPARalpha', and, 'PPARgamma'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'UCP3', expression, in, myocytes, is, 'differentiation-dependent', and, regulated, by, the, 'T3', 'receptor,', 'RXR', and, 'PPARdelta'])].
[sujeto(['A', cDNA, encoding, a, mitochondrial, protein, likely, to]), verbo([act]), complemento([as, uncoupler, '(', uncoupling, protein, 2, ',', 'UCP2)', has, been, recently, cloned])].
[sujeto(['Since', 'TZD']), verbo([have]), complemento([been, reported, to, increase, energy, expenditure, in, 'animals,', we, have, examined, the, effects, of, these, drugs, on, the, expression, of, 'UCP2', mRNA, in, cell, lines, representing, white, '(', 3, 'T3-L1', and, 3, 'T3-F442A)', and, brown, '(', 'HIB-1B)', adipose, tissues, and, skeletal, muscle, '(', 'L6)'])].
[sujeto(['Within', 4, h, of, exposing, these, cells, to, 30, microM, 'darglitazone,', there, was, an]), verbo([increase]), complemento([in, 'UCP2', mRNA, which, reached, a, plateau, of, 5, -, 10, times, the, basal, in, about, 8, h])].
[sujeto(['These', results, indicate, that, 'TZDs', can]), verbo([stimulate]), complemento([the, expression, of, 'UCP2', gene, probably, via, 'PPAR', gamma, and, hence, have, the, potential, to, increase, energy, expenditure, in, adult, 'humans,', in, whom, 'UCP2', is, expressed, ubiquitously])].
[sujeto(['The', implication, is, that, for, the, design, of, new, 'negamycin-based', 'analogs,', the, physicochemical, properties]), verbo([required]), complemento([for, cell, entry, via, the, 'low-affinity', route, need, to, be, retained, to, achieve, clinical, success, in, the, treatment, of, infectious, diseases])].
[sujeto(['Furthermore,', clinical, resistance, to, such, analogs, due, to, mutations, affecting, their, ribosomal]), verbo([target]), complemento([or, transport, is, expected, to, be, rare, and, similar, to, that, of, aminoglycosides])].
[sujeto(['Animal', models, of, experimental, branch, retinal, vein, occlusion, '(', 'BRVO)']), verbo([provide]), complemento([a, unique, opportunity, to, study, protein, changes, directly, in, retinal, tissue])].
[sujeto(['Results', from, these, experimental, models]), verbo([suggest]), complemento([that, experimental, 'BRVO', is, associated, with, an, upregulation, of, extracellular, matrix, remodeling, and, adhesion, signaling, processes])].
[sujeto(['In', six, 'Danish', 'Landrace', pigs, experimental, 'BRVO', was]), verbo([induced]), complemento([with, argon, laser, in, both, eyes])].
[sujeto(['These', five, 'proteins,', which, were, all]), verbo([decreased]), complemento([in, 'content,', included, integrin, 'β-1,', peroxisomal, 3, -, 'ketoacyl-CoA', 'thiolase,', 'OCIA', 'domain-containing', protein, 1, ',', calnexin, and, 40, 'S', ribosomal, protein, 'S5'])].
[sujeto(['As', 'anti-integrin', therapies, are, under, development, for, inhibition, of, angiogenesis, in, retinal, diseases, it, is, interesting, that, inhibition, of, 'VEGF-A', in, itself, resulted, in, a, small]), verbo([decrease]), complemento([in, the, content, of, integrin, 'β-1'])].
[sujeto(['The']), verbo([decreased]), complemento([content, of, integrin, 'β-1', indicates, that, extracellular, matrix, remodeling, and, adhesion, processes, associated, with, 'BRVO', are, at, least, partly, reversed, through, inhibition, of, 'VEGF-A'])].
[sujeto(['Successful', reproduction]), verbo([requires]), complemento([different, strategies, when, resources, are, scarce, and, when, they, are, 'abundant(1,2),', but, a, systematic, framework, for, predicting, these, reproductive, strategies, in, bacteria, has, not, been, available])].
[sujeto(['We']), verbo([find]), complemento([that, the, maximum, reproductive, rate, of, bacteria, doubles, with, a, doubling, of, rrn, copy, 'number,', and, the, efficiency, of, carbon, use, is, inversely, related, to, maximal, growth, rate, and, rrn, copy, number])].
[sujeto(['Furthermore,', comparative, analysis, of, genomes, from, 1, ',', 167, bacterial, species]), verbo([reveals]), complemento([that, rrn, copy, number, predicts, traits, associated, with, resource, 'availability,', including, chemotaxis, and, genome, streamlining])].
[sujeto(['Genome-wide', patterns, of, orthologous, gene, content, covary, with, rrn, copy, 'number,']), verbo([suggesting]), complemento([convergent, evolution, in, response, to, resource, availability])].
[sujeto(['A', 'Western', 'diet,', which, is, rich, in, saturated, fat, and, simple, 'sugars,', may]), verbo([lead]), complemento([to, changes, in, gut, microbial, composition, and, 'physiology,', which, have, recently, been, linked, to, the, development, of, metabolic, diseases])].
[sujeto(['Altered', large, intestinal, microbial, composition, may]), verbo([promote]), complemento([obesity, by, increasing, energy, harvest, through, specialized, gut, microbes])].
[sujeto(['In', both, large, and, small, 'intestine,', microbial, alterations, may]), verbo([increase]), complemento([gut, permeability, that, facilitates, the, translocation, of, whole, bacteria, or, endotoxic, bacterial, components, into, metabolic, active, tissues])].
[sujeto(['The', eukaryotic, 'chaperonin,', 'CCT', '(', 'Chaperonin', 'Containing', 'TCP1', or, 'TriC-TCP-1', 'Ring', 'Complex)']), verbo([has]), complemento([been, subjected, to, physical, and, genetic, analyses, in, 'S'])].
[sujeto(['Studies', on, hCCT, and, its, interactome, acquire, an, additional, 'dimension,', as, it]), verbo([has]), complemento([been, implicated, in, several, disease, conditions, like, neurodegeneration, and, cancer])].
[sujeto(['sapiens,', performed, 'GO', term, classification, and, enrichment, studies, which]), verbo([provide]), complemento([information, on, the, diversity, in, 'CCT', 'interactome,', in, terms, of, protein, classes, in, the, data, set])].
[sujeto(['Different', analyses, 'converge,']), verbo([suggesting]), complemento([the, significance, of, 'WD-repeat', 'proteins,', protein, kinases, and, cytoskeletal, proteins, in, the, interactome])].
[sujeto(['The', prevalence, of, proteasomal, subunits, and, ribosomal, proteins]), verbo([suggest]), complemento([a, possible, 'cross-talk', between, 'protein-synthesis,', folding, and, degradation, machinery])].
[sujeto(['The', organization, of, the, mitochondrial, genomes, was, similar, to, those]), verbo([reported]), complemento([from, other, fish, mitochondrial, genomes, containing, 37, genes, '(', 13, 'protein-coding', 'genes,', 2, ribosomal, 'RNA', and, 22, transfer, 'RNAs)', and, a, major, 'non-coding', control, region])].
[sujeto(['The', complete, mitogenome, may]), verbo([provide]), complemento([important, date, set, for, the, study, of, genetic, mechanism, of, 'S'])].
[sujeto(['The', mRNAs, that, are]), verbo([bound]), complemento([by, the, 'zinc-finger', protein, 'ZC3H11,', including, those, encoding, refolding, 'chaperones,', escape, 'heat-induced', translation, inhibition])].
[sujeto(['We']), verbo([found]), complemento([that, mRNAs, that, bind, to, 'ZC3H11', remained, in, polysomes, at, 39, °, 'C', and, were, protected, from, sequestration, in, granules, at, 41, °, 'C'])].
[sujeto([70, mRNAs, moved, towards, the, polysomal, fraction, after, the, 39, °, 'C', heat, 'shock,', and, 260]), verbo([increased]), complemento([in, relative, abundance])].
[sujeto(['Surprisingly,', many, of, these, mRNAs, are, also]), verbo([increased]), complemento([when, trypanosomes, migrate, to, the, tsetse, salivary, glands])].
[sujeto(['NMOSD', is, closely]), verbo([associated]), complemento([with, elevated, 'autoantibodies,', particularly, antinuclear, and, 'anti-SSA/Ro', antibodies])].
[sujeto(['Genomics', revealed, 90, significantly]), verbo([regulated]), complemento([genes, '(', &, 'gt;', 3, -, 'fold)', coding, for, cell, 'growth,', 'DNA', 'metabolism,', 'RNA', processing, and, ribosomal, biogenesis, and, bioinformatics, defined, 'c-Myc', binding, sites, '(', 'TFBS)', at, &, 'gt;', 95, '%', of, 'up-regulated', genes])].
[sujeto(['EMSA', assays, at, 33, novel, 'TFBS', evidenced, 'DNA']), verbo([binding]), complemento([activity, and, 'ChIP-seq', data, retrieved, from, public, repositories, confirmed, these, to, be, 'c-Myc', bound])].
[sujeto([heterogeneous]), verbo([nuclear]), complemento([ribonucleoprotein, 'A1,', 'nucleolin,', the, 'apurinic/apyrimidinic', endonuclease, 1, ',', 'triosephosphate-isomerase', 1, ',', folate, transporter, '(', 'SLC19A1)', and, nucleophosmin, to, influence, activity, of, up, to, 90, '%', of, 'PLAC-regulated', genes])].
[sujeto(['Their', expression, was]), verbo([induced]), complemento([by, 3, -, ',', 3, -, ',', 6, -, ',', 3, -, ',', 11, -, and, 7, -, 'fold,', respectively])].
[sujeto(['STRING', analysis, confirmed, 'protein-protein-interactions', of]), verbo([regulated]), complemento([genes, and, 'Western', immunoblotting, of, fatty, acid, 'synthase,', serine, 'hydroxyl-methyltransferase', 1, ',', arginine, 1, and, hexokinase, 2, showed, tumor, specific, induction])].
[sujeto(['Published', knock, down, studies, confirmed, these, proteins, to]), verbo([induce]), complemento([apoptosis, by, disrupting, neoplastic, 'lipogenesis,', by, endorsing, uracil, accumulation, and, by, suppressing, arginine, metabolism, and, 'glucose-derived', ribonucleotide, biosynthesis])].
[sujeto(['Finally,', translational, research, demonstrated, high, expression, of, 'MR', and, of, 47, 'PLAC', 'up-regulated', genes, to, be]), verbo([associated]), complemento([with, poor, survival, in, lung, adenocarcinoma, patients, '(', 'HR', 3.2, p, &, 'lt;', 0.001, ')', 'thus,', providing, a, rationale, for, molecular, targeted, therapies, in, 'PLACs'])].
[sujeto(['Studies']), verbo([have]), complemento([shown, in, vitro, activity, against, the, 'soil-borne', fungi, 'Verticillium', dahliae, 'Kleb'])].
[sujeto(['The', genome, analyses, revealed, genes, putatively, responsible, for, the, promising, plant, growth]), verbo([promoting]), complemento([and, biocontrol, properties, including, predicting, factors, such, as, secretion, 'systems,', iron, scavenging, 'siderophores,', 'chitinases,', secreted, 'proteases,', glucanases, and, 'non-ribosomal', peptide, 'synthetases,', as, well, as, unique, genomic, islands])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, case, of, a, male, infant, with, 'DBA', who, presented, with, anemic, crisis, '(', hemoglobin, '[', 'Hb]', concentration, 1.5, 'g/dL)', at, 58, days, after, birth])].
[sujeto(['On', analysis, of, 'RP', genes, when, the, infant, was, 6, months, 'old,', both, the, infant, and, the, 'father,', but, not, the, 'mother,', were]), verbo([found]), complemento([to, harbor, a, mutation, of, 'RPS19', '(', c])].
[sujeto(['The', 'A1', subunit, of, 'Shiga', toxin, 1, '(', 'Stx1A1)', and, 'Shiga', toxin, 2, '(', 'Stx2A1)']), verbo([interact]), complemento([with, the, conserved, 'C-termini', of, ribosomal, stalk, 'P-proteins', to, remove, a, specific, adenine, from, the, 'sarcin/ricin', loop])].
[sujeto(['We', previously, showed, that, 'Stx2A1']), verbo([has]), complemento([higher, affinity, for, the, ribosome, and, higher, catalytic, activity, than, 'Stx1A1'])].
[sujeto(['To', determine, if]), verbo([conserved]), complemento([arginines, at, the, distal, face, of, the, active, site, contribute, to, the, higher, affinity, of, 'Stx2A1', for, the, 'ribosome,', we, mutated, 'Arg172,', 'Arg176', and, 'Arg179', in, both, toxins])].
[sujeto(['R176A', and, 'R172A/R176A', mutations, eliminated, interaction, of, 'Stx1A1', and, 'Stx2A1', with, ribosomes, and, with, the, 'stalk,', while, mutation, of, 'Arg170', at, the, active, site, reduced]), verbo([binding]), complemento([affinity, of, 'Stx1A1', and, 'Stx2A1', for, the, 'ribosome,', but, not, for, the, stalk])].
[sujeto(['These', results, demonstrate, that]), verbo([conserved]), complemento([arginines, at, the, distal, face, of, the, active, site, are, critical, for, interactions, of, 'Stx1A1', and, 'Stx2A1', with, the, 'stalk,', while, a, conserved, arginine, at, the, active, site, is, critical, for, 'non-stalk', specific, interactions, with, the, ribosome])].
[sujeto(['Arginine', mutations, at, either, site, reduced, ribosome, interactions, of, 'Stx1A1', and, 'Stx2A1', 'similarly,', indicating, that]), verbo([conserved]), complemento([arginines, are, critical, for, ribosome, 'interactions,', but, do, not, contribute, to, the, higher, affinity, of, 'Stx2A1', for, the, ribosome])].
[sujeto(['Mapping', of, 'protein-protein', interaction, domains, revealed, the, importance, of, both, the, evolutionary]), verbo([conserved]), complemento(['WD40', repeats, in, 'NOL10', and, the, 'UTP3/SAS10', domain, in, 'NGDN', for, complex, formation])].
[sujeto(['All', complex, members, were]), verbo([required]), complemento([for, 18, 'S', rRNA, maturation, and, their, individual, depletion, affected, the, same, nucleolar, cleavage, steps, in, the, 5, '\'', 'ETS', and, 'ITS1', regions, of, the, ribosomal, 'RNA', precursor])].
[sujeto(['Programmed', ribosomal, frameshifting, '(', 'PRF)', is, commonly, used, to]), verbo([express]), complemento([many, viral, and, some, cellular, genes])].
[sujeto(['We', conducted, a, 'genome-wide', investigation, of, +, 1, 'PRF', in, ciliate, 'Euplotes', octocarinatus, through, genome, and, transcriptome, sequencing, and, our, results, demonstrated, that, approximately, 11.4, '%', of, genes]), verbo([require]), complemento([+, 1, 'PRF', to, produce, complete, gene, products])].
[sujeto(['Our', data, in, this, study]), verbo([provide]), complemento([very, useful, insight, into, the, understanding, of, the, molecular, mechanism, of, +, 1, 'PRF'])].
[sujeto(['Sequence', accessions, attributable, to, novel, plant, amalgaviruses]), verbo([have]), complemento([been, found, in, the, 'Transcriptome', 'Shotgun', 'Assembly', database])].
[sujeto(['Other', findings, include, evidence, for, 'UUU_CGN', as, a, +, 1, ribosomal, frameshifting, motif, prevalent, among, plant, 'amalgaviruses;', for, a, variant, version, of, this, motif]), verbo([found]), complemento([thus, far, in, only, two, amalgaviruses, from, solanaceous, 'plants;', for, a, region, of, 'α-helical', coiled, coil, propensity, conserved, in, a, central, region, of, the, 'ORF1', translation, product, of, plant, 'amalgaviruses;', and, for, conserved, sequences, in, a, 'C-terminal', region, of, the, 'ORF2', translation, product, '(', 'RNA-dependent', 'RNA', 'polymerase)', of, plant, 'amalgaviruses,', seemingly, beyond, the, region, of, conserved, polymerase, motifs])].
[sujeto(['In', humans, the, mitochondrial, inner, membrane, protein, 'Oxa1L', is]), verbo([involved]), complemento([in, the, biogenesis, of, membrane, proteins, and, facilitates, the, insertion, of, both, 'mitochondrial-', and, 'nuclear-encoded', proteins, from, the, mitochondrial, matrix, into, the, inner, membrane])].
[sujeto(['The', 'C-terminal', approximately, 100, -, amino, acid, tail, of, 'Oxa1L', '(', 'Oxa1L-CTT)']), verbo([binds]), complemento([to, mitochondrial, ribosomes, and, plays, a, role, in, the, 'co-translational', insertion, of, 'mitochondria-synthesized', proteins, into, the, inner, membrane])].
[sujeto(['The']), verbo([binding]), complemento([of, 'Oxa1L-CTT', to, mitochondrial, ribosomes, is, an, 'enthalpy-driven', process, with, a, 'K(d)', of, 0.3, -, 0.8, microM, and, a, stoichiometry, of, 2])].
[sujeto(['We', determined, the, protein, composition, of, tandem, 'affinity-purified', 'Trypanosoma', brucei, mt, ribosomes, by, mass, spectrometry, and, identified, 133, proteins, of, which, 77, were]), verbo([associated]), complemento([with, the, large, subunit, and, 56, were, associated, with, the, small, subunit])].
[sujeto(['Nevertheless', most, of, the, identified, proteins]), verbo([have]), complemento([no, homology, outside, 'Kinetoplastida', implying, very, low, conservation, 'and/or', a, divergent, function, in, kinetoplastid, mitochondria])].
[sujeto(['Many', proteins, synthesized, in, the, cytosol, are, delivered, to, their, appropriate, compartments, in, the, cell, by, specific]), verbo([targeting]), complemento([signals])].
[sujeto(['Here,', we]), verbo([provide]), complemento([new, insight, into, the, generation, of, the, 'chloroplast-targeting', signal, '(', called, the, transit, 'peptide)', in, rice])].
[sujeto(['The', duplicated, region, was]), verbo([transcribed]), complemento([and, found, to, encode, an, open, reading, frame, '(', 'ORF)', of, 160, amino, acids, '(', 'aa)', '(', 'orf160)'])].
[sujeto(['Examination', of, the, localization, of, the, 'ORF160', protein, tagged, with, green, fluorescent, protein, '(', 'GFP)', showed, that, it, is]), verbo([targeted]), complemento([to, the, chloroplasts])].
[sujeto(['Interestingly,', this, was]), verbo([translated]), complemento([from, the, alternative, reading, frame, of, the, duplicated, fragment, of, ppr564])].
[sujeto(['The']), verbo([expressed]), complemento(['GFP-fused', protein, was, also, located, in, the, chloroplasts])].
[sujeto(['These', results]), verbo([provide]), complemento([clear, evidence, for, the, generation, of, the, transit, peptide, through, duplication, and, subsequent, frameshifting, of, a, reading, frame, of, a, preexisting, protein, gene])].
[sujeto(['Identification', of, all, the, protein, components, of, the, large, subunit, '(', 39, 'S)', of, the, mammalian, mitochondrial, ribosome]), verbo([has]), complemento([been, achieved, by, carrying, out, proteolytic, digestions, of, whole, 39, 'S', subunits, followed, by, analysis, of, the, resultant, peptides, by, liquid, chromatography, and, mass, spectrometry])].
[sujeto(['The', human, mitochondrial, 39, 'S', subunit]), verbo([has]), complemento([48, distinct, proteins])].
[sujeto(['Almost', all, of, these, proteins]), verbo([have]), complemento([homologs, in, 'Drosophila', 'melanogaster,', 'Caenorhabditis', 'elegans,', and, 'Saccharomyces', cerevisiae, mitochondrial, ribosomes])].
[sujeto(['No', mitochondrial, homologs, to, prokaryotic, ribosomal, proteins, 'L5,', 'L6,', 'L25,', 'L29,', and, 'L31', could, be]), verbo([found]), complemento([either, in, the, peptides, obtained, or, by, analysis, of, the, available, data, bases])].
[sujeto(['Proteins', in, this, group]), verbo([have]), complemento([no, apparent, homologs, in, 'bacterial,', 'chloroplast,', 'archaebacterial,', or, cytosolic, ribosomes])].
[sujeto(['All', but, two, of, the, proteins]), verbo([has]), complemento([a, clear, homolog, in, 'D'])].
[sujeto([melanogaster, while, all, can, be]), verbo([found]), complemento([in, the, genome, of, 'C'])].
[sujeto(['Ten', of, the, 20, mitochondrial, specific, 39, 'S', proteins]), verbo([have]), complemento([homologs, in, 'S'])].
[sujeto(['The', 'Kluyveromyces', lactis]), verbo([nuclear]), complemento(['gene,', 'MRP-L23,', encodes, a, polypeptide, of, 155, amino, acids, that, shares, 70, '%', and, 43, '%', identity, to, the, ribosomal, proteins, 'L23', and, 'L13', of, 'Saccharomyces', cerevisiae, and, 'Escherichia', coli])].
[sujeto(['Structural', studies, of, eukaryotic, ribosomes, are, complicated, by, the, tendency, of, their, constituent, proteins, to, be]), verbo([expressed]), complemento([at, very, low, levels, in, 'Escherichia', coli])].
[sujeto(['We']), verbo([find]), complemento([that, this, is, mainly, due, to, their, exceptionally, high, content, of, 'AGA/AGG', arginine, 'codons,', which, are, poorly, utilized, by, the, bacterial, translational, machinery])].
[sujeto(['The', purification, procedure, simply]), verbo([involved]), complemento([metal, affinity, chromatography, 'followed,', in, some, 'cases,', by, an, additional, heparin, chromatography, step])].
[sujeto(['Recombinant', polypeptides]), verbo([bound]), complemento(['RNA', with, high, affinity, '(', 'K(d)', between, 50, and, 300, 'nM)'])].
[sujeto(['The']), verbo([nuclear]), complemento([gene, 'MRP-L13', of, 'Saccharomyces', 'cerevisiae,', which, codes, for, the, mitochondrial, ribosomal, protein, 'YmL13,', has, been, cloned, and, characterized])].
[sujeto(['Its', nucleotide, sequence, was]), verbo([found]), complemento([to, be, identical, to, that, of, the, previously, reported, 'ORF', 'YK105'])].
[sujeto(['No', sequence, similarity, was]), verbo([found]), complemento([to, any, other, ribosomal, protein, in, the, current, databases])].
[sujeto(['The', transcription, of, 'MRP-L13', was]), verbo([found]), complemento([to, be, repressed, in, the, presence, of, glucose])].
[sujeto(['Mature', ribosomal, protein, 'L13a']), verbo([has]), complemento([202, amino, acids, '(', the, 'NH2-terminal', methionine, is, removed, after, translation, of, the, 'mRNA)', and, a, 'M(r)', of, 23, ',', 330])].
[sujeto(['Hybridization', of, the, 'L13a', cDNA, to, digests, of]), verbo([nuclear]), complemento(['DNA', suggests, that, there, are, 9, -, 11, copies, of, the, 'L13a', gene])].
[sujeto(['Rat', 'L13a', is, related, to, the, 'Saccharomyces', cerevisiae, ribosomal, proteins, that]), verbo([have]), complemento([been, provisionally, designated, rp22, and, rp23, and, to, the, eubacterial, and, archaebacterial, family, of, 'L13', ribosomal, proteins])].
[sujeto(['L13a', also]), verbo([has]), complemento([a, number, of, short, amino, acid, sequences, that, are, 'repeated,', a, leucine, 'zipper-like', motif, at, its, 'NH2', 'terminus,', and, a, potential, basic, 'region-leucine', zipper, element, in, its, 'carboxyl-terminal', region])].
[sujeto(['RNA']), verbo([binding]), complemento([properties, of, proteins, from, the, large, subunit, of, bovine, mitochondrial, ribosomes, were, studied, using, four, different, 'approaches:', binding, of, radiolabeled, 'RNA', to, western, blotted, 'proteins;', disassembly, of, the, intact, 39, 'S', ribosomal, subunits, with, 'urea;', binding, of, ribosomal, proteins, to, 'RNA', in, the, presence, of, 'urea;', and, binding, of, proteins, extracted, with, lithium, chloride, to, 'RNA'])].
[sujeto(['Results', from, these, four, approaches, allowed, us, to, identify, a, set, of, six, proteins, '(', 'L7,', 'L13,', 'L14,', 'L21,', 'L26,', and, 'L44)', which, appear, to, be, strong, 'RNA']), verbo([binding]), complemento([proteins])].
[sujeto(['Seven', additional, proteins, '(', 'L8,', 'L11,', 'L28,', 'L35,', 'L40,', 'L49,', and, 'L50)', were, identified, as, secondary, 'RNA']), verbo([binding]), complemento([proteins])].
[sujeto(['RNA']), verbo([binding]), complemento([properties, of, the, proteins, in, both, of, these, sets, were, compared, with, the, topographic, disposition, and, susceptibility, towards, lithium, chloride, extraction, of, the, individual, proteins])].
[sujeto(['Proteins', from, the, first, set, are, good, candidates, for, early, assembly, proteins, since, they]), verbo([have]), complemento([a, high, affinity, for, 'RNA,', are, generally, found, in, 4, 'M', lithium, chloride, core, 'particles,', and, are, among, the, most, buried, proteins, in, the, 39, 'S', subunit])].
[sujeto(['Over', a, period, of, 8, &, 'nbsp;months,', university, students, '(', 'Study', 1, :, 'N = 292;', 'Study', 2, :, 'N = 304)']), verbo([reported]), complemento(['sleep,', physical, 'activity,', 'snacking,', positive, and, negative, 'affect,', and, learning, goal, achievement])].
[sujeto(['A', subsample, wore, an, actigraph, to]), verbo([provide]), complemento([an, additional, measurement, of, sleep, and, physical, activity, and, participated, in, a, controlled, laboratory, snacking, situation])].
[sujeto(['Multilevel', structural, equation, models, showed, that, better, 'day-to-day', sleep, quality, or, more, physical, activity, than, 'usual,', but, not, 'snacking,', were]), verbo([associated]), complemento([with, improved, daily, 'functioning,', 'namely,', affect, and, learning, goal, achievement])].
[sujeto(['These', findings]), verbo([have]), complemento([the, potential, to, inform, health, promotion, programs, aimed, at, supporting, young, adults, in, their, daily, functioning, in, good, physical, and, mental, health])].
[sujeto(['Because', emotionally, salient, material]), verbo([has]), complemento([the, capacity, to, capture, and, hold, attention, it, has, been, suggested, that, this, material, may, disrupt, this, otherwise, impressively, stable, phenomenon])].
[sujeto([40, students]), verbo([participated]), complemento([in, the, experiment])].
[sujeto(['Participants', were]), verbo([required]), complemento([to, press, a, key, whenever, the, target, picture, appeared])].
[sujeto(['IOR', appears, to, be, a, robust, phenomenon, and, the, emotional, valence, of, neither, the, cue, nor, the, emotional, valence, of, the]), verbo([target]), complemento([can, override, it])].
[sujeto(['However,', the, change, of, biting, with, such, treatment, concepts]), verbo([has]), complemento([been, quantitatively, investigated, in, only, a, limited, number, of, studies])].
[sujeto(['The', aim, of, the, present, study]), verbo([has]), complemento([been, to, measure, the, biting, forces, of, edentulous, patients, with, complete, dentures, and, after, receiving, 'implant-supported', overdentures])].
[sujeto(['After', the, insertion, of, 'implants,', the, range, of, biting, forces]), verbo([increased]), complemento([to, 167, 'N-235N', for, the, control, group, and, to, 81, 'N-138N', for, the, study, group])].
[sujeto(['However,', the]), verbo([increase]), complemento([in, biting, forces, after, the, insertion, of, implants, was, not, significant, for, either, group])].
[sujeto(['The', 'SbNHX1', gene, encodes, a, vacuolar, 'Na+/H+', antiporter, and, is]), verbo([involved]), complemento([in, the, compartmentalization, of, excess, 'Na+', ions, into, the, vacuole, and, maintenance, of, ion, homeostasis, 'Transgenic', cumin, plants, were, confirmed, by, 'PCR', using, gene, '(', 'SbNHX1,', uidA, and, 'hptII)', specific, primers])].
[sujeto(['The', ectopic, expression, of, the, 'SbNHX1', gene, confirmed]), verbo([enhanced]), complemento([salinity, stress, tolerance, in, cumin, as, compared, to, wild, type, plants, under, stress, condition])].
[sujeto(['The', present, study, is, the, first]), verbo([report]), complemento([of, engineering, salt, tolerance, in, 'cumin,', so, far, and, the, plant, may, be, utilized, for, the, cultivation, in, saline, areas])].
[sujeto(['It', is, widely, assumed, that, in, the, 'best-characterized', model, bacterium, 'Escherichia', 'coli,', transcription, units, encoding, ribosomal, proteins, '(', 'r-proteins)', and, regulation, of, their, expression]), verbo([have]), complemento([been, already, well, defined])].
[sujeto([coli, 'r-protein', operons]), verbo([have]), complemento([been, established, only, very, 'recently,', so, that, information, concerning, the, regulation, of, these, operons, at, the, transcriptional, or, posttranscriptional, level, is, still, missing])].
[sujeto(['By', using, 'single-copy', translational, fusions, with, the, chromosomal, lacZ, 'gene,', we, show, here, that, at, the, translation, level, only, one, of, these, 'operons,', 'rplM-rpsI,', is]), verbo([regulated]), complemento([by, the, mechanism, of, autogenous, repression, involving, the, 5, '\'', untranslated, region, '(', 'UTR)', of, the, operon, 'mRNA,', while, 'rpmB-rpmG', and, 'rplU-rpmA', are, not, subject, to, this, type, of, regulation])].
[sujeto(['This', may, imply, that, translational, feedback, control, is, not, a, general, rule, for]), verbo([modulating]), complemento([the, expression, of, 'E'])].
[sujeto(['Finally,', we]), verbo([report]), complemento([that, 'L13,', a, primary, protein, in, 50, 'S', ribosomal, subunit, 'assembly,', serves, as, a, repressor, of, 'rplM-rpsI', expression, in, 'vivo,', acting, at, a, target, within, the, rplM, translation, initiation, region])].
[sujeto(['In', this, 'paper,', we, highlight, the, major, role, of, a, stringent, response, in]), verbo([regulating]), complemento([transcription, of, three, previously, unexplored, 'r-protein', 'operons,', and, we, show, that, only, one, of, them, is, subject, to, feedback, regulation, at, the, translational, level])].
[sujeto(['Improved', knowledge, of, the, regulatory, pathways, controlling, ribosome, biogenesis, may]), verbo([promote]), complemento([the, development, of, novel, antibacterial, agents])].
[sujeto(['In', 'adults,', lower, numeracy, is]), verbo([associated]), complemento([with, poorer, nutrition, label, comprehension, and, higher, 'BMI'])].
[sujeto(['Parent', and, child, body, weight, were, 'measured;', parents]), verbo([reported]), complemento([both, their, own, height, and, that, of, their, children])].
[sujeto(['Lower', parental, numeracy, was, significantly]), verbo([associated]), complemento([with, having, a, child, who, was, either, underweight, '(', 'β = 0'])].
[sujeto(['Lower', parental, numeracy, was, also]), verbo([associated]), complemento([with, poorer, 'portion-size', estimation, skills, '(', 'r = -0'])].
[sujeto(['However,', these, 'weight-related', numerical, information, processing, skills, did, not]), verbo([mediate]), complemento([the, association, between, parental, numeracy, and, 'children\'s', 'BMI'])].
[sujeto(['This', study, is, the, first, to]), verbo([find]), complemento([lower, parental, numeracy, to, be, a, risk, factor, for, children, being, either, 'over-', or, underweight])].
[sujeto(['However,', 'portion-size', estimation, 'skills,', comprehension, of, nutrition, 'labels,', and, comprehension, of, growth, charts, did, not]), verbo([mediate]), complemento([the, association, between, parental, numeracy, and, 'children\'s', 'BMI'])].
[sujeto(['Parental', numeracy, is, an, as, yet, largely, overlooked, factor, that, can, be]), verbo([targeted]), complemento([when, developing, interventions, to, prevent, and, treat, malnutrition, and, to, achieve, and, maintain, a, healthy, body, weight, in, children])].
[sujeto(['The', unique, functional, attributes, of, the, two, culturable, 'microbiomes,', grown, on, a, similar, 'diet,']), verbo([reveals]), complemento([the, significance, of, proper, selection, of, earthworm, substrate, combinations, for, effective, vermicomposting])].
[sujeto(['Research']), verbo([suggests]), complemento([a, link, between, 'Persecutory', 'Delusions', '(', 'PDs)', and, early, interpersonal, difficulties])].
[sujeto(['However,', little, research]), verbo([has]), complemento([explored, the, 'first-hand', experience, of, navigating, such, adversities, in, those, who, later, developed, 'PDs'])].
[sujeto(['The', current, study]), verbo([reports]), complemento([on, a, qualitative, investigation, of, the, early, interpersonal, experiences, and, challenges, faced, by, a, sample, of, individuals, who, have, recovered, from, 'PDs,', using, a, 'semi-structured', interview])].
[sujeto(['A', sample, of, seven, individuals, who]), verbo([have]), complemento([previously, experienced, 'PDs', were, recruited, from, two, 'National', 'Health', 'Services', '(', 'NHS)', and, an, 'Early', 'Intervention', 'Psychosis', service, in, 'England'])].
[sujeto(['The', multidomain, zinc, finger, '(', 'ZnF)', protein, 'PRDM9', '(', 'PRD1-BF1-RIZ1', homologous, 'domain-containing', 9, ')', is, thought, to, influence, the, locations, of, recombination, hot, spots, during, meiosis, by, 'sequence-specific', 'DNA']), verbo([binding]), complemento([and, trimethylation, of, histone, 'H3', 'Lys4'])].
[sujeto(['The', most, common, variant, of, human, 'PRDM9,', allele, 'A', '(', 'hPRDM9A),']), verbo([recognizes]), complemento([the, consensus, sequence, 5, '\'', -, 'NCCNCCNTNNCCNCN-3\''])].
[sujeto(['We', cocrystallized, 'ZnF8-12', of, hPRDM9A, with, an, oligonucleotide, representing, a, known, hot, spot, sequence, and]), verbo([report]), complemento([the, structure, here])].
[sujeto(['The', consensus, 'C:G', base, pairs, 'H-bond', with]), verbo([conserved]), complemento(['His', or, 'Arg', residues, in, 'ZnF8,', 'ZnF9,', and, 'ZnF11,', and, the, consensus, 'T:A', base, pair, 'H-bonds', with, an, 'Asn', that, replaces, 'His', in, 'ZnF10'])].
[sujeto(['We', investigated, the]), verbo([binding]), complemento([of, various, alleles, of, hPRDM9, to, different, hot, spot, sequences])].
[sujeto(['Allele', 'C', was]), verbo([found]), complemento([to, bind, a, 'C-specific', hot, spot, with, higher, affinity, than, allele, 'A', bound, 'A-specific', hot, 'spots,', perhaps, explaining, why, the, former, is, dominant, in, 'A/C', heterozygotes])].
[sujeto(['Sixty-two', and, thirty, three, postmenopausal, women]), verbo([recruited]), complemento([to, investigate, calcaneus, and, femoral, 'neck,', 'respectively,', underwent, a, bone, mineral, density, '(', 'BMD)', measurement, to, be, classified, as, healthy, subjects, '(', n, =, 22, ')', ',', osteopenic, '(', n, =, 45, ')', ',', or, osteoporotic, '(', n, =, 28, ')', patients])].
[sujeto(['Moreover,', it]), verbo([provides]), complemento([information, about, the, metabolic, changes, occurring, in, bone, marrow, with, the, development, of, 'osteoporosis,', which, are, skeletal, site, dependent])].
[sujeto(['We']), verbo([report]), complemento([the, detection, of, 'SiS', rotational, lines, in, 'high-vibrational', states, as, well, as, 'SiO', and, 'SiC2', lines, in, their, ground, vibrational, state, toward, 'IRC+10216', during, the, 'Atacama', 'Large', 'Millimeter', 'Array', 'Cycle', 0])].
[sujeto(['The', spatial, distribution, of, these, molecules, shows, compact, emission, for, 'SiS', and, a, more, extended, emission, for, 'SiO', and, 'SiC2,', and, also, proves, the, existence, of, an]), verbo([increase]), complemento([in, the, 'SiC2', emission, at, the, outer, shells, of, the, circumstellar, envelope])].
[sujeto(['We']), verbo([found]), complemento([moderate, discrepancies, between, the, observations, and, the, models, that, could, be, explained, if, 'SiS', lines, detected, are, optically, thick])].
[sujeto(['Additionally,', the, line, profiles, of, the, detected, rotational, lines, in, the, high, energy, vibrational, states, show, a]), verbo([decreasing]), complemento([linewidth, with, increasing, energy, levels])].
[sujeto(['The', identified, reference, transcripts, were, further, used, to, evaluate, expression, profiles, of]), verbo([target]), complemento([transcripts, encoding, the, thyroid, hormone, receptor, β, '(', 'THRβ)', and, vitellogenin, '(', 'vtg),', known, to, be, involved, in, silvering, processes])].
[sujeto(['The', 'male-sterile', 'Allium', sativum, '(', 'garlic)', reproduces, exclusively, in, the, vegetative, 'mode,', and, anthropogenic, factors, seem, to, be, the]), verbo([cause]), complemento([of, the, loss, of, sexual, reproduction, capability])].
[sujeto(['There', are, many, different, hypotheses, concerning, the]), verbo([causes]), complemento([of, male, sterility, in, 'A'])].
[sujeto(['sativum;', 'however,', the, mechanisms, underlying, this, phenomenon]), verbo([have]), complemento([not, been, comprehensively, elucidated])].
[sujeto(['Numerous', attempts]), verbo([have]), complemento([been, undertaken, to, understand, the, causes, of, male, 'sterility,', but, the, tubulin, cytoskeleton, in, meiotically, dividing, cells, during, microsporogenesis, has, never, been, investigated, in, this, species])].
[sujeto([ampeloprasum, '(', 'leek),', we]), verbo([have]), complemento([analysed, the, distribution, of, the, tubulin, cytoskeleton, during, microsporogenesis])].
[sujeto(['However,', the, tubulin, cytoskeleton, in, garlic, was, distinctly, poorer, '(', composed, of, a, few, 'MT', 'filaments)', compared, with, that]), verbo([found]), complemento([in, meiotically, dividing, cells, in, 'A'])].
[sujeto(['gametogenesis,', there, were, disorders]), verbo([involving]), complemento([the, absence, of, a, normal, cortical, cytoskeleton, and, dramatically, progressive, degeneration, of, the, cytoplasm, in, garlic])].
[sujeto(['Therefore,we']), verbo([suggest]), complemento(['that,', due, to, disturbances, in, cortical, cytoskeleton, formation, at, the, very, beginning, of, 'gametogenesis,', the, intracellular, transport, governed, by, the, cytoskeleton, might, be, 'perturbed,', leading, to, microspore, decay, in, the, 'male-sterile', garlic, genotype])].
[sujeto(['Independent', of, mental, 'disorders,', nightmares, are, often]), verbo([associated]), complemento([with, sleep, problems, such, as, prolonged, sleep, 'latencies,', poorer, sleep, 'quality,', and, daytime, sleepiness])].
[sujeto(['It']), verbo([has]), complemento([not, been, well, documented, whether, this, is, reflected, in, objectively, quantifiable, physiological, indices, of, sleep, quality])].
[sujeto(['NM', participants]), verbo([reported]), complemento([worse, sleep, 'quality,', more, waking, problems, and, more, severe, insomnia, compared, to, 'HC', group])].
[sujeto(['Thus,', these, specific, problems]), verbo([require]), complemento([specific, attention, and, appropriate, treatment])].
[sujeto(['The', 'Kunitz-type', protease, inhibitor, 'ShPI-1']), verbo([inhibits]), complemento([human, neutrophil, elastase, '(', 'HNE,', 'Ki', =, 2.35, '·10-8', 'M)', but, does, not, interact, with, the, porcine, pancreatic, elastase, '(', 'PPE);', whereas, its, 'P1', site, 'variant,', 'ShPI-1/K13L,', inhibits, both, 'HNE', and, 'PPE', '(', 'Ki', =, 1.3, '·10-9', 'M,', and, 'Ki', =, 1.2, '·10-8', 'M,', 'respectively)'])].
[sujeto(['In', 'addition,', our, results]), verbo([suggest]), complemento([that, the, higher, affinity, of, 'ShPI-1/K13L', for, both, elastases, mainly, arises, from, the, lower, 'polar-desolvation', penalty, of, 'L13', compared, to, that, of, 'K13,', and, not, from, stronger, 'pair-wise', interactions, of, the, former, residue, with, those, of, each, enzyme])].
[sujeto(['These', results]), verbo([provide]), complemento([insights, into, the, 'PPE', and, 'HNE', inhibition, and, may, contribute, to, the, design, of, more, potent, 'and/or', specific, inhibitors, toward, one, of, these, proteases])].
[sujeto(['In', the, present, 'study,', expression, analysis, of, six, different, constitutively]), verbo([expressed]), complemento([genes, viz])].
[sujeto([18, 'S', ribosomal, 'RNA,', 'glyceraldehyde-3-phosphate', dehydrogenase, '(', 'gapdh),', beta, actin, '(', 'βactin),', ribosomal]), verbo([binding]), complemento([protein, 'L13,', tubulin, and, 'TATA-box-binding', protein, '(', 'tbp)', were, carried, out, to, test, their, efficacy, as, reference, genes, in, three, different, 'tissues,', namely, 'liver,', gill, and, muscle, of, murrel, 'Channa', striatus, exposed, to, high, temperature, for, variable, time, periods])].
[sujeto(['We']), verbo([have]), complemento([recently, demonstrated, that, complexation, with, '(', 'η(6)-arene)Ru(II)', fragments, confers, 4, -, anilinoquinazoline, pharmacophores, a, higher, potential, for, inducing, cellular, apoptosis, while, preserving, the, highly, inhibitory, activity, of, 4, -, anilinoquinazolines, against, 'EGFR', and, the, reactivity, of, the, ruthenium, centre, to, 9, -, ethylguanine, '(', 'Chem'])].
[sujeto(['Intriguingly,', the, ligation, of, '(', 'arene)Ru(II)', fragments, with, 4, -, anilinoquinazolines, not, only, makes, the]), verbo([target]), complemento([complexes, excellent, 'EGFR', 'inhibitors,', but, also, confers, the, complexes, high, affinity, to, bind, to, 'DNA', minor, grooves, while, maintaining, their, reactivity, towards, 'DNA', 'bases,', characterising, them, with, 'dual-targeting', properties])].
[sujeto(['Molecular', modelling, studies]), verbo([reveal]), complemento([that, the, hydrolysis, of, these, complexes, is, a, favourable, process, which, increases, the, affinity, of, the, target, complexes, to, bind, to, 'EGFR', and, 'DNA'])].
[sujeto(['In', vitro, biological, activity, assays, show, that, most, of, this, group, of, ruthenium, complexes, are, selectively, active]), verbo([inhibiting]), complemento([the, 'EGF-stimulated', growth, of, the, 'HeLa', cervical, cancer, cell, 'line,', and, the, most, active, complex, '[', '(', 'η(6)-arene)Ru(N,N-L13)Cl]PF6', '(', ',', 'IC50', =, 1.36, 'μM,', =, 4, -, '(', 3, '\'', -, 'chloro-4\'-fluoroanilino)-6-(2-(2-aminoethyl)aminoethoxy)-7-methoxyquinazoline)', is, 29, -, fold, more, active, than, its, 'analogue,', '[', '(', 'η(6)-arene)Ru(N,N-ethylenediamine)Cl]PF6,', and, 21, -, fold, more, active, than, 'gefitinib,', a, 'well-known', 'EGFR', inhibitor, in, use, clinically])].
[sujeto(['Here,', we, detected, mitophagy, deficits, evidenced, by, the]), verbo([increased]), complemento([levels, of, mitophagy, 'markers,', including, 'COX', 'IV,', 'TOMM20,', and, the, ratio, of, mtDNA, to, genomic, 'DNA', indexed, as, 'mt-Atp6/Rpl13,', in, the, 'AD', brains, and, in, the, human, wild, type, 'full-length', tau, '(', 'htau)', transgenic, mice])].
[sujeto(['More', 'interestingly,', the, mitophagy, deficit, was, only, shown, in, the, 'AD', patients, who, had, an]), verbo([increased]), complemento([total, tau, level])].
[sujeto(['Further', studies, demonstrated, that, overexpression, of, htau]), verbo([induced]), complemento([mitophagy, deficits, in, 'HEK293', 'cells,', the, primary, hippocampal, neurons, and, in, the, brains, of, 'C57', mice])].
[sujeto(['Upon', overexpression, of, 'htau,', the, mitochondrial, membrane, potential, was]), verbo([increased]), complemento([and, the, levels, of, 'PTEN-induced', kinase, 1, '(', 'PINK1)', and, 'Parkin', decreased, in, the, mitochondrial, 'fraction,', while, upregulation, of, 'Parkin', attenuated, the, 'htau-induced', mitophagy, deficits])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, intracellular, accumulation, of, htau, induces, mitophagy, deficits, by, direct, inserting, into, the, mitochondrial, membrane, and, thus, increasing, the, membrane, 'potential,', which, impairs, the, mitochondrial, residence, of, 'PINK1/Parkin'])].
[sujeto(['Our', findings]), verbo([reveal]), complemento([a, novel, mechanism, underlying, the, 'htau-induced', neuronal, toxicities, in, 'AD', and, other, tauopathies])].
[sujeto(['Despite', a, 'long-standing', 'effort,', maternal, transcription, factors]), verbo([regulating]), complemento([this, crucial, developmental, event, remain, largely, elusive])].
[sujeto(['Transcriptome', analyses, identify, 'YAP']), verbo([target]), complemento([genes, in, early, 'blastomeres;', two, of, 'which,', 'Rpl13', and, 'Rrm2,', are, required, to, mediate, maternal, 'YAP\'s', effect, in, conferring, developmental, competence, on, preimplantation, embryos])].
[sujeto(['These', observations]), verbo([provide]), complemento([insights, into, the, mechanisms, of, 'ZGA,', and, suggest, potentials, of, 'YAP', activators, in, improving, the, developmental, competence, of, cultured, embryos, in, assisted, human, reproduction, and, animal, biotechnology])].
[sujeto(['We']), verbo([have]), complemento([characterized, the, expression, patterns, of, important, genes, involved, in, the, ecdysone, pathway, from, embryos, to, 'pupa,', but, specially, during, the, different, phases, of, 'C'])].
[sujeto(['Real-Time', 'PCR', was, used, to, 'analyze:', 'EcR', and, 'usp,', two, genes, encoding, the, two]), verbo([dimerizing]), complemento([partners, of, the, functional, ecdysone, 'receptor;', 'E74,', an, early, response, gene, induced, by, 'ecdysteroids;', vg, '(', 'vitellogenin),', an, effector, 'gene;', hsp70, and, 'hsc70,', two, 'heat-shock', genes, involved, in, the, correct, folding, of, the, ecdysone, 'receptor;', and, 'rpL13,', as, a, part, of, the, ribosomal, machinery])].
[sujeto(['The', induction, in, the, expression, of, 'EcR', and, usp, during, the, 'VII-VIII', phase, of, the, fourth, instar, is, concomitant, with, a, coordinated, response, in, the, activity, of, the, other, genes, 'analyzed,']), verbo([suggesting]), complemento([the, moment, where, larvae, prepare, for, pupation])].
[sujeto(['This', work, is, particularly, relevant, given, that, most, of, the, analyzed, genes]), verbo([have]), complemento([been, proposed, previously, in, this, species, as, sensitive, biomarkers, for, the, toxicological, evaluation, of, aquatic, ecosystems])].
[sujeto(['In', 'addition,', 'RefFinder,', which, integrates, the, 'above-mentioned', software, 'tools,']), verbo([provided]), complemento([the, overall, ranking, of, the, 'stability/suitability', of, these, candidate, reference, genes])].
[sujeto(['With', the, recent]), verbo([release]), complemento([of, the, 'T'])].
[sujeto([urticae, 'genome,', results, from, this, study]), verbo([provide]), complemento([a, critical, piece, for, the, subsequent, genomics, and, functional, genomics, research, in, this, emerging, model, system])].
[sujeto(['Prior', 'RG', studies, should, precede, each, qPCR, gene, expression, study, since, 'RG', selection, is]), verbo([associated]), complemento([with, the, origin, and, proportion, of, specimens])].
[sujeto(['Two', independent, 'epigenome-wide', association, studies, of, 'Alzheimer’s', disease, cohorts]), verbo([have]), complemento([identified, overlapping, methylation, signals, in, four, 'loci,', 'ANK1,', 'RPL13,', 'RHBDF2', and, 'CDH23,', not, previously, associated, with, 'Alzheimer’s', disease])].
[sujeto(['These', studies, also]), verbo([suggest]), complemento([that, epigenetic, changes, contribute, more, to, 'Alzheimer’s', disease, than, expected])].
[sujeto(['We']), verbo([found]), complemento([that, the, level, of, methylation, at, 71, of, the, 415, ',', 848, interrogated, 'CpGs', was, significantly, associated, with, the, burden, of, 'AD', 'pathology,', including, 'CpGs', in, the, 'ABCA7', and, 'BIN1', 'regions,', which, harbor, known, 'AD', susceptibility, variants])].
[sujeto(['Our', analyses]), verbo([suggest]), complemento([that, these, 'DNA', methylation, changes, may, have, a, role, in, the, onset, of, 'AD', given, that, we, observed, them, in, presymptomatic, subjects, and, that, six, of, the, validated, genes, connect, to, a, known, 'AD', susceptibility, gene, network])].
[sujeto([has, been, 'published,', thereby, facilitating, the, analysis, of, genes]), verbo([expressed]), complemento([during, a, specific, stage, or, involved, in, parasite, development])].
[sujeto(['We', propose, the, use, of, 'EF-1α', as, a, reference, gene, for, studies]), verbo([involving]), complemento([gene, expression, analysis, in, both, 'PS', and, 'PSP', experimental, conditions, for, 'E'])].
[sujeto(['This']), verbo([report]), complemento([validates, suitable, reference, genes, for, species, of, class, 'Cestoda,', phylum, 'Platyhelminthes,', thus, providing, a, foundation, for, further, validation, in, other, epidemiologically, important, cestode, 'species,', such, as, those, from, the, 'Taenia', genus])].
[sujeto(['In', recent, 'years,', an]), verbo([increasing]), complemento([number, of, avian, species, other, than, the, chicken, has, been, investigated, 'molecularly,', highlighting, the, need, for, an, experimentally, validated, 'pan-avian', primer, set, for, reference, genes])].
[sujeto(['Here', we]), verbo([report]), complemento([testing, a, set, for, 14, candidate, reference, genes, '(', 18, 'S,', 'ABL,', 'GAPDH,', 'GUSB,', 'HMBS,', 'HPRT,', 'PGK1,', 'RPL13,', 'RPL19,', 'RPS7,', 'SDHA,', 'TFRC,', 'VIM,', 'YWHAZ)', on, different, tissues, of, the, mallard, '(', 'Anas', 'platyrhynchos),', domestic, chicken, '(', 'Gallus', gallus, 'domesticus),', common, crane, '(', 'Grus', 'grus),', 'white-tailed', eagle, '(', 'Haliaeetus', 'albicilla),', domestic, turkey, '(', 'Meleagris', gallopavo, f])].
[sujeto(['As', a, proof, of, 'principle,', we, analyzed, expression, levels, of, 10, candidate, reference, genes, as, well, as, 'FOXP2', and, the, immediate, early, 'genes,', 'EGR1', and, 'CFOS,', known, to, be, rapidly]), verbo([induced]), complemento([by, singing, in, the, avian, basal, ganglia])].
[sujeto(['Using', three, different, statistical, 'algorithms,', we, identified, five, genes, '(', 18, 'S,', 'PGK1,', 'RPS7,', 'TFRC,', 'YWHAZ)', that, were, stably]), verbo([expressed]), complemento([within, each, group, and, also, between, the, singing, and, silent, 'conditions,', establishing, them, as, suitable, reference, genes])].
[sujeto(['In', 'conclusion,', the, newly, developed, 'pan-avian']), verbo([primer]), complemento([set, allows, accurate, normalization, and, quantification, of, gene, expression, levels, in, multiple, avian, species])].
[sujeto(['Elevated', secreted, 'protein,', 'acidic,', and, rich, in, cysteine, '(', 'SPARC)', protein, expression, is]), verbo([associated]), complemento([with, tissue, scarring, and, fibrosis])].
[sujeto(['Cellular']), verbo([binding]), complemento([and, uptake, of, 'LbL', 'NPs', as, well, as, siRNA, delivery, were, studied, in, 'FibroGRO', cells])].
[sujeto(['In', 'conclusion,', the, 'LbL', 'NP', system, described]), verbo([provides]), complemento([a, 'promising,', safe, and, efficient, delivery, platform, as, a, 'non-viral', vector, for, siRNA, delivery, that, uses, biopolymers, to, enhance, the, gene, knock, down, efficiency, for, the, development, of, siRNA, therapeutics])].
[sujeto(['At', 4, ',', 16, ',', 20, ',', and, 24, &, 'nbsp;h', after, 'contusion,', expression, levels, of, 'SNAT2', mRNA, normalized, to, 'RPL13', mRNA]), verbo([increased]), complemento([by, 2.07, '(', 'P < 0'])].
[sujeto(['This', result]), verbo([suggests]), complemento([that, the, determination, of, 'SNAT2', mRNA, levels, by, 'real-time', 'PCR', may, be, useful, for, estimating, wound, age])].
[sujeto(['For', the, majority, of, eukaryotic, ribosomal, 'proteins,', residues, critical, for, rRNA, 'binding,', a, key, step, in, the, hierarchical, assembly, of, 'ribosomes,']), verbo([have]), complemento([not, been, well, defined])].
[sujeto(['This', work, identified, the, arginine, residue, at, position, 68, of, 'L13a', as, being, essential, for, 'L13a']), verbo([binding]), complemento([to, rRNA, and, incorporation, into, ribosomes])].
[sujeto(['Incorporation', of, 'L13a', into, the, 90, 'S', preribosome, was]), verbo([required]), complemento([for, rRNA, methylation, within, the, 90, 'S', complex])].
[sujeto(['However,', mutations, abolishing, ribosomal, incorporation, of, 'L13a', did, not, affect, its, ability, to, be]), verbo([phosphorylated]), complemento([or, its, extraribosomal, function, in, 'GAIT', 'element-mediated', translational, silencing])].
[sujeto(['These', results]), verbo([provide]), complemento([new, insights, into, the, mechanism, of, ribosomal, incorporation, of, 'L13a', and, will, be, useful, in, guiding, future, studies, aimed, at, fully, deciphering, mammalian, ribosome, biogenesis])].
[sujeto(['Retinoic', acid, inducible, gene, 'I', '(', 'RIG-I)', senses, viral, 'RNAs', and]), verbo([triggers]), complemento([innate, antiviral, responses, through, induction, of, type, 'I', 'IFNs', and, inflammatory, cytokines])].
[sujeto(['However,', whether, 'RIG-I']), verbo([interacts]), complemento([with, host, cellular, 'RNA', remains, undetermined])].
[sujeto(['Here', we]), verbo([report]), complemento([that, 'Rig-I', interacts, with, multiple, cellular, 'mRNAs,', especially, 'Nf-κb1'])].
[sujeto(['Rig-I', is]), verbo([required]), complemento([for, 'NF-κB', activity, via, regulating, 'Nf-κb1', expression, at, posttranscriptional, levels])].
[sujeto(['It']), verbo([interacts]), complemento([with, the, multiple, binding, sites, within, 3, '\'', -, 'UTR', of, 'Nf-κb1', mRNA])].
[sujeto(['Further', analyses]), verbo([reveal]), complemento([that, three, distinct, tandem, motifs, enriched, in, the, 3, '\'', -, 'UTR', fragments, can, be, recognized, by, 'Rig-I'])].
[sujeto(['The', 3, '\'', -, 'UTR']), verbo([binding]), complemento([with, 'Rig-I', plays, a, critical, role, in, normal, translation, of, 'Nf-κb1', by, recruiting, the, ribosomal, proteins, '[', ribosomal, protein, 'L13', '(', 'Rpl13)', and, 'Rpl8]', and, rRNAs, '(', 18, 'S', and, 28, 'S)'])].
[sujeto(['These', findings, indicate, that, 'Rig-I', functions, as, a, positive, regulator, for, 'NF-κB', signaling, and, is]), verbo([involved]), complemento([in, multiple, biological, processes, in, addition, to, host, antivirus, immunity])].
[sujeto(['The', differential, gene, expression, resulting, from, adhesion, of, macrophages, to, the, 'extra-cellular', matrix, '(', 'ECM)']), verbo([has]), complemento([been, studied, in, the, 'J774A1', murine, macrophage, cell, line, using, quantitative, polymerase, chain, reaction, '(', 'qPCR)'])].
[sujeto(['This', study, also, emphasizes, the, importance, of, evaluating, 'HKGs', used, for, normalization, to]), verbo([ensure]), complemento([the, accuracy, of, qPCR, data])].
[sujeto(['Specific', normalization, analytes, were]), verbo([found]), complemento([to, be, advantageous, for, different, classes, of, 'samples,', with, ssDNA, being, the, optimal, analyte, to, normalize, blood, contaminated, samples])].
[sujeto(['Growth', hormone, '(', 'GH)', supplementation, therapy, to, adults, with, 'GH', deficiency]), verbo([has]), complemento([beneficial, effects, on, adipose, tissue, lipid, 'metabolism,', improving, thus, adipocyte, functional, morphology, and, insulin, sensitivity])].
[sujeto(['Glucose', tolerance, was, determined, by, 'oGTT,', visceral, and, subcutaneous, abdominal, adiposity, by, 'MRI,', adipocyte, size, morphometrically, after, collagenase, 'digestion,', lipid, accumulation, and]), verbo([release]), complemento([was, studied, in, differentiated, human, primary, adipocytes, in, association, with, 'GH', treatment, and, 'zinc-α2-glycoprotein', gene, silencing])].
[sujeto(['Adipose', tissue, 'zinc-α2-glycoprotein', expression, was, positively]), verbo([associated]), complemento([with, 'whole-body', and, adipose, tissue, insulin, sensitivity, and, negatively, with, adipocyte, size])].
[sujeto(['GH', treatment, to, adipocytes, in, vitro]), verbo([increased]), complemento(['zinc-α2-glycoprotein', expression, '(', &, 'gt;50%)', and, was, paralleled, by, enhanced, lipolysis, and, decreased, triglyceride, accumulation, '(', &, 'gt;35%)'])].
[sujeto(['Effects', of, 5, -, year, 'GH', supplementation, therapy, on, adipose, tissue, lipid, metabolism, and, insulin, sensitivity, are]), verbo([associated]), complemento([with, 'zinc-α2-glycoprotein'])].
[sujeto(['Presence', of, this, adipokine, is]), verbo([required]), complemento([for, the, 'GH', action, on, adipocyte, lipid, metabolism, in, vitro])].
[sujeto(['The', administration, of, dextran, sodium, sulfate]), verbo([induced]), complemento([experimental, colitis, in, 'myeloid-specific', 'L13a-knockout', '(', 'KO)', and, control, mice])].
[sujeto(['Higher', serum, levels, of, several, 'pro-inflammatory', cytokines, and, the]), verbo([release]), complemento([of, gut, bacteria, and, endotoxins, into, the, blood, streams, of, 'KO', mice, were, 'detected,', suggesting, the, amplification, of, the, inflammatory, response, to, septicemia])].
[sujeto(['Taken', 'together,', these, results]), verbo([reveal]), complemento([an, essential, role, for, 'L13a', in, the, endogenous, protection, against, 'UC', and, demonstrate, the, potential, for, new, therapeutic, opportunities, through, the, deliberate, promotion, of, this, mechanism])].
[sujeto(['Considering', the, broad, variation, in, the, expression, of, candidate, reference, genes, among, tumor, stages, and, normal, 'brain,', studies, using, quantitative, 'RT-PCR']), verbo([require]), complemento([strict, definition, of, adequate, endogenous, controls])].
[sujeto(['This', study, aimed, at, testing, a, panel, of, nine, reference, genes, '[', 'beta-2-microglobulin,', cytochrome, 'c-1', '(', 'CYC1),', 'glyceraldehyde-3-phosphate', dehydrogenase, '(', 'GAPDH),', hydroxymethylbilane, 'synthase,', hypoxanthine, guanine, phosphoribosyl, transferase, 1, ',', ribosomal, protein, 'L13a', '(', 'RPL13A),', succinate, 'dehydrogenase,', 'TATA-box']), verbo([binding]), complemento([protein, and, 14, -, 3, -, 3, protein, 'zeta]', to, identify, and, validate, the, most, suitable, reference, genes, for, expression, studies, in, human, glioma, of, different, grades, '(', 'World', 'Health', 'Organization', grades, 'II-IV)'])].
[sujeto(['A', 32, -, nucleotide, '(', 'nt)', 'RNA', motif, located, at, the, 3, '\'', end, of, the, transmissible, gastroenteritis, coronavirus, '(', 'TGEV)', genome, was]), verbo([found]), complemento([to, specifically, interact, with, the, host, proteins, 'glutamyl-prolyl-tRNA', synthetase, '(', 'EPRS)', and, 'arginyl-tRNA', synthetase, '(', 'RRS)'])].
[sujeto(['This', 'RNA', motif]), verbo([has]), complemento([high, homology, in, sequence, and, secondary, structure, with, the, gamma, 'interferon-activated', inhibitor, of, translation, '(', 'GAIT)', 'element,', which, is, located, at, the, 3, '\'', end, of, several, mRNAs, encoding, proinflammatory, proteins])].
[sujeto(['The', 'GAIT', element, is]), verbo([involved]), complemento([in, the, translation, silencing, of, these, mRNAs, through, its, interaction, with, the, 'GAIT', complex, '(', 'EPRS,', heterogeneous, nuclear, ribonucleoprotein, 'Q,', ribosomal, protein, 'L13a,', and, glyceraldehyde, 3, -, phosphate, 'dehydrogenase)', to, favor, the, resolution, of, inflammation])].
[sujeto(['Interestingly,', we, showed, that, the, viral, 'RNA', motif]), verbo([bound]), complemento([the, 'GAIT', complex, and, inhibited, the, in, vitro, translation, of, a, chimeric, mRNA, containing, this, 'RNA', motif])].
[sujeto(['However,', an, exacerbated, innate, immune, 'response,']), verbo([mediated]), complemento([by, the, melanoma, 'differentiation-associated', gene, 5, '(', 'MDA5)', 'pathway,', was, observed, in, cells, infected, with, the, mutant, virus, compared, with, the, response, observed, in, cells, infected, with, the, parental, virus])].
[sujeto(['All', 'together,', these, data, strongly]), verbo([suggested]), complemento([that, the, viral, 'GAIT-like', 'RNA', motif, modulates, the, host, innate, immune, response])].
[sujeto(['Coronaviruses', encode, several, proteins, that, interfere, with, the, innate, immune, response, at, different, 'levels,', but, to, 'date,', no, viral, 'RNA', counteracting, antiviral, response]), verbo([has]), complemento([been, described])].
[sujeto(['In', this, 'work,', we]), verbo([have]), complemento([characterized, a, 32, -, nt, 'RNA', motif, located, at, the, 3, '\'', end, of, the, 'TGEV', genome, that, specifically, interacted, with, 'EPRS', and, 'RRS'])].
[sujeto(['This', 'RNA', motif, presented, high, homology, with, the, 'GAIT', 'element,']), verbo([involved]), complemento([in, the, modulation, of, the, inflammatory, response])].
[sujeto(['Moreover,', the, disruption, of, the, viral, 'GAIT-like', 'RNA', motif]), verbo([led]), complemento([to, an, exacerbated, innate, immune, response, triggered, by, 'MDA5,', indicating, that, the, 'GAIT-like', 'RNA', motif, counteracts, the, host, innate, immune, response])].
[sujeto(['Elevated', very, 'low-density', lipoprotein, '(', 'VLDL)-triglyceride', '(', 'TG)', secretion, from, the, liver, contributes, to, an, atherogenic, dyslipidemia, that, is]), verbo([associated]), complemento([with, 'obesity,', diabetes, and, the, metabolic, syndrome])].
[sujeto(['Numerous', models, of, obesity, and, diabetes, are, characterized, by]), verbo([increased]), complemento([central, nervous, system, '(', 'CNS)', neuropeptide, 'Y', '(', 'NPY);', in, 'fact,', a, single, intracerebroventricular, '(', 'icv)', administration, of, 'NPY', in, lean, fasted, rats, elevates, hepatic, 'VLDL-TG', secretion, and, does, 'so,', in, large, 'part,', via, signaling, through, the, 'CNS', 'NPY', 'Y1', receptor])].
[sujeto(['Thus,', our, overarching, hypothesis, is, that, elevated, 'CNS', 'NPY', action, contributes, to, dyslipidemia, by]), verbo([activating]), complemento([central, circuits, that, modulate, liver, lipid, metabolism])].
[sujeto(['Additionally,', lean, 4, -, 'h fasted', rats, with, intact, or, disrupted, hepatic, sympathetic, innervation, were, treated, with, icv, 'NPY', or, 'NPY', 'Y1', receptor, agonist, to, identify, novel, hepatic, mechanisms, by, which, 'NPY']), verbo([promotes]), complemento(['VLDL', particle, maturation, and, secretion])].
[sujeto(['Treatment', with, icv, 'NPY', or, a, selective, 'NPY', 'Y1', receptor, agonist, in, lean, fasted, rats, robustly]), verbo([activated]), complemento([key, hepatic, regulatory, 'proteins,', 'stearoyl-CoA', 'desaturase-1', '(', 'SCD-1),', 'ADP-ribosylation', 'factor-1', '(', 'ARF-1),', and, 'lipin-1,', known, to, be, involved, in, remodeling, liver, 'PL', into, 'TG', for, 'VLDL', maturation, and, secretion])].
[sujeto(['These', data, support, a, model, in, which, 'CNS', 'NPY']), verbo([modulates]), complemento([mediators, of, hepatic, 'PL', remodeling, and, 'VLDL', maturation, to, stimulate, 'VLDL-TG', secretion, that, is, dependent, on, the, 'Y1', receptor, and, sympathetic, signaling, to, the, liver])].
[sujeto(['Gene', transcription, analysis, is, important, in, cancer, 'research,', and, reverse, 'transcription‑quantitative', polymerase, chain, reaction, '(', 'RT‑qPCR)']), verbo([has]), complemento([been, demonstrated, to, be, an, effective, method, to, evaluate, gene, transcription, in, cancer])].
[sujeto(['RT‑qPCR']), verbo([requires]), complemento([an, internal, reference, gene, with, a, consistent, level, of, mRNA, transcription, across, various, experimental, conditions])].
[sujeto(['However,', it]), verbo([has]), complemento([been, suggested, that, different, 'treatments,', including, anticancer, 'therapy,', may, influence, the, transcriptional, stability, of, internal, reference, genes])].
[sujeto(['Paclitaxel', '(', 'PTX)', and, 10, &, #, 8209, ;, hydroxycamptothecin, '(', 'HCPT)', are, widely, used, to, treat, various, types, of, 'cancer,', and, a, suitable, internal, reference, gene, is]), verbo([required]), complemento([in, order, to, analyze, the, transcription, profiles, of, the, cells, following, treatment])].
[sujeto(['A', comparison, of, tissue, 'sources,', including, periodontal, ligament, '(', 'PDL)', versus, pulp, '(', 'P),', could]), verbo([provide]), complemento([critical, information, to, select, an, appropriate, 'MSC', population, for, designing, predictable, regenerative, therapies])].
[sujeto(['Fourteen', of, 84, genes, related, to, 'MSCs', were]), verbo([expressed]), complemento([differently, in, the, 'PDL-MSCs', versus, the, 'P-MSCs'])].
[sujeto(['The', results, of, this, study]), verbo([suggest]), complemento([that, 'MSCs', isolated, from, 'P', and, 'PDL', tissues, show, different, cellular, behavior])].
[sujeto(['To']), verbo([increase]), complemento([the, predictability, of, 'MSC-based', regenerative, 'treatment,', differences, in, dental, 'tissue-derived', 'MSCs', and, favorable, aspects, of, cell, sources, should, be, further, clarified])].
[sujeto(['We']), verbo([report]), complemento([a, novel, extraribosomal, innate, immune, function, of, mammalian, ribosomal, protein, 'L13a,', whereby, it, acts, as, an, antiviral, agent])].
[sujeto(['We']), verbo([found]), complemento([that, 'L13a', is, released, from, the, 60, 'S', ribosomal, subunit, in, response, to, infection, by, respiratory, syncytial, virus, '(', 'RSV),', an, 'RNA', virus, of, the, 'Pneumovirus', genus, and, a, serious, lung, pathogen])].
[sujeto(['Unexpectedly,', the, growth, of, 'RSV', was, highly]), verbo([enhanced]), complemento([in, 'L13a-knocked-down', cells, of, various, lineages, as, well, as, in, 'L13a', knockout, macrophages, from, mice])].
[sujeto(['In', silico, 'RNA', folding, analysis, and, translational, reporter, assays, revealed, a, putative, hairpin, in, the, 3, '\'', untranslated, region, '(', 'UTR)', of, 'M', mRNA, with, significant, structural, similarity, to, the, cellular, 'GAIT', '(', 'gamma-activated', inhibitor, of, 'translation)', 'RNA', 'hairpin,', previously, shown, to, be, responsible, for, assembling, a, 'large,', 'L13a-containing', ribonucleoprotein, complex, that]), verbo([promoted]), complemento([translational, silencing, in, gamma, interferon, '(', 'IFN-γ)-activated', myeloid, cells])].
[sujeto(['VAIT', is, the, first]), verbo([report]), complemento([of, an, extraribosomal, 'L13a-mediated,', 'IFN-γ-independent', innate, antiviral, complex, triggered, in, response, to, virus, infection])].
[sujeto(['We']), verbo([provide]), complemento([a, model, in, which, the, 'VAIT', complex, strongly, hinders, 'RSV', replication, by, inhibiting, the, translation, of, the, 'rate-limiting', viral, 'M', 'protein,', which, is, a, new, paradigm, in, antiviral, defense])].
[sujeto(['The', innate, immune, mechanisms, of, host, cells, are, diverse, in, nature, and]), verbo([act]), complemento([as, a, 'broad-spectrum', cellular, defense, against, viruses])].
[sujeto(['Here,', we]), verbo([report]), complemento([a, novel, innate, immune, mechanism, functioning, against, respiratory, syncytial, virus, '(', 'RSV),', in, which, the, cellular, ribosomal, protein, 'L13a', is, released, from, the, large, ribosomal, subunit, soon, after, infection, and, inhibits, the, translation, of, a, specific, viral, 'mRNA,', 'namely,', that, of, the, matrix, protein, 'M'])].
[sujeto(['Regarding', its, 'mechanism,', we, show, that, the, recognition, of, a, specific, secondary, structure, in, the, 3, '\'', untranslated, region, of, the, 'M', mRNA]), verbo([leads]), complemento([to, translational, arrest, of, the, mRNA])].
[sujeto(['We', also, show, that, the, level, of, 'M', protein, in, the, infected, cell, is, rate, limiting, for, viral, 'morphogenesis,']), verbo([providing]), complemento([a, rationale, for, 'L13a', to, target, the, 'M', mRNA, for, suppression, of, 'RSV', growth])].
[sujeto(['Previously', we, showed, that, ribosomal, protein, 'L13a-dependent', translational, silencing]), verbo([suppresses]), complemento([the, synthesis, of, a, cohort, of, inflammatory, proteins, in, monocytes, and, macrophages])].
[sujeto(['We', also]), verbo([found]), complemento([that, genetic, abrogation, of, 'L13a', expression, in, macrophages, significantly, compromised, the, resolution, of, inflammation, in, a, mouse, model, of, 'lipopolysaccharide-induced', endotoxemia])].
[sujeto(['Here,', we, examine, whether, 'L13a', in, macrophage]), verbo([has]), complemento([a, protective, role, against, 'high-fat', 'diet-induced', atherosclerosis])].
[sujeto(['In', 'addition,', macrophages, isolated, from, knockout, mice, had, higher, polyribosomal, abundance, of, several]), verbo([target]), complemento(['mRNAs,', thus, showing, defect, in, translation, control])].
[sujeto(['Our', data, demonstrate, that]), verbo([loss]), complemento([of, 'L13a', in, macrophages, increases, susceptibility, to, atherosclerosis, in, apolipoprotein, 'E-deficient', 'mice,', revealing, an, important, role, of, 'L13a-dependent', translational, control, as, an, endogenous, protection, mechanism, against, atherosclerosis])].
[sujeto(['We', hypothesised, that, 'inflammation-induced', classical, 'NF-κB', activation, contributes, to]), verbo([loss]), complemento([of, muscle, 'OXPHEN', in, 'COPD', by, reducing, 'IKK-α', expression])].
[sujeto(['Classical', 'NF-κB', signalling, was]), verbo([activated]), complemento(['(', molecularly, or, by, tumour, necrosis, factor, 'α:', 'TNF-α)', in, cultured, myotubes, and, the, impact, on, muscle, 'OXPHEN', and, 'IKK-α', levels, was, investigated])].
[sujeto(['Moreover,', the, alternative, 'NF-κB', pathway, was]), verbo([modulated]), complemento([to, investigate, the, impact, on, muscle, 'OXPHEN', in, absence, or, presence, of, an, inflammatory, stimulus])].
[sujeto(['IKK-α', 'knock-down', in, cultured, myotubes]), verbo([decreased]), complemento([expression, of, 'OXPHEN', markers, and, key, 'OXPHEN', regulators])].
[sujeto(['Moreover,', classical, 'NF-κB', activation, '(', both, by, 'TNF-α', and, 'IKK-β', 'over-expression)', reduced, 'IKK-α', levels, and, 'IKK-α', 'over-expression']), verbo([prevented]), complemento(['TNF-α-induced', impairments, in, muscle, 'OXPHEN'])].
[sujeto(['Importantly,', muscle, 'IKK-α', protein, abundance, and, 'OXPHEN', was, reduced, in, 'COPD', patients, compared, to, 'controls,', which, was, more, pronounced, in, patients, with]), verbo([increased]), complemento([muscle, 'TNF-α', mRNA, levels])].
[sujeto(['We']), verbo([have]), complemento([shown, recently, that, direct, interaction, between, 'BUBR1', and, 'MAD2', is, critical, for, assembly, and, function, of, the, human, mitotic, checkpoint, complex, '(', 'MCC),', the, 'SAC', effector])].
[sujeto(['Here', we]), verbo([report]), complemento([that, inhibition, of, 'MPS1', kinase, activity, by, reversine, disrupts, 'BUBR1-MAD2', as, well, as, 'CDC20-MAD2', 'interactions,', causing, premature, activation, of, the, 'anaphase-promoting', 'complex/cyclosome'])].
[sujeto(['The', effect, of, 'MPS1', inhibition, is, likely, due, to, reduction, of, closed, 'MAD2', '(', 'C-MAD2),', as]), verbo([expressing]), complemento([a, 'MAD2', mutant, '(', 'MAD2(L13A))', that, is, locked, in, the, 'C', conformation, rescued, the, checkpoint, defects])].
[sujeto(['Contrary', to, a, previous, 'report,', we]), verbo([found]), complemento([that, sustained, 'MPS1', activity, is, required, for, maintaining, both, the, 'MAD1·C-MAD2', complex, and, open, 'MAD2', '(', 'O-MAD2)', at, unattached, kinetochores, to, facilitate, 'C-MAD2', production])].
[sujeto(['Our', results, support, the, notion, that, 'MPS1', kinase]), verbo([promotes]), complemento(['C-MAD2', production, and, subsequent, 'MCC', assembly, to, activate, the, 'SAC'])].
[sujeto(['Selecting', stably]), verbo([expressed]), complemento([reference, genes, is, essential, for, proper, reverse, transcription, quantitative, polymerase, chain, reaction, gene, expression, analysis])].
[sujeto(['Out', of, 12, candidate, 'references,', 'beta-2-microglobulin,', ribosomal, protein, 'L13A', and, 'Alu', repeats, are]), verbo([found]), complemento([to, be, the, most, stable, for, this, experimental, 'set-up'])].
[sujeto(['Our', results, show, that, some, of, the, commonly, used, reference, genes, are, actually, not, amongst, the, most, stable, loci, during, hES, cell, differentiation]), verbo([promoted]), complemento([by, retinoic, acid])].
[sujeto(['Moreover,', a, novel, normalization, strategy, based, on]), verbo([expressed]), complemento(['Alu', repeats, is, validated, for, use, in, hES, cell, experiments])].
[sujeto(['This', stability]), verbo([has]), complemento([to, be, demonstrated])].
[sujeto(['We']), verbo([found]), complemento(['GAPDH,', 'HMBS,', 'Actb,', 'HPRT1', and, 18, 'S', cited, as, reference, genes, in, literature, on, studies, using, the, 'SNI', model])].
[sujeto(['Using', a, 0.15, 'cut-off', for, pairwise, variations, we]), verbo([found]), complemento([that, any, pair, of, stable, reference, gene, was, sufficient, for, the, normalization, process])].
[sujeto(['The', combination, of, any, two, stable, reference, genes, was, sufficient, to]), verbo([provide]), complemento([an, accurate, normalization])].
[sujeto(['Organic', anion, transporting, polypeptides, '(', 'human:', 'OATPs;', 'rodent:', 'Oatps)', were, thought, to]), verbo([have]), complemento([important, functions, in, bile, acid, '(', 'BA)', transport])].
[sujeto(['Our', previous, studies]), verbo([have]), complemento([characterized, the, 'BA', homeostasis, in, 'Oatp1a1-null', and, 'Oatp1b2-null', mice])].
[sujeto(['Oatp1a4', expression, is, 'female-predominant', in, livers, of, 'mice,', and, thereby, it, was, expected, that, female, 'Oatp1a4-null', mice, will]), verbo([have]), complemento([more, prominent, changes, than, males])].
[sujeto(['Interestingly,', the, present, study, demonstrated, that, female, 'Oatp1a4-null', mice, had, no, significant, alterations, in, 'BA', concentrations, in, serum, or, 'liver,', though, they, had]), verbo([increased]), complemento([mRNA, of, hepatic, 'BA', efflux, transporters, '(', 'Mrp4', and, 'Ostα/β)', and, ileal, 'BA', transporters, '(', 'Asbt', and, 'Ostα/β)'])].
[sujeto(['In', 'contrast,', male, 'Oatp1a4-null', mice, showed, significantly, altered, 'BA', 'homeostasis,', including]), verbo([increased]), complemento([concentrations, of, deoxycholic, acid, '(', 'DCA)', in, 'serum,', liver, and, intestinal, contents])].
[sujeto(['This']), verbo([suggested]), complemento([that, 'Oatp1a4', is, important, for, intestinal, absorption, of, secondary, 'BAs', in, male, mice])].
[sujeto(['Furthermore,']), verbo([loss]), complemento([of, 'Oatp1a4', function, did, not, decrease, 'BA', accumulation, in, serum, or, livers, of, 'bile-duct-ligated', 'mice,', suggesting, that, 'Oatp1a4', is, not, likely, a, 'BA', uptake, transporter])].
[sujeto(['In', 'summary,', the, present, study, for, the, first, time, demonstrates, that, 'Oatp1a4', does, not, appear, to]), verbo([mediate]), complemento([the, hepatic, uptake, of, 'BAs,', but, plays, an, important, 'male-predominant', role, in, secondary, 'BA', metabolism, in, mice])].
[sujeto(['Vascular', endothelial, growth, factor, '(', 'VEGF)', is, one, of, the, factors, that]), verbo([have]), complemento([been, suggested, to, play, a, role, in, the, etiology, 'and/or', development, of, this, disease])].
[sujeto(['The', obtained, results]), verbo([suggest]), complemento(['VEGF', and, the, gene, encoding, the, molecule, play, a, role, in, the, etiology, of, the, disease, and, should, be, further, investigated])].
[sujeto(['However,', unregulated, synthesis, of, proinflammatory, products, can]), verbo([have]), complemento([detrimental, effects])].
[sujeto(['Although', mechanisms, that]), verbo([lead]), complemento([to, inflammation, are, well, 'appreciated,', those, that, restrain, it, are, not, adequately, understood])].
[sujeto(['Creating', 'macrophage-specific', 'L13a-knockout', 'mice,', we]), verbo([report]), complemento([that, depletion, of, ribosomal, protein, 'L13a', abrogates, the, endogenous, translation, control, of, several, chemokines, in, macrophages])].
[sujeto(['Upon', 'LPS-induced', 'endotoxemia,', these, animals, displayed, symptoms, of, severe, inflammation]), verbo([caused]), complemento([by, widespread, infiltration, of, macrophages, in, major, organs, causing, tissue, injury, and, reduced, survival, rates])].
[sujeto(['These', macrophages, failed, to, show, 'L13a-dependent', 'RNA']), verbo([binding]), complemento([complex, formation, on, target, mRNAs])].
[sujeto(['In', 'addition,']), verbo([increased]), complemento([polyribosomal, abundance, of, these, mRNAs, shows, a, defect, in, translation, control, in, the, macrophages])].
[sujeto(['Thus,', to, our, 'knowledge,', our, studies]), verbo([provide]), complemento([the, first, evidence, of, an, essential, extraribosomal, function, of, ribosomal, protein, 'L13a', in, resolving, physiological, inflammation, in, a, mammalian, host])].
[sujeto(['While', they]), verbo([have]), complemento([been, shown, to, be, associated, with, 'ribosomes,', their, molecular, function, remains, unclear])].
[sujeto(['RsfA', silences, translation, by]), verbo([binding]), complemento([to, the, 'L14', protein, of, the, large, ribosomal, subunit, 'and,', as, a, 'consequence,', impairs, subunit, joining, '(', as, shown, by, molecular, 'modeling,', reporter, gene, 'analysis,', in, vitro, translation, 'assays,', and, sucrose, gradient, 'analysis)'])].
[sujeto(['This', particular, interaction, is]), verbo([conserved]), complemento([in, all, species, 'tested,', including, 'Escherichia', 'coli,', 'Treponema', 'pallidum,', 'Streptococcus', 'pneumoniae,', 'Synechocystis', 'PCC', 6803, ',', as, well, as, human, mitochondria, and, maize, chloroplasts, '(', as, demonstrated, by, yeast, 'two-hybrid', 'tests,', 'pull-downs,', and, 'mutagenesis)'])].
[sujeto(['RsfA', is, unrelated, to, the, eukaryotic, ribosomal, 'anti-association/60S-assembly', factor, 'eIF6,', which, also]), verbo([binds]), complemento([to, 'L14,', and, is, the, first, such, factor, in, bacteria, and, organelles])].
[sujeto(['To', identify]), verbo([nuclear]), complemento([proteins, involved, in, the, brassinosteroid, '(', 'BR)', signaling, 'pathway,', a, targeted, proteomic, approach, was, applied, to, 'Arabidopsis', thaliana, 'suspension-cultured', 'T87', cells])].
[sujeto(['Cell', growth, was]), verbo([promoted]), complemento([by, 0.1, &, 'nbsp;μM', brassinolide, '(', 'BL)', and, inhibited, by, 5, &, 'nbsp;μM', brassinazole, '(', 'Brz)'])].
[sujeto(['Fluctuations', in, eight, identified]), verbo([nuclear]), complemento([proteins, in, 'BL-treated', cells, were, investigated, in, the, first, 12, &, 'nbsp;h', of, treatment])].
[sujeto(['Three']), verbo([nuclear]), complemento(['BR-responsive', 'proteins,', 'Nucleosome', 'Assembly', 'Protein', '(', 'NAP)', 1, ;, 1, ',', 'Band', 7, 'Family', 'Protein,', and, 'Vernalization', 'Independence', 3, ',', significantly, decreased, during, this, time])].
[sujeto(['Meanwhile,', 'NAP1;2,', 'S-Adenosylmethionine', 'Synthetase', 2, ',', and, 60, 'S', 'Ribosomal', 'Protein', 'L14']), verbo([increased]), complemento([markedly, over, time])].
[sujeto(['Since', some, of, these, proteins, are, reportedly, related, to, chromosome, 'remodeling,', cell, growth]), verbo([induced]), complemento([by, 'BL', may, involve, chromatin, remodeling])].
[sujeto(['Interestingly,', 'NAP1;2', was]), verbo([found]), complemento([to, be, 'post-translationally', modified, in, response, to, cellular, 'BR', levels])].
[sujeto(['Our', study, of, quantitative, protein, changes, in, the, nucleus]), verbo([provides]), complemento([valuable, insight, into, 'BR-induced', cellular, and, physiological, responses])].
[sujeto(['Lung', cancer, results, from, a, multistep, 'process,', whereby, genetic, and, epigenetic, alterations]), verbo([lead]), complemento([to, a, malignant, phenotype])].
[sujeto(['Somatic', 'mutations,', 'deletions,', and, amplifications, can, be, detected, in, the, tumor, 'itself,', but, they, can, also, be]), verbo([found]), complemento([in, histologically, normal, bronchial, epithelium, as, a, result, of, field, cancerization])].
[sujeto(['The', present, feasibility, study, describes, a, 'computer-assisted', analysis, of]), verbo([induced]), complemento([sputum, employing, morphology, and, fluorescence, in, situ, hybridization, '(', 'target-FISH),', using, 2, biomarkers, located, at, chromosomes, 3, p22])].
[sujeto(['This', study, describes, a, new, technology, for, detecting, lung, cancer, noninvasively, in]), verbo([induced]), complemento([sputum, via, a, combination, of, morphology, and, 'FISH', analysis, '(', 'target-FISH)', using, 'computer-assisted', technology])].
[sujeto(['(', 'Compositae)', occurs, naturally, along, the, coastline, of, the, 'Ryukyu', 'Islands', and]), verbo([has]), complemento([been, traditionally, used, as, a, folk, medicine, for, the, treatment, of, liver, and, kidney, disorders])].
[sujeto(['Bacterial', transcription, elongation, factors, 'GreA', and, 'GreB']), verbo([stimulate]), complemento([the, intrinsic, 'RNase', activity, of, 'RNA', polymerase, '(', 'RNAP),', thus, helping, the, enzyme, to, read, through, pausing, and, arresting, sites, on, 'DNA'])].
[sujeto(['Here,', we, characterized, the, molecular, mechanism, by, which, 'Gre', factors, facilitate, transcription, at, two, 'Escherichia', coli, 'promoters,', 'PrplN', and, 'PompX,', that]), verbo([require]), complemento(['GreA', for, optimal, in, vivo, activity])].
[sujeto(['Using', in, vitro, transcription, 'assays,', 'KMnO(4)', 'footprinting,', and, 'Fe(2+)-induced', hydroxyl, radical, 'mapping,', we, show, that, during, transcription, initiation, at, 'PrplN', and, 'PompX', in, the, absence, of, 'Gre', 'factors,', 'RNAP', falls, into, a, condition, of, 'promoter-proximal', transcriptional]), verbo([arrest]), complemento([that, prevents, production, of, 'full-length', transcripts, both, in, vitro, and, in, vivo])].
[sujeto(['Initiation', factor, 'sigma(70)', contributes, to, the, formation, of]), verbo([arrested]), complemento([complexes, at, both, promoters])].
[sujeto(['The', signal, for, 'promoter-proximal']), verbo([arrest]), complemento([at, 'PrplN', is, bipartite, and, requires, two, 'elements:', the, extended, -, 10, promoter, element, and, the, initial, transcribed, region, from, positions, +, 2, to, +, 6])].
[sujeto(['GreA', and, 'GreB']), verbo([prevent]), complemento([arrest, at, 'PrplN', and, 'PompX', by, inducing, cleavage, of, the, 3, '\'', -, proximal, backtracked, portion, of, 'RNA', at, the, onset, of, arrested, complex, formation, and, stimulate, productive, transcription, by, allowing, 'RNAP', to, elongate, the, 5, '\'', -, proximal, transcript, cleavage, products, in, the, presence, of, substrates])].
[sujeto(['We', propose, that, 'promoter-proximal']), verbo([arrest]), complemento([is, a, common, feature, of, many, bacterial, promoters, and, may, represent, an, important, physiological, target, of, regulation, by, transcript, cleavage, factors])].
[sujeto(['We']), verbo([report]), complemento([here, a, 'high-resolution', 'NMR', solution, structure, of, recombinant, 'L14e', and, show, that, the, 'N-terminal', 57, residues, adopt, a, classic, 'SH3', fold])].
[sujeto(['The', protein, contains, a, tight, turn, between, strands, 1, and, 2, instead, of, the, typical, 'SH3', 'RT-loop,', indicating, that, it, is, unlikely, to]), verbo([interact]), complemento([with, neighboring, ribosomal, proteins, using, the, common, 'SH3', site, for, 'proline-rich', sequences])].
[sujeto(['It']), verbo([has]), complemento([the, potential, of, adopting, an, alternative, structure, to, expose, a, hydrophobic, surface, for, 'protein-protein', interactions, in, the, ribosome, without, disruption, of, the, 'SH3', fold])].
[sujeto(['Interestingly,', the, 'N-terminal', sequence, of, 'L14e', shows, the, greatest, similarity, of, any, 'Sulfolobus', protein, to, the]), verbo([reported]), complemento(['N-terminal', sequence, of, 'Sac8b,', a, 'DNA-binding', protein, reported, by, 'Grote', et, al])].
[sujeto(['A', yeast]), verbo([nuclear]), complemento([fraction, of, unknown, 'composition,', named, 'TFIIIE,', was, reported, previously, to, enhance, transcription, of, tRNA, and, 5, 'S', rRNA, genes, in, vitro])].
[sujeto(['We', show, that, 'TFIIIE', activity, 'co-purifies', with, a, specific, subset, of, ribosomal, proteins, '(', 'RPs)', 'which,', as, revealed, by, chromatin, immunoprecipitation, 'analysis,', generally]), verbo([interact]), complemento([with, tRNA, and, 5, 'S', rRNA, 'genes,', but, not, with, a, 'Pol', 'II-specific', promoter])].
[sujeto(['Only', 'Rpl6Ap', and, 'Rpl6Bp,', among, the, tested, 'RPs,', were]), verbo([found]), complemento([associated, to, a, 'TATA-containing', 'tRNA(Ile)(TAT)', gene])].
[sujeto(['The', data, delineate, a, novel, 'extra-ribosomal', role, for, one, or, a, few, 'RPs', 'which,', by, influencing, 5, 'S', rRNA, and, tRNA, 'synthesis,', could, play, a, key, role, in, the, coordinate, regulation, of, the, different, 'sub-pathways']), verbo([required]), complemento([for, ribosome, biogenesis, and, functionality])].
[sujeto(['The', translation, factor, 'IF6', is, shared, by, the, 'Archaea', and, the, 'Eukarya,', but, is, not]), verbo([found]), complemento([in, 'Bacteria'])].
[sujeto(['The', properties, of, eukaryal, 'IF6', '(', 'eIF6)']), verbo([have]), complemento([been, extensively, 'studied,', but, remain, somewhat, elusive])].
[sujeto([eIF6, behaves, as, a, 'ribosome-anti-association', factor, and, is]), verbo([involved]), complemento([in, 'miRNA-mediated', gene, 'silencing;', 'however,', it, also, seems, to, participate, in, ribosome, synthesis, and, export])].
[sujeto(['Here', we]), verbo([have]), complemento([determined, the, function, and, ribosomal, localization, of, the, archaeal, '(', 'Sulfolobus', 'solfataricus)', 'IF6', homologue, '(', 'aIF6)'])].
[sujeto(['We']), verbo([find]), complemento([that, aIF6, binds, specifically, to, the, 50, 'S', ribosomal, 'subunits,', hindering, the, formation, of, 70, 'S', ribosomes, and, strongly, inhibiting, translation])].
[sujeto([aIF6, is, uniformly]), verbo([expressed]), complemento([along, the, cell, 'cycle,', but, it, is, upregulated, following, both, 'cold-', and, heat, shock])].
[sujeto(['The', aIF6, ribosomal]), verbo([binding]), complemento([site, lies, in, the, middle, of, the, 30, -, 'S', interacting, surface, of, the, 50, 'S', 'subunit,', including, a, number, of, critical, 'RNA', and, protein, determinants, involved, in, subunit, association])].
[sujeto(['The', data]), verbo([suggest]), complemento([that, the, 'IF6', protein, evolved, in, the, 'archaeal-eukaryal', lineage, to, modulate, translational, efficiency, under, unfavourable, environmental, 'conditions,', perhaps, acquiring, additional, functions, during, eukaryotic, evolution])].
[sujeto(['Studies']), verbo([have]), complemento([shown, that, in, septic, 'rats,', heat, stress, '(', 'HS)', has, a, protective, effect, on, bile, acid, transporters, in, hepatocyte, membranes])].
[sujeto(['Endotoxemia', in, rats, was]), verbo([induced]), complemento([by, intraperitoneal, injection, of, 'Escherichia', coli, lipopolysaccharide, '(', 'LPS)', '(', 'n=24),', while, control, rats, '(', 'n=24)', received, saline])].
[sujeto(['Two-dimensional', gel, electrophoresis, differentially, identified]), verbo([expressed]), complemento([proteins, in, all, treatment, groups])].
[sujeto(['Membrane', 'proteins;', 'Wnt', 13, ',', ribosomal, protein, 'L14,', 'VLCAD,', 'BHMT', and, 'HIT-40', were]), verbo([found]), complemento([only, in, 'HS-LPS'])].
[sujeto(['We', propose, that, 'HS', during, endotoxemia, changes, hepatic, membrane, proteins, 'expression,', which, are]), verbo([involved]), complemento([in, metabolism])].
[sujeto(['Certain', mutations, in, 'S12,', a, ribosomal, protein]), verbo([involved]), complemento([in, translation, elongation, rate, and, translation, 'accuracy,', confer, resistance, to, the, aminoglycoside, streptomycin])].
[sujeto(['Here,', we]), verbo([have]), complemento([characterized, in, vivo, the, 'fitness,', translation, speed, and, translation, accuracy, of, four, different, 'L19', mutants])].
[sujeto(['When', separated, from, the, resistance, mutation, located, in, 'S12,', the, three, different, compensatory, amino, acid, substitutions, in, 'L19', at, position, 40, '(', 'Q40H,', 'Q40L', and, 'Q40R)']), verbo([caused]), complemento([a, decrease, in, fitness, while, the, 'G104A', change, had, no, effect, on, bacterial, growth])].
[sujeto(['The', rate, of, protein, synthesis, was, unaffected, or]), verbo([increased]), complemento([by, the, mutations, at, position, 40, and, the, level, of, 'read-through', of, a, 'UGA', nonsense, codon, was, increased, in, 'vivo,', indicating, a, loss, of, translational, accuracy])].
[sujeto(['The', mutations, in, 'L19']), verbo([increased]), complemento([sensitivity, to, aminoglycosides, active, at, the, 'A-site,', further, indicating, a, perturbation, of, the, decoding, step])].
[sujeto(['By', evolving, 'low-fitness', 'L19', mutants, by, serial, 'passage,', we, showed, that, the, fitness, cost]), verbo([conferred]), complemento([by, the, 'L19', mutations, could, be, compensated, by, additional, mutations, in, the, ribosomal, protein, 'L19', 'itself,', in, 'S12', and, in, 'L14,', a, protein, located, close, to, 'L19'])].
[sujeto(['Our', results]), verbo([reveal]), complemento([a, novel, functional, role, for, the, 50, 'S', ribosomal, protein, 'L19', during, protein, 'synthesis,', supporting, published, structural, data, suggesting, that, the, interaction, of, 'L14', and, 'L19', with, 16, 'S', rRNA, could, influence, function, of, the, 30, 'S', subunit])].
[sujeto(['Expanded', 'CUG', repeats, in, the, 3, '\'', -, untranslated, region, '(', 'UTR)', of, the, gene, encoding, myotonic, dystrophy, protein, kinase, '(', 'DMPK)']), verbo([cause]), complemento([myotonic, dystrophy, type, 1, disease, '(', 'DM1)'])].
[sujeto(['The', presence, of, such, repeats]), verbo([has]), complemento([been, found, to, impede, gene, expression, at, several, levels, in, model, systems])].
[sujeto(['About', 30, genes, were]), verbo([found]), complemento([to, contain, 'CUG', repeats, that, are, polymorphic, in, the, number, of, 'repeats,', suggesting, the, potential, to, expand, or, shrink])].
[sujeto(['Using', 'cell-free', translation, 'systems,', we, showed, that, extended, 'CUG', repeats, can]), verbo([inhibit]), complemento([protein, synthesis, in, vitro, in, the, rabbit, reticulocyte, 'lysate,', but, not, in, wheat, germ, 'extracts,', consistent, with, our, previous, finding, of, an, interaction, of, 'CUG', repeats, with, the, protein, kinase, 'PKR'])].
[sujeto(['In', transfected, 'cells,', 'CUG', repeats, can]), verbo([inhibit]), complemento([gene, expression, both, in, cis, and, in, trans])].
[sujeto(['This', study, was, undertaken, to, obtain, differentially]), verbo([expressed]), complemento([genes, related, to, human, glioma, by, cDNA, microarray, and, the, characterization, of, a, novel, 'full-length', gene])].
[sujeto(['Fifteen', differentially]), verbo([expressed]), complemento([genes, were, obtained, from, human, glioma, by, hybridization, and, scanning, for, four, times])].
[sujeto(['Northern', blot, analysis, confirmed, that, the, 50700000000.0, clone, was, low]), verbo([expressed]), complemento([in, human, brain, tissue, and, over, expressed, in, human, glioma, tissues])].
[sujeto([cDNA, microarray, technology, can, be, successfully, used, to, identify, differentially]), verbo([expressed]), complemento([genes])].
[sujeto(['Allelic']), verbo([loss]), complemento([on, chromosome, 3, p, occurs, frequently, in, esophageal, cancer])].
[sujeto(['In', the, tested, informative, 'cases,']), verbo([loss]), complemento([of, heterozygosity, '(', 'LOH)', of, 'RPL14', was, observed, in, 29, out, of, 68, '(', 43, '%', ')', tumors])].
[sujeto(['No', mutation, was]), verbo([found]), complemento([in, the, remaining, 'RPL14', allele, of, the, tumors, with, 'LOH'])].
[sujeto(['Of', 17, tested, dysplasia, in, which, the, tumors, showed, 'LOH,', eight, '(', 47, '%', ')', displayed, the, same, allelic]), verbo([loss]), complemento([as, their, corresponding, 'tumors,', seven, '(', 41, '%', ')', exhibited, microsatellite, instability, '(', 'MSI),', and, only, two, retained, both, the, 'RPL14', alleles])].
[sujeto(['The', data]), verbo([suggest]), complemento([that, alteration, of, 'RPL14', occurred, frequently, in, 'ESCC', and, might, be, an, earlier, event, in, the, tumorigenesis, of, the, esophagus])].
[sujeto(['In', considering, the, best, possible, solutions, for, answering, phylogenetic, questions, from, genomic, 'sequences,', we]), verbo([have]), complemento([chosen, a, strategy, that, we, suggest, is, superior, to, others, that, have, gone, previously])].
[sujeto(['We']), verbo([have]), complemento([ignored, multigene, families, and, instead, have, used, 'single-gene', families])].
[sujeto(['We']), verbo([have]), complemento([employed, strict, data, controls, and, have, reasoned, that, if, a, protein, is, not, capable, of, recovering, the, uncontroversial, parts, of, a, phylogenetic, 'tree,', then, why, should, we, use, it, for, the, more, controversial, 'parts?', 'We', have, sliced, and, diced, the, data, in, as, many, ways, as, possible, in, order, to, uncover, the, signals, in, that, data])].
[sujeto(['Using', this, 'strategy,', we]), verbo([have]), complemento([tested, two, controversial, hypotheses, concerning, eukaryotic, phylogenetic, 'relationships:', the, placement, of, arthropoda, and, nematodes, and, the, relationships, of, 'animals,', 'plants,', and, fungi])].
[sujeto(['We']), verbo([have]), complemento([constructed, phylogenetic, trees, from, 780, 'single-gene', families, from, 10, completed, genomes, and, amalgamated, these, into, a, single, supertree])].
[sujeto(['We']), verbo([have]), complemento([also, carried, out, a, total, evidence, analysis, on, the, only, universally, distributed, protein, families, that, can, accurately, reconstruct, the, uncontroversial, parts, of, the, phylogenetic, 'tree:', a, total, of, five, families])].
[sujeto(['In', doing, 'so,', we, ignore, the, majority, of, 'single-gene', families, that, are, universally, distributed, as, they, do, not]), verbo([have]), complemento([the, appropriate, signals, to, recover, the, uncontroversial, parts, of, the, tree])].
[sujeto(['We']), verbo([have]), complemento([also, ignored, every, protein, that, has, ever, been, used, previously, to, address, this, 'issue,', simply, because, none, of, them, meet, our, strict, criteria])].
[sujeto(['The', latter]), verbo([finding]), complemento([overturns, an, 11, -, year, theory, of, 'Eukaryotic', 'evolution;', the, first, confirms, what, has, already, been, said, by, others])].
[sujeto(['In', the, light, of, this, new, 'tree,', we, 're-analyze', the, evolution, of, intron]), verbo([gain]), complemento([and, loss, in, the, rpL14, gene, and, find, that, it, is, much, more, compatible, with, the, hypothesis, presented, here, than, with, the, 'Opisthokonta', hypothesis])].
[sujeto(['Interaction', between, nucleus, and, cytoplasm]), verbo([has]), complemento([essential, roles, in, plant, 'development,', including, that, of, floral, organs])].
[sujeto(['Transient', expression, analysis, using, the, green, fluorescent, protein, '(', 'GFP)', fusion, protein, showed, that, 50, amino, residues, located, on, the, 'N-terminal', of, the, wheat, 'HLP', homolog, '(', 'WHLP)', protein]), verbo([acted]), complemento([as, a, 'mt-targeting', signal, '(', 'MTS)'])].
[sujeto(['In', these, alloplasmic, 'lines,', pistillody, '(', homeotic, transformation, of, stamens, into, 'pistil-like', 'organs)', is]), verbo([induced]), complemento([by, the, alien, cytoplasm, in, the, absence, of, nuclear, restorer, genes])].
[sujeto(['The', result]), verbo([suggested]), complemento([that, the, elevated, expression, of, the, 'Whlp', gene, plays, a, role, in, aiding, the, development, of, male, reproductive, organ, but, not, in, the, determination, of, its, whorl, identity])].
[sujeto(['The', different, expression, patterns, of, different, mt, ribosomal, protein, genes]), verbo([suggest]), complemento([that, the, abundance, of, mt, ribosomal, proteins, is, differentially, regulated, in, the, 'organ/tissue', development, in, wheat])].
[sujeto([braziliensis, 'L14', recombinant, protein, is, not]), verbo([recognized]), complemento([by, sera, from, cutaneous, leishmaniasis, patients])].
[sujeto(['Immunization', of, mice, with, one, dose, of, 'L14', recombinant, protein, and, a, second, dose, of, 'L14', protein, covalently, linked, to, the, 'HSP70', from, 'Trypanosoma', cruzi]), verbo([induces]), complemento([a, high, antibody, level, against, this, 'L14', 'protein,', which, is, mostly, of, the, 'IgG2a', 'subtype,', as, well, as, a, strong, increase, in, splenocyte, proliferation, index])].
[sujeto(['Haploinsufficiency']), verbo([increases]), complemento([the, vulnerability, to, complete, loss, of, gene, function, '(', homozygous, null, 'state)', if, hit, by, a, second, mutation])].
[sujeto(['Because', of, the, homozygous, 'lethality,', it]), verbo([has]), complemento([only, been, possible, to, study, the, effects, of, 'Minute', mutations, in, heterozygous, animals])].
[sujeto(['We', 'show,', at, the, 'RNA', and, phenotypic, 'levels,', that, 'RNAi', efficiently, reduces, 'RpL14', gene, expression, throughout, 'development,']), verbo([causing]), complemento([lethality, and, distinct, and, dramatic, somatic, anomalies, in, both, developing, and, differentiated, cells])].
[sujeto(['Small', nucleolar, 'RNAs', '(', 'snoRNAs)', are]), verbo([involved]), complemento([in, precursor, ribosomal, 'RNA', '(', 'pre-rRNA)', processing, and, rRNA, base, modifications, '(', 2, '\'', -, 'O-ribose', methylation, and, 'pseudouridylation)'])].
[sujeto(['In', all, species, 'analyzed,', 'U49', contains, the, typical, hallmarks, of, 'C', and, 'D', box, 'motifs,', and, a]), verbo([conserved]), complemento([12, -, 15, nt, sequence, complementary, to, rRNA, that, define, them, as, homologs])].
[sujeto(['In', 'mouse,', 'human,', and, 'Drosophila', 'U49', is]), verbo([found]), complemento([encoded, within, introns, of, different, 'genes,', and, in, plants, it, is, transcribed, polycistronically, from, four, different, locations])].
[sujeto(['In', 'addition,', 'U49']), verbo([has]), complemento([two, copies, in, two, different, introns, of, the, 'RpL14', gene, in, 'Drosophila'])].
[sujeto(['In', light, of, its, variable, organization, we, discuss, which, of, the, two, proposed, mechanisms, of, rearrangement]), verbo([has]), complemento([acted, upon, the, 'U49', snoRNA, 'gene:', chromosomal, duplication, or, transposition, through, an, 'RNA', intermediate])].
[sujeto(['This', study, aims, to, identify, key, genes, and, pathways]), verbo([involved]), complemento([in, 'non-alcoholic', fatty, liver, disease, '(', 'NAFLD)'])].
[sujeto(['Differentially']), verbo([expressed]), complemento([genes, '(', 'DEGs)', between, controls, and, other, samples, were, screened, through, 'LIMMA', package])].
[sujeto([')', ',', ubiquitin]), verbo([mediated]), complemento([proteolysis, '(', 'UBE2A,', 'UBA7,', etc])].
[sujeto(['In', 'PPI', 'networks,', 'PRKCA']), verbo([interacted]), complemento([with, 'EGFR', and, 'CDC42'])].
[sujeto(['Besides,', 'hsa-miR-330-3p', and, 'hsa-miR-126']), verbo([modulated]), complemento([focal, adhesion, through, targeting, 'VEGFA', and, 'CDC42'])].
[sujeto(['The', identified, 'DEGs', '(', 'PRKCA,', 'EGFR,', 'CDC42,', 'VEGFA),', disturbed, pathways, '(', 'ribosome,', ubiquitin]), verbo([mediated]), complemento(['proteolysis,', focal, 'adhesion,', 'Fc?R-mediated', 'phagocytosis,', etc])].
[sujeto(['Next', generation, sequencing, methods, were, used, to]), verbo([provide]), complemento([complete, plastome, sequences, for, 12, species])].
[sujeto(['Sanger', sequencing, was, performed, to, determine, the, plastome, of, one, 'species,', 'Hakonechloa', 'macra,', to]), verbo([provide]), complemento([a, reference, for, annotation])].
[sujeto(['Divergence', estimates, were, assessed, to, determine, potential, factors, that]), verbo([led]), complemento([to, the, rapid, radiation, of, this, lineage, and, its, dominance, of, warmer, open, habitats])].
[sujeto(['An', autapomorphic, '~1140', bp, deletion, was]), verbo([found]), complemento([in, 'Hakonechloa', macra, putatively, pseudogenizing, rpl14, and, eliminating, rpl16, from, this, plastome])].
[sujeto(['Complete', plastome, sequences]), verbo([provide]), complemento([greater, support, at, deep, nodes, within, the, 'PACMAD', clade])].
[sujeto(['Phylogenomic', analyses, of, complete, plastomes]), verbo([provides]), complemento([resolution, for, deep, relationships, of, 'PACMAD', grasses])].
[sujeto(['The', 'Eocene', was, a, period, of, global, cooling, and, 'drying,', which]), verbo([led]), complemento([to, forest, fragmentation, and, the, expansion, of, open, habitats, now, dominated, by, these, grasses])].
[sujeto(['Understanding', how, these, grasses, are, related, and, determining, a]), verbo([cause]), complemento([for, their, rapid, radiation, allows, for, future, predictions, of, grassland, distribution, in, the, face, of, a, changing, global, climate])].
[sujeto(['In', order, to, better, identify, the, narcotic, 'plants,', the, relative]), verbo([nuclear]), complemento(['DNA', content, at, the, vegetative, stage, was, measured, by, flow, cytometric, '(', 'FCM)', analysis, in, 3, 'closely-related', species, of, the, genus, 'Papaver', section, 'Oxytona,', namely, 'P'])].
[sujeto(['The', results, showed, that, the]), verbo([nuclear]), complemento(['DNA', content, differed, between, these, 3, 'species,', and, that, most, of, the, commercially, distributed, plants, examined, in, this, study, could, be, identified, as, 'P'])].
[sujeto(['Synthetic', disease, refractory, genes]), verbo([have]), complemento([been, successfully, generated, for, mosquito, vectors, of, dengue, fever, and, human, malaria])].
[sujeto(['Equally', important, is, the, development, of, population, transformation, systems, to, drive, and]), verbo([maintain]), complemento([disease, refractory, genes, at, high, frequency, in, populations])].
[sujeto(['We', demonstrate, an, underdominant, population, transformation, system, in, 'Drosophila', melanogaster, that]), verbo([has]), complemento([the, property, of, being, both, spatially, 'self-limiting', and, reversible, to, the, original, genetic, state])].
[sujeto([dsRNA]), verbo([targeting]), complemento(['RNAi', to, a, haploinsufficient, gene, 'RpL14', and, '(', 2, ')', an, 'RNAi', insensitive, 'RpL14', rescue])].
[sujeto(['However,', plastid, phylogenomic, analyses]), verbo([have]), complemento([not, included, data, for, 'Tetracentron'])].
[sujeto(['The', 'Tetracentron', and, 'Trochodendron', plastomes, possess, the, typical, gene, content, and, arrangement, that, characterize, most, angiosperm, plastid, 'genomes,', but, both, genomes]), verbo([have]), complemento([the, same, unusual, '∼4', kb, expansion, of, the, inverted, repeat, region, to, include, five, genes, '(', 'rpl22,', 'rps3,', 'rpl16,', 'rpl14,', and, 'rps8)', that, are, normally, found, in, the, large, 'single-copy', region])].
[sujeto(['Molecular', dating, analyses]), verbo([suggest]), complemento([that, 'Tetracentron', and, 'Trochodendron', diverged, between, 44, -, 30, million, years, 'ago,', which, is, congruent, with, the, fossil, record, of, 'Trochodendrales', and, with, previous, estimates, of, the, divergence, time, of, these, two, taxa])].
[sujeto(['Chronic', obstructive, pulmonary, disease, '(', 'COPD)', is, an, inflammatory, lung, disease, with]), verbo([associated]), complemento([systemic, effects])].
[sujeto(['To', use, gene, expression, microarrays, in, peripheral, blood, leukocytes, of, current, and, former, cigarette, smokers, to, identify, differences]), verbo([associated]), complemento([with, 'COPD'])].
[sujeto(['These', gene, expression, profiles, represent, potential, biomarkers, for, 'COPD', and, may, help]), verbo([increase]), complemento([mechanistic, understanding, of, the, disease])].
[sujeto(['However,', genomic, research, of, mungbean]), verbo([has]), complemento([lagged, behind, other, species, in, the, 'Fabaceae', family])].
[sujeto(['Here,', we]), verbo([reported]), complemento([the, complete, chloroplast, '(', 'cp)', genome, sequence, of, mungbean, obtained, by, the, 454, pyrosequencing, technology])].
[sujeto(['Phylogenetic', analysis, demonstrated, a, close, relationship, between, 'Vigna', and, 'Phaseolus', in, the, phaseolinae, subtribe, and]), verbo([provided]), complemento([a, strong, support, for, a, monophyletic, group, of, the, eurosid, 'I'])].
[sujeto(['It', is, a, complex, process, consisting, of, the, coordinated, synthesis, and, assembly, of, four, ribosomal, 'RNAs', '(', 'rRNA)', with, about, 80, ribosomal, proteins, '(', 'r-proteins)']), verbo([involving]), complemento([more, than, 150, nonribosomal, proteins, and, other, factors])].
[sujeto(['Diamond', 'Blackfan', anemia, '(', 'DBA)', is, an, inherited, red, cell, aplasia]), verbo([caused]), complemento([by, mutations, in, one, of, several, 'r-proteins'])].
[sujeto(['How', defects, in, 'r-proteins,', essential, for, proliferation, in, all, 'cells,']), verbo([lead]), complemento([to, a, human, disease, with, a, specific, defect, in, red, cell, development, is, unknown])].
[sujeto(['Here,', we, investigated, the, role, of, 'r-proteins', in, ribosome, biogenesis, in, order, to]), verbo([find]), complemento([out, whether, those, mutated, in, 'DBA', have, any, similarities])].
[sujeto(['Depleting', 'r-proteins', in, one, of, the, subunits, 'caused,', with, a, few, 'exceptions,', a]), verbo([decrease]), complemento([in, all, 'r-proteins', of, the, same, subunit, and, a, decrease, in, the, corresponding, 'subunit,', fully, assembled, 'ribosomes,', and, polysomes])].
[sujeto(['R-protein', 'depletion,', with, a, few, 'exceptions,']), verbo([led]), complemento([to, the, accumulation, of, specific, rRNA, 'precursors,', highlighting, their, individual, roles, in, rRNA, processing])].
[sujeto(['The', genetic, background, of, hepatocellular, carcinoma, '(', 'HCC)']), verbo([has]), complemento([yet, to, be, completely, understood])].
[sujeto(['The', known, genes, identified, were]), verbo([found]), complemento([to, have, diverse, functions])].
[sujeto(['In', addition, to, the, overexpression, of, 'AFP,', these, genes, '(']), verbo([increased]), complemento([in, the, presence, of, 'HCC)', are, involved, in, many, 'processes,', such, as, transcription, and, protein, biosynthesis, '(', 'HNRPDL,', 'PABPC1,', 'POLR2K,', 'SRP9,', 'SNRPA,', and, six, ribosomal, protein, genes, including, 'RPL8,', 'RPL14,', 'RPL41,', 'RPS5,', 'RPS17,', 'RPS24),', the, metabolism, of, lipids, and, proteins, '(', 'FADS1,', 'ApoA-II,', 'ApoM,', 'FTL),', cell, proliferation, '(', 'Syndecan-2,', and, 'Annexin', 'A2),', and, signal, transduction, '(', 'LRRC28', and, 'FMR1)'])].
[sujeto(['Additionally,', a, 'glutathione-binding', protein]), verbo([involved]), complemento([in, the, detoxification, of, methylglyoxal, known, as, 'GLO1', and, an, enzyme, which, increases, the, formation, of, prostaglandin, 'E(2)', known, as, 'PLA2G10', were, 'up-regulated', in, 'HCC'])].
[sujeto(['Additionally,', we, isolated, a, zinc, transporter, '(', 'Zip14)', and, a, 'function-unknown', gene, named, 'ZBTB11', '(', 'Zinc', finger, and, 'BTB', domain, containing, 11, ')', which, were, 'underexpressed,', and, seven, expression, sequence, tags, deregulated, in, 'HCC', without, significant, homology]), verbo([reported]), complemento([in, the, public, database])].
[sujeto(['Essentially,', by, using, 'SSH', combined, with, a, cDNA, microarray, we]), verbo([have]), complemento([identified, a, number, of, genes, associated, with, 'HCC,', most, of, which, have, not, been, previously, reported])].
[sujeto(['Further', characterization, of, these, differentially]), verbo([expressed]), complemento([genes, will, provide, information, useful, in, understanding, the, genes, responsible, for, the, development, of, 'HCC'])].
[sujeto(['Mucosal', iodine, staining]), verbo([has]), complemento([improved, the, detection, of, precancerous, lesions, of, the, esophagus])].
[sujeto(['Loss', of, heterozygosity, '(', 'LOH)', was, detected, with, 35, microsatellite, markers, frequently]), verbo([reported]), complemento([to, be, deleted, in, 'ESCC'])].
[sujeto(['Interestingly,', 'D3S3644,', 'D3S1768,', 'D3S3040,', 'D3S4542,', 'RPL14', and, 'D13S263', were, also]), verbo([found]), complemento([with, high, frequency, of, 'LOH', in, 'iodine-staining', abnormal, lesions, from, the, population, screening])].
[sujeto(['Most', 'importantly,', 'LOH', frequency]), verbo([increased]), complemento([with, histological, severity])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, detection, of, these, six, markers, in, combination, with, iodine, staining, might, contribute, to, the, prediction, for, the, risk, of, 'ESCC', development, and, for, the, diagnosis, of, patients, in, preclinical, and, preneoplastic, phase, of, the, disease])].
[sujeto(['It']), verbo([has]), complemento([gene, content, similar, to, that, of, other, legume, 'plastomes,', but, contains, two, 'pseudogenes,', rpl33, and, rps16])].
[sujeto([')', de, 'Bary']), verbo([caused]), complemento([the, 19, th, century, 'Irish', 'Potato', 'Famine'])].
[sujeto([infestans, using, sequences, from, portions, of, two]), verbo([nuclear]), complemento([genes, '(', 'beta-tubulin', and, 'Ras)', and, several, mitochondrial, loci, 'P3,', '(', 'rpl14,', 'rpl5,', 'tRNA)', and, 'P4', '(', 'Cox1)', from, 94, isolates, from, 'South,', 'Central,', and, 'North', 'America,', as, well, as, 'Ireland'])].
[sujeto([infestans, for, both]), verbo([nuclear]), complemento([and, mitochondrial, loci, are, consistent, with, an, &, 'quot;out', of, 'South', 'America"', origin, for, 'P'])].
[sujeto(['Coalescent-based', genealogies, of, all, loci, were, congruent, and, demonstrate, the, existence, of, two, lineages]), verbo([leading]), complemento([to, present, day, haplotypes, of, 'P'])].
[sujeto(['The', oldest, lineage]), verbo([associated]), complemento([with, isolates, from, the, section, 'Anarrhichomenun', including, 'Solanum', tetrapetalum, from, 'Ecuador', was, identified, as, 'Phytophthora', andina, and, evolved, from, a, common, ancestor, of, 'P'])].
[sujeto(['Nuclear', and, mitochondrial, haplotypes]), verbo([found]), complemento([in, 'Toluca', 'Mexico', were, derived, from, only, one, of, the, two, 'lineages,', whereas, haplotypes, from, 'Andean', populations, in, 'Peru', and, 'Ecuador', were, derived, from, both, lineages])].
[sujeto(['Haplotypes']), verbo([found]), complemento([in, populations, from, the, 'U'])].
[sujeto([and, 'Ireland', was, derived, from, both, ancestral, lineages, that, occur, in, 'South', 'America']), verbo([suggesting]), complemento([a, common, ancestry, among, these, populations])].
[sujeto(['FESEM', revealed, that, average, particle, size, '(', in, 'Ferret', 'diameter)']), verbo([increased]), complemento([in, the, following, 'order:', 'e-waste', recycling, workshops, '(', 0.5, 'μm)<nearby', highways, '(', 1.2, 'μm)<industrial', sites, '(', 4.3, 'μm)'])].
[sujeto(['Electronic', waste, recycling, workshops, engaged, in, metal, recovery, were]), verbo([found]), complemento([with, maximum, toxicity, equivalents, '(', 'TEQs)', for, 'dl-PCBs', and, potential, cancer, risk, '(', 10, '(', -, 6, ')', -, 10, '(', -, 4, ')', ')', for, both, adult, and, children])].
[sujeto(['The', abscisic, acid, '(', 'ABA)-,', 'stress-,', and, 'ripening-induced', '(', 'ASR)', protein, is, a, 'plant-specific', hydrophilic, transcriptional, factor]), verbo([involved]), complemento([in, fruit, ripening, and, the, abiotic, stress, response])].
[sujeto(['To', 'date,', there]), verbo([have]), complemento([been, no, studies, on, the, role, of, 'ASR', genes, in, delayed, flowering, time])].
[sujeto(['Here,', we]), verbo([found]), complemento([that, the, 'ASR', from, 'banana,', designated, as, 'MaASR,', was, preferentially, expressed, in, the, banana, female, flowers, from, the, 'eighth,', 'fourth,', and, first, cluster, of, the, inflorescence])].
[sujeto(['This', study]), verbo([provides]), complemento([the, first, evidence, of, a, role, for, 'ASR', genes, in, delayed, flowering, time, in, plants])].
[sujeto(['Previous', work]), verbo([has]), complemento([identified, a, limited, number, of, 'accuracy-altering', alterations, in, protein, 'L19', of, 'Salmonella', enterica, and, 'Thermus', thermophilus])].
[sujeto(['Here,', we]), verbo([have]), complemento([targeted, the, 'Escherichia', coli, rplS, gene, encoding, 'L19', for, mutagenesis, and, have, screened, for, mutants, with, altered, levels, of, miscoding])].
[sujeto(['We']), verbo([have]), complemento([recovered, 14, distinct, 'L19', 'mutants,', all, of, which, promote, increased, stop, codon, 'readthrough,', but, do, not, have, major, effects, on, subunit, association, or, cell, growth])].
[sujeto(['In', the, first]), verbo([suggested]), complemento(['pathway,', the, reaction, involves, the, addition, of, chlorenium, ion, to, 1, forming, a, 'non-classic', carbocation, assisted, by, anchimeric, effect, of, the, nearest, aromatic, 'system,', and, then, a, nucleophilic, attack, to, the, intermediate, by, the, hydroxide, ion])].
[sujeto(['The', corresponding, data, imply, that, the, 'C₉', atom, is, the, more, suitable, site, of, the, substrate, to]), verbo([interact]), complemento([with, the, hydroxide, ion])].
[sujeto(['Data', of, the, studied, compound, indicate, an, important, reduction, in, the, cytotoxic, and, genotoxic, potential, of, the]), verbo([target]), complemento(['molecule,', as, demonstrated, previously, by, our, research, group, using, different, in, vitro, assays])].
[sujeto(['Evidence', from, 'FTIR', spectra]), verbo([suggests]), complemento([the, participation, of, 'hydroxyl,', 'amine,', 'carboxyl,', 'amide,', phosphate, and, ketone, groups, in, the, biosorption, and, the, mechanism, was, proposed, to, be, dominated, by, the, electrostatic, interaction, between, the, negatively, charged, functional, groups, and, the, positively, charged, aflatoxin, molecules])].
[sujeto([koidzumii, biomasses]), verbo([has]), complemento([been, demonstrated, to, be, an, alternative, to, conventional, systems, for, 'B-aflatoxins', removal])].
[sujeto(['Although', 'Pip', is]), verbo([reported]), complemento([to, be, the, receptor, for, many, 'C2viruses', including, species, type, phage, 'c2,', a, similar, 'cell-membrane-associated', 'protein,', 'YjaE,', was, recently, reported, as, the, receptor, for, 'C2virus', bIL67])].
[sujeto(['We', will, refer, to, 'C2viruses']), verbo([requiring]), complemento(['Pip', as, 'c2-type', andC2viruses, that, require, 'YjaE', as, 'bIL67-type'])].
[sujeto(['LN', is, more, severe, in, children, than, 'adults,', with, potential, for, irreversible, kidney, damage]), verbo([requiring]), complemento([dialysis, or, transplant])].
[sujeto(['Renal', biopsy, is, currently, the, gold, standard, for, diagnosing, and, monitoring, 'LN,', 'however,', it, is, invasive, and]), verbo([associated]), complemento([with, complications])].
[sujeto(['Urine', biomarkers]), verbo([have]), complemento([been, shown, to, be, better, than, serum, biomarkers, in, differentiating, renal, disease, from, other, organ, manifestations])].
[sujeto(['Over', the, past, 'decade,', there]), verbo([have]), complemento([been, an, increasing, number, of, studies, investigating, specific, candidate, biomarkers, implicated, in, the, pathogenesis, of, 'LN', or, screening, for, urinary, biomarkers, using, hypothesis, free, methods])].
[sujeto(['In', this, 'review,', developments, in, urine, biomarkers, for, 'LN', will, be, 'reviewed,', highlighting, those, that, are, of, relevance, to, children, and]), verbo([have]), complemento([gone, through, validation, in, independent, international, patient, 'cohorts,', bringing, them, close, to, clinical, translation])].
[sujeto(['Pocket', haematoma, is, a, common, complication, after, defibrillator, '[', implantable, cardioverter, defibrillator, '(', 'ICD)]', 'implantation,', which, is, not, only, 'painful,', but, also]), verbo([increases]), complemento([the, risk, of, 'device-related', 'infection,', and, possibly, embolic, events])].
[sujeto(['A', clinically, significant, pocket, haematoma, was, defined, as, a, haematoma, that]), verbo([required]), complemento(['re-operation', or, interruption, of, oral, anticoagulation, '(', 'OAC)', therapy])].
[sujeto([62.7, ±, 11.6, 'years,', 'P', &, 'lt;', 0.001, ')', ',', were, more, likely, to]), verbo([have]), complemento([permanent, atrial, fibrillation, '(', 30.4, vs])].
[sujeto(['Pocket', haematoma, remains, an, important, complication, of, 'ICD', implantation, and, is]), verbo([associated]), complemento([with, a, high, risk, of, infection])].
[sujeto(['It', is, debated, whether, treating, cancer, patients, in, 'high-volume', surgical, centres, can]), verbo([lead]), complemento([to, improvement, in, 'outcomes,', such, as, shorter, length, of, hospital, 'stay,', decreased, frequency, and, severity, of, 'post-operative', 'complications,', decreased, 're-admission,', and, decreased, mortality])].
[sujeto(['Hospitals', with, large, lung, cancer, surgical, resection, volumes, were, less, restrictive, in, their, selection, of, patients, for, surgical, 'management and']), verbo([provided]), complemento([a, higher, resection, rate, to, their, geographical, population])].
[sujeto(['Furthermore,', only, a, single, 'FTI']), verbo([target]), complemento([value, has, been, suggested, despite, regional, variation, in, left, atrial, wall, thickness])].
[sujeto(['Higher', minimum, 'AI', and, 'FTI', values, were]), verbo([required]), complemento([to, avoid, reconnection, in, 'anterior/roof', segments, than, for, 'posterior/inferior', segments, '(', 'P', &, 'lt;', 0.0001, ')'])].
[sujeto(['Higher', 'AI', and, 'FTI', values, are]), verbo([required]), complemento([for, 'anterior/roof', segments, than, for, 'posterior/inferior', segments, to, prevent, reconnection])].
[sujeto(['Overall', lag, time]), verbo([increased]), complemento([by, 6.5, days, between, baseline, and, two, weeks, '(', 'p = 0'])].
[sujeto(['TTD', was]), verbo([associated]), complemento([with, minimum, lag, time, '(', time, to, appearance, of, first, 'colony1)'])].
[sujeto(['Slower', elimination, of, long, lag, time, colonies]), verbo([suggests]), complemento([that, these, may, represent, a, persister, subpopulation, of, bacilli])].
[sujeto(['However,', the, origin, of, most, of, the, stem, cell, populations]), verbo([found]), complemento([in, the, adult, epidermis, is, still, unknown])].
[sujeto(['EGFR', was, mainly]), verbo([expressed]), complemento([in, the, outer, root, sheath, '(', 'ORS),', in, basal, 'and,', to, a, lesser, 'extent,', in, suprabasal, keratinocytes, and, tend, to, lie, where, the, dermis, comes, closest, to, the, skin, 'surface,', while, 'Nestin', expressed, throughout, the, dermis, in, the, early, 'embryo,', but, it, is, subsequently, restricted, to, the, follicular, connective, tissue, sheaths, later, in, development, and, to, hair, follicles, after, birth])].
[sujeto(['EGFR', and, 'Nestin', showed, to]), verbo([have]), complemento([vital, role, during, mice, 'development,', and, considered, to, be, suitable, markers, for, the, study, of, skin, stem, cells])].
[sujeto(['The', experimental, results, from, two, consecutive, years, indicated, that, higher, temperature, '(', 20, °, 'C', or, 25, °, 'C)', and, longer, photoperiod, '(', 14, 'h)', treatments, significantly]), verbo([enhanced]), complemento([the, garlic, 'bolting,', bulbing, and, cloving, with, a, shorter, growth, period, and, a, higher, bulb, weight])].
[sujeto(['Moreover,', the, endogenous, phytohormone, and, 'MeJA', levels, in, the, test, plants, were, significantly]), verbo([increased]), complemento([by, the, higher, temperature, '(', 25, °, 'C', for, the, phytohormone, 'level;', 20, °, 'C', for, the, 'MeJA', 'level)', and, longer, photoperiod, '[', 14, 'h,', except, for, abscisic, acid, '(', 'ABA),', which, had, the, highest, level, at, 8, 'h]', conditions, and, were, decreased, by, the, lowest, test, temperature, '(', 15, °, 'C)', and, shorter, photoperiod, '(', 8, 'h,', except, for, 'ABA)', conditions])].
[sujeto(['It', is, reasonable, to, assume, that, endogenous, phytohormone, '(', especially, gibberellic, 'acid)', and, 'MeJA', levels, are, highly, related, to, garlic, bolting, and, 'bulbing,', which, might]), verbo([lead]), complemento([to, the, different, responses, of, the, three, studied, cultivars, to, the, combination, of, temperature, and, photoperiod, treatments])].
[sujeto(['Furthermore,', cvs, 'G107', and, 'G025', bolt, well, and]), verbo([have]), complemento([better, bulb, formation, under, 20, °, 'C-14', h, 'conditions,', while, the, conditions, of, 25, °, 'C-14', h, are, critical, for, the, bolting, and, bulbing, of, cv])].
[sujeto(['A', similar, composition, profile, of, siloxanes, in, influent, and, sludge]), verbo([suggests]), complemento([their, same, source])].
[sujeto(['It', was]), verbo([found]), complemento([that, temperature, and, rainfall, are, the, two, important, factors, for, the, seasonal, variation, of, siloxanes])].
[sujeto(['Shorter,', all, oral, and, less, toxic, multidrug, combinations, are]), verbo([required]), complemento([to, improve, treatment, outcomes, in, these, settings])].
[sujeto(['Hip', fracture, and, myocardial, infarction]), verbo([cause]), complemento([significant, morbidity, and, mortality])].
[sujeto(['In', vivo, studies, raising, serum, cholesterol, levels, as, well, as, 'pro-inflammatory', cytokines, such, as, 'TNF α', manifest, bone]), verbo([loss]), complemento([and, atherosclerotic, vascular, 'disease,', suggesting, that, abnormalities, of, cholesterol, transport, may, contribute, to, osteoporosis])].
[sujeto(['MLO-Y4', cells, do, not]), verbo([express]), complemento([apo, 'A-I', or, apo, 'E;', 'however,', they, do, express, all, three, cholesterol, transporters, '(', 'ABCA1,', 'SRB1,', and, 'CD36)'])].
[sujeto(['Interestingly,', 'TNF α', treatment]), verbo([increased]), complemento(['ABCA1', promoter, activity, and, 'ABCA1', mRNA, 'levels,', and, increased, liver, 'X', receptor, α, protein, 'expression,', but, had, no, effect, on, retinoid, 'X', receptor, α, and, retinoic, acid, receptor, α, levels])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'pro-inflammatory', cytokines, regulate, cholesterol, metabolism, in, osteocytes, in, part, by, suppressing, 'ABCA1', levels, 'post-translationally', in, a, p38, 'MAP', 'kinase-dependent', manner])].
[sujeto(['LVOT', is]), verbo([associated]), complemento([with, higher, morbidity, and, mortality, in, patients, with, 'HCM'])].
[sujeto(['Percutaneous', septal, reduction, therapy, with, alcohol, septal, ablation, '(', 'ASA)', can]), verbo([lead]), complemento([to, a, significant, improvement, in, left, ventricle, 'haemodynamics,', patient, symptoms, and, perhaps, prognosis])].
[sujeto(['The', basal, septal, myocardium]), verbo([involved]), complemento([in, 'SAM-septal', contact, is, the, target, for, this, iatrogenic, infarct])].
[sujeto(['Securing', the, correct, diagnosis, and]), verbo([ensuring]), complemento([suitable, cardiac, anatomy, are, essential, before, considering, 'ASA'])].
[sujeto(['New', techniques]), verbo([have]), complemento([been, proposed, to, perform, percutaneous, septal, reduction])].
[sujeto(['We', also]), verbo([provide]), complemento([a, glimpse, into, emerging, techniques, to, deliver, percutaneous, septal, reduction, therapy])].
[sujeto(['This', cell, line, was, established, via, a, series, of, cell, lines, cultured, in, a, 'serum-free', and, a, 'protein-free', 'medium,', and, a, directional, cDNA, library]), verbo([has]), complemento([been, constructed, and, screened, in, search, for, the, genes, modulating, protein, synthesis, machinery, in, cell, proliferation])].
[sujeto(['The', typical, features, of, ribosomal, proteins, were, observed, in, 'hRL14,', as, seen, in]), verbo([nuclear]), complemento([targeting, sequences, necessary, for, the, transport, from, cytoplasm, to, 'nucleolus,', a, bZIP, like, '(', basic, 'region-leucine', 'zipper)', element, for, the, binding, to, 'rRNA,', and, the, internal, repeat, 'sequences;', the, pentapeptide, 'QKA(A/S)X'])].
[sujeto(['This', 'GCT', repeat, was]), verbo([found]), complemento([to, be, one, of, the, longest, uninterrupted, repeats, in, a, coding, 'sequence,', which, were, associated, with, the, highest, degree, of, polymorphism])].
[sujeto([')']), verbo([has]), complemento([attracted, much, attention, from, plant, biologists, and, breeders])].
[sujeto(['Moderate', leaf, rolling]), verbo([increases]), complemento([the, amount, of, photosynthesis, in, cultivars, and, hence, raises, grain, yield])].
[sujeto(['Here,', we, describe, the, 'map-based', cloning, of, the, gene, 'RL14,', which, was]), verbo([found]), complemento([to, encode, a, 2, 'OG-Fe', '(', 'II)', oxygenase, of, unknown, function])].
[sujeto(['In', 'addition,', rl14, mutant, plants, displayed, smaller, stomatal, complexes, and]), verbo([decreased]), complemento([transpiration, 'rates,', as, compared, with, the, wild, type])].
[sujeto(['RL14', was]), verbo([transcribed]), complemento([in, sclerenchymatous, cells, in, leaves, that, remained, wrapped, inside, the, sheath])].
[sujeto(['These', results]), verbo([reveal]), complemento([that, the, 'RL14', gene, affects, water, transport, in, leaves, by, affecting, the, composition, of, the, secondary, cell, wall])].
[sujeto(['Children', with, severe, malnutrition, who, develop, shock]), verbo([have]), complemento([a, high, mortality])].
[sujeto(['Isotonic', fluid, was]), verbo([associated]), complemento([with, modest, improvement, in, shock, and, survival, when, compared, to, 'HSD/5D', but, inconclusive, due, to, the, limitations, of, design, and, effectiveness, of, either, resuscitation, strategy])].
[sujeto(['The', adverse, performance, of, the, recommended, fluid, resuscitation, guideline, for, severe, malnutrition, should, prompt, clinical, investigation, of, isotonic, fluids, for, resuscitation, of, compensated, 'shock,', defining, rate, and, volumes]), verbo([required]), complemento([to, inform, future, guidelines])].
[sujeto([',', the, manufacturers, of, 'sertindole,', voluntarily, suspended, the, availability, of, the, drug, due, to, concerns, about, cardiac, arrhythmia, and, sudden, cardiac, death]), verbo([associated]), complemento([with, its, use])].
[sujeto(['Sertindole']), verbo([has]), complemento([therefore, been, withdrawn, from, the, market, pending, discussion, with, the, 'European', 'Regulatory', 'Authority', over, cardiac, safety])].
[sujeto(['Two', large, important, studies, were, 'excluded,', because, they, did, not]), verbo([report]), complemento([any, usable, data])].
[sujeto(['The', two, that, were, included]), verbo([suggested]), complemento([that, sertindole, was, more, antipsychotic, than, 'placebo,', as, acceptable, as, placebo, and, better, tolerated, than, haloperidol, '(', 'NNT=9,', 'RR', 0.63, 'CI', 0.41, to, 0.96, ')'])].
[sujeto(['Sertindole', was]), verbo([associated]), complemento([with, fewer, movement, disorders, than, haloperidol, but, was, shown, to, cause, more, weight, gain, '(', 'NNH=9', 'RR', 6.33, ',', 'CI', 1.92, to, 20.92, ')', ',', rhinitis, '(', 'NNH=8,', 'RR', 1.74, ',', 'CI', 1, ',', 28, to, 2.36, ')', and, possibly, male, sexual, dysfunction])].
[sujeto(['Because', of, the, cardiac, 'problems,', even, evident, within, poorly]), verbo([reported]), complemento(['studies,', at, present, sertindole, 'should,', if, 'possible,', be, avoided])].
[sujeto(['The', importance, of, the, interaction, between, lymphocyte, 'function-associated', 'antigen-1', '(', 'LFA-1)', and, intercellular, adhesion, 'molecule-1', '(', 'ICAM-1)', in, the, progression, of, inflammatory, responses, in, vivo]), verbo([has]), complemento([been, demonstrated, mainly, in, rats])].
[sujeto(['The', present, study, was, undertaken, to, develop]), verbo([binding]), complemento([assays, suitable, for, measuring, the, rat, 'ICAM-1/LFA-1', interaction, in, vitro])].
[sujeto(['We', first, examined]), verbo([binding]), complemento([of, rat, 'T', lymphoma, 'FTL43', 'cells,', which, express, 'LFA-1,', to, immobilized, rat, 'ICAM-1'])].
[sujeto(['Although', 'FTL43', cells]), verbo([bound]), complemento([avidly, to, immobilized, 'ICAM-1', and, the, binding, was, abolished, with, 'anti-LFA-1', monoclonal, antibodies, '(', 'mAbs),', the, binding, was, not, completely, inhibited, by, most, 'anti-ICAM-1', mAbs])].
[sujeto(['We', next, purified, rat, 'LFA-1', from, 'FTL43', cells, and, constructed, a, 'cell-free']), verbo([binding]), complemento([assay])].
[sujeto(['By', using, a, newly, developed, 'anti-rat', 'LFA-1', mAb, 'RL14/9,', which, does, not]), verbo([inhibit]), complemento(['ICAM-1/LFA-1', 'interactions,', binding, of, purified, rat, 'LFA-1', to, immobilized, 'ICAM-1', was, successfully, 'detected,', whereas, only, a, low, signal, to, noise, ratio, was, observed, when, binding, of, 'ICAM-1', to, immobilized, 'LFA-1', was, examined])].
[sujeto(['Moreover,', we]), verbo([found]), complemento([that, simultaneous, addition, of, purified, 'LFA-1', and, biotinylated, 'RL14/9', to, 'ICAM-1-coated', wells, resulted, in, more, sensitive, detection, of, rat, 'ICAM-1/LFA-1', binding])].
[sujeto(['The']), verbo([binding]), complemento([was, completely, blocked, with, both, 'anti-LFA-1', and, 'anti-ICAM-1', mAbs, and, was, much, more, sensitive, to, inhibition, by, the, 'ICAM-1-IgG', 'chimera,', as, compared, with, the, 'cell-based', assay])].
[sujeto(['These', results, indicate, that, the, 'cell-free']), verbo([binding]), complemento([assay, provides, a, rapid, and, sensitive, method, for, screening, rat, 'ICAM-1/LFA-1', 'antagonists,', whose, therapeutic, effect, on, inflammatory, diseases, can, further, be, evaluated, in, vivo])].
[sujeto(['Recent', work]), verbo([has]), complemento([revealed, that, a, core, group, of, transcription, factors, '(', 'TFs)', regulates, the, key, characteristics, of, embryonic, stem, '(', 'ES)', 'cells:', pluripotency, and, 'self-renewal'])].
[sujeto(['Current', efforts, focus, on, identifying, genes, that, play, important, roles, in]), verbo([maintaining]), complemento([pluripotency, and, 'self-renewal', in, 'ES', cells, and, aim, to, understand, the, interactions, among, these, genes])].
[sujeto(['We', show, that, signed, networks]), verbo([provide]), complemento([a, better, systems, level, understanding, of, the, regulatory, mechanisms, of, 'ES', cells, than, unsigned, 'networks,', using, two, independent, murine, 'ES', cell, expression, data, sets])].
[sujeto(['Specifically,', using, signed, weighted, gene, 'co-expression', network, analysis, '(', 'WGCNA),', we]), verbo([found]), complemento([a, pluripotency, module, and, a, differentiation, 'module,', which, are, not, identified, in, unsigned, networks])].
[sujeto(['We', confirmed, the, importance, of, these, modules, by, incorporating, 'genome-wide', 'TF']), verbo([binding]), complemento([data, for, key, 'ES', cell, regulators])].
[sujeto(['Interestingly,', we]), verbo([find]), complemento([that, the, pluripotency, module, is, enriched, with, genes, related, to, 'DNA', damage, repair, and, mitochondrial, function, in, addition, to, transcriptional, regulation])].
[sujeto(['Using', a, connectivity, measure, of, module, 'membership,', we, not, only, identify, known, regulators, of, 'ES', cells, but, also, show, that, 'Mrpl15,', 'Msh6,', 'Nrf1,', 'Nup133,', 'Ppif,', 'Rbpj,', 'Sh3gl2,', and, 'Zfp39,', among, other, 'genes,']), verbo([have]), complemento([important, roles, in, maintaining, 'ES', cell, pluripotency, and, 'self-renewal'])].
[sujeto(['We', also]), verbo([report]), complemento([highly, significant, relationships, between, module, membership, and, epigenetic, modifications, '(', histone, modifications, and, promoter, 'CpG', methylation, 'status),', which, are, known, to, play, a, role, in, controlling, gene, expression, during, 'ES', cell, 'self-renewal', and, differentiation])].
[sujeto(['Our', systems, biologic, 're-analysis', of, gene, 'expression,', transcription, factor, 'binding,', epigenetic, and, gene, ontology, data]), verbo([provides]), complemento([a, novel, integrative, view, of, 'ES', cell, biology])].
[sujeto(['A', number, of, 'PLS-class', 'PPR', proteins]), verbo([have]), complemento([been, characterized, as, 'RNA', recognition, factors, for, specific, 'RNA', editing, 'sites,', all, containing, a, 'C-terminal', 'extension,', the, 'E', 'domain,', and, some, an, additional, 'DYW', 'domain,', named, after, the, characteristic, 'C-terminal', amino, acid, triplet, of, this, domain])].
[sujeto(['In', order, to, characterize, these, missing, 'factors,', the, recently, proposed, computational, prediction, tool, could, be, of, use, to, assign]), verbo([target]), complemento(['RNA', editing, sites, to, 'PPR', proteins, of, yet, unknown, function])].
[sujeto(['Using', this]), verbo([target]), complemento([prediction, approach, we, identified, the, nuclear, gene, 'MEF35', '(', 'Mitochondrial', 'Editing', 'Factor', 35, ')', to, be, required, for, 'RNA', editing, at, three, sites, in, mitochondria, of, 'Arabidopsis', thaliana])].
[sujeto(['Two', 'T-DNA', insertion, 'mutants,', one, inserted, just, upstream, and, the, other, inside, the, reading, frame, encoding, the, 'DYW', 'domain,', show]), verbo([loss]), complemento([of, editing, at, a, site, in, each, of, the, mRNAs, for, protein, 16, in, the, large, ribosomal, subunit, '(', site, 'rpl16-209),', for, cytochrome, b, '(', 'cob-286)', and, for, subunit, 4, of, complex, 'I', '(', 'nad4-1373),', respectively])].
[sujeto(['The', 'MEF35', protein]), verbo([interacts]), complemento([in, 'Y2H', assays, with, the, mitochondrial, 'MORF1', and, 'MORF8', 'proteins,', mutation, of, the, latter, also, influences, editing, at, two, of, the, three, 'MEF35', target, sites])].
[sujeto(['Homozygous', mutant, plants, develop, indistinguishably, from, wild, type, 'plants,', although, the, 'RPL16', and, 'COB/CYTB', proteins, are, essential, and, the, amino, acids, encoded, after, the, editing, events, are]), verbo([conserved]), complemento([in, most, plant, species])].
[sujeto(['These', results, demonstrate, the, feasibility, of, the, computational]), verbo([target]), complemento([prediction, to, screen, for, target, 'RNA', editing, sites, of, 'E', domain, containing, 'PLS-class', 'PPR', proteins])].
[sujeto(['Forward', and, reverse, genetics, approaches]), verbo([have]), complemento([revealed, the, prevalent, role, of, pentatricopeptide, repeat, '(', 'PPR)', proteins, in, editing, in, both, plastids, and, 'mitochondria,', confirming, the, shared, origin, of, this, process, in, both, organelles])].
[sujeto(['The', 'E', domain, at, or, near, the, 'C terminus', of, these, proteins]), verbo([has]), complemento([been, shown, to, be, essential, for, 'editing,', and, is, presumed, to, recruit, the, enzyme, that, deaminates, the, target, cytidine, residue])].
[sujeto(['Comparisons', between, the, 'E', domains, of, these, proteins, and, previously]), verbo([reported]), complemento([editing, factors, from, chloroplasts, suggested, that, there, are, characteristic, differences, in, the, proteins, between, the, two, organelles])].
[sujeto(['In', all, cases, 'investigated,', 'E', domains, from, the, same, organelle, '(', chloroplast, or, 'mitochondria)', were]), verbo([found]), complemento([to, be, 'exchangeable;', 'however,', swapping, the, 'E', domain, between, organelles, led, to, 'non-functional', editing, factors])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, molecular, characterization, of, the, empty, pericarp5, '(', 'emp5)', mutants, in, maize, '(', 'Zea', 'mays)'])].
[sujeto(['Analysis', of, the, mitochondrial, transcripts, revealed, that]), verbo([loss]), complemento([of, the, 'EMP5', function, abolishes, the, 'C-to-U', editing, of, ribosomal, protein, 'L16', at, the, 'rpl16-458', site, '(', 100, '%', edited, in, the, wild, 'type),', decreases, the, editing, at, nine, sites, in, 'NADH', dehydrogenase9, '(', 'nad9),', cytochrome, c, oxidase3, '(', 'cox3),', and, ribosomal, protein, 'S12', '(', 'rps12),', and, surprisingly, increases, the, editing, at, five, sites, of, 'ATP', synthase, 'F0', subunit, a, '(', 'atp6),', apocytochrome, b, '(', 'cob),', 'nad1,', and, rpl16])].
[sujeto(['Mutant', 'EMP5-4', lacking, the, 'E+', and, 'DYW', domains, still]), verbo([retains]), complemento([the, substrate, specificity, and, editing, 'function,', only, at, reduced, efficiency])].
[sujeto(['This']), verbo([suggests]), complemento([that, the, 'E+', and, 'DYW', domains, of, 'EMP5', are, not, essential, to, the, 'EMP5', editing, function, but, are, necessary, for, efficiency])].
[sujeto(['Analysis', of, the, ortholog, in, rice, '(', 'Oryza', 'sativa)', indicates, that, rice, 'EMP5']), verbo([has]), complemento([a, conserved, function, in, 'C-to-U', editing, of, the, rice, mitochondrial, 'rpl16-458', site])].
[sujeto(['These', results, demonstrate, that, 'Emp5', encodes, a, 'PPR-DYW', protein, that, is]), verbo([required]), complemento([for, the, editing, of, multiple, transcripts, in, 'mitochondria,', and, the, editing, 'events,', particularly, the, 'C-to-U', editing, at, the, 'rpl16-458', 'site,', are, critical, to, the, mitochondrial, functions, 'and,', 'hence,', to, seed, development, in, maize])].
[sujeto(['Properties', of, an, unusual, 'atp9-rpl16', cotranscript, preferentially]), verbo([found]), complemento([in, the, maternal, distorted, leaf, mutant, of, 'Arabidopsis', 'thaliana,', which, had, arisen, from, a, genetic, cross, between, chloroplast, mutator, and, 'wild-type', 'plants,', were, examined])].
[sujeto(['The', predicted, 'L16-like', polypeptide, is, basic, '(', pl, 11.12, ')', ',', contains, 232, amino, acids, '(', 26.52, 'kDa)', and]), verbo([has]), complemento([36, '%', amino, acid, sequence, identity, to, 'E'])].
[sujeto(['We']), verbo([report]), complemento([the, sequencing, of, a, 22, ',', 470, bp, 'DNA', fragment, from, the, left, arm, of, 'Saccharomyces', cerevisiae, chromosome, 'II'])].
[sujeto(['Thirteen', open, reading, frames, longer, than, 300, bp, provisionally, called, 'YBL0520,', 'YBL0401', to, 'YBL0408', and, 'YBL0410', to, 'YBL0413']), verbo([have]), complemento([been, detected])].
[sujeto([',', 1992, ')', ',', 'ERD2,', coding, for, a, protein]), verbo([involved]), complemento([in, the, secretory, pathway, '(', 'Semeza', et, al])].
[sujeto([',', 1992, ')', ',', the, uracyl, and, allantoin, 'permeases;', 'YBL0520', is, a, 'DNA-related', 'protein,', possibly]), verbo([involved]), complemento([in, gene, 'regulation;', 'YBL0412', shares, homologies, with, the, mouse, 'alpha-adaptins', 'A', and, 'C;', and, 'YBL0413', is, homologous, to, a, protein, of, 'Pseudomonas', aeruginosa, that, is, likely, to, be, involved, in, proline, biosynthesis])].
[sujeto(['We']), verbo([have]), complemento([cloned, and, sequenced, an, 8.9, -, kb, 'mitochondrial-DNA', fragment, from, rapeseed, '(', 'Brassica', napus, 'L'])].
[sujeto(['Gene-specific', probes, for, each, ribosomal, protein, 'gene,', and, for, the, 'cp-like-trnD,', trnK, and, cob, 'genes,', hybridized, to, a, common, 'pre-mRNA', of, an, estimated, size, of, 10, 'kilobases,', indicating, that, these, seven, genes, may, be]), verbo([expressed]), complemento([as, a, single, transcription, unit])].
[sujeto(['A', deletion, eliminating, part, of, a]), verbo([transcribed]), complemento([region, of, mitochondrial, 'DNA', '(', 'mtDNA)', has, been, found, in, the, maize, nonchromosomal, stripe, 3, '(', 'NCS3)', mutant])].
[sujeto(['This', results, in, the, specific]), verbo([loss]), complemento([of, a, set, of, three, mitochondrial, 'RNAs', 'consisting,', in, normal, 'plants,', of, a, 4.9, kb, 'transcript,', its, 1.8, kb, intron, and, the, resulting, processed, mRNA, of, approximately, 2.9, kb])].
[sujeto(['This']), verbo([transcribed]), complemento([region, of, normal, maize, mtDNA, has, been, sequenced, and, the, intron, splice, junction, has, been, determined])].
[sujeto(['This', fact, and, the, impaired, ability, for, mitochondrial, protein, synthesis, by, 'NCS3', plants, indicate, that, one, or, both, of, these, reading, frames, are]), verbo([translated]), complemento([to, functional, ribosomal, proteins, in, normal, maize, mitochondria])].
[sujeto(['Mitochondria', contain, their, own, 'ribosomes,', which, specialize, in, the, synthesis, of, a, handful, of, proteins]), verbo([required]), complemento([for, oxidative, phosphorylation])].
[sujeto(['The', pathway, of, mitoribosomal, biogenesis, and, factors]), verbo([involved]), complemento([are, poorly, characterized])].
[sujeto(['An', example, is, the, 'DEAD', box, 'proteins,', widely, known, to]), verbo([participate]), complemento([in, the, biogenesis, of, bacterial, and, cytoplasmic, eukaryotic, ribosomes, as, either, 'RNA', helicases, or, 'RNA', 'chaperones,', whose, mitochondrial, counterparts, remain, completely, unknown])].
[sujeto(['Here,', we]), verbo([have]), complemento([identified, the, 'Saccharomyces', cerevisiae, mitochondrial, 'DEAD', box, protein, 'Mrh4', as, essential, for, large, mitoribosome, subunit, biogenesis])].
[sujeto(['Mrh4']), verbo([interacts]), complemento([with, the, 21, 'S', 'rRNA,', mitoribosome, 'subassemblies,', and, fully, assembled, mitoribosomes])].
[sujeto(['We', conclude, that, 'Mrh4', plays, an, essential, role, during, the, late, stages, of, mitoribosome, assembly, by]), verbo([promoting]), complemento([remodeling, of, the, 21, 'S', 'rRNA-protein', interactions])].
[sujeto(['To', investigate, alternative, or, subordinate, pathways]), verbo([involved]), complemento([in, colorectal, tumorigenesis, and, tumor, 'growth,', possibly, determining, 'at-risk', populations, and, predicting, responses, to, treatment])].
[sujeto(['Subsets', of, differentially]), verbo([expressed]), complemento([genes, were, confirmed, by, 'real-time', 'reverse-transcript', polymerase, chain, reaction, '(', 'RT-PCR)'])].
[sujeto(['The', largest, number, of, genes, identified, as, being, differentially]), verbo([expressed]), complemento([was, by, tumor, 'location,', and, the, next, largest, number, by, lymphovascular, or, neural, invasion, of, tumor, cells, and, by, mismatch, repair, '(', 'MMR)', defects])].
[sujeto(['Amongst', 47, differentially]), verbo([expressed]), complemento(['genes,', seven, '(', 'PISD,', 'NIBP,', 'BAI2,', 'STOML1,', 'MRPL21,', 'MRPL16,', and, 'MKKS)', were, newly, found, to, correlate, with, tumorigenesis, and, tumor, growth])].
[sujeto(['We', show, that, several, differentially]), verbo([expressed]), complemento([genes, were, associated, with, canonical, molecular, changes, in, sporadic, colorectal, 'cancers,', possibly, constituting, alternative, or, subordinate, pathways, of, tumorigenesis])].
[sujeto(['As', tumor, location, was, the, dominant, factor, influencing, differential, gene, 'expression,', 'location-specific', analysis, may, identify, 'location-associated', pathways, and]), verbo([enhance]), complemento([the, accuracy, of, class, prediction])].
[sujeto(['First', of, 'all,', differentially]), verbo([expressed]), complemento([genes, '(', 'DEGs)', were, identified, by, 'Limma', package, in, 'R'])].
[sujeto(['Our', findings, that, might, explore, the, potential, pathogenesis, of, 'AS', and, 'RPL17,', 'MRPL22,', 'PSMA6', and, 'PSMA4']), verbo([have]), complemento([the, potential, to, be, the, biomarkers, for, the, disease])].
[sujeto(['In', vitro, synthesized, radioactive, yeast, 35, 'S', precursor, rRNA, '(', 35, 'S', 'pre-rRNA)', molecules, were, used, to, determine, the]), verbo([binding]), complemento([characteristics, of, 13, proteins, from, the, yeast, 60, 'S', ribosome, subunit])].
[sujeto(['L4,', 'L17,', 'L20', and, 'L25', were]), verbo([found]), complemento([to, bind, the, 35, 'S', 'pre-rRNA', molecule, in, vitro, in, the, absence, of, any, other, cellular, components, as, determined, by, a, modified, membrane, filtration, assay, and, an, agarose, gel, mobility, shift, assay])].
[sujeto(['In', all, 'cases,', 'RNA-protein', complex, formation, was, proportional, to, the, amount, of, protein, added, to, the]), verbo([binding]), complemento([reaction, mixture])].
[sujeto(['Non-radioactive', 35, 'S', 'pre-rRNA', transcript, competed, for, the]), verbo([binding]), complemento([in, a, 'dosage-dependent', manner])].
[sujeto(['Presence', of, 18, 'S', rRNA, species, and, 'poly(A)', did, not, affect, their]), verbo([binding]), complemento([to, the, 35, 'S', 'RNA'])].
[sujeto(['However,', in, the, presence, of, the, 25, 'S', rRNA, 'species,', the, four, proteins, exhibited, distinct]), verbo([binding]), complemento([characteristics, for, the, 'pre-rRNA', molecule])].
[sujeto(['L4', did, not]), verbo([bind]), complemento([the, 25, 'S', rRNA, but, interacted, specifically, with, the, 35, 'S', 'pre-rRNA', molecule, with, a, binding, constant, of, 4.4, 'x10(6)/M'])].
[sujeto(['L17']), verbo([bound]), complemento([the, 'pre-rRNA', molecule, preferentially, '(', 'Ka=17x10(6)/M)', but, also, bound, the, mature, 25, 'S', rRNA, species, '(', 'Ka=10x10(6)/M)'])].
[sujeto(['L20']), verbo([bound]), complemento([both, the, 'pre-rRNA', molecule, and, the, 25, 'S', rRNA, species, equally, well, '(', 'Ka=11-12x10(6)/M)'])].
[sujeto(['L25', also]), verbo([bound]), complemento([both, the, 35, 'S', 'pre-rRNA', and, the, mature, 25, 'S', rRNA, with, slightly, different, 'affinities,', with, 'Ka=3'])].
[sujeto(['We', speculate, that, 'L4,', 'L17,', and, 'L25', are, among, the, early, assembled, ribosomal, proteins, but, 'L4', may, be, one, of, the, first, ribosomal, proteins, that]), verbo([bind]), complemento([to, the, 35, 'S', 'pre-rRNA', molecule, during, ribosome, biogenesis])].
[sujeto(['The', 'MRP-L8', gene, was]), verbo([found]), complemento([to, encode, a, 26.8, -, kDa, protein, whose, deduced, amino, acid, sequence, has, a, high, degree, of, similarity, to, ribosomal, protein, 'L17', of, 'Escherichia', coli])].
[sujeto(['The', gene, 'MRP-L20', was]), verbo([found]), complemento([to, encode, a, 22.3, -, kDa, protein, with, a, presequence, consisting, of, 18, amino, acid, residues])].
[sujeto(['Gene', disruption, experiments, indicate, that, their, 'products,', 'YmL8', and, 'YmL20', 'proteins,', are, essential, for, the, mitochondrial, function, and, the, absence, of, these, proteins]), verbo([causes]), complemento([instability, of, the, mitochondrial, 'DNA'])].
[sujeto(['The', hes, mutant, produced, uncellularized, endosperm, and, embryos]), verbo([arrested]), complemento([at, the, late, globular, stage])].
[sujeto(['HES', '(', 'At1g08845)', encodes, a, mitochondrially]), verbo([targeted]), complemento([member, of, a, highly, diverged, 'L18', ribosomal, protein, family])].
[sujeto(['The', substitution, of, a]), verbo([conserved]), complemento([amino, residue, in, the, hes, mutant, potentially, perturbs, mitoribosomal, function, via, altered, binding, of, 5, 'S', rRNA, 'and/or', influences, the, stability, of, the, 50, 'S', ribosomal, 'subunit,', affecting, mRNA, binding, and, translation])].
[sujeto(['HES', expression, is, developmentally, 'regulated,', being, preferentially]), verbo([expressed]), complemento([in, tissues, with, active, cell, division, and, 'differentiation,', including, developing, embryos, and, the, root, tips])].
[sujeto(['The', divergence, of, the, 'L18', 'family,', the, tissue, type, restricted, expression, of, 'HES,', and, the, failure, of, other, 'L18', members, to, complement, the, hes, phenotype]), verbo([suggest]), complemento([that, the, 'L18', proteins, are, involved, in, modulating, development])].
[sujeto(['Identification', of, cellular, proteins, that]), verbo([interact]), complemento([with, 'NS1', may, help, in, further, understanding, the, functions, of, 'NS1'])].
[sujeto(['In', this, paper, we, isolated, a, total, of, 64, proteins, from, 'DENV', infected, human, hepatic, cells, '(', 'Huh-7)', that]), verbo([interact]), complemento([with, 'NS1', by, affinity, chromatography, and, immunoprecipitation, assays])].
[sujeto(['Silencing', of, the, 'RPL-18', does, not, affect, cell, translation, efficiency, or, 'viability,', but, it, reduces, significantly, viral, 'translation,', replication, and, viral, 'yield,']), verbo([suggesting]), complemento([that, the, 'RPL-18', is, required, during, 'DENV', replicative, cycle])].
[sujeto(['Although', decades]), verbo([have]), complemento([passed, since, the, first, description, of, the, 'heat-shock', 'response,', how, cells, achieve, translational, control, of, 'HSP', synthesis, remains, enigmatic])].
[sujeto(['Here', we]), verbo([report]), complemento([an, unexpected, role, for, mitochondrial, ribosomal, protein, 'L18', '(', 'MRPL18)', in, the, mammalian, cytosolic, stress, response])].
[sujeto(['MRPL18', knockdown]), verbo([has]), complemento([minimal, effects, on, mitochondrial, function, but, substantially, dampens, cytosolic, 'HSP', expression, at, the, level, of, translation])].
[sujeto(['Our', results, uncover, a, 'hitherto-uncharacterized', 'stress-adaptation', mechanism, in, mammalian, 'cells,', which]), verbo([involves]), complemento([formation, of, a, '\'', 'hybrid\'', ribosome, responsible, for, translational, regulation, during, the, cytosolic, stress, response])].
[sujeto(['Gene', expression, analysis, using, quantitative, reverse, transcription, 'PCR', '(', 'qRT-PCR)', is, a, robust, method, wherein, the, expression, levels, of]), verbo([target]), complemento([genes, are, normalised, using, internal, control, 'genes,', known, as, reference, 'genes,', to, derive, changes, in, gene, expression, levels])].
[sujeto(['Although', reference, genes]), verbo([have]), complemento([recently, been, suggested, for, olive, 'tissues,', 'combined/independent', analysis, on, different, cultivars, has, not, yet, been, tested])].
[sujeto(['Therefore,', an, assessment, of, reference, genes, was]), verbo([required]), complemento([to, validate, the, recent, findings, and, select, stably, expressed, genes, across, different, olive, cultivars])].
[sujeto(['GAPDH,', 'EF1-alpha', and, 60, 'S', 'RBP', 'L18-3', were]), verbo([found]), complemento([to, be, most, stable, reference, genes, in, the, cultivar, 'Frantoio', while, 60, 'S', 'RBP', 'L18-3,', 'OUB2', and, 'PP2A', were, found, to, be, most, stable, reference, genes, in, the, cultivar, 'Picual'])].
[sujeto(['This', study, will]), verbo([provide]), complemento([guidance, to, other, researchers, to, select, reference, genes, for, normalization, against, target, genes, by, qPCR, across, tissues, obtained, from, the, mesocarp, region, of, the, olive, fruit, in, the, 'cultivars,', 'Barnea,', 'Frantoio', and, 'Picual'])].
[sujeto(['Identification', of, the, differentially]), verbo([expressed]), complemento([genes, in, 'GC', is, one, of, the, best, approaches, for, establishing, new, diagnostic, and, therapeutic, targets])].
[sujeto(['To', screen, for, the, overexpressed, genes, in, gastric, 'adenocarcinoma,', we, performed, suppression, subtractive, hybridization, '(', 'SSH)', on, gastric, adenocarcinoma, tissue, and, the, corresponding, normal, gastric, 'tissue,', and, eight, genes, were]), verbo([found]), complemento([to, be, overexpressed, in, the, tumor, compared, with, those, of, the, normal, tissue])].
[sujeto(['Our', results]), verbo([provide]), complemento([new, insights, into, the, molecular, biology, of, 'GC', and, drug, 'discovery:', each, of, the, identified, genes, could, be, further, investigated, as, targets, for, prognosis, 'evaluation,', 'diagnosis,', 'treatment,', evaluation, of, the, response, to, new, anticancer, 'drugs,', and, determination, of, the, molecular, pathogenesis, of, 'GC'])].
[sujeto(['To', 'date,', no, reference, genes, for, gene, expression, analysis, in, this, species]), verbo([have]), complemento([been, validated])].
[sujeto(['Therefore,', we]), verbo([suggest]), complemento([that, 'Ubi,', 'Rpl18', and, 'EF1α', are, suitable, reference, genes])].
[sujeto(['Through', expression, of, the, 'epitope-tagged', ribosomal, protein, in, 'cell-type', and, regional, specific, domains, of, 'Arabidopsis', thaliana, and, other, organisms, it, is, feasible, to, quantitatively, assess, the, mRNAs, that, are]), verbo([associated]), complemento([with, ribosomes, with, 'cell-specific', resolution])].
[sujeto(['Here', we, present, detailed, methods, for, development, of, transgenics, that]), verbo([express]), complemento([a, 'FLAG-tagged', version, of, ribosomal, protein, 'L18', '(', 'RPL18)', under, the, direction, of, individual, promoters, with, specific, domains, of, 'expression,', the, immunopurification, of, 'ribosomes,', and, bioinformatic, analyses, of, the, resultant, datasets, obtained, by, microarray, profiling])].
[sujeto(['This', methodology]), verbo([provides]), complemento([researchers, with, the, opportunity, to, assess, rapid, changes, at, the, 'organ,', 'tissue,', regional, or, 'cell-type', specific, level, of, mRNAs, that, are, associated, with, ribosomes, and, therefore, engaged, in, translation])].
[sujeto([mRNA, stability, or, translatability, can, be]), verbo([regulated]), complemento([by, the, action, of, small, regulatory, 'RNAs', '(', 'sRNAs),', which, control, diverse, biological, processes])].
[sujeto(['Under', low, nitrogen, 'conditions,', leguminous, plants]), verbo([associate]), complemento([with, soil, bacteria, and, develop, a, new, organ, specialized, in, nitrogen, 'fixation:', the, nodule])].
[sujeto(['To']), verbo([gain]), complemento([insight, into, the, translational, regulation, of, mRNAs, during, nodule, 'formation,', the, association, of, mRNAs, and, sRNAs, to, polysomes, was, characterized, in, roots, of, the, model, legume, 'Medicago', truncatula, during, the, symbiotic, interaction, with, 'Sinorhizobium', meliloti])].
[sujeto(['Quantitative', comparison, of, 'steady-state', and, polysomal, mRNAs, for, 15, genes]), verbo([involved]), complemento([in, nodulation, identified, a, group, of, transcripts, with, slight, or, no, change, in, total, cellular, abundance, that, were, significantly, upregulated, at, the, level, of, association, with, polysomes, in, response, to, rhizobia])].
[sujeto(['This', group, included, mRNAs, encoding, receptors, like, kinases]), verbo([required]), complemento([either, for, nodule, 'organogenesis,', bacterial, infection, or, 'both,', and, transcripts, encoding, 'GRAS', and, 'NF-Y', transcription, factors, '(', 'TFs)'])].
[sujeto(['Quantitative', analysis, of, sRNAs, in, total, and, polysomal, 'RNA', samples, revealed, that, mature, microRNAs, '(', 'miRNAs)', were]), verbo([associated]), complemento([with, the, translational, 'machinery,', 'notably,', miR169, and, 'miR172,', which, target, the, 'NF-YA/HAP2', and, 'AP2', 'TFs,', respectively])].
[sujeto(['Upon', 'inoculation,', levels, of, miR169, pronouncedly]), verbo([decreased]), complemento([in, polysomal, 'complexes,', concomitant, with, the, increased, accumulation, of, the, 'NF-YA/HAP2', protein])].
[sujeto(['Tasco(®),', a, commercial, product, manufactured, from, the, brown, alga, 'Ascophyllum', 'nodosum,']), verbo([has]), complemento([been, shown, to, impart, thermal, stress, tolerance, in, animals])].
[sujeto(['We', investigated, the, 'physiological,', biochemical, and, molecular, bases, of, this]), verbo([induced]), complemento([thermal, stress, tolerance, using, the, invertebrate, animal, 'model,', 'Caenorhabiditis', elegans])].
[sujeto(['Tasco(®)', water, extract, '(', 'TWE)', at, 300, 'μg/mL', significantly]), verbo([enhanced]), complemento([thermal, stress, tolerance, as, well, as, extended, the, life, span, of, 'C'])].
[sujeto(['On', the, 'contrary,', 'TWE', under, thermal, stress, significantly]), verbo([increased]), complemento([the, pharyngeal, pumping, rate, in, treated, animals, compared, to, the, control])].
[sujeto(['Among', them, heat, shock, 'proteins,', superoxide, 'dismutase,', glutathione, 'peroxidase,', aldehyde, 'dehydrogenase,', 'saposin-like', proteins, 20, ',', myosin, regulatory, light, chain, 1, ',', cytochrome, c, oxidase, 'RAS-like,', 'GTP-binding', protein, 'RHO', 'A,', 'OS', were, significantly, 'up-regulated,', while, eukaryotic, translation, initiation, factor, 5, 'A-1', 'OS,', 60, 'S', ribosomal, protein, 'L18', 'OS,', peroxiredoxin, protein, 2, were, down]), verbo([regulated]), complemento([by, 'TWE', treatment])].
[sujeto(['Quantitative', 'real-time', polymerase, chain, reaction, '(', 'qRT-PCR)']), verbo([has]), complemento([emerged, as, robust, methodology, for, gene, expression, 'studies,', but, reference, genes, are, crucial, for, accurate, normalization])].
[sujeto(['We']), verbo([report]), complemento([the, identification, and, validation, of, suitable, reference, genes, in, the, bed, 'bug,', 'Cimex', 'lectularius,', by, using, 'qRT-PCR'])].
[sujeto(['An', intriguing, situation, distinguishes, mammalian, 'cells:', 'Although', the, mitochondrial, genome, contains, no, 5, 'S', rRNA, 'genes,', abundant, import, of, the]), verbo([nuclear]), complemento(['DNA-encoded', 5, 'S', rRNA, into, mitochondria, was, reported])].
[sujeto(['Inside', 'mitochondria,', the, cytosolic, 5, 'S', rRNA, is, shown, to, be]), verbo([associated]), complemento([with, mitochondrial, ribosomes])].
[sujeto(['A', lack, of, suitable, reagents, and, specific, assays, for, monitoring, host, responses]), verbo([has]), complemento([limited, the, use, of, this, animal, model, to, clinical, 'observations,', pathology, and, humoral, immune, responses])].
[sujeto(['Commercially', available, mouse, and, rat, 'ELISA', and, luminex, panels, were, screened, for, potential, 'cross-reactivity,', but, were]), verbo([found]), complemento([to, be, of, limited, value, for, studying, host, responses, in, hamsters])].
[sujeto(['Multicellular', organs, are, composed, of, distinct, cell, types, with, unique, assemblages, of]), verbo([translated]), complemento([mRNAs])].
[sujeto(['Here,', 'ribosome-associated', mRNAs, were, immunopurified, from, specific, cell, populations, of, intact, seedlings, using, 'Arabidopsis', thaliana, lines]), verbo([expressing]), complemento([a, 'FLAG-epitope', tagged, ribosomal, protein, 'L18', '(', 'FLAG-RPL18)', via, developmentally, regulated, promoters])].
[sujeto(['The', profiling, of, mRNAs, in, ribosome, 'complexes,', referred, to, as, the, 'translatome,', identified, differentially]), verbo([expressed]), complemento([mRNAs, in, 21, cell, populations, defined, by, 'cell-specific', expression, of, 'FLAG-RPL18'])].
[sujeto(['In', addition, to, the, demonstration, of, the, complexity, and, plasticity, of, 'cell-specific', populations, of, 'ribosome-associated', 'mRNAs,', this, study]), verbo([provides]), complemento([an, in, silico, dataset, for, recognition, of, differentially, expressed, genes, at, the, 'cell-,', 'region-,', and, 'organ-specific', levels])].
[sujeto(['This', process, is]), verbo([regulated]), complemento([for, individual, mRNAs, by, both, development, and, the, environment])].
[sujeto(['A', modification, of, the, conventional, polysome, isolation, procedure, is, described, for, transgenic, 'Arabidopsis', thaliana, that]), verbo([express]), complemento([an, 'epitope-tagged', version, of, ribosomal, protein, 'L18', '(', 'RPL18)', that, facilitates, capture, of, ribosomes, from, crude, cell, extracts, by, a, 'one-step', immunoprecipitation, method])].
[sujeto(['Ribosomal', proteins, assist, the, assembly, and]), verbo([increase]), complemento([the, stability, of, ribosomal, 'RNA,', without, requiring, 'ATP', for, their, action])].
[sujeto(['Some', ribosomal, proteins, are, also, known, to]), verbo([have]), complemento([essential, functions, outside, the, 'ribosome,', i])].
[sujeto(['Here', we, addressed, if, certain, ribosomal, proteins, with, 'RNA', chaperone, activity, and, with, a, significant, level, of, disorder, also]), verbo([have]), complemento(['protein-chaperone', activity, in, vitro])].
[sujeto(['Four', proteins, of, the, large, subunit, of, 'Escherichia', coli, 'ribosome,', 'L15,', 'L16,', 'L18', and, 'L19']), verbo([have]), complemento([been, tested, in, three, chaperone, 'assays,', in, which, all, of, them, exhibited, potent, chaperone, 'activity,', commensurable, with, that, of, heat, shock, protein, 90, kDa])].
[sujeto(['Translation', initiation, of, hepatitis, 'C', virus, 'RNA', occurs, via, ribosome]), verbo([binding]), complemento([to, an, '\'', internal, ribosome, entry, site, '(', 'IRES)\'', located, in, the, 5, '\'', untranslated, region, of, the, viral, 'RNA'])].
[sujeto(['The', principle, interaction, between, the, 40, 'S', ribosomal, subunit, and, the, 'HCV', 'IRES']), verbo([has]), complemento([been, shown, to, be, largely, factor, 'independent,', which, is, followed, by, the, joining, of, the, 60, 'S', ribosomal, subunit, to, form, functional, 80, 'S', complex])].
[sujeto(['However', several, additional, cellular, proteins]), verbo([have]), complemento([been, reported, to, bind, to, 'HCV', 'IRES', and, enhance, the, initiation, of, translation])].
[sujeto(['In', order, to, identify, novel, factors]), verbo([involved]), complemento([in, the, ribosome, assembly, during, internal, initiation, of, 'HCV', 'RNA,', northwestern, screening, of, a, 'HeLa', cDNA, expression, library, was, 'performed,', using, 'HCV', 'IRES', 'RNA', as, probe])].
[sujeto(['We', demonstrate, 'here,', that, human, ribosomal, protein, 'L18a,', a, constituent, of, 60, 'S', 'subunit,']), verbo([interacts]), complemento([with, 'HCV', 'IRES', 'RNA'])].
[sujeto(['Interestingly,', addition, of]), verbo([increasing]), complemento([concentration, of, the, purified, recombinant, sL18a, 'protein,', showed, moderate, stimulation, of, 'HCV', 'IRES', activity, in, the, in, vitro, translation, assay])].
[sujeto(['These', observations]), verbo([suggest]), complemento([that, the, human, 'L18a', might, influence, the, 'HCV', 'IRES', mediated, translation])].
[sujeto(['A', medium, resolution, solution, structure]), verbo([has]), complemento([been, obtained, for, 'L18', from, 'Bacillus', stearothermophilus, '(', 'BstL18),', a, ribosomal, protein, that, stabilizes, the, tertiary, structure, of, 5, 'S', rRNA, and, mediates, its, interaction, with, the, rest, of, the, large, subunit])].
[sujeto(['Its', remaining, 98, residues, form, a, globular, domain, that]), verbo([has]), complemento([the, same, topology, as, the, globular, domains, of, other, 'L18s,', but, the, orientation, of, helices, is, different])].
[sujeto(['This', conformational, peculiarity, should, not]), verbo([prevent]), complemento(['BstL18', from, functioning, in, the, ribosome, the, same, way, as, other, 'L18s'])].
[sujeto(['We']), verbo([have]), complemento([determined, the, solution, structure, of, ribosomal, protein, 'L18', from, 'Thermus', thermophilus])].
[sujeto(['L18', is, a, 12.5, kDa, protein, of, the, large, subunit, of, the, ribosome, and]), verbo([binds]), complemento([to, both, 5, 'S', and, 23, 'S', rRNA])].
[sujeto([thermophilus, 'S11', as, a, structural, homologue, and]), verbo([found]), complemento([that, the, structures, of, the, 'RNA-recognition', sites, are, conserved])].
[sujeto(['Important', 'features,', for, instance, a, bulge, in, the, 'RNA-contacting', 'beta-sheet,', are]), verbo([conserved]), complemento([in, both, proteins])].
[sujeto(['We']), verbo([suggest]), complemento([that, the, 'L18', fold, recognizes, a, specific, 'RNA', motif, and, that, the, resulting, 'RNA-protein-recognition', module, is, tolerant, to, variations, in, sequence])].
[sujeto(['We']), verbo([have]), complemento([cloned, and, characterized, a, tilapia, '(', 'Oreochromis', 'mossambicus)', 'L18', ribosomal, protein, 'gene,', including, the, complete, transcribed, region, and, 488, bp, of, upstream, regulatory, sequences])].
[sujeto(['We']), verbo([have]), complemento([also, isolated, two, 'L18', cDNAs, from, another, tilapia, '(', 'Oreochromis', 'niloticus)', with, a, few, conservative, nucleotide, differences])].
[sujeto(['Our', results]), verbo([suggest]), complemento([the, presence, of, two, genes, in, both, species])].
[sujeto(['Three', 5, 'S', 'rRNA-binding', ribosomal, proteins, '(', 'L5,', 'L18,', 'TL5)', of, extremely, thermophilic, bacterium, 'Thermus', thermophilus]), verbo([have]), complemento([earlier, been, isolated])].
[sujeto(['Structural', analysis, of, their, complexes, with, rRNA]), verbo([requires]), complemento([identification, of, their, binding, sites, in, the, 5, 'S', rRNA])].
[sujeto(['Previously,', a, 'TL5-binding', site]), verbo([has]), complemento([been, 'identified,', a, 'TL5-RNA', complex, 'crystallized,', and, its, structure, determined, to, 2.3, 'A'])].
[sujeto(['Of', 'these,', a, 34, -, nt, fragment, specifically]), verbo([interacted]), complemento([with, 'L5,', and, a, 55, -, nt, fragment, interacted, with, 'L5,', 'L18,', and, with, both, proteins])].
[sujeto(['An', appropriate, normalization, strategy, with, reliable, reference, genes, is]), verbo([required]), complemento([for, calculating, gene, expression, across, diverse, experimental, conditions])].
[sujeto(['In', this, 'study,', we, aim, to, identify, the, most, stable, reference, genes, for, expression, studies, of, xenobiotic, adaptation, in, 'Tetranychus', 'urticae,', an, extremely, polyphagous, herbivore]), verbo([causing]), complemento([significant, yield, reduction, of, agriculture])].
[sujeto(['Our', study]), verbo([found]), complemento([that, 'CycA', and, 'Rp49', are, best, for, investigating, gene, expression, in, acaricide, susceptible, and, resistant, populations])].
[sujeto(['These', results, will, facilitate, research, in]), verbo([revealed]), complemento([molecular, mechanisms, underlying, the, xenobiotic, adaptation, of, this, notorious, agricultural, pest])].
[sujeto(['Therefore,', the, study, of, chemosensory, proteins]), verbo([involved]), complemento([with, a, range, of, responses, to, the, chemical, environment, will, help, not, only, on, the, understanding, of, the, species, biology, but, may, also, help, the, development, of, environmentally, friendly, pest, control, strategies])].
[sujeto(['Thereby,', our, results]), verbo([provide]), complemento([relevant, data, not, only, for, other, gene, expression, studies, in, this, 'species,', as, well, as, for, the, search, of, candidate, genes, that, may, help, in, the, development, of, new, pest, control, strategies])].
[sujeto(['Drosophila', 'suzukii,', is, an, invasive, fruit, pest, native, to, 'East', 'Asia,', and, recently, invaded, 'Europe', and, 'North', 'America,', the, stability, of, its, reference, genes]), verbo([have]), complemento([not, been, previously, investigated])].
[sujeto(['We', used, three, most, stable, genes, '(', 'α-Tubulin,', 'TBP', and, 'AK)', and, one, unstably]), verbo([expressed]), complemento([gene, to, analyze, the, expression, of, 'P-glycoprotein', in, 'abamectin-resistant', and, sensitive, 'strains,', and, the, results, were, similar, to, reference, genes, 'α-Tubulin,', 'TBP', and, 'AK,', which, show, good, 'stability,', while, the, result, of, 'HSP22', has, a, certain, bias])].
[sujeto(['The', three, validated, reference, genes, can, be, widely, used, for, quantification, of]), verbo([target]), complemento([gene, expression, with, 'qRT-PCR', technology, in, 'D'])].
[sujeto(['Due', to, the, significant, differences, in, antifungal, susceptibilities, and, epidemiologies, among, these, closely, related, 'species,', a, lot, of, studies]), verbo([have]), complemento([focused, on, the, identification, of, these, emerging, yeast, species, in, clinical, specimens])].
[sujeto(['The', first, approach, differentiates, these, species, by, use, of, restriction, fragment, length, polymorphism, analysis, of, partial, internal]), verbo([transcribed]), complemento([spacer, 2, '(', 'ITS2)', and, large, subunit, ribosomal, 'DNA', with, the, enzymes, 'BsaHI', and, 'XbaI', in, a, double, digestion])].
[sujeto(['The', second, method]), verbo([involves]), complemento([a, multiplex, 'PCR', based, on, the, intron, size, differences, of, 'RPL18,', a, gene, coding, for, a, protein, component, of, the, large, '(', 60, 'S)', ribosomal, 'subunit,', and, 'species-specific', amplification])].
[sujeto(['These', two, methods, worked, well, in, differentiation, of, these, closely, related, yeast, species, and]), verbo([have]), complemento([the, potential, to, serve, as, effective, molecular, tools, suitable, for, laboratory, diagnoses, and, epidemiological, studies])].
[sujeto(['For', the, red, imported, fire, 'ant,', 'Solenopsis', 'invicta,', reliable, reference, genes, to, assess, the, transcript, expression, levels, of, the]), verbo([target]), complemento([genes, have, not, been, previously, investigated])].
[sujeto(['Our', data, showed, that, two, of, the, five, candidate, 'genes,', rpl18, and, 'ef1-beta,', were, the, most, suitable, reference, genes, because, they]), verbo([have]), complemento([the, most, stable, expression, among, different, developmental, 'stages,', castes, and, tissues, in, 'S'])].
[sujeto([invicta, the]), verbo([act]), complemento([gene, has, high, variation, in, expression, and, was, consequently, excluded, as, a, reliable, reference, gene])].
[sujeto(['The', two, validated, reference, 'genes,', rpl18, and, 'ef1-beta,', can, be, widely, used, for, quantification, of]), verbo([target]), complemento([gene, expression, with, 'RT-qPCR', technology, in, 'S'])].
[sujeto(['This', study]), verbo([has]), complemento([further, indicated, that, suitable, reference, genes, are, different, for, each, tissue, and, study, purpose])].
[sujeto(['The', reference, genes, are]), verbo([expressed]), complemento([in, different, stability, when, a, scaffold, of, different, material, is, used])].
[sujeto(['In', this, 'study,', liquid, 'chromatography-linked', tandem, mass, spectrometry, of, purified, ebola, and, marburg, virions, was, performed, to, identify]), verbo([associated]), complemento([cellular, proteins])].
[sujeto(['Host', proteins]), verbo([involved]), complemento([in, cell, 'adhesion,', 'cytoskeleton,', cell, 'signaling,', intracellular, 'trafficking,', membrane, 'organization,', and, chaperones, were, identified])].
[sujeto(['However,', the, great, majority, of, proteins, identified, here]), verbo([have]), complemento([not, been, previously, described, to, be, incorporated, within, filovirus, particles])].
[sujeto(['These', issues, were, addressed, using, siRNA, 'library-mediated', gene, knockdown, '(']), verbo([targeting]), complemento([each, identified, 'virion-associated', host, 'protein),', followed, by, filovirus, infection])].
[sujeto(['HSPA5', and, 'RPL18)', significantly, interfered, with, ebolavirus, and, marburgvirus, 'infection,']), verbo([suggesting]), complemento([specific, and, relevant, virion, incorporation])].
[sujeto(['Notably,', select, siRNAs]), verbo([inhibited]), complemento(['ebolavirus,', but, enhanced, marburgvirus, 'infection,', suggesting, important, differences, between, the, two, viruses])].
[sujeto(['The', proteomic, analysis, presented, here, contributes, to, a, greater, understanding, of, filovirus, biology, and, potentially, identifies, host, factors, that, can, be]), verbo([targeted]), complemento([for, antiviral, drug, development])].
[sujeto(['Significant', matches, were]), verbo([found]), complemento([in, 'GenBank', for, 43, '%', of, clones, '(', 'N=78),', including, 34, known, genes])].
[sujeto(['These', sequences, included, genes]), verbo([involved]), complemento([in, protein, 'metabolism,', energy, metabolism, and, regulation, of, feeding, activity])].
[sujeto(['Expression', of, 'RPL35', was, monitored, throughout, early, larval, 'development,']), verbo([revealed]), complemento([that, these, expression, patterns, were, established, early, in, development, '(', in, 2, -, 'day-old', 'larvae)'])].
[sujeto(['Our', findings, '(', 'i)']), verbo([provide]), complemento([new, insights, into, the, mechanistic, bases, of, growth, and, highlight, genes, not, previously, considered, in, growth, 'regulation,', '(', 'ii)', support, the, general, conclusion, that, genes, involved, in, protein, metabolism, and, feeding, regulation, are, key, regulators, of, 'growth,', and, '(', 'iii)', provide, a, set, of, candidate, biomarkers, for, predicting, differential, growth, rates, during, animal, development])].
[sujeto(['Successful', tumor, immunotherapy, depends, on, the, induction, of, strong, and, sustained, tumor, 'antigen-specific', immune, responses, by]), verbo([activated]), complemento(['antigen-presenting', cells, '(', 'APCs)', such, as, dendritic, cells, '(', 'DCs)'])].
[sujeto(['Since', nanoparticles]), verbo([have]), complemento([the, potential, to, codeliver, 'tumor-specific', antigen, and, 'DC-stimulating', adjuvant, in, a, 'DC-targeting', 'manner,', we, wanted, to, assess, the, suitability, of, mannosylated, 'HPMA-LMA', block, polymers, for, immunotherapy])].
[sujeto(['Both', types, of, copolymers, were, conjugated, with, 'D-mannose', to]), verbo([target]), complemento([the, mannose, receptor, as, expressed, by, 'DCs', and, macrophages])].
[sujeto(['The', extent, and, specificity, of, micelle]), verbo([binding]), complemento([and, activation, of, 'APCs', was, monitored, using, mouse, spleen, cells, and, bone, 'marrow-derived', 'DC', '(', 'BMDC)'])].
[sujeto(['HPMA-LMA', block, copolymers]), verbo([bound]), complemento(['DC', only, when, conjugated, with, 'mannose,', and, in, a, mannose, 'receptor-specific', manner])].
[sujeto(['DC-targeting', 'HPMA-LMA', block, copolymers]), verbo([mediated]), complemento(['DC', activation, when, loaded, with, 'L18-MDP'])].
[sujeto(['It', not, only, impacts, cancer, cell, growth, and, viability, directly, but, also]), verbo([has]), complemento([a, significant, role, through, its, effects, on, the, tumor, microenvironment])].
[sujeto(['Measurement', of, autophagy, can, be, confusing, and, sometimes, misleading, due, to, the, inherent, difficulty, of, measuring, both, the, formation, and, turnover, of, molecules]), verbo([involved]), complemento([in, the, autophagic, process])].
[sujeto(['Since', each, of, the, current, assays, for, autophagy]), verbo([has]), complemento([significant, 'limitations,', the, use, of, multiple, assays, for, the, analysis, of, autophagy, in, most, contexts, is, highly, advised])].
[sujeto(['Recent', studies, identified, the, 'RNF213', gene, '(', 'RNF213)', as, an, important, susceptibility, gene, for, 'MMD;', 'however,', the, mechanisms, underlying, the, 'RNF213', abnormality, related, to, 'MMD']), verbo([have]), complemento([not, yet, been, elucidated])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, 'Rnf213-deficient', mice, and, 'Rnf213', p])].
[sujeto(['The', most, influential, secondary, insult, is, considered, to, be, an, immunological, reaction, because, 'RNF213', is, predominantly]), verbo([expressed]), complemento([in, immunological, tissues])].
[sujeto(['Therefore,', we, herein, attempted, to, evaluate, the, role, of, an, immunological, stimulation, as, a, supplementary, insult, to, the]), verbo([target]), complemento([disruption, of, 'RNF213', in, the, pathophysiology, of, 'MMD'])].
[sujeto(['The', results, obtained, did, not]), verbo([reveal]), complemento([any, characteristic, finding, of, 'MMD,', and, no, significant, difference, was, observed, in, 'MRA', findings, or, the, anatomy, of, the, circle, of, 'Willis', between, 'Rnf213-deficient', mice, and, 'wild-type', mice, after, the, administration, of, 'MDP-Lys', '(', 'L18)'])].
[sujeto(['The', ratio, of, regulatory, 'T', cells, after, the, administration, of, 'MDP-Lys', '(', 'L18)', was, significantly]), verbo([decreased]), complemento([in, 'Rnf213-deficient', mice, '(', 'p<0'])].
[sujeto([1, ')', ',']), verbo([suggesting]), complemento([the, potential, role, of, the, 'RNF213', abnormality, in, the, differentiation, of, regulatory, 'T', cells])].
[sujeto(['The', present, study, aimed, to]), verbo([provide]), complemento([a, complete, exploration, of, the, effect, of, sound, 'intensity,', 'frequency,', duty, 'cycle,', microbubble, volume, and, irradiation, time, on, 'low-frequency', 'low-intensity', ultrasound, '(', 'US)-mediated', microvessel, 'disruption,', and, to, identify, an, optimal, combination, of, the, five, factors, that, maximize, the, blockage, effect])].
[sujeto(['The', optimum, conditions, were]), verbo([found]), complemento([to, be, as, 'follows:', 'Sound', 'intensity,', 1.0, 'W/cm(2);', 'frequency,', 20, 'Hz;', duty, 'cycle,', 40, '%', ;, microbubble, 'volume,', 0.2, 'ml;', and, irradiation, 'time,', 3, min])].
[sujeto([66, subsequent, to, 'low-frequency', and, 'low-intensity']), verbo([mediated]), complemento([blood, perfusion, blockage, was, obtained])].
[sujeto(['The', objective, of, this, work, was, to]), verbo([increase]), complemento([laccase, production, by, 'Pleurotus', ostreatus, 'PLAB', through, culture, medium, optimization, using, solid, state, culture, conditions])].
[sujeto(['Data', analysis, showed, that, lignocellulose, '(', 20, '%', ')', and, glucose, '(', 10, g, 'L1)', had, positive, 'effect,', whereas, 'KH(2)PO(4),', 'MgSO(4)∙7H(2)O', and, 'MnSO(4)∙H(2)O', did, not]), verbo([have]), complemento([significant, effect, on, laccase, production])].
[sujeto(['Subdural', empyema, '(', 'SDE)', and, cerebrovascular, accident, '(', 'CVA)', are, uncommon, 'life-threatening', complications, of, bacterial, 'meningitis,', which]), verbo([require]), complemento([urgent, neurosurgical, intervention, to, prevent, adverse, outcomes])].
[sujeto(['This', case, describes, a, presentation, of, community, acquired, pneumococcal, pneumonia, in, which, the, diagnosis, of, 'SDE', with, vasculitis]), verbo([induced]), complemento(['CVA', was, confounded, by, concomitant, substance, abuse, and, sedation])].
[sujeto(['X-linked', inhibitor, of, apoptosis, '(', 'XIAP)', deficiency]), verbo([caused]), complemento([by, mutations, in, 'BIRC4', was, originally, described, in, male, patients, with, 'X-linked', lymphoproliferative, syndrome, type, 2, '(', 'XLP2)'])].
[sujeto(['Recent', observations]), verbo([have]), complemento([highlighted, a, critical, role, of, 'XIAP', for, the, regulation, of, 'NOD2', signaling, and, are, probably, the, molecular, basis, for, increasingly, recognized, further, immune, dysregulatory, symptoms, of, 'XIAP', deficient, 'patients,', such, as, inflammatory, bowel, disease, '(', 'IBD)'])].
[sujeto(['P225SfsX226', was, identified, as, the, genetic]), verbo([cause]), complemento([of, 'XIAP', deficiency, in, our, family])].
[sujeto(['The', most, severely, affected, carrier, demonstrated, random, 'X-inactivation,']), verbo([leading]), complemento([to, a, significant, expression, of, mutated, 'XIAP', protein, in, 'monocytes,', and, consequently, to, impaired, 'NOD2', responses, in, vitro])].
[sujeto(['Our']), verbo([report]), complemento([provides, further, evidence, that, clinical, symptoms, of, 'XIAP', deficiency, are, not, restricted, to, male, patients])].
[sujeto(['Random', 'X-inactivation', may, be]), verbo([associated]), complemento([with, 'EN', and, mild, 'IBD', also, in, female, carriers, of, 'BIRC4', mutations])].
[sujeto(['Protein']), verbo([targeting]), complemento([is, critical, in, all, living, organisms, and, involves, a, signal, recognition, particle, '(', 'SRP),', an, 'SRP', 'receptor,', and, a, translocase])].
[sujeto(['In', 'co-translational', 'targeting,', interactions, among, these, proteins, are]), verbo([mediated]), complemento([by, the, ribosome])].
[sujeto(['In', 'chloroplasts,', the, 'light-harvesting', 'chlorophyll-binding', protein, '(', 'LHCP)', in, the, thylakoid, membrane, is]), verbo([targeted]), complemento(['post-translationally', without, a, ribosome])].
[sujeto(['A', multidomain, 'chloroplast-specific', subunit, of, the, 'SRP,', 'cpSRP43,', is, proposed, to, take, on, the, role, of, coordinating, the, sequence, of]), verbo([targeting]), complemento([events])].
[sujeto(['Here,', we, demonstrate, that, cpSRP43, exhibits, significant, interdomain, dynamics, that, are, reduced, upon]), verbo([binding]), complemento([its, 'SRP', binding, 'partner,', cpSRP54])].
[sujeto(['We', showed, that, the, affinity, of, cpSRP43, for, the]), verbo([binding]), complemento([motif, of, 'LHCP', '(', 'L18)', increases, when, cpSRP43, is, complexed, to, the, binding, motif, of, cpSRP54, '(', 'cpSRP54pep)'])].
[sujeto(['These', results, support, the, conclusion, that, substrate]), verbo([binding]), complemento([to, the, chloroplast, 'SRP', is, modulated, by, protein, structural, dynamics, in, which, a, major, role, of, cpSRP54, is, to, improve, substrate, binding, efficiency, to, the, cpSRP])].
[sujeto(['Based', on, the, principle, of, immobilized, metal, affinity, chromatography, '(', 'IMAC),', it]), verbo([has]), complemento([been, found, that, a, 'Ni-Co', 'alloy-coated', protein, chip, is, able, to, immobilize, functional, proteins, with, a, 'His-tag', attached])].
[sujeto(['In', this, 'study,', an, intelligent, computational, approach, was, developed, to]), verbo([promote]), complemento([the, performance, and, repeatability, of, a, 'Ni-Co', 'alloy-coated', protein, chip])].
[sujeto(['Ribosomal', protein, '(', 'r-protein)', 'L25', is, one, of, the, three, 'r-proteins', '(', 'L25,', 'L5,', 'L18)', that]), verbo([interact]), complemento([with, 5, 'S', rRNA, in, eubacteria])].
[sujeto(['Specific']), verbo([binding]), complemento([of, 'L25', with, a, certain, domain, of, 5, 'S', 'r-RNA,', a, 'so-called', loop, 'E,', has, been, studied, in, 'detail,', but, information, about, regulation, of, 'L25', synthesis, has, remained, totally, lacking])].
[sujeto(['In', contrast, to, the, rplE, '(', 'L5)', and, rplR, '(', 'L18)', genes, that, belong, to, the, polycistronic, 'spc-operon', and, are]), verbo([regulated]), complemento([at, the, translation, level, by, 'r-protein', 'S8,', the, rplY, '(', 'L25)', gene, forms, an, independent, transcription, unit])].
[sujeto(['The', 5, '\'', -, untranslated, region, of, the, rplY, mRNA, comprises, specific, 'sequence/structure', 'features,', including, an, atypical, 'SD-like', 'sequence,', which, are, highly]), verbo([conserved]), complemento([in, a, subset, of, 'gamma-proteobacterial', families])].
[sujeto(['Expression', of, the, rplY, gene, in, trans]), verbo([decreased]), complemento([the, translation, 'yield,', indicating, the, mechanism, of, autogenous, repression])].
[sujeto(['Site-directed', mutagenesis, of, the, rplY, 5, '\'', 'UTR', revealed, an, important, role, of, the]), verbo([conserved]), complemento([elements, in, the, translation, control])].
[sujeto(['Prostate', cancer, '(', 'PCa)', is, the, second, most, common]), verbo([cause]), complemento([of, 'cancer-related', death, among, men, in, the, 'United', 'States'])].
[sujeto(['Due', to, the, 'lipid-driven', metabolic, phenotype, of, 'PCa,', imaging, with, 2, -, 'deoxy-2-[(18)F]fluoro-D-glucose', '(', '[', '(', 18, ')', 'F]FDG)', is, 'suboptimal,', since, tumors, tend, to]), verbo([have]), complemento([low, avidity, for, glucose])].
[sujeto(['We']), verbo([have]), complemento([used, the, fat, oxidation, inhibitor, etomoxir, '(', 2, -, '[', 6, -, '(', 4, -, 'chlorophenoxy)-hexyl]oxirane-2-carboxylate)', that, targets, 'carnitine-palmitoyl-transferase-1', '(', 'CPT-1)', to, increase, glucose, uptake, in, 'PCa', cell, lines])].
[sujeto(['Small', hairpin, 'RNA', specific, for, 'CPT1A', was, used, to, confirm, the, glycolytic, switch]), verbo([induced]), complemento([by, etomoxir, in, vitro])].
[sujeto(['Systemic', etomoxir, treatment, was, used, to]), verbo([enhance]), complemento(['[', '(', 18, ')', 'F]FDG-positron', emission, tomography, '(', '[', '(', 18, ')', 'F]FDG-PET)', imaging, in, 'PCa', xenograft, mouse, models, in, 24, h])].
[sujeto(['PCa', cells, significantly, oxidize, more, of, circulating, fatty, acids, than, benign, cells, via, 'CPT-1', 'enzyme,', and, blocking, this, lipid, oxidation, resulted, in, activation, of, the, 'Warburg', effect, and]), verbo([enhanced]), complemento(['[', '(', 18, ')', 'F]FDG', signal, in, 'PCa', mouse, models])].
[sujeto(['X-ray', crystallography, shows, that, 'M9', 'L18']), verbo([has]), complemento([the, framework, topology, predicted, by, geometric, discussion])].
[sujeto(['RNA', quality, was]), verbo([maintained]), complemento([best, in, pierced, 'samples,', with, negligible, degradation, evident, after, 10, days])].
[sujeto(['Gene', expression, studies, employing, 'real-time', 'PCR']), verbo([has]), complemento([become, an, intrinsic, part, of, biomedical, research])].
[sujeto(['Appropriate', normalization, of]), verbo([target]), complemento([gene, 'transcript(s)', based, on, stably, expressed, housekeeping, genes, is, crucial, in, individual, experimental, conditions, to, obtain, accurate, results])].
[sujeto(['In', multiple, sclerosis, '(', 'MS),', several, gene, expression, studies]), verbo([have]), complemento([been, 'undertaken,', 'however,', the, suitability, of, housekeeping, genes, to, express, stably, in, this, disease, is, not, yet, explored])].
[sujeto(['Recent', research]), verbo([suggests]), complemento([that, their, expression, level, may, vary, under, different, experimental, conditions])].
[sujeto(['Hence', it, is, indispensible, to, evaluate, their, expression, stability, to, accurately, normalize]), verbo([target]), complemento([gene, transcripts])].
[sujeto(['Both', methods]), verbo([reported]), complemento(['Tfrc', and, 'B2m', the, most, stably, expressed, genes, and, 'Gapdh', the, least, stable, one])].
[sujeto(['The', bacterial, ribosome, and, its]), verbo([associated]), complemento([translation, factors, are, frequent, targets, of, 'antibiotics,', and, antibiotic, resistance, mutations, have, been, found, in, a, number, of, these, components])].
[sujeto(['Such', mutations, can, potentially]), verbo([interact]), complemento([with, one, another, in, unpredictable, 'ways,', including, the, phenotypic, suppression, of, one, mutation, by, another])].
[sujeto(['These', phenotypic, interactions, can]), verbo([provide]), complemento([evidence, of, 'long-range', functional, interactions, throughout, the, ribosome, and, its, functional, complexes, and, potentially, give, insights, into, antibiotic, resistance, mechanisms])].
[sujeto(['In', this, 'study,', we, used, genetics, and, experimental, evolution, of, the, thermophilic, bacterium, 'Thermus', thermophilus, to, examine, the, ability, of, mutations, in, various, components, of, the, protein, synthesis, apparatus, to]), verbo([suppress]), complemento([the, streptomycin, resistance, phenotypes, of, mutations, in, ribosomal, protein, 'S12,', specifically, those, located, distant, from, the, streptomycin, binding, site])].
[sujeto(['Using', experimental, 'evolution,', we, identified, amino, acid, substitutions, in, 'EF-Tu', or, in, ribosomal, proteins, 'S4,', 'S5,', 'L14,', or, 'L19,', some, of, which, were]), verbo([found]), complemento([to, also, relieve, streptomycin, resistance])].
[sujeto(['The', thermophilic, bacterium, 'Thermus', thermophilus]), verbo([has]), complemento([become, a, model, system, for, 'high-resolution', structural, studies, of, macromolecular, 'complexes,', such, as, the, 'ribosome,', while, its, natural, competence, for, transformation, facilitates, genetic, approaches])].
[sujeto(['Using', a, combination, of, genetic, 'selections,', strain, 'constructions,', and, experimental, 'evolution,', we]), verbo([find]), complemento([that, certain, mutations, in, the, translation, apparatus, can, suppress, the, phenotype, of, certain, antibiotic, resistance, mutations])].
[sujeto(['These', observations]), verbo([suggest]), complemento([the, existence, of, 'long-range', conformational, signals, in, the, translating, 'ribosome,', particularly, during, the, decoding, of, mRNA])].
[sujeto(['Real-time', quantitative, 'RT-PCR', '(', 'qRT-PCR)', is, a, powerful, technique, used, for, the, relative, quantification, of]), verbo([target]), complemento(['genes,', using, reference, '(', 'housekeeping)', genes, for, normalization, to, ensure, the, generation, of, accurate, and, robust, data])].
[sujeto(['BestKeeper', ranked, 'MRPL19', as, the, most, stably]), verbo([expressed]), complemento([gene])].
[sujeto(['Leishmania', is, a, genus, of, protozoan, parasites]), verbo([causing]), complemento([a, wide, clinical, spectrum, of, diseases, in, humans])].
[sujeto(['Differential', expression, of, the, 'L19', gene, during, development]), verbo([has]), complemento([been, observed, for, all, 'Leishmania', species, studied, to, date, '(', 'L'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'L19', overexpression, affects, negatively, translation, elongation, or, termination])].
[sujeto(['The', lack, of, correlation, between, 'L19', transcript, and, protein, abundances]), verbo([suggest]), complemento([that, the, translation, of, 'L19', is, differentially, controlled, during, development, in, the, various, species, investigated])].
[sujeto(['RPL19', overexpression, itself, was, not, 'cytotoxic;', 'however,', cell, death, induction, was]), verbo([enhanced]), complemento([when, 'RPL19', overexpressing, cells, were, incubated, with, endoplasmic, reticulum, 'stress-inducing', 'agents,', and, this, sensitizing, effect, was, specific, to, 'MCF7', cells])].
[sujeto(['Examination', of, the, cell, signaling, pathways, that]), verbo([mediate]), complemento([the, unfolded, protein, response, '(', 'UPR)', revealed, that, overexpression, of, 'RPL19', induced, 'pre-activation', of, the, 'UPR,', including, phosphorylation, of, 'pERK-like', 'ER', kinase, '(', 'PERK),', phosphorylation, of, eukaryotic, translation, initiation, factor, 2, alpha, '(', 'eIF2α),', and, activation, of, p38, 'MAPK-associated', stress, signaling])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, upregulation, of, 'RPL19', induces, 'ER', 'stress,', resulting, in, increased, sensitivity, to, 'ER', stress, and, enhanced, cell, death, in, 'MCF7', breast, cancer, cells])].
[sujeto(['Phosphatase', and, tensin, homolog, deleted, on, chromosome, 10, '(', 'PTEN)', is, a, tumor, suppressor, gene, that]), verbo([regulates]), complemento([various, cell, processes, including, 'proliferation,', 'growth,', 'synaptogenesis,', neural, and, glioma, 'stem/progenitor', cell, renewal])].
[sujeto(['In', 'addition,', 'PTEN', can]), verbo([regulate]), complemento([sensory, cell, proliferation, and, differentiation, of, hair, bundles, in, the, mammalian, cochlea])].
[sujeto(['In', this, study, we, use, 'immunofluorescence,', 'Western', blot, and, reverse, 'transcriptase-polymerase', chain, reaction, '(', 'RT-PCR)', to]), verbo([reveal]), complemento([the, expression, of, 'PTEN', in, the, developing, cochlear, lateral, 'wall,', which, is, crucial, for, regulating, 'K(+)', homeostasis])].
[sujeto(['Relatively', high, levels, of, 'PTEN', are, initially]), verbo([expressed]), complemento([in, the, marginal, cells, '(', 'MCs)', of, the, lateral, wall, at, embryonic, day, '(', 'E)', 17.5, when, they, start, to, differentiate])].
[sujeto(['Similarly', high, levels, are, subsequently]), verbo([expressed]), complemento([in, differentiating, root, cells, '(', 'RCs)', at, postnatal, day, '(', 'P)', 3, and, then, in, spiral, ligament, fibrocytes, '(', 'SLFs)', at, 'P', 10])].
[sujeto(['The', expression, pattern, for, 'PTEN', in, the, developing, lateral, wall]), verbo([suggests]), complemento([that, it, plays, a, critical, role, in, the, differentiation, of, the, cellular, pathways, that, regulate, 'K(+)', homeostasis, in, the, cochlea])].
[sujeto(['We']), verbo([report]), complemento([our, experience, with, the, use, of, the, 105, 'K', and, 180, 'K', oligonucleotide, microarrays, in, 215, consecutive, patients, referred, with, either, autism, or, autism, spectrum, disorders, '(', 'ASD)', or, developmental, 'delay/learning', disability, for, genetic, services, at, the, 'University', of, 'Kansas', 'Medical', 'Center', during, the, past, 4, years, '(', 2009, -, 2012, ')'])].
[sujeto(['Thirteen', patients, with, 'ASD', had, a, total, of, 14, 'CNVs,', 6, 'CNVs']), verbo([recognized]), complemento([as, diagnostic, and, 8, as, 'non-diagnostic'])].
[sujeto(['The', most, common, chromosome]), verbo([involved]), complemento([in, the, 'ASD', group, was, chromosome, 15])].
[sujeto(['Many', 'tissue-engineering', approaches, for, repair, and, regeneration]), verbo([involve]), complemento([transplants, between, species])].
[sujeto(['This', study]), verbo([provides]), complemento([a, simple, molecular, strategy, to, quantify, 'species-specific', contributions, in, chimeras, and, xenografts])].
[sujeto(['After', four, decades, of, research, aimed, at, understanding, tRNA, selection, on, the, 'ribosome,', the, mechanism, by, which, ribosomal, ambiguity, '(', 'ram)', mutations]), verbo([promote]), complemento([miscoding, remains, unclear])].
[sujeto(['Each', of, these, mutations]), verbo([causes]), complemento([miscoding, in, vivo, and, stimulates, elongation, factor, thermo, unstable, '(', 'EF-Tu)-dependent', 'GTP', hydrolysis, in, vitro])].
[sujeto(['Despite', these, disparate, 'locations,', both, mutations]), verbo([induce]), complemento([almost, identical, structural, rearrangements, that, disrupt, the, 'B8', 'bridge--namely,', the, interaction, of, 'h8/h14', with, 'L14', and, 'L19'])].
[sujeto(['This', conformation, most, closely, resembles, that, seen, upon, 'EF-Tu-GTP-aminoacyl-tRNA']), verbo([binding]), complemento([to, the, 70, 'S', ribosome])].
[sujeto(['These', data]), verbo([provide]), complemento([evidence, that, disruption, 'and/or', distortion, of, 'B8', is, an, important, aspect, of, 'GTPase', activation])].
[sujeto(['We', propose, 'that,', by, destabilizing, 'B8,', 'G299A', and, 'G347U', reduce, the, energetic, cost, of, attaining, the, 'GTPase-activated', state, and, thereby]), verbo([decrease]), complemento([the, stringency, of, decoding])].
[sujeto(['The', amount, of, fat, in, the, carcass]), verbo([has]), complemento([been, proposed, as, a, regulator, of, initiation, of, puberty, in, cattle])].
[sujeto(['Diets', were, formulated, to]), verbo([promote]), complemento(['BW', gain, of, 0.4, 'kg/d', '(', groups, 'Low', and, 'LL)', or, 1.2, 'kg/d', '(', 'High', 'group)'])].
[sujeto(['Leptin', administration]), verbo([increased]), complemento(['(', 'P', =, 0.04, ')', leptin, serum, concentration, but, had, no, effect, '(', 'P', &, 'gt;', 0.05, ')', on, 'age,', 'BW,', or, 'BCS', at, puberty])].
[sujeto(['High', energy, intake]), verbo([increased]), complemento(['(', 'P', &, 'lt;', 0.01, ')', leptin, 'concentration,', accelerated, '(', 'P', =, 0.02, ')', 'puberty,', and, increased, '(', 'P', &, 'lt;', 0.01, ')', 'BCS', at, 'puberty,', without, altering, '(', 'P', =, 0.17, ')', 'BW', at, puberty])].
[sujeto(['Leptin', administration]), verbo([caused]), complemento([a, significant, '(', 'P', &, 'lt;', 0.05, ')', but, transient, increase, in, follicular, 'development,', which, was, similar, to, the, transient, increase, in, leptin, serum, concentration])].
[sujeto(['Results', from, leptin, gene, expression, demonstrated, that, high, energy, intake]), verbo([increased]), complemento(['(', 'P', &, 'lt;', 0.01, ')', and, leptin, administration, decreased, '(', 'P', &, 'lt;', 0.01, ')', leptin, expression, in, 3, adipose, tissues])].
[sujeto(['The', observed]), verbo([decrease]), complemento([in, leptin, gene, expression, after, administration, of, leptin, could, explain, the, reduction, in, leptin, serum, concentration, after, 30, d, of, treatment, and, consequently, the, failure, of, leptin, to, accelerate, puberty])].
[sujeto(['Although', exogenous, administration, of, leptin, temporarily]), verbo([enhanced]), complemento([rate, of, follicular, 'growth,', it, did, not, accelerate, puberty])].
[sujeto(['In', the, last, few, 'decades,', the, characterisation, of, genes]), verbo([involved]), complemento([in, fat, metabolism, and, technological, advances, have, enabled, the, study, of, the, effect, of, diet, on, the, milk, fatty, acid, '(', 'FA)', profile, in, the, mammary, gland, and, aided, in, the, elucidation, of, the, mechanisms, of, the, response, to, diet])].
[sujeto(['In', this, 'study,', the, forage, type, affected, the, 'C18:2', 'cis-9', 'trans-11', '(', 'CLA)', and, 'long-chain', saturated, fatty, acid, '(', 'LCFA)', 'content,', with, higher, percentages, during, grazing, than, during]), verbo([hay]), complemento([feeding])].
[sujeto(['This', may]), verbo([suggest]), complemento([that, these, 'FAs', act, as, regulatory, factors, for, the, transcriptional, control, of, the, carnitine, palmitoyltransferase, 1, 'B', '(', 'CPT1B)', 'gene,', which, was, more, highly, expressed, in, the, grazing, group, '(', 'GRE)'])].
[sujeto(['The', most, highly]), verbo([expressed]), complemento([gene, in, the, mammary, gland, at, the, fifth, week, of, lactation, is, 'CAAT/', 'enhancer-', binding, protein, beta, '(', 'CEBPB),', possibly, due, to, its, role, in, milk, fat, synthesis, in, the, mammary, gland])].
[sujeto(['hay),', can, affect, the, milk, fatty, acid, profile, and, the, expression, of, the, 'CPT1B', 'gene,', which, is]), verbo([associated]), complemento([with, the, oxidation, of, fatty, acids])].
[sujeto(['When', compared, to]), verbo([hay]), complemento([fed, 'indoors,', grazing, fresh, low, mountain, pastures, stimulates, the, milk, content, of, 'CLA', and, 'LCFA', via, mammary, uptake])].
[sujeto(['In', this, 'sense,', 'LCFA', in, milk, may, be]), verbo([acting]), complemento([as, a, regulatory, factor, for, transcriptional, control, of, the, 'CPT1B', 'gene,', which, was, more, highly, expressed, in, the, grazing, group])].
[sujeto(['In', this, present, 'study,', we, utilized, the, differential, display, reverse, 'transcription-polymerase', chain, reaction, to, isolate, potential, novel, hepatic, genes]), verbo([induced]), complemento([by, sublethal, copper, exposure, in, the, freshwater, swordtail, 'fish,', 'Xiphophorus', helleri])].
[sujeto(['Full', length, cloning, of, a, cDNA, fragment]), verbo([induced]), complemento([by, copper, exposure, to, 1, &, 'nbsp;μg/ml', during, 24, &, 'nbsp;h', resulted, in, the, positive, identification, of, a, hepatic, ribosomal, protein, 'L19', '(', 'RPL19)', gene])].
[sujeto(['This', study, describes, for, the, first, time, the, involvement, of, 'RPL19', in, copper, 'toxicity,', probably, as, a, result, of]), verbo([increase]), complemento([in, ribosome, synthesis, rate, to, support, activities, such, as, cellular, protein, 'translation,', transcriptional, activation, and, mRNA, stabilization, during, sublethal, copper, exposure])].
[sujeto(['Toll-like', receptor, 3, '(', 'TLR3)']), verbo([recognizes]), complemento(['double-stranded', 'RNA', '(', 'dsRNA)', and, induces, inflammation])].
[sujeto(['In', this, study, we]), verbo([report]), complemento([that, 'L19', acts, upon, production, of, 'IP-10', or, 'IL-8', differently, in, glioblastoma, cells])].
[sujeto([siRNA, was, introduced, to]), verbo([suppress]), complemento([expression, of, 'L19'])].
[sujeto(['L19']), verbo([increased]), complemento(['ERK', activation, to, produce, 'IL-8'])].
[sujeto(['In', 'A172', 'cells,', in, which, 'TLR3', is]), verbo([expressed]), complemento([at, 'endosomes,', 'L19', inhibited, interferon, regulatory, factor, 3, '(', 'IRF3)', activation, and, 'IP-10', production, to, facilitate, viral, 'multiplication,', whereas, 'L19', inhibited, viral, multiplication, in, 'A549', cells, bearing, 'TLR3', on, their, cell, membrane])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'L19', regulates, 'TLR3', 'signaling,', which, is, cell, type, specific, and, may, be, involved, in, pathogenesis, of, autoimmune, diseases, and, chronic, inflammatory, diseases])].
[sujeto(['In', order, to, study, changes, in, gene, expression, upon, food, 'exposure,', a, robust, set, of, stably]), verbo([expressed]), complemento([genes, is, required, for, normalization])].
[sujeto(['Here', we, present, a, set, of, reference, genes, suitable, for, 'RT-qPCR', that]), verbo([has]), complemento([been, validated, for, exposure, studies, with, the, 'intestinal-like', 'Caco-2', cell, line])].
[sujeto(['Food', homogenates, did]), verbo([provoke]), complemento([responses, in, the, 'Caco-2', 'cells,', as, was, demonstrated, by, changed, expression, of, 'NAD(P)H', 'Quinone', dehydrogenase, 1, '(', 'NQO1),', 'Claudin', 4, '(', 'CLDN4),', 'Nitric', 'Oxide', 'Synthase', 2, '(', 'NOS2),', and, 'ATP-binding', 'cassette,', subfamily, 'B,', member, 1, '(', 'ABCB1)', in, the, same, experiment])].
[sujeto(['Stably']), verbo([expressed]), complemento([reference, genes, are, used, to, normalize, data, so, observed, changes, in, expression, are, not, due, to, artifacts, but, rather, reflect, physiological, changes])].
[sujeto(['The', levels, of, both, markers]), verbo([increased]), complemento([in, a, trend, as, stage])].
[sujeto(['The', use, of, two, markers, will]), verbo([recognize]), complemento([the, high, risk, group, better, than, the, single, marker, 'usage,', though, not, reaching, independent, status, yet])].
[sujeto(['Multi-target', strategy, assay, is]), verbo([suggested]), complemento([for, fecal, 'RNA', examination])].
[sujeto(['Preadipogenic', 'delta-like', kinase1, mRNA, was, greater, in, the, 'IM', than, the, 'SQ', adipose, 'tissue;', 'conversely,', differentiating, and, adipogenic, 'genes,', lipoprotein, 'lipase,', 'PPARγ,', fatty, acid, 'synthetase,', and, fatty, acid]), verbo([binding]), complemento([protein, 4, were, greater, '(', 'P', &, 'lt;', 0.001, ')', in, the, 'SQ', than, the, 'IM', depot])].
[sujeto(['The', growth, hormone, '(', 'GH)-insulin-like', growth, factor, '(', 'IGF)', system, is]), verbo([expressed]), complemento([in, bovine, uterus, during, the, estrous, cycle, and, early, pregnancy, and, is, acknowledged, to, play, an, important, role, in, regulating, the, development, of, the, embryo, and, uterus])].
[sujeto(['The', leptin, receptor, '(', 'LEPR)', is, also]), verbo([expressed]), complemento([in, the, bovine, uterus, although, it, is, not, known, whether, its, expression, varies, during, the, estrous, cycle])].
[sujeto(['It']), verbo([has]), complemento([been, demonstrated, for, the, first, time, that, 'LEPR', mRNA, is, expressed, in, the, bovine, uterus, throughout, the, estrous, cycle, and, that, it, presents, a, 'cycle-dependent', 'variation,', with, higher, levels, observed, during, the, luteal, phase])].
[sujeto(['The', expression, of, 'IGF-I', mRNA, was, greatest, at, estrus, and, day, 5, '(', 100, '%', ')', ',', and]), verbo([decreased]), complemento([on, days, 12, and, 19, to, 47, '%', and, 35, '%', of, the, initial, values])].
[sujeto(['IGF-II', mRNA]), verbo([increased]), complemento([on, day, 12, and, decreased, sharply, thereafter, '(', to, 'one-third', of, day, 12, 'values)'])].
[sujeto(['Interestingly,', 'IGF-1R', showed, the, same, pattern, as, 'IGF-II:']), verbo([increased]), complemento([50, '%', on, day, 12, compared, to, values, at, estrus, and, presented, a, sharp, decrease, on, day, 19])].
[sujeto(['The', expression, of, 'GHR', transcript, was, greatest, at, estrus, and, on, day, 5, and, progressively]), verbo([decreased]), complemento([thereafter])].
[sujeto(['These', results, show, that, the, 'GH-IGF', system, components, are, distinctively]), verbo([regulated]), complemento([during, the, estrous, cycle, suggesting, that, modulation, of, the, 'IGF', system, may, influence, uterine, activity, during, this, period])].
[sujeto(['The']), verbo([increase]), complemento([in, the, uterine, sensitivity, to, 'IGFs', during, the, late, luteal, phase, -, as, demonstrated, by, the, increased, 'IGF-1R', expression, -, concomitant, with, the, increased, 'IGF-II', mRNA, expression, may, reinforce, the, role, of, 'IGF-II', during, early, pregnancy])].
[sujeto(['Characterizing', the, molecular, mechanism]), verbo([involved]), complemento([in, nonhost, disease, resistance, is, important, to, understand, the, adaptations, of, 'plant-pathogen', interactions])].
[sujeto(['In', this, 'study,', 'virus-induced', gene, silencing, '(', 'VIGS)-based', forward, genetics, screen, was, utilized, to, identify, genes]), verbo([involved]), complemento([in, nonhost, resistance, in, 'Nicotiana', benthamiana])].
[sujeto([benthamiana]), verbo([caused]), complemento([a, delay, in, nonhost, bacteria, induced, hypersensitive, response, '(', 'HR)', with, concurrent, increase, in, nonhost, bacterial, multiplication])].
[sujeto(['The', studies, on, 'NbRPL12', and, 'NbRPL19', double, silenced, plants]), verbo([suggested]), complemento([that, both, 'RPL12', and, 'RPL19', act, in, the, same, pathway, to, confer, nonhost, resistance])].
[sujeto(['Our', work]), verbo([suggests]), complemento([a, role, for, 'RPL12', and, 'RPL19', in, nonhost, disease, resistance, in, 'N'])].
[sujeto(['Adult', male, 'Wistar', rats, were]), verbo([provided]), complemento([either, water, or, a, fructose, solution, '(', 10, '%', ')', for, 5, weeks])].
[sujeto(['Compared', with, the, control, 'group,', the, fructose, diet]), verbo([induced]), complemento([dyslipidemia, and, significantly, higher, plasma, total, 'cholesterol,', 'HDL-cholesterol,', 'triglyceride,', and, glucose, levels, as, well, as, both, epididymal, and, retroperitoneal, adiposity])].
[sujeto(['LPS']), verbo([induced]), complemento(['Fos', protein, expression, in, several, areas, of, the, brains, of, the, control, 'rats;', 'however,', higher, numbers, of, 'Fos-positive', cells, were, observed, in, the, brains, of, the, rats, that, were, fed, a, fructose, diet])].
[sujeto(['Moreover,', larger]), verbo([increases]), complemento([in, cytokine, expression, were, observed, in, both, the, hypothalamus, and, the, adipose, tissue, of, the, obese, rats, compared, with, the, control, rats, in, response, to, 'LPS'])].
[sujeto(['Suitable', reference, genes, belonging, to, numerous, functional, classes]), verbo([have]), complemento([been, identified, for, various, types, of, species, and, tissue])].
[sujeto(['The', results, obtained, from, the, four, methods, demonstrated, a, similar, 'trend:', 'RPL19,', 'ACTB,', and, 'PGK1', were, the, most, stably]), verbo([expressed]), complemento([reference, genes, in, the, sheep, mandibular, condyle])].
[sujeto(['As', determined, by, 'RefFinder', comprehensive, 'analysis,', the, results, of, the, present, study]), verbo([suggested]), complemento([that, 'RPL19', is, the, most, suitable, reference, gene, for, studies, associated, with, the, sheep, mandibular, condyle])].
[sujeto([bowringi, transcript, sequences]), verbo([reported]), complemento([enrich, the, genomic, resources, of, this, beetle])].
[sujeto(['Importantly,', the, larger, number, of, gene, sequences, and, valid, reference, genes]), verbo([provide]), complemento([a, valuable, platform, for, future, gene, expression, 'studies,', especially, with, regard, to, exploring, the, molecular, mechanisms, of, different, physiological, processes, in, this, species])].
[sujeto(['Double-stranded', 'RNA', '(', 'dsRNA)', designed, to]), verbo([target]), complemento([pest, genes, emerges, as, a, promising, strategy, for, improving, pest, control])].
[sujeto(['In', this, 'paper,', we, investigated, the, effects, of, dsRNA]), verbo([targeting]), complemento([rpl19, from, 'Bactrocera', dorsalis, on, 'non-target', insects, in, citrus, ecological, systems, by, feeding, the, dsRNA, to, 'Bactrocera', 'minax,', 'Apis', mellifera, and, 'Diachasmimorpha', longicaudata])].
[sujeto([longicaudata]), verbo([caused]), complemento([their, respective, rpl19, genes, to, be, knocked, down, over, 50, -, 70, and, 40, '%', ',', 'respectively,', but, it, had, no, effect, on, the, expression, of, the, rpl19, gene, in, 'A'])].
[sujeto(['The', 'Bdrpl19', 3, '\'', 'UTR', dsRNA, did, not]), verbo([have]), complemento([any, silencing, effects, on, the, expression, levels, of, rpl19, in, 'non-target', insects])].
[sujeto(['This', study]), verbo([provides]), complemento([evidence, that, dsRNA, can, impact, 'non-target', 'organisms,', but, the, 3, '\'', 'UTR', dsRNA, may, not, have, effects, in, 'non-target', organisms])].
[sujeto(['Stress', granules, '(', 'SGs)', are, 'mRNA-protein', aggregates]), verbo([induced]), complemento([during, 'stress,', which, accumulate, in, many, neurodegenerative, diseases])].
[sujeto(['Previously,', the, 'autophagy-lysosome', pathway, and, 'valosin-containing', protein, '(', 'VCP),', key, players, of, the, protein, quality, control, '(', 'PQC),', were, shown, to]), verbo([regulate]), complemento(['SG', degradation])].
[sujeto(['However,', despite, these, 'observations,', it, is, currently, unknown, whether, the, 'PQC', actively]), verbo([participates]), complemento([in, 'SG', assembly])].
[sujeto(['Here,', we, describe, that, inhibition, of, 'autophagy,', lysosomes, and, 'VCP']), verbo([causes]), complemento([defective, 'SG', formation, after, induction])].
[sujeto(['Intriguingly,', 'DRIPs', and, 60, 'S,', which, are]), verbo([released]), complemento([from, disassembling, polysomes, and, are, normally, excluded, from, 'SGs,', were, significantly, retained, within, 'SGs', in, cells, with, impaired, 'autophagy,', lysosome, or, 'VCP', function])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, deregulated, 'autophagy,', lysosomal, or, 'VCP', 'activities,', which, occur, in, several, neurodegenerative, '(', 'VCP-associated)', 'diseases,', may, alter, 'SG', morphology, and, composition])].
[sujeto(['Can', the, ranked, expression, levels, of, a, cohort, of, cumulus, cell, '(', 'CC)', genes, be, used, to, select, 'MII', oocytes, with, a, potential, for, blastocyst, development, and, live, 'birth?', 'A', ranking, method, containing, four, '(', 'HAS2,', 'FSHR,', 'VCAN,', 'PR)', of, the, eight, genes, evaluated, in, this, study, for, identifying, good, quality, 'MII', oocytes]), verbo([provides]), complemento([a, significantly, better, outcome, compared, with, random, selection, and, is, equally, as, good, as, using, all, oocytes, for, 'ICSI'])].
[sujeto(['Recent', evidence]), verbo([has]), complemento([identified, a, number, of, candidate, genes, in, 'CC', that, have, the, potential, to, serve, as, markers, of, oocyte, 'quality;', 'however,', a, reliable, method, for, selecting, 'MII', oocytes, with, blastocyst, and, live, birth, potential, remains, a, challenge])].
[sujeto(['In', this, 'population,', the, selection, of, 'MII', oocytes, according, to, relative, ranking, levels, of, a, subset, of, 'CC-expressed', genes]), verbo([provided]), complemento([a, significantly, higher, chance, of, identifying, a, good, quality, oocyte, compared, with, selecting, 'MII', oocytes, randomly, '(', 'blastocyst:', 1, ×, 'MII', 'oocyte:', 52, versus, 23, '%', ',', 'P', =, 0.008, ;, 3, ×, 'MII', 'oocytes:', 80, versus, 52, '%', ',', 'P', =, 0.002, ;, live, 'birth:', 1, ×, 'MII', 'oocyte:', 31, versus, 15, '%', ',', 'P<0'])].
[sujeto(['This', is, a, retrospective, study, that]), verbo([requires]), complemento([further, validation, in, an, unselected, population])].
[sujeto(['Funding', was]), verbo([provided]), complemento([by, 'Fertility', 'Associates', 'Ltd', and, the, 'New', 'Zealand', 'Government'])].
[sujeto(['Multiple', references, genes, rather, than, a, single, gene, may]), verbo([provide]), complemento([more, robust, and, reliable, results])].
[sujeto(['Chemoprevention', offers, a, promising, strategy, to]), verbo([prevent]), complemento([or, delay, the, development, of, various, cancers])].
[sujeto(['Critical', to, this, approach, is, the, identification, of, molecular]), verbo([targets]), complemento([that, may, track, with, chemopreventive, efficacy])].
[sujeto(['PDIA3', was, of, particular, interest, given, its, potential, role, in]), verbo([regulating]), complemento([chemosensitivity, of, cancer, cells])].
[sujeto(['Immunoprecipitation', of, 'PDIA3', revealed, a, new, set, of, client, proteins, following, resveratrol, 'treatment,', including, 'α,', 'β,', and, 'δ-catenins,', and, cellular, fractionation, identified]), verbo([decreased]), complemento([nuclear, localization, of, 'α-catenin', by, resveratrol])].
[sujeto(['These', data, establish, differential, proteomic, mapping, as, a, powerful, tool, for, identifying, novel, molecular]), verbo([targets]), complemento([of, chemopreventive, agents])].
[sujeto(['Nuclear', receptor, transcriptional, activity, is]), verbo([enhanced]), complemento([by, interaction, with, coactivators])].
[sujeto(['The', highly, related]), verbo([nuclear]), complemento([receptor, 5, 'A', '(', 'NR5A)', subfamily, members, liver, receptor, homolog, 1, and, steroidogenic, factor, 1, bind, to, and, activate, several, of, the, same, 'genes,', many, of, which, are, important, for, reproductive, function])].
[sujeto(['To', better, understand, transcriptional, activation, by, these]), verbo([nuclear]), complemento(['receptors,', we, sought, to, identify, interacting, proteins, that, might, function, as, coactivators])].
[sujeto(['The', 'LIM', domain, protein, four, and, a, half, 'LIM', domain, 2, '(', 'FHL2)', was, identified, as]), verbo([interacting]), complemento([with, the, 'NR5A', receptors, in, a, yeast, 'two-hybrid', screen, of, a, human, ovary, cDNA, library])].
[sujeto(['FHL2,', and, the, closely, related, 'FHL1,', are, both]), verbo([expressed]), complemento([in, the, rodent, ovary, and, in, granulosa, cells])].
[sujeto(['Small', interfering, 'RNA-mediated', knockdown, of, 'FHL1', and, 'FHL2', in, primary, mouse, granulosa, cells, reduced, expression, of, the, 'NR5A']), verbo([target]), complemento([genes, encoding, 'inhibin-α', and, 'P450scc'])].
[sujeto(['In', vitro, assays, confirmed, the, interaction, between, the, 'FHL', and, 'NR5A', proteins, and, revealed, that, a, single, 'LIM', domain, of, 'FHL2', is, sufficient, for, this, 'interaction,', whereas, determinants, in, both, the, ligand]), verbo([binding]), complemento([domain, and, 'DNA', binding, domain, of, 'NR5A', proteins, are, important])].
[sujeto(['FHL2']), verbo([enhances]), complemento([the, ability, of, both, liver, receptor, homolog, 1, and, steroidogenic, factor, 1, to, activate, the, 'inhibin-α', subunit, gene, promoter, in, granulosa, cells, and, thus, functions, as, a, transcriptional, coactivator])].
[sujeto(['FHL2', also]), verbo([interacts]), complemento([with, cAMP, response, 'element-binding', protein, and, substantially, augments, activation, of, inhibin, gene, expression, by, the, combination, of, 'NR5A', receptors, and, 'forskolin,', suggesting, that, 'FHL2', may, facilitate, integration, of, these, two, signals])].
[sujeto(['Collectively', these, results, identify, 'FHL2', as, a, novel, coactivator, of, 'NR5A']), verbo([nuclear]), complemento([receptors, in, ovarian, granulosa, cells, and, suggest, its, involvement, in, regulating, target, genes, important, for, mammalian, reproduction])].
[sujeto(['Integrating', conjugative, elements, '(', 'ICEs)', of, the, 'SXT/R391', family]), verbo([have]), complemento([been, identified, in, 'fish-isolated', bacterial, strains, collected, from, marine, aquaculture, environments, of, the, northwestern, 'Iberian', 'Peninsula'])].
[sujeto(['Variable', 'DNA', 'regions,', which]), verbo([confer]), complemento(['element-specific', properties, to, 'ICEs', of, this, 'family,', were, characterised])].
[sujeto(['Interestingly,', the, two, 'ICEs', contained, 29, genes, not]), verbo([found]), complemento([in, variable, 'DNA', insertions, of, previously, described, 'ICEs'])].
[sujeto(['Most', 'notably,', variable, gene, content, for, 'ICEVscSpa3', showed, similarity, to, genes, potentially]), verbo([involved]), complemento([in, housekeeping, functions, of, 'replication,', nucleotide, metabolism, and, transcription])].
[sujeto(['For', these, 'genes,', closest, homologues, were]), verbo([found]), complemento([clustered, in, the, genome, of, 'Pseudomonas', psychrotolerans, 'L19,', suggesting, a, transfer, as, a, block, to, 'ICEVscSpa3'])].
[sujeto(['In', 'contrast,', the, variable, gene, content, of, 'ICEPspSpa1', included, genes]), verbo([involved]), complemento([in, 'restriction/modification', functions, in, two, different, hotspots, and, genes, related, to, 'ICE', maintenance])].
[sujeto([tsukubaensis, 'L19', unveiled, that, stw, 'ACP,', an, 'ACP', in, a, type, 'II', 'PKS,', was, phosphopantetheinylated, by, three, 'PPTases', 'FKPPT1,', 'FKPPT3,', and, 'FKACPS;', sts, 'FAS', 'ACP,', the, 'ACP', in, fatty, acid, synthase, '(', 'FAS),', was, phosphopantetheinylated, by, three, 'PPTases', 'FKPPT2,', 'FKPPT3,', and, 'FKACPS;', 'TcsA-ACP,', an, 'ACP']), verbo([involved]), complemento([in, 'FK506', 'biosynthesis,', was, phosphopantetheinylated, by, two, 'PPTases', 'FKPPT3', and, 'FKACPS;', 'FkbP-PCP,', an, 'PCP', involved, in, 'FK506', 'biosynthesis,', was, phosphopantetheinylated, by, all, of, these, five, 'PPTases', 'FKPPT1-4', and, 'FKACPS'])].
[sujeto(['Our', results, here, indicate, that, the, functions, of, these, 'PPTases', complement, each, other, for, 'ACPs/PCPs', 'substrates,']), verbo([suggesting]), complemento([a, complicate, phosphopantetheinylation, network, in, 'S'])].
[sujeto(['Furthermore,', through, saturation, 'mutagenesis,', positions, 113, and, 128, were, confirmed, to, substantially, influence, the, enantioselectivity, of, 'PpL19,', and, certain, replacements, of, the, methionine, at, position, 113, ',', in, 'particular,', were]), verbo([found]), complemento([to, reverse, the, enantioselectivity, of, 'PpL19', from, 'S-', to, 'R-selectivity'])].
[sujeto(['By', combining, the, beneficial, 'mutations,', two, enantiocomplementary, nitrilase, 'mutants,', 'PpL19-LH', and, 'PpL19-GYY,', were, 'created,', which, exhibited, high, 'S-', and, 'R-selectivity', toward, 'mandelonitrile,', 'respectively:', 'PpL19-LH', showed, the, highest, 'S-selectivity', toward, mandelonitrile, ever]), verbo([reported]), complemento(['(', 91.1, '%', 'ee),', 'and,', 'notably,', the, 'PpL19-GYY', mutant, was, identified, to, be, highly, 'R-selective', '(', 90.1, '%', 'ee)', and, thus, an, unexpected, enantiocomplementary, mutant, for, mandelonitrile])].
[sujeto(['To']), verbo([enhance]), complemento([the, specificity, of, 'anti-TNF-α', single, chain, 'Fv', antibody, '(', 'TNF-scFv)', to, inflamed, 'site,', we, constructed, a, bispecific, antibody, 'BsDb', that, targets, 'TNF-α', and, 'ED-B-containing', fibronectin, '(', 'B-FN)', by, covalently, linking, 'TNF-scFv', and, the, 'anti-ED-B', scFv, 'L19', at, the, gene, level, via, a, flexible, peptide, linker, deriving, from, human, serum, albumin])].
[sujeto(['BsDb']), verbo([retained]), complemento([the, immunoreactivity, of, its, original, antibodies, 'TNF-scFv', and, 'L19,', and, showed, a, marked, gain, in, 'antigen-binding', affinity, and, in, 'TNF-α-neutralizing', 'ability,', when, compared, to, 'TNF-scFv', and, 'L19', that, were, produced, in, 'Escherichia', coli])].
[sujeto(['These', data, indicate, that, 'BsDb', is, endowed, with, high, specificity, to, inflamed, site, and, low, toxicity, to, normal, tissues, and, holds, great, potential, for, in, vivo, application, for, the]), verbo([targeted]), complemento([therapy, of, 'RA', and, other, chronic, inflammatory, diseases])].
[sujeto([psychrotolerans, 'L19', was, mined, and, distinguished, from, other, nitrilases, as, it, was]), verbo([expressed]), complemento([as, an, active, inclusion, body, and, showed, 'S-selectivity', toward, mandelonitrile])].
[sujeto(['Canine', parvovirus, 2, '(', 'CPV-2)', remains, a, significant, worldwide, canine, pathogen, and, the, most, common]), verbo([cause]), complemento([of, viral, enteritis, in, dogs])].
[sujeto(['PLGA', nanoparticles, were, demonstrated, to]), verbo([have]), complemento([special, properties, such, 'as;', controlled, antigen, 'release,', protection, from, 'degradation,', elimination, of, 'booster-dose', and, enhancing, the, cellular, uptake, by, antigen, presenting, cells])].
[sujeto(['Additionally,', it, was, evaluated, that, free, 'NPs', and, 'W-1', 'L19', peptide, encapsulated, 'PLGA', nanoparticles]), verbo([have]), complemento(['Z-ave', of, 183.9, ±, 12.1, 'nm,', 221.7, ±, 15.8, nm, and, polydispersity, index, of, 0.107, ±, 0.08, ',', 0.135, ±, 0.12, respectively])].
[sujeto(['It', was, determined, that, peptide, loaded, 'PLGA', nanoparticles, were, successfully, phagocytized, by, macrophage, cells, and]), verbo([increased]), complemento(['NO', production, at, 2, -, folds, '(', *, 'P', &, 'lt;', 0.05, ')', in, contrast, to, free, 'peptide,', and, 3, -, folds, '(', *, 'P', &, 'lt;', 0.01, ')', in, contrast, to, control])].
[sujeto(['Obtained', results, showed, that, 'PLGA', nanoparticles]), verbo([enhanced]), complemento([the, capacity, of, 'W-1', 'L19', peptide, to, induce, nitric, oxide, production, in, vitro, due, to, its, adjuvant, properties])].
[sujeto(['Studies']), verbo([targeting]), complemento(['PLGA', nanoparticles, based, delivery, system, must, be, maintained, in, near, future, in, order, to, develop, new, and, more, effective, 'nano-vaccine', formulations])].
[sujeto(['Anti-angiogenic', therapy, of, solid, tumors]), verbo([has]), complemento([until, now, failed, to, produce, the, long, lasting, clinical, benefits, 'desired,', possibly, due, to, the, complexity, of, the, neoangiogenic, process])].
[sujeto(['Moreover,', in, a, human, melanoma, xenograft, 'model,', the, combined, therapy, using, 'OC-46F2', and, 'L19-IL2,', an, immunocytokine, specific, for, the, tumor, 'angiogenic-associated', 'B-fibronectin', 'isoform(B-FN),']), verbo([led]), complemento([to, a, complete, inhibition, of, tumor, growth, until, day, 90, from, tumor, implantation, in, 71, '%', of, treated, 'mice,', with, statistically, significant, differences, compared, to, groups, treated, with, 'OC-46F2', or, 'L19-IL2', as, monotherapy])].
[sujeto(['Furthermore,', in, the, tumors, recovered, from, mice, treated, with, 'OC-46F2', either, as, monotherapy, or, in, combination, with, 'L19-IL2,', we, observed, a, dramatic]), verbo([decrease]), complemento([of, vascular, density, and, loss, of, 'VM', structures])].
[sujeto(['These', findings, indicate, for, the, first, time, a, role, of, 'syndecan-1', in, melanoma, 'VM', and, that]), verbo([targeting]), complemento(['syndecan-1,', together, with, 'B-FN,', could, be, promising, in, improving, the, treatment, of, metastatic, melanoma])].
[sujeto(['Recently,', we]), verbo([have]), complemento([shown, that, radiotherapy, '(', 'RT)', combined, with, 'L19-IL2', can, induce, a, 'long-lasting', antitumor, 'effect,', dependent, on, 'ED-B', expression, and, infiltration, of, cytotoxic, 'T', cells])].
[sujeto(['These', findings, will, be]), verbo([translated]), complemento([to, a, 'Phase', 'I', clinical, study, '(', 'NCT02086721)', in, patients, with, oligometastatic, solid, tumors])].
[sujeto(['Recently,', we]), verbo([have]), complemento([shown, that, radiotherapy, '(', 'RT)', combined, with, the, immunocytokine, 'L19-IL2', can, induce, 'long-lasting', antitumour, 'effects,', dependent, on, 'ED-B', expression, and, infiltration, of, cytotoxic, 'T', cells])].
[sujeto(['On', the, other, 'hand,', in, certain, 'tumours,', 'IL2', treatment, can]), verbo([trigger]), complemento([a, natural, killer, cell, '(', 'NK)', immune, response])].
[sujeto(['The', intratumoral, injection, of, 'cytokines,', in, particular, 'IL2,']), verbo([has]), complemento([shown, promise, for, cutaneous, melanoma, patients, with, unresectable, disease, or, continuous, recurrence, despite, surgery])].
[sujeto(['We', recently]), verbo([reported]), complemento([that, the, intralesional, injection, of, 'L19-IL2,', an, immunocytokine, combining, 'IL2', and, the, human, monoclonal, antibody, fragment, 'L19,', resulted, in, efficient, regional, control, of, disease, 'progression,', increased, time, to, distant, metastasis, and, evidence, of, effect, on, circulating, immune, cell, populations])].
[sujeto(['We']), verbo([have]), complemento([also, shown, in, preclinical, models, of, cancer, a, remarkable, synergistic, effect, of, the, combination, of, 'L19-IL2', with, 'L19-TNF,', a, second, 'clinical-stage', 'immunocytokine,', based, on, the, same, 'L19', antibody, fused, to, 'TNF'])].
[sujeto(['There', is]), verbo([increasing]), complemento([interest, in, the, 'site-directed', pharmacodelivery, of, therapeutic, payloads, to, the, tumor, site, using, antibodies, as, transport, vehicles])].
[sujeto(['Here,', we, investigated, the, efficacy, of, 'L19-IL2,', an, 'antibody-cytokine', fusion, protein, that, specifically, delivers, 'IL-2', to, the, tumor, site, by, homing, to, the, 'extra-domain', 'B', of, fibronectin, '(', 'EDB-Fn)']), verbo([expressed]), complemento([on, 'tumor-associated', blood, 'vessels,', against, mantle, cell, lymphoma, '(', 'MCL)', in, mice])].
[sujeto(['L19-IL2', was, shown, to, selectively, localize, at, lymphoma, lesions, in, vivo, and, to]), verbo([mediate]), complemento([significant, lymphoma, growth, 'retardation,', which, was, potentiated, by, 'co-administration', of, the, 'anti-CD20', antibody, rituximab])].
[sujeto(['When', 'co-injected', with, 'rituximab,', 'L19-IL2']), verbo([induced]), complemento([complete, remissions, of, localized, 'MCL', xenografts, in, 6, /, 8, mice, '(', 75, '%', ')', ',', whereas, the, combination, of, rituximab, and, equivalent, doses, of, 'non-targeted', 'IL-2', only, slightly, delayed, tumor, growth])].
[sujeto(['Collectively,', these, results]), verbo([provide]), complemento([the, scientific, rationale, for, the, clinical, evaluation, of, 'L19-IL2', in, combination, with, 'anti-CD20', immunotherapy, in, patients, with, 'MCL'])].
[sujeto(['In', order, to]), verbo([enhance]), complemento([the, specificity, of, 'TNF-α', monoclonal, antibody, to, inflamed, 'site,', a, bispecific, antibody, 'BsDb', that, targets, 'TNF-α', and, the, 'extra-domain', 'B', '(', 'ED-B)', of, fibronectin, '(', 'FN)', was, constructed, by, covalently, linking, the, 'anti-TNF-α', single, chain, 'Fv', antibody, '(', 'TNF-scFv)', and, the, 'anti-ED-B', scFv, 'L19', via, a, flexible, peptide, linker, deriving, from, human, serum, albumin, '(', 'HSA)'])].
[sujeto(['ED-B', is, an, antigen, specifically]), verbo([expressed]), complemento([at, the, inflamed, site])].
[sujeto(['BsDb', is]), verbo([expressed]), complemento([in, 'E'])].
[sujeto(['We', demonstrated, that, 'BsDb']), verbo([retained]), complemento([the, immunoreactivity, of, its, original, antibodies, as, it, could, simultaneously, bind, to, 'TNF-α', and, 'ED-B', and, neutralize, the, biological, action, of, 'TNF-α'])].
[sujeto(['In', the, 'collagen-induced', arthritis, mice, 'model,', 'BsDb', selectively, accumulate, in, the, inflamed, joint, with, a, maximal, uptake, of, '(', 12.2, ±, 1.5, ')', '%', 'ID/g', in, a, single, inflamed, paw, and]), verbo([retain]), complemento([in, the, inflamed, paw, for, at, least, 72, h])].
[sujeto(['The', findings]), verbo([reported]), complemento([herein, indicate, that, 'BsDb', has, good, specificity, to, the, inflamed, site, and, low, toxicity, to, normal, tissues])].
[sujeto(['BsDb', is, therefore, likely, to]), verbo([have]), complemento([greater, clinical, applications, in, the, treatment, of, rheumatoid, arthritis, and, other, autoimmune, diseases])].
[sujeto(['We']), verbo([report]), complemento([the, sequence, of, an, 18, ',', 2, bp, 'DNA', fragment, from, the, right, arm, of, 'Saccharomyces', cerevisiae, chromosome, 'XI'])].
[sujeto(['The', interplay, between, copy, number, variation, '(', 'CNV)', and, differential, gene, expression, may, be, able, to, shed, light, on, molecular, process, underlying, breast, cancer, and]), verbo([lead]), complemento([to, the, discovery, of, 'cancer-related', genes])].
[sujeto(['We', used, these, genes, to, derive, signatures]), verbo([associated]), complemento([with, clinical, 'ER', and, 'HER2', status, and, 'disease-free', survival])].
[sujeto(['Processed', pseudogenes, '(', 'PPs)', are, reverse]), verbo([transcribed]), complemento([from, mRNAs])].
[sujeto(['Recent', molecular, biological, studies, show, that, mammalian, long, interspersed, element, 1, '(', 'L1)-encoded', proteins, may]), verbo([have]), complemento([been, involved, in, 'PP', reverse, transcription])].
[sujeto(['These', data]), verbo([suggest]), complemento([a, nearly, simultaneous, burst, of, 'PP', and, 'Alu', formation, in, the, genomes, of, ancestral, primates])].
[sujeto(['We']), verbo([suggest]), complemento([that, a, burst, of, formation, of, 'PPs', and, 'Alus', occurred, in, the, genome, of, ancestral, primates])].
[sujeto(['One', possible, mechanism, is, that, proteins, encoded, by, members, of, particular, 'L1', subfamilies, acquired, an]), verbo([enhanced]), complemento([ability, to, recognize, cytosolic, 'RNAs', in, trans])].
[sujeto(['In', the, present, 'study,', we]), verbo([have]), complemento([cloned, and, characterized, the, 'Hu-Surf5', gene, and, its, mRNA, multiple, transcripts])].
[sujeto(['Here,', we, show, that, this, region]), verbo([stimulates]), complemento([transcription, with, a, slightly, different, efficiency, in, both, directions])].
[sujeto(['Two', protein, 'products,', 'SURF-5A', and, 'SURF-5B']), verbo([have]), complemento([been, characterized])].
[sujeto(['The', genomic, fragment, carrying, the, human, activator, of, liver, 'function,', previously, described, as, an, episome, capable, of]), verbo([inducing]), complemento([differentiation, upon, transfection, into, a, dedifferentiated, rat, hepatoma, cell, 'line,', was, mapped, on, human, chromosome, 12, q24])].
[sujeto(['Cancer', cell, secretome, profiling]), verbo([has]), complemento([been, shown, to, be, a, promising, strategy, for, identifying, potential, body, 'fluid-accessible', cancer, biomarkers, and, therapeutic, targets])].
[sujeto(['However,', very, few]), verbo([reports]), complemento([have, investigated, 'low-molecular-mass', '(', 'LMr)', proteins, '(', &, 'lt;15kDa)', in, the, cancer, cell, secretome])].
[sujeto(['We', verified, the, overexpression, of, four]), verbo([targets]), complemento(['(', 'LSM2,', 'SUMO1,', 'RPL22,', and, 'CCL5)', in, 'NPC', tissues, by, immunohistochemistry, and, demonstrated, elevated, plasma, levels, of, two, targets, '(', 'S100A2', and, 'CCL5)', in, 'NPC', patients, by, 'ELISA'])].
[sujeto(['Additionally,', functional, assays, revealed, that, 'CCL5']), verbo([promoted]), complemento([migration, of, 'NPC', 'cells,', an, effect, that, was, effectively, blocked, by, 'CCL5-neutralizing', antibodies, and, 'maraviroc,', a, 'CCL5', receptor, antagonist])].
[sujeto(['Collectively,', our, data, indicate, the, feasibility, of, the, 'tricine-SDS-gel/LC-MS/MS', approach, for, efficient, identification, of, 'LMr', proteins, from, cancer, cell, 'secretomes,', and]), verbo([suggest]), complemento([that, 'CCL5', is, a, potential, plasma, biomarker, and, therapeutic, target, for, 'NPC'])].
[sujeto(['Our', present, study]), verbo([provides]), complemento([evidence, for, the, practicality, of, using, the, 'tricine-SDS-PAGE/LC-MS/MS', approach, for, 'in-depth', identification, of, 'LMr', proteins, from, the, 'NPC', cell, 'secretomes,', leading, to, the, discovery, of, 'CCL5', as, a, potential, plasma, biomarker, and, therapeutic, target, for, 'NPC'])].
[sujeto(['Bioinformatics:', 'Enrichment', 'Analysis:', 'The', three, most, affected, pathways, differentially]), verbo([expressed]), complemento([in, rejection, versus, a, pool, of, healthy, volunteers, were, related, to, protein, 'translation:', translation, 'initiation,', translation, elongation, 'termination,', and, translation, in, 'mitochondria,', with, 'p-values', for, all, rejection, stages, in, all, patients, in, the, 10, -, 4, to, 10, -, 18, range])].
[sujeto(['The', level, of, enrichment, was, very, high, '(', 'p-values', of, 10, -, 5, -, 10, -, 60, ')', and]), verbo([increased]), complemento([with, the, level, of, rejection, in, all, patients])].
[sujeto(['In', this, pilot, study, we]), verbo([found]), complemento([a, list, of, genes, '(', involved, in, 'translation)', significantly, downregulated, in, the, peripheral, blood, of, three, intestinal, transplant, patients, during, rejection])].
[sujeto(['These', results, will, be, verified, in, further, studies, with]), verbo([increased]), complemento([number, of, patients, and, with, isolation, of, peripheral, blood, subpopulations])].
[sujeto(['To', identify, proteins, that, can]), verbo([bind]), complemento([the, 3, '\'', untranslated, region, '(', 'UTR)', of, hepatitis, 'C', virus, '(', 'HCV)', we, screened, human, cDNA, libraries, using, the, 'Saccharomyces', cerevisiae, 'three-hybrid', system])].
[sujeto(['We', performed, preliminary, characterization, of, the]), verbo([binding]), complemento([between, the, 3, '\'', 'X', region, and, these, proteins, by, a, 'three-hybrid', mating, assay, using, mutant, 3, '\'', 'X', sequences])].
[sujeto(['We']), verbo([have]), complemento([further, characterized, the, interaction, between, 3, '\'', 'X', and, 'L22,', since, this, protein, is, known, to, be, associated, with, two, small, 'Epstein-Barr', virus, '(', 'EBV)-encoded', 'RNA', species, '(', 'EBERs)', which, are, abundantly, produced, in, cells, latently, infected, with, 'EBV'])].
[sujeto(['The', 'EBERs,', which]), verbo([have]), complemento([similar, predicted, secondary, structure, to, the, 'HCV', 3, '\'', 'X,', assemble, into, ribonucleoprotein, particles, that, include, 'L22', and, 'La', protein])].
[sujeto(['To', confirm, that, 'L22']), verbo([binds]), complemento(['HCV', 3, '\'', 'X', we, performed, in, vitro, binding, assays, using, recombinant, 'L22', '(', expressed, as, a, glutathione, 'S-transferase', '[', 'GST]', fusion, 'protein)', together, with, a, 3, '\'', 'X', riboprobe])].
[sujeto(['The', 3, '\'', 'X', region]), verbo([binds]), complemento([to, the, 'GST-L22', fusion, protein, '(', but, not, to, 'GST', 'alone),', and, this, interaction, is, subject, to, competition, with, unlabeled, 3, '\'', 'X', 'RNA'])].
[sujeto(['The', relative, amount, of, 'core-chloramphenicol', acetyltransferase, reporter, protein]), verbo([translated]), complemento([under, the, control, of, the, 'HCV', 'IRES', was, stimulated, in, the, presence, of, 'L22', and, 'La', when, these, proteins, were, supplied, in, trans])].
[sujeto(['Amino', acid, deprivation, of, rat, hepatoma, cells]), verbo([induced]), complemento([the, levels, of, a, 612, -, base, pair, mRNA, termed, 'ASI', '(', 'Shay,', 'N'])].
[sujeto(['The', corresponding, 'full-length', cDNA, was, 'cloned,', and, the, present]), verbo([report]), complemento([demonstrates, that, the, deduced, 184, -, residue, amino, acid, sequence, shares, greater, than, 30, '%', identity, to, a, number, of, bacterial, and, chloroplast, 'L22', ribosomal, 'proteins,', including, those, from, 'Escherichia', coli, and, 'Halobacterium', halobium])].
[sujeto(['A', monospecific, 'anti-peptide', antibody, was, produced, that, upon, immunochemical, analysis, of, subcellular, fractions, of, rat, liver]), verbo([recognized]), complemento([a, band, in, the, microsomal, fraction, 'and,', more, 'specifically,', reacted, with, a, single, polypeptide, in, the, ribosomal, large, subunit, fraction])].
[sujeto(['The', antibody, did, not, react, with, any, proteins, of, the, mitochondrial, large, 'subunit,', but, did]), verbo([recognize]), complemento([a, protein, in, human, liver, homogenate, at, the, same, relative, mobility, '(', 23, 'kDa)', as, that, observed, for, rat, liver])].
[sujeto(['Previous', studies]), verbo([have]), complemento([revealed, that, ribosomal, protein, 'L23', '(', 'RPL23)', inhibits, 'MDM2-mediated', p53, degradation, through, direct, binding, to, 'MDM2'])].
[sujeto(['In', 'addition,', ectopically]), verbo([expressed]), complemento(['RPL23', was, reported, to, interact, with, 'MDM2', in, both, the, nucleus, and, 'cytoplasm,', by, which, 'RPL23', indirectly, inhibited, 'MDM2-p53', binding])].
[sujeto(['To', test, this, 'hypothesis,', we, constructed, a, bicistronic, adenoviral, vector]), verbo([expressing]), complemento([both, the, 'RPL23', and, p53, genes, '(', 'Ad-RPL23/p53)', and, compared, its, 'tumor-suppressor', activity, in, human, gastric, cancer, with, that, of, a, single, gene, vector, for, p53, '(', 'Ad-p53)'])].
[sujeto(['Furthermore,', in, an, orthotopic, nude, mouse, model, of, human, gastric, 'cancer,', we]), verbo([found]), complemento([that, the, survival, benefit, was, greater, after, 'Ad-RPL23/p53', treatment, than, after, 'Ad-p53'])].
[sujeto(['Taken', 'together,', the, data, presented, here, demonstrate, that, 'co-transduction', of, 'RPL23']), verbo([enhances]), complemento([the, therapeutic, efficacy, of, 'adenoviral-mediated', p53, gene, transfer, in, models, of, human, gastric, cancer, and, support, the, use, of, this, strategy, for, cancer, treatment])].
[sujeto(['The', 'carboxy-terminal', 'mitochondrial-specific', domain, of, 'Mrp20', was]), verbo([found]), complemento([to, have, a, crucial, role, in, the, assembly, of, the, ribosomes])].
[sujeto(['Finally,', data, supporting, the, idea, that, the, inner, mitochondrial, membrane]), verbo([acts]), complemento([as, a, platform, for, the, ribosome, assembly, process, are, discussed])].
[sujeto(['Approximately', 640, spots, were, detected, on, proteome, map, of, the, 'second-generation', merozoite, stained, by, 'Coomassie', brilliant, blue, 'G-250', and, 85, spots, were]), verbo([recognized]), complemento([on, western, blot, map, as, antigens])].
[sujeto(['Here', we, present, the, structures, of, both, 'Escherichia', coli, 'YidC', and, 'Saccharomyces', cerevisiae, 'Oxa1']), verbo([bound]), complemento([to, 'E'])].
[sujeto(['Functionally', important, and]), verbo([conserved]), complemento([transmembrane, helices, of, 'YidC', and, 'Oxa1', were, localized, at, the, dimer, interface, by, cysteine, crosslinking])].
[sujeto(['Both', 'Oxa1', and, 'YidC', dimers, contact, the, ribosome, at, ribosomal, protein, 'L23', and]), verbo([conserved]), complemento([rRNA, helices, 59, and, 24, ',', similarly, to, what, was, observed, for, the, nonhomologous, 'SecYEG', translocon])].
[sujeto(['We']), verbo([suggest]), complemento([that, dimers, of, the, 'YidC', and, 'Oxa1', proteins, form, insertion, pores, and, share, a, common, overall, architecture, with, the, 'SecY', monomer])].
[sujeto(['Nucleolar', disassembly, occurs, during, mitosis, and, nucleolar, 'stress,']), verbo([releasing]), complemento([several, 'MDM2-interactive', proteins, residing, in, the, nucleolus, that, share, the, common, activity, of, p53, stabilization])].
[sujeto(['Here,', we, demonstrate, that, mobilization, of, 'nucleostemin,', a, nucleolar, protein, enriched, in, cancer, and, stem, 'cells,']), verbo([has]), complemento([the, opposite, role, of, stabilizing, 'MDM2', and, suppressing, p53, functions])].
[sujeto(['Our', results, show, that, nucleostemin]), verbo([increases]), complemento([the, protein, stability, and, nucleoplasmic, retention, of, 'MDM2,', and, competes, with, 'L23', for, 'MDM2', binding])].
[sujeto(['These', activities, were, significantly, elevated, when, nucleostemin, is]), verbo([released]), complemento([into, the, nucleoplasm, by, mutations, that, abolish, its, nucleolar, localization, or, by, chemotherapeutic, agents, that, disassemble, the, nucleoli])].
[sujeto(['Nucleostemin', depletion]), verbo([decreases]), complemento(['MDM2', 'protein,', increases, transcription, activity, without, affecting, the, level, of, p53, 'protein,', and, triggers, 'G2-M', arrest, and, cell, death, in, 'U2OS', cells, but, not, in, 'H1299', cells])].
[sujeto(['This', work]), verbo([reveals]), complemento([that, nucleoplasmic, relocation, of, nucleostemin, during, nucleolar, disassembly, safeguards, the, 'G2-M', transit, and, survival, of, continuously, dividing, cells, by, 'MDM2', stabilization, and, p53, inhibition])].
[sujeto(['The', 'anti-tumor', activity, of, 5, -, 'FU']), verbo([has]), complemento([been, attributed, in, part, to, its, ability, to, induce, 'p53-dependent', cell, growth, arrest, and, apoptosis])].
[sujeto(['Here', we]), verbo([report]), complemento([that, 5, -, 'FU', treatment, leads, to, p53, stabilization, and, activation, by, blocking, 'MDM2', feedback, inhibition, through, ribosomal, proteins])].
[sujeto([5, -, 'FU', treatment]), verbo([increased]), complemento([the, fraction, of, 'ribosome-free', 'L5,', 'L11,', and, 'L23', ribosomal, proteins, and, their, interaction, with, 'MDM2,', leading, to, p53, activation, and, 'G1/S', arrest])].
[sujeto(['Conversely,', individual, knockdown, of, these, ribosomal, proteins, by, small, interfering, 'RNA']), verbo([prevented]), complemento([the, 5, -, 'FU-induced', p53, activation, and, reversed, the, 5, -, 'FU-induced', 'G1/S', arrest])].
[sujeto(['These', results, demonstrate, that, 5, -, 'FU', treatment]), verbo([triggers]), complemento([a, ribosomal, stress, response, so, that, ribosomal, proteins, 'L5,', 'L11,', and, 'L23', are, released, from, ribosome, to, activate, p53, by, ablating, the, 'MDM2-p53', feedback, circuit])].
[sujeto(['One', clone, '(', 46, -, 5, ')', was, selected, randomly, and, subjected, to, in, vivo, excision, of, the, 'pBK-CMV', phagemid, from, the, 'ZAP']), verbo([express]), complemento([vector])].
[sujeto(['A']), verbo([conserved]), complemento([domain, for, ribosomal, protein, 'L23', was, also, identified, in, the, clone, sequence])].
[sujeto(['The', oncoprotein, 'MDM2']), verbo([associates]), complemento([with, ribosomal, proteins, 'L5,', 'L11,', and, 'L23'])].
[sujeto(['Both', 'L11', and, 'L23']), verbo([have]), complemento([been, shown, to, activate, p53, by, inhibiting, 'MDM2-mediated', p53, suppression])].
[sujeto(['Here', we]), verbo([have]), complemento([shown, that, 'L5', also, activates, p53])].
[sujeto(['Consequently,', 'L5']), verbo([enhanced]), complemento([p53, transcriptional, activity, and, induced, 'p53-dependent', 'G1', cell, cycle, arrest])].
[sujeto(['Furthermore,', like, 'L11', and, 'L23,', 'L5', also, remarkably]), verbo([inhibited]), complemento(['MDM2-mediated', p53, ubiquitination])].
[sujeto(['The', interaction, of, 'L5', with, 'MDM2', was, also]), verbo([enhanced]), complemento([by, treatment, with, a, low, dose, of, actinomycin, 'D'])].
[sujeto(['Actinomycin', 'D-induced', p53, was]), verbo([inhibited]), complemento([by, small, interference, 'RNA', against, 'L5'])].
[sujeto(['We', propose, that, the, 'MDM2-L5-L11-L23', complex, functions, to]), verbo([inhibit]), complemento(['MDM2-mediated', p53, ubiquitination, and, thus, activates, p53])].
[sujeto(['To', understand, the, differentially]), verbo([expressed]), complemento([genes, in, human, 'T', lymphocytes, induced, by, arsenic, trioxide, '(', 'As(2)O(3))', and, to, explore, mechanism, of, its, immunotoxicity, and, immune, suppression])].
[sujeto(['Then,', the, differentially]), verbo([expressed]), complemento([genes, were, cloned, and, the, subtractive, cDNA, library, from, 'Jurkat', 'T', cell, line, was, constructed, by, suppression, subtractive, hybridization, '(', 'SSH)'])].
[sujeto(['The', forward, subtracted, cDNA, library, contained, differentially]), verbo([expressed]), complemento([genes, from, 'Jurkat', 'T', cell, line, induced, by, arsenic, trioxide, was, 'constructed,', including, 29, different, gene, fragments, and, only, replicated, one, in, the, subtracted, cDNA, library, identified, by, 'PCR', and, sequencing, analysis])].
[sujeto(['The', cDNA, library, contained, oxidative, metabolic, genes, in, mitochondria, '(', triose, phosphate, 'dehydrogenase,', 'NADH4,', pyrophosphate, 'synthase,', 16, 'S', rRNA, 'ribosome,', 'succinate-CoA', ligase, and, 'ATP', synthase, 6, ')', ;, transcriptional, and, translation, genes, poly, '(', 'A)']), verbo([binding]), complemento(['protein,', 't-RNA-guanine', 'transglycoslase,', ribosomal, protein, 'L23,', ribosomal, protein, 'S15A,', eukaryotic, translation, initiation, factor, 3, ',', 'Rab', interaction, protein, 5, ',', splicing, 'factor-arginine', serine, rich, 5, ',', and, 'ADP-ribosylation', 'factor-like', 6, interacting, 'protein),', oxide, stress, related, genes, '(', ferritin, high, chain, and, 'high-mobility', group, protein, 2, ')', ;, protein, activating, and, signaling, pathway, related, genes, '(', casein, 'kinase,', serine, kinase, 2, and, 'phosphatidylinositol-four-phosphate', adaptor, 'protein-1-associated', 'protein);', cell, differentiation, and, apoptosis, associated, genes, '(', 'NB4', cell, apoptosis, related, protein, and, myeloid, differentiation, primary, response, 'protein)', and, five, genes, with, unknown, function, '(', 'KIAA0092,', 'CGI-147protein,', 'GCI-35,', nucleolar, phosphoprotein, 'Nopp34', and, 'Mus', muscular, partial, mRNA, for, hypothetical, 'protein),', as, well, as, a, novel, gene, unmatched, to, the, sequence, in, 'GenBank'])].
[sujeto(['The', forward, subtracted, cDNA, library, contained, differentially]), verbo([expressed]), complemento([genes, from, 'Jurkat', 'T', cell, line, induced, by, arsenic, trioxide, was, successfully, constructed])].
[sujeto(['And,', genes, not]), verbo([involved]), complemento([in, previous, research, on, arsenic, were, found])].
[sujeto(['Results', of, analysis, for, these, genetic, function]), verbo([suggested]), complemento([that, there, should, be, many, genes, involved, in, process, of, 'T', lymphocytes, apoptosis, or, injury, induced, by, arsenic, trioxide, and, that, there, should, still, be, many, genes, associated, with, arsenic, that, were, not, reported, in, the, past])].
[sujeto(['The', yeast, mitochondrial, 'Oxa1', protein, is, a, member, of, the]), verbo([conserved]), complemento(['Oxa1/YidC/Alb3', protein, family, involved, in, the, membrane, insertion, of, proteins])].
[sujeto(['Oxa1']), verbo([mediates]), complemento([the, insertion, of, proteins, '(', nuclearly, and, mitochondrially, 'encoded)', into, the, inner, membrane])].
[sujeto(['The', mitochondrially, encoded, substrates]), verbo([interact]), complemento([directly, with, 'Oxa1', during, their, synthesis, as, nascent, chains, and, in, a, manner, that, is, supported, by, the, associated, ribosome])].
[sujeto(['We']), verbo([have]), complemento([investigated, if, the, 'Oxa1', complex, interacts, with, the, mitochondrial, ribosome])].
[sujeto(['We', propose, that, the, interaction, of, 'Oxa1', with, the, ribosome, serves, to]), verbo([enhance]), complemento([a, coupling, of, translation, and, membrane, insertion, events])].
[sujeto(['The', 'HUELLENLOS', '(', 'HLL)', gene]), verbo([participates]), complemento([in, patterning, and, growth, of, the, 'Arabidopsis', ovule])].
[sujeto(['We']), verbo([have]), complemento([isolated, the, 'HLL', gene, and, shown, that, it, encodes, a, protein, homologous, to, the, 'L14', proteins, of, eubacterial, ribosomes])].
[sujeto(['Our', elucidation, of, the, nature, of, 'HLL', shows, that, metabolic, defects, can]), verbo([have]), complemento([specific, effects, on, developmental, patterning])].
[sujeto(['We']), verbo([have]), complemento([cloned, and, characterized, its, mouse, 'homolog,', 'L23mrp,', which, maps, to, the, conserved, syntenic, region, on, mouse, chromosome, 7])].
[sujeto(['The', promoter, of, 'L23mrp', is, a, 'CpG', island, that, is]), verbo([transcribed]), complemento(['ubiquitously,', but, at, different, 'levels,', in, different, fetal, tissues])].
[sujeto(['Since', the, enhancers, located, between, 'H19', and, 'L23mrp', had, been, shown, to, be]), verbo([involved]), complemento([in, the, imprinted, expression, of, 'Ins-2,', 'Igf-2,', and, 'H19,', we, asked, whether, they, also, influence, 'L23mrp'])].
[sujeto(['Analysis', of, mice, with, a]), verbo([targeted]), complemento([deletion, of, the, enhancers, demonstrated, that, they, were, not, disrupted, in, the, expression, of, 'L23mrp'])].
[sujeto([5, are, monoallelically]), verbo([expressed]), complemento([as, a, result, of, genomic, imprinting, and, show, altered, expression, in, 'Wilms\'', tumors, '(', 'WTs)'])].
[sujeto(['To', map, regional, imprinting, we]), verbo([have]), complemento([sought, to, isolate, additional, human, genes, close, to, 'IGF2/H19', and, to, characterize, their, allelic, expression, patterns])].
[sujeto(['Here', we]), verbo([report]), complemento([a, novel, 'gene,', provisionally, named, 'L23MRP', '[', 'L23', '(', 'mitochondrial)-related', 'protein],', which, is, oriented, '\'', 'tail-to-tail\'', with, 'H19', and, is, transcribed, to, within, 40, kb, of, the, last, 'H19', exon])].
[sujeto(['L23MRP', is]), verbo([expressed]), complemento([biallelically, in, many, 'mid-fetal', and, adult, human, tissues])].
[sujeto(['This', gene, is, also]), verbo([expressed]), complemento([at, normal, levels, in, 'WTs', which, have, lost, expression, of, 'H19', either, via, loss, of, the, maternal, chromosome, 11, p15])].
[sujeto([5, or, via, an, epigenetic, pathway]), verbo([involving]), complemento(['site-specific', 'DNA', hypermethylation])].
[sujeto(['The', levels, of, the, mRNAs, and, proteins, for, both, 'MRP20', and, 'MRP49', were]), verbo([regulated]), complemento([in, response, to, carbon, source])].
[sujeto(['Inactivation', of, 'MRP49']), verbo([caused]), complemento([a, 'cold-sensitive', 'respiration-deficient', 'phenotype,', indicating, that, 'MRP49', is, not, an, essential, ribosomal, protein])].
[sujeto(['Because', both, ovarian, and, breast, cancer, are, 'hormone-related', and, are, known, to]), verbo([have]), complemento([some, predisposition, genes, in, 'common,', we, evaluated, 11, of, the, most, significant, hits, '(', six, with, confirmed, associations, with, breast, 'cancer)', from, the, breast, cancer, 'genome-wide', association, study, for, association, with, invasive, ovarian, cancer])].
[sujeto(['Initially,', three, 'SNPs', '(', rs2107425, in, 'MRPL23,', rs7313833, in, 'PTHLH,', rs3803662, in, 'TNRC9)', were, weakly]), verbo([associated]), complemento([with, ovarian, cancer, risk, and, one, 'SNP', '(', rs4954956, in, 'NXPH2)', was, associated, with, serous, ovarian, cancer, in, 'non-Hispanic', white, subjects, '(', 'P-trend', &, 'lt;', 0.1, ')'])].
[sujeto(['Only', rs4954956, was, significantly]), verbo([associated]), complemento([with, ovarian, cancer, risk, both, in, the, replication, study, and, in, combined, analyses])].
[sujeto(['In', 'conclusion,', we]), verbo([found]), complemento([that, rs4954956, was, associated, with, increased, ovarian, cancer, 'risk,', particularly, for, serous, ovarian, cancer])].
[sujeto(['However,', none, of, the, six, confirmed, breast, cancer, susceptibility, variants, we, tested, was]), verbo([associated]), complemento([with, ovarian, cancer, risk])].
[sujeto(['Further', work, will, be, needed, to, identify, the, causal, variant]), verbo([associated]), complemento([with, rs4954956, or, elucidate, its, function])].
[sujeto(['Thirty-five', genes]), verbo([involved]), complemento([in, 'DNA', 'repair/radiation', response, were, analyzed, in, patients, accrued, in, the, 'AIROPROS', 101, 'trial,', which, investigated, the, correlation, between, 'LRB', and, dosimetric, parameters])].
[sujeto(['To']), verbo([gain]), complemento([further, insight, into, the, pathogenesis, of, this, 'disease,', gene, expression, was, analysed, in, peripheral, blood, mononuclear, cells, from, 25, patients, with, 'CFS', diagnosed, according, to, the, 'Centers', for, 'Disease', 'Control', criteria, and, 25, normal, blood, donors, matched, for, 'age,', 'sex,', and, geographical, 'location,', using, a, single, colour, microarray, representing, 9522, human, genes])].
[sujeto(['This', profile]), verbo([suggests]), complemento(['T', cell, activation, and, perturbation, of, neuronal, and, mitochondrial, function])].
[sujeto(['Upregulation', of, neuropathy]), verbo([target]), complemento([esterase, and, eukaryotic, translation, initiation, factor, 4, 'G1', may, suggest, links, with, organophosphate, exposure, and, virus, 'infection,', respectively])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, patients, with, 'CFS', have, reproducible, alterations, in, gene, regulation])].
[sujeto(['Orthologues', of, these, genes, show]), verbo([conserved]), complemento([linkage, and, imprinting, on, distal, 'Chr', 7, of, mice])].
[sujeto(['The', extended, imprinted, region]), verbo([has]), complemento([a, bipartite, 'structure,', with, at, least, two, differentially, methylated, 'DNA', elements, '(', 'DMRs)', controlling, the, imprinting, of, two, 'sub-domains'])].
[sujeto(['We', previously, described, three, biallelically]), verbo([expressed]), complemento([genes, '(', 'MRPL23,', 2, 'G7', and, 'TNNT3)', in, 100, kb, of, 'DNA', immediately, downstream, of, the, imprinted, 'H19', 'gene,', suggesting, that, 'H19', marks, one, border, of, the, imprinted, region])].
[sujeto(['We']), verbo([find]), complemento([that, these, genes, are, biallelically, expressed, in, multiple, fetal, and, adult, 'tissues,', both, in, humans, and, in, mice])].
[sujeto(['The', mouse, orthologue, of, a, third, 'gene,', 'DUSP8,', located, between, 'H19', and, 'MUCDHL,', is, also]), verbo([expressed]), complemento([biallelically])].
[sujeto(['The', 'DMR', immediately, upstream, of, 'H19', frequently, shows, a, net]), verbo([gain]), complemento([of, methylation, in, 'Wilms', 'tumors,', either, via, 'Chr', 11, p15])].
[sujeto([5]), verbo([loss]), complemento([of, heterozygosity, '(', 'LOH)', or, loss, of, imprinting, '(', 'LOI),', but, changes, in, methylation, in, 'CpG-rich', sequences, upstream, and, within, the, 'MUCDHL', gene, are, rare, in, these, tumors, and, do, not, correlate, with, 'LOH', or, 'LOI'])].
[sujeto(['L23mrp', and, other, genes, located, 3, '\'', '(', more, 'centromeric)', to, 'H19', are, not, imprinted, and, do, not]), verbo([interact]), complemento([with, the, enhancers, shared, by, 'Igf2', and, 'H19'])].
[sujeto(['It', is, therefore]), verbo([suggested]), complemento([that, the, intergenic, region, between, 'H19', and, 'L23mrp', contains, a, boundary, or, an, insulator, element])].
[sujeto(['We']), verbo([have]), complemento([identified, a, binding, site, for, 'CTCF,', a, nuclear, factor, that, mediates, insulator, activity, in, 'vertebrates,', in, the, intergenic, region])].
[sujeto(['This', site, is]), verbo([conserved]), complemento([between, human, and, 'mouse,', associated, with, a, major, 'DNase', 'I-hypersensitive', 'site,', and, bound, by, 'CTCF', in, vivo])].
[sujeto(['The', findings]), verbo([suggest]), complemento([that, this, 'CTCF', site, contributes, to, the, 3, '\'', boundary, of, this, imprinted, domain])].
[sujeto(['Together', with, the, findings, on, the, differentially, methylated, 'CTCF', sites, 5, '\'', to, 'H19,', 'CTCF-dependent', insulators, may, not, only]), verbo([regulate]), complemento([but, also, delimit, the, imprinted, domain])].
[sujeto(['H19', is]), verbo([expressed]), complemento([almost, exclusively, from, the, maternally, inherited, 'chromosome,', while, 'Igf2', expression, is, mostly, from, the, paternal, chromosome])].
[sujeto(['In', 'humans,']), verbo([loss]), complemento([of, imprinting, at, this, locus, is, associated, with, tumors, and, with, developmental, disorders])].
[sujeto(['Monoallelic', expression, at, the, imprinted, 'Igf2/H19', locus, occurs, by, at, least, two, distinct, 'mechanisms:', a, developmentally]), verbo([regulated]), complemento([silencing, of, the, paternal, 'H19', 'promoter,', and, transcriptional, insulation, of, the, maternal, 'Igf2', promoters])].
[sujeto(['Second,', we, used, this, new, information, to, further, characterize, an, ectopic, 'H19', differentially]), verbo([regulated]), complemento([region, and, the, associated, insulator])].
[sujeto(['Data']), verbo([suggests]), complemento([that, common, elements, are, used, for, expression, and, imprinting, of, both, 'genes,', and, simple, models, have, been, proposed, based, on, the, presence, of, a, single, set, of, enhancers, located, downstream, of, 'H19'])].
[sujeto(['In', this, study, we]), verbo([have]), complemento([investigated, the, 'H19', expression, pattern, from, a, 130, kb, 'YAC', 'transgene,', which, imprints, 'H19', appropriately, at, ectopic, loci])].
[sujeto(['Based', on, the, available, 'evidence,', we, conclude, that, regulation, of, 'H19', is, 'complex,']), verbo([requiring]), complemento([contribution, from, at, least, three, different, sets, of, 'cell-type', specific, enhancers])].
[sujeto(['Their', linked, organization]), verbo([suggests]), complemento(['co-ordinated', mechanisms, controlling, imprinting, and, gene, expression])].
[sujeto(['The', identification, of, local, and, regional, elements, responsible, for, the, epigenetic, control, of, imprinted, gene, expression, will, be, important, in, understanding, the, molecular, basis, of, diseases]), verbo([associated]), complemento([with, imprinting, such, as, 'Beckwith-Wiedemann', syndrome])].
[sujeto(['We']), verbo([have]), complemento([established, a, complete, contig, of, clones, along, the, murine, imprinting, cluster, on, distal, chromosome, 7, syntenic, with, the, human, imprinting, region, at, 11, p15])].
[sujeto([5]), verbo([associated]), complemento([with, 'Beckwith-Wiedemann', syndrome])].
[sujeto(['The', cluster, comprises, approximately, 1, 'Mb', of, 'DNA,', contains, at, least, eight, imprinted, genes, and, is, demarcated, by, the, two, maternally]), verbo([expressed]), complemento([genes, 'Tssc3', '(', 'Ipl)', and, 'H19', which, are, directly, flanked, by, the, 'non-imprinted', genes, 'Nap1l4', '(', 'Nap2)', and, 'Rpl23l', '(', 'L23mrp),', respectively])].
[sujeto(['The', mouse, 'Kcnq1', gene, is, maternally]), verbo([expressed]), complemento([in, most, fetal, but, biallelically, transcribed, in, most, neonatal, 'tissues,', suggesting, relaxation, of, imprinting, during, development])].
[sujeto(['Our', findings, indicate]), verbo([conserved]), complemento([control, mechanisms, between, mouse, and, 'human,', but, also, reveal, some, structural, and, functional, differences])].
[sujeto(['Our', study, opens, the, way, for, a, systematic, analysis, of, the, cluster, by, genetic, manipulation, in, the, mouse, which, will]), verbo([lead]), complemento([to, animal, models, of, 'Beckwith-Wiedemann', syndrome, and, childhood, tumours])].
[sujeto(['We']), verbo([have]), complemento([constructed, a, 1, -, 'Mb', contig, in, human, chromosomal, band, 11, p15])].
[sujeto(['However,', 'Northern', blot, analysis, demonstrated, that, its, expression, did, not, correlate, with, tumorigenicity, in, 'G401', 'Wilms', tumor, 'hybrids,']), verbo([suggesting]), complemento([that, 'TAPA1', is, not, responsible, for, the, tumor, suppression, associated, with, 11, p15])].
[sujeto([5, contains, several, genes, with, imprinted, expression, and, one, or, more, tumor, suppressor, 'genes,', our, contig, and, map]), verbo([provide]), complemento([a, framework, for, characterizing, this, intriguing, genetic, environment])].
[sujeto(['There', is]), verbo([increasing]), complemento([evidence, for, chromosomal, domains, containing, multiple, imprinted, genes, and, for, 'domain-wide', disruption, of, imprinting, in, certain, diseases])].
[sujeto(['Here', we, map, two, additional, 'genes,', the, first, encoding, a, ubiquitously]), verbo([expressed]), complemento(['RNA,', 2, 'G7,', and, the, second, encoding, the, fast, isoform, of, skeletal, muscle, 'troponin-T', '(', 'TNNT3),', in, the, 55, kb, of, 'DNA', downstream, of, 'L23MRP'])].
[sujeto([2, 'G7', and, 'TNNT3', are, biallelically]), verbo([expressed]), complemento([in, 'mid-fetal', and, adult, human, tissues, and, 2, 'G7', shows, persistent, expression, in, 'WTs'])].
[sujeto(['The', rat, homologue, of, 'L23MRP', is, highly]), verbo([conserved]), complemento([and, lies, within, 85, kb, of, 'H19', in, a, region, of, rat, chromosome, 1, which, also, contains, 'IGF2', and, 'TNNT3'])].
[sujeto(['Parallel', expression, of, 'H19', and, 'TNNT3', in, different, adult, skeletal, muscle, types]), verbo([suggests]), complemento([that, these, genes, may, share, an, enhancer])].
[sujeto(['However,', precise, information, regarding, long, 'RNAs', in, salivary, exosomes]), verbo([has]), complemento([not, been, fully, determined])].
[sujeto(['Translationally', controlled, tumor, protein, 'gene,', which, plays, an, important, role, in, cell, 'proliferation,', cell, death, and, immune, 'responses,', was, highly]), verbo([expressed]), complemento([as, pcRNA, and, pseudogenes, in, salivary, exosomes])].
[sujeto(['Our', results, show, that, salivary, exosomes, contain, various, types, of, 'RNAs', such, as, pseudogenes, and, small, 'RNAs,', and, may]), verbo([mediate]), complemento([intercellular, communication, by, transferring, these, 'RNAs', to, target, cells, as, gene, expression, regulators])].
[sujeto(['jujuba,', the, first, member, of, the, 'Rhamnaceae', family, for, which, the, chloroplast, genome, sequence]), verbo([has]), complemento([been, reported])].
[sujeto(['Sequence', analysis, showed, that, this, cp, genome, is, 161, ',', 466, &, 'nbsp;bp', long, and]), verbo([has]), complemento([a, typical, quadripartite, structure, of, large, '(', 'LSC,', 89, ',', 120, &, 'nbsp;bp)', and, small, '(', 'SSC,', 19, ',', 348, &, 'nbsp;bp)', 'single-copy', regions, separated, by, a, pair, of, inverted, repeats, '(', 'IRs,', 26, ',', 499, &, 'nbsp;bp)'])].
[sujeto(['One-third', of, mononucleotide, repeats, were]), verbo([found]), complemento([to, be, erroneously, sequenced, by, the, 454, 'pyrosequencing,', which, resulted, in, sequences, of, 1, -, 4, bases, shorter, than, that, by, the, 'Sanger', sequencing])].
[sujeto(['Although', many, efforts]), verbo([have]), complemento([recently, contributed, to, improve, our, knowledge, of, molecular, pathogenesis, of, multiple, myeloma, '(', 'MM),', the, role, and, significance, of, long, 'non-coding', 'RNAs', '(', 'lncRNAs)', in, plasma, cells, '(', 'PC)', malignancies, remains, virtually, absent])].
[sujeto(['Our', study, identified, 31, lncRNAs, deregulated, in, tumor, samples, compared, to, normal, 'controls;', among, 'these,', the, upregulation, of, 'MALAT1', appeared]), verbo([associated]), complemento([in, 'MM', patients, with, molecular, pathways, involving, cell, cycle, 'regulation,', 'p53-mediated', 'DNA', damage, 'response,', and, mRNA, maturation, processes])].
[sujeto(['Furthermore,', we]), verbo([found]), complemento([21, lncRNAs, whose, expression, were, progressively, deregulated, trough, the, more, aggressive, stages, of, 'PC', 'dyscrasia,', suggesting, a, possible, role, in, the, progression, of, the, disease])].
[sujeto(['Overall,', the, data]), verbo([provides]), complemento([an, important, resource, for, future, studies, on, the, functions, of, lncRNAs, in, the, pathology])].
[sujeto(['Strain', 'CIRM-BIA129', '(', commercially, available, as, 'ITG', 'P20)']), verbo([has]), complemento([considerable, 'anti-inflammatory', potential])].
[sujeto(['Molecular', genetics, approaches, in, 'Phytophthora', research, can, be, hampered, by, the, limited, number, of, known, constitutive, promoters, for]), verbo([expressing]), complemento([transgenes, and, the, instability, of, transgene, activity])].
[sujeto(['We']), verbo([have]), complemento([therefore, characterized, genes, encoding, the, cytoplasmic, ribosomal, proteins, of, 'Phytophthora', and, studied, their, suitability, for, expressing, transgenes, in, 'P'])].
[sujeto(['Half', of, the, genes, are]), verbo([expressed]), complemento([at, similar, levels, during, all, stages, of, asexual, 'development,', and, we, discovered, that, the, majority, share, a, novel, promoter, motif, named, the, 'PhRiboBox'])].
[sujeto(['This', sequence, is, enriched, in, genes]), verbo([associated]), complemento([with, 'transcription,', 'translation,', and, 'DNA', 'replication,', including, tRNA, and, rRNA, biogenesis])].
[sujeto([capsici, orthologs]), verbo([conferred]), complemento([stable, expression])].
[sujeto(['Since', 'cross-talk', between, native, and, transgene, loci, may]), verbo([trigger]), complemento([gene, 'silencing,', we, encourage, the, use, of, heterologous, promoters, in, transformation, studies])].
[sujeto(['When', the, cp, genome, of, 'Dianthus', was, compared, with, 31, other, angiosperm, 'lineages,', the, infA, gene, was]), verbo([found]), complemento([to, have, been, lost, in, most, members, of, 'rosids,', solanales, of, asterids, and, 'Lychnis', of, 'Caryophyllales,', whereas, rpl23, gene, loss, or, pseudogization, had, occurred, exclusively, in, 'Caryophyllales'])].
[sujeto(['Nevertheless,', the, cp, genome, of, 'Dianthus', and, 'Spinacia']), verbo([has]), complemento([two, introns, in, the, proteolytic, subunit, of, 'ATP-dependent', protease, '(', 'clpP)', 'gene,', but, 'Lychnis', has, lost, introns, from, the, clpP, gene])].
[sujeto(['Furthermore,', phylogenetic, analysis, of, individual, 'protein-coding', genes, infA, and, rpl23, revealed, that, gene]), verbo([loss]), complemento([or, pseudogenization, occurred, independently, in, the, cp, genome, of, 'Dianthus'])].
[sujeto(['The', specificity, of, many, gonococcal, 'NAATs']), verbo([has]), complemento([been, suboptimal, and, supplementary, testing, remains, recommended, in, 'Europe', and, several, additional, countries])].
[sujeto(['The', novel, 'dual-target', 'GeneProof', 'Neisseria', gonorrhoeae, 'PCR', 'kit,']), verbo([targeting]), complemento([porA, pseudogene, and, 16, 'S', rRNA, 'gene,', showed, a, high, specificity, and, sensitivity, when, isolates, of, 'non-gonococcal', 'Neisseria', and, related, species, '(', n, =, 144, ')', ',', and, gonococci, '(', n, =, 104, ')', were, tested])].
[sujeto(['However,', rare, gonococcal, porA, mutants, were, only, detected, in, the, 16, 'S', rRNA, gene]), verbo([target]), complemento([and, two, 'non-gonococcal', isolates, showed, a, 'low-level', 'cross-reactivity', in, the, 16, 'S', rRNA, gene, target])].
[sujeto(['The', detection, limit, for, both]), verbo([targets]), complemento([was, 1.5, copies, per, reaction])].
[sujeto(['In', many, 'lineages,', the, mitochondrial, copy, was, subsequently, lost, or, 'pseudogenized,', although, in, rice, it, was]), verbo([retained]), complemento([and, the, nuclear, copy, lost])].
[sujeto(['We']), verbo([have]), complemento([now, determined, that, functional, rps19, genes, are, present, in, both, the, mitochondrion, and, nucleus, in, brome, grass, '(', 'Bromus', 'inermis)'])].
[sujeto(['The', 'mitochondrion-located', rps19, 'gene,', which, is, immediately, downstream, of, an, rpl2, 'pseudogene,', is]), verbo([transcribed]), complemento([and, edited])].
[sujeto(['The', 'nuclear-located', rps19, gene, is, also, actively]), verbo([expressed]), complemento([and, it, possesses, the, same, 'intron-containing', 'hsp70-type', presequence, as, its, counterparts, in, other, 'grasses,', as, well, as, shared, derived, amino, acids, within, the, 'S19', core])].
[sujeto(['In', the, oat, 'lineage,', a, subsequent, exon, 'shuffling-type', event]), verbo([has]), complemento([resulted, in, novel, 'amino-terminal', sequences, replacing, part, of, the, hsp70, 'presequence,', and, in, the, barley, 'lineage,', there, has, been, an, additional, 'DNA-mediated', transfer, of, the, mitochondrial, rps19, gene, and, its, flanking, 'sequences,', followed, by, relatively, recent, loss, of, the, 'mitochondrion-located', copy])].
[sujeto(['The', risk, of, tendon, injury, and, disease]), verbo([increases]), complemento([significantly, with, increasing, age])].
[sujeto(['Differentially']), verbo([expressed]), complemento([genes, were, defined, by, using, 'Benjamini-Hochberg', false, discovery, rate, approach, '(', 'P<0'])].
[sujeto(['In', 'total,', the, expression, of, 325]), verbo([transcribed]), complemento(['elements,', including, 'protein-coding', transcripts, and, 'non-coding', transcripts, '(', small, 'non-coding', 'RNAs,', 'pseudogenes,', long, 'non-coding', 'RNAs', and, a, single, 'microRNA),', was, significantly, different, in, old, compared, with, young, tendon, '(', '±1'])].
[sujeto(['The', top, networks, for, genes, differentially]), verbo([expressed]), complemento([with, tendon, age, were, from, cellular, 'function,', cellular, 'growth,', and, cellular, cycling, pathways])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, ageing, is, not, primarily, associated, with, loss, of, ability, to, synthesise, matrix, proteins, and, 'matrix-degrading', enzymes])].
[sujeto(['In', 'addition,', we]), verbo([have]), complemento([identified, 'non-coding', 'RNA', genes, and, differentially, expressed, transcript, isoforms, of, known, matrix, components, with, ageing, which, require, further, investigation])].
[sujeto(['Finally,', the, mechanistic, experiments, indicate, that, 'INTS6', and, 'INTS6P1', are, reciprocally]), verbo([regulated]), complemento([through, competition, for, 'oncomiR-17-5p'])].
[sujeto(['Our', investigation, of, this, regulatory, circuit]), verbo([reveals]), complemento([novel, insights, into, the, underlying, mechanisms, of, hepatocarcinogenesis])].
[sujeto(['It', can, help, identify, pseudogenes, '(', which, accumulate, 'mutations),', analyze, raw, 'DNA', and, 'RNA', sequence, data, '(', which, may]), verbo([have]), complemento([frameshift, sequencing, 'errors),', investigate, ribosomal, 'frameshifts,', etc])].
[sujeto(['Often,', 'however,', only, ad, hoc, approximations, or, simulations, are, available, to]), verbo([provide]), complemento([the, statistical, significance, of, a, frameshift, alignment, score])].
[sujeto([')', 'We', also, illustrate, the, continuing, usefulness, of, frameshift, alignment, with, two, '\'', 'post-genomic\'', 'applications:', '(', 'i)', when]), verbo([finding]), complemento([pseudogenes, within, the, human, 'genome,', frameshift, alignments, show, that, most, anciently, conserved, 'non-coding', human, elements, are, recent, pseudogenes, with, conserved, ancestral, 'genes;', and, '(', 'ii)', when, analyzing, metagenomic, 'DNA', reads, from, polluted, 'soil,', frameshift, alignments, show, that, most, alignable, metagenomic, reads, contain, 'frameshifts,', suggesting, that, metagenomic, analysis, needs, to, use, frameshift, alignment, to, derive, accurate, results])].
[sujeto(['The', 'RNA', exosome, is, the, major, 3, '\'', -, 5, '\'', 'RNA', degradation, machine, of, eukaryotic, cells, and]), verbo([participates]), complemento([in, 'processing,', surveillance, and, turnover, of, both, nuclear, and, cytoplasmic, 'RNA'])].
[sujeto(['In', both, yeast, and, 'human,', all]), verbo([nuclear]), complemento([functions, of, the, exosome, require, the, 'RNA', helicase, 'MTR4'])].
[sujeto(['We', show, that, the, 'Arabidopsis', core, exosome, can]), verbo([associate]), complemento([with, two, related, 'RNA', 'helicases,', 'AtMTR4', and, 'HEN2'])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, the, major, role, of, 'AtMTR4', is, the, degradation, of, rRNA, precursors, and, rRNA, maturation, 'by-products'])].
[sujeto(['Here,', we, demonstrate, that, 'HEN2', is]), verbo([involved]), complemento([in, the, degradation, of, a, large, number, of, polyadenylated, nuclear, exosome, substrates, such, as, snoRNA, and, miRNA, 'precursors,', incompletely, spliced, 'mRNAs,', and, spurious, transcripts, produced, from, pseudogenes, and, intergenic, regions])].
[sujeto(['Only', a, weak, accumulation, of, these, exosome, substrate]), verbo([targets]), complemento([is, observed, in, mtr4, 'mutants,', suggesting, that, 'MTR4', can, 'contribute,', but, plays, rather, a, minor, role, for, the, degradation, of, 'non-ribosomal', 'RNAs', and, cryptic, transcripts, in, 'Arabidopsis'])].
[sujeto(['Consistently,', transgene, 'post-transcriptional', gene, silencing, '(', 'PTGS)', is, marginally, affected, in, mtr4, 'mutants,', but]), verbo([increased]), complemento([in, hen2, 'mutants,', suggesting, that, it, is, mostly, the, nucleoplasmic, exosome, that, degrades, aberrant, transgene, 'RNAs', to, limit, their, entry, in, the, 'PTGS', pathway])].
[sujeto(['Interestingly,', 'HEN2', is]), verbo([conserved]), complemento([throughout, green, 'algae,', mosses, and, land, plants, but, absent, from, metazoans, and, other, eukaryotic, lineages])].
[sujeto(['Our', data, indicate, 'that,', in, contrast, to, human, and, 'yeast,', plants]), verbo([have]), complemento([two, functionally, specialized, 'RNA', helicases, that, assist, the, exosome, in, the, degradation, of, specific, nucleolar, and, nucleoplasmic, 'RNA', 'populations,', respectively])].
[sujeto(['Despite', the, fundamental, importance, of, precise, annotation, of, genes, encoded, in, newly, sequenced, 'genomes,', the, accuracy, of, predicted, gene, structures]), verbo([has]), complemento([not, been, critically, 'evaluated,', mostly, due, to, the, scarcity, of, proper, assessment, methods])].
[sujeto(['We', present, a, 'gene-structure-aware', multiple, sequence, alignment, method, for, gene, prediction, using, amino, acid, sequences]), verbo([translated]), complemento([from, homologous, genes, from, many, genomes])].
[sujeto(['The', approach]), verbo([provides]), complemento([rich, information, concerning, the, reliability, of, each, predicted, gene, structure])].
[sujeto(['We']), verbo([have]), complemento([also, devised, an, iterative, method, that, attempts, to, improve, the, structures, of, suspiciously, predicted, genes, based, on, a, spliced, alignment, algorithm, using, consensus, sequences, or, reliable, homologs, as, templates])].
[sujeto([they, are, pseudogenes, or, gene, 'fragments,', located, in, unfinished, sequencing, 'areas,', or, corresponding, to, 'non-productive', 'isoforms,', the, defects]), verbo([found]), complemento([in, a, majority, of, the, remaining, gene, candidates, can, be, remedied, by, our, iterative, refinement, method])].
[sujeto(['Refinement', of, eukaryotic, gene, structures]), verbo([mediated]), complemento([by, 'gene-structure-aware', multiple, protein, sequence, alignment, is, a, useful, strategy, to, dramatically, improve, the, overall, prediction, quality, of, a, set, of, homologous, genes])].
[sujeto(['The', torrent, of, 'RNA-seq', data, becoming, available, not, only, furnishes, an, overview, of, the, entire, transcriptome, but, also]), verbo([provides]), complemento([tools, to, focus, on, specific, areas, of, interest])].
[sujeto(['Nevertheless,', since, the, 'RPs', are, needed, in, equimolar, 'amounts,', there, must, be, sluggish, or]), verbo([regulated]), complemento([translation, of, the, more, abundant, 'RP', mRNAs, 'and/or', substantial, turnover, of, unused, 'RPs'])].
[sujeto(['In', 'addition,', seven, of, the, 'RPs']), verbo([have]), complemento([subsidiary, 'genes,', three, of, which, are, pseudogenes, that, have, been, &, 'quot;rescued"', by, the, introduction, of, promoters, 'and/or', upstream, introns])].
[sujeto(['Several', of, these, are]), verbo([transcribed]), complemento([in, a, 'tissue-specific', 'manner,', e])].
[sujeto([',', 'RPL10L', in, testis, and, 'RPL3L', in, 'muscle,']), verbo([leading]), complemento([to, potential, variation, in, ribosome, structure, from, one, tissue, to, another])].
[sujeto(['Pseudogenes', are, very, common, in, the, genomes, of, a, wide, range, of, organisms, 'and,', although, they, were, originally, considered, as, genetic, 'junk,', now, several, functions]), verbo([have]), complemento([been, attributed, to, them])].
[sujeto(['One', important, function, of, 'pseudogenes,', as, discussed, in, this, 'chapter,', is, to]), verbo([provide]), complemento([material, for, genetic, diversity])].
[sujeto([acnes]), verbo([has]), complemento([historically, been, linked, to, the, pathogenesis, of, acne, 'vulgaris,', a, common, skin, disease, affecting, over, 80, '%', of, all, adolescents, in, the, 'US'])].
[sujeto(['To']), verbo([gain]), complemento([insight, into, potential, 'P'])].
[sujeto([acnes, strain, 'HL096PA1', that, is, highly]), verbo([associated]), complemento([with, acne])].
[sujeto(['We', also, observed, a, 'five-fold']), verbo([increase]), complemento([of, pseudogenes, in, 'HL096PA1,', several, of, which, encode, proteins, in, carbohydrate, transport, and, metabolism])].
[sujeto(['Furthermore,', the, plasmid, identified, in, 'HL096PA1', may, potentially]), verbo([provide]), complemento([a, new, opportunity, for, 'P'])].
[sujeto([acnes, genetic, manipulation, and]), verbo([targeted]), complemento([therapy, against, specific, 'disease-associated', strains])].
[sujeto(['The', genes, of, 'NADH', dehydrogenase, subunit, 5, '(', 'nad5)', and, the, control, region, '(', 'CR)', were]), verbo([found]), complemento([to, have, high, sequence, divergences, and, to, be, usable, for, population, genetics, studies])].
[sujeto(['At', 'present,', no, consensus, on, the, phylogenetic, position, of, genus, 'Babina']), verbo([has]), complemento([been, reached])].
[sujeto(['It', is, well, known, that, mt, gene, rearrangements, of, animals, can]), verbo([provide]), complemento([usable, phylogenetic, information])].
[sujeto(['The', position, of, the, trnH, pseudogene, is, consistent, with, the, translocated, trnH, position]), verbo([reported]), complemento([in, 'Odorrana'])].
[sujeto(['Based', on, the, &, 'quot;duplication', and, 'deletion"', gene, rearrangement, 'model,', a, single, genomic, duplication, event, can, explain, the, order, of, derived, mt, genes]), verbo([found]), complemento([in, 'Babina', and, 'Odorrana'])].
[sujeto(['Mouse', embryonic, stem, '(', 'ES)', cells, are, prototypical, stem, cells, that, remain, undifferentiated, in, culture, for, long, 'periods,', yet]), verbo([maintain]), complemento([the, ability, to, differentiate, into, essentially, all, cell, types])].
[sujeto(['Previously,', we]), verbo([have]), complemento([reported, that, 'ES', cells, oscillate, between, two, distinct, 'states,', which, can, be, distinguished, by, the, transient, expression, of, 'Zscan4', genes, originally, identified, for, its, specific, expression, in, mouse, 'two-cell', stage, embryos])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, the, nascent, protein, synthesis, is, globally, repressed, in, the, 'Zscan4-positive', state, of, 'ES', 'cells,', which, is, mediated, by, the, transient, expression, of, newly, identified, eukaryotic, translation, initiation, factor, 1, 'A', '(', 'Eif1a)-like', genes])].
[sujeto(['The', analysis, of, the]), verbo([expressed]), complemento([sequence, tag, database, showed, that, 'Eif1a-like', genes, are, expressed, mostly, in, the, 'two-cell', stage, mouse, embryos])].
[sujeto(['Microarray', analyses, and, quantitative, 'real-time', polymerase, chain, reaction, analyses, show, that, 'Eif1a-like', genes, are]), verbo([expressed]), complemento([specifically, in, the, 'Zscan4-positive', state, of, 'ES', cells])].
[sujeto(['These', results, indicate, a, novel, mechanism, to]), verbo([repress]), complemento([protein, synthesis, by, 'Eif1a-like', genes, and, a, unique, mode, of, protein, synthesis, regulation, in, 'ES', 'cells,', which, undergo, a, transient, and, reversible, repression, of, global, protein, synthesis, in, the, 'Zscan4-positive', state])].
[sujeto(['Identification', of, differentially]), verbo([expressed]), complemento([lncRNAs, and, mRNAs, were, performed, between, the, 2, groups])].
[sujeto(['Then,', gene, ontology, '(', 'GO)', and, pathway, enrichment, analyses, were, performed, to, analyze, the, biological, functions, and, pathways, for, the, differentially]), verbo([expressed]), complemento([mRNAs])].
[sujeto([1, were, differentially]), verbo([expressed]), complemento([and, might, play, important, roles, in, the, development, of, 'IDD'])].
[sujeto(['A', deep, understanding, of, its, underlying, molecular, mechanisms, is, the, premise, for, developing, effective]), verbo([targeted]), complemento([therapies])].
[sujeto(['Recently,', deep, transcriptional, sequencing]), verbo([has]), complemento([been, used, as, an, effective, genomic, assay, to, obtain, insights, into, diseases, and, may, be, helpful, in, the, study, of, 'PC'])].
[sujeto(['Our', findings, regarding, potential, 'PC-related', genes]), verbo([increase]), complemento([the, understanding, of, 'PC', and, provides, direction, for, future, research])].
[sujeto(['The', ubiquitin, 'A-52', residue, ribosomal, protein, fusion, product, 1, '(', 'UbA52)', is, a, gene, highly]), verbo([expressed]), complemento([specifically, in, the, inner, ear])].
[sujeto(['In', the, adult, 'mouse,', 'UbA52', protein, was, distributed, in, the, strial, marginal, cells, and, vestibular, dark, 'cells,', which]), verbo([regulate]), complemento([the, endolymphatic, ion, homeostasis])].
[sujeto(['Endolymphatic', 'K', concentration, is, elevated, between, postnatal, days, 3, -, 8, :, 'therefore,', our, results, indicate, that, 'UbA52', may]), verbo([have]), complemento([a, functional, role, in, regulation, of, ion, secretion, in, the, inner, ear])].
[sujeto(['The', expression, levels, of, the, 'miR-4516']), verbo([target]), complemento(['genes,', 'namely,', 'RPL37', and, 'UBA52,', were, involved, in, ribosome, function, and, inhibited, by, exposure, to, 'PM2'])].
[sujeto(['Autophagy', in, 'A549', cells, was]), verbo([induced]), complemento([by, 'PM2'])].
[sujeto([5, exposure, as, a, response, to]), verbo([decreased]), complemento(['RPL37', expression])].
[sujeto(['Moreover,']), verbo([enhanced]), complemento(['miR-4516', expression, was, positively, correlated, with, the, augmentation, of, the, internal, burden, of, aluminum, and, lead, in, individuals, living, in, a, city, with, moderate, air, pollution])].
[sujeto(['Hereby,', the, 'miR-4516/RPL37/autophagy', pathway, may, represent, a, novel, mechanism, that]), verbo([mediates]), complemento([responses, to, 'PM', metal, components])].
[sujeto(['Their', mRNA, expression, levels, were, positively, correlated, and]), verbo([regulated]), complemento([by, 'DNA', copy, number, alterations, '(', 'CNA)', '(', 'KCNN4:', 'p=1'])].
[sujeto(['Natural', selective, processes]), verbo([have]), complemento([been, known, to, drive, phenotypic, 'plasticity,', which, is, the, emergence, of, different, phenotypes, from, one, genome, following, environmental, stimulation])].
[sujeto(['Long', 'non-coding', 'RNAs', '(', 'lncRNAs)']), verbo([have]), complemento([been, observed, to, modulate, transcriptional, and, epigenetic, states, of, genes, in, human, cells])].
[sujeto(['Using', heat, shocked, human, cells, as, a, model, we]), verbo([find]), complemento([several, differentially, expressed, transcripts, with, the, top, candidates, being, lncRNAs, derived, from, 'retro-elements'])].
[sujeto(['One', particular, 'retro-element', derived, 'transcripts,', 'Retro-EIF2S2,', was]), verbo([found]), complemento([to, be, abundantly, 'over-expressed', in, heat, shocked, cells])].
[sujeto(['Over-expression', of, 'Retro-EIF2S2', significantly]), verbo([enhanced]), complemento([cell, viability, and, modulated, a, predisposition, for, an, adherent, cellular, phenotype, upon, heat, shock])].
[sujeto(['Mechanistically,', we]), verbo([find]), complemento([that, this, 'retro-element', derived, transcript, interacts, directly, with, a, network, of, proteins, including, 40, 'S', ribosomal, protein, 'S30', '(', 'FAU),', 'Eukaryotic', translation, initiation, factor, 5, 'A', '(', 'EIF5A),', and, 'Ubiquitin-60S', ribosomal, protein, 'L40', '(', 'UBA52)', to, affect, protein, modulated, cell, adhesion, pathways])].
[sujeto(['We']), verbo([find]), complemento([one, motif, in, 'Retro-EIF2S2', that, exhibits, binding, to, 'FAU', and, modulates, phenotypic, cell, transitions, from, adherent, to, suspension, states])].
[sujeto(['The', observations, presented, here]), verbo([suggest]), complemento([that, retroviral, derived, transcripts, actively, modulate, phenotypic, plasticity, in, human, cells, in, response, to, environmental, selective, pressures, and, suggest, that, natural, selection, may, play, out, through, the, action, of, 'retro-elements', in, human, cells])].
[sujeto(['It']), verbo([causes]), complemento([disorders, of, various, tissue, 'systems,', including, the, 'kidney,', and, is, associated, with, protein, aggregation])].
[sujeto(['Prior', to, the, appearance, of, 'Cd', 'toxicity,', the, 'UBB,', 'UBC,', and, 'UBA80', expression, levels]), verbo([increased]), complemento([following, 'Cd', treatment])].
[sujeto(['Knockdown', of, 'UBB', by, siRNA, transfection, significantly]), verbo([decreased]), complemento(['Cd', cytotoxicity])].
[sujeto(['Notably,', 'Cd']), verbo([induces]), complemento([ubiquitinated, protein, levels, in, 'HK-2', 'cells,', and, knockdown, of, 'UBB', blocked, this, process])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'UBB', is, involved, in, 'Cd-induced', increase, of, protein, 'ubiquitination,', and, that, accumulation, of, ubiquitinated, proteins, through, increased, 'UBB', expression, may, contribute, to, 'Cd', toxicity, in, 'HK-2', cells])].
[sujeto(['Protein', 'ubiquitination,', a, major, 'post-translational', modification, in, 'eukaryotes,']), verbo([requires]), complemento([an, adequate, pool, of, free, ubiquitin])].
[sujeto(['Cells']), verbo([maintain]), complemento([this, pool, by, two, 'pathways,', both, involving, deubiquitinases, '(', 'DUBs):', recycling, of, ubiquitin, from, ubiquitin, conjugates, and, processing, of, ubiquitin, precursors, synthesized, de, novo])].
[sujeto(['Although', many, advances]), verbo([have]), complemento([been, made, in, recent, years, regarding, ubiquitin, 'recycling,', our, knowledge, on, ubiquitin, precursor, processing, is, still, 'limited,', and, questions, such, as, when, are, these, precursors, processed, and, which, 'DUBs', are, involved, remain, largely, unanswered])].
[sujeto(['Here', we]), verbo([provide]), complemento([data, suggesting, that, two, of, the, four, mammalian, ubiquitin, 'precursors,', 'UBA52', and, 'UBA80,', are, processed, mostly, 'post-translationally', whereas, the, other, 'two,', 'UBB', and, 'UBC,', probably, undergo, a, combination, of, 'co-', and, 'post-translational', processing])].
[sujeto(['Using', an, unbiased, biochemical, approach, we]), verbo([found]), complemento([that, 'UCHL3,', 'USP9X,', 'USP7,', 'USP5', and, 'Otulin/Gumby/FAM105b', are, by, far, the, most, active, 'DUBs', acting, on, these, precursors])].
[sujeto(['The', identification, of, these, 'DUBs', together, with, their, properties]), verbo([suggests]), complemento([that, each, ubiquitin, precursor, can, be, processed, in, at, least, two, different, 'manners,', explaining, the, robustness, of, the, ubiquitin, de, novo, synthesis, pathway])].
[sujeto(['During', proteotoxic, 'stress,', when, the, demand, of, clearing, 'damaged/misfolded', proteins, strongly, 'increases,', cells]), verbo([activate]), complemento(['Ub', gene, transcription, to, face, the, need, of, extra, ubiquitin])].
[sujeto(['Our', results]), verbo([reveal]), complemento([that, 'UBC', and, 'RPS27A', represent, the, major, fraction, of, the, 'Ub', transcriptome, in, different, cell, 'lines,', but, when, converted, to, the, coding, 'potential,', polyubiquitin, genes, 'UBC', and, 'UBB', mainly, contribute, to, determine, the, intracellular, ubiquitin, content, under, basal, conditions])].
[sujeto(['A', similar, 'output,', with, lower, 'fold-inductions,', is, detected, in, 'heat-stressed', 'cells,', with, 'UBC']), verbo([acting]), complemento([as, the, main, contributor, to, thermotolerance])].
[sujeto(['Remarkably,', 'UV', irradiation, fails, to]), verbo([induce]), complemento(['Ub', gene, 'transcription,', but, rather, seems, to, act, at, the, 'post-transcriptional', 'level,', by, stabilizing, ubiquitin, mRNAs, at, 'UV', doses, which, induce, rapid, degradation, of, other, 'RNA', molecules])].
[sujeto(['Moreover,', the, evidence, that, the, 'UBC', core, promoter, contains, multiple, transcription, start, sites, and, their, responsiveness, to, 'stress,', is, here]), verbo([reported]), complemento([for, the, first, time])].
[sujeto(['Selenium', '(', 'Se)', and, its, derivatives, are, known, to]), verbo([have]), complemento([protective, effects, against, mercury, '(', 'Hg)', toxicity, in, mammals])].
[sujeto(['Juvenile', 'Atlantic', cod, were, exposed, to]), verbo([regular]), complemento([feed, '(', 'control),', 'Se-spiked', feed, '(', 3, mg, 'Se', 'kg(-1)),', 'MeHg-spiked', feed, '(', 10, mg, 'Hg', 'kg(-1))', or, to, 'Se-', and, 'MeHg-spiked', feed, '(', 3, mg, 'Se', 'kg(-1)', and, 10, mg, 'Hg', 'kg(-1),', 'respectively)', for, ten, weeks])].
[sujeto(['This', species, is, an, important, component, of, marine, ecosystems, and, a, model, object, for, certain, biological, 'studies,', in, particular, those]), verbo([requiring]), complemento([quantitative, estimation, of, gene, expression])].
[sujeto(['As', a, 'rule,', expression, at, the, transcriptional, level, is, estimated, by, 'real-time', qPCR, using, the, 'ΔΔCt', 'method,', which, allows, the, comparison, of, the, copy, number, of]), verbo([target]), complemento([gene, transcripts, in, samples, with, unknown, 'mRNA/cDNA', concentration])].
[sujeto(['Application', of, this, method]), verbo([requires]), complemento([normalization, of, the, results, relative, to, genes, with, stable, expression, levels, '(', reference, 'genes)'])].
[sujeto(['The', identification, of, reference, genes, is, still, a, challenging, task, since, data, of, this, kind, are, missing, for, certain, 'taxa,', whereas, the, use, of, &, 'quot;standard"', endogenous, control, genes, without, additional, tests, might]), verbo([lead]), complemento([to, erroneous, conclusions])].
[sujeto(['The', data, obtained]), verbo([suggest]), complemento([that, the, 'UBA52', gene, may, be, used, as, reference, for, normalization, of, gene, expression, at, the, mRNA, level, in, the, starfish, 'A'])].
[sujeto(['Further', analysis]), verbo([suggested]), complemento([that, 'Ub,', and, not, 'RPS27a', or, 'RPL40,', was, associated, with, apoptotic, cell, death])].
[sujeto(['An', apoptogenic, stimulus]), verbo([enhances]), complemento([the, nuclear, targeting, and, aggregation, of, 'Ub', in, the, 'nucleus,', resulting, in, histone, 'H2A', deubiquitylation, followed, by, abnormal, ubiquitylation, of, the, nuclear, envelope, and, the, lamina])].
[sujeto(['These', events, accompany, the, apoptotic]), verbo([nuclear]), complemento([morphology, in, the, late, stage, of, apoptosis])].
[sujeto(['These', results]), verbo([suggest]), complemento([a, role, for, 'Ub', hybrid, proteins, in, the, altered, nuclear, dynamics, of, 'Ub', during, tumor, cell, apoptosis, induced, by, apoptogenic, stimuli])].
[sujeto(['One', of, the, major, problems, facing, clinical, nephrology, currently, throughout, the, world, is, an, exponential]), verbo([increase]), complemento([in, patients, with, 'end-stage', renal, disease, '(', 'ESRD),', which, is, largely, related, to, a, high, incidence, of, diabetic, nephropathy])].
[sujeto(['The', latter, is, characterized, by, a, multitude, of, metabolic, and, signaling, events, following, excessive, channeling, of, 'glucose,', which]), verbo([leads]), complemento([to, an, increased, synthesis, of, extracellular, matrix, '(', 'ECM)', glycoproteins, resulting, in, 'glomerulosclerosis,', interstitial, fibrosis, and, ultimately, 'ESRD'])].
[sujeto(['In', this, 'regard,', identification, of, genes, that, are, crucially]), verbo([involved]), complemento([in, the, progression, of, diabetic, nephropathy, would, enhance, the, discovery, of, new, biomarkers, and, could, also, promote, the, development, of, novel, therapeutic, strategies])].
[sujeto(['Several', 'genes,', such, as, 'Tim44', '(', translocase, of, inner, mitochondrial, 'membrane-', 44, ')', ',', 'RSOR/MIOX', '(', renal, specific, 'oxidoreductase/myo-inositol', 'oxygenase),', 'UbA52,', 'Rap1b', '(', 'Ras-related', 'GTPase),', 'gremlin,', 'osteopontin,', hydroxysteroid, 'dehydrogenase-', 3, β, isotype, 4, and, those, of, the, 'Wnt', signaling, 'pathway,', were, identified, as, differentially]), verbo([expressed]), complemento([genes, in, kidneys, of, diabetic, rodents])].
[sujeto(['Future', trends, for, identification, of, the, biomarkers, and, therapeutic]), verbo([target]), complemento([genes, should, also, include, genome, scale, 'DNA/histonemethylation', 'profiling,', metabolomic, approaches, '(', e])].
[sujeto(['These', regions, contain, genes, such, as, 'POLR2G,', 'MXRA7', and, 'UBA52']), verbo([involved]), complemento([in, biological, processes, that, may, lead, to, the, establishment, and, maintenance, of, endometriotic, implants])].
[sujeto(['Epidemiological', studies]), verbo([suggest]), complemento([that, smoking, in, combination, with, 'HPV', infection, plays, a, significant, role, in, the, etiology, of, this, disease])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, the, tobacco, 'carcinogen,', 4, -, '(', 'methylnitrosamino)-1-(3-pyridyl)-1-butanone', '(', 'NNK),', is, present, in, human, cervical, mucus])].
[sujeto(['Here,', we, hypothesized, that, treatment, of, 'HPV-16-immortalized', human, ectocervical, cells, '(', 'Ecto1/E6E7)', with, 'NNK', would, alter, the, expression, of, genes]), verbo([involved]), complemento([in, cellular, transformation])].
[sujeto(['The', 'colony-forming', efficiency]), verbo([increased]), complemento([following, 'NNK', 'treatment;', the, maximum, effect, was, observed, after, 12, weeks, with, 100, microM, 'NNK'])].
[sujeto(['Genes', identified, are, categorized, as, immune, response, '(', 'LTB4R),', 'RNA', surveillance, pathway, '(', 'SMG1),', metabolism, '(', 'ALDH7A1),', genes, frequently]), verbo([expressed]), complemento([in, later, stages, of, neoplastic, development, '(', 'MT1F),', 'DNA', binding, '(', 'HIST3H3', and, 'CHD1L),', and, protein, biosynthesis, '(', 'UBA52)'])].
[sujeto(['Genes', that, are, highly]), verbo([expressed]), complemento([in, the, inner, 'ear,', as, revealed, by, cDNA, microarray, 'analysis,', may, have, a, crucial, functional, role, there])].
[sujeto(['Those', that, are]), verbo([expressed]), complemento([specifically, in, auditory, tissues, are, likely, to, be, good, candidates, to, screen, for, genetic, alterations, in, patients, with, 'deafness,', and, several, genes, have, been, successfully, identified, as, responsible, for, hereditary, hearing, loss])].
[sujeto(['To', understand, the, detailed, mechanisms, of, the, hearing]), verbo([loss]), complemento([caused, by, the, mutations, in, these, 'genes,', the, present, study, examined, the, immunocytochemical, localization, of, the, proteins, encoded, by, 'Crym,', 'KIAA1199', 'homolog,', 'Uba52,', 'Col9a3,', and, 'Col9a1', in, the, cochlea, of, rats, and, mice])].
[sujeto(['Collagen', type, 'IX', was]), verbo([found]), complemento([within, the, tectorial, membrane, as, well, as, fibrocytes, in, the, spiral, ligament])].
[sujeto(['The', present, results, showed, 'cell-specific', localization, of, the, encoded, proteins, of, these, highly]), verbo([expressed]), complemento(['genes,', indicating, that, the, coordinated, actions, of, various, molecules, distributed, in, different, parts, of, the, cochlea, are, essential, for, maintenance, of, auditory, processing, in, the, cochlea])].
[sujeto(['This', important, cellular, process, is, partly]), verbo([regulated]), complemento([by, the, 'ubiquitin-proteasome', system, through, posttranslational, modification, by, the, conjugation, of, ubiquitin, chains, to, proteins, targeted, for, degradation, by, proteasomes])].
[sujeto(['Quantitative', 'real-time', polymerase, chain, reaction, results, indicated, that, mRNA, levels, of, 'ubA52,', ubB, and, ubC, in, the, ipsilateral, cerebral, cortex, were, significantly]), verbo([decreased]), complemento([on, 'Day', 1, 'post-TBI,', that, ubC, mRNA, levels, also, were, significantly, lower, than, control, on, 'Day', 3, 'post-TBI,', but, that, by, 'Day', 7, 'post-TBI,', 'ubA52,', ubB, and, ubC, mRNA, levels, had, all, returned, to, control, levels])].
[sujeto(['Western', blotting]), verbo([found]), complemento([that, free, ubiquitin, protein, levels, were, significantly, reduced, in, both, ipsilateral, cerebral, cortex, and, hippocampus, on, 'Days', 1, -, 7, 'post-TBI,', while, there, was, markedly, increased, 'ubiquitin-conjugated', protein, in, ipsilateral, cerebral, cortex, on, 'Day', 7, and, in, hippocampus, on, 'Days', 3, -, 7, 'post-TBI'])].
[sujeto(['Our', study]), verbo([suggests]), complemento([that, altered, ubiquitin, system, function, in, the, 'CNS', contributes, to, the, pathological, outcomes, of, 'TBI'])].
[sujeto([4, ')', was, strongly]), verbo([released]), complemento([in, the, urine, of, healthy, 'controls,', patients, with, proteinuria, due, to, nondiabetic, 'disease,', and, 'DM-WNP', in, contrast, to, 'DM-NP', patients])].
[sujeto(['The']), verbo([release]), complemento([of, high, amounts, of, 'UbA52', in, urine, of, 'DM-NP', patients, could, serve, as, a, diagnostic, 'marker,', whereas, the, lack, of, the, short, form, of, ubiquitin, raises, interesting, questions, about, the, pathophysiology])].
[sujeto(['To']), verbo([ensure]), complemento([a, correct, interpretation, of, results, obtained, with, quantitative, 'real-time', reverse, 'transcription-polymerase', chain, reaction, '(', 'RT-qPCR),', it, is, critical, to, normalize, to, a, reference, gene, with, stable, mRNA, expression, in, the, tissue, of, interest])].
[sujeto(['The', 'Equivalence', test]), verbo([found]), complemento([variation, in, expression, within, a, 3, -, fold, expression, change, between, tumour, groups, 'for:', 'IPO8,', 'RPL40,', 'RPL30,', 'GUSB,', 'TBP,', 'RPLPO,', 'ACTB,', 'ABL1,', and, 'CDKN1A'])].
[sujeto(['Employment', of, suitable, reference, genes, '(', 'IPO8,', 'RPL4)', in, comparison, with, unsuitable, ones, '(', 'GADPH,', 'HPRT1),', demonstrated, divergent, influence, on, the, mRNA, expression, pattern, of, our]), verbo([target]), complemento([genes, -, 'GPER', and, uPAR])].
[sujeto(['We']), verbo([found]), complemento(['IPO8', and, 'RPL4', to, be, suitable, reference, genes, for, normalization, of, target, gene, expression, in, 'benign,', 'borderline,', and, malignant, ovarian, tumours])].
[sujeto(['The', gene, 'RRN10,', which, 'encodes,', a, component, of, the, upstream, activation, 'factor,', is, essential, to]), verbo([promote]), complemento(['high-level', transcription, of, rDNA])].
[sujeto(['In', our, previous, 'study,', we, isolated, 'SupE', strain, as, a, dominant, 'suppressor,', which, showed, the, ability, to, restore, the, severe, growth, defects, and, reduced, 'RNA', content]), verbo([caused]), complemento([by, disruption, of, the, 'RRN10', gene])].
[sujeto(['SupE', strain]), verbo([has]), complemento([multiple, mutations, which, we, designated, collectively, as, 'SUPE'])].
[sujeto(['Further', analysis, on, 'SUPE', mutation, indicated, that, 'RPL40A', was, responsible, for, suppression, of, defect]), verbo([caused]), complemento([by, rrn10, disruption])].
[sujeto(['However,', there, were, no, base, changes, in, this, gene, as, compared, with, the, parental, 'Δrrn10', 'strain,', thus]), verbo([suggesting]), complemento([that, an, additional, copy, of, 'RPL40A', suppress, the, defects, caused, by, 'Δrrn10', 'disruption,', and, 'that,', in, 'SupE', 'strain,', these, defects, are, suppressed, by, increased, transcription, of, 'RPL40A', whose, copy, is, doubled])].
[sujeto(['In', 'addition,']), verbo([increased]), complemento([transcription, of, 'RPL40B', also, showed, significant, effect, to, restore, the, growth, defect, and, reduced, 'RNA', content, caused, by, 'Δrrn10', disruption])].
[sujeto(['We', propose, a, model, to, explain, how, 'SUPE', mutation]), verbo([increases]), complemento([the, transcription, of, ribosomal, protein, genes, such, as, 'RPL40A', and, 'RPL40B', in, 'SupE', 'strain,', resulting, in, an, increase, in, 'RNA', content])].
[sujeto(['Initiation', is, the, primary]), verbo([target]), complemento([of, translational, control, for, all, organisms])].
[sujeto(['Here,', we, characterize, a, 'transcript-specific', translation, initiation, mechanism, that, is]), verbo([mediated]), complemento([by, the, ribosome])].
[sujeto(['This', requirement, is]), verbo([conserved]), complemento([among, members, of, the, order, 'Mononegavirales,', including, measles, virus, and, rabies, virus])].
[sujeto(['Polysome', analyses, and, in, vitro, reconstitution, of, initiation, demonstrate, that, rpL40, is]), verbo([required]), complemento([for, 80, 'S', formation, on, 'VSV', mRNAs, through, a, 'cis-regulatory', element])].
[sujeto(['Using', deep, 'sequencing,', we, further, uncover, a, subset, of, cellular, transcripts, that, are, selectively, sensitive, to, rpL40, 'depletion,']), verbo([suggesting]), complemento(['VSV', may, have, usurped, an, endogenous, translation, pathway])].
[sujeto(['Together,', these, findings, demonstrate, that, the, ribosome]), verbo([acts]), complemento([as, a, translational, regulator, outside, of, its, catalytic, role, during, protein, synthesis])].
[sujeto(['Recent', evidence]), verbo([suggests]), complemento([that, the, 'UPS', plays, a, regulatory, role, in, regeneration, processes])].
[sujeto(['Here,', we, explore, the, possibility, that, the, 'UPS', is]), verbo([involved]), complemento([during, intestinal, regeneration, of, the, sea, cucumber, 'Holothuria', glaberrima])].
[sujeto(['In', 'Saccharomyces', 'cerevisiae,', cleavage, of, the, linear, precursor, proteins]), verbo([releases]), complemento([ubiquitin, and, the, 'C-terminally', fused, ribosomal, proteins, 'Rpl40', '(', 'Ubi1/2', 'precursor)', and, 'Rps31', '(', 'Ubi3', 'precursor),', which, are, part, of, mature, 60, 'S', and, 40, 'S', ribosomal, subunits, respectively])].
[sujeto(['Strikingly,', the, lethal, 'ubi3+P77', 'mutation,', which, abolished, cleavage, almost, 'completely,']), verbo([led]), complemento([to, a, rapid, 'G1', cell, cycle, arrest, upon, genetic, depletion, of, 'wild-type', 'UBI3'])].
[sujeto(['In', contrast, to, the, 'cleavage-affecting', 'mutations,', deletion, of, the, ubiquitin, moiety, from, 'UBI3']), verbo([led]), complemento([to, a, decrease, in, 40, 'S', ribosomal, subunits, and, to, the, incorporation, of, the, 20, 'S', 'pre-rRNA', into, polyribosomes])].
[sujeto(['Altogether,', our, findings]), verbo([provide]), complemento([additional, evidence, that, the, initial, presence, of, the, ubiquitin, moiety, of, 'Ubi3', contributes, to, the, efficient, production, of, 40, 'S', ribosomal, subunits, and, they, suggest, that, ubiquitin, release, is, a, prerequisite, for, their, functional, integrity])].
[sujeto(['The', data, also]), verbo([suggest]), complemento([that, chickens, that, are, viraemic, at, hatching, are, probably, incapable, of, breaking, tolerance, and, developing, antibody])].
[sujeto(['Toxoplasmosis', can]), verbo([cause]), complemento([serious, disease, in, immunocompromised, patients, and, to, congenitally, infected, foetuses])].
[sujeto(['The', deduced, 'amino-acid', sequences, of, the, two, genes, were]), verbo([found]), complemento([to, be, completely, identical])].
[sujeto(['A', putative, 'TATA-like', 'sequence,', a, polypyrimidine, 'sequence,', and, a, similar, sequence, to, 'telo-box', were]), verbo([found]), complemento([in, the, promoter, regions, of, the, two, genes])].
[sujeto(['Furthermore,', the, putative, 'tRNA(Pro)', gene, was]), verbo([found]), complemento([in, the, 5, '\'', -, upstream, region, of, one, of, them])].
[sujeto(['These', enzymes, cleave, ubiquitin, at, its, 'C-terminus', from, two, types, of, substrates, containing, '(', 'i)', ubiquitin, in, an, 'alpha-amino', 'linkage,', as]), verbo([found]), complemento([in, the, primary, ubiquitin, translation, 'products,', polyubiquitin, and, 'ubiquitin-ribosomal', fusion, 'proteins,', or, '(', 'ii)', ubiquitin, in, an, 'epsilon-amino', 'linkage,', as, found, in, multiubiquitin, chains, either, unattached, or, conjugated, to, cellular, proteins])].
[sujeto(['We']), verbo([have]), complemento([isolated, cDNAs, for, two, 'Arabidopsis', thaliana, 'genes,', 'AtUBP3', and, 'AtUBP4,', which, encode, 'UBPs', that, are, 93, '%', identical])].
[sujeto(['Using', in, vivo, assays, in, 'Escherichia', coli, that, allow, the, coexpression, of, a, 'UBP', with, a, putative, 'substrate,', we]), verbo([have]), complemento([shown, that, 'AtUBP3', and, 'AtUBP4', can, specifically, deubiquitinate, the, artificial, substrate, 'Ub-X-beta-gal', but, cannot, act, upon, the, natural, 'alpha-amino-linked', ubiquitin, fusions, 'Arabidopsis', 'Ub-CEP52', and, 'Arabidopsis', polyubiquitin])].
[sujeto(['Affinity-purified', antibody, prepared, against, 'AtUBP3']), verbo([expressed]), complemento([in, 'E'])].
[sujeto([coli]), verbo([recognizes]), complemento([both, 'AtUBP3', and, 'AtUBP4'])].
[sujeto(['Subcellular', localization, studies, show, that, 'AtUBP3', 'and/or', 'AtUBP4', are, present, in]), verbo([nuclear]), complemento([extracts])].
[sujeto(['We']), verbo([report]), complemento([the, cDNA, sequence, encoding, 'Ub52', from, the, cnidarian, 'Acropora', millepora])].
[sujeto([millepora, 'Ub52', is, encoded, by, a, small, '(', &, 'lt;', 800, 'nt)', mRNA, present, in, eggs, and, is, first]), verbo([expressed]), complemento([after, the, early, gastrula, stage, in, embryonic, development])].
[sujeto(['Amplification', of, rat, cDNA, with, a]), verbo([primer]), complemento([specific, for, the, 3, '\'', 'non-coding', region, of, the, 'CEP52', 'gene,', in, combination, with, a, consensus, primer, for, the, 5, '\'', end, of, the, ubiquitin, coding, 'sequence,', provided, evidence, that, the, rat, 'CEP52', gene, is, fused, to, a, ubiquitin, reading, frame])].
[sujeto(['Antibodies', against, a, synthetic, 'CEP52', peptide, were, used, to, show, that]), verbo([expressed]), complemento(['CEP52', is, associated, with, the, 60, 'S', ribosomal, 'subunit,', and, that, is, is, not, linked, to, ubiquitin])].
[sujeto(['The', quantity, of, 'CEP52']), verbo([found]), complemento([in, different, tissues, is, quite, 'variable,', but, appears, to, correspond, to, the, amount, of, ribosomes, present])].
[sujeto(['The', results]), verbo([provide]), complemento([evidence, of, extensive, recombination, 'and/or', conversion, events, between, repeated, genes, in, 'Cn'])].
[sujeto(['Ribosomes', from, 'embryonic,', larval, and, adult, 'Drosophila', melanogaster, contain, equivalent, amounts, of, 'CEP52', and, the, protein, is]), verbo([associated]), complemento([with, the, large, ribosomal, subunit])].
[sujeto(['Stained', 'two-dimensional', gels, indicate, that, the, quantity, of, 'CEP52']), verbo([associated]), complemento([with, ribosomes, is, similar, to, that, of, other, ribosomal, proteins, of, corresponding, size])].
[sujeto(['However,', the, putative, fusion, protein, does, not, react, with, ubiquitin, antibodies, and]), verbo([has]), complemento([negligible, positive, charge, at, 'pH5,', demonstrating, that, it, is, not, unprocessed, 'ubiquitin-CEP52'])].
[sujeto(['Adolescent', substance, use, disorders, '(', 'SUDs)', are, a, significant, public, health, issue, due, to, the]), verbo([associated]), complemento(['morbidity,', 'mortality,', and, societal, cost])].
[sujeto(['Medication', assisted, treatments]), verbo([have]), complemento([been, shown, to, improve, adult, 'SUD', treatment, 'outcomes,', and, preliminary, studies, in, adolescents, suggest, that, combining, medication, with, psychosocial, interventions, may, also, enhance, 'SUD', outcomes, for, youth])].
[sujeto(['Diarrhoea', and, pneumonia, are, common]), verbo([causes]), complemento([of, childhood, death, in, 'sub-Saharan', 'Africa', but, there, are, few, studies, describing, specific, pathogens])].
[sujeto(['The', study, aimed, to, describe, the, pathogens]), verbo([associated]), complemento([with, 'diarrhoea,', pneumonia, and, oropharyngeal, colonization, in, children, born, to, 'HIV-infected', women, '(', 'HIV-exposed', 'infants)'])].
[sujeto(['More', 'formula-fed', infants, had, oropharyngeal, colonization, by, pathogenic, 'Gram-negative', bacteria, '(', 16.8, '%', vs, 6.2, '%', ',', 'P', =, 0.003, ')', ',', which, was]), verbo([associated]), complemento([with, a, 'non-significant', increased, risk, of, pneumonia, '(', 'OR', 2.2, ',', 95, '%', 'CI', 0.8, -, 5.7, ')'])].
[sujeto(['Although', viruses, were, most, commonly, detected, during, 'pneumonia,', respiratory, colonization, by, 'Gram-negative', bacteria, may]), verbo([have]), complemento([contributed, to, pneumonia, in, 'formula-fed', infants])].
[sujeto(['Intraventricular', hemorrhage, '(', 'IVH)', is, the, most, 'frequent,', severe, neurological, complication, of, prematurity, and, is]), verbo([associated]), complemento([with, posthemorrhagic, hydrocephalus, '(', 'PHH)', in, up, to, half, of, cases])].
[sujeto(['PHH']), verbo([requires]), complemento([lifelong, neurosurgical, care, and, is, associated, with, significant, cognitive, and, psychomotor, disability])].
[sujeto(['Cerebrospinal', fluid, '(', 'CSF)', biomarkers, may]), verbo([provide]), complemento([both, diagnostic, information, for, 'PHH', and, novel, insights, into, its, pathophysiology])].
[sujeto(['Concentrations', of, amyloid, precursor, protein, '(', 'APP),', soluble, 'APPα', '(', 'sAPPα),', soluble, 'APPβ,', neural, cell, adhesion, 'molecule-1', '(', 'NCAM-1),', 'L1', cell, adhesion, molecule, '(', 'L1CAM),', 'tau,']), verbo([phosphorylated]), complemento(['tau,', and, total, protein, '(', 'TP)', were, measured, in, lumbar, 'CSF', from, neonates, in, 6, 'groups:', '(', 1, ')', no, known, neurological, disease, '(', n, =, 33, ')', ;, '(', 2, ')', 'IVH', grades, 'I', to, 'II', '(', n, =, 13, ')', ;, '(', 3, ')', 'IVH', grades, 'III', to, 'IV', '(', n, =, 12, ')', ;, '(', 4, ')', 'PHH', '(', n, =, 12, ')', ;, '(', 5, ')', ventricular, enlargement, without, hydrocephalus, '(', n, =, 10, ')', ;, and, '(', 6, ')', hypoxic, ischemic, encephalopathy, '(', n, =, 13, ')'])].
[sujeto(['Lumbar', 'CSF', levels, of, 'APP,', 'sAPPα,', 'L1CAM,', and, 'TP', were, selectively]), verbo([increased]), complemento([in, 'PHH', compared, with, all, other, conditions, '(', all, 'P', &, 'lt;'])].
[sujeto(['Lumbar', 'CSF', 'APP,', 'sAPPα,', 'L1CAM,', and, 'TP', were, selectively]), verbo([increased]), complemento([in, 'PHH'])].
[sujeto(['These', 'proteins,', and, 'sAPPα,', in, 'particular,', hold, promise, as, biomarkers, of, 'PHH', and]), verbo([provide]), complemento([novel, insight, into, 'PHH-associated', neural, injury, and, repair])].
[sujeto(['APP,', amyloid, precursor, 'proteinELISA,', 'enzyme-linked', immunosorbent, 'assayHIE,', hypoxic, ischemic, 'encephalopathyIVH,', intraventricular, 'hemorrhageL1CAM,', 'L1', cell, adhesion, 'moleculeLP,', lumbar, 'punctureNCAM-1,', neural, cell, adhesion, 'molecule-1NICU,', neonatal, intensive, care, 'unitp-tau,']), verbo([phosphorylated]), complemento(['tauPHH,', posthemorrhagic, 'hydrocephalusPMA,', postmenstrual, 'ageRCG,', rostrocaudal, 'gradientsAPPα,', soluble, amyloid, precursor, protein, 'αsAPPβ,', soluble, amyloid, precursor, protein, 'βTP,', total, 'proteinVAD,', ventricular, access, 'deviceVEWOH,', ventricular, enlargement, without, hydrocephalus])].
[sujeto(['Patients', with, 'Duchenne', muscular, dystrophy, '(', 'DMD)']), verbo([require]), complemento([frequent, imaging, to, assess, left, ventricular, '(', 'LV)', function])].
[sujeto(['Cardiac', magnetic, resonance, imaging, '(', 'CMR)', is, the, gold, standard, for, the, assessment, of, 'LV', function, but]), verbo([has]), complemento([not, been, universally, adopted, in, patients, with, 'DMD'])].
[sujeto(['The', study, objectives, were, '(', 1, ')', to, evaluate, the, reproducibility, of, echocardiographic, measures, of, 'LV', 'function,', '(', 2, ')', to, evaluate, which, echocardiographic, methods, correlate, best, with, 'CMR', 'LV', ejection, fraction, '(', 'LVEF),', and, '(', 3, ')', to, evaluate, whether, 'CMR']), verbo([provides]), complemento([additional, value, compared, with, echocardiography])].
[sujeto(['Thirty-seven', percent, of, segments, not, visible, on, echocardiography, were, believed, to]), verbo([have]), complemento([wall, motion, abnormalities, by, 'CMR'])].
[sujeto(['TGFβ', is, a, multifunctional, cytokine, that, is, critical, in]), verbo([regulating]), complemento([mucosal, immunity])].
[sujeto(['Murine', studies]), verbo([have]), complemento([revealed, that, disruption, of, canonical, 'TGFβ', signaling, leads, to, systemic, inflammation, including, colitis])].
[sujeto(['All', patients, with, confirmed, mutations, in, 'TGFBR1', or, 'TGFBR2,', seen, in, the, 'Johns', 'Hopkins', 'Connective', 'Tissue', 'Disorders', 'clinic,', were, asked, to]), verbo([participate]), complemento([in, the, study])].
[sujeto(['We']), verbo([report]), complemento([an, increased, prevalence, of, 'IBD', in, patients, with, 'LDS', types, 'I', and, 'II'])].
[sujeto(['We']), verbo([report]), complemento([a, 10, -, fold, increase, in, the, prevalence, of, 'IBD', in, patients, with, 'LDS', compared, with, the, general, population])].
[sujeto(['This', case, series, of, patients, with, 'LDS', with, 'IBD']), verbo([suggests]), complemento([that, defective, 'TGFβ', signaling, may, have, an, influence, on, 'IBD', risk])].
[sujeto(['This', study, is, a, retrospective, review, of, inpatient, administration, deviation]), verbo([reports]), complemento([for, an, investigational, drug, that, is, administered, daily, with, infusion, times, of, 8, -, 24, 'hours,', and, variable, treatment, durations, for, each, patient])].
[sujeto(['We']), verbo([report]), complemento([study, design, modifications, made, in, 2007, -, 2008, aimed, at, minimizing, deviations, from, an, investigational, drug, infusion, protocol, approved, by, an, institutional, review, board, and, the, 'United', 'States', 'Food', and, 'Drug', 'Administration'])].
[sujeto(['We']), verbo([found]), complemento([that, the, rate, of, these, types, of, administration, errors, of, the, study, drug, was, significantly, decreased, following, adoption, of, the, specific, study, design, changes])].
[sujeto(['This']), verbo([report]), complemento([provides, guidance, in, the, design, of, clinical, trials, testing, the, safety, and, efficacy, of, study, drugs, administered, via, intravenous, infusion, in, an, inpatient, setting, so, as, to, minimize, drug, administration, protocol, deviations, and, optimize, patient, safety])].
[sujeto(['The', findings]), verbo([provided]), complemento([partial, support, for, our, 'hypotheses:', 'Consistent', with, previous, 'findings,', delinquency, history, and, moral, disengagement, were, significant, predictors, of, recent, aggressive, behavior])].
[sujeto(['Furthermore,', when, 'ethnic/racial', socialization, was, added, to, the, 'model,', promotion, of, mistrust]), verbo([provided]), complemento([additional, predictive, validity, for, aggressive, behavior, above, and, beyond, the, other, factors, assessed])].
[sujeto([',', the, number, of, specific, types, of, adversities, the, child]), verbo([reported]), complemento([being, exposed, 'to)'])].
[sujeto(['We', examined, the, association, between, 18, different, types, of, retrospectively]), verbo([reported]), complemento([adversities, '(', capturing, interpersonal, 'violence,', accidents, and, 'injuries,', social, network, or, witnessing, 'events,', and, other, adverse, 'events)', and, risk, of, 'self-reported', 'past-year', insomnia])].
[sujeto(['We', also, examined, whether, the, age, at, first, exposure, to, adversity, was]), verbo([associated]), complemento([with, the, risk, of, 'insomnia,', and, whether, exposure, to, a, greater, number, of, different, types, of, adversities, '(', 'ie,', 'accumulation)', conferred, an, elevated, risk, of, insomnia])].
[sujeto(['Almost', 'one-third', of, adolescents]), verbo([reported]), complemento(['insomnia,', with, a, higher, prevalence, among, girls, and, those, from, 'racial/ethnic', minority, groups])].
[sujeto(['Exposure', to, adversity]), verbo([confers]), complemento([an, elevated, risk, of, insomnia])].
[sujeto(['The', 'P-PAM', had, acceptable, 'test-retest', 'reliability,', but, no, previously]), verbo([reported]), complemento(['PAM', factor, structure, fit, the, study, data, adequately, for, either, language])].
[sujeto(['The', 'P-PAM']), verbo([has]), complemento([acceptable, reliability, and, validity, in, 'English', and, 'Spanish,', but, a, different, factor, structure, than, the, 'PAM'])].
[sujeto(['Activation', as, measured, by, the, 'P-PAM', may, not]), verbo([have]), complemento([the, same, associations, with, or, impact, on, 'health/healthcare', outcomes, in, pediatrics, compared, with, adults, owing, to, possible, measure, differences, between, the, 'P-PAM', and, 'PAM'])].
[sujeto(['Neuroimaging']), verbo([has]), complemento([suggested, that, amygdala, reactivity, to, emotional, facial, expressions, is, associated, with, antisocial, behavior, '(', 'AB),', particularly, among, those, high, on, 'callous-unemotional', '(', 'CU)', traits])].
[sujeto(['We']), verbo([found]), complemento([that, 'AB,', but, not, 'CU', 'traits,', was, negatively, related, to, amygdala, reactivity, to, fearful, faces])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([substantial, complexity, in, the, relationship, between, amygdala, function, and, 'AB', reflecting, moderating, effects, of, task, 'stimulus,', subregional, 'anatomy,', and, race])].
[sujeto(['Immediate', boys, '(', 'n=677)', and, delayed, girls, '(', 'n=658)']), verbo([increased]), complemento([the, percent, achieving, 30, min, 'MVPA/day', from, 35.9, '%', to, 47.0, '%', '(', odds, ratio, '[', 'OR]=1'])].
[sujeto(['Immediate', girls, '(', 'n=613)', and, delayed, boys, '(', 'n=687)', exhibited, a, nonsignificant]), verbo([increase]), complemento([from, 19.1, '%', to, 21.6, '%', '(', 'OR=1'])].
[sujeto(['STEPs', can]), verbo([have]), complemento([an, impact, on, 'children\'s', 'MVPA', and, time, spent, 'sedentary,', yet, was, unable, to, fully, achieve, the, goal, of, all, children, accumulating, 30, 'minMVPA/day'])].
[sujeto(['Candida', is, a]), verbo([leading]), complemento([cause, of, infection, in, infants, on, extracorporeal, membrane, oxygenation, '(', 'ECMO)'])].
[sujeto(['We', defined, the, therapeutic]), verbo([target]), complemento([as, the, adult, exposure, associated, with, efficacy, in, 'Phase', 'III', 'trials,', and, the, prophylactic, target, as, 'one-half', of, the, therapeutic, target])].
[sujeto(['Dose-exposure', simulations, revealed, that, doses, of, 2.5, and, 5, 'mg/kg/day', matched, exposure]), verbo([targets]), complemento([for, prophylaxis, and, treatment, of, invasive, 'candidiasis,', respectively])].
[sujeto(['Therefore,', community, mental, health, organizations, should, assess, and, understand, their, organizational, climate, and, intervene, with, empirically, based, organizational, strategies, when, necessary, to, reduce, stressful, climates, and]), verbo([maintain]), complemento([adaptable, employees])].
[sujeto(['Mothers', recorded, diarrhea, in, a, diary, and]), verbo([reported]), complemento([results, at, visits, scheduled, every, four, weeks])].
[sujeto(['Our', results]), verbo([provide]), complemento([additional, support, to, increase, 'ART', coverage, for, all, pregnant, 'mothers,', to, control, clinical, 'HIV', 'progression,', reduce, perinatal, 'HIV', 'infection,', but, also, to, reduce, the, risk, of, a, major, cause, of, death, and, morbidity, in, young, children, worldwide])].
[sujeto(['There']), verbo([has]), complemento([been, increasing, interest, in, oxytocin, '(', 'peptide:', 'OT,', 'gene:', 'OXT)', as, a, treatment, pathway, for, neurodevelopmental, disorders, such, as, 'Autism', 'Spectrum', 'Disorder', '(', 'ASD)'])].
[sujeto(['With', advances, in, molecular, 'biology,', research]), verbo([has]), complemento([connected, multiple, gene, regions, to, the, clinical, presentation, of, 'ASD'])].
[sujeto(['Studies']), verbo([have]), complemento([also, shown, that, the, neuropeptide, hormones, 'OT', and, arginine, vasopressin, '(', 'AVP)', influence, mammalian, social, and, territorial, behaviors, and, may, have, treatment, potential, for, neurodevelopmental, disorders])].
[sujeto(['Since', most, studies]), verbo([have]), complemento([focused, on, the, receptors, in, the, 'OT-AVP', 'system,', we, investigated, genetic, variation, within, peptide, genes, for, association, with, phenotypic, 'ASD', features, that, help, identify, subgroups, within, the, spectrum])].
[sujeto(['Associations', with, several, endophenotypes, were, also, 'noted:', 'OXT', rs6133010, was]), verbo([associated]), complemento([with, 'IQ', '(', full, scale, 'IQ,', p, =, 0.008, ;, nonverbal, 'IQ,', p, =, 0.01, ',', verbal, 'IQ,', p, =, 0.006, ')', ;, and, 'OXT', rs4813625, and, 'OXT', rs877172, were, associated, with, 'WB5HT', levels, '(', 'EA,', p, =, 0.027, and, p, =, 0.033, ',', 'respectively)'])].
[sujeto(['RESULTS', show, the, three, 'polymorphisms,', 'OXT', 'rs6084258,', 'OXT', 'rs11697250,', and, 'OXT', 'rs877172,']), verbo([have]), complemento([significant, association, with, pOT, '(', 'EA,', p, =, 0.011, ',', p, =, 0.01, ',', and, p, =, 0.002, ',', 'respectively)'])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'SNPs', near, 'OXT', and, 'AVP', are, associated, with, diagnosis, of, 'ASD,', social, 'behaviors,', restricted, and, repetitive, 'behaviors,', 'IQ,', 'pOT,', and, 'WB5HT'])].
[sujeto(['Mitochondria', are, essential, to]), verbo([maintaining]), complemento([and, regulating, metabolic, function, of, cells, and, organs])].
[sujeto(['Multiple', reversible, 'post-translational', protein, modifications, are, located, in, the, mitochondria, that, are, responsive, to, nutrient, availability, and, redox, 'conditions,', and, which, can]), verbo([act]), complemento([in, 'protein-protein', interactions, to, modify, diverse, mitochondrial, functions])].
[sujeto(['With', the, advent, of, mass, proteomic, screening, 'techniques,', there]), verbo([has]), complemento([been, a, vast, increase, in, the, array, of, known, mitochondrial, 'post-translational', modifications, and, their, protein, targets])].
[sujeto(['However,', many, of, these, reversible, modifications]), verbo([act]), complemento([as, regulatory, mechanisms, in, mitochondria, and, show, promise, for, 'mitochondrial-targeted', therapeutic, strategies])].
[sujeto(['Thirteen', of, 24, symptoms, were, independently]), verbo([associated]), complemento([with, reductions, in, overall, or, 'domain-specific', 'HRQOL'])].
[sujeto(['Patients', commonly]), verbo([reported]), complemento([distress, from, two, or, more, 'symptoms,', corresponding, to, larger, 'HRQOL', score, reductions])].
[sujeto(['Neither', cancer, 'type,', time, since, 'progression,', treatment, 'intensity,', 'sex,', nor, age, was]), verbo([associated]), complemento([with, 'HRQOL', scores, in, multivariable, models])].
[sujeto(['Among', 25, children, completing, surveys, during, the, last, 12, &, 'nbsp;weeks', of, 'life,', 11, distressing, symptoms, were]), verbo([associated]), complemento([with, reductions, in, 'HRQOL'])].
[sujeto(['Symptom', distress, is, strongly]), verbo([associated]), complemento([with, 'HRQOL'])].
[sujeto(['The', 'intestine\'s', ability, to, recover, from, catastrophic, injury]), verbo([requires]), complemento([quiescent, intestinal, stem, cells, '(', 'q-ISCs)'])].
[sujeto(['While', rapidly, cycling, '(', 'Lgr5+)', crypt, base, columnar, '(', 'CBC)', 'ISCs', normally]), verbo([maintain]), complemento([the, 'intestine,', they, are, highly, sensitive, to, pathological, injuries, '(', 'irradiation,', 'inflammation)', and, must, be, restored, by, 'q-ISCs', to, sustain, intestinal, homeostasis])].
[sujeto(['Despite', clear, relevance, to, human, 'health,', virtually, nothing, is, known, regarding, the, factors, that]), verbo([regulate]), complemento(['q-ISCs'])].
[sujeto(['A', comprehensive, understanding, of, these, mechanisms, would, likely]), verbo([lead]), complemento([to, targeted, new, therapies, with, profound, therapeutic, implications, for, patients, with, gastrointestinal, conditions])].
[sujeto(['MIS', admissions, were]), verbo([associated]), complemento([with, a, significantly, shorter, length, of, stay, '(', 1.0, versus, 1.8, 'days,', 'p < 0'])].
[sujeto(['After', adjusting, for, 'patient-level', confounders, '(', 'age,', 'gender,', 'insurance,', treatment, 'year,', and, 'comorbidity),', and, 'hospital-level', factors, '(', 'region,', 'bedsize,', and, teaching, 'status),', 'MIS', 'UNC', was]), verbo([associated]), complemento([with, a, significantly, higher, rate, of, postoperative, urinary, complications, such, as, 'UTIs,', urinary, 'retention,', and, renal, injury, '(', 'OR', 3.1, ',', 'p = 0'])].
[sujeto(['On', the, other, 'hand,', patients, treated, with, 'MIS', 'UNC']), verbo([required]), complemento([substantially, shorter, postoperative, 'hospitalization,', with, an, average, 'LOS', roughly, half, that, of, open, 'UNC', cases])].
[sujeto(['Compared', with, open, 'surgery,', 'MIS', 'UNC', was]), verbo([associated]), complemento([with, shorter, 'LOS', but, higher, costs, and, possibly, higher, urinary, complication, rates])].
[sujeto(['Interleukin', '(', 'IL)-18', is, an, important, effector, of, innate, and, adaptive, 'immunity,', but, its, expression, must, also, be, tightly]), verbo([regulated]), complemento([because, it, can, potentiate, lethal, systemic, inflammation, and, death])].
[sujeto(['We']), verbo([find]), complemento([that, 'IL-18-null', neonatal, mice, are, highly, protected, from, polymicrobial, 'sepsis,', whereas, replenishing, 'IL-18', increased, lethality, to, sepsis, or, endotoxemia])].
[sujeto(['Indeed,', 'IL-18', administration, in, sepsis]), verbo([increased]), complemento(['IL-17A', production, by, murine, intestinal, γδT, cells, as, well, as, 'Ly6G(+)', myeloid, 'cells,', and, blocking, 'IL-17A', reduced, 'IL-18-potentiated', mortality, to, both, neonatal, sepsis, and, endotoxemia])].
[sujeto(['Reverse-transcription', quantitative, 'real-time', 'PCR']), verbo([has]), complemento([been, used, for, target, gene, expression, analysis, on, 'M'])].
[sujeto(['However,', to, 'date,', the, stability, of, available, reference, genes]), verbo([has]), complemento([been, insufficient])].
[sujeto(['persicae,', whereas, ribosomal, protein, 'L27', '(', 'L27)', were]), verbo([found]), complemento([to, be, the, least, stable, reference, genes, for, abiotic, studies, '(', 'photoperiod,', temperature, and, insecticide, 'susceptibility)'])].
[sujeto(['Our']), verbo([finding]), complemento([not, only, sheds, light, on, establishing, an, accurate, and, reliable, normalization, of, 'qRT-PCR', data, in, 'M'])].
[sujeto([persicae]), verbo([involving]), complemento(['RNA', interference, and, functional, gene, research])].
[sujeto(['Based', on, computer, simulations, of, the, 'PTC', and, on, previous, biochemical, 'evidence,', the, 'N-terminal', 'α-amino', group, of, 'L27', was]), verbo([suggested]), complemento([to, take, part, in, the, 'peptidyl-transfer', reaction])].
[sujeto(['However,', the, contribution, of, this, group, to, catalysis]), verbo([has]), complemento([not, been, tested, experimentally])].
[sujeto(['Likewise,', 'L27', is, not]), verbo([required]), complemento([for, the, 'peptidyl-tRNA', hydrolysis, during, termination])].
[sujeto(['The', crystal, structure, of, the, 'SAV1646', protein, from, the, pathogenic, microorganism, 'Staphylococcus', aureus]), verbo([has]), complemento([been, determined, at, 1.7, 'Å', resolution])].
[sujeto(['The', protein, molecules]), verbo([associate]), complemento([as, dimers, in, the, crystal, and, in, 'solution,', with, the, monomers, related, by, a, 'pseudo-twofold', rotation, axis])].
[sujeto(['Ribosomal', protein, 'L27', is, a, component, of, the, eubacterial, large, ribosomal, subunit, that]), verbo([has]), complemento([been, shown, to, play, a, critical, role, in, substrate, stabilization, during, protein, synthesis])].
[sujeto(['This', function, is]), verbo([mediated]), complemento([by, the, 'L27', 'N-terminus,', which, protrudes, into, the, peptidyl, transferase, center])].
[sujeto(['We']), verbo([have]), complemento([identified, a, cysteine, 'protease,', conserved, among, bacteria, containing, the, 'L27', 'N-terminal', 'extension,', which, performs, 'post-translational', cleavage, of, 'L27'])].
[sujeto(['Ribosomal', biology, in, eubacteria]), verbo([has]), complemento([largely, been, studied, in, the, 'Gram-negative', bacterium, 'Escherichia', 'coli;', our, findings, indicate, that, there, are, aspects, of, the, basic, biology, of, the, ribosome, in, 'S'])].
[sujeto(['This', research, lays, the, foundation, for, the, development, of, new, therapeutic, approaches, that]), verbo([target]), complemento([this, novel, pathway])].
[sujeto(['The', 'Russian', wheat, aphid, '(', 'RWA),', 'Diuraphis', noxia, 'Kurdjumov,', is, a, major, global, pest, of, wheat, and, barley, production, that]), verbo([causes]), complemento([enormous, economic, damage])].
[sujeto(['Few', studies]), verbo([have]), complemento([been, conducted, to, explore, and, decipher, the, molecular, basis, of, 'RWA', strategies, to, evade, plant, defense, mechanisms])].
[sujeto(['Gene', expression, studies, of, 'RWA', in, response, to, wheat, genotypes, carrying, different, 'RWA', resistance, genes]), verbo([have]), complemento([been, initiated, in, our, 'group;', 'however,', a, secure, and, accurate, understanding, of, 'RWA', gene, expression, is, dependent, on, identification, of, suitable, reference, genes])].
[sujeto(['Results', of, 'geNorm,', 'NormFinder,', and, 'BestKeeper', expression, analyses, support, the, use, of, actin, and, ribosomal, protein, 'L27', in, 'RT-qPCR', studies, of, 'RWA', gene, expression, in, studies]), verbo([involving]), complemento(['RWA-wheat', interactions])].
[sujeto(['We', previously, detected, three, single, nucleotide, polymorphisms, '(', 'SNPs)']), verbo([associated]), complemento([with, 'BMS', number, of, 'Japanese', 'Black', in, 'Oita', 'prefecture:', c])].
[sujeto(['These', findings]), verbo([suggest]), complemento([the, presence, of, 'inter-allelic', interactions, among, genes, affecting, the, development, of, beef, marbling])].
[sujeto(['Single', molecule, methods]), verbo([have]), complemento([revealed, that, heterogeneity, is, common, in, biological, systems])].
[sujeto(['These', observations]), verbo([suggest]), complemento([that, the, ribosome, may, function, through, multiple, reaction, pathways])].
[sujeto(['There', is, limited, information, available, on, suitable, reference, genes, to, be, used, for, studies]), verbo([involving]), complemento([human, epicardial, adipose, tissue])].
[sujeto(['Their', use, as, reference, gene, pairs, might, contribute, to, the]), verbo([enhanced]), complemento([robustness, of, relative, quantification, in, the, studies, involving, the, human, epicardial, adipose, tissue])].
[sujeto(['Using', a, classification, algorithm, to, sort, 'single-molecule', fluorescence, resonance, energy, transfer, data, into, 'subpopulations,', we]), verbo([found]), complemento([that, the, ribosome, dynamics, detected, at, the, peptidyl, transferase, center, are, highly, inhomogeneous])].
[sujeto(['The', pretranslocation, complex]), verbo([has]), complemento([at, least, four, subpopulations, that, sample, two, hybrid, 'states,', whereas, the, posttranslocation, complex, is, mainly, static])].
[sujeto(['We', observed, transitions, among, the, ribosome, subpopulations, under, various, 'conditions,', including, 1, ')', ',', in, the, presence, of, 'EF-G;', 2, ')', ',', 'spontaneously;', 3, ')', ',', in, different, 'buffers,', and, 4, ')', ',']), verbo([bound]), complemento([to, antibiotics])].
[sujeto(['This', proposal, may]), verbo([have]), complemento([important, implications, for, the, regulation, of, cellular, translation, rates])].
[sujeto(['The', concentration, of, leptin, in, blood, plasma]), verbo([increases]), complemento([with, age, and, obesity, and, is, associated, with, the, level, of, leptin, mRNA, in, adipose, tissue])].
[sujeto(['In', our, study, we, used, a, freeware, computer, program, '(', 'geNorm)', to, evaluate, the, most, stable, among, eight, 'ICG', genes, '(', 'β-actin,', hypoxanthine, phosphoribosyltransferase, 1, ',', 'TATA']), verbo([binding]), complemento(['protein,', 'glyceraldehyde-3-phosphate', 'dehydrogenase,', ornithine, decarboxylase, antizyme, 1, ',', 60, 'S', ribosomal, protein, 'L27,', 40, 'S', ribosomal, protein, 'S29,', eukaryotic, elongation, factor, '(', 1, ')', in, 90, mRNA, samples, of, backfat, tissue])].
[sujeto(['Moreover,', we, analyzed, relationship, between, 'C3469T', 'Lep', polymorphism, and, level, of, leptin, 'mRNA,', but, did, not]), verbo([find]), complemento([significant, associations])].
[sujeto(['Our', study]), verbo([provides]), complemento([a, new, panel, of, housekeeping, genes, for, normalization, of, the, expression, of, a, gene, of, interest, in, adipose, tissue])].
[sujeto(['Although', it, is, clear, that, viomycin]), verbo([inhibits]), complemento([the, ribosome, intersubunit, 'ratcheting,', there, are, contradictory, reports, about, whether, the, antibiotic, viomycin, stabilizes, the, tRNA, hybrid, or, classical, state])].
[sujeto(['By', using, a, 'single-molecule', 'FRET', method, to, directly, observe, the, tRNA, dynamics, relative, to, ribosomal, protein, 'L27,', we]), verbo([have]), complemento([found, that, viomycin, trapped, the, hybrid, state, within, certain, ribosome, subgroups, but, did, not, significantly, suppress, the, tRNA, dynamics])].
[sujeto(['Viomycin', also]), verbo([promoted]), complemento(['peptidyl-tRNA', fluctuation, in, the, posttranslocation, 'complex,', implying, 'that,', in, addition, to, acylated, 'P-site', 'tRNA,', the, decoding, center, also, played, an, important, role, of, ribosome, locking, after, translocation])].
[sujeto(['Therefore,', viomycin]), verbo([inhibits]), complemento([translocation, by, trapping, the, hybrid, state, in, the, pretranslocation, complex, and, disturbing, the, stability, of, posttranslocation, complex])].
[sujeto(['The', widespread, occurrence, of, gene, duplication, followed, by, rapid]), verbo([loss]), complemento([of, function, of, some, of, the, duplicate, gene, copies, suggests, the, independent, evolution, of, 'loss-of-function', alleles, of, duplicate, genes, in, divergent, lineages, of, speciation])].
[sujeto(['Here,', we]), verbo([found]), complemento([a, novel, 'loss-of-function', allele, of, 'S27', in, the, 'Asian', annual, wild, species, 'Oryza', 'nivara,', designated, 'S27-niv', '(', 's),', that, leads, to, 'F(1)', pollen, sterility, in, a, cross, between, 'O'])].
[sujeto(['Our', results]), verbo([provide]), complemento([experimental, evidence, that, different, types, of, 'loss-of-function', alleles, are, distributed, in, geographically, and, phylogenetically, isolated, species, and, represent, a, potential, mechanism, for, postzygotic, isolation, in, divergent, species])].
[sujeto(['This', incompatibility]), verbo([acts]), complemento([as, postzygotic, reproductive, 'isolation,', which, results, in, the, irreversible, divergence, of, species])].
[sujeto(['Here,', we, show, that, the, reciprocal]), verbo([loss]), complemento([of, duplicated, genes, encoding, mitochondrial, ribosomal, protein, 'L27', causes, hybrid, pollen, sterility, in, 'F(1)', hybrids, of, the, cultivated, rice, 'Oryza', sativa, and, its, wild, relative, 'O'])].
[sujeto(['Functional', analysis, revealed, that, this, gene, is, essential, for, the, later, stage, of, pollen, 'development,', and, distribution, analysis]), verbo([suggests]), complemento([that, the, gene, duplication, occurred, before, the, divergence, of, the, 'AA', genome, species])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, the, upregulation, and, downregulation, of, 'RP', genes, in, tumors, of, colorectal, and, nasopharyngeal, carcinomas, '(', 'NPCs),', respectively])].
[sujeto(['Herein,', we, show, that, a, subset, of, 'RP', genes, for, the, large, ribosomal, subunit, is, differentially]), verbo([expressed]), complemento([among, cell, lines, derived, from, the, human, nasopharyngeal, epithelium])].
[sujeto(['Three', such, genes, '(', 'RPL27,', 'RPL37a', and, 'RPL41)', were]), verbo([found]), complemento([to, be, significantly, downregulated, in, all, cell, lines, derived, from, 'NPC', tissues, compared, with, a, nonmalignant, nasopharyngeal, epithelial, cell, line])].
[sujeto(['The', expression, of, 'RPL37a', and, 'RPL41', genes, in, human, nasopharyngeal, tissues]), verbo([has]), complemento([not, been, reported, previously])].
[sujeto(['Pro-inflammatory', 'stimuli,', such, as, endotoxins]), verbo([released]), complemento([by, 'Gram-negative', 'bacteria,', are, potent, stimulators, of, prostaglandin, '(', 'PG)', synthesis])].
[sujeto(['COX-2', gene, transcription, was, 19, and, 69, times, higher, in, pyometra, than, in, diestrous, and, anestrous, endometria, '(', p, &, 'lt;', 0.001, ')', ',', while, 'PGFS', gene, transcription, had, a, 3, -, and, 600, -, fold]), verbo([increase]), complemento([in, pyometra, endometria, compared, to, normal, diestrous, and, anestrous, endometria, '(', p, &, 'lt;', 0.001, ')'])].
[sujeto(['Based', on, these, 'results,', we]), verbo([suggest]), complemento([that, 'pyometra-associated', 'E'])].
[sujeto([coli, endotoxin]), verbo([release]), complemento([stimulates, the, 'up-regulation', of, 'COX-2', 'PGFS', and, 'mPGES-1', gene, transcription, in, the, endometrium])].
[sujeto(['Activity-dependent', 'long-term', synaptic, plasticity]), verbo([requires]), complemento([gene, expression, and, protein, synthesis])].
[sujeto(['Since', 'PARP-1', decondenses, 'chromatin,', we, hypothesize, that, this, enzyme]), verbo([regulates]), complemento([the, expression, of, specific, genes, essential, for, 'long-term', synaptic, plasticity, that, underlies, 'LTM'])].
[sujeto(['The']), verbo([increase]), complemento([in, the, expression, of, rRNAs, is, long, lasting, and, dynamic])].
[sujeto(['Pulse-labeling', 'RNA', studies, showed, a, 'PARP-dependent']), verbo([increase]), complemento([in, rRNAs, but, not, in, the, total, 'RNA', 24, h, after, 5, -, 'HT', treatment])].
[sujeto(['Moreover,', the, expression, of, both, the, 'AprpL27a', '(', 'Aplysia', ribosomal, protein, 'L27a)', and, the, 'ApE2N', '(', 'Aplysia', 'ubiquitin-conjugating', enzyme, 'E2N)', mRNAs, also]), verbo([increased]), complemento([after, 5, -, 'HT'])].
[sujeto(['Thus,', our, results]), verbo([suggest]), complemento([that, 5, -, 'HT,', in, part, by, regulating, 'PARP-1', 'activity,', alters, the, expression, of, transcripts, required, for, the, synthesis, of, new, ribosomes, necessary, for, 'LTF'])].
[sujeto(['No', 'high-resolution', structure, of, the, intact, ribosome]), verbo([has]), complemento([contained, a, complete, active, site, including, both, 'A-', and, 'P-site', tRNAs])].
[sujeto(['In', 'addition,', although, past, structures, of, the, 50, 'S', subunit]), verbo([have]), complemento([found, no, ordered, proteins, at, the, 'PTC,', biochemical, evidence, suggests, that, specific, proteins, are, capable, of, interacting, with, the, 3, '\'', ends, of, tRNA, ligands])].
[sujeto(['They', also]), verbo([reveal]), complemento([interactions, between, the, ribosomal, proteins, 'L16', and, 'L27', and, the, tRNA, 'substrates,', helping, to, elucidate, the, role, of, these, proteins, in, peptidyl, transfer])].
[sujeto(['Inherited', bone, marrow, failure, syndromes, comprise, a, series, of, disorders]), verbo([caused]), complemento([by, various, gene, mutations])].
[sujeto(['However,', recent, advances, in, 'next-generation', sequencing]), verbo([has]), complemento([enabled, simultaneous, testing, of, all, causative, genes, to, be, performed, at, an, acceptable, cost])].
[sujeto(['Furthermore,', we, established, a]), verbo([target]), complemento([gene, sequencing, system, to, cover, 189, genes, associated, with, pediatric, blood, diseases, to, assist, genetic, diagnoses, in, clinical, practice])].
[sujeto(['Gene', expression, 'profile‑based', taxonomy, of, breast, cancer, '(', 'BC)']), verbo([has]), complemento([been, described, as, a, significant, breakthrough, in, comprehending, the, differences, in, the, origin, and, behavior, of, cancer, to, allow, individually, tailored, therapeutic, approaches])].
[sujeto(['The', ontological, gene, analyses, revealed, that, the, majority, of, the, deregulated, genes, in, the, 'HNEpi', samples, were, part, of, the, functional, gene, group, directly]), verbo([associated]), complemento([with, 'BC', origin, and, prognosis])].
[sujeto(['Functional', analysis, showed, that, the, most, frequent, gene, deregulations, occurred, in, genes]), verbo([associated]), complemento([with, apoptosis, and, cell, cycle, regulation, in, 'BCTis', 'samples,', and, with, 'angiogenesis,', regulation, of, the, cell, cycle, and, transcriptional, activity, in, 'HNEpi', samples])].
[sujeto(['The', molecular, profiling, of, 'HNEpi', breast, tissue, revealed, gene, expression, abnormalities, that, may, represent, potential, markers, of]), verbo([increased]), complemento([risk, for, 'HER2‑positive', malignant, transformation, of, breast, 'tissue,', and, may, be, able, to, be, employed, as, predictors, of, prognosis])].
[sujeto(['Lp9', and, 'Lp91', were, also, quite, effective, in]), verbo([inducing]), complemento([the, expression, of, 'Cox-1', and, 'Cox-2', in, 'HT-29', cells, as, can, be, reflected, from, their, 'ratios,', i])].
[sujeto(['Comparing', 'WT', mice, across, three, genetic, 'backgrounds,', we]), verbo([found]), complemento([that, different, genes, were, more, tightly, regulated, in, each, strain])].
[sujeto(['We']), verbo([have]), complemento([developed, a, ranked, profile, of, the, top, performing, reference, genes, in, skeletal, muscle, across, these, common, mouse, strains])].
[sujeto(['Furthermore', we, demonstrate, that, a, poor, reference, gene, results, in]), verbo([increased]), complemento([variability, in, the, normalized, expression, of, a, gene, of, 'interest,', and, can, result, in, loss, of, significance])].
[sujeto(['For', the, most, accurate, 'normalization,', it, is, important, to, test, several, genes, and, use, the, geometric, mean, of, at, least, three, of, the, most, stably]), verbo([expressed]), complemento([genes])].
[sujeto(['We', hypothesized, that, the, risk, of, aggregation, was]), verbo([increased]), complemento([upon, hormone, stimulation, and, assessed, the, state, of, the, intracellular, protein, degradation, systems, in, the, kidney, from, control, rats, and, rats, receiving, aldosterone, or, angiotensin, 'II', treatment, for, 7, days])].
[sujeto(['Fluorescence', sorted, aggresomes, contained, various, rat, keratins, known, to, be]), verbo([expressed]), complemento([in, renal, tubules, as, assessed, by, protein, mass, spectrometry])].
[sujeto(['Aldosterone', administration]), verbo([increased]), complemento([the, abundance, of, the, proximal, tubular, aggresomal, protein, keratin, 5, ',', the, ribosomal, protein, 'RPL27,', 'ataxin-3,', and, the, chaperone, heat, shock, protein, 70, -, 4, with, no, apparent, change, in, the, 'aggresome-autophagosome', markers])].
[sujeto(['Angiotensin', 'II']), verbo([induced]), complemento([aggregation, of, 'RPL27', specifically, in, proximal, 'tubules,', again, without, apparent, change, in, antiaggregating, proteins, or, the, 'aggresome-autophagosome', markers])].
[sujeto(['Taken', 'together,', we]), verbo([find]), complemento([that, the, renal, proximal, tubules, display, aggresome, formation, and, autophagy])].
[sujeto(['Despite', an]), verbo([increase]), complemento([in, 'aggregation-prone', protein, load, in, these, tubules, during, hormone, 'treatment,', renal, proximal, tubules, seem, to, have, sufficient, capacity, for, removing, protein, aggregates, from, the, cells])].
[sujeto(['Peripheral', blood, may, be, useful, in, cancer, 'classification,', and, therefore, we, investigated, the, gene, expression]), verbo([found]), complemento([by, 'Affymetrix', 'HG-U133', 'Plus2'])].
[sujeto(['A', gene, signature, in, peripheral, blood, which, can, distinguish, 'HCC', patients, and, healthy, controls, may]), verbo([have]), complemento([been, identified])].
[sujeto(['In', 'pig,', the, high, expression, in, luteal, phases]), verbo([suggested]), complemento(['that,', 'LIF', may, be, mainly, secreted, in, respond, to, the, increased, of, progesterone, concentration, and, it, can, be, connected, with, the, preparation, of, the, uterus, for, implantation])].
[sujeto(['In', our, recent, manuscript, we]), verbo([reported]), complemento([identification, and, characterization, of, a, 'semi-dominant', mutation, in, ribosomal, protein, 'RPL27a,', which, disrupts, plant, growth, and, shoot, development])].
[sujeto(['Genetic', interactions, between, 'rpl27ac-1d', and, other, ribosomal, protein, mutants, indicates, 'rpl27ac-1d']), verbo([has]), complemento([reduced, ribosome, function])].
[sujeto(['Our', results, highlight, a, role, for, ribosomal, proteins, in, growth, and, development, and, we, propose, that, the, ribosome]), verbo([regulates]), complemento([specific, patterning, events, during, development])].
[sujeto([7, -, 'fold)', between, tumor, and, normal, mucosa, but, can, be, used, for, 'normalization,', depending, on, the, resolution]), verbo([required]), complemento([for, the, assay])].
[sujeto(['Genes', encoding, plastid, ribosomal, proteins, are, distributed, between, the]), verbo([nuclear]), complemento([and, plastid, genomes, in, higher, 'plants,', and, coordination, of, their, expression, is, likely, to, be, required, for, functional, plastid, protein, synthesis])].
[sujeto(['A', custom, microarray]), verbo([has]), complemento([been, used, to, examine, the, patterns, of, accumulation, of, transcripts, from, plastid, and, nuclear, genes, encoding, plastid, ribosomal, proteins, during, seedling, development, in, tobacco, and, 'Arabidopsis'])].
[sujeto(['Deletion', analysis, of, the, 'RPL27', promoter, in, transgenic, plants, revealed, that, the, identified, shared, 'cis-elements', were, not, all]), verbo([required]), complemento([for, 'wild-type', expression, 'patterns,', and, full, 'developmental,', 'light-', and, 'plastid-regulation', can, be, conveyed, by, a, region, of, the, promoter, from, -, 235, to, +, 1, relative, to, the, transcription, start, site])].
[sujeto(['Our', results]), verbo([reveal]), complemento([a, specific, function, of, 'DLGS97', in, the, regulation, of, the, size, of, 'GLUR', fields, and, their, subunit, composition])].
[sujeto(['Strikingly', the, absence, of, any, of, 'DLG', proteins, at, the, presynaptic, terminal, disrupts, the, clustering, and, localization, of, the, calcium, channel, 'DmCa1A', subunit, '(', 'Cacophony),']), verbo([decreases]), complemento([the, action, 'potential-evoked', release, probability, and, alters, 'short-term', plasticity])].
[sujeto(['Further,', optimized, quality, spaces, composition, was, used, via, enhancer, '(', 'Rutin)', to, design, advanced, 'bio-formulation', '(', 'ANbp)', and, done, its, evaluation, '(', entrapment, 'efficiency,', particle, 'size,', drug]), verbo([release]), complemento([&, 'amp;', 'kinetics)'])].
[sujeto(['Employing', yeast, 'two-hybrid', and, 'co-immunoprecipitation', '(', 'Co-IP)', 'assays,', we, characterized, a, 'LIN-2(CASK)']), verbo([binding]), complemento([site, overlapping, with, that, of, reported, 'UNC-104', activator, protein, 'SYD-2(Liprin-α)', on, the, 'motor\'s', stalk, domain])].
[sujeto(['Further,', we, demonstrated, that, the, 'L27', domain]), verbo([interacts]), complemento([with, the, sterile, alpha, motifs, '(', 'SAM)', domains, of, 'SYD-2,', while, the, 'GUK', domain, is, able, to, interact, with, both, the, coiled, coils, and, 'SAM', domains, of, 'SYD-2'])].
[sujeto(['The', absence, of, the, 'motor-activating', function, of, 'LIN-2', results, in]), verbo([increased]), complemento([motor, clustering, along, 'axons,', thus, retaining, 'SNB-1', cargo, in, cell, bodies])].
[sujeto(['From', our, 'study,', we, conclude, that, 'LIN-2', and, 'SYD-2']), verbo([act]), complemento([in, a, functional, complex, to, regulate, the, motor, with, 'LIN-2', being, the, more, prominent, activator])].
[sujeto(['Multiple', essential, small, 'GTPases', are]), verbo([involved]), complemento([in, the, assembly, of, the, ribosome, or, in, the, control, of, its, activity])].
[sujeto(['Among', 'them,', 'ObgE', '(', 'CgtA)']), verbo([has]), complemento([been, shown, recently, to, act, as, a, ribosome, antiassociation, factor, that, binds, to, 'ppGpp,', a, regulator, whose, 'best-known', target, is, 'RNA', polymerase])].
[sujeto(['The', present, study, was, aimed, at, elucidating, the, expression, of, obgE, in, 'Escherichia', coli, 'We', show, that, obgE, is, cotranscribed, with, ribosomal, protein, genes, rplU, and, rpmA, and, with, a, gene, of, unknown, 'function,', yhbE, 'We', show, here, that, about, 75, '%', of, the, transcripts, terminate, before, 'obgE,', because, there, is, a, transcriptional, terminator, between, rpmA, and, yhbE, 'As', expected, for, ribosomal, protein, 'operons,', expression, was, highest, during, exponential, 'growth,']), verbo([decreased]), complemento([during, entry, into, stationary, 'phase,', and, became, almost, undetectable, thereafter])].
[sujeto(['However,', regulation, by, these, factors, appears, to, occur, 'post-transcription', 'initiation,', since, no, effects, of, ppGpp, and, 'DksA', on, rplU, promoter, activity, were, observed, in, vitro, 'The']), verbo([conserved]), complemento([and, essential, 'ObgE', 'GTPase', binds, to, the, ribosome, and, affects, its, assembly])].
[sujeto(['ObgE']), verbo([has]), complemento([also, been, reported, to, impact, chromosome, 'segregation,', cell, 'division,', resistance, to, 'DNA', 'damage,', 'and,', perhaps, most, 'interestingly,', persister, formation, and, antibiotic, tolerance])].
[sujeto(['Despite', its, 'importance,', no, studies, on, 'ObgE', expression]), verbo([have]), complemento([been, reported])].
[sujeto(['We', demonstrate, here, that, obgE, is]), verbo([expressed]), complemento([from, an, operon, encoding, two, ribosomal, 'proteins,', that, the, 'operon\'s', expression, varies, with, the, growth, 'phase,', and, that, it, is, dependent, on, the, transcription, regulators, ppGpp, and, 'DksA'])].
[sujeto(['Pseudouridylation', of, messenger, 'RNA', emerges, as, an, abundant, modification]), verbo([involved]), complemento([in, gene, expression, regulation])].
[sujeto(['Here', we, present, a, 3.1, -, 'Å', crystal, structure, of, 'Escherichia', coli]), verbo([release]), complemento([factor, 1, '(', 'RF1)', bound, to, the, 70, 'S', ribosome, in, response, to, the, 'ΨAA', codon])].
[sujeto(['The', structure]), verbo([reveals]), complemento([that, recognition, of, a, modified, stop, codon, does, not, differ, from, that, of, a, canonical, stop, codon])].
[sujeto(['Our', in, vitro, biochemical, results, support, this]), verbo([finding]), complemento([by, yielding, nearly, identical, rates, for, peptide, release, from, 'E'])].
[sujeto([coli, 'RF1-specific', interactions, and]), verbo([suggests]), complemento([involvement, of, 'L27', in, bacterial, translation, termination])].
[sujeto(['Our', results, are, consistent, with, a, mechanism, in, which, read, through, of, a, pseudouridylated, stop, codon, in, bacteria, results, from]), verbo([increased]), complemento([decoding, by, 'near-cognate', tRNAs, '(', 'miscoding)', rather, than, from, decreased, efficiency, of, termination])].
[sujeto(['This', quality, improvement, orthogonal, design, array, '(', 'L27)', was, used, as, a, mathematical, tool, to]), verbo([find]), complemento([and, study, the, response, prediction, of, independent, as, well, as, significant, variables, '(', 'A=poly-concentration;', 'B=bio-enhancer', and, 'C=ratio', of, organic, 'medium)'])].
[sujeto(['The', array, orthogonal, '(', 3, ×, 3, =, 'L27)', at, each, 'level/spaces']), verbo([has]), complemento([been, studied, with, respect, to, responses, changeable, '(', dependent, 'factors);', entrapment, enhancement, '(', 'X;', evaluated, using, particle, 'size;', 'Y)'])].
[sujeto(['We']), verbo([have]), complemento([focused, on, the, exceedingly, specific, heterotetrameric, assembly, of, 'Lin-2', and, 'Lin-7', '(', 'L27)', 'domains,', which, work, as, 'protein-protein', interaction, modules, in, many, scaffold, proteins])].
[sujeto(['In', this, 'study,', we, used, a, bacterial, expression, system, to, produce, a, bispecific, antibody, that, was, heterotetramerized, through, 'L27', domains, and, that]), verbo([targeted]), complemento([both, epidermal, growth, factor, receptor, '(', 'EGFR)', and, 'Fcγ', receptor, 'III', '(', 'FcγRIII', or, 'CD16)'])].
[sujeto(['The', tetramerized, antibody]), verbo([bound]), complemento([to, 'EGFR', and, 'CD16', 'simultaneously,', according, to, results, from, flow, cytometry, and, surface, plasmon, resonance, 'spectroscopy,', respectively])].
[sujeto(['Taken', 'together,', the, results, show, that, our, method]), verbo([has]), complemento([high, potential, for, the, 'cost-efficient', production, of, highly, active, therapeutic, antibodies])].
[sujeto(['Detecting', changes, in, the, expression, levels, of, cell, antigens, could]), verbo([provide]), complemento([critical, information, for, the, diagnosis, of, many, 'diseases,', for, 'example,', 'leukemia,', 'lymphoma,', and, immunodeficiency, 'diseases,', detecting, minimal, residual, 'disease,', monitoring, immunotherapies, and, discovery, of, meaningful, clinical, disease, markers])].
[sujeto(['One', of, the, most, significant, challenges, in, flow, cytometry, is, how, to, best]), verbo([ensure]), complemento([measurement, quality, and, generate, consistent, and, reproducible, 'inter-laboratory', and, 'intra-laboratory', results, across, multiple, cytometer, platforms, and, locations, longitudinally, over, time])].
[sujeto(['CD19', quantification, was, performed, on, three, of, the, standardized, instruments, relative, to, 'CD4', expression, on, 'T', lymphocytes, with, a, known, amount, of, antibody]), verbo([bound]), complemento([per, cell, '(', 'ABC)', as, a, quantification, standard])].
[sujeto(['We', previously, demonstrated, that, 'Nrf2-deficient', mice]), verbo([have]), complemento([heightened, susceptibility, to, 'asthma,', including, elevated, oxidative, 'stress,', 'inflammation,', 'mucus,', and, airway, hyperresponsiveness, '(', 'AHR)', '(', 'Rangasamy', 'T,', 'Guo', 'J,', 'Mitzner', 'WA,', 'Roman', 'J,', 'Singh', 'A,', 'Fryer', 'AD,', 'Yamamoto', 'M,', 'Kensler', 'TW,', 'Tuder', 'RM,', 'Georas', 'SN,', 'Biswal', 'S'])].
[sujeto(['Cell-specific', activation, of, 'Nrf2', in, club, cells, of, the, airway, epithelium, significantly, reduced, 'allergen-induced', 'AHR,', 'inflammation,', 'mucus,', 'Th2', cytokine, 'secretion,', oxidative, 'stress,', and, airway, leakiness, and]), verbo([increased]), complemento([airway, levels, of, tight, junction, proteins, zonula, 'occludens-1', and, 'E-cadherin'])].
[sujeto(['In', isolated, airway, epithelial, 'cells,', 'Nrf2']), verbo([enhanced]), complemento([epithelial, barrier, function, and, increased, localization, of, zonula, 'occludens-1', to, the, cell, surface])].
[sujeto(['New', therapeutic, options, are, needed, for, 'asthma,', and, this, study, demonstrates, that, activation, of, 'Nrf2', in, lung, epithelial, cells, is, a, novel, potential, therapeutic]), verbo([target]), complemento([to, reduce, asthma, susceptibility])].
[sujeto(['In', 'contrast,', the, multiple, 'PDZ', 'domain-containing', protein, 'Pals1-associated', tight, junction, protein, '(', 'PATJ),', which]), verbo([has]), complemento([been, described, to, form, a, complex, with, 'Crb/Sdt,', is, not, essential, for, apical, basal, polarity, or, for, the, stability, of, the, 'Crb/Sdt', complex, in, the, 'Drosophila', epidermis])].
[sujeto(['Our', data, further, indicate, that, the, four, 'PDZ', domains, of, 'PATJ', 'function,', to, a, large, 'extent,', in, 'redundancy,']), verbo([regulating]), complemento([the, function, of, the, protein])].
[sujeto(['Interestingly,', the, 'PATJ-Sdt', heterodimer, is, not, only]), verbo([recruited]), complemento([to, the, apical, 'cell-cell', contacts, by, binding, to, 'Crb', but, depends, on, functional, 'Bazooka', '(', 'Baz)'])].
[sujeto(['However,', biochemical, experiments, show, that, 'PATJ']), verbo([associates]), complemento([with, both, 'complexes,', the, 'Baz-Sdt', and, the, 'Crb-Sdt', 'complex,', in, the, mature, epithelium, of, the, embryonic, 'epidermis,', suggesting, a, role, of, these, two, complexes, for, the, function, of, 'PATJ', during, the, development, of, 'Drosophila'])].
[sujeto(['Thermosensitive', genic, male, sterile, '(', 'TGMS)', lines, and, 'photoperiod-sensitive', genic, male, sterile, '(', 'PGMS)', lines]), verbo([have]), complemento([been, successfully, used, in, hybridization, to, improve, rice, yields])].
[sujeto(['Microarray-based', transcriptome, profiling, of, 'TGMS-Co27', and, 'wild-type', 'Hejiang', 19, '(', 'H1493)', plants, grown, at, high, and, low, temperatures, revealed, that, 15462, probe, sets, representing, 8303, genes, were, differentially]), verbo([expressed]), complemento([in, the, two, 'lines,', under, the, two, 'conditions,', or, both])].
[sujeto(['Some', genes, important, for, pollen, development, were, strongly]), verbo([repressed]), complemento([in, 'TGMS-Co27', at, high, temperature])].
[sujeto(['More', 'significantly,', 'series-cluster', analysis, of, differentially]), verbo([expressed]), complemento([genes, '(', 'DEGs)', between, 'TGMS-Co27', plants, grown, under, the, two, conditions, showed, that, low, temperature, induced, the, expression, of, a, gene, cluster])].
[sujeto(['This', cluster, was]), verbo([found]), complemento([to, be, essential, for, sterility, transition])].
[sujeto(['It', includes, many, meiosis, 'stage-related', genes, that, are, probably, important, for, thermosensitive, male, sterility, in, 'TGMS-Co27,', inter, 'alia:', 'Arg/Ser-rich', domain, '(', 'RS)-containing', zinc, finger, 'proteins,', polypyrimidine, 'tract-binding', proteins, '(', 'PTBs),', 'DEAD/DEAH', box, 'RNA', 'helicases,', 'ZOS', '(', 'C2H2', zinc, finger, proteins, of, 'Oryza', 'sativa),', at, least, one, 'polyadenylate-binding', protein, and, some, other, 'RNA', recognition, motif, '(', 'RRM)', 'domain-containing', proteins]), verbo([involved]), complemento([in, 'post-transcriptional', 'processes,', eukaryotic, initiation, factor, 5, 'B', '(', 'eIF5B),', ribosomal, proteins, '(', 'L37,', 'L1p/L10e,', 'L27', and, 'L24),', 'aminoacyl-tRNA', synthetases, '(', 'ARSs),', eukaryotic, elongation, factor, 'Tu', '(', 'eEF-Tu)', and, a, peptide, chain, release, factor, protein, involved, in, translation])].
[sujeto(['Findings', from, this, and, previous, studies, indicate, that, sets, of, genes]), verbo([involved]), complemento([in, 'post-transcriptional', and, translation, processes, are, involved, in, thermosensitive, male, sterility, transitions, in, 'TGMS-Co27'])].
[sujeto([gattii, was, cultivated, in, high, fluconazole, concentrations, and, developed]), verbo([decreased]), complemento([drug, susceptibility])].
[sujeto(['The', 'L27/01F', did, not, affect, the, central, nervous, 'system,', while, the, effect, in, brain]), verbo([caused]), complemento([by, 'L27/01', strain, began, after, only, 12, hours])].
[sujeto(['Mice', infected, with, 'L27/01F', presented, lower, production, of, the, 'pro-inflammatory', 'cytokines,', with]), verbo([increased]), complemento([cellular, recruitment, in, the, lungs, and, severe, pulmonary, disease])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, stress, to, fluconazole, alters, the, capsule, of, 'C'])].
[sujeto(['We', recently, identified, that, tau]), verbo([associates]), complemento([with, proteins, known, to, participate, in, endoplasmic, reticulum, '(', 'ER)-associated', degradation, '(', 'ERAD);', 'consequently,', 'ERAD', becomes, dysfunctional, and, causes, neurotoxicity])].
[sujeto(['We', hypothesized, that, tau]), verbo([associates]), complemento([with, other, 'ER', 'proteins,', and, that, this, association, could, also, lead, to, cellular, dysfunction, in, 'AD'])].
[sujeto(['Samples', from, both, conditions, containing, tau, and, its]), verbo([associated]), complemento([proteins, were, analyzed, by, mass, spectrometry])].
[sujeto(['These', proteins]), verbo([participate]), complemento([in, over, sixteen, functional, 'categories,', the, most, abundant, being, involved, in, 'RNA', translation])].
[sujeto(['We']), verbo([found]), complemento([that, tau, associated, equally, with, the, ribosomal, protein, 'L28', but, more, robustly, with, the, ribosomal, protein, 'P0'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, the, differential, association, between, tau, and, 'ER', proteins, in, disease, could, reveal, the, pathogenic, processes, by, which, tau, induces, cellular, dysfunction])].
[sujeto(['Despite', the, availability, of, an, effective, 'vaccine,', 'Japanese', encephalitis, remains, a, significant]), verbo([cause]), complemento([of, morbidity, and, mortality, in, many, parts, of, 'Asia'])].
[sujeto(['Japanese', encephalitis, is]), verbo([caused]), complemento([by, the, 'Japanese', encephalitis, virus, '(', 'JEV),', a, mosquito, transmitted, flavivirus])].
[sujeto(['This', study, sought, to, determine, whether, 'GRP78,', a, 'well-characterized', flavivirus, 'E', protein]), verbo([interacting]), complemento(['protein,', interacted, with, 'JEV', 'E', protein, in, insect, 'cells,', and, whether, this, interaction, was, mediated, at, the, cell, surface])].
[sujeto(['GRP78', was, shown, to]), verbo([interact]), complemento([with, 'JEV', 'E', protein, by, 'coimmunoprecipitation,', and, was, additionally, shown, to, interact, with, voltage, dependent, anion, protein, '(', 'VDAC)', through, the, same, methodology])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([of, relocalization, of, 'VDAC', in, response, to, 'JEV', infection, and, suggests, that, this, may, be, a, part, of, the, 'JEV', replication, strategy, in, insect, cells])].
[sujeto(['Here,', we, analyze, the, late, stages, of, assembly, of, the, 50, 'S', subunit, using, 'Bacillus', subtilis, cells, depleted, of, 'RbgA,', a, highly]), verbo([conserved]), complemento(['GTPase'])].
[sujeto(['We']), verbo([found]), complemento([that, 'RbgA-depleted', cells, accumulate, late, assembly, intermediates, bearing, 'sub-stoichiometric', quantities, of, ribosomal, proteins, 'L16,', 'L27,', 'L28,', 'L33a,', 'L35', and, 'L36'])].
[sujeto(['Cryo-electron', microscopy, and, chemical, probing, revealed, that, the, central, 'protuberance,', the, 'GTPase']), verbo([associating]), complemento([region, and, 'tRNA-binding', sites, in, this, intermediate, are, unstructured])].
[sujeto(['These', findings, demonstrate, that, key, functional, sites, of, the, 50, 'S', subunit, remain, unstructured, until, late, stages, of, 'maturation,']), verbo([preventing]), complemento([the, incomplete, subunit, from, prematurely, engaging, in, translation])].
[sujeto(['Finally,', structural, and, biochemical, analysis, of, a, ribosome, particle, depleted, of, 'L16', indicate, that, 'L16']), verbo([binding]), complemento([is, necessary, for, the, stimulation, of, 'RbgA', 'GTPase', activity, 'and,', in, 'turn,', release, of, this, 'co-factor,', and, for, conversion, of, the, intermediate, to, a, complete, 50, 'S', subunit])].
[sujeto(['The', efficiency, and, accuracy, of, the, subunit, assembly, are, tightly]), verbo([regulated]), complemento([and, closely, monitored])].
[sujeto(['Our', structural, data]), verbo([reveal]), complemento([two, major, intermediate, states, for, the, 45, 'S', particles])].
[sujeto(['Detailed', analysis, indicates, that, the, orientation, of, 'H38', accounts, for, the, global, conformational, differences, in, these, intermediate, 'structures,', and]), verbo([suggests]), complemento([that, the, reorientation, of, 'H38', to, its, native, position, is, 'rate-limiting', during, the, 'late-stage', assembly])].
[sujeto(['The', 'TsMRP-L28', transcript, was]), verbo([expressed]), complemento([in, newborn, 'larvae,', muscle, larvae, and, male, and, female, adult, worms])].
[sujeto(['Western', blot, showed, that, 'TsMRP-L28', was]), verbo([expressed]), complemento([in, muscle, larvae, and, adult, worms])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'TsMRP-L28', is, required, for, the, early, development, of, 'T'])].
[sujeto(['Among', the, 57, genes, that, encode, ribosomal, proteins, in, the, genome, of, 'Bacillus', 'subtilis,', a, 'Gram-positive', 'bacterium,', 50, genes, were]), verbo([targeted]), complemento([by, systematic, inactivation])].
[sujeto(['In', conjunction, with, previous, 'reports,', 22, ribosomal, proteins]), verbo([have]), complemento([been, shown, to, be, nonessential, in, 'B'])].
[sujeto(['These', data]), verbo([provide]), complemento([the, first, evidence, in, 'B'])].
[sujeto([subtilis, that, 'L1', and, 'S21', are]), verbo([required]), complemento([for, the, progression, of, cellular, differentiation])].
[sujeto(['A', lack, of, individual, plastid, ribosomal, proteins, '(', 'PRPs)', can]), verbo([have]), complemento([diverse, phenotypic, effects, in, 'Arabidopsis', 'thaliana,', ranging, from, embryo, lethality, to, compromised, 'vitality,', with, the, latter, being, associated, with, photosynthetic, lesions, and, decreases, in, the, expression, of, plastid, proteins])].
[sujeto(['In', this, 'study,', reverse, genetics, was, employed, to, study, the, function, of, eight, 'PRPs,', five, of, which, '(', 'PRPS1,', -, 'S20,', -, 'L27,', -, 'L28', and, -, 'L35)']), verbo([have]), complemento([not, been, functionally, characterised, before])].
[sujeto(['PRPL1', and, 'PRPL4']), verbo([have]), complemento([been, described, as, essential, for, embryo, 'development,', but, their, mutant, phenotypes, are, analysed, in, detail, here])].
[sujeto(['We']), verbo([found]), complemento([that, 'PRPS20,', -, 'L1,', -, 'L4,', -, 'L27', and, -, 'L35', are, required, for, basal, ribosome, 'activity,', which, becomes, crucial, at, the, globular, stage, and, during, the, transition, from, the, globular, to, the, heart, stage, of, embryogenesis])].
[sujeto(['Thus,', lack, of, any, of, these, 'PRPs']), verbo([leads]), complemento([to, alterations, in, cell, division, 'patterns,', and, embryo, development, ceases, prior, to, the, heart, stage])].
[sujeto(['PRPS1,', -, 'S17', and, -, 'L24', appear, not, to, be]), verbo([required]), complemento([for, basal, ribosome, activity, and, the, organism, can, complete, its, entire, life, cycle, in, their, absence])].
[sujeto(['Relative', quantification, of, gene, expression, by, 'real-time', 'PCR', relies, on, the, use, of, reference, genes, whose]), verbo([expressed]), complemento([levels, remain, consistent, across, experimental, conditions])].
[sujeto(['Several', reference, genes]), verbo([have]), complemento([been, used, to, quantify, gene, expression, in, human, epilepsy, surgery, tissue])].
[sujeto(['However,', their, reliability]), verbo([has]), complemento([not, been, validated, in, 'detail,', although, this, is, crucial, in, interpreting, 'epilepsy-related', changes, of, gene, expression])].
[sujeto(['NormFinder', 'analysis,', in, 'contrast,', indicated, 'HPRT', as, the, most, stable, single, gene, and, recommended, the, geometric, mean, of, 'TATA-box']), verbo([binding]), complemento([protein, '(', 'TBP)', and, 'NSE', levels, as, 'NF'])].
[sujeto(['Different', values, of, upregulation, of, glial, fibrillary, protein, '(', 'GFAP)', expression, were]), verbo([found]), complemento([in, 'TLE', tissue, compared, to, control, tissue, depending, on, the, 'NF', 'used:', 4.5, -, fold, '(', 'geNorm-NF),', 4.7, -, fold, '(', 'NormFinder-NF),', 4.2, -, fold, '(', vs])].
[sujeto(['However,', normalization, to, 'HPRT']), verbo([suggests]), complemento([an, apparent, increase, of, 'GARα5', expression])].
[sujeto(['In', 'contrast,', normalization, to, single, and, probably, less, stably]), verbo([expressed]), complemento([genes, may, not, deliver, accurate, results])].
[sujeto(['The', unique, metabolism, of, tumors, was, described, many, years, ago, by, 'Otto', 'Warburg,', who, identified, tumor, cells, with]), verbo([increased]), complemento([glycolysis, and, decreased, mitochondrial, activity])].
[sujeto(['However,', &, 'quot;aerobic', 'glycolysis"', generates, fewer, 'ATP', per, glucose, molecule, than, mitochondrial, oxidative, 'phosphorylation,', so, in, terms, of, energy, 'production,', it, is, unclear, how]), verbo([increasing]), complemento([a, less, efficient, process, provides, tumors, with, a, growth, advantage])].
[sujeto(['We', carried, out, a, screen, for]), verbo([loss]), complemento([of, genetic, elements, in, pancreatic, tumor, cells, that, accelerated, their, growth, as, 'tumors,', and, identified, mitochondrial, ribosomal, protein, 'L28', '(', 'MRPL28)'])].
[sujeto(['Knockdown', of, 'MRPL28', in, these, cells]), verbo([decreased]), complemento([mitochondrial, 'activity,', and, increased, 'glycolysis,', but, 'paradoxically,', decreased, cellular, growth, in, vitro])].
[sujeto(['Following', 'Warburg\'s', 'observations,', this, mutation]), verbo([causes]), complemento([decreased, mitochondrial, 'function,', compensatory, increase, in, glycolysis, and, accelerated, growth, in, vivo])].
[sujeto(['Conversely,', expression, of, the, mitochondrial, uncoupling, protein, 1, '(', 'UCP1)']), verbo([increased]), complemento([oxygen, consumption, and, decreased, tumor, growth])].
[sujeto(['Finally,', treatment, of, tumor, bearing, animals, with, dichloroacetate, '(', 'DCA)']), verbo([increased]), complemento([pyruvate, consumption, in, the, 'mitochondria,', increased, total, oxygen, 'consumption,', increased, tumor, hypoxia, and, slowed, tumor, growth])].
[sujeto(['We', interpret, these, findings, to, show, that, 'non-oncogenic', genetic, changes, that, alter, mitochondrial, metabolism, can]), verbo([regulate]), complemento([tumor, growth, through, modulation, of, the, consumption, of, 'oxygen,', which, appears, to, be, a, rate, limiting, substrate, for, tumor, proliferation])].
[sujeto(['Phosphorylation', of, bacterial, ribosomal, proteins]), verbo([has]), complemento([been, known, for, 'decades;', 'however,', there, is, still, very, limited, information, available, on, specific, locations, of, the, phosphorylation, sites, in, ribosomal, proteins, and, the, role, they, might, play, in, protein, synthesis])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([mapped, the, specific, phosphorylation, sites, in, 24, 'Escherichia', coli, ribosomal, proteins, by, tandem, mass, spectrometry])].
[sujeto(['Detection', of, phosphorylation, was, achieved, by, either, phosphorylation, specific, visualization, 'techniques,', 'ProQ', 'staining,', and, antibodies, for, 'phospho-Ser,', 'Thr,', and, 'Tyr;', or, by, mass, spectrometry, equipped, with, a, capability, to, detect, addition, and]), verbo([loss]), complemento([of, the, phosphate, moiety])].
[sujeto(['We']), verbo([found]), complemento([the, small, subunit, '(', 30, 'S)', proteins, 'S3,', 'S4,', 'S5,', 'S7,', 'S11,', 'S12,', 'S13,', 'S18,', and, 'S21', and, the, large, subunit, '(', 50, 'S)', proteins, 'L1,', 'L2,', 'L3,', 'L5,', 'L6,', 'L7/L12,', 'L13,', 'L14,', 'L16,', 'L18,', 'L19,', 'L21,', 'L22,', 'L28,', and, 'L31', to, be, phosphorylated, at, one, or, more, residues])].
[sujeto(['Cytoplasmic', stress, granules, '(', 'SGs)', are, specialized, regulatory, sites, of, mRNA, translation, that, form, under, different, stress, conditions, known, to]), verbo([inhibit]), complemento([translation, initiation])].
[sujeto(['The', formation, of, 'SG', occurs, via, two, 'pathways;', the, eukaryotic, initiation, factor, '(', 'eIF)', 2, alpha, 'phosphorylation-dependent', pathway]), verbo([mediated]), complemento([by, stress, and, the, eIF2alpha, 'phosphorylation-independent', pathway, mediated, by, inactivation, of, the, translation, initiation, factors, eIF4A, and, eIF4G])].
[sujeto(['In', this, 'study,', we, investigated, the, effects, of]), verbo([targeting]), complemento([different, translation, initiation, factors, and, steps, in, 'SG', formation, in, 'HeLa', cells])].
[sujeto(['Met-tRNAi(Met)', ternary, translation, initiation, complexes, is, sufficient, to]), verbo([induce]), complemento(['SGs'])].
[sujeto(['Likewise,', reduced, levels, of, 'eIF4B,', 'eIF4H,', or, 'polyA-binding', 'protein,', also]), verbo([trigger]), complemento(['SG', formation])].
[sujeto(['In', 'contrast,', depletion, of, the, 'cap-binding', protein, eIF4E, or]), verbo([preventing]), complemento([its, assembly, into, eIF4F, results, in, modest, 'SG', formation])].
[sujeto(['Intriguingly,', interfering, with, the, last, step, of, translation, initiation, by, blocking, the, recruitment, of, 60, 'S', ribosome, either, with, 2, -, '(', 4, -, 'methyl-2,6-dinitroanilino)-N-methylpropionamideis', or, through, depletion, of, the, large, ribosomal, subunits, protein, 'L28', does, not]), verbo([induce]), complemento(['SG', assembly])].
[sujeto(['Our', study, identifies, translation, initiation, steps, and, factors]), verbo([involved]), complemento([in, 'SG', formation, as, well, as, those, that, can, be, targeted, without, induction, of, 'SGs'])].
[sujeto(['However,', little, detail, is, known, about, how, 'DENV']), verbo([interacts]), complemento([with, the, 'host-cell', machinery, to, facilitate, its, translation, and, replication])].
[sujeto(['In', 'DENV-infected', 'HepG2', 'cells,', an]), verbo([increase]), complemento([in, the, level, of, 'LC3-II', '(', 'microtubule-associated', protein, 1, light, chain, 3, form, 'II),', the, autophagosomal, 'membrane-bound', form, of, 'LC3,', was, 'observed,', and, 'LC3', was, found, to, 'co-localize', with, dsRNA, and, 'DENV', 'NS1', 'protein,', as, well, as, ribosomal, protein, 'L28,', indicating, the, presence, of, at, least, some, of, the, 'DENV', 'translation/replication', machinery, on, autophagic, vacuoles])].
[sujeto(['Inhibition', of, fusion, of, autophagic, vacuoles, with, lysosomes, resulted, in, an]), verbo([increase]), complemento([in, both, intracellular, and, extracellular, 'virus,', and, 'co-localization', observed, between, 'mannose-6-phosphate', receptor, '(', 'MPR)', and, dsRNA, and, between, 'MPR', and, 'LC3', identified, the, autophagic, vacuoles, as, amphisomes])].
[sujeto(['Amphisomes', are, formed, as, a, result, of, fusion, between, endosomal, and, autophagic, 'vacuoles,', and, as, such]), verbo([provide]), complemento([a, direct, link, between, virus, entry, and, subsequent, replication, and, translation])].
[sujeto(['This']), verbo([report]), complemento([concerns, an, immunohistochemical, investigation, on, 'RNA-related', proteins, in, the, basophilic, inclusions, '(', 'BIs)', from, patients, with, 'adult-onset', atypical, motor, neuron, disease])].
[sujeto(['Ribonuclease', pretreatment, abolished, the, 'methylgreen-pyronin', 'staining,']), verbo([suggesting]), complemento([that, the, 'BIs', contained, 'RNA'])].
[sujeto(['Our', results, imply, that, translation, attenuation, could, be]), verbo([involved]), complemento([in, the, processes, of, 'BI', formation, in, this, disorder])].
[sujeto([pulmonis, were, compared, with, those]), verbo([reported]), complemento([for, 'Mycoplasma', genitalium, and, 'Bacillus', subtilis])].
[sujeto(['In', contrast, to, earlier]), verbo([reports]), complemento([suggesting, that, mycoplasmas, were, limited, in, their, 'DNA', repair, 'machinery,', mutations, in, 'recA,', 'uvrA,', uvrB, and, uvrC, resulted, in, a, 'DNA-repair', deficient, phenotype])].
[sujeto(['Streptomyces', coelicolor, contains, paralogous, versions, of, seven, ribosomal, proteins, '(', 'S14,', 'S18,', 'L28,', 'L31,', 'L32,', 'L33,', and, 'L36),', which, differ, in, their, potential, to]), verbo([bind]), complemento([structural, zinc])].
[sujeto(['Here,', mutational, studies]), verbo([suggest]), complemento([that, the, 'C(-)', version, of, 'L31', can, functionally, replace, its, 'C(+)', paralogue, only, when, expressed, at, an, artificially, elevated, level])].
[sujeto(['Crystal', structures, of, the, 50, 'S', ribosomal, subunit, from, 'Haloarcula', marismortui, complexed, with, two, antibiotics]), verbo([have]), complemento([identified, new, sites, at, which, antibiotics, interact, with, the, ribosome, and, inhibit, protein, synthesis])].
[sujeto([13, -, 'Deoxytedanolide']), verbo([binds]), complemento([to, the, 'E', site, of, the, 50, 'S', subunit, at, the, same, location, as, the, 'CCA', of, 'tRNA,', and, thus, appears, to, inhibit, protein, synthesis, by, competing, with, deacylated, tRNAs, for, 'E', site, binding])].
[sujeto(['Girodazole']), verbo([binds]), complemento([near, the, 'E', site, 'region,', but, is, somewhat, buried, and, may, inhibit, tRNA, binding, by, interfering, with, conformational, changes, that, occur, at, the, 'E', site])].
[sujeto(['In', 'addition,', protein, 'L28,', which, is, unique, to, the, eubacterial, 'E', 'site,', overlaps, the, site, occupied, by, 13, -, 'deoxytedanolide,', precluding, its]), verbo([binding]), complemento([to, eubacterial, ribosomes])].
[sujeto(['Focal', brain, ischemia]), verbo([leads]), complemento([to, a, slow, type, of, neuronal, death, in, the, penumbra, that, starts, several, hours, after, ischemia, and, continues, to, mature, for, days])].
[sujeto([the, ribosomes, and, their]), verbo([associated]), complemento([nascent, 'polypeptides,', protein, synthesis, initiation, factors, and, 'co-translational', chaperones])].
[sujeto(['Biochemical', study, further]), verbo([suggested]), complemento([that, translational, complex, 'components,', including, small, ribosomal, subunit, protein, 6, '(', 'S6),', large, subunit, protein, 28, '(', 'L28),', eukaryotic, initiation, factors, 2, 'alpha,', '4E', and, '3eta,', and, 'co-translational', chaperone, 'heat-shock', cognate, protein, 70, '(', 'HSC70)', and, 'co-chaperone', 'Hdj1,', were, all, irreversibly, clumped, into, large, abnormal, protein, aggregates, after, ischemia])].
[sujeto(['This', study, clearly, demonstrates, that, focal, ischemia]), verbo([leads]), complemento([to, irreversible, aggregation, of, protein, synthesis, machinery, that, contributes, to, neuronal, death, after, focal, brain, ischemia])].
[sujeto(['Furthermore,', this, is, the, first]), verbo([report]), complemento([of, a, bacteriocin, being, produced, by, 'Lactobacillus', animalis])].
[sujeto(['These', significant, findings]), verbo([suggest]), complemento([that, soil, may, be, a, common, source, for, the, isolation, of, novel, 'bacteriocin-producing', lactic, acid, bacteria])].
[sujeto(['Azacitidine', '(', 'AZA)', is, a, hypomethylating, drug, used, to, treat, disorders]), verbo([associated]), complemento([with, myelodysplasia, and, related, neoplasms])].
[sujeto(['Approximately', 50, &, 'nbsp;%', of, patients, do, not]), verbo([respond]), complemento([to, 'AZA', and, have, very, poor, outcomes])].
[sujeto(['We', searched, for, specific, genes, whose, expression, level, was]), verbo([associated]), complemento([with, response, status])].
[sujeto(['At', 'baseline,', a, comparison, of, the, responders, and, 'non-responders', showed, 52, differentially]), verbo([expressed]), complemento([genes, '(', 'P < 0'])].
[sujeto(['Functional', annotation, of, the, deregulated, genes, revealed, categories, primarily, related, to, ribosomes, and, pathways]), verbo([associated]), complemento([with, proliferation])].
[sujeto(['Our', data, indicate, that, 'AZA', treatment, failure, is]), verbo([associated]), complemento([with, the, 'up-regulation', of, ribosomal, 'genes/pathways', that, are, likely, related, to, intensive, proteosynthesis, in, 'proliferative/neoplastic', cells, of, 'non-responders'])].
[sujeto(['A', group, 'I', intron, was]), verbo([found]), complemento([in, the, rpl28, 'gene,', whereas, the, other, introns, were, group, 'II', introns])].
[sujeto([purpureum, plastid, genome]), verbo([has]), complemento([one, 'non-coding', 'RNA', '(', 'ncRNA)', 'gene,', 29, tRNA, genes, and, two, nonidentical, ribosomal, 'RNA', operons])].
[sujeto(['One', rRNA, operon]), verbo([has]), complemento([a, 'tRNA(Ala)(UGC)', gene, between, the, rrs, and, the, rrl, 'genes,', whereas, another, has, a, 'tRNA(Ile)(GAU)', gene])].
[sujeto(['Phylogenetic', analyses]), verbo([suggest]), complemento([that, the, plastids, of, 'Heterokontophyta,', 'Cryptophyta', and, 'Haptophyta', originated, from, the, subphylum, 'Rhodophytina'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, a, 'large-scale', rearrangement, occurred, in, the, plastid, genome, of, 'P'])].
[sujeto(['Comprehensive', discovery, of, genetic, mechanisms, of, drug, resistance, and, identification, of, 'in vivo', drug]), verbo([targets]), complemento([represent, significant, challenges])].
[sujeto(['Using', this, 'tool,', we, discovered, almost, all, genes, 'that,', due, to, mutations, or, modest, 'overexpression,']), verbo([confer]), complemento([resistance, to, 'rapamycin,', 'cycloheximide,', and, amphotericin, 'B'])].
[sujeto(['Most', significant, among, the, resistance, genes, were, drug, 'targets,', including, multiple]), verbo([targets]), complemento([of, a, given, drug])].
[sujeto(['With', amphotericin, 'B,', we, discovered, the, highly]), verbo([conserved]), complemento([membrane, protein, 'Pmp3', as, a, potent, resistance, factor, and, a, possible, target])].
[sujeto(['Widespread', application, of, this, tool, should, allow, rapid, identification, of]), verbo([conserved]), complemento([resistance, mechanisms, and, targets, of, many, more, compounds])].
[sujeto(['New', genes, and, alleles, that]), verbo([confer]), complemento([resistance, to, other, stresses, can, also, be, discovered])].
[sujeto(['In', contrast, to, typical, plastids, that]), verbo([have]), complemento(['∼100-200', kb, circular, 'genomes,', the, dinoflagellate, plastid, genome, is, composed, of, minicircles, that, each, encode, 0, -, 5, genes])].
[sujeto(['On', day, 0, ',', genes, with]), verbo([increased]), complemento([expression, 'were:', 'photons,', 'none;', simulated, 'SPE,', 'Id1;', photons, +, simulated, 'SPE,', 'Bax,', 'Id1,', 'Snrp70'])].
[sujeto(['Oxygen', radical, production, by, liver, phagocytes, was, significantly]), verbo([enhanced]), complemento([by, photons, on, day, 21])].
[sujeto(['Genome-wide', scans]), verbo([have]), complemento([mapped, economically, important, quantitative, trait, loci, '(', 'QTL)', for, mastitis, susceptibility, in, dairy, cattle, at, the, telomeric, end, of, bovine, chromosome, 18, '(', 'BTA18)'])].
[sujeto(['In', order, to]), verbo([increase]), complemento([the, density, of, markers, in, this, chromosomal, region, and, to, improve, breakpoint, resolution, in, the, 'human-bovine', comparative, 'map,', this, study, describes, the, chromosomal, assignment, of, seven, newly, developed, 'gene-associated', markers, and, five, microsatellites, and, eight, previously, mapped, sequence, tagged, site, markers, near, these, 'QTL'])].
[sujeto(['The', orientation, of, 'KCNJ14,', 'BAX,', 'CD37,', 'NKG7,', 'LIM2,', 'PRKCG,', 'TNNT1,', 'MGC2705,', 'RPL28,', 'EPN1,', 'ZNF582,', 'ZIM2,', 'STK13,', 'ZNF132', and, 'SLC27A5', on, the, 3000, -, rad, radiation, hybrid, '(', 'RH)', map, of, 'BTA18', is, homologous, to, the, organization]), verbo([found]), complemento([on, the, corresponding, 10, 'Mbp', of, human, chromosome, 19, q, '(', 'HSA19q)'])].
[sujeto(['The', location, of, 'KCNJ14', and, 'SLC27A5', flanking, the, 'RH', map, on, 'BTA18q25-26']), verbo([has]), complemento([been, confirmed, by, fluorescence, in, situ, hybridization])].
[sujeto(['Using', southern, 'blot,', the, clones, of, each, band, were, controlled, for, false, positive, results]), verbo([caused]), complemento([by, probable, heterogeneity, of, cDNA, population, with, the, same, size])].
[sujeto(['Corresponding', 'full-length', gene, sequences, was, predicted, using, human, genome, project, 'data,', related, transcripts, were]), verbo([translated]), complemento([and, used, for, various, 'protein/motif', searches, to, speculate, their, probable, functions])].
[sujeto(['The', expression, of, mal, gene, was, remarkably, down]), verbo([regulated]), complemento([in, all, 10, surveyed, tumor, tissues])].
[sujeto(['Akr1c2,', a, member, of, the, 'aldo-keto', reductase, 1, 'C', 'family,', which, is]), verbo([involved]), complemento([in, metabolism, of, sex, hormones, and, 'xenobiotics,', was, 'up-regulated', in, 8, out, of, 10, inspected, 'ESCC', samples])].
[sujeto(['The', mal, gene, which, is, 'switched-off', in, all, 'ESCC', samples, can, be, considered, as, a, tumor, suppressor, gene, that, more, studies, in, its, regulation, may]), verbo([lead]), complemento([to, valuable, explanations, in, 'ESCC', development])].
[sujeto(['Akr1c2', which, is, 'up-regulated', in, 'ESCC', probably, plays, an, important, role, in, tumor, development, of, esophagus, and, may, be, proposed, as, a, potential, molecular]), verbo([target]), complemento([in, 'ESCC', treatments])].
[sujeto(['Differential', display, technique, in, spite, of, many, disadvantages, is, still, a, valuable, technique, in, gene, function, exploration, studies, to]), verbo([find]), complemento([new, candidates, for, improved, ones, like, gene, chips])].
[sujeto([lactis, host, 'strains,', using, the, cloned, chromosomal, 'fragments,']), verbo([led]), complemento([to, an, increased, level, of, resistance, to, some, mitochondrial, inhibitors, and, azole, antifungals])].
[sujeto(['Along', with, three, novel, 'ORFs,', encoding, two, proteins, of, unknown, molecular, function, and, one, putative, hexose, 'transporter,', this, segment, also, contained, the, 'Kl-RPL28', 'gene,']), verbo([found]), complemento([to, be, responsible, for, the, cycloheximide, resistance, of, heterologous, transformants])].
[sujeto(['The', coding, region, of, 'Kl-RPL28', was]), verbo([found]), complemento([to, be, interrupted, with, one, intron, near, the, 5, '\'', end])].
[sujeto(['The', nucleotide, sequence, data]), verbo([reported]), complemento([in, this, paper, were, submitted, to, 'GenBank', and, assigned, the, accession, number, 'AF493565'])].
[sujeto(['The', human, ortholog, of, 'L28', is, also, 'ubiquitinated,', indicating, that, this, modification, is, highly]), verbo([conserved]), complemento([in, evolution])].
[sujeto(['L28', ubiquitination, is]), verbo([inhibited]), complemento([by, a, 'Lys63', to, 'Arg', substitution, in, 'ubiquitin,', indicating, that, 'L28', is, modified, by, a, 'variant,', 'Lys63-linked', multiubiquitin, chain])].
[sujeto(['Therefore,', these, data]), verbo([suggest]), complemento([a, regulatory, role, for, multiubiquitin, chains, that, is, reversible, and, does, not, function, to, target, the, acceptor, protein, for, degradation])].
[sujeto(['During', systematic, analysis, of, the, mRNAs]), verbo([expressed]), complemento([in, a, human, colorectal, carcinoma, with, the, aim, of, evidencing, new, makers, of, the, disease, '(', 'Frigerio', et, al])].
[sujeto(['Because', expression, of, several, mRNAs, encoding, ribosomal, proteins, was]), verbo([found]), complemento([strongly, altered, during, colorectal, 'carcinogenesis,', sequence, of, these, 'transcripts,', not, previously, described, in, 'human,', was, completed, and, their, expression, analyzed])].
[sujeto(['Sequence', analysis]), verbo([suggested]), complemento([that, 'v-Ryk', is, more, homologous, to, 'receptor-type', tyrosine, kinases, than, to, 'nonreceptor-type', kinases])].
[sujeto(['By', reconstitution, of, a, virus, from, its, 'cDNA,', the, 'v-ryk', oncogene]), verbo([has]), complemento([been, shown, to, be, fully, responsible, for, the, transforming, activity, of, the, 'RPL30', virus])].
[sujeto(['The', 'v-Ryk', protein, was, shown, to, be, first, synthesized, as, a, 150, -, kDa, precursor, and, then, cleaved, into, the, mature, 69, -, kDa, 'gp37-Ryk', fusion, 'protein,', both, parts, of, which, were]), verbo([found]), complemento([to, be, localized, to, the, membrane, fraction])].
[sujeto(['As', expected, from, the, sequence, of, 'v-Ryk,', immunoprecipitates, of, 'v-Ryk', from, 'RPL30-transformed', cells, were]), verbo([found]), complemento([to, display, a, protein, tyrosine, kinase, activity, in, 'vitro,', and, the, levels, of, 'tyrosine-phosphorylated', proteins, are, elevated, in, 'v-ryk-transformed', cells])].
[sujeto(['L27a', contains, 147, amino, acids, '(', the, 'NH2-terminal', methionine, is, removed, after, translation, of, the, 'mRNA)', and]), verbo([has]), complemento([a, molecular, weight, of, 16, 476])].
[sujeto(['Hybridization', of, the, cDNA, to, digests, of]), verbo([nuclear]), complemento(['DNA', suggests, that, there, are, 18, -, 22, copies, of, the, 'L27a', gene])].
[sujeto(['Rat', ribosomal, protein, 'L28']), verbo([has]), complemento([136, amino, acids, '(', its, 'NH2-terminal', methionine, is, also, processed, after, 'translation)', and, has, a, molecular, weight, of, 15, 707])].
[sujeto(['Hybridization', of, the, cDNA, to, digests, of]), verbo([nuclear]), complemento(['DNA', suggests, that, there, are, 9, or, 10, copies, of, the, 'L28', gene])].
[sujeto(['Corrections', are, recorded, in, the, sequences]), verbo([reported]), complemento([before, for, rat, ribosomal, proteins, 'S4', and, 'S12'])].
[sujeto(['This']), verbo([report]), complemento([characterizes, virologic, resistance, to, 'VEL', in, these, patients])].
[sujeto(['In', 'GT1a', and, 'GT3', 'patients,', pretreatment, 'RASs', were]), verbo([associated]), complemento([with, a, slightly, reduced, 'HCV', 'RNA', response, compared, to, that, of, patients, without, pretreatment, 'RASs;', among, patients, with, 'GT1b,', 'GT2,', and, 'GT4,', no, significant, difference, in, response, was, observed, in, those, with, or, without, pretreatment, 'RASs'])].
[sujeto(['(', 'This', study]), verbo([has]), complemento([been, registered, at, 'ClinicalTrials'])].
[sujeto(['Resistance', testing, was, performed, using, 'population-based', sequencing, of, the, 'NS5A', region, for, all, patients, at, 'baseline,', and, for, patients, with, virologic, failure, or, relapse, and, 'HCV-RNA', '≥', 1000, 'IU/mL,', to, investigate, any, link, between, 'NS5A', polymorphisms]), verbo([associated]), complemento([with, daclatasvir, resistance, and, virologic, outcome])].
[sujeto(['Consistent', with, these, 'observations,', a, multivariate, logistic, regression, analysis, in, 'GT1b-infected', patients, demonstrated, that, 'SVR12', was]), verbo([associated]), complemento([with, 'IL28B', host, genotype, '(', 'CC', vs, 'non-CC,', 'P', =, 0.011, ')', and, cirrhosis, status, '(', absent, vs, 'present,', 'P', =, 0.031, ')'])].
[sujeto(['NS5A', polymorphisms]), verbo([associated]), complemento([with, daclatasvir, resistance, '(', at, 'L28,', 'R30,', 'L31,', or, 'Y93)', were, observed, in, 17.3, '%', of, 'GT1b-infected', patients, at, 'baseline;', such, variants, did, not, appear, to, be, absolute, predictors, of, failure, since, 72.1, '%', of, these, patients, achieved, 'SVR12', compared, with, 86.9, '%', without, these, polymorphisms])].
[sujeto(['Compound']), verbo([has]), complemento([a, 2, -, nodal, '(', 4, ',', 8, ')', -, connected, 3, 'D', framework, where, the, dinuclear, cadmium, cluster, secondary, building, units, '(', 'SBUs)', assemble, with, isophthalate, and, ligand, 'L2', to, construct, a, rare, topological, type, sqc22, net, with, a, '{', 3, '(', 2, ')', '·5(4)}{3(4)·4(4)·5(10)·6(10)}', topology])].
[sujeto(['In', 'plants,', successful, reproduction]), verbo([requires]), complemento([the, proper, timing, of, flowering, under, changing, environmental, conditions])].
[sujeto(['Arabidopsis', 'FLOWERING', 'LOCUS', 'T', '(', 'FT),', which, encodes, a, proposed, 'phloem-mobile', 'florigen,']), verbo([has]), complemento([a, close, 'homologue,', 'TWIN', 'SISTER', 'OF', 'FT', '(', 'TSF)'])].
[sujeto(['During', the, vegetative, 'phase,', 'TSF', shows, high, levels, of, expression, in, the, hypocotyl, before, 'FT', 'induction,', but, the, tsf, mutation, does, not]), verbo([have]), complemento([an, apparent, 'flowering-time', phenotype, on, its, own, under, 'long-day', conditions])].
[sujeto(['Previous', work]), verbo([has]), complemento([shown, that, 'FT', is, 'graft-transmissible;', by, 'contrast,', this, study, did, not, detect, movement, of, 'TSF', from, the, roots, into, the, shoot, of, the, scion, plants])].
[sujeto(['A', chimeric, 'TSF', with, region, 'II', of, 'FT', '(', 'L28', to, 'G98)']), verbo([expressed]), complemento([in, the, rootstock, caused, early, flowering, in, ft, tsf, scion, 'plants;', movement, of, the, chimeric, protein, from, the, rootstocks, into, the, shoot, apical, region, of, the, ft, tsf, scion, plants, was, also, detected])].
[sujeto(['Taking', these, results, 'together,', we, propose, that, protein, mobility, of, 'FT', is, higher, than, that, of, 'TSF,', possibly, due, to, a, protein, domain, that]), verbo([confers]), complemento([mobility, 'and/or', protein, stability])].
[sujeto(['Identification', of, potentially, 'resistance-conferring', apple, proteins, is, one, of, the, most, important, aims, for, studying, apple, resistance, mechanisms, and]), verbo([promoting]), complemento([the, development, of, 'disease-resistant', apple, strains])].
[sujeto(['In', order, to]), verbo([find]), complemento([proteins, which, promote, resistance, to, 'Marssonina', 'coronaria,', a, deadly, pathogen, which, has, been, related, to, premature, apple, 'maturation,', proteomes, from, apple, leaves, inoculated, with, 'M'])].
[sujeto(['Overall,', 59, differentially, accumulated, protein, spots, between, inoculation, and, 'non-inoculation', were, successfully, identified, and, aligned, as, 35, different, proteins, or, protein, families, which]), verbo([involved]), complemento([in, 'photosynthesis,', amino, acid, 'metabolism,', 'transport,', energy, 'metabolism,', carbohydrate, 'metabolism,', 'binding,', 'antioxidant,', defense, and, stress])].
[sujeto(['Among', of, these, 'proteins,', there, are, some, 'PR', 'proteins,', for, example, class, 'III', 'endo-chitinase,', 'beta-1,3-glucanase', and, 'thaumatine-like', 'protein,', and, some, antioxidant, related, proteins, including, 'aldo/keto', reductase, 'AKR,', ascorbate, peroxidase, and, phi, class, glutathione, 'S-transferase', protein, that, were]), verbo([associated]), complemento([with, disease, resistance])].
[sujeto(['The', transcription, levels, of, class, 'III', 'endo-chitinase', '(', 'L13)', and, 'beta-1,', 3, -, glucanase, '(', 'L17)']), verbo([have]), complemento([a, good, relation, with, the, abundance, of, the, encoded, 'protein\'s', 'accumulation,', 'however,', the, mRNA, abundance, of, 'thaumatine-like', protein, '(', 'L22)', and, ascorbate, peroxidase, '(', 'L28)', are, not, correlated, with, their, protein, abundance, of, encoded, protein])].
[sujeto(['To', elucidate, the, resistant, 'mechanism,', the, data, in, the, present, study, will]), verbo([promote]), complemento([us, to, investigate, further, the, expression, regulation, of, these, target, proteins])].
[sujeto(['Fluconazole']), verbo([has]), complemento([shown, to, be, effective, in, reducing, both, colonization, and, invasive, 'Candida', infection, '(', 'ICI)', in, 'ELBW', 'neonates;', we, conducted, a, randomized, trial, to, compare, oral, nystatin, with, intravenous, fluconazole, for, prophylaxis, against, invasive, 'Candidiasis', in, high, risk, neonates])].
[sujeto(['Intravenous', 'Fluconazole', and, oral, 'Nystatin', at, the, prophylactic, doses, are, equally, effective, and, safe, in]), verbo([preventing]), complemento(['(', 'ICI)', in, preterm, 'neonates,', however, oral, 'Nystatin', is, readily, 'available,', easily, administered, with, lower, cost, per, neonate])].
[sujeto(['Distinct', 'QTLs', exist, that]), verbo([regulate]), complemento([diastolic, function, 'and/or', 'LVH', in, the, short, term, when, acting, 'alone,', but, durably, when, combined])].
[sujeto(['Statistical', analysis, and, kinetic, modeling, of, drug]), verbo([release]), complemento([data, were, evaluated])].
[sujeto(['An', inverse, correlation, was, observed, between, the, 'drug/lipid', ratio, and, the, drug]), verbo([release]), complemento([rate])].
[sujeto(['Precirol®-', and, 'Compritol®-containing', formulae, showed, more, retarded, drug]), verbo([release]), complemento([rates])].
[sujeto(['The', higher, 'surfactant\'s', 'HLB,', the, higher, drug]), verbo([release]), complemento([rate])].
[sujeto(['The', similarity, factor, '(', 'f(2))', between, the, drug]), verbo([release]), complemento([profiles, revealed, similarity, within, the, investigated, 'drug/surfactant', ratios])].
[sujeto(['ANCA', testing, can, be, improved, by, restricting, the, use, of, the, tests, to, clinical, situations, with, a, rather, high, pretest, probability, for, 'AAV,', and, carefully, searching, for, conditions, such, as, drug, exposures, and, infections, that, are, known, to, be]), verbo([associated]), complemento([with, the, occurrence, of, 'ANCA,', whether, the, vasculitis, is, present, or, not])].
[sujeto(['Exercise']), verbo([confers]), complemento(['short-term', benefits, for, individuals, with, 'Parkinson', disease, '(', 'PD)'])].
[sujeto(['Supervision', was]), verbo([provided]), complemento([3, days, per, week, for, 4, 'months,', and, then, monthly, '(', 16, months, 'total)'])].
[sujeto(['Exposure', to, ash, from, the, catastrophic, 'Santorini', eruption, radically, changed, 'Bronze', 'Age', 'medicine,']), verbo([triggering]), complemento([the, development, of, new, 'remedies,', the, wide, dissemination, of, medical, 'data,', and, the, transfer, of, technologies])].
[sujeto(['Finally,', besides]), verbo([providing]), complemento([historical, 'data,', the, medical, reaction, to, the, 'Santorini', eruption, could, still, be, of, use, today])].
[sujeto(['Reverse', 'transcription-quantitative', polymerase, chain, reaction, '(', 'RT-qPCR)']), verbo([has]), complemento([become, a, frequently, used, method, in, gene, expression, studies])].
[sujeto(['However,', to, the, best, of, our, 'knowledge,', no, suitable, reference, genes]), verbo([have]), complemento([been, identified, for, the, genetic, analysis, of, cholangiocarcinoma, '(', 'CCA)', in, humans, and, cell, lines])].
[sujeto(['In', the, present, 'study,', screening, was, conducted, using, 12, common, reference, 'genes,', which, were, selected, in, order, to]), verbo([provide]), complemento([an, experimental, basis, for, the, study, of, the, gene, expression, in, 'CCA', patients, and, cell, lines])].
[sujeto(['Based', on, a, comparison, of, the, 'results,', the, following, reference, genes, are, recommended, for, various, tissue, 'groups:', 'Total', sample, 'group,', ribosomal, protein, 'L29;', 'CCA', tissue, 'group,', 'TATA-box']), verbo([binding]), complemento(['protein;', 'CCA', cell, line, and, tissue, 'group,', 'actin-β;', 'CCA', cell, line, 'group,', 18, 'S', ribosomal, 'RNA;', 'CCA', tissue, and, adjacent, 'non-neoplastic', tissue, 'group,', 5, '\'', -, aminolevulinate, synthase, 1, ;, and, adjacent, 'non-neoplastic', tissue, 'group,', hypoxanthine, phosphoribosyltransferase, 1])].
[sujeto(['The', results, of, the, search, also, clearly]), verbo([reveal]), complemento([that, a, systematic, study, regarding, the, selection, of, suitable, reference, genes, for, studying, the, target, gene, profiling, in, 'CCA', tissues, and, cell, lines, has, not, been, previously, published])].
[sujeto(['The', present, study, may]), verbo([provide]), complemento([useful, information, for, future, studies, that, examine, the, gene, expression, of, 'CCA', for, choosing, suitable, reference, genes])].
[sujeto(['Exploitation', of, processes]), verbo([has]), complemento([led, to, the, use, of, ribosomal, parts, as, solubility, enhancer, partners, and, purification, matrices, in, protein, expression])].
[sujeto([coli, ribosomal, protein, 'L29', '(', 'L4H2)', as, a, fusion, partner, for]), verbo([enhancing]), complemento([cellular, expression, of, proteins, that, are, poorly, expressed, in, bacteria, was, exploited])].
[sujeto(['It', was, demonstrated, that, a, chimeric, fusion, of, 'L4H2', with, various, 'Fcγ', receptors]), verbo([increases]), complemento([total, expression, up, to, 3.2, -, 'fold,', relative, to, 'Fcγ', receptors, expressed, without, the, fusion])].
[sujeto(['Mechanistic', insights, using, a, novel, application, of, in, vivo, ribosome, display]), verbo([suggested]), complemento(['that,', although, total, cellular, mRNA, levels, of, 'L4H2-Fcγ', receptor, remained, unchanged, relative, to, 'wild-type', 'Fcγ', 'receptors,', mRNA, levels, of, actively, translated, 'L4H2-Fcγ', transcript, increased, about, 3.8, -, fold, relative, to, actively, translated, levels, of, 'wild-type', 'Fcγ', transcript])].
[sujeto(['Similar']), verbo([increases]), complemento([in, protein, expression, in, the, context, of, the, other, proteins, 'tested,', showing, the, generality, of, this, approach, for, proteins, beyond, human, receptors, was, observed])].
[sujeto(['These', results, extended, the, number, of, potential, schemes, by, which, orthogonal, ribosomal, parts, can, be, used, to]), verbo([enhance]), complemento([complex, protein, expression, in, bacterial, platforms])].
[sujeto(['Within', a, larger, 'scope,', this, study, features, the, possibility, of, engineering, 5, '\'', tags, that]), verbo([enhance]), complemento([mRNA, affinity, to, ribosomes, as, strategies, to, augment, translation])].
[sujeto(['It', was, envisioned, that, the, successful, application, of, profiling, active, ribosomes, in, a, highly]), verbo([targeted]), complemento([manner, could, be, beneficial, for, mechanistic, translation, studies, concerning, synthesis, of, target, proteins])].
[sujeto(['Recently,', we]), verbo([found]), complemento([the, presence, of, 'anti-60S', ribosomal, protein, 'L29', antibody, '(', 'anti-RPL29)', in, human, 'sera,', inhibiting, the, proliferation, of, pancreatic, cancer, cells, in, vitro])].
[sujeto(['Both', mitochondria, and, chloroplasts, contain, distinct, proteolytic, systems, for, precursor, protein, processing, catalyzed, by, the, mitochondrial, and, stromal, processing, peptidases, and, for, the, degradation, of]), verbo([targeting]), complemento([peptides, catalyzed, by, presequence, protease])].
[sujeto(['Here,', we]), verbo([have]), complemento([identified, and, characterized, a, component, of, the, organellar, proteolytic, systems, in, 'Arabidopsis', 'thaliana,', the, organellar, 'oligopeptidase,', 'OOP', '(', 'At5g65620)'])].
[sujeto(['Short', mitochondrial]), verbo([targeting]), complemento([peptides, '(', presequence, of, the, ribosomal, protein, 'L29', and, presequence, of, 1, -, 'aminocyclopropane-1-carboxylic', acid, deaminase, 1, ')', and, 'N-', and, 'C-terminal', fragments, derived, from, the, presequence, of, the, 'ATPase', beta, subunit, ranging, in, size, from, 11, to, 20, aa, could, be, degraded])].
[sujeto(['The', structural, and, biochemical, data]), verbo([suggest]), complemento([that, the, protein, undergoes, conformational, changes, to, allow, peptide, binding, and, proteolysis])].
[sujeto(['Accurate', evaluation, of, gene, expression]), verbo([requires]), complemento([normalization, relative, to, the, expression, of, reliable, reference, genes])].
[sujeto(['Although', quantitative, 'real-time', 'PCR', '(', 'qRT-PCR)']), verbo([has]), complemento([been, used, extensively, to, decipher, gene, function, in, the, sweetpotato, whitefly, 'Bemisia', 'tabaci,', a, 'world-wide', pest, in, many, agricultural, 'systems,', the, stability, of, its, reference, genes, has, rarely, been, validated])].
[sujeto(['Our']), verbo([finding]), complemento([is, the, first, step, toward, establishing, a, standardized, quantitative, 'real-time', 'PCR', procedure, following, the, 'MIQE', '(', 'Minimum', 'Information', for, publication, of, 'Quantitative', real, time, 'PCR', 'Experiments)', guideline, in, an, agriculturally, important, insect, 'pest,', and, provides, a, solid, foundation, for, future, 'RNA', interference, based, functional, study, in, 'B'])].
[sujeto(['Cellular', ribosomal, protein, 'L29', '(', 'RPL29)', is, known, to, be, important, in, protein, 'synthesis,', but, its, function, during, angiogenesis]), verbo([has]), complemento([never, been, described, before])].
[sujeto(['We']), verbo([have]), complemento([shown, previously, that, mice, lacking, 'β3-integrins', support, enhanced, tumour, angiogenesis, 'and,', 'therefore,', deletion, of, endothelial, αvβ3, can, provide, a, method, for, discovery, of, novel, regulators, of, tumour, angiogenesis])].
[sujeto(['Moreover,', we]), verbo([provide]), complemento([in, vivo, evidence, that, 'RPL29', can, regulate, tumour, angiogenesis])].
[sujeto(['Additionally,', depletion, of, 'Rpl29', using, 'RNA', interference]), verbo([inhibited]), complemento(['VEGF-induced', aortic, ring, 'sprouting,', suggesting, that, 'anti-RPL29', strategies, might, have, 'anti-angiogenic', potential])].
[sujeto(['Overall,', our, results, identify, that]), verbo([loss]), complemento([or, depletion, of, 'RPL29', can, reduce, angiogenesis, in, vivo, and, ex, vivo])].
[sujeto(['Mutations']), verbo([have]), complemento([been, reported, in, the, gene, that, codes, for, gigaxonin])].
[sujeto(['Also,']), verbo([nuclear]), complemento([proteins, linked, to, 'formin-binding', proteins, were, found, to, be, dysregulated])].
[sujeto(['Although', the, major, role, of, gigaxonin, is]), verbo([reported]), complemento([to, be, degradation, of, 'cytoskeleton-associated', 'proteins,', the, amount, of, 76, structural, cytoskeletal, proteins, was, unaltered])].
[sujeto(['Protein', synthesis, in, plants, is, characterized, by]), verbo([increase]), complemento([in, the, translation, rates, for, numerous, proteins, and, central, metabolic, enzymes, during, the, day, phase, of, the, photoperiod])].
[sujeto(['The', detailed, molecular, mechanisms, of, this, diurnal, regulation, are, 'unknown,', while, eukaryotic, protein, translation, is, mainly, controlled, at, the, level, of, ribosomal, initiation, 'complexes,', which, also]), verbo([involves]), complemento([multiple, events, of, protein, phosphorylation])].
[sujeto(['Relative', quantification, of, the]), verbo([phosphorylated]), complemento([peptides, using, stable, isotope, labeling, and, mass, spectrometry, revealed, a, 2.2, times, increase, in, the, 'day/night', phosphorylation, ratio, at, this, site])].
[sujeto(['Phosphorylation', of, the, 'S6-1', and, 'S6-2', variants, of, the, same, protein, at, 'Ser-240']), verbo([increased]), complemento([by, the, factors, of, 4.2, and, 1.8, ',', respectively])].
[sujeto(['The', 1.6]), verbo([increase]), complemento([in, phosphorylation, during, the, day, was, also, found, at, 'Ser-58', of, the, 60, 'S', ribosomal, protein, 'L29-1'])].
[sujeto(['It', is]), verbo([suggested]), complemento([that, differential, phosphorylation, of, the, ribosomal, proteins, 'S6-1,', 'S6-2', and, 'L29-1', may, contribute, to, modulation, of, the, diurnal, protein, synthesis, in, plants])].
[sujeto(['Here', we, investigate, the, effects, of]), verbo([expressing]), complemento([an, activated, mutant, of, 'Notch', '(', 'ICD-E)', in, an, inducible, transgenic, mouse, model])].
[sujeto(['Hepatic', expression, of, 'ICD-E', in, adult, animals]), verbo([has]), complemento([no, detectable, 'phenotype,', but, simultaneous, induction, of, 'ICD-E', in, both, the, liver, and, small, intestine, results, in, hepatic, 'steatosis,', lipogranuloma, formation, and, mild, insulin, resistance, within, 96, hours])].
[sujeto(['This', supports, work, that]), verbo([suggests]), complemento([that, fatty, liver, disease, may, result, from, disruption, of, the, 'gut-liver', axis])].
[sujeto(['We']), verbo([report]), complemento([additional, intestinal, transcriptional, changes, following, 'ICD-E', 'expression,', finding, significant, transcriptional, 'down-regulation', of, rpL29, '(', ribosomal, protein, 'L29),', which, is, implicated, in, the, regulation, of, intestinal, flora])].
[sujeto(['These', results]), verbo([provide]), complemento([further, evidence, of, a, 'gut-liver', axis, in, the, development, of, fatty, liver, disease, and, insulin, resistance, and, validate, a, new, model, for, future, studies, of, hepatic, steatosis])].
[sujeto(['Cotranslational']), verbo([targeting]), complemento([of, membrane, and, secretory, proteins, is, mediated, by, the, universally, conserved, signal, recognition, particle, '(', 'SRP)'])].
[sujeto(['Together', with, its, receptor, '(', 'SR),', 'SRP']), verbo([mediates]), complemento([the, guanine, triphosphate, '(', 'GTP)-dependent', delivery, of, translating, ribosomes, bearing, signal, sequences, to, translocons, on, the, target, membrane])].
[sujeto(['Here,', we, present, the, crystal, structure, of, the, 'SRP:SR', complex, at, 3.9, angstrom, resolution, and, biochemical, data]), verbo([revealed]), complemento([that, the, activated, 'SRP:SR', guanine, triphosphatase, '(', 'GTPase)', complex, binds, the, distal, end, of, the, 'SRP', hairpin, 'RNA', where, 'GTP', hydrolysis, is, stimulated])].
[sujeto(['Combined', with, previous, 'findings,', these, results]), verbo([suggest]), complemento([that, the, 'SRP:SR', 'GTPase', complex, initially, assembles, at, the, tetraloop, end, of, the, 'SRP', 'RNA', and, then, relocalizes, to, the, opposite, end, of, the, 'RNA'])].
[sujeto(['This', rearrangement]), verbo([provides]), complemento([a, mechanism, for, coupling, 'GTP', hydrolysis, to, the, handover, of, cargo, to, the, translocon])].
[sujeto(['Mice', lacking, 'HIP/RPL29,', a, component, of, the, ribosomal, 'machinery,', display]), verbo([increased]), complemento([bone, fragility])].
[sujeto(['While']), verbo([loss]), complemento([of, 'HIP/RPL29', consistently, reduced, total, bone, 'size,', decreased, mineral, apposition, rates, were, not, 'significant,', indicating, that, short, stature, is, not, primarily, due, to, impaired, osteoblast, function])].
[sujeto(['Interestingly,', our, microspectroscopic, studies, showed, that, a, significant]), verbo([decrease]), complemento([in, collagen, crosslinking, during, maturation, of, 'HIP/RPL29-null', bone, precedes, an, overall, enhancement, in, the, relative, extent, of, mineralization, of, both, trabecular, and, cortical, adult, bones])].
[sujeto(['This']), verbo([report]), complemento([provides, strong, genetic, evidence, that, ribosomal, insufficiency, induces, subtle, organic, matrix, deficiencies, which, elevates, calcification])].
[sujeto(['Consistent', with, the, 'HIP/RPL29-null', bone, 'phenotype,', 'HIP/RPL29-deficient', teeth, also, showed, reduced, geometric, properties, accompanied, with, relative]), verbo([increased]), complemento([mineral, densities, of, both, dentin, and, enamel])].
[sujeto(['Increased', mineralization]), verbo([associated]), complemento([with, enhanced, tissue, fragility, related, to, imperfection, in, organic, phase, microstructure, evokes, defects, seen, in, matrix, 'protein-related', bone, and, tooth, diseases])].
[sujeto(['HIP', peptide]), verbo([has]), complemento([been, reported, to, neutralize, the, anticoagulant, activity, of, heparin])].
[sujeto(['NMR', results, indicate, the, imidazolium, groups, of, the, 'His', side, chains, of, 'histidine-containing', 'Hip', analog, peptide]), verbo([interact]), complemento(['site-specifically', with, heparin, at, pH, 5.5])].
[sujeto(['Heparin']), verbo([has]), complemento([identical, affinities, for, 'HIP', analog, peptides, of, opposite, chirality])].
[sujeto(['Analysis', by, counterion, condensation, theory, indicates, the, peptide, 'AC-SRPKAKAKAKAKDQTK-NH2', makes, on, average, approximately, 3, ionic, interactions, with, heparin, that, result, in, displacement, of, approximately, 2, 'Na+', 'ions,', and, ionic, interactions, account, for, approximately, 46, '%', of, the]), verbo([binding]), complemento([free, energy, at, a, 'Na+', concentration, of, 0.15, 'M'])].
[sujeto(['The', 'site-specific']), verbo([binding]), complemento([of, protonated, histidine, side, chains, to, heparin, provides, a, 'molecular-level', explanation, for, the, 'pH-dependent', binding, of, 'beta-amyloid', peptides, by, heparin, and, heparan, sulfate, proteoglycan, and, may, have, implications, for, amyloid, formation])].
[sujeto(['Null', 'males,', and, to, a, lower, extent, null, 'females,', displayed]), verbo([increased]), complemento([bone, material, toughness, to, counteract, decreased, bone, size])].
[sujeto(['This', elevation, in, a, bone, material, property, was]), verbo([associated]), complemento([with, increased, bone, mineral, density, only, in, null, males])].
[sujeto(['Neither', male, nor, female, null, animals, could, withstand, the, same, maximum, load, as, 'gender-matched', controls, in, 'three-point', bending, 'tests,', and, smaller, 'post-yield', displacements, '(', and, thus]), verbo([increased]), complemento([bone, 'brittleness)', were, found, for, null, animals])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'HIP/RPL29-deficient', mice, exhibit, increased, bone, fragility, due, to, altered, matrix, protein, synthesis, rates, as, a, consequence, of, ribosomal, insufficiency])].
[sujeto(['Thus,', 'sub-efficient', protein, translation]), verbo([increased]), complemento([fracture, risk, in, 'HIP/RPL29-null', animals])].
[sujeto(['Taken', 'together,', these, studies]), verbo([provide]), complemento([strong, genetic, evidence, that, the, ability, to, regulate, and, amplify, protein, synthesis, 'rates,', including, those, proteins, that, regulate, the, cell, cycle, entry, during, skeletal, 'development,', are, important, determinants, for, establishment, of, normal, bone, mass, and, quality])].
[sujeto(['The', 'c-Myc', oncoprotein]), verbo([promotes]), complemento([cell, growth, by, enhancing, ribosomal, biogenesis, through, upregulation, of, 'RNA', polymerases, 'I-,', 'II-,', and, 'III-dependent', transcription])].
[sujeto(['Overexpression', of, 'c-Myc', and, aberrant, ribosomal, biogenesis]), verbo([leads]), complemento([to, deregulated, cell, growth, and, tumorigenesis])].
[sujeto(['Hence,', 'c-Myc', activity, and, ribosomal, biogenesis, must, be]), verbo([regulated]), complemento([in, cells])].
[sujeto(['L11', is, transcriptionally]), verbo([induced]), complemento([by, 'c-Myc,', and, overexpression, of, 'L11', inhibits, 'c-Myc-induced', transcription, and, cell, proliferation])].
[sujeto(['Conversely,', reduction, of, endogenous, 'L11', by, siRNA]), verbo([increases]), complemento([these, 'c-Myc', activities])].
[sujeto(['Mechanistically,', 'L11']), verbo([binds]), complemento([to, the, 'Myc', box, 'II', '(', 'MB', 'II),', inhibits, the, recruitment, of, the, coactivator, 'TRRAP,', and, reduces, histone, 'H4', acetylation, at, 'c-Myc', target, gene, promoters])].
[sujeto(['In', 'addition,', 'L11']), verbo([regulates]), complemento(['c-Myc', levels])].
[sujeto(['These', results, identify, 'L11', as, a, feedback, inhibitor, of, 'c-Myc', and]), verbo([suggest]), complemento([a, novel, role, for, 'L11', in, regulating, 'c-Myc-enhanced', ribosomal, biogenesis])].
[sujeto(['We']), verbo([found]), complemento([that, both, genes, are, 'transcribed,', with, their, polyadenylation, sites, on, opposite, strands, separated, by, only, 135, bp])].
[sujeto(['We', also]), verbo([found]), complemento([that, these, two, genes, are, linked, on, a, macronuclear, 'chromosome,', similarly, arranged, tail, to, 'tail,', in, the, three, spirotrichs, 'Stylonychia', 'lemnae,', 'Uroleptus', sp])].
[sujeto(['These', observations]), verbo([suggest]), complemento([a, possible, evolutionary, trend, towards, loss, of, chromosomal, breakage, between, these, two, genes])].
[sujeto(['This', study, is, the, first, to, examine, gene, linkage, in, the, macronucleus, of, several, spirotrichs, and, may]), verbo([provide]), complemento([insight, into, the, evolution, of, 'multi-gene', macronuclear, chromosomes, and, chromosomal, fragmentation, in, spirotrichs])].
[sujeto(['We', had, previously, shown, that, the, expression, of, 'heparin/heparan', sulfate]), verbo([interacting]), complemento(['protein/ribosomal', protein, 'L29', '(', 'HIP/RPL29)', was, upregulated, in, colon, cancer, tissues])].
[sujeto(['To', determine, whether, a, lower, expression, of, 'HIP/RPL29', could]), verbo([induce]), complemento([differentiation, in, cancer, 'cells,', small, interfering, 'RNA', '(', 'siRNA)', targeting, 'HIP/RPL29', was, transfected, into, 'LS174T', cells])].
[sujeto(['The', resultant, knockdown, of, 'HIP/RPL29', expression]), verbo([induced]), complemento([cellular, 'differentiation,', as, shown, by, the, increased, expression, of, two, known, markers, of, differentiation, in, 'LS174T', 'cells,', 'galectin-4', and, 'mucin-2'])].
[sujeto(['In', 'addition,', the, differentiation, process]), verbo([induced]), complemento([by, repression, of, 'HIP/RPL29', expression, was, accompanied, by, the, upregulation, of, p21, and, p53])].
[sujeto(['The', differentiation, process, is, at, least, partially]), verbo([mediated]), complemento([by, the, upregulation, of, p21, and, p53, pathways])].
[sujeto(['Ultraviolet-B', '(', 'UV-B)', photons, can]), verbo([cause]), complemento([substantial, cellular, damage, in, 'biomolecules,', as, is, well, established, for, 'DNA'])].
[sujeto(['Because', 'RNA']), verbo([has]), complemento([the, same, absorption, spectrum, for, 'UV', as, 'DNA,', we, have, investigated, damage, to, this, cellular, constituent])].
[sujeto(['Ribosomal', damage, accumulated, during, a, day, of, 'UV-B', exposure, correlated, with, a, progressive]), verbo([decrease]), complemento([in, new, protein, 'production;', 'however,', de, novo, synthesis, of, some, ribosomal, proteins, is, increased, after, 6, h, of, 'UV-B', exposure])].
[sujeto(['Ribosomal', protein, 'S6', and, an, 'S6', kinase, are]), verbo([phosphorylated]), complemento([during, 'UV-B', 'exposure;', these, modifications, are, associated, with, selective, translation, of, some, ribosomal, proteins, after, ribosome, damage, in, mammalian, fibroblast, cells, and, may, be, an, adaptation, in, maize])].
[sujeto([cerevisiae]), verbo([requires]), complemento([induction, of, a, transient, transcription, program, that, is, initiated, by, 'Ime1-dependent', destruction, of, the, repressor, 'Ume6'])].
[sujeto(['Although', 'IME1', mRNA, is, observed, in, vegetative, 'cultures,', 'Ime1', protein, is, not]), verbo([suggesting]), complemento([the, presence, of, a, regulatory, system, restricting, translation, to, meiotic, cells])].
[sujeto(['This', study, demonstrates, that, 'IME1', mRNA, translation]), verbo([requires]), complemento(['Rpl22A', and, 'Rpl22B,', 'eukaryotic-specific', ribosomal, protein, paralogs, of, the, 60, 'S', large, subunit])].
[sujeto(['In', the, absence, of, 'Rpl22', 'function,', 'IME1', mRNA, synthesis, is, normal, in, cultures]), verbo([induced]), complemento([to, enter, meiosis])].
[sujeto(['However,', 'Ime1', protein, production, is, reduced, and, the, 'Ume6', repressor, is, not, destroyed, in, rpl22, mutant, cells]), verbo([preventing]), complemento([early, meiotic, gene, induction, resulting, in, a, 'pre-meiosis', 'I', arrest])].
[sujeto(['This', role, for, 'Rpl22', is, not, a, general, consequence, of, mutating, 'non-essential', large, ribosomal, proteins, as, strains, lacking, 'Rpl29', or, 'Rpl39']), verbo([execute]), complemento([meiosis, with, nearly, 'wild-type', efficiencies])].
[sujeto(['Several', results, indicate, that, 'Rpl22', functions, by]), verbo([enhancing]), complemento(['IME1', mRNA, translation])].
[sujeto(['In', 'addition,', 'IME1', transcript, is]), verbo([found]), complemento([in, polysome, fractions, isolated, from, rpl22, mutant, cells, indicating, that, mRNA, nuclear, export, and, ribosome, association, occurs])].
[sujeto(['Finally,', deleting, the, unusually, long, 5, '\'', 'UTR', restores, 'Ime1', levels, and, early, meiotic, gene, transcription, in, rpl22, mutants]), verbo([suggesting]), complemento([that, 'Rpl22', enhances, translation, through, this, element])].
[sujeto(['Polysome', profiles, revealed, that, under, conditions, of, high, translational, 'output,', 'Rpl22']), verbo([maintains]), complemento([high, free, 60, 'S', subunit, levels, thus, preventing, halfmer, 'formation,', a, translation, species, indicative, of, mRNAs, bound, by, an, unpaired, 40, 'S', subunit])].
[sujeto(['In', addition, to, 'meiosis,', 'Rpl22', is, also]), verbo([required]), complemento([for, invasive, and, pseudohyphal, growth])].
[sujeto(['These', findings, indicate, that, 'Rpl22A', and, 'Rpl22B', are]), verbo([required]), complemento([to, selectively, translate, 'IME1', mRNA, that, is, required, for, meiotic, induction, and, subsequent, gametogenesis])].
[sujeto(['In', 'addition,', our, results, imply, a, more, general, role, for, 'Rpl22', in, cell, fate, switches]), verbo([responding]), complemento([to, environmental, nitrogen, signals])].
[sujeto(['Total', 'RNA', was, isolated, from, 'BMSCs', and, reverse]), verbo([transcribed]), complemento([into, complementary, 'DNA,', which, served, as, a, template, for, 'RT-qPCR'])].
[sujeto(['Based', on, comparisons, of, all, five, 'groups,', two, of, the, programs, used]), verbo([suggested]), complemento([that, 'HPRT1', was, the, most, stable, reference, 'gene,', while, 18, 'S', and, 'ACTB', were, the, most, variable])].
[sujeto(['To', validate, the, 'results,', the, mRNA, expression, of, a]), verbo([target]), complemento(['gene,', 'DNMT1,', was, quantified, using, the, different, reference, gene, combinations, suggested, by, the, various, software, packages, for, normalization])].
[sujeto(['On', the, other, 'hand,', 'ACTB', +, 'B2M', was, the, best, combination, for, all, the, cell, lines, tested, and, was, also, the, best, combination, for, analyses]), verbo([involving]), complemento([all, the, gastric, tissues, plus, cell, lines])].
[sujeto(['For', group, 'II', patients, no, statistically, significant]), verbo([increase]), complemento([of, the, level, of, the, 'c-Myc', and, 'SATB1', genes, was, observed])].
[sujeto([pylori, 'infection,', with, reversible, histopathological, changes, of, the, gastric, 'mucosa,']), verbo([have]), complemento([significantly, higher, levels, of, 'SATB1', and, 'c-Myc', genes, expression, as, compared, to, the, patients, without, family, history, of, gastric, 'cancer,', regardless, of, the, topography, of, the, stomach])].
[sujeto(['Presumably,', the, observed, effect, is]), verbo([associated]), complemento([with, hypermethylation, of, the, promoter, of, that, gene])].
[sujeto(['In', this, article, we]), verbo([report]), complemento([the, obesogenic, role, of, the, acute, phase, protein, 'PAP/HIP'])].
[sujeto(['We']), verbo([found]), complemento([that, the, transgenic, 'TgPAP/HIP', mice, develop, spontaneous, obesity, under, standard, nutritional, 'conditions,', with, high, levels, of, 'glucose,', 'leptin,', and, 'LDL', and, low, levels, of, triglycerides, and, 'HDL', in, blood])].
[sujeto(['We', also]), verbo([found]), complemento([that, expression, of, 'PAP/HIP', is, induced, in, intestinal, epithelial, cells, in, response, to, gavage, with, olive, oil, and, this, induction, is, 'AG490', sensitive])].
[sujeto(['Altogether', our, data]), verbo([suggest]), complemento([that, 'PAP/HIP', could, be, a, mediator, of, fat, tissue, 'development,', released, by, the, intestine, and, induced, by, the, presence, of, food, into, the, gut])].
[sujeto(['SKY']), verbo([has]), complemento([not, been, applied, to, 'MMt', 'before,', and, complete, karyotypes, are, reported, based, on, the, integration, of, 'SKY', and, aCGH, results])].
[sujeto(['For', the, first, 'time,', 'LINGO2,', 'RBFOX1/A2BP1,', 'RPL29,', 'DUSP7,', and, 'CCSER1/FAM190A', were]), verbo([found]), complemento([to, be, homozygously, deleted, in, 'MMt,', and, some, of, these, genes, could, be, new, tumor, suppressor, genes, for, 'MMt'])].
[sujeto(['Integration', of, 'SKY', and, aCGH, data, allowed, reconstruction, of, chromosomal, rearrangements, that]), verbo([led]), complemento([to, the, formation, of, 'HDs'])].
[sujeto(['Our', data, imply, that, only, with, acquisition, of, structural, 'and/or', numerical, karyotypic, instability, can, 'MMt', cells, attain, a, complete]), verbo([loss]), complemento([of, tumor, suppressor, genes, located, in, 9, p21])].
[sujeto([3, region]), verbo([have]), complemento([already, been, acquired])].
[sujeto(['The', evolution, of, 'RNA', interference, '(', 'RNAi)', and, the, development, of, technologies, exploiting, its, biology]), verbo([have]), complemento([enabled, scientists, to, rapidly, examine, the, consequences, of, depleting, a, particular, gene, product, in, cells])].
[sujeto(['Design', tools]), verbo([have]), complemento([been, developed, based, on, experimental, data, to, increase, the, knockdown, efficiency, of, siRNAs])].
[sujeto(['Not', all, siRNAs, that, are, developed, to, a, given]), verbo([target]), complemento([mRNA, are, equally, effective])].
[sujeto(['Currently', available, design, algorithms, take, an, 'accession,', identify]), verbo([conserved]), complemento([regions, among, their, transcript, 'space,', find, accessible, regions, within, the, 'mRNA,', design, all, possible, siRNAs, for, these, 'regions,', filter, them, based, on, 'multi-scores', 'thresholds,', and, then, perform, 'off-target', filtration])].
[sujeto(['Based', on, our, evaluation, 'results,', we, were, able, to]), verbo([suggest]), complemento([an, siRNA, sequence, pattern])].
[sujeto(['Shwachman-Diamond', syndrome, '(', 'SDS),']), verbo([associated]), complemento([with, 'SBDS', 'mutations,', is, characterized, by, pancreatic, exocrine, dysfunction, and, marrow, failure])].
[sujeto(['Sdo1', is, needed, for]), verbo([release]), complemento([of, the, 'anti-subunit', association, factor, 'Tif6', from, 60, 'S', 'subunits,', and, 'Tif6', may, not, be, recycled, to, the, nucleus, when, 'Sdo1', is, absent])].
[sujeto(['To', clarify, the, role, of, 'SBDS', in, human, ribosome, 'function,', 'TF-1', erythroleukemia, and, 'A549', lung, carcinoma, cells, were, transfected, with, vectors]), verbo([expressing]), complemento(['RNAi', against, 'SBDS'])].
[sujeto(['To', analyze, the, effect, of, 'SBDS', on, 60, 'S', subunit, maturation, in, 'A549', 'cells,', subunit, localization, was, assessed, by, transfection, with, a, vector]), verbo([expressing]), complemento([a, fusion, between, human, 'RPL29', and, 'GFP:', we, found, a, higher, percentage, of, 'SBDS-depleted', cells, with, nuclear, localization, of, 60, 'S', subunits])].
[sujeto(['Polysome', analysis, of, 'TF-1', knockdown, cells, showed, a]), verbo([decrease]), complemento([in, free, 60, 'S', and, 80, 'S', subunits])].
[sujeto(['We', also, analyzed, the, levels, of, eIF6, '(', human, ortholog, of, 'Tif6)', following, 'near-complete', knockdown, of, 'SBDS', in, 'TF-1', cells, and]), verbo([found]), complemento([an, approximately, 20, '%', increase, in, the, amount, of, eIF6, associated, with, the, 60, 'S', subunit])].
[sujeto(['We', conclude, that, knockdown, of, 'SBDS']), verbo([leads]), complemento([to, growth, inhibition, and, defects, in, ribosome, 'maturation,', suggesting, a, role, for, 'wild-type', 'SBDS', in, nuclear, export, of, 'pre-60S', subunits])].
[sujeto(['Oncogenic', 'KRAS,', an, important]), verbo([target]), complemento([for, antitumor, 'therapy,', contributes, to, pancreatic, cancer, 'tumorigenesis,', progression, and, maintenance])].
[sujeto(['However,', intracellular, compensation, regulation, can, help, cells, to, resist, the]), verbo([targeted]), complemento([therapy])].
[sujeto(['In', this, 'study,', two, stable, transfected, cell, lines, were, constructed, through, 'lentivirus-mediated', shRNA]), verbo([targeting]), complemento(['KRAS', of, 'PANC-1', 'cells,', to, investigate, cell, response, to, the, knockdown, of, 'KRAS'])].
[sujeto(['The', results, showed, that, knockdown, of, 'RPL26', or, 'RPL29', expression, significantly]), verbo([suppressed]), complemento([cell, 'proliferation,', induced, cell, arrest, at, 'G0/G1', phase, and, enhanced, cell, apoptosis])].
[sujeto(['Reactive', oxygen, species, '(', 'ROS)', assay, indicated, that, silencing, of, 'RPL26', or, 'RPL29', markedly]), verbo([decreased]), complemento([the, intracellular, 'ROS', generation])].
[sujeto(['A', new, methodology, is, developed, to, conjugate, hyaluronic, acid, '(', 'HA)', hydrogel, with, novel, 'nano-fibrous', architectures, via, 'non-covalent', assembly, that, specifically, allows, for]), verbo([targeted]), complemento(['adipose-derived', stem, cells, '(', 'ASCs)', differentiation, and, soft, tissue, engineering])].
[sujeto(['The', assembly, of, 'non-covalently']), verbo([associated]), complemento([hydrogel, network, produced, via, the, interaction, of, a, low, molecular, weight, heparin, '(', 'LMWH)', modified, 'HA', derivative, and, heparin, interacting, protein, '(', 'HIP)'])].
[sujeto(['The', multifunctional, star, 'poly(ethylene', 'glycol)', '(', 'PEG)', and, 'HIP', copolymer]), verbo([has]), complemento([the, capability, to, mediate, the, 'non-covalent', assembly, of, 'nano-fibrous', 'HA', hydrogel, networks, via, affinity, interactions, with, 'LMWH'])].
[sujeto(['The', results]), verbo([suggest]), complemento([the, potential, utility, of, this, unique, design, of, the, bioactive, 'nano-fibrous', 'HA', hydrogel, in, directing, the, differentiation, of, 'ASCs', and, adipogenesis, in, 'ECM-mimetic', scaffolds, in, vitro])].
[sujeto(['Aging', is]), verbo([associated]), complemento([with, bone, loss, and, degenerative, joint, 'diseases,', in, which, the, aging, of, bone, 'marrow-derived', mesenchymal, stem, cell, '(', 'bmMSC)[1]', may, play, an, important, role])].
[sujeto(['Pathway', analysis, of, these, genes]), verbo([suggests]), complemento([that, alterations, in, glycobiology, might, play, an, important, role, in, the, aging, of, human, bmMSC])].
[sujeto(['On', the, other, 'hand,', antigen, presentation, and, signaling, of, immune, cells, were, the, top, pathways, enriched, by, 'osteoarthritis-associated', 'genes,']), verbo([suggesting]), complemento([that, alteration, in, immunology, of, bmMSC, might, be, involved, in, the, pathogenesis, of, osteoarthritis])].
[sujeto(['Most', 'intriguingly,', we]), verbo([found]), complemento([significant, 'age-associated', differential, expression, of, 'HEXA,', 'HEXB,', 'CTSK,', 'SULF1,', 'ADAMTS5,', 'SPP1,', 'COL8A2,', 'GPNMB,', 'TNFAIP6,', and, 'RPL29;', those, genes, have, been, implicated, in, the, bone, loss, and, the, pathology, of, osteoporosis, and, osteoarthritis, in, aging])].
[sujeto(['Collectively,', our, results]), verbo([suggest]), complemento([a, pathological, role, of, bmMSC, in, 'aging-related', skeletal, 'diseases,', and, suggest, the, possibility, that, alteration, in, the, immunology, of, bmMSC, might, also, play, an, important, role, in, the, etiology, of, 'adult-onset', osteoarthritis])].
[sujeto(['We']), verbo([have]), complemento([reported, that, 'heme-dependent', activation, of, 'apo-neuronal', nitric, oxide, synthase, '(', 'apo-nNOS)', to, the, active, 'holo-enzyme', dimer, is, dependent, upon, factors, present, in, reticulocyte, lysate, and, other, cytosols])].
[sujeto(['Here,', we]), verbo([find]), complemento([that, both, 'Hsp70', and, thioredoxin, are, components, of, the, activation, system])].
[sujeto(['The', 'apo-nNOS']), verbo([activating]), complemento([activity, of, reticulocyte, lysate, is, retained, in, a, pool, of, fractions, containing, 'Hsp70', that, elute, from, 'DE52', prior, to, 'Hsp90'])].
[sujeto(['All', of, the]), verbo([activating]), complemento([activity, and, 20, -, 30, '%', of, the, 'Hsp70', elute, in, the, 'flow-through', fraction, upon, subsequent, 'ATP-agarose', chromatography])].
[sujeto(['Apo-nNOS', activation, by, this, 'flow-through', fraction, is]), verbo([inhibited]), complemento([by, 'pifithrin-μ,', a, small, molecule, inhibitor, of, 'Hsp70,', suggesting, that, a, 'non-ATP-binding', form, of, 'Hsp70', is, involved, in, 'heme-dependent', 'apo-nNOS', activation])].
[sujeto(['Previous', work]), verbo([has]), complemento([shown, that, 'apo-nNOS', can, be, activated, by, 'thiol-disulfide', 'exchange,', and, we, show, substantial, activation, with, a, small, molecule, dithiol, modeled, on, the, active, motifs, of, thioredoxin, and, protein, disulfide, isomerase])].
[sujeto(['Further', fractionation, of, the, 'ATP-agarose', 'flow-through', on, 'Sephacryl', 'S-300', separates, free, thioredoxin, from, 'apo-nNOS']), verbo([activating]), complemento(['activity,', 'Hsp70,', and, a, small, amount, of, 'thioredoxin,', all, of, which, are, eluted, throughout, the, macromolecular, peak])].
[sujeto(['Incubation', of, 'apo-nNOS', with, the, macromolecular, fraction, in, combination, either, with, the, 'thioredoxin-containing', fraction, or, with, purified, recombinant, human, thioredoxin, restores, full, 'heme-dependent']), verbo([activating]), complemento([activity])].
[sujeto(['This', supports, a, model, in, which, 'Hsp70']), verbo([binding]), complemento([to, 'apo-nNOS', stabilizes, an, open, state, of, the, 'heme/substrate', binding, cleft, to, facilitate, thioredoxin, access, to, the, active, site, cysteine, that, coordinates, with, heme, 'iron,', permitting, heme, binding, and, dimerization, to, the, active, enzyme])].
[sujeto(['Neuropathic', pain, is]), verbo([triggered]), complemento([by, damage, to, or, as, a, result, of, the, dysfunction, of, the, somatosensory, nervous, system])].
[sujeto(['Gene', expression, profiling, using, 'DNA', microarray, and, 'real-time', 'PCR']), verbo([have]), complemento([emerged, as, powerful, tools, for, the, elucidation, of, 'pain-specific', pathways, and, identification, of, candidate, biomarkers, and, therapeutic, targets])].
[sujeto(['We']), verbo([have]), complemento([evaluated, the, stability, of, six, candidate, reference, genes, which, include, three, commonly, used, housekeeping, genes, '(', 'ACTB,', 'GAPDH', and, 'HMBS)', and, three, ribosomal, protein, genes, '(', 'RPL3,', 'RPL19', and, 'RPL29)', using, 'real-time', 'PCR', in, a, rat, model, of, neuropathic, pain])].
[sujeto(['In', 'addition,', we]), verbo([have]), complemento([identified, 'RPL29', and, 'RPL3', as, novel, reference, genes])].
[sujeto(['Normalization', of, expression, data, using, 'GAPDH', or, 'HMBS']), verbo([led]), complemento([to, overestimation, of, transcriptional, changes])].
[sujeto(['Using', 'RPL29/RPL3/ACTB', as, reference, 'genes,', a, number, of, transcripts, were]), verbo([found]), complemento([to, be, specifically, and, significantly, regulated, in, injured, dorsal, root, ganglia])].
[sujeto([hRPL29]), verbo([has]), complemento([a, large, excess, of, basic, residues, over, acidic, ones])].
[sujeto(['The', large, amount, of, charged, residues, makes, the, protein, very, hydrophilic, and, the, protein]), verbo([has]), complemento([a, deduced, pI, of, 12.16])].
[sujeto(['Internal', repeats]), verbo([have]), complemento([been, characterised, in, many, ribosomal, proteins, and, a, tandem, repeat, of, 'KAKAKAKA', was, found, to, be, unique, to, hRPL29])].
[sujeto(['An', intron, of, hrpL29]), verbo([has]), complemento([also, been, cloned, and, sequenced, by, polymerase, chain, reaction, using, human, genomic, 'DNA', as, the, template])].
[sujeto(['Method:', 'A', systematic, literature, search, was, conducted, in, scientific, databases, on, degenerative, changes]), verbo([caused]), complemento([by, amputations])].
[sujeto(['A', quantitative, summary, of, the, studies, showed, that, 56, '%', of, amputees, suffered, from, back, 'pain,', radiographic, signs, of, arthritis, were]), verbo([found]), complemento([in, the, sound, knee, of, 35, '%', of, 'patients,', compared, with, clinical, signs, in, 33, '%'])].
[sujeto(['This', means, that, flexion, deformities, of, the, spine, of, amputees]), verbo([have]), complemento([become, rarer, and, are, therefore, no, longer, discussed, in, the, current, literature])].
[sujeto(['The', prevalence, of, back, pain, and, knee, osteoarthritis]), verbo([increases]), complemento([in, more, proximal, amputations])].
[sujeto(['Introduction/Background:', 'With', extended, life, 'expectancy,', the, number, of, primary, joint, arthroplasties]), verbo([has]), complemento([also, increased])].
[sujeto(['The', indications, which]), verbo([led]), complemento([to, revision, surgery, were, as, 'follows:', loosened, 'metal-on-metal', prosthesis, with, an, acetabular, defect, caused, by, a, 'metal-induced', granuloma, '(', n, =, 1, ')', ',', pseudoarthrosis, after, implantation, of, femur, nail, '(', n, =, 2, ')', ',', 'cut-out', of, a, femur, nail, '(', n, =, 1, ')', ',', aseptic, loosening, of, an, implanted, endoprosthesis, '(', n, =, 4, ')', ',', septic, loosening, of, an, implanted, endoprosthesis, '(', n, =, 1, ')', ',', periprosthetic, fracture, '(', n, =, 6, ')', and, periprosthetic, infection, after, two, stage, revision, surgery, '(', infection, consolidated, 'Girdlestone', 'situation)', '(', n, =, 10, ')'])].
[sujeto(['All', patients, were, followed, up, at]), verbo([regular]), complemento(['intervals,', both, clinically, and, radiologically])].
[sujeto(['Two', patients, suffered, periprosthetic, fracture, due, to, trauma, and, the, patient, with, the, total, femur, prosthesis, suffered, recurrent, periprosthetic, infection, of, the, silver, -, coated, 'mega-prosthesis', and, committed, suicide]), verbo([triggered]), complemento([by, an, episode, of, major, depression])].
[sujeto(['Conclusion:', 'Because', of, its]), verbo([modular]), complemento(['nature,', the, 'Modular', 'Tumor', 'And', 'Revision', 'System', '(', 'MUTARS®)', can, be, used, for, highly, variable, intraoperative, defect, adaption])].
[sujeto(['Twelve-month', 'CE/BZA', treatment]), verbo([prevented]), complemento([bone, loss, and, improved, vasomotor, function, in, 'European', postmenopausal, women])].
[sujeto(['However,', sports, specific, training, may]), verbo([have]), complemento([different, effects, on, bone, outcomes])].
[sujeto(['Serum', metal, ions, are, part, of, the]), verbo([regular]), complemento(['follow-up', routine, of, patients, with, 'metal-on-metal', total, hip, arthroplasties, '(', 'MoM-THA)'])].
[sujeto(['Increased', cobalt, levels]), verbo([have]), complemento([been, suggested, to, indicate, implant, failure, and, corrosion])].
[sujeto(['The', data]), verbo([suggest]), complemento([that, a, cut, off, level, of, 1.71, for, the, 'cobalt-chromium-ratio', has, a, sensitivity, of, 62.5, &, 'nbsp;%', and, specificity, of, 72.4, &, 'nbsp;%', to, identify, male, patients, with, osteolysis])].
[sujeto(['The', disproportional]), verbo([increase]), complemento([of, cobalt, over, 'chromium,', especially, in, male, patients, with, large, component, sizes, can, not, be, explained, by, wear, alone, and, suggests, that, other, processes, '(', 'corrosion)', might, contribute, to, metal, ion, levels, and, might, be, more, pronounced, in, patients, with, larger, component, sizes])].
[sujeto(['Similar', results, were]), verbo([found]), complemento([in, cartilage, 'AAA', '(', 12.1, ±, 2.5, °, ')', and, 'AIA', '(', 41.2, ±, 3.0, °, ')'])].
[sujeto(['Bony', 'AI', was, 24.1, ±, 2.4, °, at, the, age, of, 6, 'months,']), verbo([decreasing]), complemento([to, 12.5, ±, 2.3, °, by, 12, to, 13, years, of, 'age;', cartilage, 'AI', '(', 5.9, ±, 1.7, °, ')', maintained, a, steady, value, with, age])].
[sujeto(['The', mean, bony, 'a-TCA', and, 'c-TCA', at, 6, months, were, 117.0, ±, 5.8, °, and, 127.5, ±, 5.1, °, ',']), verbo([increasing]), complemento([to, 144.5, ±, 4.6, °, and, 140.7, ±, 2.5, °, at, the, age, of, 16, years])].
[sujeto(['At', 24, &, 'nbsp;months,', 'ZOL', administration]), verbo([increased]), complemento([bone, mineral, density, in, the, lumbar, 'spine,', femoral, 'neck,', and, total, hip, '(', t, 'test:', 'p < 0'])].
[sujeto(['Once-yearly', administration, of, 'ZOL', 5, &, 'nbsp;mg', to, 'Japanese', patients, with, primary, osteoporosis, reduced, the, risk, of, new, morphometric, vertebral, fractures, and, was]), verbo([found]), complemento([to, be, safe])].
[sujeto(['Sensory', blockade, was, evaluated, 5, ',', 10, and, 20, minutes, after, ropivacaine, administration, using]), verbo([loss]), complemento([of, perception, to, cold, in, the, 'lateral,', anterior, and, medial, part, of, the, thigh])].
[sujeto(['Before', 'FIC', block, average, 'VAS', was, 7.5, which, was]), verbo([decreased]), complemento([to, average, of, 2.94, at, 20, minutes, after, block, which, was, statistically, significant, '(', 'p<0'])].
[sujeto(['Performing', an, 'FICB', before, positioning, for, spinal, anaesthesia]), verbo([provides]), complemento([good, pain, management, and, facilitates, spinal, performance, with, wide, patient, 'acceptance,', hence, improving, overall, quality, and, efficiency, of, care])].
[sujeto(['[', 'Subjects', and, 'Methods]', 'Nineteen', healthy, male, subjects, were]), verbo([recruited]), complemento([for, this, study])].
[sujeto(['[', 'Conclusion]', 'These', findings, demonstrate, that, loaded, isometric, hip, movements, may, be, a, useful, strategy, to]), verbo([increase]), complemento([trunk, muscle, activity, during, plank, exercises])].
[sujeto(['[', 'Results]', 'The', 'lumbar-hip', ratio]), verbo([decreased]), complemento([from, 5.9, to, 3.6, in, the, descending, 'phase,', indicating, lumbar, spinal, movement, was, less, than, hip, movement])].
[sujeto(['The', lumbopelvic, rhythm, was, better]), verbo([expressed]), complemento([by, a, cubic, or, quadratic, function, rather, than, a, linear, function])].
[sujeto(['Hazard', ratios, for, hip, fracture, and]), verbo([associated]), complemento([95, '%', confidence, intervals, were, estimated])].
[sujeto(['Below', age, 70, 'years,', there, was, no, further]), verbo([decrease]), complemento([in, fracture, risk, at, 'BMIs', of, 25, or, 'more,', while, in, women, aged, 70, -, 79, 'years,', the, risk, continued, to, decrease, with, increasing, 'BMI'])].
[sujeto(['Negative', news, media]), verbo([reports]), complemento([regarding, potential, health, hazards, of, implanted, medical, devices, and, pharmaceuticals, can, lead, to, a, '\'', negative, halo, 'effect,\'', a, phenomenon, whereby, judgments, about, a, product, or, product, type, can, be, unconsciously, altered, even, though, the, scientific, support, is, tenuous])].
[sujeto(['Tysabri', patient, data, were]), verbo([reported]), complemento([by, 'Elan', 'Corporation', or, 'Biogen', 'Idec', 'Inc'])].
[sujeto(['We']), verbo([found]), complemento([that, common, factors, altered, public, risk, perceptions, and, patterns, of, continued, use])].
[sujeto(['Second,', negative]), verbo([reports]), complemento([about, one, product, can, spill, over, to, affect, the, use, of, dissimilar, products, in, the, same, category])].
[sujeto(['We', conclude, that, the, '\'', negative, halo, 'effect\'']), verbo([associated]), complemento([with, a, 'stigma,', rather, than, an, objective, 'risk-benefit', assessment, of, medical, products, can, increase, negative, health, outcomes, for, patients, due, to, reduced, or, inappropriate, product, usage])].
[sujeto(['Femoroacetabular', impingement, '(', 'FAI)', syndrome, is, increasingly, recognised, as, a]), verbo([cause]), complemento([of, hip, pain])].
[sujeto(['The', final, 'protocol,', called, 'Personalised', 'Hip', 'Therapy', '(', 'PHT),', consists, of, four, core, components]), verbo([led]), complemento([by, 'physiotherapists:', detailed, patient, 'assessment,', education, and, 'advice,', help, with, pain, relief, and, an, 'exercise-based', programme, that, is, 'individualised,', supervised, and, progressed, over, time])].
[sujeto(['In', the, pilot, 'RCT,', 42, patients, were]), verbo([recruited]), complemento([and, 21, randomised, to, 'PHT'])].
[sujeto(['Review', of, treatment, case]), verbo([report]), complemento(['forms,', completed, by, 'physiotherapists,', showed, that, 13, patients, '(', 62, '%', ')', received, treatment, that, had, closely, followed, the, 'PHT', protocol])].
[sujeto([13, patients]), verbo([reported]), complemento([some, muscle, soreness, at, 6, 'weeks,', but, there, were, no, serious, adverse, events])].
[sujeto(['PHT']), verbo([provides]), complemento([a, structure, for, the, 'non-operative', care, of, 'FAI', and, offers, guidance, to, clinicians, and, researchers, in, an, evolving, area, with, limited, evidence])].
[sujeto([22, panel, members, and, 1, patient, from, 9, countries, and, 5, different, specialties]), verbo([participated]), complemento([in, a, 1, -, day, consensus, meeting, on, 29, 'June', 2016])].
[sujeto(['Substantial', agreement, '(', range, 9.5, -, 10, ')', was, reached, for, each, of, the, 6, consensus, 'questions,', and, the]), verbo([associated]), complemento([terminology, was, agreed, on])].
[sujeto(['To', reach, a, 'diagnosis,', patients, should]), verbo([have]), complemento([appropriate, 'symptoms,', positive, clinical, signs, and, imaging, findings])].
[sujeto(['Author', note, 'The', 'Warwick', 'Agreement', on, femoroacetabular, impingement, syndrome]), verbo([has]), complemento([been, endorsed, by, the, following, 25, clinical, 'societies:', 'American', 'Medical', 'Society', for, 'Sports', 'Medicine', '(', 'AMSSM),', 'Association', of, 'Chartered', 'Physiotherapists', in, 'Sports', and, 'Exercise', 'Medicine', '(', 'ACPSEM),', 'Australasian', 'College', of, 'Sports', and, 'Exercise', 'Physicians', '(', 'ACSEP),', 'Austian', 'Sports', 'Physiotherapists,', 'British', 'Association', of, 'Sports', and, 'Exercise', 'Medicine', '(', 'BASEM),', 'British', 'Association', of, 'Sport', 'Rehabilitators', and, 'Trainers', '(', 'BASRaT),', 'Canadian', 'Academy', of, 'Sport', and, 'Exercise', 'Medicine', '(', 'CASEM),', 'Danish', 'Society', of, 'Sports', 'Physical', 'Therapy', '(', 'DSSF),', 'European', 'College', of, 'Sports', and, 'Exercise', 'Physicians', '(', 'ECOSEP),', 'European', 'Society', of, 'Sports', 'Traumatology,', 'Knee', 'Surgery', and, 'Arthroscopy', '(', 'ESSKA),', 'Finnish', 'Sports', 'Physiotherapist', 'Association', '(', 'SUFT),', 'German-Austrian-Swiss', 'Society', for, 'Orthopaedic', 'Traumatologic', 'Sports', 'Medicine', '(', 'GOTS),', 'International', 'Federation', of, 'Sports', 'Physical', 'Therapy', '(', 'IFSPT),', 'International', 'Society', for, 'Hip', 'Arthroscopy', '(', 'ISHA),', 'Groupo', di, 'Interesse', 'Specialistico', 'dell\'A'])].
[sujeto([',', inherited, or, 'iatrogenic);', elevated, anesthetic, risk, such, as, in, cerebral, 'palsy,', arthrogryposis, multiplex, 'congenital,', 'trisomies;', syndromes]), verbo([require]), complemento([explicit, interdisciplinary, clarification, to, reduce, perioperative, 'risks;', infections, as, in, other, elective, 'surgeries;', 'diseases/deformities', making, postoperative, spica, casting, impossible, or, impractical, '(', e])].
[sujeto([',', deformities, of, spinal, cord, or, urogenital, 'system,', hernias]), verbo([requiring]), complemento(['treatment);', closed, epiphyseal, plate, requires, complex, 'three-dimensional', corrections, of, the, acetabular, roof, '(', e])].
[sujeto(['Like', the, differences]), verbo([found]), complemento([by, 'age,', smoking, 'rates,', level, of, 'activity,', and, nutritional, habits, were, significantly, different, by, 'ethnicity,', but, 'BMI', was, not])].
[sujeto(['The', highest, prevalence, of, smoking, was]), verbo([found]), complemento([to, be, associated, with, gender, '(', for, females, living, 'Moscow', and, for, males, in, rural, 'regions),', and, 'Russian', ethnic, group])].
[sujeto(['Tailored', programs, to]), verbo([prevent]), complemento([common, health, behavior, risk, factors, among, future, medical, doctors, are, urgently, needed, in, the, 'Russian', 'Federation'])].
[sujeto(['The', number, of, publications]), verbo([increased]), complemento([during, the, reviewed, time, period, with, the, most, dramatic, increase, from, 2011, to, 2013])].
[sujeto(['The', percent, of, publications, which, were, levels, 1, ',', 2, and, 3]), verbo([increased]), complemento([by, almost, twofold, from, 16.1, &, 'nbsp;%', '(', 'N', =, 26, ')', to, 28.7, &, 'nbsp;%', '(', 'N', =, 51, ')', between, 2011, and, 2015])].
[sujeto(['In', comparison, to, previous, 'work,', there]), verbo([has]), complemento([been, 3.5, -, fold, increase, in, the, number, of, publications, over, the, past, 5, &, 'nbsp;years', with, a, shift, towards, improving, the, level, of, evidence, available, guiding, the, arthroscopic, management, of, 'FAI'])].
[sujeto(['The', 'methyltransferase-like', 21, 'C', gene, '(', 'METTL21C),', which, is, mainly]), verbo([expressed]), complemento([in, 'muscle,', can, promote, the, differentiation, of, myoblasts, to, myotubes, and, reduce, 'glucocorticoid-induced', apoptosis, of, osteocytes])].
[sujeto(['Fifteen', tagging, single, nucleotide, polymorphisms, were, 'genotyped,', and, haplotype, blocks, were, derived, in, 400, 'Chinese', male]), verbo([nuclear]), complemento([families])].
[sujeto(['After', 1000, 'permutations,', significant, 'within-family', associations, were]), verbo([found]), complemento([between, rs9585961, and, lumbar, spine, 'BMD', and, femoral, neck, 'BMD,', rs9518810, and, femoral, neck, 'BMD,', and, rs599976, and, body, mass, 'index,', 'TFM,', and, percentage, fat, mass, '(', all, 'P < 0'])].
[sujeto(['The', association, analyses, with, haplotypes, showed, that, haplotype, 'AG', in, 'block 1', was, significantly]), verbo([associated]), complemento([with, 'TFM', '(', 'P = 0'])].
[sujeto([31, ')', and, haplotype, 'CAG', in, 'block 2', was, significantly]), verbo([associated]), complemento([with, lumbar, spine, 'BMD', '(', 'P = 0'])].
[sujeto(['Our', 'study,', for, the, first, 'time,', demonstrates, that, the, polymorphisms, and, haplotypes, of, 'METTL21C', contribute, to, the, peak, 'BMD', and, 'TFM', in, 'Chinese', 'males,', which]), verbo([suggests]), complemento([that, as, a, quantitative, trait, locus, with, potential, pleiotropy, it, may, have, an, influence, on, osteoporosis, and, obesity])].
[sujeto(['In', 'Puerto', 'Ricans', living, on, the, 'US', 'mainland,', 'European', ancestry, was]), verbo([associated]), complemento([with, lower, 'BMD', at, the, trochanter, '(', 'P = 0'])].
[sujeto([1, ')', ',', and, 'Native', 'American', ancestry, was]), verbo([associated]), complemento([with, lower, 'BMD', of, the, trochanter, '(', 'P = 0'])].
[sujeto(['African', ancestry, was]), verbo([associated]), complemento([with, a, higher, 'BMD', at, the, trochanter, '(', 'P = 0'])].
[sujeto(['Ancestry', was, not]), verbo([associated]), complemento([with, percent, fat, mass, or, lean, mass, or, waist, circumference])].
[sujeto(['This', work, contributes, to, our, understanding, of, the, high, prevalence, of, chronic, disease, experienced, by, this, population, and]), verbo([has]), complemento([implications, for, other, ethnic, minority, 'groups,', particularly, those, with, multiple, ancestries])].
[sujeto(['Future', research, should, consider, interactions, between, ancestry, and, environmental, 'factors,', as, this, may]), verbo([provide]), complemento([individualized, approaches, for, disease, prevention])].
[sujeto(['The', integrated, system, was, able, to, automatically, 'collect,', analyze, and]), verbo([report]), complemento([the, results, for, the, mechanical, alignment, tests, specified, by, 'TG-142'])].
[sujeto(['Measurement', variability]), verbo([increased]), complemento([slightly, from, 0.1, mm, to, 0.2, mm, when, the, phantom, setup, was, 'varied,', but, no, significant, difference, in, the, mean, measurement, value, was, detected])].
[sujeto(['We']), verbo([have]), complemento([observed, significant, increase, of, bone, morphogenetic, protein, '(', 'BMP)', signaling, in, neonatal, mouse, lungs, immediately, after, birth])].
[sujeto(['Furthermore,', activation, of, 'BMP', signaling, in, cultured, lung, epithelial, cells, was, able, to]), verbo([promote]), complemento([endogenous, 'Nfatc3', expression, and, also, stimulate, the, activity, of, an, 'Nfatc3', promoter, that, contains, a, 'Smad1-binding', site])].
[sujeto(['Therefore,', our, study]), verbo([suggests]), complemento([that, the, 'BMP-Alk3-Smad1-Nfatc3', regulatory, loop, plays, an, important, role, in, enhancing, surfactant, production, in, 'neonates,', possibly, helping, neonatal, respiratory, adaptation, from, prenatal, amniotic, fluid, environment, to, neonatal, air, breathing])].
[sujeto(['To']), verbo([gain]), complemento([greater, insight, into, features, that, promote, efficient, 'ORR,', we, 'expressed,', 'characterized,', and, investigated, the, electrochemical, behavior, of, six, new, mutants, of, cytochrome, c552, from, 'Thermus', 'thermophilus:', 'V49S/M69A,', 'V49T/M69A,', 'L29D/V49S/M69A,', 'P27A/P28A/L29D/V49S/M69A,', and, 'P27A/P28A/L29D/V49T/M69A'])].
[sujeto(['Mutation', to, 'V49']), verbo([causes]), complemento([only, minor, shifts, to, 'Fe(III/II)', reduction, potentials, '(', 'E°\'),', but, introduction, of, 'Ser', provides, a, hydrogen, bond, donor, that, slightly, enhances, oxygen, reduction, activity])].
[sujeto(['Mutation', of, 'L29', to, 'D']), verbo([induces]), complemento([small, shifts, in, heme, optical, 'spectra,', but, not, to, 'E°\'', '(', within, experimental, 'error)'])].
[sujeto(['Replacement', of, 'P27', and, 'P28', with, 'A', in, both, positions]), verbo([induces]), complemento([a, -, 50, mV, shift, in, 'E°\',', again, with, small, changes, to, the, optical, spectra])].
[sujeto(['Both', the, optical, spectra, and, reduction, potentials]), verbo([have]), complemento([signatures, consistent, with, peroxidase, enzymes])].
[sujeto(['The', 'V49S', and, 'V49T', mutations]), verbo([have]), complemento([the, largest, impact, of, 'ORR', 'catalysis,', suggesting, that, increased, electron, density, at, the, 'Fe', site, does, not, improve, 'O2', reduction, chemistry])].
[sujeto(['The', 'Spine', 'Functional', 'Index', '(', 'SFI)', is, a, patient]), verbo([reported]), complemento([outcome, measure, with, sound, clinimetric, properties, and, clinical, viability, for, the, determination, of, 'whole-spine', impairment])].
[sujeto(['The', 'SFI', 'English', version, was, culturally, adapted, and]), verbo([translated]), complemento([into, 'Turkish', using, a, double, forward, and, backward, method, according, to, established, guidelines])].
[sujeto(['Kinase', 'cascades,', in, which, enzymes, are, sequentially]), verbo([activated]), complemento([by, 'phosphorylation,', are, quintessential, signaling, pathways])].
[sujeto(['Often,', kinases]), verbo([activate]), complemento([pathways, by, deactivation, of, a, negative, 'regulator;', this, indirect, 'mechanism,', pervasive, in, 'Akt', 'signaling,', has, yet, to, be, systematically, explored])].
[sujeto(['Here,', we, show, that, the, indirect, mechanism]), verbo([has]), complemento([properties, that, are, distinct, from, direct, activation])].
[sujeto(['With', comparable, 'parameters,', the, indirect, mechanism, yields, a, broader, range, of, sensitivity, to, the, 'input,', beyond, saturation, of, regulator, 'phosphorylation,', and, kinetics, that, become, progressively, 'slower,', not, 'faster,', with]), verbo([increasing]), complemento([input, strength])].
[sujeto(['The', 'DGK', family, is]), verbo([targeted]), complemento([to, distinct, subcellular, sites, in, 'cDNA-transfected', and, native, cells])].
[sujeto(['Of', 'DGKs,', 'DGKε', localizes, primarily, to, the, 'ER,']), verbo([suggesting]), complemento([that, this, isozyme, plays, a, role, in, this, organelle])].
[sujeto(['Using', experiments, with, various, deletion, and, substitution, 'mutants,', this, study, examined, the, molecular, mechanism, of, how, 'DGKε', is]), verbo([targeted]), complemento([to, the, 'ER'])].
[sujeto(['Results', demonstrate, that, the, 'N-terminal', hydrophobic, sequence, 20, -, 40, plays, a, necessary, role, in]), verbo([targeting]), complemento([of, 'DGKε', to, the, 'ER'])].
[sujeto(['These', results, indicate, that, the, 'N-terminal', hydrophobic, residues, play, a, key, role, in, 'DGKε']), verbo([targeting]), complemento([to, the, 'ER', membrane])].
[sujeto(['We', use, 'all-atom', molecular, dynamics, simulations, on, a, massive, scale, to, compute, the, standard]), verbo([binding]), complemento([free, energy, of, the, 13, -, residue, antimicrobial, peptide, indolicidin, to, a, lipid, bilayer])].
[sujeto(['The', analysis, of, statistical, convergence]), verbo([reveals]), complemento([systematic, sampling, errors, that, correlate, with, reorganization, of, the, bilayer, on, the, microsecond, timescale, and, persist, throughout, a, total, of, 1.4, ms, of, sampling])].
[sujeto(['Consistent', with, experimental, 'observations,', indolicidin]), verbo([induces]), complemento([membrane, 'thinning,', although, the, simulations, significantly, overestimate, the, lipophilicity, of, the, peptide])].
[sujeto(['Short-term', habituation, '(', 'STH)', is, the]), verbo([decrease]), complemento([in, behavioral, responding, observed, during, repeated, stimulation, at, regular, intervals])].
[sujeto(['Here', we, examined, the, role, of, the, 'L29s', in, 'STH', by, addressing, two, 'questions:', '(', 1, ')', 'What', are, the, relative, contributions, of, intrinsic, regulation, of, excitability, and, network, inhibition, on, 'L29', activity, during, 'STH', 'training?', 'By']), verbo([activating]), complemento(['L29s', with, intracellular, current, 'injection,', we, found, that, intrinsic, changes, in, excitability, 'occur,', but, only, at, short, training, intervals, '(', 1, 's)'])].
[sujeto(['We', also, demonstrated, that, network, inhibition, is, not]), verbo([required]), complemento([for, regulating, 'L29', responses, during, 'training,', indicating, that, any, expression, of, inhibition, is, redundant, to, the, excitability, changes])].
[sujeto(['(', 2, ')', 'How', does, 'L29', synaptic, plasticity, contribute, to, the, maintenance, of, training, 'site-specificity', exhibited, in, 'LFS', 'MNs?', 'When', training, stimuli, are, delivered, 1, s, apart, '[', 1, 's,', interstimulus, interval, '(', 'ISI)],', 'L29', responses]), verbo([decrease]), complemento([in, both, stimulated, '(', 'trained)', and, 'un-stimulated', '(', 'untrained)', 'pathways,', yet, 'site-specificity', of, training, is, maintained, in, the, 'LFS', 'MNs'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'activity-dependent', synaptic, facilitation, '(', 'augmentation;', 'AUG)', expressed, by, the, 'L29s', acts, to, compensate, for, the, decreased, activity, in, the, untrained, pathway])].
[sujeto(['Second,', we, showed, that, the, induction, of, 'AUG']), verbo([prevents]), complemento([the, reduction, in, 'siphon-evoked', 'LFS', responses, that, is, otherwise, observed, with, decreased, 'L29', activity])].
[sujeto(['Collectively,', our, results, support, a, role, for, the, 'L29s', in]), verbo([regulating]), complemento([network, dynamics, during, 'STH', 'training,', but, only, at, rapid, '(', 1, s, 'ISI)', training, intervals])].
[sujeto(['Whole-cell,', 'matrix-assisted', laser, 'desorption/ionization', 'time-of-flight', '(', 'MALDI-TOF)', mass, spectrometry]), verbo([has]), complemento([become, a, routine, and, reliable, method, for, microbial, characterization, due, to, its, 'simplicity,', low, 'cost,', and, high, reproducibility])].
[sujeto(['This', is, a, gold, standard, for, clinicians, who]), verbo([have]), complemento([a, finite, number, of, 'well-defined', pathogenic, strains, but, represents, a, problem, for, environmental, microbiologists, with, an, overwhelming, number, of, organisms, to, be, defined])].
[sujeto(['We', show, that, the, 'DNA']), verbo([binding]), complemento(['protein,', 'HU,', and, the, ribosomal, 'proteins,', 'L29', and, 'L30,', are, the, most, robust, biomarkers, within, the, 'Roseobacter', clade])].
[sujeto(['The', molecular, weights, of, these, three, 'biomarkers,', as, for, other]), verbo([conserved]), complemento([homologous, 'proteins,', vary, due, to, sequence, variation, above, the, genus, level])].
[sujeto(['Frequently']), verbo([found]), complemento([as, a, commensal, within, the, digestive, tracts, of, healthy, 'individuals,', 'C'])].
[sujeto([albicans, is, an, opportunistic, pathogen, that]), verbo([causes]), complemento([a, wide, variety, of, clinical, syndromes, in, 'immuno-compromised', individuals])].
[sujeto(['Intron', annotation, is, also, important, for, identifying, potential]), verbo([targets]), complemento([of, splicing, 'regulation,', a, common, mechanism, of, gene, control, in, eukaryotes])].
[sujeto(['In', this, 'study,', we]), verbo([report]), complemento([an, improved, annotation, of, 'C'])].
[sujeto(['In', addition, to, correcting, the, existing, intron, 'annotations,', 25, '%', of, which, were, 'incorrect,', we]), verbo([have]), complemento([used, novel, computational, and, experimental, approaches, to, identify, new, 'introns,', bringing, the, total, to, 415, ',', almost, double, the, number, previously, known])].
[sujeto(['albicans,', and, are, 'over-represented', in, genes]), verbo([involved]), complemento([in, specific, cellular, 'processes,', such, as, 'splicing,', 'translation,', and, mitochondrial, respiration])].
[sujeto(['This', nonrandom, distribution]), verbo([suggests]), complemento([functional, roles, for, these, 'introns,', and, we, demonstrate, that, splicing, of, two, transcripts, whose, introns, have, unusual, sequence, features, is, responsive, to, environmental, factors])].
[sujeto(['The', data, were, obtained, to, synthesize, two, kinds, of, oligonucleotide, 'primers,', which, were, used, in, the, polymerase, chain, reaction, to, amplify, and, clone, the]), verbo([nuclear]), complemento([gene, for, this, protein])].
[sujeto(['By', nucleotide, 'sequencing,', the, cloned, 'gene,', 'MRP-L33,', was]), verbo([found]), complemento([to, encode, a, basic, protein, of, 11, kDa, with, 98, amino, acid, residues])].
[sujeto(['The', protein, encoded, by, this, gene, appears, to]), verbo([have]), complemento([no, leader, sequence, at, its, 'N', terminus])].
[sujeto(['Type', 2, 'Diabetes', 'Mellitus', '(', 'T2DM)', and, obesity]), verbo([have]), complemento([become, increasingly, prevalent, in, recent, years])].
[sujeto(['Recent', studies]), verbo([have]), complemento([focused, on, identifying, causal, variations, or, candidate, genes, for, obesity, and, 'T2DM', via, analysis, of, expression, quantitative, trait, loci, '(', 'eQTL)', within, a, single, tissue])].
[sujeto(['The', majority, of, these, genes, are, known, to, be]), verbo([involved]), complemento([in, 'T2DM', and, obesity])].
[sujeto(['Therefore,', analysis, of, gene, expression, in, various, tissues, using, 'GEO', datasets, may, be, an, effective, and, feasible, method, to, determine, novel, or, causal, genes]), verbo([associated]), complemento([with, 'T2DM', and, obesity])].
[sujeto(['Gene', transfer, events, from, organelle, genomes, '(', mitochondria, and, chloroplasts, in, 'plants)', to, the]), verbo([nuclear]), complemento([genome, are, important, processes, in, the, evolution, of, the, eukaryotic, cell])].
[sujeto(['Recently,', several, exceptional, cases, of, gene]), verbo([loss]), complemento([from, the, chloroplast, genome, have, been, discovered, as, the, number, of, complete, chloroplast, genome, sequences, has, increased])].
[sujeto(['The', 'Populus', chloroplast, genome]), verbo([has]), complemento([lost, the, rpl32, 'gene,', while, the, corresponding, the, chloroplast, rpl32, '(', cp, 'rpl32)', gene, has, been, identified, in, the, nuclear, genome])].
[sujeto(['Nuclear', genes, transferred, from, the, chloroplast, genome, need, to]), verbo([gain]), complemento([a, sequence, that, encodes, a, transit, peptide])].
[sujeto(['Here,', we, revealed, that, the]), verbo([nuclear]), complemento([cp, rpl32, gene, has, acquired, the, exon, 'sequence,', which, is, highly, homologous, to, a, transit, peptide, derived, from, the, chloroplast, 'Cu-Zn', superoxide, dismutase, '(', cp, 'sod-1)', gene])].
[sujeto(['The', cp, rpl32, gene]), verbo([has]), complemento([acquired, the, sequence, that, encodes, not, only, for, the, transit, 'peptide,', but, also, for, the, conserved, 'N-terminal', portion, of, the, mature, 'SOD', protein, from, the, cp, 'sod-1', 'gene,', suggesting, the, occurrence, of, 'DNA', sequence, duplication])].
[sujeto(['This', difference, may, be]), verbo([caused]), complemento([by, mutations, accumulated, in, the, sequence, of, the, 'SOD', domain, on, the, cp, rpl32, gene])].
[sujeto(['We']), verbo([provide]), complemento([new, insight, into, the, fate, of, the, inherent, sequence, derived, from, a, transit, peptide])].
[sujeto(['Tissue', inhibitor, of, 'metalloproteinases-1', '(', 'TIMP-1)', is, a, widely, 'expressed,', secreted, protein, that, functions, primarily, to]), verbo([inhibit]), complemento([members, of, a, large, family, of, metalloproteinases, '(', 'MPs)'])].
[sujeto(['Because', of, the, ability, of, 'TIMP-1', to]), verbo([inhibit]), complemento(['MPs,', it, functions, in, many, of, the, same, pathophysiological, processes, as, these, 'enzymes,', e])].
[sujeto(['TIMP-1', can, also]), verbo([stimulate]), complemento([proliferation, '(', '[', 3, 'H]thymidine', 'incorporation)', and, cellular, anabolic, processes, '(', 'Alamar', 'Blue', 'reduction)'])].
[sujeto(['This', stimulation]), verbo([has]), complemento([been, shown, to, be, dependent, on, the, 'MP-inhibitory', ability, of, 'TIMP-1', in, the, human, breast, cancer, cell, line, 'MDA-MB-435', '(', 'Porter', et, al])].
[sujeto(['To', shed, light, on, the, mechanism, by, which, 'TIMP-1']), verbo([stimulates]), complemento([cellular, anabolic, 'processes,', an, oligonucleotide, microarray, analysis, was, performed, over, a, time, course, of, 'TIMP-1', treatment, of, 'MDA-MB-435', cells])].
[sujeto(['Fifteen', genes, whose, mRNAs, were, differentially]), verbo([regulated]), complemento([were, identified])].
[sujeto(['These', same, mRNAs, were, shown, to, be]), verbo([regulated]), complemento([by, the, synthetic, hydroxamate, 'MP-inhibitor', 'GM6001', but, not, by, its, inactive, derivative, 'GM6001*,', suggesting, that, the, differential, regulation, occurs, through, the, 'MP-inhibitory', ability, of, 'TIMP-1'])].
[sujeto(['These', results]), verbo([suggest]), complemento([a, complex, action, of, 'TIMP-1', on, cancer, cells, mediated, by, constitutively, active, cell, surface, metalloproteinases, that, release, factors, regulating, cell, signaling, 'pathways;', they, may, account, for, the, paradoxical, observation, that, elevated, levels, of, 'TIMP-1', in, tumors, can, correlate, with, an, adverse, prognosis])].
[sujeto(['Sessile', communities, of, yeast, biofilms, in, liquid, medium]), verbo([provide]), complemento([a, primitive, example, of, multicellularity, and, are, clinically, important, because, biofilms, tend, to, have, other, growth, characteristics, than, 'free-living', cells])].
[sujeto(['We', investigated, the, genetic, basis, for, 'yeast,', 'Saccharomyces', 'cerevisiae,', biofilm, on, solid, surfaces, in, liquid, medium, by, screening, a, comprehensive, deletion, mutant, collection, in, the, 'Σ1278b', background, and]), verbo([found]), complemento([71, genes, that, were, essential, for, biofilm, development])].
[sujeto(['In', a, tpk3, 'mutant,', transcription, of, 'FLO11', was]), verbo([induced]), complemento(['three-fold', compared, with, 'wild-type,', but, biofilm, development, and, 'cell-cell', adhesion, was, 'absent,', suggesting, that, 'Tpk3p', regulates, 'FLO11', positive, posttranscriptionally, and, negative, transcriptionally])].
[sujeto(['The', study]), verbo([provides]), complemento([a, resource, of, 'biofilm-influencing', genes, for, additional, research, on, biofilm, development, and, suggests, that, the, regulation, of, 'FLO11', is, more, complex, than, previously, anticipated])].
[sujeto(['The', import, of, matrix, proteins, typically, relies, on, 'N-terminal', mitochondrial]), verbo([targeting]), complemento([sequences, that, form, positively, charged, amphipathic, helices])].
[sujeto(['Interestingly,', the, 'N-terminal', regions, of, many, ribosomal, proteins, do, not, closely, match, the, characteristics, of, matrix]), verbo([targeting]), complemento(['sequences,', suggesting, that, the, import, processes, of, these, proteins, might, deviate, to, some, extent, from, the, general, import, route])].
[sujeto(['m-AAA', proteases, exert, dual, functions, in, the, mitochondrial, inner, 'membrane:', they]), verbo([mediate]), complemento([the, processing, of, specific, regulatory, proteins, and, ensure, protein, quality, control, degrading, misfolded, polypeptides, to, peptides])].
[sujeto(['Loss', of, these, activities]), verbo([leads]), complemento([to, neuronal, cell, death, in, several, neurodegenerative, disorders])].
[sujeto(['A', central, and]), verbo([conserved]), complemento([function, of, the, 'm-AAA', protease, is, the, processing, of, the, ribosomal, subunit, 'MrpL32,', which, regulates, ribosome, biogenesis, and, the, formation, of, respiratory, complexes])].
[sujeto(['Here,', we, demonstrate, that, the, formation, of, a, tightly, folded, domain, harbouring, a]), verbo([conserved]), complemento(['CxxC-X(9)-CxxC', sequence, motif, halts, degradation, initiated, from, the, 'N-terminus', and, triggers, the, release, of, mature, 'MrpL32'])].
[sujeto(['Oxidative', stress, impairs, folding, of, 'MrpL32,', resulting, in, its, degradation, by, the, 'm-AAA', protease, and]), verbo([decreased]), complemento([mitochondrial, translation])].
[sujeto(['Surprisingly,', 'MrpL32', folding, depends, on, its, mitochondrial]), verbo([targeting]), complemento([sequence])].
[sujeto(['Presequence-assisted', folding, of, 'MrpL32']), verbo([requires]), complemento([the, complete, import, of, the, 'MrpL32', precursor, before, maturation, occurs, and, therefore, explains, the, need, for, 'post-translocational', processing, by, the, 'm-AAA', protease, rather, than, 'co-translocational', cleavage, by, the, general, mitochondrial, processing, peptidase])].
[sujeto(['An', autosomal, recessive, form, of, the, disease, is]), verbo([caused]), complemento([by, mutations, in, 'paraplegin,', which, is, a, conserved, subunit, of, the, ubiquitous, and, 'ATP-dependent', 'm-AAA', protease, in, mitochondria])].
[sujeto(['The', 'm-AAA', protease, carries, out, protein, quality, control, in, the, inner, membrane, of, the, 'mitochondria,']), verbo([suggesting]), complemento([a, pathogenic, role, of, misfolded, proteins, in, 'HSP'])].
[sujeto(['A', recent, study, demonstrates, that, the, 'm-AAA', protease]), verbo([regulates]), complemento([ribosome, assembly, and, translation, within, mitochondria, by, controlling, proteolytic, maturation, of, a, ribosomal, subunit])].
[sujeto(['AAA', proteases, comprise, a]), verbo([conserved]), complemento([family, of, membrane, bound, 'ATP-dependent', proteases, that, ensures, the, quality, control, of, mitochondrial, 'inner-membrane', proteins])].
[sujeto(['Inactivation', of, 'AAA', proteases]), verbo([causes]), complemento([pleiotropic, phenotypes, in, various, 'organisms,', including, respiratory, 'deficiencies,', mitochondrial, morphology, 'defects,', and, axonal, degeneration, in, hereditary, spastic, paraplegia, '(', 'HSP)'])].
[sujeto(['Our', findings, therefore, rationalize, mitochondrial, defects]), verbo([associated]), complemento([with, 'm-AAA', protease, mutants, in, yeast, and, shed, new, light, on, the, mechanism, of, axonal, degeneration, in, 'HSP'])].
[sujeto(['While', others]), verbo([have]), complemento([described, gene, expression, patterns, in, humans, with, inflammatory, bowel, diseases, and, animals, with, chemically, induced, 'colitis,', a, 'genome-wide', comparison, of, gene, expression, in, genetically, susceptible, animals, that, develop, spontaneous, colitis, has, not, been, reported])].
[sujeto(['Expression', of, the, selected, genes, in, dextran, sodium, sulfate, '(', 'DSS)-treated', mice, with, colitis, and, epithelial, cell, lines]), verbo([activated]), complemento([with, pathophysiologic, stimuli, was, measured, by, 'real-time', 'PCR'])].
[sujeto(['MHC', 'II', was]), verbo([increased]), complemento([throughout, the, 'colon,', and, 'aquaporin-4', was, increased, in, the, basolateral, aspect, of, cecal, epithelial, cells])].
[sujeto(['MHC', 'II', mRNA, was]), verbo([increased]), complemento([in, epithelial, cells, treated, with, 'IFN-gamma,', but, not, 'TNF', or, 'Toll-like', receptor, ligands])].
[sujeto(['Although', most, upregulated, genes, in, experimental, colitis, are, 'immune-related,', 'aquaporin-4', and, mitochondrial, ribosomal, 'protein-L33,', which]), verbo([have]), complemento([not, been, previously, associated, with, 'inflammation,', were, most, highly, upregulated])].
[sujeto(['Traditional', candidate, gene, approach]), verbo([has]), complemento([been, widely, used, for, the, study, of, complex, diseases, including, obesity])].
[sujeto(['We']), verbo([found]), complemento([common, genes, including, 'FTO,', the, fat, mass, and, obesity, associated, 'gene,', identified, from, significant, 'SNPs', by, association, studies, of, each, trait])].
[sujeto(['Navigating', syntenic, regions]), verbo([suggests]), complemento([obesity, candidate, genes, on, chromosome, 2, that, are, previously, known, to, be, associated, with, 'obesity-related', 'diseases:', 'MRPL33,', 'PARD3B,', 'ERBB4,', 'STK39,', and, 'ZNF385B'])].
[sujeto(['In', current, 'study,', the, genes, which]), verbo([have]), complemento([relationships, with, breast, muscle, development, were, identified, by, suppression, subtractive, hybridization])].
[sujeto(['At', 37, degrees, 'C,', 'rpl33a-G76R']), verbo([confers]), complemento([defects, in, 60, 'S', biogenesis, comparable, to, those, produced, by, the, deletion, of, 'RPL33A', '(', 'DeltaA)'])].
[sujeto(['At', 28, degrees, 'C,', 'however,', the, 60, 'S', biogenesis, defect, is, less, severe, in, 'rpl33a-G76R', than, in, 'DeltaA', 'cells,', yet, 'rpl33a-G76R']), verbo([confers]), complemento([greater, derepression, of, 'GCN4', and, a, larger, reduction, in, general, translation])].
[sujeto(['Hence,', it, appears, that, 'rpl33a-G76R']), verbo([has]), complemento([a, stronger, effect, on, 'ribosomal-subunit', joining, than, does, a, comparable, reduction, of, 'wild-type', 60, 'S', levels, conferred, by, 'DeltaA'])].
[sujeto(['We']), verbo([suggest]), complemento([that, 'rpl33a-G76R', alters, the, 60, 'S', subunit, in, a, way, that, impedes, 'ribosomal-subunit', joining, and, thereby, allows, 48, 'S', rRNA, complexes, to, abort, initiation, at, 'uORF4,', resume, 'scanning,', and, initiate, downstream, at, 'GCN4'])].
[sujeto(['Because', overexpressing, tRNAiMet]), verbo([suppresses]), complemento([the, 'Gcd-', phenotype, of, 'rpl33a-G76R', 'cells,', dissociation, of, tRNAiMet, from, the, 40, 'S', subunit, may, be, responsible, for, abortive, initiation, at, uORF4, in, this, mutant])].
[sujeto(['Mutations', that, diminish, the, function, of, the, extracellular, matrix, receptor, 'Dystroglycan', '(', 'DG)', result, in, muscular, 'dystrophies,', with]), verbo([associated]), complemento([neuronal, migration, defects, in, the, brain, and, mental, retardation, e])].
[sujeto(['To']), verbo([gain]), complemento([insight, into, the, function, of, 'DG', in, the, nervous, system, we, initiated, a, study, to, examine, its, contribution, to, development, of, the, eye, of, 'Drosophila', melanogaster])].
[sujeto(['Immuno-histochemistry', showed, that, 'DG', is, concentrated, on, the, apical, surface, of, photoreceptors, '(', 'R)', cells, during, specification, of, 'cell-fate', in, the, third, instar, larva, and, is]), verbo([maintained]), complemento([at, this, location, through, early, pupal, stages])].
[sujeto(['Overexpression', of, 'DG', in, 'R', cells, results, in, a, small, but, significant]), verbo([increase]), complemento([in, their, size])].
[sujeto(['In', the, 'adult,', these, flies]), verbo([have]), complemento([severely, disrupted, 'R', cells, as, well, as, defects, in, the, lens, and, ommatidia])].
[sujeto(['We', conclude, that, 'DG', does, not, affect, neuronal, commitment, but, functions, 'R', cell, autonomously, to]), verbo([regulate]), complemento([neuronal, elongation, during, differentiation, in, the, pupa])].
[sujeto(['Assaying', effects, on, 'pre-rRNA', processing, and, ribosome, assembly, upon, depleting, individual, ribosomal, proteins, '(', 'r-proteins)']), verbo([provided]), complemento([an, initial, paradigm, for, assembly, of, eukaryotic, ribosomes, in, 'vivo-that', each, structural, domain, of, ribosomal, subunits, assembles, in, a, hierarchical, fashion])].
[sujeto(['However,', two, features]), verbo([suggest]), complemento([that, a, more, complex, pathway, may, 'exist:', '(', 'i)', 'Some', 'r-proteins', contain, extensions, that, reach, long, distances, across, ribosomes, to, interact, with, multiple, rRNA, domains, as, well, as, with, other, 'r-proteins'])].
[sujeto(['Here,', we, show, that, deleting, or, mutating, extensions, of, 'r-proteins', 'L7', '(', 'uL30)', and, 'L35', '(', 'uL29)', from, yeast]), verbo([reveal]), complemento([important, roles, in, early, and, middle, steps, during, 60, 'S', ribosomal, subunit, biogenesis])].
[sujeto(['Detailed', analysis, of, the, 'N-terminal', terminal, extension, of, 'L8', '(', 'eL8)', showed, that, it, is, necessary, for, late]), verbo([nuclear]), complemento([stages, of, 60, 'S', subunit, assembly, involving, two, major, remodeling, 'events:', removal, of, the, 'ITS2', 'spacer;', and, reorganization, of, the, central, protuberance, '(', 'CP)', containing, 5, 'S', rRNA, and, 'r-proteins', 'L5', '(', 'uL18)', and, 'L11', '(', 'uL5)'])].
[sujeto(['Mutations', in, the, 'L8', extension, block, processing, of, 7, 'S', 'pre-rRNA,']), verbo([prevent]), complemento([release, of, assembly, factors, 'Rpf2', and, 'Rrs1', from, 'pre-ribosomes,', which, is, required, for, rotation, of, the, 'CP,', and, block, association, of, 'Sda1,', the, 'Rix1', 'complex,', and, the, 'Rea1', 'ATPase', involved, in, late, steps, of, remodeling])].
[sujeto(['Differentially']), verbo([expressed]), complemento([genes, '(', 'DEGs)', between, 'FH', and, controls, were, identified, and, a, 'protein-protein', interaction, '(', 'PPI)', network, was, constructed])].
[sujeto(['The', 'DEGs', were]), verbo([found]), complemento([to, be, significantly, enriched, in, ribosomal, and, oxidative, phosphorylation, pathways])].
[sujeto(['Ribosomal', protein, genes, were]), verbo([found]), complemento([to, be, involved, in, the, ribosomal, pathway])].
[sujeto(['Ribosomal', and, oxidative, phosphorylation, pathways, may, be, closely]), verbo([associated]), complemento([with, atherosclerosis, development])].
[sujeto(['Ribosomal', protein, genes, and, 'cytochrome-coxidase', genes, may, be, potential, therapeutic]), verbo([targets]), complemento([for, atherosclerosis])].
[sujeto(['The', growing, consumer, demand, for, products, with, health, benefits]), verbo([has]), complemento([increased, interest, in, these, types, of, 'Citrus', cultivars, as, a, potential, source, of, nutraceuticals])].
[sujeto(['Reverse', transcription, quantitative, polymerase, chain, reaction, is, a, method, of, quantifying, gene, 'expression,', but, various, standardizations, are]), verbo([required]), complemento([to, obtain, 'precise,', 'accurate,', and, specific, results])].
[sujeto(['The', objective, of, this, study, was, to, evaluate, the, stability, of, 11, candidate, genes, using, various, tissue, and, organ, samples, from, healthy, plants, or, leaves, from, citrus, greening, disease, '(', 'Huanglongbing)-symptomatic', plants, of, a, 'Brazilian', 'red-fleshed']), verbo([cultivar]), complemento(['(', '\'', 'Sanguínea', de, 'Mombuca\'),', in, order, to, select, the, most, suitable, reference, gene, for, investigating, gene, expression, under, these, conditions])].
[sujeto([60, 'S', ribosomal, protein, 'L35', '(', 'RPL35)', is, an, important, component, of, the, 60, 'S', ribosomal, subunit, and]), verbo([has]), complemento([a, role, in, protein, translation, and, endoplasmic, reticulum, '(', 'ER)', docking])].
[sujeto(['However,', few, studies]), verbo([have]), complemento([investigated, 'RPL35', in, eukaryotes, and, much, remains, to, be, learned])].
[sujeto(['We']), verbo([found]), complemento([that, methionine, '(', 'Met)', could, promote, the, expressions, of, 'CSN2', and, 'RPL35'])].
[sujeto(['Analysis', of, overexpression, and, inhibition, of, 'RPL35', confirmed, that, it, could]), verbo([mediate]), complemento([the, 'Met', signal, and, regulate, 'CSN2', expression])].
[sujeto(['We']), verbo([found]), complemento([that, 'RPL35', could, control, ribosome, translational, elongation, during, synthesis, of, 'CSN2', by, interacting, with, eukaryotic, translational, elongation, factor, 2, '(', 'eEF2),', and, that, eEF2, was, the, signaling, molecule, downstream, of, 'RPL35', controlling, this, process])].
[sujeto(['Taken', 'together,', these, results, revealed, 'that,', 'RPL35', was, an, important, positive, regulatory, factor]), verbo([involving]), complemento([in, the, 'Met-mediated', regulation, of, 'CSN2', translational, elongation, and, secretion])].
[sujeto([pumilus, the, specific, ion, at, 'm/z', 5271, was]), verbo([associated]), complemento([with, a, small, 'acid-soluble', spore, protein, '(', 'SASP', 'O)', or, with, 50, 'S', protein, 'L35,', whereas, in, 'B'])].
[sujeto([safensis, specific, ions, at, 'm/z', 5288, and, 5568, were]), verbo([associated]), complemento([with, 'SASP', 'J', and, 'P,', 'respectively,', and, an, ion, at, 'm/z', 6413, with, 50, 'S', protein, 'L32'])].
[sujeto(['It', is, challenging, to]), verbo([find]), complemento([genes, with, stable, transcripts, for, use, as, reference, genes, for, quantitative, realtime, polymerase, chain, reaction, '(', 'qRT-PCR)', during, viral, infection])].
[sujeto(['In', addition, to, 28, 'S,', previously, known, to]), verbo([have]), complemento([stable, transcript, 'levels,', 'qRT-PCR', showed, that, 'ECD', transcript, levels, remained, constant, throughout, the, time, course, of, 'AcMNPV', infection])].
[sujeto(['Ribosome', synthesis]), verbo([involves]), complemento([the, coordinated, folding, and, processing, of, 'pre-rRNAs', with, assembly, of, ribosomal, proteins])].
[sujeto(['Here,', we]), verbo([have]), complemento([examined, the, role, of, adjacent, yeast, 'r-proteins', 'L17,', 'L35', and, 'L37', in, folding, and, processing, of, 'pre-rRNAs,', and, binding, of, other, proteins, within, assembling, ribosomes])].
[sujeto(['These', three, essential, ribosomal, 'proteins,', which, surround, the, polypeptide, exit, 'tunnel,', are]), verbo([required]), complemento([for, 60, 'S', subunit, formation, as, a, consequence, of, their, role, in, removal, of, the, 'ITS2', spacer, from, 27, 'SB', 'pre-rRNA'])].
[sujeto(['Although', the, structure, of, 'ITS2', does, not, appear, to, be, grossly, affected, in, their, 'absence,', these, three, ribosomal, proteins, are, necessary, for, efficient, recruitment, of, factors]), verbo([required]), complemento([for, 27, 'SB', 'pre-rRNA', 'processing,', 'namely,', 'Nsa2', and, 'Nog2,', which, associate, with, 'pre-60S', ribosomal, particles, containing, 27, 'SB', 'pre-rRNAs'])].
[sujeto(['Altogether,', these, data, support, that, 'L17,', 'L35', and, 'L37', are, specifically]), verbo([required]), complemento([for, a, recruiting, step, immediately, preceding, removal, of, 'ITS2'])].
[sujeto(['After']), verbo([arresting]), complemento(['L5', 'synthesis,', 'Escherichia', coli, cells, divide, a, limited, number, of, times])].
[sujeto(['These', 45, 'S', particles, lack, most, of, the, central, protuberance, '(', 'CP)', components, '(', 5, 'S', rRNA, and, proteins, 'L5,', 'L16,', 'L18,', 'L25,', 'L27,', 'L31,', 'L33', and, 'L35)', and, are, not, able, to]), verbo([associate]), complemento([with, the, small, ribosomal, subunit])].
[sujeto(['At', the, same, 'time,', 5, 'S', rRNA, is]), verbo([found]), complemento([in, the, cytoplasm, in, complex, with, ribosomal, proteins, 'L18', and, 'L25', at, quantities, equal, to, the, amount, of, ribosomes])].
[sujeto(['Lack', of, continuous, progress, in, 'Theobroma', cacao, '(', 'Malvaceae)', 'breeding,', especially]), verbo([associated]), complemento([with, seed, quality, 'traits,', requires, more, efficient, selection, methods, based, on, genomic, information])].
[sujeto(['Reverse', transcript, quantitative, 'PCR', '(', 'RT-qPCR)']), verbo([has]), complemento([become, the, method, of, choice, for, gene, expression, 'analysis,', but, relative, expression, analysis, requires, various, reference, 'genes,', which, must, be, stable, across, various, biological, conditions])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([to, define, reference, genes, for, expression, studies, in, cacao])].
[sujeto(['Environmental', metagenomics]), verbo([provides]), complemento([snippets, of, genomic, sequences, from, all, organisms, in, an, environmental, sample, and, are, an, unprecedented, resource, of, information, for, investigating, microbial, population, genetics])].
[sujeto(['The', large, majority, of, genes, '(', 98, '%', ')']), verbo([have]), complemento([evolved, under, purifying, selection, '(', 'dN/dS<1)'])].
[sujeto(['Of', the, genes, that, may]), verbo([have]), complemento([evolved, under, positive, selection, '(', 'dN/dS>1),', 77, out, of, 83, '(', 93, '%', ')', were, hypothetical])].
[sujeto(['Other', annotated, 'genes,', in, particular, a, possible, 'porin,', a, 'large-conductance', mechanosensitive, 'channel,', an, 'ATP']), verbo([binding]), complemento([component, of, an, 'ABC', 'transporter,', and, a, homologue, of, a, pilus, retraction, protein, had, regions, of, the, gene, with, elevated, 'dN/dS'])].
[sujeto(['With', the]), verbo([increasing]), complemento([use, of, 'next-generation', sequencing, in, metagenomic, investigations, of, microbial, diversity, and, 'ecology,', analytical, methods, need, to, accommodate, the, peculiarities, of, these, data, streams])].
[sujeto(['By', developing, a, means, to, analyze, population, diversity, data, from, these, environmental, 'metagenomes,', we]), verbo([have]), complemento([provided, the, first, insight, into, the, role, of, selection, in, the, evolution, of, 'Synechococcus,', a, globally, significant, primary, producer])].
[sujeto(['L20']), verbo([binds]), complemento([to, a, phylogenetically, conserved, domain, on, the, 5, '\'', untranslated, region, of, the, infC, mRNA, which, mimics, the, 'L20', binding, sites, on, 23, 'S', rRNA])].
[sujeto(['We']), verbo([have]), complemento([identified, a, second, promoter, '(', 'P1)', upstream, of, the, previously, identified, promoter, '(', 'P2)'])].
[sujeto(['However,', under, these, conditions, infC, biosynthesis, is]), verbo([repressed]), complemento([threefold])].
[sujeto(['We', show, that, the, unprocessed, 'P1', transcript, is, 'non-functional', for, 'IF3', translation, but, fully, competent, to]), verbo([express]), complemento([the, 'co-transcribed', ribosomal, protein, genes])].
[sujeto(['A', 'gene-expression', signature, for, predicting, 'PLNM', was, developed, in, patients, from, the, training, 'group,', including, 11, 'genes:', ribosomal, protein, 'L35', '(', 'RPL35);', thymosin, β, 10, '(', 'TMSB10);', tyrosine, 3, -, 'mono-oxytenase/tryptophan', 5, -, 'mono-oxygenase', activation, 'protein,', ζ, polypeptide, '(', 'YWHAZ);', biotinidase, '(', 'BTD);', lactate, dehydrogenase, 'A', '(', 'LDHA);', glucuronidase, β, '(', 'GUSB);', superoxide, dismutase, 2, '(', 'SOD2);']), verbo([nuclear]), complemento([receptor, subfamily, 3, ',', group, 'C,', member, 2, '(', 'NR3C2);', fructosamine, 3, kinase, '(', 'FN3K);', 'x-ray', repair, 'cross-complementing', 4, '(', 'XRCC4);', and, 'wingless-type', mouse, mammary, tumor, virus, integration, site, family, member, 2, '(', 'WNT2)'])].
[sujeto(['A', multivariate, analysis, demonstrated, that, patients, with, 11, -, gene, 'high-risk', scores, were, had, a, 33, -, fold]), verbo([increased]), complemento([risk, for, 'PLNM', compared, with, patients, who, had, 'low-risk', scores])].
[sujeto(['The', characteristic, ability, of, 'Gluconobacter', oxydans, to, incompletely, oxidize, numerous, 'sugars,', sugar, 'acids,', 'polyols,', and, alcohols]), verbo([has]), complemento([been, exploited, in, several, biotechnological, 'processes,', for, example, vitamin, 'C', production])].
[sujeto(['These', vectors, were, named, pBBR1p264, and, 'pBBR1p452,', 'respectively,', and]), verbo([have]), complemento([many, advantages, over, current, vectors, for, 'Gluconobacter', spp])].
[sujeto(['However,', these, subspecies]), verbo([have]), complemento([not, yet, been, reliably, discriminated])].
[sujeto(['To', 'date,', mainly, phenotypic, identification]), verbo([has]), complemento([been, 'used,', with, a, few, genotypic, identifications])].
[sujeto(['Ribosome', synthesis]), verbo([involves]), complemento([the, concomitance, of, 'pre-rRNA', processing, and, ribosomal, protein, assembly])].
[sujeto(['In', 'eukaryotes,', this, is, a, complex, process, that]), verbo([requires]), complemento([the, participation, of, specific, sequences, and, structures, within, the, 'pre-rRNAs,', at, least, 200, 'trans-acting', factors, and, the, ribosomal, proteins])].
[sujeto(['Herein,', we]), verbo([have]), complemento([analysed, the, contribution, of, ribosomal, protein, 'L35', in, ribosome, biogenesis])].
[sujeto(['Pulse-chase,', northern, hybridization, and]), verbo([primer]), complemento([extension, analyses, show, that, processing, of, the, 27, 'SB', to, 7, 'S', 'pre-rRNAs', is, strongly, delayed, upon, 'L35', depletion])].
[sujeto(['Most', likely, as, a, consequence, of, 'this,']), verbo([release]), complemento([of, 'pre-60S', ribosomal, particles, from, the, nucleolus, to, the, nucleoplasm, is, also, blocked])].
[sujeto(['Deletion', of, 'RPL35A']), verbo([leads]), complemento([to, similar, although, less, pronounced, phenotypes])].
[sujeto(['Moreover,', we, show, that, 'L35', assembles, in, the, nucleolus, and]), verbo([binds]), complemento([to, early, 'pre-60S', ribosomal, particles])].
[sujeto(['We', conclude, that, 'L35', assembly, is, a, prerequisite, for, the, efficient, cleavage, of, the, internal]), verbo([transcribed]), complemento([spacer, 2, at, site, 'C(2)'])].
[sujeto(['The', phylogenic, alignment, of, homologous, 'L35', protein]), verbo([suggests]), complemento([that, human, large, subunit, ribosomal, protein, 'L35', carries, a, 54, aa, eukaryotic, expansion, segment, '(', 'ES)', at, the, 'C-terminal', end])].
[sujeto(['Within', this, 'ES,', the, first, 25, amino, acid, residues, were]), verbo([found]), complemento([to, be, essential, for, the, nuclear, import, of, the, protein])].
[sujeto(['We', performed, a, combination, of, annealing, control]), verbo([primer]), complemento(['(', 'ACP)-based', 'PCR', and, reverse, 'transcription-quantitative', 'real-time', 'PCR', for, the, identification, of, differentially, expressed, genes, '(', 'DEGs)', associated, with, early, and, advanced, stage, primary, colorectal, tumours])].
[sujeto(['We']), verbo([recruited]), complemento([four, paired, samples, from, patients, with, colorectal, cancer, '(', 'CRC)', of, 'Dukes\'', 'A', and, 'B', for, the, preliminary, differential, expression, 'study,', and, a, total, of, 27, paired, 'samples,', ranging, from, 'CRC', stages, 'I', to, 'IV,', for, subsequent, confirmatory, test])].
[sujeto(['The']), verbo([recruited]), complemento([patients, with, 'CRC', were, newly, diagnosed, with, 'CRC,', and, were, not, associated, with, any, hereditary, 'syndromes,', previously, diagnosed, cancer, or, positive, family, history, of, 'CRC'])].
[sujeto(['The', 'RPL35,', 'RPS23', and, 'TIMP1', genes, were]), verbo([found]), complemento([to, be, overexpressed, in, both, early, and, advanced, stage, colorectal, adenocarcinomas, '(', 'p<0'])].
[sujeto(['Here,', we]), verbo([report]), complemento([a, comparative, analysis, of, nine, mtDNAs, from, five, distant, jakobid, 'genera:', 'Andalucia,', 'Histiona,', 'Jakoba,', 'Reclinomonas,', and, 'Seculamonas'])].
[sujeto(['We']), verbo([find]), complemento([that, 'Andalucia', godoyi, has, an, even, larger, mtDNA, gene, complement, than, 'R'])].
[sujeto(['The', extra, genes, are, rpl35, '(', a, large, subunit, mitoribosomal, 'protein)', and, cox15, '(']), verbo([involved]), complemento([in, cytochrome, oxidase, 'assembly),', which, are, nucleus, encoded, throughout, other, eukaryotes])].
[sujeto(['Similarly,', a, 'long,', highly]), verbo([conserved]), complemento([gene, cluster, in, jakobid, 'mtDNAs,', which, is, a, clear, vestige, of, prokaryotic, 'operons,', displays, a, gene, order, more, closely, resembling, that, in, 'free-living', 'α-proteobacteria', than, in, 'Rickettsiales', species])].
[sujeto(['The', number, of, described, species, of, 'bent-toed', geckos, of, the, 'Cyrtodactylus', irregularis, species, complex, in, 'Vietnam']), verbo([has]), complemento([increased, from, one, to, eight, in, the, last, six, years])].
[sujeto(['The', phylogeny]), verbo([required]), complemento([the, description, of, two, new, 'species,', 'Cyrtodactylus', phuocbinhensis, sp])].
[sujeto([ziegleri, were]), verbo([found]), complemento([to, require, redefinition])].
[sujeto(['The', precise, functions, of, most, of, the, '∼200', assembly, factors, and, 79, ribosomal, proteins]), verbo([required]), complemento([to, construct, yeast, ribosomes, in, vivo, remain, largely, unexplored])].
[sujeto(['Six', of, seven, assembly, factors]), verbo([required]), complemento([for, this, step, '(', 'A(3)', 'factors)', are, mutually, interdependent, for, association, with, preribosomes])].
[sujeto(['These', 'A(3)', factors, are]), verbo([required]), complemento([to, recruit, 'Rrp17,', one, of, three, exonucleases, required, for, this, processing, step])].
[sujeto(['We', conclude, that, formation, of, a, neighbourhood, in, preribosomes, containing, the, 'A(3)', factors, establishes, and]), verbo([maintains]), complemento([stability, of, functional, preribosomes, containing, 27, 'S', 'pre-rRNAs'])].
[sujeto(['NAC', is, present, as, a, homodimer, in, archaea, and, as, a, highly]), verbo([conserved]), complemento([heterodimer, in, eukaryotes])].
[sujeto(['Mutations', in, 'NAC']), verbo([cause]), complemento([severe, embryonically, lethal, phenotypes, in, 'mice,', 'Drosophila', 'melanogaster,', and, 'Caenorhabditis', elegans])].
[sujeto(['In', the, yeast, 'Saccharomyces', cerevisiae, 'NAC', is, quantitatively]), verbo([associated]), complemento([with, ribosomes])].
[sujeto(['Furthermore,', in, 'Escherichia', coli, peptide, deformylase, '(', 'PDF)']), verbo([interacts]), complemento([with, the, corresponding, surface, area, on, the, eubacterial, ribosome])].
[sujeto(['Heterozygous', mutations, in, 'RPS19']), verbo([have]), complemento([been, identified, in, 25, '%', of, patients, with, 'Diamond-Blackfan', anemia, '(', 'DBA),', but, the, relationship, between, 'RPS19', mutations, and, the, pure, 'red-cell', aplasia, of, 'DBA', is, unclear])].
[sujeto(['The', 'RPS19-deficient', animals, showed, a, dramatic]), verbo([decrease]), complemento([in, blood, cells, as, well, as, deformities, in, the, head, and, tail, regions, at, early, developmental, stages])].
[sujeto(['These', phenotypes, were, rescued, by, injection, of, zebrafish, rps19, 'mRNA,', but, not, by, injection, of, rps19, mRNAs, with, mutations, that]), verbo([have]), complemento([been, identified, in, 'DBA', patients])].
[sujeto(['The', effects, were, specific, to, 'rps19,', but, knocking, down, the, genes, for, three, other, 'RPs,', 'rpl35,', rpl35a, and, 'rplp2,', produced, similar, 'phenotypes,']), verbo([suggesting]), complemento([that, these, genes, might, have, a, common, function, in, zebrafish, erythropoiesis])].
[sujeto(['The', 'RPS19-deficient', zebrafish, will]), verbo([provide]), complemento([a, valuable, tool, for, investigating, the, molecular, mechanisms, of, 'DBA', development, in, humans])].
[sujeto(['Arx1', and, 'Rei1', are]), verbo([found]), complemento([on, late, 'pre-60S', ribosomal, particles, containing, the, export, adaptor, 'Nmd3'])].
[sujeto(['Arx1', is, related, to, methionine, aminopeptidases, '(', 'MetAPs),', and, 'Rei1', is, a, 'C2H2', zinc, finger, protein, whose, function, in, ribosome, biogenesis]), verbo([has]), complemento([not, been, previously, characterized])].
[sujeto(['Arx1', and, 'Rei1', localized, predominately, to, the, nucleus, and, 'cytoplasm,', 'respectively,', but, could, be, 'coimmunoprecipitated,']), verbo([suggesting]), complemento([that, they, are, transiently, in, the, same, 60, 'S', complex])].
[sujeto([arx1delta, mutants, showed, a, modest, accumulation, of, 60, 'S', subunits, in, the, 'nucleus,']), verbo([suggesting]), complemento([that, 'Arx1', enhances, 60, 'S', export])].
[sujeto(['Deletion', of, 'REI1']), verbo([led]), complemento([to, cold, sensitivity, and, redistribution, of, 'Arx1', to, the, 'cytoplasm,', where, it, remained, bound, to, free, 60, 'S', subunits])].
[sujeto(['However,', deletion, of, 'ARX1', or, the, fusion, of]), verbo([enhanced]), complemento(['GFP', '(', 'eGFP)', to, 'Rpl25', suppressed, the, cold, sensitivity, of, an, rei1delta, mutant])].
[sujeto(['The', presence, of, eGFP, on, 'Rpl25', or, its, neighboring, protein, 'Rpl35', reduced, the]), verbo([binding]), complemento([of, 'Arx1', to, 60, 'S', 'subunits,', suggesting, that, 'Arx1', binds, to, 60, 'S', subunits, in, the, vicinity, of, the, exit, tunnel])].
[sujeto(['Mutations', in, 'Arx1', that, disrupted, its]), verbo([binding]), complemento([to, 60, 'S', also, suppressed, an, rei1delta, mutant, and, restored, the, normal, nuclear, localization, of, 'Arx1'])].
[sujeto(['Furthermore,', these, results]), verbo([suggest]), complemento([that, 'Rei1', is, needed, for, release, of, 'Arx1', from, nascent, 60, 'S', subunits, after, export, to, the, cytoplasm, but, not, for, the, subsequent, nuclear, import, of, 'Arx1'])].
[sujeto(['Mapping', of, the, human, ribosomal, protein, '(', 'RP)', genes]), verbo([has]), complemento([been, 'completed,', and, all, 80, different, genes, were, placed, on, a, cytogenetic, map, of, the, human, genome])].
[sujeto(['Together', with, the, previous, 'results,', both, sex, chromosomes, and, 20, autosomes, '(', all, but, chromosomes, 7, and, 21, ')', were]), verbo([found]), complemento([to, carry, one, or, more, 'RP', genes])].
[sujeto(['We', compared, the, assigned, positions, with, candidate, regions, for, 'Mendelian', disorders, and]), verbo([found]), complemento([certain, genes, that, might, be, involved, in, particular, human, disorders])].
[sujeto(['We']), verbo([have]), complemento([constructed, a, 2.5, -, 'Mb', physical, and, transcription, map, that, spans, the, human, 6, p21])].
[sujeto(['These', include, a, number, of, genes, encoding]), verbo([nuclear]), complemento([and, splicing, factors, '(', 'Ndr', 'kinase,', 'HSU09564,', 'HSRP20);', cell, 'cycle,', 'DNA', 'packaging,', and, apoptosis, related, '[', 'p21,', 'HMGI(Y),', 'BAK];', immune, response, '(', 'CSBP,', 'SAPK4);', transcription, activators, and, zinc, 'finger-containing', genes, '(', 'TEF-5,', 'ZNF76);', embryogenesis, related, '(', 'Csa-19);', cell, signaling, '(', 'DIPP);', structural, '(', 'HSET),', and, other, genes, '(', 'TULP1,', 'HSPRARD,', 'DEF-6,', 'EO6811,', 'cyclophilin),', as, well, as, a, number, of, 'RP', genes, and, pseudogenes, '(', 'RPS10,', 'RPS12-like,', 'RPL12-like,', 'RPL35-like)'])].
[sujeto(['Furthermore,', several, novel, genes, '(', a, 'Br140-like,', a, 'G2S-like,', a, 'FBN2-like,', a, 'ZNF-like,', and, 'B1/KIAA0229)']), verbo([have]), complemento([been, 'identified,', as, well, as, cDNAs, and, cDNA, contigs])].
[sujeto(['The', detailed, map, of, the, gene, content, of, this, chromosomal, segment]), verbo([provides]), complemento([a, number, of, candidate, 'genes,', which, may, be, involved, in, several, biological, processes, that, have, been, associated, with, this, 'region,', such, as, 'spermatogenesis,', 'development,', 'embryogenesis,', and, neoplasia])].
[sujeto(['The', data]), verbo([provide]), complemento([useful, tools, for, synteny, studies, between, mice, and, 'humans,', for, genome, structure, 'analysis,', gene, density, 'comparisons,', and, studies, of, nucleotide, 'composition,', of, different, isochores, and, 'Giemsa', light, and, 'Giemsa', dark, bands])].
[sujeto(['The', human, ribosomal, protein, 'L29,', which, we]), verbo([reported]), complemento(['previously,', was, subsequently, shown, to, have, the, same, nucleotide, sequence, as, that, of, cell, surface, 'heparin/heparan', 'sulfate-binding', 'protein,', designated, 'HP/HS', interacting, protein])].
[sujeto(['By', somatic, cell, hybrid, 'analysis,', radiation, hybrid, 'mapping,', and, fluorescence, in, situ, 'hybridization,', we]), verbo([have]), complemento([located, 'RPL29', on, the, telomeric, region, of, the, q, arm, of, chromosome, 3])].
[sujeto(['Of', the, human, ribosomal, protein, genes, 'mapped,', 'RPL29', is, the, shortest, distance, from, another, ribosomal, protein, gene, 'marker,', 'RPL35', a, which]), verbo([has]), complemento([also, been, mapped, to, the, 3, 'q29-qter', region])].
[sujeto(['The', 'rpl35,', 'rpl20,', 'rpl5,', 'rps8,', and, a, portion, of, the, rpl6, genes, of, the, cyanelle, genome, of, 'Cyanophora', paradoxa]), verbo([have]), complemento([been, 'cloned,', mapped, and, sequenced])].
[sujeto(['Homologs', of, the, 'rpl35,', 'rpl5,', and, rpl6, genes, are, not]), verbo([found]), complemento([in, the, chloroplasts, of, higher, plants])].
[sujeto(['The', rpl35, genes, most, likely, form, a, dicistronic, operon, which, is, located, upstream, from, the, 'apcE-apcA-apcB', locus, of, the, cyanelle, and, which, is, divergently]), verbo([transcribed]), complemento([from, this, locus])].
[sujeto(['These', genes, are, organized, in, a, fashion, similar, to, that, observed, in, all, procaryotes, examined, to, 'date,', with, the, exception, that, the, rps14, gene, is, not]), verbo([found]), complemento([between, the, rpl5, and, rps8, coding, sequences])].
[sujeto(['This', may, refute, current, misconceptions, and]), verbo([ensure]), complemento([surgical, decisions, are, made, based, on, evidence, without, ageist, assumptions])].
[sujeto(['Autologous', reconstruction]), verbo([has]), complemento([better, 'long-term', outcomes, than, 'implant-based', reconstructions, in, this, age, 'group,', correlating, with, improved, survival, and, longevity, of, reconstruction])].
[sujeto(['With', effective, antibiotics, against, enteric, flora, and, computed, 'tomography-guided', drainage, for, 'abscesses,', the, initial, use, of, nonoperative, therapy, for, children, with, appendicitis]), verbo([has]), complemento([increased, both, in, recent, reports, and, at, our, hospital])].
[sujeto(['However,', it]), verbo([has]), complemento([been, reported, that, these, patients, have, a, relatively, longer, hospital, stay, and, that, their, treatment, is, more, expensive, than, those, who, undergo, aggressive, surgical, intervention])].
[sujeto(['One', hundred, and, 'twenty-five', patients, were]), verbo([recruited]), complemento([in, this, 'study,', of, whom, 53, '(', 42.4, '%', ')', had, prolonged, hospitalization])].
[sujeto(['Changes', include, the, introduction, of, new, curricula, that, embrace]), verbo([increased]), complemento([collaboration, between, the, 'laboratory-based', and, clinical, specialties, and, a, 'broad-based', infection, training, 'period,', named, '\'', 'Combined', 'Infection', 'Training\',', which, has, never, been, seen, before])].
[sujeto(['Here,', we, discuss, the, benefits, and, challenges]), verbo([associated]), complemento([with, the, collaborative, approach, to, training, with, particular, reference, to, points, that, educators, responsible, for, training, programme, design, need, to, consider])].
[sujeto(['To', critically, evaluate, the, clinical, implications, of, the, use, of, 'non-fasting', rather, than, fasting, lipid, profiles, and, to]), verbo([provide]), complemento([guidance, for, the, laboratory, reporting, of, abnormal, 'non-fasting', or, fasting, lipid, profiles])].
[sujeto(['Extensive', observational, 'data,', in, which, random, 'non-fasting', lipid, profiles]), verbo([have]), complemento([been, compared, with, those, determined, under, fasting, 'conditions,', indicate, that, the, maximal, mean, changes, at, 1, -, 6, h, after, habitual, meals, are, not, clinically, significant, '[', +, 0.3, 'mmol/L', '(', 26, 'mg/dL)', for, 'triglycerides;', -, 0.2, 'mmol/L', '(', 8, 'mg/dL)', for, total, 'cholesterol;', -, 0.2, 'mmol/L', '(', 8, 'mg/dL)', for, 'LDL', 'cholesterol;', +, 0.2, 'mmol/L', '(', 8, 'mg/dL)', for, calculated, remnant, 'cholesterol;', -, 0.2, 'mmol/L', '(', 8, 'mg/dL)', for, calculated, 'non-HDL', 'cholesterol];', concentrations, of, 'HDL', 'cholesterol,', apolipoprotein, 'A1,', apolipoprotein, 'B,', and, 'lipoprotein(a)', are, not, affected, by, 'fasting/non-fasting', status])].
[sujeto(['For', 'non-fasting', 'samples,', laboratory]), verbo([reports]), complemento([should, flag, abnormal, concentrations, as, triglycerides, '≥2', 'mmol/L', '(', 175, 'mg/dL),', total, cholesterol, '≥5', 'mmol/L', '(', 190, 'mg/dL),', 'LDL', cholesterol, '≥3', 'mmol/L', '(', 115, 'mg/dL),', calculated, remnant, cholesterol, '≥0'])].
[sujeto(['Life-threatening', concentrations]), verbo([require]), complemento([separate, referral, for, the, risk, of, pancreatitis, when, triglycerides, are, &, 'gt;10', 'mmol/L', '(', 880, 'mg/dL),', for, homozygous, familial, hypercholesterolemia, when, 'LDL', cholesterol, is, &, 'gt;13', 'mmol/L', '(', 500, 'mg/dL),', for, heterozygous, familial, hypercholesterolemia, when, 'LDL', cholesterol, is, &, 'gt;5', 'mmol/L', '(', 190, 'mg/dL),', and, for, very, high, cardiovascular, risk, when, 'lipoprotein(a)', &, 'gt;150', 'mg/dL', '(', 99, th, 'percentile)'])].
[sujeto(['Laboratory']), verbo([reports]), complemento([should, flag, abnormal, values, on, the, basis, of, desirable, concentration, cutpoints])].
[sujeto(['In', patients, receiving, combined, 'therapy,', the, addition, of, 'LT3', was]), verbo([associated]), complemento([with, normalization, of, mean, 'TSH', '(', 9.2, vs, 4.5, 'mIU/L,', 'P = '])].
[sujeto([3, ')', ',', and, a]), verbo([decrease]), complemento([in, mean, serum, 'T4', by, 23, &, 'nbsp;± 9%', '(', 'P < '])].
[sujeto(['LT3', treatment, did, not]), verbo([increase]), complemento([serum, 'T3', levels, significantly])].
[sujeto([11, ',', χ2, =, 6.533, ',', 'P', =, 0.011, ')', ',', while, no, difference, was]), verbo([found]), complemento([between, pneumonia, 7, days, after, 'CLP', group, and, 'sepsis-alone', group, '(', 9, vs])].
[sujeto(['(', 2, ')', 'The', blood, bacterial, count, and, all, the, biochemical, indexes, were, sharply]), verbo([increased]), complemento([on, 1, day, 'post-CLP', in, the, rats, of, 'sepsis-alone', 'group,', and, then, they, gradually, lowered])].
[sujeto(['Compared', with, the, rats, of, 1, day, 'post-CLP,', the, proportion, of, splenocytes, were]), verbo([decreased]), complemento([on, the, 4, th, day, 'post-CLP', '[', dendritic, cells, '(', 'DC):', '(', 0.69, ±, 0.09, ')', '%', vs])].
[sujeto(['The', levels, of, 'anti-inflammatory', cytokines, transforming, growth, 'factor-β1', '(', 'TGF-β1)', and, soluble, tumor, necrosis, factor, 'receptor-I', '(', 'sTNFR-I)']), verbo([maintained]), complemento([at, high, levels, '[', 7, days, 'post-CLP:', 'TGF-β1', was, '(', 0.9, ±, 0.56, ')', 'ng/L,', 'sTNFR-I', was, '(', 1.56, ±, 0.39, ')', 'ng/L]'])].
[sujeto(['The', spleen, pathology, became, more, marked, with, the, time, in, the, group, of, 'sepsis-alone,', meanwhile, the, number, of, apoptotic, spleencytes]), verbo([increased]), complemento([4, days, 'post-CLP', as, compared, with, that, of, the, 1, st, day, 'post-CLP', '(', 'cells/HP:', 52.99, ±, 20.79, vs])].
[sujeto([0.25, ±, 0.18, ',', 'P', &, 'lt;', 0.05, ')', ',', while, no, difference, was]), verbo([found]), complemento([between, 7, -, day, of, 'post-CLP', pneumonia, group, and, 'sepsis-alone', group, '(', log, 'cfu/mL:', 0.57, ±, 0.46, vs])].
[sujeto(['The', same, trend, of, 'changes,', with, slight, reduction, in, splenocytes, and, biochemical, indices, were]), verbo([found]), complemento([between, the, groups, of, sepsis, followed, by, pneumonia, and, 'sepsis-alone,', but, no, significant, difference, was, found])].
[sujeto(['The', level, of, 'HMGB1', in, the, 4, -, day, group, of, sepsis, with, complication, of, pneumonia, was, further]), verbo([decreased]), complemento([compared, with, 'sepsis-alone', group, '(', 'μg/L:', 1.17, ±, 0.74, vs])].
[sujeto([52.99, ±, 20.79, ',', 'P', &, 'lt;', 0.05, ')', ',', while, no, difference, was]), verbo([found]), complemento([between, the, 7, -, day, groups, of, sepsis, complicated, pneumonia, and, the, 'sepsis-alone', group, '(', 'cells/HP:', 28.7, ±, 4.13, vs])].
[sujeto(['The', &, 'quot;two-hit"', model, reproduced, on, 7, days, after, 'CLP', might]), verbo([suggest]), complemento([reconstruction, of, host, immune, 'function,', and, maybe, associated, with, the, recovery, of, immune, response])].
[sujeto(['To', critically, evaluate, the, clinical, implications, of, the, use, of, 'non-fasting', rather, than, fasting, lipid, profiles, and, to]), verbo([provide]), complemento([guidance, for, the, laboratory, reporting, of, abnormal, 'non-fasting', or, fasting, lipid, profiles])].
[sujeto(['Extensive', observational, 'data,', in, which, random, 'non-fasting', lipid, profiles]), verbo([have]), complemento([been, compared, with, those, determined, under, fasting, 'conditions,', indicate, that, the, maximal, mean, changes, at, 1, -, 6, h, after, habitual, meals, are, not, clinically, significant, '[', +, 0.3, 'mmol/L', '(', 26, 'mg/dL)', for, 'triglycerides;', -, 0.2, 'mmol/L', '(', 8, 'mg/dL)', for, total, 'cholesterol;', -, 0.2, 'mmol/L', '(', 8, 'mg/dL)', for, 'LDL', 'cholesterol;', +, 0.2, 'mmol/L', '(', 8, 'mg/dL)', for, calculated, remnant, 'cholesterol;', -, 0.2, 'mmol/L', '(', 8, 'mg/dL)', for, calculated, 'non-HDL', 'cholesterol];', concentrations, of, 'HDL', 'cholesterol,', apolipoprotein, 'A1,', apolipoprotein, 'B,', and, 'lipoprotein(a)', are, not, affected, by, 'fasting/non-fasting', status])].
[sujeto(['For', 'non-fasting', 'samples,', laboratory]), verbo([reports]), complemento([should, flag, abnormal, concentrations, as, triglycerides, '≥2', 'mmol/L', '(', 175, 'mg/dL),', total, cholesterol, '≥5', 'mmol/L', '(', 190, 'mg/dL),', 'LDL', cholesterol, '≥3', 'mmol/L', '(', 115, 'mg/dL),', calculated, remnant, cholesterol, '≥0'])].
[sujeto(['Life-threatening', concentrations]), verbo([require]), complemento([separate, referral, when, triglycerides, &, 'gt;10', 'mmol/L', '(', 880, 'mg/dL)', for, the, risk, of, 'pancreatitis,', 'LDL', cholesterol, &, 'gt;13', 'mmol/L', '(', 500, 'mg/dL)', for, homozygous, familial, 'hypercholesterolaemia,', 'LDL', cholesterol, &, 'gt;5', 'mmol/L', '(', 190, 'mg/dL)', for, heterozygous, familial, 'hypercholesterolaemia,', and, 'lipoprotein(a)', &, 'gt;150', 'mg/dL', '(', 99, th, 'percentile)', for, very, high, cardiovascular, risk])].
[sujeto(['Laboratory']), verbo([reports]), complemento([should, flag, abnormal, values, on, the, basis, of, desirable, concentration, 'cut-points'])].
[sujeto(['This', anatomical, variation, of, the, unilaterally, absent, 'FCR', was]), verbo([found]), complemento([upon, dissection, during, a, carpometacarpal, arthroplasty, of, the, thumb])].
[sujeto(['Organ', preservation]), verbo([has]), complemento([been, increasingly, utilised, in, the, management, of, 'muscle-invasive', bladder, cancer])].
[sujeto(['Phase', 'III', trials]), verbo([have]), complemento([shown, superiority, of, chemoradiotherapy, compared, to, radiotherapy, alone])].
[sujeto(['No', randomised, control, trials]), verbo([have]), complemento([yet, directly, compared, radical, cystectomy, with, 'bladder-preserving', 'chemoradiation,', leaving, the, 'age-old', question, of, superiority, of, one, modality, over, another, unanswered])].
[sujeto(['OBJECTIVES', of, the, study, were, to, characterize, blood, glucose, control, in, patients, admitted, to, the, cardiac, care, unit, '(', 'CCU)', in, 'Qatar', and, to, determine, predictive, factors]), verbo([associated]), complemento([with, high, glucose, levels, '(', &, 'gt;10 mmol/l)', on, admission, to, the, 'CCU'])].
[sujeto(['Univariate', and, multivariate, logistic, regression, were, performed, to, assess, factors]), verbo([associated]), complemento([with, high, glucose, on, admission])].
[sujeto(['To', investigate, whether, intraoperative, administration, of, a, lidocaine, infusion, to, dogs, with, septic, peritonitis, was]), verbo([associated]), complemento([with, 'short-term', '(', 48, 'hours)', survival, after, surgery])].
[sujeto(['Intraoperative', infusion, of, lidocaine]), verbo([increased]), complemento([the, odds, of, 'short-term', survival, '(', 'OR,', 8.77, ;, 95, '%', 'CI,', 1.94, to, 39.57, ')'])].
[sujeto(['During', the, intraoperative, 'period,', more, dogs, in, group, 'L', received, an, 'IV', bolus, of, a, synthetic, colloid, than, did, dogs, in, group, 'O,', but, the, number, of, 'IV', boluses, administered, was, not]), verbo([associated]), complemento([with, 'short-term', survival])].
[sujeto(['Elevated', plasma, vitamin, 'B12', levels, '(', 'cobalamin,', 'Cbl)', are]), verbo([associated]), complemento([with, increased, 'short-term', cancer, risk, among, patients, referred, for, this, laboratory, measurement])].
[sujeto(['These', findings, may]), verbo([have]), complemento([clinical, significance, for, assessing, the, prognosis, of, cancer, patients])].
[sujeto(['When', under, four, different, heavy, metal, 'treatments,', we]), verbo([found]), complemento([that, 'SaREFl', responded, most, strongly, to, 'Cd', and, the, root, was, the, plant, organ, most, sensitive, to, this, heavy, metal])].
[sujeto(['Yeast', 'two-hybrid', screening, of, 'SaREFl', as, a, bait]), verbo([led]), complemento([to, the, identification, of, five, possible, interacting, targets, in, 'Sedum', alfredii, 'Hance'])].
[sujeto(['Moreover,', subcellular, localization, of, 'SaREF1-GFP', fusion, protein, revealed, some, patchy, spots, in, cytosol]), verbo([suggesting]), complemento([potential, association, with, organelles, for, its, cellular, functions])].
[sujeto(['Our', findings, would, further, enrich, the, connotation, of, 'REF-like', genes, and]), verbo([provide]), complemento([theoretical, assistance, for, the, application, in, breeding, heavy, 'metal-tolerant', plants])].
[sujeto(['Pde6b', gene, expression, occurs, embryonically, in, mouse, 'retina,', whereas, other, proteins]), verbo([involved]), complemento([in, phototransduction, are, expressed, around, postnatal, day, 5, '(', 'P5)'])].
[sujeto(['Using', 'Western', blots, with, wild, type, and, rd1, mouse, retinas, from, 'P2', -, 'P21', we, demonstrated, that, 'PDE6β', protein, is]), verbo([expressed]), complemento([in, wild, type, retinas, by, 'P2', and, is, not, detected, in, rd1, retinas])].
[sujeto(['The', osteoblastic, expression, of, 'RANKL,', which, is, essential, for, the, communication, between, osteoblastic, cells, and, osteoclastogenic, 'cells,', is]), verbo([stimulated]), complemento([by, locally, acting, or, circulating, osteotropic, cytokines, and, hormones, such, as, 'PTH', and, 1, ',', 25, -, '(', 'OH)2-D3', during, the, bone, remodeling, process])].
[sujeto(['In', our, previous, 'study,', we]), verbo([have]), complemento([found, that, the, deficiency, of, osteoblastic, 'Arl6ip5', '(', 'ADP-ribosylation-like', factor, 6, interacting, protein, 5, ')', ',', an, endoplasmic, reticulum, '(', 'ER)-localized', protein, belonging, to, the, prenylated, 'rab-acceptor-family,', enhanced, osteoclastogenesis, by, increasing, 'RANKL', transcription, in, an, 'ER', stress, dependent, signaling])].
[sujeto(['Here', we]), verbo([found]), complemento([that, 'over-expression', of, hemagglutinin, '(', 'HA)-tagged', 'Arl6ip5', in, 'UAMS32', 'stromal/osteoblastic', cells, inhibited, 'osteoclastogenesis,', decreased, the, amount, of, soluble, 'RANKL', in, culture, supernatant, and, increased, 'RANKL', retention, in, 'ER'])].
[sujeto(['Moreover,', 'Arl6ip5']), verbo([bound]), complemento([with, 'RANKL', and, disturbed, the, 'RANKL-OPG', complex, in, 'UAMS-32 cells'])].
[sujeto(['These', findings, indicated, that, 'Arl6ip5', was, an, 'anti-catabolic', factor, by]), verbo([binding]), complemento([with, 'RANKL', and, disturbing, its, subcellular, trafficking, in, osteoblast])].
[sujeto(['Live', cell, imaging, showed, 'TNT', formation, preceding, the, transfer, of, 'Tf-RmCherry', and]), verbo([involving]), complemento([the, function, of, the, small, guanosine, triphosphatase, '(', 'GTPase)', 'Rab8,', which, colocalized, with, 'Tf-RmCherry', in, the, 'TNTs', and, was, cotransferred, to, acceptor, cells])].
[sujeto(['Tf-RmCherry', was, transferred, from, cancer, cells, to, 'fibroblasts,', a, noteworthy]), verbo([finding]), complemento([that, suggests, that, this, process, occurs, between, tumor, and, stromal, cells, in, vivo])].
[sujeto(['We', strengthened, this, hypothesis, in, a, xenograft, model, of, breast, cancer, using]), verbo([enhanced]), complemento(['(', 'e)GFP-expressing', mice])].
[sujeto(['Tf-RmCherry', transferred, from, tumor, to, stromal, cells, and, this, process, correlated, with, an]), verbo([increased]), complemento([opposite, transfer, of, eGFP, from, stromal, to, tumor, 'cells,', together, pointing, toward, complex, intercellular, communication, at, the, tumor, site])].
[sujeto(['During', the, late, stages, of, the, 'HIV-1', replication, 'cycle,', the, viral, polyprotein, 'Pr55(Gag)', is]), verbo([recruited]), complemento([to, the, plasma, membrane, '(', 'PM),', where, it, binds, phosphatidylinositol, 4, ',', 5, -, bisphosphate, '(', 'PI(4,5)P2)', and, directs, 'HIV-1', assembly])].
[sujeto(['Hence,', 'Rab27a']), verbo([promotes]), complemento([high, levels, of, 'PM', phosphatidylinositol, 4, -, phosphate, and, the, localized, production, of, 'PI(4,5)P2,', therefore, controlling, 'Pr55(Gag)', membrane, association])].
[sujeto(['By', screening, 'Rab27a', 'effectors,', we, identified, that, 'Slp2a,', 'Slp3,', and, 'Slac2b', are]), verbo([required]), complemento([for, the, association, of, 'Pr55(Gag)', with, the, 'PM', and, that, 'Slp2a', cooperates, with, 'Rab27a', in, the, recruitment, of, 'PI4KIIα', to, the, 'PM'])].
[sujeto(['Vesicle', traffic]), verbo([involves]), complemento(['budding,', 'transport,', tethering, and, fusion, of, vesicles, with, acceptor, membranes])].
[sujeto(['GTP-bound', small, 'Rab', 'GTPases']), verbo([interact]), complemento([with, the, membrane, of, 'vesicles,', promoting, their, association, with, other, factors, before, their, subsequent, fusion])].
[sujeto(['The', regulatory, mechanisms]), verbo([ensuring]), complemento([the, directionality, of, the, vesicles, that, travel, to, the, 'Spk', are, still, unknown])].
[sujeto(['Hence,', we, analyzed, 'YPT-1,', the, 'Neurospora', crassa, homologue, of, 'Saccharomyces', cerevisiae, 'Ypt1p', '(', 'Rab1),', which]), verbo([regulates]), complemento([different, secretory, pathway, events])].
[sujeto(['Co-expression', of, 'YPT-1', and, predicted, 'post-Golgi', 'Rab', 'GTPases', showed, 'YPT-1', confined, to, the, 'Spk', microvesicular, 'core,', while, 'SEC-4', '(', 'Rab8)', and, 'YPT-31', '(', 'Rab11)', occupied, the, 'Spk', macrovesicular, peripheral, 'layer,']), verbo([suggesting]), complemento([that, trafficking, and, organization, of, macro, and, microvesicles, at, the, 'Spk', are, regulated, by, distinct, 'Rabs'])].
[sujeto(['Long-term', results, after, reduction, mammaplasty, with, a, superior, pedicle, evaluating, the, postoperative, 'sensibility,', degree, of, breast, ptosis, and, the, 'patients\'', satisfaction, are, rarely]), verbo([found]), complemento([in, the, literature])].
[sujeto(['This', retrospective, analysis, answers, the, question, whether, the, resection, weight]), verbo([has]), complemento([an, influence, on, the, postoperative, sensibility, of, the, 'nipple-areola', complex, after, reduction, mammaplasty, with, a, superior, pedicle])].
[sujeto(['With', regard, to, the, sensibility, we]), verbo([found]), complemento([a, reduction, of, sensibility, especially, in, the, inferior, and, lateral, part, of, the, areola])].
[sujeto(['A', pseudoptosis, was]), verbo([found]), complemento([in, 6, patients, in, particular, in, group, 'B'])].
[sujeto(['This', may, also]), verbo([reveal]), complemento([novel, diversification, 'and/or', distinct, solutions, to, the, problems, posed, by, the, targeted, 'intra-cellular', trafficking, of, important, molecules])].
[sujeto(['To', date, two, homologs, to, 'well-known', yeast, cytosolic, vesicle, transport, 'proteins,', 'CPSAR1', and, 'CPRabA5e', '(', 'CP,', chloroplast, 'localized),']), verbo([have]), complemento([been, shown, to, have, roles, in, chloroplast, vesicle, 'transport,', both, being, 'GTPases'])].
[sujeto(['Bioinformatic', data, indicate, that, several, homologs, of, cytosolic, vesicle, transport, system, components, are, putatively, 'chloroplast-localized', and, in, addition, other, proteins]), verbo([have]), complemento([been, implicated, to, participate, in, chloroplast, vesicle, 'transport,', including, 'vesicle-inducing', protein, in, plastids, 1, ',', thylakoid, formation, 1, ',', snowy, cotyledon, 2, /, cotyledon, chloroplast, biogenesis, 'factor,', curvature, thylakoid, 1, 'proteins,', and, a, dynamin, like, 'GTPase', 'FZO-like', protein])].
[sujeto(['Several', putative, potential, cargo, proteins]), verbo([have]), complemento([also, been, 'identified,', including, building, blocks, of, the, photosynthetic, apparatus])].
[sujeto(['Polyphosphoinositides', are, an, important, class, of, lipid, that]), verbo([recruit]), complemento([specific, effector, proteins, to, organelle, membranes])].
[sujeto(['One', 'member,', phosphatidylinositol, 4, -, phosphate, '(', 'PtdIns4P)']), verbo([has]), complemento([been, localized, to, 'Golgi', membranes, based, on, the, distribution, of, lipid, binding, modules, from, 'PtdIns4P', effector, proteins])].
[sujeto(['In', this, 'paper,', we, derive, a, new, 'PtdIns4P', biosensor, using, the, 'PtdIns4P']), verbo([binding]), complemento([of, 'SidM', '(', 'P4M)', domain, of, the, secreted, effector, protein, 'SidM', from, the, bacterial, pathogen, 'Legionella', pneumophila])].
[sujeto(['PtdIns4P', was, necessary, and, sufficient, for, localization, of, 'P4M,', which, revealed, pools, of, the, lipid]), verbo([associated]), complemento([not, only, with, the, 'Golgi', but, also, with, the, plasma, membrane, and, 'Rab7-positive', late, 'endosomes/lysosomes'])].
[sujeto(['Therefore,', 'P4M']), verbo([reports]), complemento([a, wider, cellular, distribution, of, 'PtdIns4P', than, previous, probes, and, therefore, will, be, valuable, for, dissecting, the, biological, functions, of, 'PtdIns4P', in, its, assorted, membrane, compartments])].
[sujeto([1, ')']), verbo([targets]), complemento([to, the, basolateral, '(', 'BL)', membrane, in, polarized, epithelia, where, it, plays, a, key, role, in, transepithelial, ion, transport])].
[sujeto([1, is, exclusively]), verbo([targeted]), complemento([to, the, 'BL', membrane, in, these, cells, when, grown, on, filter, supports])].
[sujeto([1, degradation, is]), verbo([prevented]), complemento([by, inhibition, of, 'lysosomal/proteosomal', pathways])].
[sujeto([1, is]), verbo([increased]), complemento([following, endocytosis, from, the, 'BL', membrane, and, 'PR-619,', a, deubiquitylase, 'inhibitor,', prevents, 'degradation,', indicating, 'KCa3'])].
[sujeto([1, is]), verbo([targeted]), complemento([for, degradation, by, ubiquitylation])].
[sujeto([1, is]), verbo([targeted]), complemento([to, the, 'BL', membrane, in, polarized, 'LLC-PK1', cells, which, lack, the, μ1B, subunit, of, the, 'AP-1', 'complex,', indicating, 'BL', targeting, of, 'KCa3'])].
[sujeto(['These', results]), verbo([suggest]), complemento([these, 'Rabs', are, necessary, for, the, anterograde, trafficking, of, 'KCa3'])].
[sujeto(['Fission', yeast, 'its3(+)', encodes, an, essential, 'phosphatidylinositol-4-phosphate', 5, -, kinase, '(', 'PI4P5K)', that]), verbo([regulates]), complemento([cell, integrity, and, cytokinesis])].
[sujeto(['Its3', overproduction]), verbo([caused]), complemento([growth, defects, and, abnormal, cytoplasmic, accumulation, of, the, 'Its3', 'protein,', which, can, be, stained, by, calcofluor])].
[sujeto(['Gyp10', functionally]), verbo([interacted]), complemento([with, the, 'Rab', 'GTPases', 'Ypt3', and, 'Ryh1,', both, of, which, regulate, 'Golgi', membrane, trafficking])].
[sujeto(['Consistently,', mutation, or, deletion, of, 'Ypt3', and, 'Ryh1']), verbo([suppressed]), complemento([phenotypes, associated, with, 'Its3', overproduction])].
[sujeto(['Importantly,', the, plasma, membrane, localization, of, 'Its3', was, also, affected, by, the, impairment, of, the, 'Ypt3/Ryh1', 'Rab', membrane, 'trafficking,', thus]), verbo([suggesting]), complemento([that, membrane, trafficking, events, regulated, by, two, 'Rab', 'GTPases', functionally, interacts, with, 'PI4,5P2', signaling])].
[sujeto(['These', results]), verbo([suggest]), complemento([a, mechanism, whereby, 'PI4P5K', 'signaling/localization', is, affected, by, 'Golgi', membrane, 'trafficking,', thus, provide, a, functional, link, between, the, 'PI4,5P2', signaling, and, 'Rab-mediated', trafficking])].
[sujeto(['Moreover,', 'co-culture', of, melanocytes, and, keratinocytes]), verbo([suggests]), complemento([that, melanin, exocytosis, is, specifically, induced, by, keratinocytes])].
[sujeto(['Furthermore,', depletion, of, 'Rab11b,', but, not, 'Rab27a,']), verbo([caused]), complemento([a, marked, decrease, in, both, 'keratinocyte-stimulated', melanin, exocytosis, and, transfer, to, keratinocytes])].
[sujeto(['Thus,', we, propose, that, the, predominant, mechanism, of, melanin, transfer, is, 'keratinocyte-induced', 'exocytosis,']), verbo([mediated]), complemento([by, 'Rab11b', through, remodeling, of, the, melanosome, 'membrane,', followed, by, subsequent, endocytosis, by, keratinocytes])].
[sujeto(['We']), verbo([found]), complemento([that, high, 'PRAF2', expression, is, significantly, correlated, to, several, unfavorable, 'NB', 'characteristics:', 'MYCN', 'amplification,', high, age, at, 'diagnosis,', poor, outcome, and, high, 'INSS', stage])].
[sujeto(['The', 'shRNA-mediated', 'PRAF2', downregulation, in, the, 'SK-N-SH', 'NB', cell, line, resulted, in]), verbo([decreased]), complemento([cellular, 'proliferation,', migration, and, 'matrix-attachment'])].
[sujeto(['These', findings, were, confirmed, in, 'NB', patient, tumor, 'samples,', where, high, 'PRAF2', expression, is, significantly, correlated, to, bone, and, bone, marrow, 'metastasis,', the, main]), verbo([cause]), complemento([of, death, in, 'NB', patients])].
[sujeto(['We']), verbo([have]), complemento([used, the, rd1, retina, as, a, model, to, investigate, early, molecular, defects, in, developing, rod, photoreceptors, prior, to, the, onset, of, degeneration])].
[sujeto(['Of', the, 143, identified, differentially]), verbo([expressed]), complemento(['genes,', we, focused, on, 'Rab', acceptor, 1, '(', 'Rabac1),', which, codes, for, the, protein, 'Prenylated', rab, acceptor, 1, '(', 'PRA1)', and, plays, an, important, role, in, vesicular, trafficking])].
[sujeto(['We']), verbo([have]), complemento([identified, genes, that, are, differentially, regulated, in, the, rd1, retina, at, early, time, 'points,', which, may, give, insights, into, developmental, defects, that, precede, photoreceptor, cell, death])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([of, 'PRA1', expression, in, the, retina])].
[sujeto(['NDRG2', is, a, member, of, the, 'N-myc', downstream]), verbo([regulated]), complemento([gene, '(', 'NDRG)', 'family,', implicated, in, cell, growth, and, differentiation])].
[sujeto(['Investigation', of, 'NDRG2', molecular, interactions, by, yeast, 'two-hybrid', screening, identified, prenylated, 'Rab', 'acceptor-1', '(', 'PRA1),']), verbo([involved]), complemento([in, vesicle, trafficking, and, protein, 'transport,', as, binding, partner])].
[sujeto(['Results']), verbo([suggest]), complemento([that, 'NDRG2', and, 'PRA1', might, act, synergistically, to, prevent, signaling, of, 'TCF/β-catenin'])].
[sujeto(['We', previously, showed, that, the, 'serum-', and, 'glucocorticoid-inducible', kinase, 3, '(', 'SGK3)']), verbo([increases]), complemento([the, 'AMPA-type', glutamate, receptor, 'GluA1', protein, in, the, plasma, membrane])].
[sujeto(['The', activation, of, 'AMPA', receptors, by, 'NMDA-type', glutamate, receptors, eventually]), verbo([leads]), complemento([to, postsynaptic, neuronal, plasticity])].
[sujeto(['This', 'RAB-dependent', 'GluA1', trafficking]), verbo([requires]), complemento([phosphorylation, and, activation, of, 'phosphoinositol-3-phosphate-5-kinase', '(', 'PIKfyve)', and, the, generation, of, 'PI(3,5)P(2)'])].
[sujeto(['Prenylated', 'Rab', acceptor, 1, domain, family, member, 3, '(', 'PRAF3)', is]), verbo([involved]), complemento([in, the, regulation, of, many, cellular, processes, including, 'apoptosis,', migration, and, invasion])].
[sujeto(['The', role, of, 'PRAF3', in, 'apoptosis,', migration, and, invasion, was, studied, in, 'ESCC', cell, lines, of, 'Eca109', and, 'TE-1', through, the, adenovirus]), verbo([mediated]), complemento(['PRAF3', gene, transfer])].
[sujeto(['We']), verbo([found]), complemento([that, the, expression, of, 'PRAF3', was, significantly, 'down-regulated', in, 'ESCC', tissue, compared, with, the, matched, normal, tissue, and, was, correlated, with, the, clinical, features, of, pathological, 'grade,', tumor, stage, and, lymph, node, metastasis])].
[sujeto(['Moreover,', overexpression, of, 'PRAF3']), verbo([induced]), complemento([cell, apoptosis, through, both, 'caspase-8', and, 'caspase-9', dependent, 'pathways,', and, inhibited, cell, migration, and, invasion, by, suppressing, the, activity, of, both, 'MMP-2', and, 'MMP-9', in, human, 'ESCC', cell, lines])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, 'PRAF3', plays, an, important, role, in, the, regulation, of, tumor, progression, and, metastasis, and, serves, as, a, tumor, suppressor, in, human, 'ESCC'])].
[sujeto(['SNARE', complexes, are]), verbo([required]), complemento([for, membrane, fusion, in, the, endomembrane, system])].
[sujeto(['They', contain, 'coiled-coil', bundles, of, four, 'helices,', three, '(', 'Q(a),', 'Q(b),', and, 'Q(c))', from]), verbo([target]), complemento(['(', 't)-SNAREs', and, one, '(', 'R)', from, the, vesicular, '(', 'v)-SNARE'])].
[sujeto(['Studying', these, reactions, in, native, yeast, 'vacuoles,', we]), verbo([found]), complemento([that, 'NSF/Sec18', activates, the, vacuolar, 'cis-SNARE', complex, by, selectively, displacing, the, vacuolar, 'Q(a)', 'SNARE,', leaving, behind, a, 'Q(bc)R', subcomplex])].
[sujeto(['This', subcomplex, serves, as, an, acceptor, for, a, 'Q(a)', 'SNARE', from, the, opposite, 'membrane,']), verbo([leading]), complemento([to, 'Q(a)-Q(bc)R', 'trans-complexes'])].
[sujeto(['This']), verbo([suggests]), complemento([that, the, vacuolar, 'Rab-GTPase,', 'Ypt7,', and, 'HOPS', restrict, 'cis-SNARE', disassembly, and, thereby, bias, 'trans-SNARE', assembly, into, a, preferred, topology])].
[sujeto(['Prenylated', 'Rab', acceptors, '(', 'PRAs),', members, of, the, 'Ypt-interacting', protein, family, of, small, membrane, 'proteins,', are, thought, to, aid, the]), verbo([targeting]), complemento([of, prenylated, 'Rabs', to, their, respective, endomembrane, compartments])].
[sujeto(['B6,', a, member, of, the, 'AtPRA1', 'family,', on, the, anterograde, trafficking, of, proteins]), verbo([targeted]), complemento([to, various, endomembrane, compartments, was, investigated])].
[sujeto(['The', trafficking, of, the, vacuolar, proteins, 'sporamin:GFP', '(', for, green, fluorescent, 'protein)', and, 'AALP:GFP,', the, secretory, protein, 'invertase:GFP,', and, the, plasma, membrane, proteins, 'PMP:GFP', and, 'H+-ATPase:GFP', was]), verbo([inhibited]), complemento([in, a, 'dose-dependent', 'manner,', while, the, trafficking, of, the, 'Golgi-localized', proteins, 'ST:GFP', and, 'KAM1(ΔC):mRFP', was, not, affected])].
[sujeto(['α-Synuclein']), verbo([has]), complemento([been, implicated, in, the, pathogenesis, of, 'Parkinson\'s', disease])].
[sujeto(['Although', it, is, highly, 'conserved,', its, physiological, function]), verbo([has]), complemento([not, yet, been, elucidated, in, detail])].
[sujeto(['In', an, effort, to, define, the, function, of, 'α-synuclein,']), verbo([interacting]), complemento([proteins, were, screened, in, phage, display, assays])].
[sujeto(['Prenylated', 'Rab', acceptor, protein, 1, '(', 'PRA1)', was, identified, as, an]), verbo([interacting]), complemento([partner])].
[sujeto(['Cotransfection', of, 'α-synuclein', and, 'PRA1']), verbo([caused]), complemento([vesicles, to, accumulate, in, the, periphery, of, the, cytosol, in, neuronal, 'cells,', suggesting, that, overexpression, of, 'α-synuclein', hinders, proper, vesicle, trafficking, and, recycling, as, a, result, of, the, interaction, between, 'α-synuclein', and, 'PRA1'])].
[sujeto(['N-myc', 'downstream-regulated', gene, 1, '(', 'NDRG1)', mutations]), verbo([cause]), complemento(['Charcot-Marie-Tooth', disease, type, 4, 'D', '(', 'CMT4D)'])].
[sujeto(['However,', the, cellular, function, of, 'NDRG1', and, how, it]), verbo([causes]), complemento(['CMT4D', are, poorly, understood])].
[sujeto(['We']), verbo([report]), complemento([that, 'NDRG1', silencing, in, epithelial, cells, results, in, decreased, uptake, of, 'low-density', lipoprotein, '(', 'LDL)', due, to, reduced, 'LDL', receptor, '(', 'LDLR)', abundance, at, the, plasma, membrane])].
[sujeto(['Concomitantly,', 'LDLR', ubiquitylation, is]), verbo([increased]), complemento([but, its, degradation, is, reduced, and, 'ESCRT', '(', endosomal, sorting, complex, required, for, 'transport)', proteins, are, downregulated])].
[sujeto(['Co-depletion', of, 'IDOL', '(', inducible, degrader, of, the, 'LDLR),', which, ubiquitylates, the, 'LDLR', and]), verbo([promotes]), complemento([its, 'degradation,', rescues, plasma, membrane, 'LDLR', levels, and, 'LDL', uptake])].
[sujeto(['Both', phenotypes, are, rescued, by, 'co-silencing', of, 'Idol,']), verbo([suggesting]), complemento([that, ligand, uptake, through, 'LDLR', family, members, controls, oligodendrocyte, differentiation])].
[sujeto(['Mechanical', forces, are, known, to, alter, the, expression, of, 'genes,', but, it]), verbo([has]), complemento([so, far, not, been, reported, whether, they, may, influence, the, fidelity, of, 'nucleus-based', processes])].
[sujeto(['This', 'so-called', splicing, noise, is]), verbo([found]), complemento([at, low, frequency, in, 'pre-mRNA', splicing])].
[sujeto(['In', cells, treated, by, altered, uniaxial, cyclic, stretching, for, 18, 'h,', a, uniform, and, significant]), verbo([increase]), complemento([of, splicing, noise, was, found, for, all, detectable, exon, skips])].
[sujeto(['Our', data, demonstrate, that, application, of, cyclic, stretch, to, cultured, fibroblasts, correlates, with, a, reduced, transcriptional, fidelity]), verbo([caused]), complemento([by, increasing, splicing, noise])].
[sujeto(['The', noise, in, the, splicing, 'process,', represented, by, those, misspliced, 'products,', can, be]), verbo([increased]), complemento([by, cold, shock, treatment, or, by, inhibiting, the, nonsense, mediated, decay])].
[sujeto(['Here,', we, investigated, whether, the, splicing, noise, frequency]), verbo([increases]), complemento([with, age, in, vivo, in, peripheral, bloods, cells, or, in, vitro, in, cultured, and, aged, fibroblasts, from, healthy, donors])].
[sujeto(['No', correlation, to, the, age, of, the, donors, was]), verbo([found]), complemento([in, the, splicing, noise, frequencies])].
[sujeto(['Although', specific, proteins]), verbo([have]), complemento([been, identified, that, regulate, the, membrane, association, and, facilitate, intracellular, transport, of, prenylated, 'Rho-', and, 'Rab-family', 'proteins,', it, is, not, known, whether, cellular, proteins, fulfill, similar, roles, for, other, prenylated, 'species,', such, as, 'Ras-family', proteins])].
[sujeto(['We', used, a, previously, described, method, to, evaluate, how, several, cellular, 'proteins,', previously, identified, as, potential]), verbo([binding]), complemento([partners, '(', but, not, 'effectors)', of, 'K-ras4B,', influence, the, dynamics, of, 'K-ras', association, with, the, plasma, membrane])].
[sujeto(['Inhibition', of, calmodulin, likewise, reduces, the, rate, of, 'K-ras', dissociation, from, the, plasma, 'membrane,', in, this, case, in, a, manner, specific, for, the]), verbo([activated]), complemento([form, of, 'K-ras'])].
[sujeto(['By', 'contrast,', 'galectin-3', specifically, reduces, the, rate, of, plasma, membrane, dissociation, of]), verbo([activated]), complemento(['K-ras,', an, effect, that, is, blocked, by, the, 'K-ras', antagonist, farnesylthiosalicylic, acid, '(', 'salirasib)'])].
[sujeto(['We']), verbo([have]), complemento([previously, identified, prenylated, 'Rab', acceptor, 1, '(', 'PRA1)', as, a, novel, cellular, interacting, partner, for, 'Epstein-Barr', 'virus-encoded', 'oncoprotein,', latent, membrane, protein, 1, '(', 'LMP1)'])].
[sujeto(['The', intracellular, trafficking, and, full, signaling, of, 'LMP1']), verbo([requires]), complemento([its, interaction, with, 'PRA1'])].
[sujeto(['To', further, explore, the, role, of, 'PRA1', in, 'Epstein-Barr', 'virus-associated', nasopharyngeal, carcinoma, '(', 'NPC)', 'cells,', we, generated, several, 'PRA1-knockdown', cell, 'clones,', which, exhibited, altered, cell, morphology, and]), verbo([increased]), complemento([cell, motility])].
[sujeto(['We', identified, proteins, differentially]), verbo([expressed]), complemento([in, the, knockdown, clones, by, means, of, isobaric, mass, tags, labeling, coupled, with, multidimensional, liquid, 'chromatography-mass', spectrometry])].
[sujeto(['We', validated, a, panel, of, 'proteins,', which, showed, consistent, 'up-regulation', in, 'PRA1-knockdown', clones, and]), verbo([participated]), complemento([in, regulating, lipid, homeostasis, and, cell, migration])].
[sujeto(['Moreover,', overexpressed, 'PRA1', was, able, to, alleviate, the, dysregulation, of, these, affected, proteins, either, from, 'PRA1', knockdown, or, 'U18666A', 'treatment,', implying, a, role, for, 'PRA1', in]), verbo([regulating]), complemento([the, levels, of, these, affected, proteins, in, response, to, altered, cholesterol, homeostasis])].
[sujeto(['We', further, demonstrated, that, 'LMP1', expression]), verbo([caused]), complemento(['PRA1', sequestration, in, 'NPC', 'cells,', leading, to, a, consequence, reminiscent, of, 'PRA1', knockdown])].
[sujeto(['In', 'sum,', our, findings, delineated, novel, roles, of, 'PRA1', in, lipid, transport, and, cell, 'migration,', and]), verbo([provided]), complemento([additional, insights, into, the, molecular, basis, of, 'NPC', 'morphogenesis,', namely, a, consequence, of, 'LMP1-PRA1', interaction])].
[sujeto(['Metastasis', is, the, main]), verbo([cause]), complemento([of, mortality, in, 'non-small', cell, lung, cancer, '(', 'NSCLC)', patients])].
[sujeto(['Dexamethasone', '(', 'Dex)']), verbo([inhibits]), complemento([stimulated, adrenocorticotrophic, hormone, '(', 'ACTH)', secretion, in, 'AtT-20', 'cells,', a, mouse, corticotroph, tumor, cell, line])].
[sujeto(['Dexras1', protein, expression, is]), verbo([induced]), complemento([in, corticotrophs, by, 'Dex'])].
[sujeto(['The', function, of, 'Dexras1', is, 'unknown;', 'however,', it, may, be]), verbo([involved]), complemento([in, corticotrophic, negative, feedback])].
[sujeto(['Here', we]), verbo([report]), complemento([the, identification, of, a, 'Dexras1', 'interactor,', prenylated, 'Rab', acceptor, domain, family, member, 1, '(', 'PRAF1),', a, protein, that, localizes, to, the, 'Golgi', 'complex,', 'post-Golgi', 'vesicles,', and, endosomes])].
[sujeto(['We', determined, that, amino, acids, 54, -, 175, of, 'PRAF1', are, essential, for, interaction, with, 'Dexras1', and, that, specific, point, mutations, located, within, this, region]), verbo([enhance]), complemento(['PRAF1-Dexras1', interactions])].
[sujeto(['AtT-20', cells, stably, transfected, with, truncated, or, mutated, 'PRAF1', constructs, had, altered, responses, to, 'corticotrophin-releasing', hormone, and, 'Dex,', upregulated, expression, of, the, 'ACTH', prohormone, 'pro-opiomelanocortin', '(', 'POMC),', altered, 'POMC', 'processing,', and, altered, 'Golgi', complex, morphology, with]), verbo([decreased]), complemento(['intra-Golgi', and, intracellular, 'co-localization', of, 'PRAF1', and, 'ACTH', proteins])].
[sujeto(['Our', findings, indicate, that, 'PRAF1', plays, a, novel, role, in, 'ACTH']), verbo([stimulated]), complemento([secretion])].
[sujeto(['VAMP2', and, 'Rab3A', are, 'SNARE', proteins, that]), verbo([interact]), complemento([with, 'PRAF1,', 'and,', as, part, of, a, 'SNARE', 'complex,', 'PRAF1', may, function, in, the, regulation, of, docking, and, fusion, of, transport, vesicles, both, in, the, 'Golgi', complex, and, at, the, plasma, membrane])].
[sujeto(['In', addition, to]), verbo([interacting]), complemento([with, 'SNARE', 'proteins,', 'PRAF1', interacts, with, 'rotaviral,', 'retroviral,', and, herpes, viral, proteins])].
[sujeto(['The', function, of, viral, protein, interaction, is, 'unknown,', but, 'PRAF1', may]), verbo([enhance]), complemento([rotaviral, and, retroviral, assembly])].
[sujeto(['In', 'contrast,', 'PRAF1', may]), verbo([inhibit]), complemento([the, herpes, virus, life, cycle])].
[sujeto(['The', prenylated, 'Rab', acceptor, 1, '(', 'PRA1)', is, a, ubiquitously]), verbo([expressed]), complemento([21, kDa, protein, containing, two, transmembrane, domains, that, possibly, induce, its, localization, to, the, 'Golgi', complex])].
[sujeto(['It']), verbo([binds]), complemento([to, prenylated, 'Rab', 'GTPases', and, 'VAMP2'])].
[sujeto(['In', this, 'study,', we]), verbo([report]), complemento([that, 'PRA1-overexpressing', cells, exhibited, a, significantly, retarded, growth, rate, as, compared, to, that, of, the, 'mock-transfected', 'cells,', and, the, transcriptional, activity, of, 'TCF,', as, evaluated, by, 'TOPflash', luciferase, reporter, 'assay,', was, profoundly, reduced, in, the, 'PRA1-overexpressed', cells])].
[sujeto(['Finally,', we, observed, that, the, inhibition, of, 'TCF/beta-catenin', signaling, by, 'PRA1', is]), verbo([associated]), complemento([with, 'ERK1/2', dephosphorylation])].
[sujeto(['Therefore,', our, data]), verbo([suggest]), complemento([that, the, in, vivo, modulation, of, 'PRA1', may, be, involved, in, 'TCF/beta-catenin', 'signaling,', as, well, as, cellular, proliferation, and, tumorigenesis])].
[sujeto(['Latent', membrane, protein, 1, '(', 'LMP1),', which, is, an, 'Epstein-Barr', virus, '(', 'EBV)-encoded', 'oncoprotein,']), verbo([induces]), complemento([nuclear, 'factor-kappa', 'B', '(', 'NF-kappaB)', signaling, by, mimicking, the, tumor, necrosis, factor, receptor, '(', 'TNFR)'])].
[sujeto(['Here,', we, identify, a, new, 'LMP1-interacting', 'molecule,', prenylated, 'Rab', acceptor, 1, '(', 'PRA1),', which]), verbo([interacts]), complemento([with, 'LMP1', for, the, first, time, through, 'LMP1\'s', transmembrane, 'domain,', and, show, that, 'PRA1', is, involved, in, intracellular, 'LMP1', trafficking, and, 'LMP1-induced', 'NF-kappaB', activity])].
[sujeto(['Immunofluorescence', and, biochemical, analyses, revealed, that, 'LMP1', physically]), verbo([interacted]), complemento([with, 'PRA1', at, the, 'Golgi', 'apparatus,', and, the, colocalization, of, 'LMP1', and, 'PRA1', to, the, 'Golgi', was, sensitive, to, nocodazole, and, brefeldin, 'A'])].
[sujeto(['Coexpression', of, a, 'PRA1', export, mutant, or, knockdown, of, 'PRA1']), verbo([led]), complemento([to, redistribution, of, 'LMP1', and, its, associated, signaling, molecules, to, the, endoplasmic, reticulum, and, subsequent, impairment, of, 'LMP1-induced', 'NF-kappaB', 'activation,', but, had, no, effect, on, 'CD40-', and, 'TNFR1-mediated', signaling, or, the, functional, integrity, of, the, 'Golgi', apparatus])].
[sujeto(['These', novel, findings]), verbo([provide]), complemento([important, new, insights, into, 'LMP1,', and, identify, an, unexpected, new, role, for, 'PRA1', in, cellular, signaling])].
[sujeto(['Recently,', 'PRAF2', was]), verbo([found]), complemento([to, interact, with, the, chemokine, receptor, 'CCR5'])].
[sujeto(['The', recombinant, 'PRAF2', protein, was, readily]), verbo([expressed]), complemento([in, 'Schneider', 2, '(', 'S2)', insect, 'cells,', and, the, native, protein, was, detected, in, human, tissues, with, strong, expression, in, the, 'brain,', small, 'intestine,', 'lung,', 'spleen,', and, pancreas])].
[sujeto(['Strong', 'PRAF2', protein, expression, was, also]), verbo([found]), complemento([in, human, tumor, tissues, of, the, 'breast,', 'colon,', 'lung,', and, 'ovary,', with, a, weaker, staining, pattern, in, normal, tissues, of, the, same, patient])].
[sujeto(['Our', studies, show, for, the, first, time, that, the, 'CCR5-interacting', 'PRAF2', protein, is]), verbo([expressed]), complemento([in, several, human, tissues, with, a, possible, function, in, 'ER/Golgi', transport, and, vesicular, traffic])].
[sujeto(['PRA2', was]), verbo([found]), complemento([to, interact, with, the, 'ER-localized', protein, 'VAMP-associated', protein, of, 33, kDa, or, 'VAP-33', by, a, yeast, 'two-hybrid', screen])].
[sujeto(['PRA2', was]), verbo([found]), complemento([to, form, a, large, sodium, dodecyl, sulfate, '(', 'SDS)-insoluble', complex, upon, heat, 'denaturation,', resulting, in, significant, reduction, in, the, 'Western', immunoblot, signal])].
[sujeto(['We', also]), verbo([found]), complemento([that, protein, interaction, with, 'PRA2', is, highly, sensitive, to, detergent, and, describe, a, covalent, 'cross-linking', procedure, for, mammalian, cell, extracts, to, stabilize, the, 'PRA2-containing', complex, prior, to, membrane, solubilization, and, immunoprecipitation])].
[sujeto(['The', assembly, and]), verbo([release]), complemento([of, infectious, virus, particles, was, studied, under, conditions, of, 'PRA1', overexpression, in, a, transient, transfection, assay, or, suppression, by, 'RNA', interference])].
[sujeto(['The', remarkable, degree, of, specificity, with, which, 'Rab', 'GTPases', recognise, distinct, subsets, of, intracellular, membranes, forms, the, basis, of, their, ability, to]), verbo([act]), complemento([as, key, cellular, 'regulators,', determining, the, recruitment, of, downstream, effectors, to, the, right, membrane, at, the, right, time])].
[sujeto(['The', molecular, mechanisms, controlling, 'Rab', 'localisation,', 'however,']), verbo([have]), complemento([proved, tricky, issues, to, address])].
[sujeto(['It', is, becoming, increasingly, apparent, that, multiple, factors, contribute, to, the, specificity, of, 'Rab', localisation, and, the, close, coordination, of, membrane]), verbo([targeting]), complemento([with, 'Rab', activation])].
[sujeto(['With', important, new, insights, into, the, mode, of, action, of, the, general, 'Rab', regulators, 'REP', and, 'RabGDI,', as, well, as, the, demonstration, that, novel, factors, such, as, 'Yip3/Pra1']), verbo([act]), complemento([as, 'GDI', displacement, factors, and, that, signals, within, 'Rab', proteins, contribute, to, targeting, 'specificity,', a, better, understanding, of, the, concepts, governing, 'Rab', recruitment, and, function, is, now, beginning, to, emerge])].
[sujeto(['The', diversity, of, cellular, processes]), verbo([regulated]), complemento([by, 'Rab', family, members, is, made, 'possible,', not, only, by, the, wide, range, of, effectors, they, 'recruit,', but, also, by, the, different, mechanisms, regulating, their, own, targeting, and, activation])].
[sujeto(['Thyrotropin', '(', 'TSH)']), verbo([stimulates]), complemento([thyroid, cell, differentiation, and, proliferation, by, binding, to, its, 'G-protein', coupled, receptor, '(', 'GPCR)', 'receptor,', the, thyrotropin, receptor, '(', 'TSHR)'])].
[sujeto(['This', effect, seems, to, be, restricted, to, 'co-expression', of, 'two-membrane', proteins, because, the, expression, does, not]), verbo([decrease]), complemento([when, the, membrane, protein, is, 'co-expressed', with, a, cytosolic, protein, '(', 'Rab9,', 'Cyclin', 'D3)'])].
[sujeto(['Human', cells, contain, more, than, 60, small, 'G', proteins, of, the, 'Rab', 'family,', which, are, localized, to, the, surfaces, of, distinct, membrane, compartments, and]), verbo([regulate]), complemento([transport, vesicle, 'formation,', 'motility,', docking, and, fusion])].
[sujeto(['Prenylated', 'Rabs', also, occur, in, the, cytosol]), verbo([bound]), complemento([to, 'GDI', '(', guanine, nucleotide, dissociation, 'inhibitor),', which, binds, to, 'Rabs', in, their, inactive, state])].
[sujeto(['The', late, 'endosomal,', prenyl, 'Rab9']), verbo([binds]), complemento(['GDI', with, very, high, 'affinity,', which, led, us, to, propose, that, there, might, be, a, '\'', 'GDI-displacement', 'factor\'', to, catalyse, dissociation, of, 'Rab-GDI', complexes, and, to, enable, transfer, of, 'Rabs', from, 'GDI', onto, membranes])].
[sujeto(['Indeed,', we]), verbo([have]), complemento([previously, shown, that, endosomal, membranes, contain, a, proteinaceous, factor, that, can, act, in, this, manner])].
[sujeto(['Here', we, show, that, the, integral, membrane, 'protein,', 'Yip3,']), verbo([acts]), complemento([catalytically, to, dissociate, complexes, of, endosomal, 'Rabs', bound, to, 'GDI,', and, to, deliver, them, onto, membranes])].
[sujeto(['We', propose, that, the]), verbo([conserved]), complemento(['Yip', proteins, serve, as, 'GDI-displacement', factors, for, the, targeting, of, 'Rab', 'GTPases', in, eukaryotic, cells])].
[sujeto(['We', further]), verbo([found]), complemento([that, monomeric, and, dimeric, forms, of, 'PRAF2', are, associated, with, different, cell, 'compartments,', suggesting, possible, functional, differences])].
[sujeto(['This', study, shows, that, 'PRAF2', expression, is, elevated, in, various, tumors, with, exceptionally, high, expression, in, malignant, 'gliomas,', and, 'PRAF2', therefore, presents, a, candidate, molecular]), verbo([target]), complemento([for, therapeutic, intervention])].
[sujeto(['Prenylated', 'Rab', acceptor, 1, '(', 'PRA1)', domain, proteins, are, small, transmembrane, proteins, that]), verbo([regulate]), complemento([vesicle, trafficking, as, receptors, of, 'Rab', 'GTPases', and, the, vacuolar, soluble, 'N-ethylmaleimide-sensitive', factor, attachment, receptor, protein, 'VAMP2'])].
[sujeto(['The', 'Arabidopsis', '(', 'Arabidopsis', 'thaliana)', 'PRA1', '(', 'AtPRA1)', proteins, were]), verbo([found]), complemento([to, homodimerize, and, heterodimerize, in, a, manner, corresponding, to, their, phylogenetic, distribution])].
[sujeto(['AtPRA1', genes, were, significantly, coexpressed, with, 'Rab', 'GTPases', and, genes, encoding, vesicle, transport, 'proteins,']), verbo([suggesting]), complemento([an, involvement, in, the, vesicle, trafficking, process, similar, to, that, of, their, animal, counterparts])].
[sujeto(['Taken', 'together,', our, data]), verbo([reveal]), complemento([a, high, functional, diversity, of, 'AtPRA1', 'proteins,', probably, dealing, with, the, various, demands, of, the, complex, trafficking, system])].
[sujeto(['Our', previous, studies, revealed, that, 'PRAF2', is, highly]), verbo([expressed]), complemento([in, the, brain, and, serves, as, a, candidate, prognostic, marker, in, neuroblastoma, '(', 'NB)'])].
[sujeto(['Analysis', by, immunohistochemistry, revealed, that, in, the, human, 'cerebellum,', the, 'PRAF2', protein, was, strongly]), verbo([expressed]), complemento([in, 'Purkinje', cells, 'and,', more, 'moderately,', in, cells, of, the, molecular, and, the, granular, layers])].
[sujeto(['The', expression, of, 'PRAF2', in, specific, regions, of, the, brain, including, 'SVs']), verbo([suggest]), complemento([an, important, physiological, function, for, this, novel, 'protein,', possibly, by, participating, in, multiple, aspects, of, 'SV', 'maturation,', 'transport,', and, signal, transmission])].
[sujeto(['The', nucleotide, sequences, of, these, three, genes, revealed, that, porcine, 'RHOB', gene, encodes, a, protein, of, 196, amino, acids, that, contains, the]), verbo([conserved]), complemento([putative, 'RhoA-like', domain, and, has, high, homology, with, the, 'RHOB', precursor, of, 'human,', rat, and, mouse, '(', 100, '%', ')'])].
[sujeto(['The', porcine, 'RHOG', gene, encodes, a, protein, of, 191, amino, acids, that, contains, the]), verbo([conserved]), complemento([putative, 'RhoG', domain, and, has, high, homology, with, the, 'RhoG', precursor, '(', 'RHOG)', of, 'human,', mouse, and, 'Cricetus', cricetus, '(', 98, '%', ')'])].
[sujeto(['The', porcine, 'PRAF1', gene, encodes, a, protein, of, 185, amino, acids, that, contains, the]), verbo([conserved]), complemento([putative, 'PRA1', domain, and, has, high, homology, with, the, 'PRAF1', of, dog, '(', 97, '%', ')', ',', cattle, '(', 97, '%', ')', ',', human, '(', 96, '%', ')', ',', rat, '(', 95, '%', ')', and, mouse, '(', 95, '%', ')'])].
[sujeto(['The', tissue, expression, analysis, indicated, swine, 'RHOB', gene, was, moderately]), verbo([expressed]), complemento([in, 'lung,', weakly, in, 'fat,', 'spleen,', 'kidney,', and, almost, not, expressed, in, small, 'intestine,', large, 'intestine,', 'liver,', muscle])].
[sujeto(['The', swine, 'RHOG', gene, was, 'over-expressed', in, small, 'intestine,', large, 'intestine,', 'liver,', and, 'muscle,', moderately]), verbo([expressed]), complemento([in, 'kidney,', weakly, in, 'spleen,', and, almost, not, expressed, in, fat, and, lung])].
[sujeto(['The', swine, 'PRAF1', gene, was, 'over-expressed', in, fat, and, 'spleen,', moderately, in, lung, and, 'kidney,', weakly, in, small, intestine, and, large, 'intestine,', and, almost, not]), verbo([expressed]), complemento([in, liver, and, muscle])].
[sujeto(['Glutamate', transporter]), verbo([associated]), complemento([protein, 3, -, 18, '(', 'GTRAP3-18)', is, an, endoplasmic, reticulum, '(', 'ER)-localized', protein, belonging, to, the, prenylated, 'rab-acceptor-family', interacting, with, small, 'Rab', 'GTPases,', which, regulate, intracellular, trafficking, events])].
[sujeto(['Its', impact, on, secretory, trafficking]), verbo([has]), complemento([not, been, investigated])].
[sujeto(['We']), verbo([report]), complemento([here, that, 'GTRAP3-18', has, an, inhibitory, effect, on, 'Rab1,', which, is, involved, in, 'ER-to-Golg', trafficking])].
[sujeto(['In', accordance, with, the, known, role, of, 'Rab1', in, neurite, 'formation,', overexpression, of, 'GTRAP3-18', significantly]), verbo([inhibited]), complemento([the, length, of, outgrowing, neurites, in, differentiated, 'CAD', cells])].
[sujeto(['The', inhibitory, effect, of, 'GTRAP3-18', on, neurite, growth, was, rescued, by, 'co-expression', with, 'Rab1,', supporting, the, conclusion, that, 'GTRAP', 3, -, 18]), verbo([acted]), complemento([by, inhibiting, 'Rab1', action])].
[sujeto(['Prenylated', 'Rab', acceptor, 1, domain, 'family,', member, 2, '(', 'PRAF2)', is, a, novel, 19, -, kDa, protein, that]), verbo([has]), complemento([recently, been, implicated, in, human, cancer])].
[sujeto(['All', 110, neuroblastic, tumors]), verbo([expressed]), complemento(['PRAF2', at, higher, levels, than, any, other, tumor, examined])].
[sujeto(['PRAF2', localized, in, bright, cytoplasmic, punctae, and, protein, levels]), verbo([increased]), complemento([in, neuroblastoma, cells, that, underwent, 'cerulenin-induced', apoptosis])].
[sujeto(['Elevated', 'PRAF2', expression, levels, correlated, with, unfavorable, genetic, and, clinical, 'features,']), verbo([suggesting]), complemento(['PRAF2', as, a, candidate, prognostic, marker, of, neuroblastoma])].
[sujeto(['Double', immunofluorescence, analysis, revealed, that, addicsin, was]), verbo([expressed]), complemento([in, the, somata, of, principal, neurons, in, the, 'CNS', such, as, the, pyramidal, cells, and, 'gamma-aminobutyric', acid, '(', 'GABA)-ergic', interneurons, scattered, in, the, hippocampal, formation])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, addicsin, has, neural, expression, and, may, play, crucial, roles, in, the, basic, physiological, functions, of, the, mature, 'CNS'])].
[sujeto(['As', part, of, the, innate, immune, 'system,', natural, killer, '(', 'NK)', cells, are, directly]), verbo([involved]), complemento([in, the, response, to, fungal, infections])].
[sujeto(['Perforin']), verbo([has]), complemento([been, identified, as, the, major, effector, molecule, acting, against, many, fungal, pathogens])].
[sujeto(['While', several, studies]), verbo([have]), complemento([shown, that, perforin, mediated, fungicidal, effects, can, contribute, to, fungal, 'clearance,', neither, the, activation, of, 'NK', cells, by, fungal, pathogens, nor, the, effects, of, perforin, on, fungal, cells, are, 'well-understood'])].
[sujeto(['In', a, dual, 'approach,', we]), verbo([have]), complemento([studied, the, global, gene, expression, pattern, of, primary, and, cytokine, activated, 'NK', cells, after, 'co-incubation', with, 'Candida', albicans, and, the, transcriptomic, adaptation, of, 'C'])].
[sujeto(['NK', cells]), verbo([responded]), complemento([to, the, fungal, pathogen, with, an, 'up-regulation', of, genes, involved, in, immune, signaling, and, release, of, cytokines])].
[sujeto(['Furthermore,', we, observed, a, pronounced]), verbo([increase]), complemento([of, genes, involved, in, glycolysis, and, glycolysis, inhibitor, 2, -, 'deoxy-D-glucose', impaired, 'C'])].
[sujeto([albicans]), verbo([induced]), complemento(['NK', cell, activation])].
[sujeto(['In', the, fungal, 'pathogen,', perforin]), verbo([induced]), complemento([a, strong, 'up-regulation', of, several, fungal, genes, involved, in, the, zinc, depletion, 'response,', such, as, 'PRA1', and, 'ZRT1'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, fungal, zinc, homeostasis, is, linked, to, the, reaction, to, perforin, secreted, by, 'NK', cells])].
[sujeto(['To', draw, a, comprehensive, picture, of, this, relevant, step, in, 'host-pathogen', interaction, during, invasive, 'candidiasis,', we]), verbo([have]), complemento([optimized, a, 'gel-free', shaving, proteomic, strategy, to, identify, 'both,', human, serum, proteins, coating, 'C'])].
[sujeto([albicans, 'proteins,', we, identified, 23, 'GPI-anchored', 'proteins,', 'Gpd2', and, 'Pra1,', which, are]), verbo([involved]), complemento([in, complement, system, evasion, and, 7, other, proteins, that, are, able, to, attach, plasminogen, to, 'C'])].
[sujeto([albicans, hyphae, surface]), verbo([induced]), complemento([with, 10, '%', human, serum, were, not, detected, in, other, 'hypha-induced', conditions])].
[sujeto(['The', most, abundant, human, proteins, identified, are]), verbo([involved]), complemento([in, complement, and, coagulation, pathways])].
[sujeto([dubliniensis, to]), verbo([regulate]), complemento([zinc, uptake, mechanisms, under, zinc, 'limitation:', it, governs, the, expression, of, the, zinc, transporter, genes, 'ZRT1,', 'ZRT2,', and, 'ZRT3', and, of, the, zincophore, gene, 'PRA1'])].
[sujeto(['Importantly,', we]), verbo([found]), complemento(['that,', in, contrast, to, what, is, seen, in, 'C'])].
[sujeto(['Amilorides,', 'well-known', inhibitors, of, 'Na(+)/H(+)', 'antiporters,', were, previously, shown, to]), verbo([inhibit]), complemento([bacterial, and, mitochondrial, 'NADH-quinone', oxidoreductase, '(', complex, 'I)', but, were, markedly, less, active, for, complex, 'I'])].
[sujeto(['Because', membrane, subunits, 'ND2,', 'ND4,', and, 'ND5', of, bovine, complex, 'I', are, homologous, to, 'Na(+)/H(+)', 'antiporters,', amilorides]), verbo([have]), complemento([been, thought, to, bind, to, any, or, all, of, the, 'antiporter-like', 'subunits;', 'however,', there, is, currently, no, direct, experimental, evidence, that, supports, this, notion])].
[sujeto(['To', identify, the]), verbo([binding]), complemento([site, of, amilorides, in, bovine, complex, 'I,', we, synthesized, two, photoreactive, amilorides, '(', 'PRA1', and, 'PRA2),', which, have, a, photoreactive, azido, '(', -, 'N3)', group, and, terminal, alkyne, '(', -, 'C≡CH)', group, at, the, opposite, ends, of, the, 'molecules,', 'respectively,', and, conducted, photoaffinity, labeling, with, bovine, heart, submitochondrial, particles])].
[sujeto(['Suppressive', effects, of, ordinary, inhibitors, '(', 'bullatacin,', 'fenpyroximate,', and, 'quinazoline),', which]), verbo([bind]), complemento([to, the, putative, quinone, binding, 'pocket,', on, labeling, were, fairly, different, between, the, 'B14'])].
[sujeto([5, a, and, 49, kDa, subunits, probably, because, the]), verbo([binding]), complemento([positions, of, the, three, inhibitors, differ, within, the, pocket])].
[sujeto(['The', results, of, this, study, clearly, demonstrate, that, amilorides]), verbo([inhibit]), complemento([complex, 'I', activity, by, occupying, the, quinone, binding, pocket, rather, than, directly, blocking, translocation, of, protons, through, the, 'antiporter-like', subunits, '(', 'ND2,', 'ND4,', and, 'ND5)'])].
[sujeto(['The', structural, features, of, the, quinone]), verbo([binding]), complemento([pocket, in, bovine, complex, 'I', were, discussed, on, the, basis, of, these, results])].
[sujeto(['Amilorides,', 'well-known', inhibitors, of, 'Na(+)/H(+)', 'antiporters,']), verbo([have]), complemento([also, shown, to, inhibit, bacterial, and, mitochondrial, 'NADH-quinone', oxidoreductase, '(', complex, 'I)'])].
[sujeto(['Since', the, membrane, subunits, 'ND2,', 'ND4,', and, 'ND5', of, bovine, mitochondrial, complex, 'I', are, homologous, to, 'Na(+)/H(+)', 'antiporters,', amilorides]), verbo([have]), complemento([been, thought, to, bind, to, any, or, all, of, the, 'antiporter-like', 'subunits;', 'however,', there, is, no, direct, experimental, evidence, in, support, of, this, notion])].
[sujeto(['Photoaffinity', labeling, is, a, powerful, technique, to, identify, the]), verbo([binding]), complemento([site, of, amilorides, in, bovine, complex, 'I'])].
[sujeto(['Commercially', available, amilorides, such, as, 5, -, '(', 'N-ethyl-N-isopropyl)amiloride', are, not, suitable, as, design, templates, to, synthesize, photoreactive, amilorides, because, of, their, low]), verbo([binding]), complemento([affinities, to, bovine, complex, 'I'])].
[sujeto(['Candida', 'albicans,', the, important, human, fungal, pathogen, uses, multiple, evasion, strategies, to, 'control,']), verbo([modulate]), complemento([and, inhibit, host, complement, and, innate, immune, attack])].
[sujeto(['The', high, 'Gpm1/Pra1']), verbo([expressing]), complemento([candida, strains, bound, the, three, human, immune, regulators, more, 'efficiently,', than, the, low, expression, strains])].
[sujeto(['The', difference, was, 44, '%', for, 'Factor', 'H', 'binding,', 51, '%', for, 'C4BP']), verbo([binding]), complemento([and, 23, '%', for, plasminogen, binding])].
[sujeto(['This', higher, 'Gpm1/Pra1']), verbo([expressing]), complemento([strains, result, in, enhanced, survival, upon, challenge, with, complement, 'active,', 'Factor', 'H', depleted, human, serum, '(', difference, 40, '%', ')'])].
[sujeto(['In', addition, adhesion, to, and, infection, of, human, endothelial, cells, was]), verbo([increased]), complemento(['(', difference, 60, '%', ')', ',', and, 'C3b', surface, deposition, was, less, effective, '(', difference, 27, '%', ')'])].
[sujeto(['Candida', albicans, is, a, common, opportunistic, pathogen, that]), verbo([causes]), complemento([a, variety, of, diseases, in, immunocompromised, hosts])].
[sujeto(['The', 'DSE1', mutant, was, shown, to, lack, the, chitin, biosynthesis, protein, 'Chs5,', explaining, the, previously, observed]), verbo([decrease]), complemento([in, chitin, biosynthesis])].
[sujeto(['The', 'wild-type', strain]), verbo([expressed]), complemento(['Pra1,', involved, in, pH, response, and, zinc, 'acquisition,', 'Atg15,', a, lipase, involved, in, 'virulence,', and, 'Sod1,', required, for, oxidative, stress, 'tolerance,', in, addition, to, proteins, involved, in, protein, 'biosynthesis,', explaining, the, increase, in, total, protein, content, observed, compared, to, the, mutants, strain])].
[sujeto(['The', 'mutant,', on, the, other, 'hand,']), verbo([expressed]), complemento([glucoamylase, 1, ',', a, cell, wall, glycoprotein, involved, in, carbohydrate, metabolism, cell, wall, degradation, and, biofilm, formation])].
[sujeto(['Generalized', progressive, retinal, atrophy, '(', 'PRA)', is, a, group, of, inherited, eye, diseases, characterised, by, progressive, retinal, degeneration, that, ultimately]), verbo([leads]), complemento([to, blindness, in, dogs])].
[sujeto(['To', 'date,', more, than, 20, different, mutations]), verbo([causing]), complemento(['canine-PRA', have, been, described, and, several, breeds, including, the, 'Golden', 'Retriever', are, affected, by, more, than, one, form, of, 'PRA'])].
[sujeto(['Genetically', distinct, forms, of, 'PRA', may]), verbo([have]), complemento([different, clinical, characteristics, such, as, rate, of, progression, and, age, of, onset])].
[sujeto(['Mutations', in, two, distinct, genes]), verbo([have]), complemento([been, reported, to, cause, 'PRA', in, 'Golden', 'Retrievers', '(', 'prcd-PRA', and, 'GR_PRA1),', but, for, approximately, 39, '%', of, cases, in, this, breed, the, causal, mutation, remains, unknown])].
[sujeto(['A', 'genome-wide', association, study, of, 10, 'PRA', cases, and, 16, controls, identified, an, association, on, chromosome, 8, not, previously]), verbo([associated]), complemento([with, 'PRA', '(', praw, =, 1.3, '×10(-6)', and, corrected, with, 100, ',', 0, 'permutations,', pgenome, =, 0.148, ')'])].
[sujeto(['Two', of, the, genes, '(', 'TTC8', and, 'SPATA7)']), verbo([have]), complemento([been, associated, with, 'Retinitis', 'Pigmentosa', '(', 'RP)', in, humans])].
[sujeto(['Using']), verbo([targeted]), complemento([next, generation, sequencing, a, single, nucleotide, deletion, was, identified, in, exon, 8, of, the, 'TTC8', gene, of, affected, 'Golden', 'Retrievers'])].
[sujeto(['The', frame, shift, mutation, was, predicted, to]), verbo([cause]), complemento([a, premature, termination, codon])].
[sujeto(['Our', results, show, that, 'PRA', is, genetically, heterogeneous, in, one, of, the, 'world\'s', numerically, largest, 'breeds,', the, 'Golden', 'Retriever,', and, is]), verbo([caused]), complemento([by, 'multiple,', distinct, mutations])].
[sujeto(['Here', we, discuss, the, mutation, that]), verbo([causes]), complemento([a, form, of, 'PRA,', that, we, have, termed, 'PRA2,', that, accounts, for, approximately, 30, '%', of, 'PRA', cases, in, the, breed])].
[sujeto(['We']), verbo([have]), complemento([used, 'high-throughput', proteomics, to, display, the, differences, between, in, vitro, secretome, of, 'A'])].
[sujeto([salmonicida, species, were, proportionally, less, detected, than, proteins, common, to, the, 'Aeromonas', genus, or, those, shared, with, other, 'Aeromonas', 'species,']), verbo([suggesting]), complemento([that, in, vitro, growth, did, not, induce, the, expression, of, these, genes])].
[sujeto(['Numerous', highly]), verbo([conserved]), complemento([cytoplasmic, proteins, were, present, in, 'A'])].
[sujeto([salmonicida, and, showed, the, secretion, of, several, highly]), verbo([conserved]), complemento([cytoplasmic, proteins, with, putative, moonlighting, functions, and, roles, in, virulence])].
[sujeto(['The', opportunistic, fungus, 'Candida', albicans, is, one, of, the]), verbo([leading]), complemento([causes, of, infections, in, immunocompromised, 'patients,', and, innate, immunity, provides, a, principal, mechanism, for, protection, from, the, pathogen])].
[sujeto(['Both', purified, 'α(X)β₂', and, 'α(X)β₂-expressing', human, epithelial, kidney, 293, cells]), verbo([recognized]), complemento([and, bound, to, the, fungal, hyphae, of, 'SC5314', strain, of, 'C'])].
[sujeto(['The']), verbo([binding]), complemento([of, the, integrin, to, the, fungus, was, inhibited, by, 'β-glucans', but, not, by, 'mannans,', implicating, a, 'lectin-like', activity, in, recognition, but, distinct, in, specificity, from, that, of, 'α(M)β₂'])].
[sujeto(['Mice', deficient, in, 'α(X)β₂', were, more, prone, to, systemic, infection, with, the, 'LD₅₀', fungal, inoculum]), verbo([decreasing]), complemento([3, -, fold, in, 'α(X)β₂-deficient', mice, compared, with, 'wild-type', mice])].
[sujeto(['Organs', taken, from, 'α(X)β₂-deficient', mice, 16, h, postinfection, revealed, a, 10, -, fold]), verbo([increase]), complemento([in, fungal, invasion, into, the, brain, and, a, 2, -, fold, increase, into, the, liver])].
[sujeto(['Here', we]), verbo([report]), complemento([endothelial, zinc, sequestration, by, the, major, human, fungal, 'pathogen,', 'Candida', albicans])].
[sujeto([albicans, secretome, for, proteins, with, zinc]), verbo([binding]), complemento([motifs, identified, the, 'pH-regulated', antigen, 1, '(', 'Pra1)'])].
[sujeto(['Indeed,', recombinantly]), verbo([expressed]), complemento(['Pra1', exhibited, zinc, binding, properties, in, vitro])].
[sujeto([albicans]), verbo([prevented]), complemento([fungal, sequestration, and, utilisation, of, host, 'zinc,', and, specifically, blocked, host, cell, damage, in, the, absence, of, exogenous, zinc])].
[sujeto(['Structural', modelling, indicated, physical, interaction, between, 'Pra1', and, 'Zrt1', and, we, confirmed, this, experimentally, by, demonstrating, that, 'Zrt1', was, essential, for]), verbo([binding]), complemento([of, soluble, 'Pra1', to, the, cell, surface, of, 'C'])].
[sujeto(['Therefore,', we]), verbo([have]), complemento([identified, a, novel, metal, acquisition, system, consisting, of, a, secreted, zinc, scavenger, '(', &, 'quot;zincophore"),', which, reassociates, with, the, fungal, cell])].
[sujeto(['Furthermore,', functional, similarities, with, phylogenetically, unrelated, prokaryotic, systems, indicate, that, syntenic, zinc, acquisition, loci]), verbo([have]), complemento([been, independently, selected, during, evolution])].
[sujeto(['Candida', albicans, is, an, opportunistic, 'human-pathogenic', 'fungus,', which, can]), verbo([cause]), complemento([superficial, but, also, 'life-threatening', invasive, infections])].
[sujeto([albicans, is, a, 'surface-associated', and, secreted, protein, highly]), verbo([expressed]), complemento([in, the, hyphal, form])].
[sujeto(['Pra1', can]), verbo([bind]), complemento([to, complement, receptor, 3, '(', 'CD11b/CD18)', and, can, mediate, adhesion, to, and, migration, of, human, phagocytes])].
[sujeto([albicans, strain]), verbo([enhanced]), complemento([neutrophil, migration, and, adherence])].
[sujeto(['While', inactivated, hyphae, of, the, 'Pra1-overexpressing', mutant, with, 'surface-associated', 'Pra1']), verbo([enhanced]), complemento([the, production, and, release, of, reactive, oxygen, 'species,', 'myeloperoxidase,', 'lactoferrin,', and, interleukin, 8, by, 'neutrophils,', such, responses, were, reduced, when, stimulated, with, inactivated, hyphae, of, the, pra1Δ, strain])].
[sujeto(['However,', 'Pra1-overexpressing', living, 'hyphae,', which, secrete, large, amounts, of, 'Pra1,', also]), verbo([caused]), complemento([a, reduced, neutrophil, 'activation,', indicating, that, the, release, of, extracellular, 'Pra1', can, inhibit, the, activation, of, these, innate, immune, cells])].
[sujeto(['Similarly,', soluble, recombinant, 'Pra1']), verbo([inhibited]), complemento([the, neutrophil, responses, elicited, by, 'cell-wall', bound, 'Pra1'])].
[sujeto(['albicans,', especially, hyphal, 'cells,', by, human, neutrophils, and]), verbo([enhances]), complemento([neutrophil, antimicrobial, responses])].
[sujeto(['However,', the, fungus, can, counteract, some, of, these, defense, mechanisms, by]), verbo([releasing]), complemento([soluble, 'Pra1'])].
[sujeto(['Infectious', diseases]), verbo([caused]), complemento([by, human, pathogenic, fungi, represent, a, major, and, global, health, problem])].
[sujeto(['Based', on, the, limited, efficacy, of, existing, drugs, and, the]), verbo([increasing]), complemento([resistance, to, antifungal, 'compounds,', new, strategies, are, urgently, needed, to, fight, such, fungal, infections])].
[sujeto(['The', medically, important, pathogen, 'Candida', albicans, can, exist, as, an, opportunistic, 'yeast,', but, can, also]), verbo([cause]), complemento([severe, 'diseases,', 'septicaemia,', and, death])].
[sujeto(['This', immune, cross, talk]), verbo([has]), complemento([moved, into, the, focus, of, infectious, disease, research])].
[sujeto(['An', additional, relative, gene, expression, analysis, of, these, 'genes,', conducted, at, different, stages, of, mycoparasitism, against, 'Botrytis', cinerea, and, 'Phytophthora', 'capsici,', revealed, a, synergistic, transcription, of, various, genes]), verbo([involved]), complemento([in, cell, wall, degradation])].
[sujeto(['The', similarities, in, expression, patterns, and, the, occurrence, of, regulatory]), verbo([binding]), complemento([sites, in, the, corresponding, promoter, regions, suggest, a, possible, analog, regulation, of, these, genes, during, the, mycoparasitism, of, 'T'])].
[sujeto(['The', stimulatory, 'G', protein, α, subunit, '(', 'Gsα)']), verbo([activates]), complemento([the, 'cAMP-dependent', pathway, by, stimulating, the, production, of, cAMP, and, participates, in, diverse, cell, processes])].
[sujeto(['Loss', of, 'Gsα']), verbo([led]), complemento([to, a, fundamental, alteration, in, gene, profiles])].
[sujeto(['Among', the, altered, signaling, 'cascades,', the, 'MAPK/Erk', 'pathway,', which, is, downstream, of, growth, factor, 'signaling,', was, disrupted, secondary, to, a, defect, in]), verbo([phosphorylated]), complemento(['Raf1', '(', 'pRaf1),', resulting, in, a, deficiency, in, phosphorylated, 'CREB', '(', 'pCREB)', and, 'CDK2', ablation])].
[sujeto(['The', lack, of, pRaf1, also, resulted, in, a, failure, to]), verbo([phosphorylate]), complemento(['retinoblastoma,', which, releases, and, activates, 'E2F1,', and, a, decrease, in, cyclin, 'E1'])].
[sujeto(['Although', these, factors, could, be]), verbo([phosphorylated]), complemento([through, both, 'Gsα', and, growth, factor, 'signaling,', the, unique, function, of, 'Raf1', in, the, growth, factor, cascade, collapsed, in, response, to, the, lack, of, 'Gsα'])].
[sujeto(['The', growth, factor, signaling, pathway, that]), verbo([promotes]), complemento([hepatocyte, proliferation, is, dependent, on, 'Gsα', signaling])].
[sujeto(['Loss', of, 'Gsα']), verbo([leads]), complemento([to, a, breakdown, of, the, crosstalk, between, cAMP, and, growth, factor, signaling, and, dramatically, impairs, liver, regeneration])].
[sujeto(['In', the, model, fungus, 'Podospora', 'anserina,', the, 'PaYIP3', gene, encoding, the, orthologue, of, the, 'Saccharomyces', cerevisiae, 'YIP3', 'Rab-GDI', complex, dissociation, factor]), verbo([expresses]), complemento([two, 'polypeptides,', one, of, 'which,', the, long, 'form,', is, produced, through, a, programmed, translation, frameshift])].
[sujeto(['Inactivation', of, 'PaYIP3', results, in, slightly, delayed, growth]), verbo([associated]), complemento([with, modification, in, repartition, of, fruiting, body, on, the, 'thallus,', along, with, reduced, ascospore, production, on, wood])].
[sujeto(['Long', and, short, forms, of, 'PaYIP3', are]), verbo([expressed]), complemento([in, the, 'mycelium,', while, only, the, short, form, appears, expressed, in, the, maturing, fruiting, body, '(', 'perithecium)'])].
[sujeto(['The', frameshift]), verbo([has]), complemento([been, conserved, over, the, evolution, of, the, 'Pezizomycotina,', lasting, for, over, 400, million, 'years,', suggesting, that, it, has, an, important, role, in, the, wild])].
[sujeto(['Prenylated', 'Rab', proteins, exist, in, the, cytosol]), verbo([bound]), complemento([to, guanine, dissociation, inhibitor, '(', 'GDI)'])].
[sujeto(['We']), verbo([have]), complemento([shown, that, membranes, contain, a, proteinaceous, activity, that, is, required, for, 'Rab', 'delivery,', and, we, named, that, activity, 'GDI', displacement, factor, '(', 'GDF)'])].
[sujeto(['Biochemical', analysis, revealed, that, 'GDF', activity, was, membrane]), verbo([associated]), complemento([and, had, a, mass, of, approximately, 25, kDa])].
[sujeto(['Multiple', 'Rabs', are]), verbo([expressed]), complemento([in, all, 'cells,', and, each, is, localized, to, a, distinct, set, of, 'organelles,', but, little, is, known, regarding, the, mechanisms, by, which, 'Rabs', are, targeted, to, their, resident, organelles])].
[sujeto(['Integral', membrane, proteins]), verbo([have]), complemento([been, postulated, to, serve, as, receptors, that, recruit, 'Rabs', from, the, cytosol, in, a, complex, with, the, 'Rab', 'chaperone,', 'GDI,', to, facilitate, the, dissociation, of, 'Rab', and, 'GDI,', hence, facilitating, loading, of, 'Rabs', on, membranes])].
[sujeto(['In', 'addition,', a, member, of, the, highly]), verbo([conserved]), complemento([reticulon, protein, 'family,', 'Rtn1p,', is, also, associated, with, 'Yip3p', in, vivo])].
[sujeto(['Surprisingly,', the, intracellular, localization, of, 'Rabs', was, not, perturbed, in, yip3Delta, or, rtn1Delta, 'mutants,']), verbo([suggesting]), complemento([that, these, proteins, do, not, play, a, role, in, targeting, 'Rabs', to, intracellular, membranes])].
[sujeto(['These', data, indicate, that, 'Yip3p', may]), verbo([have]), complemento([multiple, functions, and, that, its, interaction, with, 'Rabs', is, not, critical, for, their, recruitment, to, organelle, membranes])].
[sujeto(['We']), verbo([found]), complemento([that, schizophrenia, risk, scores, calculated, at, 'P-value', thresholds, of, 5, ×, 10, '(', -, 3, ')', and, larger, predicted, 'FTND', and, cigarettes, smoked, per, day, '(', 'CPD),', suggesting, that, genes, most, significantly, associated, with, schizophrenia, were, not, associated, with, 'FTND/CPD,', consistent, with, the, 'self-medication', hypothesis])].
[sujeto(['The', 'COT', risk, scores, predicted, schizophrenia, diagnosis, at, 'P-values', of, 5, ×, 10, '(', -, 3, ')', and, 'smaller,', implying, that, genes, most, significantly]), verbo([associated]), complemento([with, 'COT', were, associated, with, schizophrenia])].
[sujeto(['Based', on, this, shared, 'liability,', we, identified, multiple, long, 'non-coding', 'RNAs', and, 'RNA']), verbo([binding]), complemento([protein, genes, '(', 'DA376252,', 'BX089737,', 'LOC101927273,', 'LINC01029,', 'LOC101928622,', 'HY157071,', 'DA902558,', 'RBFOX1', and, 'TINCR),', protein, modification, genes, '(', 'MANBA,', 'UBE2D3,', and, 'RANGAP1)', and, energy, production, genes, '(', 'XYLB,', 'MTRF1', and, 'ENOX1)', that, were, associated, with, both, conditions])].
[sujeto(['Streptozotocin-nicotinamide', experimental, model, was, used, to]), verbo([induce]), complemento([type, 2, diabetes])].
[sujeto(['The', gene, expression, of, 'MicroRNA-146a,']), verbo([nuclear]), complemento(['factor-κB', '(', 'NF-κB),', 'IRAK1', and, 'TRAF6,', as, well, as, 'NF-κB', 'activity,', 'IRAK1', and, 'TRAF6', protein, levels, were, measured])].
[sujeto(['The', expression, of, 'MicroRNA-146a', was]), verbo([increased]), complemento([in, the, heart, 'tissue,', 2, months, after, diabetes, induction, and, in, 'HUVECs'])].
[sujeto(['Also,', the, mRNA, and, protein, levels, of, 'NF-κB,', 'IRAK1', and, 'TRAF6', were]), verbo([increased]), complemento([in, the, heart, of, diabetic, rats])].
[sujeto(['Moreover,', transfection, of, 'miR-146a', mimic]), verbo([prevented]), complemento([from, a, significant, increase, of, 'NF-κB', activity, in, hyperglycemic, 'HUVECs'])].
[sujeto(['Presumably,', a, defect, in, the, regulation, of, 'IRAK1', and, 'TRAF6', can, weaken, 'miR-146a', regulatory, effect, and]), verbo([provides]), complemento([a, situation, for, sustained, activation, of, 'NF-κB', and, its, targets, to, promote, cardiac, cells, toward, abnormalities, '(', 'Fig'])].
[sujeto(['MicroRNAs']), verbo([have]), complemento([been, reported, to, play, an, important, role, in, the, invasion, and, metastasis, of, cervical, cancer])].
[sujeto(['miR-183', was]), verbo([found]), complemento([to, inhibit, or, promote, the, invasion, and, metastasis, of, multiple, solid, tumors])].
[sujeto(['We']), verbo([found]), complemento([that, 'miR-183', expression, levels, were, significantly, 'down-regulated', in, cervical, cancer, tissues, compared, with, normal, tissues, '(', 0.15, '±0'])].
[sujeto(['Bioinformatics', analysis, revealed, that, 'MMP-9', was, the, potential]), verbo([target]), complemento([of, 'miR-183', and, it, was, found, that, 'MMP-9', was, remarkably, 'up-regulated', in, cervical, cancer])].
[sujeto(['Furthermore,', a, 'dual-luciferase', reporter, assay, showed, that, 'MMP-9', as, a]), verbo([target]), complemento([of, 'miR-183', '(', 'p<0'])].
[sujeto(['The', invasion, and, metastasis, ability, of, siha, and, 'Hela', was]), verbo([suppressed]), complemento([when, 'MMP-9', was, 'down-regulated', in, vitro, '(', 'p<0'])].
[sujeto(['In', 'conclusion,', our, study, revealed, that, 'miR-183', might, be, a, tumor, suppressor, via]), verbo([inhibiting]), complemento([the, invasion, and, metastasis, of, cervical, cancer, cells, through, targeting, 'MMP-9,', indicating, that, 'miR-183', may, be, a, novel, potential, therapeutic, target, for, cervical, cancer])].
[sujeto(['Mutations', of, 'DLX3', are, closely]), verbo([associated]), complemento([with, 'Tricho-Dento-Osseous', '(', 'TDO)', syndrome, featured, with, increased, bone, formation])].
[sujeto(['However,', the, mechanism, regarding, whether, 'DLX3']), verbo([regulates]), complemento([osteoclastogenesis, remains, largely, unknown])].
[sujeto(['In', this, 'study,', we, firstly, examined, the, expression, of, 'DLX3', mounting, during, osteoclastic, differentiation, 'process,', and, then, established, stably]), verbo([expressing]), complemento([wild, type, 'DLX3', '(', 'WT-DLX3),', a, novel, mutant, 'DLX3', '(', 'Q178R)', found, in, our, laboratory, recently, '(', 'MT-DLX3)', and, 'Dlx3', knockdown, cell, lines, '(', 'Dlx3-shRNA)', in, 'Raw', 264.7, cells, using, corresponding, lentiviruses])].
[sujeto(['Our', results, indicate, that, 'DLX3', negatively]), verbo([regulates]), complemento([osteoclastic, differentiation, through, 'microRNA-124,', which, is, partially, responsible, for, the, increased, bone, density, in, 'TDO', patient])].
[sujeto(['DLX3', may, be, exploited, for, osteoclastogenesis, regulator, and, potential, therapeutic]), verbo([target]), complemento([of, osteoporosis, in, future])].
[sujeto(['PD']), verbo([has]), complemento([both, genetic, and, environmental, risk, 'factors,', and, while, processes, leading, to, aberrant, protein, aggregation, are, 'unknown,', past, work, points, to, abnormal, levels, of, 'SNCA', and, other, proteins])].
[sujeto(['Although', several, 'genome-wide', studies]), verbo([have]), complemento([been, performed, for, 'PD,', these, have, focused, on, 'DNA', sequence, variants, by, 'genome-wide', association, studies, '(', 'GWAS)', and, on, 'RNA', levels, '(', microarray, 'transcriptomics),', while, 'genome-wide', proteomics, analysis, has, been, lacking])].
[sujeto(['We']), verbo([report]), complemento([the, largest, analysis, of, proteomics, in, 'PD', to, 'date,', and, the, first, to, combine, this, technology, with, 'RNA-sequencing', to, investigate, 'GWAS', implicated, loci])].
[sujeto(['Notably,', differentially]), verbo([expressed]), complemento(['protein-coding', genes, were, more, likely, to, not, be, characterized, in, the, proteomics, 'analysis,', which, lessens, the, ability, to, compare, across, platforms])].
[sujeto(['A', complementary, 'DNA', '(', 'cDNA)', that, encodes, the, vitellogenin, receptor, '(', 'VgR)', in, the, oriental, river, 'prawn,', 'Macrobrachium', 'nipponense,', was, cloned, using]), verbo([expressed]), complemento([sequence, tag, analysis, and, a, rapid, amplification, of, cDNA, ends, approach])].
[sujeto([nipponense, 'VgR', cDNA, had, typically]), verbo([conserved]), complemento(['domains,', such, as, an, 'extracellular,', 'lipoprotein-binding', 'domain,', epidermal, growth, 'factor-like', and, 'O-glycosylation', 'domains,', a, transmembrane, domain, and, a, short, 'C-terminal,', cytosolic, tail])].
[sujeto(['Quantitative', 'real-time', 'PCR', '(', 'qPCR)', indicated, that, 'Mn-VgR', is, highly]), verbo([expressed]), complemento([in, the, female, ovary])].
[sujeto(['As', the, ovaries, 'developed,', the, expression, level, of, 'Mn-VgR', gradually]), verbo([increased]), complemento([during, the, reproductive, cycle, '(', stage, 'I),', to, reach, a, peak, in, stage, 'III'])].
[sujeto(['Eyestalk', ablation]), verbo([led]), complemento([to, a, significant, increase, in, the, expression, of, 'Mn-VgR', during, the, ovarian, development, stages, '(', 'P<0'])].
[sujeto(['In', 'addition,', 'Mn-VgR', 'RNAi']), verbo([led]), complemento([to, vitellin, depletion, in, the, oocytes, and, the, accumulation, of, vitellin, in, the, hepatopancreas])].
[sujeto(['Exercise', training]), verbo([has]), complemento([been, used, as, a, remarkable, strategy, in, the, treatment, of, heart, disease])].
[sujeto(['The', 'microRNA-1,', which]), verbo([targets]), complemento(['sodium/calcium', exchanger, 1, '(', 'NCX),', and, 'microRNA-214,', which, targets, sarcoplasmic, reticulum, calcium, 'ATPase-2a', '(', 'Serca2a),', are, involved, in, cardiac, function, regulation])].
[sujeto(['MicroRNA-1', and, -, 214, expressions, 'were,', 'respectively,']), verbo([decreased]), complemento(['(', 52, '%', ')', and, increased, '(', 54, '%', ')', in, the, 'S-INF', compared, to, the, 'S-SHAM,', while, exercise, training, normalized, the, expression, of, these, microRNAs])].
[sujeto(['The', microRNA]), verbo([targets]), complemento(['NCX', and, 'Serca-2a', protein, expression, 'were,', 'respectively,', decreased, '(', 55, '%', ')', and, increased, '(', 34, '%', ')', in, the, 'T-INF', group, compared, to, the, 'S-INF', group])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, exercise, training, restores, 'microRNA-1', and, -, 214, expression, levels, and, prevents, change, in, both, 'NCX', and, 'Serca-2a', protein, and, gene, expressions])].
[sujeto(['Altogether,', our, data]), verbo([suggest]), complemento([a, molecular, mechanism, to, restore, ventricular, function, after, exercise, training, in, myocardial, infarction, rats])].
[sujeto(['Many']), verbo([transcribed]), complemento(['RNAs', are, 'non-coding', 'RNAs,', including, microRNAs, '(', 'miRNAs),', which, bind, to, complementary, sequences, on, messenger, 'RNAs', to, regulate, the, translation, efficacy])].
[sujeto(['Therefore,', identifying, the, miRNAs]), verbo([expressed]), complemento([in, 'cells/organisms', aids, in, understanding, genetic, control, in, 'cells/organisms'])].
[sujeto(['In', this, 'report,', we, determined, the]), verbo([binding]), complemento([of, oligonucleotides, to, a, 'receptor-modified', silicon, nanowire, 'field-effect', transistor, '(', 'SiNW-FET)', by, monitoring, the, changes, in, conductance, of, the, 'SiNW-FET'])].
[sujeto(['This', 'SiNW-FET', device]), verbo([has]), complemento([7, -, fold, higher, sensitivity, than, reverse, 'transcription-quantitative', polymerase, chain, reaction, in, detecting, the, corresponding, miRNA])].
[sujeto(['Next,', we, anchored, viral, p19, 'proteins,', which]), verbo([bind]), complemento([the, 'double-strand', small, 'RNAs', '(', 'ds-sRNAs),', on, the, 'SiNW-FET'])].
[sujeto(['Finally,', this, bionanoelectronic, 'SiNW-FET,', which, is, able, to, isolate, and, identify, the]), verbo([interacting]), complemento(['protein-RNA,', adds, an, additional, tool, in, genomic, technology, for, the, future, study, of, direct, biomolecular, interactions])].
[sujeto([freudenreichii, 'DSM', 20271, '(', 'T)', is, the, type, strain, of, species, 'Propionibacterium', freudenreichii, that]), verbo([has]), complemento([a, long, history, of, safe, use, in, the, production, dairy, products, and, 'B12', vitamin])].
[sujeto(['Paulownia', 'witches\'', broom, '(', 'PaWB)']), verbo([caused]), complemento([by, a, 'phytoplasma,', has, caused, extensive, losses, in, the, yields, of, paulownia, timber, and, resulted, in, significant, economic, losses])].
[sujeto(['In', 'total,', 125]), verbo([conserved]), complemento([and, 118, novel, microRNAs, '(', 'miRNAs)', were, identified, and, 33, miRNAs, responsive, to, 'PaWB', disease, were, discovered])].
[sujeto(['Furthermore,', 166]), verbo([target]), complemento([genes, for, 18, 'PaWB', 'disease-related', miRNAs, were, 'obtained,', and, found, to, be, involved, in, 'plant-pathogen', interaction, and, plant, hormone, signal, transduction, metabolic, pathways])].
[sujeto(['Eleven', miRNAs, and]), verbo([target]), complemento([genes, responsive, to, 'PaWB', disease, were, examined, by, a, quantitative, 'real-time', 'PCR', approach])].
[sujeto(['Our', findings, will, contribute, to, studies, on, miRNAs, and, their]), verbo([targets]), complemento([in, 'Paulownia,', and, provide, new, insights, to, further, understand, 'plant-phytoplasma', interactions])].
[sujeto(['A', role, of, 'Wnt', signaling, in, 'Dupuytren', 'disease,', a, fibroproliferative, disease, of, the, hand, and, 'fingers,']), verbo([has]), complemento([not, been, fully, elucidated])].
[sujeto(['We', examined, a, large, set, of, 'Wnt', pathway, components, and, signaling]), verbo([targets]), complemento([and, found, significant, dysregulation, of, 41, 'Wnt-related', genes, in, tissue, from, the, 'Dupuytren', nodules, compared, with, 'patient-matched', control, tissue])].
[sujeto(['However,', both, canonical, 'Wnt']), verbo([targets]), complemento([and, components, of, the, noncanonical, signaling, pathway, were, upregulated])].
[sujeto(['Immunohistochemical', analysis, revealed, that, protein, expression, of, 'Wnt1-inducible', secreted, protein, 1, '(', 'WISP1),', a, known, 'Wnt', 'target,', was]), verbo([increased]), complemento([in, nodules, compared, with, control, 'tissue,', but, knockdown, of, 'WISP1', using, small, interfering, 'RNA', '(', 'siRNA)', in, the, 'Dupuytren', myofibroblasts, did, not, confirm, a, functional, role])].
[sujeto(['The', protein, expression, of, noncanonical, pathway, components, 'Wnt5A', and, 'VANGL2', as, well, as, noncanonical, coreceptors, 'Ror2', and, 'Ryk', was]), verbo([increased]), complemento([in, nodules])].
[sujeto(['Downregulation', of, these, genes, in, the, 'Dupuytren', tissue, was, mimicked, in, vitro, by, treating, normal, fibroblasts, with, transforming, growth, factor, β1, '(', 'TGF-β1),']), verbo([suggesting]), complemento([cross, talk, between, different, profibrotic, pathways])].
[sujeto(['Furthermore,', 'siRNA-mediated', knockdown, of, these, antagonists, in, normal, fibroblasts]), verbo([led]), complemento([to, increased, nuclear, translocation, of, 'Wnt', target, 'β-catenin', in, response, to, 'TGF-β1', treatment])].
[sujeto(['In', 'conclusion,', we]), verbo([have]), complemento([shown, extensive, dysregulation, of, 'Wnt', signaling, in, affected, tissue, from, 'Dupuytren', disease, patients])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, 'Ring', finger, protein, 166, '(', 'RNF166)', potentiates, 'RNA', 'virus-triggered', 'IFN-β', production])].
[sujeto(['Overexpression', of, 'RNF166', rather, than, its, homologous, proteins, 'RNF114,', 'RNF125,', and, 'RNF138,']), verbo([enhanced]), complemento(['Sendai', virus, '(', 'SeV)-induced', activation, of, the, 'IFN-β', promoter])].
[sujeto(['Knockdown', of, endogenous, 'RNF166,', but, not, other, 'RNFs,']), verbo([inhibited]), complemento([the, 'IFN-β', production, induced, by, 'SeV', and, encephalomyocarditis, virus])].
[sujeto(['RNF166']), verbo([interacted]), complemento([with, 'TRAF3', and, 'TRAF6'])].
[sujeto(['SeV-induced', ubiquitination, of, 'TRAF3', and, 'TRAF6', was]), verbo([suppressed]), complemento([when, endogenous, 'RNF166', rather, than, 'RNF114/138', was, knocked, down])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'RNF166', positively, regulates, 'RNA', 'virus-triggered', 'IFN-β', production, by, enhancing, the, ubiquitination, of, 'TRAF3', and, 'TRAF6'])].
[sujeto(['Increasing']), verbo([reports]), complemento([suggest, that, deregulated, microRNAs, '(', 'miRNAs)', might, provide, novel, therapeutic, targets, for, cancers])].
[sujeto(['Our', result]), verbo([suggested]), complemento([that, 'miR-26aexpression', level, in, osteosarcoma, bone, tissue, was, significantly, lower, than, that, in, the, paired, noncancerous, bone, tissues])].
[sujeto(['The', results, indicated, that, low, expression, level, of, 'miR-26a', and, high, expression, of, 'miR-27a', were]), verbo([associated]), complemento([with, high, 'TNM', stage, '(', 'P', =, 0.001, ;, 'P', =, 0.012, ')', ',', tumor, grade, '(', 'P', =, 0.007, ;, 'P', =, 0.016, ')', ',', and, distant, metastasis, '(', 'P', =, 0.004, ;, 'P', =, 0.001, ')'])].
[sujeto(['In', 'conclusion,', our, findings]), verbo([suggested]), complemento([that, expression, level, of, 'miR-26a', and, 'miR-27a', contributes, to, aggressive, progression, of, this, malignancy])].
[sujeto(['Therefore,', may]), verbo([have]), complemento([clinical, potentials, as, a, 'non-invasive', 'diagnostic/prognostic', biomarker, for, osteosarcoma, patients])].
[sujeto(['Xylary', element, and, fibers, develop, secondary, cell, walls, '(', 'SCWs)', that]), verbo([provide]), complemento([mechanical, strength, to, support, plant, growth, and, to, transport, water, and, minerals, to, all, above, ground, organs])].
[sujeto(['Despite', their, 'abundance,', unspliced, 'EST', data]), verbo([have]), complemento([received, little, attention, as, a, source, of, information, on, 'non-coding', 'RNAs'])].
[sujeto(['In', 'particular,', their, evolution]), verbo([has]), complemento([remained, virtually, unstudied])].
[sujeto(['Fifteen', to, twenty, percent, of, the, unspliced, 'EST', cluster, are]), verbo([conserved]), complemento([between, human, and, mouse])].
[sujeto(['Their', analysis, is, complicated, by, their, preferential, association, with, complex]), verbo([transcribed]), complemento([loci, that, usually, also, harbor, a, plethora, of, spliced, transcripts])].
[sujeto(['Unspliced', 'EST', 'data,', although, typically, disregarded, in, transcriptome, 'analysis,', can, be, used, to]), verbo([gain]), complemento([insights, into, this, rarely, investigated, transcriptome, component])].
[sujeto(['The', frequently, postulated, connection, between, lack, of, splicing, and]), verbo([nuclear]), complemento([retention, and, the, surprising, overlap, of, 'chromatin-associated', transcripts, suggests, that, this, class, of, transcripts, might, be, involved, in, chromatin, organization, and, possibly, other, mechanisms, of, epigenetic, control])].
[sujeto(['During', 'X-inactivation,', 'Xist', accumulates, in, cis, on, the, future, inactive, 'X', 'chromosome,']), verbo([triggering]), complemento([a, cascade, of, events, that, provoke, the, stable, silencing, of, the, entire, 'chromosome,', with, relatively, few, genes, remaining, active])].
[sujeto(['How', 'Xist', 'spreads,', what, are, its]), verbo([binding]), complemento(['sites,', how, it, recruits, silencing, factors, and, how, it, induces, a, specific, topological, and, nuclear, organization, of, the, chromatin, all, remain, largely, unanswered, questions])].
[sujeto(['Recent', studies]), verbo([have]), complemento([improved, our, understanding, of, 'Xist', localization, and, the, proteins, with, which, it, 'interacts,', allowing, a, reappraisal, of, ideas, about, 'Xist', function])].
[sujeto(['We', discuss, recent, advances, in, our, knowledge, of, 'Xist-mediated', 'silencing,', focusing, on, 'Xist', 'spreading,', the]), verbo([nuclear]), complemento([organization, of, the, inactive, 'X', 'chromosome,', recruitment, of, the, polycomb, complex, and, the, role, of, the, nuclear, matrix, in, the, process, of, 'X', chromosome, inactivation])].
[sujeto(['We', previously, devised, a, cucumber, mosaic, virus, '(', 'CMV)-based', vector, system, carrying, microRNA]), verbo([target]), complemento([mimic, sequences, for, analysis, of, microRNA, function, in, 'Arabidopsis', thaliana])].
[sujeto(['We', describe, an, improved, version, in, which]), verbo([target]), complemento([mimic, cloning, is, achieved, by, annealing, two, 'partly-overlapping', complementary, 'DNA', oligonucleotides, for, insertion, into, an, infectious, clone, of, 'CMV', 'RNA3', '(', 'LS', 'strain)', fused, to, the, cauliflower, mosaic, 'virus-derived', 35, 'S', promoter])].
[sujeto(['The', utility, of, using, agroinfection, to, deliver, 'LS-CMV-derived', microRNA]), verbo([target]), complemento([mimic, sequences, was, demonstrated, using, a, 'miR165/166', target, mimic, and, three, solanaceous, 'hosts:', 'Nicotiana', 'benthamiana,', tobacco, '(', 'N'])].
[sujeto(['In', all, three, hosts, the, 'miR165/166']), verbo([target]), complemento([mimic, induced, marked, changes, in, developmental, phenotype])].
[sujeto(['Inhibition', of, miRNA, accumulation, and]), verbo([increased]), complemento([target, mRNA, '(', 'HD-ZIP', 'III)', accumulation, was, demonstrated, in, tomato])].
[sujeto(['Thus,', a, 'CMV-derived']), verbo([target]), complemento([mimic, delivered, via, agroinfection, is, a, 'simple,', cheap, and, powerful, means, of, launching, 'virus-based', miRNA, mimics, and, is, likely, to, be, useful, for, 'high-throughput', investigation, of, miRNA, function, in, a, wide, range, of, plants])].
[sujeto(['Through', an, intricate, intracellular, signaling, 'systems,', the, transcriptome]), verbo([regulates]), complemento([the, pharmacological, response, of, the, cells])].
[sujeto(['Although', studies]), verbo([have]), complemento([elucidated, the, impact, of, glucocorticoids, '(', 'GCs)', 'cell-specific', gene, expression, 'signatures,', it, remains, necessary, to, comprehensively, characterize, the, impact, of, lncRNAs, to, transcriptional, changes])].
[sujeto(['The', 'Gene', 'Ontology', '(', 'GO)', analysis, was, performed, with, 'Molecular', 'Annotation', 'System']), verbo([provided]), complemento([by, 'CapitalBio', 'Corporation'])].
[sujeto(['Elucidation', of, differential, gene, expression, emphasizes, the, importance, of, regulatory, gene, networks]), verbo([induced]), complemento([by, 'GCs'])].
[sujeto(['We', identified, 73, 'up-regulated', and, 166, 'down-regulated', long, noncoding, 'RNAs,', the, expression, of, 107, of, which, significantly, correlated, with, 172, mRNAs]), verbo([induced]), complemento([by, hydrocortisone])].
[sujeto(['Transcriptome', analysis, of, 'BMECs', from, human, samples, was, performed, to, identify, specific, gene, networks]), verbo([induced]), complemento([by, 'GCs'])].
[sujeto(['The', crosstalk, between, microRNAs, '(', 'miRNAs)', and, other, epigenetic, factors, may]), verbo([lead]), complemento([to, novel, hypotheses, about, carcinogenesis, identifying, new, targets, for, research])].
[sujeto(['Because', a, single, miRNA, can]), verbo([regulate]), complemento([multiple, downstream, target, 'genes,', its, altered, expression, may, potentially, be, a, sensitive, biomarker, to, detect, early, malignant, transformation, and, improve, diagnosis, and, prognosis])].
[sujeto(['In', the, current, 'study,', we, tested, the, hypothesis, that, altered, methylation, of, miRNA, encoding, 'genes,']), verbo([associated]), complemento([with, deregulated, mature, miRNA, 'expression,', may, be, related, to, dietary, and, lifestyle, factors, and, may, contribute, to, cancer, development])].
[sujeto(['No', significant, associations, were]), verbo([found]), complemento([with, 'CRC'])].
[sujeto(['Emerging', evidence, demonstrates, that, microRNAs, '(', 'miRNAs)']), verbo([regulate]), complemento([the, expression, of, 'pain-relevant', 'genes,', yet, little, is, known, about, their, role, in, chronic, pain])].
[sujeto(['VBD + IBS', subjects]), verbo([reported]), complemento([decreased, health, and, 'function;', and, an, increase, in, 'headaches,', 'somatization,', and, remote, bodily, pain])].
[sujeto(['Furthermore,', 'VBD', subjects, exhibited, a, balance, in, proinflammatory, and, 'anti-inflammatory', 'cytokines,', whereas, 'VBD + IBS', subjects, failed, to, exhibit, a, compensatory]), verbo([increase]), complemento([in, 'anti-inflammatory', cytokines])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, miRNAs, represent, a, valuable, tool, for, differentiating, 'VBD', subtypes, '(', localized, pain, with, apparent, peripheral, neurosensory, disruption, vs, widespread, pain, with, a, central, sensory, 'contribution)', that, may, require, different, treatment, approaches])].
[sujeto(['Northern', analysis]), verbo([found]), complemento([no, transcripts, expressed, in, liver, or, any, of, the, 12, brain, regions, analyzed])].
[sujeto(['Inflammatory', response, and, oxidative, stress, play, dominant, roles, in, the, pathological, mechanism, of, 'COPD,', and]), verbo([have]), complemento([been, regarded, to, be, two, important, targets, for, the, 'COPD', therapy])].
[sujeto(['Traditional', 'Chinese', medicines, '(', 'TCMs)', possess, satisfying, curative, effects, on, 'COPD', under, guidance, of, the, 'TCM', theory, in, 'China,', and, merit, 'in-depth', investigations, as, a, resource, of]), verbo([lead]), complemento([compounds])].
[sujeto(['Our', investigation, observed, that, 38, of, the, tested, 'TCM', extracts]), verbo([induced]), complemento(['QR', activity, in, hepa, 1, c1c7, murine, hepatoma, 'cells,', and, 55, of, them, inhibited, 'NO', production, in, 'RAW', 264.7, murine, macrophages, at, the, tested, concentrations])].
[sujeto(['Noteworthily,', 20, of, 'TCM', extracts, simultaneously]), verbo([inhibited]), complemento([oxidative, stress, and, inflammatory, responses])].
[sujeto(['More', 'importantly,', the, results, of, the, present, research, afford, us, an, opportunity, to, discover, new]), verbo([lead]), complemento([molecules, as, 'COPD', therapeutic, agents, from, these, active, 'TCMs'])].
[sujeto(['An', arsenal, of, effector, proteins, is, injected, by, bacterial, pathogens, into, the, host, cell, or, its, vicinity, to]), verbo([increase]), complemento([virulence])].
[sujeto(['The', commonly, used, 'top-down', approaches, inferring, the, toxic, mechanism, of, individual, effector, proteins, from, the, 'host\'s', phenotype, are, often, impeded, by, multiple]), verbo([targets]), complemento([of, different, effectors, as, well, as, by, their, pleiotropic, effects])].
[sujeto(['Here', we, describe, our, 'bottom-up', 'approach,', showing, that, the, bacterial, type, 'III', effector, 'AvrRxo1', of, plant, pathogens, is, an, authentic, phosphotransferase, that, produces, two, novel, metabolites, by]), verbo([phosphorylating]), complemento([nicotinamide, /, nicotinic, acid, adenine, dinucleotide, at, the, adenosine, 3, '\'', -, hydroxyl, group])].
[sujeto(['Interestingly,', 3, '\'', -, 'NADP', and, 3, '\'', -, 'NAADP']), verbo([have]), complemento([previously, been, used, as, inhibitors, or, signaling, molecules, but, were, regarded, as, &, 'quot;artificial"', compounds, so, far])].
[sujeto(['Our', findings, now, necessitate, a, shift, in, thinking, about, the, biological, importance, of, 3, '\'', -]), verbo([phosphorylated]), complemento(['NAD', derivatives])].
[sujeto(['SimC7', is, a, polyketide, ketoreductase]), verbo([involved]), complemento([in, biosynthesis, of, the, angucyclinone, moiety, of, the, gyrase, inhibitor, simocyclinone, 'D8', '(', 'SD8)'])].
[sujeto(['SimC7', shares, little, sequence, similarity, with, characterized, 'ketoreductases,']), verbo([suggesting]), complemento([it, might, have, a, distinct, mechanism])].
[sujeto(['These', structures, show, that, 'SimC7', is, distinct, from, previously, characterized, polyketide, 'ketoreductases,', lacking, the]), verbo([conserved]), complemento([catalytic, 'triad,', including, the, 'active-site', tyrosine, that, acts, as, central, 'acid-base', catalyst, in, canonical, 'SDR', proteins])].
[sujeto(['Taken', together, with, functional, analyses, of, 'active-site', 'mutants,', our, data]), verbo([suggest]), complemento([that, 'SimC7', catalyzes, a, 'substrate-assisted,', 'two-step', reaction, for, reduction, of, the, 'C-7', carbonyl, group, involving, intramolecular, transfer, of, a, 'substrate-derived', proton, to, generate, a, phenolate, intermediate])].
[sujeto(['The', delayed, flowering, phenotype]), verbo([caused]), complemento([by, nitrogen, '(', 'N)', fertilizer, application, has, been, known, for, a, long, 'time,', but, we, know, little, about, the, specific, molecular, mechanism, for, this, phenomenon, before])].
[sujeto(['Our', study, indicated, that, low, nitrogen]), verbo([increases]), complemento([the, 'NADPH/NADP(+)', and, 'ATP/AMP', ratios, which, affect, adenosine, 'monophosphate-activated', protein, kinase, '(', 'AMPK)', activity, and, phosphorylation, and, abundance, of, nuclear, 'CRY1', protein])].
[sujeto(['Then', 'CRY1']), verbo([acts]), complemento([in, the, 'N', signal, input, pathway, to, the, circadian, clock])].
[sujeto(['Whereas', leaf, 'FNR', '(', 'LFNR)', is]), verbo([required]), complemento([for, 'photosynthesis,', root, 'FNR', '(', 'RFNR)', is, believed, to, provide, electrons, to, ferredoxin, '(', 'Fd)-dependent', 'enzymes,', including, nitrite, reductase, '(', 'NiR)', and, 'Fd-glutamine-oxoglutarate', aminotransferase, '(', 'Fd-GOGAT)', in, 'non-photosynthetic', conditions])].
[sujeto(['Therefore,', 'RFNR', might]), verbo([have]), complemento([a, limited, impact, on, 'N', assimilation, in, roots, grown, with, nitrate, or, ammonium, nitrogen, sources])].
[sujeto(['AtRFNRs', are, rapidly]), verbo([induced]), complemento([by, application, of, toxic, nitrite])].
[sujeto([thaliana, seedlings, of, wild, type, with, 'loss-of-function', mutants, of, 'RFNR2', 'When', these, seedlings, were, grown, under, 'nitrate,', nitrite, or, 'ammonium,', only, nitrite, nutrition]), verbo([caused]), complemento([impaired, growth, and, nitrite, accumulation, in, roots, of, rfnr2, 'Supplementation', of, nitrite, with, nitrate, or, ammonium, as, 'N', sources, did, not, restore, the, root, growth, in, rfnr2, 'Also,', a, scavenger, for, nitric, oxide, '(', 'NO)', could, not, effectively, rescue, the, growth, impairment])].
[sujeto(['Thus,', nitrite, 'toxicity,', rather, than, 'N', depletion, or, 'nitrite-dependent', 'NO', 'production,', probably]), verbo([causes]), complemento([the, rfnr2, root, growth, defect])].
[sujeto(['Our', results, strongly]), verbo([suggest]), complemento([that, 'RFNR2', has, a, major, role, in, reduction, of, toxic, nitrite, in, roots])].
[sujeto(['A', specific, set, of, genes, related, to, nitrite, reduction, and, the, supply, of, reducing, power]), verbo([responded]), complemento([to, nitrite, 'concomitantly,', suggesting, that, the, products, of, these, genes, act, cooperatively, with, 'RFNR2', to, reduce, nitrite, in, roots])].
[sujeto(['Surprisingly,', these, experiments]), verbo([reveal]), complemento([differences, in, the, low, field, relaxation, profiles, for, the, monophosphate, of, 'GMP', compared, to, 'IMP', in, their, respective, 'NADP(+)', complexes])].
[sujeto(['The', relaxation, profiles, indicate, that, the, substrate, monophosphates]), verbo([have]), complemento([distinct, interactions, in, 'E·IMP·NADP(+)', and, 'E·GMP·NADP(+)', complexes])].
[sujeto(['In', 'addition,', these, experiments, indicate, that, the, cofactor]), verbo([has]), complemento([more, internal, motion, when, bound, with, 'GMP'])].
[sujeto(['Lastly,', the, motions, of, the, substrate, and, cofactor, are, coordinately, 'regulated:', the, cofactor]), verbo([has]), complemento([faster, local, motions, than, 'GMP', in, the, deamination, complex, but, is, more, constrained, than, 'IMP', in, the, complex, leading, to, hydride, transfer])].
[sujeto(['These', results, show, that, field, cycling, can, be, used, to, investigate, the, dynamics, of, 'protein-bound', ligands, and]), verbo([provide]), complemento([new, insights, into, how, portions, of, the, substrate, remote, from, the, site, of, chemical, transformation, promote, catalysis])].
[sujeto([cereus, cells, was, observed, by, both, atomic, force, microscopy, and, transmission, electron, 'microscopy,', and, quantitative, proteomic, analysis, was, performed, on, proteins, extracted, from, treated, and, untreated, bacterial, cells, by, using, isobaric, tag, for, relative, and, absolute, quantitation, '(', 'iTRAQ)', labeling, and, 'LC-MS/MS', analysis, to, access, differentially]), verbo([expressed]), complemento([proteins])].
[sujeto(['Furthermore,', multiple, experiments, were, conducted, to, validate, the, results, of, the, proteomic, 'analysis,', including, determinations, of, 'ATP,', 'NAD((+))H,', 'NADP((+))H,', reactive, oxygen, species, '(', 'ROS),', the, activities, of, catalase, '(', 'CAT)', and, superoxide, dismutase, '(', 'SOD),', and, the, relative, expression, of]), verbo([target]), complemento([genes, by, quantitative, 'real-time', 'PCR'])].
[sujeto(['Bacterial', cells, exposed, to, 'AMP-jsa9', showed, irregular, surfaces, with, bleb, projections, and, 'concaves;', we, hypothesize, that, 'AMP-jsa9', penetrated, the, cell, wall, and, was, anchored, on, the, cytoplasmic, membrane, and, that, 'ROS', accumulated, in, the, cell, membrane, after, treatment, with, 'AMP-jsa9,']), verbo([modulating]), complemento([the, bacterial, membrane, properties, and, increasing, membrane, permeability])].
[sujeto(['iTRAQ-based', proteomic, analysis, detected, a, total, of, 1317, 'proteins,', including, 176, differentially]), verbo([expressed]), complemento([proteins, '(', 75, upregulated, '(', fold, &, 'gt;2)', and, 101, downregulated, '(', fold, &, 'lt;0'])].
[sujeto(['These', results, are, helpful, in, understanding, the, mechanism, of, 'LI-F', type, peptides, and, in]), verbo([providing]), complemento([the, theoretical, base, for, applying, 'AMP-jsa9', or, its, analogs, to, combat, 'Gram-positive', pathogenic, bacteria, in, the, food, and, feed, industries])].
[sujeto(['Thiazolinyl', imine, reductases, catalyze, the, 'NADPH-dependent', reduction, of, a, thiazoline, to, a, 'thiazolidine,', a]), verbo([required]), complemento([step, in, the, formation, of, the, siderophores, yersiniabactin, '(', 'Yersinia', spp])].
[sujeto(['Ligands', such, as, enzyme, inhibitors, stabilize, the, native, conformation, of, a, protein, upon]), verbo([binding]), complemento([to, the, native, 'state,', but, some, compounds, destabilize, the, native, conformation, upon, binding, to, the, 'non-native', state])].
[sujeto([&, 'quot;', 'Because', the, stabilization, effects, are, essential, for, the, medical, chaperone, 'hypothesis,', here, we]), verbo([have]), complemento([formulated, a, thermodynamic, system, consisting, of, a, ligand, and, a, protein, in, its, 'native-', and, 'non-native', state])].
[sujeto(['Using', the, differential, scanning, fluorimetry, and, the, circular, dichroism, varying, the, urea, concentration, and, 'temperature,', we]), verbo([found]), complemento([that, when, the, coenzyme, 'NADP(+)', was, 'absent,', inhibitors, such, as, isolithocholic, acid, stabilized, the, 'aldo-keto', reductase, 'AKR1A1', upon, 'binding,', which, showed, actually, the, three, state, 'folding,', but, destabilized, 'AKR1B10'])].
[sujeto(['Then', we]), verbo([found]), complemento([that, in, a, relatively, unstable, protein, showing, the, three, state, 'folding,', native, conformation, was, stabilized, by, the, negative, 'ΔΔH', in, association, with, the, negative, 'ΔΔS,', suggesting, that, the, stabilizer, chaperon, decreased, the, conformational, fluctuation, of, the, target, protein, or, increase, its, hydration])].
[sujeto(['These', findings, would]), verbo([promote]), complemento([the, development, of, screening, strategies, for, medical, chaperones, to, regulate, the, target, conformations])].
[sujeto([is, present, worldwide, in, treatment, wetlands, though, the, mechanisms]), verbo([involved]), complemento([in, the, phytoremediation, remain, unclear])].
[sujeto(['Adaptation', to, 'AO7']), verbo([involved]), complemento([proteins, related, with, cellular, signalling, '(', 'calreticulin,', 'Ras-related', protein, 'Rab11D', and, 20, 'S', 'proteasome),', energy, production, and, conversion, '(', adenosine, triphosphate, synthase, beta, 'subunit)', carbohydrate, transport, and, metabolism, '(', phosphoglucose, 'isomerase,', 'fructose-bisphosphate', 'aldolase,', monodehydroascorbate, 'reductase,', 'frutockinase-1', and, 'Hypothetical', protein, 'POPTR_0003s12000g', and, the, 'Uncharacterized', protein, 'LOC100272772)', and, photosynthesis, '(', 'sedoheptulose-1,7-bisphosphatase', and, 'ferredoxin-NADP(+)', 'reductase)'])].
[sujeto(['Therefore,', the, quantitative, proteomic, approach, used, in, this, work, indicates, that, mechanisms]), verbo([associated]), complemento([with, stress, cell, 'signalling,', energy, 'production,', carbohydrate, transport, and, metabolism, as, well, as, proteins, related, with, photosynthesis, are, key, players, in, the, initial, chemical, stress, response, in, the, phytoremediation, process, of, 'AO7'])].
[sujeto(['An', important]), verbo([cause]), complemento([of, 'PAH', in, children, with, congenital, heart, disease, '(', 'CHD)', is, increased, pulmonary, blood, flow, '(', 'PBF)'])].
[sujeto(['Consistent', with, 'PAH', in, 'adults,', 'PASMCs', derived, from, 4, -, week, old, lambs, exposed, to]), verbo([increased]), complemento(['PBF', '(', 'shunt)', exhibited, increased, rates, of, proliferation])].
[sujeto(['While', shunt, 'PASMCs', also, exhibited, significant]), verbo([decreases]), complemento([in, mitochondrial, oxygen, 'consumption,', membrane, 'potential,', and, 'TCA', cycle, 'function,', suggesting, a, switch, to, 'Warburg', metabolism, as, observed, in, advanced, 'PAH', in, 'adults,', they, unexpectedly, demonstrated, decreased, glycolytic, lactate, 'production,', likely, due, to, enhanced, flux, through, the, pentose, phosphate, pathway, '(', 'PPP)'])].
[sujeto(['This', may, be, a, response, to, the, marked]), verbo([increase]), complemento([in, 'NADPH', oxidase, '(', 'Nox)', activity, and, decreased, 'NADPH/NADP(+)', ratios, observed, in, shunt, 'PASMCs'])].
[sujeto(['Our', results, therefore, indicate, that, 'PASMC', 'hyper-proliferation', is, observed, early, in, the, setting, of, pulmonary, 'over-circulation', and, is, accompanied, by, a, unique, metabolic, profile, that, is, independent, of, 'HIF-1α,', 'PDHK1', or]), verbo([increased]), complemento([glycolytic, flux])].
[sujeto(['Our', results, also]), verbo([suggest]), complemento([that, 'Nox', inhibition, may, help, prevent, pulmonary, 'overcirculation-induced', 'PAH', in, children, born, with, 'CHD'])].
[sujeto(['NAD', is, a, 'well-known', 'co-enzyme', that]), verbo([mediates]), complemento([hundreds, of, redox, reactions, and, is, the, basis, of, various, processes, regulating, cell, responses, to, different, environmental, and, developmental, cues])].
[sujeto(['We', created, 'Arabidopsis', thaliana, plants, overexpressing, the, 'NAD', synthase, '(', 'NADS)', gene, that]), verbo([participates]), complemento([in, the, final, step, of, 'NAD', biosynthesis])].
[sujeto(['NADS', overexpression]), verbo([enhanced]), complemento([the, activity, of, 'NAD', biosynthesis, but, not, the, amounts, of, 'NAD(+),', 'NADH,', 'NADP(+),', or, 'NADPH'])].
[sujeto(['However,', the, amounts, of, some, intermediates, were, 'elevated,']), verbo([suggesting]), complemento([that, 'NAD', metabolism, increased])].
[sujeto(['Metabolite', profiling, and, transcriptional, analysis, revealed, that, the, drastic, modulation, of, 'NAD', redox, homeostasis]), verbo([increased]), complemento([tricarboxylic, acid, 'flux,', causing, the, ectopic, generation, of, reactive, oxygen, species])].
[sujeto(['Vascular', bundles, suffered, from, oxidative, 'stress,']), verbo([leading]), complemento([to, a, malfunction, in, amino, acid, and, organic, acid, transportation, that, caused, early, wilting, of, the, flower, stalk, and, shortened, plant, 'longevity,', probably, due, to, malnutrition])].
[sujeto(['We', concluded, that, the, mechanism]), verbo([regulating]), complemento([the, balance, between, 'NAD', synthesis, and, degradation, is, important, in, the, systemic, plant, response, to, developmental, cues, during, the, 'growth-phase', transition])].
[sujeto(['(', -, ')', -, 'Hydroxycitric', acid, '(', 'HCA)']), verbo([suppresses]), complemento([fatty, acid, synthesis, in, 'animals,', but, its, biochemical, mechanism, in, poultry, is, unclear])].
[sujeto(['This', study, identified, the, key, proteins]), verbo([associated]), complemento([with, fat, metabolism, and, elucidated, the, biochemical, mechanism, of, '(', -, ')', -, 'HCA', in, broiler, chickens])].
[sujeto(['Of', the, differentially]), verbo([expressed]), complemento([liver, 'proteins,', 40, and, 26, were, identified, in, the, mitochondrial, and, cytoplasm, respectively])].
[sujeto(['Biological', network, analysis, showed, that, the, identified, proteins, were]), verbo([involved]), complemento([in, glycometabolism, and, lipid, 'metabolism,', whereas, 'PDHA1,', 'PDHB,', 'ECHS1,', and, 'ME1', were, identified, in, the, canonical, pathway, by, 'Ingenuity', 'Pathway', 'Analysis'])].
[sujeto(['The', data, indicated, that, '(', -, ')', -, 'HCA']), verbo([inhibited]), complemento([fatty, acid, synthesis, by, reducing, the, 'acetyl-CoA', 'supply,', via, promotion, of, the, tricarboxylic, acid, cycle, '(', upregulation, of, 'PDHA1,', 'PDHB,', 'ACO2,', and, 'DLST', 'expression)', and, inhibition, of, 'ME1', expression])].
[sujeto(['Moreover,', '(', -, ')', -, 'HCA']), verbo([promoted]), complemento([fatty, acid, 'beta-oxidation', by, upregulating, 'ECHS1', expression])].
[sujeto(['Yet,', a, significant]), verbo([increase]), complemento([in, hydrogen, production, efficiency, is, necessary, for, industrial, 'scale-up'])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, a, major, challenge, to, be, resolved, is, the, inferior, competitiveness, of, 'HydA', with, 'NADPH', 'production,', catalyzed, by, 'ferredoxin-NADP(+)-reductase', '(', 'FNR)'])].
[sujeto(['In', this, 'work,', we, explored, the, in, vivo, hydrogen, production, efficiency, of, 'Fd-HydA,', where, the, electron, donor, ferredoxin, '(', 'Fd)', is, fused, to, 'HydA', and]), verbo([expressed]), complemento([in, the, model, organism, 'Chlamydomonas', reinhardtii])].
[sujeto(['We', show, that, once, the, 'Fd-HydA', fusion, gene, is]), verbo([expressed]), complemento([in, 'micro-algal', cells, of, 'C'])].
[sujeto(['We']), verbo([found]), complemento([that, 'Fd-HydA', has, a, '~4'])].
[sujeto(['Furthermore,', we]), verbo([provide]), complemento([evidence, suggesting, that, the, fusion, protein, is, more, resistant, to, oxygen, than, the, native, 'HydA'])].
[sujeto(['Therefore,', our, results]), verbo([provide]), complemento([a, solid, platform, for, further, engineering, efforts, towards, efficient, hydrogen, production, in, microalgae, through, the, expression, of, synthetic, enzymes])].
[sujeto(['The', demand, for, 'NADPH', is, particularly, high, in, proliferating, cancer, cells, where, it]), verbo([acts]), complemento([as, a, cofactor, for, the, synthesis, of, 'nucleotides,', proteins, and, fatty, acids])].
[sujeto(['Moreover,', 'NADPH', is, essential, for, the, neutralization, of, the, dangerously, high, levels, of, reactive, oxygen, species, '(', 'ROS)', generated, by]), verbo([increased]), complemento([metabolic, activity])].
[sujeto(['Given', its, key, role, in, metabolism, and, regulation, of, 'ROS,', it, is, not, surprising, that, several, recent, 'studies,', including, in, vitro, and, in, vivo, assays, of, tumor, growth, and, querying, of, patient, samples]), verbo([have]), complemento([identified, 'NADK', as, a, potential, therapeutic, target, for, the, treatment, of, cancer, 'In', this, 'review,', we, will, discuss, the, experimental, evidence, justifying, further, exploration, of, 'NADK', as, a, 'clinically-relevant', drug, 'target,', and, describe, our, studies, with, a, lead, 'compound,', thionicotinamide, '(', 'TN),', an, 'NADK', inhibitor, prodrug])].
[sujeto(['Luteolin']), verbo([has]), complemento([a, reputation, for, being, a, safe, and, effective, natural, antioxidant, that, has, strong, radical, scavenging, and, cell, protective, properties])].
[sujeto(['The', role, of, oxidative, stress, in, inflammatory, bowel, disease, '(', 'IBD)']), verbo([has]), complemento([been, well, established, and, is, increasingly, highlighted])].
[sujeto(['Experimental', acute, colitis, was]), verbo([induced]), complemento([by, administering, 3, '%', dextran, sulfate, sodium, '(', 'DSS)', in, the, drinking, water, of, mice, for, 7, days])].
[sujeto(['The', disease, activity, index, '(', 'DAI);', colon, 'length;', histological, 'assessment;', mRNA, levels, of]), verbo([nuclear]), complemento(['factor-erythroid', 2, -, related, factor, 2, '(', 'Nrf2),', tumor, necrosis, factor, '(', 'TNF-α),', 'interleukin-6', '(', 'IL-6),', heme, 'oxygenase-1', '(', 'HO-1),', and, 'NADP(H):', quinone, oxidoreductase, 1, '(', 'NQO-1);', protein, expression, of, 'Nrf2', and, inducible, nitric, oxide, synthase, '(', 'iNOS);', colon, malondialdehyde, '(', 'MDA)', 'levels;', and, the, activity, levels, of, colonic, superoxide, dismutase, '(', 'SOD)', and, catalase, '(', 'CAT)', were, examined])].
[sujeto(['In', 'addition,', luteolin, administration, effectively]), verbo([decreased]), complemento([the, expression, of, inflammatory, 'mediators,', such, as, 'iNOS,', 'TNF-α', and, 'IL-6'])].
[sujeto(['Luteolin', also]), verbo([decreased]), complemento([the, colonic, content, of, 'MDA'])].
[sujeto(['These', observations, indicate, that, luteolin, may]), verbo([suppress]), complemento([experimental, colitis, through, the, 'Nrf2', signaling, pathway])].
[sujeto(['The', urgent, need, for, major]), verbo([gains]), complemento([in, industrial, crops, productivity, and, in, biofuel, production, from, bioenergy, grasses, have, reinforced, attention, on, understanding, 'C4', photosynthesis])].
[sujeto(['Systems', biology, studies, of, 'C4', model, plants, may]), verbo([reveal]), complemento([important, features, of, 'C4', metabolism])].
[sujeto(['As', part, of, the, systems, 'approach,', we]), verbo([have]), complemento([developed, and, used, a, 'genome-scale', metabolic, reconstruction, in, combination, with, the, use, of, 'multi-omics', technologies, to, gain, more, insights, into, the, metabolism, of, 'S'])].
[sujeto(['Besides']), verbo([revealed]), complemento([similarities, and, differences, in, central, metabolism, of, mature, and, immature, 'tissues,', transcriptome, analysis, indicates, significant, gene, expression, of, two, malic, enzyme, isoforms, '(', 'NADP-', 'ME', and, 'NAD-ME)'])].
[sujeto(['Although', much, greater, expression, levels, of, 'NADP-ME', genes, are, observed, and, confirmed, by, the, correspondent, protein, abundances, in, the, 'samples,', the, expression, of, multiple, genes, combined, to, the, significant, abundance, of, metabolites, that]), verbo([participates]), complemento([in, 'C4', metabolism, of, 'NAD-ME', and, 'NADP-ME', subtypes, suggest, that, 'S'])].
[sujeto(['Altogether,', the, 'multi-omics', analysis]), verbo([reveals]), complemento([different, biological, entities, and, their, interrelation, and, regulation, over, plant, development])].
[sujeto(['Although', 'HD-Zip', transcription, factors]), verbo([have]), complemento([been, broadly, reported, to, be, involved, in, plant, resistance, to, abiotic, stresses, like, salt, and, 'drought,', their, roles, in, response, to, bicarbonate, stress, is, largely, unknown])].
[sujeto(['Our', result, of, 'qRT-PCR', showed, that, the, expression, of, 'Gshdz4', was]), verbo([induced]), complemento([by, alkaline, stress, '(', 'NaHCO3)', in, both, leaves, and, roots, of, wild, soybean])].
[sujeto(['Overexpression', of, 'Gshdz4', in, 'Arabidopsis', resulted, in]), verbo([enhanced]), complemento([tolerance, to, 'NaHCO3', and, 'KHCO3', during, the, process, of, plant, growth, and, development])].
[sujeto(['Moreover,', the, transcript, levels, of, 'stress-related', 'genes,', such, as, 'NADP-ME,', 'H', '(', +, ')', -, 'Ppase,', 'RD29B', and, 'KIN1', were]), verbo([increased]), complemento([with, greater, extent, in, the, transgenic, plants, than, the, wild, plants])].
[sujeto(['We', revealed, that, the, important, and, special, roles, of, 'Gshdz4', in]), verbo([enhancing]), complemento([bicarbonate, tolerance, and, responding, to, osmotic, stress])].
[sujeto(['All', the, evidences, broaden, our, understanding, of, functions, of, 'HD-Zip', family, and]), verbo([provide]), complemento([clues, for, uncovering, the, mechanisms, of, high, tolerance, of, wild, soybean, to, 'saline-alkaline', stresses])].
[sujeto(['A', synapomorphic, mutation, in, the, 'Altiarchaeales', tRNA, synthetase, β, 'subunit,', 'pheT,']), verbo([caused]), complemento([the, protein, to, be, encoded, as, two, subunits, at, 'non-adjacent', loci])].
[sujeto(['Phylogenies', based, on, 16, 'S', rRNA, genes, and, concatenated]), verbo([conserved]), complemento([proteins, identified, two, distinct, 'sub-clades', of, 'Altiarchaeales,', 'Alti-1', populated, by, organisms, from, actively, flowing, 'springs,', and, 'Alti-2', which, was, more, 'widespread,', 'diverse,', and, not, associated, with, visible, mats])].
[sujeto(['The', core, 'Alti-1', genome]), verbo([suggested]), complemento(['Alti-1', is, adapted, for, the, stream, environment, with, lipopolysaccharide, production, capacity, and, extracellular, hami, structures])].
[sujeto(['The', core, 'Alti-2', genome]), verbo([suggested]), complemento([members, of, this, clade, are, 'free-living', with, distinct, mechanisms, for, energy, 'maintenance,', 'motility,', 'osmoregulation,', and, sulfur, redox, reactions])].
[sujeto(['These', data]), verbo([suggested]), complemento([that, the, hamus, structures, found, in, 'Candidatus', 'Altiarchaeum', hamiconexum, are, not, present, outside, of, 'stream-adapted', 'Altiarchaeales'])].
[sujeto(['Homologs', to, a, 'Na(+)', transporter, and, membrane]), verbo([bound]), complemento([coenzyme, 'A', disulfide, reductase, that, were, unique, to, the, brackish, sediment, 'Alti-2', 'genomes,', could, indicate, adaptations, to, the, 'estuarine,', 'sulfur-rich', environment])].
[sujeto([provide, mechanistic, insight, into, this, phenomenon, by, characterizing, the, role, of, 'CCAT1-L,', a, colorectal, 'cancer-specific', 'lncRNA,', in, 'intra-chromosome', looping, between, the, 'MYC', gene, promoter, and, distal, upstream, enhancer, elements, that]), verbo([regulate]), complemento(['MYC', transcription])].
[sujeto(['As', a, 'result,', an]), verbo([increased]), complemento([endogenous, production, of, oxalate, leads, to, exessive, urinary, oxalate, excretion])].
[sujeto(['At', the, stage, of, severe, chronic, kidney, 'disease,', plasma, oxalate]), verbo([increase]), complemento([leads, to, a, systemic, oxalosis])].
[sujeto(['Early', initiation, of, conservative, treatment, including, high, fluid, intake, and, 'long-term', 'co-administration', of, inhibitors, of, calcium, oxalate, crystallization, and, 'pyridoxine,', could, efficiently]), verbo([prevent]), complemento([end, stage, renal, disease])].
[sujeto(['As', shown, by, 'Western', 'blot,', significant, 'up-regulation', of, 'GRHPR', was]), verbo([found]), complemento([in, 'TNBS-treated', mice, as, compared, with, normal, controls])].
[sujeto(['Immunohistochemistry', '(', 'IHC)', also, showed]), verbo([increased]), complemento(['GRHPR', 'expression,', and, the, molecule, was, located, in, intestinal, epithelial, cells, '(', 'IECs)'])].
[sujeto(['Furthermore,', 'knock-down', 'GRHPR', could]), verbo([inhibit]), complemento([the, accumulation, of, active, 'caspase-3', and, cleaved, 'PARP', as, shown, by, 'Western', blot, in, 'TNF-α', treated, 'HT-29', cells])].
[sujeto(['Flow', cytometry, assay, indicated, that, interference, of, 'GRHPR']), verbo([led]), complemento([to, increasing, apoptosis, of, 'IECs'])].
[sujeto(['These', data]), verbo([suggested]), complemento([that, 'GRHPR', might, exert, its, 'pro-apoptosis', function, in, 'IECs'])].
[sujeto(['Thus,', 'GRHPR', might, play, an, important, role, in]), verbo([regulating]), complemento(['IECs', 'apoptosis,', and, might, be, a, potential, therapeutic, target, for, 'CD'])].
[sujeto(['Fifteen', patients, referred, to, our, 'Centre', and, suspected, to]), verbo([have]), complemento(['PH', on, clinical, grounds, were, negative, for, pathogenic, variants, in, the, entire, coding, sequence, and, 'exon-intron', boundaries, of, the, 'AGXT', gene])].
[sujeto(['New', genetic, subtypes, of, 'PH', can, be, hypothesized, in, our, 'patients,', that, may, be]), verbo([caused]), complemento([by, mutations, in, other, gene, encoding, proteins, of, glyoxylate, metabolism])].
[sujeto(['Here,', we, investigated, the, enzyme]), verbo([involved]), complemento([in, leucate, synthesis, by, 'A'])].
[sujeto([oryzae, 'gene/cDNA', encoding, the, enzyme]), verbo([involved]), complemento([in, leucate, synthesis, was, identified, and, expressed, in, 'E'])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, strain, overexpressing, morA, would, help, to, ferment, 'high-quality', sake, with, an, excellent, flavor])].
[sujeto(['Corynebacterium', glutamicum, -, a, 'well-known', industrial, amino, acid, producer, -]), verbo([has]), complemento([recently, been, engineered, for, the, production, of, a, variety, of, new, products, including, 'diamines,', 'alcohols,', carotenoids, and, organic, acids])].
[sujeto(['A', transcriptome, analysis, of, cells, grown, in, the, presence, of, glycolate, or, potassium, chloride, revealed, nine, 'glycolate-specific', gene, expression, changes, including]), verbo([increased]), complemento([levels, of, a, putative, 'l-lactate', permease, gene, when, glycolate, was, present, in, medium])].
[sujeto(['Reducing', isocitrate, dehydrogenase, activity, by, replacing, the, translational, start, codon, '(', 'ATG', to, 'GTG)', further]), verbo([increased]), complemento([glycolate, titer, by, more, than, 30, '%'])].
[sujeto([1, 'g/L', glycolate, with, a, yield, of, 0.18, 'g/g', and, a, volumetric, productivity, of, about, 0.1, 'gL(-1)h(-1)', is, the, first]), verbo([report]), complemento([of, a, 'C'])].
[sujeto(['An', exception, is, that, mutants, of, peroxisomal, hydroxypyruvate, reductase, '(', 'HPR1)', do, not]), verbo([have]), complemento([this, 'phenotype,', indicating, the, presence, of, cytosolic, bypass, in, the, photorespiration, pathway])].
[sujeto(['These', findings, demonstrate, that, two, hydroxypyruvate, reductases, encoded, by, 'OsHPR1', and, 'OsHPR2', are]), verbo([involved]), complemento([in, photorespiratory, metabolism, in, rice])].
[sujeto(['Also,', we]), verbo([found]), complemento([that, the, c])].
[sujeto([864, '_865delTG', mutation, was]), verbo([associated]), complemento([with, the, rs35891798, 'single-nucleotide', polymorphism])].
[sujeto(['The', primary, sequence, of, cytosolic, 'AtGLYR1']), verbo([reveals]), complemento([several, sequence, elements, that, are, consistent, with, the, 'β-HAD', '(', 'β-hydroxyacid', 'dehydrogenase)', protein, 'family,', whose, members, include, 3, -, hydroxyisobutyrate, 'dehydrogenase,', tartronate, semialdehyde, reductase, and, 6, -, phosphogluconate, dehydrogenase])].
[sujeto(['Kinetic', studies, and]), verbo([binding]), complemento([assays, established, that, 'Lys170', is, essential, for, 'catalysis,', 'Phe231,', 'Asp239,', 'Ser121', and, 'Thr95', are, more, important, in, substrate, binding, than, in, 'catalysis,', and, 'Asn174', is, more, important, in, catalysis])].
[sujeto(['The', crystal, structure, of, 'AtGLYR1', in, the, absence, of, substrate, was, solved, to, 2.1, 'Å', by, molecular, replacement, using, a, previously, unrecognized, member, of, the, 'β-HAD', 'family,', 'cytokine-like']), verbo([nuclear]), complemento(['factor,', thereby, enabling, the, 3, -, 'D', structure, of, the, protein, to, be, modeled, with, substrate, and, 'co-factor'])].
[sujeto(['Structural', alignment, of, 'AtGLYR1', with, 'β-HAD', family, members]), verbo([provided]), complemento([support, for, the, essentiality, of, 'Lys170,', 'Phe173,', 'Asp239,', 'Ser121,', 'Asn174', and, 'Thr95', in, the, active, site, and, preliminary, support, for, an, 'acid/base', catalytic, mechanism, involving, 'Lys170', as, the, general, acid, and, a, conserved, 'active-site', water, molecule])].
[sujeto(['Although', different, aspects, of, hSVCT1, cell, biology]), verbo([have]), complemento([been, extensively, 'studied,', nothing, is, currently, known, about, the, broader, hSVCT1, interactome, that, modulates, its, role, in, cellular, physiology])].
[sujeto(['Here,', we, identify, the, enzyme, human, glyoxalate, 'reductase/hydroxypyruvate', reductase, '(', 'hGR/HPR)', as, an, hSVCT1]), verbo([associated]), complemento([protein, by, yeast, 'two-hybrid', '(', 'Y2H)', screening, of, a, human, liver, cDNA, library])].
[sujeto(['This', interaction, had, functional, significance, as, coexpression, of, 'hGR/HPR', with, hSVCT1]), verbo([led]), complemento([to, an, increase, in, 'AA', uptake])].
[sujeto(['Reciprocally,', 'siRNA-mediated', knockdown, of, endogenous, 'hGR/HPR']), verbo([led]), complemento([to, an, inhibition, of, 'AA', uptake])].
[sujeto(['Given', that, oxalate, is, a, degradation, product, of, vitamin, 'C', and, 'hGR/HPR']), verbo([acts]), complemento([to, limit, cellular, oxalate, 'levels,', this, association, physically, couples, two, independent, regulators, of, cellular, oxalate, production])].
[sujeto(['This']), verbo([provides]), complemento([a, possible, molecular, basis, for, organellar, 'AA', transport, and, regulation, of, local, 'glyoxylate/glycolate', concentration, in, the, vicinity, of, organelle, membranes])].
[sujeto(['Analysis', of, the, 'Cyanophora', genome]), verbo([provided]), complemento([clear, evidence, that, some, photorespiratory, enzymes, originally, acquired, from, cyanobacteria, were, 'lost,', e])].
[sujeto(['Generally,', our, analysis, supports, the, view, that, many, 'C2', cycle, enzymes, in, eukaryotic, phototrophs, were, obtained, from, the, cyanobacterial, 'endosymbiont,', but, during, the, subsequent, evolution, of, algae, and, land, plants, multiple]), verbo([losses]), complemento([and, replacements, 'occurred,', which, resulted, in, a, reticulate, provenance, of, photorespiratory, enzymes, with, different, origins, in, different, cellular, compartments])].
[sujeto(['Its', deficiency]), verbo([causes]), complemento([primary, hyperoxaluria, type, 2])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, the, 'GRHPR', defect, in, noncancerous, tissues, may, represent, an, independent, predictor, of, poor, survival, for, 'HCC', patients, after, curative, resection, and, that, there, may, be, a, link, between, 'GRHPR', and, prognosis, of, 'HCC', patients])].
[sujeto(['The', typical]), verbo([finding]), complemento([was, tubular, necrosis, with, extensive, oxalate, crystal, deposition])].
[sujeto([996, 'G>A)', that, changed, one]), verbo([conserved]), complemento([residue, '(', p])].
[sujeto(['This', preliminary, study]), verbo([reports]), complemento(['PH', as, a, cause, of, neonatal, death, in, 'Finnish', 'Coton', de, 'Tulear', and, suggests, that, genetic, testing, of, dogs, be, carried, out, before, breeding, to, prevent, the, birth, of, affected, offspring])].
[sujeto(['The']), verbo([increased]), complemento([oxalate, synthesis, that, occurs, can, lead, to, kidney, stone, 'formation,', deposition, of, calcium, oxalate, in, the, kidney, and, other, 'tissues,', and, renal, failure])].
[sujeto(['Plasma', cystatin, 'C', measurements, over, 4, -, wk, 'Hyp', feeding, indicated, no, significant]), verbo([loss]), complemento([of, renal, function, in, 'WT', and, 'AGXT', 'KO', 'animals,', and, significant, and, severe, loss, of, renal, function, in, 'GRHPR', 'KO', animals, after, 2, and, 4, 'wk,', respectively])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'GRHPR', activity, may, be, vital, in, the, kidney, for, limiting, the, conversion, of, 'Hyp-derived', glyoxylate, to, oxalate])].
[sujeto(['As', 'Hyp', catabolism, may, make, a, major, contribution, to, the, oxalate, produced, in, 'PH', 'patients,', 'Hyp', feeding, in, these, mouse, models, should, be, useful, in, understanding, the, mechanisms]), verbo([associated]), complemento([with, calcium, oxalate, deposition, in, the, kidney])].
[sujeto(['The', gene, for, the, 'PPR', '(', 'pprA)', was, cloned, and]), verbo([expressed]), complemento([in, 'Escherichia', coli, cells])].
[sujeto(['These', compounds, 'up-regulated', the, transcription, of, 'pprA,']), verbo([suggesting]), complemento([that, it, plays, a, role, in, fungal, phenylalanine, metabolism])].
[sujeto(['Primary', hyperoxaluria, type, 2, '(', 'PH2),']), verbo([caused]), complemento([by, deficiency, of, the, enzyme, glyoxylate, 'reductase/hydroxypyruvate', reductase, '(', 'GR/HPR),', is, characterized, by, recurrent, nephrolithiasis, '(', deposition, of, calcium, oxalate, in, the, renal, 'pelvis/urinary', 'tract),', nephrocalcinosis, '(', deposition, of, calcium, oxalate, in, the, renal, 'parenchyma),', and, 'end-stage', renal, disease, '(', 'ESRD)'])].
[sujeto(['Diagnosis', relies, on, detection, of]), verbo([increased]), complemento([urinary, excretion, of, oxalate, and, commonly, 'L-glycerate', '(', although, cases, without, 'L-glyceric', aciduria, have, been, 'reported),', and, either, assay, of, glyoxylate, reductase, '(', 'GR)', enzyme, activity, from, liver, biopsy, or, molecular, genetic, testing, of, 'GRHPR,', the, only, gene, known, to, be, associated, with, 'PH2'])].
[sujeto(['Ascorbate', '(', vitamin, 'C)', ingestion, and, foods, rich, in, oxalate, '(', 'chocolate,', 'rhubarb,', and, 'starfruit)', may]), verbo([cause]), complemento([additional, minimal, increase, in, urinary, oxalate, levels, in, select, 'individuals;', excess, should, be, discouraged])].
[sujeto(['Each', sib, of, an, affected, individual]), verbo([has]), complemento([a, 25, '%', chance, of, being, 'affected,', a, 50, '%', chance, of, being, an, asymptomatic, 'carrier,', and, a, 25, '%', chance, of, being, unaffected, and, not, a, carrier])].
[sujeto(['Carrier', testing, for, 'at-risk', family, members, and, prenatal, testing, for, pregnancies, at]), verbo([increased]), complemento([risk, are, possible, if, the, pathogenic, variants, in, the, family, are, known])].
[sujeto(['Prevention', of, undesirable, overflow, into, the, production, of, oxalate, definitely]), verbo([leads]), complemento([to, a, decrease, of, urolithiasis])].
[sujeto(['The', hypothesis, that, insulin, resistance]), verbo([induces]), complemento([mitochondria, 'dysfunction,', resulting, in, the, decrease, of, 'mitochondria-related', enzyme, activity, is, a, very, attractive, new, treatment, strategy, of, urolithiasis])].
[sujeto(['Namely,', the, improvement, of, insulin, resistance, might]), verbo([prevent]), complemento([stone, formation])].
[sujeto(['In', 'addition,', a, 'NADPH-dependent', cytosolic, 'HPR2']), verbo([provides]), complemento([an, efficient, extraperoxisomal, bypass])].
[sujeto(['Here,', we]), verbo([report]), complemento([on, a, third, 'enzyme,', 'HPR3', '(', 'At1g12550),', in, 'Arabidopsis', '(', 'Arabidopsis', 'thaliana),', which, also, reduces, 'HP', to, glycerate, and, shows, even, more, activity, with, 'glyoxylate,', a, more, upstream, intermediate, of, the, photorespiratory, cycle])].
[sujeto(['On', the, other, 'hand,', the, combined, deletion, of, 'HPR1,', 'HPR2,', and, 'HPR3']), verbo([causes]), complemento([increased, growth, 'retardation,', decreased, photochemical, 'efficiency,', and, reduced, 'oxygen-dependent', gas, exchange, in, comparison, with, the, hpr1xhpr2, double, mutant])].
[sujeto(['Since', in, silico, analysis, and, proteomic, studies, from, other, groups, indicate]), verbo([targeting]), complemento([of, 'HPR3', to, the, 'chloroplast,', this, enzyme, could, provide, a, compensatory, bypass, for, the, reduction, of, 'HP', and, glyoxylate, within, this, compartment])].
[sujeto(['First,', it, was, observed, that, when, glycolate, or, glyoxylate, was, fed, into, detached, 'leaves,', both, organic, acids, were, equally, effective, in]), verbo([stimulating]), complemento([oxalate, accumulation])].
[sujeto(['In', 'addition,', the, stimulation, could, be, completely]), verbo([inhibited]), complemento([by, 'cysteine,', a, glyoxylate, scavenger, that, forms, 'cysteine-glyoxylate', adducts])].
[sujeto(['To', verify, the, role, of, glyoxylate, 'further,', various, transgenic, plants, were, 'generated,', in, which, several, genes]), verbo([involved]), complemento([in, glyoxylate, metabolism, '[', i])].
[sujeto(['SGAT', '(', 'serine-glyoxylate', 'aminotransferase),', 'GGAT', '(', 'glutamate-glyoxylate', 'aminotransferase),', 'HPR', '(', hydroxypyruvate, 'reductase),', 'ICL', '(', isocitrate, 'lyase)],', were, transcriptionally]), verbo([regulated]), complemento([through, 'RNAi', or, 'over-expression'])].
[sujeto(['Analyses', on, these, transgenic, plants, consistently, revealed, that, glyoxylate]), verbo([acted]), complemento([as, an, efficient, precursor, for, oxalate, biosynthesis, in, rice])].
[sujeto(['Unexpectedly,', it, was]), verbo([found]), complemento([that, oxalate, accumulation, was, not, correlated, with, 'photorespiration,', even, though, this, pathway, is, known, to, be, a, major, source, of, glyoxylate])].
[sujeto(['Taken', 'together,', our, results, strongly]), verbo([suggest]), complemento([that, glyoxylate, rather, than, ascorbate, is, an, efficient, precursor, for, oxalate, 'biosynthesis,', and, that, oxalate, accumulation, and, regulation, do, not, necessarily, depend, on, 'photorespiration,', possibly, due, to, the, occurrence, of, the, anaplerotic, reaction, that, may, compensate, for, glyoxylate, formation, in, rice])].
[sujeto(['The', 'FT-IR', analysis, showed, an]), verbo([increase]), complemento([in, unsaturated, fatty, acids, during, ethanol, and, cold, 'exposure,', and, a, decrease, during, acid, and, heat, exposure])].
[sujeto(['Cold', conditions]), verbo([induced]), complemento([changes, in, the, carbohydrate, composition, of, the, 'cell,', possibly, related, to, the, upregulation, of, outer, membrane, genes, '(', glgAP, and, 'rcsA)'])].
[sujeto(['We']), verbo([report]), complemento([the, case, of, a, female, infant, of, one, month, of, 'age,', that, on, her, first, day, post, 'birth,', presented, myoclonic, convulsions, and, tonic, 'spasms,', both, during, wakefullness, and, sleep, 'periods,', that, became, more, frequent, and, did, not, respond, to, the, use, of, anticonvulsants])].
[sujeto(['The', determination, of, organic, acids, in, urine, revealed, an]), verbo([increase]), complemento([in, the, concentration, levels, of, oxalic, acid, '(', 3064, 'mmol/mol', of, 'creatinine)'])].
[sujeto(['Although', it, is, a, rare]), verbo([cause]), complemento([of, neonatal, 'convulsions,', 'hyperoxaluria,', due, to, new, mutations, is, an, underdiagnosed, disease, by, neonatologists, and, paediatricias])].
[sujeto(['The', aim, of, this, study, was, to]), verbo([report]), complemento([three, 'PH3', cases, carrying, mutations, in, 'HOGA1'])].
[sujeto(['Pro190Leu', mutation, was]), verbo([reported]), complemento([with, impaired, renal, function, at, 'follow-up;', 'however,', the, p])].
[sujeto(['Gly287Val', mutations]), verbo([found]), complemento([in, this, study, can, provide, a, 'first-line', investigation, in, 'Tunisian', 'PH1', patients])].
[sujeto(['In', 'humans,', it, is]), verbo([associated]), complemento([with, hyperoxaluria, type, 2, '(', 'PH2)', leading, to, renal, failure])].
[sujeto(['The', glyoxylate, content, within, cells, is]), verbo([regulated]), complemento([by, the, 'NADPH/NADH', dependent, 'glyoxylate/hydroxypyruvate', reductases, '(', 'GRHPR)'])].
[sujeto(['These', are, highly]), verbo([conserved]), complemento([enzymes, with, a, dual, activity, as, they, are, able, to, reduce, glyoxylate, to, glycolate, and, to, convert, hydroxypyruvate, into, 'D-glycerate'])].
[sujeto(['This', shows, a]), verbo([binding]), complemento([mode, conserved, between, human, and, archeal, enzymes])].
[sujeto(['These', residues]), verbo([act]), complemento([as, gatekeepers, at, the, entrance, of, a, tunnel, connecting, the, active, site, to, protein, surface])].
[sujeto(['Variants', in, genes, encoding, these, enzymes, may]), verbo([cause]), complemento([variation, in, response, to, oxaliplatin, and, could, be, potential, predictive, markers])].
[sujeto(['Nine', genes, differentially]), verbo([associated]), complemento([with, overall, survival, according, to, oxaliplatin, treatment, '(', unadjusted, p, values, &, 'lt;', 0.05, ')', were, selected])].
[sujeto(['Several', variants, in, genes]), verbo([involved]), complemento([in, metabolism, and, transport, could, thus, be, potential, predictive, markers, for, oxaliplatin, treatment, in, 'CRC', patients])].
[sujeto(['To', quantify, this, contribution, we]), verbo([have]), complemento([infused, 'Wt', 'mice,', 'Agxt', 'KO', mice, deficient, in, liver, 'alanine:glyoxylate', 'aminotransferase,', and, 'Grhpr', 'KO', mice, deficient, in, glyoxylate, 'reductase,', with, '(', 13, ')', 'C5-hydroxyproline'])].
[sujeto(['To', determine, if, blocking, steps, in, hydroxyproline, and, glycolate, metabolism, would]), verbo([decrease]), complemento([urinary, oxalate, 'excretion,', mice, were, injected, with, siRNA, targeting, the, liver, enzymes, glycolate, oxidase, and, hydroxyproline, dehydrogenase])].
[sujeto(['These', siRNAs]), verbo([decreased]), complemento([the, expression, of, both, enzymes, and, reduced, urinary, oxalate, excretion, in, 'Agxt', 'KO', 'mice,', when, compared, to, mice, infused, with, a, luciferase, control, preparation])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, siRNA, approaches, could, be, useful, for, decreasing, the, oxalate, burden, on, the, kidney, in, individuals, with, 'Primary', 'Hyperoxaluria'])].
[sujeto(['Twenty-six', 'HOGA1', mutations]), verbo([have]), complemento([been, reported, in, primary, hyperoxaluria, '(', 'PH)', type, 3, '(', 'PH3)', patients, with, c])].
[sujeto(['However,', 'PH3']), verbo([has]), complemento([never, been, described, in, 'Asians'])].
[sujeto(['Direct', sequencing, analysis, failed, to]), verbo([find]), complemento([these, mutations, in, 100, unrelated, healthy, subjects, and, the, functional, role, on, splicing, of, both, variants, found, in, this, study, was, confirmed, by, a, minigene, assay, based, on, the, pSPL3, exon, trapping, vector])].
[sujeto(['In', 'addition,', we]), verbo([found]), complemento([a, 'SNP', in, this, family, '(', c])].
[sujeto(['Three', loci]), verbo([have]), complemento([been, 'identified:', 'AGXT', '(', 'PH1),', 'GRHPR', '(', 'PH2),', and, 'HOGA1', '(', 'PH3)'])].
[sujeto(['A', group, of, patients, with, disease, progression, similar, to, that, of, 'PH3,', but, for, whom, no, mutation, was, detected, '(', 11.3, '%', of, 'families),']), verbo([suggested]), complemento([further, genetic, heterogeneity])].
[sujeto(['G170R', mistargeting, allele, resulted, in, a, milder, 'PH1', 'phenotype;', 'however,', other, potential, 'AGXT', mistargeting, alleles]), verbo([caused]), complemento([more, severe, '(', fully, 'penetrant)', disease])].
[sujeto(['Population', analysis]), verbo([suggested]), complemento([that, 'PH', is, an, order, of, magnitude, more, common, than, determined, from, clinical, cohorts, '(', 'prevalence,', approximately, 1, :, 58, ',', 0, ;, carrier, 'frequency,', approximately, 1, :, 70, ')'])].
[sujeto(['These', results, highlight, a, role, for, molecular, analyses, in, 'PH', diagnostics, and, prognostics, and]), verbo([suggest]), complemento([that, wider, analysis, of, the, idiopathic, 'stone-forming', population, may, be, beneficial])].
[sujeto(['All', remaining, patients, underwent]), verbo([targeted]), complemento([exon, sequencing, of, 'GRHPR', and, 'HOGA1', with, 8, '%', diagnosed, with, 'PH2', and, 8, '%', with, 'PH3'])].
[sujeto(['NGS']), verbo([has]), complemento([comparable, diagnostic, performance, to, 'Sanger', sequencing, for, the, diagnosis, of, 'PH', 'and,', if, 'implemented,', would, screen, for, all, forms, of, 'PH', simultaneously, ensuring, prompt, diagnosis, at, decreased, cost])].
[sujeto(['Primary', hyperoxaluria, type, 'II', is, a, recessive, genetic, disorder]), verbo([caused]), complemento([by, mutations, in, the, 'GRHPR', gene])].
[sujeto(['Although', several, dozen, mutations]), verbo([have]), complemento([been, 'described,', all, affect, coding, or, transcript, splicing])].
[sujeto(['This', latter, mechanism, may, be, underappreciated, in, 'general;']), verbo([reports]), complemento([of, clinically, significant, functional, variation, of, this, type, are, extremely, rare])].
[sujeto(['PH', type, 2, is]), verbo([caused]), complemento([by, decreased, activity, of, 'GRHPR', enzyme, that, eventually, leads, to, 'ESRD', and, systemic, oxalosis])].
[sujeto(['Diagnosis', criteria, included, a, history, of, reoccurring, calcium, oxalate, renal, stones, and, elevated, oxalate, levels, combined, with, liver, biopsy, and]), verbo([decreased]), complemento([enzymatic, activity, at, age, five])].
[sujeto(['Subsequent', biopsies, confirmed, results]), verbo([found]), complemento([in, first, biopsy])].
[sujeto(['Despite', the, immunosuppressive, 'therapy,', his, serum, creatinine, level]), verbo([increased]), complemento([again, after, 11, months])].
[sujeto(['Renal', tubular, obstruction, then]), verbo([led]), complemento([to, graft, nephrectomy])].
[sujeto(['As', the, 'GRHPR', enzyme, is, predominantly]), verbo([expressed]), complemento([in, 'liver,', we, suggest, a, combined, 'liver-kidney', transplant, may, be, beneficial, in, patients, with, 'PH2'])].
[sujeto(['Excessive', action, of, angiotensin, 'II', on, mitochondria]), verbo([has]), complemento([been, shown, to, play, an, important, role, in, mitochondrial, 'dysfunction,', a, common, feature, of, atherogenesis, and, kidney, injury])].
[sujeto(['Deficiencies', of, 'alanine-glyoxylate', aminotransferase, '(', 'AGT)', or, glyoxylate, reductase, '(', 'GRHPR)', are, the, two, known]), verbo([causes]), complemento([of, the, disease, '(', 'PH', 'I', and, 'II,', 'respectively)'])].
[sujeto(['We', determined, that, mutations, in, an, uncharacterized, 'gene,', 'DHDPSL,', on, chromosome, 10]), verbo([cause]), complemento([a, third, type, of, 'PH', '(', 'PH', 'III)'])].
[sujeto(['Genetic']), verbo([causes]), complemento([of, nephrolithiasis, are, underestimated])].
[sujeto(['Primary', hyperoxaluria, type, 2, is, a, rare, autosomal, recessive, disease]), verbo([caused]), complemento([by, mutations, in, the, 'GRHPR', 'gene,', leading, to, an, accumulation, of, oxalate, and, 'L-glycerate', with, recurrent, kidney, stone, formation, and, 'nephrocalcinosis,', and, the, later, development, of, renal, failure, and, systemic, oxalate, depositions])].
[sujeto(['Restriction', enzyme, analysis, of, the, 'patient,', 30, healthy, controls, and, 30, patients, with, nephrolithiasis, of, various]), verbo([causes]), complemento([was, done, to, confirm, the, presence, of, the, mutation])].
[sujeto(['We']), verbo([found]), complemento([the, novel, homozygous, single, missense, mutation, 'A975G', in, exon, 9, ',', creating, an, amino, acid, change, from, asparagine, to, aspartic, acid, in, position, 312])].
[sujeto(['Molecular', modeling, studies, revealed, that, the, mutation, was, likely, to, disrupt, the, correct, folding, of, the, 'GRHPR', substrate]), verbo([binding]), complemento(['domain,', hence, affecting, the, enzyme, active, site])].
[sujeto(['Primary', hyperoxaluria, type, 2, should, be, considered, in, patients, at, adult, stone, clinics, who]), verbo([have]), complemento([had, a, history, of, nephrolithiasis, since, 'childhood,', especially, in, those, with, consanguineous, parents])].
[sujeto(['Adaptive', laboratory, evolution]), verbo([has]), complemento([proven, a, valuable, strategy, for, metabolic, engineering])].
[sujeto(['Evolved', strains, featured, a, significantly, higher, growth, 'rate,']), verbo([increased]), complemento(['L-valine', titers, '(', '~25%)', and, a, 3, -, 4, -, fold, reduction, of, 'by-product', formation])].
[sujeto(['Genome', sequencing, resulted, in, the, identification, of, a, 'loss-of-function', mutation, '(', 'UreD-E188*)', in, the, gene, ureD, '(', urease, accessory, 'protein),', which, was, shown, to]), verbo([increase]), complemento(['L-valine', production, by, up, to, 100, '%'])].
[sujeto(['Furthermore,']), verbo([decreased]), complemento(['L-alanine', formation, was, attributed, to, a, mutation, in, the, global, regulator, 'GlxR'])].
[sujeto(['We', examine, the, contrast, between, mechanisms, for, allosteric, signaling, that]), verbo([involve]), complemento([structural, 'change,', and, those, that, do, 'not,', from, the, perspective, of, allosteric, pathways])].
[sujeto(['We']), verbo([find]), complemento([that, a, perturbation, theory, of, thermal, elastic, solids, and, nonperturbative, approach, '(', by, 'super-coarse-graining', elasticity, into, internal, bending, 'modes)', have, opposite, signatures, in, their, structure, of, correlated, pathways])].
[sujeto(['We']), verbo([find]), complemento([that, the, visibility, of, both, correlated, pathways, and, disconnected, sites, of, correlated, motion, in, this, protein, suggests, that, mechanisms, of, local, elastic, stretch, and, bend, are, recruited, for, the, purpose, of, creating, and, controlling, allosteric, cooperativity])].
[sujeto(['The', pstSCAB, operon, of, 'Corynebacterium', 'glutamicum,', which, encodes, an, 'ABC', transport, system, for, uptake, of, phosphate, '(', 'Pi),', is]), verbo([induced]), complemento([during, the, 'Pi', starvation, response])].
[sujeto(['The', 'two-component', regulatory, system, 'PhoRS', is]), verbo([involved]), complemento([in, this, 'response,', but, partial, 'Pi', starvation, induction, of, pstSCAB, in, a, 'ΔphoRS', mutant, indicated, the, involvement, of, additional, 'regulator(s)'])].
[sujeto(['Regulation', of, pstSCAB, also]), verbo([involves]), complemento([the, global, transcriptional, regulator, 'GlxR'])].
[sujeto(['DNA', affinity, chromatography, identified, the, regulator, of, acetate, metabolism, 'RamB', as, a, protein]), verbo([binding]), complemento([to, pstS, promoter, 'DNA', in, vitro])].
[sujeto(['Gel', mobility, shift, assays, and, mutational, analysis, of, the, pstS, promoter, region, revealed, that, 'RamB']), verbo([binds]), complemento([to, two, sites, localized, at, positions, -, 74, to, -, 88, and, -, 9, to, +, 2, with, respect, to, the, transcriptional, start, site, of, pstSCAB])].
[sujeto(['Reporter', gene, studies, supported, the, in, vivo, relevance, of, both]), verbo([binding]), complemento([sites, for, activation, of, pstSCAB, by, 'RamB'])].
[sujeto(['glutamicum,', 'RamB', is]), verbo([involved]), complemento([in, expression, control, of, pstSCAB, operon])].
[sujeto(['Thus,', transcriptional, regulation, of, pstSCAB, is, complex]), verbo([involving]), complemento([activation, by, the, 'phosphate-responsive', 'two-component', regulatory, system, 'PhoSR', and, the, regulators, of, carbon, metabolism, 'GlxR', and, 'RamB'])].
[sujeto(['However,', the, expression, profile]), verbo([revealed]), complemento([the, transcriptional, control, of, glxR, has, not, yet, been, studied, in, detail])].
[sujeto(['DNA', affinity, chromatography, experiments, revealed, the]), verbo([binding]), complemento([of, transcriptional, regulators, 'SucR,', 'RamB,', 'GlxR,', and, a, 'GntR-type', protein, '(', hereafter, denoted, as, 'GntR3)', to, the, upstream, region, of, glxR])].
[sujeto(['The']), verbo([binding]), complemento([of, different, regulators, to, the, glxR, promoter, was, confirmed, by, 'EMSA', experiments])].
[sujeto(['The', sucR, and, gntR3, deletion, mutants, showed]), verbo([decreased]), complemento([glxR, promoter, 'activities,', when, compared, with, the, wild, 'type,', irrespective, of, the, carbon, sources])].
[sujeto(['These', results, indicate, that, 'SucR', and, 'GntR3', are]), verbo([acting]), complemento([as, activators, of, 'GlxR,', while, 'RamB', plays, a, repressor])].
[sujeto(['glutamicum,', which, is, widely, used, for, the, industrial, production, of, amino, acids, and, serves, as, a, 'non-pathogenic', model, organism, for, members, of, the, 'Corynebacteriales', including, 'Mycobacterium', 'tuberculosis,', the, 'GlxR', homodimer, controls, the, transcription, of, a, large, number, of, genes]), verbo([involved]), complemento([in, carbon, metabolism])].
[sujeto(['GlxR', therefore, represents, a, key]), verbo([target]), complemento([for, understanding, the, regulation, and, coordination, of, 'C'])].
[sujeto(['Here', we, investigate, cylic, 'AMP', and, 'DNA']), verbo([binding]), complemento([of, 'GlxR', from, 'C'])].
[sujeto(['The', detailed, structural, analysis, and, comparison, of, 'GlxR', with, 'CRP']), verbo([reveals]), complemento([that, the, protein, undergoes, a, distinctive, conformational, change, upon, cyclic, 'AMP', binding, leading, to, a, dimer, structure, more, compatible, to, 'DNA-binding'])].
[sujeto(['As', the, two]), verbo([binding]), complemento([sites, in, the, 'GlxR', homodimer, are, structurally, identical, dynamic, changes, upon, binding, of, the, first, ligand, are, responsible, for, the, allosteric, behavior])].
[sujeto(['The', results, presented, here, show, how, dynamic, and, structural, changes, in, 'GlxR']), verbo([lead]), complemento([to, optimization, of, orientation, and, distance, of, its, two, 'DNA-binding', helices, for, optimal, 'DNA', recognition])].
[sujeto(['An', 'IclR-type', regulator, 'GenR']), verbo([has]), complemento([been, characterized, to, activate, the, transcription, of, genDFM, and, genKH, operons, for, 3, -, hydroxybenzoate, and, gentisate, catabolism, and, represses, its, own, expression])].
[sujeto(['On', the, other, 'hand,', 'GlxR,', a, global, regulator, of, the, cyclic, 'AMP', '(', 'cAMP)', receptor, 'protein-fumarate', nitrate, reductase, regulator, '(', 'CRP-FNR)', 'type,', was, also, predicted, to, be]), verbo([involved]), complemento([in, this, pathway])].
[sujeto(['In', this, 'study,', electrophoretic, mobility, shift, assays, and, footprinting, analyses, demonstrated, that, 'GlxR']), verbo([bound]), complemento([to, three, sites, in, the, promoter, regions, of, three, gen, operons])].
[sujeto(['A', combination, of, 'site-directed', mutagenesis, of, the, biding, 'sites,', promoter, activity, 'assay,', and, 'GlxR', overexpression, demonstrated, that, 'GlxR']), verbo([repressed]), complemento([their, expression, by, binding, these, sites])].
[sujeto(['One', 'GlxR']), verbo([binding]), complemento([site, '(', 'DFMx)', was, found, to, be, located, -, 13, to, +, 8, bp, upstream, of, the, genDFM, 'promoter,', which, was, involved, in, negative, regulation, of, genDFM, transcription])].
[sujeto(['The', 'GlxR']), verbo([binding]), complemento([site, 'R-KHx01', '(', located, between, positions, -, 11, to, +, 5, ')', was, upstream, of, the, genKH, promoter, sequence, and, involved, in, negative, regulation, of, its, transcription])].
[sujeto(['The']), verbo([binding]), complemento([site, 'R-KHx02,', at, which, 'GlxR', binds, to, genR, promoter, to, repress, its, 'expression,', was, found, within, a, footprint, extending, from, positions, -, 71, to, -, 91, bp])].
[sujeto(['These', results]), verbo([reveal]), complemento([that, 'GlxR', represses, the, transcription, of, all, three, gen, operons, and, then, contributes, to, the, synchronization, of, their, expression, for, 3, -, hydroxybenzoate, and, gentisate, catabolism, in, collaboration, with, the, specific, regulator, 'GenR'])].
[sujeto(['The', global, regulator, glxR, of, 'Corynebacterium', glutamicum, is]), verbo([involved]), complemento([in, many, cellular, activities])].
[sujeto(['Considering', its, 'role,', the, 'GlxR', protein, likely]), verbo([interacts]), complemento([with, other, proteins, to, 'obtain,', 'maintain,', and, control, its, activity])].
[sujeto(['To', isolate, proteins]), verbo([interacting]), complemento([with, 'GlxR,', we, used, a, 'two-hybrid', system, with, 'GlxR', as, the, bait])].
[sujeto(['The', proteolytic, action, of, 'SprA', on, 'GlxR', was, not, observed, in, the, presence, of, cyclic, adenosine, 'monophosphate,', which]), verbo([modulates]), complemento(['GlxR', activity])].
[sujeto(['The', activity, of, isocitrate, dehydrogenase, '(', a, tricarboxylic, acid, cycle, 'enzyme)', in, these, strains]), verbo([decreased]), complemento([to, 30, -, 50, '%', of, that, in, the, 'wild-type', strain])].
[sujeto(['In', the, 'P180-sprA', 'strain,', proteins]), verbo([involved]), complemento([in, diverse, cellular, functions, such, as, energy, and, carbon, metabolism, '(', 'NCgl2809),', nitrogen, metabolism, '(', 'NCgl0049),', methylation, reactions, '(', 'NCgl0719),', and, peptidoglycan, biosynthesis, '(', 'NCgl1267),', as, well, as, 'stress,', 'starvation,', and, survival, '(', 'NCgl0938)', were, affected, and, showed, decreased, transcription])].
[sujeto(['Taken', 'together,', these, data]), verbo([suggest]), complemento([that, 'SprA,', as, a, serine, 'protease,', performs, a, novel, regulatory, role, not, only, in, 'glxR-mediated', gene, expression, but, also, in, other, areas, of, cell, physiology])].
[sujeto(['The', cyclic, 'AMP', receptor, protein, '(', 'CRP)', 'homolog,', 'GlxR,', controls, the, expression, of, several, genes]), verbo([involved]), complemento([in, the, regulation, of, diverse, physiological, processes, in, 'Corynebacterium', glutamicum])].
[sujeto(['In', silico, analysis]), verbo([has]), complemento([revealed, the, presence, of, glxR, binding, sites, upstream, of, genes, 'adhA,', 'ald,', and, 'ptsG,', encoding, 'glucose-specific', phosphotransferase, system, 'protein,', alcohol, dehydrogenase, '(', 'ADH),', and, acetaldehyde, dehydrogenase, '(', 'ALDH),', respectively])].
[sujeto(['However,', the, involvement, of, the, 'GlxR-cAMP', complex, on, the, expression, of, these, genes]), verbo([has]), complemento([been, explored, only, in, vitro])].
[sujeto(['The', specific, activities, of, 'ADH', and, 'ALDH', were]), verbo([increased]), complemento([in, both, the, mutants, in, glucose, and, glucose, plus, ethanol, 'media,', in, contrast, to, the, wild, type])].
[sujeto(['In', 'accordance,', the, promoter, activities, of, adhA, and, ald, were, derepressed, in, the, cyaB, 'mutant,', indicating, that, glxR]), verbo([acts]), complemento([as, a, repressor, of, adhA])].
[sujeto(['Allostery', is, a, fundamental, process, by, which, ligand]), verbo([binding]), complemento([to, a, protein, alters, its, activity, at, a, distinct, site])].
[sujeto(['We']), verbo([provide]), complemento([a, foundational, theory, for, how, allostery, can, occur, as, a, function, of, 'low-frequency', dynamics, without, a, change, in, structure])].
[sujeto(['We']), verbo([have]), complemento([generated, 'coarse-grained', models, that, describe, the, protein, backbone, motions, of, the, 'CRP/FNR', family, transcription, 'factors,', 'CAP', of, 'Escherichia', coli, and, 'GlxR', of, 'Corynebacterium', glutamicum])].
[sujeto(['We', observe, that]), verbo([binding]), complemento([the, first, molecule, of, cAMP, ligand, is, correlated, with, modulation, of, the, global, normal, modes, and, negative, cooperativity, for, binding, the, second, cAMP, ligand, without, a, change, in, mean, structure])].
[sujeto(['Furthermore,', through, analyzing, 'CAP', variants, from, diverse, 'species,', we, demonstrate, an, evolutionary, selection, pressure, to]), verbo([conserve]), complemento([residues, crucial, for, allosteric, control])].
[sujeto(['This']), verbo([finding]), complemento([provides, a, link, between, the, position, of, 'CRP/FNR', transcription, factors, within, the, allosteric, free, energy, landscapes, and, evolutionary, selection, pressures])].
[sujeto(['Our', study, therefore]), verbo([reveals]), complemento([significant, features, of, the, mechanistic, basis, for, allostery])].
[sujeto(['Changes', in, 'low-frequency', dynamics, correlate, with, allosteric, effects, on, ligand]), verbo([binding]), complemento([without, the, requirement, for, a, defined, spatial, pathway])].
[sujeto(['In', addition, to, evolving, suitable, 'three-dimensional', 'structures,', 'CRP/FNR', family, transcription, factors]), verbo([have]), complemento([been, selected, to, occupy, a, dynamic, space, that, 'fine-tunes', biological, activity, and, thus, establishes, the, means, to, engineer, allosteric, mechanisms, driven, by, 'low-frequency', dynamics])].
[sujeto(['It', is, known, that, the, promoter, region, of, 'ramA,', encoding, one, of, these, 'regulators,']), verbo([interacts]), complemento([with, its, gene, 'product,', 'RamA,', as, well, as, with, the, two, other, 'regulators,', 'GlxR', and, 'SugR,', in, vitro, 'and/or', in, vivo])].
[sujeto(['Although', 'RamA']), verbo([has]), complemento([been, confirmed, to, repress, its, own, 'expression,', the, roles, of, 'GlxR', and, 'SugR', in, ramA, expression, have, remained, unclear])].
[sujeto(['In', this, 'study,', we, examined, the, effects, of, 'GlxR']), verbo([binding]), complemento([site, inactivation, on, expression, of, the, ramA, 'promoter-lacZ', fusion, in, the, genetic, background, of, single, and, double, deletion, mutants, of, sugR, and, ramA])].
[sujeto(['In', the, 'wild-type', 'background,', the, ramA, promoter, activity, was, reduced, to, undetectable, levels, by, the, introduction, of, mutations, into, the, 'GlxR']), verbo([binding]), complemento([site, but, increased, by, sugR, 'deletion,', indicating, that, 'GlxR', and, 'SugR', function, as, the, transcriptional, activator, and, 'repressor,', respectively])].
[sujeto(['The', marked, repression, of, ramA, promoter, activity, by, the, 'GlxR']), verbo([binding]), complemento([site, mutations, was, largely, compensated, for, by, deletions, of, sugR, 'and/or', ramA])].
[sujeto(['Corynebacterial', fatty, acid, metabolism]), verbo([has]), complemento([been, associated, with, human, body, 'odour,', and, is, therefore, discussed, as, a, potential, target, for, the, development, of, new, deodorant, additives])].
[sujeto(['For', this, 'reason,', the, transcription, levels, of, fad, genes]), verbo([associated]), complemento([with, lipid, metabolism, in, the, axilla, isolate, 'Corynebacterium', jeikeium, were, analysed, during, growth, on, different, lipid, sources])].
[sujeto(['The', transcription, of, several, fad, genes, was]), verbo([induced]), complemento(['two-', to, ninefold, in, the, presence, of, 'Tween', 60, ',', including, the, 'acyl-CoA', dehydrogenase, gene, fadE6])].
[sujeto(['Moreover,', 'DNA', affinity, chromatography, and, 'DNA', band, shift, assays, detected, the]), verbo([binding]), complemento([of, 'GlxR', to, the, promoter, regions, of, fadE6, and, 'famR,', revealing, a, hierarchical, control, of, fadE6, transcription, by, a, 'feed-forward', loop])].
[sujeto(['jeikeium,', a, pathway]), verbo([associated]), complemento([with, the, development, of, human, axillary, odour])].
[sujeto(['The', transcriptional, regulator, 'GlxR']), verbo([has]), complemento([been, characterized, as, a, global, hub, within, the, 'gene-regulatory', network, of, 'Corynebacterium', glutamicum])].
[sujeto(['GlxR']), verbo([binding]), complemento([sites, were, identified, in, the, sequence, of, 79, enriched, 'DNA', 'fragments,', of, which, 21, sites, were, not, previously, reported])].
[sujeto(['Electrophoretic', mobility, shift, assays, with, 40, -, mer, oligomers, covering, the, 'GlxR']), verbo([binding]), complemento([sites, were, performed, for, validation, of, the, in, vivo, results])].
[sujeto(['The', detection, of, new]), verbo([binding]), complemento([sites, confirmed, the, role, of, 'GlxR', as, a, regulator, of, carbon, source, metabolism, and, energy, 'conversion,', but, additionally, revealed, binding, of, 'GlxR', in, front, of, the, 6, 'C', 'non-coding', 'RNA', gene, and, to, 'non-canonical', 'DNA', binding, sites, within, 'protein-coding', regions])].
[sujeto(['The', present, study, underlines, the, dynamics, within, the, 'GlxR', regulon, by, identifying, in, vivo]), verbo([targets]), complemento([during, growth, on, glucose, and, contributes, to, the, expansion, of, knowledge, of, this, important, transcriptional, regulator])].
[sujeto(['The', industrially, important, organism, 'Corynebacterium', glutamicum]), verbo([has]), complemento([been, characterized, in, recent, years, for, its, robust, ability, to, assimilate, aromatic, compounds])].
[sujeto(['Disruption', of, paaR, in, strain, 'AS', 1.542, resulted, in, transcriptional]), verbo([increases]), complemento([of, all, paa, genes])].
[sujeto(['Electrophoretic', mobility, shift, assays, '(', 'EMSA)', demonstrated, specific]), verbo([binding]), complemento([of, 'PaaR', to, this, 'motif,', and, phenylacetyl, coenzyme, 'A', '(', 'PA-CoA)', blocked, binding])].
[sujeto(['In', 'addition,', 'GlxR']), verbo([binding]), complemento([sites, were, 'found,', and, binding, to, 'GlxR', was, confirmed])].
[sujeto([glutamicum, is]), verbo([regulated]), complemento([by, the, 'pathway-specific', repressor, 'PaaR,', and, also, likely, by, the, global, transcription, regulator, 'GlxR'])].
[sujeto(['By', comparative, genomic, 'analysis,', we, reconstructed, orthologous, 'PaaR', regulons, in, 57, 'species,', including, species, of, 'Actinobacteria,', 'Proteobacteria,', and, 'Flavobacteria,', that, carry, 'PAA', utilization, genes, and, operate, by]), verbo([conserved]), complemento([binding, 'motifs,', suggesting, that, 'PaaR-like', regulation, might, commonly, exist, in, these, bacteria])].
[sujeto(['Altogether,', 139, proteins, were]), verbo([found]), complemento([to, change, their, abundance, during, growth, on, protocatechuate])].
[sujeto(['A', general, adaptation, of, energy, metabolism, to, meet]), verbo([increased]), complemento([energy, production, by, oxidative, phosphorylation, and, a, stress, response, occurred])].
[sujeto(['The', different, regulation, of, porins, and, cell, wall, biosynthesis, proteins]), verbo([suggests]), complemento([a, change, in, its, architecture, upon, assimilation, of, the, aromatic, carbon, source])].
[sujeto(['Lipophilic', corynebacteria, are]), verbo([involved]), complemento([in, the, generation, of, volatile, odorous, products, in, the, process, of, human, body, odor, formation, by, degrading, skin, lipids, and, specific, odor, precursors])].
[sujeto(['To', understand, the, transcriptional, control, of, metabolic, pathways]), verbo([involved]), complemento([in, this, 'process,', the, transcriptional, regulatory, network, of, the, lipophilic, axilla, isolate, 'Corynebacterium', jeikeium, 'K411', was, reconstructed, from, the, complete, genome, sequence])].
[sujeto(['Most', genes]), verbo([involved]), complemento([in, lipid, degradation, are, under, the, combined, control, of, the, global, 'cAMP-sensing', transcriptional, regulator, 'GlxR', and, the, 'LuxR-family', regulator, 'RamA,', probably, reflecting, the, essential, role, of, lipid, degradation, in, 'C'])].
[sujeto(['This', study]), verbo([provides]), complemento([the, first, 'genome-scale', in, silico, analysis, of, the, transcriptional, regulation, of, metabolism, in, a, lipophilic, bacterium, involved, in, the, formation, of, human, body, odor])].
[sujeto(['The']), verbo([conserved]), complemento(['active-site', cysteines, adopt, canonical, 'proline/tyrosine-stabilized', geometries])].
[sujeto(['A', difference, in, the, angle, of, 'α-helix', 2, relative, to, the, 'β-sheet', surface, and, the, presence, of, an, extended, loop, in, the, human, sequence]), verbo([suggests]), complemento([potential, regulatory, regions, 'and/or', 'protein-protein', interaction, motifs])].
[sujeto(['This', observation, is, consistent, with, mutations, in, this, region, that]), verbo([suppress]), complemento([defects, in, 'GLXR-ribonucleotide', reductase, interactions])].
[sujeto([glutamicum, genome, are, predicted, in, 'silico,', studies, on, the, physiological, function, of, 'GlxR']), verbo([have]), complemento([been, hindered, by, the, severe, growth, defects, of, a, glxR, mutant])].
[sujeto(['In', vitro]), verbo([binding]), complemento([assays, and, 'promoter-reporter', assays, demonstrated, that, 'GlxR', directly, activates, expression, of, genes, for, aerobic, 'respiration,', 'ATP', 'synthesis,', and, glycolysis, and, that, it, is, required, for, expression, of, genes, for, cell, separation, and, mechanosensitive, channels])].
[sujeto(['GlxR', also, directly]), verbo([represses]), complemento([a, citrate, uptake, gene, in, the, presence, of, citrate])].
[sujeto(['Moreover,', 'ChIP-chip', analyses, showed, that, 'GlxR', was, still, able, to]), verbo([interact]), complemento([with, its, target, sites, in, a, mutant, with, a, deletion, of, 'cyaB,', the, sole, adenylate, cyclase, gene, in, the, 'genome,', even, though, binding, affinity, was, markedly, decreased])].
[sujeto(['The', alcohol, dehydrogenase, gene, adhA, in, 'Corynebacterium', glutamicum, is, subject, to, a, complex, carbon, 'source-dependent', regulation]), verbo([mediated]), complemento([by, 'RamA,', 'RamB', and, 'GlxR'])].
[sujeto(['In', this, study, we, identified, 'SucR', as, the, fourth, transcriptional, regulator]), verbo([involved]), complemento([in, expression, control, of, the, adhA, gene])].
[sujeto(['SucR', specifically]), verbo([binds]), complemento([to, the, adhA, promoter, and, acts, as, transcriptional, repressor, independent, of, the, carbon, source, used])].
[sujeto(['Furthermore,', we]), verbo([found]), complemento([that, 'SucR', negatively, controls, the, expression, of, its, own, gene])].
[sujeto(['This', negative, autoregulation, is]), verbo([mediated]), complemento([by, binding, of, 'SucR', to, at, least, one, of, four, identified, binding, sites, located, in, the, promoter, region, of, sucR])].
[sujeto(['EMSA', experiments, and, subsequent, sequence, analysis]), verbo([led]), complemento([to, the, identification, of, the, 'SucR', consensus, binding, sequence, 'YYAACAWMAW'])].
[sujeto(['This']), verbo([binding]), complemento([motif, is, different, from, the, binding, site, '(', 'ACTCTAGGGG)', recently, described, for, 'SucR', in, the, promoter, region, of, the, sucCD, operon])].
[sujeto(['Corynebacterium', 'glutamicum,', a, 'high-GC', 'Gram-positive', soil, 'bacterium,']), verbo([has]), complemento([been, used, in, development, of, bioprocesses, for, production, of, various, compounds, such, as, amino, 'acids,', organic, 'acids,', and, alcohols])].
[sujeto(['Recently,', several, transcriptional, 'regulators,', each, of, which, is]), verbo([involved]), complemento([in, multiple, carbon, metabolic, pathways, in, this, 'bacterium,', have, been, identified, and, characterized])].
[sujeto(['These', regulators, appear, to, form, a, complicated, network]), verbo([mediating]), complemento([coordinated, expression, of, a, number, of, metabolic, genes, for, efficient, utilization, of, carbon, and, energy, sources, in, response, to, changing, environmental, conditions])].
[sujeto([glutamicum, regulatory, system, should, establish, a, new, model, for, bacterial, control, of, carbon, 'metabolism,']), verbo([providing]), complemento([a, rational, basis, for, metabolic, engineering, of, this, industrial, important, microorganism, to, efficiently, direct, carbon, flow, from, available, carbon, resources, into, useful, compounds])].
[sujeto(['Specific', gene, sets]), verbo([associated]), complemento([with, iron, and, zinc, homeostasis, were, detected, among, the, 2, ',', 110, predicted, 'protein-coding', regions, and, integrated, into, a, 'gene-regulatory', network, that, is, linked, with, both, the, central, metabolism, and, the, oxidative, stress, response, of, 'FRC41'])].
[sujeto(['Two', gene, clusters, encode, proteins]), verbo([involved]), complemento([in, the, 'sortase-mediated', polymerization, of, adhesive, pili, that, can, probably, mediate, the, adherence, to, host, tissue, to, facilitate, additional, 'ligand-receptor', interactions, and, the, delivery, of, virulence, factors])].
[sujeto(['The', genome, annotation, revealed, additional, serine, 'proteases,', neuraminidase, 'H,', nitric, oxide, 'reductase,', an, 'invasion-associated', 'protein,', and, 'acyl-CoA', carboxylase, subunits]), verbo([involved]), complemento([in, mycolic, acid, biosynthesis, as, potential, virulence, factors])].
[sujeto([pseudotuberculosis, 'FRC41', is, equipped, with, a, distinct, gene, set]), verbo([promoting]), complemento([its, survival, under, unfavorable, environmental, conditions, encountered, in, the, mammalian, host])].
[sujeto(['Mutation', of]), verbo([primer]), complemento([site, for, genotyping, by, polymerase, chain, reaction, '(', 'PCR)', may, cause, allele, dropout, and, other, genotyping, failures])].
[sujeto(['Primary', hyperoxaluria, type, 2, '(', 'PH2)', is, a, rare, inherited, disease]), verbo([caused]), complemento([by, overproduction, of, endogenous, oxalate, due, to, mutations, in, the, 'glyoxylate/hydroxypyruvate', reductase, '(', 'GRHPR)', gene])].
[sujeto(['Here,', to, avoid, allele, dropout, and]), verbo([primer]), complemento([annealing, to, multiple, 'sites,', and, given, the, discrepancy, in, intron, length, between, 'GRHPR', gene, 'data,', we, updated, the, primers, used, in, the, sequence, assay, of, the, 'GRHPR', gene])].
[sujeto(['Data', from, immunohistochemistry, showed, that, 'ADB291', can]), verbo([recognize]), complemento([hepatocyte, cytoplasm])].
[sujeto(['This', kind, of, substrate, specificity]), verbo([has]), complemento([not, been, reported, previously, for, a, 'GHPR'])].
[sujeto(['The', enzyme]), verbo([has]), complemento([multiple, metabolic, roles, in, different, organisms])].
[sujeto(['In', this, paper, we, show, that, 'GOR1', '(', 'ORF', 'YNL274c)', encodes, a, glyoxylate, reductase, and, not, a, hydroxyisocaproate, dehydrogenase, in, 'Saccharomyces', 'cerevisiae,', even, though, it, also]), verbo([has]), complemento([minor, activity, on, 'alpha-ketoisocaproate'])].
[sujeto(['In', 'addition,', we, show, that, deletion, of, the, glyoxylate, 'reductase-encoding', gene]), verbo([leads]), complemento([to, higher, biomass, concentration, after, diauxic, shift])].
[sujeto(['Deficiency', of, this, enzyme, is, the, underlying]), verbo([cause]), complemento([of, primary, hyperoxaluria, type, 2, '(', 'PH2)', and, leads, to, increased, urinary, oxalate, 'levels,', formation, of, kidney, stones, and, renal, failure])].
[sujeto(['GRHPR']), verbo([has]), complemento([an, unusual, substrate, 'specificity,', preferring, glyoxylate, and, 'hydroxypyruvate,', but, not, pyruvate])].
[sujeto(['This', first, crystal, structure, of, a, human, 'GRHPR', enzyme, also, explains, the, deleterious, effects, of, naturally, occurring, missense, mutations, of, this, enzyme, that]), verbo([lead]), complemento([to, 'PH2'])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([of, a, cardiac, manifestation, of, a, primary, hyperoxaluria, type, 'II', '(', 'PH', 'II)', with, the, hemodynamic, characteristics, of, a, severe, restrictive, cardiomyopathy])].
[sujeto(['PH', 'II', is, a, rare, inherited, metabolic, disease, characterized, by, a, deficiency, of, 'D-glycerate', 'dehydrogenase,', which]), verbo([has]), complemento([also, glyoxylate, reductase, activity])].
[sujeto(['This', defect]), verbo([causes]), complemento([an, accumulation, of, hydroxypyruvate, the, precursor, of, oxalate])].
[sujeto(['The', renal, excretion, of, oxalate, is, impaired]), verbo([causing]), complemento([a, deposition, of, oxalate, mainly, in, the, kidneys])].
[sujeto(['To', 'date,', less, than, fifty, cases]), verbo([have]), complemento([been, reported])].
[sujeto(['Systemic', oxalosis, in, 'PH', 'II', is, an, occasional, 'finding;', thus, 'far,', myocardial, oxalosis, due, to, 'PH', 'II']), verbo([has]), complemento([never, been, reported])].
[sujeto(['Increased', oxalate, excretion, in, 'PH2', patients, can]), verbo([cause]), complemento([nephrolithiasis, and, 'nephrocalcinosis,', and, 'can,', in, some, 'cases,', result, in, renal, failure, and, systemic, oxalate, deposition])].
[sujeto(['GRHPR', is]), verbo([expressed]), complemento([in, virtually, every, tissue, in, the, 'body,', suggesting, that, utilization, of, more, readily, available, cells, could, be, used, to, determine, 'GRHPR', deficiency])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([evaluated, the, potential, of, determining, 'GR', and, 'd-glycerate', dehydrogenase, '(', 'DGDH)', activity, in, blood, mononuclear, cells, '(', 'BMC)', as, a, diagnostic, indicator, of, 'PH2'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, assay, of, 'DGDH', or, 'GR', activity, in, 'BMC', could, be, used, as, a, minimally, invasive, diagnostic, test, for, 'PH2'])].
[sujeto(['Reactions', of, 1, a, and, 1, b, with, 'KOtBu', or, 'KNPh2', afford, anionic, complexes, in, which, the, nucleophilic, anion]), verbo([associates]), complemento([with, the, pnictogen, centre, '(', '[', '(', 'tBuO)Pn(ONO)](-)', '(', 'Pn=P', '(', 2, 'a),', 'As', '(', 2, 'b))', and, '[', '(', 'Ph2', 'N)Pn(ONO)](-)', '(', 'Pn=P', '(', 3, 'a),', 'As', '(', 3, 'b))'])].
[sujeto(['Electrophilic', 'substrates,', such, as, 'HOTf', and, 'MeOTf,', preferentially]), verbo([associate]), complemento([with, the, nitrogen, atom, of, the, ligand, backbone, of, both, 1, a, and, 1, 'b,', giving, rise, to, cationic, species, that, can, be, rationalised, as, either, ammonium, salts, or, as, 'amine-stabilised', phosphenium, or, arsenium, complexes, '(', '[', 'Pn{ON(H)O}](+)', '(', 'Pn=P', '(', 6, 'a),', 'As', '(', 6, 'b))', and, '[', 'Pn{ON(Me)O}](+)', '(', 'Pn=P', '(', 7, 'a),', 'As', '(', 7, 'b))'])].
[sujeto(['All', studied, prototypical, drugs, specifically]), verbo([interact]), complemento([with, 'HEMA', and, nonionic, 'MAA', '(', at, 'pH2)', moieties])].
[sujeto(['To']), verbo([provide]), complemento([a, theoretical, framework, for, the, new, diffusion, 'data,', we, apply, an, 'effective-medium', model, extended, for, 'solute-specific', interactions, with, hydrogel, copolymer, strands])].
[sujeto(['The', purpose, of, this, study, was, to, elucidate, whether, 'lung-protective', 'ventilation-induced', respiratory, acidosis]), verbo([increased]), complemento([the, duration, of, neuromuscular, blockade, by, rocuronium])].
[sujeto(['Lung-protective', 'ventilation-induced', respiratory, acidosis]), verbo([increased]), complemento([the, duration, of, neuromuscular, blockade, by, rocuronium])].
[sujeto(['Our', findings, underline, the, importance, of, 'post-mortem', neuropathological, examination, also, in, the]), verbo([era]), complemento([of, advanced, imaging, techniques, and, prove, that, autopsy, is, the, ultimate, yardstick, of, our, diagnostic, and, therapeutic, efforts])].
[sujeto(['The', high, number, of, haemorrhagic, transformations, diagnosed, only, after, death, is, an, important, novel]), verbo([finding]), complemento([with, clinical, implications])].
[sujeto(['The', '[', 'Ge9', 'Sn](2-)', unit, donates, two, electrons, to, the, triangular, face, of, a, second, '[', 'Ge9', ']', '(', 2, -, ')', cluster, with, 'D3h', 'symmetry,', whereas, '[', 'Ge9', 'Zn](2-)']), verbo([acts]), complemento([as, an, electron, acceptor, when, interacting, with, the, triangular, face, of, a, 'D3h', -, symmetric, '[', 'Ge9', ']', '(', 4, -, ')', unit])].
[sujeto(['On', the, other, 'hand,', upon]), verbo([increasing]), complemento([the, ratio, of, trimethylene, carbonate, '(', 'TMC)', units, in, the, 'hydrogel,', the, pores, became, smaller, or, disappeared])].
[sujeto(['Moreover,', thickness, of, the, skin, layer, significantly]), verbo([increased]), complemento([with, the, swelling, ratio, depended, on, the, incorporation, ratios, of, the, 'PTMC', macromonomer])].
[sujeto(['Despite', 'AIS', with, underlying, 'ICAD']), verbo([requiring]), complemento([a, more, 'complex,', technically, demanding, recanalization, strategy, than, traditional, thromboembolic, 'AIS,', it, appears, 'safe,', and, good, outcomes, are, obtainable])].
[sujeto(['The', first, examples, of, essentially, 'two-coordinate,', monomeric, zinc, hydride, 'complexes,', 'LZnH', '(', 'L', =, -, 'N(Ar)(SiR3))', '(', 'Ar', =, 'C6H2{C(H)Ph2}2R\'-2,6,4;', 'R', =, 'Me,', 'R\'', =, 'Pr(i)', '(', 'L\');', 'R', =, 'Pr(i),', 'R\'', =, 'Me', '(', 'L*);', 'R', =, 'Pr(i),', 'R\'', =, 'Pr(i)', '(', 'L(†)))']), verbo([have]), complemento([been, prepared, and, shown, by, crystallographic, studies, to, have, near, linear, 'N-Zn-H', fragments])].
[sujeto(['Preliminary', reactivity, studies]), verbo([reveal]), complemento([the, compounds, to, be, effective, for, the, stoichiometric, hydrozincation, and, catalytic, hydrosilylation, of, carbonyl, compounds])].
[sujeto(['The', studies]), verbo([have]), complemento([revealed, that, the, flexible, dimethylene, linked, diphosphines, form, '[', '(', 'BX3)2{μ-R2P(CH2)2PR2}]', 'exclusively,', confirmed, by, multinuclear, 'NMR', '(', '(', 1, ')', 'H,', '(', 11, ')', 'B,', '(', 19, ')', 'F{(1)H},', and, '(', 31, ')', 'P{(1)H})', and, 'IR', spectroscopy, and, microanalytical, data])].
[sujeto(['Crystallographic', determinations, of, the, four, 'BX3', complexes, with, 'Et2P(CH2)2PEt2', confirm, the, 2, :, 1, stoichiometry, 'and,', taken, together, with, the, spectroscopic, 'data,']), verbo([reveal]), complemento([that, the, 'Lewis', acid, behavior, of, the, 'BX3', fragment, toward, phosphine, ligands, increases, in, the, order, 'F', '≪', 'Cl', '∼', 'Br', &, 'lt;', 'I'])].
[sujeto(['X-ray', crystallographic, studies, on, '[', 'BX2{o-C6H4(PMe2)2}][BX4]', '(', 'X', =, 'Cl,', 'Br),', '[', 'BI2{o-C6H4(PMe2)2}][I3],', and, '[', 'BCl2{o-C6H4(AsMe2)2}][BCl4]', confirm, the, presence, of, distorted, tetrahedral, coordination, at, boron, through, a, chelating, diphosphine, or, diarsine, and, two, 'X', 'ligands,', with, 'd(B-P)']), verbo([revealed]), complemento([a, similar, increase, in, 'Lewis', acidity, down, group, 17])].
[sujeto(['Comparison', of, 'd(B-P)', and, 'd(B-As)']), verbo([reveals]), complemento([an, increase, of, ca])].
[sujeto(['Hemodialysis-associated', amyloidosis, '(', 'HAA)']), verbo([involves]), complemento([the, fibrillization, of, 'β2-microglobulin', '(', 'β2M)', and, occurs, in, crowded, physiological, environments])].
[sujeto([5, ',', the, presence, of, a, strong, crowding, agent, '(', 'Ficoll', 70, or, dextran, 70, ')', not, only, dramatically, accelerates, the, fibrillization, of, both, 'wild-type', β2M, and, its, 'ΔN6', variant, by, reducing, the, lag, time, to, a, large, 'extent,', indicating, the, acceleration, of, the, nucleation, 'phase,', but, also, remarkably]), verbo([increases]), complemento([the, amount, of, β2M, fibrils])].
[sujeto([2, ',', such, an]), verbo([enhancing]), complemento([effect, of, macromolecular, crowding, on, fibril, formation, is, only, observed, for, pathogenic, mutant, 'ΔN6,', but, not, for, 'wild-type', β2M, which, does, not, form, amyloid, fibrils, in, the, absence, and, presence, of, a, crowding, agent])].
[sujeto(['Thus,', we, propose, that, the, monomers, of, β2M, form, the, 'nuclei,', which, is]), verbo([enhanced]), complemento([by, macromolecular, 'crowding,', followed, by, the, step, of, fibril, elongation])].
[sujeto(['Furthermore,', at, physiological, 'pH,', macromolecular, crowding, remarkably]), verbo([inhibits]), complemento([β2M, fibril, disassembly, by, decreasing, rate, constants, corresponding, to, fast, and, slow, stages, of, fibril, disaggregation])].
[sujeto(['Our', data, demonstrate, that, macromolecular, crowding, favors, the, fibrillization, of, β2M, by, accelerating, the, nucleation, step, and]), verbo([inhibiting]), complemento([fibril, disassembly])].
[sujeto(['Our', findings]), verbo([provide]), complemento([clear, evidence, for, the, pathology, of, 'HAA', that, macromolecular, crowding, should, be, taken, into, account])].
[sujeto(['A', 'pyridinebis(oxazoline)', cobalt, complex, is, a, very, efficient, precatalyst, for, the, hydrosilylation, of, terminal, alkynes, with, 'Ph2', 'SiH2', ',']), verbo([providing]), complemento(['α-vinylsilanes', with, high, '(', 'Markovnikov)', regioselectivity, and, broad, 'functional-group', tolerance])].
[sujeto(['Aqueous', solubility, and, distribution, of, 'ciprofloxacin,', 'enrofloxacin,', norfloxacin, and, levofloxacin, antimicrobials, drugs, in, 'octanol/buffer', system]), verbo([has]), complemento([been, measured, by, the, isothermal, saturation, method, using, buffer, solutions, pH2])].
[sujeto(['Thermophysical', characteristics, for, the, compounds]), verbo([have]), complemento([been, determined, by, the, 'DSC', method])].
[sujeto(['It']), verbo([has]), complemento([been, established, that, the, solubility, of, levofloxacin, in, these, buffers, is, higher, than, that, of, the, other, fluoroquinolones])].
[sujeto(['HYBOT', descriptors, for, biologically, active, compounds]), verbo([have]), complemento([been, calculated, and, the, impact, of, the, 'donor-acceptor', capacity, of, the, molecules, on, drugs, solubility, has, been, studied])].
[sujeto(['The', thermodynamic, solubility, and, distribution, functions, of, the, studied, compounds]), verbo([have]), complemento([been, obtained])].
[sujeto(['The', drugs, with, a, lower, aqueous, solubility, were, estimated, to]), verbo([have]), complemento([higher, distribution, coefficients, and, membrane, permeability])].
[sujeto(['We']), verbo([report]), complemento([here, the, release, of, toxic, metals, from, 'TT', via, 'ARD,', which, could, pose, an, environmental, threat, if, oil, sands, 'TT', deposits, are, not, properly, managed])].
[sujeto(['Trace', metal, concentrations, in, leachate, samples, collected, periodically, revealed, that, 'Mn', and, 'Sr', were]), verbo([released]), complemento([immediately, even, before, the, onset, of, 'ARD'])].
[sujeto(['For', most, elements, measured, '(', 'Fe,', 'Cr,', 'V,', 'As,', 'Cu,', 'Pb,', 'Zn,', 'Cd,', and, 'Se),', leaching, was]), verbo([associated]), complemento([with, 'ARD', production])].
[sujeto(['Though', equivalent, acidification, '(', 'pH2)', was, achieved, in, leachate, from, both, 'TT', 'types,', greater, metal]), verbo([release]), complemento([was, observed, from, 'TT2', where, concentrations, reached, 10, ',', 0, ppb, for, 'Ni,', 5000, ppb, for, 'Co,', 3000, ppb, for, 'As,', 2000, ppb, for, 'V,', and, 1000, ppb, for, 'Cr'])].
[sujeto(['Generally,', metal, concentrations]), verbo([decreased]), complemento([in, leachate, with, time, during, 'ARD', and, became, negligible, by, the, end, of, incubation, '(', '~450d)', despite, appreciable, metals, remaining, in, the, leached, 'TT'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, using, 'TT', for, land, reclamation, purposes, or, surface, deposition, for, volume, reduction, may, unfavorably, impact, the, 'environment,', and, warrants, application, of, appropriate, strategies, for, management, of, 'pyrite-enriched', oil, sands, tailings, streams])].
[sujeto(['Vascular', dementia, is, the, second, most, common]), verbo([cause]), complemento([of, dementia, affecting, over, seven, million, people, 'worldwide,', yet, there, are, no, licensed, treatments])].
[sujeto(['This', randomised, trial, will, investigate, whether, use, of, calcium, channel, blockade, with, 'amlodipine,', a, commonly, used, 'agent,', can]), verbo([provide]), complemento([the, first, 'evidence-based', pharmacological, treatment, for, subcortical, ischaemic, vascular, dementia])].
[sujeto(['A', total, of, 588, patients, will, be, randomised, in, a, 1, :, 1, ratio, to, either, amlodipine, or, 'placebo,']), verbo([recruited]), complemento([from, sites, across, the, 'UK', and, enrolled, in, the, trial, for, 104, &, 'nbsp;weeks'])].
[sujeto(['It', is, estimated, that, the, numbers, of, people, with, 'VaD', and, 'SIVD', will]), verbo([increase]), complemento([globally, in, the, future, and, the, results, of, this, study, should, inform, important, treatment, decisions])].
[sujeto(['Inflammatory', bowel, disease, '(', 'IBD)', presents, intense, inflammatory, 'infiltrate,', crypt, 'abscesses,', ulceration, and, even]), verbo([loss]), complemento([of, function])].
[sujeto(['Experimental', colitis, was]), verbo([induced]), complemento([by, acetic, acid, 7.5, '%', '(', pH2])].
[sujeto(['Colitis-induced', intestinal, transit, delay, was]), verbo([inhibited]), complemento([by, 'LED', therapy])].
[sujeto(['Colitis']), verbo([caused]), complemento([an, increase, of, colon, dimensions, '(', 'length,', 'diameter,', total, 'area)', and, colon, weight, '(', 'edema),', which, were, inhibited, by, 'LED', therapy])].
[sujeto(['LED', therapy, also]), verbo([decreased]), complemento(['colitis-induced', tissue, gross, 'lesion,', myeloperoxidase, 'activity,', microscopic, tissue, damage, score, and, the, presence, of, inflammatory, infiltrate, in, all, intestinal, layers])].
[sujeto(['Furthermore,', 'LED', therapy]), verbo([inhibited]), complemento(['colitis-induced', 'IL-1β,', 'TNF-α,', and, 'IL-6', production])].
[sujeto(['We', conclude, 'LED', therapy, at, 940, nm]), verbo([inhibited]), complemento([experimental, 'colitis-induced', colon, inflammation, in, 'mice,', 'therefore,', rendering, it, a, promising, therapeutic, approach, that, deserves, further, investigation])].
[sujeto(['This', work]), verbo([reveals]), complemento([a, 'clear-cut', example, of, the, trans, influence, in, a, 'mid-valent', uranium, 'system,', and, thus, a, strong, preference, for, the, cis, 'isomer,', which, is, computed, in, a, 'co-ligand-free', truncated, 'model-to', isolate, the, electronic, trans, influence, from, steric, 'contributions-to', be, more, stable, than, the, trans, isomer, by, approximately, 12, kJ, 'mol(-1)', with, an, isomerisation, barrier, of, approximately, 14, kJ, 'mol(-1)'])].
[sujeto(['When', using, the, mutagenicity, 'assay,', the]), verbo([decrease]), complemento([of, mutagenicity, produced, by, 'pre-meal', and, 'post-meal', samples, corresponded, to, reduction, of, 13.3, '±1'])].
[sujeto([pH, dependence, was, observed, with]), verbo([decreasing]), complemento(['Cr(VI)', reducing, capacity, at, higher, pH])].
[sujeto(['Quantum', chemical, calculations, using, density, functional, theory, with, the, 'TPSS+D3(BJ)', and, 'M06-2X+D3(ABC)', functionals]), verbo([have]), complemento([been, carried, out, to, understand, the, mechanisms, of, 'catalyst-free', 'hydrogermylation/hydrostannylation', reactions, between, the, 'two-coordinate', 'hydrido-tetrylenes', :, 'E(H)(L(+)', ')', '(', 'E=Ge', or, 'Sn,', 'L(+)', =, 'N(Ar(+)', ')', '(', 'SiiPr3', ')', ;, 'Ar(+)', =, 'C6', 'H2', '{', 'C(H)Ph2', '}', 2, 'iPr-2,6,4)', and, a, range, of, unactivated, terminal, '(', 'C2', 'H3', 'R,', 'R=H,', 'Ph,', or, 'tBu)', and, cyclic, '[', '(', 'CH)2', '(', 'CH2', ')', 2, '(', 'CH2', ')', n, ',', 'n=1,', 2, ',', or, 4, ']', alkenes])].
[sujeto(['The', calculations]), verbo([suggest]), complemento([that, the, addition, reactions, of, the, germylenes, and, stannylenes, to, the, cyclic, and, acyclic, alkenes, occur, as, 'one-step', processes, through, formal, '[', 2, +, 2, ']', addition, of, the, 'E-H', fragment, across, the, 'C-C', π, bond])].
[sujeto(['The', reactions]), verbo([have]), complemento([moderate, barriers, and, are, weakly, exergonic])].
[sujeto(['The', steric, bulk, of, the, tetrylene, amido, groups]), verbo([has]), complemento([little, influence, on, the, activation, barriers, and, on, the, reaction, energies, of, the, 'anti-Markovnikov', 'pathway,', but, the, 'Markovnikov', addition, is, clearly, disfavored, by, the, size, of, the, substituents])].
[sujeto(['The', hydrogermylation, reactions]), verbo([have]), complemento([lower, activation, energies, and, are, more, exergonic, than, the, stannylene, addition])].
[sujeto(['The', dominant, orbitals, of, the, germylene, are, the, 'σ-type', lone, pair, 'MO', of, 'Ge,', which, serves, as, a, donor, 'orbital,', and, the, vacant, 'p(π)', 'MO', of, 'Ge,', which]), verbo([acts]), complemento([as, acceptor, orbital, for, the, 'π*', and, π, 'MOs', of, the, olefin])].
[sujeto(['Inspection', of, the, transition, states, of, some, selected, reactions]), verbo([suggests]), complemento([that, the, differences, between, the, activation, energies, come, from, a, delicate, balance, between, the, deformation, energies, of, the, interacting, species, and, their, interaction, energies])].
[sujeto(['A', number, of, beneficial, effects, consisting, in, suppression, or, at, least, diminishing, of, degenerative, changes]), verbo([associated]), complemento([with, aging, is, ascribed, to, dehydroepiandrosterone, '(', 3, 'beta-hydroxy-5-androsten-17-one,', 'DHEA)', and, its, sulfate, '(', 'DHEAS),', in, spite, of, the, fact, that, it, does, not, act, as, other, hormonal, steroids, through, its, specific, intracellular, receptors])].
[sujeto(['Apart', from, the, fact, that, 'DHEA', functions, as, a, precursor, of, biologically, active, androgens, and, 'estrogens,', the, beneficial, effects]), verbo([associated]), complemento([with, this, steroid, may, be, characterized, as, 'anticancerogenic,', 'antisclerotic,', 'antidiabetic,', antiobese, and, immunostimulatory, or, immunoprotective, ones])].
[sujeto(['A', specific, chapter, represent, its, effects, in, 'brain,', where, 'DHEA']), verbo([acts]), complemento([as, one, of, neurosteroids, in, a, 'non-genomic', way])].
[sujeto(['In', this, 'mini-review', we]), verbo([have]), complemento([focused, especially, on, immunostimulatory, and, immunoprotective, effects, of, 'DHEA(S),', many, of, which, but, not, 'all,', may, be, explained, by, antiglucocorticoid, effects, of, 'DHEA', at, various, levels])].
[sujeto(['We']), verbo([have]), complemento([attempted, to, outline, at, which, sites, and, levels, 'DHEA', may, act, in, the, ligh, of, recent, knowledge, on, the, mechanism, of, glucocorticoid, action])].
[sujeto(['Finally,', the, results, of, the, recent, studies, are, 'surveyed,', indicating, that, not, only, 'DHEA', 'itself,', but, some, of, its, 'metabolites,', namely, its, 7, -, hydroxylated, 'derivatives,', may]), verbo([act]), complemento([as, locally, active, antiglucocorticoids])].
[sujeto(['A', single, intraperitoneal, injection, of, dehydroepiandrosterone, '(', 3, 'beta-hydroxy-5-androsten-17-one,', 'DHEA)', 17, hr, before, carbon, tetrachloride, '(', 'CCl4)', poisoning, protects, rats, against, liver, injury]), verbo([induced]), complemento([by, the, haloalkane])].
[sujeto(['In', liver, 'homogenates,', both, the]), verbo([increase]), complemento([in, malondialdehyde, production, and, the, formation, of, fluorescent, lipid, peroxidation, products, are, significantly, reduced])].
[sujeto(['The']), verbo([release]), complemento([of, liver, enzymes, into, the, blood, is, much, reduced, in, 'DHEA-pretreated', 'rats,', confirming, a, 'cause-effect', relationship, between, lipid, peroxidation, and, hepatocyte, death])].
[sujeto(['Treatment', with, 'DHEA']), verbo([inhibits]), complemento([neither, 'glucose-6-phosphate', dehydrogenase, activity, in, the, 'cytosol,', nor, the, microsomal, mixed, function, oxidase, system, '(', cytochrome, 'P450', 'content,', aminopyrine, demethylase, and, ethoxycoumarin, 'de-ethylase', 'activities)'])].
[sujeto([3, 'beta-Hydroxysteroid', dehydrogenase, '(', 3, 'beta-HSD)/delta', 5, -, -, &, 'gt;4-isomerase', activity, in, steroidogenic, tissues, is]), verbo([required]), complemento([for, the, synthesis, of, biologically, active, steroids])].
[sujeto(['Previously,', by, use, of, dehydroepiandrosterone, '(', 3, 'beta-hydroxy-5-androsten-17-one,', 'DHEA)', as, 'substrate,', it, was, established, that, in, addition, to, steroidogenic, tissues, 3, 'beta-HSD/delta', 5, -, -, &, 'gt;4-isomerase', activity, also, is]), verbo([expressed]), complemento([in, extraglandular, tissues, of, the, human, fetus])].
[sujeto(['A', similar]), verbo([finding]), complemento([in, regard, to, 'Kms', and, rates, of, product, formation, was, obtained, by, use, of, purified, placental, 3, 'beta-HSD', with, 'DHEA,', 'pregnenolone,', and, 3, 'beta-hydroxy-5', 'alpha-androstan-17-one', '(', 'epiandrosterone)', as, 'substrates:', the, 'Km', of, 3, 'beta-HSD', for, 'DHEA', was, 2.8, 'mumol/l,', for, pregnenolone, 1.9, 'mumol/l,', and, for, epiandrosterone, 25, 'mumol/l'])].
[sujeto(['These', studies, show, that, 'experimentally-induced', hyperinsulinemia, lowers, serum, 'DHA', and, 'DHA-sulfate', 'levels,', and]), verbo([suggest]), complemento([that, insulin, reduces, serum, concentrations, of, these, steroids, by, inhibiting, production, rather, than, by, increasing, clearance])].
[sujeto(['These', studies]), verbo([suggest]), complemento([that, 'DHA', may, possess, hypolipidemic, 'and,', 'possibly,', 'anti-obesity', properties])].
[sujeto(['They']), verbo([have]), complemento(['failed,', 'however,', to, demonstrate, any, effect, of, 'DHA', on, tissue, insulin, sensitivity])].
[sujeto(['Previous', work]), verbo([has]), complemento([demonstrated, that, the, adrenal, 'steroid,', dehydroepiandrosterone, '(', 3, -, 'beta-hydroxy-5-androsten-17-one,', 'DHEA),', has, broad, spectrum, tumor, chemopreventive, activity, in, laboratory, mice, and, 'rats,', inhibiting, the, development, of, spontaneous, breast, cancer, and, chemically, induced, tumors, of, the, 'lung,', 'colon,', 'skin,', thyroid, and, liver])].
[sujeto(['DHEA', treatment, produces, specific, 'side-effects,', including, estrogenic, and, androgenic, action, and, an]), verbo([increase]), complemento([in, liver, 'weight,', which, could, limit, its, use, as, a, cancer, chemopreventive, drug])].
[sujeto(['It', is, now, shown, that, oral, administration, of, the, synthetic, steroid, 16, 'alpha-fluoro-5-androsten-17-one,', which, lacks, the, 'side-effects', of, 'DHEA', 'treatment,', to, 'CD-1', mice]), verbo([inhibits]), complemento([7, ',', 12, -, 'dimethylbenz[a]anthracene-initiated', and, 12, -, 'O-tetradecanoylphorbol-13-acetate-promoted', skin, papilloma, formation, at, both, the, initiation, and, promotion, stage])].
[sujeto(['Low', levels, of, these, steroids]), verbo([have]), complemento([been, associated, with, the, presence, and, risk, of, development, of, cancer])].
[sujeto(['Administration', of, 'DHEA', to, rodents, produces, protection, against, spontaneous, tumors, and, chemical, 'carcinogenesis,']), verbo([suppresses]), complemento([weight, gain, without, significantly, affecting, food, 'intake,', ameliorates, the, severity, of, diabetes, in, genetically, diabetic, 'mice,', and, restrains, autoimmune, processes])].
[sujeto(['We']), verbo([have]), complemento([observed, that, the, conversion, of, 3, 'T3-L1', and, 3, 'T3-F442A', preadipocyte, clones, to, the, adipocyte, 'phenotype,', in, response, to, appropriate, differentiation, stimuli, '(', fetal, calf, 'serum,', 'insulin,', 'dexamethasone,', and, 1, -, 'methyl-3-isobutylxanthine),', is, blocked, by, 'DHEA', and, other, steroidal, inhibitors, of, 'glucose-6-phosphate', dehydrogenase])].
[sujeto(['The', structural, requirements, for, blocking, adipocyte, differentiation, and, for]), verbo([inhibiting]), complemento(['glucose-6-phosphate', dehydrogenase, are, closely, correlated])].
[sujeto(['Evidence', is, reviewed]), verbo([suggesting]), complemento([that, the, inhibition, of, 'glucose-6-phosphate', dehydrogenase, is, central, to, the, anticarcinogenic, and, 'differentiation-blocking', actions, of, 'DHEA', and, related, steroids])].
[sujeto(['The', 3, 'T3', preadipocyte, clones]), verbo([provide]), complemento([a, valuable, system, for, the, analysis, of, the, mechanisms, of, the, effects, of, 'DHEA', on, 'growth,', differentiation, and, carcinogenesis])].
[sujeto(['Dehydroepiandrosterone', '(', 3, 'beta-hydroxy-5-androsten-17-one;', 'DHEA)', and, related, steroids]), verbo([have]), complemento([widespread, protective, effects, against, spontaneous, and, chemically, induced, 'tumors,', suppress, weight, gain, without, affecting, food, 'intake,', and, depress, lipogenesis])].
[sujeto(['We']), verbo([have]), complemento([observed, that, 'DHEA', and, 16, 'alpha-bromoepiandrosterone', '(', 16, 'alpha-bromo-3', 'beta-hydroxy-5', 'alpha-androstan-17-one)', block, the, conversion, to, adipocytes, of, the, 3, 'T3-L1', and, 3, 'T3-F442A', mouse, embryo, fibroblast, clones])].
[sujeto(['The']), verbo([arrest]), complemento([of, lipogenic, conversion, was, assessed, by, measurements, of, lipid, biosynthesis, and, the, specific, activity, of, cytosolic, 'glycerol-3-phosphate', dehydrogenase])].
[sujeto(['In', the, presence, of, 215, microM, 'DHEA', or, 30, microM, 16, 'alpha-bromoepiandrosterone,', the]), verbo([increase]), complemento([in, 'glycerol-3-phosphate', activity, was, only, 50, '%', of, that, of, fully, differentiated, control, cells])].
[sujeto(['Androgen', metabolites, with, 3, 'beta-hydroxy', 'configuration--ie,', dehydroepiandrosterone, '(', 3, 'beta-hydroxy-5-androsten-17-one,', 'DHEA),', 5, -, 'androstene-3', 'beta-17', 'beta-diol', '(', 'A-Diol),', and, 5, 'alpha-androstane-3', 'beta,', 17, 'beta-diol', '(', 3, 'beta-Diol)--were', measured, by, radioimmunoassay, in, the, 'homogenate,', in, the, mechanically, separated, epithelium, and, 'stroma,', and, in, the]), verbo([nuclear]), complemento([fractions, of, epithelium, and, stroma, of, benign, hyperplastic, '(', 'BPH)', and, normal, human, prostatic, 'tissue,', in, muscle, homogenates, and, in, plasma])].
[sujeto([3, ')', 'In', the]), verbo([nuclear]), complemento([fractions, of, epithelium, and, stroma, the, values, were, low, compared, to, the, homogenates, and, could, not, be, discriminated, from, unspecific, retention])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, pulmonary, endothelium, is, an, important, site, for, the, metabolism, of, dehydroisoandrosterone, and, androstenedione, in, the, human, lung])].
[sujeto(['Steroidal', 'alpha-methylene-gamma-lactone', la]), verbo([has]), complemento([been, synthesised, from, 3, 'beta-hydroxy-5-androsten-17-one', 2, and, showed, to, be, active, against, 'HeLa', cells])].
[sujeto(['HCG']), verbo([increased]), complemento([the, conversion, of, pregnenolone, to, progesterone, and, 17, -, hydroxyprogesterone, '(', 17, -, 'hydroxy-4-pregnene-3,20-dione)', on, 5, d])].
[sujeto(['This']), verbo([suggests]), complemento([that, 'Leydig', cells, cultured, for, 5, d, have, decreased, 'C17-20', desmolase, activity, or, that, hCG, acutely, stimulates, 3, 'beta-hydroxysteroid', dehydrogenase, and, delta, 5, -, delta, 5, isomerase, activities])].
[sujeto(['We']), verbo([have]), complemento([reported, on, the, purity, of, the, enzyme, which, is, eluted, with, pyrazole, as, a, single, homogeneous, protein, using, an, 'AMP-agarose', affinity, column])].
[sujeto([3, 'beta-Hydroxy-5-androsten-17-one', '(', 'dehydroepiandrosterone)', sulphate]), verbo([has]), complemento([been, separated, from, an, extract, of, human, saliva, by, ion, exchange, gel, chromatography, and, identified, by, high, resolution, gas, 'chromatography-high', resolution, mass, spectrometry, of, the, 'tert-butyldimethylsilyl', derivative, of, the, neutral, steroid, obtained, by, enzymic, hydrolysis])].
[sujeto(['Quantitative', 'analyses,', employing, 7, ',', 7, -, 2, 'H-dehydroepiandrosterone', sulphate, as, the, internal, 'standard,']), verbo([have]), complemento([indicated, concentrations, in, the, saliva, of, young, adult, subjects, to, be, generally, in, the, range, 0.9, -, 5.7, 'nmol/l,', though, concentrations, as, high, as, 10.7, 'nmol/l', have, been, observed])].
[sujeto(['Dehydroepiandrosterone', '(', 3, 'beta-hydroxy-5-androsten-17-one,', 'I)', sulfate, '(', 'Ia)']), verbo([has]), complemento([been, characterized, in, the, anterior, and, the, posterior, parts, of, the, brain, of, adult, male, rats])].
[sujeto(['In', 'contrast,', stress, conditions, prevailing, 2, days, after, adrenalectomy, plus, orchiectomy, or, after, the, corresponding, sham, operation, resulted, in, a, significantly]), verbo([increased]), complemento([concentration, of, 'Ia', in, the, brain])].
[sujeto(['Recent', kinetic, studies, on, the, placental, microsomal, 3, 'beta-hydroxysteroid', dehydrogenase]), verbo([have]), complemento([shown, that, apparent, 'Km', values, for, 3, 'beta-hydroxy-5-androsten-17-one', '(', 'dehydroepiandrosterone)', and, 3, 'beta-hydroxy-5-pregnen-20-one', '(', 'pregnenolone)', are, 15, nM, and, 40, nM, 'respectively,', which, are, orders, of, magnitude, lower, than, found, in, earlier, studies])].
[sujeto(['The', purpose, of, this, study, was, to, investigate, the, substrate, and, nucleotide, specificity, of, the, 3, 'beta-hydroxysteroid', 'dehydrogenase,', and, the, ability, of, various, steroids, to]), verbo([inhibit]), complemento([the, reaction, at, these, lower, steroid, concentrations])].
[sujeto(['Each', steroid]), verbo([inhibited]), complemento([the, metabolism, of, the, other, 'competitively,', and, the, 'Ki', values, obtained, were, not, significantly, different, from, their, respective, 'Km', values])].
[sujeto(['The', ability, of, various, steroids, to]), verbo([inhibit]), complemento([the, reaction, at, concentrations, of, 100, nM, was, usually, less, than, that, found, at, micromolar, concentrations])].
[sujeto(['For', 'example,', estrone, and, 'estradiol-17', beta]), verbo([inhibit]), complemento([the, oxidation, of, both, substrates, competitively, with, 'Ki', values, of, between, 15, and, 24, nM])].
[sujeto(['The', pathways, of, biosynthesis, of, the, estrogens, from, 'C19', steroids]), verbo([has]), complemento([been, examined, by, in, vitro, kinetic, experiments, using, human, placental, microsomes, and, two, 'precursors,', each, labeled, with, a, different, radioisotope])].
[sujeto(['If', alternative, pathways]), verbo([involving]), complemento(['C19-hydroxylated', derivatives, of, dehydroisoandrosterone, or, its, sulfate, 'exist,', they, appear, to, be, of, minor, quantitative, significance])].
[sujeto([1.51, ')']), verbo([has]), complemento([been, developed, using, tritiated, substrates])].
[sujeto(['The', proposed, steroid, profile, is, suitable, for, routine, analysis, and]), verbo([provides]), complemento([meaningful, data, for, samples, within, normal, range, as, well, as, those, with, elevated, levels])].
[sujeto(['Dehydroepiandrosterone', sulfate, '(', 'DHEAS)', 'dose-dependently']), verbo([inhibited]), complemento(['[', 3, 'H]norepinephrine', '(', 'NE)', secretion, and, the, corresponding, '[', 'Ca2+]i', rise, induced, by, the, nicotinic, receptor, agonist, 1, ',', 1, -, 'dimethyl-4-phenylpoperazimium', '(', 'DMPP)', in, bovine, chromaffin, cells])].
[sujeto(['DHEAS', at, 10, 'microM,', the, physiological, concentration, in, human, 'serum,', significantly]), verbo([inhibited]), complemento([both, the, release, of, '[', 3, 'H]NE', and, the, rise, of, '[', 'Ca2+]i', induced, by, 'DMPP', in, chromaffin, cells])].
[sujeto(['DHEAS', also]), verbo([inhibited]), complemento([the, '[', 3, 'H]NE', release, induced, by, the, 'Na+', channel, activator, veratridine])].
[sujeto(['However,', 'DHEAS', did, not, affect, either, the, '[', 3, 'H]NE', 'release,', or, the, corresponding, '[', 'Ca2+]i', rise]), verbo([induced]), complemento([by, high, 'K+'])].
[sujeto(['Moreover,', 'DHEAS']), verbo([suppressed]), complemento([the, '[', 'Na+]i', rise, induced, by, either, 'DMPP', or, high, 'K+', as, monitored, by, the, fluorescence, 340, /, 380, ratio, of, 'SBFI', loaded, chromaffin, cells])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, the, inhibitory, effects, of, 'DHEAS', on, secretion, mainly, occur, at, nicotinic, receptors, as, well, as, at, the, 'voltage-dependent', 'Na+', channels])].
[sujeto(['However,', free, labeled, 'T4']), verbo([released]), complemento([into, the, medium, was, more, than, 'T3', after, 16, h, incubation, of, the, labeled, follicles, with, 'non-labeled', 'tyrosine,', suggesting, the, preferential, liberation, of, 'T4', from, the, labeled, peptide, 'and/or', release, from, the, cells])].
[sujeto(['By', use, of, 'site-directed', mutagenesis, and, sequence, 'comparisons,', we]), verbo([have]), complemento([identified, 'Cys-235,', 'Asp-328,', and, 'His-362', as, constituting, a, catalytic, triad, in, human, 'BACAT', '(', 'hBACAT)', and, identifying, 'BACAT', as, a, member, of, the, type, 'I', 'acyl-CoA', thioesterase, gene, family])].
[sujeto(['However,', 'BACAT', is, also]), verbo([expressed]), complemento([in, a, variety, of, tissues, unrelated, to, bile, acid, formation, and, 'transport,', suggesting, important, functions, also, in, the, regulation, of, intracellular, levels, of, very, 'long-chain', fatty, acids])].
[sujeto(['To']), verbo([prevent]), complemento(['CoASH', sequestration, and, to, facilitate, excretion, of, 'chain-shortened', carboxylic, 'acids,', 'acyl-CoA', 'thioesterases,', which, catalyze, the, hydrolysis, of, 'acyl-CoAs', to, the, free, acid, and, 'CoASH,', may, play, important, roles])].
[sujeto(['Here', we]), verbo([have]), complemento([cloned, and, characterized, a, peroxisomal, 'acyl-CoA', thioesterase, from, 'mouse,', named, 'PTE-2', '(', peroxisomal, 'acyl-CoA', thioesterase, 2, ')'])].
[sujeto(['PTE-2', is, ubiquitously]), verbo([expressed]), complemento([and, induced, at, mRNA, level, by, treatment, with, the, peroxisome, proliferator, 'WY-14,643', and, fasting])].
[sujeto(['Highest', activities, were]), verbo([found]), complemento([with, the, 'CoA', esters, of, primary, bile, acids, 'choloyl-CoA', and, 'chenodeoxycholoyl-CoA', as, substrates])].
[sujeto(['PTE-2', activity, is]), verbo([inhibited]), complemento([by, free, 'CoASH,', suggesting, that, intraperoxisomal, free, 'CoASH', levels, regulate, the, activity, of, this, enzyme])].
[sujeto(['The', 'acyl-CoA', specificity, of, recombinant, 'PTE-2', closely, resembles, that, of, purified, mouse, liver, 'peroxisomes,']), verbo([suggesting]), complemento([that, 'PTE-2', is, the, major, 'acyl-CoA', thioesterase, in, peroxisomes])].
[sujeto(['Addition', of, recombinant, 'PTE-2', to, incubations, containing, isolated, mouse, liver, peroxisomes, strongly]), verbo([inhibited]), complemento([bile, 'acid-CoA:amino', acid, 'N-acyltransferase', 'activity,', suggesting, that, this, thioesterase, can, interfere, with, 'CoASH-dependent', pathways])].
[sujeto(['However,', it]), verbo([increased]), complemento([markedly, with, age, among, 'women,', and, in, the, 'age-groups', above, 60, 'years,', the, prevalence, was, similar, between, men, and, women, '(', 26.4, vs])].
[sujeto(['FLD', was]), verbo([associated]), complemento([with, 'obesity,', increased, levels, of, total, 'cholesterol,', triglycerides, '(', 'TG),', 'low-density', 'lipoproteins,', serum, uric, 'acid,', aspartate, 'aminotransferase,', alanine, 'aminotransferase,', and, fasting, blood, 'sugar,', an, aspartate, 'aminotransferase/alanine', aminotransferase, ratio, of, less, than, 1, ',', and, a, decreased, level, of, 'high-density', lipoprotein, in, both, sexes])].
[sujeto(['Multiple', regression, analyses, showed, that, 'obesity,', elevated, levels, of, fasting, blood, 'sugar,', 'TG,', total, 'cholesterol,', and, alanine, 'aminotransferase,', an, aspartate, 'aminotransferase/alanine', aminotransferase, ratio, of, less, than, 1, ',', serum, uric, acid, 'levels,', and]), verbo([decreased]), complemento(['high-density', lipoprotein, levels, were, related, to, 'FLD', in, 'men,', whereas, age, played, a, more, prominent, role, in, women])].
[sujeto(['However,', 'female-sex', is, no, longer, protective, with]), verbo([increasing]), complemento(['age,', and, the, prevalence, of, steatohepatitis, with, advanced, fibrosis, is, estimated, to, be, considerably, higher, in, the, elderly, 'FLD', patients, than, in, the, 'non-elderly', 'FLD', controls])].
[sujeto(['Obesity', is]), verbo([associated]), complemento([with, insulin, resistance, and, type, 2, 'diabetes;', molecular, mechanisms, that, promote, energy, expenditure, can, be, utilized, for, effective, therapy])].
[sujeto(['Src-associated', in, mitosis, of, 68, kDa, '(', 'Sam68)', is, potentially, 'significant,', because, knockout, '(', 'KO)', of, 'Sam68']), verbo([leads]), complemento([to, markedly, reduced, adiposity])].
[sujeto(['In', the, present, 'study,', we, sought, to, determine, the, mechanism, by, which, 'Sam68']), verbo([regulates]), complemento([adiposity, and, energy, homeostasis])].
[sujeto(['We', first]), verbo([found]), complemento([that, 'Sam68', 'KO', mice, have, a, significantly, reduced, body, weight, as, compared, to, 'controls,', and, the, difference, is, explained, entirely, by, decreased, adiposity])].
[sujeto(['Interestingly,', these, effects, were, not]), verbo([mediated]), complemento([by, a, difference, in, food, 'intake;', 'rather,', they, were, associated, with, enhanced, physical, activity])].
[sujeto(['The', 'BAT', of, 'Sam68', 'KO', mice, exhibited, reduced, lipid, stores, and]), verbo([expressed]), complemento([higher, levels, of, 'Ucp1', and, key, thermogenic, and, fatty, acid, oxidation, genes])].
[sujeto(['Similarly,', depots, of, inguinal, and, epididymal, white, adipose, tissue, '(', 'WAT)', in, 'Sam68', 'KO', mice, appeared, 'browner,', their, multilocular, 'Ucp1-positive', cells, were, much, more, 'abundant,', and, the, expression, of, 'Ucp1,', 'Cidea,', 'Prdm16,', and, 'Ppargc1a', genes, was, greater, as, compared, to, 'WT', 'controls,', which]), verbo([suggests]), complemento([that, the, loss, of, 'Sam68', also, promotes, 'WAT', browning])].
[sujeto(['Thus,', 'Sam68', plays, a, crucial, role, in, controlling, thermogenesis, and, may, be]), verbo([targeted]), complemento([to, combat, obesity, and, associated, disorders])].
[sujeto(['Brown', adipose, tissue, '(', 'BAT)', is, a, potential, therapeutic]), verbo([target]), complemento([to, reverse, obesity])].
[sujeto(['The', purpose, of, this, study, was, to, determine, whether, primary, precursor, cells, isolated, from, human, adult, subcutaneous, white, adipose, tissue, '(', 'WAT)', can, be]), verbo([induced]), complemento([to, differentiate, 'in-vitro', into, adipocytes, that, express, key, markers, of, brown, or, beige, 'adipose,', and, whether, the, expression, level, of, such, markers, differs, between, lean, and, obese, young, adult, males])].
[sujeto(['WAT', genes, '(', 'HOXC9,', 'RB1)', were]), verbo([expressed]), complemento([equally, in, the, two, groups])].
[sujeto(['Post', 'differentiation,', the, beige, adipose, specific, genes, 'CITED1', and, 'CD137', were, significantly]), verbo([increased]), complemento([in, both, 'groups,', but, classic, 'BAT', markers, 'ZIC1', and, 'LHX8', decreased, significantly])].
[sujeto(['Cell', lines, from, both, groups, also, equally]), verbo([increased]), complemento(['post-differentiation', expression, of, the, 'thermogenic-responsive', gene, 'PPARGC1A', '(', 'PGC-1α)'])].
[sujeto(['UCP1', gene, expression, was, undetectable, prior, to, 'differentiation,', however, after, differentiation, both, gene, expression, and, protein, content, were]), verbo([increased]), complemento([in, both, groups, and, were, significantly, greater, in, cultures, from, lean, compared, with, obese, individuals, '(', 'p<0'])].
[sujeto(['Human', subcutaneous, 'WAT', cells, can, be]), verbo([induced]), complemento([to, attain, 'BAT', 'characteristics,', but, this, capacity, is, reduced, in, 'WAT', cells, from, obese, individuals])].
[sujeto(['We', investigated, 'estrogen,', 'BZA', and, 'TSEC', effects, in]), verbo([preventing]), complemento([diabetisity, in, ovariectomized, mice, during, 'high-fat', feeding])].
[sujeto(['Estrogen,', 'BZA', or, 'TSEC']), verbo([prevented]), complemento([fat, accumulation, in, adipose, 'tissue,', liver, and, skeletal, 'muscle,', and, improved, insulin, resistance, and, glucose, intolerance, without, stimulating, uterine, growth])].
[sujeto(['Estrogen,', 'BZA', and, 'TSEC', improved, energy, homeostasis, by]), verbo([increasing]), complemento([lipid, oxidation, and, energy, 'expenditure,', and, promoted, insulin, action, by, enhancing, 'insulin-stimulated', glucose, disposal, and, suppressing, hepatic, glucose, production])].
[sujeto(['While', estrogen, improved, metabolic, 'homeostasis,', at, least, 'partially,', by]), verbo([increasing]), complemento([hepatic, production, of, 'FGF21,', 'BZA', increased, hepatic, expression, of, 'Sirtuin1,', 'PPARα', and, 'AMPK', activity])].
[sujeto(['This', life, history]), verbo([confers]), complemento([variability, to, 'BAT', recruitment, and, activity])].
[sujeto(['The', heterothermic, proteome, varied, less, despite, extreme, winter, physiological, shifts, and, was, optimized, to, exploit, lipids, by]), verbo([enhanced]), complemento([fatty, acid, 'binding,', 'β-oxidation,', and, mitochondrial, protein, translocation])].
[sujeto(['During', fall, 'transition,', differential, regulation, of, two, fatty, acid]), verbo([binding]), complemento([proteins, provides, further, evidence, of, recruitment, and, separates, proteomic, preparation, from, successful, hibernation])].
[sujeto(['Metabolically', active, 'BAT', is, a]), verbo([target]), complemento([for, treating, human, obesity, and, metabolic, disorders])].
[sujeto(['Brown', adipose, tissue, '(', 'BAT)', produces, heat, using, chemical, energy, of, lipids, and, 'glucose,', a, function]), verbo([induced]), complemento([by, cold, exposure, or, diet])].
[sujeto(['MiR-27', is, also, downregulated, during, brown, adipogenesis, of, primary, preadipocytes, in, 'vitro,', and, it, directly]), verbo([targets]), complemento([and, negatively, regulates, the, essential, components, of, the, brown, transcriptional, 'network:', 'Prdm16,', 'Pparα,', 'Creb,', and, in, part, 'Pgc1β'])].
[sujeto(['Together', with, its, direct, effect, on, 'Pparγ,', and, indirect, on, 'Pgc1α,', 'mir-27']), verbo([decreases]), complemento([brown, differentiation, of, cultured, cells, and, of, primary, 'SAT', preadipocytes])].
[sujeto(['Our', results, point, to, 'miR-27', as, a, central, upstream, regulator, of, the, transcriptional, network]), verbo([involved]), complemento([in, beige, and, brown, adipogenesis, after, cold, 'exposure,', and, suggest, 'miR-27', inhibition, as, a, novel, therapeutic, approach, for, metabolic, diseases, aiming, at, increasing, the, 'beige/brown', fat, mass])].
[sujeto(['However,', this, system, necessitates, an]), verbo([increase]), complemento([of, the, 'Uncoupling', protein, 1, '(', 'Ucp1)', and, its, activation, by, free, fatty, acids])].
[sujeto(['Upon', 'cold-exposure,', 'Heat', shock, factor, 1, '(', 'HSF1)']), verbo([induced]), complemento(['Per2', in, the, 'BAT'])].
[sujeto(['Subsequently,', 'PER2', as, a, 'co-activator', of, 'PPARα']), verbo([increased]), complemento([expression, of, 'Ucp1'])].
[sujeto(['PER2', also]), verbo([increased]), complemento(['Fatty', acid, binding, protein, 3, '(', 'Fabp3),', a, protein, important, to, transport, free, fatty, acids, from, the, plasma, to, mitochondria, to, activate, 'UCP1'])].
[sujeto(['ALKO', mice, displayed, a, profound]), verbo([increase]), complemento([in, 'DNL-fatty', 'acids,', especially, palmitoleate, and, myristoleate, in, brown, adipose, tissue, '(', 'BAT)', and, white, adipose, tissue, '(', 'WAT)', depots, while, essential, dietary, fatty, acids, were, markedly, decreased])].
[sujeto(['Consequently,', we]), verbo([found]), complemento([increased, expression, in, adipose, tissues, of, genes, encoding, 'DNL', enzymes, '(', 'Fasn,', 'Scd1,', and, 'Elovl6)', as, well, as, the, lipogenic, transcription, factor, carbohydrate, response, element, binding, 'protein-β'])].
[sujeto(['No', signs, of]), verbo([increased]), complemento(['BAT', activation, or, 'WAT', browning, were, detected, in, aLKO, mice, either, on, 'HFD', or, after, 1, week, of, 'β3-adrenergic', stimulation, using, 'CL316,243'])].
[sujeto(['We', conclude, that, despite, a, profound]), verbo([increase]), complemento([in, 'DNL-derived', fatty, 'acids,', proposed, to, be, metabolically, 'favorable,', aLKO, mice, are, not, protected, from, metabolic, disease, per, se])].
[sujeto(['In', 'addition,', induction, of, 'DNL', alone, is, not, sufficient, to]), verbo([promote]), complemento([browning, of, 'WAT'])].
[sujeto(['Adipose-specific', inactivation, of, both, 'AP-1', and, 'CCAAT-enhancer-binding', protein, '(', 'C/EBP)', families, of, 'B-ZIP', transcription, factors, in, transgenic, mice]), verbo([causes]), complemento([severe, lipoatrophy])].
[sujeto(['To', evaluate, whether, inactivation, of, only, 'C/EBP', members, was, critical, for, 'lipoatrophy,', 'A-C/EBP,', a, 'dominant-negative', protein, that, specifically]), verbo([inhibits]), complemento([the, 'DNA', binding, of, the, 'C/EBP', 'members,', was, expressed, in, adipose, tissue])].
[sujeto(['In', 'adults,', 'BAT', remained, 'reduced,']), verbo([causing]), complemento([cold, intolerance])].
[sujeto(['Insulin', 'resistance,', glucose, 'intolerance,', and, reduced, free, fatty, acid]), verbo([release]), complemento([in, response, to, 'β3-adrenergic', agonist, suggest, improper, functioning, of, the, residual, 'WAT'])].
[sujeto(['Gene', expression, analysis, of, inguinal, 'WAT', identified, reduced, mRNA, levels, of, several, enzymes]), verbo([involved]), complemento([in, fatty, acid, synthesis, and, glucose, metabolism, that, are, known, 'C/EBPα', transcriptional, targets])].
[sujeto(['There', were]), verbo([increased]), complemento([levels, for, genes, involved, in, inflammation, and, muscle, differentiation])].
[sujeto(['Molecular', modeling, was, undertaken, at, aims, to, analyze, the, interactions, between, oleic, acid, and, human, leukocyte, elastase, '(', 'HLE),', plasmin, and, matrix, 'metalloproteinase-2', '(', 'MMP-2),']), verbo([involved]), complemento([in, the, inhibitory, capacity, of, fatty, acid, towards, those, proteases])].
[sujeto(['The', carboxylic, acid, group, of, the, fatty, acid, was]), verbo([found]), complemento([to, form, a, salt, bridge, with, 'Arg(217)', of, 'HLE', while, unsaturation, interacted, with, 'Phe(192)', and, 'Val(216)', at, the, 'S(3)', 'subsite,', and, alkyl, end, group, occupied, 'S(1)', subsite])].
[sujeto(['Several', residues]), verbo([involved]), complemento([in, 'Fn(II)(3)/oleic', acid, interaction, were, similarly, implicated, in, binding, of, this, domain, to, collagen])].
[sujeto(['OL-GALs', were]), verbo([found]), complemento([less, potent, 'MMP', inhibitors, as, compared, to, galardin, and, no, selectivity, for, 'MMP-2', or, 'MMP-9', could, be, demonstrated])].
[sujeto(['Docking', computations, indicated, that, contrary, to, oleic, 'acid,', 'OL-GAL']), verbo([binds]), complemento([only, to, 'MMP-2', active, site, and, 'surprisingly,', hydroxamic, acid, was, unable, to, chelate, 'Zn,', but, instead, forms, a, salt, bridge, with, the, 'N-terminal', 'Tyr(110)'])].
[sujeto(['Interestingly,', oleic, acid, and, particularly, 'OL-GALs', proved, to, potently]), verbo([inhibit]), complemento(['MMP-13'])].
[sujeto(['OL-GAL', was]), verbo([found]), complemento([as, potent, as, galardin, '(', 'K(i)', equal, to, 1.8, nM, for, 'OL-GAL', and, 1.45, nM, for, 'GAL)', and, selectivity, for, that, 'MMP', was, attained, '(', 2, -, 3, log, orders, of, difference, in, inhibitory, potency, as, compared, to, other, 'MMPs)'])].
[sujeto(['OL-GAL', also, occupied, such, pocket, but, hydroxamic, acid, did, not]), verbo([interact]), complemento([with, 'Zn', but, instead, was, located, at, 2.8, 'Å', from, 'Tyr(176)'])].
[sujeto(['Since', these, derivatives, 'retained,', as, their, oleic, acid, original, 'counterpart,', the, capacity, to]), verbo([inhibit]), complemento([the, amidolytic, activity, of, 'HLE', and, plasmin, as, well, as, to, decrease, 'HLE-', and, 'plasmin-mediated', pro, 'MMP-3', 'activation,', they, might, be, of, therapeutic, value, to, control, proteolytic, cascades, in, chronic, inflammatory, disorders])].
[sujeto(['This', thermogenic, effect, helps, to]), verbo([maintain]), complemento([body, temperature, and, also, plays, a, critical, role, in, energy, homeostasis, and, the, regulation, of, body, weight])].
[sujeto(['New', evidence]), verbo([has]), complemento([defined, the, essential, role, of, the, 'cGMP-dependent', protein, kinase, 'I', in, a, pathway, that, modulates, the, 'RhoA-ROCK', pathway, and, insulin, receptor, signaling, to, elicit, 'BAT', differentiation, and, stimulate, thermogenesis])].
[sujeto(['The', expression, of, 'FABP3', mRNA, in, 'BAT', was]), verbo([regulated]), complemento([discriminatively, in, response, to, alteration, of, the, ambient, 'temperature,', which, regulation, was, similar, and, reciprocal, to, the, regulation, of, uncoupling, protein, 1, '(', 'UCP1)', and, 'leptin,', respectively])].
[sujeto(['In', 'addition,', 'FABP3', expression, in, the, 'BAT', was]), verbo([increased]), complemento([greatly, with, the, development, of, 'diet-induced', obesity, in, mice])].
[sujeto(['These', results, indicate, that, the, induction, of, 'FABP3', in, 'BAT', correlates, with, an]), verbo([increased]), complemento([demand, for, adaptive, thermogenesis, in, rodents])].
[sujeto(['Treatment']), verbo([decreased]), complemento([liver, triglyceride, '(', 'TG)', content, by, &, 'gt;50%,', normalized, plasma, glucose, and, insulin, 'levels,', and, reduced, glucose, excursion, during, glucose, tolerance, test])].
[sujeto([5, '%']), verbo([increase]), complemento([in, metabolic, 'rate,', &, 'gt;40%', increase, in, 'UCP1', levels, in, 'BAT,', &, 'gt;45%', increase, in, 'beta(3)-adrenoceptor', 'mRNA,', and, 40, -, 55, '%', decrease, in, mitochondrial, dicarboxylate, 'carrier,', fatty, acid, 'synthase,', and, diacylglycerol, acyltransferase, 2, mRNA, levels, in, 'WAT'])].
[sujeto(['4E-BP2', 'ASO-transfected', mouse, hepatocytes, showed, an]), verbo([increased]), complemento([fatty, acid, oxidation, rate, and, a, decreased, 'TG', synthesis, rate])].
[sujeto(['In', 'addition,', '4E-BP2', 'ASO-treated', mice, demonstrated, approximately, 60, and, 29, '%']), verbo([decreases]), complemento([in, hepatic, 'glucose-6-phosphatase', and, phosphoenolpyruvate, carboxykinase, 'mRNA,', 'respectively,', implying, decreased, hepatic, glucose, output])].
[sujeto(['Furthermore,']), verbo([increased]), complemento([phosphorylation, of, 'Akt(Ser473)', in, both, liver, and, fat, of, '4E-BP2', 'ASO-treated', mice, and, increased, 'GLUT4', levels, in, plasma, membrane, in, 'WAT', of, the, 'ASO-treated', mice, were, 'observed,', indicating, enhanced, insulin, signaling, and, increased, glucose, uptake, as, a, consequence, of, reduced, '4E-BP2', expression])].
[sujeto(['To', investigate, the, relationship, between, chemical, structure, and, physiological, 'effect,', the, efficacy, and, the, molecular, mechanisms]), verbo([involved]), complemento([in, the, reduction, of, body, weight, by, 'C18', fatty, acids, '(', 'stearic,', 'elaidic,', 'oleic,', linoleic, and, 2, -, hydroxyoleic, acids, '(', 2, -, 'OHOA))'])].
[sujeto(['Only', treatment, with, oleic, acid, and, 2, -, 'OHOA']), verbo([induced]), complemento([body, weight, loss, '(', 3.3, and, 11.4, '%', ',', 'respectively)', through, reduction, of, adipose, fat, mass])].
[sujeto(['UCP1', expression, and, phosphorylation, of, 'CREB', was, drastically]), verbo([increased]), complemento([in, 'WAT,', but, not, 'BAT', of, 2, -, 'OHOA-treated', 'rats,', whereas, no, 'UCP1', expression, could, be, detected, in, 'WAT', of, rats, treated, with, oleic, acid])].
[sujeto(['Both', 'cis-configured', monounsaturated, 'C18', fatty, acids, '(', oleic, acid, and, 2, -, 'OHOA)', reduce, body, 'weight,', but, the, introduction, of, a, hydroxyl, group, in, position, 2, drastically]), verbo([increases]), complemento([loss, of, adipose, tissue, mass])].
[sujeto(['The', novel, molecular, mechanism, unique, to, 2, -, 'hydroxyoleic,', but, not, oleic, 'acid,', implies, induction, of, 'UCP1', expression, in, 'WAT', by, the, 'cAMP/PKA', 'pathway-dependent', transcription, factor, 'CREB,', most, probably, as, part, of, a, transdifferentiation, process, accompanied, by]), verbo([enhanced]), complemento([energy, expenditure])].
[sujeto(['Uptake', of, 'TG-derived', fatty, acids, 'was,', 'however,']), verbo([increased]), complemento([in, oxidative, 'tissues,', including, red, gastrocnemius, '(', +, 47, '%', ')', ',', heart, '(', +, 39, '%', ')', ',', and, brown, adipose, tissue, '(', 'BAT,', +, 46, '%', ')', at, the, expense, of, the, 'liver,', with, a, concomitant, increase, in, plasma, membrane, fatty, 'acid-binding', protein])].
[sujeto(['Lipid', oxidation, products, were]), verbo([increased]), complemento([in, red, gastrocnemius, '(', +, 35, '%', ')', and, heart, '(', +, 33, '%', ')', ',', as, were, levels, of, uncoupling, protein, 1, mRNA, in, 'BAT', '(', +, 48, '%', ')', ',', and, carnitine, palmitoyltransferase, 1, activity, tended, to, be, increased, in, some, oxidative, tissues])].
[sujeto(['These', findings, demonstrate, that, pharmacological, inhibition, of, 11, 'beta-HSD1', at, a, dose, that, does, not, affect, food, intake, improves, triglyceridemia, by, reducing, hepatic, very, low, density, 'lipoprotein-TG', 'secretion,', with, a, shift, in, the, pattern, of, 'TG-derived', fatty, acid, uptake, toward, oxidative, 'tissues,', in, which, lipid, accumulation, is]), verbo([prevented]), complemento([by, increased, lipid, oxidation])].
[sujeto(['Both', 'BAT', and, 'WAT', were, the, major, sites, of, 'RSG', action, on, 'TG', 'clearance,', the]), verbo([increase]), complemento([in, 'TG-derived', fatty, acid, '(', 'FA)', uptake, reaching, threefold, in, 'BAT', and, 60, -, 90, '%', in, 'WAT', depots])].
[sujeto(['Accelerated', 'TG', clearance, was]), verbo([associated]), complemento([with, increased, lipoprotein, lipase, '(', 'LPL)', activity, mostly, in, 'BAT'])].
[sujeto(['Serum', nonesterified, 'FA', were, lowered, '(', -, 20, '%', ')', by, a, single, dose, of, 'RSG,', an, effect]), verbo([associated]), complemento([with, increased, expression, levels, of, 'FA', 'binding/transport', '(', fatty, acid, binding, 'protein-4),', esterification, '(', diacylglycerol, 'acyltransferase-1),', and, recycling, glycerol, kinase, and, phosphoenolpyruvate, carboxykinase, enzymes, in, 'BAT', and, 'WAT,', suggesting, 'FA', trapping])].
[sujeto(['After', 4, days, of, 'RSG', 'treatment,', nonesterified, fatty, acid, '(', 'NEFA)', uptake, was, also]), verbo([stimulated]), complemento([in, both, 'BAT', '(', 2.5, -, 'fold)', and, 'WAT', '(', 40, '%', ')'])].
[sujeto(['These', findings, demonstrate, the, causal, involvement, of]), verbo([increased]), complemento([efficiency, of, 'LPL-mediated', 'TG', clearance, and, reveal, the, important, contribution, of, 'TG-derived', and, 'albumin-bound', 'FA', uptake, by, 'BAT', in, the, rapid, hypolipidemic, action, of, 'PPARgamma', agonism, in, the, rat])].
[sujeto(['Thermogenic', uncoupling]), verbo([has]), complemento([been, proven, only, for, 'UCP1', in, brown, adipose, tissue])].
[sujeto(['All', other, isoforms, of, 'UCPs', are, potentially]), verbo([acting]), complemento([in, suppression, of, mitochondrial, reactive, oxygen, species, '(', 'ROS)', production])].
[sujeto(['Respiration']), verbo([increased]), complemento([up, to, 3, times, when, related, to, the, lowest, fatty, acid, content, '(', 'BSA', present, plus, carnitine, 'cycle)'])].
[sujeto(['We', also, illustrated, that, any, effect]), verbo([leading]), complemento([to, more, coupled, states, leads, to, enhanced, 'H2O2', generation, and, any, effect, resulting, in, uncoupling, gives, reduced, 'H2O2', generation, in, 'BAT', mitochondria])].
[sujeto(['Finally,', we]), verbo([report]), complemento([doubling, of, plant, 'UCP', transcript, in, cells, as, well, as, amount, of, protein, detected, by, 3, 'H-GTP-binding', sites, in, mitochondria, of, shoots, and, roots, of, maize, seedlings, subjected, to, the, salt, stress])].
[sujeto(['Chronic', administration, of, leptin]), verbo([has]), complemento([been, shown, to, reduce, adiposity, through, energy, intake, and, expenditure])].
[sujeto(['The', present, study, aims, to, examine, how, acute, central, infusion, of, leptin]), verbo([regulates]), complemento([peripheral, lipid, 'metabolism,', as, assessed, by, markers, indicative, of, their, mobilization, and, utilization])].
[sujeto(['A', bolus, infusion, of, 1, 'microg/rat', leptin, into, the, third, cerebroventricle]), verbo([increased]), complemento([the, expression, of, mRNA, for, 'hormone-sensitive', lipase, '(', 'HSL),', an, indicator, of, 'lipolysis,', in, white, adipose, tissue, '(', 'WAT)'])].
[sujeto(['The', same, treatment, with, leptin]), verbo([decreased]), complemento([plasma, insulin, levels, but, did, not, affect, the, plasma, glucose, level, '(', 'P', &, 'lt;', 0.05, for, 'insulin)'])].
[sujeto(['Among', the, major, regulators, of, the, transportation, or, utilization, of, energy, 'substrates,', leptin, treatment]), verbo([increased]), complemento([expression, of, mRNA, for, uncoupling, protein, 1, '(', 'UCP1)', in, brown, adipose, tissue, '(', 'BAT),', 'UCP2', in, 'WAT,', and, 'UCP3', in, quadriceps, skeletal, 'muscle,', but, not, those, for, fatty, 'acid-binding', protein, in, 'WAT,', carnitine, phosphate, 'transferase-1,', a, marker, for, beta, oxidation, of, fatty, acids, in, 'muscle,', nor, glucose, transporter, 4, in, 'WAT', and, muscle, '(', 'P', &, 'lt;', 0.01, for, 'HSL,', 'P', &, 'lt;', 0.05, for, 'UCP1,', and, 'P', &, 'lt;', 0.005, for, 'UCP2', and, 'UCP3)'])].
[sujeto(['These', results, indicate, 'that,', even, in, a, single, 'bolus,', leptin, may]), verbo([regulate]), complemento([the, mobilization, 'and/or', utilization, of, energy, substrates, such, as, fatty, acids, by, affecting, lipolytic, activity, in, 'WAT', and, by, increasing, the, expression, of, 'UCPs', in, 'BAT,', 'WAT,', and, muscle])].
[sujeto(['Restricting', food, intake, to, a, level, below, that, consumed, voluntarily, '(', 85, '%', ',', 70, '%', and, 50, '%', of, the, ad, libitum, energy, intake, for, 3, or, 30, 'days)', and, 're-feeding', ad, libitum, for, 48, h, results, in, an]), verbo([increase]), complemento([of, malic, enzyme, '(', 'ME)', gene, expression, in, rat, white, adipose, tissue])].
[sujeto(['The']), verbo([increase]), complemento([of, 'ME', gene, expression, was, much, more, pronounced, in, rats, maintained, on, restricted, diet, for, 30, days, than, for, 3, days])].
[sujeto(['A', similar]), verbo([increase]), complemento([of, serum, insulin, concentration, was, observed, in, all, groups, at, different, degrees, of, caloric, restriction, and, refed, ad, libitum, for, 48, h])].
[sujeto(['Caloric', restriction, and, refeeding]), verbo([caused]), complemento([on, increase, of, 'ME', activity, also, in, brown, adipose, tissue, '(', 'BAT)', and, liver])].
[sujeto(['However,', in, liver, a, significant]), verbo([increase]), complemento([of, 'ME', activity, was, found, only, in, rats, maintained, on, the, restricted, diet, for, 30, days])].
[sujeto(['No', significant, changes, after, caloric, restriction, and, refeeding, were]), verbo([found]), complemento([in, 'heart,', skeletal, 'muscle,', kidney, 'cortex,', and, brain])].
[sujeto(['These', data, indicate, that, the]), verbo([increase]), complemento([of, 'ME', gene, expression, after, caloric, 'restriction/refeeding', occurs, only, in, lipogenic, tissues])].
[sujeto(['Thus,', one, can, conclude, that, caloric, 'restriction/refeeding']), verbo([increases]), complemento([the, enzymatic, capacity, for, fatty, acid, biosynthesis])].
[sujeto(['Two', types, of, adipose, 'tissues,', white, '(', 'WAT)', and, brown, '(', 'BAT)', are]), verbo([found]), complemento([in, mammals])].
[sujeto(['Increasingly', novel, strategies, are, being, proposed, for, the, treatment, of, obesity, and, its]), verbo([associated]), complemento([complications, by, altering, amount, 'and/or', activity, of, 'BAT', using, mouse, models])].
[sujeto(['Our', study]), verbo([provides]), complemento([evidence, for, inter, species, '(', mouse, vs, 'human)', differences, in, differential, gene, expression, between, sWAT, and, 'BAT'])].
[sujeto(['Receptor-interacting', protein, 140, '(', 'RIP140)', is, a, corepressor, of]), verbo([nuclear]), complemento([receptors, that, is, highly, expressed, in, adipose, tissues])].
[sujeto(['In', 'contrast,', 'RIP140', knockout, sc, white, adipose, tissue, '(', 'WAT)', shows]), verbo([increased]), complemento([numbers, of, multilocular, adipocytes, with, elevated, staining, for, uncoupling, protein, 1, and, 'CIDEA'])].
[sujeto(['Furthermore', in, a, white, adipocyte, cell, 'line,', the, markers, of, 'BRITE', 'adipocytes,', 'Tbx1,', 'CD137,', 'Tmem26,', 'Cited1,', and, 'Epsti1', were]), verbo([repressed]), complemento([in, the, presence, of, 'RIP140', as, was, 'Prdm16'])].
[sujeto(['Microarray', analysis, of, 'wild-type', and, 'RIP140-knockout', white, fat, revealed, elevated, expression, of, genes]), verbo([associated]), complemento([with, 'cold-induced', expression, or, high, expression, in, 'BAT'])].
[sujeto(['A', set, of, genes]), verbo([associated]), complemento([with, a, futile, cycle, of, triacylglycerol, breakdown, and, resynthesis, and, functional, assays, revealed, that, glycerol, kinase, and, 'glycerol-3-phosphate', dehydrogenase, activity, as, well, as, '[', '(', 3, ')', 'H]glycerol', incorporation, were, elevated, in, the, absence, of, 'RIP140'])].
[sujeto(['Thus,', 'RIP140', blocks, the, 'BRITE', program, in, 'WAT,']), verbo([preventing]), complemento([the, expression, of, brown, fat, genes, and, inhibiting, a, triacylglycerol, futile, 'cycle,', with, important, implications, for, energy, homeostasis])].
[sujeto(['FABP3-5', were]), verbo([expressed]), complemento([in, 'BAT', of, both, rats, maintained, at, room, temperature, and, those, exposed, to, the, cold])].
[sujeto(['FABP4', was, the, most, abundantly]), verbo([expressed]), complemento(['isoform,', but, its, transcript, level, was, not, significantly, affected, by, cold, exposure])].
[sujeto(['FABP3', was, slightly]), verbo([expressed]), complemento([in, the, 'BAT', of, rats, maintained, at, room, temperature, and, its, transcript, level, was, elevated, ten, fold, by, cold, exposure])].
[sujeto(['Indeed,', to, 'date,', no, mammal]), verbo([has]), complemento([been, known, to, have, evolved, physiological, mechanisms, to, incorporate, and, deposit, carotenoids, in, the, skin, or, 'hair,', and, mammals, have, therefore, been, assumed, to, rely, entirely, on, other, pigments, such, as, melanins, to, color, their, integument])].
[sujeto(['This', represents, a, change, of, paradigm, in, animal, physiology, showing, that, some, mammals, actually]), verbo([have]), complemento([the, capacity, to, accumulate, dietary, carotenoids, in, the, integument])].
[sujeto(['In', 'addition,', we]), verbo([have]), complemento([also, discovered, that, the, majority, of, the, lutein, in, the, skin, of, 'Honduran', white, bats, is, present, in, esterified, form, with, fatty, 'acids,', thereby, permitting, 'longer-lasting', coloration, and, suggesting, bright, color, traits, may, have, an, overlooked, role, in, the, visual, communication, of, bats])].
[sujeto(['VAAM']), verbo([enhanced]), complemento([physical, endurance, of, mice, and, have, been, used, by, athletes, as, a, supplementary, drink, before, exercise])].
[sujeto(['This', analysis, showed, that, estrogenic, and, glucagon, signals, were]), verbo([activated]), complemento([in, the, liver, and, 'WAT', and, that, 'beta-adrenergic', signaling, was, activated, in, all, three, tissues])].
[sujeto(['We']), verbo([found]), complemento([that, 'VAAM', ingestion, had, an, effect, on, multiple, tissue, transcriptomes, of, freely, moving, mice])].
[sujeto(['Utilization', of, glycogenic, amino, acids, may]), verbo([have]), complemento([been, activated, in, the, liver])].
[sujeto(['Fatty', acid, conversion, into, 'phospholipid,', not, to, 'triacylglycerol,', may]), verbo([have]), complemento([been, stimulated, in, adipocytes, contrasting, that, a, little, effect, was, observed, in, 'BAT'])].
[sujeto(['Analysis', of, upstream, factors, revealed, that, multiple, hormonal, signals, were]), verbo([activated]), complemento([in, the, 'liver,', 'WAT,', and, 'BAT'])].
[sujeto(['Our', data]), verbo([provide]), complemento([some, clues, to, understanding, the, role, of, 'VAAM', in, metabolic, regulation])].
[sujeto(['The', addition, of, 'C12TPP', to, isolated, 'brown-fat', mitochondria, resulted, in]), verbo([increased]), complemento([oxygen, consumption])].
[sujeto(['Three', hours, of, 'pre-treatment', with, 'C12TPP', also]), verbo([increased]), complemento(['oligomycin-insensitive', oxygen, consumption, in, brown, adipocyte, cultures, '(', 'P<0'])].
[sujeto(['However,', 'C12TPP', treatment]), verbo([increased]), complemento([the, mitochondrial, protein, levels, in, the, brown, adipose, tissue, '(', 'BAT)', of, both, 'wild-type', and, 'UCP1-KO', mice])].
[sujeto(['Pair-feeding', revealed, that, 'one-third', of, the, body, weight]), verbo([loss]), complemento([in, 'C12TPP-treated', mice, was, due, to, reduced, food, intake])].
[sujeto(['C12TPP', reduced, the, respiratory, exchange, ratio, '(', 'RER),', indicating]), verbo([enhanced]), complemento([fatty, acid, oxidation, in, mice])].
[sujeto(['C12TPP', combats, 'diet-induced', obesity, by, reducing, food, 'intake,']), verbo([increasing]), complemento([the, 'RMR', and, enhancing, fatty, acid, oxidation])].
[sujeto(['Emerging', evidence]), verbo([suggests]), complemento([that, 'n-3', poly, unsaturated, fatty, acids, '(', 'PUFA)', promote, 'BAT', thermogenesis])].
[sujeto(['Here,', we, hypothesize, that, 'n-3', 'PUFA']), verbo([promote]), complemento([brown, adipogenesis, by, modulating, miRNAs])].
[sujeto(['To', test, this, 'hypothesis,', murine, brown, preadipocytes, were]), verbo([induced]), complemento([to, differentiate, with, fatty, acids, of, palmitic, '(', 'PA),', oleate, '(', 'OA),', or, eicosapentaenoic, acid, '(', 'EPA)'])].
[sujeto(['The']), verbo([increase]), complemento([of, 'brown-specific', signature, genes, and, oxygen, consumption, rate, '(', 'OCR)', by, 'EPA', were, concurrent, with, upregulation, of, 'miR-30b', and, 378, ',', but, not, by, 'OA', or, 'PA'])].
[sujeto(['Next,', we, hypothesize, that, free, fatty, acid, receptor, 4, '(', 'FFAR4),', a, functional, receptor, for, 'n-3', 'PUFA,']), verbo([modulates]), complemento(['miR-30b', and, 378])].
[sujeto(['Treatment', of, 'FFAR4', agonist, '(', 'GW9805)', recapitulated, the, thermogenic, activation, of, 'EPA', by]), verbo([increasing]), complemento(['OCR,', 'brown-specific', marker, 'genes,', and, 'miR-30b', and, 378, ',', which, were, abrogated, in, 'FFAR4-silenced', cells])].
[sujeto(['Intriguingly,', addition, of, 'miR-30b', mimic, was, unable, to, restore, 'EPA-induced', 'Ucp1', expression, in, 'FFAR4-depleted', 'cells,', implicating, that, 'FFAR4', signaling, activity, is]), verbo([required]), complemento([for, upregulating, 'brown-adipogenic', program])].
[sujeto(['Moreover,', blockage, of, 'miR-30b', or, 378, by, 'LNA', inhibitors, significantly, attenuated, 'FFAR4', as, well, as, 'brown-specific', signature, gene, 'expression,']), verbo([suggesting]), complemento([the, signaling, interplay, between, 'FFAR4', and, 'miR-30b/378'])].
[sujeto(['Taken', 'together,', our, work, identifies, a, novel, function, of, 'FFAR4', in]), verbo([modulating]), complemento([brown, adipogenesis, partly, through, a, mechanism, involving, cAMP, activation, and, upregulation, of, 'miR-30b', and, 'miR-378'])].
[sujeto(['Bone', marrow, adipose, tissue, '(', 'BMAT)', emerges, as, a, distinct, fat, depot, whose, importance]), verbo([has]), complemento([been, proved, in, the, 'bone-fat', interaction])].
[sujeto(['Indeed,', it, is, well]), verbo([recognized]), complemento([that, adipokines, and, free, fatty, acids, released, by, adipocytes, can, directly, or, indirectly, interfere, with, cells, of, bone, remodeling, or, hematopoiesis])].
[sujeto(['In', pathological, 'states,', such, as, 'osteoporosis,', each, of, adipose, tissues, -, subcutaneous, white, adipose, tissue, '(', 'WAT),', visceral, 'WAT,', brown, adipose, tissue, '(', 'BAT),', and, 'BMAT', -, is, differently]), verbo([associated]), complemento([with, bone, mineral, density, '(', 'BMD)', variations])].
[sujeto(['BMAT', quantity, is, well]), verbo([associated]), complemento([with, 'BMD', loss, in, 'aging,', 'menopause,', and, other, metabolic, 'conditions,', such, as, anorexia, nervosa])].
[sujeto(['Following', an, ordered, spatiotemporal, 'expansion,', 'BMAT']), verbo([has]), complemento([turned, to, be, a, heterogeneous, fat, depot, whose, adipocytes, diverge, in, their, phenotype, and, their, response, to, stimuli, according, to, their, location, in, bone, and, 'BM'])].
[sujeto(['In', 'vitro,', in, 'vivo,', and, clinical, studies, point, to, a, detrimental, role, of, 'BM', adipocytes, '(', 'BMAs)', throughout, the]), verbo([release]), complemento([of, paracrine, factors, that, modulate, osteoblast, 'and/or', osteoclast, formation, and, function])].
[sujeto(['The', discovery, of, active, brown, adipose, tissue, '(', 'BAT)', in, adult, humans, and, the, fact, that, it, is, reduced, in, obese, and, diabetic, patients]), verbo([have]), complemento([put, a, spotlight, on, this, tissue, as, a, key, player, in, 'obesity-induced', metabolic, disorders])].
[sujeto(['BAT']), verbo([regulates]), complemento([energy, expenditure, through, 'thermogenesis;', 'therefore,', harnessing, its, thermogenic, 'fat-burning', power, is, an, attractive, therapeutic, approach])].
[sujeto(['We', aimed, to]), verbo([enhance]), complemento(['BAT', thermogenesis, by, increasing, its, fatty, acid, oxidation, '(', 'FAO)', rate])].
[sujeto(['Thus,', we]), verbo([expressed]), complemento([carnitine, palmitoyltransferase, 1, 'AM', '(', 'CPT1AM),', a, permanently, active, mutant, form, of, 'CPT1A', '(', the, 'rate-limiting', enzyme, in, 'FAO),', in, a, rat, brown, adipocyte, '(', 'rBA)', cell, line, through, adenoviral, infection])].
[sujeto(['We']), verbo([found]), complemento([that, 'CPT1AM-expressing', rBA, have, increased, 'FAO,', 'lipolysis,', 'UCP1', protein, levels, and, mitochondrial, activity])].
[sujeto(['Additionally,']), verbo([enhanced]), complemento(['FAO', reduced, the, 'palmitate-induced', increase, in, triglyceride, content, and, the, expression, of, obese, and, inflammatory, markers])].
[sujeto(['Thus,', 'CPT1AM-expressing', rBA, had]), verbo([enhanced]), complemento(['fat-burning', capacity, and, improved, 'lipid-induced', derangements])].
[sujeto(['This', indicates, that, 'CPT1AM-mediated']), verbo([increase]), complemento([in, brown, adipocytes, 'FAO', may, be, a, new, approach, to, the, treatment, of, 'obesity-induced', disorders])].
[sujeto(['WAT', is, the, main, source, of, stored, energy, and]), verbo([releases]), complemento([fatty, acids, in, times, of, energy, 'demand,', whereas, 'BAT', plays, a, role, in, regulating, 'non-shivering', thermogenesis, and, oxidizes, fatty, acids, released, from, the, lipid, droplet])].
[sujeto(['The', 'PLIN', family, of, proteins]), verbo([has]), complemento([recently, emerged, as, being, integral, in, the, regulation, of, fatty, acid, storage, and, release, in, adipose, tissue])].
[sujeto(['Previous', work]), verbo([has]), complemento([demonstrated, that, 'PLIN', protein, content, varies, among, adipose, tissue, 'depots,', however, an, examination, of, endurance, 'training-induced', depot, specific, changes, in, 'PLIN', protein, expression, has, yet, to, be, done])].
[sujeto(['Following', 'training,', under, isoflurane]), verbo([induced]), complemento([anesthesia, epidydmal, '(', 'eWAT),', inguinal, subcutaneous, '(', 'iWAT)', and, intrascapular, brown, adipose, tissue, '(', 'BAT)', was, 'excised,', and, plasma, was, collected])].
[sujeto(['Endurance', training, resulted, in, an]), verbo([increase]), complemento([in, 'BAT', 'PLIN5', and, iWAT, 'PLIN3', 'content,', while, there, was, no, difference, in, 'PLIN', protein, content, in, endurance, trained, eWAT])].
[sujeto(['Interestingly,', endurance, training, resulted, in, a, robust]), verbo([increase]), complemento([in, 'ATGL', and, 'CGI-58', in, eWAT, alone])].
[sujeto(['Together', these, results]), verbo([suggest]), complemento([the, potential, of, a, depot, specific, function, of, 'PLIN3', and, 'PLIN5', in, adipose, tissue, in, response, to, endurance, training])].
[sujeto(['Obesity']), verbo([has]), complemento([reached, epidemic, 'proportions,', leading, to, severe, associated, pathologies, such, as, insulin, 'resistance,', cardiovascular, 'disease,', cancer, and, type, 2, diabetes])].
[sujeto(['Adipose', tissue]), verbo([has]), complemento([become, crucial, due, to, its, involvement, in, the, pathogenesis, of, 'obesity-induced', insulin, 'resistance,', and, traditionally, white, adipose, tissue, has, captured, the, most, attention])].
[sujeto(['However', in, the, last, decade, the, presence, and, activity, of, 'heat-generating', brown, adipose, tissue, '(', 'BAT)', in, adult, humans]), verbo([has]), complemento([been, rediscovered])].
[sujeto(['BAT']), verbo([decreases]), complemento([with, age, and, in, obese, and, diabetic, patients])].
[sujeto(['It']), verbo([has]), complemento([thus, attracted, strong, scientific, 'interest,', and, any, strategy, to, increase, its, mass, or, activity, might, lead, to, new, therapeutic, approaches, to, obesity, and, associated, metabolic, diseases])].
[sujeto(['Autophagy']), verbo([maintains]), complemento([cellular, quality, control, by, degrading, 'organelles,', and, cytosolic, proteins, and, their, aggregates, in, lysosomes])].
[sujeto(['Lipophagy', was, discovered, in, 'hepatocytes,', and, since, then]), verbo([has]), complemento([been, shown, to, function, in, diverse, cell, types])].
[sujeto(['We']), verbo([have]), complemento([found, that, blocking, autophagy, in, brown, adipose, tissues, '(', 'BAT)', by, deleting, the, autophagy, gene, 'Atg7', in, 'BAT', 'MYF5', '(', myogenic, factor, 5, ')', -, positive, progenitors, increases, basal, lipid, content, in, 'BAT', and, decreases, lipid, utilization, during, cold, 'exposure-indicating', that, lipophagy, contributes, to, lipohomeostasis, in, the, adipose, tissue])].
[sujeto(['Surprisingly,', knocking, out, 'Atg7', in, hypothalamic, proopiomelanocortin, '(', 'POMC)', neurons, also, blocks, lipophagy, in, 'BAT', and, liver]), verbo([suggesting]), complemento([that, specific, neurons, within, the, central, nervous, system, '(', 'CNS)', exert, telemetric, control, over, lipophagy, in, 'BAT', and, liver])].
[sujeto(['Previous', studies]), verbo([have]), complemento([suggested, that, autophagosome, membranes, originate, from, lipid, droplets])].
[sujeto(['However,', it, was, recently, shown, that, rapamycin, could]), verbo([induce]), complemento([autophagy, in, cells, lacking, these, organelles])].
[sujeto(['Using', 'cerulenin,', a, potent, inhibitor, of, fatty, acid, 'synthase,', and, exogenous, addition, of, palmitic, acid, we, could, restore, 'nitrogen-starvation']), verbo([induced]), complemento([autophagy, in, the, absence, of, lipid, droplets])].
[sujeto(['Recent', studies]), verbo([suggest]), complemento([that, brown, adipose, tissue, '(', 'BAT)', plays, a, role, in, energy, and, glucose, metabolism, in, humans])].
[sujeto(['BAT', volume, was, significantly]), verbo([associated]), complemento([with, increased, 'whole-body', 'lipolysis,', 'triglyceride-free', fatty, acid, '(', 'FFA)', 'cycling,', 'FFA', 'oxidation,', and, adipose, tissue, insulin, sensitivity])].
[sujeto(['Functional', analysis, of, 'BAT', and, 'WAT', demonstrated, the, greater, thermogenic, capacity, of, 'BAT', compared, to, 'WAT,', while, molecular, analysis, revealed, a, 'cold-induced', upregulation, of, genes]), verbo([involved]), complemento([in, lipid, metabolism, only, in, 'BAT'])].
[sujeto(['Brown', adipose, tissue, '(', 'BAT)', plays, a, unique, role, in]), verbo([regulating]), complemento(['whole-body', energy, homeostasis, by, dissipating, energy, through, thermogenic, uncoupling])].
[sujeto(['Whether', 'BSCL2', directly]), verbo([participates]), complemento([in, brown, adipocyte, 'differentiation,', 'development,', and, 'function,', 'however,', is, unknown])].
[sujeto(['We', show, that, 'BSCL2', expression, is]), verbo([increased]), complemento([during, brown, adipocyte, differentiation])].
[sujeto(['Its', deletion, does, not, impair, the, classic, brown, adipogenic, program, but, rather]), verbo([induces]), complemento([premature, activation, of, differentiating, brown, adipocytes, through, cyclic, 'AMP', '(', 'cAMP)/protein', kinase, 'A', '(', 'PKA)-mediated', lipolysis, and, fatty, acid, and, glucose, 'oxidation,', as, well, as, uncoupling])].
[sujeto(['cAMP/PKA', signaling, is, physiologically]), verbo([activated]), complemento([during, neonatal, 'BAT', development, in, 'wild-type', mice, and, greatly, potentiated, in, mice, with, genetic, deletion, of, 'Bscl2', in, brown, progenitor, 'cells,', leading, to, reduced, 'BAT', mass, and, lipid, content, during, neonatal, brown, fat, formation])].
[sujeto(['However,', prolonged, overactivation, of, 'cAMP/PKA', signaling, during, 'BAT', development, ultimately]), verbo([causes]), complemento([apoptosis, of, brown, adipocytes, through, 'inflammation,', resulting, in, 'BAT', atrophy, and, increased, overall, adiposity, in, adult, mice])].
[sujeto(['These', findings]), verbo([reveal]), complemento([a, key, 'cell-autonomous', role, for, 'BSCL2', in, controlling, 'BAT', 'mass/activity', and, provide, novel, insights, into, therapeutic, strategies, targeting, 'cAMP/PKA', signaling, to, regulate, brown, adipocyte, 'function,', 'viability,', and, metabolic, homeostasis])].
[sujeto(['Biochar', incorporation, into, the, technosol]), verbo([promoted]), complemento([the, 'As,', 'Cd,', 'Cu,', 'Mo,', 'Ni,', 'Pb', and, 'Zn', solubility])].
[sujeto(['It']), verbo([decreased]), complemento([foliar, 'B,', 'Cu', and, 'Mo', 'concentrations,', and, 'Mo', concentration, in, 'stems,', pericarps, and, seeds])].
[sujeto(['But,', it, did, not, impact, neither, the, biomass, of, aerial, rapeseed, parts, '(', except, a]), verbo([decrease]), complemento([for, 'seeds),', nor, their, 'C', '(', except, a, decrease, for, 'stems),', seed, fatty, 'acid,', seed, starch, and, soluble, sugar, 'contents,', and, antioxidant, capacity, in, both, leaves, and, seeds])].
[sujeto(['Biochar', amendment]), verbo([increased]), complemento([the, phytoextraction, by, aerial, plant, parts, for, 'K,', 'P,', and, 'S,', reduced, it, for, 'N,', 'Ca,', 'B,', 'Mo,', 'Ni', and, 'Se,', whereas, it, remained, steady, for, 'Mg,', 'Zn,', 'Fe,', 'Mn,', 'Cu,', 'Cd', and, 'Co'])].
[sujeto(['The', biochar, incorporation, into, this, technosol, did, not]), verbo([promote]), complemento(['Cd,', 'Cu', and, 'Zn', phytoextraction, by, rapeseed, and, its, potential, oilseed, 'production,', but, increased, the, solubility, of, several, 'metal(loid)s'])].
[sujeto(['Here', 'Zn', and, 'Cd', concentrations, in, the, soil, pore, water, were]), verbo([decreased]), complemento([by, 'rapeseed,', showing, the, feasibility, to, strip, available, soil, 'Zn', and, 'Cd', in, combination, with, seed, production])].
[sujeto(['Dietary', polyunsaturated, fatty, acids, '(', 'PUFA)', are]), verbo([suggested]), complemento([to, modulate, immune, 'function,', but, the, effects, of, dietary, fatty, acids, composition, on, gene, expression, patterns, in, immune, organs, have, not, been, fully, characterized])].
[sujeto(['HFD-P', corrected, the, metabolic, phenotype]), verbo([induced]), complemento([by, 'HFD-S'])].
[sujeto(['Remarkably,', dietary, 'PUFA,', but, not, saturated, 'fat,', prompted, a, specific, regulation, of, immune, related, genes, in, the, 'spleen,', opening, the, possibility, that, 'PUFA', can]), verbo([regulate]), complemento([immune, function, by, influencing, gene, expression, in, this, organ])].
[sujeto(['Recently,', there]), verbo([has]), complemento([been, great, attention, given, to, the, possibility, of, combating, obesity, by, targeting, brown, fat, activity, or, increasing, differentiation, of, brown, adipocytes, in, white, fat, depots, through, a, process, termed, '\'', 'browning\''])].
[sujeto(['Sympathetic', innervation, of, brown, and, white, adipose, tissues]), verbo([provides]), complemento([adrenergic, input, that, drives, thermogenesis, and, regulates, fatty, acid, 'metabolism,', as, well, as, stimulating, adipogenesis, of, recruitable, brown, adipocyte, tissue, '(', 'rBAT,', also, known, as, beige, or, 'brite)', in, white, fat])].
[sujeto(['Other', factors]), verbo([acting]), complemento([in, an, endocrine, or, 'autocrine/paracrine', manner, in, adipose, tissue, may, also, stimulate, browning])].
[sujeto(['There']), verbo([have]), complemento([been, significant, recent, advances, in, understanding, the, mechanisms, of, increasing, adipose, tissue, energy, 'expenditure,', as, well, as, how, brown, adipocytes, appear, in, white, fat, 'depots,', including, via, de, novo, adipogenesis, from, tissue, precursor, cells])].
[sujeto(['We', also]), verbo([provide]), complemento([an, overview, of, constitutive, 'BAT', vs, rBAT, in, mouse, and, human])].
[sujeto(['We', observed, the, formation, of, substantial, quantities, of, ribose, and, a, diversity, of, structurally, related, sugar, molecules, such, as, 'arabinose,', 'xylose,', and, lyxose, in, the, 'room-temperature', organic, residues, of, 'photo-processed', interstellar, ice, analogs, initially, composed, of, 'H2O,', 'CH3OH,', and, 'NH3', 'Our', results]), verbo([suggest]), complemento([that, the, generation, of, numerous, sugar, 'molecules,', including, the, aldopentose, 'ribose,', may, be, possible, from, photochemical, and, thermal, treatment, of, cosmic, ices, in, the, late, stages, of, the, solar, nebula])].
[sujeto(['Our', detection, of, ribose]), verbo([provides]), complemento([plausible, insights, into, the, chemical, processes, that, could, lead, to, formation, of, biologically, relevant, molecules, in, suitable, planetary, environments])].
[sujeto(['Resistin']), verbo([has]), complemento([been, originally, identified, as, an, adipokine, that, links, obesity, to, insulin, resistance, in, mice])].
[sujeto(['In', our, previous, studies, in, spontaneously, hypertensive, rats, '(', 'SHR)']), verbo([expressing]), complemento([a, nonsecreted, form, of, mouse, resistin, '(', 'Retn)', transgene, specifically, in, adipose, tissue, '(', 'SHR-Retn),', we, have, observed, an, increased, lipolysis, and, serum, free, fatty, 'acids,', ectopic, fat, accumulation, in, 'muscles,', and, insulin, resistance])].
[sujeto(['Recently,', brown, adipose, tissue, '(', 'BAT)']), verbo([has]), complemento([been, suggested, to, play, an, important, role, in, the, pathogenesis, of, metabolic, disturbances])].
[sujeto(['In', the, current, 'study,', we]), verbo([have]), complemento([analyzed, autocrine, effects, of, transgenic, resistin, on, 'BAT', glucose, and, lipid, metabolism, and, mitochondrial, function, in, the, 'SHR-Retn', vs])].
[sujeto([0.91, ±, 0.08, 'g/100', g, body, 'wt,', 'P', &, 'lt;', 0.05, ')', ',', significantly, reduced, both, basal, and, insulin]), verbo([stimulated]), complemento([incorporation, of, palmitate, into, 'BAT', lipids, '(', 658, ±, 50, vs])].
[sujeto([1, ',', 86, ±, 35, 'nmol/g/2', 'h,', 'P', '≤', 0.01, ',', 'respectively),', and, significantly]), verbo([decreased]), complemento([palmitate, oxidation, '(', 37.6, ±, 4.5, vs])].
[sujeto(['In', 'addition,', in, vivo, microPET, imaging, revealed, significantly, reduced, '(', 18, ')', 'F-FDG', uptake, in, 'BAT']), verbo([induced]), complemento([by, exposure, to, cold, in, 'SHR-Retn', vs])].
[sujeto(['Gene', expression, profiles, in, 'BAT', identified, differentially]), verbo([expressed]), complemento([genes, involved, in, skeletal, muscle, and, connective, tissue, 'development,', inflammation, and, 'MAPK', and, insulin, signaling])].
[sujeto(['These', results]), verbo([provide]), complemento([evidence, that, autocrine, effects, of, resistin, attenuate, differentiation, and, activity, of, 'BAT', and, thus, may, play, a, role, in, the, pathogenesis, of, insulin, resistance, in, the, rat])].
[sujeto(['Them1', '(', -, /, -, ')', mice, exhibit]), verbo([increased]), complemento([energy, expenditure, and, resistance, to, 'diet-induced', obesity, and, 'diabetes,', but, the, mechanistic, contribution, of, 'Them1', to, the, regulation, of, cold, thermogenesis, remains, unknown])].
[sujeto(['Them1']), verbo([suppressed]), complemento([thermogenesis, in, mice, even, in, the, setting, of, ongoing, cold, exposure])].
[sujeto(['This', was, attributable, to]), verbo([decreased]), complemento([mitochondrial, oxidation, of, endogenous, but, not, exogenous, fatty, acids])].
[sujeto(['These', results, show, that, 'Them1', may]), verbo([act]), complemento([as, a, break, on, uncontrolled, heat, production, and, limit, the, extent, of, energy, expenditure])].
[sujeto(['Pharmacologic', inhibition, of, 'Them1', could]), verbo([provide]), complemento([a, targeted, strategy, for, the, management, of, metabolic, disorders, via, activation, of, brown, fat])].
[sujeto(['White', 'Nose', 'Syndrome', '(', 'WNS)', greatly]), verbo([increases]), complemento([the, 'over-winter', mortality, of, little, brown, '(', 'Myotis', 'lucifugus),', 'Indiana', '(', 'Myotis', 'sodalis),', northern, '(', 'Myotis', 'septentrionalis),', and, tricolored, '(', 'Perimyotis', 'subflavus)', bats])].
[sujeto(['It', is]), verbo([caused]), complemento([by, a, cutaneous, infection, with, the, fungus, 'Pseudogymnoascus', destructans, '(', 'Pd)'])].
[sujeto(['The', growth, of, 'Pd', was]), verbo([inhibited]), complemento(['by:', 'a)', myristic, and, stearic, acids, at, 10.5, -, 13.4, °, 'C,', but, not, at, 4.0, -, 5.0, °, 'C,', 'b)', oleic, acid, at, 5.0, -, 10.6, °, 'C,', 'c)', palmitoleic, 'acid,', 'and,', 'd)', linoleic, '(', 18, :, 2, ')', acid, at, 5.0, -, 10.6, °, 'C'])].
[sujeto(['Brown', adipose, tissue, '(', 'BAT)', is, an, emerging]), verbo([target]), complemento([to, combat, cardiometabolic, disorders, as, it, can, take, up, substantial, amounts, of, glucose, and, lipids, from, the, circulation, for, heat, production])].
[sujeto(['Mouse', studies, showed, that, 'BAT', activation, selectively]), verbo([increases]), complemento([oxidation, of, lipids, over, 'glucose,', by, recruiting, fatty, acids, from, intracellular, triglycerides])].
[sujeto(['Clinical', studies, identified, the, involvement, of, the, 'β3-adrenergic', receptor, in, 'BAT', activation, and, demonstrated, that, human, 'BAT', activation, also, selectively]), verbo([increases]), complemento([lipid, oxidation])].
[sujeto(['Notably,', insulin, resistance, during, ageing, or, weight]), verbo([gain]), complemento([reduces, the, capacity, of, 'BAT', to, internalize, 'glucose,', without, reducing, fatty, acid, uptake, or, oxidative, metabolism])].
[sujeto(['Preclinical', studies, established, 'BAT', as, an, important]), verbo([target]), complemento([to, combat, cardiometabolic, disorders, and, elucidated, underlying, mechanisms, whereas, clinical, studies, identified, therapeutic, handles])].
[sujeto(['Development', of, novel, 'lipid-based', 'PET-CT', tracers, and, identification, of, translational, biomarkers, of, 'BAT', activity, are]), verbo([required]), complemento([as, alternatives, to, '[', 'F]fluorodeoxyglucose', 'PET-CT', to, accelerate, clinical, development, of, 'BAT-activating', therapeutic, strategies])].
[sujeto([7, -, 'Morpholinomethyl-8-hydroxyquinoline', '(', 'MO-8HQ),', which, like, 8, -, hydroxyquinoline, '(', 8, 'HQ)', readily, forms, a, 'chelate,', was, synthesized, and]), verbo([found]), complemento([to, possess, cytotoxicity, and, antimicrobial, activity])].
[sujeto(['MO-8HQ', also]), verbo([inhibited]), complemento(['DNA', synthesis, of, tumor, cells, at, micromolar, 'concentrations,', suggesting, that, 'MO-8HQ', might, chelate, metals, necessary, for, the, enzymatic, catalysis, of, 'DNA', biosynthesis])].
[sujeto(['MO-8HQ:Fe', chelate, markedly]), verbo([increased]), complemento([the, susceptibility, of, 'Escherichia', coli, to, deoxycholate])].
[sujeto(['It', is]), verbo([suggested]), complemento([that, 'MO-8HQ', exerts, its, biological, activity, as, a, 'membrane-active', agent, through, metal, ion, chelation])].
[sujeto(['A', 'DNA', primase, was, isolated, from, a]), verbo([nuclear]), complemento([fraction, from, leaves, of, tobacco, '(', 'Nicotiana', tabacum, 'L'])].
[sujeto(['Primase', activity, was, dependent, on, a, 'template,', magnesium, ions, and, 'ATP;', it, was, resistant, to, aphidicolin, and, 'rifampicin,', but, was, strongly]), verbo([inhibited]), complemento([by, 'N-ethylmaleimide'])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([of, the, purification, to, homogeneity, of, a, plant, 'DNA', primase])].
[sujeto(['Nitrogenase', activity, of, washed, 'Azotobacter', vinelandii, cells, was]), verbo([enhanced]), complemento([by, the, addition, of, 'Ca2+', and, 'Mg2+,', and, the, enhancement, increased, with, the, 'O2', concentration])].
[sujeto(['In', assays]), verbo([provided]), complemento([with, a, level, of, 'O2', that, was, initially, supraoptimal, and, inhibitory, to, nitrogenase, 'activity,', the, addition, of, 'Ca2+', or, 'Mg2+', affected, both, the, maximum, respiration, rate, '(', 'Vmax)', of, the, cells, and, the, apparent, affinity, '[', 'KS(O2)]', of, cell, respiration, for, 'O2'])].
[sujeto(['Aeration-dependent']), verbo([increases]), complemento([in, 'Vmax', and, 'KS(O2)', were, inhibited, by, rifampin, and, chloramphenicol, and, were, also, observed, in, 'ammonium-grown', cultures])].
[sujeto(['Lactoferrin', and, transferrin]), verbo([have]), complemento([antimicrobial, activity, against, selected, 'Gram-negative', 'bacteria,', but, the, mechanism, of, action, has, not, been, defined])].
[sujeto(['Lipopolysaccharide']), verbo([release]), complemento([by, the, proteins, could, be, blocked, by, concurrent, addition, of, 'Ca2+', and, 'Mg2+'])].
[sujeto(['Addition', of, 'Ca2+', also, blocked, the, ability, of, lactoferrin, to]), verbo([increase]), complemento([the, susceptibility, of, 'Escherichia', coli, to, rifampicin])].
[sujeto(['Transferrin,', but, not, 'lactoferrin,']), verbo([increased]), complemento([susceptibility, of, 'Gram-negative', bacteria, to, 'deoxycholate,', with, reversal, of, sensitivity, occurring, with, exposure, to, 'Ca2+', or, 'Mg2+'])].
[sujeto(['In', transmission, electron, microscopy, studies, polymyxin, 'B']), verbo([caused]), complemento(['finger-like', membrane, 'projections,', but, no, morphological, alterations, were, seen, in, cells, exposed, to, 'EDTA,', lactoferrin, or, transferrin])].
[sujeto(['These', data]), verbo([provide]), complemento([further, evidence, that, lactoferrin, and, transferrin, act, as, 'membrane-active', agents, with, the, effects, modulated, by, 'Ca2+', and, 'Mg2+'])].
[sujeto(['QA-241']), verbo([inhibited]), complemento([90, '%', of, isolates, of, 'Enterobacteriaceae', at, a, concentration, of, less, than, or, equal, to, 2, 'micrograms/ml'])].
[sujeto(['Most', 'Haemophilus', influenzae, and, 'Neisseria', gonorrhoeae, isolates, were]), verbo([inhibited]), complemento([at, concentrations, of, less, than, or, equal, to, 0.03, 'microgram/ml'])].
[sujeto(['Many', studies]), verbo([have]), complemento([shown, that, lactoferrin, and, transferrin, have, antimicrobial, activity, against, 'gram-negative', 'bacteria,', but, a, mechanism, of, action, has, not, been, defined])].
[sujeto(['The', ability, of, lactoferrin, and, transferrin, to]), verbo([release]), complemento([radiolabeled, lipopolysaccharide, '(', 'LPS)', from, a, 'UDP-galactose', 'epimerase-deficient', 'Escherichia', coli, mutant, and, from, 'wild-type', 'Salmonella', typhimurium, strains, was, tested])].
[sujeto(['Initial', studies, in, 'barbital-acetate', buffer, showed, that, 'EDTA', and, lactoferrin]), verbo([cause]), complemento([significant, release, of, 'LPS', from, all, three, strains])].
[sujeto(['Further', studies]), verbo([found]), complemento([that, 'LPS', release, was, blocked, by, iron, saturation, of, 'lactoferrin,', occurred, between, pH, 6, and, 7.5, ',', was, comparable, for, bacterial, concentrations, from, 10, '(', 4, ')', to, 10, '(', 7, ')', 'CFU/ml,', and, increased, with, increasing, lactoferrin, concentrations])].
[sujeto(['Studies', using, 'Hanks', balanced, salt, solution, lacking, calcium, and, magnesium, showed, that, transferrin, also, could]), verbo([cause]), complemento(['LPS', release])].
[sujeto(['Additionally,', both, lactoferrin, and, transferrin]), verbo([increased]), complemento([the, antibacterial, effect, of, a, subinhibitory, concentration, of, 'rifampin,', a, drug, excluded, by, the, bacterial, outer, membrane])].
[sujeto(['Magnesium', ions, and, amino, acids]), verbo([stimulated]), complemento(['synthesis;', 'chloramphenicol,', 'rifampin,', 'oligomycin,', and, carbonyl, cyanide, 'p-trifluoromethoxyphenylhydrazone', '(', a, proton, 'ionophore)', inhibited, incorporation])].
[sujeto([')', ',', whereas, class, 'B', cohesion]), verbo([requires]), complemento([the, addition, of, calcium, ion, for, induction])].
[sujeto(['Class', 'B', cohesion]), verbo([requires]), complemento([the, presence, of, a, cation, in, the, calcium, group, and, is, energy, dependent])].
[sujeto([aurantiaca]), verbo([responds]), complemento([to, calcium, ion, by, synthesizing, the, molecular, components, of, a, system, of, cell, cohesion, '(', class, 'B)', and, that, the, functioning, of, this, system, requires, the, expenditure, of, metabolic, energy])].
[sujeto([xanthus, 'RNA', polymerase, was, capable, of]), verbo([transcribing]), complemento(['DNAs', from, 'E'])].
[sujeto(['Transcription', of, 'T7', and, phi, 29, 'DNAs', was]), verbo([stimulated]), complemento([by, 'KCl,', whereas, transcription, of, 'Mx1,', 'Mx4,', and, 'Mx8', 'DNAs', was, inhibited, by, 'KCl'])].
[sujeto([xanthus, 'RNA', polymerase, activity, were, similar, to, those]), verbo([found]), complemento([with, 'E'])].
[sujeto([xanthus, 'RNA', polymerase]), verbo([transcribe]), complemento([common, 'SalI', restriction, fragments, of, 'Mx1', 'DNA'])].
[sujeto(['Enzyme', secretion, by, washed, cell, suspensions]), verbo([required]), complemento([a, carbon, source, and, 'ammonium,', 'potassium,', and, calcium, ions])].
[sujeto(['Secretion', was]), verbo([repressed]), complemento([by, the, addition, of, inorganic, phosphate, but, not, by, organic, 'phosphates,', 'glucose,', or, sodium, succinate])].
[sujeto(['Studies', with, tetracycline, indicated, that, de, novo, protein, synthesis, was, necessary, for, the, secretion, of, phospholipase, 'C', and, that, the, exoenzyme, was, not]), verbo([released]), complemento([from, a, preformed, periplasmic, pool])].
[sujeto(['The', system]), verbo([has]), complemento([been, optimalized, with, respect, to, total, 'RNA', synthesis])].
[sujeto(['The', 'RNA', synthesizing, system, described, here]), verbo([has]), complemento([been, developed, with, the, aim, of, studying, phage, transcription, in, vitro])].
[sujeto(['A', procedure, dependent, on, multiplicity, of, 'infection,', incubation, 'time,', and, treatment, of, crude, lysates, with, diatomaceous, earth, was]), verbo([found]), complemento([to, optimize, phage, 'yield,', resulting, in, titers, of, 1, 'X', 10, '(', 10, ')', to, 2, 'X', 10, '(', 10, ')', 'PFU/ml'])].
[sujeto(['Adsorption', of, phi227, to, host, cells, was, relatively, unaffected, by, the, 'medium,', but, calcium, '(', not, substituted, by, 'magnesium)', was]), verbo([required]), complemento([for, formation, of, infectious, centers])].
[sujeto(['Single-step', growth, experiments, showed, a, latent, period, of, 39, min, and, a, burst, size, of, 100, 'PFU/infectious', 'center;', results, were, unaffected, by, omission, of, supplemental, 'Ca2+,', by, supplementation, with, 'Mg2,', addition, of, 'glucose,', or, changes, of, pH, between, 6.35, and, 8.0, ;, but]), verbo([increased]), complemento([temperature, '(', 40, to, 43, degrees, 'C)', shortened, the, latent, period, and, decreased, the, burst, size])].
[sujeto(['Phage', replication, was, sensitive, to, those, metabolic, inhibitors, which]), verbo([inhibited]), complemento([the, host, 'streptococcus:', these, included, 'rifampin,', 'fluorodeoxyuridine,', 'hydroxyurea,', 'dihydrostreptomycin,', and, 6, -, 'P-hydroxyphenylazouracil'])].
[sujeto(['The', data]), verbo([suggest]), complemento([that, phi227, does, not, code, for, a, 'rifampin-resistant', 'RNA', polymerase])].
[sujeto(['However,', in, a, 'rifampin-resistant', host, 'strain,', phage, replication, and, lysogen, formation, were, both]), verbo([decreased]), complemento([suggesting, that, altered, host, core, polymerase, had, less, affinity, for, '(', 'some)', promotors, on, the, phi227, template])].
[sujeto(['In', 'transfection,', a, 'Ca2+-dependent', stabilization, step, that, was]), verbo([inhibited]), complemento([by, 'Mg2+', was, 'demonstrated;', transformation, was, not, affected, by, either, 'Ca2+', or, 'Mg2+,', and, the, site, and, nature, of, the, stabilization, are, unknown])].
[sujeto(['More', than, one, molecule, of, 'DNA', was]), verbo([required]), complemento([for, plaque, formation])].
[sujeto(['Similar', characterizations, of, streptococcal, 'phages,', including, biophysical, 'data,']), verbo([have]), complemento([not, been, previously, available])].
[sujeto(['The', purification, of, p, protein, to, homogeneity, from, 'Escherichia', coli]), verbo([has]), complemento([shown, that, its, 'RNA-dependent', 'ATPase', activity, is, physically, inseparable, from, its, termination, activity])].
[sujeto(['The', biochemical, properties, of, pATPase]), verbo([have]), complemento([been, studied, using, 'poly(C)', as, the, activating, 'RNA'])].
[sujeto(['This', reaction, is]), verbo([stimulated]), complemento([by, 'Mg2+', ions, and, 'Mn2+', ions, and, is, prevented, by, excess, 'EDTA;', it, is, not, stimulated, by, 'Ca2+', ions])].
[sujeto(['The', reaction, is, not, affected, by, a, 'Zn2+', ion, chelator, and, is]), verbo([inhibited]), complemento([by, 1, mM, 'Zn2+'])].
[sujeto(['ATP']), verbo([has]), complemento([the, lowest, 'Km', '(', 0.009, 'mM),', while, 'CTP', has, the, highest, 'Vmax'])].
[sujeto(['The', response, of, p, 'ATPase', to, a, variety, of, inhibitors, of, other, 'ATPases', and, 'GTPases', and, of, transcription]), verbo([has]), complemento([been, studied])].
[sujeto(['Of', the, compounds, 'tested,', aurintricarboxylic, 'acid,', an, inhibitor, of, 'protein-nucleic', acid, 'interactions,', was]), verbo([found]), complemento([to, be, a, potent, inhibitor, of, p, 'ATPase,', while, rifampicin, and, heparin, had, no, effect])].
[sujeto(['The', 'RNA', synthesis]), verbo([requires]), complemento([all, four, nucleoside, triphosphates, and, manganese, ions, and, is, dependent, on, the, presence, of, sigma, subunit])].
[sujeto(['The', reaction, is]), verbo([inhibited]), complemento([by, 'rifampicin,', streptolydigin, and, ethidium, 'bromide,', but, not, by, 'DNase', and, actinomycin, 'D', which, does, not, bind, to, 'double-stranded', 'RNA'])].
[sujeto(['Although', single, marker, transfer, is, always, greater, than, double, marker, 'transfer,', the, data]), verbo([suggest]), complemento([that, rifampin, resistance, is, linked, to, 'hypoxanthine,', adenine, and, uracil, protorophy, at, intervals, of, increasing, distance])].
[sujeto(['A', number, of, different, 'DNAs', were]), verbo([transcribed]), complemento([by, the, enzyme, from, 'A'])].
[sujeto(['Higher', ionic, strengths]), verbo([led]), complemento([to, increasing, inhibition, of, transcription, and, at, mu, =, 0.4, complete, inhibition, was, observed])].
[sujeto(['It', is, 'suggested,', 'therefore,', that, the, inhibition, of, activity, at, higher, salt, concentrations, is]), verbo([caused]), complemento([by, a, decrease, in, concentration, of, the, active, enzyme, species])].
[sujeto(['Stable', messenger, 'RNAs', from, sporulating, cells, of, 'Bacillus', thuringiensis, were]), verbo([translated]), complemento([in, vitro, in, cell, free, system, from, 'E'])].
[sujeto(['The', reaction, is, 'rifampicin-resistant,']), verbo([requires]), complemento(['single-stranded', 'DNA,', 'Mg++,', deoxynucleoside, 'triphosphates,', and, 'ATP,', and, is, stimulated, by, 'KCl'])].
[sujeto([coli, strains, carrying, the, prophage, mutant, 'P1bac,', in, which, the, viral, dnaB, analog, '(', 'ban)', protein, is]), verbo([expressed]), complemento(['constitutively,', or, 'P1bacban,', in, which, the, expression, of, ban, protein, is, prevented])].
[sujeto(['It', is]), verbo([suggested]), complemento([that, the, 'temperature-resistant', 'DNA', synthesis, with, fractions, from, 'P1bac', lysogens, is, mediated, by, the, 'P1', ban, protein])].
[sujeto(['All', three, enzymes]), verbo([transcribed]), complemento(['heat-denatured', 'DNA', more, 'efficiently,', especially, the, peak, 'TII,', detecable, only, when, 'heat-denatured', 'DNA', was, used, as, a, template])].
[sujeto(['TIa,', 'TIb,', and, 'TII', were, all, insensitive, to, 'rifampicin,', while, only, 'TII', was, substantially]), verbo([inhibited]), complemento([by, 'alpha-amanitin'])].
[sujeto(['On', the, other, 'hand,', the, activity, of, 'TII', was, progressively, lowered, by]), verbo([increasing]), complemento([the, concentration, of, ammonium, sulfate, in, the, assay, 'mixture,', a, finding, incompatible, with, those, obtained, thus, far])].
[sujeto(['Rhodococcus', equi, is, an, unusual, zoonotic, pathogen, that, can]), verbo([cause]), complemento(['life-threatening', diseases, in, susceptible, hosts])].
[sujeto([equi, infection, in, 'Kentucky', were, compared, to, 137, cases]), verbo([reported]), complemento([in, the, literature])].
[sujeto(['equi-infected', 'HIV', patients, was, lower, in, the, 'HAART']), verbo([era]), complemento(['(', 8, '%', ')', than, in, 'pre-HAART', era, '(', 56, '%', ')', '(', 'P', &, 'lt;', 0.0001, ')', ',', suggesting, that, 'HAART', improves, prognosis, in, these, patients])].
[sujeto(['Guidance', is]), verbo([provided]), complemento([on, key, elements, required, for, in, vitro, and, in, vivo, antimicrobial, 'validation,', including, validation, of, microbial, 'growth,', microbial, 'recovery,', 'neutralization,', and, antimicrobial, activity])].
[sujeto(['Tuberculosis', continues, to, be, a, global, public, health, 'problem,', the, extrapulmonary, form, being, estimated, to, occur, in, 10, -, 20, '%', of, immunocompetent, 'individuals,']), verbo([increasing]), complemento([in, patients, who, are, carriers, of, the, human, immunodeficiency, virus, '(', 'HIV);', its, diagnosis, is, difficult, with, conventional, methods, due, to, the, paucibacillary, nature, of, samples])].
[sujeto(['The', 'Xpert®', 'MTB/RIF', test, represents, an, important, development, in, the, molecular, detection, of, 'Mycobacterium', tuberculosis, and]), verbo([has]), complemento([been, used, with, a, variety, of, 'non-respiratory', clinical, samples])].
[sujeto(['Sensitivities', higher, than, 75, '%', were]), verbo([found]), complemento([in, analyses, stratified, by, samples])].
[sujeto(['Combinations', of, rifampin, and, clindamycin, or, 'rifampin,', 'metronidazole,', and, moxifloxcin]), verbo([have]), complemento([been, reported, as, effective, treatments, for, hidradenitis, suppurativa, '(', 'HS)', 'Hurley', 'Stage', 1, and, 'Hurley', 'Stage', 2])].
[sujeto([&, 'nbsp;', 'Clinical', trials]), verbo([suggest]), complemento([that, for, stage, 1, and, mild, stage, 2, 'HS,', clindamycin, 300, mg, twice, daily, and, rifampin, 300, mg, twice, daily, for, 10, weeks, can, substantially, abate, 'HS', in, '~80%', of, cases, and, remit, 'HS', in, '~50%', of, cases])].
[sujeto([&, 'nbsp; ', 'The', author, typically, gives, 'HS', clindamycin, 300, mg, and, rifampin, 300, 'mg,', each, twice, 'daily,', for, 10, weeks, and, assesses, if, remission]), verbo([has]), complemento([occurred])].
[sujeto([&, 'nbsp;', 'If', the, patient]), verbo([has]), complemento([not, achieved, remission, the, author, continues, the, regimen, as, long, as, the, 'patient\'s', clinical, status, continues, to, improve, without, side, effects])].
[sujeto([&, 'nbsp;', 'The', reasons, why, rifampin, is, so, effective, against, 'HS']), verbo([have]), complemento([not, been, fully, defined, and, might, involve, 'rifampin\'s', '(', 1, ')', antibacterial, effects, '(', 2, ')', effects, on, bacterial, biofilms, '(', 3, ')', 'anti-inflammatory', effects, '(', 4, ')', effects, against, granulomas, '(', 5, ')', and, immunomodulatory, effects, on, neutrophils])].
[sujeto([&, 'nbsp;', 'Thus,', rifampin]), verbo([enhances]), complemento([safety, when, rifampin, and, clindamycin, are, combined, for, the, treatment, of, 'HS'])].
[sujeto(['No', statistically, significant, difference, was]), verbo([found]), complemento([between, the, two, groups, concerning, the, frequency, of, drug, induced, liver, injury, or, mild, elevation, of, liver, enzymes])].
[sujeto(['This', 'study,', despite, its, 'limitations,', showed, that, rifampin, with, autogenous, bone]), verbo([increased]), complemento([bone, regeneration, in, rats, with, 'critical-size', defects])].
[sujeto(['Using', 'MCBT', and, checkerboard, 'tests,', we]), verbo([found]), complemento([that, only, 'colistin-based', 'combinations,', particularly, with, 'rifampin,', 'glycopeptides,', or, 'β-lactams,', may, confer, therapeutic, benefits, against, 'colistin-resistant', 'A'])].
[sujeto(['To', review, the, evidence, about]), verbo([targeted]), complemento([screening, and, treatment, for, 'LTBI', among, adults, in, primary, care, settings, to, support, the, 'US', 'Preventive', 'Services', 'Task', 'Force', in, updating, its, 1996, recommendation])].
[sujeto(['English-language', studies, of, 'LTBI', 'screening,', 'LTBI', treatment, with, recommended, 'pharmacotherapy,', or, accuracy, of, the, tuberculin, skin, test, '(', 'TST)', or, 'interferon-gamma']), verbo([release]), complemento([assays, '(', 'IGRAs)'])].
[sujeto(['A', randomized, clinical, trial, '(', 'RCT)', of, 24, weeks, of, isoniazid, in, individuals, with, pulmonary, fibrotic, lesions, and, 'LTBI', '(', n, =, 27, ' 830)']), verbo([found]), complemento([a, reduction, in, absolute, risk, of, active, 'TB', at, 5, years, from, 1.4, '%', to, 0.5, '%', '(', relative, risk, '[', 'RR],', 0.35, '[', 95, '%', 'CI,', 0.24, -, 0.52, ']', ')', and, an, increase, in, absolute, risk, for, hepatoxicity, from, 0.1, '%', to, 0.5, '%', '(', 'RR,', 4.59, '[', 95, '%', 'CI,', 2.03, -, 10.39, ']', ')', for, 24, weeks, of, daily, isoniazid, compared, with, placebo])].
[sujeto(['An', 'RCT', '(', n, =, 6886, ')']), verbo([found]), complemento([that, 3, months, of, 'once-weekly', rifapentine, plus, isoniazid, was, noninferior, to, 9, months, of, isoniazid, alone, for, preventing, active, 'TB'])].
[sujeto(['Isoniazid', is]), verbo([associated]), complemento([with, higher, rates, of, hepatotoxicity, than, placebo, or, rifampin])].
[sujeto(['After', multivariate, logistic, regression, analysis, including, in, the, 'model,', other, potential, risk, factors, of, hepatotoxicity, 'HLA', class, 'II', 'DQB1*0201', and, 'DQA1*0102', alleles, were, not]), verbo([found]), complemento([significantly, associated, with, the, risk, of, development, 'ATDH'])].
[sujeto(['Cmax)', of, the, inducer, is, responsible, for, the, magnitude, of, subsequent, induction]), verbo([has]), complemento([not, been, thoroughly, investigated])].
[sujeto(['Additionally,', in, vitro, induction, assays, are, typically, treated, as, static, 'systems,', which, could]), verbo([lead]), complemento([to, inaccurate, induction, potency, estimation])].
[sujeto(['This', work, treated, the, typical, in, vitro, evaluation, of, rifampin, induction, as, an, in, vivo, system, by, generating, various]), verbo([target]), complemento([engagement, 'profiles,', measuring, free, rifampin, concentration, over, 3, d, of, incubation, and, evaluating, the, impact, of, these, factors, on, final, induction, response])].
[sujeto(['This', 'rifampin-based', analysis, demonstrates, that, the, induction, process, is, driven, by, 'time-averaged']), verbo([target]), complemento([engagement, '(', i])].
[sujeto(['Additionally,', depletion, of, rifampin, in, the, incubation, medium, over, 3, d, as, well, as, 'non-specific/specific']), verbo([binding]), complemento([were, observed])].
[sujeto(['Current', drug, regimens, for, brucellosis, are]), verbo([associated]), complemento([with, relatively, high, rates, of, therapeutic, failure, or, relapse])].
[sujeto([has, been, proposed, recently, as, a, potential]), verbo([cause]), complemento([of, therapeutic, failure])].
[sujeto(['Culture', of, clinical, samples, were, positive, in, 38.3, '%', ',', of, 'which,', 91.2, '%', were]), verbo([associated]), complemento([with, positive, serological, test])].
[sujeto(['No', significant, associations, were]), verbo([found]), complemento([between, serology, and, culture, method])].
[sujeto(['However,']), verbo([decreased]), complemento([sensitivity, to, rifampin, and, 'trimethoprim-sulfamethoxazole', was, found, in, 35.08, '%', and, 3.5, '%', of, 'isolates,', respectively])].
[sujeto(['Evidence']), verbo([has]), complemento([existed, for, decades, that, higher, doses, of, rifampin, may, be, more, 'effective,', but, potentially, more, 'toxic,', than, standard, doses, used, in, tuberculosis, treatment])].
[sujeto(['Whether']), verbo([increased]), complemento([doses, of, rifampin, could, safely, shorten, treatment, remains, an, open, question])].
[sujeto([180, randomized, participants, affords, 90, &, 'nbsp;%', statistical, power, to, detect, a, difference, of, at, least, 14, 'mcg/mL*hr', between, the, 20, &, 'nbsp;mg/kg', group, and, the, 10, &, 'nbsp;mg/kg', 'group,', assuming, a]), verbo([loss]), complemento([to, 'follow-up', of, up, to, 17, &, 'nbsp;%'])].
[sujeto(['Extant', evidence]), verbo([suggests]), complemento([the, potential, for, increased, doses, of, rifampin, to, shorten, tuberculosis, treatment, duration])].
[sujeto(['Previous', studies]), verbo([have]), complemento([demonstrated, that, rifampin, can, influence, drug, metabolism, by, regulating, 'drug-metabolizing', 'enzymes,', 'transporters,', and, microRNAs, '(', 'miRNAs)'])].
[sujeto(['Rifampin']), verbo([induces]), complemento([gene, 'expression,', at, least, in, 'part,', by, activating, the, pregnane, 'X', receptor, '(', 'PXR),', which, induces, gene, 'expression;', 'however,', the, impact, of, rifampin, on, global, gene, regulation, has, not, been, examined, under, the, molecular, network, frameworks])].
[sujeto(['In', this, 'study,', we, extracted, 'rifampin-induced', significant, differentially]), verbo([expressed]), complemento([genes, '(', 'SDG)', based, on, the, gene, expression, profile])].
[sujeto(['Using', the, 'Kyoto', 'Encyclopedia', of, 'Genes', and, 'Genomes', '(', 'KEGG),', we, identified, the, crucial, 'rifampin-regulated', biological, pathways, and]), verbo([associated]), complemento([genes])].
[sujeto(['In', 'addition,', genes]), verbo([targeted]), complemento([by, miRNAs, that, were, significantly, differentially, expressed, in, the, miRNA, expression, profile, were, extracted, based, on, the, 'miRNA-gene', prediction, tools])].
[sujeto(['The', 'miRNA-regulated', 'PIN', was, further, constructed, using]), verbo([associated]), complemento([genes, and, miRNAs])].
[sujeto(['RESULTS AND', 'DISCCUSSION:', 'We', extracted, the, functional, 'modules,', which, included, 84, genes, and, 89, 'interactions,', from, the, 'RrPIN,', and, identified, 19, key, 'rifampin-response', genes, that, are]), verbo([associated]), complemento([with, seven, function, pathways, that, include, drug, response, and, 'metabolism,', and, cancer, 'pathways;', many, of, the, pathways, were, supported, by, previous, studies])].
[sujeto(['In', 'addition,', we, identified, that, a, set, of, 6, genes, '(', 'CAV1,', 'CREBBP,', 'SMAD3,', 'TRAF2,', 'KBKG,', and, 'THBS1)', functioning, as, gene, hubs, in, the, subnetworks, that, are]), verbo([regulated]), complemento([by, rifampin])].
[sujeto(['It', is, also]), verbo([suggested]), complemento([that, 12, differentially, expressed, miRNAs, were, associated, with, 6, biological, pathways])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, rifampin, contributes, to, changes, in, the, expression, of, genes, by, regulating, key, molecules, in, the, protein, interaction, networks])].
[sujeto(['In', 'addition,']), verbo([he]), complemento([had, been, treated, approximately, one, year, previously, in, 'Mexico', for, 'Brucella', melitensis, bacteremia, after, eating, fresh, unpasteurized, cheese])].
[sujeto(['Resolution', of, the, acute, event, occurred, without, additional, sequelae, and]), verbo([he]), complemento([was, discharged, from, the, hospital, to, a, rehabilitation, facility])].
[sujeto(['In', this, 'case,', the, patient, was, successfully, treated, with, thoracic, and, abdominal, endovascular, stent, graft, 'exclusion,', coiling, and, 'long-term']), verbo([targeted]), complemento([antibiotics])].
[sujeto(['In', 'addition,', we, used, zidovudine, and, metformin, as, clinically, prescribed, substrate, of, 'OATs', and, 'OCTs', 'respectively,', which, was, also, strongly]), verbo([inhibited]), complemento([by, the, 'anti-tuberculosis', drugs])].
[sujeto(['Among', the, tested, drugs, highest, 'drug-drug', interaction, index]), verbo([found]), complemento([for, 'PAS', as, 9.3, -, 13.9, for, 'OAT1', and, 12.0, -, 17.7, for, 'OAT3', and, linezolid, was, 1.18, -, 2.15, for, 'OAT1', and, 1.7, -, 3.01, for, 'OAT3'])].
[sujeto(['Similarly,', 'DDI', index, of, pyrazinamide, and, 'Levofloxacin', was, 0.57, and, 0.3, for, 'OCT1', and, that, of, 'PAS', was, 3.8, for, 'OCT2,']), verbo([suggesting]), complemento([a, higher, possibility, '(', &, 'gt;0'])].
[sujeto(['This', is, the, first, comprehensive]), verbo([report]), complemento([for, the, inhibitory, potential, of, 'anti-TB', drugs, on, 'OATs-', and, 'OCTs-mediated', uptake, of, in, vitro, prototype, and, clinically, prescribed, substrate, 'drugs,', providing, such, predictive, understanding, on, the, in, vivo, clinical, 'DDI', studies, among, 'anti-TB', drugs, and, other, 'co-prescribed', drugs])].
[sujeto(['The', efficacy, and, safety, of, 'alectinib,', a, central, nervous, 'system-active', and, selective, anaplastic, lymphoma, kinase, '(', 'ALK)', 'inhibitor,']), verbo([has]), complemento([been, demonstrated, in, patients, with, 'ALK-positive', '(', 'ALK+)', 'non-small-cell', lung, cancer, '(', 'NSCLC)', progressing, on, crizotinib])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, dose, adjustments, may, not, be, needed, when, alectinib, is, 'co-administered', with, 'CYP3A', inhibitors, or, 'inducers,', or, for, 'co-administered', 'CYP3A', substrates])].
[sujeto(['Pathogenic', 'Vibrio', 'alginolyticus,', a]), verbo([cause]), complemento([of, severe, infection, in, 'shellfish,', as, well, as, in, 'humans,', has, been, found, at, high, frequency, around, all, coastal, areas, of, 'Korea'])].
[sujeto(['Nonsusceptibility', to, 'penicillin,', predicted, by, penicillin]), verbo([binding]), complemento([protein, 'types,', was, 2.7, '%', '(', 'non-meningitis', 'criteria)', and, 23.8, '%', '(', meningitis, 'criteria)'])].
[sujeto(['Rare', core, genome, mutations]), verbo([conferring]), complemento(['erythromycin-resistance', included, a, 2, codon, rplD, insertion, '(', 'rplD69-KG-70)', and, the, 23, 'S', rRNA, 'A2061G', substitution, '(', 6, total, 'isolates)'])].
[sujeto(['Intermediate', 'cotrimoxazole-resistance', was]), verbo([associated]), complemento([with, 1, -, 2, codon, insertions, within, folP, '(', 238, 'isolates)', or, the, folA, 'I100L', substitution, '(', 38, 'isolates),', while, full, 'cotrimoxazole-resistance', was, attributed, to, alterations, in, both, genes, '(', 172, 'isolates)'])].
[sujeto(['Levofloxacin-resistance', '(', 2, 'isolates)', was]), verbo([associated]), complemento([with, parC, 'and/or', gyrA, mutations])].
[sujeto(['Carbapenem', resistant, 'Acinetobacter', baumannii, is, an, important, nosocomial, pathogen]), verbo([associated]), complemento([with, a, variety, of, infections])].
[sujeto(['Genotypes', 'B', and, 'C', were]), verbo([found]), complemento([in, 28.9, '%', and, 26.8, '%', of, the, 'isolates,', respectively])].
[sujeto(['Previous', studies, show, that, feedback, inhibition, of, bile, acid, production, by, bile, acids, is]), verbo([mediated]), complemento([by, multiple, 'mechanisms,', including, activation, of, pregnane, 'X', receptor, '(', 'PXR)'])].
[sujeto(['To', delineate, the, mechanisms, underlying, 'PXR-mediated', suppression, of, bile, acid, 'biosynthesis,', we, examined, the, functional, 'cross-talk', between, human, 'PXR', and, 'HNF-4,', a, key, hepatic, activator, of, genes]), verbo([involved]), complemento([in, bile, acid, biosynthesis, including, the, cholesterol, 7, -, alpha, hydroxylase, '(', 'CYP7A1)', and, sterol, 12, -, alpha, hydroxylase, '(', 'CYP8B1)', genes])].
[sujeto(['The', coactivator, 'PGC-1']), verbo([enhanced]), complemento([transcriptional, activity, of, 'HNF-4,', and, this, enhancement, was, suppressed, by, 'rifampicin-activated', 'PXR'])].
[sujeto(['Endogenous', 'PGC-1', from, mouse, liver, extracts]), verbo([bound]), complemento([to, 'PXR,', and, recombinant, 'PGC-1', directly, interacted, with, both, 'PXR', and, 'HNF-4', in, vitro])].
[sujeto(['Rifampicin-dependent', interaction, of, 'PXR', with, 'PGC-1', was, shown, in, cells, by, 'coimmunoprecipitation,', and, intranuclear, localization, studies, using, confocal, microscopy]), verbo([provided]), complemento([further, evidence, for, this, interaction])].
[sujeto(['In', chromatin, immunoprecipitation, 'studies,', rifampicin, treatment, did, not]), verbo([inhibit]), complemento(['HNF-4', binding, to, the, native, promoters, of, 'CYP7A1', and, 'CYP8B1', but, resulted, in, dissociation, of, 'PGC-1', and, concomitant, gene, repression])].
[sujeto(['Our', study]), verbo([suggests]), complemento([that, 'ligand-activated', 'PXR', interferes, with, 'HNF-4', signaling, by, targeting, the, common, coactivator, 'PGC-1,', which, underlies, physiologically, relevant, inhibitory, 'cross-talk', between, drug, metabolism, and, 'cholesterol/glucose', metabolism])].
[sujeto(['BCL6']), verbo([interacts]), complemento([with, 'co-repressor,', 'SMRT,', and, this, is, essential, for, its, role, in, lymphomas])].
[sujeto(['Peptide', or, small, molecule, 'inhibitors,', which]), verbo([prevent]), complemento([the, association, of, 'SMRT', with, 'BCL6,', inhibit, transcriptional, repression, and, cause, apoptosis, of, lymphoma, cells, in, vitro, and, in, vivo])].
[sujeto(['In', order, to, discover, 'compounds,', which]), verbo([have]), complemento([the, potential, to, be, developed, into, 'BCL6', 'inhibitors,', we, screened, a, natural, product, library])].
[sujeto(['The', ansamycin, 'antibiotic,', rifamycin, 'SV,']), verbo([inhibited]), complemento(['BCL6', transcriptional, repression, and, 'NMR', spectroscopy, confirmed, a, direct, interaction, between, rifamycin, 'SV', and, 'BCL6'])].
[sujeto(['To', further, determine, the, characteristics, of, compounds]), verbo([binding]), complemento([to, 'BCL6-POZ', we, analyzed, four, other, members, of, this, family, and, showed, that, 'rifabutin,', bound, most, strongly])].
[sujeto(['John\'s', 'Wort,', exerts, antidepressant, properties, via, indirect, inhibition, of, serotonin, reuptake, by, selectively]), verbo([activating]), complemento([the, canonical, transient, receptor, potential, channel, 6, '(', 'TRPC6)'])].
[sujeto(['Hyperforin', treatment, can]), verbo([lead]), complemento([to, 'drug-drug', interactions, due, to, potent, activation, of, the, nuclear, receptor, 'PXR', '(', 'NR1I2),', a, key, transcriptional, regulator, of, genes, involved, in, drug, metabolism, and, transport])].
[sujeto(['It', was, previously, shown, that, synthetic, acylated, phloroglucinol, derivatives]), verbo([activate]), complemento(['TRPC6', with, similar, potency, as, hyperforin])].
[sujeto(['Here', we, investigated, five, synthetic, 'TRPC6-activating', phloroglucinol, derivatives, and, four, 'TRPC6-nonactivating', compounds, compared, with, hyperforin, and, rifampicin, for, their, potential, to]), verbo([activate]), complemento(['PXR', in, silico, and, in, vitro])].
[sujeto(['Computational', 'PXR', pharmacophore, modeling, did, not, indicate, potent, agonist, or, antagonist, interactions, for, the, 'TRPC6-activating', 'derivatives,', whereas, one, of, them, was]), verbo([suggested]), complemento([by, docking, studies, to, show, both, agonist, and, antagonist, interactions])].
[sujeto(['Hyperforin', and, rifampicin, treatment, of, primary, human, hepatocytes, resulted, in, highly, correlated, induction, of, 'PXR']), verbo([target]), complemento(['genes,', whereas, treatment, with, the, phloroglucinol, derivatives, elicited, moderate, gene, expression, changes, that, were, only, weakly, correlated, with, those, of, rifampicin, and, hyperforin, treatment])].
[sujeto(['These', results, show, that, 'TRPC6-activating', phloroglucinols, do, not]), verbo([activate]), complemento(['PXR', and, should, therefore, be, promising, new, candidates, for, further, drug, development])].
[sujeto(['To', 'date,', there, are, 198]), verbo([reported]), complemento(['SNPs', for, the, human, 'PXR/NR1I2', gene])].
[sujeto(['Some', of, these, 'SNPs', are]), verbo([found]), complemento([to, affect, the, inducing, ability, of, 'PXR', to, 'CYP3A4'])].
[sujeto(['This', 'study,', for, the, first, 'time,']), verbo([has]), complemento([investigated, the, effect, of, 'PXR', haplotype, on, basal, and, 'St', 'John\'s', 'wort-induced', 'CYP3A4', activity, in, humans])].
[sujeto(['After', administration, of, 'SJW,', the, 'AUC(0-infinity)', of, 'NIF']), verbo([decreased]), complemento(['significantly,', and, the, 'AUC(0-infinity)', of, 'DNIF', increased, significantly, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['For', 'H1/H2,', the, 'AUC(0-infinity)', of, 'NIF']), verbo([decreased]), complemento([by, 42.4, '%', ',', and, the, 'AUC(0-infinity)', of, 'DNIF', increased, by, 20.2, '%', ;, for, 'H2/H2,', the, 'AUC(0-infinity)', of, 'NIF', decreased, by, 47.9, '%', ',', and, the, 'AUC(0-infinity)', of, 'DNIF', increased, by, 33.0, '%', ;, for, 'H1/H1,', the, 'AUC(0-infinity)', of, 'NIF', decreased, by, 29.0, '%', ',', yet, the, 'AUC(0-infinity)', of, 'DNIF', increased, by, 106.7, '%'])].
[sujeto(['The']), verbo([increase]), complemento([of, the, 'AUC(0-infinity)', of, 'DNIF', in, 'H1/H1', was, significantly, different, from, the, other, two, haplotype, pairs, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['Prolonged', therapy, with, rifampicin, or, phenobarbital]), verbo([has]), complemento([been, shown, to, cause, vitamin, 'D', deficiency, or, 'osteomalacia,', particularly, in, patients, with, marginal, vitamin, 'D', stores])].
[sujeto(['Here', we, show, that, these, drugs]), verbo([lead]), complemento([to, the, upregulation, of, 25, -, hydroxyvitamin, 'D(3)-24-hydroxylase', '(', 'CYP24)', gene, expression, through, the, activation, of, the, nuclear, receptor, pregnane, 'X', receptor, '(', 'PXR;', 'NR1I2)'])].
[sujeto(['Moreover,', rifampicin]), verbo([increased]), complemento([24, -, hydroxylase, activity, in, these, 'cells,', 'while,', in, vivo, in, 'mice,', pregnenolone, 16, 'alpha-carbonitrile', increased, the, plasma, concentration, of, 24, ',', 25, -, dihydroxyvitamin, 'D(3)'])].
[sujeto(['We', demonstrated, that, 'PXR']), verbo([binds]), complemento([to, and, transactivates, the, 2, proximal, vitamin, 'D-responsive', elements, of, the, human, 'CYP24', promoter])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, xenobiotics, and, drugs, can, modulate, 'CYP24', gene, expression, and, alter, vitamin, 'D(3)', hormonal, activity, and, calcium, homeostasis, through, the, activation, of, 'PXR'])].
[sujeto(['Cytochromes', 'P450', '(', 'P450s)', are]), verbo([involved]), complemento([in, the, oxidative, metabolism, of, a, plethora, of, structurally, unrelated, 'compounds,', including, therapeutic, drugs])].
[sujeto(['Two', orphan, members, of, the]), verbo([nuclear]), complemento([receptor, 'superfamily,', the, pregnane, 'X', receptor, '(', 'PXR;', 'NR1I2)', and, constitutive, androstane, receptor, '(', 'CAR;', 'NR1I3)', have, been, implicated, in, this, phenomenon])].
[sujeto(['PXR', was, shown, to, be, capable, of]), verbo([activating]), complemento([the, 'phenobarbital-responsive', enhancer, module, '(', 'PBREM)', region, of, the, 'CYP2B6', 'gene,', a, 51, -, 'base-pair', enhancer, element, that, mediates, induction, of, 'CYP2B6', expression, by, 'CAR'])].
[sujeto(['The', two]), verbo([nuclear]), complemento(['receptor-binding', motifs, within, the, 'PBREM', effectively, bound, 'PXR', as, a, heterodimer, with, the, 9, -, cis, retinoic, acid, receptor, alpha, '(', 'NR2B1)'])].
[sujeto(['Taken', 'together,', these, observations, demonstrate, that, the, 'CYP2B6', gene, is, directly]), verbo([regulated]), complemento([by, 'PXR', and, further, establish, this, receptor, as, a, key, regulator, of, 'drug-metabolizing', 'P450s'])].
[sujeto(['Pregnane', 'X', receptor, '(', 'PXR)']), verbo([mediates]), complemento([induction, of, the, principal, xenobiotic, metabolizing, enzymes, and, transporters, in, the, liver])].
[sujeto(['Here,', we]), verbo([have]), complemento([assessed, the, 'down-regulation', of, 'OCT1', expression, by, 'PXR', activation])].
[sujeto(['Rifampicin', and, hyperforin, as, well, as, the, constitutively, active, 'PXR', mutant, 'T248D']), verbo([suppressed]), complemento([activity, of, the, 1.8, &, 'nbsp;kb', 'OCT1', promoter, construct, in, gene, reporter, assays])].
[sujeto(['PXR', ligands, reduced, the, 'HNF4α-mediated', and, 'USF-mediated', transactivation, of, 'OCT1', gene, expression, by, competing, for, 'SRC-1', and]), verbo([decreased]), complemento([delivery, of, a, model, 'OCT1', substrate, into, hepatocytes])].
[sujeto(['To', investigate, the, question, how, 'ATP-binding', cassette, '(', 'ABC)-transporters', are, 'regulated,', we, analyzed, the, influence, of, the]), verbo([nuclear]), complemento(['receptor,', pregnane, 'X', receptor, '(', 'PXR)', on, transporter, expression])].
[sujeto(['PXR', is, a, 'xenobiotic-activated', transcription, factor, that, is, highly]), verbo([expressed]), complemento([in, barrier, tissue])].
[sujeto(['Xenobiotics', like, rifampicin, and, hyperforin]), verbo([activate]), complemento(['PXR', and, induce, 'Abcb1', expression])].
[sujeto(['ABC-transporter', 'up-regulation', could]), verbo([have]), complemento([potential, effects, on, pharmacokinetics, of, different, drugs])].
[sujeto(['The', stimulation, of, the, 'PBCEC', with, rifampicin, or, hyperforin, showed, a, significant, 'up-regulation', of, both, 'ABC-transporters', on, 'RNA', level, after, 6, 'h,', whereas, an]), verbo([increased]), complemento([protein, expression, was, strongest, after, 12, h])].
[sujeto(['In', conclusion, our, data, prove, 'PXR', activation, by, rifampicin, and, hyperforin]), verbo([lead]), complemento([to, an, increased, 'ABC-transporter', expression, and, transport, activity])].
[sujeto(['Transcriptional', regulation, of, some, genes]), verbo([involved]), complemento([in, xenobiotic, detoxification, and, apoptosis, is, performed, via, the, human, pregnane, 'X', receptor, '(', 'PXR)', which, in, turn, is, activated, by, structurally, diverse, agonists, including, steroid, hormones])].
[sujeto(['Activation', of, 'PXR']), verbo([has]), complemento([the, potential, to, initiate, adverse, 'effects,', altering, drug, pharmacokinetics, or, perturbing, physiological, processes])].
[sujeto(['There']), verbo([has]), complemento([been, limited, success, with, 'structure-based', modeling, approaches, to, predict, human, 'PXR', activators])].
[sujeto(['Slightly', better, success]), verbo([has]), complemento([been, achieved, with, 'ligand-based', modeling, methods, including, quantitative, 'structure-activity', relationship, '(', 'QSAR)', 'analysis,', pharmacophore, modeling, and, machine, learning])].
[sujeto(['In', this, 'study,', we, present, a, comprehensive, analysis, focused, on, prediction, of, 115, steroids, for, ligand]), verbo([binding]), complemento([activity, towards, human, 'PXR'])].
[sujeto(['Monkeys']), verbo([have]), complemento([been, proposed, as, an, animal, model, to, predict, the, magnitude, of, human, clinical, 'drug-drug', interactions, caused, by, 'CYP3A4', enzyme, induction])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, cynomolgus, and, human, 'PXR', respond, in, a, similar, fashion, to, these, ligands])].
[sujeto(['Both', monkey, and, human, hepatocytes]), verbo([responded]), complemento([similarly, to, the, inducers, and, resulted, in, increased, 'RNA', and, enzyme, activity, changes, of, 'CYP3A8', and, 'CYP3A4,', respectively])].
[sujeto(['These', results, show, that, the, cynomolgus, monkey, can, be, a, predictive, in, vivo, animal, model, of, 'PXR-mediated', induction, of, human, 'CYP3A4', and, can]), verbo([provide]), complemento([a, useful, assessment, of, the, resulting, pharmacokinetic, changes, of, affected, drugs])].
[sujeto(['One', strategy, to]), verbo([increase]), complemento([brain, drug, levels, is, to, modulate, 'P-glycoprotein', regulation])].
[sujeto(['This', approach]), verbo([requires]), complemento([understanding, of, the, mechanisms, that, control, transporter, expression, and, function])].
[sujeto(['One', mechanism, through, which, 'P-glycoprotein', is]), verbo([regulated]), complemento([is, the, nuclear, 'receptor,', pregnane, 'X', receptor, '(', 'PXR)'])].
[sujeto(['Xenobiotics', including, drugs]), verbo([activate]), complemento(['PXR', and, induce, 'P-glycoprotein,', which, potentially, affects, 'pharmacokinetics/pharmacodynamics', of, coadministered, drugs])].
[sujeto(['To']), verbo([activate]), complemento(['PXR,', we, used, the, 'PXR', 'ligands,', 'rifampicin,', 'hyperforin,', and, 'pregnenolone-16alpha-carbonitrile', '(', 'PCN),', and, measured, abcb1, mRNA, with, quantitative, polymerase, chain, 'reaction,', 'P-glycoprotein', expression, with, 'Western', 'blotting,', and, 'P-glycoprotein', transport, activity, with, a, calcein, assay])].
[sujeto(['We']), verbo([provide]), complemento([first, proof, of, principle, that, the, human, 'PXR', 'ligands,', rifampicin, and, 'hyperforin,', but, not, the, rodent, 'PXR', 'ligand,', 'PCN,', activate, pig, 'PXR', at, the, 'blood-brain', barrier, and, induce, 'mRNA,', protein, 'expression,', and, transport, activity, of, 'P-glycoprotein'])].
[sujeto(['Our', data, indicate, functional, similarities, between, human, and, pig, 'PXR', that]), verbo([suggest]), complemento([the, pig, model, could, be, useful, for, predicting, 'xenobiotic-PXR', interactions, in, humans])].
[sujeto(['Because', 'PXR', is, crucial, in, controlling, drug, efflux, 'transporters,', our, findings, will, contribute, to, a, better, understanding, of, the, regulation, of, 'blood-brain', barrier, 'function,', which, could, potentially]), verbo([have]), complemento([important, clinical, implications, for, the, treatment, of, 'CNS', disorders])].
[sujeto(['Induction', of, cytochrome, 'P450', '(', 'CYP)', 3, 'A4,', an, enzyme, that, is]), verbo([involved]), complemento([in, the, biotransformation, of, more, than, 50, '%', of, all, 'drugs,', by, xenobiotics, is, an, important, cause, of, pharmacokinetic, 'drug-drug', interactions, in, oncology])].
[sujeto(['In', addition, to, rifampicin, and, 'hyperforin,', the, anticancer, drug, paclitaxel]), verbo([has]), complemento([also, been, shown, to, be, an, inducer, of, 'CYP3A4', via, activation, of, the, pregnane, 'X', receptor, '(', 'PXR)'])].
[sujeto(['We', therefore, screened, 18, widely, used, anticancer, drugs, for, their, ability, to]), verbo([activate]), complemento(['PXR-mediated', 'CYP3A4', induction])].
[sujeto(['Paclitaxel,', 'erlotinib,', 'tamoxifen,', 'ifosfamide,', flutamide, and, docetaxel, are, able, to]), verbo([activate]), complemento(['PXR,', while, only, strong, 'PXR', activation, leads, to, significant, induction, of, 'CYP3A4', activity])].
[sujeto(['The', identified, 'PXR', agonists, may]), verbo([have]), complemento([the, propensity, to, cause, clinically, relevant, 'drug-drug', interactions, as, a, result, of, 'CYP3A4', induction])].
[sujeto(['We']), verbo([have]), complemento([investigated, the, induction, of, 'P-glycoprotein', '(', 'Pgp;', 'MDR1)', activity, in, a, human, intestinal, epithelial, cell, line, '(', 'T84)', following, 'pre-exposure', to, a, panel, of, drug, 'compounds,', reported, to, be, 'Pgp', 'substrates,', inhibitors, or, inducers])].
[sujeto(['Net', transepithelial, digoxin, secretion, was]), verbo([increased]), complemento(['(', 1.3, 'fold,', 'n=6,', 'P<0'])].
[sujeto(['A', number, of, 'Pgp', substrates, '(', 'quinidine,', 'amprenavir,', 'irinotecan,', 'topotecan,', atorvastatin, and, 'erythromycin)']), verbo([induced]), complemento([net, digoxin, 'secretion,', as, did, the, 'non-Pgp', substrate, artemisinin])].
[sujeto(['Various', 'non-Pgp', substrates, demonstrated, inhibition, of, digoxin, secretion, '(', 'verapamil,', 'mifepristone,', 'clotrimazole,', 'mevastatin,', diltiazem, and, 'isradipine)', but, did, not]), verbo([induce]), complemento(['Pgp-mediated', digoxin, secretion])].
[sujeto(['Of', the, compounds, that]), verbo([increased]), complemento(['Pgp', 'secretion,', 'quinidine,', 'topotecan,', atorvastatin, and, amprenavir, 'pre-exposure', also, elevated, 'MDR1', mRNA, 'levels,', whereas, 'erythromycin,', irinotecan, and, artemisinin, displayed, no, change, in, transcript, levels])].
[sujeto(['In', the, last, 5, 'years,', 'SJW']), verbo([has]), complemento([been, implicated, in, drug, 'interactions,', which, are, largely, mediated, by, the, induction, of, the, drug, metabolizing, 'enzymes,', especially, 'CYP3A4'])].
[sujeto(['The', 'CYP3A4', induction, was]), verbo([mediated]), complemento([by, 'PXR,', but, not, by, 'CAR'])].
[sujeto(['A', 'temperature-induced']), verbo([decrease]), complemento([in, the, hyperforin, content, of, a, selected, dry, 'SJW', extract, abolished, the, induction, of, 'CYP3A4'])].
[sujeto(['In', 'conclusion,', commercial, 'SJW', preparations, still, exhibit, an, enormous, variability, in, 'CYP3A4', 'induction,', which, is]), verbo([mediated]), complemento([by, hyperforin, and, 'PXR'])].
[sujeto(['SJW', preparations, with, lower, hyperforin, content, should, reduce, the, frequency, of, clinical, interactions]), verbo([involving]), complemento([this, herbal, drug])].
[sujeto(['Reducing', 'P-glycoprotein', activity, dramatically]), verbo([increases]), complemento([penetration, of, many, therapeutic, drugs, into, the, 'CNS'])].
[sujeto(['Previous', studies, in, rat, showed, that, brain, capillary, 'P-glycoprotein', was, transcriptionally, 'up-regulated', by, the, pregnane, 'X', receptor, '(', 'PXR),', a, 'xenobiotic-activated']), verbo([nuclear]), complemento([receptor])].
[sujeto(['Here', we, used, a, transgenic, mouse]), verbo([expressing]), complemento([human, 'PXR', '(', 'hPXR)', to, determine, the, consequences, of, increased, 'blood-brain', barrier, 'P-glycoprotein', activity])].
[sujeto(['P-glycoprotein', expression, and, transport, activity, in, brain, capillaries, from, transgenic, mice, was, significantly]), verbo([increased]), complemento([when, capillaries, were, exposed, to, the, hPXR, 'ligands,', rifampin, and, 'hyperforin,', in, vitro, and, when, the, mice, were, dosed, with, rifampin, in, vivo])].
[sujeto(['Plasma', rifampin, levels, in]), verbo([induced]), complemento([mice, were, comparable, with, literature, values, for, patients])].
[sujeto(['In', 'rifampin-induced', 'mice,', the, methadone, effect, was, reduced, by, approximately, 70, '%', ',', even, though, plasma, methadone, levels, were, similar, to, those]), verbo([found]), complemento([in, transgenic, controls, not, exposed, to, rifampin])].
[sujeto(['Thus,', hPXR, activation, in, vivo]), verbo([increased]), complemento(['P-glycoprotein', activity, and, tightened, the, 'blood-brain', barrier, to, 'methadone,', reducing, the, 'drug\'s', 'CNS', efficacy])].
[sujeto(['Early', investigations, of, gene, regulation, revealed, that, nutrients, could]), verbo([modulate]), complemento([gene, 'expression,', an, example, being, the, discovery, of, 'metal-regulated', gene, transcription, '(', 11, ',', 19, ',', 44, ')'])].
[sujeto(['Only', more, recently]), verbo([have]), complemento([we, focused, on, the, ability, of, 'non-nutritional', botanicals, or, functional, food, components, to, affect, gene, expression, at, the, transcriptional, level])].
[sujeto(['John\'s', 'wort,', and]), verbo([activates]), complemento([gene, transcription, of, cytochrome, 'p450-3A4,', causing, significant, 'botanical-drug', interactions])].
[sujeto(['Recently,', the, 'lipid-regulating', peroxisome, 'proliferator-activated', receptors]), verbo([have]), complemento([been, studied, as, receptors, activated, by, soy, 'isoflavones,', perhaps, explaining, the, 'lipid-lowering', effect, of, soy, intake])].
[sujeto(['Epigallocatechin', gallate]), verbo([has]), complemento([been, shown, to, be, an, inhibitor, of, the, protealytic, activity, of, the, 'proteasome;', this, inhibition, has, a, significant, implication, for, cell, proliferation, and, the, stability, of, transcription, factors, in, the, nucleus])].
[sujeto(['Very', 'recently,', the, effects, of, botanicals]), verbo([have]), complemento([been, studied, as, activators, of, 'sirtuins,', important, deacetylation, enzymes, that, have, been, shown, to, enhance, lifespan, in, a, variety, of, organisms])].
[sujeto(['Sirtuins']), verbo([have]), complemento([been, implicated, in, the, 'lifespan-enhancing', effect, of, caloric, restriction])].
[sujeto(['Originally', presumed, to]), verbo([act]), complemento([mainly, on, compaction, or, accessibility, of, 'DNA,', recent, evidence, shows, important, activity, of, sirtuins, as, controllers, of, transcriptional, coactivator, availability])].
[sujeto(['This', review, focuses, on, novel, mechanisms, by, which, botanical, products]), verbo([regulate]), complemento([cell, function, via, gene, transcription])].
[sujeto(['P-glycoprotein', '(', 'Pgp)', is, a, 170, kDa]), verbo([phosphorylated]), complemento([glycoprotein, encoded, by, human, 'MDR1', gene])].
[sujeto(['Curcumin,', 'ginsenosides,', 'piperine,', some, catechins, from, green, 'tea,', and, silymarin, from, milk, thistle, were]), verbo([found]), complemento([to, be, inhibitors, of, 'Pgp,', while, some, catechins, from, green, tea, increased, 'Pgp-mediated', drug, transport, by, heterotropic, allosteric, 'mechanism,', and, 'St'])].
[sujeto(['John\'s', wort]), verbo([induced]), complemento([the, intestinal, expression, of, 'Pgp', in, vitro, and, in, vivo])].
[sujeto([',', bergamottin, and, 'quercetin)', from, grapefruit, juice, were]), verbo([reported]), complemento([to, modulate, 'Pgp', activity])].
[sujeto(['Many', of, these, herbal, 'constituents,', in, particular, 'flavonoids,', were]), verbo([reported]), complemento([to, modulate, 'Pgp', by, directly, interacting, with, the, vicinal, 'ATP-binding', 'site,', the, 'steroid-binding', 'site,', or, the, 'substrate-binding', site])].
[sujeto([',', hyperforin, and, 'kava)', were, shown, to]), verbo([activate]), complemento([pregnane, 'X', 'receptor,', an, orphan, nuclear, receptor, acting, as, a, key, regulator, of, 'MDR1', and, many, other, genes])].
[sujeto(['The', inhibition, of, 'Pgp', by, herbal, constituents, may]), verbo([provide]), complemento([a, novel, approach, for, reversing, multidrug, resistance, in, tumor, 'cells,', whereas, the, stimulation, of, 'Pgp', expression, or, activity, has, implication, for, chemoprotective, enhancement, by, herbal, medicines])].
[sujeto(['This', is, exemplified, by]), verbo([increased]), complemento([oral, bioavailability, of, phenytoin, and, rifampin, by, piperine, and, decreased, bioavailability, of, 'indinavir,', 'tacrolimus,', 'cyclosporine,', 'digoxin,', and, fexofenadine, by, coadministered, 'St'])].
[sujeto(['The', pregnane, 'X', receptor, '(', 'PXR)', is, a]), verbo([nuclear]), complemento([receptor, significantly, involved, in, the, transcriptional, regulation, of, 'drug-metabolizing', enzymes, and, transporters])].
[sujeto(['Interestingly,', certain, 'PXR', ligands, such, as, rifampin]), verbo([have]), complemento([been, shown, to, readily, induce, human, and, rabbit, but, not, rodent, members, of, the, cytochrome, 'P450', 3, 'A'])].
[sujeto(['Within', this, 'region,', the, corresponding, residues, 'Leu308', and, 'Phe305', of, human, and, rat, 'PXR,', 'respectively,', were]), verbo([found]), complemento([to, be, important, for, rifampin, activation])].
[sujeto(['Rifampin,', 'paclitaxel,', and, hyperforin, sensitivity, was]), verbo([conferred]), complemento([to, rat, 'PXR', when, 'Phe305', was, converted, to, 'leucine,', whereas, attenuation, of, sensitivity, was, observed, when, 'Leu308', of, human, 'PXR', was, replaced, with, phenylalanine])].
[sujeto(['Accordingly,', our, data]), verbo([provide]), complemento([compelling, new, insight, into, the, importance, of, the, amino, acids, comprising, the, pore, to, the, 'ligand-binding', cavity, as, a, critical, modulator, of, 'PXR', response])].
[sujeto(['Several', studies]), verbo([have]), complemento([reported, that, certain, drugs, such, as, rifampicin, and, phenobarbital, induce, 'CYP2C9,', but, the, molecular, basis, for, this, induction, remains, unknown])].
[sujeto(['In', the, present, 'study,', we, demonstrate, that, the, human, pregnane, 'X', receptor, '(', 'hPXR)']), verbo([mediates]), complemento([induction, of, 'CYP2C9', by, the, prototype, drugs, 'rifampicin,', hyperforin, '(', found, in, 'St'])].
[sujeto(['Deletion', and, mutagenesis, studies, with, luciferase, reporter, constructs, showed, that, a, functional, 'PXR-responsive', element, located, -, 1839, /, -, 1824, base, pairs, upstream, from, the, translation, start, site, was, the, primary]), verbo([binding]), complemento([site, mediating, the, rifampicin, induction, of, 'CYP2C9'])].
[sujeto(['Mutational', analysis, of, 3, -, and, 12, -, kilobase, 'CYP2C9', promoter, fragments, indicated, that, this, proximal]), verbo([binding]), complemento([site, was, essential, for, rifampicin, 'inducibility,', although, a, cooperative, effect, could, be, attributed, to, a, second, 'CAR-RE', located, at, -, 2899, /, -, 2883])].
[sujeto(['In', 'summary,', we]), verbo([have]), complemento([demonstrated, rifampicin, induction, of, 'CYP2C9', promoter, constructs, that, is, consistent, with, the, magnitude, of, induction, of, 'CYP2C9', protein, and, mRNA, reported, in, vivo, and, in, primary, human, 'hepatocytes,', and, we, have, identified, the, 'cis-element', essential, for, this, response])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([to, demonstrate, that, the, nuclear, receptor, 'PXR', mediates, induction, of, 'CYP2C9', with, 'rifampicin,', 'phenobarbital,', and, hyperforin])].
[sujeto(['Vitamin', 'K2', is, a, critical, nutrient]), verbo([required]), complemento([for, blood, clotting, that, also, plays, an, important, role, in, bone, formation])].
[sujeto(['Vitamin', 'K2', supplementation, 'up-regulates', the, expression, of, bone, 'markers,']), verbo([increases]), complemento([bone, density, in, 'vivo,', and, is, used, clinically, in, the, management, of, osteoporosis])].
[sujeto(['The', mechanism, of, vitamin, 'K2', action, in, bone, formation, was, thought, to]), verbo([involve]), complemento([its, normal, role, as, an, essential, cofactor, for, 'gamma-carboxylation', of, bone, matrix, proteins])].
[sujeto(['However,', there, is, evidence, that]), verbo([suggests]), complemento([vitamin, 'K2', also, has, a, transcriptional, regulatory, function])].
[sujeto(['Vitamin', 'K2']), verbo([bound]), complemento([to, and, activated, the, orphan, nuclear, receptor, 'SXR', and, induced, expression, of, the, 'SXR', target, 'gene,', 'CYP3A4,', identifying, it, as, a, bona, fide, 'SXR', ligand])].
[sujeto(['Vitamin', 'K2', treatment, of, osteosarcoma, cells]), verbo([increased]), complemento([mRNA, levels, for, the, osteoblast, markers, bone, alkaline, 'phosphatase,', 'osteoprotegerin,', 'osteopontin,', and, matrix, 'Gla', protein])].
[sujeto(['The', known, 'SXR', activators, rifampicin, and, hyperforin]), verbo([induced]), complemento([this, panel, of, bone, markers, to, an, extent, similar, to, vitamin, 'K2'])].
[sujeto(['Vitamin', 'K2', was, able, to]), verbo([induce]), complemento([bone, markers, in, primary, osteocytes, isolated, from, 'wild-type', murine, calvaria, but, not, in, cells, isolated, from, mice, deficient, in, the, 'SXR', ortholog, 'PXR'])].
[sujeto(['We', infer, that, vitamin, 'K2', is, a, transcriptional, regulator, of, 'bone-specific', genes, that]), verbo([acts]), complemento([through, 'SXR', to, favor, the, expression, of, osteoblastic, markers])].
[sujeto(['Thus,', 'SXR']), verbo([has]), complemento([a, novel, role, as, a, mediator, of, bone, homeostasis, in, addition, to, its, role, as, a, xenobiotic, sensor])].
[sujeto(['The']), verbo([nuclear]), complemento([xenobiotic, receptor, 'PXR', is, activated, by, a, wide, variety, of, clinically, used, drugs, and, serves, as, a, master, regulator, of, drug, metabolism, and, excretion, gene, expression, in, mammals])].
[sujeto(['This', unregulated, herbal, remedy]), verbo([leads]), complemento([to, dangerous, 'drug-drug', 'interactions,', 'however,', in, patients, taking, oral, 'contraceptives,', 'antivirals,', or, immunosuppressants])].
[sujeto(['Such', interactions, are]), verbo([caused]), complemento([by, the, activation, of, the, human, 'PXR', by, 'hyperforin,', the, psychoactive, agent, in, 'St'])].
[sujeto(['In', this, 'study,', we, show, that, hyperforin]), verbo([induces]), complemento([the, expression, of, numerous, drug, metabolism, and, excretion, genes, in, primary, human, hepatocytes])].
[sujeto(['We', present, the, 2.1, 'A', crystal, structure, of, hyperforin, in, complex, with, the, ligand]), verbo([binding]), complemento([domain, of, human, 'PXR'])].
[sujeto(['Hyperforin']), verbo([induces]), complemento([conformational, changes, in, 'PXR\'s', ligand, binding, pocket, relative, to, structures, of, human, 'PXR', elucidated, previously, and, increases, the, size, of, the, pocket, by, 250, 'A(3)'])].
[sujeto(['We']), verbo([find]), complemento([that, the, mutation, of, individual, aromatic, residues, within, the, ligand, binding, cavity, changes, 'PXR\'s', response, to, particular, ligands])].
[sujeto(['Taken', 'together,', these, results, demonstrate, that, 'PXR', employs, structural, flexibility, to, expand, the, chemical, space, it, samples, and, that, the, mutation, of, specific, residues, within, the, ligand]), verbo([binding]), complemento([pocket, of, 'PXR', tunes, the, 'receptor\'s', response, to, ligands])].
[sujeto(['The', pregnane, 'X', receptor, '(', 'PXR)', is]), verbo([involved]), complemento([in, transcriptional, regulation, of, multiple, cytochromes, 'P450', and, multidrug, 'resistance-associated', protein, '(', 'MDR1),', which, encodes, for, the, drug, transporter, 'P-glycoprotein'])].
[sujeto(['Crystal', structure, analyses]), verbo([suggest]), complemento([that, the, ligand, binding, domain, is, highly, hydrophobic, and, 'flexible,', allowing, molecules, of, differing, sizes, to, bind, in, multiple, orientations])].
[sujeto(['This', pharmacophore, supports, the, hydrophobic, nature, of, the, ligand]), verbo([binding]), complemento([domain, recently, deduced, from, the, 'X-ray', crystal, structure, because, it, contains, four, hydrophobic, regions, and, one, hydrogen, bond, acceptor])].
[sujeto(['These', features, are, consistent, with, at, least, one, of, the, three, experimentally, determined, orientations, in, which, 'SR12813']), verbo([binds]), complemento([to, 'PXR,', as, determined, by, overlay, studies])].
[sujeto(['The', pharmacophore, was, also, used, to, predict, the]), verbo([binding]), complemento([affinity, for, 28, molecules, not, in, the, model, but, known, to, be, 'PXR', ligands, of, differing, potencies])].
[sujeto(['The', model, could, be, useful, in, drug, 'development,', potentially]), verbo([acting]), complemento([as, a, 'high-throughput', filter, for, identifying, compounds, that, may, bind, to, 'PXR', before, in, vitro, determination])].
[sujeto(['The', effects, of]), verbo([increased]), complemento(['Ca2+', on, 'BDNF', 'up-regulation', and, neurite, outgrowth, remain, unclear])].
[sujeto(['We', showed, here, that, 'ES']), verbo([increased]), complemento([phosphorylation, of, the, 'cAMP-response', element, binding, protein, '(', 'CREB)'])].
[sujeto(['Blockade', of, 'Ca2+']), verbo([suppressed]), complemento(['CREB', phosphorylation, and, neurite, outgrowth])].
[sujeto(['Down-regulation', of]), verbo([phosphorylated]), complemento(['(', 'p)-CREB', reduced, 'BDNF', transcription, and, neurite, outgrowth, triggered, by, 'ES'])].
[sujeto(['Furthermore,', blockade, of, 'calmodulin-dependent', protein, kinase, 'II', '(', 'CaMKII)', using, the, inhibitors, 'KN93', or, 'KN62', reduced, 'p-CREB,', and, specific, knockdown, of, the, 'CaMKIIα', or, 'CaMKIIβ', subunit, was, sufficient, to]), verbo([suppress]), complemento(['p-CREB'])].
[sujeto(['To', our, 'knowledge,', this, is, the, first]), verbo([report]), complemento([of, the, mechanisms, of, 'Ca2+-dependent', 'BDNF', transcription, and, neurite, outgrowth, triggered, by, 'ES'])].
[sujeto(['The', herb, 'SJW', was]), verbo([associated]), complemento([with, more, treatment, responders, than, placebo, '(', relative, risk, '[', 'RR]', 1.53, ;, 95, &, 'nbsp;%', confidence, interval, '[', 'CI]', 1.19, ',', 1.97, ;, 'I(2)', 79, &, 'nbsp;%;', 18, 'RCTs;', 'N', =, 2922, ',', moderate, 'QoE;', standardized, mean, differences, '[', 'SMD]', 0.49, ;, 'CI', 0.23, ',', 0.74, ;, 16, 'RCTs;', 'I(2)', 89, &, 'nbsp;%,', 'N', =, 2888, ',', moderate, 'QoE)'])].
[sujeto(['Adverse', events]), verbo([reported]), complemento([in, 'RCTs', were, comparable, to, placebo, and, fewer, compared, with, antidepressants])].
[sujeto(['However,', assessments, were, limited, due, to, poor]), verbo([reporting]), complemento([of, adverse, events, and, studies, were, not, designed, to, assess, rare, events])].
[sujeto(['Hyperforin-induced', cell, proliferation, was, significantly]), verbo([inhibited]), complemento([by, the, estrogen, receptor, antagonist, 'ICI', 182, ',', 780])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, hyperforin, had, estrogenic, and, cell, proliferation, 'activities,', which, were, stimulated, via, the, estrogen, receptor])].
[sujeto(['A', total, of, 453, proteins, were, 'identified,', of, which, 282, proteins, were, significantly]), verbo([modulated]), complemento([in, 'hyperforin-treated', cells, compared, to, 17, 'β-estradiol-treated', cells])].
[sujeto(['Ingenuity', pathway, analysis, also, demonstrated, that, hyperforin, treatment]), verbo([induced]), complemento([less, cell, proliferation, than, 17, 'β-estradiol', by, downregulating, estrogen, receptor, 1])].
[sujeto(['Protein', network, analysis, showed, that, cell, proliferation, was]), verbo([regulated]), complemento([mainly, by, cyclin, 'D1', and, extracellular, 'signal-regulated', kinases])].
[sujeto(['In', 'conclusion,', 'although,', hyperforin, exhibited, lower, estrogenic, activity, than, 17, 'β-estradiol,', the, compound]), verbo([induced]), complemento([lower, levels, of, cancer, cell, proliferation, in, vitro])].
[sujeto(['Glomerular', mesangial, cell, '(', 'GMC)', proliferation, and, death, are]), verbo([involved]), complemento([in, the, pathogenesis, of, glomerular, disorders])].
[sujeto(['The', mechanisms, that, control, 'GMC', survival, are, poorly, 'understood,', but, may, include, signal, transduction, pathways, that, are]), verbo([modulated]), complemento([by, changes, in, intracellular, 'Ca(2+)', '(', '[', 'Ca(2+)]i)', concentration])].
[sujeto(['Hyperforin', '(', 'HF)-induced', 'TRPC6', channel, activation]), verbo([increased]), complemento(['[', 'Ca(2+)]i', 'concentration,', inhibited, 'proliferation,', and, triggered, apoptotic, cell, death, in, primary, neonatal, pig, 'GMCs'])].
[sujeto(['HF-induced', neonatal, 'GMC', apoptosis, was, not]), verbo([associated]), complemento([with, oxidative, stress])].
[sujeto(['However,', 'HF-induced', 'TRPC6', channel, activation]), verbo([stimulated]), complemento([nuclear, translocation, of, the, nuclear, factor, of, activated, 'T-cells,', cytoplasmic, 1, '(', 'NFATc1)'])].
[sujeto(['HF', also]), verbo([increased]), complemento([cell, death, surface, receptor, 'Fas', ligand, '(', 'FasL)', level, and, 'caspase-8', activity, in, the, 'cells;', effects, mitigated, by, '[', 'Ca(2+)]i', chelator, 'BAPTA,', 'calcineurin/NFAT', inhibitor, 'VIVIT,', and, 'TRPC6', channel, knockdown])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'TRPC6', 'channel-dependent', '[', 'Ca(2+)]i', elevation, and, the, ensuing, induction, of, the, 'calcineurin/NFAT,', 'FasL/Fas,', and, caspase, signaling, cascades, promote, neonatal, pig, 'GMC', apoptosis])].
[sujeto(['Hyperforin,', the, main, active, ingredient, of, the, medicinal, plant, 'Hypericum', 'perforatum,']), verbo([has]), complemento([been, shown, to, be, neuroprotective, against, acute, ischemic, stroke])].
[sujeto(['However,', the, 'long-term', actions, of, hyperforin, on, the, 'post-stroke', functional, recovery, and, underlying, mechanisms]), verbo([have]), complemento([not, been, investigated])].
[sujeto(['Here,', we]), verbo([found]), complemento([that, delayed, treatment, with, hyperforin, significantly, promoted, functional, recovery, and, increased, 'IL-17A', expression, in, the, ischemic, hemisphere, at, 28, days, 'post-ischemia', '(', 'dpi)'])].
[sujeto(['IL-17A', 'knock-out', or, 'anti-IL-17A', monoclonal, antibody, '(', 'mAb)', treatment, significantly, attenuated, the]), verbo([promoting]), complemento([effects, of, hyperforin, on, functional, recovery])].
[sujeto(['After', screening, for, neurotrophic, 'factors,', we, revealed, that, blocking, 'IL-17A', significantly, 'decreased,', whereas, recombinant, mouse, 'IL-17A', '(', 'rIL-17A)', treatment, significantly]), verbo([increased]), complemento([vascular, endothelial, growth, factor, '(', 'VEGF)', expression])].
[sujeto(['Our', data, also, showed, that, 'rIL-17A', treatment, significantly]), verbo([increased]), complemento(['CD34', expression, and, promoted, functional, recovery, at, 28, 'dpi,', and, the, promoting, effects, were, attenuated, by, 'VEGF', neutralizing, antibody, treatment])].
[sujeto(['Furthermore,', hyperforin, treatment, significantly]), verbo([increased]), complemento([the, expression, of, 'VEGF', and, 'CD34', in, the, ischemic, hemisphere, at, 28, 'dpi,', and, the, effects, were, attenuated, by, blocking, 'IL-17A'])].
[sujeto(['Furthermore,', 'VEGF', neutralizing, antibody, significantly, attenuated, the]), verbo([promoting]), complemento([role, of, hyperforin, on, the, cerebral, 'CD34', expression])].
[sujeto(['Thus,', our, results]), verbo([suggest]), complemento(['that,', in, addition, to, the, acute, neuroprotection, when, delivered, immediately, after, ischemic, 'stroke,', hyperforin, could, also, promote, functional, recovery, when, delivered, in, the, later, phases, of, stroke, recovery])].
[sujeto(['Our', results, also]), verbo([reveal]), complemento([a, previously, uncharacterized, property, of, 'IL-17A/VEGF', 'signaling-induced', angiogenesis, in, 'hyperforin-mediated', functional, recovery])].
[sujeto(['Our', previous, results]), verbo([have]), complemento([shown, that, the, combination, of, 'hypericin-mediated', photodynamic, therapy, '(', 'HY-PDT)', at, 'sub-optimal', dose, with, hyperforin, '(', 'HP)', '(', compounds, of, 'Hypericum', sp])].
[sujeto([')', ',', or, its, stable, derivative, aristoforin, '(', 'AR)']), verbo([stimulates]), complemento([generation, of, reactive, oxygen, species, '(', 'ROS)', leading, to, antitumour, activity])].
[sujeto(['This']), verbo([enhanced]), complemento([oxidative, stress, evoked, the, need, for, an, explanation, for, 'HY', accumulation, in, colon, cancer, cells, pretreated, with, 'HP', or, 'AR'])].
[sujeto(['We']), verbo([found]), complemento([that, 'HP', or, 'AR', treatment, affected, the, protein, levels, of, 'MRP2', and, 'P-gp,', whereas, 'HP', decreased, 'MRP2', and, 'P-gp', expression, mostly, in, the, 'T0+', and, 'T6+', 'conditions,', while, 'AR', decreased, 'MRP2', in, 'T0-', and, 'T6+'])].
[sujeto(['Moreover,', 'HY-PDT', treatment]), verbo([induced]), complemento([the, expression, of, 'MRP1'])].
[sujeto(['Our', data, demonstrate, that, 'HP', or, 'AR', treatment, in, light, or, dark, 'PDT', conditions, had, an, inhibitory, effect, on, the, activity, of, individual, membrane, transport, proteins, and, significantly]), verbo([decreased]), complemento(['CYP3A4', activity, in, 'HT-29', cells])].
[sujeto(['We']), verbo([found]), complemento([that, 'HP', or, 'AR', significantly, affected, intracellular, accumulation, of, 'HY', in, 'HT-29', colon, adenocarcinoma, cells])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'HY,', 'HP', and, 'AR', might, affect, the, efficiency, of, 'anti-cancer', 'drugs,', through, interaction, with, membrane, transporters, and, 'CYP3A4'])].
[sujeto(['In', 'addition,', many, 'TRPC6-interacting', proteins]), verbo([have]), complemento([been, identified, like, some, 'enzymes,', 'channels,', 'pumps,', 'cytoskeleton-associated', 'proteins,', 'immunophilins,', or, 'cholesterol-binding', 'proteins,', indicating, that, 'TRPC6', are, engaged, into, macromolecular, complexes])].
[sujeto(['Depending', on, the, cell, type, and, the, experimental, conditions, 'used,', 'TRPC6', activity]), verbo([has]), complemento([been, reported, to, be, controlled, by, diverse, modalities])].
[sujeto(['For', 'instance,', the, second, messenger, 'diacylglycerol,', 'store-depletion,', the, plant, extract, hyperforin, or, 'H2O2']), verbo([have]), complemento([all, been, shown, to, trigger, the, opening, of, 'TRPC6', channels])].
[sujeto(['This', latter, response, can, reflect, the, entry, of, 'Ca(2+)', through, open, 'TRPC6', channels, but, it, can, also, be, due, to, the, 'Na(+)/Ca(2+)', exchanger, '(', operating, in, its, reverse, 'mode)', or, 'voltage-gated', 'Ca(2+)', channels, '(']), verbo([recruited]), complemento([in, response, to, a, 'TRPC6-mediated', 'depolarization)'])].
[sujeto(['Hyp-GNP', and, hyperforin, significantly, reduced, clinical, severity, of, 'EAE,', which, was, accompanied, by, a]), verbo([decrease]), complemento([in, the, number, of, inflammatory, cell, infiltration, in, the, spinal, cord])].
[sujeto(['Additionally,', treatment, with, 'Hyp-GNP', significantly]), verbo([inhibited]), complemento(['disease-associated', cytokines, as, well, as, an, increase, in, the, 'anti-inflammatory', cytokines, in, comparison, to, all, groups, including, the, 'free-hyp', group])].
[sujeto(['Furthermore,', hyperforin, and, 'Hyp-GNP']), verbo([inhibited]), complemento([the, differentiation, of, 'Th1', and, 'Th17', cells, while, promoting, 'Treg', and, 'Th2', cell, differentiation, via, regulating, their, master, transcription, factors])].
[sujeto(['Context', 'The', genus, 'Hypericum', '(', 'Hypericaceae)']), verbo([has]), complemento([attracted, remarkable, scientific, interest, as, its, members, have, yielded, many, bioactive, compounds])].
[sujeto(['Discussion', 'For', the, first, 'time,', the, detailed, chemical, profiles, of, corresponding, 'Turkish', 'Hypericum', species, were]), verbo([reported]), complemento([and, the, results, were, discussed, from, a, phytochemical, point, of, view])].
[sujeto(['Conclusions', 'The', present, data]), verbo([have]), complemento([importance, in, evaluation, of, plant, resources, of, 'Hypericum', genus, in, selecting, the, new, potential, sources, of, bioactive, compounds])].
[sujeto(['The', chemical, investigation, of, the, chloroform, extract, of, 'Hypericum', lanceolatum, guided, by, '(', 1, ')', 'H', 'NMR,', 'ESIMS,', and, 'TLC', profiles]), verbo([led]), complemento([to, the, isolation, of, 11, new, tricyclic, acylphloroglucinol, 'derivatives,', named, selancins, 'A-I', '(', 1, -, 9, ')', and, hyperselancins, 'A', and, 'B', '(', 10, and, 11, ')', ',', along, with, the, known, compound, 3, -, 'O-geranylemodin', '(', 12, ')', ',', which, is, described, for, a, 'Hypericum', species, for, the, first, time])].
[sujeto(['We']), verbo([have]), complemento([established, in, vitro, cultures, of, 'auxin-induced', 'roots,', which, are, capable, of, producing, 'hyperforin,', as, indicated, by, 'HPLC-DAD', and, 'ESI-MS', analyses])].
[sujeto([perforatum, root, cultures, may]), verbo([provide]), complemento([an, alternative, platform, for, the, preparation, of, medicinal, extracts, and, the, isolation, of, 'APIs'])].
[sujeto([',', a, 'South', 'American', species, lacking, 'hyperforin,', antidepressant, effects]), verbo([have]), complemento([not, been, demonstrated])].
[sujeto([connatum, in, rats, and, identifies, the, components]), verbo([involved]), complemento([in, this, activity])].
[sujeto(['Results', 'Hypericum', connatum]), verbo([increased]), complemento([reactivity, of, unavoidable, 'stress-exposed', rats, after, acute, '(', 0.5, and, 1, 'g/kg:', 'ED', =, 18.6, /, 30, and, 19.8, /, 30, ',', 'respectively)', and, repeated, administration, '(', 0.5, 'g/kg', twice, 'daily:', 'ED', =, 17.8, /, 30, ')'])].
[sujeto(['The', study, also, showed, that, hyperforin]), verbo([caused]), complemento([increased, 'Treg', cell, levels, in, the, spleen])].
[sujeto(['These', results, indicated, that, hyperforin, and, 'HPE', could, attenuate, 'EAE', autoimmune, responses, by]), verbo([inhibiting]), complemento([immune, cell, infiltration, and, expansion, of, 'Treg', cell, and, could, eventually, be, considered, as, a, potential, candidate, for, use, in, the, treatment, of, 'MS'])].
[sujeto(['In', recent, 'years,', a, number, of, natural, medicines]), verbo([have]), complemento([been, reported, to, have, inductive, or, inhibitive, effects, on, the, activity, of, drug, metabolizing, 'enzymes,', upon, 'co-administration', with, prescribed, medicines])].
[sujeto(['Therefore,', to, understand, whether, 'P450', activity, is, affected, by, natural, medicine, in, small, 'intestines,', we]), verbo([have]), complemento([established, frozen, recombinant, 'P450-expressing', cells, infected, with, human, 'CYP3A4', expressing, adenovirus, '(', 'Ad-CYP3A4)', to, evaluate, the, effect, of, natural, medicines, on, 'CYP3A4', activity])].
[sujeto(['Ad-CYP3A4', cells, were, created, by, infecting, 'HepG2', cells, with, 'Ad-CYP3A4', at, 10, multiplicity, of, infection, '(', 'MOI)', and, these, cells, were, stored, using, cryopreservation, medium, '(', 'fAd-CYP3A4', 'cells)', to, obtain, 'long-term', consistent, data, and, stable, supplies, of, cells]), verbo([expressing]), complemento([a, constant, level, of, 'CYP3A4', activity])].
[sujeto(['Cat\'s', 'Claw,', 'Peppermint', 'Oil', and, 'Siberian', 'Eleuthero']), verbo([inhibited]), complemento(['CYP3A4', activity, more, potently, than, 0.1, μM, ketoconazole, in, 'fAd-CYP3A4', cells])].
[sujeto(['In', the, present, 'study,', we]), verbo([have]), complemento([successfully, developed, a, highly, reproducible, system, to, evaluate, 'CYP3A4', inhibition, in, small, intestines, by, natural, medicines])].
[sujeto(['However,', it]), verbo([has]), complemento([been, associated, with, relevant, interactions, with, several, drugs])].
[sujeto(['This', situation, is, probably]), verbo([mediated]), complemento([by, cytochrome, 'P450', enzymes, '(', 'CYP450),', namely, the, 1, 'A2', '(', 'CYP1A2)', and, 2, 'D6', '(', 'CYP2D6)', isoforms, 'This', study, aims, to, assess, the, cytotoxic, and, 'CYP1A2', and, 'CYP2D6', inductive, 'and/or', inhibitory, effects, of, a, 'H'])].
[sujeto(['These', products]), verbo([have]), complemento([relevant, cytotoxicity, at, a, 10, μM, concentration, and, it, was, also, demonstrated, for, the, first, time, that, 'H'])].
[sujeto([perforatum, can]), verbo([lead]), complemento([to, a, significant, 'CYP1A2', and, 'CYP2D6', induction, in, all, cell, lines])].
[sujeto(['Moreover,', hypericin, seems, to]), verbo([induce]), complemento(['CYP1A2', in, 'HepG2', cells, and, to, inhibit, its, expression, in, 'HepaRG', cells, while, hyperforin, induced, 'CYP1A2', in, 'HepG2', and, in, 'WRL-68', cells])].
[sujeto(['Additionally,', hypericin, and, hyperforin]), verbo([induce]), complemento(['CYP2D6', in, 'HepG2', cells, but, inhibits, its, expression, in, 'HepaRG', and, in, 'WRL-68', cells])].
[sujeto([perforatum, extract, and, two, of, its, bioactive, components, can]), verbo([have]), complemento([toxic, effects, in, hepatic, cell, lines, but, also, emphasized, the, potential, risk, of, the, consumption, of, 'H'])].
[sujeto(['After', 'separation,', adult, rats, were, evaluated, by, using, the, open, field, test, '(', 'OFT),', novelty]), verbo([suppressed]), complemento([feeding, test, '(', 'NSF)', and, forced, swimming, test, '(', 'FST)'])].
[sujeto(['In', 'conclusion,', these, results]), verbo([suggest]), complemento([that, hyperforin, is, able, to, alleviate, anxiety, and, remit, depression, in, 'ESP', rats])].
[sujeto(['The', acylphloroglucinols, hyperforin, '(', 'Hypf)', and, myrtucommulone, 'A', '(', 'MC', 'A)']), verbo([induce]), complemento([death, of, cancer, cells, by, triggering, the, 'intrinsic/mitochondrial', pathway, of, 'apoptosis,', accompanied, by, a, loss, of, the, mitochondrial, membrane, potential, and, release, of, cytochrome, c])].
[sujeto(['However,', the, upstream]), verbo([targets]), complemento([and, mechanisms, leading, to, these, mitochondrial, events, in, cancer, cells, remain, elusive])].
[sujeto(['Here', we, show, that, 'Hypf', and, 'MC', 'A', directly]), verbo([act]), complemento([on, mitochondria, derived, from, human, leukemic, 'HL-60', cells, and, 'thus,', disrupt, mitochondrial, functions])].
[sujeto([2, and, 0.9, &, 'nbsp;µM,', 'respectively),']), verbo([caused]), complemento([loss, of, the, mitochondrial, membrane, potential, '(', at, 0.03, and, 0.1, &, 'nbsp;µM,', 'respectively),', and, suppressed, mitochondrial, 'ATP', synthesis, '(', 'IC50 = 0'])].
[sujeto(['Consequently,', the, compounds]), verbo([activated]), complemento([the, adenosine, 'monophosphate-activated', protein, kinase, '(', 'AMPK)', in, 'HL-60', 'cells,', a, cellular, energy, sensor, involved, in, apoptosis, of, cancer, cells])].
[sujeto(['Side', by, side, comparison, with, the, protonophore, 'CCCP', and, the, 'ATP', synthase, inhibitor, oligomycin]), verbo([suggest]), complemento([that, 'Hypf', and, 'MC', 'A', act, as, protonophores, that, primarily, dissipate, the, mitochondrial, membrane, potential, by, direct, interaction, with, the, mitochondrial, membrane])].
[sujeto(['Together,', 'Hypf', and, 'MC', 'A', abolish, the, mitochondrial, proton, motive, force, that, on, one, hand, impairs, mitochondrial, viability, and, on, the, other]), verbo([cause]), complemento([activation, of, 'AMPK', due, to, lowered, 'ATP', levels, which, may, further, facilitate, the, intrinsic, mitochondrial, pathway, of, apoptosis])].
[sujeto(['With', the, decline, of, this, scientific, 'discussion,', another, controversial, aspect]), verbo([has]), complemento([been, 'arisen,', the, question, regarding, the, underlying, mechanism, leading, to, the, pharmacological, profile, of, the, plant, extract, used, in, therapy, of, depression])].
[sujeto(['It', is, well]), verbo([recognized]), complemento([that, herbal, supplements, or, herbal, medicines, are, now, commonly, used])].
[sujeto(['Such', interactions, can]), verbo([enhance]), complemento([the, risk, for, an, individual, 'patient,', especially, with, regard, to, drugs, with, a, narrow, therapeutic, index, such, as, 'warfarin,', cyclosporine, 'A', and, digoxin])].
[sujeto(['The', most, common, pharmacokinetic, interactions, usually]), verbo([involve]), complemento([either, the, inhibition, or, induction, of, the, metabolism, of, drugs, catalyzed, by, the, important, 'enzymes,', cytochrome, 'P450', '(', 'CYP)'])].
[sujeto(['The', aim, of, the, present, article, is, to]), verbo([provide]), complemento([an, updated, review, of, clinically, relevant, metabolic, 'CYP-mediated', drug, interactions, between, selected, herbal, supplements, and, prescription, drugs])].
[sujeto(['To', 'date,', several, significant, herbal, drug, interactions]), verbo([have]), complemento([their, origins, in, the, alteration, of, 'CYP', enzyme, activity, by, various, phytochemicals])].
[sujeto(['Numerous', herbal, drug, interactions]), verbo([have]), complemento([been, reported])].
[sujeto(['John\'s', 'wort,', may]), verbo([have]), complemento([critical, clinical, consequences])].
[sujeto(['John\'s', wort, is, a, source, of, 'hyperforin,', an, active, ingredient, that]), verbo([has]), complemento([a, strong, affinity, for, the, pregnane, xenobiotic, receptor, '(', 'PXR)'])].
[sujeto(['As', a, 'PXR', 'ligand,', hyperforin]), verbo([promotes]), complemento([expression, of, 'CYP3A4', enzymes, in, the, small, intestine, and, liver])].
[sujeto(['This', in, turn]), verbo([causes]), complemento([induction, of, 'CYP3A4', and, can, reduce, the, oral, bioavailability, of, many, drugs, making, them, less, effective])].
[sujeto(['The', available, evidence, indicates, 'that,', at, commonly, recommended, 'doses,', other, selected, herbs, including, 'Echinacea,', 'Ginkgo', 'biloba,', 'garlic,', goldenseal, and, milk, thistle, do, not]), verbo([act]), complemento([as, potent, or, moderate, inhibitors, or, inducers, of, 'CYP', enzymes])].
[sujeto(['However,', the, mechanisms]), verbo([involved]), complemento([in, its, pathogenesis, are, not, fully, understood])].
[sujeto(['Many']), verbo([nuclear]), complemento([receptors, '(', 'NRs)', involved, in, energy, homeostasis, and, biotransformation, constitute, a, network, connecting, fatty, 'acids,', cholesterol, and, xenobiotic, 'metabolisms;', 'therefore,', multiple, 'NRs', and, their, ligands, may, play, a, prominent, role, in, liver, fat, metabolism, and, accumulation])].
[sujeto(['In', this, study, we]), verbo([have]), complemento([attempted, to, gain, insight, into, the, relevance, of, the, 'NR', superfamily, in, 'NAFLD', by, investigating, the, steatogenic, potential, of, 76, different, 'NR', ligands, in, fatty, acid, overloaded, human, hepatocytes, and, hepatoma, cells])].
[sujeto(['Moreover,', we]), verbo([have]), complemento([determined, the, mRNA, expression, level, of, 24, 'NRs', to, correlate, the, steatogenic, potential, of, the, ligands, with, the, expression, of, their, associated, 'NRs', in, the, cultured, cells])].
[sujeto(['Our', results, demonstrate, that, 18, '%', of, the, examined, 'NR', ligands]), verbo([enhanced]), complemento([lipid, accumulation, in, human, hepatocytes, 'and/or', hepatoma, cells])].
[sujeto(['By', comparing, the, steatogenic, effect, of, 'NR', ligands, with, the, 'NR', expression, 'levels,', we, conclude, that, 'LXR,', 'PXR,', 'RAR', and, 'PPARgamma', ligands, likely]), verbo([induce]), complemento([fat, accumulation, by, a, 'NR-dependent', mechanism])].
[sujeto(['Indeed,', 'over-expression', of, 'PXR', in, 'HepG2', cells]), verbo([enhanced]), complemento([the, steatogenic, effect, of, hyperforin, and, rifampicin])].
[sujeto(['However,', the, accumulation, of, fat]), verbo([induced]), complemento([by, other, ligands, did, not, correlate, with, the, expression, of, their, associated, 'NR'])].
[sujeto(['Our', results, also]), verbo([suggest]), complemento([that, human, hepatocytes, cultured, with, free, fatty, acids, offer, a, highly, valuable, in, vitro, system, to, investigate, the, pathogenesis, and, therapeutics, of, the, human, fatty, liver])].
[sujeto(['The', 'CYP2C', enzymes, are]), verbo([found]), complemento([predominantly, in, the, 'liver,', where, they, comprise, approximately, 20, '%', of, the, total, cytochrome, 'P450'])].
[sujeto(['A', variety, of, xenobiotics, such, as, 'phenobarbital,', 'rifampicin,', and, hyperforin]), verbo([have]), complemento([been, shown, to, induce, the, transcriptional, expression, of, 'CYP2C', genes, in, primary, human, hepatocytes, and, to, increase, the, metabolism, of, 'CYP2C', substrates, in, vivo, in, man])].
[sujeto(['Several', 'drug-activated']), verbo([nuclear]), complemento([receptors, including, 'CAR,', 'PXR,', 'VDR,', and, 'GR', recognize, drug, responsive, elements, within, the, 5, '\'', flanking, promoter, region, of, 'CYP2C', genes, to, mediate, the, transcriptional, upregulation, of, these, genes, in, response, to, xenobiotics, and, steroids])].
[sujeto(['Other']), verbo([nuclear]), complemento([receptors, and, transcriptional, factors, including, 'HNF4alpha,', 'HNF3gamma,', 'C/EBPalpha', and, more, recently, 'RORs,', have, been, reported, to, regulate, the, constitutive, expression, of, 'CYP2C', genes, in, liver])].
[sujeto(['The', maximum, transcriptional, induction, of, 'CYP2C', genes, appears, to, be, achieved, through, a, coordinative, 'cross-talk', between, drug, responsive]), verbo([nuclear]), complemento(['receptors,', hepatic, 'factors,', and, coactivators])].
[sujeto(['The', transcriptional, regulatory, mechanisms, of, the, expression, of, 'CYP2C', genes, in, extrahepatic, tissues]), verbo([has]), complemento([received, less, 'study,', but, these, may, be, altered, by, perturbations, from, pathological, conditions, such, as, ischemia, as, well, as, some, of, the, receptors, mentioned, above])].
[sujeto(['Previous']), verbo([reports]), complemento([on, other, 'SJW', products, had, shown, remarkably, decreased, plasma, concentrations, of, certain, 'co-medicated', 'drugs,', which, was, attributed, to, an, inducing, effect, of, 'SJW', on, cytochrome, 'P-450', '(', 'CYP)', and, 'p-glycoprotein', '(', 'p-gp)', activity])].
[sujeto(['No', statistically, significant, differences, were]), verbo([found]), complemento([in, the, primary, kinetic, 'parameter,', 'AUC0', -, 24, ',', of, 'alprazolam,', caffeine, '(', 'AUC0', -, 12, ')', ',', 'paraxanthine,', 'tolbutamide,', 4, -, 'hydroxytolbutamide,', and, digoxin, between, the, placebo, group, and, the, 'SJW', group, at, the, end, of, the, study])].
[sujeto(['This', may, be, due, in, particular, to, the, low, hyperforin, plasma, concentration, as, this, 'SJW', component]), verbo([has]), complemento([been, shown, to, activate, the, 'PXR', receptor, which, regulates, expression, of, 'CYP3A4', and, 'p-gp'])].
[sujeto(['Our', findings, corroborate, the, view, that]), verbo([reports]), complemento([about, interactions, of, other, 'SJW', extracts, seem, not, to, be, predictive, for, the, product, we, studied])].
[sujeto(['Information', about, case]), verbo([reports]), complemento([classified, as, 'St', 'John\'s', wort, drug, interactions, was, retrieved, from, the, 'WHO', 'Collaborating', 'Centre', for, 'International', 'Drug', 'Monitoring', and, from, the, 'UK', 'Medicines', and, 'Healthcare', products, 'Regulatory', 'Agency', in, 'June', 2003])].
[sujeto(['Against', the, background, of, proven, efficacy, in, mild, to, moderate, depressive, disorders, and, an, excellent, tolerability, profile, in, 'monotherapy,', there, is, sufficient, evidence, from, interaction, studies, and, case]), verbo([reports]), complemento([to, suggest, that, 'St', 'John\'s', wort, may, induce, the, cytochrome, 'P450', '(', 'CYP)', 3, 'A4', enzyme, system, and, the, 'P-glycoprotein', drug, transporter, in, a, clinically, relevant, 'manner,', thereby, reducing, efficacy, of, 'co-medications'])].
[sujeto(['Efficacy', of, hormonal, contraceptives, may, be, impaired, as, reflected, by, case]), verbo([reports]), complemento([of, irregular, bleedings, and, unwanted, pregnancies])].
[sujeto(['The', 'St', 'John\'s', wort, constituent, hyperforin, is, probably, responsible, for, 'CYP3A4', induction, via, activation, of, a]), verbo([nuclear]), complemento(['steroid/pregnane', and, xenobiotic, receptor, '(', 'SXR/PXR)', and, hypericin, may, be, assumed, to, be, the, 'P-glycoprotein', inducing, 'compound,', although, the, available, evidence, is, less, convincing])].
[sujeto(['In', 'conclusion,']), verbo([providing]), complemento([certain, precautions, and, contraindications, are, 'followed,', and, adequate, information, is, given, to, healthcare, professionals, and, 'patients,', the, safe, and, effective, use, of, 'quality-tested', 'St', 'John\'s', wort, products, can, be, ensured])].
[sujeto(['John\'s', wort]), verbo([has]), complemento([been, reported, to, have, minimal, side, effects, compared, with, other, 'antidepressants,', here, we, show, that, 'hyperforin,', the, active, component, of, 'St'])].
[sujeto(['John\'s', 'wort,', can]), verbo([stimulate]), complemento(['interleukin-8', '(', 'IL-8)', expression, in, human, intestinal, epithelia, cells, '(', 'IEC)', and, primary, hepatocytes])].
[sujeto(['Hyperforin', is, also, able, to]), verbo([induce]), complemento([expression, of, 'mRNA,', encoding, another, major, inflammatory, 'mediator--intercellular', adhesion, 'molecule-1', '(', 'ICAM-1)'])].
[sujeto(['IEC']), verbo([participate]), complemento([in, the, intestinal, inflammatory, process, and, serve, as, a, first, line, of, defense, through, bidirectional, communication, between, host, and, infectious, pathogens])].
[sujeto(['Although', hyperforin, is, a, potent, ligand, for, the, steroid, and, xenobiotic, receptor, '(', 'SXR),', we]), verbo([found]), complemento([that, hyperforin, induced, 'IL-8', mRNA, through, an, 'SXR-independent', transcriptional, activation, pathway])].
[sujeto(['IL-8', induction, by, hyperforin]), verbo([required]), complemento([the, activation, of, 'AP-1', but, not, the, 'NF-kappaB', transcription, 'factor,', thereby, distinguishing, it, from, the, 'NF-kappaB-dependent', 'IL-8', induction, mediated, by, tumor, necrosis, factor, alpha, '(', 'TNFalpha)'])].
[sujeto(['Further', study, revealed, that, extracellular, 'signal-regulated', kinase, 1, and, 2, '(', 'ERK1/2)', were]), verbo([required]), complemento([for, the, 'hyperforin-induced', expression, of, 'IL-8'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([a, previously, unsuspected, effect, of, 'St'])].
[sujeto(['John\'s', wort, in]), verbo([modulating]), complemento([the, immune, and, inflammatory, responses])].
[sujeto(['Recently,', this, agent]), verbo([has]), complemento([been, found, to, adversely, affect, the, metabolism, of, various, coadministered, drugs])].
[sujeto(['Steroid', 'X', receptor, '(', 'SXR),', an, orphan]), verbo([nuclear]), complemento(['receptor,', induces, hepatic, cytochrome, 'P450', gene, expression, in, response, to, diverse, endogenous, 'steroids,', xenobiotics, and, drugs])].
[sujeto(['Here,', we]), verbo([report]), complemento(['that,', when, coexpressed, with, 'SXR,', a, reporter, construct, derived, from, the, cytochrome, 'P450', 3, 'A', promoter, is, activated, by, 'St', 'John\'s', wort])].
[sujeto(['A', 'GAL4-SXR', ligand]), verbo([binding]), complemento([domain, '(', 'LBD)', fusion, mediates, 'concentration-dependent', transactivation, by, 'SJW,', whereas, a, mutant, 'GAL4-SXR', 'fusion,', containing, substitutions, in, key, residues, in, a, transactivation, 'domain,', is, inactive])].
[sujeto(['SJW']), verbo([recruits]), complemento([steroid, receptor, 'coactivator-1', to, 'SXR', in, a, 'two-hybrid', assay, and, competes, with, radiolabelled, ligand, in, binding, 'studies,', suggesting, it, interacts, directly, with, the, receptor, 'LBD'])].
[sujeto(['Of', two, constituents, of, 'SJW,', we]), verbo([find]), complemento([that, 'hyperforin,', but, not, 'hypericin,', mediates, both, transactivation, and, coactivator, recruitment, by, 'SXR'])].
[sujeto(['Our', observations]), verbo([suggest]), complemento([that, 'SXR', activation, by, 'St', 'John\'s', wort, mediates, its, adverse, interaction, with, drugs, metabolised, via, the, 'CYP', 3, 'A', pathway])].
[sujeto(['GBP1', and, 'PIM1', are, known, to]), verbo([interact]), complemento([with, a, molar, ratio, 1, :, 1])].
[sujeto(['GBP1:PIM1']), verbo([binding]), complemento([initiates, a, signaling, pathway, that, induces, resistance, to, common, chemotherapeutics, such, as, paclitaxel])].
[sujeto(['Since', 'GBP1', is, a, large, 'GTPase', which, undergoes, conformational, changes, in, a, 'nucleotide-dependent', 'manner,', we, investigated, the, effect, of, 'GTP/GDP']), verbo([binding]), complemento([on, 'GBP1:PIM1', interaction, by, using, computational, and, biological, studies])].
[sujeto(['It', resulted, that, only, 'GTP']), verbo([decreases]), complemento([the, formation, of, the, 'GBP1:PIM1', complex, through, an, allosteric, 'mechanism,', putting, the, bases, for, the, identification, of, new, compounds, potentially, able, to, revert, resistance, to, paclitaxel])].
[sujeto(['It']), verbo([has]), complemento([been, demonstrated, that, 'Tau', exists, on, the, microtubule, lattice, in, both, diffusing, and, static, 'populations,', but, how, this, may, relate, to, 'Tau', function, is, currently, unclear])].
[sujeto(['Tau', isoforms, are, developmentally]), verbo([regulated]), complemento([and, have, been, shown, to, have, disparate, effects, on, microtubule, 'polymerization,', the, ability, to, bind, 'microtubules,', and, the, ability, to, inhibit, kinesin])].
[sujeto(['It']), verbo([has]), complemento([also, been, shown, that, 'Tau', is, sensitive, to, microtubule, stabilizing, agents, and, the, ability, to, affect, the, persistence, length, of, microtubules, and, to, inhibit, kinesin, can, be, altered, by, stabilizing, microtubules, with, various, nucleotide, analogs])].
[sujeto(['On', 'paclitaxel-stabilized', 'microtubules,', we]), verbo([find]), complemento([3, 'RS-Tau', favors, the, static, conformation, and, forms, complexes, consisting, of, 2, -, 3, 'molecules,', while, 4, 'RL-Tau', predominantly, exists, as, a, single, molecule, equally, distributed, between, the, static, and, diffusing, populations])].
[sujeto(['We']), verbo([find]), complemento([both, isoforms, of, 'Tau', interconvert, between, static, and, diffusing, populations, on, the, microtubule, 'surface,', and, the, equilibrium, between, these, two, states, depends, on, both, the, isoform, of, 'Tau', and, the, structure, of, the, underlying, microtubule, lattice])].
[sujeto(['The', bradykinin, '(', 'BK)', 'B₂', receptor, '(', 'B₂R)', is, 'G', protein, coupled, and]), verbo([phosphorylated]), complemento([upon, agonist, 'stimulation;', its, endocytosis, and, recycling, are, documented])].
[sujeto(['These', drugs, were]), verbo([targeted]), complemento([to, tubulin, '(', 'paclitaxel,', or, the, novel, combretastatin, 'A-4', mimetic, 3, ',', 4, ',', 5, -, 'trimethoxyphenyl-4-(2-oxoimidazolidin-1-yl)benzenesulfonate', '[', 'IMZ-602])', and, actin, '(', cytochalasin, 'D)'])].
[sujeto(['Cytochalasin', 'D', selectively]), verbo([inhibited]), complemento([the, recycling, of, endocytosed, 'B₂R-GFP', '(', 'B₂R-GFP', 'imaging,', '[', '³H]BK', 'binding)'])].
[sujeto(['GDP-locked-Rab4', also]), verbo([inhibited]), complemento(['B₂R-GFP', recycling, to, the, cell, surface])].
[sujeto(['However,', tubulin, ligands, do, not]), verbo([suppress]), complemento([the, tested, desensitization, or, resensitization, mechanisms, of, the, 'B₂R'])].
[sujeto(['In', 'cells,', 'MTs', and, their, assemblies, are, critical, components, in, a, range, of, functions, from]), verbo([providing]), complemento([tracks, for, the, transport, of, cargo, to, forming, the, spindle, structure, during, mitosis])].
[sujeto(['Previous', studies, 'have,', shown, that, while, cations, with, valence, equal, to, or, larger, than, 3, +, tend, to, assemble, tight, 3, 'D', bundles, of, 'taxol-stabilized', 'MTs,', certain, divalent, cations]), verbo([induce]), complemento([relatively, loose, 2, 'D', bundles, of, different, symmetry, '(', 'D'])].
[sujeto(['Although', previous, cryogenic, 'TEM']), verbo([has]), complemento([shown, 'that,', in, the, absence, of, 'taxol,', 'Ca2+', depolymerizes, 'MTs', assembling, in, buffers, containing, 'GTP', '(', guanosine, 'triphosphate),', our, finding, is, surprising, given, the, know, stabilizing, effects, of, taxol, on, 'GDP', '(', guanosine, 'diphosphate)-MTs'])].
[sujeto(['The', ion, concentration]), verbo([required]), complemento([for, 'MT', depolymerization, decreases, with, increasing, atomic, number, for, the, divalents, 'Mg2+,', 'Mn2+,', 'Co2+,', and, 'Zn2+'])].
[sujeto(['GdCl3', '(', 3, +, ')', is]), verbo([found]), complemento([to, be, extremely, efficient, at, 'MT', depolymerization, requiring, ion, concentrations, of, about, 1, 'mM,', while, 'oligolysine(2+),', is, observed, not, to, depolymerize, 'MTs', at, concentrations, as, high, as, 144, mM])].
[sujeto(['The', surprising, 'MT', depolymerization, results, are, discussed, in, the, context, of, divalents, either, disrupting, lateral, interactions, between, 'PFs', '(', which, are, strengthened, for, taxol, containing, 'beta-tubulin)', or, interfering, with, 'taxol\'s', ability, to]), verbo([induce]), complemento([flexibility, at, the, interface, between, two, tubulin, dimers, in, the, same, 'PF', '(', which, has, been, recently, suggested, as, a, mechanism, by, which, taxol, stabilizes, 'MTs', 'post-hydrolysis', with, the, induced, flexibility, counteracting, the, kink, between, 'GDP-tublin', dimers, in, a, 'PF)'])].
[sujeto(['Microtubule', dynamics, are]), verbo([regulated]), complemento([by, guanosine, triphosphate, '(', 'GTP)', hydrolysis, by, 'β-tubulin,', but, the, mechanism, of, this, regulation, remains, elusive, because, 'high-resolution', microtubule, structures, have, only, been, revealed, for, the, guanosine, diphosphate, '(', 'GDP)', state])].
[sujeto(['These', findings, are, consistent, with, the, structural, plasticity, or, lattice, model, and]), verbo([suggest]), complemento([the, structural, basis, not, only, for, the, regulatory, mechanism, of, microtubule, dynamics, but, also, for, the, recognition, of, the, nucleotide, state, of, the, microtubule, by, several, 'microtubule-binding', 'proteins,', such, as, 'EB1', or, kinesin])].
[sujeto(['One', novel, family, of, 'MT-associated', proteins, that]), verbo([regulates]), complemento(['MT', dynamics, is, the, 'MT-severing', enzymes])].
[sujeto(['In', this, 'work,', we, investigate, how, katanin, '(', 'p60),', believed, to, be, the, first, discovered, severing, 'enzyme,']), verbo([binds]), complemento([and, severs, 'MTs', via, single, molecule, total, internal, reflection, fluorescence, microscopy])].
[sujeto(['We']), verbo([find]), complemento([that, severing, activity, depends, on, katanin, concentration])].
[sujeto(['We', also]), verbo([find]), complemento([that, katanin, can, remove, tubulin, dimers, from, the, ends, of, 'MTs,', appearing, to, depolymerize, 'MTs'])].
[sujeto(['Strikingly,', katanin, localizes, and, severs, at, the, interface, of, 'GMPCPP-tubulin', and, 'GDP-tubulin']), verbo([suggesting]), complemento([that, it, targets, to, 'protofilament-shift', defects])].
[sujeto(['Finally,', we, observe, that]), verbo([binding]), complemento(['duration,', 'mobility,', and, oligomerization, are, 'ATP', dependent])].
[sujeto(['Widely']), verbo([conserved]), complemento([among, 'eukaryotes,', the, 'microtubule-associated', protein, 215, '(', 'MAP215)', family, enhances, microtubule, dynamic, instability])].
[sujeto(['The', family, member, studied, most, 'extensively,', 'Xenopus', laevis, 'XMAP215,']), verbo([has]), complemento([been, reported, to, enhance, both, assembly, and, disassembly, 'parameters,', although, the, mechanism, whereby, one, protein, can, exert, these, apparently, contradictory, effects, has, not, been, clarified])].
[sujeto(['We', show, 'that,', like, 'XMAP215,', 'MAP200']), verbo([promotes]), complemento([both, assembly, and, disassembly, 'parameters,', including, microtubule, growth, rate, and, catastrophe, frequency])].
[sujeto(['When', 'GDP', partially, replaces, 'GTP,', the]), verbo([increase]), complemento([of, catastrophe, frequency, by, 'MAP200', is, strongly, 'diminished,', even, though, this, replacement, stimulates, catastrophe, in, the, absence, of, 'MAP200'])].
[sujeto(['This', implies, that, 'MAP200']), verbo([induces]), complemento([catastrophes, by, a, 'specific,', 'GTP-requiring', pathway])].
[sujeto(['GDP']), verbo([inhibits]), complemento(['paclitaxel-induced', tubulin, assembly, without, 'GTP', when, the, tubulin, bears, 'GDP', in, the, exchangeable, site, '(', 'E-site)'])].
[sujeto(['Initially,', we, thought, inhibition, was]), verbo([mediated]), complemento([through, the, 'E-site,', since, small, amounts, of, 'GTP', or, 'Mg(2+),', which, favors, 'GTP', binding, to, the, 'E-site,', reduced, inhibition, by, 'GDP'])].
[sujeto(['We', thought, trace, 'GTP']), verbo([released]), complemento([from, the, nonexchangeable, site, '(', 'N-site)', by, tubulin, denaturation, was, required, for, polymer, 'nucleation,', but, microtubule, length, was, unaffected, by, 'GDP'])].
[sujeto(['Further,']), verbo([enhancing]), complemento([polymer, nucleation, reduced, inhibition, by, 'GDP'])].
[sujeto(['Other', mechanisms]), verbo([involving]), complemento([the, 'E-site', were, eliminated, experimentally])].
[sujeto(['Upon']), verbo([finding]), complemento([that, 'ATP', weakly, inhibited, 'paclitaxel-induced', 'assembly,', we, concluded, that, another, ligand, binding, site, was, responsible, for, these, inhibitory, 'effects,', and, we, found, that, 'GDP', was, not, binding, at, the, 'taxoid,', 'colchicine,', or, vinca, sites])].
[sujeto(['There', may, therefore, be, a, lower, affinity, site, on, tubulin, to, which, 'GDP', can]), verbo([bind]), complemento([distinct, from, the, 'E-', and, 'N-sites,', possibly, on, 'alpha-tubulin,', based, on, molecular, modeling, studies])].
[sujeto(['Microtubules', exist, in, dynamic, 'equilibrium,', growing, and, shrinking, by, the, addition, or]), verbo([loss]), complemento([of, tubulin, dimers, from, the, ends, of, protofilaments])].
[sujeto(['The', hydrolysis, of, 'GTP', in, 'beta-tubulin', destabilizes, the, microtubule, lattice, by]), verbo([increasing]), complemento([the, curvature, of, protofilaments, in, the, microtubule, and, putting, strain, on, the, lattice])].
[sujeto(['The', observation, that, protofilament, curvature, depends, on, 'GTP', hydrolysis]), verbo([suggests]), complemento([that, microtubule, destabilizers, and, stabilizers, work, by, modulating, the, curvature, of, the, microtubule, lattice, itself])].
[sujeto(['Indeed,', the, microtubule, destabilizer, 'MCAK']), verbo([has]), complemento([been, shown, to, increase, the, curvature, of, protofilaments, during, depolymerization])].
[sujeto(['Here,', we, show, that, the, atomic, force, microscopy, '(', 'AFM)', of, individual, tubulin, protofilaments]), verbo([provides]), complemento([sufficient, resolution, to, allow, the, imaging, of, single, protofilaments, in, their, native, environment])].
[sujeto(['Many', agents, to, be, tested, are, poorly, soluble, in, aqueous, solution, and]), verbo([require]), complemento([a, cosolvent, such, as, dimethyl, sulfoxide, '(', 'DMSO)'])].
[sujeto(['However,', 'DMSO', itself, can]), verbo([promote]), complemento([tubulin, 'assembly,', and, its, inclusion, in, assays, for, compounds, that, induce, tubulin, assembly, complicates, interpretation, of, the, results])].
[sujeto(['Substituting', 'GDP', for, 'GTP', in, the, exchangeable, nucleotide]), verbo([binding]), complemento([site, of, tubulin, produces, a, less, active, form, of, the, 'protein,', 'tubulin-GDP'])].
[sujeto(['To', determine, the, role, of, the, constitutive, activity, of, 'RelA', in, 'tumorigenesis,', we, generated, pancreatic, tumor, cell, lines, that]), verbo([express]), complemento([a, dominant, negative, mutant, of, 'IkappaBalpha', '(', 'IkappaBalphaM)'])].
[sujeto(['We', identified, two, putative, 'NF-kappaB']), verbo([binding]), complemento([sites, '(', 'kappaB/A', and, 'B)', in, the, 'bcl-xl', promoter, and, found, that, these, two, sites, interact, with, different, 'NF-kappaB', proteins])].
[sujeto(['p65/p50', heterodimer]), verbo([interacts]), complemento([with, 'kappaB/A', site, whereas, 'p50/p50', homodimer, interacts, with, 'kappaB/B'])].
[sujeto(['The', 'bcl-xl', promoter, reporter, gene, assays]), verbo([reveal]), complemento([that, 'NF-kappaB', dependent, transcriptional, activation, is, mainly, mediated, by, 'kappaB/A', 'site,', indicating, that, 'bcl-xl', is, one, of, the, downstream, target, genes, regulated, by, 'RelA/p50'])].
[sujeto(['Both', 'IkappaBalphaM', and, 'PS-341', completely, abolish, 'NF-kappaB', 'DNA']), verbo([binding]), complemento(['activity;', 'however,', 'PS-341,', but, not, ectopic, expression, of, 'IkappaBalphaM,', sensitized, cells, to, apoptosis, induced, by, 'Taxol'])].
[sujeto(['This', is, due, to, the, 'Taxol-mediated', reactivation, of, 'RelA', through, phosphorylation, and, degradation, of, 'IkappaBbeta', and, the, 're-expression', of, 'NF-kappaB']), verbo([regulated]), complemento(['bcl-xl', gene, in, these, cancer, cells, as, ectopic, expression, of, the, 'bcl-xl', gene, confers, resistance, to, 'Taxol-induced', apoptosis, in, 'PS-341', sensitized, cells])].
[sujeto(['These', results, demonstrate, the, important, function, of, various, 'NF-kappaB/IkappaB', complexes, in]), verbo([regulating]), complemento(['anti-apoptotic', genes, in, response, to, apoptotic, 'stimuli,', and, they, raise, the, possibility, that, 'NF-kappaB', :, 'IkappaBalpha', and, 'NF-kappaB', :, 'IkappaBbeta', complexes, are, regulated, by, different, upstream, 'activators,', and, that, 'NF-kappaB', plays, a, key, role, in, pancreatic, tumorigenesis])].
[sujeto(['A', fluorescent, derivative, of, 'paclitaxel,', 3, '\'', -, 'N-m-aminobenzamido-3\'-N-debenzamidopaclitaxel', '(', 'N-AB-PT),']), verbo([has]), complemento([been, prepared, in, order, to, probe, 'paclitaxel-microtubule', interactions])].
[sujeto(['N-AB-PT', was]), verbo([found]), complemento([equipotent, with, paclitaxel, in, promoting, microtubule, polymerization])].
[sujeto(['The', equilibrium]), verbo([binding]), complemento([parameters, for, 'N-AB-PT', to, microtubules, assembled, from, 'GTP-tubulin', were, derived, through, fluorescence, titration])].
[sujeto(['N-AB-PT']), verbo([bound]), complemento([to, two, types, of, sites, on, microtubules, '(', 'K(d1)', =, 61, +, /, -, 7.0, nM, and, 'K(d2)', =, 3.3, +, /, -, 0.54, 'microM)'])].
[sujeto(['The']), verbo([binding]), complemento([experiments, were, repeated, after, exchanging, the, 'GTP', for, 'GDP', or, for, 'GMPCPP'])].
[sujeto(['It', was]), verbo([found]), complemento([that, 'N-AB-PT', bound, to, a, single, site, on, microtubules, assembled, from, 'GDP-tubulin', with, a, dissociation, constant, of, 2.5, +, /, -, 0.29, 'microM,', and, that, 'N-AB-PT', bound, to, a, single, site, on, microtubules, assembled, from, 'GMPCPP-tubulin', with, a, dissociation, constant, of, 15, +, /, -, 4.0, nM])].
[sujeto(['It', therefore, appears, that, microtubules, contain, two, types, of]), verbo([binding]), complemento([sites, for, paclitaxel, and, that, the, binding, site, affinity, for, paclitaxel, depends, on, the, nucleotide, content, of, tubulin])].
[sujeto(['It']), verbo([has]), complemento([been, established, that, paclitaxel, binding, does, not, inhibit, 'GTP', hydrolysis, and, microtubules, assembled, from, 'GTP-tubulin', in, the, presence, of, paclitaxel, contain, almost, exclusively, 'GDP', at, the, 'E-site'])].
[sujeto(['We', propose, that, although, all, the, subunits, of, the, microtubule, at, steady, state, are, the, same, &, 'quot;GDP-tubulin-paclitaxel",', they, are, formed, through, two, 'paths:', paclitaxel]), verbo([binding]), complemento([to, a, tubulin, subunit, before, its, 'E-site', 'GTP', hydrolysis, is, of, high, 'affinity,', and, paclitaxel, binding, to, a, tubulin, subunit, containing, hydrolyzed, 'GDP', at, its, 'E-site', is, of, low, affinity])].
[sujeto(['Although', the, mechanism, underlying, mRNA, localization, is, 'unknown,', 'mRNA-staufen', complexes]), verbo([have]), complemento([been, shown, to, move, in, a, 'microtubule-dependent', 'manner,', and, it, has, been, suggested, that, staufen, associates, with, a, motor, protein, which, generates, the, movement])].
[sujeto(['We']), verbo([have]), complemento([investigated, this, possibility, using, 'Notonecta', glauca, in, which, nurse, cells, also, supply, the, oocytes, with, 'mRNA,', but, via, greatly, extended, nutritive, tubes, comprised, of, large, aggregates, of, parallel, microtubules])].
[sujeto(['Using', a, staufen, peptide, antibody, and, 'RNA', probes, we]), verbo([have]), complemento([identified, a, 'staufen-like', 'protein,', which, specifically, binds, 'double-stranded', 'RNA,', in, the, nutritive, tubes, of, 'Notonecta'])].
[sujeto(['Nucleotide-dependent']), verbo([binding]), complemento([to, microtubules, is, typical, of, a, 'motor-mediated', interaction, and, the, pattern, of, attachment, and, detachment, of, the, 'staufen-like', protein, correlates, with, that, of, a, kinesin, protein, within, the, ovaries])].
[sujeto(['It']), verbo([inhibits]), complemento([microtubule, assembly, in, tubulin, systems, either, with, or, without, 'microtubule-associated', proteins, '(', 'ID50', was, 0.1, microM, and, 1.2, 'microM,', 'respectively)', and, microtubule, depolymerization, was, not, 'affected,', indicating, an, inhibition, of, polymerization, by, binding, of, 3, -, 'IAABU', to, the, heterodimeric, subunit, of, tubulin])].
[sujeto([3, -, 'IAABU', was, shown, to]), verbo([inhibit]), complemento([the, binding, of, 'colchicine,', a, subunit, binding, 'compound,', but, did, not, inhibit, binding, of, vinblastine, and, guanosine, 5, '\'', -, 'triphosphate/guanosine', 5, '\'', -, 'diphosphate,', indicating, that, colchicine, site, corresponds, to, the, site, that, 3, -, 'IAABU', locates])].
[sujeto(['Normal', microtubule, architecture, or, spindle, apparatus, was, absent, in, these, 'cells;', 'instead,', punctuated, aggregates, of, tubulin, were]), verbo([found]), complemento([by, an, immunofluorescent, staining])].
[sujeto(['The']), verbo([phosphorylated]), complemento(['bcl-2', representative, of, an, inactivated, form, of, the, oncoprotein, was, found, in, the, cells, 12, h, after, treatment, with, 3, -, 'IAABU'])].
[sujeto(['Different', models]), verbo([have]), complemento([been, proposed, that, link, the, tubulin, heterodimer, nucleotide, content, and, the, role, of, 'GTP', hydrolysis, with, microtubule, assembly, and, dynamics])].
[sujeto(['The', thermodynamic, parameters, of, tubulin, assembly, in, 30, -, 100, mM, 'piperazine-N,N\'-bis(2-ethanesulfonic', 'acid),', 1, mM, 'MgSO4,', 2, mM, 'EGTA,', pH, 6.9, ',', in, the, presence, of, a, weakly, hydrolyzable, 'analog,', 'GMPCPP,', the, dinucleotide, analog, 'GMPCP', plus, 2, 'M', 'glycerol,', and, 'GTP', plus, 2, 'M', glycerol, were, obtained, together, with, data, for, 'taxol-GTP/GDP', tubulin, assembly, '(', 'GMPCPP', and, 'GMPCP', are, the, 'GTP', and, 'GDP', nucleotide, analogs, where, the, alpha, beta, oxygen]), verbo([has]), complemento([been, replaced, by, a, 'methylene,', -, 'CH2-)'])].
[sujeto(['GMPCP-induced', assembly]), verbo([has]), complemento([the, largest, negative, heat, capacity, change, and, 'GMPCPP', has, the, second, 'largest,', whereas, 'GTP/2', 'M', 'glycerol-', and, 'taxol-induced', assembly, have, more, positive, 'values,', respectively])].
[sujeto(['A', 'large,', negative, heat, capacity, is, most, consistent, with, the, burial, of, 'water-accessible', hydrophobic, surface, 'area,', which, gives, rise, to, the]), verbo([release]), complemento([of, bound, water])].
[sujeto(['Entropy', analysis]), verbo([suggests]), complemento([that, assembly, with, 'GTP/2', 'M', glycerol, and, with, taxol, is, consistent, with, conformational, rearrangements, in, 3, -, 6, '%', of, the, total, amino, acids, in, the, heterodimer])].
[sujeto(['In', 'addition,', taxol]), verbo([binding]), complemento([contributes, to, the, thermodynamics, of, the, overall, process, by, reducing, the, delta, 'H', degree, and, delta, 'S', degree, for, microtubule, assembly])].
[sujeto(['In', the, presence, of, 'GMPCPP', or, 'GMPCP,', tubulin, subunits]), verbo([associate]), complemento([with, extensive, conformational, 'rearrangement,', corresponding, to, 10, '%', and, 26, '%', of, the, total, amino, acids, in, the, 'heterodimer,', 'respectively,', which, gives, rise, to, a, large, loss, of, configurational, entropy])].
[sujeto(['An', 'alternative,', and, probably, 'preferable,', interpretation, of, these, data, is, 'that,', especially, with, 'GMPCP-tubulin,', additional, isomerization, or, protonation, events, are]), verbo([induced]), complemento([by, the, presence, of, the, methylene, moiety, and, linked, to, microtubule, assembly])].
[sujeto(['Structural', analysis, shows, that, 'GTP', hydrolysis, is, not]), verbo([required]), complemento([for, sheet, closure, into, a, microtubule, 'cylinder,', but, only, increases, the, probability, of, this, event, occurring])].
[sujeto(['Sheet', extensions, and, sheet, polymers, appear, to]), verbo([have]), complemento([a, similar, average, length, under, various, 'conditions,', suggesting, that, the, minimum, cooperative, unit, for, closure, of, sheets, into, a, microtubule, cylinder, is, approximately, 400, nm, long])].
[sujeto(['Direct', photoaffinity, labeling, of, microtubule, protein, with, '[', 14, 'C]estramustine', resulted, in, the, labeling, of, both, 'alpha-', and, 'beta-tubulin,', and, this, was]), verbo([inhibited]), complemento([with, unlabeled, estramustine, in, a, 'dose-dependent', manner])].
[sujeto(['The', affinity, constant, for, estramustine]), verbo([binding]), complemento([to, tubulin, was, determined, by, equilibrium, dialysis, to, be, 23, +, /, -, 5, mM])].
[sujeto(['Both', rhizoxin, and, paclitaxel]), verbo([decreased]), complemento([the, covalent, labeling, of, tubulin, with, '[', 14, 'C]estramustine', in, a, 'dose-dependent', fashion, and, were, noncompetitive, inhibitors, of, the, binding, of, estramustine, to, tubulin])].
[sujeto(['The']), verbo([binding]), complemento([of, colchicine, to, tubulin, was, not, inhibited, by, estramustine, as, detected, by, fluorescence, and, 'DEAE', filter, assays])].
[sujeto(['The', estramustine]), verbo([binding]), complemento([site, on, tubulin, is, therefore, distinct, from, that, of, colchicine, and, vinblastine, and, may, at, least, partially, overlap, with, the, binding, site, for, paclitaxel])].
[sujeto(['In', both, bovine, brain, microtubules, and, cytoskeletal, proteins, from, human, prostatic, carcinoma, 'cells,', the, incorporation, of, '[', 14, 'C]estramustine', into, the, beta, 'III', isotype, of, tubulin, was]), verbo([found]), complemento([to, occur, with, a, reduced, efficiency, compared, to, that, of, the, other, 'beta-tubulin', isotypes, and, 'alpha-tubulin'])].
[sujeto(['We']), verbo([have]), complemento([studied, the, 'self-association', reactions, of, purified, 'GDP-liganded', tubulin, into, double, rings, and, 'taxoid-induced', 'microtubules,', employing, synchrotron, 'time-resolved', 'x-ray', solution, scattering])].
[sujeto(['The', experimental, scattering, profiles]), verbo([have]), complemento([been, interpreted, by, reference, to, the, known, scattering, profiles, to, 3, nm, resolution, and, to, the, 'low-resolution', structures, of, the, tubulin, 'dimer,', tubulin, double, 'rings,', and, 'microtubules,', and, by, comparison, with, oligomer, models, and, model, mixtures])].
[sujeto(['Upon', addition, of, the, divalent, 'cations,', it]), verbo([associates]), complemento([into, either, 'double-ring', aggregates, or, 'taxoid-induced', microtubules, by, different, pathways])].
[sujeto(['Both', processes]), verbo([have]), complemento([the, formation, of, small, linear, '(', short, 'protofilament-like)', tubulin, oligomers, in, common])].
[sujeto(['The', tubulin, 'self-association']), verbo([leading]), complemento([to, double, 'rings,', as, determined, by, sedimentation, 'velocity,', is, endothermic])].
[sujeto(['The', formation, of, the, 'double-ring', aggregates, from, 'oligomers,', which]), verbo([involves]), complemento([additional, intermolecular, 'contacts,', is, 'exothermic,', as, shown, by, 'x-ray', and, light, scattering])].
[sujeto(['Under', fast, polymerization, 'conditions,', after, a, short, lag, 'time,', open, 'taxoid-induced', microtubular, sheets]), verbo([have]), complemento([been, clearly, detected, '(', monitored, by, the, central, scattering, and, the, maximum, corresponding, to, the, 'J(n)', 'Bessel', 'function),', which, slowly, close, into, microtubules, '(', monitored, by, the, appearance, of, their, characteristic, 'J(0),', 'J(3),', and, 'J', '(', 'n)', -, '(', 3, ')', 'Bessel', function, 'maxima)'])].
[sujeto(['This']), verbo([provides]), complemento([direct, evidence, for, the, bidimensional, assembly, of, 'taxoid-induced', microtubule, polymers, in, solution, and, argues, against, helical, growth])].
[sujeto(['The', rate, of, microtubule, formation, was]), verbo([increased]), complemento([by, the, same, factors, known, to, enhance, 'taxoid-induced', microtubule, stability])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, taxoids, induce, the, accretion, of, the, existing, 'Mg(2+)-induced', 'GDP-tubulin', 'oligomers,', thus, forming, small, bidimensional, polymers, that, are, necessary, to, nucleate, the, microtubular, 'sheets,', possibly, by, binding, to, or, modifying, the, lateral, interaction, sites, between, tubulin, dimers])].
[sujeto(['The', bacterial, cell, division, protein, 'FtsZ', is, a, homolog, of, 'tubulin,', but, it]), verbo([has]), complemento([not, been, determined, whether, 'FtsZ', polymers, are, structurally, related, to, the, microtubule, lattice])].
[sujeto(['In', the, present, 'study,', we]), verbo([have]), complemento([obtained, 'high-resolution', electron, micrographs, of, two, 'FtsZ', polymers, that, show, remarkable, similarity, to, tubulin, polymers])].
[sujeto(['This']), verbo([suggests]), complemento([that, the, curved, conformation, occurs, at, every, 'FtsZ', 'subunit,', but, in, tubulin, rings, the, conformation, occurs, at, either, 'beta-', or, 'alpha-tubulin', subunits, but, not, both])].
[sujeto(['Despite', reduced, affinity, for, the, exchangeable, nucleotide]), verbo([binding]), complemento([site, of, tubulin, relative, to, 'GTP,', 2, '\'', ',', 3, '\'', -, dideoxyguanosine, 5, '\'', -, triphosphate, '(', 'ddGTP)', and, guanosine, 5, '\'', -, '[', 'alpha,', 'beta-methylene]triphosphate', '[', 'pp(CH2)pG]', are, highly, active, in, promoting, tubulin, assembly])].
[sujeto(['Like', the, antimitotic, drug, 'paclitaxel,', which]), verbo([interacts]), complemento([with, the, same, part, of, the, 'beta-tubulin', molecule, as, 'exchangeable-site', 'GTP,', both, analogs, enhance, nucleation, reactions, and, promote, formation, hyperstable, polymers])].
[sujeto(['These', observations]), verbo([led]), complemento([us, to, synthesize, the, doubly, modified, analog, 2, '\'', ',', 3, '\'', -, dideoxyguanosine, 5, '\'', -, '[', 'alpha,', 'beta-methylene]triphosphate', '[', 'pp(CH2)pddG]'])].
[sujeto(['We']), verbo([found]), complemento([that, 'pp(CH2)pddG', was, as, active, as, ddGTP, and, 'pp(CH2)pG', in, supporting, formation, of, polymer, of, increased, 'stability,', but, that, its, affinity, for, the, exchangeable, site, was, lower, than, that, of, both, singly, modified, analogs, '[', relative, affinities, for, the, exchangeable, site, for, 'pp(CH2)pddG:ddGTP:pp(CH2)-pG:GTP', were, 1, :, 2.8, :, 10, :, 273, ']'])].
[sujeto(['The', equilibrium, assembly, of, purified, 'GDP-tubulin', into, microtubules]), verbo([induced]), complemento([by, taxol, and, 'Taxotere', has, been, studied, as, a, function, of, solution, 'variables,', 'ligand,', and, 'nucleotide,', in, 10, mM, sodium, phosphate, buffers])].
[sujeto(['Assembly', is, coupled, to, the]), verbo([binding]), complemento([of, one, taxoid, molecule, per, tubulin, 'heterodimer,', while, binding, to, the, unassembled, protein, is, not, detected, within, ligand, solubility, limits])].
[sujeto(['Linked', functions, analysis]), verbo([has]), complemento([indicated, that, two, 'Mg2+', and, no, more, 'H+', ions, are, bound, per, 'tubulin-taxoid', 'polymerized,', and, the, heat, capacity, change, is, negligible, within, experimental, error, '(', determined, by, 'van\'t', 'Hoff', analysis, and, by, differential, scanning, 'calorimetry),', in, contrast, with, 'drug-free', control, microtubule, assembly, and, with, the, abnormal, polymerization, of, the, 'tubulin-colchicine', complex])].
[sujeto(['This', is, independent, of, taxoid, 'excess,', which]), verbo([has]), complemento([indicated, that, the, process, measured, corresponds, to, the, elongation, equilibrium, of, the, fully, liganded, protein])].
[sujeto(['Comparison', to, elongation, in, the, absence, of, drug]), verbo([suggests]), complemento([an, apparent, linkage, free, energy, change, of, binding, and, polymerization, of, -, 11.3, +, /, -, 1.2, kJ, 'mol-1'])].
[sujeto(['It', is, proposed, that, the, taxoid]), verbo([binding]), complemento([changes, the, conformation, of, 'GDP-tubulin', from, inactive, to, 'active,', allowing, productive, binding, and, elongation, at, the, microtubule, end])].
[sujeto(['Among', several, possible, model, mechanisms, 'discussed,', it, is, particularly, attractive, to, think, of, taxoids, as, 'double-sided', 'ligands,', which]), verbo([bind]), complemento([to, tubulin, at, the, microtubule, end, and, participate, in, a, lateral, contact, interface, with, the, newly, added, tubulin, molecule])].
[sujeto(['In', the, kinetic, pathway, of, 'assembly,', these, ligands, should]), verbo([bind]), complemento([first, to, inactive, 'Mg(2+)-induced', linear, 'GDP-tubulin', oligomers, and, transform, them, into, active, bidimensional, polymerization, nuclei])].
[sujeto(['Geiparvarin,', a, natural, compound, isolated, from, the, leaves, of, 'Geijera', 'parviflora,']), verbo([inhibits]), complemento([the, growth, of, various, tumor, cell, lines, with, a, mode, of, action, which, may, be, attributed, to, its, 'anti-microtubular', activity])].
[sujeto(['Our', previous, findings, indicated, that, geiparvarin, is, able, to]), verbo([inhibit]), complemento([the, in, vitro, polymerization, of, tubulin, and, to, derange, the, microtubular, network, in, fibroblasts, more, effectively, in, the, presence, of, paclitaxel])].
[sujeto(['To', further, explore, its, biological, activity, here, we]), verbo([have]), complemento([studied, the, effects, exerted, on, the, other, components, of, the, cytoskeleton, by, geiparvarin, and, two, derivatives, obtained, by, conjugating, the, 3, '(', 2, 'H)-furanone', ring, of, geiparvarin, with, diethylstilbestrol, '(', 'DES)'])].
[sujeto(['Firstly,', observations, by, electron, microscopy, confirmed, 'anti-microtubular', 'properties,', a, 'near-total', absence, of, microtubules, is, detected, when, tubulin, is, incubated, with, drugs, in, the, presence, of, 'paclitaxel,', whereas, microtubule, formation, is, not]), verbo([inhibited]), complemento([by, drugs, when, assembly, is, induced, by, guanosine, 5, '\'', -, triphosphate, '(', 'GTP)'])].
[sujeto(['Immunofluorescence', assays, demonstrated, that, geiparvarin, and, 'DES']), verbo([act]), complemento([in, a, 'vinblastine-like', 'fashion,', causing, a, marked, depletion, of, intermediate, filaments, while, the, network, of, microfilaments, is, not, affected])].
[sujeto(['The', cell, growth]), verbo([inhibiting]), complemento([effects, of, geiparvarin, and, derivatives, are, 'dose-dependent;', they, vary, according, to, the, cell, line, 'used,', when, compounds, were, administered, either, alone, or, simultaneously, with, paclitaxel])].
[sujeto(['When', atrial, tissue, 'contracts,', mechanically]), verbo([induced]), complemento([potentials, '(', 'MIPs)', are, generated, in, 'fibroblasts,', presumably, by, activation, of, a, 'non-selective', cation, conductance, 'Gns'])].
[sujeto(['The', slope, of, the, function, relating, 'AMIP', to, 'Vm', can, be, regarded, as, a, mechanosensitive, factor, '(', 'Xms)', that, describes, the, relative]), verbo([increase]), complemento([in, 'Gns', during, a, 'MIP'])].
[sujeto(['Promoting', 'F-actin', stability, with, exogenous, adenosine, 5, '\'', -, triphosphate, '(', 'ATP)']), verbo([increased]), complemento(['AMIP', and, 'Xms', and, attenuated, the, effects, of, cytochalasin, 'D'])].
[sujeto(['Similarly,', facilitation, of, tubulin, stability, with, guanosine, 5, '\'', -, triphosphate, '(', 'GTP)', or, taxol]), verbo([increased]), complemento(['AMIP', and, 'Xms', and, attenuated, the, effects, of, colchicine])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, transfer, of, mechanical, energy, from, the, deformed, fibroblast, surface, to, the, 'Gns', channel, protein, depends, on, intact, 'F-actin', and, tubulin, fibres])].
[sujeto(['TZT-1027,', a, derivative, of, dolastatin, 10, isolated, from, the, 'Indian', 'Ocean']), verbo([sea]), complemento([hare, 'Dolabella', auricularia, in, 1987, by, 'Pettit', et, al])].
[sujeto(['We']), verbo([have]), complemento([compared, the, activity, of, 'TZT-1027', with, that, of, dolastatin, 10, as, well, as, the, vinca, alkaloids, vinblastine, '(', 'VLB),', vincristine, '(', 'VCR)', and, vindesine, '(', 'VDS)'])].
[sujeto(['TZT-1027', and, dolastatin, 10]), verbo([inhibited]), complemento([microtubule, polymerization, 'concentration-dependently', at, 1, -, 100, microM, with, 'IC50', values, of, 2.2, +, /, -, 0.6, and, 2.3, +, /, -, 0.7, 'microM,', respectively])].
[sujeto(['VLB,', 'VCR', and, 'VDS']), verbo([inhibited]), complemento([microtubule, polymerization, at, 1, -, 3, microM, with, 'IC50', values, of, 2.7, +, /, -, 0.6, ',', 1.6, +, /, -, 0.4, and, 1.6, +, /, -, 0.2, 'microM,', 'respectively,', but, showed, a, slight, decrease, in, inhibitory, effect, at, concentrations, of, 10, microM, or, more])].
[sujeto(['TZT-1027', also]), verbo([inhibited]), complemento([monosodium, 'glutamate-induced', tubulin, polymerization, 'concentration-dependently', at, 0.3, -, 10, 'microM,', with, an, 'IC50', of, 1.2, 'microM,', whereas, 'VLB', was, only, effective, at, 0.3, -, 3, 'microM,', with, an, 'IC50', of, 0.6, 'microM,', and, caused, 'so-called', &, 'quot;aggregation"', of, tubulin, at, 10, microM])].
[sujeto(['Scatchard', analysis, of, the]), verbo([binding]), complemento([data, for, '[', '(', 3, ')', 'H]VLB', suggested, one, binding, site, '(', 'Kd', 0.2, +, /, -, 0.04, microM, and, 'Bmax', 6.0, +, /, -, 0.26, nM, /, mg, 'protein),', while, that, for, '[', '(', 3, ')', 'H]TZT-1027', suggested, two, binding, 'sites,', one, of, high, affinity, '(', 'Kd', 0.2, +, /, -, 0.01, microM, and, 'Bmax', 1.7, +, /, -, 0.012, nM, /, mg, 'protein)', and, the, other, of, low, affinity, '(', 'Kd', 10])].
[sujeto(['Furthermore,', 'TZT-1027']), verbo([prevented]), complemento(['[', '(', 3, ')', 'H]VLB', from, binding, to, tubulin, in, a, 'non-competitive', manner, according, to, 'Lineweaver-Burk', analysis])].
[sujeto(['TZT-1027', 'concentration-dependently']), verbo([inhibited]), complemento([both, '[', '(', 3, ')', 'H]guanosine', 5, '\'', -, triphosphate, '(', 'GTP)', binding, to, and, 'GTP', hydrolysis, on, tubulin])].
[sujeto(['VLB']), verbo([inhibited]), complemento([the, hydrolysis, of, 'GTP', on, tubulin, 'concentration-dependently', to, a, lesser, extent, than, 'TZT-1027,', but, no, inhibitory, effect, of, 'VLB', on, '[', '(', 3, ')', 'H]GTP', binding, to, tubulin, was, evident, even, at, 100, microM])].
[sujeto(['Thus,', 'TZT-1027', affected, the]), verbo([binding]), complemento([of, 'VLB', to, 'tubulin,', but, its, binding, site, was, not, completely, identical, to, that, of, 'VLB'])].
[sujeto(['Distances', between, the, 'paclitaxel,', 'colchicine,', and, exchangeable, 'GTP']), verbo([binding]), complemento([sites, on, tubulin, polymers, have, been, probed, using, fluorescence, spectroscopy])].
[sujeto(['Techniques', for, measuring, fluorescence, resonance, energy, transfer, '(', 'FRET)', between, fluorescent, or, chromophoric, ligands, for, each]), verbo([binding]), complemento([site, were, employed])].
[sujeto([2, -, 'Debenzoyl-2-(m-aminobenzoyl)paclitaxel', '(', 2, -, 'AB-PT)', was, the, fluorophore, ligand, for, the, paclitaxel]), verbo([binding]), complemento(['site;', 'thiocolchicine,', 'allocolchicine,', and, 'MDL', 27048, were, probes, for, the, colchicine, 'site,', and, 2, '\'', '(', or, 3, '\'', ')', -, 'O-(trinitrophenyl)guanosine', 5, '\'', -, triphosphate, '(', 'TNP-GTP)', was, the, fluorophore, ligand, for, the, exchangeable, 'GTP', site])].
[sujeto(['The', distance, between, the, colchicine, and, paclitaxel]), verbo([binding]), complemento([sites, was, determined, with, two, different, acceptor, ligands, in, the, colchicine, site])].
[sujeto(['An', average, distance, distribution, of, 17, 'A', was]), verbo([found]), complemento([in, both, cases])].
[sujeto(['Energy', transfer, between, 2, -, 'AB-PT']), verbo([bound]), complemento([to, the, paclitaxel, site, and, 'TNP-GTP', '(', 'acceptor)', bound, to, the, exchangeable, 'GTP', site, was, observed, in, the, polymer])].
[sujeto(['No', 'FRET', was, observed, between, ligands]), verbo([bound]), complemento([to, the, colchicine, and, exchangeable, 'GTP', 'sites,', indicating, that, the, result, of, colchicine, binding, on, the, 'GTP', region, of, 'beta-tubulin', is, a, long, 'range,', allosteric, effect])].
[sujeto(['Taxol']), verbo([has]), complemento([been, used, as, a, tool, to, investigate, the, relationship, between, microtubule, assembly, and, guanosine, 5, '\'', -, triphosphate, '(', 'GTP)', hydrolysis])].
[sujeto(['A', slower, subsequent, turbidity]), verbo([increase]), complemento([corresponds, to, the, length, redistribution, of, these, short, microtubules, into, 3, -, 5, -, fold, longer, ones, without, any, change, in, the, weight, amount, of, polymer])].
[sujeto(['The', evolution, of, the, rate, of, length, redistribution, with, the, concentration, of, taxol]), verbo([suggests]), complemento([a, model, within, which, taxol, would, bind, to, dimeric, tubulin, and, to, tubulin, present, at, the, ends, of, microtubules, with, a, somewhat, 10, -, fold, lower, affinity, than, to, polymerized, tubulin, embedded, in, the, bulk, of, microtubules])].
[sujeto(['In', agreement, with, this, 'model,']), verbo([binding]), complemento([of, taxol, to, the, 'tubulin-colchicine', complex, in, the, dimeric, form, could, be, measured, from, the, increase, in, the, 'GTPase', activity, of, the, 'tubulin-colchicine', complex, accompanying, taxol, binding])].
[sujeto(['Taxol']), verbo([increases]), complemento([the, rate, and, extent, of, microtubule, assembly, in, vitro, and, stabilizes, microtubules, in, vitro, and, in, cells, '[', 'Schiff,', 'P'])].
[sujeto(['We']), verbo([report]), complemento([herein, that, taxol, has, the, ability, to, promote, microtubule, assembly, in, the, absence, of, 'microtubule-associated', 'proteins,', 'rings,', and, added, guanosine, 5, '\'', -, triphosphate, '(', 'GTP', or, organic, buffer])].
[sujeto(['The', drug]), verbo([enhances]), complemento([additional, microtubule, assembly, when, added, to, microtubules, at, apparent, steady, state])].
[sujeto(['Taxol-treated', microtubules]), verbo([have]), complemento([depressed, dissociation, reactions, as, determined, by, dilution, experiments])].
[sujeto(['The', drug, does, not]), verbo([inhibit]), complemento([the, binding, of, 'GTP', or, the, hydrolysis, of, 'GTP', or, guanosine, 5, '\'', -, diphosphate, '(', 'GDP)', in, our, microtubule, protein, preparations])].
[sujeto(['Taxol', does, not, competitively]), verbo([inhibit]), complemento([the, binding, of, colchicine, to, tubulin])].
[sujeto(['Vascular', stent, design, continues, to, evolve, to, further, improve, the, efficacy, and, minimize, the, risks]), verbo([associated]), complemento([with, these, devices])].
[sujeto(['Drug-eluting', coatings]), verbo([have]), complemento([been, widely, adopted, 'and,', more, 'recently,', biodegradable, stents, have, been, the, focus, of, extensive, evaluation])].
[sujeto(['The', dynamic, degradation, 'behavior,', hemocompatibility, and, drug]), verbo([release]), complemento([were, investigated, for, 'poly(carbonate', 'urethane)', urea, '(', 'PCUU)', and, 'poly(ester', 'urethane)', urea, '(', 'PEUU)', coated, magnesium, alloy, '(', 'AZ31)', stents])].
[sujeto(['This', was, confirmed, by, electron, 'microscopy,', 'energy-dispersive', 'x-ray', spectroscopy, and, magnesium, ion]), verbo([release]), complemento([experiments])].
[sujeto(['PCUU-coating', of, 'AZ31', was, also]), verbo([associated]), complemento([with, significantly, reduced, platelet, adhesion, in, acute, blood, contact, testing])].
[sujeto(['Rat', vascular, smooth, muscle, cell, '(', 'rSMC)', proliferation, was, successfully]), verbo([inhibited]), complemento([when, paclitaxel, was, released, from, 'pre-loaded', 'PCUU', coatings])].
[sujeto(['PVP-b-PDLLA', was]), verbo([found]), complemento([to, be, a, suitable, emulsifier, for, 'dichloromethane/water', 'emulsions,', yielding, narrowly, distributed, nanoparticles, '(', &, 'lt;250', 'nm)', surrounded, by, a, hydrophilic, 'PVP', corona])].
[sujeto(['The', entrapment, efficiency, of, etoposide, was, significantly]), verbo([enhanced]), complemento([by, adding, 'MgCl2', to, the, aqueous, phase])].
[sujeto(['It', was]), verbo([found]), complemento([that, the, nanoparticles, released, the, drugs, progressively, over, several, days, in, vitro])].
[sujeto(['An', improved, experimental, density, for, the, 'zinc-induced', tubulin, sheets, was, obtained, by, adding, 114, electron, diffraction, patterns, at, 40, -, 60, degrees, tilt, and]), verbo([increasing]), complemento([the, completeness, of, structure, factor, amplitudes, to, 84.7, '%'])].
[sujeto(['In', light, of, the, new, model, we, discuss, details, of, the, tubulin, structure, such, as, nucleotide, and, taxol]), verbo([binding]), complemento(['sites,', lateral, contacts, in, 'zinc-sheets,', and, the, significance, of, the, location, of, highly, conserved, residues])].
[sujeto(['We']), verbo([report]), complemento([the, activities, of, taxol, '(', an, anticancer, 'drug)', and, 'colchicine,', which, are, inhibitors, of, microtubule, 'organization,', on, the, complexation, and, transport, of, 'Na+,', 'K+,', 'Mg2+', and, 'Ca2+', ions, across, a, liquid, 'membrane,', using, a, spectrophotometric, procedure])].
[sujeto(['Taxol,', a, diterpenoid, 'compound,', that]), verbo([has]), complemento([been, demonstrated, to, possess, a, potent, antitumour, 'activity,', is, shown, to, extract, 'Na+,', 'K+,', 'Mg2+', and, 'Ca2+', ions, from, the, aqueous, solution, to, the, organic, phase, with, preference, for, 'Ca2+', ions])].
[sujeto(['In', both, complexation, and, 'transport,', the, flux, of, the, ions]), verbo([increases]), complemento([with, the, concentration, of, taxol, or, colchicine])].
[sujeto(['GaCl3', '(', 250, 'microM)', does, not, mimic, the, effect, of, 10, microM, paclitaxel, 'and,', 'therefore,', is, not, a, microtubule, '(', 'MT)-stabilizing', agent, that, can]), verbo([promote]), complemento([tubulin, polymerization, in, the, absence, of, glycerol, and, block, 'MT', disassembly])].
[sujeto(['In', 'contrast,', 'GaCl3', mimics, the, effect, of, 1, microM, vincristine, '(', 'VCR)', and]), verbo([inhibits]), complemento(['glycerol-induced', tubulin, polymerization, in, a, 'concentration-dependent', manner, '(', 'IC50:', 125, 'microM),', indicating, that, 'GaCl3', is, a, 'MT', 'de-stabilizing', agent, that, prevents, 'MT', assembly])].
[sujeto(['However,', 150, microM, 'GaCl3', must, be, used, to, match, or, surpass, the, inhibitions, of, tubulin, polymerization]), verbo([caused]), complemento([by, 0.25, microM, of, known, 'MT', 'de-stabilizing', 'agents,', such, as, colchicine, '(', 'CLC),', 'nocodazole,', 'podophyllotoxin,', 'tubulozole-C', and, 'VCR'])].
[sujeto(['The', inhibitory, effect, of, 250, microM, 'GaCl3', persists, in, the, presence, of, up, to, 9, mM, 'MgCl2,']), verbo([suggesting]), complemento([that, the, exogenous, 'Mg2+', cations, absolutely, required, for, the, binding, of, 'GTP', to, tubulin, and, 'MT', assembly, cannot, overcome, the, antitubulin, action, of, 'Ga3+', ions, of, a, higher, valence])].
[sujeto(['The']), verbo([binding]), complemento([of, '[', 3, 'H]vinblastine', '(', 'VBL)', to, tubulin, '(', 0.5, 'mg/ml)', is, inhibited, by, unlabeled, 'VBL', but, enhanced, by, concentrations, of, 'GaCl3', &, 'gt;', 200, microM])].
[sujeto(['However,']), verbo([increasing]), complemento([concentrations, of, 'GaCl3', mimic, the, ability, of, cold, 'CLC', to, reduce, the, amount, of, '[', 3, 'H]CLC', bound, to, 'tubulin,', suggesting, that, 'GaCl3', may, interact, with, the, 'CLC', binding, site, to, inhibit, tubulin, polymerization])].
[sujeto(['The']), verbo([binding]), complemento([of, '[', 3, 'H]GTP', to, tubulin, is, decreased, by, unlabeled, 'GTP', but, markedly, enhanced, by, 'GaCl3,', especially, when, concentrations, of, this, metal, salt, of, 32, microM, or, higher, are, added, to, the, reaction, mixture, before, rather, than, after, the, radiolabeled, nucleotide])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, changes, in, protein, conformation, following, 'GaCl3', binding, might, increase, the, interactions, of, tubulin, with, nucleotides, and, 'Vinca', alkaloids])].
[sujeto(['Since', 'GaCl3', '(', 100, -, 625, 'microM)']), verbo([increases]), complemento([the, percentage, of, mitotic, cells, at, 2, -, 4, 'days,', it, might, arrest, tumor, cell, progression, in, 'M', 'phase,', but, its, antimitotic, activity, is, much, weaker, than, that, of, 0.25, microM, 'VCR'])].
[sujeto(['Because', the, concentrations, of, 'GaCl3', that]), verbo([inhibit]), complemento([tubulin, polymerization, also, increase, the, mitotic, index, and, decrease, the, viability, of, 'L1210', cells, in, 'vitro,', the, antitubulin, and, antimitotic, effects, of, 'GaCl3', might, 'contribute,', at, least, in, 'part,', to, its, antitumor, activity])].
[sujeto(['This', parent, olefin, of, the, taxane, diterpenoids, is, then, elaborated, to, taxol, and, related, compounds, by, a, complex, series, of, reactions]), verbo([involving]), complemento([oxidations, and, 'side-chain', acylations])].
[sujeto(['In', general, properties, '(', divalent, metal, ion, 'requirement,', kinetic, 'constants,', molecular, 'weight),', the, taxadiene, synthase, of, 'Pacific', yew, is, similar, to, the, diterpene, cyclase, abietadiene, synthase]), verbo([involved]), complemento([in, resin, acid, biosynthesis, in, other, gymnosperms])].
[sujeto(['In', comparison, with, standard, buffer, conditions, '(', 100, 'mM-Pipes', 'buffer,', pH, 6.5, ',', containing, 0.1, 'mM-EGTA,', 1.8, 'mM-MgC12', and, 1, 'M-glycerol),', the, rate, and, extent, of, 'exchange,', and, thus, of, dynamic, 'instability,', are]), verbo([suppressed]), complemento([by, increasing, the, concentration, of, glycerol, above, 2, 'M'])].
[sujeto(['Exchange', is]), verbo([enhanced]), complemento([by, the, addition, of, further, 'Mg2+', '(', up, to, 17, 'mM)', or, by, the, addition, of, 'Ca2+', '(', up, to, 0.4, 'mM)'])].
[sujeto(['Phosphate', ion, '(', 150, 'mM)']), verbo([has]), complemento([relatively, little, effect, on, the, dynamic, behaviour, of, 'microtubules,', as, judged, by, the, exchange, method])].
[sujeto(['A']), verbo([decrease]), complemento([in, the, extent, of, 'exchange,', and, hence, in, dynamic, 'activity,', is, associated, with, a, decreased, value, for, this, rate, 'constant,', and, vice, versa])].
[sujeto(['The', results, also, show, good, agreement, of, predictions, of, the, model, in, treating, the, observed, variations, in, the, dynamic, properties, of, individual, 'microtubules,']), verbo([induced]), complemento([by, different, solution, conditions])].
[sujeto(['A', comparative, study]), verbo([has]), complemento([been, carried, out, of, the, effects, of, taxol, on, the, polymerizations, into, microtubules, of, 'microtubule-associated', 'protein-free', 'tubulin,', prepared, by, the, modified, 'Weisenberg', 'procedure,', and, of, the, 'tubulin-colchicine', complex, into, large, aggregates])].
[sujeto(['The', polymerization, of, 'tubulin-colchicine']), verbo([requires]), complemento([both, heat, and, 'GTP,', and, the, process, is, reversed, by, cooling])].
[sujeto(['In', the, case, of, microtubule, 'formation,', the, linkage, free, energy]), verbo([provided]), complemento([by, taxol, binding, is, approximately, -, 3.0, 'kcal/mol', of, 'alpha-beta-tubulin', 'dimer,', whereas, this, quantity, is, reduced, to, approximately, -, 0.5, 'kcal/mol', in, 'tubulin-colchicine,', indicating, the, expenditure, of, much, more, binding, free, energy, in, the, latter, case, for, overcoming, unfavorable, 'factors,', such, as, steric, hindrance, and, geometric, strain])].
[sujeto(['The', difference, in, the, effect, of, 'GTP', on, the, two, polymerization, processes, reflects, the, respective, abilities, of, the, bindings, of, taxol, to, the, two, states, of, tubulin, to, overcome, the]), verbo([loss]), complemento([of, the, linkage, free, energy, of, 'GTP', binding])].
[sujeto(['Analysis', of, the, linkages]), verbo([leads]), complemento([to, the, conclusions, that, taxol, need, not, change, qualitatively, the, mechanism, of, microtubule, assembly, and, that, tubulin, with, the, 'E-site', unoccupied, by, nucleotide, should, have, the, capacity, to, form, 'microtubules,', the, reaction, being, extremely, weak])].
[sujeto(['The', present, investigation, was, aimed, to, utilize, the, stealth, property, of, polyethylene, glycol, '(', 'PEG)', modified, chitosan, nanoparticles, '(', 'NPs)', and, active]), verbo([targeting]), complemento([function, of, transferrin, '(', 'Tf)', by, transferrin, 'receptor-mediated', endocytosis, to, promote, drug, delivery, to, cancer, cells])].
[sujeto(['The', uptake, of, 'NP-PEG-Tf', into, cancer, cells, was]), verbo([found]), complemento([to, be, higher, as, compared, to, 'non-targeted', 'NPs'])].
[sujeto(['Tf', conjugated, 'NPs', showed]), verbo([increased]), complemento([retention, time, in, the, lungs, as, well, as, in, blood])].
[sujeto(['Previously,', it, was, shown, that, 'Tau,', a, 'microtubule-associated', protein, '(', 'MAP)', localized, to, neuronal, 'axons,']), verbo([regulates]), complemento([the, average, number, of, 'PFs', in, microtubules, with, increasing, inner, radius, &, 'lt;Rin(MT)>', observed, for, increasing, 'Tau/tubulin-dimer', molar, ratio, 'ΦTau', at, 'paclitaxel/tubulin-dimer', molar, ratio, 'ΛPtxl=1/1'])].
[sujeto(['We']), verbo([report]), complemento([a, synchrotron, 'SAXS', and, 'TEM', study, of, the, phase, behavior, of, microtubules, as, a, function, of, varying, concentrations, of, paclitaxel, '(', 1, /, 32, '≤ΛPtxl≤1/4)', and, 'Tau', '(', human, isoform, 3, 'RS,', 0, '≤Φ3RS≤1/2)', at, room, temperature])].
[sujeto(['Tau', and, paclitaxel]), verbo([have]), complemento([opposing, regulatory, effects, on, microtubule, bundling, architectures, and, microtubule, diameter])].
[sujeto(['Surprisingly', and, in, contrast, to, previous, results, at, 'ΛPtxl=1/1', where, microtubule, bundles, are, 'absent,', in, the, lower, paclitaxel, concentration, regime, '(', 'ΛPtxl≤1/4),', we, observe, both, microtubule, doublets, and, triplets, with]), verbo([increasing]), complemento(['Tau'])].
[sujeto(['Furthermore,']), verbo([increasing]), complemento([paclitaxel, concentration, '(', up, to, 'ΛPtxl=1/1)', slightly, decreased, the, average, microtubule, diameter, '(', by, '~1', 'PF)', while, increasing, 'Tau', concentration, '(', up, to, 'Φ3RS=1/2)', significantly, increased, the, diameter, '(', by, '~2-3', 'PFs)'])].
[sujeto(['The', suppression, of, 'Tau-mediated', microtubule, bundling, with]), verbo([increasing]), complemento([paclitaxel, is, consistent, with, paclitaxel, seeding, 'more,', but, 'shorter,', microtubules, by, rapidly, exhausting, tubulin, available, for, polymerization])].
[sujeto(['Microtubule', bundles]), verbo([require]), complemento([the, aggregate, 'Tau-Tau', attractions, along, the, microtubule, length, to, overcome, individual, microtubule, thermal, energies, disrupting, bundles])].
[sujeto(['Investigating', 'MAP-mediated', interactions, between, microtubules, '(', as, it, relates, to, in, vivo, 'behavior)']), verbo([requires]), complemento([the, elimination, or, minimization, of, paclitaxel])].
[sujeto(['A', literature, search, was, 'started,', and, we]), verbo([found]), complemento([all, studies, conducted, from, 2005, to, 2016])].
[sujeto(['There', is, a, significant]), verbo([decrease]), complemento([of, target, lesion, revascularization, '(', 'TLR)', '(', 'MD = 0'])].
[sujeto(['A', significant]), verbo([decrease]), complemento([of, target, vessel, revascularization, '(', 'TVR)', in, more, than, 1, &, 'nbsp;year', is, '(', 'MD = 0'])].
[sujeto(['A', significant]), verbo([decrease]), complemento([of, major, adverse, cardiac, events, '(', 'MACE)', in, more, than, 1, &, 'nbsp;year', is, '(', 'MD = 0'])].
[sujeto(['SES', may, be, more, significant, in]), verbo([decreasing]), complemento(['TLR,', 'TVR,', and, 'MACE', than, 'PES', without, significantly, increasing, 'mortality,', 'ST', and, 'MI', in, diabetes, patients])].
[sujeto(['Gallbladder', toxicity, was]), verbo([reported]), complemento([in, most, motesanib, studies, with, varying, frequency, and, at, variable, times, after, initiation, of, treatment])].
[sujeto(['Endoscopic', sphincterotomy, was, performed, to]), verbo([prevent]), complemento([biliary, obstruction, and, recurrent, pancreatitis, after, removal, of, mucoid, material])].
[sujeto(['To', the, best, of, our, 'knowledge,', this, is, the, first]), verbo([report]), complemento([of, obstructive, cholangitis, and, acute, pancreatitis, associated, with, sludge, formation, during, motesanib, therapy])].
[sujeto(['Endoscopic', sphincterotomy, appears, to, be, useful, to, treat, and]), verbo([prevent]), complemento([biliary, obstruction, caused, by, 'motesanib-induced', biliary, sludge])].
[sujeto(['Bevacizumab']), verbo([has]), complemento([become, a, '\'', community, 'standard\'', at, many, 'UK', centres, as, part, of, 'first-line', treatment, of, patients, with, ovarian, cancer, at, high, risk, of, progression, '[', 'International', 'Federation', of, 'Gynecology', and, 'Obstetrics', '(', 'FIGO)', stage, 'IV,', or, suboptimally, debulked, stage, 'III]', based, on, the, results, of, phase, 'III', trials, such, as, 'ICON-7'])].
[sujeto(['In', 'conclusion,', our, study]), verbo([provides]), complemento([encouraging, evidence, that, the, routine, use, of, bevacizumab, as, part, of, 'first-line', treatment, of, patients, with, ovarian, cancer, at, high, risk, of, progression, may, be, associated, with, outcomes, comparable, with, those, obtained, in, clinical, trials])].
[sujeto(['Unfortunately,', due, to, the, rapid, genetic, and, epigenetic, changes, in, adaptation, to, stress]), verbo([induced]), complemento([by, anticancer, 'drugs,', cancer, cells, are, often, able, to, become, resistant, to, single, or, multiple, anticancer, agents])].
[sujeto(['Immunoblotting', revealed, significant, alterations, in, 'cell-cycle-related', and, 'apoptotic-related', proteins]), verbo([involved]), complemento([in, key, signaling, pathways])].
[sujeto(['In', 'particular,', phosphorylation, of, 'p38,', which]), verbo([activates]), complemento(['H2AX,', was, significantly, decreased, in, 'A2780T', cells, compared, to, the, parental, 'A2780', cells])].
[sujeto(['Furthermore,', treatment, of, 'A2780', and, 'A2780T', cells, with, 'GA', significantly]), verbo([enhanced]), complemento([sensitivity, to, paclitaxel])].
[sujeto(['Meanwhile,', 'GA', cooperated, with, paclitaxel, to]), verbo([suppress]), complemento([tumor, growth, in, a, mouse, ovarian, cancer, xenograft, model])].
[sujeto(['Multiple', lung, and, lymph, nodes, metastases, were, also, detected, upon, computed, 'tomography,', along, with]), verbo([increased]), complemento([serum, 'alpha-fetoprotein', '(', 33.9, 'ng/mL)', and, human, chorionic, gonadotropin, '(', 182.5, 'mIU/mL)', levels])].
[sujeto(['Consequently,']), verbo([he]), complemento([received, chemotherapy, comprising, three, courses, of, 'BEP', '(', 'bleomycin,', 'etoposide,', and, 'cisplatin)', as, 'first-line', 'therapy,', followed, by, four, courses, of, 'TGN', '(', 'paclitaxel,', 'gemcitabine,', and, 'nedaplatin)', as, 'second-line', treatment])].
[sujeto(['As', a, 'result,', the, spinal, cord, lesion, area, was, significantly]), verbo([decreased]), complemento([and, the, 'alpha-fetoprotein', and, human, chorionic, gonadotropin, levels, were, normalized])].
[sujeto(['In-stent', hyperplasia, '(', 'ISH)', may, develop, in, regions, of, low, endothelial, shear, stress, '(', 'ESS),', but, the, relationship, between, the, magnitude, of, low, 'ESS,', the, extent, of, 'ISH,', and, subsequent, clinical, events]), verbo([has]), complemento([not, been, investigated])].
[sujeto(['In', 'BMS,', low, 'ESS', 'post-PCI', at, baseline, was, independently]), verbo([associated]), complemento([with, 'ISH', '(', 'β=1'])].
[sujeto(['There', was, no, significant, association, between, 'post-PCI', 'ESS', and, 'in-stent', restenosis]), verbo([requiring]), complemento(['PCI'])].
[sujeto(['Low', 'ESS', after, 'BMS', implantation, is]), verbo([associated]), complemento([with, subsequent, 'ISH'])].
[sujeto(['ISH', is, strongly]), verbo([inhibited]), complemento([by, 'drug-eluting', stents])].
[sujeto(['Post-PCI', 'ESS', is, not]), verbo([associated]), complemento([with, 'in-stent', restenosis, requiring, repeat, 'PCI'])].
[sujeto(['ESS', is, an, important, determinant, of, 'ISH', in, 'BMS,', but, 'ISH', of, large, magnitude, to]), verbo([require]), complemento(['PCI', for, 'in-stent', restenosis, is, likely, attributed, to, factors, other, than, 'ESS', within, the, stent])].
[sujeto(['A', unique, biomimetic, 'drug-delivery', system, composed, of, 4, 'T1-breast-cancer-cell', membranes, and, 'paclitaxel-loaded', polymeric, nanoparticles, '(', 'PPNs)', '(', 'cell-membrane-coated', 'PPNs),', demonstrates, superior, interactions, to, its, source, tumor, cells, and, elongated, blood, 'circulation,', and, displays, highly, 'cell-specific']), verbo([targeting]), complemento([of, the, homotypic, primary, tumor, and, 'metastases,', with, successful, inhibition, of, the, growth, and, lung, metastasis, of, the, breast, cancer, cells])].
[sujeto(['Here', we, delineate, the, natural, history, of, metastasis, in, an, autochthonous, model, of, pancreatic, ductal, adenocarcinoma, '(', 'PDAC),', using, lineage, tracing, to, examine, the, evolution, of, disseminated, cancer, cells, and, their]), verbo([associated]), complemento([microenvironment])].
[sujeto(['With']), verbo([increasing]), complemento(['size,', lesions, shift, from, mesenchymal, to, epithelial, 'histology,', become, hypovascular, and, accumulate, a, desmoplastic, 'stroma,', ultimately, recapitulating, the, primary, tumours, from, which, they, arose])].
[sujeto(['Moreover,', treatment, with, gemcitabine, and, 'nab-paclitaxel', significantly, reduces, the, overall, number, of, metastases, by]), verbo([inducing]), complemento([cell, death, in, lesions, of, all, 'sizes,', challenging, the, paradigm, that, 'PDAC', stroma, imposes, a, critical, barrier, to, drug, delivery])].
[sujeto(['These', results, illuminate, the, cellular, dynamics, of, metastatic, progression, and]), verbo([suggest]), complemento([that, adjuvant, chemotherapy, affords, a, survival, benefit, by, directly, targeting, micrometastases])].
[sujeto(['CITED2', '(', 'Cbp/p300-interacting', 'transactivator,', with, 'Glu/Asp-rich', 'carboxy-terminal', 'domain,', 2, ')', is, a, member, of, 'CITED', family, and]), verbo([involved]), complemento([in, various, cellular, functions, during, development, and, differentiation])].
[sujeto(['Mounting', evidence]), verbo([suggests]), complemento([importance, of, 'CITEDs', in, the, progression, of, human, 'malignancies,', but, significance, of, 'CITED2', protein, has, not, yet, been, examined, in, breast, carcinoma])].
[sujeto(['CITED2', immunoreactivity, was, significantly]), verbo([associated]), complemento([with, 'stage,', pathological, 'T', 'factor,', lymph, node, 'metastasis,', histological, 'grade,', 'HER2', and, 'Ki-67,', and, inversely, correlated, with, estrogen, receptor])].
[sujeto(['Moreover,', the, immunohistochemical, 'CITED2', status, was, significantly]), verbo([associated]), complemento([with, increased, incidence, of, recurrence, and, breast, 'cancer-specific', death, of, the, breast, cancer, 'patients,', and, multivariate, analyses, demonstrated, 'CITED2', status, as, an, independent, worse, prognostic, factor, for, 'disease-free', and, breast, 'cancer-specific', survival])].
[sujeto(['Subsequent', in, vitro, experiments, showed, that, 'CITED2', expression, significantly]), verbo([increased]), complemento([proliferation, activity, and, migration, property, in, 'MCF-7', and, 'SKBR-3', breast, carcinoma, cells])].
[sujeto(['Moreover,', 'CITED2']), verbo([caused]), complemento([chemoresistance, to, epirubicin, and, 5, -, 'fluorouracil,', but, not, 'paclitaxel,', in, these, 'cells,', and, it, inhibited, p53, accumulation, after, 5, -, fluorouracil, treatment, in, 'MCF-7', cells])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'CITED2', plays, important, roles, in, the, progression, and, chemoresistance, of, breast, carcinoma, and, 'CITED2', status, is, a, potent, prognostic, factor, in, breast, cancer, patients])].
[sujeto(['The', toxicity, of, 'anti-cancer', chemotherapeutic, agents, can, be, reduced, by]), verbo([associating]), complemento([these, 'compounds,', such, as, the, 'anti-proliferative', agent, 'paclitaxel,', with, a, 'cholesterol-rich', nanoemulsion, '(', 'LDE)', that, mimics, the, lipid, composition, of, 'low-density', lipoprotein, '(', 'LDL)'])].
[sujeto(['None', of, the, patients, in, this, group, exhibited, a, reduction, in, plaque, 'volume;', in, 'contrast,', the, plaque, volume]), verbo([increased]), complemento([in, three, patients, and, remained, stable, in, four, patients])].
[sujeto(['Ovarian', cancer, is, the, most, lethal, gynecologic, disease, because, 'usually,', it, is, lately, 'sensed,', easily, acquires, 'chemoresistance,', and]), verbo([has]), complemento([a, high, recurrence, rate])].
[sujeto(['Recent', studies]), verbo([suggest]), complemento([that, ovarian, cancer, stem, cells, '(', 'CSCs)', are, involved, in, these, malignancies])].
[sujeto(['Here,', we, demonstrated, that, 'galectin-3']), verbo([maintains]), complemento([ovarian, 'CSCs', by, activating, the, 'Notch1', intracellular, domain, '(', 'NICD1)'])].
[sujeto(['The', number, and, size, of, ovarian, 'CSCs']), verbo([decreased]), complemento([in, the, absence, of, 'galectin-3,', and, overexpression, of, 'galectin-3', increased, them])].
[sujeto(['Overexpression', of, 'galectin-3']), verbo([increased]), complemento([the, resistance, for, cisplatin, and, 'paclitaxel-induced', cell, death])].
[sujeto(['Silencing', of, 'galectin-3']), verbo([decreased]), complemento([the, migration, and, invasion, of, ovarian, cancer, 'cells,', and, overexpression, of, 'galectin-3', reversed, these, effects])].
[sujeto(['The', 'Notch', signaling, pathway, was, strongly]), verbo([activated]), complemento([by, 'galectin-3', overexpression, in, 'A2780', cells])].
[sujeto(['Silencing', of, 'galectin-3', reduced, the, levels, of, cleaved, 'NICD1', and, expression, of, the, 'Notch']), verbo([target]), complemento(['genes,', 'Hes1', and, 'Hey1'])].
[sujeto(['Overexpression', of, 'galectin-3']), verbo([induced]), complemento(['NICD1', cleavage, and, increased, expression, of, 'Hes1', and, 'Hey1'])].
[sujeto(['Moreover,', overexpression, of, 'galectin-3']), verbo([increased]), complemento([the, nuclear, translocation, of, 'NICD1'])].
[sujeto(['Interestingly,', the, carbohydrate, recognition, domain, of, 'galectin-3']), verbo([interacted]), complemento([with, 'NICD1'])].
[sujeto(['Overexpression', of, 'galectin-3']), verbo([increased]), complemento([tumor, burden, in, 'A2780', ovarian, cancer, xenografted, mice])].
[sujeto(['Increased', expression, of, 'galectin-3', was, detected, in, advanced, 'stages,', compared, to, stage, 1, or, 2, in, ovarian, cancer, 'patients,']), verbo([suggesting]), complemento([that, 'galectin-3', supports, stemness, of, these, cells])].
[sujeto(['Based', on, these, 'results,', we]), verbo([suggest]), complemento([that, targeting, 'galectin-3', may, be, a, potent, approach, for, improving, ovarian, cancer, therapy])].
[sujeto(['TGFBI']), verbo([has]), complemento([been, shown, to, sensitize, ovarian, cancer, cells, to, the, cytotoxic, effects, of, paclitaxel, via, an, integrin, 'receptor-mediated', mechanism, that, modulates, microtubule, stability])].
[sujeto(['We', determined, that, suppression, of, 'SPARC', expression, by, shRNA]), verbo([decreased]), complemento([the, deposition, of, 'TGFBI', in, 'mesothelial-derived', 'ECM,', without, affecting, its, overall, protein, expression, or, secretion])].
[sujeto(['Conversely,', overexpression, of, 'SPARC']), verbo([increased]), complemento(['TGFBI', deposition])].
[sujeto(['A', 'SPARC-YFP', fusion, construct]), verbo([expressed]), complemento([by, the, 'Met5a', cell, line, 'co-localized', with, 'TGFBI', in, the, 'cell-derived', 'ECM'])].
[sujeto(['Interestingly,', in, vitro, produced, 'SPARC', was, capable, of, precipitating, 'TGFBI', from, cell, lysates, dependent, on, an, intact, 'SPARC', 'carboxy-terminus', with, in, vitro]), verbo([binding]), complemento([assays, verifying, a, direct, interaction])].
[sujeto(['The', last, 37, amino, acids, of, 'SPARC', were, shown, to, be]), verbo([required]), complemento([for, the, 'TGFBI', interaction, while, expression, of, a, 'SPARC-YFP', construct, lacking, this, region, '(', aa, 1, -, 256, ')', did, not, interact, and, 'co-localize', with, 'TGFBI', in, the, 'ECM'])].
[sujeto(['Furthermore,', ovarian, cancer, cells]), verbo([have]), complemento([a, reduced, motility, and, decreased, response, to, the, chemotherapeutic, agent, paclitaxel, when, plated, on, 'ECM', derived, from, mesothelial, cells, lacking, 'SPARC', compared, to, control, 'mesothelial-derived', 'ECM'])].
[sujeto(['In', 'conclusion,', 'SPARC']), verbo([regulates]), complemento([the, fibrillar, 'ECM', deposition, of, 'TGFBI', through, a, novel, 'interaction,', subsequently, influencing, cancer, cell, behavior])].
[sujeto(['Peripheral', arterial, 'disease,', particularly, critical, limb, 'ischemia,', is, an, area, with, urgent, need, for, optimized, therapies, 'because,', to, 'date,', vascular, interventions, often]), verbo([have]), complemento([limited, life, spans])].
[sujeto(['Antiproliferative', drugs, administered, via, 'DCBs', or, 'drug-eluting', stents, are, able, to]), verbo([suppress]), complemento([neointimal, 'hyperplasia,', the, main, cause, of, restenosis])].
[sujeto(['Although', the, mechanical, abrasion, of, calcium, via, atherectomy, or, laser, ablation, showed, favorable, periprocedural, 'results,', the, 'long-term', impact, on, restenosis, and, clinical, outcome]), verbo([has]), complemento([to, be, demonstrated])].
[sujeto(['Major', advantages, of, the, 'DCBs', are, the, rapid, delivery, of, drug, at, uniform, concentrations, with, a, single, 'dose,', their, efficacy, in, areas, wherein, stents]), verbo([have]), complemento([been, contraindicated, until, now, '(', 'ie,', 'bifurcation,', ostial, 'lesions),', and, in, leaving, no, stent, scaffold, behind])].
[sujeto(['Despite', a, better, understanding, of, the, genomic, landscape, and, the, importance, of, the, tumor, 'microenvironment,', we]), verbo([have]), complemento([not, made, a, seismic, shift, in, the, overall, survival, for, this, disease])].
[sujeto(['The', thrust, of, ongoing, efforts, can, be, divided, into, broad, 'categories,', including, exploiting, the, 'DNA', damage, repair, 'phenotype,', stroma, and, specific, 'pathway-targeting', 'agents,', and]), verbo([enhancing]), complemento([immune, destruction, of, pancreatic, ductal, adenocarcinoma])].
[sujeto(['To', investigate, the, efficacy, of, using, surgical, glove, '(', 'SG)', compression, therapy, to]), verbo([prevent]), complemento([nanoparticle, 'albumin-bound', paclitaxel, '(', 'nab-PTX)-induced', peripheral, neuropathy])].
[sujeto(['SG', compression, therapy, significantly]), verbo([decreased]), complemento([the, temperature, of, each, fingertip, by, 1.6, -, 2.2, &, 'nbsp;°C', as, compared, with, the, temperature, before, chemotherapy, '(', 'p < 0'])].
[sujeto(['The', 'nab-PTX', exposure, to, the, peripheral, nerve, may, be]), verbo([decreased]), complemento([because, the, 'SG', decreases, microvascular, flow, to, the, fingertip])].
[sujeto(['Thirty-two']), verbo([target]), complemento([and, twenty, 'non-target', metastatic, brain, lesions, were, analyzed])].
[sujeto(['The', median, tumor, reduction, by, 'MRI', after, cycle, 1, was, -, 17.5, &, 'nbsp;%', '(', 'n = 10', 'patients,', 'lower,', upper, 'quartiles:', -, 25.5, ',', -, 4.8, &, 'nbsp;%)', in]), verbo([target]), complemento([lesion, size, compared, with, baseline])].
[sujeto(['Fifteen', of, 'twenty-nine']), verbo([target]), complemento([lesions, '(', 52, &, 'nbsp;%)', and, 12, /, 20, nontarget, lesions, '(', 60, &, 'nbsp;%)', showed, a, '≥20 %', decrease, 'post-therapy', in, 'FLT-PET', 'SUV', change, '(', odds, ratio, 0.71, ',', 95, &, 'nbsp;%', 'CI:', 0.19, ',', 2.61, ')'])].
[sujeto(['Gastric', cancer, is, the, third, most, common]), verbo([cause]), complemento([of, cancer, mortality, 'worldwide,', and, paclitaxel, '(', 'PTX)', is, one, of, the, most, widely, used, traditional, drugs, in, gastric, cancer, therapy])].
[sujeto(['Jesridonin', '(', 'JD),', and, 'low-dose', 'PTX', for, gastric, cancer, cells, '(', 'MKN45)', to, investigate, whether, the, 'anti-tumour', activity, of, 'low-dose', 'PTX', could, be]), verbo([enhanced]), complemento([when, combined, with, 'JD'])].
[sujeto(['The', apoptotic, mechanism]), verbo([induced]), complemento([by, 'JD', plus, 'PTX', revealed, that, the, combination, therapy, synergistically, activated, the, mitochondrial, pathway])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, 'JD', enhances, the, 'anti-tumour', effect, of, 'low-dose', 'PTX', on, gastric, carcinoma, cancer, cells, in, both, vitro, and, in, 'vivo,', accompanied, by, activation, of, the, mitochondrial, 'pathway,', which, may, present, a, more, effective, therapeutic, strategy, in, gastric, cancer, treatment])].
[sujeto(['The', microtubule, cytoskeleton, is, composed, of, 'α-tubulin', and, 'β-tubulin', 'heterodimers,', and, it, serves, to]), verbo([regulate]), complemento([the, 'shape,', 'motility,', and, division, of, a, cell])].
[sujeto(['Post-translational', modifications, including, acetylation, are, closely]), verbo([associated]), complemento([with, the, functional, aspects, of, the, 'microtubule,', involving, in, a, number, of, pathological, diseases])].
[sujeto(['However,', the, role, of, microtubule, acetylation, in, acute, kidney, injury, '(', 'AKI)', and, progression, of, 'AKI', to, chronic, kidney, disease]), verbo([have]), complemento([yet, to, be, understood])].
[sujeto(['In', this, 'study,', 'ischemia/reperfusion', '(', 'I/R),', a, major]), verbo([cause]), complemento([of, 'AKI,', resulted, in, deacetylation, of, the, microtubules, with, a, decrease, in, 'α-tubulin', acetyltransferase, 1, '(', 'α-TAT1)'])].
[sujeto(['Paclitaxel', '(', 'taxol),', an, agent, that, stabilizes, microtubules, by, tubulin, 'acetylation,', treatment, during, the, recovery, phase, following, 'I/R', injury]), verbo([inhibited]), complemento([tubular, cell, 'proliferation,', impaired, renal, functional, 'recovery,', and, worsened, fibrosis])].
[sujeto(['Taxol']), verbo([induced]), complemento(['α-tubulin', acetylation, and, 'post-I/R', cell, cycle, arrest])].
[sujeto(['Our', studies]), verbo([have]), complemento([demonstrated, for, the, first, time, that, 'I/R', induced, deacetylation, of, the, 'microtubules,', and, that, inhibition, of, microtubule, dynamics, retarded, repair, of, injured, tubular, epithelial, cells, leading, to, an, acceleration, of, fibrosis])].
[sujeto(['This']), verbo([suggests]), complemento([that, microtubule, dynamics, plays, an, important, role, in, the, processes, of, repair, and, fibrosis, after, 'AKI'])].
[sujeto(['One', of, the, 'paralogues,', 'Kin13Ap,', localizes, to, the, nuclei, and, is, essential, for]), verbo([nuclear]), complemento([divisions])].
[sujeto(['Thus', 'kinesin-13', positively]), verbo([regulates]), complemento([the, axoneme, 'length,', influences, the, properties, of, ciliary, 'tubulin,', and, likely, 'indirectly,', through, its, effects, on, the, axonemal, 'microtubules,', affects, the, ciliary, 'dynein-dependent', motility])].
[sujeto(['Paclitaxel/cisplatin', combination, is, the, standard, chemotherapeutic, treatment, for, this, 'disease,', although, some, patients, do, not]), verbo([respond]), complemento([to, therapy])].
[sujeto(['Sequence', analysis, did, not]), verbo([find]), complemento([any, mutation, in, 'TUBB', exon, 4])].
[sujeto(['Microtubule', plays, many, different, essential, roles, in, the, process, of, tumorigenesis, in, many, 'eukaryotes,', and]), verbo([targeting]), complemento([mitotic, progression, by, disturbing, microtubule, dynamics, is, used, as, a, common, strategy, for, cancer, treatment])].
[sujeto(['Microtubule-targeted', 'drugs,', including, paclitaxel, and, 'Vinca', 'alkaloids,', were, previously, considered, to, work, primarily, by]), verbo([increasing]), complemento([or, decreasing, the, cellular, microtubule, mass])].
[sujeto(['The', 'tubulin/microtubule', 'system,', which, is, an, integral, component, of, the, 'cytoskeleton,', is, a, therapeutic]), verbo([target]), complemento([for, prostate, cancer])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([a, novel, synthetic, 'compound,', 8, -, 'fluoro-N-phenylacetyl-1,', 3, ',', 4, ',', 9, -, 'tetrahydro-β-carboline', '(', 'LG308),', which, disrupted, the, microtubule, organization, via, inhibiting, the, polymerization, of, microtubule, in, 'PC-3M', and, 'LNCaP', prostate, cancer, cell, lines])].
[sujeto(['Further', study, proved, that, 'LG308']), verbo([induced]), complemento([mitotic, phase, arrest, and, inhibited, 'G2/M', progression, significantly, in, 'LNCaP', and, 'PC-3M', cell, lines, in, a, 'dose-dependent', 'manner,', and, these, were, associated, with, the, upregulation, of, cyclin, 'B1', and, mitotic, marker, 'MPM-2', and, the, dephosphorylation, of, cdc2])].
[sujeto(['Besides,', the, cell, proliferation, and, colony, formation, of, 'PC-3M', and, 'LNCaP', cells, were, effectively]), verbo([inhibited]), complemento([by, 'LG308'])].
[sujeto(['Furthermore,', 'LG308']), verbo([induced]), complemento([apoptosis, and, cell, death, in, 'PC-3M', and, 'LNCaP', cell, lines, in, vitro])].
[sujeto(['In', 'vivo,', 'LG308', dramatically]), verbo([suppressed]), complemento([the, growth, and, metastasis, of, prostate, cancer, in, both, xenograft, and, orthotopic, models])].
[sujeto(['Polymeric', nanomicelle, strategies]), verbo([have]), complemento([been, pursued, to, overcome, these, 'issues;', however, current, formulations, are, often, limited, by, low, drug, loading, and, poor, serum, stability])].
[sujeto(['To', achieve, a, drug, delivery, system, that, addresses, these, 'issues,', 'poly(D,L-lactide-co-2-methyl-2-carboxytrimethylene', 'carbonate)-g-poly(ethylene', 'glycol)', was, covalently, modified, with, the, taxol]), verbo([binding]), complemento([peptide, '–', a, peptide, from, the, 'β-tubulin-taxane', binding, site])].
[sujeto(['Unlike', many, formulations, with, high, drug, 'loading,', these, nanomicelles, were, stable, in, serum, for, up, to, 24, h, and]), verbo([maintained]), complemento([docetaxel, cytotoxicity])].
[sujeto(['By', incorporating, the, taxane]), verbo([binding]), complemento([peptide, into, the, polymer, 'chemistry,', a, new, twist, was, applied, to, an, old, 'problem,', which, is, broadly, applicable, to, other, polymeric, micelle, systems, and, 'drug-peptide', combinations, in, general])].
[sujeto(['KRAS', is, the, most, commonly, mutated, oncogene, in, human, cancers, and, is]), verbo([associated]), complemento([with, poor, prognosis, and, drug, resistance])].
[sujeto(['Let-7', is, a, family, of, tumor, suppressor, microRNAs, that, are, frequently]), verbo([suppressed]), complemento([in, solid, 'tumors,', where, 'KRAS', mutations, are, highly, prevalent])].
[sujeto(['We']), verbo([found]), complemento([that, 'let-7b', repletion, selectively, sensitized, 'KRAS', mutant, tumor, cells, to, the, cytotoxicity, of, paclitaxel, and, gemcitabine])].
[sujeto(['Combination', of, 'let-7b', mimic, with, paclitaxel, or, gemcitabine, diminished, 'MEK/ERK', and, 'PI3K/AKT', signaling, 'concurrently,']), verbo([triggered]), complemento([the, onset, of, 'apoptosis,', and, reverted, the, 'epithelial-mesenchymal', transition, in, 'KRAS', mutant, tumor, cells])].
[sujeto(['In', 'addition,', 'let-7b', repletion, downregulated, the, expression, of, 'β-tubulin', 'III', and, ribonucleotide, reductase, subunit, 'M2,', two, proteins, known, to]), verbo([mediate]), complemento([tumor, resistance, to, paclitaxel, and, 'gemcitabine,', respectively])].
[sujeto(['Recent', studies]), verbo([have]), complemento([demonstrated, that, paclitaxel, might, inhibit, renal, fibrosis])].
[sujeto(['The', results, showed, that, paclitaxel, treatment, resulted, in, a, 'dose-', and, 'time-dependent']), verbo([decrease]), complemento([in, 'tyrosine-phosphorylated', 'STAT3,', and, inhibited, the, expression, of, 'fibronectin,', 'alpha-smooth', muscle, actin, '(', 'α-SMA),', and, collagen, 'I', in, cultured, 'NRK-49F', cells])].
[sujeto(['S3I-201,', an, 'STAT3', 'inhibitor,', also]), verbo([suppressed]), complemento([the, expression, of, 'fibronectin,', 'α-SMA,', and, collagen, 'I', in, cultured, 'NRK-49F', cells])].
[sujeto(['Mechanistically,', paclitaxel, treatment, blocked, the, 'STAT3', activity, by, disrupting, the, association, of, 'STAT3', with, tubulin, and]), verbo([inhibiting]), complemento(['STAT3', nucleus, translocation])].
[sujeto(['Furthermore,', paclitaxel, also, ameliorated, renal, fibrosis, by, 'down-regulating', the, expression, of, 'fibronectin,', 'α-SMA,', and, collagen, 'I,', and]), verbo([suppressed]), complemento([the, infiltration, of, macrophages, and, production, of, 'TNF-α,', 'IL-1β,', 'TGF-β,', and, 'ICAM-1', '(', intercellular, adhesion, molecule, 1, ')', by, inhibition, of, 'STAT3', activity, in, obstructive, nephropathy])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, paclitaxel, may, block, the, 'STAT3', activity, by, disrupting, the, association, of, 'STAT3', with, tubulin, and, inhibiting, 'STAT3', nucleus, 'translocation,', consequently, leading, to, the, suppression, of, renal, interstitial, fibroblast, activation, and, the, development, of, renal, 'fibrosis,', and, inhibition, of, proinflammatory, cytokine, production])].
[sujeto(['Inhibition', of, 'mTOR-kinase', by, everolimus, only, minimally, reduced, the, proliferative, activity, of, β, 'tubulin-mutated', lung, adenocarcinoma, cells, alone, and, in, combination, with, the, 'MSA', 'patupilone,', but, everolimus]), verbo([inhibited]), complemento([expression, and, secretion, of, vascular, endothelial, growth, factor, '(', 'VEGF)', from, these, cells])].
[sujeto(['Treatment', combination, also, strongly, reduced, microvessel, 'density,', corroborating, the, relevance, of, 'VEGF']), verbo([targeting]), complemento([for, the, known, 'antivasculature-directed', potency, of, 'MSA', alone, in, 'MSA-sensitive', tumor, models])].
[sujeto(['MT', structure, and, function, must, be]), verbo([maintained]), complemento([throughout, the, cell, cycle, to, ensure, proper, execution, of, mitosis, and, cellular, homeostasis])].
[sujeto(['We']), verbo([have]), complemento([previously, demonstrated, that, the, 'HPV16', 'E6', oncoprotein, binds, 'PTPN13', and, leads, to, its, degradation])].
[sujeto(['Here', we]), verbo([report]), complemento([that, 'EphrinB1', 'co-localizes', with, 'MTs', during, all, phases, of, the, cell, cycle])].
[sujeto(['Specifically,', a, 'cleaved,', unphosphorylated, 'EphrinB1', fragment, directly]), verbo([binds]), complemento(['tubulin,', while, its, phosphorylated, form, lacks, 'MT', binding, capacity])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'EphrinB1', is, a, novel, microtubule, associated, protein, '(', 'MAP)'])].
[sujeto(['We', speculate, that, this, reflects, 'PTPN13\'s', modulation, of, 'EphrinB1', phosphorylation, and]), verbo([suggest]), complemento([that, 'EphrinB1', is, an, important, contributor, to, taxane, 'sensitivity/resistance', phenotypes, in, epithelial, cancers])].
[sujeto(['The', 'MCF-7/CTAX-P', variant, did, not]), verbo([express]), complemento(['ABCB1,', nor, did, it, efflux, 'rhodamine-123,', 'BODIPY-labeled', 'paclitaxel,', and, '[', '(', 3, ')', 'H]-docetaxel'])].
[sujeto(['These', cells, are, hypersensitive, to, depolymerizing, agents, '(', vinca, alkaloids, and, 'colchicine),']), verbo([have]), complemento([reduced, baseline, levels, of, stabilized, 'microtubules,', and, impaired, tubulin, polymerization, in, response, to, taxanes, '(', cabazitaxel, or, 'docetaxel)', relative, to, 'MCF-7', parental, cells])].
[sujeto(['Decreased', 'BRCA1', and, altered, 'epithelial-mesenchymal', transition, '(', 'EMT)', markers, are, also]), verbo([associated]), complemento([with, cabazitaxel, resistance, in, these, 'MCF-7', 'variants,', and, may, serve, as, predictive, biomarkers, for, its, activity, in, the, clinical, setting])].
[sujeto(['In', 'summary,', cabazitaxel, resistance, mechanisms, include, 'MDR', '(', although, at, a, lower, level, than, paclitaxel, and, 'docetaxel),', and, alterations, in, microtubule, 'dynamicity,', as, manifested, by, higher, expression, of, 'TUBB3,']), verbo([decreased]), complemento(['BRCA1,', and, by, the, induction, of, 'EMT'])].
[sujeto(['The', anticancer, drug, paclitaxel, '(', 'TXL)', that, polymerizes, microtubules, is]), verbo([associated]), complemento([with, arrhythmias, and, sinus, node, dysfunction])].
[sujeto(['Calcium/calmodulin-dependent', protein, kinase, 'II', '(', 'CaMKII)', can, be]), verbo([activated]), complemento([by, 'β-adrenergic', stimulation, and, regulates, 'INa', gating])].
[sujeto(['In', 'wild-type', mouse, 'myocytes,', the, addition, of, 'ISO', '(', 1, 'µmol/L)', resulted, in]), verbo([increased]), complemento(['CaMKII', 'auto-phosphorylation', '(', western, 'blotting)'])].
[sujeto(['This']), verbo([increase]), complemento([was, completely, abolished, after, 'pre-treatment', with, 'TXL', '(', 100, 'µmol/L,', 1.5, 'h)'])].
[sujeto(['TXL']), verbo([inhibited]), complemento([the, 'ISO-induced', 'β-arrestin', translocation])].
[sujeto(['Interestingly,', both, knockdown, of, 'β-arrestin2', expression, using, small, interfering, 'RNA', and, inhibition, of, exchange, protein, directly]), verbo([activated]), complemento([by, cAMP, '(', 'Epac)', blocked, the, 'ISO-induced', 'CaMKII', 'auto-phosphorylation', similar, to, 'TXL'])].
[sujeto(['ISO', stimulation, failed, to]), verbo([induce]), complemento(['CaMKII-dependent', enhancement, of, late, 'INa', and, 'Na', channel, inactivation, '(', negative, voltage, shift, in, 'steady-state', activation, and, enhanced, intermediate, 'inactivation)', after, 'pre-incubation', with, 'TXL'])].
[sujeto(['Consistent', with, 'this,', 'TXL', also]), verbo([inhibited]), complemento(['ISO-induced', 'CaMKII-specific', 'Na', channel, phosphorylation, '(', at, serine, 571, of, 'NaV1'])].
[sujeto(['This', may, be, important, for, patients, receiving, 'TXL', 'treatments,', but, also, relevant, for, conditions, of]), verbo([increased]), complemento(['CaMKII', expression, and, enhanced, 'β-adrenergic', stimulation, like, in, heart, failure])].
[sujeto(['A', significant, positive, correlation, was]), verbo([found]), complemento([between, class, 'III', 'β-tubulin', and, 'MAPT', expression, at, mRNA, and, protein, levels, '(', 'mRNA:', 'P', =, 0.037, ;, 'protein:', 'P', =, 0.001, ')'])].
[sujeto(['Our', data, indicate, that, 'IC138', and, 'IC140']), verbo([bind]), complemento([directly, to, microtubules])].
[sujeto(['Mass-spectrometry', analysis, of, the, crosslinked, product, identified, both, 'α-', and, 'β-tubulin', as, the, 'IC138', and, 'IC140']), verbo([binding]), complemento([partners])].
[sujeto(['This', was, further, confirmed, by, crosslinking, experiments, carried, out, on, purified, 'I1', fractions]), verbo([bound]), complemento([to, 'Taxol-stabilized', microtubules])].
[sujeto(['Our', studies, support, previous, findings, that, intermediate, chains, play, critical, roles, in, the, 'assembly,', axonemal]), verbo([targeting]), complemento([and, regulation, of, the, 'I1', dynein, complex])].
[sujeto(['CCP5', was, proposed, to, selectively, cleave, the, branch, point, of, glutamylated, 'tubulin,', based, on, studies]), verbo([involving]), complemento([overexpression, of, 'CCP5', in, cell, lines, and, detection, of, tubulin, forms, with, antisera])].
[sujeto(['Tumor', 'resistance,', especially, that]), verbo([mediated]), complemento([by, 'P-glycoprotein', '(', 'P-gp)', and, 'β-III', 'tubulin,', is, a, major, obstacle, to, the, efficacy, of, most, 'microtubule-targeting', anticancer, drugs, in, clinics])].
[sujeto([siRNA, transfection, experiments, also, confirmed, that, 'Yg-3-46a', can, circumvent, 'P-gp', and, 'β-III', tubulin]), verbo([mediated]), complemento([drug, resistance])].
[sujeto(['In', 'addition,', its, cytotoxicity, was, lower, than, that, of, paclitaxel, in, the, human, mammary, cell, line, 'HBL-100', and, the, human, 'telomerase-immortalized', retinal, pigment, epithelium, cell, line, '(', 'hTERT-RPE1),']), verbo([suggesting]), complemento([a, better, safety, margin, for, this, compound, in, vivo])].
[sujeto(['It', exhibited, more, potent, microtubule, polymerization, ability, than, paclitaxel, in, 'vitro,', and, also]), verbo([induced]), complemento(['G2/M', phase, arrest, in, 'MCF-7/ADR', cells])].
[sujeto(['Moreover,', it, was]), verbo([found]), complemento([to, induce, apoptosis, in, 'MCF-7/ADR', cells, through, the, 'caspase-dependent', 'death-receptor', pathway, by, enhancing, levels, of, 'Fas', and, 'FasL,', and, activating, 'caspase-8', and, 3])].
[sujeto(['Yg-3-46a', was]), verbo([found]), complemento([to, be, a, poorer, substrate, of, 'P-gp', compared, to, 'paclitaxel,', in, both, binding, and, 'ATPase', 'experiments,', which, is, likely, responsible, for, its, ability, to, circumvent, 'P-gp', mediated, multidrug, resistance, '(', 'MDR)'])].
[sujeto(['All', of, these, results, indicate, that, 'Yg-3-46a', is, a, novel, 'microtubule-stabilizing', agent, that]), verbo([has]), complemento([the, potential, to, evade, drug, resistance, mediated, by, 'P-gp', and, 'β-III', tubulin, overexpression])].
[sujeto(['To', investigate, the, effects, of, 'miRNA-mediated', 'down-regulation', of, the, 'Bcl-2', gene, on, the, chemotherapeutic, sensitivities, and, mRNA, transcriptions, of, sensitivity]), verbo([associated]), complemento([genes, in, human, lung, adenocarcinoma, cell, line, 'A549', 'cells,', and, therefore, to, provide, experimental, data, for, improving, the, chemotherapeutic, effects, on, 'non-small', cell, lung, cancer, '(', 'NSCLC)'])].
[sujeto(['The', miRNA, recombinant, plasmid]), verbo([targeting]), complemento([to, human, 'Bcl-2', gene, was, 'designed,', synthesized, and, stably, transferred, into, 'A549', cells, by, lipofectin, technique, as, the, experiment, group])].
[sujeto(['The', transcription, of, 'Bcl-2', mRNA, dramatically]), verbo([decreased]), complemento([by, 98.1, '%', in, the, experiment, group, '(', 'RQ', =, 0.002, ±, 0.001, ')', compared, to, that, in, the, negative, control, group, '(', 'RQ', =, 0.104, ±, 0.003, ')', by, 'real-time', 'PCR', '(', t, =, 98.7, ',', 'P', &, 'lt;', 0.05, ')', ;, and, the, protein, level, of, 'Bcl-2', in, the, experiment, group, decreased, by, 57.6, '%', by, 'Western', blot, '(', t, =, 7.66, ',', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['The', cell, cycle, profile, showed, that, the, low, expression, of, 'Bcl-2', gene]), verbo([led]), complemento([to, 'A549', cell, cycle, arrest, at, 'G1-phase'])].
[sujeto(['The', sensitivities, of, 'A549', cells, to, 'etoposide,', 'cisplatin,', 'paclitaxel,', and, navelbine, were, significantly]), verbo([enhanced]), complemento(['[', 'IC₅₀', values, in, the, experiment, group, were, '(', 107.3, ±, 0.1, ')', 'mg/L,', '(', 7.7, ±, 0.6, ')', 'mg/L,', '(', 11.5, ±, 1.9, ')', 'mg/L', and, '(', 10.8, ±, 1.6, ')', 'mg/L;', 'IC₅₀', values, in, the, negative, control, group, were, '(', 145.8, ±, 0.1, ')', 'mg/L,', '(', 60.7, ±, 1.4, ')', 'mg/L,', '(', 80.6, ±, 1.7, ')', 'mg/L', and, '(', 20.6, ±, 1.7, ')', 'mg/L],', the, respective, t, values, being, 655.33, ',', 108.04, ',', 82.16, and, 12.48, ',', all, 'P', &, 'lt;', 0.05])].
[sujeto(['The', mRNA, level, of, 'ERCC1,', 'TYMS,', and, 'TOP2α', genes, in, the, experiment, group]), verbo([decreased]), complemento([by, 99.6, '%', ',', 92.9, '%', and, 96.1, '%', 'respectively,', but, 'Class', 'III', 'β-tubulin', mRNA, increased, by, 122, '%', compared, to, the, negative, control, group, '(', 1.154, ±, 0.008, ',', 0.52, ±, 0.009, ')', ',', the, respective, t, values, being, 689.79, ',', 689.37, ',', 768.04, and, 160.07, ',', all, 'P', &, 'lt;', 0.05])].
[sujeto(['Targeting', to]), verbo([inhibit]), complemento([antiapoptotic, mitochondrial, gene, 'Bcl-2', expression, in, 'A549', cells, specifically, decreased, the, mRNA, of, 'ERCC1,', 'TYMS,', and, 'TOP2α', 'genes,', and, significantly, increased, the, sensitivities, of, 'A549', cells, to, chemotherapeutic, agents, such, as, 'etoposide,', 'cisplatin,', paclitaxel, and, navelbine])].
[sujeto(['BPR0L075']), verbo([induces]), complemento([cell, death, by, a, dual, mechanism, in, parental, and, 'paclitaxel-resistant', ovarian, cancer, cells])].
[sujeto(['In', the, parental, cells, '(', 'OVCAR-3', and, 'SKOV-3),', 'BPR0L075']), verbo([induced]), complemento(['apoptosis,', evidenced, by, 'poly(ADP-ribose)', polymerase, '(', 'PARP)', cleavage, and, 'DNA', ladder, formation])].
[sujeto(['BPR0L075']), verbo([induced]), complemento([cell, death, in, 'paclitaxel-resistant', ovarian, cancer, cells, '(', 'OVCAR-3-TR', and, 'SKOV-3-TR)', is, primarily, due, to, mitotic, 'catastrophe,', evidenced, by, formation, of, 'giant,', multinucleated, cells, and, absence, of, 'PARP', cleavage])].
[sujeto(['Immunoblotting', analysis, shows, that, 'BPR0L075', treatment]), verbo([induced]), complemento(['up-regulation', of, cyclin, 'B1,', 'BubR1,', 'MPM-2,', and, survivin, protein, levels, and, 'Bcl-XL', phosphorylation, in, parental, 'cells;', 'however,', in, resistant, 'cells,', the, endogenous, expressions, of, 'BubR1', and, survivin, were, 'depleted,', 'BPR0L075', treatment, failed, to, induce, 'MPM-2', expression, and, phosphorylation, of, 'Bcl-XL'])].
[sujeto(['BPR0L075']), verbo([induced]), complemento([cell, death, in, both, parental, and, 'paclitaxel-resistant', ovarian, cancer, cells, proceed, through, 'caspase-3', independent, mechanisms])].
[sujeto(['In', 'conclusion,', 'BPR0L075', displays, potent, cytotoxic, effects, in, ovarian, cancer, cells, with, a, potential, to, overcome, paclitaxel, resistance, by, bypassing, efflux, transporters, and]), verbo([inducing]), complemento([mitotic, catastrophe])].
[sujeto(['BPR0L075', represents, a, novel, microtubule, therapeutic, to, overcome, multidrug, resistance, and]), verbo([trigger]), complemento([alternative, cell, death, by, mitotic, catastrophe, in, ovarian, cancer, cells, that, are, 'apoptosis-resistant'])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, myofibroblast, differentiation, is, mediated, by, the, activity, of, serum, response, factor, '(', 'SRF),', which, is, tightly, controlled, by, the, actin, polymerization, state])].
[sujeto(['In', this, 'study,', we, investigated, the, role, of, the, microtubule, cytoskeleton, in]), verbo([modulating]), complemento([myofibroblast, phenotype])].
[sujeto(['These', effects, of, colchicine, were, independent, of, 'Smad', signaling, but, were]), verbo([mediated]), complemento([by, 'Rho', signaling, and, 'SRF,', as, they, were, attenuated, by, the, 'Rho', kinase, 'inhibitor,', 'Y27632,', or, by, the, 'SRF', 'inhibitor,', 'CCG-1423'])].
[sujeto(['Paclitaxel', had, no, effect, on, 'TGF-β-induced', 'Smad', activation, and, 'Smad-dependent', gene, transcription, but]), verbo([inhibited]), complemento([actin, 'polymerization,', nuclear, accumulation, of, megakaryoblastic, 'leukemia-1', 'protein,', and, 'SRF', activation])].
[sujeto(['The', 'microtubule-associated', 'formin,', 'mDIA2,', localized, to, actin, stress, fibers, upon, treatment, with, 'TGF-β,', and, paclitaxel]), verbo([prevented]), complemento([this, localization])].
[sujeto(['Treatment', with, the, formin, 'inhibitor,', 'SMI', formin, homology, 2, 'domain,']), verbo([inhibited]), complemento([stress, fiber, formation, and, myofibroblast, differentiation, induced, by, 'TGF-β,', without, affecting, 'Smad-phosphorylation', or, microtubule, polymerization])].
[sujeto(['Together,', these, data]), verbo([suggest]), complemento([that, '(', 'a)', 'TGF-β', promotes, association, of, mDia2, with, actin, stress, 'fibers,', which, further, drives, stress, fiber, formation, and, myofibroblast, 'differentiation,', and, '(', 'b)', microtubule, polymerization, state, controls, myofibroblast, differentiation, through, the, regulation, of, mDia2, localization])].
[sujeto(['Microtubules']), verbo([have]), complemento([been, known, for, decades, to, be, basic, elements, of, the, cytoskeleton])].
[sujeto(['More', 'recently,', in, vitro, studies]), verbo([have]), complemento([implicated, microtubules, as, signaling, molecules, 'that,', through, changes, in, their, 'stability,', have, the, potential, to, trigger, growth, of, axons, and, dendrites, in, developing, neurons])].
[sujeto(['In', this, 'study,', we, show, that, specific, mutations, in, the, 'Caenorhabditis', elegans, 'mec-7/β-tubulin', gene]), verbo([cause]), complemento([ectopic, axon, formation, in, mechanosensory, neurons, in, vivo])].
[sujeto(['In', 'mec-7', 'mutants,', the, 'ALM', mechanosensory, neuron, forms, a, long, ectopic, neurite, that, extends, 'posteriorly,', a, phenotype, that, can, be, mimicked, in, 'wild-type', worms, with, a, 'microtubule-stabilizing', drug, '(', 'paclitaxel),', and]), verbo([suppressed]), complemento([by, mutations, in, 'unc-33/CRMP2', and, the, 'kinesin-related', 'gene,', 'vab-8'])].
[sujeto(['Our', results, also]), verbo([reveal]), complemento([that, these, ectopic, neurites, contain, 'RAB-3,', a, marker, for, presynaptic, 'loci,', suggesting, that, they, have, 'axon-like', properties])].
[sujeto(['Interestingly,', in, contrast, with, the, excessive, axonal, growth, observed, during, 'development,', 'mec-7', mutants, are]), verbo([inhibited]), complemento([in, axonal, regrowth, and, remodeling, following, axonal, injury])].
[sujeto(['Together', our, results]), verbo([suggest]), complemento([that, 'MEC-7/β-tubulin', integrity, is, necessary, for, the, correct, number, of, neurites, a, neuron, generates, in, vivo, and, for, the, capacity, of, an, axon, to, regenerate])].
[sujeto(['The', oocyte, meiotic, spindle, is, comprised, of, microtubules, '(', 'MT)', that]), verbo([bind]), complemento([chromatin, and, regulate, both, metaphase, plate, formation, and, karyokinesis, during, meiotic, 'maturation;', 'however,', little, information, is, known, about, their, role, in, meiosis, reinitiation])].
[sujeto(['This', study, was, conducted, to, determine, if, microtubule, integrity, is]), verbo([required]), complemento([for, meiotic, induction, and, to, ascertain, how, it, affects, activation, of, 'AMP-activated', protein, kinase, '(', 'AMPK),', an, important, participant, in, the, meiotic, induction, process])].
[sujeto(['Treatment', with, 'microtubule-disrupting', agents, nocodazole, and, vinblastine]), verbo([suppressed]), complemento([meiotic, resumption, in, a, 'dose-dependent', manner, in, both, arrested, cumulus, 'cell-enclosed', oocytes, '(', 'CEO)', stimulated, with, 'follicle-stimulating', hormone, '(', 'FSH)', and, arrested, denuded, oocytes, '(', 'DO)', stimulated, with, the, 'AMPK', 'activator,', 5, -, 'aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside', '(', 'AICAR)'])].
[sujeto(['Treatment', with, the, 'MT', stabilizer, paclitaxel, also]), verbo([suppressed]), complemento([meiotic, induction])].
[sujeto(['Treatment', with, nocodazole]), verbo([led]), complemento([to, disruption, of, proper, spindle, pole, localization, of, active, 'AMPK,', while, paclitaxel, induced, excessive, polymerization, of, spindle, 'MT', and, formation, of, ectopic, asters, with, accentuated, 'AMPK', colocalization])].
[sujeto(['Although', stimulation, of, 'AMPK']), verbo([increased]), complemento([the, rate, of, germinal, vesicle, breakdown, '(', 'GVB),', spindle, formation, and, polar, body, '(', 'PB)', 'extrusion,', the, kinase, had, no, effect, on, peripheral, movement, of, the, spindle])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, the, 'meiosis-inducing', action, and, localization, of, 'AMPK', are, regulated, by, 'MT', spindle, integrity, during, mouse, oocyte, maturation])].
[sujeto(['Measurement', of, transport, kinetics, may]), verbo([provide]), complemento([a, sensitive, method, to, monitor, progression, of, neurodegeneration, and, treatment, effects])].
[sujeto(['Rotenone,', a, mitochondrial, complex, 'I', 'inhibitor,']), verbo([has]), complemento([been, used, to, generate, animal, and, cell, culture, models, of, 'Parkinson\'s', disease])].
[sujeto(['Recent', studies]), verbo([suggest]), complemento([that, microtubule, destabilization, causes, selective, dopaminergic, neuronal, loss])].
[sujeto(['Tau,', a, 'microtubule-associated', protein, and, substrate, for, 'GSK3β,']), verbo([has]), complemento([been, implicated, in, the, pathogenesis, of, tauopathies, such, as, 'Alzheimer\'s', disease])].
[sujeto(['Rotenone']), verbo([induced]), complemento([an, increase, in, phosphorylated, 'tau,', the, effect, of, which, was, attenuated, by, concomitant, treatment, with, 'SB216763'])].
[sujeto(['Rotenone', treatment, also]), verbo([decreased]), complemento([tau, expression, in, the, microtubule, fraction, and, increased, tau, expression, in, the, cytosol, fraction])].
[sujeto(['These', effects, were]), verbo([suppressed]), complemento([by, 'SB216763,', which, suggests, that, rotenone, reduces, the, capacity, of, tau, to, bind, microtubules])].
[sujeto(['Rotenone', treatment]), verbo([increased]), complemento([the, amount, of, free, tubulin, and, reduced, the, amount, of, polymerized, 'tubulin,', indicating, that, rotenone, destabilizes, microtubules])].
[sujeto(['Rotenone-induced', microtubule, destabilization, was]), verbo([suppressed]), complemento([by, 'SB216763', and, 'taxol,', a, microtubule, stabilizer])].
[sujeto(['Taxol']), verbo([prevented]), complemento(['rotenone-induced', cytotoxicity, and, morphological, changes])].
[sujeto(['Taken', 'together,', these, results]), verbo([suggest]), complemento([that, 'rotenone-induced', cytotoxicity, is, mediated, by, microtubule, destabilization, via, 'GSK3β', 'activation,', and, that, microtubule, destabilization, is, caused, by, reduction, in, the, binding, capacity, of, tau, to, 'microtubules,', which, is, a, result, of, tau, phosphorylation, via, 'GSK3β', activation])].
[sujeto(['The', efficacy, of, chemotherapy, is, hindered, by, both, tumor, heterogeneity, and, acquired, or, intrinsic, 'multi-', drug, resistance]), verbo([caused]), complemento([by, the, contribution, of, multidrug, resistance, proteins, and, 'stemness-associated', prosurvival, markers])].
[sujeto(['Therefore,']), verbo([targeting]), complemento(['multi-drug', resistant, cells, would, be, much, more, effective, against, cancer])].
[sujeto(['We']), verbo([found]), complemento([that, under, 'PPSS,', both, cell, lines, were, highly, resistant, to, 'Paclitaxel,', 'Colchicine,', 'Hydroxyurea,', 'Obatoclax,', 'Wortmannin', and, 'LY294002'])].
[sujeto(['Levels', of, several, proteins]), verbo([associated]), complemento([with, increased, stemness, such, as, 'Sox2,', 'MDR1,', 'ABCG2', and, 'Bcl-2', were, found, to, be, elevated, in, 'H460', cells, but, not, in, 'MCF-7', cells])].
[sujeto(['While', pharmacological, inhibition, of, either, 'MDR1,', 'ABCG2,', 'Bcl-2', with, 'Verapamil,', 'Sorafenib', or, 'Obatoclax', respectively]), verbo([decreased]), complemento([the, levels, of, their, target, proteins, under, routine, culture, conditions, as, 'expected,', such, inhibition, did, not, reverse, 'PX', resistance, in, 'PPSS', conditions])].
[sujeto(['Paradoxically,', treatment, with, inhibitors, in, 'serum-starved', conditions, produced, an, elevation, of, their, respective]), verbo([target]), complemento([proteins])].
[sujeto(['In', 'addition,', we]), verbo([found]), complemento([that, 'Digitoxin,', an, 'FDA', approved, drug, that, decrease, the, viability, of, cancer, cells, growing, under, 'PPSS,', downregulates, the, expression, of, 'Sox2,', 'MDR1,', 'phospho-', 'AKT,', 'Wnt5a/b', and, 'β-catenin'])].
[sujeto(['Our', data]), verbo([suggests]), complemento([that, 'PPSS-induced', chemoresistance, is, the, result, of, extensive, rewiring, of, intracellular, signaling, networks, and, that, 'multi-resistance', can, be, effectively, overcome, by, simultaneously, targeting, multiple, targets, of, the, rewired, network])].
[sujeto(['Furthermore,', our, 'PPSS', model]), verbo([provides]), complemento([a, simple, and, useful, tool, to, screen, drugs, for, their, ability, to, target, multiple, pathways, of, cancer, resistance])].
[sujeto(['The', correlation, of, point, mutations, in, class, 'III', 'β-tubulin', '(', 'TUBB3)', and, the, prominent, overexpression, of, 'ATP-binding', cassette, 'P-glycoprotein', '(', 'ABCB1),', a, multidrug, resistance, 'gene,']), verbo([have]), complemento([been, protruding, mechanisms, of, resistance, to, microtubule, disruptors, such, as, paclitaxel, '(', 'PTX)', for, many, cancers])].
[sujeto(['However,', the, precise, underlying, mechanism, of, the, rapid, onset, of, 'cross-resistance', to, an, array, of, structurally, and, functionally, unrelated, drugs, in, 'PTX-resistant', cancers]), verbo([has]), complemento([been, poorly, understood])].
[sujeto(['We']), verbo([found]), complemento([that, feedback, activation, of, 'TUBB3', can, be, triggered, through, the, 'FOXO3a-dependent', regulation, of, 'ABCB1,', which, resulted, in, the, accentuation, of, induced, 'PTX', resistance, and, encouraged, multiplicity, in, acquired, 'cross-resistance'])].
[sujeto(['FOXO3a-directed', regulation, of, 'P-glycoprotein', '(', 'P-gp)', function]), verbo([suggests]), complemento([that, control, of, 'ABCB1', involves, 'methylation-dependent', activation])].
[sujeto(['In', 'addition,', we]), verbo([found]), complemento([that, secretome, factors, from, 'PTX-resistant', cancer, cells, with, acquired, 'cross-resistance', support, a, 'P-gp-dependent', association, in, multidrug, resistance, '(', 'MDR)', 'development,', which, assisted, the, 'FOXO3a-mediated', control, of, 'TUBB3', feedback])].
[sujeto(['The', direct, silencing, of, 'TUBB3', reverses]), verbo([induced]), complemento([multiple, 'cross-resistance,', reduces, 'drug-resistant', tumor, 'mass,', and, suppresses, the, impaired, microtubule, stability, status, of, 'PTX-resistant', cells, with, transient, 'cross-resistance'])].
[sujeto(['Noscapine']), verbo([has]), complemento([low, toxicity, and, recently, it, was, also, found, to, possess, cytotoxic, activity, which, led, to, the, development, of, many, noscapine, analogues])].
[sujeto(['In', this, paper, we]), verbo([report]), complemento([on, the, synthesis, and, testing, of, a, novel, noscapine, analogue])].
[sujeto(['To', compare, the]), verbo([binding]), complemento([affinity, of, noscapine, and, the, novel, compound, to, 'tubulin,', we, have, done, a, fluorescence, quenching, assay])].
[sujeto(['Finally,', in, silico, methods, using, docking, calculations, were, used, to, illustrate, the]), verbo([binding]), complemento([mode, of, the, new, compound, to, 'α,β-tubulin'])].
[sujeto(['This', was, confirmed, by, the, stronger]), verbo([binding]), complemento([affinity, of, the, new, 'compound,', compared, to, 'noscapine,', to, tubulin])].
[sujeto(['Surprisingly,', our, new, compound, was]), verbo([found]), complemento([to, have, strong, 'microtubule-destabilizing', 'properties,', while, noscapine, is, shown, to, slightly, stabilize, microtubules])].
[sujeto(['Our', calculation, indicated, that, the, new, compound]), verbo([has]), complemento([more, binding, affinity, to, the, 'colchicine-binding', site, than, to, the, noscapine, site])].
[sujeto(['This', novel, compound]), verbo([has]), complemento([a, more, potent, cytotoxic, effect, on, cancer, cell, lines, than, its, 'parent,', 'noscapine,', and, hence, should, be, of, interest, as, a, potential, 'anti-cancer', drug])].
[sujeto(['Drug', resistance, poses, a, threatening, challenge, for, 'mankind,', as, the, development, of, resistance, to, already, 'well-established', drugs]), verbo([causes]), complemento([serious, therapeutic, problems])].
[sujeto(['Microtubule', stabilizer, 'drugs,', stabilises, microtubules, upon]), verbo([binding]), complemento([to, 'β-tubulin', subunit, of, tubulin, heterodimer, thus, causing, mitotic, arrest, leading, to, death, of, cancer, cell])].
[sujeto(['L215H,', 'L217R,', and, 'L225M', were]), verbo([reported]), complemento([for, 'Ptxl', resistance, in, various, cancers])].
[sujeto(['In', the, current, 'study,', molecular, mechanism, of, these, resistance]), verbo([causing]), complemento([mutations, was, explored, using, molecular, 'docking,', molecular, dynamics, '(', 'MD)', 'simulation,', binding, energy, estimation, '(', 'MMPBSA),', free, energy, 'decomposition,', principle, component, analysis, '(', 'PCA)', and, free, energy, landscape, '(', 'FEL)', methods])].
[sujeto(['Binding', energy, estimation, indicated, that, leucine, mutation, reduces, the]), verbo([binding]), complemento([affinity, of, 'Ptxl', in, mutant, types, '(', 'MTs)', as, compared, to, wild, type, '(', 'WT)'])].
[sujeto(['Moreover,', 'PCA', and, 'FEL', analysis, revealed, that, 'M-loop', flexible, region, '(', 'THR274-LEU284)', was, strongly]), verbo([bound]), complemento([with, 'Ptxl', in, 'WT', preventing, its, flexible, movement, and, the, causing, factor, for, microtubule, stabilization])].
[sujeto(['In', 'MTs', due, to, poor, interaction, with, 'Ptxl,', 'M-loop', flexible, region]), verbo([retains]), complemento([its, 'flexibility,', therefore, unable, to, stabilize, microtubule])].
[sujeto(['In', 'addition,', it, clearly]), verbo([provides]), complemento([the, molecular, basis, of, 'Ptxl', resistance, mechanism, in, leucine, 'MTs'])].
[sujeto(['A', few, studies]), verbo([have]), complemento([shown, that, elevated, serum, levels, of, the, ovarian, cancer, biomarker, 'HE4', correlate, with, tumor, 'chemoresistance,', response, to, 'treatment,', and, survival])].
[sujeto(['Regulation', of, mitogen]), verbo([activated]), complemento([protein, kinases, '(', 'MAPKs)', and, tubulins, were, assessed, by, western, blot])].
[sujeto(['HE4-overexpressing', 'SKOV3', and, 'OVCAR8', clones, displayed]), verbo([increased]), complemento([resistance, to, cisplatin, and, paclitaxel])].
[sujeto(['Microarray', analysis, revealed, that, 'HE4', overexpression, resulted, in, suppression, of, 'cisplatin-mediated', upregulation, of, 'EGR1,', a, 'MAPK-regulated', gene]), verbo([involved]), complemento([in, promoting, apoptosis])].
[sujeto(['Upregulation', of, 'p38,', a, 'MAPK']), verbo([activated]), complemento([in, response, to, 'cisplatin,', was, suppressed, in, 'HE4-overexpressing', clones])].
[sujeto(['No', differences, in, extracellular, 'signal-regulated', kinase, '(', 'ERK)', activation, were, noted, in, 'HE4-overexpressing', clones, treated, with, 25, &, 'nbsp;μM', 'cisplatin,', but, 'ERK', activation, was, partially]), verbo([suppressed]), complemento([in, 'HE4-overexpressing', clones, treated, with, 80, &, 'nbsp;μM', cisplatin])].
[sujeto(['Recombinant', 'HE4', also, upregulated, 'α-tubulin', and, 'β-tubulin', levels, in, 'SKOV3', and, 'OVCAR8', 'cells,', and, microtubule]), verbo([associated]), complemento([protein, tau, '(', 'MAPT)', gene, expression, was, increased, in, 'SKOV3', 'HE4-overexpressing', clones])].
[sujeto(['Overexpression', of, 'HE4']), verbo([promotes]), complemento([collateral, resistance, to, cisplatin, and, 'paclitaxel,', and, downregulation, of, 'HE4', partially, reverses, this, chemoresistance])].
[sujeto(['Multiple', factors, could, be]), verbo([involved]), complemento([in, 'HE4-mediated', 'chemoresistance,', including, deregulation, of, 'MAPK', 'signaling,', as, well, as, alterations, in, tubulin, levels, or, stability])].
[sujeto(['Paclitaxel', is, an, effective, chemotherapeutic, agent, against, various, human, tumors]), verbo([inducing]), complemento([apoptosis, via, binding, to, 'β-tubulin', of, microtubules, and, arresting, cells, mainly, in, the, 'G2/M', phase, of, the, cell, cycle])].
[sujeto(['However,', the, underlying, specific, molecular, mechanisms, of, paclitaxel, on, head, and, neck, squamous, cell, carcinoma, '(', 'HNSCC)']), verbo([have]), complemento([not, been, identified, yet])].
[sujeto(['Paclitaxel']), verbo([induced]), complemento([a, 'G2/M', arrest, in, 'HNSCC', cell, lines, followed, by, an, increased, amount, of, apoptotic, cells])].
[sujeto(['Moreover,', the, activation, of, caspase, 8, ',', caspase, 10, and, caspase, 3, ',', and, the]), verbo([loss]), complemento([of, the, mitochondrial, outer, membrane, potential, could, be, 'observed,', whereas, an, activation, of, caspase, 9, could, barely, be, detected])].
[sujeto(['Our', results, can, show, that, the, promoter, region, of, apoptotic, protease]), verbo([activating]), complemento([factor, 1, '(', 'Apaf-1)', was, not, methylated, in, the, 'HNSCC', cell, lines])].
[sujeto(['The', 'anti-apoptotic', caspase, 9, b, is, missing, the, catalytic, site, and]), verbo([acts]), complemento([as, an, endogenous, inhibitor, of, apoptosis, by, blocking, the, binding, of, caspase, 9, to, 'Apaf-1', to, form, the, apoptosome])].
[sujeto(['Our', data, indicate, the, presence, of, 'anti-apoptotic', caspase, 9, b, in, 'HNSCC,', which, may, serve, as, a, promising]), verbo([target]), complemento([to, increase, chemotherapeutic, apoptosis, induction])].
[sujeto(['Previous', studies, in, the, estrogen, 'receptor-positive', breast, cancer, cell, line, 'MCF-7', indicate, that, persin]), verbo([acts]), complemento([as, a, 'microtubule-stabilizing', agent])].
[sujeto(['Persin', and, tetrahydropersin]), verbo([cause]), complemento(['G2M', cell, cycle, arrest, and, increase, intracellular, microtubule, polymerization])].
[sujeto(['One', analog, '(', 4, -, 'nitrophenyl)-deshydroxypersin']), verbo([prevents]), complemento([cell, proliferation, and, blocks, cells, in, 'G1', of, the, cell, cycle, rather, than, 'G2M,', suggesting, an, additional, mode, of, action, of, these, compounds, independent, of, microtubules])].
[sujeto(['Evidence', from, 'Flutax-1', competition, experiments]), verbo([suggests]), complemento([that, while, the, persin, binding, site, on, 'β-tubulin', overlaps, the, classical, taxoid, site, where, paclitaxel, and, epothilone, 'bind,', persin, retains, activity, in, cell, lines, with, single, amino, acid, mutations, that, affect, these, other, taxoid, site, ligands])].
[sujeto(['This', implies, the, existence, of, a, unique]), verbo([binding]), complemento([location, for, persin, at, the, taxoid, site])].
[sujeto(['DNA', damage, was, examined, by, γH2AX, expression, 'level,', and, cell, cycle]), verbo([arrest]), complemento([by, flow, cytometry])].
[sujeto(['Addition', of, the, 'thieno[2,3-b]pyridine', derivative, 3, to, the, 'MDA-MB-231', cells]), verbo([induced]), complemento(['G2/M', growth, 'inhibition,', cell, cycle, arrest, in, 'G2-phase,', membrane, blebbing, and, the, formation, of, multinucleated, cells])].
[sujeto(['It', did, not]), verbo([induce]), complemento(['DNA', 'damage,', mitotic, arrest, or, changes, in, calcium, ion, flux])].
[sujeto(['The', results, are, consistent, with, a, mechanism, in, which, 'thieno[2,3-b]pyridine', derivatives]), verbo([interact]), complemento([with, 'PLC', isoforms, '(', possibly, 'PLC-δ),', which, in, turn, affect, the, cellular, dynamics, of, 'tubulin-β,', inducing, cell, cycle, arrest, in, 'G2-phase'])].
[sujeto(['We', conclude, that, these, compounds]), verbo([have]), complemento([novelty, because, of, their, 'PLC', target, and, may, have, utility, in, combination, with, mitotic, poisons, for, cancer, treatment])].
[sujeto(['Covering:', 2000, up, to, 2016, 'Peloruside', 'A,', a, macrocyclic, secondary, metabolite, from, a, 'New', 'Zealand', marine, 'sponge,', 'Mycale', 'hentscheli,']), verbo([has]), complemento([shown, potent, antiproliferative, activity, in, cultured, cancer, cells, as, well, as, inhibitory, effects, on, tumor, growth, in, mouse, models])].
[sujeto(['The', compound, also]), verbo([has]), complemento([promising, effects, against, cell, models, of, neurodegenerative, and, autoimmune, diseases])].
[sujeto(['In', mechanistic, 'studies,', peloruside, 'A', shares, with, paclitaxel, '(', 'Taxol®)', the, ability, to, stabilize, microtubules, by]), verbo([binding]), complemento([to, 'β-tubulin'])].
[sujeto(['As', 'such,', peloruside, 'A']), verbo([has]), complemento([been, of, central, importance, in, defining, a, new, 'microtubule-stabilizer', binding, site, localized, on, the, exterior, surface, of, the, microtubule, that, has, led, to, increased, interest, in, the, design, of, an, upscaled, total, synthesis, of, the, natural, product, and, its, analogues])].
[sujeto(['In', 'fact,', several, 'DEBs']), verbo([have]), complemento([been, clinically, available, for, the, treatment, of, coronary, 'in-stent', restenosis, '(', 'ISR),', de, novo, coronary, 'lesions,', and, peripheral, artery, disease])].
[sujeto(['Because', paclitaxel, is, a, 'tubulin-disrupting', agent, that]), verbo([binds]), complemento([preferentially, to, 'β-tubulin,', we, measured, 'β-tubulin', expression, in, aortal, stent, specimens, via, immunohistochemistry])].
[sujeto(['Meanwhile,', immunohistochemistry, revealed, that, 'β-tubulin', expression, in, the, 'DEB', group]), verbo([increased]), complemento([compared, with, the, control, 'group,', indirectly, suggesting, successful, uptake, of, paclitaxel, by, vessel, walls, after, 'DEB', dilation])].
[sujeto(['The', novel, 'DEB', is, safe, and]), verbo([has]), complemento([a, favorable, vascular, healing, response, on, neointimal, hyperplasia])].
[sujeto(['The', chemosensitivity, of, 'CTCs', appears, to, correlate, with, the, response, of, metastatic, cancer, patients, to, 'therapy,', but, chemoresistance, is, also, frequently, observed, in, advanced, stage, cancer, 'patients,', who]), verbo([have]), complemento([never, previously, received, chemotherapy])].
[sujeto(['We', hypothesize, that, adaptation, of, epithelial, cancer, cells, to, become, floating, 'CTCs', could]), verbo([lead]), complemento([to, development, of, chemoresistance])].
[sujeto(['Here,', we, explore, whether, chemoresistance, is]), verbo([induced]), complemento([in, epithelial, cancer, cells, when, cultured, under, 'non-adherent', conditions])].
[sujeto(['Increased', 'paclitaxel-specific', resistance, was, observed, in, floating, cells, compared, to, attached, cells, in, 'H460,', 'MCF-7,', and, 'HepG2', human, cancer, cell, 'lines,', by, 15.6, -, ',', 3.9, -, ',', and, 2.6, -, fold]), verbo([increases]), complemento([in, 'IC50', 'values,', respectively])].
[sujeto(['ERK', inhibitor, treatment, could, attenuate, the, 'up-regulation', of, 'βIVa-tubulin,', and]), verbo([decreased]), complemento([the, paclitaxel, resistance, of, 'H460', floating, 'cells,', even, though, other, 'β-tubulin', isotypes, were, 'up-regulated', when, the, 'ERK', activation, was, blocked])].
[sujeto(['Microtubule']), verbo([targeting]), complemento([based, therapies, have, revolutionized, cancer, 'treatment;', 'however,', resistance, and, side, effects, remain, a, major, limitation])].
[sujeto(['Fisetin']), verbo([binds]), complemento([to, tubulin, and, stabilizes, microtubules, with, binding, characteristics, far, superior, than, paclitaxel])].
[sujeto(['Surface', plasmon, resonance, and, computational, docking, studies]), verbo([suggested]), complemento([that, fisetin, binds, to, 'β-tubulin', with, superior, affinity, compared, to, paclitaxel])].
[sujeto(['Fisetin', treatment, of, human, prostate, cancer, cells, resulted, in, robust, 'up-regulation', of, microtubule]), verbo([associated]), complemento([proteins, '(', 'MAP)-2', and, -, 4])].
[sujeto(['Fisetin', significantly]), verbo([inhibited]), complemento(['PCa', cell, 'proliferation,', 'migration,', and, invasion])].
[sujeto(['Nudc,', a, protein]), verbo([associated]), complemento([with, microtubule, motor, 'dynein/dynactin', complex, that, regulates, microtubule, 'dynamics,', was, inhibited, with, fisetin, treatment])].
[sujeto(['Further,', fisetin, treatment, of, a, 'P-glycoprotein', overexpressing, 'multidrug-resistant', cancer, cell, line, 'NCI/ADR-RES']), verbo([inhibited]), complemento([the, viability, and, colony, formation])].
[sujeto(['Our', results, offer, in, vitro, 'proof-of-concept', for, fisetin, as, a, microtubule]), verbo([targeting]), complemento([agent])].
[sujeto(['We']), verbo([suggest]), complemento([that, fisetin, could, be, developed, as, an, adjuvant, for, treatment, of, prostate, and, other, cancer, types])].
[sujeto(['Microtubule', stabilizers]), verbo([provide]), complemento([an, important, mode, of, treatment, via, mitotic, cell, arrest, of, cancer, cells])].
[sujeto(['Recently,', we]), verbo([reported]), complemento([two, novel, neolignans, derivatives, 'Cmp10', and, 'Cmp19', showing, anticancer, activity, and, working, as, microtubule, stabilizers, at, micromolar, concentrations])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([explored, the, binding, 'site,', mode, of, 'binding,', and, stabilization, by, two, novel, microtubule, stabilizers, 'Cmp10', and, 'Cmp19', using, in, silico, molecular, 'docking,', molecular, dynamics, '(', 'MD)', 'simulation,', and, binding, free, energy, calculations])].
[sujeto(['Molecular', docking, studies, were, performed, to, explore, the, 'β-tubulin']), verbo([binding]), complemento([site, of, 'Cmp10', and, 'Cmp19'])].
[sujeto(['Binding', affinity, was, also, compared, for, 'Cmp10', and, 'Cmp19', using]), verbo([binding]), complemento([free, energy, calculations])].
[sujeto(['Our', docking, results, revealed, that, both, the, compounds]), verbo([bind]), complemento([at, 'Ptxl', binding, site, in, 'β-tubulin'])].
[sujeto(['MD', simulation, studies, showed, that, 'Cmp10', and, 'Cmp19']), verbo([binding]), complemento([stabilizes, 'M-loop', '(', 'Phe272-Val288)', residues, of, 'β-tubulin', and, prevent, its, 'dynamics,', leading, to, a, better, packing, between, α, and, β, subunits, from, adjacent, tubulin, dimers])].
[sujeto(['In', 'addition,', 'His229,', 'Ser280', and, 'Gln281,', and, 'Arg278,', 'Thr276,', and, 'Ser232', were]), verbo([found]), complemento([to, be, the, key, amino, acid, residues, forming, 'H-bonds', with, 'Cmp10', and, 'Cmp19,', respectively])].
[sujeto(['Consequently,']), verbo([binding]), complemento([free, energy, calculations, indicated, that, 'Cmp10', '(', -, 113.655, &, 'nbsp;kJ/mol)', had, better, binding, compared, to, 'Cmp19', '(', -, 95.216, &, 'nbsp;kJ/mol)'])].
[sujeto(['This', study]), verbo([provides]), complemento([useful, insight, for, better, understanding, of, the, binding, mechanism, of, 'Cmp10', and, 'Cmp19', and, will, be, helpful, in, designing, novel, microtubule, stabilizers])].
[sujeto(['The', expression, of, 'HDAC3', was]), verbo([decreased]), complemento([in, cancer, cell, lines, resistant, to, 'anti-cancer', drugs, such, as, celastrol, and, taxol])].
[sujeto(['HDAC3']), verbo([conferred]), complemento([sensitivity, to, these, 'anti-cancer', drugs])].
[sujeto(['HDAC3', activity, was, necessary, for]), verbo([conferring]), complemento([sensitivity, to, these, 'anti-cancer', drugs])].
[sujeto(['The', 'down-regulation', of, 'HDAC3']), verbo([increased]), complemento([the, expression, of, 'MDR1', and, conferred, resistance, to, 'anti-cancer', drugs])].
[sujeto(['The', expression, of, tubulin, β3, was]), verbo([increased]), complemento([in, 'drug-resistant', cancer, cell, lines])].
[sujeto(['ChIP', assays, showed, the]), verbo([binding]), complemento([of, 'HDAC3', to, the, promoter, sequences, of, tubulin, β3, and, 'HDAC6'])].
[sujeto(['The', 'down-regulation', of, 'HDAC6']), verbo([decreased]), complemento([the, expression, of, 'MDR1', and, tubulin, 'β3,', but, did, not, affect, 'HDAC3', expression])].
[sujeto(['The', 'down-regulation', of, 'HDAC6']), verbo([conferred]), complemento([sensitivity, to, taxol])].
[sujeto(['The', 'down-regulation', of, tubulin, β3]), verbo([conferred]), complemento([sensitivity, to, 'anti-cancer', drugs])].
[sujeto(['Our', results, showed, that, tubulin, β3, serves, as, a, downstream]), verbo([target]), complemento([of, 'HDAC3', and, mediates, resistance, to, 'microtubule-targeting', drugs])].
[sujeto(['Our', previous, work, identified, an, intermediate]), verbo([binding]), complemento([site, for, taxanes, in, the, microtubule, nanopore])].
[sujeto(['The', goal, of, this, study, was, to, test, derivatives, of, paclitaxel, designed, to]), verbo([bind]), complemento([to, this, intermediate, site, differentially, depending, on, the, isotype, of, 'β-tubulin'])].
[sujeto(['Since', 'β-tubulin', isotypes]), verbo([have]), complemento(['tissue-dependent', 'expression--specifically,', the, βIII, isotype, is, very, abundant, in, aggressive, tumors, and, much, less, common, in, normal, 'tissues--this', is, expected, to, lead, to, tubulin, targeted, drugs, that, are, more, efficacious, and, have, less, side, effects])].
[sujeto(['None', of, the, derivatives, studied, were, superior, to, currently, used, 'taxanes,', however, computer, simulations]), verbo([provided]), complemento([insights, into, the, activity, of, the, derivatives])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, neither, binding, to, the, intermediate, binding, site, nor, the, final, binding, site, is, sufficient, to, explain, the, activities, of, the, derivative, taxanes, studied])].
[sujeto(['Knowledge', gained, on, the, ability, of, the, engineered, drugs, to]), verbo([bind]), complemento([to, targets, and, bring, about, activity, in, a, predictable, manner, is, a, step, towards, personalizing, therapies])].
[sujeto(['The', interactions, of, 'PLA', and, 'LAU', with, tubulin]), verbo([have]), complemento([attracted, a, great, deal, of, 'attention,', mainly, because, they, bind, to, 'β-tubulin', at, a, site, that, is, different, from, the, classical, taxoid, site])].
[sujeto(['Multiple', 'βI-tubulin', amino, acid, residues]), verbo([have]), complemento([been, predicted, by, computer, modelling, studies, and, more, recently, by, protein, crystallography, to, participate, in, the, binding, of, 'PLA', and, 'LAU', to, tubulin])].
[sujeto(['To', determine, the, role, of, four]), verbo([binding]), complemento([site, 'residues,', 'Q291,', 'D295,', 'V333,', and, 'N337', on, 'PLA', and, 'LAU', 'activity,', we, introduced, single, mutations, to, these, sites, by, 'site-directed', mutagenesis, and, transfected, each, mutant, tubulin, separately, into, 'HEK', 'and/or', 'HeLa', cells])].
[sujeto(['We']), verbo([found]), complemento([that, a, 'Q291M', 'βI-tubulin', mutation, increased, sensitivity, of, the, cells, to, 'PLA,', but, not, to, 'LAU,', paclitaxel, '(', 'PTX),', or, vinblastine, '(', 'VBL)'])].
[sujeto(['In', 'contrast,', 'V333W', and, 'N337L', mutations]), verbo([led]), complemento([to, less, stable, 'microtubules,', with, the, 'V333W', causing, resistance, to, 'PLA', and, 'PTX,', but, not, 'LAU,', and, the, 'N337L', causing, resistance, to, 'PLA,', 'LAU,', and, 'PTX'])].
[sujeto(['Moreover,', cells]), verbo([expressing]), complemento([either, 'W333', or, 'L337', were, hypersensitive, to, the, 'microtubule-destabilizing', 'agent,', 'VBL'])].
[sujeto(['The', 'D295I', mutation]), verbo([conferred]), complemento([resistance, to, both, 'PLA', and, 'LAU', without, affecting, microtubule, stability, or, sensitivity, to, 'PTX', or, ixabepilone, '(', 'IXB)'])].
[sujeto(['This', study, identifies, the, first, mammalian, 'βI-tubulin', mutation, that, specifically]), verbo([increases]), complemento([sensitivity, to, 'PLA,', and, reports, mutations, at, 'PLA', and, 'LAU', binding, site, residues, that, can, either, reduce, microtubule, stability, or, impair, 'drug-tubulin', 'binding,', conferring, resistance, to, these, 'microtubule-stabilizing', agents])].
[sujeto(['This', information]), verbo([provides]), complemento([insights, on, 'β-tubulin', residues, important, for, maintaining, microtubule, structural, integrity, and, for, sensitivity, to, 'microtubule-targeting', 'agents,', and, suggests, novel, directions, for, rational, 'structure-based', design, of, new, and, more, potent, agents, for, cancer, treatment, that, target, the, 'LAU/PLA', site])].
[sujeto(['Mechanistically,', mutational, 'selection,', epigenetic, 'alteration,', activation, of, the, 'Wnt', pathway, or, impaired, p53, function]), verbo([have]), complemento([been, implicated])].
[sujeto(['Using', complementary]), verbo([gain]), complemento([and, loss, of, function, 'approaches,', we, demonstrate, that, the, expression, of, 'MDR1', is, positively, regulated, by, 'BMI1,', a, 'stem-cell', factor, classically, known, as, a, transcriptional, repressor])].
[sujeto(['Chromatin', immunoprecipitation, '(', 'ChIP)', assays, further, establish, that, the, proximal, 'MDR1', promoter]), verbo([responds]), complemento([to, cisplatin, in, a, 'BMI1', dependent, manner])].
[sujeto(['BMI1']), verbo([interacts]), complemento([with, a, cluster, of, 'E-box', elements, on, the, 'MDR1', promoter, and, recruits, 'TIP60', resulting, in, acetylation, of, histone, 'H2A', and, 'H3'])].
[sujeto(['Collectively,', our, data, establish, a, hitherto, unknown, liaison, among, 'MDR1,', 'BMI1', and, 'TIP60', and]), verbo([provide]), complemento([mechanistic, insights, into, 'cisplatin-induced', 'MDR1', expression, resulting, in, acquired, 'cross-resistance', against, 'paclitaxel,', doxorubicin, and, likely, other, drugs])].
[sujeto(['Ovarian', cancer, is, the, first]), verbo([leading]), complemento([cause, of, death, among, gynecologic, malignancies, worldwide])].
[sujeto(['AB23', obviously]), verbo([inhibited]), complemento([proliferation, of, the, three, ovarian, cancer, cell, 'lines,', 'down-regulated', the, protein, levels, of, 'CDK4,', 'CDK6,', and, cyclin, 'D1,', and, blocked, the, cell, cycle, progressions, in, 'G1', phase])].
[sujeto(['Meanwhile,', 'AB23']), verbo([induced]), complemento([accumulation, of, the, 'sub-G1', phase, in, the, three, cell, lines, in, a, concentration, dependent, manner])].
[sujeto(['Further', study, showed, that, 'AB23']), verbo([induced]), complemento([endoplasmic, reticulum, stress, through, 'IRE1', signaling, pathway, and, silencing, of, 'IRE1α', partially, enhanced, 'AB23-induced', apoptosis])].
[sujeto(['Wound', healing, and, transwell, assays, showed, that, 'AB23', could, also]), verbo([suppress]), complemento([the, migration, and, invasion, of, 'HEY', cells])].
[sujeto(['Blockade', of, human, epidermal, growth, factor, receptor, type, 2, '(', 'HER2)']), verbo([has]), complemento([dramatically, improved, outcome, for, patients, with, 'HER2-positive', breast, cancer])].
[sujeto(['Trastuzumab,', an, 'anti-HER2', monoclonal, 'antibody,']), verbo([has]), complemento([previously, demonstrated, improvement, in, overall, survival, '(', 'OS)', in, patients, with, metastatic, and, early, stage, 'HER2-positive', breast, cancer])].
[sujeto(['However,', trastuzumab, can]), verbo([cause]), complemento([congestive, heart, failure, '(', 'CHF)', with, an, increased, frequency, for, patients, who, have, also, received, an, anthracycline])].
[sujeto(['The', primary, end, point, was, to, evaluate, the, safety, of, this, variable, duration, of, trastuzumab, 'therapy,', particularly, cardiac, toxicity, defined, as, 'CHF', or, left, ventricular, ejection, fraction]), verbo([decrease]), complemento([&, 'gt;10%'])].
[sujeto(['Compared', with, 12, -, week, treatment, with, 'trastuzumab,', 1, year, of, 'trastuzumab-based', therapy, did, not]), verbo([increase]), complemento([the, frequency, or, severity, of, cardiac, 'toxicity:', three, patients, on, the, abbreviated, 'Arm', and, four, on, the, conventional, 'Arm', experienced, 'CHF'])].
[sujeto(['Compared', with, 12, weeks, of, 'treatment,', 1, year, of, treatment, with, trastuzumab, did, not, significantly]), verbo([increase]), complemento([the, risk, of, cardiac, toxicity])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, paclitaxel, tumor, 'priming,', by, inducing, 'apoptosis,', expands, the, tumor, interstitial, 'space,', improves, the, penetration, and, dispersion, of, nanoparticles, and, 'siRNA-lipoplexes', in, 3, -, dimensional, tumor, 'histocultures,', and, promotes, the, delivery, and, transfection, efficiency, of, 'siRNA-lipoplexes', under, the, locoregional, setting, in, vivo, '(', i])].
[sujeto(['The']), verbo([target]), complemento([gene, was, 'survivin,', an, inducible, chemoresistance, gene])].
[sujeto(['The', results, show, single, agent, paclitaxel, delayed, tumor, growth, but, also, significantly]), verbo([induced]), complemento([the, survivin, protein, level, in, residual, 'tumors,', whereas, addition, of, 'PCat-siSurvivin', completely, reversed, the, 'paclitaxel-induced', survivin, and, enhanced, the, paclitaxel, activity, '(', 'p<0'])].
[sujeto(['In', 'comparison,', 'PCat-siSurvivin', alone, did, not, yield, survivin, knockdown, or, antitumor, 'activity,', indicating, the, in, vivo, effectiveness, of, intravenous, 'siRNA-mediated', gene, silencing]), verbo([requires]), complemento([paclitaxel, cotreatment])].
[sujeto(['Additional', in, vitro, studies, showed, that, paclitaxel]), verbo([promoted]), complemento([the, cytoplasmic, release, of, 'siGLO,', a, 22, nucleotide, 'double-stranded', 'RNA', that, has, no, mRNA, 'targets,', from, its, 'PCat', lipoplex, 'and/or', 'endosomes/lysosomes'])].
[sujeto(['Taken', 'together,', our, earlier, and, current, data, show, paclitaxel, tumor, 'priming,', by]), verbo([promoting]), complemento([the, interstitial, transport, and, cytoplasmic, 'release,', is, critical, to, promote, the, delivery, and, transfection, of, siRNA, in, vivo])].
[sujeto(['In', 'addition,', because, paclitaxel]), verbo([has]), complemento([broad, spectrum, activity, and, is, used, to, treat, multiple, types, of, solid, tumors, including, the, 'hard-to-treat', pancreatic, 'cancer,', the, synergistic, 'paclitaxel+siSurvivin', combination, represents, a, potentially, useful, 'chemo-gene', therapy])].
[sujeto(['After', operative, pericardial, 'drainage,', intrapericardial, instillations, of, cisplatin, and, 'OK-432', successfully]), verbo([prevented]), complemento(['re-accumulation', of, pericardial, effusion])].
[sujeto(['One', year, and, 10, months, after, pericardial, 'drainage,', she, underwent, 'surgery(mastectomy', and, axillary, lymph, node, dissection, level, 'II)because', of, two, small, tumors, in, the, left, breast, which, were]), verbo([found]), complemento([to, be, malignant, using, 'PET-CT'])].
[sujeto(['One', 'tumor(diameter', 1.6, 'cm)was']), verbo([found]), complemento([pathologically, to, consist, of, degenerated, cancer, 'cells,', and, another, 'tumor(diameter', 2, 'cm)was', diagnosed, as, recurrent, cancer])].
[sujeto(['Since', having, the, 'surgery,', she]), verbo([has]), complemento([not, experienced, recurrence, on, hormone, therapy, with, 'fulvestrant,', and, to, date, she, is, still, 'alive,', 3, years, and, 5, months, since, the, left, pleural, metastasis, episode])].
[sujeto(['Compared', with, patients, who, received, chemotherapy, 'alone,', patients, who, received, chemotherapy, plus, bevacizumab]), verbo([reported]), complemento(['FACT-Cx', 'TOI', scores, that, were, an, average, of, 1, '·2', points, lower, '(', 98, '·75%', 'CI', -, 4, '·1', to, 1, '·7;', 'p=0·30)'])].
[sujeto(['Patients']), verbo([responding]), complemento([to, 'anti-angiogenesis', therapy, who, maintain, an, acceptable, quality, of, life, could, be, suitable, at, progression, for, treatment, with, other, novel, therapies, that, might, confer, additional, benefit])].
[sujeto(['Randomized', patients]), verbo([reported]), complemento([similar, changes, in, 'QoL,', except, for, less, change, from, baseline, in, neurotoxicity, on, the, pemetrexed, 'arm;', investigators, reported, greater, neurotoxicity, on, the, paclitaxel, arm, and, greater, fatigue, on, the, pemetrexed, arm])].
[sujeto(['African', 'Americans']), verbo([have]), complemento([a, greater, incidence, of, lung, cancer, than, whites, and, have, been, underrepresented, in, clinical, trials])].
[sujeto(['To', date, several, phase, 'III', trials]), verbo([have]), complemento([shown, both, approaches, to, be, effective, strategies, for, the, frontline, treatment, of, ovarian, cancer, over, standard, every, 21, day, chemotherapy, alone])].
[sujeto([',', residual, 'disease)']), verbo([have]), complemento([been, able, to, identify, patients, more, likely, to, benefit, from, 'anti-angiogenic', agents])].
[sujeto(['And', more, 'recently,', molecular, profiling, of, tumor, genetics]), verbo([has]), complemento([shown, similar, promising, results])].
[sujeto(['Ongoing', research, will, help]), verbo([enhance]), complemento([our, ability, to, match, patients, to, therapeutic, strategies, most, likely, to, optimize, outcomes, and, minimize, risk])].
[sujeto(['Ixabepilone', is, a, 'semi-synthetic', analog, of, epothilone, 'B', that]), verbo([binds]), complemento([to, the, same, site, on, beta, tubulin, as, paclitaxel, and, may, be, a, more, potent, polymerizer, of, tubulin])].
[sujeto(['Seventeen', patients, '(', 73.9, '%', ')', had]), verbo([increasing]), complemento([disease, '(', 'PD)', and, two, patients, were, inevaluable, per, 'RECIST'])].
[sujeto(['Treatment', in, the, metastatic, setting, is, challenging, due, to, the, rarity, of, metastatic, disease, with, the, majority, of, patients, presenting, with, curative, locally, advanced, 'disease,', and, the, ability, to, design, clinical, trials, for, metastatic, disease]), verbo([has]), complemento([yet, to, be, explored])].
[sujeto(['We', hereby]), verbo([report]), complemento([our, experience, in, using, aggressive, combinations, in, the, 'second-', and, 'third-line', settings])].
[sujeto(['Toxicity', was, assessed, by, patient]), verbo([report]), complemento(['(', 'CTCAE', v])].
[sujeto(['Adjuvant', therapy, with, 'VCB', and, chemotherapy, is, well, tolerated, in, a, population, of, patients, with, 'H-IR', endometrial, carcinoma, and]), verbo([provides]), complemento([2, year, 'PFS', of, 91, '%'])].
[sujeto(['Patients', with, no, residual, disease, following, primary, surgery, that, are, treated, with, adjuvant, platinum, based, 'IP', chemotherapy]), verbo([have]), complemento([survival, measures, that, exceed, any, rates, previously, seen, in, this, population])].
[sujeto(['Zinc', at, cytotoxic, concentrations]), verbo([has]), complemento([been, shown, to, regulate, gene, transcription, in, cancer, 'cells,', though, 'zinc\'s', involvement, in, posttranscriptional, regulation, is, less, characterized])].
[sujeto(['Clioquinol,', a, 'well-established', zinc, 'ionophore,', was, used, to, raise, intracellular, zinc, to]), verbo([reported]), complemento([cytotoxic, levels])].
[sujeto(['Several', parameters, were, used, as, indictors, of, posttranscriptional, 'regulation,', including, 'p-body', 'formation,', microRNA, 'profiling,', expression, level, of, proteins, known, to]), verbo([regulate]), complemento([mRNA, 'degradation,', microRNA, 'processing,', and, protein, translation])].
[sujeto(['Clioquinol', plus, zinc]), verbo([enhanced]), complemento(['p-body', assembly, in, 'MCF-7', cells])].
[sujeto(['The', enhancement, does, not, seem, to, be, due, to, a, stress, 'response,', as, 'paclitaxel,', a, commonly, used, 'chemotherapeutic,', did, not]), verbo([cause]), complemento([enhanced, 'p-body', formation, at, a, highly, cytotoxic, concentration])].
[sujeto([microRNA, profiling, indicated, that, clioquinol, plus, zinc, globally, 'down-regulates', microRNA, expression, in, this, model, 'system,', which, is]), verbo([associated]), complemento([with, the, reduced, expression, of, 'Dicer,', an, enzyme, key, to, microRNA, 'maturation,', and, 'Ago2,', a, protein, essential, for, microRNA, stability])].
[sujeto(['This', study, demonstrates, that, ionophoric, zinc, can]), verbo([induce]), complemento([cytotoxicity, in, cancer, cells, by, globally, regulating, posttranscriptional, events])].
[sujeto(['The', pneumothorax]), verbo([required]), complemento([3, weeks, to, cure])].
[sujeto(['Pneumothorax', was, a, serious, adverse, event]), verbo([associated]), complemento([with, 'bevacizumab-containing', chemotherapy])].
[sujeto([3.0, as, well, as, subjective]), verbo([reporting]), complemento([by, patients, after, each, cycle])].
[sujeto(['The', epidermoid, tumor, line, 'KB-3-1', was, exposed, to]), verbo([increasing]), complemento([concentrations, of, paclitaxel, and, 5, 'micromol/L', 'CL-347099', for, up, to, 1, year])].
[sujeto(['They', grew, well, and]), verbo([retained]), complemento([resistance, to, paclitaxel, when, grown, in, athymic, mice])].
[sujeto(['KB-15-PTX/099-resistant', cells, did, not, overexpress, 'P-glycoprotein', nor, did, they]), verbo([have]), complemento([an, alteration, of, '[', 14, 'C]paclitaxel', accumulation, compared, with, parental, cells])].
[sujeto(['Based', on, an, electron, crystallography, structure, of, 'Zn-stabilized', tubulin, 'sheets,', the, phenyl, ring, of, 'C-3\'', 'NHCO-C6H5', of, paclitaxel, makes, contact, with, 'Asp26', of, 'beta-tubulin,']), verbo([suggesting]), complemento([a, 'ligand-induced', mutation])].
[sujeto(['However,', a, mutation, in, the, paclitaxel]), verbo([binding]), complemento([pocket, does, not, explain, the, phenotype, completely])].
[sujeto(['KB-15-PTX/099', cells]), verbo([have]), complemento([impaired, microtubule, stability, as, determined, by, a, reduced, percentage, of, tubulin, in, microtubules, and, reflected, by, less, acetylated, tubulin])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, a, mutation, in, tubulin, might, affect, microtubule, stability, as, well, as, drug, binding, and, contribute, to, the, observed, resistance, profile])].
[sujeto(['To', identify, a, molecular, basis, for, acquired, 2, -, methoxyestradiol, 'resistance,', we, generated, a, stable, 2, -, 'methoxyestradiol-resistant', '(', 2, 'ME2R)', 'MDA-MB-435', human, cancer, cell, line, by, stepwise, exposure, to]), verbo([increasing]), complemento([2, -, methoxyestradiol, concentrations])].
[sujeto([2, 'ME2R', cells]), verbo([maintained]), complemento([in, the, presence, of, the, drug, and, 'W435', cells, maintained, in, the, absence, of, the, drug, showed, 32.34, -, to, 40.07, -, fold, resistance, to, 2, -, methoxyestradiol])].
[sujeto(['Upon', 2, -, methoxyestradiol, 'treatment,', levels, of, acetylated, and, detyrosinated, tubulins]), verbo([decreased]), complemento([in, 'P435', 'cells,', while, remaining, constant, in, 2, 'ME2R', cells])].
[sujeto(['Mutations', in, the, 'beta-tubulin', gene]), verbo([have]), complemento([been, proposed, as, a, resistance, mechanism, to, paclitaxel])].
[sujeto(['Hemiasterlins', are, 'sponge-derived', tripeptides, that]), verbo([inhibit]), complemento([cell, growth, by, depolymerizing, existing, microtubules, and, inhibiting, microtubule, assembly])].
[sujeto(['Since', hemiasterlins, are, poor, substrates, for, 'P-glycoprotein,', they, are, attractive, candidates, for, cancer, therapy, and]), verbo([have]), complemento([been, undergoing, clinical, trials])].
[sujeto(['Unlike']), verbo([reports]), complemento([of, mutations, resulting, in, reduced, drug, 'affinity,', the, experimental, data, and, location, of, mutations, are, consistent, with, resistance, to, 'HTI-286', mediated, by, 'microtubule-stabilizing', mutations, in, 'beta-', or, 'alpha-tubulin'])].
[sujeto(['In', 'addition,', no, amino, acid, replacements, were]), verbo([found]), complemento([in, 'chimpanzee,', 'gorilla,', and, orangutan, in, comparison, to, human])].
[sujeto(['Our', data, demonstrate, a, very, high, degree, of, sequence, conservation, in, class, 'I', 'beta-tubulin,']), verbo([suggesting]), complemento([that, all, residues, are, important, in, tubulin, structure, and, function])].
[sujeto(['Individual', variation, in, response, to, treatment, with, paclitaxel, is, not, likely, to, be]), verbo([caused]), complemento([by, genetic, variations, in, the, 'beta-tubulin', drug, target])].
[sujeto(['Moreover,', acquired, mutations, in, class, 'I', 'beta-tubulin', are, unlikely, to, be, a, clinically, relevant]), verbo([cause]), complemento([of, drug, resistance])].
[sujeto(['The', compound]), verbo([enhances]), complemento([tubulin, 'assembly,', and, laulimalide, is, quantitatively, comparable, to, paclitaxel, in, its, effects, on, the, reaction])].
[sujeto(['Laulimalide', is, also, active, in, 'P-glycoprotein', overexpressing, 'cells,', while, 'isolaulimalide,', a, congener, without, the, 'drug\'s', epoxide, 'moiety,', was]), verbo([reported]), complemento([to, have, negligible, cytotoxic, and, biochemical, activity, '[', 'Mooberry', et, al])].
[sujeto(['We']), verbo([report]), complemento([here, that, laulimalide, binds, at, a, site, on, tubulin, polymer, that, is, distinct, from, the, taxoid, site])].
[sujeto(['We']), verbo([found]), complemento([that, 'laulimalide,', while, as, active, as, 'paclitaxel,', epothilone, 'A,', and, eleutherobin, in, promoting, the, assembly, of, 'cold-stable', 'microtubules,', was, unable, to, inhibit, the, binding, of, radiolabeled, paclitaxel, or, of, 7, -, 'O-[N-(2,7-difluoro-4\'-fluoresceincarbonyl)-L-alanyl]paclitaxel,', a, fluorescent, paclitaxel, 'derivative,', to, tubulin])].
[sujeto(['We', also]), verbo([report]), complemento([that, a, laulimalide, analogue, lacking, the, epoxide, 'moiety,', while, less, active, than, laulimalide, in, biochemical, and, cellular, 'systems,', is, probably, more, active, than, isolaulimalide])].
[sujeto(['We', demonstrated, that, indanocine, specifically]), verbo([induces]), complemento([apoptosis, in, malignant, 'B', cells, from, patients, with, chronic, lymphocytic, leukemia])].
[sujeto(['The', cloned, cells, are, 'cross-resistant', to, colchicine, and, 'vinblastine,', but, not, to, 'paclitaxel,', and, do, not]), verbo([have]), complemento([increased, expression, of, the, 'multidrug-resistant', p170, glycoprotein])].
[sujeto(['In', both, parental, cells, and, cell, 'extracts,', indanocine, treatment]), verbo([caused]), complemento([tubulin, depolymerization])].
[sujeto(['Both', extract, mixing, and, cell, fusion, experiments]), verbo([suggested]), complemento([that, a, stable, structural, change, in, 'microtubules,', rather, than, a, soluble, 'factor,', was, responsible, for, indanocine, resistance])].
[sujeto(['Sequence', analysis, of, parental, and, resistant, cells, revealed, a, single, point, mutation, in, the, 'M40', isotype, of, 'beta-tubulin', at, nucleotide, 1050, '(', 'G-->T,', 'Lys(350)-->Asn)', in, the, 'indanocine-resistant', 'clone,', in, a, region, close, to, the, putative, colchicine]), verbo([binding]), complemento([site])].
[sujeto(['Analysis', of, variance, supported, the, hypothesis, of, spontaneous, mutations]), verbo([conferring]), complemento([vinblastine, 'resistance,', rather, than, induction, of, adaptive, response, elements])].
[sujeto(['No', elevation, was]), verbo([found]), complemento([in, the, expression, of, the, mrp, 'gene,', the, 'LRP-56', major, vault, protein, and, 'beta-tubulin', isotypes, '(', 'M40,', 'beta4,', 5, 'beta,', and, 'beta9)', in, these, mutants])].
[sujeto(['Acquired', resistance, to, paclitaxel, can, be]), verbo([mediated]), complemento([by, 'P-glycoprotein', or, by, alterations, involving, tubulin])].
[sujeto(['We']), verbo([report]), complemento([two, 'paclitaxel-resistant', sublines, derived, from, 1, 'A9', human, ovarian, carcinoma, cells])].
[sujeto(['Total', tubulin, content, is, 'similar,', but, the, polymerized, fraction]), verbo([increased]), complemento([in, parental, but, not, in, resistant, cells, following, the, paclitaxel, addition])].
[sujeto(['Purified', tubulin, from, parental, cells, demonstrated, 'paclitaxel-driven']), verbo([increased]), complemento(['polymerization,', in, contrast, to, resistant, cell, 'tubulin,', which, did, not, polymerize, under, identical, conditions])].
[sujeto(['In', 'contrast,', epothilone, 'B,', an, agent, to, which, the, resistant, cells]), verbo([retained]), complemento(['sensitivity,', increased, assembly])].
[sujeto(['Comparable', expression, of, 'beta-tubulin', isotypes, was]), verbo([found]), complemento([in, parental, and, resistant, 'cells,', with, predominant, expression, of, the, 'M40', and, beta2, isotypes])].
[sujeto(['Surviving', colonies, were]), verbo([found]), complemento([in, 12, 'populations,', 9, of, which, had, clones, that, remained, resistant, to, paclitaxel, after, a, 2, -, month, period, of, propagation])].
[sujeto(['Accumulation', of, '[', '(', 3, ')', 'H]paclitaxel', was]), verbo([decreased]), complemento([in, these, clones, but, not, in, the, 'mdr1-negative', clones, compared, with, parental, cells])].
[sujeto(['Because', tubulins, are, the]), verbo([target]), complemento([molecules, for, paclitaxel, 'cytotoxicity,', we, evaluated, total, tubulin, content, by, immunoblotting, and, performed, semiquantitative, reverse, transcription, 'PCR', analysis, for, expression, of, the, 'alpha-tubulin', isotypes, 'B', alpha, 1, ',', 'K', alpha, 1, and, 'H', alpha, 44, ',', the, 'beta-tubulin', isotypes, 'M40,', 'beta9,', 5, 'beta,', beta2, and, 'beta4,', and, 'gamma-tubulin'])].
[sujeto(['Total', tubulin, content, was]), verbo([decreased]), complemento([significantly, in, one, of, the, 'single-step', mutants])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, stringent, exposure, to, paclitaxel, selected, clones, with, reduced, transcript, levels, of, 5, beta, and, beta4, 'beta-tubulin', 'isotypes,', but, that, these, reduced, levels, were, not, directly, involved, in, the, resistance, of, the, clones, to, paclitaxel])].
[sujeto(['The', results]), verbo([suggest]), complemento([an, important, role, for, 'non-multidrug-resistant', mechanisms, of, resistance, to, paclitaxel])].
[sujeto(['These', mechanisms, do, not]), verbo([involve]), complemento([reduced, drug, accumulation, and, provide, 'cross-resistance', among, both, paclitaxel, and, tubulin, depolymerizing, agents])].
[sujeto(['We']), verbo([found]), complemento([that, in, 'Xenopus', embryo, neurons, in, 'culture,', cell, 'body-derived', vesicles, were, rapidly, transported, all, the, way, down, to, the, growth, cone, 'region,', where, they, fused, with, the, plasma, membrane])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, the, local, destabilization, of, axonal, 'MTs', is, necessary, and, sufficient, for, the, delivery, of, membrane, material, to, specific, neuronal, sites])].
[sujeto(['Synapsin', 'I,', a, synaptic, vesicle, 'protein,', is, thought, to, be]), verbo([involved]), complemento([in, the, regulation, of, neurotransmission, through, its, phosphorylation, by, the, cyclic, 'AMP-dependent', and, 'Ca2+/calmodulin-dependent', protein, kinases, which, become, activated, upon, depolarization, of, nerve, endings])].
[sujeto(['We']), verbo([report]), complemento([here, that, synapsin, 'I', can, 'co-cycle', with, microtubules, through, three, cycles, of, warm, polymerization, and, cold, depolymerization])].
[sujeto(['Synapsin', 'I']), verbo([binds]), complemento([saturably, to, microtubules, stabilized, by, 'taxol,', with, an, estimated, dissociation, constant, '(', 'Kd)', of, 4.5, microM, and, a, stoichiometry, of, 1.2, mol, of, synapsin, binding, sites, per, mol, tubulin, dimer])].
[sujeto(['Synapsin', 'I', also]), verbo([increases]), complemento([the, turbidity, of, tubulin, solutions, at, 37, degrees, 'C,', but, without, causing, detectable, alterations, in, the, critical, concentration, required, for, polymerization])].
[sujeto(['Synapsin', 'I', is, thus, a, candidate, to]), verbo([mediate]), complemento([or, regulate, the, interaction, of, synaptic, vesicles, with, microtubules])].
[sujeto(['Micropatterned', cocultures, '(', 'MPCCs)', of, 'PHHs', and, 3, 'T3-J2', fibroblasts]), verbo([have]), complemento([been, shown, previously, to, display, major, liver, functions, for, several, weeks, in, vitro])].
[sujeto(['Finally,', we]), verbo([modulated]), complemento([drug, clearance, in, 'MPCCs', by, inducing, or, inhibiting, 'P450s'])].
[sujeto(['Rifampin-mediated', 'CYP3A4', induction]), verbo([increased]), complemento([midazolam, clearance, by, 73, '%', ',', while, 'CYP3A4', inhibition, with, ritonavir, decreased, midazolam, clearance, by, 79, '%'])].
[sujeto(['Ritonavir', pharmacokinetics, are, complicated, by, 'inhibition,', induction, and, pharmacogenetics, of, cytochrome, 'P450', '(', 'CYP)', enzymes]), verbo([mediating]), complemento([its, clearance])].
[sujeto(['In', 'plasma,', metabolite, abundance, was, well, above, previously]), verbo([reported]), complemento([levels, with, circulating, concentrations, measured, at, 2, μM, for, the, main, hydroxylisopropyl, metabolite])].
[sujeto(['A', modest, '(', 2, -, 6, '%', ')', contribution, of, 'CYP2J2', to, ritonavir, clearance, is, predicted, which]), verbo([increases]), complemento([to, more, than, 20, '%', in, subjects, carrying, 'CYP2D6', poor, metabolizer, polymorphisms, and, 'CYP3A4', irreversible, inhibition])].
[sujeto(['Plasma', raltegravir, 'AUC(0,τ)', and, 'C(max)']), verbo([increased]), complemento([by, 18, '%', with, no, change, in, 'Cτ', when, raltegravir, was, 'co-administered', with, 'GSK2248761'])].
[sujeto(['Lopinavir', '(', 'LPV)', plasma, 'AUC(0,τ),', 'C(max)', and, 'Cτ']), verbo([decreased]), complemento([by, 23, '%', ',', 14, '%', and, 40, '%', ',', 'respectively,', following, administration, of, 'lopinavir/ritonavir', with, 'GSK2248761'])].
[sujeto(['Atorvastatin,', rosuvastatin, and, simvastatin, 'AUC(0,∞)', and, 'C(max)']), verbo([increased]), complemento([following, 'co-administration', with, 'GSK2248761,', with, the, largest, changes, observed, for, simvastatin, '(', 3.7, -, fold, and, 4.3, -, 'fold)'])].
[sujeto(['Co-administration', of, 'GSK2248761', with, 'DRV/RTV', and, 'LPV/RTV']), verbo([increased]), complemento([plasma, 'GSK2248761', exposures, by, 1.25, -, to, '≤2-fold', compared, with, 'GSK2248761', administered, 'alone,', and, increases, in, 'GSK2248761', exposure, were, higher, following, single, dose, 'co-administration', of, 'DRV/RTV', or, 'LPV/RTV', compared, with, multiple, doses])].
[sujeto([',', 'ritonavir/alprazolam),', and]), verbo([involve]), complemento([multiple, mechanisms])].
[sujeto(['With', specific, inhibitors, of, 'CYP3A,', 'CYP2B6,', 'CYP2D6,', 'CYP2C9,', and, 'CYP2C19,', active, metabolite, production, was]), verbo([decreased]), complemento([by, 38, '%', ±, 15, '%', with, 4, -, '(', 4, -, 'chlorobenzyl)pyridine', '(', 'CYP2B6', 'inhibitor)', and, by, 45, ±, 16, '%', with, ketoconazole, '(', 'CYP3A', 'inhibitor)'])].
[sujeto(['In', this, 'in-vitro', 'study,', we]), verbo([found]), complemento([a, potent, inhibition, of, prasugrel, bioactivation, by, ritonavir, compared, to, the, specific, inhibitors, of, 'CYP3A', and, 'CYP2B6', due, to, the, simultaneous, inhibition, of, 'CYP2B6', and, 'CYP3A', by, ritonavir])].
[sujeto(['This']), verbo([finding]), complemento([suggests, a, potential, significant, 'drug-drug', interaction, between, these, two, drugs])].
[sujeto(['To']), verbo([report]), complemento([a, case, of, increased, aripiprazole, concentrations, during, coadministration, with, 'darunavir,', 'ritonavir,', and, duloxetine])].
[sujeto(['A', month, after, the, aripiprazole, dosage, was]), verbo([increased]), complemento([to, 50, mg, 'daily,', the, patient, developed, confusion, and, loss, of, coordination])].
[sujeto(['Weeks', 'later,']), verbo([he]), complemento([presented, to, the, emergency, department, with, 'fever,', 'cough,', 'headache,', neck, 'stiffness,', back, 'pain,', and, blurred, vision, and, was, admitted, for, possible, meningitis])].
[sujeto(['Because', symptoms, improved, with, pain, control, and, intravenous, fluids, during, 'hospitalization,']), verbo([he]), complemento([was, discharged, within, a, couple, days, after, admission])].
[sujeto(['One', month, later]), verbo([he]), complemento([was, readmitted, for, worsening, 'symptoms,', and, the, resulting, diagnostic, workup, showed, unremarkable, findings, except, for, lymphadenopathy, '(', 'LAD)'])].
[sujeto(['This']), verbo([finding]), complemento([was, attributed, to, discontinuing, 'ARTs', after, his, first, admission])].
[sujeto(['The', 'Horn', 'Drug', 'Interaction', 'Probability', 'Scale', demonstrated, a, possible, relationship, between, the]), verbo([increased]), complemento([aripiprazole, concentration, and, coadministration, of, 'darunavir/ritonavir', and, 'duloxetine,', which, inhibit, 'CYP3A4', and, 2, 'D6'])].
[sujeto(['Potential', confounders, to, the]), verbo([increased]), complemento([concentration, include, duloxetine, inhibition, of, 'CYP2D6', 'polymorphism,', possible, 2, 'D6', 'polymorphism,', and, exceeding, 'aripiprazole\'s', maximum, dose])].
[sujeto(['The', initial, presentation, of, confusion, and]), verbo([loss]), complemento([of, coordination, may, have, been, early, signs, of, aripiprazole, 'toxicity,', which, relapsed, as, shown, by, his, symptoms, prior, to, admission])].
[sujeto(['Clinicians', should, be, cognizant, of]), verbo([increased]), complemento([risk, of, aripiprazole, toxicity, in, 'HIV-positive', patients, concurrently, taking, 'ritonavir-boosted', 'ART', and, other, cytochrome, 'P450', inhibitors, like, duloxetine])].
[sujeto(['A', single, dose, of, 'TPV/r', had, no, effect, on, the, activity, of, 'CYP1A2', and, 'CYP2C9;', it, weakly]), verbo([inhibited]), complemento(['CYP2C19', and, 'P-gp;', and, it, potently, inhibited, 'CYP2D6', and, 'CYP3A'])].
[sujeto(['Clinically,', 'TPV', is, coadministered, with, ritonavir, '(', 'RTV)', to, boost, blood, concentrations, and]), verbo([increase]), complemento([therapeutic, efficacy])].
[sujeto(['The', mechanism, of, 'metabolism-mediated', drug, interactions]), verbo([associated]), complemento([with, 'RTV-boosted', 'TPV', is, not, fully, understood])].
[sujeto(['TPV', and, its, metabolites, were]), verbo([found]), complemento([in, the, feces, of, mice, but, not, in, the, urine])].
[sujeto(['In', vitro, study, using, human, liver, microsomes, recapitulated, five, 'TPV', 'metabolites,', all, of, which, were]), verbo([suppressed]), complemento([by, 'RTV'])].
[sujeto(['In', 'vivo,', 'RTV', cotreatment, significantly]), verbo([inhibited]), complemento([eight, 'TPV', metabolic, pathways])].
[sujeto(['In', 'summary,', metabolomic, analysis, revealed, two, known, and, six, novel, 'TPV', metabolites, in, 'mice,', all, of, which, were]), verbo([suppressed]), complemento([by, 'RTV'])].
[sujeto(['The', current, study]), verbo([provides]), complemento([solid, evidence, that, the, 'RTV-mediated', boosting, of, 'TPV', is, due, to, the, modulation, of, 'P450-dependent', metabolism])].
[sujeto(['Numerous', pharmacokinetic, studies]), verbo([suggested]), complemento([that, ritonavir, induces, cytochrome, 'P450', enzymes, 3, 'A,', 1, 'A2,', 2, 'B6,', 2, 'C9,', and, 2, 'C19,', as, well, as, glucuronyl, transferase])].
[sujeto(['Additionally,', several, case]), verbo([reports]), complemento([described, clinically, significant, subtherapeutic, effects, of, drugs, metabolized, by, these, isoenzymes, when, coadministered, with, ritonavir])].
[sujeto(['Both', therapeutic, and, boosting, doses, of, ritonavir, appear, to]), verbo([induce]), complemento([these, 'enzymes;', 'however,', most, of, the, studies, of, 'low-dose', ritonavir, involved, a, second, protease, inhibitor, such, as, 'lopinavir,', 'darunavir,', or, tipranavir])].
[sujeto(['A']), verbo([decrease]), complemento([or, loss, of, therapeutic, effect, may, be, observed, when, ritonavir, is, coadministered, with, medications, that, are, substrates, for, these, enzymes])].
[sujeto(['Oral', midazolam, clearance, '(', overall, 'CYP3A', 'activity)']), verbo([decreased]), complemento([to, 0.19, -, fold, '(', 90, '%', confidence, interval, '(', 'CI),', 0.15, -, 0.23, ')', ',', hepatic, midazolam, clearance, and, intestinal, midazolam, availability, changed, to, 0.24, -, fold, '(', 0.2, -, 0.29, ')', and, 1.12, -, fold, '(', 1.0, -, 1.26, ')', ',', respectively])].
[sujeto(['In', 'CYP2D6', extensive, 'metabolizers,', the, plasma, ratio, 'AUC(dextromethorphan)/AUC(dextrorphan)']), verbo([increased]), complemento([to, 2.92, -, fold, '(', 2.31, -, 3.69, ')'])].
[sujeto(['Digoxin', area, under, the, curve, '(', 'AUC)(0-12)', '(', 'P-glycoprotein', 'activity)']), verbo([increased]), complemento([to, 1.81, -, fold, '(', 1.56, -, 2.09, ')'])].
[sujeto(['In', 'conclusion,', 'CYP3A,', 'CYP2D6,', and, 'P-glycoprotein', are, profoundly]), verbo([inhibited]), complemento([in, patients, receiving, ritonavir, boosted, lopinavir])].
[sujeto(['Ritonavir', '(', 1, 'micromol/L)', completely]), verbo([inhibited]), complemento(['CYP3A4-mediated', metabolism, of, imatinib, to, 'CGP74588', but, inhibited, metabolism, in, microsomes, by, only, 50, '%'])].
[sujeto(['Imatinib', significantly]), verbo([inhibited]), complemento(['CYP3A4', activity, in, vitro])].
[sujeto(['For', agents, with, complex, elimination, pathways, that]), verbo([involve]), complemento(['autoinhibition,', interaction, studies, that, are, done, after, a, single, dose, may, not, be, applicable, when, drugs, are, administered, chronically])].
[sujeto(['Human', immunodeficiency, 'virus-infected', patients]), verbo([have]), complemento([an, increased, risk, for, depression])].
[sujeto(['Theoretically,', 'ritonavir-boosted', protease, inhibitors, may]), verbo([inhibit]), complemento(['CYP2D6-mediated', metabolism, of, paroxetine])].
[sujeto(['Addition', of, 'fosamprenavir-ritonavir', to, paroxetine, resulted, in, a, significant]), verbo([decrease]), complemento([in, paroxetine, 'exposure:', the, geometric, mean, ratios, '(', 90, '%', confidence, 'intervals)', of, paroxetine, plus, 'fosamprenavir-ritonavir', to, paroxetine, alone, were, 0.45, '(', 0.41, to, 0.49, ')', for, the, area, under, the, 'concentration-time', curve, from, 0, to, 24, h, '(', 'AUC(0-24)),', 0.49, '(', 0.45, to, 0.53, ')', for, the, maximum, concentration, of, the, drug, in, plasma, '(', 'C(max)),', and, 0.75, '(', 0.71, to, 0.8, ')', for, the, apparent, elimination, 'half-life', '(', 't(1/2))'])].
[sujeto(['The', free, fraction, of, paroxetine, showed, a, median, '(', interquartile, 'range)']), verbo([increase]), complemento([of, 30, '%', '(', 18, to, 42, '%', ')', after, the, addition, of, 'fosamprenavir-ritonavir'])].
[sujeto(['A', correlation, between, 'HCV-associated', 'liver-fibrosis', severity, and, the, risk, of, 'HAART']), verbo([associated]), complemento([hepatoxicity, has, been, demonstrated, '(', 'Aranzabal', et, al])].
[sujeto(['This', high, liver, toxicity, rate, might, be, due, to]), verbo([increased]), complemento([drug, exposure, in, patients, with, liver, disease, '(', 'Veronese', et, al])].
[sujeto(['It']), verbo([has]), complemento([been, reported, that, patients, with, chronic, hepatitis, 'C', show, significantly, reduced, 'CPY3A4', and, 'CYP2D6', activity, in, comparison, with, healthy, volunteers, '(', 'Becquemont', et, al])].
[sujeto(['Although', many, of, the, clinically, significant, drug, interactions, of, the, 'anti-human', immunodeficiency, virus, '(', 'HIV)', protease, inhibitors, '(', 'PIs)', can, be, explained, by, their, propensity, to, inactivate, 'CYP3A', 'enzymes,', paradoxically, these, drugs]), verbo([cause]), complemento(['(', or, 'lack)', interactions, with, 'CYP3A', substrates, that, cannot, be, explained, by, this, mechanism, '(', e])].
[sujeto(['To', better, understand, these, paradoxical, interactions, '(', or, lack, 'thereof),', we, determined, the, cytochromes, 'P450', and, transporters]), verbo([induced]), complemento([by, various, concentrations, '(', 0, -, 25, 'microM)', of, two, 'PIs,', ritonavir, and, 'nelfinavir,', and, rifampin, '(', positive, 'control)', in, primary, human, hepatocytes])].
[sujeto(['At', 10, 'microM,', ritonavir, and, nelfinavir]), verbo([suppressed]), complemento(['CYP3A4', activity, but, induced, its, transcripts, and, protein, expression, '(', 19, -, and, 12, -, and, 12, -, and, 6, -, 'fold,', 'respectively;', a, &, 'gt;2-fold', change, over, control, was, interpreted, as, 'induction)'])].
[sujeto(['At', 10, 'microM,', rifampin]), verbo([induced]), complemento(['CYP3A4', 'transcripts,', 'CYP3A', 'protein,', and, activity, by, 23, -, ',', 12, -, ',', and, 13, -, 'fold,', respectively])].
[sujeto(['All', three, drugs, '(', 10, 'microM)']), verbo([induced]), complemento(['CYP2B6', activity, by, 2, -, to, 4, -, 'fold,', 'CYP2C8', and, 2, 'C9', activity, by, 2, -, to, 4, -, fold, and, the, transcripts, of, 'CYP2B6,', 2, 'C8,', and, 2, 'C9', by, &, 'gt;3-,', 5, -, ',', and, 3, -, 'fold,', respectively])].
[sujeto(['CYP2C19', and, 1, 'A2', activity, and, transcripts, were, modestly]), verbo([induced]), complemento(['(', 2, -, 'fold),', 'whereas,', as, 'expected,', 'CYP2D6', was, not, induced, by, any, of, the, drugs])].
[sujeto(['Of', the, transporters, 'studied,', protease, inhibitors, moderately]), verbo([induced]), complemento([multidrug, resistance, 1, '(', 'ABCB1)', and, multidrug, 'resistance-associated', protein, '(', 'ABCC1)', transcripts, but, had, no, or, minimal, effect, on, the, transcripts, of, breast, cancer, resistance, protein, '(', 'ABCG2),', organic, 'anion-transporting', peptide, '(', 'OATP)', 1, 'B1', '(', 'SLCO1B1),', or, 'OATP1B3', '(', 'SLCO1B3)'])].
[sujeto(['Tipranavir', is, a, nonpeptidic, protease, inhibitor, that]), verbo([has]), complemento([activity, against, human, immunodeficiency, virus, strains, resistant, to, multiple, protease, inhibitors])].
[sujeto(['Tipranavir', is, metabolized, by, cytochrome, 'P450', '(', 'CYP)', 3, 'A', 'and,', when, combined, with, ritonavir, in, 'vitro,']), verbo([causes]), complemento([inhibition, of, 'CYP1A2,', 'CYP2C9,', 'CYP2C19,', 'CYP2D6,', and, 'CYP3A', in, addition, to, induction, of, glucuronidase, and, the, drug, transporter, 'P-glycoprotein'])].
[sujeto(['In', addition, to, interactions, with, other, 'antiretrovirals,', 'tipranavir-ritonavir', interactions, with, 'antifungals,', 'antimycobacterials,', oral, 'contraceptives,', 'statins,', and, antidiarrheals]), verbo([have]), complemento([been, specifically, evaluated])].
[sujeto(['The', highly, complex, nature, of, drug, interactions, dictates, that, cautious, prescribing, should, occur, with, 'narrow-therapeutic-index', drugs, that]), verbo([have]), complemento([not, been, specifically, studied])].
[sujeto(['Thus,', the, known, interaction, potential, of, 'tipranavir-ritonavir', is, 'reported,', and, in, vitro, and, in, vivo, data, are]), verbo([provided]), complemento([to, assist, clinicians, in, predicting, interactions, not, yet, studied])].
[sujeto(['Clinical', studies]), verbo([have]), complemento([shown, that, escitalopram, is, effective, and, well, tolerated, in, the, treatment, of, depression, and, anxiety, disorders])].
[sujeto(['Escitalopram']), verbo([has]), complemento([low, protein, binding, '(', 56, '%', ')', and, is, not, likely, to, cause, interactions, with, highly, 'protein-bound', drugs])].
[sujeto(['Adolescents,', elderly, individuals, and, patients, with, hepatic, impairment, do, not]), verbo([have]), complemento([clinically, relevant, differences, in, pharmacokinetics, compared, with, healthy, young, 'adults,', implying, that, adjustment, of, the, dosage, is, not, necessary, in, these, patient, groups])].
[sujeto(['Coadministration', of, escitalopram, 20, mg, following, 'steady-state', administration, of, cimetidine, or, omeprazole]), verbo([led]), complemento([to, a, 72, '%', and, 51, '%', 'increase,', 'respectively,', in, escitalopram, exposure, compared, with, administration, alone])].
[sujeto(['In', vitro, studies]), verbo([have]), complemento([shown, that, escitalopram, has, negligible, inhibitory, effects, on, 'CYP', isoenzymes, and, 'P-glycoprotein,', suggesting, that, escitalopram, is, unlikely, to, cause, clinically, significant, 'drug-drug', interactions])].
[sujeto(['The', favourable, pharmacokinetic, profile, of, escitalopram]), verbo([suggests]), complemento([clinical, utility, in, a, broad, range, of, patients])].
[sujeto(['This', combination]), verbo([has]), complemento([the, advantage, of, simplifying, treatment, and, improving, 'long-term', tolerance])].
[sujeto(['By', multivariable, 'analysis,', the, risk, of, treatment, discontinuation, due, to, 'VF', was, similar, between, 'ABC/3TC/NVP', and, other, 'ARV', 'regimens,', except, for, 'TDF/FTC/ATV', and, 'ABC/3TC/ATV,', which, were]), verbo([associated]), complemento([with, a, higher, risk, of, treatment, interruption, due, to, 'VF', '(', hazard, ratio, '[', 'HR]', 1.99, ;, 95, '%', confidence, interval, '[', 'CI]', 1.29, -, 3.06, and, 'HR', 2.19, ;, 95, '%', 'CI', 1.51, -, 3.18, ',', 'respectively)'])].
[sujeto(['Other', 'ARV', regimens, were]), verbo([associated]), complemento([with, a, 1.8, -, to, 3.19, -, fold, increase, in, the, risk, of, treatment, discontinuation, due, to, 'ADR', '(', 'P', &, 'lt;', 0.0001, for, all, 'comparisons)'])].
[sujeto(['Because', the, viral, load]), verbo([increased]), complemento([to, 222, ',', 0, 'copies/mL', at, the, initiation, of, antiretroviral, 'therapy,', we, added, raltegravir])].
[sujeto(['The']), verbo([decrease]), complemento([in, the, viral, load, was, 'satisfactory,', and, a, caesarean, delivery, was, performed])].
[sujeto(['SALT', is, a, 'multicentre,', 'open-label,', 'non-inferiority', clinical, trial, in, 'HIV-1-infected', virologically]), verbo([suppressed]), complemento([patients])].
[sujeto(['Non-inferiority', was, demonstrated, if, the, lower]), verbo([bound]), complemento([of, the, 95, '%', 'CI', for, the, difference, was, not, below, -, 12, '%'])].
[sujeto(['In', both, 'groups,', similar, values, were, observed, for, patients, with, confirmed, virological, failure, in, 'ATV/r', +, 3, 'TC', versus, 'ATV/r', +, 2, 'NUCs', '(', 9, versus, 5, ')', ',', death, '(', 1, versus, 0, ')', ',', discontinuation, due, to, 'ART-related', toxicity, '(', 7, versus, 11, ')', ',', withdrawal, from, the, study, '(', 7, versus, 9, ')', and]), verbo([loss]), complemento([to, 'follow-up', '(', 6, versus, 6, ')'])].
[sujeto(['The', 'long-term', results, of, switching, to, 'ATV/r', +, 3, 'TC', show, that, this, strategy, is, 'effective,', safe, and, 'non-inferior', to, 'ATV', +, 2, 'NUCs', in, virologically]), verbo([suppressed]), complemento(['HIV-infected', patients])].
[sujeto(['A', retrospective, analysis, was, conducted, on, adults, who, had, plasma, viral, load, '(', 'pVL)<200', 'copies/mL', 'for≥six', months, while, receiving, 'TDF/lamivudine', '(', 3, 'TC) - or', 'TDF/emtricitabine', '(', 'FTC)-based', antiretroviral, therapy, '(', 'ART),', then, switched, to, 'ABC/3TC', while]), verbo([retaining]), complemento([the, third, drug, in, the, 'ART', regimen])].
[sujeto(['Median', serum, creatinine, was, 93, 'µmol/L', '(', 'IQR', 80, -, 111, ')', at, baseline, and]), verbo([decreased]), complemento([to, 88, 'µmol/L', '(', 'IQR', 78, -, 98, ')', at, 12, months, after, the, switch, to, 'ABC'])].
[sujeto(['Median', eGFR]), verbo([increased]), complemento([from, 74, '(', 'IQR', 60, -, 88, ')', 'mL/min', at, baseline, to, 80, 'mL/min', '(', 'IQR', 69, -, 89, ')', at, 12, months])].
[sujeto(['Viral', suppression, was]), verbo([maintained]), complemento([among, patients, who, switched, from, 'TDF/3TC', or, 'TDF/FTC', to, 'ABC/3TC'])].
[sujeto(['Virologic', and, safety, outcomes, of, 'ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin', '(', 'OBV/PTV/r ± DSV ± RBV)', therapy]), verbo([have]), complemento([shown, high, sustained, virologic, response, '(', 'SVR)', rates, and, good, tolerability, in, most, patient, populations, in, 'pre-registration', studies])].
[sujeto(['Adverse', events, occurred, in, 151, '(', 72.2, '%', ')', patients, and, were, mostly, mild, and]), verbo([associated]), complemento([with, the, use, of, 'RBV'])].
[sujeto(['Serious', adverse, 'events,', including, hepatic, 'decompensation,', renal, 'insufficiency,', 'anaemia,', hepatotoxicity, and, 'diarrhoea,', were]), verbo([reported]), complemento([in, eight, '(', 3.8, '%', ')', patients])].
[sujeto(['In', five, '(', 2.4, '%', ')', 'patients,', adverse, events]), verbo([led]), complemento([to, treatment, discontinuation])].
[sujeto(['Prophylactic', treatment, regimens, to]), verbo([prevent]), complemento(['mother-to-child', 'HIV', transmission, include, protease, inhibitors, 'Lopinavir', and, 'Ritonavir'])].
[sujeto(['Lopinavir', and, 'Ritonavir']), verbo([have]), complemento([been, reported, to, be, able, to, induce, intracellular, oxidative, stress, in, diverse, cellular, 'models,', however, scarce, informations, are, available, about, protease, inhibitor, effects, of, in, the, central, nervous, system, '(', 'CNS)'])].
[sujeto(['We', treated, a, neuroblastoma, cell, line, '(', 'SH-SY5Y)', with]), verbo([increasing]), complemento([doses, of, 'Lopinavir', and, 'Ritonavir', '(', 0.1, -, 1, -, 10, -, 25, -, 50, 'µM),', used, alone, or, in, 'combination,', evaluating, the, impact, of, these, drugs, in, terms, of, mitochondrial, 'activity,', with, 'MTT', cell, proliferation, 'assay;', mRNA, expression, of, heme, oxygenase, '(', 'HemeOH)', and, reactive, oxygen, species, '(', 'ROS)', levels, with, 2, '\'', ',', 7, '\'', -, dichlorofluorescin, diacetate, '(', 'H2DCFDA)', in, order, to, assess, oxidative, 'stress;', apoptotic, cell, death, with, flow, cytometry])].
[sujeto(['We', observed, that, 'Lopinavir', and, 'Ritonavir', 'treatment,', at, 25, 'and/or', 50, µM, 'concentrations,']), verbo([induced]), complemento([mitochondrial, 'damage,', increase, of, heme, oxygenase, 'RNA', expression, levels, and, 'ROS', 'generation,', followed, by, apoptosis, in, 'SH-SY5Y'])].
[sujeto(['We']), verbo([report]), complemento([a, 57, years, old, female, with, 'AIDS', treated, with, 'lamivudine,', 'zidovudine,', 'atazanavir,', ritonavir, and, cotrimoxazole, presenting, with, ischemic, signs, in, the, four, limbs])].
[sujeto(['The', efflux, transporter, 'P-glycoprotein', '(', 'P-gp)', significantly]), verbo([modulates]), complemento([drug, transport, across, the, intestinal, 'mucosa,', strongly, reducing, the, systemic, absorption, of, various, active, pharmaceutical, ingredients])].
[sujeto(['P-gp', inhibitors, could, serve, as, helpful, tools, to]), verbo([enhance]), complemento([the, oral, bioavailability, of, those, substances])].
[sujeto(['Some', synthetic, phospholipids]), verbo([have]), complemento([been, found, to, strongly, reduce, 'P-gp´s', activity])].
[sujeto(['Both', phospholipids, not, only]), verbo([led]), complemento([to, the, strongest, absorption, of, 'RH123,', but, a, permeability, enhancing, effect, was, detected, in, addition, to, the, 'P-gp', inhibition])].
[sujeto(['Their', effects, on, membrane, fluidity, were, not, consistent, with, their, 'P-gp']), verbo([inhibiting]), complemento(['effects,', and, therefore, suggested, a, more, complex, mode, of, action])].
[sujeto(['Both', phospholipids, significantly]), verbo([increased]), complemento([the, area, under, the, ritonavir, plasma, level, curve, '(', 'AUC)', within, 150, min, by, more, than, 'tenfold,', but, were, inferior, to, 'Tween®', 80, ',', which, showed, superior, solubilizing, effects])].
[sujeto(['Formulating', 'P-gp', substrates, with, an, originally, low, oral, bioavailability, is, a, difficult, 'task,']), verbo([requiring]), complemento([concerted, interplay, of, all, excipients])].
[sujeto(['P-gp']), verbo([inhibiting]), complemento([phospholipids, offer, a, new, tool, to, help, cope, with, these, challenges])].
[sujeto(['A', regimen, of, 'ABC/3TC + DRV/r', was, more, likely, to, be, prescribed, in, the, later, years, of, the, study, 'period,']), verbo([leading]), complemento([to, a, shorter, median, 'follow-up', in, the, 'DRV/r', treatment, group, '(', 'as-treated', 'analysis:', 14, vs])].
[sujeto([72, ')', and]), verbo([gains]), complemento([in, 'CD4', 'T cell', counts, '(', median, darunavir, vs])].
[sujeto(['The', 'patient-centric', quality]), verbo([target]), complemento([product, profile, '(', 'QTPP)', was, defined, and, critical, quality, attributes, '(', 'CQAs)', earmarked])].
[sujeto(['Liposome', vesicle, 'size,', drug, entrapment, efficiency, and, '%', drug]), verbo([release]), complemento([after, 60, min, were, selected, as, 'CQAs', and, mathematical, relationship, between, 'CQAs', and, 'CMAs', was, derived, using, multiple, linear, regression, analysis])].
[sujeto(['Optimum', composition, of, 'CMAs,', identified, using, numerical, optimization, and, desirability, 'function,', demonstrated, excellent, entrapment, efficiency, '(', &, 'gt;90%),', drug]), verbo([release]), complemento([characteristics, '(', &, 'gt;95%', in, 60, 'min)', and, had, vesicle, size, of, 659.7, '±23'])].
[sujeto(['Solid', state, characterization, studies, '(', 'Differential', 'Scanning', 'Calorimetry,', scanning, electron, microscopy, and, 'X-ray', 'diffraction)', were, performed, for, optimized, 'proliposome,']), verbo([suggested]), complemento([transformation, of, crystalline, to, amorphous, form])].
[sujeto(['Stability', study, of, the, optimized, 'LPV', loaded, proliposome, was, performed, as, per, 'ICH', guideline, and, was]), verbo([found]), complemento([to, be, stable, for, period, of, 6, months])].
[sujeto(['Overall', results, of, the, study, indicate, that, the, proliposome, offers, advantages, of]), verbo([enhanced]), complemento([oral, bioavailability, for, poorly, soluble, 'LPV'])].
[sujeto(['Interactions', resulting, in, a, greater, than, 50, '%', reduction, or, 100, '%']), verbo([increase]), complemento([in, an, 'AUC24,ss', value, were, examined, as, covariates, for, an, effect, on, apparent, clearance, '(', 'CL/F)'])].
[sujeto(['No', comedication, 'class/category']), verbo([decreased]), complemento([or, increased, 'ombitasvir,', 'dasabuvir,', 'ritonavir,', or, ribavirin, 'AUC24,ss', by, more, than, half, or, 2, -, 'fold,', respectively])].
[sujeto(['Opioids,', 'antipsychotics,', 'anti-epileptics,', antidiabetics, and, 'non-ethinyl', 'estradiol-containing', hormone, replacement, therapies, appeared, to]), verbo([have]), complemento([an, effect, '(', 'AUC24,ss', ratio, '≤', 0.5, or, '≥', 2.0, ')', on, paritaprevir, exposures])].
[sujeto(['However,', when, these, classes, were, included, in, the, paritaprevir, population, pharmacokinetic, 'model,', only, opioids, and, antidiabetics, had, a, statistically, significant, effect, on, 'CL/F,', but, with, no, clinically, meaningful]), verbo([increase]), complemento([in, exposures, '(', '≤', 55, '%', ')'])].
[sujeto(['However,', the]), verbo([target]), complemento([antiretroviral, concentrations, associated, with, long, term, viral, suppression, have, not, been, adequately, defined, in, children])].
[sujeto(['We', assessed, the, relationship, between, plasma, lopinavir, or, nevirapine, concentrations, and, the, risk, of, subsequent, viremia, in, children, initially]), verbo([suppressed]), complemento([on, antiretroviral, therapy])].
[sujeto(['The', hazard, of, subsequent, viremia, during, 'follow-up', was]), verbo([increased]), complemento([for, lopinavir, concentrations, &, 'lt;1mg/L', vs, '≥1mg/L', '(', adjusted, hazard, ratio, 0.62, '[', 95, '%', 'CI,', 0.4, -, 0.94, ']', ')', and, for, children, with, viral, loads, 51, -, 400, 'copies/mL', at, randomization])].
[sujeto(['Nevirapine', concentrations, were, not, significantly]), verbo([associated]), complemento([with, subsequent, viremia])].
[sujeto(['Our', findings, support, a, minimum]), verbo([target]), complemento([concentration, of, '≥1mg/L', of, lopinavir, to, ensure, sustained, viral, suppression])].
[sujeto(['Atazanavir', 400, mg, 'once-daily']), verbo([provided]), complemento([suboptimal, exposure])].
[sujeto(['Presence', of, confirmed, virologic, failure, was, not]), verbo([associated]), complemento([with, growth])].
[sujeto(['We', identified, patients, with, 'LDL', above]), verbo([targets]), complemento([defined, by, the, 'French', expert, group, on, 'HIV', and, by, the, 'HIV', 'Medicine', 'Association', of, the, 'Infectious', 'Disease', 'Society', of, 'America', and, the, 'Adult', 'AIDS', 'Clinical', 'Trials', 'Group', '(', 'IDSA-AACTG)'])].
[sujeto(['Fifty', one, '(', 44.4, '%', ')', and, 36, '(', 31.3, '%', ')', patients, had, not, reached, their, 'LDL']), verbo([target]), complemento([according, to, 'IDSA-AACTG', and, 'French', 'recommendations,', respectively])].
[sujeto(['Roughly', one, third, had, high, 'LDL', levels]), verbo([requiring]), complemento([specific, intervention])].
[sujeto(['All', patients]), verbo([maintained]), complemento(['HIV-RNA', &, 'lt;50', 'copies/mL;', the, median, 'CD4+', cell, count, remained, stable])].
[sujeto(['Mean', triglycerides]), verbo([decreased]), complemento([from, 124, 'mg/dL', '(', 'range,', 39, -, 625, ')', at, enrolment, to, 108.7, 'mg/dL', '(', 'range,', 39, -, 561, ')', at, study, end, '(', 'P', =, 0.25, ')'])].
[sujeto(['At', 'baseline,', mean, cholesterol, was, 172.8, ±, 38.1, 'mg/dL', and]), verbo([decreased]), complemento([to, 161.9, ±, 38.6, 'mg/dL', '(', 'P', =, 0.038, ')', ;, 'likewise,', median, total, bilirubin, decreased, from, 1.07, 'mg/dL', '(', 'range,', 0.2, -, 4.7, ')', to, 0.6, 'mg/dL', '(', 'range,', 0.13, -, 3.1, ')', '(', 'P', &, 'lt;0'])].
[sujeto(['Switching', to, 'RPV/FTC/TDF', from, an, unboosted, 'PI', in, virologically]), verbo([suppressed]), complemento(['HIV-infected', patients, is, safe, and, is, associated, with, a, reduction, in, 'triglycerides,', cholesterol, and, 'cART-related', costs])].
[sujeto(['Renal', toxicity, due, to, tenofovir, '(', 'TDF)']), verbo([has]), complemento([been, largely, described, in, patients, with, 'HIV', infection])].
[sujeto(['This', study, aimed, at, exploring, evolution, of, renal, function, and, lipid, profile, after, switching, from, 'tenofovir/emtricitabine', '(', 'TDF/FTC)', to, 'abacavir/lamivudine', '(', 'ABC/3TC),']), verbo([maintaining]), complemento([the, 'ATV/r', component, of, the, regimen])].
[sujeto(['Patients', in, the, 'Italian', 'MASTER', 'Cohort,', who, switched, from, 'TDF/FTC', plus, 'ATV/r', to, 'ABC/3TC', plus, 'ATV/r', were, 'included,']), verbo([provided]), complemento([that, major, renal, diseases, were, not, diagnosed, before, switching, '(', i])].
[sujeto(['A', small, but, significant]), verbo([decrease]), complemento([in, serum, creatinine, '[', from, 1.06, 'mg/dl', '(', 'SD:', 0.3, ')', to, 0.94, 'mg/dl', '(', 'SD:', 0.2, ')', ;, 'p<0'])].
[sujeto(['Also', 'ITT', analysis, showed, a]), verbo([decrease]), complemento([in, mean, serum, creatinine, '[', from, 1.08, 'mg/dl', '(', 'SD:', 0.35, ')', to, 0.95, 'mg/dl', '(', 'SD:', 0.24, ')', ;, 'p<0'])].
[sujeto(['Total', cholesterol]), verbo([increased]), complemento(['[', from, 188, 'mg/dl', '(', 'SD:', 42, ')', to, 206, 'mg/dl', '(', 'SD:', 44, ')', ;, 'p<0'])].
[sujeto([1, ']', but, also, 'HDL']), verbo([increased]), complemento([as, well, '[', from, 46, 'mg/dl', '(', 'SD:', 14, ')', to, 54, 'mg/dl', '(', 'SD:', 19, ')', ;, 'p=0'])].
[sujeto(['An']), verbo([increase]), complemento([in, triglycerides, concentration, was, observed, '[', from, 162, 'mg/dl', '(', 'SD:', 144, ')', to, 214, 'mg/dl', '(', 'SD:', 109, ')', ;, 'p=0'])].
[sujeto(['Also', 'ITT', analysis, showed]), verbo([increases]), complemento([of, both, total, cholesterol, '[', from, 187, 'mg/dl', '(', 'SD:', 43.69, ')', to, 203, 'mg/dl', '(', 'SD:', 44.1, ')', ;, 'p<0'])].
[sujeto(['This', analysis]), verbo([reports]), complemento([an, improvement, in, eGFR, and, an, increase, in, total, cholesterol, and, 'HDL', fraction, at, month, 18, after, switching, to, 'ABC/3TC', plus, 'ATV/r'])].
[sujeto(['Given', the, fact, that, renal, function, was, not, significantly, affected, at, 'baseline,', our, findings, may]), verbo([suggest]), complemento([the, utility, of, a, proactive, switch, from, 'TDF', to, 'ABC,', when, otherwise, 'indicated,', in, patients, who, cannot, avoid, using, a, nucleoside, backbone])].
[sujeto(['In', this, 'international,', 'randomised,', 'controlled,', 'double-blind,', phase, 3, study, '(', 'Women', 'AntiretroViral', 'Efficacy', and, 'Safety', study, '[', 'WAVES]),', we]), verbo([recruited]), complemento(['treatment-naive', 'HIV-infected', women, with, an, estimated, creatinine, clearance, of, 70, 'mL/min', or, higher, from, 80, centres, in, 11, countries])].
[sujeto(['HIV', protease, inhibitors, are, important, antiretroviral, drugs, which]), verbo([have]), complemento([substantially, reduced, the, morbidity, and, mortality, associated, with, 'HIV-1', infection])].
[sujeto(['Recent', data]), verbo([have]), complemento([shown, relationships, between, plasma, concentrations, of, the, protease, inhibitors, and, clinical, 'response,', which, makes, therapeutic, drug, monitoring, valuable])].
[sujeto(['We']), verbo([have]), complemento([developed, and, validated, an, 'assay,', using, liquid, chromatography, coupled, with, electrospray, tandem, mass, spectrometry, '(', 'LC/MS/MS),', for, the, routine, quantification, of, the, six, licensed, protease, inhibitors, '(', 'amprenavir,', 'indinavir,', 'lopinavir,', 'nelfinavir,', ritonavir, and, 'saquinavir)', and, the, pharmacologically, active, nelfinavir, metabolite, 'M8', in, plasma])].
[sujeto(['HIV', protease, inhibitors, '(', 'HIV', 'PI)', reduce, morbidity, and, mortality, of, 'HIV', infection, but]), verbo([cause]), complemento([multiple, untoward, effects])].
[sujeto(['Because', certain, 'HIV', 'PI', evoke, production, of, reactive, oxygen, species, '(', 'ROS)', and, 'volume-sensitive', 'Cl(-)', current, '(', 'I(Cl,swell))', is]), verbo([activated]), complemento([by, 'ROS,', we, tested, whether, 'HIV', 'PI', stimulate, 'I(Cl,swell)', in, ventricular, myocytes])].
[sujeto(['In', 'contrast,', 'amprenavir,', 'nelfinavir,', and, 'raltegravir,', an, integrase, 'inhibitor,', did, not]), verbo([modulate]), complemento(['I(Cl,swell)', acutely])].
[sujeto(['I(Cl,swell)', activation, was, attributed, to, 'ROS', because, 'ebselen,', an, 'H(2)O(2)', 'scavenger,']), verbo([suppressed]), complemento(['ritonavir-', and, 'lopinavir-induced', 'I(Cl,swell)'])].
[sujeto(['In', 'contrast,', 'rotenone,', a, mitochondrial, 'e(-)', transport, 'inhibitor,']), verbo([suppressed]), complemento([both, 'ritonavir-', and, 'lopinavir-induced', 'I(Cl,swell)'])].
[sujeto(['Flow', cytometry, confirmed, that, ritonavir, and, lopinavir, but, not, 'amprenavir,', 'nelfinavir,', or, raltegravir, augmented, 'ROS', 'production,', and, 'HIV', 'PI-induced', 'ROS', production, was]), verbo([suppressed]), complemento([by, rotenone, but, not, 'NADPH', oxidase, blockade])].
[sujeto(['These', data]), verbo([suggest]), complemento([ritonavir, and, lopinavir, activated, 'I(Cl,swell)', via, mitochondrial, 'ROS', production, that, was, independent, of, 'NADPH', oxidase])].
[sujeto(['Acidification', of, the, dog, stomach, by, coadministration, of, 'HCl']), verbo([increased]), complemento([the, bioavailability, of, the, calcium, salt, to, levels, near, those, of, the, sodium, salt])].
[sujeto(['Taken', 'together,', these, results]), verbo([suggest]), complemento([that, 'GW433908', is, primarily, metabolized, to, 'APV', at, or, in, the, epithelial, cells, of, the, intestine, and, that, the, prodrug, is, not, substantially, absorbed])].
[sujeto(['The', first]), verbo([requires]), complemento([a, mobile, phase, containing, sodium, phosphate, 'buffer+ion', 'pair-acetonitrile', '(', 50, :, 50, ',', 'v/v)', through, a, 'C18', 'Symmetry', column, '(', 250, x4])].
[sujeto(['The', second, system]), verbo([requires]), complemento([three, mobile, phases, '(', potassium, phosphate, 'buffer+ion', 'pair-acetonitrile)', for, different, elution, through, a, 'C18', 'Symmetry', 'Shield', column, '(', 250, x4])].
[sujeto(['We', here]), verbo([report]), complemento([that, 'GRL-10413,', a, novel, 'non-peptidic', 'HIV-1', protease, inhibitor, '(', 'PI)', containing, a, modified, 'P1', moiety, and, a, sulfonamide, 'isostere,', is, highly, active, against, laboratory, 'HIV-1', strains, and, primary, clinical, isolates, '(', 'EC50:', 0.00035, -, 0.0018, 'μM)', with, minimal, cytotoxicity, '(', 'CC50:', 35.7, 'μM)'])].
[sujeto(['GRL-10413', also]), verbo([maintained]), complemento([its, strong, antiviral, activity, against, 'multi-drug-resistant', clinical, 'HIV-1', variants, isolated, from, 'patients,', who, no, longer, responded, to, various, antiviral, regimens, after, 'long-term', antiretroviral, therapy])].
[sujeto(['Analysis', of, the, crystal, structure, of, 'HIV-1', protease, in, complex, with, 'GRL-10413', demonstrated, that, the, modified, 'P1', moiety, of, 'GRL-10413']), verbo([has]), complemento([a, greater, hydrophobic, surface, area, and, makes, greater, van, der, 'Waals', contacts, with, 'active-site', amino, acids, of, protease, than, in, the, case, of, darunavir])].
[sujeto(['Moreover,', the, chlorine, substituent, in, the, 'P1', moiety]), verbo([interacts]), complemento([with, protease, in, two, distinct, configurations])].
[sujeto(['The', present, data, demonstrate, that, 'GRL-10413']), verbo([has]), complemento([desirable, features, for, treating, patients, infected, with, 'wild-type', 'and/or', 'multi-drug-resistant', 'HIV-1', variants, with, favorable, 'CNS-penetration', capability, and, that, the, newly, modified, 'P1-moiety', may, confer, desirable, features, in, designing, novel, 'anti-HIV-1', 'PIs'])].
[sujeto(['Studies']), verbo([have]), complemento([shown, that, transgender, women, '(', 'TGW)', are, disproportionately, affected, by, 'HIV,', with, an, estimated, 'HIV', prevalence, of, 19.1, '%', among, 'TGW', worldwide])].
[sujeto(['After', receiving, a, 'diagnosis,', 'HIV-positive', 'TGW']), verbo([have]), complemento([challenges, accessing, effective, 'HIV', 'treatment,', as, demonstrated, by, lower, rates, of, virologic, suppression, and, higher, 'HIV-related', mortality])].
[sujeto(['These', adverse, 'HIV', outcomes]), verbo([have]), complemento([been, attributed, to, the, multiple, sociocultural, and, structural, barriers, that, negatively, affect, their, engagement, within, the, 'HIV', care, continuum])].
[sujeto(['Pharmacokinetic', studies]), verbo([have]), complemento([shown, that, certain, antiretroviral, therapy, '(', 'ART)', 'agents,', such, as, protease, inhibitors, '(', 'PIs),', 'non-nucleoside', reverse, transcriptase, inhibitors, '(', 'NNRTIs)', and, 'cobicistat,', interact, with, ethinyl, 'estradiol,', the, key, oestrogen, component, of, oral, contraceptives, '(', 'OCPs)'])].
[sujeto(['The', goal, of, this, article, is, to]), verbo([provide]), complemento([an, overview, of, hormonal, regimens, used, by, 'TGW,', to, summarize, the, known, 'drug-drug', interactions, '(', 'DDIs)', between, feminizing, hormonal, regimens, and, 'ART,', and, to, provide, clinical, care, recommendations])].
[sujeto(['No', studies, examined, interactions, between, 'ART', and, the, types, and, doses, of, oestrogens]), verbo([found]), complemento([in, feminizing, regimens])].
[sujeto(['DDIs', that, may]), verbo([have]), complemento([the, potential, to, result, in, loss, of, virologic, suppression, included, ethinyl, estradiol, and, 'amprenavir,', unboosted, fosamprenavir, and, stavudine])].
[sujeto(['Computational', modeling, could]), verbo([provide]), complemento([a, more, general, assessment, of, drug, resistance, and, could, be, made, available, to, clinicians, through, the, 'Internet'])].
[sujeto(['We']), verbo([have]), complemento([created, a, protocol, involving, sequence, comparison, and, 'all-atom', 'protein-ligand', induced, fit, simulations, to, predict, resistance, at, the, molecular, level])].
[sujeto(['Our', computational, approach, detected, all, of, the, genotype, changes]), verbo([triggering]), complemento(['high-level', 'resistance,', even, those, involving, a, large, number, of, mutations])].
[sujeto(['We']), verbo([have]), complemento([systematically, validated, the, activity, and, inhibition, of, a, 'HIV-1', protease, '(', 'PR)', variant, bearing, 17, mutations, '(', 'PR(S17)),', selected, to, represent, high, resistance, by, machine, learning, on, 'genotype-phenotype', data])].
[sujeto(['PR(S17),', which, forms, a, stable, dimer, '(', &, 'lt;10', 'nM),', is, '∼10-', and, 2, -, fold, less, efficient, in, processing, the, 'Gag', polyprotein, than, the, wild, type, and, 'PR20,', 'respectively,', but]), verbo([maintains]), complemento([the, same, cleavage, order])].
[sujeto(['Resistance', of, 'PR(S17)', to, eight, protease, inhibitors, '(', 'PIs)', relative, to, 'PR', '(', 'Ki)']), verbo([increases]), complemento([by, 1.5, -, 5, orders, of, magnitude, from, 0.01, to, 8.4, μM])].
[sujeto(['Amprenavir,', 'darunavir,', 'atazanavir,', and, 'lopinavir,', the, most, effective, of, the, eight, 'PIs,']), verbo([inhibit]), complemento([precursor, autoprocessing, at, the, 'p6pol/PR', site, with, 'IC50', values, ranging, from, '∼7'])].
[sujeto(['TFP/p6pol', 'cleavage,', which, occurs, 'faster,', is]), verbo([inhibited]), complemento([even, more, weakly, by, all, 'PIs', except, darunavir, '(', 'IC50', =, 15, 'μM);', amprenavir, shows, a, 2, -, fold, increase, in, 'IC50', '(', '∼15', 'μM),', and, atazanavir, and, lopinavir, show, increased, 'IC50', values, of, &, 'gt;42', and, &, 'gt;70', 'μM,', respectively])].
[sujeto(['Although', several, antiretroviral, 'drugs,', including, the, 'd-drugs', stavudine, '(', 'd4T)', and, didanosine, '(', 'ddI),', may]), verbo([cause]), complemento(['biomarker-defined', 'hepatotoxicity,', their, association, with, clinically, defined, 'end-stage', liver, disease, '(', 'ESLD)', and, hepatocellular, carcinoma, '(', 'HCC)', remains, unknown])].
[sujeto(['After', 'adjustment,', cumulative, '(', per, 5, 'years)', exposure, to, d4T, '[', relative, rate, 1.46, '(', 95, '%', confidence, interval, 1.2, -, 1.77, ')', ']', ',', ddI, '[', 1.32, '(', 1.07, -, 1.63, ')', ']', ',', tenofovir, '[', 'TDF,', 1.46, '(', 1.11, -, 1.93, ')', ']', and, '(', 'fos)amprenavir', '[', 'APV;', 1.47, '(', 1.01, -, 2.15, ')', ']', was]), verbo([associated]), complemento([with, increased, 'ESLD/HCC', rates])].
[sujeto(['Longer', exposure, to, emtricitabine, '[', 0.51, '(', 0.32, -, 0.83, ')', ']', and, nevirapine, '[', 0.76, '(', 0.58, -, 0.98, ')', ']', were]), verbo([associated]), complemento([with, lower, 'ESLD/HCC', rates])].
[sujeto(['The', 'ddI/d4T-associated']), verbo([increased]), complemento(['ESLD/HCC', rate, only, started, to, decline, 6, years, after, cessation])].
[sujeto(['Cumulative', use, of, 'd4T,', 'ddI,', 'TDF', and, 'APV', were, independently]), verbo([associated]), complemento([with, increased, 'ESLD/HCC', 'rates,', and, intensified, monitoring, of, liver, function, should, hence, be, considered, among, all, individuals, exposed, for, longer, time, periods])].
[sujeto(['The', use, of, 'd-drugs', should, furthermore, be, 'avoided,', where, there, are, alternatives, 'available,', and, focus, should, be, put, on, those, with, 'longer-term', 'd-drugs', exposure, who, remain, at]), verbo([increased]), complemento(['ESLD/HCC', risk])].
[sujeto(['The', current]), verbo([report]), complemento([describes, a, mucosal, 'pre-exposure', prophylaxis, '(', 'mPrEP)', strategy, that, utilizes, nanocarrier, conjugates, '(', 'NC)', consisting, of, 'poly(ethylene', 'glycol)', '(', 'PEG),', amprenavir, '(', 'APV),', and, a, 'cell-penetrating', peptide, '(', 'CPP;', namely, 'Bac7,', a, fragment, derived, from, bactenecin, 7, ')'])].
[sujeto(['There', was, no, detectable, punctate, fluorescence, in, either, cell, line]), verbo([suggesting]), complemento([that, 'BPF', directly, enters, the, cytosol, thus, avoiding, endosomal, entrapment])].
[sujeto(['BPF', concentrations, also, remained, constant, for, the, 5, days, of, the, study]), verbo([suggesting]), complemento([that, '(', 1, ')', the, 'NC\'s', structural, characteristics, '(', i])].
[sujeto(['These', encouraging, results]), verbo([suggest]), complemento([that, 'Bac7', functionalized, 'NCs', delivered, locally, to, the, colorectal, mucosa, may, form, drug, delivery, depots, that, are, capable, of, sustaining, colorectal, drug, concentrations])].
[sujeto(['Although', the, exact, mechanisms, for, tissue, persistence, are, unclear, and, will]), verbo([require]), complemento([further, 'study,', these, results, provide, 'proof-of-concept', feasibility, for, mPrEP])].
[sujeto(['The', significant, role, of, 'HIV-1', protease, in, viral, replication]), verbo([has]), complemento([made, it, a, potential, drug, target])].
[sujeto(['In', the, recent, 'past,', phytochemical, 'Gallic', 'Acid', '(', 'GA)', derivatives]), verbo([have]), complemento([been, screened, for, protease, inhibitor, activity])].
[sujeto(['The', 'GA4', derivative]), verbo([provided]), complemento([a, lead, for, designing, more, effective, 'HIV-1', 'PR', inhibitors])].
[sujeto(['Using', a]), verbo([modular]), complemento(['HIV-2', protease, cassette, 'system,', inhibition, profiling, assays, were, carried, out, for, protease, inhibitors, both, in, enzymatic, and, cell, culture, assays])].
[sujeto(['Moreover,', the, 'treatment-associated', resistance, mutations, '(', 'I54M,', 'L90M)', were, introduced, into, the]), verbo([modular]), complemento(['system,', and, comparative, inhibition, assays, were, performed, to, determine, their, effect, on, the, susceptibility, of, the, protease])].
[sujeto(['Our', results, indicate, that, 'darunavir,', 'saquinavir,', indinavir, and, lopinavir, were, very, effective, 'HIV-2', protease, 'inhibitors,', while, 'tipranavir,', nelfinavir, and, amprenavir, showed, a]), verbo([decreased]), complemento([efficacy])].
[sujeto(['To', our, 'knowledge,', this]), verbo([modular]), complemento([system, constitutes, a, novel, approach, in, the, field, of, 'HIV-2', protease, characterization, and, susceptibility, testing])].
[sujeto(['In', this, 'work,']), verbo([have]), complemento([investigated, the, binding, affinities, of, nine, 'FDA-approved', protease, inhibitor, drugs, against, a, new, 'HIV-1', subtype, 'C', mutated, 'protease,', 'I36T↑T'])].
[sujeto(['Molecular', dynamics, simulations, were, carried, out, on, the, complexes, to, calculate, the, average]), verbo([binding]), complemento([free, energies, for, each, inhibitor, using, the, molecular, mechanics, generalized, 'Born', surface, area, '(', 'MM-GBSA)', method])].
[sujeto(['When', compared, to, the]), verbo([binding]), complemento([free, energies, of, the, 'HIV-1', subtype, 'B', and, subtype, 'C', proteases, '(', calculated, previously, by, our, group, using, the, same, 'method),', it, was, clear, that, the, 'I36T↑T', proteases, mutations, and, insertion, had, a, significant, negative, effect, on, the, binding, energies, of, the, 'non-pepditic', inhibitors, 'nelfinavir,', darunavir, and, tipranavir])].
[sujeto(['On', the, other, 'hand,', 'ritonavir,', amprenavir, and, indinavir, show, improved, calculated]), verbo([binding]), complemento([energies, in, comparison, with, the, corresponding, data, for, 'wild-type', 'C-SA', protease])].
[sujeto(['HIV-2', exhibits, intrinsic, resistance, to, most, 'FDA-approved', 'HIV-1', 'PI,']), verbo([retaining]), complemento([clinically, useful, susceptibility, only, to, 'lopinavir,', 'darunavir,', and, saquinavir])].
[sujeto(['Structural', studies]), verbo([have]), complemento([implicated, four, amino, acids, in, the, 'ligand-binding', pocket, '(', positions, 32, ',', 47, ',', 76, ',', and, 82, ')'])].
[sujeto(['Single', amino, acid, replacements, 'I32V,', 'V47I,', and, 'M76L']), verbo([increased]), complemento([the, susceptibility, of, 'HIV-2', to, multiple, 'PI,', but, no, single, change, conferred, 'class-wide', sensitivity])].
[sujeto(['These', models]), verbo([suggest]), complemento([that, the, amprenavir, sensitivity, of, 'PRΔ4', is, attributable, to, stabilizing, 'enzyme-inhibitor', interactions, in, the, 'P2', and, 'P2\'', pockets, of, the, protease, dimer])].
[sujeto(['Together,', our, results, show, that, the, combination, of, four, amino, acid, changes, in, 'HIV-2', protease]), verbo([confer]), complemento([a, pattern, of, 'PI', susceptibility, comparable, to, that, of, 'HIV-1,', providing, a, structural, rationale, for, intrinsic, 'HIV-2', 'PI', resistance, and, resolving, 'long-standing', questions, regarding, the, determinants, of, differential, 'PI', susceptibility, in, 'HIV-1', and, 'HIV-2'])].
[sujeto(['We']), verbo([found]), complemento([that, the, 'HIV-2', clone, containing, all, four, changes, '(', 'PRΔ4)', was, as, susceptible, as, 'HIV-1', to, all, nine, 'PI'])].
[sujeto(['Our', findings, demonstrate, that, four, positions, in, the, 'ligand-binding', cleft, of, protease, are, the, primary]), verbo([cause]), complemento([of, 'HIV-2', 'PI', resistance])].
[sujeto(['Treatment', of, astrocytes, with, 'APV', or, 'LPV', reduced, the, expression, of, proliferating, cell]), verbo([nuclear]), complemento([antigen, '(', 'PCNA)', and, 'Ki-67', '(', 'P', &, 'lt;', 0.05, ')', although, cell, survival, was, unaffected])].
[sujeto(['Total', errors, in, 'T-maze', assessment, were]), verbo([increased]), complemento([in, 'LPV', and, 'APV-treated', animals, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['EAAT2', expression, was, reduced, in, the, brains, of, protease, 'inhibitor-treated', 'animals,', which, was]), verbo([associated]), complemento([with, gliosis, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['These', results, indicated, that, contemporary, protease, inhibitors, disrupt, astrocyte, functions, at, therapeutic, concentrations, with]), verbo([enhanced]), complemento([sensitivity, to, 'glutamate,', which, can, lead, to, neurobehavioral, impairments])].
[sujeto(['Given', its, crucial, role, in, viral, 'replication,', 'HIV-1', protease, '(', 'HIV-1', 'PR)', is, a, prime, therapeutic]), verbo([target]), complemento([in, 'AIDS', therapy])].
[sujeto(['In', the, present, 'contribution,', the, effect, of, 'HIV-1', 'PR', flexibility, '(', within, multiple, crystallographic, structures, of, 'HIV-1', 'PR)', on]), verbo([binding]), complemento([to, the, 'Amprenavir', was, elucidated, via, an, ensemble, docking, approach])].
[sujeto(['Analysis', of]), verbo([binding]), complemento([factors, in, terms, of, docking, false, 'negatives/positives', revealed, a, determinant, role, of, enzyme, conformational, variation, in, prediction, of, optimum, induced, fit, '(', 'PDB', 'ID:', 1, 'HPV)'])].
[sujeto(['Furthermore;', some, strategies, to, 're-score', the, docking, results, in, 'HIV-1', 'PR']), verbo([targeted]), complemento([docking, studies, were, proposed])].
[sujeto(['Drug', resistance, of, mutations, 'V32I,', 'G48V,', 'I50V,', 'I54V,', and, 'I84V', in, 'HIV-1', protease, '(', 'PR)', was]), verbo([found]), complemento([in, clinical, treatment, of, 'HIV', patients, with, the, drug, amprenavir, '(', 'APV)'])].
[sujeto(['In', order, to, elucidate, the, molecular, mechanism, of, drug, resistance]), verbo([associated]), complemento([with, these, 'mutations,', the, thermodynamic, integration, '(', 'TI)', and, molecular, mechanics, 'Poisson-Boltzmann', surface, area, '(', 'MM-PBSA)', methods, were, applied, to, calculate, binding, free, energies, of, 'APV', to, 'wild-type', 'PR', and, these, mutated, 'PRs'])].
[sujeto(['The', relative]), verbo([binding]), complemento([free, energy, differences, from, the, 'TI', calculations, reveal, that, the, decrease, in, van, der, 'Waals', interactions, of, 'APV', with, mutated, 'PRs', relative, to, the, 'wild-type', 'PR', mainly, drives, the, drug, resistance])].
[sujeto(['Analyses', based, on, molecular, dynamics, trajectories, show, that, these, mutations, can, adjust, the, shape, and, conformation, of, the]), verbo([binding]), complemento(['pocket,', which, provides, main, contributions, to, the, decrease, in, the, van, der, 'Waals', interactions, of, 'APV', with, mutated, 'PRs'])].
[sujeto(['The', present, study, could]), verbo([provide]), complemento([important, guidance, for, the, design, of, new, potent, inhibitors, that, could, alleviate, drug, resistance, of, 'PR', due, to, mutations])].
[sujeto(['The', substrate, exhibits, a, kcat, of, 7.4, 's(-1),', 'KM', of, 15, 'μM,', and, an]), verbo([increase]), complemento([in, fluorescence, intensity, of, 104, -, fold, upon, 'cleavage,', thus, providing, sensitivity, that, is, unmatched, in, a, continuous, assay, of, 'HIV-1', protease])].
[sujeto(['Coadministration', significantly]), verbo([increased]), complemento([lopinavir, unbound, 'clearance,', while, significant, changes, in, fraction, unbound, '(', 'fu)', were, not, detected])].
[sujeto(['For', 'amprenavir,', significant]), verbo([increases]), complemento([in, fu, and, unbound, clearance, occurred, with, coadministration])].
[sujeto(['Human', immunodeficiency, virus, '(', 'HIV)-1', protease, is, one, of, the, most, promising, drug]), verbo([target]), complemento([commonly, utilized, to, combat, 'Acquired', 'Immune', 'Deficiency', 'Syndrome', '(', 'AIDS)'])].
[sujeto(['However,', with, the, emergence, of, drug, resistance, arising, from, 'mutations,', the, efficiency, of, protease, inhibitors, '(', 'PIs)', as, a, viable, treatment, for, 'AIDS']), verbo([has]), complemento([been, greatly, reduced])].
[sujeto(['Molecular', dynamics, '(', 'MD)', simulation, was, utilized, to, examine, the, effect, of, 'I50V', mutation, on, the]), verbo([binding]), complemento([of, two, 'PIs', namely, indinavir, and, amprenavir, to, 'HIV-1', protease])].
[sujeto(['The', atomic, charges, of, the]), verbo([binding]), complemento([complex, are, subsequently, fitted, using, delta, restrained, electrostatic, potential, '(', 'delta-RESP)', method, to, overcome, the, poor, charge, determination, of, buried, atom])].
[sujeto(['In', 'addition,', the, mechanism, governing, the]), verbo([decrease]), complemento([in, the, binding, affinity, of, 'PI', in, the, presence, of, 'I50V', mutation, was, also, explored, to, provide, insights, pertaining, to, the, design, of, the, next, generation, of, 'anti-HIV', drugs])].
[sujeto(['Molecular', dynamics, simulations, are, performed, to, investigate, the, dynamic, properties, of, 'wild-type', 'HIV-1', protease, and, its, two, 'multi-drug-resistant', variants, '(', 'Flap', +, '(', 'L10I/G48V/I54V/V82A)', and, 'Act', '(', 'V82T/I84V))', as, well, as, their]), verbo([binding]), complemento([with, 'APV', and, 'DRV', inhibitors])].
[sujeto(['The', hydrophobic, interactions, between, flap, and, 80, s, '(', 80, '\'', 's)', loop, residues, '(', mainly, 'I50-I84\'', and, 'I50\'-I84)', play, an, important, role, in]), verbo([maintaining]), complemento([the, closed, conformation, of, 'HIV-1', protease])].
[sujeto(['The', double, mutation, in, 'Act', variant, weakens, the, hydrophobic, 'interactions,']), verbo([leading]), complemento([to, the, transition, from, closed, to, 'semi-open', conformation, of, apo, 'Act'])].
[sujeto(['APV', or, 'DRV']), verbo([binds]), complemento([with, 'HIV-1', protease, via, both, hydrophobic, and, hydrogen, bonding, interactions])].
[sujeto(['The', present, study, sheds, light, on, the, microscopic, mechanism, underlying, the, mutation, effects, on, the, dynamics, of, 'HIV-1', protease, and, the, inhibition, by, 'APV', and, 'DRV,']), verbo([providing]), complemento([useful, information, to, the, design, of, more, potent, and, effective, 'HIV-1', protease, inhibitors])].
[sujeto(['Since', 2010, ',', 'raltegravir,', 'etravirine,', and, darunavir]), verbo([have]), complemento([been, spotlighted, as, new, drugs, for, highly, active, antiretroviral, therapy, '(', 'HAART)-experienced', adults, with, resistant, 'HIV-1', in, 'South', 'Korea'])].
[sujeto(['Etravirine', and, darunavir]), verbo([have]), complemento([been, used, in, 'HAART', since, 2010, in, 'South', 'Korea'])].
[sujeto(['This', study, may, help, to]), verbo([find]), complemento([a, more, effective, 'HAART', in, the, case, of, 'HIV-1', infected, patients, that, have, difficulty, being, treated])].
[sujeto(['Complex', 'drug-drug', interactions]), verbo([have]), complemento([been, reported, with, concurrent, administration, of, telaprevir, '(', 'TVR)', and, human, immunodeficiency, virus, '(', 'HIV)', protease, inhibitors, '(', 'PIs),', leading, to, relevant, limitations, of, the, therapeutic, options, for, patients, coinfected, with, hepatitis, 'C', virus, '(', 'HCV)', and, 'HIV'])].
[sujeto(['Here', we]), verbo([report]), complemento([the, pharmacokinetics, of, 'TVR', and, antiretrovirals, in, a, cohort, of, 'HIV/HCV', genotype, 1, -, coinfected, patients, with, advanced, liver, fibrosis, treated, with, 'TVR-based', triple, 'anti-HCV', therapy])].
[sujeto(['In', 'conclusion,', this, study, highlighted, the, feasibility, of]), verbo([maintaining]), complemento([the, current, antiretroviral, regimen, in, 'HIV/HCV-coinfected', 'patients,', even, when, significant, interactions, with, 'TVR', are, 'predictable,', whenever, a, change, of, 'HIV', 'PIs', is, not, deemed, appropriate])].
[sujeto(['We']), verbo([report]), complemento([here, that, 'GRL-0739,', a, novel, nonpeptidic, 'HIV-1', protease, inhibitor, containing, a, tricycle, '(', 'cyclohexyl-bis-tetrahydrofuranylurethane', '[', 'THF])', and, a, sulfonamide, 'isostere,', is, highly, active, against, laboratory, 'HIV-1', strains, and, primary, clinical, isolates, '(', 50, '%', effective, concentration, '[', 'EC50],', 0.0019, to, 0.0036, 'μM),', with, minimal, cytotoxicity, '(', 50, '%', cytotoxic, concentration, '[', 'CC50],', 21.0, 'μM)'])].
[sujeto(['GRL-0739', was, also, highly, active, against, 'multidrug-resistant', clinical, 'HIV-1', variants, isolated, from, patients, who, no, longer]), verbo([responded]), complemento([to, existing, antiviral, regimens, after, 'long-term', antiretroviral, 'therapy,', as, well, as, against, the, 'HIV-2ROD', variant])].
[sujeto(['The', effects, of, the, nonspecific]), verbo([binding]), complemento([of, human, serum, proteins, on, the, 'anti-HIV-1', activity, of, 'GRL-0739', were, insignificant])].
[sujeto(['Molecular', modeling, demonstrated, that, the, tricyclic, ring, and, methoxybenzene, of, 'GRL-0739']), verbo([have]), complemento([a, larger, surface, and, make, greater, van, der, 'Waals', contacts, with, protease, than, in, the, case, of, darunavir])].
[sujeto(['The', present, data, demonstrate, that, 'GRL-0739']), verbo([has]), complemento([desirable, features, as, a, compound, with, good, 'CNS-penetrating', capability, for, treating, patients, infected, with, 'wild-type', 'and/or', 'multidrug-resistant', 'HIV-1', variants, and, that, the, newly, generated, 'cyclohexyl-bis-THF', moiety, with, methoxybenzene, confers, highly, desirable, 'anti-HIV-1', potency, in, the, design, of, novel, protease, inhibitors, with, greater, 'CNS', penetration, profiles])].
[sujeto(['Abnormal', levels, of, tumour, necrosis, factor, '(', 'TNF)-alpha,', interleukin, '(', 'IL)-6', and, adiponectin]), verbo([have]), complemento([been, observed, in, 'HIV', patients, with, lipodystrophy])].
[sujeto(['However,', because, these, patients]), verbo([have]), complemento([long, drug, and, disease, 'histories,', it, is, unclear, which, drugs, are, responsible, for, these, abnormalities])].
[sujeto(['We']), verbo([have]), complemento([therefore, investigated, the, effects, of, individual, antiretrovirals, on, adipokine, expression, and, adipogenesis, using, a, murine, cell, line, in, vitro])].
[sujeto(['Nelfinavir,', ritonavir, and, saquinavir]), verbo([inhibited]), complemento([adipogenesis, and, 'up-regulated', the, expression, of, 'TNF-alpha', and, 'IL-6,', but, this, effect, was, not, seen, with, 'indinavir,', zidovudine, and, stavudine])].
[sujeto(['Adiponectin', expression, was, significantly, reduced, in, both, 'NRTI-', and, 'PI-treated', 'cells,', although, the, most, profound, reductions, were]), verbo([found]), complemento([with, ritonavir, and, saquinavir])].
[sujeto(['Co-incubation', with, rosiglitazone]), verbo([led]), complemento([to, a, partial, attenuation, of, the, change, in, 'TNF-alpha,', 'IL-6', and, adiponectin, secretion])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, the, 'PIs', 'nelfinavir,', ritonavir, and, saquinavir, have, potent, effects, in, inhibiting, adipocyte, differentiation, whilst, 'up-regulating', 'TNF-alpha', and, 'IL-6', mRNA, levels, and, decreasing, adiponectin, levels])].
[sujeto(['Taken', 'together,', the, data, show, that, antiretrovirals]), verbo([have]), complemento([complex, effects, on, adipocyte, 'function,', which, may, be, mediated, by, an, altered, adipokine, response])].
[sujeto(['The', pathogenesis, of, lipodystrophy]), verbo([caused]), complemento([by, the, 'HIV', protease, inhibitors, '(', 'PIs)', and, nucleoside, reverse, transcriptase, inhibitors, '(', 'NRTIs)', is, unclear])].
[sujeto(['We']), verbo([have]), complemento([investigated, the, disposition, of, these, drugs, in, adipocytes, and, the, consequent, effect, on, adipocyte, metabolism, and, viability])].
[sujeto(['The', 'NRTIs', were, not, 'cytotoxic,', did, not, affect, preadipocyte, protein, synthesis, and, did, not]), verbo([inhibit]), complemento([adipogenesis, or, induce, lipolysis])].
[sujeto(['All', 'PIs,', except, 'indinavir,', were, cytotoxic, and]), verbo([inhibited]), complemento(['adipogenesis,', increased, lipolysis, and, impaired, preadipocyte, protein, synthesis])].
[sujeto(['PIs']), verbo([inhibited]), complemento([glucose, uptake, in, the, rank, 'order:', 'indinavir>saquinavir>ritonavir>nelfinavir'])].
[sujeto(['NRTIs', alone, do, not, seem, to]), verbo([have]), complemento([any, effect, on, adipocyte, metabolism, despite, undergoing, phosphorylation, to, their, triphosphorylated, 'anabolites,', although, their, effects, in, combination, with, 'PIs', in, perturbing, adipocyte, metabolism, warrants, further, investigation])].
[sujeto(['Recently,', 'HPI', therapy]), verbo([has]), complemento([been, linked, to, the, development, of, a, metabolic, syndrome, in, which, adipocyte, insulin, resistance, appears, to, play, a, major, role])].
[sujeto(['Basal', glycerol, and, free, fatty, acid, '(', 'FFA)']), verbo([release]), complemento([were, significantly, enhanced, with, as, low, as, 5, 'micromol/l', 'nelfinavir,', displaying, fivefold, stimulation, of, 'FFA', release, at, 10, 'micromol/l'])].
[sujeto(['Potential', underlying, mechanisms, for, these, metabolic, effects, included, both, impaired, insulin, stimulation, of, protein, kinase, 'B', 'Ser', 473, phosphorylation, with, preserved, insulin, receptor, substrate, tyrosine, phosphorylation, and]), verbo([decreased]), complemento([expression, of, the, lipolysis, regulator, perilipin])].
[sujeto(['Troglitazone', 'pre-', and, cotreatment, with, nelfinavir, partly, protected, the, cells, from, the]), verbo([increase]), complemento([in, basal, 'lipolysis,', but, it, had, no, effect, on, the, impairment, in, 'insulin-stimulated', glucose, uptake, induced, by, this, 'HPI'])].
[sujeto(['This', study, demonstrates, that, nelfinavir]), verbo([induces]), complemento([insulin, resistance, and, activates, basal, lipolysis, in, differentiated, 3, 'T3-L1', 'adipocytes,', providing, potential, cellular, mechanisms, that, may, contribute, to, altered, adipocyte, metabolism, in, treated, 'HIV', patients])].
[sujeto(['A', gradient, 'LC', method, for, the, determination, of, related, substances, in, nelfinavir, mesilate, '(', 'NFVM)']), verbo([has]), complemento([been, recently, published, in, the, 'International', 'Pharmacopoeia'])].
[sujeto(['Activation', of, the, elongation, factor, 2, kinase, '(', 'eEF2K)']), verbo([leads]), complemento([to, the, phosphorylation, and, inhibition, of, the, elongation, factor, 'eEF2,', reducing, mRNA, translation, rates])].
[sujeto(['Emerging', evidence, indicates, that, the, regulation, of, factors]), verbo([involved]), complemento([in, protein, synthesis, may, be, critical, for, controlling, diverse, biological, processes, including, cancer, progression])].
[sujeto(['Here', we, show, that, inhibitors, of, the, 'HIV', aspartyl, protease, '(', 'HIV-PIs),', nelfinavir, in, 'particular,']), verbo([trigger]), complemento([a, robust, activation, of, eEF2K, leading, to, the, phosphorylation, of, eEF2])].
[sujeto(['Beyond', its, 'anti-viral', 'effects,', nelfinavir]), verbo([has]), complemento([antitumoral, activity, and, promotes, cell, death])].
[sujeto(['Decreased', cell, viability]), verbo([induced]), complemento([by, nelfinavir, is, impaired, in, cells, lacking, eEF2K])].
[sujeto(['Antiretroviral', therapy, '(', 'ART)', agents, potentially]), verbo([associated]), complemento([with, adverse, metabolic, profiles, are, commonly, used, in, 'low-', and, 'middle-income', countries])].
[sujeto(['In', multivariable, 'models,', detectable, 'HIV-1', 'RNA', prior, to, the, 'event,', prior, 'CVD,', less, time, on, 'ART,', age, '≥40', at, study, 'baseline,', nadir, 'CD4(+)', 'T', lymphocyte, count, '≤50', 'cells/mm(3),', 'non-white', 'race,', male, 'gender,', and, a, history, of, hypertension, were, significantly]), verbo([associated]), complemento([with, 'CVD', event, incidence, '(', p, &, 'lt;', 0.05, ')', ',', in, order, of, decreasing, strength])].
[sujeto(['In', multivariate, 'models,', cumulative, use, of, 'tenofovir,', 'zidovudine,', efavirenz, and, 'ritonavir-boosted', 'atazanavir,', darunavir, 'and/or', lopinavir, were]), verbo([associated]), complemento([with, decreased, 'CVD', event, risk])].
[sujeto(['Recent', tenofovir, and, boosted, atazanavir, use, were]), verbo([associated]), complemento([with, decreased, 'risk,', while, recent, 'stavudine,', nevirapine, and, unboosted, nelfinavir, 'and/or', indinavir, use, were, associated, with, increased, 'CVD', event, risk])].
[sujeto(['In', this, 'regard,', we]), verbo([have]), complemento([verified, the, impact, of, human, immunodeficiency, virus, aspartic, peptidase, inhibitors, '(', 'HIV-PIs)', on, the, viability, and, morphology, of, infective, trypomastigote, forms, of, 'Trypanosoma', cruzi, as, well, as, on, the, aspartic, peptidase, and, proteasome, activities, produced, by, this, parasite])].
[sujeto(['The', majority, of, the, 'HIV-PIs', '(', 6, /, 9, ')', were, able, to, drastically]), verbo([decrease]), complemento([the, viability, of, trypomastigotes, after, 4, h, of, 'treatment,', with, nelfinavir, and, lopinavir, being, the, most, effective, compounds, presenting, 'LD50', values, of, 8.6, µM, and, 10.6, 'µM,', respectively])].
[sujeto(['Treatment', with, nelfinavir, and, lopinavir]), verbo([caused]), complemento([many, 'morphological/ultrastructural', alterations, in, 'trypomastigotes;', parasites, became, round, in, 'shape,', with, reduced, cell, size, and, flagellar, shortening])].
[sujeto(['Nelfinavir', and, lopinavir, were, also, capable, of, significantly]), verbo([inhibiting]), complemento([the, aspartic, peptidase, and, proteasome, activities, measured, in, trypomastigote, extracts])].
[sujeto(['These', results, strengthen, the, data, on, the, positive, effects, of, 'HIV-PIs', on, parasitic, 'infections,', possibly, by]), verbo([targeting]), complemento([the, parasite, aspartic, 'peptidase(s)', and, 'proteasome(s),', opening, a, new, possibility, for, the, use, of, these, clinically, approved, drugs, as, an, alternative, chemotherapy, to, treat, 'Chagas\'', disease])].
[sujeto(['Treatment', with, either, naringin, or, glibenclamide, significantly, reduced, lipid, 'peroxidation,', 'Superoxide', 'Dismutase', '(', 'SOD)', activities, and, also]), verbo([increased]), complemento([glutathione, '(', 'GSH)', and, 'ATP', levels, in, the, cells, that, were, treated, with, 'PIs'])].
[sujeto(['PIs', impair, 'β-cell', functions, by]), verbo([increasing]), complemento([oxidative, stress, and, apoptosis])].
[sujeto(['Our', results, therefore]), verbo([suggest]), complemento([that, nutritional, supplements, with, naringin, could, prevent, pancreatic, 'β-cell', dysfunction, and, the, attendant, metabolic, complications, caused, by, 'PIs', in, patients, on, antiretroviral, therapy])].
[sujeto(['Inflammasomes', are, critical, sensors, that, convey, cellular, stress, and, pathogen, presence, to, the, immune, system, by]), verbo([activating]), complemento([inflammatory, caspases, and, cytokines, such, as, 'IL-1β'])].
[sujeto(['The', nature, of, endogenous, stress, signals, that]), verbo([activate]), complemento([inflammasomes, remains, unclear])].
[sujeto(['Here', we, show, that, an, inhibitor, of, the, 'HIV', aspartyl, 'protease,', 'Nelfinavir,']), verbo([triggers]), complemento([inflammasome, formation, and, elicits, an, 'IL-1R-dependent', inflammation, in, mice])].
[sujeto(['We']), verbo([found]), complemento([that, 'Nelfinavir', impaired, the, maturation, of, lamin, 'A,', a, structural, component, of, the, nuclear, 'envelope,', thereby, promoting, the, release, of, 'DNA', in, the, cytosol])].
[sujeto(['These', findings, identify, a, pharmacologic, activator, of, inflammasome, and, demonstrate, the, role, of, 'AIM2', in, detecting, endogenous, 'DNA']), verbo([release]), complemento([upon, perturbation, of, nuclear, envelope, integrity])].
[sujeto(['Cell', culture, techniques]), verbo([have]), complemento([many, advantages, for, investigation, of, drug, transport, to, target, organ, like, liver])].
[sujeto(['This', study, indicates, that, 'HepG2', might, be, a, more, suitable, in, vitro, model, than, 'Huh-7', to, study, drug, transport, in, hepatocytes]), verbo([involving]), complemento([drug, transporters])].
[sujeto(['In', both, 'groups,', mutations, in, 'N88D', protease, inhibitor, were, 'identified,', 'D67N', and, 'T69D', were]), verbo([found]), complemento([for, nucleoside, reverse, transcriptase, inhibitors, '(', 'NRTIs),', and, 'K103N', was, found, for, 'non-nucleoside', reverse, transcriptase, inhibitors])].
[sujeto(['Here', we, examine, the, impact, of, 'nelfinavir,', an, 'off-patent', viral, protease, 'inhibitor,', which]), verbo([has]), complemento([shown, promise, as, an, antineoplastic, agent])].
[sujeto(['It']), verbo([acts]), complemento([by, burdening, the, autophagy, pathway, to, impair, tumor, cell, survival, and, a, modest, induction, of, apoptosis])].
[sujeto(['The', discovery, of, the, 'anti-proliferative', activity, of, nelfinavir, in, 'HIV-free', models]), verbo([has]), complemento([encouraged, its, investigation, as, anticancer, drug])].
[sujeto(['Although', the, molecular, mechanism, by, which, nelfinavir, exerts, antitumor, activity, is, still, 'unknown,', its, effects]), verbo([have]), complemento([been, related, to, 'Akt', inhibition])].
[sujeto(['Nelfinavir', reduced, breast, cancer, cell, viability, by]), verbo([inducing]), complemento([apoptosis, and, 'necrosis,', without, affecting, primary, normal, breast, cells])].
[sujeto(['The', antitumor, activity, of, nelfinavir, was, related, to, alterations, of, the, cell, redox, 'state,', coupled, with, an]), verbo([increase]), complemento([of, intracellular, 'ROS', production, limited, to, cancer, cells])].
[sujeto(['These', effects, resulted, to, be, 'ROS', 'dependent,']), verbo([suggesting]), complemento([that, 'ROS', production, is, the, primary, step, of, nelfinavir, anticancer, activity])].
[sujeto(['We', demonstrated, that, 'ROS', enhancement, represents, the, main, molecular, mechanism]), verbo([required]), complemento([to, induce, cell, death, by, nelfinavir, in, breast, cancer, 'cells,', thus, supporting, the, development, of, new, and, more, potent, oxidizing, molecules, for, breast, cancer, therapy])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, in, a, phase, 'I', trial, that, nelfinavir, '(', 'NFV)', is, safe, with, chemoradiation, in, 'PDAC', with, good, signs, for, efficacy])].
[sujeto(['Reverse', 'translationally,', we, aimed, to, test, the, influence, of, 'PSCs', on, nelfinavir]), verbo([mediated]), complemento([radiosensitization, to, 'PDAC', 'preclinically,', because, 'PDAC', is, very, rich, in, desmoplasia, and, 'PSCs', are, known, to, mediate, radioresistance])].
[sujeto(['Human', pancreatic, stellate, cells, '(', 'hPSC)', were, also, sensitized, by, 'NFV', which, reduced, 'p-FAK', levels, in, 'hPSC,', an, effect, that, we, previously]), verbo([found]), complemento([to, sensitize, specifically, 'PDAC/PSC', coculture])].
[sujeto(['In', 'PSN-1', 'xenografts,', +, 'PSC']), verbo([led]), complemento([to, faster, tumor, regrowth, after, radiation, vs, -, 'PSC'])].
[sujeto(['NFV']), verbo([mediated]), complemento([radiosensitization, in, 'PDAC', with, stroma, is, partly, mediated, by, 'p-FAK', inhibition, '(', 'Chen', et, al])].
[sujeto(['The', dramatic]), verbo([increased]), complemento([effect, of, xenograft, regrowth, inhibition, by, nelfinavir, in, tumors, with, 'PSC', is, attributed, to, vascular, normalization, '(', 'Brunner', et, al])].
[sujeto(['After', adjusting, for, birth, cohort, and, other, 'factors,', there, was, no, significant]), verbo([increase]), complemento([in, the, likelihood, of, meeting, overall, case, status, '(', case, in, any, 'domain)', with, exposure, to, combination, 'ARVs', '(', 'cARVs),', any, 'ARV', 'class,', or, any, specific, 'ARV'])].
[sujeto(['However,', several, individual, 'ARVs', were, significantly]), verbo([associated]), complemento([with, case, status, in, individual, 'domains,', including, zidovudine, for, a, metabolic, 'case,', first, trimester, stavudine, for, a, language, 'case,', and, didanosine, plus, stavudine, for, a, 'ND', case])].
[sujeto(['We']), verbo([found]), complemento([an, increased, rate, of, preterm, birth, with, first, trimester, exposure, to, protease, 'inhibitor-based', cARV])].
[sujeto(['Although', there, was, no, overall]), verbo([increase]), complemento([in, congenital, anomalies, with, first, trimester, 'cARV,', a, significant, increase, was, seen, with, exposure, to, 'atazanavir,', 'ritonavir,', and, didanosine, plus, stavudine])].
[sujeto(['Tenofovir', exposure, was]), verbo([associated]), complemento([with, significantly, lower, mean, 'whole-body', bone, mineral, content, in, the, newborn, period, and, a, lower, length, and, head, circumference, at, 1, year, of, age])].
[sujeto(['With', 'ND', testing, at, 1, year, of, 'age,', specific, 'ARVs', '(', 'atazanavir,', 'ritonavir-boosted', 'lopinavir,', 'nelfinavir,', and, 'tenofovir)', were]), verbo([associated]), complemento([with, lower, 'performance,', although, all, groups, were, within, the, normal, range])].
[sujeto(['No', 'ARVs', or, classes, were]), verbo([associated]), complemento([with, lower, performance, between, 5, and, 13, years, of, age])].
[sujeto(['Atazanavir', and, saquinavir, exposure, were]), verbo([associated]), complemento([with, late, language, emergence, at, 1, 'year,', but, not, at, 2, years, of, age])].
[sujeto(['Results', 'None', of, the, tested, concentrations, of, 'Tenofovir,', 'Emtricitabine,', 'Nevirapine,', 'Maraviroc', or, 'Raltegravir']), verbo([induced]), complemento([any, significant, apoptosis, activation, at, our, experimental, conditions])].
[sujeto(['In', parallel, 'experiments,', protease, inhibitors, used, in, combination, with, 'Tenofovir', and, 'Emtricitabine,']), verbo([increased]), complemento([apoptosis])].
[sujeto(['Furthermore,', we, performed, a, study, of, mRNA, expression, of, specific, genes]), verbo([involved]), complemento([in, osteoblast, biology, and, in, bone, synthesis, and, observed, that, some, protease, inhibitors, induced, a, selective, decrease, of, some, osteogenic, markers])].
[sujeto(['Conclusion', 'All', the, protease, inhibitors, included, in, this, study]), verbo([trigger]), complemento([apoptosis, at, the, highest, concentration, 'analysed,', suggesting, great, caution, in, 'HIV-patients', 'co-infected', with, 'HBV', or, 'HCV,', where, elevated, plasma, concentrations, of, drugs, could, be, reached, as, a, consequence, of, liver, failure])].
[sujeto(['Lastly,', an]), verbo([increased]), complemento([apoptosis, rate, and, an, impairment, of, osteogenic, markers, were, recorded, only, in, presence, of, 'Nelfinavir,', suggesting, a, role, of, protease, inhibitors, in, the, alteration, of, osteoblast, biology])].
[sujeto(['In', this, predominantly, protease, 'inhibitor-treated', 'population,', 'lopinavir/ritonavir', was]), verbo([associated]), complemento([with, the, lowest, rate, of, infant, 'AE'])].
[sujeto(['Cellular', resistance, in, tumour, cells, to, different, therapeutic, approaches]), verbo([has]), complemento([been, a, limiting, factor, in, the, curative, treatment, of, cancer])].
[sujeto(['One', of, the, mechanisms, of, acquiring, resistance, to, ionizing, radiation, is, the, overexpression, or, activation, of, various, oncogenes, like, the, 'EGFR', '(', epidermal, growth, factor, 'receptor),', 'RAS', '(', rat, 'sarcoma)', oncogene, or]), verbo([loss]), complemento([of, 'PTEN', '(', phosphatase, and, tensin, 'homologue)', which, in, turn, activates, the, phosphatidyl, inositol, 3, -, 'kinase/protein', kinase, 'B', '(', 'PI3-K)/AKT', pathway, responsible, for, radiation, resistance, in, various, tumours])].
[sujeto(['Blocking', the, pathway]), verbo([enhances]), complemento([the, radiation, response, both, in, vitro, and, in, vivo])].
[sujeto(['Due', to, the, differential, activation, of, this, pathway, '(', constitutively]), verbo([activated]), complemento([in, tumour, cells, and, not, in, the, normal, host, 'cells),', it, is, an, excellent, candidate, target, for, molecular, targeted, therapy, to, enhance, radiation, sensitivity])].
[sujeto(['In', this, 'regard,', 'HIV', protease, inhibitors, '(', 'HPIs)', known, to, interfere, with, 'PI3-K/AKT', signaling, in, tumour, 'cells,']), verbo([have]), complemento([been, shown, to, sensitize, various, tumour, cells, to, radiation, both, in, vitro, and, in, vivo])].
[sujeto(['This', review, describes, the, mechanisms, by, which, 'PI3-K/AKT', pathway]), verbo([causes]), complemento([radioresistance, and, the, role, of, 'HIV', protease, inhibitors, especially, nelfinavir, as, a, potential, candidate, drug, to, target, the, 'AKT', pathway, for, overcoming, radioresistance, and, its, use, in, various, clinical, trials, for, different, malignancies])].
[sujeto(['Nelfinavir', can]), verbo([enhance]), complemento([intrinsic, 'radiosensitivity,', reduce, hypoxia, and, improve, vascularity])].
[sujeto(['The', study, closed, after]), verbo([recruiting]), complemento([23, 'patients,', due, to, 'non-availability', of, 'Nelfinavir', in, 'Europe'])].
[sujeto(['Four', of, 6, patients, on, the, imaging, 'sub-study', demonstrated, reduced, hypoxia, and]), verbo([increased]), complemento([perfusion, 'post-nelfinavir'])].
[sujeto(['Endoplasmic', reticulum, '(', 'ER)', stress, disrupts, among, others, protein, homeostasis, in, cells]), verbo([leading]), complemento([to, the, activation, of, the, unfolded, protein, response, '(', 'UPR)', that, is, crucial, for, restoring, this, balance, and, cell, survival])].
[sujeto(['Hypoxia,', reactive, oxygen, species, and, nutrient, 'deprivation,', conditions, commonly, present, in, the, tumor, 'microenvironment,', are, 'well-known']), verbo([triggers]), complemento([of, the, 'UPR'])].
[sujeto(['Apart', from, being, an, adaptive, 'response,', recently, the, 'UPR']), verbo([has]), complemento([been, implicated, in, oncogenesis])].
[sujeto(['In', orthotopic, 'GBM', mouse, models, 'IRE1', was]), verbo([reported]), complemento([to, control, 'angiogenesis,', invasion, and, mesenchymal, differentiation])].
[sujeto(['Furthermore,', 'PERK', also, was]), verbo([found]), complemento([to, stimulate, 'GBM', growth])].
[sujeto(['Patient', samples, display, chronic, activation, of, the, 'UPR', and, in, vitro, standard, 'chemo-', and, radiotherapy, partially]), verbo([act]), complemento([by, aggravating, 'ER', stress, leading, to, cell, death])].
[sujeto(['The', 'UPR']), verbo([has]), complemento([been, linked, to, enhanced, sensitivity, for, 'apoptosis-inducing', agents, such, as, 'TRAIL', and, 'MDA-7'])].
[sujeto(['A', number, of, agents, such, as, proteasome, inhibitors, and, several, natural, products, were]), verbo([reported]), complemento([to, exert, cytotoxicity, by, enhancing, 'ER', stress, in, 'GBM', 'cells,', and, some, demonstrated, activity, in, clinical, studies])].
[sujeto(['Finally,', 'ER', stress, was]), verbo([suggested]), complemento([to, be, implicated, in, the, maintenance, of, homeostasis, in, 'GBM', stem, cells])].
[sujeto(['Taken', 'together,', the, 'UPR', appears, to, play, an, important, role, in, 'GBM', tumor, progression, and, is, a, promising]), verbo([target]), complemento([for, developing, novel, therapeutic, interventions])].
[sujeto([bortezomib, and, 'nelfinavir,']), verbo([induce]), complemento(['ER', stress, implying, that, this, could, be, a, successful, therapeutic, strategy, against, several, forms, of, cancer])].
[sujeto(['To']), verbo([find]), complemento([novel, 'ER-stress', inducers, we, screened, a, panel, of, natural, and, synthetic, 'Toll-like', receptor, '(', 'TLR)', agonists, against, human, keratinocytes, and, identified, the, 'anti-cancer', drug, imiquimod, '(', 'IMQ)', as, a, potent, inducer, of, 'ER', stress])].
[sujeto(['Other', 'TLR7', and, 'TLR8', 'agonists,', including, resiquimod, and, 'gardiquimod,', did, not]), verbo([induce]), complemento(['ER', 'stress,', demonstrating, that, 'IMQ', induces, 'ER', stress, independently, of, 'TLR7', and, 'TLR8'])].
[sujeto(['We', further, confirmed, this, by, showing, that, 'IMQ', could, still]), verbo([induce]), complemento(['ER', stress, in, mouse, 'Tlr7(-/-)', cells])].
[sujeto(['IMQ', also]), verbo([induced]), complemento([a, rapid, and, transient, influx, of, extracellular, 'Ca(2+)', together, with, the, release, of, 'Ca(2+)', from, internal, stores])].
[sujeto(['Depletion', of, 'Ca(2+)', from, the, 'ER', is, a, known]), verbo([cause]), complemento([of, 'ER', stress, suggesting, that, 'IMQ', induces, 'ER', stress, via, depletion, of, 'ER', 'Ca(2+)'])].
[sujeto(['The', 'ER-stress']), verbo([inducing]), complemento([property, of, 'IMQ', is, possibly, of, importance, for, its, efficacy, in, treating, basal, cell, 'carcinoma,', in, situ, 'melanoma,', and, squamous, cell, carcinoma])].
[sujeto(['At', four, months, of, 'age,', each, infant, was]), verbo([found]), complemento([to, be, 'HIV-negative'])].
[sujeto(['A', prophylactic, regimen, that, included, 'nelfinavir,', 'lamivudine,', and, zidovudine, was, used, to]), verbo([prevent]), complemento([perinatal, transmission, of, 'HIV', in, two, neonates])].
[sujeto(['Once', melanomas]), verbo([have]), complemento([progressed, with, acquired, resistance, to, 'mitogen-activated', protein, kinase, '(', 'MAPK)-targeted', 'therapy,', mutational, heterogeneity, presents, a, major, challenge])].
[sujeto(['We', therefore, examined, the, therapy, phase, before, acquired, resistance, had, developed, and, discovered, the, melanoma, survival, oncogene, 'MITF', as, a, driver, of, an, early, 'non-mutational', and, reversible, 'drug-tolerance', 'state,', which, is]), verbo([induced]), complemento([by, 'PAX3-mediated', upregulation, of, 'MITF'])].
[sujeto(['We', demonstrate, that]), verbo([inhibiting]), complemento(['a driver', of, 'MAPKi-induced', drug, tolerance, could, improve, current, approaches, of, targeted, melanoma, therapy])].
[sujeto(['(', 2016, ')']), verbo([report]), complemento([that, nelfinavir, suppresses, 'MITF', expression, induced, by, 'MAPK', pathway, inhibition, in, melanoma, cells, and, sensitizes, melanoma, cells, with, 'NRAS', or, 'BRAF', plus, 'NRAS', mutations, to, 'MEK', inhibitors])].
[sujeto(['The', introduction, of, antiretroviral, therapy, '(', 'ART)']), verbo([led]), complemento([to, huge, reductions, in, human, immunodeficiency, virus, '(', 'HIV)-related', 'deaths,', turning, 'HIV-infection', into, a, chronic, condition])].
[sujeto(['In', 'sub-Saharan', 'Africa,', efavirenz, '(', 'EFV)', forms, the, preferred, 'first-line', 'ART', but, adverse, drug, events]), verbo([have]), complemento([also, been, reported])].
[sujeto(['We']), verbo([express]), complemento([our, concern, on, 'EFV-based', regimens, being, part, of, mass, rollout, programs, without, full, attention, to, toxicities])].
[sujeto(['EFV', is]), verbo([associated]), complemento([with, various, neuropsychiatric, adverse, events, '(', 'AEs)'])].
[sujeto(['According', to, this, ambitious, treatment, 'target,', by, 2020, ',', 90, '%', of, all, people, living, with, 'HIV', will, know, their, 'HIV', 'status;', 90, '%', of, all, people, with, diagnosed, 'HIV', infection, will, receive, sustained, 'ART;', and, 90, '%', of, all, people, receiving, 'ART', will]), verbo([have]), complemento([viral, suppression])].
[sujeto(['On', the, other, 'hand,', 'HIV', patients, of, 'African', origin, are, predisposed, to, developing, 'EFV-induced', neuropsychiatric, 'AEs', due, to, specific, 'CYP2B6', genetic, variants]), verbo([causing]), complemento([impaired, metabolism, of, 'EFV'])].
[sujeto(['The', 'first-generation', integrase, inhibitors, '(', 'INIs)', raltegravir, '(', 'RAL)', and, elvitegravir, '(', 'EVG)']), verbo([have]), complemento([shown, efficacy, against, 'HIV', 'infection,', but, they, have, the, limitations, of, 'once-more', daily, dosing, and, extensive, 'cross-resistance'])].
[sujeto(['Efavirenz-containing', therapy]), verbo([has]), complemento([become, associated, with, the, occurrence, of, 'CNS', side, 'effects,', including, sleep, 'disturbances,', depression, and, even, psychosis])].
[sujeto(['The', investigation, of, efavirenz, distribution]), verbo([required]), complemento([the, development, of, a, versatile, and, sensitive, method])].
[sujeto(['In', addition, to, 'plasma,', quantification, was]), verbo([required]), complemento([in, brain, tissue, and, phosphate, buffered, saline])].
[sujeto(['The', assay]), verbo([has]), complemento([been, applied, to, in, vitro, and, in, vivo, samples, demonstrating, reliable, efavirenz, quantification, in, multiple, matrices])].
[sujeto(['The', mean, 'CD4', count, at, treatment, initiation, was, 191, 'cells/', 'µl,', and]), verbo([increased]), complemento([to, 359, 'cells/µl', after, 1, year, and, to, 521, cells, /, µl, after, 5, years])].
[sujeto(['Stavudine', was, stopped, in, 16.7, '%', due, to, 'side-effects,', abacavir]), verbo([associated]), complemento([hypersensitivity, reactions, developed, in, 13, '%', ',', zidovudine, associated, anemia, developed, in, 5.2, '%', and, tenofovir, was, discontinued, due, to, nephrotoxicity, in, 1.4, '%'])].
[sujeto(['Efavirenz,', a, 'non-nucleoside', 'HIV-1', reverse, transcriptase, 'inhibitor,', is, mainly, cleared, by, 'CYP2B6,', an, enzyme, strongly]), verbo([inhibited]), complemento([in, vitro, by, voriconazole])].
[sujeto(['Compared', to, 'control,', voriconazole, prolonged, the, elimination, 'half-life', '(', 't1/2),']), verbo([increased]), complemento([both, the, 'Cmax', and, 'AUC0-t', of, efavirenz, '(', mean, change, by, 51, '%', ',', 36, '%', ',', and, 89, '%', ',', 'respectively)', '(', 'P', &, 'lt;', 0.0001, ')', with, marked, intersubject, variability, '(', e])].
[sujeto(['Voriconazole']), verbo([decreased]), complemento([efavirenz, 8, -, hydroxylation, by, greater, than, 60, '%', '(', 'P', &, 'lt;', 0.0001, ')', whereas, its, effect, on, 7, -, hydroxylation, was, marginal])].
[sujeto(['The', plasma, concentration, ratio, of, efavirenz, to, 8, -, 'hydroxyefavirenz,', determined, 1, to, 6, hour, after, dosing, was, significantly]), verbo([increased]), complemento([by, voriconazole, and, correlated, with, the, efavirenz, 'AUC0-t', '(', 'Pearson', r, =, &, 'gt;0'])].
[sujeto(['This', study, demonstrates, the, mechanisms, of, 'voriconazole-efavirenz', 'interaction,', establishes, the, use, of, a, low, dose, of, efavirenz, as, a, safe, and, selective, in, vivo, probe, for, phenotyping, 'CYP2B6', 'activity,', and, identified, several, 'easy-to-use', indices, that, should]), verbo([enhance]), complemento([understanding, of, the, mechanisms, of, 'CYP2B6', 'inter-individual', variability])].
[sujeto(['Predictions', can, be, 'challenging,', especially, when, antiretroviral, drugs]), verbo([induce]), complemento([and, inhibit, multiple, cytochrome, 'P450', '(', 'CYP)', isoenzymes, simultaneously])].
[sujeto(['PBPK', modeling, constitutes, a, useful, mechanistic, approach, for, the, quantitative, prediction, of, 'DDI']), verbo([involving]), complemento([simultaneous, inducing, or, inhibitory, effects, on, multiple, 'CYPs', as, often, encountered, with, antiretroviral, drugs])].
[sujeto(['Efavirenz', is, well, known, to]), verbo([cause]), complemento(['CNS', toxicity])].
[sujeto(['Mini-tablets', were, produced, and, demonstrated, good, physical, 'characteristics,', expected, drug, content, and, immediate]), verbo([release]), complemento([profiles, for, all, drug, formulations])].
[sujeto(['We', conclude, that, the, 'CombiCap', formulation, platform, can, be, easily, adopted, for, different, types, of, phenotyping, cocktails, due, to, its, scalable, and]), verbo([modular]), complemento(['design,', which, allows, a, simple, and, convenient, combination, of, variable, doses, of, different, probe, drugs])].
[sujeto(['Non-inferiority', of]), verbo([maintaining]), complemento([virological, suppression, in, 'children,', 'adolescents,', and, young, adults, was, shown, for, short, cycle, therapy, versus, continous, therapy, at, 48, 'weeks,', with, similar, resistance, and, a, better, safety, profile])].
[sujeto(['Initiation', of, 'efavirenz-based', combination, antiretroviral, therapy, '(', 'cART)', is]), verbo([associated]), complemento([with, 'Vitamin', 'D', 'deficiency,', but, the, risk, factors, including, efavirenz, pharmacokinetics, for, 'cART-induced', severe, vitamin, 'D', deficiency, '(', 'SVDD)', and, the, impact, of, 'anti-tuberculosis', '(', 'TB)', cotreatment, are, not, explored])].
[sujeto(['We', investigated, the, prevalence, of, 'SVDD', in, 'HIV', and, 'TB-HIV', coinfected, patients, and]), verbo([associated]), complemento([risk, factors, for, 'treatment-induced', 'SVDD'])].
[sujeto(['In', 'HIV-only', 'patients,', initiation, of, 'efavirenz-based', cART]), verbo([increased]), complemento([the, prevalence, of, 'SVVD', from, 27, '%', at, baseline, to, 76, '%', ',', 79, '%', ',', and, 43, '%', at, 4, ',', 16, ',', and, 48, weeks, of, 'cART,', respectively])].
[sujeto(['In', 'TB-HIV', 'patients,', previous, 'anti-TB', therapy, had, no, influence, on, 25, '(', 'OH)D3', 'levels,', but, the, initiation, of, 'efavirenz-based', cART]), verbo([increased]), complemento([the, prevalence, of, 'SVDD', from, 57, '%', at, baseline, to, 70, '%', and, 72, '%', at, the, 4, and, 16, weeks, of, 'cART,', respectively])].
[sujeto(['Low', plasma, 25, '(', 'OH)D3', level, at, baseline, is]), verbo([associated]), complemento([with, 'TB', 'co-infection', and, 'HIV', diseases, progression])].
[sujeto(['Initiation', of, 'efavirenz-based', cART, is]), verbo([associated]), complemento([with, high, incidence, of, 'SVDD,', whereas, rifampicin, based, 'anti-TB', therapy, 'co-treatment', has, no, significant, effect])].
[sujeto(['Antiretroviral', therapy, '(', 'ART)']), verbo([has]), complemento([increased, the, life, span, of, the, people, living, with, 'HIV', '(', 'PLHIV),', but, their, virological, and, immunological, outcomes, are, not, well, documented, in, 'Nepal'])].
[sujeto(['With']), verbo([increasing]), complemento(['age,', average, 'CD4(+)', count, was, found, to, be, decreasing, '(', p, =, 0.005, ')'])].
[sujeto(['Of', the, total, 'cases,', 82, '(', 9.92, '%', ')', were]), verbo([found]), complemento([to, have, virological, failure, '(', viral, 'load:', &, 'gt;1000', 'copies/ml)'])].
[sujeto(['The', study]), verbo([suggests]), complemento([there, are, still, some, chances, of, virological, and, immunological, failures, despite, the, success, of, highly, active, 'ART', '(', 'HAART)'])].
[sujeto(['An', association, between, efavirenz, and, 8, -, 'hydroxy-efavirenz-glucuronide', was]), verbo([found]), complemento(['(', 'Spearman', 'r=0'])].
[sujeto(['We', conclude, that, metabolism, to, 8, -, 'hydroxy-efavirenz', is]), verbo([associated]), complemento([with, 'efavirenz-related', mood, 'changes,', which, suggests, that, the, concentration, of, this, metabolite, is, a, suitable, parameter, for, therapeutic, drug, monitoring, aimed, at, controlling, these, manifestations])].
[sujeto(['Moreover,', our, data]), verbo([suggest]), complemento([that, 8, -, 'hydroxy-efavirenz', is, able, to, cross, the, 'blood-brain', barrier, and, that, the, peripheral, detoxification, of, 8, -, 'hydroxy-efavirenz', by, glucuronidation, may, be, inhibited, by, toxic, efavirenz, concentrations])].
[sujeto(['HIV-positive', patients, with, hematologic, malignancies, are, frequently, not, considered, for, treatment, with, allogeneic, hematopoietic, stem, cell, transplantation, '(', 'alloHSCT)', because, of]), verbo([reported]), complemento([high, morbidity, and, mortality, with, this, procedure, and, scant, published, experience])].
[sujeto(['HIV', viral, load, remained, undetectable, and, 'CD4+', cell, count]), verbo([increased]), complemento([progressively])].
[sujeto(['The', development, of, antiretroviral, therapy, '(', 'ART)']), verbo([has]), complemento([dramatically, increased, the, lifespan, of, 'HIV', patients, but, treatment, is, complicated, by, numerous, adverse, effects, and, toxicities])].
[sujeto(['ART', complications, include, 'neuropsychiatric,', 'metabolic,', 'gastrointestinal,', 'cardiac,', and, numerous, other, 'toxicities,', and, clinicians, often]), verbo([have]), complemento([to, choose, one, toxicity, over, another, to, offer, the, best, medication, regimen, for, a, patient])].
[sujeto(['Some', antiviral, drugs]), verbo([cause]), complemento([significant, neuropsychiatric, 'complications,', including, 'depression,', cognitive, 'impairment,', and, sleep, disturbance])].
[sujeto(['Of', the, six, currently, marketed, classes, of, antiviral, 'drugs,', the, nucleoside, reverse, transcriptase, inhibitors, and, the, 'non-nucleoside', reverse, transcriptase, inhibitors]), verbo([have]), complemento([been, most, commonly, associated, with, neuropsychiatric, complications])].
[sujeto(['Within', these, 'classes,', certain, drugs, are, more, likely, to]), verbo([cause]), complemento([difficulty, than, others])].
[sujeto(['Integrase', strand, transfer, inhibitors, '(', 'INSTIs)', are, a, novel, class, of, 'anti-HIV', agents, that, show, high, activity, in]), verbo([inhibiting]), complemento(['HIV-1', replication])].
[sujeto(['Currently,', licensed, 'INSTIs', include, raltegravir, '(', 'RAL),', elvitegravir, '(', 'EVG)', and, dolutegravir, '(', 'DTG);', these, drugs]), verbo([have]), complemento([played, a, critical, role, in, 'AIDS', 'therapy,', serving, as, additional, weapons, in, the, arsenal, for, treating, patients, infected, with, 'HIV-1'])].
[sujeto(['The', rates, of, resistance, to, 'RAL', that, were]), verbo([associated]), complemento([with, 'HIV', subtypes, 'A,', 'B,', and, 'C', as, well, as, with, more, complex, subtypes, were, 0.1, '%', '(', 95, '%', 'CI', =, -, 0.7, '%', -, 0.9, '%', ')', ',', 2.5, '%', '(', 95, '%', 'CI', =, 0.5, '%', -, 4.5, '%', ')', ',', 4.6, '%', '(', 95, '%', 'CI', =, 2.7, '%', -, 6.6, '%', ')', and, 2.2, '%', '(', 95, '%', 'CI', =, 0.7, '%', -, 3.7, '%', ')', ',', respectively])].
[sujeto(['Furthermore,', we]), verbo([found]), complemento([that, the, 'RRs', for, antiviral, resistance, were, 0.414, '(', 95, '%', 'CI', =, 0.21, -, 0.816, ')', between, 'DTG', and, 'RAL', and, 0.499, '(', 95, '%', 'CI', =, 0.255, -, 0.977, ')', between, 'EVG', and, 'RAL'])].
[sujeto(['When', 'RAL', was, separately, 'co-administered', with]), verbo([nuclear]), complemento([nucleoside, reverse, transcriptase, inhibitors, '(', 'NRTIs)', or, protease, inhibitors, '(', 'PIs),', the, rates, of, resistance, to, 'RAL', were, 0.2, '%', '(', 95, '%', 'CI', =, -, 0.1, '%', -, 0.5, '%', ')', and, 0.2, '%', '(', 95, '%', 'CI', =, -, 0.2, '%', -, 0.6, '%', ')', ',', respectively])].
[sujeto(['Our', results]), verbo([reveal]), complemento([that, the, 'DTG', resistance, rate, was, lower, than, the, 'RAL', resistance, rate, in, a, 'head-to-head', comparison])].
[sujeto(['HIV-infected', individuals, are, at]), verbo([increased]), complemento([risk, of, cardiovascular, disease, '(', 'CVD),', but, the, arterial, vascular, functions, affected, by, persistent, innate, and, cellular, immune, activation, are, not, well, described])].
[sujeto(['We', also, measured, circulating, naive, '(', 'CD45RO(-)CCR7(+)CD27(+)),']), verbo([activated]), complemento(['(', 'CD38(+)', and, 'CD38(+)DR(+)),', exhausted, '(', 'PD1(+)),', senescent, '(', 'CD57(+)),', and, memory, '(', 'CD45RO(+))', 'CD4(+)', and, 'CD8(+)', 'T', cell, subsets, by, flow, 'cytometry,', and, macrophage, activation, markers, by, 'ELISA', and, multiple, immunoassay])].
[sujeto(['Lower', brachial, 'FMD', was]), verbo([associated]), complemento([with, a, higher, percentage, of, activated, 'CD8(+)', 'T', cells, '(', p, &, 'lt;'])].
[sujeto([1, ')', ',', but, not]), verbo([associated]), complemento([with, macrophage, activation])].
[sujeto(['In', 'contrast,', higher, 'ICAM-1', and, 'VCAM-1', were]), verbo([associated]), complemento([with, sCD163, '(', p, &, 'lt;', =])].
[sujeto(['These', findings, are, consistent, with, the, hypothesis, that, circulating, 'CD8(+)', 'T', cell, activation, may, impair, arterial, smooth, muscle, 'relaxation,', while, macrophage, activation]), verbo([has]), complemento([a, role, in, the, expression, of, endothelial, cell, proteins, involved, in, immune, cell, translocation])].
[sujeto(['Both', innate, and, cellular, immune, activation, appear, to]), verbo([promote]), complemento([arterial, vascular, disease, in, 'HIV-infected', persons, on, 'ART', using, differing, mechanisms])].
[sujeto(['These', new, findings]), verbo([provide]), complemento([some, important, insights, to, the, elucidation, of, the, advantages, of, 'SSF', for, the, synthesis, of, fungal, secondary, metabolites])].
[sujeto(['Moreover,', recent, studies]), verbo([have]), complemento([shown, several, important, applications, for, lovastatin, including, antimicrobial, agents, and, treatments, for, cancers, and, bone, diseases])].
[sujeto(['Studies', regarding, the, lovastatin, biosynthetic, pathway]), verbo([have]), complemento([also, demonstrated, that, lovastatin, is, synthesized, from, 'two-chain', reactions, using, acetate, and, 'malonyl-CoA', as, a, substrate])].
[sujeto(['It', is, also, known, that, there, are, two, key, enzymes]), verbo([involved]), complemento([in, the, biosynthetic, pathway, called, polyketide, synthases, '(', 'PKS)'])].
[sujeto(['Since', it, is, a, secondary, 'metabolite,', cultivation, process, optimization, for, lovastatin, biosynthesis]), verbo([has]), complemento([included, nitrogen, limitation, and, 'non-fermentable', carbon, sources, such, as, lactose, and, glycerol])].
[sujeto(['Additionally,', the, influences, of, 'temperature,', 'pH,', 'agitation/aeration,', and, particle, and, inoculum, size, on, lovastatin, production]), verbo([have]), complemento([been, also, described])].
[sujeto(['Although', many, reviews]), verbo([have]), complemento([been, published, covering, different, aspects, of, lovastatin, 'production,', this, review, 'brings,', for, the, first, 'time,', complete, information, about, the, genetic, basis, for, lovastatin, 'production,', detection, and, 'quantification,', strain, screening, and, cultivation, process, optimization])].
[sujeto(['The', relatively, effective, doses, were]), verbo([found]), complemento([to, possess, the, most, considerable, renoprotective, properties])].
[sujeto(['All', the, statins, were, established, to]), verbo([cause]), complemento([the, restoration, of, functional, activity, of, the, kidneys, under, conditions, of, experimental, rhabdomyolytic, acute, renal, failure, at, various, 'doses,', but, with, the, dose, of, 20, 'mg/kg', they, showed, the, most, significant, improvement, in, key, indices, of, kidney, 'function:', an, increase, in, diuresis, by, an, average, of, 32, '%', and, glomerular, filtration, rate, by, an, average, of, 90, '%', ',', reduction, of, proteinuria, in, more, than, twice])].
[sujeto(['At', the, same, 'time,', in, the, animals, with, acute, renal, failure, the, level, of, creatine, phosphokinase, was]), verbo([increased]), complemento([by, 141, '%'])].
[sujeto(['This', amount, was]), verbo([found]), complemento([to, be, 50, times, higher, than, that, produced, under, unoptimized, conditions, in, submerged, fermentation, by, 'P'])].
[sujeto([',']), verbo([have]), complemento([each, been, proven, to, be, beneficial, compounds, as, antihypercholesterolemic, and, 'anti-inflammation', 'agents,', respectively])].
[sujeto(['Contrast', 'media-', '(', 'CM-)']), verbo([induced]), complemento([nephropathy, is, a, serious, complication, of, radiodiagnostic, procedures])].
[sujeto(['Available', data]), verbo([suggests]), complemento([that, the, development, of, prophylaxis, strategies, is, limited, by, poor, understanding, of, pathophysiology, of, 'CM-induced', nephropathy])].
[sujeto(['The', results, showed, that, 'SSTN', dose, dependently, attenuated, 'CM-induced', rise, of, 'creatinine,', 'urea,', and, structural, abnormalities]), verbo([suggesting]), complemento([its, nephroprotective, effect])].
[sujeto(['A', significant]), verbo([increase]), complemento([in, oxidative, stress, '(', increased, lipid, hydroperoxides, and, reduced, glutathione, 'levels)', and, myeloperoxidase, '(', 'MPO)', and, decreased, nitric, oxide, in, 'CM', group, were, reversed, by, 'SSTN'])].
[sujeto(['Heavy-ion', 'beams,', possessing, a, wide, mutation, spectrum, and]), verbo([increased]), complemento([mutation, 'frequency,', have, been, used, effectively, as, a, breeding, method])].
[sujeto([terreus, 'Z15-7']), verbo([has]), complemento([been, selected, from, the, clone, irradiated, by, the, 'heavy-ion', beam])].
[sujeto([terreus, 'Z15-7']), verbo([increased]), complemento([4, -, fold])].
[sujeto(['The', application, of, glycerol, 'feed,', when, lactose, is, the, initial, 'substrate,']), verbo([leads]), complemento([to, the, appreciable, lovastatin, concentration, in, the, broth, '(', 122.4, mg, 'l⁻¹),', nevertheless, the, abundant, '(', +, ')', -, geodin, level, is, at, the, same, time, obtained, '(', 255.5, mg, 'l⁻¹)'])].
[sujeto(['The', application, of, the, various, combined, glycerol, 'and/or', lactose, feeds, allows, for, improving, lovastatin, production, up, to, 161.8, mg, 'l⁻¹', and]), verbo([decreases]), complemento(['(', +, ')', -, geodin, concentration, to, 98.7, mg, 'l⁻¹'])].
[sujeto(['In', addition, to, fundamental, cholesterol, lowering, activity, statins, give, other, effects, as, 'well,', for, example, immunomodulating, and, 'anti-inflammatory', 'effect,', they]), verbo([promote]), complemento([bone, mineralization])].
[sujeto(['The', 'anti-inflammatory', activity]), verbo([has]), complemento([been, described, in, few, articles, and, clinical, letters])].
[sujeto(['The', objective, of, this, study, was, to, develop, solid, lipid, nanoparticles, '(', 'SLNs)', of, simvastatin, and, to, optimize, it, for, independent, variables, '(', amount, of, glycerol, 'monostearate,', concentration, of, 'poloxamer,', and, volume, of, isopropyl, 'alcohol)', in, order, to, achieve, desired, particle, size, with, maximum, percent, entrapment, efficiency, '(', '%', 'EE)', and, percent, cumulative, drug]), verbo([release]), complemento(['(', '%', 'CDR)'])].
[sujeto(['The']), verbo([release]), complemento([kinetics, of, the, optimized, formulation, best, fitted, the, 'Higuchi', 'model,', and, the, recrystallization, index, of, optimized, formulation, was, found, to, be, 65.51, '%'])].
[sujeto(['This', study]), verbo([has]), complemento([investigated, the, efficacy, of, 'statins,', which, inhibit, activation, of, 'RhoA,', in, opposing, the, 'thrombin-induced', loss, of, barrier, integrity, of, monolayers, of, cultured, bovine, corneal, endothelium])].
[sujeto(['Lovastatin,', a, prototype, of, lipophilic, 'statins,']), verbo([induced]), complemento(['MLC', dephosphorylation, under, basal, conditions])].
[sujeto(['It', opposed]), verbo([increase]), complemento([in, phosphorylation, of, 'MLC', and, 'MYPT1', in, response, to, thrombin, and, 'nocodazole,', agents, known, to, activate, 'RhoA', in, the, endothelium])].
[sujeto(['Lovastatin', also, opposed, the, 'thrombin-', and, 'nocodazole-induced']), verbo([increase]), complemento([in, permeability, to, 'FITC', dextran, and, redistribution, of, 'ZO-1'])].
[sujeto(['This', underlies, the, suppression, of, the, 'thrombin-induced']), verbo([loss]), complemento([in, barrier, integrity, of, the, corneal, endothelium])].
[sujeto(['Using', genetic, engineering, tools, available, for, the, model, organism, 'Aspergillus', 'nidulans,', we, constructed, two, recombinant, 'strains,', one]), verbo([expressing]), complemento([the, 'Penicillium', griseofulvum, 6, -, methylsalicylic, acid, '(', 6, -, 'MSA)', synthase, gene, and, one, expressing, the, 6, -, 'MSA', synthase, gene, and, overexpressing, the, native, 'xylulose-5-phosphate', phosphoketolase, gene, '(', 'xpkA)', for, increasing, the, pool, of, polyketide, precursor, levels])].
[sujeto(['Glucose', was]), verbo([found]), complemento([to, be, the, preferred, carbon, source, for, 6, -, 'MSA', 'production,', and, 6, -, 'MSA', concentrations, up, to, 455, 'mg/liter', were, obtained, for, the, recombinant, strain, harboring, the, 6, -, 'MSA', gene])].
[sujeto(['All', parameters, were]), verbo([found]), complemento([to, be, significant, except, pH, and, 'KH(2)PO(4)'])].
[sujeto(['The', present, study, demonstrates, that, 'agro-industrial', residues, can, be, successfully, used, for, compactin, 'production,', and, statistical, experiment, designs]), verbo([provide]), complemento([an, easy, tool, to, improve, the, process, conditions, for, secondary, metabolite, production])].
[sujeto(['Dissolution', studies, revealed, remarkable]), verbo([increase]), complemento([in, dissolution, of, the, drug, compared, to, plain, drug])].
[sujeto(['One', of, the, optimized, formulations]), verbo([provided]), complemento([10, -, fold, enhancement, in, the, dissolution, compared, to, drug, powder])].
[sujeto(['Significant']), verbo([increase]), complemento([in, the, 'high-density', lipoprotein, levels, were, also, observed, after, 4, days, of, treatment, compare, to, positive, control, '(', p, &, 'lt;', 0.01, ')'])].
[sujeto(['Self-microemulsifying', drug, delivery, systems, '(', 'SMEDDS)', are, useful, to, improve, the, bioavailability, of, poorly, 'water-soluble', drugs, by]), verbo([increasing]), complemento([their, apparent, solubility, through, solubilization])].
[sujeto(['However,', very, few, 'studies,', to, 'date,']), verbo([have]), complemento([systematically, examined, the, level, of, drug, apparent, solubility, in, 'o/w', microemulsion, formed, by, 'self-microemulsifying'])].
[sujeto(['Moreover,', this, technique, showed, that, simvastatin, apparent, solubility, was, mainly, influenced, by, microemulsion, concentration, 'and,']), verbo([suggested]), complemento([that, the, drug, would, precipitate, in, the, gastrointestinal, tract, due, to, dilution, by, gastrointestinal, fluids])].
[sujeto([pilosus]), verbo([required]), complemento([a, suitable, concentration, of, organic, nitrogen, peptone, for, high, lovastatin, production])].
[sujeto(['As', sole, carbon, source, with, 'peptone,', although, glucose, strongly]), verbo([repressed]), complemento([lovastatin, 'production,', maltose, was, responsible, for, high, production])].
[sujeto(['Interestingly,', glycerol, combined, with, maltose]), verbo([enhanced]), complemento([lovastatin, 'production,', up, to, 444, 'mg/l', in, the, most, effective, case])].
[sujeto([pilosus, is]), verbo([regulated]), complemento([by, strict, glucose, repression, and, that, an, appropriate, release, from, this, repression, by, optimizing, medium, composition, 'and/or', by, a, 'mutation(s)', is, required, for, high, lovastatin, production])].
[sujeto(['Statins']), verbo([decrease]), complemento([triglycerides, '(', 'TGs)', in, addition, to, decreasing, low, density, 'lipoprotein-cholesterol'])].
[sujeto(['Although', the, mechanism, for, the, latter, effect, is, well, 'understood,', it, is, still, unclear, how, 'TG']), verbo([decrease]), complemento([is, achieved, with, statin, therapy])].
[sujeto(['However,', 'TRL-TG', clearance, was, significantly]), verbo([increased]), complemento([in, the, diabetic, subjects, during, simvastatin, treatment, compared, with, placebo, '(', 0.25, +, /, -, 0.03, vs])].
[sujeto(['This', change, was, accompanied, by, a, 49, '%']), verbo([increase]), complemento([in, preheparin, plasma, lipase, activity, '(', 'P', &, 'lt;', 0.03, ')', and, a, 21, '%', increase, in, postheparin, 'LPL', activity, '(', 'P', &, 'lt;', 0.01, ')'])].
[sujeto(['Together,', these, findings]), verbo([provide]), complemento([strong, evidence, that, the, effect, of, statins, on, serum, 'TGs', is, related, to, an, increase, in, 'LPL', 'activity,', resulting, in, accelerated, delipidation, of, 'TRL', particles])].
[sujeto(['We', tested, whether, hyporeactivity, to, the, 'endothelium-dependent', vasodilator, acetylcholine, '(', 'ACh)', and, the, vasoconstrictor, norepinephrine, '(', 'NE)', during, acute, experimental, inflammation, could, be]), verbo([prevented]), complemento([by, simvastatin])].
[sujeto(['LPS', administration]), verbo([decreased]), complemento([the, responses, of, 'FBF', to, 'NE', by, 43, '%', '(', 'P<0'])].
[sujeto([5, ')', and]), verbo([decreased]), complemento([responses, to, 'ACh', by, 48, '%', '(', 'P<0'])].
[sujeto([5, ')', but, did, not]), verbo([decrease]), complemento(['FBF', responses, to, 'NTG'])].
[sujeto(['The', 'LPS-induced']), verbo([increases]), complemento([in, neutrophil, oxidative, burst, and, plasma, tumor, necrosis, 'factor-alpha', concentrations, were, mitigated, by, simvastatin, '(', 'P<0'])].
[sujeto(['This', study, demonstrates, potent, vasoprotective, properties, of, 'high-dose', simvastatin, during, endotoxemia, that, may, be, useful, for, patients, with, acute, systemic, inflammation, and]), verbo([associated]), complemento([vascular, hyporeactivity])].
[sujeto(['Serum', triacylglycerol, '(', 'TAG)', levels]), verbo([associate]), complemento([positively, with, the, risk, for, coronary, heart, disease, '(', 'CHD)'])].
[sujeto(['First,', 'GEH', activity]), verbo([increased]), complemento([to, values, similar, to, those, found, in, healthy, subjects, 'and,', 'simultaneously,', 'GECAT', activity, decreased])].
[sujeto(['In', 'conclusion,', by]), verbo([increasing]), complemento(['GEH', and, reducing, 'GECAT,', simvastatin, seems, not, only, to, affect, cholesterol, synthesis, but, also, to, alter, triacylglycerol, metabolism])].
[sujeto(['The', mevalonate, pathway]), verbo([provides]), complemento([metabolites, for, 'post-translational', modifications, such, as, 'farnesylation,', which, are, critical, for, the, activity, of, 'RAS', downstream, signaling])].
[sujeto(['Subsequently', occurring, regulatory, processes, can]), verbo([induce]), complemento([an, aberrant, stimulation, of, 'DNA', methyltransferase, '(', 'DNMT1)', as, well, as, changes, in, histone, deacetylases, '(', 'HDACs)', and, microRNAs, in, many, cancer, cell, lines])].
[sujeto(['Inhibitors', of, the, mevalonate, pathway, are, increasingly]), verbo([recognized]), complemento([as, anticancer, drugs])].
[sujeto(['Moreover,', since, the, mevalonate, metabolism, is, part, of, a, signaling, 'network,', including, vitamin, 'D', metabolism, or, fatty, acid, 'synthesis,', the, epigenetic, activity, of]), verbo([associated]), complemento([pathways, is, also, presented])].
[sujeto(['This', emphasizes, the, 'far-reaching', epigenetic, impact, of, metabolic, therapies, on, cancer, cells, and]), verbo([provides]), complemento([some, explanation, for, clinical, 'observations,', which, indicate, the, anticancer, activity, of, statins, and, bisphosphonates])].
[sujeto(['Lovastatin,', a, natural, byproduct, of, some, 'fungi,', is, able, to]), verbo([inhibit]), complemento(['HMG-CoA', '(', 3, -, 'hydroxy-3', methyl, glutaryl, 'CoA)', reductase])].
[sujeto(['This', is, a, key, enzyme]), verbo([involved]), complemento([in, isoprenoid, synthesis, and, essential, for, cell, membrane, formation, in, methanogenic, 'Archaea'])].
[sujeto(['In', this, 'paper,', experiments, were, designed, to, test, the, hypothesis, that, lovastatin, secreted, by, 'Aspergillus', terreus, in, fermented, rice, straw, extracts, '(', 'FRSE)', can]), verbo([inhibit]), complemento([growth, and, 'CH4', production, in, 'Methanobrevibacter', smithii, '(', a, test, 'methanogen)'])].
[sujeto(['Real-time', 'PCR', confirmed, that, both, commercial, lovastatin, and, 'FRSE']), verbo([increased]), complemento(['(', 'P', &, 'lt;', 0.01, ')', the, expression, of, 'HMG-CoA', reductase, gene, '(', 'hmg)'])].
[sujeto(['Experimental', confirmation, that, 'CH4', production, is]), verbo([inhibited]), complemento([by, lovastatin, in, 'A'])].
[sujeto(['Such', 'trans-acting', 'ERs']), verbo([have]), complemento([been, reported, across, a, variety, of, other, fungal, 'PKS', enzymes, as, a, strategy, in, nature, to, diversify, polyketides])].
[sujeto(['The', 1.9, -, 'Å', structure, of, 'LovC']), verbo([reveals]), complemento([that, 'LovC', possesses, a, 'medium-chain', 'dehydrogenase/reductase', '(', 'MDR)', fold, with, a, unique, monomeric, assembly])].
[sujeto(['We']), verbo([report]), complemento([here, a, novel, selectable, marker, for, the, hyperthermophilic, crenarchaeon, 'Sulfolobus', islandicus])].
[sujeto(['The', marker, cassette, is, composed, of, the, sac7d, promoter, and, the, hmg, gene, coding, for, the, 3, -, 'hydroxy-3-methylglutaryl', coenzyme, 'A', '(', 'HMG-CoA)', reductase, '(', 'P(sac7d)-hmg),', which]), verbo([confers]), complemento([simvastatin, resistance, to, this, crenarchaeon])].
[sujeto(['Characterization', of, 'Sulfolobus', transformants, carrying, pSSRlacS, indicated, that, the, plasmid, was, properly]), verbo([maintained]), complemento([under, selection])].
[sujeto(['The', amino, acid, sequences, of, the, 'TbHMGRs', show, the, typical, motifs, described, for, plant, 'HMGRs', such, as, two, transmembrane, domains, and, a, catalytic, domain, containing, two, 'HMG-CoA', and, two, 'NADP(H)']), verbo([binding]), complemento([sites])].
[sujeto(['The', enzyme, 'HMG-CoA', reductase, '(', 'HMGCR),', the, main, site, of, action, of, 'statins,', undergoes, alternative, splicing, of, exon, 13, ',', which, encodes, the]), verbo([binding]), complemento([domain, of, statins, to, the, enzyme])].
[sujeto(['This']), verbo([translates]), complemento([into, interindividual, differences, in, the, response, to, treatment, with, these, drugs])].
[sujeto(['A', recent, discovery, in, the, field, of, genetics]), verbo([has]), complemento([brought, about, the, identification, of, the, single, nucleotide, polymorphism, rs4363657, of, the, 'SLCO1B1', gene, located, on, chromosome, 12])].
[sujeto(['This', polymorphism, is, strongly]), verbo([associated]), complemento([with, myopathy, induced, by, statins])].
[sujeto(['From', the, available, 'literature,', a, clinical, study]), verbo([has]), complemento([evaluated, the, relationship, between, gene, polymorphisms, and, myopathy, during, statin, therapy])].
[sujeto(['The', study]), verbo([involved]), complemento([12, 0, patients, treated, with, simvastatin, at, a, dose, of, 80, 'mg/day'])].
[sujeto(['Genomic', typing, may, allow, the, identification, of, these, 'variants,']), verbo([leading]), complemento([to, a, tailored, statin, therapy, with, higher, benefits, to, the, patients, and, less, adverse, side, effects])].
[sujeto(['Therefore,', it, may]), verbo([act]), complemento([as, potential, target, for, blocking, the, process, of, methane, formation])].
[sujeto([1, ')', however, no]), verbo([report]), complemento([has, been, found, about, its, 3, 'D', protein, structure])].
[sujeto(['In', 'addition,', we, investigated, that, the, substrate, 'F420']), verbo([bound]), complemento([at, the, cavity, of, the, model])].
[sujeto(['It', indicates, that, the, 'Lovastatin', and, 'Compactin', '(', 'Mevastatin)', compounds, '(', 'Negative', 'regulator)', may]), verbo([act]), complemento([as, potential, inhibitor, of, 'F420', dependent, 'NADP', oxidoreducatse, protein])].
[sujeto(['Pilot-scale', libraries, of, 'eight-membered', medium, ring, lactams, '(', 'MRLs)', and, related, tricyclic, compounds, '(', either, 'seven-membered', 'lactams,', thiolactams, or, 'amines)', were, screened, for, their, ability, to]), verbo([inhibit]), complemento([the, catalytic, activity, of, human, recombinant, 3, -, 'hydroxy-3-methylglutaryl-coenzyme', 'A', '(', 'HMG-CoA)', reductase, in, vitro])].
[sujeto(['A', dozen, of, the, synthetic, compounds, mimic, the, inhibition, of, purified, 'HMG-CoA', reductase, activity]), verbo([caused]), complemento([by, 'pravastatin,', fluvastatin, and, sodium, salts, of, 'lovastatin,', mevastatin, and, simvastatin, in, this, 'cell-free', 'assay,', suggesting, direct, interaction, with, the, 'rate-limiting', enzyme, of, cholesterol, biosynthesis])].
[sujeto(['Moreover,', several, 'MRLs']), verbo([inhibit]), complemento([the, metabolic, activity, of, 'L1210', tumor, cells, in, vitro, to, a, greater, degree, than, 'fluvastatin,', 'lovastatin,', mevastatin, and, 'simvastatin,', whereas, pravastatin, is, inactive])].
[sujeto(['The', 'HMG-CoA', 'reductase-inhibiting', activities, of, pravastatin, and, an, 'MRL', persist, in, the, presence, of]), verbo([increasing]), complemento([concentrations, of, 'NADPH'])].
[sujeto(['But']), verbo([increasing]), complemento([concentrations, of, 'HMG-CoA', block, the, 'HMG-CoA', 'reductase-inhibiting', activity, of, pravastatin, without, altering, that, of, an, 'MRL,', suggesting, that, 'MRLs', and, existing, statins, may, have, different, mechanisms, of, enzyme, interaction, and, inhibition])].
[sujeto(['When', tested, 'together,', suboptimal, concentrations, of, synthetic, 'MRLs', and, existing, statins]), verbo([have]), complemento([additive, inhibitory, effects, on, 'HMG-CoA', reductase, activity])].
[sujeto(['The', isolated, 'Rhizomucor', gene, was]), verbo([expressed]), complemento([in, the, related, 'fungus,', 'Mucor', circinelloides])].
[sujeto(['With', potentially, neuroprotective, 'properties,', heme, 'oxygenase-1', '(', 'HO-1)']), verbo([has]), complemento([been, suggested, to, be, the, main, mediator, of, 'cholesterol-independent', 'anti-inflammatory', and, antioxidant, actions, of, statins])].
[sujeto(['However,', we, had, demonstrated, that, 'simvastatin-induced', 'HO-1']), verbo([increased]), complemento([apoptosis, of, 'Neuro', 2, 'A', cells, in, glucose, 'deprivation,', and, iron, production, from, 'HO-1', activity, may, be, responsible, for, the, toxicity])].
[sujeto(['We']), verbo([found]), complemento([that, the, 'HO-1', upregulation, was, significantly, associated, with, increased, nuclear, factor, kappa, 'B', '(', 'NF-kappaB)', 'activation,', manifested, as, 'IkappaBalpha', phosphorylation, and, p65, nuclear, 'translocation,', as, well, as, increased, production, of, superoxides])].
[sujeto(['Inhibition', of, the]), verbo([induced]), complemento(['HO-1', by, zinc, protoporphyrin, reduced, the, increased, 'NF-kappaB', activation, and, superoxides, production])].
[sujeto(['In', 'addition,', the, viable, cells, were, significantly]), verbo([decreased]), complemento([in, 48, h, in, those, cells, receiving, simvastatin, pretreatment, plus, 'LPS', compared, to, those, in, control, or, exposed, to, simvastatin, or, 'LPS', alone])].
[sujeto(['This', study, revealed, that, 'simvastatin-induced', 'HO-1']), verbo([led]), complemento([to, increased, 'NF-kappaB', activation, and, superoxides, production, in, the, neuronal, cells, when, exposed, to, 'LPS,', and, iron, production, may, play, a, role, in, such, a, response])].
[sujeto(['Previous', studies]), verbo([have]), complemento([shown, that, 'HRIs', can, induce, apoptosis, in, colon, cancer, cells])].
[sujeto(['The', 'HRI', lovastatin]), verbo([induced]), complemento([apoptosis, in, the, human, colon, cancer, cell, line, 'SW480', by, blocking, the, cholesterol, synthesis, pathway])].
[sujeto(['Immunoblot', analysis, of, antiapoptotic, 'molecules,', including, 'survivin,', 'XIAP,', 'cIAP-1,', 'cIAP-2,', 'Bcl-2,', and, 'Bcl-X(L),', revealed, that, only, survivin, expression, was]), verbo([decreased]), complemento([by, lovastatin])].
[sujeto(['Survivin', 'down-regulation', by, 'RNA', interference]), verbo([induced]), complemento(['apoptosis,', and, survivin, overexpression, rendered, the, cells, resistant, to, 'lovastatin-induced', growth, inhibition])].
[sujeto(['We', conclude, that, survivin, 'down-regulation', is, crucial, in, 'lovastatin-induced', apoptosis, in, cancer, cells, and, that, lovastatin]), verbo([decreases]), complemento([survivin, expression, by, inhibiting, 'Ras-mediated', 'PI3-kinase', activation, via, the, blocking, of, 'Ras', isoprenylation])].
[sujeto(['This', study, explores, the, role, of, heme, oxygenase, 1, '(', 'HO-1)', as, a]), verbo([target]), complemento([and, mediator, of, statins])].
[sujeto(['In', cultured, endothelial, cells, derived, from, human, umbilical, 'vein,', simvastatin, and, lovastatin]), verbo([increased]), complemento(['HO-1', mRNA, levels, in, a, 'concentration-', and, 'time-dependent', fashion])].
[sujeto(['In', cells, transfected, with, a, reporter, gene, construct, containing, the, proximal, 4, kB, of, the, 'HO-1', gene, promoter, 5, '\'', -, flanking, 'region,', significant, upregulation, of, promoter, activity, was, 'detected,', indicating, that, regulatory, elements]), verbo([binding]), complemento([to, this, region, were, involved, in, transcriptional, 'HO-1', induction, by, statins])].
[sujeto(['Increased', transcriptional, expression, of, 'HO-1', was]), verbo([associated]), complemento([with, elevated, 'HO-1', protein, levels, and, reduction, of, free, radical, formation])].
[sujeto(['Our', results, show, that, the, antioxidant, defense, protein, 'HO-1', is, a]), verbo([target]), complemento([site, of, statins, in, endothelial, cells])].
[sujeto(['Statins']), verbo([lead]), complemento([to, 'HO-1', promoter, 'activation,', transcript, and, protein, accumulation])].
[sujeto(['Several', prospective, clinical, studies]), verbo([have]), complemento([indicated, that, 'hydroxymethylglutaryl-coenzyme', 'A', reductase, 'inhibitors,', 'statins,', prevent, cardiovascular, events, in, part, through, their, antiinflammatory, properties])].
[sujeto(['Because', inflammation, is, positively, and, negatively]), verbo([regulated]), complemento([by, 'T', helper, '(', 'Th)', 1, cells, and, 'Th2', 'cells,', 'respectively,', we, examined, the, effects, of, statins, on, the, 'Th', polarization, in, vitro, and, in, vivo])].
[sujeto(['Here', we, demonstrated, that, the, statins, 'tested,', 'ie,', 'cerivastatin,', 'simvastatin,', 'lovastatin,', and, 'atorvastatin,']), verbo([promoted]), complemento(['Th2', polarization, through, both, inhibition, of, 'Th1', development, and, augmentation, of, 'Th2', development, of, 'CD4+', 'T', cells, primed, in, vitro, with, 'anti-CD3', antibody, and, splenic, 'antigen-presenting', cells])].
[sujeto(['Consistent', with, in, vitro, 'experiments,', cerivastatin, treatment]), verbo([decreased]), complemento(['IFN-gamma', production, of, lymph, node, cells, from, mice, immunized, with, ovalbumin, emulsified, in, complete, 'Freund\'s', 'adjuvant,', indicating, that, 'Th1', development, is, also, suppressed, in, an, in, vivo, proinflammatory, environment])].
[sujeto(['The']), verbo([decrease]), complemento([of, glomerular, sclerosis, by, cerivastatin, treatment, was, positively, related, to, the, suppression, of, interferon, '(', 'IFN)-gamma-producing', 'Th1', response, in, draining, lymph, node, cells])].
[sujeto(['Hence,', these, findings, strongly]), verbo([suggest]), complemento([that, 'statins\'', inhibition, of, 3, -, 'hydroxy-3-methylglutaryl-coenzyme', 'A', reductase, regulates, 'Th1/Th2', polarization, in, vivo, and, such, a, mechanism, possibly, plays, a, pathophysiological, role, in, 'immune-related', glomerular, injury])].
[sujeto(['Cytochrome', 'P450', '(', 'P450)-dependent', arachidonic, acid, metabolites, may]), verbo([act]), complemento([as, mediators, in, the, regulation, of, vascular, tone, and, renal, function])].
[sujeto(['Treatment', with, 'DOCA-salt', resulted, in, significantly]), verbo([decreased]), complemento([hydroxylase, activities, '(', to, 84, +, /, -, 4, pmol])].
[sujeto(['mg(-1))', of, the, total, microsomal, 'P450', content, and, a]), verbo([decrease]), complemento([in, immunodetectable, 'Cyp4a', proteins])].
[sujeto(['Lovastatin', had, no, effect, on, these, 'variables,', whereas, bezafibrate]), verbo([increased]), complemento([arachidonic, acid, hydroxylase, activities, to, 163, +, /, -, 12, pmol])].
[sujeto(['In', situ, hybridization, with, probes, for, 'Cyp4a-10,', 12, ',', and, 14, revealed, that, 'Cyp4a-14', was, the, 'P450', isoform, most, strongly]), verbo([induced]), complemento([by, bezafibrate])].
[sujeto(['In', 'conclusion,', these, results]), verbo([suggest]), complemento([that, the, capacity, to, produce, 20, -, hydroxyarachidonic, acid, is, impaired, in, the, kidneys, of, 'DOCA-salt', hypertensive, mice])].
[sujeto(['Comparison', of, the, inferred, amino, acid, sequence, of, orf, 'AF1736', of, 'Archaeoglobus', fulgidus, to, that, of, 'Pseudomonas', mevalonii, 'HMG-CoA', reductase]), verbo([suggested]), complemento([that, 'AF1736', might, encode, a, 'Class', 'II', 'HMG-CoA', reductase])].
[sujeto(['Activity', was, optimal, at, 85, degrees, 'C,', deltaHa, was, 54, 'kJ/mol,', and, the, statin, drug, mevinolin]), verbo([inhibited]), complemento([competitively, with, 'HMG-CoA', '(', 'Ki', 180, 'microM)'])].
[sujeto(['The', results, indicate, the, importance, of, the, protonated, status, of, active, site, residues, 'His390', and, 'Lys277,', shown, by, altered, 'K(M)', and, 'k(cat)', 'values,', and, indicate, that, 'NAD(H)', and, 'NADP(H)']), verbo([have]), complemento([comparable, affinity, for, the, same, site])].
[sujeto(['In', 'plants,', environmental, insults, like, heat, and, sunlight]), verbo([trigger]), complemento([the, synthesis, of, 'isoprene,', also, derived, from, 'MVA,', and, this, phenomenon, has, been, associated, with, enhanced, tolerance, to, heat])].
[sujeto(['Here,', we, show, that, in, human, prostate, adenocarcinoma, 'PC-3M', cells, heat, shock]), verbo([leads]), complemento([to, activation, of, the, 'MVA', pathway])].
[sujeto(['This', is, characterized, by, a, 'dose-', and, 'time-dependent', elevation, in, 3, -, 'hydroxy-3-methylglutaryl-coenzyme', 'A', reductase, '(', 'HMGR)', 'activity,']), verbo([enhanced]), complemento([sterol, and, isoprenoid, 'synthesis,', and, increased, protein, prenylation])].
[sujeto(['Furthermore,', prenylation, and, subsequent, membrane, localization, of, 'Ras,', a, central, player, in, cell, 'signaling,', was, rapidly]), verbo([induced]), complemento([following, heat, stress])].
[sujeto(['These', effects, were, 'dose-dependent,', augmented, with, repeated, 'insults,', and, were]), verbo([prevented]), complemento([by, culturing, cells, in, the, presence, of, 'lovastatin,', a, competitive, inhibitor, of, 'HMGR'])].
[sujeto(['Enhanced', 'Ras', maturation, by, heat, stress, was, also]), verbo([associated]), complemento([with, a, heightened, activation, of, extracellular, 'signal-regulated', kinase, '(', 'ERK),', a, key, mediator, of, both, mitogenic, and, stress, signaling, 'pathways,', in, response, to, subsequent, growth, factor, stimulation])].
[sujeto(['Thus,', activation, of, the, 'MVA', pathway, may, constitute, an, important, adaptive, host, response, to, 'stress,', and]), verbo([have]), complemento([significant, implications, to, carcinogenesis])].
[sujeto(['Regulated', degradation, of, specific, proteins, is, often]), verbo([mediated]), complemento([by, discrete, regions, of, primary, sequence, known, as, 'degrons,', whereas, protein, quality, control, involves, recognition, of, structural, features, common, to, damaged, or, misfolded, 'proteins,', rather, than, specific, features, of, an, individual, protein])].
[sujeto(['The', yeast, 'HMG-CoA', reductase, isozyme, 'Hmg2p', undergoes, stringently]), verbo([regulated]), complemento([degradation, by, machinery, that, is, also, required, for, 'ER', quality, control])].
[sujeto(['The', 523, residue, 'N-terminal', transmembrane, domain, of, 'Hmg2p', is, necessary, and, sufficient, for]), verbo([regulated]), complemento([degradation])].
[sujeto(['To', understand, how, 'Hmg2p', undergoes]), verbo([regulated]), complemento([degradation, by, the, 'ER', quality, control, 'pathway,', we, analyzed, over, 300, mutants, of, 'Hmg2p'])].
[sujeto(['Regulated', degradation, of, 'Hmg2p']), verbo([requires]), complemento([information, distributed, over, the, entire, transmembrane, domain])].
[sujeto(['Accordingly,', we, refer, to, this, determinant, as, a, '\'', 'distributed\'', 'degron,', which]), verbo([has]), complemento([functional, aspects, consistent, with, both, regulation, and, quality, control])].
[sujeto(['The', 'Hmg2p', degron, functions, in, the, 'specific,']), verbo([regulated]), complemento([degradation, of, 'Hmg2p', and, can, impart, regulated, degradation, to, fusion, proteins])].
[sujeto(['This', mode, of]), verbo([targeting]), complemento([has, important, consequences, both, for, the, prediction, of, degradation, substrates, and, as, a, potential, therapeutic, strategy, for, targeted, protein, degradation, using, endogenous, degradation, pathways])].
[sujeto(['The', objective, of, this, study, was, to, investigate, the, cholesterol, uptake, and, accumulation]), verbo([triggered]), complemento([by, agLDL, in, comparison, with, native, 'LDL', '(', 'nLDL)', on, unstimulated, and, 'platelet-derived', growth, 'factor-stimulated', human, aortic, 'VSMCs', and, the, role, of, 3, -, 'hydroxy-3-methylglutaryl', coenzyme, 'A', reductase, inhibitors, on, these, processes])].
[sujeto(['Esterified', cholesterol, '(', 'EC)', accumulation]), verbo([induced]), complemento([by, agLDL, in, 'VSMCs', was, correlated, with, the, degree, of, aggregation, and, concentration])].
[sujeto(['The', 'EC', content, of, 'VSMCs', treated, with, 100, 'microg/mL', of, agLDL, '(', 80, '%', 'aggregated)']), verbo([increased]), complemento([approximately, 70, -, fold, over, that, in, 'VSMCs', incubated, with, the, same, concentration, of, nLDL])].
[sujeto(['Whereas', 'nLDL-derived', 'EC', was]), verbo([increased]), complemento([approximately, twofold, in, 'platelet-derived', growth, 'factor-stimulated', 'VSMCs,', there, was, no, effect, of, 'platelet-derived', growth, factor, '(', 10, '(', -, 9, ')', 'mol/L)', on, the, uptake, of, agLDL])].
[sujeto(['Fluorescence', microscopy, of, the, cellular, internalization, of, agLDL, labeled, with, the, fluorochrome, 1, ',', 1, '\'', -, 'dioctadecyl-3,3,3\',3\'-tetramethylindocarbocyanine', demonstrated, that, simvastatin, reduces, 'EC', accumulation, derived, from, agLDL, by]), verbo([inhibiting]), complemento([its, endocytosis, and, that, the, effect, is, completely, reversed, by, geranygeraniol])].
[sujeto(['These', results, indicate, that, agLDLs, are, rapidly, internalized, by, human, 'VSMCs', and, that, 3, -, 'hydroxy-3-methylglutaryl', coenzyme, 'A', reductase, inhibitors]), verbo([modulate]), complemento(['EC', accumulation])].
[sujeto(['These', data]), verbo([suggest]), complemento([a, possible, mechanism, by, which, statins, could, contribute, to, the, passivation, and, stabilization, of, actively, growing, atherosclerotic, lesions])].
[sujeto(['Although', the, molecular]), verbo([targets]), complemento([of, bisphosphonates, have, not, been, 'identified,', these, compounds, inhibit, bone, resorption, by, mechanisms, that, can, lead, to, osteoclast, apoptosis])].
[sujeto(['Bisphosphonates', also]), verbo([induce]), complemento([apoptosis, in, mouse, 'J774', macrophages, in, 'vitro,', probably, by, the, same, mechanisms, that, lead, to, osteoclast, apoptosis])].
[sujeto(['We']), verbo([have]), complemento([found, 'that,', in, 'J774', 'macrophages,', 'nitrogen-containing', bisphosphonates, '(', such, as, 'alendronate,', 'ibandronate,', and, 'risedronate)', inhibit, 'post-translational', modification, '(', 'prenylation)', of, 'proteins,', including, the, 'GTP-binding', protein, 'Ras,', with, farnesyl, or, geranylgeranyl, isoprenoid, groups])].
[sujeto(['Clodronate', did, not]), verbo([inhibit]), complemento([protein, prenylation])].
[sujeto(['Mevastatin,', an, inhibitor, of, 3, -, 'hydroxy-3-methylglutatyl', '(', 'HMG)-CoA', reductase, and, hence, the, biosynthetic, pathway]), verbo([required]), complemento([for, the, production, of, farnesyl, pyrophosphate, and, geranylgeranyl, 'pyrophosphate,', also, caused, apoptosis, in, 'J774', macrophages, and, murine, osteoclasts, in, vitro])].
[sujeto(['Furthermore,', 'alendronate-induced', 'apoptosis,', like, 'mevastatin-induced', 'apoptosis,', could, be]), verbo([suppressed]), complemento([in, 'J774', cells, by, the, addition, of, farnesyl, pyrophosphate, or, geranylgeranyl, 'pyrophosphate,', while, the, effect, of, alendronate, on, osteoclast, number, and, bone, resorption, in, murine, calvariae, in, vitro, could, be, overcome, by, the, addition, of, mevalonic, acid])].
[sujeto(['These', observations]), verbo([suggest]), complemento([that, 'nitrogen-containing', bisphosphonate, drugs, cause, apoptosis, following, inhibition, of, 'post-translational', prenylation, of, proteins, such, as, 'Ras'])].
[sujeto(['It', is, likely, that, these, potent, antiresorptive, bisphosphonates, also]), verbo([inhibit]), complemento([bone, resorption, by, preventing, protein, prenylation, in, osteoclasts, and, that, enzymes, of, the, mevalonate, pathway, or, prenyl, protein, transferases, are, the, molecular, targets, of, the, 'nitrogen-containing', bisphosphonates])].
[sujeto(['Furthermore,', the, data, support, the, view, that, clodronate]), verbo([acts]), complemento([by, a, different, mechanism])].
[sujeto(['We']), verbo([report]), complemento([here, the, characterization, of, an, 'HMG-CoA', reductase, from, the, third, 'domain,', the, archaea])].
[sujeto(['Following', purification, to, electrophoretic, 'homogeneity,', the, specific, activity, of, the]), verbo([expressed]), complemento(['enzyme,', 24, 'microU/mg,', equaled, that, of, homogeneous, hamster, or, 'P'])].
[sujeto(['(', 'R)-HMG-CoA', and, lovastatin]), verbo([inhibited]), complemento([competitively, with, '(', 'S)-HMG-CoA'])].
[sujeto([mevalonii, 'HMG-CoA', 'reductases,']), verbo([suggesting]), complemento([a, similar, catalytic, mechanism])].
[sujeto(['Statin', drugs, are]), verbo([leading]), complemento([medication, prescribed, for, treatment, of, dyslipidemic, patients, aimed, at, preventing, both, primary, and, secondary, incidences, of, 'atherosclerosis-related', cardiovascular, events])].
[sujeto(['Statin', drugs, competitively]), verbo([inhibit]), complemento(['HMG-CoA', reductase, enzyme, 'activity,', thereby, inhibiting, 'cell-mediated', cholesterol, synthesis, and, reducing, the, 'low-density', lipoprotein, '(', 'LDL)', cholesterol, concentration, of, plasma])].
[sujeto(['Conversely,', the, mechanism, by, which, statins]), verbo([increase]), complemento(['high-density', lipoprotein, '(', 'HDL)', cholesterol, concentration, of, plasma, is, not, well, understood])].
[sujeto(['We', observed, that, statins]), verbo([induced]), complemento(['high-density', cholesterol, particle, formation, in, buffer, solution, with, or, without, the, addition, of, human, serum])].
[sujeto(['Besides,', simvastatin, and, lovastatin, in, their, inactive, 'pro-drug', forms]), verbo([modulate]), complemento([formation, of, 'LDL', and, 'HDL', cholesterol, 'particles,', indicating, a, novel, nonenzymatic, mechanism, of, statins])].
[sujeto(['Taken', 'together,', our, data, indicate, that, 'statins,', in, addition, to]), verbo([inhibiting]), complemento(['enzyme-mediated', cholesterol, 'synthesis,', have, the, capability, to, nonenzymatically, modulate, formation, of, 'LDL', and, 'HDL', cholesterol, particles, 'in vitro'])].
[sujeto(['Similar', interactions, occurring, in, serum, may]), verbo([provide]), complemento([a, means, to, alter, cholesterol, particle, formation, 'in vivo'])].
[sujeto(['Muscle', biopsy, was, compatible, with, 'statin-associated', 'rhabdomyolysis,', probably]), verbo([caused]), complemento([by, a, 'drug-drug', interaction, between, simvastatin, and, itraconazole])].
[sujeto(['Statins', are, 'HMG-CoA', reductase, inhibitors, that, are, used, to]), verbo([decrease]), complemento([the, blood, levels, of, 'low-density', lipoprotein, '(', 'LDL)'])].
[sujeto(['In', 'addition,', they]), verbo([have]), complemento([been, shown, to, exert, pleiotropic, protective, effects, in, the, absence, of, 'LDL-lowering', activity])].
[sujeto(['The', results]), verbo([suggested]), complemento([that, numerous, genes, were, regulated, by, 'lovastatin,', including, certain, genes, associated, with, cell, 'survival,', such, as, 'PTK2B,', 'BCL2', and, 'MAP3K3'])].
[sujeto(['In', 'particular,', 'PTK2B,', which]), verbo([has]), complemento([been, shown, to, exert, 'anti-apoptotic', effects, against, 'ox-LDL-induced', cell, 'injury,', was, upregulated, by, lovastatin])].
[sujeto(['Knockdown', of, 'PTK2B', was, able, to, attenuate, 'ox-LDL-induced', cell, 'injury,', and, this, was]), verbo([associated]), complemento([with, decreased, levels, of, 'phosphorylated-AKT', and, 'eNOS,', and, inhibition, of, 'mitochondrial-dependent', apoptosis])].
[sujeto(['In', 'conclusion,', the, results, of, the, present, study]), verbo([suggested]), complemento([that, lovastatin, protects, against, 'ox-LDL-induced', cell, 'injury,', potentially, via, the, upregulation, of, 'PTK2B,', which, regulates, the, 'anti-apoptosis', signaling, pathway])].
[sujeto(['The', activities, of, 'sucrose-phosphate', synthase, '(', 'SPS),', sucrose, synthase, '(', 'SuSy),', and, cell, wall, invertase, '(', 'CW-invertase)', were, higher, in, 'tasg1,']), verbo([suggesting]), complemento([an, altered, metabolism, and, transport, of, soluble, sugars])].
[sujeto(['Furthermore,', when, tasg1, was, treated, with, the, 'CK', inhibitor, 'lovastatin,', the, activity, of, invertase, was]), verbo([inhibited]), complemento([and, was, associated, with, premature, senescence, phenotype])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'CKs', might, regulate, the, 'stay-green', phenotype, of, tasg1, by, regulating, the, invertase, activity, involved, in, 'Suc', remobilization])].
[sujeto(['Chemotherapeutic', interventions, of, gliomas]), verbo([have]), complemento([poor, prognostic, outcomes, due, to, drug, resistance, and, drug, toxicity])].
[sujeto(['Our', results]), verbo([provide]), complemento([insight, into, 'C6', glioma, drug, resistance, as, well, as, the, inhibitory, effects, of, these, 2, 'phase-specific', inhibitors, and, their, chemotherapeutic, potential])].
[sujeto([',', neurofibromatosis, 1, '(', 'NF1)],', neurocognitive, impairments, are, frequent, and, are, affected, by, components, of, the, 'RAS', pathway, which]), verbo([lead]), complemento([to, impairments, in, synaptic, plasticity])].
[sujeto(['Transcranial', magnetic, stimulation, '(', 'TMS)']), verbo([provides]), complemento([a, 'non-invasive', method, to, investigate, synaptic, plasticity, in, humans])].
[sujeto(['In', 'contrast,']), verbo([increased]), complemento(['LTP-like', synaptic, plasticity, has, been, shown, in, 'Costello', syndrome])].
[sujeto(['Notably,', lovastatin, normalized, impaired, 'LTP-like', plasticity, and]), verbo([increased]), complemento([intracortical, inhibition, in, patients, with, 'NF1'])].
[sujeto(['TMS']), verbo([has]), complemento([been, shown, to, be, a, safe, and, efficient, method, to, investigate, synaptic, plasticity, and, intracortical, inhibition, in, patients, with, 'RASopathies'])].
[sujeto(['Around', 1, in, 200, to, 1, in, 500, persons, in, 'North', 'America', and, 'Europe', are, estimated, to]), verbo([have]), complemento([heterozygous, 'FH'])].
[sujeto(['When', 'untreated,', 'FH', is]), verbo([associated]), complemento([with, a, high, incidence, of, premature, clinical, atherosclerotic, cardiovascular, disease])].
[sujeto(['Lipid', concentrations, and, measures, of, atherosclerosis, were]), verbo([expressed]), complemento([as, percent, change, from, baseline, or, as, differences, from, baseline])].
[sujeto(['For', the, randomized, trials, of, statins, that]), verbo([reported]), complemento([means, and, standard, deviations, for, percent, change, '(', 'k=6),', we, summarized, the, results, using, forest, plots])].
[sujeto(['We']), verbo([found]), complemento([no, direct, evidence, for, five, 'KQs:', the, effectiveness, of, screening, children, and, adolescents, for, 'FH', in, improving, health, outcomes, '(', myocardial, infarction, '[', 'MI]', or, 'stroke)', in, adulthood, '(', 'KQ1)', or, intermediate, outcomes, '(', lipid, concentrations, and, 'atherosclerosis)', in, childhood, '(', 'KQ2),', the, harms, of, screening, for, 'FH', in, children, and, adolescents, '(', 'KQ4),', the, effectiveness, of, treating, children, and, adolescents, with, 'FH', on, health, outcomes, '(', 'MI', or, 'stroke)', in, adulthood, '(', 'KQ5),', and, the, association, between, intermediate, outcomes, in, childhood, and, adolescence, and, the, future, incidence, or, timing, of, 'MI', and, stroke, in, adulthood, '(', 'KQ8)'])].
[sujeto(['What', is, the, diagnostic, yield, of, appropriate, screening, tests, for, 'FH', in, children, and, 'adolescents?', 'Two', studies]), verbo([provided]), complemento([data, allowing, determination, of, the, diagnostic, yield, of, pediatric, 'FH', screening, programs])].
[sujeto(['A', statewide, universal, screening, program, screened, more, than, 80, ',', 0, 10, -, to, 11, -, 'year-olds', in, 'West', 'Virginia', schools, and]), verbo([reported]), complemento([a, diagnostic, yield, of, about, 1.3, cases, per, 1, ',', 0, screened])].
[sujeto(['A', 'Danish', 'school-based', study, of, more, than, 2, ',', 85, 6, -, to, 8, -, 'year-olds', used, the, 'ApoB:ApoA-1', ratio, and]), verbo([reported]), complemento([a, diagnostic, yield, of, 4.8, cases, per, 1, ',', 0, screened])].
[sujeto(['We']), verbo([found]), complemento([no, studies, reporting, diagnostic, yield, or, effectiveness, of, selective, screening, for, 'FH', in, youth, '(', i])].
[sujeto([',', screening, subjects, with, a, family, history, or, other]), verbo([targeting]), complemento(['factor)'])].
[sujeto(['Treatment', with, statins, lowered, 'LDL-C', and, 'TC', concentrations, in, the, short, term, in, children, and, adolescents, with, 'FH,', with, most, studies]), verbo([reporting]), complemento([that, statins, lowered, 'LDL-C', by, 20, to, 40, percent, compared, to, placebo])].
[sujeto(['Participants', who, received, the, highest, dose, '(', 20, 'mg/day)', experienced, a, 50, percent]), verbo([decrease]), complemento(['(', least, mean, 'squares)', in, 'LDL-C', from, baseline, compared, to, a, 1, percent, decrease, among, controls, '(', 'p<0'])].
[sujeto(['Eight', studies]), verbo([reported]), complemento([the, effect, of, statins, on, 'TC,', all, showing, decreases, of, about, 20, to, 30, percent, from, baseline, '(', compared, to, no, change, with, 'placebo)'])].
[sujeto(['A', single, study, assessed, the, effect, on, a, measure, of, atherosclerosis, and]), verbo([found]), complemento([that, pravastatin, reduced, carotid, 'intima-media', thickness, '(', 'CIMT)', by, 2.01, percent, '(', compared, to, a, 1.02, '%', increase, in, the, control, 'group;', 'p=0'])].
[sujeto(['The', two, studies, that, compared, different, doses, of, statins]), verbo([reported]), complemento([a, dose, response, with, pravastatin, and, rosuvastatin])].
[sujeto(['In', the, 2010, rosuvastatin, 'trial,', the, only, statin, study]), verbo([reporting]), complemento([how, many, subjects, attained, the, target, 'LDL-C', 'concentration,', only, 12, to, 41, percent, of, participants, reached, a, target, 'LDL-C', of, less, than, 110, 'mg/dL,', with, greater, effect, at, higher, doses])].
[sujeto(['Six', studies, of, statins]), verbo([provided]), complemento([the, necessary, data, to, create, a, forest, plot, of, mean, difference, across, statins, between, percent, change, from, baseline, of, 'TC,', 'LDL-C,', and, 'HDL-C'])].
[sujeto(['All', trials]), verbo([reported]), complemento([decreases, in, 'LDL-C', from, baseline])].
[sujeto(['A', 'good-quality', trial, of, colestipol]), verbo([found]), complemento([a, mean, reduction, in, 'LDL-C', of, 19.5, percent, after, 8, weeks, of, treatment, compared, to, a, 1, percent, decrease, in, the, control, group])].
[sujeto(['One', 'fair-quality', 'RCT', of, cholestyramine]), verbo([found]), complemento([an, 18.6, percent, reduction, in, 'LDL-C', after, 1, year, compared, to, a, 1.5, percent, increase, in, the, control, group])].
[sujeto(['One', 'good-quality', 8, -, week, 'RCT', of, colesevelam, published, after, the, 2007, 'USPSTF', review]), verbo([found]), complemento([a, least, squares, mean, decrease, in, 'LDL-C', of, 10, percent, '(', standard, error, '[', 'SE],', 2.1, '%', ')', at, the, higher, of, two, doses, compared, to, a, least, squares, mean, increase, of, 2.5, percent, '(', 'SE,', 2.0, '%', ')'])].
[sujeto(['A', lower, dose]), verbo([provided]), complemento([a, 'smaller,', nonsignificant, reduction])].
[sujeto(['One']), verbo([reported]), complemento([that, 'LDL-C', decreased, by, a, mean, of, 54.0, percent, '(', 'SE,', 1.4, '%', ')', in, participants, who, received, a, combination, of, ezetimibe, and, 'simvastatin,', whereas, the, mean, decrease, was, 38.1, percent, '(', 'SE,', 1.4, '%', ')', in, the, 'simvastatin-only', group, at, 33, weeks])].
[sujeto(['The', second]), verbo([found]), complemento(['that,', at, 12, 'weeks,', ezetimibe, monotherapy, decreased, 'LDL-C', by, 28, percent, '(', 95, '%', 'CI,', -, 31, to, -, 25, ')', from, baseline, compared, to, a, negligible, change, in, the, placebo, group])].
[sujeto(['One', study]), verbo([found]), complemento([lower, dehydroepiandrosterone, sulfate, concentrations, in, men, with, 'FH', treated, with, statins, compared, to, unaffected, siblings])].
[sujeto(['Bile-acid']), verbo([binding]), complemento([resins, were, commonly, associated, with, adverse, gastrointestinal, symptoms, and, poor, palatability])].
[sujeto(['population,', and, the, other]), verbo([provides]), complemento([few, details, as, to, the, screening, and, confirmatory, testing, for, 'FH'])].
[sujeto(['We']), verbo([found]), complemento([no, studies, comparing, outcomes, between, groups, of, children, or, adolescents, who, initiated, treatment, at, different, ages])].
[sujeto(['We']), verbo([found]), complemento([no, direct, evidence, of, the, effect, of, screening, on, intermediate, or, health, outcomes])].
[sujeto(['Statins', were, generally, 'well-tolerated', in, the, short, 'term,', although, reversible, elevations, of, liver, enzymes, 'and/or', creatine, kinase, concentrations, were, noted, in, some, studies, and, a]), verbo([decrease]), complemento([in, dehydroepiandrosterone, sulfate, was, noted, in, one, study])].
[sujeto(['Bile-acid']), verbo([binding]), complemento([resins, were, commonly, associated, with, adverse, gastrointestinal, symptoms, and, poor, palatability])].
[sujeto(['Compared', with, the, statin, 'nonusers,', the, adjusted, hazard, ratio, '(', 'aHR)', for, colon, cancer]), verbo([decreased]), complemento([in, the, statin, users, '(', aHR, =, 0.52, ',', 95, '%', confidence, interval, =, 0.44, ',', 0.62, ')'])].
[sujeto(['Compared', with, the, statin, 'nonusers,', the, aHRs, for, colon, cancer]), verbo([decreased]), complemento([in, the, individual, statin, users, '(', 'rosuvastatin,', 'simvastatin,', and, 'atorvastatin:', aHRs, =, 0.28, ',', 0.64, ',', and, 0.65, ',', 'respectively)'])].
[sujeto(['Untreated', 'FH', is]), verbo([associated]), complemento([with, premature, cardiovascular, disease, in, adulthood])].
[sujeto(['MEDLINE,', the, 'Cochrane', 'Central', 'Register', of, 'Controlled', 'Trials,', and, 'PubMed', were, searched, for, studies, published, between, 'January', 1, ',', 2005, ',', and, 'June', 2, ',', 2015, ;, studies, included, in, a, previous, 'USPSTF']), verbo([report]), complemento([were, also, searched])].
[sujeto(['Eight', placebo, trials, of, statin, drugs, '(', n, =, 1071, ',', 6, -, 104, 'weeks)']), verbo([found]), complemento(['low-density', lipoprotein, cholesterol, '(', 'LDL-C)', decreases, of, 20, '%', to, 40, '%', ;, 1, trial, '(', n, =, 214, ')', showed, a, 2.01, '%', decrease, in, carotid, 'intima-media', thickness, with, 'statins,', compared, with, 1.02, '%', with, placebo, '(', 'P', =])].
[sujeto(['One', trial, of, ezetimibe, monotherapy, '(', n, =, 138, ')', showed, mean, 'LDL-C']), verbo([decreases]), complemento([of, 28, '%', '(', 95, '%', 'CI,', -, 31, '%', to, -, 25, '%', ')', from, baseline, and, negligible, change, with, placebo, at, 12, weeks])].
[sujeto(['Eighteen', studies]), verbo([found]), complemento([statins, generally, well, tolerated])].
[sujeto(['One', observational, study]), verbo([found]), complemento(['lower,', but, still, 'normal,', dehydroepiandrosterone, sulfate, concentrations, in, 'statin-treated', males, with, 'FH', at, 10, -, year, 'follow-up'])].
[sujeto(['Bile', 'acid-sequestering', agents, were, commonly]), verbo([associated]), complemento([with, adverse, gastrointestinal, symptoms, and, poor, palatability])].
[sujeto(['Inflammation', is, a, 'well-known']), verbo([cause]), complemento([of, colorectal, cancer, carcinogenesis])].
[sujeto(['Metabolic', inflammation, '(', 'metaflammation)', and, altered, gut, microbiota, '(', 'dysbiosis)']), verbo([have]), complemento([contributed, to, colorectal, cancer])].
[sujeto(['Recently,', various, polypharmacologic, molecules, that, dually]), verbo([inhibit]), complemento([histone, deacetylases, '(', 'HDAC)', and, other, therapeutic, targets, have, been, developed])].
[sujeto(['We', synthesized, a, statin, hydroxamate, that, simultaneously]), verbo([inhibited]), complemento(['HDAC', and, 3, -, 'hydroxy-3-methylglutaryl', coenzyme, 'A', reductase, '(', 'HMGR)'])].
[sujeto(['Oral', administration, of, this, statin, hydroxamate, could]), verbo([prevent]), complemento([acute, inflammation, in, the, 'DSS-induced', colitis, and, 'AOM/DSS-induced', colorectal, cancer, with, superior, activity, than, the, combination, of, lovastatin, and, 'SAHA'])].
[sujeto(['It', also, reduced, proinflammatory, 'cytokines,', 'chemokines,', expression, of, 'COX-II,', and, cyclin, 'D1', in, inflammation, and, tumor, 'tissues,', as, well, as]), verbo([decreasing]), complemento([the, infiltration, of, macrophages, and, neutrophils, in, 'tumor-surrounding', regions])].
[sujeto(['Stemness', of, colorectal, cancer, and, the]), verbo([release]), complemento([of, endotoxin, in, 'AOM/DSS', mouse, models, were, also, attenuated, by, this, small, molecule])].
[sujeto(['This', study, demonstrates, that, the, polypharmacological, 'HDAC', inhibitor]), verbo([has]), complemento([promising, effect, on, the, chemoprevention, of, colorectal, 'cancer,', and, serum, endotoxin, level, might, serve, as, a, potential, biomarker, for, its, chemoprevention])].
[sujeto(['Chronic', obstructive, pulmonary, disease, '(', 'COPD)', is]), verbo([associated]), complemento([with, increased, lung, cancer, risk])].
[sujeto(['Currently', used, guided, tissue, regeneration, '(', 'GTR)', membranes, are, mainly, used, as, a, barrier, to]), verbo([prevent]), complemento([epithelial, cells, growth, into, defects, before, new, bone, formation])].
[sujeto(['Successful', 'EGCG', grafting, was, demonstrated, using, 'Fourier', transform, infrared, spectroscopy, and, 'EGCG', grafting, significantly]), verbo([enhanced]), complemento([adhesion, and, proliferation, of, human, gingival, fibroblasts])].
[sujeto(['The']), verbo([release]), complemento([duration, of, lovastatin, reached, 21, days])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, 'EGCG14-CS-Lovastatin1', membrane, has, the, potential, to, be, used, as, a, novel, 'GTR', membrane])].
[sujeto(['Statin', 'users,', except, lovastatin, 'users,', are, 'dose-dependently']), verbo([associated]), complemento([with, a, decreased, incidence, of, 'PD', compared, with, nonusers, of, statins])].
[sujeto(['This']), verbo([finding]), complemento([provides, a, new, indication, for, statin, beyond, lipid, control, and, cardiovascular, events, in, diabetic, patients])].
[sujeto(['Metabolic', engineering, and, heterologous, expression, methods, can, be, applied, to, improve, desired, metabolite, 'production,', when, their, biosynthesis, pathways]), verbo([have]), complemento([been, revealed])].
[sujeto(['The', biosynthesis, pathways, of, nine, 'PKS', genes]), verbo([have]), complemento([been, 'reported,', and, their, downstream, metabolites, are, 'lovastatin,', terreic, 'acid,', 'terrein,', 'geodin,', 'terretonin,', 'citreoviridin,', and, 'asperfuranone,', respectively])].
[sujeto(['Physician']), verbo([reported]), complemento([symptomatic, late, rectal, injury, occurs, in, about, 5, '%', to, 25, '%', of, patients, treated, with, radiation, therapy, for, prostate, 'cancer,', depending, on, the, treatment, technique])].
[sujeto(['Patients,', 'however,']), verbo([report]), complemento([clinically, meaningful, declines, in, 'bowel/rectal', function, regardless, of, the, technique, used])].
[sujeto(['Lovastatin']), verbo([has]), complemento([been, shown, to, protect, mice, from, late, radiation, injury])].
[sujeto(['The', percentage, of, 'NSSPP', beneficiaries, dispensed, any, statin]), verbo([increased]), complemento([from, 5.3, '%', in, 'April', 1999, to, 20.7, '%', in, 'March', 2013])].
[sujeto(['Atorvastatin', was, not, significantly, affected, by, any, of, the, three, 'interventions,', although, it]), verbo([maintained]), complemento([an, overall, decreasing, trend])].
[sujeto(['Only', upon, the, availability, of, generic, atorvastatin, did, the, upward, trend, in, rosuvastatin, use]), verbo([decrease]), complemento([significantly, '(', slope, 'change,', -, 0.001, ',', 95, '%', 'CI,', '(', -, 0.0015, ',', -, 0.0005, ')', ')'])].
[sujeto(['The', overall, proportion, of, 'NSSPP', beneficiaries, dispensed, a, statin]), verbo([increased]), complemento([approximately, 4, -, fold, during, the, study, period])].
[sujeto(['The', role, of, 'Wharton\'s', 'jelly-derived', human, mesenchymal, stem, cells, '(', 'WJ-MSCs)', in]), verbo([inhibiting]), complemento([muscle, cell, death, has, been, elucidated, in, this, study])].
[sujeto(['Apoptosis']), verbo([induced]), complemento([by, serum, deprivation, in, mouse, skeletal, myoblast, cell, lines, '(', 'C2C12)', was, significantly, reduced, when, the, cell, lines, were, cocultured, with, 'WJ-MSCs'])].
[sujeto(['Apoptosis', of, 'C2C12', cells, and]), verbo([loss]), complemento([of, differentiated, 'C2C12', myotubes, induced, by, 'lovastatin,', another, muscle, cell, death, 'inducer,', was, also, inhibited, by, 'XCL1', treatment])].
[sujeto(['However,', 'XCL1', treatment, did, not]), verbo([inhibit]), complemento([apoptosis, of, cell, lines, other, than, 'C2C12'])].
[sujeto(['When', 'XCL1-siRNA', pretreated, 'WJ-MSCs', were, cocultured, with, 'serum-starved', 'C2C12', 'cells,', apoptosis, was, not, 'inhibited,', thus, confirming, that, 'XCL1', is, a, key, factor, in]), verbo([preventing]), complemento(['C2C12', cell, apoptosis])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, human, 'WJ-MSCs', and, 'XCL1', protein, may, act, as, promising, and, novel, therapeutic, agents, for, treatment, of, myopathies, and, other, skeletal, muscle, diseases])].
[sujeto(['Dengue', virus, '(', 'DENV)', susceptibility, to, cholesterol, depleting, treatments]), verbo([has]), complemento([been, previously, reported])].
[sujeto(['The', aim, of, the, present, study, was, to, evaluate, the, mechanisms]), verbo([involved]), complemento([in, the, negative, regulation, of, 'DENV', replication, induced, by, agents, that, diminish, intracellular, cholesterol, levels])].
[sujeto(['Comparison', between, the, cellular, antiviral, response]), verbo([triggered]), complemento([by, 'DENV2', 'infection,', statin, treatment, and, 'HMGCR‑siRNA', in, 'infected,', 'uninfected,', treated, and, untreated, 'Huh7', 'cells,', showed, different, expression, profiles, for, the, antiviral, genes, evaluated])].
[sujeto(['All', downregulating, cholesterol, agents, evaluated, reduced, the, expression, of, genes]), verbo([associated]), complemento([with, cellular, immune, and, 'pro‑inflammatory', responses])].
[sujeto(['These', results, indicate, that, 'statin-mediated', downregulation, of, 'DENV2', infectious, particles, number, is, independent, of, cholesterol, levels, and, it, is, partially]), verbo([mediated]), complemento([by, the, modulation, of, the, cellular, antiviral, profile])].
[sujeto(['T-cell-dependent', airway, and, systemic, inflammation]), verbo([triggers]), complemento([the, progression, of, chronic, obstructive, pulmonary, disease, '(', 'COPD)', and, asthma])].
[sujeto(['Retrospective', studies]), verbo([suggest]), complemento([that, simvastatin, has, 'anti-inflammatory', effects, in, both, diseases, but, it, is, 'unclear,', which, cell, types, are, targeted])].
[sujeto(['We', hypothesized, that, simvastatin]), verbo([modulates]), complemento(['T-cell', activity])].
[sujeto(['Circulating', 'CD4+', and, 'CD8+', 'T-cells,', either, 'pure,', 'co-cultured', with, monocytes, or, alveolar, macrophages, '(', 'AM)', or, in, peripheral, blood, mononuclear, cells, '(', 'PBMCs),', were, ex, vivo]), verbo([activated]), complemento([towards, 'Th1/Tc1', or, 'Th2/Tc2', and, incubated, with, simvastatin])].
[sujeto(['T-cell', activation]), verbo([induced]), complemento(['IFNγ,', 'IL-5', and, 'IL-13', in, the, presence, and, absence, of, accessory, cells])].
[sujeto(['Simvastatin', did, not]), verbo([modulate]), complemento([cytokine, expression, in, pure, 'T-cell', fractions])].
[sujeto(['β-hydroxy-simvastatin', acid, '(']), verbo([activated]), complemento(['simvastatin)', suppressed, 'IL-5', and, 'IL-13', in, pure, 'Th2-', and, 'Tc2-cells'])].
[sujeto(['Simvastatin']), verbo([suppressed]), complemento(['IL-5', and, 'IL-13', in, 'Th2-cells', 'co-cultivated', with, monocytes, or, 'AM,', which, was, partially, reversed, by, the, carboxylesterase, inhibitor, benzil])].
[sujeto(['Simvastatin']), verbo([suppressed]), complemento(['IL-5', production, of, 'Th2/Tc2-cells', in, 'PBMCs', without, differences, between, cohorts, and, 'IL-13', stronger, in, 'never-smokers', and, asthma, compared, to, 'COPD'])].
[sujeto(['Simvastatin']), verbo([induced]), complemento(['IFNγ', in, 'Th1/Tc1-cells', in, 'PBMCs', of, all, cohorts, except, asthmatics])].
[sujeto(['Simvastatin']), verbo([requires]), complemento([activation, in, accessory, cells, likely, by, carboxylesterase, to, suppress, 'IL-5', and, 'IL-13', in, 'Th2/Tc2-cells'])].
[sujeto(['Asthma', pathogenesis]), verbo([prevents]), complemento(['simvastatin-induced', 'IFNγ', 'up-regulation'])].
[sujeto(['Simvastatin']), verbo([has]), complemento(['anti-inflammatory', effects, that, could, be, of, interest, for, asthma, therapy])].
[sujeto(['However,', the, plasma, concentrations, of, 'SV', and, 'SVA', did, not, directly, correlate, with, the, observed, gastrointestinal, 'concentrations,']), verbo([suggesting]), complemento([that, gut, wall, and, hepatic, metabolism, have, a, greater, impact, on, systemic, exposure, of, 'SV', than, the, intraluminal, interconversion, between, 'SV', and, 'SVA'])].
[sujeto(['Sacubitril/valsartan', '(', 'LCZ696)']), verbo([has]), complemento([been, recently, approved, for, the, treatment, of, heart, failure, '(', 'HF)', patients, with, reduced, ejection, fraction])].
[sujeto(['Although', no, significant, inhibition, by, 'LBQ657', '(', an, active, metabolite, of, 'sacubitril)', and, valsartan, was, 'observed,', sacubitril]), verbo([inhibited]), complemento(['OATP1B1', and, 'OATP1B3', in, 'vitro,', with, 'IC50', of, 1, '·91', and, 3, '·81', 'μm,', respectively])].
[sujeto(['Upon', 'co-administration', of, simvastatin, with, 'LCZ696,', the, 'Cmax', of, simvastatin, and, simvastatin, acid]), verbo([decreased]), complemento([by, 7, '%', and, 13, '%', ',', respectively])].
[sujeto(['When', administered, 1, h, after, 'LCZ696', 'dosing,', the, corresponding, 'Cmax', of, simvastatin, and, simvastatin, acid]), verbo([decreased]), complemento([by, 16, '%', and, 4, '%', ',', respectively])].
[sujeto(['When', administered, 2, h, after, 'LCZ696', 'dosing,', the, 'Cmax', of, simvastatin]), verbo([decreased]), complemento([by, 33, '%', and, that, of, simvastatin, acid, increased, by, 16, '%'])].
[sujeto(['Overall,', the, results, of, this, study]), verbo([suggest]), complemento([that, although, sacubitril, inhibited, 'OATP1B1', and, 'OATP1B3', in, 'vitro,', it, does, not, translate, into, any, clinically, relevant, in, vivo, effect])].
[sujeto(['The', method]), verbo([has]), complemento([shown, tremendous, 'reproducibility,', with, 'intra-', and, 'inter-day', precision, &, 'lt;7'])].
[sujeto(['The', results, showed, that, areas, under, 'concentration-time', '(', 'AUC)', curves, of, simvastatin, and, simvastatin, acid]), verbo([increased]), complemento([by, 2.21, -, and, 1.4, -, fold, while, the, clearance, was, reduced, by, 2.29, -, and, 1.4, -, 'fold,', 'respectively,', when, 'co-administered', with, 'EGCG'])].
[sujeto(['In', vitro, experiments]), verbo([suggested]), complemento([the, inhibitory, effect, of, 'EGCG', on, 'CYP', enzymes, '(', 'IC50:', 18.37, ±, 1.36, 'μM,', 26.08, ±, 1.51, μM, for, simvastatin, and, simvastatin, 'acid,', 'respectively)'])].
[sujeto(['Simvastatin', transport, by, 'OATP1B1', and, 'OATP1B3', was, also]), verbo([inhibited]), complemento([by, 'EGCG', '(', 'IC50:', 8.68, ±, 1.27, μM, and, 22.67, ±, 1.42, 'μM,', 'respectively)'])].
[sujeto(['The', presently]), verbo([reported]), complemento([novel, 'food-drug', interaction, between, 'EGCG', and, simvastatin, involves, the, inhibition, of, not, only, 'CYP450', enzymes, but, also, 'OATPs', by, 'EGCG'])].
[sujeto(['A', 'simple,', 'selective,', sensitive, and, 'high-throughput', liquid, 'chromatography-tandem', mass, spectrometry, '(', 'LC-MS-MS)', method]), verbo([has]), complemento([been, developed, and, validated, for, the, simultaneous, quantification, of, simvastatin, '(', 'SS),', simvastatin, acid, '(', 'SSA,', active, metabolite, of, 'SS)', and, ezetimibe, '(', 'EZM)', in, 'K2', 'EDTA', containing, human, 'plasma,', using, simvastatin, 'D6,', simvastatin, acid, 'D3', and, ezetimibe, 'D4', as, internal, standards, '(', 'ISTDs),', respectively])].
[sujeto(['The', method]), verbo([has]), complemento([been, successfully, applied, in, clinical, pharmacokinetic, study, in, the, 'Indian', population])].
[sujeto(['Finding', pleiomorphic]), verbo([targets]), complemento([for, drugs, allows, new, indications, or, warnings, for, treatment, to, be, identified])].
[sujeto(['As', test, of, 'concept,', we, applied, a, new, chemical, genomics, approach, to, uncover, additional]), verbo([targets]), complemento([for, the, widely, prescribed, 'lipid-lowering', 'pro-drug', simvastatin])].
[sujeto(['We', then, studied, interactions, of, clones, of, the, 'bacteriophage,', each]), verbo([expressing]), complemento([a, different, cardiovascular, 'polypeptide,', with, 'surface-bound', simvastatin, in, 96, -, well, plates])].
[sujeto(['To', maximise, likelihood, of, identifying, meaningful, interactions, between, simvastatin, and, vascular, 'peptides,', we, used, a, validated, 'photo-immobilisation', method, to, apply, a, series, of, different, chemical, linkers, to]), verbo([bind]), complemento([simvastatin, so, as, to, present, multiple, orientations, of, its, constituent, components, to, potential, targets])].
[sujeto(['Three', rounds, of, biopanning, identified, consistent, interaction, with, the, clone]), verbo([expressing]), complemento([part, of, the, gene, 'GJC3,', which, maps, to, 'Homo', sapiens, chromosome, 7, ',', and, codes, for, gap, junction, 'gamma-3', 'protein,', also, known, as, connexin, 30.2, /, 31.3, '(', mouse, connexin, 'Cx29)'])].
[sujeto(['Further', analysis, indicated, the]), verbo([binding]), complemento([site, to, be, for, the, 'N-terminal', domain, putatively, '\'', 'regulating\'', connexin, hemichannel, and, gap, junction, pores])].
[sujeto(['Using', immunohistochemistry, we]), verbo([found]), complemento([connexin, 30.2, /, 31.3, to, be, present, in, samples, of, artery, similar, to, those, used, to, prepare, the, bacteriophage, library])].
[sujeto(['Surface', plasmon, resonance, revealed, that, a, 25, amino, acid, synthetic, peptide, representing, the, discovered, 'N-terminus', did, not]), verbo([interact]), complemento([with, simvastatin, 'lactone,', but, did, bind, to, the, hydrolysed, 'HMG', 'CoA', 'inhibitor,', simvastatin, acid])].
[sujeto(['The', gap, junction, blockers, carbenoxolone, and, flufenamic, acid, also]), verbo([interacted]), complemento([with, the, same, peptide, providing, insight, into, potential, site, of, binding])].
[sujeto(['Among', 3, -, 'hydroxy-3-methylglutaryl', coenzyme, 'A', inhibitors, that, had, activity, in, 'vitro,', we, prioritized, simvastatin, '(', 'SV)', as, the]), verbo([lead]), complemento([compound, for, preclinical, pharmacokinetic, studies, based, on, its, potential, for, central, nervous, system, penetration, as, determined, from, in, silico, models])].
[sujeto(['Compared', with, in, vitro, washout, 'IC50', 'values,', we, did, not, achieve, sufficient, exposure, of, 'SVA', in, tECF, to]), verbo([suggest]), complemento([tumor, growth, 'inhibition;', 'therefore,', 'SV', was, not, carried, forward, in, subsequent, preclinical, efficacy, studies])].
[sujeto(['These', three, drugs, were, selected, because, differences, in, 'PK', parameters]), verbo([have]), complemento([been, 'reported,', even, though, the, backgrounds, of, these, 'East', 'Asian', populations, are, similar])].
[sujeto(['Fostamatinib', is, a, spleen, tyrosine, kinase, inhibitor, that]), verbo([has]), complemento([been, investigated, as, therapy, for, rheumatoid, arthritis, and, immune, thrombocytopenic, purpura])].
[sujeto(['Fostamatinib', 'co-administration', with, 'OC']), verbo([increased]), complemento([exposure, to, ethinyl, estradiol, '[', area, under, the, plasma, 'concentration-time', curve, at, steady, state, '(', 'AUCss)', 28, '%', '[', confidence, interval, '(', 'CI', 90, '%', ')', 21, -, 36, ']', ;, maximum, plasma, concentration, '(', 'Cmax)', at, steady, state, '(', 'Cmax,ss)', 34, '%', '(', 'CI', 26, -, 43, ')', ']', ',', but, not, levonorgestrel, '(', 'AUCss', 5, '%', ;, 'Cmax,ss', -, 3, '%', ')', ',', while, exposure, to, luteinizing, hormone, and, 'follicle-stimulating', hormone, decreased, '(', '≈', 20, '%', ')'])].
[sujeto(['Fostamatinib', did, not, affect, the, 'pharmacokinetics/pharmacodynamics', of, warfarin, to, a, clinically, relevant, 'extent,', but]), verbo([caused]), complemento([an, upward, trend, in, 'AUC', for, both, 'R-', and, 'S-warfarin', '[', 18, '%', '(', 'CI', 13, -, 23, ')', and, 13, '%', '(', 'CI', 7, -, 19, ')', ']'])].
[sujeto(['Fostamatinib']), verbo([increased]), complemento([rosuvastatin, 'AUC', by, 96, '%', '(', 'CI', 78, -, 115, ')', and, 'Cmax', by, 88, '%', '(', 'CI', 69, -, 110, ')', ',', and, increased, simvastatin, acid, 'AUC', by, 74, '%', '(', 'CI', 50, -, 102, ')', and, 'Cmax', by, 83, '%', '(', 'CI', 57, -, 113, ')'])].
[sujeto(['To', evaluate, the, potential, pharmacokinetic, '(', 'PK)', and, pharmacodynamic, '(', 'PD,', 'glucose-lowering', 'effect)', interaction, between, simvastatin, and, 'piragliatin,', both, 'CYP3A', 'substrates,', 30, patients, with, type, 2, diabetes, mellitus]), verbo([participated]), complemento([in, this, 'open-label,', 'randomized,', 6, -, 'sequence,', 3, -, way, crossover, '(', 'William\'s', 'design)', study])].
[sujeto(['The', ratio, of, geometric, means, '(', 90, '%', confidence, 'intervals)', of, the, 'AUCinf', of, piragliatin, coadministered, with, simvastatin, compared, with, piragliatin, alone, was, 0.98, '(', 0.92, -, 1.05, ')', ',', whereas, that, of, the, 'AUCinf', of, simvastatin, acid, '(', active, 'metabolite)', coadministered, with, piragliatin, compared, with, simvastatin, 'alone,', was, 1.02, '(', 0.9, -, 1.16, ')', ',']), verbo([suggesting]), complemento([lack, of, pharmacokinetic, interaction, between, piragliatin, and, simvastatin])].
[sujeto(['Concomitant', administration, of, simvastatin, and, 'piragliatin,', both, 'CYP3A', 'substrates,']), verbo([has]), complemento([no, clinically, relevant, effect, on, the, pharmacokinetics, of, either, piragliatin, or, simvastatin, or, on, the, pharmacodynamics, for, piragliatin])].
[sujeto(['CYP2D6*5', and, 'CYP2D6*14', were]), verbo([found]), complemento([to, be, associated, with, a, higher, area, under, the, curve, '(', 'AUC)', for, 'simvastatin,', whereas, the, 'AUC', of, simvastatin, acid, was, significantly, increased, in, patients, with, the, 'SLCO1B1', 'rs4149056,', 'ABCG2', 'rs2231142,', and, 'CYP2D6*41', allele, variants])].
[sujeto(['The', 'SLCO1B1', rs4149056, and, rs4149015, polymorphisms, were]), verbo([associated]), complemento([with, an, increased, 'AUC', ratio, '(', i])].
[sujeto(['The', 'CYP2D6*5,', 'CYP2D6*14,', 'CYP2D6*41,', 'CYP3A5*3,', 'SLCO1B1', rs4149056, and, 'rs4149015,', and, 'ABCG2', rs2231142, genetic, polymorphisms, are]), verbo([associated]), complemento([with, the, 'PK', of, both, simvastatin, and, simvastatin, acid])].
[sujeto(['Clopidogrel', and, its, metabolites]), verbo([inhibit]), complemento(['OATP1B1', and, 'CYP3A4', in, vitro])].
[sujeto(['Clopidogrel', 300, mg, '(', day, 1, ')']), verbo([increased]), complemento([the, concentrations, of, simvastatin, and, simvastatin, acid, during, the, absorption, phase])].
[sujeto(['In', 'conclusion,', as, clopidogrel, did, not]), verbo([have]), complemento([significant, effects, on, the, total, exposure, to, simvastatin, or, simvastatin, 'acid,', clopidogrel, does, not, seem, to, inhibit, 'OATP1B1', or, 'CYP3A4', to, a, clinically, relevant, extent])].
[sujeto(['CYP3A5*3', was, not, significantly]), verbo([associated]), complemento([with, 12, -, hour, plasma, 'SV', or, 'SVA', concentration])].
[sujeto(['In', 'conclusion,', 'CYP3A4*22', and, 'SLCO1B1', 521, 'C', were, significantly]), verbo([associated]), complemento([with, increased, 12, -, hour, plasma, 'SV', and, 'SVA', 'concentrations,', respectively])].
[sujeto(['CYP3A5*3', was, not, significantly]), verbo([associated]), complemento([with, 12, -, hour, plasma, 'SV', or, 'SVA', concentrations])].
[sujeto(['The', combination, of, 'CYP3A4*22', and, 'SLCO1B1', 521, 'C', was, significantly]), verbo([associated]), complemento([with, 'SVA/SV', 'ratio,', which, may, translate, into, different, clinical, 'SV', 'risk/benefit', profiles])].
[sujeto(['Organic', anion, transporting, polypeptide, 1, 'B1', '(', 'OATP1B1,', encoded, by, 'SLCO1B1', 'gene)', is, a, hepatic, uptake, 'transporter,', and, its, genetic, variability, is]), verbo([associated]), complemento([with, pharmacokinetics, and, muscle, toxicity, risk, of, simvastatin])].
[sujeto(['SLCO1B1*5/*15', and, *, 15, /, *, 15, genotypes, markedly]), verbo([increase]), complemento([the, exposure, to, active, lovastatin, 'acid,', but, have, no, significant, effect, on, lovastatin, 'lactone,', similar, to, their, effects, on, simvastatin, and, simvastatin, acid])].
[sujeto(['Accordingly,', it, is, probable, that, the, risk, of, muscle, toxicity, during, lovastatin, treatment, is]), verbo([increased]), complemento([in, individuals, carrying, the, 'SLCO1B1*5', or, *, 15, allele])].
[sujeto(['The', 'SLCO1B1*1B/*1B', genotype, is]), verbo([associated]), complemento([with, reduced, lovastatin, acid, 'concentrations,', consistent, with, enhanced, hepatic, uptake])].
[sujeto(['Hepatic', statin, clearances, were, 'well-predicted', by, the, 'ECCCS', with, six, out, of, eight, clearances, projected, within, a, 'two-fold', deviation, to]), verbo([reported]), complemento([values])].
[sujeto(['Canagliflozin', did, not, affect, the, peak, concentration, of, 'metformin;', 'however,', 'AUC']), verbo([increased]), complemento([by, 20, '%'])].
[sujeto(['Though', 'Cmax', and, 'AUC', were, slightly]), verbo([increased]), complemento([for, simvastatin, '(', 9, '%', and, 12, '%', ')', and, simvastatin, acid, '(', 26, '%', and, 18, '%', ')', following, coadministration, with, 'canagliflozin,', compared, with, simvastatin, administration, 'alone;', 'however,', no, effect, on, active, 3, -, 'hydroxy-3-methyl-glutaryl-CoA', '(', 'HMG-CoA)', reductase, inhibitory, activity, was, observed])].
[sujeto(['Previous', in, vitro, and, in, vivo, investigations]), verbo([reported]), complemento([controversial, results, for, the, inhibitory, potential, of, pomegranate, on, 'Cytochrome', 'P450', '(', 'CYP)', 3, 'A', activity])].
[sujeto(['In', the, period, of, grapefruit, 'juice,', the, mean, 'C', max, and, 'AUCinf', of, simvastatin, '[', the, geometric, mean, ratio, '(', 90, &, 'nbsp;%', 'CI)', 15.6, '(', 11.6, -, 21.0, ')', and, 9.1, '(', 6.0, -, 13.7, ')', ']', were]), verbo([increased]), complemento([significantly, when, compared, with, the, control, 'period,', whereas, they, were, not, significantly, different, in, the, period, of, pomegranate, juice, '[', 'C', max, and, 'AUCinf', 1.2, '(', 0.89, -, 1.62, ')', and, 1.29, '(', 0.85, -, 1.94, ')', ']'])].
[sujeto(['The', mean, 'C', max, and, 'AUCinf', of, simvastatin, acid, were]), verbo([increased]), complemento([significantly, after, intake, of, grapefruit, 'juice,', but, not, pomegranate, juice])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, pomegranate, juice, affects, little, on, the, disposition, of, simvastatin, in, humans])].
[sujeto(['Pomegranate', juice, does, not, seem, to]), verbo([have]), complemento([a, clinically, relevant, inhibitory, potential, on, 'CYP3A4', activity])].
[sujeto(['This', 'Account', describes, the, use, of, molecular, dynamics, '(', 'MD)', simulations, to]), verbo([reveal]), complemento([how, mutations, alter, the, structure, and, organization, of, enzyme, active, sites])].
[sujeto(['We']), verbo([find]), complemento([that, the, dynamics, of, the, active, site, is, influenced, not, only, by, the, original, sequence, design, and, subsequent, mutations, but, also, by, the, nature, of, the, ligand, present, in, the, active, site])].
[sujeto(['In', the, second, 'example,', we, show, how, microsecond, 'MD']), verbo([has]), complemento([been, used, to, uncover, the, role, of, remote, mutations, in, the, active, site, dynamics, and, catalysis, of, a, 'transesterase,', 'LovD'])].
[sujeto(['X-ray', analysis, of, inactive, and, active, mutants, did, not]), verbo([reveal]), complemento([differences, in, the, active, 'sites,', but, relatively, long, time, scale, 'MD', in, solution, showed, that, the, active, site, of, the, 'wild-type', enzyme, preorganizes, only, upon, binding, of, the, acyl, carrier, protein, '(', 'ACP)', that, delivers, the, natural, acyl, group, to, the, active, site])].
[sujeto(['In', the, absence, of]), verbo([bound]), complemento(['ACP,', a, noncatalytic, arrangement, of, the, catalytic, triad, is, dominant])].
[sujeto(['Unnatural', truncated, substrates, are, inactive, because, of, the, lack, of, 'protein-protein', interactions]), verbo([provided]), complemento([by, the, 'ACP'])].
[sujeto(['Each', of, these, examples]), verbo([reveals]), complemento([something, different, about, how, mutations, can, influence, enzyme, activity, and, shows, that, directed, 'evolution,', like, natural, 'evolution,', can, increase, catalytic, activity, in, a, variety, of, remarkable, and, often, subtle, ways])].
[sujeto(['Elevated', saturated, 'FFAs', including, palmitate, '(', 'C16:0)', are, a, primary]), verbo([trigger]), complemento([for, peripheral, insulin, resistance, characterized, by, impaired, glucose, 'uptake/disposal', in, skeletal, 'muscle,', resulting, from, impaired, 'GLUT4', translocation, in, response, to, insulin])].
[sujeto(['We', herein, demonstrate, that, palmitate]), verbo([induces]), complemento(['down-regulation', of, 'sortilin,', a, sorting, receptor, implicated, in, the, formation, of, 'insulin-responsive', 'GLUT4', 'vesicles,', via, mechanisms, involving, 'PKC', and, 'TNF-α-converting', 'enzyme,', but, not, 'p38,', 'JNK,', or, mitochondrial, reactive, oxygen, species, 'generation,', leading, to, impaired, 'GLUT4', trafficking, in, 'C2C12', myotubes])].
[sujeto(['Intriguingly,', unsaturated, 'FFAs', such, as, palmitoleate, '(', 'C16:1)', and, oleate, '(', 'C18:1)', had, no, such, detrimental, 'effects,', appearing, instead, to, effectively, reverse, 'palmitate-induced', impairment, of, 'insulin-responsive', 'GLUT4', recycling, along, with, restoration, of, sortilin, abundance, by]), verbo([preventing]), complemento([aberrant, 'PKC', activation])].
[sujeto(['On', the, other, 'hand,', 'shRNA-mediated', reduction, of, sortilin, in, intact, 'C2C12', myotubes]), verbo([inhibited]), complemento(['insulin-induced', 'GLUT4', recycling, without, dampening, 'Akt', phosphorylation])].
[sujeto(['We']), verbo([found]), complemento([that, the, peroxisome, 'proliferator-activated', receptor, γ, agonist, troglitazone, prevented, the, 'palmitate-induced', sortilin, reduction, and, also, ameliorated, 'insulin-responsive', 'GLUT4', recycling, without, altering, the, 'palmitate-evoked', insults, on, signaling, 'cascades;', neither, highly, phosphorylated, 'PKC', states, nor, impaired, 'insulin-responsive', 'Akt', phosphorylation, was, affected])].
[sujeto(['Taken', 'together,', our, data]), verbo([provide]), complemento([novel, insights, into, the, pathogenesis, of, 'PKC-dependent', insulin, resistance, with, respect, to, 'insulin-responsive', 'GLUT4', 'translocation,', which, could, occur, not, only, through, defects, of, insulin, signaling, but, also, via, a, reduction, of, 'sortilin,', which, directly, controls, 'trafficking/sorting', of, 'GLUT4', in, skeletal, muscle, cells])].
[sujeto(['In', 'addition,', our, data]), verbo([suggest]), complemento([the, 'insulin-sensitizing', action, of, peroxisome, 'proliferator-activated', receptor, γ, agonists, to, be, at, least, partially, mediated, through, the, restoration, of, proper, 'GLUT4', 'trafficking/sorting', events, governed, by, sortilin])].
[sujeto(['We', tested, the, hypothesis, that, 'TZDs']), verbo([prevent]), complemento(['FA-induced', insulin, resistance, by, attenuating, proinflammatory, signaling, independently, of, myocellular, lipid, levels])].
[sujeto(['TZD', treatment]), verbo([led]), complemento([to, a, significant, increase, in, plasma, membrane, content, of, 'CD36', protein, in, muscle, '(', 'red:', 'P', =, 0.01, ',', and, 'white:', 'P', =, 0.001, ')', that, correlated, with, increased, 'FA', uptake, '(', 45, '%', ',', 'P', =, 0.002, ')', and, triacylglycerol, '(', 'TG)', synthesis, '(', 46, '%', ',', 'P', =, 0.03, ')', during, the, perfusion])].
[sujeto(['Importantly,', whereas, 'HF', feeding]), verbo([caused]), complemento([increased, basal, 'TG', '(', 'P', =, 0.047, ')', ',', diacylglycerol, '(', 'P', =, 0.002, ')', ',', and, ceramide, '(', 'P', =, 0.01, ')', 'levels,', 'TZD', treatment, only, prevented, the, increase, in, muscle, ceramide])].
[sujeto(['Consistent', with, 'this,', 'HFD-induced', decrements, in, insulin, action, were, also]), verbo([prevented]), complemento([by, 'TZD', treatment])].
[sujeto(['Thus', our, findings, support, the, notion, that, 'TZD', treatment]), verbo([causes]), complemento([increased, 'FA', uptake, and, 'TG', accumulation, in, skeletal, muscle, under, 'insulin-stimulated', conditions])].
[sujeto(['Despite', 'this,', 'TZDs']), verbo([suppress]), complemento([the, inflammatory, response, to, dietary, lipid, 'overload,', and, it, is, this, mechanism, that, correlates, strongly, with, insulin, sensitivity])].
[sujeto(['The']), verbo([binding]), complemento([characteristics, of, a, series, of, 'PPARgamma', ligands, '(', 'GW9662,', 'GI', 262570, ',', 'cis-parinaric', 'acid,', 15, -, 'deoxy-Delta(12,14)-prostaglandin', 'J(2),', 'LY171883,', 'indomethacin,', linoleic, 'acid,', palmitic, acid, and, 'troglitazone)', to, human, 'PPARgamma', ligand, binding, domain, have, been, investigated, for, the, first, time, by, using, surface, plasmon, resonance, biosensor, 'technology,', 'CD', spectroscopy, and, molecular, docking, simulation])].
[sujeto(['The', surface, plasmon, resonance, biosensor, determined, equilibrium, dissociation, constants, '(', 'KD', 'values)', are, in, agreement, with, the, results]), verbo([reported]), complemento([in, the, literature, measured, by, other, 'methods,', indicating, that, the, surface, plasmon, resonance, biosensor, can, assume, a, direct, assay, method, in, screening, new, 'PPARgamma', agonists, or, antagonists])].
[sujeto(['Conformational', changes, of, 'PPARgamma']), verbo([caused]), complemento([by, the, ligand, binding, were, detected, by, 'CD', determination])].
[sujeto(['It', is, interesting, that, the, thermal, stability, of, the, 'receptor,', reflected, by, the]), verbo([increase]), complemento([of, the, transition, temperature, '(', 'T(m)),', was, enhanced, by, the, binding, of, the, ligands])].
[sujeto(['The', increment, of, the, transition, temperature, '(', 'DeltaT(m))', of, 'PPARgamma', owing, to, ligand]), verbo([binding]), complemento([correlated, well, with, the, binding, affinity])].
[sujeto(['This']), verbo([finding]), complemento([implies, that, 'CD', could, possibly, be, a, complementary, technology, with, which, to, determine, the, binding, affinities, of, ligands, to, 'PPARgamma'])].
[sujeto(['Molecular', docking, simulation]), verbo([provided]), complemento([reasonable, and, reliable, binding, models, of, the, ligands, to, 'PPARgamma', at, the, atomic, 'level,', which, gave, a, good, explanation, of, the, 'structure-binding', affinity, relationship, for, the, ligands, interacting, with, 'PPARgamma'])].
[sujeto(['Moreover,', the, predicted]), verbo([binding]), complemento([free, energies, for, the, ligands, correlated, well, with, the, binding, constants, measured, by, the, surface, plasmon, resonance, 'biosensor,', indicating, that, the, docking, paradigm, used, in, this, study, could, possibly, be, employed, in, virtual, screening, to, discover, new, 'PPARgamma', 'ligands,', although, the, docking, program, cannot, accurately, predict, the, absolute, 'ligand-PPARgamma', binding, affinity])].
[sujeto(['Palmitate', uptake, included, a, 'protein-mediated', component, that, was]), verbo([inhibited]), complemento([by, phloretin])].
[sujeto(['Acute', insulin, exposure]), verbo([caused]), complemento([a, modest, '(', 16, +, /, -, 5, '%', ',', 'P', &, 'lt;', 0.025, ')', but, significant, increase, in, 'protein-mediated', uptake, in, nondiabetic, muscle])].
[sujeto(['Chronic', '(', 4, 'day)', treatment, with, a, series, of, 'thiazolidinediones,', troglitazone, '(', 'Tgz),', rosiglitazone, '(', 'Rgz),', and, pioglitazone, '(', 'Pio)']), verbo([increased]), complemento(['FFA', uptake])].
[sujeto(['Only', the, 'phloretin-inhibitable', component, was]), verbo([increased]), complemento([by, 'treatment,', which, normalized, this, activity, in, diabetic, muscle, cells])].
[sujeto(['Under', the, same, 'conditions,', 'FFA', oxidation, was, also]), verbo([increased]), complemento([by, thiazolidinedione, treatment])].
[sujeto(['Increases', in, 'FFA', uptake, and, oxidation, were]), verbo([associated]), complemento([with, upregulation, of, fatty, acid, translocase, '(', 'FAT/CD36)', expression])].
[sujeto(['FAT/CD36', protein, was]), verbo([increased]), complemento([by, 'Tgz', '(', 90, +, /, -, 22, '%', over, 'control),', 'Rgz', '(', 146, +, /, -, 42, '%', ')', ',', and, 'Pio', '(', 111, +, /, -, 37, '%', ',', 'P', &, 'lt;', 0.05, for, all, 3, ')', treatment])].
[sujeto(['We', conclude, that, 'FFA', uptake, into, cultured, muscle, cells, 'is,', in, 'part,', protein]), verbo([mediated]), complemento([and, acutely, insulin, responsive])].
[sujeto(['In', 'addition,', chronic, thiazolidinedione, treatment]), verbo([increased]), complemento(['FFA', uptake, and, oxidation, into, cultured, human, skeletal, muscle, cells, in, concert, with, upregulation, of, 'FAT/CD36', expression])].
[sujeto(['The', putative, role, played, by, insulin, sensitizers, in]), verbo([modulating]), complemento([adipose, tissue, lipolysis, in, the, fasting, state, was, evaluated, in, obese, conscious, 'Zucker', rats, treated, with, troglitazone, or, 'beta,beta\'-tetramethylhexadecanedioic', acid, '(', 'MEDICA', 16, ')', and, compared, with, nontreated, lean, and, obese, animals])].
[sujeto(['The', overall, lipolytic, flux, '(', 'R(a)', 'glycerol)', was]), verbo([increased]), complemento([1.7, -, and, 1.4, -, fold, in, obese, animals, treated, with, troglitazone, or, 'MEDICA', 16, ',', 'respectively,', resulting, in, increased, 'FFA', export, '(', 'R(a)', 'FFA)', in, the, 'troglitazone-treated', rats])].
[sujeto(['Primary', 'intra-adipose', reesterification, of, 'lipolysis-derived', fatty, acids, was]), verbo([enhanced]), complemento([twofold, by, insulin, 'sensitizers,', whereas, reesterification, of, plasma, fatty, acids, was, unaffected, by, either, treatment])].
[sujeto(['Despite', the, unchanged, 'R(a)', 'FFA', in, 'MEDICA', 16, or, the]), verbo([increased]), complemento(['R(a)', 'FFA', induced, by, 'troglitazone,', very, low, density, lipoprotein, production, rates, were, robustly, curtailed])].
[sujeto(['Total', adipose, tissue, 'reesterification,', used, as, an, estimate, of, glucose, conversion, to, 'glyceride-glycerol,', was]), verbo([increased]), complemento([1.9, -, fold, by, treatment, with, the, insulin, sensitizers])].
[sujeto(['To', elucidate, the, mechanisms, by, which, 'troglitazone,', which, is, a, direct, ligand, for, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)', 'gamma,', ameliorates, insulin, 'resistance,', we]), verbo([have]), complemento([demonstrated, that, 'PPAR', gamma, is, expressed, in, a, pancreatic, beta, cell, 'line,', 'INS-1,', using, reverse, 'transcription-polymerase', chain, reaction, '(', 'RT-PCR)'])].
[sujeto(['Our', results, 'showed:', '(', 1, ')', treatment, with, troglitazone, for, 48, h]), verbo([caused]), complemento([enhancement, of, 'GSIS,', although, troglitazone, significantly, suppressed, cell, viability, assessed, by, 'MTT', assay])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, insulin, secretion, from, the, rat, insulinoma, cell, 'line,', 'INS-1,', is, modulated, by, 'troglitazone,', acting, somewhere, in, the, 'ATP-sensitive', 'K(+)', channel, 'pathway,', possibly, through, 'PPAR', gamma])].
[sujeto(['The', combination, of, both, agents]), verbo([increased]), complemento([glucose, uptake, '(', 60, +, /, -, 9, '%', compared, to, control, 'subjects)', but, not, either, agent, alone, '(', 16, +, /, -, 9, and, 26, +, /, -, 6, '%', for, 'LG100268', and, 'troglitazone,', p, &, 'lt;', 0.01, ',', 'respectively)'])].
[sujeto(['The', agent, 'LG100268', alone, had, little, effect, on, the, activity, of, glycogen, synthase, but, the, effect, of, troglitazone]), verbo([increased]), complemento([with, 'LG100268', '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['Treatment', with, either, agent]), verbo([led]), complemento([to, about, a, twofold, increase, in, the, expression, of, fatty, acid, transporter, '(', 'FAT/CD36)'])].
[sujeto(['Fatty', acid, overload]), verbo([has]), complemento([been, proposed, as, a, cause, of, decreased, responsiveness, in, the, major, insulin, target, tissues, of, the, body, such, as, muscle, and, liver, tissue])].
[sujeto(['When', administered, orally, to, 'ZDF', rats, for, 2, 'weeks,', the, thiazolidinediones, troglitazone, '(', 300, 'mg/kg)', and, 'KRP-297', '(', 10, 'mg/kg)']), verbo([increased]), complemento([palmitic, acid, oxidation, in, the, soleus, muscle, of, 'ZDF', rats, '(', 'P', &, 'lt;'])].
[sujeto(['KRP-297,', but, not, 'troglitazone,']), verbo([increased]), complemento([palmitic, acid, oxidation, in, the, liver, of, 'ZDF', rats, '(', 'P', &, 'lt;'])].
[sujeto([5, ')', ',', and, both, troglitazone, and, 'KRP-297']), verbo([inhibited]), complemento([triglyceride, accumulation, in, the, skeletal, muscle, of, 'ZDF', rats])].
[sujeto(['Hepatic', triglyceride, accumulation, in, 'ZDF', rats, was]), verbo([inhibited]), complemento([by, 'KRP-297,', but, not, by, troglitazone])].
[sujeto(['A', reduction, of, fatty, acid, oxidation, in, the, liver, of, 'ZDF', rats, and, an]), verbo([increase]), complemento([in, response, to, 'KRP-297', were, observed, only, when, 'C16:0', and, 'C18:0', fatty, 'acids,', not, 'C8:0,', were, used, as, substrates])].
[sujeto(['These', results, indicate, that, 'KRP-297']), verbo([has]), complemento([advantages, over, troglitazone, in, the, amelioration, of, these, lipid, metabolic, abnormalities, in, insulin, resistance, associated, with, obesity])].
[sujeto(['In', order, to, study, the, effects, of, troglitazone, on, insulin, resistance]), verbo([associated]), complemento([with, elevated, plasma, free, fatty, acid, '(', 'FFA),', the, hindquarters, of, rats, treated, with, troglitazone, for, 14, days, were, perfused, with, a, medium, containing, 15, 'mmol/l', 'glucose,', 0, -, 1, ',', 0, 'microU/ml', 'insulin,', and, 0, or, 1.0, 'mmol/l', palmitate])].
[sujeto(['Addition', of, palmitate, abolished, insulin, stimulation, of, net, glucose, uptake, in, control, rat, hindquarter, but, did, not]), verbo([decrease]), complemento([it, in, 'troglitazone-treated', rat, hindquarter, '(', 60, +, /, -, 11, vs, 99, +, /, -, 12, mumol, for, 30, min, at, 1, ',', 0, 'microU/ml', 'insulin,', p, &, 'lt;', 0.01, ')'])].
[sujeto(['It', is]), verbo([suggested]), complemento([that, the, &, 'quot;FFA-tolerant', 'effect"', is, one, mechanism, by, which, troglitazone, reduces, insulin, resistance])].
[sujeto(['Like', obese, 'humans,', 'Zucker', diabetic, fatty, '(', 'ZDF)', rats, exhibit, early, beta, cell, compensation, for, insulin, resistance, '(', 4, -, fold, beta, cell, 'hyperplasia)', followed, by, decompensation, '(', &, 'gt;50%']), verbo([loss]), complemento([of, beta, 'cells)'])].
[sujeto(['In', prediabetic, and, diabetic, 'ZDF', 'islets,', apoptosis, measured, by, 'DNA', laddering, is]), verbo([increased]), complemento([3, -, and, &, 'gt;7-fold,', 'respectively,', compared, with, lean, 'ZDF', controls])].
[sujeto(['Ceramide,', a, fatty, 'acid-containing', messenger, in, 'cytokine-induced', 'apoptosis,', was, significantly]), verbo([increased]), complemento(['(', 'P', &, 'lt;', 0.01, ')', in, prediabetic, and, diabetic, islets])].
[sujeto([4.6, '%', in, lean, control, 'islets,', preceded, by, an, 82, '%']), verbo([increase]), complemento([in, ceramide])].
[sujeto(['C2-Ceramide', without, 'FFA']), verbo([induced]), complemento(['DNA', 'laddering,', but, fumonisin, 'B1,', a, ceramide, synthetase, 'inhibitor,', completely, blocked, 'FFA-induced', 'DNA', laddering, in, cultured, 'ZDF', islets])].
[sujeto(['These', agents, also, reduced, inducible, nitric, oxide, '(', 'NO)', synthase, mRNA, and, 'NO', 'production,', which, are]), verbo([involved]), complemento([in, 'FFA-induced', apoptosis])].
[sujeto(['In', 'ZDF', 'obesity,', beta, cell, apoptosis, is]), verbo([induced]), complemento([by, increased, 'FFA', via, de, novo, ceramide, formation, and, increased, 'NO', production])].
[sujeto(['Thiazolidinediones', '(', 'TZDs)', are, known, to]), verbo([have]), complemento([potent, increases, of, insulin, sensitivity])].
[sujeto(['Because', peroxisome, 'proliferator-activated', 'receptor-gamma', '(', 'PPAR-gamma),', a, receptor, for, 'TZDs,', is, mainly]), verbo([expressed]), complemento([in, 'adipocytes,', we, tried, to, search, the, 'TZD-targeted', genes, in, mouse, 3, 'T3-L1', adipocytes])].
[sujeto(['By', the, mRNA, differential, display, 'method,', one, band]), verbo([repressed]), complemento([by, troglitazone, was, 'obtained,', which, corresponded, to, the, partial, sequences, of, the, 'stearoyl-CoA', desaturase, 1, '(', 'SCD1)', gene])].
[sujeto(['Troglitazone', dramatically]), verbo([decreased]), complemento(['SCD1', mRNA, levels, in, 3, 'T3-L1', adipocytes, in, a, 'dose-dependent', manner])].
[sujeto(['Pioglitazone', also]), verbo([repressed]), complemento([the, 'SCD1', mRNA, 'expression,', whereas, 'WY-14,643', had, no, apparent, effect])].
[sujeto(['These', results, indicate, that, 'TZDs']), verbo([repress]), complemento(['SCD1', activity, in, 3, 'T3-L1', adipocytes, via, downregulating, 'SCD1', enzyme, gene, expression])].
[sujeto(['To', clarify, the, relationship, between, lipid, and, glucose, metabolism, abnormalities, in, 'fructose-fed', 'rats,', we, examined, whether, an, improvement, of, insulin, sensitivity, by, troglitazone, '(', 'CS-045)', or, a]), verbo([decrease]), complemento([in, plasma, lipids, by, bezafibrate, affects, the, relationship, between, serum, levels, of, lipid, and, glucose])].
[sujeto(['In', 'addition,', it, augmented, glycogen, synthase, activity, by, 53, '%', ',', and]), verbo([decreased]), complemento([the, mitochondrial, palmitic, acid, 'beta-oxidation', rate, and, ketone, body, production, rate, by, 27, '%', and, 55, '%', ',', respectively])].
[sujeto(['However,', hyperglycemia, and, liver, glycogen, synthase, activity, were, not, improved, by, bezafibrate, treatment, despite, a, marked, reduction, of, serum, triglyceride, '(', 'TG)', levels, resulting, from, a, 1.76, -, fold]), verbo([increase]), complemento([in, mitochondrial, oxidation, and, a, 2.04, -, fold, increase, in, hepatic, ketone, body, production])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, abnormalities, in, glucose, and, lipid, metabolism, in, 'fructose-fed', 'rats,', which, are, ameliorated, by, 'troglitazone,', may, be, closely, linked, to, reduced, glycogen, synthase, activity, in, the, liver])].
[sujeto(['Fatty', acids, and, thiazolidinediones]), verbo([act]), complemento([as, potent, activators, of, the, adipose, differentiation, program, in, established, preadipose, cell, lines])].
[sujeto(['In', this, 'report,', the, effects, of, these, agents, on, the, differentiation, pathway, of, myoblasts]), verbo([have]), complemento([been, investigated])].
[sujeto(['Exposure', of, 'C2C12N', myoblasts, '(', a, subclone, of, the, 'C2C12', cell, 'line)', to, thiazolidinediones, or, fatty, acids]), verbo([prevents]), complemento([the, expression, of, 'myogenin,', 'alpha-actin,', and, creatine, 'kinase,', thus, abolishing, the, formation, of, multinucleated, myotubes])].
[sujeto(['These', treatments]), verbo([lead]), complemento([in, parallel, to, the, expression, of, a, typical, adipose, differentiation, program, including, acquisition, of, adipocyte, morphology, and, activation, of, 'adipose-related', genes])].
[sujeto(['A', similar, transition, toward, the, adipose, differentiation, pathway, also, occurs, in, mouse, muscle, satellite, cells]), verbo([maintained]), complemento([in, primary, culture])].
[sujeto(['Continuous', exposure, to, inducers, after, growth]), verbo([arrest]), complemento([is, not, required, to, maintain, the, adipose, 'phenotype,', but, proliferation, of, 'adipose-like', 'C2C12N', cells, leads, to, a, complete, reversion, toward, undifferentiated, cells, able, to, undergo, either, myogenic, or, adipogenic, differentiation, depending, on, the, composition, of, culture, medium])].
[sujeto(['The', authors]), verbo([report]), complemento([here, higher, throughput, screening, '(', 'HTS)', assays, for, the, evaluation, of, 'CYP3A4', inhibition, and, 'CYP3A4', induction, in, human, hepatocytes, using, a, novel, 'CYP3A4', 'substrate,', luciferin, 'IPA', '(', 'LIPA)'])].
[sujeto(['Using', human, recombinant, 'CYP450', 'isoforms,', 'LIPA', was]), verbo([found]), complemento([to, be, metabolized, extensively, by, 'CYP3A4', but, not, by, 'CYP1A2,', 'CYP2C9,', 'CYP2C19,', 'CYP2D6,', or, 'CYP2E1'])].
[sujeto(['In', the, 384, -, well, plate, 'CYP3A4', inhibition, 'assay,', the, known, inhibitors, 1, -, 'aminobenzotriazole,', 'erythromycin,', 'ketoconazole,', and, verapamil, were]), verbo([found]), complemento([to, cause, extensive, '(', maximum, inhibition, of, &, 'gt;80%),', 'dose-dependent,', statistically, significant, inhibition, of, 'LIPA', metabolism])].
[sujeto(['The', 'non-CYP3A4', inhibitors, 'diethyldithiocarbamate,', 'quercetin,', 'quinidine,', 'sulfaphenazole,', 'ticlopidine,', and, tranylcypromine, were]), verbo([found]), complemento([to, have, substantially, lower, '(', maximum, inhibition, of, &, 'lt;50%)', or, no, apparent, inhibitory, effects, in, the, 'HTS', assay])].
[sujeto(['The', high, sensitivity, and, specificity, of, the, 'assays,', the, relative, ease, of, 'execution,', and, reduced, 'cost,', 'time,', and, test, material, requirements]), verbo([suggest]), complemento([that, the, 'HTS', assays, may, be, applied, routinely, for, screening, a, large, number, of, chemicals, in, the, drug, discovery, phase, for, 'CYP3A4', inhibitory, and, inducing, potential])].
[sujeto(['The', 'three-step', screening, procedure]), verbo([has]), complemento([been, validated, with, acceptable, accuracy, and, precision, for, detection, and, confirmation, of, 'mechanism-based', inactivators, in, drug, discovery])].
[sujeto(['We']), verbo([report]), complemento([here, the, apparent, partition, ratios, for, 19, 'mechanism-based', inactivators, and, four, 'quasi-irreversible', inhibitors, obtained, under, the, same, experimental, conditions])].
[sujeto(['The', apparent, partition, ratio, screen, was, automated, to]), verbo([provide]), complemento([throughput, for, determining, 'structure-mechanism-based', inactivation, relationships])].
[sujeto(['Information', about, reversibility, can, be, used, to, assess, potential, toxicity]), verbo([mediated]), complemento([by, covalent, 'adducts,', as, well, as, the, potential, for, pharmacokinetic, 'drug-drug', interactions])].
[sujeto(['Direct', comparison, of, known, 'mechanism-based', inactivators, and, 'quasi-irreversible', 'inhibitors,', based, on, our, screening, of, apparent, partition, 'ratios,']), verbo([has]), complemento([identified, 'ritonavir,', 'mibefradil,', and, azamulin, as, highly, effective, 'mechanism-based', 'inactivators;', e])].
[sujeto(['Other', 'mechanism-based', inactivators, we, identified, include, bergamottin, '(', 'CYP1A2', besides, previously]), verbo([reported]), complemento(['CYP3A4),', troglitazone, '(', 'CYP3A4),', rosiglitazone, '(', 'CYP3A4),', and, pioglitazone, '(', 'CYP3A4)'])].
[sujeto(['Comparison', of, the, apparent, partition, ratios, and, inactivation, clearance, data, for, the, three, glitazones]), verbo([suggests]), complemento([that, the, chromane, moiety, on, troglitazone, contributes, to, its, greater, potency, for, 'mechanism-based', inactivation])].
[sujeto(['These', 'compounds,', along, with, 'troglitazone,', were, evaluated, for, the, ability, to]), verbo([induce]), complemento([cytochrome, 'P450', enzymes, '(', 'P450)', in, primary, human, hepatocyte, cultures, and, to, inhibit, 'P450', in, human, microsomes])].
[sujeto(['In', induction, 'studies,', all, three, thiazolidinediones]), verbo([caused]), complemento([a, 'dose-dependent', increase, in, 'CYP3A4', activity, and, immunoreactive, protein])].
[sujeto(['A', comparable, 'concentration-dependent']), verbo([increase]), complemento([in, 'CYP2B6', immunoreactive, protein, was, observed, with, all, three, thiazolidinediones])].
[sujeto(['Troglitazone,', in, 'addition,']), verbo([inhibited]), complemento(['CYP2C9', '(', 'K(i)', 0.6, 'microM)'])].
[sujeto(['Although', the, inhibitory, effects, of, the, thiazolidinediones]), verbo([have]), complemento([not, been, demonstrated, 'clinically,', our, results, suggest, there, is, potential, for, interactions, with, 'CYP2C8', substrates])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([of, in, vitro, induction, of, 'P450', enzymes, by, rosiglitazone, and, pioglitazone])].
[sujeto(['While', only, the, induction, of, 'CYP3A4', by, troglitazone]), verbo([has]), complemento([been, demonstrated, in, 'vivo,', these, results, suggest, that, other, thiazolidinediones, may, have, the, potential, to, cause, clinically, significant, drug, interactions, at, sufficiently, high, doses])].
[sujeto(['Based', on, the, 'correlation,', we, hypothesize, that, 'TRO', and, 'TRO', sulfate, are, direct]), verbo([acting]), complemento(['toxicants,', whereas, 'CYP3A4', oxidation, and, glucuronidation, are, detoxification, pathways])].
[sujeto(['Oxidative', ring, opening, of, troglitazone, '(', 'TGZ)(1)', a, thiazolidine, 2, ',', 4, -, dione, derivative, used, for, the, treatment, of, type, 'II', diabetes, 'mellitus,']), verbo([leads]), complemento([to, the, formation, of, a, quinone, metabolite])].
[sujeto(['The', formation, of, 'TGZ', quinone, was, shown, to, be, 'NADPH', dependent, and, to]), verbo([require]), complemento([active, microsomal, enzymes])].
[sujeto(['Quinone', formation, was, not, affected, by, 'co-incubation', with, catalase, or, sodium, azide, and, was, partially]), verbo([inhibited]), complemento(['(', 25, '%', ')', by, superoxide, dismutase, '(', 'SOD)'])].
[sujeto(['CYP3A', isoforms, were, characterized, as, the, primary, enzymes]), verbo([involved]), complemento([in, quinone, formation, by, several, lines, of, evidence, 'including:', '(', 'a)', troleandomycin, and, ketoconazole, almost, completely, inhibited, microsomal, quinone, formation, when, 'SOD', was, 'present,', whereas, other, 'CYP', inhibitors, had, minimal, effects, '(', &, 'lt;20%);', '(', 'b)', 'TGZ', quinone, formation, was, highly, correlated, with, regard, to, both, contents, '(', 'r(2):', 0.9374, ')', and, activities, '(', 'r(2):', 0.7951, ')', of, 'CYP3A4', in, human, liver, microsomes, '(', 'HLM);', '(', 'c)', baculovirus, insect, 'cell-expressed', human, 'CYP3A4', was, able, to, catalyze, 'TGZ', quinone, formation, at, a, higher, capacity, '(', 'V(max)/K(m))', than, other, human, 'CYPs', with, the, relative, contribution, of, 'CYP3A4', in, 'HLM', estimated, to, be, 20, -, fold, higher, than, that, of, other, 'CYPs;', '(', 'd)', 'TGZ', quinone, formation, was, increased, by, 350, '%', in, liver, microsomes, from, rats, pretreated, with, dexamethasone, '(', 'DEX);', and, '(', 'e)', plasma, concentrations, of, 'TGZ', quinone, were, increased, by, 260, -, 680, '%', in, rats, pretreated, with, 'DEX'])].
[sujeto(['The', chemical, nature, of, the, quinone, metabolite]), verbo([suggests]), complemento([an, atypical, 'CYP', reaction, consistent, with, a, 'one-electron', oxidation, mechanism, where, an, intermediate, phenoxy, radical, combines, with, ferryl, oxygen, to, subsequently, form, the, quinone, metabolite])].
[sujeto(['From', ancient, 'times,', marine, algae]), verbo([have]), complemento([emerged, as, alternative, medicine, and, 'foods,', contains, the, rich, source, of, natural, products, like, 'proteins,', 'vitamins,', and, secondary, 'metabolites,', especially, 'Chlorella', vulgaris, '(', 'C'])].
[sujeto(['Type', 2, diabetes, mellitus, is, closely]), verbo([associated]), complemento([with, adipogenesis, and, their, factors])].
[sujeto(['Further,', the, effect, of, 'EECV', on, lipid, accumulation, along, with, genes, and, proteins, expressions, which, are]), verbo([associated]), complemento([with, adipogenesis, and, lipogenesis, were, evaluated, using, oil, red, 'O', 'staining,', qPCR, and, western, blot, techniques])].
[sujeto(['The', data, indicated, that, that, 'EECV', treatment]), verbo([increased]), complemento([differentiation, and, lipid, accumulation, in, 3, 'T3-L1', 'cells,', which, indicates, positive, regulation, of, adipogenic, and, lipogenic, activity])].
[sujeto(['These']), verbo([increases]), complemento([were, associated, with, 'up-regulation', of, 'PPAR-γ2,', 'C/EBP-α,', 'adiponectin,', 'FAS,', and, leptin, mRNA, and, protein, expressions])].
[sujeto(['Also,', 'EECV', treatments]), verbo([increased]), complemento([the, concentration, of, glycerol, releases, as, compared, with, control, cells])].
[sujeto(['Troglitazone', is, a, 'PPAR-γ', agonist, that]), verbo([stimulates]), complemento([the, 'PPAR-γ2,', 'adiponectin,', and, 'GLUT-4', expressions])].
[sujeto(['Further,', 'EECV', treatment]), verbo([decreased]), complemento(['AMPK-α', expression, as, compared, with, control, and, metformin, treated, cells])].
[sujeto(['The', present, research, findings, confirmed, that, the, 'EECV', effectively]), verbo([modulates]), complemento([the, lipid, accumulation, and, differentiation, in, 3, 'T3-L1', cells, through, 'AMPK-α', mediated, signalling, pathway])].
[sujeto(['Glycogen', 'Synthase', 'Kinase-3β', '(', 'GSK3β)', is, a, 'serine/threonine', 'kinase,', known, to]), verbo([regulate]), complemento([various, cellular, processes, including, 'proliferation,', 'differentiation,', 'survival,', apoptosis, as, well, as, 'TRAIL-resistance'])].
[sujeto(['Thus', pathways, that, can]), verbo([modulate]), complemento(['GSK3β', axis, are, important, targets, for, cancer, drug, development])].
[sujeto(['Our', earlier, studies]), verbo([have]), complemento([shown, that, combinatorial, treatment, with, 'Troglitazone', '(', 'TZD)', and, 'TRAIL', can, induce, apoptosis, in, 'TRAIL-resistant', cancer, cells])].
[sujeto(['The', current, studies, were, undertaken, to, investigate, whether, 'GSK3β', pathway, was]), verbo([modulated]), complemento([during, this, apoptosis])].
[sujeto(['Our', results, indicated, an]), verbo([increase]), complemento([in, inhibitory, 'GSK3βSer9', phosphorylation, during, 'apoptosis,', mediated, via, 'AKT'])].
[sujeto(['Since', 'TZD', is, a, ligand, for, transcription, factor, 'PPARγ', and, can]), verbo([activate]), complemento(['AMPK,', we, determined, their, roles, on, antagonism, of, 'GSK3β'])].
[sujeto(['These', studies]), verbo([suggested]), complemento([a, novel, 'PPARγ-AMPK-independent', mechanism, of, targeting, 'GSK3β', by, 'TZD,', elucidation, of, which, might, provide, newer, insights, to, improve, our, understanding, of, 'TRAIL-resistance'])].
[sujeto(['The', aim, of, this, study, was, to, investigate, whether, the, peroxisomal, 'proliferator-activated', receptor, gamma, '(', 'PPARγ)', ligand, troglitazone, in, combination, with, photodynamic, therapy, '(', 'PDT)']), verbo([enhances]), complemento([the, apoptotic, response, of, 'DLD-1', colon, cancer, cells])].
[sujeto(['Treatment', of, troglitazone, and, 'PDT']), verbo([induced]), complemento([the, growth, retardation, and, cell, death, of, 'DLD-1', cells, in, a, 'dose-dependent', 'manner,', respectively])].
[sujeto(['The', combination, treatment, significantly]), verbo([suppressed]), complemento([cell, growth, and, increased, the, apoptotic, response, of, 'DLD-1', and, resulted, in, apoptosis, rather, than, 'necrosis,', as, shown, by, 'PI/annexin', 'V', staining, and, degradation, of, 'procaspase-3'])].
[sujeto(['These', results, document, the, 'anti-proliferative', and, apoptotic, activities, of, 'PDT', in, combination, with, the, 'PPARγ', ligand, troglitazone, and]), verbo([provide]), complemento([a, strong, rationale, for, testing, the, therapeutic, potential, of, combination, treatment, in, colon, cancer])].
[sujeto(['However,', there, is, little, information, regarding, 'Adeno-associated', virus, '(', 'AAV)', carrying, 'PDX1', gene, transduced, to, human, liver, 'in vivo', because, accidental, death]), verbo([caused]), complemento([by, unpredicted, factors, cannot, be, 'denied,', such, as, the, hypoglycemic, agent, troglitazone, with, hepatic, failure])].
[sujeto(['This', study, aims, to, investigate, whether, phytochemicals, are, agonists, of, the, 'PPARγ/RXRα', pathway, and]), verbo([modulate]), complemento([the, target, gene, 'OCTN2'])].
[sujeto(['Kaempferol,', 'curcumin,', and, puerarin, were]), verbo([found]), complemento([to, show, the, significant, 'PPRE-mediated', luciferase, activities, '(', &, 'gt;150%)', at, 20, μM, and, showed, a, 'dose-dependent', manner])].
[sujeto(['These', induction, effects, were, gradually]), verbo([inhibited]), complemento([by, 'PPARγ', antagonist, 'GW9662', in, the, luciferase, reporter, gene, system, and, in, 'SW480', cells])].
[sujeto(['Moreover,', the, results, of, cell, viability, assay, imply, that, three, phytochemicals, probably]), verbo([induce]), complemento(['OCTN2', expression, leading, to, the, enhanced, uptake, of, its, 'substrate,', 'oxaliplatin,', thereby, making, cells, more, sensitive, to, oxaliplatin])].
[sujeto(['The', molecular, docking, study, showed, the, possible]), verbo([binding]), complemento([sites, of, phytochemicals, in, 'PPARγ', 'protein,', and, all, of, the, docked, phytochemicals, fitted, the, same, active, pocket, in, 'PPARγ', as, troglitazone])].
[sujeto(['Peroxisome', 'proliferator-activated', 'receptor-γ', '(', 'PPAR-γ)', agonists, were]), verbo([reported]), complemento([to, be, able, to, regulate, extracellular, matrix, production, in, human, dermal, fibroblasts])].
[sujeto(['Level', of, 'Egr1', were, closely]), verbo([associated]), complemento([with, 'KF-induced', fibrosis])].
[sujeto(['The', miRNA, profiling, data, revealed, that, 'miR-543', was, transcriptionally]), verbo([activated]), complemento([after, troglitazone, treatment])].
[sujeto(['Bioinformatic', analysis, and, experimental, data, showed, that, 'miR-543', was, able, to]), verbo([target]), complemento(['Egr1'])].
[sujeto(['ELISA', data, confirmed, that, 'Col1', protein, in, the, supernatant, were]), verbo([modulated]), complemento([by, the, feedback, regulatory, axis, of, 'PPAR-γ', 'agonist-induced', 'miR-543', to, inhibit, 'Egr1', 'expression,', whereas, 'PPAR-γ', antagonist, treatment, abolished, such, effect, on, 'Col1', suppression, in, 'KFs'])].
[sujeto(['Our', previous, study, demonstrated, that, 'quercetin-metabolite-enriched', plasma, '(', 'QP)', but, not, quercetin, itself, upregulates, peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPAR-γ)', expression, to]), verbo([induce]), complemento(['G2/M', arrest, in, 'A549', cells])].
[sujeto(['The', results, showed, that, 'QP', significantly]), verbo([suppressed]), complemento([cell, invasion, and, 'migration,', as, well, as, matrix, metalloproteinases, '(', 'MMPs)-2', activity, and, expression, in, a, 'dose-dependent', manner])].
[sujeto(['However,', 'QP', and, 'TGZ', rather, than, quercetin, itself]), verbo([increased]), complemento([the, expressions, of, 'nm23-H1', and, tissue, inhibitor, of, metalloproteinase, '(', 'TIMP-2)'])].
[sujeto(['Furthermore,', we, demonstrated, that, 'Q3G', and, 'Q3\'S', also]), verbo([inhibited]), complemento([the, protein, expression, of, 'MMP-2'])].
[sujeto(['Taken', 'together,', our, study, demonstrated, that, 'QP']), verbo([inhibited]), complemento([cell, invasion, and, migration, through, 'nm23-H1/TIMP-2/MMP-2', associated, mechanisms])].
[sujeto(['Although', many, preclinical, screening, methods]), verbo([have]), complemento([been, 'proposed,', it, remains, difficult, to, identify, compounds, associated, with, this, rare, but, potentially, fatal, liver, condition])].
[sujeto(['In', 'conclusion,', inhibitory, effect, on, the, bile, canalicular, network, formation, observed, in, in, vitro, sandwich, cultured, hepatocytes, evaluates, a, new, aspect, of, drug, 'toxicity,', particularly]), verbo([associated]), complemento([with, aggravation, of, liver, injury])].
[sujeto(['Huangkui', capsule, '(', 'HKC),', an, extract, from, 'AM,']), verbo([has]), complemento([been, proved, clinically, effective, in, improving, renal, inflammation, and, glomerular, injury, in, 'CKD'])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, '(', 'PPAR)-α/γ', dual, agonists]), verbo([have]), complemento([the, potential, to, be, used, as, therapeutic, agents, for, the, treatment, of, type, 2, diabetes, and, diabetic, nephropathy, '(', 'DN)'])].
[sujeto(['ChIP', and, reporter, gene, assays, were, performed, and, the, expression, of, 'PPARα/γ']), verbo([target]), complemento([genes, was, monitored, to, examine, the, ability, of, 'HKC', to, activate, 'PPARα/γ'])].
[sujeto(['DN', was]), verbo([induced]), complemento([in, male, 'Sprague-Dawley', rats, via, unilateral, nephrectomy, and, intraperitoneal, injection, of, streptozotocin])].
[sujeto(['HKC']), verbo([enhanced]), complemento([the, transcriptional, activity, of, 'PPARα', and, 'PPARγ', in, cultured, 'cells,', livers, and, kidneys, of, 'DN', 'rats,', and, it, reduced, serum, triglyceride, and, cholesterol, levels, and, fat, in, livers, of, 'DN', rats])].
[sujeto(['Our', results, show, that, 'HKC', improved, lipid, metabolic, disorders, by]), verbo([activating]), complemento(['PPARα/γ', and, attenuating, 'ER', stress])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'HKC', has, potential, as, an, 'anti-DN', agent, for, the, treatment, of, 'DN', in, humans])].
[sujeto(['The', phenotypic, changes, resemble, human, type, 2, diabetes]), verbo([associated]), complemento([with, obesity, and, therefore, the, strain, is, used, as, a, pharmacological, model, for, type, 2, diabetes])].
[sujeto(['The', results, revealed, that, the, activity, for, 'CYP3A', and, 'UGT', was]), verbo([decreased]), complemento([in, 'ZDF', rats, using, the, probe, 'substrates,', and, decreased, unbound, intrinsic, clearance, in, vitro, for, 'glibenclamide,', 'canagliflozin,', and, troglitazone, was, consistent, with, lower, plasma, clearance, in, vivo])].
[sujeto(['Our', previous, research]), verbo([has]), complemento([revealed, that, 'glycation-serum', '(', 'GS)', induced, pancreatic, 'beta-cell', demise, through, the, 'AGEs-RAGE', pathway])].
[sujeto(['Using', pancreatic, islets, 'beta-cell', line, 'INS-1', 'cells,', we]), verbo([found]), complemento([that, with, 'GS', 'treatment,', the, transcriptional, activity, of, p53, was, significantly, evoked, due, to, the, increased, amount, of, nuclear, p53, protein])].
[sujeto(['Resveratrol', '(', 'RSV)', was, capable, of, further]), verbo([enhancing]), complemento([this, transcriptional, ability, and, consequently, increased, the, population, of, dead, beta, cells, under, 'GS', exposure])].
[sujeto(['In', 'contrast,']), verbo([inhibiting]), complemento([this, transcriptional, activity, via, p53, interference, greatly, protected, beta, cells, from, the, damage, provoked, by, 'GS,', as, well, as, damage, strengthened, by, 'RSV'])].
[sujeto(['However,', the, pharmacological, activation, of, 'PPARγ', with, troglitazone, '(', 'TRO)', only]), verbo([suppressed]), complemento(['GS-induced,', not, 'RSV-induced,', p53, activity])].
[sujeto(['Further,', p53, activation, could]), verbo([induce]), complemento([cellular, apoptosis, in, primary, rat, islets])].
[sujeto(['Our', findings, explore, the, broader, role, of, p53, in]), verbo([regulating]), complemento([pancreatic, 'beta-cell', demise, in, the, presence, of, 'GS', and, may, provide, a, therapeutic, target, for, the, treatment, and, prevention, of, diabetes])].
[sujeto(['This', protocol]), verbo([induced]), complemento([prominent, general, adipocyte, gene, 'expression,', including, markers, for, both, brown, and, white, adipocytes, and, triglyceride, accumulation])].
[sujeto(['Moreover,', the, cells, were, sensitive, to, insulin, as, observed, from]), verbo([increased]), complemento([glucose, uptake, and, inhibition, of, lipolysis])].
[sujeto(['This', differentiation, protocol]), verbo([provides]), complemento([a, promising, approach, for, the, induction, of, hASC, adipogenesis, to, obtain, functional, and, mature, human, adipocytes])].
[sujeto(['CES1', inhibition, '(', 'troglitazone)', was, greater, than, 'CES2', '(', 'loperamide),']), verbo([suggesting]), complemento([a, primary, metabolic, role, for, 'CES1'])].
[sujeto(['However,', keratinocytes, from, skin]), verbo([provide]), complemento([a, small, contribution, to, the, overall, metabolism, of, 'C2E5'])].
[sujeto(['The', antifungal, 'azoles,', 'posaconazole,', 'itraconazole,', and, 'ketoconazole,', significantly]), verbo([inhibited]), complemento(['MDR3-mediated', phosphatidylcholine, secretion])].
[sujeto(['Drug-induced', cholestasis, '(', 'DIC)', is]), verbo([recognized]), complemento([as, one, of, the, prime, mechanisms, for, 'DILI'])].
[sujeto(['Several', batches, of, human, hepatocytes, in, 'sandwich-culture', were, qualified, for, 'DIC', assessment, by, verifying, the, bile, 'acid-dependent']), verbo([increase]), complemento([in, sensitivity, to, the, toxic, effects, of, cyclosporin, 'A'])].
[sujeto(['The', cholestatic, potential, of, the, 'TCs', was]), verbo([expressed]), complemento([by, determining, the, 'drug-induced', cholestasis, index, '(', 'DICI)'])].
[sujeto(['This', 'hepatocyte-based', in, vitro, assay]), verbo([provides]), complemento([a, unique, tool, for, early, and, reliable, identification, of, drug, candidates, with, cholestasis, risk])].
[sujeto(['Microfluidic', 'organ-on-a-chip', technology, aims, to, replace, animal, toxicity, 'testing,', but, thus, far]), verbo([has]), complemento([demonstrated, few, advantages, over, traditional, methods])].
[sujeto(['Here,', we, present, a, 'liver-on-chip', device, capable, of]), verbo([maintaining]), complemento([human, tissue, for, over, a, month, in, vitro, under, physiological, conditions])].
[sujeto(['A', 'computer-controlled', microfluidic, switchboard, allowed, contiguous, electrochemical, measurements, of, glucose, and, 'lactate,']), verbo([providing]), complemento(['real-time', analysis, of, minute, shifts, from, oxidative, phosphorylation, to, anaerobic, 'glycolysis,', an, early, indication, of, mitochondrial, stress])].
[sujeto(['We', show, troglitazone, shifts, metabolic, fluxes, at, concentrations, previously, regarded, as, 'safe,']), verbo([suggesting]), complemento([a, mechanism, for, its, observed, idiosyncratic, effect])].
[sujeto(['Our', microfluidic, platform]), verbo([reveals]), complemento([the, dynamics, and, strategies, of, cellular, adaptation, to, mitochondrial, 'damage,', a, unique, advantage, of, 'organ-on-chip', technology])].
[sujeto(['Connectivity', mapping, is, a, method, used, in, the, pharmaceutical, industry, to]), verbo([find]), complemento([connections, between, small, 'molecules,', disease, 'states,', and, genes])].
[sujeto(['The', concept, can, be, applied, to, a, predictive, toxicology, paradigm, to]), verbo([find]), complemento([connections, between, 'chemicals,', adverse, 'events,', and, genes])].
[sujeto(['Connectivity', mapping, was, used, to]), verbo([find]), complemento([linkages, between, each, chemical, and, between, chemical, classes])].
[sujeto(['The', results]), verbo([provide]), complemento([an, example, of, an, alternate, data, analysis, process, for, 'high-content', 'data,', beneficial, for, predictive, 'toxicology,', especially, when, grouping, chemicals, for, read, across, purposes])].
[sujeto(['Catalpol,', a, major, iridoid, glycoside, present, in, 'Rehmannia', 'glutinosa,']), verbo([has]), complemento([been, reported, to, show, a, variety, of, pharmacological, properties])].
[sujeto(['Catalpol', significantly]), verbo([inhibited]), complemento(['IL-1β-induced', mRNA, synthesis, and, protein, production, of, 'pro-inflammatory', 'cytokines,', including, 'IL-6,', 'IL-8,', and, 'MCP-1'])].
[sujeto(['Further', investigation, of, the, molecular, mechanism, revealed, that, the, 'anti-inflammatory', effect, of, catalpol, in, 'Caco-2', cells, is, similar, to, that, of, 'troglitazone-a', synthetic, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)-γ', 'agonist-on', intestinal, inflammation]), verbo([mediated]), complemento([by, 'PPAR-γ', activation])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, clinical, application, of, medicinal, plants, that, contain, catalpol, may, lead, to, a, partial, prevention, of, intestinal, inflammation])].
[sujeto(['We', developed, a, novel, bile, salt, transport, activity, assay]), verbo([involving]), complemento([in, situ, biosynthesis, of, bile, salts, from, their, precursors, in, primary, 'human,', 'monkey,', 'dog,', 'rat,', and, mouse, hepatocytes, in, suspension, as, well, as, 'LC-MS/MS', determination, of, extracellular, bile, salts, transported, out, of, hepatocytes])].
[sujeto(['The', transport, activity, was]), verbo([inhibited]), complemento([by, the, bile, salt, export, pump, '(', 'BSEP)', inhibitors, 'ketoconazole,', 'saquinavir,', 'cyclosporine,', and, troglitazone])].
[sujeto(['The', assay, was, used, to, test, 86, drugs, for, their, potential, to]), verbo([inhibit]), complemento([bile, salt, transport, activity, in, human, 'hepatocytes,', which, included, 35, drugs, associated, with, severe, 'DILI', '(', 'sDILI)', and, 51, with, 'non-severe', 'DILI', '(', 'non-sDILI)'])].
[sujeto(['Approximately', 60, '%', of, the, sDILI, drugs, showed, potent, inhibition, '(', with, 'IC50', values, &, 'lt;50 μM),', but, only, about, 20, '%', of, the, 'non-sDILI', drugs, showed, this, strength, of, inhibition, in, primary, human, hepatocytes, and, these, drugs, are]), verbo([associated]), complemento([only, with, cholestatic, and, mixed, hepatocellular, cholestatic, '(', 'mixed)', injuries])].
[sujeto(['The', sDILI, 'drugs,', which, did, not, show, substantial, inhibition, of, bile, salt, transport, 'activity,', are, likely, to, be]), verbo([associated]), complemento([with, 'immune-mediated', liver, injury])].
[sujeto(['In', 'summary,', a, novel, assay]), verbo([has]), complemento([been, developed, using, hepatocytes, in, suspension, from, human, and, animal, species, that, can, be, used, to, assess, the, potential, for, drugs, 'and/or', 'drug-derived', metabolites, to, inhibit, bile, salt, transport, 'and/or', formation, activity])].
[sujeto(['Drugs']), verbo([causing]), complemento(['sDILI,', except, those, by, 'immune-mediated', 'mechanism,', are, highly, associated, with, potent, inhibition, of, bile, salt, transport])].
[sujeto([fruticosa]), verbo([increased]), complemento([the, transcriptional, activity, of, both, 'PPARα', and, 'PPARγ', which, 'was,', in, 'part,', driven, by, the, active, ingredient, 'DGF'])].
[sujeto(['Treatment', with, 'DGF', markedly]), verbo([enhanced]), complemento([the, adipogenesis, of, 3, 'T3-L1', 'preadipocytes,', which, was, comparable, to, the, effect, of, the, 'PPARγ', 'agonist,', troglitazone])].
[sujeto(['In', 'addition,', 'DGF', was]), verbo([found]), complemento([to, enhance, fatty, acid, oxidation, and, glucose, utilization, through, the, dual, activation, of, 'PPARα/γ'])].
[sujeto(['In', addition, treatment, with, 'DGF']), verbo([led]), complemento([to, an, improvement, in, insulin, 'sensitivity,', resulting, in, enhanced, glucose, uptake, in, muscle, cells])].
[sujeto(['The', findings, of, our, study, data]), verbo([suggest]), complemento([that, 'DGF', may, be, used, as, potential, therapeutic, agent, in, the, treatment, of, type, 2, diabetes, and, related, metabolic, disorders, by, enhancing, glucose, and, lipid, metabolism])].
[sujeto(['The', outcome, of, the, 'Selenium', and, 'Vitamin', 'E', 'Cancer', 'Prevention', 'Trial,', demonstrating, harm, and, no, preventive, activity, of, selenomethionine, and, 'α-tocopherol', for, prostate, 'cancer,', and, the, lack, of, approval, by, the, 'FDA', for, the, use, of, 5, 'α-reductase', inhibitors, to]), verbo([prevent]), complemento([prostate, cancer, have, cast, doubt, about, the, future, of, chemoprevention, of, prostate, cancer])].
[sujeto(['This', article, attempts, to, critically, assess, whether, the, notion, that, chemoprevention, of, prostate, cancer]), verbo([has]), complemento([no, future, is, warranted])].
[sujeto(['However,', the, approach, to, prostate, 'cancer-chemopreventive', agent, development]), verbo([has]), complemento([not, followed, a, rational, and, systematic, process])].
[sujeto(['Long-term', vitamin, 'E', supplementation]), verbo([decreases]), complemento([urine, 8, -, 'iso-PGF2α', among, male, cigarette, 'smokers,', but, we, observed, little, to, no, evidence, for, an, effect, of, selenium, 'supplementation,', alone, or, combined, with, vitamin, 'E'])].
[sujeto(['Despite', major, progress, in, the, understanding, of, the, genetic, basis, of, 'FSHD,', the, exact, mechanisms, that]), verbo([lead]), complemento([to, 'FSHD', defects, are, not, completely, understood, and, no, curative, treatment, is, available])].
[sujeto(['We', recently]), verbo([reported]), complemento([that, reduced, physical, performance, in, patients, with, 'FSHD', is, associated, with, important, redox, unbalance, and, oxidative, stress, in, blood])].
[sujeto(['Hence,', we, hypothesized, that, insufficient, intake, of, antioxidant, vitamins, and, minerals, may, reduce, the, body, capacity, to]), verbo([regulate]), complemento([free, radical, 'insults,', leading, to, a, condition, known, as, oxidative, stress, that, could, affect, muscle, function, performance, in, patients, with, 'FSHD'])].
[sujeto(['The', results, of, this, randomized, 'double-blind', 'placebo-controlled', trial, show, that, supplementation, with, vitamin, 'C,', vitamin, 'E', '(', as, alpha, 'tocopherol),', zinc, gluconate, and, selenomethionine, in, patients, with, 'FSHD', significantly, improves, the, maximal, voluntary, contraction, and, endurance, of, both, quadriceps, by]), verbo([enhancing]), complemento([the, antioxidants, defences, and, reducing, oxidative, stress])].
[sujeto(['The', intake, of, nutrients, with, antioxidant, properties, is, hypothesized, to, augment, antioxidant, 'defenses,']), verbo([decrease]), complemento([oxidant, damage, to, 'tissues,', and, attenuate, 'age-related', rate, of, decline, in, lung, function])].
[sujeto(['Egg', production, '(', rate, of, lay, and, eggs, per, 'breeder),', egg, characteristics, '(', 'egg,', 'yolk,', 'eggshell,', and, albumen, 'weights),', 'fertility,', incubation, responses, '(', egg, weight]), verbo([loss]), complemento([during, 'incubation,', 'hatchability,', and, hatching, 'window),', and, hatchling, characteristics, '(', weight, and, 'yield)', were, evaluated])].
[sujeto(['The', dietary, inclusion, of, organic, selenium, also]), verbo([promoted]), complemento([heavier, hatchling, weight, until, egg, production, peak, '(', 33, 'wk),', but, did, not, influence, hatchling, quality, or, hatching, window])].
[sujeto(['As', growing, evidence]), verbo([suggests]), complemento([that, oxidative, stress, may, contribute, to, 'FSHD', 'pathology,', antioxidants, that, might, modulate, or, delay, oxidative, insults, could, help, in, maintaining, 'FSHD', muscle, function])].
[sujeto(['In', 'conclusion,', vitamin, 'E,', vitamin, 'C,', 'zinc,', and, selenium, supplementation]), verbo([has]), complemento([no, significant, effect, on, the, 2, -, 'MWT,', but, improves, 'MVCQ', and, 'TlimQ', of, both, quadriceps, by, enhancing, the, antioxidant, defenses, and, reducing, oxidative, stress])].
[sujeto(['Observational', studies]), verbo([suggest]), complemento([a, role, for, dietary, nutrients, such, as, vitamin, 'E', and, selenium, in, cataract, prevention])].
[sujeto(['However,', the, results, of, randomized, clinical, trials, of, vitamin, 'E', supplements, and, cataract]), verbo([have]), complemento([been, disappointing, and, are, not, yet, available, for, selenium])].
[sujeto(['The', 'Selenium', and, 'Vitamin', 'E', 'Cancer', 'Prevention', 'Trial', '(', 'SELECT)', 'Eye', 'Endpoints', 'Study', was, an, ancillary, study, of, the, 'Southwest', 'Oncology', 'Group-coordinated', 'SELECT,', a, randomized, 'placebo-controlled', 4, -, arm, trial, of, selenium, and, vitamin, 'E', conducted, among, 35, ',', 533, 'men,', 50, years, and, older, for, 'African', 'American', participants, and, 55, years, and, older, for, all, other, 'men,', at, 427]), verbo([participating]), complemento([sites, in, the, 'United', 'States,', 'Canada,', and, 'Puerto', 'Rico'])].
[sujeto(['A', total, of, 11, ',', 267, 'SELECT', participants, from, 128, 'SELECT', sites]), verbo([participated]), complemento([in, the, 'SELECT', 'Eye', 'Endpoints', ancillary, study])].
[sujeto(['These', data, from, a, large, cohort, of, apparently, healthy, men, indicate, that, 'long-term', daily, supplementation, with, selenium, 'and/or', vitamin, 'E', is, unlikely, to]), verbo([have]), complemento([a, large, beneficial, effect, on, 'age-related', cataract])].
[sujeto(['Studies']), verbo([have]), complemento([shown, that, vitamin, 'E', and, selenium, possess, antiproliferative, effects, against, prostate, cancer, '(', 'PCa)'])].
[sujeto(['However,', results, from, the, 'Selenium', and, 'Vitamin', 'E', 'Cancer', 'Prevention', 'Trial', '(', 'SELECT)']), verbo([suggest]), complemento([that, vitamin, 'E', '(', 'α-tocopheryl', 'acetate;', 400, 'mg)', 'and/or', selenium, '(', 'L-selenomethionine;', 200, 'μg)', were, ineffective, against, 'PCa', in, humans])].
[sujeto(['MSA', '(', 41, 'µg/kg)', and, γT, '(', 20.8, 'mg/kg)', combination, was, most, consistent, in, imparting, 'anti-proliferative', 'response;', resulting, in, a, significant]), verbo([decrease]), complemento([in, 'i)', tumor, 'volume/weight,', 'ii)', serum, 'PSA,', and, 'iii)', 'Ki-67', immunostaining])].
[sujeto(['Further,', we, observed, 'i)', an, upregulation, of, 'pro-apoptosis', 'Bax', and, a, 'down-regulation', of, the, 'pro-survival', 'Bcl2,', and, 'ii)', an]), verbo([increase]), complemento([in, 'pro-apoptosis', 'Bad'])].
[sujeto(['Overall,', our, study]), verbo([suggested]), complemento([that, a, combination, of, 'MSA', and, 'γT,', at, lower, dose, 'regimen,', could, be, useful, in, 'PCa', management])].
[sujeto(['We,', 'therefore,', examined, whether, presupplementation, plasma, 'α-tocopherol', or, 'γ-tocopherol', was]), verbo([associated]), complemento([with, overall, or, 'high-grade', prostate, cancer])].
[sujeto(['Plasma', 'γ-tocopherol', was, not]), verbo([associated]), complemento([with, prostate, cancer])].
[sujeto(['Men', with, higher, 'α-tocopherol', concentrations, seemed, to]), verbo([have]), complemento([risk, similar, to, that, of, men, with, lower, concentrations, '[', overall, 'HR', for, fifth, '(', 'Q5)', vs])].
[sujeto(['We']), verbo([found]), complemento([a, strong, positive, plasma, 'α-tocopherol', association, among, men, receiving, the, trial, selenomethionine, supplement, '[', 'Q5', 'HR,', 2.04, ;, 95, '%', 'CI,', 1.29, -, 3.22, ;, 'P-trend', =, 0.005, ']'])].
[sujeto(['Our', findings, indicate, that, higher, plasma, 'α-tocopherol', concentrations, may]), verbo([interact]), complemento([with, selenomethionine, supplements, to, increase, 'high-grade', prostate, cancer, 'risk,', suggesting, a, biologic, interaction, between, 'α-tocopherol', and, selenium, itself, or, selenomethionine])].
[sujeto(['Two', 'large,', 'population-based,', phase, 3, prostate, cancer, prevention, trials]), verbo([reported]), complemento([that, 5, -, alpha, reductase, inhibitors, significantly, reduce, prostate, cancer, risk])].
[sujeto(['However,', this, class, of, agents, were, also]), verbo([associated]), complemento([with, increased, detection, of, 'high-grade', prostate, cancer])].
[sujeto(['Paradoxically,', a, significant]), verbo([increase]), complemento([in, prostate, cancer, was, observed, among, men, randomized, to, receive, vitamin, 'E', alone])].
[sujeto(['Epidemiologic', research]), verbo([suggests]), complemento([that, increased, cancer, risk, due, to, chronic, arsenic, exposure, persists, for, several, decades, even, after, the, exposure, has, terminated])].
[sujeto(['Observational', studies]), verbo([suggest]), complemento([that, antioxidants, exert, a, protective, effect, on, arsenical, skin, lesions, and, cancers, among, those, chronically, exposed, to, arsenic, through, drinking, water])].
[sujeto(['This', study]), verbo([reports]), complemento([on, the, 'design,', methods, and, baseline, analyses, from, the, 'Bangladesh', 'Vitamin', 'E', and, 'Selenium', 'Trial', '(', 'BEST),', a, 'population-based', chemoprevention, study, conducted, among, adults, in, 'Bangladesh', with, visible, arsenic, toxicity])].
[sujeto(['We']), verbo([report]), complemento([novel, associations, between, arsenical, skin, lesions, with, several, common, chronic, diseases])].
[sujeto(['With', the, rapidly]), verbo([increasing]), complemento([burden, of, preventable, cancers, in, developing, 'countries,', efficient, and, feasible, chemoprevention, study, designs, and, 'approaches,', such, as, employed, in, 'BEST,', may, prove, both, timely, and, potentially, beneficial, in, conceiving, cancer, chemoprevention, trials, in, 'Bangladesh', and, beyond])].
[sujeto(['The', possibility, that, 'SeMet', and, 'Se-yeast', are, not, equipotent, in]), verbo([promoting]), complemento([homeostasis, and, cancer, risk, reduction, in, the, aging, prostate, has, not, been, adequately, 'investigated;', no, direct, comparison, has, ever, been, reported, in, man, or, animals])].
[sujeto(['After', seven, months, of, 'supplementation,', we]), verbo([found]), complemento([no, significant, selenium, 'form-dependent', differences, in, toenail, or, intraprostatic, selenium, concentration])].
[sujeto(['Next,', we, determined, whether, 'SeMet', or, 'Se-yeast']), verbo([acts]), complemento([with, different, potency, on, six, markers, of, prostatic, homeostasis, that, likely, contribute, to, prostate, cancer, risk, 'reduction-intraprostatic', dihydrotestosterone, '(', 'DHT),', testosterone, '(', 'T),', 'DHT:T,', and, epithelial, cell, 'DNA', 'damage,', 'proliferation,', and, apoptosis])].
[sujeto(['By', analyzing, dogs, supplemented, with, 'SeMet', or, 'Se-yeast', that, achieved, equivalent, intraprostatic, selenium, concentration, after, 'supplementation,', we, showed, no, significant, differences, in, potency, of, either, selenium, form, on, any, of, the, six, parameters, over, three, different, ranges, of]), verbo([target]), complemento([tissue, selenium, concentration])].
[sujeto(['In', this, 'study,', 'SeMet', and, 'SeMet+Vit-E']), verbo([increased]), complemento([oocyte, 'maturation,', fertilization, and, incorporation, and, oxidation, of, '(', 14, ')', 'C(U)-glucose', significantly, '(', 'P<0'])].
[sujeto(['In', 'addition,', embryo, 'development,', specifically, in, terms, of, the, numbers, of, morulae, and, 'blastocysts,', significantly]), verbo([increased]), complemento(['(', 'P<0'])].
[sujeto(['These', findings, indicate, that, 'SeMet', and, 'SeMet+Vit-E', may, play, important, roles, in, reducing, the, accumulation, of, ammonia, and, subsequently, in]), verbo([increasing]), complemento([the, rate, of, maturation, of, porcine, oocytes, and, 'fertilization,', as, well, as, development, of, the, blastocyst, and, utilization, of, glucose, in, in, vitro, 'maturation,', fertilization, and, culture, to, blastocysts, of, porcine, oocytes])].
[sujeto(['The', initial]), verbo([report]), complemento([of, the, 'Selenium', and, 'Vitamin', 'E', 'Cancer', 'Prevention', 'Trial', '(', 'SELECT)', found, no, reduction, in, risk, of, prostate, cancer, with, either, selenium, or, vitamin, 'E', supplements, but, a, statistically, nonsignificant, increase, in, prostate, cancer, risk, with, vitamin, 'E'])].
[sujeto(['Longer', 'follow-up', and, more, prostate, cancer, events]), verbo([provide]), complemento([further, insight, into, the, relationship, of, vitamin, 'E', and, prostate, cancer])].
[sujeto(['This']), verbo([report]), complemento([includes, 54, ',', 464, additional, 'person-years', of, 'follow-up', and, 521, additional, cases, of, prostate, cancer, since, the, primary, report])].
[sujeto(['Compared', with, 'placebo,', the, absolute]), verbo([increase]), complemento([in, risk, of, prostate, cancer, per, 1000, 'person-years', was, 1.6, for, vitamin, 'E,', 0.8, for, 'selenium,', and, 0.4, for, the, combination])].
[sujeto(['Dietary', supplementation, with, vitamin, 'E', significantly]), verbo([increased]), complemento([the, risk, of, prostate, cancer, among, healthy, men])].
[sujeto(['The', recently, published]), verbo([report]), complemento([of, the, 'SELECT', evaluation, of, selenium, and, vitamin, 'E', provided, strong, evidence, that, selenium, 200, μg, per, day, in, the, form, of, selenomethionine, does, not, protect, 'selenium-replete', men, against, prostate, or, any, other, cancer])].
[sujeto(['One', of, the, organic, selenium, forms, suspected, of, having, strong, chemopreventive, 'effects,', and, which, may]), verbo([have]), complemento([been, present, in, the, 'NPC', 'agent,', is, methyl, selenocysteine])].
[sujeto(['Regardless', of, dose, and, 'source,', the, selenium, supplementation, to, feeds, for, groups, 2, ',', 3, and, 4, resulted, in, significantly]), verbo([increased]), complemento(['α-tocopherol', concentration, in, egg, yolk, compared, to, control, group, 1, '(', 'P', &, 'lt;', 0.001, ')'])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, data, from, a, 'long-term', carcinogenesis, study, indicating, that, dietary, antioxidant, supplements, can, suppress, 'radiation-induced', malignant, lymphoma, and, harderian, gland, tumors, induced, by, space, radiations, '(', 'specifically,', 1, 'GeV/n', iron, ions, or, 'protons)', in, 'CBA/J', mice])].
[sujeto(['In', the, present, 'report,', the, results, from, the, earlier, analysis, of, the, harderian, gland, data, from, the, published, 'long-term', animal, study]), verbo([have]), complemento([been, combined, with, new, data, derived, from, the, same, 'long-term', animal, study])].
[sujeto(['The', new, data, presented, here, focused, on, the, histopathological, results, obtained, from, analyses, of, the, harderian, glands, of, mice, that, did, not]), verbo([have]), complemento([visible, abnormalities, around, the, eyes, at, the, time, of, necropsy, in, the, 'long-term', animal, study])].
[sujeto(['In', this, 'paper,', the, original, published, data, and, the, new, data]), verbo([have]), complemento([been, combined, to, provide, a, more, complete, evaluation, of, the, harderian, glands, from, animals, in, the, 'long-term', carcinogenesis, 'study,', with, all, available, harderian, glands, from, the, animals, processed, and, prepared, for, histopathological, evaluation])].
[sujeto(['The', results, indicate, 'that,', although, dietary, antioxidant, supplements]), verbo([suppressed]), complemento([harderian, gland, tumors, in, a, statistically, significant, fashion, when, all, glands, were, 'analyzed,', the, antioxidant, diets, were, less, effective, at, suppressing, the, incidence, of, all, harderian, gland, tumors, than, they, were, at, suppressing, the, incidence, of, large, harderian, gland, tumors, '(', &, 'gt;2', 'mm)', observed, at, animal, necropsy])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, dietary, antioxidant, formulations, had, major, suppressive, effects, in, the, later, stages, of, 'radiation-induced', carcinogenesis, in, vivo])].
[sujeto(['It', is, hypothesized, that, the, dietary, antioxidant, formulations]), verbo([prevented]), complemento([the, 'early-stage', neoplastic, growths, from, progressing, to, fully, 'developed,', malignant, tumors])].
[sujeto(['In', 'addition,', the, antioxidant, dietary, formulations, were, very, effective, at]), verbo([preventing]), complemento([the, development, of, 'proton-', or, 'iron-ion-induced', malignant, 'tumors,', 'because,', in, contrast, to, irradiated, 'controls,', no, malignant, tumors, were, observed, in, the, irradiated, animals, maintained, on, either, of, the, dietary, antioxidant, diets])].
[sujeto(['The', hypotheses, underlying, 'SELECT,', that, selenium, and, vitamin, 'E', individually, and, together]), verbo([decrease]), complemento([prostate, cancer, 'incidence,', derived, from, epidemiologic, and, laboratory, evidence, and, significant, secondary, endpoints, in, the, 'Nutritional', 'Prevention', of, 'Cancer', '(', 'selenium)', and, 'Alpha-Tocopherol', 'Beta-Carotene', '(', vitamin, 'E)', trials])].
[sujeto(['Statistically', nonsignificant]), verbo([increased]), complemento([risks, of, prostate, cancer, with, vitamin, 'E', alone, '[', relative, risk, '(', 'RR)', =, 1.13, ',', 'P', =, 0.06, ')', and, newly, diagnosed, 'Type', 2, diabetes, mellitus, with, selenium, alone, '(', 'RR', =, 1.07, ',', 'P', =, 0.16, ')', were, observed])].
[sujeto(['SELECT', data, show, that, neither, selenium, nor, vitamin, 'E,', alone, or, 'together,', in, the, doses, and, formulations, 'used,']), verbo([prevented]), complemento([prostate, cancer, in, this, heterogeneous, population, of, healthy, men])].
[sujeto(['We']), verbo([have]), complemento([recently, shown, significant, preventive, benefit, of, methylseleninic, acid, '(', 'MSeA)', and, 'Se-methylselenocysteine', '(', 'MSeC)', in, the, transgenic, adenocarcinoma, mouse, prostate, '(', 'TRAMP)', model, by, oral, administration])].
[sujeto(['MSeA', mainly, affected, proteins, related, to, prostate, functional, 'differentiation,', androgen, receptor, 'signaling,', protein, '(', 'mis)folding,', and, endoplasmic, 'reticulum-stress', 'responses,', whereas, 'MSeC', affected, proteins]), verbo([involved]), complemento([in, phase, 'II', detoxification, or, 'cytoprotection,', and, in, stromal, cells])].
[sujeto(['Although', 'MSeA', and, 'MSeC', are, presumed, precursors, of, methylselenol, and, were, equally, effective, against, the, 'TRAMP', 'model,', their, distinct, affected, protein, profiles]), verbo([suggest]), complemento([biological, differences, in, their, molecular, targets, outweigh, similarities])].
[sujeto(['During', 'cooking,', high, levels, of, vitamin, 'E', reduced, oxysterol, 'formation,', whereas, high, levels, of, 'SeMet', were, inconsistent, and, even]), verbo([increased]), complemento([oxysterols, during, roasting])].
[sujeto(['TBARs', in, 'frozen-raw', meat, stored, for, 6, mo, were]), verbo([inhibited]), complemento([by, high, levels, of, either, antioxidant])].
[sujeto(['However,', the, origin, of, this, transport, protein, is, controversial, and, many, organ, sources]), verbo([have]), complemento([been, suggested])].
[sujeto(['The', cells, contained, 'TC', 'II', '(', 2.3, 'pmol/10(8)', 'cells)', and]), verbo([released]), complemento([progressively, increasing, amounts, of, the, protein, into, the, surrounding, medium, during, the, 3, -, day, incubation, period])].
[sujeto(['This']), verbo([release]), complemento([exceeded, the, starting, intracellular, content, of, 'TC', 'II'])].
[sujeto(['In', 'contrast,', endothelial, cells, did, not, contain, or, elaborate, 'R', 'binder,', the, other, major, circulating]), verbo([binding]), complemento([protein, for, 'cobalamin,', 'Cycloheximide', inhibited, the, elaboration, of, 'TC', 'II,', suggesting, that, the, endothelial, cells, synthesize, the, protein])].
[sujeto(['Thrombin,', which]), verbo([stimulates]), complemento([tissue, plasminogen, activator, 'release,', did, not, enhance, 'TC', 'II', 'release,', and, neither, did, endotoxin, or, mellitin])].
[sujeto(['However,', thrombin, did, appear, to, partially, protect, 'TC', 'II']), verbo([release]), complemento([from, inhibition, by, cycloheximide])].
[sujeto(['Among', other, cells, 'studied,', human, fibroblasts, also]), verbo([released]), complemento(['TC', 'II', into, the, incubation, 'medium,', while, 'K562', human, leukemia, 'cells,', 'ARH-77', and, 'HS', 'Sultan', human, plasma, cell, 'lines,', and, 'Raji', strain, lymphoblasts, did, not])].
[sujeto(['The', data]), verbo([suggest]), complemento([that, endothelial, cells, are, an, important, source, of, the, metabolically, crucial, 'TC', 'II'])].
[sujeto(['The', conditions, for]), verbo([inducing]), complemento([germination, are, soaking, time, in, water, 24, ',', 48, ',', or, 72, 'h;', temperature, 26, or, 36, °, 'C;', incubation, in, light, or, 'darkness;', and, open, or, closed, 'vessels,', in, which, the, antioxidative, activities, and, bioactive, compounds, of, 'GBR', were, determined])].
[sujeto(['We']), verbo([found]), complemento(['that,', in, order, to, maximize, antioxidative, activity, and, bioactive, 'compounds,', germination, should, be, under, higher, temperature, '(', 36, °, 'C),', long, soaking, time, '(', 72, 'h),', 'darkness,', and, closed, vessel])].
[sujeto(['We']), verbo([found]), complemento([a, strong, correlation, between, antioxidative, activities, '(', 'DPPH', radical, scavenging, 'ability,', reducing, 'power,', and, 'Trolox', equivalent, antioxidant, 'capacity)', and, bioactive, compounds, '(', 'γ-oryzanols,', 'tocopherol,', and, 'tocotrienol)'])].
[sujeto(['C57Bl/6', female, mice, were, divided, into, three, groups, and, fed, the, 'AIN-76A', liquid, 'EtOH', diet, containing, 'EtOH', to]), verbo([provide]), complemento([31, '%', of, total, caloric, intake, '(', 'TCI),', the, same, basic, diet, containing, 'EtOH', to, provide, 35, '%', of, 'TCI,', or, an, isocaloric, 'AIN-76A', liquid, control, diet])].
[sujeto(['Liver', reduced, glutathione, '(', 'GSH)', 'levels,', and, activities, of, both, 'Mn-superoxide', dismutase, '(', 'SOD)', and, 'Cu/Zn-SOD', were, significantly]), verbo([decreased]), complemento([by, both, levels, of, 'EtOH'])].
[sujeto(['Our', previous, study, using, the, 'Lieber-DeCarli', liquid, 'EtOH', diet]), verbo([caused]), complemento([a, decline, of, total, 'SOD', and, 'GP', activities])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, chronic, 'EtOH', administration, decreases, liver, antioxidant, 'defenses;', 'however,', the, mice, fed, the, 'AIN-76A', 'EtOH', liquid, diet, can, maintain, a, higher, antioxidant, defense, capability, than, those, fed, 'Lieber-DeCarli', 'EtOH', liquid, diet])].
[sujeto([1, ',', 4, -, 'Dihydroxy-2-naphthoic', acid, '(', 'DHNA),', a, precursor, of, menaquinone, '(', vitamin, 'K2),']), verbo([has]), complemento([an, effect, on, growth, stimulation, of, bifidobacteria, and, prevention, of, 'osteoporosis,', making, it, a, promising, functional, food, material])].
[sujeto([',', 'CP000414),', a]), verbo([primer]), complemento([set, '(', 'Leu_menBfull_F', and, 'Leu_menBfull_R)', was, designed, for, the, 'PCR', amplification, of, menB, gene, of, 'CJNU', 147])].
[sujeto(['The', 'DHNA', was, produced, from, it, at, a, detectable, 'level,', indicating, that, the, cloned, menB, gene, of, 'CJNU', 147, encoded, a, 'DHNA', synthase, which, is, responsible, for, the, production, of, 'DHNA,', resulting, in, an]), verbo([increase]), complemento([of, bifidogenic, growth, stimulation, activity])].
[sujeto(['In', 'vertebrates,', 'menaquinone-4', serves, as, an, enzymatic, 'co-factor', that, is]), verbo([required]), complemento([for, posttranslational, protein, 'modification,', i])].
[sujeto([the, 'γ-carboxylation', of, glutamate, residues, in, specific, proteins]), verbo([involved]), complemento([in, blood, 'coagulation,', bone, metabolism, and, vascular, biology])].
[sujeto(['This', 'view,', 'however,']), verbo([has]), complemento([been, recently, challenged, by, the, exclusive, localization, of, the, 6, th, pathway, enzyme, '(', 'MenB/NS)', to, peroxisomes, in, 'Arabidopsis'])].
[sujeto(['Phylloquinone', biosynthesis]), verbo([reveals]), complemento([several, branching, points, leading, to, the, synthesis, of, important, defence, signalling, 'molecules,', such, as, salicylic, acid, and, benzoic, acid, derivatives])].
[sujeto(['Numerous', mechanisms, to]), verbo([regulate]), complemento([intermediate, flux, and, the, 'fine-tuned', inducible, production, of, secondary, 'metabolites,', including, signalling, 'molecules,', await, their, characterization, at, the, molecular, level])].
[sujeto(['PCC6803', at, 2.04, 'Å,', in, which, the, bicarbonate, cofactor, is]), verbo([bound]), complemento([to, the, enzyme, active, site, at, a, position, equivalent, to, that, of, the, side, chain, carboxylate, of, an, aspartate, residue, conserved, among, 'bicarbonate-insensitive', 'DHNA-CoA', synthases])].
[sujeto(['Binding', of, the, planar, anion]), verbo([involves]), complemento([both, nonspecific, electrostatic, attraction, and, specific, hydrogen, bonding, and, hydrophobic, interactions])].
[sujeto(['In', the, absence, of, 'bicarbonate,', the, anion]), verbo([binding]), complemento([site, is, occupied, by, a, chloride, ion, or, 'nitrate,', an, inhibitor, directly, competing, with, bicarbonate])].
[sujeto(['These', results]), verbo([provide]), complemento([a, solid, structural, basis, for, the, bicarbonate, dependence, of, the, enzymatic, activity, of, type, 'I', 'DHNA-CoA', synthases])].
[sujeto(['The', unique, location, of, the, bicarbonate, ion, in, relation, to, the, expected, position, of, the, substrate, 'α-proton', in, the, 'enzyme\'s', active, site]), verbo([suggests]), complemento([a, critical, catalytic, role, for, the, anionic, cofactor, as, a, catalytic, base, in, enolate, formation])].
[sujeto(['Mechanistic', studies, on, this, crotonase, family, member]), verbo([have]), complemento([been, hindered, by, partial, active, site, disorder, in, existing, 'MenB', 'X-ray', structures])].
[sujeto(['In', the, current, work, the, 2.0, 'Å', structure, of, 'O-succinylbenzoyl-aminoCoA', '(', 'OSB-NCoA)']), verbo([bound]), complemento([to, the, 'MenB', from, 'Escherichia', coli, provides, important, insight, into, the, catalytic, mechanism, by, revealing, the, position, of, all, active, site, residues])].
[sujeto(['This']), verbo([has]), complemento([been, accomplished, by, the, use, of, a, stable, analogue, of, the, 'O-succinylbenzoyl-CoA', '(', 'OSB-CoA)', substrate, in, which, the, 'CoA', thiol, has, been, replaced, by, an, amine])].
[sujeto(['The', resulting, 'OSB-NCoA', is, 'stable,', and, the, 'X-ray', structure, of, this, molecule]), verbo([bound]), complemento([to, 'MenB', reveals, the, structure, of, the, 'enzyme-substrate', complex, poised, for, 'carbon-carbon', bond, formation])].
[sujeto(['The', structural, data, support, a, mechanism, in, which, two]), verbo([conserved]), complemento([active, site, 'Tyr', 'residues,', 'Y97', and, 'Y258,', participate, directly, in, the, intramolecular, transfer, of, the, substrate, 'α-proton', to, the, benzylic, carboxylate, of, the, 'substrate,', leading, to, protonation, of, the, electrophile, and, formation, of, the, required, carbanion])].
[sujeto(['Y97', and, 'Y258', are, also, ideally, positioned, to, function, as, the, second, oxyanion, hole]), verbo([required]), complemento([for, stabilization, of, the, tetrahedral, intermediate, formed, during, 'carbon-carbon', bond, formation])].
[sujeto(['In', 'contrast,', 'D163,', which, is, structurally, homologous, to, the, 'acid-base', catalyst, 'E144', in, crotonase, '(', 'enoyl-CoA', 'hydratase),', is, not, directly]), verbo([involved]), complemento([in, carbanion, formation, and, may, instead, play, a, structural, role, by, stabilizing, the, loop, that, carries, 'Y97'])].
[sujeto(['When', similar, studies, were, performed, on, the, 'MenB', from, 'Mycobacterium', 'tuberculosis,', a, twisted, hexamer, was, unexpectedly, 'observed,', demonstrating, the, flexibility, of, the, interfacial, loops, that, are]), verbo([involved]), complemento([in, the, generation, of, the, novel, tertiary, and, quaternary, structures, found, in, the, crotonase, superfamily])].
[sujeto(['This', work, reinforces, the, utility, of, using, a, stable, substrate, analogue, as, a, mechanistic, probe, in, which, only, one, atom]), verbo([has]), complemento([been, altered, leading, to, a, decrease, in, 'α-proton', acidity])].
[sujeto([1, ',', 4, -, 'Dihydroxy-2-naphthoyl-coenzyme', 'A', '(', 'DHNA-CoA)', 'synthase,', or, 'MenB,', catalyzes, an, intramolecular, 'Claisen', condensation]), verbo([involving]), complemento([two, oxyanion, intermediates, in, the, biosynthetic, pathway, of, 'menaquinone,', an, essential, respiration, electron, transporter, in, many, microorganisms])].
[sujeto(['Here', we]), verbo([report]), complemento([the, finding, that, the, 'DHNA-CoA', product, and, its, analogues, bind, and, inhibit, the, synthase, from, 'Escherichia', coli, with, significant, 'ultraviolet--visible', spectral, 'changes,', which, are, similar, to, the, changes, induced, by, deprotonation, of, the, free, inhibitors, in, a, basic, solution])].
[sujeto(['Dissection', of, the, 'structure--affinity', relationships, of, the, inhibitors, identifies, the, hydroxyl, groups, at, positions, 1, '(', 'C1-OH)', and, 4, '(', 'C4-OH)', of, 'DHNA-CoA', or, their, equivalents, as, the, dominant, and, minor, 'sites,', 'respectively,', for, the, 'enzyme--ligand', interaction, that, polarizes, or, deprotonates, the]), verbo([bound]), complemento([ligands, to, cause, the, observed, spectral, changes])].
[sujeto(['In', the, 'meantime,', spectroscopic, studies, with, active, site, mutants, indicate, that, 'C4-OH', of, the, 'enzyme-bound', 'DHNA-CoA']), verbo([interacts]), complemento([with, conserved, polar, residues, 'Arg-91,', 'Tyr-97,', and, 'Tyr-258', likely, through, a, hydrogen, bonding, network, that, also, includes, 'Ser-161'])].
[sujeto(['In', 'addition,', 'site-directed', mutation, of, the]), verbo([conserved]), complemento(['Asp-163', to, alanine, causes, a, complete, loss, of, the, ligand, binding, ability, of, the, 'protein,', suggesting, that, the, 'Asp-163', side, chain, is, most, likely, 'hydrogen-bonded', to, 'C1-OH', of, 'DHNA-CoA', to, provide, the, dominant, polarizing, effect])].
[sujeto(['Moreover,', this, mutation, also, completely, eliminates, the, enzyme, 'activity,', strongly, supporting, the, possibility, that, the, 'Asp-163', side, chain]), verbo([provides]), complemento([a, strong, stabilizing, hydrogen, bond, to, the, tetrahedral, 'oxyanion,', which, takes, a, position, similar, to, that, of, 'C1-OH', of, the, 'enzyme-bound', 'DHNA-CoA', and, is, the, second, 'high-energy', intermediate, in, the, intracellular, 'Claisen', condensation, reaction])].
[sujeto(['Their', involvement, in, the, interaction, with, the, small, molecule, ligands]), verbo([suggests]), complemento([that, the, disordered, loop, is, folded, in, interaction, with, the, substrates, or, reaction, 'intermediates,', supporting, an, 'induced-fit', catalytic, mechanism, for, the, enzyme])].
[sujeto([coli, was, significantly]), verbo([enhanced]), complemento([by, modulating, two, precursor, 'pools,', which, supply, a, 'non-polar', side, chain, and, a, polar, head, 'group,', and, further, increased, by, blocking, formation, of, the, competitor, 'ubiquinone-8', '(', 'Q-8)'])].
[sujeto([coli, 'IspA,', 'DXR,', or, 'IDI']), verbo([increased]), complemento(['MK-8', content, up, to, twofold])].
[sujeto(['The', 'Q-8-deficient', ubiCA, mutant]), verbo([enhanced]), complemento(['MK-8', content, by, 30, '%', compared, to, 'wild-type', 'E'])].
[sujeto(['When', 'MenA', or, 'MenD', was, 'overexpressed,', 'MK-8', content, was]), verbo([enhanced]), complemento([fivefold, compared, with, 'wild-type', 'E'])].
[sujeto(['Mycobacterium', tuberculosis]), verbo([has]), complemento([been, classified, for, decades, as, a, strict, aerobic, species])].
[sujeto(['Whole', genome, sequencing, of, the, type, culture, strain, 'H37Rv']), verbo([has]), complemento([revealed, the, presence, of, a, full, set, of, genes, allowing, for, anaerobic, metabolism])].
[sujeto(['Naphthoate', synthase, '(', 'menB)', is, a, key, enzyme]), verbo([required]), complemento([for, the, synthesis, of, 'menaquinone,', which, plays, a, crucial, role, in, anaerobic, electron, 'transport,', ultimately, resulting, in, the, formation, of, energy, generating, intermediates])].
[sujeto(['A', systematic]), verbo([increase]), complemento([in, the, expression, of, the, menB, gene, product, was, observed, over, the, incubation, period, with, a, 4.3, -, fold, increase, seen, at, week, 6, '(', 'P < 0'])].
[sujeto([1, ')', relative, to, day, 0, and, an, 85.8, -, fold]), verbo([increase]), complemento([at, week, 15, '(', 'P < 0'])].
[sujeto([tuberculosis]), verbo([increase]), complemento([menaquinone, production, during, prolonged, incubation, in, broth, culture, as, a, mechanism, of, survival])].
[sujeto(['We', characterized, the, quinones, synthesized, by, 'Lactococcus', 'lactis,', a, fermenting, bacterium, that]), verbo([activates]), complemento([aerobic, respiration, when, a, haem, source, is, provided])].
[sujeto(['We', previously, showed, that, a, respiratory, metabolism, is]), verbo([activated]), complemento([in, 'Group', 'B', 'Streptococcus', '(', 'GBS)', by, exogenous, haem, and, 'MK,', and, that, this, activity, is, implicated, in, virulence])].
[sujeto(['Here', we, show, that, growing, lactococci, donate, '(', 'D)MK', to, 'GBS', to]), verbo([activate]), complemento([respiration, and, stimulate, growth, of, this, opportunist, pathogen])].
[sujeto(['Vitamin', 'K(2),', or, 'menaquinone,', is, an, essential, cofactor, for, many, organisms, and, the, enzymes]), verbo([involved]), complemento([in, its, biosynthesis, are, potential, antimicrobial, drug, targets])].
[sujeto(['One', of, these, 'enzymes,', 1, ',', 4, -, 'dihydroxy-2-naphthoyl-CoA', synthase, '(', 'MenB)', from, the, pathogen, 'Staphylococcus', 'aureus,']), verbo([has]), complemento([been, obtained, in, recombinant, form, and, its, quaternary, structure, has, been, analyzed, in, solution])].
[sujeto(['The', presence, of, 'acetoacetyl-CoA', in, one, of, the, two, active, sites, present, in, the, asymmetric, unit, indicates, how, part, of, the, substrate]), verbo([binds]), complemento([and, facilitates, comparisons, with, the, structure, of, 'Mycobacterium', tuberculosis, 'MenB'])].
[sujeto(['Bacterial', enzymes, of, the, menaquinone, '(', 'Vitamin', 'K2)', pathway, are, potential, drug]), verbo([targets]), complemento([because, they, lack, human, homologs])].
[sujeto(['MenB,', 1, ',', 4, -, 'dihydroxy-2-naphthoyl-CoA', 'synthase,', the, fourth, enzyme, in, the, biosynthetic, pathway]), verbo([leading]), complemento([from, chorismate, to, 'menaquinone,', catalyzes, the, conversion, of, 'O-succinylbenzoyl-CoA', '(', 'OSB-CoA)', to, 1, ',', 4, -, 'dihydroxy-2-naphthoyl-CoA', '(', 'DHNA-CoA)'])].
[sujeto(['Based', on, our, interest, in, developing, novel, tuberculosis, 'chemotherapeutics,', we]), verbo([have]), complemento([solved, the, structures, of, 'MenB', from, 'Mycobacterium', tuberculosis, and, its, complex, with, 'acetoacetyl-coenzyme', 'A', at, 1.8, and, 2.3, 'A', 'resolution,', respectively])].
[sujeto(['The', highly]), verbo([conserved]), complemento([active, site, of, 'MenB', contains, a, deep, pocket, lined, by, 'Asp-192,', 'Tyr-287,', and, hydrophobic, residues])].
[sujeto(['Transformation', of, carbon, tetrachloride, '(', 'CT)', by, 'Shewanella', oneidensis, 'MR-1']), verbo([has]), complemento([been, proposed, to, involve, the, anaerobic, 'respiratory-chain', component, menaquinone])].
[sujeto(['We', conclude, that, a, derivative, of, 'DHNA,', that, is, distinct, from, 'menaquinone,', is]), verbo([involved]), complemento([in, the, reduction, of, 'CT', by, aerobically, grown, 'S'])].
[sujeto(['These', pieces, of, information]), verbo([led]), complemento([us, to, identify, the, 'ORF-2', gene, product])].
[sujeto([coli, with, an, expression, vector, of, 'ORF-2', catalyzed, the, incorporation, of, 'S-adenosyl-L-methionine', into, 'menaquinone-8,', indicating, that, 'ORF-2', encodes, 2, -, 'heptaprenyl-1,4-naphthoquinone', 'methyltransferase,', which]), verbo([participates]), complemento([in, the, terminal, step, of, the, menaquinone, biosynthesis])].
[sujeto(['Thus', it, is, concluded, that, the, 'ORF-1,', 'ORF-2,', and, 'ORF-3', 'genes,', designated, 'heps-1,', 'menG,', and, 'heps-2,', 'respectively,', form, another, cluster]), verbo([involved]), complemento([in, menaquinone, biosynthesis, in, addition, to, the, cluster, of, 'menB,', 'menC,', 'menD,', and, menE, already, identified, in, the, 'Bacillus', subtilis, and, 'E'])].
[sujeto(['In', 'Escherichia', 'coli,', the, biosynthesis, of, the, electron, carrier, menaquinone, '(', vitamin, 'K2)']), verbo([involves]), complemento([at, least, seven, identified, enzymatic, 'activities,', five, of, which, are, encoded, in, the, men, cluster])].
[sujeto(['One', of, 'these,', the, conversion, of, 'o-succinylbenzoic', acid, to, 1, ',', 4, -, 'dihydroxy-2-naphthoic', 'acid,']), verbo([requires]), complemento([the, formation, of, 'o-succinylbenzoyl-CoA', '(', 'OSB-CoA)', as, an, intermediate])].
[sujeto(['Formation', of, the, intermediate, is]), verbo([mediated]), complemento([by, 'OSB-CoA', synthetase, encoded, by, the, menE, locus, known, to, be, located, either, 5, '\'', of, 'menB,', or, 3, '\'', of, menC])].
[sujeto(['Nucleotide', sequence, analysis, of, the, fragment, identified, a, 1.355, -, kb, open, reading, frame, '(', 'ORF)', 'which,', when, deleted, at, either, the, 5, '\'', or, 3, '\'', 'end,', failed, to, generate]), verbo([increased]), complemento([enzymatic, activity])].
[sujeto(['An', oppositely]), verbo([transcribed]), complemento([unidentified, gene, cluster, follows, the, menE, 'ORF'])].
[sujeto(['All', loci, are]), verbo([transcribed]), complemento(['counter-clockwise'])].
[sujeto(['A', 1.3, -, kb, 'PstI-PvuII', fragment, was]), verbo([found]), complemento([to, complement, the, menC, mutation])].
[sujeto(['A', consensus, sequence, for, a, ribosomal]), verbo([binding]), complemento([site, but, no, promoter, consensus, sequences, were, found])].
[sujeto(['However,', the, first, base, of, the, initiating, codon, of, this, open, reading, frame, overlaps, the, upstream, menB, gene, termination, 'codon,']), verbo([suggesting]), complemento([an, 'operon-like', organization, for, these, genes])].
[sujeto(['In', 'Escherichia', 'coli,', the, biosynthesis, of, the, electron, carrier, menaquinone, '(', vitamin, 'K2)']), verbo([involves]), complemento([at, least, seven, identified, enzymes])].
[sujeto(['The', gene, for, this, enzyme]), verbo([has]), complemento([been, previously, identified, as, menB])].
[sujeto(['The', 'ORF', is, preceded, by, consensus, sequences, for, a, ribosomal]), verbo([binding]), complemento([site, and, a, sigma, 70, promoter])].
[sujeto(['Four', independent, menaquinone, '(', vitamin, 'K(2))-deficient', mutants, of, 'Escherichia', 'coli,', blocked, in, the, conversion, of, 'o-succinylbenzoate', '(', 'OSB)', to, 1, ',', 4, -, 'dihydroxy-2-naphthoate', '(', 'DHNA),', were]), verbo([found]), complemento([to, represent, two, distinct, classes])].
[sujeto(['Menaquinone', '(', vitamin, 'K2)-deficient', mutants, of, 'Bacillus', 'subtilis,', whose, growth, requirement, is, satisfied, by, 1, ',', 4, -, 'dihydroxy-2-naphthoic', acid, but, not, by, 'o-succinylbenzoic', acid, '(', 'OSB),']), verbo([have]), complemento([been, analyzed, for, enzymatic, defects])].
[sujeto(['Mutants']), verbo([found]), complemento([to, lack, dihydroxynaphthoate, 'synthase,', and, which, therefore, complement, with, dihydroxynaphthoate, synthase, of, 'M'])].
[sujeto(['Although,', drone, milk, is, traditionally, used, to, treat, infertility, and, to]), verbo([promote]), complemento([vitality, in, both, men, and, women, in, certain, 'countries,', the, literature, furnishes, no, information, concerning, effects, of, the, drone, milk])].
[sujeto(['The', oestrogenic, and, androgenic, effects, of, drone, milk]), verbo([have]), complemento([recently, been, reported, in, rats, and, the, effective, compounds, have, also, been, identified])].
[sujeto(['Maintenance', of, pregnancy, assays, revealed, that, drone, milk, was, able, to]), verbo([increase]), complemento([the, number, of, surviving, fetuses])].
[sujeto(['This', results]), verbo([suggested]), complemento([some, gestagenic, effects])].
[sujeto(['These', results]), verbo([lead]), complemento([us, to, suppose, that, raw, drone, milk, shows, weak, gestagenic, effect, and, this, effect, can, be, increased, by, another, weak, gestagen])].
[sujeto(['Further', studies, are]), verbo([required]), complemento([to, clarify, the, gestagenic, mechanisms, of, action, of, drone, milk])].
[sujeto(['The', major, role, of, liver, glycogen, is, to, supply, glucose, to, the, circulation]), verbo([maintaining]), complemento([the, normal, blood, glucose, level])].
[sujeto(['In', muscle, and, liver, the, accumulation, and, breakdown, of, glycogen, are]), verbo([regulated]), complemento([by, the, reciprocal, activities, of, glycogen, phosphorylase, and, glycogen, synthase])].
[sujeto(['Glycogen', phosphorylase, catalyses, the, key, step, of, glycogen, degradation, and, its, activity, can, be]), verbo([inhibited]), complemento([by, glucose, and, its, analogues])].
[sujeto(['Hepatic', glycogen, phosphorylase]), verbo([has]), complemento([been, identified, as, a, new, target, for, drugs, that, control, blood, glucose, concentration])].
[sujeto(['The', 'streptozotocin-treated', rats, failed, to]), verbo([gain]), complemento([weight, and, exhibited, stable, hyperglycemia, '(', 4.7, ±, 0.5, 'mmol/L', glucose, in, control, vs])].
[sujeto(['When', insulin, supplementation, with, 'slow-release', implants, '(', 2, 'IU/day)', was, started, 8, weeks, after, streptozotocin, 'injection,', blood, glucose, concentration, remained, 'suppressed,', plasma, insulin, level, dramatically]), verbo([increased]), complemento([and, the, insulin, sensitivity, restored])].
[sujeto(['Removal', of, the, 'O-benzoyl', protecting, groups, by, the, 'Zemplén', protocol]), verbo([led]), complemento([to, test, compounds, most, of, which, proved, micromolar, inhibitors, of, rabbit, muscle, glycogen, phosphorylase, b, '(', 'RMGPb)'])].
[sujeto(['Crystallographic', studies, of, the, unsubstituted, 'spiro-thiazolidinone', and, the, above, most, efficient, inhibitors, in, complex, with, 'RMGPb', confirmed, the, preference, and, inhibitory, effect, that, aromatic, '(', and, especially, 2, -, 'naphthyl)', derivatives, show, for, the, catalytic, site]), verbo([promoting]), complemento([the, inactive, conformation, of, the, enzyme])].
[sujeto(['The', major, role, of, liver, glycogen, is, to, supply, glucose, to, the, circulation, in, order, to]), verbo([maintain]), complemento([normal, blood, glucose, levels])].
[sujeto(['In', the, muscle, and, 'liver,', the, accumulation, and, breakdown, of, glycogen, are]), verbo([regulated]), complemento([by, the, reciprocal, activities, of, glycogen, phosphorylase, and, glycogen, synthase])].
[sujeto(['Glycogen', phosphorylase, catalyses, the, key, step, of, glycogen, degradation, and, its, activity, is]), verbo([inhibited]), complemento([by, glucose, and, its, analogues])].
[sujeto(['Hepatic', glycogen, phosphorylase]), verbo([has]), complemento([been, identified, as, a, novel, target, for, drugs, that, control, blood, glucose, concentration])].
[sujeto(['Glucopyranosylidene-spiro-thiohydantoin', '(', 'TH)', was]), verbo([found]), complemento([to, be, one, of, the, most, potent, glucose, 'derivates,', inhibiting, the, catalytic, activity, of, both, muscle, and, liver, glycogen, phosphorylase])].
[sujeto(['Furthermore,', intravenous, administration, of, 'TH', to, 'Zucker', diabetic, fatty, rats, significantly]), verbo([decreased]), complemento([hepatic, glycogen, phosphorylase, a, 'levels,', and, the, activation, of, synthase, was, initiated, without, any, delay])].
[sujeto(['The', 'X-ray', structures, of, the, 'enzyme-ligand', complexes, show, that, the, inhibitors]), verbo([bind]), complemento([preferentially, at, the, catalytic, site, of, the, enzyme, retaining, the, less, active, 'T-state', conformation])].
[sujeto(['Docking', calculations, with, 'GLIDE', in, 'extra-precision', '(', 'XP)', mode, yielded, excellent, agreement, with, 'experiment,', as, judged, by, comparison, of, the, predicted]), verbo([binding]), complemento([modes, of, the, five, ligands, with, the, crystallographic, conformations, and, the, good, correlation, between, the, docking, scores, and, the, experimental, free, binding, energies])].
[sujeto([2, -, 'Naphthyl-substituted', 'glucopyranosylidene-spiro-oxathiazole', prepared, following, a, novel, design, principle, was]), verbo([found]), complemento([to, be, the, best, known, glucose, analogue, inhibitor, of, rabbit, muscle, glycogen, phosphorylase, b, '(', 'K(i)', 160, 'nM)'])].
[sujeto(['Glucopyranosylidene', spirothiohydantoin, '(', 'TH)']), verbo([has]), complemento([been, identified, as, a, potential, inhibitor, of, both, muscle, and, liver, glycogen, phosphorylase, b, '(', 'GPb)', and, a, '(', 'GPa)', and, shown, to, diminish, liver, 'GPa', activity, in, vitro])].
[sujeto(['Kinetic', experiments]), verbo([reported]), complemento([here, show, that, 'TH', inhibits, muscle, 'GPb', competitively, with, respect, to, both, substrates, phosphate, '(', 'K(i)=2'])].
[sujeto(['The', structure, of, the, 'GPb-TH', complex]), verbo([has]), complemento([been, determined, at, a, resolution, of, 2.26, 'A', and, refined, to, a, crystallographic, 'R', value, of, 0.193, '(', 'R(free)=0'])].
[sujeto(['The', structure, of, 'GPb-TH', complex]), verbo([reveals]), complemento([that, the, inhibitor, can, be, accommodated, in, the, catalytic, site, of, 'T-state', 'GPb', with, very, little, change, of, the, tertiary, 'structure,', and, provides, a, basis, of, understanding, potency, and, specificity, of, the, inhibitor])].
[sujeto(['In', the, key, step, of, the, syntheses, 'C-(1-bromo-1-deoxy-beta-D-glycopyranosyl)formamides', were, reacted, with, cyanate, ion, to, give, 'spiro-hydantoins', with, a]), verbo([retained]), complemento([configuration, at, the, anomeric, center, as, the, major, products])].
[sujeto(['The', study, of, epimeric, pairs, of, 'D-gluco', and, 'D-xylo', configurated, 'spiro-hydantoins', and, 'N-(D-glucopyranosyl)amides', corroborated, the, role, of, specific, hydrogen, bridges, in]), verbo([binding]), complemento([the, inhibitors, to, the, enzyme])].
[sujeto(['The', synthesis, and, biochemical, screening, of, four, novel, spironucleosides, 1, -, 4, against, rabbit, liver, glycogen, phosphorylase, b, '(', 'Gpb),', along, with, molecular, modeling, studies, on, compound, 2, and, its, 4, -, hydroxy, analogue, 'VII,']), verbo([have]), complemento([been, presented])].
[sujeto(['Gpb', is, a, key, enzyme, of, glycogen, 'metabolism,', and, is, known, to, be]), verbo([involved]), complemento([in, the, control, of, diabetes, mellitus])].
[sujeto(['The', general, strategy, for, synthesis]), verbo([involved]), complemento(['base-catalyzed', condensation, of, diethyl, 2, ',', 4, -, 'dioxoimidazolidine-5-phosphonate', '(', 5, ')', with, either, 2, -, 'deoxy-D-ribose', or, 'D-ribose,', followed, by, sequential, reactions, involving, 'ring-closure', with, phenylselenenyl, chloride, and, reduction, with, 'tri-n-butyltin', hydride, catalyzed, by, azobisisobutyronitrile])].
[sujeto(['Compounds', 2, and, 4, were]), verbo([found]), complemento([to, be, weak, competitive, inhibitors, of, 'Gpb,', whereas, 1, and, 3, were, inactive])].
[sujeto(['Glycogen', phosphorylase, '(', 'GP)', is, a]), verbo([target]), complemento([for, the, treatment, of, hyperglycaemia, in, the, context, of, type, 2, diabetes])].
[sujeto(['Twelve', new, 'd-glucopyranosylidene-spiro-isoxazolines']), verbo([have]), complemento([been, prepared, from, 'O-peracylated', 'exo-D-glucals', by, 'regio-', and, stereoselective, 1, ',', 3, -, dipolar, cycloaddition, of, nitrile, oxides, generated, in, situ, by, treatment, of, the, corresponding, oximes, with, bleach])].
[sujeto(['The', most, promising, compounds, were, investigated, in, 'Zucker', 'fa/fa', rat, model, in, acute, and, 'sub-chronic', assays, and]), verbo([decreased]), complemento([hepatic, glucose, 'production,', which, is, known, to, be, elevated, in, type, 2, diabetes])].
[sujeto(['Glycogen', phosphorylase, '(', 'GP)', is, a, promising, molecular]), verbo([target]), complemento([for, the, treatment, of, 'Type', 2, diabetes])].
[sujeto(['Kinetic', and, crystallographic, study, of, the, interactions, of, these, inhibitors, with, 'GP']), verbo([has]), complemento([increased, our, understanding, of, the, importance, of, the, various, functional, groups, within, the, catalytic, site, and, has, pointed, the, way, towards, the, in, silico, prediction, and, design, of, potent, 'inhibitors,', which, are, both, synthetically, viable, and, pharmacologically, relevant])].
[sujeto(['Both', the, academia, and, health, companies]), verbo([participate]), complemento([in, the, search, of, potent, 'inhibitors,', that, might, be, suitable, for, 'long-term', treatment])].
[sujeto(['As', several, inhibitory, sites]), verbo([have]), complemento([been, identified, for, 'GP,', interest, focuses, mainly, on, structures, that, can, bind, at, either, the, 'catalytic,', the, 'allosteric,', or, the, new, allosteric, sites])].
[sujeto(['Glucose-based', motifs, and, azasugars, that]), verbo([bind]), complemento([at, the, active, site, constitute, the, most, populated, class, of, 'GPis'])].
[sujeto(['During', the, last, two, 'years,', significant, progresses]), verbo([have]), complemento([been, 'made,', since, newly, proposed, motifs, have, 'K(i)', values, in, the, low, micromolar, and, even, 'sub-', micromolar, range])].
[sujeto(['Without', ignoring, previously]), verbo([reported]), complemento(['structures,', new, series, based, on, 'β-D-glucopyranosyl-pyrimidine,', 'D-glucopyranosylidene-spiro-isoxazoline', and, 'D-glucopyranosylidene-spiro-oxathiazole', motifs, appear, promising])].
[sujeto(['While', no, inhibition, was]), verbo([found]), complemento([for, sulfonium, 'analogs,', 'D-DAB', remains, the, best, inhibitor, among, five, and, 'six-membered', iminosugars, that, showed, inhibitory, properties, toward, 'GP'])].
[sujeto(['A', study, of, 'glucagon-induced', glucose, production, in, primary, rat, hepatocytes]), verbo([has]), complemento([suggested, that, 'amylo-1,6-glucosidase', inhibitors, in, combination, with, 'GPis', may, lower, glucose, level, in, 'T2DM'])].
[sujeto(['Considering', the, limitations]), verbo([found]), complemento([for, other, potent, 'GPis', binding, at, other, sites, and, the, complexity, of, pharmacological, 'development,', the, potential, of, 'glucose-based', 'GPis', is, still, not, established, firmly, and, more, tests, with, 'cells,', 'tissues,', animals, are, required, to, better, establish, the, risks, and, merits, of, these, 'structures,', as, antidiabetic, drugs])].
[sujeto(['The', worldwide, epidemic, of, type, 2, diabetes]), verbo([has]), complemento([been, stimulating, the, quest, for, new, concepts, and, targets, for, the, treatment, of, this, incurable, disease])].
[sujeto(['A', new]), verbo([target]), complemento([is, glycogen, phosphorylase, '(', 'GP),', the, main, regulatory, enzyme, in, the, liver, responsible, for, the, control, of, blood, glucose, levels])].
[sujeto(['The', present, paper, surveys, the, recent, developments, of, this, field, achieved, mainly, in, the, last, five, 'years:', the, synthesis, and, evaluation, of, 'glucopyranosylidene-spiro-thiohydantoin', 18, '(', 'K(i)', =, 5, micro, 'M)', which]), verbo([has]), complemento([proven, equipotent, with, 16, ',', and, is, available, in, gram, 'amounts;', 'furanosylidene-', and, 'xylopyranosylidene-spiro-(thio)hydantoins', whose, ineffectiveness, '(', 'K(i)', &, 'gt;', 10, 'mM)', confirmed, the, high, specificity, of, the, catalytic, site, of, 'GP', towards, the, 'D-glucopyranosyl', 'unit;', &, 'quot;open"', hydantoins, like, methyl, 'N-(1-carboxamido-D-glucopyranosyl)carbamate', 37, '(', 'K(i)', =, 16, micro, 'M)', and, 'N-acyl-N\'-(beta-D-glucopyranosyl)ureas', among, them, the, to, date, best, glucose, analog, inhibitor, 'N-(2-naphthoyl)-N\'-(beta-D-glucopyranosyl)urea', '(', 35, ',', 'K(i)', =, 0.4, micro, 'M)', which, can, also, bind, to, the, 'so-called', new, allosteric, site, of, 'GP;', 'C-(beta-D-glucopyranosyl)heterocycles', '(', 'tetrazole,', 1, ',', 3, ',', 4, -, 'oxadiazoles,', benzimidazole, '(', 'K(i)', =, 11, micro, 'M),', and, 'benzothiazole)'])].
[sujeto(['Iminosugars', like, isofagomine, '(', 45, ',', 'IC(50)', =, 0.7, micro, 'M),', noeuromycin, '(', 53, ',', 'IC(50)', =, 4, micro, 'M),', and, azafagomine, '(', 54, ',', 'IC(50)', =, 13.5, micro, 'M)', also]), verbo([bind]), complemento([strongly, to, the, active, site, of, 'GP,', 'however,', substitution, on, the, nitrogens, makes, the, binding, weaker])].
[sujeto(['Physiological', investigations]), verbo([have]), complemento([been, carried, out, with, 'N-acetyl-beta-D-glucopyranosylamine', 6, ',', 'spiro-thiohydantoin', 18, ',', isofagomine, 45, ',', and, 'DAB', 56, to, underline, the, potential, use, of, these, compounds, in, the, treatment, of, type, 2, diabetes])].
[sujeto(['Computational', methods]), verbo([suggest]), complemento([to, synthesize, further, anomerically, bifunctional, glucose, derivatives, which, may, be, good, inhibitors, of, 'GP'])].
[sujeto(['To', review, preclinical, and, clinical, pharmacokinetic, studies, of, the, three, most, important, chemotherapy, drugs, used, for, intraocular, retinoblastoma, and, the, contribution, of, the]), verbo([reported]), complemento([results, to, optimize, treatment])].
[sujeto(['Others,', despite, encouraging, preclinical, data, as]), verbo([reported]), complemento([for, periocular, topotecan, did, not, correlate, with, clinical, use])].
[sujeto(['Nonetheless,', results, obtained, in, preclinical, models, should, be]), verbo([translated]), complemento([with, care, to, the, clinics])].
[sujeto(['This', antimetabolite]), verbo([has]), complemento([demonstrated, efficacy, in, clinical, 'trials,', including, a, global, phase, 3, trial, in, metastatic, colorectal, cancer])].
[sujeto(['As', this, agent]), verbo([has]), complemento([shown, activity, greater, than, cisplatin, in, small, cell, lung, cancer, xenograft, mouse, 'models,', the, objective, of, this, study, was, to, evaluate, 'TAS-102', in, the, 'second-line', treatment, of, small, cell, lung, cancer])].
[sujeto(['Patients']), verbo([requiring]), complemento(['second-line', chemotherapy, for, treatment, of, small, cell, lung, 'cancer,', either, refractory, or, sensitive, to, frontline, 'platinum-based', 'chemotherapy,', were, enrolled])].
[sujeto(['Similar', to, the, results, of, intracellular, uptake, 'study,', it, was]), verbo([found]), complemento([that, '(', 131, ')', 'I-TPT', could, more, interact, with, the, cancer, 'DNA', than, healthy, 'DNA', according, to, the, impedimetric, results])].
[sujeto(['(', 131, ')', 'I-TPT', is, promising, in, terms, of, a, new]), verbo([nuclear]), complemento([imaging, agent, for, lung, cancer])].
[sujeto(['In', this, study, the]), verbo([binding]), complemento([of, the, topoisomerase, 'I', inhibitor, 'drug,', topotecan, to, hemoglobin, was, probed, using, various, biophysical, and, microcalorimetry, techniques])].
[sujeto(['Spectrofluorimetric', data, confirmed, the, static, nature, of, the, quenching, mechanism, of, the, protein]), verbo([induced]), complemento([by, the, drug])].
[sujeto(['Synchronous', fluorescence, study, revealed, an]), verbo([increase]), complemento([in, the, polarity, around, the, 'Trp', residues, of, the, protein, while, atomic, force, microscopy, study, enabled, to, obtain, images, of, the, bound, molecules])].
[sujeto(['Isothermal', titration, calorimetry, studies, indicated, an, exothermic]), verbo([binding]), complemento([with, a, negative, 'Gibbs', energy, 'change;', ionic, strength, variation, suggested, a, greater, contribution, from, 'non-polyelectrolytic', forces, in, the, binding, process])].
[sujeto(['Differential', scanning, calorimetry, studies, indicated, an]), verbo([increased]), complemento([thermal, stabilization, of, the, protein, upon, topotecan, binding, which, is, also, in, close, agreement, with, the, results, obtained, from, absorbance, and, circular, dichroism, melting, studies])].
[sujeto(['Overall', this, manuscript, presents, results, on, the, molecular, interaction, from, structural, and, energetic, perspectives]), verbo([providing]), complemento([an, in, depth, insight, into, 'drug-protein', interaction])].
[sujeto(['A', single, dose, of, topotecan, ointment]), verbo([increased]), complemento([threefold, and, sevenfold, the, aqueous, humor, 'Cmax', ',', and, exposure, compared, to, the, aqueous, formulation])].
[sujeto(['Topotecan', ointment, may]), verbo([translate]), complemento([to, the, clinical, treatment, of, anterior, segment, disseminated, retinoblastoma])].
[sujeto(['However,', detailed, knowledge, of, the, initial, molecular, events, in, the, response, of, cancer, cells, to, these, chemotherapeutic, and, stress, 'responses,', and, how, these]), verbo([lead]), complemento([to, the, development, of, 'chemoresistance,', remains, incompletely, understood])].
[sujeto(['Using', microRNA, array, and, washout, and, rechallenge, 'experiments,', we]), verbo([found]), complemento([that, short, term, treatment, of, leukemia, cells, with, etoposide, led, a, few, days, later, to, transient, resistance, that, was, associated, with, a, corresponding, transient, increase, in, expression, of, 'ABCB1', 'mRNA,', as, well, as, microRNA, '(', 'miR)-135b', and, 'miR-196b'])].
[sujeto(['This', phenomenon, was]), verbo([associated]), complemento([with, 'short-term', exposure, to, genotoxic, 'agents,', such, as, 'etoposide,', 'topotecan,', doxorubicin, and, ionizing, 'radiation,', but, not, agents, that, do, not, directly, damage, 'DNA'])].
[sujeto(['Treatment', of, leukemic, cells, with, either, 5, -, 'aza-deoxycytidine', or, tricostatin, 'A', produced, similar]), verbo([increased]), complemento([expression, of, 'ABCB1,', 'miR-135b,', and, 'miR-196b,', suggesting, a, role, for, epigenetic, regulation, of, this, phenomenon])].
[sujeto(['Bioinformatics', analyses, revealed, that, 'CACNA1E,', 'ARHGEF2,', 'PTK2,', 'SIAH1,', 'ARHGAP6,', and, 'NME4', may, be]), verbo([involved]), complemento([in, the, initial, events, in, the, development, of, drug, resistance, following, the, upregulation, of, 'ABCB1,', 'miR-135b', and, 'miR-196b'])].
[sujeto(['In', 'summary,', we]), verbo([report]), complemento([herein, that, 'short-term', exposure, of, cells, to, 'DNA', damaging, agents, leads, to, transient, drug, 'resistance,', which, is, associated, with, elevations, in, 'ABCB1,', 'miR-135b', and, 'miR-196b,', and, suggests, novel, components, that, may, be, involved, in, the, development, of, anticancer, drug, resistance])].
[sujeto(['The', herbal, medicine]), verbo([has]), complemento([been, used, as, 'anti-cancer', and, 'anti-inflammatory', drug, in, local, folk, medicine, for, several, hundred, years])].
[sujeto(['We']), verbo([found]), complemento([that, a, myrsinol, 'diterpene,', 'J196-10-1', could, reverse, multidrug, resistance])].
[sujeto(['The', diterpene]), verbo([inhibited]), complemento(['P-gp', mediated, efflux, and, did, not, alter, transcription, of, the, target, gene, significantly])].
[sujeto(['The', compound]), verbo([stimulated]), complemento(['ATP', hydrolysis, at, a, low, concentration, and, inhibited, it, at, a, high, concentration])].
[sujeto(['J196-10-1']), verbo([inhibits]), complemento(['P-gp', competitively, and, reverses, 'P-gp', induced, 'MDR', in, breast, cancer, cells])].
[sujeto(['Although', 'Camptothecin', and, its, analogs, as, 'Topoisomerase', 'I', poisons, can, effectively, treat, 'cancers,', serious, drug, resistance]), verbo([has]), complemento([been, identified, for, this, class, of, drugs])].
[sujeto(['Recent', computational, studies]), verbo([have]), complemento([indicated, that, the, mutations, near, the, active, binding, site, of, the, drug, can, significantly, weaken, the, drug, binding, and, cause, drug, resistance])].
[sujeto(['However,', only, 'Topotecan', and, three, mutations]), verbo([have]), complemento([been, previously, analyzed])].
[sujeto(['Here', we, present, a, comprehensive]), verbo([binding]), complemento([study, of, 10, 'Topoisomerase', 'I', mutants, '(', 'N722S,', 'N722A,', 'D533G,', 'D533N,', 'G503S,', 'G717V,', 'T729A,', 'F361S,', 'G363C,', and, 'R364H)', and, 8, poisons, including, 7, 'Camptothecin', analogs, as, well, as, a, new, generation, 'Topoisomerase', 'I', 'drug,', 'Lucanthone'])].
[sujeto(['Utilizing', 'Glide', docking, followed, by, 'MMGBSA', 'calculations,', we, determined, the]), verbo([binding]), complemento([energy, for, each, complex])].
[sujeto(['We', examine, the, relative]), verbo([binding]), complemento([energy, changes, with, reference, to, the, wild, 'type,', which, are, linked, to, the, degree, of, drug, resistance])].
[sujeto(['On', this, set, of, mutant, 'complexes,', 'Topotecan', and, 'Camptothecin', showed, much, smaller]), verbo([binding]), complemento([energies, than, a, set, of, new, 'Camptothecin', derivatives, '(', 'Lurtotecan,', 'SN38,', 'Gimatecan,', 'Exatecan,', and, 'Belotecan)', currently, under, clinical, trials])].
[sujeto(['In', addition, to, a, good, agreement, on, the, 'MMGBSA']), verbo([binding]), complemento([energy, 'change,', our, simulation, data, also, shows, there, is, larger, conformation, fluctuation, upon, the, mutations])].
[sujeto(['Few', randomized, trials]), verbo([have]), complemento([been, conducted, in, children, with, 'relapsed/refractory', neuroblastoma, and, data, about, outcomes, including, 'progression-free', survival, '(', 'PFS)', in, these, patients, are, scarce])].
[sujeto(['The', response, rate, was, 33, '%', overall, '(', 33, /, 99, :, 14, 'CR,', 11, 'CRi,', 8, 'PR)', but, was, 64, '%', '(', 14, /, 22, ')', for, patients, with, antecedent, or]), verbo([associated]), complemento([aggressive, 'MPNs', or, 'CMML'])].
[sujeto(['A', single, 80, mg, dose, of, 'veliparib,', as, well, as, veliparib, in, combination, with, topotecan, +, 'carboplatin,']), verbo([induced]), complemento(['DNA', damage, as, manifested, by, histone, 'H2AX', phosphorylation, in, 'CD34+', leukemia, 'cells,', with, greater, phosphorylation, in, cells, from, responders])].
[sujeto(['The', two]), verbo([eras]), complemento([encompassed, 2008, to, 2012, '(', 'intra-arterial', chemotherapy, 'alone,', 'Era', 'I)', and, 2012, to, 2015, '(', 'intra-arterial', chemotherapy, plus, intravitreal, 'chemotherapy,', 'Era', 'II)'])].
[sujeto(['Four', of, the, eyes, that, initiated, therapy, in, 'Era', 'I', later]), verbo([required]), complemento([intravitreal, chemotherapy, during, 'Era', 'II'])].
[sujeto(['The', enucleation, rate, was, 0, '%', for, groups, 'B', and, 'C', in, both]), verbo([eras]), complemento([and, 'non-significant', for, group, 'D', '(', 23, '%', vs, 13, '%', ')'])].
[sujeto(['The', current]), verbo([era]), complemento([of, retinoblastoma, management, using, 'intra-arterial', chemotherapy, plus, additional, intravitreal, chemotherapy, '(', as, needed, for, vitreous, 'seeding)', has, improved, globe, salvage, in, eyes, with, advanced, retinoblastoma])].
[sujeto(['The', anticancer, drugs, camptothecin, '(', 'CPT)', and, topotecan, '(', 'TPT)', are, known, 'DNA', topoisomerase, 'I', inhibitors, which]), verbo([cause]), complemento(['DNA', damage, and, lead, to, cell, death])].
[sujeto(['In', this, study, we]), verbo([provide]), complemento([evidence, that, 'CPT', and, 'TPT', also, interfere, with, the, elements, of, cytoskeleton, -, microtubules, and, actin, filaments, which, could, be, partly, responsible, for, their, cytotoxic, properties])].
[sujeto(['CPT', and, 'TPT', apparently, affected, microtubule, structures, in, living, cells, '(', 'Hela', and, 'U2OS)', and]), verbo([inhibited]), complemento([tubulin, polymerization, in, vitro, with, 'IC50', values, of, 74.57, '±9'])].
[sujeto(['CPT', and, 'TPT']), verbo([induced]), complemento(['G2/M', arrest, and, promoted, the, population, to, 76.94, '±11'])].
[sujeto(['Current', treatment, of, retinoblastoma]), verbo([involves]), complemento([using, the, maximum, dose, of, chemotherapy, that, induces, tumor, control, and, is, tolerated, by, patients])].
[sujeto(['The', impact, of, dose, and, schedule, on, the, cytotoxicity, of, chemotherapy]), verbo([has]), complemento([not, been, studied])].
[sujeto(['Our', aim, was, to]), verbo([gain]), complemento([insight, into, the, cytotoxic, and, antiangiogenic, effect, of, the, treatment, scheme, of, chemotherapy, used, in, retinoblastoma, by, means, of, different, in, vitro, models, and, to, evaluate, potential, effects, on, 'multi-drug', resistance, proteins])].
[sujeto(['Two', commercial, and, two, 'patient-derived', retinoblastoma, cell, types, and, two, human, vascular, endothelial, cell, types, were, exposed, to]), verbo([increasing]), complemento([concentrations, of, melphalan, or, topotecan, in, a, conventional, '(', single, 'exposure)', or, metronomic, '(', 7, -, day, continuous, 'exposure)', treatment, scheme])].
[sujeto(['The', concentration, of, chemotherapy]), verbo([causing]), complemento([a, 50, '%', decrease, in, cell, proliferation, '(', 'IC50)', was, determined, by, 'MTT', and, induction, of, apoptosis, was, evaluated, by, flow, cytometry])].
[sujeto(['A', significant]), verbo([decrease]), complemento([in, the, 'IC50', '(', 'median,', 13, -, 'fold;', 'range:', 3, -, 23, ')', was, observed, following, metronomic, chemotherapy, treatment, in, retinoblastoma, and, endothelial, cell, types, compared, to, conventional, treatment, '(', 'p<0'])].
[sujeto(['Metronomic', topotecan, or, melphalan, significantly]), verbo([inhibited]), complemento([in, vitro, tube, formation, in, 'HUVEC', and, 'EPC', compared, to, 'vehicle-treated', cells, '(', 'p<0'])].
[sujeto(['Both', treatment, schemes]), verbo([induced]), complemento([apoptosis, 'and/or', necrosis, in, all, cell, models])].
[sujeto(['In', 'mice,', continuous, topotecan]), verbo([lead]), complemento([to, significantly, lower, tumor, volumes, compared, to, conventional, treatment, after, 14, days, of, treatment, '(', 'p<0'])].
[sujeto(['Continuous', exposure, to, melphalan, or, topotecan]), verbo([increased]), complemento([the, chemosensitivity, of, retinoblastoma, and, endothelial, cells, to, both, chemotherapy, agents, with, lower, 'IC50', values, compared, to, 'short-term', treatment])].
[sujeto(['None', of, the, dosing, modalities]), verbo([induced]), complemento([multidrug, resistance, mechanisms, while, apoptosis, was, the, mechanism, of, cell, death, after, both, treatment, schedules])].
[sujeto(['Disease', control, rate, is, lower, than]), verbo([reported]), complemento([for, 'SCLC'])].
[sujeto(['Cordyceps']), verbo([has]), complemento([long, been, used, to, treat, cancer])].
[sujeto(['To', further, investigate, the, mechanism, that, 'MHP-1']), verbo([inhibited]), complemento([breast, cancer, 'EMT,', western, 'blot,', 'ELISA,', luciferase, reporter, gene, 'assay,', 'siRNA,', quantitative, 'PCR,', 'immunohistochemistry,', and, xenograft, tumor, model, were, performed])].
[sujeto(['MHP-1']), verbo([inhibited]), complemento([breast, cancer, cell, migration, but, did, not, cause, any, cytotoxicity])].
[sujeto(['MHP-1', significantly, surpressed, breast, cancer, 'EMT,', and, slightly]), verbo([decreased]), complemento(['MMP-9', secretion])].
[sujeto(['TGF-β', signaling, was, selectively]), verbo([inhibited]), complemento([after, 'MHP-1', 'treatment,', and, other, 'EMT-related', 'pathways,', like, 'Wnt', and, 'Notch,', were, not, affected])].
[sujeto(['Dual', luciferase, assay, and, 'Smad2/3', phosphorylation, analysis, indicated, that, 'MHP-1']), verbo([suppressed]), complemento(['TGF-β', signaling])].
[sujeto(['Similarly,', the, effect, of, 'TPT', on, resistant, 'MCF-7', cells, was, also]), verbo([increased]), complemento([either, by, 'ALK5', '(', 'TGFβRI)', siRNA, or, by, a, small, molecular, inhibitor, of, 'ALK5,', 'SB-431542'])].
[sujeto(['MHP-1']), verbo([inhibited]), complemento([breast, cancer, metastasis, in, the, 'MDA-MB-231', xenograft, 'model,', and, the, immunohistochemical, staining, showed, dramatically, decreased, expression, of, 'ALK5', and, 'vimentin,', and, increased, expression, of, 'E-cadherin'])].
[sujeto(['MHP-1', significantly]), verbo([inhibited]), complemento([breast, cancer, metastasis, and, restored, drug, sensitivity, in, 'TPT-resistant', cells, via, 'down-regulation', of, 'TGF-β', signaling, and, 'EMT', program])].
[sujeto(['The', high, mortality, of, ovarian, cancer, patients, results, from, the, failure, of, treatment]), verbo([caused]), complemento([by, the, inherent, or, acquired, chemotherapy, drug, resistance])].
[sujeto(['It', was]), verbo([reported]), complemento([that, overexpression, of, aldehyde, dehydrogenase, 'A1', '(', 'ALDH1A1)', in, cancer, cells, can, be, responsible, for, the, development, of, drug, resistance])].
[sujeto(['To', add, the, high, expression, of, the, drug, transporter, proteins, the, 'ALDHA1', is, considered, as, a, molecular]), verbo([target]), complemento([in, cancer, therapy])].
[sujeto(['ATRA', treatment]), verbo([led]), complemento([to, downregulation, of, the, 'ALDH1A1,', 'P-gp', and, 'BCRP', proteins])].
[sujeto(['DEAB', treatment]), verbo([led]), complemento([to, downregulation, of, the, 'P-gp', protein, and, 'BCRP', transcript, and, protein])].
[sujeto(['Developing', more, specific, 'ALDH1A1', inhibitors, can]), verbo([increase]), complemento([chemotherapy, effectiveness, in, ovarian, cancer])].
[sujeto(['Compelling', evidence]), verbo([has]), complemento([shown, that, the, length, of, a, 'person\'s', life, is, dictated, by, the, limited, number, of, times, that, a, human, cell, can, divide])].
[sujeto(['The', enzyme, telomerase]), verbo([has]), complemento([been, shown, to, bind, to, and, extend, the, length, of, telomeres])].
[sujeto(['Thus,', strategies, for]), verbo([activating]), complemento([telomerase, may, help, maintain, telomere, length, 'and,', 'thus,', may, lead, to, improved, health, during, aging])].
[sujeto(['Results', '•', 'Certain', of, the, compounds]), verbo([increased]), complemento([telomerase, 'activity,', and, combinations, of, the, 'top-ranking', compounds, were, able, to, increase, telomerase, activity, 'significantly,', from, 51, '%', to, 290, '%', ',', relative, to, controls])].
[sujeto(['Conclusions', '•', 'The', results]), verbo([have]), complemento([confirmed, that, many, naturally, occurring, compounds, hold, the, potential, to, activate, telomerase, and, that, certain, of, those, compounds, have, demonstrated, synergistic, effects, to, produce, more, potent, blends])].
[sujeto(['Given', the, relationship, between, telomere, 'shortening,', 'aging,', and, the, decline, of, tissue, 'function,', it, is, reasonable, to, hypothesize, that, such, 'telomerase-activating', blends, may]), verbo([have]), complemento(['health-promoting', 'benefits,', particularly, in, relation, to, 'aging-associated', conditions])].
[sujeto(['Treatment', of, 'retinoblastoma,', the, most, common, primary, ocular, malignancy, in, 'children,']), verbo([has]), complemento([greatly, improved, over, the, last, decade])].
[sujeto(['The', aim, of, this, project, was, to, develop, an, ocular, drug, delivery, system, for, topotecan, '(', 'TPT)', loaded, in, biocompatible, hydrogels, of, 'poly(ε-caprolactone)-poly(ethyleneglycol)-poly(ε-caprolactone)', block, copolymers, '(', 'PCL-PEG-PCL)', for, sustained, 'TPT']), verbo([release]), complemento([in, the, vitreous, humor])].
[sujeto(['Rheological', properties, and, in, vitro, and, in, vivo, 'TPT']), verbo([release]), complemento([were, studied])].
[sujeto(['In', vitro]), verbo([release]), complemento([profiles, showed, a, sustained, release, of, 'TPT', from, 'PCL-PEG-PCL', up, to, 7, days, and, drug, loading, did, not, affect, the, release, pattern])].
[sujeto(['Intra-arterial', chemotherapy]), verbo([involves]), complemento([the, administration, of, a, 'super-selective', drug, through, the, ophthalmic, 'artery,', resulting, in, better, ocular, penetration, and, low, systemic, toxicity])].
[sujeto(['The', aim, of, this]), verbo([report]), complemento([was, to, evaluate, the, feasibility, of, 'intra-arterial', chemotherapy, in, a, large, referral, center, in, 'Mexico', 'City'])].
[sujeto(['Super-selective', 'intra-arterial', chemotherapy, is, safe, and, effective, for]), verbo([preventing]), complemento([the, enucleation, of, 55, '%', of, affected, eyes, in, this, group, of, patients])].
[sujeto(['The', 'X-ray', powder, diffraction, data]), verbo([suggested]), complemento([the, intercalation, of, 'VP16', into, layers, with, the, increased, basal, spacing, from, 0.84, -, 1.18, nm, was, successful])].
[sujeto(['The', mechanism, of, 'VP16-LDH']), verbo([release]), complemento([in, the, phosphate, buffered, saline, solution, at, pH, 7.4, is, likely, controlled, by, the, diffusion, of, 'VP16', anions, from, inside, to, the, surface, of, 'LDH', particles])].
[sujeto(['A', novel, cyclolignanic, 'quinone,', 7, -, 'acetyl-3\',4\'-didemethoxy-3\',4\'-dioxopodophyllotoxin', '(', 'CLQ),']), verbo([inhibits]), complemento([topoisomerase, 'II', '(', 'TOPO', 'II)', activity])].
[sujeto(['Semiquinone', 'EPR', spectra, change, with, 'quinone/GSH', mol, 'ratio,']), verbo([suggesting]), complemento([covalent, binding, of, 'GSH', to, the, quinones])].
[sujeto(['These', orthoquinones, also, react, with, nucleophilic, groups, from, 'BSA', to]), verbo([bind]), complemento([covalently, under, anaerobic, conditions])].
[sujeto(['BSA', thiol, consumption, and, covalent]), verbo([binding]), complemento([by, these, quinones, are, enhanced, by, 'MgCl(2)'])].
[sujeto(['Density', functional, calculations, predict, the, observed, 'blue-shifts', in, the, absorption, spectra, peaks, and, large]), verbo([decreases]), complemento([in, the, partial, negative, charge, of, electrophilic, carbons, at, the, quinone, ring, when, the, quinones, are, complexed, to, 'Mg(+2)'])].
[sujeto(['These', observations]), verbo([suggest]), complemento([a, possible, role, of, 'Mg(+2)', chelation, by, these, quinones, in, increasing, 'TOPO', 'II', thiol, 'and/or', 'amino/imino', reactivity, with, these, orthoquinones])].
[sujeto(['The', anti, cancer, drug, methyl, 'N-(4\'-(9-acridinylamino)-3-methoxy-phenyl)', methane, sulfonamide, '(', 'mAMSA)']), verbo([targets]), complemento([human, 'DNA', topoisomerase, 'IIbeta'])].
[sujeto(['We']), verbo([report]), complemento([here, the, first, selection, with, mAMSA, of, resistant, human, topoisomerase, 'IIbeta'])].
[sujeto([betaP732L, is, functional, but]), verbo([has]), complemento([reduced, strand, passage, activities, and, altered, 'DNA', binding, compared, with, the, 'wild-type', protein])].
[sujeto(['It']), verbo([has]), complemento([drastically, altered, cleavage, properties, compared, with, the, 'wild-type', enzyme])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([of, a, topoisomerase, 'II', mutation, abolishing, the, ability, of, calcium, to, support, 'DNA', cleavage])].
[sujeto(['This']), verbo([provides]), complemento([evidence, for, metal, ion, requirement, for, the, phosphoryltransfer, reaction, of, topoisomerase, 'II', and, a, possible, mechanism, for, drug, resistance])].
[sujeto(['Weekly', administrations, of, 'CPT-11', plus, cisplatin, together, with, 'Oral', 'Alkalization', and, 'Control', of, 'Defecation']), verbo([provide]), complemento([a, practical, and, well, tolerated, regimen, that, was, active, for, refractory, or, relapsed, small, cell, lung, cancer])].
[sujeto(['Since', the, toxic, events]), verbo([induced]), complemento([by, cobalt, resemble, those, of, topoisomerase, 'II', 'poisons,', the, effect, of, the, metal, on, human, topoisomerase, 'IIalpha', was, examined])].
[sujeto(['The', level, of, 'enzyme-mediated', 'DNA', scission]), verbo([increased]), complemento([6, -, 13, -, fold, when, 'cobalt(II)', replaced, 'magnesium(II)', in, cleavage, reactions])].
[sujeto(['Cobalt(II)']), verbo([stimulated]), complemento([cleavage, at, all, 'DNA', sites, observed, in, the, presence, of, 'magnesium(II),', and, the, enzyme, cut, 'DNA', at, several, &, 'quot;cobalt-specific"', sites])].
[sujeto(['The']), verbo([increased]), complemento([level, of, 'DNA', cleavage, in, the, presence, of, 'cobalt(II)', was, partially, due, to, a, decrease, in, the, rate, of, 'enzyme-mediated', religation])].
[sujeto(['Topoisomerase', 'IIalpha']), verbo([retained]), complemento([many, of, its, catalytic, properties, in, reactions, that, included, 'cobalt(II),', including, sensitivity, to, the, anticancer, drug, etoposide, and, the, ability, to, relax, and, decatenate, 'DNA'])].
[sujeto(['Finally,', 'cobalt(II)']), verbo([stimulated]), complemento([topoisomerase, 'IIalpha-mediated', 'DNA', cleavage, in, the, presence, of, 'magnesium(II)', in, purified, systems, and, in, human, 'MCF-7', cells])].
[sujeto(['These', findings, demonstrate, that, 'cobalt(II)', is, a, topoisomerase, 'II', poison, in, vitro, and, in, cultured, cells, and]), verbo([suggest]), complemento([that, at, least, some, of, the, genotoxic, effects, of, the, metal, are, mediated, through, topoisomerase, 'IIalpha'])].
[sujeto(['There', was, a, dramatic]), verbo([decrease]), complemento([in, serum, 'bicarbonate,', 'potassium,', and, magnesium, levels, immediately, after, 'chemotherapy,', and, they, remained, significantly, decreased, throughout, the, 'patient\'s', hospital, 'stay,', despite, massive, replacement, efforts, '(', 'P', ranging, between, &, 'lt;', 0.008, and, &, 'lt;', 0.001, ')'])].
[sujeto(['The', mobility, of, the, native, enzyme, on, a, 'Superose', 12, column]), verbo([suggests]), complemento([that, the, active, form, of, the, enzyme, is, a, monomer])].
[sujeto(['The', apparent, 'K(m)', for, the, substrate, 'p-nitrophenyl', phosphate, is, 1.3, mM, and, the, enzyme, is]), verbo([inhibited]), complemento([by, inorganic, phosphate])].
[sujeto(['Enzymatic', activity, is]), verbo([enhanced]), complemento([by, the, addition, of, divalent, cations, such, as, 'Mg+2', and, 'Mn+2', and, inhibited, by, addition, of, a, chelator, such, as, 'EDTA', suggesting, a, metal, ion, requirement])].
[sujeto(['The', enzyme, was]), verbo([found]), complemento([to, be, an, inexpensive, catalyst, for, the, conversion, of, etoposide, phosphate, to, etoposide, in, the, manufacture, of, this, 'anti-tumor', compound])].
[sujeto(['A', 3, -, 'year-old', boy, had, localized, esthesioneuroblastoma, and, received, 2, courses, of, carboplatin, '(', 200, 'mg/m2/day', during, a, 1, -, hour, infusion, for, 3, consecutive, 'days)']), verbo([associated]), complemento([with, etoposide, '(', 150, 'mg/m2/day', after, 'carboplatin)'])].
[sujeto(['The', association, of, urinary, bicarbonate]), verbo([loss]), complemento([with, elevated, 'N-acetyl-beta-glucosaminidase', suggested, a, proximal, tubular, damage])].
[sujeto(['Standard', doses, of, carboplatin, may]), verbo([lead]), complemento([to, recurrent, renal, salt, wasting, in, children, with, initially, normal, renal, function])].
[sujeto(['Cytotoxic', drugs]), verbo([induce]), complemento([apoptosis, in, human, tumour, cell, lines, and, this, is, characterised, by, fragmentation, of, the, 'cell\'s', 'DNA', into, nucleosome, size, units, or, multiples, thereof])].
[sujeto(['This', contrasts, with, what]), verbo([has]), complemento([previously, been, shown, for, a, number, of, rodent, cell, types, in, which, apoptosis, has, been, studied])].
[sujeto(['The', lack, of, ion, sensitivity, is, also]), verbo([found]), complemento([in, the, nuclei, of, peripheral, blood, 'granulocytes,', indicating, the, data, are, not, peculiar, to, cell, lines])].
[sujeto(['The', previously, demonstrated, lack, of, calcium, flux, in, 'HL-60', cells, undergoing, 'apoptosis,', and, the, current, demonstration, of, a, lack, of, an, endonuclease, dependent, on, this, ion, for, its, 'activity,']), verbo([suggest]), complemento([that, the, mechanism, of, apoptosis, in, human, cells, may, be, different, from, that, in, rodent, cells])].
[sujeto(['Based', on, the, observation, that, 'VP-16-induced', 'DNA', damage, can, be, demonstrated, in, isolated, nuclei, but, not, in, purified, 'DNA,', and, that, this, effect, is, 'temperature-dependent,', it, is, postulated, that, the, mechanism, of, action, of, 'VP-16']), verbo([involves]), complemento([an, essential, intranuclear, 'event,', perhaps, 'enzyme-mediated,', which, is, a, prerequisite, for, the, cleavage, of, 'DNA'])].
[sujeto(['Using', alkaline, elution, to, assay, 'single-strand', breaks, in, isolated, 'L1210', 'nuclei,', we]), verbo([have]), complemento([further, characterized, conditions, influencing, this, putative, intranuclear, reaction])].
[sujeto(['We']), verbo([have]), complemento([found, drug, activity, to, be, dependent, on, magnesium, and, pH, and, to, be, stimulated, by, low, concentrations, of, 'ATP', '(', 0.05, -, 1, 'mM),', an, effect, which, was, not, observed, with, a, nonhydrolyzable, analog, of, 'ATP'])].
[sujeto(['Heat-labile', activity, in, a]), verbo([nuclear]), complemento(['non-histone', protein, extract, was, critical, to, 'VP-16-mediated', 'DNA', damage])].
[sujeto(['Combined', treatment, of, magnolol, with, chemotherapeutic, 'drugs,', such, as, gemcitabine, and, cisplatin, '(', 'TGCM)', or, gemcitabine, '(', 'TGM),', markedly, attenuates, the, body, weight]), verbo([loss]), complemento([and, skeletal, muscle, atrophy, compared, with, conventional, chemotherapy, '(', 'TGC)'])].
[sujeto(['The', antiatrophic, effect, of, magnolol, may, be]), verbo([associated]), complemento([with, inhibition, of, myostatin, and, activin, 'A', 'formation,', as, well, as, 'FoxO3', transcriptional, activity, resulting, from, 'Akt', 'activation,', thereby, suppressing, ubiquitin, ligases, 'MuRF-1', and, 'MAFbx/atrogin-1', 'expression,', as, well, as, proteasomal, enzyme, activity])].
[sujeto(['The']), verbo([decreased]), complemento([food, 'intake,', and, intestinal, injury, and, dysfunction, observed, in, the, mice, of, 'TGC', group, were, significantly, improved, in, the, 'TGCM', and, 'TGM', groups])].
[sujeto(['Moreover,', the]), verbo([increased]), complemento([inflammatory, responses, evidenced, by, elevation, of, proinflammatory, cytokine, formation, and, 'NF-κB', activation, occurred, in, the, atrophying, muscle, of, 'TGC', group, were, markedly, inhibited, in, mice, of, combined, treatment, with, magnolol])].
[sujeto(['In', 'summary,', these, findings, support, that, magnolol, is, a, promising, chemopreventive, supplement, for]), verbo([preventing]), complemento(['chemotherapy-induced', skeletal, muscle, atrophy, associated, with, cancer, cachexia, by, suppressing, muscle, protein, 'degradation,', and, inflammatory, 'responses,', as, well, as, increasing, 'IGF-1-mediated', protein, synthesis])].
[sujeto(['Cholinesterase', inhibition, is, a, vital]), verbo([target]), complemento([for, the, development, of, novel, and, mechanism, based, 'inhibitors,', owing, to, their, role, in, the, breakdown, of, acetylcholine, '(', 'ACh)', neurotransmitter, to, treat, various, neurological, disorders, including, 'Alzheimer\'s', disease, '(', 'AD)'])].
[sujeto(['FO']), verbo([caused]), complemento([82.66, *, *, *, '(', 'IC50', 130, 'μg/ml)', and, 77.5, *, *, *, '%', '(', 'IC50', 225, 'μg/ml)', inhibitions, respectively, at, 1000, 'μg/ml', concentration])].
[sujeto(['In', 'humans,', depression, is, often]), verbo([triggered]), complemento([by, prolonged, exposure, to, psychosocial, stressors, and, is, often, associated, with, cardiovascular, comorbidity])].
[sujeto(['Mounting', evidence]), verbo([suggests]), complemento([a, role, for, endocannabinoid, signaling, in, the, regulation, of, both, emotional, behavior, and, cardiovascular, function])].
[sujeto(['Repeated', social, stress]), verbo([triggered]), complemento([biological, and, behavioral, changes, that, mirror, symptoms, of, human, 'depression,', such, as, '(', 'i)', reductions, in, body, weight, gain, and, sucrose, solution, 'preference,', '(', 'ii)', hyperactivity, of, the, 'hypothalamic-pituitary-adrenocortical', 'axis,', and, '(', 'iii)', increased, immobility, in, the, forced, swim, test])].
[sujeto(['Daily', treatment, with, 'URB694', '(', 'i)']), verbo([increased]), complemento([central, and, peripheral, anandamide, 'levels,', '(', 'ii)', corrected, 'stress-induced', alterations, of, biological, and, behavioral, 'parameters,', and, '(', 'iii)', protected, the, heart, against, the, adverse, effects, of, social, stress])].
[sujeto(['GPR120,', a, 'G', 'protein-coupled', receptor, for, 'long-chain', unsaturated, fatty, 'acids,']), verbo([has]), complemento([been, reported, to, mediate, adipogenesis, in, lipid, metabolism])].
[sujeto(['However,', whether, 'GPR120', also]), verbo([mediates]), complemento([osteogenesis, and, regulates, 'BMMSCs', remain, unclear])].
[sujeto(['In', this, 'study,', we, showed, that, 'GPR120']), verbo([targeted]), complemento([the, 'bi-potential', differentiation, of, 'BMMSCs', in, a, ligand, 'dose-dependent', manner])].
[sujeto(['High', concentrations, of, 'TUG-891', '(', a, highly, selective, agonist, of, 'GPR120)']), verbo([promoted]), complemento([osteogenesis, via, the, 'Ras-ERK1/2', 'cascade,', while, low, concentrations, elevated, 'P38', and, increased, adipogenesis])].
[sujeto(['The', administration, of, high, doses, of, 'TUG-891', rescued, 'oestrogen-deficient', bone]), verbo([loss]), complemento([in, 'vivo,', further, supporting, an, essential, role, of, 'GPR120', in, bone, metabolism])].
[sujeto(['Additionally,', the, induction, of, different, integrin, subunits, was]), verbo([involved]), complemento([in, the, cytoplasmic, regulation, of, a, 'seesaw-like', balance, between, 'ERK', and, p38, phosphorylation])].
[sujeto(['These', findings]), verbo([provide]), complemento([new, hope, for, developing, novel, remedies, to, treat, osteoporosis, by, adjusting, the, 'GPR120-mediated', differentiation, balance, of, 'BMMSCs'])].
[sujeto(['Novel', pharmacological]), verbo([targets]), complemento([have, emerged, in, the, recent, 'years,', and, attention, has, focused, on, the, endocannabinoid, '(', 'eCB)', 'system,', given, the, increasing, evidence, that, supports, its, central, role, in, 'emotion,', coping, with, stress, and, anxiety])].
[sujeto(['In', the, management, of, anxiety, 'disorders,', drug, development, strategies]), verbo([have]), complemento([left, apart, the, direct, activation, of, 'type-1', cannabinoid, receptors, to, indirectly, enhance, eCB, signalling, through, the, inhibition, of, eCB, 'deactivation,', that, 'is,', the, inhibition, of, the, fatty, acid, amide, hydrolase, '(', 'FAAH)', enzyme])].
[sujeto(['In', the, present, 'study,', we]), verbo([provide]), complemento([evidence, for, the, 'anxiolytic-like', properties, of, a, 'novel,', potent, and, selective, reversible, inhibitor, of, 'FAAH,', 'ST4070,', orally, administered, to, rodents])].
[sujeto(['ST4070', '(', 3, to, 30, 'mg/kg', per, 'os)', administered, to, 'CD1', male, mice]), verbo([induced]), complemento([an, increase, of, time, spent, in, the, exploration, of, the, open, arms, of, the, 'elevated-plus', maze])].
[sujeto(['ST4070', clearly]), verbo([inhibited]), complemento(['FAAH', activity, and, augmented, the, levels, of, two, of, its, 'substrates,', 'N-arachidonoylethanolamine', '(', 'anandamide)', and, 'N-palmitoylethanolamine,', in, 'anxiety-relevant', brain, regions])].
[sujeto(['By', 'contrast,', the, 'RE1-silencing', transcription, factor, '(', 'REST)', is]), verbo([involved]), complemento([in, the, neurotoxic, effects, following, exposure, to, polychlorinated, biphenyl, '(', 'PCB)', mixture, 'A1254'])].
[sujeto(['Further,', we, investigated, the, possible, relationship, between, the, 'non-dioxin-like', '(', 'NDL)', 'PCB-95', and, 'REST', through, 'SIRT1', to]), verbo([regulate]), complemento([neuronal, death, in, rat, cortical, neurons])].
[sujeto(['Our', results, revealed, that, 'RSV', significantly]), verbo([decreased]), complemento(['REST', gene, and, protein, levels, in, a, 'dose-', and, 'time-dependent', manner])].
[sujeto(['Interestingly,', overexpression, of, 'SIRT1', reduced, 'REST', 'expression,', whereas, 'EX-527,', an, inhibitor, of, 'SIRT1,']), verbo([increased]), complemento(['REST', expression, and, blocked, 'RSV-induced', 'REST', downregulation])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'RSV', downregulates, 'REST', through, 'SIRT1'])].
[sujeto(['In', 'addition,', 'RSV']), verbo([enhanced]), complemento([activator, protein, 1, '(', 'AP-1)', transcription, factor, 'c-Jun', expression, and, its, binding, to, the, 'REST', promoter, gene])].
[sujeto(['Intriguingly,', in, 'SH-SY5Y', cells, and, rat, cortical, neurons, the, 'NDL', 'PCB-95']), verbo([induced]), complemento([necrotic, cell, death, in, a, 'concentration-dependent', manner, by, increasing, 'REST', mRNA, and, protein, expression])].
[sujeto(['Collectively,', these, results, indicate, that, 'RSV', via, 'SIRT1']), verbo([activates]), complemento(['c-Jun,', thereby, reducing, 'REST', expression, in, 'SH-SY5Y', cells, under, physiological, conditions, and, blocks, 'PCB-95-induced', neuronal, cell, death, by, activating, the, same, 'SIRT1/c-Jun/REST', pathway])].
[sujeto(['Each', of, the, two, benzamidine, moieties, of, 16, can, potentially, be, accommodated, in, the, 'S1', pocket, of, the]), verbo([target]), complemento(['enzyme,', but, only, the, benzamidine, close, to, the, phosphonate, group, would, then, promote, an, irreversible, interaction])].
[sujeto(['The', 'Janus-faced', inhibitor, 16, was, evaluated, against, several, serine, proteases, and]), verbo([caused]), complemento([a, pronounced, inactivation, of, human, thrombin, with, a, 'second-order', rate, constant, '(', kinac, /, 'Ki)', of, 59, 500, 'M(-1)', 's(-1)'])].
[sujeto(['The', cytosolic, phospholipase, 'A2α(cPLA2α)', is, one, of, the, potential]), verbo([targets]), complemento([for, 'anti-inflammatory', 'drugs,', since, this, enzyme, plays, a, key, role, in, the, inflammation, processes, seen, in, health, 'disorders,', like, 'asthma,', allergic, 'reactions,', arthritis, and, neuronal, diseases])].
[sujeto(['This', study]), verbo([provides]), complemento([evidence, that, cPLA2α, may, be, a, relevant, target, for, 'anti-inflammatory', agents])].
[sujeto(['Photodynamic', therapy, '(', 'PDT)', is, a, technique, that, uses, light, and, a, 'photosensitizer,', converting, local, molecular, oxygen, into, singlet, 'oxygen,', which, eliminates, a]), verbo([target]), complemento([unhealthy, tissue])].
[sujeto(['It']), verbo([has]), complemento([been, increasingly, used, for, the, treatment, of, several, diseases, including, skin, disorders])].
[sujeto(['Psoriasis', is, a, chronic, inflammatory, skin, disease]), verbo([expressing]), complemento([immune, and, hyperproliferative, features])].
[sujeto(['The', antiinflammation, and, antiproliferative, activities, of, 'Di-cis-Py+', photoactivated, was, measured, by, myeloperoxidase, '(', 'MPO)', and, 'N-acetyl-β-d-glucosaminidase', '(', 'NAG)', enzyme, activity, 'assay,', measurement, of, 'IL-6,', 'IL-1β', and, 'TNF-α', 'levels,', evaluation, of, proliferating, cell]), verbo([nuclear]), complemento([antigen, '(', 'PCNA)', levels, by, immunohistochemistry, and, by, 'Western', blot])].
[sujeto(['Treatment']), verbo([involving]), complemento(['PDT', and, 'Di-cis-Py+', resulted, in, reduction, of, 'edema,', cellular, 'infiltration,', proinflammatory, 'cytokines,', as, well, as, reduced, hyperproliferation, of, the, epidermis])].
[sujeto(['All', the, evaluated, parameters, were]), verbo([promoted]), complemento([by, topical, application, of, phlogistic, agents, and, are, similar, to, that, observed, in, lesions, of, psoriatic, skin])].
[sujeto(['The', results, shows, the, advantage, of, topical, 'application,', do, not]), verbo([cause]), complemento([apparently, photosensitivity, and, have, effects, comparable, to, 'dexamethasone,', a, 'first-line', drug, for, the, treatment, of, the, disease])].
[sujeto(['The', present, study, demonstrates, that, 'fucose-containing', sulfated, polysaccharides, '(', 'FCSP)', from, brown, algae, interfere, with, the, 'CXCL12/CXCR4', axis, in, human, 'Burkitt\'s', lymphoma, cells, by]), verbo([binding]), complemento(['CXCL12', and, thereby, blocking, both, 'CXCL12-induced', 'CXCR4', receptor, activation, and, downstream, effects, like, migration, and, secretion, of, matrix, 'metalloproteinase-9'])].
[sujeto(['However,', the, mechanisms, responsible, for, the, observed, effects]), verbo([have]), complemento([not, yet, been, clarified])].
[sujeto(['Expression', of, alkaline, phosphatase, and, osteocalcin, were]), verbo([decreased]), complemento([by, both, 'Aroclor', 1254, and, 'TCDD', 'exposure,', while, the, 'PCB-congeners', 'PCB19', and, 'PCB52', slightly, induced, the, expression])].
[sujeto(['Inhibition', of, the, enzyme, fatty, acid, amide, hydrolase, '(', 'FAAH)', counteracts, 'reward-related', effects, of, nicotine, in, 'rats,', but, it]), verbo([has]), complemento([not, been, tested, for, this, purpose, in, 'non-human', primates])].
[sujeto(['Both', 'FAAH', 'inhibitors:', '(', 1, ')', blocked, 'FAAH', activity, in, brain, and, 'liver,']), verbo([increasing]), complemento([levels, of, endogenous, ligands, for, cannabinoid, and, 'α-type', peroxisome, 'proliferator-activated', '(', 'PPAR-α)', 'receptors;', '(', 2, ')', shifted, nicotine, 'self-administration', 'dose-response', functions, in, a, manner, consistent, with, reduced, nicotine, 'reward;', '(', 3, ')', blocked, reinstatement, of, nicotine, seeking, induced, by, reexposure, to, either, nicotine, priming, or, 'nicotine-associated', 'cues;', and, '(', 4, ')', had, no, effect, on, cocaine, or, food, 'self-administration'])].
[sujeto(['In', additional, experiments, in, 'rats,', 'URB694', was, devoid, of, 'THC-like', or, 'nicotine-like', interoceptive, effects, under, 'drug-discrimination', 'procedures,', and, neither, of, the, 'FAAH', inhibitors]), verbo([induced]), complemento([dopamine, release, in, the, nucleus, accumbens, 'shell--consistent', with, their, lack, of, robust, reinforcing, effects, in, monkeys])].
[sujeto(['Overall,', both, 'URB597', and, 'URB694', show, promise, for, the, initialization, and, maintenance, of, smoking, cessation, because, of, their, ability, to, block, the, rewarding, effects, of, nicotine, and]), verbo([prevent]), complemento([nicotine, 'priming-induced', and, 'cue-induced', reinstatement])].
[sujeto(['Periapical', 'disease,', an, inflammatory, disease, mainly]), verbo([caused]), complemento([by, dental, 'caries,', is, one, of, the, most, prevalent, infectious, diseases, of, 'humans,', affecting, both, children, and, adults])].
[sujeto(['The', infection, travels, through, the, 'root,']), verbo([leading]), complemento([to, 'inflammation,', bone, 'destruction,', and, severe, pain, for, the, patient])].
[sujeto(['While', 'Ctsk', was, originally]), verbo([found]), complemento([in, osteoclasts, as, an, 'osteoclast-specific', lysosomal, 'protease,', we, were, surprised, to, find, that, 'ODN', can, suppress, the, 'bacterium-induced', immune, response, as, well, as, bone, destruction, in, the, lesion, area])].
[sujeto(['Immunohistochemical', and, immunofluorescent, staining, show, that, 'ODN', treatment, dramatically]), verbo([decreased]), complemento(['F4/80+', macrophages, and, 'CD3+', 'T', cells, in, the, lesion, areas, 42, days, after, infection])].
[sujeto(['The', levels, of, mRNA, for, 'Toll-like', receptors, 4, ',', 5, ',', and, 9, also, largely]), verbo([decreased]), complemento([in, the, 'ODN-treated', disease, group])].
[sujeto(['Our', results, demonstrated, that, 'ODN', can]), verbo([inhibit]), complemento([endodontic, disease, 'development,', bone, 'erosion,', and, immune, response])].
[sujeto(['These', results, indicate, that, application, of, this, small, molecule, offers, a, new, opportunity, to, design, effective, therapies, that, could]), verbo([prevent]), complemento([periapical, inflammation, and, revolutionize, current, treatment, options])].
[sujeto(['Meyer', '(', 'Family', 'Araliaceae)', is, an, important, medicinal, plant, which]), verbo([has]), complemento([been, employed, as, a, panacea, for, more, than, 2, ',', 0, years, in, 'China'])].
[sujeto(['It']), verbo([has]), complemento([the, actions, of, invigorating, primordial, 'qi,', recovering, pulse, and, 'desertion,', engendering, 'liquid,', and, calming, spirit])].
[sujeto(['The', water, extract, of, 'Panax', ginseng, '(', 'WEG)']), verbo([has]), complemento([been, used, to, treat, kinds, of, central, nervous, system, 'disorders,', such, as, 'depression,', 'insomnia,', 'Alzheimer<span', 'lang="hi-IN">׳</span>s', disease, and, 'Parkinson<span', 'lang="hi-IN">׳</span>s', disease])].
[sujeto(['Our', previous, work]), verbo([has]), complemento([demonstrated, that, 'WEG', possessed, 'antidepressant-like', activities, in, both, acute, and, chronic, stress, models, of, depression])].
[sujeto(['Then,', mitochondrial, permeability, transition, pore, '(', 'mPTP),', mitochondrial, membrane, potential, '(', 'MMP),', intracellular, 'Ca(2+)', '(', '[', 'Ca(2+)]i),', reactive, oxygen, species, '(', 'ROS)', 'concentration,', and, the, expression, level, of, glucocorticoid, receptor, '(', 'GR),', heat, shock, protein, 90, '(', 'Hsp90),', histone, deactylase, 6, '(', 'HDAC6),', 'glucose-regulated', protein, 78, '(', 'GRP78),', growth]), verbo([arrest]), complemento([and, 'DNA', damage, inducible, protein, 153, '(', 'GADD153),', 'X-box', 'DNA-binding', 'protein-1', '(', 'XBP-1),', 'caspase-12,', cytochrome, 'C,', inhibitor, of, 'caspase-activated', deoxyribonuclease, '(', 'ICAD),', 'caspase-3', and, 'caspase-9', were, assessed, by, 'Western', 'Blot', analysis, to, understand, the, molecule, mechanisms, of, neuroprotection, of, 'WEG'])].
[sujeto(['WEG', partly, reversed, 'corticosterone-induced', damage, in, 'PC12', 'cells,', which]), verbo([increased]), complemento([cell, 'viability,', decreased, 'LDH', 'release,', and, attenuated, 'corticosterone-induced', apoptosis, as, compared, with, the, 'corticosterone-treated', group])].
[sujeto(['Human', plasma, 'paraoxonase-1', '(', 'PON1)', and, bleomycin, hydrolase, '(', 'Blmh)']), verbo([have]), complemento([been, reported, as, the, physiological, 'HCTL', detoxifying, enzymes])].
[sujeto(['To', further, characterize, this, newly, described, 'HCTLase', 'activity,', 'BPHL', was]), verbo([expressed]), complemento([in, 'Escherichia', coli, and, purified])].
[sujeto(['We']), verbo([found]), complemento([that, the, catalytic, efficiency, '(', 'kcat/Km)', of, rBPHL, for, 'HCTL', hydrolysis, was, 7.7, ×, 10, '(', 4, ')', 'M(-1)s(-1),', orders, of, magnitude, higher, than, that, of, 'PON1', or, 'Blmh,', indicating, a, more, significant, physiological, role, for, 'BPHL', in, detoxifying, 'HCTL'])].
[sujeto(['Sonic', hedgehog, '(', 'Shh)', is, an, essential, morphogen]), verbo([involved]), complemento([in, vertebrate, organogenesis])].
[sujeto(['Perturbation', of, 'Hh', signaling, is]), verbo([associated]), complemento([with, pathological, consequences, like, tumor, formation, and, chronic, lung, fibrosis])].
[sujeto(['Platelets', are, highly, sensitive, circulating, blood, cells, responsible, for, 'hemostasis,', while, hyperactivity, of, these, cells]), verbo([lead]), complemento([to, morbidities, like, ischemic, heart, diseases, and, stroke])].
[sujeto(['Despite', being, terminally, differentiated, cells, with, life, span, of, 10, -, 12, 'days,', platelets]), verbo([have]), complemento([recently, been, shown, to, respond, to, 'Wnt', 'ligand,', another, developmental, signal, similar, to, 'Shh'])].
[sujeto(['In', this, 'study,', we, demonstrate, that, components, of, 'Shh', 'signaling,', 'Patched', and, 'Gli3,', are]), verbo([expressed]), complemento([in, human, platelets, consistent, with, existence, of, functional, 'Hedgehog', signaling, in, these, cells])].
[sujeto(['Shh', had, potent, inhibitory, effect, on, platelet, apoptosis]), verbo([induced]), complemento([by, 'ABT-737', or, thrombin, through, attenuation, of, 'caspase-3', activity])].
[sujeto(['The', 'Shh-mediated', pathway, may, thus, represent, a, novel, endogenous, mechanism, for]), verbo([regulating]), complemento([platelet, activity, and, life, span])].
[sujeto(['A', forward, chemical, genetic, approach, was, followed, to, discover, new]), verbo([targets]), complemento([and, lead, compounds, for, 'Parkinson\'s', disease, '(', 'PD)', treatment])].
[sujeto(['On', the, basis, of, these, 'data,', a, diverse, family, of, diphenyl, sulfides]), verbo([has]), complemento([been, developed, and, pharmacologically, evaluated, in, the, present, work])].
[sujeto(['Moreover,', to]), verbo([gain]), complemento([insight, into, the, safety, of, 'PDE7', inhibitors, for, human, chronic, 'treatment,', we, evaluated, the, new, compounds, in, a, surrogate, emesis, 'model,', showing, nonemetic, effects])].
[sujeto(['We']), verbo([found]), complemento([that, iminosugars, featuring, 'N-pentyloxymethylaryl', substituents, are, considerably, more, potent, inhibitors, of, glucosylceramide, synthase, than, their, aliphatic, counterparts])].
[sujeto(['In', a, next, optimization, 'round,', we, explored, a, series, of, 'biphenyl-substituted', iminosugars, of, both, configurations, '(', 'D-gluco', and, 'L-ido)', with, the, aim, to, introduce, structural, features, known, to]), verbo([confer]), complemento([metabolic, stability, to, 'drug-like', molecules])].
[sujeto(['From', these, 'series,', two, sets, of, molecules, emerge, as]), verbo([lead]), complemento([series, for, further, profiling])].
[sujeto(['Biphenyl-substituted', 'L-ido-configured', deoxynojirimycin, derivatives, are, selective, for, glucosylceramidase, and, the, nonlysosomal, 'glucosylceramidase,', and, we, consider, these, as]), verbo([leads]), complemento([for, the, treatment, of, neuropathological, lysosomal, storage, disorders])].
[sujeto(['The', results, demonstrated, that, the, addition, of, an, organoselenium, group, to, '(', 'R)-citronellal']), verbo([increased]), complemento([its, antioxidant, 'properties,', since, 'PhSeCIT', showed, better, activity, than, 'CIT'])].
[sujeto(['The', treatment, of, mice, with, both, compounds, did, not]), verbo([cause]), complemento([death, of, any, animals])].
[sujeto(['We', here]), verbo([report]), complemento([the, identification, of, the, binding, sites, of, an, organometallic, ruthenium, anticancer, complex, '[', '(', 'η(6)-biphenyl)Ru(en)Cl](+)', '(', 1, ')', to, 'single-stranded', oligodeoxynucleotides, '(', 'ODNs)', 5, '\'', -, 'CCCA4G5C6CC-3\'', '(', 'I)', and, 5, '\'', -, 'CCC3G4A5CCC-3\'', '(', 'II)', by, mass, spectrometry])].
[sujeto(['The', 'MS', analysis, of, exonuclease, ladders, demonstrated, that, the, 5, '\'', -, exonuclease, bovine, spleen, phosphodiesterase, digestion, of, 'I', and, 'II', 'mono-ruthenated', by, complex, 1, was]), verbo([arrested]), complemento([solely, at, 'A4', and, partially, at, 'C3', and, 'G4,', 'respectively,', and, that, the, 3, '\'', -, exonuclease, snake, venom, phosphodiesterase, digestion, of, the, ruthenated, 'ODNs', was, arrested, solely, at, 'G5', and, 'G4,', 'respectively,', due, to, the, ruthenation])].
[sujeto(['In', 'contrast,', tandem, mass, spectrometry, analysis, with, 'CID', fragmentation, of, the, 'mono-ruthenated', 'ODNs']), verbo([provided]), complemento([sequential, and, complementary, '[', 'a(i)', -, 'B]/wi', 'fragments,', leading, to, unambiguous, identification, of, 'G5', in, 'I', and, 'G4', in, 'II', as, the, ruthenation, sites, on, the, 'ODN', 'adducts,', which, is, in, line, with, the, high, selectivity, of, the, complex, towards, guanine, base, as, reported, previously])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, caution, should, be, raised, with, regard, to, the, identification, of, the, binding, sites, of, metal, 'complexes,', in, particular, complexes, with, bulky, 'ligands,', like, biphenyl, in, complex, 1, ',', to, 'DNA', by, 'MS', analysis, of, exonuclease, ladders, of, the, metallated, 'adducts,', because, the, bulky, ligands, may, adopt, such, an, orientation, that, they, block, the, exonuclease, cleavage, of, the, 5, '\'', -, or, 3, '\'', -, side, phosphodiester, bonds, adjacent, to, the, binding, 'sites,', leading, to, digestion, stalling, at, the, nucleotides, before, the, binding, sites])].
[sujeto(['Here', we]), verbo([report]), complemento([the, development, and, analyses, of, the, first, large, scale, 'Expressed', 'Sequence', 'Tag', '(', 'EST)', resource, for, the, 'American', black, bear, '(', 'Ursus', 'americanus)'])].
[sujeto(['We', identified, 18, 'genes,']), verbo([involved]), complemento([in, functions, such, as, lipid, 'catabolism,', cell, 'cycle,', and, 'vesicle-mediated', 'transport,', that, are, showing, rapid, evolution, in, the, bear, lineage, 'Three', 'genes,', 'Phospholamban', '(', 'PLN),', cysteine, 'glycine-rich', protein, 3, '(', 'CSRP3)', and, 'Troponin', 'I', type, 3, '(', 'TNNI3),', are, related, to, heart, 'contraction,', and, defects, in, these, genes, in, humans, lead, to, heart, disease])].
[sujeto(['Global', analysis, of, evolution, rates, of, 'hibernation-related', genes, in, bear, showed, that, they, are, largely]), verbo([conserved]), complemento([and, slowly, evolving, 'genes,', rather, than, novel, and, 'fast-evolving', genes])].
[sujeto(['We']), verbo([provide]), complemento([a, genomic, resource, for, an, important, mammalian, organism, and, our, study, sheds, new, light, on, the, possible, functions, and, evolution, of, bear, genes])].
[sujeto(['Biphenyl', 'hydrolase-like', '(', 'BPHL)', protein, is, a, novel, serine, hydrolase, which]), verbo([has]), complemento([been, identified, as, human, valacyclovirase, '(', 'VACVase),', catalyzing, the, hydrolytic, activation, of, valine, ester, prodrugs, of, the, antiviral, drugs, acyclovir, and, ganciclovir, as, well, as, other, amino, acid, ester, prodrugs, of, therapeutic, nucleoside, analogues])].
[sujeto(['The', broad, specificity, for, nucleoside, analogues, as, parent, drugs]), verbo([suggests]), complemento([that, 'BPHL', may, be, particularly, useful, as, a, molecular, target, for, prodrug, activation])].
[sujeto(['The', 'BPHL', model]), verbo([has]), complemento([residues, 'S122,', 'H255,', and, 'D227', comprising, the, putative, catalytic, triad, in, proximity, and, potential, 'charge-charge', interaction, 'sites,', 'M52', or, 'D123', for, the, 'alpha-amino', group])].
[sujeto(['The', model, also]), verbo([suggested]), complemento([that, the, structural, preference, of, 'BPHL', for, hydrophobic, amino, acyl, promoieties, and, its, limited, activity, for, the, secondary, alcohol, substrates, may, be, attributed, to, the, hydrophobic, 'acyl-binding', site, formed, by, residues, 'I158,', 'G161,', 'I162,', and, 'L229,', and, the, spatial, constraint, around, the, catalytic, site, by, a, loop, on, one, 'side,', the, active, serine, and, histidine, on, the, other, 'side,', and, 'L53', and, 'L179', on, top])].
[sujeto(['The', homology, model, of, 'BPHL']), verbo([provides]), complemento([a, basis, for, further, investigation, of, the, catalytic, and, active, site, 'residues,', can, account, for, the, observed, structure, activity, profile, of, 'BPHL,', and, will, be, useful, in, the, design, of, nucleoside, prodrugs])].
[sujeto(['The', substrate, specificity]), verbo([suggests]), complemento([that, the, 'substrate-binding', pocket, of, 'BPHL', has, a, hydrophobic, acyl, binding, site, which, can, accommodate, the, positively, charged, 'alpha-amino', 'group,', while, having, an, alcohol, leaving, group, binding, site, that, can, accommodate, nucleoside, analogues, with, a, relatively, generous, spatial, allowance])].
[sujeto(['In', 'conclusion,', 'BPHL', catalyzes, the, hydrolytic, activation, of, amino, acid, esters, of, a, broad, range, of, therapeutic, nucleoside, analogues, in, addition, to, valacyclovir, and, valganciclovir, and]), verbo([has]), complemento([considerable, potential, for, utilization, as, an, activation, target, for, design, of, antiviral, and, anticancer, nucleoside, analogue, prodrugs])].
[sujeto(['The']), verbo([increased]), complemento([bioavailability, of, valacyclovir, is, attributed, to, 'carrier-mediated', intestinal, 'absorption,', via, the, hPEPT1, peptide, 'transporter,', followed, by, the, rapid, and, complete, conversion, to, acyclovir])].
[sujeto(['The', one, or, more, human, enzymes, responsible, for, in, vivo, activation, of, the, prodrug, to, the, active, drug, and, its, conversion, 'sites,', 'however,']), verbo([have]), complemento([not, been, identified])].
[sujeto(['In', this, 'report,', we, describe, the, 'purification,', 'identification,', and, characterization, of, a, human, enzyme, that]), verbo([activates]), complemento([valacyclovir, to, acyclovir])].
[sujeto(['We', conclude, that, 'BPHL', may, be, an, important, enzyme]), verbo([activating]), complemento([valacyclovir, and, valganciclovir, in, humans, and, an, important, new, target, for, prodrug, design])].
[sujeto(['The', gene, encoding, human, biphenyl, 'hydrolase-related', protein, '(', 'Bph-rp),', a, serine, hydrolase, with, sequence, similarity, to, prokaryotic, enzymes]), verbo([involved]), complemento([in, the, degradation, of, polychlorinated, 'biphenyls,', has, been, cloned, and, its, overall, organization, established])].
[sujeto(['The', number, and, distribution, of, exons, and, introns, differ, from, those]), verbo([reported]), complemento([for, the, genes, encoding, other, serine, hydrolases, with, sequence, similarity, to, 'Bph-rp,', indicating, that, these, genes, are, distantly, related])].
[sujeto(['A', 'full-length', cDNA, coding, for, a, novel, human, serine, hydrolase]), verbo([has]), complemento([been, cloned, from, a, breast, carcinoma, cDNA, library])].
[sujeto(['Nucleotide', sequence, analysis]), verbo([has]), complemento([shown, that, the, isolated, cDNA, contains, an, open, reading, frame, coding, for, a, polypeptide, of, 274, amino, acids, and, a, complete, 'Alu', repetitive, sequence, within, its, 3, '\'', -, untranslated, region])].
[sujeto(['The', predicted, amino, acid, sequence, contains, the, 'Gly-X-Ser-X-Gly', motif, characteristic, of, serine, hydrolases, and, displays, extensive, similarity, to, several, prokaryotic, hydrolases]), verbo([involved]), complemento([in, the, degradation, of, aromatic, compounds])].
[sujeto(['On', the, basis, of, these, sequence, 'similarities,', this, novel, human, enzyme]), verbo([has]), complemento([been, tentatively, called, 'Biphenyl', 'hydrolase-related', protein, '(', 'Bph-rp)'])].
[sujeto(['The', 'Bph-rp', cDNA, was]), verbo([expressed]), complemento([in, 'Escherichia', 'coli,', and, after, 'purification,', the, recombinant, protein, was, able, to, degrade, 'p-nitrophenylbutyrate,', a, 'water-soluble', substrate, commonly, used, for, assaying, serine, hydrolases])].
[sujeto(['This', hydrolytic, activity, was, abolished, by, diisopropyl, 'fluorophosphate,', a, covalent, inhibitor, of, serine, 'hydrolases,']), verbo([providing]), complemento([additional, evidence, that, the, isolated, cDNA, encodes, a, member, of, this, protein, superfamily])].
[sujeto(['Northern', blot, analysis, of, 'poly(A)+', 'RNAs', isolated, from, a, variety, of, human, tissues, revealed, that, 'Bph-rp', is, mainly]), verbo([expressed]), complemento([in, liver, and, 'kidney,', which, was, also, confirmed, at, the, protein, level, by, 'Western', blot, analysis, with, antibodies, raised, against, purified, recombinant, 'Bph-rp'])].
[sujeto(['We']), verbo([found]), complemento([no, overall, association, between, dietary, 'PCB', exposure, and, any, of, these, cancer, forms])].
[sujeto(['This', study]), verbo([suggests]), complemento([that, dietary, exposure, to, 'PCBs', play, no, critical, role, in, the, development, of, 'breast,', endometrial, or, ovarian, cancer, during, 'middle-age', and, old, ages])].
[sujeto(['Human', biomonitoring, '(', 'HBM)', often]), verbo([reveals]), complemento([statistical, associations, between, persistent, organic, pollutant, '(', 'POP)', concentrations, and, body, mass, index, '(', 'BMI)'])].
[sujeto(['Both', negative, and, positive, associations]), verbo([have]), complemento([been, 'observed,', which, has, been, hypothesized, to, reflect, variable, toxicokinetics, in, lean, and, obese, individuals, during, times, of, increasing, and, decreasing, exposure])].
[sujeto(['In', the, neutral, 'fraction,', 2, '\'', -, 'MeO-BDE68', was, primarily]), verbo([found]), complemento([at, a, similar, concentration, '(', mean, 5.6, 'pgg(-1)', 'ww)', to, 'BDE-47'])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([of, profiles, and, dietary, sources, of, 'OH/MeO-PBDEs', in, human, serum, from, 'Japan'])].
[sujeto(['Polychlorinated', biphenyls, '(', 'PCBs)', are, persistent, and, bioaccumulative, environmental, toxicants]), verbo([acting]), complemento([as, endocrine, disruptors])].
[sujeto(['The', gene, expression, level, of, 'FSHR,', 'ABP,', 'ERβ', and, 'AR', was]), verbo([decreased]), complemento([in, a, 'dose-dependent', 'manner,', whereas, 'Inhibinβ', gene, expression, level, was, increased, in, 'PCB-treated', groups])].
[sujeto(['Polychlorinated', biphenyls, '(', 'PCBs)', produced, in, 'Slovakia', as, a, commercial, mixture, 'Delor', 103]), verbo([cause]), complemento([the, main, contamination, of, 'sediment,', water, and, fish, in, the, eastern, part, of, 'Slovakia'])].
[sujeto(['This']), verbo([report]), complemento([presents, a, simple, and, inexpensive, fabrication, approach, to, a, flexible, transparent, composite, film, as, a, &, 'quot;cut-and-paste&quot;', 'surface-enhanced', 'Raman', scattering, '(', 'SERS)', substrate, for, in, situ, detection, of, organic, pollutants])].
[sujeto(['Type', 1, diabetes, '(', 'T1D)', incidence]), verbo([has]), complemento([been, steadily, rising, across, the, globe])].
[sujeto(['Exposure', to, persistent, organic, pollutants, '(', 'POP)']), verbo([has]), complemento([been, implied, as, one, potential, cause, of, increased, 'T1D', occurrence])].
[sujeto(['A', significant]), verbo([decrease]), complemento([in, incidence, of, 'T1D', was, observed, in, both, 'low-', and, 'high-dose', subchronically, exposed, mice])].
[sujeto(['Analysis', of, various, immune, 'parameters,', including, 'T-cell', types, and, 'subtypes,', 'T-cell', proliferative, responses, -, as, well, as, their, cytokine, 'secretions,', revealed, that, both, 'short-', and, 'long-term', exposure, to, 'PCB-153']), verbo([caused]), complemento([significant, immunosuppression])].
[sujeto(['In', 'agreement,']), verbo([decreased]), complemento([levels, of, 'TH', 'cells,', reduced, proliferation, and, 'IL-2', secretion, seemed, to, be, a, mechanism, of, 'PCB-153', action, in, the, development, of, 'T1D', in, subchronically, exposed, mice])].
[sujeto(['A', comparison, of, 'whole-fish', polychlorinated, biphenyl, '(', 'PCB)', and, total, mercury, '(', 'Hg)', concentrations, in, mature, males, with, those, in, mature, females, may]), verbo([provide]), complemento([insights, into, sex, differences, in, 'behavior,', 'metabolism,', and, other, physiological, processes])].
[sujeto(['A', higher, rate, of, energy, expenditure]), verbo([led]), complemento([to, a, higher, rate, of, food, 'consumption,', 'which,', in, 'turn,', resulted, in, a, higher, rate, of, 'PCB', accumulation])].
[sujeto(['In']), verbo([sea]), complemento([lamprey, '(', 'Petromyzon', 'marinus),', a, very, primitive, 'fish,', the, two, ratios, were, nearly, identical])].
[sujeto(['The', most, plausible, explanation, for, this, pattern, was, that, certain, 'androgens,', such, as, testosterone, and, 11, -, 'ketotestosterone,']), verbo([enhanced]), complemento(['Hg-elimination', rate, in, males])].
[sujeto(['According', to, this, 'explanation,', males, not, only, ingest, 'Hg', at, a, higher, rate, than, females, but, also, eliminate, 'Hg', at, a, higher, rate, than, 'females,', in, fish, species, other, than]), verbo([sea]), complemento([lamprey])].
[sujeto(['Male']), verbo([sea]), complemento([lamprey, do, not, possess, either, of, the, 'above-specified', androgens])].
[sujeto(['Early', life, exposure, to, endocrine, disrupting, chemicals, '(', 'EDCs)']), verbo([has]), complemento([been, frequently, associated, with, impaired, perinatal, 'growth,', an, important, risk, factor, for, later, onset, of, metabolic, disorders])].
[sujeto(['Transcriptional', changes, at, birth]), verbo([suggest]), complemento([a, role, for, specific, metabolic, targets, as, a, link, between, prenatal, 'EDC', exposure, and, metabolic, disorders, later, in, life])].
[sujeto(['The', ecological, effects, and, human, health, risks]), verbo([associated]), complemento([with, combined, persistent, organic, 'pollutants,', including, 'PCBs,', organochlorine, pesticides, '(', 'OCPs),', phthalate, esters, '(', 'PAEs)', and, polybrominated, diphenyl, ethers, '(', 'PBDEs),', were, further, estimated])].
[sujeto(['The', four, toxic, organic, compounds, and, seven, physicochemical, parameters, together, could, only, explain, 12.7, '%', of, the, variation, in, microbial, community, 'composition,']), verbo([suggesting]), complemento([the, soil, ecosystem, function, was, not, strongly, influenced, by, the, combined, pollution, at, low, concentrations])].
[sujeto(['However,', egg, concentrations, of, 'PCBs', as, well, as, 'DDE', '(', 1, ',', 1, -, 'bis(p-chlorophenyl)-2,2-dichloroethene),', the, degradation, product, of, the, ubiquitous, global, contaminant, 'DDT', '(', 1, ',', 1, ',', 1, -, 'trichloro-2,2-bis(p-chlorophenyl)', 'ethane),']), verbo([have]), complemento([since, declined])].
[sujeto(['To', estimate, the, toxic, effects, on, tern, eggs, of, 'PCB', 'dioxin-like', congener, '(', 'DLC)', 'exposures,', we, extrapolated, published, laboratory, data, on, common, terns, to, roseate, terns, by, characterizing, genetic, and, functional, similarities, in, species, aryl, hydrocarbon, receptors, '(', 'AHRs),', which]), verbo([mediate]), complemento(['DLC', sensitivity])].
[sujeto(['Our', assessment, of, contaminant, risks]), verbo([suggests]), complemento([that, terns, breeding, near, 'NBH', were, exposed, historically, to, toxic, levels, of, 'PCBs', and, 'DDE;', 'however,', acute, effects, on, tern, egg, development, have, become, less, likely, since, the, 1970, s])].
[sujeto(['Our', approach, demonstrates, how, comparative, genetics, at]), verbo([target]), complemento([loci, can, effectively, increase, the, range, of, inference, for, chemical, risk, assessments, from, tested, to, untested, and, untestable, species])].
[sujeto(['In', 'addition,', the, effect, of, 'PCB', congeners, on, condition, factor, '(', 'CF)', and]), verbo([associated]), complemento([human, health, risk, was, assessed, using, muscle, levels, for, a, noncarcinogenic, hazard, quotient, '(', 'HQ)', calculation])].
[sujeto(['Significant']), verbo([decreases]), complemento([in, fish, body, 'weight,', length, and, 'CF', were, observed, downstream, compared, to, upstream, in, the, 'Ona', 'River'])].
[sujeto(['Overall,', our, results]), verbo([suggest]), complemento([that, industrial, discharges, contribute, significantly, to, 'PCB', inputs, into, these, 'rivers,', with, potential, for, significant, health, implications, for, neighboring, communities, that, utilize, these, rivers, for, fishing, and, other, domestic, purposes])].
[sujeto(['Polychlorinated', biphenyls, '(', 'PCBs)', and, organochlorine, pesticides, '(', 'OCPs)', are, neurodevelopmental, 'toxicants,', but, few, studies]), verbo([have]), complemento([examined, associations, with, autism, spectrum, disorder, '(', 'ASD)'])].
[sujeto(['PCB138/158', was, also]), verbo([associated]), complemento([with, increased, 'ID', '(', 'AOR=2'])].
[sujeto(['OCPs', were, not]), verbo([associated]), complemento([with, increased, risk, of, 'ASD', in, primary, 'analyses,', while, 'non-monotonic', increases, in, risk, of, 'ID', were, found, with, 'p,p\'-DDE'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([higher, levels, of, some, organochlorine, compounds, during, pregnancy, are, associated, with, 'ASD', and, 'ID'])].
[sujeto(['Concentrations', of, 'PCBs', in, nestling, carcasses, were, elevated, at, some, 'AOCs,', but, were, modest, compared, to, highly, 'PCB-contaminated', sites, where, reproductive, effects]), verbo([have]), complemento([been, documented])].
[sujeto(['Both', 'PAH', and, 'PCB', concentrations, in, nestling, stomach, 'contents,', and, 'PCBs', in, 'carcasses,', were, significantly, correlated, with, concentrations, in, sediment]), verbo([reported]), complemento([in, another, 'study,', thereby, reinforcing, the, utility, of, using, tree, swallows, to, assess, bioavailability, of, sediment, contamination])].
[sujeto([96, ')', but, not, in, outfalls, '(', higher, turbulences, and, potential]), verbo([release]), complemento([of, 'PRCs', to, 'air)'])].
[sujeto(['PCB', sources, could, efficiently, be, localized, when, 'PRCs', were, used, '(']), verbo([increases]), complemento([of, 'PCB', loads, in, 'river)', but, the, impact, of, high, differences, of, water, velocity, was, overcorrected, '(', leading, sometimes, to, false, positives, and, 'negatives)'])].
[sujeto(['Simulation', results, showed, that, as, the, media, refractive, index, was, changed, from, 1.0, to, 1.2, ',', the, maximum, peak, intensity, of, 'LSPRs', spectra, had, no, apparent, change, and, the, wavelength, to]), verbo([reveal]), complemento([the, maximum, peak, intensity, of, 'LSPRs', spectra, was, shifted, lower, value])].
[sujeto(['Finally,', the, fabricated, hexagonal, lattices, of, triangular, 'PNAs', were, investigated, as, a, sensor, of, polychlorinated, biphenyl, solution, '(', 'PCB-77)', by, observing, the, wavelength, to]), verbo([reveal]), complemento([the, maximum, extinction, efficiency, '(', 'λmax)'])].
[sujeto(['We', show, that, the, adhesion, of, 'β-cyclodextrins', '(', 'SH-β-CD)', on, the, hybrid, 'Au-Ag', hexagonal, lattice, of, triangular, 'PNAs', could, be, used, to]), verbo([increase]), complemento([the, variation, of, λmax])].
[sujeto(['We', also, demonstrate, that, the, adhesion, of, 'SH-β-CD']), verbo([increases]), complemento([the, sensitivity, and, detection, effect, of, 'PCB-77', in, hexagonal, lattice, of, triangular, 'PNAs'])].
[sujeto(['The', total, oxidant, status, '(', 'TOS)', level, in, the, serum, and, 'testis,', number, of, apoptotic, 'cells,', vacuolization, at, the, basal, 'membrane,', immature, spermatids, in, the, tubular, 'lumen,', heme, 'oxygenase-1', '(', 'HO-1)', staining, 'density,', and, abnormal, spermatozoa, were, significantly]), verbo([increased]), complemento([in, the, 'PCB', group])].
[sujeto(['Moreover,', in, the, 'PCB', 'group,', the, seminiferous, tubule, diameter, '(', 'STD)', was]), verbo([decreased]), complemento([in, stage, 'VII-VIII', and, 'XII-XIV', tubules])].
[sujeto(['The', 'TOS', level, in, the, serum, and, 'testis,', vacuolization, at, the, basal, 'membrane,', immature, spermatids, in, the, tubular, 'lumen,', and, apoptosis, were, significantly]), verbo([decreased]), complemento([in, the, 'ALA+PCB', groups])].
[sujeto(['These', findings]), verbo([suggested]), complemento([that, 'ALA', has, a, protective, role, against, 'PCB-induced', testicular, toxicity])].
[sujeto(['This', paper, studies, the, synergism, between, transition, metals, '(', 'TMs)', and]), verbo([activated]), complemento([carbon, '(', 'AC)', as, a, catalyst, support, used, in, the, catalytic, decomposition, of, 'PCBs'])].
[sujeto(['In', this, 'study,', the, synergism, between]), verbo([activated]), complemento([carbon, '(', 'AC)', as, a, catalyst, support, and, transition, metals, '(', 'TMs)', is, used, to, destroy, low, concentrations, of, 'PCBs'])].
[sujeto(['Although', 'CuCl2']), verbo([acted]), complemento([as, a, promoter, of, 'aromatic-Cls', 'generation,', statistical, analyses, implied, that, 'FeCl3', also, largely, influenced, the, generation, of, 'aromatic-Cls', under, mixture, conditions])].
[sujeto(['The', aqueous, washing, suspension, was, then, regenerated, by, precipitation, of, the, 'HMs']), verbo([induced]), complemento([by, corrosion, and, hydrolysis, of, 'zero-valent', 'Mg', to, provide, a, cleaned, soil, and, innocuous, extract])].
[sujeto(['After', ultrasonic, 'equilibration,', 'EDTA', in, admixture, with, a, nonionic, surfactant, did, not, appreciably, change, the, efficiency, of, mobilization, of, most, heavy, metals, '(', 'Al,', 'Cd,', 'Cr,', 'Fe', 'Mn,', 'Ni,', and, 'Zn),', but, did]), verbo([increase]), complemento([the, recovery, of, 'Cu', and, 'Pb'])].
[sujeto(['The']), verbo([release]), complemento([of, 'EDTA', from, 'HM', complexes, was, efficient, for, most, metals, '(', 99, '%', ')', but, was, influenced, by, the, chemical, characteristics, of, the, surfactant])].
[sujeto(['PCDD', photodegradation, rates]), verbo([decreased]), complemento([with, the, number, of, chlorine, atoms])].
[sujeto(['From', the, 'Frontier', electron, density, 'calculation,', the, first, 'OH*', radical, attack, positions, on, 'TeCDD', were]), verbo([found]), complemento([to, be, four, 'C', atoms, neighboring, two, 'O', atoms])].
[sujeto(['Because', the, active, site, 'Fe(II)', ion, of, the, extradiol, dioxygenase, is, 'colorless,', it]), verbo([has]), complemento([been, difficult, to, monitor, the, reaction, cycle, kinetics])].
[sujeto(['Here,', we]), verbo([have]), complemento([found, that, 'BphC', binds, strongly, the, chromophoric, substrate, 3, -, formylcatechol, '(', 3, 'FC)', as, a, monoanion, '(', 'Kd=0'])].
[sujeto(['The']), verbo([binding]), complemento([of, 3, 'FC', occurred, in, a, 'three-step', process, involving, rapid, deprotonation, of, 3, 'FC'])].
[sujeto(['The']), verbo([bound]), complemento([monoanionic, 3, 'FC', reacted, slowly, with, 'O2', in, three, 'steps,', occurring, in, 'sequence,', the, ring, opening, step, being, the, slowest, one])].
[sujeto(['Wastewater', contaminated, by, 'PCBs', obtained, from, three, different, sources, was, treated, at, both, laboratory, and, pilot, plant, scale, conditions, by, ultraviolet, oxidation, of, organics, at, the, presence, of, hydrogen, peroxide, after, partial, adsorption, of, impurities, and, 'PCBs', on]), verbo([activated]), complemento([carbon, 'and/or', activated, bentonite])].
[sujeto(['In', pilot, plant, scale, 'experiments,']), verbo([activated]), complemento([carbon, polishing, step, followed, 'UV', oxidation])].
[sujeto(['The', presence, of, 'Mn(II)', in, culture, medium, was]), verbo([found]), complemento([to, be, essential, for, production, of, active, recombinant, 'NahC_JF8,', while, 'Fe(II)', was, necessary, for, active, recombinant, 'NahH_JF8'])].
[sujeto(['Stability', studies, on, the, 'Mn(II)-dependent', 'NahC_JF8', indicated, that, it, was, 'thermostable,']), verbo([retaining]), complemento([50, '%', activity, after, incubation, at, 80, degrees, 'C', for, 20, 'min,', and, it, exhibited, resistance, to, 'EDTA', and, 'H(2)O(2)'])].
[sujeto(['Northern', hybridization, studies, clarified, that, both, 'NahC_JF8', and, 'NahH_JF8', were]), verbo([induced]), complemento([by, 'naphthalene;', 'RT-PCR', showed, that, nahHLOMmocBnahC, is, expressed, as, a, single, transcript])].
[sujeto(['Kinetics', of, simultaneous, iron, and, polychlorophenol, '(', 'CP)', oxidation, by, groundwater, enriched, cultures, were, studied, in, laboratory, and, during, actual, remediation, in, order, to]), verbo([reveal]), complemento([the, fate, and, effects, of, iron, on, aerobic, 'on-site', bioremediation, of, boreal, groundwater])].
[sujeto(['Mineralization', of, 'CPs', was, confirmed, by, 'DOC', removal, and, chloride]), verbo([release]), complemento([of, 158, '%', and, 78, '%', ',', respectively])].
[sujeto(['The', batch, assays, at, various, 'TCP', and, 'Fe(II)', ratios, and, 'DO', concentrations, showed, simultaneous, oxygen, consumption, by, 'TCP', and, 'Fe-oxidizers', and, that]), verbo([increased]), complemento(['Fe', concentrations, do, not, outcompete, the, bioremediation, of, 'CP\'s', for, available, oxygen])].
[sujeto(['Little', difference, in, adsorption, was]), verbo([found]), complemento([between, acidic, '(', 2.3, ')', and, unamended, solutions, '(', pH, 5.5, ')', ',', even, though, significant, differences, in, iron, oxidation, state, and, 'Fe2+', concentrations, were, measured, in, solution])].
[sujeto(['PCB', adsorption, also, occurs, on, steel, electrodes, regardless, of, the, pH, or, electric, current, applied, '(', 'AC', or, 'DC),']), verbo([suggesting]), complemento([the, combination, of, oxidizing, '(', free, 'radical-mediated', 'reactions)', and, reducing, '(', dechlorination, 'reactions)', 'iron-mediated', degradation, pathways, may, be, possible])].
[sujeto(['Extraction', of, the, iron, powder, after, 48, h, of, contact, time, yielded, the, progressive, recovery, of, biphenyl, with]), verbo([increasing]), complemento(['Fe', 'mass(from', 0.4, '%', to, 3.5, '%', ')', and, changes, of, the, 'PCB', 'congener-specific', pattern, as, a, consequence, of, dechlorination])].
[sujeto(['Cell', extracts, of, 'Pseudomonas', aeruginosa, 142, ',', which, was, previously, isolated, from, a, polychlorinated, 'biphenyl-degrading', 'consortium,', were, shown, to, degrade, 2, ',', 4, -, 'dichlorobenzoate,', 2, -, 'chlorobenzoate,', and, a, variety, of, other, substituted, 'ortho-halobenzoates', by, a, reaction, that]), verbo([requires]), complemento(['oxygen,', 'NADH,', 'Fe(II),', and, flavin, adenine, dinucleotide])].
[sujeto([aeruginosa, enzyme, was, resolved, by, 'ion-exchange', chromatography, into, three, 'components,', each, of, which, is]), verbo([required]), complemento([for, activity])].
[sujeto(['To', verify, the, distinct, nature, of, this, 'enzyme,', we, 'purified,', 'characterized,', and, identified, one, component, as, a, ferredoxin, '(', 'M(r),', approximately, 13, ',', 0, ')', containing, a, single, '[', 2, 'Fe-2S]', 'Rieske-type', cluster, '(', electron, paramagnetic, resonance, spectroscopic, values, of, gx, =, 1.82, ',', gy, =, 1.905, ',', and, gz, =, 2.02, in, the, reduced, 'state)', that, is, related, in, sequence, to, ferredoxins]), verbo([found]), complemento([in, the, naphthalene, and, biphenyl, 'three-component', dioxygenase, systems])].
[sujeto(['Cannabis-based', medicines]), verbo([have]), complemento([a, number, of, therapeutic, 'indications,', including, 'anti-inflammatory', and, analgesic, effects])].
[sujeto(['Pre-clinical', and, clinical, studies]), verbo([have]), complemento([demonstrated, that, 'cannabis-based', drugs, have, therapeutic, potential, in, inflammatory, 'diseases,', including, rheumatoid, arthritis, '(', 'RA)', and, multiple, sclerosis])].
[sujeto(['The', aim, of, this, study, was, to, determine, whether, the, key, elements, of, the, endocannabinoid, signalling, 'system,', which, produces, immunosuppression, and, 'analgesia,', are]), verbo([expressed]), complemento([in, the, synovia, of, patients, with, osteoarthritis, '(', 'OA)', or, 'RA'])].
[sujeto(['Our', data, predict, that, the, cannabinoid, receptor, system, present, in, the, synovium, may, be, an, important, therapeutic]), verbo([target]), complemento([for, the, treatment, of, pain, and, inflammation, associated, with, 'OA', and, 'RA'])].
[sujeto(['Biological', functions, of, 'lysozyme,', including, its, 'antimicrobial,', 'antitumor,', and, 'immune-modulatory', activities]), verbo([have]), complemento([been, suggested, to, be, largely, determined, by, the, lipid, binding, properties, of, this, protein])].
[sujeto(['To']), verbo([gain]), complemento([further, insight, into, these, interactions, on, a, molecular, level, the, association, of, lysozyme, to, liposomes, composed, of, either, 1, -, 'palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine', or, its, mixtures, with, 1, -, 'palmitoyl-2-oleoyl-sn-glycero-3-phospho-rac-glycerol,', 1, -, 'palmitoyl-2-oleoyl-sn-glycero-3-phospho-rac-phosphatidylserine,', or, bovine, heart, cardiolipin, was, studied, by, a, combination, of, fluorescence, techniques])].
[sujeto(['The', characteristics, of, the, adsorption, of, lysozyme, to, lipid, bilayers, were, investigated, using, fluorescein, 5, '\'', -, isothiocyanate, labeled, 'protein,']), verbo([responding]), complemento([to, membrane, association, by, a, decrease, in, fluorescence])].
[sujeto(['Upon']), verbo([increasing]), complemento([the, content, of, anionic, phospholipids, in, lipid, 'vesicles,', the, binding, isotherms, changed, from, 'Langmuir-like', to, sigmoidal])].
[sujeto(['Using', adsorption, models, based, on, scaled, particle, and, 'double-layer', 'theories,', this]), verbo([finding]), complemento([was, rationalized, in, terms, of, 'self-association', of, the, 'membrane-bound', protein])].
[sujeto(['The', extent, of, quenching, of, lysozyme, tryptophan, fluorescence, by, acrylamide]), verbo([decreased]), complemento([upon, membrane, 'binding,', revealing, a, conformational, transition, for, the, protein, upon, its, surface, 'association,', resulting, in, a, diminished, access, of, the, fluorophore, to, the, aqueous, phase])].
[sujeto(['Lysozyme', was]), verbo([found]), complemento([to, increase, 'acyl-chain', order, for, liposomes, with, the, content, of, acidic, phospholipid, exceeding, 10, mol, '%'])].
[sujeto(['Both', electrostatic, and, hydrophobic, 'protein-lipid', interactions, can, be, concluded, to]), verbo([modulate]), complemento([the, aggregation, behavior, of, lysozyme, when, bound, to, lipid, bilayers])].
[sujeto(['Modulation', of, lysozyme, aggregation, propensity, by, membrane]), verbo([binding]), complemento([may, have, important, implications, for, protein, fibrillogenesis, in, vivo])].
[sujeto(['This']), verbo([report]), complemento([represents, the, conclusions, of, a, 'Joint', 'FAO/WHO', 'Expert', 'Committee', convened, to, evaluate, the, safety, of, various, food, additives, and, contaminants, and, to, prepare, specifications, for, identity, and, purity])].
[sujeto(['The', first, part, of, the]), verbo([report]), complemento([contains, a, brief, description, of, general, considerations, addressed, at, the, 'meeting,', including, updates, on, matters, of, interest, to, the, work, of, the, 'Committee'])].
[sujeto(['A', summary, follows, of, the, 'Committee\'s', evaluations, of, 'technical,', toxicological, 'and/or', dietary, exposure, data, for, seven, food, additives, '(', 'benzoates;', lipase, from, 'Fusarium', heterosporum]), verbo([expressed]), complemento([in, 'Ogataea', 'polymorpha;', magnesium, 'stearate;', maltotetraohydrolase, from, 'Pseudomonas', stutzeri, expressed, in, 'Bacillus', 'licheniformis;', mixed, 'β-glucanase,', cellulase, and, xylanase, from, 'Rasamsonia', 'emersonii;', mixed, 'β-glucanase', and, xylanase, from, 'Disporotrichum', 'dimorphosporum;', polyvinyl, alcohol, '(', 'PVA)-', polyethylene, glycol, '(', 'PEG)', graft, 'copolymer)', and, two, groups, of, contaminants, '(', 'non-dioxin-like', polychlorinated, biphenyls, and, pyrrolizidine, 'alkaloids)'])].
[sujeto(['Annexed', to, the]), verbo([report]), complemento([are, tables, or, text, summarizing, the, toxicological, and, dietary, exposure, information, and, information, on, specifications, as, well, as, the, 'Committees', recommendations, on, the, food, additives, and, contaminants, considered, at, this, meeting])].
[sujeto(['Coplanar', and, noncoplanar, polychlorinated, biphenyls, '(', 'PCBs)', are, known, to]), verbo([have]), complemento([different, routes, and, degree, of, toxicity])].
[sujeto(['The', first, '∼2', layers, of, lipids, around, each, 'PCB', 52, in, the, bilayer, form, a, high, fluidity, lamellar, 'phase,', whereas, lipids, beyond, these, layers, form, a, lamellar, phase, with, a, slight]), verbo([increase]), complemento([in, fluidity, compared, to, a, bilayer, without, 'PCB', 52])].
[sujeto(['The', explanation, for, this, is, the, interference, of, several, high, fluidity, lamellar, phases]), verbo([caused]), complemento([by, interactions, of, 'PCB', 52, molecules, in, different, leaflets, of, the, model, bilayer])].
[sujeto(['This']), verbo([causes]), complemento([formation, of, high, curvature, toroidal, region, in, the, bilayer, and, might, induce, formation, of, channels])].
[sujeto(['Dioxins', and, 'dioxin-like', compounds, encompass, a, group, of, structurally, related, heterocyclic, compounds, that]), verbo([bind]), complemento([to, and, activate, the, aryl, hydrocarbon, receptor, '(', 'AhR)'])].
[sujeto(['Additionally,', 'PCB', 126]), verbo([suppressed]), complemento(['forskolin-stimulated', gluconeogenesis, from, lactate])].
[sujeto(['These', effects, were, independent, of, acute, 'toxicity,', as, 'PCB', 126, did, not]), verbo([increase]), complemento([lactate, dehydrogenase, release, nor, affect, lipid, metabolism, or, total, intracellular, 'ATP'])].
[sujeto(['In', concordance, with, this, 'finding,', 'PCB', 126, blunted, the, 'forskolin-stimulated']), verbo([increase]), complemento([in, phosphoenolpyruvate, carboxykinase, '(', 'PEPCK)', mRNA, levels, without, affecting, 'glucose-6-phosphatase', expression])].
[sujeto(['Furthermore,', other, 'dioxin-like', 'PCBs', demonstrated, similar, effects, on, 'PEPCK', expression, in, parallel, with, their, ability, to]), verbo([activate]), complemento(['AhR'])].
[sujeto(['It', therefore, appears, that, 'AhR', activation]), verbo([mediates]), complemento([the, suppression, of, 'PEPCK', expression, by, 'dioxin-like', 'PCBs,', suggesting, a, role, for, these, pollutants, as, disruptors, of, energy, metabolism])].
[sujeto(['We']), verbo([found]), complemento([that, human, recombinant, prostaglandin, 'H', 'synthase-2', '(', 'hPGHS-2)', biotransforms, 'dihydroxy-PCBs,', such, as, 4, -, 'chlorobiphenyl-2\',5\'-hydroquinone', '(', 4, -, 'CB-2\',5\'-H(2)Q),', into, semiquinone, radicals, via, 'one-electron', oxidation])].
[sujeto(['Hindered', rotation, of, the, 4, -, 'CB-2\',5\'-SQ()(-)', appears, not, to, be, a, major, factor, for, the, change, in, lineshape, because]), verbo([increasing]), complemento([the, viscosity, of, the, medium, with, glycerol, produced, no, significant, change, in, lineshape])].
[sujeto(['Introduction', of, a, 'fluorine,', which]), verbo([increases]), complemento([the, steric, hindrance, for, rotation, of, the, 'dihydroxy-PCB', 'studied,', also, produced, no, significant, changes])].
[sujeto(['This', study]), verbo([provides]), complemento([new, insights, into, the, formation, of, semiquinones, from, 'PCB', metabolites, and, underscores, the, potential, role, of, 'PGHS-2', in, the, metabolic, activation, of, 'PCBs'])].
[sujeto(['PCBs']), verbo([induce]), complemento([deleterious, effects, on, developing, amphibians, including, deformities, and, delays, in, metamorphosis])].
[sujeto(['However,', the, molecular, mechanisms, by, which, they]), verbo([express]), complemento([their, toxicity, during, the, development, of, tadpoles, are, still, largely, unknown])].
[sujeto(['Two-dimensional', 'DIGE', with, a, minimal, labeling, method, coupled, to, nanoflow, liquid, 'chromatography-tandem', mass, spectrometry, was, used, to, detect, and, identify, proteins, differentially]), verbo([expressed]), complemento([under, 'PCBs', conditions])].
[sujeto(['Results', showed, that, 59, spots, from, the, 0.1, ppm, 'Aroclor', 1254, condition, and, 57, spots, from, the, 1, ppm, 'Aroclor', 1254, condition, displayed, a, significant]), verbo([increase]), complemento([or, decrease, of, abundance, compared, with, the, control])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, 'PCBs', induce, mechanisms, against, oxidative, stress, '(', peroxiredoxins, 1, and, 2, ')', ',', adaptative, changes, in, the, energetic, metabolism, '(', enolase, 1, ',', 'glycerol-3-phosphate', 'dehydrogenase,', and, creatine, kinase, muscle, and, brain, 'types),', and, the, implication, of, the, unfolded, protein, response, system, '(', 'glucose-regulated', 'protein,', 58, 'kDa)'])].
[sujeto(['They', also, 'affect,', at, least, at, the, highest, concentration, 'tested,', the, synthesis, of, proteins]), verbo([involved]), complemento([in, normal, cytogenesis, '(', 'alpha-tropomyosin,', myosin, heavy, 'chain,', and, 'alpha-actin)'])].
[sujeto(['For', the, first, 'time,', proteins, such, as, aldehyde, dehydrogenase, 7, 'A1,', 'CArG']), verbo([binding]), complemento(['factor-A,', prolyl, 4, -, hydroxylase, 'beta,', and, nuclear, matrix, protein, 200, were, also, shown, to, be, 'up-regulated', by, 'PCBs', in, developing, amphibians])].
[sujeto(['Obesity,', an, inflammatory, condition, linked, to, cardiovascular, 'disease,', is]), verbo([associated]), complemento([with, expansion, of, adipose, tissue])].
[sujeto(['Highly', prevalent, coplanar, polychlorinated, biphenyls, '(', 'PCBs)', such, as, 3, ',', 3, '\'', ',', 4, ',', 4, '\'', -, tetrachlorobiphenyl, '(', 'PCB-77)', accumulate, in, adipose, tissue, because, of, their, lipophilicity, and]), verbo([increase]), complemento([with, obesity])].
[sujeto(['Low', concentrations, of, 'PCB-77', or, 'TCDD']), verbo([increased]), complemento([adipocyte, 'differentiation,', 'glycerol-3-phosphate', dehydrogenase, 'activity,', and, expression, of, peroxisome, 'proliferator-activated', receptor, 'gamma,', whereas, higher, concentrations, inhibited, adipocyte, differentiation])].
[sujeto(['PCB-77']), verbo([promoted]), complemento([the, expression, and, release, of, various, proinflammatory, cytokines, from, 3, 'T3-L1', adipocytes])].
[sujeto(['Administration', of, 'PCB-77']), verbo([increased]), complemento([body, weight, gain, in, 'WT', but, not, 'AhR(-/-)', mice])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, 'PCB-77', may, contribute, to, the, development, of, obesity, and, 'obesity-associated', atherosclerosis])].
[sujeto(['Aroclor', 1242, treatment, significantly]), verbo([decreased]), complemento([testicular, size, and, testosterone, levels, in, plasma, and, adversely, affected, spermatogenic, activity, by, disrupting, epithelial, organization])].
[sujeto(['The', spermatogonia, were, either, hypertrophied, or, had, shrunken, vesiculated, cytoplasm, with, distorted, mitochondria, and]), verbo([nuclear]), complemento([pyknosis])].
[sujeto(['Changes', were, milder, in, the, 'Sertoli', 'cells,', where]), verbo([nuclear]), complemento([infoldings, were, reduced])].
[sujeto(['Characteristic', features, of, treated, 'Leydig', cells, were, the, presence, of, 'electron-dense', and, 'electron-opaque', 'zones,', appearing, as, 'plaques,', cell, membrane, 'abnormalities,', and, high, variability, in]), verbo([nuclear]), complemento([shape, and, heterochromatin, distribution])].
[sujeto(['In', 'conclusion,', 'Aroclor', 1242, treatment]), verbo([causes]), complemento([severe, structural, alterations, on, gonads, and, accessory, organs, in, adult, male, rhesus, 'monkeys,', and, these, effects, could, be, mediated, through, both, estrogen, and, 'Ah', receptors])].
[sujeto(['This']), verbo([report]), complemento([represents, the, conclusions, of, a, 'Joint', 'FAO/WHO', 'Expert', 'Committee', convened, to, evaluate, the, safety, of, various, food, additives, and, 'contaminants,', with, a, view, to, recommending, 'Acceptable', 'Daily', 'Intakes', '(', 'ADIs)', and, tolerable, 'intakes,', 'respectively,', and, to, prepare, specifications, for, the, identity, and, purity, of, food, additives])].
[sujeto(['The', first, part, of, the]), verbo([report]), complemento([contains, a, general, discussion, of, the, principles, governing, the, toxicological, evaluation, of, food, additives, '(', including, flavouring, 'agents)', and, 'contaminants,', assessments, of, 'intake,', and, the, establishment, and, revision, of, specifications, for, food, additives])].
[sujeto(['Annexed', to, the]), verbo([report]), complemento([are, tables, summarizing, the, 'Committee\'s', recommendations, for, 'ADIs', of, the, food, additives, and, tolerable, intakes, of, the, contaminants, 'considered,', changes, in, the, status, of, specifications, of, these, food, additives, and, specific, flavouring, 'agents,', and, further, information, required, or, desired])].
[sujeto(['Polychlorinated', biphenyls, '(', 'PCBs)']), verbo([induce]), complemento([apoptotic, cell, death, of, 'HL-60', cells])].
[sujeto(['Treatment', of, cells, with, phorbol, 12, -, myristate, 13, -, acetate, '(', 'PMA),', an, activator, of, 'PKC,']), verbo([suppressed]), complemento(['DNA', fragmentation, induced, by, 'PCBs', in, 'HL-60', cells])].
[sujeto(['Treatment', with, another, active, phorbol, 'ester,', 'phorbol-12,13-dibutyrate', '(', 'PDBu),', also]), verbo([suppressed]), complemento(['PCB-induced', 'DNA', 'fragmentation,', whereas, 4, 'alpha-phorbol-12,13-didecanoate', '(', 4, 'alphaPDD),', an, inactive, phorbol, 'ester,', did, not, affect, 'PCB-induced', apoptosis, of, 'HL-60', cell])].
[sujeto(['Moreover,', 1, -, 'oleoyl-2-acetyl-sn-glycerol', '(', 'OAG),', an, activator, of, 'PKC', that, is, not, a, phorbol, 'ester,', also]), verbo([suppressed]), complemento(['PCB-induced', 'DNA', fragmentation])].
[sujeto(['However,', 1, -, '(', 5, -, 'isoquinolinylsulfonyl)-2-methylpiperazine', '(', 'H-7),', an, inhibitor, of, 'PKC,']), verbo([increased]), complemento(['DNA', fragmentation, induced, by, 'PCBs'])].
[sujeto(['Furthermore,', inhibition, of, 'PKC']), verbo([promotes]), complemento(['DNA', fragmentation, of, 'HL-60', cells, treated, with, 'PCBs,', thereby, suggesting, the, involvement, of, 'PKC', activity, in, 'PCB-induced', apoptosis, of, 'HL-60', cells])].
[sujeto(['Biodegradation', of, 2, ',', 3, -, 'DCB', was]), verbo([enhanced]), complemento([with, the, microbial, 'amendment;', 'however,', the, addition, of, sunflower, oil, did, not, help, the, 'PCB', degrading, bacteria, and, may, have, enhanced, the, growth, of, the, indigenous, 'population,', thereby, decreasing, the, amended, 'PCB-degrading', population])].
[sujeto(['The', addition, of, both, carvone, and, limonene, as, potential, inducers, of, the, dioxygenase, metabolic, pathway, exerted, an]), verbo([enhancing]), complemento([effect, on, 'PCB', biodegradation, when, glycerol, and, xylose, were, used, as, carbon, 'sources,', whereas, no, such, effect, could, be, determined, with, biphenyl, and, glucose, as, substrates])].
[sujeto(['At', this, dose, the, compound]), verbo([provokes]), complemento([a, wasting, syndrome])].
[sujeto(['Our', current, study, revealed, that, 'PenCB']), verbo([suppresses]), complemento(['ADH', at, the, protein, expression, level])].
[sujeto(['The', suppression, of, triose, phosphate, metabolism, could, be, a]), verbo([cause]), complemento([of, the, wasting, syndrome, provoked, by, highly, toxic, coplanar, 'PCB'])].
[sujeto(['Strain', 'JB2', was, subsequently]), verbo([found]), complemento([also, to, grow, on, 3, -, 'chlorobenzoate,', 2, ',', 3, -, and, 2, ',', 5, -, 'dichlorobenzoates,', 2, ',', 3, ',', 5, -, 'trichlorobenzoate,', and, a, wide, range, of, other, 'mono-', and, dihalogenated, benzoic, acids])].
[sujeto(['The', initial, attack, on, chlorobenzoates, was, oxygen, dependent, and, most, likely]), verbo([mediated]), complemento([by, dioxygenases])].
[sujeto(['These', findings]), verbo([suggested]), complemento([that, strain, 'JB2', 'possessed,', in, addition, to, the, benzoate, 'dioxygenase,', a, halobenzoate, dioxygenase, that, was, necessary, for, the, degradation, of, chlorobenzoates, substituted, in, the, ortho, position])].
[sujeto(['The', ferrochelatase, inhibitory, activity, of, the, 4, -, 'butyl,', 4, -, 'pentyl,', and, 4, -, hexyl, analogues, was, considered, to, be, due, to, catalytic, activation, by, cytochrome, 'P-450']), verbo([leading]), complemento([to, heme, alkylation, and, formation, of, the, corresponding, 'N-alkylporphyrins'])].
[sujeto(['The', relative, ferrochelatase, inhibitory, activity, of, the, 'DDC', analogues]), verbo([has]), complemento([implications, for, a, postulated, model, of, the, binding, of, porphyrins, in, the, ferrochelatase, active, site])].
[sujeto([3, -, '[', 2, -, '(', 2, ',', 4, ',', 6, -, 'Trimethylphenyl)thioethyl]-4-methylsydnone', '(', 'TTMS)', was, shown, to, be, a, potent, porphyrinogenic, agent, and, to]), verbo([inhibit]), complemento([ferrochelatase, in, chick, embryo, liver, cells])].
[sujeto(['A', related, 'sydnone,', 3, -, 'benzyl-4-phenylsydnone', did, not]), verbo([inhibit]), complemento([ferrochelatase, activity])].
[sujeto(['These', results, supported, the, idea, that, the, porphyrinogenicity, of, 'TTMS', was, due, to, catalytic, activation, by, cytochrome, 'P-450']), verbo([leading]), complemento([to, heme, alkylation, and, formation, of, 'N-vinylprotoporphyrin', which, inhibits, ferrochelatase])].
[sujeto(['Polychlorinated', 'biphenyls,', 'phenobarbital,', 'nifedipine,', and, a, large, number, of, structurally, different, chemicals, which, are, porphyrinogenic, in, chick, embryo, liver, cells]), verbo([inhibit]), complemento([uroporphyrinogen, decarboxylase, by, an, unknown, mechanism])].
[sujeto(['Thus', 'drug-induced', porphyrin, biosynthesis, in, chick, embryo, liver, cell, culture, appears, to, be]), verbo([caused]), complemento([by, inhibition, of, either, ferrochelatase, or, uroporphyrinogen, decarboxylase])].
[sujeto(['(', 'ABSTRACT', 'TRUNCATED', 'AT', 250, 'WORDS)', 'Epididymal', 'adipocytes,', isolated, from, rats, pretreated, with, '[', 14, 'C]-2,4,5,2\',4\',5\'-hexachlorobiphenyl', '(', 6, -, 'CB),', were, utilized, to, examine, the, relationship, between, the, mobilization, of, lipid, and, 6, -, 'CB', and, to, determine, whether, 6, -, 'CB', was, differentially]), verbo([associated]), complemento([with, subcellular, organelles, over, time, as, has, been, demonstrated, for, newly, synthesized, lipid])].
[sujeto(['Lipolysis,']), verbo([induced]), complemento([by, the, presence, of, 8, 'X', 10, '(', -, 7, ')', 'M', isoproterenol, '(', 'ISO)', for, 50, 'min,', depleted, approximately, 1, '%', of, total, cellular, triacylglycerols, '(', 'TG)', regardless, of, time, from, treatment, with, 6, -, 'CB'])].
[sujeto(['The', percentage, of, cellular, 6, -, 'CB']), verbo([released]), complemento([from, adipocytes, to, incubation, buffer, infranatants, was, not, correlated, with, the, magnitude, of, lipolysis, produced, over, the, 50, -, min, incubation, 'period;', nor, was, the, percentage, of, 6, -, 'CB', released, to, the, buffers, correlated, with, the, length, of, the, incubation, 'period,', regardless, of, the, presence, of, 'ISO'])].
[sujeto(['Although', adipocytes]), verbo([responded]), complemento([similarly, to, lipolytic, stimuli, independent, of, time, '(', 'days)', since, 6, -, 'CB', 'treatment,', significant, decreases, were, found, in, the, percentage, of, 6, -, 'CB', released, from, adipocytes, over, time])].
[sujeto([6, -, 'CB', was, not]), verbo([released]), complemento([in, a, similar, 'fashion,', since, radioactivity, associated, with, the, chemical, levels, of, '[', 14, 'C]-6-CB', and, 'glucose-derived', 14, 'C', in, buffers, were, not, correlated, over, time])].
[sujeto([6, -, 'CB', was]), verbo([found]), complemento([to, redistribute, to, all, available, lipid, pools, during, the, subcellular, fractionation, procedure, and, thus, did, not, resemble, 'TG'])].
[sujeto(['However,', it, is, possible, that, 6, -, 'CB', may, exist, in, equilibrium, among, organelle, fractions, and, that, it, becomes, sequestered, within, the, nonsoluble, lipid, compartment, with, 'time,', thus]), verbo([decreasing]), complemento([its, appearance, in, the, soluble, buffer, infranatants, over, the, experimental, time, course])].
[sujeto(['Inhibition', and, stimulation, of, synthesis, of, phospholipids, by, polychlorinated, biphenyls, '(', 'PCB)']), verbo([have]), complemento([been, reported, by, several, authors])].
[sujeto(['The', mode, of, action, of, 'PCB', on, the, synthesis, of, phospholipids]), verbo([has]), complemento([not, been, determined])].
[sujeto(['Results', of, experiments, in, the, present]), verbo([report]), complemento([indicate, that, both, 'PCB', and, polychlorinated, biphenylols, alter, the, activities, of, key, enzymes, of, glyceride, and, phospholipid, synthesis])].
[sujeto([4, -, 'Chloro-4-biphenylol', '(', 'CB-OH),', 2, '\'', ',', 3, '\'', ',', 4, '\'', ',', 5, ',', 5, '\'', -, pentachlorobiphenylol, '(', 'PCB-OH)', and, 2, ',', 4, ',', 5, ',', 2, '\'', ',', 4, '\'', ',', 5, '\'', -, hexachlorobiphenyl, '(', 'HCB)']), verbo([inhibited]), complemento(['sn-glycerol-3-phosphate', acyltransferase, activity])].
[sujeto(['PCB-OH']), verbo([stimulated]), complemento([phosphatidase, 'activity,', but, no, apparent, change, was, observed, with, 'CB-OH'])].
[sujeto(['PCB']), verbo([inhibited]), complemento([phosphorylcholine, glyceride, transferase, 'activity,', but, had, no, significant, effect, on, diglyceride, acyl, transferase])].
[sujeto(['HCB']), verbo([caused]), complemento([enhanced, incorporation, of, '[', 2, -, 14, 'C]acetate', into, phospholipids, and, glycerides, at, low, concentration, and, reduced, incorporation, at, high, concentrations])].
[sujeto(['Triglyceride', cellular, content, was]), verbo([increased]), complemento([29, '%'])].
[sujeto(['(', 14, 'C)palmitate', and, '(', 'U-14C)sn-glycerol-3-phosphate', were, differently, incorporated, when, assayed, in, the, same, 'preparation,']), verbo([suggesting]), complemento([compartmentation, of, the, substrates])].
[sujeto(['Acyl', 'CoA', 'sn-glycerol-3-phosphate', acyl, transferase, was]), verbo([inhibited]), complemento([by, 'PCB', in, vitro])].
[sujeto(['After', 30, days, of, dietary, pretreatment, with, 'PCB,', acyl, 'CoA', 'sn-glycerol-3-phosphate', acyl, transferase, activity, was]), verbo([increased]), complemento([in, the, liver])].
[sujeto(['In', 'vitro,', the, total, radioactivity, incorporated, into, phospholipids, and, glycerides, was]), verbo([decreased]), complemento([in, the, presence, of, 'PCB'])].
[sujeto(['PCB', initially, did, not]), verbo([inhibit]), complemento(['phosphatidate,', but, after, prolonged, incubation, there, was, a, small, increase, or, decrease, under, in, vitro, and, in, vivo, conditions, respectively])].
[sujeto(['Phosphorylase', 'b,', but, not, phosphorylase, 'a,', was]), verbo([inhibited]), complemento([by, 'PCB'])].
[sujeto([2, ',', 4, ',', 5, ',', 2, '\'', 4, '\'', ',', 5, '\'', -, hexachlorobiphenyl]), verbo([inhibited]), complemento(['sn-glycerol-3-phosphate', acyl, 'transferase,', phospholipid, 'biosynthesis,', and, glyceride, biosynthesis])].
[sujeto(['In', 'May', 2015, ',', 'Zika', virus, was]), verbo([reported]), complemento([to, be, circulating, in, 'Brazil'])].
[sujeto(['Since', that, 'time,', 'Zika', virus]), verbo([has]), complemento([rapidly, spread, throughout, the, region])].
[sujeto(['As', of, 'April', 20, ',', 2016, ',', the, 'Florida', 'Department', of, 'Health', 'Bureau', of, 'Public', 'Health', 'Laboratories', '(', 'BPHL)']), verbo([has]), complemento([tested, specimens, from, 913, persons, who, met, state, criteria, for, 'Zika', virus, testing])].
[sujeto(['On', the, basis, of, previous, small, case, studies]), verbo([reporting]), complemento([real, time, 'reverse-transcription', polymerase, chain, reaction, '(', 'RT-PCR)', detection, of, 'Zika', virus, 'RNA', in, 'urine,', 'saliva,', and, semen, '(', 2, -, 6, ')', ',', the, 'Florida', 'Department', of, 'Health', collected, multiple, specimen, types, from, persons, with, suspected, 'Zika', virus, disease])].
[sujeto(['BPHL', testing, results]), verbo([suggest]), complemento([urine, might, be, the, preferred, specimen, type, to, identify, acute, 'Zika', virus, disease])].
[sujeto(['Blue', clones, were]), verbo([found]), complemento([in, 'QDO/5-bromo-4-chloro-3-indolyl-alpha-D-galactoside', '(', 'X-alpha-gal)', 'plate,', eukaryotic, expression, vectors, named, as, 'pCMV-HA-PML-C', and, 'pCMV-myc-BPHL', were, constructed, and, confirmed, with, double, restriction, enzyme, digestion, and, 'co-transfected', into, 'HEK', 293, cells, successfully])].
[sujeto(['After', immunoprecipitation, of, 'HA-PML-C', with, 'anti-HA', polyclonal, 'antibody,']), verbo([expressed]), complemento(['myc-BPHL', protein, was, identified, by, 'Western', blot, with, 'anti-c-myc', monoclonal, antibody, from, immunoprecipitated, complex])].
[sujeto(['In', 'hVACVase-catalyzed', 'reactions,', the, leaving, group, of, the, substrate, corresponds, to, the, drug, moiety, of, the, 'prodrug,', making, the, leaving, group, effect, essential, for, the, rational, design, of, new, prodrugs]), verbo([targeting]), complemento([hVACVase, activation])].
[sujeto(['In', 'conclusion,', the, substrate, leaving, group]), verbo([has]), complemento([been, shown, to, affect, both, binding, and, specific, activity, of, 'hVACVase-catalyzed', activation])].
[sujeto(['It', is, proposed, that, hVACVase, is, an, ideal]), verbo([target]), complemento([for, 'α-amino', acid, ester, prodrugs, with, relatively, labile, leaving, groups, while, it, is, relatively, inactivate, toward, amide, prodrugs])].
[sujeto(['A', prodrug, strategy, was, applied, to, 'guanidino-containing', analogues, to]), verbo([increase]), complemento([oral, absorption, via, hPEPT1, and, hVACVase])].
[sujeto(['All', the, 'l-amino', acid, 3, -, 'HPG', esters, were, effectively]), verbo([activated]), complemento([in, 'HeLa', and, 'Caco-2', cell, homogenates, and, were, found, to, be, good, substrates, of, hVACVase, '(', 'k(cat)/K(m)', in, 'mM(-1)', x, 's(-1):', 'Val-3-HPG,', 3370, ;, 'Ile-3-HPG,', 1580, ;, 'Phe-3-HPG,', 1660, ')'])].
[sujeto(['In', 'conclusion,', a, prodrug, strategy, is, effective, at]), verbo([increasing]), complemento([the, intestinal, permeability, of, polar, guanidino, analogues, via, targeting, hPEPT1, for, transport, and, hVACVase, for, activation])].
[sujeto(['We', evaluated, the, chemical, and, enzymatic, stabilities, of, prodrugs, containing, 'methoxy,', ethoxy, and, propylene, glycol, linkers, in, order, to]), verbo([find]), complemento([a, suitable, linker, for, prodrugs, of, carboxylic, acids, with, amino, acids])].
[sujeto(['It', was, observed, that, the, stability, of, the, prodrugs]), verbo([increases]), complemento([with, the, linker, length, '(', propyl, &, 'gt;', ethyl, &, 'gt;', 'methyl)'])].
[sujeto(['This', work]), verbo([suggests]), complemento([that, the, propylene, glycol, linker, is, an, optimal, linker, for, amino, acid, prodrugs, since, it, has, good, chemical, stability, and, is, enzymatically, hydrolyzed, to, yield, the, parent, drug])].
[sujeto(['This', approach, can, be, further, extended, to, other, 'non-amino', acid, prodrugs, and, to]), verbo([provide]), complemento([a, chemical, handle, to, modify, lead, molecules, containing, carboxylic, 'group(s)'])].
[sujeto(['This']), verbo([report]), complemento([describes, the, crystal, structure, and, specificity, of, a, novel, activating, enzyme, for, valacyclovir, and, valganciclovir])].
[sujeto(['Our', structural, insights, show, that, human, valacyclovirase]), verbo([has]), complemento([a, unique, binding, mode, and, specificity, for, amino, acid, esters])].
[sujeto(['Crystal', structures, of, the, 'enzyme,', two, mechanistic, 'mutants,', and, a, complex, with, a, product, 'analogue,', when, combined, with, biochemical, 'analysis,']), verbo([reveal]), complemento([the, key, determinants, for, substrate, 'recognition;', that, 'is,', a, flexible, and, mostly, hydrophobic, acyl, 'pocket,', a, localized, negative, electrostatic, 'potential,', a, large, open, leaving, 'group-accommodating', 'groove,', and, a, pivotal, acidic, 'residue,', 'Asp-123,', after, the, nucleophile, 'Ser-122'])].
[sujeto(['This', is, the, first, time, that, a, residue, immediately, after, the, nucleophile]), verbo([has]), complemento([been, found, to, have, its, side, chain, directed, into, the, substrate, binding, pocket, and, play, an, essential, role, in, substrate, discrimination, in, serine, hydrolases])].
[sujeto(['Valacyclovirase', is, a, valuable]), verbo([target]), complemento([for, amino, acid, ester, 'prodrug-based', oral, drug, delivery, enhancement, strategies])].
[sujeto(['Abstract', 'Few', genes, are, known, to, be]), verbo([involved]), complemento([in, renal, cell, carcinoma, '(', 'RCC)', development, and, progression])].
[sujeto(['The', 'cell-specific', transcription, factor, hepatocyte]), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF4', 'alpha)', is, 'down-regulated', in, 'RCC', and, we, have, shown, that, 'HNF4', alpha, inhibits, cell, proliferation, in, the, embryonic, kidney, cell, line, 'HEK293'])].
[sujeto(['By', comparing]), verbo([induced]), complemento([and, uninduced, 'cells,', we, identified, 1411, differentially, expressed, genes])].
[sujeto(['Using', 'RNA', 'interference,', we, screened, 56, 'HNF4', 'alpha-regulated', genes, for, their, possible, role, in]), verbo([mediating]), complemento([inhibition, of, cell, proliferation, triggered, by, 'HNF4', alpha])].
[sujeto(['We', demonstrate, that, 14, of, these]), verbo([regulated]), complemento([genes, are, able, to, contribute, to, the, inhibitory, effect, of, 'HNF4', alpha, on, cell, 'proliferation,', including, 'well-known', cancer, 'genes,', such, as, 'CDKN1A', '(', 'p21),', 'TGFA,', 'MME', '(', 'NEP)', and, 'ADAMTS1'])].
[sujeto(['In', 'addition,', the, genes, 'SEPP1,', 'THEM2,', 'BPHL,', 'DSC2,', 'ANK3,', 'ALDH6A1,', 'EPHX2,', 'NELL2,', 'EFHD1', and, 'PROS1', are, also, part, of, the, network, of, 'HNF4', alpha]), verbo([target]), complemento([genes, that, regulate, proliferation, in, 'HEK293', cells])].
[sujeto(['Therefore,', we, postulate, that, 'HNF4', alpha, 'orchestrates,', at, 'least,', these, 14, genes, to]), verbo([regulate]), complemento([cell, proliferation, in, 'HEK293', cells, and, that, 'down-regulation', of, 'HNF4', alpha, could, contribute, to, the, progression, of, kidney, cancer])].
[sujeto(['We', used, global, gene, expression, monitoring, by, cDNA, microarrays, to, identify, age]), verbo([associated]), complemento([genes, in, human, kidney, samples])].
[sujeto(['We', identified, approximately, 500, genes, that, were, differentially]), verbo([expressed]), complemento([among, the, three, age, groups])].
[sujeto(['Old', kidneys, appeared, to]), verbo([have]), complemento([increased, extracellular, matrix, turnover, and, a, nonspecific, inflammatory, 'response,', combined, with, a, reduction, in, processes, dependent, on, energy, metabolism, and, mitochondrial, function])].
[sujeto(['Output']), verbo([provides]), complemento([information, on, a, daily, basis, with, respect, to, daily, and, accumulated, deposition, and, current, bird, status, for, 'protein,', 'fat,', 'water,', and, ash, body, content])].
[sujeto(['The', approach, employs, empirically, derived, 'first-limiting', amino, acid, coefficients, relating, to, accretion, efficiency, and, dietary, concentration, to, define, limits, of, protein, 'retention,', uses, mathematical, expressions, describing, feed, intake, and, heat]), verbo([loss]), complemento([trajectories, as, datum, patterns, prescriptive, of, the, 'strain,', introduces, calibration, as, a, device, for, improving, correspondence, between, simulated, and, field, 'performance,', and, relies, on, an, assumption, that, deviations, to, the, datum, patterns, of, food, intake, and, heat, output, caused, by, strain, and, environmental, factors, can, be, duplicated, by, simple, multiplers, acting, on, the, expressions])].
[sujeto(['Qy-excitation', resonance, 'Raman', '(', 'RR)', spectra, are]), verbo([reported]), complemento([for, two, mutant, reaction, centers, '(', 'RCs)', from, 'Rhodobacter', capsulatus, in, which, the, photoactive, bacteriopheophytin, '(', 'BPhL)', is, replaced, by, a, bacteriochlorophyll, '(', 'BChl)', 'molecule,', designated, beta])].
[sujeto(['The', pigment, change, in, both, mutants, is]), verbo([induced]), complemento([via, introduction, of, a, histidine, residue, near, the, photoactive, cofactor])].
[sujeto(['The', different, axial, ligation, for, beta, in, the, 'F(L121)H/F(L97)V', versus, 'L(M212)H', 'RCs', in, turn]), verbo([leads]), complemento([to, different, conformations, of, the, 'BChl', macrocycles])].
[sujeto(['Nonetheless,', previous, studies]), verbo([have]), complemento([shown, that, the, primary, electron, transfer, reactions, are, very, similar, in, the, two, mutants, but, differ, in, significant, respects, compared, to, 'wild-type', 'RCs'])].
[sujeto(['Collectively,', these, observations, indicate, that, changes, in, the, conformation, of, a, photoactive, tetrapyrrole, macrocycle, or, its, interactions, with, the, protein, do, not, necessarily]), verbo([lead]), complemento([to, significantly, perturbed, photochemistry, and, do, not, underlie, the, altered, primary, events, in, 'beta-type', 'RCs'])].
[sujeto(['It', was]), verbo([found]), complemento(['that:', '(', 'a)', in, control, samples, the, molecular, rate, constants, 'km,', ke, and, kQ, were, about, '(', 3.4, 'ps)-1,', '(', 4.5, 'ps)-1', and, '(', 200, 'ps)-1,', 'respectively;', '(', 'b)', under, modification, by, 'DMSO', these, rates, decrease, up, to, '(', 5.3, 'ps)-1,', '(', 10.3, 'ps)-1', and, '(', 500, 'ps)-1,', 'respectively;', '(', 'c)', as, the, temperature, drops, from, 300, 'K', to, 77, 'K', the, rate, constant, km, decreases, by, 1.8, times, in, control, and, by, 3.2, times, in, modified, samples])].
[sujeto(['In', contrast, to, the, observed, km, changes, the]), verbo([increase]), complemento([in, ke, and, kQ, values, by, 2, and, more, times, under, cooling, was, found, in, control, and, modified, 'RC;', '(', 'd)', in, control, preparations, with, 'QA', acceptor, 'pre-reduced', in, the, dark, the, lowering, of, the, temperature, caused, the, increase, in, the, time, of, 'P+I-', recombination, from, 10, to, 20, ns])].
[sujeto(['The', results, obtained]), verbo([reveal]), complemento([that, in, 'RC', isolated, from, 'Rb'])].
[sujeto(['Qy-excitation', resonance, 'Raman', '(', 'RR)', studies, are]), verbo([reported]), complemento([for, a, series, of, 'Rhodobacter', capsulatus, reaction, centers, '(', 'RCs)', containing, mutations, at, 'L-polypeptide', residue, 121, near, the, photoactive, bacteriopheophytin, '(', 'BPhL)'])].
[sujeto(['The', studies, focus, on, the, 'electronic/structural', perturbations, of, 'BPhL']), verbo([induced]), complemento([by, replacing, the, native, 'Phe', with, an, 'Asp', residue])].
[sujeto(['Earlier', work]), verbo([has]), complemento([shown, that, the, 'electron-transfer', properties, of, 'F(L121)D', 'RCs', are, closely, related, to, those, of, 'RCs', in, which, 'BPhL', is, replaced, by, bacteriochlorophyll, '(', 'BChl)', '(', 'beta-type', 'RCs)', or, by, pheophytin])].
[sujeto(['The', replacement, of, the, aromatic, 'Phe', residue, with, 'Leu']), verbo([has]), complemento([no, discernible, effect, on, the, vibrational, properties, of, 'BPhL,', a, finding, in, concert, with, the, previously, reported, absence, of, an, effect, of, the, mutation, on, the, 'electron-transfer', characteristics, of, the, 'RC'])].
[sujeto(['The', negative, charge, of, the, carboxyl, group, of, 'Asp', 'L121']), verbo([interacts]), complemento([with, the, 'pi-electron', system, of, 'BPhL', in, a, relatively, nonspecific, 'fashion,', diminishing, the, contribution, of, 'charge-separated', resonance, forms, of, the, 'C9-keto', group, to, the, electronic, structure, of, the, cofactor])].
[sujeto(['Qy-excitation', resonance, 'Raman', '(', 'RR)', spectra, are]), verbo([reported]), complemento([for, two, mutant, reactions, centers, '(', 'RCs)', from, 'Rhodobacter', sphaeroides, in, which, the, photoactive, bacteriopheophytin, '(', 'BPhL)', is, replaced, by, a, bacteriochlorophyll, '(', 'BChl)', 'molecule,', designated, by, beta, 'L'])].
[sujeto(['The', spectroscopic, data]), verbo([reveal]), complemento([the, 'following:', '(', 1, ')', 'The', beta, 'L', cofactor, is, a, 'five-coordinate', 'BChl', molecule, with, a, histidine, axial, ligand])].
[sujeto(['(', 4, ')', 'The', hydrogen, bonding, interaction, at, the, 'C9-keto', site]), verbo([induces]), complemento([secondary, 'cofactor-protein', interactions, which, involve, the, 'C2a-acetyl', and, 'Cb-alkyl', substituent, groups])].
[sujeto(['This', transient, is, proposed, to]), verbo([involve]), complemento(['P+BPhL-', and, probably, 'P+BChlL-', as, well, '(', 'BChlL', is, the, 'L-side', bacteriochlorophyll, 'molecule)'])].
[sujeto(['These', results, indicate, that, the, 'F(L121)D', mutant, is, closely, 'related,', in, terms, of, its, electron, transfer, 'properties,', to, previously]), verbo([reported]), complemento(['RCs', in, which, 'BPhL', is, replaced, with, a, bacteriochlorophyll, '(', 'beta-type', 'RCs)', or, a, pheophytin])].
[sujeto(['However,', the, native, 'BPhL', pigment, is]), verbo([retained]), complemento([in, the, 'F(L121)D', mutant])].
[sujeto(['At', 77, 'K,', the, 'P+I-', lifetime, is, shortened, slightly, to, approximately, 120, ps, and, the, yield, of, 'P+QA-', is]), verbo([increased]), complemento([to, approximately, 88, '%'])].
[sujeto(['Achieving', all, the, nutrient, recommendations, through, the, 'NUT', model, mainly]), verbo([required]), complemento([increases, in, 'fruit,', 'vegetable,', and, fish, intake, and, decreases, in, 'meat,', 'cheese,', and, animal, fat, intake])].
[sujeto(['These', changes, were]), verbo([associated]), complemento([with, significantly, increased, dietary, exposure, to, some, 'contaminants,', but, without, exceeding, 57, '%', of, 'TRVs'])].
[sujeto(['The', highest]), verbo([increases]), complemento([were, found, for, 'NDL-PCBs', '(', from, 26, '%', to, 57, '%', of, 'TRV', for, 'women)'])].
[sujeto(['Reaching', nutritional, adequacy, without, exceeding, observed, contaminant, exposure, '(', 'NUTOX', 'model)', was, possible, but]), verbo([required]), complemento([further, departure, from, observed, food, quantities])].
[sujeto(['Based', on, a, broad, range, of, nutrients, and, 'contaminants,', this, first, assessment, of, compatibility, between, nutritional, adequacy, and, toxicological, exposure, showed, that, reaching, nutritional, adequacy, might]), verbo([increase]), complemento([exposure, to, food, 'contaminants,', but, within, tolerable, levels])].
[sujeto(['Considering', the, worst, situation, '(', highly, polluted, foods, were, 'consumed),', the, estimated, dietary, intake, for, local, residents, were, 244, '(', 'MWI)', and, 240, 'pgTEQ(kgbw)(-1)month(-1)', '(', 'E-waste', disassembling, 'sites),', approximately, 3.5, -, fold, greater, compared, to, the, standard, 70, 'pgTEQ(kgbw)(-1)month(-1)', set, by, 'JECFA,', indicating, high, risk, could]), verbo([have]), complemento([been, imposed, on, the, health, of, local, residents])].
[sujeto(['Although', some, experimental, studies]), verbo([have]), complemento([suggested, an, association, between, the, levels, of, 'PCBs', and, semen, 'quality,', the, direct, effects, of, 'PCBs', on, human, sperm, parameters, remain, largely, unexplored])].
[sujeto(['The', proportion, of, sperm, with, high, mitochondrial, membrane, potential, '(', 'ΔΨm)', and, the, levels, of, intracellular, reactive, oxygen, species, '(', 'ROS)', were, detected, to, explore, the, probable]), verbo([cause]), complemento([of, sperm, impairment])].
[sujeto(['Human', sperm, exposed, to, continuous, 'Aroclor', 1254, 'exhibited:', '(', 'i)', reduced, sperm, motility, and, kinematic, 'parameters,', '(', 'ii)', a, proportion, of, sperm, with, high, 'ΔΨm', that]), verbo([decreased]), complemento([in, a, 'dose-dependent', manner, '(', 'P', &, 'lt;', 0.05, ')', ',', and, '(', 'iii)', increased, levels, of, 'ROS', compared, with, controls, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['In', 'conclusion,', 'Aroclor', 1254, can]), verbo([decrease]), complemento([sperm, 'motility,', which, may, culminate, in, increased, 'ROS', and, general, mitochondrial, 'dysfunction,', thus, affecting, the, fertilization, potential, of, sperm])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([a, broader, understanding, of, the, effect, of, 'Aroclor', 1254, on, human, sperm])].
[sujeto([5, ')']), verbo([increased]), complemento([after, wet, 'season,', suggesting, that, atmospheric, deposition, and, surface, runoff, played, an, important, role, in, distribution, of, historical, pollutants])].
[sujeto(['In', 'general,', the, concentrations]), verbo([found]), complemento([in, air, are, similar, 'to,', or, 'below,', the, levels, at, coastal, or, 'near-coastal', sites, in, 'Europe'])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, declining, trends, of, 'HCH', in, seawater, have, been, continuing, for, 'γ-HCH', but, have, somewhat, levelled, off, for, 'α-HCH'])].
[sujeto(['This', 'region,', close, to, the, 'English', 'coast,', showed, remarkably]), verbo([increased]), complemento([surface, seawater, concentrations])].
[sujeto(['The', repeatability, of, the, method, for, all]), verbo([target]), complemento(['compounds,', expressed, as, mean, relative, standard, 'deviations,', ranged, from, 2.5, to, 5.1, &, 'nbsp;%', for, 'PCBs,', from, 3.9, to, 5.5, &, 'nbsp;%', for, 'PCNs,', and, from, 8.6, to, 17.9, &, 'nbsp;%', for, 'PAHs;', the, first, value, of, each, pair, refers, to, the, 'freeze-dried', matrix, and, the, second, to, the, fresh, 'one,', for, each, of, the, classes, of, compounds, examined])].
[sujeto(['These', results, show, that, this, method, allows, one, to]), verbo([increase]), complemento([the, laboratory, sample, throughput, while, requiring, a, small, amount, of, tissue, and, saving, time])].
[sujeto(['Additional', two, subsequent, mineral, layers, were, analyzed, to, identify, the, 'BEQ/TEQ', gradient, 'vertically,', showing, a, 'TEQ']), verbo([decrease]), complemento([of, 85.1, and, 93.8, &, 'nbsp;%', from, the, humic, to, the, first, and, second, mineral, 'layers,', respectively])].
[sujeto(['For', 'BEQ', 'values,', a]), verbo([decrease]), complemento([as, well, as, an, increase, was, detected])].
[sujeto(['Omitting', 'clean-up', revealed, about, 20, times]), verbo([increased]), complemento(['BEQ', values, presumably, due, to, 'non-persistent', bioactive, compounds, not, detected, by, chemical, analysis])].
[sujeto(['The', results, we, present]), verbo([suggest]), complemento([that, the, 'EROD', assay, can, be, used, for, the, screening, of, large, sample, quantities, for, the, identification, of, samples, showing, dioxin, and, 'dioxin-like', contaminations, even, at, low, 'levels,', which, can, then, be, further, analyzed, by, chemical, analysis, to, identify, the, congener, composition])].
[sujeto(['The', levels]), verbo([suggest]), complemento([significant, pollution, in, 'Jobos', 'Bay', with, respect, to, 'PCBs'])].
[sujeto(['Total', 'PCBs', were, measured, in, mangal, leaves, '(', 14, -, 747, 'ngg(-1)', 'dw),', roots, '(', 0.26, -, 120, 'ngg(-1)', 'dw),', and, seeds, '(', 16, -, 93, 'ngg(-1)', 'dw),']), verbo([suggesting]), complemento([bioaccumulation, from, sediments])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([of, a, historical, profile, of, 'PCBs', in, the, study, area, and, of, 'PCB', bioaccumulation, in, mangroves])].
[sujeto(['This', article]), verbo([provides]), complemento([new, and, useful, information, on, 'PCBs', in, the, 'Caribbean', area, of, the, 'GRULAC', region])].
[sujeto(['A', number, of, cases, around, the, world]), verbo([have]), complemento([been, reported, where, animals, were, found, dead, or, dying, with, symptoms, resembling, a, thiamine, '(', vitamin, 'B)', 'deficiency,', and, for, some, of, 'these,', a, link, to, pollutants, has, been, suggested])].
[sujeto(['Here,', we, investigate, whether, biomolecules]), verbo([involved]), complemento([in, thiamin, binding, and, transport, could, be, blocked, by, a, range, of, different, pollutants])].
[sujeto(['We', used, in, silico, docking, of, five, compound, classes, '(', 25, compounds, in, 'total)', to, each, of, five]), verbo([targets]), complemento(['(', prion, 'protein,', 'ECF-type', 'ABC', 'transporter,', 'thi-box', riboswitch, 'receptor,', thiamin, 'pyrophosphokinase,', and, 'YKoF', 'protein)', and, subsequently, performed, molecular, dynamics, '(', 'MD)', simulations, to, assess, the, stability, of, the, complexes])].
[sujeto(['A', few, anthropogenic, compounds, were]), verbo([found]), complemento([to, bind, the, 'ECF-type', 'ABC', 'transporter,', but, none, binds, stably, to, prion, protein])].
[sujeto(['For', the, 'riboswitch,', most, compounds, remained, in, their]), verbo([binding]), complemento([pockets, during, 50, ns, of, 'MD', 'simulation,', indicating, that, 'RNA', provides, a, promiscuous, binding, site])].
[sujeto(['Although', most, compounds, are]), verbo([found]), complemento([to, bind, to, some, of, these, 'targets,', a, larger, data, set, is, needed, along, with, more, quantitative, methods, like, free, energy, perturbation, calculations, before, firm, conclusions, can, be, drawn])].
[sujeto(['The', biomonitoring, component, of, the, 'Canadian', 'Health', 'Measures', 'Survey', '(', 'CHMS)', is, the, most, comprehensive, initiative]), verbo([providing]), complemento([general, population, 'HBM', data, in, 'Canada'])].
[sujeto(['It']), verbo([provides]), complemento(['nationally-representative', data, on, 'health,', nutritional, 'status,', environmental, 'exposures,', and, related, risks, and, protective, characteristics])].
[sujeto(['The', survey, follows, a, robust, 'planning,', design, and, sampling, protocol, as, well, as, a, comprehensive, quality, assurance, and, quality, control, regime, implemented, for, all, aspect, of, the, survey, to]), verbo([ensure]), complemento([the, validity, of, the, 'HBM', results])].
[sujeto(['Field', collection]), verbo([has]), complemento([been, completed, for, cycle, 4, '(', 2014, -, 2015, ')', ',', with, cycle, 5, '(', 2016, -, 2017, ')', in, progress, and, cycle, 6, planning, '(', 2018, -, 2019, ')', being, finalized])].
[sujeto(['CHMS', biomonitoring, data]), verbo([have]), complemento([been, used, to, establish, baseline, 'HBM', concentrations, in, 'Canadians;', inform, public, 'health,', regulatory, risk, assessment, and, management, 'decisions;', and, fulfil, national, and, international, reporting, requirements])].
[sujeto(['The', aquatic, foodweb, of, the, 'Great', 'Lakes']), verbo([has]), complemento([been, contaminated, with, polychlorinated, biphenyls, '(', 'PCBs)', since, the, 'mid-20th', 'Century'])].
[sujeto(['Threats', of, 'PCB', exposures, to, 'long-lived', species, of, 'fish,', such, as, lake, sturgeon, '(', 'Acipenser', 'fulvescens),']), verbo([have]), complemento([been, uncertain, due, to, a, lack, of, information, of, the, relative, sensitivity, of, the, species])].
[sujeto(['The', resulting, relative, potency, value, for, 'PCB', 126, '(', 'REP', =, 0.11, ')', was, greater, than, the, 'World', 'Health', 'Organization', estimate, for, fish, '(', toxic, equivalency, factor, =, 0.005, ')', ',']), verbo([suggesting]), complemento([current, risk, assessments, may, underestimate, 'PCB', toxicity, toward, lake, sturgeon])].
[sujeto(['Threshold', and, median, toxicity, values, indicate, lake, 'sturgeon,', like, other, 'Acipenser', 'species,', are, more, sensitive, to, 'PCB', and, 'TCDD', than, the, other, genera, of, 'sturgeon,', 'Scaphirhynchus,']), verbo([found]), complemento([in, 'North', 'America'])].
[sujeto(['Relatively', high, tolerance, of, the, 'DSI', technique, for, lipids, in, the, final, extracts, enabled, a, streamlined, sample, preparation, procedure, that, only]), verbo([required]), complemento([gel, permeation, chromatography, '(', 'GPC)', and, 'solid-phase', extraction, '(', 'SPE)', cleanup, with, graphitized, carbon, black])].
[sujeto(['Therefore,', instead, of, congener, specific, 'analysis,', this, streamlined, analytical, screening, method, for, 'TCDF', and, 'CB126']), verbo([has]), complemento([the, potential, to, monitor, fish, oil, contaminated, with, dioxin, and, 'dioxin-like', 'PCBs', at, or, above, current, food, safety, limits])].
[sujeto(['The', lower, 'AEs']), verbo([found]), complemento([in, this, study, might, be, attributable, to, differences, in, the, food, administered, '(', live, sandworms, vs])].
[sujeto(['In', 'addition,', the, 'AEs', in, this, study, tended, to]), verbo([increase]), complemento([with, increasing, log, 'octanol-water', partition, coefficients, '(', 'K(OW))', up, to, about, 'seven,', although, 'AEs', in, the, other, studies, using, commercial, pelletized, food, did, not, increase, with, increasing, 'logK(OW)'])].
[sujeto(['This', result]), verbo([suggests]), complemento([the, 'co-transport', of, highly, hydrophobic, 'PCB', congeners, along, with, lipids, and, fatty, acids, from, the, digested, sandworms, into, the, 'GIT', epithelium, cells])].
[sujeto(['When', prenatal, and, postnatal, exposure, were, modeled, 'together,', we]), verbo([found]), complemento([no, association, between, total, 'PCB', exposure, and, the, mental, development, index, '(', 'MDI)', or, the, physical, development, index, '(', 'PDI)'])].
[sujeto(['In', examining, 'PCB', 153, ',', we]), verbo([found]), complemento([no, association, between, 'PCB', 153, and, 'MDI,', while, higher, levels, of, postnatal, exposure, was, associated, with, a, decrease, in, 'PDI', after, adjustment, '[', β, for, highest, 'tertile=-24'])].
[sujeto(['Higher', levels, of, prenatal, 'PCB', 153, exposure, were]), verbo([associated]), complemento([with, a, statistically, significant, increased, odds, of, screening, positive, for, a, motor, delay])].
[sujeto(['In', 'sum,', when, prenatal, and, postnatal, exposures, were, considered, 'together,', breast, milk, exposure, to, 'PCB', 153, appears, to, be]), verbo([associated]), complemento([with, decrements, in, motor, 'development;', 'however,', we, cannot, rule, out, that, the, finding, was, due, to, chance])].
[sujeto(['Based', on, final, 'multivariate-adjusted', linear, regression, 'model,', maternal, 'mono-ortho-substituted', 'PCBs', were, significantly]), verbo([associated]), complemento([with, lower, scores, on, both, the, psychomotor, '(', 'PDI)', and, mental, development, indices, '(', 'MDI)'])].
[sujeto(['Evidence', from, this, and, other, studies]), verbo([suggests]), complemento([that, prenatal, 'dioxin-like', 'PCB', 'exposure,', including, 'mono-ortho', 'congeners,', may, interfere, with, brain, development, in, utero])].
[sujeto(['Non-dioxin-like', 'di-ortho-substituted', 'PCBs']), verbo([require]), complemento([further, investigation])].
[sujeto(['Active', transport, of, 'OH-PCBs', across, the, placenta, and, hydroxylation, of, 'PCBs', by, the, fetus]), verbo([suggest]), complemento([the, potential, for, greater, impact, on, the, fetus, compared, with, the, parent, 'PCB', 'compounds,', but, little, is, known, about, their, health, 'effects,', particularly, in, humans])].
[sujeto(['Cord', 4, -, 'OH-CB-107', was, significantly]), verbo([associated]), complemento([with, lower, 'MDI', '(', beta, =, -, 2.27, ;, p, =, 0.01, ')', and, 'PDI', '(', beta, =, -, 4.5, ;, p, =, 0.004, ')'])].
[sujeto(['Also,', maternal, 4, -, 'OH-CB-107', was, significantly]), verbo([associated]), complemento([with, lower, 'MDI', '(', beta, =, -, 1.76, ;, p, =, 0.03, ')', but, not, 'PDI'])].
[sujeto(['No', other, 'OH-PCB', metabolites, were]), verbo([associated]), complemento([with, decreased, 'PDI', or, 'MDI'])].
[sujeto(['Our', findings, showed, a, significant, association, of, 4, -, 'OH-CB-107', with]), verbo([decreased]), complemento(['MDI,', which, can, possibly, be, mediated, by, endocrine, 'disruption,', altered, neurotransmitter, 'functions,', or, reduced, thyroid, hormone, concentrations, in, brain])].
[sujeto(['Protein', disulfide, isomerase, '(', 'PDI)', is, a, catalyst, of, isomerization, of, substrate, protein, 'intra-', and, 'extra-molecular', disulfide, bridges, and, also]), verbo([has]), complemento([3, ',', 3, '\'', ',', 5, -, 'triiodo-l-thyronine', '(', 'T(3))-binding', activity, and, molecular, 'chaperone-like', activity])].
[sujeto(['We', previously]), verbo([found]), complemento([that, halogenated, derivatives, of, bisphenol, 'A', as, well, as, bisphenol, 'A', itself, bind, to, 'PDI', and, thereby, suppress, the, oxidative, refolding, of, reduced, 'RNaseA', by, 'PDI'])].
[sujeto(['Polychlorinated', biphenyls, '(', 'PCBs)', are, environmental, 'endocrine-disrupting', chemicals, that]), verbo([cause]), complemento([various, abnormalities, in, many, organs, such, as, the, central, nervous, system])].
[sujeto(['PCBs', are, metabolized, to, hydroxylated, compounds, '(', 'HO-PCBs)', in, humans, and, other, 'animals,', and, 'HO-PCBs']), verbo([gain]), complemento([toxicity, by, metabolism])].
[sujeto(['In', the, present, 'study,', 2, '\'', ',', 3, ',', 3, '\'', ',', 4, '\'', ',', 5, '\'', -, pentachlorobiphenyl, '(', 'penCB),', 2, '\'', ',', 3, ',', 3, '\'', ',', 5, ',', 5, '\'', ',', 6, '\'', -, hexachlorobiphenyl, '(', 'hexCB),', and, their, 4, -, hydroxylated, metabolites, '(', 'HO-penCB', and, 'HO-hexCB,', 'respectively)', were, used, to, examine, whether, they]), verbo([interact]), complemento([with, 'PDI', and, inhibit, its, activity])].
[sujeto(['HO-penCB', and, 'HO-hexCB', markedly]), verbo([inhibited]), complemento([the, binding, of, 'T(3)', to, 'PDI'])].
[sujeto(['Both', 'HO-PCBs']), verbo([inhibited]), complemento([the, oxidative, refolding, of, reduced, 'RNaseA', by, 'PDI'])].
[sujeto(['We', also, assessed, the, effects, of, 'HO-PCBs', and, 'PCBs', on, the, chaperone, activity, of, 'PDI,', which, was, measured, by, a, thermal, aggregation, 'assay,', and]), verbo([found]), complemento([that, neither, 'HO-PCBs', nor, 'PCBs', have, significant, inhibitory, or, promoting, effects])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, metabolites, of, 'PCBs', have, the, potential, to, cause, defective, protein, folding, via, 'PDI'])].
[sujeto(['Several', studies]), verbo([have]), complemento([shown, that, prenatal, 'and/or', postnatal, 'background-level', exposure, to, environmental, 'chemicals,', such, as, polychlorinated, biphenyls, '(', 'PCBs)', and, 'dioxins,', induces, adverse, effects, on, the, neurodevelopment, of, children])].
[sujeto(['However,', other, studies]), verbo([have]), complemento([not, detected, any, harmful, influences, on, neurodevelopment])].
[sujeto(['Furthermore,', except, in, western, 'countries,', no, developmental, tests]), verbo([have]), complemento([been, carried, out, in, relation, to, detailed, assessment, of, exposure, to, 'PCBs', and, dioxins])].
[sujeto(['After', adjustment, for, potential, confounding, 'variables,', the, total, 'TEQ', value, was, shown, not, to, be, significantly]), verbo([associated]), complemento([with, mental, developmental, index, '(', 'MDI)', or, psychomotor, developmental, index, '(', 'PDI)'])].
[sujeto(['However,', the, levels, of, one, polychlorinated, 'dibenzo-p-dioxin', '(', 'PCDD)', 'isomer,', total, 'PCDDs,', and, total, 'PCDDs/polychlorinated', dibenzofurans, '(', 'PCDFs)', were, significantly, negatively]), verbo([associated]), complemento([with, 'MDI,', and, the, levels, of, two, 'PCDD', isomers, and, three, 'PCDF', isomers, were, significantly, negatively, associated, with, the, 'PDI'])].
[sujeto(['Although', the, 'steam:soil', mass, ratios]), verbo([required]), complemento([to, achieve, a, given, percentage, removal, were, lower, for, lower, initial, 'PCB', soil, 'concentrations,', 'steam:', soil, mass, ratios, required, to, achieve, a, given, unit, mass, removal, were, higherfor, lower, initial, 'PCB', soil, concentrations])].
[sujeto(['Removal', efficiency, was]), verbo([found]), complemento([to, be, dependent, upon, the, amount, of, steam, 'employed,', expressed, as, a, mass, ratio, of, steam, applied, to, soil, mass])].
[sujeto(['Together', these, effects]), verbo([increase]), complemento(['mass-transfer', 'rates,', thus, enhancing, removal, of, 'PCBs', from, the, soil])].
[sujeto(['Neurobehavioral', effects, of, polychlorinated, biphenyls, '(', 'PCBs)', at, environmental, levels, of, exposure]), verbo([have]), complemento([been, reported, in, 'cross-sectional', and, prospective, studies, in, infants, and, children])].
[sujeto(['This']), verbo([report]), complemento([covers, the, 'Bayley', 'II', mental, '(', 'MDI)', and, psychomotor, development, index, '(', 'PDI)', as, well, as, the, 'Fagan', 'Test', of, 'Infant', 'Intelligence', '(', 'Visual', 'Recognition', 'Memory)', taken, at, 7, months, of, age, in, relation, to, neonatal, sigma, 'PCB'])].
[sujeto(['After', 'confounder-adjustment', significant, negative, associations, were]), verbo([found]), complemento([between, sigma, 'PCB', in, milk, and, 'MDI', '(', 'P', &, 'lt;', 0.05, ')', ',', whereas, the, other, associations, proved, insignificant])].
[sujeto(['All', intelligence, tests, are, for, children, old, than, two, and, a, half, 'years;', we, still, do, not]), verbo([have]), complemento([an, intelligence, assessment, tool, for, children, younger, than, this, age])].
[sujeto(['For', the, matched, 'controls,', we]), verbo([found]), complemento([practically, no, significant, correlation, between, the, 'BSID', developmental, indices, and, the, 'S-B', 'IQ', '(', r, =])].
[sujeto(['We', conclude, that, the, development, indices, of, 'BSID']), verbo([has]), complemento([a, better, predictive, power, on, the, intelligence, among, the, 'at-risk', group, such, as, 'Yu-Cheng', children])].
[sujeto([20, '(', 'OH)D3', displays, similar, therapeutic, properties, to, 1, ',', 25, -, dihydroxyvitamin, 'D3', '[', 1, ',', 25, '(', 'OH)2D3],', but, without]), verbo([causing]), complemento([hypercalcaemia, and, therefore, has, potential, for, development, as, a, therapeutic, drug])].
[sujeto(['CYP24A1,', the, kidney, mitochondrial, 'P450']), verbo([involved]), complemento([in, inactivation, of, 1, ',', 25, '(', 'OH)2D3,', can, hydroxylate, 20, '(', 'OH)D3', at, 'C24', and, 'C25,', with, the, products, displaying, more, potent, inhibition, of, melanoma, cell, proliferation, than, 20, '(', 'OH)D3'])].
[sujeto(['We']), verbo([found]), complemento([that, 'CYP3A4', metabolises, 20, '(', 'OH)D3', to, three, major, 'products,', 20, ',', 24, 'R-dihydroxyvitamin', 'D3', '[', 20, ',', 24, 'R(OH)2D3],', 20, ',', 24, 'S-dihydroxyvitamin', 'D3', '[', 20, ',', 24, 'S(OH)2D3]', and, 20, ',', 25, -, dihydroxyvitamin, 'D3', '[', 20, ',', 25, '(', 'OH)2D3]'])].
[sujeto(['Addition', of, 'CYP3A', 'family-specific', 'inhibitors,', troleandomycin, and, 'azamulin,', almost, completely]), verbo([inhibited]), complemento([production, of, 20, ',', 24, 'R(OH)2D3,', 20, ',', 24, 'S(OH)2D3', and, 20, ',', 25, '(', 'OH)2D3', by, human, liver, 'microsomes,', further, supporting, that, 'CYP3A4', plays, the, major, role, in, 20, '(', 'OH)D3', metabolism, by, microsomes])].
[sujeto(['Since', both, 20, ',', 24, 'R(OH)2D3', and, 20, ',', 25, '(', 'OH)2D3']), verbo([have]), complemento([previously, been, shown, to, display, enhanced, biological, activity, in, inhibiting, melanoma, cell, 'proliferation,', our, results, show, that, 'CYP3A4', further, 'activates,', rather, than, 'inactivates,', 20, '(', 'OH)D3'])].
[sujeto(['A', novel, cytochrome, 'P450', '(', 'P450)', reaction, phenotyping, method, for, 'low-clearance', compounds]), verbo([has]), complemento([been, developed, for, eight, 'P450', enzymes, '(', 'CYP1A2,', 2, 'B6,', 2, 'D6,', 2, 'C8,', 2, 'C9,', 2, 'C19,', 3, 'A,', and, 3, 'A4)', and, 'pan-cytochrome', using, the, hepatocyte, relay, approach])].
[sujeto(['This', novel, method]), verbo([provides]), complemento([a, new, approach, for, determining, the, fraction, metabolized, of, 'low-turnover', compounds, that, are, otherwise, challenging, with, the, traditional, 'methods,', such, as, chemical, inhibitors, with, human, liver, microsomes, and, hepatocytes, or, human, recombinant, 'P450', enzymes])].
[sujeto(['Carbamazepine', '(', 'CBZ)', is, widely, used, as, an, antiepileptic, agent, and]), verbo([causes]), complemento([rare, but, severe, liver, injury, in, humans])].
[sujeto(['It']), verbo([has]), complemento([been, generally, recognized, that, reactive, metabolites, formed, via, the, metabolic, activation, reaction, contribute, to, the, onset, of, liver, injuries, by, several, drugs])].
[sujeto(['In', this, 'study,', we, developed, a, novel, rat, model, of, 'CBZ-induced', liver, injury, and, attempted, to, elucidate, the]), verbo([associated]), complemento([mechanisms, by, focusing, on, the, metabolism, of, 'CBZ'])].
[sujeto(['The', repeated, administration, of, 'CBZ', for, 5, days, in, combination, with, 'l-buthionine', sulfoximine, '(', 'BSO),', a, glutathione, '(', 'GSH)', synthesis, 'inhibitor,', resulted, in]), verbo([increases]), complemento([in, the, plasma, alanine, aminotransferase, '(', 'ALT)', levels, and, centrilobular, necrosis, in, the, liver, that, were, observed, in, various, degrees])].
[sujeto(['The', 'CBZ', and, 2, -, 'hydroxy-CBZ', concentrations, in, the, plasma, after, the, last, 'CBZ', administration, were, lower, in, the, rats, with, high, plasma, 'ALT', levels, compared, with, those, with, normal, plasma, 'ALT', 'levels,', showing, the, possibility, that, the, further, metabolism, of, 'CBZ', 'and/or', 2, -, 'hydroxy-CBZ', is]), verbo([associated]), complemento([with, the, liver, injury])].
[sujeto(['Although', a, single, administration, of, 'CBZ', did, not, affect, the, plasma, 'ALT', 'levels,', even, when, cotreated, with, 'BSO,', pretreatment, with, 'dexamethasone,', a, 'CYP3A', 'inducer,']), verbo([increased]), complemento([the, plasma, 'ALT', levels])].
[sujeto(['In', 'addition,', the, rats, cotreated, with, troleandomycin, or, 'ketoconazole,', 'CYP3A', 'inhibitors,']), verbo([suppressed]), complemento([the, increased, plasma, 'ALT', levels])].
[sujeto(['In', 'conclusion,', reactive, 'metabolite(s)', of, 'CBZ', produced, by, 'CYP3A', under, the, 'GSH-depleted', condition, might, be]), verbo([involved]), complemento([in, the, development, of, liver, injury, in, rats])].
[sujeto(['The', novel, isolate, does, not]), verbo([require]), complemento(['NaCl;', growth, was, observed, between, 0, and, 8.8, '%', '(', 1.5, 'M)', 'NaCl', with, optimal, growth, at, 0.5, '%', '(', 'w/v)', 'NaCl'])].
[sujeto(['Most', cynomolgus, monkey, 'P450s', are, almost, identical, '(', '≥90%)', to, human, 'P450s;', 'however,', 'CYP2C76']), verbo([has]), complemento([low, sequence, identity, '(', approximately, 80, '%', ')', to, any, human, 'CYP2Cs'])].
[sujeto(['Although', 'CYP2C76']), verbo([has]), complemento([no, ortholog, in, humans, and, is, partly, responsible, for, species, differences, in, drug, metabolism, between, cynomolgus, monkeys, and, 'humans,', a, broad, evaluation, of, potential, substrates, for, 'CYP2C76', has, not, yet, been, conducted])].
[sujeto(['In', this, 'study,', a, screening, of, 89, marketed, 'compounds,', including, human, 'CYP2C', and, 'non-CYP2C', substrates, or, 'inhibitors,', was, conducted, to]), verbo([find]), complemento([potential, 'CYP2C76', substrates])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, monkey, 'CYP2C76', contributes, to, bupropion, hydroxylation, and, formation, of, different, nifedipine, oxidative, metabolites, as, a, result, of, its, relatively, large, substrate, cavity])].
[sujeto(['In', 'summary,', this, study, established, that, 'CYP3A-dependent', hydroxylation, is, the, main, metabolic, pathway, for, 9, -, 'AC', in, rat, and, human, 'liver,', which]), verbo([have]), complemento([to, be, taken, into, consideration, during, cancer, therapy, of, patients])].
[sujeto(['Several', 'CYP3A', enzymes]), verbo([have]), complemento([been, annotated, in, the, horse, 'genome,', but, functional, characterization, is, missing])].
[sujeto(['Chemical', inhibitors, were, used, to, determine, the, 'CYPs']), verbo([involved]), complemento([in, 'TES', biotransformation, in, equine, microsomes])].
[sujeto(['Single', 'CYPs', 3, 'A89,', 3, 'A94,', and, 3, 'A95,', recombinantly]), verbo([expressed]), complemento([in, 'V79', hamster, lung, 'fibroblasts,', were, incubated, with, 'TES', and, the, fluorescent, metabolite, 7, -, 'benzyloxy-4-trifluoromethylcoumarin', '(', 'BFC)'])].
[sujeto(['Formation', of, 6, -, 'β-hydroxytestosterone', and, 11, -, 'β-hydroxytestosterone', in, liver, microsomes, was]), verbo([inhibited]), complemento([by, 'ketoconazole,', 'troleandomycin,', and, quercetin])].
[sujeto(['Metabolism', of, 'BFC', was, significantly]), verbo([inhibited]), complemento([by, ketoconazole, in, 'CYP3A95,', whereas, troleandomycin, affected, the, activities, of, 'CYP3A94', and, 'CYP3A95'])].
[sujeto(['This']), verbo([has]), complemento([to, be, considered, in, future, in, vitro, studies])].
[sujeto(['Cynomolgus', monkeys, are, a, commonly, used, species, in, preclinical, drug, 'discovery,', and]), verbo([have]), complemento([high, genetic, similarity, to, 'humans,', especially, for, the, 'drug-metabolizing', cytochrome, 'P450s'])].
[sujeto(['However,', species, differences, are, frequently, observed, in, the, metabolism, of, drugs, between, cynomolgus, monkeys, and, 'humans,', and, delineating, these, differences]), verbo([requires]), complemento([expressed, 'CYPs'])].
[sujeto(['Toward', this, 'end,', cynomolgus, monkey, 'CYP3A4', '(', 'c3A4)', was, cloned, and]), verbo([expressed]), complemento([in, a, novel, human, embryonic, kidney, 293, -, '6E', cell, suspension, system])].
[sujeto(['All', five, substrates, were]), verbo([found]), complemento([to, be, good, substrates, of, 'c3A4,', although, some, differences, were, observed, in, the, 'Km', values])].
[sujeto(['Overall,', the, data]), verbo([suggest]), complemento([a, strong, substrate, similarity, between, c3A4, and, h3A4])].
[sujeto(['Additionally,', c3A4, exhibited, no, activity, against, 'non-h3A4', probe, 'substrates,', except, for, a, known, human, 'CYP2D6', substrate, '(', 'bufuralol),', which]), verbo([suggests]), complemento([potential, metabolism, of, human, cytochrome, 'CYP2D6-substrates', by, c3A4])].
[sujeto(['Ketoconazole', and, troleandomycin, showed, similar, inhibitory, potencies, toward, c3A4, and, 'h3A4,', whereas, 'non-h3A4', inhibitors, did, not]), verbo([inhibit]), complemento([c3A4, activity])].
[sujeto(['Drug-drug', interactions, '(', 'DDIs)', may]), verbo([cause]), complemento([serious, drug, toxicity, and, delay, development, of, candidate, drugs])].
[sujeto(['Screening', using, human, liver, microsomes, and, hepatocytes, can, help, predict, 'DDIs', but, do, not, always]), verbo([provide]), complemento([the, degree, of, certainty, required, for, confident, progression, of, a, candidate, drug])].
[sujeto(['The', impact, of, 'Cyp3a', inhibition, produced, a, further]), verbo([increase]), complemento([in, circulating, 'MDZ', concentrations, in, all, individuals, from, both, strains, of, mice, though, the, impact, of, the, elimination, of, the, 'Cyp2c', pathway, in, the, 'KO', mice, on, the, 'AUC', was, less, than, perhaps, expected])].
[sujeto(['We']), verbo([have]), complemento([shown, that, 'TAO', produces, an, increase, in, the, 'MDZ', concentration, and, a, reduction, in, the, 1, '\'', 'hydroxymidazolam/midazolam', formation, ratio, but, the, expected, difference, in, the, magnitude, of, this, effect, between, the, wild, type, and, the, 'Cyp2c', 'KO', mice, was, not, seen])].
[sujeto(['The', magnitude, of, the, 'TAO', effect, was, also, smaller, than, is]), verbo([reported]), complemento([in, humans])].
[sujeto(['Hence', further, work, is]), verbo([required]), complemento([before, this, animal, model, could, be, used, to, predict, clinical, interactions])].
[sujeto(['In', 'RHM,', 'GTE']), verbo([inhibited]), complemento(['MDZ', 1, '\'', -, hydroxylation, with, 'IC₅₀', and, 'K(i)(app)', values, of, 12.5, and, 18.8, 'µg/mL,', 'respectively,', in, a, noncompetitive, manner])].
[sujeto(['Area', under, plasma, 'concentration-time', curves, for, 'SIM', in, the, 'GTE', and, 'TAO', groups, were]), verbo([increased]), complemento([by, 3.4, -, and, 10.2, -, 'fold,', 'respectively,', compared, with, the, control])].
[sujeto(['GTE', alters, the, pharmacokinetics, of, 'SIM,', probably, by]), verbo([inhibiting]), complemento([intestinal, 'CYP3A'])].
[sujeto(['The', 'CYP2B6*6', allele, is]), verbo([associated]), complemento([with, reduced, enzyme, expression, and, activity, that, may, lead, to, interindividual, variability, in, ketamine, metabolism])].
[sujeto(['The', 'Michaelis-Menten', constants, '(', 'K(m))', for, the, 'high-affinity', enzyme, and, the, 'low-affinity', enzyme, were, similar, to, those, for, the]), verbo([expressed]), complemento(['CYP2B6', and, 'CYP3A4,', respectively])].
[sujeto(['N,N\'N\'-triethylenethiophosphoramide', '(', 'thioTEPA)', '(', 'CYP2B6', 'inhibitor,', 25, 'μM)', and, the, monoclonal, antibody, against, 'CYP2B6', but, not, troleandomycin, '(', 'CYP3A4', 'inhibitor,', 25, 'μM)', or, the, monoclonal, antibody, against, 'CYP3A4']), verbo([inhibited]), complemento([ketamine, 'N-demethylation', at, clinically, relevant, concentrations])].
[sujeto(['These', results, indicate, a, major, role, of, 'CYP2B6', in, ketamine, 'N-demethylation', in, vitro, and, a, significant, impact, of, the, 'CYP2B6*6', allele, on, 'enzyme-ketamine']), verbo([binding]), complemento([and, catalytic, activity])].
[sujeto(['The', aim, of, this, study, was, to, investigate, specificities, of, several, known, 'CYP', inhibitors, to, these, 'enzymes;', whether, they]), verbo([inhibit]), complemento([only, the, 'CYP', enzymes, and, do, not, inhibit, peroxidases])].
[sujeto(['The', 'CYP', inhibitors, 'metyrapone,', 'troleandomycine,', 'disulfiram,', 'sulfaphenazole,', quinidine, and, 1, -, aminobenzotriazole, do, not]), verbo([inhibit]), complemento(['o-anisidine', oxidation, catalyzed, by, 'HRP'])].
[sujeto(['In', 'contrast,', 'ketoconazole,', 'diethyldithiocarbamate,', 'ellipticine,', 'α-naphtoflavone,', proadifen, 'SKF525A,', 'piperonylbutoxide,', were]), verbo([found]), complemento([to, inhibit, not, only, the, 'CYPs,', but, also, the, 'HRP-mediated', oxidation, of, 'o-anisidine'])].
[sujeto(['Interestingly,', 'α-naphtoflavone']), verbo([inhibits]), complemento([oxidation, of, 'o-anisidine', by, 'HRP', with, respect, to, 'H2O2,', but, not, with, respect, to, 'o-anisidine'])].
[sujeto(['Moreover,', precaution, to]), verbo([prevent]), complemento([misinterpretation, of, results, is, necessary, in, cases, when, proadifen, 'SKF525A,', 'piperonylbutoxide,', 'diethyldithiocarbamate,', 'ketoconazole,', 'α-naphtoflavone', and, ellipticine, are, used, in, similar, studies, '(', as, 'CYP', inhibitors, in, various, complex, biological, materials, containing, both, 'CYP', and, peroxidase, 'enzymes),', since, these, chemicals, can, except, of, 'CYP', enzymes, inhibit, also, 'peroxidase-mediated', reactions])].
[sujeto(['However,', 'GSK1292263']), verbo([inhibited]), complemento(['BCRP', and, 'OATP1B1,', which, are, transporters, involved, in, statin, disposition])].
[sujeto(['In', the, clinical, 'study,', small]), verbo([increases]), complemento([in, the, 'AUC(0-inf)', of, simvastatin, '[', mean, ratio, '(', 90, '%', 'CI)', of, 1.34, '(', 1.22, ',', 1.48, ')', ']', and, rosuvastatin, '[', mean, ratio, '(', 90, '%', 'CI)', of, 1.39, '(', 1.3, ',', 1.49, ')', ']', were, observed, when, 'co-administered', with, 'GSK1292263,', which, is, consistent, with, an, inhibitory, effect, on, intestinal, 'BCRP', and, 'CYP3A4'])].
[sujeto(['In', 'contrast,', 'GSK1292263', did, not]), verbo([inhibit]), complemento(['OATP1B1', based, on, the, lack, of, changes, in, simvastatin, acid, exposure, '[', mean, 'AUC(0-inf)', ratio, '(', 90, '%', 'CI)', of, 1.05, '(', 0.91, ',', 1.21, ')', ']'])].
[sujeto(['GSK1292263']), verbo([has]), complemento([a, weak, drug, interaction, with, simvastatin, and, rosuvastain])].
[sujeto(['This', study]), verbo([provides]), complemento([a, mechanistic, understanding, of, the, in, vivo, inhibition, of, transporters, and, enzymes, by, 'GSK1292263'])].
[sujeto(['Chemical', interactions, were, investigated, on, efflux, 'pumps,', 'P-glycoprotein', '(', 'Pgp)', and, multidrug, resistance]), verbo([associated]), complemento([proteins, '(', 'MRP1/MRP2),', and, on, biotransformation, 'enzymes,', cytochrome, 'P450', '(', 'CYP1A/CYP3A)'])].
[sujeto(['Diclofenac', and, troleandomycin]), verbo([inhibited]), complemento([efflux, 'activities,', whereas, ethinylestradiol, activated, efflux, function])].
[sujeto(['Exposure', to, troleandomycin, and, 'β-naphthoflavone']), verbo([induced]), complemento(['MRP2', mRNA, 'levels,', but, no, effects, were, seen, on, 'MRP1', or, 'Pgp', expressions])].
[sujeto(['This', study, revealed, multiple, interactions, on, key, detoxification, 'systems,', which, illustrates, the, importance, of, study, effects, on, regulation, combined, with, functional, studies, to]), verbo([provide]), complemento([a, better, picture, of, the, dynamics, of, the, chemical, defense, system])].
[sujeto(['Despite', some, of, the, observed, differences, in, inactivation, kinetic, 'parameters,', the, estimated, 'DDIs', derived, from, each, of, the, tested, systems, generally, agreed, with, the, clinically]), verbo([reported]), complemento(['DDI', within, approximately, 2, -, fold])].
[sujeto(['Overall,', results, from, these, studies]), verbo([suggest]), complemento([that, in, vitro, inactivation, parameters, generated, from, plated, cell, systems, may, be, a, practical, approach, for, identifying, 'time-dependent', inhibitors, and, for, estimating, the, magnitude, of, clinical, 'DDIs'])].
[sujeto(['It']), verbo([has]), complemento([been, reported, that, hypertension, exponentially, increases, in, the, patients, with, type, 2, diabetes, mellitus])].
[sujeto(['After', the, simultaneous, single, oral, administration, of, both, 'drugs,', the, significantly, greater, 'AUCs', of, each, drug, than, that, in, each, drug, alone, could]), verbo([have]), complemento([mainly, been, due, to, the, competitive, inhibition, for, the, metabolism, of, nifedipine, and, metformin, by, each, other, via, intestinal, 'CYP3A1/2', in, addition, to, competitive, inhibition, for, the, hepatic, metabolism, of, each, drug, as, same, as, the, intravenous, study])].
[sujeto(['The', use, of, human, liver, microsomes, '(', 'HLM)', is, the, most, common, in, vitro, matrix, to, assess, 'TDI,', but, this, often]), verbo([leads]), complemento([to, an, overprediction, of, an, actual, effect, observed, clinically])].
[sujeto(['Recently,', the, use, of, human, hepatocytes]), verbo([has]), complemento([been, hypothesized, as, a, more, relevant, and, possibly, predictive, matrix, for, the, assessment, of, 'CYP3A4', 'TDI'])].
[sujeto([',', 4, -, 'hydroxynonenal,']), verbo([involves]), complemento([oxidation, to, carboxylic, 'acids,', reduction, to, 'alcohols,', and, glutathionylation, to, eventually, form, mercapturide, conjugates])].
[sujeto(['Recently,', we, demonstrated, that, 'P450s', can, oxidize, aldehydes, to, carboxylic, 'acids,', a, reaction, previously, thought, to]), verbo([involve]), complemento([aldehyde, dehydrogenase])].
[sujeto(['Metabolism', by, isolated, rat, hepatocytes, showed, that, 'HNA', formation, was]), verbo([inhibited]), complemento([by, 'cyanamide,', while, 'DHN', formation, was, not, affected])].
[sujeto(['Troleandomycin']), verbo([increased]), complemento(['HNA', production, 1.6, -, fold, while, inhibiting, 'DHN', 'formation,', suggesting, that, 'P450', 3, 'A11', is, a, major, enzyme, involved, in, rat, hepatic, clearance, of, 4, -, 'HNE'])].
[sujeto(['Feeding', mice, a, diet, containing, 't-butylated', hydroxyanisole]), verbo([increased]), complemento([the, level, of, both, activities, with, hepatic, microsomal, fractions, but, not, proportionally])].
[sujeto(['Miconazole', '(', 0.5, 'mM)', was, a, potent, inhibitor, of, these, microsomal, reduction, 'reactions,', while, phenytoin, and, 'α-naphthoflavone', '(', both, at, 0.5, 'mM)', were, partial, 'inhibitors,']), verbo([suggesting]), complemento([the, role, of, multiple, 'P450', enzymes])].
[sujeto(['The', oxidative, metabolism, of, these, aldehydes, was]), verbo([inhibited]), complemento([&, 'gt;90%', in, an, 'Ar', or, 'CO', 'atmosphere,', while, the, reductive, reactions, were, not, greatly, affected])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'P450s', are, significant, catalysts, of, the, reduction, of, 'α,β-unsaturated', aldehydes, in, the, liver])].
[sujeto(['They', show, considerable, resistance, to, food, and, feed, processing, technologies, and, might]), verbo([cause]), complemento([intoxication, of, humans, and, animals])].
[sujeto(['The', observed, difference, of, in, vitro, and, in, vivo, toxicities]), verbo([suggests]), complemento([low, absorption, or, fast, elimination, of, the, enniatins, after, oral, uptake])].
[sujeto(['Here', we, asked, if, insulin, activation, of, the, nucleus, accumbens, in, vitro, is, reflected, by, an]), verbo([increase]), complemento([in, '(', 3, ')', 'H-deoxyglucose', '(', '[', '(', 3, ')', 'H]DG)', 'uptake,', thus, subserving, a, new, model, to, study, molecular, mechanisms, of, central, insulin, actions])].
[sujeto(['We']), verbo([found]), complemento([that, in, acute, accumbal, 'slices,', insulin, '(', 3, and, 300, nM, but, not, at, 0.3, 'nM)', produced, an, increase, in, '[', '(', 3, ')', 'H]DG', uptake])].
[sujeto(['The', glucocorticoid, receptor, '(', 'GcR)', 'antagonist,', mifepristone, '(', 10, 'μM)']), verbo([prevented]), complemento([dexamethasone, from, inhibiting, 'insulin\'s', action])].
[sujeto(['On', the, other, 'hand,', the, blockade, of, the, 'post-synaptic', 2, -, 'AG', metabolizing, 'enzymes,', 'α,β-serine', hydrolase, domain, 6, /, 12, by, 'WWL70', '(', 1, 'μM)', also]), verbo([prevented]), complemento([the, action, of, 'insulin,', probably, via, increasing, endogenous, 2, -, 'AG', tone])].
[sujeto(['Altogether,', insulin]), verbo([stimulates]), complemento([glucose, uptake, in, the, nucleus, accumbens])].
[sujeto(['Accumbal', 'GcR', activation]), verbo([triggers]), complemento([the, synthesis, of, 2, -, 'AG', that, in, turn, binds, to, the, known, 'CB1R-InsR', 'heteromer,', thus, impeding, insulin, signaling])].
[sujeto(['Among', this, population, with, 'Type', 2, diabetes, high, liver, fat, was]), verbo([associated]), complemento([with, 'hyperinsulinemia,', higher, fasting, glucose, 'levels,', peripheral, and, hepatic, insulin, 'resistance,', and, impaired, suppression, of, 'FFA', oxidation, and, 'FFA', and, glycerol, turnover, during, hyperinsulinemia])].
[sujeto(['Longer', term, treatments]), verbo([targeting]), complemento([glucocorticoid, action, may, be, useful, in, 'Type', 2, diabetes, with, and, without, fatty, liver])].
[sujeto(['Signals', from, intracellular, glucocorticoids, '(', 'GCs)', via, 11, 'β-hydroxysteroid', dehydrogenase, type, 1, '(', 11, 'β-HSD1)', in, adipose, tissues]), verbo([have]), complemento([been, reported, to, serve, as, amplifiers, leading, to, deterioration, of, glucose, metabolism, associated, with, obesity])].
[sujeto(['Cortisone', 'pellet-implanted', 'DIO', mice, '(', 'DIO/CP', 'mice)', showed, 'hyperglycemia,', insulin, 'resistance,', 'hyperlipidemia,', and, ectopic, fat, 'accumulation,', whereas, cortisone, pellet, implantation, in, lean, mice, did, not]), verbo([induce]), complemento([hyperglycemia])].
[sujeto(['In', 'DIO/CP', 'mice,', indexes, of, lipolysis, such, as, plasma, glycerol, and, nonesterified, fatty, acids, '(', 'NEFAs)']), verbo([increased]), complemento([before, hyperglycemia, appeared])].
[sujeto(['RU486', '(', 'mifepristone,', 11, 'β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one),', a, glucocorticoid, receptor, 'antagonist,']), verbo([decreased]), complemento([adipose, mRNA, levels, of, 11, 'β-HSD1', as, well, as, adipose, triglyceride, lipase])].
[sujeto(['These', results, demonstrate, that, lipolysis, in, adipose, tissues]), verbo([caused]), complemento([by, 'GC', activation, via, 11, 'β-HSD1', serves, as, a, trigger, for, diabetes, with, ectopic, fat, accumulation])].
[sujeto(['Clear', cells]), verbo([express]), complemento([the, vacuolar, 'proton-pumping', 'H(+)-ATPase', '(', 'V-ATPase)', and, acidify, the, lumen, of, the, 'epididymis,', a, process, that, is, essential, for, male, fertility])].
[sujeto(['The', 'renin-angiotensin-aldosterone', system, '(', 'RAAS)']), verbo([regulates]), complemento([fluid, and, electrolyte, balance, in, the, 'epididymis,', and, a, previous, study, showed, binding, of, aldosterone, exclusively, to, epididymal, clear, cells, '(', 'Hinton', 'BT,', 'Keefer', 'DA'])].
[sujeto(['RT-PCR', showed, expression, of, the, mineralocorticoid, receptor, '[', 'MR;']), verbo([nuclear]), complemento([receptor, subfamily, 3, ',', group, 'C', member, 2, '(', 'NR3C2)]', and, 11, -, 'β-dehydrogenase', isozyme, 2, '(', 'HSD11β2)', mRNAs, specifically, in, clear, 'cells,', isolated, by, 'fluorescence-activated', cell, sorting, from, 'B1-enhanced', green, fluorescent, protein, '(', 'EGFP)', mice])].
[sujeto(['Tail', vein, injection, of, adult, rats, with, 'aldosterone,', 1, ',', 2, -, 'dioctanoyl-sn-glycerol', '(', 'DOG),', or, 8, -, '(', 4, -, 'chlorophenylthio)-cAMP', '(', 'cpt-cAMP)']), verbo([induced]), complemento(['V-ATPase', apical, membrane, accumulation, and, extension, of, 'V-ATPase-labeled', microvilli, in, clear, cells, in, the, caput, epididymis, but, not, in, the, cauda])].
[sujeto(['Aldosterone']), verbo([induced]), complemento([a, rapid, increase, in, the, rate, of, 'Na(+)-', and, 'bicarbonate-independent', pHi, recovery, following, an, 'NH4Cl-induced', acid, load, in, clear, cells, isolated, from, the, caput, but, not, the, cauda])].
[sujeto(['Thus', aldosterone]), verbo([increases]), complemento(['V-ATPase-dependent', proton, secretion, in, clear, cells, in, the, caput, epididymis, via, 'MR/NR3C2', and, 'PKC', activation])].
[sujeto(['ATP']), verbo([binding]), complemento([cassette, 'A1', '(', 'ABCA1)', transports, 'cholesterol,', phospholipids, and, lipophilic, molecules, to, and, across, cellular, membranes])].
[sujeto(['Mock', 'BHK', cells, or, cells]), verbo([expressing]), complemento([a, 'mifepristone-inducible', 'ABCA1', '(', 'ABCA1)', were, incubated, plus, or, minus, mifepristone, and, then, with, '[', '(', 3, ')', 'H]serine', or, '[', '(', 3, ')', 'H]inositol', or, '[', '(', 3, ')', 'H]ethanolamine', or, '[', 'methyl-(3)H]choline', or, '[', '(', 3, ')', 'H]glycerol', or, '[', '(', 14, ')', 'C]oleate', and, radioactivity, incorporated, into, glycerolipids, determined])].
[sujeto([5, ')', ',', 'respectively,', upon, 'ABCA1', induction, confirming]), verbo([increased]), complemento(['PtdSer', biosynthesis, from, these, precursors])].
[sujeto(['However,', mifepristone]), verbo([inhibited]), complemento(['[', '(', 3, ')', 'H]serine', uptake, and, incorporation, into, 'PtdSer', indicating, that, 'PtdSer', synthesis, from, serine, in, 'BHK', cells, is, dependent, on, serine, uptake])].
[sujeto(['Mifepristone']), verbo([stimulated]), complemento(['[', '(', 3, ')', 'H]inositol', uptake, in, mock, and, 'ABCA1', cells, but, not, its, incorporation, into, phosphatidylinositol, indicating, that, its, synthesis, from, inositol, is, independent, of, inositol, uptake, in, 'BHK', cells])].
[sujeto(['[', '(', 3, ')', 'H]glycerol', and, '[', '(', 14, ')', 'C]oleate', incorporated, into, triacylglycerol, were, reduced, and, into, diacylglycerol, elevated, only, in, 'mifepristone-induced', 'ABCA1']), verbo([expressing]), complemento([cells, due, to, a, decrease, in, diacylglycerol, 'acyltransferase-1', '(', 'DGAT-1)', activity])].
[sujeto(['Thus,', mifepristone]), verbo([has]), complemento([diverse, effects, on, de, novo, glycerolipid, synthesis])].
[sujeto(['We']), verbo([suggest]), complemento([that, caution, should, be, exercised, when, using, 'mifepristone-inducible', systems, for, studies, of, glycerolipid, metabolism, in, cells, expressing, glucocorticoid, responsive, receptors])].
[sujeto(['Glucocorticoids', '(', 'GCs)']), verbo([have]), complemento([long, been, thought, to, be, lipolytic, in, nature])].
[sujeto(['Recently,', 'however,']), verbo([increased]), complemento([exposure, to, 'GCs', in, 'insulin-sensitive', tissues, has, been, associated, with, lipid, accumulation, and, metabolic, 'complications,', regardless, of, plasma, concentrations])].
[sujeto(['We', hypothesized, that, exercise, training, would]), verbo([increase]), complemento([11, betaHSD1, and, 'GR', protein, in, adipose, 'tissue,', resulting, in, increased, lipolysis])].
[sujeto(['Young', '(', 6, week, 'old)', 'hamsters,', 'fructose-fed', to]), verbo([induce]), complemento([an, obese, 'phenotype,', and, older, '(', 6, month, 'old)', hamsters, were, randomly, divided, into, exercising, and, sedentary, groups])].
[sujeto(['Exercise', training]), verbo([decreased]), complemento([adipose, tissue, mass, in, both, 'fructose-fed', and, older, hamsters])].
[sujeto(['In', 'addition,', exercise, training]), verbo([increased]), complemento([11, betaHSD1, '(', 31.5, '%', +, /, -, 15, '%', and, 20.0, '%', +, /, -, 7, '%', ',', 'fructose-fed', and, 'older,', 'respectively)', and, 'GR', '(', 45.6, '%', +, /, -, 14, '%', and, 61.1, '%', +, /, -, 27, '%', ',', 'fructose-fed', and, 'older,', 'respectively)', protein, expression, in, the, perirenal, adipose, depot, and, increased, 11, betaHSD1, '(', 16.7, '%', +, /, -, 7, '%', ',', 'P', =])].
[sujeto(['To', determine, the, metabolic, effect, of]), verbo([increased]), complemento(['GC', exposure, in, 'adipocytes,', 3, 'T3-L1', adipocytes, were, treated, with, corticosterone, for, 24, 'hours;', and, measures, of, lipolytic, rates, were, conducted])].
[sujeto(['Low', concentrations, of, 'GCs', '(', 0.01, -, 0.1, 'micromol/L)']), verbo([increased]), complemento(['GR', '(', 44.1, '%', +, /, -, 18, '%', ',', 'P', &, 'lt;'])].
[sujeto(['The']), verbo([increased]), complemento([lipolysis, was, blocked, by, 'RU486,', a, 'GR', 'antagonist,', suggesting, that, the, elevated, lipolysis, was, a, direct, result, of, 'GC', action])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, exercise, training, amplifies, the, activity, of, 'GCs', in, adipose, tissue, of, overweight, animals, through, alterations, in, 11, betaHSD1, and, 'GR', despite, differences, in, age, and, amounts, of, adiposity])].
[sujeto(['In', 'vitro,', 'GCs', are, capable, of]), verbo([increasing]), complemento(['lipolysis,', but, depend, upon, the, presence, of, 'GR'])].
[sujeto(['We', propose, that, 'GCs', play, a, significant, role, in, changing, the, phenotype, of, adipose, tissue, during, exercise, 'training,', resulting, in]), verbo([decreased]), complemento([fat, mass])].
[sujeto(['PMA', and, 'OAG', significantly]), verbo([increased]), complemento(['ROS', in, platelets, '(', 'P&lt;0'])].
[sujeto(['The', 'PMA-induced', 'ROS']), verbo([increase]), complemento([was, significantly, reduced, in, the, presence, of, 10, 'micromol/l', prednisolone, to, 9, +, /, -, 1, '%', '(', 'n=31;', 'P&lt;0'])].
[sujeto(['It', is, concluded, that, 'glucocorticoids,', prednisolone, and, 'dexamethasone,', directly]), verbo([inhibit]), complemento([production, of, intracellular, 'ROS'])].
[sujeto(['A', gradual]), verbo([increase]), complemento([in, 'IL-6', secretion, by, adipocytes, during, differentiation, was, observed])].
[sujeto(['A', positive, correlation, was]), verbo([found]), complemento([between, basal, 'IL-6', release, and, both, glycerol, 3, -, phosphate, dehydrogenase, 'activity--a', marker, of, adipocyte, 'differentiation-and', leptin, release])].
[sujeto(['Dexamethasone']), verbo([decreased]), complemento(['IL-6', secretion, and, increased, leptin, secretion, in, a, 'dose-dependent', manner])].
[sujeto(['Both', catecholamines]), verbo([increased]), complemento(['IL-6', and, leptin, secretion])].
[sujeto(['Furthermore', it, is, a, hormonally]), verbo([regulated]), complemento(['cytokine,', suppressed, by, 'glucocorticoids,', and, stimulated, by, catecholamines, and, insulin, in, physiological, concentrations])].
[sujeto(['At', 10, '(', -, 8, ')', 'M,', progesterone]), verbo([stimulated]), complemento([the, activity, of, 'glycerol-3-phosphate', dehydrogenase, and, triglyceride, deposition])].
[sujeto(['Progesterone,', 'R5020,', 'cortisol,', and, 'RU38486']), verbo([increased]), complemento([triglycerides, about, 2, -, fold, at, 10, '(', -, 7, ')', 'M'])].
[sujeto(['When', the, cells, were, cultured, in, presence, of, 10, '(', -, 5, ')', 'M', metyrapone, the, effect, of, progesterone, was, 'unchanged,']), verbo([suggesting]), complemento([that, the, progesterone, was, not, metabolized, to, a, glucocorticoid])].
[sujeto(['These', results, indicate, a, 'significant,', reproducible, 'dose-dependent', effect, of, progestins, on, differentiation, of, the, 'preadipocytes,', which, appears, to, be]), verbo([mediated]), complemento([via, the, glucocorticoid, receptor])].
[sujeto(['RU38486', accelerated, the, onset, of, 'differentiation,', as, monitored, by, cell, morphological, 'changes,', accumulation, of, lipid, droplets, and, widespread]), verbo([increases]), complemento([in, the, rate, of, expression, of, several, enzyme, adipose, markers, and, specific, mRNAs])].
[sujeto(['RU38486', induction, of, 'G3PDH-specific', activity, ran, parallel, to, an]), verbo([increase]), complemento([in, 'G3PDH', mRNA, content, '(', 2.4, -, fold, the, control, content, 4, days, after, 'confluence)'])].
[sujeto(['RU38486', responsiveness, observed, in, differentiating, 3, 'T3-F442A', cells, is, dependent, upon, their, prior, developmental, 'activation;', none, of, the, studied, markers, could, be]), verbo([induced]), complemento([by, the, drug, in, the, undifferentiating, 3, 'T3-C2', cell, subclone])].
[sujeto(['We']), verbo([have]), complemento([examined, and, compared, the, binding, characteristics, and, transformation, in, vitro, of, human, uterine, cytosolic, progesterone, receptor, '(', 'PR)', bound, to, either, the, progestin, 'agonist,', 'R5020', or, the, 'antiprogestin,', 'RU486'])].
[sujeto(['The', '[', 3, 'H]R5020']), verbo([binding]), complemento([in, the, 4, 'S', peak, was, not, competable, with, either, steroid])].
[sujeto(['In', 'contrast,', the]), verbo([binding]), complemento([of, '[', 3, 'H]RU486', in, the, 4, 'S', peak, could, be, abolished, by, a, pretreatment, of, uterine, cytosol, with, excess, 'RU486,', but, not, progesterone])].
[sujeto(['The', thermal, '(', 23, degrees, 'C)', transformation, of, the, '[', 3, 'H]RU486-receptor', 'complex,', as, a, function, of, the]), verbo([loss]), complemento([of, the, area, under, the, 8, 'S', 'peak,', appeared, to, be, comparable, to, that, achieved, with, '[', 3, 'H]R5020-receptor', complex])].
[sujeto(['These', results, demonstrate, that, in, human, uterine, 'cytosol,', 'R5020', and, 'RU486']), verbo([bind]), complemento([in, a, specific, and, saturable, manner, to, an, 8, 'S', 'PR,', which, is, susceptible, to, thermal, 8, 'S', to, 4, 'S', transformation])].
[sujeto(['In', 'addition,', '[', 3, 'H]R5020', also]), verbo([interacts]), complemento([with, a, nonsaturable, 4, 'S', 'macromolecule,', whereas, the, 4, 'S', '[', 3, 'H]RU486', binder, is, saturable, and, specific, for, 'RU486'])].
[sujeto(['The', above, observations, indicate, the, heterogeneity, of, the, steroid]), verbo([binding]), complemento([components, present, in, the, human, uterine, 'cytosol,', and, suggest, that, caution, should, be, taken, when, interpreting, data, which, shows, the, presence, of, different, molecular, forms, of, the, steroid, receptors])].
[sujeto(['We']), verbo([have]), complemento([examined, and, compared, the, binding, characteristics, of, the, progesterone, agonist, 'R5020', '[', 'promegestone,', 17, ',', 21, -, 'dimethylpregna-4,9(10)-diene-3,20-dione]', and, the, progesterone, antagonist, 'RU486', '[', 'mifepristone,', 17, 'beta-hydroxy-11', 'beta-[4-(dimethylamino)', 'phenyl]-17', 'alpha-(prop-1-ynyl)-estra-4,9-dien-3-one]', in, calf, uterine, cytosol])].
[sujeto(['Both', steroids]), verbo([bound]), complemento([cytosol, 'macromolecule(s)', with, high, 'affinity,', exhibiting, 'Kd', values, of, 5.6, and, 3.6, nM, for, 'R5020', and, 'RU486', 'binding,', respectively])].
[sujeto(['The']), verbo([binding]), complemento([of, the, steroids, to, the, 'macromolecule(s)', was, rapid, at, 4, degrees, 'C,', showing, saturation, of, binding, sites, at, 1, -, 2, h, for, '[', 3, 'H]progesterone', and, 2, -, 4, h, for, both, '[', 3, 'H]R5020', and, '[', 3, 'H]RU486'])].
[sujeto(['Addition', of, molybdate, and, glycerol, to, cytosol]), verbo([increased]), complemento([the, extent, of, '[', 3, 'H]R5020', binding])].
[sujeto(['The', extent, of, '[', 3, 'H]RU486']), verbo([binding]), complemento([remained, unchanged, in, the, presence, of, 'molybdate,', whereas, glycerol, had, an, inhibitory, effect])].
[sujeto(['Competitive', steroid]), verbo([binding]), complemento([analysis, revealed, that, '[', 3, 'H]progesterone,', '[', 3, 'H]R5020,', and, '[', 3, 'H]RU486', compete, for, the, same, 'site(s)', in, the, uterine, 'cytosol,', suggesting, that, all, three, bind, to, the, progesterone, receptor, '(', 'PR)'])].
[sujeto(['Sedimentation', rate, analysis, showed, that, both, steroids, were]), verbo([bound]), complemento([to, a, molecule, that, sediments, in, the, 8, 'S', region])].
[sujeto(['(', 'ABSTRACT', 'TRUNCATED', 'AT', 250, 'WORDS)', 'The', relative, rate, of, ovalbumin, transcription, was, significantly]), verbo([increased]), complemento(['(', 'P', less, than, 0.001, ')', when, purified, chick, liver, glucocorticosteroid, receptor, '(', 'GR)', was, incubated, with, purified, nuclei, prepared, from, the, oviducts, of, diethylstilboestrol, '(', 'DES)-primed', chickens, 24, h, after, oestrogen, withdrawal])].
[sujeto(['This']), verbo([increase]), complemento([was, observed, whether, 'GR', was, bound, by, the, agonist, triamcinolone, acetonide, '(', 'TA,', +, 80.3, '%', ')', or, the, antiglucocorticosteroid, 'RU', 486, '(', +, 89.4, '%', ')'])].
[sujeto(['No', significant]), verbo([increase]), complemento(['(', 'P', greater, than, 0.05, ')', in, the, relative, rate, of, ovalbumin, transcription, occurred, when, oviduct, nuclei, were, incubated, with, 'TA', or, 'RU', 486, alone, or, when, purified, 'GR', was, incubated, with, chicken, liver, nuclei, prepared, from, the, same, animals])].
[sujeto(['Furthermore,', the]), verbo([binding]), complemento([of, in, vitro, transformed, '(', 4, 'S)', 'TA-', and, 'RU', 486, -, 'GR', complexes, to, either, 'DNA-cellulose', or, mouse, mammary, tumor, virus, '(', 'MMTV)', long, terminal, repeat, '(', 'LTR)', 'DNA', were, indistinguishable, when, performed, under, 'steady-state', conditions])].
[sujeto(['These', data, showing, an, agonist, behaviour, of, the, transformed, 4, 'S-form', of, 'RU', 486, -, 'GR', 'complexes,', together, with, those, previously, 'reported,']), verbo([suggest]), complemento([that, in, vivo, the, antagonistic, activity, of, 'RU', 486, stands, at, the, level, of, receptor, transformation])].
[sujeto(['The', synthetic, compound, effectively, '(', 100, '%', ')']), verbo([inhibited]), complemento([implantation, when, administered, on, day, 2, as, well, as, on, day, 4, postconception, '(', 2.5, 'mg/kg,', in, 'glycerol)'])].
[sujeto(['A', light, microscopic, study, of, the, endometrium, showed]), verbo([decreased]), complemento([cytoplasmic, vacuole, formation, but, estrogenic, effects, were, apparently, preserved])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, administration, of, 'RU38486', immediately, after, conception, could, successfully, prevent, implantation, without, altering, early, luteotropic, functions, in, rats])].
[sujeto(['Also', the, high, dose, of, the, compound, was]), verbo([found]), complemento([to, have, no, significant, toxic, effects, on, fertilized, 'ovum,', indicating, that, the, anticonceptional, action, of, 'RU38486', mainly, functions, at, the, uterine, endometrial, level])].
[sujeto(['Effects', of, different, transforming, agents, were, examined, on, the, sedimentation, characteristics, of, calf, uterine, progesterone, receptor, '(', 'PR)']), verbo([bound]), complemento([to, the, synthetic, progestin, '[', 3, 'H]R5020', or, the, known, progesterone, antagonist, '[', 3, 'H]RU38486', '(', 'RU486)'])].
[sujeto(['Incubation', of, cytosol, containing, '[', 3, 'H]PRc', at, 23, degrees, 'C', for, 10, -, 60, 'min,', or, at, 0, degrees, 'C', with, 0.15, -, 0.3, 'M', 'KCl', or, 1, -, 10, mM, 'ATP,']), verbo([caused]), complemento([a, gradual, transformation, of, 'PRc', to, a, slow, sedimenting, 4, 'S', form])].
[sujeto(['Treatment', with, all, three, activation, agents]), verbo([caused]), complemento([a, decrease, in, the, 8, 'S', form, but, no, concomitant, transformation, of, the, '[', 3, 'H]RU486-receptor', complex, into, the, 4, 'S', form])].
[sujeto(['However,', the, cytosol, 'PR', transformed, in, the, absence, of, any, added, ligand, failed, to]), verbo([bind]), complemento(['[', 3, 'H]RU486'])].
[sujeto(['Heat', treatment, of, both, '[', 3, 'H]R5020-', and, '[', 3, 'H]RU486-receptor', complexes]), verbo([caused]), complemento([an, increase, in, 'DNA-cellulose', 'binding,', although, the, extent, of, this, binding, was, lower, when, 'RU486', was, bound, to, receptors])].
[sujeto(['An', aqueous, 'two-phase', partitioning, analysis, revealed, a, significant, change, in, the, surface, properties, of, 'PR', following, both]), verbo([binding]), complemento([to, ligand, and, subsequent, transformation])].
[sujeto(['The', partition, coefficient, '(', 'Kobsd)', of, the, 'heat-transformed', '[', 3, 'H]R5020-receptor', complex]), verbo([increased]), complemento([about, 5, -, fold, over, that, observed, with, 'PR', at, 0, degrees, 'C'])].
[sujeto(['Treatment', with, 'E2', benzoate, alone, resulted, in, a, marked]), verbo([decrease]), complemento([of, plasma, 'gonadotropins;', in, those, patients, who, received, either, 'P,', 'RU', 486, ',', or, 'both,', in, addition, to, 'E2', 'benzoate,', the, concentrations, of, plasma, 'LH', and, 'FSH', were, further, decreased, to, premenopausal, levels])].
[sujeto(['Glycerol']), verbo([decreased]), complemento([markedly, the, affinity, of, 'RU', 486, ',', whereas, the, affinity, of, 'P', for, the, 'PR', was, unchanged])].
[sujeto(['Either', 'P', or, 'RU', 486, ',', but, not, both, 'together,']), verbo([induced]), complemento([secretory, changes, in, the, endometrium, as, determined, from, histologic, sections, of, tissue, biopsies])].
[sujeto(['Either', 'P', or, 'RU', 486]), verbo([decreased]), complemento(['DNA', polymerase, alpha, and, increased, 'E2-DH', activities, in, the, endometrium])].
[sujeto(['E2-DH', activity, remained, at, the, level]), verbo([found]), complemento([in, 'E2-treated', women])].
[sujeto(['In', vitro, cultures, of, proliferative, endometrium, treated, with, the, synthetic, progestagen, 'R', 5020, or, with, 'RU', 486, also, had]), verbo([increased]), complemento(['E2-DH', 'activity;', 'RU', 486, counteracted, 'R', 5020, effects])].
[sujeto(['We', conclude, 'that,', contrary, to, previous, results, with, experimental, 'animals,', the, 'anti-P', 'RU', 486]), verbo([has]), complemento([some, progestomimetic, activity, in, humans, under, specific, conditions])].
[sujeto(['Transient', 'Receptor', 'Potential', 'Melastatin', 3, '(', 'TRPM3)', is, a, widely]), verbo([expressed]), complemento(['calcium-permeable', 'non-selective', cation, channel, that, is, stimulated, by, high, concentrations, of, nifedipine, or, by, physiological, steroids, that, include, pregnenolone, sulphate])].
[sujeto(['Here', we, sought, to, identify, steroids, that]), verbo([inhibit]), complemento(['TRPM3'])].
[sujeto(['Progesterone', '(', 0.01, -, 10, 'μM)']), verbo([suppressed]), complemento(['TRPM3', activity, evoked, by, pregnenolone, sulphate])].
[sujeto(['Overlay', assays, indicated, that, pregnenolone, 'sulphate,', progesterone, and, dihydrotestosterone]), verbo([bound]), complemento([to, 'TRPM3'])].
[sujeto(['In', contrast, to, 'dihydrotestosterone,', progesterone]), verbo([inhibited]), complemento(['nifedipine-evoked', 'TRPM3', activity, or, activity, in, the, absence, of, an, exogenous, 'activator,', suggesting, a, pregnenolone, 'sulphate-independent', mechanism, of, action])].
[sujeto(['Dihydrotestosterone,', like, a, 'non-steroid', 'look-alike', 'compound,']), verbo([acted]), complemento([as, a, competitive, antagonist, at, the, pregnenolone, sulphate, binding, site])].
[sujeto(['Progesterone']), verbo([inhibited]), complemento([endogenous, 'TRPM3', in, vascular, smooth, muscle, cells])].
[sujeto(['Relevance', of, 'TRPM3', or, the, progesterone, effect, to, ovarian, 'cells,', which]), verbo([have]), complemento([been, suggested, to, express, 'TRPM3,', was, not, identified])].
[sujeto(['The', data, further, define, a, chemical, framework, for, competition, with, pregnenolone, sulphate, at, 'TRPM3', and, expand, knowledge, of, steroid, interactions, with, 'TRPM3,']), verbo([suggesting]), complemento([direct, steroid, binding, and, pregnenolone, 'sulphate-independent', inhibition, by, progesterone])].
[sujeto(['Recent', studies]), verbo([have]), complemento([shown, that, changes, in, glomerular, proteoglycan, expression, may, play, a, major, role, in, the, pathogenesis, of, renal, disease])].
[sujeto(['Treatment', of, cultured, 'RMC', with, dexamethasone, resulted, in, a, 'dose-', and, 'time-dependent']), verbo([decrease]), complemento(['(', 'P', &, 'lt;', 0.05, ')', in, both, 'cell-associated', and, secreted, proteoglycan, synthesis, to, approximately, 50, '%', of, control, levels])].
[sujeto(['This', effect, was]), verbo([inhibited]), complemento([by, the, glucocorticoid, antagonist, 'mifepristone,', and, mimicked, by, prednisolone, or, corticosterone, treatment])].
[sujeto(['Separation', of, proteoglycans, by, 'ion-exchange', and, gel, permeation, chromatography]), verbo([suggested]), complemento([that, chondroitin, 'sulfate/dermatan', sulfate, proteoglycans, were, 'down-regulated', after, steroid, treatment])].
[sujeto(['Northern', blot, 'analysis,', 'RT-PCR,', 'Western', 'blot,', and, promoter, activity, assays, revealed, that, dexamethasone]), verbo([caused]), complemento([a, significant, decrease, in, decorin, mRNA, '(', to, 61, +, /, -, 8, '%', of, 'controls),', whereas, biglycan, expression, and, promoter, activity, were, increased, after, steroid, treatment])].
[sujeto(['A', similar, trend, was]), verbo([found]), complemento([in, glomeruli, isolated, from, rats, treated, in, vivo, with, dexamethasone])].
[sujeto(['These', results, demonstrate, that, treatment, of, mesangial, cells, with, steroids, results, in, a]), verbo([decrease]), complemento([in, total, proteoglycan, 'synthesis,', as, well, as, 'subtype-specific', changes, in, proteoglycan, core, protein, gene, expression, by, transcriptional, 'control,', furthering, our, understanding, of, the, effects, of, steroid, treatment, on, the, renal, glomeruli])].
[sujeto(['Estrogen', sulfation, is, reportedly]), verbo([increased]), complemento([during, the, secretory, phase, in, response, to, the, high, levels, of, progesterone, secreted, by, the, ovaries])].
[sujeto(['Estrogen', sulfotransferase, '(', 'hEST),', a, distinct, form, of, human, cytosolic, sulfotransferase, '(', 'ST)', with, an, affinity, for, 'E2', and, estrone, at, low, nanomolar, 'concentrations,']), verbo([has]), complemento([recently, been, cloned, and, expressed, in, mammalian, cells, and, in, bacteria, '(', 'J', 'Steroid', 'Biochem', 'Mol', 'Biol', 52, :, 529, ',', 1995, ')'])].
[sujeto(['This']), verbo([report]), complemento([describes, the, specific, induction, of, hEST, in, human, 'Ishikawa', endometrial, adenocarcinoma, cells, by, progesterone, as, a, model, for, the, increases, in, estrogen, sulfation, observed, in, women, during, the, secretory, phase, of, the, menstrual, cycle])].
[sujeto(['Treatment', of, 'Ishikawa', cells, with, 10, microns, progesterone, for, 48, h, resulted, in, a, 7, -, fold]), verbo([increase]), complemento([in, the, sulfation, of, 20, nM, 'E2'])].
[sujeto(['The', levels, of, immunoreactive, hEST, and, hEST, mRNA, in, the, 'Ishikawa', cells, were, both]), verbo([increased]), complemento([by, 'progesterone,', whereas, the, levels, of, immunoreactive, 'hDHEA-ST,', 'hP-PST,', and, 'hM-PST', were, not, altered])].
[sujeto([hEST, activity, was, not]), verbo([induced]), complemento([by, treatment, of, 'Ishikawa', cells, with, varying, concentrations, of, 'E2,', 'testosterone,', or, cortisol])].
[sujeto(['The', induction, of, hEST, by, progesterone, was]), verbo([inhibited]), complemento([by, 'RU-486,', indicating, that, progesterone, is, acting, via, the, progesterone, receptor])].
[sujeto(['These', results, indicate, that, progesterone, is, capable, of, specifically]), verbo([inducing]), complemento([hEST, and, estrogen, sulfation, in, human, 'Ishikawa', adenocarcinoma, cells, and, suggest, a, mechanism, for, increasing, estrogen, sulfation, in, the, endometrium, during, the, secretory, phase, of, the, menstrual, cycle])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, progesterone, increased, sulfate, uptake, in, glandular, epithelial, cells, of, guinea, pig, endometrium])].
[sujeto(['To', investigate, whether, cAMP, might, be, the]), verbo([cause]), complemento([of, the, progesterone, effect, on, sulfate, 'uptake,', cAMP, accumulation, and, the, effect, of, cAMP, on, sulfate, uptake, were, evaluated, in, cells, treated, with, 17, 'beta-estradiol', alone, or, with, progesterone])].
[sujeto(['Progesterone']), verbo([provoked]), complemento([an, increase, in, the, intracellular, cAMP, accumulation, in, cells, treated, with, 17, 'beta-estradiol'])].
[sujeto(['Moreover,', cAMP, or, forskolin, elicited, the, same, marked]), verbo([increase]), complemento([in, sulfate, uptake, as, that, observed, with, progesterone])].
[sujeto(['This', study, is, the, first, evidence, of, cAMP, activation, of, sulfate, uptake, and]), verbo([suggests]), complemento([a, genomic, effect, of, progesterone, on, the, production, of, cAMP, which, activates, the, sulfate, transport, system, in, a, short, term, activation, and, a, long, term, activation, independent, of, transcriptional, or, translational, events])].
[sujeto(['The', endometrium, is, a, unique, tissue, that, undergoes, profound, highly]), verbo([regulated]), complemento([modifications, during, the, secretory, phase, in, providing, a, suitable, environment, for, embryo, implantation])].
[sujeto(['The', regulation, of, sulfate, uptake, could]), verbo([participate]), complemento([in, this, process])].
[sujeto(['Glucocorticoid', receptors, are, basally]), verbo([phosphorylated]), complemento([in, the, absence, of, hormone, and, become, hyperphosphorylated, after, hormone, treatment, of, intact, cells])].
[sujeto(['No', major, differences, were]), verbo([found]), complemento([between, these, two, cell, types])].
[sujeto(['Hormone-induced']), verbo([increases]), complemento([in, phosphorylation, were, seen, as, early, as, 5, min, after, adding, hormone, and, persisted, for, 20, h])].
[sujeto(['Analysis', of, newly, formed, cytosolic, and, 'nuclear-bound']), verbo([activated]), complemento(['(', 'DNA-binding)', receptors, showed, that, activation, precedes, hyperphosphorylation])].
[sujeto(['Nonactivated', 'receptors,', both, unliganded, and, 'hormone-liganded,', also, became, hyperphosphorylated, but, more, slowly, than]), verbo([activated]), complemento([receptors])].
[sujeto(['The', rate, of, receptor, 'dephosphorylation,', determined, by, chasing, with, unlabeled, 'P(i),', was, much, slower, than, the, rate, of, phosphorylation, or, of, hormone, dissociation, and, appeared, to, be, slightly]), verbo([increased]), complemento([by, agonists, and, by, the, antagonist, 'RU486', '(', which, does, not, cause, 'hyperphosphorylation)'])].
[sujeto(['We', conclude, that, '(', 'a)', the, substrate, for, 'hormone-dependent', hyperphosphorylation, is, the]), verbo([activated]), complemento(['hormone-receptor', 'complex;', '(', 'b)', most, hyperphosphorylated, receptors, are, recycled, and, reutilized, in, hyperphosphorylated, 'form;', '(', 'c)', control, of, receptor, phosphorylation, may, not, be, 'cell-specific;', '(', 'd)', 'cAMP-dependent', protein, kinase, is, not, involved, directly, or, indirectly, in, phosphorylating, major, sites, on, the, receptor, in, vivo])].
[sujeto(['Progesterone']), verbo([increased]), complemento([in, a, 'dose-dependent', fashion, the, sulfate, uptake, specifically, in, glandular, epithelial, 'cells,', preferentially, from, the, basal, surface])].
[sujeto(['Progesterone', effect, on, the, sulfate, uptake, occurred, only, in, 'estradiol-primed', epithelial, cells, and, was]), verbo([inhibited]), complemento([by, the, antiprogestin, steroid, 'RU-486'])].
[sujeto(['The', 'progesterone-dependent']), verbo([increase]), complemento([in, sulfate, uptake, was, inhibited, by, the, inhibitor, of, anion, 'exchange,', 4, ',', 4, '\'', -, 'diisothiocyanostilbene-2,2\'-disulfonic', acid, '(', 'DIDS)'])].
[sujeto(['At', physiological, sulfate, 'concentrations,', progesterone, essentially]), verbo([induces]), complemento([a, 'high-affinity', 'DIDS-sensitive', transport, system])].
[sujeto(['Progesterone', in, concert, with, 17, 'beta-estradiol', was, shown, to]), verbo([cause]), complemento([an, increase, in, the, available, intracellular, sulphate, pool])].
[sujeto(['This', effect, of, progesterone, on, the, available, intracellular, sulphate, pool, essentially, concerned, the, intracellular, inorganic, sulphate, and, was]), verbo([inhibited]), complemento([by, the, antiprogesterone, steroid, 'RU', 486, '(', 5, x, 10, '(', -, 7, ')', 'M)'])].
[sujeto(['Sulphate', incorporation, into, the, endometrial, epithelial, cells, was]), verbo([suppressed]), complemento([by, the, inhibitor, of, anion, transport, 'diisothiocyanostilbene-2,2\'-disulfonic', acid, '(', 'DIDS)', and, the, protein, synthesis, 'inhibitor,', cycloheximide])].
[sujeto(['These', results, would]), verbo([suggest]), complemento([that, a, sulphate, transport, system, may, be, involved, in, the, accumulation, of, the, intracellular, 'sulphate,', stimulated, by, progesterone])].
[sujeto(['This', study, aimed, to, examine, factors, related, to, completeness, of, medical, abortion, with, mifepristone, and, 'misoprostol,', and, then, to]), verbo([provide]), complemento([a, new, direction, for, research, into, establishing, complete, abortion, with, mifepristone, and, misoprostol])].
[sujeto(['However,', compared, with, the, complete, abortion, 'group,', there, was, a, marked]), verbo([decrease]), complemento([in, the, expression, of, 'insulin-like', growth, 'factor-1', and, a, significant, increase, in, the, expression, of, vascular, endothelial, growth, factor, '(', 'p&lt;0'])].
[sujeto(['Preterm', delivery, was]), verbo([induced]), complemento([by, subcutaneous, mifepristone, and, intravaginal, prostaglandin, 'E2'])].
[sujeto(['The', amount, of, 'AQP5', significantly]), verbo([increased]), complemento([after, progesterone, and, progesterone, analogs, treatment, on, 18, and, 22, days, of, pregnancy])].
[sujeto(['The', 17, 'β-estradiol', and, estrogen, receptor, agonists, did, not, influence, the, 'AQP5', mRNA, 'level;', 'however,', estradiol]), verbo([induced]), complemento([a, significant, increase, in, the, 'AQP5', protein, level, on, the, investigated, days, of, gestation])].
[sujeto(['Tamoxifen']), verbo([increased]), complemento([the, 'AQP5', protein, expression, on, day, 18, ',', while, clomiphene, citrate, was, ineffective])].
[sujeto(['The', 'hormonally-induced', preterm, birth, significantly]), verbo([decreased]), complemento([the, 'AQP5', level, similarly, to, the, day, of, delivery])].
[sujeto(['Endocrine', active, compounds, '(', 'EACs)', remain, an, important, group, of, chemicals, that]), verbo([require]), complemento([additional, evaluation, to, determine, their, environmental, impacts])].
[sujeto(['While', estrogens, and, androgens, were, previously, demonstrated, to, impact, organisms, during, environmental, 'exposures,', progestagens]), verbo([have]), complemento([recently, been, shown, to, have, strong, impacts, on, aquatic, organisms])].
[sujeto(['To']), verbo([gain]), complemento([an, understanding, of, the, impacts, of, these, types, of, chemicals, on, aquatic, 'species,', experiments, evaluating, the, mechanisms, of, action, of, progestagen, exposure, were, conducted, with, the, 'Eastern', 'Mosquitofish', '(', 'Gambusia', 'holbrooki)'])].
[sujeto(['In', 'addition,', we, evaluated, the, ability, of, 'levonorgestrel,', a, synthetic, progesterone, '(', 'progestin),', to]), verbo([induce]), complemento([anal, fin, elongation, and, to, determine, how, anal, fin, growth, is, modulated, during, 'co-exposures', with, progesterone, and, androgen, receptor, antagonists])].
[sujeto(['Microarray', analysis, revealed, that, mifepristone, does, not]), verbo([act]), complemento([as, an, 'anti-progestagen', in, 'G'])].
[sujeto(['Levonorgestrel', was, also, demonstrated, to]), verbo([induce]), complemento([male, secondary, sexual, characteristic, formation, in, 'females,', and, 'co-exposure', of, either, an, androgen, or, levonorgestrel, in, the, presence, of, the, 'anti-androgen', flutamide, prevented, anal, fin, elongation])].
[sujeto(['These', results]), verbo([provide]), complemento([indications, as, to, the, potential, impacts, of, 'progestins,', including, 'non-target', effects, such, as, secondary, sexual, characteristic, 'formation,', and, demonstrate, the, importance, of, this, class, of, chemicals, on, aquatic, organisms])].
[sujeto(['While', the, neuroprotection]), verbo([conferred]), complemento([by, progesterone, was, not, affected, by, 'SU-10603,', an, inhibitor, of, cytochrome, 'P45017α,', 'finasteride,', a, 5, 'α-reductase', inhibitor, that, blocks, the, conversion, of, progesterone, to, 'allopregnanolone,', partially, reversed, the, neuroprotection, induced, by, progesterone])].
[sujeto(['The', progesterone, 'metabolite,', allopregnanolone, attenuated, neuronal, injury]), verbo([induced]), complemento([by, 'OGD/reoxygenation'])].
[sujeto(['Treatment', with, 5, 'α-dihydrotestosterone', significantly]), verbo([suppressed]), complemento([neuronal, injury])].
[sujeto(['ICI182,780,', an, estrogen, receptor, 'antagonist,', showed, no, effect, on, neuroprotection]), verbo([mediated]), complemento([by, 17, 'β-estradiol'])].
[sujeto(['Pretreatment', with, actinomycin, 'D', or, cycloheximide, clearly, abolished, the, neuroprotective, effects, of, progesterone, and, 'testosterone,', while, actinomycin, 'D', and, cycloheximide, did, not, show, any, effect, on, neuroprotection]), verbo([mediated]), complemento([by, 17, 'β-estradiol'])].
[sujeto(['Taken', 'together,', progesterone, protects, neurons, via, progesterone, 'receptor-dependent', genomic, 'pathway,', and, allopregnanolone, is]), verbo([involved]), complemento([in, 'progesterone-mediated', neuroprotection])].
[sujeto(['Daily', injections, of, 'NaCl', reduced, the, levels, of, 'pregnenolone,', 'progesterone,', and, corticosterone, in, the, adrenal, 'glands,']), verbo([increased]), complemento([corticosterone, excretion, with, 'urine,', enhanced, activity, of, the, first, isoform, of, 11, 'β-hydroxysteroid', dehydrogenase, in, the, liver, and, reduction, in, activity, of, the, second, isoform, of, this, enzyme, in, the, kidneys])].
[sujeto(['Mifepristone', restored, pregnenolone, content, in, the, adrenal, glands, and]), verbo([increase]), complemento([in, corticosterone, concentration, in, the, blood])].
[sujeto(['Under', these, 'conditions,', activity, of, the, first, isoform, of, 11, 'β-hydroxysteroid', dehydrogenase, in, the, liver, did, not, 'change,', and, a]), verbo([decrease]), complemento([in, activity, of, the, second, isoform, of, the, enzyme, in, the, kidneys, was, less, pronounced])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, mifepristone, abolished, the, 'stress-mediated', increase, in, activity, of, the, first, isoform, of, 11, 'β-hydroxysteroid', dehydrogenase, in, the, liver, and, reduced, local, production, of, glucocorticoid, hormones, and, their, metabolic, effects, in, hepatocytes])].
[sujeto(['Comparing', the, two, 'groups,', none, of, the, total, effective, 'rate,', pregnancy, rate, one, year, of, 'follow-up,', and, recurrence, rates, were, significantly, 'different;', hormone, levels, in, the, both, groups, were, significantly]), verbo([decreased]), complemento([or, increased, '(', p, &, 'lt;', 0.05, ')', after, treatment])].
[sujeto(['With', laparoscopic, minimally, invasive, combined, drug, 'therapy,', mifepristone]), verbo([has]), complemento([a, significant, 'effect,', with, a, more, 'followed-up', pregnancy, 'rate,', less, 'recurrence,', and, no, drug, accumulation, 'side-effects,', hence, it, is, worthy, of, clinical, application])].
[sujeto(['This', study, determined, whether, a, progesterone, '(', 'P)', receptor, '(', 'PR)-mediated', mechanism]), verbo([regulates]), complemento([morphological, characteristics, associated, with, prepartum, cervix, remodeling, at, term, and, with, preterm, birth])].
[sujeto(['With', focus, on, the, transition, from, a, soft, to, ripe, 'cervix,', the, cervix, stroma, of, untreated, controls, had, reduced, cell, nuclei, 'density/area', and, less, organized, extracellular, 'collagen,', while, the, density, of, 'macrophages/area,', but, not, 'neutrophils,']), verbo([increased]), complemento([just, 2, days, before, birth, '(', day, 17, vs, day, 15, or, 16.5, 'postbreeding)'])].
[sujeto(['Preterm', birth, was]), verbo([induced]), complemento([within, 24, hours, of, treatment, on, day, 16, postbreeding, with, 'PR', antagonist, or, ovariectomy, '(', 'Ovx)'])].
[sujeto(['Pure', or, mixed, 'PR', antagonists]), verbo([increased]), complemento([the, density, of, macrophages, in, the, cervix, within, 8, hours, '(', day, 16.5, 'postbreeding),', in, advance, of, preterm, birth])].
[sujeto(['These', treatments, forestalled, preterm, birth, and]), verbo([prevented]), complemento([further, morphological, remodeling, of, the, cervix])].
[sujeto(['The', resulting]), verbo([increase]), complemento([in, macrophage, density, in, cervix, stroma, following, 'Ovx', was, only, blocked, by, a, pure, 'PR', agonist])].
[sujeto(['These', findings, support, the, hypothesis, that, inflammatory, processes, in, the, prepartum, cervix, that, include, residency, of, 'macrophages,', cellular, 'hypertrophy,', and, extracellular, collagen, structure, are]), verbo([regulated]), complemento([by, genomic, actions, of, 'PR', in, a, final, common, mechanism, both, at, term, and, with, induced, preterm, birth])].
[sujeto(['The', main, findings, 'were:', '(', 1, ')', 'DZP']), verbo([caused]), complemento([memory, impairment, and, anxiolysis, in, both, 'sexes,', but, only, the, highest, dose, induced, the, anxiolytic, effect, in, 'females;', '(', 2, ')', females, in, proestrus, did, not, present, the, amnestic, and, anxiolytic, effects, of, 'DZP', '(', at, 2.0, and, 4.0, 'mg/kg,', 'respectively)', and, '(', 3, ')', the, 'co-administration', of, mifepristone, reestablished, both, amnestic, and, anxiolytic, effects, of, 'DZP,', while, finasteride, reinstated, the, amnestic, effect, in, proestrus, female, rats])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, changes, in, the, endogenous, levels, of, progesterone, and, its, metabolites, are, important, in, the, modulation, of, 'emotional/cognitive', behavior, in, female, rats])].
[sujeto(['To', determine, if, mifepristone, can, lower, serum, levels, of, a, progesterone, '(', 'P)']), verbo([induced]), complemento([immunomodulatory, protein, believed, to, be, needed, for, the, fetus, to, escape, immune, surveillance])].
[sujeto(['A', female, volunteer, had, her, serum, 'P']), verbo([induced]), complemento([blocking, factor, '(', 'PIBF)', increased, by, ingestion, of, oral, micronized, 'P'])].
[sujeto(['It']), verbo([increased]), complemento([further, to, 737, 'ng/ml', despite, taking, six, days, of, 200, mg, mifepristone])].
[sujeto(['The', mechanism, for]), verbo([inducing]), complemento([abortion, by, mifepristone, does, not, seem, to, be, related, to, decreasing, serum, levels, of, 'PIBF'])].
[sujeto(['This', does, not, eliminate, the, possibility, that, the, mechanism]), verbo([involves]), complemento([reducing, the, intracytoplasmic, 'PIBF', levels])].
[sujeto(['Our', previous, study, showed, that, the, in, vivo, positive, effects, of, 17, 'α,20β-dihydroxy-4-pregnen-3-one', '(', 'DHP),', the, major, progestin, in, 'zebrafish,', on, early, spermatogenesis, was, much, stronger, than, the, ex, vivo, 'ones,', which, may]), verbo([suggest]), complemento([an, effect, of, 'DHP', on, the, expression, of, gonadotropins])].
[sujeto(['In', our, present, 'study,', we, first, observed, that, fshb, and, lhb, mRNA, levels, in, the, pituitary, of, male, adult, zebrafish, were, greatly]), verbo([inhibited]), complemento([by, 3, weeks, exposure, to, 10, nM, estradiol, '(', 'E2)'])].
[sujeto(['However,', an, additional, 24, h, 100, nM, 'DHP', exposure, not, only, reversed, the, 'E2-induced', 'inhibition,', but, also, significantly]), verbo([increased]), complemento([the, expression, of, fshb, and, lhb, mRNA])].
[sujeto(['These', stimulatory, effects, were, also, observed, in, male, adult, fish, without, 'E2', 'pretreatment,', and, a, time, course, experiment, showed, that, it, took, 24, h, for, fshb, and, 12, h, for, lhb, to]), verbo([respond]), complemento([significantly])].
[sujeto(['Because', these, stimulatory, activities, were, partially, antagonized, by, a]), verbo([nuclear]), complemento([progesterone, receptor, '(', 'Pgr)', antagonist, 'mifepristone,', we, generated, a, 'Pgr-knockout', '(', 'pgr(-/-))', model, using, the, 'TALEN', technique])].
[sujeto(['With', and, without, 'DHP', in, vivo, 'treatment,', fshb, and, lhb, mRNA, levels, of, 'pgr(-/-)', were, significantly, lower, than, those, of, 'pgr(+/+)', 'Furthermore,', ex, vivo, treatment, of, pituitary, fragments, of, 'pgr(-/-)', with, 'DHP']), verbo([stimulated]), complemento(['lhb,', but, not, fshb, mRNA, expression])].
[sujeto(['Results', from, 'double-colored', fluorescent, in, situ, hybridization, showed, that, pgr, mRNA, was]), verbo([expressed]), complemento([only, in, 'fshb-expressing', cells])].
[sujeto(['Taken', 'together,', our, results, indicated, that, 'DHP']), verbo([participated]), complemento([in, the, regulation, of, neuroendocrine, control, of, reproduction, in, male, 'zebrafish,', and, exerted, a, 'Pgr-mediated', direct, stimulatory, effect, on, fshb, mRNA, at, pituitary, level])].
[sujeto(['Emergency', contraception, is, a, safe, and, effective, method, to]), verbo([prevent]), complemento([an, unwanted, pregnancy, after, an, unprotected, or, inadequately, protected, sexual, intercourse])].
[sujeto(['Several', methods, for, emergency, contraception, '(', 'EC)', are, currently, registered, in, many, countries, for, use, in, an, emergency, to]), verbo([prevent]), complemento([a, pregnancy, following, an, 'unprotected,', possibly, fertile, intercourse, or, after, a, contraceptive, accident, like, condom, rupture])].
[sujeto(['Different', methods]), verbo([have]), complemento([varying, modes, of, 'action,', time, frame, of, 'efficacy,', dosage, schedule, and, unwanted, effects])].
[sujeto(['In', this, article, the, available, literature, on, emergency, contraception]), verbo([has]), complemento([been, reviewed, and, an, attempt, has, been, made, to, discuss, the, need, for, emergency, contraception, and, compare, different, options, for, emergency, contraception, in, terms, of, their, efficacy, in, pregnancy, 'prevention,', their, safety, profile, and, unwanted, side, effects])].
[sujeto(['EC', repeated, use, and, initiating, a]), verbo([regular]), complemento([method, after, 'EC', use, are, also, discussed])].
[sujeto(['There', is, a, marginal, difference, in, the, mechanism, of, 'action,', efficacy, including, time, frame, and, ability, to, protect, from, pregnancy, with]), verbo([regular]), complemento([doses, in, obese, 'women,', drug, interactions, and, side, effects])].
[sujeto(['Copper', 'IUD', is, the, most, effective, emergency, contraceptive, with, advantage, of]), verbo([providing]), complemento([continued, contraception])].
[sujeto(['UPA']), verbo([has]), complemento([a, wider, window, of, 'efficacy,', in, 'LNG', efficacy, declines, after, 72, hours])].
[sujeto(['We']), verbo([report]), complemento([preclinical, data, evaluating, telapristone, acetate, '(', 'TPA),', ulipristal, acetate, '(', 'UPA),', and, mifepristone])].
[sujeto(['Tumors', were]), verbo([induced]), complemento([with, medroxyprogesterone, acetate, '(', 'MPA)', plus, 7, ',', 12, -, 'dimethylbenz[a]anthracene', '(', 'DMBA)', in, 'mice,', and, 'MPA', or, progesterone, plus, 'N-methyl-N-nitrosourea', '(', 'MNU)', in, rats])].
[sujeto(['In', 'rats,', 'TPA']), verbo([decreased]), complemento([tumor, incidence, '(', p, =, 0.037, for, 'MPA', +, 'TPA', vs])].
[sujeto(['progesterone),', with, significant]), verbo([decreases]), complemento([in, pHH3, and, 'CD34', positive, cells])].
[sujeto(['TPA']), verbo([has]), complemento([consistent, 'anti-tumorigenic', effects, in, several, 'models,', which, are, accompanied, by, decreases, in, cell, 'proliferation,', 'angiogenesis,', and, hormone, receptor, expression])].
[sujeto(['The', scope, of, new, therapeutic, modalities, includes, restoring, the, progesterone, receptor, ratio, using, progestin, or, progesterone, receptor, modulators, and]), verbo([decreasing]), complemento([local, oestrogen, production, through, an, aromatase, inhibitor])].
[sujeto(['In', 'addition,', free, radical, production, can, be, blocked, by, antioxidants, and, the, autophagic, process, by]), verbo([increasing]), complemento([apoptosis])].
[sujeto(['Many', of, these, pharmacological, treatments, lend, themselves, to, local, administration, and, can, be, applied, through, intracystic, drug, 'administration;', in, 'fact,', the, intracystic, route]), verbo([has]), complemento([already, been, tried, with, recombinant, 'interleukin-2,', methotrexate, and, 'ethanol;', the, latter, to, obtain, sclerotization])].
[sujeto(['Specifically,', it, is, proposed, that, endometrial, growth, in, the, endometrioma, is]), verbo([suppressed]), complemento([by, 'intra-cystic', application, of, synthetic, 'progestins,', such, as, levonorgestrel, or, 'danazol,', selective, progesterone, receptor, 'modulators,', such, as, 'mifepristone,', ulipristal, or, 'asoprisnil,', without, affecting, ovarian, activity])].
[sujeto(['We', studied, the, expression, of, 16]), verbo([reported]), complemento([endometrial, receptivity, markers, in, the, endometrial, constructs, using, 'real-time', polymerase, chain, reaction])].
[sujeto(['We']), verbo([found]), complemento([that, most, of, the, studied, receptivity, markers, were, significantly, altered, with, mifepristone, exposure, in, a, similar, direction, in, both, treatment, groups])].
[sujeto(['Only', 'IL6', was, significantly, differentially]), verbo([expressed]), complemento([between, the, treatment, groups, '(', 'p='])].
[sujeto(['We']), verbo([report]), complemento([for, the, first, time, that, exposure, to, a, low, concentration, '(', 0.5, 'μM)', of, mifepristone, during, the, receptive, period, successfully, inhibits, human, embryo, implantation, process, in, vitro])].
[sujeto(['This', study, contributes, new, knowledge, that, low, dose, of, mifepristone, during, the, short, period, of, receptive, phase, can]), verbo([inhibit]), complemento([endometrial, 'receptivity,', which, further, promotes, mifepristone, as, a, contraceptive, agent])].
[sujeto(['The', aim, of, this, study, is, to]), verbo([report]), complemento([a, series, of, unruptured, interstitial, pregnancy, managed, by, in, situ, injection, of, methotrexate])].
[sujeto(['A', great]), verbo([decrease]), complemento([of, serum, hCG, without, surgery, was, considered, a, success])].
[sujeto(['Mean', time, for]), verbo([decrease]), complemento([of, serum, hCG, until, 2, &, 'nbsp;UI/L', was, 54.4, days, '[', 34.0, -, 74.8, ']'])].
[sujeto(['This', treatment]), verbo([has]), complemento([a, great, efficiency, and, low, rate, of, complications])].
[sujeto(['MicroRNA-10a', '(', 'miR-10a)']), verbo([has]), complemento([a, wide, range, of, functions, in, nearly, all, mammalian, tissues, and, is, involved, in, the, occurrence, of, many, diseases])].
[sujeto(['However,', it, remains, unknown, whether, 'miR-10a', is]), verbo([associated]), complemento([with, human, recurrent, spontaneous, abortion, '(', 'RSA)'])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, rs3809783, 'A', &, 'gt;', 'T', in, 'miR-10a', coding, region, was, significantly, associated, with, the, increase, of, the, risk, of, human, unexplained, 'RSA', '(', 'URSA)', acquisition, in, a, 'Han-Chinese', population])].
[sujeto(['A', to, 'T', substitution, in, 'miR-10a', rs3809783]), verbo([repressed]), complemento([cell, proliferation, and, migratory, capacity])].
[sujeto(['Further', investigation, discovered, that, 'Bcl-2-interacting', mediator, '(', 'Bim)', was, the, functional]), verbo([target]), complemento([of, 'miR-10a', and, inversely, regulated, 'Bim', expression])].
[sujeto(['Dual-luciferase', assay, indicated, that, 'A', allele, in, 'miR-10a', rs3809783, could, more, effectively]), verbo([suppress]), complemento(['Bim', expression, than, 'T', allele])].
[sujeto(['Collectively,', our, data]), verbo([suggest]), complemento([that, rs3809783, 'A', &, 'gt;', 'T', in, 'pri-miR-10a', may, be, conductive, to, the, genetic, predisposition, to, 'RSA', by, disrupting, the, production, of, mature, 'miR-10a', and, reinforcing, the, expression, of, 'Bim'])].
[sujeto(['Treatment', with, progestin]), verbo([stimulated]), complemento([production, of, 'COL1A1,', 'fibronectin,', 'versican,', and, dermatopontin])].
[sujeto(['Mifepristone', treatment]), verbo([inhibited]), complemento([protein, production, of, these, 'genes,', most, notably, with, versican, expression])].
[sujeto(['Combination', treatment, with, both, the, agonist, and, antagonist, further]), verbo([inhibited]), complemento([protein, expression, of, these, genes])].
[sujeto(['Our', study, demonstrated, that, the, progesterone, agonist, 'R5020', directly]), verbo([stimulated]), complemento([extracellular, matrix, components, 'COL1A1,', 'fibronectin,', 'versican,', and, dermatopontin, production, in, human, leiomyoma, cells])].
[sujeto(['Progesterone', antagonist, mifepristone]), verbo([decreased]), complemento([protein, production, of, these, genes, to, levels, comparable, with, untreated, leiomyoma, cells])].
[sujeto(['Glucocorticoids', '(', 'GCs)', and, progesterone]), verbo([have]), complemento([been, employed, as, immunosuppressive, agents, during, pregnancy, for, many, years])].
[sujeto(['NHE1', is, tethered, to, the, cortical, actin, cytoskeleton, through, 'ezrin/radixin/moesin', '(', 'ERM)', proteins, within, lipid, 'rafts;', these]), verbo([regulate]), complemento([cell, 'shape,', migration, and, resistance, to, apoptosis])].
[sujeto(['GCs']), verbo([stimulate]), complemento([a, rapid, 'non-genomic', 'cp-ERM', response, in, cells, within, 5, min])].
[sujeto(['RU486', antagonized, the, 'GC-induced', rapid]), verbo([decrease]), complemento([in, 'NHE1', 'activity,', and, arrested, 'PHA-stimulated', 'T', cells, at, 'G0/G1', phase, but, had, no, effect, on, the, rapid, increase, in, 'cp-ERM,', which, persisted, for, 24, h])].
[sujeto(['However,', the, 'cp-ERM', response, was, blocked, by, staurosporine, in, both, resting, and, 'GC']), verbo([stimulated]), complemento([cells])].
[sujeto(['The', results, of, 'RU486', antagonized, the, 'GC']), verbo([induced]), complemento([rapid, decrease, in, 'NHE1', ion, transport, 'activity,', but, not, the, increase, 'cp-ERM'])].
[sujeto(['This']), verbo([suggests]), complemento([that, 'RU486', in, 'T', cells, exerts, its, antagonistic, effects, at, 'NHE1', containing, plasma, membrane, sites, and, not, where, 'cp-ERM', links, lipid, rafts, to, cortical, cytoskeletons])].
[sujeto(['Progesterone']), verbo([regulates]), complemento([uterine, function, during, the, luteal, phase, and, is, essential, for, the, acquisition, of, endometrial, receptivity])].
[sujeto(['The', objective, of, the, present, study, was, to, identify, endometrial, transcripts, whose, expression, is, altered, during, the, window, of, implantation, after, the, administration, of, 200, mg, of, the, antiprogestin, 'mifepristone,', 48, h, after, the, 'LH', peak, '(', 'LH+2,', 'LH+0=LH', 'peak),', and, to, determine, the, relationship, of, these, transcripts, with, those]), verbo([regulated]), complemento([during, the, acquisition, of, receptivity])].
[sujeto(['DNA', microarrays, were, used, to, identify, transcripts, significantly]), verbo([regulated]), complemento(['(', defined, as, '≥', 2.0, -, fold, change, with, false, discovery, rate, below, 1, '%', using, 't-test)', with, the, administration, of, mifepristone, vs, 'placebo,', or, during, the, transition, from, 'pre-receptive', to, receptive, '(', 'LH+2', vs, 'LH+7)'])].
[sujeto(['Approximately', 2000, transcripts, were, significantly]), verbo([regulated]), complemento([in, both, comparisons, '(', mifepristone, vs, placebo, and, 'LH+2', vs, 'LH+7),', but, only, 777, of, them, were, coincident, and, displayed, opposite, regulation, except, for, 25])].
[sujeto(['The', mRNA, level, for, eight, selected, genes]), verbo([regulated]), complemento([by, mifepristone, was, confirmed, by, 'real-time', 'RT-PCR'])].
[sujeto(['We', conclude, that, not, all, changes, in, endometrial, transcript, levels, occurring, in, the, transition, from, 'LH+2', to, 'LH+7', seem, to, be]), verbo([regulated]), complemento([by, the, progesterone, receptor, and, '∼', 37, '%', of, the, genes, whose, transcript, levels, changed, by, effect, of, mifepristone, could, be, associated, with, the, acquisition, of, receptivity])].
[sujeto(['Cerebellar', 'Purkinje', cells, '(', 'PC)', physiologically]), verbo([reveal]), complemento([an, 'age-dependent', expression, of, progesterone, with, high, endogenous, concentrations, during, the, neonatal, period])].
[sujeto(['Even', if, progesterone]), verbo([has]), complemento([been, previously, shown, to, induce, 'spinogenesis,', dendritogenesis, and, synaptogenesis, in, immature, 'PC,', data, about, the, effects, of, progesterone, on, mature, 'PC', are, 'missing,', even, though, they, could, be, of, significant, therapeutic, interest])].
[sujeto(['Comparable', with, the, physiological, course, of, the, progesterone, 'concentration,', experimental, treatment, with, progesterone, for, 24, &, 'nbsp;h', achieves, the, highest, effects, on, the, dendritic, tree, during, the, early, 'neonate,']), verbo([inducing]), complemento([an, highly, significant, increase, in, dendritic, 'length,', spine, number, and, spine, 'area,', while, spine, density, in, mature, 'PC', could, not, be, further, stimulated, by, progesterone, incubation])].
[sujeto(['Observed', progesterone, effects, are, certainly]), verbo([mediated]), complemento([by, classical, progesterone, 'receptors,', as, spine, area, and, number, were, comparable, to, controls, when, progesterone, incubation, was, combined, with, mifepristone, '(', incubation, for, 24, &, 'nbsp;h),', an, antagonist, of, progesterone, receptors, 'A', and, 'B', '(', 'PR-A/PR-B)'])].
[sujeto(['In', 'contrast,', an]), verbo([increase]), complemento([in, the, spine, number, and, area, of, both, immature, and, mature, 'PC', was, detected, when, slice, cultures, were, incubated, with, mifepristone, for, more, than, 72, &, 'nbsp;h', '(', mifepristone, 'long-time', 'incubation,', 'MLTI)'])].
[sujeto(['Thus,', our, results]), verbo([provide]), complemento([new, insights, into, the, function, and, signaling, mechanisms, of, the, recently, described, progesterone, receptor, membrane, component, 1, '(', 'PGRMC1)', in, 'PC'])].
[sujeto(['It', is, highly, suitable, that, progesterone, does, not, just]), verbo([induce]), complemento([effects, by, the, 'well-known', genomic, mechanisms, of, the, classical, progesterone, receptors, but, also, acts, through, 'PGRMC1', mediated, 'non-genomic', mechanisms])].
[sujeto(['Thus,', our, results]), verbo([provide]), complemento([first, proofs, for, a, previously, discussed, 'progesterone-dependent', induction, of, neurosteroidogenesis, in, 'PC', by, interaction, with, 'PGRMC1'])].
[sujeto(['But', while, genomic, progesterone, effects]), verbo([mediated]), complemento([through, classical, 'PR-A', and, 'PR-B', seem, to, be, restricted, to, the, neonatal, period, of, 'PC,', 'PGRMC1', also, transmits, signals, by, 'non-genomic', mechanisms, like, regulation, of, the, neurosteroidogenesis, in, mature, 'PC'])].
[sujeto(['Thus,', 'PGRMC1', might, be, an, interesting]), verbo([target]), complemento([for, future, clinical, studies, and, therapeutic, interventions])].
[sujeto(['We', stratified, enrollment, into, two, gestational, 'cohorts,', &, 'lt;', 49, days, and, 49, -, 63, 'days,', to]), verbo([ensure]), complemento([gestational, variability])].
[sujeto(['For', women, who]), verbo([require]), complemento([confirmation, of, complete, abortion, sooner, than, one, week, after, 'mifepristone,', due, to, patient, 'preference,', logistical, constraints, or, in, the, setting, of, pregnancy, of, unconfirmed, 'location,', a, single, repeat, hCG, on, 'Day', 5, may, be, clinically, useful])].
[sujeto(['Chronic', stress]), verbo([has]), complemento([been, reported, to, increase, basal, pain, sensitivity, 'and/or', exacerbate, existing, persistent, pain])].
[sujeto(['However,', most, surgical, patients]), verbo([have]), complemento([normal, physiological, and, psychological, health, status, such, as, normal, pain, perception, before, surgery, although, they, do, experience, 'short-term', stress, during, 'pre-', and, 'post-operative', periods])].
[sujeto(['Short-term', stress]), verbo([induced]), complemento([by, immobilization, was, demonstrated, by, an, elevation, in, the, level, of, serum, 'corticosterone,', an, increase, in, swim, 'immobility,', and, a, decrease, in, sucrose, consumption])].
[sujeto(['Depot', medroxyprogesterone, acetate, administration, with, mifepristone, did, not, appreciably]), verbo([increase]), complemento([the, risk, of, surgery, after, medical, abortion, but, did, increase, the, risk, of, ongoing, pregnancy])].
[sujeto(['It']), verbo([enhanced]), complemento([patient, 'satisfaction,', but, we, found, no, evidence, that, it, decreased, 6, -, month, risk, of, repeat, pregnancy])].
[sujeto(['The', impact, of, the, foods, we, eat, on, metabolism, and, cardiac, physiology]), verbo([has]), complemento([been, studied, for, 'decades,', yet, less, is, known, about, the, effects, of, foods, on, the, 'CNS,', or, the, behavioral, manifestations, that, may, result, from, these, effects])].
[sujeto(['Previous', studies]), verbo([have]), complemento([shown, that, 'long-term', consumption, of, 'high-fat', foods, leading, to, 'diet-induced', obesity, sensitizes, the, inflammatory, response, of, the, brain, to, subsequent, challenging, 'stimuli,', causing, deficits, in, the, formation, of, 'long-term', memories])].
[sujeto(['The', new, findings]), verbo([reported]), complemento([here, demonstrate, that, 'short-term', consumption, of, a, 'high-fat', diet, '(', 'HFD)', produces, the, same, 'outcomes,', thus, allowing, the, examination, of, mechanisms, involved, in, this, process, long, before, obesity, and, associated, comorbidities, occur])].
[sujeto(['Rats', fed, an, 'HFD', for, 3, d, exhibited]), verbo([increases]), complemento([in, 'corticosterone,', the, 'inflammasome-associated', protein, 'NLRP3', '(', 'nod-like', receptor, protein, 3, ')', ',', and, the, endogenous, danger, signal, 'HMGB1', '(', 'high-mobility', group, box, 1, ')', in, the, hippocampus])].
[sujeto(['A', 'low-dose', '(', 10, 'μg/kg)', lipopolysaccharide, '(', 'LPS)', immune, challenge, potentiated, the, neuroinflammatory, response, in, the, hippocampus, of, rats, fed, the, 'HFD,', and]), verbo([caused]), complemento([a, deficit, in, the, formation, of, 'long-term', 'memory,', effects, not, observed, in, rats, fed, regular, chow])].
[sujeto(['The', blockade, of, corticosterone, action, with, the, glucocorticoid, receptor, antagonist, mifepristone]), verbo([prevented]), complemento([the, 'NLRP3', and, 'HMGB1', increases, in, unchallenged, 'animals,', normalized, the, proinflammatory, response, to, 'LPS,', and, prevented, the, memory, impairment])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'short-term', 'HFD', consumption, increases, vulnerability, to, memory, disruptions, caused, by, an, immune, challenge, by, upregulating, important, neuroinflammatory, priming, and, danger, signals, in, the, 'hippocampus,', and, that, these, effects, are, mediated, by, increases, in, hippocampal, corticosterone])].
[sujeto(['Even', though, overall, rates, of, abortion, are]), verbo([decreasing]), complemento(['slightly,', medical, abortion, rates, are, expected, to, increase, in, 'Canada', following, approval, by, 'Health', 'Canada', of, a, combination, of, mifepristone, and, misoprostol, for, use, in, medical, abortion])].
[sujeto(['Drugs', used, for, medical, abortion, are, 'safe;', 'however,', clinicians, who]), verbo([provide]), complemento([medical, abortion, and, those, who, provide, care, to, women, who, have, undergone, medical, abortion, should, have, an, understanding, of, the, pharmacokinetics, and, clinical, effects, of, the, medications, used, to, improve, outcomes, and, mitigate, risk])].
[sujeto(['Women']), verbo([recruited]), complemento([to, the, study, in, 2008, '(', n, =, 84, ')', and, 2010, '(', n, =, 58, ')', received, misoprostol, only])].
[sujeto(['Those']), verbo([recruited]), complemento([in, 2014, '(', n, =, 208, ')', received, mifepristone, and, misoprostol])].
[sujeto(['The', introduction, of, a, combined, 'mifepristone-misoprostol', regimen, into, public, sector, 'second-trimester', medical, abortion, services, in, 'South', 'Africa']), verbo([has]), complemento([been, successful, with, shorter, 'time-to-abortion', 'events,', less, extreme, pain, and, greater, acceptability, for, women])].
[sujeto(['Other', state, legislatures]), verbo([have]), complemento([passed, or, enacted, similar, laws, requiring, use, of, the, 'FDA-approved', protocol, for, medication, abortion])].
[sujeto(['The', main, outcomes, were, as, 'follows:', need, for, additional, intervention, following, medication, abortion, '(', such, as, 'aspiration,', repeat, 'misoprostol,', and, blood, 'transfusion),', frequency, of, continuing, 'pregnancy,']), verbo([reports]), complemento([of, side, 'effects,', and, the, proportion, of, abortions, that, were, medication, abortions, '(', versus, other, abortion, 'procedures)'])].
[sujeto(['Among', the, 2, ',', 783, medication, abortions, '≤49', d, 'gestation,', 4.9, '%', '(', 95, '%', 'CI:', 3.7, '%', -, 6.2, '%', ')', in, the, prelaw, and, 14.3, '%', '(', 95, '%', 'CI:', 12.6, '%', -, 16.0, '%', ')', in, the, postlaw, period]), verbo([required]), complemento([one, or, more, additional, interventions])].
[sujeto(['Women', obtaining, a, medication, abortion, in, the, postlaw, period, had, three, times, the, odds, of]), verbo([requiring]), complemento([an, additional, intervention, as, women, in, the, prelaw, period, '(', adjusted, odds, ratio, '[', 'AOR]', =, 3.11, ',', 95, '%', 'CI:', 2.27, -, 4.27, ')'])].
[sujeto(['In', a, mixed, effects, multivariable, model, that, uses, 'facility-months', as, the, unit, of, analysis, to, account, for, lack, of, independence, by, 'site,', we]), verbo([found]), complemento([that, the, law, change, was, associated, with, a, 9.4, '%', '(', 95, '%', 'CI:', 4.0, '%', -, 18.4, '%', ')', absolute, increase, in, the, rate, of, requiring, an, additional, intervention])].
[sujeto(['The', percentage, of, women]), verbo([requiring]), complemento([two, or, more, 'follow-up', visits, increased, from, 4.2, '%', '(', 95, '%', 'CI:', 3.0, '%', -, 5.3, '%', ')', in, the, prelaw, period, to, 6.2, '%', '(', 95, '%', 'CI:', 5.5, '%', -, 8.0, '%', ')', in, the, postlaw, period, '(', p, =, 0.003, ')'])].
[sujeto(['Overall,', 12.6, '%', of, women]), verbo([reported]), complemento([at, least, one, side, effect, during, their, medication, 'abortion:', 8.4, '%', '(', 95, '%', 'CI:', 6.8, '%', -, 10.0, '%', ')', in, the, prelaw, period, and, 15.6, '%', '(', 95, '%', 'CI:', 13.8, '%', -, 17.3, '%', ')', in, the, postlaw, period, '(', p, &, 'lt;', 0.001, ')'])].
[sujeto(['The', average, patient, charge]), verbo([increased]), complemento([from, 'US$426', in, 2010, to, 'US$551', in, 2014, ',', representing, a, 16, '%', increase, after, adjusting, for, inflation, in, medical, prices])].
[sujeto(['Ohio', law]), verbo([required]), complemento([use, of, a, medication, abortion, protocol, that, is, associated, with, a, greater, need, for, additional, 'intervention,', more, 'visits,', more, side, 'effects,', and, higher, costs, for, women, relative, to, the, 'evidence-based', protocol])].
[sujeto(['There', is, no, evidence, that, the, change, in, law]), verbo([led]), complemento([to, improved, abortion, outcomes])].
[sujeto(['Indeed,', our, findings]), verbo([suggest]), complemento([the, opposite])].
[sujeto(['In', 'March', 2016, ',', the, 'FDA-protocol', was, 'updated,', so, 'Ohio', providers, may, now, legally]), verbo([provide]), complemento([current, 'evidence-based', protocols])].
[sujeto(['Expectant', management, is, preferred, for, hCG, 'levels&lt;1000IU/l', or, in, the, process, of, spontaneous]), verbo([decreasing]), complemento(['(', 'Grade', 'B)'])].
[sujeto(['In', pregnancies, of, unknown, location, persisting, more, than, 10, days, in, an, asymptomatic, woman, who]), verbo([has]), complemento([an, hCG, 'level&gt;2000IU/l,', routine, 'MTX', treatment, is, an, option])].
[sujeto(['Repeated', use, of, mifepristone, and, levonorgestrel, significantly, lengthened, the, estrous, cycle, and]), verbo([decreased]), complemento(['FSHR', and, 'LHR', mRNA, and, protein, expression, in, the, ovaries, of, mice, at, 4, ',', 24, ',', and, 48, days, after, discontinuing, drug, use])].
[sujeto(['Repeated', use, of, mifepristone, and, levonorgestrel, can]), verbo([lead]), complemento([to, sustained, damage, to, ovarian, function, through, inhibition, of, ovarian, 'FSHR', and, 'LHR', expression, in, mice])].
[sujeto(['We', credit, this]), verbo([increase]), complemento([to, the, adjusted, medication, schema, as, well, as, to, targeted, physician, education, on, the, expected, course, and, interpretation, of, outcome, measures])].
[sujeto(['To', compare, the, physical, and, emotional, effects, of, two, medical, protocols, for]), verbo([induced]), complemento([abortion, during, the, second, trimester])].
[sujeto(['The', 'second-trimester', medical, abortions, constitute, 10, -, 15, &, 'nbsp;%', of, all]), verbo([induced]), complemento([abortions, 'worldwide,', but, are, responsible, for, 'two-thirds', of, major, abortion, related, complications])].
[sujeto(['During', the, last, 'decade,', medical, methods, for, the, 'second-trimester-induced', abortion]), verbo([have]), complemento([been, become, safer, and, more, accessible])].
[sujeto(['Nulliparous', women, and, women, with, gestation, more, than, 16, &, 'nbsp;weeks']), verbo([required]), complemento([opiate, analgesia, more, often, '(', 'P&nbsp;=&nbsp;0'])].
[sujeto(['The', 'second-trimester', medical, abortion, can, be]), verbo([provided]), complemento([by, a, 'nurse-midwife', with, the, 'back-up', of, a, gynecologist])].
[sujeto(['Exposure', to, 'cocaine-associated', stimuli]), verbo([triggers]), complemento([a, robust, rise, in, circulating, glucocorticoid, levels])].
[sujeto(['Glucocorticoid', receptors, '(', 'GR)', are, richly]), verbo([expressed]), complemento([in, the, basolateral, amygdala, '(', 'BLA),', a, brain, region, that, controls, the, reinstatement, of, 'cocaine-seeking', behavior, upon, exposure, to, a, previously, 'cocaine-paired', environmental, context])].
[sujeto(['Intra-BLA,', but, not, 'intra-pCPu,', mifepristone, 'dose-dependently', attenuated, drug, 'context-induced', 'cocaine-seeking', behavior, relative, to, 'vehicle,', such, that]), verbo([responding]), complemento([was, similar, to, that, observed, in, the, extinction, context])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'BLA', 'GR', stimulation, is, necessary, for, drug, 'context-induced', motivation, to, seek, cocaine])].
[sujeto(['To', 'date,', no, pharmacological, therapy]), verbo([has]), complemento([been, shown, to, hasten, recovery, of, the, 'hypothalamic-pituitary-adrenal', '(', 'HPA)', axis, in, this, clinical, scenario])].
[sujeto(['Tagetes', 'erecta,', the, 'marigold,']), verbo([has]), complemento([commercial, and, ethnomedicinal, 'use;', 'however,', reports, concerning, its, efficacy, for, the, treatment, of, depression, are, lacking])].
[sujeto([erecta, significantly]), verbo([inhibited]), complemento([the, immobility, period, in, forced, swim, test, in, mice, 'P&lt;0'])].
[sujeto([')']), verbo([enhanced]), complemento([the, 'anti-immobility', effect, of, antidepressant, drugs, like, 'imipramine,', 'fluoxetine,', and, 'p-chlorophenylalanine,', an, inhibitor, of, serotonin, synthesis, significantly, attenuated, its, antidepressant, effect])].
[sujeto([erecta, in, the, forced, swim, test, was]), verbo([prevented]), complemento([by, pretreatment, with, 'L-arginine', and, 'sildenafil,', whereas, pretreatment, of, mice, with, nitric, oxide, synthase, inhibitors, potentiated, the, action])].
[sujeto(['Serotonergic,', nitrergic, 'pathway,', and, sigma, receptors, are, possibly]), verbo([involved]), complemento([in, mediating, antidepressant, action, of, 'T'])].
[sujeto(['Median', '(', 'Me)', 'H(2)O(2)', was]), verbo([increased]), complemento([up, to, 0.44, microM, '(', interquartile, range, 'IR:', 0.2, -, 1.25, 'microM)', compared, with, healthy, control, of, 0.36, microM, '(', 'IR:', 0.12, -, 0.48, 'microM;', p, &, 'lt;', 0.05, ')'])].
[sujeto(['The', 'H(2)O(2)', concentration, in, 'EBC', was, significantly, correlated, '(', tau, =, 0.27, ;, p, =, 0.03, ')', and]), verbo([increased]), complemento([in, cases, with, nodal, metastases, '(', n, =, 12, ;, p, =, 0.04, ')'])].
[sujeto(['Serum', 'TNFalpha', was]), verbo([increased]), complemento([up, to, 51.7, +, /, -, 21.0, 'pg/ml', compared, with, controls, 17.2, +, /, -, 3.65, 'pg/ml', '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['FRAP', was]), verbo([increased]), complemento([to, 1.41, +, /, -, 0.37, mM, 'Fe(2+)', compared, with, control, 1.19, +, /, -, 0.17, mM, 'Fe(2+);', '(', p, =, 0.006, ')'])].
[sujeto(['This', is, the, first, study, to, demonstrate]), verbo([increased]), complemento(['H(2)O(2)', in, exhaled, breath, condensate, in, patients, with, localized, breast, malignancy, and, its, relation, with, clinical, severity])].
[sujeto(['The', comparative, dose, and, 'time-dependent', effects, of, male, and, female, sex, steroid, hormones, on, nitrite]), verbo([release]), complemento([by, murine, peritoneal, macrophages, '(', 'M', 'phi)', stimulated, by, 'LPS', were, studied])].
[sujeto(['M', phi, from, gonadectomized, mice]), verbo([released]), complemento([larger, amounts, of, nitrite, on, 'LPS', stimulation, than, 'controls;', although, nitrite, release, was, significantly, greater, in, castrated, males, than, in, ovariectomized, 'females,', suggesting, that, sex, hormone, deprivation, results, in, an, increase, in, nitrite, release])].
[sujeto(['E2', '(', except, at, 10, '(', -, 2, ')', 'ng/ml),', 'T', and, 'P', significantly, '(', 'P', &, 'lt;', 0.05, ')']), verbo([suppressed]), complemento([the, nitrite, release, in, a, 'dose-dependent', manner])].
[sujeto(['Nitrite']), verbo([release]), complemento([from, 'M', phi, increased, with, decreasing, exposure, time, to, 'E2,', 'T', and, 'P'])].
[sujeto(['Sex', steroid, receptor, antagonists, tamoxifen, 'citrate,', cyproterone, 'acetate/flutamide', and, 'RU486', markedly, reduced, the, inhibitory, effect, of, 'E2,', 'T', and, 'P,', 'respectively,']), verbo([suggesting]), complemento([that, sex, hormones, modulate, 'M', phi, nitrite, release, via, a, 'receptor-mediated', system])].
[sujeto(['The', 'sigma-1', receptor, is, a, 'ligand-regulated', endoplasmic, reticulum, '(', 'ER)', resident, chaperone]), verbo([involved]), complemento([in, the, maintenance, of, cellular, homeostasis])].
[sujeto(['Coupling', of, the, 'sigma-1', receptor, with, various, 'ER', 'and/or', plasma, membrane, ion, channels, is]), verbo([associated]), complemento([with, its, ability, to, regulate, the, locomotor, activity, and, cellular, proliferation, produced, in, response, to, 'sigma-1', receptor, ligands])].
[sujeto(['A', number, of, endogenous, small, molecules]), verbo([bind]), complemento([to, the, 'sigma-1', receptor, and, have, been, shown, to, regulate, its, 'activity;', these, include, 'progesterone,', 'N,N-dimethyltryptamine,', 'd-erythro-sphingosine,', 'and/or', other, endogenous, lipids])].
[sujeto(['We', previously]), verbo([reported]), complemento([the, synthesis, of, long, chain, 'N-alkylamine', derivatives, and, the, characterization, of, the, 'structure-activity', relationship, between, the, chain, length, of, 'N-alkylamine', and, affinities, at, the, 'sigma-1', receptor])].
[sujeto(['Interestingly,', 'light-dependent', photoinsertion, of, 4, -, 'NPPC12', resulted, in, an]), verbo([enhanced]), complemento([electrophoretic, mobility, of, only, 50, '%', of, the, derivatized, receptor, molecules, as, assessed, by, sodium, dodecyl, 'sulfate-polyacrylamide', gel, electrophoresis])].
[sujeto(['The', proposed]), verbo([binding]), complemento([and, reactivity, of, 4, -, 'NPPC12', evoke, a, ligand, binding, model, for, the, 'sigma-1', receptor, that, likely, involves, a, receptor, dimer, 'and/or', oligomer])].
[sujeto(['Neuroactive', steroids, refer, to, steroids, that, are, capable, of]), verbo([regulating]), complemento([neuronal, activities])].
[sujeto(['Neuroactive', 'steroids,', synthesized, either, de, novo, in, the, nervous, tissue, or, in, the, peripheral, endocrine, glands, or, as, synthetic, 'steroids,']), verbo([have]), complemento([exhibited, numerous, important, modulatory, effects, on, brain, functions, and, brain, diseases])].
[sujeto(['At', the, cellular, 'level,', in, addition, to, the, effect, on, postsynaptic, 'receptors,', most, neuroactive, 'steroids,', including, 'pregnenolone,', pregnenolone, 'sulfate,', 'progesterone,', 'allopregnanolone,', 'dehydroepiandrosterone,', dehydroepiandrosterone, 'sulfate,', testosterone, and, 'estradiol,']), verbo([have]), complemento([modulatory, effects, on, the, release, of, multiple, neurotransmitters, like, 'glutamate,', 'GABA,', 'acetylcholine,', 'norepinephrine,', dopamine, and, 5, -, 'HT'])].
[sujeto(['Many', of, these, effects, occur, in, the, brain, regions]), verbo([involved]), complemento([in, learning, and, 'memory,', 'emotion,', 'motivation,', motor, and, cognition])].
[sujeto(['Many', of, them]), verbo([involve]), complemento([rapid, 'non-genomic', effects, on, presynaptic, receptors, and, ion, channels, like, 'sigma-1', 'receptor,', 'alpha(1)', 'receptor,', nicotine, 'receptor,', 'D1', 'receptor,', 'NMDA', 'receptor,', 'GABA(A)', receptor, and, 'L-type', 'Ca(2+)', channels])].
[sujeto(['These', effects]), verbo([have]), complemento([made, neuroactive, steroids, important, regulators, of, synaptic, transmission, in, the, central, nervous, system, and, constitute, the, major, basis, for, many, important, actions, of, neuroactive, steroids, on, brain, functions, and, brain, diseases])].
[sujeto(['Dysfunction', of, 'GABA', receptor]), verbo([mediated]), complemento(['inhibition,', and, increased, glutamatergic, neurotransmission, has, been, implicated, in, the, development, of, orofacial, dyskinesia, in, rats, and, tardive, dyskinesia, in, humans])].
[sujeto(['Neurosteroids']), verbo([modulate]), complemento([both, 'GABAergic', as, well, as, glutamatergic, neurotransmission, in, various, brain, areas])].
[sujeto([')', for, a, period, of, 21, days, exhibited, marked]), verbo([increase]), complemento([in, vacuous, chewing, 'movements,', tongue, 'protrusions,', and, facial, jerkings, as, compared, to, 'vehicle-treated', controls])].
[sujeto(['It', also, resulted, in]), verbo([increased]), complemento([superoxide, anion, levels, and, lipid, 'peroxidation,', whereas, decreased, levels, of, endogenous, antioxidant, enzymes, '(', catalase, and, superoxide, 'dismutase)', in, rat, brain, striatum, homogenates])].
[sujeto(['Neurochemical', studies, revealed, that, chronic, administration, of, haloperidol, resulted, in, significant]), verbo([decrease]), complemento([in, the, levels, of, 'dopamine,', 'serotonin,', and, norepinephrine, in, rat, brain, striatum, 'homogenates,', whereas, urine, biogenic, amines, metabolite, levels, were, increased])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, neurosteroids, may, play, a, significant, role, in, the, pathophysiology, of, vacuous, chewing, movements, and, related, behaviors, by, virtue, of, their, action, on, either, the, 'GABA', or, 'NMDA', modulation])].
[sujeto(['Although', sigma, receptors, were, discovered, in, 1982, ',', the, biochemical, and, physiological, roles, of, sigma, receptors]), verbo([have]), complemento([just, begun, to, unveil])].
[sujeto(['The', 'sigma-1', receptor]), verbo([has]), complemento([been, cloned, and, its, sequence, does, not, resemble, that, of, any, mammalian, protein])].
[sujeto(['Sigma-2', receptors]), verbo([have]), complemento([not, been, cloned])].
[sujeto(['Many', pharmacological, and, physiological, actions]), verbo([have]), complemento([been, attributed, to, 'sigma-1', receptors])].
[sujeto(['These', include, the, regulation, of, 'IP3', receptors, and, calcium, signaling, at, the, endoplasmic, 'reticulum,', mobilization, of, cytoskeletal, adaptor, 'proteins,', modulation, of, nerve, growth, 'factor-induced', neurite, 'sprouting,', modulation, of, neurotransmitter]), verbo([release]), complemento([and, neuronal, 'firing,', modulation, of, potassium, channels, as, a, regulatory, 'subunit,', alteration, of, 'psychostimulant-induced', gene, 'expression,', and, blockade, of, spreading, depression])].
[sujeto(['Behaviorally,', 'sigma-1', receptors, are]), verbo([involved]), complemento([in, learning, and, 'memory,', 'psychostimulant-induced', 'sensitization,', 'cocaine-induced', conditioned, place, 'preference,', and, pain, perception])].
[sujeto(['Notably,', in, almost, all, the, aforementioned, biochemical, and, behavioral, 'tests,', 'sigma-1', 'agonists,', while, having, no, effects, by, 'themselves,']), verbo([caused]), complemento([the, amplification, of, signal, transductions, incurred, upon, the, stimulation, of, the, 'glutamatergic,', 'dopaminergic,', 'IP3-related', 'metabotropic,', or, nerve, growth, 'factor-related', systems])].
[sujeto(['A', common, genetic, variant, '(', 'V)', of, luteinizing, hormone, '(', 'LH),', with, two, mutations, '(', 'Trp(8)Arg', and, 'Ile(15)Thr)', and, an, extra, glycosylation, consensus, site, '(', 'Asn(13)-Ala-Thr),', is]), verbo([associated]), complemento([with, abnormalities, of, reproductive, function])].
[sujeto(['Although', the, mutations, in, 'V-LHbeta', did, not, significantly, affect, the, affinity, of, 'LH', receptor, '(', 'LHR)']), verbo([binding]), complemento(['(', 'Kd', approximately, 0.4, 'nmol/L),', 'V-LH', had, higher, in, vitro, biopotency, than, 'WT-LH,', in, terms, of, 'mLTC-1', mouse, 'Leydig', tumor, cell, cAMP, and, progesterone, '(', 'P)', 'production,', and, steroidogenic, acute, regulatory, protein, '(', 'StAR)', expression])].
[sujeto(['In', 'addition,', in, 'HEK', 293, cells]), verbo([expressing]), complemento([the, human, 'LHR,', 'V-LH', demonstrated, 1.8, -, fold, higher, response, of, inositol, trisphosphate, '(', 'IP(3))', production, than, 'WT-LH'])].
[sujeto(['Furthermore,', 'HEK', 293, cells]), verbo([expressing]), complemento([the, 'ElK1', 'trans-reporting', plasmids, displayed, 2.7, -, fold, greater, luciferase, response, to, 'V-LH', than, 'WT-LH,', documenting, stimulation, of, the, 'mitogen-activated', protein, kinase, '(', 'MAPK)', pathway])].
[sujeto(['It', is, worth, noting, that, analysis, by, 'matrix-assisted', laser, desorption, 'ionization-mass', spectrometry, '(', 'MALDI-MS)', demonstrated, clear, differences, in, structures, of, carbohydrate, side, chains, attached, to, the, two, forms, of, rec, 'LHs,', including, incomplete, processing, of, high, mannose, glycans, '(', 'Man(5,8,9))', in, 'V-LH,']), verbo([suggesting]), complemento([different, pathways, in, its, intracellular, trafficking])].
[sujeto(['Collectively,', the, present, findings]), verbo([provide]), complemento([the, molecular, basis, for, the, qualitative, and, quantitative, differences, in, 'LH', action, that, are, observed, in, carriers, of, the, 'V-LHbeta', allele])].
[sujeto(['Steroids,', synthesized, in, peripheral, glands, or, centrally, in, the, 'brain--the', latter, being, named, 'neurosteroids--exert', an, important, role, as, modulators, of, the, neuronal, activity, by]), verbo([interacting]), complemento([with, different, receptors, or, ion, channels])].
[sujeto(['In', addition, to, the, modulation, of, 'GABA(A),', 'NMDA', or, cholinergic, 'receptors,', neuroactive, steroids]), verbo([interact]), complemento([with, an, atypical, intracellular, 'receptor,', the, 'sigma(1)', protein])].
[sujeto(['This', receptor]), verbo([has]), complemento([been, cloned, in, several, 'species,', and, highly, selective, synthetic, ligands, are, available])].
[sujeto(['At', the, cellular, 'level,', sigma1, agonists]), verbo([modulate]), complemento([intracellular, calcium, mobilization, and, extracellular, calcium, 'influx,', 'NMDA-mediated', 'responses,', acetylcholine, 'release,', and, alter, monoaminergic, systems])].
[sujeto(['At', the, behavioral, 'level,', the, sigma1, receptor, is]), verbo([involved]), complemento([in, learning, and, memory, 'processes,', the, response, to, 'stress,', 'depression,', neuroprotection, and, pharmacodependence])].
[sujeto(['Such', effects, were]), verbo([found]), complemento([in, 'GABA', 'receptor,', nicotinic, 'receptors,', yet, not, investigated, in, 'P2X', purinoceptors])].
[sujeto(['Results', show, that, dehydroepiandrosterone, sulfate, acutely]), verbo([inhibits]), complemento(['P2X', purinoceptor, functions, in, 'PC12', cells])].
[sujeto(['Dehydroepiandrosterone', sulfate]), verbo([suppressed]), complemento(['ATP-induced', cytosolic, free, calcium, concentration, '(', '[', 'Ca(2+)](i))', 'rise,', cytosolic, free, sodium, concentration, '(', '[', 'Na(+)](i))', 'rise,', and, dopamine, secretion, in, the, presence, of, external, 'calcium,', but, had, no, effect, on, 'ATP-induced', '[', 'Ca(2+)](i)', rise, in, the, absence, of, external, calcium, or, on, 'UTP-induced', '[', 'Ca(2+)](i)', rise, in, the, absence, or, presence, of, external, calcium])].
[sujeto(['Our', data, show, that, dehydroepiandrosterone, sulfate, exerted, its, effect, on, 'P2X,', but, not, on, the, 'P2Y', purinoceptors]), verbo([found]), complemento([in, 'PC12', cells])].
[sujeto(['Estradiol', and, estrone]), verbo([have]), complemento([similar, effects, on, 'P2X', 'purinoceptor,', but, dehydroepiandrosterone, and, progesterone, do, not])].
[sujeto(['Steroid', hormones, mostly]), verbo([act]), complemento([via, nuclear, receptors])].
[sujeto(['Dehydroepiandrosterone', '(', 'DHEA),', pregnenolone, '(', 'PREG)', and, their, 'sulphate(s),', classically, known, only, as, hormonal, 'precursors,', are, also, neurosteroidal, efficacious, 'signals,']), verbo([modulating]), complemento([neurotransmitter, receptor, function, at, the, membrane, level])].
[sujeto(['An', additional, unforeseen, mechanism, of, steroid, action, is]), verbo([reported]), complemento(['here:', 'PREG', binds, to, neural, 'microtubule-associated', protein, 'MAP2', and, increases, both, the, rate, and, extent, of, tubulin, polymerization, studied, in, vitro, with, purified, tubulin, and, 'MAP2,', forming, microtubules, of, normal, electron, microscopic, appearance])].
[sujeto(['Progesterone', and, 'PREGS', also]), verbo([bind]), complemento([to, 'MAP2,', but, counteract, 'PREG', activity])].
[sujeto(['In', cultured, 'neurons,', 'PREG', specifically]), verbo([increased]), complemento([immunostaining, by, an, antiMAP2, monoclonal, antibody, and, its, extension, into, neurites])].
[sujeto(['This', novel, mechanism, may, play, a, role, in]), verbo([regulating]), complemento([microtubule, formation, and, 'dynamics,', which, are, altered, in, brain, ageing, and, diseases])].
[sujeto(['The', present, study, was, designed, to, investigate, the, neurosteroid, pregnenolone, sulfate, '(', 'PS),', known, for, its, ability, to]), verbo([modulate]), complemento(['NMDA', receptors, and, interfere, with, acute, 'excitotoxicity,', in, delayed, retinal, cell, death])].
[sujeto(['Three', hours, after, exposure, of, the, isolated, and, intact, retina, to, a, 30, -, min, 'PS', 'pulse,', 'DNA', fragmentation, as, assessed, by, genomic, 'DNA', gel, electrophoresis, and, a, modified, in, situ, terminal, deoxynucleotidyl, 'transferase-mediated', 'dUTP-biotin', nick, 'end-labeling', '(', 'TUNEL)', method, appeared, concurrently, with, an]), verbo([increase]), complemento([in, superoxide, dismutase, '(', 'SOD)', activity, and, thiobarbituric, 'acid-reactive', substances, '(', 'TBARS)', levels])].
[sujeto(['At', 7, 'h,', the]), verbo([increased]), complemento([amount, of, 'DNA', laddering, was, accompanied, by, a, higher, number, of, 'TUNEL-positive', cells, in, the, inner, nuclear, and, ganglion, cell, layers])].
[sujeto(['Necrotic', signs, were, characterized, by, 'DNA', smear, 'migration,', lactate, dehydrogenase, '(', 'LDH)', 'release,', and, damage, mainly, in, the, inner]), verbo([nuclear]), complemento([layer])].
[sujeto(['Steroids', with, antioxidant, properties, '(', 'progesterone,', dehydroepiandrosterone, and, its, sulfate, 'ester,', and, 17, 'beta-estradiol)', differently]), verbo([prevented]), complemento(['PS-induced', delayed, cell, death])].
[sujeto(['Cycloheximide', treatment, protected, against, 'DNA', fragmentation, and, 'LDH']), verbo([release]), complemento([but, failed, to, prevent, the, rise, in, 'SOD', activity, and, 'TBARS', level])].
[sujeto(['We', conclude, that, a, brief, 'PS', pulse]), verbo([causes]), complemento([delayed, cell, death, in, a, slowly, evolving, apoptotic, fashion, characterized, by, a, 'cycloheximide-sensitive', death, program, downstream, of, reactive, oxygen, species, generation, and, lipid, 'peroxidation,', turning, into, secondary, necrosis, in, a, retinal, cell, subset])].
[sujeto(['The', 3, 'alpha-hydroxy', ring, 'A-reduced', pregnane, steroids, allopregnanolone, and, tetrahydrodeoxycorticosterone]), verbo([have]), complemento([been, thought, not, to, interact, with, intracellular, 'receptors,', but, enhance, 'gamma-aminobutyric', acid, '(', 'GABA)-mediated', chloride, 'currents,', whereas, pregnenolone, sulfate, and, dehydroepiandrosterone, '(', 'DHEA)', sulfate, display, functional, antagonistic, properties, at, 'GABA(A)', receptors])].
[sujeto(['We', demonstrated, that, these, neuroactive, steroids, can]), verbo([regulate]), complemento([also, gene, expression, via, the, progesterone, receptor, after, intracellular, oxidation])].
[sujeto(['Thus,', in, physiological, concentrations, these, neuroactive, steroids]), verbo([regulate]), complemento([neuronal, function, through, their, concurrent, influence, on, 'transmitter-gated', ion, channels, and, gene, expression])].
[sujeto(['When', administered, in, animal, 'studies,', 'memory-enhancing', effects]), verbo([have]), complemento([been, shown, for, pregnenolone, sulfate, and, 'DHEA'])].
[sujeto(['These', findings, extend, the, concept, of, a, &, 'quot;cross-talk&quot;', between, membrane, and]), verbo([nuclear]), complemento([hormone, effects, and, provide, a, new, role, for, the, therapeutic, application, of, these, steroids, in, neurology, and, psychiatry])].
[sujeto(['We', previously]), verbo([reported]), complemento([evidence, for, two, subpopulations, of, several, classes, of, steroid, receptors, that, could, be, distinguished, by, their, requirement, of, a, low, molecular, weight, factor, '(', 'Mr=700-3000', 'Da)', for, binding, to, 'nonspecific,', calf, thymus, 'DNA-cellulose', '[', 'Cavanaugh,', 'A'])].
[sujeto(['This', factor, appeared, to, be, enriched, in, '(', 'NH4)2SO4', precipitates, of]), verbo([nuclear]), complemento([extracts])].
[sujeto(['Using', human, progesterone, receptors, '(', 'PRs)', and, biologically, active, 'DNA', sequences, in, a, modified, 'avidin/biotin-coupled', 'DNA', '(', 'ABCD)']), verbo([binding]), complemento(['assay,', we, now, report, a, 'factor-mediated', increase, in, 'PR', binding, to, specific, 'DNA', sites, that, was, indistinguishable, from, that, seen, with, nonspecific, sites])].
[sujeto(['The', main, advantages, of, this, modified, assay, are, that, both, kinetic, and, equilibrium]), verbo([binding]), complemento([of, 'receptor-steroid', complexes, to, 'DNA', can, be, directly, monitored, in, solution])].
[sujeto(['The', ability, of, either, 'Sephadex', 'G-50', chromatography, or, sodium, arsenite, to]), verbo([prevent]), complemento([that, binding, which, is, increased, by, added, factor, supported, the, existence, of, 'PR', subpopulations, that, are, independent, of, the, acceptor, 'DNA', sequence])].
[sujeto(['Kinetic', analyses, demonstrated, that, the, mechanism, of, action, of, salt, was, to, accelerate, the, rate, of]), verbo([binding]), complemento([of, 'PR'])].
[sujeto(['Salt', also, had, a, much, greater, effect, on, the, nonspecific]), verbo([binding]), complemento([of, 'PR,', such, that, the, ratio, of, specific, to, nonspecific, 'DNA', binding, was, greatest, at, elevated, salt, concentrations, '(', approximately, 75, 'mM)', that, afforded, submaximal, levels, of, 'PR', binding, to, specific, 'DNA', sites])].
[sujeto(['Further', analysis, of, the, 'DNA-bound', receptors, revealed, that, the, 'smaller,', 'A-form', of, 'PR', is, preferentially]), verbo([bound]), complemento([to, specific, 'DNA', sequences, both, in, the, presence, and, in, the, absence, of, various, salt, concentrations])].
[sujeto(['Thus,', the, differences, in, 'DNA']), verbo([binding]), complemento([of, 'PR', +, /, -, salt, do, not, correlate, with, the, preferential, binding, of, 'A', or, 'B', isoform])].
[sujeto(['The', unequal, behavior, of, 'PR', subpopulations, 'and/or', isoforms, for]), verbo([binding]), complemento([to, specific, 'DNA', sequences, offers, added, mechanisms, for, selective, transcriptional, regulation, of, genes, in, intact, cells])].
[sujeto(['The', 'hippocampus,', which, is, critically]), verbo([involved]), complemento([in, learning, and, memory, 'processes,', is, known, to, be, a, target, for, the, neuromodulatory, actions, of, steroid, hormones, produced, by, the, adrenal, glands, and, gonads])].
[sujeto(['McEwen', and, collaborators]), verbo([has]), complemento([focused, on, the, role, of, glucocorticosteroids, and, estrogen, in, modulating, hippocampal, plasticity, and, functions])].
[sujeto(['In', contrast, to, hormones, derived, from, the, 'circulation,', neurosteroids]), verbo([have]), complemento([paracrine, 'and/or', autocrine, activities])].
[sujeto(['In', the, 'hippocampus,', they]), verbo([have]), complemento([been, shown, to, have, trophic, effects, on, neurons, and, glial, cells, and, to, modulate, the, activity, of, a, variety, of, neurotransmitter, receptors, and, ion, 'channels,', including, type, 'A', 'gamma-aminobutyric', 'acid,', 'N-methyl-D-aspartate', and, sigma, receptors, and, 'N-', and, 'L-type', 'Ca2+', channels])].
[sujeto(['There', is, accumulating, evidence, that, some, 'neurosteroids,', in, particular, pregnenolone, 'sulfate,']), verbo([have]), complemento([strong, influences, on, learning, and, memory, 'processes,', most, likely, by, regulating, neurotransmission, in, the, hippocampus])].
[sujeto(['However,', the, hippocampus, is, not, the, only]), verbo([target]), complemento([for, the, mnesic, effects, of, neurosteroids])].
[sujeto(['Steroid', hormone, action]), verbo([involves]), complemento([binding, to, cognate, intracellular, receptors, 'that,', in, 'turn,', bind, to, respective, response, elements, and, thus, modulate, gene, expression])].
[sujeto(['The', present, study, shows, that, the, gonadal, 'steroids,', 17, 'beta-estradiol', and, 'progesterone,', may, also]), verbo([act]), complemento([as, functional, antagonists, at, the, 5, -, hydroxytryptamine, type, 3, '(', 5, -, 'HT3)', receptor, in, 'whole-cell', 'voltage-clamp', recordings, of, 'HEK', 293, cells, stably, expressing, the, 5, -, 'HT3', receptor])].
[sujeto(['The', antagonistic, action, of, steroids, at, the, 5, -, 'HT3', receptor, is, not]), verbo([mediated]), complemento([via, the, serotonin, binding, site, because, the, steroids, did, not, alter, the, binding, affinity, of, '[', 3, 'H]GR65630', to, the, 5, -, 'HT3', 'receptor,', and, kinetic, experiments, revealed, a, quite, different, response, pattern, to, 17, 'beta-estradiol', when, compared, with, the, competitive, antagonist, metoclopramide])].
[sujeto(['BSA-conjugated', gonadal, steroids, labeled, with, fluorescein, isothiocyanate]), verbo([bound]), complemento([to, membranes, of, 'HEK', 293, cells, expressing, the, 5, -, 'HT3', receptor, in, contrast, to, native, 'HEK', 293, cells])].
[sujeto(['However,', there, was, no, 'dose-dependent', displacement, of, the]), verbo([binding]), complemento([of, gonadal, steroids, to, membranes, of, cells, expressing, the, 5, -, 'HT3', receptor, in, binding, experiments, or, fluorescence, studies])].
[sujeto(['Thus,', gonadal, steroids, probably]), verbo([interact]), complemento([allosterically, with, the, 5, -, 'HT3', receptor, at, the, 'receptor-membrane', interface])].
[sujeto(['The', 3, 'alpha-hydroxy', ring, 'A-reduced', pregnane, steroids, allopregnanolone, and, tetrahydrodeoxycorticosterone]), verbo([have]), complemento([been, thought, not, to, interact, with, intracellular, receptors, but, enhance, 7, -, aminobutyric, acid, '(', 'GABA)-mediated', chloride, 'currents,', whereas, pregnenolone, sulfate, and, dehydroepiandrosterone, '(', 'DHEA)', sulfate, display, functional, antagonistic, properties, at, 'GABAA', receptors])].
[sujeto(['We', demonstrated, that, these, neuroactive, steroids, can]), verbo([regulate]), complemento([also, gene, expression, via, the, progesterone, receptor, after, intracellular, oxidation])].
[sujeto(['Thus,', in, physiological, concentrations, these, neuroactive, steroids]), verbo([regulate]), complemento([neuronal, function, through, their, concurrent, influence, on, 'transmitter-gated', ion, channels, and, gene, expression])].
[sujeto(['When', administered, in, animal, 'studies,', memory]), verbo([enhancing]), complemento([effects, have, been, shown, for, pregnenolone, sulfate, and, 'DHEA'])].
[sujeto(['These', findings, extend, the, concept, of, &, 'quot;cross-talk&quot;', between, membrane, and]), verbo([nuclear]), complemento([hormone, effects, and, provide, a, new, role, for, the, therapeutic, application, of, these, steroids, in, neurology, and, psychiatry])].
[sujeto(['We']), verbo([have]), complemento([described, previously, the, presence, of, binding, sites, in, particulate, fractions, of, the, porcine, corpus, luteum, '(', 'CL)', which, were, specific, for, progesterone])].
[sujeto(['We', now, demonstrate, the, presence, of, similar, 'progesterone-specific']), verbo([binding]), complemento([sites, in, particulate, fractions, of, the, ovine, 'CL'])].
[sujeto(['Preincubation', of, ovine, luteal, membranes, with, radiolabelled, steroids, demonstrated]), verbo([binding]), complemento([of, progesterone, and, pregnenolone, to, a, 'low-density', particulate, fraction, '(', 1.07, -, 1.09, 'g/cm3)'])].
[sujeto(['Preincubation', with, digitonin, perturbed, the, buoyant, density, of, this, fraction, '(', to, 1.1, -, 1.14, 'g/cm3)', without]), verbo([causing]), complemento([release, of, steroid])].
[sujeto(['Androgens', and, oestrogens, did, not]), verbo([bind]), complemento([appreciably, to, control, luteal, 'membranes,', but, were, bound, when, preincubated, with, digitonin])].
[sujeto(['In', 'contrast,', steroid, conjugates, '(', oestrone, 'sulfate,', pregnanediol, 'glucuronide),', 'cortisol,', fatty, acids, '(', arachidonic, 'acid,', prostaglandin, 'F2', 'alpha)', and, cholesterol, ester, failed, to]), verbo([bind]), complemento([to, ovine, luteal, 'membranes,', with, or, without, digitonin, pretreatment])].
[sujeto(['The', effects, of, digitonin, on, steroid]), verbo([binding]), complemento([led, us, to, examine, its, effects, on, steroid, binding, to, ovine, luteal, membrane, fractions, in, vitro])].
[sujeto(['Specific', progesterone]), verbo([binding]), complemento([was, absent, in, the, absence, of, 'digitonin,', even, at, very, high, membrane, concentrations])].
[sujeto(['However,']), verbo([binding]), complemento([of, 3, 'H-labelled', progesterone, was, stimulated, 5, -, 15, -, fold, in, a, 'dose-dependent', fashion, by, increasing, digitonin, 'concentrations,', reaching, a, plateau, at, about, 100, microM])].
[sujeto(['In', the, presence, of, 'digitonin,', '[', 3, 'H]progesterone']), verbo([binding]), complemento([increased, linearly, with, luteal, membrane, concentration])].
[sujeto(['Other', 'detergents,', saponins, and, cardiotonic, steroids, tested, did, not]), verbo([stimulate]), complemento([progesterone, binding, to, ovine, luteal, membranes])].
[sujeto(['[', 3, 'H]Progesterone']), verbo([binding]), complemento([was, dependent, on, the, 'pH,', duration, and, temperature, of, incubation])].
[sujeto(['Unlabelled', progesterone]), verbo([decreased]), complemento([binding, of, '[', 3, 'H]progesterone', '(', 'half-maximal', displacement, of, specific, binding, '(', 'IC50)', at, about, 60, 'nM)', whereas, androgens, were, less, potent, '(', 'IC50,', 500, -, 3300, 'nM),', whilst, a, wide, range, of, other, steroids, and, inhibitors, of, steroidogenic, enzymes, were, 'ineffective,', except, at, very, high, concentrations])].
[sujeto(['Similarly,', a, number, of, progesterone, receptor, agonist, and, antagonist, analogues, failed, to, compete, for, progesterone]), verbo([binding]), complemento([to, luteal, 'membranes,', suggesting, that, these, binding, sites, were, unrelated, to, progesterone, receptors])].
[sujeto(['Modifications', to, the, 3, ',', 4, ',', 5, and, 11, positions, of, 'progesterone,', removal, of, the, steroid, 'side-chain', or, aromatization, of, the, 'A-ring']), verbo([decreased]), complemento([binding, potency, 'dramatically,', whereas, changes, to, the, 17, or, 20, positions, had, relatively, minor, effects])].
[sujeto(['Our', results, indicate, the, presence, of, a, low, density, particulate, fraction, in, ovine, corpora, lutea, which, contains, specific]), verbo([binding]), complemento([sites, for, endogenous, and, exogenous, progesterone])].
[sujeto(['The', 'progesterone-initiated', human, sperm, acrosome, reaction, '(', 'AR)']), verbo([requires]), complemento([a, rise, in, intracellular, 'Ca2+', '(', '[', 'Ca2+]i),', extracellular, 'Cl-', and, apparently, increased, 'Cl-', flux, through, a, unique, steroid, 'receptor/Cl-', channel, resembling, but, not, identical, to, a, 'GABA(A)/Cl-', channel, complex])].
[sujeto(['The', present, study, uses, 'fura-2', loaded, human, 'sperm,', 'GABA(A)/Cl-', channel, blockers, '(', picrotoxin, and, pregnenolone, 'sulfate)', and, 'Cl(-)-containing', and, 'Cl(-)-deficient', media, to, determine, whether, the, 'progesterone-mediated']), verbo([increase]), complemento([in, '[', 'Ca2+]i', is, dependent, on, the, 'Cl-', requirement])].
[sujeto(['There', was, no, significant, difference, between, the, 'progesterone-mediated']), verbo([increases]), complemento([of, '[', 'Ca2+]i', obtained, in, 'Cl(-)-containing', and, 'Cl(-)-deficient', media])].
[sujeto(['Picrotoxin', did, not, significantly]), verbo([inhibit]), complemento([the, 'progesterone-mediated', increase, in, '[', 'Ca2+]i,', and, pregnenolone, sulfate, increased, '[', 'Ca2+]i', to, the, same, extent, as, progesterone])].
[sujeto(['These', results, strongly]), verbo([suggest]), complemento([that, the, increase, in, '[', 'Ca2+]i', essential, to, the, 'AR', is, independent, of, the, 'AR', 'Cl-', requirement, and, could, be, explained, by, the, existence, of, two, different, sperm, plasma, membrane, progesterone, receptors])].
[sujeto(['Naturally', occurring, 3, -, 'alpha-hydroxy', ring, 'A-reduced', metabolites, of, progesterone, and, deoxycorticosterone, and, their, synthetic, analogues]), verbo([bind]), complemento([to, specific, sites, within, the, hydrophobic, channel, domain, of, the, 'GABAA', receptor, complex])].
[sujeto(['Acting', at, these, 'sites,', these, ligands, function, as, positive, allosteric, effectors, of, the, 'complex;', they, potentiate, 'GABA-stimulated', membrane, chloride, ion, 'conductance,']), verbo([enhance]), complemento([the, binding, of, '[', 3, 'H]muscimol', and, '[', 3, 'H]flunitrazepam,', and, displace, the, binding, of, '[', 35, 'S]t-butylbicyclophosphorothionate', '(', '[', 35, 'S]TBPS),', a, channel, ligand, that, is, a, specific, marker, of, the, 'GABA-associated', chloride, ionophore])].
[sujeto(['Moreover,', steroid, metabolites, '(', namely, pregnenolone, sulfate, and, dehydroepiandrosterone, 'sulfate)']), verbo([have]), complemento([been, identified, that, display, properties, of, 'GABA-negative', allosteric, effectors])].
[sujeto(['The', identification, of, this, 'membrane-associated', steroid]), verbo([binding]), complemento([should, stimulate, development, of, new, classes, of, 'anxiolytic,', 'sedative-hypnotic,', 'anticonvulsant,', 'anesthetic,', and, 'muscle-relaxant', medications, that, may, be, devoid, of, many, of, the, side, effects, associated, with, benzodiazepines, and, barbiturates])].
[sujeto(['Also,', elucidation, of, the, physiologic, role, of, this]), verbo([binding]), complemento([site, should, contribute, both, to, our, understanding, of, endogenous, mechanisms, for, modulating, inhibitory, 'neurotransmission,', and, the, pathophysiologic, role, of, the, 'GABAA', receptor, complex, in, a, variety, of, neuropsychiatric, disorders])].
[sujeto(['Progestin', addition, to, cells, '(', in, 'vivo)']), verbo([causes]), complemento([a, 2, -, fold, increase, in, total, phosphorylation, of, 'PR', and, an, increase, in, the, apparent, mol, wt, of, both, 'PR-A', and, 'PR-B', on, sodium, dodecyl, sulfate, '(', 'SDS)-gels'])].
[sujeto(['Time-course', experiments, showed, that]), verbo([increased]), complemento(['PR', phosphorylation, that, results, from, hormone, addition, is, a, multistep, process, and, involves, a, rapid, increase, into, total, 32, 'P', labeling, that, takes, place, before, the, more, slowly, occurring, 'phosphorylation(s)', responsible, for, the, change, in, electrophoretic, mobility, of, 'PR', on, 'SDS-gels'])].
[sujeto(['As', an, approach, to, test, whether, phosphorylation, is]), verbo([involved]), complemento([in, regulating, 'PR', 'activity,', we, have, examined, the, effects, of, cellular, modulators, of, protein, phosphorylation, on, 'PR-mediated', target, gene, transcription, in, vivo, using, a, 'T47D', cloned, cell, line, containing, a, stably, transfected, mouse, mammary, tumor, 'virus-chloramphenicol', acetyltransferase, construct])].
[sujeto(['Treatment', with, 8, -, 'bromo-cAMP', '(', activator, of, 'cAMP-dependent', protein, 'kinases)', or, okadaic, acid, '(', protein, 'phosphatase-1', and, -, 2, 'A', 'inhibitor)', did, not]), verbo([stimulate]), complemento([target, gene, expression, in, the, absence, of, progestin])].
[sujeto(['When', added, together, with, 'progestin,', either, compound, augmented, 'PR-mediated']), verbo([target]), complemento([gene, transcription, by, 3, -, to, 4, -, fold])].
[sujeto(['The', cyclic, 'nucleotide-dependent', protein, kinase, inhibitor, 'H8', completely, blocked]), verbo([target]), complemento([gene, responsiveness, to, hormone])].
[sujeto(['These', 'agents,', 'therefore,', appeared, to, selectively]), verbo([modulate]), complemento(['PR', transcriptional, activity])].
[sujeto(['Moreover,', none, of, these, compounds, altered, expression, from, a, control, reporter, 'gene,', 'pSV2CAT,', indicating, that, these, agents, affect, 'PR-mediated', processes, directly, and, are, not]), verbo([acting]), complemento([through, a, general, effect, on, transcription])].
[sujeto(['This']), verbo([suggests]), complemento([that, these, agents, modulate, 'PR', transcriptional, activity, either, through, phosphorylation, of, another, protein, intimately, involved, in, 'PR-mediated', transcription, or, through, modification, of, a, key, 'site(s)', not, measurable, as, a, change, in, total, 'PR', phosphorylation, or, electrophoretic, mobility, on, 'SDS', gels])].
[sujeto(['Adrenal', suppression, with, dexamethasone, for, 4, days, does, not]), verbo([decrease]), complemento([the, concentrations, of, brain, 'P', and, 3, rd, ventricle, 'CSFP', and, 'D'])].
[sujeto(['The', concentrations, of, brain, 'D', are]), verbo([decreased]), complemento([to, a, much, smaller, extent, than, plasma, 'D'])].
[sujeto(['D']), verbo([inhibits]), complemento([the, aggressive, behavior, of, castrated, male, mice, exposed, to, lactating, female, intruders])].
[sujeto(['The', 'D', analog, 3, 'beta-methyl-androst-5-en-17-one,', which, is, not, estrogenic, and, cannot, be, metabolized, to, testosterone, or, 'estradiol,', is, as, active, as, 'D', in]), verbo([inhibiting]), complemento([the, aggressive, behavior, of, castrated, mice])].
[sujeto(['In', 'cattle,', 'pro-oestrous', oestradiol, and, dioestrous, progesterone, concentrations]), verbo([modulate]), complemento([endometrial, gene, expression, and, fertility])].
[sujeto(['Expression', of, the, 'HER2', protein, was]), verbo([found]), complemento([in, 10, '(', 33.8, '%', ')', 'cases,', whereas, extra, copies, were, found, in, 3, '(', 7.1, '%', ')'])].
[sujeto(['In', univariable, 'analysis,']), verbo([loss]), complemento([of, 'AR', was, significantly, associated, with, shorter, 'disease-free', survival, '(', 'P=0'])].
[sujeto([20, ')', ',', whereas, the, expression, of, 'HER2', was]), verbo([associated]), complemento([with, a, better, outcome, with, borderline, significance, '(', 'P=0'])].
[sujeto(['Expression', of, 'hypoxia-inducible', factor, 1, α, '(', 'HIF-1α)', reflects, the, degree, of, cell, hypoxia, and, its]), verbo([increased]), complemento([expression, was, found, in, most, 'neoplasms,', their, metastasis, as, well, as, in, some, precancerous, lesions])].
[sujeto(['Expression', of, 'HIF-1α', was, more, often, noted, in, invasive, 'HER2+', cancers, characterized, by, high, degree, of, aggressiveness, and, poorer, 'prognosis,', which, might]), verbo([suggest]), complemento([that, presence, of, 'HIF-1α', protein, expression, in, 'HER2+', cancers, could, be, an, additional, prognostic, 'factor,', the, frequent, occurrence, of, the, phenotype, of, 'HIF-1α', and, 'EPO-R', in, cancers, invasive, 'HER2', +, ',', in, the, absence, of, 'ER', and, 'PR,', may, suggest, that, 'HIF-1α', and, 'EPO-R', may, be, an, indicator, of, the, aggressiveness, of, invasive, breast, 'cancers,', indicating, the, need, for, a, specific, forms, of, treatment, in, this, group, of, patients])].
[sujeto(['Preterm', birth, remains, the, major]), verbo([cause]), complemento([of, neonatal, morbidity, and, mortality, throughout, the, world])].
[sujeto(['In', this, 'article,', we, review, our, current, knowledge, of, the, 'complex,', interrelated, and, concerted, mechanisms, whereby, progesterone]), verbo([maintains]), complemento([myometrial, quiescence, throughout, most, of, 'pregnancy,', as, well, as, those, that, mediate, the, upregulation, of, the, inflammatory, response, and, decline, in, progesterone, receptor, function, leading, to, parturition])].
[sujeto(['Specifically,', we, focus, on, our, own, studies, indicating, that, maturation, of, the, fetal, lung, and]), verbo([enhanced]), complemento([secretion, of, the, surfactant, 'components,', surfactant, protein, 'A', '(', 'SP-A),', and, the, potent, inflammatory, 'glycerophospholipid,', 'platelet-activating', factor, '(', 'PAF)', initiate, a, signaling, cascade, culminating, in, parturition])].
[sujeto(['Our', studies]), verbo([suggest]), complemento([an, essential, role, of, steroid, receptor, 'coactivators,', 'SRC-1', and, 'SRC-2,', which, activate, expression, of, genes, encoding, 'SP-A', and, 'LPCAT1'])].
[sujeto(['Thus,', we, describe, a, novel, pathway, through, which, the, fetus, contributes, to, the, initiation, of, labor, by, signaling, the, mother, when, its, lungs]), verbo([have]), complemento([achieved, sufficient, maturity, for, survival, in, an, aerobic, environment])].
[sujeto(['For', each, 'case,', we, extracted, information, on, age, at, 'diagnosis,', tumour, 'size,', nodal, 'status,', oestrogen, receptor, 'status,', progesterone, receptor, 'status,', 'ethnicity,']), verbo([cause]), complemento([of, death, and, date, of, death])].
[sujeto(['Women', diagnosed, with, stage, 'IV', breast, cancer, before, age, 50]), verbo([have]), complemento([better, survival, at, 10, &, 'nbsp;years', compared, to, older, women])].
[sujeto(['AA', reduced, the, secretion, of, both, cortisol, and, 'androgens,']), verbo([increased]), complemento([production, of, progesterone, and, induced, a, 'concentration-dependent', decrease, of, cell, viability, in, the, 'NCI-H295R', cells, and, primary, secreting, 'ACC', cultures])].
[sujeto(['AA', also, reduced, 'beta-catenin']), verbo([nuclear]), complemento([accumulation, in, 'NCI-H295R', cells])].
[sujeto(['AA', administration, to, 'NCI-H295R-bearing', mice]), verbo([enhanced]), complemento([progesterone, levels, and, inhibited, tumor, growth])].
[sujeto(['The', cytotoxic, effect, of, 'AA', was]), verbo([prevented]), complemento([by, either, blocking, 'PgR', or, by, gene, silencing])].
[sujeto(['AA', is, able, to]), verbo([inhibit]), complemento([hormone, secretion, and, growth, of, 'ACC', both, in, vitro, and, in, vivo])].
[sujeto(['It', also, reduces, 'beta-catenin']), verbo([nuclear]), complemento([accumulation])].
[sujeto(['The', cytotoxic, effect, of, 'AA', appears, to]), verbo([require]), complemento(['PgR'])].
[sujeto(['The', majority, of]), verbo([reports]), complemento([showed, the, presence, of, estrogen, and, progesterone, receptors, in, astrocytomas])].
[sujeto(['Overall,', higher, tumor, grades, were]), verbo([associated]), complemento([with, decreased, estrogen, receptor, expression, and, increased, progesterone, receptor, expression])].
[sujeto(['The', 'IRS', scores, were, then, statistically]), verbo([associated]), complemento([with, various, tumor, 'traits,', including, tumor, 'size,', lymph, node, 'status,', 'metastasis,', 'grade,', expression, of, steroid, hormone, receptors, and, patient, survival])].
[sujeto(['These', mechanisms, also]), verbo([have]), complemento([an, important, role, in, the, formation, of, remote, 'metastases,', which, is, the, main, cause, for, 'tumor-associated', mortality])].
[sujeto(['The', results, of, the, present, study]), verbo([suggested]), complemento([that, patients, with, endometrial, adenocarcinoma, may, benefit, from, treatment, with, inhibitors, of, 'ERα,', 'PR,', 'VEGFR2', or, 'LHCGR,', since, it, could, lead, to, a, better, prognosis])].
[sujeto(['However,', further, studies, are]), verbo([required]), complemento([in, order, to, elucidate, the, roles, of, these, receptors, in, endometrial, adenocarcinoma])].
[sujeto(['The', 'Phosphatase', and, tensin, homolog, '(', 'PTEN)', protein, is, a, negative, regulator, of, the, 'Akt', 'pathway,']), verbo([leading]), complemento([to, suppression, of, apoptois, and, increased, cell, survival])].
[sujeto(['Its', role, as, a, 'tumor-suppressor', gene]), verbo([has]), complemento([been, adequately, 'substantiated,', and, 'PTEN', hypermethylation, has, been, demonstrated, in, familial, and, sporadic, cancers])].
[sujeto(['The', pooled, 'OR,', 22.3, ',', 95, '%', confidential, 'intervals,', 'CI', =, 1.98, -, 251.51, ',', 'P', =, 0.01, ',', which, demonstrates, that]), verbo([loss]), complemento([of, 'PTEN', expression, by, hypermethylation, plays, a, critical, role, in, the, early, tumorigenesis, of, ductal, carcinoma, in, situ, '(', 'DCIS)'])].
[sujeto(['These', results, indicate, the, 'PTEN', hypermethylation, is, significantly]), verbo([associated]), complemento([with, both, 'DCIS', and, 'IDCs'])].
[sujeto(['Endometritis', reduces, fertility, and, is, responsible, for, major, economic]), verbo([losses]), complemento([in, beef, and, dairy, industries])].
[sujeto(['Effect', of, 'PRP', on, endometrial, cell, proliferation, and, on, the, expression, of, genes, '[', 'prostaglandin-endoperoxide', synthase, 2, '(', 'COX2),', tumor, protein, p53, '(', 'TP53),', oestrogen, receptors, '(', 'ER-α', and, 'ER-β),', progesterone, receptor, '(', 'PR)', and, 'c-Myc]']), verbo([involved]), complemento([in, the, regulation, of, oestrus, cycle, and, 'fetal-maternal', interaction, were, evaluated])].
[sujeto(['The', expression, of, genes, such, as, interleukin, 1, β, '(', 'IL-1β),', 'interleukin-8', '(', 'IL-8),', inducible, nitric, oxide, synthase, '(', 'iNOS),', 'prostaglandin-endoperoxide', synthase, 2, '(', 'COX2/PTGS2),', and, the]), verbo([release]), complemento([of, 'PGE-2,', 'IL-1β', and, 'IL-8', were, evaluated])].
[sujeto(['In', vivo, treatment, with, 'PRP']), verbo([increased]), complemento([the, detection, of, 'PR'])].
[sujeto(['In', 'vitro,', 5, &, 'nbsp;%', 'PRP', at, passage, 5]), verbo([increased]), complemento([proliferation, rate, and, induced, a, significant, increase, in, the, expression, of, all, studied, genes])].
[sujeto(['Furthermore,', the, results, revealed, that, 10, &, 'nbsp;ng/ml', of, 'LPS', is, the, most, effective, dose, to, obtain, an, inflammatory, 'response,', and, that, 'PRP', treatment, significantly, down]), verbo([regulated]), complemento([the, expression, of, 'pro-inflammatory', genes])].
[sujeto(['However,', the, luminal, type, of, breast, cancer, is, heterogeneous, and, can]), verbo([have]), complemento([aggressive, clinical, features])].
[sujeto(['However,', the, 'ER-', or, 'PR-negative', group, was]), verbo([associated]), complemento([with, older, age, '(', '≥45&nbsp;years),', higher, histological, 'grade,', lower, 'Bcl-2', 'expression,', and, far, higher, 'Ki', 67, '(', &, 'gt;50&nbsp;%)'])].
[sujeto(['Do', microRNAs, '(', 'miRNAs)', contribute, to, aberrant, progesterone, receptor, '(', 'PGR)', expression, in, the, eutopic, endometrium, of, women, with, 'endometriosis?', 'miR-196a', upregulates, 'MEK/ERK', 'signalling,']), verbo([mediating]), complemento([a, downregulation, of, 'PGR', expression, in, the, eutopic, endometrium, of, women, with, minimal, or, mild, endometriosis])].
[sujeto(['Implantation', failure, is, strongly]), verbo([suggested]), complemento([as, an, underlying, cause, for, the, observed, infertility, in, minimal, or, mild, endometriosis])].
[sujeto(['Progesterone', 'resistance,', which, is, mainly]), verbo([caused]), complemento([by, aberrantly, expressed, progesterone, receptor, in, the, eutopic, 'endometrium,', is, considered, as, a, key, factor, of, decreased, endometrial, 'receptivity;', thus, 'far,', 'epigenetics,', but, not, 'miRNA,', has, been, shown, to, affect, 'PGR', expression, in, the, endometrium])].
[sujeto(['Bioinformatics', analysis, predicted, that, 'miR-196a']), verbo([targets]), complemento([the, 3, '\'', -, untranslated, region, '(', 'UTR)', of, the, 'PGR'])].
[sujeto(['miR-196a', and, 'P-MEK/P-ERK', were, both]), verbo([found]), complemento([to, be, significantly, upregulated, in, the, eutopic, endometrium, in, patients, with, 'mild/minimal', endometriosis])].
[sujeto(['PGR', and, 'PGR-B', mRNA, were]), verbo([inhibited]), complemento([by, 'miR-196a', overexpression, and, upregulated, by, 'miR-196a', inhibition])].
[sujeto(['Luciferase', reporter, failed, to, confirm, the]), verbo([target]), complemento([regulation, of, 'miR-196a', on, 'PGR'])].
[sujeto(['Transfection', of, 'ESCs', with, a, 'miR-196a', mimic]), verbo([led]), complemento([to, an, increase, in, the, 'P-MEK/P-ERK', protein, 'levels,', decrease, in, the, 'PGR', protein, 'levels,', and, atypical, decidualization])].
[sujeto(['Inhibition', of, 'P-MEK/P-ERK', also]), verbo([increased]), complemento(['PGR', expression])].
[sujeto(['This', study, focused, on, the, role, of, 'miR-196a,', and, therefore, does, not]), verbo([involve]), complemento([other, 'miRNAs;', 'hence,', it, is, possible, that, other, miRNAs, may, also, be, responsible, for, progestin, resistance, in, endometriosis])].
[sujeto(['Our', data, revealed, altered, miRNA, expression, and]), verbo([activated]), complemento(['MEK/ERK', signalling, in, the, eutopic, endometrium, in, minimal, or, mild, endometriosis])].
[sujeto(['We', showed, that, the, 'miR-196a', level, is]), verbo([associated]), complemento([with, reduced, expression, of, 'PGR', isoforms, through, 'MEK/ERK,', suggesting, that, 'miR-196a', and, 'MEK/ERK', are, both, potential, biomarkers, of, endometriosis])].
[sujeto(['These', results]), verbo([provide]), complemento([a, novel, approach, to, target, the, mechanisms, behind, progesterone, resistance, in, endometriosis])].
[sujeto(['The', authors]), verbo([have]), complemento([no, conflicts, of, interest])].
[sujeto(['Menopause', is, a, critical, stage, of, 'women\'s', life]), verbo([associated]), complemento([with, various, complaints, and, distresses])].
[sujeto(['Obviously,', these, 'symptoms,', resulting, from, estrogen, deficiency, during, 'menopause,', can, exert, negative, effects, on, 'women\'s', health, and, quality, of, life, and, thus]), verbo([require]), complemento([to, be, managed, through, approaches, such, as, hormone, replacement, therapy, '(', 'HRT)'])].
[sujeto(['Recent', 'in-vivo', studies]), verbo([have]), complemento([highlighted, the, ability, of, 8, -, prenylnaringenin, to, reduce, 'serum-luteinizing', hormone, '(', 'LH)', and, 'follicle-stimulating', hormone, '(', 'FSH),', to, increase, serum, prolactin, levels, and, uterine, 'weight,', and, to, induce, vaginal, hyperplastic, epithelium])].
[sujeto(['Previous', research]), verbo([has]), complemento([shown, that, hops, extract, can, strongly, bind, to, both, estrogen, 'receptors,', stimulate, alkaline, phosphatase, activity, in, 'Ishikawa', 'cells,', and, upregulate, 'presenelin-2', and, progesterone, receptor, mRNA, in, 'Ishikawa', cells])].
[sujeto(['Numerous', clinical, trials]), verbo([have]), complemento([documented, significant, reductions, in, the, frequency, of, hot, flushes, following, the, administration, of, 'hop-containing', preparations])].
[sujeto(['Estrogen', signaling, pathways, are]), verbo([modulated]), complemento([by, exogenous, factors])].
[sujeto(['The', affinity, of, these, compounds, for, estrogen, receptor, '(', 'ER)-alpha', and, beta, '(', 'ERα', and, 'ERβ)-was', assessed, in, receptor]), verbo([binding]), complemento([assays])].
[sujeto(['Zearalenol', also]), verbo([decreased]), complemento([spontaneous, 'AR', and, increased, chromatin, decondensation])].
[sujeto(['Ginseng']), verbo([decreased]), complemento([chromatin, decondensation, in, response, to, calcium, ionophore, and, decreased, 'AR', in, response, to, progesterone, '(', 'P4)', and, ionophore])].
[sujeto(['Zearalenol']), verbo([has]), complemento([adverse, effects, on, sperm, motility, and, function, by, targeting, multiple, signaling, 'cascades,', including, 'P4,', 'E2,', and, calcium, pathways])].
[sujeto(['Before', 'treatment,', the, numbers, of, endometrial, glands, were, significantly, 'decreased,', while, fibrosis, area, rate, was]), verbo([increased]), complemento([in, 'IUA', model, group, '(', 'P&lt;0'])].
[sujeto(['By', 'contrast,', the, therapies, by, 'BMSCs', transplantation, through, either, tail, vein, injection, or, intrauterine, injection, significantly, elevated, the, numbers, of, endometrial, glands, and]), verbo([decreased]), complemento([the, fibrosis, area, rate, '(', 'P&lt;0'])].
[sujeto(['BMSCs', transplantation, was, effective, to, repair, the, damaged, endometrium, likely, through]), verbo([promoting]), complemento([the, 'ER', and, 'PR', expressions])].
[sujeto(['Over', the, past, few, 'decades,', human, papillomavirus, '(', 'HPV)']), verbo([has]), complemento([been, recorded, as, a, key, player, in, the, development, of, various, genital, 'cancers,', most, notably, cervical, cancer])].
[sujeto(['It']), verbo([has]), complemento([also, been, associated, with, some, 'non-genital', cancers])].
[sujeto(['A', subset, of, oropharyngeal, cancers, are, known, to, be]), verbo([caused]), complemento([by, 'HPV'])].
[sujeto(['Its', aetiological, involvement]), verbo([has]), complemento([been, suggested, for, breast, and, lung, cancer, as, well])].
[sujeto(['However,']), verbo([reports]), complemento([regarding, the, 'HPV', 'DNA', detection, vary, widely, from, different, parts, of, the, world])].
[sujeto(['HPV16', 'DNA', was]), verbo([found]), complemento([in, both, breast, and, lung, carcinoma, samples, with, the, prevalence, rate, of, 17, and, 11, &, 'nbsp;%,', respectively])].
[sujeto(['An', interesting, 'association&nbsp;was']), verbo([found]), complemento([between, 'ER/PR', '(', 'Oestrogen/Progesterone', 'receptor)', and, 'HER2/Neu', '(', 'Human', epidermal, growth, factor, 'receptor-2)', positivity, with, 'HPV', occurrence, in, breast, tumours])].
[sujeto(['A', positive, correlation, of, 'HPV16', presence, was]), verbo([found]), complemento([with, 'ER/PR', and, 'HER2-positive', breast, cancers])].
[sujeto(['There', are, currently, no]), verbo([reports]), complemento([describing, mammary, gland, development, in, the, 'Harlan', 'Sprague-Dawley', '(', 'HSD)', 'rat,', the, current, strain, of, choice, for, 'National', 'Toxicology', 'Program', '(', 'NTP)', testing])].
[sujeto(['Research', on, endocrine, disrupting, chemicals, in, animal, models]), verbo([has]), complemento([highlighted, chemically, induced, mammary, gland, anomalies, that, may, potentially, impact, human, health])].
[sujeto(['We']), verbo([provide]), complemento([illustrations, of, normal, and, chemically, altered, mammary, gland, development, in, 'HSD', male, and, female, rats, to, help, inform, researchers, unfamiliar, with, the, tissue, and, may, facilitate, enhanced, evaluation, of, both, male, and, female, mammary, glands, in, juvenile, toxicity, studies])].
[sujeto(['Among', 205, 'TNBCs,', 91, '%', of, cases, were, core, 'BLBCs,', and, absence, of, ductal, carcinoma, in, situ, '(', 'DCIS)', was, significantly]), verbo([associated]), complemento(['(', 'P', =])].
[sujeto(['A', 'ribbon-like', trabecular, pattern, and, absence, of, 'DCIS', were]), verbo([associated]), complemento([with, 'CK17', '(', 'P', =])].
[sujeto(['Clinicopathological', parameters, including, 'age,', 'ethnicity,', tumour, 'size,', histological, 'grade,', histological, 'subtype,']), verbo([associated]), complemento([ductal, carcinoma, in, 'situ,', lymphovascular, invasion, and, lymph, node, status, were, evaluated])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, 'ER(-)/PR(+)', 'BCs', 'exist,', although, 'rare,', with, distinct, pathological, and, clinical, characteristics, from, patients, with, 'ER(+)/PR(+)', 'BCs'])].
[sujeto(['High', temperature, severely, affected, rice, 'morphology,', and, also, reduced, leaf, 'area,', 'above-,', and, 'below-ground', 'biomass,', 'photosynthesis,', and, water, use, 'efficiency,', while]), verbo([increased]), complemento([the, leaf, water, potential, of, both, rice, cultivars])].
[sujeto(['The', highest, grain, production, by, 'Vc+Ve+MejA+Br', treated, plants, was, due, to]), verbo([enhanced]), complemento(['photosynthesis,', spikelet, fertility, and, grain, 'filling,', which, compensated, the, adversities, of, high, temperature, stress])].
[sujeto(['Despite', the, 'well-known', influence, of, environmental, context, on, episodic, 'memory,', little]), verbo([has]), complemento([been, done, to, increase, contextual, richness, within, the, lab])].
[sujeto(['Replicating', 'lab-based', subsequent, memory, effects, '(', 'SMEs),', we, identified, significant, low, to, mid, frequency, power]), verbo([decreases]), complemento(['(', &, 'lt;30Hz),', including, beta, power, decreases, over, the, left, inferior, frontal, gyrus])].
[sujeto(['When', investigating, the, oscillatory, correlates, of, temporal, and, spatial, context, 'binding,', we]), verbo([found]), complemento([that, items, strongly, bound, to, spatial, context, exhibited, significantly, greater, theta, power, decreases, than, items, strongly, bound, to, temporal, context])].
[sujeto(['The', number, of]), verbo([involved]), complemento([axillary, lymph, nodes, '(', 'LNs)', found, pathologically, is, regarded, as, a, significant, prognostic, factor, in, 'early-stage', breast, cancer, '(', 'EBC)'])].
[sujeto(['Recently,', there, is, speculation, that, 'LN', ratio, '(', 'LNR)', may, be, a, better, surrogate, at, predicting, 'cancer-specific', outcome, than, number, of]), verbo([involved]), complemento(['LNs'])].
[sujeto(['Proportional', hazard, modeling, was, undertaken, to, evaluate, whether, 'LNR', was]), verbo([associated]), complemento([with, overall, survival, '(', 'OS)'])].
[sujeto(['Curcumin', '(', diferuloyl, 'methane)', is, an, antioxidant, that, exerts, antiproliferative, and, apoptotic, effects, and]), verbo([has]), complemento(['anti-invasive', and, 'anti-metastatic', properties])].
[sujeto(['Evidence', strongly, implicates, that, 'epithelial-mesenchymal', transition, '(', 'EMT)', is]), verbo([involved]), complemento([in, malignant, progression, affecting, genes, such, as, 'Slug,', 'AXL', and, 'Twist1'])].
[sujeto(['These', genes, are, abnormally]), verbo([expressed]), complemento([in, many, tumors, and, favor, metastasis])].
[sujeto(['Results', showed, that, curcumin]), verbo([decreased]), complemento(['E-cadherin,', 'N-cadherin,', 'β-catenin,', 'Slug,', 'AXL,', 'Twist1,', 'Vimentin', and, 'Fibronectin', protein, 'expression,', independently, of, the, positivity, of, the, markers, in, the, cell, lines])].
[sujeto(['Curcumin', also]), verbo([decreased]), complemento([migration, and, invasive, capabilities, in, comparison, to, their, own, controls])].
[sujeto(['It', can, be, concluded, that, curcumin, influenced, biochemical, changes]), verbo([associated]), complemento([with, 'EMT-related', genes, that, seems, to, promote, such, transition, and, are, at, the, core, of, several, signaling, pathways, that, mediate, the, transition])].
[sujeto(['Thus,', it, can, be]), verbo([suggested]), complemento([that, curcumin, is, able, to, prevent, or, delay, cancer, progression, through, the, interruption, of, this, process])].
[sujeto(['In', breast, cancer, '(', 'BC)', laminin, expression, is, speculated, to, be]), verbo([associated]), complemento([with, unfavourable, clinicopathological, and, molecular, characteristics])].
[sujeto(['Laminin', was]), verbo([expressed]), complemento([in, 146, '(', 57.3, '%', ')', cases, and, significantly, correlated, with, younger, age, at, diagnosis, '(', 'p=0'])].
[sujeto([3, ')', ',', but, not]), verbo([associated]), complemento([in, 'Cox', multivariate, analysis])].
[sujeto(['This', study, demonstrates, that, laminin, expression, may]), verbo([have]), complemento([important, roles, in, the, aggressive, nature, observed, in, the, 'basal-like', and, triple, negative, molecular, subtype, of, 'Nigerian', 'BC', women])].
[sujeto(['Proper', cell, models, for, breast, cancer, primary, tumors]), verbo([have]), complemento([long, been, the, focal, point, in, the, 'cancer\'s', research])].
[sujeto(['These', important, drug]), verbo([targets]), complemento([in, breast, 'cancer,', 'ESR1,', 'PGR,', 'HER2,', 'EGFR', and, 'AR', have, a, high, similarity, in, mRNA, and, protein, variation, in, both, tumors, and, cell, lines])].
[sujeto(['GATA3', and, 'RP56KB1', are, two, promising, drug]), verbo([targets]), complemento([for, breast, cancer])].
[sujeto(['A', total, score, developed, from, the, four, correlations, among, four, molecular, profiles]), verbo([suggests]), complemento([that, cell, 'lines,', 'BT483,', 'T47D', and, 'MDAMB453', have, the, highest, similarity, with, tumors])].
[sujeto(['Increasingly,', evidence]), verbo([suggests]), complemento([a, role, for, polyphenols, in, blood, glucose, control])].
[sujeto(['Although', glycaemic, and, insulin, responses, differed, depending, on, the, 'polyphenol-carbohydrate', 'combination,', 'overall,', polyphenol, sources, were, shown, to, reduce, the, peak, and, 'early-phase', glycaemic, response, and]), verbo([maintain]), complemento([the, glycaemic, response, in, the, later, stages, of, digestion])].
[sujeto(['This', review, supports, epidemiological, data]), verbo([suggesting]), complemento([that, polyphenols, in, foods, and, beverages, may, have, a, beneficial, effect, on, reducing, the, risk, of, type, 2, diabetes])].
[sujeto(['Hormone', 'receptor-positive', '(', 'HR+)', breast, cancers]), verbo([express]), complemento([the, estrogen, '(', 'ERα)', 'and/or', progesterone, '(', 'PgR)', receptors])].
[sujeto(['Inherited', single, nucleotide, polymorphisms, '(', 'SNPs)', in, 'ESR1,', the, gene, encoding, 'ERα,']), verbo([have]), complemento([been, reported, to, predict, tamoxifen, effectiveness])].
[sujeto(['One', 'SNP', in, 'ESR1', '(', 'rs9322336)', was, significantly]), verbo([associated]), complemento([with, 'ESR1', gene, transcript, expression, '(', 'P', =, 0.006, ')', but, not, 'ERα', protein, expression, '(', 'P', &, 'gt;', 0.05, ')'])].
[sujeto(['A', 'PGR', 'SNP', '(', 'rs518162)', was]), verbo([associated]), complemento([with, decreased, 'PGR', gene, transcript, expression, '(', 'P', =, 0.003, ')', and, 'PgR', protein, expression, measured, by, 'IHC', '(', 'P', =, 0.016, ')', ',', but, not, 'AQUA', '(', 'P', =, 0.054, ')'])].
[sujeto(['Both', the, structure, and, the, protein, composition, of, thylakoid, membranes]), verbo([have]), complemento([an, impact, on, light, harvesting, and, electron, transfer, in, the, photosynthetic, chain])].
[sujeto(['Light-harvesting', complexes, 'II', can, be]), verbo([associated]), complemento([to, either, 'PSII', or, 'PSI', depending, on, the, redox, state, of, the, plastoquinone, 'pool,', and, their, distribution, is, governed, by, state, transitions])].
[sujeto(['This', potentially]), verbo([provides]), complemento([objective, parameters, for, pathological, evaluation])].
[sujeto(['Large', 'C-positive', heterochromatins, were]), verbo([found]), complemento([in, the, centromeric, region, of, chromosome, 9, in, 'HN31', and, 'HN4,', which, suggests, complex, structural, amplification, of, the, repetitive, sequence])].
[sujeto([33, in, all, cell, lines]), verbo([involved]), complemento([with, tumorigenesis, and, inflammation, genes])].
[sujeto(['Interestingly,', partial]), verbo([loss]), complemento([of, 'PTPRD', '(', 9, 'p23)', and, 'WWOX', '(', 16, q23])].
[sujeto(['This']), verbo([suggests]), complemento([that, the, scarcity, of, 'PTPRD', and, 'WWOX', genes, might, have, played, an, important, role, in, progression, of, 'HNSCC,', and, could, be, considered, as, a, target, for, cancer, therapy, or, a, biomarker, in, molecular, pathology])].
[sujeto(['We,', 'therefore,', hypothesized, that, endometrial, breakdown, might]), verbo([involve]), complemento([functional, progesterone, withdrawal])].
[sujeto(['Using', 'co-immunoprecipitation', 'assays,', we, observed, the, constitutive, activation, of]), verbo([nuclear]), complemento([factor, 'kappa-b', '(', 'NF-κB)', p65, and, its, interaction, with, the, progesterone, receptor, '(', 'PGR);', 'moreover,', transcriptional, activity, of, the, 'PGR', was, also, repressed, by, 'NF-κB', activity, in, primary, mouse, and, human, decidual, stromal, cells, that, mimic, progesterone, maintenance])].
[sujeto(['Yet', the, ratio, of, 'PGR-B', to, 'PGR-A', was, not]), verbo([increased]), complemento([in, the, mouse, model])].
[sujeto(['In', vivo, comparison, of, endometrial, breakdown]), verbo([induced]), complemento([by, progesterone, withdrawal, to, that, seen, during, sustained, progesterone, 'exposure,', in, the, presence, of, 'NF-κB', 'inhibitors,', revealed, that, 'NF-κB-mediated', functional, progesterone, withdrawal, is, involved, in, endometrial, breakdown, in, this, implant, model])].
[sujeto(['The', 'Nottingham', 'Prognostic', 'Index', 'Plus', '(', 'NPI+)', is, a, clinical, decision, making, tool, in, breast, cancer, '(', 'BC)', that, aims, to]), verbo([provide]), complemento([improved, patient, outcome, stratification, superior, to, the, traditional, 'NPI'])].
[sujeto(['Subsequently,', 'NPI+', 'Prognostic', 'Groups', '(', 'PGs)', were, assigned, for, each, class, using, bespoke, 'NPI-like', 'formulae,', previously, developed, in, each, 'NPI+', biological, class, of, the, 'Nottingham', 'series,', utilising, clinicopathological, 'parameters:', number, of, positive, 'nodes,', pathological, tumour, 'size,', 'stage,', tubule, 'formation,']), verbo([nuclear]), complemento([pleomorphism, and, mitotic, counts])].
[sujeto(['The', biological, classes, were, significantly]), verbo([associated]), complemento([with, patient, outcome, '(', p, &, 'lt;', 0.001, ')'])].
[sujeto(['This', study, now, evaluates, whether, expression, of, mRNAs, and, miRs, are, linked, to, 'PIK3CA', genotype, and, are, independently, related, to, 'AI', therapy, response, in, order, to, define, potential]), verbo([expressed]), complemento([biomarkers, for, treatment, outcome])].
[sujeto(['BRB', 'Array', tools, class, comparison, was, performed, to, define, miRs, and, mRNAs, whose, expression]), verbo([associate]), complemento([with, 'PIK3CA', exon, 9, and, 20, status])].
[sujeto(['All', except, 'miR-301a-3p', had, an]), verbo([increased]), complemento([expression, in, tumors, with, 'PIK3CA', mutations])].
[sujeto(['Validation', in, a, publicly, available, dataset, showed, that, 'LRG1,', 'PGR,', and, 'SERPINA3', levels, were]), verbo([decreased]), complemento([after, 'neo-adjuvant', 'AI-treatment'])].
[sujeto(['Further', analyses, showed, 'LRG1', and, 'PLCL1', expression, to, be, unrelated, with, luminal, subtype, and, to]), verbo([associate]), complemento([with, 'OS', and, with, 'PFS,', the, latter, independent, from, traditional, predictive, factors])].
[sujeto(['We', showed, in, two, datasets, of, 'ER', positive, and, luminal, breast, tumors, that, the, expression, of, 3, miRs, and, 9, mRNAs]), verbo([associate]), complemento([with, the, 'PIK3CA', status])].
[sujeto(['Expression', of, 'LRG1', is, independent, of, luminal, '(', 'A', or, 'B)', 'subtype,']), verbo([decreased]), complemento([after, 'neo-adjuvant', 'AI-treatment,', and, is, proposed, as, potential, biomarker, for, 'AI', therapy, outcome])].
[sujeto(['The', results, were, then, validated, in, a, rat, model, of, 'BPH']), verbo([induced]), complemento([by, testosterone, propionate, and, estradiol, benzoate])].
[sujeto(['In', both, human, and, rat, prostate, 'tissues,', 'AR', was, localized, mainly, to, epithelial, and, stromal, cell, 'nuclei;', 'ERα', was, distributed, mainly, to, stromal, 'cells,', but, not, 'exclusively;', 'ERβ', was, interspersed, in, the, basal, layer, of, 'epithelium,', but, sporadically, in, epithelial, and, stromal, 'cells;', 'PGR', was]), verbo([expressed]), complemento([abundantly, in, cytoplasm, of, epithelial, and, stromal, cells])].
[sujeto(['There', were]), verbo([decreased]), complemento([expression, of, 'ERα', and, increased, expression, of, 'PGR,', but, no, difference, in, the, expression, of, 'ERβ', in, the, 'BPH', compared, to, the, normal, prostate, of, both, human, and, rat])].
[sujeto(['This', study, identified, the, activation, of, 'AR', and, 'PGR', and, repression, of, 'ERα', in, 'BPH,', which, indicate, a]), verbo([promoting]), complemento([role, of, 'AR', and, 'PGR', and, an, inhibitory, role, of, 'ERα', in, the, pathogenesis, of, 'BPH'])].
[sujeto(['The', adoption, of, mobile, phones]), verbo([has]), complemento([created, an, opportunity, for, assessing, and, improving, nutrient, intake, as, they, can, be, used, for, digitalizing, dietary, assessments, and, providing, feedback])].
[sujeto(['In', the, last, few, 'years,', hundreds, of, 'nutrition-related', mobile, apps]), verbo([have]), complemento([been, launched, and, installed, by, millions, of, users])].
[sujeto(['None', of, the, apps, had, a, decision, engine, capable, of]), verbo([providing]), complemento([personalized, diet, advice])].
[sujeto(['Although', 'Hmgn5', is]), verbo([involved]), complemento([in, the, regulation, of, cellular, proliferation, and, 'differentiation,', its, physiological, function, during, decidualization, is, still, unknown])].
[sujeto(['Here', we, showed, that, 'Hmgn5', was, highly]), verbo([expressed]), complemento([in, the, decidual, cells])].
[sujeto(['Simultaneously,', 'Hmgn5', might]), verbo([induce]), complemento([the, expression, of, 'Prl8a2', and, 'Prl3c1', which, were, 2, 'well-known', differentiation, markers, for, decidualization])].
[sujeto(['Further', studies]), verbo([found]), complemento([that, regulation, of, cAMP, and, progesterone, on, 'Hmgn5', expression, was, mediated, by, 'Hoxa10'])].
[sujeto(['In', the, stromal, cells, undergoing, 'decidualization,', 'Hmgn5', might]), verbo([act]), complemento([downstream, of, 'Hoxa10', to, regulate, the, expression, of, 'Cox-2,', 'Vegf', and, 'Mmp2'])].
[sujeto(['It', is, widely, acknowledged, that, the, 'GS', system, is, 'leaky,', with, low, level, expression, of, 'UAS', transgenes, in, absence, of, the, inducer, 'RU-486', '(', the, progesterone, analog, that]), verbo([activates]), complemento([the, modified, 'GAL4', 'protein)'])].
[sujeto(['However,', in, the, course, of, our, 'experiments,', we]), verbo([have]), complemento([observed, that, the, extent, of, this, leak, depends, on, the, nature, of, the, transgene, being, expressed])].
[sujeto(['In', the, absence, of, 'RU-486,', when, strong, drivers, are, used, to]), verbo([express]), complemento([protein, coding, 'transgenes,', leaky, expression, is, low, or, 'negligible,', however, expression, of, 'RNA', interference, '(', 'RNAi)', transgenes, results, in, complete, depletion, of, protein, levels])].
[sujeto(['The', majority, of, published, 'studies,', using, the, 'GS', system, and, 'RNAi', transgenes, validate, 'knock-down', efficiency, by, comparing]), verbo([target]), complemento([gene, mRNA, levels, between, induced, and, 'non-induced', groups])].
[sujeto(['Here,', we, demonstrate, that, this, approach, is, lacking, and, that, both, additional, control, groups, and, further, validation, is]), verbo([required]), complemento([at, the, protein, level])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'EIDD-1723', represents, a, substantial, advantage, over, current, 'PROG', formulations, because, it, overcomes, 'storage,', formulation, and, delivery, limitations, of, 'PROG', and, can, thereby, reduce, the, time, between, injury, and, treatment])].
[sujeto(['However,', the, underlying, mechanisms]), verbo([have]), complemento([not, been, fully, elucidated])].
[sujeto(['Expression', of, 'CD36,', a, receptor, for, oxidized, 'LDL', '(', 'oxLDL)', that]), verbo([enhances]), complemento(['macrophage/foam', cell, 'formation,', is, activated, by, the, transcription, factor, peroxisome, 'proliferator-activated', receptor, γ, '(', 'PPARγ)'])].
[sujeto(['In', this, 'study,', we, determined, that, progesterone]), verbo([induced]), complemento([macrophage, 'CD36', 'expression,', which, is, related, to, progesterone, receptor, '(', 'PR)', activity])].
[sujeto(['Progesterone']), verbo([enhanced]), complemento([cellular, oxLDL, uptake, in, a, 'CD36-dependent', manner])].
[sujeto(['Mechanistically,', progesterone]), verbo([increased]), complemento(['PPARγ', expression, and, 'PPARγ', promoter, activity, in, a, 'PR-dependent', manner, and, the, binding, of, 'PR', with, the, progesterone, response, element, in, the, 'PPARγ', promoter])].
[sujeto(['We', also, determined, 'that,']), verbo([associated]), complemento([with, gestation, and, increased, serum, progesterone, 'levels,', 'CD36', and, 'PPARγ', expression, in, mouse, adipose, 'tissue,', skeletal, 'muscle,', and, peritoneal, macrophages, were, substantially, activated])].
[sujeto(['Taken', 'together,', our, study, demonstrates, that, progesterone, can, play, dual, pathophysiological, roles, by]), verbo([activating]), complemento(['PPARγ', 'expression,', in, which, progesterone, increases, macrophage, 'CD36', expression, and, oxLDL, 'accumulation,', a, negative, effect, on, 'atherosclerosis,', and, enhances, the, 'PPARγ-CD36', pathway, in, adipose, tissue, and, skeletal, 'muscle,', a, protective, effect, on, pregnancy])].
[sujeto(['We']), verbo([report]), complemento([the, case, of, a, 44, -, 'year-old', obese, woman, '(', 'BMI', 45.5, ')', who, underwent, surgery, to, remove, uterine, leiomyomata, and, then, continued, to, take, a, drug, containing, the, hormone, estradiol, for, a, period, of, 15, years])].
[sujeto(['Thus', alternative, approaches, of, drug, development, for, 'TNBC']), verbo([have]), complemento([gained, utmost, importance, in, the, present, times])].
[sujeto(['Dietary', indole, and, its, derivatives]), verbo([have]), complemento([gained, prominence, as, 'anti-cancer', agents, and, new, therapeutic, approaches, are, being, developed, to, target, them, against, 'TNBC'])].
[sujeto(['In', the, current, study, we]), verbo([report]), complemento([the, synthesis, of, a, novel, synthetic, aryl, methyl, ring, substituted, analog, of, 'DIM,', named, as, 'Phemindole', as, an, effective, 'anti-tumor', agent, against, 'TNBC', cells])].
[sujeto(['Furthermore,', we, enumerated, that, 'Phemindole']), verbo([caused]), complemento([reactive, oxygen, species, mediated, 'mitochondrial-dependent', apoptosis, in, 'MDAMB-231', cells])].
[sujeto(['Furthermore,', 'Phemindole']), verbo([mediated]), complemento(['Store', 'Operated', 'Calcium', 'Entry', '(', 'SOCE)', retardation, favored, inactivation, of, 'STIM1', and, henceforth, activated, 'ER', stress, to, induce, apoptosis, in, 'TNBC', cells])].
[sujeto(['Simultaneously,', 'Phemindole', was, also]), verbo([found]), complemento([to, restrict, the, in, vitro, cell, migration, through, its, anti, mitotic, property, and, pFAK, regulation])].
[sujeto(['Thus', our, results, cumulatively, propose, 'Phemindole', as, a, new, chemotherapeutic, regime, which, might, be, effective, to]), verbo([target]), complemento([the, deadly, aspects, of, the, 'TNBC'])].
[sujeto(['The', objectives, were, to, '(', 1, ')', evaluate, the, effectiveness, of, induction, of, luteolysis, in, superovulated, '(', 'SOV)', cows, at, two, distinct, time, points, after, embryo, 'flushing;', and, '(', 2, ')', compare, the, pattern, of, 'LH']), verbo([release]), complemento([after, treatment, with, 'PGF', in, cows, with, single, vs])].
[sujeto(['In', 'Day', 11, 'cows,', 'P4', continued, to]), verbo([decrease]), complemento(['thereafter,', whereas, 'Day', 7, animals, had, no, further, reduction, in, plasma, 'P4'])].
[sujeto(['In', cows, without, 'luteolysis,', plasma, 'P4']), verbo([increased]), complemento([after, the, initial, 'PGF-induced', decline])].
[sujeto(['The', slower]), verbo([decrease]), complemento([in, plasma, 'P4', in, the, 'SOV', group, prevented, an, increase, in, 'LH', for, up, to, 96, &, 'nbsp;hours', after, luteolysis, 'induction,', whereas, 'LH', values, increased, '(', 'P&nbsp;&lt;&nbsp;0'])].
[sujeto(['In', 'conclusion,', '(', 1, ')', luteolysis, may, fail, or, be, incomplete, when, 'PGF', treatment, is, given, on, the, day, of, uterine, flushing, '(', 'Day', 7, ')', in, 'SOV', 'cows;', '(', 2, ')', induction, of, luteolysis, 4, &, 'nbsp;days', later, '(', 'Day', 11, ')', is, 'effective,', but, the, initial, 'high-plasma', 'P4', concentrations, result, in, a, slower, slope, of, 'P4', decline, to, basal, 'levels,', and, 'consequently,', delayed]), verbo([increase]), complemento([in, 'LH', pulses])].
[sujeto(['Premenopausal', patients, with, breast, cancer, and, more, than, 10, positive, axillary, nodes, '(', 'BC&gt;10)']), verbo([have]), complemento([a, poor, 'prognosis:', 'In', these, patients, the, best, adjuvant, therapy, '(', 'CT)', has, not, yet, been, established])].
[sujeto(['Forty-two', 'BC&gt;10', 'received,', in, 'sequence,', the, following, adjuvant, 'treatments:', luteinizing, hormone]), verbo([releasing]), complemento([hormone, '(', 'LH-RH)', analog, for, 5, 'years;', 'anthracycline-based', induction, 'chemotherapy;', radiation, 'therapy;', 'platinum-based', 'high-dose', 'CT,', with, autologous, bone, marrow, 'transplantation;', immunotherapy, with, interleukin, 2, '(', 'IL2)', and, 13, -, cis, retinoic, acid, '(', 'RA);', anastrazole, given, 5, years, to, estrogen, 'receptor-positive', patients])].
[sujeto(['Treatment', with, 'LH-RH', 'analog,', 'high-dose', 'CT,', peripheral, blood, progenitor, cells, and, 'IL2', with, 'RA', for, patients, with, 'BC&gt;10', is, 'feasible,']), verbo([has]), complemento([moderate, 'toxicity,', while, preserving, ovarian, 'function,', seems, to, improve, the, expected, 'DFS', and, 'OS', for, these, 'high-risk', patients])].
[sujeto(['Although', 'Hmgn1', is]), verbo([involved]), complemento([in, the, regulation, of, gene, expression, and, cellular, 'differentiation,', its, physiological, roles, on, the, differentiation, of, uterine, stromal, cells, during, decidualization, still, remain, unknown])].
[sujeto(['Here', we, showed, that, 'Hmgn1', mRNA, was, highly]), verbo([expressed]), complemento([in, the, decidua, on, days, 6, -, 8, of, pregnancy])].
[sujeto(['Simultaneously,']), verbo([increased]), complemento([expression, of, 'Hmgn1', was, also, observed, in, the, artificial, and, in, vitro, induced, decidualization, models])].
[sujeto(['Hmgn1']), verbo([induced]), complemento([the, proliferation, of, uterine, stromal, cells, and, expression, of, 'Ccna1,', 'Ccnb1,', 'Ccnb2', and, 'Cdk1', in, the, absence, of, estrogen, and, progesterone])].
[sujeto(['Overexpression', of, 'Hmgn1', could]), verbo([enhance]), complemento([the, expression, of, 'Prl8a2', and, 'Prl3c1', which, were, 2, 'well-known', differentiation, markers, for, 'decidualization,', whereas, inhibition, of, 'Hmgn1', with, specific, siRNA, could, reduce, their, expression])].
[sujeto(['Further', studies]), verbo([found]), complemento([that, 'Hmgn1', could, mediate, the, effects, of, 'C/EBPβ', on, the, expression, of, 'Prl8a2', and, 'Prl3c1', during, in, vitro, decidualization])].
[sujeto(['In', the, uterine, stromal, 'cells,', cAMP, analog, 8, -, 'Br-cAMP', could]), verbo([stimulate]), complemento([the, expression, of, 'Hmgn1', via, 'C/EBPβ'])].
[sujeto(['During', in, vitro, 'decidualization,', 'Hmgn1', might]), verbo([act]), complemento([downstream, of, 'C/EBPβ', to, regulate, the, expression, of, 'Cox-2,', 'mPGES-1', and, 'Vegf'])].
[sujeto(['Ovarian', function, was, checked, by, administration, of, a, 'short-acting', 'GnRH', agonist, to]), verbo([induce]), complemento([ovulation, and, pseudopregnancy, '(', 0.8, &, 'nbsp;μg', of, buserelin, per, animal, 'intramuscularly)'])].
[sujeto(['After', implant, 'insertion,', the, first, blood, collection, '(', 'Day', 10, ')', was, done, without, preceding, induction, of, ovulation, to, screen, for, implant]), verbo([induced]), complemento([ovulation, and, pseudopregnancy])].
[sujeto(['The', insertion, of, the, implant]), verbo([led]), complemento([to, the, establishment, of, a, pseudopregnancy, in, 2, of, 7, 'animals;', the, remaining, 5, animals, did, not, show, elevated, progesterone, values])].
[sujeto(['Attempts', to]), verbo([induce]), complemento([ovulation, by, administration, of, the, 'short-acting', 'GnRH', analog, while, the, 'slow-release', 'GnRH', analog, implant, was, in, place, were, not, successful, in, treated, 'animals,', and, progesterone, concentrations, were, basal])].
[sujeto(['The', effect, was, reversible, as, ovulation, could, be]), verbo([induced]), complemento([in, 2, subsequent, cycles, in, all, animals, by, the, third, induction, of, ovulation, after, implant, removal])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, in, 5, of, 7, 'rabbits,', puberty, was, delayed, by, the, treatment, with, the, 4.7, -, mg, deslorelin, 'slow-release', analog, until, the, implant, had, been, removed])].
[sujeto(['In', the, other, 'animals,', the, treatment]), verbo([induced]), complemento([an, initial, 'flare-up', phenomenon])].
[sujeto(['Afterward,', the, treatment, could, reversibly]), verbo([suppress]), complemento([ovarian, function, in, all, 7, treated, animals])].
[sujeto(['Ovarian', ultrasonography, was, conducted, on, the, day, of]), verbo([induced]), complemento([estrus, and, on, days, 0, ',', 5, ',', 12, ',', 16, and, 21, 'post-ovulation', to, assess, preovulatory, follicle, or, corpus, luteum, '(', 'CL)', diameter])].
[sujeto(['In', 'conclusion,', buserelin, acetate, and, hCG, administration, on, day, 5, 'post-ovulation']), verbo([leads]), complemento([to, accessory, 'CL', formation, that, may, have, a, role, in, enhancing, conception, rate])].
[sujeto(['Classical', signaling, cascades]), verbo([triggered]), complemento([by, 'follicle-stimulating', hormone, induce, estrogen, synthesis, via, the, upregulation, of, 'Cyp19a1', in, granulosa, cells, '(', 'GCs)'])].
[sujeto(['Quantitative', real, time, 'PCR', and, western, blot, were, performed, to, identify, the, effect, of, 'miR-132', on, 'Cyp19a1,', 'Cyp11a1', and, an, orphan]), verbo([nuclear]), complemento(['receptor-Nurr1', expression, in, 'GCs'])].
[sujeto(['The', synthesis, of, estradiol]), verbo([increased]), complemento([after, the, overexpression, of, 'miR-132', in, mouse, 'GCs'])].
[sujeto(['The', 'real-time', 'PCR', results, demonstrated, that, 'miR-132']), verbo([induced]), complemento([the, expression, of, 'Cyp19a1', significantly])].
[sujeto(['Nurr1,', an, orphan]), verbo([nuclear]), complemento([receptor, that, suppresses, 'Cyp19a1', 'expression,', was, found, to, be, a, direct, target, of, 'miR-132'])].
[sujeto(['Nurr1', was]), verbo([suppressed]), complemento([by, 'miR-132,', as, indicated, by, a, luciferase, assay, and, 'Western', blotting])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, 'miR-132', is, involved, in, the, cAMP, signaling, pathway, and, promotes, estradiol, synthesis, via, the, translational, repression, of, 'Nurr1', in, ovarian, 'GCs'])].
[sujeto(['Endometrial', carcinoma, is, the, most, common, gynecologic, malignancy, which, is]), verbo([associated]), complemento([with, a, poor, prognosis, when, diagnosed, at, an, advanced, 'stage;', 'therefore,', the, discovery, of, efficacious, new, drugs, is, required, to, reinforce, conventional, chemotherapy])].
[sujeto(['Low', dose, oral, contraceptive, pills, '(', 'OCPs)', that, contain, synthetic, estrogen, and, progestin, are, often, used, to, relieve, chronic, pelvic, pain]), verbo([associated]), complemento([with, endometriosis])].
[sujeto(['The', maximum, diameter, and, volume, of, the, ovarian, endometrioma, significantly]), verbo([decreased]), complemento([after, 3, and, 6, cycles, compared, with, pretreatment])].
[sujeto(['The', levels, of, serum, 'CA125', and, 'AMH', concentration, were]), verbo([decreased]), complemento([after, 6, cycles])].
[sujeto(['While', sacrococcygeal, extraneural, ependymomas, are, equally, distributed, among, males, and, 'females,', pelvic, and, extra, pelvic, ependymomas]), verbo([have]), complemento([been, exclusively, reported, in, 'women,', mainly, of, child, bearing, age])].
[sujeto(['Although', the, underlying, mechanism, is, not, entirely, 'clear,', 'stress-induced', alteration, in, adrenal, hormone, secretion, can]), verbo([cause]), complemento([these, ovarian, pathologies])].
[sujeto(['Treatment', cows, '(', n, =, 3, ')', were, administered, with, 'ACTH', analog, every, 12, &, 'nbsp;h', from, day, 15, to, day, 21, of, the, cycle, to]), verbo([induce]), complemento([formation, of, follicular, cysts])].
[sujeto(['Control', cows, '(', n, =, 3, ')', were, administered, 'placebo,', 'resynchronized,', and, administered, 'PGF2α', on, day, 6, of, the, new, cycle, to]), verbo([induce]), complemento([development, of, a, preovulatory, follicle])].
[sujeto(['Administration', of, 'ACTH']), verbo([increased]), complemento(['(', 'P', &, 'lt;', 0.02, ')', plasma, cortisol, concentration, and, reduced, '(', 'P', &, 'lt;', 0.01, ')', milk, production])].
[sujeto(['This', experiment, investigated, whether, 'allopregnanolone,', a, neurosteroid, metabolite, from, 'progesterone,']), verbo([modulates]), complemento([the, stress, response, during, early, pregnancy])].
[sujeto(['On', days, 5, ',', 12, and, 19, of, 'pregnancy,', all, sows, were, subjected, to, social, stress, by, submitting, them, individually, to, a, 'resident-intruder', 'test,']), verbo([acting]), complemento([as, the, intruder])].
[sujeto(['Allopregnanolone', was]), verbo([associated]), complemento([with, lower, aggression, in, social, encounters])].
[sujeto(['Estrogen', 'receptor-α', '(', 'ERα)-negative', breast, cancer, is, clinically, aggressive, and, does, not]), verbo([respond]), complemento([to, conventional, hormonal, therapies])].
[sujeto(['Strategies', that]), verbo([lead]), complemento([to, 're-expression', of, 'ERα', could, sensitize, 'ERα-negative', breast, cancers, to, selective, 'ER', modulators])].
[sujeto(['FTY720', '(', 'fingolimod,', 'Gilenya),', a, sphingosine, 'analog,', is, the, 'Food', and, 'Drug', 'Administration', '(', 'FDA)-approved', prodrug, for, treatment, of, multiple, sclerosis, that, also]), verbo([has]), complemento([anticancer, actions, that, are, not, yet, well, understood])].
[sujeto(['We']), verbo([found]), complemento([that, 'FTY720', is, phosphorylated, in, breast, cancer, cells, by, nuclear, sphingosine, kinase, 2, and, accumulates, there])].
[sujeto(['Nuclear', 'FTY720-P', is, a, potent, inhibitor, of, class, 'I', histone, deacetylases, '(', 'HDACs)', that]), verbo([enhances]), complemento([histone, acetylations, and, regulates, expression, of, a, restricted, set, of, genes, independently, of, its, known, effects, on, canonical, signaling, through, 'sphingosine-1-phosphate', receptors])].
[sujeto(['High-fat', diet, '(', 'HFD)', and, 'obesity,', which, is, now, 'endemic,']), verbo([increase]), complemento([breast, cancer, risk, and, have, been, associated, with, worse, prognosis])].
[sujeto(['HFD', accelerated, the, onset, of, tumors, with, more, advanced, lesions, and]), verbo([increased]), complemento(['triple-negative', spontaneous, breast, tumors, and, 'HDAC', activity, in, 'MMTV-PyMT', transgenic, mice])].
[sujeto(['Oral', administration, of, clinically, relevant, doses, of, 'FTY720']), verbo([suppressed]), complemento(['development,', progression, and, aggressiveness, of, spontaneous, breast, tumors, in, these, 'mice,', reduced, 'HDAC', activity, and, strikingly, reversed, 'HFD-induced', loss, of, estrogen, and, progesterone, receptors, in, advanced, carcinoma])].
[sujeto(['In', 'ERα-negative', human, and, murine, breast, cancer, 'cells,', 'FTY720']), verbo([reactivated]), complemento([expression, of, silenced, 'ERα', and, sensitized, them, to, tamoxifen])].
[sujeto(['Moreover,', treatment, with, 'FTY720', also, 're-expressed', 'ERα', and]), verbo([increased]), complemento([therapeutic, sensitivity, of, 'ERα-negative', syngeneic, breast, tumors, to, tamoxifen, in, vivo, more, potently, than, a, known, 'HDAC', inhibitor])].
[sujeto(['Our', work]), verbo([suggests]), complemento([that, a, multipronged, attack, with, 'FTY720', is, a, novel, combination, approach, for, effective, treatment, of, both, conventional, hormonal, 'therapy-resistant', breast, cancer, and, 'triple-negative', breast, cancer])].
[sujeto(['In', the, 'LC,', small]), verbo([increases]), complemento([in, the, basal, concentrations, of, 'LH', were, observed, after, 'TAK-683', administration, from, 0, to, 6, 'h,', which, were, associated, with, an, increase, in, estradiol, 'concentration,', followed, by, a, 'surge-like', release, of, 'LH', with, a, peak, at, 12.5, '±1'])].
[sujeto(['In', the, 'FC,', a, 'surge-like']), verbo([release]), complemento([of, 'LH', occurred, immediately, after, 'TAK-683', administration, with, a, peak, at, 6.0, '±3'])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, timing, of, 'surge-like', release, of, 'LH', after, 'TAK-683', administration, is, associated, with, blood, estradiol, concentration, at, the, time, of, treatment])].
[sujeto(['Multiple', regression, analysis, indicated, that, age, '(', β, =, 0.363, ')', and, the, number, of, myomas, '(', β, =, 0.296, ')', were, independently]), verbo([associated]), complemento([with, 'PR-B', mRNA, levels, in, leiomyoma, tissue])].
[sujeto(['The', levels, of, 'PR-B', mRNA, in, leiomyoma, tissue, are, directly]), verbo([associated]), complemento([with, the, number, of, tumors, and, inversely, correlated, with, the, intensity, of, intermenstrual, bleeding, and, 'dysmenorrhea,', suggesting, that, 'PR', signaling, may, favor, leiomyoma, growth, while, attenuating, clinical, symptoms])].
[sujeto(['Previously,', using, chromatin, 'immunoprecipitation-based', 'cloning,', we, uncovered, 'L-type', amino, acid, transporter, 2, '(', 'LAT2)', as, a, novel, 'PR']), verbo([target]), complemento([gene])].
[sujeto(['In', primary, 'LSM', 'cells,', progesterone, significantly]), verbo([induced]), complemento(['LAT2', mRNA, 'levels,', and, this, was, blocked, by, cotreatment, with, mifepristone])].
[sujeto(['Progesterone', did, not, alter, 4, 'F2hc', mRNA, 'levels,', whereas, mifepristone, significantly]), verbo([induced]), complemento([4, 'F2hc', mRNA, expression])].
[sujeto(['Small', interfering, 'RNA', knockdown, of, 'LAT2', or, 4, 'F2hc', markedly]), verbo([increased]), complemento(['LSM', cell, proliferation])].
[sujeto(['We', present, evidence, that, progesterone, and, its, antagonist, mifepristone]), verbo([regulate]), complemento([the, amino, acid, transporter, system, 'LAT2/4F2hc', in, leiomyoma, tissues, and, cells])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, products, of, the, 'LAT2/4F2hc', genes, may, play, important, roles, in, leiomyoma, cell, proliferation])].
[sujeto(['We', speculate, that, critical, ratios, of, 'LAT2', to, 4, 'F2hc']), verbo([regulate]), complemento([leiomyoma, growth])].
[sujeto(['Triple', negative, breast, cancer, '(', 'TNBC)', is, a, 'heterogeneous,', aggressive, cancer, for, which, there, is, no, effective, chemotherapy, or]), verbo([targeted]), complemento([therapy])].
[sujeto(['HER2', and, 'TN', subtypes]), verbo([expressed]), complemento(['LAT1', and, 'CD98', at, higher, levels, than, luminal, 'A', and, 'B', subtypes, '(', both, 'P', &, 'lt;', 0.001, ')'])].
[sujeto(['LAT1', and, 'CD98', expression, correlated, with, tumor, size, '(', 'LAT1,', 'P', =, 0.01, ;, 'CD98,', 'P', =, 0.007, ')', ',']), verbo([nuclear]), complemento([grade, '(', 'LAT1,', 'P', &, 'lt;', 0.001, ;, 'CD98,', 'P', &, 'lt;', 0.001, ')', and, 'Ki67', labeling, index, '(', 'LAT1,', 'P', &, 'lt;', 0.001, ;, 'CD98,', 'P', =, 0.001, ')'])].
[sujeto(['LAT1', and, 'CD98', expression, was, negatively]), verbo([associated]), complemento([with, 'ER', and, 'PgR', '(', both, 'P', &, 'lt;', 0.001, ')'])].
[sujeto(['Inhibition', of, these, proteins, might]), verbo([provide]), complemento([a, new, therapeutic, strategy, in, 'TNBC'])].
[sujeto(['Accumulation', of, 'amyloid-beta', '(', 'Aβ)', is, one, of, the, hallmarks, of, 'Alzheimer\'s', disease, '(', 'AD),', and, efficient, clearance, of, 'Aβ', by, cells, of, the, innate, immune, system, may, be, an, important, mechanism, for, controlling, or]), verbo([preventing]), complemento([disease, onset])].
[sujeto(['It', was]), verbo([reported]), complemento([that, peripheral, blood, mononuclear, cells, '(', 'PBMCs)', of, most, 'AD', patients, are, defective, in, the, phagocytosis, of, soluble, 'Aβ'])].
[sujeto(['Bisdemethoxycurcumin', '(', 'BDC),', a, minor, component, of, natural, 'curcumin,', was, shown, to]), verbo([have]), complemento([the, greatest, potency, for, stimulating, 'AD', 'PBMCs'])].
[sujeto(['Because', natural, curcumins]), verbo([have]), complemento([inherent, limitations, with, regard, to, physicochemical, 'properties,', synthetic, curcumin, analogues, were, developed, that, showed, improved, 'solubility,', 'stability,', and, bioavailability])].
[sujeto(['From', more, than, 45, curcuminoids, 'analyzed,', the, most, potent, compounds, possessing]), verbo([enhanced]), complemento([pharmaceutical, properties, were, identified])].
[sujeto(['In', vivo, studies, showed, compound, '(', 5, ')', substantially]), verbo([increased]), complemento([bioavailability, by, combining, several, promising, structural, modifications])].
[sujeto(['In', vitro, studies, using, monocytic, cell, lines]), verbo([reported]), complemento([herein, complement, those, using, human, 'PBMCs', and, represent, a, routinely, accessible, and, uniform, cellular, resource, allowing, direct, comparisons, between, compounds])].
[sujeto([1, ',', 25, -, dihydroxyvitamin, 'D(3)']), verbo([has]), complemento([quite, significant, anticancer, 'properties,', but, its, strong, calcemic, effect, in, principle, excludes, it, as, a, potential, anticancer, drug])].
[sujeto(['Currently,', a, lot, of, effort, is, being, devoted, to, develop, potent, anticancer, analogs, of, 1, ',', 25, -, dihydroxyvitamin, 'D(3)', that, would, not]), verbo([induce]), complemento([hypercalcemia, during, therapy])].
[sujeto(['In', this, 'work,', the, free]), verbo([binding]), complemento([energy, of, the, 'VDR', receptor, with, 1, ',', 25, -, dihydroxyvitamin, 'D(3)', and, its, three, potent, analogs, '(', 'EB', 1089, ',', 'KH', 1060, and, 'RO', 25, -, 9022, ')', is, calculated, and, compared, with, each, other])].
[sujeto(['With', this, 'approach,', we, could, estimate, the, relative]), verbo([binding]), complemento([affinity, of, the, most, potent, 'analog,', 'RO', 25, -, 9022, ',', and, also, revealed, a, quite, distinct, mechanism, of, its, interaction, with, 'VDR'])].
[sujeto(['Population', studies]), verbo([suggest]), complemento([putative, links, between, vitamin, 'D', '(', 'VD)-deficiency', and, risk, of, cancer, and, diabetes])].
[sujeto(['The', 'insulin/IGF-I', receptor, represents, a, signaling]), verbo([target]), complemento([of, the, carcinoembryonic, 'antigen-related', cell, adhesion, molecule, 1, '(', 'CEACAM1)', that, is, implicated, in, both, diabetes, and, 'cancer,', therefore, we, hypothesized, that, 'VD', actions, may, be, mediated, through, this, adhesion, molecule])].
[sujeto(['In', this, 'study,', we, show, that, 1, ',', 25, vitamin, 'D3', and, its, analogues, 'EB1089', and, 'KH1060', potently]), verbo([inhibit]), complemento(['CEACAM1', expression, in, cancer, cells])].
[sujeto(['This', effect, was]), verbo([associated]), complemento([with, significant, reductions, in, mRNA, and, protein, 'levels,', resulting, from, transcriptional, and, posttranslational, actions, respectively])].
[sujeto(['Insulin/IGF-I-mediated', 'IRS-1', and, 'Akt', activation, were]), verbo([enhanced]), complemento([by, 'VD', treatment])].
[sujeto(['Similarly,', 'CEACAM1', downregulation, significantly, upregulated, the, insulin, and, 'IGF-I', receptors, and, mimicked, the, effect, of, 'VD-mediated']), verbo([enhanced]), complemento(['insulin/IGF-I', receptor, signaling])].
[sujeto(['Our', findings, highlight, 'CEACAM1', as, a]), verbo([target]), complemento([of, 'VD', action])].
[sujeto(['The', resulting, inhibition, of, 'CEACAM1']), verbo([has]), complemento([potentially, beneficial, effects, on, metabolic, disorders, without, necessarily, compromising, the, anticancer, properties, of, this, vitamin])].
[sujeto(['In', addition, to, classical, roles, in, calcium, homeostasis, and, bone, 'development,', 1, ',', 25, dihydroxyvitamin, 'D3', '[', 1, ',', 25, '(', 'OH)2D3]']), verbo([inhibits]), complemento([the, growth, of, several, cancer, 'types,', including, breast, cancer])].
[sujeto(['Although', cellular, effects, of, 1, ',', 25, '(', 'OH)2D3', traditionally]), verbo([have]), complemento([been, attributed, to, activation, of, a, nuclear, vitamin, 'D', receptor, '(', 'VDR),', a, novel, receptor, for, 1, ',', 25, '(', 'OH)2D3', called, 1, ',', 25, 'D3-MARRS', '(', 'membrane-associated,', rapid, response, 'steroid-binding)', protein, was, identified, recently])].
[sujeto(['The', purpose, of, this, study, was, to, determine, if, the, level, of, 1, ',', 25, 'D3-MARRS', expression]), verbo([modulates]), complemento([1, ',', 25, '(', 'OH)2D3', activity, in, breast, cancer, cells])].
[sujeto(['To', determine, if, 1, ',', 25, 'D3-MARRS', receptor, was]), verbo([involved]), complemento([in, the, growth, inhibitory, effects, of, 1, ',', 25, '(', 'OH)2D3', in, 'MCF-7', 'cells,', a, ribozyme, construct, designed, to, knock, down, 1, ',', 25, 'D(3)-MARRS', mRNA, was, stably, transfected, into, 'MCF-7', cells])].
[sujeto(['MCF-7', clones, in, which, 1, ',', 25, 'D3-MARRS', receptor, expression, was, reduced, showed]), verbo([increased]), complemento([sensitivity, to, 1, ',', 25, '(', 'OH)2D3', '(', 'IC(50)', 56, +, /, -, 24, 'nM)', compared, to, controls, '(', 319, +, /, -, 181, 'nM;', 'P&lt;0'])].
[sujeto(['Knockdown', of, 1, ',', 25, 'D3-MARRS', receptor, also]), verbo([increased]), complemento([the, sensitivity, of, 'MCF-7', cells, to, the, vitamin, 'D', analogs, 'KH1060', and, 'MC903,', but, not, to, unrelated, agents, '(', 'all-trans', retinoic, 'acid,', 'paclitaxel,', 'serum/glucose', 'starvation,', or, the, 'isoflavone,', 'pomiferin)'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 1, ',', 25, 'D3-MARRS', receptor, expression, interferes, with, the, growth, inhibitory, activity, of, 1, ',', 25, '(', 'OH)2D3', in, breast, cancer, 'cells,', possibly, through, the, nuclear, 'VDR'])].
[sujeto(['Vitamin', 'D']), verbo([nuclear]), complemento([receptor, '(', 'VDR),', a, 'ligand-dependent', transcriptional, 'regulator,', is, an, important, target, for, multiple, clinical, 'applications,', such, as, osteoporosis, and, cancer])].
[sujeto(['Since', exacerbated]), verbo([increase]), complemento([of, calcium, serum, level, is, currently, associated, with, 'VDR', ligands, 'action,', superagonists, with, low, calcium, serum, levels, have, been, developed])].
[sujeto(['Based', on, the, crystal, structures, of, human, 'VDR', '(', 'hVDR)']), verbo([bound]), complemento([to, 1, 'alpha,25-dihydroxyvitamin', 'D(3)', and, 'superagonists-notably,', 'KH1060-we', designed, a, superagonist, ligand])].
[sujeto(['The', crystal, structures, of, the, complexes, between, the, ligand]), verbo([binding]), complemento([domain, of, hVDR, and, these, ligands, provide, a, rational, approach, to, the, design, of, more, potent, superagonist, ligands, for, potential, clinical, application])].
[sujeto(['The', aim, of, this, study, was, to, investigate, whether, 'KH', 1060, ',', a, vitamin, 'D', 'analogue,', could]), verbo([decrease]), complemento([tumor, necrosis, 'factor-alpha', '(', 'TNF-alpha)', levels, in, patients, with, inflammatory, bowel, disease, '(', 'IBD)'])].
[sujeto(['KH', 1060]), verbo([inhibited]), complemento(['PBMC', proliferation, and, decreased, 'TNF-alpha', levels, in, 'IBD', patients, and, this, effect, was, synergistic, with, 'anti-TNF-alpha'])].
[sujeto(['VDR', protein, levels, were, significantly]), verbo([increased]), complemento([by, 'PBMC', treatment, with, 'KH', 1060, or, 'anti-TNF-alpha', or, their, combination, in, ulcerative, colitis, '(', 'UC)', 'patients,', and, decreased, in, 'Crohn\'s', disease, '(', 'CD)', 'patients,', treating, the, cells, with, 'KH', 1060])].
[sujeto(['In', 'UC', patients, an]), verbo([increase]), complemento([in, 'Bcl-2', and, 'Bax', levels, was, observed, 'incubating,', 'PBMC', with, 'KH', 1060, or, 'anti-TNF-alpha', or, their, combination])].
[sujeto(['In', 'CD', patients, a, slight]), verbo([decrease]), complemento([in, 'Bcl-2', levels, was, registered, when, 'anti-TNF', alone, or, in, association, with, 'KH', 1060, was, used])].
[sujeto(['Bax', protein, levels, were, slightly]), verbo([increased]), complemento([in, the, presence, of, 'KH', 1060, alone, or, in, combination, with, 'anti-TNF'])].
[sujeto(['This', study, shows, that, 'KH', 1060]), verbo([acts]), complemento([as, an, immunomodulator, on, 'PBMC,', acting, as, 'TNF-alpha', inhibitor])].
[sujeto(['This']), verbo([finding]), complemento([provides, strong, evidence, that, vitamin, 'D', status, could, be, an, important, regulator, of, immunity, 'IBD'])].
[sujeto(['The', plethora, of, actions, of, 1, 'alpha,25(OH)(2)D(3)', in, various, systems]), verbo([suggested]), complemento([wide, clinical, applications, of, vitamin, 'D', nuclear, receptor, '(', 'VDR)', ligands, in, treatments, of, 'inflammation,', dermatological, 'indication,', 'osteoporosis,', 'cancers,', and, autoimmune, diseases])].
[sujeto(['More', than, 3000, vitamin, 'D', analogues]), verbo([have]), complemento([been, synthesized, in, order, to, reduce, the, calcemic, side, effects, while, maintaining, the, transactivation, potency, of, these, ligands])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, crystal, structures, of, 'VDR', ligand, binding, domain, bound, to, two, vitamin, 'D', agonists, of, therapeutical, 'interest,', calcipotriol, and, 'seocalcitol,', which, are, characterized, by, their, side, chain, modifications])].
[sujeto(['Epidemiologic', studies]), verbo([have]), complemento([associated, vitamin, 'D,', attained, through, nutrition, and, sun, 'exposure,', with, reduced, cancer, risk])].
[sujeto(['Although', 'dose-limiting', hypercalcemia]), verbo([has]), complemento([limited, the, use, of, natural, vitamin, 'D', in, cancer, 'prevention,', several, promising, new, synthetic, vitamin, 'D', analogs, '(', 'deltanoids)', are, under, development])].
[sujeto(['Clinical']), verbo([targets]), complemento([for, deltanoids, include, 'colon,', 'prostate,', and, breast])].
[sujeto(['Antitumor', effects, of, 1, 'alpha,25-dihydroxyvitamin', 'D3', analogs]), verbo([have]), complemento([recently, become, one, of, the, major, topics, of, the, vitamin, 'D', research, field])].
[sujeto(['We', focused, on, the, 'structure-activity', relationships, of, the, 'A-ring', moiety, of, the, vitamin, 'D', molecule, and]), verbo([found]), complemento([several, strong, agonists, of, the, vitamin, 'D', 'receptor,', using, a, design, of, introducing, a, functional, group, into, the, 'C2', position])].
[sujeto(['We', studied, conformational, analysis, of, each, isomer, based, on, 1, 'H', 'NMR', and, computer, 'calculations;', and, 'biologically,', 'VDR']), verbo([binding]), complemento(['affinity,', potency, of, induction, of, 'HL-60', cell, 'differentiation,', and, apoptosis, were, investigated, in, detail])].
[sujeto(['We']), verbo([found]), complemento([that, five, of, our, new, 2, 'alpha-modified', analogs, show, higher, 'VDR-binding', affinity, than, that, of, the, natural, hormone])].
[sujeto(['This', study, could]), verbo([stimulate]), complemento([the, development, of, antitumor, medicines, of, the, vitamin, 'D', analogs])].
[sujeto(['Abstract', vitamin, 'D', receptor, '(', 'VDR)', and, retinoid, 'X', receptor, '(', 'RXR)']), verbo([heterodimerize]), complemento([to, mediate, the, genomic, actions, of, 1, 'alpha,25-dihydroxyvitamin', 'D(3)', '(', 1, 'alpha,25(OH)(2)D(3),', 'calcitriol),', the, biologically, active, form, of, vitamin, 'D(3)'])].
[sujeto(['Calcitriol', and, its, synthetic, analog, 'KH1060', '(', 1, 'nM)']), verbo([induced]), complemento([osteocalcin, secretion, after, a, 96, -, h, incubation, period, as, detected, by, radioimmunoassay])].
[sujeto(['In', combination, 'treatments,', 9, -, cisRA, rapidly]), verbo([stimulated]), complemento([osteocalcin, mRNA, synthesis, induced, by, the, different, vitamin, 'D(3)', compounds])].
[sujeto(['The', reduction, was, accompanied, by, an]), verbo([increased]), complemento([degradation, rate, of, both, 'VDR', and, 'RXRbeta', in, the, presence, of, 9, -, cisRA])].
[sujeto(['Furthermore,', 9, -, cisRA]), verbo([increased]), complemento([the, formation, of, 'RXRbeta-VDR-VDRE', complex, on, the, osteocalcin, gene, 'VDRE'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 9, -, cisRA, accelerates, 'calcitriol-induced', osteocalcin, production, in, human, osteoblastic, cells, through, increased, formation, of, transcriptionally, active, chromatin, complexes, 'and,', 'subsequently,', promotes, degradation, of, the, heterodimeric, complex, of, 'VDR', and, 'RXR'])].
[sujeto(['The', active, vitamin, 'D', metabolite, 1, ',', 25, -, dihydroxyvitamin, 'D(3)', '(', 1, ',', 25, -, '(', 'OH)(2)D(3))', and, related, substances]), verbo([have]), complemento([previously, been, tested, in, tissue, culture, and, animal, models, of, retinoblastoma, for, their, use, as, 'anti-tumor', drugs])].
[sujeto(['However,', despite, of, the, potential, therapeutic, 'value,', the, molecular, mechanisms, through, which, 1, ',', 25, -, '(', 'OH)(2)D(3)']), verbo([inhibits]), complemento([the, growth, of, retinoblastoma, cells, are, incompletely, understood])].
[sujeto(['Incubation', with, 1, ',', 25, -, '(', 'OH)(2)D(3)', and, 'KH1060', '(', 10, '(', -, 10, ')', -, 10, '(', -, 6, ')', 'moll(-1))']), verbo([decreased]), complemento([the, number, of, 'Y79', cells, in, a, timely, and, 'dose-dependent', manner])].
[sujeto(['Treatment', with, 1, ',', 25, -, '(', 'OH)(2)D(3)', '(', 10, '(', -, 10, ')', 'moll(-1))', for, 24, hr]), verbo([caused]), complemento([cell, cycle, arrest, in, the, 'G0/1', phase])].
[sujeto([1, ',', 25, -, '(', 'OH)(2)D(3)-induced', programmed, death, of, 'Y79', cells, was, accompanied, by, a, 'concentration-dependent']), verbo([increase]), complemento([in, 'Bax', protein, and, a, reduction, in, 'Bcl-2', content])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 1, ',', 25, -, '(', 'OH)(2)D(3)', inhibits, the, growth, of, retinoblastoma, cells, by, causing, cell, cycle, arrest, and, apoptosis])].
[sujeto([1, ',', 25, -, '(', 'OH)(2)D(3)-induced', programmed, death, of, retinoblastoma, cells, appears, to]), verbo([involve]), complemento([reciprocal, changes, in, 'Bcl-2', and, 'Bax', proteins])].
[sujeto(['The', ability, of, these, compounds, to]), verbo([inhibit]), complemento([cell, growth, and, 'DNA', synthesis, was, evaluated, by, 3, -, '(', 4, ',', 5, -, 'dimethylthiazol-2-yl)-2,5-diphenyl', tetrazolium, bromide, assay, and, 'BrdU', 'incorporation,', respectively])].
[sujeto(['KH1060', was, more, effective, than, 1, ',', 25, 'D(3)', in]), verbo([inhibiting]), complemento([cell, growth, and, 'DNA', synthesis])].
[sujeto(['This', growth, inhibition, was, also, accompanied, by, induction, of, 'caspase-3', 'activity,', indicating, that, these, compounds]), verbo([induce]), complemento([cell, death, in, a, 'caspase-dependent', fashion])].
[sujeto(['Moreover,', 'KH1060', exerted, potent, antineoplastic, activity, by]), verbo([suppressing]), complemento([the, clonal, proliferation, of, the, six, 'NB', cells])].
[sujeto(['For', the, first, time, we, demonstrate, that, 'KH1060']), verbo([induces]), complemento([the, expression, of, retinoic, acid, 'receptor-beta', and, 'p21(Cip1)', suggesting, that, these, proteins, in, part, mediate, the, growth, inhibitory, effects])].
[sujeto(['Taken', 'together,', all, the, six, 'NB', cells, were, more, susceptible, to, growth, inhibition, by, 'KH1060', than, 1, ',', 25, -, 'D(3),']), verbo([suggesting]), complemento([its, possible, use, in, 'NB', to, potentiate, the, action, of, 'retinoids,', which, are, in, clinical, use, for, this, disease])].
[sujeto(['The', crystal, structures, of, the, ligand]), verbo([binding]), complemento([domain, of, human, vitamin, 'D', receptor, '(', 'VDR)', complexed, with, its, natural, ligand, or, the, superagonists, 'MC1288', or, 'KH1060', have, recently, been, reported])].
[sujeto(['The', crystallized, ligand]), verbo([binding]), complemento([domain, '(', 'LBD)', of, 'VDR,', 'however,', differs, from, the, 'full-length', 'VDR', with, respect, to, deletion, of, 50, amino, acids, between, its, helices, 2, and, 3])].
[sujeto(['In', this, 'study,', we, investigated, structurally, and, functionally, important, amino, acid, interactions, within, the, ligand]), verbo([binding]), complemento([pocket, of, the, 'full-length', 'VDR', in, the, presence, of, several, synthetic, vitamin, 'D(3)', analogs])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, structurally, different, agonists, have, distinct, 'ligand-receptor', interactions, and, that, the, amino, acid, residues, 'H229,', 'D232,', 'E269,', 'F279,', and, 'Y295', are, critical, for, the, agonistic, conformation, of, the, 'VDR'])].
[sujeto(['Our', biological, 'data,', which, were, obtained, with, the, 'full-length', 'VDR,', fit, well, with, the, crystal, structure, of, the, truncated, 'VDR', 'LBD', and]), verbo([suggest]), complemento([that, removal, of, the, insertion, domain, between, helices, 2, and, 3, of, the, receptor, does, not, markedly, influence, the, functionality, of, the, 'VDR'])].
[sujeto(['Subsequently,', we]), verbo([have]), complemento([shown, that, vitamin, 'D', 'receptor/retinoid', 'X', receptor, alpha, '(', 'VDR/RXRalpha)', heterodimers, bind, more, tightly, to, the, osteopontin, 'VDRE', than, to, the, osteocalcin, 'VDRE'])].
[sujeto(['Studies', using, point, mutants, revealed, that, the, internal, dinucleotide, at, positions, 3, and, 4, of, the, proximal, steroid, 'half-element', are, most, important, for]), verbo([modulating]), complemento([the, strength, of, receptor, binding])].
[sujeto(['In', 'addition,', studies, with, 'VDRE-driven', luciferase, reporter, gene, constructs, revealed, that, the, central, dinucleotide, influences, the, transactivation, potential, of, 'VDR/RXRalpha', with, the, same, order, of, magnitude, as, that, observed, in, the, 'DNA']), verbo([binding]), complemento([studies])].
[sujeto(['The', synthetic, vitamin, 'D', analog, 'KH1060', is, a, more, potent, stimulator, of, transcription, and, inducer, of, 'VDRE']), verbo([binding]), complemento([of, 'VDR/RXR', in, the, presence, of, nuclear, factors, isolated, from, 'ROS', 17, /, 2.8, 'osteoblast-like', cells, than, the, natural, ligand, 1, ',', 25, -, '(', 'OH)(2)D(3)'])].
[sujeto(['Interestingly,', 'however,', 'KH1060', is, comparable, or, even, less, potent, than, 1, ',', 25, -, '(', 'OH)(2)D(3)', in]), verbo([stimulating]), complemento(['VDRE', binding, of, in, vitro, synthesized, 'VDR/RXRalpha'])].
[sujeto(['Thus,', the, extent, of, 1, ',', 25, -, '(', 'OH)(2)D(3)-', and, 'KH1060-dependent']), verbo([binding]), complemento([of, 'VDR/RXRalpha', is, specified, by, a, central, dinucleotide, in, the, 'VDRE,', and, the, 'ligand-induced', effects, on, 'DNA', binding, are, in, part, controlled, by, the, cellular, context, of, nuclear, proteins])].
[sujeto(['We', show, that, these, compounds]), verbo([promote]), complemento([the, differentiation, of, human, colon, carcinoma, 'SW480', cells, expressing, vitamin, 'D', receptors, '(', 'VDRs)', '(', 'SW480-ADH)', but, not, that, of, a, malignant, subline, '(', 'SW480-R)', or, metastasic, derivative, '(', 'SW620)', cells, lacking, 'VDR'])].
[sujeto([1, 'alpha,25(OH)2D(3)']), verbo([induced]), complemento([the, expression, of, 'E-cadherin', and, other, adhesion, proteins, '(', 'occludin,', 'Zonula', occludens, '[', 'ZO]-1,', 'ZO-2,', 'vinculin)', and, promoted, the, translocation, of, 'beta-catenin,', 'plakoglobin,', and, 'ZO-1', from, the, nucleus, to, the, plasma, membrane])].
[sujeto(['Accordingly,', 1, 'alpha,25(OH)2D(3)']), verbo([repressed]), complemento(['beta-catenin-TCF-4', transcriptional, activity])].
[sujeto(['Moreover,', 'VDR', activity, was]), verbo([enhanced]), complemento([by, ectopic, 'beta-catenin', and, reduced, by, 'TCF-4'])].
[sujeto(['Also,', 1, 'alpha,25(OH)2D(3)']), verbo([inhibited]), complemento([expression, of, 'beta-catenin-TCF-4-responsive', 'genes,', 'c-myc,', peroxisome, 'proliferator-activated', receptor, 'delta,', 'Tcf-1,', and, 'CD44,', whereas, it, induced, expression, of, 'ZO-1'])].
[sujeto(['Our', results, show, that, 1, 'alpha,25(OH)2D(3)']), verbo([induces]), complemento(['E-cadherin', and, modulates, 'beta-catenin-TCF-4', target, genes, in, a, manner, opposite, to, that, of, 'beta-catenin,', promoting, the, differentiation, of, colon, carcinoma, cells])].
[sujeto(['The', crystal, structures, of, the, 'ligand-binding', domain, '(', 'LBD)', of, the, vitamin, 'D', receptor, complexed, to, 1, 'alpha,25(OH)(2)D(3)', and, the, 20, -, epi, 'analogs,', 'MC1288', and, 'KH1060,', show, that, the, protein, conformation, is, 'identical,']), verbo([conferring]), complemento([a, general, character, to, the, observation, first, made, for, retinoic, acid, receptor, '(', 'RAR)', 'that,', for, a, given, 'LBD,', the, agonist, conformation, is, 'unique,', the, ligands, adapting, to, the, binding, pocket])].
[sujeto(['The', inverted, geometry, of, the, 'C20', methyl, group]), verbo([induces]), complemento([different, paths, of, the, aliphatic, chains])].
[sujeto(['Based', on, the, present, 'data,', the, explanation, of, the, superagonist, effect, is, to, be]), verbo([found]), complemento([in, higher, stability, and, longer, 'half-life', of, the, active, 'complex,', thereby, excluding, different, conformations, of, the, ligand, binding, domain])].
[sujeto(['In', helices, 'three,', four, and, 'five,', 'His229,', 'Asp232,', 'Ser237', and, 'Arg274', seem, to]), verbo([have]), complemento([an, important, role, in, the, binding, of, calcitriol])].
[sujeto(['Surprisingly,', the, 20, -, epi, analog, 'MC', 1288, did, not]), verbo([bind]), complemento([to, 'Ser237'])].
[sujeto(['The', 20, -, epi, analogs, effectively]), verbo([prevented]), complemento([its, formation])].
[sujeto(['Thus,', the, 20, -, epi, analogs]), verbo([induce]), complemento([a, 'VDR', 'conformation,', which, prevents, binding, of, factors, mediating, 'VDR', degradation])].
[sujeto(['Third,', the, analogs, were]), verbo([found]), complemento([to, be, powerful, regulators, of, cell, cycle, progression, in, 'MG-63', cells])].
[sujeto(['They']), verbo([arrested]), complemento([cell, cycle, in, the, 'G0/G1', phase, at, lower, concentrations, and, earlier, time, points, than, calcitriol])].
[sujeto(['This', correlated, with]), verbo([increased]), complemento([levels, of, p27])].
[sujeto(['Thus,', a, similar, sequence, of, events, with, calcitriol, and, the, analogs, in]), verbo([inhibiting]), complemento(['MG-63', cell, growth, was, detected, but, the, analogs, had, much, longer, lasting, and, stronger, effects, than, calcitriol])].
[sujeto(['Because', the, estrogen, receptor, '(', 'ER)', plays, a, key, role, in, breast, cancer, 'progression,', we]), verbo([have]), complemento([studied, the, effects, of, 1, ',', 25, '(', 'OH)2D3', on, the, regulation, of, 'ER', in, the, 'estrogen-responsive', 'MCF-7', human, breast, cancer, cell, 'line,', which, is, known, to, predominantly, express, 'ERalpha'])].
[sujeto([1, ',', 25, '(', 'OH)2D3']), verbo([causes]), complemento([significant, inhibition, of, 'MCF-7', cell, 'growth,', and, it, also, decreases, the, 'growth-stimulatory', effect, of, 17, 'beta-estradiol', '(', 'E2)'])].
[sujeto(['Treatment', of, 'MCF-7', cells, with, 1, ',', 25, '(', 'OH)2D3', reduces, 'ER', levels, in, a, 'dose-dependent', 'manner,', as, shown, by, ligand]), verbo([binding]), complemento([assays, and, 'Western', blot, analysis])].
[sujeto(['Treatment', with, 1, ',', 25, '(', 'OH)2D3', shows, that, the, reduction, in, 'ER', is, accompanied, by, a, significant]), verbo([decrease]), complemento([in, the, 'steady-state', levels, of, 'ER', mRNA])].
[sujeto(['The']), verbo([decrease]), complemento([in, 'ER', mRNA, is, not, abolished, by, the, protein, synthesis, inhibitor, cycloheximide])].
[sujeto(['Inhibition', of, mRNA, synthesis, with, actinomycin, 'D']), verbo([reveals]), complemento([no, significant, differences, between, 'ER', mRNA, 'half-life', in, control, and, 1, ',', 25, '(', 'OH)2D3-treated', cells])].
[sujeto(['Nuclear', 'run-on', experiments, demonstrate, significant]), verbo([decreases]), complemento([in, 'ER', gene, transcription, at, the, end, of, 17, h, of, treatment, with, 1, ',', 25, '(', 'OH)2D3'])].
[sujeto(['Coincident', with, the]), verbo([decrease]), complemento([in, 'ER', levels, there, is, an, attenuation, of, 'E2-mediated', bioresponses, after, 1, ',', 25, '(', 'OH)2D3', treatment])].
[sujeto(['Induction', of, progesterone, receptor, by, 'E2', is]), verbo([suppressed]), complemento([by, 1, ',', 25, '(', 'OH)2D3,', and, the, 'E2-mediated', increase, in, breast, cancer, susceptibility, gene, '(', 'BRCA1)', protein, is, reduced, by, 1, ',', 25, '(', 'OH)2D3', treatment])].
[sujeto(['Overall,', these, results]), verbo([suggest]), complemento([that, the, antiproliferative, effects, of, 1, ',', 25, '(', 'OH)2D3', and, its, analogues, on, 'MCF-7', cells, could, partially, be, mediated, through, their, action, to, 'down-regulate', 'ER', levels, and, thereby, attenuate, estrogenic, 'bioresponses,', including, breast, cancer, cell, growth])].
[sujeto(['We', previously, showed, that, 'KH1060']), verbo([increases]), complemento(['VDR', stability, in, 'ROS', 17, /, 2.8, osteoblastic, cells, by, inducing, a, specific, conformational, change, in, the, 'VDR'])].
[sujeto(['In', the, present, 'study,', we, investigated, whether, these, metabolites, might, contribute, to, the]), verbo([increased]), complemento([biological, activity, of, 'KH1060'])].
[sujeto(['We']), verbo([found]), complemento([that, the, potencies, of, two, of, these, 'metabolites,', 24, 'a-OH-KH1060', and, 26, -, 'OH-KH1060,', were, similar, to, that, of, 1, ',', 25, -, '(', 'OH)(2)D(3)', in, inducing, osteocalcin, production, by, the, osteoblast, cell, line, 'ROS', 17, /, 2.8])].
[sujeto(['This']), verbo([report]), complemento([further, showed, that, these, metabolites, had, the, same, effects, as, 'KH1060', on, 'VDR:', they, increased, 'VDR', stability, in, 'ROS', 17, /, 2.8, 'cells,', while, limited, proteolytic, analysis, revealed, that, they, caused, a, conformational, change, in, the, 'VDR,', resulting, in, an, increased, resistance, against, proteolytic, cleavage])].
[sujeto(['Furthermore,', as, shown, in, gel, mobility, shift, 'assays,', both, compounds, clearly]), verbo([induced]), complemento(['VDR', binding, to, vitamin, 'D', response, elements])].
[sujeto(['We', and, others]), verbo([have]), complemento([previously, shown, that, selected, vitamin, 'D', analogs, potentiate, the, vitamin, 'D', receptor, '(', 'VDR)', mediated, transcription, much, more, efficiently, than, the, natural, hormone, itself])].
[sujeto(['The', conformationally, 'epi-like', analog, 'EB', 1089, did, not, significantly, alter, the, 'half-life', of, 'VDR', '(', 10.3, 'h),', but]), verbo([retained]), complemento([the, 'VDR', levels, over, longer, periods, of, time, than, calcitriol])].
[sujeto(['The', transcriptionally, weak, analog, 'GS', 1558, ',', on, the, other, 'hand,']), verbo([enhanced]), complemento(['VDR', degradation, even, more, than, what, was, observed, with, the, unliganded, receptor, '(', 't(1/2)', 4.5, h, and, 5, 'h,', 'respectively)'])].
[sujeto(['Inhibition', of, proteasome, activity, by, the, inhibitor, 'MG-132', resulted, in, a, marked]), verbo([increase]), complemento([in, the, 'VDR', levels, in, cells, treated, with, the, vehicle, or, 'GS', 1558, '(', 2.5, -, fold, and, 2.7, -, 'fold,', 'respectively),', more, than, twice, the, levels, observed, in, the, presence, of, calcitriol, or, 'EB', 1089, '(', 1.2, -, fold, and, 1.1, -, 'fold,', 'respectively)'])].
[sujeto(['MG-132', treatment, did, not]), verbo([increase]), complemento([the, 'VDR', levels, in, cells, treated, with, 'KH', 1060, or, 'MC', 1288])].
[sujeto(['The', electrophoretic, mobility, shift, assay, '(', 'EMSA)', with]), verbo([nuclear]), complemento([extracts, from, 'MG-132-treated', cells, revealed, formation, of, a, 'high-molecular-weight', 'RXRbeta-VDR-VDRE', 'complex,', which, also, contained, 'Sug1'])].
[sujeto(['In', the, presence, of, 'calcitriol,', 34, '%', of, total, 'VDR', in, its, 'DNA']), verbo([binding]), complemento([state, was, present, in, this, complex])].
[sujeto(['The', 20, -, epi, analogs, effectively]), verbo([prevented]), complemento([the, formation, of, this, 'complex,', 'since,', in, this, 'case,', only, 16, '%', of, total, 'VDR', was, found, in, this, complex])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'KH', 1060, and, 'MC', 1288, induce, a, 'VDR', 'conformation,', which, prevents, binding, of, proteins, mediating, receptor, degradation])].
[sujeto(['As', a, 'result,', the, regulation, of, 'VDR', degradation, differs, from, that]), verbo([found]), complemento([with, the, 'calcitriol-VDR', complex, resulting, in, superactive, transcriptional, action, of, the, analogs])].
[sujeto(['KH', 1060, '(', 0.01, ',', 0.1, ',', 1, 'nM)', significantly]), verbo([inhibited]), complemento([cell, 'proliferation,', determined, after, 5, days, by, '[', 3, 'H]thymidine', 'incorporation,', when, peripheral, blood, mononuclear, cells, '(', 'PBMC),', obtained, from, healthy, 'subjects,', were, stimulated, with, phytohaemagglutinin, '(', 'PHA)', and, incubated, for, 24, h, in, the, absence, and, in, the, presence, of, lipopolysaccharide, '(', 'LPS)'])].
[sujeto([0.1, nM, 'KH', 1060, produced, a, significant]), verbo([decrease]), complemento([in, 'TNF-alpha', 'levels,', determined, by, 'ELISA,', although, less, remarkable, than, in, the, presence, of, 'anti-TNF'])].
[sujeto(['This']), verbo([decrease]), complemento([was, 'synergistic,', associating, 0.1, nM, 'KH', 1060, and, 0.1, 'microg/ml', 'anti-TNF'])].
[sujeto(['VDR', protein, levels, were]), verbo([increased]), complemento([by, 0.1, nM, 'KH', 1060, ',', 0.1, 'microg/ml', 'anti-TNF', or, their, combination])].
[sujeto(['The', protein, levels, of, two, 'oncogenes,', 'Bax', and, 'Bcl-2,', remained, 'unchanged,', when, 'PBMC', were, incubated, with, 'KH', 1060, ',', 'anti-TNF', or, their, combination, in, the, absence, of, 'LPS,', 'while,', in, its, 'presence,', an]), verbo([increase]), complemento([was, registered])].
[sujeto(['The', demonstrated, 'anti-TNF-alpha', effect, of, 'KH', 1060, may]), verbo([suggest]), complemento([for, this, compound, an, immunosuppressive, action, and, the, possibility, to, synergistically, act, with, other, drugs])].
[sujeto(['At', day, 5, of, 'culture,', the, proliferation, of, 'PBMC', obtained, from, patients, responsive, to, the, therapy, showed, a, remarkable]), verbo([decrease]), complemento(['(', about, 60, '%', ')', at, 'T6', '(', after, two, 'infusions)', with, respect, to, 'T0', '(', before, the, first, 'infusion)'])].
[sujeto(['Vitamin', 'D', derivatives]), verbo([induced]), complemento([a, decrease, in, cell, proliferation, higher, in, responsive, patients, than, in, the, unresponsive, one])].
[sujeto(['The', incubation, with, 1, ',', 25, '(', 'OH)2D3', was, ineffective, on, either, cell, proliferation, or, '[', 3, 'H]thymidine', incorporation, '(']), verbo([expressed]), complemento([as, 'DPM', per, 'cell)', or, protein, content, per, cell])].
[sujeto(['On', the, 'contrary,', all, the, other, treatments]), verbo([inhibited]), complemento([cell, 'proliferation,', this, inhibition, being, synergistic, when, the, vitamin, 'D', derivatives, were, combined, with, 9, -, cis, or, 'all-trans', retinoic, 'acid,', and, increased, '[', 3, 'H]thymidine', incorporation, and, protein, content, per, cell])].
[sujeto(['The', levels, of, the, 'VDR', protein, remarkably]), verbo([increased]), complemento([in, comparison, with, control, 'cells,', except, for, the, incubation, with, 9, -, cis, retinoic, acid])].
[sujeto(['This']), verbo([increase]), complemento([was, particularly, accentuated, in, 'C2C12', cells, treated, with, 'KH', 1060, and, 9, -, cis, retinoic, acid, in, combination])].
[sujeto(['These', 'results,', taken, 'together,']), verbo([suggest]), complemento([a, role, for, vitamin, 'D', derivatives, and, retinoids, on, 'C2C12', cells])].
[sujeto(['Vitamin', 'D', receptor, '(', 'VDR)']), verbo([acts]), complemento([as, a, transcription, factor, mediating, genomic, actions, of, calcitriol])].
[sujeto(['Our', earlier, studies]), verbo([suggested]), complemento([that, calcitriol, induces, translocation, of, cytoplasmic, 'VDR,', but, the, physiologic, relevance, of, this, finding, remained, uncertain])].
[sujeto(['Western', blot, 'analysis,', fluorescent, 'microscopy,', and, transactivation, assays, showed, that, the, generated, chimeras, are]), verbo([expressed]), complemento([and, fluoresce, and, that, 'VDR-GFP', is, transcriptionally, active])].
[sujeto(['Our', data, confirm, a, 'hormone-dependent', 'VDR', 'translocation,', demonstrate, that, an, intact, 'AF-2', domain, is]), verbo([required]), complemento([for, this, 'translocation,', and, indicate, that, translocation, is, part, of, the, receptor, activation, process])].
[sujeto(['Vitamin', 'D', analogs]), verbo([have]), complemento([received, increased, attention, because, of, their, possible, therapeutic, benefits, in, treating, osteoporosis, and, various, proliferative, disorders])].
[sujeto(['Several', analogs, were, examined, for, their, effects, on, 'DNA']), verbo([binding]), complemento([of, the, vitamin, 'D', receptor, '(', 'VDR)', homodimer, complex, with, the, murine, osteopontin, vitamin, 'D', response, element])].
[sujeto(['All', of, the, tested, analogs]), verbo([increased]), complemento([complex, binding, by, recombinant, human, 'VDR', in, the, electrophoretic, mobility, shift, assay, and, notable, differences, in, mobility, of, these, complexes, were, observed])].
[sujeto(['A', panel, of, 'C-terminal', 'anti-VDR', antisera, were, screened, for, their, ability, to]), verbo([interact]), complemento([with, 'analog-bound', 'VDR', homodimer, complexes, or, as, a, heterodimer, complex, with, recombinant, human, retinoid, 'X', receptor, alpha, '(', rhRXR, 'alpha)'])].
[sujeto(['Like', 'calcitriol,', 'analog-bound', heterodimer, complexes, were, largely, resistant, to, interaction, with, these, 'antisera;', 'however,', striking, differences, were, observed, with, the, various, antisera, in, an, analogous, homodimer]), verbo([binding]), complemento([experiment])].
[sujeto(['Although', new, heterodimer, complexes, appeared, in, a, 'time-dependent', 'fashion,', the, preformed, homodimer, complexes, exhibited, stable]), verbo([binding]), complemento([throughout, the, time, course, of, the, experiment])].
[sujeto(['The', results, indicate, that, 'VDR', homodimers, are]), verbo([targets]), complemento([of, vitamin, 'D', analogs, with, differential, effects, on, 'C-terminal', protein, conformation, that, may, partially, explain, the, varied, biological, responses, of, these, compounds])].
[sujeto(['Stereoselective', reduction, of, 'C-20', ketone, of, vitamin, 'D', 'CD-ring', precursor, using, 'Corey\'s', 'CBS', 'reagents,', '(', 'R)-(+)-2-methyl-CBS-oxazaborolidine', and, '(', 'S)-(-)-2-methyl-CBS-oxazaborolidine,']), verbo([led]), complemento([to, the, '(', 20, 'S)-alcohol', 5, and, '(', 20, 'R)-epimer', 4, in, approximately, 17, :, 1, selectivity])].
[sujeto(['Sulfasalazine', is, 'effective,', but]), verbo([has]), complemento([an, unfavorable, safety, profile])].
[sujeto(['Treatment', of, human, myeloblastic, leukemia, 'ML-1', cells, with, the, phorbol, ester, 'TPA', in, combination, with, the, vitamin, 'D(3)', analogue, 'KH1060', will]), verbo([induce]), complemento([a, synergistic, differentiation, to, mature, macrophage, with, multinuclei])].
[sujeto(['Results', show, that, 'KH1060']), verbo([enhanced]), complemento([several, 'TPA-induced', gene, expressions, and, that, 'TPA', enhanced, several, 'KH1060-induced', gene, expressions])].
[sujeto(['Studies', with, inhibitors, of, signaling, molecules]), verbo([suggested]), complemento([that, 'PKC', and, 'MAPK', pathways, play, an, important, role, in, the, differentiation, induced, by, 'TPA', and, 'KH1060,', and, that, they, are, associated, with, the, synergistic, induction, of, genes])].
[sujeto(['The', results, of, this, study, indicate, the, possibility, that, the, expression, of, various, genes, are]), verbo([induced]), complemento([synergistically, by, 'cross-talk', between, 'TPA', and, 'KH1060', signals])].
[sujeto(['It', is, likely, that, the, synergistic, effect, on, gene, expression]), verbo([leads]), complemento([to, the, synergistic, induction, of, differentiation, by, both, reagents])].
[sujeto(['Modest', changes, in, the, basal, expression, of, genes]), verbo([involved]), complemento([in, 1, ',', 25, '(', 'OH)(2)D(3)', metabolism, and, calcium, homeostasis, were, observed, in, 'vivo;', 'however,', these, changes, seemed, unlikely, to, explain, the, normal, calcium, balance, seen, in, 'DBP-null', mice])].
[sujeto(['Thus,', the, presence, of, 'DBP']), verbo([has]), complemento([limited, impact, on, the, extracellular, pool, of, 1, ',', 25, '(', 'OH)(2)D(3)', that, is, biologically, active, and, that, accumulates, within, target, tissues])].
[sujeto(['Collectively,', these, experiments]), verbo([suggest]), complemento([that, whereas, 'DBP', is, important, to, total, circulating, 1, ',', 25, '(', 'OH)(2)D(3)', and, sequesters, extracellular, levels, of, this, hormone, both, in, vivo, and, in, 'vitro,', the, binding, protein, does, not, influence, the, 'hormone\'s', biologically, active, pool])].
[sujeto(['Targacept', active, conformation, search, '(', 'TACS)', is, a, novel, variation, of, 'well-established', 'three-dimensional', quantitative, 'structure--activity', relationship, methodologies, that, seeks, to, determine, probable, 'conformation(s)', of, ligands]), verbo([bound]), complemento([to, their, protein, targets])].
[sujeto(['Recursive', pruning, is, used, to, reduce, the, size, of, both, the, conformational, ensemble, and, the, descriptor, space, until, the, 'TACS', data, model, contains, just, enough, information, to, determine, probable, 'conformation(s)', of, ligands]), verbo([bound]), complemento([to, their, protein, targets])].
[sujeto(['The', 'TACS', algorithm, is, comprised, of, five, 'components:', '(', 1, ')', conformational, ensemble, 'generation,', '(', 2, ')', 3, -, 'D', sensitive, descriptor, 'calculation,', '(', 3, ')', ensemble, descriptor, 'preprocessing,', '(', 4, ')', model, 'generation,', and, '(', 5, ')', prediction, of]), verbo([bound]), complemento(['conformation(s)'])].
[sujeto(['We']), verbo([report]), complemento([the, application, of, this, technique, to, five, benchmark, 'protein-ligand', couples, where, the, conformation, of, a, bound, ligand, has, been, previously, established, using, 'X-ray', 'crystallography:', 9, -, 'cis-retinoic', '(', 1, ')', and, 9, -, 'trans-retinoic', acid, '(', 2, ')', ',', both, agonists, for, the, retinoic, acid, receptor, 'gamma,', compounds, 'KH1060', '(', 3, ')', and, 'MC1288', '(', 4, ')', ',', which, bind, to, the, vitamin, 'D3', 'receptor,', and, 'R04', '(', 5, ')', ',', an, inhibitor, bound, to, human, rhinovirus, 14, thermolysin])].
[sujeto(['The']), verbo([binding]), complemento([conformations, predicted, by, 'TACS', were, compared, to, the, crystallographic, structures, extracted, from, their, respective, binding, sites, using, 'root-mean-squared', deviation, '(', 'rmsd)', criteria])].
[sujeto(['Three', of, the, conformations]), verbo([found]), complemento([using, 'TACS', were, within, crystallographic, error])].
[sujeto(['Progression', through, eukaryotic, cell, division, cycle, is]), verbo([regulated]), complemento([by, synergistic, activities, of, both, positive, and, negative, regulatory, factors])].
[sujeto(['The', active, form, of, vitamin, 'D(3)', '(', 1, 'alpha,25(OH)(2)D(3),', 1, ',', 25, 'D)', and, a, number, of, its, synthetic, analogs]), verbo([have]), complemento([been, shown, to, arrest, cells, in, the, 'G(1)', phase, of, the, cell, cycle])].
[sujeto(['In', the, present, 'study,', 1, 'alpha,25(OH)(2)D(3)', and, the, analogs, 'KH1060,', 'EB1089,', and, 'CB1093', were, used, to, study, the, mechanism, of, the, cell, cycle]), verbo([arrest]), complemento([and, to, compare, the, effectiveness, of, these, compounds, in, human, 'MG-63', osteosarcoma, cells])].
[sujeto(['The', 20, -, epi, analogs, 'KH1060', and, 'CB1093,', as, well, as, the, 20, -, normal, analog, 'EB1089,', were]), verbo([found]), complemento([to, be, more, potent, than, 1, 'alpha,25(OH)(2)D(3)', in, inhibiting, cell, proliferation, and, arresting, the, 'MG-63', cells, in, the, 'G(1)', phase])].
[sujeto(['These', analogs, were, more, active, than, 1, 'alpha,25(OH)(2)D(3)', in]), verbo([increasing]), complemento([the, cyclin, dependent, kinase, inhibitor, p27, protein, levels, '(', approximately, 2.3, -, 2.5, -, fold, compared, to, 1, 'alpha,25(OH)(2)D(3))', by, both, increasing, its, formation, and, decreasing, its, degradation, rate])].
[sujeto(['The']), verbo([increased]), complemento([p27, formation, was, accompanied, by, stabilization, of, binding, of, nuclear, proteins, to, the, 'Sp1+NF-Y', responsive, promoter, region, of, the, p27, gene])].
[sujeto(['The']), verbo([increase]), complemento([in, p27, protein, levels, and, the, simultaneous, decrease, in, cyclin, 'E', protein, levels, was, accompanied, by, decreased, 'Cdk2', kinase, 'activity,', retinoblastoma, '(', 'Rb)', protein, hypophosphorylation, 'and,', 'finally,', cell, cycle, arrest, in, the, 'G(1)', phase])].
[sujeto(['In', 'summary,', the, analogs, 'KH1060,', 'EB1089,', and, 'CB1093', keep, 'Rb', protein, in, its, 'growth-suppressing,', hypophosphorylated, form, and]), verbo([prevent]), complemento([cell, cycle, progression, through, the, restriction, point])].
[sujeto(['Studies']), verbo([have]), complemento([identified, analogs, of, 1, ',', 25, -, dihydroxyvitamin, 'D3', '[', 1, ',', 25, '(', 'OH)2D3],', which, in, vitro, are, 10, -, to, 3, ',', 0, -, fold, more, active, than, 1, ',', 25, '(', 'OH)2D3'])].
[sujeto(['Each', of, the, analogs, equally, and, markedly]), verbo([inhibited]), complemento([growth, of, the, prostate, cancer, xenografts])].
[sujeto(['The', 1, ',', 25, '(', 'OH)2D3', initially]), verbo([inhibited]), complemento([growth, 'but,', by, the, time, of, 'sacrifice,', the, tumors, were, nearly, the, same, size, as, diluant, controls])].
[sujeto(['The', 'MTD', of, the, analogs, varied, by, 400, -, fold, but, each, had, similar, efficacy]), verbo([suggesting]), complemento(['that,', when, choosing, a, vitamin, 'D', analog, for, clinical, 'study,', overall, efficacy, without, toxicity, is, more, important, than, the, total, amount, of, the, compound, that, can, be, administered])].
[sujeto(['In', 'summary,', we]), verbo([have]), complemento([identified, three, vitamin, 'D', analogs, that, show, marked, potency, in, vivo, to, inhibit, growth, of, human, prostate, cancer, 'xenografts;', each, had, no, detectable, toxicity])].
[sujeto(['Vitamin', 'D', '(', 'VitD)', is, now]), verbo([recognized]), complemento([for, its, pleiotrophic, roles, in, regulating, immune, function])].
[sujeto(['In', the, current, 'study,', we, demonstrate, that, 'VitD']), verbo([enhanced]), complemento([glucocorticoid, '(', 'GC)', responses, in, human, peripheral, blood, mononuclear, cells, because, it, stimulated, 'GC', induction, of, 'mitogen-activated', protein, kinase, 'phosphatase-1', '(', 'MKP-1)', and, enhanced, 'GC', inhibition, of, 'LPS-induced', 'IL-6'])].
[sujeto(['GM-CSF,']), verbo([found]), complemento([in, culture, supernatants, from, 'CD14(-)', 'cells,', was, shown, to, mediate, 'VitD', enhancement, of, 'GC-induced', 'MKP-1', production, in, monocytes, via, increased, production, of, mediator, complex, subunit, 14, '(', 'MED14)'])].
[sujeto(['Recruitment', of, 'VitD', receptor, and, 'MED14,', 4.7, kbp, upstream, of, the, human, 'MKP-1', gene, transcription, start, 'site,']), verbo([enhanced]), complemento([binding, of, glucocorticoid, receptor, and, histone, 'H4', acetylation, at, the, 4.6, -, kbp, glucocorticoid, response, element, of, the, 'MKP-1', promoter, in, the, presence, of, 'GM-CSF', in, 'U937', cells])].
[sujeto(['Nephrin', plays, a, key, role, in]), verbo([maintaining]), complemento([the, structure, of, the, slit, diaphragm, in, the, glomerular, filtration, barrier])].
[sujeto(['Our', previous, studies]), verbo([have]), complemento([demonstrated, potent, renoprotective, activity, for, 1, ',', 25, -, dihydroxyvitamin, 'D', '(', 1, ',', 25, '(', 'OH)(2)D(3))'])].
[sujeto(['Here', we, showed, that, in, podocytes, 1, ',', 25, '(', 'OH)(2)D(3)', markedly]), verbo([stimulated]), complemento([nephrin, mRNA, and, protein, expression])].
[sujeto(['ChIP', scan, of, the, 6, -, kb, 5, '\'', upstream, region, of, the, mouse, nephrin, gene, identified, several, putative, vitamin, 'D', response, elements, '(', 'VDREs),', and, 'EMSA', confirmed, that, the, 'VDRE', at, -, 312, '(', a, 'DR4-type', 'VDRE)', could, be]), verbo([bound]), complemento([by, vitamin, 'D', receptor, '(', 'VDR)/retinoid', 'X', receptor])].
[sujeto(['ChIP', assays, showed, 'that,', upon, 1, ',', 25, '(', 'OH)(2)D(3)', 'activation,', 'VDR']), verbo([bound]), complemento([to, this, 'VDRE', leading, to, recruitment, of, 'DRIP205', and, 'RNA', polymerase, 'II', and, histone, 4, acetylation])].
[sujeto(['Treatment', of, mice, with, a, vitamin, 'D', analog]), verbo([induced]), complemento([nephrin, mRNA, and, protein, in, the, 'kidney,', accompanied, by, increased, 'VDR', binding, to, the, -, 312, 'VDRE', and, histone, 4, acetylation])].
[sujeto([1, ',', 25, '(', 'OH)(2)D(3)', reversed, high, 'glucose-induced', nephrin, reduction, in, 'podocytes,', and, vitamin, 'D', analogs]), verbo([prevented]), complemento([nephrin, decline, in, both, type, 1, and, 2, diabetic, mice])].
[sujeto(['Together', these, data, demonstrate, that, 1, ',', 25, '(', 'OH)(2)D(3)']), verbo([stimulates]), complemento([nephrin, expression, in, podocytes, by, acting, on, a, 'VDRE', in, the, proximal, nephrin, promoter])].
[sujeto(['Prochlorococcus']), verbo([has]), complemento([remained, a, genetically, intractable, bacterium, due, to, slow, growth, rates, and, low, transformation, efficiencies, using, standard, techniques])].
[sujeto(['Prochlorococcus', 'MED4']), verbo([has]), complemento([an, 'AT-rich', 'genome,', with, a, 'GC', content, of, 30.8, '%', ',', similar, to, that, of, 'Saccharomyces', cerevisiae, '(', 38, '%', ')', ',', and, contains, abundant, yeast, replication, origin, consensus, sites, '(', 'ACS)', evenly, distributed, around, its, 1.66, 'Mb', genome])].
[sujeto(['We', thus]), verbo([provide]), complemento([evidence, of, 'transformation,', replication, and, maintenance, of, this, 1.66, 'Mb', intact, bacterial, genome, in, 'S'])].
[sujeto(['These', alternative, mechanisms, of, nutrient, thrift, might]), verbo([respond]), complemento([differently, to, 'selection,', but, this, possibility, remains, untested])].
[sujeto(['We', hypothesized, that, relatively, invariant, sequence, composition]), verbo([responds]), complemento([to, 'long-term', variation, in, nutrient, 'concentrations,', whereas, dynamic, expression, profiles, vary, with, nutrient, predictability])].
[sujeto(['We']), verbo([suggest]), complemento([that, fluctuating, nutrient, availability, favours, mechanisms, involving, 'short-term', downregulation, of, 'nutrient-rich', proteins])].
[sujeto(['MIT9313']), verbo([responded]), complemento([similarly, to, nitrogen, and, phosphorus, 'limitation,', with, 'slow,', sustained, downregulation, of, 'nitrogen-rich', ribosomal, proteins])].
[sujeto(['MED4\'s', 'specific,', rapid, nitrogen, response]), verbo([suggests]), complemento([adaptation, to, fluctuating, 'conditions,', supporting, previous, work])].
[sujeto(['Both', bidirectional, best, 'BLASTP', '(', basic, local, alignment, search, tool, for, 'proteins)', search, and, the, conservation, of, gene, order, against, each, other, were, utilized, to, identify, genomic, 'islands,', and, 7, genomic, islands, were]), verbo([found]), complemento([to, be, immediately, adjacent, to, tRNAs, in, 'Prochlorococcus', marinus, 'AS9601,', 11, in, 'P'])].
[sujeto(['The', tRNA, genes]), verbo([associated]), complemento([with, genomic, islands, showed, the, following, 'characteristics:', '(', 1, ')', the, association, was, biased, towards, a, specific, subset, of, all, 'iso-accepting', tRNA, 'genes;', '(', 2, ')', the, codon, usages, of, genes, within, genomic, islands, appear, to, be, unrelated, to, the, codons, recognized, by, associated, 'tRNAs;', 'and,', '(', 3, ')', the, majority, of, the, 3, '\'', ends, of, associated, tRNAs, lack, 'CCA', ends])].
[sujeto(['The', analysis, of, a, genomic, island]), verbo([associated]), complemento([with, a, 'tRNA-Asn', gene, in, 'P'])].
[sujeto([marinus, 'MIT9301']), verbo([suggests]), complemento([that, foreign, genetic, material, is, inserted, into, the, host, genomes, by, means, of, 'site-specific', 'recombination,', with, the, 3, '\'', end, of, the, tRNA, as, the, 'target,', and, during, the, 'process,', a, direct, repeat, of, the, 3, '\'', end, sequence, of, a, boundary, tRNA, '(', 'namely,', a, scar, from, the, process, of, 'insertion)', is, formed, elsewhere, in, the, genomic, island])].
[sujeto(['However,', amino, acid, usages, were, markedly, different, between, the, highly, and, lowly]), verbo([expressed]), complemento([genes, in, this, organism, and, in, 'particular,', 'GC', rich, amino, acids, were, found, to, occur, significantly, higher, in, highly, expressed, genes, than, the, lowly, expressed, genes])].
[sujeto(['WH8102', and, 'Prochlorococcus', marinus, 'MED4', shows, that, amino, acids, conservation, in, highly]), verbo([expressed]), complemento([genes, is, significantly, higher, than, lowly, expressed, genes])].
[sujeto(['Based', on, our, results, we, concluded, that, conservation, of, 'GC', rich, amino, acids, in, the, highly]), verbo([expressed]), complemento([genes, to, its, ancestor, is, the, major, source, of, variation, in, amino, acid, usages, in, the, organism])].
[sujeto(['Our', recent, studies]), verbo([have]), complemento([shown, that, the, vitamin, 'D', analog, 'Ro-26-9228', restores, bone, mineral, density, without, inducing, hypercalcemia, in, osteopenic, rats])].
[sujeto(['We']), verbo([found]), complemento([that, the, abilities, of, 'Ro-26-9228', and, the, natural, 'hormone,', 1, ',', 25, -, dihydroxyvitamin, 'D(3)', '(', 1, ',', 25, 'D(3))', to, induce, 'VDRE-reporter', gene, expression, in, transiently, transfected, human, osteoblasts, are, similar])].
[sujeto(['In', 'contrast,', in, 'Caco-2', 'cells,', 'Ro-26-9228']), verbo([induces]), complemento([40, -, fold, less, reporter, gene, expression, than, 1, ',', 25, 'D(3)', does])].
[sujeto(['We', also, examined, the, abilities, of, the, vitamin, 'D', receptor, '(', 'VDR)-ligand', complexes, from, these, two, cell, lines, to]), verbo([interact]), complemento([with, partners, of, transcription, '(', glucocorticoid, 'receptor-interacting', 'protein,', 'VDR-interacting', 'protein,', and, retinoid, 'X', 'receptor),', in, 'pull-down', assays])].
[sujeto(['These', assays, revealed, that, 1, ',', 25, 'D(3)']), verbo([induces]), complemento([similar, levels, of, interaction, of, these, 'co-factors', with, 'VDR', from, both, osteoblasts, and, intestinal, cells])].
[sujeto(['In', 'contrast,', 'Ro-26-9228']), verbo([induces]), complemento([significant, interaction, of, 'VDR', from, osteoblast, cells, with, these, 'co-factors,', but, less, of, 'VDR', from, 'Caco-2', cells])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, cellular, environment, of, intestinal, 'cells,', unlike, that, of, 'osteoblasts,', represses, the, ability, of, 'VDR-Ro-26-9228', complexes, to, interact, with, transcription, partners])].
[sujeto(['Implementing', precision, medicine, for, complex, diseases, such, as, chronic, obstructive, lung, disease, '(', 'COPD)', will]), verbo([require]), complemento([extensive, use, of, biomarkers, and, an, 'in-depth', understanding, of, how, 'genetic,', 'epigenetic,', and, environmental, variations, contribute, to, phenotypic, diversity, and, disease, progression])].
[sujeto(['A', 'meta-analysis', from, two, large, cohorts, of, current, and, former, smokers, with, and, without, 'COPD', '[', 'SPIROMICS', '(', 'N', =, 750, ')', ;, 'COPDGene', '(', 'N', =, 590, ')', ']', was, used, to, identify, single, nucleotide, polymorphisms, '(', 'SNPs)']), verbo([associated]), complemento([with, measurement, of, 88, blood, proteins, '(', protein, quantitative, trait, 'loci;', 'pQTLs)'])].
[sujeto(['Features', of, pQTLs, were, compared, to, previously]), verbo([reported]), complemento([expression, 'QTLs', '(', 'eQTLs)'])].
[sujeto(['The', pQTL, 'SNPs', explained, &, 'gt;10%', of, measured, variation, in, 13, protein, 'biomarkers,', with, a, single, 'SNP', '(', 'rs7041;', p, =, 10, -, 392, ')', explaining, 71, '%', -, 75, '%', of, the, measured, variation, in, vitamin, 'D']), verbo([binding]), complemento([protein, '(', gene, =, 'GC)'])].
[sujeto([',', pQTLs, for, 'VDBP,', sRAGE, '(', gene, =, 'AGER),', surfactant, protein, 'D', '(', gene, =, 'SFTPD),', and, 'TNFRSF10C]']), verbo([have]), complemento([been, previously, associated, with, 'COPD', phenotypes])].
[sujeto(['Causal', modeling]), verbo([provided]), complemento([insight, into, specific, 'pQTL-disease', relationships, for, airflow, obstruction, and, emphysema])].
[sujeto(['Disagreement', exists, regarding, the, 'O-glycan', structure, attached, to, human, vitamin, 'D']), verbo([binding]), complemento([protein, '(', 'DBP)'])].
[sujeto(['Previously']), verbo([reported]), complemento([evidence, indicated, that, the, 'O-glycan', of, the, 'Gc1S', allele, product, is, the, linear, core, 1, 'NeuNAc-Gal-GalNAc-Thr', trisaccharide])].
[sujeto(['Here,', glycan, structural, evidence, is]), verbo([provided]), complemento([from, glycan, linkage, analysis, and, over, 30, serial, 'glycosidase-digestion', experiments, which, were, followed, by, analysis, of, the, intact, protein, by, electrospray, ionization, mass, spectrometry, '(', 'ESI-MS)'])].
[sujeto(['Results', demonstrate, that, the, 'O-glycan', from, the, 'Gc1F', protein, is, the, same, linear, trisaccharide]), verbo([found]), complemento([on, the, 'Gc1S', protein, and, that, the, hexose, residue, is, galactose])].
[sujeto(['In', 'addition,', the, putative, 'anti-cancer', derivative, of, 'DBP', known, as, 'Gc', 'Protein-derived', 'Macrophage', 'Activating', 'Factor', '(', 'GcMAF,', which, is, formed, by, the, combined, action, of, 'β-galactosidase', and, neuraminidase, upon, 'DBP)', was, analyzed, intact, by, 'ESI-MS,']), verbo([revealed]), complemento([that, the, activating, 'E'])].
[sujeto(['Moreover,', glycosidase, digestion, results, show, that, 'α-N-Acetylgalactosamindase', '(', 'nagalase)', lacks, endoglycosidic, function, and, only, cleaves, the, 'DBP', 'O-glycan', once, it]), verbo([has]), complemento([been, trimmed, down, to, a, 'GalNAc-Thr', 'monosaccharide-precluding', the, possibility, of, this, enzyme, removing, the, 'O-glycan', trisaccharide, from, 'cancer-patient', 'DBP', 'in&nbsp;vivo'])].
[sujeto(['Improvements', in, longevity, could]), verbo([increase]), complemento([the, average, number, of, lactations, per, 'cow,', thereby, affecting, the, profitability, of, the, dairy, cattle, industry])].
[sujeto(['Using', 'whole-genome', sequencing, variants, in, 3, dairy, cattle, 'breeds,', we, carried, out, an, association, study, and, identified, 7, genomic, regions, in, 'Holstein', and, 5, regions, in, 'Red', 'Dairy', 'Cattle', that, were]), verbo([associated]), complemento([with, longevity])].
[sujeto(['META-CHR18-58MB', overlaps, with, zinc, finger, protein, 717, '(', 'ZNF717;', 58, ',', 130, ',', 465, -, 58, ',', 141, ',', 877, 'bp)', and, zinc, finger, protein, 613, '(', 'ZNF613;', 58, ',', 115, ',', 782, -, 58, ',', 117, ',', 110, 'bp),', which]), verbo([have]), complemento([been, associated, with, calving, difficulties])].
[sujeto(['Information', on, 'longevity-associated', genomic, regions, could, be, used, to]), verbo([find]), complemento([causal, 'genes/variants', influencing, longevity, and, exploited, to, improve, the, reliability, of, genomic, prediction])].
[sujeto(['Vitamin', 'D', deficiency, is]), verbo([suggested]), complemento([to, be, associated, with, 'Parkinson\'s', disease, '(', 'PD)'])].
[sujeto(['Our', aim, was, to, investigate, the, serum, 25, -, hydroxyvitamin, 'D3', '(', 25, 'OHD)', levels, of, 'PD', patients, in, 'Turkish', 'cohort,', to, investigate, any, association, of, vitamin, 'D']), verbo([binding]), complemento([protein, '(', 'GC)', genotypes, with, 'PD', due, to, the, significant, role, of, 'GC', in, vitamin, 'D', 'transport,', to, determine, whether, vitamin, 'D', receptor, '(', 'VDR)', haplotype, that, we, previously, demonstrated, to, be, a, risk, haplotype, for, 'AD', is, also, a, common, haplotype, for, 'PD', and, to, investigate, any, relevant, consequence, of, serum, 25, 'OHD', 'levels,', 'GC', or, 'VDR', genotypes, on, clinical, features, of, 'PD'])].
[sujeto([rs7041, of, 'GC', and, 'ApaI', of, 'VDR', were]), verbo([associated]), complemento([with, the, 'PD', risk, '(', 'p&nbsp;&lt;&nbsp;0'])].
[sujeto(['The', relationship, between, 'PD\'s', clinical, features, and, low, 25, 'OHD', or, risk, genotypes, might]), verbo([have]), complemento([effects, on, 'PD', independently])].
[sujeto(['Studies', using, vitamin, 'D-binding', protein, '(', 'DBP)', concentrations, to, estimate, free, and, bioavailable, vitamin, 'D']), verbo([have]), complemento([increased, dramatically, in, recent, years])].
[sujeto(['In', chronic, obstructive, pulmonary, disease, '(', 'COPD),', the, blood, vitamin, 'D3', level, is, generally, 'low,', and, genetic, polymorphisms, of, vitamin, 'D-binding', protein, encoded, by, the, 'GC', gene, are]), verbo([associated]), complemento([with, 'COPD', development])].
[sujeto(['Among', 'COPD', clinical, 'parameters,', vitamin, 'D', deficiency, was]), verbo([associated]), complemento([with, a, lower, ratio, of, forced, expiratory, volume, in, 1, second, to, forced, vital, capacity, '(', 'FEV1/FVC)', regardless, of, 'GC', polymorphisms])].
[sujeto(['Whether', this, difference, holds, for, free, 25, 'OHOD', '(', 'f25OHD)', is, 'unclear,', considering]), verbo([reported]), complemento(['genetic-racial', differences, in, vitamin, 'D', binding, protein, '(', 'DBP)', used, to, calculate, f25OHD])].
[sujeto(['Previously']), verbo([reported]), complemento([racial, differences, in, 'DBP', concentration, are, likely, from, monoclonal, assay, 'bias,', as, there, was, no, racial, difference, in, 'DBP', concentration, by, other, methods])].
[sujeto(['Although', 'glucagon-secreting', 'α-cells', and, 'insulin-secreting', 'β-cells']), verbo([have]), complemento([opposing, functions, in, regulating, plasma, glucose, 'levels,', the, two, cell, types, share, a, common, developmental, origin, and, exhibit, overlapping, transcriptomes, and, epigenomes])].
[sujeto(['Notably,', destruction, of, 'β-cells', can]), verbo([stimulate]), complemento([repopulation, via, transdifferentiation, of, 'α-cells,', at, least, in, 'mice,', suggesting, plasticity, between, these, cell, fates])].
[sujeto(['Furthermore,', dysfunction, of, both, 'α-', and, 'β-cells', contributes, to, the, pathophysiology, of, type, 1, and, type, 2, 'diabetes,', and, 'β-cell', 'de-differentiation']), verbo([has]), complemento([been, proposed, to, contribute, to, type, 2, diabetes])].
[sujeto(['Our', objective, was, to, delineate, the, molecular, properties, that]), verbo([maintain]), complemento([islet, cell, type, specification, 'yet&nbsp;allow', for, cellular, plasticity])].
[sujeto(['We', hypothesized, that, correlating, cell, 'type-specific', transcriptomes, with, an, atlas, of, open, chromatin, will, identify, novel, genes, and, transcriptional, regulatory, elements, such, as, enhancers]), verbo([involved]), complemento([in, 'α-', and, 'β-cell', specification, and, plasticity])].
[sujeto(['The', &, 'quot;group', specific, 'protein&quot;', '(', 'GC;', or, vitamin, 'D']), verbo([binding]), complemento(['protein)', was, restricted, to, 'α-cells,', while, 'CHODL', '(', 'chondrolectin)', immunoreactivity, was, only, present, in, 'β-cells'])].
[sujeto(['Furthermore,', 'α-cell-', and, 'β-cell-selective', 'ATAC-seq', peaks, were, identified, to, overlap, with, known]), verbo([binding]), complemento([sites, for, islet, transcription, 'factors,', as, well, as, with, single, nucleotide, polymorphisms, '(', 'SNPs)', previously, identified, as, risk, loci, for, type, 2, diabetes])].
[sujeto(['We']), verbo([have]), complemento([determined, the, genetic, landscape, of, human, 'α-', and, 'β-cells', based, on, chromatin, accessibility, and, transcript, 'levels,', which, allowed, for, detection, of, novel, 'α-', and, 'β-cell', signature, genes, not, previously, known, to, be, expressed, in, islets])].
[sujeto(['Using', 'fine-mapping', of, open, 'chromatin,', we]), verbo([have]), complemento([identified, thousands, of, potential, 'cis-regulatory', elements, that, operate, in, an, endocrine, cell, 'type-specific', fashion])].
[sujeto(['Insulin', resistance, '(', 'IR)', is]), verbo([found]), complemento([in, chronic, hepatitis, 'C', '(', 'CHC)', more, frequently, than, in, other, chronic, liver, diseases])].
[sujeto(['After', backward, logistic, regression, 'analysis,', independent, variables]), verbo([associated]), complemento([with, 'IR', were, 'Gc1s/Gc1s', 'DBP', 'phenotype,', that, results, from, the, homozygous, carriage, of, the, 'rs7041G/rs4588C', haplotype, '(', 'P', =, 0.033, ')', ;, low, 'retinol/RBP4', 'ratio,', reflecting, a, greater, rate, of, unbound, 'RBP4', '(', 'P', =, 0.005, ')', ;, older, age, '(', 'P', =, 0.01, ')', ;, high, serum, tryglicerides, '(', 'P', =, 0.026, ')', ;, and, advanced, '(', 'F3-F4)', fibrosis, stage])].
[sujeto(['The', 'AUROC']), verbo([provided]), complemento([by, the, multivariate, model, was, 0.95, '(', 95, '%', 'CI', =, 0.906, -, 0.993, ')'])].
[sujeto(['The', gene, '(', 'GC)', for, the, vitamin, 'D']), verbo([binding]), complemento([protein, '(', 'DBP)', shows, significant, genetic, variation])].
[sujeto(['However,', less, common, 'variants,', identified, 'biochemically,']), verbo([have]), complemento([been, reported, previously])].
[sujeto(['Loss', of, a, disulfide, bond, due, to]), verbo([loss]), complemento([of, 'cysteine-311', was, accompanied, by, the, appearance, of, a, novel, mixed, disulfide, 'species,', consistent, with, 'S-cysteinylation', of, the, remaining, unpaired, 'cysteine-299', in, the, mutant, protein])].
[sujeto(['Previous', studies]), verbo([have]), complemento([produced, inconsistent, results, regarding, the, contribution, of, 'single-nucleotide', polymorphisms, '(', 'SNPs)', in, the, vitamin, 'D', receptor, '(', 'VDR)', gene, to, ovarian, cancer, '(', 'OC)', in, various, ethnicities])].
[sujeto(['Additionally,', little]), verbo([has]), complemento([been, established, with, regard, to, the, role, of, 'SNPs', located, in, the, retinoid, 'X', receptor, α, '(', 'RXRA),', vitamin, 'D-binding', protein, '[', also, know, as, 'group-specific', component, '(', 'GC)]', and, 'VDR', genes, in, 'non-carriers', of, the, breast, cancer, 1, /, 2, early, onset, '(', 'BRCA1/BRCA2)', gene, mutations])].
[sujeto(['All']), verbo([participating]), complemento([individuals, in, the, present, study, were, evaluated, for, 'BRCA1', mutations, '(', 5382, 'incC,', 'C61G', and, 4153, 'delA)', with, 'HybProbe', 'assays,', and, for, 'BRCA2', mutation, '(', 5946, 'delT)', using, 'high-resolution', melting, '(', 'HRM)', analysis])].
[sujeto(['It', was, also]), verbo([found]), complemento(['that,', in, the, dominant, inheritance, 'model,', 'VDR', 'BsmI', contributed, to, an, increased, risk, of, 'OC', '[', odds, ratio, '(', 'OR),', 1.57, ;, 95, '%', confidence, interval, '(', 'CI),', 1.136, -, 2.171, ;, 'P=0'])].
[sujeto(['We', investigated, a, possible, association, between, polymorphisms, in, vitamin, 'D']), verbo([binding]), complemento([protein, '(', 'GC)', and, vitamin, 'D', receptor, '(', 'VDR)', genes, and, obesity, in, 'Bahraini', adults])].
[sujeto(['We']), verbo([found]), complemento([that, the, rs7041, minor, allele, '(', 'G)', and, rare, genotype, '(', 'GG)', were, associated, with, higher, 'BMI', '(', p, =, 0.007, and, p, =, 0.012, ',', 'respectively),', but, they, did, not, influence, 25, 'OHD3', levels])].
[sujeto(['However,', the, minor, alleles, of, rs2282679, '(', 'A)', and, rs4588, '(', 'C)', were]), verbo([associated]), complemento([with, low, 25, 'OHD3', plasma, levels, '(', p, =, 0.039, and, p, =, 0.021, ',', 'respectively),', but, not, with, 'BMI'])].
[sujeto(['Having', categorized, the, subjects, based, on, their, 'sex,', we]), verbo([found]), complemento([that, '(', 'i)', rs7041, 'GG', associated, with, high, 'BMI', in, females, '(', p, =, 0.003, ')', ',', '(', 'ii)', rs4588, 'CC', associated, with, high, 'BMI', in, females, '(', p, =, 0.034, ')', and, low, 25, 'OHD3', levels, in, males, '(', p, =, 0.009, ')', ',', and, '(', 'iii)', rs12721377, 'AA', associated, with, low, 25, 'OHD3', levels, in, females, '(', p, =, 0.039, ')'])].
[sujeto(['Notably,', none, of, the, common, haplotypes, '(', 6, in, the, 'GC', gene, and, 3, in, the, 'VDR', 'gene)', were]), verbo([associated]), complemento([with, 'BMI'])].
[sujeto(['Therefore,', polymorphisms, in, the, 'GC', '(', 'rs2282679,', 'rs4588,', 'rs7041)', and, 'VDR', '(', 'rs12721377)', genes, were, independently]), verbo([associated]), complemento([with, obesity, and, 25, 'OHD3', levels, with, a, clear, sex, dimorphism])].
[sujeto(['Mechanistic', hypotheses]), verbo([suggest]), complemento([that, vitamin, 'D', may, contribute, to, the, prevention, of, breast, cancer])].
[sujeto(['However,', epidemiologic, evidence, is, 'inconsistent,']), verbo([suggesting]), complemento([a, potential, effect, modification, by, individual, factors])].
[sujeto(['MAX)', cohort, '(', 1994, -, 2007, ')', ',']), verbo([involving]), complemento([233, women, with, breast, cancer, and, 466, matched, controls, '(', mean, ±, 'SD', 'age:', 49, ±, 6, 'y)'])].
[sujeto(['A', higher, plasma, 25, '(', 'OH)D', concentration, was]), verbo([associated]), complemento([with, a, decreased, risk, of, breast, cancer, for, women, with, a, 'BMI', &, 'lt;', the, median, of, 22.4, '[', 'OR', quartile, '(', 'Q)4', compared, with, 'Q1:', 0.46, ;, 95, '%', 'CI:', 0.23, ',', 0.89, ;, 'P-trend', =, 0.01, ',', 'P-interaction', =, 0.002, ']', ',', whereas, it, was, associated, with, an, increased, risk, for, women, with, a, 'BMI', '≥', the, median, '(', 'OR', 'Q4', compared, with, 'Q1:', 2.45, ;, 95, '%', 'CI:', 1.13, ',', 5.28, ;, 'P-trend', =, 0.02, ',', 'P-interaction', =, 0.002, ')'])].
[sujeto(['A', plasma, 25, '(', 'OH)D', concentration, '≥', 10, 'ng/mL', was]), verbo([associated]), complemento([with, a, decreased, risk, of, breast, cancer, for, women, with, alcohol, intakes, '≥', the, median, of, 7.1, 'g/d', '(', 'OR', '≥10', compared, with, &, 'lt;10', 'ng/mL:', 0.5, ;, 95, '%', 'CI:', 0.26, ',', 0.95, ;, 'P', =, 0.03, ',', 'P-interaction', =, 0.03, ')'])].
[sujeto(['These', effect, modifications]), verbo([suggest]), complemento([explanations, for, discrepancies, in, results, of, previous, studies])].
[sujeto(['With', the, current, developments, on, novel, therapeutic, strategies, for, 'DMD,', the, need, to, carefully, monitor, disease, progression, or, regression, upon, treatment, using, molecular, markers]), verbo([has]), complemento([become, urgent])].
[sujeto(['Previously']), verbo([reported]), complemento(['biomarkers,', such, as, 'muscle-derived', 'titin,', 'myosin,', and, carbonic, anhydrase, 'I', '(', 'CA1),', were, verified])].
[sujeto(['MS-based', results, were, compared, with, 'ELISA', for, vitamin, 'D']), verbo([binding]), complemento([protein, '(', 'GC),', 'fibulin-1', '(', 'FBLN1),', gelsolin, '(', 'GSN),', and, carbonic, anhydrase, 1, '(', 'CA1)'])].
[sujeto(['With', these, data, promising, candidate, biomarkers]), verbo([have]), complemento([been, identified, for, a, rare, genetic, disease, using, serum, proteome, analysis])].
[sujeto(['This', study, was, a, 'cross-sectional', design, that, assessed, the, associations, of, traditional, diet, '(', via, a, 'biomarker,', the, 'RBC', 'δ(15)N', 'value),', 'age,', 'gender,', body, mass, index, '(', 'BMI),', community, 'location,', and, genotype, of, select, single, nucleotide, polymorphisms, '(', 'SNPs)', in, cytochrome, 'P450', family, 2, ',', subfamily, 'R,', peptide, 1, '(', 'CYP2R1),', 7, -, dehydrocholesterol, reductase, '(', 'DHCR7),', and, vitamin, 'D']), verbo([binding]), complemento([protein, '(', 'GC)', with, serum, 25, '(', 'OH)D3', concentrations, in, 743, 'Yup\'ik', male, and, female, 'participants,', aged, 14, -, 93, 'y,', recruited, between, 'September', 2009, and, 'December', 2013])].
[sujeto(['Variations', in, 'diet,', 'BMI,', 'age,', 'gender,', season, of, sample, 'collection,', and, inland, or, coastal, community, geography, were, all, significantly]), verbo([associated]), complemento([with, serum, 25, '(', 'OH)D3', concentration])].
[sujeto(['Of', the, 8, 'SNPs', interrogated, in, 'CYP2R1', and, 'DHCR7,', only, rs11023374, in, 'CYP2R1', was, significantly]), verbo([associated]), complemento([with, serum, 25, '(', 'OH)D3,', explaining, 1.5, '%', of, variability])].
[sujeto(['Lower', consumption, of, the, traditional, diet, was]), verbo([associated]), complemento([with, lower, serum, concentrations, of, 25, '(', 'OH)D3'])].
[sujeto(['Younger', adults, and, youth, in, this, community, may, be, at]), verbo([increased]), complemento([risk, of, adverse, outcomes, associated, with, vitamin, 'D', insufficiency, compared, with, older, members, of, the, 'community,', especially, during, seasons, of, low, sunlight, 'exposure,', because, of, lower, consumption, of, dietary, sources, of, vitamin, 'D'])].
[sujeto(['Genetic', polymorphisms, in, vitamin, 'D', metabolism, and, signaling, genes]), verbo([have]), complemento([been, inconsistently, associated, with, risk, of, breast, 'cancer,', though, few, studies, have, examined, 'SNPs', in, vitamin, 'D-related', genes, other, than, the, vitamin, 'D', receptor, '(', 'VDR)', gene, and, particularly, have, not, examined, the, association, with, the, retinoid, 'X', receptor, alpha, '(', 'RXRA)', gene, which, may, be, a, key, vitamin, 'D', pathway, gene])].
[sujeto(['SNPs', in, the, 'CYP2R1,', 'DHCR7,', and, 'VDBP', gene, regions, that, were]), verbo([associated]), complemento([with, circulating, 25, '(', 'OH)D', concentration, in, 'GWAS', were, also, associated, with, plasma, 25, '(', 'OH)D', in, our, study, '(', 'p-trend', &, 'lt;0'])].
[sujeto(['After', taking, into, account, the, false, discovery, 'rate,', these, 'SNPs', were, not, significantly]), verbo([associated]), complemento([with, breast, cancer, 'risk,', nor, were, any, of, the, other, 'SNPs', or, haplotypes, in, 'VDR,', 'RXRA,', and, 'CYP24A1'])].
[sujeto(['We', undertook, a, 'cross-sectional', study, in, rural, 'Jehlum', and, urban, 'Karachi', to, evaluate, the, prevalence, of, vitamin, 'D', deficiency, in, 'Pakistani', pregnant, women, and, neonates, and, to, assess, any, association, of, serum, 25, '(', 'OH)', vitamin, 'D', '[', 25, '(', 'OH)D]', concentration, with, vitamin, 'D']), verbo([binding]), complemento([protein, '(', 'Gc)', genotypes])].
[sujeto(['Altogether,', 390, women, and, 266, neonates, were]), verbo([recruited]), complemento([from, urban, and, rural, 'sites,', respectively])].
[sujeto(['Gc', genotypes, were, not]), verbo([associated]), complemento([with, serum, 25, '(', 'OH)D', concentrations, in, both, women, and, their, neonates])].
[sujeto(['We', conclude, that, vitamin, 'D', deficiency, is, highly, prevalent, in, 'Pakistani', women, and, their, 'neonates,', and, 'Gc', genotypes, are, not]), verbo([associated]), complemento([with, serum, 25, '(', 'OH)D', concentrations])].
[sujeto(['To', investigate, whether, single, nucleotide, polymorphisms, '(', 'SNPs)', within, 4, representative, genes, '(', 'VDR,', 'GC,', 'CYP2R1,', and, 'CYP24A1)', encoding, the, core, proteins]), verbo([involved]), complemento([in, vitamin, 'D', 'production,', 'degradation,', and, 'ligand-dependent', signaling, pathway, are, associated, with, gestational, diabetes, mellitus, '(', 'GDM)', in, a, 'Chinese', population])].
[sujeto(['A', total, of, 1494, pregnant, 'Han', 'Chinese', women, '(', 692, women, with, 'GDM', and, 802, women, with, normal, glucose, served, as, 'controls)', were]), verbo([recruited]), complemento([through, a, 2, -, step, approach])].
[sujeto(['However,', in, the, obese, subgroup, '(', 'pre-BMI', '≥', 25, 'kg/m2),', the, risk, 'allele-A', of, rs3733359, showed, an, association, with]), verbo([increased]), complemento([risk, of, 'GDM', '(', 'OR', =, 1.739, ',', 95, '%', 'CI', =, 1.066, -, 2.837, ',', 'P', =, 0.027, ')'])].
[sujeto(['Rs2060793', and, rs10741657, were]), verbo([associated]), complemento([with, insulin, area, under, the, curve, '(', 'P', =, 0.028, ',', 'P', =, 0.042, ',', 'respectively),', while, rs739837, and, rs6013897, demonstrated, a, correlation, with, fasting, glucose, '(', 'P', =, 0.019, ',', 'P', =, 0.049, ',', 'respectively)'])].
[sujeto(['Our', findings, may]), verbo([provide]), complemento([information, for, identifying, biomarkers, for, early, risk, prediction, of, 'GDM', and, the, pathways, involved, in, disease, progression])].
[sujeto(['Bioactive', vitamin, 'D', is, a, steroid, hormone, transported, in, blood, via, the, vitamin, 'D']), verbo([binding]), complemento([protein, '(', 'DBP)'])].
[sujeto(['Four', allelic, versions, of, the, 'GC', gene, were, 'observed,', one, of, 'which,', 'GC*3,', was, encountered, for, the, first, time, in, this, 'study,', and, was]), verbo([found]), complemento([to, be, associated, with, both, normal, vitamin, 'D', and, high, 'DBP', levels])].
[sujeto(['The', genotype, 'group-specific', component, '(', 'GC)*1F-1F', was, significantly]), verbo([associated]), complemento([with, 'COPD', in, 'Asians', '[', odds, ratio, '(', 'OR)', =, 1.73, ',', 95, '%', confidence, interval, '(', 'CI)', =, 1.07, -, 2.81, ',', 'P', =, 0.03, ']', ',', but, not, in, 'Caucasians', '(', 'OR', =, 1.44, ',', 95, '%', 'CI', =, 0.57, -, 3.66, ',', 'P', =, 0.45, ')'])].
[sujeto(['The', genotype, 'GC*1F-1F', or, allele, 'GC*1F', was]), verbo([associated]), complemento([with, increased, susceptibility, to, 'COPD', in, 'Asians'])].
[sujeto(['Imaging', 'methods,', such, as, joint, and, color, duplex, 'sonography,', magnetic, resonance, imaging, '(', 'MRI)', and, positron, emission, tomography, '(', 'PET)', nowadays, facilitate, the, diagnosis, of, polymyalgia, rheumatica, and, large, vessel, vasculitides, and]), verbo([have]), complemento([now, been, included, in, the, new, classification, criteria])].
[sujeto(['Antibodies', against, tumor, necrosis, factor, alpha, '(', 'TNF', 'alpha)', were, ineffective, for, polymyalgia, rheumatica, and, 'GCA', in, 'placebo-controlled', trials, but, data, from, open, label, studies]), verbo([suggested]), complemento([some, efficacy, in, refractory, 'TA'])].
[sujeto(['This']), verbo([causes]), complemento([weakening, 'and,', in, case, of, severe, 'infestation,', death, of, the, tree])].
[sujeto(['We']), verbo([report]), complemento([identification, of, the, sex, pheromone, produced, by, females, of, this, species])].
[sujeto(['Oral,', 'intraperitoneal,', or, intravenous]), verbo([have]), complemento([been, the, common, routes, of, administration, used, to, study, the, behavioral, and, neurochemical, pharmacology, of, 'caffeine,', one, of, the, most, widely, used, psychoactive, substances, worldwide])].
[sujeto(['We']), verbo([have]), complemento([reported, that, caffeine, is, an, active, adulterant, frequently, found, in, 'coca-paste', '(', 'CP)-seized', 'samples,', a, highly, addictive, form, of, smokable, cocaine])].
[sujeto(['The', role, of, caffeine, in, the, psychostimulant, and, neurochemical, effects]), verbo([induced]), complemento([by, 'CP', remains, under, study])].
[sujeto(['No', preclinical, animal, studies]), verbo([have]), complemento([been, performed, so, far, to, characterize, the, effects, of, caffeine, when, it, is, administered, through, the, pulmonary, inhalation, route])].
[sujeto(['Caffeine', capability, '(', 50, &, 'nbsp;mg)', to]), verbo([increase]), complemento([extracellular, dopamine, '(', 'DA)', levels, in, nucleus, accumbens, shell, was, also, studied, by, in, vivo, microdialysis, in, 'non-anesthetized', animals])].
[sujeto(['A', 'dose-dependent', stimulant, effect]), verbo([induced]), complemento([by, volatilized, caffeine, was, observed, and, this, effect, was, directly, related, with, caffeine, plasmatic, levels])].
[sujeto(['A', significant]), verbo([increase]), complemento([in, the, extracellular, 'DA', was, achieved, after, 50, &, 'nbsp;mg', of, volatilized, caffeine, exposure])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([showing, pharmacological, acute, effects, of, caffeine, through, the, pulmonary, inhalation, route, of, administration, and, suggests, that, this, could, be, a, condition, under, which, caffeine, can, elevate, its, weak, reinforcing, effect, and, even, enhance, the, psychostimulant, effect, and, abuse, liability, of, smokable, adulterated, psychostimulant, drugs])].
[sujeto(['There', were, no, differences, in, the, baseline, information, among, the, 5, groups, '(', 'P', &, 'gt;', 0.05, ')', ',', and, the, proportion, of, advanced, 'GC', patients, with, 'LADG', slightly]), verbo([increased]), complemento([from, 58.7, '%', to, 77.4, '%', during, the, 6, years])].
[sujeto(['In', 'addition,', the, operation, time]), verbo([decreased]), complemento([from, 299.2, to, 267.8, 'minutes,', while, the, estimated, blood, loss, dropped, from, 175.2, to, 146.8, mL])].
[sujeto(['However,', no, difference, on, overall, survival, was]), verbo([found]), complemento([among, these, 5, 'groups,', and, multivariate, analysis, indicated, that, 'factors,', such, as, 'age,', tumor, 'differentiation,', tumor, 'size,', and, 'T', stage, as, well, as, 'N', 'stage,', were, independent, prognostic, factors, for, patients, with, 'LADG'])].
[sujeto(['The', prevalence, of, gastric, cancer, '(', 'GC)', with, high, level, of, serum, 'AFP', is, extremely, 'rare,', but]), verbo([has]), complemento([unique, clinical, features])].
[sujeto(['With', the, progression, of, 'disease,', the, tumor, widely, metastasized, and, the, serum, 'AFP', level]), verbo([increased]), complemento([progressively, with, the, highest, level, of, 3396, 'ng/mL'])].
[sujeto(['She', successively, entered, into, 3, lines, palliative, systematic, chemotherapy, and, 'fourth-line']), verbo([targeted]), complemento([therapy, of, 'apatinib,', a, small, molecule, tyrosine, kinase, inhibitor, targeting, vascular, endothelial, growth, factor, 'receptor-2'])].
[sujeto(['Although', previous, studies]), verbo([suggested]), complemento([that, the, prognosis, of, this, special, type, of, 'GC', was, 'poor,', this, patient, lived, for, 22, months, after, tumor, transfer])].
[sujeto(['Teachers']), verbo([reported]), complemento([a, decrease, of, 'ADHD', symptoms, on, all, measures, for, 'methylphenidate,', but, not, for, neurofeedback, or, physical, activity, '(', range, of, 'ηp²', =, 0.14, -, 0.29, ',', 'P', &, 'lt;'])].
[sujeto(['The', current, study]), verbo([found]), complemento([that, optimally, titrated, methylphenidate, is, superior, to, neurofeedback, and, physical, activity, in, decreasing, 'ADHD', symptoms, in, children, with, 'ADHD'])].
[sujeto(['Recent', studies]), verbo([have]), complemento([recognized, the, 'ATPase-encoding', comM, gene, as, a, hot, spot, for, the, integration, of, 'Acinetobacter', baumannii, resistance, islands, '(', 'RIs)'])].
[sujeto(['This', study, demonstrated, that, the, comM, gene, is]), verbo([targeted]), complemento([by, transposons, in, 'Iranian', 'MDR-AB', isolates, belonging, to, different, 'GCs'])].
[sujeto(['Few', studies]), verbo([have]), complemento([addressed, resin, bonding, to, primary, teeth])].
[sujeto(['No', significant, morphological, or, genetic, differences, were]), verbo([associated]), complemento([with, the, species, of, the, intermediate, host])].
[sujeto(['The', phylogenetic, analysis]), verbo([suggests]), complemento([that, all, variants, of, 'T'])].
[sujeto([multiceps, can]), verbo([cause]), complemento([cerebral, coenurosis, in, sheep, '(', which, may, be, the, ancestral, 'phenotype),', and, some, 'variants,', predominantly, from, one, genetic, 'cluster,', acquired, the, additional, capacity, to, produce, 'non-cerebral', forms, in, goats, and, more, rarely, in, sheep])].
[sujeto(['Cushing\'s', disease, '(', 'CD),', a, state, of, chronic, glucocorticoid, '(', 'GC)', excess, characterized, by, visceral, obesity, and, insulin, 'resistance,', may, be]), verbo([associated]), complemento([with, increased, systemic, inflammation])].
[sujeto(['It', is, unclear, if, a, chronic, low, grade, inflammatory, state, persists, even, after, remission, of, 'CD,', which, may, account, for, the]), verbo([increased]), complemento(['CVD', mortality])].
[sujeto([5, ')', ',', and, remained, elevated, in, 'CD', after, surgical, 'remission,', despite]), verbo([decreases]), complemento([in, 'BMI', '(', 'p&lt;0'])].
[sujeto(['Despite', 'long-term', remission, and, improvements, in, fat, distribution, and, insulin, 'sensitivity,', patients, with, 'CD', may, suffer, from, a, state, of, chronic, 'low-grade', 'inflammation,', which, could, contribute, to]), verbo([increased]), complemento([cardiovascular, mortality])].
[sujeto(['Chemotherapy', failure, eventually]), verbo([led]), complemento([to, uncontrollable, neurological, symptoms])].
[sujeto(['We', determine, whether, 'Dorper', rams, treated, with, testosterone, in, the, sexual, resting, season]), verbo([trigger]), complemento([both, appetitive, and, consummatory, sexual, behaviors, and, sexual, and, reproductive, outcomes, in, anestrous, ewes, at, 26, °, 'North', during, 'March-April'])].
[sujeto(['Results', confirm, that, adult, 'Dorper', rams, treated, with, exogenous, testosterone, had, improved, consummatory, sexual, behavior, and]), verbo([induced]), complemento([increased, ovulation, and, pregnancy, rates, when, exposed, to, anestrus, ewes])].
[sujeto(['This', feasible, and, inexpensive, 'testosterone-based', protocol, through, the, male, effect, also]), verbo([enhanced]), complemento([both, sexual, and, reproductive, outcomes, in, previously, anestrous, 'Dorper', ewes, during, the, natural, 'out-of-season'])].
[sujeto(['Antibodies', against, programmed, death, 1, '(', 'PD-1)', and, its, ligand, programmed, death, 'ligand&nbsp;1', '(', 'PD-L1)']), verbo([have]), complemento([recently, demonstrated, promising, results, in, gastric, cancer, '(', 'GC)'])].
[sujeto(['PD-L1', 'expression,', the, presence, of, 'tumor-infiltrating', lymphocytes, '(', 'TILs),', and, mismatch, repair, '(', 'MMR)', deficiency]), verbo([have]), complemento([been, proposed, as, predictive, biomarkers, for, 'anti-PD-1/PD-L1', antibodies])].
[sujeto(['In', 'GC,', 'PD-L1', expression, was]), verbo([associated]), complemento([with, distinct, clinicopathological, 'features,', including, high, densities, of, 'TILs,', 'MMR', 'deficiency,', and, 'EBV', 'positivity,', but, was, not, a, prognostic, factor])].
[sujeto(['Cell', cycle, control]), verbo([involving]), complemento([retinoblastoma, 1, '(', 'RB1)', gene, is, one, of, the, main, regulatory, pathways, reported, to, be, altered, in, gastric, carcinogenesis])].
[sujeto([pylori, positive, individuals, may]), verbo([suggest]), complemento([an, elevated, risk, of, gastric, cancer, occurrence])].
[sujeto(['Semi-quantitative', characteristics, of, head, space, volatile, pyrazines, which, constituted, around, 1, '%', by, weight, of, the, final, product]), verbo([have]), complemento([been, previously, described])].
[sujeto(['The', influence, of, reactant, 'concentration,', reaction, 'temperature,', and, reaction, time, on, both, the, yield, of, total, alkyl, pyrazines, and, the, distribution, pattern, of, specific, identified, pyrazines]), verbo([has]), complemento([not, been, reported])].
[sujeto(['The', greatest, total, amount, of, pyrazines, obtained, was, 17, ',', 280, µg, of, extracted, product, which]), verbo([translated]), complemento([into, 31, '%', 2, ',', 6, -, 'Dimethyl', 'Pyrazine,', 17, '%', 2, -, 'Methyl', 'Pyrazine,', 15, '%', 2, -, 'Ethyl-6', 'Methyl', 'Pyrazine,', and, 16, '%', 2, -, 'Isoamyl-6-Methyl', 'Pyrazine'])].
[sujeto(['The', yield, of, synthesized, pyrazines]), verbo([increased]), complemento([at, higher, temperatures])].
[sujeto(['The', acetone, partition, coefficient]), verbo([decreased]), complemento([as, either, acetone, or, water, was, added, to, the, 'HPMCAS-L'])].
[sujeto(['A', representation, of, the, 'HPMCAS-L', structure, in, terms, of, 'UNIFAC', groups]), verbo([has]), complemento([been, developed])].
[sujeto(['A', simultaneous, method, for, quantifying, eight, metabolites, of, organophosphate, pesticides, and, pyrethroid, pesticides, in, urine, samples]), verbo([has]), complemento([been, established])].
[sujeto(['This', 'efficient,', 'stable,', and, 'cost-effective', method, is, adequate, to, handle, the, large, number, of, samples]), verbo([required]), complemento([for, surveying, the, exposure, level, of, organophosphorus, and, pyrethroid, pesticides, in, the, general, population])].
[sujeto(['For', an, 'example,', the, 'SFE-sample']), verbo([expressed]), complemento([relatively, stronger, fumigant, toxicity, on, 'Lasioderma', serricorne, adults, '(', 'LC50', =, 3.99, 'μg/mL', 'air)', than, that, of, the, 'HD-sample', '(', 'LC50', =, 12.54, 'μg/mL', 'air)'])].
[sujeto(['This', work]), verbo([provides]), complemento([theoretical, basis, for, traditional, 'Chinese', concept, of, antagonistic, 'storage,', and, it, also, provides, important, information, for, the, development, and, comprehensive, utilization, of, 'Zanthoxylum', bungeanum])].
[sujeto(['There', is, only, a, couple, of]), verbo([reports]), complemento([indicating, essential, oil, composition, of, 'Asphodelus', species, in, the, literature])].
[sujeto([can, be]), verbo([found]), complemento([abundantly, in, all, regions, of, the, island])].
[sujeto(['This', plant]), verbo([has]), complemento([various, ethnobotanical, uses, in, 'Cyprus'])].
[sujeto(['There', is, no]), verbo([report]), complemento([on, the, volatiles, nor, the, essential, oil, composition, of, 'A'])].
[sujeto(['Therefore,', we]), verbo([have]), complemento([carried, out, 'GC,', 'GC/MS', analysis, of, the, essential, oil, '(', 'yield:', 0.01, 'v/w)', obtained, from, 'Asphodelus', aestivus, flowers])].
[sujeto(['According', to, the]), verbo([binding]), complemento([mode, of, 14, -, 'epi-1α,25-dihydroxy-19-nortachysterol', in, the, ligand, binding, domain, of, human, vitamin, 'D', receptor, '(', 'hVDR),', i])].
[sujeto(['The', 'A-ring', and, 'CD-ring', precursors, for, the, 'Julia-Kociensky', coupling, reaction, to, create, a, diene, system, of, the]), verbo([target]), complemento([molecules, were, prepared, using, our, original, methods])].
[sujeto([hVDR]), verbo([binding]), complemento([affinity, and, osteocalcin, promoter, transactivation, activity, of, the, new, 7, ',', 8, -, 'cis-14-epi-vitamin', 'D3', analogs, were, evaluated])].
[sujeto(['Patients', undergoing, elective, spinal, fusion]), verbo([have]), complemento([an, alarming, rate, of, vitamin, 'D', 'deficiency,', but, its, impact, on, bone, fusion, and, patient, outcomes, is, unclear])].
[sujeto(['We', investigated, the, association, of, perioperative, vitamin, 'D', 'levels,', fusion, 'rates,', and, 'patient-']), verbo([reported]), complemento([outcome, in, patients, undergoing, spinal, fusion, for, cervical, spondylotic, myelopathy])].
[sujeto(['There', were, no, differences, in, mean, time, to, fusion, between, the, two, 'groups,', but, patients, with, low, vitamin, 'D']), verbo([reported]), complemento([more, postoperative, disability, '(', 'p&lt;0'])].
[sujeto(['Low', vitamin, 'D', levels, were]), verbo([associated]), complemento([with, worse, 'patient-reported', outcomes, and, were, an, independent, predictor, of, greater, 'disability,', which, suggests, vitamin, 'D', supplementation, may, offer, some, benefit, in, these, patients])].
[sujeto(['Four']), verbo([reported]), complemento([synthetic, strategies, to, generate, calcitroic, acid, are, presented, that, highlight, the, scientific, progress, in, the, field, of, chemistry, directed, to, vitamin, 'D', analog, synthesis])].
[sujeto(['The', endogenous, formation, of, calcitroic, acid]), verbo([has]), complemento([been, demonstrated, in, perfused, rat, kidney, using, 24, ',', 25, ',', 26, ',', 27, -, 'tetranor-1,23(OH)2D3'])].
[sujeto(['Although,', the, majority, of, vitamin, 'D', metabolism, is]), verbo([mediated]), complemento([by, 24, -, hydoxylase, '(', 'CYP24A1),', it, is, not, clear, why, the, formation, of, calcitroic, acid, was, not, observed, in, the, presence, of, recombinant, 'CYP24A1', enzyme])].
[sujeto(['Only', a, few]), verbo([reports]), complemento([mentioned, the, biological, activity, of, calcitroic, acid, in, connection, with, the, vitamin, 'D', receptor, '(', 'VDR)'])].
[sujeto(['When', administered, 'subcutaneously,', calcitroic, acid]), verbo([has]), complemento([anthracitic, properties, and, elevates, calcium, blood, levels, when, administered, intravenously])].
[sujeto(['In', 'vitro,', calcitroic, acid, at, higher, concentrations]), verbo([has]), complemento([been, shown, to, bind, 'VDR', and, induce, gene, transcription])].
[sujeto(['However,', these, studies, were, not, carried, out, in, cells, derived, from]), verbo([target]), complemento([organs, of, calcitroic, acid, such, as, 'kidney,', 'liver,', and, intestine])].
[sujeto(['AHAMP', was]), verbo([found]), complemento([to, be, present, in, 37, '(', 47.7, '%', ')', patients])].
[sujeto(['In', multivariate, regression, 'analysis,', having, a, normal, body, mass, index, '(', &, 'lt;30', 'kg/m(2)),', cigarette, 'smoking,', and, low, serum, vitamin, 'D', level, '(', 20, 'ng/mL)', were]), verbo([found]), complemento([to, be, independent, risk, factors])].
[sujeto(['In', 'HRQOL', 'assessment,', physical, and, mental, scores, were]), verbo([found]), complemento([to, be, significantly, lower, in, patients, with, joint, arthralgia])].
[sujeto(['AHAMP']), verbo([has]), complemento([an, adverse, effect, on, the, quality, of, life, of, breast, cancer, patients, receiving, adjuvant, antihormonal, 'treatment,', and, assessment, of, predictive, factors, is, important, for, identification, of, patient, groups, at, risk, of, developing, this, condition])].
[sujeto(['Ultraviolet', radiation, 'B']), verbo([stimulates]), complemento([both, the, production, of, vitamin, 'D3', in, the, skin, and, the, activation, of, the, skin, analog, of, the, 'hypothalamic-pituitary-adrenal', axis, '(', 'HPA)', as, well, as, the, central, 'HPA'])].
[sujeto(['The', noncalcemic, analogues, showed, similar, efficacy, to, 1, ',', 25, '(', 'OH)2D3', in]), verbo([stimulating]), complemento([the, expression, of, 'neuropeptides,', 'CRF,', urocortins, and, 'POMC,', and, their, 'receptors,', 'CRFR1,', 'CRFR2,', 'MC1R,', 'MC2R,', 'MC3R', and, 'MC4R'])].
[sujeto(['Interestingly,', unlike, other, 'secosteroids,', the, activity, of, 21, '(', 'OH)pD', did, not, correlate, with, induction, of, 'differentiation,']), verbo([suggesting]), complemento([a, separate, but, overlapping, mechanism, of, action])].
[sujeto(['Thus,', biologically, active, forms, of, vitamin, 'D', can]), verbo([regulate]), complemento([different, elements, of, the, local, equivalent, of, the, 'HPA', with, implications, for, the, systemic, 'HPA'])].
[sujeto(['Vitamin', 'D', '(', 'VD)', is, essential, for, the, human, body, and]), verbo([involved]), complemento([in, a, wide, variety, of, critical, physiological, processes, including, 'bone,', 'muscle,', and, cardiovascular, 'health,', as, well, as, innate, immunity, and, antimicrobial, responses])].
[sujeto(['Here,', we, elucidated, the, significance, of, the, 'VD', system, in, cytomegalovirus, '(', 'CMV)', 'infection,', which, is, one, of, the, most, common, opportunistic, infections, in, immunocompromised, or, -]), verbo([suppressed]), complemento([patients])].
[sujeto(['We']), verbo([found]), complemento([that, expression, of, vitamin, 'D', receptor, '(', 'VDR)', was, downregulated, in, 'CMV-infected', cells, within, 12, h, '[', 'hrs]', post, infection, '[', p])].
[sujeto(['None', of, the, biologically, active, metabolites, of, 'VD,', 'cholecalciferol,', 'calcidiol,', or, 'calcitriol,']), verbo([inhibit]), complemento(['CMV', replication, significantly, in, human, fibroblasts])].
[sujeto([and, expression, of, 'CYP27B1']), verbo([increased]), complemento([gradually, during, the, replication, cycle, of, 'CMV', to, 970, '%', probably, as, a, consequence, of, 'VDR', inhibition])].
[sujeto(['The', potent, synthetic, vitamin, 'D', analog, 'EB-1089', was, not, able, to]), verbo([inhibit]), complemento(['CMV', replication, or, antagonize, its, effect, on, 'VDR', expression])].
[sujeto(['Only', 'CMV', 'replication,', and, none, of, the, other, viral, pathogens, 'evaluated,']), verbo([inhibited]), complemento([the, vitamin, 'D', system, in, vitro])].
[sujeto(['In', view, of, the, pleiotropism, of, 'VDR,', 'CMV-mediated', downregulation, may]), verbo([have]), complemento(['far-reaching', 'virological,', 'immunological,', and, clinical, implications, and, thus, warrant, further, evaluations, in, vitro, and, in, vivo])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, advanced, 'glycation-endproducts', '(', 'AGEs)', induced, 'NFx03BA;B', activation, in, differentiated, mouse, podocytes])].
[sujeto(['Cytoplasmic', and]), verbo([nuclear]), complemento([protein, expression, of, the, 'NFx03BA;B', subunit, p65, '(', 'Rel', 'A)', were, determined, by, 'Western', blotting])].
[sujeto(['Furthermore,', the, ratio, of]), verbo([phosphorylated]), complemento([to, 'non-phosphorylated', 'Ix03BA;B-α', was, measured, using, specific, antibodies])].
[sujeto(['Podocytes']), verbo([expressed]), complemento([the, receptor, for, vitamin, 'D'])].
[sujeto(['The', vitamins, did, not]), verbo([suppress]), complemento([receptor, for, 'AGEs', '(', 'RAGE)', 'expression;', 'instead,', they, rather, upregulated, 'RAGE'])].
[sujeto(['Although', vitamin, 'D3', and, paricalcitol, partly, and, differentially, modified, some, of, the, studied, 'parameters,', both, hormones]), verbo([inhibited]), complemento(['AGE-BSA-induced', 'NFx03BA;B', 'transactivation,', presumably, by, various, mechanisms, including, the, upregulation, of, 'Ix03BA;B-α', 'protein,', keeping, 'NFx03BA;B', sequestered, in, an, inactive, state, in, the, cytoplasm])].
[sujeto(['Vitamin', 'D3', or, its, analog, paricalcitol, partly]), verbo([prevented]), complemento(['AGE-mediated', 'NFx03BA;B', 'activation,', an, important, feature, of, diabetic, nephropathy, '(', 'DN)'])].
[sujeto(['Whether', this, in, vitro]), verbo([finding]), complemento([is, of, clinical, relevance, to, 'prevent/treat', 'DN', requires, further, studies])].
[sujeto(['Endoplasmic', reticulum, '(', 'ER)', stress, and, oxidative, stress]), verbo([promote]), complemento([endothelial, dysfunction, and, atherosclerosis])].
[sujeto(['Since', vitamin, 'D']), verbo([has]), complemento([been, shown, in, several, studies, to, lower, the, risk, of, cardiovascular, 'disease,', we, examined, the, effects, of, vitamin, 'D', on, 'ER', stress, and, oxidative, stress, in, endothelial, cells])].
[sujeto(['Expression', of, 'ER', stress, 'markers,', including, 'glucose-regulated', protein, 78, ',', 'c-jun', 'N-terminal', kinase, 1, 'phosphorylation,', and, eukaryotic, initiation, factor, 2, α, 'phosphorylation,', as, well, as, 'X-box']), verbo([binding]), complemento(['protein-1', splicing, were, measured, in, tunicamycin, '(', 'TM)-treated', human, umbilical, endothelial, cells, '(', 'HUVEC)', treated, with, 1, ',', 25, -, dihydroxyvitamin, 'D3', '(', 1, ',', 25, -, '(', 'OH)2D3)', and, other, vitamin, 'D', analogs])].
[sujeto(['When', 'TM', and, 1, ',', 25, -, '(', 'OH)2D3', were, added, 'simultaneously,', 1, ',', 25, -, '(', 'OH)2D3']), verbo([prevented]), complemento(['ER', stress])].
[sujeto(['However,', 'ER', stress, was, not]), verbo([inhibited]), complemento([by, 25, -, 'OH', vitamin, 'D3', '(', 25, -, 'OHD3)', or, the, vitamin, 'D', analog, 'EB1089'])].
[sujeto(['Both', 'ZK191784', and, the, vitamin, 'D', metabolite, 24, ',', 25, -, dihydroxyvitamin, 'D3', were, as, effective, as, 1, ',', 25, -, '(', 'OH)2D3', in]), verbo([preventing]), complemento(['ER', stress])].
[sujeto(['All', of, the, compounds, 'tested,', except, for, 25, -, 'OHD3,']), verbo([inhibited]), complemento(['dextrose-induced', '(', 27.5, 'mM)', oxidative, stress, and, 'ER', stress])].
[sujeto(['Although', 'TM', with, and, without, 1, ',', 25, -, '(', 'OH)2D3', had, no, effect, on, 'VDR', 'expression,', inhibition, of, 'VDR', expression, via, siRNA]), verbo([prevented]), complemento([1, ',', 25, -, '(', 'OH)2D3,', 'ZK191784,', 'EB1089,', and, 24, ',', 25, -, dihydroxyvitamin, 'D3', from, inhibiting, 'dextrose-mediated', 'SO', generation])].
[sujeto(['Furthermore,', each, vitamin, 'D', 'analog,', with, the, exception, of, 25, -, 'OHD3,']), verbo([prevented]), complemento(['dextrose-induced', toxicity])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, vitamin, 'D', has, a, protective, effect, on, vascular, endothelial, cells])].
[sujeto(['Previously,', 19, -, 'Nor-2α-(3-hydroxypropyl)-1α,25(OH)2D3', '(', 'MART-10),', the, new, brand, 1, 'α,25(OH)2D3', 'analog,']), verbo([has]), complemento([been, demonstrated, to, be, an, effective, drug, to, inhibit, 'HNSCC', growth, in, vitro])].
[sujeto(['Our', results]), verbo([reveal]), complemento([that, both, 1, 'α,25(OH)2D3', and, 'MART-10', effectively, repressed, the, migration, and, invasion, of, 'HNSCC', 'cells,', with, 'MART-10', being, much, more, potent, than, 1, 'α,25(OH)2D3'])].
[sujeto(['The', antimetastatic, effect, of, 1, 'α,25(OH)2D3', and, 'MART-10', was]), verbo([mediated]), complemento([by, attenuation, of, 'epithelial-mesenchymal', transition, '(', 'EMT),', which, was, supported, by, the, finding, that, the, expression, of, 'EMT-inducing', transcriptional, 'factors,', 'Sail', and, 'Twist,', was, inhibited, by, 1, 'α,25(OH)2D3', and, 'MART-10'])].
[sujeto(['The', upregulation, of, 'E-cadherin', and, downregulation, of, 'N-cadherin', in, 'FaDu', cells]), verbo([induced]), complemento([by, both, drugs, further, confirmed, the, repression, of, 'EMT'])].
[sujeto(['In', 'addition,', 1, 'α,25(OH)2D3', and, 'MART-10', treatment]), verbo([inhibited]), complemento([intracellular, 'MMP-9', expression, and, extracellular, 'MMP', activity, in, 'FaDu', cells])].
[sujeto(['Collectively,', our, results]), verbo([suggest]), complemento([that, the, 'less-calcemia', 1, 'α,25(OH)2D3', 'analog,', 'MART-10,', is, a, promising, drug, for, 'HNSCC', treatment])].
[sujeto(['In', this, 'study,', we, investigated, whether, 'OCT']), verbo([increases]), complemento([the, production, of, 'LL-37/CAP-18,', a, human, cathelicidin, antimicrobial, 'peptide,', in, human, 'gingival/oral', epithelial, cells])].
[sujeto(['A', human, gingival, epithelial, cell, line, '(', 'Ca9-22)', and, human, oral, epithelial, cell, lines, '(', 'HSC-2,', 'HSC-3,', and, 'HSC-4)', exhibited, the]), verbo([enhanced]), complemento([expression, of, 'LL-37', mRNA, upon, stimulation, with, 'OCT', as, well, as, active, metabolites, of, vitamins, 'D3', and, 'D2'])].
[sujeto(['OCT']), verbo([induced]), complemento([the, higher, production, of, 'CAP-18', '(', 'ng/mL', 'order)', until, 6, days, 'time-dependently', in, 'Ca9-22', cells, in, culture])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'OCT', induces, the, production, of, 'hCAP-18/LL-37', in, a, manner, similar, to, that, induced, by, the, active, metabolite, of, vitamin, 'D3'])].
[sujeto(['Vitamin', 'D']), verbo([has]), complemento([emerged, as, a, promising, anticancer, drug])].
[sujeto(['We', demonstrated, that, 'RIN-m', 'cells,', neuroendocrine, tumor, 'cells,']), verbo([expressed]), complemento([vitamin, 'D', receptor, '(', 'VDR)', and, 'VDR', expression, increased, with, increasing, exposure, to, 1, 'α,25-dihydroxyvitamin', 'D3', '[', 1, 'α,25(OH)2D3]', or, 'MART-10,', a, 1, 'α,25(OH)2D3', analog])].
[sujeto(['MART-10', had, 'anti-growth', effect, on, 'RIN-m', cells, comparable, to, those, of, 1, 'α,25(OH)2D3', 'The', growth, inhibition, of, both, drugs, was]), verbo([mediated]), complemento([by, induction, of, 'cell-cycle', arrest, at, 'G0/G1', phase, and, apoptosis])].
[sujeto(['Western', blot, assay, further, revealed, that, this, 'G0/G1']), verbo([arrest]), complemento([was, due, to, the, 'up-regulation', of, p27, and, 'down-regulation', of, cyclin, dependent, kinase, 4, '(', 'CDK4),', with, 'MART-10', also, reducing, 'CDK6'])].
[sujeto(['Apoptosis', induction, was, further, supported, by]), verbo([increased]), complemento([cleaved, 'caspase-3', expression, after, treatment])].
[sujeto(['Cases', of, renal, tubular, dysfunction]), verbo([have]), complemento([been, reported, in, patients, with, hepatitis, 'B', and, in, patients, with, human, immunodeficiency, virus, who, are, undergoing, tenofovir, treatment])].
[sujeto(['The', 'TDF', group, was]), verbo([associated]), complemento([with, altered, levels, of, 'retinol-binding', protein, '(', 'RBP)/creatinine', '(', 'TDF', 25, '%', vs])].
[sujeto(['The', multivariate, analysis, showed, that, the, use, of, 'TDF', was, independently]), verbo([associated]), complemento([with, a, higher, risk, of, altered, excretion, of, 'RBP/creatinine', '(', 4.4, ;, interquartile, 'range:', 1.4, to, 14, ;, 'P=0'])].
[sujeto(['We']), verbo([found]), complemento([an, independent, association, between, 'TDF', use, and, altered, 'RBP', excretion])].
[sujeto(['This']), verbo([finding]), complemento([indicates, subclinical, tubular, damage])].
[sujeto(['In', this, 'study,', these, differences, in, tubular, function, were, not]), verbo([associated]), complemento([with, concomitant, changes, in, markers, of, bone, turnover])].
[sujeto(['While', low, vitamin, 'D', status]), verbo([has]), complemento([been, shown, to, be, associated, with, decreased, quality, of, life, in, unhealthy, populations, and, 'women,', only, limited, data, are, available, regarding, healthy, adult, men])].
[sujeto(['High-tech', employees, aged, 25, -, 65, year, were]), verbo([recruited]), complemento([from, an, occupational, periodic, examination, clinic, at, 'Rambam', 'Health', 'Campus'])].
[sujeto(['Every', 1, 'ng/mL']), verbo([increase]), complemento([of, 25, '(', 'OH)D', was, associated, with, 9, '%', reduction, in, the, odds, of, reporting, 'self-rated', health, as, fair, or, poor])].
[sujeto(['In', 'conclusion,', serum, levels, of, 25, '(', 'OH)D', were]), verbo([associated]), complemento([with, 'self-rated', health, and, with, physically, unhealthy, days, of, 'HRQOL', in, healthy, 'high-tech', male, workers])].
[sujeto(['Future', intervention, studies, are]), verbo([required]), complemento([to, test, the, impact, of, vitamin, 'D', supplementation, on, 'QoL'])].
[sujeto(['The', authors, aimed, to, determine, the, effect, of, combined, 'calcium-vitamin', 'D', and, 'calcium-alone', on, pain, intensity, and, menstrual, blood]), verbo([loss]), complemento([in, women, with, primary, dysmenorrhea])].
[sujeto(['Pain', intensity, and, menstrual, blood]), verbo([loss]), complemento([were, assessed, one, cycle, 'before,', three, cycles, 'under,', and, one, cycle, following, intervention, using, 10, -, cm, visual, analog, scale, and, pictorial, blood, loss, assessment, 'chart,', respectively])].
[sujeto(['Menstrual', blood]), verbo([loss]), complemento([was, not, significantly, different, in, the, either, 'calcium-vitamin', 'D', '(', -, 4.7, ',', -, 21.9, to, 12.4, ')', or, 'calcium-alone', '(', -, 0.4, ',', -, 17.4, to, 16.4, ')', groups, compared, to, placebo])].
[sujeto(['It']), verbo([has]), complemento([been, previously, reported, that, vitamin, 'D', deficiency, is, more, prevalent, among, 'SLE', patients, than, in, the, general, population])].
[sujeto(['Vitamin', 'D', insufficiency, was]), verbo([found]), complemento([in, 50, &, 'nbsp;%', of, supplemented, and, 60, &, 'nbsp;%', of, 'non-supplemented', patients])].
[sujeto(['Among', 'non-supplemented', female, 'SLE', 'patients,', it, was]), verbo([found]), complemento([that, patients, with, vitamin, 'D', insufficiency, showed, more, fatigue, '(', 'p&nbsp;=&nbsp;0'])].
[sujeto(['These', data, were, not]), verbo([found]), complemento([in, supplemented, patients, although, having, a, high, prevalence, of, vitamin, 'D', insufficiency, '(', up, to, 50, &, 'nbsp;%)'])].
[sujeto(['A', total, of, 85, healthy, older, subjects, aged, 64, -, 96, years, were]), verbo([recruited]), complemento([in, this, study])].
[sujeto(['Also,', significant]), verbo([increase]), complemento([in, the, levels, of, serum, 25, '(', 'OH)D', 'concentrations,', 'calcium,', and, 'TAC', activity, along, with, reduction, in, the, levels, of, muscle, fatigue, 'biomarkers:', creatine, 'kinase,', lactic, acid, 'dehydrogenase,', troponin, 'I,', 'hydroxyproline,', and, fatigue, scores, '(', visual, analog, 'scale)', were, reported, in, physically, active, participants, compared, to, those, of, lower, physical, activity])].
[sujeto(['These', results, demonstrate, that, 25, '(', 'OH)D', concentrations, and, calcium, might]), verbo([prevent]), complemento([muscle, fatigue, by, regulation, of, the, biosynthesis, of, creatine, 'kinase,', lactic, acid, 'dehydrogenase,', troponin, 'I,', and, hydroxyproline, via, a, proposed, antifree, radical, mechanism, reported, by, higher, 'TAC', activity])].
[sujeto(['It', was]), verbo([suggested]), complemento([that, vitamin, 'D', status, could, be, reported, as, a, marker, of, the, improvement, of, muscle, 'performance,', especially, in, healthy, older, adults, with, lower, physical, activity])].
[sujeto(['Acute', 'Myeloid', 'Leukemia', '(', 'AML)']), verbo([has]), complemento([grave, prognosis, due, to, aggressive, nature, of, the, 'disease,', the, toxicity, of, standard, 'treatment,', and, overall, low, cure, rates])].
[sujeto(['Importantly,', although, 'AraC', is, also, toxic, to, normal, bone, marrow, cell, 'population,', the]), verbo([enhanced]), complemento([cell, kill, by, 'D2/CA', was, limited, to, malignant, blasts])].
[sujeto(['This', enhancement, of, cell, death, was]), verbo([associated]), complemento([with, activation, of, the, monocytic, differentiation, program, as, shown, by, molecular, 'markers,', and, the, increased, expression, of, vitamin, 'D', receptor, '(', 'VDR)'])].
[sujeto(['Apoptosis', elicited, by, this, treatment, is, 'caspase-dependent,', and, the, optimal, blast, killing]), verbo([required]), complemento([the, increased, expression, of, the, apoptosis, regulator, 'Bim'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, testing, of, this, regimen, in, the, clinic, is, warranted])].
[sujeto(['MART-10', '(', 19, -, 'nor-2α-(3-hydroxypropyl)-1α,25(OH)₂D₃),', the, 'newly-synthesized', 1, 'α,25(OH)₂D₃', 'analog,']), verbo([has]), complemento([been, shown, to, be, much, more, potent, in, cancer, growth, inhibition, than, 1, 'α,25(OH)₂D₃', and, be, active, in, vivo, without, inducing, obvious, side, effect])].
[sujeto(['In', this, 'study,', we, demonstrated, that, both, 1, 'α,25(OH)₂D₃', and, 'MART-10', could, effectively]), verbo([repress]), complemento(['TNBC', cells, migration, and, invasion, with, 'MART-10', more, effective])].
[sujeto(['MART-10', and, 1, 'α,25(OH)₂D₃']), verbo([induced]), complemento([cadherin, switching, '(', upregulation, of, 'E-cadherin', and, downregulation, of, 'N-cadherin)', and, downregulated, 'P-cadherin', expression, in, 'MDA-MB-231', cells])].
[sujeto(['The', 'EMT(epithelial', mesenchymal, 'transition)', process, in, 'MDA-MB-231', cells, was]), verbo([repressed]), complemento([by, 'MART-10', through, inhibiting, 'Zeb1,', 'Zeb2,', 'Slug,', and, 'Twist', expression])].
[sujeto(['LCN2,', one, kind, of, breast, cancer, metastasis, 'stimulator,', was, also]), verbo([found]), complemento([for, the, first, time, to, be, repressed, by, 1, 'α,25(OH)₂D₃', and, 'MART-10', in, breast, cancer, cells])].
[sujeto(['Based', on, our, 'result,', we, conclude, that, 'MART-10', could, effectively]), verbo([inhibit]), complemento(['TNBC', cells, metastatic, potential, and, deserves, further, investigation, as, a, new, regimen, to, treat, 'TNBC'])].
[sujeto([2, -, 'Methylene-19-nor-(20S)-1α,25-dihydroxyvitamin', 'D3', '(', 2, 'MD;', 'DP001)', is, a, novel, and, a, more, potent, vitamin, 'D', receptor, activator, '(', 'VDRA)', that, more, selectively, localizes, in, the, parathyroid, 'gland,', and]), verbo([has]), complemento([a, wider, therapeutic, margin, in, the, uremic, rat, model, than, calcitriol, and, paricalcitol])].
[sujeto(['Plasma', drug, concentration]), verbo([increased]), complemento([with, increasing, 'dose,', and, all, responders, achieved, a, 2, 'MD', concentration, of, '≥1'])].
[sujeto(['In', hemodialysis, patients, with, 'SHPT,', 2, 'MD,', at, thrice, weekly, oral, doses, of, 440, and, 550, 'ng,', is, well, tolerated, and, effectively]), verbo([suppresses]), complemento(['PTH', without, hypercalcemia])].
[sujeto(['Vitamin', 'D', receptor]), verbo([interacting]), complemento([protein, '(', 'DRIP150)', coactivates, estrogen, receptor, alpha, '(', 'ERalpha)-mediated', transactivation, in, breast, cancer, cell, lines, transfected, with, a, construct, '(', 'pERE(3))', containing, three, estrogen, responsive, elements, '(', 'EREs)'])].
[sujeto(['Studies', on, coactivation, of, 'wild-type', and, variant, 'ERalpha/Sp1', by, 'DRIP150', indicates, that, the, 'DNA-binding', domain, and, helix, 12, in, the, ligand]), verbo([binding]), complemento([domain, of, 'ERalpha', are, required, and, the, coactivation, response, is, squelched, by, overexpressing, an, 'NR-box', peptide, that, contains, two, 'LXXLL', motifs, from, 'GRIP2'])].
[sujeto(['Deletion', analysis, of, 'DRIP150', demonstrates, that, coactivation]), verbo([requires]), complemento([an, 'alpha-helical', 'NIFSEVRVYN', '(', amino, acids, 795, -, 804, ')', motif, within, 23, amino, acid, sequence, '(', 789, -, 811, ')', in, the, central, region, of, 'DRIP150', and, similar, results, were, obtained, for, coactivation, of, 'ERalpha', by, 'DRIP150'])].
[sujeto(['Thus,', although, different, domains, of, 'ERalpha', are]), verbo([required]), complemento([for, 'hormone-dependent', activation, of, 'ERalpha', and, 'ERalpha/Sp1,', coactivation, of, these, transcription, factors, by, 'DRIP150', requires, the, 'alpha-helical', amino, acids, 795, -, 804])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([of, a, coactivator, that, enhances, 'ERalpha/Sp1-mediated', transactivation, in, breast, cancer, cells])].
[sujeto(['The', nucleolar, 58, -, kDa, microspherule, protein, '(', 'MSP58)', is]), verbo([involved]), complemento([in, a, variety, of, cellular, processes])].
[sujeto(['Though', 'MSP58', was, identified, as, a, candidate, oncogene, in, many, cancer, 'types,', it]), verbo([has]), complemento([both, oncogenic, and, tumor, suppressive, properties])].
[sujeto(['MSP58', was, highly]), verbo([expressed]), complemento([in, 'MGC803,', 'BGC823,', and, 'NCI-N87', cell, lines, compared, with, normal, gastric, mucosa, cells])].
[sujeto(['The', study, thus]), verbo([provided]), complemento([evidence, that, knockdown, of, 'MSP58', expression, significantly, suppressed, cell, proliferation, and, 'colony-forming', ability])].
[sujeto(['Immunohistochemical', analysis, showed, 'MSP58', was, highly]), verbo([expressed]), complemento([in, 51.5, '%', of, 'GC', tissues, and, in, 11.9, '%', of, normal, corresponding, mucosal, tissues])].
[sujeto(['Depth', of, 'invasion,', lymph, node, 'metastasis,', and, 'MSP58', expression, were]), verbo([found]), complemento([to, be, independent, prognostic, factors])].
[sujeto(['These', findings]), verbo([suggested]), complemento([that, 'MSP58', plays, an, important, role, in, tumorigenesis, and, progression, and, may, help, predict, the, prognosis, of, 'GC', patients])].
[sujeto(['The', receptor, for]), verbo([activated]), complemento([protein, kinase, 'C', 1, '(', 'RACK1)', is, known, to, regulate, tumor, 'development,', whereas, the, underlined, mechanism, has, not, been, described, clearly])].
[sujeto(['RACK1', was, significantly]), verbo([decreased]), complemento([in, 'GC', samples])].
[sujeto(['Knockdown', of, 'RACK', elevated, 'GC', cell, 'viabilities,', whereas, overexpression, of, 'RACK1']), verbo([suppressed]), complemento([tumorigenesis, of, 'GC', cells])].
[sujeto(['Importantly,', 'NF-kB', signaling, was]), verbo([enhanced]), complemento([after, 'RACK1', expression, was, 'inhibited,', suggesting, the, negative, regulation, of, the, 'pro-oncogenic', 'NF-kB', activity, by, 'RACK1', might, contribute, to, its, tumor, suppressor, role, in, 'GC', cells])].
[sujeto(['Our', results, support, that, 'RACK1']), verbo([suppresses]), complemento([gastric, tumor, progression, through, the, 'NF-kB', signaling, pathway])].
[sujeto(['Airway', smooth, muscle, is, a, major]), verbo([target]), complemento([tissue, for, glucocorticoid, '(', 'GC)-based', asthma, 'therapies,', 'however,', molecular, mechanisms, through, which, the, 'GC', receptor, '(', 'GR)', exerts, therapeutic, effects, in, this, key, airway, cell, type, have, not, been, fully, elucidated])].
[sujeto(['We', previously, identified, the]), verbo([nuclear]), complemento(['factor-κB', '(', 'NF-κB)', 'inhibitor,', 'A20', '(', 'TNFAIP3),', as, a, mediator, of, cytokine, repression, by, glucocorticoids, '(', 'GCs)', in, airway, epithelial, cells, and, defined, cooperative, regulation, of, 'anti-inflammatory', genes, by, 'GR', and, 'NF-κB', as, a, key, mechanistic, underpinning, of, airway, epithelial, 'GR', function])].
[sujeto(['We', applied, chromatin, immunoprecipitation, and, reporter, analysis, to, show, that, 'GR', and, 'NF-κB', directly]), verbo([regulate]), complemento(['A20', expression, in, 'HASM', through, cooperative, induction, of, an, intronic, enhancer])].
[sujeto(['Using', 'overexpression,', we, show, for, the, first, time, that, 'A20', and, its]), verbo([interacting]), complemento(['partner,', 'TNIP1,', repress, 'TNF', signaling, in, 'HASM', cells])].
[sujeto(['Moreover,', we, applied, small, interfering, 'RNA-based', gene, knockdown, to, demonstrate, that, 'A20', is]), verbo([required]), complemento([for, maximal, cytokine, repression, by, 'GCs', in, 'HASM'])].
[sujeto(['Taken', 'together,', our, data]), verbo([suggest]), complemento([that, inductive, regulation, of, 'A20', by, 'GR', and, 'NF-κB', contributes, to, cytokine, repression, in, 'HASM'])].
[sujeto(['Neurotrophin', 'receptor-interacting', melanoma, 'antigen-encoding', protein, '(', 'NRAGE)']), verbo([regulates]), complemento([apoptosis, and, metastasis, via, interactions, with, various, genes])].
[sujeto(['The', expression, of, 'NRAGE', and, its, putative]), verbo([interacting]), complemento([genes, apoptosis, antagonizing, transcription, factor, '(', 'AATF),', p75, neurotrophin, receptor, '(', 'p75NTR),', and, proliferating, cell, nuclear, antigen, '(', 'PCNA)', were, determined, in, 'GC', cell, lines, using, reverse, 'transcription-polymerase', chain, reaction, '(', 'RT-PCR)'])].
[sujeto(['Expression', of, 'NRAGE', mRNA, positively, correlated, with, that, of, 'AATF,', and, 'NRAGE', knockdown, significantly]), verbo([decreased]), complemento([the, 'proliferation,', 'migration,', and, invasion, of, 'GC', cells])].
[sujeto(['A', stepwise, elevation, in, 'NRAGE', mRNA, expression, in, 'GC', tissues, was, observed, with]), verbo([increasing]), complemento(['Union', for, 'International', 'Cancer', 'Control', '(', 'UICC)', stage])].
[sujeto(['High', 'NRAGE', expression, in, 'GCs', was]), verbo([associated]), complemento([with, shortened, 'recurrence-free', survival, and, identified, as, an, independent, prognostic, factor, '(', hazard, 'ratio,', 1.83, ;, 95, '%', 'CI,', 1.12, -, 3.02, ',', p, =, 0.017, ')'])].
[sujeto(['The', results, indicate, that, 'NRAGE', represents, a, putative, oncogene]), verbo([associated]), complemento([with, a, malignant, phenotype, of, 'GC'])].
[sujeto(['In', 'GC,', 'NRAGE', may, serve, as, a, predictive, biomarker, and, a]), verbo([target]), complemento([of, molecular, therapy])].
[sujeto(['The', mechanism, by, which, nucleocapsids, of, 'Autographa', californica, multiple, nucleopolyhedrovirus, '(', 'AcMNPV)', egress, from, the, nucleus, to, the, plasma, 'membrane,']), verbo([leading]), complemento([to, the, formation, of, budded, virus, '(', 'BV),', is, not, known])].
[sujeto(['AC141', is, a, 'nucleocapsid-associated', protein]), verbo([required]), complemento([for, 'BV', egress, and, has, previously, been, shown, to, be, associated, with, 'β-tubulin'])].
[sujeto(['In', 'addition,', 'AC141', and, 'VP39', were, previously, shown, by, fluorescence, resonance, energy, transfer, by, fluorescence, lifetime, imaging, to]), verbo([interact]), complemento([directly, with, the, 'Drosophila', melanogaster, 'kinesin-1', light, chain, '(', 'KLC)', tetratricopeptide, repeat, '(', 'TPR)', domain])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, microtubule, transport, systems, may, be, involved, in, baculovirus, nucleocapsid, egress, and, 'BV', formation])].
[sujeto(['We', show, that, nucleocapsid, 'AC141']), verbo([associates]), complemento([with, the, lepidopteran, 'Trichoplusia', ni, 'KLC', and, 'kinesin-1', heavy, chain, '(', 'KHC)', by, coimmunoprecipitation, and, colocalization])].
[sujeto([ni, 'kinesin-1', by, downregulation, of, 'KLC', by, siRNA, resulted, in, a, significant]), verbo([decrease]), complemento([in, 'BV', production])].
[sujeto(['Yeast', 'two-hybrid', analysis, showed, no, evidence, of, a, direct, interaction, between, 'kinesin-1', and, 'AC141', or, 'VP39,']), verbo([suggesting]), complemento([that, either, other, nucleocapsid, proteins, or, adaptor, proteins, may, be, required])].
[sujeto(['These', results, further, support, the, conclusion, that, microtubule, transport, is]), verbo([required]), complemento([for, 'AcMNPV', 'BV', formation])].
[sujeto(['Prior', studies]), verbo([have]), complemento([shown, that, the, entry, of, nucleocapsids, involves, the, polymerization, of, actin, to, propel, nucleocapsids, to, nuclear, pores, and, entry, into, the, nucleus])].
[sujeto(['In', this, 'study,', we, examined, whether, nucleocapsids]), verbo([interact]), complemento([with, lepidopteran, 'kinesin-1', motor, molecules, and, are, potentially, carried, as, cargo, on, microtubules, to, the, plasma, membrane, in, 'AcMNPV-infected', cells])].
[sujeto(['Glucocorticoid', signaling]), verbo([regulates]), complemento([target, genes, by, multiple, 'mechanisms,', including, the, repression, of, transcriptional, activities, of, nuclear, factor, 'κ-light-chain-enhancer', of, activated, 'B', cells, '(', 'NF-κB)', though, direct, 'protein-protein', interactions, and, subsequent, 'O-GlcNAcylation', of, 'RNA', polymerase, 'II', '(', pol, 'II)'])].
[sujeto(['Recent', studies]), verbo([have]), complemento([shown, that, overexpression, of, 'O-linked', 'β-N-acetylglucosamine', transferase, '(', 'OGT),', which, adds, an, 'O-linked', 'β-N-acetylglucosamine', '(', 'O-GlcNAc)', group, to, the, 'C-terminal', domain, of, 'RNA', pol, 'II,', increases, the, transrepression, effects, of, glucocorticoids, '(', 'GC)'])].
[sujeto(['As', 'O-GlcNAcase', '(', 'OGA)', is, an, enzyme, that, removes, 'O-GlcNAc', from, 'O-GlcNAcylated', 'proteins,', we, hypothesized, that, the, potentiation, of, 'GC', effects, following, 'OGT', overexpression, could, be, similarly, observed, via, the, direct, inhibition, of, 'OGA,']), verbo([inhibiting]), complemento(['O-GlcNAc', removal, from, pol, 'II'])].
[sujeto(['Here', we, show, that, despite, pharmacological, evidence, of]), verbo([target]), complemento([engagement, by, a, selective, small, molecule, inhibitor, of, 'OGA,', there, is, no, evidence, for, a, sensitizing, effect, on, 'glucocorticoid-mediated', effects, on, 'TNF-α', promoter, 'activity,', or, gene, expression, 'generally,', in, human, cells])].
[sujeto(['Thus,', despite, evidence, for, 'O-GlcNAc', modification, of, 'RNA', pol, 'II', in, 'GR-mediated', 'transrepression,', our, data, indicate, that, pharmacological, inhibition, of, 'OGA', does, not, potentiate, or]), verbo([enhance]), complemento(['glucocorticoid-mediated', transrepression])].
[sujeto(['In', prokaryotes, these, repeats, are, much, more, frequent, in, thermophile, compared, to, mesophile, or, psychrophile, 'species,', and]), verbo([have]), complemento([similar, frequency, in, both, large, 'RNAs'])].
[sujeto(['The', two, large, 'RNAs', of, eukaryotic, cytoplasmic, ribosomes]), verbo([have]), complemento([expanded, to, a, different, degree, across, the, evolutionary, ladder])].
[sujeto(['In', the, examined, eukaryotes, abundance, of, rRNA, homoiterons, generally, follows, size, and, nucleotide, bias, of, the, expansion, 'segments,', and]), verbo([increases]), complemento([with, 'GC', content, and, especially, with, phylogenetic, rank])].
[sujeto(['Metastatic', and, refractory, gastric, cancer, '(', 'GC)', are]), verbo([associated]), complemento([with, a, poor, 'prognosis;', 'therefore,', the, identification, of, prognostic, factors, and, chemosensitivity, markers, is, extremely, important])].
[sujeto(['PRMT1', and, 'FOXO1', in, 'GC', samples, were, predominantly]), verbo([expressed]), complemento([in, the, nucleus])].
[sujeto(['Patients', with, lower, 'PRMT1', expression, '(', 'n&nbsp;=&nbsp;131)', had]), verbo([suppressed]), complemento([nuclear, accumulation, of, 'FOXO1,', higher, recurrence, after, adjuvant, 'chemotherapy,', and, poorer, prognosis, than, those, with, higher, 'PRMT1', expression, '(', 'n&nbsp;=&nbsp;64)'])].
[sujeto(['PRMT1', downregulation, in, 'GC', cells, by, 'RNA', interference]), verbo([inhibited]), complemento([cisplatin, and, 5, -, fluorouracil, sensitivity])].
[sujeto(['The', expression, of]), verbo([phosphorylated]), complemento(['FOXO1', and, phosphorylated, 'BCL-2', antagonist, of, cell, death, was, upregulated, in, 'PRMT1', small, interfering, 'RNA', groups])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, the, evaluation, of, 'PRMT1', expression, in, 'GC', is, a, useful, predictor, of, poor, prognosis, and, recurrence, after, adjuvant, chemotherapy])].
[sujeto(['Moreover,', these, data]), verbo([suggest]), complemento([that, 'PRMT1', is, a, promising, therapeutic, tool, for, overcoming, refractory, 'GC'])].
[sujeto(['Increasing', evidence]), verbo([has]), complemento([demonstrated, that, long, 'non-coding', 'RNAs', '(', 'lncRNAs)', play, essential, roles, in, the, occurrence, and, development, of, human, 'cancers,', including, gastric, cancer, '(', 'GC)'])].
[sujeto(['The', results, from, 'qRT-PCR', showed, that, the, expression, of, 'HNF1A-AS1', was, not, only, downregulated, in, three, 'GC', cell, lines, '(', 'AGS,', 'BGC-823,', and, 'MKN-45)', relative, to, that, in, a, normal, gastric, mucosal, epithelial, cell, line, '(', 'GES-1),', but, also]), verbo([decreased]), complemento([in, 'GC', tissues, relative, to, that, in, paired, adjacent, 'non-neoplastic', tissues, '(', low, 'expression,', 94, of, 161, ;, low, expression, 'rate,', 58.38, '%', ')'])].
[sujeto(['Furthermore,', low, 'HNF1A-AS1', expression, was]), verbo([associated]), complemento([with, tumor, 'size/diameter', '(', p, =, 0.005, ',', multivariate, 'analysis),', levels, of, serum, carcinoembryonic, antigen, '(', 'CEA),', and, carbohydrate, antigen, 19, -, 9, '(', 'CA19-9),', and, 'RRM1', expression, in, tissue, samples, '(', p, =, 0.028, ',', p, =, 0.009, ',', and, p, =, 0.006, ',', 'respectively)'])].
[sujeto(['Taken', 'together,', our, data, indicate, that, lncRNA, 'HNF1A-AS1', may, be, a, regulator, of, 'GC,', and, 'thus,', it, may]), verbo([have]), complemento([potential, as, a, novel, biomarker, and, treatment, target, for, this, type, of, cancer])].
[sujeto(['Chemoresistance', is, a, major]), verbo([cause]), complemento([of, treatment, failure, and, high, mortality, in, advanced, gastric, cancer, '(', 'AGC)'])].
[sujeto(['In', the, present, 'study,', we, established, human, gastric, cancer, '(', 'GC)', cell, lines, resistant, to, 5, -, fluorouracil, '(', 5, 'FU),', paclitaxel, '(', 'TA),', or, cisplatin, '(', 'DDP)', by, gradient, drug, treatment, and, generated, a, novel, monoclonal, antibody, 5, 'B2']), verbo([targeting]), complemento([heterogeneous, nuclear, ribonucleoproteins, 'C1/C2', '(', 'HNRNPC)', overexpressed, in, chemoresistant, 'GC', cells])].
[sujeto(['Overexpressing', 'HNRNPC', in, 'GC', cells]), verbo([promoted]), complemento(['chemoresistance,', and, knockdown, of, 'HNRNPC', by, small, interfering, 'RNA', '(', 'siRNA)', reversed, chemoresistance])].
[sujeto(['These', data]), verbo([suggest]), complemento([the, potential, usefulness, of, 'HNRNPC', as, a, prognostic, and, therapeutic, marker, of, 'GC'])].
[sujeto(['Cells']), verbo([expressing]), complemento(['LGR5,', an, intestinal, stem, cell, 'marker,', have, been, suggested, as, cancer, stem, cells, in, human, colon, cancers])].
[sujeto(['Previously,', we, discovered, that, 'LGR5-expressing', cells, exist, in, the, gastric, antrum, and, remarkably]), verbo([increase]), complemento([in, number, in, intestinal, metaplasia])].
[sujeto(['LGR5', positivity, was]), verbo([associated]), complemento([with, old, 'age,', well, to, moderate, 'differentiation,', and, nuclear, 'β-catenin', positivity])].
[sujeto(['Although', 'LGR5', did, not, show, any, prognostic, significance, for, all, 'GC', 'cases,', it, was]), verbo([associated]), complemento([with, poor, survival, in, 'GCs', with, nuclear, 'β-catenin', expression])].
[sujeto(['LGR5', expression, was]), verbo([induced]), complemento([by, transfection, in, 'GC', cell, lines, with, abnormal, 'Wnt', 'activation,', 'which,', 'however,', showed, no, influence, on, the, growth, and, migration, of, 'GC', cells])].
[sujeto(['A', small, portion, of, 'GCs']), verbo([expressed]), complemento(['LGR5'])].
[sujeto(['Although', 'LGR5', was]), verbo([associated]), complemento([with, poor, survival, in, 'GCs', with, nuclear, 'β-catenin,', 'LGR5', expression, in, 'GC', cells, had, no, effects, on, the, growth, and, 'migration,', requiring, a, further, study, exploring, a, biological, role, of, 'LGR5', in, 'GCs'])].
[sujeto(['The', 'AT-hook']), verbo([has]), complemento([been, defined, as, a, 'DNA', binding, peptide, motif, that, contains, a, 'glycine-arginine-proline', '(', 'G-R-P)', tripeptide, core, flanked, by, basic, amino, acids])].
[sujeto(['Recent']), verbo([reports]), complemento([documented, variations, in, the, sequence, of, 'AT-hooks', and, revealed, 'RNA', binding, activity, of, some, canonical, 'AT-hooks,', suggesting, a, higher, structural, and, functional, variability, of, this, protein, domain, than, previously, anticipated])].
[sujeto(['Microscale', thermophoresis, and, electrophoretic, mobility, shift, assays]), verbo([reveal]), complemento([the, nucleic, acid, binding, features, of, this, peptide, 'motif,', and, show, that, 'eAT-hooks', bind, 'RNA', with, one, order, of, magnitude, higher, affinity, than, 'DNA'])].
[sujeto(['In', 'addition,', cellular, localization, studies]), verbo([suggest]), complemento([a, role, for, the, 'N-terminal', 'eAT-hook', of, 'PTOV1', in, nucleocytoplasmic, shuttling])].
[sujeto(['In', 'summary,', our, findings, classify, the, 'eAT-hook', as, a, novel, nucleic, acid]), verbo([binding]), complemento(['motif,', which, potentially, mediates, various, 'RNA-dependent', cellular, processes])].
[sujeto(['Studies', over, the, past, decade]), verbo([have]), complemento([shown, a, significant, role, of, synonymous, mutations, in, posttranscriptional, regulation, of, gene, 'expression,', which, is, particularly, associated, with, messenger, 'RNA', '(', 'mRNA)', secondary, structure, alterations])].
[sujeto(['Most', studies, focused, on, prokaryote, genomes, and, the]), verbo([nuclear]), complemento([genomes, of, eukaryotes, while, little, is, known, about, the, regulation, of, mitochondrial, 'DNA', '(', 'mtDNA)', gene, expression])].
[sujeto(['This', paper]), verbo([reveals]), complemento([signs, of, selection, in, synonymous, sites, of, the, mitochondrial, cytochrome, b, gene, '(', 'Cytb)', of, 'Baikal', oilfish, or, golomyankas, '(', 'Comephoridae)', directed, towards, altering, the, secondary, structure, of, the, mRNA, and, probably, altering, the, character, of, mtDNA, gene, expression])].
[sujeto(['The', 'most-documented', function, of, the, 'SMN-Gemins', complex, concerns, the, assembly, of, spliceosomal, small]), verbo([nuclear]), complemento([ribonucleoproteins, '(', 'snRNPs)'])].
[sujeto(['Despite', multiple, genetic, 'studies,', the, 'Gemin', proteins]), verbo([have]), complemento([not, been, identified, as, prominent, modifiers, of, 'SMN-associated', mutant, phenotypes])].
[sujeto(['In', the, present, 'report,', we, make, use, of, the, 'Drosophila', model, organism, to, investigate, whether, viability, and, motor, phenotypes]), verbo([associated]), complemento([with, a, hypomorphic, 'Gemin3', mutant, are, enhanced, by, changes, in, the, levels, of, 'SMN,', 'Gemin2', and, 'Gemin5', brought, about, by, various, genetic, manipulations])].
[sujeto(['Interestingly,', 'muscle-specific', overexpression, of, 'Gemin2', was, by, itself, sufficient, to, depress, normal, motor, function, and, its]), verbo([enhanced]), complemento([upregulation, in, all, tissues, leads, to, a, decline, in, fly, viability])].
[sujeto(['The', toxicity]), verbo([associated]), complemento([with, increased, 'Gemin2', levels, is, conserved, in, the, yeast, 'S'])].
[sujeto([pombe, in, which, we]), verbo([find]), complemento([that, the, cytoplasmic, retention, of, 'Sm', 'proteins,', likely, reflecting, a, block, in, the, snRNP, assembly, 'pathway,', is, a, contributing, factor])].
[sujeto(['Whether', 'CpdA']), verbo([inhibits]), complemento(['GC', 'resistance,', a, central, feature, of, severe, 'asthma,', has, not, been, addressed])].
[sujeto(['We', investigated, whether, 'CpdA']), verbo([modulates]), complemento(['cytokine-induced', 'GC', resistance, in, human, airway, smooth, muscle, '(', 'ASM)', cells])].
[sujeto(['CpdA']), verbo([inhibited]), complemento([production, of, 'fluticasone-resistant', chemokines, 'CCL5,', 'CX3CL1,', and, 'CXCL10', at, protein, and, mRNA, levels, in, both, asthmatic, and, healthy, cells])].
[sujeto(['CpdA', failed, to]), verbo([induce]), complemento([expression, of, 'GC-induced', 'Leucine', 'Zipper', while, transiently, inducing, 'mitogen-activated', protein, kinase, phosphatase, 1, '(', 'MKP-1)', at, both, mRNA, and, protein, levels])].
[sujeto(['CpdA', inhibitory, action, was, not]), verbo([associated]), complemento([with, 'GRα', nuclear, 'translocation,', nor, was, it, prevented, by, 'RU486', antagonism])].
[sujeto(['Activation', of, 'IRF-1', by, 'TNF-α/IFN-γ', was]), verbo([inhibited]), complemento([by, 'CpdA'])].
[sujeto([siRNA, 'MKP-1']), verbo([prevented]), complemento([the, inhibitory, effect, of, 'CpdA', on, 'cytokine-induced', 'CXCL10', production])].
[sujeto(['For', the, first, 'time,', we, show, that, 'CpdA']), verbo([inhibits]), complemento([the, production, of, 'GC-resistant', chemokines, via, 'GRα-independent', mechanisms, involving, the, inhibition, of, 'IRF-1', and, 'up-regulation', of, 'MKP-1'])].
[sujeto(['Thus,']), verbo([targeting]), complemento(['CpdA-sensitive', pathways, in, 'ASM', cells, represents, an, alternative, therapeutic, approach, to, treat, 'GC', resistance, in, asthma])].
[sujeto(['Proteomic,', 'co-immunoprecipitation,', and, sedimentation, analyses, described, here, indicate, that, 'SF3B1,', an, essential, splicing, component, of, the, 'U2', snRNP, 'complex,', is, strongly]), verbo([associated]), complemento([with, nucleosomes])].
[sujeto(['ChIP-seq', and, 'RNA-seq', analyses]), verbo([reveal]), complemento([that, 'SF3B1', specifically, binds, nucleosomes, located, at, exonic, positions])].
[sujeto(['SF3B1']), verbo([binding]), complemento([is, enriched, at, nucleosomes, positioned, over, short, exons, flanked, by, long, introns, that, are, also, characterized, by, differential, 'GC', content, between, exons, and, introns])].
[sujeto(['Disruption', of, 'SF3B1']), verbo([binding]), complemento([to, such, nucleosomes, affects, splicing, of, these, exons, similarly, to, 'SF3B1', knockdown])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, the, association, of, 'SF3B1', with, nucleosomes, is, functionally, important, for, 'splice-site', recognition, and, that, 'SF3B1', conveys, 'splicing-relevant', information, embedded, in, chromatin, structure])].
[sujeto(['Germinal', center, '(', 'GC)', reaction, is, a, 'T', 'cell-dependent', process, in, which]), verbo([activated]), complemento(['B', cells, undergo, clonal, expansion, and, functional, maturation, to, produce, high, affinity, antibodies, and, differentiate, into, memory, 'B', 'cells(1)'])].
[sujeto(['We']), verbo([found]), complemento([that, during, 'B', cell, differentiation, stage, there, was, an, elevated, expression, of, 'BRD4', in, 'GC', 'B', cells, and, inhibition, of, 'BRD4', by, small, molecule, inhibitors, led, to, the, suppression, of, 'GC', formation, and, correspondent, antibody, responses, in, a, 'Td', antigen, immunization, model])].
[sujeto(['At', the, molecular, 'level,', we]), verbo([found]), complemento([that, the, effects, of, 'BRD4', in, primary, 'GC', 'B', cell, differentiation, and, 'B', cell, lymphoma, were, mediated, through, the, impaired, phosphorylation, and, translocation, of, 'NF-κBp65', and, further, 'down-regulation', of, 'B-cell', lymphoma, 6, '(', 'Bcl6)', expression])].
[sujeto(['Thus', this, study]), verbo([reveals]), complemento([a, novel, function, of, 'BRD4', in, controlling, the, 'GC', 'B', cell, development, pathway])].
[sujeto(['The', ascomycete, fungus, 'Ophiostoma', 'novo-ulmi', is, responsible, for, the, pandemic, of, 'Dutch', elm, disease, that]), verbo([has]), complemento([been, ravaging, 'Europe', and, 'North', 'America', for, 50, years])].
[sujeto(['The', 31.784, -, 'Mb']), verbo([nuclear]), complemento([genome, '(', 50.1, '%', 'GC)', is, organized, into, 8, chromosomes, containing, a, total, of, 8, ',', 640, 'protein-coding', genes, that, we, validated, with, 'RNA', sequencing, analysis])].
[sujeto(['Approximately', 53, '%', of, these, genes]), verbo([have]), complemento([their, closest, match, to, 'Grosmannia', clavigera, 'kw1407,', followed, by, 36, '%', in, other, close, 'Sordariomycetes,', 5, '%', in, other, 'Pezizomycotina,', and, surprisingly, few, '(', 5, '%', ')', orphans])].
[sujeto(['Approximately', 76, '%', of, the, proteins, could, be, assigned, functions, using, 'Gene', 'Ontology', 'analysis;', we, identified, 311, 'carbohydrate-active', 'enzymes,', 48, cytochrome, 'P450s,', and, 1, ',', 731, proteins, potentially]), verbo([involved]), complemento([in, 'pathogen-host', 'interaction,', along, with, 7, clusters, of, fungal, secondary, metabolites])].
[sujeto(['The', expression, of, 'AKT,', proliferating, cell]), verbo([nuclear]), complemento([antigen, '(', 'PCNA)', and, matrix, 'metallopeptidase-9', '(', 'MMP-9)', was, detected, by, 'real-time', 'PCR', and, western, blotting, assays])].
[sujeto(['EGFR', was]), verbo([found]), complemento([highly, expressed, in, cancer, tissues, compared, with, the, 'ANCT', and, correlated, with, lymph, node, metastases])].
[sujeto(['Knockdown', of, 'EGFR', reduced, cell, proliferation, and, invasion, of, 'GC', with]), verbo([decreased]), complemento([expression, of, 'AKT,', 'PCNA', and, 'MMP-9', and, induced, cell, apoptosis, and, cycle, arrest])].
[sujeto(['Upregulation', of, 'EGFR', expression, is]), verbo([associated]), complemento([with, lymph, node, metastases, of, 'GC,', and, blockade, of, 'EGFR', signaling, suppresses, growth, and, invasion, of, 'GC', cells, through, 'AKT', 'pathway,', suggesting, that, 'EGFR', may, represent, a, potential, therapeutic, target, for, this, aggressive, malignancy])].
[sujeto(['Here,', the, authors]), verbo([report]), complemento([a, novel, 'cell-permeable', and, red, fluorescent, 'hemicyanine-based', thiazole, coumarin, '(', 'TC)', probe, for, 'DNA', 'recognition,', nuclear, staining, and, cell, cycle, analysis])].
[sujeto(['Probe', 'TC', may]), verbo([find]), complemento([multiple, applications, in, fluorescence, 'spectroscopy,', 'diagnostics,', bioimaging, and, molecular, and, cell, biology])].
[sujeto(['Levels', of, 'ASBT', protein, and, mRNA, were, low, in, the, duodenum, and, high, in, the, 'ileum,', and, both, were]), verbo([induced]), complemento([by, 1, ',', 25, '(', 'OH)(2)D(3)'])].
[sujeto(['The']), verbo([nuclear]), complemento([receptor, 'protein,', 'VDR,', was, present, uniformly, in, the, 'duodenum,', 'jejunum,', and, ileum, of, the, rat, small, intestine])].
[sujeto(['Absorption', of, cholylsarcosine, was, much, greater, from, the, ileal, segment, '(', 28, -, fold, that, of, the, duodenum, under, control, 'conditions)', and, was]), verbo([enhanced]), complemento([with, 1, ',', 25, '(', 'OH)(2)D(3)', treatment])].
[sujeto(['Gel-shift', mobility, assays, of]), verbo([nuclear]), complemento([extracts, from, rat, ileum, showed, that, both, rat, retinoid, 'X', receptor, and, 'VDR', were, bound, to, the, 'VDRE'])].
[sujeto(['The', results, indicate, that, rat, 'ASBT', gene, expression, is]), verbo([activated]), complemento([by, 1, ',', 25, '(', 'OH)(2)D(3)', by, specific, binding, to, the, 'VDRE', and, that, such, activation, enhances, ileal, bile, acid, transport])].
[sujeto(['Human', 'ABST', mRNA, and, promoter, activity, were, also]), verbo([increased]), complemento([in, 'Caco-2', cells, treated, with, 1, ',', 25, '(', 'OH)(2)D(3),', suggesting, a, physiological, role, of, 'VDR', in, human, ileal, bile, acid, homeostasis])].
[sujeto(['Employing', 'transmission-', and, immunoelectronmicroscopy, as, well, as, detection, of, 'autophagosome-associated', 'LC3-beta', protein, in, the, vacuolar, 'structures,', we, show, here, that, 'EB1089', also]), verbo([induces]), complemento([massive, autophagy, in, 'MCF-7', cells])].
[sujeto(['Interestingly,', inhibition, of, autophagy, effectively, hindered, 'apoptosis-like']), verbo([nuclear]), complemento([changes, and, cell, death, in, response, to, 'EB1089'])].
[sujeto(['Furthermore,', restoration, of, normal, levels, of, beclin, 1, ',', an, 'autophagy-inducing', tumor, suppressor, gene, that, is, monoallelically, deleted, in, 'MCF-7', 'cells,', greatly]), verbo([enhanced]), complemento([the, 'EB1089-induced', nuclear, changes, and, cell, death])].
[sujeto(['Thus,', 'EB1089']), verbo([triggers]), complemento([nuclear, apoptosis, via, a, pathway, involving, 'Beclin', 1, -, dependent, autophagy])].
[sujeto(['Surprisingly,', tumor, cells, depleted, for, 'Beclin', 1, failed, to, proliferate]), verbo([suggesting]), complemento([that, even, though, the, monoallelic, depletion, of, beclin, 1, in, human, cancer, cells, suppresses, 'EB1089-induced', autophagic, 'death,', one, intact, beclin, 1, allele, is, essential, for, tumor, cell, proliferation])].
[sujeto(['Systemic', 'GC', is]), verbo([released]), complemento([through, the, 'hypothalamic-pituitary-adrenal', '(', 'HPA)', axis, in, response, to, various, stressors])].
[sujeto(['Over', the, last, 'decade,', 'extra-adrenal', 'production/activation', of, 'cortisol/corticosterone']), verbo([has]), complemento([been, reported, in, many, tissues])].
[sujeto(['The', 11, 'β-HSD1', isoform, is, predominantly, a, 'reductase,', which, catalyzes, nicotinamide, adenine, dinucleotide, phosphate, 'hydrogen-dependent', conversion, of, 'cortisone/11-DHC', to, 'cortisol/corticosterone,', and, is, widely]), verbo([expressed]), complemento([and, present, at, the, highest, levels, in, the, 'liver,', 'lungs,', adipose, 'tissues,', 'ovaries,', and, central, nervous, system])].
[sujeto(['The', 11, 'β-HSD2', 'isoform,', which, catalyzes, nicotinamide, adenine, 'dinucleotide(+)-dependent', inactivation, of, 'cortisol/corticosterone', to, 'cortisone/11-DHC,', is, highly]), verbo([expressed]), complemento([in, distal, 'nephrons,', the, 'colon,', sweat, 'glands,', and, the, placenta])].
[sujeto(['In', healthy, 'skin,', 11, 'β-HSD1', is]), verbo([expressed]), complemento([in, the, epidermis, and, in, dermal, fibroblasts])].
[sujeto(['On', the, other, 'hand,', 11, 'β-HSD2', is]), verbo([expressed]), complemento([in, sweat, glands, but, not, in, the, epidermis])].
[sujeto(['The', role, of, 11, 'β-HSD', in, skin, physiology, and, pathology]), verbo([has]), complemento([been, reported, recently])].
[sujeto(['In', this, 'review,', we, summarize, the, recently]), verbo([reported]), complemento([role, of, 11, 'β-HSD', in, the, 'skin,', focusing, on, its, function, in, cell, 'proliferation,', wound, 'healing,', 'inflammation,', and, aging])].
[sujeto([3, 'β-Hydroxysteroid', dehydrogenase, '(', 3, 'β-HSD)', deficiency, is, a, rare]), verbo([cause]), complemento([of, congenital, adrenal, hyperplasia, '(', 'CAH)', caused, by, inactivating, mutations, in, the, 'HSD3B2', gene])].
[sujeto(['We']), verbo([report]), complemento([the, molecular, and, structural, analysis, of, the, 'HSD3B2', gene, in, a, 46, ',', 'XY', child, born, to, apparently, nonconsanguineous, parents, and, presenting, ambiguous, genitalia, and, salt, wasting])].
[sujeto(['Molecular', homology, modeling, and, secondary, structure, predictions]), verbo([suggested]), complemento([that, the, variant, sequence, might, both, alter, the, 'substrate-binding', cleft, and, compromise, the, overall, stability, of, the, enzyme])].
[sujeto(['We']), verbo([have]), complemento([described, the, first, 'HSD3B2', gene, mutation, in, the, 'Italian', population, and, analyzed, its, effect, in, the, context, of, the, 3, 'β-HSD2', structure, and, function])].
[sujeto(['Further', analysis]), verbo([suggests]), complemento([that, the, 11, 'β-Hsd2', was, negatively, correlated, to, 'Nr3c1'])].
[sujeto(['In', the, transcription, 'level,', the, expression, level, of, 11, 'β-Hsd2', mRNA]), verbo([decreased]), complemento([in, the, 'IUGR', 'group,', while, the, mRNA, expression, level, of, 'Nr3c1', significantly, increased])].
[sujeto(['In', the, protein, 'level,', the, expression, of, 11, 'β-Hsd2', significantly]), verbo([decreased]), complemento([in, the, 'IUGR', 'group;', while, the, expression, of, 'Nr3c1', significantly, increased, in, the, 'IUGR', group])].
[sujeto(['However,', there, were, no, significant, differences, in, 'Nr3c1']), verbo([phosphorylated]), complemento([at, 'S211', and, 'S266', between, the, 'IUGR', and, control, groups])].
[sujeto(['The', expression, of, 'Nr3c1', was, mainly]), verbo([regulated]), complemento([by, 11, 'β-Hsd2,', which, could, significantly, inhibit, its, expression, in, 'IUGR', rats])].
[sujeto(['Phosphorylation', on, site, 'S211', was, the, major]), verbo([activated]), complemento([form, of, 'Nr3c1'])].
[sujeto(['We', speculate, that, 'IUGR', brain, damage, was]), verbo([caused]), complemento([by, excessive, amounts, of, 'GC', due, to, significant, activation, by, 'Nr3c1'])].
[sujeto([11, 'β-hydroxysteroid', dehydrogenase, type, 1, '(', 11, 'β-HSD1)', controls, the, production, of, active, glucocorticoid, '(', 'GC)', and]), verbo([has]), complemento([been, proposed, as, a, new, target, for, the, treatment, of, type, 2, diabetes])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, that, a, natural, 'product,', 'curcumin,', exhibited, moderate, inhibition, and, selectivity, on, 11, 'β-HSD1'])].
[sujeto(['In', vitro, studies, revealed, that, 'LG13', selectively]), verbo([inhibited]), complemento([11, 'β-HSD1', with, 'IC50', values, at, nanomolar, level, and, high, selectivity, over, 11, 'β-HSD2'])].
[sujeto(['Targeting', 11, 'β-HSD1,', 'LG13', could]), verbo([inhibit]), complemento(['prednisone-induced', adverse, changes, in, 'mice,', but, had, no, effects, on, 'dexamethasone-induced', ones])].
[sujeto(['Further,', the, 11, 'β-HSD1', inhibitors, also]), verbo([suppressed]), complemento([11, 'β-HSD1', and, 'GR', 'expression,', indicating, a, possible, positive, feedback, system, in, the, 11, 'β-HSD1/GR', cycle])].
[sujeto(['In', type, 2, diabetic, mice]), verbo([induced]), complemento([by, high, fat, diet, plus, 'low-dosage', 'STZ', 'injection,', oral, administration, with, 'LG13', for, 6, weeks, significantly, decreased, fasting, blood, 'glucose,', hepatic, glucose, 'metabolism,', structural, 'disorders,', and, lipid, deposits])].
[sujeto(['These', pharmacological, and, mechanistic, insights, on, 'LG13', also]), verbo([provide]), complemento([us, novel, 'agents,', leading, 'structures,', and, strategy, for, the, development, of, 11, 'β-HSD1', inhibitors, treating, metabolic, syndromes])].
[sujeto(['Two', isoforms]), verbo([have]), complemento([been, 'identified;', in, key, metabolic, target, tissues, '(', including, liver, and, 'adipose),', expression, of, 11, β, '(', 'Beta)-HSD1', predominates, that, in, vivo, converts, cortisone, to, cortisol, and, thus, amplifies, local, 'GC', action])].
[sujeto(['In', 'contrast,', in, mineralocorticoid]), verbo([target]), complemento([tissues, 11, β, '(', 'Beta)-HSD2', is, the, isoform, that, is, most, abundantly, expressed])].
[sujeto(['Dysregulated', 11, β, '(', 'Beta)-HSD1', activity]), verbo([has]), complemento([been, implicated, in, many, metabolic, diseases, such, as, obesity, and, diabetes, and, inhibition, of, 11, β, '(', 'Beta)-HSD1', represents, a, promising, therapeutic, target])].
[sujeto(['Mutations', within, the, gene, encoding, 11, β, '(', 'Beta)-HSD2']), verbo([cause]), complemento([the, 'Syndrome', of, 'Apparent', 'Mineralocorticoid', 'Excess', and, decreases, in, activity, are, linked, to, hypertension, as, well, as, impairment, in, placental, function, and, neonatal, growth])].
[sujeto(['The', genes, normally]), verbo([involved]), complemento([in, 'GC', synthesis, in, adrenals, are, 'co-expressed', with, 20, 'α-hydroxysteroid', dehydrogenase, '(', 20, 'α-HSD)', in, the, developing, lung])].
[sujeto(['The', temporal, correlation, observed, between, levels, of, progesterone, inactivation, by, 20, 'α-HSD', '(', higher, after, 'birth)', and, the, sensitivity, of, lung, development, to, 'GCs']), verbo([suggests]), complemento([a, role, for, 20, 'α-HSD', in, the, modulation, of, 'GR', occupancy, through, the, control, of, 21, -, hydroxylase, substrate, and, product, levels])].
[sujeto(['Coexistence', of, this, 'GC', synthesis, pathway, with, 20, 'α-HSD', activity, strongly]), verbo([suggests]), complemento([local, regulation, of, 'GC', action, and, is, compatible, with, 'intracrine/paracrine', actions, of, 'GC'])].
[sujeto(['Chronic', endogenous, glucocorticoid, '(', 'GC)', excess, in, mammals, is]), verbo([associated]), complemento([with, metabolic, dysfunction, and, dyslipidemia, that, are, characterized, by, increased, plasma, triglyceride, and, total, cholesterol, '(', 'Tch)', levels])].
[sujeto(['Chronic', 'CORT', treatment, significantly]), verbo([increased]), complemento(['Tch', levels, in, pectoralis, major, muscle, '(', 'PMC)', '(', 'p&lt;0'])].
[sujeto([1, ')', ',', and, 'CORT']), verbo([enhanced]), complemento([triglyceride, levels, in, the, 'PMC', '(', 'p&lt;0'])].
[sujeto([8, ')', tended, to, be]), verbo([increased]), complemento([and, nuclear, 'GR', protein, '(', 'p&lt;0'])].
[sujeto([5, ')', was]), verbo([increased]), complemento([in, 'PMC', by, 'CORT', administration])].
[sujeto(['Parallel', to, an]), verbo([increase]), complemento([in, gene, 'expression,', 'HMGCR', protein, expression, in, 'PMC', was, significantly, increased, '(', 'p&lt;0'])].
[sujeto([7, ')', protein, expression, in, 'PMC', tended, to, be]), verbo([increased]), complemento([by, 'CORT', compared, to, control])].
[sujeto(['These', results, indicate, that, chronic, 'CORT', administration]), verbo([causes]), complemento([cholesterol, accumulation, in, 'PMC', tissues, of, broiler, chickens, by, increasing, cholesterol, synthesis, and, uptake])].
[sujeto(['Animal', models]), verbo([suggest]), complemento([that, neuroactive, steroids, contribute, to, 'alcohol\'s', acute, effects])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, a, common, nonsynonymous, 'polymorphism,', 'AKR1C3', 2, in, the, gene, encoding, the, enzyme, 3, 'α-HSD2/17β-HSD5,', and, a, synonymous, single, nucleotide, polymorphism, '(', 'SNP),', 'rs248793,', in, 'SRD5A1,', which, encodes, 5, 'α-reductase,', were, associated, with, alcohol, dependence, '(', 'AD)'])].
[sujeto(['Sixty-five', 'Caucasian', men, '(', 34, lighter, and, 31, heavier, 'drinkers;', mean, age, 26.2, 'years)']), verbo([participated]), complemento([in, a, 'double-blind', laboratory, study, where, they, consumed, drinks, containing, no, ethanol, or, 0.8, 'g/kg', of, ethanol])].
[sujeto(['AKR1C3', 2, 'G', allele, carriers, exhibited, greater]), verbo([increases]), complemento([in, heart, rate, and, stimulant, and, sedative, effects, of, alcohol, than, 'C', allele, homozygotes])].
[sujeto(['Glucocorticoid', '(', 'GC)', excess]), verbo([inhibits]), complemento([wound, healing, causing, increased, patient, discomfort, and, infection, risk])].
[sujeto([11, 'β-hydroxysteroid', dehydrogenase, type, 1, '(', 11, 'β-HSD1)']), verbo([activates]), complemento(['GCs', '(', converting, 11, -, dehydrocorticosterone, to, corticosterone, in, 'rodents)', in, many, tissues, including, 'skin,', where, de, novo, steroidogenesis, from, cholesterol, has, also, been, reported])].
[sujeto(['Although', several, steroidogenic, enzymes, displayed, variable, expression, during, 'healing,', expression, of, the, final, enzyme]), verbo([required]), complemento([for, the, conversion, of, 11, -, deoxycorticosterone, to, 'corticosterone,', 11, 'β-hydroxylase', '(', 'CYP11B1),', was, lacking, in, unwounded, skin, and, 'post-wounding'])].
[sujeto(['Our', findings, demonstrate, that, 11, 'β-HSD1']), verbo([activates]), complemento([considerably, more, corticosterone, than, is, generated, de, novo, from, progesterone, in, mouse, skin, and, drives, 'GC', exposure, during, 'healing,', demonstrating, the, basis, for, 11, 'β-HSD1', inhibitors, to, accelerate, wound, repair])].
[sujeto(['Our', previous, studies]), verbo([have]), complemento([demonstrated, that, prenatal, caffeine, ingestion, induces, an, increased, susceptibility, to, metabolic, syndrome, with, alterations, of, glucose, and, lipid, metabolic, phenotypes, in, adult, first, generation, '(', 'F1)', of, intrauterine, growth, retardation, '(', 'IUGR)', 'rats,', and, the, underlying, mechanism, is, originated, from, a, 'hypothalamic-pituitary-adrenal', '(', 'HPA)', 'axis-associated', neuroendocrine, metabolic, programming, alteration, in, utero])].
[sujeto(['Particularly,', comparing, with, the, control, 'group,', caffeine, groups, had, an]), verbo([enhanced]), complemento([corticosterone, levels, after, chronic, stress])].
[sujeto(['Compared', with, before, 'stress,', the, serum, glucose, levels, were]), verbo([increased]), complemento([in, some, groups, whereas, the, triglyceride, levels, were, decreased])].
[sujeto(['Furthermore,', total, cholesterol]), verbo([gain]), complemento([rates, were, enhanced, but, the, 'high-density', 'lipoprotein-cholesterol', gain, rates, were, decreased, in, most, caffeine, groups, after, stress])].
[sujeto(['Taken', 'together,', these, results, indicate, that, the, reproductive, and, developmental, toxicities, and, the, neuroendocrine, metabolic, programming, mechanism, by, prenatal, caffeine, ingestion]), verbo([have]), complemento([transgenerational, effects, in, 'rats,', which, may, help, to, explain, the, susceptibility, to, metabolic, syndrome, and, associated, diseases, in, 'F2'])].
[sujeto([11, 'β-Hydroxysteroid', dehydrogenases, type, 2, '(', 11, 'β-HSD2),', a, key, regulator, for, 'pre-receptor', metabolism, of, glucocorticoids, '(', 'GCs)', by, converting, active, 'GC,', 'cortisol,', to, inactive, 'cortisone,']), verbo([has]), complemento([been, shown, to, be, present, in, a, variety, of, tumors])].
[sujeto(['But', its, expression, and, roles]), verbo([have]), complemento([rarely, been, discussed, in, hematological, malignancies])].
[sujeto(['Proteasome', inhibitor, bortezomib]), verbo([has]), complemento([been, shown, to, not, only, possess, antitumor, effects, but, also, potentiate, the, activity, of, other, chemotherapeutics])].
[sujeto(['In', this, 'study,', we, demonstrated, that, 11, 'β-HSD2', was, highly]), verbo([expressed]), complemento([in, two, 'GC-resistant', 'T-cell', leukemic, cell, lines, 'Jurkat', and, 'Molt4'])].
[sujeto(['In', 'contrast,', no, 11, 'β-HSD2', expression, was]), verbo([found]), complemento([in, two, 'GC-sensitive', 'non-hodgkin', lymphoma, cell, lines, 'Daudi', and, 'Raji', as, well, as, normal, peripheral, blood, 'T', cells])].
[sujeto(['Inhibition', of, 11, 'β-HSD2', by, 11, 'β-HSD', inhibitor, 18, 'β-glycyrrhetinic', acid, or, 11, 'β-HSD2', shRNA, significantly]), verbo([increased]), complemento(['cortisol-induced', apoptosis, in, 'Jurkat', cells])].
[sujeto(['Additionally,', pretreatment, of, 'Jurkat', cells, with, 'low-dose', bortezomib, resulted, in]), verbo([increased]), complemento([cellular, sensitivity, to, 'GC', as, shown, by, elevated, induction, of, 'apoptosis,', more, cells, arrested, at, 'G1', stage, and, 'up-regulation', of, 'GC-induced', leucine, zipper, which, is, an, important, mediator, of, 'GC', action])].
[sujeto(['Furthermore,', we, clarified, that, bortezomib, could, 'dose-dependently']), verbo([inhibit]), complemento([11, 'β-HSD2', messenger, 'RNA', and, protein, levels, as, well, as, activity, '(', 'cortisol-cortisone', 'conversion)', through, p38, 'mitogen-activated', protein, kinase, signaling, pathway])].
[sujeto(['Therefore,', we]), verbo([suggest]), complemento([11, 'β-HSD2', 'is,', at, least, partially, if, not, 'all,', responsible, for, impaired, 'GC', suppression, in, 'Jurkat', cells, and, also, indicate, a, novel, mechanism, by, which, proteasome, inhibitor, bortezomib, may, influence, 'GC', action])].
[sujeto(['UVB']), verbo([enhanced]), complemento([the, 'HSD11B1', gene, and, protein, expression, in, a, 'dose-dependent', 'manner,', while, 'UVA', had, no, effect])].
[sujeto(['Similarly,', 'UVC']), verbo([increased]), complemento([11, 'β-HSD1', protein, product, as, measured, by, 'IHC'])].
[sujeto(['UVB', and, 'UVC']), verbo([enhanced]), complemento([cortisol, production, and, decreased, epidermal, 'GR', 'expression,', while, 'UVA', had, no, detectable, effects])].
[sujeto(['Although', both, 'UVA', and, 'UVB']), verbo([stimulated]), complemento(['HSD11B2', gene, 'expression,', only, 'UVA', increased, 11, 'β-HSD2', protein, product, levels, with, 'UVB', and, 'UVC', having, no, effect])].
[sujeto(['We']), verbo([suggest]), complemento([that, these, 'differential,', 'waveband-dependent', effects, of, 'UV', radiation, on, the, expression, of, cutaneous, 'HSD11B1,', 'HSD11B2', and, 'GRα', genes, and, their, corresponding, protein, 'products,', and, cortisol, production, are, to, protect, 'and/or', restore, the, epidermal, barrier, homeostasis, against, disruption, caused, by, the, elevated, cortisol, level, induced, by, 'UVB', and, 'UVC'])].
[sujeto(['Endogenous', glucocorticoid, '(', 'GC)', activation, is]), verbo([regulated]), complemento([by, the, intracellular, 'GC-activating', and, -, inactivating, enzymes, 11, 'β-hydroxysteroid', dehydrogenase, '(', 11, 'β-HSD)1', and, 11, 'β-HSD2,', 'respectively,', that, catalyze, interconversion, of, inert, cortisone, and, its, bioactive, metabolite, cortisol])].
[sujeto(['Because', endogenous, 'GCs', are, critically, implicated, in]), verbo([suppressing]), complemento([the, asthmatic, 'state,', this, study, examined, the, roles, of, the, 11, 'β-HSD', enzymes, in, regulating, 'GC', activation, and, bronchoprotection, during, proasthmatic, stimulation])].
[sujeto(['These', responses, were]), verbo([inhibited]), complemento([by, pretreatment, with, 'CBX,', suggesting, a, permissive, proasthmatic, role, for, 11, 'β-HSD2'])].
[sujeto(['Supporting', this, 'concept,', extended, studies, demonstrated, that, 1, ')', 'IL-13-treated', tracheal, epithelium, and, peripheral, lung, tissues, exhibit, upregulated, 11, 'β-HSD2', 'activity,', 2, ')', the, latter, impairs, 'cortisone-induced', cortisol, accumulation, and, the, ability, of, administered, cortisol, to]), verbo([prevent]), complemento([both, 'IL-13-induced', heightened, airway, contractility, and, 'eotaxin-3', release, from, epithelial, 'cells,', and, 3, ')', these, proasthmatic, responses, are, prevented, by, cortisol, administration, in, the, presence, of, 11, 'β-HSD2', inhibition])].
[sujeto(['However', prolonged, 'GC', therapy, frequently]), verbo([leads]), complemento([to, 'GC-resistance', with, an, unclear, molecular, mechanism])].
[sujeto(['The', 11, 'β-HSD', 'inhibitor,', carbenoxolone, 'pre-treatment', resulted, in, greater, cell, death, with, prednisolone, assessed, by, 'methyl-thiazol-tetrazolium', assay, and, 'caspase-3/7', 'assay,']), verbo([suggesting]), complemento([that, 11, 'β-HSD2', is, a, cause, of, 'GC-resistance', in, 'ALL'])].
[sujeto(['Maternal', undernutrition]), verbo([inhibited]), complemento([maternal, adrenal, expression, of, 'P450', cholesterol, 'side-chain', cleavage, enzyme, '(', 'CYP11A1),', 11, 'beta-hydroxylase', '(', 'CYP11B1),', aldosterone, synthase, '(', 'CYP11B2),', and, adrenocorticotropic, hormone, '(', 'ACTH)', receptor, '(', 'ACTH-R;', 'MC2', 'gene)', compared, with, control, offspring])].
[sujeto(['In', 9, -, month, adult, male, 'MUN', 'offspring,', the, expression, of, 'HSD1,', 'CYP11A1,', 'CYP11B2,', 'Ob-Ra/Ob-Rb,', and, 'GCR', mRNA, were, significantly, upregulated, with, a, trend, toward, an]), verbo([increase]), complemento([in, 'ACTH-R', and, a, decrease, in, 17, 'alpha-hydroxylase', '(', 'CYP17A1)', expression])].
[sujeto(['These', results, indicate, that, the, adrenal, gland, is, a]), verbo([target]), complemento([of, nutritional, programming])].
[sujeto(['In', utero, undernutrition]), verbo([has]), complemento([a, global, suppressive, effect, on, maternal, and, 'P1', offspring, adrenal, steroidogenic, enzymes, in, association, with, reduced, circulating, corticosterone, levels, in, 'P1', 'offspring,', which, may, be, secondary, to, a, negative, feedback, from, elevated, maternal, 'GC', levels, and, or, leptin, levels, in, 'MUN', dams])].
[sujeto(['Gender-specific', differences, in, steroidogenic, enzyme, expression, were]), verbo([found]), complemento([in, adult, 'MUN', offspring])].
[sujeto(['The', common]), verbo([finding]), complemento([of, increased, 'ACTH', receptor, expression, in, 'MUN', adults, of, both, genders, suggests, an, increased, sensitivity, of, these, offspring, to, stress])].
[sujeto(['Homeostasis', of, circulating, cortisol, is]), verbo([maintained]), complemento([by, the, 11, 'β-HSD2', enzyme, which, inactivates, cortisol, into, cortisone])].
[sujeto(['It', is, abundantly]), verbo([expressed]), complemento([in, the, placenta, where, it, protects, the, fetus, from, high, levels, of, maternal, glucocorticoids, '(', 'GCs)'])].
[sujeto(['Maternal', administration, of, 'Carbenoxolone', '(', 'Cbx),', a, powerful, 11, 'β-HSD2', 'inhibitor,']), verbo([leads]), complemento([to, an, increase, in, fetal, cortisol])].
[sujeto(['Exposure', of, pregnant, rats, to, high, levels, of, 'GC']), verbo([leads]), complemento([to, low, birth, weight, in, offspring, and, an, increased, risk, of, age, related, memory, and, cognitive, deficits, later, in, life])].
[sujeto(['We', showed, that, injecting, pregnant, rats, with, 'Cbx', injections, '(', 30, 'mg/kg)', during, 'GD', 14, -, 21]), verbo([leads]), complemento([to, a, significant, decrease, in, 'SPAR', '(', 'Spine', 'Associated', 'Rap', 'Guanylate', kinase, activating, 'protein)', '(', 'p&lt;0'])].
[sujeto([5, ')', but, a, significant]), verbo([increase]), complemento([in, 'Snk', '(', 'Serum', inducible, 'kinase)', '(', 'p&lt;0'])].
[sujeto(['In', 'general,', 'Snk', is]), verbo([induced]), complemento([by, neuronal, activity, and, plays, an, important, role, in, phosphorylating, 'SPAR'])].
[sujeto(['The']), verbo([phosphorylated]), complemento(['SPAR', is, then, recognized, and, degraded, by, ubiquitin, proteasome, system, '(', 'UPS),', causing, the, depletion, of, 'SPAR', and, 'PSD-95', from, the, spines])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, fetal, exposure, to, excessive, 'GC', levels, may, activate, the, 'Snk/SPAR', pathway, and, lead, to, the, depletion, of, 'SPAR', and, 'PSD-95'])].
[sujeto(['Since', 'GCs', drugs, are, commonly, used, in, various, obstetric, and, pediatric, 'conditions,', it, is, important, to, consider, the, risks, and, benefits, of, prenatal, 'GCs', exposure, in, order, to]), verbo([prevent]), complemento([neurodevelopmental, delay, in, the, offspring])].
[sujeto(['The', results, demonstrated, that, 11, 'β-HSD2', highly]), verbo([expressed]), complemento([in, 'Jurkat', 'cells,', but, not, in, 'Daudi,', 'Raji', cells, and, normal, blood, 'T', cells])].
[sujeto(['Furthermore,', the, inhibition, of, 11, 'β-HSD2', by, 18, 'β-GA', resulted, in]), verbo([increased]), complemento([cellular, sensitivity, to, 'GC', as, shown, by, elevated, induction, of, apoptosis])].
[sujeto([11, 'β-HSD2', may, be, a, potential]), verbo([target]), complemento([for, reduction, of, 'GC-resistance', in, therapeutic, applications])].
[sujeto([11, 'β-HSD1', is, a, predominant, 'reductase,']), verbo([activating]), complemento(['GCs', from, inert, 'metabolites,', whereas, 11, 'β-HSD2', is, a, potent, dehydrogenase, inactivating, 'GCs'])].
[sujeto(['Knowing', the, metabolic, effects, of, 'GCs,', a, selective, inhibition, of, 11, 'β-HSD1', represents, a, potential]), verbo([target]), complemento([for, therapy, of, impaired, glucose, 'tolerance,', insulin, insensitivity, and, central, obesity])].
[sujeto(['In', 'vitro,', 11, 'β-HSD1', is, selectively]), verbo([inhibited]), complemento([by, chenodesoxycholic, acid, '(', 'CDCA)', and, upregulated, under, 'GC', exposure])].
[sujeto(['Prednisolone', therapy]), verbo([leads]), complemento([to, a, marked, rise, in, serum, 'F', concentrations, and, an, elevated, 'F/E', serum, ratio])].
[sujeto(['This', proves, 'GC-induced', activation, of, hepatic, 11, 'β-HSD1,', which, could, not, be, extinguished, by, a, parallel]), verbo([increase]), complemento([of, 'IGF-1', under, prednisolone])].
[sujeto(['During', 'GC', 'treatment,']), verbo([increased]), complemento([hepatic, activation, of, 'E', to, 'F', may, aggravate, metabolic, side, effects, of, 'GCs', such, as, seen, in, the, metabolic, syndrome])].
[sujeto(['Within']), verbo([target]), complemento(['tissues,', 'GC', availability, is, regulated, at, a, prereceptor, 'level,', independently, of, systemic, 'levels,', by, isozymes, of, 11, 'β-hydroxysteroid', dehydrogenase, '(', 11, 'β-HSD)', that, interconvert, active, cortisol, and, inactive, cortisone])].
[sujeto([11, 'β-HSD1', '(', which]), verbo([activates]), complemento(['cortisol),', but, not, 11, 'β-HSD2', '(', which, inactivates, 'cortisol),', was, expressed, in, epidermal, keratinocytes, and, dermal, fibroblasts, in, human, skin, and, also, in, outer, hair, follicle, root, sheath, cells, in, murine, skin])].
[sujeto([11, 'β-HSD1', activity, was, present, ex, vivo, in, both, species, and]), verbo([increased]), complemento([with, age, in, human, skin, tissue, explants])].
[sujeto(['In', primary, human, dermal, fibroblasts, '(', 'HDF)', from, both, photoprotected, and, photoexposed, 'sites,', 11, 'β-HSD1', also]), verbo([increased]), complemento([with, donor, age])].
[sujeto(['GC', treatment, of, 'HDF']), verbo([caused]), complemento([upregulation, of, 11, 'β-HSD1', mRNA, levels, independent, of, donor, age, or, site])].
[sujeto(['The', 'age-', and, 'site-associated']), verbo([increase]), complemento([in, dermal, 11, 'β-HSD1,', and, the, ensuing, increased, local, 'GC', 'activation,', may, contribute, to, the, adverse, changes, in, skin, morphology, and, function, associated, with, chronological, aging, and, photoaging])].
[sujeto(['Increasing', evidence, in, humans, and, experimental, animals]), verbo([suggests]), complemento([that, altered, tissue, cortisol, metabolism, may, predispose, to, diabetes, mellitus, '(', 'DM)'])].
[sujeto(['Once', 'DM', is, 'established,', hyperglycemia, and, hyperlipidemia, may, further]), verbo([maintain]), complemento([the, abnormal, metabolism, of, cortisol])].
[sujeto(['To']), verbo([gain]), complemento([further, insight, in, this, 'regard,', healthy, cats, were, infused, for, 10, d, with, lipids, '(', n, =, 6, ')', or, saline, '(', n, =, 5, ')'])].
[sujeto(['Leptin', and, body, weight]), verbo([increased]), complemento([in, 'lipid-infused', cats])].
[sujeto(['In', spite, of, comparable, circulating, cortisol, 'levels,', 'up-regulation', of, 11, 'β-HSD1', and, 'down-regulation', of, 11, 'β-HSD2', expression, may, result, in]), verbo([increased]), complemento([tissue, cortisol, concentrations, in, fat, depots, of, hyperlipidemic, cats])].
[sujeto(['Down-regulation', of, 'GC', receptor, may, represent, a, 'self-protective', mechanism, against]), verbo([increased]), complemento([tissue, cortisol, levels])].
[sujeto(['In', 'conclusion,', hyperlipidemia]), verbo([has]), complemento([a, profound, effect, on, 11, 'β-HSD', expression, and, supports, the, connection, between, high, lipid, concentrations, and, tissue, cortisol, metabolism])].
[sujeto(['The', enzyme, is, highly]), verbo([expressed]), complemento([in, the, prostate, gland, and, previous, studies, indicate, that, genetic, variation, in, the, 'AKR1C3', gene, may, influence, the, prostate, volume, and, risk, of, prostate, cancer])].
[sujeto(['Moreover,', we]), verbo([have]), complemento([studied, the, basal, and, androgen, induced, promoter, activity, of, the, 'AKR1C3', gene])].
[sujeto(['We']), verbo([found]), complemento([that, carriers, of, the, promoter, 'A-allele', had, a, borderline, significant, decreased, risk, of, prostate, cancer, '(', 'OR', =, 0.59, ;, 95, '%', 'CI', =, 0.32, -, 1.08, ')'])].
[sujeto(['We', also, show, that, dihydrotestosterone, '(', 'DHT)']), verbo([induced]), complemento([the, promoter, activity, of, the, 'A-allele', 2.2, -, fold, '(', p, =, 0.048, ')'])].
[sujeto(['Sp3', seem, to, play, an, important, role, in]), verbo([regulating]), complemento([the, transcription, activity, of, 'AKR1C3', and, 'site-directed', mutagenesis, of, a, 'GC-box', 78, 'base-pair', upstream, the, 'ATG-site', significantly, inhibited, the, basal, 'AKR1C3', promoter, activity, by, 70, '%'])].
[sujeto(['After', lesions, to, the, mammalian, optic, 'nerve,', the, great, majority, of, retinal, ganglion, cells, '(', 'RGCs)', die, before, their, axons]), verbo([have]), complemento([even, had, a, chance, to, regenerate])].
[sujeto(['Frog', 'RGCs,', on, the, other, 'hand,', suffer, only, an, approximately, 50, '%', cell, 'loss,', and, we]), verbo([have]), complemento([previously, investigated, the, mechanisms, by, which, the, application, of, growth, factors, can, increase, their, survival, rate])].
[sujeto(['Axotomy', elicited, a, strong, activation, of, the, 'MAPK,', 'STAT3', and, 'AKT', 'pathways;', this, activation, was]), verbo([prevented]), complemento([by, disulfiram, or, by, 'RAR', antagonists])].
[sujeto(['Finally,', addition, of, exogenous, 'ATRA']), verbo([stimulated]), complemento([the, activation, of, the, first, two, of, these, pathways])].
[sujeto(['Future', experiments, will, investigate, whether, these, strong, 'survival-promoting', effects, of, 'RA', are]), verbo([mediated]), complemento([via, the, upregulation, of, neurotrophins])].
[sujeto(['SB', 9200, is, thought, to]), verbo([activate]), complemento([the, viral, sensor, 'proteins,', retinoic, 'acid-inducible', gene, 1, '(', 'RIG-I)', and, 'nucleotide-binding', oligomerization, 'domain-containing', protein, 2, '(', 'NOD2)', resulting, in, interferon, '(', 'IFN)', mediated, antiviral, immune, responses, in, 'virus-infected', cells])].
[sujeto(['Additionally,', the]), verbo([binding]), complemento([of, 'SB', 9200, to, these, sensor, proteins, could, also, sterically, block, the, ability, of, the, viral, polymerase, to, access, 'pre-genomic', 'RNA', for, nucleic, acid, synthesis])].
[sujeto(['The', immune]), verbo([stimulating]), complemento([and, direct, antiviral, properties, of, 'SB', 9200, were, evaluated, in, woodchucks, chronically, infected, with, woodchuck, hepatitis, virus, '(', 'WHV)', by, 'daily,', oral, dosing, at, 15, and, 30, 'mg/kg', for, 12, weeks])].
[sujeto(['The', antiviral, effects, were]), verbo([associated]), complemento([with, 'dose-dependent', and, 'long-lasting', induction, of, 'IFN-α,', 'IFN-β', and, 'IFN-stimulated', genes, in, blood, and, 'liver,', which, correlated, with, the, prolonged, activation, of, the, 'RIG-I/NOD2', pathway, and, hepatic, presence, of, elevated, 'RIG-I', protein, levels])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, in, addition, to, a, direct, antiviral, 'activity,', 'SB', 9200, induces, antiviral, immunity, during, chronic, hepadnaviral, infection, via, activation, of, the, viral, sensor, pathway])].
[sujeto(['Stimulated', by, retinoic, acid, gene, homolog, 6, '(', 'STRA6)', and, retinoic, acid, receptor]), verbo([responder]), complemento([2, '(', 'RARRES2)', are, candidate, genes, involved, in, the, pathogenesis, of, type, 2, diabetes, mellitus, '(', 'T2DM)'])].
[sujeto(['Rs736118', in, 'STRA6', gene, were, significantly]), verbo([associated]), complemento([with, 'T2DM', occurrence, in, the, recessive, genetic, model])].
[sujeto(['The', genotype, of, rs974456, was, significantly]), verbo([associated]), complemento([with, 'T2DM', in, the, dominant, genetic, model, correlated, to, 'sex,', 'MBI,', and, triglyceride])].
[sujeto(['This', study]), verbo([suggested]), complemento([that, a, role, of, 'STRA6', polymorphism, could, also, be, of, value, in, predicting, the, risk, of, 'T2DM', while, 'RARRES2', polymorphism, could, not, predict, the, risk, of, 'T2DM'])].
[sujeto(['We']), verbo([have]), complemento([investigated, transcriptional, and, epigenetic, differences, in, peripheral, blood, mononuclear, cells, '(', 'PBMCs)', of, monozygotic, female, twins, discordant, in, the, diagnosis, of, amyotrophic, lateral, sclerosis, '(', 'ALS)'])].
[sujeto(['The', 'ALS', 'twin\'s', 'PBMCs', spontaneously, produced, 'IL-6', and, 'TNF-α,', whereas, 'PBMCs', of, the, healthy, twin, produced, these, cytokines, only, when]), verbo([stimulated]), complemento([by, superoxide, dismutase, '(', 'SOD)-1'])].
[sujeto(['These', results, and, flow, cytometric, detection, of, 'CD45', and, 'CD127']), verbo([suggest]), complemento([the, presence, of, memory, 'T', cells, in, both, 'twins,', but, effector, 'T', cells, only, in, the, 'ALS', twin])].
[sujeto(['The', 'ALS', 'twin\'s', 'PBMC', 'supernatants,', but, not, the, healthy, 'twin\'s,', were, toxic, to, rat, cortical, 'neurons,', and, this, toxicity, was, strongly]), verbo([inhibited]), complemento([by, an, 'IL-6', receptor, antibody, '(', 'tocilizumab)', and, less, well, by, 'TNF-α', and, 'IL-1β', antibodies])].
[sujeto(['We', hypothesize, that, higher, macrophage, abundance, and]), verbo([increased]), complemento([neurotoxic, cytokines, have, a, fundamental, role, in, the, phenotype, and, treatment, of, certain, individuals, with, 'ALS'])].
[sujeto(['Here,', we]), verbo([provide]), complemento([the, first, evidence, that, a, small, percentage, of, 'APL', cells, undergo, a, novel, cell, death, pathway, by, releasing, extracellular, 'DNA', traps, '(', 'ETs)', in, untreated, patients])].
[sujeto(['Both', 'APL', and, 'NB4', cells]), verbo([stimulated]), complemento([with, 'APL', serum, had, nuclear, budding, of, vesicles, filled, with, chromatin, that, leaked, to, the, extracellular, space, when, nuclear, and, cell, membranes, ruptured])].
[sujeto(['Using', 'immunofluorescence,', we]), verbo([found]), complemento([that, 'NB4', cells, undergoing, 'ETosis', extruded, 'lattice-like', structures, with, a, 'DNA-histone', backbone])].
[sujeto(['The', levels, of, tumor, necrosis, 'factor-α', '(', 'TNF-α)', and, 'interleukin-6', '(', 'IL-6)', were, significantly, elevated, at, 3, 'days,', and, combined, treatment, with, 'TNF-α', and, 'IL-6']), verbo([stimulated]), complemento(['NB4', cells, to, release, 'ETs'])].
[sujeto(['Furthermore,', inhibition, of, autophagy, by, pharmacological, inhibitors, or, by, small, interfering, 'RNA', against, 'Atg7', attenuated, 'LC3', autophagy, formation, and, significantly]), verbo([decreased]), complemento(['ET', generation])].
[sujeto(['Our', results, identify, a, previously, unrecognized, mechanism, for, death, in, promyelocytes, and]), verbo([suggest]), complemento([that, 'ATRA', may, accelerate, 'ET', release, through, increased, cytokines, and, autophagosome, formation])].
[sujeto(['Targeting', this, cellular, death, pathway, in, addition, to, conventional, chemotherapy, may]), verbo([provide]), complemento([new, therapeutic, modalities, for, 'APL'])].
[sujeto(['Drosophila', 'Hyperplastic', 'Discs', '(', 'Hyd),', a, 'ubiquitin-protein', 'ligase,', represents, one, of, the, few, 'non-transcription', factors, that, independently]), verbo([regulates]), complemento([both, hh, mRNA, expression, and, pathway, activity])].
[sujeto(['Using', a, murine, embryonic, stem, cell, 'system,', we, revealed, that, shRNAi, of, the, mammalian, homologue, of, 'hyd,', 'Ubr5,', effectively]), verbo([prevented]), complemento(['retinoic-acid-induced', 'Sonic', hedgehog, '(', 'Shh)', expression])].
[sujeto(['Conditionally', deleting, 'Ubr5', in, the, early, embryonic, 'limb-bud', mesenchyme, resulted, in, a, transient]), verbo([decrease]), complemento([in, 'Indian', hedgehog, ligand, expression, and, decreased, 'Hh', pathway, 'activity,', around, 'E13'])].
[sujeto(['Hence,', while]), verbo([loss]), complemento([of, 'UBR5', perturbed, 'Hedgehog', signalling, in, the, developing, 'limb,', there, were, no, obvious, morphological, defects])].
[sujeto(['In', 'summary,', we]), verbo([report]), complemento([the, first, conditional, 'Ubr5', mutant, mouse, and, provide, evidence, for, a, role, for, 'UBR5', in, influencing, 'Hh', 'signalling,', but, are, uncertain, to, whether, the, effects, on, 'Hedgehog', signaling, were, direct, '(', cell, 'autonomous)', or, indirect, '(', 'non-cell-autonomous)'])].
[sujeto(['Elaboration', of, the, 'cellular/molecular', 'mechanism(s)']), verbo([involved]), complemento([may, help, our, understanding, on, diseases, and, developmental, disorders, associated, with, aberrant, 'Hh', signalling])].
[sujeto(['Treatments', included, direct, 'VA', combined, with, retinoic, acid, '(', 'RA)', '[', 'D-VARA;', 'VA', '(', 6, 'mg/kg)', +, 10, '%', 'RA,', given, orally, to, neonates, on, postnatal, day, '(', 'P)2', and, 'P3]', and, indirect, 'VA', supplementation, through]), verbo([increased]), complemento(['M-VA,', compared, with, each, other, and, 'oil-treated', neonates])].
[sujeto(['D-VARA', versus, placebo, dramatically]), verbo([increased]), complemento([liver, and, lung, 'retinol,', but, only, in, the, first, 8, -, 10, days])].
[sujeto(['In', 'M-VA', 'neonates,', liver, and, lung, 'VA']), verbo([increased]), complemento([progressively, throughout, the, study])].
[sujeto(['Compartmental', models, of, individual, tissues, predicted, that, 'D-VARA']), verbo([stimulated]), complemento([the, uptake, of, 'VA', in, chylomicrons, to, extrahepatic, 'tissues,', especially, 'intestine,', while, the, uptake, was, not, observed, in, 'M-VA', neonates])].
[sujeto(['Dyslipidemia']), verbo([has]), complemento([been, proven, to, capably, develop, and, aggravate, chronic, kidney, disease])].
[sujeto(['We', also]), verbo([report]), complemento([that, electronegative, 'LDL', '(', 'L5)', is, the, most, atherogenic, 'LDL'])].
[sujeto(['On', the, other, 'hand,', retinoic, acid, '(', 'RA)', and, 'RA', receptor, '(', 'RAR)', agonist, are]), verbo([reported]), complemento([to, be, beneficial, in, some, kidney, diseases])].
[sujeto([&, 'quot;Stimulated', by, retinoic, acid, 6, &, 'quot;', '(', 'STRA6),', one, 'retinol-binding', protein, 4, 'receptor,', was, recently, identified, to]), verbo([regulate]), complemento([retinoid, homeostasis])].
[sujeto(['Here,', we, observed, that, 'L5']), verbo([suppressed]), complemento(['STRA6', cascades, '[', 'STRA6,', cellular, 'retinol-binding', protein, 1, '(', 'CRBP1),', 'RARs,', retinoid, 'X', receptor, 'α,', and, 'retinol,', 'RA],', but, 'L5', simultaneously, induced, apoptosis, and, fibrosis, '(', 'TGFβ1,', 'Smad2,', collagen, 1, ',', 'hydroxyproline,', and, 'trichrome)', in, kidneys, of, 'L5-injected', mice, and, 'L5-treated', renal, tubular, cells])].
[sujeto(['For', mimicking, 'STRA6', 'deficiency,', efficient, silencing, of, 'STRA6', 'RNA', was, performed, and, was]), verbo([found]), complemento([to, repress, 'STRA6', cascades, and, caused, apoptosis, and, fibrosis, in, 'L1-treated', renal, tubular, cells])].
[sujeto(['In', 'summary,', this, study]), verbo([reveals]), complemento([that, electronegative, 'L5', can, cause, kidney, apoptosis, and, fibrosis, via, the, suppression, of, 'STRA6', 'cascades,', and, implicates, that, 'STRA6', signaling, may, be, involved, in, 'dyslipidemia-mediated', kidney, disease])].
[sujeto(['Aged', subjects, display]), verbo([increased]), complemento([susceptibility, to, mucosal, diseases])].
[sujeto(['Retinoic', 'Acid', '(', 'RA)', plays, a, major, role, in]), verbo([inducing]), complemento([tolerance, in, the, mucosa])].
[sujeto(['RA']), verbo([acts]), complemento([on, 'Dendritic', cells, '(', 'DCs)', to, induce, mucosal, tolerance])].
[sujeto(['Here', we, compared, the, response, of, 'DCs', from, aged, and, young, individuals, to, 'RA', with, a, view, to, understand, the, role, of, 'DCs', in, 'age-associated']), verbo([increased]), complemento([susceptibility, to, mucosal, diseases])].
[sujeto(['Our', investigations, revealed, that, compared, to, young, 'DCs,', 'RA']), verbo([stimulated]), complemento(['DCs', from, aged, subjects, are, defective, in, inducing, 'IL-10', and, 'T', regulatory, cells])].
[sujeto(['Examinations', of, the, underlying, mechanisms, indicated, that, 'RA', exposure]), verbo([led]), complemento([to, the, upregulation, of, 'CD141', and, 'GARP', on, 'DCs', which, rendered, the, 'DCs', tolerogenic])].
[sujeto(['CD141(hi),', 'GARP(+)', 'DCs', displayed]), verbo([enhanced]), complemento([capacity, to, induce, 'T', regulatory, cells, compared, to, 'CD141(lo)', and, 'GARP(-)', 'DCs'])].
[sujeto(['Unlike', 'RA']), verbo([stimulated]), complemento(['DCs', from, 'young,', 'DCs', from, aged, subjects, exhibited, diminished, upregulation, of, both, 'CD141', and, 'GARP'])].
[sujeto(['The', percentage, of, 'DCs']), verbo([expressing]), complemento(['CD141', and, 'GARP', on, 'RA', treatment, was, significantly, reduced, in, 'DCs', from, aged, individuals])].
[sujeto(['Furthermore,', the, remaining, 'CD141(hi),', 'GARP(+)', 'DCs', from, aged, individuals, were, also, deficient, in]), verbo([inducing]), complemento(['T', regs])].
[sujeto(['In', 'summary,', reduced, response, of, aged, 'DCs', to, 'RA']), verbo([enhances]), complemento([mucosal, inflammation, in, the, 'elderly,', increasing, their, susceptibility, to, mucosal, diseases])].
[sujeto(['Mounting', evidence]), verbo([has]), complemento([suggested, that, inflammation, is, associated, with, 'IL-6/Stat3', pathway, in, dendritic, cells, '(', 'DCs)', and, 'Th17', 'cells,', which, are, critical, for, development, of, allergic, contact, dermatitis, '(', 'ACD)'])].
[sujeto(['Paeoniflorin', '(', 'PF)']), verbo([has]), complemento([been, clinically, proved, to, be, effective, in, the, treatment, of, inflammatory, skin, diseases, such, as, 'ACD'])].
[sujeto(['We']), verbo([have]), complemento([previously, demonstrated, the, effect, of, 'PF', on, 'DCs', stimulated, with, 1, -, 'chloro-2,4-dinitrobenze', '(', 'DNCB)', and, naïve, 'CD4(+)CD45RA(+)', 'T', cells, for, 'Th17', cell, differentiation])].
[sujeto(['In', this, 'study,', we, show, clearly, that, 'PF', markedly]), verbo([decreases]), complemento(['IL-6/Stat3', in, 'DCs', stimulated, with, 'DNCB', at, both, gene, and, protein, levels, compared, with, control, 'DCs', in, vitro])].
[sujeto(['Such']), verbo([decreased]), complemento([expression, of, 'IL-6/Stat3', is, abolished, in, 'DCs', that, were, transfected, with, 'Socs3', short, interfering, 'RNA', '(', 'siRNA)'])].
[sujeto(['When', mice, 'CD4(+)CD45', 'RA(+)', 'T', cells, were, 'co-cultured', with, 'PF-treated', 'DCs']), verbo([stimulated]), complemento(['with/without', 'DNCB,', the, gene, expression, of, the, 'Th17', cell, markers, such, as, retinoic, 'acid-related', orphan, nuclear, hormone, receptor, γt, '(', 'RORγt),', 'IL-17A,', and, 'IL-23R', 'decreased,', in, accordance, with, the, less, secretions, of, 'IL-17', and, 'IL-23', in, vitro, and, in, vivo])].
[sujeto(['Finally,', the]), verbo([suppressed]), complemento(['Th17', differentiation, induced, by, 'PF', can, be, abolished, by, additional, recombinant, mouse, 'IL-6'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, the, 'anti-inflammatory', mechanisms, introduced, by, depletion, of, 'Socs3', expression, or, inactivation, of, the, negative, regulator, such, as, 'Socs3', may, represent, a, promising, strategy, for, the, prevention, of, 'ACD'])].
[sujeto(['Vitamin', 'A']), verbo([bound]), complemento([to, retinol, binding, protein, 4, '(', 'RBP4)', constitutes, the, major, transport, mode, for, retinoids, in, fasting, circulation])].
[sujeto(['Emerging', evidence]), verbo([suggests]), complemento([that, membrane, 'protein,', 'STRA6', '(', stimulated, by, retinoic, acid, 6, ')', ',', is, the, 'RBP4', receptor, and, vitamin, 'A', 'channel;', 'however,', the, role, of, 'STRA6', in, vitamin, 'A', homeostasis, remains, to, be, defined, in, vivo, 'We', subjected, 'Stra6-knockout', mice, to, diets, sufficient, and, insufficient, for, vitamin, 'A', and, used, heterozygous, siblings, as, controls])].
[sujeto(['We', determined, vitamin, 'A', levels, of, the, 'eyes,', 'brain,', and, 'testis,', which, highly]), verbo([express]), complemento(['Stra6,', as, well, as, of, tissues, with, low, 'expression,', such, as, lung, and, fat])].
[sujeto(['In', testis, and, 'brain,', 'Stra6', expression, was]), verbo([regulated]), complemento([by, vitamin, 'A'])].
[sujeto(['The', actions, of, 'RA', are]), verbo([mediated]), complemento([by, the, nuclear, receptors, retinoic, acid, receptor, '(', 'RAR)', and, retinoid, 'X', receptor, '(', 'RXR),', which, regulate, gene, expression])].
[sujeto(['RAR', and, 'RXR', are, widely]), verbo([expressed]), complemento([in, the, anterior, pituitary, gland])].
[sujeto(['RA', was]), verbo([reported]), complemento([to, stimulate, growth, hormone, '(', 'GH)', gene, expression, in, the, anterior, pituitary, cells])].
[sujeto(['Quantitative', 'real-time', 'PCR', revealed, that, treatment, with, 'all-trans', retinoic, acid, '(', 'ATRA;', 10, '(', -, 6, ')', 'M)', for, 24, h]), verbo([increased]), complemento([gene, expression, levels, of, 'Ghrh-r', and, 'Ghs-r;', 'however,', expressions, of, 'Sst-r2', and, 'Sst-r5', were, unchanged])].
[sujeto(['In', 'contrast,', 'ATRA']), verbo([increased]), complemento([growth, 'hormone-releasing', hormone, '(', 'GHRH)-', and, 'ghrelin-stimulated', 'GH', release, from, cultured, anterior, pituitary, cells])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, expressions, of, 'Ghrh-r', and, 'Ghs-r', are, regulated, by, 'RA', through, the, 'RAR-RXR', receptor, complex, and, that, 'RA', enhances, the, effects, of, 'GHRH', and, ghrelin, on, 'GH', release, from, the, anterior, pituitary, gland])].
[sujeto(['Melanoma', 'differentiation-associated', gene, 5, '(', 'MDA5)', is, a, critical, member, of, retinoic, 'acid-inducible', gene, 'I', '(', 'RIG-I)-like', receptor, '(', 'RLR)', family, which, can]), verbo([recognize]), complemento([viral, 'RNA', and, enhances, antiviral, response, in, host, cells])].
[sujeto(['Interestingly,', during, virus, 'infection,', the, distribution, pattern, of, 'EcMDA5', was, significantly, altered, in, 'SGIV', infected, 'cells,', but, not, in, red, spotted, grouper, nervous, necrosis, virus, '(', 'RGNNV)', infected, 'cells,']), verbo([suggested]), complemento([that, 'EcMDA5', might, interact, with, viral, proteins, during, 'SGIV', infection])].
[sujeto(['The', ectopic, expression, of, 'EcMDA5', 'in&nbsp;vitro', obviously, delayed, virus, infection]), verbo([induced]), complemento([cytopathic, effect, '(', 'CPE)', progression, and, significantly, inhibited, viral, gene, transcription, of, 'RGNNV', and, 'SGIV'])].
[sujeto(['Moreover,', overexpression, of, 'EcMDA5', not, only, significantly]), verbo([increased]), complemento([interferon, '(', 'IFN)', and, 'IFN-stimulated', response, element, '(', 'ISRE)', promoter, activities, in, a, dose, dependent, 'manner,', but, also, enhanced, the, expression, of, 'IRF3,', 'IRF7', and, 'TRAF6'])].
[sujeto(['In', 'addition,', the, transcription, level, of, the, proinflammatory, 'factors,', including, 'TNF-α,', 'IL-6', and, 'IL-8', were, differently, altered, by, 'EcMDA5', overexpression, during, 'SGIV', or, 'RGNNV', 'infection,']), verbo([suggesting]), complemento([that, the, regulation, on, proinflammatory, cytokines, by, 'EcMDA5', were, also, important, for, 'RGNNV', infection])].
[sujeto(['IL-6', and, 'IL-23', '(', 'IL-6/23)']), verbo([induce]), complemento(['IL-17A', '(', 'IL-17)', production, by, a, subpopulation, of, murine, and, human, 'neutrophils,', resulting, in, autocrine, 'IL-17', 'activation,', enhanced, production, of, reactive, oxygen, 'species,', and, increased, fungal, killing])].
[sujeto(['As', 'IL-6', and, 'IL-23', receptors]), verbo([trigger]), complemento(['JAK1,', -, 3, /, 'STAT3', and, 'JAK2/STAT3', 'phosphorylation,', 'respectively,', we, examined, the, role, of, this, pathway, in, a, murine, model, of, fungal, keratitis, and, also, examined, neutrophil, elastase, and, gelatinase, '(', matrix, metalloproteinase, 9, ')', activity, by, 'IL-6/23-stimulated', human, neutrophils, in, vitro])].
[sujeto(['We']), verbo([found]), complemento([that, 'STAT3', phosphorylation, of, neutrophils, in, 'Aspergillus', 'fumigatus-infected', corne, as, was, inhibited, by, the, 'JAK/STAT', inhibitor, 'Ruxolitinib,', resulting, in, impaired, fungal, killing, and, decreased, matrix, metalloproteinase, 9, activity])].
[sujeto(['This', was, also]), verbo([associated]), complemento([with, decreased, reactive, oxygen, 'species,', 'IL-17A', 'production,', and, retinoic, acid, 'receptor-related', orphan, receptor, γt, translocation, to, the, nucleus])].
[sujeto(['We', also, demonstrate, that, 'IL-6/23-activated', neutrophils, exhibit]), verbo([increased]), complemento([elastase, and, gelatinase, '(', matrix, metalloproteinase, 9, ')', 'activity,', which, is, inhibited, by, 'Ruxolitinib', and, 'Stattic', but, not, by, 'SR1001'])].
[sujeto(['Taken', 'together,', these, observations, indicate, that, the, regulation, of, activity, of, 'IL-17-producing', neutrophils, by, 'JAK/STAT', inhibitors, impairs, reactive, oxygen, species, production, and, fungal, killing, activity, but, also, blocks, elastase, and, gelatinase, activity, that, can]), verbo([cause]), complemento([tissue, damage])].
[sujeto(['Previous', studies]), verbo([found]), complemento([that, retinoic, acid, could, influence, the, metabolism, of, scleral, remodeling, by, promoting, retinal, pigment, epithelium, '(', 'RPE)', cells, to, secrete, secondary, signaling, factors])].
[sujeto(['RARβ', mRNA, levels, significantly]), verbo([increased]), complemento([in, the, 'ARPE-19', cells, treated, with, 'ATRA', for, 24, h, and, 48, h])].
[sujeto(['These']), verbo([increases]), complemento([in, 'RARβ', mRNA, levels, were, dose, dependent, '(', at, concentrations, of, 10, -, 9, to, 10, -, 5, 'mol/l)', with, a, maximum, effect, observed, at, 10, -, 6, 'mol/l'])].
[sujeto(['Western', blot, assay, revealed, that, 'RARβ', protein, levels, were]), verbo([increased]), complemento([significantly, in, a, 'time-dependent', manner, in, 'ARPE-19', cells, treated, with, 10, -, 6, 'mol/l', 'ATRA', from, 12, h, to, 72, 'h,', with, a, marked, increase, observed, at, 24, h, and, 48, h])].
[sujeto(['The', upregulation, of, 'RARβ', and, the, 'ATRA-induced', secretion, in, 'ARPE-19', cells, could, be]), verbo([inhibited]), complemento([by, the, 'RARβ', antagonist, 'LE135'])].
[sujeto(['ATRA']), verbo([induced]), complemento([upregulation, of, 'RARβ', in, 'ARPE-19', cells, and, stimulated, these, cells, to, secrete, 'BMP-2', and, 'MMP-2'])].
[sujeto(['(', 'Anacardiaceae', 'family)', contain, neomangiferin, as, the, main, active, constituent, and]), verbo([have]), complemento([been, used, to, treat, 'inflammation,', 'asthma,', and, pain])].
[sujeto(['A', preliminary, study]), verbo([found]), complemento([that, neomangiferin, inhibited, splenic, 'T', cell, differentiation, into, 'Th17', cells, and, promoted, 'Treg', cell, production, in, vitro])].
[sujeto(['Colitis', was, either]), verbo([induced]), complemento([in, vivo, by, intrarectal, administration, of, 2, ',', 4, ',', 6, -, trinitrobenzene, sulfonic, acid, '(', 'TNBS)', to, 'C57BL/6J', mice, or, occurred, spontaneously, in, colitis, caused, by, interleukin, '(', 'IL)-10', knockout, at, age, of, 13, weeks])].
[sujeto(['Neomangiferin']), verbo([suppressed]), complemento([retinoic, acid, 'receptor-related', orphan, receptor, gamma, t, '(', 'RORγt)', and, 'IL-17', expression, in, 'IL-6/transforming', growth, factor, 'β-stimulated', 'Th17', splenocytes, and, increased, 'IL-10', expression, in, vitro])].
[sujeto(['Mouse', 'TNBS-induced', colon, 'shortening,', macroscopic, 'score,', and, myeloperoxidase, activity, were]), verbo([inhibited]), complemento([by, 'neomangiferin,', which, also, reduced, 'TNBS-induced', activation, of, nuclear, 'factor-κB', and, extracellular, 'signal-regulated', 'kinases,', as, well, as, expression, of, inducible, nitric, oxide, synthase, and, 'cyclooxygenase-2'])].
[sujeto(['In', 'addition,', neomangiferin]), verbo([inhibited]), complemento(['TNBS-induced', expression, of, tumor, necrosis, 'factor-α,', 'IL-17,', 'IL-6,', and, 'IL-1β,', and, increased, 'IL-10', expression])].
[sujeto(['Neomangiferin']), verbo([inhibited]), complemento(['TNBS-induced', differentiation, to, 'Th17', cells, and, promoted, the, development, of, 'Treg', cells])].
[sujeto(['Moreover,', in, 'IL-10(-/-)', 'mice,', neomangiferin]), verbo([inhibited]), complemento([colonic, myeloperoxidase, 'activity,', suppressed, 'Th17', cell, 'differentiation,', and, reduced, levels, of, 'TNF-α', and, 'IL-17'])].
[sujeto(['Neomangiferin', may, restore, the, balance, between, 'Th17/Treg', cells, by]), verbo([suppressing]), complemento(['IL-17', and, 'RORγt', expression, and, inducing, 'IL-10', and, forkhead, box, 'P3', 'expression,', thus, ameliorating, colitis])].
[sujeto(['Fenretinide', is, a, synthetic, retinoid, analogue, that]), verbo([promotes]), complemento([apoptosis, but, has, decreased, toxicity, when, compared, to, other, retinoids])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, retinoic, acid, '(', 'RA)', production, in, endometriotic, tissue, is, 'decreased,', resulting, in, reduced, estrogen, metabolism, and, apoptotic, resistance])].
[sujeto(['We', hypothesize, fenretinide, may]), verbo([induce]), complemento([apoptosis, in, endometriotic, cells, and, 'tissues,', thereby, reducing, disease, burden])].
[sujeto(['Quantitative', reverse, 'transcription-polymerase', chain, reaction, from, endometriotic, cells, treated, with, fenretinide, was, used, to, examine, expression, of, genes]), verbo([involved]), complemento([in, 'RA', signaling, including, stimulated, by, 'RA', 6, '(', 'STRA6),', cellular, 'RA', binding, protein, 2, '(', 'CRABP2),', and, fatty, acid, binding, protein, 5, '(', 'FABP5)'])].
[sujeto(['Treatment', with, fenretinide, significantly]), verbo([decreased]), complemento([total, cell, count, '(', doses, 5, -, 20, 'µL)', and, viability, '(', doses, 10, -, 20, 'µmol/L)'])].
[sujeto(['Fenretinide']), verbo([increased]), complemento([protein, levels, of, the, apoptotic, marker, poly, '(', 'ADP', 'ribose)', polymerase, '(', starting, at, 10, 'µmol/L)', and, decreased, proliferation, marker, proliferating, cell, nuclear, antigen, '(', 10, 'µmol/L,', starting, at, 8, -, day, 'treatment)'])].
[sujeto(['Examination', of, genes]), verbo([involved]), complemento([in, retinoid, uptake, and, action, showed, that, treatment, induced, 'STRA6', expression, while, expression, of, 'CRABP2', and, 'FABP5', remained, unchanged])].
[sujeto(['Fenretinide', also, significantly]), verbo([decreased]), complemento([the, endometriotic, lesion, xenograft, volume])].
[sujeto(['Fenretinide']), verbo([increases]), complemento(['STRA6', expression, thereby, potentially, reversing, the, pathological, loss, of, retinoid, availability])].
[sujeto(['Treatment', with, this, compound]), verbo([induces]), complemento([apoptosis])].
[sujeto(['In', vivo, treatments]), verbo([decrease]), complemento([lesion, volume])].
[sujeto(['When', retinoic, 'acid-inducible', gene, 1, protein, '(', 'RIG-I)-like', receptors, sense, viral, dsRNA, in, the, 'cytosol,', 'RIG-I', and, melanoma, 'differentiation-associated', gene, 5, '(', 'MDA5)', are]), verbo([recruited]), complemento([to, the, mitochondria, to, interact, with, mitochondrial, antiviral, signaling, protein, '(', 'MAVS)', and, initiate, antiviral, immune, responses])].
[sujeto(['In', this, 'study,', we, demonstrate, that, the, 'biotin-containing', enzyme, pyruvate, carboxylase, '(', 'PC)', plays, an, essential, role, in, the, 'virus-triggered', activation, of]), verbo([nuclear]), complemento([factor, kappa, 'B', '(', 'NF-κB)', signaling, mediated, by, 'MAVS'])].
[sujeto(['PC', contributes, to, the]), verbo([enhanced]), complemento([production, of, type, 'I', interferons, '(', 'IFNs)', and, 'pro-inflammatory', 'cytokines,', and, 'PC', knockdown, inhibits, the, 'virus-triggered', innate, immune, response])].
[sujeto(['Furthermore,', 'PC']), verbo([mediates]), complemento([antiviral, action, by, targeting, the, 'MAVS', signalosome, and, induces, 'IFNs', and, 'pro-inflammatory', cytokines, by, promoting, phosphorylation, of, 'NF-κB', 'inhibitor-α', '(', 'IκBα)', and, the, 'IκB', kinase, '(', 'IKK)', 'complex,', as, well, as, 'NF-κB', nuclear, 'translocation,', which, leads, to, activation, of, 'interferon-stimulated', genes, '(', 'ISGs),', including, 'double-stranded', 'RNA-dependent', protein, kinase, '(', 'PKR)', and, myxovirus, resistance, protein, 1, '(', 'Mx1)'])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, 'PC', is, an, important, player, in, host, antiviral, signaling])].
[sujeto([9, -, 'cis-Retinoic', acid, '(', 9, 'cRA),', which]), verbo([binds]), complemento([to, both, retinoic, acid, receptors, and, retinoic, 'X', 'receptors,', inhibits, prostate, cancer, induction, in, rats, and, reduces, growth, of, prostate, cancer, cells])].
[sujeto([9, cRA]), verbo([inhibited]), complemento([cell, proliferation, in, a, 'dose-dependent', 'manner,', plateauing, at, 10, 'mol/l'])].
[sujeto(['Treatment', of, cells, with, 10, 'mol/l', 9, cRA]), verbo([inhibited]), complemento([5, 'α-dihydroxytestosterone', '(', 'DHT)-stimulated', 'proliferation,', the, effect, of, which, was, maximal, at, 10, 'mol/l', 'DHT'])].
[sujeto(['Treatment', of, 'DHT', '(', 10, 'mol/l)-exposed', cells, with, 9, cRA]), verbo([caused]), complemento([a, 'dose-dependent', increase, in, 'prostate-specific', antigen, in, the, medium, after, 6, 'days,', but, not, 3, days])].
[sujeto([9, cRA]), verbo([caused]), complemento([a, 'dose-dependent', increase, in, apoptotic, cells, stained, with, 'H33258', after, 3, 'days,', but, not, 6, 'days;', 'however,', on, using, flow, 'cytometry,', apoptosis, was, apparent, at, both, 3, and, 6, days])].
[sujeto([9, cRA]), verbo([inhibited]), complemento([growth, and, induced, differentiation, of, human, 'LNCaP', prostate, cancer, cells, in, vitro, and, inhibited, 'anchorage-independent', growth, of, 'PC-3', cells])].
[sujeto(['Because', 9, cRA, and, 13, -, 'cis-retinoic', 'acid,', which, is, retinoic, acid, 'receptor-selective,']), verbo([prevent]), complemento([prostate, carcinogenesis, in, 'rats,', and, 13, -, 'cis-retinoic', acid, also, inhibits, growth, of, human, prostate, cancer, 'cells,', the, 'RAR', is, a, potential, molecular, target, for, prostate, cancer, prevention, and, therapy])].
[sujeto(['(', -, ')', -, 'Epigallocatechin-3-gallate', '(', 'EGCG),', a, major, polyphenol, component, of, green, 'tea,']), verbo([has]), complemento([recently, been, identified, as, an, inhibitor, of, hepatitis, 'C', virus, '(', 'HCV)', entry])].
[sujeto(['Here,', we, examined, whether, 'EGCG', can]), verbo([enhance]), complemento(['hepatocyte-mediated', intracellular, innate, immunity, against, 'HCV'])].
[sujeto(['HCV', dsRNAs, '(', 'Core,', 'E1-P7,', 'NS-3\'NTR', and, 'NS5A)']), verbo([induced]), complemento(['interferon-λ1', '(', 'IFN-λ1)', expression, in, human, hepatocytes])].
[sujeto(['These', 'HCV', dsRNAs, also]), verbo([induced]), complemento([the, expression, of, 'Toll-like', receptor, 3, '(', 'TLR3),', retinoic, 'acid-inducible', gene, 'I', '(', 'RIG-I)', and, several, antiviral, 'IFN-stimulated', genes, '(', 'ISGs)', expression])].
[sujeto(['Although', 'EGCG', treatment, of, hepatocytes, alone, had, little, effect, on, 'TLR3', and, 'RIG-I', signaling, 'pathways,', 'EGCG', significantly]), verbo([enhanced]), complemento(['HCV', 'dsRNAs-induced', the, expression, of, 'IFN-λ1,', 'TLR3,', 'RIG-I', and, antiviral, 'ISGs', in, hepatocytes])].
[sujeto(['Furthermore,', treatment, of, 'HCV-infected', hepatocytes, with, 'EGCG', and, 'HCV', dsRNAs]), verbo([inhibited]), complemento([viral, replication])].
[sujeto(['Given', that, 'EGCG']), verbo([has]), complemento([the, ability, to, enhance, 'HCV', 'dsRNAs-induced', intracellular, antiviral, innate, immunity, against, 'HCV,', suggesting, the, potential, application, of, 'EGCG', as, a, new, 'anti-HCV', agent, for, 'HCV', therapy])].
[sujeto(['We']), verbo([have]), complemento([recently, characterized, the, role, of, lipocalin, 2, '(', 'Lcn2)', as, a, new, 'adipose-derived', cytokine, in, the, regulation, of, adaptive, thermogenesis, via, a, 'non-adrenergic', pathway])].
[sujeto(['Herein,', we, explored, a, potential, 'non-adrenergic', mechanism, by, which, 'Lcn2']), verbo([regulates]), complemento([thermogenesis, and, lipid, metabolism])].
[sujeto(['We']), verbo([found]), complemento([that, 'Lcn2', is, a, retinoic, acid, target, 'gene,', and, retinoic, acid, concurrently, stimulated, 'UCP1', and, 'Lcn2', expression, in, adipocytes])].
[sujeto(['We', further, demonstrated, that, 'Lcn2', is]), verbo([required]), complemento([for, the, full, action, of, 'ATRA', on, the, induction, of, 'UCP1', and, 'PGC-1α', expression, in, brown, adipocytes, and, the, restoration, of, cold, intolerance, in, 'Lcn2', 'KO', mice])].
[sujeto(['Interestingly,', we, discovered, that, 'Lcn2', 'KO', mice]), verbo([have]), complemento([decreased, levels, of, retinoic, acid, and, retinol, in, adipose, tissue])].
[sujeto(['The', protein, levels, of, 'STRA6', responsible, for, retinol, uptake, were, significantly]), verbo([decreased]), complemento([in, adipose, tissue])].
[sujeto(['The', retinol, transporter, 'RBP4', was]), verbo([increased]), complemento([in, adipose, tissue, but, decreased, in, the, 'circulation,', suggesting, the, impairment, of, 'RBP4', secretion, in, 'Lcn2', 'KO', adipose, tissue])].
[sujeto(['All', the, data]), verbo([suggest]), complemento([that, the, decreased, retinoid, level, and, action, are, associated, with, impaired, retinol, transport, and, storage, in, adipose, tissue, in, 'Lcn2', 'KO', mice])].
[sujeto(['We', conclude, that, 'Lcn2', plays, a, critical, role, in]), verbo([regulating]), complemento([metabolic, homeostasis, of, retinoids, and, 'retinoid-mediated', thermogenesis, in, adipose, tissue])].
[sujeto(['We', also, investigated, the, response, to, supplementation, with, 'VARA,', a, combination, of, 'VA', and, 10, '%', 'all-trans-retinoic', acid, that, previously, was, shown, to, synergistically]), verbo([increase]), complemento([retinol, uptake, and, storage, in, lung])].
[sujeto(['VARA', supplementation]), verbo([increased]), complemento([total, retinol, in, 'plasma,', liver, and, 'lung,', with, a, 'dose-by-dose', accumulation, in, neonatal, liver, and, 'lung,', while, transcripts, for, 'Lrat', in, 'liver,', megalin, in, 'kidney,', 'Cyp26A1/B1', in, liver, and, 'lung,', 'respectively,', and, 'Stra6', in, 'lung,', were, all, 'increased,', suggesting, pathways, of, 'VA', 'uptake,', storage, and, 'RA', oxidation, were, each, augmented, after, 'VARA'])].
[sujeto(['VARA']), verbo([decreased]), complemento([hepatic, expression, of, 'Rbp4,', responsible, for, 'VA', trafficking, from, liver, to, 'plasma,', 'and,', in, 'lung,', of, 'Raldh-1', and, 'Raldh-2,', which, function, in, 'RA', production])].
[sujeto(['Our', results, define, retinoid, homeostatic, gene, expression, from, neonatal, and, adult, age, and, show, that, while, supplementation, with, 'VARA', acutely, alters, retinol, content, and, retinoid, homeostatic, gene, expression, in, neonatal, and, adult, 'lung,', liver, and, 'kidney,', 'VARA', supplementation, of, neonates]), verbo([increased]), complemento(['adult-age', 'VA', content, only, in, the, liver])].
[sujeto(['Vitamin', 'A,', 'retinol,', circulates, in, blood]), verbo([bound]), complemento([to, 'retinol-binding', protein, '(', 'RBP4)', 'which,', in, 'turn,', associates, with, another, serum, 'protein,', transthyretin, '(', 'TTR),', to, form, a, ternary, 'retinol-RBP4-TTR', complex])].
[sujeto(['At', some, 'tissues,', 'retinol-bound', '(', 'holo-)', 'RBP4', is, recognised, by, a, receptor, termed]), verbo([stimulated]), complemento([by, retinoic, acid, 6, '(', 'STRA6)', which, transports, retinol, into, cells])].
[sujeto(['This', 'mini-review', summarises, evidence, demonstrating, 'that,', in, addition, to, functioning, as, a, retinol, 'transporter,', 'STRA6', is, also, a, signalling, receptor, which, is]), verbo([activated]), complemento([by, 'holo-RBP4'])].
[sujeto(['The', data, show, that, 'STRA6-mediated', retinol, transport]), verbo([induces]), complemento([receptor, 'phosphorylation,', in, turn, activating, a, 'Janus', 'kinases2/signal', transducers, and, activators, of, transcription, '(', 'STAT)3/5', cascade, that, culminates, in, induction, of, 'STAT', target, genes])].
[sujeto(['For', 'example,', by]), verbo([inducing]), complemento([the, expression, of, the, 'STAT', target, gene, suppressor, of, cytokine, signalling, 3, ',', 'STRA6', potently, suppresses, insulin, responses])].
[sujeto(['These', observations]), verbo([provide]), complemento([a, rationale, for, understanding, the, reports, that, elevation, in, serum, levels, of, 'RBP4,', often, observed, in, obese, mice, and, human, 'subjects,', causes, insulin, resistance])].
[sujeto(['The', observations, indicate, that, the, 'holo-RBP4', /, 'STRA6', signalling, cascade, may, comprise, an, important, link, through, which, obesity]), verbo([leads]), complemento([to, insulin, resistance, and, suggest, that, the, pathway, may, be, a, novel, target, for, treatment, of, metabolic, diseases])].
[sujeto(['Up', to, 'now,', it]), verbo([has]), complemento([been, accepted, that, the, effects, of, vitamin, 'A', are, exerted, by, active, 'metabolites,', the, major, ones, being, 11, -, cis, retinal, for, 'vision,', and, all, 'trans-retinoic', acid, '(', 'RA)', for, cell, growth, and, differentiation])].
[sujeto(['Basically', 'RA']), verbo([binds]), complemento([nuclear, 'receptors,', 'RARs,', which, regulate, the, expression, of, a, battery, of, target, genes, in, a, ligand, dependent, manner])].
[sujeto(['During', the, last, 'decade,', new, scenarios]), verbo([have]), complemento([been, 'discovered,', providing, a, rationale, for, the, understanding, of, other, 'long-noted', but, not, explained, functions, of, retinol])].
[sujeto(['These', novel, scenarios, 'involve:', '(', 'i)', other]), verbo([nuclear]), complemento([receptors, such, as, 'PPAR', 'β/δ,', which, regulate, the, expression, of, other, target, genes, with, other, 'functions;', '(', 'ii)', extranuclear, and, nontranscriptional, 'effects,', such, as, the, activation, of, 'kinases,', which, phosphorylate, 'RARs', and, other, transcription, 'factors,', thus, expanding, the, list, of, the, 'RA-activated', 'genes;', '(', 'iii)', 'finally,', vitamin, 'A', is, active, per, se, and, can, work, as, a, cytokine, that, regulates, gene, transcription, by, activating, 'STRA6'])].
[sujeto(['New', effects, of, vitamin, 'A', and, 'RA', are, continuously, being, discovered, in, new, 'fields,']), verbo([revealed]), complemento([new, targets, and, new, mechanisms, thus, improving, the, understanding, the, pleiotropicity, of, their, effects])].
[sujeto(['The', disorder, is]), verbo([caused]), complemento([by, mutations, in, 'STRA6,', an, important, regulator, of, vitamin, 'A', and, retinoic, acid, metabolism])].
[sujeto(['The', phenotypic, spectrum, of, 'PDAC', syndrome]), verbo([has]), complemento([until, now, not, included, contractures, or, camptodactyly])].
[sujeto(['We', also]), verbo([provide]), complemento([a, focused, review, of, all, published, 'PDAC', syndrome, cases, with, confirmed, or, inferred, 'STRA6', 'mutations,', illustrating, the, phenotypic, and, molecular, variability, that, characterizes, this, disorder])].
[sujeto(['Distribution', of, vitamin, 'A', throughout, the, body, is, important, to]), verbo([maintain]), complemento([retinoid, function, in, peripheral, tissues, and, to, ensure, optimal, vision])].
[sujeto(['Increasing', evidence, indicates, that, this, process, is]), verbo([mediated]), complemento([by, a, multidomian, membrane, protein, that, is, encoded, by, the, stimulated, by, retinoic, acid, 6, '(', 'STRA6)', gene])].
[sujeto(['Biochemical', studies, revealed, that, 'STRA6', is, a, transmembrane, pore, which, transports, vitamin, 'A', bidirectionally, between, 'extra-', and, intracellular, retinoid]), verbo([binding]), complemento([proteins])].
[sujeto(['Loss-of-function', studies, in, zebrafish, and, mouse, models]), verbo([have]), complemento([unraveled, the, critical, importance, of, 'STRA6', for, vitamin, 'A', homeostasis, of, peripheral, tissues])].
[sujeto(['Impairment', in, vitamin, 'A', transport, and, uptake, homeostasis, are]), verbo([associated]), complemento([with, diseases, including, type, 2, diabetes, and, a, microphthalmic, syndrome, known, as, 'Matthew', 'Wood', 'Syndrome'])].
[sujeto(['Obesity,', insulin, 'resistance,', metabolic, syndrome, and, type, 2, diabetes]), verbo([have]), complemento([reached, epidemic, 'proportions,', from, the, 'term:', diabesity])].
[sujeto(['Vitamin', 'A', is, delivered, by, a, specific]), verbo([binding]), complemento([protein, called, 'retinol-binding', protein, 4, '(', 'RBP4)', a, soluble, 'protein,', emerging, to, have, a, role, in, insulin, 'resistance,', the, major, cause, of, diabetes, is, highly, associated, with, adipose, tissue, inflammation, and, obesity, with, action])].
[sujeto(['RBP4,']), verbo([interacts]), complemento([with, two, 'receptors,', the, 'Toll-like', receptor, 4, '(', 'TLR4)', and, the, plasma, membrane, protein, are, stimulated, by, retinoic, acid, 6, '(', 'STRA6),', leading, to, the, activation, of, 'c-Jun', 'N-terminal', protein, kinase, '(', 'JNK)', pathways, and, 'JAK2/STAT5', 'cascade,', respectively])].
[sujeto(['Not', only, proteins, in, vitamin, 'A', shuttle, and, signaling, are, emerging, in, 'diabesity,', 'recently,', the, discovery, of, 9, cis, retinoic, acid, '(', 9, 'cRA)', with, effects, on, controlling, glucose, levels]), verbo([have]), complemento([opened, a, new, scenario])].
[sujeto(['So', 'far,', only, pancreas, 'β-cells']), verbo([have]), complemento([been, shown, to, synthesize, 'it,', and, high, levels, of, 9, cRA, correlate, with, obesity, mice, models])].
[sujeto(['Nearly', a, decade, of, intense, research]), verbo([has]), complemento([passed, since, the, first, report, linking, circulating, retinol, binding, protein, 4, '(', 'RBP4)', to, the, development, of, insulin, resistance])].
[sujeto(['By', 'now,', a, variety, of, underlying, mechanisms]), verbo([have]), complemento([been, 'identified;', some, of, them, are, adherent, to, the, canonical, role, of, this, circulating, 'protein,', which, is, to, transport, and, deliver, retinol, to, target, 'tissues,', and, others, that, seem, rather, independent, of, retinol, transport])].
[sujeto(['Despite', all, these, 'efforts,', a, consensus, in, the, basic, principles, of, 'RBP4\'s', metabolic, effects]), verbo([has]), complemento([not, been, reached, and, some, controversy, remains])].
[sujeto(['We', pay, special, attention, to, the, involvement, of, 'RBP4', membrane, receptors, that, were, identified, during, these, 'years,', such, as, '\'']), verbo([stimulated]), complemento([by, retinoic, acid, 6, '\'', '(', 'STRA6),', and, whose, identification, added, another, layer, of, complexity, to, 'RBP4\'s', diverse, actions])].
[sujeto(['A', better, understanding, of, 'RBP4\'s', functions, might, allow, its, therapeutic, 'exploitations,', urgently, needed, in, our, period, that, is, defined, by, an, epidemic]), verbo([increase]), complemento([in, metabolic, diseases, such, as, obesity, and, type, 2, diabetes])].
[sujeto(['Activated', hepatic, stellate, cells, '(', 'HSCs)', play, a, key, role, in, liver, 'fibrosis,', and, inactivating, 'HSCs']), verbo([has]), complemento([been, considered, a, promising, therapeutic, approach])].
[sujeto(['R-III', treatment, and, albumin, expression, downregulated, retinoic, acid, '(', 'RA)', signaling, which, was]), verbo([involved]), complemento([in, 'HSC', activation])].
[sujeto(['R-III', uptake, into, cultured, 'HSCs', was, significantly]), verbo([decreased]), complemento([by, 'siRNA-STRA6,', and, injected, 'R-III', was, localized, predominantly, in, 'HSCs', in, liver])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, 'anti-fibrotic', effect, of, 'albumin/R-III', 'is,', at, least, in, 'part,', mediated, by, downregulation, of, 'RA', signaling, and, that, 'R-III', is, a, good, candidate, as, a, novel, 'anti-fibrotic', drug])].
[sujeto(['The', 'Stra6', protein]), verbo([binds]), complemento([the, serum, 'retinol-binding', 'protein,', 'RBP4,', and, acts, in, conjunction, with, the, enzyme, 'lecithin:retinol', acyltransferase, to, facilitate, retinol, uptake, in, some, cell, types])].
[sujeto(['We', show, that, in, embryonic, stem, '(', 'ES)', cells, and, in, some, 'tissues,', the, 'Stra6', gene, encodes, two, distinct, mRNAs]), verbo([transcribed]), complemento([from, two, different, promoters])].
[sujeto(['Whereas', both, are, 'all-trans-retinoic', acid, '(', 'RA)-responsive', in, 'ES', 'cells,', the, downstream, promoter, contains, a, 'half-site', 'RA', response, element, '(', 'RARE)', and, drives, an, '∼', 13, -, 'fold,', 'RA-associated']), verbo([increase]), complemento([in, luciferase, reporter, activity])].
[sujeto(['We', employed, 'CRISPR-Cas9', genome, editing, to, show, that, the, endogenous, 'RARE', is]), verbo([required]), complemento([for, 'RA-induced', transcription, of, both, 'Stra6', isoforms])].
[sujeto(['We', further, demonstrate, that, in, 'ES', 'cells,', 1, ')', both, 'RARγ', and, 'RXRα', are, present, at, the, 'Stra6', 'RARE;', 2, ')', 'RA']), verbo([increases]), complemento(['co-activator', p300, '(', 'KAT3B)', binding, and, histone, 'H3', 'Lys-27', acetylation, at, both, 'promoters;', 3, ')', 'RA', decreases, 'Suz12', levels, and, histone, 'H3', 'Lys-27', trimethylation, epigenetic, marks, at, both, 'promoters;', and, 4, ')', these, epigenetic, changes, are, diminished, in, the, absence, of, 'RARγ'])].
[sujeto(['In', the, brains, of, 'WT', 'mice,', both, the, longer, and, the, shorter, 'Stra6', transcript, '(', 'Stra6L', and, 'Stra6S,', 'respectively)', are, highly, 'expressed,', whereas, these, transcripts, are]), verbo([found]), complemento([only, at, low, levels, in, 'RARγ(-/-)', mice])].
[sujeto(['Our', data, show, that, kidneys]), verbo([respond]), complemento([to, retinol, deficiency, by, differential, 'Stra6', promoter, 'usage,', which, may, play, a, role, in, the, retention, of, retinol, when, vitamin, 'A', is, low])].
[sujeto(['(', 'Gly773Arg),', expanding, the, phenotype]), verbo([associated]), complemento([with, 'COL4A1', to, include, cardiomyopathy])].
[sujeto([401, -, 1, 'G&gt;A,', and, we, describe, eye, defects]), verbo([associated]), complemento([with, this, gene, for, the, first, time])].
[sujeto(['Seasonal', or, photoperiodically, sensitive, animals]), verbo([respond]), complemento([to, altered, day, length, with, changes, in, physiology, '(', 'growth,', food, intake, and, reproductive, 'status)', and, behaviour, to, adapt, to, predictable, yearly, changes, in, the, climate])].
[sujeto(['Although', laboratory, rats, are, generally, considered, 'nonphotoperiodic,', one, rat, 'strain,', the, inbred, 'Fischer', 344, '(', 'F344)', 'rat,']), verbo([has]), complemento([been, shown, to, be, sensitive, to, the, length, of, daylight, exposure, by, changing, its, physiological, phenotype, and, reproductive, status, according, to, the, season])].
[sujeto(['We']), verbo([found]), complemento([that, rats, held, under, photoperiods, of, '≥&nbsp;12&nbsp;h', of, 'light/day', showed, increased, growth, and, food, intake, relative, to, rats, held, under, photoperiods, of, '≤&nbsp;10&nbsp;h', of, 'light/day'])].
[sujeto(['Fenretinide', is, a, synthetic, retinoid, that]), verbo([has]), complemento([been, evaluated, in, clinical, trials, as, a, cancer, therapeutic, and, 'chemo-preventive', agent])].
[sujeto(['Fenretinide']), verbo([has]), complemento([been, established, to, be, cytotoxic, to, many, kinds, of, cancer, cells])].
[sujeto(['In', the, present, 'study,', we, demonstrate, that, fenretinide]), verbo([decreased]), complemento([cell, viability, and, induced, apoptosis, in, 'Ishikawa', 'cells,', which, are, an, endometrial, cancer, cell, 'line,', in, dose, dependent, manner, 'in-vitro'])].
[sujeto(['This', effect, was]), verbo([found]), complemento([to, be, independent, of, retinoic, acid, nuclear, receptor, signaling, pathway])].
[sujeto(['Further,', we]), verbo([have]), complemento([shown, that, this, induction, of, apoptosis, by, fenretinide, may, be, caused, by, increased, retinol, uptake, via, 'STRA6'])].
[sujeto(['Silencing', of, 'STRA6', was, shown, to]), verbo([decrease]), complemento([apoptosis, which, was, inhibited, by, knockdown, of, 'STRA6', expression, in, 'Ishikawa', cells])].
[sujeto(['Results', of, an, 'in-vivo', study, demonstrated, that, intraperitoneal, injections, of, fenretinide, in, endometrial, cancer, tumors, '(', created, using, 'Ishikawa', 'cells)', in, mice]), verbo([inhibited]), complemento([tumor, growth, effectively])].
[sujeto(['Immunohistochemistry', of, mice, tumors, showed, a]), verbo([decrease]), complemento([in, 'Ki67', expression, and, an, increase, in, cleaved, 'caspase-3', staining, after, fenretinide, treatment, when, compared, to, vehicle, treated, mice])].
[sujeto(['Collectively,', our, results, are, the, first, to, establish, the, efficacy, of, fenretinide, as, an, antitumor, agent, for, endometrial, cancer, both, 'in-vitro', and, 'in-vivo,']), verbo([providing]), complemento([a, valuable, rationale, for, initiating, more, preclinical, studies, and, clinical, trials, using, fenretinide, for, the, treatment, of, endometrial, cancer])].
[sujeto(['Stimulated', by, retinoic, acid, 6, '(', 'STRA6)', is, the, receptor, for, retinol]), verbo([binding]), complemento([protein, and, is, relevant, for, the, transport, of, retinol, to, specific, sites, such, as, the, eye])].
[sujeto(['The', adaptive, evolution, mechanism, that, vertebrates]), verbo([have]), complemento([occupied, nearly, every, habitat, available, on, earth, and, adopted, various, lifestyles, associated, with, different, light, conditions, and, visual, 'challenges,', as, well, as, their, role, in, development, and, adaptation, is, thus, far, unknown])].
[sujeto(['In', this, 'work,', we]), verbo([have]), complemento([investigated, different, aspects, of, vertebrate, 'STRA6', evolution, and, used, molecular, evolutionary, analyses, to, detect, evidence, of, vertebrate, adaptation, to, the, lightless, habitat])].
[sujeto(['Branch-site', model, 'A', test, revealed, that, 'STRA6']), verbo([has]), complemento([undergone, positive, selection, in, the, different, phyla, of, mammalian, except, for, the, branch, of, rodent])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, interactions, between, different, light, environments, and, host, may, be, driving, adaptive, change, in, 'STRA6', by, competition, between, species])].
[sujeto(['In', support, of, 'this,', we]), verbo([found]), complemento([that, altered, functional, constraints, may, take, place, at, some, amino, acid, residues, after, speciation])].
[sujeto(['We']), verbo([suggest]), complemento([that, 'STRA6', has, undergone, adaptive, evolution, in, different, branch, of, vertebrate, relation, to, habitat, environment])].
[sujeto(['An', essential, 'retinoid-metabolizing', enzyme, known, as, lecithin, retinol, acyltransferase, '(', 'LRAT)', is]), verbo([expressed]), complemento([in, melanoma, cells, but, not, in, melanocytes, catalysing, the, esterification, of, 'all-trans', retinol, '(', 'ATRol)'])].
[sujeto(['In', this, 'study,', we, show, that, a, stable, 'LRAT', knockdown, '(', 'KD)', in, the, human, melanoma, cell, line, 'SkMel23']), verbo([leads]), complemento([to, significantly, increased, levels, of, the, substrate, 'ATRol', and, biologically, active, 'ATRA'])].
[sujeto(['PCR', analysis, revealed, a, significant, upregulation, of, 'retinoid-regulated', genes, such, as, 'CYP26A1', and, 'STRA6', in, 'LRAT', 'KD', 'cells,']), verbo([suggesting]), complemento([their, possible, involvement, in, mediating, retinoid, resistance, in, melanoma, cells])].
[sujeto(['We', propose, that, reduction, in, 'ATRol', levels, in, melanoma, cells, by, 'LRAT']), verbo([leads]), complemento([to, a, disturbance, in, cellular, retinoid, level])].
[sujeto(['Balanced', 'LRAT', expression, and, activity, may]), verbo([provide]), complemento([protection, against, melanoma, development, and, progression])].
[sujeto(['Vitamin', 'A', must, be, adequately, distributed, within, the, body, to]), verbo([maintain]), complemento([the, functions, of, retinoids, in, the, periphery, and, chromophore, production, in, the, eyes])].
[sujeto(['Blood', transport, of, the, lipophilic, vitamin, is]), verbo([mediated]), complemento([by, the, 'retinol-binding', 'protein,', 'RBP4'])].
[sujeto(['Biochemical', evidence]), verbo([suggests]), complemento([that, cellular, uptake, of, vitamin, 'A', from, 'RBP4', is, facilitated, by, a, membrane, receptor])].
[sujeto(['This', 'receptor,', identified, as, the, 'Stimulated', by, retinoic, acid, gene, 6, '(', 'Stra6)', gene, 'product,', is, highly]), verbo([expressed]), complemento([in, epithelia, that, constitute, 'blood-tissue', barriers])].
[sujeto(['Furthermore,', under, conditions, mimicking, vitamin, 'A', excess, and, 'deficiency,', our, analyses, revealed, that, 'STRA6-mediated', vitamin, 'A', uptake, is, a]), verbo([regulated]), complemento([process, mandatory, for, ocular, vitamin, 'A', uptake, when, 'RBP4', constitutes, the, only, transport, mode, in, vitamin, 'A', deficiency])].
[sujeto(['These', findings, identifying, 'STRA6', as, a, bona, fide, vitamin, 'A', transporter]), verbo([have]), complemento([important, implications, for, disease, states, associated, with, impaired, blood, vitamin, 'A', homeostasis])].
[sujeto(['The', integral, membrane, receptor, 'STRA6']), verbo([mediates]), complemento([cellular, uptake, of, vitamin, 'A', by, recognizing, 'RBP-retinol', to, trigger, release, and, internalization, of, retinol])].
[sujeto(['STRA6']), verbo([has]), complemento([one, intramembrane, and, nine, transmembrane, helices, in, an, intricate, dimeric, assembly])].
[sujeto(['Unexpectedly,', calmodulin, is]), verbo([bound]), complemento([tightly, to, 'STRA6', in, a, noncanonical, arrangement])].
[sujeto(['Residues']), verbo([involved]), complemento([with, 'RBP', binding, map, to, an, archlike, structure, that, covers, a, deep, lipophilic, cleft])].
[sujeto(['This', cleft, is, open, to, the, 'membrane,']), verbo([suggesting]), complemento([a, possible, mode, for, internalization, of, retinol, through, direct, diffusion, into, the, lipid, bilayer])].
[sujeto(['When', 'VYS', cells, at, 11.5, days, of, gestation, were, cultured, 'in&nbsp;vitro', for, 7, 'days,', the, number, of, 'HNF1β-,', 'HNF4α-,', 'E-cadherin-', and, 'cytokeratin-positive', 'VYS', epithelial, cells, was, significantly, reduced, 'and,', 'instead,', 'Stra6-and', 'vimentin-positive', 'PYS-like', cells]), verbo([increased]), complemento([with, culture])].
[sujeto(['RT-PCR', analyses, also, demonstrated, that, gene, expression, of, 'VYS', markers, 'decreased,', whereas, that, of, 'PYS', markers]), verbo([increased]), complemento([in, the, primary, culture, of, 'VYS', cells])].
[sujeto(['These', data, indicate, that, 'VYS', epithelial, cells, rapidly, transdifferentiate, into, 'PYS', cells, having, mesenchymal, characteristics, 'in&nbsp;vitro,', which, may]), verbo([provide]), complemento([a, culture, system, suitable, for, studying, molecular, mechanisms, of, 'VYS', transdifferentiation, into, 'PYS', cells, and, also, 'epithelial-mesenchymal', transition])].
[sujeto([',', 'GuangZhou,', 'China)', on, gene, expression]), verbo([associated]), complemento([with, carotenoid, cleavage, enzymes, '(', 'β-carotene', 15, ',', 15, '\'', -, 'monooxygenase,', 'BCMO1;', and, 'β-carotene', 9, '\'', ',', 10, '\'', -, 'dioxygenase,', 'BCDO2)', and, retinoid, metabolism, '(', 'lecithin:retinol', acyl, transferase, '(', 'LRAT)', and, 'STRA6)', of, breeding, hens, and, chicks])].
[sujeto(['Results', showed, that, 40, 'mg/kg', xanthophyll, supplementation]), verbo([increased]), complemento(['BCDO2', mRNA, in, the, 'liver,', 'duodenum,', and, 'jejunum;', 'LRAT', mRNA, in, the, 'jejunum;', and, 'STRA6', mRNA, in, the, 'liver,', while, it, decreased, 'LRAT', mRNA, in, the, liver])].
[sujeto(['Results', showed, that, in, ovo, xanthophyll]), verbo([modulated]), complemento([carotenoid, and, retinoid, metabolism, mainly, within, one, wk, after, hatching])].
[sujeto(['Dietary', xanthophyll]), verbo([regulated]), complemento([carotenoid, and, retinoid, metabolism, mainly, from, 2, wk, onward])].
[sujeto(['In', 'conclusion,', xanthophyll, supplementation, could]), verbo([modulate]), complemento([carotenoid, and, retinoid, metabolism, in, different, tissues, of, hens, and, chicks])].
[sujeto(['Retinol']), verbo([binding]), complemento([protein, '(', 'RBP)', and, its, membrane, 'receptor,', 'STRA6,', are, vital, for, the, management, of, vitamin, 'A', in, the, body])].
[sujeto(['Recently,', elevated, serum, 'RBP', levels]), verbo([have]), complemento([been, implicated, as, a, contributing, factor, to, the, development, of, insulin, resistance, and, type, 2, diabetes])].
[sujeto(['However,', conflicting, opinions, exist, as, to, how, these]), verbo([increased]), complemento([levels, can, cause, insulin, resistance])].
[sujeto(['In', order, to, better, understand, the, influences, of, 'RBP,', a, proteomic, study, was, devised, to, determine, the, direct, effect, of, 'RBP', on, a, mouse, muscle, cell, 'line,', because, the, muscle, is, the, principal, site, of, insulin]), verbo([induced]), complemento([glucose, uptake])].
[sujeto(['A', number, of, changes, were, observed, in, response, to, retinol]), verbo([binding]), complemento([protein, 'treatment,', of, which, the, most, interesting, were, decreased, levels, of, the, 'phosphatase,', protein, phosphatase, 1, β])].
[sujeto(['This', phosphatase, is, responsible, for]), verbo([regulating]), complemento([glycogen, synthase, and, glycogen, 'phosphorylase,', the, 'rate-limiting', enzymes, involved, in, glycogen, storage, and, utilization])].
[sujeto(['Retinol']), verbo([binding]), complemento([protein, treatment, resulted, in, increased, phosphorylation, and, inhibition, of, glycogen, 'synthase,', with, detrimental, effects, on, insulin, stimulated, glycogen, production, in, these, cells])].
[sujeto(['The', results, indicate, that, 'RBP', may]), verbo([have]), complemento([a, negative, effect, on, energy, storage, in, the, cell, and, could, contribute, to, the, development, of, insulin, resistance, in, muscle, tissue])].
[sujeto(['Understanding', how, retinol]), verbo([binding]), complemento([protein, influences, insulin, resistance, may, reveal, novel, strategies, to, target, this, disease])].
[sujeto(['Vitamin', 'A']), verbo([has]), complemento([biological, functions, as, diverse, as, sensing, light, for, 'vision,', regulating, stem, cell, 'differentiation,', maintaining, epithelial, 'integrity,', promoting, immune, 'competency,', regulating, learning, and, 'memory,', and, acting, as, a, key, developmental, morphogen])].
[sujeto(['Vitamin', 'A', derivatives]), verbo([have]), complemento([also, been, used, in, treating, human, diseases])].
[sujeto(['If', vitamin, 'A', is, considered, a, drug, that, everyone, needs, to, take, to, 'survive,', evolution]), verbo([has]), complemento([come, up, with, a, natural, drug, delivery, system, that, combines, sustained, release, with, precise, and, controlled, delivery, to, the, cells, or, tissues, that, depend, on, it])].
[sujeto(['This', &, 'quot;drug', delivery, 'system&quot;', is]), verbo([mediated]), complemento([by, plasma, retinol, binding, protein, '(', 'RBP),', the, principle, and, specific, vitamin, 'A', carrier, protein, in, the, 'blood,', and, 'STRA6,', the, 'cell-surface', receptor, for, 'RBP', that, mediates, cellular, vitamin, 'A', uptake])].
[sujeto(['This', review, summarizes, recent, progress, in, elucidating, the, fundamental, molecular, mechanism]), verbo([mediated]), complemento([by, the, 'RBP', receptor, and, multiple, newly, discovered, catalytic, activities, of, this, 'receptor,', and, compares, this, transport, system, with, retinoid, transport, independent, of, 'RBP/STRA6'])].
[sujeto(['How', to]), verbo([target]), complemento([this, new, type, of, transmembrane, receptor, using, small, molecules, in, treating, diseases, is, also, discussed])].
[sujeto(['Retinol']), verbo([binding]), complemento([protein, 4, '(', 'RBP4)', is, synthesized, in, the, liver, where, it, binds, vitamin, 'A,', 'retinol,', and, transports, it, to, tissues, throughout, the, body])].
[sujeto(['It']), verbo([has]), complemento([been, shown, in, some, studies, that, the, level, of, circulating, 'RBP4', increases, with, body, 'mass,', and, the, protein, has, been, implicated, as, a, mediator, in, the, development, of, insulin, resistance, and, the, metabolic, disease])].
[sujeto(['In', addition, to, its, function, as, a, transport, 'protein,', 'RBP4', serves, as, a, signaling, molecule, 'which,', by]), verbo([binding]), complemento([to, the, membrane, receptor, 'STRA6,', triggers, downstream, activation, of, 'pro-oncogenic', pathways, including, 'JAK2/STAT3/5'])].
[sujeto(['Taken', 'together,', available, information]), verbo([suggests]), complemento([the, possibility, that, 'RBP4', may, be, a, link, between, obesity, and, cancer])].
[sujeto(['We', identified, missense, mutations, in, 'RBP4,', encoding, serum, retinol]), verbo([binding]), complemento(['protein,', in, three, families, with, eye, malformations, of, differing, 'severity,', including, bilateral, anophthalmia])].
[sujeto(['Maternal', transmission, significantly]), verbo([increases]), complemento([the, probability, of, phenotypic, expression])].
[sujeto(['The', disease, mutations, greatly, reduce, retinol]), verbo([binding]), complemento([to, 'RBP,', yet, paradoxically, increase, the, affinity, of, 'RBP', for, its, cell, surface, 'receptor,', 'STRA6'])].
[sujeto(['These', findings, establish, a, previously, uncharacterized, mode, of, maternal, 'inheritance,', distinct, from, imprinting, and, 'oocyte-derived', 'mRNA,', and, define, a, group, of, hereditary, disorders, plausibly]), verbo([modulated]), complemento([by, dietary, vitamin, 'A'])].
[sujeto(['Previous', work]), verbo([has]), complemento([implicated, the, cytoplasmic, transcription, factor, signal, transducer, and, activator, of, transcription, 1, '(', 'STAT1)', as, a, potential, mediator, of, 'drug-induced', 'ototoxicity,', but, role, in, aminoglycosides, is, largely, unknown])].
[sujeto(['Hair', cell, morphology, was, evaluated, and, hair, cell]), verbo([loss]), complemento([was, quantified, with, cytocochleograms])].
[sujeto(['Co-administration', of, 50, μM, 'EGCG']), verbo([conferred]), complemento([protection, from, 4, μM, gentamicin, toxicity, '(', p, &, 'lt;', 0.001, ')', ',', whereas, atRA, potentiated, 'gentamicin-induced', hair, cell, death, '(', p, &, 'lt;', 0.001, ')'])].
[sujeto(['On', 'immunohistochemistry,', 'STAT1', phosphorylation, at, theserine, 727, '(', 'Ser)', residues, was]), verbo([increased]), complemento([at, 72, hours, with, 4, μM, gentamicin])].
[sujeto(['EGCG', protected, outer, hair, cells, from, gentamicin, toxicity, in, a, cochlear, explant, 'model,', with, the, underlying, mechanism]), verbo([involving]), complemento([both, reactive, oxygen, species, '(', 'ROS)', suppression, and, 'STAT1', inhibition])].
[sujeto(['In', this, 'study,', due, to, the, failure, of]), verbo([maintaining]), complemento([the, undifferentiated, state, of, goat, embryotic, 'stem-', and, induced, pluripotent, 'stem-like', cells, in, 'vitro,', we, explored, an, alternative, way, to, directly, convert, goat, fibroblasts, to, 'lineage-specific', cells])].
[sujeto(['The', '\'', 'Yamanaka', 'factors\'', was, ectopically]), verbo([expressed]), complemento([in, fibroblasts, for, a, short, term, to, situate, cells, in, a, metastable, state])].
[sujeto(['This', primary, follicular, structure, could, be, developed, further, in, oocyte, mature, medium, and]), verbo([expressed]), complemento([germ, 'cell-specific', markers])].
[sujeto(['In', 'addition,', we]), verbo([found]), complemento([that, the, induction, efficiency, was, higher, and, 'OLC', cell, size, was, bigger, in, bFF, than, in, 'RA', treatment])].
[sujeto(['Drug-induced', osteoporosis, is, a, significant, health, 'problem,', as, many, drugs]), verbo([have]), complemento([deleterious, effects, on, bone, metabolism])].
[sujeto(['Flexural', yield, stress, was, slightly, '(', 2, '%', ')']), verbo([decreased]), complemento([in, the, tazarotene, 'group,', but, the, difference, was, not, statistically, significant])].
[sujeto(['Tazarotene', worsened, bone, mechanical, properties, and]), verbo([inhibited]), complemento([bone, turnover, in, rats])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, tazarotene, has, a, negative, impact, on, bone, metabolism, and, that, it, exerts, osteoporotic, activity])].
[sujeto(['A', susceptibility, gene, analysis, on, cellular, retinoic, acid]), verbo([binding]), complemento(['protein-II', '(', 'CRABP-II),', acting, on, keratinocyte, 'differentiation,', was, also, performed])].
[sujeto(['All', parameters, were, highly]), verbo([expressed]), complemento([in, psoriatic, lesions, and, reduced, after, 12, weeks, of, 'anti-TNFα', treatments])].
[sujeto(['If', confirmed, in, a, larger, series, 'and/or', in, different, hyperproliferative, and, inflammatory, 'dermatoses,', 'MITE', score, could, be, proposed, as, additional, monitoring, system, to, evaluate, treatment, protocols, in, skin, disorders, and]), verbo([targeted]), complemento([biomolecular, pathways, supporting, clinical, efficacy])].
[sujeto(['Acute', promyelocitic, leukemia, '(', 'APL)', is, characterized, by, the, pathognomonic, presence, in, leukemic, blasts, of, the, hybrid, protein, 'PML/RARA,', that]), verbo([acts]), complemento([as, a, transcriptional, repressor, impairing, the, expression, of, genes, that, are, critical, to, myeloid, differentiation])].
[sujeto(['Here,', we, show, that, primary, blasts, from, 'APL', patients]), verbo([express]), complemento([lower, levels, of, the, oncosuppressor, protein, 'PTEN,', as, compared, to, blast, cells, from, other, 'AML', subtypes, or, normal, bone, 'marrow,', and, demonstrate, that, 'PML-RARA', directly, inhibits, 'PTEN', expression])].
[sujeto(['We', show, that, 'All-Trans', 'Retinoic', 'Acid', '(', 'ATRA)']), verbo([triggers]), complemento([in, 'APL', cells, an, active, chromatin, status, at, the, core, regulatory, region, of, the, 'PTEN', 'promoter,', that, allows, the, binding, of, the, 'myeloid-regulating', transcription, factor, 'PU'])].
[sujeto(['ATRA,', via, 'PML/RARA', 'degradation,', also]), verbo([promotes]), complemento(['PTEN', nuclear, 're-localization', and, decreases, expression, of, the, 'PTEN', target, 'Aurora', 'A', kinase])].
[sujeto(['In', 'conclusion,', our, findings, support, the, notion, that, 'PTEN', is, one, of, the, primary]), verbo([targets]), complemento([of, 'PML/RARA', in, 'APL'])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, case, of, an, acute, promyelocytic, leukemia, '(', 'APL)', patient, 'who-although', negative, for, 'FLT3', mutations, at, 'diagnosis-developed', isolated, 'FLT3', tyrosine, kinase, 'II', domain, '(', 'FLT3-TKD)-positive', meningeal, 'relapse,', 'which,', in, 'retrospect,', could, be, traced, back, to, a, minute, bone, marrow, subclone, present, at, first, diagnosis])].
[sujeto(['Whole-exome', sequencing, and, subsequent, ultradeep]), verbo([targeted]), complemento([resequencing, revealed, a, heterozygous, 'FLT3-TKD', mutation, in, 'CSF', leukemic, cells, '(', p])].
[sujeto(['This', case, highlights, the, concept, of, clonal, evolution, with, a, subclone, harboring, an, additional, mutation, being, selected, as, the, &, 'quot;fittest&quot;', and]), verbo([leading]), complemento([to, meningeal, relapse])].
[sujeto(['In', the, 2, -, week, control, 'period,', all, parameters, showed, no, statistically, significant, 'difference;', after, 4, weeks, of, 'consumption,', significant, improvement, in, the, antioxidant, status, was, observed, with]), verbo([increased]), complemento([total, antioxidant, capacity, and, reduced, malondialdehyde, and, protein, hydroperoxide, 'levels,', as, well, as, significantly, increased, levels, of, 'Vit', 'C', and, 'Vit', 'A,', when, compared, to, the, 'two-time', evaluation, during, the, baseline, periods])].
[sujeto(['This', preliminary, study]), verbo([suggested]), complemento([that, consumption, of, star, fruit, juice, twice, daily, for, 1, month, improved, the, elderly, 'people\'s', antioxidant, status, and, 'vitamins,', as, well, as, improved, the, lipoproteins, related, to, 'Vit', 'C', and, 'Vit', 'A', in, the, star, fruit, extract])].
[sujeto(['The', aim, of, this, study, was, the, characterization, of, transcriptional, regulatory, pathways]), verbo([mediated]), complemento([by, retinoic, acid, '(', 'RA)', in, 'Senegalese', sole, larvae])].
[sujeto(['Nevertheless,', gene, expression, analysis, revealed, a, total, of, 20, transcripts, differentially]), verbo([expressed]), complemento([during, larval, development, and, only, six, related, with, 'DEAB', treatments, directly, involved, in, 'RA', metabolism, and, actions, '(', 'rdh10a,', 'aldh1a2,', 'crbp1,', 'igf2r,', rarg, and, 'cyp26a1)', to, adapt, to, a, 'low-RA', environment])].
[sujeto(['In', a, second, 'experiment,', 'post-metamorphic', larvae, were, exposed, to, the, 'all-trans', 'RA', '(', 'atRA)', observing, an, opposite, regulation, for, those, genes]), verbo([involved]), complemento([in, 'RA', synthesis, and, degradation, '(', 'rdh10a,', 'aldh1a2,', crbp1, and, 'cyp26a1)', as, well, as, other, related, with, 'thyroid-', '(', 'dio2)', and, 'IGF-axes', '(', 'igfbp1,', igf2r, and, 'igfbp5)', to, balance, 'RA', levels])].
[sujeto(['Moreover,', five, retinoic, receptors, that]), verbo([mediate]), complemento(['RA', 'actions,', the, thyroid, receptor, 'thrb,', and, five, 'IGF', binding, proteins, changed, differentially, their, expression])].
[sujeto(['Overall,', this, study, demonstrates, that, exogenous, 'RA']), verbo([modulates]), complemento([the, expression, of, some, genes, involved, in, the, 'RA', 'synthesis,', degradation, and, cellular, transport, through, 'RAR-mediated', regulatory, pathways, establishing, a, negative, feedback, regulatory, mechanism, necessary, to, balance, endogenous, 'RA', levels, and, gradients])].
[sujeto(['A', variety, of, chemicals]), verbo([stimulates]), complemento([differentiation, of, leukemic, 'cells,', such, as, dimethyl, sulfoxide, '(', 'DMSO)', and, 'all-trans', retinoic, acid, '(', 'ATRA)'])].
[sujeto(['Tumor', suppressor, genes]), verbo([have]), complemento([a, vital, role, in, the, gateway, to, terminal, cell, differentiation])].
[sujeto(['In', this, 'study,', we]), verbo([inhibited]), complemento(['PTEN', tumor, suppressor, gene, expression, by, siRNA, to, investigate, the, effect, of, potentiating, cell, survival, and, inhibiting, apoptosis, on, 'HL-60', cell, differentiation, by, 'DMSO', and, 'ATRA'])].
[sujeto(['Our', results, show, that, 'PTEN', siRNA]), verbo([increases]), complemento(['HL-60', cell, differentiation, in, the, presence, of, 'DMSO', and, 'ATRA'])].
[sujeto(['Our', study]), verbo([suggests]), complemento([that, manipulation, of, 'PTEN', could, hold, promise, for, enhancing, efficacy, of, differentiation, therapy, of, acute, myelogenous, leukemia])].
[sujeto(['Mouse', model, studies]), verbo([have]), complemento([revealed, that, the, retinoic, 'acid-inducible', 1, gene, '(', 'RAI1)', within, the, 'SMS', and, 'PTLS', critical, genomic, interval, is, the, 'dosage-sensitive', gene, responsible, for, the, major, phenotypic, features, in, these, disorders])].
[sujeto(['The', main, goal, is, to]), verbo([increase]), complemento([awareness, of, these, rare, disorders, because, an, earlier, diagnosis, will, lead, to, more, timely, developmental, intervention, and, medical, management, which, will, improve, clinical, outcome])].
[sujeto(['Irradiation', did, not, affect, the, amount, of, subunits, of, 'OxPhos', complexes, and, other, 'non-OxPhos', mitochondrial, 'proteins,', except, for, heat, shock, protein, 70, ',', which, was]), verbo([increased]), complemento([depending, on, oxygen, level, and, differentiation, status])].
[sujeto(['These', two, factors, were, proven, to]), verbo([modulate]), complemento([mitochondrial, membrane, potential, and, the, bioenergetic, status, of, cells])].
[sujeto(['The', 'sodium/iodide', symporter, '(', 'NIS),', which, is, essential, for, iodide, concentration, in, the, 'thyroid,', was]), verbo([reported]), complemento([to, be, transcriptionally, regulated, by, sterol, regulatory, 'element-binding', proteins, '(', 'SREBP)', in, rat, 'FRTL-5', thyrocytes])].
[sujeto(['The', 'SREBP', are, strongly]), verbo([activated]), complemento([after, parturition, and, throughout, lactation, in, the, mammary, gland, of, cattle, and, are, important, for, mammary, epithelial, cell, synthesis, of, milk, lipids])].
[sujeto(['In', this, 'study,', we, tested, the, hypothesis, that, the, 'NIS', gene, is]), verbo([regulated]), complemento([also, by, 'SREBP', in, mammary, epithelial, 'cells,', in, which, 'NIS', is, functionally, expressed, during, lactation])].
[sujeto(['Knockdown', of, 'SREBP-1c', and, 'SREBP-2', by, 'RNA', interference]), verbo([decreased]), complemento([the, mRNA, and, protein, concentration, of, 'NIS', by, 30, to, 50, '%', 48, h, after, initiating, 'knockdown,', whereas, overexpression, of, nuclear, 'SREBP', '(', 'nSREBP)-1c', and, 'nSREBP-2', increased, the, expression, of, 'NIS', in, 'MCF-7', cells, by, 45, to, 60, '%', ',', 'respectively,', 48, h, after, initiating, overexpression])].
[sujeto(['Reporter', gene, experiments, with, varying, length, of, 'NIS', promoter, reporter, constructs, revealed, that, the, 'NIS', 5, '\'', -, flanking, region, is]), verbo([activated]), complemento([by, 'nSREBP-1c', and, 'nSREBP-2', approximately, 1.5, -, and, 4.5, -, 'fold,', 'respectively,', and, activation, involves, a, 'SREBP-binding', motif, '(', 'SRE)', at, -, 38, relative, to, the, transcription, start, site, of, the, 'NIS', gene])].
[sujeto(['Gel', shift, assays, using, oligonucleotides, spanning, either, the, 'wild-type', or, the, mutated, 'SRE', at, -, 38, of, the, 'NIS', 5, '\'', -, flanking, region, showed, that, in, 'vitro-translated', 'nSREBP-1c', and, 'nSREBP-2']), verbo([bind]), complemento([only, the, 'wild-type', but, not, the, mutated, 'SRE', at, -, 38, of, 'NIS'])].
[sujeto(['Collectively,', the, present, results, from, cell, culture, experiments, with, human, mammary, epithelial, 'MCF-7', cells, and, from, genetic, studies, show, for, the, first, time, that, the, 'NIS', gene, and, iodide, uptake, are]), verbo([regulated]), complemento([by, 'SREBP', in, cultured, human, mammary, epithelial, cells])].
[sujeto(['The', 'RNA-binding', protein, 'HuR']), verbo([binds]), complemento([to, 'AU-rich', elements, in, target, mRNAs, and, stabilizes, them, against, degradation])].
[sujeto(['The', complete, spectrum, of, genes, whose, expression, is]), verbo([regulated]), complemento([by, 'HuR', and, thus, the, basis, for, the, broad, range, of, cellular, functions, of, the, protein, are, incompletely, understood])].
[sujeto(['We', show, that, 'HuR', controls, the, expression, of, multiple, components, of, the]), verbo([nuclear]), complemento([import, machinery])].
[sujeto(['Consequently,', 'HuR', is, critical, for, the]), verbo([nuclear]), complemento([import, of, cellular, retinoic, 'acid-binding', protein, 2, '(', 'CRABP2),', which, delivers, 'RA', to, the, nuclear, receptor, 'RAR', and, whose, mobilization, to, the, nucleus, is, mediated, by, a, '\'', 'classical-like\'', nuclear, localization, signal, '(', 'NLS)'])].
[sujeto(['HuR', is, also]), verbo([required]), complemento([for, 'heregulin-induced', nuclear, translocation, of, the, 'NFκB', subunit, 'p65,', which, contains, both, classical, and, 'non-canonical', 'NLS'])].
[sujeto(['HuR', thus]), verbo([regulates]), complemento([the, transcriptional, activities, of, both, 'RAR', and, 'NFκB'])].
[sujeto(['The', observations]), verbo([reveal]), complemento([that, 'HuR', plays, a, central, role, in, regulating, protein, nuclear, import])].
[sujeto(['Breast', cancer, is, the, most, common, form, of, cancer, diagnosed, in, women, worldwide, and, the, second]), verbo([leading]), complemento([cause, of, 'cancer-related', deaths, in, the, 'USA'])].
[sujeto(['Despite', the, development, of, newer, diagnostic, 'methods,', selective, as, well, as]), verbo([targeted]), complemento([chemotherapies, and, their, 'combinations,', 'surgery,', hormonal, 'therapy,', 'radiotherapy,', breast, cancer, 'recurrence,', metastasis, and, drug, resistance, are, still, the, major, problems, for, breast, cancer])].
[sujeto(['Emerging', evidence]), verbo([suggest]), complemento([the, existence, of, cancer, stem, cells, '(', 'CSCs),', a, population, of, cells, with, the, capacity, to, 'self-renew,', differentiate, and, be, capable, of, initiating, and, sustaining, tumor, growth])].
[sujeto(['Hence,', compounds]), verbo([targeting]), complemento([breast, 'CSCs', may, be, better, therapeutic, agents, for, treating, breast, cancer, and, control, recurrence, and, metastasis])].
[sujeto(['Naturally', occurring, 'compounds,', mainly, phytochemicals]), verbo([have]), complemento([gained, immense, attention, in, recent, times, because, of, their, wide, safety, 'profile,', ability, to, target, heterogeneous, populations, of, cancer, cells, as, well, as, 'CSCs,', and, their, key, signaling, pathways])].
[sujeto(['These', phytochemicals, may, serve, as, novel, therapeutic, agents, for, breast, cancer, treatment, and, future]), verbo([leads]), complemento([for, drug, development])].
[sujeto(['The', 'curcumin,', a, natural, compound, obtained, from, turmeric, is, an, interesting, therapeutic, molecule, as, it]), verbo([has]), complemento([been, reported, in, the, literature, to, combat, both, 'FA', as, well, as, leukemia])].
[sujeto(['Herein,', a, systems, biology, approach, for, elucidating, the, therapeutic, potential, of, curcumin, against, 'FA', and, leukemia, is, investigated, by, analyzing, the, computational, molecular, interactions, of, curcumin, ligand, with, 'FANC', 'G', of, 'FA', and, seven, other, key, disease]), verbo([targets]), complemento([of, leukemia])].
[sujeto(['The', proteins, namely, 'DOT1L,', farnesyl, transferase, '(', 'FDPS),', histone, decetylase, '(', 'EP3000),', 'Polo-like', kinase, '(', 'PLK-2),', 'aurora-like', kinase, '(', 'AUKRB),', tyrosine, kinase, '(', 'ABL1),', and, retinoic, acid, receptor, alpha, '(', 'RARA)', were, chosen, as, disease]), verbo([targets]), complemento([for, leukemia, and, modeled, structure, of, 'FANC', 'G', protein, as, the, disease, target, for, 'FA'])].
[sujeto(['The', docking, investigations, showed, that, curcumin, had, a, very, high]), verbo([binding]), complemento([affinity, of, -, 8.1, 'kcal/mol', with, 'FANC', 'G', protein])].
[sujeto(['The', key, disease]), verbo([targets]), complemento([of, leukemia, namely, tyrosine, kinase, '(', 'ABL1),', 'aurora-like', kinase, '(', 'AUKRB),', and, 'polo-like', kinase, '(', 'PLK-2)', showed, that, they, had, the, comparable, binding, affinities, of, -, 9.7, k, 'cal/mol,', -, 8.7, k, 'cal/mol,', and, -, 8.6, k, 'cal/mol,', respectively, with, curcumin])].
[sujeto(['Further,', the, percentage, similarity, scores, obtained, from, 'PAM50', using, 'EMBOSS', 'MATCHER', was, shown, to]), verbo([provide]), complemento([a, clue, to, understand, the, structural, relationships, to, an, extent, and, to, predict, the, binding, affinity])].
[sujeto(['This', investigation, shows, that, curcumin, effectively]), verbo([interacts]), complemento([with, the, disease, targets, of, both, 'FA', and, leukemia])].
[sujeto(['Translocator', protein, 18, kDa, '(', 'TSPO)', is, a, high, affinity, 'cholesterol-', and, 'drug-binding', protein, highly]), verbo([expressed]), complemento([in, steroidogenic, 'cells,', such, as, 'Leydig', 'cells,', where, it, plays, a, role, in, cholesterol, mitochondrial, transport])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, 'TSPO', is, expressed, in, postnatal, day, 3, rat, 'gonocytes,', precursors, of, spermatogonial, stem, cells])].
[sujeto(['Gonocytes', undergo]), verbo([regulated]), complemento([phases, of, proliferation, and, 'migration,', followed, by, retinoic, acid, '(', 'RA)-induced', differentiation])].
[sujeto(['Understanding', these, processes, is, important, since, their, disruption, may]), verbo([lead]), complemento([to, the, formation, of, carcinoma, in, 'situ,', a, precursor, of, testicular, germ, cell, tumors, '(', 'TGCTs)'])].
[sujeto(['Previously,', we, showed, that, 'TSPO', ligands, do, not]), verbo([regulate]), complemento([gonocyte, proliferation])].
[sujeto(['In', the, present, 'study,', we]), verbo([found]), complemento([that, 'TSPO', expression, is, downregulated, in, differentiating, gonocytes])].
[sujeto(['Similarly,', in, 'F9', embryonal, carcinoma, 'cells,', a, mouse, 'TGCT', cell, line, with, embryonic, stem, cell, 'properties,', there, is, a, significant]), verbo([decrease]), complemento([in, 'TSPO', expression, during, 'RA-induced', differentiation])].
[sujeto(['Silencing', 'TSPO', expression, in, gonocytes]), verbo([increased]), complemento([the, stimulatory, effect, of, 'RA', on, the, expression, of, the, differentiation, marker, 'Stra8,', suggesting, that, 'TSPO', exerts, a, repressive, role, on, differentiation])].
[sujeto(['TSPO', protein, was]), verbo([expressed]), complemento([in, the, cytoplasmic, compartment, of, seminoma, 'cells,', identified, by, their, nuclear, expression, of, the, transcription, factors, 'OCT4', and, 'AP2G'])].
[sujeto(['Thus,', 'TSPO', appears, to, be, tightly]), verbo([regulated]), complemento([during, germ, cell, 'differentiation,', and, to, be, deregulated, in, 'seminomas,', suggesting, a, role, in, germ, cell, development, and, pathology])].
[sujeto(['We', generated]), verbo([induced]), complemento(['Tregs', '(', 'iTregs)', and, explored, their, therapeutic, potential, in, a, murine, model, of, rapidly, progressive, glomerulonephritis])].
[sujeto(['To']), verbo([enhance]), complemento([their, suppressive, 'phenotype,', iTreg, cultures, were, modified, with, the, addition, of, a, monoclonal, antibody, against, 'IL-12p40', or, by, using, 'RORγt-/-', 'CD4+', 'T', cells])].
[sujeto([iTregs, exhibited, comparable, surface, receptor, expression, and, in, vitro, suppressive, ability, to, natural, 'Tregs,', but, did, not]), verbo([regulate]), complemento(['antigen-specific', delayed, type, hypersensitivity, or, systemic, inflammatory, immune, 'responses,', losing, 'Foxp3', expression, in, vivo])].
[sujeto(['In', 'glomerulonephritis,', transferred, iTregs, did, not]), verbo([prevent]), complemento([renal, injury, or, modulate, systemic, 'Th1', immune, responses])].
[sujeto([iTregs, cultured, with, 'anti-IL-12p40', had, an]), verbo([enhanced]), complemento([suppressive, phenotype, in, vitro, and, regulated, dermal, delayed, type, hypersensitivity, in, 'vivo,', but, were, not, protective, against, renal, 'injury,', losing, 'Foxp3', 'expression,', especially, in, the, transferred, cells, recruited, to, the, kidney])].
[sujeto(['Use', of, 'RORγt-/-', 'CD4+', 'T', cells, or, iTregs, generated, from, sensitised, 'CD4+Foxp3-', cells, did, not]), verbo([regulate]), complemento([renal, or, systemic, inflammatory, responses, in, vivo])].
[sujeto(['In', 'conclusion,', iTregs]), verbo([suppress]), complemento(['T', cell, proliferation, in, 'vitro,', but, do, not, regulate, experimental, 'glomerulonephritis,', being, unstable, in, this, inflammatory, milieu, in, vivo])].
[sujeto(['Herein,', we, show, that, mothers, against, decapentaplegic, homolog, 4, '(', 'SMAD4)', in, germ, cells, is]), verbo([required]), complemento([for, 'female-type', differentiation])].
[sujeto(['Germ', cells, in, 'Smad4-deficient', ovaries]), verbo([respond]), complemento([to, retinoic, acid, signaling, but, fail, to, undergo, meiotic, prophase, 'I,', which, coincides, with, the, weaker, expression, of, genes, required, for, follicular, 'formation,', indicating, that, 'SMAD4', signaling, is, essential, for, oocyte, differentiation, and, meiotic, progression])].
[sujeto(['Intriguingly,', 'germline-specific', deletion, of, 'Smad4', in, 'Stra8-null', female, germ, cells, resulted, in, the, 'up-regulation', of, genes]), verbo([required]), complemento([for, male, gonocyte, 'differentiation,', including, 'Nanos2', and, 'PLZF,', suggesting, the, initiation, of, 'male-type', differentiation, in, ovaries])].
[sujeto(['Our', results, demonstrate, that, 'SMAD4', and, 'STRA8', are, essential, factors, that]), verbo([regulate]), complemento([the, female, fate, of, germ, cells])].
[sujeto(['All-trans', retinoic, acid, '(', 'ATRA)']), verbo([binds]), complemento([the, promyelocytic, 'leukemia/retinoic', acid, receptor, α, '(', 'PML/RARα)', fusion, protein, and, is, an, effective, 'oncogene-targeted', therapy, for, acute, promyelocytic, leukemia, '(', 'APL)'])].
[sujeto(['Previous', studies]), verbo([have]), complemento([shown, that, the, 'PML/RARα', fusion, protein, behaves, as, a, type, 'II', nuclear, 'receptor,', binding, to, 'DNA', regardless, of, ligand, status])].
[sujeto(['Here,', we, performed, a, series, of, chromatin, immunoprecipitation, '(', 'ChIP)-quantitative', 'PCR', '(', 'qPCR)', 'experiments,', demonstrating, that, there, is, an, additional, mode, of, action, of, 'PML/RARα,', wherein, 'PML/RARα', does, not]), verbo([bind]), complemento(['DNA', in, the, absence, of, 'ATRA', but, binds, 'DNA', and, activates, adjacent, genes, in, the, presence, of, 'ATRA'])].
[sujeto(['This', mode, of, action, is, similar, to, that, of, a, type, 'I']), verbo([nuclear]), complemento([receptor, and, is, highlighted, by, activation, of, 'G0/G1', switch, gene, 2, '(', 'G0S2)', during, 'ATRA-induced', neutrophil, differentiation, of, leukemia, cell, lines, '(', 'NB4', and, 'PR9)', and, primary, human, 'APL', cells])].
[sujeto(['Furthermore,', we, verified, that, the, p30, isoform, of, 'C/EBPε', is, crucial, for, activation, of, 'G0S2', and, that, 'PML/RARα']), verbo([interacts]), complemento([physically, and, cooperates, functionally, with, 'C/EBPε', to, 'up-regulate', 'G0S2', 'Our', data, not, only, demonstrate, a, new, mode, of, action, of, 'PML/RARα', but, also, suggest, a, novel, model, in, which, 'PML/RARα', synergizes, with, 'C/EBPε', to, reactivate, the, 'C/EBPε', target, 'G0S2,', thereby, contributing, to, 'ATRA-mediated', 'APL', differentiation, and, 'potentially,', clinical, remission])].
[sujeto(['In', the, ocular, mucosa, '(', 'conjunctiva),', fibrosis]), verbo([leads]), complemento([to, blindness, in, 'trachoma,', 'pemphigoid,', and, allergy])].
[sujeto(['However,', here, we, demonstrate, that, 'DCs', can, directly]), verbo([induce]), complemento([fibrosis])].
[sujeto(['In', the, mouse, model, of, allergic, eye, disease, '(', 'AED),', classical, 'CD11b(+)', 'DCs', in, the, ocular, mucosa, showed]), verbo([increased]), complemento([activity, of, aldehyde, dehydrogenase, '(', 'ALDH),', the, enzyme, required, for, retinoic, acid, synthesis])].
[sujeto(['In', 'vitro,', 'CD11b(+)', 'DC-derived', 'ALDH', was]), verbo([associated]), complemento([with, 9, -, 'cis-retinoic', acid, ligation, to, retinoid, x, receptor, '(', 'RXR),', which, induced, conjunctival, fibroblast, activation])].
[sujeto(['In', 'vivo,']), verbo([stimulating]), complemento(['RXR', led, to, rapid, onset, of, ocular, mucosal, 'fibrosis,', whereas, inhibiting, 'ALDH', activity, in, 'DCs', or, selectively, depleting, 'DCs', markedly, reduced, fibrosis])].
[sujeto(['Collectively,', these, data]), verbo([reveal]), complemento([a, profibrotic, 'ALDH-dependent', pathway, by, 'DCs', and, uncover, a, role, for, 'DC', retinoid, metabolism])].
[sujeto(['The', addition, of, growth, factors, and, vitamins]), verbo([enhances]), complemento([goat, embryonic, development, in, vitro])].
[sujeto(['However,', few, attempts]), verbo([have]), complemento([been, reported, trying, to, identify, supplementation, regimens, for, oocyte, maturation, or, embryo, culture, with, additive, properties])].
[sujeto(['The', present]), verbo([report]), complemento([was, aimed, to, evaluate, if, retinoids, '[', 0.3, μM, retinyl, acetate, '(', 'RAc)', and, 0.5, μM, 9, -, 'cis-retinoic', acid, '(', 'RA)]', supplementation, during, goat, oocyte, maturation, and, retinoids, 'and/or', 50, ng, 'mL-1', 'IGF-I', during, embryo, culture, synergically, enhanced, embryonic, development, while, diminishing, the, incidence, of, apoptosis])].
[sujeto(['All', combinations, of, 'RAc', and, 'RA', treatment, produced, blastocysts, with, similar, 'efficiencies,', while, 'IGF-I']), verbo([enhanced]), complemento([embryos, yields, irrespectively, of, retinoid, addition])].
[sujeto(['In', 'conclusion,', supplementation, with, retinoids, and, 'IGF-I', during, goat, embryo, culture]), verbo([enhances]), complemento([blastocysts, development, without, synergic, reduction, of, apoptosis])].
[sujeto(['Cholesterol', efflux, from, macrophages, is, a, key, process, in, reverse, cholesterol, transport, 'and,', 'therefore,', might]), verbo([inhibit]), complemento([atherogenesis])].
[sujeto([9, -, 'cis-β-carotene', '(', 9, -, 'cis-βc)', is, a, precursor, for, 9, -, 'cis-retinoic-acid', '(', 9, -, 'cis-RA),', which]), verbo([regulates]), complemento([macrophage, cholesterol, efflux])].
[sujeto(['Our', objective, was, to, assess, whether, 9, -, 'cis-βc']), verbo([increases]), complemento([macrophage, cholesterol, efflux, and, induces, the, expression, of, cholesterol, transporters])].
[sujeto(['Enrichment', of, a, mouse, diet, with, βc, from, the, alga, 'Dunaliella']), verbo([led]), complemento([to, βc, accumulation, in, peritoneal, macrophages])].
[sujeto([9, -, 'cis-βc']), verbo([increased]), complemento([the, mRNA, levels, of, 'CYP26B1,', an, enzyme, that, regulates, 'RA', cellular, 'levels,', indicating, the, formation, of, 'RA', from, βc, in, 'RAW264'])].
[sujeto(['Furthermore,', 9, -, 'cis-βc,', as, well, as, 'all-trans-βc,', significantly]), verbo([increased]), complemento([cholesterol, efflux, to, 'high-density', lipoprotein, '(', 'HDL)', by, 50, '%', in, 'RAW264'])].
[sujeto([9, -, 'cis-βc']), verbo([increased]), complemento([both, the, mRNA, and, protein, levels, of, 'ABCA1', and, apolipoprotein, 'E', '(', 'APOE)', and, the, mRNA, level, of, 'ABCG1'])].
[sujeto(['Our', study, 'shows,', for, the, first, 'time,', that, 9, -, 'cis-βc', from, the, diet, accumulates, in, peritoneal, macrophages, and]), verbo([increases]), complemento([cholesterol, efflux, to, 'HDL'])].
[sujeto(['Although', skin, protection, measures, and, topical, therapies, are, fundamental, in, its, 'management,', some, patients, are, refractory, to, 'first-line', therapy, with, topical, corticosteroids, and]), verbo([require]), complemento([systemic, treatment])].
[sujeto(['Alitretinoin', '(', 9, -, 'cis-retinoic', 'acid;', 'Toctino(®))', is, an, endogenous, 'vitamin&nbsp;A', derivative, with, high]), verbo([binding]), complemento([affinity, for, both, retinoic, acid, receptors, and, retinoid, 'X', receptors])].
[sujeto(['VDR', and, 'RXR', agonists, delayed, atherosclerosis, progression, independent, of, serum, lipid, and, glucose, 'levels,', and, significantly, reduced, the, protein, expression, of, nicotinamide, adenine, dinucleotide, phosphate, '(', 'NADPH)', oxidase, subunit, gp91phox, and]), verbo([nuclear]), complemento(['factor-kappa', 'B', '(', 'NF-κB)', subunit, 'p65,', as, well, as, plasma, biomarkers, of, oxidative, stress, and, inflammation])].
[sujeto(['Combination', therapy, alleviated, atherosclerosis, and]), verbo([inhibited]), complemento([indexes, of, oxidative, stress, and, inflammation, to, a, greater, extent, than, either, monotherapy])].
[sujeto(['In', the, 'in&nbsp;vitro', 'study,', naturally, occurring, 'VDR', ligand, 1, 'α,25-dihydroxyvitamin', 'D3', '(', 1, ',', 25, '[', 'OH]2D3)', and, 'RXR', ligand, 9, -, cis, retinoic, acid, '(', 9, -, 'cis-RA),', both, significantly]), verbo([inhibited]), complemento(['high-glucose-induced', endothelial, cell, apoptosis])].
[sujeto(['Mantle', cell, lymphoma, '(', 'MCL)', is, an, aggressive, haematological, malignancy, in, which, the, response, to, therapy, can, be, limited, by, aberrantly]), verbo([activated]), complemento([molecular, and, cellular, 'pathways,', among, which, autophagy, was, recently, listed])].
[sujeto(['Our', study, shows, that, the, 9, -, 'cis-retinoic', acid, '(', 'RA)/Interferon(IFN)-α', combination]), verbo([induces]), complemento([protective, autophagy, in, 'MCL', cell, lines, and, primary, cultures, reducing, the, extent, of, 'drug-induced', apoptosis])].
[sujeto(['In', 'particular,', 'RA/IFN-α', combination, concomitantly]), verbo([increases]), complemento(['PLSCR1', transcription, and, controls, 'PLSCR1', protein, levels, via, lysosomal, degradation])].
[sujeto(['Indeed,', 'PLSCR1', overexpression, reduced, 'MCL', cell, susceptibility, to, autophagy]), verbo([induced]), complemento([by, 'RA/IFN-α,', serum, deprivation, or, mTOR, pharmacological, inhibition])].
[sujeto(['Moreover,', 'PLSCR1', can]), verbo([bind]), complemento([the, 'ATG12/ATG5', complex, preventing, 'ATG16L1', recruitment, and, its, full, 'activation,', as, indicated, by, 'co-immunoprecipitation', experiments])].
[sujeto(['The', combination, of, doxorubicin, or, bortezomib, with, 'RA/IFN-α', strengthened, 'PLSCR1', 'up-regulation', and]), verbo([enhanced]), complemento(['apoptosis,', as, a, likely, consequence, of, the, blockade, of, 'RA/IFN-α-induced', autophagy])].
[sujeto(['Immunohistochemical', analysis, of, 32, 'MCL', biopsies, revealed, heterogeneous, expression, of, 'PLSCR1', and]), verbo([suggests]), complemento([its, possible, implication, in, the, response, to, anticancer, 'therapies,', especially, to, drugs, promoting, protective, autophagy])].
[sujeto(['Nuclear', 9, -, cis, retinoic, acid, receptors, '(', retinoid, 'X', 'receptors,', 'RXR)', are, promiscuous, dimerization, partners, for, a, number, of]), verbo([nuclear]), complemento([receptors])].
[sujeto(['In', the, present, 'study,', we, established, a, novel, in, vitro, method, for, quantitative, determination, of, the]), verbo([nuclear]), complemento([retinoid, 'X', receptors, in, rat, liver])].
[sujeto(['One', type, of, high, affinity, and, limited, capacity, 'RXR', specific]), verbo([binding]), complemento([sites, with, the, 'Ka', value, ranging, from, 1.011, to, 1.727, '×10(9)l/mol', and, the, 'Bmax', value, ranging, from, 0.346, to, 0.567, 'pmol/mg,', was, demonstrated])].
[sujeto(['Maximal', 9, -, cis, retinoic, acid, '(', 9, 'cRA)', specific]), verbo([binding]), complemento([to, nuclear, retinoid, 'X', receptors, was, achieved, at, 20, °, 'C,', and, the, optimal, incubation, time, for, the, 9, 'cRA-RXR', complex, formation, was, 120, min])].
[sujeto(['Our', data, confirmed, the, property, of, tributyltin, chloride, or, triphenyltin, chloride, to]), verbo([bind]), complemento([to, a, high, affinity, and, limited, capacity, 'RXR', binding, sites])].
[sujeto(['Described', optimal, conditions, for, ligand]), verbo([binding]), complemento([to, 'RXR', molecules, enabled, us, to, calculate, maximal, binding, capacity, '(', 'Bmax)', and, affinity, '(', 'Ka)', values])].
[sujeto(['This', study]), verbo([provides]), complemento([an, original, 'RXR', radioligand, binding, assay, that, can, be, employed, for, investigation, of, novel, 'RXR', ligands, that, comprise, both, drugs, and, endocrine, disruptors])].
[sujeto(['Since', 'then,', the, endogenous, presence, of, this, compound]), verbo([has]), complemento([never, been, rigorously, confirmed])].
[sujeto(['Instead,', concerns]), verbo([have]), complemento([been, raised, by, other, groups, that, have, reported, that, 9, -, 'cis-retinoic', acid, is, undetectable, or, that, its, presence, occurs, at, very, low, levels])].
[sujeto(['Alternative', 'ligands,', among, them, various, 'lipids,']), verbo([have]), complemento([also, been, 'identified,', but, also, did, not, fulfill, criteria, for, rigorous, endogenous, 'relevance,', and, their, consideration, as, bona, fide, endogenous, mammalian, 'RXR', ligand, has, likewise, been, questioned])].
[sujeto(['Our', aim, was, to, dissect, the, antitumoral, effects, of, 9, -, cisRA, on, 'ACC', in, a, 'large-scale', xenograft, study]), verbo([involving]), complemento(['mitotane,', 9, -, cisRA, and, their, combination])].
[sujeto([9, -, cis, 'RA']), verbo([promotes]), complemento([lymphangiogenesis, in, vitro, and, in, vivo, and, has, promise, as, a, therapeutic, agent, to, limit, the, development, of, postsurgical, lymphedema])].
[sujeto(['Lymphedema', was]), verbo([induced]), complemento([in, the, right, hind, limb, after, a, single, fraction, of, 20, 'Gy', 'radiation,', popliteal, 'lymphadenectomy,', and, lymphatic, vessel, ablation])].
[sujeto([9, -, cis, 'RA-treated', animals, had, significantly, faster, lymphatic, drainage, as, measured, by, indocyanine, green, clearance, and]), verbo([increased]), complemento([lymphatic, vessel, density, as, measured, by, podoplanin, immunohistochemistry, '(', 'P', &, 'lt;', 0.001, ')', and, whole, mount, skin, analysis, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['We']), verbo([have]), complemento([developed, a, highly, reproducible, model, of, secondary, lymphedema, and, have, demonstrated, that, 9, -, cis, 'RA', significantly, prevents, postsurgical, lymphedema])].
[sujeto(['Treatment', with, 9, -, cis, 'RA', is]), verbo([associated]), complemento([with, increased, lymphatic, clearance, and, lymphangiogenesis])].
[sujeto(['Because', 9, -, cis, 'RA', '(', 'alitretinoin)', is, already, approved, for, clinical, use, by, the, 'US', 'Food', and, 'Drug', 'Administration', for, other, 'conditions,', it]), verbo([has]), complemento([the, potential, to, be, repurposed, as, a, preventative, agent, for, postsurgical, lymphedema, in, humans])].
[sujeto(['Here,', we, would, like, to, propose, the, &, 'quot;helix', 'H3', 'three-point', 'initial-binding', 'hypothesis,&quot;', which, was, instrumental, in, simulating, the]), verbo([nuclear]), complemento([receptor, '(', 'NR)', superfamily])].
[sujeto(['It', is, hoped, that, this, hypothesis, will, facilitate, novel, understanding, of, both, the, 'ligand-trapping', mechanism, and, the, simultaneous, 'C-terminal', folding, process, in, 'NR', 'LBDs,', as, well, as]), verbo([provide]), complemento([a, new, approach, to, drug, design, using, a, 'structure-based', perspective])].
[sujeto(['At', 'present,', the, use, of, systemic, alitretinoin]), verbo([has]), complemento([proved, extremely, efficacious, in, the, management, of, recalcitrant, chronic, hand, eczema])].
[sujeto(['Furthermore,', there]), verbo([have]), complemento([been, other, retinoid, responsive, dermatosis, that, have, demonstrated, remission, post, usage, of, systemic, alitretinoin])].
[sujeto(['Apolipoprotein', 'E', '(', 'apoE),', a, protein, mainly]), verbo([involved]), complemento([in, lipid, 'metabolism,', is, associated, with, several, neurodegenerative, disorders, including, 'Alzheimer\'s', disease])].
[sujeto(['The', mechanism, of, apoE, gene, regulation, in, the, brain]), verbo([involves]), complemento([the, proximal, promoter, and, multienhancers, 'ME'])].
[sujeto(['Herein', we, questioned, whether, thyroid, hormones, and, their]), verbo([nuclear]), complemento([receptors, have, a, role, in, apoE, gene, regulation, in, astrocytes])].
[sujeto(['Our', data, showed, that, thyroid, hormones]), verbo([increase]), complemento([apoE, gene, expression, in, 'HTB14', astrocytes, in, a, 'dose-dependent', manner])].
[sujeto(['This', effect, can, be, intermediated, by, the, thyroid, receptor, β, '(', 'TRβ)', which, is]), verbo([expressed]), complemento([in, these, cells])].
[sujeto(['In', the, presence, of, triiodothyronine, '(', 'T3)', and, 9, -, cis, retinoic, 'acid,', in, astrocytes, transfected, to, overexpress, 'TRβ', and, retinoid, 'X', receptor, α, '(', 'RXRα),', apoE, promoter, was, indirectly]), verbo([activated]), complemento([through, the, interaction, with, 'ME'])].
[sujeto(['To', determine, the, location, of, 'TRβ/RXRα']), verbo([binding]), complemento([site, on, 'ME'])].
[sujeto([2, ',', we, performed, 'DNA', pull, down, assays, and]), verbo([found]), complemento([that, 'TRβ/RXRα', complex, bound, to, the, region, 341, -, 488, of, 'ME'])].
[sujeto(['These', data, support, the, existence, of, a, biologically, active, 'TRβ']), verbo([binding]), complemento([site, starting, at, 409, in, 'ME'])].
[sujeto(['In', 'conclusion,', our, data, revealed, that, 'ligand-activated', 'TRβ/RXRα', heterodimers]), verbo([bind]), complemento([with, high, efficiency, on, 'tissue-specific', distal, regulatory, element, 'ME'])].
[sujeto([2, and, thus]), verbo([modulate]), complemento([apoE, gene, expression, in, the, brain])].
[sujeto(['The', retinoid]), verbo([binding]), complemento([protein, 4, '(', 'RBP4),', the, epididymal, 'retinoid-binding', protein, '(', 'ERBP),', and, the, interphotoreceptor, matrix, 'retinoid-binding', protein, '(', 'IRBP)', play, a, central, role, in, 'ROL', 'transport,', whereas, 'lipocalin-type', prostaglandin, 'D', synthase, '(', also, named, 'β-trace)', and, human, serum, albumin, '(', 'HSA)', transport, preferentially, 'all-trans-RA'])].
[sujeto(['Here,', the, modulatory, effect, of, 'all-trans-RA', and, 'all-trans-ROL', on, ferric, heme, '(', 'heme-Fe(III))']), verbo([binding]), complemento([to, 'HSA', is, reported])].
[sujeto(['All-trans-RA', and, 'all-trans-ROL']), verbo([binding]), complemento([to, the, 'FA1', site, of, 'HSA', competitively, inhibit, 'heme-Fe(III)', association])].
[sujeto(['Docking', simulations, and, local, structural, comparison, of, 'HSA', with, 'all-trans-RA-', and, 'all-trans-ROL-binding', proteins, support, functional, data, indicating, the, preferential]), verbo([binding]), complemento([of, 'all-trans-RA', and, 'all-trans-ROL', to, the, 'FA1', site, of, 'HSA'])].
[sujeto(['Present', results, may, be, relevant, 'in&nbsp;vivo,', in, fact, 'HSA', could]), verbo([act]), complemento([as, a, secondary, carrier, of, retinoids, in, human, diseases, associated, with, reduced, levels, of, 'RBP4', and, 'IRBP'])].
[sujeto(['Slc10a6,', an, incompletely, characterized, member, of, the, 'SLC10A', bile, acid, transporter, 'family,', was, one, of, the, most, highly]), verbo([induced]), complemento(['RNA', transcripts, identified, in, a, screen, for, 'inflammation-responsive', genes, in, mouse, liver])].
[sujeto(['Cells', were, treated, with, 'LPS', '(', 1, &, 'nbsp;μg/mL)', at, various, time, 'points,', with, cell, signaling, 'inhibitors,']), verbo([nuclear]), complemento([receptor, ligands, and, 'Slc10a6', substrates])].
[sujeto(['Both', absence, of, the]), verbo([nuclear]), complemento([receptor, 'Fxr', and, pretreating, mice, with, the, synthetic, retinoid, 'X', 'receptor-α', ligand, 'LG268', attenuated, the, 'LPS', upregulation, of, 'Slc10a6', mRNA, by, 60, -, 75, '%'])].
[sujeto(['In', 'vitro,', 'Slc10a6', mRNA, was]), verbo([induced]), complemento([30, -, fold, by, 'LPS', in, mouse, 'RAW264'])].
[sujeto(['The', 'Slc10a6', substrate, dehydroepiandrosterone, sulfate, '(', 'DHEAS)']), verbo([enhanced]), complemento(['LPS', induction, of, 'CCL5', 'mRNA,', a, 'pro-inflammatory', 'chemokine,', by, 50, '%', in, 'RAW264'])].
[sujeto(['This', effect, was, abrogated, in, the, presence, of, 'anti-inflammatory']), verbo([nuclear]), complemento([receptor, ligands, 9, -, 'cis-retinoic', acid, and, dexamethasone])].
[sujeto(['Dramatic', upregulation, of, 'Slc10a6', mRNA, by, 'LPS', combined, with]), verbo([enhanced]), complemento(['LPS', stimulation, of, 'CCL5', expression, by, the, 'Slc10a6', substrate, 'DHEAS', in, macrophages, suggests, that, 'Slc10a6', function, contributes, to, the, hepatic, inflammatory, response])].
[sujeto(['Patients', with, severe, oral, lichen, planus, refractory, to, standard, topical, treatment, currently]), verbo([have]), complemento([limited, options, of, therapy, suitable, for, 'long-term', use])].
[sujeto(['Oral', alitretinoin, '(', 9, -, cis, retinoic, 'acid)', was, never, systematically, investigated, in, clinical, 'trials,', although, case]), verbo([reports]), complemento([suggest, its, possible, efficacy])].
[sujeto(['Adverse', events, were, mild, and, included, 'headache,', mucocutaneous, 'dryness,', musculoskeletal, 'pain,']), verbo([increased]), complemento(['thyroid-stimulating', hormone, and, dyslipidaemia])].
[sujeto(['Retinoid', 'X', receptors, '(', 'RXRs)', are, 'ligand-controlled', transcription, factors, which]), verbo([heterodimerize]), complemento([with, other, nuclear, receptors, to, regulate, gene, transcriptions, associated, with, crucial, biological, events])].
[sujeto(['All-trans', retinoic, acid, '(', 'ATRA)', is, a, natural, ligand, for, retinoic, acid, receptors, '(', 'RARs),', which]), verbo([heterodimerize]), complemento([with, 'RXRs'])].
[sujeto(['Although', the, concentration, of, 9, cRA, in, tissues, is, very, 'low,', 'ATRA', is, relatively, abundant, and, some]), verbo([reports]), complemento([show, that, 'ATRA', activates, 'RXRs'])].
[sujeto(['We', computationally, studied, the, possibility, of, 'ATRA']), verbo([binding]), complemento([to, 'RXRs', using, two, different, docking, methods, with, our, developed, programs, to, assess, the, binding, affinities, of, naturally, occurring, retinoids])].
[sujeto(['The', simulations, showed, good, correlations, to, the]), verbo([reported]), complemento([binding, affinities, of, these, molecules, for, 'RXRs', and, 'RARs'])].
[sujeto(['The', immunopathogenesis, of, this, disease]), verbo([involves]), complemento([an, impaired, balance, of, 'T', helper, '(', 'Th)', 17, cells, and, regulatory, 'T', '(', 'Tregs)', cells])].
[sujeto(['For', many, 'years,', 'MS']), verbo([has]), complemento([been, considered, to, be, an, autoreactive, 'Th1', and, 'Th17', 'cell-dominated', disease])].
[sujeto(['The', activity, and, number, of, 'Th17', cells, are]), verbo([increased]), complemento([in, 'MS;', 'however,', the, function, and, number, of, 'Treg', cells, are, reduced])].
[sujeto(['However,', 'Treg', 'cell-mediated', production, of, cytokines]), verbo([maintains]), complemento([immune, homeostasis, and, can, ameliorate, the, progression, of, 'MS'])].
[sujeto(['These', 'observations,', 'therefore,', confirm, the, pathogenic, and, protective, role, of, 'Th17', and, 'Treg', 'cells,', 'respectively,', and, highlight, the, importance, of]), verbo([maintaining]), complemento([the, balance, of, both, of, these, cell, types])].
[sujeto(['Evidence']), verbo([suggests]), complemento([that, vitamin, 'A', and, its, active, metabolites, '(', 'all-trans-retinoic', acid, and, 9, -, 'cis-retinoic', 'acid)', modulate, the, imbalance, of, 'Th17', and, 'Treg', cells, through, multiple, molecular, pathways, and, can, be, considered, as, a, promising, target, in, the, prevention, and, treatment, of, 'MS'])].
[sujeto(['The', literature]), verbo([provides]), complemento([compelling, evidence, pointing, to, tight, metabolic, interactions, between, retinoids, and, xenobiotics])].
[sujeto(['This', article, summarizes, data, that, establish, the, importance, of, 'retinoid-dependent', metabolic, pathways, for, sustaining, the, 'body\'s', responses, to, xenobiotic, 'exposure,', including, the, roles, of, 'all-trans-', and, 9, -, 'cis-retinoic', acid, for, protecting, mammals, from, harmful, xenobiotic, effects, and, for]), verbo([ensuring]), complemento([xenobiotic, elimination, from, the, body])].
[sujeto(['Special', attention, is, paid, to, xenobiotic, molecular]), verbo([targets]), complemento(['(', nuclear, 'receptors,', regulatory, 'proteins,', 'enzymes,', and, 'transporters)', which, affect, retinoid, metabolism, and, signaling])].
[sujeto(['Regulation', of, 'ROS', metabolism, plays, a, major, role, in, cellular, adaptation, to, oxidative, stress, in, cancer, 'cells,', but, the, molecular, mechanism, that]), verbo([regulates]), complemento(['catalase,', a, key, antioxidant, enzyme, responsible, for, conversion, of, hydrogen, peroxide, to, water, and, 'oxygen,', remains, to, be, elucidated])].
[sujeto(['Here', we, identify, a, novel, promoter, region, responsible, for, the, regulation, of, catalase, expression, at, -, 1518, /, -, 1226, locus, and, the, key, molecules, that]), verbo([interact]), complemento([with, this, promoter, and, affect, catalase, transcription])].
[sujeto(['We', show, that, the, 'AP-1', family, member, 'JunB', and, retinoic, acid, receptor, alpha, '(', 'RARα)']), verbo([mediate]), complemento([catalase, transcriptional, activation, and, 'repression,', 'respectively,', by, controlling, chromatin, remodeling, through, a, histone, 'deacetylases-dependent', mechanism])].
[sujeto(['Our', study]), verbo([suggests]), complemento([that, cancer, adaptation, to, oxidative, stress, may, be, regulated, by, transcriptional, factors, through, chromatin, 'remodeling,', and, reveals, a, potential, new, mechanism, to, target, cancer, cells])].
[sujeto(['Arsenic', trioxide, '(', 'ATO)']), verbo([mediates]), complemento(['PML-RARA', '(', promyelocytic, 'leukemia-retinoic', acid, 'receptor-α)', oncoprotein, degradation, via, the, proteasome, pathway, and, this, degradation, appears, to, be, critical, for, achieving, cure, in, acute, promyeloytic, leukemia, '(', 'APL)'])].
[sujeto(['We']), verbo([have]), complemento([previously, demonstrated, significant, 'micro-environment-mediated', drug, resistance, '(', 'EMDR)', to, 'ATO', in, 'APL'])].
[sujeto(['The', mechanism, of, this, synergy]), verbo([involved]), complemento([downregulation, of, the, nuclear, 'factor-κB', 'pathway,', increase, in, unfolded, protein, response, '(', 'UPR)', and, an, increase, in, reactive, oxygen, species, generation, in, the, malignant, cell])].
[sujeto(['We', also, noted, that, 'PML-RARA', oncoprotein, is, effectively, cleared, with, this, combination, in, spite, of, proteasome, inhibition, by, 'bortezomib,', and, that, this, clearance, is]), verbo([mediated]), complemento([through, a, 'p62-dependent', autophagy, pathway])].
[sujeto(['We', further, demonstrated, that, proteasome, inhibition, along, with, 'ATO', had, an, additive, effect, in]), verbo([inducing]), complemento([autophagy])].
[sujeto(['Retinoic', acid, receptor, '(', 'RAR)']), verbo([has]), complemento([been, implicated, in, pathological, 'stimuli-induced', cardiac, remodeling])].
[sujeto(['To', determine, whether, the, impairment, of, 'RARα', signaling, directly, contributes, to, the, development, of, heart, dysfunction, and, the]), verbo([involved]), complemento(['mechanisms,', 'tamoxifen-induced', myocardial, specific, 'RARα', deletion, '(', 'RARαKO)', mice, were, utilized])].
[sujeto(['DHE', staining, showed]), verbo([increased]), complemento([intracellular, reactive, oxygen, species, '(', 'ROS)', generation, in, the, hearts, of, 'RARαKO', mice])].
[sujeto(['Significantly']), verbo([increased]), complemento(['NOX2', '(', 'NADPH', oxidase, 2, ')', and, 'NOX4', levels, and, decreased, 'SOD1', and, 'SOD2', levels, were, observed, in, 'RARαKO', mouse, 'hearts,', which, were, rescued, by, overexpression, of, 'RARα', in, cardiomyocytes])].
[sujeto(['Decreased', 'SERCA2a', expression, and, phosphorylation, of, phospholamban, '(', 'PLB),', along, with]), verbo([decreased]), complemento([phosphorylation, of, 'Akt', and, 'Ca(2+)/calmodulin-dependent', protein, kinase, 'II', δ, '(', 'CaMKII', 'δ)', was, observed, in, 'RARαKO', mouse, hearts])].
[sujeto(['Overexpression', of, 'RARα', or, inhibition, of, 'ROS', generation, or, 'NOX', activation]), verbo([prevented]), complemento(['RARα', 'deletion-induced', decrease, in, 'SERCA2a', 'expression/activation', and, delayed, 'Ca(2+)', reuptake])].
[sujeto(['Moreover,', the, gene, and, protein, expression, of, 'RARα', was, significantly]), verbo([decreased]), complemento([in, aged, or, metabolic, stressed, mouse, hearts])].
[sujeto(['In', 'conclusion,', myocardial, 'RARα', deletion]), verbo([promoted]), complemento([diastolic, 'dysfunction,', with, a, relative, preserved, 'LVEF'])].
[sujeto(['Increased', oxidative, stress]), verbo([have]), complemento([an, important, role, in, the, decreased, 'expression/activation', of, 'SERCA2a', and, 'Ca(2+)', mishandling, in, 'RARαKO', 'mice,', which, are, major, contributing, factors, in, the, development, of, diastolic, dysfunction])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, impairment, of, cardiac, 'RARα', signaling, may, be, a, novel, mechanism, that, is, directly, linked, to, pathological, 'stimuli-induced', diastolic, dysfunction])].
[sujeto(['Fasci', et, al, proposed, that, a, 'SENP1-mediated', switch, from, 'SUMO2', to, 'SUMO1', conjugation, on, 'Lys(65)', in, promyelocytic, leukemia, protein, '(', 'PML)', is]), verbo([required]), complemento([for, 'arsenic-induced', 'PML', 'degradation,', the, basis, for, the, antileukemic, activity, of, arsenic])].
[sujeto(['We']), verbo([found]), complemento([that, 'PML', or, 'PML/RARA', '(', retinoic, acid, receptor, 'α)', mutants, that, cannot, be, 'SUMO-conjugated', on, this, specific, site, nevertheless, underwent, immediate, 'arsenic-triggered', 'SUMO', modification])].
[sujeto(['We']), verbo([found]), complemento([that, 'all-trans', retinoic, 'acid(ATRA)', could, promote, differentiation, while, inhibit, proliferation, of, 'APL', 'NB4', cells, via, upregulating, the, expression, of, phosphorylated, p38α, 'mitogen-activated', protein, 'kinase(p-p38α', 'MAPK)'])].
[sujeto(['We', also]), verbo([found]), complemento([that, 'NLS-RARα', could, inhibit, differentiation, while, accelerate, proliferation, of, 'NB4', cells, via, downregulating, the, expression, of, 'p-p38α', protein, in, the, presence, of, 'ATRA'])].
[sujeto(['Furthermore,', immunofluorescence, and, 'co-immunoprecipitation', assays, confirmed, 'NLS-RARα']), verbo([interacted]), complemento([with, p38α, protein, directly])].
[sujeto(['Finally,', application, of, 'PD169316,', an, inhibitor, of, p38α, 'protein,']), verbo([suggested]), complemento([that, recruitment, 'p38α-combinded', 'NLS-RARα', by, 'ATRA', eventually, caused, activation, of, p38α, protein])].
[sujeto(['In', 'summary,', our, study, demonstrated, that, 'ATRA', cound]), verbo([promote]), complemento([differentiation, while, inhibit, proliferation, of, 'APL', 'NB4', cells, via, activating, p38α, protein, after, recruiting, 'p38α-combinded', 'NLS-RARα,', while, 'NLS-RARα', could, inhibit, the, effects, of, 'ATRA', in, the, process])].
[sujeto(['In', this, paper, we, explore, whether, selected, vitamins, and, fatty, acids, known, to]), verbo([modulate]), complemento([inflammation, exert, an, effect, on, 'microglia,', the, key, cell, type, involved, in, neuroinflammation])].
[sujeto(['Previously', these, nutrients]), verbo([have]), complemento([been, shown, to, exert, 'anti-inflammatory', properties, acting, on, specific, inflammatory, pathways])].
[sujeto(['We', hypothesized, that, combining, nutrients]), verbo([acting]), complemento([on, converging, 'anti-inflammatory', pathways, may, lead, to, enhanced, 'anti-inflammatory', properties, as, compared, to, the, action, of, a, single, nutrient])].
[sujeto(['In', this, 'study,', we, investigated, the, 'anti-inflammatory', effect, of, combinations, of, nutrients, based, on, the, ability, to]), verbo([inhibit]), complemento([the, 'LPS-induced', release, of, nitric, oxide, and, 'interleukin-6', from, 'BV-2&nbsp;cells'])].
[sujeto(['The', conclusion, of, this, study, is, that, combining, different, nutrients]), verbo([acting]), complemento([on, convergent, 'anti-inflammatory', pathways, may, result, in, an, increased, 'anti-inflammatory', efficacy])].
[sujeto(['Since', the, application, of, arsenic, trioxide, and, 'all-trans', retinoic, acid, in, the, treatment, of, 'APL,', the, prognosis]), verbo([has]), complemento([greatly, improved])].
[sujeto(['Recently,', 'Ets', variant, 6, '(', 'ETV6)', was]), verbo([reported]), complemento([to, be, involved, in, a, variety, of, translocations, associated, with, hematological, malignancies, of, myeloid, and, lymphoid, origin])].
[sujeto(['The', data]), verbo([suggested]), complemento([that, 'ETV6', rearrangement, may, be, an, independent, unfavorable, prognostic, factor, for, overall, survival, in, 'APL', patients])].
[sujeto(['Transcription', factors, such, as, retinoic, acid, receptor, alpha, '(', 'RARα)', and, beta, '(', 'RARβ)', and, 'Yin', 'Yang', 1, '(', 'YY1)', are]), verbo([associated]), complemento([with, the, progression, of, 'non-small', cell, lung, cancer, '(', 'NSCLC)'])].
[sujeto(['In', 'particular,', a, lack, of, 'RARβ', expression, is]), verbo([associated]), complemento([with, 'NSCLC', development])].
[sujeto(['The', mean, and, standard, deviation, of, the]), verbo([nuclear]), complemento([expression, of, 'RARα,', 'RARβ', and, 'YY1', were, 184.5, &, 'nbsp;±&nbsp;124'])].
[sujeto(['The']), verbo([nuclear]), complemento([expression, of, 'RARβ', was, associated, with, the, nuclear, expression, of, 'YY1', '(', 'R', '(', 2, ')', &, 'nbsp;=&nbsp;0'])].
[sujeto(['Patients', with, high]), verbo([nuclear]), complemento([expression, of, 'YY1', were, likely, to, be, 'non-smokers', '(', 61.9, vs, 40.5, &, 'nbsp;%)'])].
[sujeto(['Low', expression, of, 'RARα', was, independently]), verbo([associated]), complemento([with, worse, 'PFS', following, chemotherapy, '(', 10.3, vs, 5.46, &, 'nbsp;months', 'p&nbsp;=&nbsp;0'])].
[sujeto(['Median', overall, survival, '(', 'OS)', was, 15.6, &, 'nbsp;months', '(', 4.5, -, 26.7, ')', ',', and, lower]), verbo([nuclear]), complemento([expression, of, 'RARβ', was, independently, associated, with, shorter, 'OS', '(', 27.5, vs, 8.7, &, 'nbsp;months;', 'p&nbsp;=&nbsp;0'])].
[sujeto(['Our', study]), verbo([suggests]), complemento([that, the, loss, of, 'RARs', is, associated, with, a, worse, prognosis, and, these, receptors, could, be, a, potential, molecular, target, for, 'NSCLC'])].
[sujeto(['This', work, presents, a, comprehensive, description, of, changes, in, the, expression, of, 23, genes, that]), verbo([regulate]), complemento([retinoid, metabolism, and, signaling, in, 'non-small-cell', lung, cancer, tumors, compared, to, adjacent, normal, tissues, obtained, using, 'RT-PCR'])].
[sujeto(['Even', at, early, stages, of, malignant, 'transformation,', a, significant]), verbo([decrease]), complemento([in, 'ADH1B,', 'ADH3,', 'RDHL,', and, 'RALDH1', mRNA, levels, was, observed, in, 82, ',', 79, ',', 73, ',', and, 64, '%', of, tumor, 'specimens,', 'respectively,', and, a, considerable, increase, in, 'AKR1B10', mRNA, content, was, observed, in, 80, '%', of, tumors])].
[sujeto(['Apart', from, 'that,', it, was]), verbo([found]), complemento([that, mRNA, levels, of, nuclear, retinoid, receptor, genes, 'RXRγ,', 'RARα,', 'RXRα,', and, gene, 'RDH11', were, significantly, decreased, in, 80, ',', 67, ',', 57, ',', and, 66, '%', of, tumor, 'specimens,', respectively])].
[sujeto(['Vorinostat', and, 'ATO,', alone, and, in, 'combination,']), verbo([inhibited]), complemento([the, proliferation, of, 'NB4', cells, in, a, 'time-', and, 'dose-dependent', manner, and, the, effect, was, additive])].
[sujeto(['Both', vorinostat, and, 'ATO', alone, and, in, combination, resulted, in, lower, levels, of, promyelocytic, 'leukaemia/retinoic', acid, receptor, alpha, fusion, protein, and]), verbo([increased]), complemento([levels, of, 'acetyl-histone', 'H3', and, 'acetyl-histone', 'H4', proteins, compared, with, controls])].
[sujeto(['The', combination, of, vorinostat, and, 'ATO']), verbo([inhibited]), complemento([cell, 'proliferation,', induced, 'apoptosis,', and, enhanced, the, chemosensitivity, of, 'NB4', cells])].
[sujeto(['The', mechanism, might, be]), verbo([associated]), complemento([with, increasing, histone, acetylation, levels, as, well, as, downregulation, of, the, 'Akt', signalling, pathway])].
[sujeto(['The', data, also]), verbo([suggest]), complemento([that, 'ATRA-ATO', may, abrogate, the, negative, prognostic, impact, of, 'FLT3-ITD'])].
[sujeto(['After', dexamethasone, was, administered, at, a, dose, of, 8, 'mg/m', to]), verbo([prevent]), complemento(['all-trans', retinoic, acid, syndrome, on, day, 1, ',', 'all-trans', retinoic, acid, was, started, at, a, dose, of, 45, 'mg/m', on, day, 4])].
[sujeto(['The', 'WBC', count, gradually]), verbo([increased]), complemento([to, 270, '×10/μL', on, day, 8, ',', and, then, decreased, beginning, on, day, 9])].
[sujeto(['In', our, 'patient,', rTM, may]), verbo([have]), complemento([prevented, fatal, 'DIC', and, made, it, possible, to, safely, administer, induction, chemotherapy])].
[sujeto(['Besides', the, presence, of, chromosomal, rearrangement, 't(15;17),']), verbo([leading]), complemento([to, the, formation, of, 'PML-RARA', '(', promyelocytic, 'leukemia-retinoic', acid, receptor, 'alpha)', 'fusion,', other, genetic, alterations, have, also, been, implicated, in, 'APL'])].
[sujeto(['We', explored, the, mutational, landscape, using, 'whole-exome', '(', 'n=12)', and, subsequent]), verbo([targeted]), complemento([sequencing, of, 398, genes, in, 153, primary, and, 69, relapse, 'APL'])].
[sujeto(['However,', 'APL', is, now, one, of, the, most, curable, hematological, malignancies, because, of, molecularly]), verbo([targeted]), complemento([therapies])].
[sujeto(['With', the, advent, of, 'all-trans', retinoic, acid, '(', 'ATRA)', containing, chemotherapy, 'regimens,', rates, of, complete, remission, and, 'long-term,', 'disease-free', survival]), verbo([have]), complemento([improved, dramatically])].
[sujeto(['More', 'recently,', regimens, incorporating, both, 'ATRA', and, arsenic, trioxide, '(', 'ATO)']), verbo([have]), complemento([allowed, a, substantial, number, of, patients, to, be, treated, with, little, or, no, additional, cytotoxic, chemotherapy])].
[sujeto(['While', many, posttranslational, regulators, of, nSMase2, are, 'known,', emerging, evidence]), verbo([suggests]), complemento([a, more, protracted, regulation, of, nSMase2, at, the, transcriptional, level])].
[sujeto(['Previously,', we]), verbo([reported]), complemento([that, nSMase2, is, induced, by, 'all-trans', retinoic, acid, '(', 'ATRA)', in, 'MCF7', cells, and, implicated, nSMase2, in, 'ATRA-induced', growth, arrest])].
[sujeto(['Here,', we, further, investigated, how, 'ATRA']), verbo([regulates]), complemento([nSMase2])].
[sujeto(['We']), verbo([find]), complemento([that, 'ATRA', regulates, nSMase2, transcriptionally, through, the, retinoic, acid, 'receptor-α,', but, this, is, independent, of, previously, identified, transcriptional, regulators, of, nSMase2, '(', 'Sp1,', 'Sp3,', 'Runx2)', and, is, not, through, increased, promoter, activity])].
[sujeto(['However,', inhibition, of, histone, deacetylases, '(', 'HDACs)', with, trichostatin, 'A', '(', 'TSA)']), verbo([induced]), complemento([nSMase2, comparably, to, 'ATRA;', 'furthermore,', combined, 'ATRA', and, 'TSA', treatment, was, not, 'additive,', suggesting, 'ATRA', regulates, nSMase2, through, direct, modulation, of, histone, acetylation])].
[sujeto(['Confirming', 'this,', the, histone, acetyltransferases, 'CREB-binding', protein, and, p300, were]), verbo([required]), complemento([for, 'ATRA', induction, of, nSMase2])].
[sujeto(['Finally,', use, of, 'class-specific', 'HDAC', inhibitors]), verbo([suggested]), complemento([that, 'HDAC4', 'and/or', 'HDAC5', are, negative, regulators, of, nSMase2, expression])].
[sujeto(['Collectively,', these, results, identify, a, novel, pathway, of, nSMase2, regulation, and]), verbo([suggest]), complemento([that, physiological, or, pharmacological, modulation, of, histone, acetylation, can, directly, affect, nSMase2, levels])].
[sujeto(['However,', some, conventional, drugs, like, 'all-transretinoic', acid, '(', 'ATRA)', and, arsenic, trioxide, '(', 'ATO),', as, the, preferred, ones, for, 'APL', 'therapy,']), verbo([induce]), complemento([irreversible, resistance, and, responsible, for, clinical, failure, of, complete, remission])].
[sujeto(['Herein,', we, screened, a, library, of, novel, chemical, compounds, with, structural, diversity, and, discovered, a, novel, synthetic, small, 'compound,', named, 'LG-362B,', specifically]), verbo([inhibited]), complemento([the, proliferation, of, 'APL', and, induced, apoptosis])].
[sujeto(['Notably,', the, differentiation]), verbo([arrest]), complemento([was, also, relieved, by, 'LG-362B', in, cultured, 'APL', cells, and, 'APL', mouse, models])].
[sujeto(['The', mechanism, of, transcriptional, regulation, of, 'VDR', in, response, to, 'ATRA']), verbo([has]), complemento([not, been, fully, elucidated])].
[sujeto(['Here,', we, show, that, the, retinoic, acid, receptor, α, '(', 'RARα)', is, responsible, for]), verbo([regulating]), complemento(['VDR', transcription, in, 'AML', cells])].
[sujeto(['We']), verbo([have]), complemento([shown, that, a, 'VDR', transcriptional, 'variant,', originating, in, exon, 1, 'a,', is, regulated, by, 'RARα', agonists, in, 'AML', cells])].
[sujeto(['Moreover,', in, cells, with, a, high, basal, level, of, 'RARα', 'protein,', the, 'VDR', gene, is, transcriptionally]), verbo([repressed]), complemento([as, long, as, 'RARα', agonist, is, absent])].
[sujeto(['In', these, cells, 'down-regulation', of, the, level, of, 'RARα']), verbo([leads]), complemento([to, increased, expression, of, 'VDR'])].
[sujeto(['We', consider, that, our, findings]), verbo([provide]), complemento([a, mechanistic, background, to, explain, the, different, outcomes, from, treating, 'AML', cell, lines, with, a, combination, of, 'ATRA', and, 1, ',', 25, 'D'])].
[sujeto(['MDI', 301, is, a, novel, 9, -, cis, retinoic, acid, derivative, in, which, the, terminal, carboxylic, acid, group]), verbo([has]), complemento([been, replaced, by, a, picolinate, ester])].
[sujeto(['MDI', 301, ',', a, retinoic, acid, 'receptor-α', -, 'agonist,']), verbo([suppressed]), complemento([the, growth, of, several, human, myeloid, leukemia, cell, lines, '(', 'HL60,', 'NB4,', 'OCI-M2,', and, 'K562)', in, vitro, and, induced, 'cell-substrate', adhesion, in, conjunction, with, upregulation, of, 'CD11b'])].
[sujeto(['Most', 'importantly,', unlike, what, was]), verbo([found]), complemento([with, 'ATRA', 'treatment,', 'MDI', 301, did, not, induce, a, cytokine, response, in, the, treated, animals, and, the, severe, inflammatory, changes, and, systemic, toxicity, seen, with, 'ATRA', did, not, occur])].
[sujeto(['We']), verbo([reported]), complemento([previously, that, increased, expression, of, aldehyde, dehydrogenase, 1, '(', 'ALDH1)', in, multiple, myeloma, '(', 'MM)', is, a, marker, of, 'tumor-initiating', cells, '(', 'TICs)', that, is, further, associated, with, chromosomal, instability, '(', 'CIN)'])].
[sujeto(['Here', we, demonstrate, that, member, 'A1', of, the, 'ALDH1', family, of, 'proteins,', 'ALDH1A1,', is, most, abundantly]), verbo([expressed]), complemento([in, myeloma])].
[sujeto(['Enforced', expression, of, 'ALDH1A1', in, myeloma, cells]), verbo([led]), complemento([to, increased, 'clonogenicity,', tumor, formation, in, 'mice,', and, resistance, to, myeloma, drugs, in, vitro, and, in, vivo])].
[sujeto(['Over', expression, of, 'ALDH1A1', in, myeloma, cells]), verbo([led]), complemento([to, increased, mRNA, and, protein, levels, of, 'NIMA-related', kinase, 2, '(', 'NEK2),', whereas, 'shRNA-mediated', knock, down, of, 'NEK2', decreased, drug, efflux, pump, activity, and, drug, resistance])].
[sujeto(['These', findings, implicate, the, 'ALDH1A1-RXRα-NEK2', pathway, in, drug, resistance, and, disease, relapse, in, myeloma, and]), verbo([suggest]), complemento([that, specific, inhibitors, of, 'ALDH1A1', are, worthy, of, consideration, for, clinical, development, of, new, approaches, to, overcome, drug, resistance, in, myeloma])].
[sujeto(['Estrogen', synthesis, in, adipose, tissue, is]), verbo([associated]), complemento([with, the, development, of, breast, cancer])].
[sujeto(['Tumors', are, preferentially]), verbo([found]), complemento([in, breast, quadrants, with, strongest, expression, of, the, cytochrome, 'P450', aromatase, '(', encoded, by, the, gene, 'CYP19A1)'])].
[sujeto(['Several', promoters]), verbo([regulated]), complemento([by, various, hormonal, factors, drive, aromatase, expression, in, human, breast, adipose, fibroblasts, '(', 'BAFs)'])].
[sujeto(['The', retinoids, 'all-trans-retinoic', acid, '(', 'at-RA)', and, 9, -, 'cis-RA']), verbo([induce]), complemento([aromatase, activity, in, human, 'BAFs'])].
[sujeto(['In', 'BAFs,', 'at-RA']), verbo([induces]), complemento([aromatase, gene, expression, via, promoter, 'I'])].
[sujeto(['Site-directed', mutagenesis, revealed, that, only, 'RARE2', '(', +, 91, /, +, 105, ')']), verbo([mediates]), complemento([the, 'retinoid-dependent', induction, of, reporter, gene, activity])].
[sujeto(['Electrophoretic', mobility, shift, assays, with]), verbo([nuclear]), complemento([extracts, obtained, from, human, 'BAFs', and, 3, 'T3-L1', cells, identified, a, specific, 'RARE2-binding', complex])].
[sujeto(['Retinoids']), verbo([enhanced]), complemento([complex, 'formation,', whereas, 'pre-incubation', with, 'anti-RARα', antibodies, prohibited, the, binding, of, 'RARα', to, 'RARE2'])].
[sujeto(['Chromatin', immunoprecipitation, showed, 'RA-dependent']), verbo([binding]), complemento([of, 'RARα', to, the, 'RARE2-containing', promoter, region, in, vivo])].
[sujeto(['Furthermore,', we]), verbo([provide]), complemento([evidence, that, 'RARE2', is, also, necessary, for, the, basal, activation, of, promoter, 'I'])].
[sujeto(['We', herein, show, that, the, combination, of, 9, -, 'cis-retinoic', acid, '(', 'RA)', and, 'IFN-α']), verbo([induces]), complemento([marked, antiproliferative, and, proapoptotic, effects, in, 'MCL', cells, through, the, modulation, of, critical, targets])].
[sujeto(['Particularly,', 'IFN-α']), verbo([enhances]), complemento(['RA-mediated', 'G(0)-G(1)', cell, accumulation, by, downregulating, cyclin, 'D1', and, increasing, 'p27(Kip1)', and, 'p21(WAF1/Cip1)', protein, levels])].
[sujeto(['Furthermore,', 'RA/IFN-α', combination, also]), verbo([induces]), complemento([apoptosis, by, triggering, both, 'caspases-8', and, -, 9, resulting, in, 'Bax', and, 'Bak', activation])].
[sujeto(['Sequestration', of, 'Mcl-1', and, 'Bfl-1', by, upregulated, 'Noxa', results, in, the, activation, of, 'Bid,', and, the, consequent, induction, of, apoptosis, is]), verbo([inhibited]), complemento([by, 'Noxa', silencing])].
[sujeto(['Noxa', upregulation, is]), verbo([associated]), complemento([with, nuclear, translocation, of, the, 'FOXO3a', transcription, factor, as, consequence, of, 'RA/IFN-α-induced', 'Akt', inhibition])].
[sujeto(['Pharmacologic', suppression, of, 'Akt,', but, not, of, 'TORC1,']), verbo([increases]), complemento(['Noxa', protein, levels, and, downregulates, 'Bfl-1', protein, supporting, the, conclusion, that, the, inhibition, of, the, 'Akt', 'pathway,', the, resulting, 'FOXO3a', activation, and, 'Noxa', upregulation, are, critical, molecular, mechanisms, underlying, 'RA/IFN-α-dependent', 'MCL', cell, apoptosis])].
[sujeto(['Using', the, 'light-induced', retinal, degeneration, '(', 'LIRD)', mouse, 'model,', which]), verbo([provides]), complemento([a, unique, platform, for, exploring, the, mechanisms, underlying, 'neuritogenesis,', we, found, that, retinoid, 'X', receptors, '(', 'RXRs)', control, neuritogenesis])].
[sujeto(['LIRD', rapidly]), verbo([triggered]), complemento([retinal, neuron, neuritogenesis, and, 'up-regulated', several, key, elements, of, retinoic, acid, '(', 'RA)', 'signaling,', including, retinoid, 'X', receptors, '(', 'RXRs)'])].
[sujeto(['We', further]), verbo([found]), complemento([that, 'LIRD', rapidly, increased, the, expression, of, glutamate, receptor, 2, and, β, 'Ca(2+)/calmodulin-dependent', protein, kinase, 'II', '(', 'βCaMKII)'])].
[sujeto(['Pulldown', assays, demonstrated, interaction, between, βCaMKII, and, 'RXRs,']), verbo([suggesting]), complemento([that, 'CaMKII', pathway, regulates, the, activities, of, 'RXRs'])].
[sujeto(['RXR', antagonists, completely]), verbo([prevented]), complemento([and, 'RXR', agonists, were, more, effective, than, 'RA', in, inducing, neuritogenesis])].
[sujeto(['Thus,', 'RXRs', are, in, the, final, common, path, and, may, be, therapeutic]), verbo([targets]), complemento([to, attenuate, retinal, remodeling, and, facilitate, global, intervention, methods, in, blinding, diseases, and, other, neurodegenerative, disorders])].
[sujeto(['The', biological, actions, of, retinoids, are]), verbo([mediated]), complemento([by, nuclear, retinoic, acid, receptors, '(', 'RARs)', and, retinoid, 'X', receptors, '(', 'RXRs)'])].
[sujeto(['We']), verbo([have]), complemento([recently, reported, that, decreased, expression, of, 'RARα', and, 'RXRα', has, an, important, role, in, high, glucose, '(', 'HG)-induced', cardiomyocyte, apoptosis])].
[sujeto(['Using', neonatal, 'cardiomyocytes,', we]), verbo([found]), complemento([that, 'ligand-induced', promoter, activity, of, 'RAR', and, 'RXR', was, significantly, suppressed, by, 'HG'])].
[sujeto(['HG']), verbo([promoted]), complemento([protein, destabilization, and, 'serine-phosphorylation', of, 'RARα', and, 'RXRα'])].
[sujeto(['In', 'contrast,', 'H(2)O(2)', stimulation]), verbo([suppressed]), complemento([the, expression, and, 'ligand-induced', promoter, activity, of, 'RARα', and, 'RXRα'])].
[sujeto(['HG']), verbo([promoted]), complemento([phosphorylation, of, 'ERK1/2,', 'JNK', and, p38, 'MAP', 'kinases,', which, was, abrogated, by, an, 'ROS', inhibitor])].
[sujeto(['Activation', of, 'JNK', by, over]), verbo([expressing]), complemento(['MKK7', and, 'MEKK1,', resulted, in, significant, downregulation, of, 'RARα', and, 'RXRα'])].
[sujeto(['Ligand-induced', promoter, activity, of, 'RARα', and, 'RXRα', was, also]), verbo([suppressed]), complemento([by, overexpression, of, 'MEKK1'])].
[sujeto(['HG-induced', cardiomyocyte, apoptosis, was, potentiated, by, activation, of, 'JNK,', and]), verbo([prevented]), complemento([by, 'all-trans', retinoic, acid, and, inhibition, of, 'JNK'])].
[sujeto(['Silencing', the, expression, of, 'RARα', and, 'RXRα']), verbo([activated]), complemento([the, 'JNK', pathway])].
[sujeto(['In', 'conclusion,', 'HG-induced', oxidative, stress, and, activation, of, the, 'JNK', pathway, negatively]), verbo([regulated]), complemento(['expression/activation', of, 'RAR', and, 'RXR'])].
[sujeto(['The', impaired, 'RAR/RXR', signaling, and, oxidative, 'stress/JNK', pathway, forms, a, vicious, 'circle,', which, significantly, contributes, to, hyperglycemia]), verbo([induced]), complemento([cardiomyocyte, apoptosis])].
[sujeto(['Increased', vitamin, 'A', '(', 'retinol)', intake]), verbo([has]), complemento([been, suggested, to, increase, bone, fragility])].
[sujeto(['All-trans-retinoic', acid, '(', 'ATRA),', 'retinol,', 'retinalaldehyde,', and, 9, -, 'cis-retinoic', acid]), verbo([stimulated]), complemento([release, of, '(', 45, ')', 'Ca', from, calvarial, bones])].
[sujeto(['The', resorptive, effect, of, 'ATRA', was, characterized, by, mRNA, expression, of, genes]), verbo([associated]), complemento([with, osteoclast, 'differentiation,', enhanced, osteoclast, 'number,', and, bone, matrix, degradation])].
[sujeto(['In', 'addition,', the, 'RANKL/OPG', ratio, was]), verbo([increased]), complemento([by, 'ATRA,', release, of, '(', 45, ')', 'Ca', stimulated, by, 'ATRA', was, blocked, by, exogenous, 'OPG,', and, mRNA, expression, of, genes, associated, with, bone, formation, was, decreased, by, 'ATRA'])].
[sujeto(['All', retinoid, acid, receptors, '(', 'RARα/β/γ)', were]), verbo([expressed]), complemento([in, calvarial, bones])].
[sujeto(['Agonists', with, affinity, to, all, receptor, subtypes, or, specifically, to, 'RARα']), verbo([enhanced]), complemento([the, release, of, '(', 45, ')', 'Ca', and, mRNA, expression, of, 'Rankl,', whereas, agonists, with, affinity, to, 'RARβ/γ', or, 'RARγ', had, no, effects])].
[sujeto(['Stimulation', of, 'Rankl', mRNA, by, 'ATRA', was, competitively]), verbo([inhibited]), complemento([by, the, 'RARα', antagonist, 'GR110'])].
[sujeto(['Exposure', of, calvarial, bones, to, 'GC']), verbo([inhibited]), complemento([the, stimulatory, effects, of, 'ATRA', on, '(', 45, ')', 'Ca', release, and, 'Rankl', mRNA, and, protein, expression])].
[sujeto(['Increased', 'Rankl', mRNA]), verbo([stimulated]), complemento([by, 'ATRA', was, also, blocked, by, 'GC', in, calvarial, bones, from, mice, with, a, 'GR', mutation, that, blocks, dimerization, '(', 'GR(dim)', 'mice)'])].
[sujeto(['The', data]), verbo([suggest]), complemento([that, 'ATRA', enhances, periosteal, bone, resorption, by, increasing, the, 'RANKL/OPG', ratio, via, 'RARα', 'receptors,', a, response, that, can, be, inhibited, by, monomeric, 'GR'])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, a, deficiency, of, 'β-arrestin-1', expression, affects, 'PPARγ-mediated', expression, of, lipid, metabolic, genes, and, inflammatory, genes])].
[sujeto(['Further', mechanistic, studies, revealed, that, 'β-arrestin-1']), verbo([interacts]), complemento([with, 'PPARγ'])].
[sujeto(['β-Arrestin-1']), verbo([suppressed]), complemento([the, formation, of, a, complex, between, 'PPARγ', and, 9, -, 'cis-retinoic', acid, 'receptor-α', through, its, direct, interaction, with, 'PPARγ'])].
[sujeto(['The', interaction, of, 'β-arrestin-1', with, 'PPARγ']), verbo([repressed]), complemento(['PPARγ/9-cis-retinoic', acid, 'receptor-α', function, but, promoted, 'PPARγ/nuclear', receptor, corepressor, function, in, 'PPARγ-mediated', adipogenesis, and, inflammatory, gene, expression])].
[sujeto(['Consistent', with, these, 'results,', a, deficiency, of, 'β-arrestin-1']), verbo([binding]), complemento([to, 'PPARγ', abolished, its, suppression, of, 'PPARγ-dependent', adipogenesis, and, inflammatory, responses])].
[sujeto(['Furthermore,', in, vivo, expression, of, 'β-arrestin-1', '(', but, not, the, 'binding-deficient', 'mutant)', significantly]), verbo([repressed]), complemento(['adipogenesis,', macrophage, 'infiltration,', and, 'diet-induced', obesity, and, improved, glucose, tolerance, and, systemic, insulin, sensitivity])].
[sujeto(['Therefore,', our, findings, not, only]), verbo([reveal]), complemento([a, molecular, mechanism, for, the, modulation, of, obesity, by, 'β-arrestin-1', but, also, suggest, a, potential, tactical, approach, against, obesity, and, its, associated, metabolic, disorders])].
[sujeto(['The', addition, of, 9, -, cis, retinoic, acid, to, the, oocyte, maturation, culture, medium]), verbo([has]), complemento([a, beneficial, effect, on, in, vitro, fertilized, embryos])].
[sujeto(['The', addition, of, 5, nM, 9, -, cis, retinoic, 'acid-stimulated', cumulus, cells, reaches, full, expansion, by]), verbo([suppressing]), complemento([their, excessive, expression, of, 'prostaglandin-endoperoxide', synthase, 2])].
[sujeto(['Alitretinoin', '(', 9, -, 'cis-retinoic', 'acid)', is, an, endogenous, derivative, of, vitamin, 'A', and, functions, as, an, agonist, of, both, families, of]), verbo([nuclear]), complemento([receptors, '(', retinoic, acid, 'receptor-α,', -, 'β,', -, 'γ;', retinoid, 'X', 'receptor-α,', -, 'β,', -, 'γ)'])].
[sujeto(['It']), verbo([has]), complemento([been, investigated, in, the, treatment, of, chronic, hand, eczema, in, many, studies, in, recent, years, and, the, results, have, been, promising])].
[sujeto(['A', complete, 'response,', with, &, 'quot;clear&quot;', hands, was, obtained, in, 7, patients, '(', 47, '%', ')', ',', 5, patients, '(', 33, '%', ')', achieved, a, partial, response, '(', almost, clear, 'hands),', 1, patient, '(', 7, '%', ')', showed, substantial, 'improvement,', 1, '(', 7, '%', ')', showed, moderate, 'improvement,', and, 1, patient, '(', 7, '%', ')', did, not]), verbo([respond]), complemento([to, treatment])].
[sujeto(['Side', 'effects,', observed, in, 50, '%', of, 'cases,', were, mild, '(', 'headache,', elevated, lipid, 'levels,', slightly, elevated, transaminase, 'levels,', and, epigastric, 'pain),', except, in, 1, 'patient,', who, had, a, substantial, reduction, in, thyroid]), verbo([stimulating]), complemento([hormone, levels])].
[sujeto(['Glucocorticoid-induced', apoptosis, of, thymocytes, is, one, of, the, first]), verbo([recognized]), complemento([forms, of, programmed, cell, death])].
[sujeto(['It', was, shown, to]), verbo([require]), complemento([gene, activation, induced, by, the, glucocorticoid, receptor, '(', 'GR)', translocated, into, the, nucleus, following, ligand, binding])].
[sujeto(['In', 'addition,', the, necessity, of, the, 'glucocorticoid-induced,', but, 'transcription-independent', phosphorylation, of, 'phosphatidylinositol-specific', phospholipase, 'C', '(', 'PI-PLC)']), verbo([has]), complemento([also, been, shown])].
[sujeto(['Here', we]), verbo([report]), complemento([that, retinoic, 'acids,', physiological, ligands, for, the, nuclear, retinoid, 'receptors,', enhance, 'glucocorticoid-induced', death, of, mouse, thymocytes, both, in, vitro, and, in, vivo])].
[sujeto(['The', effect, is]), verbo([mediated]), complemento([by, retinoic, acid, receptor, '(', 'RAR)', 'alpha/retinoid', 'X', receptor, '(', 'RXR)', 'heterodimers,', and, occurs, when, both, 'RARα', and, 'RXR', are, ligated, by, retinoic, acids])].
[sujeto(['We', show, that, the, ligated, 'RARα/RXR']), verbo([interacts]), complemento([with, the, ligated, 'GR,', resulting, in, an, enhanced, transcriptional, activity, of, the, 'GR'])].
[sujeto(['The', mechanism, through, which, this, interaction]), verbo([promotes]), complemento(['GR-mediated', transcription, does, not, require, 'DNA', binding, of, the, retinoid, receptors, and, does, not, alter, the, phosphorylation, status, of, 'Ser232,', known, to, regulate, the, transcriptional, activity, of, 'GR'])].
[sujeto(['Besides', 'thymocytes,', retinoids, also]), verbo([promoted]), complemento(['glucocorticoid-induced', apoptosis, of, various, 'T-cell', 'lines,', suggesting, that, they, could, be, used, in, the, therapy, of, 'glucocorticoid-sensitive', 'T-cell', malignancies])].
[sujeto(['The', 'long-term', survival, of, osteosarcoma, patients, hinges, on, our, ability, to]), verbo([prevent]), complemento(['and/or', treat, recurrent, and, metastatic, lesions])].
[sujeto(['Ligands', or, 'adenovirus-mediated', overexpression, of, these, receptors, were, tested, to]), verbo([inhibit]), complemento([proliferation, and, induce, apoptosis, of, osteosarcoma, cells])].
[sujeto(['Troglitazone,', 9, -, cis, retinoic, acid, '(', 'RA),', and, 'all-trans', 'RA,', as, well, as, overexpression, of, 'PPARgamma,', 'RARalpha,', and, 'RXRalpha,']), verbo([inhibit]), complemento([osteosarcoma, cell, proliferation, and, induce, apoptosis])].
[sujeto(['Overexpression', of, 'PPARgamma,', 'RARalpha,', 'RXRalpha,', or, in, combinations]), verbo([inhibits]), complemento([osteosarcoma, tumor, growth, and, cell, proliferation, in, vivo])].
[sujeto(['Retinoids', '(', and, to, a, lesser, 'extent,', 'troglitazone)', are, shown, to]), verbo([promote]), complemento([osteogenic, differentiation, of, osteosarcoma, cells, and, mesenchymal, stem, cells])].
[sujeto(['Activation', of, 'PPARgamma,', 'RARalpha,', and, 'RXRalpha', may]), verbo([act]), complemento([synergistically, on, inhibiting, osteosarcoma, cell, proliferation, and, tumor, 'growth,', which, is, at, least, partially, mediated, by, promoting, osteoblastic, differentiation, of, osteosarcoma, cells])].
[sujeto(['Mechanisms']), verbo([regulating]), complemento(['CYP4F', genes, remain, under, 'investigation,', although, characterization, of, 'CYP4F', regulatory, modalities, would, facilitate, the, discovery, of, new, drug, targets])].
[sujeto(['This', present, study, shows, that, 'all-trans-', and, 9, -, 'cis-retinoic', acids, can]), verbo([inhibit]), complemento(['CYP4F11', expression, in, human, 'keratinocyte-derived', 'HaCaT', cells])].
[sujeto(['Transrepression', of, many, genes, by, retinoic, acids, is]), verbo([mediated]), complemento([by, interactions, between, retinoid, receptors, and, the, activator, protein, 1, '(', 'AP-1)', complex])].
[sujeto(['Proinflammatory', cytokines, tumor, necrosis, factor, alpha, '(', 'TNF-alpha)', and, interleukin, 1, 'beta,', which, can]), verbo([activate]), complemento([the, 'AP-1', 'complex,', induce, 'CYP4F11', transcription, in, 'HaCaT', cells])].
[sujeto(['Furthermore,', 'TNF-alpha', failed, to]), verbo([induce]), complemento(['CYP4F11', transcription, when, 'HaCaT', cells, were, preincubated, with, retinoic, acids])].
[sujeto(['The', 'RXR', agonist, 6, -, '(', 1, '(', 3, ',', 5, ',', 5, ',', 8, ',', 8, -, 'pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)', nicotinic, acid, '(', 'LG268)', greatly]), verbo([induced]), complemento(['CYP4F11', 'transcription,', whereas, the, 'RAR', agonist, 4, -, '(', 2, -, '(', 5, ',', 6, ',', 7, ',', 8, -, 'tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic', acid, '(', 'TTNPB)', markedly, inhibited, 'CYP4F11', 'transcription,', indicating, that, 'down-regulation', of, 'CYP4F11', transcription, by, retinoic, acid, is, mediated, by, 'RARs', and, may, also, be, related, to, ligand, competition, for, 'RXRs'])].
[sujeto(['Thus,', the, 'CYP4F11', gene, is, positively]), verbo([regulated]), complemento([by, multiple, signaling, pathways, in, 'HaCaT', 'keratinocytes,', including, 'RXR', and, 'JNK', signaling, pathways])].
[sujeto(['Retinoic', acid, receptor, '(', 'RAR)', and, retinoid, 'X', receptor, are, 'ligand-induced', transcription, factors, that, belong, to, the]), verbo([nuclear]), complemento([receptor, family])].
[sujeto(['The', receptors, are]), verbo([activated]), complemento([by, small, hydrophobic, 'compounds,', such, as, 'all-trans-retinoic', acid, and, 9, -, 'cis-retinoic', 'acid,', respectively])].
[sujeto(['Interestingly,', these, receptors, are, also]), verbo([targets]), complemento([for, a, number, of, exogenous, compounds])].
[sujeto(['The', endogenous, levels, of, this, metabolite, in, 'wild-type', mice, and, rats, were]), verbo([found]), complemento([to, be, higher, than, those, of, 'all-trans-retinoic', 'acid,', especially, in, the, liver])].
[sujeto(['Using', 'cell-based', luciferase, reporter, 'systems,', we, showed, that, 'S-4o9cDH-RA']), verbo([activates]), complemento([the, transcription, of, retinoic, acid, response, 'element-containing', genes, in, several, cell, 'types,', both, from, a, simple, 2, xDR5, element, and, from, the, promoter, of, the, natural, retinoid, target, gene, 'RARbeta2'])].
[sujeto(['In', 'addition,', quantitative, 'RT-PCR', analysis, demonstrated, that, 'S-4o9cDH-RA', treatment, significantly]), verbo([increases]), complemento([the, endogenous, mRNA, levels, of, the, 'RAR', target, gene, 'RARbeta2'])].
[sujeto(['Utilizing', a, limited, proteolytic, digestion, 'assay,', we, showed, that, 'S-4o9cDH-RA']), verbo([induces]), complemento([conformational, changes, to, both, 'RARalpha', and, 'RARbeta', in, the, same, manner, as, does, 'all-trans-retinoic', 'acid,', suggesting, that, 'S-4o9cDH-RA', is, indeed, an, endogenous, ligand, for, these, receptors])].
[sujeto(['These', in, vitro, results, were, corroborated, in, an, in, vivo, 'system,', where, 'S-4o9cDH-RA']), verbo([induced]), complemento([morphological, changes, similar, to, those, of, 'all-trans-retinoic', acid, in, the, developing, chicken, wing, bud])].
[sujeto(['When', locally, applied, to, the, wing, 'bud,', 'S-4o9cDH-RA']), verbo([induced]), complemento([digit, pattern, duplications, in, a, 'dose-dependent', fashion])].
[sujeto(['Finally,', using, quantitative, 'RT-PCR', 'analysis,', we, showed, that, 'S-4o9cDH-RA']), verbo([induces]), complemento([the, transcription, of, several, retinoic, 'acid-regulated', genes, in, chick, wing, 'buds,', including, 'Hoxb8,', 'RARbeta2,', 'shh,', 'Cyp26', and, bmp2])].
[sujeto(['Although', 'S-4o9cDH-RA', was, less, potent, when, compared, with, 'all-trans-retinoic', 'acid,', the, findings, clearly, demonstrate, that, 'S-4o9cDH-RA']), verbo([has]), complemento([the, capacity, to, bind, and, activate, nuclear, retinoid, receptors, and, regulate, gene, transcription, both, in, vitro, and, in, vivo])].
[sujeto(['We']), verbo([have]), complemento([recently, demonstrated, that, 'all-trans-retinoic', acid, '(', 'ATRA)', and, 9, -, 'cis-retinoic', acid, '(', 9, -, cis, 'RA)', promote, 'IL-4,', 'IL-5', and, 'IL-13', 'synthesis,', while, decreasing, 'IFN-gamma', and, 'TNF-alpha', expression, by, activated, human, 'T', cells, and, reduces, the, synthesis, of, 'IL-12p70', from, accessory, cells])].
[sujeto(['Here,', we]), verbo([have]), complemento([demonstrated, that, the, observed, effects, using, 'ATRA', and, 9, -, cis, 'RA', are, shared, with, the, clinically, useful, 'RAR', 'ligand,', 13, -, cis, retinoic, acid, '(', 13, -, cis, 'RA),', and, the, retinoic, acid, 'receptor-alpha', '(', 'RAR-alpha)-selective', 'agonist,', 'AM580', but, not, with, the, 'RAR-beta/gamma', 'ligand,', 4, -, hydroxyphenylretinamide, '(', 4, -, 'HPR)'])].
[sujeto(['The']), verbo([increase]), complemento([in, type, 2, cytokine, production, by, these, retinoids, correlated, with, the, expression, of, the, 'T', cell, activation, 'markers,', 'CD69', and, 'CD38'])].
[sujeto(['The', 'RAR-alpha-selective', 'agonist,', 'AM580', recapitulated, all, of, the, 'T', cell, activation, and, type, 2, 'cytokine-inducing', effects, of, 'ATRA', and, 9, -, 'cis-RA,', while, the, 'RAR-alpha-selective', 'antagonist,', 'RO', 41, -, 5253, ',']), verbo([inhibited]), complemento([these, effects])].
[sujeto(['These', results, strongly, support, a, role, for, 'RAR-alpha', engagement, in, the, regulation, of, genes, and, proteins]), verbo([involved]), complemento([with, human, 'T', cell, activation, and, type, 2, cytokine, production])].
[sujeto(['The', biological, functions, of, vitamin, 'A', are]), verbo([mediated]), complemento([through, the, retinoid, acid, receptors, '(', 'RARs)', and, retinoid, 'X', receptors, '(', 'RXRs)'])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([investigated, the, molecular, interactions, between, vitamin, 'A', and, 'AhR', signalling, pathways, using, juvenile, 'Atlantic', salmon, and, agonists, for, both, receptor, pathways])].
[sujeto(['Our', data, showed, that, exposure, to, 'RA', alone, did, not, produce, a, significant]), verbo([increase]), complemento([of, 'RARalpha', mRNA, 'levels,', and, the, presence, of, 'PCB-77', attenuated, the, expression, of, 'RARalpha', in, 'RA', 'dose-', and, 'time-specific', manner])].
[sujeto(['In', 'addition,', 'RA', produced, a, 'dose-dependent']), verbo([increase]), complemento([of, 'CYP1A1', mRNA, and, activity, '(', 'EROD)', levels, without, concomitant, increase, in, 'AhR2', isoforms])].
[sujeto(['When', administered, 'alone,', 'PCB-77', produced]), verbo([increased]), complemento(['CYP1A1,', 'UGT1', and, 'GSTpi', mRNA, and, enzyme, levels])].
[sujeto(['The', 'PCB-77-induced', 'CYP1A1,', 'UGT1', and, 'GSTpi', '(', mRNA, and, 'activity)', levels, were]), verbo([modulated]), complemento([by, 'RA,', in, a, parameter, and, 'dose-specific', manner])].
[sujeto(['The', regulation, of, cell, growth, and, differentiation, and, also, expression, of, a, number, of, genes, by, retinoids, are]), verbo([mediated]), complemento([by, nuclear, retinoid, receptors, '(', 'RARs', 'and/or', 'RXRs)'])].
[sujeto(['We']), verbo([have]), complemento([shown, that, 'RXRbeta', expression, was, decreased, significantly, '(', 'p=0'])].
[sujeto(['Distribution', of, retinoic, acid, receptor, subtype, expression, in, 'PBMCs', was]), verbo([found]), complemento([in, the, 'order:', 'RXRbeta&gt;RARgamma&gt;RXRalpha&gt;RARalpha'])].
[sujeto(['The', tTG, activity, in, 'PBMCs', reflected, a, trend, to, be]), verbo([enhanced]), complemento([after, 13, -, cis, retinoic, acid, supplementation])].
[sujeto(['In', 'conclusion,', we, demonstrate, a, significant]), verbo([decrease]), complemento([in, the, expression, of, 'RXRbeta', subtype, of, rexinoid, receptors, in, 'PBMCs', of, healthy, elderly, men])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, in, healthy, elderly, men, reduction, of, 'RXRbeta', expression, in, 'PBMCs', might, be, a, common, feature, of, physiological, senescence])].
[sujeto(['Mutation', of, this, motif]), verbo([led]), complemento([to, full, restoration, of, promoter, activity, in, 'TE671', medulloblastoma, and, 'JEG-3', placenta, choriocarcinoma, cells])].
[sujeto(['Supershift', and, chromatin, immunoprecipitation, assays, showed, in, vitro, and, in, vivo]), verbo([binding]), complemento([of, 'NF-kappaB', subunit, p65, and, the, retinoic, acid, 'receptors,', 'RARalpha', and, 'RXRalpha,', to, the, promoter, sequences])].
[sujeto(['Over-expression', of, these, protein, factors, indicated, that, p65, is, a, potent, 'repressor,', and, the, 'RARalpha/RXRalpha', heterodimer, is]), verbo([involved]), complemento([in, the, differential, regulation, of, the, 'GnRH', 'II', gene, in, neuronal, and, placental, cells])].
[sujeto(['Treatment', of, cells, with, the, 'RARalpha/RXRalpha', 'ligands,', 'all-trans', retinoic, acid, and, 9, -, 'cis-retinoic', 'acid,', reduced, and]), verbo([increased]), complemento(['GnRH', 'II', gene, expression, in, 'TE671', and, 'JEG-3', 'cells,', respectively])].
[sujeto(['Taken', 'together,', these, data, demonstrate, the, differential, roles, of, 'NF-kappaB', p65, and, 'RARalpha/RXRalpha,']), verbo([interacting]), complemento([with, the, same, sequence, in, the, promoter, of, the, human, 'GnRH', 'II', gene, to, influence, gene, expression, in, a, 'cell-specific', manner])].
[sujeto(['Continuous', treatment, with, 'all-trans-RA']), verbo([inhibited]), complemento([the, mineralization, in, a, 'dose-dependent', 'manner,', with, complete, inhibition, over, 1, microm, 'RA'])].
[sujeto(['Furthermore,', addition, of, 'RA', for, just, the, first, 4, days, completely]), verbo([inhibited]), complemento([the, 'mineralization;', 'however,', as, 'RA', was, added, at, later, stages, of, 'culture,', the, inhibitory, effect, was, 'diminished,', suggesting, that, 'RA', had, a, 'phase-dependent', inhibition, of, mineralization])].
[sujeto(['RA', receptor, '(', 'RAR)-alpha', agonist, '(', 'AM-580),', but, not, retinoid, 'X', receptor, agonist, '(', methoprene, 'acid),']), verbo([inhibited]), complemento([the, 'mineralization,', and, reverse, 'transcription-polymerase', chain, reaction, analysis, revealed, that, 'RAR-alpha', was, expressed, on, the, 'cells,', suggesting, that, 'RAR-alpha', was, involved, in, the, inhibitory, mechanism])].
[sujeto(['This', inhibition, was, accompanied, by, inhibition, of, alkaline, phosphatase, 'activity;', 'however,', neither, expression, of, 'platelet-derived', growth, factor, '(', 'PDGF)', 'receptor-alpha,', 'PDGF', 'receptor-beta,', or, epidermal, growth, factor, '(', 'EGF)', 'receptor,', nor, phosphorylation, of, extracellular, 'signal-regulated', kinases]), verbo([triggered]), complemento([by, 'PDGF-ascorbic', acid, or, 'PDGF-BB', was, 'changed,', as, assessed, by, flow, cytometry, or, western, blot, analyses])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'RA', is, a, potential, negative, regulator, for, differentiation, of, human, periodontal, ligament, cells])].
[sujeto(['All-trans', retinoic, acid, and, 9, -, 'cis-retinoic', acid]), verbo([stimulate]), complemento([the, activity, of, steroid, sulfatase, in, 'HL60', acute, myeloid, leukemia, cells, in, a, 'concentration-', and, 'time-dependent', manner])].
[sujeto(['Neither', of, these, '\'', natural, 'retinoids\'', augmented, steroid, sulfatase, activity, in, a, 'HL60', 'sub-line', that]), verbo([expresses]), complemento([a, 'dominant-negative', retinoic, acid, receptor, alpha, '(', 'RARalpha)'])].
[sujeto(['Experiments', with, synthetic, 'RAR', and, 'RXR', agonists, and, antagonists]), verbo([suggest]), complemento([that, 'RARalpha/RXR', heterodimers, play, a, role, in, the, 'retinoid-stimulated', increase, in, steroid, sulfatase, activity])].
[sujeto(['The', 'retinoid-driven']), verbo([increase]), complemento([in, steroid, sulfatase, activity, was, attenuated, by, inhibition, of, phospholipase, 'D', '(', 'PLD),', but, not, by, inhibitors, of, phospholipase, 'C'])].
[sujeto(['Experiments', with, inhibitors, of, protein, kinase, 'C', '(', 'PKC)', show, that, 'PKCalpha', and, 'PKCdelta', play, an, important, role, in]), verbo([modulating]), complemento([the, 'retinoid-stimulation', of, steroid, sulfatase, activity, in, 'HL60', cells])].
[sujeto(['Furthermore,', we, show, that, pharmacological, inhibition, of, the, 'RAF-1', and, 'ERK', 'MAP', kinases, blocked, the, 'retinoid-stimulated']), verbo([increase]), complemento([in, steroid, sulfatase, activity, in, 'HL60', cells, 'and,', by, 'contrast,', inhibition, of, the, 'p38-MAP', kinase, or, 'JNK-MAP', kinase, had, no, effect])].
[sujeto(['Pharmacological', inhibitors, of, the, phosphatidylinositol, 3, -, 'kinase,', 'Akt,', and, 'PDK-1', also, abrogated, the, 'retinoid-stimulated']), verbo([increase]), complemento([in, steroid, sulfatase, activity, in, 'HL60', cells])].
[sujeto(['These', results, show, that, crosstalk, between, the, 'retinoid-stimulated', genomic, and, 'non-genomic', pathways, is, necessary, to]), verbo([increase]), complemento([steroid, sulfatase, activity, in, 'HL60', cells])].
[sujeto(['Tigecycline', resistance, among, 'Klebsiella', pneumoniae, isolates]), verbo([has]), complemento([been, increasingly, reported])].
[sujeto([pneumoniae, isolates, were]), verbo([associated]), complemento([with, upregulation, of, 'RamA', 'and/or', 'RarA', and, the, corresponding, 'AcrAB', 'and/or', 'OqxAB', efflux, 'pump(s),', respectively])].
[sujeto([pneumoniae, strains, belonging, to, capsular, types, 'K1', and, 'K20']), verbo([retained]), complemento([their, high, virulence])].
[sujeto(['Cluster', 1, ',', &, 'quot;Severe', peanut, allergy, with, little, allergic, 'multimorbidity&quot;', '(', 123, 'subjects),', had, the, highest, proportion, of, patients, with, positive, 'OFC', '(', 92, '%', ')', ',', a, medium, level, of, peanut, protein]), verbo([inducing]), complemento([a, positive, 'OFC', '(', 235, 'mg),', lower, percentage, of, allergic, multimorbidity, '(', 2, '%', asthma, plus, atopic, dermatitis, '(', 'A+AD),', no, cases, of, 'A+AD', +, multiple, food, allergies, '(', 'MFA))'])].
[sujeto(['Cluster', 2, ',', &, 'quot;Severe', peanut, allergy, with, frequent, allergic, 'multimorbidity&quot;', '(', 62, 'subjects),', had, a, high, proportion, of, patients, with, positive, 'OFC', '(', 85, '%', ')', with, the, lowest, level, of, peanut, protein]), verbo([inducing]), complemento([a, positive, 'OFC', '(', 112, 'mg),', 89, '%', allergic, 'subjects,', 100, '%', with, allergic, multimorbidity, '(', 'A+AD)', and, 84, '%', with, 'A+AD+MFA'])].
[sujeto(['Cluster', 3, ',', &, 'quot;Mild', peanut, 'allergic/sensitized', 'phenotype&quot;', '(', 62, 'subjects),', had, the, lowest, mean, 'age,', the, lowest, proportion, of, patients, with, positive, 'OFC', '(', 53, '%', ')', with, a, high, level, of, peanut, protein]), verbo([inducing]), complemento([a, positive, 'OFC', '(', 770, 'mg),', a, low, percentage, of, allergic, multimorbidity, '(', 48, '%', 'A+AD+MFA)'])].
[sujeto(['The', same, clusters, were]), verbo([found]), complemento([in, the, subgroup, of, patients, without, 'OFC'])].
[sujeto(['Besides', the, classic, markers]), verbo([associated]), complemento([with, lower, threshold, doses, of, 'OFC', '(', such, as, 'SPT', and, rAra, 'h2),', allergic, multimorbidity, and, female, gender, should, also, be, taken, into, account, to, better, adapt, the, progressive, dosage, of, provocation, tests])].
[sujeto(['Gain', of, chromosome, 8, is, the, most, common, chromosomal]), verbo([gain]), complemento([in, human, acute, myeloid, 'leukaemia,', including, acute, promyelocytic, leukaemia])].
[sujeto(['We', previously, demonstrated, that]), verbo([gain]), complemento([of, chromosome, 8, -, containing, 'MYC', is, of, central, importance, in, trisomy, 8, ',', but, the, role, of, the, nearby, 'TRIB1', gene, has, not, been, experimentally, addressed, in, this, context])].
[sujeto(['We']), verbo([have]), complemento([now, tested, the, hypothesis, that, both, 'MYC', and, 'TRIB1', have, functional, roles, underlying, leukaemogenesis, of, trisomy, 8, by, using, retroviral, vectors, to, express, 'MYC', and, 'TRIB1', in, 'wild-type', bone, marrow, and, in, marrow, that, expressed, a, 'PML/RARA', transgene])].
[sujeto(['Interestingly,', although, 'MYC', and, 'TRIB1', readily, cooperated, in, leukaemogenesis, for, 'wild-type', bone, 'marrow,', 'TRIB1']), verbo([provided]), complemento([no, selective, advantage, to, cells, expressing, 'PML/RARA'])].
[sujeto(['We', hypothesized, that, this, lack, of, cooperation, between, 'PML/RARA', and, 'TRIB1', reflected, a, common, pathway, for, their, 'effect:', both, proteins]), verbo([targeting]), complemento([the, myeloid, transcription, factor, 'C/EBPα'])].
[sujeto(['Our', data, delineate, the, common, and, redundant, inhibitory, effects, of, 'TRIB1', and, 'PML/RARA', on, 'C/EBPα']), verbo([providing]), complemento([a, potential, explanation, for, the, lack, of, selection, of, 'TRIB1', in, human, acute, promyelocytic, 'leukaemia,', and, highlighting, the, key, role, of, 'C/EBPs', in, acute, promyelocytic, leukaemia, pathogenesis, and, therapeutic, response])].
[sujeto(['In', 'addition,', the, cooperativity, we, observed, between, 'MYC', and, 'TRIB1', in, the, absence, of, 'PML/RARA', show, 'that,', outside, of, acute, promyelocytic, 'leukaemia,']), verbo([gain]), complemento([of, both, genes, may, drive, selection, for, trisomy, 8])].
[sujeto(['Thirty', patients, '(', 79, '%', ')']), verbo([required]), complemento([ventilation, from, the, neonatal, period, 'onwards,', and, 8, '(', 21, '%', ')', later, on, in, life, '(', late, 'onset/presentation)'])].
[sujeto(['Five', of, them, were, infants, with, neonatal, 'onset,', two, of, 'them,', both, having, a, severe, 'mutation,', were, switched, to, tracheostomy, after, cardiorespiratory]), verbo([arrest]), complemento([at, home])].
[sujeto(['Educational', reinforcement, was]), verbo([required]), complemento([in, 29.4, '%', of, children, attending, school])].
[sujeto(['The', implementation, of, the, 'EuCHS', 'Registry', in, 'Spain']), verbo([has]), complemento([identified, some, relevant, issues, for, optimising, 'healthcare,', such, as, the, importance, of, genetic, study, for, diagnosis, and, assessment, of, 'severity,', the, high, frequency, of, eye, disease, and, educational, 'reinforcement,', as, well, as, some, limitations, in, ventilatory, techniques])].
[sujeto(['Vitamin', 'A']), verbo([has]), complemento([been, linked, to, the, development, of, allergic, diseases, although, its, role, is, not, fully, 'understood,', 'Retinoic', acid, '(', 'RA),', a, metabolite, of, 'Vitamin', 'A,', has, been, previously, associated, with, the, prostaglandin, 'pathway,', and, 'PTGDR,', a, receptor, of, 'PGD2,', has, been, proposed, as, a, candidate, gene, in, allergy, and, asthma])].
[sujeto(['A549', lung, epithelial, cells, were, transfected, with, 4, combinations, of, genetic, variants, of, the, 'PTGDR', promoter, and]), verbo([stimulated]), complemento([with, 'all-trans', 'RA', '(', 'ATRA);', luciferase, assays, were, performed, using, the, 'Dual', 'Luciferase', 'Reporter', 'System,', and, 'real-time', quantitative, polymerase, chain, reaction, was, used, to, measure, the, expression, of, 'PTGDR,', 'CYP26A1,', 'RARA,', 'RARB,', 'RARG,', and, 'RXRA', in, basal, 'A549', cell, cultures, and, after, 'ATRA', treatment])].
[sujeto(['After', 'ATRA', treatment]), verbo([increased]), complemento([expression, of, 'CYP26A1', '(', 12, -, 'fold)', and, 'RARB', '(', 4, -, 'fold)', was, detected])].
[sujeto(['ATRA']), verbo([activated]), complemento(['PTGDR', promoter, activity, in, transfected, cells, '(', 'P&lt;'])].
[sujeto(['RA']), verbo([modulated]), complemento(['PTGDR', promoter, activity])].
[sujeto(['Transformation', of, 'JAK2', positive, 'MPNs', to, acute, leukemia]), verbo([has]), complemento([been, reported])].
[sujeto(['We', here]), verbo([report]), complemento([a, case, of, acute, promyelocytic, leukemia, which, was, later, confirmed, to, have, a, 'co-existing', 'JAK2', 'V617F', positive, 'MPN'])].
[sujeto(['In', 'addition,', the, patient, was]), verbo([found]), complemento([to, have, 'FLT3-TKD', 'mutation,', 'which,', together, with, 'PML/RARa,', could, play, a, role, in, the, 'MPN', transformation, to, 'APL'])].
[sujeto(['Among', 20, cases, of, 'non-M3,', 12, cases, achieved, 'CR1', '(', 60, '%', ')', ',', 4, cases, achieved, partial, response, '(', 'PR)', '(', 20, '%', ')', ',', 4, cases, did, not]), verbo([respond]), complemento(['(', 'NR);', 5, cases, relapsed, in, 'follow-up', for, 3, years, after, 'CR1', '(', 41.7, '%', ')', ',', 3, cases, achieved, 'CR2', after, 're-induction', 'chemotherapy,', and, 2, cases, remained, 'NR'])].
[sujeto(['M3', with, trisomy, 8, and, 'RARA', gene]), verbo([has]), complemento([a, very, good, prognosis])].
[sujeto(['Trisomy', 8, may]), verbo([increase]), complemento([the, risk, of, primary, 'AML', except, for, 'M3,', so, 'allo-HSCT', with, 'HLA-matched', sibling, donor, should, be, carried, out, as, much, as, possible, after, 'CR1'])].
[sujeto(['Shortage', of, vitamin, 'B12,', 'iron,', calcium, and, also, cholelithiasis, are]), verbo([caused]), complemento([at, least, partially, by, excluding, the, duodenum, and, proximal, jejunum, from, food, transit])].
[sujeto(['We', designed, a, new, 'procedure,', with, the, maintenance, of, the, duodenum, and, proximal, jejunum, in, the, gastrointestinal, transit, through, interposition, of, jejunal, 'loop,', as, a, primary, operation, to]), verbo([prevent]), complemento([such, deficiencies, or, as, corrective, surgery, for, severe, malnutrition, after, 'RYGB', with, failure, in, responding, to, conservative, treatment])].
[sujeto(['However,', tigecycline, nonsusceptible, 'Enterobacteriaceae']), verbo([has]), complemento([emerged, recently, in, 'China'])].
[sujeto(['Moreover,', mutations, in, the, ramR, gene]), verbo([led]), complemento([to, the, overexpression, of, 'RamA'])].
[sujeto(['These', results, indicated, that, the, mutation, of, the, ramR, gene, through, the, upregulated, expression, of, 'RamA', contributed, to, tigecycline, resistance, and, that, several, of, the, newly, identified, types, of, mutations, in, ramR, and, acrR, were, not, previously]), verbo([reported]), complemento([in, 'K'])].
[sujeto(['This', is, the, second]), verbo([report]), complemento([of, 'IRF2BP2', involvement, in, 'APL,', and, we, describe, various, breakpoints, for, the, 'IRF2BP2-RARA', fusion, gene])].
[sujeto(['Mutations', in, the, ribosomal, 16, 'S', rRNA, operon, 'rrnBC,', also, yielded, resistance, to, tigecycline, through]), verbo([target]), complemento([site, modifications])].
[sujeto(['The', 'mcr-1', gene]), verbo([conferring]), complemento([resistance, to, colistin, was, identified, via, 'WGS,', 'trans-complementation', and, a, murine, thigh, infection, model, studies])].
[sujeto(['The', minor, allele, 'T,', at, 'rs10851685,', was, potentially]), verbo([associated]), complemento([with, an, increased, risk, of, 'T2DM', in, the, dominant, 'model,', displaying, 'OR', of, 1.38, '(', 95, '%', 'CI:', 1.04, -, 1.82, ',', p, =, 0.025, ')', in, subjects, with, genotypes, 'TA+TT', vs])].
[sujeto(['In', haplotype, 'analysis,', we, observed, that, haplotypes, 'GGTGTAACT,', 'GGTGTAACC,', and, 'GATATAACT', were, significantly]), verbo([associated]), complemento([with, increased, risk, of, 'T2DM,', while, haplotypes, 'GATGAAGTT,', 'AGTGAAGTT,', and, 'AATGAAATT', were, protective, against, 'T2DM'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, the, genetic, variation, in, 'RORA', might, determine, a, 'Chinese', 'Han', 'individual\'s', susceptibility, to, 'T2DM'])].
[sujeto(['Focusing', on, therapeutic, protocols, in]), verbo([targeting]), complemento([subventricular, zone, '(', 'SVZ)', neurogenesis, has, been, investigated, recently])].
[sujeto(['Male', 'Wistar', rats, were, used, to]), verbo([induce]), complemento([focal, cerebral, ischemia, by, middle, cerebral, artery, occlusion, '(', 'MCAO)'])].
[sujeto(['Mumps', virus, '(', 'MuV)', infection, may]), verbo([lead]), complemento([to, oophoritis, and, perturb, ovarian, function])].
[sujeto(['However,', the, mechanisms, underlying, the, activation, of, innate, immune, responses, to, 'MuV', infection, in, the, ovary]), verbo([have]), complemento([not, been, investigated])].
[sujeto(['Knockdown', of, 'RIG-I', significantly]), verbo([decreased]), complemento(['MuV-induced', cytokine, expression])].
[sujeto(['Intraperitoneal', injection, of, 'MuV']), verbo([induced]), complemento([the, ovarian, innate, immune, responses, 'in&nbsp;vivo,', which, suppressed, estradiol, synthesis, and, induced, granulosa, cell, apoptosis])].
[sujeto(['The', results]), verbo([provide]), complemento([novel, insights, into, the, mechanisms, underlying, 'MuV-induced', innate, immune, responses, in, the, mouse, ovary])].
[sujeto(['Here,', we]), verbo([have]), complemento([investigated, the, effects, of, receptor, selective, agonists, and, antagonists, on, the, primitive, human, hematopoietic, cell, lines, 'KG1', and, 'NB-4', and, purified, normal, human, hematopoietic, stem, cells, '(', 'HSCs)'])].
[sujeto(['Treatment', of, cultures, of, human, 'HSCs', '(', supplemented, with, stem, cell, 'factor&nbsp;±&nbsp;interleukin', 3, ')', with, an, antagonist, of, all, 'RARs', '(', 'AGN194310)', or, of, 'RARα', '(', 'AGN196996)', prolonged, the, lifespan, of, 'cultures,', up, to, 55, &, 'nbsp;days,', and]), verbo([increased]), complemento([the, production, of, neutrophils, and, monocytes])].
[sujeto(['Studies', of, 'CV-1', and, 'LNCaP', cells, transfected, with, 'RAR', expression, vectors, and, a, reporter, vector, revealed, that, 'RARγ', and, 'RARβ', are]), verbo([activated]), complemento([by, 'sub-nM', 'all-trans', retinoic, acid, '(', 'EC50-0'])].
[sujeto([3, &, 'nbsp;nM):&nbsp;~50-fold', more, is]), verbo([required]), complemento([for, activation, of, 'RARα', '(', 'EC50-16&nbsp;nM)'])].
[sujeto(['Due', to, these, 'properties,', 'RA']), verbo([has]), complemento([proven, 'anti-cancer', capacity])].
[sujeto(['Several', breast, cancer, cells]), verbo([respond]), complemento([to, the, antiproliferative, effects, of, 'RA,', while, others, are, 'RA-resistant'])].
[sujeto(['However,', the, overall, signaling, and, transcriptional, pathways, that, are, altered, in, such, cells]), verbo([have]), complemento([not, been, elucidated])].
[sujeto(['Using', 'high-resolution', 'nano-LC-LTQ-Orbitrap', mass, spectrometry]), verbo([associated]), complemento([to, phosphopeptide, 'enrichment,', we, found, that, several, proteins, involved, in, signaling, and, in, 'transcription,', are, differentially, phosphorylated, before, and, after, 'RA', addition])].
[sujeto(['The', paradigm, of, these, proteins, is, the, 'RA', receptor, α, '(', 'RARα),', which, was]), verbo([phosphorylated]), complemento([in, 'MCF7', cells, but, not, in, 'BT474', cells, after, 'RA', addition])].
[sujeto(['Accumulating', lines, of, evidence]), verbo([suggest]), complemento([that, retinoic, acid, receptor, agonists, such, as, 'Am80', exerts, 'anti-inflammatory', actions, in, the, central, nervous, 'system,', although, detailed, mechanisms, of, the, action, remain, largely, unknown])].
[sujeto(['Our', previous, findings]), verbo([suggest]), complemento([that, 'Am80', provides, therapeutic, effect, on, intracerebral, hemorrhage, in, mice, via, suppression, of, expression, of, chemokine, '(', 'C-X-C', 'motif)', ligand, 2, '(', 'CXCL2)'])].
[sujeto(['Pretreatment', with, 'Am80', markedly]), verbo([suppressed]), complemento([lipopolysaccharide, '(', 'LPS)-induced', expression, of, 'CXCL2', mRNA, and, release, of, 'CXCL2', protein])].
[sujeto(['On', the, other, 'hand,', 'Am80']), verbo([prevented]), complemento(['LPS-induced', nuclear, translocation, of, p65, subunit, of, 'NF-κB', complex])].
[sujeto(['We', additionally]), verbo([found]), complemento([that, 'Am80', attenuated, 'LPS-induced', 'up-regulation', of, 'CD14,', a, 'co-receptor', for, 'Toll-like', receptor, 4, '(', 'TLR4)'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, inhibitory, effect, on, 'TLR4', signaling, mediated, by, 'NF-κB', pathway, underlies, the, 'anti-inflammatory', action, of, retinoic, acid, receptor, agonists, in, microglia])].
[sujeto(['Current', diagnostic, methods, of, acute, promyelocytic, leukemia, '(', 'APL)']), verbo([have]), complemento([some, inevitable, 'shortcomings;', 'therefore,', further, studies, are, needed, to, develop, more, effective, diagnostic, methods])].
[sujeto(['Using', the, 'probe,', only, cells, which, contain, 'L', type, 'PML/RARα', fusion, gene, will]), verbo([have]), complemento([fluorescent, signals, compared, to, no, signals, '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['The', 'GO', detection, method, was, accurate, and]), verbo([has]), complemento([clinical, diagnostic, values, '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['The', 'GO', detection, method]), verbo([has]), complemento([the, advantages, of, 'accurate,', 'time-saving,', 'energy-saving', simple, 'operation,', and, no, pollution])].
[sujeto(['Since', the, isolation, and, identification, of, the, retinoid, 'X', receptor, '(', 'RXR)', as, a, member, of, the]), verbo([nuclear]), complemento([receptor, '(', 'NR)', superfamily, in, 1990, ',', its, analysis, has, ushered, in, a, new, understanding, of, physiological, regulation, by, nuclear, 'receptors,', and, novel, methods, to, identify, other, unknown, and, orphan, receptors])].
[sujeto(['Expression', of, one, or, more, of, the, three, isoforms, of, 'RXR-α,', 'β,', and, 'ϒ-', can, be]), verbo([found]), complemento([in, every, human, cell, type])].
[sujeto(['Biologically,', 'RXR', plays, a, critical, role, through, its, ability, to, partner, with, other]), verbo([nuclear]), complemento([receptors])].
[sujeto(['RXR', is, able, to]), verbo([regulate]), complemento([nutrient, metabolism, by, forming, &, 'quot;permissive&quot;', heterodimers, with, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR),', 'liver-X-receptor', '(', 'LXR),', farnesoid, 'X', receptor, '(', 'FXR),', pregnane, 'X', receptor, '(', 'PXR)', and, constitutive, androstane, receptor, '(', 'CAR),', which, function, when, ligands, are, bound, to, one, or, both, of, the, heterodimer, partners])].
[sujeto(['Furthermore,', 'RXR', can, form, homodimers, in, the, presence, of, a, selective, 'agonist,', 'rexinoid,', to]), verbo([regulate]), complemento([gene, expression, and, to, either, inhibit, proliferation, or, induce, apoptosis, in, human, cancers])].
[sujeto(['Thus,', over, the, last, 25, years, there]), verbo([have]), complemento([been, several, reports, on, the, design, and, synthesis, of, small, molecule, 'RXR', selective, 'agonists,', rexinoids])].
[sujeto(['But', few, efficient, therapeutic, methods]), verbo([have]), complemento([been, reported])].
[sujeto(['Results', showed, that, in, retinas, of, 'STZ-induced', diabetic, 'mice,', 9, -, 'cis-RA', significantly]), verbo([inhibited]), complemento([expression, of, 'SHP-1', '(', 'P', &, 'lt;', 0.01, ')', ',', thus, promoting, 'p-AKT', and, 'p-ERK1/2,', which, reflected, the, improved, sensitivity, to, 'PDGF-BB'])].
[sujeto(['In', 'BRPC,', 9, -, 'cis-RA', also, improved, sensitivity, to, 'PDGF-BB', and]), verbo([suppressed]), complemento([cell, apoptosis, '(', 'P', &, 'lt;', 0.01, ')', via, 'down-regulating', 'SHP-1'])].
[sujeto(['Further', mechanism, analyses, showed, that, the, efficient, functioning, of, 9, -, 'cis-RA', relied, on, the, existence, of, its, 'receptor,', retinoic, 'X', receptor, α, '(', 'RXRα),', independent, of, the, previous]), verbo([reported]), complemento([protein, kinase, 'C', delta, '(', 'PKCδ)/SHP-1', axis])].
[sujeto(['Because', 9, -, 'cis-RA', could, not]), verbo([inhibit]), complemento(['SHP-1', or, improve, sensitivity, to, 'PDGF-BB', when, 'RXRα', was, knocked, 'down,', while, it, still, suppressed, 'SHP-1', after, overexpression, of, 'PKCδ'])].
[sujeto(['Taken', 'together,', these, results, indicated, the, vital, roles, of, 9, -, 'cis-RA', in, improving, sensitivity, to, 'PDGF-BB', of, retinal, pericytes, in, 'DR,', and]), verbo([provided]), complemento([basic, evidences, of, new, therapeutic, targets, like, 'RXRα', for, further, 'DR', treatment])].
[sujeto(['It']), verbo([has]), complemento([been, suggested, that, retinoic, acid, '(', 'RA)', has, a, potential, role, in, the, prevention, of, atherosclerotic, 'CVD'])].
[sujeto([1, macrophages, with, 9, -, 'cis-RA', '(', 0, '·1,', 1, and, 10, 'μmol/l)']), verbo([induced]), complemento([cholesterol, efflux, in, a, 'dose-dependent', manner])].
[sujeto(['Moreover,', treatment, with, 9, -, 'cis-RA', significantly]), verbo([increased]), complemento([the, protein, expression, levels, of, 'ABCA1', and, 'ABCG1', in, 'J774A'])].
[sujeto(['Furthermore,', 9, -, 'cis-RA', 'dose-dependently']), verbo([enhanced]), complemento([the, protein, expression, level, of, liver, 'X', 'receptor-α', '(', 'LXRα),', the, upstream, regulator, of, 'ABCA1', and, 'ABCG1'])].
[sujeto(['Taken', 'together,', the, present, results, show, that, 9, -, 'cis-RA']), verbo([suppresses]), complemento([foam, cell, formation, and, prevents, 'HFD-induced', atherogenesis, via, the, 'LXRα-dependent', 'up-regulation', of, 'ABCA1', and, 'ABCG1'])].
[sujeto(['Retinoid', 'X', receptor, α, '(', 'RXRα)', and, its, 'N-terminally', truncated, version, tRXRα, play, important, roles, in, 'tumorigenesis,', while, some, 'RXRα', ligands, possess, potent, 'anti-cancer', activities, by]), verbo([targeting]), complemento([and, modulating, the, tumorigenic, effects, of, 'RXRα', and, tRXRα])].
[sujeto(['Here', we, describe, 'NSC-640358', '(', 'N-6),', a, 'thiazolyl-pyrazole', derived, 'compound,']), verbo([acts]), complemento([as, a, selective, 'RXRα', ligand, to, promote, 'TNFα-mediated', apoptosis, of, cancer, cell])].
[sujeto(['N-6']), verbo([binds]), complemento([to, 'RXRα', and, inhibits, the, transactivation, of, 'RXRα', homodimer, and, 'RXRα/TR3', heterodimer])].
[sujeto(['Using', mutational, analysis, and, computational, 'study,', we, determine, that, 'Arg316', in, 'RXRα,', essential, for, 9, -, 'cis-retinoic', acid]), verbo([binding]), complemento([and, activating, 'RXRα', 'transactivation,', is, not, required, for, antagonist, effects, of, 'N-6,', whereas, 'Trp305', and, 'Phe313', are, crucial, for, 'N-6', binding, to, 'RXRα', by, forming, extra, 'π-π', stacking, interactions, with, 'N-6,', indicating, a, distinct, 'RXRα', binding, mode, of, 'N-6'])].
[sujeto(['N-6']), verbo([inhibits]), complemento(['TR3-stimulated', transactivation, of, 'Gal4-DBD-RXRα-LBD', by, binding, to, the, ligand, binding, pocket, of, 'RXRα-LBD,', suggesting, a, strategy, to, regulate, 'TR3', activity, indirectly, by, using, small, molecules, to, target, its, interacting, partner, 'RXRα'])].
[sujeto(['For', its, physiological, 'activities,', we, show, that, 'N-6', strongly]), verbo([inhibits]), complemento([tumor, necrosis, factor, α, '(', 'TNFα)-induced', 'AKT', activation, and, stimulates, 'TNFα-mediated', apoptosis, in, cancer, cells, in, an, 'RXRα/tRXRα', dependent, manner])].
[sujeto(['The', inhibition, of, 'TNFα-induced', 'tRXRα/p85α', complex, formation, by, 'N-6', implies, that, 'N-6']), verbo([targets]), complemento([tRXRα, to, inhibit, 'TNFα-induced', 'AKT', activation, and, to, induce, cancer, cell, apoptosis])].
[sujeto(['Together,', our, data, illustrate, a, new, 'RXRα', ligand, with, a, unique, 'RXRα']), verbo([binding]), complemento([mode, and, the, abilities, to, regulate, 'TR3', activity, indirectly, and, to, induce, 'TNFα-mediated', cancer, cell, apoptosis, by, targeting, 'RXRα/tRXRα'])].
[sujeto(['Organotins,', such, as, tributyltin, '(', 'TBT)', and, triphenyltin, '(', 'TPT),', may, disrupt, endocrine, activity, in, mammals, arising, from, their, ability, to]), verbo([act]), complemento([as, ligands, for, the, retinoid, 'X', receptor, '(', 'RXR)', and, the, peroxisome, 'proliferator-activated', receptor, γ, '(', 'PPARγ)'])].
[sujeto(['The', structure, of, 'TBT', is, completely, different, from, that, of, 9, -, cis, retinoic, acid, '(', 9, 'cRA),', an, endogenous, 'RXR', 'ligand;', and, 'X-ray', crystallographic, studies]), verbo([have]), complemento([revealed, that, 'TBT', and, 9, cRA, have, distinct, binding, interactions, with, human, 'RXRα'])].
[sujeto(['Therefore,', organotins, and, rexinoids, likely]), verbo([activate]), complemento(['RXR', by, different, mechanisms])].
[sujeto(['Here,', we, used, human, 'RXRα', mutants, to, investigate, which, amino, acid, residues, of, the, receptor, are, critical, for, transactivation]), verbo([induced]), complemento([by, rexinoids, and, organotins])].
[sujeto(['We']), verbo([found]), complemento([that, 9, cRA, and, a, synthetic, 'RXR', agonist, '(', 'LG100268)', failed, to, activate, 'R316A', and, 'L326A', 'RXRα', mutants])].
[sujeto(['In', 'contrast,', all, the, tested, organotins]), verbo([activated]), complemento([the, 'R316A', 'mutant,', the, 'L326A', 'mutant,', or, both, but, failed, to, activate, a, 'C432A', mutant])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, importance, of, 'L326,', which, is, located, in, the, 'β-strand,', for, 'rexinoid-induced', transactivation, of, 'RXRα', is, comparable, to, that, of, 'R316;', in, 'contrast,', 'C432', is, critical, for, 'organotin-induced', 'transactivation,', whereas, 'R316', and, 'L326', are, not, required])].
[sujeto(['We', used, a, 'PPARγ/RXRα', 'C432A', heterodimer, to, determine, whether, 'TBT', and, 'TPT', could]), verbo([activate]), complemento([the, heterodimer, by, binding, to, 'PPARγ'])].
[sujeto(['We']), verbo([found]), complemento([that, 'TBT', and, 'TPT', activated, the, 'PPARγ/RXRα', 'C432A', 'heterodimer,', which, suggests, that, both, compounds, can, activate, the, heterodimer, through, 'PPARγ'])].
[sujeto(['These', findings, indicate, that, the, amino, acid, residues, that, are, critical, for, 'organotin-induced', transactivation, of, 'RXRα', are, distinct, from, those]), verbo([required]), complemento([for, 'rexinoid-induced', transactivation])].
[sujeto(['Mitochondrial', dysfunction, is]), verbo([associated]), complemento([with, insulin, resistance, and, diabetes])].
[sujeto(['We', previously, showed, that, retinoid, 'X', receptor, α, '(', 'RXRα)', played, an, important, role, in, transcriptional, regulation, of, oxidative, phosphorylation, '(', 'OXPHOS)', genes, in, cells, with, mitochondrial, dysfunction]), verbo([caused]), complemento([by, mitochondrial, 'DNA', mutation])].
[sujeto(['In', this, 'study,', we, investigated, whether, mitochondrial, dysfunction]), verbo([induced]), complemento([by, incubation, with, 'OXPHOS', inhibitors, affects, insulin, receptor, substrate, 1, '(', 'IRS1)', mRNA, and, protein, levels, and, whether, 'RXRα', activation, or, overexpression, can, restore, 'IRS1', expression])].
[sujeto(['The', addition, of, 'RXRα', 'agonists,', 9, -, cis, retinoic, acid, '(', 9, 'cRA)', and, 'LG1506,']), verbo([increased]), complemento(['IRS1', transcription, and, protein, levels, and, restored, mitochondrial, 'function,', which, ultimately, improved, insulin, signaling])].
[sujeto(['RXRα', overexpression, also]), verbo([increased]), complemento(['IRS1', transcription, and, mitochondrial, function])].
[sujeto(['Because', 'RXRα', 'overexpression,', 'knock-down,', or, activation, by, 'LG1506']), verbo([regulated]), complemento(['IRS1', transcription, mostly, independently, of, mitochondrial, 'function,', it, is, likely, that, 'RXRα', directly, regulates, 'IRS1', transcription])].
[sujeto(['Consistent', with, the, 'hypothesis,', we, showed, that, 'RXRα']), verbo([bound]), complemento([to, the, 'IRS1', promoter, as, a, heterodimer, with, peroxisome, 'proliferator-activated', receptor, δ, '(', 'PPARδ)'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'RXRα', overexpression, or, activation, alleviates, insulin, resistance, by, increasing, 'IRS1', expression])].
[sujeto(['Retinoid', 'X', receptor, '(', 'RXRα)', is]), verbo([activated]), complemento([by, 9, -, 'cis-retinoic', acid, '(', 9, 'cRA)', and, regulates, transcription, as, a, homodimer, or, as, a, heterodimer, with, other, nuclear, receptors])].
[sujeto(['We']), verbo([have]), complemento([previously, demonstrated, that, 'β-apo-13-carotenone,', an, eccentric, cleavage, product, of, 'β-carotene,', antagonizes, the, activation, of, 'RXRα', by, 9, cRA, in, mammalian, cells, overexpressing, this, receptor])].
[sujeto(['In', 'contrast,', the, results, of, assays, using, a, hybrid, 'Gal4-DBD:RXRαLBD', receptor, reporter, cell, assay, that, detects, 9, 'cRA-induced', coactivator]), verbo([binding]), complemento([to, the, ligand, binding, domain, demonstrated, that, 'UVI3003', significantly, inhibited, 9, 'cRA-induced', coactivator, binding, to, 'RXRαLBD,', but, 'β-apo-13-carotenone', did, not])].
[sujeto(['However,', both, 'β-apo-13-carotenone', and, 'UVI3003']), verbo([inhibited]), complemento([9, -, cRA, induction, of, caspase, 9, gene, expression, in, the, mammary, carcinoma, cell, line, 'MCF-7'])].
[sujeto(['β-Apo-13-carotenone']), verbo([induces]), complemento([tetramerization, of, the, 'RXRαLBD,', although, 'UVI3003', had, no, effect, on, the, oligomeric, state])].
[sujeto(['These', observations]), verbo([suggest]), complemento([that, 'β-apo-13-carotenone', regulates, 'RXRα', transcriptional, activity, by, inducing, the, formation, of, the, &, 'quot;transcriptionally', 'silent&quot;', 'RXRα', tetramer])].
[sujeto(['Activation', of, 'RAS/ERK', signaling, 'pathway,', depletion, of, 'retinoid,', and, phosphorylation, of, retinoid, 'X', receptor, alpha, '(', 'RXRα)', are, frequent, events]), verbo([found]), complemento([in, liver, tumors, and, thought, to, play, important, roles, in, hepatic, tumorigenesis])].
[sujeto(['By', exploring, the, transgenic, mouse, model, of, hepatic, tumorigenesis]), verbo([induced]), complemento([by, 'liver-specific', expression, of, 'H-ras12V', 'oncogene,', the, activation, of, 'RAS/ERK,', the, mRNA, expression, levels, of, retinoid, 'metabolism-related', 'genes,', the, contents, of, retinoid, 'metabolites,', and, phosphorylation, of, 'RXRα', were, determined])].
[sujeto(['RAS/ERK', signaling, pathway, was, gradually, and, significantly]), verbo([activated]), complemento([in, hepatic, tumor, adjacent, normal, liver, tissues, '(', 'P)', and, hepatic, tumor, tissues, '(', 'T)', of, 'H-ras12V', transgenic, mice, compared, with, normal, liver, tissues, '(', 'Wt)', of, wild, type, mice])].
[sujeto(['Interestingly,', the, retinoid, metabolites, 9, -, 'cis-retinoic', acid, '(', 9, 'cRA)', and, 'all-trans-retinoic', acid, '(', 'atRA),', the, well, known, ligands, for]), verbo([nuclear]), complemento([transcription, factor, 'RXR', and, retinoic, acid, receptor, '(', 'RAR),', were, significantly, decreased, only, in, 'T', compared, with, 'Wt', and, 'P,', although, the, oxidized, polar, metabolite, of, 'atRA,', 4, -, 'keto-all-trans-retinoic-acid', '(', 4, -, 'keto-RA)', was, significantly, decreased, in, both, 'P', and, 'T', compared, with, 'Wt'])].
[sujeto(['Namely,', the, total, protein, levels, of, 'RXRα', were, significantly, reduced, and, the, phosphorylation, levels, of, 'RXRα', were, significantly]), verbo([increased]), complemento([only, in, 'T', compared, with, 'Wt', and, 'P'])].
[sujeto(['These', events, imply, that, the, depletion, of, 9, cRA, and, atRA, and, the, inhibition, of, 'RXRα', function, in, hepatic, tumors]), verbo([involve]), complemento([more, complex, mechanisms, besides, the, activation, of, 'RAS/ERK', pathway])].
[sujeto(['The', retinoid, 'X', receptor, '(', 'RXR)', partners, with, numerous]), verbo([nuclear]), complemento(['receptors,', such, as, the, peroxisome, proliferator, activated, receptor, '(', 'PPAR)', 'family,', liver, 'X', receptors, '(', 'LXRs),', and, farnesoid, 'X', receptor, '(', 'FXR)'])].
[sujeto(['Although', each, heterodimer, can, be]), verbo([activated]), complemento([by, specific, 'ligands,', a, subset, of, these, 'receptors,', defined, as, permissive, nuclear, 'receptors,', can, also, be, activated, by, 'RXR', agonists, known, as, rexinoids])].
[sujeto(['Many', individual, 'RXR', heterodimers]), verbo([have]), complemento([beneficial, effects, in, vascular, smooth, muscle, cells, '(', 'SMCs)'])].
[sujeto(['Because', rexinoids, can, potently]), verbo([activate]), complemento([multiple, 'RXR', 'pathways,', we, hypothesized, that, treating, 'SMCs', with, rexinoids, would, more, effectively, reverse, the, pathophysiologic, effects, of, angiotensin, 'II', than, an, individual, heterodimer, agonist])].
[sujeto(['Bexarotene', also]), verbo([decreased]), complemento([angiotensin, 'II-mediated', 'inflammation,', as, measured, by, decreased, expression, of, monocyte, chemoattractant, 'protein-1', '(', 'MCP-1)'])].
[sujeto(['We', compared, bexarotene, to, five, agonists, of]), verbo([nuclear]), complemento([receptors, '(', 'PPARα,', 'PPARγ,', 'PPARδ,', 'LXR,', and, 'FXR)'])].
[sujeto(['Retinoid', 'X', receptor, α, '(', 'RXRα)', forms, a, heterodimer, with, numerous]), verbo([nuclear]), complemento([receptors, to, regulate, 'drug-', or, 'lipid-metabolizing', enzymes])].
[sujeto(['In', this, 'study,', we, investigated, whether, human, 'RXRα', is]), verbo([regulated]), complemento([by, microRNAs])].
[sujeto(['Luciferase', assays, revealed, that, 'miR-34a']), verbo([recognizes]), complemento([the, element, in, the, coding, region])].
[sujeto(['The', overexpression, of, 'miR-34a', in, 'HepG2', cells, significantly]), verbo([decreased]), complemento([the, endogenous, 'RXRα', protein, and, mRNA, levels])].
[sujeto(['The', stability, of, 'RXRα', mRNA, was]), verbo([decreased]), complemento([by, the, overexpression, of, 'miR-34a,', indicating, that, 'miR-34a', negatively, regulates, 'RXRα', expression, by, facilitating, mRNA, degradation])].
[sujeto(['We']), verbo([found]), complemento([that, the, 'miR-34a-dependent', 'down-regulation', of, 'RXRα', decreases, the, induction, of, 'CYP26', and, the, transactivity, of, 'CYP3A4'])].
[sujeto(['miR-34a']), verbo([has]), complemento([been, reported, to, be, 'up-regulated', by, 'p53,', which, has, an, ability, to, promote, liver, fibrosis])].
[sujeto(['The', p53, activation, resulted, in, an]), verbo([increase]), complemento([of, the, 'miR-34a', level, and, a, decrease, of, the, 'RXRα', protein, level])].
[sujeto(['In', 'addition,', the, 'miR-34a', levels, in, eight, fibrotic, livers, were, higher, than, those, in, six, normal, 'livers,', and, the, reverse, trend, was]), verbo([found]), complemento([for, the, 'RXRα', protein, levels])].
[sujeto(['Taken', 'together,', the, data, show, that, 'miR-34a', negatively]), verbo([regulates]), complemento(['RXRα', expression, in, human, 'liver,', and, affects, the, expression, of, its, downstream, genes])].
[sujeto(['This', 'miR-34a-dependent', regulation, might, be, the, underlying, mechanism, responsible, for, the]), verbo([decreased]), complemento([expression, of, the, 'RXRα', protein, in, fibrotic, livers])].
[sujeto(['Retinoid', 'X', receptors, '(', 'RXRs)', are, obligate, partners, for, several, other]), verbo([nuclear]), complemento(['receptors,', and, they, play, a, key, role, in, several, signaling, processes])].
[sujeto(['Despite', being, a, promiscuous, heterodimer, 'partner,', this]), verbo([nuclear]), complemento([receptor, is, a, target, of, therapeutic, intervention, through, activation, using, selective, 'RXR', agonists, '(', 'rexinoids)'])].
[sujeto(['Agonist']), verbo([binding]), complemento([to, 'RXR', initiates, a, large, conformational, change, in, the, receptor, that, allows, for, coactivator, recruitment, to, its, surface, and, enhanced, transcription])].
[sujeto(['Here', we]), verbo([reveal]), complemento([the, structural, and, dynamical, changes, produced, when, a, coactivator, peptide, binds, to, the, human, 'RXRα', ligand, binding, domain, containing, two, clinically, relevant, 'rexinoids,', 'Targretin', and, 9, -, 'cis-UAB30'])].
[sujeto(['The', four, structural, changes]), verbo([involve]), complemento([key, residues, on, helix, 3, ',', helix, 4, ',', and, helix, 11, that, move, from, a, 'solvent-exposed', environment, to, one, that, interacts, extensively, with, helix, 12])].
[sujeto(['Hydrogen-deuterium', exchange, mass, spectrometry]), verbo([reveals]), complemento([that, the, dynamics, of, helices, 3, ',', 11, ',', and, 12, are, significantly, decreased, when, the, two, rexinoids, are, bound, to, the, receptor])].
[sujeto(['When', the, 'pan-agonist', 9, -, 'cis-retinoic', acid, is]), verbo([bound]), complemento([to, the, 'receptor,', only, the, dynamics, of, helices, 3, and, 11, are, reduced])].
[sujeto(['The', four, structural, changes, are]), verbo([conserved]), complemento([in, all, 'x-ray', structures, of, the, 'RXR', 'ligand-binding', domain, in, the, presence, of, agonist, and, coactivator, peptide])].
[sujeto(['The', progesterone, receptor, '(', 'PR),', a, member, of]), verbo([nuclear]), complemento([receptor, 'superfamily,', is, closely, associated, with, 'gestational,', type, 1, and, type, 2, diabetes])].
[sujeto(['Here', we]), verbo([found]), complemento([that, 'PR', activation, increased, the, 'pro-inflammatory', cytokines, '(', 'PIC)-induced', injury, in, 'Min6', 'cells,', and, 'PR', blockage, with, siRNA, interference, protected, the, cells, from, damage])].
[sujeto(['Immunoblotting', assays, indicated, that, either, 'PR', agonist, progesterone, '(', 'P4)', or, 'PR-B', 'over-expression']), verbo([promoted]), complemento([the, 'PIC-induced', reinforces, of, 'extracellular-signal-regulated', kinase, 1, /, 2, phosphorylation, '(', 'p-Erk)', and, protein, 53, '(', 'p53),', and, the, attenuations, of, protein, kinase, 'B', phosphorylation, '(', 'p-AKT)', and, tumor, necrosis, factor, 'receptor-associated', factor, 2, '(', 'TRAF2)'])].
[sujeto(['SC51089', could, reverse, all, the, 'P4-', or, 'PR-B', 'over-expression']), verbo([induced]), complemento([effects])].
[sujeto(['In', 'addition,', 'PR', siRNA, inference, based, assay, further, supported, that, 'SC51089', protected, pancreatic, islet, beta, cells, from, the, 'PR', activation, or, 'PIC-induced', injury, by]), verbo([targeting]), complemento(['PR', and, this, protective, action, was, mediated, by, 'AKT', signaling, pathway])].
[sujeto(['To', our, 'knowledge,', this, current, work, might, be, the, first]), verbo([report]), complemento([on, the, regulation, of, 'PR', in, pancreatic, islet, beta, cell, survival])].
[sujeto(['It', is, expected, that, 'SC51089,', as, a, 'non-steroid', 'PR', 'antagonist,', might, also]), verbo([find]), complemento([its, potential, in, 'anti-diabetic', research])].
[sujeto(['Retinoid', 'X', receptor, α, '[', 'RXRα;']), verbo([nuclear]), complemento([receptor, '(', 'NR)2B1]', is, a, crucial, regulator, in, the, expression, of, a, broad, array, of, hepatic, genes, under, both, normal, and, pathologic, conditions])].
[sujeto(['Inflammation', and, other, stressors, alter]), verbo([nuclear]), complemento([receptor, function, in, liver, and, induce, 'SUMOylation', of, several, 'NRs', as, part, of, proinflammatory, gene, 'regulation,', but, linkages, between, these, two, pathways, in, 'liver,', or, for, 'RXRα', 'directly,', remain, unexplored])].
[sujeto(['We', sought, to, determine, if, inflammation]), verbo([induces]), complemento(['SUMOylation', of, 'RXRα', in, human, 'liver-derived', '(', 'HuH-7)', cells])].
[sujeto(['Lipopolysaccharide,', 'interleukin-1β,', and, tumor, necrosis, factor, α, '(', 'TNFα)', rapidly, and, substantially]), verbo([stimulated]), complemento(['SUMOylation', of, 'RXRα'])].
[sujeto(['Two', 'RXRα', 'ligands,', 9, -, cis, retinoic, acid, '(', 9, 'cRA)', and, 'LG268,']), verbo([induced]), complemento(['SUMOylation', of, 'RXRα,', whereas, both, 'inflammation-', and, 'ligand-induced', 'SUMOylation', of, 'RXRα', require, the, 'K108', residue])].
[sujeto(['These', results, indicate, that, inflammatory, signaling, pathways, rapidly]), verbo([induce]), complemento(['SUMOylation', of, 'RXRα,', adding, to, the, repertoire, of, 'RXRα', molecular, species, in, the, hepatocyte, that, respond, to, inflammation])].
[sujeto(['Retinoic', acid, '(', 'RA)', signaling, is]), verbo([mediated]), complemento([by, specific, nuclear, hormone, receptors])].
[sujeto([9, -, 'cis-RA']), verbo([inhibits]), complemento([the, lipid, accumulation, of, adipogenetically, induced, 3, 'T3-L1', cells])].
[sujeto(['The', complex, of, retinoid, 'X', receptor, α, '(', 'RXRα)', with, peroxisome, 'proliferator-activated', receptor, γ, '(', 'PPARγ)', is, a, major, transcription, factor, in, the, process, of, 'adipogenesis,', and, the, levels, of, these, molecules, were]), verbo([decreased]), complemento([by, 9, -, 'cis-RA', treatment])].
[sujeto(['A', 'RXR', 'pan-antagonist']), verbo([suppressed]), complemento([9, -, 'cis-RA\'s', inhibitory, effects, on, 'adipogenesis,', but, not, on, the, intracellular, levels, of, both, 'RXRα', and, 'PPARγ'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 9, -, 'cis-RA', could, inhibit, adipogenesis, by, activating, 'RXR,', and, decrease, both, 'RXR', and, 'PPARγs', levels, in, a, 'RXR', 'activation-independent', manner])].
[sujeto(['De', novo, 'H3K4me1', peaks, in, infected, cells, were]), verbo([associated]), complemento([with, genes, implicated, in, host, defenses, and, apoptosis])].
[sujeto(['These', contained, several, transcription, factor]), verbo([binding]), complemento(['sites,', including, those, for, members, of, the, 'MEF2', and, 'ATF', 'families,', and, 'LXR', and, 'RAR', nuclear, 'receptors,', all, of, which, have, been, implicated, in, macrophage, 'differentiation,', 'survival,', and, responses, to, stress, and, infection])].
[sujeto(['In', 'particular,', we, show, that, 'LXRα', 'signaling,', which, reduced, 'Mtb', viability, 18, -, fold, by, altering, cholesterol, metabolism, and]), verbo([enhancing]), complemento([macrophage, 'apoptosis,', can, be, initiated, at, response, elements, present, in, 'Alu', repeats])].
[sujeto(['Th17', and, regulatory, 'T', '(', 'Treg)', cells, are, two, subsets, of, 'CD4+T-cells', which]), verbo([have]), complemento([critical, functions, in, the, onset, and, progression, of, 'MS'])].
[sujeto(['Putative', and, validated]), verbo([targets]), complemento([of, 'miR-223', were, investigated, in, the, miRWalk, and, miRTarBase, 'databases,', respectively])].
[sujeto(['Additionally,', potential]), verbo([targets]), complemento([of, 'miR-223,', 'STAT1,', 'FORKHEAD', 'BOX', 'O', '(', 'FOXO1)', and, 'FOXO3', were, predicted, by, in, silico, studies])].
[sujeto(['miR-223', may]), verbo([have]), complemento([a, potential, role, in, 'MS', progression])].
[sujeto(['Here', we]), verbo([report]), complemento([that, 'ATRA,', an, active, metabolite, of, vitamin, 'A,', restores, mechanical, quiescence, in, 'PSCs', via, a, mechanism, involving, a, retinoic, acid, receptor, beta, '(', 'RAR-β)-dependent', downregulation, of, actomyosin, '(', 'MLC-2)', contractility])].
[sujeto(['We', show, that, 'ATRA', reduces, the, ability, of, 'PSCs', to, generate, high, traction, forces, and, adapt, to, extracellular, mechanical, cues, '(', 'mechanosensing),', as, well, as]), verbo([suppresses]), complemento(['force-mediated', extracellular, matrix, remodelling, to, inhibit, local, cancer, cell, invasion, in, 3, 'D', organotypic, models])].
[sujeto(['Our', findings, implicate, a, 'RAR-β/MLC-2', pathway, in, peritumoural, stromal, remodelling, and, 'mechanosensory-driven', activation, of, 'PSCs,', and, further]), verbo([suggest]), complemento([that, mechanical, reprogramming, of, 'PSCs', with, retinoic, acid, derivatives, might, be, a, viable, alternative, to, stromal, ablation, strategies, for, the, treatment, of, 'PDAC'])].
[sujeto(['Graft-versus-host', disease, '(', 'GVHD)', is, the, major]), verbo([cause]), complemento([of, morbidity, and, mortality, after, allogeneic, hematopoietic, stem, cell, transplantation, '(', 'HSCT)'])].
[sujeto(['Recent', studies]), verbo([have]), complemento([identified, the, potential, role, of, retinoic, acid, '(', 'RA)/retinoic', acid, receptor, '(', 'RAR)', pathway, in, the, pathogenesis, of, 'GVHD'])].
[sujeto(['It']), verbo([has]), complemento([been, previously, reported, that, recipient, vitamin, 'A', deficiency, is, associated, with, reduced, intestinal, 'GVHD', and, prolonged, overall, survival, after, experimental, allogeneic, 'HSCT'])].
[sujeto(['In', the, current, 'study,', we]), verbo([report]), complemento([that, chronic, vitamin, 'A', deficiency, changes, the, composition, of, 'T', cell, compartment, of, donor, mice, with, a, reduction, in, the, percentage, of, 'CD4(+)', 'T', cells])].
[sujeto(['We', showed, that, although, vitamin, 'A', deficiency, does, not, affect, donor, 'T', cell, alloreactivity, on, a, per, cell, 'basis,', a]), verbo([decreased]), complemento([proportion, of, donor, 'CD4(+)', 'T', cells, in, marrow, graft, inoculums, leads, to, reduced, incidence, and, severity, of, 'GVHD'])].
[sujeto(['Furthermore,', our, proof, of, principle, studies, using, a, 'pan-RAR', antagonist, demonstrated, that, transient, inhibition, of, donor, 'T', cell, 'RAR', signaling, can, reduce, 'T', cell, alloreactivity, and, their, ability, to]), verbo([cause]), complemento([lethal, 'GVHD'])].
[sujeto(['Our', studies]), verbo([provide]), complemento(['pre-clinical', evidence, that, donor, vitamin, 'A', deficiency, may, be, a, 'non-genetic', factor, that, can, modulate, the, severity, of, 'GVHD', and, pharmacological, interfering, 'RA/RAR', pathway, in, donor, 'T', cells, might, be, a, valuable, approach, for, mitigating, 'GVHD', after, allogeneic, 'HSCT'])].
[sujeto(['Many', airway, sensory, units]), verbo([respond]), complemento([to, both, lung, inflation, and, deflation])].
[sujeto(['Two', major, types, of, mechanical, sensors, operate, in, the, 'lung:', inflation, and, deflation]), verbo([activated]), complemento([receptors, '(', 'DARs)'])].
[sujeto(['Inflation']), verbo([activated]), complemento([sensors, can, be, further, divided, into, slowly, adapting, receptors, '(', 'SARs)', and, rapidly, adapting, receptors, '(', 'RARs)'])].
[sujeto(['Many', 'SAR', and, 'RAR', units, also]), verbo([respond]), complemento([to, lung, deflation, because, they, contain, 'DARs'])].
[sujeto(['Pure', 'DARs,', which]), verbo([respond]), complemento([to, lung, deflation, 'only,', are, rare, in, large, animals, but, are, easily, identified, in, small, animals])].
[sujeto(['Lung', deflation]), verbo([induced]), complemento([reflex, effects, previously, attributed, to, 'RARs', should, be, assigned, to, 'DARs', '(', including, pure, 'DARs,', and, 'DARs', associated, with, 'SARs', and, 'RARs)', if, the, 'multiple-sensor', theory, is, accepted])].
[sujeto(['Thus,', based, on, the, 'information,', it, is, proposed, that, activation, of, 'DARs', can, attenuate, lung, 'deflation,', shorten, expiratory, 'time,']), verbo([increase]), complemento([respiratory, 'rate,', evoke, 'inspiration,', and, cause, airway, secretion, and, dyspnea])].
[sujeto(['RAR']), verbo([has]), complemento([been, widely, observed, in, vivo, using, as, endpoint, less, induction, of, apoptosis])].
[sujeto(['However,', sex, differences]), verbo([associated]), complemento([with, 'RAR', and, variations, between, males, and, females, on, global, gene, expression, influenced, by, 'RAR', have, not, been, still, investigated])].
[sujeto(['In', 'addition,', the, response, to, 'radiation-induced', apoptosis, is]), verbo([associated]), complemento([with, phosphorylation, of, 'TRP53', at, both, the, serine, 15, '(', 'ser-18', in, the, 'mouse)', and, serine, 392, '(', 'ser-389', in, 'mice)', 'residues,', but, the, role, of, these, two, phosphorylated, forms, in, male, and, female, 'RAR', remains, to, be, elucidated])].
[sujeto(['Here,', we]), verbo([provide]), complemento([the, first, evidence, of, a, differential, sex, effect, of, 'RAR', on, the, reduction, of, thymocyte, apoptosis, with, males, showing, lesser, levels, of, 'caspase-3-mediated', apoptosis, than, females])].
[sujeto(['Analysis', of, transcriptomic, profiles, of, 1944, genes]), verbo([involved]), complemento([in, apoptosis, signaling, in, 'radio-adapted', thymocytes, identified, 17, transcripts, exhibiting, differential, expression, between, both, sexes])].
[sujeto(['Among', 'them,', 'Dlc1', and, 'Fis1', are, closely, related, to, the, apoptosis]), verbo([mediated]), complemento([by, the, 'TRP53', protein])].
[sujeto(['In', an, opposite, 'way,', both, 'down-modulation', of, 'Fis1', and, 'phosphoserine-389-TRP53', accumulation, appear, to, be]), verbo([associated]), complemento([with, protection, from, thymocyte, apoptosis, mediated, by, 'caspase-3', in, males])].
[sujeto(['Transcriptomic', analysis, performed, in, this, work]), verbo([reveals]), complemento([for, the, first, time, 'sex-specific', differences, in, gene, expression, influenced, by, 'RAR'])].
[sujeto(['Our', results, also]), verbo([suggest]), complemento([a, 'sex-dependent', dual, role, for, 'phosphoserine-18-TRP53', and, 'phosphoserine-389-TRP53', in, the, regulation, of, the, 'radio-adaptive', response, in, mouse, thymocytes])].
[sujeto(['Active', expiration, during, exercise, can]), verbo([increase]), complemento([intrathoracic, pressure, yielding, concavity, in, the, expiratory, 'flow-volume', loop, in, 'COPD'])].
[sujeto(['Dysmorphic', nuclei, are, commonly, seen, in, cancers, and]), verbo([provide]), complemento([strong, motivation, for, studying, the, main, structural, proteins, of, 'nuclei,', the, 'lamins,', in, cancer])].
[sujeto(['Past', studies]), verbo([have]), complemento([also, demonstrated, the, significance, of, microenvironment, mechanics, to, cancer, 'progression,', which, is, extremely, interesting, because, the, lamina, was, recently, shown, to, be, mechanosensitive])].
[sujeto(['In', 'addition,', lamins, can, influence, transcriptional, regulators, '(', 'RAR,', 'SRF,', 'YAP/TAZ)', and, chromosome, conformation, in, lamina]), verbo([associated]), complemento([domains])].
[sujeto(['Further', investigation, of, the, roles, for, lamins, in, cancer, and, even, 'DNA', damage, may]), verbo([lead]), complemento([to, new, therapies, or, at, least, to, a, clearer, understanding, of, lamins, as, 'bio-markers', in, cancer, progression])].
[sujeto(['Retinoic', acid, '(', 'RA),', an, active, form, of, vitamin, 'A,']), verbo([regulates]), complemento([the, embryonic, 'development,', male, and, female, reproduction, and, induces, important, effects, on, the, cell, 'development,', 'proliferation,', and, differentiation])].
[sujeto(['These', effects, are]), verbo([mediated]), complemento([by, the, retinoid, '(', 'RAR)', and, rexinoid, nuclear, receptors, '(', 'RXR),', which, are, considered, to, be, a, 'ligand-activated,', 'DNA-binding,', 'trans-acting,', and, 'transcription-modulating', 'proteins,', involved, in, a, general, molecular, mechanism, responsible, for, the, transcriptional, responses, in, target, genes])].
[sujeto(['They', may, affect, processes, of, reproductive, system, in, 'mammals,', predominantly, via]), verbo([nuclear]), complemento([receptor, signaling, pathways])].
[sujeto(['Triorganotins,', such, as, tributyltin, chloride, '(', 'TBTCl)', and, triphenyltin, chloride, '(', 'TPTCl),', are, capable, to]), verbo([bind]), complemento([to, 'RXR', 'molecules,', and, thus, represent, potent, agonists, of, 'RXR', subtypes, of, nuclear, receptors, not, sharing, any, structural, characteristics, with, endogenous, ligands, of, nuclear, receptors])].
[sujeto(['A', qualitative, examination, of, the, mean, change, scores]), verbo([suggested]), complemento(['that,', compared, to, 'PLA,', 'RAR', 'CLA', supplementation, was, associated, with, a, small, improvement, in, joint, discomfort, in, both, men, and, women])].
[sujeto(['Cell', type, specification, relies, on, the, capacity, of, undifferentiated, cells, to, properly]), verbo([respond]), complemento([to, specific, 'differentiation-inducing', signals])].
[sujeto(['Using', genomic, approaches, along, with, 'loss-', and, 'gain-of-function', genetic, 'models,', we, identified, 'OCT4-dependent', mechanisms, that]), verbo([provide]), complemento([embryonic, stem, cells, with, the, means, to, customize, their, response, to, external, cues])].
[sujeto(['OCT4']), verbo([binds]), complemento([a, large, set, of, 'low-accessible', genomic, regions])].
[sujeto(['At', these, 'sites,', 'OCT4', is]), verbo([required]), complemento([for, proper, enhancer, and, gene, activation, by, recruiting, 'co-regulators', and, 'RAR:RXR', or, 'β-catenin,', suggesting, an, unexpected, collaboration, between, the, 'lineage-determining', transcription, factor, and, these, 'differentiation-initiating,', 'signal-dependent', transcription, factors])].
[sujeto(['Our', results, uncover, 'OCT4', as, an, integral, and, necessary, component, of, 'signal-regulated', transcriptional, processes]), verbo([required]), complemento([for, 'tissue-specific', responses])].
[sujeto(['We', show, that, a, severe, 'asthma-associated', polymorphism, in, the, gene, encoding, the, interleukin, '(', 'IL)-4', receptor, alpha, chain, '(', 'Il4ra(R576))']), verbo([promotes]), complemento([conversion, of, induced, 'Treg', '(', 'iTreg)', cells, toward, a, 'T', helper, 17, '(', 'TH17)', cell, fate])].
[sujeto(['This', skewing, is]), verbo([mediated]), complemento([by, the, recruitment, by, 'IL-4Rα(R576)', of, the, 'growth-factor-receptor-bound', protein, 2, '(', 'GRB2)', adaptor, 'protein,', which, drives, 'IL-17', expression, by, activating, a, pathway, that, involves, 'extracellular-signal-regulated', 'kinase,', 'IL-6', and, the, transcription, factor, 'STAT3'])].
[sujeto(['Treg', 'cell-specific', deletion, of, genes, that]), verbo([regulate]), complemento(['TH17', cell, 'differentiation,', including, 'Il6ra', and, 'RAR-related', orphan, receptor, gamma, '(', 'Rorc),', but, not, of, 'Il4', or, 'Il13,', prevented, exacerbated, airway, inflammation, in, mice, expressing, 'Il4ra(R576)', '(', hereafter, referred, to, as, 'Il4ra(R576)', 'mice)'])].
[sujeto(['Furthermore,', treatment, of, 'Il4ra(R576)', mice, with, a, neutralizing, 'IL-6-specific', antibody]), verbo([prevented]), complemento([iTreg, cell, reprogramming, into, 'TH17-like', cells, and, protected, against, severe, airway, inflammation])].
[sujeto(['This', 'meta-analysis', aimed, to, determine, whether, exercise, interventions, were, effective, in]), verbo([preventing]), complemento(['fall-related', fractures, in, older, people])].
[sujeto(['Randomized', controlled, trials, '(', 'RCTs)', that, conducted, exercise, interventions, and]), verbo([reported]), complemento(['fall-related', fracture, data, in, older, people, were, included])].
[sujeto(['The', treatment, effects, on, 'falls,', leg, strength, and, balance, were, also]), verbo([reported]), complemento([using, rate, ratio, '(', 'RaR)', with, 95, '%', 'CI', and, standardized, mean, difference, '(', 'SMD)', with, 95, '%', 'CI,', respectively])].
[sujeto(['Our', findings, implied, that, exercise, interventions, were, effective, in]), verbo([preventing]), complemento(['fall-related', fractures, and, reducing, risk, factors, of, 'fall-related', fractures, in, older, people])].
[sujeto(['All-trans', retinoic, acid, '(', 'ATRA),', a, member, of, the, retinoid, drug, 'class,']), verbo([acts]), complemento([as, a, regulator, in, several, biological, processes])].
[sujeto(['ATRA']), verbo([increased]), complemento([the, protein, expression, and, mRNA, levels, of, 'AQP3', in, a, 'dose-dependent', manner, '(', 'P', &, 'lt;'])].
[sujeto(['ATRA', also]), verbo([increased]), complemento([the, protein, expression, of, 'RARα', '(', 'P', &, 'lt;'])].
[sujeto(['Treatment', of, 'CRL2616', cells, with, an, 'RAR', antagonist, '(', 'Ro', 41, -, 5253, ')', significantly]), verbo([decreased]), complemento(['AQP3', protein, expression, '(', 'P', &, 'lt;'])].
[sujeto(['ATRA']), verbo([mediated]), complemento([by, 'RARα', increased, 'AQP3', gene, and, protein, expression, in, human, vaginal, mucosal, epithelial, cells])].
[sujeto(['These', results, imply, that, 'AQP3']), verbo([regulated]), complemento([by, 'ATRA', could, play, an, important, role, in, the, mechanism, of, vaginal, lubrication])].
[sujeto(['The', department, also]), verbo([has]), complemento([a, hepatology, 'ICU'])].
[sujeto(['Data', were, sourced, from, the, electronic, database, of, patient, records, in, the, form, of, automated, summary, discharge, forms, and, from, annual]), verbo([reports]), complemento([from, the, year, 2004, until, the, year, 2013, ',', which, are, available, in, the, 'Medical', 'Record', 'Unit', in, 'TBRI', 'Hospital'])].
[sujeto(['Inpatient', cases]), verbo([increased]), complemento([by, 40.5, '%', '(', from, 2003, to, 2829, ')'])].
[sujeto(['RAR']), verbo([decreased]), complemento([over, the, 10, years, '(', from, 14.2, to, 0.6, ')'])].
[sujeto(['ALOS', also]), verbo([decreased]), complemento(['(', from, 9.4, to, 6.1, ')'])].
[sujeto(['BOR']), verbo([increased]), complemento([from, 2004, to, 2012, only, '(', from, 54.3, to, 86.3, ')'])].
[sujeto(['Bed', turnover, rate, ranged, from, 21.1, to, 28.5, ',', but, in, 2012, it]), verbo([increased]), complemento([to, 47.7, as, a, result, of, the, increased, 'BOR', that, year])].
[sujeto(['MR']), verbo([decreased]), complemento([from, 8.9, in, 2004, to, 0.3, in, 2013])].
[sujeto(['Ultrasonography']), verbo([increased]), complemento([from, 3384, to, 3973])].
[sujeto(['Over', the, 10, 'years,', the, number, of, endoscopies]), verbo([increased]), complemento([about, 'two-fold', '(', from, 2677, to, 5100, ')', and, endoscopic, ligation, increased, more, than, 10, -, fold])].
[sujeto(['There', is, an, improvement, in, the, hospital, performance, indicators, represented, in, the, form, of]), verbo([increased]), complemento([outpatient, 'services,', decreased, 'RAR,', decreased, 'ALOS,', decreased, 'MR,', and, increased, utilization, of, endoscopies])].
[sujeto(['The', development, of, the, most, common, multidrug, resistance, '(', 'MDR)', phenotype, is]), verbo([associated]), complemento([with, 'a massive', overexpression, of, 'P-glycoprotein', '(', 'P-gp)', in, neoplastic, cells])].
[sujeto(['Several', authors]), verbo([have]), complemento([described, the, induction, of, 'P-gp', 'expression/activity', in, malignant, cell, lines, after, treatment, with, 'all-trans', retinoic, acid, '(', 'AtRA;', ligand, of, retinoic, acid, nuclear, 'receptors,', 'RARs)'])].
[sujeto(['An', isomer, of, 'AtRA', also, 'exists,', 9, -, cis, retinoic, 'acid,', which, is, 'a ligand', of, both, 'RARs', and]), verbo([nuclear]), complemento([retinoid, 'X receptors', '(', 'RXRs)'])].
[sujeto(['In', 'a previous', 'work,', we, described, that, the, combined, treatment, of, 'R cells', with, verapamil, and, 'AtRA']), verbo([induces]), complemento([the, downregulation, of, 'P-gp', 'expression/activity'])].
[sujeto(['We']), verbo([found]), complemento([that, the, overexpression, of, 'P-gp', in, 'L1210', cells, is, associated, with, several, changes, in, the, specific, transcription, of, both, subgroups, of, nuclear, 'receptors,', 'RARs', and, 'RXRs'])].
[sujeto(['We', also, demonstrated, that, treatment, with, 'AtRA,', 9, cRA, and, verapamil]), verbo([induces]), complemento([alterations, in, 'P-gp', expression, in, 'R and', 'T cells'])].
[sujeto(['Particularly,', combined, treatment, of, 'R cells', with, verapamil, and, 'AtRA']), verbo([induced]), complemento([downregulation, of, 'P-gp', 'content/activity'])].
[sujeto(['In', 'contrast,', similar, treatment, of, 'T cells']), verbo([induced]), complemento([slight, increase, of, 'P-gp', content, without, any, changes, in, efflux, activity, of, this, protein])].
[sujeto(['The']), verbo([binding]), complemento([of, such, bulky, ligands, suggests, that, the, 'RXR', 'ligand-binding', domain, is, endowed, with, some, degree, of, structural, elasticity])].
[sujeto(['Peroxisome', proliferator, activator, receptors, '(', 'PPAR)', ligands, such, as, 15, -, 'Δ12,13-prostaglandin', 'L(2)', '[', 'PJ]', and, all, trans, retinoic, acid, '(', 'ATRA)']), verbo([have]), complemento([been, shown, to, inhibit, the, development, of, liver, fibrosis])].
[sujeto(['We']), verbo([found]), complemento([that, the, 'anti-proliferative', effect, of, the, combined, treatment, of, 'PJ,', 'ATRA', and, 9, -, cis, on, 'HSCs', was, additive])].
[sujeto(['Further', experiments, revealed, that, this, inhibition, was, due, to, cell, cycle]), verbo([arrest]), complemento([at, the, 'G0/G1', phase, as, demonstrated, by, 'FACS', analysis])].
[sujeto(['In', 'addition,', the, combined, treatment, reduced, cyclin, 'D1', expression, and]), verbo([increased]), complemento([p21, and, p27, protein, levels])].
[sujeto(['Furthermore,', we]), verbo([found]), complemento([that, the, three, ligands, down, regulated, the, phosphorylation, of, mTOR, and, 'p70(S6K)'])].
[sujeto(['The', activation, of, 'HSCs', was, also]), verbo([inhibited]), complemento([by, the, three, ligands, as, shown, by, inhibition, of, vitamin, 'A', lipid, droplets, depletion, from, 'HSCs'])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, combined, use, of, 'PJ,', 'ATRA', and, 9, -, cis, causes, inhibition, of, cell, proliferation, by, cell, cycle, arrest, and, 'down-regulation', of, fibrotic, markers, to, a, greater, extent, compared, to, each, of, the, ligands, alone])].
[sujeto(['Retinoids', are, biologically, active, compounds, of, either, natural, or, synthetic, origin, that, are]), verbo([involved]), complemento([in, complex, physiological, and, developmental, processes, in, many, tissues, including, cell, proliferation, and, activation, of, tumour, suppression, genes])].
[sujeto(['This', article, reviews, the, role, of, retinoids, and, their, cognate]), verbo([nuclear]), complemento(['retinoid/rexinoid', receptors, in, relation, to, renal, cell, carcinoma])].
[sujeto(['A', literature, search, using, 'ScienceDirect', and, 'Medline', with, a, focus, on, the, relationship, between, renal, cell, carcinoma, and]), verbo([nuclear]), complemento(['retinoid/rexinoid', receptors])].
[sujeto(['Combination', therapy, with, other, preparations]), verbo([has]), complemento([greater, efficacy, than, treatment, with, retinoids, alone])].
[sujeto(['Since']), verbo([nuclear]), complemento([retinoid, receptors, play, 'a&nbsp;crucial', role, as, 'ligand-activated,', 'DNA', 'binding,', 'trans-acting,', 'transcription-modulating', proteins, involved, in, 'a&nbsp;general', molecular, mechanism, responsible, for, transcriptional, responses, in, target, 'genes,', retinoids, might, be, an, alternative, approach, for, the, treatment, of, renal, cell, carcinoma])].
[sujeto(['The', thymus]), verbo([provides]), complemento([the, microenvironment, in, which, thymocytes, develop, into, mature, 'T-cells,', and, interactions, with, thymic, stromal, cells, are, thought, to, provide, the, necessary, signals, for, thymocyte, maturation])].
[sujeto(['Recognition', of, 'self-MHC', by, 'T-cells', is, a, basic, requirement, for, mature, 'T-cell', 'functions,', and, those, thymocytes, that, do, not]), verbo([recognize]), complemento([or, respond, too, strongly, to, the, 'peptide-loaded', 'self-MHC', molecules, found, in, the, thymus, undergo, apoptosis])].
[sujeto(['This', review, describes, a, complex, crosstalk, between, developing, thymocytes, and, engulfing, macrophages, which, is]), verbo([mediated]), complemento([by, retinoids, produced, by, engulfing, macrophages])].
[sujeto(['There', is]), verbo([increasing]), complemento([appreciation, of, the, involvement, of, this, receptor, network, in, the, metabolic, programming, of, macrophages, and, dendritic, cells, '(', 'DCs),', essential, members, of, the, innate, immune, system])].
[sujeto(['We', also]), verbo([provide]), complemento([an, overview, of, the, contribution, of, 'macrophage-', and, 'DC-expressed', nuclear, receptors, to, various, immunopathologic, 'conditions,', such, as, rheumatoid, 'arthritis,', inflammatory, bowel, 'disease,', systemic, lupus, 'erythematosus,', 'asthma,', and, some, others])].
[sujeto(['We']), verbo([suggest]), complemento([that, systematic, analyses, of, the, roles, of, these, receptors, and, their, activating, lipid, ligands, in, immunopathologies, combined, with, complementary, and, focused, translational, and, clinical, research, will, be, crucial, for, the, development, of, new, therapies, using, the, many, molecules, available, to, target, nuclear, receptors])].
[sujeto(['There', is, widespread, interest, in, defining, factors, and, mechanisms, that]), verbo([suppress]), complemento([the, proliferation, of, cancer, cells])].
[sujeto(['However,', the, molecular, mechanisms, by, which, 9, -, 'cis-RA', signaling]), verbo([induces]), complemento([growth, inhibition, in, 'RA-sensitive', breast, cancer, and, embryonic, cells, are, not, apparent])].
[sujeto(['Here,', we]), verbo([provide]), complemento([evidence, that, the, inhibitory, effect, of, 9, -, 'cis-RA', on, cell, proliferation, depends, on, 9, -, 'cis-RA-dependent', interaction, of, retinoid, 'X', receptor, α, '(', 'RXRα)', with, replication, factor, 'C3', '(', 'RFC3),', which, is, a, subunit, of, the, 'RFC', heteropentamer, that, opens, and, closes, the, circular, proliferating, cell, nuclear, antigen, '(', 'PCNA)', clamp, on, 'DNA'])].
[sujeto(['An', 'RFC3', ortholog, in, a]), verbo([sea]), complemento([urchin, cDNA, library, was, isolated, by, using, the, 'ligand-binding', domain, of, 'RXRα', as, bait, in, a, yeast, 'two-hybrid', screening])].
[sujeto(['Truncation', and, mutagenesis, experiments, demonstrated, that, the, 'C-terminal', 'LXXLL', motifs, in, both, human, and]), verbo([sea]), complemento([urchin, 'RFC3', are, critical, for, the, interaction, with, 'RXRα'])].
[sujeto(['Furthermore,', we]), verbo([found]), complemento([that, knockdown, of, 'RXRα', or, overexpression, of, 'RFC3', impairs, the, ability, of, 9, -, 'cis-RA', to, inhibit, proliferation, of, 'MCF-7', breast, cancer, cells, and, sea, urchin, embryogenesis])].
[sujeto(['Our', results, indicate, that, 9, -, 'cis-RA-activated', 'RXRα']), verbo([suppresses]), complemento([the, growth, of, 'RA-sensitive', breast, cancer, and, embryonic, cells, through, 'RFC3'])].
[sujeto(['Retinoid', 'X', receptors, '(', 'RXRs)', are, members, of, the]), verbo([nuclear]), complemento([receptor, superfamily, and, can, be, activated, by, 9, -, cis, retinoic, acid, '(', 9, 'CRA)'])].
[sujeto(['RXRs', form, homodimers, and, heterodimers, with, other]), verbo([nuclear]), complemento([receptors, such, as, the, retinoic, acid, receptor, and, 'NR4', subfamily, nuclear, 'receptors,', 'Nur77', and, 'NURR1'])].
[sujeto(['Potential', physiological, roles, of, the, 'Nur77-RXR', and, 'NURR1-RXR', heterodimers]), verbo([have]), complemento([not, been, elucidated])].
[sujeto(['In', this, 'study,', we, identified, a, gene]), verbo([regulated]), complemento([by, these, heterodimers, utilizing, 'HX600,', a, selective, 'RXR', agonist, for, 'Nur77-RXR', and, 'NURR1-RXR'])].
[sujeto(['While', 9, 'CRA']), verbo([induced]), complemento([many, 'genes,', including, 'RAR-target', 'genes,', 'HX600', effectively, induced, only, carnitine, palmitoyltransferase, 1, 'A', '(', 'CPT1A)', in, human, teratocarcinoma, 'NT2/D1', 'cells,', which, express, 'RXRα,', 'Nur77', and, 'NURR1'])].
[sujeto(['HX600', also]), verbo([increased]), complemento(['CPT1A', expression, in, human, embryonic, kidney, '(', 'HEK)', 293, cells, and, 'hepatocyte-derived', 'HepG2', cells])].
[sujeto(['Although', 'HX600']), verbo([induced]), complemento(['CPT1A', less, effectively, than, 9, 'CRA,', overexpression, of, 'Nur77', or, 'NURR1', increased, the, 'HX600', response, to, levels, similar, to, 9, 'CRA', in, 'NT2/D1', and, 'HEK293', cells])].
[sujeto(['A', 'dominant-negative', form, of, 'Nur77', or, 'NURR1']), verbo([repressed]), complemento([the, induction, of, 'CPT1A', by, 'HX600'])].
[sujeto(['Thus,', the, rexinoid, 'HX600', directly]), verbo([induces]), complemento([expression, of, 'CPT1A', through, a, 'Nur77', or, 'NURR1-mediated', mechanism])].
[sujeto(['CPT1A,', a, gene]), verbo([involved]), complemento([in, fatty, acid, 'β-oxidation,', could, be, a, target, of, 'RXR-NR4', receptor, heterodimers])].
[sujeto([9, -, 'cis-retinoic', acid, '(', 9, 'cRA),', an, active, metabolite, of, vitamin, 'A,', is, a, high, affinity, ligand, for, retinoid, 'X', receptor, '(', 'RXR)', and, also]), verbo([activates]), complemento([retinoic, acid, receptor, '(', 'RAR)'])].
[sujeto(['Understanding', both, the]), verbo([nuclear]), complemento(['receptor-mediated', and, 'non-genomic', mechanisms, of, 9, cRA, will, aid, in, the, elucidation, of, disease, physiology, and, possibly, lead, to, the, development, of, new, 'retinoid-based', therapeutics])].
[sujeto(['Triphenyltin', '(', 'TPT)']), verbo([has]), complemento([high, binding, affinity, with, the, retinoid, 'X', receptor, '(', 'RXR)', in, animals])].
[sujeto(['The', natural, ligand, of, 'RXR,', 9, -, 'cis-retinoic', acid, '(', 'RA),', is, known, to]), verbo([induce]), complemento([featured, malformations, in, vertebrate, embryos, by, disrupting, 'RA', signal])].
[sujeto(['TPT']), verbo([induced]), complemento([multiple, malformations, including, enlarged, proctodaeum, and, narrow, fins])].
[sujeto(['TPT', at, 5, μg, 'Sn/L']), verbo([inhibited]), complemento([the, differentiation, of, skins, and, muscles])].
[sujeto(['The', reduced, 'brain,']), verbo([loss]), complemento([of, external, eyes, and, bent, axis, were, observed, in, 'RXR', and, 'RAR', ligands, treatments])].
[sujeto(['TPT', and, tributyltin, '(', 'TBT)']), verbo([inhibited]), complemento([the, mRNA, expression, of, 'RXRα', and, increased, that, of, 'TRβ'])].
[sujeto(['The', phenotypes, of, malformations]), verbo([induced]), complemento([by, 'TPT', were, similar, to, those, by, 'TBT', and, were, much, different, from, those, by, the, 'RXR', and, 'RAR', ligands])].
[sujeto(['These', results, indicated, that, 'TPT', was, acute, toxic, and, had, high, teratogenicity, to, amphibian, 'embryos,', and, that, 'TPT']), verbo([induced]), complemento([phenotypes, of, malformations])].
[sujeto(['TPT', and, 'TBT', might]), verbo([have]), complemento([a, similar, teratogenic, 'mechanism,', which, seems, not, to, be, mainly, mediated, through, 'RA', signal])].
[sujeto(['Thus,', we, were, interested, in, establishing, what, kind, of, ring, skeleton, is]), verbo([required]), complemento([for, 'RXR-selective', agonistic, activity])].
[sujeto(['Our', previously]), verbo([reported]), complemento(['CsF-promoted', 'Stille', coupling, reaction, was, employed, as, a, key, step, for, the, comprehensive, synthesis, of, 5, and, 6])].
[sujeto(['Retinoids,', vitamin, 'A', 'derivatives,', are, natural, or, synthetic, molecules, with, pleiotropic, 'effects,', which]), verbo([regulate]), complemento([cell, 'differentiation,', proliferation, and, apoptosis])].
[sujeto(['In']), verbo([target]), complemento(['cell,', the, active, natural, metabolites, retinoic, acid, '(', 'RA)', and, 9, -, 'cis-retinoic', acid, are, synthetized, from, retinol, by, a, 'two-step', process, with, intermediate, metabolite, retinaldehyde])].
[sujeto(['In', 1987, ',', the, identification, of, the]), verbo([nuclear]), complemento([retinoic, acid, receptors, that, belong, to, the, superfamily, of, nuclear, receptors, led, to, a, significant, progress, in, the, comprehension, of, the, mechanism, of, action, of, retinoids])].
[sujeto([3, regions, are, of, 'importance:', the, 'A/B', region]), verbo([has]), complemento([a, 'ligand-independent', transcriptional, activation, 'function,', the, 'C', region, harbors, the, 'DNA', binding, 'domain,', the, 'E', region, harbors, the, ligand, binding, domain])].
[sujeto(['To']), verbo([regulate]), complemento([the, expression, of, target, 'genes,', 'NRR', have, to, dimerize])].
[sujeto(['Dimers']), verbo([binds]), complemento([specific, sequences, of, 'DNA,', present, in, the, promoters, of, target, genes])].
[sujeto(['When', the, 'ligand,', natural, or, 'synthetic,']), verbo([bind]), complemento([to, 'RNR,', coactivators, are, recruited, and, transcription, factors, are, activated])].
[sujeto(['In']), verbo([target]), complemento(['cell,', retinoids, not, utilized, are, degradated, in, polar, metabolites, by, enzymes, of, cytochrome, 'P450'])].
[sujeto(['Retinoid', 'X', receptors, '(', 'RXRs)', are, heterodimerization, partners, for, many]), verbo([nuclear]), complemento([receptors, and, also, act, as, homodimers])].
[sujeto([retinoic, acid, receptor, '(', 'RAR)', and, vitamin, 'D', receptor, '(', 'VDR),', can, be]), verbo([activated]), complemento([only, by, the, agonist, of, the, partner, receptor])].
[sujeto([liver, 'X', receptor, '(', 'LXR)', and, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR),', can, be]), verbo([activated]), complemento([by, agonists, for, either, the, partner, receptor, or, 'RXR,', raising, the, possibility, of, pleiotropic, 'RXR', signaling])].
[sujeto(['However,', it, is, not, known, to, what, extent, the, 'receptor\'s', activation, results, in]), verbo([triggering]), complemento([mechanisms, dependent, or, independent, of, permissive, heterodimers])].
[sujeto(['Using', 'pharmacological,', microarray, and, quantitative, 'RT-PCR', 'techniques,', we, identified, and, characterized, gene, sets]), verbo([regulated]), complemento([by, 'RXR', agonists, '(', 'LG100268', and, 9, -, cis, retinoic, 'acid)', and, agonists, for, 'LXRs,', 'PPARs,', 'RARα,', and, 'VDR'])].
[sujeto(['Our', results, demonstrated, that, permissiveness, was, partially, impaired, in, 'Mo-DCs,', because, a, large, number, of, genes]), verbo([regulated]), complemento([by, 'PPAR', or, 'LXR', agonists, was, not, affected, by, 'RXR-specific', agonists, or, was, regulated, to, a, lesser, extent])].
[sujeto(['As', 'expected,', we]), verbo([found]), complemento([that, 'RXR', agonists, regulated, only, small, portions, of, 'RARα', or, 'VDR', targets])].
[sujeto(['Importantly,', we, could, identify, and, characterize, 'PPAR-', and, 'LXR-independent', pathways, in, 'Mo-DCs', most, likely]), verbo([mediated]), complemento([by, 'RXR', homodimers])].
[sujeto(['These', data]), verbo([suggested]), complemento([that, 'RXR', signaling, in, 'Mo-DCs', was, mediated, via, multiple, permissive, heterodimers, and, also, by, 'mechanism(s)', independent, of, permissive, 'heterodimers,', and, it, was, controlled, in, a, 'cell-type', and, 'gene-specific', manner])].
[sujeto(['Nuclear', 'receptors,', such, as, the, retinoic, acid, receptor, '(', 'RAR)', or, the, 9, -, cis, retinoic, acid, receptor, '(', 'RXR),']), verbo([interact]), complemento([not, only, with, their, ligands, but, also, with, other, types, of, receptors, and, with, 'DNA'])].
[sujeto(['After', 'cross-linking,', 'high-mass', 'MALDI', mass, spectra, showed, that, the, 'RAR']), verbo([binds]), complemento([the, single, stranded, 'DR5,', and, the, 'RAR', dimer, binds, both, single, and, double, stranded, 'DR5'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, a, 'gene-regulatory', site, on, 'DNA', can, induce, quaternary, structural, changes, in, a, transcription, factor, such, as, 'RAR'])].
[sujeto(['Chronic', hand, eczema, is, a, significant]), verbo([cause]), complemento([of, morbidity])].
[sujeto(['Retinoids', are, known, to, influence, keratinization, and, 'inflammation,', and, acitretin]), verbo([has]), complemento([shown, some, effect, in, the, treatment, of, chronic, hand, eczema])].
[sujeto(['Alitretinoin', '(', 9, -, 'cis-retinoic', 'acid)', is, a, panagonist, retinoid]), verbo([binding]), complemento([to, all, six, known, retinoid, receptors, '(', 'RAR-alpha,', -, 'beta,', -, gamma, and, 'RXR-alpha,', -, 'beta,', -, 'gamma)'])].
[sujeto(['Several', studies]), verbo([have]), complemento([been, carried, out, with, this, new, 'drug,', and, it, has, been, shown, to, be, effective, in, 28, '%', to, 89, '%', of, patients, with, previously, intractable, hand, eczema])].
[sujeto(['In', 'addition,', alitretinoin, appears, to]), verbo([have]), complemento([some, potential, in, the, treatment, of, 'AIDS-related', 'Kaposi', sarcoma])].
[sujeto(['Attempts', to, use, the, drug, in, secondary, prophylaxis]), verbo([has]), complemento([shown, some, promise, in, former, tobacco, 'smokers,', whereas, no, effect, was, seen, in, patients, with, cervical, intraepithelial, neoplasia])].
[sujeto(['We']), verbo([have]), complemento([recently, proposed, that, retinoic, acid, receptor, '(', 'NR1B)', is, a, promising, target, of, neuroprotective, therapy, for, intracerebral, 'hemorrhage,', since, pretreatment, of, mice, with, an, 'NR1B1/NR1B2', agonist, 'Am80', attenuated, various, pathological, and, neurological, abnormalities, associated, with, the, disease])].
[sujeto(['Daily', oral, administration, of, 'all-trans', retinoic, acid, '(', 'ATRA;', 5, and, 15, 'mg/kg),', a, naturally, occurring, 'NR1B', 'agonist,', from, 1, day, before, collagenase, injection, significantly]), verbo([inhibited]), complemento([loss, of, neurons, within, the, hematoma])].
[sujeto(['ATRA', in, the, same, treatment, regimen, also]), verbo([decreased]), complemento([the, number, of, activated, 'microglia/macrophages', around, the, hematoma, but, did, not, affect, the, hematoma, volume])].
[sujeto(['However,', in, this, 'post-treatment', 'regimen,', only, 'Am80', significantly]), verbo([decreased]), complemento([the, number, of, activated, 'microglia/macrophages'])].
[sujeto(['An', important, model, system, for, studying, the, process]), verbo([leading]), complemento([to, productive, transcription, is, provided, by, the, superfamily, of, nuclear, 'receptors,', which, are, for, the, most, part, 'ligand-controlled', transcription, factors])].
[sujeto(['Over', the, past, years, several, '\'', 'orphan\'']), verbo([nuclear]), complemento([receptors, have, been, isolated, for, which, no, ligand, has, yet, been, identified])].
[sujeto(['Very', little, is, known, about, how, these, '\'', 'orphan\'', receptors]), verbo([regulate]), complemento([transcription])].
[sujeto(['In', this, study, we]), verbo([have]), complemento([analysed, the, biochemical, and, transcriptional, properties, of, the, neuronally, expressed, orphan, nuclear, receptor, 'RORbeta', '(', 'NR1F2)', and, compared, them, with, the, retinoic, acid, receptor, heterodimer, 'RXRalpha-RARalpha', '(', 'NR2B1-NR1B1)', and, 'Gal-VP16', in, vitro])].
[sujeto(['Although', 'RORbeta']), verbo([binds]), complemento([to, its, 'DNA-binding', sites, with, comparatively, low, 'affinity,', it, efficiently, directs, transcription, in, nuclear, extracts, derived, from, a, neuronal, cell, 'line,', 'Neuro2A,', but, not, in, nuclear, extracts, from, 'non-neuronal', 'HeLa', cells])].
[sujeto(['In', 'contrast,', 'RXRalpha-RARalpha', and, the, acidic, transcription, factor, 'Gal-VP16', support, transcription, in, 'Neuro2A', and, 'HeLa']), verbo([nuclear]), complemento([extracts, equally, efficiently])].
[sujeto(['These', observations, point, to, a, different, '(', 'co)factor', requirement, for, transactivation, by, members, of, the, 'NR1', subfamily, of]), verbo([nuclear]), complemento([receptors])].
[sujeto(['In', the, current, 'model,', histone, deacetylases, and, acetyltransferases, are]), verbo([recruited]), complemento([to, chromatin, by, 'DNA-bound', repressors, and, 'activators,', respectively])].
[sujeto([active, chromatin, can]), verbo([lead]), complemento([to, aberrant, gene, transcription, and, cancer])].
[sujeto(['In', human, acute, promyelocytic, leukemia, '(', 'APL)', and, avian, erythroleukemia, '(', 'AEL),', chromosomal, translocations, 'and/or', mutations, in]), verbo([nuclear]), complemento([hormone, 'receptors,', 'RARalpha', '[', 'NR1B1]', and, 'TRalpha', '[', 'NR1A1],', yielded, oncoproteins, that, deregulate, transcription, and, alter, chromatin, structure])].
[sujeto(['The', oncogenic, receptors, are, locked, in, their, '\'', 'off\'', mode, thereby, constitutively]), verbo([repressing]), complemento([transcription, of, genes, that, are, critical, for, differentiation, of, hematopoietic, cells])].
[sujeto(['AEL']), verbo([involves]), complemento([an, oncogenic, version, of, the, chicken, 'TRalpha,', 'v-ErbA'])].
[sujeto(['Apart', from, repression, by, 'v-ErbA', via, recruitment, of, corepressor, 'complexes,', other, repressors, and, corepressors, appear, to, be]), verbo([involved]), complemento([in, repression, of, 'v-ErbA', target, 'genes,', such, as, carbonic, anhydrase, 'II', '(', 'CAII)'])].
[sujeto(['Reactivation', of]), verbo([repressed]), complemento([genes, in, 'APL', and, 'AEL', by, chromatin, modifying, agents, such, as, inhibitors, of, histone, deacetylase, or, of, methylation, provides, new, therapeutic, strategies, in, the, treatment, of, acute, myeloid, leukemia])].
[sujeto(['To', analyze, retinoic, acid, '(', 'RA)', receptor, '(', 'RAR)', expression, during, early, development, in, the, urodele, 'embryo,', we]), verbo([have]), complemento([isolated, cDNAs, for, four, members, of, the, axolotl, '(', 'Ambystoma', 'mexicanum)', 'RAR', 'family,', namely, 'RAR', alpha, '(', 'NR1B1),', aRAR, gamma, 1, '(', 'NR1B3a),', aRAR, gamma, 2, '(', 'NR1B3b),', and, a, new, splicing, variant, of, aRAR, gamma, 2, ',', aRAR, gamma, 3, '(', 'NR1B3c),', which, contains, an, insertion, of, five, hydrophobic, amino, acids, in, the, 'C-terminal', region, of, the, 'DNA', binding, domain])].
[sujeto(['The', expression, of, aRAR, gamma, 2, coincides, with, neurulation, and, is]), verbo([enhanced]), complemento([in, the, extremities, of, the, 'embryo\'s', anteroposterior, axis])].
[sujeto(['The', aRAR, gamma, 3, is, specifically]), verbo([expressed]), complemento([during, gastrulation, and, early, 'neurulation,', whereas, aRAR, gamma, 1, is, expressed, later, during, organogenesis])].
[sujeto(['These', results, show, that, several, 'RARs', are]), verbo([expressed]), complemento([in, the, axolotl, embryo, during, early, 'development,', and, reveal, the, existence, of, a, new, 'RAR', gamma, variant])].
[sujeto(['Co-injecting', synthetic, mRNA, encoding, retinoic, acid, receptor, alpha, '(', 'NR1B1)', and, retinoid, 'X', receptor, beta, '(', 'NR2B2)', results, in, an]), verbo([increase]), complemento([in, the, number, of, primary, neurons, and, this, is, further, enhanced, by, the, addition, of, retinoic, acid, indicating, that, elevated, retinoid, signalling, promotes, an, increase, in, the, number, of, cells, undergoing, primary, neurogenesis])].
[sujeto(['However,', primary, neurogenesis, remains, confined, to, the, three, domains, that, normally, give, rise, to, primary, neurons, indicating, that, not, all, regions, of, the, neurectoderm]), verbo([respond]), complemento([equivalently, to, elevated, retinoid, signalling])].
[sujeto(['The', inhibition, of, retinoid, signalling, with, a, dominant, negative, retinoid, receptor, or, treatment, with, 'citral,', an, inhibitor, of, retinoid, 'metabolism,']), verbo([inhibits]), complemento([the, formation, of, primary, neurons])].
[sujeto(['However,', the, lateral, extent, of, the, neurectoderm, does, not, differ, following, these, experimental, manipulations]), verbo([suggesting]), complemento([that, changes, in, primary, neuron, cell, 'number,', in, response, to, changes, in, retinoid, 'signalling,', cannot, be, accounted, for, by, significant, gains, or, losses, of, neurectoderm])].
[sujeto(['In', 'addition,', two, lines, of, evidence, are, presented, to]), verbo([suggest]), complemento([that, retinoid, signalling, affects, primary, neurogenesis, by, acting, directly, on, the, neurectoderm])].
[sujeto(['First,', animal, caps, neuralized, by, noggin, undergo, primary, neurogenesis, in, response, to, retinoid, signalling, and, second, primary, neurogenesis, is, elevated, in, neural, conjugates, in, which, the, 'ectodermal,', but, not, the, 'mesodermal,', component]), verbo([has]), complemento([been, 'co-injected', with, 'RAR/RXR', mRNA])].
[sujeto([2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dixion', '(', 'TCDD)', is, the, most, potent, of, the, dioxin, 'congeners,', capable, of]), verbo([causing]), complemento([a, wide, range, of, toxic, effects, across, numerous, animal, models])].
[sujeto(['Previous', studies]), verbo([have]), complemento([demonstrated, that, males, and, females, of, the, same, species, can, display, divergent, sensitivity, phenotypes, to, 'TCDD', toxicities])].
[sujeto(['Although', it, is, now, clear, that, most, 'TCDD-induced', toxic, outcomes, are]), verbo([mediated]), complemento([by, the, aryl, hydrocarbon, receptor, '(', 'AHR),', the, mechanism, of, differential, responses, to, 'TCDD', exposure, between, sexes, remains, largely, unknown])].
[sujeto([4, ')', 'A', subset, of, genes, demonstrated, 'sex-dependent', 'TCDD-induced', transcriptional, 'changes,', including, 'Fmo3', and, 'Nr1i3,', which, were, significantly]), verbo([induced]), complemento([in, livers, of, male, mice, only])].
[sujeto(['Sex-dependent', sensitivities, to, 'TCDD', exposure, are]), verbo([associated]), complemento([with, a, set, of, 'sex-specific', 'TCDD-responsive', genes])].
[sujeto(['Advanced', age, '(', 'OR', =, 1.47, '[', 1.01, -, 2.15, ']', ',', p, =, 0.048, ')', and, high, sunitinib, exposure, '(', 'OR', =, 1.16, '[', 1.05, -, 1.28, ']', ',', p, =, 0.005, ')', were, independently]), verbo([associated]), complemento([with, any, grade, '≥', 3, acute, 'toxicity,', and, high, 'SU12662', exposure, was, associated, with, grade, '≥', 2, thrombocytopenia, '(', 'OR', =, 1.27, '[', 1.03, -, 1.57, ']', ',', p, =, 0.028, ')'])].
[sujeto(['A', high, composite, area, under, the, curve, '(', 'AUC)', &, 'gt;1,973', 'ng/mL∙h', at, day, 21, was]), verbo([associated]), complemento([with, a, doubled, survival, '(', 35.2, vs, 16.7, 'months;', 'log-rank', p, =, 0.0051, ')', in, renal, cancer, patients])].
[sujeto(['Considerable', 'inter-individual', variability, in, plasma, concentrations]), verbo([has]), complemento([been, reported])].
[sujeto(['A', population, pharmacokinetic, study, was, performed, including, data, from, 108, patients]), verbo([recruited]), complemento([in, a, naturalistic, setting])].
[sujeto(['Patients', were, genotyped, for, common, polymorphisms, in, renal, cation, transporters, '(', 'SLC22A1/2/5,', 'SLC47A1,', 'ABCB1)', and]), verbo([nuclear]), complemento([receptors, '(', 'NR1I2,', 'NR1I3,', 'RXR,', 'PPAR)', involved, in, transporter, expression])].
[sujeto(['Here,', we]), verbo([have]), complemento([demonstrated, that, xenobiotic, activation, of, the, nuclear, receptor, '(', 'CAR,', 'NR1I3)', can, result, in, arresting, 'DNA-damaged', human, hepatocellular, carcinoma, 'Huh7', cells, at, the, 'G2/M', phase])].
[sujeto(['FACS', analysis, revealed, that, 'CAR-activation', by, 'TCPOBOP']), verbo([increased]), complemento([the, rate, of, arrested, 'Huh7', cells, at, the, 'G2/M', phase, '(', 4, 'N', 'DNA', 'content)', after, 'DNA', damage, by, adriamycin])].
[sujeto(['This']), verbo([increase]), complemento([correlated, with, the, increase, of, cell, viability, in, 'TCPOBOP-treated', 'Huh7', 'cells,', as, determined, by, 'MTT', assays])].
[sujeto(['Real-time', polymerase, chain, reaction, analysis, determined, 'that,', as]), verbo([regulated]), complemento([by, 'CAR,', the, growth, arrest, and, 'DNA', 'damage-inducible', γ, '(', 'GADD45γ)', and, 'Cyclin', 'G2', genes, increased, and, 'decreased,', 'respectively,', as, 'TCPOBOP', increased, the, number, of, 'Huh7', cells, arrested, at, the, 'G2/M', phase])].
[sujeto(['Thus,', the, results]), verbo([suggest]), complemento([that, 'CAR', regulates, cell, 'cycle,', increasing, 'G2/M', 'arrest,', and, delaying, the, death, of, 'DNA-damaged', cells])].
[sujeto(['The', constitutive, androstane, receptor, '(', 'CAR;', 'NR1I3)', is, a, key, transcriptional, factor, that]), verbo([regulates]), complemento([genes, encoding, 'drug-metabolizing', enzymes, and, drug, transporters])].
[sujeto(['However,', studies, on, regulation, of, 'CAR']), verbo([target]), complemento([genes, via, 'up-', or, 'down-regulation', of, 'CAR', are, limited])].
[sujeto(['In', this, 'study,', we, examined, the, effects, of, 'PPARalpha', agonists, '(', 'ciprofibrate,', 'bezafibrate,', fenofibrate, and, 'WY14643)', on, the, expression, of, 'CAR', and, its]), verbo([target]), complemento([gene, 'CYP2B1/2', in, rat, primary, hepatocytes])].
[sujeto(['Results', from, 'real-time', 'PCR', analysis, showed, that, 'CAR', and, 'CYP2B1/2', mRNAs, exhibit]), verbo([increases]), complemento([in, response, to, all, 'PPARalpha', agonists, studied, '(', 5, to, 10, -, folds, of, 'control)'])].
[sujeto(['Pretreatment', of, cells, with, 'cycloheximide,', an, inhibitor, of, protein, 'synthesis,', completely]), verbo([suppressed]), complemento([increase, in, 'CYP2B1/2', mRNA, in, response, to, 'ciprofibrate,', suggesting, that, protein, synthesis, is, required, in, this, process])].
[sujeto(['In', 'addition,', the, induction, of, 'CAR', by, ciprofibrate, on, the, protein, level, was, observed, with]), verbo([nuclear]), complemento([extracts, as, well, as, total, cell, lysates])].
[sujeto(['These', results, indicate, that, 'CYP2B1/2', mRNAs, are]), verbo([induced]), complemento([by, 'PPARalpha', agonists, and, that, this, effect, is, accompanied, by, increase, in, the, expression, of, 'CAR', gene, at, both, mRNA, and, nuclear, protein, levels])].
[sujeto(['Activated', 'PPARalpha', may]), verbo([increase]), complemento([functional, 'CAR', 'protein,', which, can, induce, the, expression, of, 'CAR', target, genes, such, as, 'CYP2B'])].
[sujeto(['To', identify, chromosomal, segments]), verbo([associated]), complemento([with, these, 'traits,', we, intercrossed, 'NZO', mice, with, the, lean, and, 'diabetes-resistant', 'C57BL/6J', '(', 'B6)', strain])].
[sujeto(['Introgression', of, two, segments, of, 'Nob3', into, 'B6', confirmed, the, adipogenic, effect, of, the, 'QTL', and]), verbo([suggested]), complemento([the, presence, of, at, least, one, causal, gene])].
[sujeto(['We', conclude, that, obesity, and, hyperglycemia, of, 'NZO', is, to, a, large, part]), verbo([caused]), complemento([by, variant, genes, located, in, 'Nob3', on, chromosome, 1])].
[sujeto(['Since', these, exert, robust, effects, on, a, 'B6', 'background,', the, 'QTL', 'Nob3', is, a, prime]), verbo([target]), complemento([for, identification, of, a, novel, diabesity, gene])].
[sujeto(['To', identify, a, genetic, 'factor(s)', determining, the, risk, of, 'docetaxel-induced', 'leukopenia/neutropenia,', we, selected, subjects, who, received, docetaxel, chemotherapy, from, samples]), verbo([recruited]), complemento([at, 'BioBank', 'Japan,', and, conducted, a, 'case-control', association, study])].
[sujeto(['We', genotyped, 84, 'patients,', 28, patients, with, grade, 3, or, 4, 'leukopenia/neutropenia,', and, 56, with, no, toxicity, '(', patients, with, grade, 1, or, 2, were, 'excluded),', for, a, total, of, 79, single, nucleotide, polymorphisms, '(', 'SNPs)', in, seven, genes, possibly]), verbo([involved]), complemento([in, the, metabolism, or, transport, of, this, 'drug:', 'CYP3A4,', 'CYP3A5,', 'ABCB1,', 'ABCC2,', 'SLCO1B3,', 'NR1I2,', and, 'NR1I3'])].
[sujeto(['When', patients, were, classified, into, three, groups, by, the, scoring, system, based, on, the, genotypes, of, these, two, 'SNPs,', patients, with, a, score, of, 1, or, 2, were, shown, to]), verbo([have]), complemento([a, significantly, higher, risk, of, 'docetaxel-induced', 'leukopenia/neutropenia', as, compared, to, those, with, a, score, of, 0, '(', 'P', =, 5.7e-6, ;, odds, ratio, '[', 'OR],', 7.0, ;, 95, '%', 'CI', '[', confidence, 'interval],', 2.95, -, 16.59, ')'])].
[sujeto(['This', prediction, system, correctly, classified, 69.2, '%', of, severe, 'leukopenia/neutropenia', and, 75.7, '%', of, 'non-leukopenia/neutropenia', into, the, respective, 'categories,', indicating, that, 'SNPs', in, 'ABCC2', and, 'SLCO1B3', may, predict, the, risk, of, 'leukopenia/neutropenia']), verbo([induced]), complemento([by, docetaxel, chemotherapy])].
[sujeto(['Gugulipid']), verbo([has]), complemento([been, used, for, nearly, 3000, years, in, 'Ayurvedic', 'medicine,', mainly, as, a, treatment, for, arthritis])].
[sujeto(['We', show, herein, that, guggulsterone, treatment]), verbo([represses]), complemento([the, expression, of, cytochrome, 'P450', 2, b10, '(', 'Cyp2b10)', gene, expression, by, inhibiting, constitutive, androstane, receptor, '(', 'CAR;', 'NR1I3)', activity, in, hepatocytes, lacking, functional, 'PXR', '(', 'PXR-knockout)'])].
[sujeto(['Using', mammalian, 'two-hybrid', 'assays,', we, show, that, treatment, with, guggulsterone, differentially, affects, protein, cofactor, recruitment, to, these, two]), verbo([nuclear]), complemento([receptors])].
[sujeto(['These', data, identify, guggulsterone, as, an, inverse, agonist, of, the]), verbo([nuclear]), complemento([receptor, 'CAR'])].
[sujeto(['When', viewed, together, with, the, data, showing, that, 'PXR', and, 'CAR', expression, is, highly, variable, in, different, ethnic, populations, and, that, 'CAR', expression, is, under, the, control, of, a, circadian, 'rhythm,', our, data]), verbo([provide]), complemento([important, insight, into, the, molecular, mechanism, of, interindividual, variability, of, drug, metabolism])].
[sujeto(['The', 'X-ray', crystal, structure, of, the, human, constitutive, androstane, receptor, '(', 'CAR,', 'NR1I3)/retinoid', 'X', receptor, alpha, '(', 'RXRalpha,', 'NR2B1)', heterodimer, sheds, light, on, the, mechanism, of, 'ligand-independent', activation, of, transcription, by]), verbo([nuclear]), complemento([receptors])].
[sujeto(['Helix', 'X', and, 'AF2', sit, atop, four, amino, acids, that, shield, the, 'CAR', ligand]), verbo([binding]), complemento([pocket])].
[sujeto(['A', fatty, acid, ligand, was, identified, in, the, 'RXRalpha']), verbo([binding]), complemento([pocket])].
[sujeto(['The', structure]), verbo([suggests]), complemento([that, upon, 'translocation,', 'CAR/RXRalpha', heterodimers, are, preorganized, in, an, active, conformation, in, cells, such, that, they, can, regulate, transcription, of, target, genes])].
[sujeto(['We', previously]), verbo([reported]), complemento([the, protein, expression, profiles, of, nine, cytochrome, 'P450', isozymes, '(', 'CYPs)', in, pregnant, 'rat\'s', 'liver,', fetal, 'liver,', and, placenta, after, treatment, with, 'pregnenolone-16alpha-carbonitrile', '(', 'PCN),', dexamethasone, '(', 'DEX),', or, phenobarbital, '(', 'PB)'])].
[sujeto(['In', this, 'study,', the, gene, expression, of, 40, 'CYPs', and, 2, orphan]), verbo([nuclear]), complemento([receptors, for, 'CYP', 'inducers,', that, 'is,', 'Nr1i2', '(', 'CYP3A', subfamily, inducible, by, 'PCN)', and, 'Nr1i3', '(', 'CYP2B', subfamily, inducible, by, 'PB),', in, pregnant, 'rat\'s', 'liver,', fetal, 'liver,', and, placenta, was, investigated, at, one, time])].
[sujeto(['Ten', genes, expression, significantly]), verbo([increased]), complemento([in, 'dam\'s', liver, in, 'PCN', 'group,', and, seven, genes, expression, in, 'PB', group])].
[sujeto(['On', the, other, 'hand,', four, genes, expression]), verbo([increased]), complemento([in, fetal, liver, in, 'PCN', 'group,', and, three, genes, expression, increased, in, 'PB', group])].
[sujeto(['Being', common, to, 'dam\'s', and, fetal, 'livers,', the, gene, expression, of, 'Cyp3A1', '(', 'CYP3A', 'subfamily)', and, cytochrome, 'P-450e', '(', 'CYP2B', 'subfamily)']), verbo([increased]), complemento([in, both, 'PCN', and, 'PB', groups])].
[sujeto(['In', 'placenta,', the, expression, of, 'Cyp3A1', gene, was, significantly]), verbo([induced]), complemento([in, 'PB', 'group,', and, it, also, showed, a, tendency, to, increase, in, 'PCN', group])].
[sujeto(['The', results, of, the, present, study, of, 40, 'CYPs', gene, expression, mostly, corresponded, to, our, previous]), verbo([reports]), complemento([on, 9, 'CYPs', protein, expression])].
[sujeto(['Upon', exposure, to, drugs, that]), verbo([induce]), complemento([cytochromes, 'P450', and, other, 'drug-metabolizing', 'enzymes,', 'ALAS1', is, transcriptionally, 'up-regulated,', increasing, the, rate, of, heme, biosynthesis, to, provide, heme, for, cytochrome, 'P450', hemoproteins])].
[sujeto(['We', used, a, combined, in, 'silico-in', vitro, approach, to, identify, sequences, in, the, 'ALAS1', gene, that]), verbo([mediate]), complemento([direct, transcriptional, response, to, xenobiotic, challenge])].
[sujeto(['We']), verbo([have]), complemento([characterized, two, enhancer, 'elements,', located, 20, and, 16, kb, upstream, of, the, transcriptional, start, site])].
[sujeto(['Both', elements]), verbo([respond]), complemento([to, prototypic, inducer, drugs, and, interact, with, the, human, pregnane, 'X', receptor, 'NR1I2', and, the, human, constitutive, androstane, receptor, 'NR1I3'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, the, fundamental, mechanism, of, drug, induction, is, the, same, for, cytochromes, 'P450', and, 'ALAS1'])].
[sujeto(['Although', evidence, regarding, cytogenetic, and, molecular, genetic, alterations, in, hepatoblastomas]), verbo([has]), complemento([been, 'reported,', the, molecular, events, affecting, the, biologic, characteristics, of, this, 'tumor,', including, alterations, of, the, gene, expression, 'profile,', are, largely, unknown])].
[sujeto(['To', identify, genes, differentially]), verbo([expressed]), complemento([between, nondiseased, liver, '(', 'NDL)', and, hepatoblastoma, tumor, '(', 'HBT),', we, analyzed, the, gene, expression, profile, in, 14, 'NDL', and, 16, 'HBT', samples, using, a, 'high-density', oligonucleotide, 'DNA', array])].
[sujeto(['In', the, 26, predictor, 'genes,', we]), verbo([found]), complemento([alteration, of, the, expression, of, genes, regulating, cell, division, '(', 'NAP1L1,', 'STMN1,', 'CCNG2,', and, 'CDC7L1)', and, tumor, cell, growth, '(', 'IGF2', and, 'IGFBP4)', in, 'HBT'])].
[sujeto(['Four', predictor, genes, '(', 'ETV3,', 'TPR,', 'CD34,', and, 'NR1I3)', were, also]), verbo([found]), complemento([to, be, mapped, to, the, chromosomal, region, 1, q21, approximately, 'q32,', which, has, been, reported, to, be, frequently, involved, in, the, development, of, hepatoblastoma])].
[sujeto(['The', findings, obtained, in, this, study]), verbo([suggest]), complemento([that, alteration, of, the, expression, of, some, genes, regulating, cell, division, and, tumor, cell, growth, may, be, characteristics, of, the, gene, expression, profile, in, 'HBT,', and, that, alteration, of, the, expression, of, the, four, predictor, genes, mapped, to, chromosomal, region, 1, q21, approximately, q32, may, also, contribute, to, the, differences, in, gene, expression, profile, between, 'NDL', and, 'HBT'])].
[sujeto(['In', this, 'study,', we, carried, out, 'QTL', analyses, in, '(', 'C57BL/6J', x, 'NZB/BlNJ)', x, 'C57BL/6J', backcross, progeny, fed, either, chow, or, an, atherogenic, diet, to, detect, 'QTLs', that]), verbo([regulate]), complemento(['high-density', lipoprotein, cholesterol, '(', 'HDL)concentrations,', and, in, '(', 'C57BL/6J', x, 'NZB/BlNJ)', 'F11', 'AIL', progeny, to, confirm, and, narrow, those, 'QTLs'])].
[sujeto(['QTLs', for, 'HDL', concentrations, were]), verbo([found]), complemento([on, chromosomes, 1, ',', 5, ',', and, 16])].
[sujeto(['We', tested, 27, candidate, genes, and]), verbo([found]), complemento([significant, mRNA, expression, differences, for, 12, '(', 'Nr1i3,', 'Apoa2,', 'Sap,', 'Tgfb2,', 'Fgfbp1,', 'Prom,', 'Ppargc1,', 'Tcf1,', 'Ncor2,', 'Srb1,', 'App,', and, 'Ifnar)'])].
[sujeto(['All', the, major, 'HDL', 'QTLs', in, our, study, had, homologous, counterparts, in, 'humans,', implying, that, their, underlying, genes]), verbo([regulate]), complemento(['HDL', in, humans])].
[sujeto(['The', 'NR1I', subfamily, of]), verbo([nuclear]), complemento([receptors, contains, a, phylogenetically, diverse, array, of, receptors, related, to, the, mammalian, pregnane, 'X', receptor, '(', 'PXR)', '(', 'NR1I2)', and, constitutive, androstane, receptor, '(', 'CAR)', '(', 'NR1I3)'])].
[sujeto(['We']), verbo([have]), complemento([carried, out, an, extensive, comparative, analysis, of, this, subgroup, with, representatives, from, 'fish,', 'birds,', 'amphibians,', and, mammals])].
[sujeto(['Four', novel, receptors, were, isolated, from, 'fish,', 'dog,', 'pig,', and, monkey, for, this, study, and, combined, with, a, previously]), verbo([reported]), complemento([set, of, related, receptors, including, human, 'PXR,', rabbit, 'PXR,', mouse, 'PXR,', chicken, 'CXR,', frog, benzoate, 'X', receptors, '(', 'BXRalpha,', 'BXRbeta),', and, human, and, mouse, 'CAR'])].
[sujeto(['A', broad, range, of, 'xenobiotics,', 'steroids,', and, bile, acids, were, tested, for, their, ability, to]), verbo([activate]), complemento([the, ligand, binding, domain, of, each, receptor])].
[sujeto(['Three', distinct, groups, of, receptors, were, identified, based, on, their, pharmacological, 'profiles:', 1, ')', the, 'PXRs', were]), verbo([activated]), complemento([by, a, broad, range, of, xenobiotics, 'and,', along, with, the, mammalian, 'PXRs,', included, the, chicken, and, fish, 'receptors;', 2, ')', the, 'CARs', were, less, 'promiscuous,', had, high, basal, 'activities,', and, were, generally, repressed, rather, than, activated, by, those, compounds, that, modulated, their, 'activity;', and, 3, ')', the, 'BXRs', were, selectively, activated, by, a, subset, of, benzoate, analogs, and, are, likely, to, be, specialized, receptors, for, this, chemical, class, of, ligands])].
[sujeto(['Modeling', studies]), verbo([suggest]), complemento([that, the, 'H1-3', insert, contributes, to, the, promiscuity, of, the, 'PXRs', by, facilitating, the, unwinding, of, 'helices-6', and, -, 7, ',', thereby, expanding, the, ligand, binding, pocket])].
[sujeto(['The', barbiturate, phenobarbital]), verbo([induces]), complemento([the, transcription, of, cytochromes, 'P450', '(', 'CYPs)', 2, 'B', through, the, constitutive, androstane, receptor, '(', 'CAR;', 'NR1I3)'])].
[sujeto(['CAR', is, a, member, of, the]), verbo([nuclear]), complemento([receptor, family, '(', 'NR1)', mostly, expressed, in, the, 'liver,', which, heterodimerizes, with, retinoid, 'X', receptor, '(', 'RXR)', and, was, shown, to, transactivate, both, the, phenobarbital, responsive, element, module, of, the, human, 'CYP2B6', gene, and, the, 'CYP3A4', xenobiotic, response, element])].
[sujeto(['Because', previous, studies, in, rodent, hepatocyte, cultures]), verbo([have]), complemento([shown, that, the, 'phenobarbital-mediated', induction, of, 'CYP2B', genes, is, potentiated, by, 'glucocorticoids,', we, examined, the, role, of, activated, glucocorticoid, receptor, in, this, process])].
[sujeto(['We', show, that, submicromolar, concentrations, of, dexamethasone]), verbo([enhance]), complemento(['phenobarbital-mediated', induction, of, 'CYP3A4,', 'CYP2B6,', and, 'CYP2C8', mRNA, in, cultured, human, hepatocytes])].
[sujeto(['In', 'parallel,', we, observed, that, glucocorticoid, 'agonists,', such, as, 'dexamethasone,', 'prednisolone,', or, 'hydrocortisone,', specifically]), verbo([increase]), complemento([human, car, '(', 'hCAR)', mRNA, expression])].
[sujeto(['Moreover,', the, effect, of, dexamethasone, on, hCAR, mRNA, accumulation, appears, to, be, of, transcriptional, origin, because, the, addition, of, protein, synthesis, inhibitor, cycloheximide]), verbo([has]), complemento([no, 'effect,', and, dexamethasone, does, not, affect, the, degradation, of, hCAR, mRNA])].
[sujeto(['Furthermore,', dexamethasone]), verbo([increases]), complemento([both, basal, and, 'phenobarbital-mediated', nuclear, translocation, of, 'CAR', immunoreactive, protein, in, human, hepatocytes])].
[sujeto(['Compound', 3, was]), verbo([found]), complemento([to, be, moderately, active, with, an, 'IC50', of, 33.43, '±4'])].
[sujeto(['We', examined, a, series, of, naproxen, analogues, and]), verbo([find]), complemento([that, '(', 'R)-2-(6-methoxynaphthalen-2-yl)butanoic', acid, '(', in, which, the, methyl, group, of, 'R-naproxen', was, replaced, by, an, ethyl, 'group)', acts, as, a, potent, 'AKR1C3', inhibitor, that, displays, selectivity, for, 'AKR1C3', over, other, 'AKR1C', enzymes])].
[sujeto(['This', compound, was, devoid, of, inhibitory, activity, on, 'COX', isozymes, and, blocked, 'AKR1C3']), verbo([mediated]), complemento([production, of, 'T', and, induction, of, 'PSA', in, 'LNCaP-AKR1C3', cells, as, a, model, of, a, 'CRPC', cell, line])].
[sujeto(['R-Profens', are, substrate, selective, 'COX-2', inhibitors, and, block, the, oxygenation, of, endocannabinoids, and, in, the, context, of, advanced, prostate, cancer, 'R-profens', could]), verbo([inhibit]), complemento([intratumoral, androgen, synthesis, and, act, as, analgesics, for, metastatic, disease])].
[sujeto(['The', serum, 'T', level, was, significantly]), verbo([decreased]), complemento([in, the, rats, of, the, castration, group, as, compared, with, those, of, the, control, and, 'TR', groups, '(', '[', 0.41, ±, 0.04, ']', vs, '[', 16.01, ±, 1.02, ']', and, '[', 15.84, ±, 1.32, ']', 'nmol/L,', 'P', &, 'lt;', 0.01, ')', ',', with, no, statistically, significant, difference, between, the, latter, two, groups])].
[sujeto(['Androgen', deficiency]), verbo([induces]), complemento([significant, reduction, of, 'ICPmax/', 'MAP', in, male, 'rats,', which, is, possibly, associated, with, the, decline, of, 'S1P1', in, the, corpus, 'cavernosum,', inhibition, of, the, 'eNOS/NO/cGMP', signaling, 'pathway,', increased, expressions, of, 'S1P2', and, 'S1P3,', and, activation, of, the, 'RhoA/Rho', kinase, signaling, pathway])].
[sujeto(['Female', pattern, hair]), verbo([loss]), complemento(['(', 'FPHL),', or, androgenic, 'alopecia,', is, the, most, common, type, of, hair, loss, affecting, women])].
[sujeto(['Hair']), verbo([loss]), complemento([can, have, a, serious, psychological, impact, on, women])].
[sujeto(['To', determine, the, efficacy, and, safety, of, the, available, options, for, the, treatment, of, female, pattern, hair]), verbo([loss]), complemento([in, women])].
[sujeto(['Pooled', data, from, six, studies, indicated, that, a, greater, proportion, of, participants, '(', 157, /, 593, ')', treated, with, minoxidil, '(', 2, '%', and, one, study, with, 1, '%', ')']), verbo([reported]), complemento([a, moderate, to, marked, increase, in, their, hair, regrowth, when, compared, with, placebo, '(', 77, /, 555, ')', '(', risk, ratio, '(', 'RR)', =, 1.93, ',', 95, '%', confidence, interval, '(', 'CI)', 1.51, to, 2.47, ;, moderate, quality, 'evidence)'])].
[sujeto(['Only', one, study]), verbo([reported]), complemento([on, quality, of, life, '(', 'QoL)', '(', 260, 'participants),', albeit, inadequately, '(', low, quality, 'evidence)'])].
[sujeto(['There', was, an, important]), verbo([increase]), complemento([of, 13.18, in, total, hair, count, per, 'cm²', in, the, minoxidil, group, compared, to, the, placebo, group, '(', 95, '%', 'CI', 10.92, to, 15.44, ;, low, quality, 'evidence)', in, eight, studies, '(', 1242, 'participants)'])].
[sujeto(['In', one, 'study,', 25, /, 57, participants, in, the, minoxidil, 2, '%', group, experienced, moderate, to, greatly]), verbo([increased]), complemento([hair, regrowth, versus, 22, /, 56, in, the, 5, '%', group, '(', 'RR', 1.12, ',', 95, '%', 'CI', 0.72, to, 1.73, ')'])].
[sujeto(['One', study, assessed, 'QoL', '(', 209, 'participants)', and]), verbo([reported]), complemento([limited, data, '(', low, quality, 'evidence)'])].
[sujeto(['Both', concentrations, did, not, show, a, difference, in]), verbo([increase]), complemento([in, total, hair, count, at, end, of, study, in, three, trials, with, 631, participants, '(', mean, difference, '(', 'MD)', -, 2.12, ',', 95, '%', 'CI', -, 5.47, to, 1.23, ;, low, quality, 'evidence)'])].
[sujeto(['These', studies, did, not, assess, 'QoL', and, did, not]), verbo([report]), complemento([adverse, events, per, treatment, arm, and, only, in, a, generic, way, '(', low, quality, 'evidence)'])].
[sujeto(['Low-level', laser, therapy, against, sham, comparisons, in, two, separate, studies, also, showed, an]), verbo([increase]), complemento([in, total, hair, count, but, with, limited, further, data])].
[sujeto(['Single', studies, addressed, the, other, comparisons, and]), verbo([provided]), complemento([limited, evidence, of, either, the, efficacy, or, safety, of, these, 'interventions,', or, were, unlikely, to, be, examined, in, future, trials])].
[sujeto(['Patients', had, to]), verbo([have]), complemento([a, 'history,', or, be, at, increased, 'risk,', of, cardiovascular, disease])].
[sujeto(['No']), verbo([reported]), complemento([excess, risks, of, pneumonia, '(', 5, '%', in, the, placebo, 'group,', 6, '%', in, the, combination, 'group,', 5, '%', in, the, fluticasone, furoate, 'group,', and, 4, '%', in, the, vilanterol, 'group)', or, adverse, cardiac, events, '(', 17, '%', in, the, placebo, 'group,', 18, '%', in, the, combination, 'group,', and, 17, '%', in, the, fluticasone, furoate, 'group,', and, 17, '%', in, the, vilanterol, 'group)', were, noted, in, the, treatment, groups])].
[sujeto(['Most', guidelines, recommend, either, a, 'long-acting', 'beta-agonist', '(', 'LABA)', plus, an, inhaled, glucocorticoid, or, a, 'long-acting', muscarinic, antagonist, '(', 'LAMA)', as, the, 'first-choice', treatment, for, patients, with, chronic, obstructive, pulmonary, disease, '(', 'COPD)', who]), verbo([have]), complemento([a, high, risk, of, exacerbations])].
[sujeto(['Indacaterol-glycopyrronium', was, more, effective, than, 'salmeterol-fluticasone', in]), verbo([preventing]), complemento(['COPD', exacerbations, in, patients, with, a, history, of, exacerbation, during, the, previous, year])].
[sujeto(['Dupilumab,', a, fully, human, 'anti-interleukin-4', receptor, α, monoclonal, 'antibody,']), verbo([inhibits]), complemento(['interleukin-4', and, 'interleukin-13', 'signalling,', key, drivers, of, 'type-2-mediated', inflammation])].
[sujeto(['Adults', with, uncontrolled, persistent, asthma, who, are, receiving, 'medium-to-high-dose', inhaled, corticosteroids, plus, a, 'long-acting', β2, agonist]), verbo([require]), complemento([additional, treatment, options, as, 'add-on', therapy])].
[sujeto(['In', the, subgroup, with, at, least, 300, eosinophils, per, 'μL,', the, greatest]), verbo([increases]), complemento(['(', 200, mg, every, 2, 'weeks,', 'p=0·0008;', 300, mg, every, 2, 'weeks,', 'p=0·0063)', in, 'FEV1', compared, with, placebo, were, observed, at, week, 12, with, doses, every, 2, weeks, in, the, 300, mg, group, '(', mean, change, 0, '·39', 'L', '[', 'SE', 0, '·05];', mean, difference, 0, '·21', '[', 95, '%', 'CI', 0, '·06-0·36;', 'p=0·0063])', and, in, the, 200, mg, group, '(', mean, change, 0, '·43', 'L', '[', 'SE', 0, '·05];', mean, difference, 0, '·26', '[', 0, '·11-0·40;', 'p=0·0008])', compared, with, placebo, '(', 0, '·18', 'L', '[', 'SE', 0, '·05])'])].
[sujeto(['Similar', significant]), verbo([increases]), complemento([were, observed, in, the, overall, population, and, in, the, fewer, than, 300, eosinophils, per, μL, subgroup, '(', overall, 'population:', 200, mg, every, 2, 'weeks,', 'p&lt;0·0001;', 300, mg, every, 2, 'weeks,', 'p&lt;0·0001;', &, 'lt;300', eosinophils, per, 'μL:', 200, mg, every, 2, 'weeks,', 'p=0·0034;', 300, mg, every, 2, 'weeks,', 'p=0·0086),', and, were, maintained, to, week, 24])].
[sujeto(['Dupilumab']), verbo([increased]), complemento([lung, function, and, reduced, severe, exacerbations, in, patients, with, uncontrolled, persistent, asthma, irrespective, of, baseline, eosinophil, count, and, had, a, favourable, safety, 'profile,', and, hence, in, addition, to, inhaled, corticosteroids, plus, 'long-acting', 'β2-agonist', therapy, could, improve, the, lives, of, patients, with, uncontrolled, persistent, asthma, compared, with, standard, therapy, alone])].
[sujeto(['The', analyses, were, performed, for, the, 1, ')', original, 'dataset,', 2, ')', limited, dataset, with, small, size, for, which, the, number, of, subjects, was]), verbo([decreased]), complemento([to, 'half,', and, 3, ')', limited, dataset, with, 'minimal-sampling', timepoint, of, 9, samples])].
[sujeto(['Compartmental', approaches, can]), verbo([provide]), complemento([a, complementary, method, for, 'BE', 'assessment,', as, well, as, being, used, for, 'restricted-design', studies])].
[sujeto(['Severe', gonadal, steroid, deficiency]), verbo([induces]), complemento([bone, loss, in, adult, 'men;', 'however,', the, specific, roles, of, androgen, and, estrogen, deficiency, in, hypogonadal, bone, loss, are, unclear])].
[sujeto(['Additionally,', the, threshold, levels, of, testosterone, and, estradiol, that, initiate, bone]), verbo([loss]), complemento([are, uncertain])].
[sujeto(['One', hundred, 'ninety-eight', healthy, 'men,', ages, 20, -, 50, ',', received, goserelin, 'acetate,', which]), verbo([suppresses]), complemento([endogenous, gonadal, steroid, 'production,', and, were, randomized, to, treatment, with, 0, ',', 1.25, ',', 2.5, ',', 5, ',', or, 10, grams, of, testosterone, gel, daily, for, 16, weeks])].
[sujeto(['An', additional, cohort, of, 202, men, was, randomized, to, receive, these, treatments, plus, 'anastrozole,', which]), verbo([suppresses]), complemento([conversion, of, androgens, to, estrogens])].
[sujeto(['These']), verbo([increases]), complemento([were, considerably, greater, when, aromatization, of, testosterone, to, estradiol, was, also, 'suppressed,', suggesting, effects, of, both, testosterone, and, estradiol, deficiency])].
[sujeto(['Decreases', in, 'DXA', 'BMD', were, observed, when, aromatization, was]), verbo([suppressed]), complemento([but, were, modest, in, most, groups])].
[sujeto(['Estradiol', levels, above, 10, 'pg/ml', and, testosterone, levels, above, 200, 'ng/dl', were, generally, sufficient, to]), verbo([prevent]), complemento([increases, in, bone, resorption, and, decreases, in, 'BMD', in, men])].
[sujeto(['Estrogens', primarily]), verbo([regulate]), complemento([bone, homeostasis, in, adult, 'men,', and, testosterone, and, estradiol, levels, must, decline, substantially, to, impact, the, skeleton])].
[sujeto(['Case-control', 'study,']), verbo([involving]), complemento([97, women, with, 'PCOS', and, 116, 'age,', 'BMI,', fasting, plasma, glucose, and, insulin, 'levels,', homeostasis, model, 'assessment-insulin', resistance, index, '(', 'HOMA-IR)', matched, controls])].
[sujeto(['To', comprehensively, characterize, androgens, and, androgen, precursors, in, classic, 21, -, hydroxylase, deficiency, '(', 21, 'OHD)', and, to]), verbo([gain]), complemento([insights, into, the, mechanisms, of, their, formation])].
[sujeto(['Only', trace, amounts, of, 11, oxC19, steroids, were]), verbo([found]), complemento([in, the, sera, of, patients, with, 11, 'β-hydroxylase', deficiency, and, adrenal, 'insufficiency,', confirming, their, adrenal, origin])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, 11, oxC19, steroids, are, specific, biomarkers, of, 'adrenal-derived', androgen, excess])].
[sujeto(['Results', from, group, analysis]), verbo([suggested]), complemento([that, high, 'IL-6', levels, in, 'PCOS', were, significantly, associated, with, 'Homeostasis', 'Model', 'Assessment', of, 'Insulin', 'Resistance', '(', 'HOMA2-IR)', ratio, and, total, testosterone, ratio, '(', 'T', 'ratio),', and, was, found, in, both, lean, and, obese, women, with, 'PCOS'])].
[sujeto(['Among', many, possible, 'candidates,', oxidative, stress, may, be, one, of, the, mediators, of, 'neuroprogression,', grey, matter]), verbo([loss]), complemento([and, subsequent, cognitive, and, functional, impairment])].
[sujeto(['They', may]), verbo([act]), complemento([from, directly, scavenging, free, radicals, to, increasing, 'anti-oxidative', defences])].
[sujeto(['As', 'such,', there]), verbo([has]), complemento([been, interest, in, developing, interventions, aimed, at, restoring, this, oxidative, balance, beyond, the, benefits, of, antipsychotics, in, this, direction])].
[sujeto(['If', antioxidants, are, to]), verbo([have]), complemento([a, place, in, the, treatment, of, this, serious, 'condition,', the, relevant, and, 'up-to-date', information, should, be, available, to, clinicians, and, investigators])].
[sujeto(['To', evaluate, the, effect, of, antioxidants, as, 'add-on', treatments, to, standard, antipsychotic, medication, for, improving, acute, psychotic, episodes, and, core, 'symptoms,', and]), verbo([preventing]), complemento([relapse, in, people, with, schizophrenia])].
[sujeto(['We', searched, the, 'Cochrane', 'Schizophrenia', 'Group\'s', 'Study-Based', 'Register', of, 'Trials', which, is, based, on]), verbo([regular]), complemento([searches, of, 'CINAHL,', 'BIOSIS,', 'AMED,', 'Embase,', 'PubMed,', 'MEDLINE,', 'PsycINFO,', and, registries, of, clinical, trials])].
[sujeto(['We', included]), verbo([reports]), complemento([if, they, were, randomised, controlled, trials, '(', 'RCTs)', involving, people, with, schizophrenia, who, had, been, allocated, to, either, a, substance, with, antioxidant, potential, or, to, a, placebo, as, an, adjunct, to, standard, antipsychotic, treatment])].
[sujeto(['Only', three, studies, including, a, minority, of, the, participants]), verbo([reported]), complemento([our, a, priori, selected, primary, outcome, of, clinically, important, response])].
[sujeto(['Studies', usually]), verbo([reported]), complemento([only, endpoint, psychopathology, rating, scale, scores])].
[sujeto(['Three', studies]), verbo([reported]), complemento([useable, data, for, '\'', any, serious, adverse, 'effect\',', results, were, equivocal, '(', 3, 'RCTs,', n, =, 234, ',', 'RR', 0.65, ',', 95, '%', 'CI', 0.19, to, 2.27, ',', low, quality, 'evidence)'])].
[sujeto(['Although', 22, trials, could, be, included, in, this, 'review,', the, evidence]), verbo([provided]), complemento([is, limited, and, mostly, not, relevant, to, clinicians, or, consumers])].
[sujeto(['Overall,', although, there, was, low, risk, of, attrition, and, selective, data]), verbo([reporting]), complemento([bias, within, the, 'trials,', the, trials, themselves, were, not, adequately, powered, and, need, more, substantial, 'follow-up', periods])].
[sujeto(['Radiotherapy', or, radical, hysterectomy, with, 'salpingo-oophorectomy', '(', 'SOE)', as, treatment, for, uterine, cervical, cancer]), verbo([causes]), complemento([estrogen, deprivation, in, premenopausal, women])].
[sujeto(['The', effects, on, androgen, production]), verbo([have]), complemento([rarely, been, examined, but, could, be, relevant, for, survivors, of, cervical, cancer, because, insufficiency, has, been, associated, with, low, sexual, function])].
[sujeto(['In', women, treated, with, radiotherapy, '(', 'n&nbsp;=', 38, ')', ',', median, total, and, free, testosterone, levels, were, significantly]), verbo([decreased]), complemento([at, 1, -, year, 'follow-up', compared, with, baseline, in, premenopausal, women, '(', 'n&nbsp;=', 16, ;, total, 'testosterone&nbsp;-29%,', 'P&nbsp;='])].
[sujeto(['Androstenedione', was]), verbo([decreased]), complemento([in, premenopausal, women, only, and, dehydroepiandrosterone, sulfate, was, decreased, in, postmenopausal, women, only, after, radiotherapy])].
[sujeto(['Female', 'Sexual', 'Function', 'Index', scores, 'lower&nbsp;than', 26.5, in, sexually, active, women, were]), verbo([reported]), complemento([by, 80, '%', 1, year, after, 'radiotherapy,', by, 44, '%', after, hysterectomy, with, 'SOE,', and, by, 40, '%', after, surgery, without, 'SOE,', with, no, significant, differences, compared, with, baseline, values])].
[sujeto(['No', direct, correlation, between, androgen, levels, and, 'Female', 'Sexual', 'Function', 'Index', scores, were]), verbo([found]), complemento([at, 1, -, year, 'follow-up'])].
[sujeto(['Total', and, free, testosterone, levels]), verbo([decreased]), complemento([slightly, but, significantly, after, pelvic, radiotherapy, in, 'pre-', and, postmenopausal, women])].
[sujeto(['The', clinical, importance, of, this]), verbo([decrease]), complemento([is, 'unclear,', but, androgen, levels, were, not, directly, related, to, sexual, function, in, this, pilot, setting])].
[sujeto(['A', brief, historical, background, on, 'Autism', &, 'amp;', some, of, the, important, symptoms]), verbo([associated]), complemento([with, 'Autism', are, summarized])].
[sujeto(['Although', 'Autism', 'Spectrum', 'Disorder', and, 'Alzheimer\'s', disease, are, completely, different, diseases, they]), verbo([have]), complemento([some, similar, biochemical, changes])].
[sujeto(['Most', of, 'Autism', patients, improved, significantly, by, removing, the, source, or]), verbo([preventing]), complemento([intake, of, 'Asbestos,', 'TiO2,', 'Al', &, 'amp;', 'Hg', or, enhancing, urinary, output, of, above, abnormal, substances, &, 'amp;', coexisting, 'infections,', if, treatment, is, given, early])].
[sujeto(['When', 'HPV-16', &, 'amp;', 'HPV-18', 'coexist,', at, triangular, central, area, of, the, top, of, 'head,', in, addition, to, inability, to, 'talk,', severe, neuromuscular, problems, of, lower, extremity, were]), verbo([found]), complemento([to, also, exist])].
[sujeto(['In', addition, the, optimal, doses, of, 'Vitamin', 'D3', and, 'Taurine', may, play, an, important, role, in, the, future, treatment, of, 'Autism,', 'Alzheimer\'s', 'Disease', and, memory, disturbances, by, significantly]), verbo([increasing]), complemento(['Acetylcholine', and, 'DHEA', 'levels,', enhancing, the, excretion, of, toxic, substances, in, the, 'urine,', as, well, as, having, an, anticancer, effect])].
[sujeto(['Most', chemically]), verbo([mediated]), complemento([sexual, communication, in, humans, remains, uncharacterized])].
[sujeto(['Here', we]), verbo([provide]), complemento([the, evidence, to, consider, 4, ',', 16, -, 'androstadien-3-one', '(', 'AND)', as, a, 'man\'s', sexual, pheromone])].
[sujeto(['Our', experiment]), verbo([provides]), complemento([support, for, the, physiological, effect, of, 'AND', on, nasal, airway, resistance, '(', 'Rna)', in, 'women,', as, assessed, by, anterior, rhinomanometry])].
[sujeto(['We']), verbo([found]), complemento([that, 'AND', administration, increased, the, area, of, turbinate, during, the, ovulatory, 'phase,', resulting, in, an, increase, of, 'Rna'])].
[sujeto(['Thus,', we, discovered, that, minute, amounts, of, 'AND,']), verbo([acting]), complemento([through, neuroendocrine, brain, 'control,', regulate, 'Rna', and, consequently, affect, the, sexual, physiology, and, behavior])].
[sujeto(['Fascinatingly,', this]), verbo([finding]), complemento([provides, the, evidence, of, the, preservation, of, chemosexual, communication, in, 'humans,', which, it, has, been, largely, neglected, due, to, its, unconscious, perception, and, concealed, nature])].
[sujeto(['Microsurgical', varicocelectomy, combined, with, aescine, could, improve, sperm, 'quality,', relieve, 'pain,', and]), verbo([prevent]), complemento([complications, occurrence, to, some, extent, compared, with, microsurgical, varicocelectomy])].
[sujeto(['There', are, two, possible, methods, of, activation, for, 'CAR,', direct, ligand]), verbo([binding]), complemento([and, a, 'ligand-independent', 'method,', which, makes, this, a, unique, nuclear, receptor])].
[sujeto(['Both', of, these, mechanisms]), verbo([require]), complemento([translocation, of, 'CAR', from, the, cytoplasm, into, the, nucleus])].
[sujeto(['Interestingly,', 'CAR', is, constitutively, active, in, immortalized, cell, lines, due, to, the, basal]), verbo([nuclear]), complemento([location, of, this, receptor])].
[sujeto(['This', creates, an, important, challenge, in, most, in, vitro, assay, models, because, immortalized, cells, cannot, be, used, without]), verbo([inhibiting]), complemento([the, high, basal, activity])].
[sujeto(['Using', this, 'line,', we, are, able, to, identify, 'activators,', as, well, as, 'deactivators,', of, the, challenging]), verbo([nuclear]), complemento(['receptor,', 'CAR'])].
[sujeto(['The', pregnane, 'X', receptor, '(', 'PXR)', '(', 'PXR/NR1I3)', and, constitutive, androstane, receptor, '(', 'CAR)', '(', 'CAR/NR1I2)', members, of, the]), verbo([nuclear]), complemento([receptor, '(', 'NR)', superfamily, of, 'ligand-regulated', transcription, factors, are, 'well-characterized', mediators, of, xenobiotic, and, 'endocrine-disrupting', chemical, signaling])].
[sujeto(['The', 'Nuclear', 'Receptor', 'Signaling', 'Atlas']), verbo([maintains]), complemento([a, growing, library, of, transcriptomic, datasets, involving, perturbations, of, 'NR', signaling, 'pathways,', many, of, which, involve, perturbations, relevant, to, 'PXR', and, 'CAR', xenobiotic, signaling])].
[sujeto(['Here,', we, generated, a, reference, transcriptome, based, on, the, frequency, of, differential, expression, of, genes, across, 159, experiments, compiled, from, 22, datasets]), verbo([involving]), complemento([perturbations, of, 'CAR', and, 'PXR', signaling, pathways])].
[sujeto(['In', addition, to, the, anticipated, overrepresentation, in, the, reference, transcriptome, of, genes, encoding, components, of, the, xenobiotic, stress, 'response,', the, ranking, of, genes]), verbo([involved]), complemento([in, carbohydrate, metabolism, and, gonadotropin, action, sheds, mechanistic, light, on, the, suspected, role, of, xenobiotics, in, metabolic, syndrome, and, reproductive, disorders])].
[sujeto(['The', reference, xenobiotic, transcriptome, will, be, supplemented, with, additional, future, datasets, to]), verbo([provide]), complemento([the, community, with, a, continually, updated, reference, transcriptomic, dataset, for, 'CAR-', and, 'PXR-mediated', xenobiotic, signaling])].
[sujeto(['The', 'Constitutive', 'Androstane', 'Receptor', '(', 'CAR,', 'NR1I3)']), verbo([has]), complemento([been, newly, described, as, a, regulator, of, energy, metabolism])].
[sujeto(['A', relevant, number, of, studies, using, animal, models, of, obesity]), verbo([suggest]), complemento([that, 'CAR', activation, could, be, beneficial, on, the, metabolic, balance])].
[sujeto(['Pnpla3', is, a, gene, whose, polymorphism, is]), verbo([associated]), complemento([with, the, pathogenesis, of, nonalcoholic, fatty, liver, disease, '(', 'NAFLD)', development])].
[sujeto(['Studying', the, molecular, mechanisms, controlling, 'Pnpla3', gene, 'expression,', we, demonstrated, that, 'CAR', does, not]), verbo([act]), complemento([by, a, direct, regulation, of, 'Pnpla3', transcription, or, via, the, 'Liver', 'X', 'Receptor', but, may, rather, involve, the, transcription, factor, 'Carbohydrate', 'Responsive', 'Element-binding', protein])].
[sujeto(['These', data]), verbo([provide]), complemento([new, insights, into, the, regulation, by, 'CAR', of, glycolytic, and, lipogenic, genes, and, on, pathogenesis, of, steatosis])].
[sujeto(['MRP2', transports, a, wide, range, of, 'substrates,', mainly, organic, anions, conjugated, with, glucuronic, 'acid,', glutathione, and, sulfate, and, its, expression, can, be]), verbo([modulated]), complemento([by, xenobiotics, at, 'transcriptional-', and, 'post-transcriptional', levels])].
[sujeto(['Transcriptional', regulation, is, usually]), verbo([mediated]), complemento([by, a, group, of, nuclear, receptors])].
[sujeto(['The', constitutive, androstane, receptor, '(', 'CAR,', 'NR1I3)', was, also]), verbo([reported]), complemento([to, modulate, 'MRP2', 'expression,', phenobarbital, being, a, typical, activator])].
[sujeto(['Dietary', 'compounds,', including, micronutrients, and, other, natural, 'products,', are, also, capable, of]), verbo([regulating]), complemento([intestinal, 'MRP2', expression, transcriptionally])].
[sujeto(['We']), verbo([have]), complemento([given, them, particular, attention, since, the, composition, of, the, food, ingested, daily, is, not, necessarily, supervised, and, may, result, in, interactions, with, therapeutic, drugs])].
[sujeto(['Unfortunately,', only, few, studies]), verbo([report]), complemento([on, 'drug-drug', or, 'nutrient-drug', interactions, as, a, consequence, of, modulation, of, intestinal, 'MRP2', activity, by, xenobiotics])].
[sujeto(['Nuclear', receptors, 'PXR', '(', pregnane, 'X', 'receptor,', 'NR1I2)', and, 'CAR', '(', constitutive, androstane, 'receptor,', 'NR1I3)', are, key, regulators, of, irinotecan, 'metabolism,', and, 'ligand-dependent', modulation, of, their, activity]), verbo([leads]), complemento([to, significant, 'drug-drug', interactions])].
[sujeto(['After', adjustment, of, the, tests, by, the, 'UGT1A1*28', genotype, and, correction, for, multiple, 'testing,', the, 'A', allele, of, 'NR1I2-rs10934498', was]), verbo([associated]), complemento([with, a, decreased, exposition, and, an, increased, degradation, of, 'SN-38,', the, active, metabolite, '(', 'p&nbsp;=&nbsp;0'])].
[sujeto(['The', risk, of, hematological, toxicity, was]), verbo([associated]), complemento([with, 'NR1I2-rs10934498', and, 'NR1I2-rs2472677', '(', 'p&nbsp;=&nbsp;0'])].
[sujeto(['Our', results]), verbo([reveal]), complemento([for, the, first, time, the, involvement, of, 'NR1I2', in, the, pharmacogenetics, of, irinotecan, and, suggest, that, it, may, help, to, predict, the, toxicity, of, 'low-dose', irinotecan])].
[sujeto(['The', constitutive, androstane, receptor, '(', 'CAR;', 'NR1I3)', is, a, member, of, the]), verbo([nuclear]), complemento([receptor, superfamily, that, functions, as, a, 'xenosensor,', serving, to, regulate, xenobiotic, 'detoxification,', lipid, homeostasis, and, energy, metabolism])].
[sujeto(['MicroRNAs', '(', 'miRNAs)']), verbo([have]), complemento([emerged, as, critical, modulators, of, gene, expression, and, appear, to, impact, many, cellular, 'pathways,', including, those, involved, in, chemical, detoxification, and, liver, tumor, development])].
[sujeto(['Bioinformatic', analyses, and, pathway, evaluations, were, performed]), verbo([leading]), complemento([to, the, identification, of, 51, miRNAs, whose, expression, levels, were, significantly, altered, by, 'TCPOBOP', 'treatment,', including, 'mmu-miR-802-5p', and, 'miR-485-3p'])].
[sujeto(['Ingenuity', 'Pathway', 'Analysis', of, the, differentially]), verbo([expressed]), complemento([microRNAs, revealed, altered, effector, 'pathways,', including, those, involved, in, liver, cell, growth, and, proliferation])].
[sujeto(['A', functional, network, among, 'CAR']), verbo([targeted]), complemento([genes, and, the, affected, microRNAs, was, constructed, to, illustrate, how, 'CAR', modulation, of, microRNA, expression, may, potentially, mediate, its, biological, role, in, mouse, hepatocyte, proliferation])].
[sujeto(['This', article, is, part, of, a, 'Special', 'Issue', 'entitled:', 'Xenobiotic']), verbo([nuclear]), complemento(['receptors:', 'New', 'Tricks', for, 'An', 'Old', 'Dog,', edited, by, 'Dr'])].
[sujeto(['Nuclear', receptor, constitutive, androstane, receptor, '(', 'CAR,', 'NR1I3),', which]), verbo([regulates]), complemento([hepatic, drug, and, energy, metabolisms, as, well, as, cell, growth, and, 'death,', is, sequestered, in, the, cytoplasm, as, its, inactive, form, phosphorylated, at, threonine, 38])].
[sujeto(['CAR', activators, elicit, 'dephosphorylation,', and, nonphosphorylated, 'CAR', translocates, into, the, nucleus, to]), verbo([activate]), complemento([its, target, genes])].
[sujeto(['CAR', was, previously]), verbo([found]), complemento([to, require, p38, 'mitogen-activated', protein, kinase, '(', 'MAPK)', to, transactivate, the, cytochrome, 'P450', 2, 'B', '(', 'CYP2B)', genes])].
[sujeto(['Here', we]), verbo([have]), complemento([demonstrated, that, p38, 'MAPK', forms, a, complex, with, 'CAR,', enables, it, to, bind, to, the, response, 'sequence,', 'phenobarbital-responsive', enhancer, module, '(', 'PBREM),', within, the, 'CYP2B', 'promoter,', and, thus, recruits, 'RNA', polymerase, 'II', to, activate, transcription])].
[sujeto(['Thus,']), verbo([nuclear]), complemento([p38, 'MAPK', exerted, dual, regulation, by, sequentially, activating, and, inactivating, 'CAR-mediated', transcription, through, phosphorylation, of, threonine, 38])].
[sujeto(['The', 'ligand-activated']), verbo([nuclear]), complemento([receptor, pregnane, 'X', receptor, '(', 'PXR,', 'NR1I2)', and, the, constitutive, androstane, receptor, '(', 'CAR,', 'NR1I3)', are, two, master, transcriptional, regulators, of, many, important, drug, metabolizing, enzymes, and, transporter, genes, '(', 'DMET)', in, response, to, xenobiotics, including, many, drugs])].
[sujeto(['The', peroxisome, 'proliferator-activated', receptor, alpha, '(', 'PPARα,', 'NR1C1),', the]), verbo([target]), complemento([of, lipid, lowering, fibrate, 'drugs,', primarily, regulates, fatty, acid, catabolism, and, 'energy-homeostasis'])].
[sujeto(['Recent', research]), verbo([has]), complemento([shown, that, there, are, substantial, overlaps, in, the, regulated, genes, of, these, receptors])].
[sujeto(['For', 'example,', both, 'CAR', and, 'PXR', also]), verbo([modulate]), complemento([the, transcription, of, key, enzymes, involved, in, lipid, and, glucose, metabolism, and, 'PPARα', also, functions, as, a, direct, transcriptional, regulator, of, important, 'DMET', genes, including, cytochrome, 'P450s', 'CYP3A4', and, 'CYP2C8'])].
[sujeto(['The', major, objective, of, this, study, was, to, directly, compare, the, 'genome-wide', transcriptional, changes, elucidated, by, the, activation, of, these, three]), verbo([nuclear]), complemento([receptors, in, primary, human, hepatocytes])].
[sujeto(['Genomewide', mRNA, profiles, determined, with, 'Affymetrix', microarrays, were, analyzed, for, differentially]), verbo([expressed]), complemento([genes, and, metabolic, functions])].
[sujeto(['The', results, confirmed, known, prototype]), verbo([target]), complemento([genes, and, revealed, strongly, overlapping, sets, of, coregulated, but, also, distinctly, regulated, and, novel, responsive, genes, and, pathways])].
[sujeto(['This', article, is, part, of, a, 'Special', 'Issue', 'entitled:', 'Xenobiotic']), verbo([nuclear]), complemento(['receptors:', 'New', 'Tricks', for, 'An', 'Old', 'Dog,', edited, by, 'Dr'])].
[sujeto(['If', tissue]), verbo([loss]), complemento([is, too, 'excessive,', 'however,', liver, failure, will, develop, as, is, known, from, the, 'small-for-size-syndrome', '(', 'SFSS)'])].
[sujeto(['Excessive', tissue]), verbo([loss]), complemento([causing, liver, failure, is, associated, with, deficient, induction, of, 'Car'])].
[sujeto(['Reactivation', of, 'Car', by, an, agonist, normalizes, all, features]), verbo([associated]), complemento([with, experimental, 'SFSS'])].
[sujeto(['Impaired', hepatic, 'Car-Foxm1', signaling]), verbo([provides]), complemento([a, first, molecular, characterization, of, liver, that, fails, to, recover, after, tissue, loss])].
[sujeto(['Our', findings, place, deficient, regeneration, as, a, principal]), verbo([cause]), complemento([behind, the, 'SFSS', and, suggest, 'CAR', agonists, may, bear, clinical, potential, against, liver, failure])].
[sujeto(['The', unique, regenerative, capacity, of, liver]), verbo([has]), complemento([its, natural, limits])].
[sujeto(['Following', tissue]), verbo([loss]), complemento([that, is, too, 'excessive,', such, as, through, extended, resection, in, the, 'clinic,', liver, failure, may, develop])].
[sujeto(['This', is, known, as, 'small-for-size-syndrome', '(', 'SFSS)', and, represents, the, most, frequent]), verbo([cause]), complemento([of, death, due, to, liver, surgery])].
[sujeto(['Here', we, show, that, deficient, induction, of, the, protein, 'Car,', a, central, regulator, of, liver, function, and, 'growth,', is, a]), verbo([cause]), complemento([of, liver, failure, following, extended, 'resection;', reactivation, of, 'Car', through, pharmacological, means, is, sufficient, to, prevent, or, rescue, the, 'SFSS'])].
[sujeto(['Acifluorfen', '(', 'ACI),', a, protoporphyrinogen, oxidase, '(', 'PROTOX)', inhibitor, 'herbicide,']), verbo([promotes]), complemento([the, accumulation, of, protoporphyrin, 'IX', '(', 'PPIX),', and, induces, tumors, in, the, rodent, liver])].
[sujeto(['Porphyria', is, a, risk, factor, for, liver, tumors, in, 'humans;', 'however,', the, specific, mechanisms, through, which, 'ACI']), verbo([induces]), complemento([hepatocarcinogenesis, in, rodents, are, unclear])].
[sujeto(['Dietary', treatment, with, 2500, ppm, 'ACI', for, up, to, 13, weeks]), verbo([increased]), complemento(['Cyp2b10', expression, in, the, livers, of, 'wild-type', '(', 'WT)', 'mice,', but, not, in, 'CAR-knockout', '(', 'CARKO)', mice])].
[sujeto(['Microscopically,', 'ACI', 'treatment-induced', cytotoxic, 'changes,', including, hepatocellular, necrosis, and, 'inflammation,', and]), verbo([caused]), complemento([regenerative, changes, accompanied, by, prolonged, increases, in, the, numbers, of, proliferating, cell, nuclear, 'antigen-positive', hepatocytes, in, 'WT', mice])].
[sujeto(['ACI', treatment, also]), verbo([increased]), complemento([liver, 'PPIX', levels, similarly, in, both, 'genotypes;', 'however,', no, morphological, evidence, of, porphyrin, deposition, was, found, in, hepatocytes, from, either, genotype])].
[sujeto(['Treatment', with, 2500, ppm, 'ACI', for, 26, weeks, after, initiation, with, diethylnitrosamine]), verbo([increased]), complemento([the, incidence, and, multiplicities, of, altered, foci, and, adenomas, in, hepatocytes, from, 'WT', 'mice;', these, effects, were, significantly, reduced, in, 'CARKO', mice])].
[sujeto(['Previous', studies, from, our, laboratory, illustrated, that, 'CAR', activation]), verbo([increases]), complemento([the, formation, of, 4, -, 'OH-CPA;', 'however,', 'CPA', is, rarely, used, clinically, outside, of, combination, therapies])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([developed, a, novel, multiorgan, coculture, system, containing, human, primary, hepatocytes, for, hepatic, 'metabolism,', lymphoma, cells, as, a, model, target, for, 'CHOP,', and, cardiomyocytes, as, a, major, site, of, 'off-target', toxicity, associated, with, this, regimen])].
[sujeto(['We']), verbo([found]), complemento([that, a, selective, human, 'CAR', 'activator,', 'CITCO', '(', 6, -, '(', 4, -, 'chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime),', altered, expression, of, key, 'drug-metabolizing', enzymes, and, transporters, in, human, 'hepatocytes,', which, positively, affects, the, metabolic, profile, of, 'CHOP'])].
[sujeto(['Coadministration', of, 'CITCO', and, 'CHOP', in, the, coculture, model]), verbo([led]), complemento([to, significantly, enhanced, cytotoxicity, in, lymphoma, cells, but, not, in, cardiomyocytes])].
[sujeto(['Importantly,', synergistic, anticancer, effects, were, observed, between, 'CITCO', and, 'CHOP,', in, that, inclusion, of, 'CITCO', alongside, the, 'CHOP', regimen, offers, comparable, antineoplastic, activity, toward, lymphoma, cells, at, significantly, reduced, drug, 'concentrations,', and, the]), verbo([decreased]), complemento(['CHOP', load, attenuates, cardiotoxicity])].
[sujeto(['Overall,', these, findings]), verbo([provide]), complemento([a, potentially, promising, novel, strategy, for, facilitating, 'CHOP-based', chemotherapy])].
[sujeto(['Significant', research, efforts]), verbo([have]), complemento([focused, on, elucidating, the, contribution, of, the, host, genetic, 'variability,', but, only, a, few, markers, have, been, identified, for, use, in, clinical, practice])].
[sujeto(['Several', studies, demonstrated, that, 'PXR', and, 'CAR', activation, can, affect, the, expression, of, genes]), verbo([involved]), complemento([in, 'absorption,', 'distribution,', metabolism, and, excretion, '(', 'ADME)', of, antineoplastic, drugs])].
[sujeto(['Pharmacogenetics', studies, published, up, to, date]), verbo([provide]), complemento([encouraging, even, if, exploratory, results])].
[sujeto(['Because', 'CAR', is, constitutively, active, in, certain, cellular, 'contexts,']), verbo([inhibiting]), complemento(['CAR', might, reduce, 'drug-induced', hepatotoxicity, and, resensitize, 'drug-resistant', cancer, cells, to, chemotherapeutic, drugs])].
[sujeto(['We', recently]), verbo([reported]), complemento([a, novel, 'CAR', 'inhibitor/inverse', agonist, 'CINPA1', '(', 11, ')'])].
[sujeto(['Here,', we]), verbo([have]), complemento([obtained, or, designed, 54, analogs, of, 'CINPA1', and, used, a, 'time-resolved', fluorescence, resonance, energy, transfer, '(', 'TR-FRET)', assay, to, evaluate, their, 'CAR', inhibition, potency])].
[sujeto(['Many', of, the, 54, analogs, showed, 'CAR', inverse, agonistic, activities, higher, than, those, of, 'CINPA1,', which]), verbo([has]), complemento([an, 'IC50', value, of, 687, &, 'nbsp;nM'])].
[sujeto(['Among', 'them,', 72]), verbo([has]), complemento([an, 'IC50', value, of, 11.7, &, 'nbsp;nM,', which, is, about, 59, -, fold, more, potent, than, 'CINPA1', and, over, 10, -, fold, more, potent, than, clotrimazole, '(', an, 'IC50', value, of, 126.9, &, 'nbsp;nM),', the, most, potent, 'CAR', inverse, agonist, in, a, biochemical, assay, previously, reported, by, others])].
[sujeto(['Docking', studies]), verbo([provide]), complemento([a, molecular, explanation, of, the, 'structure-activity', relationship, '(', 'SAR)', observed, experimentally])].
[sujeto(['To', our, 'knowledge,', this, effort, is, the, first, chemistry, endeavor, in, designing, and, identifying, potent, 'CAR', inverse, agonists, based, on, a, novel, chemical, 'scaffold,']), verbo([leading]), complemento([to, 72, as, the, most, potent, 'CAR', inverse, agonist, so, far])].
[sujeto(['To']), verbo([gain]), complemento([insight, into, the, influence, of, 'TFs', on, their, regulatory, 'subpathways,', we, constructed, a, global, 'TF-subpathways', network, '(', 'TSN)', to, analyze, systematically, the, regulatory, effect, of, 'common-motif,', 'common-family,', or, 'common-tissue', 'TFs', on, subpathways])].
[sujeto(['We', performed, cluster, analysis, to, show, that, the, 'common-motif,', 'common-family,', or, 'common-tissue', 'TFs', that]), verbo([regulated]), complemento([the, same, pathway, classes, tended, to, cluster, together, and, contribute, to, the, same, biological, function, that, led, to, disease, initiation, and, progression])].
[sujeto(['We', analyzed, the, 'Jaccard', coefficient, to, show, that, the, functional, consistency, of, subpathways]), verbo([regulated]), complemento([by, the, 'TF', pairs, with, common, 'motif,', common, 'family,', or, common, tissue, was, significantly, greater, than, the, random, 'TF', pairs, at, the, subpathway, 'level,', pathway, 'level,', and, pathway, class, level])].
[sujeto(['For', 'example,', 'HNF4A', '(', hepatocyte]), verbo([nuclear]), complemento([factor, 4, ',', 'alpha)', and, 'NR1I3', '(', nuclear, receptor, subfamily, 1, ',', group, 'I,', member, 3, ')', were, a, pair, of, 'TFs', with, common, 'motif,', common, 'family,', and, common, tissue])].
[sujeto(['They', were]), verbo([involved]), complemento([in, drug, metabolism, pathways, and, were, 'liver-specific', factors, required, for, physiological, transcription])].
[sujeto(['In', 'short,', we, inferred, that, the, cofunctional, subpathways, were]), verbo([regulated]), complemento([by, 'common-motif,', 'common-family,', or, 'common-tissue', 'TFs'])].
[sujeto(['Polychlorinated', biphenyls, '(', 'PCBs)', are, environmental, pollutants]), verbo([associated]), complemento([with, 'non-alcoholic-steatohepatitis', '(', 'NASH),', 'diabetes,', and, obesity])].
[sujeto(['We', previously, demonstrated, that, the, 'PCB', 'mixture,', 'Aroclor', 1260, ',']), verbo([induced]), complemento([steatohepatitis, and, activated, nuclear, receptors, in, a, 'diet-induced', obesity, mouse, model])].
[sujeto(['Pxr']), verbo([repressed]), complemento(['Car', expression, as, evident, by, increased, basal, 'Car/Cyp2b10', expression, in, 'Pxr(-/-)', mice])].
[sujeto(['Both', 'Pxr(-/-)', and, 'Car(-/-)', mice, showed]), verbo([decreased]), complemento([basal, respiratory, exchange, rate, '(', 'RER)', consistent, with, preferential, lipid, metabolism])].
[sujeto(['Aroclor']), verbo([increased]), complemento(['RER', and, carbohydrate, 'metabolism,', associated, with, increased, light, cycle, activity, in, both, 'knockouts,', and, decreased, food, consumption, in, the, 'Car(-/-)', mice])].
[sujeto(['The', 'Aroclor-exposed,', 'Pxr(-/-)', mice, displayed]), verbo([increased]), complemento([gluconeogenic, gene, expression])].
[sujeto(['Lipid-oxidative', gene, expression, was, higher, in, 'WT', and, 'Pxr(-/-)', mice, although, 'RER', was, not, 'changed,']), verbo([suggesting]), complemento(['PCB-mediated', mitochondrial, dysfunction])].
[sujeto(['Therefore,', 'Pxr', and, 'Car']), verbo([regulated]), complemento(['inflammation,', 'behavior,', and, energy, metabolism, in, 'PCB-mediated', 'NASH'])].
[sujeto(['Constitutive', androstane, receptor, '(', 'CAR)', encoded, by, the]), verbo([nuclear]), complemento([receptor, subfamily, 1, ',', group, 'I,', member, 3, '(', 'NR1I3)', gene, regulates, the, elimination, of, bilirubin, through, activating, the, components, of, the, bilirubin, clearance, pathway])].
[sujeto(['Thus', 'far,', research, which, investigates, the, association, between, 'NR1I3', variants, and, neonatal, hyperbilirubinemia]), verbo([has]), complemento([not, been, undertaken, in, any, population])].
[sujeto(['This', study, demonstrates, that, the, homozygous, variant, genotype, of, 'MPJ6_1I3008', was]), verbo([associated]), complemento([with, a, significant, reduced, risk, of, neonatal, hyperbilirubinemia, in, the, females])].
[sujeto(['Differences', in, xenobiotic, selectivity, between, the, human, and, rodent, receptors, are, well]), verbo([recognized]), complemento([but, there, is, lack, of, such, information, on, properties, of, 'CAR', and, 'PXR', in, important, domestic, animals])].
[sujeto(['Our', findings]), verbo([have]), complemento([implications, for, regulation, of, 'drug-metabolizing', enzymes, and, transporters, and, pharmacokinetics, in, cattle, and, pigs])].
[sujeto(['This', snapshot, reviews, the, current, state, of, knowledge, on, genetic, variants, of]), verbo([nuclear]), complemento([receptors, '(', 'NRs)', involved, in, regulating, various, aspects, of, liver, metabolism])].
[sujeto(['Interindividual', differences, in, responses, to, diet, and, other, '\'', 'in-\'', and, environmental, stressors, can, be]), verbo([caused]), complemento([by, variants, in, components, of, the, 'NR', regulatory, gene, network])].
[sujeto(['In', 'particular,', 'NR1H4', variants]), verbo([have]), complemento([been, associated, with, intrahepatic, cholestasis, of, pregnancy, and, gallstone, disease])].
[sujeto(['Associations', of, 'NR', gene, variants]), verbo([have]), complemento([been, identified, in, patients, with, dyslipidemia, and, other, metabolic, 'syndrome-associated', traits, by, 'genome-wide', studies])].
[sujeto(['The', constitutive, androstane, receptor, '(', 'CAR,', 'NR1I3)', plays, a, key, role, in, governing, the, transcription, of, numerous, hepatic, genes, that]), verbo([involve]), complemento([xenobiotic, 'metabolism/clearance,', energy, 'homeostasis,', and, cell, proliferation])].
[sujeto(['Thus,', identification, of, novel, human, 'CAR', '(', 'hCAR)', modulators, may, not, only]), verbo([enhance]), complemento([early, prediction, of, 'drug-drug', interactions, but, also, offer, potentially, novel, therapeutics, for, diseases, such, as, metabolic, disorders, and, cancer])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([generated, a, double, stable, cell, line, expressing, both, hCAR, and, a, 'CYP2B6-driven', luciferase, reporter, for, quantitative, 'high-throughput', screening, '(', 'qHTS)', of, hCAR, modulators])].
[sujeto(['Activators', '(', 115, ')', and, deactivators, '(', 152, ')', of, hCAR, were, identified, from, the, primary, 'qHTS,', among, which, 10, agonists, and, 10, antagonists, were, further, validated, in, the, physiologically, relevant, human, primary, hepatocytes, for, 'compound-mediated', hCAR]), verbo([nuclear]), complemento([translocation, and, target, gene, expression])].
[sujeto(['Collectively,', our, results]), verbo([reveal]), complemento([that, hCAR, modulators, can, be, efficiently, identified, through, this, newly, established, qHTS, assay])].
[sujeto(['Profiling', drug, collections, for, hCAR, activity, would, facilitate, the, prediction, of, 'metabolism-based', 'drug-drug', 'interactions,', and, may]), verbo([lead]), complemento([to, the, identification, of, potential, novel, therapeutics])].
[sujeto(['The', human, constitutive, androstane, receptor, '(', 'hCAR;', 'NR1I3)', is, a, member, of, the]), verbo([nuclear]), complemento([receptor, superfamily])].
[sujeto(['The', activity, of, hCAR, is]), verbo([regulated]), complemento([by, a, variety, of, xenobiotics, including, clotrimazole, and, acetaminophen, metabolites])].
[sujeto(['hCAR,', in, 'turn,']), verbo([regulates]), complemento([a, number, of, genes, responsible, for, xenobiotic, metabolism, and, transport, including, several, cytochrome, 'P450s', '(', 'CYP', 2, 'B5,', 2, 'C9,', and, 3, 'A4)', and, the, multidrug, 'resistance-associated', protein, 2, '(', 'MRP2,', 'ABCC2)'])].
[sujeto(['Both', hCAR2, and, hCAR3, mRNAs, are]), verbo([expressed]), complemento([in, a, pattern, similar, to, the, initially, described, 'MB67', '(', 'hCAR1)', with, some, key, distinctions])].
[sujeto(['Analysis', of, the, activity, of, these, variants, indicates, that, both, hCAR2, and, hCAR3, lose, the, ability, to]), verbo([heterodimerize]), complemento([with, 'RXR', and, lack, transactivation, activity, in, cotransfection, experiments, where, either, 'full-length', receptor, or, 'GAL4', 'DNA-binding', 'domain/CAR', ligand, binding, domain, chimeras, were, utilized])].
[sujeto(['Although', the, role, of, hCAR2, and, hCAR3, is, currently, 'unclear,', these, additional, splice, variants, may]), verbo([provide]), complemento([for, increased, diversity, in, terms, of, responsiveness, to, xenobiotics])].
[sujeto(['We']), verbo([have]), complemento([identified, a, new, murine, orphan, member, of, the, nuclear, hormone, receptor, 'superfamily,', termed, 'mCAR,', that, is, closely, related, to, the, previously, described, human, orphan, 'MB67,', referred, to, here, as, hCAR])].
[sujeto(['In', addition, to, the, most, abundant, mCAR1, 'isoform,', the, mCAR, gene]), verbo([expresses]), complemento([a, truncated, mCAR2, variant, that, is, missing, the, 'C-terminal', portion, of, the, ligand, 'binding/dimerization', domain])].
[sujeto(['The', mCAR, gene]), verbo([has]), complemento([8, 'introns,', and, this, mCAR2, variant, is, generated, by, a, splicing, event, that, skips, the, 8, th, exon])].
[sujeto(['mCAR1,', like, 'hCAR,']), verbo([binds]), complemento([as, a, heterodimer, with, the, retinoid, 'X', receptor, to, the, retinoic, acid, response, element, from, the, promoter, of, the, retinoic, acid, receptor, beta2, isoform])].
[sujeto(['Consistent', with, its, lack, of, a, critical, heterodimerization, 'interface,', the, mCAR2, variant, does, not]), verbo([bind]), complemento([this, site])].
[sujeto(['This', activity, is, dependent, on, the, presence, of, the]), verbo([conserved]), complemento(['C-terminal', 'AF-2', transcriptional, activation, motif])].
[sujeto(['As', expected, from, its, inability, to]), verbo([bind]), complemento(['DNA,', the, mCAR2, variant, neither, transactivates, by, itself, nor, inhibits, transactivation, by, hCAR, or, mCAR1])].
[sujeto(['Recent', evidence]), verbo([suggests]), complemento([that, this, large, protease, has, more, specific, functions, in, a, number, of, important, cellular, 'processes,', ranging, from, activation, of, the, transcription, factor, 'NFkB', and, antigen, processing, to, transit, through, mitosis])].
[sujeto(['We']), verbo([have]), complemento([identified, a, component, of, the, 26, 'S', proteasome, that, interacts, specifically, with, 'MB67,', an, orphan, member, of, the, nuclear, hormone, receptor, superfamily])].
[sujeto(['MIP224', '(', 'MB67']), verbo([interacting]), complemento(['protein)', was, isolated, using, the, yeast, two, hybrid, system, and, is, apparently, identical, to, the, human, 26, 'S', proteasome, component, 'TBP7'])].
[sujeto(['MIP224/TBP7', is, one, of, several, proteasomal, proteins, that, share, a, strongly]), verbo([conserved]), complemento(['ATPase', domain, '(', 'CAD)', which, is, also, present, in, a, rapidly, expanding, superfamily, of, proteins, with, diverse, functions])].
[sujeto(['In', 'yeast,', 'MIP224']), verbo([interacts]), complemento([specifically, with, 'MB67', and, another, closely, related, orphan, 'receptor,', but, does, not, interact, with, several, other, receptor, superfamily, members, tested])].
[sujeto(['In', mammalian, 'cells,', coexpression, of, 'MIP224']), verbo([inhibits]), complemento([transactivation, by, 'MB67'])].
[sujeto(['MIP224', also]), verbo([interacts]), complemento([in, yeast, with, other, 'CAD', 'proteins,', including, 'MSS1,', which, is, 'proteasomal,', and, 'TRIP1,', which, is, associated, with, transcriptional, activation])].
[sujeto(['This', interaction, of, a, proteasomal, protein, with, a, transcriptional, protein]), verbo([suggests]), complemento([a, previously, unexpected, link, between, the, processes, of, protein, degradation, and, transcriptional, regulation])].
[sujeto(['We']), verbo([have]), complemento([identified, and, characterized, a, new, orphan, member, of, the, nuclear, hormone, receptor, 'superfamily,', called, 'MB67,', which, is, predominantly, expressed, in, liver])].
[sujeto(['MB67']), verbo([binds]), complemento([and, transactivates, the, retinoic, acid, response, elements, that, control, expression, of, the, retinoic, acid, receptor, beta, 2, and, alcohol, dehydrogenase, 3, 'genes,', both, of, which, consist, of, a, direct, repeat, hexamers, related, to, the, consensus, 'AGGTCA,', separated, by, 5, bp])].
[sujeto(['MB67']), verbo([binds]), complemento([these, elements, as, a, heterodimer, with, the, 9, -, 'cis-retinoic', acid, 'receptor,', 'RXR'])].
[sujeto(['However,', 'MB67', does, not]), verbo([bind]), complemento([or, activate, other, retinoic, acid, response, elements, with, alternative, hexamer, arrangements, or, any, of, several, other, 'wild-type', and, synthetic, hormone, response, elements, examined])].
[sujeto(['The', transactivation, of, retinoic, acid, response, elements, by, 'MB67', is, weaker, than, that]), verbo([conferred]), complemento([by, the, retinoic, acid, receptors, but, does, not, require, the, presence, of, 'all-trans', retinoic, 'acid,', 9, -, 'cis-retinoic', 'acid,', or, any, exogenously, added, ligand])].
[sujeto(['Regulation', of, gene, transcription, is, controlled, in, part, by]), verbo([nuclear]), complemento([receptors, that, function, coordinately, with, coregulator, proteins])].
[sujeto(['The', human, constitutive, androstane, receptor, '(', 'CAR;', 'NR1I3)', is]), verbo([expressed]), complemento([primarily, in, liver, and, regulates, the, expression, of, genes, involved, in, xenobiotic, metabolism, as, well, as, 'hormone,', 'energy,', and, lipid, homeostasis])].
[sujeto(['In', this, 'report,', 'DAX-1,', a]), verbo([nuclear]), complemento([receptor, family, member, with, corepressor, 'properties,', was, identified, as, a, potent, 'CAR', regulator])].
[sujeto(['Deletion', of, 'DAX-1\'s', 'C-terminal', transcription, silencing, domain, restored, 'CAR1', transactivation, activity, in, reporter, assays, to, approximately, 90, '%', of, 'control,', demonstrating, its, critical, function, in]), verbo([mediating]), complemento([the, 'CAR', repression, activities])].
[sujeto(['Furthermore,', results, obtained, from, mammalian, 'two-hybrid', experiments, assessing, various, domain, configurations, of, the, respective, receptors, showed, that, 'full-length', 'DAX-1']), verbo([inhibited]), complemento([the, 'CAR-SRC1', interaction, by, approximately, 50, '%', ',', whereas, the, same, interaction, was, restored, to, 90, '%', of, control, when, the, 'DAX-1', transcription, silencing, domain, was, deleted])].
[sujeto(['Direct', interaction, between, 'CAR', and, 'DAX-1', was, demonstrated, with, both, 'alpha-screen', and, coimmunoprecipitation, 'experiments,', and, this, interaction, was]), verbo([enhanced]), complemento([in, the, presence, of, the, 'CAR', activator, 6, -, '(', 4, -, 'chlorophenyl)imidazo[2,1-b]thiazole-5-carbaldehyde', 'O-(3,4-dichlorobenzyl)oxime', '(', 'CITCO)'])].
[sujeto(['Results', obtained, in, primary, human, hepatocytes, further, demonstrated, 'DAX-1', inhibition, of, 'CAR-mediated', 'CITCO', induction, of, the, 'CYP2B6']), verbo([target]), complemento([gene])].
[sujeto(['The', results, of, this, investigation, identify, 'DAX-1', as, a, novel, and, potent, 'CAR', corepressor, and]), verbo([suggest]), complemento([that, 'DAX-1', functions, as, a, coordinate, hepatic, regulator, of, 'CAR\'s', biological, function])].
[sujeto(['The', constitutive, androstane, receptor, '(', 'CAR;', 'NR1I3)', is, a, member, of, the]), verbo([nuclear]), complemento([receptor, superfamily, and, functions, as, an, important, xenochemical, sensor, and, transcriptional, modulator, in, mammalian, cells])].
[sujeto(['Upon', chemical, 'activation,', 'CAR', undergoes]), verbo([nuclear]), complemento([translocation, and, heterodimerization, with, the, retinoid, 'X', receptor, subsequent, to, its, 'DNA', target, interaction])].
[sujeto(['CAR', is, unusual, among]), verbo([nuclear]), complemento([receptors, in, that, it, possesses, a, high, level, of, constitutive, activity, in, 'cell-based', 'assays,', obscuring, the, detection, of, ligand, activators])].
[sujeto(['In', 'addition,', 'CAR3', is]), verbo([activated]), complemento([by, ligands, with, similar, specificity, as, the, reference, form, of, the, receptor])].
[sujeto(['The', results, demonstrate, that, the, 5, -, amino, acid, insertion, that, typifies, human, 'CAR3', also, imparts, 'ligand-activated', receptor, function, in, other, 'species\'', 'CAR', while]), verbo([maintaining]), complemento([signature, responses, in, each, species, to, select, 'CAR', ligands])].
[sujeto(['The', constitutive, androstane, receptor, '(', 'CAR)']), verbo([mediates]), complemento([the, hepatic, induction, of, various, xenobiotic, metabolizing, enzymes, and, transporters, after, specific, chemical, exposures])].
[sujeto(['Recent']), verbo([reports]), complemento([have, established, the, existence, of, several, human, 'CAR', mRNA, splice, 'variants,', including, a, prominently, expressed, form, termed, 'CAR3,', a, receptor, that, possesses, a, 5, amino, acid, insertion, within, its, ligand, binding, domain])].
[sujeto(['The', transactivation, response]), verbo([requires]), complemento([the, 'DNA', binding, domain, and, 'AF-2', motif, of, 'CAR3', and, is, markedly, enhanced, by, retinoid, 'X', 'receptor-alpha', '(', 'RXR)', cotransfection])].
[sujeto(['The', stimulatory, effects, of, 'RXR']), verbo([involve]), complemento([a, unique, 'mechanism,', because, they, were, completely, dependent, on, the, 'RXR', 'AF-2', function, but, independent, of, both, the, 'RXR', 'A/B', domain, and, its, 'C', 'domain/heterodimerization', region])].
[sujeto(['Mammalian', 'two-hybrid', results, demonstrated, that, 'RXR']), verbo([enhanced]), complemento(['CITCO-dependent', interaction, of, 'CAR3', with, the, receptor, interaction, domain, of, 'SRC-1,', indicating, that, 'RXR', augments, 'CAR3', activity, by, facilitating, coactivator, recruitment])].
[sujeto(['Furthermore,', results, of, transfection, assays]), verbo([reveal]), complemento([that, 'CAR3', is, capable, of, transactivating, the, natural, 'CYP2B6', and, 'CYP3A4', gene, 'enhancers,', exhibiting, both, 'ligand-', and, 'RXR-dependence'])].
[sujeto(['These', results, demonstrate, that, 'CAR3,', unlike, 'CAR1,', is, a, 'ligand-activated', receptor, and, that, 'CAR3', may]), verbo([regulate]), complemento([gene, expression, in, vivo, in, a, manner, distinct, from, the, reference, form, of, the, receptor])].
[sujeto(['Widespread', resistance, to, antimalarial, drugs]), verbo([requires]), complemento([combination, therapies, with, increasing, risk, of, pharmacokinetic, 'drug-drug', interactions])].
[sujeto(['Here,', we, explore, the, capacity, of, antimalarial, drugs, to]), verbo([induce]), complemento([drug, metabolism, via, activation, of, constitutive, androstane, receptors, '(', 'CAR)', by, ligand, binding])].
[sujeto(['A', total, of, 21, selected, antimalarials, and, 11, major, metabolites, were, screened, for]), verbo([binding]), complemento([to, 'CAR', isoforms, using, cellular, and, in, vitro, 'CAR-coactivator', interaction, 'assays,', combined, with, in, silico, molecular, docking])].
[sujeto(['Only', two, artemisinin, derivatives, arteether, and, 'artemether,', the, metabolite, deoxyartemisinin, and, artemisinin, itself, demonstrated, agonist]), verbo([binding]), complemento([to, the, major, isoforms, 'CAR1', and, 'CAR3,', while, arteether, and, artemether, were, also, inverse, agonists, of, 'CAR2'])].
[sujeto(['Dihydroartemisinin', and, artesunate]), verbo([acted]), complemento([as, weak, inverse, agonists, of, 'CAR1'])].
[sujeto(['While', arteether, showed, the, highest, activities, in, 'vitro,', it, was, less, active, than, artemisinin, in]), verbo([inducing]), complemento([hepatic, 'CYP3A4', gene, expression, in, hepatocytes])].
[sujeto(['This', negates, a, common, effect, of, these, drugs, on, 'CAR/PXR-dependent', induction, of, drug, metabolism, and, further]), verbo([provides]), complemento([an, explanation, for, artemisinin, consistently, inducing, cytochrome, 'P450', genes, in, 'vivo,', whereas, arteether, and, artemether, do, not])].
[sujeto(['For', better, understanding, of, pharmacokinetic, 'drug-drug', interaction, 'possibilities,', the]), verbo([inducing]), complemento([properties, of, artemisinin, metabolites, should, be, considered])].
[sujeto(['Activation', of, 'CAR,', pregnane, 'X', receptor, '(', 'PXR),', and, aryl, hydrocarbon, receptor, by, 'CPA', and, 'IFO', was, assessed, in, 'cell-based', reporter, assays, in, 'HepG2', cells, 'and/or']), verbo([nuclear]), complemento([translocation, assays, in, 'HPHs'])].
[sujeto(['CYP2B6', reporter, activity, was, significantly]), verbo([enhanced]), complemento([by, 'CPA', and, 'IFO', in, 'HepG2', cells, 'co-transfected', with, 'CYP2B6', reporter, plasmid, and, a, 'chemical-responsive', human, 'CAR', variant, '(', 'CAR1', +, 'A)', construct])].
[sujeto(['Real-time', 'RT-PCR', and, 'Western', blotting, analysis, in, 'HPHs', showed, that, both, 'CPA', and, 'IFO']), verbo([induced]), complemento([the, expressions, of, 'CYP2B6', and, 'CYP3A4'])].
[sujeto(['Notably,', treatment, of, 'HPHs', with, 'CPA', but, not, 'IFO', resulted, in, significant]), verbo([nuclear]), complemento([accumulation, of, 'CAR,', which, represents, the, initial, step, of, 'CAR', activation])].
[sujeto(['Further', studies, in, 'HPHs', demonstrated, that, selective, inhibition, of, 'PXR', by, sulforaphane, preferentially]), verbo([repressed]), complemento(['IFO-', over, 'CPA-mediated', induction, of, 'CYP2B6'])].
[sujeto(['These', results]), verbo([provide]), complemento([novel, insights, into, the, differential, roles, of, 'CAR', in, the, regulation, of, 'CPA-', and, 'IFO-induced', 'DME', expression, and, potential, 'drug-drug', interactions])].
[sujeto(['Constitutive', androstane, receptor, '(', 'CAR)', and, pregnane, 'X', receptor, '(', 'PXR)']), verbo([regulate]), complemento([xenobiotic, sensing, and, metabolism, through, interactions, with, multiple, exogenous, and, endogenous, chemicals])].
[sujeto(['Compounds', that]), verbo([activate]), complemento(['CAR', are, often, ligands, of, 'PXR;', attention, is, therefore, given, to, discovery, of, 'new,', 'receptor-specific', chemical, entities, that, may, be, exploited, for, therapeutic, and, basic, research, purposes])].
[sujeto(['Recently,', ligands, of, the, peripheral, benzodiazepine, receptor, '(', 'PBR),', 'PK11195', and, 'FGIN-1-27,', were, shown, to]), verbo([modulate]), complemento([both, 'CAR', and, 'PXR'])].
[sujeto(['To', investigate, possible, new, roles, for, 'PBR', involvement, in, metabolic, 'regulation,', expression, of, the, 'CAR', and, 'PXR']), verbo([target]), complemento(['genes,', 'CYP2B6', and, 'CYP3A4,', was, measured, in, human, hepatocytes, following, treatment, with, a, targeted, 'PBR', ligand, set])].
[sujeto(['Luciferase', reporter, assays, with, transiently]), verbo([expressed]), complemento(['wild-type', 'CAR', '(', 'CAR1),', splice, variant, 'CAR3,', or, 'PXR', in, 'HuH-7', cells, were, used, to, further, study, activation, of, these, receptors])].
[sujeto(['Four', structurally, related, 'PBR', ligands, '(', 'benzothiazepines)', differentially]), verbo([modulate]), complemento(['CAR1,', 'CAR3', and, 'PXR', activity])].
[sujeto(['Benzothiazepine', 'NF49', is, an, agonist, ligand, of, 'CAR3,', a, partial, agonist, of, 'PXR,', exhibits, greater, inverse, agonist, activity, on, 'CAR1', than, does, 'PK11195,', and, is, a, new, tool, for, studying, these, closely, related]), verbo([nuclear]), complemento([receptors])].
[sujeto(['Constitutive', androstane, receptor, '(', 'CAR)', and, pregnane, 'X', receptor, '(', 'PXR)', are, closely, related, orphan]), verbo([nuclear]), complemento([receptor, proteins, that, share, several, ligands, and, target, overlapping, sets, of, genes, involved, in, homeostasis, and, all, phases, of, drug, metabolism])].
[sujeto(['CAR', and, 'PXR', are]), verbo([involved]), complemento([in, the, development, of, certain, 'diseases,', including, 'diabetes,', metabolic, syndrome, and, obesity])].
[sujeto(['Ligand', screens, for, these, receptors, so, far]), verbo([have]), complemento([typically, focused, on, steroid, hormone, analogs, with, 'pharmacophore-based', 'approaches,', only, to, find, relatively, few, new, hits])].
[sujeto(['Multiple', 'CAR', isoforms]), verbo([have]), complemento([been, detected, in, human, 'liver,', with, the, most, abundant, being, the, constitutively, active, 'reference,', 'CAR1,', and, the, 'ligand-dependent', isoform, 'CAR3'])].
[sujeto(['It']), verbo([has]), complemento([been, assumed, that, any, compound, that, binds, 'CAR1', should, also, activate, 'CAR3,', and, so, 'CAR3', can, be, used, as, a, 'ligand-activated', surrogate, for, 'CAR1', studies])].
[sujeto(['The', possibility, of, 'CAR3-specific', ligands]), verbo([has]), complemento(['not,', so, 'far,', been, addressed])].
[sujeto(['This', work]), verbo([provides]), complemento([evidence, for, new, 'CAR', 'ligands,', some, of, which, have, 'CAR3-specific', 'effects,', and, provides, observational, data, on, 'CAR', and, 'PXR', ligands, with, which, to, inform, in, silico, strategies])].
[sujeto(['The', human, constitutive, androstane, receptor, '(', 'CAR,', 'CAR1)']), verbo([regulates]), complemento([the, expression, of, genes, involved, in, xenobiotic, metabolism, in, the, liver])].
[sujeto(['The', 'CAR', gene, uses, multiple, alternative, splicing, events, during, 'pre-mRNA', 'processing,', thereby]), verbo([enhancing]), complemento([the, 'CAR', transcriptome])].
[sujeto(['Previous']), verbo([reports]), complemento([have, identified, two, prominent, human, 'CAR', 'variants,', 'CAR2', and, 'CAR3,', that, possess, 'four-', and, 'five-amino', acid, insertions, in, their, ligand, binding, 'domains,', respectively])].
[sujeto(['Results', from, reporter, transactivation, and, mammalian, 'two-hybrid', assays]), verbo([reveal]), complemento([that, 'DEHP', activates, 'CAR2', at, low, nanomolar, 'concentrations,', results, further, supported, by, analysis, of, 'CAR', target, gene, expression, in, primary, human, hepatocytes])].
[sujeto(['The', discovery, that, 'CAR2', is, an, ultimate, human, 'DEHP', receptor, identifies, a, novel, pathway]), verbo([modulating]), complemento([human, 'DEHP', toxicity, with, potential, clinical, implications, for, a, subset, of, patients, undergoing, critical, care, medical, interventions])].
[sujeto(['Although', not, well, 'characterized,', 'LS180', cells, could, be, an, excellent, cell, line, to, study, induction, of, 'P450s', and, transporters, because, they]), verbo([express]), complemento([pregnane, 'X', receptor, '(', 'PXR)'])].
[sujeto(['Among', these, 'proteins,', the, various, 'PIs', significantly]), verbo([induced]), complemento(['(', n, =, 3, -, 5, ')', only, 'CYP3A4', and, multidrug, resistance, transporter, 1, '(', 'MDR1)', transcripts, '(', 2, -, to, 50, -, 'fold)'])].
[sujeto(['CYP3A4', activity, '(', 1, '\'', -, hydroxymidazolam, 'formation)', was]), verbo([increased]), complemento(['(', 2, -, 'fold)', by, rifampin, '(', 10, 'microM)', but, was, reduced, by, the, 'PIs', '(', 1.5, -, to, 7, -, 'fold)'])].
[sujeto(['Surprisingly,', constitutive, androstane, receptor, 1, '(', 'CAR1)', was, not]), verbo([found]), complemento([to, be, expressed, in, these, cells])].
[sujeto(['Additionally,', using, a, reporter, 'assay,', we]), verbo([found]), complemento([that, 'PIs', did, not, activate, 'CAR3', '(', the, natural, splice, variant, of, 'CAR1)', but, significantly, activated, 'PXR', '(', 2, -, to, 24, -, 'fold),', which, correlated, well, with, induction, of, 'CYP3A4', and, 'MDR1', transcripts, '(', approximately, r, =, 0.9, ')'])].
[sujeto(['These', data, also, indicate, that, the, majority, of, the, 'PIs', are, likely, to, produce, intestinal, 'drug-drug', interactions, by, inactivating, or]), verbo([inhibiting]), complemento(['CYP3A', enzymes, even, though, they, induce, 'CYP3A4', and, 'MDR1', transcripts, via, 'PXR'])].
[sujeto(['The', 'DeltaNCARs', are]), verbo([expressed]), complemento([in, liver, and, in, vitro, cell, systems, following, translation, from, 'in-frame', methionine, 'AUG', start, codons, at, positions, 76, ',', 80, ',', 125, ',', 128, ',', 168, and, 265, within, the, 'full-length', 'CAR', mRNA])].
[sujeto(['Although', the, 'DeltaNCARs']), verbo([maintain]), complemento([full, retinoid, 'X', receptor, alpha, '(', 'RXRalpha)', heterodimerization, 'capacity,', the, 'DeltaNCARs', are, inactive, on, classical, 'CAR-inducible', direct, repeat, '(', 'DR)-4', 'elements,', yet, efficiently, transactivate, a, 'DR-1', element, derived, from, the, endogenous, 'PPAR-inducible', 'acyl-CoA', oxidase, gene, promoter])].
[sujeto(['A', new, model, of, 'CAR', 'DBD-independent', transactivation, is, 'proposed,', such, that, in, the, context, of, a, 'DR-1', peroxisome, 'proliferator-activated', response, 'element,', only, the, 'RXRalpha', portion, of, the, 'CAR-RXRalpha', heterodimer]), verbo([binds]), complemento([directly, to, 'DNA,', with, the, 'AF-2', domain, of, tethered, 'CAR', mediating, transcriptional, activation, of, the, receptor, complex])].
[sujeto(['The', currently, described, 'CAR1', and, 'CAR2', isoforms, are, not]), verbo([expressed]), complemento([in, rat, uterine, 'tissue;', 'therefore,', they, do, not, appear, to, participate, in, parturition, in, the, pregnant, rat])].
[sujeto(['The', pharmacogenetics, and, pharmacokinetics, of, efavirenz, '(', 'EFV)']), verbo([have]), complemento([been, widely, 'studied,', although, data, in, the, 'Italian', population, are, limited])].
[sujeto(['Single', nucleotide, polymorphisms, '(', 'SNPs)', in, the, 'CYP2B6', gene]), verbo([have]), complemento([been, associated, with, increased, 'EFV', plasma, concentrations, and, central, nervous, system, toxicity])].
[sujeto(['The', aim, of, this, work, was, to, evaluate, 'EFV', plasma, exposure, according, to, 'SNPs', in, genes]), verbo([involved]), complemento([in, drug, metabolism, and, elimination, in, a, cohort, of, 'Italian', 'HIV-1-positive', patients, treated, with, 'EFV'])].
[sujeto(['No', significant, associations, were]), verbo([found]), complemento([for, 'MRP2,', 'CYP2A6,', 'UGT2B7,', 'PXR', and, 'CAR', 'SNPs;', 'conversely,', an, association, of, 'CYP2B6', 516, 'G&gt;T,', 'ABCB1', 3435, 'C&gt;T', and, 2677, 'G&gt;T,', and, 'HNF4α', 975, 'C&gt;G', polymorphisms, with, 'EFV', 'C12', was, observed])].
[sujeto(['In', multivariate, 'analysis,', only, 'CYP2B6', 516, 'TT', and, 'ABCB1', 3435, 'TT', genotypes, were, independently]), verbo([associated]), complemento([with, an, 'EFV', 'C12', of, &, 'gt;4000ng/mL', '(', toxicity, 'cut-off)'])].
[sujeto(['Data', regarding, some, of, the, studied, 'SNPs', are, the, first, obtained, in, an, 'Italian', cohort, of, 'HIV', patients, and]), verbo([lead]), complemento([to, a, global, vision, about, 'EFV', pharmacogenetics])].
[sujeto(['Female', mice, demonstrated, a, large, number, of, altered, transcripts, as, early, as, 6, h, following, 'treatment,']), verbo([suggesting]), complemento([a, large, primary, response])].
[sujeto(['Nr1i3', was, statistically, significantly]), verbo([induced]), complemento([at, all, 'time-points', in, the, sensitive, male, animals])].
[sujeto(['This', mRNA, encodes, the, constitutive, androstane, receptor, '(', 'CAR),', a, transcription, factor]), verbo([involved]), complemento([in, the, regulation, of, xenobiotic, 'metabolism,', lipid, 'metabolism,', cell, cycle, and, apoptosis])].
[sujeto(['However,', recent, biochemical, and, structural, data]), verbo([suggest]), complemento([that, 'NR1I3', is, activated, in, response, to, metabolic, and, nutritional, stress, in, a, 'ligand-independent', manner])].
[sujeto(['We']), verbo([found]), complemento([24, 'SNPs', in, the, 'NR1I3', gene, and, choose, a, statistically, different, 'SNP', between, 'HFE', and, 'LFE', groups, for, further, analysis])].
[sujeto(['This', 'SNP', is, located, in, the, 5, '\'', flanking, promoter, region, of, 'NR1I3', gene, and, different, alleles, alter, the]), verbo([binding]), complemento([site, for, predicted, transcriptional, factors, as, 'HNF4alpha,', 'CREM', and, 'c-MYB,', leading, us, to, conclude, that, 'NR1I3', expression, and, regulation, might, be, important, to, feed, efficiency])].
[sujeto(['Great', research, effort]), verbo([has]), complemento([been, focused, on, elucidating, the, contribution, of, host, genetic, variability, on, pharmacological, outcomes, in, cancer])].
[sujeto(['Nuclear', receptors]), verbo([have]), complemento([emerged, as, mediators, between, environmental, stimuli, and, drug, pharmacokinetics, and, pharmacodynamics])].
[sujeto(['The', pregnane, 'X', 'receptor,', constitutive, androstane, receptor, and, hepatocyte]), verbo([nuclear]), complemento([factors, have, been, reported, to, regulate, transcription, of, genes, that, encode, drug, metabolizing, enzymes, and, transporters])].
[sujeto(['Altered']), verbo([nuclear]), complemento([receptor, expression, has, been, shown, to, affect, the, metabolism, and, pharmacological, profile, of, traditional, chemotherapeutics, and, targeted, agents])].
[sujeto(['Accordingly,', polymorphic, variants, in, these, genes]), verbo([have]), complemento([been, studied, as, pharmacogenetic, markers, of, outcome, variability])].
[sujeto(['This', review, summarizes, the, state, of, knowledge, about, the, roles, played, by, pregnane, 'X', 'receptor,', constitutive, androstane, receptor, and, hepatocyte]), verbo([nuclear]), complemento([factor, expression, and, genetics, as, predictive, markers, of, anticancer, drug, toxicity, and, 'efficacy,', which, can, improve, cancer, precision, medicine])].
[sujeto(['Previous', studies, from, our, laboratory, and, others]), verbo([have]), complemento([shown, that, various, phthalates, activate, several, mammalian, nuclear, 'receptors,', in, particular, the, constitutive, androstane, receptor, '(', 'CAR),', the, pregnane, 'X', receptor, '(', 'PXR),', and, the, peroxisomal, 'proliferator-activated', receptors, '(', 'PPARs),', although, often, at, concentration, levels, of, questionable, relevance, to, human, exposure])].
[sujeto(['Although', 'MEHP', and, 'MiNP', are]), verbo([reported]), complemento([activators, of, the, rodent, 'PPARs,', with, lower, affinities, for, the, corresponding, human, 'PPARs,', it, remains, unclear, whether, these, monophthalate, metabolites, activate, hCAR2, or, hPXR])].
[sujeto(['Using', transactivation, and, mammalian, 'two-hybrid', protein, interaction, 'assays,', we, demonstrate, that, these, substances, indeed]), verbo([activate]), complemento([hCARs, and, hPXR, but, to, varying, degrees])].
[sujeto(['Results', from, primary, hepatocyte, experiments, also, reflect, the, 'MEHP', and, 'MiNP', upregulation, of, the, respective, human]), verbo([target]), complemento([genes])].
[sujeto(['These', results, implicate, these]), verbo([targets]), complemento([as, important, mediators, of, selective, phthalate, effects, in, humans])].
[sujeto(['The', striking, differential, affinities, for, these, compounds, between, human, and, rodent]), verbo([nuclear]), complemento([receptors, further, implies, that, biological, results, obtained, from, rodent, models, may, be, of, only, limited, relevance, for, interpolating, 'phthalate-mediated', effects, in, humans])].
[sujeto(['If', a, drug, is]), verbo([found]), complemento([to, be, an, inducer, of, hepatic, drug, metabolizing, enzymes, via, activation, of, nuclear, receptors, such, as, pregnane, 'X', receptor, '(', 'PXR)', or, constitutive, androstane, receptor, '(', 'CAR),', it, is, likely, that, drug, transporters, regulated, through, these, same, receptors, will, be, induced, as, well])].
[sujeto(['This', review, highlights, what, is, currently, known, about, the, molecular, mechanisms, that]), verbo([regulate]), complemento([transporter, expression, and, where, the, research, is, directed])].
[sujeto(['This', review, is, focused, on, publications, that, describe, the, role, of]), verbo([activated]), complemento([hepatic, nuclear, receptors, in, the, subsequent, regulation, of, drug, uptake, 'and/or', efflux, transporters, following, exposure, to, xenobiotics])].
[sujeto(['Many', of, the, published, studies, on, the, role, of]), verbo([nuclear]), complemento([receptors, in, the, regulation, of, drug, transporters, involve, 'non-human', test, animals])].
[sujeto(['For', this, 'reason,', some, relevant, human, in, vitro, models]), verbo([have]), complemento([been, 'developed,', such, as, primary, or, cryopreserved, human, 'hepatocytes,', human, liver, 'slices,', or, 'HepG2', or, 'HuH7', cell, lines, transiently, or, stably, transfected, with, 'PXR', expression, and, reporter, constructs, as, well, as, in, vivo, models, such, as, 'PXR-humanized', mice])].
[sujeto(['Rodent', liver, tumors]), verbo([promoted]), complemento([by, constitutive, androstane, receptor, '(', 'CAR)', activation, are, known, to, be, mediated, by, key, events, that, include, 'CAR-dependent', gene, expression, and, hepatocellular, proliferation])].
[sujeto(['Hepatocytes', from, all, three, species, demonstrated, 'CAR', activation, in, response, to, the, 'CAR', agonists, 'TCPOBOP,', 'CITCO,', and, phenobarbital, based, on]), verbo([increased]), complemento([gene, expression, for, 'Cyp2b', isoforms])].
[sujeto(['When', evaluated, for, a, proliferation, 'phenotype,', 'TCPOBOP', and, 'CITCO', exhibited, significant, 'dose-dependent']), verbo([increases]), complemento([in, frequency, of, 'EdU', labeling, in, mouse, and, rat, hepatocytes, that, was, not, observed, in, hepatocytes, from, three, human, donors])].
[sujeto(['The', observed, species, differences, are, consistent, with, 'CAR', activators]), verbo([inducing]), complemento([a, proliferative, response, in, 'rodents,', a, key, event, in, the, liver, tumor, mode, of, action, that, is, not, observed, in, humans])].
[sujeto(['It', is, 'well-known', that, constitutive, androstane, receptor, '(', 'CAR)', activation, by, 1, ',', 4, -, 'bis[2-(3,5-dichloropyridyloxy)]benzene', '(', 'TCPOBOP)']), verbo([increases]), complemento([the, 'liver-to-body', weight, ratio])].
[sujeto(['CAR-mediated', liver, growth, is, correlated, with]), verbo([increased]), complemento([expression, of, the, pleiotropic, transcription, factor, 'cMyc,', which, stimulates, cell, cycle, regulatory, genes, and, drives, proliferating, cells, into, 'S', phase])].
[sujeto(['Because', glycolysis, supports, cell, proliferation, and, cMyc, is, essential, for, the, activation, of, glycolytic, 'genes,', we, hypothesized, that, 'CAR-mediated', 'up-regulation', of, cMyc, in, mouse, livers, might, play, a, role, in]), verbo([inducing]), complemento([the, expression, of, glycolytic, genes])].
[sujeto(['We', demonstrated, that, 'long-term', 'CAR', activation, by, 'TCPOBOP']), verbo([increases]), complemento([expression, of, 'cMyc,', which, was, correlated, with, reduced, expression, of, gluconeogenic, genes, and, 'up-regulation', of, glucose, 'transporter,', glycolytic, and, mitochondrial, pyruvate, metabolising, genes])].
[sujeto(['Thus,', our, findings]), verbo([provide]), complemento([evidence, to, support, the, conclusion, that, 'CAR', activation, initiates, a, transcriptional, program, that, facilitates, the, coordinated, metabolic, activities, required, for, cell, proliferation])].
[sujeto(['The', constitutive, androstane, receptor, '(', 'CAR)']), verbo([regulates]), complemento([the, expression, of, genes, involved, in, drug, metabolism, and, other, processes])].
[sujeto(['A', specific, inhibitor, of, 'CAR', is, critical, for]), verbo([modulating]), complemento([the, constitutive, activity, of, 'CAR'])].
[sujeto(['We', recently, described, a, specific, 'small-molecule', inhibitor, of, 'CAR,', 'CINPA1,', which, is, capable, of, reducing, 'CAR-mediated', transcription, by, changing, the, coregulator, recruitment, pattern, and, reducing, 'CAR', occupancy, at, the, promoter, regions, of, its]), verbo([target]), complemento([genes])].
[sujeto(['By', using, 'cell-based', reporter, gene, and, biochemical, coregulator, recruitment, 'assays,', we, showed, 'that,', while, metabolite, 1, was, very, weak, in]), verbo([inhibiting]), complemento(['CAR', function, and, disrupting, 'CAR-coactivator', 'interaction,', metabolite, 2, was, inactive, in, this, regard])].
[sujeto(['Docking', studies, using, the, 'CAR', ligand]), verbo([binding]), complemento([domain, '(', 'LBD)', structure, showed, 'that,', whereas, 'CINPA1', and, metabolite, 1, can, bind, in, the, 'CAR', ligand, binding, 'pocket,', metabolite, 2, may, be, incapable, of, the, molecular, interactions, required, for, binding])].
[sujeto(['Identification', and, characterization, of, the, metabolites, of, 'CINPA1', enabled, the, structure, activity, relationship, studies, of, this, family, of, small, 'molecules,', and]), verbo([provided]), complemento([information, to, guide, in, vivo, pharmacological, studies])].
[sujeto(['Polychlorinated', biphenyls, '(', 'PCBs)', are, persistent, environmental, pollutants, that, disrupt, hepatic, xenobiotic, and, intermediary, 'metabolism,']), verbo([leading]), complemento([to, metabolic, syndrome, and, nonalcoholic, steatohepatitis, '(', 'NASH)'])].
[sujeto(['Since', phenobarbital, indirectly]), verbo([activates]), complemento(['Constitutive', 'Androstane', 'Receptor', '(', 'CAR)', by, antagonizing, growth, factor, binding, to, the, epidermal, growth, factor, receptor, '(', 'EGFR),', we, hypothesised, that, 'PCBs', may, also, diminish, 'EGFR', signaling])].
[sujeto(['The', effects, of, the, 'PCB', mixture, 'Aroclor', 1260, on, the, protein, phosphorylation, cascade]), verbo([triggered]), complemento([by, 'EGFR', activation, were, determined, in, murine, '(', in, vitro, and, in, 'vivo)', and, human, models, '(', in, 'vitro)'])].
[sujeto(['EGFR', tyrosine, residue, phosphorylation, was]), verbo([decreased]), complemento([by, 'PCBs', in, all, models, tested])].
[sujeto(['The', 'IC50', values, for, 'Aroclor', 1260, concentrations, that]), verbo([decreased]), complemento(['Y1173', phosphorylation, of, 'EGFR', were, similar, in, murine, 'AML-12', and, human, 'HepG2', cells, '(', '∼2-4', 'μg/mL)'])].
[sujeto(['Both', dioxin, and, 'non-dioxin-like', 'PCB', congeners]), verbo([decreased]), complemento(['EGFR', phosphorylation, in, cell, culture])].
[sujeto(['PCB', treatment, reduced, phosphorylation, of, downstream, 'EGFR', effectors, including, 'Akt', and, 'mTOR,', as, well, as, other, phosphoprotein]), verbo([targets]), complemento([including, 'STAT3', and, 'c-RAF', in, vivo])].
[sujeto(['PCBs', diminish, 'EGFR', signaling, in, human, and, murine, hepatocyte, models, and, may, dysregulate, critical, phosphoprotein, regulators, of, energy, metabolism, and, 'nutrition,']), verbo([providing]), complemento([a, new, mechanism, of, action, in, environmental, diseases])].
[sujeto(['Hepatocellular', carcinoma, '(', 'HCC),', one, of, the, most, dangerous, malignancies, with, an]), verbo([increasing]), complemento([incidence, and, a, high, mortality, 'rate,', represents, a, major, international, health, problem])].
[sujeto(['HCC', progression, is, known, to]), verbo([involve]), complemento(['genome-wide', alteration, of, epigenetic, 'modifications,', leading, to, aberrant, gene, expression, patterns])].
[sujeto(['The', activity, of, 'CYP2C19,', an, important, member, of, the, cytochrome, 'P450', 'superfamily,', was]), verbo([reported]), complemento([to, be, compromised, in, 'HCC,', but, the, underlying, mechanism, remains, unclear])].
[sujeto(['To', understand, whether, epigenetic, modification, in, 'HCC', is]), verbo([associated]), complemento([with, a, change, in, 'CYP2C19', 'activity,', we, evaluated, the, expression, levels, of, 'CYP2C19', and, its, transcription, factors, by, quantitative, 'real-time', polymerase, chain, reaction, using, mRNA, extracted, from, both, primary, hepatocytes, and, paired, tumor, versus, nontumor, liver, tissues, of, patients, infected, with, hepatitis, 'B', virus, '(', 'HBV)'])].
[sujeto(['Our', results, indicated, that, 'CYP2C19', could, be]), verbo([regulated]), complemento([by, 'e-box', methylation, of, the, constitutive, androstane, receptor, '(', 'CAR)'])].
[sujeto(['Decreased', 'CYP2C19', expression, in, tumorous, tissues, of, 'HBV-infected', patients, with, 'HCC', was, highly, correlated, with]), verbo([suppressed]), complemento([expression, and, promoter, hypermethylation, of, 'CAR'])].
[sujeto(['Our', study, demonstrates, that, aberrant, 'CAR', methylation, is]), verbo([involved]), complemento([in, 'CYP2C19', regulation, in, 'HBV-related', 'HCC', and, may, play, a, role, in, liver, tumorigenesis])].
[sujeto(['The', expression, of, 'P450', enzymes, is, partly]), verbo([regulated]), complemento([by, the, constitutive, androstane, receptor, '(', 'CAR)'])].
[sujeto(['Fasting']), verbo([regulates]), complemento([the, expression, of, both, 'P450', enzymes, and, 'CAR', and, affects, hepatic, drug, clearance])].
[sujeto(['We', hypothesized, that, the, 'fasting-induced', alterations, in, 'P450']), verbo([mediated]), complemento([drug, clearance, are, mediated, by, 'CAR'])].
[sujeto(['Fasting']), verbo([decreased]), complemento(['Cyp1a2', and, 'Cyp2d22', expression, and, increased, 'Cyp3a11', and, 'Cyp2c38', expression, in, both, 'WT', and, 'CAR-/-', mice])].
[sujeto(['The']), verbo([decrease]), complemento([in, 'Cyp1a2', was, diminished, in, 'CAR-/-', in, comparison, with, 'WT', mice])].
[sujeto(['Fasting']), verbo([decreased]), complemento([the, clearance, of, all, drugs, tested, in, both, 'WT', and, 'CAR-/-', mice])].
[sujeto(['The', absence, of, 'CAR', was]), verbo([associated]), complemento([with, an, decrease, in, the, clearance, of, 'omeprazole,', metoprolol, and, midazolam, in, fed, mice])].
[sujeto(['However', the, 'fasting-induced', alterations, in, 'P450']), verbo([mediated]), complemento([drug, clearance, are, largely, independent, of, 'CAR'])].
[sujeto(['These', responses, are]), verbo([induced]), complemento([by, short, term, and, prolonged, 'PB', 'exposure,', 'respectively,', with, the, latter, treatments, being, difficult, to, examine, mechanistically, in, primary, hepatocytes, due, to, rapid, loss, of, the, original, hepatic, phenotype, and, limited, sustainability, in, culture])].
[sujeto(['We', demonstrate, that, 'PB', with, 'Egf', treatment, in, the, 'B13/H', cells, resulted, in, a, significant]), verbo([increase]), complemento([in, 'Erk', 'activation,', as, determined, by, the, ratio, of, 'phospho-Erk', to, total, 'Erk,', compared, to, 'Egf', alone])].
[sujeto(['Additionally,', we, confirm, that, 'B13/H', cells]), verbo([respond]), complemento([to, 'Car', activators, in, a, typical, 'rat-specific', manner])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, the, 'B13/H', cells, produce, temporal, responses, to, 'PB', that, are, comparable, to, those, reported, in, 'short-term', primary, rat, hepatocyte, cultures, and, in, the, longer, term, are, similar, to, those, in, the, rat, in, vivo])].
[sujeto(['Finally,', we, also, show, that, 'Car-associated', 'miR-122', expression, is]), verbo([decreased]), complemento([by, 'PB', treatment, in, 'B13/H', 'cells,', a, 'PB-induced', response, that, is, common, to, the, 'rat,', mouse, and, human])].
[sujeto(['The', constitutive, androstane, receptor, '(', 'CAR)']), verbo([has]), complemento([been, reported, to, decrease, insulin, resistance, along, with, obesity])].
[sujeto(['We', also, studied, whether, 'DE', treatment, during, pregnancy, could]), verbo([prevent]), complemento([maternal, 'hypertension,', glucose, intolerance, and, 'hyperlipidemia,', and, fetal, overgrowth, in, 'high-fat', diet, '(', 'HFD)-induced', obese, pregnant, mice])].
[sujeto(['Dimethylesculetin']), verbo([suppressed]), complemento([the, mRNA, expression, of, gluconeogenic, 'genes,', phosphoenolpyruvate, carboxykinase, and, 'glucose-6-phosphatase,', and, lipogenic, 'genes,', sterol, regulatory, 'element-binding', protein, 1, and, 'stearoyl-CoA', desaturase, 1, ',', and, enhanced, 'CAR-mediated', transcription])].
[sujeto(['DE', treatment, during, pregnancy, could]), verbo([prevent]), complemento([maternal, 'hypertension,', glucose, intolerance, and, 'hyperlipidemia,', and, fetal, overgrowth, in, 'HFD-induced', obese, pregnant, mice, in, vivo])].
[sujeto(['Our', data, indicate, that, 'DE', might, be, a, potential, therapeutic, agent, for, obese, pregnant, patients, with, insulin, resistance, through, 'CAR', to]), verbo([prevent]), complemento([the, perinatal, outcomes, such, as, 'preeclampsia,', gestational, 'diabetes,', and, macrosomia])].
[sujeto(['Safety', concerns]), verbo([have]), complemento([emerged, regarding, the, potential, 'long-lasting', effects, due, to, developmental, exposure, to, xenobiotics])].
[sujeto(['The', pregnane, 'X', receptor, '(', 'PXR)', and, constitutive, androstane, receptor, '(', 'CAR)', are, critical, 'xenobiotic-sensing']), verbo([nuclear]), complemento([receptors, that, are, highly, expressed, in, liver])].
[sujeto(['The', goal, of, this, study, was, to, test, our, hypothesis, that, neonatal, exposure, to, 'PXR-', or, 'CAR-activators', not, only, acutely, but, also, persistently]), verbo([regulates]), complemento([the, expression, of, 'drug-processing', genes, '(', 'DPGs)'])].
[sujeto(['Neonatal', exposure, to, both, 'PCN', and, 'TCPOBOP', persistently, 'down-regulated', multiple, 'Cyp4a', 'members,', which, are, 'prototypical-target', genes, of, the, 'lipid-sensor', 'PPARα,', and, this, correlated, with]), verbo([decreased]), complemento(['PPARα-binding', to, the, 'Cyp4a', gene, loci])].
[sujeto(['In', 'conclusion,', neonatal, exposure, to, 'PXR-', and, 'CAR-activators', both, acutely, and, persistently]), verbo([regulates]), complemento([critical, genes, involved, in, xenobiotic, and, lipid, metabolism, in, liver])].
[sujeto(['Over', the, last, decade, 'HepaRG', cells]), verbo([have]), complemento([emerged, as, a, promising, alternative, to, primary, human, hepatocytes, '(', 'PHH)', and, have, been, featured, in, over, 300, research, publications])].
[sujeto(['Most', of, these]), verbo([reports]), complemento([employed, freshly, differentiated, 'HepaRG', cells, that, require, 'time-consuming', culture, '(', '∼28', 'days)', for, full, differentiation])].
[sujeto(['Recently,', a, 'cryopreserved,', predifferentiated, format, of, 'HepaRG', cells, '(', termed, here, &, 'quot;cryo-HepaRG&quot;)']), verbo([has]), complemento([emerged, as, a, new, model, that, improves, global, availability, and, experimental, 'flexibility;', 'however,', it, is, largely, unknown, whether, 'HepaRG', cells, in, this, format, fully, retain, their, hepatic, characteristics])].
[sujeto(['Pharmacologically', important, 'drug-metabolizing', alleles, were, genotyped, in, 'HepaRG', cells, and, poor, metabolizer, alleles, for, 'CYP2D6,', 'CYP2C9,', and, 'CYP3A5', were, identified, and, consistent, with, higher, frequency, alleles]), verbo([found]), complemento([in, individuals, of, 'Caucasian', decent])].
[sujeto(['Taken', 'together,', these, data]), verbo([reveal]), complemento([important, considerations, for, the, use, of, this, cell, model, and, demonstrate, that, 'cryo-HepaRG', are, suitable, for, metabolism, and, toxicology, screening])].
[sujeto(['Constitutive', androstane, receptor, '(', 'CAR)']), verbo([regulates]), complemento([hepatic, xenobiotic, and, energy, 'metabolism,', as, well, as, promotes, cell, growth, and, hepatocarcinogenesis])].
[sujeto(['Here', we]), verbo([report]), complemento([that, berberine, is, able, to, be, cellular, uptake, and, accessible, to, chromatin, in, human, hepatoma, 'HepG2', cells])].
[sujeto(['Berberine']), verbo([induces]), complemento([more, 'apoptosis,', cell, cycle, 'arrest,', but, less, 'ROS', production, in, 'CAR', overexpressed, 'mCAR-HepG2', cells])].
[sujeto(['Moreover,', berberine]), verbo([inhibits]), complemento([expressions, of, 'CAR', and, its, target, genes, 'CYP2B6', and, 'CYP3A4'])].
[sujeto(['Furthermore,', berberine]), verbo([enhances]), complemento(['DNA', methylation, level, in, whole, genome, but, reduces, that, in, promoter, regions, 'CpG', sites, of, 'CYP2B6', and, 'CYP3A4', genes, under, the, presence, of, 'CAR', condition])].
[sujeto(['These', results, indicated, that, the, antiproliferation, of, berberine, might, be]), verbo([mediated]), complemento([by, the, unique, epigenetic, modifying, mechanism, of, 'CAR', metabolic, 'pathway,', suggesting, that, berberine, is, a, promising, candidate, in, anticancer, adjuvant, 'chemotherapy,', due, to, its, distinct, pharmacological, properties, in, clinic])].
[sujeto(['We']), verbo([have]), complemento([used, 'CAR(-/-)', 'C57BL/6', and, wild, type, mice, and, performed, a, battery, of, behavioral, tests, '(', 'recognition,', 'memory,', motor, 'coordination,', learning, and, 'anxiety)', as, well, as, longitudinal, 'video-electroencephalographic', recordings, '(', 'EEG)'])].
[sujeto(['We', observed, recognition, memory, impairment, and]), verbo([increased]), complemento(['anxiety-like', behavior, in, 'CAR(-/-)', 'mice,', while, locomotor, activity, was, not, affected])].
[sujeto(['Concomitantly', to, memory, 'deficits,', 'EEG', monitoring, revealed, a]), verbo([decrease]), complemento([in, 3.5, -, 7, 'Hz', waves, during, the, 'awake/exploration', and, sleep, periods])].
[sujeto(['At', the, cellular, level, we]), verbo([found]), complemento([reduced, 'ZO-1,', but, not, 'CLDN5,', tight, junction, protein, expression, in, cortical, and, hippocampal, isolated, microvessel, preparations])].
[sujeto(['Interestingly,', the, neurotoxin, kainic, 'acid,', when, injected, 'peripherally,']), verbo([provoked]), complemento([a, rapid, onset, of, generalized, convulsions, in, 'CAR(-/-)', as, compared, to, 'WT', 'mice,', supporting, the, hypothesis, of, vascular, permeability])].
[sujeto(['Neuronal', defects, were, also, observed, including]), verbo([increased]), complemento([cortical, 'NEUN(+)', cell, 'density,', hippocampal, granule, cell, dispersion, and, increased, 'NPY', immunoreactivity, in, the, 'CA1', region, in, 'CAR(-/-)', mice])].
[sujeto(['The', latter, could]), verbo([increase]), complemento([the, vulnerability, to, neurotoxins])].
[sujeto(['The', possibility, that, interfering, with]), verbo([nuclear]), complemento([receptors, during, development, could, contribute, to, adulthood, brain, changes, is, proposed])].
[sujeto(['A', limited, repertoire, of, 'PPP', family, of, 'serine/threonine', phosphatases, with, a, highly]), verbo([conserved]), complemento([catalytic, domain, acts, on, thousands, of, protein, targets, to, orchestrate, myriad, central, biological, roles])].
[sujeto(['A', major, structural, reorganization, of, human, 'calcineurin,', a, ubiquitous, 'Ser/Thr', 'PPP']), verbo([regulated]), complemento([by, calcium, and, calmodulin, and, targeted, by, immunosuppressant, drugs, cyclosporin, 'A', and, 'FK506,', is, unveiled, here])].
[sujeto(['The', new, conformation]), verbo([involves]), complemento(['trans-', to, 'cis-isomerization', of, proline, in, the, 'SAPNY', 'sequence,', highly, conserved, across, 'PPPs,', and, remodels, the, main, regulatory, site, where, 'NFATc', transcription, factors, bind])].
[sujeto(['Transitions', between, 'cis-', and, 'trans-conformations', may]), verbo([involve]), complemento([peptidyl, prolyl, isomerases, such, as, cyclophilin, 'A', and, 'FKBP12,', which, are, known, to, physically, interact, with, and, modulate, calcineurin, even, in, the, absence, of, immunosuppressant, drugs])].
[sujeto(['Alternative', conformations, in, 'PPPs']), verbo([provide]), complemento([a, new, perspective, on, interactions, with, substrates, and, other, protein, partners, and, may, foster, development, of, more, specific, inhibitors, as, drug, candidates])].
[sujeto(['Agonist-activated', 'μ-opioid', receptor, '(', 'OPRM1)', undergoes, robust, receptor, phosphorylation, by, 'G', 'protein-coupled', receptor, kinases, and, subsequent, 'β-arrestin', 'recruitment,']), verbo([triggering]), complemento([receptor, internalization, and, desensitization])].
[sujeto(['Morphine,', a, widely, prescribed, 'opioid,']), verbo([induces]), complemento([receptor, phosphorylation, inefficiently])].
[sujeto(['Previously', we]), verbo([reported]), complemento([that, 'FK506', binding, protein, 12, '(', 'FKBP12)', specifically, interacts, with, 'OPRM1', and, such, interaction, attenuates, receptor, phosphorylation, and, facilitates, 'morphine-induced', recruitment, and, activation, of, protein, kinase, 'C'])].
[sujeto(['Morphine']), verbo([induced]), complemento([faster, receptor, internalization, and, adenylyl, cyclase, desensitization, in, cells, expressing, 'OPRM1', with, 'Pro(353)', mutated, to, 'Ala', '(', 'OPRM1P353A),', which, does, not, interact, with, 'FKBP12,', or, in, the, presence, of, 'FK506', which, dissociates, the, 'receptor-FKBP12', interaction])].
[sujeto(['We']), verbo([have]), complemento([previously, demonstrated, that, 'AICD', interacts, with, 'FKBP12,', a, 'peptidyl-prolyl', 'cis-trans', isomerase, '(', 'PPIase)', ubiquitous, in, nerve, systems])].
[sujeto(['This', interaction, was, interfered, by, 'FK506,', a, clinically, used, immunosuppressant, that]), verbo([has]), complemento([recently, been, reported, to, be, neuroprotective])].
[sujeto(['These', findings, support, our, hypothesis, that, 'FKBP12', may]), verbo([participate]), complemento([in, the, regulation, of, 'APP', processing])].
[sujeto(['FKBP12', overexpression, may]), verbo([lead]), complemento([to, the, stabilization, of, a, certain, isomer, '(', presumably, the, cis, 'form)', of, the, 'Thr668-Pro669', peptide, bond, in, 'AICD,', therefore, change, its, affinity, to, 'flotillin-1', or, other, 'raft-associated', 'proteins,', and, eventually, change, the, localization, pattern, and, cause, a, shift, in, the, proteolytic, processing, of, 'APP'])].
[sujeto(['The', 'G89A', variant, shifted, the, 'trans-cis', peptide, equilibrium, from, 88, :, 12, to, 33, :, 67, ',', whereas, a, proline, residue, substitution]), verbo([induced]), complemento([fully, the, 'cis-peptide', configuration])].
[sujeto(['The', 80, '\'', s, loop, conformation, in, the, 'G89P', crystal, structure, at, 1.5, 'Å', resolution, differed, from, 'wild-type', 'FKBP12', primarily, at, residues, 88, ',', 89, and, 90, ',', and, it, closely, resembled, that]), verbo([reported]), complemento([for, 'FKBP52'])].
[sujeto(['Differences', in, the, residues, that, underlie, the, 'Trp59', indole, ring, and, altered, interactions, linking, the, 50, '\'', s, loop, to, the, active, site]), verbo([suggested]), complemento([that, reorientation, of, this, ring, may, be, disfavoured, in, the, other, six, members, of, the, 'FKBP', domain, family, that, bear, this, 'active-site', tryptophan, residue])].
[sujeto(['This']), verbo([suggests]), complemento([that, hydrophilic, interactions, are, the, main, cause, of, aggregation])].
[sujeto(['We', then, investigated, the, function, of, 'FK506-binding', protein, '(', 'FKBP)', 12, ',', which, is, known, to, accumulate, in, neurofibrillary, tangles, in, 'vivo,', on, aggregation, of, the, 'R3', peptide, and]), verbo([found]), complemento([that, 'FKBP12', completely, prevented, the, peptide, from, aggregating, at, a, concentration, ratio, of, 1, :, 4, '(', 'peptide:FKBP12)'])].
[sujeto(['The', aryl, hydrocarbon, 'receptor-interacting', protein, '(', 'AIP)']), verbo([has]), complemento([been, predicted, to, consist, of, an, 'N-terminal', 'FKBP-type', 'peptidyl-prolyl', 'cis/trans', isomerase, '(', 'PPIase)', domain, and, a, 'C-terminal', tetratricopeptide, repeat, '(', 'TPR)', 'domain,', as, typically, found, in, 'FK506-binding', immunophilins])].
[sujeto(['AIP,', 'however,', exhibited, no, inherent, 'FK506']), verbo([binding]), complemento([or, 'PPIase', activity])].
[sujeto(['Diminution', of, the, latter, insert, did, not, generate, 'PPIase', activity, or, 'FK506']), verbo([binding]), complemento(['capability,', indicating, that, the, lack, of, catalytic, activity, in, 'AIP', is, the, result, of, structural, differences, within, the, 'PPIase', domain])].
[sujeto(['Moreover,', 'Hsp90', was, identified, as, potential, physiological, interaction, partner, of, 'AIP,', which, revealed]), verbo([binding]), complemento([contacts, not, only, at, the, 'TPR', domain, but, uncommonly, also, at, the, 'PPIase', domain])].
[sujeto(['It']), verbo([interacts]), complemento([with, the, immunosuppressive, drug, rapamycin, inhibiting, the, formation, of, 'TORC2', complex, leading, to, parasite, death, by, inhibiting, cell, proliferation, through, cytokinesis, blockade])].
[sujeto(['Both', facts, make, 'TbFKBP12', an, attractive]), verbo([target]), complemento([for, ligand, development, and, thus, structural, data, is, desirable])].
[sujeto(['In', this, work, we]), verbo([report]), complemento([the, 'NMR', resonance, assignments, for, '(', 1, ')', 'H,', '(', 15, ')', 'N', and, '(', 13, ')', 'C', nuclei, in, the, backbone, and, side, chains, of, the, 'TbFKBP12', as, basis, for, further, studies, of, 'structure,', backbone, 'dynamics,', interaction, mapping, and, drug, screening])].
[sujeto(['FK506']), verbo([binding]), complemento([proteins, '(', 'FKBPs)', represent, a, subfamily, of, peptidyl, prolyl, 'cis/trans', isomerases, that, can, control, 'receptor-mediated', intracellular, signaling])].
[sujeto(['The', prototypic, 'PPIase', 'FKBP12', functionally]), verbo([interacts]), complemento([with, 'EGFR'])].
[sujeto(['FKBP12', was, shown, to]), verbo([inhibit]), complemento(['EGF-induced', 'EGFR', autophosphorylation, with, all, internal, phosphorylation, sites, equally, affected])].
[sujeto(['The', inhibition, of, 'EGFR', catalytic, activity, is, conducted, by]), verbo([targeting]), complemento([the, 'EGFR', kinase, domain])].
[sujeto(['Collectively,', our, results, demonstrate, that, 'FKBP12', forms, an, endogenous, inhibitor, of, 'EGFR', phosphorylation, directly]), verbo([involved]), complemento([in, the, control, of, cellular, 'EGFR', activity])].
[sujeto(['FK506']), verbo([binding]), complemento([protein, '(', 'FKBP)12', is, a, known, 'cis-trans', peptidyl, prolyl, isomerase, and, highly, expressed, in, the, heart])].
[sujeto(['Its', role, in]), verbo([regulating]), complemento([postnatal, cardiac, function, remains, largely, unknown])].
[sujeto(['A', high, incidence, '(', 38, '%', ')', of, sudden, death, was]), verbo([found]), complemento([in, 'αMyHC-FKBP12', mice])].
[sujeto(['Whole-cell', 'patch-clamp', analyses, demonstrated, an, '≈', 80, '%', reduction, in, peak, density, of, the, 'tetrodotoxin-resistant,', 'voltage-gated', sodium, current, 'I(Na)', in, 'αMyHC-FKBP12', ventricular, 'cardiomyocytes,', a, slower, recovery, of, 'I(Na)', from, 'inactivation,', shifts, of, 'steady-state', activation, and, inactivation, curves, of, 'I(Na)', to, more, depolarized, 'potentials,', and, augmentation, of, late, 'I(Na),']), verbo([suggesting]), complemento([that, the, arrhythmogenic, phenotype, of, 'αMyHC-FKBP12', mice, is, attributable, to, abnormal, 'I(Na)'])].
[sujeto(['Ventricular', cardiomyocytes, isolated, from, 'FKBP12(f/f)/αMyHC-Cre', hearts, showed, faster, action, potential, upstrokes, and, a, more, than, 2, -, fold]), verbo([increase]), complemento([in, peak, 'I(Na)', density])].
[sujeto(['FKPB12-mediated', dysregulation, of, 'I(Na)', may, underlie, clinical, arrhythmias]), verbo([associated]), complemento([with, 'FK506', administration])].
[sujeto(['A', cycle, of, 'palmitoylation/depalmitoylation', of, 'H-Ras']), verbo([mediates]), complemento([bidirectional, trafficking, between, the, 'Golgi', apparatus, and, the, plasma, 'membrane,', but, nothing, is, known, about, how, this, cycle, is, regulated])].
[sujeto(['We', show, that, the, prolyl, isomerase, '(', 'PI)', 'FKBP12']), verbo([binds]), complemento([to, 'H-Ras', in, a, 'palmitoylation-dependent', fashion, and, promotes, depalmitoylation])].
[sujeto(['A', variety, of, inhibitors, of, the, 'PI', activity, of, 'FKBP12,', including, 'FK506,', 'rapamycin,', and, 'cycloheximide,']), verbo([increase]), complemento(['steady-state', palmitoylation])].
[sujeto(['FK506']), verbo([inhibits]), complemento([retrograde, trafficking, of, 'H-Ras', from, the, plasma, membrane, to, the, 'Golgi', in, a, proline, 179, -, dependent, 'fashion,', augments, early, 'GTP', loading, of, 'Ras', in, response, to, growth, 'factors,', and, promotes, 'H-Ras-dependent', neurite, outgrowth, from, 'PC12', cells])].
[sujeto(['These', data, demonstrate, that, 'FKBP12']), verbo([regulates]), complemento(['H-Ras', trafficking, by, promoting, depalmitoylation, through, 'cis-trans', isomerization, of, a, 'peptidyl-prolyl', bond, in, proximity, to, the, palmitoylated, cysteines])].
[sujeto(['Drugs', can, affect, function, in, proteins, by]), verbo([modulating]), complemento([their, flexibility])].
[sujeto(['Despite', this, 'possibility,', there, are, very, few, studies, on, how, drug]), verbo([binding]), complemento([affects, the, dynamics, of, target, macromolecules])].
[sujeto(['FKBP12', '(', 'FK506']), verbo([binding]), complemento([protein, 12, ')', is, a, prolyl, 'cis-trans', isomerase, and, a, drug, target])].
[sujeto(['The', immunosuppressant, drug, rapamycin, exerts, its, therapeutic, effect, by, serving, as, an, adaptor, molecule, between, 'FKBP12', and, the, cell, proliferation, regulator, mTOR, '(', mammalian]), verbo([target]), complemento([of, 'rapamycin)'])].
[sujeto(['To', understand, the, role, of, dynamics, in, 'rapamycin-based', immunosuppression, and, to]), verbo([gain]), complemento([insight, into, the, role, of, dynamics, in, the, assembly, of, supramolecular, 'complexes,', we, used, '(', 15, ')', 'N,', '(', 13, ')', 'C,', and, '(', 2, ')', 'H', 'NMR', spin, relaxation, to, characterize, 'FKBP12', along, the, binding, coordinate, that, leads, to, cell, cycle, arrest])].
[sujeto(['We', show, that, sequential, addition, of, rapamycin, and, mTOR]), verbo([leads]), complemento([to, incremental, rigidification, of, the, 'FKBP12', backbone, on, the, 'picosecond-nanosecond', timescale])].
[sujeto(['Both']), verbo([binding]), complemento([events, lead, to, perturbation, of, 'main-chain', and, 'side-chain', dynamics, at, sites, distal, to, the, binding, 'interfaces,', suggesting, tight, coupling, interactions, dispersed, throughout, the, 'FKBP12-rapamycin', interface])].
[sujeto(['This', loop]), verbo([provides]), complemento([much, of, the, surface, buried, at, the, 'protein-protein', interface, of, the, ternary, 'complex,', leading, us, to, assert, that, preorganization, upon, rapamycin, binding, facilitates, binding, of, the, second, 'molecule,', mTOR])].
[sujeto(['Widespread', 'microsecond-millisecond', motions, of, the, backbone, persist, in, the, 'drug-bound', 'enzyme,', and, we]), verbo([provide]), complemento([evidence, that, these, slow, motions, represent, coupled, dynamics, of, the, enzyme, and, isomerization, of, the, bound, drug])].
[sujeto(['Finally,', the, pattern, of, 'microsecond-millisecond', dynamics]), verbo([reported]), complemento([here, in, the, rapamycin, complex, is, dramatically, different, from, the, pattern, in, the, complex, with, the, structurally, related, drug, 'FK506'])].
[sujeto(['This', raises, the, important, question, of, how, two, complexes, that, are, highly, isomorphic, based, on, 'high-resolution', static, models]), verbo([have]), complemento([such, different, flexibilities, in, solution])].
[sujeto(['The', pathological, features, of, 'PD', are, the]), verbo([loss]), complemento([of, dopaminergic, neurons, in, the, substantia, nigra, pars, compacta, and, the, presence, of, 'Lewy', bodies])].
[sujeto(['The', aggregation, of, this, natively, unfolded, protein, is, accelerated, in, vitro, by, 'FK506']), verbo([binding]), complemento([proteins, '(', 'FKBPs)', showing, 'peptidyl-prolyl', 'cis-trans', isomerase, activity])].
[sujeto(['Several', prolyl, isomerases, of, the, 'FK506-binding', protein, 'family,', such, as]), verbo([trigger]), complemento(['factor,', 'SlyD,', and, 'FkpA,', contain, chaperone, domains, and, are, assumed, to, assist, protein, folding, in, vivo])].
[sujeto(['Accordingly,', we, constructed, a, library, of, protein, variants, with, all, 20, aa, at, position, 'Xaa', before, a, 'rate-limiting', cis, proline, and, used, it, to, investigate, the, performance, of]), verbo([trigger]), complemento([factor, and, 'SlyD', as, catalysts, of, 'proline-limited', folding])].
[sujeto(['Apparently,', the, almost, indiscriminate]), verbo([binding]), complemento([of, the, chaperone, domain, to, the, refolding, protein, chain, overrides, the, inherently, high, sequence, specificity, of, the, prolyl, isomerase, site])].
[sujeto(['This', proximity, also]), verbo([leads]), complemento([to, a, strong, quenching, of, 'Abz', 'fluorescence,', 'which,', in, combination, with, a, solvent, 'jump,', was, used, to, devise, a, sensitive, assay, for, prolyl, isomerases])].
[sujeto(['The', peptide, library, was, used, to]), verbo([provide]), complemento([a, complete, set, of, 'P1-site', specificities, for, prototypic, human, members, of, the, three, prolyl, isomerase, 'families,', 'FKBP12,', cyclophilin, 18, ',', and, parvulin, 14])].
[sujeto(['Intense', immunoreactivity, was]), verbo([found]), complemento([in, large, neurons, such, as, pyramidal, cells])].
[sujeto(['Labeling', for, 'FKBP12', was, dense, in, axons, stained, for, highly]), verbo([phosphorylated]), complemento([neurofilament, protein])].
[sujeto(['Thus', our, results]), verbo([suggest]), complemento([that, 'FKBP12', may, be, involved, in, neuronal, or, astrocytic, cytoskeletal, organization, and, in, the, abnormal, metabolism, of, tau, protein, in, 'AD', damaged, neurons])].
[sujeto(['The', macrolide, 'FK506', is, a, 'transition-state', analog, of, the, catalyzed, reaction, and, displaces, 'FKBP12', from, its, natural]), verbo([target]), complemento([proteins])].
[sujeto(['The', residual, 'side-chain', dynamics, in, the, 'transition-state', 'analog-bound', state]), verbo([suggests]), complemento([that, the, 'transition-state', ensemble, involves, multiple, 'conformations,', a, finding, that, challenges, the, 'long-standing', concept, of, conformational, restriction, in, the, 'transition-state', complex])].
[sujeto(['Furthermore,', exchange, between, alternative, conformations, is, observed, in, the]), verbo([bound]), complemento([state, for, an, extended, network, of, methyl, groups, that, includes, locations, remote, from, the, active, site])].
[sujeto(['Several', of, these, locations, are, known, to, be, important, for, interactions, with, cellular]), verbo([target]), complemento(['proteins,', including, calcineurin, and, the, ryanodine, 'receptor,', suggesting, that, the, conformational, heterogeneity, might, play, a, role, in, the, promiscuous, binding, of, 'FKBP12', to, different, targets])].
[sujeto(['Inhibitors', of, 'FKBP12,', in, 'particular,']), verbo([have]), complemento([potent, neurotrophic, properties, both, in, vivo, and, in, vitro])].
[sujeto(['Here,', we, describe, a, 'fragment-based', unbiased]), verbo([nuclear]), complemento([magnetic, resonance, drug, discovery, approach, for, the, identification, of, novel, classes, of, chemical, inhibitors, against, 'FKBP12'])].
[sujeto(['FKBP-12']), verbo([mediates]), complemento([the, immunosuppressive, actions, of, 'FK506', and, 'rapamycin,', and, modulates, the, activities, of, the, 'ryanodine,', 'IP3', and, type, 1, 'TGF-ss', receptors])].
[sujeto(['We']), verbo([have]), complemento([discovered, that, recombinant, 'FKBP-12', readily, forms, a, dimer, and, a, small, amount, of, trimer, under, nonreducing, conditions])].
[sujeto(['The', multimers, of, 'FKBP-12', could]), verbo([interact]), complemento([with, molecular, targets, distinctly, from, the, 'FKBP-12', 'monomer,', for, 'example,', by, facilitating, the, assembly, of, multimeric, receptors, or, coordinating, the, activity, of, receptor, subunits])].
[sujeto(['Two', families, of, 'PPIases,', cyclophilins, and, 'FKBPs,']), verbo([have]), complemento([been, extensively, studied, because, of, their, high, affinity, for, immunosuppressive, drugs, in, particular, cyclosporine, 'A', and, 'FK506'])].
[sujeto(['Despite', apparent, 'differences,', these, protein, families, share]), verbo([conserved]), complemento([amino, acid, sequences, in, their, catalytic, domains, and, impose, similar, enzymatic, functions, to, their, substrates])].
[sujeto(['PPIases']), verbo([have]), complemento([been, implicated, in, multiple, aspects, of, cell, cycle, regulation, and, cellular, processes, related, to, a, number, of, human, 'pathologies,', including, cancer])].
[sujeto(['More', recent, studies]), verbo([provide]), complemento([evidence, for, participation, of, 'PPIases', in, regulation, of, immune, cell, functions])].
[sujeto(['PPIase-mediated', isomerization, of, proteins, represents, a, unique, signaling, mechanism, that]), verbo([regulates]), complemento([normal, immune, functions, and, contributes, to, the, development, of, immunopathologies])].
[sujeto(['Fkbp1a', '(', 'FKBP12)', is, a, ubiquitously]), verbo([expressed]), complemento(['cis-trans', 'peptidyl-prolyl', isomerase])].
[sujeto(['To', determine, the, physiological, function, of, 'Fkbp1a', in]), verbo([regulating]), complemento([the, intercellular, and, intracellular, signaling, pathways, involved, in, ventricular, trabeculation, and, 'compaction,', we, generated, a, series, of, 'Fkbp1a', conditional, knockouts])].
[sujeto(['Surprisingly,', 'cardiomyocyte-restricted', ablation, of, 'Fkbp1a', did, not, give, rise, to, the, ventricular, developmental, 'defect,', whereas, endothelial, 'cell-restricted', ablation, of, 'Fkbp1a', recapitulated, the, ventricular, hypertrabeculation, and, noncompaction, observed, in, 'Fkbp1a', systemically, deficient, 'mice,']), verbo([suggesting]), complemento([an, important, contribution, of, 'Fkbp1a', within, the, developing, endocardia, in, regulating, the, morphogenesis, of, ventricular, trabeculation, and, compaction])].
[sujeto(['Further', analysis, demonstrated, that, 'Fkbp1a', is, a, novel, negative, modulator, of]), verbo([activated]), complemento(['Notch1'])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, 'Fkbp1a-mediated', regulation, of, 'Notch1', plays, an, important, role, in, intercellular, communication, between, endocardium, and, 'myocardium,', which, is, crucial, in, controlling, the, formation, of, the, ventricular, walls])].
[sujeto(['Although', 'Xenopus', 'FKBP1A', '(', 'xFKBP1A)']), verbo([induces]), complemento([an, ectopic, dorsal, axis, in, 'Xenopus', 'embryos,', involvement, of, 'xFKBP1B,', a, vertebrate, paralogue, of, 'FKBP1A,', in, embryogenesis, remains, undetermined])].
[sujeto(['Here,', we, demonstrate, that, xFKBP1B]), verbo([induces]), complemento([ectopic, dorsal, axis, and, involves, in, eye, formation, of, 'Xenopus', embryos])].
[sujeto(['Injection', of, the, xFKBP1B, mRNA, in, ventral, blastomeres, of, 4, -, cell, stage, 'Xenopus', embryos]), verbo([induced]), complemento([a, secondary, axis, and, showed, multiplier, effect, to, that, of, xFKBP1A, on, this, when, xFKBP1A, was, 'co-injected'])].
[sujeto(['In', 'addition,', 'BMP4', and, 'Smad1', mRNAs, did, not, affect, the, ability, of, xFKBP1B, to]), verbo([induce]), complemento([the, ectopic, secondary, axis, when, either, was, 'co-injected', with, xFKBP1B, in, ventral, 'blastomeres,', whereas, they, downed, out, that, of, 'xFKBP1A,', suggesting, that, xFKBP1A, and, xFKBP1B, induce, the, ectopic, secondary, axis, through, affecting, different, pathways, from, each, other])].
[sujeto(['On', the, other, 'hand,', the, injection, of, the, 'FKBP1B', mRNA, in, dorsal, blastomeres, showed, eye, 'malformation,', and]), verbo([suppressed]), complemento([almost, completely, the, expression, of, 'Rx1,', 'Mitf,', and, 'Vax2', mRNAs])].
[sujeto([xFKBP1B, was]), verbo([expressed]), complemento([in, the, dorsal, side, of, the, embryo, including, the, eye, during, embryogenesis, at, least, until, stage, 46])].
[sujeto(['Injection', of, morpholino, of, the, xFKBP1B, mRNA, in, dorsal, blastomeres]), verbo([induced]), complemento([additional, retina, or, failed, to, close, tapetum, nigrum, in, the, ventral, side, within, the, optic, 'cap,', whereas, it, did, not, affect, the, dorsal, organ, development])].
[sujeto(['These', observations]), verbo([suggest]), complemento([that, xFKBP1B, is, a, key, factor, that, regulates, the, expression, levels, of, the, genes, involved, in, eye, formation, during, 'Xenopus', embryogenesis])].
[sujeto(['In', 'contrast,', lentiviral, vectors, are, readily, available, and, versatile, tools, for, the, transfer, of, genetic, information, into, a, wide, variety, of]), verbo([target]), complemento(['cells,', and, can, be, produced, at, high, titer, in, a, timely, manner])].
[sujeto(['To', combine, the, advantages, of, both, 'approaches,', we, generated, a, 'tight,', 'drug-controlled', 'FLP', recombinase, consisting, of, a, 5, '\'', 'FKBP12', derived, conditional, destruction, domain, and, a, 3, '\'', estrogen, receptor, ligand]), verbo([binding]), complemento(['(', 'ERT2)', domain])].
[sujeto(['We', successfully, constructed, lentiviral, vectors]), verbo([expressing]), complemento(['drug-controlled', 'FLP', in, combination, with, a, fluorescent, reporter, for, recombination, of, 'FLP', recognition, target, '(', 'FRT)', sites, located, in, trans, as, well, as, with, target, alleles, located, in, cis, '(', 'all-in-one', 'configuration)'])].
[sujeto(['In', this, 'chapter,', we, describe, the, design, of, the, drug, controlled, 'FLP', 'recombinase,', the, construction, of, molecular, switches, consisting, of, 'FLP']), verbo([expressing]), complemento([lentiviral, vectors, for, inducible, recombination, of, target, sites, located, in, cis, and, in, 'trans,', as, well, as, the, details, for, the, characterization, of, lentiviral, 'FLP', vectors, in, cell, lines])].
[sujeto(['Invasive', fungal, infections, remain, difficult, to, treat, and]), verbo([require]), complemento([novel, targeting, strategies])].
[sujeto(['The', 12, -, kDa, 'FK506-binding', protein, '(', 'FKBP12)', is, a, ubiquitously]), verbo([expressed]), complemento(['peptidyl-prolyl', isomerase, with, considerable, homology, between, fungal, pathogens, and, is, thus, a, prime, candidate, for, future, targeting, efforts, to, generate, a, panfungal, strategy])].
[sujeto([&, 'nbsp;albicans', 'FKBP12', crystal, structures, revealed, a, 'symmetric,', intermolecular, interaction]), verbo([involving]), complemento([the, deep, insertion, of, an, 'active-site', loop, proline, into, the, 'active-site', pocket, of, an, adjacent, subunit])].
[sujeto(['Such', interactions]), verbo([have]), complemento([not, been, observed, in, previous, 'FKBP', structures])].
[sujeto(['This']), verbo([finding]), complemento([indicates, the, possibility, that, this, is, a, 'self-substrate', interaction, unique, to, the, 'A'])].
[sujeto(['Structures', obtained, with, the, proline, in, the, cis, and, trans, states]), verbo([provide]), complemento([more, data, in, support, of, 'self-catalysis'])].
[sujeto(['Moreover,', cysteine, 'cross-linking', experiments, captured, the]), verbo([interacting]), complemento(['dimer,', supporting, the, idea, that, it, forms, in, solution])].
[sujeto(['Finally,', genetic, studies, exploring, the, impact, of, mutations, altering, the, central, proline, and, an, adjacent, residue]), verbo([provide]), complemento([evidence, that, any, dimeric, state, formed, in, 'vivo,', where, 'FKBP12', concentrations, are, 'low,', is, transient])].
[sujeto(['Taken', 'together,', these, findings]), verbo([suggest]), complemento([a, unique, mechanism, of, 'self-substrate', regulation, by, fungal, 'FKBP12s,', lending, further, novel, understanding, of, this, protein, for, future, 'drug-targeting', efforts])].
[sujeto(['FKBP12s', also]), verbo([bind]), complemento([the, immunosuppressive, drug, 'FK506', to, inhibit, the, phosphatase, calcineurin, '(', 'CaN)'])].
[sujeto(['CaN', is]), verbo([required]), complemento([for, virulence, of, 'A'])].
[sujeto([&, 'nbsp;albicans', 'FKBP12', structures]), verbo([reveal]), complemento([the, insertion, of, a, 'proline,', conspicuously, conserved, in, these, 'proteins,', into, the, active, sites, of, adjacent, molecules])].
[sujeto(['This']), verbo([suggests]), complemento([that, these, proteins, might, serve, as, their, own, substrates])].
[sujeto(['Cysteine', disulfide, trapping, experiments]), verbo([provide]), complemento([support, for, this, 'self-interaction', and, hence, possible, intermolecular, catalysis, by, these, enzymes])].
[sujeto(['Pin1']), verbo([regulates]), complemento([the, levels, and, functions, of, phosphoproteins, by, catalyzing, 'phosphorylation-dependent', 'cis/trans', isomerization, of, 'peptidyl-prolyl', bonds])].
[sujeto(['Previous', 'Pin1', inhibitors, contained, phosphoamino, 'acids,', which, are, metabolically, unstable, and]), verbo([have]), complemento([poor, membrane, permeability])].
[sujeto(['In', this, 'work,', we]), verbo([report]), complemento([a, 'cell-permeable', and, metabolically, stable, nonphosphorylated, bicyclic, peptide, as, a, potent, and, selective, 'Pin1', 'inhibitor,', which, inhibited, the, intracellular, 'Pin1', activity, in, cultured, mammalian, cells, but, had, little, effect, on, other, isomerases, such, as, 'Pin4,', 'FKBP12,', or, cyclophilin, 'A'])].
[sujeto(['FK506']), verbo([binding]), complemento([proteins, '(', 'FKBPs)', are, a, family, of, highly, conserved, proteins, in, eukaryotes])].
[sujeto(['The', prototype, of, this, protein, 'family,', 'FKBP12,', is, the]), verbo([binding]), complemento([partner, for, immunosuppressive, drugs, 'FK506', and, rapamycin])].
[sujeto(['FKBPs', are]), verbo([involved]), complemento([in, diverse, cellular, functions, including, protein, 'folding,', cellular, 'signaling,', apoptosis, and, transcription])].
[sujeto(['They', elicit, their, function, through, direct]), verbo([binding]), complemento([and, altering, conformation, of, their, target, 'proteins,', hence, acting, as, molecular, switches])].
[sujeto(['In', this, 'review,', we]), verbo([provide]), complemento([a, general, summary, for, the, structures, and, diverse, functions, of, 'FKBPs', found, in, mammalian, cells])].
[sujeto(['The', current, work, uses, high, performance, docking, methods, to, model, different, substrates]), verbo([binding]), complemento([into, the, active, sites, of, varying, 'Homo', sapien, and, 'Plasmodium', 'peptidyl-prolyl', 'cis/trans', isomerase, enzymes, and, compares, their, subsequent, docking, scores])].
[sujeto(['This', approach]), verbo([has]), complemento([shown, that, the, substrates, 'ILS-920', and, 'WYE-592', will, bind, 'less-favourably', with, hFKBP12, and, 'PfFKBP35', compared, to, a, competing, substrate, 'rapamycin;', 'however,', the, binding, appears, to, be, more, favourable, in, 'PvFKBP35'])].
[sujeto(['This', could]), verbo([suggest]), complemento([a, possible, target, for, inhibition, of, the, 'Plasmodium', vivax, parasite])].
[sujeto(['These', proteins, belong, to, the, 'FK506']), verbo([binding]), complemento([protein, '(', 'FKBP)', family, of, 'peptidyl-prolyl-cis/trans-isomerases', '(', 'PPIases)'])].
[sujeto(['pneumophila,', the, 'PPIase', activity, of, 'Mip', is]), verbo([required]), complemento([for, invasion, of, 'macrophages,', transmigration, through, an, in, vitro, 'lung-epithelial', 'barrier,', and, full, virulence, in, the, guinea, pig, infection, model])].
[sujeto(['Additionally,', 'Mip', is, a, moonlighting, protein, that]), verbo([binds]), complemento([to, collagen, 'IV', in, the, extracellular, matrix])].
[sujeto(['All', compounds, efficiently]), verbo([inhibited]), complemento(['PPIase', activity, of, the, prototypic, human, 'FKBP12', as, well, as, 'Mip', with, 'IC50-values', as, low, as, 180, nM, and, 1.7, 'μM,', respectively])].
[sujeto(['Five', of, these, derivatives]), verbo([inhibited]), complemento([the, growth, of, 'L'])].
[sujeto(['Accordingly,', by, applying, a, combinatorial, 'approach,', we, were, able, to, generate, 'novel,', hybrid, inhibitors, consisting, of, cycloheximide, and, 'adamantane,', two, known, 'FKBP', inhibitors, that]), verbo([interact]), complemento([with, different, parts, of, the, 'PPIase', 'domain,', respectively])].
[sujeto(['Hence,', we, also, propose, that, cycloheximide, derivatives, with, adamantyl, moieties, are, potent, 'PPIase', inhibitors, with, multiple]), verbo([targets]), complemento([in, 'L'])].
[sujeto(['Peptidyl-prolyl', 'cis/trans', isomerases, '(', 'PPIases),', a, unique, family, of, molecular, 'chaperones,']), verbo([regulate]), complemento([protein, folding, at, proline, residues])].
[sujeto(['Tau']), verbo([has]), complemento([been, shown, to, become, hyperphosphorylated, and, accumulate, as, one, of, the, two, main, pathological, hallmarks, in, 'Alzheimer\'s', 'disease,', the, other, being, amyloid, beta, '(', 'Ab)'])].
[sujeto(['PPIases,', including, 'Pin1,', 'FK506-binding', protein, '(', 'FKBP)', 52, ',', 'FKBP51,', and, 'FKBP12,']), verbo([have]), complemento([been, shown, to, interact, with, and, regulate, tau, biology])].
[sujeto(['This', interaction, is, particularly, important, given, the, numerous, 'proline-directed', phosphorylation, sites]), verbo([found]), complemento([on, tau, and, the, role, phosphorylation, has, been, found, to, play, in, pathogenesis])].
[sujeto(['However,', many, 'PPIases']), verbo([have]), complemento([yet, to, be, explored, for, their, effects, on, tau, 'biology,', despite, the, high, likelihood, of, interaction, based, on, proline, content])].
[sujeto(['Moreover,', 'Pin1,', 'FKBP12,', 'FKBP52,', cyclophilin, '(', 'Cyp)', 'A,', 'CypB,', and, 'CypD']), verbo([have]), complemento([been, shown, to, also, regulate, 'Ab', production, or, the, toxicity, associated, with, 'Ab', pathology])].
[sujeto(['Therefore,', 'PPIases', directly, and, indirectly]), verbo([regulate]), complemento([pathogenic, protein, multimerization, in, 'Alzheimer\'s', disease, and, represent, a, family, rich, in, targets, for, modulating, the, accumulation, and, toxicity])].
[sujeto(['We', present, a, new, computational, strategy, for, calculating, the, absolute]), verbo([binding]), complemento([free, energy, for, protein, ligand, association, in, the, context, of, atomistic, simulation, in, explicit, solvent])].
[sujeto(['The', hydrophilicity, of, the, solute, and, the, solute, torsional, plus, nonbonded, intrasolute, interactions, are]), verbo([increased]), complemento([and, 'decreased,', 'respectively,', along, the, replica, 'progression,', thus, favoring, the, extrusion, of, the, drug, form, the, active, site, in, the, scaled, states, of, the, generalized, ensemble])].
[sujeto(['The', proposed, 'technique,', named, &, 'quot;Energy', 'Driven', 'Undocking&quot;', '(', 'EDU-HREM),', completely, bypasses, the, need, for, defining, 'and/or', identifying, the, relevant, reaction, coordinates, in, a, ligand, receptor, interactions, and, allows, the, calculation, of, the, absolute]), verbo([binding]), complemento([free, energy, in, one, single, generalized, simulation, of, the, 'drug-receptor', system])].
[sujeto(['The', methodology, is, 'applied,', with, encouraging, 'results,', to, the, calculation, of, the, absolute]), verbo([binding]), complemento([free, energy, of, some, 'FK506-related', ligands, of, the, peptidyl, prolyl, 'cis-trans', isomerase, protein, '(', 'FKBP12)', with, known, dissociation, constants])].
[sujeto([6, ')', are, 'cis-trans', peptidyl, prolyl, isomerases, that, are]), verbo([expressed]), complemento([in, the, heart])].
[sujeto([6, were, previously, known, to]), verbo([interact]), complemento([with, ryanodine, receptors, in, striated, muscles])].
[sujeto(['Recently,', by, generating, 'FKBP12', transgenic, overexpression, and, 'cardiac-restricted', knockout, 'mice,', we, showed, that, 'FKBP12', is, critically, important, in]), verbo([regulating]), complemento(['trans-sarcolemmal', ionic, 'currents,', predominately, the, 'voltage-gated', 'Na+', 'current,', 'I(Na),', but, it, appears, to, be, less, important, for, regulating, cardiac, ryanodine, receptor, function])].
[sujeto([6, in]), verbo([regulating]), complemento([cardiac, ryanodine, receptors])].
[sujeto([6]), verbo([have]), complemento([very, different, physiologic, functions, in, the, heart])].
[sujeto(['Yeast', 'Fpr4p', belongs, to, the, 'FK506-binding', protein, '(', 'FKBP)', class, of, peptidyl, proline, isomerases, '(', 'PPIases),', and]), verbo([has]), complemento([been, implicated, in, regulating, the, 'cis-trans', conversion, of, proline, residues, within, histone, tails])].
[sujeto(['Here', we]), verbo([report]), complemento([the, '(', 1, ')', 'H,', '(', 13, ')', 'C', and, '(', 15, ')', 'N', chemical, shift, assignments, for, the, bacterially, expressed, 'C-terminal', 'PPIase', catalytic, domain, of, 'Fpr4p'])].
[sujeto(['Prediction', of, secondary, structure]), verbo([reveals]), complemento([similarity, to, domains, from, other, members, of, the, 'FKBP', proline, 'isomerases,', including, yeast, 'Fpr1p', and, the, prototypic, 'PPIase', region, from, human, 'FKBP12'])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, specificities, of, members, of, these, three, prolyl, isomerase, families, for, the, residue, following, the, 'proline,', again, in, short, peptide, and, in, refolding, protein, chains])].
[sujeto(['Protein', quantification, based, on, peptides, using, 'LC-MS/MS']), verbo([has]), complemento([emerged, as, a, promising, method, to, measure, 'biomarkers,', protein, 'drugs,', and, endogenous, proteins])].
[sujeto(['However,', the, best, practices, for, 'selection,', 'optimization,', and, validation, of, the, quantification, peptides, are, not, well, 'established,', and, the, influence, of, different, matrices, on, protein, 'digestion,', peptide, 'stability,', and, 'MS', detection]), verbo([has]), complemento([not, been, systematically, addressed])].
[sujeto(['The', microsomal, retinol, dehydrogenase, '(', 'RDH11)', and, cytosolic, soluble, aldehyde, dehydrogenases, '(', 'ALDH1As)']), verbo([involved]), complemento([in, the, synthesis, of, retinoic, acid, '(', 'RA)', were, chosen, as, model, proteins])].
[sujeto(['Considerable', differences, in, the, digestion, 'efficiency,', 'sensitivity,', and, matrix, effects, between, peptides, were, observed, regardless, of, the]), verbo([target]), complemento(['protein\'s', subcellular, localization])].
[sujeto(['The', results, demonstrate, that, different, sample, matrices]), verbo([have]), complemento(['peptide,', 'time,', and, matrix, specific, effects, on, protein, digestion, and, absolute, quantification])].
[sujeto(['Regeneration', of, the, visual, 'chromophore,', 11, -, 'cis-retinal,', is, a, crucial, step, in, the, visual, cycle]), verbo([required]), complemento([to, sustain, vision])].
[sujeto(['Double', deletion, of, 'Rdh5', and, 'Rdh10', '(', 'cDKO)', in, mice]), verbo([caused]), complemento([elevated, 11, /, 13, -, 'cis-retinyl', ester, content, also, seen, in, 'Rdh5(-/-)Rdh11(-/-)', mice, as, compared, with, 'Rdh5(-/-)', mice])].
[sujeto(['Normal', retinal, morphology, was, observed, in, 6, -, 'month-old', 'Rdh10', cKO, and, cDKO, 'mice,']), verbo([suggesting]), complemento([that, loss, of, 'Rdh10', in, the, 'RPE', does, not, negatively, affect, the, health, of, the, retina])].
[sujeto(['These', results, indicate, that, 'RDH10']), verbo([acts]), complemento([in, cooperation, with, other, 'RDH', isoforms, to, produce, the, 11, -, 'cis-retinal', chromophore, needed, for, vision])].
[sujeto(['Understanding', these, steps, will, help, to, elucidate, the, basis, of, specific, diseases]), verbo([associated]), complemento([with, abnormal, production, of, red, blood, cells])].
[sujeto(['In', this, 'study,', we, continued, our, efforts, to, identify, genes]), verbo([involved]), complemento([in, erythroid, proliferation])].
[sujeto(['Lentivirally', transduced, 'UT-7/Epo', erythroleukemic, cells]), verbo([expressing]), complemento([ribosomal, protein, 'L11', '(', 'RPL11)', or, retinol, dehydrogenase, 11, '(', 'RDH11)', could, proliferate, in, the, absence, of, 'erythropoietin,', and, their, 'cell-cycle', profiles, revealed, 'G0/G1', prolongation, and, low, percentages, of, apoptosis])].
[sujeto(['The', antiapoptotic, proteins, 'BCL-XL', and, 'BCL-2', were]), verbo([expressed]), complemento([in, both, cell, lines])].
[sujeto(['Several', signal, transduction, 'pathways,', including, 'STAT5,', were, highly]), verbo([activated]), complemento([in, transduced, 'cells;', 'furthermore,', expression, of, the, downstream, target, genes, of, 'STAT5,', such, as, 'CCND1,', was, upregulated, in, the, transduced, cells])].
[sujeto(['Retinol', dehydrogenase, 11, '(', 'RDH11)']), verbo([has]), complemento([been, postulated, to, be, anchored, to, membranes, by, means, of, its, 'N-terminal', segment, in, retinal, pigment, epithelial, '(', 'RPE)', cells, where, it, participates, to, the, visual, cycle])].
[sujeto(['The', analysis, of, the, primary, sequence, of, 'RDH11', revealed, that, its, 'N-terminal', hydrophobic, segment, could, be]), verbo([involved]), complemento([in, the, anchoring, of, this, enzyme, to, membranes])].
[sujeto(['The', secondary, structure, and, membrane]), verbo([binding]), complemento([of, two, 'N-terminal', peptides, of, 'RDH11', with, different, lengths, have, thus, been, investigated, to, provide, this, information])].
[sujeto(['Infrared', spectroscopy, and, circular, dichroism]), verbo([have]), complemento([shown, that, the, 'α-helix', of, the, 'Long-peptide', '(', 35, amino, 'acids)', is, longer, and, more, rigid, than, that, of, the, 'Short-peptide', '(', 25, amino, 'acids)', regardless, of, the, type, of, solvent])].
[sujeto(['Langmuir', monolayers]), verbo([have]), complemento([been, used, as, a, model, membrane, to, study, 'lipid-peptide', interactions])].
[sujeto(['Values', of, maximum, insertion, pressure, and, synergy]), verbo([suggested]), complemento([a, preferential, binding, of, the, 'Long-peptide', to, lipids, with, a, phosphoethanolamine, polar, head, 'group,', which, are, abundant, in, the, 'RPE'])].
[sujeto(['Furthermore,', infrared, spectroscopy, in, monolayers]), verbo([has]), complemento([shown, that, the, 'α-helical', structure, of, the, 'Long-peptide', is, more, stable, in, the, presence, of, saturated, phospholipids, whereas, the, structure, of, the, 'Short-peptide', is, mainly, disordered])].
[sujeto(['Retinitis', pigmentosa, '(', 'RP),', a, genetically, heterogeneous, group, of, retinopathies, that, occur, in, both, 'non-syndromic', and, syndromic, 'forms,', is]), verbo([caused]), complemento([by, mutations, in, '∼100', genes])].
[sujeto(['Although', recent, advances, in, 'next-generation', sequencing]), verbo([have]), complemento([aided, in, the, discovery, of, novel, 'RP', 'genes,', a, number, of, the, underlying, contributing, genes, and, loci, remain, to, be, identified])].
[sujeto(['We', investigated, three, 'siblings,', born, to, asymptomatic, parents, of, 'Italian-American', 'descent,', who, each, presented, with, atypical, 'RP', with, systemic, 'features,', including, facial, 'dysmorphologies,', psychomotor, developmental, delays]), verbo([recognized]), complemento([since, early, 'childhood,', learning, disabilities, and, short, stature])].
[sujeto(['In', 'summary,', deleterious, mutations, in, 'RDH11,', an, important, enzyme, for, 'vision-related', and, systemic, retinoic, acid, 'metabolism,']), verbo([cause]), complemento([a, new, syndrome, with, 'RP'])].
[sujeto(['The', 'male-specific', region, of, the, human, 'Y', chromosome, '(', 'MSY)', is, passed, down, clonally, from, father, to]), verbo([son]), complemento([and, mutation, is, the, single, driving, force, for, 'Y-chromosomal', diversification])].
[sujeto(['For', forensic, 'applications,', 'however,', any]), verbo([targeted]), complemento([marker, has, to, be, unequivocally, interpretable])].
[sujeto(['Here,', we]), verbo([report]), complemento([findings, for, 17, samples, from, a, population, study, comprising, specimens, from, '∼3700', men, living, in, 'Tyrol', '(', 'Austria),', indicating, apparent, homoplasic, mutations, at, four, 'Y-SNP', loci, on, haplogroup, 'R-M412/L51/S167,', 'R-U152/S28,', and, 'L-M20', 'Y', chromosomes])].
[sujeto(['The', poor, quality, of, prepubertally, derived, oocytes]), verbo([suggests]), complemento([that, essential, processes, during, cytoplasmic, maturation, have, not, been, completed])].
[sujeto(['The', objective, of, this, experiment, was, to, identify, genes, in, oocytes, that, are]), verbo([associated]), complemento([with, good, '(', cyclic, 'females)', and, poor, '(', prepubertal, 'females)', developmental, competence])].
[sujeto(['Development', to, the, blastocyst, stage, in, vitro, was, significantly]), verbo([decreased]), complemento([in, oocytes, derived, from, prepubertal, females, compared, with, cyclic, females, '(', 5.26, and, 12.86, '%', ',', 'respectively)'])].
[sujeto(['Approximately', 10, '%', of, the, oocyte, transcriptome, was, differentially]), verbo([expressed]), complemento([between, in, 'vitro-matured', oocytes, derived, from, cyclic, and, prepubertal, females, '(', 'P', &, 'lt;', 0.05, ')', ;, 58, '%', of, differentially, expressed, genes, had, increased, transcript, abundance, in, oocytes, derived, from, cyclic, females])].
[sujeto(['Genes']), verbo([involved]), complemento([in, the, metabolism, and, regulation, of, biological, processes, had, increased, transcript, abundance, in, oocytes, derived, from, cyclic, 'females,', whereas, genes, involved, in, translation, were, increased, in, prepubertally, derived, oocytes])].
[sujeto(['Quantitative', 'PCR', confirmed, differential, expression, '(', 'P', &, 'lt;', 0.05, ')', for, 6, out, of, 11, selected, genes, '[', 'DPYD', '(', dihydropyrimidine, 'dehydrogenase),', 'RDH11', '(', retinol, dehydrogenase, 11, ')', ',', 'SFRS4', '(', 'serine/arginine-rich', splicing, factor, 4, ')', ',', 'SFRS7', '(', 'serine/arginine-rich', splicing, factor, 7, ')', ',', 'TL4', '(']), verbo([transcribed]), complemento([loci, 4, ')', ',', and, 'TOP2B', '(', topoisomerase, 'II', 'β)]', that, were, differentially, expressed, with, greater, than, a, 2, -, fold, change, by, 'microarray,', although, 3, of, these, 'genes,', 'DPYD,', 'TL4,', and, 'TOP2B,', were, in, opposing, directions, by, the, 2, methods])].
[sujeto(['In', 'conclusion,', expression, of, multiple, genes]), verbo([involved]), complemento([in, metabolism, and, translation, was, significantly, altered, in, oocytes, from, prepubertal, females, compared, with, cyclic, 'females,', which, was, associated, with, reduced, in, vitro, development, to, the, blastocyst, stage])].
[sujeto(['These', genes, may, represent, important, cellular, mechanisms, that]), verbo([regulate]), complemento([oocyte, quality])].
[sujeto(['The', visual, cycle, 'RDHs']), verbo([have]), complemento([been, extensively, 'studied,', but, because, multiple, 'RDHs', are, capable, of, catalyzing, each, 'step,', the, exact, 'RDHs', responsible, for, each, reaction, remain, unknown])].
[sujeto(['Here,', we, review, the, characteristics, of, each, 'RDH', in, vitro, and, the, findings, from, knockout, models, that]), verbo([suggest]), complemento([the, roles, for, each, in, the, visual, cycle])].
[sujeto(['To', identify, genes, and, molecular, mechanisms]), verbo([associated]), complemento([with, photoreceptor, degeneration, in, a, canine, model, of, 'XLRP', caused, by, an, 'RPGR', exon, 'ORF15', microdeletion])].
[sujeto(['At', 7, and, 16, 'weeks,', 'respectively,', 56, and, 18, transcripts, were, downregulated, in, the, mutant, 'retinas,', but, none, were, differentially]), verbo([expressed]), complemento(['(', 'DE)', at, both, 'ages,', suggesting, the, involvement, of, temporally, distinct, pathways])].
[sujeto(['At', 7, 'weeks,', a, combination, of, nonclassic, 'anti-', and, proapoptosis, genes, appear, to, be]), verbo([involved]), complemento([in, photoreceptor, 'degeneration,', whereas, at, both, 7, and, 16, 'weeks,', the, expression, of, 'mitochondria-related', genes, indicates, that, they, may, play, a, relevant, role, in, the, disease, process])].
[sujeto(['Mutations', of, the, photoreceptor, retinol, dehydrogenase, 12, '(', 'RDH12)', gene]), verbo([cause]), complemento([the, early, onset, retinal, dystrophy, 'Leber', congenital, amaurosis, '(', 'LCA)', by, mechanisms, not, completely, resolved])].
[sujeto(['In', the, 'retina,', exposure, to, bright, light]), verbo([induced]), complemento([lipid, 'peroxidation,', 4, -, 'HNE', 'production,', and, 4, -, 'HNE', modification, of, proteins, in, photoreceptor, inner, 'segments,', where, 'RDH11', and, 'RDH12', are, located])].
[sujeto(['In', mouse, 'retina,', 'RDH12-but', not, 'RDH11-protected', against, adduct, 'formation,']), verbo([suggesting]), complemento([that, 4, -, 'HNE', is, a, physiological, substrate, of, 'RDH12'])].
[sujeto(['High-level', amplifications, observed, in, tumor, cells, are, usually, indicative, of, genes]), verbo([involved]), complemento([in, oncogenesis])].
[sujeto(['We']), verbo([report]), complemento([here, a, high, resolution, characterization, of, a, new, amplified, region, in, the, 'SW613-S', carcinoma, cell, line])].
[sujeto(['Both', amplicons, were, stably]), verbo([maintained]), complemento([upon, in, vitro, and, in, vivo, propagation])].
[sujeto([1, amplicon, was, not]), verbo([found]), complemento([in, cells, with, 'high-level', 'MYC', amplification, in, the, form, of, 'HSRs,', either, obtained, after, spontaneous, integration, of, endogenous, 'DM', 'MYC', copies, or, after, transfection, of, 'DM(-)', cells, with, a, 'MYC', gene, expression, vector])].
[sujeto(['Efficacy', of, camptothecins, '(', 'CPTs)', such, as, irinotecan]), verbo([has]), complemento([been, recognized, in, chemotherapy, of, cancers, including, melanoma])].
[sujeto(['However,', the, majority, of]), verbo([responding]), complemento([patients, will, gradually, acquire, drug, resistance])].
[sujeto(['To']), verbo([gain]), complemento([global, insight, into, acquired, 'CPT-resistance,', we, established, 'irinotecan-resistant', clones, derived, from, melanoma, cells, and, compared, their, whole, genomes, by, high, resolution, 'array-CGH'])].
[sujeto(['A', novel]), verbo([gain]), complemento([at, 14, q23])].
[sujeto(['Further', analysis, of, this, amplicon, indicates, that, it, encompassed, genes]), verbo([involved]), complemento([in, 'DNA', repair, '(', 'RAD51L,', 'MLH3),', reactive, oxygen, species, '(', 'GPX2,', 'CSTZ1,', 'NGB,', 'RDH11,', 'ZADH1),', and, transportome, '(', 'ABCD4,', 'ATP6V1D,', 'SLC10A6)'])].
[sujeto(['Moreover,']), verbo([losses]), complemento([were, also, detected, at, the, loci, of, topoisomerases, '(', 'TOP1,', 'SPO11,', 'TOP3B)', as, well, as, at, the, loci, of, genes, guarding, chromosomal, stability, '(', 'TP53,', 'ZW10,', 'H2AFX,', 'CHK1,', 'CCDN1,', 'MCM5,', 'CENPB,', 'DNMT3B),', which, would, facilitate, the, development, of, drug, resistance])].
[sujeto(['Taken', 'together,', our, data]), verbo([suggest]), complemento([that, genes, involved, in, genome, stability, may, greatly, contribute, to, the, development, of, 'CPTs-resistance'])].
[sujeto([3, -, 31.1, would, be, promising]), verbo([targets]), complemento([to, overcome, acquired, 'CPT-resistance', in, melanoma])].
[sujeto(['RDH11', and, 'RDH12', are, closely, related, retinol, dehydrogenases]), verbo([expressed]), complemento([in, the, retina])].
[sujeto(['RDH12']), verbo([has]), complemento([been, linked, to, the, 'early-onset', retinal, dystrophy, 'Leber', congenital, 'amaurosis,', whereas, 'RDH11', has, not, been, associated, with, human, disease])].
[sujeto(['RDH12', expression, started, at, 'P7', and]), verbo([increased]), complemento([until, 'P30', to, approximately, sevenfold, higher, than, 'RDH11'])].
[sujeto(['Oxidative', stress]), verbo([induced]), complemento([by, exposure, to, constant, bright, light, led, to, a, rapid, and, significant, decrease, of, 'RDH12', protein])].
[sujeto(['The', low, and, constant, expression, of, 'RDH11']), verbo([suggested]), complemento([a, housekeeping, function, for, this, enzyme])].
[sujeto(['The', onset, of, 'RDH12', expression, during, the, maturation, of, photoreceptor, cells]), verbo([suggested]), complemento([a, function, related, to, the, visual, process])].
[sujeto(['The', 'light-induced', rapid]), verbo([decrease]), complemento([of, 'RDH12', 'protein,', preceding, the, decrease, of, the, 'mRNA,', suggested, a, specific, degradation, of, the, protein, rather, than, a, regulation, of, gene, expression])].
[sujeto(['As', the, substrates, for, 'retinoid-metabolizing', enzymes, are, water, 'insoluble,', they, must, be, transported, intracellularly]), verbo([bound]), complemento([to, cellular, 'retinol-binding', proteins])].
[sujeto(['Our', studies]), verbo([suggest]), complemento([that, cellular, 'retinol-binding', 'protein,', type, 'I', '(', 'RBP1)', acts, as, an, intracellular, sensor, of, retinoid, status, 'that,', when, present, as, 'apo-RBP1,', stimulates, 'BCMO1', activity, and, the, conversion, of, carotenoids, to, retinoids])].
[sujeto(['Our', studies]), verbo([provide]), complemento([new, insights, into, the, regulation, of, 'BCMO1', activity, and, the, physiological, role, of, 'BCMO1', in, living, organisms])].
[sujeto(['Protease', protection, assays]), verbo([suggest]), complemento([that, 'RDH13', is, localized, on, the, outer, side, of, the, inner, mitochondrial, membrane])].
[sujeto(['Kinetic', analysis, of, the, purified, protein, shows, that, 'RDH13', is, catalytically, active, and]), verbo([recognizes]), complemento([retinoids, as, substrates])].
[sujeto(['Similar', to, the, microsomal, 'RDHs,', 'RDH11,', 'RDH12', and, 'RDH14,', 'RDH13', exhibits, a, much, lower, 'Km', value, for, 'NADPH', than, for, 'NADH', and]), verbo([has]), complemento([a, greater, catalytic, efficiency, in, the, reductive, than, in, the, oxidative, direction])].
[sujeto(['The', localization, of, 'RDH13', at, the, entrance, to, the, mitochondrial, matrix]), verbo([suggests]), complemento([that, it, may, function, to, protect, mitochondria, against, oxidative, stress, associated, with, the, highly, reactive, retinaldehyde, produced, from, dietary, 'beta-carotene'])].
[sujeto(['Mutations', in, 'RDH12']), verbo([cause]), complemento([severe, and, progressive, childhood, onset, 'autosomal-recessive', retinal, 'dystrophy,', including, 'Leber', congenital, amaurosis])].
[sujeto(['RDH12', was, localized, to, photoreceptor, inner, segments, and, the, outer]), verbo([nuclear]), complemento([layer, in, both, mouse, and, human, retinas, by, immunohistochemistry])].
[sujeto(['The', present, 'findings,', together, with, those, of, earlier, studies, showing, only, minor, functional, deficits, in, mice, deficient, for, 'Rdh5,', 'Rdh8,', or, 'Rdh11,']), verbo([suggest]), complemento([that, the, activity, of, any, one, isoform, is, not, rate, limiting, in, the, visual, response])].
[sujeto(['Production', of, 11, -, 'cis-retinal,', the, visual, pigment, 'chromophore,', was]), verbo([suppressed]), complemento([with, a, potent, inhibitor, of, the, retinoid, 'cycle,', 'all-trans-retinylamine', '(', 'Ret-NH2)'])].
[sujeto(['Administration', of, 9, -, 'cis-retinal']), verbo([increased]), complemento([the, rate, of, dark, adaptation, and, improved, cone, function, in, 'Rdh5-/-Rdh11-/-', mice])].
[sujeto(['Disruption', of, 11, -, 'cis-RDHs']), verbo([causes]), complemento([a, slowly, developing, cone, dystrophy, caused, by, inefficient, cone, pigment, regeneration])].
[sujeto([albipunctatus, after, treatment, with, 9, -, 'cis-retinal,']), verbo([suggesting]), complemento([a, potential, approach, to, slow, the, progression, of, cone, dystrophy, in, affected, humans])].
[sujeto(['Protein', splicing, by, inteins]), verbo([has]), complemento([found, diverse, applications, in, 'biotechnology,', protein, chemistry, and, chemical, biology])].
[sujeto(['Here,', we, identified, positions, 'T22S', and, 'S35', in, the, 'LacZα', peptide, as, intein, insertion, sites, that, strictly]), verbo([require]), complemento([protein, 'splicing,', in, contrast, to, cleavage, 'side-reactions,', to, allow, for, complementation, of, 'β-galactosidase', activity])].
[sujeto(['Furthermore,', we]), verbo([report]), complemento([the, two, 'novel,', naturally, split, 'VidaL', 'T4Lh-1', and, 'VidaL', 'UvsX-2', inteins, whose, 'N-terminal', fragments, consist, of, only, 15, and, 16, amino, 'acids,', respectively])].
[sujeto(['Finally,', we, used, the, 'LacZα', host, system, to, rapidly, identify, amino, acid, substitutions, from, a, small, randomized, library, at, the, structurally]), verbo([conserved]), complemento([intein, position, 2, next, to, the, catalytic, 'center,', that, are, tolerated, for, protein, splicing, activity, of, the, 'M86', intein])].
[sujeto(['No', previous, study]), verbo([has]), complemento([evaluated, the, associations, of, dairy, 'products,', 'lactose,', calcium, and, vitamin, 'D', with, the, risk, of, ovarian, cancer, in, 'African-American', 'women,', who, are, known, to, have, high, mortality, from, the, 'disease,', as, well, as, to, be, at, risk, for, calcium, and, vitamin, 'D', deficiency])].
[sujeto(['We', evaluated, these, associations, among, 490, ovarian, cancer, cases, and, 656, 'age-', and, 'site-matched', controls, of, 'African-American', descent]), verbo([recruited]), complemento([into, the, 'African', 'American', 'Cancer', 'Epidemiology', 'Study,', a, 'population-based', 'case-control', study, in, 11, geographical, areas, in, the, 'US'])].
[sujeto(['An']), verbo([increased]), complemento([ovarian, cancer, risk, was, observed, for, whole, milk, consumption, and, lactose, intake, '(', highest, quartile, vs, 'lowest:', 'OR=1'])].
[sujeto(['Calcium', intake, was]), verbo([associated]), complemento([with, a, decreased, risk, of, ovarian, cancer, '(', 'OR=0'])].
[sujeto(['Longer', sun, exposure, in, summer, months, was]), verbo([found]), complemento([to, predict, a, lower, risk, '(', 'OR=0'])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, a, 'high-calcium,', 'low-lactose', 'diet,', and, sun, exposure, in, summer, months, may, reduce, the, risk, of, ovarian, cancer, in, 'African-American', women])].
[sujeto(['Polygalacturonases', '(', 'PGs)', can, degrade, pectins, and]), verbo([participate]), complemento([in, multiple, developmental, processes, of, plants])].
[sujeto(['We']), verbo([found]), complemento([that, this, disparity, was, the, result, of, less, duplication, and, more, gene, losses, in, grasses])].
[sujeto(['More', duplications, occurred, in, clades, 'D', and, 'E,', and, expression, analysis, showed, that, most, of, clade, 'E', members, were]), verbo([expressed]), complemento([ubiquitously, at, a, high, overall, level, and, clade, 'D', members, were, closely, related, to, male, reproduction, in, both, grasses, and, 'dicots,', suggesting, their, biological, functions, were, highly, conserved, across, species])].
[sujeto(['Taiwan']), verbo([has]), complemento([the, highest, renal, disease, incidence, and, prevalence, in, the, world])].
[sujeto(['Statins', and, 'RASIs', independently]), verbo([have]), complemento([a, significant, 'dose-dependent', protective, effect, against, dialysis, risk, in, hypertensive, patients])].
[sujeto(['We', evaluated, whether]), verbo([regular]), complemento([mobile, phone, text, reminders, improved, 'patients\'', retention, in, antiretroviral, therapy, '(', 'ART)', care, in, 'Mozambique'])].
[sujeto(['SMSaúde', was, a, randomized, control, trial, of, 'HIV-infected', patients, on, 'ART', who, received]), verbo([regular]), complemento([text, message, reminder, vs])].
[sujeto(['We', used, 'Kaplan-Meier', estimators, and, 'log-rank', tests, to, compare, proportions, of, patients, who, received, 'SMS', reminders, who, were]), verbo([retained]), complemento([in, 'HIV', care, compared, to, the, control, group, who, received, standard, of, care])].
[sujeto(['However,', 'high-throughput', experiments, frequently]), verbo([provide]), complemento([only, initial, information, that, a, particular, protein, might, play, a, role, in, regulating, structure, and, function, of, the, 'Golgi', complex])].
[sujeto(['In', order, to, speed, up, the, 'discovery,', we]), verbo([have]), complemento([established, a, system, for, correlative, screening, microscopy, that, combines, rapid, data, collection, and, 'high-resolution', imaging, in, one, experiment])].
[sujeto([&, 'quot;', 'This', article, summarizes, our, current, knowledge, of, poor, 'CI', 'performance,', and]), verbo([provides]), complemento([suggestions, to, clinicians, managing, these, patients])].
[sujeto(['The', broad, array, of, factors, that, contribute, to, speech, recognition, performance, in, adult, 'CI', users]), verbo([suggests]), complemento([the, potential, both, for, novel, diagnostic, assessment, batteries, to, explain, poor, 'performance,', and, also, new, rehabilitation, strategies, for, patients, who, exhibit, poor, outcomes])].
[sujeto(['Moreover,', this, broad, array, of, factors, determining, outcome, performance]), verbo([suggests]), complemento([the, need, to, treat, individual, 'CI', patients, using, a, personalized, rehabilitation, approach])].
[sujeto(['Biostimulation', is, widely, used, to]), verbo([enhance]), complemento([reductive, dechlorination, of, chlorinated, ethenes, in, contaminated, aquifers])].
[sujeto(['Consistent', with, anoxic, conditions, and, sulfate, reduction, after, 'biostimulation,', 'MiSeq', 16, 'S', rRNA, gene, sequencing, revealed, temporarily]), verbo([increased]), complemento([relative, abundance, of, 'Firmicutes,', 'Bacteriodetes', and, sulfate, reducing, 'Deltaproteobacteria'])].
[sujeto(['In', line, with, '(', 13, ')', 'C', cDCE, enrichment, and]), verbo([increased]), complemento(['Dehalococcoides', mccartyi, '(', 'Dcm)', 'numbers,', dechlorination, was, observed, towards, the, end, of, the, field, 'experiment,', albeit, being, incomplete, with, accumulation, of, vinyl, chloride])].
[sujeto(['This', was, concurrent, with, 'i)']), verbo([decreased]), complemento([concentrations, of, dissolved, organic, carbon, '(', 'DOC),', reduced, relative, abundances, of, fermenting, and, sulfate, reducing, bacteria, that, have, been, suggested, to, promote, 'Dcm', growth, by, providing, electron, donor, '(', 'H2', ')', and, essential, corrinoid, 'cofactors,', 'ii)', increased, sulfate, concentration, and, increased, relative, abundance, of, 'Epsilonproteobacteria', and, 'Deferribacteres', as, putative, oxidizers, of, reduced, sulfur, compounds])].
[sujeto(['Tracking', microbial, and, environmental, parameters, that, 'promote/preclude']), verbo([enhanced]), complemento([reductive, dechlorination, should, aid, development, of, sustainable, bioremediation, strategies])].
[sujeto(['The', reactivity, of, sulfonic, acids, could, be, significantly]), verbo([enhanced]), complemento([in, the, presence, of, strong, hydrogen, bonding, donors])].
[sujeto([1, ')', ',', less, blood]), verbo([loss]), complemento(['(', 'WMD', =, -, 25.9, ',', 95, '%', 'CI:', -, 43.11, to, -, 8.7, ',', 'P&lt;0'])].
[sujeto(['Pneumonia', is, a, frequent, complication, in, dementia, patients, and, is]), verbo([associated]), complemento([with, high, mortality, rates])].
[sujeto(['The', aim, of, this, retrospective, cohort, study, was, to, determine, whether, traditional, 'Chinese', medicine, '(', 'TCM)', therapy, can]), verbo([decrease]), complemento([pneumonia, risk, in, dementia, patients])].
[sujeto(['Patients', who, received, 'TCM', therapy, at, higher, cumulative, doses, or, for, longer, periods, experienced]), verbo([increased]), complemento([protection, from, pneumonia, admission])].
[sujeto(['TCM', might, be]), verbo([associated]), complemento([with, a, lower, risk, of, pneumonia, in, dementia, patients])].
[sujeto(['Previous', studies]), verbo([have]), complemento([investigated, the, relationship, between, 'GSTA1,', 'GSTM1,', 'GSTP1,', and, 'GSTT1', polymorphisms, and, bladder, cancer, '(', 'BCa)', 'susceptibility,', 'respectively,', but, the, results, remain, inconsistent])].
[sujeto(['Besides,', meaningful, association, between, individuals, who, carried, the, 'GSTM1', null, genotype, and]), verbo([increased]), complemento(['BCa', risk, was, detected, '(', 'OR', =, 1.39, ',', 95, '%', 'CI', 1.28, -, 1.51, ')'])].
[sujeto(['When', stratified, by, 'ethnicity,', significant, difference, was]), verbo([found]), complemento([in, both, 'Caucasian', '(', 'OR', =, 1.39, ',', 95, '%', 'CI', 1.23, -, 1.58, ')', and, 'Asian', populations, '(', 'OR', =, 1.45, ',', 95, '%', 'CI', 1.31, -, 1.61, ')'])].
[sujeto(['Furthermore,', when, stratified, by, 'SOC,', no, obvious, relationship, was]), verbo([found]), complemento([between, the, 'GSTT1', null, genotype, polymorphism, with, 'hospital-based', population, '(', 'OR', =, 1.11, ',', 95, '%', 'CI', 0.97, -, 1.28, ')', or, 'population-based', population, '(', 'OR', =, 1.1, ',', 95, '%', 'CI', 0.96, -, 1.27, ')'])].
[sujeto(['This', study]), verbo([suggested]), complemento([that, 'GSTM1', null, genotype, and, 'GSTT1', null, genotype, might, be, related, to, higher, 'BCa', 'risk,', respectively])].
[sujeto(['The', matrix, 'metalloproteinase/tissue', inhibitor, of, metalloproteinase, '(', 'MMP/TIMP)', system, was]), verbo([found]), complemento([to, play, a, significant, role, in, the, development, of, 'ONFH'])].
[sujeto(['We']), verbo([found]), complemento([that, the, minor, alleles, of, rs1940475, and, rs11225395, in, 'MMP8', were, associated, with, a, 1.32, -, fold, increased, risk, of, 'steroid-induced', 'ONFH', in, the, allelic, model, analysis, '(', 'P', =, 0.021, and, 0.022, ',', 'respectively)'])].
[sujeto(['In', the, genetic, model, 'analysis,', we]), verbo([found]), complemento([that, 'rs3740938,', 'rs2012390,', 'rs1940475,', and, rs11225395, were, associated, with, an, increased, risk, of, 'steroid-induced', 'ONFH'])].
[sujeto(['In', further, stratification, 'analysis,', rs3740938, and, rs2012390, displayed, a, significantly]), verbo([increased]), complemento([risk, of, 'steroid-induced', 'ONFH', in, females, under, the, dominant, '(', 'rs3740938,', 'OR', =, 2.69, ',', 95, '%', 'CI:', 1.5, -, 4.83, ',', 'P', =, 0.001, ;, 'rs2012390,', 'OR', =, 2.3, ',', 95, '%', 'CI:', 1.31, -, 4.03, ',', 'P', =, 0.012, ')', and, additive, '(', 'rs3740938,', 'OR', =, 2.02, ',', 95, '%', 'CI:', 1.24, -, 3.29, ',', 'P', =, 0.01, ;, 'rs2012390,', 'OR', =, 1.77, ',', 95, '%', 'CI:', 1.12, -, 2.8, ',', 'P', =, 0.047, ')', models])].
[sujeto(['In', 'addition,', haplotype, &, 'quot;AGTCA&quot;', of, 'MMP8', was]), verbo([found]), complemento([to, be, associated, with, a, 1.4, -, fold, increased, risk, of, 'steroid-induced', 'ONFH', '(', 95, '%', 'CI:', 1.04, -, 1.88, ',', 'P', =, 0.025, ')'])].
[sujeto(['In', 'addition,', we]), verbo([found]), complemento([that, gender, differences, might, interact, with, 'MMP8', polymorphisms, to, contribute, to, the, overall, susceptibility, to, 'steroid-induced', 'ONFH'])].
[sujeto(['Similarly,', subgroup, analysis, by, detection, 'method,', ethnicity, and, cancer, subtype, analysis]), verbo([suggested]), complemento([that, lower, expression, of, 'miR-218', correlated, with])].
[sujeto(['Our', data, demonstrated, that, lower, 'miR-218', expression, is, significantly]), verbo([associated]), complemento([with, poorer, overall, survival, '(', 'OS)', and, 'DFS/PFS/RFS', and, may, be, a, novel, prognostic, biomarker, in, some, cancer, types])].
[sujeto(['Multivariate', analysis, revealed, that, 'LVI', positivity, and, poorly, differentiated, histology, were, independently]), verbo([associated]), complemento([with, lymph, node, metastasis, '(', 'LNM;', 'P', &, 'lt;', 0.001, and, 'P', =, 0.001, ',', 'respectively)'])].
[sujeto(['In', 'addition,', when, the, depth, of, submucosal, invasion, was, extended, up, to, 2000, 'μm,', 'LNM', was]), verbo([increased]), complemento(['(', 4, /, 271, patient, '[', 1.5, '%', ']', ')'])].
[sujeto(['Endoscopic', treatment, is, 'safe,', 'effective,', and, is]), verbo([associated]), complemento([with, favorable, 'long-term', outcomes, compared, to, surgery, for, initial, treatment, of, 'T1', 'CRC', patients, with, 'CIs'])].
[sujeto(['The', nasal, bone, did, not]), verbo([reveal]), complemento([any, abnormality, in, any, case])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, that, caffeine, can, enhance, chemotherapy, efficacy, of, bone, and, 'soft-tissue', sarcoma, via, 'cell-cycle', perturbation])].
[sujeto(['Valproic', acid]), verbo([has]), complemento([histone, deacetylase, '(', 'HDAC)', inhibitory, activity])].
[sujeto(['Both', valproic, acid, and, caffeine]), verbo([caused]), complemento(['concentration-dependent', cell, death, of, the, osteosarcoma, cell, lines, in, vitro])].
[sujeto(['The', combination, of, valproic, acid, and, caffeine, showed, effective, 'anti-tumor', activity, in, vivo, without, the, need, for, conventional, anticancer, drugs, or, any, observable, toxicity, 'Conclusion:', 'Efficacy', of, combination, therapy, with, caffeine, and, valproic, acid, in, osteosarcoma, was, observed, in, vitro, and, in, vivo, without, 'toxicity,']), verbo([suggesting]), complemento([that, either, or, both, drugs, can, be, effectively, combined, with, appropriate, chemotherapy, in, the, future])].
[sujeto(['To', investigate, whether, the, circadian, rhythm, disruption, following, the, transition, into, and, out, of, daylight, saving, time, '(', 'DST)', is]), verbo([associated]), complemento([with, an, increased, risk, of, spontaneous, delivery])].
[sujeto(['Our', results, do, not, support, the, hypothesis, that, a, minor, circadian, rhythm, disruption, is]), verbo([associated]), complemento([with, an, increased, 'short-term', risk, of, spontaneous, delivery])].
[sujeto(['Enrichment', analysis, conducted, on, 485, differentially]), verbo([expressed]), complemento([genes, between, nodular, and, diffuse, parathyroid, hyperplasia, revealed, highly, significant, differences, in, 'GO', terms, and, the, 'KEGG', database, in, ribosome, structure, '(', 'p=3'])].
[sujeto(['Next,', 'RT-qPCR', validation, of, the, top, differently]), verbo([expressed]), complemento([genes, from, microarray, analysis, proved, higher, expression, of, 'RAN', guanine, nucleotide, release, factor, '(', 'RANGRF,', 'p&lt;0'])].
[sujeto([1, ')', ',', calcyclin]), verbo([binding]), complemento([protein, '(', 'CACYBP,', 'p&lt;0'])].
[sujeto(['Multivariate', analysis, revealed, higher, 'RANGRF', and, lower, 'PIN1', expression, along, with, parathyroid, weight, to, be]), verbo([associated]), complemento([with, nodular, hyperplasia])].
[sujeto(['Our', study]), verbo([suggests]), complemento([the, 'RANGRF', transcript, which, controls, the, 'RNA', metabolism, to, be, likely, involved, in, pathways, associated, with, the, switch, to, nodular, parathyroid, growth])].
[sujeto(['This', transcript, along, with, 'PIN1', transcript, which, influences, the, 'PTH', secretion, may, represent, new, therapeutical]), verbo([targets]), complemento([to, cure, secondary, hyperparathyroidism])].
[sujeto(['Currently,', we, used, 'two-dimensional', gel, electrophoresis, '(', 2, 'DE)', to, identify, differentially]), verbo([expressed]), complemento([proteins, in, abdominal, adipose, tissues, of, birds, at, 4, &, 'nbsp;week', of, age, derived, from, 'Northeast', 'Agricultural', 'University', broiler, lines, divergently, selected, for, abdominal, fat, content, '(', 'NEAUHLF)'])].
[sujeto(['Thirteen', differentially]), verbo([expressed]), complemento([protein, spots, were, screened, out, and, identified, by, 'matrix-assisted', laser, 'desorption-ionization', 'time-of-flight', mass, spectrometry, '(', 'MALDI-TOF-MS)'])].
[sujeto(['These', differentially]), verbo([expressed]), complemento([proteins, are, involved, mainly, in, lipid, 'metabolism,', amino, acid, 'metabolism,', signal, 'transduction,', energy, 'conversion,', 'antioxidant,', and, cytoskeleton])].
[sujeto(['Quantitative', 'real-time', 'RT-PCR', analyses, showed, 'that,', of, these, 13, differentially]), verbo([expressed]), complemento(['proteins,', only, 'PPIase', 'FKBP4', and, cytokeratin, otokeratin, were, differentially, expressed, at, mRNA, level, between, the, two, lines])].
[sujeto(['Our', results]), verbo([have]), complemento([provided, further, information, for, understanding, the, basic, genetics, control, of, growth, and, development, of, broiler, adipose, tissue])].
[sujeto(['The', bacteria, 'Burkholderia', pseudomallei, and, 'Legionella', pneumophila]), verbo([cause]), complemento([severe, diseases, like, melioidosis, and, 'Legionnaire\'s', disease, with, high, mortality, rates, despite, antibiotic, treatment])].
[sujeto(['Due', to]), verbo([increasing]), complemento([antibiotic, resistances, against, these, and, other, 'Gram-negative', 'bacteria,', alternative, therapeutical, strategies, are, in, urgent, demand])].
[sujeto(['In', previous, 'studies,', the, pipecolic, acid, moiety, proved, to, be, a, valuable, scaffold, for]), verbo([inhibiting]), complemento([this, 'PPIase', activity])].
[sujeto(['Thus,', a, library, of, pipecolic, acid, derivatives, was, established, guided, by, structural, information, and, computational, analyses, of, the]), verbo([binding]), complemento([site, and, possible, binding, modes])].
[sujeto(['The', activities, can, be, interpreted, in, terms, of, a, common]), verbo([binding]), complemento([mode, obtained, by, docking, calculations])].
[sujeto(['Beside', various, other, immunological, 'functions,', 'CypA']), verbo([induces]), complemento([leucocytes, migration, in, vitro, in, teleost])].
[sujeto(['In', the, current, 'study,', we]), verbo([have]), complemento([discovered, several, novel, 'immune-relevant', proteins, in, yellow, catfish, skin, mucus, by, mass, spectrometry, '(', 'MS)'])].
[sujeto(['Interestingly,', asparagine, '(', like, arginine, in, 'mammals)', at, position, 69, was, the, critical, site, in, yellow, catfish, 'CypA']), verbo([involved]), complemento([in, leucocyte, attraction])].
[sujeto(['These', novel, efforts, do, not, only, highlight, the, enzymatic, texture, of, skin, 'mucus,', but, signify, 'CypA', to, be]), verbo([targeted]), complemento([for, 'anti-inflammatory', therapeutics])].
[sujeto(['Derivative', 1, was, used, to, capture, 'Cyps', from, the, sample, while, derivative, 2, was, applied, for, selective]), verbo([release]), complemento([from, the, affinity, matrix])].
[sujeto(['Moreover,', extracellular, 'CypA', was]), verbo([found]), complemento([to, be, partially, modified, by, 'N(ε)', acetylation, on, residues, 'Lys44,', 'Lys133,', 'Lys155,', as, well, as, 'N(α)', &, 'nbsp;acetylation', at, the, 'N-terminal', 'Val', residue])].
[sujeto(['N(α&nbsp;)', acetylation, of, 'Ser2', residue, was, also]), verbo([found]), complemento([for, 'Cyp40'])].
[sujeto(['PD']), verbo([involves]), complemento([a, progressive, loss, of, dopaminergic, neurons, in, the, substantia, nigra, pars, compacta])].
[sujeto([1, -, 'Methyl-4-phenyl-1,', 2, ',', 3, ',', 6, -, tetrahydropyidine, '(', 'MPTP)', and, its, toxic, metabolite, 1, -, 'methyl-4-phenylpyridinium', ion, '(', 'MPP+)']), verbo([inhibit]), complemento([the, complex, 'I', of, the, mitochondrial, electron, transport, 'chain,', and, have, been, widely, used, to, construct, 'PD', models])].
[sujeto(['Cyclophilin', 'B', '(', 'CypB)', is, an, endoplasmic, reticulum, protein, that]), verbo([binds]), complemento([to, cyclosporine, 'A', as, a, cyclophilin, family, member])].
[sujeto(['CypB']), verbo([has]), complemento(['peptidyl-prolyl', 'cis-trans', isomerase, '(', 'PPIase)', activity])].
[sujeto(['Overexpressed', 'CypB']), verbo([decreased]), complemento(['MPP(+)-induced', oxidative, stress, through, the, modulation, of, antioxidant, enzymes, including, manganese, superoxide, dismutase, and, 'catalase,', and, prevented, neurocytotoxicity, via, 'mitogen-activated', protein, 'kinase,', especially, the, 'c-Jun', 'N-terminal', kinase, pathway])].
[sujeto(['In', 'addition,', 'CypB']), verbo([inhibited]), complemento([the, activation, of, 'MPP(+)-induced', the, 'pro-apoptotic', molecules, poly, '(', 'ADP-ribose)', 'polymerase,', 'Bax,', and, 'Bcl-2,', and, attenuated, 'MPP(+)-induced', mitochondrial, dysfunction])].
[sujeto(['The', data]), verbo([suggest]), complemento([that, overexpressed, 'CypB', protects, neuronal, cells, from, 'MPP+-induced', dopaminergic, neuronal, cell, death])].
[sujeto(['Peptidylprolyl', isomerases, '(', 'PPIase)', cyclophilin, 'A', '(', 'CypA,', encoded, by, 'PPIA)', is, a, typical, member, of, the, 'Cyclophilin', family, and, is]), verbo([involved]), complemento([in, protein, 'folding/translocation,', signal, 'transduction,', 'inflammation,', immune, system, 'regulation,', apoptosis, and, virus, replication])].
[sujeto(['According', to, the, 'GenBank', reference, 'sequences,', vertebrate, 'PPIA', genes, were, 'cloned,', among, which, the, bat, '(', 'Myotis', 'davidi)', and, duck, '(', 'Anas', 'platyrhynchos)', 'PPIA', genes, were]), verbo([reported]), complemento([for, the, first, time])].
[sujeto(['Then', 'PPIA', genes, were, 'sub-cloned', into, the, expression, vector, 'pGEX-6p-1', and]), verbo([expressed]), complemento([in, 'Escherichia', coli])].
[sujeto(['In', 'addition,', the, genetic, variation, and, molecular, evolution, analysis, showed, that, these, vertebrate, 'CypA', proteins, had, the, same, 'CsA']), verbo([binding]), complemento([site, and, the, 'PPIase', active, sites])].
[sujeto(['Our', data]), verbo([suggested]), complemento([that, the, important, residues, of, 'CypA', were, highly, 'conserved,', which, is, crucial, for, its, 'PPIase', activity, and, cellular, functions])].
[sujeto(['Pin1', is, a, peptidylprolyl, 'cis/trans', isomerase, and, it]), verbo([has]), complemento([a, unique, enzymatic, activity, of, catalyzing, isomerization, of, the, peptide, bond, between, 'phospho-serine/threonine', and, proline])].
[sujeto(['Through', the, conformational, change, of, its, 'substrates,', 'Pin1']), verbo([regulates]), complemento([diverse, biological, processes, including, adipogenesis])].
[sujeto(['In', mouse, embryonic, fibroblasts, and, 3, 'T3-L1', 'preadipocytes,', overexpression, of, 'Pin1']), verbo([enhances]), complemento([adipocyte, differentiation, whereas, inhibition, of, 'Pin1', activity, suppresses, it])].
[sujeto(['In', the, present, 'study,', we, investigated, the, potential]), verbo([targets]), complemento([of, 'Pin1', during, adipogenesis])].
[sujeto(['We']), verbo([found]), complemento([that, 'Pin1', interacts, directly, with, and, regulates, the, transcriptional, activity, of, 'PPARγ,', a, key, regulator, of, adipogenesis])].
[sujeto(['In', 'addition,', 'ERK', activity, and, 'Ser273', of, 'PPARγ,', a, potential, 'ERK', phosphorylation]), verbo([target]), complemento(['site,', are, important, for, the, regulation, of, 'PPARγ', function, by, 'Pin1', in, 3, 'T3-L1', cells])].
[sujeto(['Taken', together, our, results]), verbo([suggest]), complemento([a, novel, regulatory, mechanism, of, 'Pin1', during, 'adipogenesis,', in, which, 'Pin1', enhances, adipocyte, differentiation, by, regulating, the, function, of, 'PPARγ'])].
[sujeto(['Earlier', crystallographic, study]), verbo([has]), complemento([proposed, that, the, 'PPIase', domains, are, flexible, and, might, form, a, cradle, for, holding, the, substrate, and, these, aspects, of, 'Peb4', were, explored, using, 'sub-microsecond', molecular, dynamics, simulations, in, solution, environment])].
[sujeto(['Our', simulations]), verbo([have]), complemento([revealed, that, 'PPIase', domains, are, highly, flexible, and, undergo, a, large, structural, change, where, they, move, apart, from, each, other, by, 8, &, 'nbsp;nm', starting, at])].
[sujeto(['Further,', this, large, conformational, change, renders, 'Peb4', as, a, compact, protein, with, 'crossed-over', 'conformation,', forms, a, central, 'cavity,', which, can, &, 'quot;cradle&quot;', the]), verbo([target]), complemento([substrate])].
[sujeto(['As']), verbo([reported]), complemento([for, other, chaperone, 'proteins,', flexibility, of, linker, region, connecting, the, chaperone, and, 'PPIase', domains, is, key, to, forming, the, &, 'quot;crossed-over&quot;', conformation])].
[sujeto(['PPIases', catalyze, the, 'cis/trans', isomerization, of, 'proline,']), verbo([acting]), complemento([as, a, regulatory, switch, during, 'folding,', 'activation,', 'and/or', degradation, of, many, proteins])].
[sujeto(['These', &, 'quot;clients&quot;', include, proteins, with, key, roles, in, 'cancer,', 'neurodegeneration,', and, psychiatric, 'disorders,']), verbo([suggesting]), complemento([that, 'PPIase', inhibitors, could, be, important, therapeutics])].
[sujeto(['However,', the, active, site, of, 'PPIases', is, 'shallow,', 'solvent-exposed,', and, well]), verbo([conserved]), complemento([between, family, 'members,', making, selective, inhibitor, design, challenging])].
[sujeto(['Despite', these, 'hurdles,', macrocyclic, natural, 'products,', including, 'FK506,', 'rapamycin,', and, 'cyclosporin,']), verbo([bind]), complemento(['PPIases', with, nanomolar, or, better, affinity])].
[sujeto(['De', novo, attempts, to, derive, new, classes, of, inhibitors]), verbo([have]), complemento([been, somewhat, less, 'successful,', often, showcasing, the, &, 'quot;undruggable&quot;', features, of, 'PPIases'])].
[sujeto(['Moreover,', 'PPIA', expression, was, significantly]), verbo([associated]), complemento([with, tumor, size, in, these, tissues])].
[sujeto(['Moreover,', 'PPIA', siRNA, knockdown, appears, to]), verbo([promote]), complemento(['doxorubicin-induced', apoptosis, in, 'HCC', 'cells,', altering, the, expression, of, downstream, apoptotic, factors])].
[sujeto(['In', 'summary,', our, results, indicate, that, 'PPIA', may, play, a, pivotal, role, in, 'HCC', by]), verbo([regulating]), complemento([cell, growth, and, could, serve, as, a, novel, marker, and, therapeutic, molecular, target, for, 'HCC', patients])].
[sujeto(['The', 'parvulins,', which, is, one, family, of, 'PPIases,']), verbo([have]), complemento([been, extensively, investigated, in, several, eukaryotes])].
[sujeto(['A', detailed, topological, analysis, revealed, a, positively, charged, 'lysine-rich', patch, on, the, protein, 'surface,', which, is]), verbo([conserved]), complemento([in, all, known, parvulin, sequences, of, thaumarchaeotes, and, targets, 'NmPin', to, lipids, in, vitro])].
[sujeto(['Transmission', electron, microscopy, uncovered, that, 'NmPin']), verbo([has]), complemento([a, uniform, distribution, at, the, membrane, 'surface,', which, is, correlated, with, a, native, cell, shape, of, the, prokaryote])].
[sujeto(['Our', results]), verbo([reveal]), complemento([that, a, 'lysine-rich', patch, in, 'NmPin', mediates, membrane, localization])].
[sujeto(['These', findings]), verbo([provide]), complemento([a, model, whereby, 'NmPin', is, located, between, the, archaeal, membrane, and, the, surface, layer, and, hence, suggest, proteins, of, the, 'S-layer', as, the, key, target, substrates, of, this, parvulin])].
[sujeto(['Bruck', syndrome, '(', 'BS)', is, a, connective, tissue, disorder, characterized, at, the, molecular, level, by, a]), verbo([loss]), complemento([of, telopeptide, lysine, 'hydroxylation,', resulting, in, reduced, collagen, pyridinoline, 'cross-linking'])].
[sujeto(['In', this, 'report,', we]), verbo([provide]), complemento([insights, regarding, the, interplay, between, 'LH2', and, 'FKBP65'])].
[sujeto(['We']), verbo([found]), complemento([that, 'FKBP65', forms, complexes, with, 'LH2', splice, variants, 'LH2A', and, 'LH2B', but, not, with, 'LH1', and, 'LH3'])].
[sujeto(['Both', depletion, of, 'FKBP65', and, inhibition, of, 'FKBP65', 'PPIase', activity, reduced, the, dimeric, '(', 'active)', form, of, 'LH2', but, did, not, affect, the]), verbo([binding]), complemento([of, monomeric, '(', 'inactive)', 'LH2', to, procollagen, 'Iα1'])].
[sujeto(['Collectively,', our, results, indicate, that, 'FKBP65', is, linked, to, pyridinoline, 'cross-linking', by, specifically]), verbo([mediating]), complemento([the, dimerization, of, 'LH2'])].
[sujeto(['Moreover,', 'FKBP65', does, not]), verbo([interact]), complemento([with, 'LH1', and, 'LH3,', explaining, why, in, 'BS', 'triple-helical', hydroxylysines, are, not, affected])].
[sujeto(['Our', results]), verbo([provide]), complemento([a, mechanistic, link, between, 'FKBP65', and, the, loss, of, pyridinolines, and, may, hold, the, key, to, future, treatments, for, diseases, related, to, collagen, 'cross-linking', 'anomalies,', such, as, fibrosis, and, cancer])].
[sujeto(['Cyclophilins', are, ubiquitous, 'cis-trans-prolyl', isomerases, '(', 'PPIases)']), verbo([found]), complemento([in, all, kingdoms, of, life])].
[sujeto(['The', crystal, structures, of, two, representatives, from, 'Hirschia', 'baltica,', 'AquaCyp293', and, 'AquaCyp300,']), verbo([reveal]), complemento([the, formation, of, a, compact, 'domain,', the, 'NIC', 'domain,', by, the, 'N-', and, 'C-terminal', extensions, together, with, a, central, insertion])].
[sujeto(['The', 'NIC', domain, adopts, a, novel, mixed, 'alpha-helical,', 'beta-sheet', fold, that, is, linked, to, the, cyclophilin, domain, via, a]), verbo([conserved]), complemento([disulfide, bond])].
[sujeto(['Cyclophilins', '(', 'CyPs)', are, a, family, of, proteins, that]), verbo([bind]), complemento([the, immunosuppressive, agent, cyclosporin, 'A', '(', 'CsA)', with, 'high-affinity', and, belong, to, one, of, the, three, superfamilies, of, 'peptidyl-prolyl', 'cis-trans', isomerases, '(', 'PPIase)'])].
[sujeto(['Tissue', distribution, study, revealed, that, 'Ca-CyPs', were, ubiquitously]), verbo([expressed]), complemento([in, all, examined, tissues, and, the, highest, levels, were, observed, in, hemocytes])].
[sujeto(['RLO', incubation, upregulated, the, mRNA, expression, levels, of, 'Ca-CyPs,', indicating, that, three, 'Ca-CyPs', might, be]), verbo([involved]), complemento([in, oyster, immune, response, against, 'RLO', infection])].
[sujeto(['They', display, an, 'AB-type', 'structure:', 'The', enzymatically, active, 'A-domain', attaches, to, the, 'binding/translocation', 'B-domain', which, then]), verbo([binds]), complemento([to, a, receptor, on, the, cell, surface])].
[sujeto(['Here,', the, 'A-domain', transfers, an, 'ADP-ribose', moiety, onto, its, specific, substrate, which]), verbo([leads]), complemento([to, characteristic, cellular, effects, and, thus, to, severe, clinical, symptoms])].
[sujeto(['Since', the, 'A-domain']), verbo([has]), complemento([to, reach, the, cytosol, to, achieve, a, cytotoxic, 'effect,', the, membrane, translocation, represents, a, crucial, step, during, toxin, uptake])].
[sujeto(['Moreover,', the, medical, implications, of, host, cell, chaperones, and, 'PPIases', as, new, drug]), verbo([targets]), complemento([for, the, development, of, novel, therapeutic, strategies, against, diseases, caused, by, bacterial, 'ADP-ribosylating', toxins, are, discussed])].
[sujeto(['Cyclophilins', are, ubiquitous, proteins]), verbo([found]), complemento([in, all, domains, of, 'life,', catalyzing, 'peptidyl-prolyl', 'cis-trans', isomerization, '(', 'PPIase', 'activity)', and, functioning, in, diverse, cellular, processes])].
[sujeto(['BbCypA', was]), verbo([found]), complemento([to, be, the, most, highly, expressed, cyclophilin, during, growth, and, purified, recombinant, 'BbCypA', displayed, cyclosporine, sensitive, 'PPIase', activity])].
[sujeto(['Except', for, 'ΔBbCypA,']), verbo([targeted]), complemento([gene, knockouts, or, overexpression, of, any, cyclophilin, resulted, in, temperature, sensitivity, '(', 'TS)'])].
[sujeto(['Insect', bioassays, revealed]), verbo([decreased]), complemento([virulence, for, two, cyclophilins, '(', 'ΔBbCypE', and, 'ΔBbCyp6)', and, the, simultaneous, gene, knockdown, mutant, constructs, '(', 'SiRNA30)'])].
[sujeto(['The', 'BbSiRNA30', strains, were, unaffected, in, 'growth,', 'conidiation,', or, under, osmotic, or, cell, wall, perturbing, 'stress,', but, did, show]), verbo([increased]), complemento([resistance, to, cyclosporine, and, a, 'TS', phenotype])].
[sujeto(['Peptidyl', prolyl, 'cis/trans', isomerization, by, 'Pin1']), verbo([regulates]), complemento([various, oncogenic, signals, during, cancer, 'progression,', and, its, inhibition, through, multiple, approaches, has, established, 'Pin1', as, a, therapeutic, target])].
[sujeto(['However,', lack, of, simplified, screening, systems]), verbo([has]), complemento([limited, the, discovery, of, potent, 'Pin1', inhibitors])].
[sujeto(['We', utilized, 'phosphorylation-dependent']), verbo([binding]), complemento([of, 'Pin1', to, its, specific, substrate, to, develop, a, screening, system, for, 'Pin1', inhibitors])].
[sujeto(['Based', on, 'structure-activity', guided, chemical, 'synthesis,', we, developed, more, potent, 'Pin1', inhibitors, that]), verbo([inhibited]), complemento([cancer, cell, proliferation])].
[sujeto(['Cyclophilin', 'A', '(', 'CypA)', is, a, key, member, of, immunophilins, that]), verbo([has]), complemento(['peptidyl-prolyl', 'cis/trans', isomerase, '(', 'PPIase)', activity])].
[sujeto(['Besides']), verbo([acting]), complemento([as, a, cellular, receptor, for, immunosuppressive, drug, cyclosporine, 'A', '(', 'CsA),', 'CypA', is, involved, in, various, cellular, activities])].
[sujeto(['CypA']), verbo([has]), complemento([an, important, role, in, viral, infection, which, either, facilitates, or, inhibits, their, replication])].
[sujeto(['Inhibition', of, 'CypA', via, inhibitors, is, useful, for, overcoming, several, viral, 'infections,', indicating, that, 'CypA', is, an, attractive]), verbo([target]), complemento([for, 'anti-viral', therapy])].
[sujeto(['Collectively,', these, facts, demonstrate, the, critical, roles, of, 'CypA', in]), verbo([mediating]), complemento([or, inhibiting, viral, 'infections,', suggesting, that, 'CypA', can, be, an, attractive, cellular, target, for, the, development, of, 'anti-viral', therapy])].
[sujeto(['Extensive', phosphorylation, of, the, microtubule]), verbo([binding]), complemento([protein, tau, has, been, implicated, in, neurodegeneration, and, 'Alzheimer\'s', disease])].
[sujeto(['For', the, past, 15, 'years,', these, two, players]), verbo([have]), complemento([been, the, focus, of, an, enormous, research, effort, to, unravel, the, biological, relevance, of, their, interplay, in, health, and, 'disease,', resulting, in, a, series, of, proposed, molecular, mechanism, of, how, 'Pin1', catalysis, of, tau, results, in, biological, phenotypes])].
[sujeto(['Using', 'NMR,', isothermal, calorimetry, '(', 'ITC),', and, small, angle, 'x-ray', scattering, '(', 'SAXS),', we, dissect]), verbo([binding]), complemento([and, catalysis, on, multiple, phosphorylated, tau, with, particular, emphasis, toward, the, 'Alzheimer\'s', associated, 'AT180', tau, epitope, containing, phosphorylated, 'THR231', and, 'SER235'])].
[sujeto(['We']), verbo([find]), complemento([that, phosphorylated, '(', 'p-)', 'SER235-PRO,', but, not, 'pTHR231-PRO,', is, exclusively, catalyzed, by, 'full-length', 'Pin1', and, isolated, 'PPIase', domain])].
[sujeto(['Importantly,', 'site-specific', measurements, of, 'Pin1-catalysis', of, 'CDK2/CycA-phosphorylated', 'full-length', tau]), verbo([reveal]), complemento([a, number, of, sites, that, are, catalyzed, simultaneously, with, different, efficiencies])].
[sujeto(['Our', mechanistic, results, on, 'site-specific']), verbo([binding]), complemento([and, catalysis, together, with, the, lack, of, an, increase, of, dephosphorylation, rates, by, 'PP2A', counter, a, series, of, previously, published, models, for, the, role, of, 'Pin1', catalysis, of, tau, in, 'Alzheimer\'s', disease])].
[sujeto(['Together,', our, data, reemphasize, the, complicated, scenario, between]), verbo([binding]), complemento([and, catalysis, of, multiple, phosphorylated, tau, by, 'Pin1', and, the, need, for, directly, linking, biological, phenotypes, and, 'residue-specific', turnover, in, 'Pin1', substrates])].
[sujeto(['Research', into, lipoprotein, metabolism]), verbo([has]), complemento([developed, because, understanding, lipoprotein, metabolism, has, important, clinical, indications])].
[sujeto(['These', included, the, identification, of, microsomal, transfer, 'protein,', the, cotranslational]), verbo([targeting]), complemento([of, apoproteinB, '(', 'apoB)', for, degradation, regulated, by, the, availability, of, 'lipids,', and, the, characterization, of, transport, vesicles, transporting, primordial, apoB, containing, particles, to, the, 'Golgi'])].
[sujeto(['The', lipase, maturation, factor, 1, ',', 'glycosylphosphatidylinositol-anchored', high, density, lipoprotein]), verbo([binding]), complemento([protein, 1, and, an, 'angiopoietin-like', protein, play, a, role, in, lipoprotein, lipase, '(', 'LPL)-mediated', hydrolysis, of, secreted, 'CMs', and, 'VLDL', so, that, the, right, amount, of, fatty, acid, is, delivered, to, the, right, tissue, at, the, right, time])].
[sujeto(['Expression', of, the, low, density, lipoprotein, '(', 'LDL)', receptor, is]), verbo([regulated]), complemento([at, both, transcriptional, and, 'post-transcriptional', level])].
[sujeto(['Proprotein', convertase, 'subtilisin/kexin', type, 9, '(', 'PCSK9)']), verbo([has]), complemento([a, pivotal, role, in, the, degradation, of, 'LDL', receptor])].
[sujeto(['Plasma', remnant, lipoproteins]), verbo([bind]), complemento([to, specific, receptors, in, the, 'liver,', the, 'LDL', 'receptor,', 'VLDL', receptor, and, 'LDL', 'receptor-like', proteins, prior, to, removal, from, the, plasma])].
[sujeto(['Reverse', cholesterol, transport, occurs, when, lipid, free, apoAI]), verbo([recruits]), complemento([cholesterol, and, phospholipid, to, assemble, high, density, lipoprotein, '(', 'HDL)', particles])].
[sujeto(['The', discovery, of, 'ABC', transporters, '(', 'ABCA1', and, 'ABCG1)', and, scavenger, receptor, class, 'B', type, 'I', '(', 'SR-BI)']), verbo([provided]), complemento([further, information, on, the, biogenesis, of, 'HDL'])].
[sujeto(['Cholesterol', content, in, cells, is]), verbo([regulated]), complemento([by, several, transcription, 'factors,', including, the, liver, 'X', receptor, and, sterol, regulatory, element, binding, protein])].
[sujeto(['This', review, summarizes, recent, advances, in, knowledge, of, the, molecular, mechanisms]), verbo([regulating]), complemento([lipoprotein, metabolism])].
[sujeto(['Apolipoprotein', '(', 'apo)', 'A-V', functions, to]), verbo([modulate]), complemento([intracellular, and, extracellular, triacylglycerol, metabolism])].
[sujeto(['Expression', of, recombinant, 'apoA-V', in, hepatocarcinoma, cells, results, in]), verbo([increased]), complemento([lipid, droplet, size, and, number, at, the, expense, of, triacylglycerol, secretion])].
[sujeto(['ApoA-V']), verbo([modulates]), complemento([atherosclerosis, in, hypercholesterolemic, apoE, null, mice])].
[sujeto(['ApoE', 'null/human', 'apoA-V', transgenic, mice, had, reduced, levels, of, triacylglycerol, and, cholesterol, in, plasma, along, with]), verbo([decreased]), complemento([aortic, lesion, size])].
[sujeto(['ApoA-V']), verbo([modulates]), complemento([triacylglycerol, metabolic, fate])].
[sujeto(['Following', its, 'synthesis,', 'apoA-V', enters, the, endoplasmic, reticulum, and]), verbo([associates]), complemento([with, membrane, defects, created, by, triacylglycerol, accumulation])].
[sujeto(['Association', of, 'apoA-V', with, endoplasmic, reticulum, membrane, defects]), verbo([promotes]), complemento([nascent, lipid, droplets, budding, toward, the, cytosol])].
[sujeto(['Despite', its, low, concentration, in, plasma, '(', '∼150', 'ng/ml),', 'apoA-V']), verbo([modulates]), complemento([lipoprotein, metabolism, by, binding, to, 'glycosylphosphatidylinositol-anchored', 'high-density', lipoprotein, binding, protein, 1])].
[sujeto(['This', interaction, effectively, localizes, 'triacylglycerol-rich', lipoproteins, in, the, vicinity, of, 'glycosylphosphatidylinositol-anchored', 'high-density', lipoprotein]), verbo([binding]), complemento(['protein1\'s', other, 'ligand,', lipoprotein, lipase])].
[sujeto(['To', investigate, the, mechanisms, by, which, macrophage, scavenger, receptor, 'BI', '(', 'SR-BI)']), verbo([regulates]), complemento([macrophage, cholesterol, homeostasis, and, protects, against, atherosclerosis])].
[sujeto(['SR-BI,', the, other, scavenger, receptors, 'SRA', and, 'CD36', and, the, 'ATP-binding', cassette, transporters, 'ABCA1', and, 'ABCG1', were, each, distinctly]), verbo([regulated]), complemento([during, 'BMM', differentiation])].
[sujeto(['SR-BI', levels]), verbo([increased]), complemento([transiently, to, significant, levels, during, culture])].
[sujeto(['BMM', exhibited, selective, 'HDL', 'CE', 'uptake,', 'however,', this, was, not, dependent, on, 'SR-BI', or, another, potential, candidate, glycosylphosphatidylinositol, anchored, high, density, lipoprotein]), verbo([binding]), complemento([protein, 1, '(', 'GPIHBP1)'])].
[sujeto(['SR-BI', expression]), verbo([enhanced]), complemento([both, cell, cholesterol, efflux, and, cholesterol, influx, from, 'HDL,', but, did, not, lead, to, altered, cellular, cholesterol, mass])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'SR-BI', plays, a, significant, role, in, macrophage, cholesterol, flux, that, may, partly, account, for, its, effects, on, atherogenesis])].
[sujeto(['Apolipoprotein', 'A-V', '(', 'apoA-V),', a, minor, protein]), verbo([associated]), complemento([with, 'lipoproteins,', has, a, major, effect, on, triacylglycerol, '(', 'TG)', metabolism])].
[sujeto(['We', investigated, whether, 'apoA-V', complexed, with, phospholipid, in, the, form, of, a, reconstituted, 'high-density', lipoprotein, '(', 'rHDL)']), verbo([has]), complemento([potential, utility, as, a, therapeutic, agent, for, treatment, of, hypertriglyceridemia, '(', 'HTG)', when, delivered, intravenously])].
[sujeto(['This', decline, can, be, attributed, to]), verbo([enhanced]), complemento(['catabolism/clearance', of, 'very-low-density', lipoprotein, '(', 'VLDL),', where, 'VLDL', 'TG', and, cholesterol, were, reduced, '≈60%'])].
[sujeto(['ApoA-V', that]), verbo([associated]), complemento([with, 'VLDL', after, injection, was, also, rapidly, cleared])].
[sujeto(['Site-specific', mutations, in, the, 'heparin-binding', region, of, 'apoA-V', '(', amino, acids, 186, to, 227, ')', attenuated, 'apoA-V', rHDL, 'TG-lowering', activity, by, 50, '%', ',']), verbo([suggesting]), complemento([that, this, sequence, element, is, required, for, optimal, 'TG-lowering', activity, in, vivo])].
[sujeto(['Unlike', 'apoav-/-', 'mice,', injection, of, 'apoA-V', rHDL, into, 'gpihbp1-/-', mice, had, no, effect, on, plasma, 'TG', 'levels,', and, 'apoA-V', remained]), verbo([associated]), complemento([with, plasma, 'VLDL'])].
[sujeto(['Its', intravenous, administration, may]), verbo([have]), complemento([therapeutic, benefit, in, human, subjects, with, severe, 'HTG,', especially, in, cases, involving, 'apoA-V', variants, associated, with, 'HTG'])].
[sujeto(['By', expression, cloning, using, 'fluorescent-labeled', high, density, lipoprotein, '(', 'HDL),', we, isolated, two, clones, that]), verbo([conferred]), complemento([the, cell, surface, binding, of, 'HDL'])].
[sujeto(['The', primary, structure, of, the, newly, identified, 'HDL-binding', protein, resembles, 'GPI-anchored', proteins, consisting, of, an, 'N-terminal', signal, 'sequence,', an, acidic, region, with, a, cluster, of, aspartate, and, glutamate, 'residues,', an, 'Ly-6', motif, highly]), verbo([conserved]), complemento([among, the, lymphocyte, antigen, 'family,', and, a, 'C-terminal', hydrophobic, region])].
[sujeto(['This', newly, identified, 'HDL-binding', protein, designated, 'GPI-anchored', 'HDL-binding', protein, 1, '(', 'GPI-HBP1),', was, susceptible, to, 'phosphatidylinositol-specific', phospholipase, 'C', treatment, and]), verbo([binds]), complemento(['HDL', with, high, affinity, '(', calculated, 'K(d)', =, 2, -, 3, 'microg/ml)'])].
[sujeto(['Similar', to, 'SRBI,', 'GPI-HBP1']), verbo([mediates]), complemento([selective, lipid, uptake, but, not, the, protein, component, of, 'HDL'])].
[sujeto(['Among', various, ligands, for, 'SRBI,', 'HDL', was, most, preferentially]), verbo([bound]), complemento([to, 'GPI-HBP1'])].
[sujeto(['Numerous', communications]), verbo([have]), complemento([indicated, that, specific, binding, proteins, for, high, density, lipoprotein, '(', 'HDL)', exist, in, addition, to, the, well, characterized, candidate, 'HDL', receptor, 'SR-BI,', but, structural, information, was, presented, only, in, a, few, 'cases,', and, most, of, the, work, was, aimed, at, the, liver, and, steroidogenic, glands])].
[sujeto(['The', apparent, dissociation, constant, of, the, 'HDL']), verbo([binding]), complemento([was, determined, by, solid, phase, assay, to, be, 2.1, 'microg/ml', '(', 'HB2)', and, 25, 'microg/ml', '(', 'MDP)'])].
[sujeto(['The', level, in, type, 'II', pneumocyte, membranes, of, both]), verbo([binding]), complemento(['proteins,', 'MDP', and, 'HB2,', increased, when, the, plasma, lipoprotein, concentration, was, reduced, by, treatment, of, rats, with, 4, -, 'aminopyrazolo[3,4-d]-pyrimidine,', consistent, with, a, function, to, facilitate, lipid, uptake, in, vivo])].
[sujeto(['The']), verbo([binding]), complemento([proteins, were, also, dramatically, upregulated, by, feeding, rats, a, vitamin, 'E-depleted', diet])].
[sujeto(['Vitamin', 'E', uptake]), verbo([requires]), complemento([interaction, between, 'HDL', and, type, 'II', 'cells,', suggesting, a, role, of, 'HB2', and, 'MDP', also, in, this, process])].
[sujeto(['Metabolic', syndrome, in, the, proband, explains, the, extremely, low, 'HDL', cholesterol, level, '(', 0.31, &, 'nbsp;mmol/L),', which, was, half, of, that]), verbo([found]), complemento([in, the, other, carriers])].
[sujeto(['The', 'proband\'s', mother, and, 'grandfather,', both, presenting, low, plasma, 'low-density', lipoprotein, 'cholesterol,', were, carriers, of, the, 'β-thalassemic', 'trait,', a, condition, known, to, be]), verbo([associated]), complemento([with, a, reduced, 'low-density', lipoprotein, cholesterol, and, a, reduced, prevalence, of, cardiovascular, disease])].
[sujeto(['This', trait, might]), verbo([have]), complemento([delayed, the, development, of, atherosclerosis, related, to, 'HDL', deficiency])].
[sujeto(['In', these, heterozygotes, for, 'apoA-I', 'truncation,', the, metabolic, syndrome]), verbo([has]), complemento([deleterious, effect, on, 'HDL', 'system,', whereas, 'β-thalassemia', trait, may, delay, the, onset, of, cardiovascular, disease])].
[sujeto(['Although', secondary, factors, play, a, role, in, clinical, 'expression,', dyslipidemias]), verbo([have]), complemento([a, strong, genetic, component])].
[sujeto(['Familial', hypercholesterolemia, is, usually, due, to, 'loss-of-function', mutations, in, 'LDLR,', the, gene, coding, for, low, density, lipoprotein, receptor, and, genes, encoding, for, proteins, that]), verbo([interact]), complemento([with, the, 'receptor:', 'APOB,', 'PCSK9', and, 'LDLRAP1'])].
[sujeto(['Monogenic', hypertriglyceridemia, is, the, result, of, mutations, in, genes, that]), verbo([regulate]), complemento([the, metabolism, of, triglyceride, rich, lipoproteins, '(', eg, 'LPL,', 'APOC2,', 'APOA5,', 'LMF1,', 'GPIHBP1)'])].
[sujeto(['Conversely', familial, hypobetalipoproteinemia, is]), verbo([caused]), complemento([by, inactivation, of, the, 'PCSK9', gene, which, increases, the, number, of, 'LDL', receptors, and, decreases, plasma, cholesterol])].
[sujeto(['Mutations', in, the, genes, 'APOB,', and, 'ANGPTL3', and, 'ANGPTL4', '(', that, encode, 'angiopoietin-like', proteins, which]), verbo([inhibit]), complemento([lipoprotein, lipase, 'activity)', can, further, cause, low, levels, of, apoB, containing, lipoproteins])].
[sujeto(['ApoE', deficiency, can]), verbo([cause]), complemento([a, similar, phenotype, or, rarely, mutations, in, apoE, can, be, associated, with, lipoprotein, glomerulopathy])].
[sujeto(['Low', 'HDL', can, result, from, mutations, in, a, number, of, genes]), verbo([regulating]), complemento(['HDL', production, or, 'catabolism;', 'apoAI,', 'lecithin:', cholesterol, acyltransferase, and, the, 'ATP-binding', cassette, transporter, 'ABCA1'])].
[sujeto(['Patients', with, cholesteryl, ester, transfer, protein, deficiency]), verbo([have]), complemento([markedly, increased, 'HDL', cholesterol])].
[sujeto(['In', contrast, to, rare, familial, 'syndromes,', in, most, 'patients,', dyslipidemias]), verbo([have]), complemento([a, complex, genetic, etiology, consisting, of, multiple, genetic, variants, as, established, by, genome, wide, association, studies])].
[sujeto(['Secondary', 'factors,', 'obesity,', metabolic, 'syndrome,', 'diabetes,', renal, 'disease,', estrogen, and, antipsychotics, can]), verbo([increase]), complemento([the, likelihood, of, clinical, presentation, of, an, individual, with, predisposed, genetic, susceptibility, to, hyperlipoproteinemia])].
[sujeto(['This', review, will, present, the, current, information, on, the, genetics, and, pathophysiology, of, disorders, that]), verbo([cause]), complemento([dyslipidemias])].
[sujeto(['To', determine, if, diabetic, lipaemia, is]), verbo([caused]), complemento([by, loss, of, function, mutations, in, the, lipoprotein, lipase, 'gene,', 'LPL'])].
[sujeto(['Only', one, patient, with, lipaemia, had, a]), verbo([loss]), complemento([of, function, mutation, in, 'LPL', and, no, functional, mutations, in, 'APOC2', or, 'GPIHBP1', were, identified])].
[sujeto(['The', majority, of, patients, with, severe, hypertriglyceridaemia, in, diabetic, ketoacidosis, may]), verbo([have]), complemento(['ketosis-prone', 'Type', 2, ',', rather, than, 'Type', 1, ',', diabetes])].
[sujeto(['Significant', knowledge, regarding, different, molecules]), verbo([involved]), complemento([in, the, transport, of, dietary, fat, into, the, circulation, has, been, garnered])].
[sujeto(['This', article]), verbo([provides]), complemento([a, brief, overview, of, dietary, lipid, metabolism, and, studies, in, mice, supporting, the, hypothesis, that, intestinal, lipoproteins, contribute, to, atherosclerosis])].
[sujeto(['Deficiencies', in, lipoprotein, lipase, and, 'Gpihbp1,', and, overexpression, of, heparanse, in, 'mice,', are]), verbo([associated]), complemento([with, increases, in, 'atherosclerosis,', suggesting, that, defects, in, catabolism, of, larger, lipoproteins, in, the, plasma, contribute, to, atherosclerosis])].
[sujeto(['Thus,']), verbo([increases]), complemento([in, plasma, intestinal, lipoproteins, due, to, either, overproduction, or, reduced, catabolism, result, in, augmented, atherosclerosis])].
[sujeto(['Intestinal', lipoproteins, tend, to, adhere, strongly, to, subendothelial, 'proteoglycans,', elicit, an, inflammatory, response, by, endothelial, cells, and]), verbo([activate]), complemento(['macrophages,', contributing, to, the, initiation, and, progression, of, the, disease])].
[sujeto(['The', three, major, pathways, of, lipoprotein, metabolism]), verbo([provide]), complemento([a, superb, paradigm, to, delineate, systematically, the, familial, dyslipoproteinemias])].
[sujeto(['Such', understanding]), verbo([leads]), complemento([to, improved, diagnosis, and, treatment, of, patients])].
[sujeto(['In', the, endogenous, '(', 'hepatic)', 'pathway,', six, disorders, affect, the, activity, of, the, 'LDLR', and, markedly]), verbo([increase]), complemento(['LDL'])].
[sujeto(['These', include, 'FH,', 'FDB,', 'ARH,', 'PCSK9', 'gain-of-function', 'mutations,', sitosterolemia, and]), verbo([loss]), complemento([of, 7, alpha, hydroxylase])].
[sujeto(['Defects', in, 'APOB-100', and, 'loss-of-function', mutations, in, 'PCSK9', are]), verbo([associated]), complemento([with, low, 'LDL-C,', decreased, 'CVD', and, longevity])].
[sujeto(['An', absence, of, 'MTP']), verbo([leads]), complemento([to, marked, reduction, in, chylomicrons, and, 'VLDL,', causing, abetalipoproteinemia])].
[sujeto(['Mutations', in, either, 'CETP', or, 'SR-B1', and, familial, high, 'HDL']), verbo([lead]), complemento([to, increased, large, 'HDL', 'particles,', the, effect, of, which, on, 'CVD', is, not, resolved])].
[sujeto(['The', major, goal, is, to]), verbo([prevent]), complemento([or, ameliorate, the, major, complications, of, many, familial, 'dyslipoproteinemias,', 'namely,', premature, 'CVD', or, pancreatitis])].
[sujeto(['Genome-wide', association, studies, '(', 'GWASs)']), verbo([have]), complemento([identified, many, 'SNPs', underlying, variations, in, 'plasma-lipid', levels])].
[sujeto(['We', explore, whether, additional, loci]), verbo([associated]), complemento([with, 'plasma-lipid', 'phenotypes,', such, as, 'high-density', lipoprotein, cholesterol, '(', 'HDL-C),', 'low-density', lipoprotein, cholesterol, '(', 'LDL-C),', total, cholesterol, '(', 'TC),', and, triglycerides, '(', 'TGs),', can, be, identified, by, a, dense, 'gene-centric', approach])].
[sujeto(['The', proportion, of, explained, phenotypic, variance, in, the, subset, of, studies]), verbo([providing]), complemento(['individual-level', data, was, 9.9, '%', for, 'HDL-C,', 9.5, '%', for, 'LDL-C,', 10.3, '%', for, 'TC,', and, 8.0, '%', for, 'TGs'])].
[sujeto(['The', explained, phenotypic, variance, from, this, approach, was, comparable, to, that, from, a, 'meta-analysis', of, 'GWAS', 'data,']), verbo([suggesting]), complemento([that, a, focused, genotyping, approach, can, further, increase, the, understanding, of, heritability, of, plasma, lipids])].
[sujeto(['The', 'high-cholesterol', diet, significantly]), verbo([increased]), complemento(['Lpl', expression, in, the, liver, and, lowered, plasma, triglyceride, levels])].
[sujeto(['Treatment', of, 'Gpihbp1(-/-)', mice, with, ezetimibe, lowers, 'Lpl', expression, in, the, liver, and]), verbo([increases]), complemento([plasma, triglyceride, levels])].
[sujeto(['Thus,', cholesterol, intake]), verbo([modulates]), complemento([plasma, triglyceride, levels, in, 'Gpihbp1(-/-)', mice])].
[sujeto(['The', study, by, 'Weinstein', et, 'al(1)']), verbo([provides]), complemento([evidence, to, suggest, that, intact, chylomicrons, might, be, atherogenic, by, using, genetically, altered, mice, lacking, 'Gpihbp1', 'protein,', which, may, play, a, major, role, in, the, lipolysis, of, 'triglyceride-rich', lipoproteins])].
[sujeto(['The', risk, of, atherosclerosis, in, the, setting, of, chylomicronemia]), verbo([has]), complemento([been, a, topic, of, debate])].
[sujeto(['Gpihbp1(-/-)', mice, on, a, chow, diet]), verbo([have]), complemento([plasma, triglyceride, and, cholesterol, levels, of, 2812, +, /, -, 209, and, 319, +, /, -, 27, 'mg/dL,', respectively])].
[sujeto(['In', other, 'experiments,', we]), verbo([found]), complemento([that, both, 'Gpihbp1-deficient', &, 'quot;apo-B48-only&quot;', mice, and, 'Gpihbp1-deficient', &, 'quot;apo-B100-only&quot;', mice, manifest, severe, chylomicronemia])].
[sujeto(['Thus,', 'GPIHBP1', is]), verbo([required]), complemento([for, the, processing, of, both, 'apo-B48-', and, 'apo-B100-containing', lipoproteins])].
[sujeto(['Chylomicronemia']), verbo([causes]), complemento([atherosclerosis, in, mice])].
[sujeto(['Also,', we]), verbo([found]), complemento([that, 'GPIHBP1', is, required, for, the, lipolytic, processing, of, both, 'apo-B48-', and, 'apo-B100-containing', lipoproteins])].
[sujeto(['This', 'finding,', backed, by, decades, of, animal, and, human, 'studies,']), verbo([has]), complemento([sparked, interest, in, defining, which, classes, of, 'apo-B-containing', lipoprotein, particles, are, most, atherogenic])].
[sujeto(['Although', small, 'LDL', particles, and, larger, remnant, lipoproteins, both, appear, to, be, 'atherogenic,', it]), verbo([has]), complemento([been, difficult, to, discern, which, particles, are, the, most, atherogenic])].
[sujeto(['Here,', we, summarize, several, mouse, models, that]), verbo([have]), complemento([provided, insights, into, this, issue])].
[sujeto(['GPIHBP1', is, an, endothelial, cell, platform, for, 'lipolysis,', and, mice, lacking, this, protein]), verbo([have]), complemento([an, accumulation, of, 'large,', 'triglyceride-rich', lipoproteins])].
[sujeto(['Defining', the, extent, of, atherosclerosis, in, these, mice, should]), verbo([provide]), complemento([new, insights, into, the, atherogenicity, of, 'large,', 'triglyceride-rich', lipoproteins])].
[sujeto(['Vitamin', 'D']), verbo([has]), complemento([new, roles, in, lipid, and, glucose, metabolism])].
[sujeto(['Compared', with, the, 'placebo,', reductions, in, triglyceride, and, an]), verbo([increase]), complemento([in, 'HDL', cholesterol, were, seen, over, the, 12, weeks, of, intervention, in, the, calcitriol, group, '(', 'P', =, 0.002, and, 'P', =, 0.004, ')'])].
[sujeto(['AST', level, was]), verbo([decreased]), complemento([in, the, calcitriol, group, '(', -, 4.2, ±, 4.3, 'µmol/L,', 'P', &, 'lt;', 0.001, ')', ',', but, increased, in, the, placebo, group, '(', 12.6, ±, 6.1, 'µmol/L,', 'P', =, 0.02, ')', after, 12, weeks])].
[sujeto(['Calcitriol', supplementation, combined, with, weight]), verbo([loss]), complemento([diet, showed, no, significant, effects, on, anthropometric, measures, in, 'NAFLD', patients])].
[sujeto(['However,', it, may]), verbo([have]), complemento([positive, effects, on, lipid, 'profile,', liver, enzyme, tests, and, insulin, sensitivity, during, a, 'weight-loss', program])].
[sujeto(['Chronic', inflammation]), verbo([caused]), complemento([by, 'Helicobacter', pylori, '(', 'H'])].
[sujeto(['pylori)', infection]), verbo([has]), complemento([a, pathogenic, role, in, 'Cardiac', 'Syndrome', 'X', '(', 'CSX)'])].
[sujeto(['In', 'addition,', it]), verbo([has]), complemento([shown, that, bacterial, infection, may, affect, blood, lipids])].
[sujeto([pylori, infection, were]), verbo([associated]), complemento([with, 'CSX;', it, seems, that, plasma, lipid, disorders, have, a, significant, role, in, the, development, of, 'CSX'])].
[sujeto(['[', 'Purpose]', 'This', study, investigated, the, serologic, factors]), verbo([associated]), complemento([with, metabolic, syndrome, and, gallstones])].
[sujeto(['Blood', sampling, was, performed, for, 'high-density', lipoprotein, 'cholesterol,', 'triglyceride,', fasting, blood, 'glucose,', total, 'bilirubin,', direct, 'bilirubin,', indirect, 'bilirubin,', aspartate, 'aminotransferase,', alanine, 'aminotransferase,', alkaline, 'phosphatase,', uric, 'acid,', total, 'cholesterol,', 'low-density', lipoprotein, 'cholesterol,', thyroid]), verbo([stimulating]), complemento(['hormone,', and, red, and, white, blood, cell, counts])].
[sujeto(['We', conducted, logistic, regression, analysis, to, assess, the, risk, factors]), verbo([associated]), complemento([with, metabolic, syndrome])].
[sujeto(['[', 'Results]', 'The', risk, factors, for, metabolic, syndrome, in, 'men,', in, order, of]), verbo([decreasing]), complemento(['weight,', were, red, blood, cell, 'count,', body, mass, 'index,', maximum, size, of, 'gallstones,', white, blood, cell, 'count,', waist, 'circumference,', and, uric, acid, level])].
[sujeto(['The', factors, in, 'women,', in, order, of]), verbo([decreasing]), complemento(['weight,', were, red, blood, cell, 'count,', 'presence/absence', of, 'gallstones,', uric, acid, 'level,', body, mass, 'index,', fasting, blood, 'glucose,', and, waist, circumference])].
[sujeto(['Apolipoprotein', 'A-I', '(', 'apoA-I)', is, the, major, component, of, 'HDL', and, central, to, the, ability, of, 'HDL', to]), verbo([stimulate]), complemento(['ATP-binding', cassette, transporter, 'A1', '(', 'ABCA1)-dependent,', antiatherogenic, export, of, cholesterol, from, macrophage, foam, 'cells,', a, key, player, in, the, pathology, of, atherosclerosis])].
[sujeto(['To', investigate, 'this,', human, 'monocyte-derived', macrophages, '(', 'HMDM)', were, incubated, with, human, 'apoA-I', under, conditions, used, to]), verbo([induce]), complemento([cholesterol, export])].
[sujeto(['Mass', spectrometry, analysis, identified, a, novel, 'C-terminal', cleavage, site, of, 'apoA-I', between, 'Ser(228)-Phe(229)', 'Recombinant', 'apoA-I', truncated, at, 'Ser(228)', demonstrated, profound]), verbo([loss]), complemento([of, capacity, to, solubilize, lipid, and, to, promote, 'ABCA1-dependent', cholesterol, efflux])].
[sujeto(['Cleavage', at, 'Ser(228)', is, a, 'novel,', functionally, important, 'post-translational', modification, of, 'apoA-I']), verbo([mediated]), complemento([by, 'HMDM', that, limits, the, antiatherogenic, properties, of, 'apoA-I'])].
[sujeto(['Objective', 'The', close, relationship, between, fatty, liver, and, metabolic, syndrome]), verbo([suggests]), complemento([that, individuals, with, fatty, liver, may, have, multiple, coronary, risk, factors])].
[sujeto(['However,', the, plasma, levels, of, apolipoprotein, 'B,', 'RLP-C,', and, oxidized, 'LDL', were, only, higher, and, closely]), verbo([associated]), complemento([with, fatty, liver, in, men])].
[sujeto(['Many', epidemiological, studies]), verbo([have]), complemento([proven, that, local, infection, may, influence, the, levels, of, systemic, lipid, profile, and, inflammatory, mediators])].
[sujeto(['No', correlations, were]), verbo([found]), complemento([regarding, hsCRP, serum, concentration])].
[sujeto(['To', our, 'knowledge,', this, study, demonstrated, for, the, first, time, that, local, inflammatory, processes, in, the, oral, cavity, are, positively]), verbo([associated]), complemento([with, the, systemic, levels, of, 'LDL-C,', fibrinogen, and, 'WBC', in, adult, 'Poles'])].
[sujeto(['Subclinical', hypothyroidism, '(', 'SCH)', is, a, common, endocrine, 'disorder,', probably]), verbo([increasing]), complemento([cardiovascular, '(', 'CV)', risk])].
[sujeto(['Total', 'cholesterol,', 'LDL-cholesterol', and, triglycerides, concentrations, as, well, as, 'LDL-C/HDL-C', ratio, and, 'Castelli', index, were, higher, in, 'SCH', than, in, controls, and]), verbo([decreased]), complemento([after, 'L-thyroxin', substitution])].
[sujeto(['Also', in, this, group, the, systolic, and, diastolic, blood, pressure]), verbo([decreased]), complemento([significantly, after, treatment])].
[sujeto(['Dyslipidemia', in, obese, 'SCH', women, is, not, 'severe,', but, if, untreated, for, many, 'years,', it, may]), verbo([lead]), complemento([to, atherosclerosis])].
[sujeto(['An', excessive, accumulation, of, cholesterol, in, erythrocyte, membranes]), verbo([leads]), complemento([to, disruption, of, the, erythrocytes])].
[sujeto(['We', observed, a]), verbo([decrease]), complemento([in, 'TC', '(', 20, '%', ')', ',', 'LDL-C', '(', 35, '%', ')', ',', level, of, lipid, peroxidation, '(', 25, '%', ')', and, total, cholesterol, in, erythrocytes, '(', 23, '%', ')', ',', and, an, increase, in, 'HDL-C', '(', 8, '%', ')', and, erythrocyte, membrane, fluidity, of, subsurface, layers, '(', 14, '%', ')', after, 6, months, of, 10, mg, atorvastatin, +, 10, mg, ezetimibe, 'therapy,', in, comparison, with, healthy, controls])].
[sujeto(['In', the, group, treated, with, 40, mg, atorvastatin, for, 6, 'months,']), verbo([decreased]), complemento(['LDL-C', '(', 23, '%', ')', ',', lipid, peroxidation, '(', 37, '%', ')', and, membrane, cholesterol, concentration, '(', 18, '%', ')', was, 'noted,', as, well, as, an, increase, in, erythrocyte, membrane, fluidity, in, the, subsurface, layers, '(', 12, '%', ')'])].
[sujeto(['Both', the, combination, therapy, and, the, monotherapy]), verbo([lead]), complemento([to, an, improvement, of, erythrocyte, membrane, 'structure,', whose, parameters, reached, values, close, to, those, in, the, control, healthy, group])].
[sujeto(['Visit-to-visit', variability, '(', 'VVV)', in, blood, pressure, '(', 'BP)']), verbo([has]), complemento([been, shown, to, be, a, predictor, of, cardiovascular, events])].
[sujeto(['We', enrolled, 84, patients, who, had, cardiovascular, disease, '(', 'CVD)', and]), verbo([participated]), complemento([in, a, 3, -, month, 'CR', program])].
[sujeto(['We', measured, systolic, and, diastolic, 'BP', '(', 'SBP', and, 'DBP),', pulse, pressure, '(', 'PP),', and, heart, rate, '(', 'HR)', before, exercise, training, at, each, visit, and, determined, 'VVV', in, 'BP', or, 'HR']), verbo([expressed]), complemento([as, the, standard, deviation, of, the, average, 'BP', or, 'HR'])].
[sujeto(['Patients', who, had, uncontrolled, 'BP', at, baseline, and, who, did, not, change, their, antihypertensive, drugs, throughout, the, study, period, showed, a, significant, reduction, of, both, 'SBP', and, 'DBP', with, a]), verbo([decrease]), complemento([in, 'PP', after, 3, months])].
[sujeto(['In', the, 'L-VVV', in, the, 'SBP', and, 'DBP', 'groups,', 'VVV', in, 'SBP', and, 'DBP', in, the, 1, st, month, was, significantly]), verbo([decreased]), complemento([after, the, 3, rd, month, in, both, groups])].
[sujeto(['HR', at, baseline, was, significantly]), verbo([decreased]), complemento([after, 3, months])].
[sujeto(['In', 'addition,', 'CR']), verbo([induced]), complemento([a, significant, increase, in, the, level, of, 'high-density', lipoprotein, cholesterol, '(', 'HDL-C)', in, blood])].
[sujeto(['In', 'conclusion,', 'CR', improved, 'VVV', in, 'BP', in, patients, with, 'L-VVV', in, 'BP', and, evoked, a, significant, reduction, in, 'HR', and, an]), verbo([increase]), complemento([in, 'HDL-C'])].
[sujeto(['In', 1995, ',', the, 'South', 'Korean', government, made, nutrition, labeling, 'compulsory,', which]), verbo([has]), complemento([positively, impacted, patients, with, certain, chronic, 'diseases,', such, as, dyslipidemia])].
[sujeto(['Based', on, our, 'findings,', we, recommend, that, health, policymakers, and, medical, professionals, consider]), verbo([promoting]), complemento([nutrition, labeling, as, an, alternative, method, for, managing, certain, chronic, diseases, in, 'South', 'Korean', patients])].
[sujeto(['The', treatment, group, '(', n, =, 25, ')', was]), verbo([provided]), complemento([camellia, 'oil-enriched', diets, and, the, control, group, '(', n, =, 25, ')', was, provided, diets, cooked, with, soybean, oil, three, meals, '(', 45, mL, 'oil)', a, day, for, 8, weeks])].
[sujeto(['Camellia', oil, consumption, significantly]), verbo([decreased]), complemento([malondialdehyde, '(', 11.2, '%', ;, 'P', &, 'lt;'])].
[sujeto(['Moreover,', the, camellia, oil, group, exhibited, a, statistically, significant]), verbo([decrease]), complemento([in, oxidized, 'LDL-C', '(', 8.7, '%', ;, 'P', &, 'lt;'])].
[sujeto(['Furthermore,', camellia, oil, consumption, significantly]), verbo([decreased]), complemento(['high-sensitivity', 'C-reactive', protein, '(', 12.3, '%', ;, 'P', &, 'lt;'])].
[sujeto(['These', data, indicate, that, the, consumption, of, camellia, 'oil-enriched', diet, could]), verbo([decrease]), complemento([oxidative, stress, and, inflammatory, markers, in, hypercholesterolemic, women])].
[sujeto(['HTWP', was, defined, by, the, presence, of]), verbo([increased]), complemento([plasma, triglycerides, '(', 'TGs)', and, increased, waist, circumference, '(', 'WC)', according, to, cutoff, points, obtained, in, 'ROC', curve, analysis, given, the, 'HOMA1-IR', index, as, a, reference, method])].
[sujeto(['The', findings]), verbo([suggest]), complemento(['HTWP', as, an, 'IR', status, in, adolescents])].
[sujeto(['The', testing, for, 'GADA', and, 'CP', levels, with, regard, to, the, other, relevant, characteristics]), verbo([led]), complemento([to, 're-classification,', or, more, precisely, adding, of, 'DM1T/LADA', '(', as, the, 'main,', or, parallel, cause, of, 'DM)', for, 2.9, '%', of, all, the, patients, included, and, a, clinically, significant, proportion, of, 'AI', could, be, assumed, in, 6.1, '%', of, the, patients])].
[sujeto(['The', results, of, our, study, show, that, the, pathogenesis, of, 'DM', in, patients, initially, diagnosed, and, registered, with, 'DM2T', and, with, concurrent, presence, of, 'GADA', includes, mechanisms, characteristic, of, both, 'DM2T', '(', insulin, 'resistance)', and, 'DM1T', '(', autoimmune, 'insulitis)']), verbo([acting]), complemento([in, 'parallel,', with, different, 'intensity,', in, differing, proportions, and, time, sequence, as, a, fluid, 'continuum,', which, also, accounts, for, the, differences, between, individual, patients])].
[sujeto(['Thus,', this, study, sought, to, examine, levels, of, immune, activation, and, exhaustion, in, this, 'population,', investigate]), verbo([associated]), complemento(['HIV-', and, 'non-HIV-related', 'variables,', and, compare, results, with, a, matched, healthy, control, group])].
[sujeto(['Current', 'CD4', 'count,', 'low-density', lipoprotein, 'cholesterol,', and, age, were, the, variables, most]), verbo([associated]), complemento([with, 'CD4+', and, 'CD8+', 'T-cell', activation])].
[sujeto(['The', clinical, significance, of, the]), verbo([increased]), complemento([immune, activation, and, exhaustion, should, be, further, explored])].
[sujeto(['In', a, series, of, studies, of, atomic, bomb, 'survivors,', 'radiation-dose-dependent', alterations, in, peripheral, 'T-cell', populations]), verbo([have]), complemento([been, reported])].
[sujeto(['Since', telomere, shortening]), verbo([has]), complemento([been, recently, demonstrated, in, 'obesity-related', metabolic, abnormalities, and, 'diseases,', the, modifying, effects, of, metabolic, status, were, also, examined])].
[sujeto([',', longer, telomeres, with, lower, dose, exposure, and, a]), verbo([decreasing]), complemento([trend, of, telomere, length, with, individuals, exposed, to, doses, higher, than, 0.5, 'Gy'])].
[sujeto(['In', naïve, and, memory, 'CD4', 'T', 'cells,', radiation, dose, and, 'high-density', lipoprotein, '(', 'HDL)', cholesterol, were]), verbo([found]), complemento([to, positively, interact, with, telomere, 'length,', suggesting, that, the, decreasing, trend, of, telomere, length, from, a, higher, radiation, dose, was, less, conspicuous, in, individuals, with, a, higher, 'HDL', cholesterol])].
[sujeto(['It', is, therefore, likely, that, radiation, exposure, perturbs, 'T-cell', homeostasis]), verbo([involving]), complemento([telomere, length, maintenance, by, multiple, biological, 'mechanisms,', depending, on, 'dose,', and, that, 'long-term-radiation-induced', effects, on, the, maintenance, of, 'T-cell', telomeres, may, be, modified, by, the, subsequent, metabolic, conditions, of, individuals])].
[sujeto(['Hypertension,', coronary, artery, 'disease,', 'monocyte/HDL', ratio, and, 'C-reactive', protein, were, independently]), verbo([associated]), complemento([with, 'AAA', diameter])].
[sujeto(['Monocyte/HDL', ratio, is, independently]), verbo([associated]), complemento([with, 'AAA', size])].
[sujeto(['We', investigated, the, associations, between, the, plasma, levels, of, growth, factors, and, chemokines, that]), verbo([regulate]), complemento([myeloid, cell, homeostasis, and, function, and, the, risk, of, 'first-time', acute, coronary, events, in, 'middle-aged', persons])].
[sujeto(['Study', participants, were]), verbo([recruited]), complemento([from, the, 'Malmö', 'Diet', and, 'Cancer', 'Study', population, cohort, and, had, no, previous, history, of, coronary, artery, disease])].
[sujeto(['We']), verbo([found]), complemento([a, strong, independent, negative, association, between, macrophage, 'colony-stimulating', factor, and, incident, coronary, events, in, a, forward, stepwise, 'Cox', proportional, hazards, model, including, all, biomarkers, alongside, the, classic, 'Framingham', risk, factors, '(', 'age,', 'sex,', 'smoking,', total, 'cholesterol,', 'high-density', lipoprotein, 'cholesterol,', systolic, blood, 'pressure),', diabetes, 'mellitus,', and, medication])].
[sujeto(['The', combined, model]), verbo([led]), complemento([to, a, 54, '%', net, downclassification, of, participants, who, did, not, have, a, coronary, event, during, 'follow-up', and, was, particularly, effective, in, the, 'intermediate-risk', group])].
[sujeto(['Self-report', questionnaires]), verbo([suggested]), complemento([improved, dietary, intake, and, increased, physical, activity])].
[sujeto(['Participants']), verbo([reported]), complemento([high, satisfaction, with, and, acceptance, of, the, program])].
[sujeto(['Results']), verbo([suggest]), complemento([that, the, culturally, adapted, 'Group', 'Lifestyle', 'Balance', program, for, 'Chinese', 'Americans', was, both, acceptable, and, effective])].
[sujeto(['This', systematic, review, and, 'meta-analysis', was, performed, to, assess, the, effects, of, 'inulin-type', fructans, '(', 'ITF)', on, human, blood, lipids, and, glucose, homeostasis]), verbo([associated]), complemento([with, metabolic, 'abnormalities,', including, 'dyslipidemia,', overweight, or, 'obesity,', and, 'type-2', diabetes, mellitus, '(', 'T2DM)'])].
[sujeto(['Within', the, 'T2DM', subgroup, 'analysis,', 'ITF', supplementation, was, positively]), verbo([associated]), complemento([with, a, decreased, fasting, insulin, concentration, '(', 'MD:', -, 4.01, ;, 95, '%', 'CI:', -, 5.92, ',', -, 2.09, ;, 'P&lt;0'])].
[sujeto([1, ')', and]), verbo([increased]), complemento([high, density, 'lipoprotein-cholesterol', '(', 'HDL-c)', '(', 'MD:', 0.07, ;, 95, '%', 'CI:', 0, ',', 0.14, ;, 'P=0'])].
[sujeto(['In', 'summary,', the, use, of, 'ITF', may]), verbo([have]), complemento([benefits, for, 'LDL-c', reduction, across, all, study, 'populations,', whereas, 'HDL-c', improvement, and, glucose, control, were, demonstrated, only, in, the, 'T2DM', subgroup])].
[sujeto(['Thus,', 'additional,', 'well-powered,', 'long-term,', randomized, clinical, trials, are]), verbo([required]), complemento([for, a, definitive, conclusion])].
[sujeto(['Overall,', 'ITF', supplementation, may]), verbo([provide]), complemento([a, novel, direction, for, improving, the, lipid, profile, and, glucose, metabolism])].
[sujeto([is, one, of, the, most, prevalent, canine, intestinal, nematode, infections, which, usually]), verbo([causes]), complemento([subclinical, disease, in, adult, dogs, and, has, zoonotic, implications])].
[sujeto(['Significant']), verbo([increases]), complemento([in, 'CRP', '(', 'μg/mL)', '(', 'median):', 'non-infected', 'dogs:', 5.5, ;, subclinically, infected, dogs, 18.7, ;, 'P', =, 0.03, ',', 'Hp', '(', 'g/L)', '(', 'median):', 'G1:', 2.4, ;, 'G2:', 3.3, ;, 'P', =, 0.03, ',', and, 'UIBC', '(', 'μg/dL)', '(', 'median):', 'non-infected', 'dogs:', 139.4, ;, subclinically, infected, 'dogs:', 216, ;, 'P', =, 0.0015, ',', and, significantly, decreased, iron, '(', 'μg/dL)', '(', 'median):', 'non-infected', 'dogs:', 202.5, ;, subclinically, infected, 'dogs:', 125.7, ;, 'P', =, 0.0041, ',', 'IGF-1', '(', 'ng/mL)', '(', 'median):', 'non-infected', 'dogs:', 224, ;, subclinically, infected, 'dogs:', 123, ;, 'P', =, 0.02, ',', and, albumin, '(', 'g/dL)', '(', 'median):', 'non-infected', 'dogs:', 2.8, ;, subclinically, infected, 'dogs:', 2.5, ;, 'P', =, 0.04, concentrations, were, observed, in, dogs, with, subclinical, 'Ancylostoma', spp])].
[sujeto(['These', findings]), verbo([provide]), complemento([an, overview, of, the, biochemical, effects, produced, by, patent, 'Ancylostoma', spp])].
[sujeto(['However,', no, study]), verbo([has]), complemento([looked, its, correlation, with, 'HDL', components, nor, with, 'HDL', function, in, patients, with, type, 2, diabetes, mellitus, '(', 'T2DM)'])].
[sujeto(['We', studied, 298, 'non-diabetic', subjects, and, 300, 'T2DM', patients, who, were, randomly]), verbo([recruited]), complemento([in, the, tertiary, referral, centre])].
[sujeto(['After', adjusting, for, confounding, 'factors,', one, 'SD']), verbo([increase]), complemento([of, 'ANGPTL3', '(', 164.6, &, 'nbsp;ng/ml)', associated, with, increase, of, 2.57, &, 'nbsp;mg/dL', cholesterol, and, 1.14, &, 'nbsp;μg/mL', 'apoA-I', but, decrease, of, 47.07, &, 'nbsp;μg/L', of, 'SAA', in, 'HDL', particles, of, 'non-diabetic', females, '(', 'p&nbsp;&lt;&nbsp;0'])].
[sujeto(['By', 'contrast,', 1, -, 'SD']), verbo([increase]), complemento([of, 'ANGPTL3', '(', 159.9, &, 'nbsp;ng/ml)', associated, with, increase, of, 1.69, &, 'nbsp;mg/dl', cholesterol, and, 1.25, &, 'nbsp;μg/mL', 'apoA-I', but, decrease, of, 11.7, &, 'nbsp;μg/L', of, 'SAA', in, 'HDL', particles, of, female, diabetic, patients, '(', 'p&nbsp;&lt;&nbsp;0'])].
[sujeto(['Moreover,', one, 'SD']), verbo([increase]), complemento([of, 'ANGPTL3', associated, with, increase, of, 2.11, &, 'nbsp;%', cholesterol, efflux, against, 'HDLs', in, 'non-diabetic', females, '(', 'p&nbsp;=&nbsp;0'])].
[sujeto([71, ')', but]), verbo([decrease]), complemento([of, 1.46, &, 'nbsp;%', in, female, 'T2DM', patients, '(', 'p&nbsp;=&nbsp;0'])].
[sujeto(['The']), verbo([decrease]), complemento([of, 'ANGPTL3', level, in, female, 'T2DM', patients, might, contribute, to, its, weak, association, to, 'HDL', components, and, function])].
[sujeto(['ANGPTL3', could, be, considered, as, a, novel, therapeutic]), verbo([target]), complemento([for, 'HDL', metabolism, for, treating, diabetes])].
[sujeto(['The', apolipoprotein, 'E', '(', 'APOE)', gene, is, the, most, highly]), verbo([associated]), complemento([susceptibility, locus, for, late, onset, 'Alzheimer\'s', 'Disease', '(', 'AD),', and, augmenting, the, beneficial, physiological, functions, of, apoE, is, a, proposed, therapeutic, strategy])].
[sujeto(['In', a, high, throughput, phenotypic, screen, for, small, molecules, that]), verbo([enhance]), complemento([apoE, secretion, from, human, 'CCF-STTG1', astrocytoma, 'cells,', we, show, the, chrysanthemic, ester, 82879, robustly, increases, expressed, apoE, up, to, 9.4, -, fold, and, secreted, apoE, up, to, 6, -, fold, and, is, associated, with, increased, total, cholesterol, in, conditioned, media])].
[sujeto([82879, also]), verbo([stimulates]), complemento([liver, x, receptor, '(', 'LXR)', target, genes, including, 'ATP', binding, cassette, 'A1', '(', 'ABCA1),', 'LXRα', and, inducible, degrader, of, low, density, lipoprotein, receptor, '(', 'IDOL)', at, both, mRNA, and, protein, levels])].
[sujeto(['In', 'particular,', the, lipid, transporter, 'ABCA1', was]), verbo([increased]), complemento([by, up, to, 10.6, -, fold, upon, 82879, treatment])].
[sujeto(['The', findings, from, 'CCF-STTG1', cells, were, confirmed, in, primary, human, astrocytes, from, three, 'donors,', where]), verbo([increased]), complemento([apoE, and, 'ABCA1', was, observed, along, with, elevated, secretion, of, 'high-density', lipoprotein, '(', 'HDL)-like', apoE, particles])].
[sujeto(['Nuclear', receptor, transactivation, assays, revealed, modest, direct, 'LXR', agonism, by, compound, 82879, ',', yet, 10, μM, of, 82879, significantly, upregulated, apoE, mRNA, in, mouse, embryonic, fibroblasts, '(', 'MEFs)', depleted, of, both, 'LXRα', and, 'LXRβ,', demonstrating, that, 82879, can, also]), verbo([induce]), complemento([apoE, expression, independent, of, 'LXR', transactivation])].
[sujeto(['By', 'contrast,', deletion, of, 'LXRs', in, 'MEFs', completely, blocked, mRNA, changes, in, 'ABCA1', even, at, 10, μM, of, 82879, ',', indicating, the, ability, of, 82879, to]), verbo([stimulate]), complemento(['ABCA1', expression, is, entirely, dependent, on, 'LXR', transactivation])].
[sujeto(['Taken', 'together,', compound, 82879, is, a, novel, chrysanthemic, ester, capable, of]), verbo([modulating]), complemento([apoE, secretion, as, well, as, 'apoE-associated', lipid, metabolic, pathways, in, 'astrocytes,', which, is, structurally, and, mechanistically, distinct, from, known, 'LXR', agonists])].
[sujeto(['A', total, of, 272, children]), verbo([participated]), complemento([in, the, study, in, both, 'cohorts,', prepubertal, '(', 'baseline;', age, 6, -, 8, 'years)', and, adolescents, '(', 'follow-up;', age, 12, -, 16, 'years)'])].
[sujeto(['High-density', lipoprotein, cholesterol, and, apolipoprotein, 'A-I', levels]), verbo([decreased]), complemento([across, the, 'hs-CRP', tertile, in, both, prepubertal, children, and, 'adolescents,', with, significant, differences, '(', 'P', &, 'lt;'])].
[sujeto(['The', 'hs-CRP', levels, were, also, significantly]), verbo([associated]), complemento([with, leptin, levels, in, both, prepubertal, children, and, 'adolescents,', with, a, significant, increase, across, 'hs-CRP', tertiles, '(', 'P', &, 'lt;'])].
[sujeto(['The', shift, from, 'OW', to, 'NW', throughout, childhood, is]), verbo([associated]), complemento([with, a, decrease, in, 'hs-CRP', level, to, below, that, observed, in, children, who, maintain, 'NW', throughout, childhood])].
[sujeto(['Leptin', levels, were, strongly]), verbo([associated]), complemento([with, 'hs-CRP', levels, in, our, population, independent, of, 'BMI'])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, an, 'obesity-related', chronic, inflammatory, state, may, be, reversible, by, improving, weight, status])].
[sujeto(['Expression', of, 'ATP']), verbo([binding]), complemento([cassette, transporter, '(', 'ABC)', 'A1,', a, key, membrane, protein, for, biogenesis, of, 'high-density', lipoprotein, '(', 'HDL),', is, regulated, not, only, by, its, gene, transcription, but, also, by, its, intracellular, degradation, to, modulate, plasma, 'HDL', concentration])].
[sujeto(['We', previously, showed, that, inhibition, of, 'ABCA1', degradation, by, probucol, oxidative, 'products,', spiroquinone, '(', 'SQ)', and, diphenoquinone, '(', 'DQ),']), verbo([increased]), complemento(['HDL', biogenesis, and, reverse, cholesterol, 'transport,', and, achieved, reduction, of, atherosclerosis, in, animal, models])].
[sujeto(['The', background, mechanism]), verbo([has]), complemento([thus, been, investigated])].
[sujeto(['Involvement', of, 'caveolin-1,', a, protein, of, multiple, functions, in, cell, 'biology,', particularly, in, cholesterol, 'trafficking,']), verbo([has]), complemento([been, examined, for, its, roles, in, 'ABCA1', degradation, as, well, as, the, effects, of, 'SQ', and, 'DQ', on, the, reaction])].
[sujeto(['ABCA1', protein, was]), verbo([increased]), complemento([in, 'caveolin-1-deficient', mouse, embryonic, 'fibroblasts,', not, by, increase, of, transcription, but, by, decrease, in, its, internalization, and, degradation])].
[sujeto(['The', effects, of, 'SQ', and, 'DQ', to]), verbo([increase]), complemento(['ABCA1', and, cell, cholesterol, release, induced, by, apolipoprotein, 'A-I', were, dependent, on, expression, of, 'caveolin-1'])].
[sujeto(['Caveolin-1']), verbo([enhances]), complemento([internalization, and, degradation, of, 'ABCA1', by, its, association, with, 'ABCA1'])].
[sujeto(['Interference', of, this, interaction, by, probucol, oxidative, products]), verbo([suppresses]), complemento(['ABCA1', degradation, and, increase, 'HDL', biogenesis])].
[sujeto(['Our', aim, was, to]), verbo([gain]), complemento([insight, into, the, role, that, lipoprotein, lipase, '(', 'LPL)', and, hepatic, lipase, '(', 'HL)', plays, in, 'HDL', metabolism, and, to, better, understand, 'LPL-', and, 'HL-deficiency', states])].
[sujeto(['LPL-deficient', homozygotes, had, marked, hypertriglyceridemia, and, significant]), verbo([decreases]), complemento([in, 'LDL-C,', 'HDL-C,', and, 'apoA-I'])].
[sujeto(['HL-deficient', homozygotes, had, moderate, 'hypertriglyceridemia,', modest]), verbo([increases]), complemento([in, 'LDL-C', and, 'HDL-C', 'level,', but, normal, 'apoA-I', concentration])].
[sujeto(['Apolipoprotein', 'A1', '(', 'apoA1)', is, the, major, protein, component, of, 'high-density', lipoprotein, '(', 'HDL)', and]), verbo([has]), complemento([well, documented, 'anti-inflammatory', properties])].
[sujeto(['Acute', '(', 20, -, 60, 'min)', apoA1, treatment]), verbo([induced]), complemento([a, substantial, '(', 50, -, 90, '%', ')', reduction, in, macrophage, chemotaxis, to, a, range, of, chemoattractants])].
[sujeto(['We']), verbo([find]), complemento([that, apoA1, rapidly, disrupts, membrane, lipid, 'rafts,', and, as, a, 'consequence,', dampens, the, 'PI3K/Akt', signalling, pathway, that, coordinates, reorganization, of, the, actin, cytoskeleton, and, cell, migration])].
[sujeto(['Our', data, strengthen, the, evidence, base, for, therapeutic, apoA1, infusions, in, situations, where, reduced, monocyte, recruitment, to, sites, of, inflammation, could]), verbo([have]), complemento([beneficial, outcomes])].
[sujeto(['Apabetalone', '(', 'RVX-208)']), verbo([inhibits]), complemento([the, interaction, between, epigenetic, regulators, known, as, bromodomain, and, extraterminal, '(', 'BET)', proteins, and, 'acetyl-lysine', marks, on, histone, tails])].
[sujeto(['It', shows, that, 'RVX-208', and, a, comparator, 'BET', inhibitor, '(', 'BETi)', 'JQ1']), verbo([increase]), complemento([mRNA, expression, and, production, of, apolipoprotein, 'A-I', '(', 'ApoA-I),', the, main, protein, component, of, high, density, 'lipoproteins,', in, primary, human, and, 'African', green, monkey, hepatocytes])].
[sujeto(['In', 'addition,']), verbo([reported]), complemento([here, are, gene, expression, changes, from, a, 'microarray-based', analysis, of, human, whole, blood, and, of, primary, human, hepatocytes, treated, with, 'RVX-208'])].
[sujeto(['Patients', with, marked, deficiency, of, 'HDL-C', '(', &, 'lt;', 20, 'mg/dL)', in, the, absence, of, secondary]), verbo([causes]), complemento([are, much, less, common, '(', &, 'lt;', 1, '%', of, the, 'population)'])].
[sujeto(['These', patients, may]), verbo([have]), complemento(['homozygous,', compound, 'heterozygous,', or, heterozygous, defects, involving, the, apolipoprotein, '(', 'APO)AI,', 'ABCA1,', or, 'lecithin:cholesterol', acyl, transferase, 'genes,', associated, with, 'Apo', 'A-I', 'Deficiency,', 'ApoA-I', 'Variants,', 'Tangier', 'Disease', ',', 'Familial', 'Lecithin:Cholesteryl', 'Ester', 'Acyltransferase', 'Deficiency,', and, 'Fish', 'Eye', 'Disease'])].
[sujeto(['Wnt', proteins]), verbo([modulate]), complemento(['development,', stem, cell, fate, and, cancer, through, interactions, with, cell, surface, receptors])].
[sujeto(['The', culprit, responsible, for, this, behavior, is, a, covalently]), verbo([bound]), complemento([palmitoleoyl, moiety, in, the, 'N-terminal', domain])].
[sujeto(['In', signaling, 'assays,', 'Wnt3a', 'ND']), verbo([induced]), complemento(['β-catenin', stabilization, in, mouse, fibroblasts, as, well, as, hematopoietic, stem, and, progenitor, cells, '(', 'HSPC)'])].
[sujeto(['Prolonged', exposure, of, 'HSPC', to, 'Wnt3a', 'ND']), verbo([stimulated]), complemento([proliferation, and, expansion, of, 'Lin(-)', 'Sca-1(+)', 'c-Kit(+)', cells])].
[sujeto(['Surprisingly,', 'ND', lacking, 'Wnt3a', contributed, to, 'Lin(-)', 'Sca-1(+)', 'c-Kit(+)', cell, 'expansion,', an, effect, that, was, not]), verbo([mediated]), complemento([through, 'β-catenin'])].
[sujeto(['The', data, indicate, 'Wnt3a', 'ND', constitute, a, 'water-soluble', transport, vehicle, capable, of]), verbo([promoting]), complemento([ex, vivo, expansion, of, 'HSPC'])].
[sujeto(['Therefore,', we, used]), verbo([nuclear]), complemento([magnetic, resonance, '(', 'NMR)', to, examine, lipoprotein, particle, concentrations, and, sizes, in, 'overweight/obese', 'AAW', and, 'WAW', with, 'pre-diabetes'])].
[sujeto(['We']), verbo([found]), complemento([that, 'AAW', with, 'pre-diabetes', were, more, obese, '(', 'BMI', 38.8, '±6'])].
[sujeto(['We']), verbo([found]), complemento([a, more, favorable, 'NMR-derived', lipoprotein, profile, in, 'AAW', that, extends, the, traditional, antiatherogenic, 'lipid/lipoprotein', profiles])].
[sujeto(['The', prototype, of, the, 'HDL-mimicking', 'α-tocopherol-coated', 'NPs', contained, phosphatidylserine, '(', a, negative, charged, 'phospholipid)', and, 'D-', 'α-Tocopheryl', polyethylene, glycol, succinate, '(', a, source, of, vitamin, 'E)', to]), verbo([enhance]), complemento([the, entrapment, efficiency, of, apolipoprotein, 'A-I', in, the, 'NPs'])].
[sujeto(['In', vitro]), verbo([release]), complemento([studies, demonstrated, a, slow, release, of, 'NGF', from, 'NGF', 'NPs', in, 'PBS', containing, 5, '%', 'BSA', at, 37, °, 'C', for, 72, hours])].
[sujeto(['Further', biodistribution, studies, showed, that, intravenously, injected, 'NGF', 'NPs', significantly]), verbo([increased]), complemento(['NGF', concentration, in, plasma, and, decreased, the, uptake, in, 'liver,', spleen, and, 'kidney,', compared, to, free, 'NGF', in, mice])].
[sujeto(['High-density', lipoprotein, '(', 'HDL)', is]), verbo([involved]), complemento([in, innate, immunity, toward, various, infectious, diseases])].
[sujeto(['Concerning', 'bacteria,', 'HDL', is, known, to]), verbo([bind]), complemento([to, lipopolysaccharide, '(', 'LPS)', and, to, neutralize, its, physiological, activity])].
[sujeto(['avium)', 'infection,', which, tends, to]), verbo([increase]), complemento(['worldwide,', remains, poorly, studied])].
[sujeto(['Here', we]), verbo([report]), complemento([that, 'HDL', indicated, a, stronger, interaction, with, 'M'])].
[sujeto(['A']), verbo([binding]), complemento([of, apolipoprotein, '(', 'apo)', 'A-I,', the, main, protein, component, of, 'HDL,', with, a, specific, lipid, of, 'M'])].
[sujeto([avium, might]), verbo([participate]), complemento([in, this, interaction])].
[sujeto(['HDL', did, not]), verbo([have]), complemento([a, direct, bactericidal, activity, toward, 'M'])].
[sujeto(['Furthermore,', 'HDL', strongly]), verbo([promoted]), complemento([the, formation, of, lipid, droplets, in, 'M'])].
[sujeto(['These', observations]), verbo([provide]), complemento([new, insights, into, the, relationship, between, 'M'])].
[sujeto(['The', molecular, mechanism, by, which, 'ABCA1']), verbo([mediates]), complemento([cellular, binding, of, apolipoprotein, 'A-(apoA1)', and, nascent, 'HDL', assembly, is, not, well, understood])].
[sujeto(['To', determine, the, cell, surface, lipid, that]), verbo([mediates]), complemento([apoA1, binding, to, 'ABCA1', expressing, cells, and, the, role, it, plays, in, nascent, 'HDL', assembly])].
[sujeto(['Using', multiple, biochemical, and, biophysical, 'methods,', we]), verbo([found]), complemento([that, apoA1, binds, specifically, to, phosphatidylinositol, '(', 4, ',', 5, ')', 'bis-phosphate', '(', 'PIP2)'])].
[sujeto(['Flow', cytometry, and, 'PIP2', reporter]), verbo([binding]), complemento([assays, demonstrated, that, 'ABCA1', led, to, 'PIP2', redistribution, from, the, inner, to, the, outer, leaflet, of, the, plasma, membrane])].
[sujeto(['Enzymatic', cleavage, of, cell, surface, 'PIP2', or]), verbo([decreased]), complemento([cellular, 'PIP2', by, knockdown, of, 'phosphatidylinositol-5-phosphate', 4, -, kinase, impaired, apoA1, binding, and, cholesterol, efflux, to, apoA1])].
[sujeto(['PIP2', also]), verbo([increased]), complemento([the, spontaneous, solubilization, of, phospholipid, liposomes, by, apoA1])].
[sujeto(['Using', site, directed, 'mutagenesis;', we]), verbo([found]), complemento([that, 'ABCA1\'s', 'PIP2', and, phosphatidylserine, translocase, activities, are, independent, from, each, other])].
[sujeto(['Furthermore,', we, discovered, that, 'PIP2', is, effluxed, from, cells, to, 'apoA1,', where, it, is]), verbo([associated]), complemento([with, 'HDL', in, 'plasma,', and, that, 'PIP2', on, 'HDL', is, taken, up, by, target, cells, in, a, scavenger, 'receptor-BI', '(', 'SR-BI)', dependent, manner])].
[sujeto(['ABCA1']), verbo([has]), complemento([a, 'PIP2', floppase, 'activity,', which, increases, cell, surface, 'PIP2', levels, that, mediate, apoA1, binding, and, lipid, efflux, during, nascent, 'HDL', assembly])].
[sujeto(['We']), verbo([found]), complemento([that, 'PIP2', itself, is, effluxed, to, apoA1, and, it, circulates, on, plasma, 'HDL,', where, it, can, be, taken, up, via, the, 'HDL', receptor, 'SR-BI'])].
[sujeto(['In', this, 'study,', quercetin, 7, -, 'O-sialic', acid, '(', 'QA)', was, synthesized, aiming, to, put, together, the, cardiovascular, protective, effect, of, quercetin, and, the, recently]), verbo([reported]), complemento(['anti-oxidant', and, 'anti-atherosclerosis', functions, of, 'N-acetylneuraminic', acid])].
[sujeto(['QA']), verbo([decreased]), complemento(['lipopolysaccharide-induced', secretion, of, tumour, necrosis, 'factor-α', '(', 'TNF-α)', and, monocyte, chemoattractant, 'protein-1', '(', 'MCP-1),', and, it, significantly, reduced, the, expression, of, intercellular, adhesion, 'molecule-1,', vascular, cell, adhesion, 'molecule-1,', 'TNF-α', and, 'MCP-1'])].
[sujeto(['Furthermore,', 'QA', effectively]), verbo([promoted]), complemento([cholesterol, efflux, from, 'Raw', 264.7, macrophages, to, apolipoprotein, 'A-1', and, 'high-density', lipoprotein, by, 'up-regulating', 'ATP-binding', cassette, transporter, 'A1', and, 'G1,', respectively])].
[sujeto(['Hypothyroidism', is, one, of, the, most, common, metabolic, disorders]), verbo([associated]), complemento([with, dyslipidemia, which, poses, a, higher, risk, of, 'Coronary', 'Artery', 'Disease', '(', 'CAD)', in, such, patients])].
[sujeto(['We']), verbo([found]), complemento([significantly, high, levels, of, sd, 'LDL,', ox, 'LDL,', 'Apo', 'B,', 'Lp', '(', 'a),', 'TC,', 'TG,', 'LDL-C', in, cases, as, compared, to, the, controls])].
[sujeto(['Ox', 'LDL']), verbo([has]), complemento([shown, maximum, correlation, with, serum, 'TSH', '(', 'p&lt;0'])].
[sujeto(['Moreover,', ox, 'LDL', and, sd, 'LDL', were]), verbo([found]), complemento([to, be, increased, in, normolipidemic, hypothyroid, patients, thereby, giving, a, strong, supportive, evidence, that, estimation, of, these, parameters, can, become, fundamental, in, prompt, identification, of, the, high, risk, patients, of, 'CAD', in, hypothyroid, population])].
[sujeto(['However,', 'lipid-free', 'apoA-I']), verbo([has]), complemento([a, 'three-dimensional', '(', 3, 'D)', conformation, that, is, significantly, different, from, that, of, lipidated, 'apoA-I', on, nHDL])].
[sujeto(['Patients', with, 'PCOS', with, 'HA']), verbo([have]), complemento([higher, oxidative, stress, levels, compared, with, those, without, 'HA'])].
[sujeto(['The']), verbo([increased]), complemento([oxidative, stress, in, 'PCOS', is, related, to, 'HA', 'status,', increased, plasma, 'glucose,', 'TG,', 'HDL-C', and, 'E2', 'levels,', decreased, apoA1, concentrations, and, a, relative, shortage, of, antioxidant, capacity])].
[sujeto(['Glycation', of, apolipoproteins, is, a, major, feature, of, the, production, of, dysfunctional, 'high-density', lipoprotein, '(', 'HDL),', which, is]), verbo([associated]), complemento([with, the, incidence, of, several, metabolic, diseases, such, as, coronary, artery, disease, and, diabetes])].
[sujeto(['In', this, 'report,', fructated, 'apoA-I', '(', 'fA-I)']), verbo([induced]), complemento([by, fructose, treatment, showed, a, covalently, multimerized, band, without, 'cross-linking,', and, lysine, residues, were, irreversibly, modified, to, prevent, crosslinking])].
[sujeto(['Treatment', of, human, umbilical, vein, endothelial, cells, '(', 'HUVECs)', with, 'fA-I', and, 'HDL', from, elderly, patients]), verbo([caused]), complemento([a, 1.8, -, fold, and, 1.5, -, fold, increased, cellular, 'senescence,', 'respectively,', along, with, increased, lysosomal, enlargement])].
[sujeto(['In', the, 'lipid-free', and, rHDL, 'states,', 'fA-I']), verbo([increased]), complemento([embryo, death, by, 1.5, -, fold, and, 2.5, -, 'fold,', 'respectively,', along, with, the, production, of, oxidized, species])].
[sujeto(['In', 'conclusion,', 'fructose-mediated', 'apoA-I', fructation, resulted, in, the, severe]), verbo([loss]), complemento([of, several, beneficial, functions, of, 'apoA-I', and, 'HDL,', including, 'anti-senescence', and, insulin, secretion, 'activities,', accompanied, with, increased, susceptibility, to, protein, degradation, and, structural, modification])].
[sujeto(['HDL', functional, assays, were, performed, on, 'human-brain', endothelial, cells]), verbo([stimulated]), complemento([with, 'TNFα'])].
[sujeto(['HDLs', reduced, the, expression, of, 'VCAM1,', 'MCP1', and, 'MMP3', mRNA]), verbo([induced]), complemento([by, 'TNFα', in, 'blood-brain', barrier, endothelial, cells])].
[sujeto(['HDLs', from, patients, were, less, effective, in]), verbo([inhibiting]), complemento(['TNFα-induced', transcription, of, these, genes, '(', respectively, 38.6, vs])].
[sujeto(['ACI', may, be]), verbo([associated]), complemento([with, a, modified, distribution, of, 'HDL', particles, '(', increased, proportion, of, large, 'particles)', and, 'HDL-binding', 'proteins,', resulting, in, an, inappropriate, protection, of, endothelial, cells, under, ischemic, conditions])].
[sujeto(['Heterozygous', familial, hypercholesterolemia, and, dyslipidemia, are, the, predominant]), verbo([causes]), complemento([for, cardiovascular, disease, '(', 'CVD)'])].
[sujeto(['Clinical', guidelines, for, lowering, 'CVD', risk]), verbo([have]), complemento([advocated, that, low, density, 'lipoprotein-cholesterol', '(', 'LDL-C)', must, be, reduced])].
[sujeto(['The', primary, choice, of, therapy, for, controlling, lipidemia]), verbo([has]), complemento([been, 'statins,', which, are, not, completely, effective])].
[sujeto(['The']), verbo([loss]), complemento([of, statin, efficacy, is, likely, due, to, increased, circulating, 'PCSK9', and, antibody, therapy, against, 'PCSK9', has, been, found, to, be, efficacious, in, lowering, 'LDL-C'])].
[sujeto(['Overall,', 'add-on', therapy, with, 'PCSK9-mAb', to, the, ongoing, statin, therapy, was]), verbo([found]), complemento([to, achieve, greater, reduction, in, 'LDL-C,', 'ApoB,', 'TC,', compared, to, statin, therapy])].
[sujeto(['n-3', polyunsaturated, fatty, acid, '(', 'n-3', 'PUFA)', intake, is]), verbo([associated]), complemento([with, protection, from, 'obesity;', 'however,', the, mechanisms, of, protection, remain, poorly, characterized])].
[sujeto(['The', stearoyl, 'CoA', desaturase, '(', 'SCD),', 'insulin-sensitive', glucose, transporter, '(', 'SLC2A4),', and, sterol, regulatory, element]), verbo([binding]), complemento([protein, '(', 'SREBF1)', genes, are, transcriptionally, regulated, by, 'n-3', 'PUFA', intake, and, harbor, polymorphisms, associated, with, obesity])].
[sujeto(['SCD', polymorphisms, were]), verbo([associated]), complemento([with, 'ApoA1', concentration, and, 'n-3', 'PUFA', interactions, with, 'SCD', polymorphisms, were, associated, with, reduced, fasting, cholesterol, levels, and, 'waist-to-hip', ratio])].
[sujeto(['SLC2A4', polymorphisms, were]), verbo([associated]), complemento([with, hip, 'circumference,', 'high-density', lipoprotein, and, 'ApoA1', concentrations])].
[sujeto(['SREBF1', polymorphisms, were]), verbo([associated]), complemento([with, 'low-density', lipoprotein, and, 'HOMA-IR', and, 'n-3', 'PUFA', interactions, were, associated, with, reduced, fasting, insulin, and, 'HOMA-IR', levels])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, an, 'individual\'s', genotype, may, interact, with, dietary, 'n-3', 'PUFAs', in, ways, that, are, associated, with, protection, from, 'obesity-related', diseases, in, 'Yup\'ik', people])].
[sujeto(['In', patients, with, 'sepsis,', total, 'cholesterol,', 'HDL-C,', and, apolipoprotein, 'A', 1, '(', apoA, 1, ')', were, significantly]), verbo([decreased]), complemento([in, this, group])].
[sujeto(['Particularly', 'HDL-C', was]), verbo([decreased]), complemento([1, &, 'nbsp;day', after, admission])].
[sujeto(['The', 24, -, h, change, ratio, of, 'HDL-C', can, be, used, as, a, sepsis, diagnosis, maker, and, to, distinguish, between, the, bacteria]), verbo([involved]), complemento([in, sepsis])].
[sujeto(['High', density, lipoprotein, '(', 'HDL)']), verbo([has]), complemento([been, proposed, to, be, internalized, and, to, promote, reverse, cholesterol, transport, in, endothelial, cells, '(', 'ECs)'])].
[sujeto(['However,', the, mechanism, underlying, these, processes]), verbo([has]), complemento([not, been, studied])].
[sujeto(['We']), verbo([found]), complemento([mature, 'HDL', particles, were, reduced, in, patients, with, coronary, artery, disease, '(', 'CAD),', which, was, associated, with, an, increase, in, 'CC-chemokine', ligand, 2, '(', 'CCL2)'])].
[sujeto(['In', cultured, primary, human, coronary, artery, endothelial, cells, and, human, umbilical, vein, endothelial, 'cells,', we, determined, that, 'CCL2']), verbo([suppressed]), complemento([the, binding, '(', 4, °, 'C)', and, association, '(', 37, °, 'C)', of, 'HDL', 'to/with', 'ECs', and, 'HDL', cellular, internalization])].
[sujeto(['Furthermore,', 'CCL2']), verbo([inhibited]), complemento(['[', '(', 3, ')', 'H]cholesterol', efflux, to, 'HDL/apoA1', in, 'ECs'])].
[sujeto(['We', further]), verbo([found]), complemento([that, 'CCL2', induced, 'CC-chemokine', receptor, 2, '(', 'CCR2)', expression, and, 'siRNA-CCR2', reversed, 'CCL2', suppression, on, 'HDL', 'binding,', 'association,', 'internalization,', and, on, cholesterol, efflux, in, 'ECs'])].
[sujeto(['Moreover,', 'CCL2']), verbo([induced]), complemento(['p42/44', 'mitogen-activated', protein, kinase, '(', 'MAPK)', phosphorylation, via, 'CCR2,', and, 'p42/44', 'MAPK', inhibition, reversed, the, suppression, of, 'CCL2', on, 'HDL', metabolism, in, 'ECs'])].
[sujeto(['Our', study]), verbo([suggests]), complemento([that, 'CCL2', was, elevated, in, 'CAD', patients])].
[sujeto(['CCL2']), verbo([suppressed]), complemento(['HDL', internalization, and, cholesterol, efflux, via, 'CCR2', induction, and, 'p42/44', 'MAPK', activation, in, 'ECs'])].
[sujeto(['Liver-enriched', transcription, factor, 'cAMP-responsive', 'element-binding', protein, 'H', '(', 'CREBH)']), verbo([regulates]), complemento([plasma, triglyceride, clearance, by, inducing, lipoprotein, lipase, 'cofactors,', such, as, apolipoprotein, 'A-IV', '(', 'apoA-IV),', 'apoA-V,', and, 'apoC-II'])].
[sujeto(['CREBH', also]), verbo([regulates]), complemento(['apoA-I', transcription])].
[sujeto(['This', study, aims, to, determine, whether, 'CREBH']), verbo([has]), complemento([a, role, in, lipoprotein, metabolism, and, development, of, atherosclerosis])].
[sujeto(['We', showed, that, 'CREBH', deletion, in, 'Ldlr(-/-)', mice]), verbo([increased]), complemento([very, 'low-density', 'lipoprotein-associated', triglyceride, and, cholesterol, 'levels,', consistent, with, the, impairment, of, lipoprotein, 'lipase-mediated', triglyceride, clearance, in, these, mice])].
[sujeto(['In', 'contrast,', 'high-density', lipoprotein, cholesterol, levels, were]), verbo([decreased]), complemento([in, 'CREBH-deficient', 'mice,', which, was, associated, with, decreased, production, of, 'apoA-I', from, the, liver])].
[sujeto(['The', results, indicate, that, 'CREBH', directly]), verbo([activated]), complemento(['Apoa1', gene, transcription])].
[sujeto(['We', identified, 'CREBH', as, an, important, regulator, of, lipoprotein, metabolism, and]), verbo([suggest]), complemento([that, increasing, hepatic, 'CREBH', activity, may, be, a, novel, strategy, for, prevention, and, treatment, of, atherosclerosis])].
[sujeto(['Dispryosl', and, 'Ebenaceae,', is]), verbo([reported]), complemento([to, possess, many, beneficial, health, effects])].
[sujeto(['In', the, present, 'study,', the, phospholipid, complexes, of, total, flavonoids, from, 'Persimmon', leaves, '(', 'PLF-PC)', was, prepared, to]), verbo([enhance]), complemento([the, oral, bioavailability, of, 'PLF', and, to, evaluate, its, antiatherosclerotic, properties, in, atherosclerosis, rats, in, comparison, to, 'PLF'])].
[sujeto(['The', effect, of, 'PLF', '(', 50, 'mg/kg/d)', and, 'PLF-PC', '(', equivalent, to, 'PLF', 50, 'mg/kg/d)', on, atherosclerosis, rats]), verbo([induced]), complemento([by, excessive, administration, of, vitamin, 'D', '(', 600, ',', 0, 'IU/kg)', and, cholesterol, '(', 0.5, 'g/kg/d)', was, assessed, after, orally, administered, for, 4, weeks])].
[sujeto(['Thus,', 'PLF-PC', holds, a, promising, potential, for]), verbo([increasing]), complemento([the, oral, bioavailability, of, 'PLF'])].
[sujeto(['Analysis', of, various, clinical, paradigms]), verbo([suggests]), complemento([that, the, lipid, and, apolipoprotein, composition, of, 'HDL', defines, its, 'size,', 'shape,', and, functions, and, may, determine, its, beneficial, effects, on, human, health])].
[sujeto(['Previously,', we]), verbo([reported]), complemento([that, like, apolipoprotein, 'A-I', '(', 'Apoa1),', apolipoprotein, 'E', '(', 'Apoe)', is, also, capable, of, promoting, the, de, novo, biogenesis, of, 'HDL', with, the, participation, of, 'ATP', binding, cassette, 'A', lipid, transporter, member, 1, '(', 'Abca1)', and, plasma, enzyme, 'lecithin:cholesterol', acyltransferase, '(', 'Lcat),', in, a, manner, independent, of, a, functional, 'Apoa1'])].
[sujeto([7, 'cells,']), verbo([suggesting]), complemento([that, the, 'anti-inflammatory', effects, of, 'APOA1', are, dependent, on, 'APOE', expression])].
[sujeto(['Taken', 'together,', our, data, indicate, that, 'APOA1', and, 'APOE3']), verbo([recruit]), complemento([different, apolipoproteins, and, lipids, on, the, 'HDL', 'particle,', leading, to, structurally, and, functionally, distinct, 'HDL', subpopulations])].
[sujeto(['Pravastatin', treatment]), verbo([induced]), complemento([a, significant, decrease, in, the, 'TC,', 'LDL-c,', and, 'ApoB', levels, in, patients, expressing, the, 'ApoA1', 'AA+GA', genotype, '(', 'P', &, 'lt;', 0.05, ')', ',', and, not, in, those, expressing, the, 'GG', genotype, '(', 'P', &, 'gt;', 0.05, ')'])].
[sujeto(['However,', policosanol, treatment]), verbo([induced]), complemento([a, 'non-significant', decrease, in, the, serum, 'TC', levels, '(', 'P', &, 'gt;', 0.05, ')', and, a, significant, decrease, in, the, 'ApoB', levels, '(', 'P', &, 'lt;', 0.05, ')', ',', and, did, not, induce, a, decrease, in, the, 'LDL-c', '(', 'P', &, 'gt;', 0.05, ')', levels, in, patients, with, the, 'AA+GA', genotype])].
[sujeto(['Policosanol', also]), verbo([induced]), complemento([a, significant, decrease, in, the, 'TC', and, 'LDL-c', levels, in, patients, with, the, 'GG', genotype, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['Apolipoprotein', 'A1', '(', 'ApoA1),', a, major, constituent, of, 'high-density', lipoprotein, '(', 'HDL),']), verbo([has]), complemento([antiinflammatory, and, antioxidative, properties, and, plays, a, prognostic, role, in, chronic, heart, failure, '(', 'CHF)'])].
[sujeto(['Despite']), verbo([increased]), complemento([tumor, necrosis, factor, α, '(', 'TNFα)', levels, being, linked, to, worse, outcome, of, 'HF,', the, results, are, ambiguous, about, the, association, of, functionally, active, 308, promoter, polymorphism, of, the, 'TNFα', gene])].
[sujeto(['Low', 'ApoA1', and, high, 'TNFα', levels, were]), verbo([associated]), complemento([with, more, severe, 'disease,', and, 'ApoA1', showed, the, strongest, relationship, with, 'HDL,', total, 'cholesterol,', 'C-reactive', 'protein,', and, 'N-terminal', 'pro-B-type', natriuretic, peptide, '(', 'NT-proBNP)'])].
[sujeto(['Decreased', 'ApoA1', levels, were, significant, predictors, of, 5, -, year, mortality, '(', 'NT-proBNP-adjusted', 'HR', for, 1, decile]), verbo([decrease]), complemento([in, 'ApoA1', level, was, 1.1, '(', 'P', =])].
[sujeto(['Interaction', was]), verbo([found]), complemento([between, the, 'ApoA1', level, and, 'TNFα', -, 308, 'polymorphism,', because, in, patients, with, 'GG', haplotype, the, adverse, effect, of, low, 'ApoA1', level, on, survival, was, more, prevalent])].
[sujeto(['Lower', 'ApoA1', levels, were, strongly]), verbo([associated]), complemento([with, adverse, outcome, in, 'CHF', patients, in, a, 'TNFα', -, 308, polymorphism, dependent, manner])].
[sujeto(['Many', metabolic, perturbations, are]), verbo([associated]), complemento([with, 'obesity;', e])].
[sujeto(['A', number, of, 'genetic,', 'lifestyle,', and, environmental, factors]), verbo([have]), complemento([been, shown, to, contribute, to, the, lowering, of, 'HDL-cholesterol'])].
[sujeto(['One', of, these, factors, is, cholesteryl, ester, transfer, protein, '(', 'CETP)']), verbo([promoting]), complemento([the, redistribution, of, cholesteryl, 'esters,', 'triglycerides,', and, phospholipids, between, plasma, proteins])].
[sujeto(['Moreover,', obesity, and, 'ORD', are, often, linked, with, chronic, 'low-grade', inflammation]), verbo([leading]), complemento([to, insulin, resistance, and, endothelial, and, microvascular, dysfunctions])].
[sujeto(['The', aim, of, this, study, was, to, detect, differences, in, the, hepatic, expression, of, genes]), verbo([involved]), complemento([in, 'low-grade', inflammation, and, of, 'obesity-', and, 'cholesterol-related', microRNAs, in, two, mixed, breed, populations, of, pigs, '(', 'Yorkshire-Göttingen', 'minipig,', 'YM', and, 'Duroc-Göttingen', 'minipig,', 'DM)', including, males, and, 'females,', with, extreme, phenotypes, for, 'CETP', activity, levels, '(', designated, as, 'CETP-high', and, 'CETP-low,', 'respectively)'])].
[sujeto(['We']), verbo([found]), complemento([significant, difference, '(', 'P&nbsp;&lt;&nbsp;0'])].
[sujeto(['We', conclude, that]), verbo([increased]), complemento(['CETP', activity, is, accompanied, by, a, modest, differential, hepatic, expression, of, several, microRNAs, and, 'inflammatory-related', genes])].
[sujeto(['Neutrophil', myeloperoxidase]), verbo([has]), complemento([a, prominent, role, in, this, mechanism])].
[sujeto(['Indeed,', these, epitopes, may, be]), verbo([recognized]), complemento([by, immune, cells, and, induce, production, of, proatherogenic, 'ApoA1-specific', 'IgG', antibodies])].
[sujeto(['These', antibodies, are, biologically, relevant, because, they, are, able, to, react, with, 'Toll-like', receptor, '(', 'TLR)-2', and, 'TLR4', in]), verbo([target]), complemento([cells, and, induce, a, variety, of, 'pro-inflammatory', responses])].
[sujeto([1, ')', ',', and]), verbo([increased]), complemento(['HDL-C', '(', 110.0, '%', ;, 'p&nbsp;&lt;&nbsp;0'])].
[sujeto(['In', 'Japanese', patients, with, 'HeFH,', treatment, with, anacetrapib, 100, &, 'nbsp;mg', for, 12, weeks, resulted, in, substantial, reductions, in, 'LDL-C', and]), verbo([increases]), complemento([in, 'HDL-C', and, was, well, tolerated])].
[sujeto(['We', observed, that, sera, of, cirrhotic, patients, showed, reduced, levels, of, 'HDL-cholesterol', and, profoundly]), verbo([suppressed]), complemento([activities, of, several, enzymes, involved, in, 'HDL', maturation, and, metabolism])].
[sujeto(['With', regard, to, 'function,', these, alterations, in, 'levels,', composition, and, structure, of, 'HDL', were, strongly]), verbo([associated]), complemento([with, metrics, of, function, of, 'apoB-depleted', 'sera,', including, cholesterol, efflux, 'capability,', paraoxonase, 'activity,', the, ability, to, inhibit, monocyte, production, of, cytokines, and, endothelial, regenerative, activities])].
[sujeto(['Of', particular, 'interest,', cholesterol, efflux, capacity, appeared, to, be, strongly]), verbo([associated]), complemento([with, liver, disease, mortality])].
[sujeto(['Obesity', is]), verbo([associated]), complemento([with, vascular, 'inflammation,', fibrosis, and, reduced, 'high-density', lipoproteins, '(', 'HDL)-cholesterol'])].
[sujeto(['A-I']), verbo([led]), complemento([to, a, 1.8, -, fold, '(', p, &, 'lt;', 0.05, ')', increase, in, 'HDL-cholesterol', versus, control, 'ob/ob', mice, at, the, day, of, 'sacrifice,', which, was, paralleled, by, a, decrease, in, aortic, 'TNF-α', and, 'VCAM-1', mRNA, expression])].
[sujeto(['Pre-culture', of, 'MNC', with, 'HDL']), verbo([decreased]), complemento([their, adhesion, to, 'TNF-α-activated', 'HAEC'])].
[sujeto(['A-I', exerted, immunomodulatory, effects, as, evidenced, by, a, downregulation, of, aortic, 'NOD2', and, 'NLRP3', mRNA, expression, and, by, a, 12, &, 'nbsp;%,', 6.9, &, 'nbsp;%,', and, 15, &, 'nbsp;%']), verbo([decrease]), complemento([of, the, induced, 'proliferation/activity', of, total, splenic, 'MNC,', 'CD4+,', and, 'CD8+', cells, in, 'ob/ob', 'Ad'])].
[sujeto(['A-I', further, reduced, aortic, collagen, 'I', and, 'III', mRNA, expression, by, 62, &, 'nbsp;%', and, 66, &, 'nbsp;%,', respectively, '(', p, &, 'lt;', 0.0005, ')', ',', and, abrogated, the, potential, of, 'ob/ob', splenocytes, to]), verbo([induce]), complemento([the, collagen, content, in, murine, fibroblasts, upon, 'co-culture'])].
[sujeto(['Finally,', 'HDL']), verbo([decreased]), complemento([the, 'TGF-ß1-induced', collagen, deposition, of, murine, fibroblasts, in, vitro])].
[sujeto(['Hypothyroidism', '(', 'HO)', can, significantly, impair, lipid, metabolism, and]), verbo([increase]), complemento([cardiovascular, disease, risk])].
[sujeto(['Our', previous, study, demonstrated, that, 'HHcy', significantly]), verbo([induced]), complemento([insulin, resistance, and, impaired, coronary, artery, endothelial, function, in, patients, with, either, hypertension, or, 'HO'])].
[sujeto(['In', the, present, 'study,', we, studied, whether, plasma, levels, of, 'high-density', 'lipoprotein-cholesterol', '(', 'HDL-C)', and, apolipoprotein, 'A-I', '(', 'Apo', 'A-I)', were, altered, in, patients, with, 'HO,', and, if, 'so,', whether, this, change, was]), verbo([mediated]), complemento([by, 'HHcy'])].
[sujeto(['Hcy', levels, were, significantly]), verbo([increased]), complemento([in, patients, with, 'HO', or, 'SHO'])].
[sujeto(['These']), verbo([increased]), complemento(['Hcy', levels, may, impair, cardiovascular, function, via, the, inhibition, of, 'Apo', 'A-1', expression, and, impairment, of, its, antioxidant, capacity])].
[sujeto(['Our', findings]), verbo([provide]), complemento([new, insights, into, the, pathogenesis, of, 'hypothyroidism-induced', metabolic, disorders])].
[sujeto(['CETP', is]), verbo([involved]), complemento([in, the, transfer, of, cholesteryl, ester, from, 'HDL', to, apolipoprotein, 'B-containing', 'lipoproteins,', a, key, step, of, reverse, cholesterol, transport, '(', 'RCT)'])].
[sujeto(['CETP', inhibitors]), verbo([have]), complemento([been, developed, to, raise, serum, 'HDL-cholesterol', '(', 'HDL-C)', levels, and, reduce, cardiovascular, events])].
[sujeto(['However,', outcome, studies, of, three, 'CETP', inhibitors, '(', 'torcetrapib,', dalcetrapib, and, 'evacetrapib)', were, prematurely, terminated, because, of]), verbo([increased]), complemento([mortality, or, futility, despite, marked, increases, in, 'HDL-cholesterol', and, decreases, in, 'LDL-cholesterol', except, for, dalcetrapib])].
[sujeto(['CETP', inhibition]), verbo([induces]), complemento([formation, of, small, dense, 'LDL', and, possibly, dysfunctional, 'HDL', and, downregulates, hepatic, scavenger, receptor, class, 'B', type, 'I', '(', 'SR-BI)'])].
[sujeto(['For', future, drug, 'development,', the, opposite, 'strategy,', namely, enhancers, of, 'RCT', via, 'CETP', and, 'SR-BI', activation, as, well, as, the, inducers, of, apolipoprotein, 'A-I', or, 'HDL', production, might, be, a, better, approach, rather, than, delaying, 'HDL', metabolism, by]), verbo([inhibiting]), complemento([a, main, stream, of, 'RCT', in, vivo])].
[sujeto(['Serum', lipids, and, lipoproteins, are, used, for, the, prognosis, of, certain, 'diseases;', 'however,', the, prognostic, value, of, serum, apolipoprotein, 'A-I', '(', 'ApoA-I)', in, 'ESCC']), verbo([has]), complemento([not, been, described])].
[sujeto(['On', univariate, 'analysis,', 'ApoA-I,', alcohol, 'index,', pT, 'status,', pN, status, and, pTNM, status, were]), verbo([associated]), complemento([with, significantly, poor, 'survival,', and, 'ApoA-I', '(', p, =, 0.039, ')', ',', alcohol, index, '(', p, =, 0.037, ')', and, pTNM, status, '(', p, =, 0.0, ')', were, identified, as, prognostic, factors, associated, with, shorter, survival, in, the, multivariate, analysis])].
[sujeto(['Overall', survival, was, shorter, in, 'ESCC', patients, with]), verbo([decreased]), complemento(['pre-treatment', 'ApoA-I', levels])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, serum, 'ApoA-I', level, should, be, evaluated, as, a, predictor, of, survival, in, patients, with, 'ESCC'])].
[sujeto(['CSL112,', human, apolipoprotein, 'A-I', '(', 'apoA-I)', reconstituted, with, 'phosphatidylcholine,', is, known, to]), verbo([cause]), complemento([a, dramatic, rise, in, small, 'high-density', lipoprotein, '(', 'HDL)'])].
[sujeto(['To', explore, the, mechanisms, by, which, the, formation, of, small, 'HDL', particles, is]), verbo([induced]), complemento([by, 'CSL112'])].
[sujeto(['Infusion', of, 'CSL112', into, humans]), verbo([caused]), complemento([elevation, of, 2, small, diameter, 'HDL', fractions, and, 1, large, diameter, fraction])].
[sujeto(['Rather,', interaction, of, 'CSL112', with, purified, 'HDL', spontaneously, gave, rise, to, 3, 'HDL', 'species:', a, 'large,', spherical, species, composed, of, 'apoA-I', from, native, 'HDL', and, 'CSL112;', a, 'small,', 'disc-shaped', species, composed, of, 'apoA-I', from, 'CSL112,', but, smaller, because, of, the]), verbo([loss]), complemento([of, 'phospholipids;', and, the, smallest, 'species,', 'lipid-poor', 'apoA-I', composed, of, 'apoA-I', from, 'HDL', and, 'CSL112'])].
[sujeto(['Time-course', studies]), verbo([suggest]), complemento([that, remodeling, occurs, by, an, initial, fusion, of, 'CSL112', with, 'HDL', and, subsequent, fission, leading, to, the, smaller, forms])].
[sujeto(['We']), verbo([have]), complemento([described, a, mechanism, for, the, formation, of, 'small,', highly, functional, 'HDL', species, involving, spontaneous, fusion, of, discoidal, 'HDL', with, spherical, 'HDL', and, subsequent, fission])].
[sujeto(['For', the, convenience, of, risk, stratification, of, 'PMI', following, 'PCI,', the, aim, of, present, review]), verbo([provides]), complemento([a, unique, opportunity, to, summarize, the, relationship, of, 'non-cardiac', biomarkers, with, 'PMI', by, extensively, searching, in, the, 'MEDLINE', to, identify, all, the, relevant, studies])].
[sujeto(['In', 'conclusion,', we]), verbo([found]), complemento([that, 'PCI', related, 'PMI', might, be, correlated, positively, to, those, 'non-cardiac', biomarkers, such, as, 'low-density', lipoprotein, cholesterol, '(', 'LDL-C),', 'non-high-density', lipoprotein, 'cholesterol,', total, 'cholesterol,', 'triglyceride,', the, ratios, of, 'LDL-C', to, 'high-density', lipoprotein, cholesterol, '(', 'HDL-C),', the, ratios, of, 'HDL-C', to, apolipoprotein, 'A-I,', the, ratio, of, eicosapentaenoic, acid, to, arachidonic, 'acid,', 'lectin-like', oxidized, 'low-density', lipoprotein, 'receptor-1,', 'C-reactive', 'protein,', high, 'on-treatment', platelet, 'reactivity,', 'platelet-monocyte', 'aggregates,', 'N-term', 'pro-B-type', natriuretic, 'peptide,', hemoglobin, and, albuminuria])].
[sujeto(['However,', almost, all, studies, failed, to]), verbo([provide]), complemento([definite, mechanism, of, its, 'findings,', and, further, reaches, are, needed, to, focus, on, the, potential, mechanisms, of, association, between, 'non-cardiac', biomarkers, and, 'PMI', related, to, 'PCI'])].
[sujeto(['Serum', amyloid, 'A', '(', 'SAA)', levels]), verbo([increase]), complemento([during, acute, and, chronic, inflammation, and, are, mainly, associated, with, 'high-density', lipoprotein, '(', 'HDL)'])].
[sujeto(['We', confirmed, that, rhSAA]), verbo([bound]), complemento([to, 'HDL3', and, released, apolipoprotein, 'A-I', '(', 'apoA-I)', from, 'HDL', without, an, apparent, change, in, particle, size])].
[sujeto(['Antioxidant', ability, of, 'rhSAA,', evaluated, as, the, effect, on, the, formation, of, conjugated, diene, in, 'low-density', lipoprotein, '(', 'LDL)']), verbo([induced]), complemento([by, oxidation, using, copper, 'sulfate,', was, higher, than, that, of, 'apoA-I'])].
[sujeto(['Consequently,', 'SAA', affects, the, composition, and, surface, charge, of, 'HDL', by, displacement, of, 'apoA-I', and]), verbo([enhances]), complemento([its, antioxidant, ability])].
[sujeto(['The', structure, and, stability, of, apolipoprotein, '(', 'apo)A-I,', the, major, apolipoprotein, of, human, plasma, 'high-density', lipoproteins, '(', 'HDL),', determine, the, efficiency, of, the, protein, in, the, process, of, 'HDL', generation, and, affect, 'HDL', properties, in]), verbo([binding]), complemento([and, exchanging, its, 'constituents,', thus, playing, an, essential, role, in, reverse, cholesterol, transport])].
[sujeto(['Significant', negative, correlation, was]), verbo([found]), complemento([between, this, stability, and, the, efficiency, of, 'cAMP-stimulated', cholesterol, efflux])].
[sujeto(['LRP1', is, susceptible, to, proteolytic, shedding, at, the, cell, 'surface,', which]), verbo([prevents]), complemento([endocytic, transport, of, ligands])].
[sujeto(['Previously,', we]), verbo([reported]), complemento([a, strong, inverse, correlation, between, 'LRP1', shedding, in, the, brain, and, 'Aβ', transit, across, the, 'BBB'])].
[sujeto(['In', the, current, 'studies,', inhibition, of, 'ADAM10', reduced, 'LRP1', shedding, in, brain, endothelial, cultures, and]), verbo([increased]), complemento(['Aβ42', transit, across, an, in, vitro, model, of, the, 'BBB'])].
[sujeto(['Similarly,', transgenic, 'ADAM10', endothelial, knockout, mice, displayed, lower, 'LRP1', shedding, in, the, brain, and, significantly]), verbo([enhanced]), complemento(['Aβ', clearance, across, the, 'BBB', compared, to, 'wild-type', animals])].
[sujeto(['Acute', treatment, with, the, 'ADAM10-selective', inhibitor, 'GI254023X', in, an, 'AD', mouse, model, substantially, reduced, brain, 'LRP1', shedding, and]), verbo([increased]), complemento(['Aβ40', levels, in, the, 'plasma,', indicating, enhanced, 'Aβ', transit, from, the, brain, to, the, periphery])].
[sujeto(['Furthermore,', both, soluble, and, insoluble, 'Aβ40', and, 'Aβ42', brain, levels, were]), verbo([decreased]), complemento([following, 'GI254023X', 'treatment,', but, these, effects, lacked, statistical, significance])].
[sujeto(['These', studies, demonstrate, a, role, for, 'ADAM10', in, the, ectodomain, shedding, of, 'LRP1', in, the, brain, and, the, clearance, of, 'Aβ', across, the, 'BBB,', which, may]), verbo([provide]), complemento([a, novel, strategy, for, attenuating, 'Aβ', accumulation, in, the, 'AD', brain])].
[sujeto(['Cellular', mechanisms, that]), verbo([mediate]), complemento(['steatohepatitis,', an, increasingly, prevalent, condition, in, the, 'Western', world, for, which, no, therapies, are, 'available,', are, poorly, understood])].
[sujeto(['Despite', the, fact, that, its, synthetic, agonists]), verbo([induce]), complemento([fatty, 'liver,', the, liver, 'X', receptor, '(', 'LXR)', transcription, factor, remains, a, target, of, interest, because, of, its, 'anti-atherogenic,', cholesterol, 'removal,', and, 'anti-inflammatory', activities])].
[sujeto(['Here', we, show, that, tetratricopeptide, repeat, domain, protein, 39, 'B', '(', 'Ttc39b,', 'C9orf52)', '(', 'T39),', a, 'high-density', lipoprotein, gene, discovered, in, human, 'genome-wide', association, 'studies,']), verbo([promotes]), complemento([the, ubiquitination, and, degradation, of, 'LXR'])].
[sujeto(['Chow-fed', mice, lacking, 'T39', '(', 'T39(-/-))', display]), verbo([increased]), complemento(['high-density', lipoprotein, cholesterol, levels, associated, with, increased, enterocyte, 'ATP-binding', cassette, transporter, 'A1', '(', 'Abca1)', expression, and, increased, 'LXR', protein, without, change, in, 'LXR', messenger, 'RNA'])].
[sujeto(['When', challenged, with, a, high, 'fat/high', 'cholesterol/bile', salt, 'diet,', 'T39(-/-)', mice, or, mice, with, 'hepatocyte-specific', 'T39', deficiency, show]), verbo([increased]), complemento([hepatic, 'LXR', protein, and, target, gene, 'expression,', and, unexpectedly, protection, from, steatohepatitis, and, death])].
[sujeto(['Mice', fed, a, 'Western-type', diet, and, lacking, 'low-density', lipoprotein, receptor, '(', 'Ldlr(-/-)T39(-/-))', show]), verbo([decreased]), complemento([fatty, 'liver,', increased, 'high-density', 'lipoprotein,', decreased, 'low-density', 'lipoprotein,', and, reduced, atherosclerosis])].
[sujeto(['In', addition, to]), verbo([increasing]), complemento([hepatic, 'Abcg5/8', expression, and, limiting, dietary, cholesterol, 'absorption,', 'T39', deficiency, inhibits, hepatic, sterol, regulatory, 'element-binding', protein, 1, '(', 'SREBP-1,', 'ADD1)', processing])].
[sujeto(['This', is, explained, by, an]), verbo([increase]), complemento([in, microsomal, phospholipids, containing, polyunsaturated, fatty, 'acids,', linked, to, an, 'LXRα-dependent', increase, in, expression, of, enzymes, mediating, phosphatidylcholine, biosynthesis, and, incorporation, of, polyunsaturated, fatty, acids, into, phospholipids])].
[sujeto(['The', preservation, of, endogenous, 'LXR', protein]), verbo([activates]), complemento([a, beneficial, profile, of, gene, expression, that, promotes, cholesterol, removal, and, inhibits, lipogenesis])].
[sujeto(['Emerging', roles, are, being]), verbo([recognized]), complemento([increasingly, for, apolipoproteins, in, the, pathogenesis, and, treatment, of, lung, diseases, on, the, basis, of, their, ability, to, suppress, 'inflammation,', oxidative, 'stress,', and, tissue, 'remodeling,', and, to, promote, adaptive, immunity, and, host, defense])].
[sujeto(['ApoE-containing', lipoprotein, particles, are, internalized, into, cells, by, 'low-density', lipoprotein, receptors, '(', 'LDLRs),', whereas, 'apoA-I', can]), verbo([interact]), complemento([with, the, 'ATP-binding', cassette, subfamily, 'A', member, 1, '(', 'ABCA1)', transporter, to, efflux, cholesterol, and, phospholipids, out, of, cells])].
[sujeto(['ApoE', and, 'apoA-I', also]), verbo([mediate]), complemento(['receptor-independent', 'effects,', such, as, binding, to, and, neutralizing, 'LPS'])].
[sujeto(['Both', apoE, and, 'apoA-I', are]), verbo([expressed]), complemento([by, lung, 'cells,', which, allows, 'apoE/LDLR-', and, 'apoA-I/ABCA1-dependent', pathways, to, modulate, normal, lung, health, and, the, pathogenesis, of, respiratory, 'diseases,', including, 'asthma,', acute, lung, 'injury,', 'cancer,', 'emphysema,', pulmonary, 'fibrosis,', and, pulmonary, hypertension])].
[sujeto(['Data', from, human, studies, and, research, using, experimental, murine, model, systems]), verbo([have]), complemento([shown, that, both, apoE, and, 'apoA-I', pathways, play, primarily, protective, roles, in, lung, biology, and, respiratory, disease])].
[sujeto(['Furthermore,', apolipoprotein, mimetic, 'peptides,', corresponding, to, the, 'LDLR-binding', domain, of, apoE, or, the, class, 'A', amphipathic, 'α-helical', structure, of, 'apoA-I,']), verbo([have]), complemento([antiinflammatory, and, antioxidant, effects, that, attenuate, the, severity, of, lung, disease, in, murine, models])].
[sujeto(['Thus,', the, development, of, inhaled, apolipoprotein, mimetic, peptides, as, a, novel, treatment, paradigm, could, represent, a, significant, advance, for, patients, with, respiratory, disease, who, do, not]), verbo([respond]), complemento([to, current, therapies])].
[sujeto(['FG-4497', administration, to, 'LDL', 'receptor-deficient', mice, reduced, the, area, of, atherosclerotic, plaques, by, '≈50%', when, compared, with, 'vehicle-treated', controls, and, also, reduced, their, weight, 'gain,', insulin, 'resistance,', liver, and, white, adipose, tissue, '(', 'WAT)', 'weights,', adipocyte, 'size,', number, of, 'inflammation-associated', 'WAT', macrophage, aggregates, and, the, 'high-fat', 'diet-induced']), verbo([increases]), complemento([in, serum, cholesterol, levels])].
[sujeto(['The']), verbo([decrease]), complemento([in, atherosclerotic, plaque, areas, correlated, with, the, reductions, in, 'weight,', serum, cholesterol, 'levels,', and, 'WAT', macrophage, aggregates, and, the, autoantibody, increase])].
[sujeto(['The', 'HIF-P4H-2-hypomorphic/C699Y-LDL', 'receptor-mutant', mice, likewise, had, a, '≈50%', reduction, in, atherosclerotic, plaque, 'areas,', reduced, 'WAT', macrophage, aggregate, 'numbers,', and]), verbo([increased]), complemento([autoantibodies, against, oxidized, 'LDL,', but, did, not, have, reduced, serum, cholesterol, levels])].
[sujeto(['The', mechanisms]), verbo([involve]), complemento([beneficial, modulation, of, the, serum, lipid, profile, and, innate, immune, system, and, reduced, inflammation])].
[sujeto(['Further,', randomized, trial, data, addressing, hsCRP]), verbo([have]), complemento([been, central, to, understanding, the, 'anti-inflammatory', effects, of, statin, therapy, and, have, consistently, demonstrated, 'on-treatment', hsCRP, levels, to, be, as, powerful, a, predictor, of, residual, cardiovascular, risk, as, 'on-treatment', levels, of, 'low-density', lipoprotein, cholesterol])].
[sujeto(['Yet,', although, hsCRP, is, clinically, useful, as, a, biomarker, for, risk, 'prediction,', most, mechanistic, studies]), verbo([suggest]), complemento([that, 'CRP', itself, is, unlikely, to, be, a, target, for, intervention])].
[sujeto(['Moving', upstream, in, the, inflammatory, cascade, from, 'CRP', to, interleukin, '(', 'IL)-6', to, 'IL-1']), verbo([provides]), complemento([novel, therapeutic, opportunities, for, atheroprotection, that, focus, on, the, central, 'IL-6', signaling, system, and, ultimately, on, inhibition, of, the, 'IL-1β-producing', 'NOD-like', receptor, family, pyrin, domain, containing, 3, inflammasome])].
[sujeto(['Cholesterol', 'crystals,', neutrophil, extracellular, 'traps,', atheroprone, 'flow,', and, local, tissue, hypoxia]), verbo([activate]), complemento([the, 'NOD-like', receptor, family, pyrin, domain, containing, 3, inflammasome])].
[sujeto(['As', 'such,', a, unifying, concept, of, hsCRP, as, a, downstream, surrogate, biomarker, for, upstream, 'IL-1β', activity]), verbo([has]), complemento([emerged])].
[sujeto(['A', phase, 'IIb', study, conducted, among, diabetic, patients, at, high, vascular, risk, indicates, that, 'canakinumab,', a, human, monoclonal, antibody, that]), verbo([targets]), complemento(['IL-1β,', markedly, reduces, plasma, levels, of, 'IL-6,', 'hsCRP,', and, fibrinogen, with, little, change, in, atherogenic, lipids])].
[sujeto(['Canakinumab', in, now, being, tested, as, a, method, to]), verbo([prevent]), complemento([recurrent, cardiovascular, events, in, a, randomized, trial, of, 10, 65, 'post-myocardial', infarction, patients, with, elevated, hsCRP, that, is, fully, enrolled, and, due, to, complete, in, 2017])].
[sujeto(['If', 'successful,', these, trials, will, close, the, loop, on, the, inflammatory, hypothesis, of, atherosclerosis, and, serve, as, examples, of, how, fundamental, biologic, principles, can, be]), verbo([translated]), complemento([into, personalized, medical, practice])].
[sujeto(['C-type', lectins, '(', 'CTLs)', play, important, roles, in, invertebrate, innate, immunity, by]), verbo([recognizing]), complemento([and, eliminating, pathogens])].
[sujeto(['The', mRNA, transcripts, of, 'MnCTLDcp1', was]), verbo([expressed]), complemento([the, highest, in, heart])].
[sujeto(['Sugar']), verbo([binding]), complemento([assay, revealed, that, the, 'MnCTLDcp1', could, bind, to, the, glycoconjugates, of, bacteria, 'surface,', such, as, 'LPS,', 'PGN', and, they, can, compete, with, bacterial, as, competitors])].
[sujeto(['hydrophila,', 'Vibrio', 'parahaemolyticus,', 'Escherichia', coli, and, 'Pseudomonas', 'aeruginosa)', in, the, presence, of, calcium, and, also, could]), verbo([bind]), complemento([to, these, bacteria])].
[sujeto(['These', results, clearly]), verbo([suggested]), complemento([that, 'MnCTLDcp1', functions, as, a, 'pattern-recognition', receptor, involved, in, the, innate, immunity, of, 'M'])].
[sujeto(['Since', disturbance, of, angiogenesis, predisposes, to, ischemic, 'injuries,', attempts, to]), verbo([promote]), complemento([angiogenesis, have, been, made, to, improve, clinical, outcomes, of, patients, with, many, ischemic, disorders])].
[sujeto(['While', hypoxia, inducible, factors, '(', 'HIFs)']), verbo([stimulate]), complemento([vascular, remodeling, and, 'angiogenesis,', hyperlipidemia, impairs, angiogenesis, in, response, to, various, 'pro-angiogenic', factors])].
[sujeto(['However,', it, remains, uncertain, how, 'HIFs']), verbo([regulate]), complemento([angiogenesis, under, hyperlipidemia])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, exposure, to, 'low-density', lipoprotein, '(', 'LDL)', suppressed, in, vitro, angiogenesis, of, human, brain, microvascular, endothelial, cells])].
[sujeto(['Whereas', 'LDL', exposure, diminished, expression, of, 'HIF-1α', and, 'HIF-2α']), verbo([induced]), complemento([by, 'hypoxia,', it, inhibited, 'DMOG-', and, 'TNFα-induced', 'HIF-1α', and, 'HIF-2α', expression, in, normoxia])].
[sujeto(['Notably,', in, both, hypoxia, and, 'normoxia,', 'LDL', markedly, reduced, expression, of, 'HIF-1β,', a, constitutively, stable, 'HIF', 'subunit,', an, event]), verbo([associated]), complemento([with, 'NF-κB', inactivation])].
[sujeto(['Moreover,', knockdown, of, 'HIF-1β', 'down-regulated', 'HIF-1α', and, 'HIF-2α', 'expression,', in, association, with]), verbo([increased]), complemento(['HIF-1α', hydroxylation, and, 20, 'S', proteasome, activity, after, 'LDL', exposure])].
[sujeto(['Significantly,', the, proteasome, inhibitor, 'BSc2118']), verbo([prevented]), complemento([angiogenesis, attenuation, by, 'LDL', through, restoring, expression, of, 'HIFs'])].
[sujeto(['Together,', these, findings, argue, that, 'HIF-1β', might]), verbo([act]), complemento([as, a, novel, 'cross-link', between, the, 'HIF', and, 'NF-κB', pathways, in, suppression, of, angiogenesis, by, 'LDL,', while, proteasome, inhibitors, might, promote, angiogenesis, by, reactivating, this, signaling, cascade, under, hyperlipidemia])].
[sujeto(['Activation', of, apolipoprotein, 'E', 'receptor-2', '(', 'apoER2)', and, very, low, density, lipoprotein, receptor, '(', 'VLDLR)']), verbo([inhibits]), complemento([foam, cell, formation])].
[sujeto(['Here', we, generated, two, reelin, subregions, containing, the, receptor]), verbo([binding]), complemento([domain, with, or, without, its, 'C-terminal', region, '(', 'R5-6C', and, 'R5-6,', 'respectively)', and, studied, the, impact, of, these, peptides, on, macrophage, cholesterol, metabolism])].
[sujeto(['We']), verbo([found]), complemento([that, both, 'R5-6C', and, 'R5-6', can, be, secreted, by, cells])].
[sujeto(['Purified', 'R5-6', protein, can]), verbo([bind]), complemento([apoER2, and, 'VLDLR'])].
[sujeto(['Overexpression', of, apoER2, in, macrophages]), verbo([increased]), complemento([the, amount, of, 'R5-6', bound, to, the, cell, surface])].
[sujeto(['Treatment', of, macrophages, with, 0.2, 'μg/ml', 'R5-6', elevated, 'ATP']), verbo([binding]), complemento([cassette, 'A1', '(', 'ABCA1)', protein, level, by, '~72%', and, 'apoAI-mediated', cholesterol, efflux, by, '~39%'])].
[sujeto(['In', 'addition,', the, medium, harvested, from, cells, overexpressing, 'R5-6', or, 'R5-6C', '(', 'R5-6-', and, 'R5-6C-conditioned', 'media,', 'respectively)', also, 'up-regulated', 'ABCA1', protein, 'expression,', which, was]), verbo([associated]), complemento([with, accelerated, cholesterol, efflux, and, enhanced, phosphorylation, of, phosphatidylinositol, 3, kinase, '(', 'PI3K)', and, specificity, 'protein-1', '(', 'Sp1)', in, macrophages])].
[sujeto(['The']), verbo([increased]), complemento(['ABCA1', expression, and, cholesterol, efflux, by, 'R5-6-', and, 'R5-6C-conditioned', media, were, diminished, by, 'Sp1', or, 'PI3K', inhibitors, mithramycin, 'A', and, 'LY294002'])].
[sujeto(['Further,', the, cholesterol, accumulation]), verbo([induced]), complemento([by, 'apoB-containing,', 'apoE-free', lipoproteins, was, significantly, less, in, macrophages, incubated, with, 'R5-6-', or, 'R5-6C-conditioned', medium, than, in, those, incubated, with, control, conditioned, medium])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, reelin, subregion, 'R5-6', can, serve, as, a, tool, for, studying, the, role, of, apoER2, and, 'VLDLR', in, atherogenesis])].
[sujeto(['Competition', and, inhibition, studies, indicate, that, the, uptake, is, by, receptor]), verbo([mediated]), complemento([endocytosis, via, the, 'LDLr,', with, 'co-localization', of, apoE3, and, 'res/NBD', in, late, 'endosomes/lysosomes'])].
[sujeto(['We', propose, that, rHDL]), verbo([provides]), complemento([an, ideal, hydrophobic, milieu, to, sequester, resveratrol, and, that, rHDL, containing, apoE3, serves, as, an, effective, &, 'quot;nanovehicle&quot;', to, transport, and, deliver, resveratrol, to, targeted, intracellular, sites])].
[sujeto(['Reverse', transcription, 'PCR', showed, that, 'MnCTLDcp2', was]), verbo([expressed]), complemento([in, the, 'heart,', 'gill,', nerve, hepatopancreas, and, 'intestine;', 'MnCTLDcp3', was, expressed, in, the, 'hepatopancreas,', 'heart,', 'nerve,', gill, and, muscle])].
[sujeto(['Their', expression, in, the, heart, tissue, was]), verbo([regulated]), complemento([following, challenge, with, bacteria])].
[sujeto(['All', these, results]), verbo([suggested]), complemento([that, 'MnCTLDcp2', and, 'MnCTLDcp3', functioned, as, pattern, recognition, receptors, in, the, immune, system, of, 'M'])].
[sujeto(['Our', recent, study, revealed, that, fibrin]), verbo([interacts]), complemento([with, the, very, low, density, lipoprotein, receptor, '(', 'VLDLR)', on, endothelial, cells, through, its, βN, 'domains,', and, this, interaction, promotes, transendothelial, migration, of, leukocytes, and, thereby, inflammation])].
[sujeto(['To', localize, the, 'fibrin-binding', 'site,', we]), verbo([expressed]), complemento([a, soluble, extracellular, portion, of, this, 'receptor,', 'sVLDLRHT,', its, 'N-', and, 'C-terminal', 'regions,', 'VLDLR(1-8)HT', and, 'des(1-8)VLDLRHT,', 'respectively,', and, a, number, of, 'VLDLR', fragments, containing, various, combinations, of, 'CR', domains, and, confirmed, their, proper, folding, by, fluorescence, spectroscopy])].
[sujeto(['Our', experiments, performed, by, an, 'enzyme-linked', immunosorbent, assay, and, surface, plasmon, resonance, revealed, that, the, 'VLDLR(1-8)HT', fragment, containing, eight, 'CR', domains, of, 'VLDLR', and, its, 'subfragments,', 'VLDLR(1-4)HT', and, 'VLDLR(2-4)HT,']), verbo([interact]), complemento([with, '(', 'β15-66)2', with, practically, the, same, affinity, as, sVLDLRHT, while, the, affinity, of, 'VLDLR(2-3)HT', was, '∼2-fold', lower])].
[sujeto(['Thus,', the, results, obtained, indicate, that, minimal, 'fibrin-binding', structures, are, located, within, the, second, and, third, 'CR', domains, of, the, 'VLDL', receptor, and, the, presence, of, the, fourth, 'CR', domain, is]), verbo([required]), complemento([for, 'high-affinity', binding])].
[sujeto(['They', also, indicate, that, tryptophan, residues, of, 'CR', domains, are]), verbo([involved]), complemento([in, this, binding])].
[sujeto(['Sprague-Dawley', male, rats, were, given, 10, '%', fructose, in, drinking, water, and, standard, laboratory, chow, for, 4, weeks, to]), verbo([induce]), complemento([hyperuricemia, and, metabolic, syndrome])].
[sujeto(['Glomerular', protein, levels, of, 'nephrin,', 'podocin,', 'CD2-associated', protein, '(', 'CD2AP),', interleukin, '(', 'IL)-1β,', sirtuin, 1, '(', 'Sirt1),']), verbo([nuclear]), complemento([factor, kappaB, '(', 'NF-κB)', and, pyrin, domain, containing, 3, '(', 'NLRP3)', inflammasome, were, measured, by, 'Western', blot])].
[sujeto(['Simiao', pill, significantly]), verbo([increased]), complemento([protein, levels, of, 'nephrin,', podocin, and, 'CD2AP', in, renal, 'glomeruli,', improved, renal, inflammatory, cell, infiltration, into, interstitium, and, glomerular, injury, in, high, 'fructose-fed', rats, with, reduction, of, urine, albumin, levels])].
[sujeto(['Furthermore,', 'Simiao', pill, 'up-regulated', 'Sirt1', protein, levels, and]), verbo([suppressed]), complemento(['NF-κB/NLRP3', inflammasome, activation, to, reduce, 'IL-1β', in, renal, glomeruli, of, high, 'fructose-fed', rats])].
[sujeto(['The', renal, protective, effects, of, 'Simiao', pill, may, be]), verbo([associated]), complemento([with, 'up-regulation', of, 'Sirt1', expression, and, suppression, of, 'NF-κB/NLRP3', inflammasome, activation, to, reduce, renal, glomerular, injury, in, high, 'fructose-fed', rats, with, metabolic, syndrome])].
[sujeto(['Lysine', residues, are, implicated, in, driving, the, ligand]), verbo([binding]), complemento([to, the, 'LDL', receptor, family])].
[sujeto(['However,', it]), verbo([has]), complemento([remained, unclear, how, specificity, is, regulated])].
[sujeto(['None', of, the, individual, lysine, residues, account, completely, for, 'LRP1', 'binding,']), verbo([suggesting]), complemento([an, additive, binding, model])].
[sujeto(['Together', with, structural, docking, 'studies,', our, data]), verbo([suggest]), complemento([that, 'FVIII', interacts, with, 'LRP1', via, an, extended, surface, of, multiple, lysine, residues, that, starts, at, the, bottom, of, the, 'C1', domain, and, winds, around, the, 'FVIII', molecule])].
[sujeto(['Mice', constitutively]), verbo([expressing]), complemento([or, lacking, the, 'EDA', domain, of, fibronectin, '(', 'EDA+/+', or, 'EDA-/-)were', crossed, with, 'ApoE-/-', or, 'LDL-R-/-', mice, and, fed, with, a, western, type, diet, for, 12, weeks])].
[sujeto(['Lack', of, 'FN-EDA', resulted, in, reduced, atherosclerosis, and, in, a, plaque, phenotype, characterised, by]), verbo([decreased]), complemento([calponin, positive, 'VSMC\'s', '(', -, 15, '%', ')', and, increased, macrophages, '(', +, 20, '%', ')'])].
[sujeto(['This', was, paralleled, by]), verbo([increased]), complemento(['MMP2,', 'MMP9,', and, reduced, 'TIMP2,', collagen, 1, 'A1,', 1, 'A2', and, 3, 'A1', gene, expression, compared, to, that, of, 'wild-type', and, 'EDA+/+', mice])].
[sujeto(['In', 'vitro,', 'VSMCs', and, macrophages, isolated, from, 'EDA-/-', miceshowed]), verbo([increased]), complemento(['MMPs', expression, and, activity, compared, to, 'wild-type', or, 'EDA+/+', mice])].
[sujeto(['Atherosclerosis', '(', 'AS)', is, an, inflammatory, disease]), verbo([involved]), complemento([in, vascular, inflammatory, injury])].
[sujeto(['The', inflammasome, is, an, important, part, of, inflammatory, diseases, and]), verbo([participates]), complemento([in, the, vascular, inflammatory, injury])].
[sujeto(['The', effects, of, 'RSV', were, closely, related, to, hypolipidemia, '(']), verbo([decrease]), complemento([in, the, levels, of, total, 'cholesterol,', 'triglycerides,', and, 'low-density', lipoprotein, cholesterol, combined, with, the, expression, of, the, 'lectin-like', 'ox-LDL', receptor, and, increase, in, 'high-density', lipoprotein, 'cholesterol),', antioxidation, '(', decrease, in, 'MDA', levels, and, increase, in, 'SOD', and, 'GPx', 'activities),', and, 'anti-inflammation', '(', downregulation, of, the, expression, of, 'IL-1β,', intracellular, adhesion, 'molecule-1,', and, monocyte, chemotactic, 'protein-1)'])].
[sujeto(['This', study, proved, that, 'RSV']), verbo([inhibited]), complemento([inflammasome, activation, to, protect, vascular, injury, in, vivo])].
[sujeto(['Oxidative', stress]), verbo([activates]), complemento([endothelial, innate, immunity, and, disrupts, endothelial, 'functions,', including, endothelial, nitric, oxide, 'synthase-derived', nitric, oxide, bioavailability])].
[sujeto(['Here,', we, postulated, that, oxidative, stress]), verbo([induces]), complemento([sterol, regulatory, 'element-binding', protein, 2, '(', 'SREBP2)', and, 'microRNA-92a', '(', 'miR-92a),', which, in, turn, activate, endothelial, innate, immune, 'response,', leading, to, dysfunctional, endothelium])].
[sujeto(['The', 'SREBP2-induced', 'miR-92a']), verbo([targets]), complemento([key, molecules, in, endothelial, 'homeostasis,', including, sirtuin, 1, ',', 'Krüppel-like', factor, 2, ',', and, 'Krüppel-like', factor, 4, ',', leading, to, 'NOD-like', receptor, family, pyrin, 'domain-containing', 3, inflammasome, activation, and, endothelial, nitric, oxide, synthase, inhibition])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, 'SREBP2-miR-92a-inflammasome', exacerbates, endothelial, dysfunction, during, oxidative, stress])].
[sujeto(['Identification', of, this, mechanism, may, help, in, the, diagnosis, or, treatment, of, disorders]), verbo([associated]), complemento([with, oxidative, 'stress,', innate, immune, 'activation,', and, endothelial, dysfunction])].
[sujeto(['Lectin-like', oxidized, 'low-density', lipoprotein, 'receptor-1', '(', 'LOX-1)']), verbo([regulates]), complemento([blood, pressure, and, is, important, for, the, development, of, 'inflammation,', oxidative, stress, and, autophagy])].
[sujeto(['As', 'expected,', these, mice, developed, significant]), verbo([increase]), complemento([in, blood, pressure])].
[sujeto(['Corpus', callosum, in, the, brains, of, these, hypertensive, mice, revealed, intense, expression, of, 'NADPH', oxidase, '(', subunits, 'P22phox', and, 'P47phox),', activation, of, 'P38', 'MAPK', and]), verbo([nuclear]), complemento(['factor-kappaB', '(', 'P65),', 'autophagy-related', proteins, '(', 'beclin-1', and, conversion, of, 'LC3-I', to, 'LC3-II),', and, 'TLR4', '(', and, associated, signaling, molecules, myeloid, differentiation, primary, response, gene, '(', 88, ')', and, 'TIR-domain-containing', 'adapter-inducing', 'interferon-β)'])].
[sujeto(['These', observations]), verbo([suggested]), complemento([activation, of, redox, 'signals,', autophagy, and, immune, system])].
[sujeto(['In', parallel, 'experiments,', mice, with, 'LOX-1', deletion, given, similar, infusion, of, angiotensin, 'II', showed, much, less, expression, of, 'NADPH', 'oxidase,', activation, of, 'P38', 'MAPK', and]), verbo([nuclear]), complemento(['factor-kappaB,', 'autophagy-related', proteins, and, 'TLR4', '[', and, myeloid, differentiation, primary, response, gene, '(', 88, ')', and, 'TIR-domain-containing', 'adapter-inducing', 'interferon-β]'])].
[sujeto(['These', studies]), verbo([suggest]), complemento([immune, activation, in, the, brains, of, mice, with, angiotensin, 'II-induced', hypertension])].
[sujeto(['The', 'Clock', gene]), verbo([regulates]), complemento([diurnal, plasma, triglyceride, fluctuation, through, nuclear, receptor, small, heterodimer, partner, '(', 'Shp;', 'Nr0b2)'])].
[sujeto(['Several', components, of, the, liver, 'clock,', including, peroxisome, 'proliferator-activated', 'receptor-γ,', coactivator, 1, '(', 'Pgc-1α),', neuronal, 'PAS', 'domain-containing', protein, 2, '(', 'Npas2),', and, retinoic, 'acid-related', orphan, receptor, '(', 'Ror)α/γ', were, sharply]), verbo([induced]), complemento([in, 'Shp(-/-)', liver])].
[sujeto(['At', the, molecular, 'level,', 'SHP']), verbo([inhibited]), complemento(['Npas2', gene, transcription, and, promoter, activity, through, interaction, with, 'Rorγ', to, repress, 'Rorγ', transactivation, and, by, interacting, with, 'Rev-erbα', to, enhance, its, inhibition, of, 'Rorα', activity])].
[sujeto(['Conversely,', 'Npas2', controlled, the, circadian, rhythm, of, 'Shp', expression, by]), verbo([binding]), complemento([rhythmically, to, the, 'Shp', 'promoter,', which, was, enhanced, by, nicotinamide, adenine, 'dinucleotide,', but, not, nicotinamide, adenine, dinucleotide, phosphate])].
[sujeto(['Phenotypically,', 'Npas2', deficiency]), verbo([induced]), complemento([severe, steatosis, in, 'Shp(-/-)', 'mice,', which, was, attributed, to, the, dysregulation, of, lipoprotein, metabolism])].
[sujeto(['Shp', and, 'Npas2', crosstalk, is, essential, to]), verbo([maintain]), complemento([hepatic, lipid, homeostasis])].
[sujeto(['Collectin', placenta, 1, '(', 'CL-P1)', showed, scavenger, receptor, activity, as, functions, in, 'vitro,', and]), verbo([has]), complemento([three, candidate, 'domains:', a, 'coiled-coil', 'domain,', a, 'collagen-like', domain, and, 'CRD'])].
[sujeto(['We', constructed, seven, types, of, 'CL-P1', deletion, mutants, to, determine, the, site, of, each, ligand]), verbo([binding]), complemento(['domain,', and, observed, whether, the, specific, binding, to, sugar, 'ligand,', 'microbes,', or, oxidized, 'LDL', decreases, or, not, in, cells, with, 'CL-P1', deletion, mutants, and, 'CL-P1', containing, mutations, of, amino, 'acid,', respectively])].
[sujeto(['CL-P1', mainly]), verbo([interacted]), complemento([with, ligands, of, microbes, through, the, 'collagen-like', domain, and, it, binds, a, sugar, ligand, through, the, 'CRD'])].
[sujeto(['Additionally', it, could]), verbo([bind]), complemento([oxidized, low, density, lipoprotein, '(', 'OxLDL)', due, to, the, 'coiled-coil', domain, as, well, as, the, 'collagen-like', domain])].
[sujeto(['This']), verbo([binding]), complemento([study, using, mutants, at, three, positively, charged, sites, in, the, 'collagen-like', domain, reveals, that, the, site, of, 'R496', 'K499', 'K502', plays, the, most, important, role, in, ligand, binding, functions, for, microbes, and, 'OxLDL'])].
[sujeto(['CL-P1']), verbo([has]), complemento([three, unique, functional, 'domains:', the, 'collagen-like', domain, mainly, acts, against, most, negatively, charged, 'ligands,', and, the, 'CRD', specifically, does, against, sugar, 'substances,', while, the, 'coiled-coil', domain, additionally, acts, on, modified, 'LDL'])].
[sujeto(['We', considered, that, the]), verbo([binding]), complemento([activity, for, various, ligands, due, to, the, association, of, a, 'coiled-coil', 'domain,', a, 'collagen-like', domain, 'and/or', a, 'CRD', in, 'CL-P1,', might, play, a, role, in, physiological, functions, in, the, animal, body])].
[sujeto(['Objective', of, the, present, study, was, to]), verbo([report]), complemento([on, constitutive, and, 'CRH-', and, 'dexamethasone-regulated', 'POMC,', 'CRH', '(', 'CRH-R1),', and, glucocorticoid, receptor, '(', 'NR3C1)', gene, expression, in, a, large, series, of, human, corticotrope, adenomas])].
[sujeto(['POMC']), verbo([increased]), complemento([during, 'CRH', in, most, 'specimens;', 'conversely,', changes, induced, by, dexamethasone, were, 'varied,', ranging, from, decrease, to, paradoxical, increase])].
[sujeto(['CRH-R1', expression, was, not, linked, to, the, response, to, 'CRH', while, 'NR3C1', was]), verbo([expressed]), complemento([at, greater, levels, in, specimens, who, failed, to, inhibit, during, 'dexamethasone;', glucocorticoid, receptor, α, was, the, more, abundant, isoform, and, subject, to, 'down-regulation', by, dexamethasone])].
[sujeto(['Our', results, demonstrate, a, considerable, variability, in, 'POMC', expression, among, tumors, and, no, correlation, between, 'POMC', and, 'ACTH,']), verbo([suggesting]), complemento([that, 'POMC', peptide, 'processing/transport', plays, a, major, role, in, modulating, 'ACTH', secretion])].
[sujeto(['Generalized', glucocorticoid, resistance, is]), verbo([associated]), complemento([with, glucocorticoid, receptor, '(', 'GR;', 'NR3C1)', mutations])].
[sujeto(['Dexamethasone', '(', 'DXM)']), verbo([binding]), complemento([studies, demonstrated, that, the, affinity, of, 'GRR477S', and, 'GRY478C', 'mutants,', located, in, the, 'DNA-binding', domain, '(', 'DBD)', of, 'GR,', was, similar, to, 'wild-type', 'GR', '(', 'Kd', &, 'nbsp;=&nbsp;2-3&nbsp;nM)'])].
[sujeto(['In', 'contrast,', 'GRL672P', 'mutant,', located, in, the, 'ligand-binding', domain, '(', 'LBD)', of, 'GR,', was, unable, to]), verbo([bind]), complemento([glucocorticoids, and, was, more, sensitive, to, protein, degradation])].
[sujeto(['GR', subcellular, distribution, revealed, a, marked]), verbo([decrease]), complemento([in, 'DXM-induced', nuclear, translocation, of, 'GRR477S', and, 'GRY478C', 'mutants,', whereas, 'GRL672P', remained, exclusively, cytoplasmic])].
[sujeto(['Three-dimensional', modeling, indicated, that, 'R477S', lost, two, essential, hydrogen, bonds, with, 'DNA,', 'Y478C', resulted, in, altered, interaction, with, surrounding, 'amino-acids,', destabilizing, 'DBD,', whereas, 'L672P', altered, the, 'H8', helix, 'folding,']), verbo([leading]), complemento([to, unstructured, 'LBD'])].
[sujeto(['This', study, identifies, novel, 'NR3C1', mutations, with, their, molecular, consequences, on, altered, 'GR', signaling, and]), verbo([suggests]), complemento([that, genetic, screening, of, 'NR3C1', should, be, conducted, in, patients, with, subclinical, hypercorticism])].
[sujeto(['We', 'oligo-labelled', 5, '\'', -, 'm(7)G-capped', mRNA, from, two, 'genes,', the, simple, 'mono-exonic', 'Beta-2-Adrenoceptor', '(', 'ADRB2R)and', the, complex, 'multi-exonic', 'Glucocorticoid', 'Receptor', '(', 'GR,', 'NR3C1),', and, detected, a, variability, in, 'TSS', location, that]), verbo([has]), complemento([received, little, attention, up, to, now])].
[sujeto(['Complete', demethylation, of, the, epigenetically, sensitive, 'GR', promoter, with, 5, -, azacytidine]), verbo([induced]), complemento([one, new, locus, and, 127, 'TSSs,', 12, of, which, were, unique])].
[sujeto(['We']), verbo([induced]), complemento(['GR', transcription, with, dexamethasone, and, 'Interferon-γ,', adding, one, new, locus, and, 185, additional, 'TSSs', distributed, throughout, the, promoter, region])].
[sujeto(['In-vitro', the, 'TSS', microvariability]), verbo([regulated]), complemento([mRNA, translation, efficiency, and, the, relative, abundance, of, the, different, 'GRN-terminal', protein, isoform, levels])].
[sujeto(['Glucocorticoids', '(', 'GCs)']), verbo([have]), complemento([been, widely, used, as, coadjuvants, in, the, treatment, of, solid, 'tumours,', but, 'GC', treatment, may, be, associated, with, poor, pharmacotherapeutic, response, or, prognosis])].
[sujeto(['Here', we]), verbo([find]), complemento([that, dexamethasone, '(', 'Dex,', a, synthetic, 'GC)-regulated', genes, in, 'triple-negative', breast, cancer, '(', 'TNBC)', cells, are, associated, with, drug, resistance])].
[sujeto(['Importantly,', these, 'GC-regulated', genes, are, aberrantly]), verbo([expressed]), complemento([in, 'TNBC', patients, and, are, associated, with, unfavourable, clinical, outcomes])].
[sujeto(['Interestingly,', in, 'TNBC', 'cells,', 'Compound', 'A', '(', 'CpdA,', a, selective, 'GR', 'modulator)', only]), verbo([regulates]), complemento([a, small, number, of, genes, not, involved, in, carcinogenesis, and, therapy, resistance])].
[sujeto(['Mechanistic', studies, using, a, 'ChIP-exo', approach]), verbo([reveal]), complemento([that, 'Dex-', but, not, 'CpdA-liganded', glucocorticoid, receptor, '(', 'GR)', binds, to, a, single, glucocorticoid, response, element, '(', 'GRE),', which, drives, the, expression, of, 'pro-tumorigenic', genes])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, development, of, safe, coadjuvant, therapy, should, consider, the, distinct, genomic, function, between, 'Dex-', and, 'CpdA-liganded', 'GR'])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, in, vitro, sensitivity, to, dexamethasone, '(', 'DEX)', stimulation, in, human, endothelial, cells, is, positively, regulated, by, the, glucocorticoid, receptor, '(', 'NR3C1,', 'GR)'])].
[sujeto(['Real-time', 'PCR', analysis, of, 'GR', 5, '\'', 'UTR', mRNA, isoforms, showed, that, all, 'HUVECs']), verbo([expressed]), complemento([isoforms, 1, 'B,', 1, 'C,', 1, 'D,', 1, 'F,', and, 1, 'H,', and, isoforms, 1, 'B', and, 1, 'C', were, predominantly, expressed])].
[sujeto(['DEX-resistant', cells]), verbo([expressed]), complemento([higher, basal, levels, of, the, 5, '\'', 'UTR', mRNA, isoforms, 1, 'C', and, 1, 'D,', but, lower, levels, of, the, 5, '\'', 'UTR', mRNA, isoform, 1, 'F', than, 'DEX-sensitive', cells])].
[sujeto(['DEX', treatment, significantly]), verbo([decreased]), complemento(['GRα', and, 'GR-1C', mRNA, isoform, expression, in, 'DEX-resistant', cells, only])].
[sujeto(['Analysis', of, promoter, 'methylation,', 'however,', showed, that, 'DEX-sensitive', cells]), verbo([have]), complemento([higher, methylation, levels, of, promoter, 1, 'D', and, lower, methylation, levels, of, promoter, 1, 'F', than, 'DEX-resistant', cells])].
[sujeto(['In', 'sum,', human, endothelial, 'GR', 5, '\'', 'UTR', mRNA, expression, is]), verbo([regulated]), complemento([by, promoter, methylation, with, 'DEX-sensitive', and, 'DEX-resistant', cells, having, different, 'GR', promoter, methylation, patterns])].
[sujeto(['Chronic', fatigue, syndrome, '(', 'CFS)']), verbo([has]), complemento([been, associated, with, 'hypothalamic-pituitary-adrenal', axis, hypofunction, and, enhanced, glucocorticoid, receptor, '(', 'GR)', sensitivity])].
[sujeto(['We']), verbo([found]), complemento([evidence, of, 'NR3C1', promoter, hypomethylation, in, female, patients, with, 'CFS', and, the, functional, relevance, of, these, differences, was, consistent, with, the, 'hypothalamic-pituitary-adrenalaxis', hypofunction, hypothesis, '(', 'GR', 'hypersuppression)'])].
[sujeto(['However,', we]), verbo([found]), complemento([no, evidence, of, an, additional, effect, of, childhood, trauma, on, 'CFS', via, alterations, in, 'NR3C1', methylation])].
[sujeto(['However,', the, use, of, 'ICGs']), verbo([has]), complemento([become, increasingly, problematic, given, that, any, 'genes,', including, housekeeping, 'genes,', thought, to, be, stable, across, different, tissue, 'types,', ages, and, treatment, 'protocols,', can, be, regulated, at, transcriptomic, level])].
[sujeto(['Our', interest, in, prenatal, glucocorticoid, '(', 'GC)', effects, on, fetal, growth]), verbo([has]), complemento([resulted, in, our, investigation, of, suitable, 'ICGs', relevant, in, this, model])].
[sujeto(['The', effect, of, the, two, approaches, used, to, select, the, best, 'ICG(s)', was, compared, by, normalization, of, 'NR3C1', '(', glucocorticoid, 'receptor)', mRNA, 'expression,', as, an, example, for, a]), verbo([target]), complemento([gene])].
[sujeto(['Using', approach, '(', 1, ')', all, tested, 'ICGs', would]), verbo([have]), complemento([been, rejected, because, they, would, initially, appear, as, not, reliable, for, normalization])].
[sujeto(['However,', geNorm, analysis, '(', approach, 2, ')', of, the, 'ICGs', indicated, that, the, geometrical, mean, of, 'PPIA,', 'HPRT1,', 'RNA18S', and, 'RPLPO', can, be, considered, a, reliable, approach, for, normalization, of]), verbo([target]), complemento([genes, in, both, control, and, 'DEX', treated, groups])].
[sujeto(['Different', subset, of, 'ICGs', were, tested, for, normalization, of, 'NR3C1', expression, 'and,', despite, the, overall, pattern, of, the, mean, was, not, extremely, 'different,', the, statistical, analysis, uncovered, a, significant, influence, of, the, use, of, different, normalization, approaches, on, the, expression, of, the]), verbo([target]), complemento([gene])].
[sujeto(['We', observed, a]), verbo([decrease]), complemento([of, total, 'RNA', through, 'gestation,', a, lower, decrease, in, raw, 'RT-qPCR', data, of, the, two, rRNA, measured, compared, to, 'ICGs,', and, a, positive, correlation, between, raw, 'RT-qPCR', data, of, 'ICGs', and, total, 'RNA'])].
[sujeto(['Based', on, the, same, amount, of, total, 'RNA', to, performed, 'RT-qPCR', 'analysis,', those, data, indicated, that, other, mRNA, might]), verbo([have]), complemento([had, a, large, increase, in, expression, 'and,', as, 'consequence,', had, artificially, diluted, the, stably, expressed, 'genes,', such, as, 'ICGs'])].
[sujeto(['Our', data, indicated, that, the, use, of, the, geometrical, mean, of, 'PPIA,', 'HPRT1,', 'RNA18S', and, 'RPLPO', can]), verbo([provide]), complemento([a, reliable, normalization, for, the, proposed, study])].
[sujeto(['Finally,', the, observed, change, in, the, composition, of, 'RNA', species, through, time]), verbo([reveals]), complemento([the, limitation, of, the, use, of, 'ICGs', to, normalize, 'RT-qPCR', 'data,', especially, if, absolute, quantification, is, required])].
[sujeto(['Only', a, few, cases, of, 'Chrousos', syndrome]), verbo([have]), complemento([been, described, to, 'date,', ranging, from, asymptomatic, to, severe, forms, of, mineralocorticoid, 'and/or', androgen, excess])].
[sujeto(['All']), verbo([reported]), complemento([cases, have, been, associated, with, point, mutations, or, deletions, in, the, 'NR3C1', gene])].
[sujeto(['The', tremendous, progress, of, molecular, biology]), verbo([has]), complemento([enabled, us, to, apply, standard, methods, to, investigate, the, molecular, mechanisms, of, action, of, the, mutant, glucocorticoid, receptors, '(', 'GRs)'])].
[sujeto(['We', and, others]), verbo([have]), complemento([identified, and, functionally, characterized, novel, mutations, causing, 'Chrousos', 'syndrome,', while, structural, biology, has, enabled, us, to, have, a, better, understanding, of, how, conformational, changes, of, the, receptor, cause, glucocorticoid, resistance])].
[sujeto(['Glucocorticoids', '(', 'GCs)', selectively]), verbo([trigger]), complemento([cell, death, in, the, multiple, myeloma, cell, line, 'MM1S', which, express, 'NR3C1/Glucocorticoid', 'Receptor', '(', 'GR)', 'protein,', but, fail, to, kill, 'MM1R', cells, which, lack, 'GR', protein])].
[sujeto(['Transcriptome', analysis, revealed, that, 'GCs']), verbo([regulate]), complemento([expression, of, multiple, genes, involved, in, cell, cycle, 'control,', cell, 'organization,', cell, death, and, immunological, disease, in, 'MM1S', 'cells,', which, remain, unaffected, in, 'MM1R', cells])].
[sujeto(['With', respect, to, 'microRNAs,', 'mir-150-5p', was, identified, as, the, most, time, persistent, 'GC']), verbo([regulated]), complemento(['microRNA,', out, of, 5, 'QPCR', validated, microRNAs, '(', 'mir-26b,', 'mir-125a-5p,', 'mir-146-5p,', 'mir-150-5p,', and, 'mir-184),', which, are, 'GC', inducible, in, 'MM1S', but, not, in, 'MM1R', cells])].
[sujeto(['Functional', studies, further, revealed, that, ectopic, transfection, of, a, synthetic, 'mir-150-5p', mimics, 'GR', dependent, gene, expression, changes]), verbo([involved]), complemento([in, cell, death, and, cell, proliferation, pathways])].
[sujeto(['Remarkably,', despite, the, gene, expression, changes, 'observed,', overexpression, of, 'mir-150-5p', in, absence, of, 'GCs', did, not]), verbo([trigger]), complemento([significant, cytotoxicity, in, 'MM1S', or, 'MM1R', cells])].
[sujeto(['This']), verbo([suggests]), complemento([the, requirement, of, additional, steps, in, 'GC', induced, cell, 'death,', which, can, not, be, mimicked, by, 'mir-150-5p', overexpression, alone])].
[sujeto(['Interestingly,', a, combination, of, 'mir-150-5p', transfection, with, low, doses, 'GC', in, 'MM1S', cells, was]), verbo([found]), complemento([to, sensitize, therapy, 'response,', whereas, opposite, effects, could, be, observed, with, a, 'mir-150-5p', specific, antagomir])].
[sujeto(['Although', 'mir-150-5p', overexpression, did, not, substantially, change, 'GR', expression, 'levels,', it, was]), verbo([found]), complemento([that, 'mir-150-5p', evokes, 'GR', specific, effects, through, indirect, mRNA, regulation, of, 'GR', interacting, transcription, factors, and, hormone, 'receptors,', 'GR', 'chaperones,', as, well, as, various, effectors, of, unfolded, protein, stress, and, chemokine, signalling])].
[sujeto(['Chronic', 'stress,', the, administration, of, glucocorticoids, and, the, prolonged, activation, of, glucocorticoid, receptors, '(', 'GRs)', are]), verbo([reported]), complemento([to, induce, affective, changes, in, humans, and, rodents, that, resemble, a, depressive, state])].
[sujeto(['DEX-treated', mice, exhibited, a, variety, of, 'depression-like', 'behaviors:']), verbo([increased]), complemento([time, of, immobility, in, the, 'FST,', a, reduced, preference, for, saccharin, consumption, and, increased, 'anxiety-like', behavior])].
[sujeto(['Behavioral', alterations, were, accompanied, by, a]), verbo([decrease]), complemento([in, the, mRNA, expression, of, 'GR', and, the, increased, expression, of, 'Fkbp5', and, 'Sgk1', in, the, prefrontal, 'cortex,', hippocampus, and, striatum, of, 'DEX-treated', mice])].
[sujeto(['Furthermore,', our, results, indicate, a]), verbo([decrease]), complemento([in, the, mRNA, expression, of, glutamate, aspartate, transporter, '(', 'GLAST,', 'Slc1a3),', an, astroglial, cell, 'marker,', in, the, hippocampus, and, prefrontal, cortex])].
[sujeto(['These', results, demonstrate, that, the, prolonged, activation, of, 'GR', receptors]), verbo([induced]), complemento([a, 'depression-like', state, in, 'mice,', activated, 'stress-related', genes, and, induced, a, decrease, in, the, mRNA, expression, of, 'GLAST,', an, astroglial, 'marker,', in, the, prefrontal, cortex, and, hippocampus])].
[sujeto(['Together,', the, results]), verbo([reported]), complemento([here, challenge, several, hypotheses, concerning, the, role, of, 'GRs', in, the, development, of, behavioral, and, molecular, alterations, relevant, to, 'stress-related', 'disorders,', such, as, 'depression,', under, the, same, experimental, conditions])].
[sujeto(['To', determine, the, mechanism, of]), verbo([decreased]), complemento([testosterone, 'biosynthesis,', stallions, were, treated, with, 0.1, 'mg/kg', dexamethasone, 12, h, prior, to, castration])].
[sujeto(['Dexamethasone']), verbo([decreased]), complemento([serum, concentrations, of, testosterone, by, 60, '%', compared, to, 'saline-treated', control, stallions])].
[sujeto(['Transcriptome', analyses, '(', 'microarrays,', northern, blots, and, quantitative, 'PCR)', of, testes, discovered, that, dexamethasone, treatment]), verbo([decreased]), complemento([concentrations, of, glucocorticoid, receptor, alpha, '(', 'NR3C1),', alpha, actinin, 4, '(', 'ACTN4),', luteinizing, hormone, receptor, '(', 'LHCGR),', squalene, epoxidase, '(', 'SQLE),', 24, -, dehydrocholesterol, reductase, '(', 'DHCR24),', glutathione, 'S-transferase', 'A3', '(', 'GSTA3)', and, aromatase, '(', 'CYP19A1)', mRNAs])].
[sujeto(['Dexamethasone']), verbo([increased]), complemento([concentrations, of, 'NFkB', inhibitor, 'A', '(', 'NFKBIA)', mRNA, in, testes])].
[sujeto(['SQLE,', 'DHCR24', and, 'GSTA3', mRNAs, were, predominantly]), verbo([expressed]), complemento([by, 'Leydig', cells])].
[sujeto(['In', man, and, 'livestock,', the, 'GSTA3', protein]), verbo([provides]), complemento([a, major, 3, -, ketosteroid, isomerase, 'activity:', conversion, of, 'Δ(5)-androstenedione', to, 'Δ(4)-androstenedione,', the, immediate, precursor, of, testosterone])].
[sujeto(['Consistent', with, the]), verbo([decrease]), complemento([in, 'GSTA3', 'mRNA,', dexamethasone, decreased, the, 3, -, ketosteroid, isomerase, activity, in, testicular, extracts])].
[sujeto(['In', 'conclusion,', dexamethasone, acutely]), verbo([decreased]), complemento([the, expression, of, genes, involved, in, hormone, signaling, '(', 'NR3C1,', 'ACTN4', and, 'LHCGR),', cholesterol, synthesis, '(', 'SQLE', and, 'DHCR24)', and, steroidogenesis, '(', 'GSTA3', and, 'CYP19A1)', along, with, testosterone, production])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([of, dexamethasone, 'down-regulating', expression, of, the, 'GSTA3', gene, and, a, very, late, step, in, testosterone, biosynthesis])].
[sujeto(['Elucidation', of, the, molecular, mechanisms]), verbo([involved]), complemento([may, lead, to, new, approaches, to, modulate, androgen, regulation, of, the, physiology, of, humans, and, livestock, in, health, and, disease])].
[sujeto(['With', the, aim, to]), verbo([reveal]), complemento([common, genomic, regions, influencing, phenotypes, related, to, 'HPA', axis, function, and, 'metabolism,', we, did, a, quantitative, trait, loci, '(', 'QTL)', study, in, a, 'F2', population, obtained, from, the, 'cross-breeding', between, 2, contrasted, rat, 'strains,', 'LOU/C', and, 'Fischer', 344])].
[sujeto(['Adverse', fetal, environments, predispose, offspring, to, pathologies]), verbo([associated]), complemento([with, the, metabolic, syndrome])].
[sujeto(['Previously', we, demonstrated, that, adult, offspring, of, 'dexamethasone-treated', mothers, had, elevated, plasma, insulin, and, 'pro-inflammatory', 'cytokines,', effects]), verbo([prevented]), complemento([by, a, postnatal, diet, enriched, with, omega, '(', 'n)-3', fatty, acids])].
[sujeto(['Serum', total, fatty, acid, levels, were, elevated, '(', 'P', &, 'lt;', 0.01, ')', in, male, offspring, of, 'dexamethasone-treated', 'mothers,', an, effect]), verbo([prevented]), complemento([by, 'Hn3', consumption])].
[sujeto(['Prenatal', dexamethasone, also, programmed]), verbo([increased]), complemento([adipose, expression, of, 'Il6,', 'Il1b', '(', both, 'P', &, 'lt;', 0.05, ')', and, 'Tnfa', '(', 'P', &, 'lt;', 0.001, ')', mRNAs, regardless, of, fetal, 'sex,', but, again, this, effect, was, prevented, '(', for, 'Il6', and, 'Il1b)', by, 'Hn3', consumption])].
[sujeto(['Offspring', of, 'dexamethasone-treated', mothers, had]), verbo([increased]), complemento([adipose, expression, of, 'Gr', '(', 'P', =, 0.008, ')', and, 'Ppara', '(', 'P', &, 'lt;', 0.05, ')', regardless, of, sex, or, postnatal, 'diet,', while, 11, bHsd1, was, upregulated, in, males, only])].
[sujeto(['The', 'Hn3', diet]), verbo([increased]), complemento(['Ppard', expression, and, reduced, adipocyte, size, in, all, offspring, '(', both, 'P', &, 'lt;', 0.05, ')', irrespective, of, prenatal, treatment])].
[sujeto(['Prenatal', glucocorticoid, exposure, programmed]), verbo([increased]), complemento([expression, of, inflammatory, markers, and, enhanced, glucocorticoid, sensitivity, of, adipose, tissue])].
[sujeto(['A', putative, mechanism, is, that, elevated, bile, acids]), verbo([inhibit]), complemento([inactivation, of, cortisol, in, liver, by, 5, 'α-reductases', type, 1, and, type, 2, and, 5, 'β-reductase,', resulting, in, compensatory, downregulation, of, the, 'hypothalamic-pituitary-adrenal', axis, and, adrenocortical, atrophy])].
[sujeto(['To', test, the, hypothesis, that, impaired, glucocorticoid, clearance, can]), verbo([cause]), complemento([relative, adrenal, 'insufficiency,', we, investigated, the, consequences, of, 5, 'α-reductase', type, 1, deficiency, in, mice])].
[sujeto(['In', adrenalectomised, male, mice, with]), verbo([targeted]), complemento([disruption, of, 5, 'α-reductase', type, 1, ',', clearance, of, corticosterone, was, lower, after, acute, or, chronic, '(', 'eightfold,', 'P&lt;0'])].
[sujeto([mRNA, levels, of, 'Nr3c1', '(', glucocorticoid, 'receptor),', 'Crh', and, 'Avp', in, pituitary, or, hypothalamus, were, 'altered,', consistent, with]), verbo([enhanced]), complemento([negative, feedback])].
[sujeto(['These', findings, confirm, that, impaired, peripheral, clearance, of, glucocorticoids, can]), verbo([cause]), complemento(['\'', relative, adrenal, 'insufficiency\'', in, 'mice,', an, observation, with, important, implications, for, patients, with, critical, illness, or, hepatic, 'failure,', and, for, patients, receiving, 5, 'α-reductase', inhibitors, for, prostatic, disease])].
[sujeto(['Differential', effects, of, maternal, and, paternal, posttraumatic, stress, disorder, '(', 'PTSD)']), verbo([have]), complemento([been, observed, in, adult, offspring, of, 'Holocaust', survivors, in, both, glucocorticoid, receptor, sensitivity, and, vulnerability, to, psychiatric, disorder])].
[sujeto(['Lower', 'GR-1F', promoter, methylation, was, significantly]), verbo([associated]), complemento([with, greater, postdexamethasone, cortisol, suppression])].
[sujeto(['The', clustering, analysis, revealed, that, maternal, and, paternal, 'PTSD', effects, were, differentially]), verbo([associated]), complemento([with, clinical, indicators, and, 'GR-1F', promoter, methylation])].
[sujeto(['The', moderation, of, paternal, 'PTSD', effects, by, maternal, 'PTSD']), verbo([suggests]), complemento([different, mechanisms, for, the, intergenerational, transmission, of, 'trauma-related', vulnerabilities])].
[sujeto(['Nuclear', receptors, '(', 'NR)']), verbo([act]), complemento([as, an, integrated, conduit, for, environmental, and, hormonal, signals, to, govern, genomic, 'responses,', which, relate, to, cell, fate, decisions])].
[sujeto(['Steroid', hormone]), verbo([nuclear]), complemento([receptors, are, oncogenic, drivers, in, breast, and, prostate, cancer, and, blockade, of, signaling, is, a, major, therapeutic, goal])].
[sujeto(['By', contrast, to, blockade, of, 'receptors,', in, other, cancers]), verbo([enhanced]), complemento([receptor, function, is, 'attractive,', as, illustrated, initially, with, targeting, of, retinoic, acid, receptors, in, leukemia])].
[sujeto(['In', the, 'post-genomic']), verbo([era]), complemento([large, 'consortia,', such, as, 'The', 'Cancer', 'Genome', 'Atlas,', have, developed, a, remarkable, volume, of, genomic, data, with, which, to, examine, multiple, aspects, of, nuclear, receptor, status, in, a, 'pan-cancer', manner])].
[sujeto(['Therefore', to, extend, the, review, of, 'NR', function, we]), verbo([have]), complemento([also, undertaken, bioinformatics, analyses, of, 'NR', expression, in, over, 3000, 'tumors,', spread, across, six, different, tumor, types, '(', 'bladder,', 'breast,', 'colon,', head, and, 'neck,', liver, and, 'prostate)'])].
[sujeto(['Specifically,', to, ask, how, the, 'NR', expression, was, distorted, '(', altered, 'expression,', mutation, and, 'CNV)', we]), verbo([have]), complemento([applied, bootstrapping, approaches, to, simulate, data, for, 'comparison,', and, also, compared, these, 'NR', findings, to, 12, other, transcription, factor, families])].
[sujeto(['The', downregulation, was, not, driven, by, copy, number, variation, or, mutation, and, epigenetic, mechanisms, maybe, responsible, for, the, altered]), verbo([nuclear]), complemento([receptor, expression])].
[sujeto(['It', is, well, 'established,', that, epidermal, keratinocytes]), verbo([express]), complemento([functional, equivalent, of, 'hypothalamus-pituitary-adrenal', axis, '(', 'HPA)', in, order, to, respond, to, changing, environment, and, maintain, internal, homeostasis])].
[sujeto(['We', are, presenting, data, indicating, that, differentiation, of, primary, neonatal, human, keratinocytes, '(', 'HPEKp),']), verbo([induced]), complemento([by, prolonged, incubation, or, calcium, is, accompanied, by, significant, changes, in, the, expression, of, the, elements, of, skin, analog, of, 'HPA', '(', 'sHPA)'])].
[sujeto(['POMC', expression, was]), verbo([enhanced]), complemento([in, more, differentiated, 'keratinocytes,', which, corresponded, to, detection, of, 'ACTH', 'immunoreactivity,', predominantly, in, the, stratum, spinosum, and, stratum, granulosum])].
[sujeto(['Summarizing,', preferential, expression, of, 'CRF', and, 'POMC', '(', 'ACTH)', by, populations, of, keratinocytes, on, different, stage, of, differentiation, resembles, organization, of, central, 'HPA', axis]), verbo([suggesting]), complemento([their, distinct, role, in, physiology, and, pathology, of, the, epidermis])].
[sujeto(['This', was]), verbo([associated]), complemento([with, increased, 'DNMT3a', protein, association, with, a, discreet, region, of, the, 'Nr3C1', '(', 'GR', 'gene)', 'promoter,', shown, here, to, undergo, increased, 'DNA', methylation, after, 'FSS'])].
[sujeto(['FSS', also]), verbo([caused]), complemento([a, 'time-dependent', increase, in, the, expression, of, 'miR-124a,', a, microRNA, known, to, reduce, 'GR', mRNA, 'expression,', which, was, inversely, correlated, with, a, reduction, in, 'GR', mRNA, levels, at, 30, min, 'post-FSS'])].
[sujeto(['FSS', did, not, affect, 'GR']), verbo([binding]), complemento([to, a, putative, negative, glucocorticoid, response, element, '(', 'GRE)', within, the, 'Nr3c1', gene])].
[sujeto(['Acute', stress, results, in]), verbo([decreased]), complemento(['GR', mRNA, expression, specifically, in, the, dentate, gyrus])].
[sujeto(['Our', results, indicate, that, a, complex, interplay, of, multiple, molecular, mechanisms, including]), verbo([increased]), complemento(['DNA', methylation, of, discrete, 'CpG', residues, within, the, 'Nr3c1', 'gene,', most, likely, facilitated, by, 'DNMT3a,', and, increased, expression, of, 'miR-124a', could, be, responsible, for, these, changes])].
[sujeto(['Various', specific, human, glucocorticoid, receptor, '(', 'NR3C1)', gene, polymorphisms]), verbo([have]), complemento([been, described, in, multiple, sclerosis, '(', 'MS)', patients, and, correlated, with, disease, 'progression,', susceptibility, and, aggressiveness])].
[sujeto(['Sequencing', the, coding, sequences, and, 'intron-exon', boundaries, of, the, 'NR3C1', did, not]), verbo([reveal]), complemento([the, presence, of, 'mutation(s)', in, any, of, the, 'MS', patients])].
[sujeto(['None', of, the, identified, 'alleles/genotypes', were]), verbo([found]), complemento([to, be, associated, with, the, severity, of, 'disease,', response, to, glucocorticoids, and, disease, subtypes])].
[sujeto(['Known', 'polymorphism,', such, as, 'ER22/23EK', that]), verbo([has]), complemento([been, previously, detected, in, 'MS', 'patients,', was, not, detected])].
[sujeto(['Accumulating', evidence]), verbo([suggests]), complemento([that, early, adversity, is, linked, to, methylation, of, the, glucocorticoid, receptor, '(', 'GR)', 'gene,', 'NR3C1,', which, is, a, key, regulator, of, the, 'hypothalamic-pituitary-adrenal', axis])].
[sujeto(['Yet', no, prior, work]), verbo([has]), complemento([considered, the, contribution, of, methylation, of, 'NR3C1', to, emerging, behavior, problems, and, psychopathology, in, childhood])].
[sujeto(['Parents']), verbo([reported]), complemento([on, child, internalizing, and, externalizing, behavior, problems])].
[sujeto(['Methylation', of, 'NR3C1', at, exons, 1, 'D', and, 1, 'F', was, positively]), verbo([associated]), complemento([with, internalizing, '(', r, =])].
[sujeto(['Furthermore,', 'NR3C1', methylation]), verbo([mediated]), complemento([effects, of, early, adversity, on, internalizing, behavior, problems])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, methylation, of, 'NR3C1', contributes, to, psychopathology, in, young, 'children,', and, 'NR3C1', methylation, from, saliva, 'DNA', is, salient, to, behavioral, outcomes])].
[sujeto(['As', several, studies, 'show,', individually, variable, response, to, 'GCs', in, population]), verbo([has]), complemento([a, genetic, background, and, may, depend, on, gene, variability, encoding, proteins, involved, in, the, function, and, metabolism, of, 'GCs'])].
[sujeto(['To', those, genes, 'belong:', 'NR3C1--responsible', for, the, synthesis, of, 'GC', receptor, '(', 'GR);', 'Hsp90,', 'HSP70,', 'STIP1,', 'FKB5--genes', of, 'GR', protein, 'complex;', 'ABCB1', and, 'IPO13', coding, glycoprotein, 'p170;', and, importin, 13, -, -]), verbo([involved]), complemento([in, 'GCs', 'transport;', 'IL1A,', 'IL1B,', 'IL2,', 'IL4,', 'IL8,', 'IL10,', 'TNF,', and, 'MIF--genes', of, the, epithelial, 'pro-inflammatory', factors, 'synthesis,', which, excessive, activation, causes, steroid, resistance, as, well, as, 'CYP3A4', and, 'CYP3A5--encoding', 'GCs', biotransformation, enzymes])].
[sujeto(['Chronic', psychological, stress, is]), verbo([associated]), complemento([with, enhanced, abdominal, pain, and, altered, intestinal, barrier, function, that, may, result, from, a, perturbation, in, the, 'hypothalamic-pituitary-adrenal', '(', 'HPA)', axis])].
[sujeto(['The', glucocorticoid, receptor, '(', 'GR)', exploits, diverse, mechanisms, to]), verbo([activate]), complemento([or, suppress, congeneric, gene, 'expression,', with, regulatory, variation, associated, with, 'stress-related', disorders, in, psychiatry, and, gastroenterology])].
[sujeto(['During', acute, and, chronic, 'stress,', 'corticotropin-releasing', hormone, drives, secretion, of, adrenocorticotropic, hormone, from, the, 'pituitary,', ultimately]), verbo([leading]), complemento([to, the, release, of, cortisol, '(', 'human)', and, corticosterone, '(', 'rodent)', from, the, adrenal, glands])].
[sujeto(['Cortisol']), verbo([binds]), complemento([with, the, 'GR', in, the, 'cytosol,', translocates, to, the, 'nucleus,', and, activates, the, 'NR3C1', '(', nuclear, receptor, subfamily, 3, ',', group, 'C,', member, 1, '[', 'GR])', gene])].
[sujeto(['Glucocorticoid', receptor]), verbo([regulates]), complemento([different, sets, of, transcripts, in, a, 'tissue-specific', 'manner,', through, pulsatile, waves, of, gene, expression, that, includes, occupancy, of, glucocorticoid, response, elements, located, within, constitutively, open, spatial, domains, in, chromatin])].
[sujeto(['Emerging', evidence, supports, a, potentially, pivotal, role, for, epigenetic, regulation, of, how, 'GR']), verbo([interacts]), complemento([with, other, chromatin, regulators, to, control, the, expression, of, its, target, genes])].
[sujeto(['Dysregulation', of, the, central, and, peripheral, 'GR', regulome]), verbo([has]), complemento([potentially, significant, consequences, for, 'stress-related', disorders, affecting, the, 'brain-gut', axis])].
[sujeto(['An', impairment, of, the, 'GR', not, only, alters, the, level, of, 'glucocorticoids,', but, also]), verbo([modulates]), complemento([cognitive, functions, and, the, processing, of, emotional, stimuli])].
[sujeto(['In', a, sample, of, 'n=182', 'participants,', we]), verbo([found]), complemento([a, haplotype, '(', 'NR3C1-CTGGACA)', to, modulate, the, performance, in, an, emotional, reaction, time, task])].
[sujeto(['Hypothalamic-pituitary-adrenal', '(', 'HPA)', axis, functioning]), verbo([has]), complemento([been, implicated, in, the, development, of, 'stress-related', psychiatric, diagnoses, and, response, to, adverse, life, experiences])].
[sujeto(['Children', with, anxiety, disorders, were]), verbo([recruited]), complemento([into, the, 'Genes', for, 'Treatment', project, '(', 'GxT,', 'N', =, 1, ',', 152, ')'])].
[sujeto(['Treatment', response, was, not]), verbo([associated]), complemento([with, 'FKBP5', and, 'GR', 'polymorphisms,', or, pretreatment, percentage, 'DNA', methylation])].
[sujeto(['However,', change, in, 'FKBP5', 'DNA', methylation, was, nominally, significantly]), verbo([associated]), complemento([with, treatment, response])].
[sujeto(['Participants', who, demonstrated, the, greatest, reduction, in, severity]), verbo([decreased]), complemento([in, percentage, 'DNA', methylation, during, 'treatment,', whereas, those, with, 'little/no', reduction, in, severity, increased, in, percentage, 'DNA', methylation])].
[sujeto(['No', significant, association, was]), verbo([found]), complemento([between, 'GR', methylation, and, response])].
[sujeto(['Allele-specific', change, in, 'FKBP5', methylation, was]), verbo([associated]), complemento([with, treatment, response])].
[sujeto(['Furthermore,', this, is, the, first, study, to, demonstrate, that, 'DNA', methylation, changes, may, be]), verbo([associated]), complemento([with, response, to, psychological, therapies, in, a, 'genotype-dependent', manner])].
[sujeto(['Environmental', stress, is, among, the, most, important, contributors, to]), verbo([increased]), complemento([susceptibility, to, develop, psychiatric, disorders])].
[sujeto([5, -, hydroxymethylcytosine, '(', 5, 'hmC)', is, a, novel, environmentally, sensitive, epigenetic, modification, that, is, highly, enriched, in, neurons, and, is]), verbo([associated]), complemento([with, active, neuronal, transcription])].
[sujeto(['Recently,', we]), verbo([reported]), complemento([a, 'genome-wide', disruption, of, hippocampal, 5, hmC, in, male, mice, following, acute, stress, that, was, correlated, to, altered, transcript, levels, of, genes, in, known, stress, related, pathways])].
[sujeto(['Since', 'sex-specific', endocrine, mechanisms]), verbo([respond]), complemento([to, environmental, stimulus, by, altering, the, neuronal, 'epigenome,', we, examined, the, 'genome-wide', profile, of, hippocampal, 5, hmC, in, female, mice, following, exposure, to, acute, stress, and, identified, 363, differentially, hydroxymethylated, regions, '(', 'DhMRs)', linked, to, known, '(', e])].
[sujeto([',', 'Nr3c1', and, 'Ntrk2)', and, potentially, novel, genes]), verbo([associated]), complemento([with, stress, response, and, psychiatric, disorders])].
[sujeto(['Integration', of, hippocampal, expression, data, from, the, same, female, mice]), verbo([found]), complemento(['stress-related', hydroxymethylation, correlated, to, altered, transcript, levels])].
[sujeto(['Together,', the, alterations, in, 5, hmC, presented, here]), verbo([provide]), complemento([a, possible, molecular, mechanism, for, the, adaptive, 'sex-specific', response, to, stress, that, may, augment, the, design, of, novel, therapeutic, agents, that, will, have, optimal, effectiveness, in, each, sex])].
[sujeto(['Statins', are, 3, -, 'hydroxy-3-methylglutaryl', coenzyme, 'A', '(', 'HMG-CoA)', reductase, '(', 'HMGR)', inhibitors]), verbo([decreasing]), complemento([serum, cholesterol, and, have, shown, promise, in, cancer, prevention])].
[sujeto(['In', this, 'study,', we, demonstrated, the, oncogenic, role, of, 'HMGR', in, colorectal, cancer, '(', 'CRC)', by, disclosing]), verbo([increased]), complemento(['HMGR', activity, in, 'CRC', patients, and, its, enhancement, of, 'anti-apoptosis', and, stemness])].
[sujeto(['JMF', mostly]), verbo([regulated]), complemento([the, genes, related, to, apoptosis, and, inflammation, through, 'genome-wide', 'ChIP-on-chip', 'analysis,', and, 'Ingenuity', 'Pathways', 'Analysis', '(', 'IPA)', predicted, their, respective, regulation, by, 'NR3C1', and, 'NF-κB'])].
[sujeto(['Furthermore,', 'JMF']), verbo([inhibited]), complemento(['metastasis,', angiogenesis, and, cancer, 'stemness,', and, potentiated, the, effect, of, oxaliplatin, in, 'CRC', mouse, models])].
[sujeto(['MicroRNA', '(', 'miR)', are, a, subset, of, small, 'RNA', 'molecules,', which, posttranscriptionally]), verbo([modulate]), complemento([target, gene, expression])].
[sujeto(['Although', miR]), verbo([have]), complemento([been, demonstrated, to, impact, a, number, of, processes, during, development, and, 'tumorigenesis,', little, is, known, about, the, expression, and, the, role, of, miR, in, the, adrenal, gland])].
[sujeto(['Because', tight, regulation, of, steroid, synthesis, is, crucial, for]), verbo([maintaining]), complemento([homeostasis, upon, stressful, 'stimuli,', 'here,', we, determined, the, miR, expression, pattern, in, mouse, adrenal, glands, under, baseline, 'conditions,', as, well, as, 10, ',', 30, ',', and, 60, min, upon, 'ACTH', 'stimulation,', using, miR, microarray])].
[sujeto(['Changes', in, miR, expression, levels, detected, by, array, analysis, were, confirmed, by, 'real-time', 'PCR', and, further, analyzed, by, bioinformatic, tools, to, identify, miR, that, putatively]), verbo([target]), complemento([genes, involved, in, adrenal, function])].
[sujeto(['After', selecting, 'miR,', with, a, significant, change, in, their, expression, level, upon, 'ACTH', 'stimulation,', four, of, the, predefined, miR, '(', 'miR-96,', 'miR-101a,', 'miR-142-3p,', and, 'miR-433)', were]), verbo([found]), complemento([to, putatively, target, the, glucocorticoid, receptor, '[', nuclear, receptor, subfamily, 3, ',', group, 'C,', member, 1, '(', 'Nr3c1)]'])].
[sujeto(['Nr3c1', expression, levels, were, elevated, 10, min, after, 'ACTH', stimulation, but]), verbo([decreased]), complemento([after, 60, min, in, comparison, with, baseline, conditions])].
[sujeto(['Thereby,', we, could, confirm, that, 'miR96,', 'miR101a,', 'miR142-3p,', and, miR433]), verbo([target]), complemento([the, 'Nr3c1-3\'-untranslated', region, and, result, in, a, 20, -, 40, '%', repression, of, it])].
[sujeto(['Taken', 'together,', 'ACTH', stimulation, could, be, demonstrated, to, acutely, influence, adrenal, miR, expression, pattern, in, 'vivo;', 'thus,', potentially]), verbo([modulating]), complemento([adrenal, response, to, acute, stressors])].
[sujeto(['Maternal', emotional, distress, 'symptoms,', including, life, 'satisfaction,', anxiety, and, depressed, 'mood,', are, worse, in, 'Severely', 'Obese', '(', 'SO)', than, lean, pregnancy, and, may, alter, placental, genes]), verbo([regulating]), complemento([fetal, glucocorticoid, exposure, and, placental, growth])].
[sujeto(['We', hypothesised, that, the, associations, between]), verbo([increased]), complemento([maternal, distress, symptoms, and, changes, in, placental, gene, expression, including, 'IGF2', and, genes, regulating, fetal, glucocorticoid, exposure, are, more, pronounced, in, 'SO', pregnancy])].
[sujeto(['The', mRNA, levels, of, genes, with, a, similar, role, in]), verbo([regulating]), complemento([fetal, glucocorticoid, exposure, were, strongly, 'inter-correlated'])].
[sujeto(['Increased', maternal, distress, symptoms]), verbo([associated]), complemento([with, increased, 'NR3C2', and, 'IGF2', isoform, 1, '(', 'IGF2-1)', in, both, lean, and, 'SO', group, '(', 'p≤0'])].
[sujeto(['Increased', distress, was]), verbo([associated]), complemento([with, higher, 'ABCB1', and, 'ABCG2', mRNA, levels, in, 'SO', but, lower, 'ABCB1', and, higher, 11, 'β-HSD1', mRNA, levels, in, lean, '(', 'p≤0'])].
[sujeto([5, ')']), verbo([suggesting]), complemento([a, protective, adaptive, response, in, 'SO', placentas])].
[sujeto(['Increased', maternal, distress]), verbo([associated]), complemento([with, reduced, mRNA, levels, of, 'ABCB1,', 'ABCG2,', 11, 'β-HSD2,', 'NR3C1-α', and, 'IGF2-1', in, placentas, of, female, but, not, male, offspring])].
[sujeto(['The', observed, sex, differences, in, placental, responses]), verbo([suggest]), complemento([greater, vulnerability, of, female, fetuses, to, maternal, distress, with, potentially, greater, fetal, glucocorticoid, exposure, and, excess, 'IGF2'])].
[sujeto(['Further', studies, are, needed, to, replicate, these, findings, and, to, test, whether, this]), verbo([translates]), complemento([to, potentially, greater, negative, outcomes, of, maternal, distress, in, female, offspring, in, early, childhood])].
[sujeto(['Exposure', to, maternal, mood, disorder, in, utero, may, program, infant, neurobehavior, via, 'DNA', methylation, of, the, glucocorticoid, receptor, '(', 'NR3C1)', and, 11, 'β-hydroxysteroid', dehydrogenase, type, 2, '(', 11, 'β-HSD-2),', two, placental, genes, that]), verbo([have]), complemento([been, implicated, in, perturbations, of, the, hypothalamic, pituitary, adrenocortical, '(', 'HPA)', axis])].
[sujeto(['Controlling', for, relevant, 'covariates,', infants, whose, mothers]), verbo([reported]), complemento([depression, during, pregnancy, and, showed, greater, methylation, of, placental, 'NR3C1', 'CpG2', had, poorer, 'self-regulation,', more, 'hypotonia,', and, more, lethargy, than, infants, whose, mothers, did, not, report, depression])].
[sujeto(['On', the, other, 'hand,', infants, whose, mothers]), verbo([reported]), complemento([anxiety, during, pregnancy, and, showed, greater, methylation, of, placental, 11, 'β-HSD-2', 'CpG4', were, more, hypotonic, compared, with, infants, of, mothers, who, did, not, report, anxiety, during, pregnancy])].
[sujeto(['Our', results, support, the, fetal, programming, hypothesis, and]), verbo([suggest]), complemento([that, fetal, adjustments, to, cues, from, the, intrauterine, 'environment,', in, this, case, an, environment, that, could, be, characterized, by, increased, exposure, to, maternal, 'cortisol,', may, lead, to, poor, neurodevelopmental, outcomes])].
[sujeto(['DNA', methylation, is, known, to, play, a, critical, role, in]), verbo([regulating]), complemento([development, of, placental, morphology, and, physiology])].
[sujeto(['The', methylation, of, genes]), verbo([mediated]), complemento([by, glucocorticoid, hormones, may, be, particularly, vulnerable, to, intrauterine, stress, in, the, placenta])].
[sujeto(['Very', low, levels, of, methylation, were]), verbo([found]), complemento([across, all, three, 'stress-related', 'genes;', no, gene, showed, a, median, methylation, level, greater, than, 4.2, '%', across, placental, regions])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, these, frequently, studied, 'stress-related', genes, have, low, levels, of, methylation, in, healthy, placenta, tissue])].
[sujeto(['Minimal', variation, between, sites]), verbo([suggests]), complemento([that, sampling, location, does, not, affect, 'DNA', methylation, analyses, of, these, genes, or, of, 'LINE-1', repetitive, elements])].
[sujeto(['Platelet', 'aggregation,', 'ATP', 'secretion,', 'TxB2', 'release,', 'intra-platelet', calcium, 'mobilization,', protein, tyrosine, 'phosphorylation,', 'GPIIbIIIa', activation, by, 'PAC1', labelling, and, sCD40L]), verbo([release]), complemento(['(', 'enzyme-linked', immunosorbent, 'assay)', was, monitored, using, various, concentrations, of, 'DPV-Asn'])].
[sujeto(['Platelet', aggregation]), verbo([induced]), complemento([by, 'DPV-Asn', was, chiefly, regulated, by, dense, granule, 'secretion,', thromboxane, 'A2', '(', 'TxA2)', 'generation,', 'intra-platelet', '[', 'Ca(2+)]', 'influx,', 'GPIIbIIIa', activation, and, sCD40L, 'release,', which, were, significantly, reduced, in, presence, of, 'U73122', '(', 'PLC', 'inhibitor),', aspirin, '(', 'COX),', 'SB203580', '(', p38, 'inhibitor),', and, 'PD98059', '(', 'ERK', 'inhibitor)'])].
[sujeto(['This', was, further, corroborated, by]), verbo([enhanced]), complemento([tyrosine, phosphorylation, of, numerous, platelet, proteins, including, 'PLC-γ2,', which, apparently, played, a, central, role, in, transducing, peroxide, signals, to, regulate, '[', 'Ca(2+)]', influx, and, phosphorylation, of, p38, and, 'ERK1/2', 'MAP', kinase])].
[sujeto(['Peroxide', radicals, critically]), verbo([regulate]), complemento([the, 'thrombo-inflammatory', functions, of, platelets, via, the, 'PLCγ2-p38-ERK1/2-TxA2', 'pathway,', which, closely, resembles, the, clinical, scenario, of, various, pathologies, like, hyperglycemia, and, atherosclerosis, during, which, oxidative, stress, disrupts, platelet, functions])].
[sujeto(['The', vasculotropic, pathogen, 'Bartonella', henselae, '(', 'Bh)', intimately]), verbo([interacts]), complemento([with, human, endothelial, cells, '(', 'ECs)', and, subverts, multiple, cellular, functions])].
[sujeto(['Here', we]), verbo([report]), complemento([that, 'Bh', specifically, interferes, with, vascular, endothelial, growth, factor, '(', 'VEGF)', signalling, in, 'ECs'])].
[sujeto(['Consistently,', we, observed, that, 'Bh', infection, diminished, downstream, events, of, the, 'tyrosine(1175)', -, dependent, 'VEGFR2-signalling', pathway]), verbo([leading]), complemento([to, 'EC', 'proliferation,', i])].
[sujeto(['Pervanadate', treatment, neutralized, the, inhibitory, activity, of, 'Bh', on, 'VEGF', 'signalling,']), verbo([suggesting]), complemento([that, 'Bh', infection, may, activate, a, phosphatase, that, alleviates, 'VEGFR2', phosphorylation])].
[sujeto(['The', data, presented, in, this, study, underscore, the, role, of, the, 'VirB/Bep', system, as, important, factor, controlling, 'EC', proliferation, in, response, to, 'Bh', 'infection;', not, only, as, previously]), verbo([reported]), complemento([by, 'counter-acting', an, intrinsic, bacterial, mitogenic, 'stimulus,', but, also, by, restricting, the, exogenous, angiogenic, stimulation, by, 'Bh-induced', 'VEGF'])].
[sujeto(['B-1a', cells, constitutively]), verbo([express]), complemento(['phosphorylated,', activated, 'ERK,', but, the, origin, of, pERK, in, 'B-1', cells, has, not, been, determined])].
[sujeto(['We']), verbo([found]), complemento([that, constitutive, pERK, was, rapidly, lost, from, 'B-1a', cells, following, addition, of, metabolic, inhibitors, that, block, src, 'kinase,', 'Syk,', 'PI-3K,', and, 'PLC', function])].
[sujeto(['We', examined, 'Syk', and, 'PLC', in, more, detail, and]), verbo([found]), complemento([rapid, accumulation, of, phosphorylated, forms, of, these, molecules, in, 'B-1a', 'cells,', but, not, 'B-2', 'cells,', when, phosphatase, activity, was, 'inhibited,', and, this, change, occurred, in, the, majority, of, 'B-1a', cells])].
[sujeto(['We']), verbo([found]), complemento([that, when, 'Syk', or, 'PI-3K', was, 'inhibited,', 'CD86', expression, was, diminished, in, a, reversible, fashion])].
[sujeto(['All', 'together,', these, results, indicate, that, continual, activation, of, intracellular, signaling]), verbo([leads]), complemento([to, constitutive, activation, of, 'ERK', in, 'B-1', 'cells,', with, attendant, consequences, for, 'co-stimulatory', molecule, expression])].
[sujeto(['Tyrosine', 'kinase-catalyzed', protein, tyrosine, phosphorylation, plays, an, important, role, in, initiating, and]), verbo([modulating]), complemento([vascular, smooth, muscle, contraction])].
[sujeto(['Na3VO4', '(', 10, '(', -, 4, ')', 'm)']), verbo([induced]), complemento([a, gradually, sustained, contraction, and, significant, increase, in, protein, tyrosine, phosphorylation, of, a, set, of, substrates, including, 'PLCgamma-1', and, 'p42MAPK,', all, of, which, were, markedly, inhibited, by, genistein, '(', 5, x, 10, '(', -, 5, ')', 'm),', a, tyrosine, kinase, inhibitor])].
[sujeto(['The', findings, of, the, current, 'study,', that, isoflurane, 'dose-dependently']), verbo([inhibits]), complemento([both, the, 'Na3VO4-stimulated', contraction, and, tyrosine, phosphorylation, of, a, set, of, proteins, including, 'PLCgamma-1', and, p42MAPK, in, rat, aortic, smooth, 'muscle,', suggest, that, isoflurane, depresses, protein, tyrosine, 'phosphorylation-modulated', contraction, of, vascular, smooth, 'muscle,', especially, that, mediated, by, the, 'tyrosine-phosphorylated', 'PLCgamma-1', and, 'MAPK', signaling, pathways])].
[sujeto(['Reactive', oxygen, species, '(', 'ROS)']), verbo([mediate]), complemento([cell, damage, and, have, been, implicated, in, the, pathogenesis, of, diseases, that, involve, endothelial, injury])].
[sujeto(['Cells', possess, antioxidant, 'systems,', including, intracellular, antioxidants, and, 'ROS', scavenging, 'enzymes,', that, control, the, redox, state, and]), verbo([prevent]), complemento([cell, damage])].
[sujeto(['In', addition, to, intracellular, 'antioxidants,', certain, growth, factor, receptors, can, be]), verbo([activated]), complemento([under, oxidative, stress, and, trigger, downstream, cell, survival, signaling, cascades])].
[sujeto(['Here,', we]), verbo([provide]), complemento([evidence, that, activation, of, 'VEGFR-3', signaling, in, response, to, hydrogen, peroxide, '(', 'H(2)O(2))', promotes, endothelial, cell, survival])].
[sujeto(['Treatment', with, 'H(2)O(2)']), verbo([induced]), complemento([the, tyrosine, phosphorylation, of, 'VEGFR-3', and, its, association, with, the, signaling, adaptor, proteins, 'Shc,', growth, factor, receptor, binding, protein, 2, ',', 'Sos,', 'p85,', 'SHP-2,', and, phospholipase, 'C-gamma'])].
[sujeto(['Of', 'note,', a, hereditary, 'lymphoedema-linked', mutant, of, 'VEGFR-3', was, not]), verbo([phosphorylated]), complemento([by, 'H(2)O(2)', treatment])].
[sujeto(['However,', only, the, delta, isoform, of, 'PKC', was]), verbo([required]), complemento([for, 'H(2)O(2)-induced', phosphorylation, of, 'VEGFR-3'])].
[sujeto(['The', tyrosine, phosphorylation, of, 'VEGFR-3', or, isoforms, of, 'PKC', was, completely]), verbo([inhibited]), complemento([by, treatment, with, 4, -, 'amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine,', a, specific, inhibitor, for, 'Src', family, 'kinases,', indicating, that, 'Src', family, kinases, are, upstream, of, 'PKC', and, 'VEGFR-3'])].
[sujeto(['Furthermore,', expression, of, the, 'wild-type', but, not, the, 'lymphoedema-linked', mutant, form, of, 'VEGFR-3', in, porcine, artery, endothelial, cells, significantly]), verbo([enhanced]), complemento([the, activation, of, 'Akt', after, 'H(2)O(2)', stimulation])].
[sujeto(['Consistent', with, these, biochemical, 'changes,', we, observed, that, expression, and, activation, of, the, 'wild-type', but, not, the, mutant, form, of, 'VEGFR-3']), verbo([inhibited]), complemento(['H(2)O(2)-induced', apoptosis])].
[sujeto(['These', studies]), verbo([suggest]), complemento([that, 'VEGFR-3', protects, against, oxidative, damage, in, endothelial, 'cells,', and, that, patients, with, hereditary, lymphoedema, may, be, susceptible, to, 'ROS-induced', cell, damage])].
[sujeto(['While', 'lamellipodia-like', structures, are, also]), verbo([found]), complemento([in, cultured, keratinocytes, exposed, to, epidermal, growth, factor, '(', 'EGF),', the, signaling, pathway, that, regulates, the, formation, of, these, structures, is, not, defined])].
[sujeto(['In', cultured, human, keratinocytes, seeded, on, 'fibronectin,', we]), verbo([found]), complemento([that, 'protein-serine/threonine', kinase, inhibitors, including, 'staurosporine,', induced, 'concentration-dependent', formation, of, extended, lamellipodia, '(', 'E-lams)'])].
[sujeto(['The', formation, of, 'E-lams', was]), verbo([inhibited]), complemento([by, the, proteintyrosine, kinase, inhibitors, herbimycin, 'A', and, genistein, and, augmented, by, the, 'protein-tyrosine', phosphatase, inhibitor, sodium, orthovanadate])].
[sujeto(['Staurosporine', treatment]), verbo([induced]), complemento([relocation, of, tyrosine, phosphorylated, phospholipase, 'C-gamma1', '(', 'PLC-gamma1)', to, the, tips, of, lamellipodia, where, actin, assembly, was, initiated])].
[sujeto(['Notably,', glycogen, synthase, 'kinase-3alpha/beta', '(', 'GSK-3alpha/beta)', was]), verbo([activated]), complemento([by, staurosporine, as, evidenced, by, reduced, phosphorylation, on, 'Ser-21/9'])].
[sujeto(['We', previously, described, that, 'pervanadate,', a, potent, tyrosine, phosphatase, 'inhibitor,']), verbo([induced]), complemento([contraction, of, rat, myometrium, via, phospholipase, '(', 'PL)', 'C-gamma1', activation, '[', 'Biol', 'Reprod', 54, '(', 1996, ')', 1383, ']'])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, pervanadate, induced, tyrosine, phosphorylation, of, the, 'platelet-derived', growth, factor, '(', 'PDGF)-beta', 'receptor,', interaction, of, the, phosphorylated, 'PDGF', receptor, with, the, phosphorylated, 'PLC-gamma1,', production, of, inositol, phosphates, '(', 'InsPs),', extracellular, 'signal-regulated', kinase, '(', 'ERK)', activation, and, 'DNA', synthesis])].
[sujeto(['We', showed, that, 'Src', family, kinases, were]), verbo([activated]), complemento([by, 'pervanadate,', and, that, 'InsPs', production, and, phosphorylation, of, both, 'PLC-gamma1', and, the, 'PDGF', receptor, were, blocked, by, 'PP1,', an, 'Src', inhibitor])].
[sujeto(['These', results, demonstrated, that, the, activation, of, 'Src', by, pervanadate, is]), verbo([involved]), complemento([in, 'PLC-gamma1/InsPs', signalling, but, does, not, play, a, major, role, in, 'ERK', activation])].
[sujeto(['In', latently, infected, 'B', 'lymphocytes,', the, 'Epstein-Barr', virus, '(', 'EBV)']), verbo([suppresses]), complemento([signal, transduction, from, the, antigen, receptor, through, expression, of, the, integral, latent, membrane, protein, 2, 'A', '(', 'LMP2A)'])].
[sujeto(['At', the, same, 'time,', 'LMP2A']), verbo([triggers]), complemento(['B', cell, survival, by, a, yet, uncharacterized, maintenance, signal, that, is, normally, provided, by, the, antigen, receptor])].
[sujeto(['The', molecular, mechanisms, are, unknown, as, 'LMP2A-regulated', signaling, cascades]), verbo([have]), complemento([not, been, described, so, far])].
[sujeto(['Using', a, novel, mouse, model, we]), verbo([have]), complemento([identified, the, intracellular, adaptor, protein, 'Src', homology, 2, '(', 'SH2)', 'domain-containing', leukocyte, protein, '(', 'SLP)-65', as, a, critical, downstream, effector, of, 'LMP2A', in, vivo])].
[sujeto(['Biochemical', analysis, of, the, underlying, signaling, pathways, revealed, that, 'EBV', infection]), verbo([causes]), complemento([constitutive, tyrosine, phosphorylation, of, one, of, the, two, 'SLP-65', isoforms, and, complex, formation, between, 'SLP-65', and, the, protooncoprotein, 'CrkL', '(', 'CT10', regulator, of, kinase, 'like)'])].
[sujeto(['This']), verbo([leads]), complemento([to, antigen, 'receptor-independent', phosphorylation, of, 'Cbl', '(', 'Casitas', 'B', lineage, 'lymphoma)', and, 'C3G'])].
[sujeto(['Our', data, show, that, in, order, to, establish, a, latent, 'EBV', 'infection,', 'LMP2A', selectively]), verbo([activates]), complemento([or, represses, 'SLP-65-regulated', signaling, pathways])].
[sujeto(['Here', we, tested, the, hypothesis, that, 'PtdIns', hydrolysis, is]), verbo([mediated]), complemento([by, 'PLCgamma1,', which, is, known, to, be, regulated, by, activation, of, tyrosine, kinases, and, 'PtdIns', 3, -, kinase])].
[sujeto(['Conversely,', the, tyrosine, phosphatase, 'inhibitor,', 'vanadate,', alone]), verbo([promoted]), complemento(['PtdIns', hydrolysis, and, acted, 'non-additively', with, carbachol])].
[sujeto(['Vanadate', did, not]), verbo([stimulate]), complemento(['PtdInsP(2)', breakdown])].
[sujeto(['Carbachol', also]), verbo([stimulated]), complemento([a, rapid, '(', maximal, at, 1, -, 2, 'min)', tyrosine, phosphorylation, of, several, islet, 'proteins,', although, not, of, 'PLCgamma1', itself])].
[sujeto(['Adenovirally']), verbo([mediated]), complemento([overexpression, of, 'PLCgamma1', significantly, increased, 'carbachol-stimulated', 'PtdIns', hydrolysis, without, affecting, that, of, 'PtdInsP(2)'])].
[sujeto(['These', results, indicate, that, the, hydrolysis, of, 'PtdIns', and, 'PtdInsP(2)', are, independently]), verbo([regulated]), complemento([in, pancreatic, islets, and, that, 'PLCgamma1', selectively, mediates, the, breakdown, of, 'PtdIns'])].
[sujeto(['The', activation, mechanism, of, 'PLCgamma']), verbo([involves]), complemento([tyrosine, phosphorylation, '(', but, not, of, 'PLCgamma', 'directly)', and, 'PtdIns', 3, -, kinase])].
[sujeto(['Our', findings, point, to, a, novel, bifurcation, of, signaling, pathways, downstream, of, muscarinic, receptors, and]), verbo([suggest]), complemento([that, hydrolysis, of, 'PtdIns', and, 'PtdInsP(2)', might, serve, different, physiological, ends])].
[sujeto(['In', cultured, chick, skeletal, muscle, cells, loaded, with, 'Fura-2,', the, tyrosine, kinase, inhibitors, herbimycin, 'A', and, genistein, abolished, both, the, fast, inositol, 1, ',', 4, ',', 5, -, trisphosphatedependent, 'Ca(2+)']), verbo([release]), complemento([from, internal, stores, and, extracellular, 'Ca(2+)', influx, induced, by, 1, 'alpha,', 25, '(', 'OH)(2)-vitamin', 'D(3)', '(', 1, 'alpha,25(OH)(2)D(3))'])].
[sujeto(['Tyrosine', phosphatase, inhibition, by, orthovanadate]), verbo([increased]), complemento([cytosolic, 'Ca(2+)'])].
[sujeto(['Anti-phosphotyrosine', immunoblot, analysis, revealed, that, 1, 'alpha,', 25, '(', 'OH)(2)D(3)', rapidly, '(', 0.5, -, 10, 'min)']), verbo([stimulates]), complemento([in, a, concentrationdependent, fashion, '(', 0.1, -, 10, 'nm)', tyrosine, phosphorylation, of, several, myoblast, 'proteins,', among, which, the, major, targets, of, the, hormone, could, be, immunochemically, identified, as, phospholipase, 'Cgamma', '(', 127, 'kDa),', which, mediates, intracellular, store, 'Ca(2+)', mobilization, and, external, 'Ca(2+)', 'influx,', and, the, 'growth-related', proteins, 'mitogen-activated', protein, '(', 'MAP)', kinase, '(', 42, /, 44, 'kDa)', and, 'c-myc', '(', 65, 'kDa)'])].
[sujeto(['Genistein']), verbo([suppressed]), complemento([the, increase, in, phosphorylation, and, concomitant, elevation, of, 'MAPK', activity, elicited, by, the, sterol])].
[sujeto(['The', 'sterol-induced']), verbo([increase]), complemento([in, tyrosine, phosphorylation, of, 'c-myc,', a, finding, not, reported, before, for, cell, growth, 'regulators,', was, totally, suppressed, by, the, specific, 'Src', inhibitor, 'PP1'])].
[sujeto(['These', results, demonstrate, that, tyrosine, phosphorylation, is, a, previously, unrecognized, mechanism]), verbo([involved]), complemento([in, 1, 'alpha,25(OH)(2)D(3)', regulation, of, 'Ca(2+)', homeostasis, in, hormone, target, cells])].
[sujeto(['In', 'addition,', the, data]), verbo([involve]), complemento([tyrosine, kinase, cascades, in, the, mitogenic, effects, of, 1, 'alpha,', 25, '(', 'OH)(2)D(3)', on, skeletal, muscle, cells])].
[sujeto(['We', show, here, that, 'HGF']), verbo([promoted]), complemento([chemokinesis, of, rat, primary, astrocytes, through, the, activation, of, phosphatidylinositol, 3, '(', 'PI3)-kinase', without, any, influence, on, mitogenesis, of, the, cells])].
[sujeto(['A', tyrosine, 'phosphatase,', 'SHP-1,', was]), verbo([associated]), complemento([with, both, 'PI3-kinase', and, 'PLCgamma1', before, 'HGF', 'stimulation,', but, it, was, dissociated, only, from, 'PI3-kinase', after, the, stimulation])].
[sujeto(['These', results, indicate, that, 'PLCgamma1', is, selectively]), verbo([prevented]), complemento([from, being, a, signal, mediator, by, constitutive, association, of, 'SHP-1,', and, that, this, selective, inhibition, of, 'PLCgamma1', may, determine, the, cellular, response, of, astrocytes, to, 'HGF'])].
[sujeto(['CD19', is, a, coreceptor, on, 'B', cells, that]), verbo([enhances]), complemento([the, increase, in, cytoplasmic, calcium, and, 'ERK2', activation, when, coligated, with, the, 'B', cell, 'Ag', receptor])].
[sujeto(['Constructs', containing, point, mutations, and, truncations, were]), verbo([expressed]), complemento([in, 'Daudi', human, 'B', lymphoblastoid, cells, to, systematically, determine, the, requirement, for, individual, 'CD19', cytoplasmic, tyrosines, in, these, responses])].
[sujeto(['Evidence', for, activity, was]), verbo([found]), complemento([for, 'Y330,', 'Y360,', and, 'Y421', as, well, as, that, previously, published, for, 'Y391'])].
[sujeto(['Precipitates', formed, with, phosphopeptides, consisting, of, 'CD19', sequences, flanking, these, residues, were, used, to, screen, for, cytoplasmic, proteins, that]), verbo([mediate]), complemento([signaling])].
[sujeto(['These', molecules, also, were]), verbo([found]), complemento([associated, with, native, 'CD19'])].
[sujeto(['In', mapping, studies, with, altered, 'constructs,', 'CD19', 'Y330', 'and/or', 'Y360', were, necessary, for]), verbo([binding]), complemento(['Grb2', and, 'Sos'])].
[sujeto(['Vav']), verbo([associated]), complemento([with, 'CD19', constitutively, in, unstimulated, cells, by, a, 'tyrosine-independent', mechanism, requiring, the, portion, of, 'CD19', encoded, by, exons, 9, -, 12])].
[sujeto(['After', 'B', cell, 'Ag', receptor, 'stimulation,', 'Vav', association, was, 'tyrosine-dependent,', but]), verbo([binding]), complemento([was, influenced, by, multiple, residues])].
[sujeto(['However,', when, maximally]), verbo([phosphorylated]), complemento([by, 'pervanadate,', 'Y391', 'and,', to, a, lesser, 'extent,', 'Y421', were, sufficient])].
[sujeto(['CD19', 'Y391', was, also, both, necessary, and, sufficient, for]), verbo([binding]), complemento([phospholipase, 'C-gamma2'])].
[sujeto(['Thus,', different, tyrosines, along, the, 'CD19', cytoplasmic, domain]), verbo([provide]), complemento([scaffolding, for, the, formation, of, complexes, of, different, signaling, molecules])].
[sujeto(['We', recently]), verbo([found]), complemento([that, a, thioether, analog, of, 'K', vitamin, '(', 'Cpd', 5, ')', inhibited, the, activity, of, 'protein-tyrosine', phosphatases, '(', 'PTPases)', and, induced, 'protein-tyrosine', phosphorylation, in, a, human, hepatoma, cell, line, '(', 'Hep3B)'])].
[sujeto(['We']), verbo([have]), complemento([now, examined, the, structural, requirements, for, induction, of, 'protein-tyrosine', phosphorylation, and, 'PTPase', inhibition, by, several, 'K', vitamin, analogs])].
[sujeto(['Thioether', analogs, with, sulfhydryl, arylation, 'capacity,', especially, those, with, a, hydroxy, '(', 'Cpd', 5, ')', or, a, methoxy, group, at, the, end, of, the, side, 'chain,']), verbo([induced]), complemento(['protein-tyrosine', 'phosphorylation,', but, 'non-arylating', 'analogs,', such, as, those, with, an, 'all-carbon', or, 'O-ether', side, 'chain,', did, not])].
[sujeto(['An']), verbo([increase]), complemento([in, 'tyrosine-phosphorylated', 'ERK2', 'mitogen-activated', protein, kinase, was, also, observed])].
[sujeto(['The', activity, of, purified, 'T', cell, 'PTPase', was]), verbo([inhibited]), complemento([only, by, the, thioether, 'analogs,', but, not, by, 'non-arylating', analogs])].
[sujeto(['Furthermore,', the, epidermal, growth, factor, receptor, dephosphorylation, activity, of, 'Hep3B', cell, lysates, was]), verbo([inhibited]), complemento([by, 'Cpd', 5, treatment])].
[sujeto(['However,', one, cell, line, '(', 'HepG2),', which, was, relatively, resistant, to, growth, inhibition, by, 'Cpd', 5, ',', did, not]), verbo([increase]), complemento([its, phosphorylation, levels, upon, 'Cpd', 5, treatment])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, cell, growth, inhibition, by, thioether, analogs, is, closely, associated, with, inhibition, of, 'PTPases', by, sulfhydryl, arylation, and, with, tyrosine, phosphorylation, of, selected, proteins])].
[sujeto(['Recent', studies]), verbo([have]), complemento([shown, 'that,', in, addition, to, its, role, as, an, adhesion, 'receptor,', platelet, endothelial, cell, adhesion, molecule, 1, /, 'CD31', becomes, phosphorylated, on, tyrosine, residues, 'Y663', and, 'Y686', and, associates, with, protein, tyrosine, phosphatases, 'SHP-1', and, 'SHP-2'])].
[sujeto(['In', this, 'study,', we, screened, for, additional, proteins, which]), verbo([associate]), complemento([with, phosphorylated, platelet, endothelial, cell, adhesion, molecule, 1, ',', using, surface, plasmon, resonance])].
[sujeto(['We']), verbo([found]), complemento(['that,', besides, 'SHP-1', and, 'SHP-2,', platelet, endothelial, cell, adhesion, molecule, 1, binds, the, cytoplasmic, signalling, proteins, 'SHIP', and, 'PLC-gamma1', via, their, 'Src', homology, 2, domains])].
[sujeto(['Using', two, 'phosphopeptides,', 'NSDVQpY663TEVQV', and, 'DTETVpY686SEVRK,', we, demonstrate, differential]), verbo([binding]), complemento([of, 'SHP-1,', 'SHP-2,', 'SHIP', and, 'PLC-gamma1'])].
[sujeto(['All', four, cytoplasmic, signalling, proteins, directly]), verbo([associate]), complemento([with, cellular, platelet, endothelial, cell, adhesion, molecule, 1, ',', immunoprecipitated, from, 'pervanadate-stimulated', 'THP-1', cells])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, overlapping, immunoreceptor, 'tyrosine-based', inhibition, 'motif/immunoreceptor', 'tyrosine-based', activation, 'motif-like', motifs, within, platelet, endothelial, cell, adhesion, molecule, 1, mediate, differential, interactions, between, the, 'Src', homology, 2, containing, signalling, proteins, 'SHP-1,', 'SHP-2,', 'SHIP', and, 'PLC-gamma1'])].
[sujeto(['Antigen', stimulation, via, 'TCR', in, mature, 'T', cells]), verbo([provides]), complemento([rapid, induction, of, tyrosine, phosphorylation, of, intracellular, substrates, including, 'ZAP-70'])].
[sujeto(['DP', thymocytes, were, obtained, from, 'TCR', transgenic, mice, '(', 'TCR-Tg)']), verbo([expressing]), complemento(['MHC', class, 'I-', or, class, 'II-restricted', 'TCR', in, selecting, and, 'non-selecting', 'MHC', backgrounds, respectively])].
[sujeto(['However,', such, a, phosphorylation, difference, between, selecting, and, 'non-selecting', 'TCR-Tg', was]), verbo([found]), complemento([to, be, considerably, less, in, class, 'II-restricted', 'TCR-Tg'])].
[sujeto(['These', ex, vivo, studies]), verbo([suggest]), complemento([that, 'TCR-mediated', signaling, on, 'DP', thymocytes, induces, 'ZAP-70', phosphorylation, under, a, different, manner, of, engagement, of, 'TCR', to, class, 'I', and, class, 'II', molecules, in, the, positive, selection, process])].
[sujeto(['TCR', engagement]), verbo([activates]), complemento([phospholipase, 'C', gamma, 1, '(', 'PLC', gamma, 1, ')', via, a, tyrosine, 'phosphorylation-dependent', mechanism])].
[sujeto(['PLC', gamma, 1, contains, a, pair, of, 'Src', homology, 2, '(', 'SH2)', domains, whose, function, is, that, of]), verbo([promoting]), complemento([protein, interactions, by, binding, phosphorylated, tyrosine, and, adjacent, amino, acids])].
[sujeto(['The', role, of, the, 'PLC', gamma, 1, 'SH2', domains, in, 'PLC', gamma, 1, phosphorylation, was, explored, by, mutational, analysis, of, an, 'epitope-tagged', protein, transiently]), verbo([expressed]), complemento([in, 'Jurkat', 'T', cells])].
[sujeto(['In', 'addition,', the, 'PLC', gamma, 1, 'SH2(N)', domain, mutant, failed, to]), verbo([associate]), complemento([with, 'Grb2', and, a, 36, -, to, 38, -, kDa, phosphoprotein, '(', 'p36-38),', which, has, previously, been, recognized, to, interact, with, 'PLC', gamma, 1, ',', 'Grb2,', and, other, molecules, involved, in, 'TCR', signal, transduction])].
[sujeto(['Furthermore,']), verbo([binding]), complemento([of, 'p36-38', to, 'PLC', gamma, 1, was, not, abrogated, by, mutations, of, the, 'SH2(C)', domain])].
[sujeto(['In', contrast, to, 'TCR/CD3', 'ligation,', treatment, of, cells, with, pervanadate]), verbo([induced]), complemento([tyrosine, phosphorylation, of, either, 'PLC', gamma, 1, 'SH2(N)', or, 'SH2(C)', domain, mutants, to, a, level, comparable, with, that, of, the, 'wild-type', 'protein,', indicating, that, pervanadate, treatment, induces, an, alternate, mechanism, of, 'PLC', gamma, 1, phosphorylation])].
[sujeto(['These', data, indicate, that, the, 'SH2(N)', domain, is]), verbo([required]), complemento([for, 'TCR-induced', 'PLC', gamma, 1, 'phosphorylation,', presumably, by, participating, in, the, formation, of, a, complex, that, promotes, the, association, of, 'PLC', gamma, 1, with, a, tyrosine, kinase])].
[sujeto(['Three', of, the, 'tyrosine-phosphorylated', proteins]), verbo([have]), complemento([been, identified, as, the, receptors, for, epidermal, growth, 'factor,', 'insulin,', and, hepatocyte, growth, factor])].
[sujeto(['The', injection, of, peroxovanadate, also]), verbo([enhanced]), complemento([the, tyrosine, phosphorylation, of, many, of, the, proteins, known, to, function, downstream, of, these, 'receptors,', including, 'SHC,', signal, transducer, and, activator, of, transcription, '(', 'Stat)', 1, 'alpha,beta,', 'Stat', 3, ',', 'Stat', 5, ',', phospholipase, 'C-gamma,', insulin, receptor, substrate, 1, ',', 'GTPase-activating', 'protein,', 'beta-catenin,', 'gamma-catenin,', 'p120cas,', 'SHP-1,', and, 'SHP-2'])].
[sujeto(['The', administration, of, peroxovanadate, also]), verbo([induced]), complemento([nuclear, translocation, of, a, number, of, 'tyrosine-phosphorylated', 'Stat', proteins])].
[sujeto(['The', 'pervanadate,', generated, from, a, combination, of, 'H2O2', and, 'orthovanadate,']), verbo([induced]), complemento([concomitantly, tyrosine, phosphorylation, of, 145, ',', 120, ',', 104, ',', 76, ',', 68, ',', 60, ',', 53, ',', 42, ',', 37, ',', 28, ',', and, 25, kDa, proteins, and, superoxide, anion, '(', 'O2-)', production, of, 'PMNs'])].
[sujeto(['The', pretreatment, of, 'PMNs', with, genistein]), verbo([caused]), complemento([an, inhibition, of, tyrosine, phosphorylation, of, these, 'proteins,', and, also, markedly, depressed, 'O2-', production])].
[sujeto(['Among', the, above, 'proteins,', a, 145, kDa, protein, was]), verbo([found]), complemento([to, be, identical, with, the, protein, recognized, by, the, 'anti-PLC', gamma, 2, antibody, on, 'Western', blots])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, tyrosine, 'residue(s)', of, 'PLC', gamma, 2, is, phosphorylated, and, the, enzyme, is, translocated, from, the, cytosol, to, membrane, fractions, in, 'PMNs', by, pervanadate, treatment])].
[sujeto(['We']), verbo([report]), complemento([here, that, activation, of, resident, tyrosine, kinases, by, the, addition, of, adenosine, triphosphate, '(', 'ATP),', 'orthovanadate,', and, 'Mg2+', to, rat, basophilic, leukemia, cell, '(', 'RBL)', lysates, induces, an, association, of, 'PLC', gamma, 2, with, the, 'Triton-insoluble', particulate, 'fraction,', with, a, parallel, increase, in, tyrosine, phosphorylation, of, cellular, proteins])].
[sujeto(['Both', tyrosine, phosphorylation, and, 'PLC', gamma, 2, translocation, are]), verbo([inhibited]), complemento([by, genistein])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, in, vitro, activation, of, tyrosine, kinase, activity, in, broken, cell, preparations, induces, the, formation, of, association, between, 'PLC', gamma, 2, and, ligands, with, the, 'Triton-insoluble', fraction])].
[sujeto(['Stimulation', of, '[', 3, 'H]inositol-labeled', rat, myometrial, strips, with, 'pervanadate,', formed, by, mixing, orthovanadate, and, 'H2O2,']), verbo([induced]), complemento([a, 'dose-dependent', accumulation, of, '[', 3, 'H]inositol', phosphates])].
[sujeto(['Pervanadate']), verbo([induced]), complemento([a, 'time-sequential', formation, of, inositol, phosphates, in, the, order, inositol, 'trisphosphate,', inositol, 'bisphosphate,', and, inositol, monophosphate])].
[sujeto(['Pervanadate']), verbo([induced]), complemento([contraction, of, the, 'myometrium;', the, response, was, 'dose-dependent'])].
[sujeto(['Pervanadate-mediated', contraction, was]), verbo([inhibited]), complemento(['(', 50, '%', ')', by, genistein, and, tyrphostin, 47, '(', 100, 'microM)'])].
[sujeto(['Western', blot, 'analysis,', using, 'anti-phosphotyrosine', 'antibodies,', revealed, that]), verbo([phosphorylated]), complemento([proteins, were, present, in, detergent, extracts, from, 'pervanadate-stimulated', myometrium])].
[sujeto(['Ion', homeostasis, dysregulations]), verbo([have]), complemento([severe, effects, on, human, 'health,', impairing, the, effectiveness, and, appropriateness, of, major, cellular, 'events,', including, immune, responses])].
[sujeto(['One', crucial, aspect, of, 'TRPM7', function, we]), verbo([have]), complemento([extensively, studied, is, the, relationship, between, its, ion, channel, portion, and, its, 'C-terminal', 'Ser/Thr', kinase, domain])].
[sujeto(['The', modulation, of, ion, channels, by, phosphorylation, through, exogenous, kinases, is, 'common,', however, the, covalent]), verbo([bound]), complemento([between, the, 'TRPM7', channel, and, its, kinase, suggests, a, novel, kind, of, link, between, 'ion-entry', and, signal, transduction, events])].
[sujeto(['Current', knowledge, supports, a, reciprocal, &, 'quot;two-way', 'street&quot;', model, where, 'TRPM7-kinase']), verbo([modulates]), complemento([ion, transport, function, through, 'Ser/Thr', 'phosphorylation,', and, in, 'turn,', channel, gating, and, ionic, conditions, in, close, proximity, to, the, pore, regulate, 'TRPM7-kinase', mediated, signaling])].
[sujeto(['We']), verbo([have]), complemento([shown, that, 'TRPM7', acts, as, a, sensor, of, 'Mg(2+)-availability,', adjusting, key, cellular, functions, such, as, the, rate, of, cellular, protein, translation, to, the, 'Mg(2+)', nutritional, status])].
[sujeto(['Since', molecular, mechanisms, controlling, rates, of, protein, translation, are, critical, for, cell, growth, and, division, in, response, to, nutrient, 'availability,', this, could]), verbo([have]), complemento([relevance, for, example, for, therapies, targeted, at, molecules, shaping, the, cancerous, translational, apparatus])].
[sujeto(['In', our, quest, to, understand, the, biology, of, 'Mg(2+)', in, the, context, of, immune, 'responses,', we]), verbo([found]), complemento([that, 'TRPM7', associates, 'with,', and, phosphorylates, phospholipase, 'C', gamma, 2, '(', 'PLCγ2),', a, pivotal, molecule, in, the, signaling, pathway, following, 'B-cell', receptor, '(', 'BCR)', activation])].
[sujeto(['This', contributes, to, the, 'Mg(2+)-dependent', modulation, of, the, 'Ca(2+)', response, elicited, by, 'BCR', 'ligation,', and]), verbo([provides]), complemento([the, first, molecular, pathway, underlying, the, 'Mg(2+)-sensitivity', of, immune, responses])].
[sujeto(['Although', the, interaction, between, the, 'C2', domain, of, several, 'PLC-isozymes', and, 'TRPM7', is, well, 'established,', previous, studies]), verbo([have]), complemento([focused, on, the, effect, of, 'PLC-activity', on, 'TRPM7'])].
[sujeto(['We', show, that, 'TRPM7-kinase']), verbo([phosphorylates]), complemento(['PLCγ2', in, its, 'C2-domain', at, position, 'Ser1164', and, in, the, linker, region, preceding, the, 'C2-domain', at, position, 'Thr1045'])].
[sujeto(['Using', a, complementation, approach, in, 'PLCγ2(-/-)', 'DT40', 'cells,', we]), verbo([found]), complemento([that, the, 'PLCγ2-S1164A', mutant, fully, restores, 'BCR', mediated, 'Ca(2+)-responses', under, standard, growth, conditions])].
[sujeto(['However,', under, hypomagnesic, 'conditions,', 'PLCγ2-S1164A', fails, to, reach, 'Ca(2+)-levels', seen, in, cells]), verbo([expressing]), complemento(['PLCγ2', wildtype])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'Mg(2+)-sensitivity', of, the, 'BCR', signaling, pathway, may, be, regulated, by, 'Ser/Thr', phosphorylation, of, 'PLCγ2'])].
[sujeto(['We', demonstrate, that, a, rapid, transient, 'Mg(2+)', influx, is]), verbo([induced]), complemento([by, antigen, receptor, stimulation, in, normal, 'T', cells, and, by, growth, factor, stimulation, in, 'non-lymphoid', cells])].
[sujeto(['MAGT1', deficiency, abrogates, the, 'Mg(2+)', 'influx,']), verbo([leading]), complemento([to, impaired, responses, to, antigen, receptor, 'engagement,', including, defective, activation, of, phospholipase, 'Cγ1', and, a, markedly, impaired, 'Ca(2+)', influx, in, 'T', cells, but, not, 'B', cells])].
[sujeto(['These', observations]), verbo([reveal]), complemento([a, role, for, 'Mg(2+)', as, an, intracellular, second, messenger, coupling, 'cell-surface', receptor, activation, to, intracellular, effectors, and, identify, 'MAGT1', as, a, possible, target, for, novel, therapeutics])].
[sujeto(['Here', we, show, that, sustained, 'interictal-like', activity, in, hippocampal, slices, downregulates, 'KCC2', mRNA, and, protein, expression, in, 'CA1', pyramidal, 'neurons,', which]), verbo([leads]), complemento([to, a, reduced, capacity, for, neuronal, 'Cl-', extrusion])].
[sujeto(['This', effect, is]), verbo([mediated]), complemento([by, endogenous, 'BDNF', acting, on, tyrosine, receptor, kinase, 'B', '(', 'TrkB),', with, 'down-stream', cascades, involving, both, 'Shc/FRS-2', '(', src, homology, 2, domain, containing, transforming, 'protein/FGF', receptor, substrate, 2, ')', and, 'PLCgamma', '(', phospholipase, 'Cgamma)-cAMP', response, 'element-binding', protein, signaling])].
[sujeto(['The', plasmalemmal, 'KCC2']), verbo([has]), complemento([a, very, high, rate, of, 'turnover,', with, a, time, frame, that, suggests, a, novel, role, for, changes, in, 'KCC2', expression, in, diverse, manifestations, of, neuronal, plasticity])].
[sujeto(['A', downregulation, of, 'KCC2', may, be, a, general, early, response]), verbo([involved]), complemento([in, various, kinds, of, neuronal, trauma])].
[sujeto(['The', molecular, basis, by, which, receptor, tyrosine, kinases, '(', 'RTKs)']), verbo([recruit]), complemento([and, phosphorylate, 'Src', 'Homology', 2, '(', 'SH2)', 'domain-containing', substrates, has, remained, elusive])].
[sujeto(['We', show, that, the, engagement, of, 'pTyr-binding', pocket, of, the, cSH2, domain, of, 'PLCγ', by, the]), verbo([phosphorylated]), complemento([tail, of, an, 'FGFR', kinase, induces, a, conformational, change, at, the, region, past, the, cSH2, core, domain, encompassing, 'Tyr-771', and, 'Tyr-783', to, facilitate, the, 'binding/phosphorylation', of, these, tyrosines, by, another, 'FGFR', kinase, in, trans])].
[sujeto(['We', used, low, molecular, weight, '(', 'LMW,', 18, 'kDa)', 'FGF-2', and, high, molecular, weight, '(', 'HMW)', 'FGF-2', 'isoforms,', 'which,', 'respectively,']), verbo([activate]), complemento([cell, surface, 'FGF', receptors, and, intranuclear, 'FGFR1,', to, determine, the, roles, of, membrane, 'FGFRs', and, integrative, nuclear, 'FGFR1', signaling, '(', 'INFS)', in, the, regulation, of, 'FGF-23', gene, transcription, in, osteoblasts])].
[sujeto(['We']), verbo([found]), complemento([that, 'LMW-FGF-2', induced, 'NFAT', and, 'Ets1', binding, to, conserved, 'cis-elements', in, the, proximal, 'FGF-23', promoter, and, stimulated, 'FGF-23', promoter, activity, through, 'PLCγ/calcineurin/NFAT', and, 'MAPK', pathways, in, 'SaOS-2', and, 'MC3T3-E1', osteoblasts])].
[sujeto(['In', 'contrast,', 'HMW-FGF-2']), verbo([stimulated]), complemento(['FGF-23', promoter, activity, in, osteoblasts, through, a, 'cAMP-dependent', binding, of, 'FGFR1', and, 'cAMP-response', 'element-binding', protein, '(', 'CREB)', to, a, conserved, cAMP, response, element, '(', 'CRE)', contiguous, with, the, 'NFAT', binding, site, in, the, 'FGF-23', promoter])].
[sujeto(['Mutagenesis', of, the, 'NFAT', and, 'CRE']), verbo([binding]), complemento(['sites,', 'respectively,', inhibited, the, effects, of, 'LMW-FGF-2', and, 'HMW-FGF-23', to, stimulate, 'FGF-23', promoter, activity])].
[sujeto(['FGF-2', activation, of, both, membrane, 'FGFRs', and, 'INFS-dependent', 'FGFR1', pathways, may]), verbo([provide]), complemento([a, means, to, integrate, systemic, and, local, regulation, of, 'FGF-23', transcription, under, diverse, physiological, and, pathological, conditions])].
[sujeto(['This']), verbo([causes]), complemento([constitutive, activation, of, the, kinase, resulting, in, 'aberrant,', proliferative, signaling])].
[sujeto(['To', test, the, relative, contributions, of, localization, and, dimerization, on, kinase, 'signaling,', we]), verbo([targeted]), complemento([inducibly, dimerizable, 'FGFR1', to, the, centrosome, and, other, subcellular, locations, and, generated, a, mutant, of, the, 'FOP-FGFR1', 'MPN', fusion, defective, in, centrosome, localization])].
[sujeto(['Expression', in, mammalian, cells, followed, by, western, blot, analysis, revealed, a, significant]), verbo([decrease]), complemento([in, kinase, signaling, upon, loss, of, 'FOP-FGFR1', centrosome, localization])].
[sujeto(['Kinase', dimerization, alone, resulted, in, phosphorylation, of, the, 'FGFR1', signaling]), verbo([target]), complemento(['PLCγ,', however, levels, comparable, to, 'FOP-FGFR1', required, subcellular, targeting, in, addition, to, kinase, dimerization])].
[sujeto(['This', is, distinct, from, acute, myeloid, leukemia, '(', 'AML)', 'cells,', which, are, not]), verbo([associated]), complemento([with, 'centrosome-kinase', fusions, and, had, normal, centrosomes])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, effective, proliferative, 'MPN', signaling, requires, both, subcellular, localization, and, dimerization, of, 'MPN', 'kinases,', both, of, which, may, be, provided, by, centrosome, protein, fusion, partners])].
[sujeto(['Intramolecular', interactions, within, the, regulatory, region, center, on, the, cSH2, 'domain,', the, only, domain, that, also]), verbo([interacts]), complemento([with, the, 'PLC-core'])].
[sujeto(['In', the, context, of, fibroblast, 'growth-factor', receptor, 'signaling,', the, coordinated, involvement, of, nSH2, and, cSH2, domains]), verbo([mediates]), complemento([efficient, phosphorylation, of, 'PLCγ1', resulting, in, the, interruption, of, an, autoinhibitory, interface, by, direct, competition, 'and,', 'independently,', dissociation, of, 'PLCγ1', from, the, receptor])].
[sujeto(['Further', structural, insights, into, the, autoinhibitory, surfaces]), verbo([provide]), complemento([a, framework, to, interpret, 'gain-of-function', mutations, in, 'PLCγ', isoforms, linked, to, immune, disorders, and, illustrate, a, distinct, mechanism, for, regulation, of, 'PLC', activity, by, common, interaction, domains])].
[sujeto(['Tumour', invasion, and, metastasis, is, the, most, common]), verbo([cause]), complemento([of, death, from, cancer])].
[sujeto(['We']), verbo([have]), complemento([demonstrated, that, 'FGFR1', expression, is, increased, in, bladder, cancer, and, that, activation, of, 'FGFR1', induces, an, 'EMT', in, urothelial, carcinoma, '(', 'UC)', cell, lines])].
[sujeto(['FGFR1', activation]), verbo([promoted]), complemento(['EMT', over, a, period, of, 72, hours])].
[sujeto(['Initially', a, rapid]), verbo([increase]), complemento([in, actin, stress, fibres, 'occurred,', followed, by, an, increase, in, cell, 'size,', altered, morphology, and, increased, migration, and, invasion])].
[sujeto(['By', using, 'site-directed', mutagenesis, and, small, molecule, inhibitors, we, demonstrated, that, combined, activation, of, the, mitogen]), verbo([activated]), complemento([protein, kinase, '(', 'MAPK)', and, phospholipase, 'C', gamma, '(', 'PLCγ)', pathways, regulated, this, 'EMT'])].
[sujeto(['Actin', stress, fibre, formation, was]), verbo([regulated]), complemento([by, 'PLCγ', 'activation,', and, was, also, important, for, the, increase, in, cell, 'size,', migration, and, altered, morphology])].
[sujeto(['MAPK', activation]), verbo([regulated]), complemento([migration, and, 'E-cadherin', 'expression,', indicating, that, combined, activation, of, 'PLCγ', and, 'MAPK', is, required, for, a, full, 'EMT'])].
[sujeto(['COX-2', was, transcriptionally, upregulated, by, 'FGFR1', and]), verbo([caused]), complemento([increased, intracellular, prostaglandin, 'E(2)', 'levels,', which, promoted, migration])].
[sujeto(['In', 'conclusion,', we]), verbo([have]), complemento([demonstrated, that, 'FGFR1', activation, in, 'UC', cells, lines, promotes, 'EMT', via, coordinated, activation, of, multiple, signalling, pathways, and, by, promoting, activation, of, prostaglandin, synthesis])].
[sujeto(['To', decipher, the, mechanism]), verbo([involved]), complemento([in, 'Grb14', binding, to, the, activated, fibroblast, growth, factor, receptor, '(', 'FGFR),', we, used, the, bioluminescence, resonance, energy, transfer, '(', 'BRET)', technique, and, the, 'Xenopus', oocyte, model])].
[sujeto(['We', showed, that, 'Grb14', was]), verbo([recruited]), complemento([to, 'FGFR1', into, a, trimeric, complex, containing, also, phospholipase, 'C', gamma, '(', 'PLCγ)'])].
[sujeto(['Grb14-FGFR', interaction]), verbo([involved]), complemento([the, 'Grb14-SH2', domain, and, the, 'FGFR', pY766, 'residue,', which, is, the, 'PLCγ', binding, site])].
[sujeto(['Our', data]), verbo([led]), complemento([to, a, molecular, model, whereby, 'Grb14', binding, to, the, phosphorylated, 'FGFR', induces, a, conformational, change, that, unmasks, a, 'PLCγ', binding, motif, on, 'Grb14,', allowing, trapping, and, inactivation, of, 'PLCγ'])].
[sujeto(['It', is, largely, accepted, that, neurogenesis, in, the, adult, brain]), verbo([decreases]), complemento([with, age, and, reduced, levels, of, local, neurotrophic, support, is, speculated, to, be, a, contributing, factor])].
[sujeto(['Among', neurotrophic, factors]), verbo([involved]), complemento([on, 'neurogenesis,', we, focused, our, attention, on, the, neurotrophic, system, fibroblast, growth, 'factor-2', '(', 'FGF-2)', and, its, receptor, 'FGFR1,', a, potent, modulator, of, precursor, cell, proliferation])].
[sujeto(['The', levels, of]), verbo([phosphorylated]), complemento(['FGFR1', form, did, not, show, significant, variations, suggesting, that, also, the, level, of, receptor, activation, does, not, change, during, aging])].
[sujeto(['No', changes, were, also, observed, in, the, phosphorylation, of, two, 'FGFR1', related, proteins]), verbo([involved]), complemento([in, intracellular, 'signaling,', the, canonical, extracellular, 'signal-regulated', kinase, 'Erk1/2', and, the, 'phospholipase-Cγ1'])].
[sujeto(['Using', 'Western', blotting, 'assay,', we, demonstrated, that, 'PGE(2)']), verbo([induced]), complemento([upregulation, of, components, of, the, 'FGF-2', 'pathway:', 'FGF-2', 'protein,', phosphorylation, of, 'FGF', receptor, type, 1, '(', 'FGFR1),', activation, of, 'FRS2alpha', '(', 'FGFR', substrate, 2, 'alpha),', phospholipase, 'Cgamma,', endothelial, nitric, oxide, 'synthase,', extracellular, 'signal-regulated', kinase, 1, /, 2, ',', and, the, transcription, factor, 'STAT-3'])].
[sujeto(['Synergism', between, 'PGE(2)', and, 'FGF-2']), verbo([promoted]), complemento([endothelial, cell, proliferation, and, robust, angiogenesis, in, 'vivo,', in, rabbit, cornea, and, 'Matrigel', assays])].
[sujeto(['In', 'fact,', 'PGE(2)', induction, of, angiogenesis, in, vitro, was, impaired, in, 'FGF-2(-/-)', endothelial, cells, and, 'FGFR1', blockade, abrogated, 'PGE(2)', action, on, the, 'endothelium,']), verbo([preventing]), complemento([the, activation, of, 'FGF-2', signaling])].
[sujeto(['In', 'culture,', fibroblast, growth, 'factor-2', '(', 'FGF-2)', is, sufficient, to]), verbo([maintain]), complemento([the, 'self-renewal', of, adult, 'NSCs', derived, from, the, adult, rat, hippocampus])].
[sujeto(['In', the, established, adult, rat, 'NSC', 'culture,', 'FGF-2']), verbo([promotes]), complemento(['self-renewal', by, increasing, proliferation, and, inhibiting, spontaneous, differentiation, of, adult, 'NSCs,', accompanied, with, activation, of, 'MAPK', and, 'PLC', pathways])].
[sujeto(['Using', a, molecular, genetic, 'approach,', we, demonstrate, that, activation, of, 'FGF', receptor, 1, '(', 'FGFR1),', largely, through, two, key, cytoplasmic, amino, acid, residues, that, are, linked, to, 'MAPK', and, 'PLC', 'activation,', suffices, to]), verbo([promote]), complemento([adult, 'NSC', 'self-renewal'])].
[sujeto(['The', canonical, 'MAPK,', 'Erk1/2', 'activation,', is, both]), verbo([required]), complemento([and, sufficient, for, the, 'NSC', expansion, and, 'anti-differentiation', effects, of, 'FGF-2'])].
[sujeto(['These', studies]), verbo([reveal]), complemento([two, amino, acid, residues, in, 'FGFR1', with, linked, downstream, intracellular, signal, transduction, pathways, that, are, essential, for, maintaining, adult, 'NSC', 'self-renewal'])].
[sujeto(['The', findings]), verbo([provide]), complemento([novel, insights, into, the, molecular, mechanism, regulating, adult, 'NSC', 'self-renewal,', and, pose, implications, for, using, these, cells, in, potential, therapeutic, applications])].
[sujeto(['To', understand, the, specificity, of, the, signal, transduction, cascades]), verbo([involved]), complemento([in, the, control, of, these, 'processes,', we, used, pharmacological, inhibitors, of, the, three, main, effectors, known, to, act, downstream, of, the, bFGF, receptor, '(', 'FGFR):', phospholipase, 'Cgamma', '(', 'PLCgamma),', 'mitogen-activated', protein, kinase, '(', 'MAPK),', and, phosphatidylinositol, 3, -, kinase, '(', 'PI3-K)'])].
[sujeto(['Our', data, show, that, only, the, 'PI3-K', pathway, is]), verbo([involved]), complemento([in, the, 'survival-promoting', effect, of, 'bFGF;', on, the, other, 'hand,', all, three, effectors, converge, on, the, enhancement, of, neurite, 'outgrowth,', both, on, isolated, neurons, and, in, whole, ganglia])].
[sujeto(['It']), verbo([has]), complemento([been, reported, recently, that, bone, marrow, stromal, cells, '(', 'BMSCs)', are, able, to, differentiate, into, various, neural, cells, both, in, vivo, and, in, vitro, '(', 'Egusa,', 'H'])].
[sujeto(['In', this, 'report,', we]), verbo([have]), complemento([demonstrated, that, basic, fibroblast, growth, factor, '(', 'bFGF)', alone, effectively, induces, mouse, 'BMSC', neuronal, differentiation])].
[sujeto(['FGF', 'receptor-1,', -, 2, ',', and, -, 3, were, 'detected,', but, only, 'FGFR-1', was, shown, to, be]), verbo([activated]), complemento([by, bFGF])].
[sujeto(['Small', interfering, 'RNA', knock, down, of, 'FGFR-1', in, 'BMSCs', significantly]), verbo([inhibited]), complemento([neuronal, differentiation])].
[sujeto(['Moreover,', we]), verbo([have]), complemento([shown, that, the, 'mitogen-activated', protein, kinase, '(', 'ERK1/2)', is, persistently, activated, and, blockage, of, 'ERK', activity, with, the, 'ERK-specific', inhibitor, 'U0126', prevents, neuronal, differentiation])].
[sujeto(['It', appears, that, activation, of, 'ERK', cascade, and, neuronal, differentiation, of, 'BMSCs']), verbo([induced]), complemento([by, bFGF, are, independent, of, 'Ras', activity, but, require, functions, of, phospholipase, 'C-gamma', pathway])].
[sujeto(['Lastly,', we, examined, the, role, of, the, 'immediate-early', transcription, factors, 'AP-1', and, 'NF-kappaB', and]), verbo([have]), complemento([found, that, phospholipase, 'C-gamma-dependent', 'c-Jun', and, 'ERK-dependent', 'c-fos,', but, not, the, 'NF-kappaB,', are, strongly, activated, by, 'bFGF,', which, in, turn, regulates, the, neuronal, differentiation, of, 'BMSCs'])].
[sujeto(['We', demonstrate, that, 'ZNF198-FGFR1']), verbo([induces]), complemento(['EMS-like', disease, in, 'mice,', with, myeloproliferation, and, 'T', lymphoma, arising, from, common, multipotential, progenitors])].
[sujeto(['Bcr-FGFR1']), verbo([binds]), complemento(['Grb2', via, 'Bcr', 'Tyr177', and, induces, 'CML-like', leukemia, in, 'mice,', whereas, 'Bcr-FGFR1/Y177F', lacks, 'Grb2', binding, and, causes, 'EMS-like', disease])].
[sujeto(['Constitutive', activation, of, aberrant, fibroblast, growth, factor, receptor, 1, '(', 'FGFR1)', kinase, as, a, consequence, of, gene, fusion, such, as, 'FOP-FGFR1']), verbo([associated]), complemento([with, 't(6;', 8, ')', '(', 'q27;p11-12)', 'translocation,', is, the, hallmark, of, an, atypical, aggressive, stem, cell, myeloproliferative, disorder, '(', 'MPD)', in, humans])].
[sujeto(['In', this, 'study,', we, show, that, expression, of, 'FOP-FGFR1', in, primary, bone, marrow, cells]), verbo([induced]), complemento([by, retroviral, transduction, generates, a, 'MPD', in, mice])].
[sujeto(['Constitutive', 'FOP-FGFR1', kinase, activity, was, both, essential, and, sufficient, to]), verbo([cause]), complemento([a, chronic, myeloproliferative, syndrome, in, the, murine, bone, marrow, transplantation, model])].
[sujeto(['Lymphoid', 'symptoms,', 'however,', appeared, when, onset, of, the, disease, was, delayed, as, the, result, of, mutation, of, 'FOP-FGFR1', at, tyrosine, 511, ',', the, phospholipase, 'C', gamma, '(', 'PLCgamma)']), verbo([binding]), complemento([site])].
[sujeto(['We']), verbo([have]), complemento([studied, the, mechanism, whereby, heparin, directs, 'FGF-2-induced', 'FGF', 'receptor-1', '(', 'FGFR-1)', signal, transduction])].
[sujeto(['FGF-2', alone]), verbo([stimulated]), complemento([maximal, phosphorylation, of, 'Src', homology, domain, 2, tyrosine, phosphatase, '(', 'SHP-2)', and, the, adaptor, molecule, 'Crk,', in, heparan, 'sulfate-deficient', 'Chinese', hamster, ovary, '(', 'CHO)', 677, cells, expressing, 'FGFR-1'])].
[sujeto(['In', 'contrast,', for, phospholipase, 'Cgamma(1)', '(', 'PLCgamma(1))', and, the, adaptor, molecule, 'Shb', to, be, maximally, 'tyrosine-phosphorylated,', cells, had, to, be]), verbo([stimulated]), complemento([with, both, 'FGF-2', and, heparin, '(', 100, 'ng/ml)'])].
[sujeto(['Tyrosine', residues, 463, in, the, juxtamembrane, domain, and, 766, in, the, 'C-terminal', tail, in, 'FGFR-1', are, known, to]), verbo([bind]), complemento(['Crk', and, 'PLCgamma(1),', respectively])].
[sujeto(['Analysis', of, tryptic, phosphopeptide, maps, of, 'FGFR-1', from, cells]), verbo([stimulated]), complemento([with, 'FGF-2', alone, and, 'FGF-2', together, with, heparin, showed, that, 'FGF-2', alone, stimulated, a, 'several-fold', increase, in, tyrosine, 463, in, the, juxtamembrane, domain])].
[sujeto(['In', 'contrast,', heparin, had, to, be, included, in, order, for, tyrosine, 766, to, be]), verbo([phosphorylated]), complemento([to, the, same, fold, level])].
[sujeto(['Our', data, imply, that, tyrosine, 463, is]), verbo([phosphorylated]), complemento([and, able, to, transduce, signals, in, response, to, 'FGF-2', treatment, 'alone;', 'furthermore,', we, suggest, that, 'FGFR-1', 'dimerization/kinase', activation, is, stabilized, by, heparin])].
[sujeto(['To', assess, the, role, of, tyrosine, 766, in, endothelial, cell, 'function,', we, generated, endothelial, cells]), verbo([expressing]), complemento([a, chimeric, 'receptor,', composed, of, the, extracellular, domain, of, the, 'PDGF', 'receptor-alpha', and, the, intracellular, domain, of, 'FGFR-1'])].
[sujeto(['Mutation', of, tyrosine, 766, to, phenylalanine]), verbo([prevented]), complemento(['PLC-gamma', activation, and, resulted, in, a, reduced, phosphorylation, of, 'FRS2', and, reduced, activation, of, the, 'Ras/MEK/MAPK', pathway, relative, to, the, 'wild-type', chimeric, receptor])].
[sujeto(['We']), verbo([report]), complemento([that, the, adaptor, protein, 'Shb', is, also, able, to, bind, tyrosine, 766, in, the, 'FGFR-1,', via, its, 'SH2', 'domain,', resulting, in, its, subsequent, phosphorylation])].
[sujeto(['Overexpression', of, an, 'SH2', domain, mutant, 'Shb']), verbo([caused]), complemento([a, dramatic, reduction, in, 'FGFR-1-mediated', 'FRS2', phosphorylation, with, concomitant, perturbment, of, the, 'Ras/MEK/MAPK', pathway])].
[sujeto(['We', 'conclude,', that, 'Shb']), verbo([binds]), complemento([to, tyrosine, 766, in, the, 'FGFR-1', and, regulates, 'FGF-mediated', mitogenicity, via, 'FRS2', phosphorylation, and, the, subsequent, activation, of, the, 'Ras/MEK/MAPK', pathway])].
[sujeto(['Dissection', of, processes, that]), verbo([promote]), complemento([the, slow, progression, to, malignancy, from, those, that, drive, the, malignant, 'phenotype,', once, 'acquired,', is, important, for, identification, of, molecular, targets, for, rational, design, of, dietary, and, pharmaceutical, intervention, to, hold, premalignant, cancer, in, check])].
[sujeto(['In', adult, parenchymal, 'organs,', fibroblast, growth, factor, receptor, '(', 'FGFR)', kinase, isotypes, are, partitioned, between, stroma, and, 'epithelium,', 'respectively,', and]), verbo([mediate]), complemento([communication, between, the, two, compartments, to, maintain, organ, homeostasis])].
[sujeto(['Phospholipase', 'Cgamma-interactive', phosphotyrosine, 766, of, 'FGFR1', is]), verbo([required]), complemento([for, the, 'age-dependent', acquisition, of, the, proliferative, response, to, 'FGFR1,', although, it, appears, not, to, be, required, for, the, mitogenic, response])].
[sujeto(['Although', of, little, utility, in, 'late-stage', 'therapy,', this]), verbo([suggests]), complemento([that, pathways, linked, to, 'FGFR1', tyrosine, 766, may, be, specific, targets, for, prevention, of, progression, of, latent, nonmalignant, tumors, to, the, 'life-threatening', malignant, state])].
[sujeto(['The', development, of, red, blood, cells, from, hematopoietic, progenitors]), verbo([requires]), complemento([the, interplay, of, specific, extracellular, factors, and, transcriptional, regulators])].
[sujeto(['Here', we]), verbo([have]), complemento([identified, an, erythroid, progenitor, that, is, critically, dependent, on, bFGF, and, requires, expression, of, 'AMV', 'v-Myb', for, sustained, proliferation, in, 'vitro,', indicating, that, bFGF, and, 'Myb', proteins, cooperate, in, these, cells])].
[sujeto(['We', also, demonstrate, that, these, cells]), verbo([express]), complemento([high, levels, of, 'FGF', receptor, type, 1, '(', 'FGFR1)', and, that, phospholipase, 'C(gamma)', '(', 'PLC(gamma))', is, one, of, the, important, molecules, in, 'FGF', receptor, signaling])].
[sujeto(['Our', studies]), verbo([suggest]), complemento([that, 'bFGF,', in, cooperation, with, 'Myb', 'proteins,', represents, an, important, factor, for, determining, erythroid, lineage, choice])].
[sujeto(['The', 'FOP-fibroblast', growth, factor, receptor, 1, '(', 'FGFR1)', fusion, protein, is]), verbo([expressed]), complemento([as, a, consequence, of, a, 't(6;8)', '(', 'q27;p12)', translocation, associated, with, a, stem, cell, myeloproliferative, disorder, with, 'lymphoma,', myeloid, hyperplasia, and, eosinophilia])].
[sujeto(['Phosphorylation', of, 'STAT1', and, of, 'STAT3,', but, not, 'STAT5,', is, observed, in, cells]), verbo([expressing]), complemento(['FOP-FGFR1'])].
[sujeto(['The', survival, function, of, 'FOP-FGFR1', is, abrogated, by, mutation, of, the, phospholipase, 'C', gamma]), verbo([binding]), complemento([site])].
[sujeto(['Mitogen-activated', protein, kinase, '(', 'MAPK)', is, also]), verbo([activated]), complemento([in, 'FOP-FGFR1-expressing', cells, and, confers, 'cytokine-independent', survival, to, hematopoietic, cells])].
[sujeto(['Furthermore,', we, show, that, 'FOP-FGFR1']), verbo([phosphorylates]), complemento([phosphatidylinositol, 3, '(', 'PI3)-kinase', and, 'AKT', and, that, specific, inhibitors, of, 'PI3-kinase', impair, its, ability, to, promote, cell, survival])].
[sujeto(['In', 'addition,', 'FOP-FGFR1-expressing', cells, show, constitutive, phosphorylation, of, the, positive, regulator, of, translation, p70S6, 'kinase;', this, phosphorylation, is]), verbo([inhibited]), complemento([by, 'PI3-kinase', and, mTOR, '(', mammalian, target, of, 'rapamycin)', inhibitors])].
[sujeto(['These', results, indicate, that, translation, control, is, important, to]), verbo([mediate]), complemento([the, cell, survival, effect, induced, by, 'FOP-FGFR1'])].
[sujeto(['Elucidation', of, signaling, events, downstream, of, 'FOP-FGFR1', constitutive, activation]), verbo([provides]), complemento([insight, into, the, mechanism, of, leukemogenesis, mediated, by, this, oncogenic, fusion, protein])].
[sujeto(['When']), verbo([stimulated]), complemento([by, 'platelet-derived', growth, 'factor,', derivatives, in, which, the, 'A,', 'B,', or, 'A', +, 'B', blocs, of, tyrosines, were, mutated, were, about, 'two-thirds', as, active, as, the, unmodified, chimera, at, 48, h, but, achieved, full, activity, by, 96, h, in, a, neurite, outgrowth, assay, in, transfected, 'PC12', cells])].
[sujeto(['PLC', gamma, activity, was, dependent, on, the, presence, of, 'Tyr(766)', but, also]), verbo([required]), complemento(['Tyr(677)', 'and/or', 'Tyr(701)'])].
[sujeto(['Although', fully, active, chimeras, did, not]), verbo([require]), complemento(['PLC', 'gamma,', the, responses, of, chimeras, showing, reduced, activation, of, 'FRS2', were, significantly, enhanced, by, this, activity])].
[sujeto(['These', results, establish, that, 'PFR1', does, not, utilize, any, tyrosine, 'residues,']), verbo([phosphorylated]), complemento([or, 'not,', to, activate, 'FRS2'])].
[sujeto(['However,', it, does]), verbo([require]), complemento(['Tyr(677)', 'and/or', 'Tyr(701),', which, may, function, to, stabilize, the, active, conformation, directly, or, indirectly])].
[sujeto(['The']), verbo([activated]), complemento([fibroblast, growth, factor, receptor, '(', 'FGFR)-1', is, phosphorylated, on, five, tyrosine, residues, outside, the, catalytic, site])].
[sujeto(['Although', one, such, 'residue,', 'Tyr730,', is, flanked, by, potential]), verbo([binding]), complemento([sites, for, 'phosphotyrosine-interacting', 'molecules,', a, physiological, role, for, this, region, is, still, controversial])].
[sujeto(['We']), verbo([report]), complemento([that, a, 'cell-permeant', phosphopeptide, mimic, of, this, 'site,', 'FGFR730(p)Y,', inhibits, 'FGF-mediated', mitogenesis, in, cells, with, no, effect, on, responses, stimulated, by, other, growth, factors])].
[sujeto(['A', similar, phosphopeptide, corresponding, to, the, phospholipase, 'Cgamma']), verbo([binding]), complemento([site, on, the, receptor, had, no, effect, on, the, mitogenic, response])].
[sujeto(['The', 'FGFR730(p)Y', peptide, did, not]), verbo([inhibit]), complemento([phosphorylation, of, 'p90/FRS2', or, 'Erk,', suggesting, that, it, does, not, act, by, inhibiting, the, 'Erk-kinase', cascade])].
[sujeto(['However,', the, 'FGFR730(p)Y', peptide]), verbo([bound]), complemento(['Shc', in, a, manner, requiring, both, phosphorylated, tyrosine, and, a, putative, 'PTB', domain, binding, determinant])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, the, peptide, might, inhibit, mitogenesis, by, competing, with, the, corresponding, site, on, the, 'FGFR', for, the, ability, to, bind, 'SHC'])].
[sujeto(['We']), verbo([found]), complemento([that, 'FGFR', substrate, 2, alpha, '(', 'FRS2alpha),', 'Src', homologous, and, collagen, 'A', '(', 'ShcA),', and, 'phospholipase-Cgamma', '(', 'PLCgamma)', were, all, required, for, neurite, outgrowth, from, cerebellar, granule, neurons, '(', 'CGNs)', induced, by, 'FGF1', and, 'FGL', '(', an, 'NCAM-derived', peptide, agonist, of, 'FGFR1)'])].
[sujeto(['Like', 'FGF1,', 'FGL']), verbo([induced]), complemento([tyrosine, phosphorylation, of, 'FGFR1,', 'FRS2alpha,', 'ShcA,', and, 'PLCgamma', in, a, 'time-', and, 'dose-dependent', manner])].
[sujeto(['However,', the, activation, of, 'FRS2alpha', by, 'FGL', was, significantly, lower, than, the, activation, by, 'FGF1,', indicating, a, differential, signaling, profile]), verbo([induced]), complemento([by, 'NCAM', compared, with, the, cognate, growth, factor])].
[sujeto(['Molecular', genetic, analysis, of, 'FGFR1', signaling]), verbo([reveals]), complemento([distinct, roles, of, 'MAPK', and, 'PLCgamma1', activation, for, 'self-renewal', of, adult, neural, stem, cells])].
[sujeto(['These', novel, findings]), verbo([provide]), complemento([insights, into, basic, neural, stem, cell, biology, and, clinical, applications, of, potential, 'stem-cell-based', therapy])].
[sujeto(['The', 't(6;8)', translocation]), verbo([found]), complemento([in, rare, and, agressive, myeloproliferative, disorders, results, in, a, chimeric, gene, encoding, the, 'FOP-FGFR1', fusion, protein])].
[sujeto(['We', show, that, 'FOP-FGFR1']), verbo([interacts]), complemento([with, the, large, centrosomal, protein, 'CAP350', and, that, 'CAP350', is, necessary, for, 'FOP-FGFR1', localisation, at, centrosome])].
[sujeto(['FOP-FGFR1']), verbo([activates]), complemento([the, 'phosphoinositide-3', kinase, '(', 'PI3K)', pathway])].
[sujeto(['We', show, that, p85]), verbo([interacts]), complemento([with, tyrosine, 475, of, 'FOP-FGFR1,', which, is, located, in, a, 'YXXM', consensus, binding, sequence, for, an, 'SH2', domain, of, p85])].
[sujeto(['Ba/F3', cells, that]), verbo([express]), complemento(['FOP-FGFR1', mutated, at, tyrosine, 475, have, reduced, proliferative, ability])].
[sujeto(['Treatment', with, 'PI3K', pathway, inhibitors]), verbo([induces]), complemento([death, of, 'FOP-FGFR1', expressing, cells])].
[sujeto(['FOP-FGFR1', also]), verbo([recruits]), complemento([phospholipase, 'Cgamma1', '(', 'PLCgamma1)', at, the, centrosome])].
[sujeto(['We', show, that, this, enzyme, is]), verbo([recruited]), complemento([by, 'FOP-FGFR1', at, the, centrosome, during, interphase])].
[sujeto(['These', results, delineate, a, particular, type, of, oncogenic, mechanism, by, which, an, ectopic, kinase]), verbo([recruits]), complemento([its, substrates, at, the, centrosome, whence, unappropriate, signaling, induces, continuous, cell, growth, and, 'MPD'])].
[sujeto(['Keratinocyte', growth, factor, receptor, '(', 'KGFR)', is, a, receptor, tyrosine, kinase]), verbo([expressed]), complemento([on, epithelial, cells, which, belongs, to, the, family, of, fibroblast, growth, factor, receptors, '(', 'FGFRs)'])].
[sujeto(['Following', ligand, 'binding,', 'KGFR', is, rapidly, autophosphorylated, on, specific, tyrosine, residues, in, the, intracellular, 'domain,']), verbo([recruits]), complemento([substrate, 'proteins,', and, is, rapidly, internalized, by, 'clathrin-mediated', endocytosis])].
[sujeto(['The', role, of, different, autophosphorylation, sites, in, 'FGFRs,', and, in, particular, the, role, of, the, tyrosine, 766, in, 'FGFR1,', first, identified, as, 'PLCgamma']), verbo([binding]), complemento(['site,', has, been, extensively, studied])].
[sujeto(['Our', results, indicate, that, tyrosine, 769, is]), verbo([required]), complemento([for, the, binding, to, 'KGFR', and, tyrosine, phosphorylation, of, 'PLCgamma', as, well, as, for, the, full, activation, of, 'MAPKs', and, for, cell, proliferation, through, the, regulation, of, 'FRS2', tyrosine, 'phosphorylation,', suggesting, that, this, residue, represents, a, key, regulator, of, 'KGFR', signal, transduction])].
[sujeto(['Our', data, also, show, that, tyrosine, 769, is, not]), verbo([involved]), complemento([in, the, regulation, of, the, endocytic, process, of, 'KGFR'])].
[sujeto(['FGF2', signaling, in, glioblastoma]), verbo([induces]), complemento([resistance, to, 'radiotherapy,', so, targeting, 'FGF2/FGFR', pathways, might, offer, a, rational, strategy, for, tumor, radiosensitization])].
[sujeto(['Silencing', 'FGFR1']), verbo([decreased]), complemento([radioresistance, in, a, manner, associated, with, 'radiation-induced', centrosome, overduplication, and, mitotic, cell, death])].
[sujeto(['Finally,', 'FGFR1', silencing, delayed, the, growth, of, irradiated, tumor, 'xenografts,', in, a, manner, that, was]), verbo([associated]), complemento([with, reduced, 'HIF1α', levels, but, not, blood, vessel, alterations])].
[sujeto(['Taken', 'together,', our, results, offer, a, preclinical, proof, of, concept, that, 'FGFR1']), verbo([targeting]), complemento([can, degrade, radioresistance, in, 'glioblastoma,', a, widespread, problem, in, this, 'tumor,', prompting, clinical, investigations, of, the, use, of, 'FGFR1', inhibitors, for, radiosensitization])].
[sujeto(['Since', its, initial, 'description,', there]), verbo([has]), complemento([been, a, continuous, debate, regarding, the, nature, of, its, 'etiology:', 'Whether', congenital, or, traumatic])].
[sujeto(['We']), verbo([have]), complemento([evaluated, a, pair, of, identical, twins, both, with, os, odontoideum])].
[sujeto(['CACNG6,', 'PHEX,', 'CACNAD3,', 'IL2,', 'FAS,', 'TUFT1,', 'KIT,', 'TGFBR2,', and, 'IGF2', were]), verbo([expressed]), complemento([at, levels, greater, than, 100, -, fold, more, in, the, twins])].
[sujeto(['Os', odontoideum]), verbo([has]), complemento([multiple, 'etiologies,', both, traumatic, and, congenital, and, perhaps, some, represent, a, combination, of, the, two])].
[sujeto(['This', work]), verbo([has]), complemento([identified, a, number, of, genes, that, show, increased, expression, in, a, pair, of, twins, with, congenital, os, odontoideum, and, also, demonstrates, trends, in, gene, expression, profiles, between, a, larger, group, of, os, odontoideum, patients, and, 'non-os', patients])].
[sujeto(['The', specific, 'TLR2/1', complex, activator, 'Pam3CSK4']), verbo([has]), complemento([been, shown, to, provoke, prominent, activation, and, aggregation, of, human, 'non-nucleated', platelets])].
[sujeto(['As', 'Pam3CSK4-evoked', platelet, activation, does, not, employ, the, major, signalling, pathway, established, in, nucleated, immune, 'cells,', we, investigated, if, the, 'TLR2/1', complex, on, platelets, may, initiate, signalling, pathways, known, to, be]), verbo([induced]), complemento([by, physiological, agonists, such, as, collagen, via, 'GPVI', or, thrombin, via, 'PARs'])].
[sujeto(['We']), verbo([found]), complemento([that, triggering, 'TLR2/1', 'complex-signalling', with, 'Pam3CSK4,', in, common, with, that, induced, via, 'GPVI,', and, in, contrast, to, that, provoked, by, 'PARs,', involves, tyrosine, phosphorylation, of, the, adaptor, protein, 'LAT', as, well, as, of, 'PLCγ2', in, a, 'src-', and, 'Syk-dependent', manner])].
[sujeto(['In', this, 'respect,', we]), verbo([provide]), complemento([evidence, that, 'Pam3CSK4', does, not, 'cross-activate', 'GPVI'])].
[sujeto(['Further,', by, the, use, of, platelets, from, a, 'Glanzmann\'s', thrombasthenia, patient, lacking, 'β(3),', in, contrast, to, findings, in, nucleated, immune, 'cells,', we, show, that, the, initiation, of, platelet, activation, by, 'Pam3CSK4', does, not]), verbo([involve]), complemento([integrin, 'β(3)', 'signalling;', whereas, the, 'latter,', subsequent, to, intermediate, 'TXA2', synthesis, and, 'signalling,', was, found, to, be, indispensable, for, proper, dense, granule, secretion, and, full, platelet, aggregation])].
[sujeto(['Together,', our, findings]), verbo([reveal]), complemento([that, triggering, the, 'TLR2/1', complex, with, 'Pam3CSK4', initiates, human, platelet, activation, by, engaging, tyrosine, kinases, of, the, src, family, and, 'Syk,', the, adaptor, protein, 'LAT,', as, well, as, the, key, mediator, 'PLCγ2'])].
[sujeto(['Cimetidine,', a, 'histamine-2', '(', 'H2)', receptor, 'antagonist,']), verbo([has]), complemento([been, demonstrated, to, have, anticancer, effects, on, colorectal, 'cancer,', melanoma, and, renal, cell, carcinoma])].
[sujeto(['In', the, current, 'study,', we, clarified, that, cimetidine]), verbo([inhibits]), complemento([both, epidermal, growth, factor, '(', 'EGF)-induced', cell, proliferation, and, migration, in, hepatocellular, carcinoma, '(', 'HCC)', cell, lines])].
[sujeto(['Cimetidine']), verbo([inhibited]), complemento([both, 'EGF-induced', cell, proliferation, and, migration, in, 'Hep3B,', 'HLF,', 'SK-Hep-1', and, 'JHH-2,', while, cimetidine, did, not, affect, 'EGF-induced', cell, proliferation, and, migration, in, 'PLC/PRF/5', and, 'HLE'])].
[sujeto(['Cimetidine', was, revealed, to, disrupt, the, 'EGF-induced', autophosphorylation, of, 'EGFR', and, its, downstream, 'effectors,', mitogen]), verbo([activated]), complemento([protein, kinases, and, phospholipase, 'C-gamma'])].
[sujeto(['To', define, the, molecular, basis, of, this, negative, 'regulation,', we, identified, that, cimetidine, significantly]), verbo([decreased]), complemento([intracellular, cAMP, levels, and, that, decrement, of, cAMP, inhibited, autophosphorylation, of, 'EGFR'])].
[sujeto(['Cimetidine']), verbo([inhibited]), complemento(['EGF-induced', cell, proliferation, and, migration, in, 'HCC', cell, lines, by, decreasing, the, concentration, of, intracellular, cAMP, levels])].
[sujeto(['The', influenza, virus, hemagglutinin, glycoprotein, '(', 'HA)']), verbo([induces]), complemento([a, vigorous, 'B', cell, proliferation, and, 'Ig-synthesis', by, an, unknown, activation, 'mechanism,', which, is, susceptible, to, the, inhibitory, effects, of, 'anti-Ig', and, 'anti-class', 'II', mAbs])].
[sujeto(['To']), verbo([gain]), complemento([further, insight, into, the, activation, mode, of, this, 'T', 'cell-independent,', 'B', cell, &, 'quot;superstimulatory&quot;', 'virus,', we, analyzed, the, sensitivity, of, 'H2-subtype', 'virus-mediated', 'B', cell, activation, to, the, inhibitory, effects, of, various, signal, 'transduction-blocking', agents, and, compared, it, to, the, well, characterized, 'anti-mu-mediated', and, the, 'LPS-employed', pathway])].
[sujeto(['Cyclic-AMP', agonists, '(', 'cAMP-analogues,', 'pentoxifylline,', cholera, 'toxin,', and, 'forskolin)', blocked, 'HA-mediated', activation, of, 'B', cells, only, at, concentrations, at, least, 50, -, fold, higher, than]), verbo([required]), complemento([for, blocking, of, 'anti-mu-induced', activation])].
[sujeto(['However,', 'HA-treatment', failed, to]), verbo([induce]), complemento([an, increase, in, intracellular, cAMP, levels, in, responding, 'B', cells])].
[sujeto(['Similarly,', 'HA', failed, to]), verbo([induce]), complemento([an, increase, in, tyrosine, 'phosphorylations,', including, phosphorylation, of, phospholipase, 'C', gamma, 2])].
[sujeto(['HA-activated', 'B', cells, showed, an]), verbo([increase]), complemento([in, 'membrane-associated', protein, kinase, 'C', 'activity,', and, depletion, of, protein, kinase, 'C', by, pretreatment, of, 'B', cells, with, phorbol, esters, inhibited, a, subsequent, activation, by, 'HA'])].
[sujeto(['Collectively,', our, results]), verbo([provide]), complemento([a, new, example, of, 'B', cell, stimulation, by, multivalent, 'type-2', 'Ags,', which, seems, to, be, mediated, by, a, 'phosphatidylinositol-', and, 'Ca(2+)-independent', signaling, pathway])].
[sujeto(['Apicidin,', a, fungal, metabolite, that, functions, as, a, histone, deacetylase, 'inhibitor,']), verbo([induces]), complemento([apoptosis, in, cancer, cells])].
[sujeto(['Apicidin']), verbo([induced]), complemento([apoptotic, cell, death, and, activation, of, 'caspase-12,', -, 9, ',', and, -, 3])].
[sujeto(['Apicidin']), verbo([induced]), complemento([expression, of, endoplasmic, reticulum, '(', 'ER)', 'stress-associated', 'proteins,', including, 'CCAAT/enhancer', binding, protein, homologous, protein, '(', 'CHOP),', cleavage, of, activating, transcription, factor, 6, 'α,', and, phosphorylation, of, eukaryotic, initiation, factor, 2, α])].
[sujeto(['Apicidin']), verbo([induced]), complemento([reactive, oxygen, species, accumulation, and, mitochondrial, membrane, potential, loss])].
[sujeto(['In', 'addition,', apicidin]), verbo([increased]), complemento([cytosolic, 'Ca(2+),', which, was, blocked, by, 2, -, aminoethoxydiphenyl, 'borate,', an, antagonist, of, inositol, 1, ',', 4, ',', 5, -, trisphosphate, 'receptor,', and, 'BAPTA-AM,', an, intracellular, 'Ca(2+)', chelator])].
[sujeto([2, -, 'Aminoethoxydiphenyl', borate, and, 'BAPTA-AM']), verbo([inhibited]), complemento(['apicidin-induced', cell, death, and, 'ER', stress])].
[sujeto(['Interestingly,', apicidin]), verbo([induced]), complemento([phosphorylation, of, phospholipase, 'Cγ1', '(', 'PLCγ1)', and, epidermal, growth, factor, receptor, '(', 'EGFR),', and, inhibition, of, 'PLCγ1', and, 'EGFR', reduced, cell, death, and, 'ER', stress])].
[sujeto(['Taken', 'together,', the, results]), verbo([suggest]), complemento([that, apicidin, induces, apoptosis, by, 'ER', stress, and, mitochondrial, dysfunction, via, 'PLCγ1', 'activation,', 'Ca(2+)', 'release,', and, reactive, oxygen, species, accumulation, in, 'Neuro-2a', neuroblastoma, cells])].
[sujeto(['In', response, to, fibroblast, growth, factor, '(', 'FGF),', 'FGF', 'receptor-1', '(', 'FGFR-1)', '(', 'flg)', becomes, tyrosine]), verbo([phosphorylated]), complemento([and, associates, with, phospholipase, 'C', gamma, '(', 'PLC', 'gamma)', and, a, 90, kDa, protein])].
[sujeto(['We']), verbo([report]), complemento([here, that, in, cells, transformed, by, 'v-Src,', 'FGFR-1', becomes, phosphorylated, on, 'tyrosine;', 'however,', neither, 'PLC', gamma, nor, p90, was, found, to, be, associated, with, 'tyrosine-phosphorylated', 'FGFR-1'])].
[sujeto(['Suramin', did, not]), verbo([prevent]), complemento([either, tyrosine, phosphorylation, or, 'Shc/Grb2/Sos', 'association,', indicating, a, 'non-autocrine', mechanism])].
[sujeto(['Thus,', in, cells, transformed, by, 'v-Src,', tyrosine, phosphorylation, of, 'FGFR-1', results, not, in, the, expected, association, with, 'PLC', gamma, and, 'p90,', but, rather, in, the, recruitment, of, the, 'Ras']), verbo([activating]), complemento(['Shc/Grb2/Sos', complex])].
[sujeto(['These', data]), verbo([suggest]), complemento([a, mechanism, for, 'Ras', activation, by, 'v-Src', involving, phosphorylation, of, novel, 'tyrosine(s)', on, 'FGFR-1'])].
[sujeto(['Ischemia-reperfusion', injury, was]), verbo([induced]), complemento([in, rats, by, compression, of, the, optic, nerve, for, 2, hours])].
[sujeto(['Protein', tyrosine, phosphorylation]), verbo([increased]), complemento([after, 'ischemia-reperfusion', 'injury,', reaching, a, peak, at, 48, hours, of, reperfusion])].
[sujeto(['The', amount, of, bFGF]), verbo([decreased]), complemento([after, 'injury,', but, the, amounts, of, 'VEGF', and, 'PDGF-B', chain, increased])].
[sujeto(['Tyrosine', phosphorylation, of, 'PLC', 'gamma,', 'SHC,', and, 'MAPK', was]), verbo([increased]), complemento([at, 48, hours, of, 'reperfusion,', and, tyrosine, phosphorylation, of, 'PDGF-beta', receptor, and, 'PI3K', was, increased, at, 168, hours, of, reperfusion])].
[sujeto(['Ischemia-reperfusion', injury, in, the, rat, retina]), verbo([leads]), complemento([to, activation, of, the, tyrosine, kinase, 'pathway,', increasing, the, amounts, of, angiogenic, growth, factors])].
[sujeto(['Extracellular', matrix, controls, capillary, endothelial, cell, sensitivity, to, soluble, mitogens, by]), verbo([binding]), complemento([integrin, receptors, and, thereby, activating, a, chemical, signaling, response, that, rapidly, integrates, with, growth, 'factor-induced', signaling, mechanisms])].
[sujeto(['Here', we]), verbo([report]), complemento([that, in, addition, to, 'integrins,', growth, factor, receptors, and, multiple, molecules, that, transduce, signals, conveyed, by, both, types, of, receptors, are, immobilized, on, the, cytoskeleton, '(', 'CSK)', and, spatially, integrated, within, the, focal, adhesion, complex, '(', 'FAC)', at, the, site, of, integrin, binding])].
[sujeto(['FACs', were, rapidly]), verbo([induced]), complemento([in, round, cells, and, physically, isolated, from, the, remainder, of, the, 'CSK', after, 'detergent-extraction', using, magnetic, microbeads, coated, with, fibronectin, or, a, synthetic, 'RGD-containing', peptide])].
[sujeto([',', 'pp60c-src,', 'pp125FAK,', 'phosphatidylinositol-3-kinase,', phospholipase, 'C-gamma,', and, 'Na+/H+', 'antiporter)']), verbo([involved]), complemento([in, both, integrin, and, growth, factor, receptor, signaling, pathways, became, associated, with, the, 'CSK', framework, of, the, 'FAC', within, 15, min, after, binding, to, beads, coated, with, integrin, ligands])].
[sujeto(['Recruitment', of, tyrosine, kinases, to, the, 'FAC', was, also, accompanied, by, a, local]), verbo([increase]), complemento([in, tyrosine, 'phosphorylation,', as, indicated, by, enhanced, phosphotyrosine, staining, at, the, site, of, integrin, binding])].
[sujeto(['In', 'contrast,', neither, recruitment, of, signaling, molecules, nor]), verbo([increased]), complemento([phosphotyrosine, staining, was, observed, when, cells, bound, to, beads, coated, with, a, control, ligand, '(', acetylated, low, density, 'lipoprotein)', that, ligates, transmembrane, scavenger, 'receptors,', but, does, not, induce, 'FAC', formation])].
[sujeto(['Western', blot, analysis, confirmed, that, 'FACs', isolated, using, 'RGD-beads', were, enriched, for, 'pp60c-src,', 'pp125FAK,', phospholipase, 'C-gamma,', and, the, 'Na+/H+', antiporter, when, compared, with, intact, 'CSK', or, basal, cell, surface, preparations, that]), verbo([retained]), complemento([lipid, bilayer])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, many, of, the, chemical, signaling, events, that, are, induced, by, integrins, and, growth, factor, receptors, in, capillary, cells, may, effectively, function, in, a, &, 'quot;solid-state&quot;', on, insoluble, 'CSK', scaffolds, within, the, 'FAC', and, that, the, 'FAC', may, represent, a, major, site, for, signal, integration, between, these, two, regulatory, pathways])].
[sujeto(['Future', investigations, into, the, biochemical, and, biophysical, basis, of, signal, transduction, may, be, facilitated, by, this, 'method,', which, results, in, isolation, of, 'FACs', that]), verbo([retain]), complemento([the, 'CSK', framework, as, well, as, multiple, associated, chemical, signaling, activities])].
[sujeto(['Signaling', via, the, fibroblast, growth, factor, receptor, 1, '(', 'FGFR1,', 'flg)', was, analyzed, in, 'Ba/F3', hematopoietic, cells]), verbo([expressing]), complemento([either, 'wild-type', or, a, mutant, 'FGF', receptor, '(', 'Y766F)', unable, to, activate, phospholipase, 'C-gamma', '(', 'PLC-gamma)', and, stimulate, phosphatidylinositol, '(', 'PI)', hydrolysis])].
[sujeto(['Stimulation', of, cells]), verbo([expressing]), complemento(['wild-type', or, mutant, 'FGFR', with, acidic, 'FGF', '(', 'aFGF)', caused, similar, activation, of, 'Ras'])].
[sujeto(['However,', an, approximately, 3, -, fold, reduced, activation, of, 'Raf-1', and, 'MAP', kinase, was, observed, in, 'aFGF-stimulated', cells]), verbo([expressing]), complemento([mutant, receptors, as, compared, to, cells, expressing, 'wild-type', 'FGF', receptors])].
[sujeto(['Comparison', of, phosphopeptide, maps, of, 'Raf-1', immunoprecipitated, from, the, two, cell, types]), verbo([activated]), complemento([by, either, aFGF, or, the, phorbol, ester, '(', 12, -, 'O-tetradecanoylphorbol-13-acetate)', suggests, that, 'Raf-1', is, phosphorylated, by, both, 'Ras-dependent', and, 'PLC-gamma-dependent', mechanisms])].
[sujeto(['In', spite, of, the, differential, effect, on, 'Raf-1', and, 'MAP', kinase, 'activation,', aFGF]), verbo([stimulated]), complemento([similar, proliferation, of, cells, expressing, 'wild-type', or, mutant, receptors, indicating, that, 'Ras-dependent', activation, of, 'Raf-1', and, 'MAP', kinase, is, sufficient, for, transduction, of, 'FGFR', mitogenic, signals])].
[sujeto(['Ras', may, also]), verbo([activate]), complemento([signal, transduction, pathways, that, are, complementary, or, parallel, to, the, 'MAP', kinase, pathway, to, stimulate, cell, proliferation])].
[sujeto(['Binding', of, fibroblast, growth, factor, '(', 'FGF)', to, the, fibroblast, growth, factor, receptor]), verbo([leads]), complemento([to, autophosphorylation, of, the, receptor, on, several, tyrosine, residues])].
[sujeto(['Wild-type', 'FGF', receptor, 1, '(', 'flg)', and, a, mutated, receptor, '(', 'Y766F),', in, which, an, autophosphorylation, site, '(', 'Tyr-766)', was, mutated, to, 'phenylalanine,', were]), verbo([expressed]), complemento([in, rat, myoblasts, and, in, hematopoietic, 'Ba/F3', cells])].
[sujeto(['It', was]), verbo([found]), complemento([that, the, point, mutation, at, 'Tyr-766', resulted, in, a, decrease, in, 'FGF', receptor, 'internalization,', as, well, as, a, reduction, in, both, 'ligand-induced', 'FGF', receptor, 'down-regulation', and, degradation])].
[sujeto(['It']), verbo([has]), complemento([been, shown, previously, that, phosphorylation, of, 'Tyr-766', is, essential, for, interaction, with, phospholipase, 'C', gamma, and, that, the, 'Y766F', 'FGF', receptor, mutant, is, unable, to, stimulate, phosphatidylinositol, hydrolysis, and, 'Ca2+', release, from, internal, stores])].
[sujeto(['The', results, presented, in, this]), verbo([report]), complemento([indicate, that, 'Tyr-766', is, also, essential, for, cellular, trafficking, of, 'FGF', receptor])].
[sujeto(['Fibroblast', growth, factors, '(', 'FGF)']), verbo([stimulate]), complemento([growth, arrest, and, differentiation, in, rat, pheochromocytoma, 'PC12', cells])].
[sujeto(['We', show, that, point, mutation, at, 'Tyr-766', '(', 'Y766F)', of, the, 'FGF', receptor]), verbo([prevents]), complemento([tyrosine, phosphorylation, of, phospholipase, 'C', gamma, and, eliminates, acidic, 'FGF', '(', 'aFGF)-induced', stimulation, of, 'PI', hydrolysis, in, 'PC12', cells])].
[sujeto(['Treatment', of, 'PC12', cells]), verbo([expressing]), complemento([either, 'wild-type', or, the, 'Y766F', mutant, with, aFGF, led, to, tyrosine, phosphorylation, of, 'Shc,', the, association, of, 'Shc', with, 'GRB2,', a, shift, in, the, electrophoretic, mobility, of, the, 'Ras', guanine, 'nucleotide-releasing', 'factor,', 'Sos', '(', son, of, 'sevenless),', and, enhancement, in, 'mitogen-activated', protein, kinase, phosphorylation])].
[sujeto(['Moreover,', stimulation, with, aFGF]), verbo([led]), complemento([to, a, typical, neurite, outgrowth, of, 'PC12', cells, expressing, either, 'wild-type', or, the, 'Y766F', 'FGF', receptor, mutant])].
[sujeto(['A', differentiated, liver, cell, '(', 'HepG2),', which, exhibits, a, 'dose-dependent', 'growth-stimulatory', and, 'growth-inhibitory', response, to, 'heparin-binding', fibroblast, growth, factor, type, 1, '(', 'FGF-1),', displays, 'high-', and, 'low-affinity', receptor, phenotypes, and]), verbo([expresses]), complemento([specific, combinatorial, splice, variants, alpha, 1, ',', beta, 1, ',', and, alpha, 2, of, the, 'FGF', receptor, '(', 'FGF-R)', gene, '(', 'flg)'])].
[sujeto(['The', three, combinatorial, splice, variants]), verbo([dimerized]), complemento([in, all, combinations])].
[sujeto(['FGF']), verbo([enhanced]), complemento([dimerization, and, kinase, 'activity,', as, assessed, by, receptor, autophosphorylation])].
[sujeto(['The', 'SH2', domain, 'substrate,', phospholipase, 'C', gamma, 1, '(', 'PLC', gamma, 1, ')', ',']), verbo([associated]), complemento([with, the, phosphorylated, type, 1, -, type, 2, heterodimers, but, was, phosphorylated, only, in, preparations, containing, the, type, 1, kinase, homodimer])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, phosphorylation, of, 'Tyr-653', within, the, kinase, catalytic, 'domain,', but, not, 'Tyr-766', in, the, 'COOH-terminal', 'domain,', may, be, stringently, dependent, on, a, trans, intermolecular, mechanism, within, 'FGF-R', kinase, homodimers])].
[sujeto(['Although', phosphotyrosine, 766, is, sufficient, for, interaction, of, 'PLC', gamma, 1, and, other, 'SH2', substrates, with, the, 'FGF-R', 'kinase,', phosphorylation, and, presumably, activation, of, substrates]), verbo([require]), complemento([the, kinase, homodimer, and, phosphorylation, of, 'Tyr-653'])].
[sujeto(['The', results]), verbo([suggest]), complemento([a, mechanism, for, control, of, signal, transduction, by, different, concentrations, of, ligand, through, heterodimerization, of, combinatorial, splice, variants, from, the, same, receptor, gene])].
[sujeto(['It']), verbo([has]), complemento([been, demonstrated, that, the, src, homology, region, 2, '(', 'SH2', 'domain)', of, 'PLC-gamma', and, of, other, signalling, molecules, such, as, 'GTPase-activating', protein, and, phosphatidylinositol, 3, -, 'kinase-associated', p85, direct, their, binding, toward, 'tyrosine-autophosphorylated', regions, of, the, epidermal, growth, factor, or, 'platelet-derived', growth, factor, receptor])].
[sujeto(['In', this, 'report,', we, describe, the, identification, of, 'Tyr-766', as, an, autophosphorylation, site, of, 'flg-encoded', 'FGFR', by, direct, sequencing, of, a, 'tyrosine-phosphorylated', tryptic, peptide, isolated, from, the, cytoplasmic, domain, of, 'FGFR']), verbo([expressed]), complemento([in, 'Escherichia', coli])].
[sujeto(['The', same, phosphopeptide, was]), verbo([found]), complemento([in, 'wild-type', 'FGFR', phosphorylated, either, in, vitro, or, in, living, cells])].
[sujeto(['Like', other, growth, factor, 'receptors,', 'tyrosine-phosphorylated', 'wild-type', 'FGFR', or, its, cytoplasmic, domain, becomes]), verbo([associated]), complemento([with, intact, 'PLC-gamma', or, with, a, fusion, protein, containing, the, 'SH2', domain, of, 'PLC-gamma'])].
[sujeto(['To', delineate, the, site, of, 'association,', we]), verbo([have]), complemento([examined, the, capacity, of, a, 28, -, 'amino-acid', tryptic, peptide, containing, phosphorylated, 'Tyr-766', to, bind, to, various, constructs, containing, 'SH2', and, other, domains, of, 'PLC-gamma'])].
[sujeto(['It', is, demonstrated, that, the, 'tyrosine-phosphorylated', peptide]), verbo([binds]), complemento([specifically, to, the, 'SH2', domain, but, not, to, the, 'SH3', domain, or, other, regions, of, 'PLC-gamma'])].
[sujeto(['Hence,', 'Tyr-766', and, its, flanking, sequences, represent, a, major]), verbo([binding]), complemento([site, in, 'FGFR', for, 'PLC-gamma'])].
[sujeto(['Alignment', of, the, amino, acid, sequences, surrounding, 'Tyr-766', with, corresponding, regions, of, other, 'FGFRs', revealed]), verbo([conserved]), complemento([tyrosine, residues, in, all, known, members, of, the, 'FGFR', family])].
[sujeto(['We', propose, that, homologous, 'tyrosine-phosphorylated', regions, in, other, 'FGFRs', also, function, as]), verbo([binding]), complemento([sites, for, 'PLC-gamma', and, therefore, are, involved, in, coupling, to, phosphatidylinositol, breakdown])].
[sujeto(['The', candidate, abnormalities, were, validated, and, then, screened, by]), verbo([targeted]), complemento([sequencing, and, fluorescence, in, situ, hybridization, in, a, large, cohort, of, 120, 'well-characterized', 'AS', cases])].
[sujeto(['MYC', amplification, was, present, in, most, secondary, 'AS', related, to, breast, cancer, '(', 91, '%', ')', compared, with, other]), verbo([causes]), complemento(['(', 25, '%', ')', or, primary, 'AS', '(', 7, '%', ')'])].
[sujeto(['Interleukin-2', '(', 'IL-2)-inducible', 'T', cell, kinase, '(', 'ITK)']), verbo([mediates]), complemento(['T', cell, receptor, '(', 'TCR)', signaling, primarily, to, stimulate, the, production, of, 'cytokines,', such, as, 'IL-4,', 'IL-5,', and, 'IL-13,', from, 'T', helper, 2, '(', 'TH2)', cells])].
[sujeto(['Compared', to, 'wild-type', 'mice,', 'ITK', knockout, mice, are, resistant, to, asthma, and, exhibit, reduced, lung, inflammation, and]), verbo([decreased]), complemento([amounts, of, 'TH2-type', cytokines, in, the, bronchoalveolar, lavage, fluid])].
[sujeto(['We']), verbo([found]), complemento([that, a, 'small-molecule', selective, inhibitor, of, 'ITK', blocked, 'TCR-mediated', signaling, in, cultured, 'TH2', 'cells,', including, the, tyrosine, phosphorylation, of, phospholipase, 'C-γ1', '(', 'PLC-γ1)', and, the, secretion, of, 'IL-2', and, 'TH2-type', cytokines])].
[sujeto(['Rather,', in, 'mice,', pharmacological, inhibition, of, 'ITK', resulted, in, 'T', cell, hyperplasia, and, the]), verbo([increased]), complemento([production, of, 'TH2-type', cytokines])].
[sujeto(['In', 'contrast,', seven, other, 'mutations,', including, phospholipase, 'C-gamma1', '(', 'PLCG1)', 'R707Q', 'mutation,', were]), verbo([found]), complemento([only, in, the, metastatic, 'tumor,', indicating, selection, of, cells, with, the, resistant, genotype, under, sunitinib, pressure])].
[sujeto(['Our', study, supports, the, notion, that, 'PLCG1-R707Q', mutation, may]), verbo([confer]), complemento(['VEGFR2-independent', signaling, and, may, thus, cause, resistance, against, 'VEGF(R)-directed', therapies])].
[sujeto(['This', case, illustrates, also, the, advantages, of, using, 'next-generation', technologies, in, identifying, individualized]), verbo([targeted]), complemento([therapy])].
[sujeto(['Sézary', syndrome, '(', 'SS)', is, an, aggressive, leukaemia, of, mature, 'T', cells, with, poor, prognosis, and, limited, options, for]), verbo([targeted]), complemento([therapies])].
[sujeto(['We', identify, previously, unknown, recurrent, 'loss-of-function', aberrations]), verbo([targeting]), complemento([members, of, the, chromatin, 'remodelling/histone', modification, and, trithorax, 'families,', including, 'ARID1A', in, which, functional, loss, from, nonsense, and, frameshift, mutations, 'and/or', targeted, deletions, is, observed, in, 40.3, '%', of, 'SS', genomes])].
[sujeto(['We', also, identify, recurrent, 'gain-of-function', mutations]), verbo([targeting]), complemento(['PLCG1', '(', 9, '%', ')', and, 'JAK1,', 'JAK3,', 'STAT3', and, 'STAT5B', '(', 'JAK/STAT', total, '∼11%)'])].
[sujeto(['Functional', studies]), verbo([reveal]), complemento([sensitivity, of, 'JAK1-mutated', primary, 'SS', cells, to, 'JAK', inhibitor, treatment])].
[sujeto(['The', underlying]), verbo([cause]), complemento([is, considered, to, be, because, of, a, nonspecific, immunological, mechanism, in, which, mast, cells, are, key, players])].
[sujeto(['We', studied, the, association, of, nine, single, nucleotide, polymorphisms, in, five, genes]), verbo([involved]), complemento([in, mast, cell, activation, '(', 'SYK,', 'LAT1,', 'PLCG1,', 'PLA2G4A,', and, 'TNFRSF11A)', in, 450, 'NIUA', patients, and, 500, controls])].
[sujeto(['Kaposi\'s', sarcoma, '(', 'KS),']), verbo([caused]), complemento([by, 'Kaposi\'s', sarcoma, herpesvirus, '(', 'KSHV),', is, a, highly, vascularised, tumour, of, endothelial, origin])].
[sujeto(['KSHV', infected, endothelial, cells, show]), verbo([increased]), complemento([invasiveness, and, angiogenesis])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, the, 'KSHV', 'K15', 'protein,', which, we, showed, previously, to, contribute, to, 'KSHV-induced', 'angiogenesis,', is, also, involved, in, 'KSHV-mediated', invasiveness, in, a, 'PLCγ1-dependent', manner])].
[sujeto(['We', identified, 'βPIX,', 'GIT1', and, 'cdc42,', downstream, effectors, of, 'PLCγ1', in, cell, 'migration,', as, 'K15']), verbo([interacting]), complemento([partners, and, as, contributors, to, 'KSHV-triggered', invasiveness])].
[sujeto(['We']), verbo([found]), complemento([that, the, 'PLCγ2', cSH2, 'domain,', by, binding, to, 'K15P,', can, be, used, as, dominant, negative, inhibitor, of, the, 'K15P-PLCγ1', 'interaction,', 'K15P-dependent', 'PLCγ1', 'phosphorylation,', 'NFAT-dependent', promoter, activation, and, the, increased, invasiveness, and, angiogenic, properties, of, 'KSHV', infected, endothelial, cells])].
[sujeto(['We']), verbo([increased]), complemento([the, binding, of, the, 'PLCγ2', cSH2, domain, for, 'K15P', by, substituting, two, amino, 'acids,', thereby, creating, an, improved, dominant, negative, inhibitor, of, the, 'K15P-dependent', 'PLCγ1', activation])].
[sujeto(['Taken', 'together,', these, results, demonstrate, a, necessary, role, of, 'K15', in, the]), verbo([increased]), complemento([invasiveness, and, angiogenesis, of, 'KSHV', infected, endothelial, cells, and, suggest, the, 'K15-PLCγ1', interaction, as, a, possible, new, target, for, inhibiting, the, angiogenic, and, invasive, properties, of, 'KSHV'])].
[sujeto(['S345F', was, shown, to, be, 'activating)', are, frequent, '(', 20, '%', ')', in, tumoral, cutaneous, 'T-cell', lymphoma, '(', 'CTCL)', samples, raised, the, possibility, of]), verbo([targeting]), complemento([therapies, against, the, 'PLCG1', signaling, pathway])].
[sujeto(['This', new, study]), verbo([finds]), complemento([that, only, 3, -, 5, '%', of, the, 'CTCL', tumor, genomes, '(', mycosis, fungoides, and, 'Sézary', 'syndrome)', harbor, 'PLCG1', mutations])].
[sujeto(['Linker', for, activation, of, 'T', cells, '(', 'LAT)', is, a, transmembrane, adaptor, protein, that, is, highly, tyrosine]), verbo([phosphorylated]), complemento([upon, engagement, of, the, 'TCR'])].
[sujeto(['Phosphorylated', 'LAT']), verbo([binds]), complemento(['Grb2,', 'Gads,', and, phospholipase, 'C', '(', 'PLC)γ1', to, mediate, 'T', cell, 'activation,', 'proliferation,', and, cytokine, production])].
[sujeto(['T', cells, from, mice, harboring, a, mutation, at, the, 'PLCγ1']), verbo([binding]), complemento([site, of, 'LAT', '(', 'Y136F)', have, impaired, calcium, flux, and, 'Erk', activation])].
[sujeto(['In', this, 'study,', we, showed, that, the, 'LATY136F', 'T', cells, could, also, overproduce, 'IL-6', due, to]), verbo([activated]), complemento(['NF-κB,', 'AKT,', and, p38, pathways])].
[sujeto(['By', crossing, 'LATY136F', mice, with, 'IL-6-deficient', 'mice,', we, demonstrated, that, 'IL-6', is]), verbo([required]), complemento([for, uncontrolled, 'T', cell, expansion, during, the, early, stage, of, disease, development])].
[sujeto(['Reduced', 'CD4(+)', 'T', cell, expansion, was, not, due, to, a, further, block, in, thymocyte, development, or, an]), verbo([increase]), complemento([in, the, number, of, regulatory, 'T', 'cells,', but, was, caused, by, reduction, in, cell, survival])].
[sujeto(['In', aged, 'IL-6(-/-)', 'LATY136F', 'mice,', 'CD4(+)', 'T', cells, began, to, hyperproliferate, and]), verbo([induced]), complemento(['splenomegaly;', 'however,', isotype, switching, and, autoantibody, production, were, diminished])].
[sujeto(['Two', different, members, of, the, 'NK', 'pathway,', 'HCST', and, 'GRZB,', which]), verbo([act]), complemento([at, different, steps, in, the, 'NK-pathway,', were, actively, transcribed, and, translated, into, proteins, in, the, same, cells, in, the, 'AAA', tissue, demonstrated, by, double, staining])].
[sujeto(['Furthermore,', double, staining, with, antibodies, against, 'CD68', or, 'CD8', together, with, 'HCST,', 'TYROBP,', 'PTK2B', or, 'PLCG2', revealed, that, 'CD68', and, 'CD8', positive, cells]), verbo([expressed]), complemento([proteins, of, the, 'NK-pathway', but, were, not, the, only, inflammatory, cells, involved, in, the, 'NK-pathway', in, the, 'AAA', tissue])].
[sujeto(['The', results]), verbo([provide]), complemento([strong, evidence, that, the, 'NK', 'Cell', 'Mediated', 'Cytotoxicity', 'Pathway', is, activated, in, human, 'AAA', and, valuable, insight, for, future, studies, to, dissect, the, pathogenesis, of, human, 'AAA'])].
[sujeto(['Gastric', signet, ring, cell, carcinoma, '(', 'GSRCC)', is, a, unique, pathological, type, of, gastric, carcinoma, that, is, extremely, invasive, and]), verbo([has]), complemento([a, poor, prognosis, after, diagnosis])].
[sujeto(['The', expression, of, microRNAs]), verbo([has]), complemento([been, closely, linked, to, the, carcinogenesis, of, gastric, cancer, and, has, been, considered, as, a, powerful, prognostic, marker])].
[sujeto(['Samples', of, 'GSRCC', were, compared, to, that, of, intestinal, gastric, adenocarcinoma, using, 'Agilent', microarray, 'technique,', and, two, differentially]), verbo([expressed]), complemento([miRNAs, were, 'identified,', 'hsa-miR-665', and, 'hsa-miR&#8209;95'])].
[sujeto(['Target', gene, prediction, using, online, databases]), verbo([conferred]), complemento([two, strong, candidate, 'genes,', 'GLI2', and, 'PLCG1'])].
[sujeto(['It', was, concluded, that, 'hsa-miR-665', and, 'hsa-miR-95', were, downregulated, in, 'GSRCC', but, upregulated, in, intestinal, gastric, 'adenocarcinoma,', and, the, relatively, differential, expression, of, the, miRNAs, negatively, controlling, their]), verbo([target]), complemento([genes, could, be, closely, related, to, the, high, invasive, metastasis, and, chemoresistance, of, 'GSRCC'])].
[sujeto(['Clostridium', perfringens, 'alpha-toxin', elicits, various, immune, responses, such, as, the]), verbo([release]), complemento([of, 'cytokines,', 'chemokines,', and, superoxide, via, the, 'GM1a/TrkA', complex])].
[sujeto(['Annexin', 'V']), verbo([binding]), complemento([assays, showed, that, 'alpha-toxin', induced, the, exposure, of, phosphatidylserine, on, the, outer, leaflet, of, the, plasma, membrane])].
[sujeto(['However,', 'H148G,', a, variant, toxin, which]), verbo([binds]), complemento([cell, membrane, and, has, no, enzymatic, 'activity,', did, not, induce, 'DAG', 'translocation,', 'GM1a', 'clustering,', or, 'TrkA', phosphorylation])].
[sujeto(['Alpha-toxin', also, specifically]), verbo([activated]), complemento([endogenous, phospholipase, 'Cγ-1', '(', 'PLCγ-1),', a, 'TrkA', adaptor, 'protein,', via, phosphorylation])].
[sujeto(['U73122,', an, endogenous, 'PLC', 'inhibitor,', and, siRNA, for, 'PLCγ-1']), verbo([inhibited]), complemento([the, formation, of, 'DAG', and, release, of, 'IL-8'])].
[sujeto(['GM1a', accumulation, and, 'TrkA', phosphorylation, in, 'A549', cells, treated, with, 'alpha-toxin', were, also]), verbo([inhibited]), complemento([by, 'U73122'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, 'flip-flop', motion, of, hydrophobic, lipids, such, as, 'DAG', leads, to, the, accumulation, of, 'GM1a', and, 'TrkA'])].
[sujeto(['We', conclude, that, the, formation, of, 'DAG', by, 'alpha-toxin', itself, '(', first, 'step)', and, activation, of, endogenous, 'PLCγ-1', '(', second, 'step)']), verbo([leads]), complemento([to, alterations, in, membrane, 'dynamics,', followed, by, strong, phosphorylation, of, 'TrkA'])].
[sujeto(['We', show, that, 'PLCγ1']), verbo([regulates]), complemento(['Golgi', structure, and, cell, migration, independently, of, its, catalytic, activity, but, in, a, manner, that, depends, on, interaction, with, the, tethering, protein, p115])].
[sujeto(['PLCγ1']), verbo([regulates]), complemento([the, dynamics, of, p115, in, the, early, secretory, 'pathway,', thereby, controlling, trafficking, from, the, endoplasmic, reticulum, to, the, 'Golgi'])].
[sujeto(['Receptor-mediated', platelet, activation]), verbo([requires]), complemento([phospholipase, 'C', '(', 'PLC)', activity, to, elevate, intracellular, calcium, and, induce, actin, cytoskeleton, reorganization])].
[sujeto(['Platelets']), verbo([express]), complemento([both, 'PLCγ1', and, 'PLCγ2'])].
[sujeto(['Although', 'PLCγ2']), verbo([has]), complemento([been, shown, to, play, a, dominant, role, in, platelet, 'activation,', the, extent, to, which, 'PLCγ1', contributes, has, not, been, evaluated])].
[sujeto(['To', ascertain, the, relative, contributions, of, 'PLCγ1', and, 'PLCγ2', to, platelet, 'activation,', we, generated, conditionally, 'PLCγ1-deficient,', 'wild-type', '(', 'WT),', 'PLCγ2-deficient,', and, 'PLCγ1/PLCγ2', 'double-deficient', mice, and, measured, the, ability, of, platelets, to]), verbo([respond]), complemento([to, different, agonists])].
[sujeto(['We']), verbo([found]), complemento([that, 'PLCγ2', deficiency, abrogated, 'αIIbβ3-dependent', platelet, 'spreading,', 'GPVI-dependent', platelet, 'aggregation,', and, thrombus, formation, on, 'collagen-coated', surfaces, under, shear, 'conditions,', which, is, dependent, on, both, 'GPVI', and, αIIbβ3])].
[sujeto(['Addition', of, exogenous, 'ADP', overcame, defective, spreading, of, 'PLCγ2-deficient', platelets, on, immobilized, 'fibrinogen,']), verbo([suggesting]), complemento([that, 'PLCγ2', is, required, for, granule, secretion, in, response, to, αIIbβ3, ligation])].
[sujeto(['Consistently,', 'αIIbβ3-mediated']), verbo([release]), complemento([of, granule, contents, was, impaired, in, the, absence, of, 'PLCγ2'])].
[sujeto(['In', 'contrast,', 'PLCγ1-deficient', platelets, spread, and]), verbo([released]), complemento([granule, contents, normally, on, 'fibrinogen,', exhibited, normal, levels, of, 'GPVI-dependent', 'aggregation,', and, formed, thrombi, normally, on, 'collagen-coated', surfaces])].
[sujeto(['We', conclude, that, platelet, activation, through, 'GPVI', and, αIIbβ3, utilizes, 'PLCγ2', because, 'PLCγ1', levels, are, insufficient, to, support, 'responsiveness,', but, that, 'PLCγ1', can, restore, responsiveness, if]), verbo([expressed]), complemento([at, levels, normally, achieved, by, 'PLCγ2'])].
[sujeto(['Diacylglycerol', '(', 'DAG)', is]), verbo([required]), complemento([for, membrane, traffic, and, structural, organization, at, the, 'Golgi'])].
[sujeto(['DAG', is, a, lipid, metabolite, of, several, enzymatic, reactions, present, at, this, 'organelle,', but, the, mechanisms, by, which, they, are]), verbo([regulated]), complemento([are, still, unknown])].
[sujeto(['Here,', we, show, that, cargo, arrival, at, the, 'Golgi']), verbo([increases]), complemento([the, recruitment, of, the, 'DAG-sensing', constructs, 'C1-PKCθ-GFP', and, the, 'PKD-wt-GFP'])].
[sujeto(['Under', basal, 'conditions,', 'PLCγ1', contributed, to, the, maintenance, of, the, pool, of, 'DAG']), verbo([associated]), complemento([with, the, 'Golgi', and, to, the, structural, organization, of, the, organelle])].
[sujeto(['The', surge, in, genetic, and, genomic, investigations, over, the, past, 5, years]), verbo([has]), complemento([resulted, in, many, discoveries, of, causative, variants, relevant, to, disease, pathophysiology])].
[sujeto(['Although', phospholipase, 'C', '(', 'PLC)', enzymes]), verbo([have]), complemento([long, been, recognized, as, important, components, in, intracellular, signal, 'transmission,', it, is, only, recently, that, this, approach, highlighted, their, role, in, disease, development, through, 'gain-of-function', mutations])].
[sujeto(['Methoxychlor,', an, organochlorine, insecticide, developed, to, replace, 'DDT', '(', 'dichlorodiphenyltrichloroethane),']), verbo([has]), complemento([been, reported, to, induce, mast, cell, degranulation, and, to, enhance, 'IgE-mediated', allergic, responses])].
[sujeto(['Phosphorylation', of, enzymes, related, to, signaling, events]), verbo([associated]), complemento([with, mast, cell, degranulation, was, analyzed, by, immunoblotting])].
[sujeto(['The', results, indicated, that, methoxychlor]), verbo([caused]), complemento([increased, mast, cell, degranulation, in, the, presence, of, 'antigen,', whereas, it, had, no, effect, on, calcium, 'ionophore-induced', degranulation, of, 'RBL-2H3', cells])].
[sujeto(['Immunoblot', analyses, demonstrated, that, the, phosphorylation, level, of, phosphoinositide, 3, -, kinase, '(', which, plays, a, central, role, in, mast, cell, 'signaling)', was]), verbo([increased]), complemento([by, methoxychlor, during, 'antigen-induced', degranulation])].
[sujeto(['In', 'addition,', methoxychlor]), verbo([activated]), complemento([the, signaling, pathway, via, the, 'high-affinity', 'IgE', receptor, by, inducing, phosphorylation, of, 'Syk', and, 'PLCγ1/2,', which, transfer, the, signal, for, degranulation, downstream])].
[sujeto(['Lastly,', oral, administration, of, methoxychlor, exhibited, a, tendency, to]), verbo([promote]), complemento([vascular, permeability, in, passive, cutaneous, anaphylaxis, model, mice])].
[sujeto(['Taken', 'together,', the, results, here]), verbo([suggested]), complemento([that, methoxychlor, enhanced, degranulation, through, 'FcεRI-mediated', signaling, and, promoted, allergenic, symptoms, involved, in, mast, cell, degranulation])].
[sujeto(['We', therefore, analyzed, a, collection, of, cases, for, genomic, aberrations, using, 'SNP', arrays, and]), verbo([targeted]), complemento(['next-generation', sequencing, '(', 'tNGS)', of, oncogenes, and, 'tumor-suppressor', genes])].
[sujeto(['Recurrent']), verbo([gains]), complemento([of, chromosome, 1, q, and, a, small, region, of, chromosome, 4, encompassing, 'KDR', and, 'KIT', were, identified, by, 'SNP', array, analysis])].
[sujeto(['Repeatedly', mutated, genes, identified, by, tNGS, were, 'KDR', with, different, nonsynonymous, 'mutations,', 'MLL2', with, different, nonsense, 'mutations,', and, 'PLCG1', with, a, recurrent, nonsynonymous, mutation, '(', 'R707Q)', in, the, highly]), verbo([conserved]), complemento([autoinhibitory, 'SH2', domain, in, three, of, 10, cases])].
[sujeto(['PLCγ1', is, usually]), verbo([activated]), complemento([by, 'Y783', phosphorylation, and, activates, protein, kinase, 'C', and, 'Ca(2+)-dependent', second, 'messengers,', with, effects, on, cellular, 'proliferation,', 'migration,', and, invasiveness])].
[sujeto(['Ectopic', expression, of, the, 'PLCγ1-R707Q', mutant, in, endothelial, cells, revealed, reduced, 'PLCγ1-Y783', phosphorylation, with, concomitant]), verbo([increased]), complemento(['c-RAF/MEK/ERK1/2', 'phosphorylation,', increased, 'IP3', 'amounts,', and, increased, 'Ca(2+)-dependent', calcineurin, activation, compared, with, ectopic, expressed, 'PLCγ1-wild-type'])].
[sujeto(['Furthermore,', 'cofilin,', whose, activation, is]), verbo([associated]), complemento([with, actin, skeleton, 'reorganization,', showed, decreased, 'phosphorylation,', and, thus, activation, after, expression, of, 'PLCγ1-R707Q', compared, with, 'PLCγ1-wild-type'])].
[sujeto(['At', the, cellular, 'level,', expression, of, 'PLCγ1-R707Q', in, endothelial, cells, had, no, influence, on, proliferation, 'rate,', but]), verbo([increased]), complemento([apoptosis, resistance, and, migration, and, invasiveness, in, in, vitro, assays])].
[sujeto(['Together,', these, findings, indicate, that, the, 'PLCγ1-R707Q', mutation]), verbo([causes]), complemento([constitutive, activation, of, 'PLCγ1', and, may, represent, an, alternative, way, of, activation, of, 'KDR/PLCγ1', signaling, besides, 'KDR', activation, in, 'angiosarcomas,', with, implications, for, 'VEGF/KDR', targeted, therapies])].
[sujeto(['Reactive', oxygen, 'species,', such, as, the, superoxide, 'anion,', 'H2O2,', and, the, hydroxyl, 'radical,']), verbo([have]), complemento([been, considered, as, cytotoxic, 'by-products', of, cellular, metabolism])].
[sujeto(['However,', recent, studies]), verbo([have]), complemento([provided, evidence, that, 'H2O2', serves, as, a, signaling, molecule, modulating, various, physiological, functions])].
[sujeto(['H2O2']), verbo([triggered]), complemento([the, generation, of, oscillations, of, intracellular, 'Ca2+', concentration, '(', '[', 'Ca2+]i)', in, a, 'concentration-dependent', manner, over, the, range, 10, -, 100, microM])].
[sujeto(['The', 'H2O2-induced', '[', 'Ca2+]i', oscillations, persisted, in, the, absence, of, extracellular, 'Ca2+', and, were]), verbo([prevented]), complemento([by, depletion, of, intracellular, 'Ca2+', stores, with, thapsigargin])].
[sujeto(['The', 'H2O2-induced', '[', 'Ca2+]i', oscillations, were, not]), verbo([inhibited]), complemento([by, pretreatment, with, ryanodine, but, were, prevented, by, 2, -, aminoethoxydiphenyl, borate, and, 'caffeine,', known, antagonists, of, inositol, 1, ',', 4, ',', 5, -, trisphosphate, receptors])].
[sujeto(['H2O2']), verbo([activated]), complemento([phospholipase, 'C', '(', 'PLC)', gamma1, in, a, 'dose-dependent', 'manner,', and, 'U73122,', an, inhibitor, of, 'PLC,', completely, abolished, the, 'H2O2-induced', '[', 'Ca2+]i', oscillations])].
[sujeto(['In', 'addition,', 'RNA', interference, against, 'PLCgamma1', and, the, expression, of, the, inositol, 1, ',', 4, ',', 5, -, 'trisphosphate-sequestering', &, 'quot;sponge&quot;']), verbo([prevented]), complemento([the, generation, of, '[', 'Ca2+]i', oscillations])].
[sujeto(['H2O2-induced', '[', 'Ca2+]i', oscillations, and, 'PLC1', phosphorylation, were]), verbo([inhibited]), complemento([by, pretreatment, with, 'dithiothreitol,', a, 'sulfhydryl-reducing', agent])].
[sujeto(['Finally,', epidermal, growth, factor]), verbo([induced]), complemento(['H2O2', 'production,', 'PLCgamma1', 'activation,', and, '[', 'Ca2+]i', 'increases,', which, were, attenuated, by, 'N-acetylcysteine', and, diphenyleneiodonium, and, by, the, overexpression, of, peroxiredoxin, type, 'II'])].
[sujeto(['Therefore,', we, conclude, that, low, concentrations, of, exogenously, applied, 'H2O2', generate, '[', 'Ca2+]i', oscillations, by]), verbo([activating]), complemento(['PLCgamma1', through, sulfhydryl, 'oxidation-dependent', mechanisms])].
[sujeto(['Upon', sperm]), verbo([binding]), complemento([to, the, oocyte, plasma, 'membrane,', a, 'sperm-associated', phospholipase, 'C', '(', 'PLC)', 'isoform,', 'PLC', zeta, '(', 'PLCζ),', is, released, into, the, oocyte, cytoplasm])].
[sujeto(['PLCζ', hydrolyzes, phosphatidylinositol, 4, ',', 5, -, bisphosphate, '(', 'PIP2)', to, produce, diacylglycerol, '(', 'DAG),', which]), verbo([activates]), complemento([protein, kinase, 'C', '(', 'PKC),', and, inositol, 1, ',', 4, ',', 5, -, trisphosphate, '(', 'IP3),', which, induces, the, release, of, 'Ca(2+)', from, endoplasmic, reticulum, '(', 'ER)', 'Ca(2+)', stores])].
[sujeto(['Ca(2+)', ionophores, such, as, ionomycin]), verbo([have]), complemento([been, successfully, used, to, induce, artificial, human, oocyte, 'activation,', facilitating, fertilization, during, 'intra-cytoplasmic', sperm, injection, '(', 'ICSI)', procedures])].
[sujeto(['Early', studies]), verbo([have]), complemento([also, demonstrated, that, the, 'PKC', activator, phorbol, 12, -, myristate, 13, -, acetate, '(', 'PMA)', acts, synergistically, with, 'Ca(2+)', ionophores, to, induce, parthenogenetic, activation, of, mouse, oocytes])].
[sujeto(['PMA', and, ionomycin, 'combined,', used, as, positive, controls, in, 'HIV-1', latency, reversal, 'studies,']), verbo([have]), complemento([been, shown, to, be, extremely, efficient, in, reactivating, latent, 'HIV-1', in, 'CD4(+)', memory, 'T', cells, by, inducing, 'T', cell, activation])].
[sujeto(['Similar', to, oocyte, 'activation,', 'T', cell, activation, by, 'PMA', and, ionomycin]), verbo([induces]), complemento([an, increase, in, intracellular, 'Ca(2+)', concentrations, and, activation, of, 'DAG,', 'PKC,', and, downstream, 'Ca(2+)-dependent', signaling, pathways, necessary, for, proviral, transcription])].
[sujeto(['Interestingly,', 'AMPK,', a, master, regulator, of, cell, metabolism, that, is]), verbo([activated]), complemento([thorough, the, induction, of, cellular, stress, '(', e])].
[sujeto([increase, in, 'Ca(2+)', 'concentration,', reactive, oxygen, species, 'generation,']), verbo([increase]), complemento([in, 'AMP/ATP', 'ratio)', is, essential, for, oocyte, 'maturation,', 'T', cell, 'activation,', and, mitochondrial, function])].
[sujeto(['In', addition, to, the, 'AMPK', kinase, 'LKB1,', 'CaMKK2,', a, 'Ca(2+)/calmodulin-dependent', kinase, that, also]), verbo([activates]), complemento(['AMPK,', is, present, in, and, activated, on, 'T', cell, activation, and, is, also, present, in, mouse, oocytes, and, persists, until, the, zygote, and, 'two-cell', stages])].
[sujeto(['We', further, propose, the, novel, observation, that, various, compounds, that]), verbo([have]), complemento([been, shown, to, reactivate, latent, 'HIV-1', '(', e])].
[sujeto([')', or]), verbo([activate]), complemento([oocytes, '(', 'PMA,', 'ionomycin,', 'ethanol,', 'puromycin,', etc])].
[sujeto(['Our', previous]), verbo([reports]), complemento([indicate, that, 'ligand-induced', αVβ3, integrin, and, 'Syndecan-4', engagement, increases, focal, adhesion, formation, and, migration, of, astrocytes])].
[sujeto(['Additionally,', ligated, integrins]), verbo([trigger]), complemento(['ATP', release, through, unknown, 'mechanisms,', activating, 'P2X7', receptors, '(', 'P2X7R),', and, the, uptake, of, 'Ca(2+)', to, promote, cell, adhesion])].
[sujeto(['However,', whether, the, activation, of, 'P2X7R', and, 'ATP']), verbo([release]), complemento([are, required, for, astrocyte, migration, and, whether, αVβ3, integrin, and, 'Syndecan-4', receptors, communicate, with, 'P2X7R', via, 'ATP', remains, unknown])].
[sujeto(['Here,', cells, were]), verbo([stimulated]), complemento([with, 'Thy-1,', a, reported, αVβ3, integrin, and, 'Syndecan-4', ligand])].
[sujeto(['Results', obtained, indicate, that, 'ATP', was]), verbo([released]), complemento([by, 'Thy-1', upon, integrin, engagement, and, required, the, participation, of, 'phosphatidylinositol-3-kinase', '(', 'PI3K),', 'phospholipase-C', gamma, '(', 'PLCγ)', and, inositol, trisphosphate, '(', 'IP3)', receptors, '(', 'IP3R)'])].
[sujeto(['IP3R', activation]), verbo([leads]), complemento([to, increased, intracellular, 'Ca(2+),', hemichannel, '(', 'Connexin-43', and, 'Pannexin-1)', 'opening,', and, 'ATP', release])].
[sujeto(['Finally,', 'Thy-1', lacking, the, 'integrin-binding', site, did, not]), verbo([stimulate]), complemento(['ATP', 'release,', whereas, 'Thy-1', mutated, in, the, 'Syndecan-4-binding', domain, increased, 'ATP', 'release,', albeit, to, a, lesser, extent, and, with, delayed, kinetics, compared, to, 'wild-type', 'Thy-1'])].
[sujeto(['Thus,', hemichannels]), verbo([activated]), complemento([downstream, of, an, αVβ3, 'integrin-PI3K-PLCγ-IP3R', pathway, are, responsible, for, 'Thy-1-induced,', 'hemichannel-mediated', and, 'Syndecan-4-modulated', 'ATP', release, that, transactivates, 'P2X7Rs', to, induce, 'Ca(2+)', entry])].
[sujeto(['These', findings, uncover, a, hitherto, unrecognized, role, for, hemichannels, in, the, regulation, of, astrocyte, migration, via, 'P2X7R', transactivation]), verbo([induced]), complemento([by, 'integrin-mediated', 'ATP', release])].
[sujeto(['We', investigated, whether, 'radiation-induced', nontargeted, effects, are]), verbo([involved]), complemento([in, the, cytotoxic, effects, of, anticell, surface, monoclonal, antibodies, labeled, with, 'Auger', electron, 'emitters,', such, as, iodine, 125, '(', monoclonal, antibodies, labeled, with, '(', 125, ')', 'I', '[', '(', 125, ')', 'I-mAbs])'])].
[sujeto(['We', showed, that, the, cytotoxicity, of, '(', 125, ')', 'I-mAbs']), verbo([targeting]), complemento([the, cell, membrane, of, 'p53(+/+)', 'HCT116', colon, cancer, cells, is, mainly, due, to, nontargeted, effects])].
[sujeto(['Targeted', and, nontargeted, cytotoxicities, were]), verbo([inhibited]), complemento([in, vitro, following, lipid, raft, disruption, with, 'Methyl-β-cyclodextrin', '(', 'MBCD)', or, filipin, or, use, of, radical, oxygen, species, scavengers])].
[sujeto(['(', 125, ')', 'I-mAb', efficacy, was]), verbo([associated]), complemento([with, acid, sphingomyelinase, activation, and, modulated, through, activation, of, the, 'AKT,', extracellular, 'signal-related', kinase, ½, '(', 'ERK1/2),', p38, 'kinase,', 'c-Jun', 'N-terminal', kinase, '(', 'JNK)', signaling, 'pathways,', and, also, of, phospholipase, 'C-γ', '(', 'PLC-γ),', 'proline-rich', tyrosine, kinase, 2, '(', 'PYK-2),', and, 'paxillin,', involved, in, 'Ca(2+)', fluxes])].
[sujeto(['Moreover,', the, nontargeted, response]), verbo([induced]), complemento([by, directing, 5, -, '[', '(', 125, ')', 'I]iodo-2\'-deoxyuridine', to, the, nucleus, was, comparable, to, that, of, '(', 125, ')', 'I-mAb', against, cell, surface, receptors])].
[sujeto(['In', 'vivo,', we]), verbo([found]), complemento([that, the, statistical, significance, of, tumor, growth, delay, induced, by, '(', 125, ')', 'I-mAb', was, removed, after, 'MBCD', treatment, and, observed, oxidative, 'DNA', damage, beyond, the, expected, 'Auger', electron, range])].
[sujeto(['These', results]), verbo([suggest]), complemento([the, involvement, of, nontargeted, effects, in, vivo, also])].
[sujeto(['Low-energy', 'Auger', 'electrons,', such, as, those, emitted, by, '(', 125, ')', 'I,']), verbo([have]), complemento([a, short, tissue, range, and, are, usually, targeted, to, the, nucleus, to, maximize, their, cytotoxicity])].
[sujeto(['In', this, 'study,', we, show, that]), verbo([targeting]), complemento([the, cancer, cell, surface, with, '(', 125, ')', 'I-mAbs', produces, a, lipid, 'raft-mediated', nontargeted, response, that, compensates, for, the, inferior, efficacy, of, 'non-nuclear', targeting])].
[sujeto(['Our', findings, describe, the, mechanisms]), verbo([involved]), complemento([in, the, efficacy, of, '(', 125, ')', 'I-mAbs', targeting, the, cancer, cell, surface])].
[sujeto(['Natural', killer, '(', 'NK)', cells, discriminate, between, healthy, cells, and, virally, infected, or, transformed, 'self-cells', by, tuning]), verbo([activating]), complemento([and, inhibitory, signals, received, through, cell, surface, receptors])].
[sujeto(['Inhibitory', receptors]), verbo([inhibit]), complemento(['NK', cell, function, by, recruiting, and, activating, the, tyrosine, phosphatase, 'Src', homology, 2, '(', 'SH2)', 'domain-containing', protein, tyrosine, 'phosphatase-1', '(', 'SHP-1)', to, the, plasma, membrane])].
[sujeto(['We']), verbo([reveal]), complemento([that, the, adaptor, protein, linker, for, activation, of, 'T', cells, '(', 'LAT)', as, well, as, phospholipase, 'C-γ1', '(', 'PLC-γ1)', and, 'PLC-γ2', are, 'SHP-1', substrates])].
[sujeto(['Dephosphorylation', of, 'Tyr(132)', in, 'LAT', by, 'SHP-1', in, 'NK', cells, abrogated, the, recruitment, of, 'PLC-γ1', and, 'PLC-γ2', to, the, immunological, synapse, between, the, 'NK', cell, and, a, cancer, cell, 'target,', which, reduced, 'NK', cell, degranulation, and]), verbo([target]), complemento([cell, killing])].
[sujeto(['Furthermore,', the, ubiquitylation, of, 'LAT', by, the, 'E3', ubiquitin, ligases, 'c-Cbl', and, 'Cbl-b,', which, was]), verbo([induced]), complemento([by, 'LAT', 'phosphorylation,', led, to, the, degradation, of, 'LAT', in, response, to, the, engagement, of, inhibitory, receptors, on, 'NK', 'cells,', which, abrogated, 'NK', cell, cytotoxicity])].
[sujeto(['Knockdown', of, the, 'Cbl', proteins, blocked, 'LAT', 'ubiquitylation,', which]), verbo([promoted]), complemento(['NK', cell, function])].
[sujeto(['Natural', killer, '(', 'NK)', cells, are, innate, lymphoid, cells, that]), verbo([have]), complemento([adopted, activating, and, inhibitory, signaling, mechanisms, enabling, them, to, be, tolerant, of, normal, cells, but, to, distinguish, and, eliminate, tumor, cells, and, 'virus-infected', cells])].
[sujeto(['In', this, issue, of, 'Science', 'Signaling,', 'Matalon', et, al, show, how, inhibitory, receptors, disrupt, 'NK', cell, activation, by]), verbo([stimulating]), complemento([dephosphorylation, of, the, adaptor, protein, 'LAT', '(', linker, of, activated, 'T', 'cells)', and, phospholipase, 'C-γ', by, the, phosphatase, 'SHP-1', '[', 'Src', homology, 2, '(', 'SH2)', 'domain-containing', protein, tyrosine, phosphatase, 1, ']', ',', as, well, as, ubiquitylation, of, 'LAT', by, 'Cbl', family, 'E3', ubiquitin, ligases])].
[sujeto(['Porcine', circovirus, type, 2, '(', 'PCV2)']), verbo([induces]), complemento([autophagy, via, the, 5, '\'', adenosine, 'monophosphate-activated', protein, kinase, '(', 'AMPK)/extracellular', 'signal-regulated', kinase, '(', 'ERK)/tuberous', sclerosis, complex, 2, '(', 'TSC2)/mammalian', target, of, rapamycin, '(', 'mTOR)', pathway, in, pig, kidney, 'PK-15', cells])].
[sujeto(['With', specific, inhibitors, and, 'RNA', interference, '(', 'RNAi),', we, show, that, 'PCV2', infection, upregulated, 'calcium/calmodulin-dependent', protein, kinase, 'kinase-beta', '(', 'CaMKKβ)', by]), verbo([increasing]), complemento([cytosolic, 'Ca(2+)', via, inositol, 1, ',', 4, ',', 5, -, trisphosphate, receptor, '(', 'IP3R)'])].
[sujeto(['Elevation', of, cytosolic, calcium, ion, '(', 'Ca(2+))', did, not, seem, to]), verbo([involve]), complemento([inositol, 1, ',', 4, ',', 5, -, trisphosphate, '(', 'IP3)', release, from, phosphatidylinositol, 4, ',', 5, -, bisphosphate, '(', 'PIP2)', by, phosphoinositide, phospholipase, 'C-gamma', '(', 'PLC-γ)'])].
[sujeto(['CaMKKβ', then]), verbo([activated]), complemento([both, 'AMPK', and, 'calcium/calmodulin-dependent', protein, kinase, 'I', '(', 'CaMKI)'])].
[sujeto(['Further', research, is, warranted, to, study, if, 'PCV2']), verbo([interacts]), complemento([directly, with, 'IP3R', or, indirectly, with, the, molecules, that, antagonize, 'IP3R', activity, responsible, for, increased, cytosolic, 'Ca(2+)', both, in, 'PK-15', cells, and, 'PCV2-targeted', primary, cells, from, pigs])].
[sujeto(['It']), verbo([has]), complemento([been, proven, that, carbon, nanoparticles, or, diesel, exhaust, particles, stimulate, platelet, activation])].
[sujeto([5, significantly]), verbo([inhibited]), complemento([rather, than, potentiated, 'collagen-induced', platelet, aggregation, and, 'P-selectin', 'expression,', whereas, it, had, no, significant, effect, on, 'ADP-induced', platelet, aggregation, and, 'P-selectin', expression])].
[sujeto([5]), verbo([inhibited]), complemento([platelet, adhesion, on, immobilized, 'collagen-coated', 'surfaces;', 'however,', it, almost, did, not, impact, the, platelet, spreading])].
[sujeto(['Whether', the, transcription, factors, 'Etv4', and, 'Etv5', are]), verbo([involved]), complemento([in, these, 'BDNF-induced', effects, remains, unclear])].
[sujeto(['BDNF']), verbo([promoted]), complemento([the, mRNA, and, protein, expression, of, 'Etv4', and, 'Etv5', in, 'DRG', neurons])].
[sujeto(['Etv4', siRNA, and, 'Etv5', siRNA, effectively, blocked, the, 'VGLUT3', expression, and, neurite, elongation]), verbo([induced]), complemento([by, 'BNDF'])].
[sujeto(['The', overexpression, of, 'Etv4', or, 'Etv5', potentiated, the, effects, of, 'BNDF-induced', neurite, elongation, and, 'growth-associated', protein, 43, '(', 'GAP-43),', medium, neurofilament, '(', 'NF-M),', and, light, neurofilament, '(', 'NF-L)', expression, while, these, effects, could, be]), verbo([inhibited]), complemento([by, 'Etv4', and, 'Etv5', siRNA])].
[sujeto(['These', data, imply, that, 'Etv4', and, 'Etv5', are, essential, transcription, factors, in]), verbo([modulating]), complemento(['BDNF/TrkB', 'signaling-mediated', 'VGLUT3', expression, and, neurite, outgrowth])].
[sujeto(['BDNF,', through, the, 'ERK1/2', signaling, 'pathway,']), verbo([activates]), complemento(['Etv4', and, 'Etv5', to, initiate, 'GAP-43', 'expression,', promote, neurofilament, '(', 'NF)', protein, 'expression,', induce, neurite, 'outgrowth,', and, mediate, 'VGLUT3', expression, for, neuronal, function, improvement])].
[sujeto(['Studies']), verbo([suggest]), complemento([that, 'Gentiana', lutea, '(', 'GL),', and, its, component, 'isovitexin,', may, exhibit, 'anti-atherosclerotic', properties])].
[sujeto(['Both', the, extract, and, isovitexin, blocked, 'TNF-α']), verbo([induced]), complemento([expression, of, 'ICAM-1', and, 'VCAM-1', in, 'HUVECs'])].
[sujeto(['PDGF-BB']), verbo([induced]), complemento([migration, of, 'RASMCs', and, phospholipase, 'C-γ', 'activation,', were, also, abrogated, by, 'GL', extract, and, isovitexin])].
[sujeto(['Fura-2', based, ratiometric, measurements, demonstrated, 'that,', both, the, 'extact,', and, 'isovitexin,']), verbo([inhibit]), complemento(['PDGF-BB', mediated, intracellular, calcium, rise, in, 'RASMCs'])].
[sujeto(['Supplementation', of]), verbo([regular]), complemento([diet, with, 2, '%', 'GL', root, powder, for, 'STZ', 'rats,', reduced, total, cholesterol, in, blood])].
[sujeto(['Oil', 'Red', 'O', staining, demonstrated]), verbo([decreased]), complemento([lipid, accumulation, in, aortic, wall, of, diabetic, animals, upon, treatment, with, 'GL'])].
[sujeto(['Protection', of, the, gastric, mucosa, from, acute, lesions]), verbo([induced]), complemento([by, various, irritants, is, a, pertinent, issue, in, the, field, of, critical, care, medicine])].
[sujeto(['As', a, means, to]), verbo([induce]), complemento([gastric, 'lesions,', 'Groups', 2, -, 6, were, subjected, to, water, immersion, and, restraint, stress, for, 12, hours, after, treatment])].
[sujeto(['Our', present, studies, show, that, compared, to, rats, in, group, 2, ',', treatment, with, 1, to, 50, 'mg/kg', astragaloside, 'IV', significantly]), verbo([decreased]), complemento([the, size, of, gastric, 'lesions,', 'MDA,', 'TNFα', and, 'MCP1', 'levels,', in, addition, to, normalizing, gastric, 'pH,', gastric, mucus, and, 'SOD', levels, '(', 'P&lt;0'])].
[sujeto(['The', acute, gastric, lesions]), verbo([induced]), complemento([are, attenuated, by, pretreatment, with, astragaloside, 'IV', which, is, possibly, due, to, the, enhancing, of, the, expression, of, 'HSP70', with, concomitant, 'antioxidant,', 'anti-inflammatory', and, 'anti-apoptotic', capacity])].
[sujeto(['Phospholipase', 'C', 'gamma-2', '(', 'PLCγ2)-dependent', calcium, '(', 'Ca(2+))', oscillations, are, indispensable, for]), verbo([nuclear]), complemento([factor, of, activated, 'T-cells,', cytoplasmic, 1, '(', 'NFATc1)', activation, and, downstream, gene, transcription, driving, osteoclastogenesis, during, skeletal, remodeling, and, pathological, bone, loss])].
[sujeto(['Here', we, 'describe,', to, our, 'knowledge,', the, first, known, function, of, transmembrane, protein, 178, '(', 'Tmem178),', a, 'PLCγ2', downstream]), verbo([target]), complemento(['gene,', as, a, critical, modulator, of, the, 'NFATc1', axis])].
[sujeto(['In', surprising, contrast, to, the, osteopetrotic, phenotype, of, 'PLCγ2(-/-)', 'mice,', 'Tmem178(-/-)', mice, are, osteopenic, in, basal, conditions, and, are, more, susceptible, to, inflammatory, bone, 'loss,', owing, to]), verbo([enhanced]), complemento([osteoclast, formation])].
[sujeto(['Mechanistically,', 'Tmem178', localizes, to, the, 'ER', membrane, and]), verbo([regulates]), complemento(['RANKL-induced', 'Ca(2+)', 'fluxes,', thus, controlling, 'NFATc1', induction])].
[sujeto(['In', 'sum,', these, findings, identify, an, essential, role, for, 'Tmem178', to]), verbo([maintain]), complemento([skeletal, mass, and, limit, pathological, bone, loss])].
[sujeto(['T', cell, '(', or, 'transmembrane)', immunoglobulin, and, mucin, domain, protein, 3, '(', 'Tim-3)']), verbo([has]), complemento([attracted, significant, attention, as, a, novel, immune, checkpoint, receptor, '(', 'ICR)', on, chronically, 'stimulated,', often, 'dysfunctional,', 'T', cells])].
[sujeto(['Antibodies', to, 'Tim-3', can]), verbo([enhance]), complemento([antiviral, and, antitumor, immune, responses])].
[sujeto(['Tim-3', is, also, constitutively]), verbo([expressed]), complemento([by, mast, 'cells,', 'NK', cells, and, specific, subsets, of, macrophages, and, dendritic, cells])].
[sujeto(['At', this, 'point,', little, is, known, about, the, molecular, mechanisms, by, which, 'Tim-3']), verbo([regulates]), complemento([the, function, of, 'T', cells, or, other, cell, types])].
[sujeto(['We']), verbo([have]), complemento([focused, on, defining, the, effects, of, 'Tim-3', ligation, on, mast, cell, 'activation,', as, these, cells, constitutively, express, 'Tim-3', and, are, activated, through, an, 'ITAM-containing', receptor, for, 'IgE', '(', 'FcεRI),', using, signaling, pathways, analogous, to, those, in, 'T', cells])].
[sujeto(['Using', a, variety, of, 'gain-', and, 'loss-of-function', 'approaches,', we]), verbo([find]), complemento([that, 'Tim-3', acts, at, a, 'receptor-proximal', point, to, enhance, 'Lyn', 'kinase-dependent', signaling, pathways, that, modulate, both, 'immediate-phase', degranulation, and, 'late-phase', cytokine, production, downstream, of, 'FcεRI', ligation])].
[sujeto(['Acquired', aplastic, anemia, is, an, 'immune-mediated', 'disease,', in, which, 'T', cells]), verbo([target]), complemento([hematopoietic, 'cells;', at, 'presentation,', the, bone, marrow, is, replaced, by, fat])].
[sujeto(['It', was]), verbo([reported]), complemento([that, bone, marrow, adipocytes, were, negative, regulators, of, hematopoietic, microenvironment])].
[sujeto(['While', 'bisphenol-A-diglycidyl-ether']), verbo([inhibited]), complemento([adipogenesis, as, 'expected,', it, also, suppressed, 'T', cell, infiltration, of, bone, 'marrow,', reduced, plasma, inflammatory, 'cytokines,', decreased, expression, of, multiple, inflammasome, 'genes,', and, ameliorated, marrow, failure])].
[sujeto(['In', 'vitro,', 'bisphenol-A-diglycidyl-ether']), verbo([suppressed]), complemento([activation, and, 'proliferation,', and, reduced, phospholipase, 'C', gamma, 1, and, nuclear, factor, of, activated, 'T-cells', 1, 'expression,', as, well, as, inhibiting, calcium, flux, in, 'T', cells])].
[sujeto(['Genetically', &, 'quot;fatless&quot;', mice, developed, bone, marrow, failure, with, accumulation, of, marrow, adipocytes, in, our, 'model,', even, in, the, absence, of, body, 'fat,']), verbo([suggesting]), complemento([different, mechanisms, of, systematic, and, marrow, adipogenesis, and, physiologic, versus, pathophysiologic, fat, accumulation])].
[sujeto(['Ras', 'GTPases', are]), verbo([activated]), complemento([by, 'RasGEFs', and, inactivated, by, 'RasGAPs,', which, stimulate, the, hydrolysis, of, 'RasGTP', to, inactive, 'RasGDP'])].
[sujeto(['Here,', we, demonstrate, that, 'IL-2/7/9', stimulation]), verbo([activates]), complemento(['Erk', and, 'Akt', pathways, downstream, of, 'Ras', in, 'RasGRP1', 'T-ALL', but, not, in, normal, thymocytes])].
[sujeto(['In', normal, 'lymphocytes,', 'RasGRP1', is]), verbo([recruited]), complemento([to, the, membrane, by, diacylglycerol, '(', 'DAG)', in, a, phospholipase, 'C-γ', '(', 'PLCγ)-dependent', manner])].
[sujeto(['Surprisingly,', we]), verbo([find]), complemento([that, leukemic, 'RasGRP1-triggered', 'Ras-Akt', signals, do, not, depend, on, acute, activation, of, 'PLCγ', to, generate, 'DAG', but, rely, on, baseline, 'DAG', levels, instead])].
[sujeto(['Thus,', we]), verbo([reveal]), complemento([an, entirely, novel, type, of, leukemogenic, 'Ras', signals, that, is, based, on, a, 'RasGRP1-driven', increased, in, flux, through, the, 'RasGTP/GDP', 'cycle,', which, is, mechanistically, very, different, from, 'KRAS(G12D)', signals])].
[sujeto(['Our', studies, highlight, the, dynamic, balance, between, 'RasGEF', and, 'RasGAP', in, these, 'T-ALLs', and, put, forth, a, new, model, in, which, 'IL-2/7/9']), verbo([decrease]), complemento(['RasGAP', activity])].
[sujeto(['In', 'T', 'cells,', protein, phosphorylation, is, the, key, mechanism]), verbo([regulating]), complemento(['T', cell, 'receptor-driven', signaling, pathways])].
[sujeto(['In', order, to]), verbo([gain]), complemento([insights, into, the, phosphoproteome, evolution, of, 'T', cell, 'activation,', we, performed, a, 'large-scale', quantitative, phosphoproteomics, study, of, 'Jurkat', 'E6'])].
[sujeto(['A', significantly, lower, number, of, proteins, containing]), verbo([regulated]), complemento([phosphorylation, sites, were, identified, in, 'Jurkat', gamma1, in, comparison, to, 'Jurkat', 'E6'])].
[sujeto(['Our', data, may, contribute, to, the, current, human, 'T', cell, phosphoproteome, and]), verbo([provide]), complemento([a, better, understanding, on, 'T', cell, receptor, signaling])].
[sujeto(['Although', the, signaling, events]), verbo([leading]), complemento([to, the, former, are, well, 'studied,', those, driving, 'Ca(2+)', waves, remain, uncertain])].
[sujeto(['GRGDSP,', a, peptide, that, preferentially, blocks, αvβ3, 'integrin,', attenuated, myogenic, 'tone,', indicating, the, modest, role, for, sarcoplasmic, reticulum, 'Ca(2+)']), verbo([release]), complemento([in, myogenic, tone, generation])].
[sujeto(['Subsequent', experiments, revealed, that, elevated, pressure]), verbo([enhanced]), complemento([phospholipase, 'Cγ1', phosphorylation, in, an, 'RGD-dependent', manner, and, that, phospholipase, 'C', inhibition, attenuated, 'Ca(2+)', wave, generation])].
[sujeto(['Our', investigation]), verbo([reveals]), complemento([a, hitherto, unknown, role, for, αvβ3, integrin, as, a, cerebral, arterial, pressure, sensor])].
[sujeto(['The', membrane, receptor, facilitates, 'Ca(2+)', wave, generation, through, a, signaling, 'cascade,']), verbo([involving]), complemento([phospholipase, 'Cγ1,', inositol, 1, ',', 3, ',', 4, triphosphate, 'production,', and, inositol, 1, ',', 4, ',', 5, -, triphosphate, receptor, activation])].
[sujeto(['We']), verbo([reported]), complemento([previously, that, 'panaxydol,', a, component, of, 'Panax', ginseng, 'roots,', induced, 'mitochondria-mediated', apoptosis, preferentially, in, transformed, cells])].
[sujeto(['This', study, demonstrates, that, 'EGFR', activation, and, the, resulting, 'ER', stress]), verbo([mediate]), complemento(['panaxydol-induced', 'apoptosis,', and, that, panaxydol, suppresses, in, vivo, tumor, growth, in, syngeneic, and, xenogeneic, mouse, tumor, models])].
[sujeto(['In', 'addition,', we, elucidated, that, 'CaMKII', and, 'TGF-β-activated', kinase, '(', 'TAK1)']), verbo([participate]), complemento([in, 'p38/JNK', activation, by, elevated, cytoplasmic, 'Ca(2+)', concentration, '(', '[', 'Ca(2+)]c)'])].
[sujeto(['In', 'MCF-7', 'cells,', 'EGFR', was]), verbo([activated]), complemento([immediately, after, exposure, to, 'panaxydol,', and, this, activation, was, necessary, for, induction, of, 'apoptosis,', suggesting, that, panaxydol, might, be, a, promising, anticancer, 'candidate,', especially, for, 'EGFR-addicted', cancer])].
[sujeto(['Activation', of, 'PLCγ', followed, 'EGFR', 'activation,', resulting, in, 'Ca(2+)']), verbo([release]), complemento([from, the, endoplasmic, reticulum, '(', 'ER)', via, inositol, triphosphate, and, ryanodine, receptors])].
[sujeto(['ER', 'Ca(2+)']), verbo([release]), complemento([triggered, mitochondrial, 'Ca(2+)', uptake, indirectly, through, oxidative, stress, and, ensuing, 'ER', stress])].
[sujeto(['Elevated', '[', 'Ca(2+)]c']), verbo([triggered]), complemento([sequential, activation, of, 'calmodulin/CaMKII,', 'TAK1', and, 'p38/JNK'])].
[sujeto(['As', shown, 'previously,', p38, and, 'JNK']), verbo([activate]), complemento(['NADPH', oxidase])].
[sujeto(['Here,', it, was, shown, that, the, resulting, oxidative, stress]), verbo([triggered]), complemento(['ER', stress])].
[sujeto(['Among', the, three, signaling, branches, of, the, unfolded, protein, 'response,', protein, kinase, 'R-like', 'ER', kinase, '(', 'PERK),', but, not, 'inositol-requiring', enzyme, 1, or]), verbo([activating]), complemento([transcription, factor, 6, ',', played, a, role, in, transmitting, the, apoptosis, signal])].
[sujeto(['PERK']), verbo([induced]), complemento(['C/EBP', homologous, protein, '(', 'CHOP),', and, 'CHOP', elevated, 'Bim', 'expression,', initiating, mitochondrial, 'Ca(2+)', uptake, and, apoptosis])].
[sujeto(['The', 'TRAIL-receptor/TRAIL', system, originally, described, to]), verbo([induce]), complemento([apoptosis, preferentially, in, malignant, cells, is, also, known, to, be, involved, in, 'T', cell, homeostasis, and, the, response, to, viral, infections, and, autoimmune, diseases])].
[sujeto(['Whereas', the, expression, of, 'TRAIL', on]), verbo([activated]), complemento(['NK', and, 'T', cells, increases, their, 'cytotoxicity,', induction, of, 'TRAIL', on, 'APCs', can, turn, them, into, apoptosis, inducers, but, might, also, change, their, immunostimulatory, capacity])].
[sujeto(['Therefore,', we, analyzed, how, 'TRAIL-receptor', '(', 'TRAIL-R)', costimulation, is]), verbo([modulating]), complemento(['TCR-mediated', activation, of, human, 'T', cells])].
[sujeto(['T', cells]), verbo([triggered]), complemento([by, rTRAIL, in, combination, with, 'anti-CD3', and, -, 'CD28', 'Abs', exhibited, a, strong, decrease, in, the, expression, of, activation, markers, and, 'Th1', and, 'Th2', cytokines, compared, with, 'CD3/CD28-activated', 'T', cells])].
[sujeto(['Addition', of, exogenous, 'IL-2', could, not, rescue, 'T', cells, silenced, by, 'TRAIL-R', 'costimulation,', and, 'TRAIL-mediated', inhibition, of, 'T', cell, proliferation, only]), verbo([prevented]), complemento(['TCR-triggered', proliferation, but, was, ineffective, if, 'T', cells, were, activated, downstream, of, the, 'TCR'])].
[sujeto(['Inhibition', of, 'T', cell, proliferation, was]), verbo([associated]), complemento([with, abrogation, of, proximal, 'TCR', signaling, by, inhibiting, recruitment, of, 'TCR-associated', signaling, molecules, to, lipid, 'rafts,', followed, by, abrogation, of, protein, tyrosine, phosphorylation, of, 'ZAP70,', phospholipase, 'C-γ1,', and, protein, kinase, 'C-θ,', and, impaired, nuclear, translocation, of, 'NFAT,', 'AP-1,', and, 'NF-κB'])].
[sujeto(['Most', 'importantly,', 'TRAIL-R', costimulation, efficiently]), verbo([inhibited]), complemento(['alloantigen-induced', 'T', cell, proliferation, and, 'CD3/28-induced', activation, and, proliferation, of, autoreactive, 'T', cells, derived, from, patients, with, 'Omenn', 'syndrome,', indicating, that, coactivation, of, 'TRAIL-R', and, 'TCR', represents, a, mechanism, to, downmodulate, 'T', cell, immune, responses])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'PLCG1', expression, could, be, used, as, a, prognostic, biomarker, for, patients, with, advanced, 'OSCC;', 'however,', it, was, not, an, adequate, predictive, biomarker, for, 'TPF', induction, chemotherapy])].
[sujeto(['An']), verbo([increase]), complemento([in, pressure, within, the, artery, lumen, causes, the, vessel, to, constrict, through, depolarization, and, contraction, of, the, encircling, smooth, muscle, cells])].
[sujeto(['This', 'pressure-sensing', mechanism]), verbo([involves]), complemento([activation, of, two, types, of, transient, receptor, potential, '(', 'TRP)', 'channels:', 'TRPC6', and, 'TRPM4'])].
[sujeto(['We']), verbo([provide]), complemento([evidence, that, the, activation, of, the, γ1, isoform, of, phospholipase, 'C', '(', 'PLCγ1)', is, critical, for, pressure, sensing, in, cerebral, arteries])].
[sujeto(['Inositol', 1, ',', 4, ',', 5, -, trisphosphate, '(', 'IP3),', generated, by, 'PLCγ1', in, response, to, 'pressure,', sensitized, 'IP3', receptors, '(', 'IP3Rs)', to, 'Ca(2+)', influx]), verbo([mediated]), complemento([by, the, mechanosensitive, 'TRPC6', 'channel,', synergistically, increasing, 'IP3R-mediated', 'Ca(2+)', release, to, activate, 'TRPM4', 'currents,', leading, to, smooth, muscle, depolarization, and, constriction, of, isolated, cerebral, arteries])].
[sujeto(['Proximity', ligation, assays, demonstrated, colocalization, of, 'PLCγ1', and, 'TRPC6', with, 'TRPM4,']), verbo([suggesting]), complemento([the, presence, of, a, 'force-sensitive,', local, signaling, network, comprising, 'PLCγ1,', 'TRPC6,', 'TRPM4,', and, 'IP3Rs'])].
[sujeto(['Src', tyrosine, kinase, activity, was, necessary, for, 'stretch-induced', 'TRPM4', activation, and, myogenic, 'constriction,', consistent, with, the, ability, of, 'Src', to]), verbo([activate]), complemento(['PLCγ', isoforms])].
[sujeto(['We', conclude, that, contraction, of, cerebral, artery, smooth, muscle, cells]), verbo([requires]), complemento([the, integration, of, 'pressure-sensing', signaling, pathways, and, their, convergence, on, 'IP3Rs,', which, mediate, localized, 'Ca(2+)-dependent', depolarization, through, the, activation, of, 'TRPM4'])].
[sujeto(['The']), verbo([nuclear]), complemento(['factor-κB', '(', 'NF-κB)', transcription, factor, family, plays, an, important, role, in, many, immune, and, inflammatory, 'responses,', including, the, response, to, cancer])].
[sujeto(['These', associations, highlight, the, potential, importance, of, genes]), verbo([associated]), complemento([with, host, inflammation, and, immunity, in, modulating, clinical, outcomes, in, distinct, 'EOC', histologies])].
[sujeto(['In', addition, to, the, classical]), verbo([nuclear]), complemento([receptor, 'pathway,', there, is, a, nongenomic, pathway, in, the, cell, membrane, that, regulates, gene, expression, in, animal, steroid, hormone, 'signaling;', 'however,', this, mechanism, is, unclear])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, the, insect, steroid, hormone, 20, -, hydroxyecdysone, '(', '20E)', regulates, calcium, influx, via, phospholipase, 'Cγ1', '(', 'PLCG1)', to, modulate, the, protein, kinase, 'C', phosphorylation, of, the, transcription, factor, ultraspiracle, '(', 'USP1)', in, the, lepidopteran, insect, 'Helicoverpa', armigera])].
[sujeto(['The', 'PLCG1', mRNA, levels, are]), verbo([increased]), complemento([during, the, molting, and, metamorphic, stages])].
[sujeto(['The', depletion, of, 'PLCG1', by, 'RNA', interference, can, block, '20E-enhanced', 'pupation,']), verbo([cause]), complemento([larvae, death, and, pupation, 'defects,', and, repress, '20E-induced', gene, expression])].
[sujeto(['20E', may]), verbo([induce]), complemento([the, tyrosine, phosphorylation, of, 'PLCG1', at, the, cytosolic, tyrosine, kinase, '(', 'Src)', homology, 2, domains, and, then, determine, the, migration, of, 'PLCG1', toward, the, plasma, membrane])].
[sujeto(['PLCG1']), verbo([participates]), complemento([in, the, '20E-induced', 'Ca(2+)', influx])].
[sujeto(['The', inhibition, of, 'GPCR,', 'PLC,', inositol, 1, ',', 4, ',', 5, -, trisphosphate, 'receptor,', and, calcium, channels]), verbo([represses]), complemento([the, '20E-induced', 'Ca(2+)', influx])].
[sujeto(['Through', calcium, 'signaling,', 'PLCG1']), verbo([mediates]), complemento([the, transcriptional, activation, driven, by, the, 'ecdysone-response', element])].
[sujeto(['Through', 'PLCG1', and, calcium, 'signaling,', '20E']), verbo([regulates]), complemento(['PKC', phosphorylation, of, 'USP1', at, 'Ser-21', to, determine, its, 'ecdysone-response', element, binding, activity])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, '20E', activates, 'PLCG1', via, the, 'ErGPCR', and, 'Src', family, kinases, to, regulate, 'Ca(2+)', influx, and, 'PKC', phosphorylation, of, 'USP1', to, subsequently, modulate, gene, transcription, for, metamorphosis])].
[sujeto(['Previous', work]), verbo([has]), complemento([identified, aberrant, 'angiogenesis,', including, occasional, somatic, mutations, in, angiogenesis, signaling, 'genes,', as, a, key, driver, of, angiosarcoma])].
[sujeto(['Here', we, employed, 'whole-genome,', 'whole-exome', and]), verbo([targeted]), complemento([sequencing, to, study, the, somatic, changes, underpinning, primary, and, secondary, angiosarcoma])].
[sujeto(['PLCG1,', a, signal, transducer, of, tyrosine, 'kinases,', encoded, a, 'recurrent,', likely]), verbo([activating]), complemento([p])].
[sujeto(['Our', findings, inform, and, reinforce, current, therapeutic, efforts, to]), verbo([target]), complemento([angiogenesis, signaling, in, angiosarcoma])].
[sujeto(['In', nonstimulated, 'cells,', the, 'SH3', domain, '(', and, not, the, 'SH2', 'domains)', of, 'Plcγ1', directly, competes, for, a]), verbo([binding]), complemento([site, at, the, very, 'C', terminus, of, 'FGFR2', with, the, 'C-terminal', 'SH3', domain, of, 'Grb2'])].
[sujeto(['This', results, in, elevated, phosphatidylinositol, 4, ',', 5, -, bisphosphate, turnover, and, intracellular, calcium, 'levels,', thus]), verbo([leading]), complemento([to, increased, cell, motility, and, promotion, of, 'cell-invasive', behavior, in, the, absence, of, extracellular, receptor, stimulation])].
[sujeto(['Therefore,', metastatic, outcome, can, be, dictated, by, the, constitutive, competition, between, 'Grb2', and, 'Plcγ1', for, the, 'phosphorylation-independent']), verbo([binding]), complemento([site, on, 'FGFR2'])].
[sujeto(['Tumor', cells]), verbo([express]), complemento([vascular, endothelial, growth, factor, '(', 'VEGF),', which, induces, angiogenesis])].
[sujeto(['VEGF', also]), verbo([activates]), complemento(['VEGF', receptors, '(', 'VEGFRs)', on, or, within, tumor, cells, to, promote, their, proliferation, in, an, autocrine, fashion])].
[sujeto(['We', studied, the, effects, of]), verbo([inhibiting]), complemento([factors, in, this, pathway, on, levels, of, phosphorylated, phospholipase, 'Cγ1', '(', 'PLCG1),', protein, kinase, 'C,', and, extracellular, 'signal-regulated', kinases, '(', 'ERK)1/2'])].
[sujeto(['We', performed, immunohistochemical, analysis, of]), verbo([phosphorylated]), complemento(['VEGFR2', on, esophageal, adenocarcinoma, tissues])].
[sujeto(['Neoplastic', and, 'non-neoplastic', 'Barrett\'s', cells]), verbo([expressed]), complemento(['VEGF', and, 'VEGFR2', messenger, 'RNA', and, 'protein,', with, higher, levels, in, neoplastic, cells])].
[sujeto(['Incubation', with, recombinant, human, 'VEGF', significantly]), verbo([increased]), complemento([secretion, of, 'VEGF', protein, and, cell, 'number;', knockdown, of, 'PLCG1', markedly, reduced, the, recombinant, human, 'VEGF-stimulated', increase, in, levels, of, phosphorylated, 'PLCG1', and, phosphorylated, 'ERK1/2', in, neoplastic, cells])].
[sujeto(['Esophageal', adenocarcinoma, tissues, showed, immunostaining, for]), verbo([phosphorylated]), complemento(['VEGFR2'])].
[sujeto(['Sunitinib']), verbo([inhibited]), complemento(['VEGF', signaling, in, neoplastic, cells, and, reduced, weight, and, volume, of, xenograft, tumors, in, mice])].
[sujeto(['Neoplastic', and, 'non-neoplastic', 'Barrett\'s', epithelial, cells]), verbo([have]), complemento([autocrine, 'VEGF', signaling])].
[sujeto(['In', neoplastic, 'Barrett\'s', 'cells,', 'VEGF', activation, of, 'VEGFR2', initiates, a, 'PLCG1-protein', kinase, 'C-ERK', pathway, that]), verbo([promotes]), complemento([proliferation, and, is, 'self-sustaining', '(', by, causing, more, 'VEGF', 'production)'])].
[sujeto(['Strategies', to, reduce, autocrine, 'VEGF', signaling, '(', 'eg,', with, 'sunitinib)', might, be, used, to]), verbo([prevent]), complemento([or, treat, cancer, in, patients, with, 'Barrett\'s', esophagus])].
[sujeto(['miR-218,', a, miRNA, 'down-regulated', in, several, kinds, of, cancers, and]), verbo([associated]), complemento([with, multiple, cancer, 'phenotypes,', is, transcribed, from, 2, loci, located, on, chromosomes, 4, p15])].
[sujeto(['We']), verbo([found]), complemento([that, 'miR-218-2', and, its, host, gene, 'SLIT3', were, 'down-regulated', concomitantly, in, thyroid, cancer])].
[sujeto(['Moreover,', the, effects, of, 'miR-218-2', on, thyroid, cancer, cells, were, 'due,', at, least, 'partially,', to]), verbo([targeting]), complemento(['PDGFRA', and, 'PLCG1'])].
[sujeto(['TXNIP', knockdown]), verbo([inhibited]), complemento(['VEGF-induced', endothelial, cell, tube, formation, and, proliferation, in, cultured, human, umbilical, vein, endothelial, cell])].
[sujeto(['TXNIP', knockdown, significantly]), verbo([decreased]), complemento([phosphorylation, of, 'VEGFR2', and, 'PLCγ1', at, times, &, 'gt;5', 'minutes,', but, phosphorylation, was, unchanged, at, 2, 'minutes,', as, was, 'Akt', and, endothelial, 'NO', synthase, phosphorylation])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, 'TXNIP', was, required, for, sustained, 'VEGFR2', 'signaling,', which, is, mediated, largely, by, internalized, 'VEGFR2'])].
[sujeto(['Rab5', knockdown, to]), verbo([inhibit]), complemento([the, trafficking, and, fusion, of, early, endosomes, significantly, blocked, 'VEGF-induced', 'VEGFR2', internalization, and, phosphorylation, of, 'VEGFR2', and, 'PLCγ1'])].
[sujeto(['Finally,', 'TXNIP', knockdown]), verbo([prevented]), complemento([the, association, of, 'VEGFR2', and, 'Rab5'])].
[sujeto(['Our', results, show, that, 'TXNIP', is, essential, for, 'VEGFR2', internalization, in, 'Rab5', positive, 'endosomes,', which, is]), verbo([required]), complemento([for, endothelial, cell, growth, and, angiogenesis])].
[sujeto(['Connexin43', '(', 'Cx43)', plays, a, critical, role, in, osteoblast, function, and, bone, mass, 'accrual,', yet, the, identity, of, the, second, messengers, communicated, by, 'Cx43', gap, 'junctions,', the]), verbo([targets]), complemento([of, these, second, messengers, and, how, they, regulate, osteoblast, function, remain, largely, unknown])].
[sujeto(['We']), verbo([have]), complemento([shown, that, alterations, of, 'Cx43', expression, in, osteoblasts, can, impact, the, responsiveness, to, fibroblast, growth, 'factor-2', '(', 'FGF2),', by, modulating, the, transcriptional, activity, of, 'runt-related', transcription, factor, 2, '(', 'Runx2)'])].
[sujeto(['Knockdown', of, expression, 'and/or', inhibition, of, function, of, phospholipase, 'Cγ1,', inositol, polyphosphate, 'multikinase,', which, generates, inositol, 1, ',', 3, ',', 4, ',', 5, -, tetrakisphosphate, '(', 'InsP₄)', and, 'InsP₅,', and, inositol, hexakisphosphate, kinase, 1, /, 2, ',', which, generates, inositol, 'pyrophosphates,']), verbo([prevented]), complemento([the, ability, of, 'Cx43', to, potentiate, 'FGF2-induced', signaling, through, 'Runx2'])].
[sujeto(['Conversely,', overexpression, of, phospholipase, 'Cγ1', and, inositol, hexakisphosphate, kinase, 1, /, 2]), verbo([enhanced]), complemento(['FGF2', activation, of, 'Runx2', and, the, effect, of, 'Cx43', overexpression, on, this, response])].
[sujeto(['Disruption', of, these, pathways, blocked, the]), verbo([nuclear]), complemento([accumulation, of, 'PKCδ', and, the, 'FGF2-dependent', interaction, of, 'PKCδ', and, 'Runx2,', reducing, 'Runx2', transcriptional, activity])].
[sujeto(['These', data]), verbo([reveal]), complemento([that, 'FGF2-signaling', involves, the, inositol, polyphosphate, 'cascade,', including, inositol, hexakisphosphate, kinase, '(', 'IP6K),', and, demonstrate, that, 'IP6K', regulates, 'Runx2', and, osteoblast, gene, expression])].
[sujeto(['Additionally,', these, data, implicate, the, 'water-soluble', inositol, polyphosphates, as, mediators, of, the, 'Cx43-dependent', amplification, of, the, osteoblast, response, to, 'FGF2,', and]), verbo([suggest]), complemento([that, these, low, molecular, weight, second, messengers, may, be, biologically, relevant, mediators, of, osteoblast, function, that, are, communicated, by, 'Cx43-gap', junctions])].
[sujeto(['An', extensive, number, of, studies, were, published, during, the, last, year, and]), verbo([have]), complemento([led, to, a, better, understanding, of, the, pathogenesis, of, infections, with, 'NHPH'])].
[sujeto(['These', infections, are, increasingly]), verbo([reported]), complemento([in, human, 'patients,', including, infections, with, 'H'])].
[sujeto(['Vaccination', based, on, 'UreB', proteins, or, bacterial, lysate, with, 'CCR4', antagonists, as, well, as, oral, glutathione, supplementation, may, be, promising, strategies, to, dampen, the, pathogenic, effects]), verbo([associated]), complemento([with, gastric, 'NHPH', infections])].
[sujeto(['Several', virulent, factors, such, as, outer, membrane, 'proteins,', phospholipase, 'C-gamma', 2, ',', 'Bak', 'protein,', and, 'nickel-binding', proteins, are]), verbo([associated]), complemento([with, colonization, of, the, gastric, mucosae, and, development, of, gastritis])].
[sujeto(['The', development, of, 'high-throughput', sequencing]), verbo([has]), complemento([led, to, new, insights, in, the, gastric, microbiota, composition, and, its, interaction, with, 'H'])].
[sujeto(['Alterations', in, the, gastric, microbiota]), verbo([caused]), complemento([by, the, 'pH-increasing', effect, of, a, 'H'])].
[sujeto([&, 'nbsp;pylori', infection, may]), verbo([increase]), complemento([the, risk, for, gastric, cancer])].
[sujeto(['Primary', afferent, neuronal, plasticity, marked, by, alterations, in, neuroactive, compounds, such, as, calcitonin, 'gene-related', peptide, is]), verbo([suggested]), complemento([to, underlie, the, heightened, sensory, responses])].
[sujeto(['Signal', transduction, that]), verbo([leads]), complemento([to, calcitonin, 'gene-related', peptide, expression, thereby, sensory, neuroplasticity, during, colitis, remains, to, be, elucidated])].
[sujeto(['In', a, rat, model, with, colitis]), verbo([induced]), complemento([by, 2, ',', 4, ',', 6, -, trinitrobenzene, sulfonic, 'acid,', we, found, that, endogenously, elevated, 'brain-derived', neurotrophic, factor, elicited, an, 'up-regulation', of, calcitonin, 'gene-related', peptide, in, the, lumbar, 'L1', dorsal, root, ganglia])].
[sujeto(['Colitis-induced', calcitonin, 'gene-related', peptide, transcription, was, also]), verbo([inhibited]), complemento([by, 'brain-derived', neurotrophic, factor, antibody, treatment])].
[sujeto(['Signal', transduction, studies, with, dorsal, root, ganglia, explants, showed, that, 'brain-derived', neurotrophic, 'factor-induced', calcitonin, generelated, peptide, expression, was]), verbo([mediated]), complemento([by, the, phospholipase, 'C', 'gamma,', but, not, the, phosphatidylinositol, 3, -, 'kinase/Akt', or, the, 'mitogen-activated', protein, 'kinase/extracellular', 'signal-regulated', protein, kinase, pathway])].
[sujeto(['Application', of, 'PLC', inhibitor, 'U73122', in, vivo, confirmed, that, 'colitis-induced', and, 'brain-derived', neurotrophic, 'factor-mediated', calcitonin, 'gene-related', peptide, 'up-regulation', in, the, dorsal, root, ganglia, was]), verbo([regulated]), complemento([by, the, phospholipase, 'C', gamma, pathway])].
[sujeto(['Calcitonin', 'gene-related', peptide, 'up-regulation', during, colitis, correlated, to, the, activation, of, 'cAMP-responsive', element]), verbo([binding]), complemento([protein, in, the, same, neurons])].
[sujeto(['Consistently,', 'colitis-induced', 'cAMP-responsive', element]), verbo([binding]), complemento([protein, activation, in, the, dorsal, root, ganglia, was, attenuated, by, 'brain-derived', neurotrophic, factor, antibody, treatment])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'colitis-induced', and, 'brain-derived', neurotrophic, 'factor-mediated', calcitonin, generelated, peptide, expression, in, sensory, activation, is, regulated, by, a, unique, pathway, involving, 'brain-derived', neurotrophic, factorphospholipase, 'C', 'gamma-cAMP-responsive', element, binding, protein, axis])].
[sujeto(['Deletions', in, the, gene, encoding, 'signal-transducing', inositol, 'phospholipid-specific', phospholipase, 'C-γ2', '(', 'PLCγ2)', are]), verbo([associated]), complemento([with, the, novel, human, hereditary, disease, 'PLAID', '(', 'PLCγ2-associated', antibody, deficiency, and, immune, 'dysregulation)'])].
[sujeto(['PLAID', is, characterized, by, a, rather, puzzling, concurrence, of, augmented, and, diminished, functions, of, the, immune, 'system,', such, as, cold, urticaria]), verbo([triggered]), complemento([by, only, minimal, decreases, in, 'temperature,', 'autoimmunity,', and, immunodeficiency])].
[sujeto(['PLCγ2', is, critically]), verbo([involved]), complemento([in, coupling, various, cell, surface, receptors, to, regulation, of, important, functions, of, immune, cells, such, as, mast, 'cells,', 'B', 'cells,', 'monocytes/macrophages,', and, neutrophils])].
[sujeto(['Prevailing', evidence]), verbo([suggests]), complemento([that, activation, of, 'PLCγ2', is, primarily, due, to, loss, of, 'SH-region-mediated', autoinhibition, 'and/or', enhanced, plasma, membrane, translocation])].
[sujeto(['Here,', we, show, that, the, two, 'PLAID', 'PLCγ2', mutants, lacking, portions, of, the, 'SH', region, are, strongly, '(', &, 'gt;100-fold),', 'rapidly,', and, reversibly]), verbo([activated]), complemento([by, cooling, by, only, a, few, degrees])].
[sujeto(['We']), verbo([found]), complemento([that, the, 'mechanism(s)', underlying, 'PLCγ2', 'PLAID', mutant, activation, by, cool, temperatures, is, distinct, from, a, mere, loss, of, 'SH-region-mediated', autoinhibition, and, dependent, on, both, the, integrity, and, the, pliability, of, the, spPH, domain])].
[sujeto(['The', results]), verbo([suggest]), complemento([a, new, mechanism, of, 'PLCγ', activation, with, unique, thermodynamic, features, and, assign, a, novel, regulatory, role, to, its, spPH, domain])].
[sujeto(['Involvement', of, this, mechanism, in, other, human, disease, states]), verbo([associated]), complemento([with, cooling, such, as, exertional, asthma, and, certain, acute, coronary, events, appears, an, intriguing, possibility])].
[sujeto(['In', a, previous, 'study,', it, was]), verbo([found]), complemento([that, 'MicroRNA-221', '(', 'miR-221)', was, associated, with, asthma])].
[sujeto(['Phosphoinositide', 3, -, kinase, '(', 'PI3K)-inhibitor', '(', 'LY294002)', and, 'NF-κB-inhibitor', '[', pyrrolidine, dithiocarbamate, '(', 'PDTC)]', were, used, to, investigate, the, role, of, 'PI3K/Akt', pathway, and, 'NF-κB', in, 'miR-221']), verbo([promoting]), complemento(['IgE-mediated', activation, of, mast, cells, degranulation])].
[sujeto(['The', degranulation, was]), verbo([found]), complemento([to, be, significantly, increased, in, 'miR-221', overexpressed, cells, while, it, was, found, to, be, significantly, decreased, in, 'miR-221', downregulated, cells])].
[sujeto(['The', expression, of, 'p-PLCγ1,', 'p-Akt,', 'p-IκB-α', as, well, as, 'NF-κB', and, 'Ca(2+)']), verbo([release]), complemento([were, increased, in, 'miR-221', overexpressed, cells])].
[sujeto(['PI3K-inhibitor', '(', 'LY294002)', could, rescue, the, promotion, of, degranulation]), verbo([caused]), complemento([by, 'miR-221', in, 'IgE-mediated', activation, of, mast, cells])].
[sujeto(['However,', 'NF-κB-inhibitor', '(', 'PDTC)', could, not, rescue, the, promotion, of, degranulation]), verbo([caused]), complemento([by, 'miR-221', in, 'IgE-mediated', activation, of, mast, cells])].
[sujeto(['MiR-221']), verbo([promotes]), complemento(['IgE-mediated', activation, of, mast, cells, degranulation, by, 'PI3K/Akt/PLCγ/Ca(2+)', signaling, 'pathway,', in, a, 'non-NF-κB', dependent, manner])].
[sujeto(['Macropinocytosis', can, be]), verbo([induced]), complemento([in, several, cell, types, by, stimulation, with, growth, factors])].
[sujeto(['We']), verbo([report]), complemento([that, constitutive, macropinocytosis, is, stringently, calcium, 'dependent,', while, 'stimulus-induced', macropinocytosis, is, not])].
[sujeto(['These', pathways]), verbo([promote]), complemento([the, recruitment, of, exchange, factors, that, stimulate, 'Rac', 'and/or', 'Cdc42,', driving, 'actin-dependent', formation, of, ruffles, and, macropinosomes])].
[sujeto(['In', 'addition,', the, heterologous, expression, of, 'CaSR', in, 'HEK293', cells]), verbo([confers]), complemento([on, them, the, ability, to, perform, constitutive, macropinocytosis])].
[sujeto(['Finally,', we, show, that, 'CaSR-induced', constitutive, macropinocytosis, facilitates, the, sentinel, function, of, 'macrophages,']), verbo([promoting]), complemento([the, efficient, delivery, of, ligands, to, cytosolic, 'pattern-recognition', receptors])].
[sujeto(['Infected', 'Plcg2Ali5/+', mice, showed, downregulation, of, proinflammatory, cytokines, and]), verbo([decreased]), complemento(['H'])].
[sujeto(['These', results]), verbo([suggested]), complemento([a, blunted, immune, response, of, 'Plcg2Ali5/+', mice, towards, 'H'])].
[sujeto(['Intriguingly,', 'Plcg2Ali5/+', mice, harboured, higher, numbers, of, 'CD73']), verbo([expressing]), complemento([regulatory, 'T', cells, '(', 'Tregs),', possibly, responsible, for, impaired, immune, response, towards, 'Helicobacter', infection])].
[sujeto(['We']), verbo([suggest]), complemento([that, 'Plcg2Ali5/+', mice, may, be, protected, from, developing, gastric, 'MALT', lymphomas, as, a, result, of, elevated, 'Treg', 'numbers,', reduced, response, to, 'H'])].
[sujeto([felis, and]), verbo([decrease]), complemento([of, proinflammatory, cytokines])].
[sujeto(['Accordingly,', we, generated, a, mouse, line, that, conditionally]), verbo([expresses]), complemento([endogenous, 'Plcg2', in, a, 'Cre/loxP', 'recombination-dependent', 'manner,', and, found, that, 'Tie2-Cre-', or, 'Pf4-Cre-driven', reactivation, of, 'Plcg2', rescues, 'PLCγ2-deficient', mice, from, the, vascular, phenotype])].
[sujeto(['As', judged, from, 'immunostaining,', 'PLCγ2', was]), verbo([expressed]), complemento([in, clear, cells, in, the, epididymis])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'PLCγ2-deficient', clear, cells, cause, impaired, luminal, 'expansion,', stenosis, of, the, epididymal, 'duct,', attenuation, of, luminal, 'flow,', and, subsequent, sperm, granulomas])].
[sujeto(['Clear', 'cell-mediated', luminal, expansion, is, also, supported, by, the, observation, that, 'PLCγ2-deficient', males, were, rescued, from, infertility, by, epididymal, 'epithelium-specific', reactivation, of, 'Plcg2,', although, the, edematous, and, hemorrhagic, phenotype]), verbo([associated]), complemento([with, 'PLCγ2', deficiency, also, caused, spontaneous, epididymal, sperm, granulomas, in, aging, males])].
[sujeto(['Collectively,', our, findings, demonstrate, that, 'PLCγ2', in, clear, cells, plays, an, essential, role, in, luminal, expansion, of, the, epididymis, during, the, prepubertal, period, in, 'mice,', and]), verbo([reveal]), complemento([an, unexpected, link, between, 'PLCγ2,', clear, 'cells,', and, epididymal, development])].
[sujeto(['The', results, indicated, that, sFasL]), verbo([released]), complemento([by, cumulus, cells, activated, 'Fas', on, the, oocyte, by, increasing, reactive, oxygen, species, via, activating, 'NADPH', oxidase])].
[sujeto(['The']), verbo([activated]), complemento(['Fas', triggered, 'Ca2+', release, from, the, endoplasmic, reticulum, by, activating, phospholipase, 'C-γ', pathway, and, cytochrome, c, pathway])].
[sujeto(['The', cytoplasmic, 'Ca2+', rises]), verbo([activated]), complemento(['calcium/calmodulin-dependent', protein, kinase, 'II', '(', 'CaMKII)', and, 'caspase-3'])].
[sujeto(['While']), verbo([activated]), complemento(['CaMKII', increased, oocyte, susceptibility, to, activation, by, inactivating, 'maturation-promoting', factor, '(', 'MPF)', through, cyclin, 'B', 'degradation,', the, activated, 'caspase-3', facilitated, further, 'Ca2+releasing', that, activates, more, 'caspase-3', leading, to, oocyte, fragmentation])].
[sujeto(['Furthermore,', 'caspase-3', activation, and, fragmentation, were]), verbo([prevented]), complemento([in, oocytes, with, a, high, 'MPF', 'activity,', suggesting, that, an, oocyte, must, be, in, interphase, to, undergo, apoptosis])].
[sujeto(['AXL']), verbo([has]), complemento([oncogenic, potential, and, interacts, with, other, membrane, 'receptors,', depending, on, their, relative, abundance, and, availability])].
[sujeto(['The']), verbo([increased]), complemento([expression, of, 'AXL', in, cancer, is, often, the, result, of, pharmacologic, selective, pressure, to, a, number, of, chemotherapies, and, targeted, therapies, and, acts, as, a, mechanism, of, acquired, drug, resistance])].
[sujeto(['In', tumors, with, high, levels, of, 'EGFR,', including, 'lung,', head, and, 'neck,', and, 'triple-negative', breast, 'cancer,', 'AXL']), verbo([dimerizes]), complemento([with, this, receptor, and, initiates, signaling, that, circumvents, the, antitumor, effects, of, 'anti-EGFR', therapies])].
[sujeto(['Likewise,', 'AXL', overexpression, and, dimerization, with, 'EGFR', can, overcome, 'PI3K', inhibition, by]), verbo([activating]), complemento([the, phospholipase, 'C-γ-PKC', cascade, 'that,', in, 'turn,', sustains, mTORC1, activity])].
[sujeto(['The', causative, role, of, 'AXL', in]), verbo([inducing]), complemento([drug, resistance, is, underscored, by, the, fact, that, the, suppression, of, 'AXL', restores, sensitivity, to, these, agents])].
[sujeto(['Hence,', these, observations, indicate, that, 'AXL', is, selectively]), verbo([expressed]), complemento([in, tumor, cells, refractory, to, therapy, and, that, cotargeting, 'AXL', in, this, setting, would, potentially, overcome, drug, resistance])].
[sujeto(['Bilateral', cooperation, of, pancreatic, beta, cells, and, immune, cells]), verbo([has]), complemento([been, proposed, in, progression, of, 'T1D,', but, there, is, no, systems, study, to, investigate, it])].
[sujeto(['Here,', we, aimed, to, explicate, etiological, molecular, basis, and, identify, key, genes]), verbo([associated]), complemento([to, 'T1D', risk, by, network, biology, approach, in, two, circumstances])].
[sujeto(['We', integrated, interactome, '(', 'protein-protein', interaction, '(', 'PPI))', and, transcriptomes, data, data, of, transcriptomes, to, construct, networks, of, differentially]), verbo([expressed]), complemento([genes, in, peripheral, blood, mononuclear, cells, '(', 'PBMCs)', and, pancreatic, beta, cells])].
[sujeto(['By', analysis, of, genes, expression, 'profiles,', we]), verbo([found]), complemento([several, cytokines, and, chemokines, in, beta, cells, and, their, receptors, in, 'PBMCs,', which, is, propagation, in, the, dialog, between, these, two, tissues, within, their, 'protein-protein', interactions])].
[sujeto(['Then,', functional, modules, and, complexes, were, determined, to]), verbo([reveal]), complemento([biological, pathways])].
[sujeto(['Finally,', 'YBX1,', 'SRPK1,', 'PSMA1,', 'PSMA3,', 'XRCC6,', 'CBL,', 'SRC,', 'PIK3R1,', 'PLCG1,', 'SHC1', and, 'UBE2N', were, identified, as, key, markers, which, were, 'hub-bottleneck', nodes]), verbo([involved]), complemento([in, functional, modules, and, complexes])].
[sujeto(['Our', results]), verbo([provided]), complemento([a, better, understanding, of, 'T1D', pathogenesis, as, well, as, new, insight, into, network, biomarkers, which, may, be, considered, as, potential, therapeutic, targets])].
[sujeto(['Non-typhoidal', 'Salmonella', enterica]), verbo([induces]), complemento([an, 'early,', 'short-lived', 'pro-inflammatory', response, in, chickens, that, is, asymptomatic, of, clinical, disease, and, results, in, a, persistent, colonization, of, the, gastrointestinal, '(', 'GI)', tract, that, transmits, infections, to, naïve, hosts, via, fecal, shedding, of, bacteria])].
[sujeto(['We', hypothesize, that, alteration, of, host, signaling, pathways]), verbo([mediate]), complemento([the, induction, of, a, tolerance, response])].
[sujeto(['Using', 'chicken-specific', kinomic, immune, peptide, arrays, and, quantitative, 'RT-PCR', of, infected, cecal, 'tissue,', we]), verbo([have]), complemento([previously, evaluated, the, development, of, disease, tolerance, in, chickens, infected, with, 'Salmonella', enterica, serovar, 'Enteritidis', '(', 'S'])].
[sujeto(['Here,', we]), verbo([have]), complemento([further, outlined, the, induction, of, an, tolerance, defense, strategy, in, the, cecum, of, chickens, infected, with, 'S'])].
[sujeto(['The', response, is, characterized, by, alterations, in, the, activation, of, 'T', cell, signaling]), verbo([mediated]), complemento([by, the, dephosphorylation, of, phospholipase, 'c-γ1', '(', 'PLCG1)', that, inhibits, 'NF-κB', signaling, and, activates, nuclear, factor, of, activated, 'T-cells', '(', 'NFAT)', signaling, and, blockage, of, 'interferon-γ', '(', 'IFN-γ)', production, through, the, disruption, of, the, 'JAK-STAT', signaling, pathway, '(', dephosphorylation, of, 'JAK2,', 'JAK3,', and, 'STAT4)'])].
[sujeto(['These', 'studies,', combined, with, our, previous, 'findings,', describe, global, phenotypic, changes, in, the, avian, cecum, of, 'Salmonella', 'Enteritidis-infected', chickens, that]), verbo([decreases]), complemento([the, host, responsiveness, resulting, in, the, establishment, of, persistent, colonization])].
[sujeto(['The', identified, tissue, protein, kinases, also, represent, potential]), verbo([targets]), complemento([for, future, antimicrobial, compounds, for, decreasing, 'Salmonella', loads, in, the, intestines, of, food, animals, before, going, to, market])].
[sujeto(['So', far, the, pathogenesis, of, atherosclerosis]), verbo([has]), complemento([not, been, fully, understood])].
[sujeto(['MiRNAs', are, widely, detected, in, human, coronary, artery, endothelial, cells, '(', 'HCAECs),', which, might]), verbo([participate]), complemento([in, diverse, biological, functions, through, targeting, different, atherosclerosis, associated, genes])].
[sujeto(['Our', study]), verbo([found]), complemento([the, high, expression, of, 'miR-30b', and, 'miR-30e', in, atherosclerosis, clinical, 'samples,', identified, the, regulatory, relationship, of, 'miR-30b', and, 'miR-30e', to, 'ITGA4', and, 'PLCG1', 'respectively,', and, initially, explored, the, effects, of, 'miR-30b', and, 'miR-30e', on, cell, cycle, and, apoptosis, through, targeting, 'ITGA4', and, 'PLCG1'])].
[sujeto(['These', data, may]), verbo([provide]), complemento([a, theoretical, basis, for, clarifying, the, mechanism, of, 'miR-30s', in, atherosclerosis])].
[sujeto(['We', investigated, a, series, of, 85, patients, with, 'AITL', '(', 'n=72)', or, other, 'TFH-derived', 'PTCL', '(', 'n=13)', by]), verbo([targeted]), complemento([deep, sequencing, of, a, gene, panel, enriched, in, 'T-cell', receptor, '(', 'TCR)', signaling, elements])].
[sujeto(['RHOA', mutations, were, identified, in, 51, /, 85, cases, '(', 60, '%', ')', consisting, of, the, highly, recurrent, dominant, negative, 'G17V', variant, in, most, cases, and, a, novel, 'K18N', in, 3, 'cases,', the, latter, showing]), verbo([activating]), complemento([properties, in, in, vitro, assays])].
[sujeto(['By', in, vitro, assays, in, transfected, 'cells,', we, demonstrated, that, 9, /, 10, 'PLCG1', and, 3, /, 3, 'CARD11', variants]), verbo([induced]), complemento(['MALT1', protease, activity, and, increased, transcription, from, 'NFAT', or, 'NF-kB', response, element, 'reporters,', respectively])].
[sujeto(['Thus,']), verbo([targeting]), complemento([of, 'TCR-related', events, may, hold, promise, for, the, treatment, of, 'TFH-derived', lymphomas])].
[sujeto(['In', the, face, of, 'SS', 'diversity,', the, great, hope, is, to, develop]), verbo([targeted]), complemento([therapies, based, on, 'next-generation', sequencing, to, define, the, genetic, landscape, of, 'Sézary', syndrome])].
[sujeto(['At', the, individual, 'level,', 'Sézary', cells, may, combine, alterations, of, genes]), verbo([involved]), complemento([in, 'T-cell', 'signaling,', 'NF-kB', and, 'JAK-signal', transducer, and, activator, of, transcription, 'pathways,', apoptosis, 'control,', chromatin, 'remodeling,', and, 'DNA', damage, response])].
[sujeto(['The', therapeutic, relevance, of, these, potential]), verbo([targets]), complemento([needs, to, be, evaluated, with, tests, of, function])].
[sujeto(['Adult', 'T-cell', 'leukemia/lymphoma', '(', 'ATL)', is, a, peripheral, 'T-cell', malignancy]), verbo([associated]), complemento([with, 'HTLV-1', infection])].
[sujeto(['To', decipher, the, genetic, landscape, of, 'ATL,', we, performed, an, integrated, molecular, 'analysis,', which, included, 'whole-genome,', 'whole-exome,', transcriptome, and]), verbo([targeted]), complemento(['sequencing,', as, well, as, 'array-based', copy, number, and, methylation, analyses])].
[sujeto(['The', somatic, alterations, are, highly, enriched, for, 'T-cell', 'receptor/NF-κB', 'signaling,', the, 'G-protein', coupled, receptor]), verbo([associated]), complemento([with, 'T-cell', 'migration,', and, other, 'T-cell-related', pathways, as, well, as, immune, surveillance, related, genes])].
[sujeto(['Among', 'these,', 'PLCG1,', 'PRKCB,', 'CARD11,', 'VAV1,', 'IRF4,', 'CCR4,', and, 'CCR7']), verbo([activating]), complemento([mutations, and, 'CTLA4-CD28', and, 'ICOS-CD28', fusion, genes, have, been, identified])].
[sujeto(['These', results]), verbo([provide]), complemento([an, important, basis, for, the, development, of, new, 'ATL', diagnostics, and, therapeuticsregimens])].
[sujeto(['We', describe, 'whole-exome', and, 'single-nucleotide', polymorphism, 'array-based', copy, number, analyses, of, 'CD4(+)', tumor, cells, from, untreated, patients, at, diagnosis, and]), verbo([targeted]), complemento([resequencing, of, 101, 'SS', cases])].
[sujeto(['Driver', genes, identified, using, 'MutSigCV', include, 'POT1,', which]), verbo([has]), complemento([not, been, previously, reported, in, 'CTCL;', and, 'TP53', and, 'DNMT3A,', which, were, also, identified, consistent, with, previous, reports])].
[sujeto(['Aberrations', in, 'PRKCQ', were]), verbo([found]), complemento([to, occur, in, 20, '%', of, tumors, highlighting, selection, for, activation, of, 'T-cell', 'receptor/NF-κB', signaling])].
[sujeto(['A', complex, but, consistent, pattern, of, copy, number, variants, '(', 'CNVs)', was, detected, and, many, 'CNVs']), verbo([involved]), complemento([genes, identified, as, putative, drivers])].
[sujeto(['Frequent', defects]), verbo([involving]), complemento([the, 'POT1', and, 'ATM', genes, responsible, for, telomere, maintenance, were, detected, and, may, contribute, to, genomic, instability, in, 'SS'])].
[sujeto(['This', study, now]), verbo([provides]), complemento([the, basis, for, a, detailed, functional, analysis, of, malignant, transformation, of, mature, 'T', cells, and, improved, patient, stratification, and, treatment])].
[sujeto(['Primary', duck, hepatocytes, '(', 'PDH)', displays, differential, susceptibility, to, duck, hepatitis, 'B', virus, when]), verbo([maintained]), complemento([in, the, media, supplemented, with, fetal, bovine, serum, or, dimethyl, sulfoxide, '(', 'DMSO)', which, has, been, widely, used, for, the, maintenance, of, 'hepatocytes,', and, prolonging, susceptibility, to, hepadnavirus])].
[sujeto(['The', 384, differential]), verbo([expressed]), complemento([genes, '(', 'DEGs)', were, identified, by, comparisons, between, each, library, pair, '(', 'PDHs', cultured, with, or, without, 'DMSO', or, fresh, isolated, 'PDH)'])].
[sujeto(['The', combination, of]), verbo([decreased]), complemento([expression, of, 'liver-specific', genes, '(', 'CYP3A4,', 'CYP1E1,', 'CFI,', 'RELN', and, 'GSTA1', et, 'al)', with, increased, expression, of, 'hepatocyte-dedifferentiation-associated', genes, '(', 'PLA2G4A', and, 'PLCG1)', suggested, that, in, vitro, culture, conditions, results, in, the, fading, of, hepatocyte, phenotype, in, 'PDHs'])].
[sujeto(['The', expression, of, seven, 'DEGs']), verbo([associated]), complemento([with, tight, junction, formation, '(', 'JAM3,', 'PPP2R2B,', 'PRKAR1B,', 'PPP2R2C,', 'MAGI2,', 'ACTA2', and, 'ACTG2)', was, 'up-regulated', after, 'short-term', culture, in, 'vitro,', which, was, attenuated, in, the, presence, of, 'DMSO'])].
[sujeto(['Those', results, could, shed, light, on, 'DHBV', infection]), verbo([associated]), complemento([molecular, events, affected, by, 'DMSO'])].
[sujeto(['Sézary', syndrome, is, a, rare, leukemic, form, of, cutaneous, 'T', cell, lymphoma, characterized, by, generalized, 'redness,', 'scaling,', itching, and]), verbo([increased]), complemento([numbers, of, circulating, atypical, 'T', lymphocytes])].
[sujeto(['Our', results, demonstrate, profound, disruption, of, key, signaling, pathways, in, 'Sézary', syndrome, and]), verbo([suggest]), complemento([potential, targets, for, new, therapies])].
[sujeto(['Limma', package, in, 'R', was, used, to, screen, differentially]), verbo([expressed]), complemento([genes, '(', 'DEGs)'])].
[sujeto(['They', might, be]), verbo([involved]), complemento([in, 'smoking-induced', lung, cancer, by, interacting, with, each, other, '(', e])].
[sujeto(['The', genetic, bases, of, these, tumors]), verbo([have]), complemento([been, partially, revealed, in, recent, studies, reporting, genetic, alterations, such, as, amplifications, of, 'MYC', '(', primarily, in, 'radiation-associated', 'angiosarcomas),', inactivating, mutations, in, 'PTPRB', and, 'R707Q', hotspot, mutations, of, 'PLCG1'])].
[sujeto(['Here,', we, performed, a, comprehensive, genomic, analysis, of, 34, angiosarcomas, using, a, 'clinically-approved,', 'hybridization-based']), verbo([targeted]), complemento(['next-generation', sequencing, assay, for, 341, 'well-established', oncogenes, and, tumor, suppressor, genes])].
[sujeto(['Over', half, of, the, angiosarcomas, '(', n, =, 18, ',', 53, '%', ')', harbored, genetic, alterations, affecting, the, 'MAPK', 'pathway,']), verbo([involving]), complemento([mutations, in, 'KRAS,', 'HRAS,', 'NRAS,', 'BRAF,', 'MAPK1', and, 'NF1,', or, amplifications, in, 'MAPK1/CRKL,', 'CRAF', or, 'BRAF'])].
[sujeto(['The', most, frequently, detected, genetic, aberrations, were, mutations, in, 'TP53', in, 12, 'tumors(35%)', and]), verbo([losses]), complemento([of, 'CDKN2A', in9, tumors, '(', 26, '%', ')'])].
[sujeto(['MYC', amplifications, were, generally, mutually, exclusive, of, 'TP53', alterations, and, 'CDKN2A']), verbo([loss]), complemento([and, were, identified, in, 8, tumors, '(', 24, '%', ')', ',', most, of, which, '(', n, =, 7, ',', 88, '%', ')', arose, 'post-irradiation'])].
[sujeto(['Previously']), verbo([reported]), complemento([mutations, in, 'PTPRB', '(', n, =, 10, ',', 29, '%', ')', and, one, '(', 3, '%', ')', 'PLCG1', 'R707Q', mutation, were, also, identified])].
[sujeto(['The', high, frequency, of, genetic, events, affecting, the, 'MAPK', pathway]), verbo([suggests]), complemento([that, targeted, therapies, inhibiting, 'MAPK', signaling, may, be, promising, therapeutic, avenues, in, patients, with, advanced, angiosarcomas])].
[sujeto(['Adult', 'T', cell, 'leukemia/lymphoma', '(', 'ATL)', is, a, peripheral, 'T', cell, neoplasm, of, largely, unknown, genetic, 'basis,']), verbo([associated]), complemento([with, human, 'T', cell, leukemia, virus, 'type-1', '(', 'HTLV-1)', infection])].
[sujeto(['Here', we, describe, an, integrated, molecular, study, in, which, we, performed, 'whole-genome,', 'exome,', transcriptome, and]), verbo([targeted]), complemento(['resequencing,', as, well, as, 'array-based', copy, number, and, methylation, 'analyses,', in, a, total, of, 426, 'ATL', cases])].
[sujeto(['Other', notable, features, include, a, predominance, of]), verbo([activating]), complemento([mutations, '(', in, 'PLCG1,', 'PRKCB,', 'CARD11,', 'VAV1,', 'IRF4,', 'FYN,', 'CCR4', and, 'CCR7)', and, gene, fusions, '(', 'CTLA4-CD28', and, 'ICOS-CD28)'])].
[sujeto(['We', also, discovered, frequent, intragenic, deletions]), verbo([involving]), complemento(['IKZF2,', 'CARD11', and, 'TP73', and, mutations, in, 'GATA3,', 'HNRNPA2B1,', 'GPR183,', 'CSNK2A1,', 'CSNK2B', and, 'CSNK1A1'])].
[sujeto(['Our', findings, not, only]), verbo([provide]), complemento([unique, insights, into, key, molecules, in, 'T', cell, signaling, but, will, also, guide, the, development, of, new, diagnostics, and, therapeutics, in, this, intractable, tumor])].
[sujeto(['Platelet-derived', growth, factor, '(', 'PDGF)']), verbo([stimulates]), complemento([the, proliferation, of, quiescent, fibroblasts, through, a, series, of, events, initiated, by, activation, of, tyrosine, kinase, activity, of, the, 'PDGF', receptor, at, the, cell, surface])].
[sujeto(['Physiologically', significant, substrates, for, this, or, other, growth, factor, receptor, or, oncogene, tyrosine, kinases]), verbo([have]), complemento([been, difficult, to, identify])].
[sujeto(['Treatment', of, 'BALB/c', 3, 'T3', cells, with, 'PDGF']), verbo([led]), complemento([to, a, rapid, '(', within, 1, 'min)', and, significant, '(', greater, than, 50, -, 'fold)', increase, in, 'PLC', 'activity,', as, detected, in, eluates, of, proteins, from, a, phosphotyrosine, immunoaffinity, matrix])].
[sujeto(['This', 'PDGF-stimulated']), verbo([increase]), complemento([in, 'phosphotyrosine-immunopurified', 'PLC', activity, occurred, for, up, to, 12, h, after, addition, of, growth, factor, to, quiescent, cells])].
[sujeto(['Furthermore,', these, immunoprecipitation, studies, showed, that, 'PLC-gamma', is, rapidly]), verbo([phosphorylated]), complemento([on, tyrosine, residues, after, 'PDGF', stimulation])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, mitogenic, signaling, by, 'PDGF', is, coincident, with, tyrosine, phosphorylation, of, 'PLC-gamma'])].
[sujeto(['Excessive', activation, of, 'TrkB']), verbo([caused]), complemento([by, status, epilepticus, promotes, development, of, temporal, lobe, epilepsy, '(', 'TLE),', revealing, 'TrkB', as, a, therapeutic, target, for, prevention, of, 'TLE'])].
[sujeto(['Our', studies, of, a, mouse, model]), verbo([reveal]), complemento([that, phospholipase, 'Cγ1', '(', 'PLCγ1)', is, the, dominant, signaling, effector, by, which, excessive, activation, of, 'TrkB', promotes, epilepsy])].
[sujeto(['Treatment', with, pY816, following, status, epilepticus]), verbo([inhibited]), complemento(['TLE', and, prevented, 'anxiety-like', disorder, yet, preserved, neuroprotective, effects, of, endogenous, 'TrkB', signaling])].
[sujeto(['We']), verbo([provide]), complemento(['proof-of-concept', evidence, for, a, novel, strategy, targeting, receptor, tyrosine, signaling, and, identify, a, therapeutic, with, promise, for, prevention, of, 'TLE', caused, by, status, epilepticus, in, humans])].
[sujeto(['Our', previous, study, shows, that, 'PLCγ1', and, mTOR, are]), verbo([involved]), complemento([in, the, matrix, metabolism, of, 'OA', cartilage])].
[sujeto(['The', results, manifested, that, the, expression, level, of, 'ERK', in, human, 'OA', chondrocytes, was, lower, than, that, in, human, normal, articular, 'chondrocytes,', and, the, 'up-regulation', of, 'ERK', could]), verbo([promote]), complemento([matrix, 'synthesis,', including, the, decrease, in, 'MMP-13', level, and, the, increase, in, 'Aggrecan', level, in, human, 'OA', chondrocytes])].
[sujeto(['Interestingly,']), verbo([activated]), complemento(['ERK', had, no, inhibitory, effect, on, 'MMP-13', expression, in, 'PLCγ1-transformed', 'OA', chondrocytes])].
[sujeto(['Therefore,', the, study, indicates, that, the, mutual, inhibition, of, 'ERK', and, mTOR, is]), verbo([involved]), complemento([in, 'PLCγ1-mediated', 'MMP-13', expression, in, human, 'OA', 'chondrocytes,', with, important, implication, for, the, understanding, of, 'OA', pathogenesis, as, well, as, for, its, prevention, and, therapy])].
[sujeto(['Oncogenic', gene, fusions]), verbo([have]), complemento([been, identified, in, many, cancers, and, many, serve, as, biomarkers, or, targets, for, therapy])].
[sujeto(['These', tumours, lack]), verbo([activating]), complemento([mutations, in, other, established, melanoma, oncogenes])].
[sujeto(['We', functionally, characterize, two, of, the, identified, fusion, proteins, '(', 'TRIM4-MET', and, 'ZKSCAN1-MET)', and]), verbo([find]), complemento([that, they, constitutively, activate, the, 'mitogen-activated', protein, kinase, '(', 'MAPK),', 'phosphoinositol-3', kinase, '(', 'PI3K)', and, phospholipase, 'C', gamma, 1, '(', 'PLCγ1)', pathways])].
[sujeto(['MET', fusion, kinases, thus]), verbo([provide]), complemento([a, potential, therapeutic, target, for, a, rare, subset, of, melanoma, for, which, currently, no, targeted, therapeutic, options, currently, exist])].
[sujeto(['Hinokitiol,', a, tropolone, derivative]), verbo([found]), complemento([in, 'Chamacyparis', 'taiwanensis,', has, been, found, to, exhibit, anticancer, activity, in, a, variety, of, cancers, through, inhibition, of, cell, proliferation])].
[sujeto(['Hinokitiol']), verbo([suppressed]), complemento([the, expression, of, proliferating, cell, nuclear, antigen, '(', 'PCNA),', a, maker, for, cell, cycle, 'arrest,', and, caused, 'G0/G1', phase, arrest, in, cell, cycle, progression])].
[sujeto(['Phospholipase', 'C', '(', 'PLC)-γ1', 'phosphorylation,', its]), verbo([phosphorylated]), complemento([substrates, and, p27kip1, expression, was, also, analyzed])].
[sujeto(['Pre-treatment', of, 'VSMCs', with, hinikitiol, was]), verbo([found]), complemento([to, significantly, inhibit, the, 'PDGF-BB-induced', phosphorylations, of, 'JNK1/2', and, 'PLC-γ1,', however, no, effects, on, 'Akt,', 'ERK1/2,', and, p38])].
[sujeto(['Taken', 'together,', our, results]), verbo([suggest]), complemento([that, hinokitiol, inhibits, 'PDGF-BB-induced', proliferation, of, 'VSMCs', by, inducing, cell, cycle, 'arrest,', suppressing, 'JNK1/2', phosphorylation, and, 'PLC-γ1,', and, stimulating, p27kip1, expression])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, hinokitiol, may, be, beneficial, for, the, treatment, of, 'vascular-related', disorders, and, diseases])].
[sujeto(['In', 'T', 'cells,', the, 'Tec', family, 'kinase,', 'interleukin-2-induced', tyrosine, kinase, '(', 'ITK),']), verbo([phosphorylates]), complemento(['PLCγ1', at, tyrosine, 783, '(', 'Y783)', leading, to, activation, of, phospholipase, function, and, subsequent, production, of, the, second, messengers, inositol, 1, ',', 4, ',', 5, -, trisphosphate, and, diacylglycerol])].
[sujeto(['The', 'SLP-76', 'phosphotyrosine-containing', 'sequence,', 'pY(173)IDR,', does, not, conform, to, the, canonical, recognition, motif, for, an, 'SH2', domain, yet]), verbo([binds]), complemento([with, significant, affinity, to, the, 'C-terminal', 'SH2', domain, of, 'PLCγ1', '(', 'SH2C)'])].
[sujeto(['The', 'SLP-76', 'pY(173)', motif, competes, with, the, autoinhibited, conformation, surrounding, the, 'SH2C', domain, of, 'PLCγ1']), verbo([leading]), complemento([to, exposure, of, the, 'ITK', recognition, element, on, the, 'PLCγ1', 'SH2', domain, and, release, of, the, target, 'tyrosine,', 'Y783'])].
[sujeto(['Yet,', when, 'WASP', function, is, eliminated, there, is, negligible, effect, on, actin, polymerization, at, the, immunological, 'synapse,']), verbo([leading]), complemento([to, gaps, in, our, understanding, of, the, events, connecting, 'WASP', and, calcium, ion, signaling])].
[sujeto(['We', conclude, that, 'WASP', generates, a, dynamic, 'F-actin', architecture, in, the, context, of, the, immunological, 'synapse,', which, then, amplifies, the, downstream, signals]), verbo([required]), complemento([for, an, optimal, immune, response])].
[sujeto(['Despite', intense, research, 'efforts,', drug, resistance, remains, a, major]), verbo([cause]), complemento([of, treatment, failure, in, 'CLL,', particularly, in, patients, with, dysfunctional, 'TP53'])].
[sujeto(['The', objective, of, our, work, was, to, identify, potential, approaches, that, might, overcome, 'CLL', drug, refractoriness, by, examining, the, 'pro-apoptotic', potential, of]), verbo([targeting]), complemento([the, cell, surface, receptor, 'CD47', with, 'serum-stable', agonist, peptides])].
[sujeto(['In', peripheral, blood, samples, collected, from, 80, patients, with, 'CLL', with, positive, and, adverse, prognostic, 'features,', we, performed, in, vitro, genetic, and, molecular, analyses, that, demonstrate, that, the]), verbo([targeting]), complemento([of, 'CD47', with, peptides, derived, from, the, 'C-terminal', domain, of, 'thrombospondin-1', efficiently, kills, the, malignant, 'CLL', 'B', 'cells,', including, those, from, 'high-risk', individuals, with, a, dysfunctional, 'TP53', 'gene,', while, sparing, the, normal, 'T', and, 'B', lymphocytes, from, the, 'CLL', patients])].
[sujeto(['Further', studies]), verbo([reveal]), complemento([that, the, differential, response, of, normal, 'B', 'lymphocytes,', collected, from, 20, healthy, 'donors,', and, leukemic, 'B', cells, to, 'CD47', peptide, targeting, results, from, the, sustained, activation, in, 'CLL', 'B', cells, of, phospholipase, 'C', 'gamma-1', '(', 'PLCγ1),', a, protein, that, is, significantly, 'over-expressed', in, 'CLL'])].
[sujeto(['Once']), verbo([phosphorylated]), complemento([at, tyrosine, 783, ',', 'PLCγ1', enables, a, 'Ca2+-mediated,', 'caspase-independent', programmed, cell, death, '(', 'PCD)', pathway, that, is, not, 'down-modulated', by, the, lymphocyte, microenvironment])].
[sujeto(['Additionally,', in, a, 'CLL-xenograft', model, developed, in, 'NOD/scid', gamma, 'mice,', we, demonstrate, that, the, injection, of, 'CD47', agonist, peptides, reduces, tumor, burden, without]), verbo([inducing]), complemento([anemia, or, toxicity, in, 'blood,', 'liver,', or, kidney])].
[sujeto(['The', limitations, of, our, study, are, mainly, linked, to, the, affinity, of, the, peptides]), verbo([targeting]), complemento(['CD47,', which, might, be, improved, to, reach, the, standard, requirements, in, drug, 'development,', and, the, lack, of, a, 'CLL', animal, model, that, fully, mimics, the, human, disease])].
[sujeto(['Our', work]), verbo([provides]), complemento([substantial, progress, in, '(', 'i)', the, development, of, 'serum-stable', 'CD47', agonist, peptides, that, are, highly, effective, at, inducing, 'PCD', in, 'CLL,', '(', 'ii)', the, understanding, of, the, molecular, events, regulating, a, novel, 'PCD', pathway, that, overcomes, 'CLL', apoptotic, 'avoidance,', '(', 'iii)', the, identification, of, 'PLCγ1', as, an, 'over-expressed', protein, in, 'CLL', 'B', 'cells,', and, '(', 'iv)', the, description, of, a, novel, 'peptide-based', strategy, against, 'CLL'])].
[sujeto(['MS4A', family, members, differentially]), verbo([regulate]), complemento([the, cell, 'cycle,', and, 'aberrant,', or, loss, 'of,', expression, of, 'MS4A', family, proteins, has, been, observed, in, colon, and, lung, cancer])].
[sujeto(['Here', we]), verbo([report]), complemento([that, 'MS4A4', facilitates, trafficking, of, the, receptor, tyrosine, kinase, 'KIT', through, endocytic, recycling, rather, than, degradation, pathways, by, a, mechanism, that, involves, recruitment, of, 'KIT', to, 'caveolin-1-enriched', microdomains])].
[sujeto(['Silencing', of, 'MS4A4', in, human, mast, cells, altered, 'ligand-induced', 'KIT', endocytosis, pathways, and, reduced, receptor, recycling, to, the, cell, 'surface,', thus]), verbo([promoting]), complemento(['KIT', signaling, in, the, endosomes, while, reducing, that, in, the, plasma, 'membrane,', as, exemplified, by, 'Akt', and, 'PLCγ1', 'phosphorylation,', respectively])].
[sujeto(['The', altered, endocytic, trafficking, of, 'KIT', also, resulted, in, an]), verbo([increase]), complemento([in, 'SCF-induced', mast, cell, proliferation, and, 'migration,', which, may, reflect, altered, signaling, in, these, cells])].
[sujeto(['Our', data]), verbo([reveal]), complemento([a, novel, function, for, 'MS4A', family, proteins, in, regulating, trafficking, and, 'signaling,', which, could, have, implications, in, both, proliferative, and, immunological, diseases])].
[sujeto(['For', 'example,', a, protein, with, 10, sites, that, can, each, be, 'unphosphorylated,']), verbo([phosphorylated]), complemento([or, bound, to, adaptor, protein, requires, 3, '(', 10, ')', 'ODEs'])].
[sujeto(['This', problem, is, often, dealt, with, by, making, ad, hoc, assumptions, which]), verbo([have]), complemento([unclear, validity, and, disallow, modelling, of, 'site-specific', dynamics])].
[sujeto(['We', show, here, that, for, a, common, biological, situation, where, adaptors]), verbo([bind]), complemento([modified, 'sites,', binding, is, slow, relative, to, 'modification/demodification,', and, binding, to, one, modified, site, hinders, binding, to, other, 'sites,', for, a, protein, with, n, modification, sites, and, m, adaptor, proteins, the, number, of, 'ODEs', needed, to, simulate, the, 'site-specific', dynamics, of, biologically, 'relevant,', lumped, bound, adaptor, states, is, independent, of, the, number, of, modification, sites, and, equal, to, m, +, 1, ',', giving, a, significant, reduction, in, system, size])].
[sujeto(['These', considerations, can, be, relaxed, considerably, while]), verbo([retaining]), complemento([reasonably, accurate, descriptions, of, the, true, system, dynamics])].
[sujeto(['The', model, quantitatively, accounts, for, experimentally, determined, 'site-specific', phosphorylation, and, dephosphorylation, 'rates,', differential, affinities, of]), verbo([binding]), complemento([proteins, for, the, phosphorylated, sites, and, binding, protein, expression, levels])].
[sujeto(['Analysis']), verbo([suggests]), complemento([that, local, concentration, of, 'site-specific', phosphatases, such, as, 'SHP2', in, membrane, subdomains, by, a, factor, of, approximately, 10, '(', 7, ')', is, critical, for, effective, 'site-specific', regulation])].
[sujeto(['We', further, show, how, our, framework, can, be, extended, with, minimal, effort, to, consider]), verbo([binding]), complemento([cooperativity, between, 'Grb2', and, 'c-Cbl,', which, is, important, for, receptor, trafficking])].
[sujeto(['Our', theory]), verbo([has]), complemento([potentially, broad, application, to, reduce, combinatorial, complexity, and, allow, practical, simulation, of, a, variety, 'ODE', models, relevant, to, systems, biology, and, pharmacology, applications, to, allow, exploration, of, key, aspects, of, complexity, that, control, signal, flux])].
[sujeto(['Erythropoiesis', is, a, tightly]), verbo([regulated]), complemento([process])].
[sujeto(['Binding', of, erythropoietin, '(', 'Epo)', to, its, receptor, '(', 'EpoR)', is]), verbo([required]), complemento([for, erythropoiesis, as, it, promotes, survival, and, late, maturation, of, erythroid, progenitors])].
[sujeto(['In', vivo, and, in, vitro, studies]), verbo([have]), complemento([highlighted, the, requirement, of, 'EpoR', signaling, through, 'Janus', kinase, 2, '(', 'Jak2)', tyrosine, kinase, and, 'Stat5a/b', as, a, central, pathway])].
[sujeto(['Here,', we, demonstrate, that, phospholipase, 'C', gamma, 1, '(', 'Plcγ1)', is]), verbo([activated]), complemento([downstream, of, 'EpoR-Jak2', independently, of, 'Stat5'])].
[sujeto(['To', identify, 'Plcγ1', effector, molecules]), verbo([involved]), complemento([in, regulation, of, erythroid, 'differentiation,', we, assessed, changes, occurring, at, the, global, transcriptional, and, 'DNA', methylation, level, after, inactivation, of, 'Plcγ1'])].
[sujeto(['Taken', 'together,', our, findings, identify, 'Plcγ1', and, its, downstream]), verbo([target]), complemento(['mH2A2,', as, a, '\'', 'non-canonical\'', 'Epo', signaling, pathway, essential, for, erythroid, differentiation])].
[sujeto(['T-cell', receptor, '(', 'TCR)-transduced', signaling, is, critical, to, thymocyte, development, at, the, 'CD4/CD8', 'double-positive', 'stage,', but, the, molecules]), verbo([involved]), complemento([in, this, process, are, not, yet, fully, characterized])].
[sujeto(['We', previously, demonstrated, that, 'GM-CSF/IL-3/IL-5', receptor, common, 'β-chain-associated', protein, '(', 'CBAP)']), verbo([modulates]), complemento(['ZAP70-mediated', 'T-cell', migration, and, adhesion])].
[sujeto(['Loss', of, 'CBAP']), verbo([led]), complemento([to, reduced, 'TCR-induced', phosphorylation, of, proteins, involved, in, both, proximal, and, distal, signaling, 'events,', including, 'ZAP70,', 'LAT,', 'PLCγ1,', and, 'JNK1/2'])].
[sujeto(['Our', data, demonstrate, that, 'CBAP', is, a, novel, component, in, the, 'TCR', signaling, pathway, and]), verbo([modulates]), complemento([thymocyte, apoptosis, during, negative, selection])].
[sujeto(['Pre-treatment', of, 'VSMCs', with, 'MDGA']), verbo([inhibited]), complemento(['PDGF-BB-induced', phosphorylation, of, extracellular, 'signal-regulated', kinases, 1, /, 2, '(', 'ERK1/2),', 'p38,', and, 'C-Jun', 'N-terminal', kinase, '(', 'JNK)'])].
[sujeto(['MDGA', also, effectively]), verbo([inhibited]), complemento([phosphorylation, of, 'Akt,', phospholipase, 'C', gamma, 1, '(', 'PLCγ1),', and, 'PDGF', receptor, beta, '(', 'PDGFRβ)'])].
[sujeto(['These', results, indicate, that, 'MDGA', may]), verbo([inhibit]), complemento([proliferation, of, 'VSMCs', by, suppressing, autophosphorylation, of, 'PDGFRβ,', and, may, be, useful, in, the, treatment, of, 'VSMC-associated', vascular, disease, such, as, 'atherosclerosis,', 'restenosis,', and, neointimal, hyperplasia, after, angioplasty])].
[sujeto(['Here,', we, established, a, novel, monoclonal, 'antibody,', 'Dow2,', that, temporarily]), verbo([induces]), complemento([downmodulation, of, the, 'TCR/CD3', complex, in, mouse, 'CD4(+)', 'T', cells, without, activating, 'T', cells])].
[sujeto(['Dow2']), verbo([recognized]), complemento([the, determinant, on, 'CD3ε;', 'however,', differences, were, observed, in, the, binding, mode, between, 'Dow2', and, the, agonistic, 'anti-CD3ε', 'Ab,', 145, -, 2, 'C11'])].
[sujeto(['An', injection, of, 'Dow2', in, vivo, resulted, in, 'T-cell', 'anergy,', and, prolonged, the, survival, of, cardiac, allografts, without, a, marked]), verbo([increase]), complemento([in, cytokine, release])].
[sujeto(['The']), verbo([phosphorylated]), complemento([forms, of, the, signaling, proteins, 'PLC-γ1', and, 'LAT', in, 'Dow2-induced', anergic, 'T', cells, were, markedly, decreased, upon, stimulation])].
[sujeto(['However,', the, levels, of]), verbo([phosphorylated]), complemento(['LAT', and, 'PLCγ1', in, 'Dow2-induced', anergic, 'T', cells, could, be, rescued, in, the, presence, of, the, proteasome, inhibitor, 'MG-132'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'proteasome-mediated', degradation, is, involved, in, hypophosphorylated, 'LAT', and, 'PLCγ1', in, 'Dow2-induced', anergic, 'T', cells])].
[sujeto(['The', novel, 'CD3-specific', 'Ab,', 'Dow2,', may]), verbo([provide]), complemento([us, with, a, unique, tool, for, inducing, immunosuppression])].
[sujeto(['Elucidating', molecular, mechanisms, underlying, limbic, epileptogenesis, may]), verbo([reveal]), complemento([novel, targets, for, preventive, therapy])].
[sujeto(['Studies', of, 'TrkB', mutant, mice]), verbo([led]), complemento([us, to, hypothesize, that, signaling, through, a, specific, phospholipase, '(', 'PLC),', 'PLCγ1,', promoted, development, of, kindling])].
[sujeto(['This', study, implicates, 'PLCγ1', signaling, as, the, dominant, pathway, by, which, 'TrkB', activation]), verbo([promotes]), complemento([limbic, epileptogenesis])].
[sujeto(['These', findings, advance, 'PLCγ1', as, a, novel]), verbo([target]), complemento([for, therapies, aimed, at, preventing, temporal, lobe, epilepsy, induced, by, status, epilepticus])].
[sujeto(['Acute', mechanical, stretch]), verbo([has]), complemento([been, closely, associated, with, vascular, 'inflammation,', although, the, precise, mechanism, is, unknown])].
[sujeto(['Here,', we, show, that, hypertensive, stretch]), verbo([regulates]), complemento([the, exocytosis, of, 'WPBs', of, endothelial, cells, '(', 'ECs)', through, 'VEGF', receptor, 2, '(', 'VEGFR2)', signaling, pathways])].
[sujeto(['Stretch']), verbo([triggers]), complemento([a, rapid, release, '(', within, 'minutes)', of, von, 'Willebrand', factor, and, 'interleukin-8', from, 'WPBs', in, cultured, human, 'ECs,', promoting, the, interaction, between, leukocytes, and, 'ECs', through, the, translocation, of, 'P-selectin', to, the, cell, membrane])].
[sujeto(['We', further, show, that, hypertensive, stretch, significantly]), verbo([induces]), complemento(['P-selectin', translocation, of, intact, 'ECs', and, enhances, leukocyte, adhesion, both, ex, vivo, and, in, vivo])].
[sujeto(['Stretch-induced', endothelial, exocytosis, is]), verbo([mediated]), complemento([via, a, 'VEGFR2/PLCγ1/calcium', pathway])].
[sujeto(['Interestingly,', stretch, also]), verbo([induces]), complemento([a, negative, feedback, via, a, 'VEGFR2/Akt/nitric', oxide, pathway])].
[sujeto(['These', studies]), verbo([reveal]), complemento([mechanical, stretch, as, a, potent, agonist, for, endothelial, 'exocytosis,', which, is, modulated, by, 'VEGFR2', signaling])].
[sujeto(['Thus,', 'VEGFR2', signaling, pathways, may, represent, novel, therapeutic]), verbo([targets]), complemento([in, limiting, hypertensive, 'stretch-related', inflammation])].
[sujeto(['Many', types, of, human, tumor, cells]), verbo([have]), complemento([overexpressed, pyruvate, kinase, 'M2', '(', 'PKM2)'])].
[sujeto(['However,', the, mechanism, underlying, this]), verbo([increased]), complemento(['PKM2', expression, remains, to, be, defined])].
[sujeto(['We', demonstrate, here, that, 'EGFR', activation]), verbo([induces]), complemento(['PLCγ1-dependent', 'PKCε', monoubiquitylation, at, 'Lys321', mediated, by, 'RINCK1', ubiquitin, ligase])].
[sujeto(['Monoubiquitylated', 'PKCε']), verbo([interacts]), complemento([with, a, 'ubiquitin-binding', domain, in, 'NEMO', zinc, finger, and, recruits, the, cytosolic, 'IKK', complex, to, the, plasma, 'membrane,', where, 'PKCε', phosphorylates, 'IKKβ', at, 'Ser177', and, activates, 'IKKβ'])].
[sujeto(['Activated', 'RelA']), verbo([interacts]), complemento([with, 'HIF1α,', which, is, required, for, 'RelA', to, bind, the, 'PKM', promoter])].
[sujeto(['PKCε-', and, 'NF-κB-dependent', 'PKM2', upregulation, is]), verbo([required]), complemento([for, 'EGFR-promoted', glycolysis, and, tumorigenesis])].
[sujeto(['Previously', we]), verbo([reported]), complemento([that, saucerneol, 'D', '(', 'SD),', a, naturally, occurring, sesquilignan, isolated, from, 'Saururus', chinensis, '(', 'S'])].
[sujeto(['chinensis)']), verbo([suppressed]), complemento([lipopolysaccharide, '(', 'LPS)-induced', nitric, oxide, '(', 'NO)', production, in, 'RAW', 264.7, cells])].
[sujeto(['The', aim, of, this, study, was, to, elucidate, whether, 'SD']), verbo([modulates]), complemento([the, generation, of, other, inflammatory, mediators, in, activated, mast, cells])].
[sujeto(['Biochemical', analyses, of, the, 'cytokine-mediated', signaling, pathways, showed, that, 'SD']), verbo([suppressed]), complemento([the, phosphorylation, of, 'Syk', kinase, and, multiple, downstream, signaling, processes, including, phospholipase, 'Cγ1', '(', 'PLCγ1)-mediated', intracellular, 'Ca(2+)', influx, and, activation, of, 'mitogen-activated', protein, kinases, '(', 'MAPKs;', including, extracellular, 'signal-regulated', kinase, 1, /, 2, '(', 'ERK1/2),', 'c-Jun', 'NH(2)-terminal', kinase, '(', 'JNK)', and, 'p38)', and, the, nuclear, 'factor-κB', '(', 'NF-κB)', pathway])].
[sujeto(['Taken', 'together,', the, present, study]), verbo([suggests]), complemento([that, 'SD', suppresses, eicosanoid, generation, and, degranulation, through, 'Syk-dependent', pathway, in, 'BMMCs'])].
[sujeto(['Robust', elevation, of, the, cytosolic, calcium, concentration, is, a, crucial, early, step, for, 'T', cell, activation]), verbo([triggered]), complemento([by, the, 'T', cell, antigen, receptor])].
[sujeto(['Vav1', is, a, 'proto-oncogene']), verbo([expressed]), complemento([in, hematopoietic, cells, that, is, indispensable, for, transducing, the, 'calcium-mobilizing', signal])].
[sujeto(['Following', 'T', cell, receptor, 'stimulation,', 'Vav1', facilitates, formation, of, signaling, microclusters, through, multiple, interactions, with, other, proteins]), verbo([participating]), complemento([in, the, signaling, cascade])].
[sujeto(['This', alteration, is, accompanied, by, a]), verbo([decrease]), complemento([in, 'PLCγ1', phosphorylation, and, inhibition, of, inositol, 1, ',', 4, ',', 5, -, trisphosphate, production])].
[sujeto(['We']), verbo([suggest]), complemento([that, the, structural, integrity, of, the, 'N-terminal', region, of, 'Vav1', is, important, for, the, proper, formation, of, the, 'Vav1-associated', signaling, complexes])].
[sujeto(['The', oncogenic, truncation, of, this, region, elicits, conformational, changes, that, interfere, with, the, 'Vav1-mediated', activation, of, 'PLCγ1', and, that]), verbo([inhibit]), complemento([calcium, mobilization])].
[sujeto(['BDNF', '(', 'brain-derived', neurotrophic, 'factor)', and, its, receptor, 'TrkB', '(', tropomyosin, receptor, kinase, 'B)', play, important, roles, in, the, progression, of, 'cancer,', including, transitional, cell, carcinoma, '(', 'TCC)', cells]), verbo([reported]), complemento([in, our, previous, investigation])].
[sujeto(['The', 'TrkB', 'Ab', at, 3, 'microg/ml', also]), verbo([induced]), complemento([apoptosis, of, 'TCC', 'cells,', which, may, result, from, 'up-regulation', of, 'phospho-p38', plus, 'down-regulation', of, survivin, and, securin, expression])].
[sujeto(['The', 'TrkB', 'Ab', at, 0.5, 'microg/ml,', which, did, not, show, 'cytotoxicity,']), verbo([suppressed]), complemento([migration, of, 'TCC', cells, and, invasion, of, 'BFTC905', 'cells,', possibly, mediated, through, increased, 'E-cadherin,', decreased, 'BDNF-stimulated', 'phospho-PLCgamma1', and, reduced, 'MMP-9', activity])].
[sujeto(['The', constitutive, interaction, between, the, 'P1', domain, '(', a, 67, -, 'amino-acid', functional, domain, within, the, 'proline-rich', 'region)', of, 'SLP76', and, the, 'SH3', domain, of, phospholipase, 'Cγ1', '(', 'PLCγ1)']), verbo([has]), complemento([been, shown])].
[sujeto(['To', determine, the, significance, of, the, interaction, between, 'SLP76', and, 'PLCγ1', in, resting, 'T', 'cells,', we, examined, molecules]), verbo([associated]), complemento([with, 'PLCγ1', in, the, absence, of, both, 'SLP76', 'and,', more, 'specifically,', the, 'P1', domain, of, 'SLP76'])].
[sujeto(['Using', a, mutant, 'Jurkat', 'T-cell', 'line,', we, showed, that, 'PLCγ1']), verbo([associated]), complemento([with, 'LAT', when, the, constitutive, association, with, 'SLP76', was, blocked])].
[sujeto(['We', also]), verbo([found]), complemento([that, the, 'PLCγ1', association, with, 'LAT', occurred, in, the, membranes, of, resting, 'T', cells])].
[sujeto(['Further', experiments, demonstrated, that, 'LAT', competed, with, 'SLP76', for, 'PLCγ1']), verbo([binding]), complemento([and, that, the, 'LAT', interaction, with, 'PLCγ1', was, mediated, by, the, 'SH3', domain, of, 'PLCγ1'])].
[sujeto(['Collectively,', these, results]), verbo([suggest]), complemento([that, the, constitutive, association, of, 'SLP76', with, 'PLCγ1', is, required, to, prevent, the, association, with, 'LAT', as, well, as, the, premature, recruitment, of, 'PLCγ1', to, the, cell, membrane])].
[sujeto(['Although', having, been]), verbo([reported]), complemento([to, regulate, 'epithelial-to-mesenchymal', transition, and, transforming, growth, 'factor-beta-driven', cell, 'invasion,', the, role, of, the, 'miR-200', family, in, 'EGF-driven', breast, cancer, cell, 'invasion,', 'viability,', apoptosis, and, cell, cycle, progression, is, still, unknown])].
[sujeto(['In', this, 'study,', we, show, for, the, first, time, that, 'miR-200', family, members, differentially]), verbo([regulate]), complemento(['EGF-driven', 'invasion,', 'viability,', apoptosis, and, cell, cycle, progression, of, breast, cancer, cells])].
[sujeto(['We', showed, 'that,', all, 'miR-200', family, members]), verbo([regulate]), complemento(['EGF-driven', 'invasion,', with, the, 'miR-200bc/429', cluster, showing, stronger, effects, than, the, 'miR-200a/141', cluster])].
[sujeto(['Furthermore,', expression, of, the, 'miR-200a/141', cluster, results, in, 'G1']), verbo([arrest]), complemento([supported, by, increased, 'p27/Kip1', and, decreased, cyclin, dependent, kinase, 6, expression])].
[sujeto(['In', 'contrast,', expression, of, the, 200, 'bc/429', cluster]), verbo([decreases]), complemento(['G1', population, and, increases, 'G2/M', 'phase,', in, line, with, the, observed, reduction, of, 'p27/Kip1', and, upregulation, of, the, inhibitory, phosphorylation, of, 'Cdc25C,', respectively])].
[sujeto(['To', test, the, hypothesis, that, phenotypical, differences, observed, between, the, two, clusters, are]), verbo([caused]), complemento([by, differential, targeting, 'spectrums,', we, performed, 'genome-wide', microarray, profiling, in, combination, with, 'gain-of-function', studies])].
[sujeto(['Luciferase', reporter, assays, validated, 'PLCG1', as, a, direct, functional]), verbo([target]), complemento([of, 'miR-200bc/429', 'cluster,', but, not, of, 'miR-200a/141', cluster])].
[sujeto(['Finally,']), verbo([loss]), complemento([of, 'PLCG1', in, part, mimicked, the, effect, of, 'miR-200bc/429', overexpression, in, 'viability,', apoptosis, and, 'EGF-driven', cell, invasion, of, breast, cancer, cells])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, the, 'miR-200', family, has, a, 'tumor-suppressor', function, by, negatively, regulating, 'EGF-driven', cell, 'invasion,', viability, and, cell, cycle, progression, in, breast, cancer])].
[sujeto(['We', showed, that, atRA, treatment]), verbo([increased]), complemento(['VEGF-C,', 'VEGF-D,', and, 'VEGFR3', protein, and, mRNA, contents, in, 'dose-dependent', manner])].
[sujeto(['atRA-mediated']), verbo([increase]), complemento([of, both, ligands, and, receptor, expression, correlated, with, the, elevated, level, of, retinoic, acid, receptor, α, '(', 'RARα)', 'expression,', while, the, level, of, another, atRA, 'receptor,', peroxisome, 'proliferator-activated', receptor, 'β/δ', '(', 'PPARβ/δ),', was, decreased])].
[sujeto(['On', the, 'contrary,', the]), verbo([nuclear]), complemento([quantity, of, another, possible, 'RARα', 'counterpart,', transcription, factor, 'Sp1,', was, increased, after, atRA, treatment])].
[sujeto(['Tyrosine', kinase, inhibitors, '(', 'TKIs)']), verbo([provide]), complemento([more, effective, targeted, treatments, for, 'cancer,', but, are, subject, to, a, variety, of, adverse, 'effects,', such, as, hypothyroidism])].
[sujeto(['While', sunitinib, is, suspected, for]), verbo([causing]), complemento([thyroid, dysfunction, more, often, than, other, 'TKIs,', sorafenib, is, believed, to, be, less, risky])].
[sujeto(['Then,', we, used, docking, method, and, identified, 3, proteins, specifically]), verbo([binding]), complemento([to, sunitinib, but, not, 'sorafenib,', i])].
[sujeto(['Our', results, revealed, that, 'CDDP', treatment, significantly]), verbo([increased]), complemento([serum, levels, of, creatinine, and, 'urea,', with, concomitant, decrease, in, serum, albumin])].
[sujeto(['Moreover,', reduced, glutathione, '(', 'GSH)', content, as, well, as, superoxide, dismutase, '(', 'SOD)', and, catalase, '(', 'CAT)', activities, were, significantly, reduced, with, concurrent]), verbo([increase]), complemento([in, kidney, malondialdehyde, '(', 'MDA)', content, following, 'CDDP', treatment])].
[sujeto(['In', 'addition,', 'CDDP/ATRA', 'co-treatment', significantly]), verbo([increased]), complemento(['RAR-α,', 'RXR-α,', 'fibrin,', and, iNOS, protein, expression, compared, to, 'CDDP', alone])].
[sujeto(['Albeit', 'all-trans', retinoic, acid, '(', 'RA)']), verbo([has]), complemento([been, associated, with, axon, outgrowth, and, nerve, 'regeneration,', the, maintenance, of, differentiated, 'neurons,', the, association, with, degenerative, disease, like, 'Parkinson\'s', 'disease,', and, its, regulatory, molecular, mechanism, from, pluripotent, stem, cells, to, neural, stem, cells, remain, fragmented])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, that, 'RA', is, capable, of, differentiation, of, human, trophoblast, stem, cells, to, dopamine, '(', 'DA)', committed, progenitor, cells])].
[sujeto(['We']), verbo([found]), complemento([that, at, the, early, 'stage,', integration, of, 'TrkA', and, 'G', protein, signalings, aims, for, axonogenesis, and, 'morphogenesis,', involving, the, novel, 'RXRα/Gαq/11', and, 'RARβ/Gβ', signaling, pathways])].
[sujeto(['While', at, the, later, 'stage,', five, distinct, signaling, pathways, together, with, epigenetic, histone, modifications, emerged, to]), verbo([regulate]), complemento([expression, of, 'TH,', a, precursor, of, dopamine])].
[sujeto(['Our', results]), verbo([provided]), complemento([substantial, mechanistic, evidence, that, human, trophoblast, stem, 'cell-derived', neural, stem, cells, can, potentially, be, used, for, neurobiological, 'study,', drug, 'discovery,', and, as, an, alternative, source, of, 'cell-based', therapy, in, neurodegenerative, diseases, like, 'Parkinson\'s', disease])].
[sujeto(['Evidence', from, previous, studies]), verbo([suggests]), complemento([that, the, male, reproductive, system, can, be, disrupted, by, fetal, or, neonatal, exposure, to, diethylstilbestrol, '(', 'DES)'])].
[sujeto(['To', evaluate, the, effects, of, 'DES', on, mouse, spermatocytes, and, to, explore, its, potential, mechanism, of, 'action,', the, levels, of, 'DNA', methyltransferases, '(', 'DNMTs)', and, 'DNA', methylation]), verbo([induced]), complemento([by, 'DES', were, detected])].
[sujeto(['The', results, showed, that, low, doses, of, 'DES']), verbo([inhibited]), complemento([cell, proliferation, and, cell, cycle, progression, and, induced, apoptosis, in, 'GC-2', 'cells,', an, immortalized, mouse, pachytene, 'spermatocyte-derived', cell, 'line,', which, reproduces, primary, cells, responses, to, 'E2'])].
[sujeto(['Furthermore,', global, 'DNA', methylation, levels, were]), verbo([increased]), complemento([and, the, expression, levels, of, 'DNMTs', were, altered, in, 'DES-treated', 'GC-2', cells])].
[sujeto(['Rxra,', an, important, component, of, the, retinoic, acid, signaling, 'pathway,', and, 'mybph,', a, 'RhoA', 'pathway-related', 'protein,', were]), verbo([found]), complemento([to, be, 'hypermethylated,', and, 'Prkcd,', an, 'apoptosis-related', 'protein,', was, hypomethylated])].
[sujeto(['Taken', 'together,', these, data, demonstrate, that, 'DNA', methylation, likely, plays, an, important, role, in]), verbo([mediating]), complemento(['DES-induced', spermatocyte, toxicity, in, vitro])].
[sujeto(['Hepatic', retinyl, palmitate, in, broiler, breeders, and, hatchlings, '(', within, 12, 'h)']), verbo([increased]), complemento([with, increasing, 'VA', '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['VA', supplementation]), verbo([increased]), complemento(['insulin-like', growth, factor, 1, '(', 'IGF-I)', receptor, transcripts, in, the, ovarian, stroma, and, the, walls, of, yellow, 'follicles,', follicle, stimulating, hormone, '(', 'FSH)', receptor, expression, in, the, walls, of, white, and, yellow, 'follicles,', and, luteinizing, hormone, '(', 'LH)', receptor, and, growth, hormone, '(', 'GH)', receptor, transcripts, in, the, walls, of, yellow, follicles, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['Caspase-3', and, 'Fas', mRNA, levels, in, the, ovarian, stroma, and, the, walls, of, white, and, yellow, follicles]), verbo([decreased]), complemento([with, 'VA', supplementation, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['The', relative, expression, of, retinol, dehydrogenase, 10, '(', 'RDH10)', transcripts, in, the, walls, of, white, follicles]), verbo([increased]), complemento([with, 5, ',', 400, 'IU/kg', 'VA', supplementation, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['Supplemental', 21, ',', 600, 'IU/kg', 'VA']), verbo([increased]), complemento([cytochrome, 'P450', 26, 'A1', '(', 'CYP26A1)', transcripts, in, the, ovarian, stroma, and, the, walls, of, white, follicles, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['It', was, concluded, that, 'VA', supplementation, improved, reproductive, performance, and, hepatic, storage, of, 'VA,', and, this, was]), verbo([associated]), complemento([with, the, regulation, of, ovarian, hormone, receptor, expression, and, suppression, of, apoptosis, gene, transcripts, through, its, active, metabolite, retinoic, acid, '(', 'RA)'])].
[sujeto(['The', optimal, dietary, 'VA', level, for, 'Chinese', 'yellow-feathered', broiler, breeders, at, 46, to, 54, wk, of, age, was]), verbo([found]), complemento([to, be, 10, ',', 800, 'IU/kg'])].
[sujeto(['Understanding', of, the, genetic, regulation, of, puberty, timing]), verbo([has]), complemento([come, largely, from, studies, of, rare, disorders, and, 'population-based', studies, in, women])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, largest, genomic, analysis, for, puberty, timing, in, 55, ',', 871, 'men,', based, on, recalled, age, at, voice, breaking])].
[sujeto(['Analysis', across, all, genomic, variants]), verbo([reveals]), complemento([strong, genetic, correlation, '(', 0.74, ',', 'P=2'])].
[sujeto(['We']), verbo([find]), complemento([five, novel, loci, for, puberty, timing, '(', 'P&lt;5', ×, 10, '(', -, 8, ')', ')', ',', in, addition, to, nine, signals, in, men, that, were, previously, reported, in, women])].
[sujeto(['The', 'Wnt', activator, 'WAY-262611', and, 'β-catenin', activator, lithium, chloride, '(', 'LiCl)', were, used, to]), verbo([activate]), complemento([the, pathway, at, distinct, levels, in, 'HSCs'])].
[sujeto(['Both', 'WAY-262611', and, 'LiCl']), verbo([promoted]), complemento([proliferation, and, upregulated, the, expression, of, 'α-smooth', muscle, actin, and, 'α1(I)', 'procollagen,', but, they, decreased, the, contents, of, intracellular, lipids, and, triglyceride, in, 'HSCs'])].
[sujeto(['Analyses', of, adipogenic, transcription, pattern, showed, that, the, two, compounds, reduced, the, expression, of, peroxisome, 'proliferator-activated', receptor, 'γ,', 'CCAAT/enhancer']), verbo([binding]), complemento([protein, 'α,', retinoid, 'X', 'receptor-α,', and, retinoic, acid, 'receptor-β,', four, key, transcription, regulators, of, 'HSC', adipogenic, phenotype])].
[sujeto(['Wnt/β-catenin', pathway, was, a, profibrogenic, signaling, and]), verbo([inhibited]), complemento([lipogenesis, by, suppressing, adipogenic, transcription, pattern, in, 'HSCs'])].
[sujeto(['Blockade', of, this, pathway, was]), verbo([associated]), complemento([with, curcumin, stimulation, of, 'HSC', lipogenesis])].
[sujeto(['The', inflammatory, process, is, related, to, a, variety, of, immune, 'cells,', including, 'macrophages,', helper, 'T', 'cells,', 'neutrophils,', dendritic, 'cells,', and, 'Treg', 'cells,', and, is]), verbo([associated]), complemento([with, 'proinflammatory,', chemotactic, and, regulatory, cytokines])].
[sujeto(['All-trans', retinoic, acids, '(', 'ATRA)']), verbo([have]), complemento([diverse, immunomodulatory, actions, in, a, number, of, inflammatory, and, autoimmune, conditions])].
[sujeto(['These', retinoids]), verbo([regulate]), complemento([the, transcriptional, levels, of, target, genes, through, the, activation, of, nuclear, receptors])].
[sujeto(['Retinoic', acid, receptor, α, '(', 'RAR', 'α),', retinoic, acid, receptor, γ, '(', 'RAR', 'γ),', and, retinoid, 'X', receptor, α, '(', 'RXR', 'α)', are]), verbo([expressed]), complemento([in, the, cornea, and, immune, cells])].
[sujeto(['The', 'StAR', protein, predominantly]), verbo([regulates]), complemento([steroid, biosynthesis, in, steroidogenic, tissues])].
[sujeto(['We']), verbo([have]), complemento([reported, that, regulation, of, 'retinoid,', especially, atRA, and, 9, -, cis, 'RA,', responsive, 'StAR', transcription, is, largely, mediated, by, an, 'LXR-RXR/RAR', heterodimeric, motif, in, the, mouse, 'StAR', promoter])].
[sujeto(['Herein', we, demonstrate, that, retinoids, are, capable, of]), verbo([enhancing]), complemento(['StAR', 'protein,', 'P-StAR,', and, steroid, production, in, 'granulosa,', 'adrenocortical,', 'glial,', and, epidermal, cells])].
[sujeto(['Whereas', transient, expression, of, 'RARα', and, 'RXRα']), verbo([enhanced]), complemento([9, -, cis, 'RA', induced, 'StAR', gene, 'transcription,', silencing, of, 'RXRα', with, 'siRNA,', decreased, 'StAR', and, steroid, levels])].
[sujeto(['An', oligonucleotide, probe, encompassing, an, 'LXR-RXR/RAR', motif]), verbo([bound]), complemento([to, adrenocortical, and, epidermal, keratinocyte, nuclear, proteins, in, 'EMSAs'])].
[sujeto(['Further', studies, demonstrated, that, 'StAR', mRNA, levels]), verbo([decreased]), complemento([in, diseased, and, elderly, men, and, women, skin, tissues, and, that, atRA, could, restore, steroidogenesis, in, epidermal, keratinocytes, of, aged, individuals])].
[sujeto(['These', findings]), verbo([provide]), complemento([novel, insights, into, the, relevance, of, retinoid, signaling, in, the, 'up-regulation', of, steroid, biosynthesis, in, various, target, 'tissues,', and, indicate, that, retinoid, therapy, may, have, important, implications, in, 'age-related', complications, and, diseases])].
[sujeto(['Although', considerable, data]), verbo([have]), complemento([been, obtained, about, 'RA,', ghrelin, and, bombesin, in, the, congenital, diaphragmatic, hernia, '(', 'CDH)', rat, 'model,', neuroendocrine, factors, have, never, been, associated, with, the, 'RA', signalling, pathway, in, this, animal, model])].
[sujeto(['The', authors]), verbo([found]), complemento([that, normal, fetal, lung, explants, treated, with, 'RA,', bombesin, and, ghrelin, showed, an, increase, in, lung, growth])].
[sujeto(['Moreover', bombesin, and, ghrelin, 'supplementation,', in, 'vitro,', to, normal, lungs]), verbo([increased]), complemento(['RA', receptor, 'α/γ', expression, whereas, administration, of, bombesin, and, ghrelin, antagonists, to, normal, and, hypoplastic, lungs, decreased, it])].
[sujeto(['These', data]), verbo([reveal]), complemento([for, the, first, time, that, there, is, a, link, between, neuroendocrine, factors, and, 'RA,', and, that, neuroendocrine, factors, sensitise, the, lung, to, the, 'RA', action, through, 'RA', receptor, modulation])].
[sujeto(['Congenital', diaphragmatic, hernia, '(', 'CDH)', is, characterised, by, a, spectrum, of, lung, hypoplasia, and, consequent, pulmonary, 'hypertension,']), verbo([leading]), complemento([to, high, morbidity, and, mortality, rates])].
[sujeto(['Moreover,', 'CDH']), verbo([has]), complemento([been, associated, with, an, increase, in, the, levels, of, pulmonary, neuroendocrine, 'factors,', such, as, bombesin, and, 'ghrelin,', and, a, decrease, in, the, action, of, retinoic, acid, '(', 'RA)'])].
[sujeto(['Furthermore', considering, hypoplastic, 'lungs,', bombesin, and, ghrelin, antagonists]), verbo([decreased]), complemento(['RARα/γ', expression])].
[sujeto(['Normal', lung, explants, '(', 13.5, 'dpc)', treated, with, 'RA,', bombesin, plus, 'RA,', ghrelin, plus, 'RA,', bombesin, or, ghrelin, exhibited]), verbo([increased]), complemento([lung, growth])].
[sujeto(['Moreover,', bombesin, and, ghrelin]), verbo([increased]), complemento(['RARα/γ', expression, 'levels,', whereas, the, bombesin, and, ghrelin, antagonists, decreased, 'RARα/γ', expression])].
[sujeto(['In', addition, to, its, actions, outside, the, 'cell,', cellular, uptake, and]), verbo([nuclear]), complemento([import, of, 'insulin-like', growth, factor, binding, 'protein-3', '(', 'IGFBP-3)', has, been, recognized, for, almost, two, 'decades,', but, knowledge, of, its, nuclear, actions, has, been, slow, to, emerge])].
[sujeto(['IGFBP-3']), verbo([has]), complemento([a, functional, nuclear, localization, signal, and, interacts, with, the, nuclear, transport, protein, 'importin-β'])].
[sujeto(['Within', the, nucleus, 'IGFBP-3', appears, to]), verbo([have]), complemento([a, role, in, transcriptional, regulation])].
[sujeto(['It', can]), verbo([bind]), complemento([to, the, nuclear, 'receptor,', retinoid, 'X', 'receptor-α', and, several, of, its, dimerization, 'partners,', including, retinoic, acid, 'receptor,', vitamin, 'D', receptor, '(', 'VDR),', and, peroxisome, 'proliferator-activated', 'receptor-γ', '(', 'PPARγ)'])].
[sujeto(['These', interactions]), verbo([modulate]), complemento([the, functions, of, these, 'receptors,', for, example, inhibiting, 'VDR-dependent', transcription, in, osteoblasts, and, 'PPARγ-dependent', transcription, in, adipocytes])].
[sujeto(['Nuclear', 'IGFBP-3', can, be, detected, by, immunohistochemistry, in, cancer, and, other, 'tissues,', and, its, presence, in, the, nucleus]), verbo([has]), complemento([been, shown, in, many, cell, culture, studies, to, be, necessary, for, its, 'pro-apoptotic', 'effect,', which, may, also, involve, interaction, with, the, nuclear, receptor, 'Nur77,', and, export, from, the, nucleus])].
[sujeto(['IGFBP-3', is, 'p53-inducible', and, in, response, to, 'DNA', 'damage,', forms, a, complex, with, the, epidermal, growth, factor, receptor, '(', 'EGFR),', translocating, to, the, nucleus, to]), verbo([interact]), complemento([with, 'DNA-dependent', protein, kinase])].
[sujeto(['Inhibition', of, 'EGFR', kinase, activity, or, downregulation, of, 'IGFBP-3', can]), verbo([inhibit]), complemento(['DNA', double, 'strand-break', repair, by, nonhomologous, end, joining])].
[sujeto(['IGFBP-3', thus]), verbo([has]), complemento([the, ability, to, influence, many, cell, functions, through, its, interactions, with, intranuclear, 'pathways,', but, the, importance, of, these, interactions, in, 'vivo,', and, their, potential, to, be, targeted, for, therapeutic, 'benefit,', require, further, investigation])].
[sujeto(['To', address, this, 'question,', we]), verbo([have]), complemento([analyzed, the, phenotypes, of, mice, 'lacking,', in, 'spermatogonia,', all, rexinoid, receptors, '(', 'RXRA,', 'RXRB', and, 'RXRG)', or, all, 'ATRA', receptors, '(', 'RARA,', 'RARB', and, 'RARG)'])].
[sujeto(['We', also, show, that, 'ATRA']), verbo([activates]), complemento(['RAR', and, 'RXR', bound, to, a, conserved, regulatory, region, to, increase, expression, of, the, 'SALL4A', transcription, factor, in, spermatogonia])].
[sujeto(['Our', results]), verbo([reveal]), complemento([that, this, major, pluripotency, gene, is, a, target, of, 'ATRA', signaling, and, that, 'RAR/RXR', heterodimers, are, the, functional, units, driving, its, expression, in, spermatogonia])].
[sujeto(['They', add, to, the, mechanisms, through, which, 'ATRA']), verbo([promote]), complemento([expression, of, the, 'KIT', tyrosine, kinase, receptor, to, trigger, a, critical, step, in, spermatogonia, differentiation])].
[sujeto(['Importantly,', they, indicate, also, that, meiosis, eventually, occurs, in, the, absence, of, a, 'RAR/RXR', pathway, within, germ, cells, and]), verbo([suggest]), complemento([that, instructing, this, process, is, either, 'ATRA-independent', or, requires, an, 'ATRA', signal, originating, from, 'Sertoli', cells])].
[sujeto(['Efforts', to, unravel, the, complex, molecular, mechanisms, underlying, 'RMS', pathogenesis, and, progression]), verbo([have]), complemento([revealed, that, microRNAs, '(', 'miRNAs)', play, a, key, role, in, tumorigenesis])].
[sujeto(['Attention', was, focused, on, the, role, of, 'miR-27a', that, is, 'up-regulated', in, the, more, aggressive, 'RMS', cell, lines, '(', 'translocation-positive', 'ARMS)', in, which, it, probably]), verbo([acts]), complemento([as, an, oncogene])].
[sujeto(['MiR-27a', overexpressing, cells, showed, a, significant]), verbo([increase]), complemento([in, their, proliferation, rate, that, was, paralleled, by, a, decrease, in, the, number, of, cells, in, the, 'G1', phase, of, the, cell, cycle])].
[sujeto(['It', was, possible, to, demonstrate, that, 'miR-27a', is, implicated, in, cell, cycle, control, by]), verbo([targeting]), complemento([the, retinoic, acid, alpha, receptor, '(', 'RARA)', and, retinoic, 'X', receptor, alpha, '(', 'RXRA)'])].
[sujeto(['Study', results]), verbo([have]), complemento([demonstrated, that, miRNA, expression, signature, profiling, can, be, used, to, classify, different, 'RMS', subtypes, and, suggest, that, 'miR-27a', may, have, a, therapeutic, potential, in, 'RMS', by, modulating, the, expression, of, retinoic, acid, receptors])].
[sujeto(['While', the, nucleoporin, 98, -, retinoic, acid, receptor, gamma, '(', 'NUP98-RARG)', is, the, first, 'RARG', fusion, protein]), verbo([found]), complemento([in, acute, 'leukemia,', its, roles, and, the, molecular, basis, in, oncogenic, transformation, are, currently, unknown])].
[sujeto(['Here,', we, showed, that, homodimeric, 'NUP98-RARG', not, only, acquired, unique]), verbo([nuclear]), complemento([localization, pattern, and, ability, of, recruiting, both, 'RXRA', and, 'wild-type', 'NUP98,', but, also, exhibited, similar, transcriptional, properties, as, 'RARA', fusions, found, in, acute, promyelocytic, leukemia, '(', 'APL)'])].
[sujeto(['Using', murine, bone, marrow, retroviral, 'transduction/transformation', 'assay,', we, further, demonstrated, that, 'NUP98-RARG', fusion, protein, had, gained, transformation, ability, of, primary, hematopoietic, 'stem/progenitor', 'cells,', which, was, critically, dependent, on, the, 'C-terminal', 'GLFG', domain, of, 'NUP98', and, the, 'DNA']), verbo([binding]), complemento([domain, '(', 'DBD)', of, 'RARG'])].
[sujeto(['Interestingly,', while, 'pan-RXR', 'agonists,', 'SR11237', and, 'LGD1069', could, specifically]), verbo([inhibit]), complemento(['NUP98-RARG', transformed, 'cells,', mutation, of, the, 'RXR', interaction, domain, in, 'NUP98-RARG', had, little, effect, on, its, 'transformation,', revealing, that, therapeutic, functions, of, rexinoid, can, be, independent, of, the, direct, biochemical, interaction, between, 'RXR', and, the, fusion])].
[sujeto(['Together,', these, results, indicate, that, deregulation, of, the, 'retinoid/rexinoid', signaling, pathway]), verbo([has]), complemento([a, major, role, and, may, represent, a, potential, therapeutic, target, for, 'NUP98-RARG-mediated', transformation])].
[sujeto(['PML/RARA,', a, potent, transcriptional, inhibitor, of]), verbo([nuclear]), complemento([receptor, 'signaling,', represses, myeloid, differentiation, genes, and, drives, acute, promyelocytic, leukemia, '(', 'APL)'])].
[sujeto(['Association', of, the, retinoid, 'X', 'receptor-α', '(', 'RXRA)', coreceptor, to, 'PML/RARA', is]), verbo([required]), complemento([for, 'transformation,', with, 'RXRA', promoting, its, efficient, 'DNA', binding])].
[sujeto(['APL', is, exquisitely, sensitive, to, retinoic, acid, '(', 'RA)', and, arsenic, trioxide, '(', 'arsenic),', which, both]), verbo([trigger]), complemento([cell, differentiation, in, vivo])].
[sujeto(['Whereas', 'RA', elicits, transcriptional, activation, of, 'PML/RARA', 'targets,', how, arsenic]), verbo([triggers]), complemento([differentiation, remains, unclear])].
[sujeto(['Here', we, demonstrate, that, extinction, of, 'PML/RARA']), verbo([triggers]), complemento([terminal, differentiation, in, vivo])].
[sujeto(['Similarly,', ablation, of, retinoid, 'X', receptors, loosens, 'PML/RARA', 'DNA', 'binding,']), verbo([inducing]), complemento([terminal, differentiation, of, 'APL', cells, ex, vivo, or, in, vivo])].
[sujeto(['RXRA', sumoylation, directly, contributes, to, 'PML/RARA-dependent', transformation, ex, 'vivo,', presumably, by]), verbo([enhancing]), complemento([transcriptional, repression])].
[sujeto(['Thus,', 'APL', differentiation, is, a, default, program]), verbo([triggered]), complemento([by, clearance, of, 'PML/RARA-bound', 'promoters,', rather, than, obligatory, active, transcriptional, 'activation,', explaining, how, arsenic, elicits, 'APL', maturation, through, 'PML/RARA', degradation])].
[sujeto(['The', response, rate, of, 'non-M3', acute, myeloid, leukemia, '(', 'AML)', to, all, trans, retinoic, acid]), verbo([has]), complemento([been, limited])].
[sujeto(['Using', 'Affymetrix', expression, 'arrays,', we]), verbo([found]), complemento([that, in, diverse, 'AML', blasts, 'RXRA', was, expressed, at, higher, levels, than, 'RARA', and, that, mouse, 'Ctsg-PML-RARA', leukemia, responded, to, 'bexarotene,', a, ligand, for, 'RXRA'])].
[sujeto(['We']), verbo([found]), complemento([that, this, combination, was, well, 'tolerated,', although, outcomes, were, modest, '(', 1, 'CRi,', and, 3, 'PR', among, 19, 'patients)'])].
[sujeto(['Correlative', studies]), verbo([found]), complemento([that, patients, with, clinical, response, had, increased, differentiation, to, bexarotene, both, in, vivo, and, ex, 'vivo,', suggesting, that, 'pre-treatment', analysis, might, identify, a, more, susceptible, subgroup, of, patients])].
[sujeto(['At', 'present,', eight, other, genes, fusing, with, 'RARA']), verbo([have]), complemento([been, identified])].
[sujeto(['The', resulting, fusion, proteins]), verbo([retain]), complemento([domains, of, the, 'RARA', protein, allowing, binding, to, retinoic, acid, response, elements, '(', 'RARE)', and, dimerization, with, the, retinoid, 'X', receptor, protein, '(', 'RXRA)'])].
[sujeto(['They']), verbo([participate]), complemento([in, 'protein-protein', 'interactions,', associating, with, 'RXRA', to, form, 'hetero-oligomeric', complexes, that, can, bind, to, 'RARE'])].
[sujeto(['They']), verbo([have]), complemento([a, 'dominant-negative', effect, on, 'wild-type', 'RARA/RXRA', transcriptional, activity])].
[sujeto(['Moreover,', 'RARA', fusion, proteins, can, 'homodimerize,']), verbo([conferring]), complemento([the, ability, to, regulate, an, expanded, repertoire, of, genes, normally, not, affected, by, 'RARA'])].
[sujeto(['RARA', fusion, proteins, behave, as, potent, transcriptional, repressors, of, retinoic, acid, 'signalling,']), verbo([inducing]), complemento([a, differentiation, blockage, at, the, promyelocyte, stage, which, can, be, overcome, with, therapeutic, doses, of, 'ATRA', or, arsenic, trioxide])].
[sujeto(['RA', similarly]), verbo([inhibited]), complemento([proliferation, of, palatal, 'KC', from, cleft, and, 'non-cleft', subjects])].
[sujeto(['RA', treatment, reduced, the, expression, of, several, of, the, investigated, 'genes;', the, proliferating, cell]), verbo([nuclear]), complemento([antigen, '(', 'PCNA)', was, reduced, in, 'CLP', 'KCs', only])].
[sujeto(['Two', 'P63']), verbo([target]), complemento([genes, '(', 'GJB6', and, 'DLX5)', were, strongly, downregulated, by, 'RA', in, all, cell, lines])].
[sujeto(['Overall,', 'RA', similarly]), verbo([inhibits]), complemento([proliferation, of, palatal, 'KCs', from, cleft, and, 'non-cleft', subjects, and, reduces, the, expression, of, specific, genes])].
[sujeto(['We', characterized, the, expression, of, 'RA', receptors, and, retinoid, 'X', receptors, '(', 'RARs', and, 'RXRs)', in, a, series, of, 111, thyroid, tumors, and, investigated, the, mechanisms, responsible, for, their, 'deregulation:', hypermethylation, of, the, 'RARB2', 'promoter,']), verbo([loss]), complemento([of, heterozygosity, '(', 'LOH)', in, the, regions, of, 'RARB', and, 'RXRA,', and, altered, expression, of, 'CRBP1', and, enzymes, involved, in, 'RA', biosynthesis, '(', 'RDH10', and, 'RALDH2)'])].
[sujeto(['Expression', of, 'RALDH2', and, 'RDH10', was]), verbo([conserved]), complemento([in, 100, '%', of, adenomas, and, in, 90, and, 98, '%', ',', 'respectively,', of, 'carcinomas,', whereas, staining, for, 'CRBP1', was, decreased, in, 9, '%', of, 'FAs', and, 28, '%', of, 'carcinomas,', mainly, anaplastic, carcinomas, '(', 55, '%', ')'])].
[sujeto(['We']), verbo([found]), complemento([an, abnormal, expression, of, 'RARA,', 'RARB,', 'RXRA,', and, 'RXRB', in, 67, ',', 69, ',', 66, ',', and, 73, '%', ',', 'respectively,', of, thyroid, carcinomas, '(', n, =, 78, ')', and, in, 9, ',', 9, ',', 9, ',', and, 33, '%', of, follicular, adenomas, '(', n, =, 33, ')', '(', p, &, 'lt;', 0.001, ')'])].
[sujeto(['LOH', was]), verbo([found]), complemento([to, be, common, at, the, 'RARB', locus, '(', 3, 'p24-3p25)', and, the, 'RXRA', locus, '(', 9, 'q34),', 'respectively,', in, 44, and, 55, '%', of, carcinomas, and, in, 27, and, 43, '%', of, adenomas])].
[sujeto(['Objectives', were, to, '(', 1, ')', determine, the, feasibility, of, performing, hoof, biopsies, without, impairing, 'locomotion;', '(', 2, ')', evaluate, the, feasibility, of, using, biopsied, tissue, for, quantitative, 'PCR;', and, '(', 3, ')', compare, relative, gene, expression, among, claws, for, several]), verbo([target]), complemento([genes])].
[sujeto(['Biotinidase', '(', 'BTD)', expression, was, greater, in, claw, 3, versus, claw, 5, ',', whereas, the, 'ligand-activated']), verbo([nuclear]), complemento([receptor, retinoic, acid, 'receptor-α', '(', 'RXRA)', was, greater, in, claws, 3, +, 5, compared, with, claw, 7])].
[sujeto(['Overall,', results, from, this, pilot, study, revealed, modest, differences, at, the, transcriptome, 'level,']), verbo([suggesting]), complemento([that, biotin, availability, and, lipid, metabolism, differ, between, claw, 'positions,', whereas, inflammation, and, oxidative, stress, seem, to, play, an, important, role, across, claws])].
[sujeto(['More', comprehensive, studies, of, the, hoof, transcriptome, are]), verbo([required]), complemento([to, improve, our, understanding, of, the, mechanisms, that, link, environmental, and, dietary, factors, to, development, of, lameness])].
[sujeto(['Acute', promyelocytic, leukaemia, '(', 'APL)', is]), verbo([induced]), complemento([by, fusion, proteins, always, implying, the, retinoic, acid, receptor, 'RARa'])].
[sujeto(['Although', 'PML-RARa', and, other, fusion, oncoproteins, are, able, to]), verbo([bind]), complemento(['DNA', as, 'homodimers,', in, vivo, they, are, always, found, in, association, with, the, nuclear, receptor, 'RXRa', '(', 'Retinoid', 'X', 'Receptor)'])].
[sujeto(['Actually,', 'RXRa', contributes, to, several, aspects, of, in, vivo, -, 'transformation:', 'RARa', 'fusion:RXRa', 'hetero-oligomeric', complexes]), verbo([bind]), complemento(['DNA', with, a, much, greater, affinity, than, 'RARa', fusion, homodimers])].
[sujeto(['Besides,', 'PML-RARa:RXRa']), verbo([recognizes]), complemento([an, enlarged, repertoire, of, 'DNA', binding, sites])].
[sujeto(['Thus', the, association, between, fusion, proteins, and, 'RXRa']), verbo([regulates]), complemento([more, genes, than, the, homodimer, alone])].
[sujeto(['Finally,', 'RXRa', is]), verbo([required]), complemento([for, 'rexinoid-induced', 'APL', differentiation])].
[sujeto(['The', 'RARB', haplotype, '(', 'rs6800566/rs6550976/rs9834818)', was, significantly]), verbo([associated]), complemento([with, variations, in, both, measles, antibody, '(', 'global,', 'P=0'])].
[sujeto(['Specifically,', the, 'RARB', 'haplotype,', 'AAC,', was]), verbo([associated]), complemento([with, higher, '(', 't-statistic:', 3.27, ',', 'P=0'])].
[sujeto(['At', the, other, end, of, the, 'spectrum,', haplotype, 'GG', for, 'rs6550978/rs6777544', was]), verbo([associated]), complemento([with, lower, antibody, levels, '(', 't-statistic:', -, 2.32, ',', 'P=0'])].
[sujeto(['A', significant, association, was]), verbo([found]), complemento([between, lower, 'measles-specific', 'IFN-γ', 'Enzyme-linked', immunosorbent, spot, responses, and, haplotypes, 'rs11102986/rs11103473/rs11103482/rs10776909/rs12004589/rs35780541/rs2266677/rs875444', '(', 'global,', 'P=0'])].
[sujeto(['We', also]), verbo([found]), complemento([associations, between, multiple, 'RARB,', 'VDR,', and, 'RXRA', 'SNPs/haplotypes', and, 'measles-specific', 'IL-2,', 'IL-6,', 'IL-10,', 'IFN-α,', 'IFN-γ,', 'IFNλ-1,', and, 'TNF-α', cytokine, secretions])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, specific, allelic, variations, and, haplotypes, in, the, vitamin, 'A', receptor, and, 'VDR', genes, may, influence, adaptive, immune, responses, to, measles, vaccine])].
[sujeto(['Head', and, neck, squamous, cell, carcinoma, '(', 'HNSCC)', patients, are, at, an]), verbo([increased]), complemento([risk, of, developing, a, second, primary, tumor, '(', 'SPT)', or, recurrence, following, curative, treatment])].
[sujeto([13, -, 'cis-retinoic', acid, '(', 13, -, 'cRA)']), verbo([has]), complemento([been, tested, in, chemoprevention, clinical, 'trials,', but, the, results, have, been, inconclusive])].
[sujeto(['Patients', carrying, the, common, genotype, of, rs3118570, in, the, retinoid, 'X', receptor, '(', 'RXRA)', were, at, a, 3.33, -, fold]), verbo([increased]), complemento([risk, '(', 95, '%', 'CI,', 1.67, -, 6.67, ')', and, represented, more, than, 70, '%', of, the, study, population])].
[sujeto(['Epicardial', signaling, and, 'Rxra', are]), verbo([required]), complemento([for, expansion, of, the, ventricular, myocardial, compact, zone])].
[sujeto(['Although', 'RA', activity, is, completely, lost, in, 'Raldh2(-/-)', epicardium, and, the, adjacent, 'myocardium,', 'RA', activity, is, not, lost, in, 'Rxra(-/-)', 'hearts,']), verbo([suggesting]), complemento([that, 'RA', signaling, in, the, 'epicardium/myocardium', is, not, required, for, myocardial, compact, zone, formation])].
[sujeto(['We', explored, the, possibility, that, 'RA-mediated']), verbo([target]), complemento([gene, transcription, in, 'non-cardiac', tissues, is, required, for, this, process])].
[sujeto(['We']), verbo([found]), complemento([that, hepatic, expression, of, erythropoietin, '(', 'EPO),', a, secreted, factor, implicated, in, myocardial, 'expansion,', is, dependent, on, both, 'Raldh2', and, 'Rxra'])].
[sujeto(['Chromatin', immunoprecipitation, studies, support, 'Epo', as, a, direct]), verbo([target]), complemento([of, 'RA', signaling, in, embryonic, liver])].
[sujeto(['We', propose, a, new, model, for, the, mechanism, of, 'RA-mediated', myocardial, expansion, in, which, 'RA', directly]), verbo([induces]), complemento([hepatic, 'Epo', resulting, in, activation, of, epicardial, 'Igf2', that, stimulates, compact, zone, growth])].
[sujeto(['During', the, in, vitro, differentiation, of, human, villous, cytotrophoblast, '(', 'CTB)', cells, to, a, syncytiotrophoblast, '(', 'STB)', 'phenotype,', mRNA, levels, for, the]), verbo([nuclear]), complemento([hormone, receptor, 'NR2F2', '(', 'ARP-1,', 'COUP-TFII)', increase, 'rapidly,', reaching, a, peak, at, day, 1, of, differentiation, that, is, 8.8, -, fold, greater, than, that, in, undifferentiated, 'CTB', cells])].
[sujeto(['To', examine, whether, 'NR2F2', is]), verbo([involved]), complemento([in, the, regulation, of, villous, 'CTB', cell, 'differentiation,', studies, were, performed, to, determine, whether, 'NR2F2', regulates, the, expression, of, 'TFAP2A', '(', 'AP-2alpha),', a, transcription, factor, that, is, critical, for, the, terminal, differentiation, of, these, cells, to, a, 'STB', phenotype])].
[sujeto(['Overexpression', of, 'NR2F2', in, primary, cultures, of, human, 'CTB', cells, and, 'JEG-3', human, choriocarcinoma, cells]), verbo([induced]), complemento(['dose-dependent', increases, in, 'TFAP2A', promoter, activity])].
[sujeto(['Conversely,', siRNA]), verbo([mediated]), complemento([silencing, of, the, 'NR2F2', gene, in, villous, 'CTB', undergoing, spontaneous, differentiation, blocked, the, induction, of, the, mRNAs, for, 'TFAP2A', and, several, 'STB', cell, specific, marker, 'genes,', including, human, placental, lactogen, '(', 'hPL),', pregnancy, specific, glycoprotein, 1, '(', 'PSG1)', and, corticotropin, releasing, hormone, '(', 'CRH)', by, 51, -, 59, '%'])].
[sujeto(['The', induction, of, 'TFAP2A', promoter, activity, by, 'NR2F2', was, potentiated, by, the]), verbo([nuclear]), complemento([hormone, receptors, retinoic, acid, receptor, alpha, '(', 'RARA)', and, retinoid, 'X', receptor, alpha, '(', 'RXRA)'])].
[sujeto(['Taken', 'together,', these, results, strongly]), verbo([suggest]), complemento([that, 'NR2F2', is, involved, in, villous, 'CTB', cell, differentiation, and, that, 'NR2F2', 'acts,', at, least, in, 'part,', by, directly, activating, 'TFAP2A', gene, expression, and, by, potentiating, the, transactivation, of, 'TFAP2A', by, 'RARA', and, 'RXRA'])].
[sujeto(['Toll-like,', vitamin, 'A', and, 'D', receptors, and, other, innate, proteins]), verbo([participate]), complemento([in, various, immune, functions])].
[sujeto(['We', determined, whether, innate, 'gene-sequence', variations, are]), verbo([associated]), complemento([with, rubella, 'vaccine-induced', cytokine, immune, responses])].
[sujeto(['Twenty-two', significant, associations, '(', range, of, 'P', values, 0.002, -, 0.048, ')', were]), verbo([found]), complemento([between, 'SNPs', in, the, vitamin, 'A', receptor, family, '(', 'RARA,', 'RARB,', 'TOP2B', and, 'RARG),', vitamin, 'D', receptor, and, downstream, mediator, of, vitamin, 'D', signaling, '(', 'RXRA)', genes, and, rubella, 'virus-specific', '(', 'IFN-gamma,', 'IL-2,', 'IL-10,', 'TNF-alpha,', and, 'GM-CSF)', cytokine, immune, responses])].
[sujeto(['A', 'TLR3', gene, promoter, region, 'SNP', '(', 'rs5743305,', -, 8441, 'A', &, 'gt;', 'T)', was]), verbo([associated]), complemento([with, 'rubella-specific', 'GM-CSF', secretion])].
[sujeto(['Importantly,', 'SNPs', in, the, 'TRIM5', gene, coding, 'regions,', rs3740996, '(', 'His43Tyr)', and, rs10838525, '(', 'Gln136Arg),', were]), verbo([associated]), complemento([with, an, allele, 'dose-related', secretion, of, rubella, 'virus-specific', 'TNF-alpha', and, 'IL-2/GM-CSF,', 'respectively,', and, have, been, previously, shown, to, have, functional, consequences, regarding, the, antiviral, activity, and, susceptibility, to, 'HIV-1', infection])].
[sujeto(['Rxr', genes, also]), verbo([have]), complemento([either, widespread, '(', 'Rxra,', 'Rxrb),', or, 'highly-restricted', '(', 'Rxrg)', expression, patterns])].
[sujeto(['The', eventual, characterization, of, specific, enzymes]), verbo([involved]), complemento([in, the, synthesis, of, retinoic, acid, '(', 'retinol/retinaldehyde', 'dehydrogenases),', or, the, triggering, of, its, catabolism, '(', 'CYP26', cytochrome, 'P450s),', all, of, them, showing, differential, expression, 'patterns,', led, to, a, clearer, understanding, of, the, phenomenons, regulated, by, retinoic, acid, signaling, during, development])].
[sujeto(['Functional', studies]), verbo([involving]), complemento([targeted, gene, disruptions, in, the, 'mouse,', and, additional, approaches, such, as, dominant, negative, receptor, expression, in, other, 'models,', have, pinpointed, the, 'specific,', versus, partly, 'redundant,', roles, of, the, 'RARs', and, 'RXRs', in, many, developing, organ, systems])].
[sujeto(['Retinoic', acid, '(', 'RA)', receptors, '(', 'RARs)', 'alpha,', 'beta,', and, gamma]), verbo([heterodimerized]), complemento([with, rexinoid, receptors, '(', 'RXRs)', 'alpha,', 'beta,', and, gamma, mediate, the, 'RA', signal])].
[sujeto(['To', analyze, the, contribution, of, the, transcriptional, activity, of, 'RXRalpha,', the, main, 'RXR', during, 'embryogenesis,', we]), verbo([have]), complemento([engineered, a, mouse, line, harboring, a, transcriptionally, silent, 'RXRalpha', mutant, that, lacks, the, activation, functions, 'AF1', and, 'AF2'])].
[sujeto(['All', homozygous, mutants, '(', 'Rxra(afo))', display, the, ocular, defects, previously, observed, in, compound, 'Rar-null', and, 'Rxra/Rar-null', 'mutants,', thus, demonstrating, that, a, transcriptionally, active, 'RXRalpha', is]), verbo([required]), complemento([during, eye, development])].
[sujeto(['In', 'contrast,', the, vast, majority, of, 'Rxra(afo)', fetuses, do, not, display, the, 'Rxra-null', mutant, hypoplasia, of, the, 'myocardium,', thus, demonstrating, that, 'RXRalpha', can]), verbo([act]), complemento([as, a, transcriptionally, silent, heterodimerization, partner])].
[sujeto(['Along', the, same, 'line,', we, show, that, a, silent, 'RXRalpha', mutant, is, sufficient, to, allow, the, initial, formation, of, the, placental, 'labyrinth,', whereas, later, steps, of, trophoblast, cell, differentiation, critically]), verbo([requires]), complemento([the, 'AF2,', but, not, the, 'AF1,', function, of, 'RXRalpha'])].
[sujeto(['We', recently]), verbo([reported]), complemento([on, a, series, of, 'retinoid-related', molecules, containing, an, adamantyl, 'group,', a])].
[sujeto([adamantyl, arotinoids, '(', 'AdArs),', that, showed, significant, cancer, cell, growth, inhibitory, activity, and]), verbo([activated]), complemento(['RXRα', '(', 'NR2B1)', in, transient, transfection, assays, while, devoid, of, 'RAR', transactivation, capacity])].
[sujeto(['We']), verbo([have]), complemento([now, explored, whether, these, 'AdArs', could, also, bind, and, inhibit, 'IKKβ,', a, known, target, that, mediates, the, induction, of, apoptosis, and, cancer, cell, growth, inhibition, by, related, 'AdArs', containing, a, chalcone, functional, group])].
[sujeto(['In', 'addition,', we]), verbo([have]), complemento([prepared, and, evaluated, novel, 'AdArs', that, incorporate, a, central, heterocyclic, ring, connecting, the, 'adamantyl-phenol', and, the, carboxylic, acid, at, the, polar, termini])].
[sujeto(['Our', results, indicate, that, the, majority, of, the, 'RXRα']), verbo([activating]), complemento([compounds, lacked, 'IKKβ', inhibitory, activity])].
[sujeto(['In', 'contrast,', the, novel, heterocyclic, 'AdArs', containing, a, thiazole, or, pyrazine, ring, linked, to, a, benzoic, acid, motif, were, potent, inhibitors, of, both, 'IKKα', and, 'IKKβ,', which, in, most, cases, paralleled, significant, growth, inhibitory, and, apoptosis]), verbo([inducing]), complemento([activities])].
[sujeto(['This', chapter, presents, an, overview, of, the, current, status, of, studies, on, the, structural, and, molecular, biology, of, the, retinoid, 'X', receptor, subtypes, 'α,', 'β,', and, γ, '(', 'RXRs,', 'NR2B1-3),', their]), verbo([nuclear]), complemento([and, cytoplasmic, 'functions,', 'post-transcriptional', 'processing,', and, recently, reported, ligands])].
[sujeto(['Points', of, interest, are, the, different, changes, in, the, 'ligand-binding', pocket]), verbo([induced]), complemento([by, variously, shaped, 'agonists,', the, communication, of, the, 'ligand-bound', pocket, with, the, coactivator, binding, surface, and, the, heterodimerization, 'interface,', and, recently, identified, ligands, that, are, natural, 'products,', those, that, function, as, environmental, toxins, or, drugs, that, had, been, originally, designed, to, interact, with, other, 'targets,', as, well, as, those, that, were, deliberately, designed, as, 'RXR-selective', transcriptional, 'agonists,', 'synergists,', or, antagonists])].
[sujeto(['The', 'Liver', 'X', 'Receptors', '(', 'LXR', 'alpha,', 'NR1H3;', 'LXR', 'beta,', 'NR1H2)', encode, highly, homologous, transcription, factors, that, are, members, of, the]), verbo([nuclear]), complemento([receptor, superfamily, of, proteins])].
[sujeto(['LXR/RXR', heterodimers, function, as, sensors, for, cellular, oxysterols, 'and,', when]), verbo([activated]), complemento([by, these, 'agonists,', increase, the, expression, of, genes, that, control, sterol, and, fatty, acid, 'metabolism/homeostasis'])].
[sujeto(['These', conclusions, are, based, on, studies, 'that:', '(', 'i)', identified, oxysterols, as, the, natural, ligands, for, both, 'LXR', alpha, and, 'LXR', 'beta;', '(', 'ii)', identified]), verbo([target]), complemento([genes, that, are, activated, by, 'LXR/RXR;', '(', 'iii)', generated, mice, that, were, deficient, in, 'LXR', 'alpha,', 'LXR', beta, or, both, 'LXR', alpha, and, 'LXR', 'beta;', '(', 'iv)', identified, synthetic, 'LXR', ligands, that, were, extremely, potent, in, 'vivo;', and, '(', 'v)', demonstrated, significant, alterations, in, cholesterol, and, fatty, acid, homeostasis, in, animals, in, which, 'LXR', had, been, either, activated, or, deleted])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, synthetic, 'LXR', ligands, may, prove, useful, in, the, treatment, of, certain, dyslipidemias])].
[sujeto(['Retinoid', 'receptors,', including, retinoid, 'X', receptor, '(', 'RXR),', and, retinoic, acid, receptor, '(', 'RAR)', are, vitamin, 'A', receptors, that, are, highly]), verbo([expressed]), complemento([in, the, liver, and, regulate, important, physiological, processes, through, regulation, of, different, genes])].
[sujeto(['Our', results, demonstrated, that, treatment, with, 'MTX', resulted, in, significant]), verbo([decrease]), complemento([in, reduced, glutathione, '(', 'GSH)', content, and, superoxide, dismutase, '(', 'SOD)', 'activity,', with, concomitant, increase, in, 'ALT,', 'AST,', and, 'MDA', levels])].
[sujeto(['Moreover,', 'ATRA', administration]), verbo([increased]), complemento([the, expression, and, nuclear, translocation, of, 'RXR-α', in, rat, hepatocytes])].
[sujeto(['Previously,', we]), verbo([reported]), complemento([that, vitamin, 'A-enriched', diet, '(', 129, &, 'nbsp;mg/kg', 'diet)', intake, reduces, the, adiposity, development, in, obese, rats, of, 'WNIN/Ob', strain])].
[sujeto(['Vitamin', 'A', supplementation, to, obese, rats, at, doses, of, 52, and, 129, &, 'nbsp;mg/kg', diet, showed, reduced, body, weight]), verbo([gain]), complemento([and, adiposity, compared, to, control, 'diet-fed', obese, rats, receiving, 2.6, &, 'nbsp;mg', of, vitamin, 'A/kg', diet])].
[sujeto(['In', 'BAT', of, obese, 'rats,', vitamin, 'A', supplementation, at, doses, of, 26, and, 52, &, 'nbsp;mg', of, vitamin, 'A/kg', diet, resulted, in]), verbo([increased]), complemento(['UCP1', expression, with, concomitant, decrease, in, 'RARα', and, 'RXRα', levels, compared, to, control, 'diet-fed', obese, rats])].
[sujeto(['Further,', transmission, electron, microscopy, study, revealed, an]), verbo([increase]), complemento([in, number, of, 'BAT', mitochondria, of, obese, rats, supplemented, with, 26, and, 52, &, 'nbsp;mg', of, vitamin, 'A/kg', diet])].
[sujeto(['Also,', obese, rats, fed, on, 52, &, 'nbsp;mg/kg', diet, resulted, in]), verbo([increased]), complemento([apoptosis, by, altering, the, ratio, of, 'Bcl2', to, 'Bax', protein, levels, in, eWAT])].
[sujeto(['The', expression, of, hepatic, glucokinase, gene, '(', 'Gck)', is]), verbo([regulated]), complemento([by, hormonal, and, nutritional, signals])].
[sujeto(['How', these, signals, integrate, to]), verbo([regulate]), complemento([the, hepatic, 'Gck', expression, is, unclear])].
[sujeto(['We']), verbo([have]), complemento([shown, that, the, hepatic, 'Gck', expression, is, affected, by, 'Vitamin', 'A', status, and, synergistically, induced, by, insulin, and, retinoids, in, primary, rat, hepatocytes])].
[sujeto(['We', hypothesized, that, this, is]), verbo([mediated]), complemento([by, a, retinoic, acid, responsive, element, '(', 'RARE)', in, the, hepatic, 'Gck', promoter])].
[sujeto(['We']), verbo([have]), complemento([optimized, experimental, conditions, for, performing, electrophoresis, mobility, shift, assay, and, demonstrated, the, interactions, of, the, retinoic, acid, receptor, α, '(', 'RARα),', retinoid, 'X', receptor, α, '(', 'RXRα),', hepatocyte, nuclear, factor, 4, α, '(', 'HNF4α)', and, chicken, ovalbumin, upstream, 'promoter-transcription', factor, 'II', '(', 'COUP-TFII)', in, the, rat, nuclear, extract, with, this, 'RARE,', suggesting, their, roles, in, the, regulation, of, 'Gck', expression])].
[sujeto(['Chromatin', immunoprecipitation, assays, demonstrated, that, recombinant, 'adenovirus-mediated', overexpression, of, 'RARα,', 'HNF4α', and, 'COUP-TFII,', but, not, 'RXRα,', significantly]), verbo([increased]), complemento([their, occupancy, in, the, hepatic, 'Gck', promoter, in, primary, rat, hepatocytes])].
[sujeto(['In', 'summary,', this, hepatic, 'Gck', promoter, 'RARE']), verbo([interacts]), complemento([with, 'RARα,', 'HNF4α', and, 'COUP-TFII', to, integrate, 'Vitamin', 'A', and, insulin, signals])].
[sujeto(['Although', the, 'PML-RARα', fusion, gene, can, be, detected, in, &, 'gt;98%', of, 'APL', 'cases,', 'RARα', is, also]), verbo([found]), complemento([to, be, fused, with, other, partner, 'genes,', which, are, also, related, to, 'all-trans', retinoic, acid, '(', 'ATRA)-dependent', transcriptional, activity, and, cell, differentiation])].
[sujeto(['To', our, 'knowledge,', 'TBLR1-RARα', is, the, 10, th, 'RARα', chimeric, gene, that]), verbo([has]), complemento([been, reported, up, to, now])].
[sujeto(['Moreover,', when, treated, with, 'ATRA,', 'TBLR1-RARα', could]), verbo([mediate]), complemento([the, dissociation, and, degradation, of, transcriptional, 'corepressors,', consequent, transactivation, of, 'RARα', target, 'genes,', and, cell, differentiation, induction, in, a, 'dose-', and, 'time-dependent', manner])].
[sujeto(['The', recent]), verbo([finding]), complemento([that, almost, all, patients, with, acute, promyelocytic, leukaemia, '(', 'APL)', may, be, cured, using, a, combination, of, retinoic, acid, '(', 'RA)', and, arsenic, trioxide, '(', 'As(2)O(3))', '(', 'N', 'Engl', 'J', 'Med,', 369, ',', 2013, and, 111, ')', highlights, the, progress, made, in, our, understanding, of, 'APL', pathogenesis, and, therapeutic, approaches, over, the, past, 25, years])].
[sujeto(['The', study, of, 'APL']), verbo([has]), complemento([revealed, many, important, lessons, related, to, transcriptional, 'control,', nuclear, 'organization,', epigenetics, and, the, role, of, proteolysis, in, biological, control])].
[sujeto(['Even', more, important]), verbo([has]), complemento([been, the, clinical, demonstration, that, molecularly, targeted, therapy, can, eradicate, disease])].
[sujeto(['Retinoic', acids, are, essential, for, embryonic, 'development,', tissue, 'organization,', and, homeostasis, and]), verbo([act]), complemento([via, retinoic, acid, receptors, '(', 'RARs)', that, form, heterodimers, with, retinoid, 'X', receptors, '(', 'RXRs)'])].
[sujeto(['Human', 'RARs', and, 'RXRs', include, the, three, subtypes, 'α,', 'β,', and, 'γ,', which]), verbo([have]), complemento([varying, distributions, and, physiological, functions, among, human, tissues])].
[sujeto(['Recent']), verbo([reports]), complemento([show, that, 'subtype-specific', binding, of, several, chemicals, to, 'RARs', or, 'RXRs', may, lead, to, endocrine, disruption])].
[sujeto(['To', screen, 'RAR', 'ligands,', yeasts, were, engineered, to]), verbo([express]), complemento(['RAR', subtypes, with, defective, 'RXRα,', which, fails, to, bind, to, coactivators, because, of, its, shortened, 'c-terminus'])].
[sujeto(['Retinoic', acid, '(', 'RA)', analogs]), verbo([have]), complemento([been, used, in, the, treatment, of, a, variety, of, 'cancers;', 'however,', their, application, is, limited, due, to, serious, 'therapy-related', sequelae])].
[sujeto(['The']), verbo([binding]), complemento([affinity, of, 'ATPR', to, the, retinoic, acid, 'receptors,', retinoic, acid, 'receptor-α', '(', 'RAR-α)', and, retinoid, 'X', 'receptor-α', '(', 'RXR-α),', was, determined, using, 'ligand-binding', assays])].
[sujeto(['ATPR', preferentially]), verbo([bound]), complemento(['RXR-α', '(', 0.04, 'nM)', as, compared, with, 'RAR-α', '(', 20.96, 'nM)'])].
[sujeto(['Although', both, 'ATRA', and, 'ATPR']), verbo([inhibited]), complemento([the, growth, of, 'AGS,', 'MKN-74', and, 'SC-M1', cells, in, a, 'dose-dependent', 'manner,', a, significantly, greater, inhibitory, effect, was, observed, with, treatment, with, 5, and, 500, µM, 'ATPR', for, 3, days, '(', 'P&lt;0'])].
[sujeto(['In', 'addition,', 'ATPR', '(', 50, 'µM),', but, not, 'ATRA,', significantly]), verbo([increased]), complemento([the, population, of, 'AGS', and, 'MKN-74', cells, in, the, subG1, phase, and, decreased, the, 'Bcl-2/Bax', ratio, '(', 'P&lt;0'])].
[sujeto(['Furthermore,', in, 'MNK-74', and, 'SC-M1', cells, treated, with, 12, -, 'O-tetradecanoylphorbol-13-acetate', '(', 'TPA)', and, 5, or, 10, µM, of, 'ATPR', significantly]), verbo([suppressed]), complemento([the, activity, of, the, 'AP-1', reporter, as, compared, to, treatment, with, 'ATRA', '(', 'P&lt;0'])].
[sujeto(['Thus,', 'ATPR']), verbo([inhibits]), complemento([cancer, cell, proliferation, to, a, greater, extent, compared, to, 'ATRA,', possibly, through, the, 'RXR-mediated', inhibition, of, 'AP-1', activity])].
[sujeto(['The', studies, demonstrated, that, the, 'RARE', is, also, a, constitutive, androstane, receptor, '(', 'CAR)']), verbo([binding]), complemento([site, for, 'OSTβ', gene, regulation])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'OSTβ', is, a, target, of, both, 'FXR-mediated', '(', by, binding, to, 'IR-1', 'element)', and, 'RARα-', and, 'CAR-mediated', '(', by, binding, to, 'DR5', 'element)', gene, regulation, pathways])].
[sujeto(['In', 'summary,', this, study]), verbo([has]), complemento([uncovered, a, novel, 'RARE', '(', 'DR5)', element, in, the, promoter, of, 'OSTβ', that, binds, 'RARα', or, 'CAR', heterodimerized, with, 'RXRα', and, appears, to, function, synergistically, with, the, 'IR-1', element, to, provide, maximal, induction, of, 'OSTβ', in, response, to, 'RA'])].
[sujeto(['Various', organophosphate, flame, retardants, '(', 'OPFRs)', are, widely, used, in, building, 'materials,', textiles, and, electric, 'appliances,', and]), verbo([have]), complemento([been, reported, to, cause, indoor, environmental, pollution, in, houses, and, office, buildings])].
[sujeto(['In', this, 'study,', using, 'cell-based', transactivation, 'assays,', we, characterized, the, agonistic, 'and/or', antagonistic, activities, of, 11, 'OPFRs', against, human]), verbo([nuclear]), complemento(['receptors;', estrogen, receptor, α, '(', 'ERα),', 'ERβ,', androgen, receptor, '(', 'AR),', glucocorticoid, receptor, '(', 'GR),', thyroid, hormone, receptor, α1, '(', 'TRα1),', 'TRβ1,', retinoic, acid, receptor, α, '(', 'RARα),', retinoid, 'X', receptor, α, '(', 'RXRα),', pregnane, 'X', receptor, '(', 'PXR),', peroxisome, 'proliferator-activated', receptor, α, '(', 'PPARα),', and, 'PPARγ'])].
[sujeto(['Furthermore,', we]), verbo([found]), complemento([that, seven, 'compounds,', 'TBP,', 'tris(2-chloro-1-methylethyl)', phosphate, '(', 'TCPP),', 'TEHP,', 'tris(2-butoxyethyl)', phosphate, '(', 'TBEP),', 'TDCPP,', 'TPhP,', and, 'TCP,', display, 'PXR', agonistic, activity])].
[sujeto(['Taken', 'together,', these, results]), verbo([suggest]), complemento([that, several, 'OPFRs', may, have, potential, endocrine, disrupting, effects, via, 'ERα,', 'ERβ,', 'AR,', 'GR', and, 'PXR'])].
[sujeto(['The', eyes, and, skin, are, obvious, retinoid]), verbo([target]), complemento([organs])].
[sujeto(['Vitamin', 'A', deficiency]), verbo([causes]), complemento([night, blindness, and, retinoids, are, widely, used, to, treat, acne, and, psoriasis])].
[sujeto(['In', 'addition,', hepatocytes, produce, the, largest, amount, of, retinol]), verbo([binding]), complemento([protein, and, cellular, retinoic, acid, binding, protein, to, mobilize, retinol, from, the, hepatic, storage, pool, and, deliver, retinol, to, its, 'receptors,', respectively])].
[sujeto(['Furthermore,', hepatocytes]), verbo([express]), complemento([the, highest, amount, of, retinoid, x, receptor, alpha, '(', 'RXRα)', among, all, the, cell, types])].
[sujeto(['Surprisingly,', the, function, of, endogenous, retinoids, in, the, liver]), verbo([has]), complemento([received, very, little, attention])].
[sujeto(['Based', on, the, data, generated, from, chromatin, immunoprecipitation, followed, by, 'sequencing,', the, global, 'DNA']), verbo([binding]), complemento([of, transcription, factors, including, retinoid, x, receptor, α, '(', 'RXRα)', along, with, its, partners, i])].
[sujeto([retinoic, acid, receptor, α, '(', 'RARα),', pregnane, x, receptor, '(', 'PXR),', liver, x, receptor, '(', 'LXR),', farnesoid, x, receptor, '(', 'FXR),', and, peroxisome, 'proliferator-activated', receptor, α, '(', 'PPARα)']), verbo([has]), complemento([been, established])].
[sujeto(['Based', on, the, 'binding,', functional, annotation, illustrated, the, role, of, those, receptors, in]), verbo([regulating]), complemento([hepatic, lipid, homeostasis])].
[sujeto(['To', correlate, the, 'DNA']), verbo([binding]), complemento([data, with, gene, expression, 'data,', the, expression, patterns, of, 576, genes, that, regulate, lipid, homeostasis, were, studied, in, wild, type, and, liver, 'RXRα-null', mice, treated, with, and, without, 'RA'])].
[sujeto(['The', data, showed, that, 'RA', treatment, and, 'RXRα-deficiency', had, opposite, effects, in]), verbo([regulating]), complemento([lipid, homeostasis])].
[sujeto(['The', expression, data]), verbo([suggested]), complemento([that, 'RA', treatment, could, produce, unsaturated, fatty, acids, and, induce, triglyceride, 'breakdown,', bile, acid, 'secretion,', 'lipolysis,', and, retinoids, elimination])].
[sujeto(['In', 'contrast,', 'RXRα', deficiency, might]), verbo([induce]), complemento([the, synthesis, of, saturated, fatty, 'acids,', 'triglyceride,', 'cholesterol,', bile, 'acids,', and, retinoids])].
[sujeto(['In', 'addition,', 'DNA']), verbo([binding]), complemento([data, indicated, extensive, 'cross-talk', among, 'RARα,', 'PXR,', 'LXR,', 'FXR,', and, 'PPARα', in, regulating, those, 'RA/RXRα-dependent', gene, expression, levels])].
[sujeto(['We']), verbo([have]), complemento([characterized, the, role, of, hepatic, 'RA', for, the, first, time])].
[sujeto(['Hepatic', 'RA']), verbo([mediated]), complemento([through, 'RXRα', and, its, partners, regulates, lipid, homeostasis])].
[sujeto(['Retinoid', 'signaling,', 'brain-derived', neurotrophic, factor, '(', 'BDNF),', and, its, receptor, 'TrkB', are]), verbo([reported]), complemento([to, be, involved, in, depression])].
[sujeto(['Here,', we]), verbo([found]), complemento([that, mRNA, levels, of, key, elements, of, retinoid, signaling, were, significantly, reduced, in, the, postmortem, dorsolateral, prefrontal, 'cortex/anterior', cingulate, cortex, '(', 'ACC)', from, elderly, depressed, patients, who, did, not, die, from, suicide])].
[sujeto(['Along', with, neurons, immunopositive, for, both, retinoic, acid, 'receptor-α', '(', 'RARα)', and, 'TrkB,', a, positive, correlation, between, mRNA, levels, of, the, 2, receptors, was]), verbo([found]), complemento([in, the, 'ACC', of, control, subjects, but, not, of, depressed, patients])].
[sujeto(['In', vitro, studies, showed, that, 'RARα', was, able, to]), verbo([bind]), complemento([to, and, transactivate, the, 'TrkB', promoter, via, a, putative, 'RA', response, element, within, the, 'TrkB', promoter])].
[sujeto(['In', 'conclusion,', the, retinoid, and, 'BDNF-TrkB', signaling, in, the, prefrontal, cortex, are, compromised, in, mood, 'disorders,', and, the, transcriptional, upregulation, of, 'TrkB', by, 'RARα']), verbo([provide]), complemento([a, possible, mechanism, for, their, interaction])].
[sujeto(['The', retinoid, signaling, pathway, that, may]), verbo([activate]), complemento(['TrkB', expression, will, be, an, alternative, novel, target, for, 'BDNF-based', antidepressant, treatment])].
[sujeto(['Although', 'PML-enforced', 'RARA', homodimerization, allows, 'PML/RARA', to]), verbo([bind]), complemento(['DNA', independently, of, its, coreceptor, 'RXR,', the, latter, was, identified, within, the, 'PML/RARA', complex])].
[sujeto(['We', demonstrate, that, a, 'PML/RARA', mutant, defective, for, 'RXR']), verbo([binding]), complemento([fails, to, trigger, 'APL', development, in, transgenic, 'mice,', although, it, still, transforms, primary, hematopoietic, progenitors, ex, vivo])].
[sujeto(['RXR']), verbo([enhances]), complemento(['PML/RARA', binding, to, 'DNA', and, is, required, for, 'rexinoid-induced', 'APL', differentiation])].
[sujeto(['In', 'RA-treated', 'PML/RARA-transformed', 'cells,', the, absence, of, 'RXR']), verbo([binding]), complemento([results, in, 'monocytic,', rather, than, 'granulocytic,', differentiation])].
[sujeto(['PML/RARA']), verbo([enhances]), complemento([posttranslational, modifications, of, 'RXRA,', including, its, 'sumoylation,', suggesting, that, 'PML-bound', sumoylation, enzymes, target, 'RXRA', and, possibly, other, 'PML/RARA-bound', chromatin, 'proteins,', further, contributing, to, deregulated, transcription])].
[sujeto(['HSD17B2', is, highly]), verbo([expressed]), complemento([in, human, placental, tissue, where, it, is, localized, to, placental, endothelial, cells, lining, the, fetal, compartment])].
[sujeto(['HSD17B2', mRNA, expression, was, not]), verbo([regulated]), complemento([by, 'progesterone,', the, progesterone, agonist, 'R5020,', or, estradiol, treatment])].
[sujeto(['RA', significantly]), verbo([induced]), complemento(['HSD17B2', mRNA, levels, and, enzyme, activity, in, a, 'dose-', and, 'time-dependent', manner])].
[sujeto(['RNA', interference, directed, against, 'RARA', or, 'RXRA']), verbo([led]), complemento([to, reduced, basal, levels, of, 'HSD17B2', mRNA, levels, and, significantly, abolished, 'RA-stimulated', 'HSD17B2', expression])].
[sujeto(['Together,', these, data, indicate, that, regulation, of, 'HSD17B2', mRNA, levels, and, enzymatic, activity, by, 'RA', in, the, placenta, is]), verbo([mediated]), complemento([by, 'RARA', and, 'RXRA'])].
[sujeto(['Hematopoietic', differentiation, is]), verbo([regulated]), complemento([by, 'RARα,', and, several, types, of, leukemia, show, aberrant, 'RARα', activity])].
[sujeto(['Through', microarray, expression, 'analysis,', we, identified, transcripts, differentially]), verbo([expressed]), complemento([between, 'F9', 'wild-type', '(', 'Wt)', and, 'RARα', knockout, cells, cultured, in, the, absence, or, presence, of, the, 'RAR-specific', ligand, all, trans, retinoic, acid, '(', 'RA)'])].
[sujeto(['We', validated, the]), verbo([decreased]), complemento(['Mest,', 'Tex13,', 'Gab1,', 'Bcl11a,', 'Tcfap2a', and, 'HMGcs1', transcript, 'levels,', and, increased, 'Slc38a4,', 'Stmn2,', 'RpL39l,', 'Ref2L,', 'Mobp', and, 'Rlf1', transcript, levels, in, the, 'RARa', knockout, cells])].
[sujeto(['The']), verbo([decreased]), complemento(['Mest', and, 'Tex13', transcript, levels, were, associated, with, increased, promoter, 'CpG-island', methylation, and, increased, repressive, histone, modifications, '(', 'H3K9me3)', in, 'RARα', knockout, cells])].
[sujeto(['Increased', 'Slc38a4', and, 'Stmn2', transcript, levels, were]), verbo([associated]), complemento([with, decreased, promoter, 'CpG-island', methylation, and, increased, permissive, histone, modifications, '(', 'H3K9/K14ac,', 'H3K4me3)', in, 'RARα', knockout, cells])].
[sujeto(['Importantly,', stable, expression, of, a, dominant, 'negative,', oncogenic, 'PML-RARα', fusion, protein, in, 'F9', 'Wt', cells, recapitulated, the]), verbo([decreased]), complemento(['Mest', transcript, levels, observed, in, 'RARα', knockout, cells])].
[sujeto(['We', propose, that, 'RARα', plays, an, important, role, in, cellular, memory, and, imprinting, by]), verbo([regulating]), complemento([the, 'CpG', methylation, status, of, specific, promoter, regions])].
[sujeto(['In', a, small, 'subset,', 'RARA', is, fused, to, a, different, 'partner,', usually]), verbo([involved]), complemento([in, regulating, cell, growth, and, differentiation])].
[sujeto(['BCOR', is, a, transcriptional, corepressor, through, the, 'proto-oncoprotein,', 'BCL6,']), verbo([recruiting]), complemento([histone, deacetylases, and, polycomb, repressive, complex, 1, components])].
[sujeto(['BCOR-RARA', was]), verbo([found]), complemento([to, possess, common, features, with, other, 'RARA', fusion, proteins])].
[sujeto(['These', 'included:', '(', 1, ')', the, same, break, point, in, 'RARA', 'cDNA;', '(', 2, ')', 'self-association;', '(', 3, ')', retinoid, 'X', receptor, alpha, is, necessary, for, 'BCOR-RARA', to]), verbo([associate]), complemento([with, the, 'RARA', responsive, 'element;', '(', 4, ')', action, in, a, 'dominant-negative', manner, on, 'RARA', transcriptional, 'activation;', and, '(', 5, ')', aberrant, subcellular, relocalization])].
[sujeto(['It', should, be, noted, that, there, was, no, intact, 'BCOR']), verbo([found]), complemento([in, the, 45, ',', -, 'Y,t(X;17)(p11;q12)', 'APL', cells, because, they, featured, only, a, rearranged, 'X', chromosome])].
[sujeto(['BCOR', appears, to, be]), verbo([involved]), complemento([not, only, in, human, congenital, 'diseases,', but, also, in, a, human, cancer])].
[sujeto(['Similarly,', 'FSH', is, known, to]), verbo([regulate]), complemento(['Sertoli', cell, proliferation, and, 'differentiation,', indirectly, controlling, the, quantity, of, the, spermatogenic, output])].
[sujeto(['Interestingly,', 'FSH', 'inhibited,', via, activation, of, 'FSH', 'receptor,', 'cAMP,', and, protein, kinase, 'A', '(', 'PKA),', the]), verbo([nuclear]), complemento([localization, and, transcriptional, activity, of, 'RARA'])].
[sujeto(['Given', that, retinoic, 'acid,', the, ligand, for, 'RARA,', is, known, to]), verbo([regulate]), complemento([cell, proliferation, and, 'differentiation,', we, investigated, whether, 'FSH', regulates, 'RARA', by, a, direct, posttranslational, phosphorylation, mechanism])].
[sujeto(['The', negative, charges, at, the, 'PKA', 'sites,', whether, they, are, from, glutamic, acids, or, phosphorylation, of, 'serines,']), verbo([decreased]), complemento([the, nuclear, localization, of, 'RARA,', heterodimerization, with, retinoid, 'X', 'receptor-alpha,', and, the, transcriptional, activity, of, the, receptor])].
[sujeto(['On', the, other, 'hand,', the, 'double-alanine', mutant, that, cannot, be]), verbo([phosphorylated]), complemento([at, the, 219, and, 369, amino, acid, positions, did, not, respond, to, cAMP, and, 'PKA', activation])].
[sujeto(['Wild-type', and, 'double-mutant', 'RARA']), verbo([interacted]), complemento([with, 'PKA,', but, only, in, the, presence, of, cAMP, or, 'FSH'])].
[sujeto(['These', results, together]), verbo([suggest]), complemento([that, 'FSH', may, regulate, cell, proliferation, and, differentiation, of, 'Sertoli', 'cells,', at, least, 'partially,', by, directly, affecting, the, 'PKA', sites, of, 'RARA', and, controlling, the, transcriptional, function, of, the, receptor])].
[sujeto(['The', 'Caf', diet, enriched, in, vitamin, 'A', resulted, in, an]), verbo([increased]), complemento(['adiposity,', due, to, increased, adipocyte, hypertrophy])].
[sujeto(['In', 'conclusion,', lipids, and, vitamin, 'A']), verbo([act]), complemento([synergistically, on, the, normal, growth, of, the, adipose, tissue, in, young, 'rats,', concomitant, with, an, imbalance, in, the, pattern, of, the, nuclear, receptors])].
[sujeto(['It', additionally]), verbo([induces]), complemento([testis, degeneration, and, delays, spermatogonial, expression, of, 'Stra8,', two, hallmarks, of, 'RA', deficiency])].
[sujeto(['They', further, indicate, that, 'RARalpha', is, a, master, regulator, of, the, cyclical, activity, of, 'SC', and, controls, paracrine, pathways]), verbo([required]), complemento([for, spermatogonia, differentiation, and, germ, cell, survival])].
[sujeto(['Most', 'importantly,', we, show, that, the, ablation, of, all, 'RXR', '(', 'alpha,', beta, and, gamma, 'isotypes)', in, 'SC', does, not, recapitulate, the, phenotype, generated, upon, ablation, of, all, three, 'RARs,', thereby]), verbo([providing]), complemento([the, first, evidence, that, 'RARs', exert, functions, in, vivo, independently, of, 'RXRs'])].
[sujeto(['We']), verbo([have]), complemento([now, cloned, cDNAs, encoding, 'PLZF-RAR', alpha, chimeric, proteins, and, studied, their, transactivating, activities])].
[sujeto(['A', &, 'quot;dominant', 'negative&quot;', effect, was, observed, when, 'PLZF-RAR', alpha, fusion, proteins, were, cotransfected, with, vectors]), verbo([expressing]), complemento(['RAR', alpha, and, retinoid, 'X', receptor, alpha, '(', 'RXR', 'alpha)'])].
[sujeto(['Uromodulin', is, a, kidney, specific, glycoprotein, whose, expression, can]), verbo([modulate]), complemento([kidney, homeostasis])].
[sujeto(['However,', the, set, of, sequence, specific, transcription, factors, that]), verbo([regulate]), complemento([the, uromodulin, gene, 'UMOD', and, their, upstream, binding, locations, are, not, well, characterized])].
[sujeto(['We', applied, in, silico, phylogenetic, footprinting, on, the, upstream, regulatory, regions, of, a, diverse, set, of, human, 'UMOD', orthologs, to, identify]), verbo([conserved]), complemento([binding, motifs, and, corresponding, position, specific, weight, matrices])].
[sujeto(['We', further, analyzed, the, predicted]), verbo([binding]), complemento([motifs, by, motif, 'comparison,', which, identified, transcription, factors, likely, to, bind, these, discovered, motifs])].
[sujeto(['Analysis', allowed, the, identification, of, a, reliable, set, of]), verbo([binding]), complemento([motifs, 'in&nbsp;the', upstream, regulatory, regions, of, 'UMOD', to, build, a, high, confidence, compendium, of, transcription, factors, that, could, bind, these, 'motifs,', such, as, 'GATA3,', 'HNF1B,', 'SP1,', 'SMAD3,', 'RUNX2', and, 'KLF4'])].
[sujeto(['ENCODE', deoxyribonuclease, 'I', hypersensitivity, sites, in, the, 'UMOD', upstream, region, of, the, mouse, kidney, confirmed, that, some, of, these]), verbo([binding]), complemento([motifs, were, open, to, binding, by, predicted, transcription, factors])].
[sujeto(['Expression', levels, of, these, transcription, factors, in, the, kidney]), verbo([suggest]), complemento([their, central, role, in, controlling, 'UMOD', expression])].
[sujeto(['The', active, metabolite, of, vitamin, 'A', '(', retinoic, 'acid,', 'RA)']), verbo([acts]), complemento([through, the, nuclear, receptors, 'RARalpha,', beta, and, gamma, and, 'RXRalpha,', beta, and, gamma])].
[sujeto(['These', receptors, form, 'RAR/RXR', 'heterodimers,', which]), verbo([bind]), complemento([to, genetic, regulatory, 'DNA', sequences, and, activate, transcription, of, 'RA', target, genes])].
[sujeto(['As', 'RXR', form, heterodimers, with, a, number, of, other]), verbo([nuclear]), complemento(['receptors,', such, as, the, vitamin, 'D3', receptor, '(', 'VDR)', and, are, involved, in, several, signaling, pathways])].
[sujeto(['On', the, one, 'hand,', null, mutations, for, 'RARa', or, 'RXRbeta']), verbo([have]), complemento([no, effect, on, the, 'skin,', whereas, a, 'RARgamma-null', mutation, induces, alterations, in, the, granular, cell, layer])].
[sujeto(['On', the, 'other,', genetic, inactivation, of, 'RXRa']), verbo([leads]), complemento([to, embryonic, lethality, before, epidermal, development])].
[sujeto(['Using', this, novel, genetic, 'approach,', mutant, mice, were, obtained, in, which, 'RXRalpha', was, not]), verbo([expressed]), complemento([in, the, skin])].
[sujeto(['These', mice, developed, hair, follicle, 'degeneration,', then, 'alopecia,', similar, to, that, observed, in, 'VDR-null', 'mutants,']), verbo([suggesting]), complemento([that, hair, follicle, homeostasis, depends, on, 'RXRalpha/VDR', heterodimers])].
[sujeto(['A', similar, genetic, approach, applied, to, the, 'RARgamma', locus, demonstrated, that, topical, administration, of, 'RA', on, the, skin]), verbo([activates]), complemento(['RARgamma/RXR', heterodimers, in, suprabasal, 'cells,', and, induces, expression, of, a, paracrine, growth, factor, '(', 'HB-EGF)', in, these, cells, 'which,', in, 'turn,', stimulates, the, proliferation, of, basal, cells])].
[sujeto(['A', particular, feature, of, 'RXRs', is, their, ability, to]), verbo([act]), complemento([as, obligatory, heterodimerization, partners, of, class, 'II', nuclear, receptors])].
[sujeto(['At', the, same, 'time,', these, receptors, are, also, able, to, form, homodimers, that]), verbo([bind]), complemento([to, direct, repeat, separated, by, one, nucleotide, hormone, response, elements])].
[sujeto(['Since', the, discovery, of, 'RXRs,', most, of, the, studies, focused, on, its, ligand]), verbo([binding]), complemento([and, 'DNA', binding, 'domains,', while, its, 'N-terminal', domain, '(', 'NTD)', harboring, a, 'ligand-independent', activation, function, remained, poorly, characterized])].
[sujeto(['Here,', we, investigated, the, solution, properties, of, the, 'NTD', of, 'RXRα', alone, and, in, the, context, of, the, 'full-length', receptor, using, 'small-angle', 'X-ray', scattering, and]), verbo([nuclear]), complemento([magnetic, resonance, spectroscopy])].
[sujeto(['We']), verbo([report]), complemento([the, solution, structure, of, the, 'full-length', homodimeric, 'RXRα', on, 'DNA', and, show, that, the, 'NTD', remains, highly, flexible, within, this, complex])].
[sujeto(['To', address, the, question, whether, a, common, mechanism, is]), verbo([involved]), complemento([we, treated, human, primary, hepatocytes, with, 'IL-6,', the, major, mediator, of, the, acute, phase, response, in, 'liver,', and, characterized, acute, phase, and, detoxification, responses, in, quantitative, gene, expression, and, '(', 'phospho-)proteomics', data, sets])].
[sujeto(['Our', model]), verbo([suggests]), complemento([a, greater, role, of, 'MAPK/PI3K', compared, to, 'JAK/STAT', with, the, orphan, nuclear, receptor, 'RXRα', playing, a, central, role, in, mediating, transcriptional, downregulation])].
[sujeto(['Validation', experiments, revealed, a, striking, similarity, of, 'RXRα', gene, silencing, versus, 'IL-6']), verbo([induced]), complemento([negative, gene, regulation, '(', rs, =, 0.79, ;, 'P&lt;0'])].
[sujeto(['These', results, concur, with, 'RXRα', functioning, as, obligatory, heterodimerization, partner, for, several]), verbo([nuclear]), complemento([receptors, that, regulate, drug, and, lipid, metabolism])].
[sujeto(['In', this, 'study,', we, show, that, expression, of, genes]), verbo([involved]), complemento([in, the, retinoid, 'X', receptor, pathway, are, decreased, with, ageing, in, both, 'myelin-phagocytosing', human, monocytes, and, mouse, macrophages, using, a, combination, of, in, vivo, and, in, vitro, approaches])].
[sujeto(['Macrophage-specific', 'RXRα', '(', 'Rxra)', knockout, mice, revealed, that]), verbo([loss]), complemento([of, function, in, young, mice, caused, delayed, myelin, debris, uptake, and, slowed, remyelination, after, 'experimentally-induced', demyelination])].
[sujeto(['The', agonist, 'bexarotene,', when, used, in, concentrations, achievable, in, human, 'subjects,']), verbo([caused]), complemento([a, reversion, of, the, gene, expression, profile, in, multiple, sclerosis, patient, monocytes, to, a, more, youthful, profile, and, enhanced, myelin, debris, phagocytosis, by, patient, cells])].
[sujeto(['These', results]), verbo([reveal]), complemento([the, retinoid, 'X', receptor, pathway, as, a, positive, regulator, of, myelin, debris, clearance, and, a, key, player, in, the, 'age-related', decline, in, remyelination, that, may, be, targeted, by, available, or, 'newly-developed', therapeutics])].
[sujeto(['Increasing', evidence, indicates, that, 'Liver', 'X', 'Receptors', '(', 'LXRs)']), verbo([have]), complemento([some, anticancer, properties])].
[sujeto(['We', recently, demonstrated, that, 'LXR', ligands]), verbo([induce]), complemento([colon, cancer, cell, pyroptosis, through, an, 'LXRβ-dependent', pathway])].
[sujeto(['Moreover', 't-RXRα', was, not]), verbo([expressed]), complemento([in, normal, colon, epithelial, cells])].
[sujeto(['These', cells, presented, a, predominantly]), verbo([nuclear]), complemento([localization, of, 'LXRβ', and, were, resistant, to, 'LXR', ligand, cytotoxicity])].
[sujeto(['This', study, strengthens, the, hypothesis, that, 'LXRβ', could, be, a, promising]), verbo([target]), complemento([in, cancer, therapy])].
[sujeto(['Experimental', evidence]), verbo([has]), complemento([suggested, that, vitamin, 'D', may, be, protective, against, 'tobacco-related', cancers, through, the, inhibition, of, the, formation, of, tumors, induced, by, tobacco, carcinogens])].
[sujeto(['To', our, 'knowledge,', only, one, previous, epidemiologic, study, investigated, the, association, between, vitamin, 'D', status, and, 'tobacco-related', cancer, 'risk,', and, no, study]), verbo([has]), complemento([focused, on, vitamin, 'D-related', gene, polymorphisms])].
[sujeto(['A', 25, '(', 'OH)D', concentration, '≥30', 'ng/mL', was]), verbo([associated]), complemento([with, reduced, risk, of, 'tobacco-related', cancers, '(', 'OR', for, '≥30', compared, with, &, 'lt;30', 'ng/mL:', 0.59, ;, 95, '%', 'CI', 0.35, ',', 0.99, ;, 'P', =, 0.046, ')'])].
[sujeto(['The', vitamin, 'D', receptor, '(', 'VDR)', 'FokI', 'AA', genotype, and, retinoid, 'X', receptor, '(', 'RXR)', rs7861779, 'TT', genotype, were]), verbo([associated]), complemento([with, increased, risk, of, 'tobacco-related', cancers, '[', 'OR', for, homozygous, mutant, type, '(', 'MT)', compared, with, wild, type, '(', 'WT):', 1.87, ;, 95, '%', 'CI:', 1.08, ',', 3.23, ;, 'P-trend', =, 0.02, ;, 'OR', for, heterozygous, type, '(', 'HT)', plus, 'MT', compared, with, 'WT:', 1.6, ;, 95, '%', 'CI:', 1.07, ',', 2.38, ;, 'P', =, 0.02, ']'])].
[sujeto(['In', this, prospective, 'study,', high, vitamin, 'D', status, '[', 25, '(', 'OH)D', concentration, '≥30', 'ng/mL]', was]), verbo([associated]), complemento([with, decreased, risk, of, 'tobacco-related', 'cancers,', especially, in, smokers])].
[sujeto(['These', 'results,', which, are, supported, by, mechanistic, 'plausibility,']), verbo([suggest]), complemento([that, vitamin, 'D', may, contribute, to, the, prevention, of, 'tobacco-induced', cancers, in, smokers, and, deserve, additional, investigation])].
[sujeto(['DSG']), verbo([inhibited]), complemento([3, 'T3-L1', adipocyte, differentiation, and, reduced, adipocyte, size, through, regulating, key, factors])].
[sujeto(['DSG']), verbo([inhibited]), complemento(['PPARγ', and, its, target, gene, expression, both, in, differentiated, 3, 'T3-L1', adipocytes, and, fat, tissues, in, 'HF', 'diet-fed', mice])].
[sujeto(['Overexpression', of, 'PPARγ']), verbo([suppressed]), complemento(['DSG-inhibited', adipocyte, differentiation])].
[sujeto(['DSG', significantly]), verbo([increased]), complemento([nuclear, expression, of, 'ERβ'])].
[sujeto(['Inhibition', of, 'ERβ', significantly]), verbo([suppressed]), complemento(['DSG-exerted', suppression, of, adipocyte, differentiation, and, 'PPARγ', expression])].
[sujeto(['In', response, to, 'DSG', 'stimulation,', 'ERβ']), verbo([bound]), complemento([with, 'RXRα', and, dissociated, 'RXRα', from, 'PPARγ,', leading, to, the, reduction, of, transcriptional, activity, of, 'PPARγ'])].
[sujeto(['These', data]), verbo([provide]), complemento([new, insight, into, the, mechanisms, underlying, the, inhibitory, effect, of, 'DSG', on, adipocyte, differentiation, and, demonstrate, that, 'ERβ-exerted', regulation, of, 'PPARγ', expression, and, activity, is, critical, for, 'DSG-inhibited', adipocyte, differentiation])].
[sujeto(['It']), verbo([has]), complemento([recently, been, reported, that, vitamin, 'D', blood, plasma, levels, are, associated, with, reduced, risk, of, endometriosis])].
[sujeto(['The', present, study, aimed, to, investigate, whether, the, vitamin, 'D']), verbo([binding]), complemento([protein, '(', 'GC),', vitamin, 'D', receptor, '(', 'VDR),', and, retinoid, 'X', receptor, '(', 'RXR)', gene, variants, may, be, genetic, risk, factors, for, 'endometriosis&#8209;associated', infertility])].
[sujeto(['The', results, of, the, present, study]), verbo([suggested]), complemento([that, 'VDR', gene, variants, act, as, genetic, risk, factors, for, 'endometriosis&#8209;associated', infertility])].
[sujeto(['HULC', is, a, long, noncoding, 'RNA', overexpressed, in, hepatocellular, carcinoma, '(', 'HCC),', but, its, functional, contributions, in, this, setting]), verbo([have]), complemento([not, been, determined])].
[sujeto(['HULC']), verbo([modulated]), complemento([the, deregulation, of, lipid, metabolism, in, 'HCC', by, activating, the, 'acyl-CoA', synthetase, subunit, 'ACSL1'])].
[sujeto(['Mechanistic', investigations, showed, that, 'HULC', upregulated, the, transcriptional, factor, 'PPARA,', which]), verbo([activated]), complemento([the, 'ACSL1', promoter, in, hepatoma, cells])].
[sujeto(['HULC', also]), verbo([suppressed]), complemento(['miR-9', targeting, of, 'PPARA', mRNA, by, eliciting, methylation, of, 'CpG', islands, in, the, 'miR-9', promoter])].
[sujeto(['We', documented, the, ability, of, 'HULC', to]), verbo([promote]), complemento(['lipogenesis,', thereby, stimulating, accumulation, of, intracellular, triglycerides, and, cholesterol, in, vitro, and, in, vivo])].
[sujeto(['Strikingly,', 'ACSL1', overexpression, that, generates, cholesterol, was, sufficient, to]), verbo([enhance]), complemento([the, proliferation, of, hepatoma, cells])].
[sujeto(['Further,', cholesterol, addition, was, sufficient, to, upregulate, 'HULC', expression, through, a, positive, feedback, loop]), verbo([involving]), complemento([the, retinoid, receptor, 'RXRA,', which, activated, the, 'HULC', promoter])].
[sujeto(['Overall,', we, concluded, that, 'HULC', functions, as, an, oncogene, in, hepatoma, 'cells,']), verbo([acting]), complemento([mechanistically, by, deregulating, lipid, metabolism, through, a, signaling, pathway, involving, 'miR-9,', 'PPARA,', and, 'ACSL1', that, is, reinforced, by, a, 'feed-forward', pathway, involving, cholesterol, and, 'RXRA', to, drive, 'HULC', signaling])].
[sujeto(['T-cell', cytokine, gene, polymorphisms, and, vitamin, 'D', pathway, gene, polymorphisms, were, evaluated, as, possibly]), verbo([associated]), complemento([with, 'end-stage', renal, disease, '(', 'ESRD)', resulting, from, type, 2, diabetes, mellitus, '(', 'DM)', nephropathy])].
[sujeto(['A', difference, was]), verbo([found]), complemento([in, 'IL18', rs360719, polymorphic, distribution, between, the, former, group, and, chronic, infective, tubulointerstitial, nephritic, patients, '(', 'P', trend, =, 0.033, ')', ',', which, also, differed, in, this, polymorphism, from, controls, '(', 'P', trend, =, 0.005, ')'])].
[sujeto(['T-cell', cytokine, and, vitamin, 'D', pathway, gene, polymorphisms, are, not]), verbo([associated]), complemento([with, 'ESRD', due, to, type, 2, 'DM', nephropathy, in, 'Polish', 'HD', patients])].
[sujeto(['IL18', rs360719, is, probably]), verbo([associated]), complemento([with, the, pathogenesis, of, chronic, infective, tubulointerstitial, nephritis])].
[sujeto(['The', retinoid, 'X', receptor, α, '(', 'RXRα),', a, key]), verbo([nuclear]), complemento([receptor, in, metabolic, 'processes,', is, downregulated, during, host, antiviral, response])].
[sujeto(['Here', we, show, that, 'RXRα', overexpression, or, ligand, activation]), verbo([increases]), complemento([host, susceptibility, to, viral, infections, in, vitro, and, in, 'vivo,', while, 'Rxra-/-', or, antagonist, treatment, reduces, infection, by, the, same, viruses])].
[sujeto(['Consistent', with, these, functional, 'studies,', ligand, activation, of, 'RXR']), verbo([inhibits]), complemento([the, expression, of, antiviral, genes, including, type, 'I', interferon, '(', 'IFN)', and, 'Rxra-/-', macrophages, produce, more, 'IFNβ', than, 'WT', macrophages, in, response, to, 'polyI:C', stimulation])].
[sujeto(['Further', results, indicate, that, ligand, activation, of, 'RXR']), verbo([suppresses]), complemento([the, nuclear, translocation, of, 'β-catenin,', a, 'co-activator', of, 'IFNβ', enhanceosome])].
[sujeto(['Thus,', our, studies]), verbo([have]), complemento([uncovered, a, novel, 'RXR-dependent', innate, immune, regulatory, 'pathway,', suggesting, that, the, downregulation, of, 'RXR', expression, or, 'RXR', antagonist, treatment, benefits, host, antiviral, 'response,', whereas, 'RXR', agonist, treatment, may, increase, the, risk, of, viral, infections])].
[sujeto(['Vitamin', 'D', '(', 'VD)', was, recently]), verbo([associated]), complemento([with, response, to, hepatitis, 'B', vaccination, in, chronic, kidney, disease])].
[sujeto(['We', investigated, whether, polymorphisms, in, 'VD']), verbo([binding]), complemento([protein, '(', 'GC),', 'VD', receptor, '(', 'VDR)', and, retinoid, 'X', receptor, α, '(', 'RXRA)', genes, were, associated, with, response, to, hepatitis, 'B', vaccination, in, renal, replacement, therapy, '(', 'RRT)', patients])].
[sujeto(['After', adjustment, for, 'gender,', age, at, the, 'RRT', 'onset,', 'RRT', 'vintage,', chronic, glomerulonephritis, as, a]), verbo([cause]), complemento([of, renal, failure, and, mean, serum, parathyroid, hormone, 'level,', 'VDR', rs1544410, polymorphism, was, the, only, one, significantly, associated, with, response, to, hepatitis, 'B', 'vaccination:', homozygotes, 'AA', '(', adjusted, 'OR', 1.5, ',', 95, '%', 'CI:', 1.17, -, 1.94, ',', p, =, 0.002, ')', had, higher, risk, to, be, 'non-responders', than, 'GG', homozygotes])].
[sujeto(['The', mRNA, expression, of, 'RXRA', in, the, right, ventricular, outflow, tract, '(', 'RVOT)', myocardium, was, significantly]), verbo([decreased]), complemento([in, patients, with, 'TOF', compared, with, that, in, the, controls])].
[sujeto(['The', aim, of, the, present, study, was, investigate, the, association, between, six, genetic, variants, in, the]), verbo([nuclear]), complemento([receptor, genes, 'PPARA,', 'RXRA,', 'NR1I2', and, 'NR1I3', and, the, 'lipid-lowering', efficacy, and, safety, of, statin, therapy])].
[sujeto(['Maternal', vitamin, 'D', deficiency]), verbo([has]), complemento([been, associated, with, reduced, offspring, bone, mineral, accrual])].
[sujeto(['Retinoid-X', 'receptor-alpha', '(', 'RXRA)', is, an, essential, cofactor, in, the, action, of, 1, ',', 25, -, dihydroxyvitamin, 'D', '(', 1, ',', 25, '[', 'OH]2', -, vitamin, 'D),', and, 'RXRA', methylation, in, umbilical, cord, 'DNA']), verbo([has]), complemento([been, associated, with, later, offspring, adiposity])].
[sujeto(['We', tested, the, hypothesis, that, 'RXRA', methylation, in, umbilical, cord, 'DNA', collected, at, birth, is]), verbo([associated]), complemento([with, offspring, skeletal, 'development,', assessed, by, 'dual-energy', 'X-ray', 'absorptiometry,', in, a, 'population-based', 'mother-offspring', cohort, '(', 'Southampton', 'Women\'s', 'Survey)'])].
[sujeto(['The', maternal, free, 25, '(', 'OH)-vitamin', 'D', index, was, negatively]), verbo([associated]), complemento([with, methylation, at, one, of, these, 'RXRA', 'CpG', sites, '(', β, =, -, 3.3, 'SD/unit,', p, =, 0.03, ')'])].
[sujeto(['Thus,', perinatal, epigenetic, marking, at, the, 'RXRA', promoter, region, in, umbilical, cord, was, inversely]), verbo([associated]), complemento([with, offspring, 'size-corrected', 'BMC', in, childhood])].
[sujeto(['The', potential, mechanistic, and, functional, significance, of, this]), verbo([finding]), complemento([remains, a, subject, for, further, investigation])].
[sujeto(['Recent', studies, of, 25, -, hydroxyvitamin, 'D', '(', 25, '(', 'OH)D)', levels, and, pancreas, cancer]), verbo([have]), complemento([suggested, a, potential, role, of, the, vitamin, 'D', pathway, in, the, etiology, of, this, fatal, disease])].
[sujeto(['SNPs', in, the, 'CYP24A1,', 'CYP2R1,', calcium, sensing, receptor, '(', 'CASR),', vitamin, 'D']), verbo([binding]), complemento([protein, '(', 'GC),', retinoid, 'X', 'receptor-alpha', '(', 'RXRA)', and, megalin, '(', 'LRP2)', genes, were, significantly, associated, with, pancreas, cancer, risk])].
[sujeto(['For', 'example,', pancreas, cancer, risk, was, inversely]), verbo([associated]), complemento([with, 'CYP2R1', rs10741657, '(', 'AA', versus, 'GG,', 'OR', =, 0.7, ;, 95, '%', 'CI:', 0.51, -, 0.95, ')', and, positively, with, 'CYP24A1', rs6127119, '(', 'TT', versus, 'CC'])].
[sujeto(['Vitamin', 'D', pathway, gene, variants, may, be]), verbo([associated]), complemento([with, pancreas, cancer, risk, and, future, studies, are, needed, to, understand, the, possible, role, of, vitamin, 'D', in, tumorigenesis, and, may, have, implications, for, 'cancer-prevention', strategies])].
[sujeto(['Here', we, describe, the, first, 'genome-wide', association, study, '(', 'GWAS)']), verbo([report]), complemento([of, 'CCT', in, 'Latinos'])].
[sujeto(['We', performed, a, 'GWAS', for, 'CCT', on, 1768, 'Latinos']), verbo([recruited]), complemento([in, the, 'Los', 'Angeles', 'Latino', 'Eye', 'Study', '(', 'LALES)', using, 'Illumina\'s', 'HumanOmniExpress', 'BeadChip', '(', '∼730K', 'markers)'])].
[sujeto(['To', discover, additional]), verbo([associated]), complemento(['single-nucleotide', polymorphisms, '(', 'SNPs),', we, imputed, 'SNPs', based, on, the, 1000, 'Genomes', 'Project', reference, panels])].
[sujeto([we, replicated, the, involvement, of, several, previously]), verbo([reported]), complemento(['loci,', 'SUCH', 'AS', 'RXRA-COL5A1,', 'FOXO1,', and, 'ZNF469,', for, 'CCT', in, 'Latinos', '(', 'P', 0.002, ')'])].
[sujeto(['Moreover,', multiple, sources, of, 'ENCODE', evidence]), verbo([suggest]), complemento([that, rs3118515, is, in, a, regulatory, region])].
[sujeto(['Reverse-transcription', 'PCR', products, indicated, that, transcripts, of, 'LOC100506532', surrounding, rs3118515, were]), verbo([expressed]), complemento([in, human, corneas])].
[sujeto(['We', discovered, novel, 'SNPs', for, 'CCT', in, 'Latinos', and]), verbo([provided]), complemento([the, first, reported, evidence, of, the, corneal, expression, of, 'LOC100506532'])].
[sujeto(['These', results, help, to, further]), verbo([increase]), complemento([our, understanding, of, the, genetic, architecture, of, 'CCT'])].
[sujeto(['Mitochondrial', dysfunctions]), verbo([activate]), complemento([retrograde, signaling, from, mitochondria, to, the, nucleus])].
[sujeto(['To', identify, transcription, factors, and, their]), verbo([associated]), complemento([pathways, that, underlie, mitochondrial, retrograde, 'signaling,', we, performed, gene, expression, profiling, of, the, cells, engineered, to, have, varying, amounts, of, mitochondrial, 'DNA', with, an, 'A3243G', mutation, '(', 'mt3243)', in, the, leucine, transfer, 'RNA', '(', 'tRNA(Leu)),', which, reduces, the, abundance, of, proteins, involved, in, oxidative, phosphorylation, that, are, encoded, by, the, mitochondrial, genome])].
[sujeto(['The', cells, with, the, mutation, exhibited, reduced, mitochondrial, 'function,', including, compromised, oxidative, 'phosphorylation,', which, would]), verbo([activate]), complemento([diverse, mitochondrial, retrograde, signaling, pathways])].
[sujeto(['By', analyzing, the, gene, expression, profiles, in, cells, with, the, mutant, 'tRNA(Leu)', and, the, transcription, factors, that]), verbo([recognize]), complemento([the, differentially, regulated, 'genes,', we, identified, 72, transcription, factors, that, were, potentially, involved, in, mitochondrial, retrograde, signaling])].
[sujeto(['We', experimentally, validated, that, the, mt3243, mutation]), verbo([induced]), complemento([a, retrograde, signaling, pathway, involving, 'RXRA', '(', retinoid, 'X', receptor, 'α),', reactive, oxygen, 'species,', kinase, 'JNK', '(', 'c-JUN', 'N-terminal', 'kinase),', and, transcriptional, coactivator, 'PGC1α', '(', peroxisome, 'proliferator-activated', receptor, 'γ,', coactivator, 1, 'α)'])].
[sujeto(['This', 'RXR', pathway, contributed, to, the]), verbo([decrease]), complemento([in, mRNA, abundances, of, oxidative, phosphorylation, enzymes, encoded, in, the, nuclear, 'genome,', thereby, aggravating, the, dysfunction, in, oxidative, phosphorylation, caused, by, the, reduced, abundance, of, 'mitochondria-encoded', enzymes, of, oxidative, phosphorylation])].
[sujeto(['Thus,', matching, transcription, factors, to, differentially]), verbo([regulated]), complemento([gene, expression, profiles, was, an, effective, approach, to, understand, mitochondrial, retrograde, signaling, pathways, and, their, roles, in, mitochondrial, dysfunction])].
[sujeto(['Epidemiological', studies]), verbo([have]), complemento([investigated, the, association, between, vitamin, 'D', pathway, genes, and, breast, cancer, 'risk;', 'however,', little, is, known, about, the, association, between, vitamin, 'D', pathway, genes, and, breast, cancer, prognosis])].
[sujeto(['Using', a, false, discovery, rate, of, 10, '%', ',', six, intronic, 'SNPs', were, significantly]), verbo([associated]), complemento([with, poorer, 'DFS:', 'retinoid-X', receptor, alpha, '(', 'RXRA)', 'SNPs', '(', 'rs881658,', 'rs11185659,', 'rs10881583,', rs881657, and, 'rs7864987)', and, plasminogen, activator, and, urokinase, receptor, '(', 'PLAUR)', 'SNP', '(', 'rs4251864)'])].
[sujeto(['Among', patients, who, did, not, receive, systemic, 'therapy,', 'RXRA', 'SNP', '[', rs10881583, '(', 'P', =, 0.02, ')', ']', was]), verbo([associated]), complemento([with, poorer, 'DFS,', and, among, patients, who, received, 'chemotherapy,', 'RXRA', 'SNPs', '(', 'rs881658,', 'rs11185659,', 'rs10881583,', rs881657, and, 'rs7864987)', were, associated, with, poorer, 'DFS', '(', 'P', &, 'lt;', 0.001, for, all, 'SNPs)'])].
[sujeto(['However,', 'RXRA', 'SNPs:', rs10881583, '(', 'P', &, 'lt;', 0.001, ')', and, rs881657, '(', 'P', =, 0.02, ')', were]), verbo([associated]), complemento([with, improved, 'DFS', in, patients, treated, with, hormone, therapy, alone])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'SNPs', in, the, 'RXRA', and, 'PLAUR', genes, in, the, vitamin, 'D', pathway, may, contribute, to, breast, cancer, 'DFS'])].
[sujeto(['Several']), verbo([nuclear]), complemento([receptors, are, being, increasingly, recognized, for, their, role, as, master, xenosensors])].
[sujeto(['Among', 'them,', 'CAR-RXRα', 'heterodimer,', as, encoded, by, 'NR1I3', and, 'NR2B1,']), verbo([responds]), complemento([to, the, presence, of, drug, compounds, and, regulates, the, transcription, of, a, wide, array, of, genes, involved, in, their, disposition])].
[sujeto(['Notably,', the, genetic, variations, in, the, 'NR1I3', and, 'NR2B1', genes, were, mainly, confined, to, the, introns, whilst, the, exons, were, highly]), verbo([conserved]), complemento([across, the, ethnic, populations])].
[sujeto(['Our', data, would, be, valuable, for, future, pharmacogenetic, studies, on, the, drug, substrates, of, 'CAR-RXRα']), verbo([target]), complemento([genes])].
[sujeto(['In', the, present, 'study,', transcriptional, and, 'post-translational', effects, of, culturing, time, and, prototypical, cytochrome, 'P450', 3, 'A', '(', 'CYP3A)', inducers, on, principal]), verbo([nuclear]), complemento([receptors, '(', 'NRs),', 'CYP2B22,', 2, 'C', and, 3, 'A', were, investigated, in, 'long-term', stored, '(', '~10', 'years)', cryopreserved, pig, hepatocytes, '(', 'CPHs)'])].
[sujeto(['In', the, 'time-course', 'study,', a, crush, and, rise, effect, was, observed, for, pregnane, 'X', receptor, '(', 'NR1I2)', and, constitutive, androstane, receptor, '(', 'NR1I3)', 'mRNAs,', while, a, 'time-dependent']), verbo([increase]), complemento([of, retinoid, 'X', receptor, alpha, '(', 'NR2B1)', was, noticed])].
[sujeto(['In', the, induction, 'study,', an]), verbo([increase]), complemento([of, 'NR1I2,', 'NR1I3', and, 'NR2B1', mRNAs, was, observed, in, 'dexamethasone-exposed', 'CPHs'])].
[sujeto(['The', present, data, demonstrate, that, 'long-term', stored, 'CPHs', may, be, used, to, investigate, mechanisms]), verbo([involved]), complemento([in, 'CYPs', 'regulation,', expression, and, 'function;', provide, further, info, about, 'NR', regulation, of, 'CYPs,', and, confirm, 'species-differences', in, these, mechanisms, of, 'regulation;', 'finally,', they, suggest, the, usefulness, and, relevance, of, gene, expression, profiling, to, early, detect, any, modulation, of, 'CYP', expression, and, bioactivity])].
[sujeto(['We']), verbo([have]), complemento([isolated, primary, rat, 'HSCs', and, investigated, the, effect, of, mechanical, pressure, and, tensile, strain, on, retinol, metabolism, in, the, cells])].
[sujeto(['Mechanical', force, and, tensile, strain, significantly]), verbo([increased]), complemento([the, expression, of, 'α-smooth', muscle, actin, '(', 'α-SMA)', and, collagen, 'I,', and, notably, inhibited, the, expression, of, cellular, 'retinol-binding', protein, 'I', '(', 'CRBP-I),', 'lecithin-retinol', acyltransferase, '(', 'LRAT),', retinyl, ester, hydrolase, '(', 'REH),', retinoic, acid, 'receptor-β', '(', 'RAR-β)', and, retinoid, 'X', 'receptor-α', '(', 'RXR-α)'])].
[sujeto(['Mechanical', force, and, tensile, strain, significantly]), verbo([activate]), complemento(['HSCs', by, regulating, the, retinoid, metabolic, pathway])].
[sujeto(['All-trans', retinoic, acid, '(', 'ATRA),', the, main, active, metabolite, of, vitamin, 'A,', is, a, powerful, signaling, molecule, that]), verbo([regulates]), complemento(['large-scale', morphogenetic, processes, during, vertebrate, embryonic, 'development,', but, is, also, involved, 'post-natally', in, regulating, neural, plasticity, and, cognition])].
[sujeto(['The', distribution, of, the, 'ATRA-synthesizing', 'enzyme,', 'zRalDH,', and, of, 'ATRA', receptors, '(', 'RARs)']), verbo([have]), complemento([been, 'described,', but, information, on, the, distribution, of, other, components, of, the, retinoid, signaling, pathway, is, still, lacking])].
[sujeto(['To', address, this, 'gap,', we]), verbo([have]), complemento([determined, the, expression, patterns, of, two, obligatory, 'RAR', 'co-receptors,', the, retinoid, 'X', receptors, '(', 'RXR)', α, and, 'γ,', and, of, the, three, 'ATRA-degrading', cytochromes, 'CYP26A1,', 'CYP26B1,', and, 'CYP26C1'])].
[sujeto(['We']), verbo([have]), complemento([also, studied, the, distribution, of, zRalDH, protein, using, 'immunohistochemistry,', and, generated, a, refined, map, of, 'ATRA', 'localization,', using, a, modified, reporter, cell, assay, to, examine, entire, brain, sections])].
[sujeto(['This', could, be, due, to, 'long-range', transport, of, zRalDH, enzyme, between, different, nuclei, of, the, song, 'system:', 'Experimental', lesions, of, putative, zRalDH, peptide, source, regions, diminish, 'ATRA-induced', transcription, in]), verbo([target]), complemento([regions])].
[sujeto(['(', 2, ')', 'Four', telencephalic, song, nuclei]), verbo([express]), complemento([different, and, specific, subsets, of, 'retinoid-related', receptors, and, could, be, targets, of, retinoid, 'regulation;', in, the, case, of, the, lateral, magnocellular, nucleus, of, the, anterior, nidopallium, '(', 'lMAN),', receptor, expression, is, dynamically, regulated, in, a, circadian, and, 'age-dependent', manner])].
[sujeto(['(', 3, ')', 'High-order', auditory, areas, exhibit, a, complex, distribution, of, transcripts, representing, 'ATRA', synthesizing, and, degrading, enzymes, and, could, also, be, a]), verbo([target]), complemento([of, retinoid, signaling])].
[sujeto(['Together,', our, survey, across, multiple, connected, song, nuclei, and, auditory, brain, regions, underscores, the, prominent, role, of, retinoid, signaling, in]), verbo([modulating]), complemento([the, circuitry, that, underlies, the, acquisition, and, production, of, learned, vocalizations])].
[sujeto(['The', retinoic, acid, receptor, '(', 'RAR)', α, system, plays, a, key, role, in, the, adult, 'brain,']), verbo([participating]), complemento([in, the, homeostatic, control, of, synaptic, 'plasticity,', essential, for, memory, function])].
[sujeto(['Here', we, show, that, 'RARα', signalling, is, 'down-regulated', by, amyloid, beta, '(', 'Aβ),', which]), verbo([inhibits]), complemento([the, synthesis, of, the, endogenous, 'ligand,', retinoic, acid, '(', 'RA)'])].
[sujeto(['RARα', signalling, improves, cognition, in, the, 'Tg2576', 'mice,', it]), verbo([has]), complemento([an, 'anti-inflammatory', effect, and, promotes, 'Aβ', clearance, by, increasing, insulin, degrading, enzyme, and, neprilysin, activity, in, both, microglia, and, neurons])].
[sujeto(['In', 'addition,', 'RARα', signalling]), verbo([prevents]), complemento([tau, phosphorylation])].
[sujeto(['All-trans', retinoic, acid, '(', 'atRA)', is, the, active, form, of, vitamin, 'A,', known, to]), verbo([activate]), complemento([retinoid, 'receptors,', especially, the, heterodimer, retinoid, 'X', receptor, '(', 'RXR):retinoic', acid, receptor, '(', 'RAR)', that, otherwise, may, play, a, role, in, regulation, of, some, drug, transporters])].
[sujeto(['The', present, study, was, designed, to, characterize, the, nature, of, human, hepatic, transporters, that, may, be]), verbo([targeted]), complemento([by, atRA, and, the, heterodimer, 'RXR:RAR'])].
[sujeto(['Exposure', of, human, hepatoma, 'HepaRG', cells, and, primary, human, hepatocytes, to, 5, μM, atRA, 'down-regulated', mRNA, levels, of, various, sinusoidal, solute, carrier, '(', 'SLC)', influx, 'transporters,', including, organic, anion, transporting, polypeptide, '(', 'OATP)', 2, 'B1,', 'OATP1B1,', organic, cation, transporter, '(', 'OCT)', 1, and, organic, anion, transporter, '(', 'OAT)', 2, ',', and]), verbo([induced]), complemento([those, of, the, canalicular, breast, cancer, resistance, protein, '(', 'BCRP)'])].
[sujeto(['The', retinoid, concomitantly, reduced, protein, expression, of, 'OATP2B1', and, 'OATP1B1', and, activity, of, 'OATPs', and, 'OCT1', and]), verbo([induced]), complemento(['BCRP', protein, expression, in, 'HepaRG', cells])].
[sujeto(['Some', transporters, such, as, 'OATP1B3', and, the, bile, salt, export, pump, '(', 'BSEP)', were, however, 'down-regulated', by, atRA, in, primary, human, 'hepatocytes,', but]), verbo([induced]), complemento([in, 'HepaRG', 'cells,', thus, pointing, out, discrepancies, between, these, two, liver, cell, models, in, terms, of, detoxifying, protein, regulation])].
[sujeto([atRA, thus, differentially]), verbo([regulated]), complemento([human, hepatic, drug, 'transporters,', mainly, in, a, 'RXR:RAR-dependent', 'manner,', therefore, establishing, retinoids, and, retinoid, receptors, as, modulators, of, liver, drug, transporter, expression])].
[sujeto(['A', malfunction, of, retinoid, 'X', 'receptor-α', '(', 'RXR-α)', due, to, phosphorylation, by, 'Ras/mitogen-activated', protein, kinase, is, closely]), verbo([associated]), complemento([with, liver, carcinogenesis, and, acyclic, retinoid, '(', 'ACR)', can, prevent, 'HCC', development, by, inhibiting, 'RXR-α', phosphorylation])].
[sujeto(['The', present, study, examined, the, possible, combined, effects, of, 'ACR', plus, 'branched-chain', amino, acids, '(', 'BCAA),', which, can, also]), verbo([prevent]), complemento([the, development, of, 'HCC', in, obese, patients, with, liver, 'cirrhosis,', in, human, 'HCC', xenografts, in, nude, mice])].
[sujeto(['The', combined, treatment, with, 'ACR', plus, 'BCAA', significantly]), verbo([inhibited]), complemento([the, growth, of, 'Huh7', xenografts])].
[sujeto(['The', combination, of, these, agents]), verbo([caused]), complemento([a, marked, inhibition, of, the, phosphorylation, of, 'RXR-α,', 'ERK,', 'Akt', and, 'IGF-1R', proteins, in, the, xenografts])].
[sujeto(['In', 'addition,', the, expression, levels, of, 'RAR-β', and, 'p21(CIP1)', mRNA, significantly]), verbo([increased]), complemento([by, these, agents])].
[sujeto(['The', combination, of, 'ACR', and, 'BCAA', restores, the, function, of, 'RXR-α', by]), verbo([inhibiting]), complemento([its, phosphorylation, and, increasing, the, level, of, 'RAR-β,', a, heterodimeric, partner, for, 'RXR-α,', and, thus, suppresses, the, growth, of, 'HCC', xenografts])].
[sujeto(['Previous', studies]), verbo([have]), complemento([shown, that, arsenic, decreases, expression, of, 'CYP3A,', a, critical, drug, metabolizing, enzyme, in, human, and, rat, liver])].
[sujeto(['In', 'addition,', acute, and, chronic, arsenic, exposure, in, liver]), verbo([stimulates]), complemento([an, inflammatory, response])].
[sujeto(['Our', work]), verbo([has]), complemento([shown, that, arsenite, decreases, nuclear, levels, of, 'RXRα', the, nuclear, receptor, 'that,', as, a, heterodimer, partner, with, 'PXR,', transactivates, the, 'CYP3A', gene])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, arsenite, decreases, transcription, of, 'CYP3A', by, decreasing, 'RXRα'])].
[sujeto(['The', present]), verbo([report]), complemento([shows, that, exposure, to, 5, μM, arsenite, decreased, the, activity, of, a, rat, 'CYP3A', promoter, luciferase, reporter, in, 'HepG2', cells])].
[sujeto(['Previous', studies]), verbo([have]), complemento([shown, that, arsenic, in, the, concentration, range, of, 2, -, 5, μM, affects, 'CYP3A', mRNA])].
[sujeto(['Treatment', of, primary, human, hepatocytes, with, the, proteasome, inhibitor, 'MG132']), verbo([increased]), complemento(['RXRα', suggesting, the, involvement, of, the, proteasome, pathway, in, regulation, of, 'RXRα'])].
[sujeto(['Finally,', arsenic]), verbo([induces]), complemento([a, 'pro-inflammatory', response, in, liver])].
[sujeto(['Surprisingly,', we, show, that, in, hepatocytes, arsenite]), verbo([decreases]), complemento([expression, of, two, inflammatory, 'mediators,', 'TNF', and, 'VEGF,', an, effect, that, is, not, predicted, from, suppression, of, 'RXRα', activity])].
[sujeto(['Retinoic', acid, '(', 'RA)']), verbo([triggers]), complemento([physiological, processes, by, activating, heterodimeric, transcription, factors, '(', 'TFs)', comprising, retinoic, acid, receptor, '(', 'RARα,', 'β,', 'γ)', and, retinoid, 'X', receptor, '(', 'RXRα,', 'β,', 'γ)'])].
[sujeto(['How', a, single, signal]), verbo([induces]), complemento([highly, complex, temporally, controlled, networks, that, ultimately, orchestrate, physiological, processes, is, unclear])].
[sujeto(['Using', an, 'RA-inducible', differentiation, 'model,', we, defined, the, temporal, changes, in, the, 'genome-wide']), verbo([binding]), complemento([patterns, of, 'RARγ', and, 'RXRα', and, correlated, them, with, transcription, regulation])].
[sujeto(['Unexpectedly,', both, receptors, displayed, a, highly, dynamic, 'binding,', with, different, 'RXRα', heterodimers]), verbo([targeting]), complemento([identical, loci])].
[sujeto(['Comparison', of, 'RARγ', and, 'RXRα', 'co-binding', at, 'RA-regulated', genes, identified, putative, 'RXRα-RARγ']), verbo([target]), complemento([genes, that, were, validated, with, 'subtype-selective', agonists])].
[sujeto(['This', analysis, revealed, six, distinct, 'co-expression', paths, of, which, 'RXRα-RARγ', is]), verbo([associated]), complemento([with, transcription, 'activation,', while, 'Sox2', and, 'Egr1', were, predicted, to, regulate, repression])].
[sujeto(['Our', analysis]), verbo([provides]), complemento([a, dynamic, view, of, 'RA', signalling, during, cell, 'differentiation,', reveals, 'RAR', heterodimer, dynamics, and, 'promiscuity,', and, predicts, decisions, that, diversify, the, 'RA', signal, into, distinct, 'gene-regulatory', programs])].
[sujeto(['Retinoic', acid, receptor, '(', 'RAR)', signaling, is, important, for]), verbo([regulating]), complemento([transcriptional, activity, of, genes, involved, in, 'growth,', 'differentiation,', metabolism, and, reproduction])].
[sujeto(['Defects', in, 'RAR', signaling]), verbo([have]), complemento([been, implicated, in, cancer])].
[sujeto(['Here,', we, identify, 'TEL', as, a, transcriptional, repressor, of, 'RAR', signaling, by, its, direct]), verbo([binding]), complemento([to, both, 'RAR', and, its, dimerisation, 'partner,', the, retinoid, x, receptor, '(', 'RXR)', in, a, 'ligand-independent', fashion])].
[sujeto(['TEL', is]), verbo([found]), complemento([in, two, 'isoforms,', created, by, the, use, of, an, alternative, startcodon, at, amino, acid, 43])].
[sujeto(['Although', both, isoforms]), verbo([bind]), complemento([to, 'RAR', and, 'RXR', in, vitro, and, in, 'vivo,', the, shorter, form, of, 'TEL', represses, 'RAR', signaling, much, more, efficiently])].
[sujeto(['Binding', studies, revealed, that, 'TEL']), verbo([binds]), complemento([closely, to, the, 'DNA', binding, domain, of, 'RAR', and, that, both, 'Helix', 'Loop', 'Helix', '(', 'HLH)', and, 'DNA', binding, domains, of, 'TEL', are, mandatory, for, interaction])].
[sujeto(['We']), verbo([have]), complemento([shown, that, repression, by, 'TEL', does, not, involve, recruitment, of, histone, deacetylases, and, suggest, that, polycomb, group, proteins, participate, in, the, process])].
[sujeto(['Transcriptional', regulation, by, transcriptional, regulatory, factors, '(', 'TRFs)', of, their]), verbo([target]), complemento(['TRF', genes, is, central, to, the, control, of, gene, expression])].
[sujeto(['To', study, a, static, 'multi-tiered', 'inter-TRF', regulatory, network, in, the, human, hepatoma, 'cells,', we]), verbo([have]), complemento([applied, a, 'Matrix', 'RNAi', approach, in, which, siRNA, knockdown, and, quantitative, 'RT-PCR', are, used, in, combination, on, the, same, set, of, 'TRFs', to, determine, their, interdependencies])].
[sujeto(['These', include, the, 'cross-talks', between, hepatocyte]), verbo([nuclear]), complemento([factors, '(', 'HNFs)', and, the, other, 'TRF', groups, such, as, 'CCAAT/enhancer-binding', proteins, '(', 'CEBPs),', retinoic, acid, receptors, '(', 'RARs),', retinoid, receptors, '(', 'RXRs)', and, 'RAR-related', orphan, receptors, '(', 'RORs),', which, play, key, regulatory, functions, in, human, hepatocytes, and, liver])].
[sujeto(['Dietary', factors, can, be]), verbo([associated]), complemento([with, colorectal, cancer])].
[sujeto(['Fatty', acids]), verbo([modulate]), complemento([gene, expression, in, various, 'tissues,', mediated, by, activation, of, the, peroxisome, proliferator, activated, 'receptor:', 'PPAR'])].
[sujeto(['Vitamin', 'A', signalling, is]), verbo([mediated]), complemento([by, retinoic, acid, '(', 'RA)', receptors, '(', 'RAR)', and, retinoid, 'X', receptors, '(', 'RXR)'])].
[sujeto(['The', steroid]), verbo([nuclear]), complemento([receptors, 'PPAR,', 'RAR,', 'RXR,', are, 'DNA-binding', proteins, and, they, induce, gene, transcription, upon, activation, by, specific, ligands, and, interacting, with, distinct, promoter, sequences, in, the, target, genes])].
[sujeto(['The', cafeteria, diet, and, the, 'HFD']), verbo([induced]), complemento([a, significant, decrease, in, 'RARb', 'mRNA:', -, 36, '%', '(', 'p&lt;0'])].
[sujeto(['Simultaneously,', an]), verbo([increased]), complemento([expression, of, 'PPARg', mRNA, was, observed, for, cafeteria, diet, +, 35, '%', '(', 'P&lt;0'])].
[sujeto(['The', level, of, 'RXRa', mRNA, was, significantly]), verbo([increased]), complemento([for, cafeteria, 'diet:', +, 53, '%', '(', 'P&lt;0'])].
[sujeto(['These', results, showed, that, an, hyperlipidic, diet, could]), verbo([induce]), complemento([early, modifications, in, the, pattern, of, expression, of, nuclear, receptors, in, rat, colon])].
[sujeto(['Many', mechanisms, could, be, probably]), verbo([involved]), complemento([but, one, hypothesis, is, that, a, modification, of, the, balance, between, the, nuclear, 'receptors,', resulting, from, an, increased, expression, of, 'PPARg,', could, induce, a, decreased, expression, of, 'RARb', in, rat, colon])].
[sujeto(['Prostate-specific', antigen, '(', 'PSA)', is, a, member, of, the, kallikrein, family, and]), verbo([has]), complemento([been, an, important, biological, marker, for, prostate, cancer])].
[sujeto(['The', mechanisms]), verbo([regulating]), complemento(['PSA', expression, in, prostatic, cancer, cells, are, unclear])].
[sujeto(['The', tumorigenic, potential, of, prostate, cancer, cells, was, analyzed, by, soft, agar, 'colony-forming', 'assay,', in, vitro, invasion, 'assay,', type, 'IV', collagenase, assay, and]), verbo([binding]), complemento([to, extracellular, matrix, assay])].
[sujeto(['The']), verbo([nuclear]), complemento([receptors, for, retinoic, acid, '(', 'RAR', 'alpha,', -, 'beta,', -, gamma, and, 'RXR', 'alpha,', -, 'beta,', -, 'gamma)', as, well, as, 'PSA', mRNA, were, determined, by, 'Northern', blot, using, specific, oligonucleotide, probes])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 13, -, 'cis-RA', significantly, inhibits, 'PSA', secretion, and, expression, both, at, the, mRNA, and, protein, levels, compared, with, untreated, cells])].
[sujeto(['Electron', microscopic, studies]), verbo([suggest]), complemento([that, after, 13, -, 'cis-RA', 'treatment,', cells, become, more, differentiated, as, they, contain, 'lumina,', lined, by, plasma, membrane, and, microvilli])].
[sujeto(['Prostate', cancer, cell, growth, and, tumorigenic, potential, after, 13, -, 'cis-RA', treatment, was, significantly]), verbo([decreased]), complemento([compared, with, controls])].
[sujeto(['There', was, also, a, significant]), verbo([increase]), complemento([in, the, expression, of, 'RXRa', mRNA, after, 13, -, 'cis-RA', treatment, compared, with, untreated, cells])].
[sujeto(['The', recently, described, retinoid, 'X', receptors, '(', 'RXRs)']), verbo([respond]), complemento([to, the, novel, retinoid, 9, -, 'cis-retinoic', acid, and, also, serve, as, heterodimeric, partners, for, the, vitamin, 'D,', thyroid, 'hormone,', and, retinoic, acid, receptors, '(', 'VDR,', 'TR,', and, 'RAR,', 'respectively)'])].
[sujeto(['In', this, 'work,', we]), verbo([report]), complemento(['high-resolution', localization, of, the, human, 'RXR', genes, within, cytogenetic, bands, and, also, within, a, standard, reference, map, of, cosmid, 'DNA', markers, on, human, chromosomes])].
[sujeto(['We']), verbo([have]), complemento([determined, the, location, of, the, human, 'RXR', genes, by, pairwise, hybridization, of, the, 'RXR', cosmids, and, reference, 'markers,', using, fluorescence, in, situ, hybridization])].
[sujeto(['Six', 'retinoid-responsive', transcription, factors]), verbo([have]), complemento([been, identified, so, 'far,', including, three, retinoic, acid, receptors, in, addition, to, the, three, 'RXRs'])].
[sujeto(['The', proximity, of, 'RXR', genes, to, loci, known, to, be]), verbo([associated]), complemento([with, genetic, disorders, suggests, that, their, location, may, be, useful, in, establishing, a, link, between, 'RXRs', and, certain, human, diseases])].
[sujeto(['Recently,', a, novel, subgroup, of]), verbo([nuclear]), complemento([hormone, receptors, called, 'RXRs', implicated, for, 'retinoid-mediated', gene, regulation, have, been, identified])].
[sujeto(['RXRs', appear, to]), verbo([interact]), complemento([with, many, other, nuclear, hormone, receptors, and, modulate, their, functions])].
[sujeto(['We']), verbo([have]), complemento([mapped, genetic, loci, 'Rxra,', 'Rxrb,', and, 'Rxrg', encoding, three, 'RXR', 'subtypes,', 'RXR', 'alpha,', 'RXR', 'beta,', and, 'RXR', 'gamma,', 'respectively,', using, interspecific, backcross, mice])].
[sujeto(['Whether', plasma, 25, '(', 'OH)D']), verbo([interacts]), complemento([with, breast, tumor, expression, of, vitamin, 'D', receptor, '(', 'VDR)', and, retinoid, 'X', 'receptor-alpha', '(', 'RXR)', has, not, been, investigated])].
[sujeto(['Plasma', 25, '(', 'OH)D', levels, were, not]), verbo([associated]), complemento([with, breast, cancer, risk, overall, '(', top, '(', '{', greater, than, or, equal, 'to}32'])].
[sujeto([25, '(', 'OH)D', measured, in, summer, '(', 'May-October)', was, significantly, inversely]), verbo([associated]), complemento([with, risk, '(', top, vs])].
[sujeto([25, '(', 'OH)D', levels, were, inversely]), verbo([associated]), complemento([with, risk, of, tumors, with, high, expression, of, stromal, nuclear, 'VDR', '(', '{', greater, than, or, equal, 'to}30ng/mL', vs])].
[sujeto(['However,', our, results]), verbo([suggest]), complemento([women, with, 'high,', compared, with, 'low,', plasma, 25, '(', 'OH)D', levels, in, the, summer, have, a, reduced, breast, cancer, 'risk,', and, plasma, 25, '(', 'OH)D', may, be, inversely, associated, with, risk, of, tumors, expressing, high, levels, of, 'VDR'])].
[sujeto(['Although', many, diseases, and, traits, show, large, 'heritability,', few, genetic, variants]), verbo([have]), complemento([been, found, to, strongly, separate, phenotype, groups, by, genotype])].
[sujeto(['Complex', regulatory, networks, of, variants, and, expression, of, multiple, genes]), verbo([lead]), complemento([to, small, 'individual-variant', effects, and, difficulty, replicating, the, effect, of, any, single, variant, in, an, affected, pathway])].
[sujeto(['Interaction', network, modeling, of, 'GWAS', identifies, effects, ignored, by, univariate, 'models,', but, population, differences, may, still]), verbo([cause]), complemento([specific, genes, to, not, replicate])].
[sujeto(['In', this, 'study,', we, used, 'gene-level', functional, interaction, information, from, the, 'Integrative', 'Multi-species', 'Prediction', '(', 'IMP)', tool, to]), verbo([reveal]), complemento([important, genes, associated, with, a, complex, phenotype, through, evidence, from, epistasis, networks, and, pathway, enrichment])].
[sujeto(['The', integrative, analysis, spotlights, the, role, of, genes, related, to, retinoid, 'X', receptor, alpha, '(', 'RXRA),', which]), verbo([has]), complemento([been, implicated, in, a, previous, epistasis, network, analysis, of, smallpox, vaccine])].
[sujeto(['Previously', we, identified, the, first, retinoid, 'X', 'receptor-alpha', '(', 'RXRα)', modulators, that]), verbo([regulate]), complemento([the, 'RXRα', biological, function, via, binding, to, the, 'coregulator-binding', site])].
[sujeto(['Here', we]), verbo([report]), complemento([the, characterization, of, the, interactions, between, the, hit, molecule, and, 'RXRα', through, computational, 'modeling,', 'mutagenesis,', 'SAR', and, biological, evaluation])].
[sujeto(['In', 'addition,', we]), verbo([reported]), complemento([studies, of, additional, new, compounds, and, identified, a, molecule, that, mediated, the, 'NF-κB', pathway, by, inhibiting, the, 'TNFα-induced', 'IκBα', degradation, and, p65, nuclear, translocation])].
[sujeto(['The', biologically, active, form, of, vitamin, 'D,', 1, 'α,25-dihydroxyvitamin', 'D3', '(', 1, ',', 25, 'D3),']), verbo([has]), complemento([been, reported, to, positively, regulate, the, human, cathelicidin, 'anti-microbial', peptide, '(', 'CAMP)', gene, coding, for, 'LL-37,', but, the, mechanisms, are, not, completely, understood])].
[sujeto(['We']), verbo([have]), complemento([determined, the, expression, of, 'CAMP,', vitamin, 'D', receptor, '(', 'VDR),', and, the, retinoid, 'X', receptor, '(', 'RXR)', isoforms, in, human, skin, and, gingival, tissue, biopsies, and, investigated, the, signaling, pathways, involved, in, 1, ',', 25, 'D3-induced', upregulation, of, 'CAMP'])].
[sujeto(['Gene', analysis, revealed, that, human, skin, biopsies]), verbo([expressed]), complemento([higher, levels, of, both, 'CAMP', and, 'RXRα', mRNA, than, human, gingival, 'biopsies,', whereas, 'VDR', and, 'RXRβ', transcript, levels, were, similar, in, skin, and, gingiva])].
[sujeto(['In', 'HaCaT', 'cells,', treatment, with, 1, ',', 25, 'D3', '(', 5, nM, and, 1, &, 'nbsp;μM)', for, 4, and, 24, &, 'nbsp;h', 'up-regulated', 'CAMP', mRNA, several, 'fold,', and, treatment, with, 1, ',', 25, 'D3', for, 24, &, 'nbsp;h']), verbo([increased]), complemento([protein, expression, of, the, 'pro-form', of, 'LL-37', '(', 'hCAP-18)', by, about, 13, times])].
[sujeto(['The', 1, ',', 25, 'D3-evoked', stimulation, of, 'HaCaT', 'CAMP', expression, was]), verbo([associated]), complemento([with, attenuated, 'VDR', mRNA, and, protein, expression])].
[sujeto(['Treatment', with, 'RXRα', short, interfering, 'RNA', reversed, the, 1, ',', 25, 'D3-induced', 'CAMP', expression, in, 'HaCaT', 'cells,', showing, that, 'RXRα', is]), verbo([involved]), complemento([in, the, 'up-regulation', of, 'CAMP', by, 1, ',', 25, 'D3'])].
[sujeto(['We', conclude, that, the, 1, ',', 25, 'D3-evoked', stimulation, of, 'CAMP', expression, in, human, skin, keratinocytes, is, dependent, on, 'RXRα', but, is, not]), verbo([associated]), complemento([with, the, 'up-regulation', of, 'VDR', expression])].
[sujeto(['Cecropin', 'B', can]), verbo([inhibit]), complemento([the, expression, of, 'CYP3A29,', but, the, underlying, mechanisms, remain, unclear])].
[sujeto(['Our', results, indicated, that, the, 'CYP3A29', expression, was]), verbo([inhibited]), complemento([by, cecropin, 'B,', which, was, regulated, by, pregnane, 'X', receptor, '(', 'PXR)', in, a, 'time-', and, 'dose-dependent', manner])].
[sujeto(['NF-κB', p65, directly]), verbo([interacted]), complemento([with, the, 'DNA-binding', domain, of, 'PXR,', suppressed, its, 'expression,', and, inhibited, its, 'transactivation,', leading, to, the, downregulation, of, the, 'PXR-regulated', 'CYP3A29', expression])].
[sujeto(['Furthermore,', cecropin, 'B']), verbo([activated]), complemento([pig, liver, cells, by, interacting, with, 'TLRs', 2, and, 4, ',', which, modulated, 'NF-κB-mediated', signaling, pathways])].
[sujeto(['In', 'conclusion,', cecropin, 'B']), verbo([inhibited]), complemento([the, expression, of, 'CYP3A29', in, a, 'TLR/NF-κB/PXR-dependent', 'manner,', which, should, be, considered, in, future, development, of, cecropins, and, other, antimicrobial, peptides])].
[sujeto(['The', vitamin, 'D', metabolite, 24, ',', 25, -, dihydroxyvitamin, 'D3', '(', 24, ',', 25, '[', 'OH]2D3)', was, shown, to]), verbo([induce]), complemento([nongenomic, signaling, pathways, in, resting, zone, chondrocytes, and, other, cells, involved, in, bone, remodeling])].
[sujeto(['Recently,', our, laboratory, demonstrated, that, 24, ',', 25, -, '[', 'OH]2D3', but, not, 25, -, hydroxyvitamin, 'D3,']), verbo([suppresses]), complemento([apolipoprotein, 'A-I', '(', apo, 'A-I)', gene, expression, and, 'high-density', lipoprotein, '(', 'HDL)', secretion, in, hepatocytes])].
[sujeto(['Since', 24, ',', 25, -, '[', 'OH]2D3']), verbo([has]), complemento([low, affinity, for, the, vitamin, 'D', receptor, '(', 'VDR)', and, little, is, known, with, regard, to, how, 24, ',', 25, -, '[', 'OH]2D3', modulates, nongenomic, signaling, in, 'hepatocytes,', we, investigated, the, capacity, of, 24, ',', 25, -, '[', 'OH]2D3', to, activate, various, signaling, pathways, relevant, to, apo, 'A-I', synthesis, in, 'HepG2', cells])].
[sujeto(['Treatment', with, 24, ',', 25, -, '[', 'OH]2D3', resulted, in]), verbo([decreased]), complemento([peroxisome, 'proliferator-activated', receptor, alpha, '(', 'PPARα)', expression, and, 'retinoid-X-receptor', alpha, '(', 'RXRα)', expression])].
[sujeto(['Similarly,', treatment, of, hepatocytes, with, 50, nM, 24, ',', 25, -, '[', 'OH]2D3', for, 1, -, 3, h]), verbo([induced]), complemento(['PKCα', activation, as, well, as, 'c-jun-N-terminal', kinase, 1, '(', 'JNK1)', activity, and, 'extracellular-regulated', kinase, 1, /, 2, '(', 'ERK1/2)', activity])].
[sujeto(['These', changes, in, kinase, activity, correlated, with, changes, in, 'c-jun', 'phosphorylation,', an]), verbo([increase]), complemento([in, 'AP-1-dependent', transcriptional, 'activity,', as, well, as, repression, of, apo, 'A-I', promoter, activity])].
[sujeto(['Furthermore,', treatment, with, 24, ',', 25, -, '[', 'OH]2D3']), verbo([increased]), complemento(['IL-1β,', 'IL-6,', and, 'IL-8', expression, by, 'HepG2', cells])].
[sujeto(['These', observations]), verbo([suggest]), complemento([that, 24, ',', 25, -, '[', 'OH]2D3', elicits, several, novel, rapid, 'nongenomic-mediated', 'pro-inflammatory', protein, kinases, targeting, 'AP1', 'activity,', increasing, 'pro-inflammatory', cytokine, 'expression,', potentially, impacting, lipid, metabolism, and, hepatic, function])].
[sujeto(['The', aim, of, the, present, study, was, to]), verbo([find]), complemento([out, whether, 'α-linolenic', acid, '(', 'ALA)', or, 'DHA', uptake, can, have, an, effect, on, activities, and, gene, expressions, of, enzymes, involved, in, lipid, metabolism, in, the, 'liver,', subcutaneous, adipose, tissue, and, longissimus, dorsi, '(', 'LD)', muscle, of, 'growing-finishing', pigs])].
[sujeto(['The', results, showed, that, activities, of, malic, enzyme, '(', 'ME)', and, fatty, acid, synthase, '(', 'FAS)']), verbo([decreased]), complemento([linearly, in, the, liver, with, dietary, 'DHA'])].
[sujeto(['Although', the, expression, of, the, genes, of, these, enzymes, and, their, activities, were, poorly, 'correlated,', 'ME', and, 'FAS', expressions, also]), verbo([decreased]), complemento([linearly, with, 'DHA', intake])].
[sujeto(['The', intake, of, 'DHA', 'down-regulates', the, expressions, of, other, genes]), verbo([involved]), complemento([in, fatty, acid, '(', 'FA)', metabolism, in, some, tissues, of, 'pigs,', such, as, fatty, acid, desaturase, 2, and, 'sterol-regulatory', element, binding, transcription, factor, 1, in, the, liver, and, 2, ',', 4, -, dienoyl, 'CoA', reductase, 2, in, the, 'LD', muscle])].
[sujeto(['FA', oxidation, in, the, 'LD', muscle, and, 'FA', synthesis]), verbo([decreased]), complemento([in, the, liver, with, increasing, amount, of, dietary, 'DHA,', whereas, a, retroconversion, of, 'DHA', into, 'EPA', seems, to, be, set, up, in, this, last, tissue])].
[sujeto(['Their', functional, processing]), verbo([suggested]), complemento([the, occurrence, in, 'HFF', of, a, tight, and, highly, dynamic, 'functional-network,', which, is, balanced, by, specific, 'effectors,', primarily, involved, in, extracellular, matrix, degradation, and, 'remodelling,', inflammation, and, coagulation])].
[sujeto(['Despite', future, accurate, clinical, investigations, are, absolutely, 'needed,', the, present, analysis, may]), verbo([provide]), complemento([a, starting, point, for, more, accurate, oocyte, quality, estimation, and, for, defining, personalised, therapies, in, reproductive, medicine])].
[sujeto(['Obesity']), verbo([has]), complemento([reached, pandemic, 'proportions,', and, there, is, mounting, evidence, that, environmental, exposures, to, endocrine, disrupting, chemicals, known, as, &, 'quot;obesogens&quot;', may, contribute, to, obesity, and, associated, medical, conditions])].
[sujeto(['The', 'Deepwater', 'Horizon', '(', 'DWH)', oil, spill, resulted, in, a, massive, environmental]), verbo([release]), complemento([of, crude, oil, and, remediation, efforts, applied, large, quantities, of, 'Corexit', dispersants, to, the, oil, spill])].
[sujeto(['Because', 'PPARγ', functions, as, a, heterodimer, with, 'RXRα', to, transcriptionally]), verbo([regulate]), complemento([adipogenesis, we, investigated, the, potential, of, 'CWAF', to, transactivate, 'RXRα', and, herein, demonstrated, that, the, 'Corexit', component, 'Span', 80, has, 'RXRα', transactivation, activity])].
[sujeto(['Span', 80]), verbo([bound]), complemento([to, 'RXRα', in, the, low, micromolar, range, and, promoted, adipocyte, differentiation, of, 3, 'T3-L1', preadipocytes])].
[sujeto(['Further,', the, combination, of, 'DOSS', and, 'Span', 80]), verbo([increased]), complemento([3, 'T3-L1', adipocyte, differentiation, substantially, more, than, treatment, with, either, chemical, 'individually,', likely, increasing, the, obesogenic, potential, of, 'Corexit', dispersants])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, gamma, '(', 'PPARG),', 'CCAAT/enhancer']), verbo([binding]), complemento([protein, alpha, '(', 'CEBPA)', and, retinoid, 'X', receptor, alpha, '(', 'RXRA)', are, nuclear, transcription, factors, that, play, important, roles, in, regulation, of, adipogenesis, and, fat, deposition])].
[sujeto(['Some', of, these, 'SNPs']), verbo([caused]), complemento([slight, differences, in, mRNA, structure, stability, 'and/or', putative, binding, sites, for, proteins])].
[sujeto(['Epigallocatechin-3-gallate', '(', 'EGCG),', a, major, component, of, green, 'tea,']), verbo([inhibits]), complemento([a, variety, of, viruses])].
[sujeto(['In', the, present, 'study,', we, examined, the, 'anti-HBV', '(', hepatitis, 'B', 'virus)', effects, of, catechins, from, green, tea, at, the, transcriptional, and, 'antigen-expression', 'levels,', as, well, as, the]), verbo([associated]), complemento([molecular, 'mechanisms,', because, 'HBV-associated', liver, diseases, have, become, a, key, public, health, issue, due, to, their, serious, impact, on, human, physical, and, mental, health])].
[sujeto(['By', using, fluorescence, quenching, and, affinity, 'binding,', we, demonstrated, that, 'EGCG', is, an, important, transcriptional, regulator, of, the, 'HBV', 'genome,', which, it, achieves, by]), verbo([interacting]), complemento([with, farnesoid, 'X', receptor, alpha, '(', 'FXRα)'])].
[sujeto(['Luciferase', assay, showed, that, 'EGCG', effectively]), verbo([inhibited]), complemento([the, transcription, of, the, 'HBV', promoter, 'dose-dependently', when, expression, plasmids, of, 'FXRα', and, retinoid, 'X', receptor, α, '(', 'RXRα)', were, 'co-transfected', into, 'HEK293', cells])].
[sujeto(['These', results, indicate, that, the, downregulation, of, the, 'HBV', antigen, and, the]), verbo([decrease]), complemento([in, the, transcriptional, activation, of, the, 'HBV', 'EnhII/core', promoter, by, 'FXRα/RXRα', are, mainly, due, to, the, interaction, between, 'EGCG', and, 'FXRα'])].
[sujeto(['Therefore,', 'EGCG,', an, antagonist, of, 'FXRα', in, liver, 'cells,']), verbo([has]), complemento([the, potential, to, be, employed, as, an, effective, 'anti-HBV', agent])].
[sujeto(['Many', transcription, factors, '(', 'TFs)']), verbo([have]), complemento([the, ability, to, cooperate, on, 'DNA', elements, as, heterodimers])].
[sujeto(['Despite', the, significance, of, 'TF', heterodimerization, for, gene, 'regulation,', a, quantitative, understanding, of, cooperativity, between, various, 'TF', dimer, partners, and, its, impact, on, heterodimer, 'DNA']), verbo([binding]), complemento([specificity, models, is, still, lacking])].
[sujeto(['Here,', we, used, a, novel, integrative, 'approach,', combining, 'microfluidics-steered', measurements, of, 'dimer-DNA', assembly, with, mechanistic, modeling, of, the, implicated, 'protein-protein-DNA', interactions, to, quantitatively, interrogate, the, cooperative, 'DNA']), verbo([binding]), complemento([behavior, of, the, adipogenic, peroxisome, 'proliferator-activated', receptor, γ, '(', 'PPARγ):retinoid', 'X', receptor, α, '(', 'RXRα)', heterodimer])].
[sujeto(['Using', the, high, throughput, 'MITOMI', '(', mechanically]), verbo([induced]), complemento([trapping, of, molecular, 'interactions)', 'platform,', we, derived, equilibrium, 'DNA', binding, data, for, 'PPARγ,', 'RXRα,', as, well, as, the, 'PPARγ:RXRα', heterodimer, to, more, than, 300, target, 'DNA', sites, and, variants, thereof])].
[sujeto(['We', then, quantified, cooperativity, underlying, 'heterodimer-DNA']), verbo([binding]), complemento([and, derived, an, integrative, heterodimer, 'DNA', binding, constant])].
[sujeto(['Using', this, 'cooperativity-inclusive', 'constant,', we, were, able, to, build, a, 'heterodimer-DNA']), verbo([binding]), complemento([specificity, model, that, has, superior, predictive, power, than, the, one, based, on, a, regular, 'one-site', equilibrium])].
[sujeto(['Our', data, further, revealed, that, individual, nucleotide, substitutions, within, the]), verbo([target]), complemento([site, affect, the, extent, of, cooperativity, in, 'PPARγ:RXRα-DNA', binding])].
[sujeto(['Our', study, therefore, emphasizes, the, importance, of, assessing, cooperativity, when, generating, 'DNA']), verbo([binding]), complemento([specificity, models, for, heterodimers])].
[sujeto(['IL-1β', significantly]), verbo([induced]), complemento([cytoplasmic, expression, of, 'RXRα', in, a, 'time-dependent', manner])].
[sujeto(['Co-incubation', with, 'IL-1β']), verbo([enhanced]), complemento(['phospho-IKKα', '(', 'p-IKKα)', expression, and, this, effect, could, be, inhibited, by, the, specific, inhibitor, for, 'NF-κB', '(', all, 'P&lt;0'])].
[sujeto(['IL-1β', upregulated, 'RXRα', through, activation, of, 'NF-κB', signaling, and, these]), verbo([suggested]), complemento([a, possible, clinic, significance, of, retinoid, receptor, expression, in, the, diagnosis, and, treatment, of, 'GC'])].
[sujeto(['Different', types, of, insults, to, the, 'CNS']), verbo([lead]), complemento([to, axon, demyelination])].
[sujeto(['Remyelination', occurs, when, the, 'CNS', attempts, to, recover, from, myelin]), verbo([loss]), complemento([and, requires, the, activation, of, oligodendrocyte, precursor, cells])].
[sujeto(['With', the, rationale, that, 'CB1', receptor, is]), verbo([expressed]), complemento([in, oligodendrocytes, and, marijuana, consumption, alters, 'CNS', 'myelination,', we, study, the, effects, of, the, cannabinoid, agonist, 'WIN55212'])].
[sujeto([2, at, 1, μM]), verbo([increased]), complemento([the, myelin, basic, protein, mRNA, and, protein, expression, in, vitro])].
[sujeto([2]), verbo([confers]), complemento([more, myelinated, 'axons,', increased, the, expression, of, retinoid, 'X', receptor, 'alpha,', and, declined, nogo, receptor, expression])].
[sujeto(['Controversially,', 1, 'mg/kg', of, the, drug]), verbo([increased]), complemento([the, number, of, demyelinated, axons, and, reduced, the, expression, of, nerve, growth, factor, 'inducible,', calreticulin, and, 'myelin-related', genes, coupling, specifically, with, a, decrease, in, 2, '\'', ',', 3, '\'', -, cyclic, nucleotide, 3, '\'', phosphodiesterase, expression])].
[sujeto([2]), verbo([promotes]), complemento([oligodendrocyte, differentiation, in, vitro])].
[sujeto(['Moreover,', 0.5, 'mg/kg', of, the, drug]), verbo([confers]), complemento([neuroprotection, during, 'cuprizone-induced', 'demyelination,', while, 1, 'mg/kg', aggravates, the, demyelination, process])].
[sujeto(['In', recent, 'years,', chromosomal, microarray, analysis, '(', 'CMA)']), verbo([has]), complemento([led, to, the, identification, of, numerous, copy, number, variations, '(', 'CNV)', in, patients, with, 'CHD'])].
[sujeto(['Microduplications', of, 9, q, '(', 9, 'q+)']), verbo([have]), complemento([been, described, in, patients, with, 'CHD,', 'however,', the, critical, gene, locus, remains, undetermined])].
[sujeto(['Here', we, discuss, an, infant, with, tetralogy, of, 'Fallot', with, absent, pulmonary, 'valve,', fetal, 'hydrops,', and, a, 3.76, 'Mb', de, novo, contiguous]), verbo([gain]), complemento([of, 9, q34])].
[sujeto(['We', also, review, 'CHD', findings, among, previously]), verbo([reported]), complemento([patients, with, 9, q, '(', 9, 'q+)', duplication, syndrome])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([implicating, 'RXRA', in, 'CHD', with, 9, q, 'duplication,', providing, additional, data, in, understanding, the, genetic, etiology, of, tetralogy, of, 'Fallot,', 'CHD,', and, disorders, linked, to, 9, q, microduplication, syndrome])].
[sujeto(['This']), verbo([report]), complemento([also, highlights, the, significance, of, 'CMA', in, the, clinical, diagnosis, and, genetic, counseling, of, patients, and, families, with, complex, 'CHD'])].
[sujeto(['Although', no, effect, of, 'OPAA', on, expression, of, 'PPARG', was, 'observed,', compared, with, the, 'control,', 'OPAA', 'up-regulated', expression, of, the, 'PPAR']), verbo([targets]), complemento(['ACSS2,', 'FABP3,', 'ACACA,', 'FASN,', 'SCD,', 'LPIN1,', 'INSIG1,', and, 'SREBF1'])].
[sujeto(['The', observed, 'up-regulation', of, lipogenic, gene, networks, and, the, changes, in, expression, of, key, miRNA]), verbo([involved]), complemento([in, the, control, of, lipogenic, balance, are, indicative, of, a, potentially, important, role, of, 'EAA', ratios, and, mTOR, signaling, in, the, regulation, of, milk, fat, synthesis])].
[sujeto(['We', aligned, &, 'gt;50', million, 2, 'X150', bp, 'paired-end', 'sequences/sample', to, the, hg19, human, genome, and, applied, three, different, algorithms, '(', 'Cuffdiff2,', 'DEseq2,', 'EdgeR)', for, identification, of, differentially]), verbo([expressed]), complemento([genes, '(', 'DEG\'s)'])].
[sujeto(['Ingenuity', 'Pathways', 'Analysis', '(', 'IPA)', and, 'Weighted', 'Gene', 'Co-expression', 'Network', 'Analysis', '(', 'WGCNA)', identified, inflammatory, processes, as, significantly, elevated, in, our, 'ALS', 'samples,', with, tumor, necrosis, factor, '(', 'TNF)']), verbo([found]), complemento([to, be, a, major, pathway, regulator, '(', 'IPA)', and, 'TNFα-induced', protein, 2, '(', 'TNFAIP2)', as, a, major, network, &, 'quot;hub&quot;', gene, '(', 'WGCNA)'])].
[sujeto(['Using', the, oPOSSUM, 'algorithm,', we, analyzed, transcription, factors, '(', 'TF)', controlling, expression, of, the, nine, 'DEG/hub', genes, in, the, 'ALS', samples, and, identified, 'TF\'s']), verbo([involved]), complemento([in, inflammation, '(', 'NFkB,', 'REL,', 'NFkB1)', and, macrophage, function, '(', 'NR1H2::RXRA', 'heterodimer)'])].
[sujeto(['Transient', expression, in, human, 'iPSC-derived', motor, neurons, of, 'TNFAIP2', '(', also, a, 'DEG', identified, by, all, three, 'algorithms)', reduced, cell, viability, and]), verbo([induced]), complemento([caspase, 3, /, 7, activation])].
[sujeto(['Overexpression', of, the, 'DEG', 'TNFAIP2', in, human, motor, 'neurons,', the, population, most, vulnerable, to, die, in, 'ALS,']), verbo([increased]), complemento([cell, death, and, caspase, 3, /, 7, activation])].
[sujeto(['We', propose, that, therapies]), verbo([targeted]), complemento([to, reduce, inflammatory, 'TNFα', signaling, may, be, helpful, in, 'ALS', patients])].
[sujeto(['Major', homozygotes, of, 'ENHO', rs2281997, seemed, to]), verbo([have]), complemento([higher, circulating, 'adropin,', whereas, major, homozygotes, of, 'RXRA', '(', 'rs749759,', 'rs10776909)', showed, lower, levels])].
[sujeto(['In', 'HD', 'patients,', lower, plasma, adropin, concentration, is]), verbo([associated]), complemento([with, dyslipidemia])].
[sujeto(['Major', homozygosity, of, 'RXRA', seems, to]), verbo([have]), complemento([an, opposite, effect, on, plasma, adropin, compared, with, that, of, 'ENHO', rs2281997])].
[sujeto(['There', is, evidence, that, 'n-3', polyunsaturated, fatty, acids, '(', 'n-3-PUFAs)', can]), verbo([inhibit]), complemento(['mTORC1,', which, should, potentiate, autophagy, and, eliminate, 'NLRP3', inflammasome, activity])].
[sujeto(['We', examined, the, mRNA, expression, by, 'RT-PCR', of, 'Mtor,', 'Nlrp3,', and, other, 22, genes]), verbo([associated]), complemento([with, inflammation, in, rats, livers, after, a, 9, -, week, diet])].
[sujeto(['Compared', to, the, 'control,', the, 'HF', group, showed, a, significant]), verbo([increase]), complemento(['(', between, p, &, 'lt;', 0.05, and, p, &, 'lt;', 0.0001, ')', in, 20, of, these, genes, '(', 'Il1b,', 'Il18,', 'Rxra,', 'Nlrp3,', 'Casp1,', 'Il33,', 'Tnf,', 'Acaca,', 'Mtor,', 'Eif2s1,', 'Eif2ak4,', 'Nfkb1,', 'Srebf1,', 'Hif1a,', 'Ppara,', 'Ppard,', 'Pparg,', 'Mlxipl,', 'Fasn', y, 'Scd1),', and, a, decrease, in, 'Sirt1', '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['With', the, 'HF-Fr', 'diet,', a, significant]), verbo([increase]), complemento(['(', between, p, &, 'lt;', 0.05, and, p, &, 'lt;', 0.005, ')', was, also, found, in, the, expression, of, 16, evaluated, genes, '(', 'Srebf1,', 'Mlxipl,', 'Rxra,', 'Abca1,', 'Il33,', 'Nfkb1,', 'Hif1a,', 'Pparg,', 'Casp1,', 'Il1b,', 'Il-18,', 'Tnf,', 'Ppard,', 'Acaca,', 'Fasn,', 'Scd1),', along, with, a, decrease, in, the, transcription, of, 'Mtor', and, 'Elovl6', '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['Contrarily,', many, of, the, genes, whose, expression]), verbo([increased]), complemento([with, the, 'HF', and, 'HF-Fr', diets, did, not, significantly, increase, with, the, 'HF-n-3-PUFAs', or, 'HF-Fr-n-3-PUFAs', diet])].
[sujeto(['We']), verbo([found]), complemento([the, interrelation, of, the, genes, for, the, mTORC1, 'complex,', the, 'NLRP3', 'inflammasome,', and, other, metabolically, important, 'proteins,', and, that, these, genes, respond, to, 'n-3-PUFAs'])].
[sujeto(['The', detected, 'CNVRs', harboured, 3130, 'genes,', including, genes]), verbo([associated]), complemento([with, fat, 'deposition,', such, as, 'PPARA,', 'RXRA,', 'KLF11,', 'ADD1,', 'FASN,', 'PPP1CA,', 'PDGFA,', and, 'PEX6'])].
[sujeto(['Our', results]), verbo([provide]), complemento([valuable, information, that, will, support, investigations, of, genomic, structural, variation, underlying, traits, of, interest, in, sheep])].
[sujeto(['Recent', advances, in, 'long-range', 'Hi-C', contact, mapping]), verbo([have]), complemento([revealed, the, importance, of, the, 3, 'D', structure, of, chromosomes, in, gene, expression])].
[sujeto(['Using', 'Drosophila', 'Hi-C', data, at, a, very, high, resolution, of, 1, 'kb,', our, model]), verbo([suggests]), complemento(['that,', among, architectural, 'proteins,', 'BEAF-32', and, 'CP190', are, the, main, positive, drivers, of, 3, 'D', domain, borders])].
[sujeto(['The', model, also]), verbo([reveals]), complemento([the, existence, of, several, negative, drivers, that, counteract, the, presence, of, domain, borders, including, 'P300,', 'RXRA,', 'BCL11A', and, 'ELK1'])].
[sujeto(['However,', little, is, known, about, the, function, of, mast, cells, in, patients, with, chronic, allergic, inflammation, or, the, effect, of, repeated, 'FcεRI']), verbo([triggering]), complemento([occurring, in, such, responses])].
[sujeto(['We', aimed, to, identify, changes, in, mast, cell, function, after, repeated, 'FcεRI']), verbo([triggering]), complemento([and, to, correlate, these, changes, to, chronic, allergic, responses, in, tissue])].
[sujeto(['Most', of, these, genes, '(', 84, '%', ')', were, not, upregulated, after, a, single, 'anti-IgE', 'stimulus,', indicating, a, significantly, different, response, mode, characterized, by]), verbo([increased]), complemento([antigen, 'presentation,', response, to, 'bacteria,', and, chemotaxis])].
[sujeto(['Importantly,', we]), verbo([found]), complemento([a, substantial, overlap, between, genes, upregulated, after, repeated, 'anti-IgE', triggering, and, genes, upregulated, in, tissue, from, patients, with, chronic, 'allergy,', in, particular, those, of, patients, with, chronic, rhinosinusitis])].
[sujeto(['Our', study]), verbo([provides]), complemento([evidence, for, intrinsic, modulation, of, mast, cell, function, on, repeated, 'FcεRI-mediated', activation])].
[sujeto(['The', metabolism, of, over, 400, substances, was, affected, by, the, downregulation, of, genes]), verbo([involved]), complemento([in, xenobiotic, metabolism])].
[sujeto(['Functional', characterization, of, the, altered, proteins, may]), verbo([enhance]), complemento([understanding, of, the, host, responses, to, 'T'])].
[sujeto([gondii, infection, and]), verbo([lead]), complemento([to, the, identification, of, new, therapeutic, targets])].
[sujeto(['As', 'expected,', 'OVE']), verbo([increased]), complemento([liver, lipid, content, 'postpartum;', 'however,', cows, fed, 'OVE', +, 'SM', or, 'CON', had, lower, concentrations, than, 'OVE'])].
[sujeto(['Adaptations', in, 'PMN', gene, expression, in, 'OVE', +, 'SM', cows]), verbo([associated]), complemento([with, the, lower, 'SCC', were, gradual, increases, from, -, 10, to, 21, d, in, genes, that, facilitate, migration, into, inflammatory, sites, '(', 'SELL,', 'ITGAM),', enzymes, essential, for, reducing, reactive, oxygen, metabolites, '(', 'SOD1,', 'SOD2),', and, a, transcription, 'factor(s)', required, for, controlling, 'PMN', development, '(', 'RXRA)'])].
[sujeto(['The', greater, expression, of, 'TLR4', on, d, 3, ',', key, for, activation, of, innate, immunity, due, to, 'inflammation,', in, 'OVE', compared, with, 'CON', cows]), verbo([suggests]), complemento([a, more, pronounced, inflammatory, state])].
[sujeto(['Although', 'CON', cows, appeared, to]), verbo([have]), complemento([a, less, stressful, transition, into, 'lactation,', 'SM', supplementation, was, effective, in, alleviating, negative, effects, of, 'energy-overfeeding'])].
[sujeto(['Highly', sensitive, and, specific, 'urine-based', tests, to, detect, either, primary, or, recurrent, bladder, cancer]), verbo([have]), complemento([proved, elusive, to, date])].
[sujeto(['Our', ever]), verbo([increasing]), complemento([knowledge, of, the, genomic, aberrations, in, bladder, cancer, should, enable, the, development, of, such, tests, based, on, urinary, 'DNA'])].
[sujeto(['Analysing', only, previously]), verbo([reported]), complemento([point, 'mutations,', 'TERT', mutations, were, found, in, 55, '%', of, patients, with, bladder, cancer, '(', independent, of, 'stage),', 'FGFR3', mutations, in, 30, '%', of, patients, with, bladder, 'cancer,', 'PIK3CA', in, 14, '%', and, 'TP53', mutations, in, 12, '%', of, patients, with, bladder, cancer])].
[sujeto(['Overall,', these, previously]), verbo([reported]), complemento([bladder, cancer, mutations, were, detected, in, 86, out, of, 122, bladder, cancer, patients, '(', 70, '%', 'sensitivity)', and, in, only, 3, out, of, 109, patients, with, no, detectable, bladder, cancer, '(', 97, '%', 'specificity)'])].
[sujeto(['The', method]), verbo([has]), complemento([a, low, 'DNA', input, requirement, and, can, detect, low, levels, of, mutant, 'DNA', in, a, large, excess, of, normal, 'DNA'])].
[sujeto(['In', the, two, adipose, 'tissues,', the, most, apparent, effect, of, the, 'HF', diet, was, the, 'down-regulation', of, several, genes]), verbo([associated]), complemento([with, the, 'ubiquitin-proteasome', 'system,', which, therefore, may, be, associated, with, 'dietary-induced', modulations, in, genes, acting, in, apoptotic, and, cell, cycle, regulatory, pathways])].
[sujeto(['Genes']), verbo([involved]), complemento([in, glucose, metabolic, processes, were, also, 'down-regulated', by, the, 'HF', 'diet,', with, no, significant, variation, or, decreased, expression, of, important, 'lipid-related', genes, such, as, the, 'low-density', lipoprotein, receptor, and, leptin, in, the, two, fat, pads])].
[sujeto(['PPARγ', which]), verbo([has]), complemento([pleiotropic, functions, including, lipid, metabolism, and, adipocyte, 'differentiation,', was, however, 'up-regulated', by, this, diet, in, 'PRAT', and, 'SCAT'])].
[sujeto(['Dietary-related', modulations, in, the, expression, of, genes]), verbo([associated]), complemento([with, immunity, and, inflammation, were, mainly, revealed, in, 'PRAT'])].
[sujeto(['Interaction', effects, between, dietary, intake, of, fiber, and, lipids, on, gene, expression, may]), verbo([modulate]), complemento([innate, immunity, and, 'inflammation,', a, response, which, is, of, interest, with, regard, to, chronic, inflammation, and, its, adverse, effects, on, health, and, performance])].
[sujeto(['Polymorphisms', in, genes, encoding, proteins]), verbo([involved]), complemento([in, vitamin, 'D', metabolism, and, transport, are, recognised, to, influence, vitamin, 'D', status])].
[sujeto(['We', therefore, conducted, a, literature, review, to, identify]), verbo([reports]), complemento([of, statistically, significant, associations, between, single, nucleotide, polymorphisms, '(', 'SNP)', in, 11, vitamin, 'D', pathway, genes, '(', 'DHCR7,', 'CYP2R1,', 'CYP3A4,', 'CYP27A1,', 'DBP,', 'LRP2,', 'CUB,', 'CYP27B1,', 'CYP24A1,', 'VDR', and, 'RXRA)', and, 'non-bone', health, outcomes, and, circulating, levels, of, 25, -, hydroxyvitamin, 'D', '(', 25, '[', 'OH]D', and, 1, ',', 25, -, dihydroxyvitamin, 'D', '(', 1, ',', 25, '[', 'OH]2D)'])].
[sujeto(['A', total, of, 120, genetic, association, studies]), verbo([reported]), complemento([positive, 'associations,', of, which, 44, investigated, determinants, of, circulating, 25, '(', 'OH)D', 'and/or', 1, ',', 25, '(', 'OH)2D', 'concentrations,', and, 76, investigated, determinants, of, 'non-skeletal', health, outcomes])].
[sujeto(['Statistically', significant, associations, were]), verbo([reported]), complemento([for, a, total, of, 55, 'SNP', in, the, 11, genes, investigated])].
[sujeto(['There', was, limited, overlap, between, genetic, determinants, of, vitamin, 'D', status, and, those]), verbo([associated]), complemento([with, 'non-skeletal', health, 'outcomes:', polymorphisms, in, 'DBP,', 'CYP2R1', and, 'DHCR7', were, the, most, frequent, to, be, reported, to, associate, with, circulating, concentrations, of, 25, '(', 'OH)D,', while, polymorphisms, in, 'VDR', were, most, commonly, reported, to, associate, with, 'non-skeletal', health, 'outcomes,', among, which, infectious, and, autoimmune, diseases, were, the, most, represented])].
[sujeto(['Our', study, demonstrated, that, nonylphenol]), verbo([activated]), complemento(['caspase-3', and, induced, lactate, dehydrogenase, '(', 'LDH)', release, in, hippocampal, 'cells,', which, was, accompanied, by, an, increase, in, the, mRNA, expression, and, protein, levels, of, 'RXRα,', 'PXR', and, 'CAR'])].
[sujeto(['Nonylphenol']), verbo([stimulated]), complemento(['Rxra,', 'Pxr,', and, 'Car', mRNA, expression])].
[sujeto(['These', effects, were, followed, by]), verbo([increase]), complemento([in, the, protein, levels, of, particular, receptors])].
[sujeto(['These', new, data, give, prospects, for, the]), verbo([targeting]), complemento([xenobiotic, nuclear, receptors, to, protect, the, developing, nervous, system, against, endocrine, disrupting, chemicals])].
[sujeto(['BACKGROUND', 'Vitamin', 'D', '(', 'VD),', 'VD']), verbo([binding]), complemento(['protein,', 'VD', receptor, '(', 'VDR),', and, retinoids, are, involved, in, pathogenesis, of, chronic, glomerulonephritis, '(', 'ChGN)'])].
[sujeto(['MATERIAL', 'AND', 'METHODS', 'GFR', category, 1, -, 3, 'ChGN', patients, '(', 'n=195),', 'GFR', category, 5, 'D', 'ChGN', patients, '(', 'n=178),', and, controls, '(', 'n=751)', underwent, testing, for, polymorphisms, of, genes, encoding, 'VD']), verbo([binding]), complemento([protein, '(', 'GC,', 'rs2298849,', 'rs7041,', 'rs1155563),', 'VDR', '(', 'VDR,', 'rs2228570,', 'rs1544410),', and, retinoid, 'X', receptor, alpha, '(', 'RXRA,', 'rs10776909,', 'rs10881578,', 'rs749759)'])].
[sujeto(['CONCLUSIONS', 'RXRA', rs10776909, allele, 'T', is, specifically]), verbo([involved]), complemento([in, the, pathogenesis, of, 'ChGN'])].
[sujeto(['This', risk, allele, may, be, also]), verbo([associated]), complemento([with, worse, clinical, course, of, 'ChGN'])].
[sujeto(['This', exploratory, study, was, aimed, at, elucidating, the, pharmacogenetics, of, regulatory]), verbo([nuclear]), complemento([receptors, '(', 'PXR,', 'CAR,', 'RXRα', and, 'HNF4α)', and, their, implications, on, docetaxel, pharmacokinetics, and, pharmacodynamics, in, local, 'Chinese', nasopharyngeal, cancer, patients])].
[sujeto(['A', total, of, 59, single, nucleotide, polymorphisms, '(', 'SNPs),', including, 'tag-SNPs', and, functionally, relevant, 'SNPs', of, the, genes, encoding, these, regulatory]), verbo([nuclear]), complemento([receptors, '(', 'PXR/NR1I2,', 'CAR/NR1I3,', 'RXRα/NR2B1', and, 'HNF4α/NR2A1),', were, profiled, in, the, patients, enrolled, in, our, study, by, direct, sequencing, '(', 'N', =, 50, ')'])].
[sujeto(['Subsequent', haplotype, association, analysis, identified, the, 'NR2B1', 'LD', block, 2, 'AG', haplotype, '[', *, +, 4458, 'G&gt;A(rs3132291)', and, *, +, 4988, 'A&gt;G(rs4842198)]', to, be, significantly]), verbo([associated]), complemento([with, altered, 'pharmacokinetics,', in, which, patients, carrying, two, copies, of, the, 'AG', haplotype, had, approximately, a, 20, '%', decreased, 'Cmax', and, 'AUC0-∞', and, a, 21, '%', increased, 'CL', compared, to, those, who, carried, only, one, copy, or, no, copies, of, the, haplotype])].
[sujeto(['A', number, of, 'SNPs', in, 'NR1I2,', 'NR1I3,', 'NR2B1', and, 'NR2A1', were, also]), verbo([associated]), complemento([with, a, significant, decrease, in, blood, counts, from, baseline])].
[sujeto(['No', haplotype, was]), verbo([found]), complemento([to, exert, any, effects, on, the, pharmacodynamics, parameters])].
[sujeto(['The', present, exploratory, study, identified, several, 'SNPs', in, the, genes, encoding, regulatory]), verbo([nuclear]), complemento([receptors, which, may, account, for, the, interpatient, variability, in, docetaxel, pharmacokinetics, and, pharmacodynamics])].
[sujeto(['These', findings, highlight, the, important, role, of, regulatory]), verbo([nuclear]), complemento([receptors, on, the, disposition, of, docetaxel])].
[sujeto(['We', aimed, to, study, the, contribution, of, other, regulatory, 'pathways,', including, transcription, factors, and]), verbo([nuclear]), complemento(['receptors,', toward, this, variability])].
[sujeto(['This', is, the, first, 'in-vivo', demonstration, of, the, influence, of, genes]), verbo([involved]), complemento([in, 'CYP1A2', regulatory, pathways, on, its, basal, activity, and, inducibility, by, smoking])].
[sujeto(['In', rodent, 'models,', rexinoids, and, partner, agonists, '(', mainly, 'PPARγ,', 'LXR,', 'FXR)', produce, beneficial, effects, on, insulin, 'sensitization,', diabetes, and, 'obesity,', but, secondary, effects]), verbo([have]), complemento([also, been, 'noted,', such, as, a, raise, in, tryglyceride, 'levels,', supression, of, the, thyroid, hormone, axis, and, induction, of, hepatomegaly])].
[sujeto(['The', synthetic, chemistry, toolbox]), verbo([has]), complemento([provided, a, panel, of, 'agonists,', partial, '(', 'ant)agonists', 'and/or', 'heterodimer-selective', rexinoids, starting, from, 'existing,', naturally, occurring, or, serendipitously, discovered, scaffolds])].
[sujeto(['These', compounds]), verbo([have]), complemento([an, unexplored, therapeutic, potential, that, might, overcome, some, of, the, current, limitations, of, rexinoids, in, 'therapy,', such, as, hypertriglyceridemia])].
[sujeto(['Several', 'signals,', such, as, hormones, and, signaling, 'molecules,']), verbo([have]), complemento([been, identified, as, important, regulators, of, 'Leydig', cell, differentiation, and, function])].
[sujeto(['Conveying', these, signals, and]), verbo([translating]), complemento([them, into, a, genomic, response, to, ensure, an, accurate, physiological, output, requires, the, action, of, a, network, of, transcription, 'factors,', including, those, belonging, to, the, nuclear, receptor, superfamily])].
[sujeto(['Nuclear', receptors]), verbo([regulate]), complemento([expression, of, genes, important, for, 'growth,', 'differentiation,', 'development,', and, homeostasis])].
[sujeto(['Several']), verbo([nuclear]), complemento(['receptors,', such, as, steroid, hormone, receptors, '(', 'NR3A', and, 'NR3C', 'families),', are, activated, upon, ligand, 'binding,', whereas, 'others,', including, members, of, the, 'NR2C,', 'NR2F,', and, 'NR4A', 'families,', either, do, not, require, a, ligand, or, ligands, have, yet, to, be, identified])].
[sujeto(['Several']), verbo([nuclear]), complemento([receptors, '(', e])].
[sujeto([',', 'NR2F2', and, 'NR5A1)']), verbo([have]), complemento([been, shown, to, play, essential, roles, in, 'Leydig', 'cells,', whereas, for, others, '(', e])].
[sujeto([',', 'NR2B1', and, 'NR4A1),', the, assessment, of, their, function]), verbo([has]), complemento([been, precluded, by, the, early, embryonic, lethality, associated, with, null, mice, or, by, redundancy, mechanisms, by, other, family, members])].
[sujeto(['This', review]), verbo([provides]), complemento([an, overview, of, the, nuclear, receptor, family, of, transcription, factors, as, they, relate, to, 'Leydig', cell, gene, expression, and, function])].
[sujeto(['Cell', culture, experiments, revealed, a, 'time-dependent']), verbo([decrease]), complemento([of, 'ABCB1', expression, upon, 'IL8', exposure])].
[sujeto(['The', liver, 'X', receptors, '(', 'LXRs)', are]), verbo([nuclear]), complemento([receptors, that, are, activated, by, endogenous, 'oxysterols,', oxidized, derivatives, of, cholesterol])].
[sujeto(['Both', 'LXRalpha', and, 'LXRbeta']), verbo([regulate]), complemento([gene, expression, by, binding, to, 'DNA', sequences, associated, with, target, genes, as, heterodimers, with, isoforms, of, the, retinoid, 'X', receptor, '(', 'RXR),', 'RXRalpha', '(', 'NR2B1),', 'RXRbeta', '(', 'NR2B2),', and, 'RXRgamma', '(', 'NR2B3)'])].
[sujeto(['LXRs']), verbo([act]), complemento([as, cholesterol, 'sensors:', when, cellular, oxysterols, accumulate, as, a, result, of, increasing, concentrations, of, 'cholesterol,', 'LXR', induces, the, transcription, of, genes, that, protect, cells, from, cholesterol, overload])].
[sujeto(['The', overlapping, and, distinct, roles, of, the, 'LXRalpha', and, 'LXRbeta', 'isoforms,', and, the, potential, use, of, 'LXRs', as, attractive]), verbo([targets]), complemento([for, treatment, of, cardiovascular, disease, are, also, discussed])].
[sujeto(['Numerous', chemicals]), verbo([increase]), complemento([the, metabolic, capability, of, organisms, by, their, ability, to, activate, genes, encoding, various, 'xenochemical-metabolizing', 'enzymes,', such, as, cytochromes, 'P450', '(', 'CYPs),', transferases, and, transporters])].
[sujeto(['For', 'example,', natural, and, synthetic, glucocorticoids, '(', agonists, and, 'antagonists)', as, well, as, other, clinically, important, drugs]), verbo([induce]), complemento([the, hepatic, 'CYP2B,', 'CYP2C', and, 'CYP3A', subfamilies, in, 'man,', and, these, inductions, might, lead, to, clinically, important, 'drug-drug', interactions])].
[sujeto(['Only', 'recently,', the, key, cellular, receptors, that]), verbo([mediate]), complemento([such, inductions, have, been, identified])].
[sujeto(['They', include]), verbo([nuclear]), complemento(['receptors,', such, as, the, constitutive, androstane, receptor, '(', 'CAR,', 'NR1I3),', the, retinoid, 'X', receptor, '(', 'RXR,', 'NR2B1),', the, pregnane, 'X', receptor, '(', 'PXR,', 'NR1I2),', and, the, vitamin, 'D', receptor, '(', 'VDR,', 'NR1I1)', and, steroid, receptors, such, as, the, glucocorticoid, receptor, '(', 'GR,', 'NR3C1)'])].
[sujeto(['Indeed,', this, adaptive, system, appears, now, as, a, tangle, of, 'networks,', where, receptors, share, 'partners,', 'ligands,', 'DNA', response, elements, and]), verbo([target]), complemento([genes])].
[sujeto(['Expression', of, hepatic, cholesterol, 7, 'α-hydroxylase', '(', 'CYP7A1)', is, negatively]), verbo([regulated]), complemento([by, orphan, nuclear, receptor, small, heterodimer, partner, '(', 'SHP)'])].
[sujeto(['In', this, 'study,', we, aimed, to]), verbo([find]), complemento([whether, thyroid, hormone, regulates, 'SHP', expression, by, modulating, the, transcriptional, activities, of, liver, receptor, 'homolog-1', '(', 'LRH-1)'])].
[sujeto(['Initial', microarray, results, indicated, that, 'SHP', expression, is, markedly]), verbo([decreased]), complemento([in, livers, of, 'T3', treated, mice])].
[sujeto(['We', confirmed, that, 'T3']), verbo([repressed]), complemento(['SHP', expression, in, the, liver, of, mice, as, well, as, in, mouse, primary, hepatocytes, and, human, hepatoma, cells, by, 'real-time', 'PCR', analysis])].
[sujeto(['LRH-1']), verbo([increased]), complemento([the, promoter, activity, of, 'SHP;', 'however,', this, increased, activity, was, markedly, decreased, after, thyroid, hormone, receptor, 'β/retinoid', 'X', receptor, 'α/T3', administration])].
[sujeto(['EMSA', revealed, that, 'T3']), verbo([inhibits]), complemento([specific, 'LRH-1', 'DNA', binding])].
[sujeto(['We']), verbo([found]), complemento([that, thyroid, hormone, regulates, the, expression, of, 'SHP', mRNA, through, interference, with, the, transcription, 'factor,', 'LRH-1'])].
[sujeto(['In', nontransformed, bovine, mammary, epithelial, 'cells,', the, intrinsic, apoptosis, inducer, anisomycin, '(', 'ANS)']), verbo([induces]), complemento(['IGFBP-3', expression, and, nuclear, localization, and, knockdown, of, 'IGFBP-3', attenuates, 'ANS-induced', apoptosis])].
[sujeto(['Others']), verbo([have]), complemento([shown, in, prostate, cancer, cells, that, exogenous, 'IGFBP-3', induces, apoptosis, by, facilitating, nuclear, export, of, the, orphan, nuclear, receptor, 'Nur77', and, its, binding, 'partner,', retinoid, 'X', 'receptor-α', '(', 'RXRα)'])].
[sujeto(['The', goal, of, the, present, work, was, to, determine, whether, endogenous, 'IGFBP-3', plays, a, role, in, 'ANS-induced', apoptosis, by, facilitating]), verbo([nuclear]), complemento([transport, of, 'Nur77', 'and/or', 'RXRα', in, nontransformed, cells])].
[sujeto(['Knockdown', of, 'Nur77', with, siRNA]), verbo([decreased]), complemento(['ANS-induced', cleavage, of, 'caspase-3', and, -, 7, and, their, downstream, 'target,', 'PARP,', indicating, a, role, for, 'Nur77', in, 'ANS-induced', apoptosis])].
[sujeto(['In', cells, transfected, with, 'IGFBP-3,', 'IGFBP-3']), verbo([associated]), complemento([with, 'RXRα', but, not, 'Nur77', under, basal, 'conditions,', 'however,', 'IGFBP-3', 'co-precipitated', with, phosphorylated, forms, of, both, proteins, in, 'ANS-treated', cells])].
[sujeto(['Indirect', immunofluorescence, and, cell, fractionation, techniques, showed, that, 'ANS']), verbo([induced]), complemento([phosphorylation, and, transport, of, 'Nur77', from, the, nucleus, to, the, cytoplasm, and, these, effects, were, attenuated, by, knockdown, of, 'IGFBP-3'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, endogenous, 'IGFBP-3', plays, a, role, in, intrinsic, apoptosis, by, facilitating, phosphorylation, and, nuclear, export, of, 'Nur77', to, the, cytoplasm, where, it, exerts, its, apoptotic, effect])].
[sujeto(['Whether', this, mechanism]), verbo([involves]), complemento([a, physical, association, between, endogenous, 'IGFBP-3', and, 'Nur77', or, 'RXRα', remains, to, be, determined])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, γ, '(', 'PPARγ)', is, a, member, of, the]), verbo([nuclear]), complemento([receptor, family, and, plays, key, roles, in, glucose, and, lipid, metabolism])].
[sujeto(['Its', transcriptional, control, of]), verbo([target]), complemento([genes, is, mediated, by, 'ligand-dependent', recruitment, of, coactivators])].
[sujeto(['In', this, 'study,', we, demonstrate, that, a, novel, transcriptional, modulator, of, 'PPARγ,', 'Flightless-I', '(', 'FLII)']), verbo([binds]), complemento([directly, to, and, suppresses, the, transcriptional, activity, of, 'PPARγ'])].
[sujeto(['The', 'LXXLL', motif, within, the, 'leucine-rich', repeat, '(', 'LRR)', domain, of, 'FLII']), verbo([interacts]), complemento([directly, with, the, 'DNA-binding', domain, of, 'PPARγ'])].
[sujeto(['When', 'FLII', was, 'overexpressed,', both, the, transcriptional, activity, of, 'PPARγ', and, adipogenesis, were]), verbo([suppressed]), complemento(['significantly,', whereas, specific, knockdown, of, 'FLII', reversed, these, effects])].
[sujeto(['Furthermore,', 'DNA', occupancy, of, 'PPARγ', on, its]), verbo([target]), complemento([gene, promoters, was, enhanced, by, 'FLII', 'knockdown,', and, the, interaction, between, 'PPARγ', and, retinoid, 'X', receptor, α, '(', 'RXRα)', was, blocked, by, 'FLII'])].
[sujeto(['Together,', these, findings, strongly]), verbo([suggest]), complemento([that, 'FLII', functions, in, 'PPARγ', activation, as, a, molecular, switch, to, repress, transcriptional, activity, by, interrupting, formation, of, the, 'PPARγ/RXRα', 'complex,', and, 'FLII', may, serve, as, a, novel, therapeutic, target, in, the, treatment, of, 'adiposity-related', metabolic, syndromes])].
[sujeto(['Small', 'ubiquitin-like', modifiers, '(', 'SUMO)', are, covalently, conjugated, to, other, proteins, including]), verbo([nuclear]), complemento([receptors, leading, to, modification, of, various, cellular, processes])].
[sujeto(['Ligand-dependent', 'SUMOylation', of, farnesoid, 'X', receptor, '(', 'FXR)', negatively]), verbo([regulates]), complemento([the, expression, of, its, target, genes])].
[sujeto(['Defining', 'post-translation', modification, of, 'FXR', bySUMOis, important, to, understanding, how, this]), verbo([nuclear]), complemento([receptor, functions, in, health, and, disease])].
[sujeto(['The', farnesoid, 'X', receptor, '(', 'FXR)', belongs, to, a, family, of, 'ligand-activated', transcription, factors, that]), verbo([regulate]), complemento([many, aspects, of, metabolism, including, bile, acid, homeostasis])].
[sujeto(['Well']), verbo([conserved]), complemento([consensus, sites, at, lysine, 122, and, 275, in, the, 'AF-1', and, ligand, binding, 'domains,', 'respectively,', of, 'FXR', were, subject, to, 'SUMOylation', in, vitro, and, in, vivo])].
[sujeto(['Chromatin', immunoprecipitation, '(', 'ChIP)', analysis, showed, that, 'Sumo1', was]), verbo([recruited]), complemento([to, the, bile, salt, export, pump, '(', 'BSEP),', the, small, heterodimer, partner, '(', 'SHP),', and, the, 'OSTα-OSTβ', organic, solute, transporter, loci, in, a, 'ligand-dependent', fashion])].
[sujeto(['Sequential', chromatin, immunoprecipitation, '(', 'ChIP-ReChIP)', verified, the, concurrent]), verbo([binding]), complemento([of, 'FXR', and, 'Sumo1', to, the, 'BSEP', and, 'SHP', promoters])].
[sujeto(['Overexpression', of, 'Sumo1', markedly]), verbo([decreased]), complemento([binding, 'and/or', recruitment, of, 'FXR', to, the, 'BSEP', and, 'SHP', promoters, on, 'ChIP-ReChIP'])].
[sujeto(['SUMOylation', did, not]), verbo([have]), complemento([an, apparent, effect, on, nuclear, localization, of, 'FXR'])].
[sujeto(['Expression', of, 'Sumo1', markedly]), verbo([inhibited]), complemento([the, 'ligand-dependent,', transactivation, of, 'BSEP', and, 'SHP', promoters, by, 'FXR/retinoid', 'X', receptor, α, '(', 'RXRα)', in, 'HepG2', cells])].
[sujeto(['Pathways', for, 'SUMOylation', were, significantly, altered, during, obstructive, cholestasis, with, differential, 'Sumo1', recruitment, to, the, promoters, of, 'FXR']), verbo([target]), complemento([genes])].
[sujeto(['In', 'conclusion,', 'FXR', is, subject, to, 'SUMOylation', that]), verbo([regulates]), complemento([its, capacity, to, transactivate, its, target, genes, in, normal, liver, and, during, obstructive, cholestasis])].
[sujeto(['CYP3A5', levels, as, well, as]), verbo([nuclear]), complemento([translocation, and, promoter, binding, of, transcription, factors, regulating, 'CYP3A5', expression, were, measured, in, primary, hepatocyte, cultures, derived, from, men, and, women, exposed, to, 'physiological-like', levels, of, growth, hormone, 'alone,', dexamethasone, alone, and, the, combined, regimen])].
[sujeto(['We', observed, a, dramatic, inherent, 'CYP3A5', sexual, dimorphism, '(', women, &, 'gt;', 'men)', with, all, treatments, as, a, result, of, a, '~2-fold', greater, level, of, 'hormone-induced', activation, and]), verbo([nuclear]), complemento([accumulation, of, hepatocyte, nuclear, 'factor-4α', '(', 'HNF-4α),', pregnane, 'X', receptor, '(', 'PXR)', and, retinoic, 'X', receptorα, '(', 'RXRα)', in, female, hepatocytes])].
[sujeto(['Furthermore,', 'PXR', :, 'RXRα', exhibited, significantly, higher, 'DNA']), verbo([binding]), complemento([levels, to, its, specific, binding, motif, on, the, 'CYP3A5', promoter, in, female, 'hepatocytes,', inferring, a, possible, explanation, for, the, elevated, expression, of, the, isoform, in, women])].
[sujeto(['Interestingly,', under, physiological, flow, 'conditions,', 'TNF-α-induced', endothelial, adhesion, of, human, mononuclear, cells, was, 'concentration-dependently']), verbo([inhibited]), complemento([by, preincubation, of, the, human, umbilical, arterial, endothelial, cells, with, 'RXR', agonists, such, as, bexarotene, or, 9, -, 'cis-retinoid', acid])].
[sujeto(['RXR', agonists, also]), verbo([prevented]), complemento(['TNF-α-induced', 'VCAM-1', and, 'ICAM-1', 'expression,', as, well, as, endothelial, 'growth-related', 'oncogene-α', and, 'MCP-1', release])].
[sujeto(['Furthermore,', inhibition, of, 'MAPKs', and, 'NF-κB', pathways, were]), verbo([involved]), complemento([in, these, events])].
[sujeto(['RXR', 'agonist-induced', antileukocyte, adhesive, effects, seemed, to, be]), verbo([mediated]), complemento([via, 'RXRα/peroxisome', 'proliferator-activated', receptor, '(', 'PPAR)γ', 'interaction,', since, endothelial, 'PPARγ', silencing, abolished, their, inhibitory, responses])].
[sujeto(['Furthermore,', 'RXR', agonists]), verbo([increased]), complemento(['RXR/PPARγ', 'interaction,', and, combinations, of, suboptimal, concentrations, of, both, nuclear, receptor, ligands, inhibited, 'TNF-α-induced', mononuclear, leukocyte, arrest, by, 60, -, 65, '%'])].
[sujeto(['In', 'vivo,', bexarotene, 'dose-dependently']), verbo([inhibited]), complemento(['TNF-α-induced', leukocyte, adhesion, to, the, murine, cremasteric, arterioles, and, decreased, 'VCAM-1', and, 'ICAM-1', expression])].
[sujeto(['Therefore,', these, results]), verbo([reveal]), complemento([that, 'RXR', agonists, can, inhibit, the, initial, inflammatory, response, that, precedes, the, atherogenic, process, by, targeting, different, steps, of, the, mononuclear, recruitment, cascade])].
[sujeto(['Thus,', 'RXR', agonists, may, constitute, a, new, therapeutic, tool, in, the, control, of, the, inflammatory, process]), verbo([associated]), complemento([with, cardiovascular, disease])].
[sujeto(['Cytotrophoblast', '(', 'CT)', cell, fusion, into, a, syncytiotrophoblast, is, obligatory, for, placentation, and]), verbo([mediated]), complemento([by, the, human, endogenous, retrovirus, '(', 'HERV)-W', envelope, gene, 'Syncytin-1'])].
[sujeto(['Abnormal', placentation, is]), verbo([associated]), complemento([with, preeclampsia, '(', 'PE),', 'HELLP', and, intrauterine, growth, restriction, '(', 'IUGR)'])].
[sujeto(['In', 'placentogenesis,', the, 'MAP-kinase', p38α]), verbo([regulates]), complemento(['PPARγ/RXRα', signaling, and, target, 'genes,', like, 'leptin,', 'resistin,', 'ABCG2,', and, hCG])].
[sujeto(['The', aim, of, this, study, was, to, analyze, 'PPARγ/RXRα', signaling, and]), verbo([target]), complemento([gene, regulation, using, primary, 'CT', 'cultures,', the, trophoblastic, cell, line, 'BeWo', and, placental, tissues, from, patients, with, normal, and, abnormal, placentation])].
[sujeto(['CT', from, four, different, human, control, placentae, and, 'BeWo', cells, demonstrated, that, 'Syncytin-1,', other, signaling, members, and, 'CT', cell, fusions, were]), verbo([regulated]), complemento([with, 'PPARγ/RXRα', activators, troglitazone, and, 9, -, cis, retinoic, 'acid,', via, protein, kinase, 'A', and, p38α, inhibition])].
[sujeto(['Two', 'PPARγ/RXRα-response-elements', from, upstream, regulatory, elements, and, the, 5, '\'', 'LTR', of, 'HERV-W', were, confirmed, with, 'DNA-protein']), verbo([binding]), complemento([assays, using, nuclear, extracts, and, recombinant, 'PPARγ/RXRα', proteins])].
[sujeto(['Our', study, characterized, 'PPARγ/RXRα', signaling, in, human, 'CT', and, cell, fusions, identifying, 'Syncytin-1', as, a, new]), verbo([target]), complemento([gene])].
[sujeto(['Multiple']), verbo([nuclear]), complemento(['receptors,', including, hepatocyte, nuclear, factor, 4, α, '(', 'HNF4α),', retinoid, 'X', receptor, α, '(', 'RXRα)', plus, peroxisome, 'proliferator-activated', receptor, α, '(', 'PPARα),', 'RXRα', plus, farnesoid, 'X', receptor, α, '(', 'FXRα),', liver, receptor, homolog, 1, '(', 'LRH1),', and, 'estrogen-related', receptors, '(', 'ERRs),', have, been, shown, to, support, efficient, viral, biosynthesis, in, nonhepatoma, cells, in, the, absence, of, additional, 'liver-enriched', transcription, factors])].
[sujeto(['Although', 'HNF4α']), verbo([has]), complemento([been, shown, to, be, critical, for, the, developmental, expression, of, hepatitis, 'B', virus, '(', 'HBV)', biosynthesis, in, the, 'liver,', the, relative, importance, of, the, various, nuclear, receptors, capable, of, supporting, viral, transcription, and, replication, in, the, adult, in, vivo, has, not, been, clearly, established])].
[sujeto(['To', investigate, the, role, of, the]), verbo([nuclear]), complemento([receptor, 'FXR', and, the, corepressor, small, heterodimer, partner, '(', 'SHP)', in, viral, biosynthesis, in, 'vivo,', 'SHP-expressing', and, 'SHP-null', 'HBV', transgenic, mice, were, fed, a, bile, 'acid-supplemented', diet])].
[sujeto(['The']), verbo([increased]), complemento(['FXR', activity, and, 'SHP', expression, levels, resulting, from, bile, acid, treatment, did, not, greatly, modulate, 'HBV', 'RNA', and, 'DNA', synthesis])].
[sujeto(['Therefore,', 'FXR', and, 'SHP', appear, to, play, a, limited, role, in]), verbo([modulating]), complemento(['HBV', 'biosynthesis,', suggesting, that, alternative, nuclear, receptors, are, more, critical, determinants, of, viral, transcription, in, the, 'HBV', transgenic, mouse, model, of, chronic, viral, infection])].
[sujeto(['These', observations]), verbo([suggest]), complemento([that, hepatic, bile, acid, levels, or, therapeutic, agents, targeting, 'FXR', may, not, greatly, modulate, viremia, during, natural, infection])].
[sujeto(['The', current, study, tests, a, hypothesis, that]), verbo([nuclear]), complemento([receptor, signaling, is, altered, in, chronic, hepatitis, 'C', patients, and, that, the, altered, pattern, is, specific, to, alcohol, drinking, history])].
[sujeto(['The', expression, of, a, panel, of, more, than, 100, genes, encoding]), verbo([nuclear]), complemento(['receptors,', 'coregulators,', and, their, 'direct/indirect', targets, was, studied, in, human, livers])].
[sujeto(['HCV', infection]), verbo([increased]), complemento([the, expression, of, nuclear, receptors, small, heterodimer, partner, and, constitutive, androstane, receptor, '(', 'CAR)', as, well, as, genes, involved, in, fatty, acid, 'trafficking,', bile, acid, synthesis, and, 'uptake,', and, inflammatory, response])].
[sujeto(['However,', the, expression, of, retinoid, 'X', receptor, '(', 'RXR)', 'α,', peroxisomal, 'proliferator-activated', receptor, '(', 'PPAR)', α, and, β, as, well, as, steroid, regulatory, 'element-binding', protein, '(', 'SREBP)-1c', was]), verbo([decreased]), complemento([in, 'HCV-infected', livers])].
[sujeto(['Alcohol', drinking]), verbo([increased]), complemento([the, expression, of, genes, involved, in, fatty, acid, 'uptake,', 'trafficking,', and, 'oxidation,', but, decreased, the, expression, of, genes, responsible, for, gluconeogenesis])].
[sujeto(['The', messenger, 'RNA', levels, of, fibroblast, growth, factor, 21, ',', 'interleukin-10,', and, fatty, acid, 'synthase,', which, are, all]), verbo([regulated]), complemento([by, nuclear, 'receptors,', showed, independent, correlation, with, hepatic, 'HCV', 'RNA', levels])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, those, genes, and, pathways, that, showed, altered, expression, could, potentially, be, therapeutic, targets, for, 'HCV', infection, 'and/or', alcohol, 'drinking-induced', liver, injury])].
[sujeto(['Activation', of, the, retinoic, acid, receptor, '(', 'RAR)', and, retinoid, 'X', receptor, '(', 'RXR)']), verbo([has]), complemento([an, 'anti-diabetic', 'effect;', 'but,', a, role, in, diabetic, cardiomyopathy, remains, unclear])].
[sujeto(['Decreased']), verbo([nuclear]), complemento([expression, of, 'RARα', and, 'RXRα,', activation, of, apoptotic, signaling, and, cell, apoptosis, was, observed, in, high, glucose, '(', 'HG)', treated, neonatal, and, adult, cardiomyocytes, and, diabetic, hearts, in, 'Zucker', diabetic, fatty, '(', 'ZDF)', rats])].
[sujeto(['HG-induced', apoptosis, and, reactive, oxygen, species, '(', 'ROS)', generation, was]), verbo([prevented]), complemento([by, both, 'RAR', and, 'RXR', agonists])].
[sujeto(['Silencing', expression, of, 'RARα', and, 'RXRα,', by, small, interference, 'RNA,']), verbo([promoted]), complemento([apoptosis, under, normal, conditions, and, significantly, enhanced, 'HG-induced', 'apoptosis,', indicating, that, 'RARα', and, 'RXRα', are, required, in, regulating, cell, apoptotic, signaling])].
[sujeto(['Moreover,', 'HG']), verbo([induced]), complemento([gene, expression, of, 'angiotensinogen,', 'renin,', 'AT(1)', 'R,', and, angiotensin, 'II', '(', 'Ang', 'II)', synthesis, were, inhibited, by, 'RARα', agonists, and, promoted, by, silencing, 'RARα'])].
[sujeto(['Activation', of, 'RXRα,', downregulated, the, expression, of, 'AT(1)', 'R;', and, 'RXRα', silencing, accelerated, 'HG']), verbo([induced]), complemento([expression, of, angiotensinogen, and, 'Ang', 'II', 'synthesis,', whereas, there, was, no, significant, effect, on, renin, gene, expression])].
[sujeto(['These', results, indicate, that, reduction, in, the, expression, of, 'RARα', and, 'RXRα']), verbo([has]), complemento([an, important, role, in, hyperglycemia, mediated, apoptosis, and, expression, of, 'RAS', components])].
[sujeto(['Cholesterol', 7, 'alpha-hydroxylase', '(', 'CYP7A1)', plays, a, key, role, in]), verbo([maintaining]), complemento([lipid, and, bile, salt, homeostasis, as, it, is, the, 'rate-limiting', enzyme, converting, cholesterol, to, bile, acids])].
[sujeto(['Deficiency', of, 'CYP7A1']), verbo([leads]), complemento([to, hyperlipidemia, in, man, and, mouse])].
[sujeto(['Our', present, study, revealed, that, 'CYP7A1', mRNA, expression, is, greatly]), verbo([repressed]), complemento([by, 'RA', in, both, human, hepatocytes, and, 'HepG2', cells, where, increased, fibroblast, growth, factor, 19, '(', 'FGF19)', and, small, heterodimer, partner, '(', 'SHP)', expressions, were, also, 'observed,', suggesting, farnesoid, 'X', receptor, '(', 'FXR)', and, retinoid, 'X', receptor, '(', 'RXR)', were, activated])].
[sujeto(['Promoter', reporter, assays, demonstrate, that, 'all-trans', 'RA', '(', 'atRA)', specifically]), verbo([activated]), complemento(['FXR/RXR'])].
[sujeto(['Knocking', down, of, 'FXR', or, 'RXRalpha', by, small, interference, 'RNA', '(', 'siRNA)', in, human, hepatocytes]), verbo([increased]), complemento(['CYP7A1', basal, 'expression,', but, the, repressive, effect, of, atRA, 'persisted,', suggesting, there, are, also, 'FXR/RXR-independent', mechanisms, mediating, atRA, repression, of, 'CYP7A1', expression])].
[sujeto(['Our', findings, may]), verbo([provide]), complemento([a, potential, explanation, for, hyperlipidemic, side, effects, observed, in, some, patients, treated, with, 'high-dose', 'RA'])].
[sujeto(['The', development, of, alcoholic, fatty, liver, is]), verbo([associated]), complemento([with, reduced, 'adipocyte-derived', adiponectin, 'levels,', decreased, hepatic, adiponectin, 'receptors,', and, deranged, hepatic, adiponectin, signaling, in, animals])].
[sujeto(['Coadministration', of, rosiglitazone, and, ethanol]), verbo([increased]), complemento([the, expression, and, circulating, levels, of, adiponectin, and, enhanced, the, expression, of, hepatic, adiponectin, receptors, '(', 'AdipoRs)', in, mice])].
[sujeto(['These']), verbo([increases]), complemento([correlated, closely, with, the, activation, of, a, hepatic, sirtuin, 1, '(', 'SIRT1)-AMP-activated', kinase, '(', 'AMPK)', signaling, system])].
[sujeto(['In', concordance, with]), verbo([stimulated]), complemento(['SIRT1-AMPK', 'signaling,', rosiglitazone, administration, enhanced, expression, of, fatty, acid, oxidation, 'enzymes,', normalized, lipin, 1, 'expression,', and, blocked, elevated, expression, of, genes, encoding, lipogenic, enzymes, 'which,', in, 'turn,', led, to, increased, fatty, acid, 'oxidation,', reduced, 'lipogenesis,', and, alleviation, of, steatosis, in, the, livers, of, 'ethanol-fed', mice])].
[sujeto(['The']), verbo([nuclear]), complemento([bile, acid, receptor, 'FXR', is, critical, for, regulation, of, lipid, and, glucose, metabolism])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, 'FXR', is, a, target, of, 'SIRT1,', a, deacetylase, that, mediates, nutritional, and, hormonal, modulation, of, hepatic, metabolism])].
[sujeto(['Lysine', 217, of, 'FXR', is, the, major, acetylation, site]), verbo([targeted]), complemento([by, p300, and, 'SIRT1'])].
[sujeto(['Acetylation', of, 'FXR']), verbo([increases]), complemento([its, stability, but, inhibits, heterodimerization, with, 'RXRalpha,', 'DNA', 'binding,', and, transactivation, activity])].
[sujeto(['Downregulation', of, hepatic, 'SIRT1']), verbo([increased]), complemento(['FXR', acetylation, with, deleterious, metabolic, outcomes])].
[sujeto(['Our', data, demonstrate, that, 'FXR', acetylation, is, normally, dynamically]), verbo([regulated]), complemento([by, p300, and, 'SIRT1', but, is, constitutively, elevated, in, metabolic, disease, states])].
[sujeto(['Small', molecules, that]), verbo([inhibit]), complemento(['FXR', acetylation, by, targeting, 'SIRT1', or, p300, may, be, promising, therapeutic, agents, for, metabolic, disorders])].
[sujeto(['Hepatitis', 'B', virus, '(', 'HBV)', biosynthesis]), verbo([involves]), complemento([the, transcription, of, the, 3.5, -, kb, viral, pregenomic, 'RNA,', followed, by, its, reverse, transcription, into, viral, 'DNA'])].
[sujeto(['The', coactivator, peroxisome, 'proliferator-activated', receptor, gamma, coactivator, 1, alpha, '(', 'PGC1alpha)', and, corepressor, small, heterodimer, partner, '(', 'SHP)']), verbo([have]), complemento([central, roles, in, regulating, energy, homeostasis, in, the, liver, by, modulating, the, transcriptional, activities, of, nuclear, receptors])].
[sujeto(['Therefore,', the, effect, of, 'PGC1alpha', and, 'SHP', on, 'HBV', transcription, and, replication]), verbo([mediated]), complemento([by, nuclear, receptors, was, examined, in, the, context, of, individual, nuclear, receptors, in, nonhepatoma, cells, and, in, hepatoma, cells])].
[sujeto(['This', analysis, indicated, that, viral, replication]), verbo([mediated]), complemento([by, hepatocyte, nuclear, factor, 4, 'alpha,', retinoid, 'X', receptor, alpha, '(', 'RXRalpha)', plus, peroxisome, 'proliferator-activated', receptor, alpha, '(', 'PPARalpha),', and, 'estrogen-related', receptor, '(', 'ERR)', displayed, differential, sensitivity, to, 'PGC1alpha', activation, and, 'SHP', inhibition])].
[sujeto(['The', effects, of, 'PGC1alpha', and, 'SHP', on, viral, biosynthesis, in, the, human, hepatoma, cell, line, 'Huh7', were, similar, to, those, observed, in, the, nonhepatoma, cells]), verbo([expressing]), complemento(['ERRalpha', and, 'ERRgamma'])].
[sujeto(['This']), verbo([suggests]), complemento([that, these, nuclear, 'receptors,', potentially, in, combination, with, 'RXRalpha', plus, 'PPARalpha,', may, have, a, major, role, in, governing, 'HBV', transcription, and, replication, in, this, cell, line])].
[sujeto(['The', human, hepatoma, cell, lines, 'HepG2', and, 'Huh7']), verbo([have]), complemento([been, used, extensively, to, study, hepatitis, 'B', virus, '(', 'HBV)', transcription, and, replication])].
[sujeto(['The', effects, of, the, coactivator, peroxisome, 'proliferator-activated', receptor, gamma, coactivator, 1, alpha, '(', 'PGC1alpha)', and, corepressor, small, heterodimer, partner, '(', 'SHP)', on, 'HBV', transcription, and, replication]), verbo([mediated]), complemento([by, nuclear, receptors, were, examined, in, the, context, of, individual, nuclear, receptors, in, nonhepatoma, cells, and, in, hepatoma, cells, in, an, attempt, to, determine, the, relative, contribution, of, the, various, nuclear, receptors, to, viral, biosynthesis, in, the, hepatoma, cells])].
[sujeto(['PGC1alpha', and, 'SHP']), verbo([modulated]), complemento([viral, biosynthesis, differently, in, the, human, hepatoma, cell, lines, 'HepG2', and, 'Huh7,', indicating, distinct, modes, of, transcriptional, regulation])].
[sujeto(['The']), verbo([nuclear]), complemento([peroxisome, 'proliferator-activated', receptors, '(', 'PPAR)', have, been, shown, to, play, crucial, roles, in, regulating, energy, homeostasis, including, lipid, and, carbohydrate, 'metabolism,', inflammatory, 'responses,', and, cell, 'proliferation,', 'differentiation,', and, survival])].
[sujeto(['Because', 'PPAR', agonists]), verbo([have]), complemento([the, potential, to, prevent, or, ameliorate, diseases, such, as, 'hyperlipidemia,', 'diabetes,', 'atherosclerosis,', and, 'obesity,', we, have, explored, new, natural, agonists, for, 'PPAR'])].
[sujeto(['Milk']), verbo([increased]), complemento([human, 'PPARalpha', activity, in, a, 'dose-dependent', manner, with, a, 3.2, -, fold, increase, at, 0.5, '%', '(', 'vol/vol)'])].
[sujeto(['It', also]), verbo([enhanced]), complemento([human, 'PPARdelta', activity, in, a, 'dose-dependent', manner, with, an, 11.5, -, fold, increase, at, 0.5, '%'])].
[sujeto(['Ice', 'cream,', 'butter,', and, yogurt, also]), verbo([increased]), complemento([the, activities, of, 'PPARalpha', and, 'PPARdelta,', whereas, vegetable, cream, affected, activity, of, 'PPARdelta', but, not, 'PPARalpha'])].
[sujeto(['Skim', milk]), verbo([enhanced]), complemento([the, activity, of, 'PPAR', to, a, lesser, degree, than, regular, milk])].
[sujeto(['Milk', and, fresh, cream]), verbo([increased]), complemento([the, activity, of, human, retinoid, 'X', receptor, '(', 'RXR)alpha', as, well, as, 'PPARalpha', and, 'PPARdelta,', whereas, neither, affected, vitamin, 'D3', 'receptor,', estrogen, receptors, alpha, and, 'beta,', or, thyroid, receptors, alpha, and, beta])].
[sujeto(['Both', milk, and, fresh, cream, were, shown, by, quantitative, 'real-time', 'PCR', to]), verbo([increase]), complemento([the, quantity, of, mRNA, for, uncoupling, protein, 2, '(', 'UCP2),', an, energy, expenditure, 'gene,', in, a, 'dose-dependent', manner])].
[sujeto(['The']), verbo([increase]), complemento([in, 'UCP2', mRNA, was, found, to, be, reduced, by, treatment, with, 'PPARdelta-short', interfering, '(', 'si)RNA'])].
[sujeto(['This', study, unambiguously, clarified, at, the, cellular, level, that, 'cow\'s', milk]), verbo([increased]), complemento([the, activities, of, human, 'PPARalpha,', 'PPARdelta,', and, 'RXRalpha'])].
[sujeto(['The', possible, role, in]), verbo([enhancing]), complemento([the, activities, of, 'PPARalpha,', 'PPARdelta,', and, 'RXRalpha,', and, the, health, benefits, of, 'cow\'s', milk, were, discussed])].
[sujeto(['Long-term', use, of, 'non-steroidal', 'anti-inflammatory', drugs, '(', 'NSAIDs)']), verbo([has]), complemento([been, found, beneficial, for, 'AD', and, several, reports, suggest, that, 'NSAIDs', reduce, the, generation, of, 'Abeta,', especially, the, more, amyloidogenic, form, 'Abeta42'])].
[sujeto(['Recent', studies]), verbo([have]), complemento([shown, that, some, 'NSAIDs', can, bind, to, certain, nuclear, 'receptors,', suggesting, that, nuclear, receptors, may, be, involved, in, 'NSAID\'s', effect, on, 'AD', risk])].
[sujeto(['Here', we]), verbo([find]), complemento([that, '(', 'R)-flurbiprofen,', the, 'R-enantiomer', of, the, racemate, 'NSAID', 'flurbiprofen,', can, significantly, reduce, 'Abeta', 'secretion,', but, at, the, same, 'time,', increases, the, level, of, intracellular, 'Abeta'])].
[sujeto(['In', 'addition,', we]), verbo([find]), complemento([that, a, nuclear, 'receptor,', retinoid, 'X', receptor, alpha, '(', 'RXRalpha),', can, regulate, 'Abeta', generation, and, that, 'down-regulation', of, 'RXRalpha', significantly, increases, 'Abeta', secretion])].
[sujeto(['We', also, show, that, '(', 'R)-flurbiprofen', can, interfere, with, the, interaction, between, 'RXRalpha', and, 9, -, 'cis-retinoid', 'acid,', and, that, 9, -, 'cis-retinoid', acid]), verbo([decreases]), complemento(['(', 'R)-flurbiprofen\'s', reduction, of, 'Abeta', secretion])].
[sujeto(['Together,', these, results]), verbo([suggest]), complemento([that, 'RXRalpha', can, regulate, 'Abeta', generation, and, is, also, required, for, '(', 'R)-flurbiprofen-mediated', 'Abeta', generation])].
[sujeto(['There', are, some, evidences, indicating, 'DNA', damage, by, oxidant, and, mutant, agents]), verbo([has]), complemento([an, essential, role, in, the, chronic, renal, failure, and, end, stage, renal, disease, '(', 'ESRD)'])].
[sujeto(['We']), verbo([found]), complemento([that, 'GSTM1', and, 'GSTT1', null, genotypes, '(', 'GSTT1-/GSTM1-)', increased, the, risk, of, 'ESRD', by, 1.8, times, '(', p, &, 'lt;', 0.001, ')', and, the, increased, risk, of, 'ESRD', for, 'GSTM-null', '(', 'T1+-M1-)', genotype, was, 3.04, times, '(', p, =, 0.002, ')'])].
[sujeto(['ESRD', patients, carriers, the, 'GST', '(', 'GSTM1-null', +, 'GSTT1-null', +, 'GST-null)', genotypes, compared, to, 'GST', normal, genotype]), verbo([increased]), complemento([the, risk, of, 'ESRD', by, 3.3, '(', p, &, 'lt;', 0.001, ')', times])].
[sujeto(['Our', results, indicated, that, the, 'GST-null', allele, '(', 'GSTT1-null/GSTM1-null)', is, a, risk, factor, for, 'ESRD', and, carriers, of, this, allele]), verbo([have]), complemento([high, levels, of, 'MDA'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, patients, with, 'ESRD', are, more, susceptible, to, vascular, diseases])].
[sujeto(['Bladder', cancer, is, highly, recurrent, after, 'therapy,', which]), verbo([has]), complemento([an, enormous, impact, on, the, health, and, financial, condition, of, the, patient])].
[sujeto(['In', our, previous, 'study,', we]), verbo([found]), complemento([that, the, bladder, carcinogen, 'BBN', increased, urothelial, global, 'DNA', 'CpG', methylation, and, decreased, 'GSTM1', protein, expression, in, mice])].
[sujeto(['BBN', treatment]), verbo([decreased]), complemento([the, protein, and, mRNA, expression, of, 'GSTM1,', and, the, 'CpG', methylation, ratio, of, 'GSTM1', gene, promoter, was, slightly, increased, in, mice, bladders])].
[sujeto(['The', 'CpG', methylation, level, of, 'GSTM1', was, 9.9, '%', and, 5, -, 'aza-dC', did, not, significantly]), verbo([increase]), complemento(['GSTM1', protein, and, mRNA, expression, in, 'T24', 'cells;', 'however,', the, 'GSTM5', gene, was, 'CpG', hypermethylated, '(', 65.4, '%', ')', and, 5, -, 'aza-dC', also, did, not, affect, the, methylation, ratio, and, mRNA, expression])].
[sujeto(['However,', in, other, cell, lines, without, 'GSTM1,', 5, -, 'aza-dC']), verbo([increased]), complemento(['GSTM5', expression, and, decreased, its, 'CpG', 'DNA', methylation, ratio, from, 84.6, '%', to, 61.5, '%', in, 5637, ',', and, from, 97.4, '%', to, 75, '%', in, 'J82', cells])].
[sujeto(['For', 'GSTP1', 313, 'A', '→', 'G', '(', 'GSTP1', 'Ile105Val)', 'polymorphism,', 'It', was]), verbo([found]), complemento([that, the, wild, genotype, '(', 'AA)', was, significantly, higher, among, control, subjects, '(', 'P', value, =, 0.0277, ')', ',', while, the, frequency, of, heteromutant, genotype, '(', 'AG)', and, mutant, 'G', allele, '(', 'AG', +, 'GG)', was, significantly, higher, among, patients, '(', 'P', value, =, 0.0402, ',', 'P', value, =, 0.0277, ',', 'respectively)'])].
[sujeto(['For', 'GSTM1', and, 'GSTT1gene,', we]), verbo([found]), complemento([statistically, significantly, higher, frequency, among, patients, regarding, homozygous, gene, deletion, '(', 'P', value, =, 0.0005, ')'])].
[sujeto(['This', figure, is, an, estimated]), verbo([increase]), complemento([of, 78, '%', from, the, figure, in, 2002])].
[sujeto(['The', 'CDC']), verbo([suggests]), complemento([that, more, investigation, is, needed, to, understand, this, astounding, increase, in, autism, in, such, a, short, period])].
[sujeto(['Children', did, not, demonstrate, elevated, urine, pyruvate, or, lactate, but, did]), verbo([have]), complemento([abnormal, detoxification, markers])].
[sujeto(['The', expression, of, these, enzymes, in, human, brain, tumor, tissue]), verbo([has]), complemento([not, been, investigated, sufficiently])].
[sujeto(['A', negative, correlation, between, the, 'WHO', degree, of, malignancy, and, the, strength, of, expression, was, identified, on, both, transcriptional, and, translational, level, for, 'AOX1,', 'GSTM3', and, 'GSTP1,', although, the, results, could]), verbo([have]), complemento([been, biased, by, the, prevalence, of, meningiomas, and, glioblastomas, in, the, inevitably, bipolar, distribution, of, the, 'WHO', grades])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, the, most, important, factor, governing, the, expression, of, these, enzymes, is, the, histological, subtype, and, to, a, far, lesser, extent, the, degree, of, malignancy, itself])].
[sujeto(['A', diagnosis, of, 'RTIs', was, based, on, parental]), verbo([report]), complemento([of, a, 'physician\'s', diagnosis])].
[sujeto(['TaqMan', was, used, for, genotyping, of]), verbo([nuclear]), complemento([factor, erythroid, 2, -, related, factor, '(', 'Nrf2)', '(', 'rs6726395),', 'glutathione-S-transferase-pi', '(', 'GSTP)', 1, '(', 'rs1695),', and, 'glutathione-S-transferase-mu', '(', 'GSTM)', 1])].
[sujeto(['₅']), verbo([increased]), complemento([the, susceptibility, of, lower, 'RTIs', '(', 'LRTIs)', in, infancy, '(', adjusted, odds, ratio, '[', 'aOR]=2'])].
[sujeto(['₅', and, 'ETS,', prenatal, exposure, to, both, pollutants]), verbo([increased]), complemento([susceptibility, to, 'LRTIs', '(', 'aOR=6'])].
[sujeto([56, ')', ;, 'however,', this, association, was, not]), verbo([found]), complemento([for, postnatal, exposure])].
[sujeto([37, ')', genotypes]), verbo([increased]), complemento([the, combined, 'LRTIs-promoting', effects, of, prenatal, exposure, to, the, 2, indoor, pollutants])].
[sujeto(['₅', and, 'ETS', exposure, were, not]), verbo([found]), complemento([for, upper, 'RTIs'])].
[sujeto(['₅', and, 'ETS', may]), verbo([increase]), complemento([susceptibility, to, 'LRTIs'])].
[sujeto(['The', association, between, polymorphisms, of, 'glutathione-related', enzyme, '(', 'GST)', genes, and, the, risk, of, schizophrenia]), verbo([has]), complemento([been, investigated, in, many, published, studies])].
[sujeto(['However,', more, 'meta-analysis', with, a, larger, sample, size, were, needed, to]), verbo([provide]), complemento([more, precise, evidence])].
[sujeto(['Glutathione', 'S-transferases', '(', 'GSTs)', are, enzymes, which]), verbo([expressed]), complemento([in, many, tissues, and, play, important, roles, in, neutralization, of, toxic, 'compounds,', and, protecting, hosts, against, cancer])].
[sujeto(['Among', several, 'GSTs,', 'Glutathione', 'S-transferases', mu, '(', 'GSTM)']), verbo([has]), complemento([been, drawn, attention, upon, the, association, with, the, genetic, risk, for, many, types, of, cancers])].
[sujeto(['But', whether, the, 'GSTM1', polymorphisms]), verbo([confer]), complemento([the, susceptibility, to, colorectal, cancer, in, 'Asians', has, not, been, well, established])].
[sujeto(['The', pooled, 'meta-analysis']), verbo([suggested]), complemento([that, 'GSTM1', null, variant, was, correlated, to, the, colorectal, cancer, risk, in, 'Asians'])].
[sujeto(['In', 'summary,', the, 'meta-analysis']), verbo([suggested]), complemento([that, 'GSTM1', null, polymorphism, confer, the, susceptibility, to, colorectal, cancer, in, 'Asians,', especially, in, 'Chinese', populations])].
[sujeto(['Genetic', variations, in, metabolic, enzyme, genes, may]), verbo([enhance]), complemento([hematotoxicity, in, 'benzene-exposed', populations])].
[sujeto(['Three', hundred, and, 'eighty-five', 'benzene-exposed', workers, and, 220, unexposed, indoor, workers, were]), verbo([recruited]), complemento([in, 'China'])].
[sujeto(['Increased', susceptibility, to, 'hematotoxicity,', as, evidenced, by, lower, 'WBC', 'counts,', was]), verbo([found]), complemento([in, workers, with, 'null-GSTT1', '(', 'P', =, 0, '·045),', 'null-GSTM1', '(', 'P', =, 0, '·030),', rs2031920, '(', 'P', =, 0, '·020),', and, rs3813867, '(', 'P', =, 0, '·014)', genotypes])].
[sujeto(['However,', the, contribution, of, aldehydes, to, myocardial, 'I/R', injury]), verbo([has]), complemento([not, been, assessed])].
[sujeto(['mGstp1/2', deletion, reduced, total, 'GST', 'activity,', but, no, compensatory]), verbo([increase]), complemento([in, 'GSTA', and, 'GSTM', or, major, antioxidant, enzymes, was, observed])].
[sujeto(['Disruption', of, the, 'GSTP', gene, also]), verbo([increased]), complemento([infarct, size, after, coronary, occlusion, in, situ])].
[sujeto(['Ischemia', significantly]), verbo([increased]), complemento([acrolein, in, 'hearts,', and, 'GSTP', deficiency, induced, significant, deficits, in, the, metabolism, of, the, unsaturated, 'aldehyde,', 'acrolein,', but, not, in, the, metabolism, of, 4, -, 'hydroxy-trans-2-nonenal', or, 'trans-2-hexanal;', on, 'ischemia,', the, 'GSTP-null', hearts, accumulated, more, 'acrolein-modified', proteins, than, 'wild-type', hearts])].
[sujeto(['Acrolein', exposure]), verbo([induced]), complemento([a, hyperpolarizing, shift, in, 'INa,', and, 'acrolein-induced', cell, death, was, delayed, by, 'SN-6,', a, 'Na(+)/Ca(++)', exchange, inhibitor])].
[sujeto(['Gene', expressions]), verbo([associated]), complemento([with, embryonic, development, and, 'GSH', metabolism, were, measured, using, quantitative, 'real-time', polymerase, chain, reaction])].
[sujeto(['At', the, concentrations, of, 1, ',', 3, ',', and, 5, 'mM,', 'GSH', significantly]), verbo([increased]), complemento([the, blastocyst, rate, and, embryo, quality])].
[sujeto(['Intracellular', content, of, 'GSH', of, embryos, at, the, 'two-', to, 'four-cell', stage, significantly, 'increased,', and, the, reactive, oxygen, species, level]), verbo([decreased]), complemento([accordingly, with, 3, -, mM, 'GSH', 'treatment,', but, no, significant, differences, were, found, in, the, 'four-', to, 'eight-cell', stage, and, blastocysts])].
[sujeto(['In', 'conclusion,', exogenous, 'GSH', during, 'IVC', improved, developmental, potential, and, quality, of, bovine, 'IVF', 'embryos,', which, was, probably]), verbo([caused]), complemento([by, the, ability, of, 'GSH', to, maintain, the, redox, balance])].
[sujeto(['Age-related', cataract, '(', 'ARC)', is, the]), verbo([leading]), complemento([cause, of, visual, disability, and, reversible, blindness, all, over, the, world])].
[sujeto(['The', different, expressions, of, 'GST', isozymes, among, animals, may, explain, the, variations, in, the, cataract, formation]), verbo([caused]), complemento([by, oxidative, stress])].
[sujeto(['The', 'GSTM', 1, null, genotype, was]), verbo([found]), complemento([to, carry, an, increased, risk, for, developing, 'ARC', '(', 'OR:', 1.84, ',', 95, '%', 'CI:', 1.13, -, 2.99, ')'])].
[sujeto(['Also,', carrying, the, combined, genotypes, of, 'GSTM', 1, 'null,', 'GSTT', 1, and, 'GSTP', 1, 105, -, 'Val', allele, was, seen, to]), verbo([have]), complemento([an, increased, risk, of, developing, 'ARC', '(', 'OR:', 2.91, ',', 95, '%', 'CI:', 1.31, -, 6.44, ')'])].
[sujeto(['This', data, may]), verbo([provide]), complemento([evidence, that, 'GSTM', 1, gene, polymorphisms, may, be, associated, with, genetic, susceptibility, to, develop, 'ARC'])].
[sujeto(['The', study, shows, that, patients, with, either, 'GSTM1', or, 'GSTT1', null, genotypes]), verbo([have]), complemento([significantly, higher, risk, of, oral, cancer, '(', adjusted, odds, '(', 'OR):', '(', 3.019, '(', 1.861, -, 4.898, ')', and, 3.011, '(', 1.865, -, 4.862, ')', ',', 'respectively),', which, further, increased, when, either, one, or, both, null, genes, were, present, in, combination, '(', adjusted, odds, '(', 'OR):', '(', 3.627, '(', 1.981, -, 6.642, and, 9.261, '(', 4.495, -, 19.079, ')', ',', 'respectively)'])].
[sujeto(['CYP1A1', rs4646903, gene, variants, individually, showed, weak, association, 'OR:', 1.121, '(', 0.717, -, 1.752, ')', ;, 'however,', in, the, presence, of, 'GSTM1', 'and/or', 'GSTT1', null, genotypes, further]), verbo([increasing]), complemento([the, association, '(', adjusted, odds, '(', 'ORs):', 4.576, '(', 2.038, -, 10.273, ')', ',', 5.593, '(', 2.53, -, 12.362, ')', and, 16.1, '(', 3.854, -, 67.26, for, 'GSTM/GSTT', null, and, 'CYP1A1', wild, 'type,', 'GSTM/GSTT', either, null, and, 'CYP1A1', variant, 'alleles,', and, all, 3, gene, polymorphisms, 'combinations,', 'respectively)'])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, presence, of, 'GSTM1', 'and/or', 'GSTT1', null, genotypes, along, with, variant, alleles, of, 'CYP1A1', may, be, the, risk, alleles, for, oral, cancer, susceptibility, in, 'Pashtun', population])].
[sujeto(['Genetic', variations, due, to, polymorphisms, in, host, genes, encoding, antioxidant, enzymes, such, as, glutathione, 'S-transferases-theta,', 'mu,', pi, '(', 'GSTT,', 'GSTM,', 'GSTP),', superoxide, dismutases, '(', 'SOD)', and, catalase, '(', 'CAT),', may, 'therefore,', influence, 'inter-individual', response, to, malaria, pathology, and, propensity, of, infection]), verbo([caused]), complemento([by, 'Plasmodium', vivax, '(', 'Pv)', and, 'Plasmodium', falciparum, '(', 'Pf)'])].
[sujeto(['Our', data]), verbo([suggest]), complemento([a, significant, role, for, 'GSTM1', deletions, in, complicated, 'Pv', '(', 'p&nbsp;=&nbsp;0'])].
[sujeto(['The', results, also, indicated, that, polymorphisms, present, in, 'GSTP1,', 'SOD1', and, 'CAT', genes, may, be]), verbo([associated]), complemento([with, malaria, susceptibility, '(', 'p&nbsp;&lt;&nbsp;0'])].
[sujeto(['In', 'conclusion,', our, results]), verbo([provide]), complemento([convincing, evidence, for, a, relationship, between, polymorphisms, in, host, antioxidant, enzymes, and, susceptibility, to, malaria, infection])].
[sujeto(['This', 'case-control', study, compared, equal, groups, '(', 'n=102', 'each)', of, patients, with, 'PHC', and, healthy, individuals]), verbo([recruited]), complemento([from, 'Qinghai,', 'Tibet'])].
[sujeto(['The', risk, of, 'PHC']), verbo([increased]), complemento([2.275, times, '(', 95, '%', 'CI,', 1.04, -, 4.98, ')'])].
[sujeto([17, ')', ',']), verbo([suggesting]), complemento([this, as, an, exposure, factor])].
[sujeto(['With', both, the, 'XPD751C', mutation, and, the, 'GSTM1', genotype, as, exposure, 'factors,', the, risk, incidence]), verbo([increased]), complemento([to, 3.03, times, '(', 95, '%', 'CI,', 1.165, -, 7.881, ')', ',', indicating, that, the, combined, genotypes, have, a, synergistic, effect])].
[sujeto(['Qinghai', 'Tibetans', who, carry, the, 'XPD751C', gene, mutation, and, the, 'GSTM', 1, genotype, are, at]), verbo([increased]), complemento([risk, of, 'PHC,', compared, to, individuals, carrying, only, one, or, the, other])].
[sujeto(['The', 'XPD751C', mutation, may]), verbo([increase]), complemento([risk, of, 'PHC', when, combined, with, the, environmental, factors])].
[sujeto(['Glutathione-S-transferases', '(', 'GSTs)', are, one, of, the, key, enzymes, that]), verbo([mediate]), complemento([phase, 'II', of, cellular, detoxification])].
[sujeto(['Further', insights, into, the, orthology, relationships, between, human, and, zebrafish, 'GSTs/Gsts', were, obtained, by, the]), verbo([conserved]), complemento([synteny, analysis])].
[sujeto(['We']), verbo([suggest]), complemento([that, 'Gstp1,', 'Gstp2,', 'Gstt1a,', 'Gstz1,', 'Gstr1,', 'Mgst3a', and, 'Mgst3b', have, important, role, in, the, biotransformation, of, 'xenobiotics,', while, 'Gst', 'Alpha,', 'Mu,', 'Pi,', 'Zeta', and, 'Rho', classes, are, involved, in, the, crucial, physiological, processes])].
[sujeto(['In', 'summary,', this, study]), verbo([provides]), complemento([the, first, comprehensive, analysis, of, 'GST', superfamily, in, 'zebrafish,', presents, new, insight, into, distinct, functions, of, individual, 'Gsts,', and, offers, methodological, protocols, that, can, be, used, for, further, verification, of, interaction, of, environmental, contaminants, with, fish, 'Gsts'])].
[sujeto(['We', aimed, to, determine, which, sperm, head, proteins]), verbo([interact]), complemento([with, 'ZP2,', 'ZP3', and, 'ZP4', in, humans])].
[sujeto(['Two', approaches, were, combined, to, identify, these, 'proteins:', immunoblotting, human, spermatozoa]), verbo([targeted]), complemento([by, antisperm, antibodies, '(', 'ASAs)', from, infertile, men, and, 'far-Western', blotting, of, human, sperm, proteins, overlaid, by, each, of, the, human, recombinant, 'ZP', '(', 'hrZP)', proteins])].
[sujeto(['We', used, a, proteomic, approach, with, 2, 'D', electrophoretic, separation, of, sperm, protein, revealed, using, either, 'ASAs', eluted, from, infertile, patients, or, recombinant, human, 'ZP', glycoproteins]), verbo([expressed]), complemento([in, 'Chinese-hamster', ovary, '(', 'CHO)', cells])].
[sujeto(['These', results, confirm, the, complexity, of, the, 'sperm-ZP', recognition, process, in, humans, with, the, implication, of, different, proteins]), verbo([interacting]), complemento([with, the, main, three, 'ZP', glycoproteins])].
[sujeto(['The', multiple, roles, of, these, proteins]), verbo([suggest]), complemento([that, they, are, multifaceted, or, moonlighting, proteins])].
[sujeto([3, -, 'M-4\'-MTS', '(', 'S2),', 3, ',', 5, -, 'DM-4\'-MTS', '(', 'S5)', and, 3, ',', 4, ',', 5, -, 'TM-4\'-MTS', '(', 'S7)', could]), verbo([activate]), complemento(['Nrf2', signaling, in, the, mouse, epidermis, and, in, human, keratinocytes])].
[sujeto(['All', of, the, tested, stilbenes]), verbo([increased]), complemento(['GST', 'activity,', but, resveratrol, was, the, most, effective, inducer])].
[sujeto(['Moreover,', only, resveratrol]), verbo([increased]), complemento([the, protein, level, of, 'GSTP', in, the, mouse, epidermis])].
[sujeto(['GSTM', was]), verbo([enhanced]), complemento([in, 'HaCaT', cells, after, the, treatment, with, derivatives, 'S2', and, 'S5'])].
[sujeto(['Thus,', it, is, possible, that]), verbo([increased]), complemento([expression, of, 'GSTP', or, 'GSTM', and, 'GST', activity, was, linked, with, 'NQO2', inhibition, in, these, cells])].
[sujeto(['The', results, of, this, study, indicate, that, resveratrol, and, its, methylthioderivatives]), verbo([activate]), complemento(['Nrf2', not, only, in, the, mouse, 'epidermis,', but, also, in, human, keratinocytes])].
[sujeto(['Moreover,', the, most, highly]), verbo([expressed]), complemento([of, the, 'ABC', genes, were, 'ABCB1', and, 'ABCC2', in, all, eight, of, the, tissues, tested])].
[sujeto(['The', 'ABCB11', gene, was, almost, exclusively]), verbo([expressed]), complemento([in, the, liver, of, the, rare, 'minnow,', whereas, 'ABCC1', and, 'ABCG2', showed, weak, expression, in, all, eight, tissues, compared, to, 'ABCB1', and, 'ABCC2'])].
[sujeto(['Our', results]), verbo([provide]), complemento([the, first, thorough, examination, of, the, expression, patterns, of, toxicologically, relevant, 'ABC', transporters, in, the, rare, minnow, and, serve, as, a, necessary, basis, for, further, studies, of, these, 'ABC', transporters, in, fish])].
[sujeto(['The', synergistic, 'up-regulation', of, the, 'xenobiotic-metabolizing', enzymes, and, 'ABC', transporters, by, pyrene]), verbo([suggests]), complemento([a, possible, involvement, and, cooperation, of, these, genes, in, the, detoxification, process, in, rare, minnows])].
[sujeto(['We', aim, to, investigate, the, influence, of, variants, and]), verbo([associated]), complemento([methylation, in, the, 'GSTM', gene, cluster, with, changes, in, lung, function, growth, during, adolescence])].
[sujeto(['Diplotypes', within, 'GSTM2-5', genes, are]), verbo([associated]), complemento([with, lung, function, growth, across, 'adolescence,', but, do, not, appear, to, modify, the, effect, of, tobacco, smoke, exposures, on, adolescent, lung, growth])].
[sujeto(['Interactions', between, 'DNA', methylation, and, diplotypes, should, be, taken, into, account, to]), verbo([gain]), complemento([further, understanding, on, lung, function, in, adolescence])].
[sujeto(['The', combined, 'P', values, were, robust, '(', 10, '(', -, 6, ')', ')', and, the, false, positive]), verbo([report]), complemento([probability, '(', 'FPRP)', values, were, low])].
[sujeto(['Based', on, epidemiological, 'observations,', we, further, identified, two, genetic, variants, in, the, 'GSTM3', locus, accounting, for, differential, expression, of, 'GSTM3', in, normal, breast, tissues, by, such, means, as, altering]), verbo([binding]), complemento([of, 'RNA-pol-II'])].
[sujeto(['Although', 'Gstm1', is, a, member, of, a, family, of, highly, homologous, 'genes,', with, the, exception, of, 'Gstm2,', there, was, no, evidence, for, compensatory]), verbo([increase]), complemento([in, expression, of, other, 'Gstm', isoforms])].
[sujeto(['Untreated', 'SHRSPs', demonstrated]), verbo([increased]), complemento([renal, and, vascular, oxidative, 'stress,', both, of, which, were, not, significantly, affected, by, the, antihypertensive, treatments])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, reduced, 'Gstm1', expression, in, 'SHRSPs', is, due, to, 'strain-dependent', genetic, 'abnormalities,', playing, a, causative, role, in, the, development, of, 'hypertension,', probably, through, oxidative, stress, pathway])].
[sujeto(['Renal', changes, occur, as, a, consequence, of]), verbo([increased]), complemento([blood, pressure, and, can, be, improved, when, treated, with, antihypertensive, drugs])].
[sujeto(['Because', it]), verbo([has]), complemento([been, suggested, that, the, effectiveness, of, antisense, 'ODNs', is, dependent, on, the, secondary, mRNA, structures, of, their, target, 'sites,', we, made, mRNA, secondary, structure, predictions, with, two, software, 'packages,', 'Mfold', and, 'STAR'])].
[sujeto(['Four', phosphodiester, 'ODNs', specific, for, 'GSTM1,', two, 'ODNs', specific, for, 'GSTM2,', and, four, 'ODNs']), verbo([targeted]), complemento([at, both, 'GSTM', isoforms, were, found, to, be, 'potent,', 'sequence-specific,', and, 'RNase', 'H-dependent', inhibitors, of, protein, expression])].
[sujeto(['Antisense', 'ODNs']), verbo([targeted]), complemento([against, regions, that, were, predicted, by, 'STAR', to, be, predominantly, single, stranded, were, more, potent, than, antisense, 'ODNs', against, 'double-stranded', regions])].
[sujeto(['Such', a, correlation, was, not]), verbo([found]), complemento([for, the, 'Mfold', prediction])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, simulation, of, the, local, folding, of, 'RNA', facilitates, the, discovery, of, potent, antisense, sequences])].
[sujeto(['It', is, most, likely]), verbo([caused]), complemento([by, homologous, recombination, between, the, repeats, flanking, the, gene])].
[sujeto(['However,', taking, into, account, that, the, deletion]), verbo([has]), complemento([no, crucial, effects, on, human, 'well-being,', and, the, ability, of, other, 'GSTMs', to, compensate, for, the, lack, of, 'GSTM1,', a, role, for, additional, factors, affecting, 'GSTM1', deletion, can, be, proposed])].
[sujeto(['The', observed, differences, in, haplotype, patterns]), verbo([suggest]), complemento([the, potential, role, of, genetic, context, in, 'GSTM1', deletion, frequency, '(', 'appearance)', and, in, the, determination, of, the, 'deletion-related', effects])].
[sujeto(['Domestic', turkeys, '(', 'Meleagris', 'gallopavo)', are, one, of, the, most, sensitive, animals, known, to, 'AFB1,', a, condition]), verbo([associated]), complemento([with, a, deficiency, of, hepatic, 'GST-mediated', detoxification, of, 'AFBO'])].
[sujeto(['We']), verbo([have]), complemento([recently, shown, that, unlike, their, domestic, 'counterparts,', wild, turkeys, '(', 'Meleagris', gallopavo, 'silvestris),', which, are, relatively, 'resistant,', express, hepatic, 'GST-mediated', detoxification, activity, toward, 'AFBO'])].
[sujeto(['Because', of, the, importance, of, 'GSTs', in, species, 'susceptibility,', and, to, explore, possible, 'GST', classes]), verbo([involved]), complemento([in, 'AFB1', 'detoxification,', we, 'amplified,', 'cloned,', expressed, and, functionally, characterized, the, hepatic, 'mu-class', 'GSTs', tGSTM3, '(', 'GenBank', accession, no])].
[sujeto([tGSTM4]), verbo([has]), complemento([89, '%', amino, acid, sequence, identity, to, chicken, 'GSTM2,', while, tGSTM3, has, 73, '%', sequence, identity, to, human, 'GSTM3', '(', 'hGSTM3)'])].
[sujeto(['There', is]), verbo([increasing]), complemento([data, suggesting, that, 'African', 'Americans', with, 'NAFLD', tend, to, have, less, progressive, liver, disease])].
[sujeto(['African-American', patients, with, 'biopsy-proven', 'obesity-related', 'NAFLD', and, 'NASH']), verbo([have]), complemento([a, specific, hepatic, gene, expression, pattern, that, may, explain, their, differences, from, 'Caucasian', patients, with, 'NAFLD', in, developing, progressive, liver, disease])].
[sujeto(['Here,', we, show, that, the, 'Wnt/beta-catenin', pathway, is, also]), verbo([involved]), complemento([in, the, transcriptional, regulation, of, 'GSTs:', 'GSTm2,', 'GSTm3,', and, 'GSTm6', are, overexpressed, in, mouse, hepatomas, with, activating, 'Ctnnb1', '(', encoding, 'beta-catenin)', mutations, and, in, transgenic, hepatocytes, expressing, activated, 'beta-catenin'])].
[sujeto(['Activation', of, 'beta-catenin-dependent', signaling]), verbo([stimulates]), complemento(['GSTm', expression, in, vitro])].
[sujeto(['Activation', of, 'beta-catenin', in, mouse, hepatoma, cells]), verbo([activates]), complemento(['GSTm3', 'promoter-driven', reporter, 'activity,', independently, of, 'beta-catenin/T-cell', factor, 'sites,', via, a, retinoid, 'X', 'receptor-binding', site])].
[sujeto(['By', 'contrast,', 'GSTm', expression, is]), verbo([inhibited]), complemento([upon, 'Ras', activation, in, mouse, liver, tumors, and, transgenic, hepatocytes])].
[sujeto(['Recent', studies, by, different, groups]), verbo([have]), complemento([shown, that, 'beta-catenin-dependent', signaling, is, involved, in, the, transcriptional, control, of, &, 'quot;perivenous&quot;', expression, of, various, cytochrome, 'P450s', in, mouse, 'liver,', whereas, 'Ras', signaling, was, hypothesized, to, antagonize, the, perivenous, hepatocyte, phenotype])].
[sujeto(['Glutathione', 'S-transferases', are]), verbo([involved]), complemento([in, defences, against, oxidative, stress])].
[sujeto(['We']), verbo([have]), complemento([recently, demonstrated, reduced, expression, of, glutathione, 'S-transferase', mu, type, 1, '(', 'Gstm1)', in, a, rat, model, of, hypertension])].
[sujeto(['In', the, 'British', 'Genetics', of, 'Hypertension', transmission, disequilibrium, test, 'resource,', a, single, nucleotide, polymorphism, in, the, 3, '\'', region, of, 'GSTM5', '(', 'rs11807)', was]), verbo([found]), complemento([to, be, associated, with, hypertension, '(', 'P', =, 0.01, ')', with, the, 'T-allele', being, 'over-transmitted', to, hypertensive, offspring])].
[sujeto(['GSTM5', mRNA, expression, was]), verbo([found]), complemento([to, be, reduced, in, kidney, tissue, of, subjects, homozygous, for, the, 'T-allele', of, rs11807, as, compared, to, 'C-allele', homozygous, and, 'CT', heterozygous, subjects, '(', 'P', =, 0.02, ')'])].
[sujeto(['Nevertheless,', rs11807, was, not]), verbo([associated]), complemento([with, hypertension, in, the, 'British', 'Genetics', of, 'Hypertension', 'case-control', cohort, '(', 'P', =, 0.61, ')'])].
[sujeto(['Our', studies, do, not]), verbo([provide]), complemento([an, evidence, of, an, association, of, 'GSTM', gene, variants, with, hypertension, in, humans])].
[sujeto(['In', a, previous, 'study,', expression, of, mu, class, 'GST', '(', 'GSTM)', was]), verbo([associated]), complemento([with, poor, prognosis, in, childhood, acute, lymphoblastic, leukaemia, '(', 'ALL),', 'however,', that, study, did, not, differentiate, between, individual, 'GSTM', isoforms])].
[sujeto(['GSTM2', transcript, was]), verbo([expressed]), complemento([in, all, patients, in, contradistinction, to, 'GSTM5,', which, was, not, detected, in, any, sample])].
[sujeto(['GSTM3', and, 'GSTM4', expression, varied, between, 'individuals,', with, 'GSTM3']), verbo([expressed]), complemento([in, 62, '%', and, 'GSTM4', in, 24, '%', of, patients])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, expression, of, 'GSTM3', may, play, a, role, in, determining, prognosis, in, childhood, 'ALL', and, could, provide, more, information, for, accurate, stratification, of, treatment])].
[sujeto(['Further', studies, are]), verbo([required]), complemento([to, determine, whether, there, is, a, causal, relationship, between, 'GSTM3', expression, and, clinical, outcome])].
[sujeto(['Fusion', constructs, of, the, gene, of, interest, and, the, gene, encoding, the]), verbo([enhanced]), complemento([green, fluorescent, protein, '(', 'EGFP)', are, cotransfected, with, 'AS-ODNs', to, 'COS-7', cells])].
[sujeto(['We']), verbo([found]), complemento([several, 'AS-ODNs', that, demonstrated, 'potent,', 'sequence-specific,', and, 'concentration-dependent', inhibition, of, fusion, protein, expression])].
[sujeto(['At', 0.5, 'microm,', 'AS-6', and, 'AS-8']), verbo([inhibited]), complemento(['EGFP-GSTM1', expression, by, 95, +, /, -, 4, '%', and, 81, +, /, -, 6, '%', ',', respectively])].
[sujeto(['AS-2', and, 'AS-3,']), verbo([targeted]), complemento([at, homologous, regions, in, 'GSTM1', and, 'GSTM2,', inhibited, both, isoforms, '(', 77, -, 95, '%', 'decrease)'])].
[sujeto(['The', observed]), verbo([decrease]), complemento([in, 'EGFP', expression, was, accompanied, by, a, decrease, in, 'GSTM', enzyme, activity])].
[sujeto(['The', medical, consequences, of, this, deficiency]), verbo([have]), complemento([been, extensively, investigated, in, molecular, epidemiological, 'studies,', but, possible, differences, of, the, highly, active, homozygous, genotype, versus, the, moderately, active, heterozygous, genotype, could, not, be, considered, because, many, currently, used, polymerase, chain, reaction, '(', 'PCR)', assays, cannot, distinguish, the, homozygous, genotypes, 'GSTM1', *, 'A/A', and, 'GSTM1*B/B', from, the, heterozygous, genotypes, 'GSTM1*A/0', and, 'GSTM1*B/0'])].
[sujeto(['Based', on, the, published, cluster, of, 'GSTM', genes, '(', 'GSTM1', to, -, 'M5),', a, 13, -, kb, segment, spanning, the, site, of, the, 'GSTM1', deletion, was, amplified, using, a, 'GSTM2-specific', forward]), verbo([primer]), complemento(['(', 5, '\'', -, 'CATCGCTTATGATGTCCTTGAGAGAAACCAAG-3\')', and, a, reverse, 'primer,', which, is, specific, for, the, upstream, region, of, 'GSTMS', '(', 5, '\'', -, 'GCGTTTCTGAGGACTGGACTGATGATCG-3\')'])].
[sujeto(['The', 'GSTM1,', 'GSTM2,', 'GSTM3,', 'GSTM4,', and, 'GSTM5', glutathione, transferase, genes]), verbo([have]), complemento([been, mapped, to, human, chromosome, 1, by, using, 'locus-specific', 'PCR', primer, pairs, spanning, exon, 6, ',', intron, 6, ',', and, exon, 7, ',', as, probes, on, 'DNA', from, 'human/hamster', somatic, cell, hybrids])].
[sujeto(['The', 'GSTM1-specific']), verbo([primer]), complemento([pairs, can, be, used, to, identify, individuals, carrying, 'non-null', 'GSTM1', alleles])].
[sujeto(['Both', regional, assignment, using, the, fractional, length, method, and, examination, of, probe, signal, with, reference, to, 'R-banded', chromosomes]), verbo([induced]), complemento([by, 'BrdU', places, the, gene, cluster, in, or, near, the, 1, p13])].
[sujeto(['The', close, physical, proximity, of, the, 'GSTM1', and, 'GSTM2', 'loci,', which, share, 99, '%', nucleotide, sequence, identity, over, 460, nucleotides, of, 3, '\'', -, untranslated, 'mRNA,']), verbo([suggests]), complemento([that, the, 'GSTM1-null', allele, may, result, from, unequal, 'crossing-over'])].
[sujeto(['Two', of, 'them,', pyruvate, kinase, isozymes, 'M1/M2', isoform, 'M2', and, enolase, 1, are, enzymes]), verbo([involved]), complemento([in, glycolytic, pathway])].
[sujeto(['Furthermore,', we, observed, 107, cases, with, gastric, adenocarcinoma, and]), verbo([found]), complemento([that, the, high, expression, of, pyruvate, kinase, isozymes, 'M1/M2', isoform, 'M2', and, enolase, 1, correlates, with, tumor, size, '(', 'P', =])].
[sujeto(['Some', of, them, would, be, 'differentiation-related', cancer, biomarkers, and, are]), verbo([associated]), complemento([with, tumor, 'metastasis,', 'invasion,', and, prognosis])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, overexpression, of, catalase, upregulated, 'xenobiotic-', metabolizing, enzyme, '(', 'XME)', expression, and, diminished, 'benzo(a)pyrene', '(', 'BaP)', intermediate, accumulation, in, mouse, aortic, endothelial, cells, '(', 'MAECs)'])].
[sujeto(['Endoplasmic', reticulum, '(', 'ER)', is, the, most, active, organelle]), verbo([involved]), complemento([in, 'BaP', metabolism])].
[sujeto(['Treatment', of, 'wild-type', 'MAECs', with, 1, μM, 'BaP', for, 2, h]), verbo([increased]), complemento([the, expression, of, microsomal, 'CYP1A1,', 1, 'B1', and, 'NQO1', by, '~300,', 64, and, 116, '%', ',', respectively])].
[sujeto(['Overexpression', of, catalase, did, not, significantly]), verbo([increase]), complemento(['EH1,', but, upregulated, 'BaP-induced', expression, of, microsomal, 'CYP1A1,', 1, 'B1,', 'NQO1', and, 'GSTP', in, the, following, 'order:', 1, 'A1&gt;NQO1&gt;GSTP&gt;1B1'])].
[sujeto(['In', contrast, to, our, previous]), verbo([report]), complemento([showing, lower, level, of, 'BaP', phenols, versus, 'BaP', 'diols/diones', in, the, 'whole-cell,', this, report, demonstrated, that, the, sum, of, microsomal, 'BaP', phenolic, metabolites, were, '~60%', greater, than, that, of, the, 'BaP', 'diols/diones', after, exposure, of, microsomes, to, 'BaP'])].
[sujeto(['This', process]), verbo([enhanced]), complemento([the, ratio, of, 'BaP', phenol, versus, 'diol/dione', metabolites, in, a, potent, manner])].
[sujeto(['Taken', 'together,', upregulation, of, phase, 'II', 'XMEs', and, 'CYP1', 'proteins,', but, not, 'EH1', in, the, 'ER', might, be, the, mechanism, by, which, overexpression, of, catalase, reduces, the, levels, of, all, the, 'BaP', 'metabolites,', and]), verbo([enhances]), complemento([the, ratio, of, 'BaP', phenolic, metabolites, versus, 'diol/diones', in, endothelial, microsomes])].
[sujeto(['Piperlongumine', '(', 2.5, -, 10, &, 'nbsp;μmol/L)', and, auranofin, '(', 0.25, -, 4, &, 'nbsp;μmol/L)', were, used, to]), verbo([inhibit]), complemento([glutathione, 'S-transferase', π, and, thioredoxin, 'reductase,', respectively])].
[sujeto(['Piperlongumine', or, auranofin, alone, 'up-regulated', the, expression, of, 'NRF2']), verbo([target]), complemento(['genes,', but, not, 'TP53', targets])].
[sujeto(['The', dual, inhibition, successfully]), verbo([decreased]), complemento(['CD44v9', surface, presentation, and, delayed, tumor, emergence, in, nude, mouse])].
[sujeto(['However,', a, small, subpopulation, persistently, survived, and, accumulated]), verbo([phosphorylated]), complemento([histone, 'H2A'])].
[sujeto(['Such', &, 'quot;persisters&quot;', still]), verbo([retained]), complemento([lesser, but, significant, tumorigenicity])].
[sujeto(['Thus,', dual, inhibition, of, glutathione, 'S-transferase', π, and, thioredoxin, reductase, could, be, a, feasible, option, for]), verbo([decreasing]), complemento([the, tumor, mass, and, 'CD44v9-positive', fraction, by, disrupting, redox, regulation])].
[sujeto(['They', not, only]), verbo([induce]), complemento(['DNA', demethylation, but, also, have, significant, cytostatic, and, cytotoxic, 'effects;', 'however,', the, relationships, between, these, characteristics, have, not, been, established, yet, due, to, the, lack, of, a, method, to, induce, only, 'DNA', demethylation])].
[sujeto(['Interestingly,', 65, '%', of, the, genes, upregulated, fivefold, or, more, by, 'MBD-TET1-CDwt', were, also]), verbo([reactivated]), complemento([after, treatment, with, a, 'DNMT', 'inhibitor,', 5, -, azacytidine, '(', 'Aza-CR),', suggesting, that, gene, reactivation, by, both, methods, primarily, shares, the, same, 'mechanism,', 'DNA', demethylation])].
[sujeto(['In', order, to, examine, whether, 'DNA', demethylation, affects, the, growth, of, cancer, 'cells,', we]), verbo([have]), complemento([established, a, tetracycline, inducible, system, that, can, regulate, the, expression, of, 'MBD-TET1-CDwt', in, a, prostate, cancer, cell, 'line,', 'LNCaP'])].
[sujeto(['In', accordance, with, the, reactivation, of, methylated, 'genes,', induction, of, 'MBD-TET1-CDwt', extensively]), verbo([suppressed]), complemento([the, growth, of, 'LNCaP', cells, through, 'G1/S', arrest])].
[sujeto(['These', results, clearly, indicate, that, 'TET', oxidase, activity]), verbo([recruited]), complemento([at, 'methyl-CpG', sites, through, 'MBD', induces, reactivation, of, hypermethylated, genes, by, 'DNA', demethylation, and, allows, us, to, analyze, the, effect, of, only, global, 'DNA', demethylation, in, a, wide, variety, of, cancer, cells])].
[sujeto(['Glutathione', 'S-transferases', '(', 'GSTs)', are, a, family, of, multifunctional, phase, 'II', enzymes, that, are]), verbo([involved]), complemento([in, the, detoxification, of, exogenous, and, endogenous, compounds])].
[sujeto(['A']), verbo([conserved]), complemento([domain, of, 'GST_N_Mu_like', '(', 'PSSM:', 'cd03075)', and, 'GST_C_family_superfamily_like', '(', 'PSSM:', 'cl02776)', was, indentified, in, 'PmMuGST'])].
[sujeto(['PmMuGST', transcripts, both, in, the, hepatopancreas, and, in, the, muscle, were, significantly]), verbo([induced]), complemento([after, 14, &, 'nbsp;days', of, treatment, with, a, low, dosage, of, 'AFB1', '(', 50, &, 'nbsp;μg/kg)', exposure, and, were, significantly, inhibited, after, 42, and, 56, &, 'nbsp;days', of, a, high, dosage, of, 'AFB1', '(', 1000, ',', 2500, &, 'nbsp;μg/kg', 'AFB1)', exposure])].
[sujeto([monodon, was, inducible, and, was]), verbo([involved]), complemento([in, the, response, to, 'AFB1', exposure])].
[sujeto(['Beta-2', adrenoreceptor, '(', 'ADRB2)', is, a, functional, 'G-coupled', protein]), verbo([expressed]), complemento([in, the, vascular, endothelium, of, 'lungs,', alveolar, 'walls,', and, the, ganglions, of, cholinergic, nerves, which, induces, bronchodilation, in, response, to, catecholamines])].
[sujeto(['In', this, study, we, determined, the, relationship, between, the, 'ADRB2', 'Arg16Gly', polymorphism, and, 'GSTP1', 'polymorphisms,']), verbo([involved]), complemento([in, bronchodilator, response, and, oxidative, 'stress,', 'respectively,', with, susceptibility, to, asthma])].
[sujeto(['In', this, 'study,', 129, asthmatic, patients, and, 127, healthy, control, cases, were]), verbo([recruited]), complemento([to, determine, 'ADRB2', and, 'GSTP1', genotypes, by, 'allele-specific', polymerase, chain, reaction, and, restriction, fragment, length, polymorphism, 'assays,', respectively])].
[sujeto(['The', 'ADRB2', genotype, frequencies, of, the, patients, and, control, cases, were]), verbo([found]), complemento([to, be, 10.9, '%', '(', 'Arg16Arg),', 48.8, '%', '(', 'Arg16Gly),', and, 40.3, '%', '(', 'Gly16Gly)', and, 24.4, '%', '(', 'Arg16Arg),', 36.2, '%', '(', 'Arg16Gly),', and, 39.4, '%', '(', 'Gly16Gly),', respectively])].
[sujeto(['GSTP1', genotype, frequencies, of, patients, and, control, cases, were]), verbo([found]), complemento([to, be, 55, '%', '(', 'Ile105Ile),', 43.4, '%', '(', 'Ile105Val),', and, 1.6, '%', '(', 'Val105Val)', and, 75.6, '%', '(', 'Ile105Ile),', 22, '%', '(', 'Ile105Val),', and, 2.4, '%', '(', 'Val105Val),', respectively])].
[sujeto(['In', the, case, of, the, 'GSTP1', 'gene,', we]), verbo([found]), complemento([statistically, significant, differences, in, the, genotype, frequency, of, 'Ile105Val', and, the, allele, frequency, of, 'Val105', in, the, asthmatic, group, compared, with, the, controls])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, the, 'GSTP1', 'Ile105Val', polymorphism, may, be, linked, to, the, severeness, of, airway, dysfunction])].
[sujeto(['Type', 2, diabetes, mellitus, is, characterized, by, chronic, hyperglycemia, and]), verbo([associated]), complemento([with, oxidative, stress, resulting, from, accumulation, of, free, radicals, in, 'body\'s', 'tissues,', which, especially, affects, beta, cells, in, pancreas, and, is, an, important, factor, in, the, development, of, diabetes, and, its, complications])].
[sujeto(['Glutathione', 'S-transferases', '(', 'GSTs)', are, a, family, of, antioxidant, enzymes, that, play, important, roles, in]), verbo([decreasing]), complemento(['ROS', species, and, act, as, a, kind, of, antioxidant, defense])].
[sujeto(['Our', data, indicate, that, 'G', allele, '(', 'Val)', is]), verbo([associated]), complemento([with, an, increased, risk, for, 'T2DM', in, this, population, in, any, combination, '(', 'OR', 4.101, ',', 95, &, 'nbsp;%', 'CI', 1.986, -, 8.469, ',', 'P&nbsp;=&nbsp;0'])].
[sujeto(['SIRT3,', a, class, 'III', histone, 'deacetylase,']), verbo([has]), complemento([been, implicated, in, various, cancers, as, a, novel, therapeutic, target])].
[sujeto(['In', hepatocellular, carcinoma, '(', 'HCC),', we, previously]), verbo([reported]), complemento([that, 'SIRT3', induced, cell, apoptosis, by, regulating, 'GSK-3β/Bax', signaling, pathway])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, chemotherapeutic, agents, '(', 'doxorubicin,', cisplatin, and, 'epirubicin)', and, sorafenib, treatment, downregulated, 'SIRT3', mRNA, and, protein, levels, in, three, 'HCC', cell, lines])].
[sujeto(['MTS', assay]), verbo([found]), complemento([that, 'SIRT3', overexpression, sensitized, liver, cancer, cells, to, chemotherapeutic, agents, and, sorafenib, in, 'SMMC-7721,', 'Huh-7', and, 'PLC/PRF/5', cell, lines])].
[sujeto(['Moreover,', 'SIRT3', overexpression]), verbo([promoted]), complemento([chemotherapeutic, 'agents-induced', or, 'sorafenib-induced', apoptosis, as, evidenced, by, flow, 'cytometry,', enhanced, 'PARP', cleavage, and, enhanced, 'Caspase-9', cleavage, in, three, 'HCC', cells])].
[sujeto(['In', 'contrast,', 'SIRT3', silencing]), verbo([increased]), complemento([drug, resistance, of, 'HCC', cells, to, chemotherapeutic, agents])].
[sujeto(['Mechanistic', study]), verbo([found]), complemento([that, 'SIRT3', downregulated, the, mRNA, and, protein, levels, of, glutathione, 'S-transferase', pi, 1, '(', 'GSTP1),', which, is, a, member, of, phase, 'II', detoxification, enzymes, families, involved, in, metabolizing, for, chemotherapeutic, agents])].
[sujeto(['Moreover,', 'SIRT3']), verbo([decreased]), complemento([the, amount, of, 'GSTP1', that, was, associated, with, 'JNK,', which, finally, contributed, the, activation, of, 'JNK', activity, and, activation, of, downstream, target, 'c-Jun', and, 'Bim'])].
[sujeto(['Together,', our, findings, revealed, 'SIRT3', could]), verbo([enhance]), complemento([the, drug, sensitivity, of, 'HCC', cells, to, an, array, of, chemotherapeutic, agents])].
[sujeto(['SIRT3', may, serve, as, a, potential]), verbo([target]), complemento([for, improving, the, chemosensitivity, of, 'HCC', patients])].
[sujeto(['Apoptosis', in, lung, epithelial, cells, is, critical, in, 'IPF', 'pathogenesis,', as, heightened]), verbo([loss]), complemento([of, these, cells, promotes, fibroblast, activation, and, remodeling])].
[sujeto(['Changes', in, glutathione, redox, status]), verbo([have]), complemento([been, reported, in, 'IPF', patients])].
[sujeto(['We', hypothesized, that, 'GSTP']), verbo([mediates]), complemento([lung, fibrogenesis, in, part, through, 'FAS', 'S-glutathionylation,', a, critical, event, in, epithelial, cell, apoptosis])].
[sujeto(['Our', results, demonstrate, that, 'GSTP', immunoreactivity, is]), verbo([increased]), complemento([in, the, lungs, of, 'IPF', 'patients,', notably, within, type, 'II', epithelial, cells])].
[sujeto(['The', 'FAS-GSTP', interaction, was, also]), verbo([increased]), complemento([in, 'IPF', lungs])].
[sujeto(['Bleomycin-', and, 'AdTGFβ-induced']), verbo([increases]), complemento([in, collagen, 'content,', 'α-SMA,', 'FAS', 'S-glutathionylation,', and, total, protein, 'S-glutathionylation', were, strongly, attenuated, in, 'Gstp(-/-)', mice])].
[sujeto(['To', assess, epigenetic, regulation, of, 'GSTP1', and, its, potential, role, in, 'age-related']), verbo([nuclear]), complemento([cataract, '(', 'ARNC)', 'pathogenesis,', we, evaluated, 'GSTP1', mRNA, 'expression,', 'methylation,', and, chromatin, modifications, in, lenses, from, 'ARNC', patients])].
[sujeto(['The']), verbo([loss]), complemento([of, 'GSTP1', mRNA, and, protein, and, the, increased, 'DNA', promoter, methylation, might, be, correlated, with, the, severity, of, the, 'ARNC'])].
[sujeto(['Demethylation', treatment, of, 'HLE-B3', cells, with, 5, -, 'aza-dC']), verbo([enhanced]), complemento([the, expression, of, 'GSTP1'])].
[sujeto(['Epigenetic', alteration, of, 'GSTP1']), verbo([regulates]), complemento([its, expression, in, lens, epithelial, and, cortical, tissues])].
[sujeto(['Effective', control, of, breast, cancer]), verbo([has]), complemento([been, primarily, hampered, by, a, lack, of, tumor, specificity, in, treatments])].
[sujeto(['One', potential, way, to, improve]), verbo([targeting]), complemento([specificity, is, to, develop, novel, vectors, that, specifically, bind, to, and, are, internalized, by, tumor, cells])].
[sujeto(['Our', previous, study, established, that, 'PI-FITC', also, shows, affinity, to, 'Calu-1', human, lung, carcinoma, cells, and, major, histocompatibility, complex, class, 'I', antigen, 'molecules;', 'therefore,', the, cytomembrane, proteins, of, the, cell, lines, were, analyzed, to, determine, those, that, were, common, to, the, two, cell, lines, and, may, be]), verbo([associated]), complemento([with, transmembrane, transduction])].
[sujeto(['Use', of, membrane, transport, inhibitors, indicated, that, macropinocytosis, and, 'caveolin-mediated', endocytosis, may, be]), verbo([involved]), complemento([in, the, endocytosis, of, 'PI'])].
[sujeto(['In', 'addition,', 11, membrane, proteins, common, to, 'MDA-MB-231', and, 'Calu-1', may, be]), verbo([associated]), complemento([with, transmembrane, transduction])].
[sujeto(['Thus,', 'PI', could, be, modified, to, be, a, potential, 'vector,', and, may, contribute, to, the, development, of]), verbo([targeted]), complemento([therapeutic, strategies, for, breast, cancer])].
[sujeto(['To', determine, the, value, of, molecular, biomarkers, '(', 'BMs)']), verbo([associated]), complemento([with, tubular, epithelial, damage, in, developing, and, predicting, acute, kidney, injury, '(', 'AKI)', after, hematopoietic, stem, cell, transplantation, '(', 'HSCT)'])].
[sujeto(['The', elevated, urinary, levels, of, 'BMs', '(', above, the, 'median)', were]), verbo([found]), complemento([to, be, substantially, more, common, than, 'AKI', cases])].
[sujeto(['The', urinary, excretion, of, the, majority, of, 'BMs', dramatically]), verbo([increased]), complemento([in, the, early, 'HSCT', period])].
[sujeto(['The', higher, urinary, 'KIM-1', 'and/or', 'MCP-1', excretion, regardless, of, other, clinical, indicators, was]), verbo([associated]), complemento([with, the, higher, relative, risk, '(', 'RR)', of, 'AKI,', which, increased, by, 2.3, times, with, a, rise, in, one, of, these, indicators, and, by, 3.4, times, with, a, rise, in, both, indicators])].
[sujeto(['Previous', 'NMR', studies, demonstrated, that, lonidamine, '(', 'LND)', selectively, diminishes, the, intracellular, pH, '(', 'pHi)', of, 'DB-1', melanoma, and, mouse, xenografts, of, a, variety, of, other, prevalent, human, cancers, while]), verbo([decreasing]), complemento([their, bioenergetic, status, '(', tumor, 'βNTP/Pi', 'ratio)', and, enhancing, the, activities, of, melphalan, and, doxorubicin, in, these, cancer, models])].
[sujeto(['Since', melphalan, and, doxorubicin, are, highly, toxic, 'agents,', we]), verbo([have]), complemento([examined, three, other, nitrogen, '(', 'N)-mustards,', 'chlorambucil,', cyclophosphamide, and, 'bendamustine,', to, determine, if, they, exhibit, similar, potentiation, by, 'LND'])].
[sujeto(['The', effect, of, 'LND', on, the, activities, of, these, 'N-mustards', is, generally, attributed, to, acid, stabilization, of, the, aziridinium, active, 'intermediate,', acid, inhibition, of, 'glutathione-S-transferase,', which]), verbo([acts]), complemento([as, a, scavenger, of, 'aziridinium,', and, acid, inhibition, of, 'DNA', repair, by, 'O6-alkyltransferase'])].
[sujeto(['Depletion', of, 'ATP', by, 'LND', may, also]), verbo([decrease]), complemento([multidrug, resistance, and, increase, tumor, response])].
[sujeto(['While', many, metabolic, drivers, of, breast, cancers]), verbo([have]), complemento([been, 'identified,', the, metabolic, pathways, that, mediate, breast, cancer, malignancy, and, poor, prognosis, are, less, well, understood])].
[sujeto(['Here,', we, used, a, 'reactivity-based', chemoproteomic, platform, to, profile, metabolic, enzymes, that, are, enriched, in, breast, cancer, cell, types, linked, to, poor, 'prognosis,', including, 'triple-negative', breast, cancer, '(', 'TNBC)', cells, and, breast, cancer, cells, that]), verbo([have]), complemento([undergone, an, 'epithelial-mesenchymal', 'transition-like', state, of, heightened, malignancy])].
[sujeto(['We', identified, glutathione, 'S-transferase', 'Pi', 1, '(', 'GSTP1)', as, a, novel, 'TNBC']), verbo([target]), complemento([that, controls, cancer, pathogenicity, by, regulating, glycolytic, and, lipid, 'metabolism,', 'energetics,', and, oncogenic, signaling, pathways, through, a, protein, interaction, that, activates, 'glyceraldehyde-3-phosphate', dehydrogenase, activity])].
[sujeto(['Among', the, fractions, 'assayed,', a, solvent, extract, from, 'Pulicaria', incisa, had, potent, 'NQO1']), verbo([inducing]), complemento([activity])].
[sujeto([incisa, as, a, promising]), verbo([target]), complemento([for, future, phytochemical, characterization, for, cancer, preventive, components])].
[sujeto(['Glutathione', 'S-transferase', pi, '(', 'GSTP)', is, a, neuroprotective, antioxidant, enzyme]), verbo([regulated]), complemento([at, the, transcriptional, level, by, the, antioxidant, master, regulator, nuclear, 'factor-erythroid', 2, -, related, factor, 2, '(', 'Nrf2)'])].
[sujeto(['S-glutathionylation', of, 'Keap1']), verbo([leads]), complemento([to, 'Nrf2', activation, and, subsequently, increases, expression, of, 'GSTP'])].
[sujeto(['N-nitrosodiethylamine', '(', 'NDEA),', a, nitrosamine, 'compound,', is, known, to]), verbo([cause]), complemento([liver, damage, through, the, generation, of, reactive, oxygen, species, '(', 'ROS),', resulting, in, oxidative, damage, to, macromolecules, such, as, 'DNA,', and, the, consequent, development, of, cancer])].
[sujeto(['The', results, show, that, treatment, with, 'Umb', '(', 0.5, '%', 'w/w)', and, 'Esc', '(', 0.5, '%', 'w/w)', in, the, diet, for, 7, days, significantly, attenuates, 'NDEA-induced', liver, 'damage,', lowering, serum, alanine, transaminase, '(', 'ALT)', 'levels,']), verbo([decreasing]), complemento([hepatic, lipid, 'peroxidation,', and, restoring, total, glutathione, levels])].
[sujeto(['The', results, showed, that, 'Umb', and, 'Esc', administration, significantly]), verbo([increased]), complemento([the, expression, of, 'NQO1', by, 3.6, -, and, 2.7, -, 'fold,', 'HO1', by, 2.7, -, and, 3.2, -, 'fold,', and, 'GSTP1', by, 2.8, -, and, 3.2, -, 'fold,', respectively])].
[sujeto(['In', 'conclusion,', 'Umb', and, 'Esc', are, capable, of, protecting, liver, from, 'NDEA-induced', 'hepatotoxicity,', and, this, is]), verbo([associated]), complemento([with, the, induction, of, protective, enzymes])].
[sujeto(['Reactive', oxygen, species, generated, under, oxidative, stress, are]), verbo([involved]), complemento([in, neuronal, 'diseases,', including, ischemia])].
[sujeto(['PEP-1-GSTpi', was, transduced, into, 'HT-22', cells, and, significantly, protected, against, 'H2O2-treated', cell, death, by, reducing, the, intracellular, toxicity, and]), verbo([regulating]), complemento([the, signal, 'pathways,', including, 'MAPK,', 'Akt,', 'Bax,', and, 'Bcl-2'])].
[sujeto(['These', results, indicate, that, 'PEP-1-GSTpi']), verbo([acts]), complemento([as, a, regulator, or, an, antioxidant, to, protect, against, oxidative, stressinduced, cell, death])].
[sujeto(['Our', study]), verbo([suggests]), complemento([that, 'PEP-1-GSTpi', may, have, potential, as, a, therapeutic, agent, for, the, treatment, of, ischemia, and, a, variety, of, oxidative, 'stress-related', neuronal, diseases])].
[sujeto(['The', significant]), verbo([increase]), complemento([of, 'GSTP1', and, 'GSTT1', expressions, in, pterygium, may, be, because, of, the, increased, activation, of, 'GST', in, response, to, excessive, free, radical, formation, from, ultraviolet, exposure, to, maintain, antioxidant, capacity, in, pterygium])].
[sujeto(['Investigation', of, 'structure-activity', relationships, of, 6, 'S', derivatives, indicates, that, the, combination, of, an, 'α,β-unsaturated', carbonyl, entity, and, a, catechol, moiety, in, one, compound]), verbo([enhances]), complemento([the, 'Tg(gstp1:GFP)', fluorescence, signal, in, zebrafish, embryos])].
[sujeto(['Chemical', reaction, and, in, vivo, metabolism, studies, of, the, four, most, potent, 6, 'S', derivatives, showed, that, both, 'α,β-unsaturated', carbonyl, entity, and, catechol, moiety]), verbo([act]), complemento([as, major, active, groups, for, conjugation, with, the, sulfhydryl, groups, of, the, cysteine, residues])].
[sujeto(['In', 'addition,', we, further, demonstrated, that, 6, 'S', derivatives]), verbo([increased]), complemento([the, expression, of, 'Nrf2', downstream, 'target,', heme, 'oxygenase-1,', in, both, a, 'dose-', and, 'time-dependent', manner])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'α,β-unsaturated', carbonyl, entity, and, catechol, moiety, of, 6, 'S', derivatives, may, react, with, the, cysteine, residues, of, 'Keap1,', disrupting, the, 'Keap1-Nrf2', 'complex,', thereby, liberating, and, activating, 'Nrf2'])].
[sujeto(['Our', findings, of, natural, 'product-derived', 'Nrf2', activators]), verbo([lead]), complemento([to, design, options, of, potent, 'Nrf2', activators, for, further, optimization])].
[sujeto(['Cumulative', exposure, to]), verbo([lead]), complemento([is, associated, with, cardiovascular, outcomes])].
[sujeto(['We', assessed, possible, effect, modification, by, genetic, polymorphisms, in, 'ALAD,', 'HFE,', 'HMOX1,', 'VDR,', 'GSTP1,', 'GSTT1,', 'GSTM1,', 'APOE,', 'AGTR1', and, 'AGT', individually, and, as, the, genetic, risk, score, '(', 'GRS)', on, the, association, between, cumulative]), verbo([lead]), complemento([exposure, and, incident, coronary, heart, disease, '(', 'CHD)', events])].
[sujeto(['We', used, 'K-shell-X-ray', fluorescence, to, measure, bone]), verbo([lead]), complemento([levels])].
[sujeto(['We', applied, inverse, probability, weighting, to, account, for, potential, selection, bias, due, to, recruitment, into, the, bone]), verbo([lead]), complemento(['sub-study'])].
[sujeto(['Significant', effect, modification, was]), verbo([found]), complemento([by, 'VDR,', 'HMOX1,', 'GSTP1,', 'APOE,', and, 'AGT', genetic, polymorphisms, when, evaluated, individually])].
[sujeto(['After', adjusting, for, potential, 'confounders,', a, 'HR', of, 'CHD', was, 2.27, '(', 95, '%', 'CI:', 1.5, -, 3.42, ')', with, 2, -, fold]), verbo([increase]), complemento([in, patella, lead, 'levels,', among, participants, in, the, top, tertile, of, 'GRS'])].
[sujeto(['We', also, detected, an]), verbo([increasing]), complemento([trend, in, 'HRs', across, tertiles, of, 'GRS', '(', 'p-trend', =, 0.0063, ')'])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, 'lead-related', loci, as, a, whole, may, play, an, important, role, in, susceptibility, to, 'lead-related', 'CHD', risk])].
[sujeto(['Male', 'Wistar', rats, with, different, thyroid, status, '(', 'eu-,', 'hypothyroid)', were, exposed, to, 0, ',', 3, or, 30, &, 'nbsp;mg/kg', body, weight, of, the, flame, retardant, 'HBCD', for, 7, days, and, obtained, data, compared, with, a, previous, study, in, 'females,', &, 'quot;Hexabromocyclododecane', '(', 'HBCD)']), verbo([induced]), complemento([changes, in, the, liver, proteome, of, 'eu-', and, hypothyroid, female, 'rats&quot;', '(', 'Miller', et, al])].
[sujeto(['In', 'erythrocytes,', the, isoenzyme, '(', 'e-GST)', mainly, present, is, 'GSTP1-1,', which, is, overexpressed, in, humans, in, case, of]), verbo([increased]), complemento([blood, 'toxicity,', as, it, occurs, in, nephrophatic, patients, or, in, healthy, subjects, living, in, polluted, areas])].
[sujeto(['Possibly', disturbing, factors]), verbo([have]), complemento([been, examined, to, avoid, artifact, determinations])].
[sujeto(['This', study]), verbo([provides]), complemento([the, basis, for, future, screening, studies, to, verify, if, animals, have, been, exposed, to, toxicologic, insults])].
[sujeto(['Preliminary', data, on, cows, reared, in, polluted, areas, show]), verbo([increased]), complemento([expression, of, 'e-GST,', which, parallels, the, results, found, for, humans])].
[sujeto(['Phase', 'I', and, 'II', enzymes, are]), verbo([involved]), complemento([in, the, metabolism, of, endogenous, reactive, compounds, as, well, as, 'xenobiotics,', including, toxicants, and, drugs])].
[sujeto(['Genotyping', studies]), verbo([have]), complemento([established, several, drug, metabolizing, enzymes, as, markers, for, risk, of, drug, hypersensitivity])].
[sujeto(['However,', other, candidates, are, emerging, that, are]), verbo([involved]), complemento([in, drug, metabolism, but, also, in, the, generation, of, danger, or, costimulatory, signals])].
[sujeto(['In', 'addition,', their, metabolic, activity, can]), verbo([have]), complemento([important, consequences, for, the, cellular, redox, 'status,', and, impacts, the, inflammatory, response, as, well, as, the, balance, of, inflammatory, 'mediators,', which, can, modulate, epigenetic, factors, and, cooperate, or, interfere, with, 'drug-adduct', formation])].
[sujeto(['These', enzymes, 'are,', in, 'turn,']), verbo([targets]), complemento([for, covalent, modification, and, regulation, by, oxidative, 'stress,', inflammatory, 'mediators,', and, drugs])].
[sujeto(['Therefore,', they, constitute, a, platform, for, a, complex, set, of, interactions]), verbo([involving]), complemento([drug, 'metabolism,', protein, 'haptenation,', modulation, of, the, inflammatory, 'response,', 'and/or', generation, of, danger, signals, with, implications, in, drug, hypersensitivity, reactions])].
[sujeto(['Moreover,']), verbo([increasing]), complemento([evidence, supports, their, involvement, in, allergic, processes])].
[sujeto(['Here,', we, will, focus, on, 'GSTP1-1', and, aldose, reductase, '(', 'AKR1B1)', and]), verbo([provide]), complemento([a, perspective, for, their, involvement, in, drug, hypersensitivity])].
[sujeto(['Numerous', studies]), verbo([have]), complemento([evaluated, the, association, between, the, 341, 'C/T', polymorphism, in, glutathione, 'S-transferase', 'P1', '(', 'GSTP1)', and, lung, cancer, risk])].
[sujeto(['The', 'meta-analysis', results, showed, that, the, 'GSTP1', 341, 'C/T', polymorphism, was, significantly]), verbo([associated]), complemento([with, lung, cancer, risk, '(', 'TT', vs, 'CC:', 'OR', =, 3.33, ',', 95, '%', 'CI', =, 1.49, -, 7.44, ;, 'CT', vs, 'CC:', 'OR', =, 1.35, ',', 95, '%', 'CI', =, 1.1, -, 1.65, ;, dominant, 'model:', 'OR', =, 1.43, ',', 95, '%', 'CI', =, 1.05, -, 1.96, ;, recessive, 'model:', 'OR', =, 0.31, ',', 95, '%', 'CI', =, 0.14, -, 0.7, ')'])].
[sujeto(['We']), verbo([recruited]), complemento([284, 'NSCLC', patients, at, advanced, stage, from, 'Department', of, 'Radiotherapy', in, 'Peace', 'Hospital', 'Attached', to, 'Changzhi', 'Medical', 'College', between, 'May', 2009, and, 'May', 2011, ',', who, had, received, 'cisplatin-based', chemotherapy])].
[sujeto(['In', the, 'Cox', proportional, hazards, 'model,', the, 'IIe/Val', and, 'Val/Val', genotypes, of, 'GSTP1', were]), verbo([associated]), complemento([with, lower, risk, of, disease, progression, compared, with, the, 'IIe/IIe', 'genotype,', and, the, 'HRs', '(', 95, '%', 'CIs)', were, 0.37, '(', 0.18, -, 0.74, ')', and, 0.15, '(', 0.06, -, 0.35, ')', ',', respectively])].
[sujeto(['The', 'IIe/Val', and, 'Val/Val', genotypes, significantly]), verbo([decreased]), complemento([risk, of, death, from, all, causes, in, patients, with, 'NSCLC,', and, the, 'HRs', '(', 95, '%', 'CIs)', were, 0.52, '(', 0.29, -, 0.92, ')', and, 0.37, '(', 0.17, -, 0.79, ')', ',', respectively, 'No', significant, association, was, observed, between, 'GSTM1', and, 'GSTT1', polymorphisms, and, 'progression-free', survival, and, overall, survival, in, the, 'NSCLC', patients])].
[sujeto(['In', 'summary,', we]), verbo([suggest]), complemento([that, 'GSTP1', polymorphisms, might, influence, the, treatment, outcome, of, advanced, 'NSCLC', 'patients,', and, our, results, could, help, improve, individualized, therapy])].
[sujeto(['Significant', association, between, 'GST', genotype, and, risk, of, cRCC, development, was]), verbo([found]), complemento([for, the, 'GSTM1-null', and, 'GSTP1-variant', genotype, '(', p, =, 0.02, and, 'p&lt;0'])].
[sujeto(['Furthermore,', 22, '%', of, all]), verbo([recruited]), complemento([cRCC, patients, were, carriers, of, combined, 'GSTM1-null,', 'GSTT1-active,', 'GSTA1-low', activity, and, 'GSTP1-variant', 'genotype,', exhibiting, 9.32, -, fold, elevated, cRCC, risk, compared, to, the, reference, genotype, combination, '(', p, =, 0.04, ')'])].
[sujeto(['Significant', association, between, 'GST', genotype, and, cRCC, risk, in, smokers, was]), verbo([found]), complemento([only, for, the, 'GSTP1', 'genotype,', while, 'GSTM1-null/GSTP1-variant/GSTA1', 'low-activity', genotype, combination, was, present, in, 94, '%', of, smokers, with, 'cRCC,', increasing, the, risk, of, cRCC, up, to, 7.57, '(', p, =, 0.02, ')'])].
[sujeto(['GSTM1,', 'GSTT1,', 'GSTA1', and, 'GSTP1', polymorphisms, might, be]), verbo([associated]), complemento([with, the, risk, of, 'cRCC,', with, special, emphasis, on, 'GSTM1-null', and, 'GSTP1-variant', genotypes])].
[sujeto(['Worldwide', prostate, cancer, '(', 'PCa)', represents, the, 2, nd]), verbo([leading]), complemento([cause, of, cancer, related, deaths, among, men])].
[sujeto(['Chronic', myeloid, leukemia, '(', 'CML)', is]), verbo([associated]), complemento([to, the, 'BCR-ABL1', oncogene, and, can, successfully, be, treated, with, tyrosine, kinase, inhibitors, '(', 'TKIs)'])].
[sujeto([7, ')', for, a, recessive, model, was]), verbo([found]), complemento([for, 'GSTP1', '(', 'OR:', 2.04, ;, 'CI:', 0.94, -, 4.4, ')'])].
[sujeto(['However,', the, combined, analysis, showed, that, 'GSTM1-null/GSTP1-GG', as, well, as, 'GSTT1-null/GSTP1-GG', were]), verbo([associated]), complemento([with, 'CML', development, '(', 'p=0'])].
[sujeto(['Furthermore,', a, group, of, patients, with, 'GSTP1-GG', genotype, were, significantly]), verbo([associated]), complemento([with, reduced, 'EFS', comparing, to, those, carrying, other, 'GSTP1', genotypes, '(', 'p=0'])].
[sujeto(['The', new, 'EA', derivatives]), verbo([have]), complemento([been, tested, 'in&nbsp;vitro', in, 'anti-proliferative', assays, on, both, tumor, 'KB', '(', epidermal, 'carcinoma)', and, leukemia, 'HL60', '(', 'promyelocytic)', cells, suitable, targets, for, anticancer, activity])].
[sujeto(['Doxorubicin', '(', 'DOX),', one, of, the, most, effective, anticancer, 'drugs,']), verbo([acts]), complemento([in, a, variety, of, ways, including, 'DNA', 'damage,', enzyme, inhibition, and, generation, of, reactive, oxygen, species])].
[sujeto(['Resistant', cells]), verbo([have]), complemento([also, shown, significantly, elevated, expression, of, 'GSTA1', and, 'GSTA2', genes, '(', 200, -, fold, and, 50, -, 'fold)', as, a, result, of, 'DOX', treatment])].
[sujeto(['In', 'HeLa', 'cells,', exposure, to, 'DOX']), verbo([increased]), complemento([expression, of, all, 'genes:', 'GSTM1', '(', 7, -, 'fold)', and, 'GSTA1-3', '(', 550, -, 'fold,', 150, -, fold, and, 300, -, 'fold)'])].
[sujeto(['Exposure', to, 'DOX']), verbo([led]), complemento([to, the, slight, increase, of, 'GCS', expression, as, well, as, 'GPX', activity, in, 'KB-V1', 'cells,', while, in, 'HeLa', cells, it, did, not])].
[sujeto(['Expression', of, 'ABCC1', '(', 'MRP1)', was, not]), verbo([increased]), complemento([in, any, of, the, tested, cell, lines])].
[sujeto(['Our', results, indicate, that, expression, of, 'GSTM1', and, 'GSTA1-3', genes, is, 'up-regulated', by, 'DOX', treatment, and]), verbo([suggest]), complemento([that, activity, of, these, genes, may, be, associated, with, drug, resistance, of, the, tested, cells])].
[sujeto(['At', day, 5, and, 15, 'post-infection', '(', 'PI),', an]), verbo([increase]), complemento([in, the, 'TBARS', levels, and, a, decrease, in, the, 'SOD', activity, '(', 'P&lt;0'])].
[sujeto(['GSH', and, 'GST', activities, were]), verbo([decreased]), complemento([in, infected, animals, at, day, 15, 'PI', '(', 'P&lt;0'])].
[sujeto(['Considering', the, proper, functioning, of, the, 'heart,', it, is, possible, that, the, changes, in, the, activity, of, these, enzymes]), verbo([involved]), complemento([in, the, oxidative, stress, may, be, 'related,', at, least, in, 'part,', in, the, pathophysiology, of, rats, infected, with, 'T'])].
[sujeto(['Exposure', to, particulate, air, pollution]), verbo([has]), complemento([been, associated, with, increased, cardiovascular, morbidity, and, 'mortality,', and, lower, blood, 'DNA', methylation, has, been, found, in, processes, related, to, cardiovascular, morbidity])].
[sujeto(['We', hypothesized, that, prolonged, exposure, to, particulate, pollution, would, be]), verbo([associated]), complemento([with, hypomethylation, of, repetitive, 'DNA', elements, and, that, this, association, would, be, modified, by, genes, involved, in, glutathione, metabolism, and, other, host, characteristics])].
[sujeto(['We', estimated, changes, in, repetitive, element, 'DNA', methylation]), verbo([associated]), complemento([with, ambient, particles, '(', particulate, matter, '≤', 2.5, µm, in, aerodynamic, 'diameter),', black, carbon, '(', 'BC),', and, sulfates, '(', 'SO₄),', with, mixed, models])].
[sujeto(['An', interquartile, range, '(', 'IQR)']), verbo([increase]), complemento([in, 'BC', over, a, 90, -, day, period, was, associated, with, a, decrease, of, 0.31, '%', 5, -, methylcytosine, '(', 5, 'mC)', '(', 95, '%', confidence, 'interval,', 0.12, -, 0.5, '%', ')', in, 'Alu'])].
[sujeto(['An', 'IQR']), verbo([increase]), complemento([in, 'SO₄', over, a, 90, -, day, period, was, associated, with, a, decrease, of, 0.27, '%', 5, mC, '(', 0.02, -, 0.52, '%', ')', in, 'LINE-1'])].
[sujeto(['Prolonged', exposure, to, 'BC', and, 'SO₄', particles, was]), verbo([associated]), complemento([with, hypomethylation, of, two, types, of, repetitive, elements])].
[sujeto(['Mouse', models, of, cystic, fibrosis, '(', 'CF)', indicate, that, sulfotransferase, '(', 'SULT)', 10.0, is, significantly]), verbo([induced]), complemento([in, livers, of, many, mice, lacking, cystic, fibrosis, transmembrane, receptor, '(', 'CFTR)', activity])].
[sujeto(['In', this, 'study,', human, 'MMNK-1', cholangiocytes, with]), verbo([repressed]), complemento(['CFTR', function, were, used, to, induce, 'SULT1E1', expression, in, human, 'HepG2', hepatocytes, to, investigate, whether, 'SULT1E1', can, be, increased, in, human, 'CF', liver])].
[sujeto(['CFTR', expression, was]), verbo([inhibited]), complemento([in, 'MMNK-1', cholangiocytes, using, 'CFTR-siRNA,', then, the, 'MMNK-1', and, 'HepG2', cells, were, 'co-cultured', in, a, 'membrane-separated', 'Transwell', system])].
[sujeto(['The', expression, of, 'estrogen-regulated', proteins, including, 'insulin-like', growth, factor, '(', 'IGF)-1,', 'glutathione-S-transferase', '(', 'GST)', 'P1', and, carbonic, anhydrase, '(', 'CA)', 'II', expression, are]), verbo([repressed]), complemento([in, the, 'HepG2', cells, cultured, with, the, 'CFTR-siRNA-MMNK-1', cells, apparently, in, response, to, the, increased, sulfation, of, 'beta-estradiol'])].
[sujeto(['Thus,', we]), verbo([have]), complemento([shown, that, 'co-culture', of, 'HepG2', hepatocytes, with, 'MMNK-1', cholangiocytes, with, siRNA, repressed, 'CFTR', expression, results, in, the, selective, induction, of, 'SULT1E1', in, the, 'HepG2', cells])].
[sujeto(['Loss', of, 'CFTR', function, in, cholangiocytes, may]), verbo([have]), complemento([a, paracrine, regulatory, effect, on, hepatocytes, via, the, induction, of, 'SULT1E1', and, the, increased, sulfation, of, 'beta-estradiol'])].
[sujeto(['The', four, cysteines, '(', 'Cys', 14, ',', 'Cys', 47, ',', 'Cys', 101, ',', and, 'Cys', 169, in, the, primary, 'sequence)', in, hGST, 'P1-1', are, susceptible, to, electrophilic, attack, 'and/or', oxidative, damage]), verbo([leading]), complemento([to, loss, of, enzymatic, activity])].
[sujeto(['Mutation', of, 'Cys', 47]), verbo([decreased]), complemento([the, affinity, for, the, substrate, 'GSH', but, not, for, the, cosubstrate, 1, -, 'chloro-2,4-dinitrobenzene', '(', 'CDNB)'])].
[sujeto([4, -, 'OHEN', also]), verbo([caused]), complemento([oxidative, damage, as, demonstrated, by, the, appearance, of, 'disulfide-bonded', species, on, nonreducing, 'SDS--PAGE', and, protection, of, 4, -, 'OHEN-mediated', enzyme, inhibition, by, free, radical, scavengers])].
[sujeto(['The', studies, of, thiol, group, titration, and, irreversible, kinetic, experiments, indicated, that, the, different, cysteines]), verbo([have]), complemento([distinct, reactivity, for, 4, -, 'OHEN;', 'Cys', 47, was, the, most, reactive, thiol, group, whereas, 'Cys', 169, was, resistant, to, modification])].
[sujeto(['These', results, demonstrate, that, hGST, 'P1-1', is, inactivated, by, 4, -, 'OHEN', through, two, possible, 'mechanisms:', '(', 1, ')', covalent, modification, of, cysteine, residues, and, '(', 2, ')', oxidative, damage]), verbo([leading]), complemento([to, proteins, inactivated, by, disulfide, bond, formation])].
[sujeto(['Immunoblot', analysis, showed, that, 'alpha-class', glutathione, 'S-transferase', '(', 'GST),', which, is, one, of, the, major, forms, in, adult, human, 'liver,', was]), verbo([expressed]), complemento([in, human, fetal, liver])].
[sujeto(['Mu-class', 'GST', was, also]), verbo([expressed]), complemento([in, fetal, liver])].
[sujeto(['The', majority, of, 'mu-class', 'GST']), verbo([expressed]), complemento([in, adult, liver, consisted, of, a, subunit, with, a, molecular, weight, of, 27, kDa, on, sodium, dodecyl, 'sulfate-polyacrylamide', gel, electrophoresis, '(', 'SDS-PAGE),', whereas, two, subunits, of, 27, and, 26, kDa, were, detected, in, fetal, liver, as, proteins, immunochemically, related, to, 'mu-class', 'GST'])].
[sujeto(['In', 'addition,', the, 'N-terminal', amino, acid, sequence, of, these, subunits]), verbo([suggested]), complemento([that, 'GSTs', related, to, rat, 'GST', 3, -, 3, expressed, in, fetal, liver, may, be, homodimeric, and, heterodimeric, proteins])].
[sujeto(['As', 'expected,', 'pi-class', 'GST', was]), verbo([found]), complemento([to, be, a, major, form, of, 'GST', in, fetal, liver, but, not, in, adult, liver])].
[sujeto(['These', results, indicate, that, several, isoenzymes, of, 'GST', are]), verbo([expressed]), complemento([in, human, fetal, 'liver,', but, they, are, not, the, same, as, those, in, adult, liver])].
[sujeto([&, 'quot;', 'GST', 'Yrs-Yrs', could, neither, be]), verbo([retained]), complemento([on, the, 'S-hexylglutathione', gel, column, nor, showed, any, activity, toward, 1, ',', 2, -, 'dichloro-4-nitrobenzene,', 4, -, nitrobenzyl, 'chloride,', and, 1, ',', 2, -, 'epoxy-3-(4\'-nitrophenoxy)propane'])].
[sujeto(['The', level, of, the, enzyme, varied, with, the, growth, 'cycle,']), verbo([increasing]), complemento([in, early, stationary, phase])].
[sujeto(['On', sodium, dodecyl, 'sulfate-polyacrylamide', gel, 'electrophoresis,', peak, 1, showed, two, bands, at, the, molecular, weights, of, 24, ',', 500, and, 25, ',', 0, ',', and, peak, 2, showed, a, single, band, at, the, molecular, weight, of, 25, ',', 0, ',', results]), verbo([suggesting]), complemento([that, both, were, dimeric, proteins])].
[sujeto(['GSH', was]), verbo([required]), complemento([for, the, catalysis, of, both, 'enzymes,', and, no, other, sulfhydryl, compounds, could, support, the, reaction])].
[sujeto(['Prostaglandin', 'H-E', isomerase, activity, of, peak, 2, enzyme, was, competitively]), verbo([inhibited]), complemento([by, 1, -, 'chloro-2,4-dinitrobenzene,', a, substrate, of, glutathione, 'S-transferase'])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, prostaglandin, 'H-E', isomerases, in, human, brain, cytosol, were, identical, with, anionic, forms, of, glutathione, 'S-transferase'])].
[sujeto(['The', enzyme, preparation]), verbo([has]), complemento([a, specific, activity, of, 44, 'mumol/min/mg', protein, and, recovery, was, more, than, 85, '%', of, the, enzyme, activity, in, the, crude, extract])].
[sujeto(['Different', storage, conditions]), verbo([have]), complemento([been, found, to, affect, the, enzyme, activity, and, the, loss, in, activity, was, marked, at, room, temperature, and, upon, repeated, freezing, and, thawing])].
[sujeto(['Air', pollution, is]), verbo([associated]), complemento([with, adverse, human, 'health,', but, mechanisms, through, which, pollution, exerts, effects, remain, to, be, clarified])].
[sujeto(['One']), verbo([suggested]), complemento([pathway, is, that, pollution, causes, oxidative, stress])].
[sujeto(['We']), verbo([found]), complemento([that, glutathione, 'S-tranferase', 'P1', '(', 'GSTP1,', 'rs1799811),', 'M1', and, catalase, '(', 'rs2284367)', and, 'group-specific', component, '(', 'GC,', 'rs2282679,', 'rs1155563)', significantly, or, marginally, significantly, modified, effects, of, 'OC', 'and/or', sulfate, with, larger, effects, among, those, carrying, the, wild, type, of, 'GSTP1,', 'catalase,', 'non-wild', type, of, 'GC', and, the, 'non-null', of, 'GSTM1'])].
[sujeto(['Polymorphisms', of, oxidative, 'stress-related', genes, modified, effects, of, 'OC', 'and/or', sulfate, on, 8, -, 'OHdG,']), verbo([suggesting]), complemento([that, effects, of, 'OC', or, sulfate, on, 8, -, 'OHdG', and, other, endpoints, may, be, through, the, oxidative, stress, pathway])].
[sujeto(['We']), verbo([have]), complemento([previously, demonstrated, that, glutathione, 'S-transferase', pi, '(', 'GST', 'pi)', is, overexpressed, in, 'SA7', 'cells,', an, arsenic, resistant, cell, line, derived, from, 'Chinese', hamster, ovary, '(', 'CHO)', cells])].
[sujeto(['However,', the, excretion, of, arsenic, from, 'SA7', cells, was, significantly]), verbo([inhibited]), complemento([by, the, 'GST', inhibitors, ethacrynic, acid, and, 'Cibacron', blue])].
[sujeto(['Furthermore,', when, 'GST', pi, levels, in, 'SA7N', cells, were, 're-elevated', by, zinc, sulfate, 'pretreatment,', arsenic, accumulation]), verbo([decreased]), complemento([and, arsenic, excretion, increased, to, levels, similar, to, those, in, 'SA7', cells])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'GST', pi, can, facilitate, the, excretion, of, arsenic])].
[sujeto(['Such', facilitation, by, 'GST', pi, is, unlikely, to, be]), verbo([associated]), complemento([with, 'multi-drug', resistant, 'P-glycoprotein,', since, no, overexpression, of, 'P-glycoprotein', was, detected, in, 'SA7N', and, 'SA7', cells])].
[sujeto(['Its', 'N-terminal', 'amino-acid', sequence]), verbo([has]), complemento([80, '%', identical, residues, to, that, of, rat, 'GST', 'P', and, human, 'GST', pi])].
[sujeto(['Treatment', with, 'Cibacron', 'Blue', or, ethacrynic, 'acid,', which, are, 'GST', 'inhibitors,', significantly]), verbo([decreased]), complemento([the, resistance, of, 'SA7', cells, to, sodium, arsenite])].
[sujeto(['The', regained, arsenic, resistance, was, well, correlated, with, the, levels, of, 'GST', pi, which, were]), verbo([induced]), complemento(['dose-dependently', by, zinc, sulphate])].
[sujeto(['Heat-shock', treatment, '(', 45, degrees, 'C', for, 10, 'min)', did, not]), verbo([increase]), complemento(['GST', pi, expression, or, arsenic, resistance, of, 'SA7N', cells])].
[sujeto(['The', results, indicate, that, 'GST', pi, is, possibly]), verbo([involved]), complemento([in, the, mechanism, of, arsenic, detoxification])].
[sujeto(['The', urinary, results, were]), verbo([expressed]), complemento([in, nanograms, per, milligram, of, creatinine, '(', 'ng/mg)'])].
[sujeto(['Both', children, with, 'SDNS', and, those, with, 'SRNS', were, characterized, by]), verbo([increased]), complemento([tubular, injury, marker, levels])].
[sujeto(['The', selectivity, of, certain, benzophenones, and, their, carbonyl, 'N-analogues', was, investigated, towards, the, human, 'GSTP1-1', allozymes, 'A,', 'B', and, 'C']), verbo([involved]), complemento([in, 'MDR'])].
[sujeto(['Enzyme', inhibition, 'kinetics,', aided, by, molecular, modelling, and, 'docking,', revealed, that, there, is, competition, with, the, substrate, 'CDNB', for, the, same]), verbo([binding]), complemento([site, on, the, allozyme, '(', 'Ki(13/A)', &, 'nbsp;=&nbsp;63'])].
[sujeto(['These', data, were, brought, into, context, by, an, in, silico, structural, comparative, analysis, of, the]), verbo([targeted]), complemento([proteins])].
[sujeto(['The', results, revealed, that, 'TCDD']), verbo([induce]), complemento(['Cyp1a1&gt;Cyp1a2&gt;Cyp1b1,', while, 'PAHs', and, 'PAH-containing', environmental, mixtures, induce, 'Cyp1a2&gt;Cyp1a1&gt;Cyp1b1', gene, expression, pattern])].
[sujeto(['In', all, 'samples,', 'Gsta2', was, predominantly]), verbo([expressed]), complemento([relative, to, 'Gstp'])].
[sujeto(['Alpha-', and, 'pi-GST', levels, significantly]), verbo([increased]), complemento([during, machine, perfusion])].
[sujeto(['The', adjusted, relative, risks, '(', 95, '%', confidence, 'interval)', of, 'DGF', with, each, 'log-unit']), verbo([increase]), complemento([in, base, and, post, 'pi-GST', were, 1.14, '(', 1.0, -, 1.3, ')', and, 1.36, '(', 1.1, -, 1.8, ')', ',', respectively])].
[sujeto(['Alpha-GST', was, not, independently]), verbo([associated]), complemento([with, 'DGF'])].
[sujeto(['We']), verbo([found]), complemento(['pi-GST', at, the, end, of, machine, perfusion, to, be, independently, associated, with, 'DGF'])].
[sujeto(['Diabetes', mellitus, and, its, complications]), verbo([have]), complemento([been, attributed, in, part, to, oxidative, 'stress,', against, which, antioxidant, enzymes, constitute, a, major, protective, mechanism])].
[sujeto(['But,', hepatic, level, and, activity, of, 'alpha-class', 'GST', were]), verbo([decreased]), complemento([and, 'peroxiredoxin-1', level, was, increased, in, 'GK', 'rats,', suggesting, that, upregulation, of, 'peroxiredoxin-1', compensates, for, downregulation, of, 'alpha-class', 'GST'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'alpha-class', 'GST', and, 'peroxiredoxin-1', in, liver, can, be, altered, during, the, early, stages, of, type, 2, diabetes, in, the, absence, of, obesity, and, severe, oxidative, stress])].
[sujeto(['The', 'Activator', 'Protein', 1, '(', 'AP-1)', transcription, factor, subunit, 'Fos-related', antigen, 1, '(', 'Fra-1)']), verbo([has]), complemento([been, implicated, in, liver, fibrosis])].
[sujeto(['Interestingly,', 'hepatocyte-specific', 'Fra-1', expression, is, not, sufficient, to]), verbo([trigger]), complemento([the, 'disease,', although, 'Fra-1', expression, leads, to, dysregulation, of, 'fibrosis-associated', genes])].
[sujeto(['Strikingly,', manipulating, 'Fra-1', expression, affects, genes]), verbo([involved]), complemento([in, hepatic, transport, and, 'detoxification,', in, particular, glutathione, 'S-transferases'])].
[sujeto(['Molecular', analyses, indicate, that, 'Fra-1']), verbo([binds]), complemento([to, the, promoters, of, cxcl9, and, gstp1, in, vivo])].
[sujeto(['Furthermore,']), verbo([loss]), complemento([of, 'Fra-1', 'sensitizes,', while, hepatic, 'Fra-1', expression, protects, from, 'acetaminophen-induced', liver, 'damage,', a, paradigm, for, 'glutathione-mediated', acute, liver, failure])].
[sujeto(['These', data, define, a, novel, function, of, 'Fra-1/AP-1', in]), verbo([modulating]), complemento([the, expression, of, detoxification, genes, and, the, adaptive, response, of, the, liver, to, bile, 'acids/xenobiotic', overload])].
[sujeto(['Lung', cancer, '(', 'LC)', and, chronic, obstructive, pulmonary, disease, '(', 'COPD)', commonly, coexist, in, 'smokers,', and, the, presence, of, 'COPD']), verbo([increases]), complemento([the, risk, of, developing, 'LC'])].
[sujeto(['A', total, of, 40, proteins, were, differentially]), verbo([expressed]), complemento([in, the, 'LC', 'and/or', 'COPD', groups, as, compared, with, the, control, group])].
[sujeto(['The', main, networks]), verbo([involved]), complemento([were, related, to, inflammatory, 'signalling,', free, radical, scavenging, and, oxidative, stress, 'response,', and, glycolysis, and, gluconeogenesis, pathways])].
[sujeto(['In', 'conclusion,', the, protein, profiles, identified, contribute, to, elucidate, the, underlying, pathogenic, pathways, of, both, 'diseases,', and]), verbo([provide]), complemento([new, tools, of, potential, use, as, biomarkers, for, the, early, diagnosis, of, 'LC'])].
[sujeto(['Mapping', of, our, proteins, onto, biological, pathways, and, disease, networks, demonstrated, that, 22, proteins, were, linked, to, inflammatory, signalling, '(', 'p-value:', 1.35, 10, '(', -, 8, ')', -, 1.42, 10, '(', -, 2, ')', ')', ',', 15, proteins, were]), verbo([associated]), complemento([with, free, radical, scavenging, and, oxidative, stress, response, '(', 'p-value:', 4.93, 10, '(', -, 11, ')', -, 1.27, 10, '(', -, 2, ')', ')', ',', and, 9, proteins, were, related, with, glycolysis, and, gluconeogenesis, pathways, '(', 'p-value:', 7.39, 10, '(', -, 9, ')', -, 1.58, 10, '(', -, 2, ')', ')'])].
[sujeto(['We', looked, specifically, for, 'TLR', expression, as, they, may]), verbo([mediate]), complemento([kidney, injury])].
[sujeto(['Urinary', 'TLR4', was, significantly, higher, in, patients, with, renal, dysfunction]), verbo([associated]), complemento([with, 'infection/inflammation'])].
[sujeto(['Kidney', biopsies, from, 'non-HRS', renal, dysfunction, patients, showed, tubular, damage, with, evidence, of]), verbo([increased]), complemento([tubular, expression, of, 'TLR4,', and, 'caspase-3'])].
[sujeto(['The', data]), verbo([provide]), complemento([proof, of, concept, that, renal, dysfunction, in, patients, with, cirrhosis, with, superimposed, inflammation, is, associated, with, significant, tubular, injury, and, apoptosis, and, with, increased, renal, expression, and, urinary, excretion, of, the, 'TLR4,', suggesting, a, potential, role, of, 'TLR4', as, mediator, of, renal, injury])].
[sujeto(['Glycidamide', '(', 'GA),', formed, via, 'epoxidation,', presumably]), verbo([mediated]), complemento([by, cytochrome, 'P450', 20.0, ',', is, considered, to, be, the, active, metabolite, that, plays, a, central, role, in, the, genotoxicity, of, 'AA'])].
[sujeto(['The', aim, of, this, work, was, to, evaluate, the, cytogenetic, damage]), verbo([induced]), complemento([by, 'AA', and, 'GA', in, cultured, human, lymphocytes, by, use, of, the, sister, chromatid, exchange, '(', 'SCE)', assay])].
[sujeto(['Furthermore,', this]), verbo([report]), complemento([addresses, the, role, of, individual, genetic, polymorphisms, in, key, genes, involved, in, detoxification, and, 'DNA-repair', pathways, '(', 'BER,', 'NER,', 'HRR', and, 'NHEJ)', on, the, induction, of, 'SCE', by, 'GA'])].
[sujeto(['While', 'AA']), verbo([induced]), complemento([the, number, of, 'SCE/metaphase', only, 'slightly,', especially, for, the, highest, concentration, tested, '(', 2000, 'μM),', 'GA', markedly, induced, 'SCEs', in, a, 'concentration-dependent', manner, up, to, concentrations, of, 750, 'μM,', leading, to, an, increase, in, 'SCEs', of, up, to, about, 10, -, fold, compared, with, controls])].
[sujeto(['The', role, of, metallothionein, '(', 'MT)', in, mitigation, of, oxidative, 'DNA', damage, '(', 'ODD)']), verbo([induced]), complemento([by, either, cadmium, '(', 'Cd)', or, the, direct, oxidant, hydrogen, peroxide, '(', 'H(2)O(2))', was, systematically, examined, using, 'MT-I/II', double, knockout, '(', 'MT-null)', or, 'MT-competent', 'wild-type', '(', 'WT)', cells])].
[sujeto(['Cd']), verbo([induced]), complemento(['concentration-related', 'MT', increases, in, 'WT', 'cells,', while, the, basal, levels, were, undetectable, and, not, increased, by, 'Cd', in, 'MT-null', cells])].
[sujeto(['ODD,', measured, by, the, 'immuno-spin', trapping, 'method,', was, minimally]), verbo([induced]), complemento([by, 'sub-toxic', 'Cd', levels, '(', 1, or, 5, 'μM;', 24, 'h)', in, 'WT', 'cells,', but, markedly, increased, in, 'MT-null', cells, '(', &, 'gt;430', '%', ')'])].
[sujeto(['Similarly,', 'ODD', was]), verbo([induced]), complemento([to, higher, levels, by, lower, concentrations, of, 'H(2)O(2)', in, 'MT-null', cells, than, 'WT', cells])].
[sujeto(['Cd']), verbo([increased]), complemento([the, expression, of, the, oxidant, defense, 'genes,', 'HO-1,', and, 'GSTa2', to, a, much, greater, extent, in, 'MT-null', cells, than, in, 'WT'])].
[sujeto(['Cd', or, 'H(2)O(2)', exposure]), verbo([increased]), complemento([the, expression, of, key, transport, 'genes,', 'Mrp1', and, 'Mrp2,', in, 'WT', cells, but, not, in, 'MT-null', cells])].
[sujeto(['MT-deficient', cells, appear, to, adapt, to, 'Cd', primarily, by, turning, on, oxidant, response, 'systems,', while, 'MT-competent', cells]), verbo([activate]), complemento(['MT', and, transport, systems])].
[sujeto(['In', patients, above, 40, 'years,', the, 'IL-10', rs1800890, 'T-allele', was]), verbo([associated]), complemento([with, lower, risk, for, 'HL', '(', 'TT', genotype, vs])].
[sujeto(['AG/AA', combined, 'genotypes,', 'OR', 0.7, '[', 0.47, -, 1.04, ']', ',', p, =, 0.07, ')', ',', and, the, 'GSTT1', deleted, genotype]), verbo([increased]), complemento([the, risk, for, 'HL', '(', 'OR', 3.17, '[', 1.97, -, 5.09, ']', ',', p, &, 'lt;', 0.001, ')', regardless, of, age])].
[sujeto(['GST', isozymes]), verbo([have]), complemento([been, implicated, in, chemotherapeutic, drug, resistance])].
[sujeto(['When', the, varied, substrate, was, 'GSH,', amitriptyline]), verbo([inhibited]), complemento([both, isozymes, competitively, and, similar, 'K(i)', values, were, found, for, 'GST-π', '(', 'K(i)', =, 1.61, ±, 0.17, 'mM)', and, 'GST-α', '(', 'K(i)', =, 1.45, ±, 0.2, 'mM)'])].
[sujeto(['Amitriptyline,', in, addition, to, its, antidepressant, 'effect,', might, also]), verbo([have]), complemento([a, minor, supportive, role, on, the, effectiveness, of, the, anticancer, drugs, by, decreasing, their, elimination, through, inhibiting, 'GST-π', and, 'GST-α'])].
[sujeto(['Glutathione', 'S-transferase', '(', 'GST)', 'M1', null, genotype]), verbo([has]), complemento([been, reported, playing, a, significant, role, in, the, diabetes, mellitus, '(', 'DM)', susceptibility, in, 'Turkish', population])].
[sujeto(['We', investigated, whether, the, 'GSTM1,', 'GSTA1,', and, 'GSTP1', gene, polymorphisms, are]), verbo([associated]), complemento([with, posttransplantation, diabetes, mellitus, '(', 'PTDM)', in, 'Taiwan'])].
[sujeto(['These', overall, results]), verbo([suggested]), complemento([a, lack, of, strong, association, with, 'GSTA1,', 'GSTP1,', and, 'GSTM1', genetic, polymorphisms, to, the, susceptibility, of, 'PTDM', in, 'Taiwanese', 'RTRs'])].
[sujeto(['Glutathione-S-transferase', '(', 'GST)', subtype, α, and, π, are, differentially]), verbo([expressed]), complemento([in, adult, liver, tissue])].
[sujeto(['Patients', '(', 'R)', and, donors, '(', 'D)', were, grouped, according, to, graft]), verbo([loss]), complemento(['(', 'R1/D1)', or, positive, outcome, '(', 'R2/D2)', and, above, named, serum, parameters, were, compared, between, the, groups])].
[sujeto(['R1', showed, significantly]), verbo([increased]), complemento(['GST-α', and, significantly, lower, 'GST-π', levels, than, 'R2', patients, or, the, donors])].
[sujeto(['Graft', failure, was]), verbo([associated]), complemento([with, combined, low, 'GST-π', levels, in, donors, and, their, recipients, before, living, donor, liver, transplantation])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, high, 'GST-α', serum, levels, reflect, ongoing, liver, damage, while, 'GST-π', indicates, the, capacity, and, process, of, liver, regeneration])].
[sujeto(['Early-stage', invasive, breast, cancer, patients]), verbo([have]), complemento([commonly, undergone, 'breast-conserving', surgery, and, radiotherapy])].
[sujeto(['Deregulated', redox, systems]), verbo([provide]), complemento([cancer, cells, protection, from, increased, oxidative, 'stress,', such, as, that, induced, by, ionizing, radiation])].
[sujeto(['The']), verbo([nuclear]), complemento([and, cytoplasmic, expression, of, nine, redox, proteins, '(', 'glutathione,', glutathione, 'reductase,', 'glutaredoxin,', glutathione, peroxidase, 1, ',', 3, ',', and, 4, ',', and, glutathione, 'S-transferase-θ,', -, 'π,', and, -, 'α)', was, assessed, using, conventional, immunohistochemistry, on, a, tissue, microarray, of, 224, tumors])].
[sujeto([8, ')', 'and,', when, combined, with, a, low]), verbo([nuclear]), complemento([expression, '(', p, =])].
[sujeto(['Low']), verbo([nuclear]), complemento([and, cytoplasmic, expression, of, glutathione, peroxidase, 3, '(', p, =])].
[sujeto(['These', proteins, did, not, correlate, with, tumor, 'grade,']), verbo([suggesting]), complemento([their, function, might, be, specific, to, the, regulation, of, oxidative, stress, rather, than, alterations, of, tumor, phenotype])].
[sujeto(['Only']), verbo([nuclear]), complemento(['(', p, =])].
[sujeto(['If', incorporated, into, routine, diagnostic, 'tests,', they]), verbo([have]), complemento([the, potential, to, aid, clinicians, in, their, stratification, of, patients, into, more, tailored, treatment, regimens])].
[sujeto(['Future']), verbo([targeted]), complemento([therapies, to, these, systems, might, improve, the, efficacy, of, reactive, oxygen, 'species-inducing', 'therapies,', such, as, radiotherapy])].
[sujeto(['Since', the, early, 1960, 's,', glutathione, transferases, '(', 'GSTs)']), verbo([have]), complemento([been, described, as, detoxification, enzymes])].
[sujeto(['In', 'fact,', 'GSTs', are, the, most, important, enzymes]), verbo([involved]), complemento([in, the, metabolism, of, electrophilic, 'xenobiotic/endobiotic', compounds])].
[sujeto(['In', the, present, 'work,', we]), verbo([have]), complemento([resorted, to, density, functional, theory, '(', 'DFT)', and, to, potential, of, mean, force, '(', 'PMF)', calculations, to, determine, the, 'GSH', activation, mechanism, of, 'GSTP1-1', and, 'GSTM1-1', isoenzymes])].
[sujeto(['For', the, 'GSTP1-1', 'enzyme,', we]), verbo([have]), complemento([demonstrated, that, a, water, 'molecule,', after, an, initial, conformational, rearrangement, of, 'GSH,', can, assist, a, proton, transfer, between, the, 'GSH', cysteine, thiol, '(', 'GSH-SH)', and, the, 'GSH', glutamate, alpha, carboxylate, '(', 'GSH-COO(-))', groups])].
[sujeto(['The', energy, barrier]), verbo([associated]), complemento([with, the, proton, transfer, is, 11.36, 'kcal·mol(-1)'])].
[sujeto(['In', this, 'case,', two, water, 'molecules,', positioned, between, the, 'GSH-SH', and, the, ξ, 'N', atom, of, 'His107,', working, like, a, 'bridge,', are, able, to]), verbo([promote]), complemento([the, proton, transfer, between, these, two, active, groups, with, an, energy, barrier, of, 7.98, 'kcal·mol(-1)'])].
[sujeto(['Although', 'GST', 'A4-4', and, 'GST', 'A1-1']), verbo([have]), complemento([striking, structural, 'similarity,', 'GST', 'A4-4', was, insensitive, to, adduction, by, 'HNE', under, conditions, that, yield, modest, adduction, of, 'GST', 'A1-1', and, extensive, adduction, of, 'GST', 'P1-1'])].
[sujeto(['The', results, indicate, that, enzymes, that, metabolize, 'HNE', may]), verbo([have]), complemento([evolved, structurally, to, resist, covalent, adduction, by, it])].
[sujeto(['The', proportion, of, patients, with, abnormal, biomarker, results]), verbo([increased]), complemento([across, the, 'normo-,', 'micro-', and, macroalbuminuria, 'groups,', with, collagen, 'IV', '(', 26, ',', 58, ',', 65, '%', ')', and, πGST, '(', 11, ',', 25, ',', 35, '%', ')', but, not, αGST])].
[sujeto(['Longitudinal', studies, are, now]), verbo([required]), complemento([to, assess, whether, these, biomarkers, can, detect, early, renal, disease, with, greater, specificity, and, sensitivity, than, the, 'albumin/creatinine', ratio])].
[sujeto(['The', serum, glutathione, 'S-transferase', alpha, '(', 'α-GST)', concentration]), verbo([has]), complemento([been, used, as, a, marker, of, hepatic, condition])].
[sujeto(['We']), verbo([found]), complemento([serum, 'α-GST', concentrations, in, homozygous, changes, c])].
[sujeto(['Moreover,', 'GSTA1', wild, type, genotype, was]), verbo([associated]), complemento([with, increased, 'α-GST', concentration, at, 24, h, after, the, end, of, anaesthesia])].
[sujeto(['GSTP1', gene, polymorphism]), verbo([has]), complemento([an, impact, on, the, perioperative, serum, 'α-GST', concentration, in, patients, undergoing, sevoflurane, anaesthesia])].
[sujeto(['GM', administration, resulted, in, a, more, pronounced]), verbo([increase]), complemento([of, sCr, compared, with, control, '(', 13, '[', 12, -, 28, ']', vs])].
[sujeto(['GM', administration, to, neonates, is]), verbo([associated]), complemento([with, renal, damage, reflected, by, a, more, pronounced, increase, in, sCr, preceded, by, urinary, excretion, of, biomarkers])].
[sujeto(['Two', 'SNPs', '(', 'GSTO2:', rs7085725, and, 'GSTP1:', 'rs4147581)', were, significantly]), verbo([associated]), complemento([with, overall, survival, in, 'HCC', patients, '(', 'P', =, 0.035, and, 0.042, ',', 'respectively)'])].
[sujeto(['In', stratified, 'analysis,', they, were, more, significantly]), verbo([associated]), complemento([with, overall, survival, in, patients, with, younger, 'age,', male, gender, and, cirrhosis])].
[sujeto(['Compared', with, the, patients, carrying, no, unfavorable, 'genotypes,', those, carrying, 2, unfavorable, genotypes, had, a, 1.7, -, fold]), verbo([increased]), complemento([risk, of, death, '(', 'P', &, 'lt;', 0.001, ')'])].
[sujeto(['Additionally,', we]), verbo([found]), complemento([that, heavy, smoking, resulted, in, a, significantly, worse, overall, survival, in, those, patients, carrying, variant, alleles, of, rs7085725, '(', 'HR', =, 2.07, ',', 95, '%', 'CI:', 1.13, -, 3.76, ',', 'P', =, 0.018, ')'])].
[sujeto(['The', distributions, of, 'GSTO2:', rs7085725, and, 'GSTP1:', rs4147581, genotypes, were]), verbo([associated]), complemento([with, altered, gene, expression, and, contributed, to, influences, on, overall, survival])].
[sujeto(['Our', study]), verbo([provides]), complemento([the, first, evidence, that, 'GSTO2', and, 'GSTP1', gene, polymorphisms, may, serve, as, independent, prognostic, markers, for, 'HCC', patients])].
[sujeto(['Glutathione', 'S-transferases', '(', 'GST)', 'A1', and, 'P1', are, crucial, enzymes]), verbo([involved]), complemento([in, the, biotransformation, of, 'drugs,', 'carcinogens,', and, 'toxins,', and, their, activity, may, influence, drug, 'response,', susceptibility, to, 'diseases,', and, carcinogenesis])].
[sujeto(['The', genes, encoding, these, 'enzymes,', 'GSTA1', and, 'GSTP1,']), verbo([have]), complemento([been, examined, in, many, studies, because, of, their, genetic, 'variability,', which, may, affect, enzymatic, activity])].
[sujeto(['We']), verbo([found]), complemento([that, the, distribution, of, the, alleles, 'GSTA1*A/*B', and, 'GSTP1*A,', *, 'B,', and, *, 'C', in, the, 'Polish', population, correspond, to, the, results, of, studies, in, 'Caucasians'])].
[sujeto(['Although', chemoresistance, is, a, multifactorial, 'phenomenon,', many, studies]), verbo([have]), complemento([demonstrated, that, altered, drug, metabolism, through, the, expression, of, phase, 'II', conjugating, 'enzymes,', including, glutathione, transferases, '(', 'GSTs),', in, tumor, cells, can, be, directly, correlated, with, resistance, against, a, wide, range, of, marketed, anticancer, drugs])].
[sujeto(['Former', and, ongoing, clinical, trials]), verbo([have]), complemento([confirmed, 'GSTP1', inhibition, as, a, principle, for, antitumor, therapy])].
[sujeto(['A', set, of, novel, inhibitors, exhibit, low, micromolar, to, high, nanomolar, inhibition, of, 'GSTP1,']), verbo([revealed]), complemento([preliminary, 'SAR', for, further, lead, optimization])].
[sujeto(['Importantly,', high, selectivity, over, another, two, human, 'GST', classes, '(', 'GSTA1', and, 'GSTM2)']), verbo([has]), complemento([been, achieved])].
[sujeto(['NRF2', transcription, factor, is]), verbo([involved]), complemento([in, modulation, of, various, antioxidant, and, metabolic, genes, 'and,', 'therefore,', may, modulate, 'anti-carcinogenic', potential])].
[sujeto(['A', significantly, higher, 'BC', risk, was]), verbo([associated]), complemento([with, 'GSTM1', null, genotype, after, adjusting, to, 'age,', sex, and, smoking, habit, '(', 'OR', 1.85, ',', 95, '%', 'CI', 1.3, -, 2.62, ;, 'P', =, 0.001, ')'])].
[sujeto(['GSTT1', null, '(', 'OR', 0.5, ',', 95, '%', 'CI', 0.31, -, 0.81, ;, 'P', =, 0.005, ')', and, 'GSTP1', 'Val105Val', '(', 'OR', 0.52, ',', 95, '%', 'CI', 0.27, -, 0.98, ;, 'P', =, 0.04, ')', genotypes, were]), verbo([associated]), complemento([with, reduced, 'BC', risk, separately, or, in, combination, '(', 'OR', 0.24, ',', 95, '%', 'CI', 0.11, -, 0.51, ;, 'P', &, 'lt;', 0.0001, ')', '(', 'P', heterogeneity, =, 0.01, ')'])].
[sujeto(['The', 'gene-gene', and, 'gene-environment', interactions]), verbo([associated]), complemento([with, combined, 'GSTP1/GSTT1', and, combined, 'GSTT1/SOD2', genetic, polymorphisms, along, with, cigarette, smoking, habit, may, play, a, significant, role, in, 'BC', risk, modulation])].
[sujeto(['The', glutathione, 'S-transferase', 'M1-null', genotype, also]), verbo([enhanced]), complemento([the, risk, of, bladder, cancer, among, subjects, exposed, to, solvents, '(', 'OR', =, 6, ',', 5, ',', 95, '%', 'CI', =, 2.1, -, 19.7, ',', p, =, 0.001, ')'])].
[sujeto(['However,', in, association, with, occupational, 'exposure,', low, activity, glutathione, 'S-transferase', 'A1', and, glutathione, 'S-transferase', 'M1-null', as, well, as, glutathione, 'S-transferase', 'T1-active', genotypes]), verbo([increase]), complemento([individual, susceptibility, to, bladder, cancer])].
[sujeto(['SM']), verbo([increases]), complemento([the, endogenous, production, of, reactive, oxygen, species, '(', 'ROS)'])].
[sujeto(['Seven', normal, and, 20, 'SM']), verbo([induced]), complemento(['COPD', individuals, were, studied])].
[sujeto(['GSTP1-immunoreactivity', was, strongly]), verbo([expressed]), complemento([in, luminal, border, of, normal, samples])].
[sujeto(['Patients', with, localized, 'high-risk', soft, tissue, sarcomas, '(', 'STS)', of, the, limbs, and, trunk, wall, still]), verbo([have]), complemento([a, considerable, metastatic, recurrence, rate, of, more, than, 50, '%', ',', in, spite, of, adjuvant, chemotherapy])].
[sujeto(['The', series, of, 102, patients]), verbo([found]), complemento([41, events, of, recurrence, and, 37, of, death, with, a, median, 'follow-up', of, 68, months])].
[sujeto(['This']), verbo([finding]), complemento([deserves, attention, as, it, points, to, a, new, targetable, protein, in, 'STS'])].
[sujeto(['The', genetic, variants, of, 'xenobiotic-metabolizing', 'enzymes,', such, as, those, encoded, by, 'glutathione-S-transferase', '(', 'GST)', 'genes,', may, be]), verbo([associated]), complemento([with, the, risk, of, coronary, artery, disease, '(', 'CAD)'])].
[sujeto(['Both', univariate, and, multivariate, logistic, regression, analyses]), verbo([found]), complemento([no, significant, associations, between, 'CAD', and, the, other, genetic, 'variants,', either, separately, or, in, combination])].
[sujeto(['In', 'addition,', no, effects, of, interactions, between, the, genotypes, and, environmental, 'factors,', such, as, cigarette, 'smoking,', were, significantly]), verbo([associated]), complemento([with, the, risk, of, 'CAD'])].
[sujeto(['The', 'GST', genetic, variants, examined, were, not]), verbo([associated]), complemento([with, susceptibility, to, 'CAD', in, our, 'Taiwanese', cohort])].
[sujeto(['This', null, association]), verbo([requires]), complemento([further, confirmation, with, larger, samples])].
[sujeto(['To', construct, the, vectors, of, human, glutathione, 'S-transferase', 'A1', '(', 'GSTA1),', 'P1', '(', 'GSTP1),', 'T1(GSTT1)', genes, and]), verbo([express]), complemento([in, 'Escherichia', coli, '(', 'E'])].
[sujeto(['The', proteins, were]), verbo([expressed]), complemento([in, 'E'])].
[sujeto(['And', soluble, 'GSTA1,', 'GSTT1,', 'GSTP1', proteins, were]), verbo([expressed]), complemento([in, 'E'])].
[sujeto(['The', expression, plasmids, for, 'GSTA1,', 'GSTT1', and, 'GSTP1']), verbo([have]), complemento([been, constructed, and, the, recombinant, proteins, are, expressed, successfully])].
[sujeto(['Additionally,', 'RTR', that, had, 'DM', before, transplantation, '(', 'aHR:', 3.31, ;, 95, '%', 'CI:', 1.77, -, 6.2, ;, 'P', =, 0.0002, ')', or, changes, in, 'SCr', 6, to, 12, months, after, transplantation, '(', 'aHR:', 2.83, ;, 95, '%', 'CI:', 1.29, -, 6.19, ;, 'P', =, 0.0095, ')', had, an]), verbo([increased]), complemento([risk, of, developing, the, primary, outcome])].
[sujeto(['In', addition, to, the, adverse, role, played, by, 'DM,', the, 'GSTM1', null, genotype, also]), verbo([has]), complemento([an, unfavorable, influence, on, the, 'long-term', allograft, outcome, of, 'RTR'])].
[sujeto(['Nitrogen', monoxide, '(', 'NO)', plays, a, role, in, the, cytotoxic, mechanisms, of]), verbo([activated]), complemento([macrophages, against, tumor, cells, by, inducing, iron, release])].
[sujeto(['We', showed, that, 'NO-mediated', iron, efflux, from, cells]), verbo([required]), complemento([glutathione, '(', 'GSH)', '(', 'Watts,', 'R'])].
[sujeto([276, ',', 4724, -, 4732, ')', and, that, the, 'GSH-conjugate', 'transporter,', multidrug, 'resistance-associated', protein, 1, '(', 'MRP1),']), verbo([mediates]), complemento([this, release, potentially, as, a, 'dinitrosyl-dithiol', iron, complex, '(', 'DNIC;', 'Watts,', 'R'])].
[sujeto(['Recently,', glutathione, 'S-transferase', 'P1-1', '(', 'GST', 'P1-1)', was, shown, to]), verbo([bind]), complemento(['DNICs', as, 'dinitrosyl-diglutathionyl', iron, complexes])].
[sujeto(['Considering', this, and, that, 'GSTs', and, 'MRP1', form, an, integrated, detoxification, unit, with, 'chemotherapeutics,', we, assessed, whether, these, proteins, coordinately]), verbo([regulate]), complemento([storage, and, transport, of, 'DNICs', as, long, lived, 'NO', intermediates])].
[sujeto(['Cells', transfected, with, 'GSTP1', '(', but, not, 'GSTA1', or, 'GSTM1)', significantly]), verbo([decreased]), complemento(['NO-mediated', 59, 'Fe', release, from, cells])].
[sujeto(['This', 'NO-mediated', 59, 'Fe', efflux, and, the, effect, of, 'GST', 'P1-1', on]), verbo([preventing]), complemento([this, were, observed, with, 'NO-generating', agents, and, also, in, cells, transfected, with, inducible, nitric, oxide, synthase])].
[sujeto(['These', investigations, indicate, that, 'GST', 'P1-1']), verbo([acts]), complemento([to, sequester, 'NO', as, 'DNICs,', reducing, their, transport, out, of, the, cell, by, 'MRP1'])].
[sujeto(['To']), verbo([provide]), complemento([new, insights, into, the, genetic, basis, of, normal, tissue, 'radiosensitivity,', we, evaluated, the, association, between, eight, polymorphic, variants, located, in, six, genes, related, to, 'DNA', repair, 'mechanisms,', oxidative, 'stress,', and, fibroblast, proliferation, '(', 'XRCC1', 'Arg399Gln,', 'XRCC1', 'Arg194Trp,', 'TP53', 'Arg72Pro,', 'GSTP1', 'Ile105Val,', 'GSTA1', 'C-69T,', eNOS, 'G894T,', 'TGFβ1', 'C-509T,', and, 'TGFβ1', 'T869C)', and, the, risk, of, subcutaneous, fibrosis, in, a, retrospective, series, of, patients, who, received, radiotherapy, after, 'breast-conserving', surgery])].
[sujeto(['After', adjustment, of, confounding, 'factors,', 'GSTP1', 'Ile105Val', '(', odds, ratio, '[', 'OR]', 2.756, ;, 95, '%', 'CI,', 1.188, -, 6.393, ;, p, =, 0.018, ')', ',', 'GSTA1', 'C-69T', '(', 'OR', 3.223, ;, 95, '%', 'CI,', 1.176, -, 8.826, ;, p, =, 0.022, ')', ',', and, 'TGFβ1', 'T869C', '(', 'OR', 0.295, ;, 95, '%', 'CI,', 0.09, -, 0.964, ;, p, =, 0.043, ')', polymorphisms, were]), verbo([found]), complemento([to, be, significantly, associated, with, the, risk, of, 'Grade', 2, -, 3, 'radiation-induced', fibrosis])].
[sujeto(['In', the, combined, 'analysis,', carriers, of, three, risk, genotypes, were]), verbo([found]), complemento([to, be, at, higher, odds, for, the, development, of, 'Grade', 2, -, 3, fibrosis, than, were, patients, with, two, risk, genotypes, '(', 'OR', 4.415, ;, 95, '%', 'CI,', 1.553, -, 12.551, ',', p, =, 0.005, ')', or, with, no, or, one, risk, genotype, '(', 'OR', 8.563, ;, 95, '%', 'CI,', 2.671, -, 27.447, ;, p, =, 0.0003, ')'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, functional, variations, in, genes, involved, in, oxidative, stress, response, and, fibroblast, proliferation, may, modulate, the, development, of, 'radiation-induced', fibrosis, in, breast, cancer, patients])].
[sujeto(['The', results, of, the, combined, analysis, support, the, notion, that, approaches, based, on, the, combination, of, different, genetic, markers]), verbo([have]), complemento([the, potential, to, predict, normal, tissue, responses])].
[sujeto(['To', evaluate, the, association, between, polymorphisms]), verbo([involved]), complemento([in, 'DNA', repair, and, oxidative, stress, genes, and, mean, dose, to, whole, breast, on, acute, skin, reactions, '(', 'erythema)', in, breast, cancer, '(', 'BC)', patients, following, single, shot, partial, breast, irradiation, '(', 'SSPBI)', after, breast, conservative, surgery])].
[sujeto(['Similarly', a, higher, erythema, rate, was, also]), verbo([found]), complemento([in, the, presence, of, 'mut/het', of, 'XRCC1Arg194Trp', or, wt, of, 'GSTA1'])].
[sujeto(['The', 'Whole', breast, mean, dose, together, with, the, presence, of, some, polymorphic, genes]), verbo([involved]), complemento([in, 'DNA', repair, or, oxidative, stress, could, explain, the, erythema, observed, after, 'SSPBI,', but, further, studies, are, needed, to, confirm, these, results, in, a, larger, cohort])].
[sujeto(['Odds', ratios, for, grade, 3, and, 4, hematologic, toxicity, in, the, treated, group, and, hazard, ratios, for, 'DFS']), verbo([associated]), complemento([with, selected, functional, polymorphisms, in, 'CYP2B6CYP3A4GSTA1', and, 'GSTP1', were, estimated, by, logistic, regression, and, 'Cox', proportional, hazard, regression])].
[sujeto(['No', other, associations, between, single, nucleotide, polymorphisms, and, toxicity, or, survival, were]), verbo([found]), complemento([in, the, treated, or, untreated, group])].
[sujeto(['Known', genetic, variants, in, genes]), verbo([involved]), complemento([in, 'CP', pharmacokinetics, may, not, have, major, effects, on, 'DFS', in, breast, cancer, patients])].
[sujeto(['The', lower, risk, of, developing, 'high-grade', hematologic, toxicity, among, women, with, variant, 'GSTP1', alleles]), verbo([suggests]), complemento([that, genetic, markers, in, combination, with, clinical, factors, may, be, useful, in, defining, a, subgroup, of, women, who, are, less, susceptible, to, adverse, hematologic, toxicities, with, 'CP-containing', therapies])].
[sujeto(['Glutathione', 'S-transferases', '(', 'GSTs)', are, a, family, of, enzymes]), verbo([involved]), complemento([in, the, detoxification, of, noxious, agents])].
[sujeto(['Genes', encoding, for, 'GSTA1,', 'GSTP1,', 'GSTT1,', and, 'GSTM1', proteins, are, polymorphic, in, 'humans,', which, can, result, in, '(', 'partial)']), verbo([loss]), complemento([of, enzyme, activity])].
[sujeto(['Previous', epidemiologic, studies]), verbo([have]), complemento([associated, dysfunction, of, these, 'GST', genes, with, a, higher, risk, of, 'cancer,', but, this, is, still, controversial])].
[sujeto(['The', present, work, shows, that, the, homozygous, 'wild-type', 'GSTA1', genotype, is]), verbo([associated]), complemento([with, gastric, cancer, in, a, 'Vietnamese', 'population,', whereas, there, was, no, relationship, with, polymorphisms, in, 'GSTP1,', 'GSTT1,', or, 'GSTM1'])].
[sujeto(['To', selectively]), verbo([target]), complemento([these, cells, and, to, overcome, this, resistance, we, previously, have, developed, prodrugs, that, are, derivatives, of, existing, anticancer, drugs, '(', e])].
[sujeto(['When', cleaved, by, 'GSTs,', the, prodrug]), verbo([releases]), complemento([the, cytostatic, moiety, predominantly, in, 'GST', overexpressing, 'cells,', thus, sparing, normal, cells, with, moderate, enzyme, levels])].
[sujeto(['By', modifying, the, sulfonamide, it, is, possible, to, control, the, rate, of, drug]), verbo([release]), complemento([and, specifically, target, different, 'GSTs'])].
[sujeto(['ANS-DOX,', in, 'particular,', showed, a, desirable, cytotoxic, profile, by]), verbo([inducing]), complemento([toxicity, and, 'DNA', damage, in, a, 'GST-dependent', manner, compared, to, control, cells])].
[sujeto(['Furthermore,', we, show, that, the, mechanism, of, these, prodrugs]), verbo([involves]), complemento([a, reduction, in, 'GSH', levels, as, well, as, inhibition, of, the, redox, regulatory, enzyme, thioredoxin, reductase, 1, '(', 'TrxR1)', by, virtue, of, their, electrophilic, sulfonamide, moiety])].
[sujeto(['TrxR1', is, upregulated, in, many, tumors, and]), verbo([associated]), complemento([with, resistance, to, chemotherapy, and, poor, patient, prognosis])].
[sujeto(['Additionally,', the, prodrugs, potentially]), verbo([acted]), complemento([as, a, general, shuttle, system, for, 'DOX,', by, overcoming, resistance, mechanisms, in, cells])].
[sujeto(['Here', we, propose, that, 'GST-dependent', prodrugs]), verbo([require]), complemento([a, conversion, rate, &, 'quot;window&quot;', in, order, to, selectively, target, 'GST', overexpressing, 'cells,', while, limiting, their, effects, on, normal, cells])].
[sujeto(['Prodrugs', are, furthermore, a, suitable, system, to, specifically]), verbo([target]), complemento(['GSTs', and, to, overcome, various, drug, resistance, mechanisms, that, apply, to, the, parental, drug])].
[sujeto(['To', understand, the, impact, of, feeding, a, 'high-concentrate', diet, to, 'mid-lactating', goats, for, a, long, time, on, liver, metabolism, and, inflammatory, 'response,', two, dimensional, polyacrylamide, gel, electrophoresis, '(', 2, -, 'DE)', and, 'real-time', 'PCR', method, were, employed, to, detect, proteins, differentially]), verbo([expressed]), complemento([in, liver, and, their, mRNAs, expression, in, goats, fed, high, concentrate, diet, '(', 'HC)', or, low, concentrate, diet, '(', 'LC)'])].
[sujeto(['Twenty', differentially]), verbo([expressed]), complemento([spots, '(', '≥2'])].
[sujeto(['Differential']), verbo([expressed]), complemento([proteins, including, alpha, enolase, 1, '(', 'ENO1),', glutamate, dehydrogenase, 1, '(', 'GLUD1),', glutathione, 'S-transferase', 'A1', '(', 'GSTA1),', 'ATP', synthase, subunit, 5, β, '(', 'ATP5β),', superoxide, dismutase, '[', 'Cu-Zn]', '(', 'SOD1),', cytochrom, c, oxidase, subunit, 'Via', '(', 'COX6A1)', and, heat, shock, protein, 60, '(', 'HSP60)', were, further, verified, by, 'real-time', 'PCR', 'and/or', western, blot, at, mRNA, or, protein, expression, level])].
[sujeto(['Consistent', with, the, 2, -, 'DE', 'results,', a, significant]), verbo([decrease]), complemento([of, 'β-actin', protein, expression, and, 'SOD', enzyme, activity, was, observed, in, liver, of, 'HC', goats, '(', 'P', &, 'lt;', 0.05, ')', ',', while, 'ENO1', protein, expression, was, significantly, 'up-regulated', in, 'HC', compared, to, 'LC', goats, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['However,', western, blot, analysis, did, not, show, a, significant, difference, of, hepatic, 'HSP60', protein, between, 'HC', and, 'LC', 'group,', which, did, not, match, the]), verbo([decrease]), complemento([of, 'HSP60', content, detected, by, 2, -, 'DE', analysis])].
[sujeto(['Real-time', 'PCR', showed, that, glutathione, 'S-transferase', 'P1', '(', 'GSTP1)', and, 'SOD1', mRNA, expression, was, significantly]), verbo([decreased]), complemento([in, liver, of, 'HC', 'goats,', while, cytochrom, c, oxidase, '(', 'COX3)', and, 'ATPase', 8, '(', 'ATP8)', mRNAs, expression, were, markedly, increased, compared, to, 'LC', '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['Gene', 'Ontology', '(', 'GO)', analysis, revealed, that, 'HC', diet, resulted, in, altered, expression, of, proteins, related, to, catalytic, and, mitochondrial, metabolism, in, the, 'liver,', and, may]), verbo([increase]), complemento([the, stress, response, with, 'up-regulating', the, expression, of, differentiation, 14, '(', 'CD14)', cluster, and, serum, amyloid, 'A', '(', 'SAA)', as, well, as, 'C-reactive', protein, '(', 'CRP)', in, the, liver])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, feeding, high, concentrate, diet, to, lactating, goats, for, 10, wk, leads, to, the, activation, of, the, inflammatory, 'response,', and, decreases, the, 'anti-oxidant', 'capacity,', and, subsequently, impairs, the, mitochondrial, function, in, the, liver])].
[sujeto(['In', both, univariate, and, multivariate, 'analyses,', nominally, significant, associations, were]), verbo([found]), complemento([among, body, mass, index, '(', 'OR,', 3.14, ;, 95, '%', 'CI,', 8.5338, to, 1.1274, ;, 'p=0'])].
[sujeto(['The', analysis, of, the, factors]), verbo([involved]), complemento([in, individual, radiosensitivity, contributed, to, the, understanding, of, the, mechanisms, underlying, this, trait])].
[sujeto(['Benzene', is, a, known, human, carcinogen, which, must, be]), verbo([activated]), complemento([to, benzene, oxide, '(', 'BO)', to, exert, its, carcinogenic, potential])].
[sujeto(['This', process, may, be, catalyzed, by, glutathione, 'S-transferases', '(', 'GSTs),', but, kinetic, data, for, this, reaction]), verbo([have]), complemento([not, been, published])].
[sujeto(['Oxidative', stress, is]), verbo([recognized]), complemento([as, an, important, factor, in, progressive, myoclonus, epilepsy, '(', 'PME)'])].
[sujeto(['Genetic', polymorphism, of, glutathione, 'S-transferases', '(', 'GSTs),', which, are]), verbo([involved]), complemento([in, both, protection, from, oxidative, damage, and, 'detoxification,', might, alter, the, capacity, for, protecting, tissues, from, exogenous, and, endogenous, oxidants])].
[sujeto(['Carriers', of, combined, 'GSTA1-', active, and, 'GSTT1-null', genotype, were, at, 'highest,', 7.55, -, fold]), verbo([increased]), complemento([risk, of, 'PME'])].
[sujeto(['Only', 'SOD', activity, was]), verbo([increased]), complemento([in, 'GSTT1-null', when, compared, to, corresponding, active, genotype])].
[sujeto(['GSTT1-null', genotype, might, be]), verbo([associated]), complemento([with, the, increased, risk, and, enhanced, susceptibility, to, oxidative, stress, in, 'PME', patients])].
[sujeto(['BU']), verbo([has]), complemento([been, proven, to, have, better, 'bioavailability,', reliable, systemic, drug, exposure, with, more, predictable, blood, levels, and, lower, toxicity, than, oral, 'BU', when, used, as, part, of, conditioning, regimens, before, hematopoietic, 'SCT', '(', 'HSCT)'])].
[sujeto(['Some', studies]), verbo([have]), complemento([shown, that, 'once-daily', i])].
[sujeto(['Recently,', valuable, characteristics, of, menstrual, blood, stem, cells, '(', 'MenSCs)']), verbo([have]), complemento([impelled, scientists, to, take, its, advantages, for, cell, therapy, of, different, diseases, including, liver, disorders])].
[sujeto(['Based', on, immunofluorescent, staining, and, 'real-time', 'PCR', 'data,', the, differentiated, 'MenSCs', could]), verbo([express]), complemento([functional, hepatocyte, markers, at, mRNA, 'and/or', protein, levels, suggesting, development, of, 'hepatocyte-like', cells, from, 'MenSCs'])].
[sujeto(['Animal', studies, in, rodent, and, in, vitro, studies, indicate, compensatory, role, of]), verbo([nuclear]), complemento([factor, '(', 'erythroid-derived', 2, ')', -, like, '(', 'Nrf2)', and, 'Nrf2-regulated', antioxidant, and, phase, 'II', biotransformation, enzymes, for, the, dietary, selenium, '(', 'Se)', deficiency, or, for, the, loss, of, selenoproteins])].
[sujeto(['Mean', plasma, 'Se', level, was]), verbo([found]), complemento([to, be, 51.1, '±15'])].
[sujeto(['The', multivariate, linear, regression, adjusting, for, selenium, status, showed, that, plasma, 'Se', level, was, significantly, inversely]), verbo([associated]), complemento([only, with, expression, of, 'GSTP1', '(', 'β-coef'])].
[sujeto(['NRF2', expression, was, inversely]), verbo([associated]), complemento([with, age, '(', 'r=-0'])].
[sujeto(['The', findings, may]), verbo([suggest]), complemento([a, possible, link, between, plasma, 'Se', level, and, cytoprotective, response, at, gene, level, in, humans])].
[sujeto(['Recently,', neferine]), verbo([has]), complemento([attracted, attention, for, its, 'anti-tumor', activities])].
[sujeto(['Approaches', using, chemical, inhibitors, and, recombinant, human, enzymes, to, characterize, the]), verbo([involved]), complemento([enzymes, and, kinetic, studies, indicated, that, the, demethylation, of, neferine, by, cytochrome, 'P450', '(', 'CYP)', 2, 'D6', and, 'CYP3A4', fitted, a, biphasic, kinetic, profile])].
[sujeto(['Based', on, its, structure, containing, 'para-methylene', phenol, and, results, from, a, product, ion, 'scan,', 'GSH', tends, to, conjugate, with, 'C9\'', after, undergoing, oxidative, metabolism, to, form, the]), verbo([binding]), complemento([site, predominated, by, 'CYP3A4'])].
[sujeto(['In', a, 3, -, '[', 4, ',', 5, -, 'dimethylthiazol-2-yl]-2,5', diphenyltetrazolium, bromide, 'assay,', combined, with, the, 'GSH', modulators, 'l-buthionine', sulfoximine, or, 'N-acetyl-l-cysteine,', neferine, treatment, of, 'MDCK-hCYP3A4', and, 'HepG2', cells, revealed, that, 'CYP3A4', expression, and, cellular, 'GSH', content, could]), verbo([cause]), complemento([an, 'EC50', shift])].
[sujeto(['Metabolic', activation]), verbo([mediated]), complemento([by, 'CYP3A4', and, 'GSH', depletion, significantly, enhanced, 'neferine-induced', cytotoxicity])].
[sujeto(['Genotypes', '(', 'A', /, 'B', +, 'B', /, 'B)', were]), verbo([associated]), complemento([with, protection, '(', 'OR', =, 0.61, ',', 95, '%', 'CI', =, 0.4, -, 0.92, ')', for, 'PCa', in, comparison, to, genotype, 'A', /, 'A'])].
[sujeto(['The', distribution, of, genotype, frequencies, of, the, polymorphism, 'GSTA1', was, statistically, different, between, the, case, and, control, groups, '(', p, =, 0.023, ')', ',', and, the, presence, of, genotypes, 'A', /, 'B', and, 'B', /, 'B']), verbo([suggests]), complemento([a, protective, role, against, the, risk, of, 'PCa', compared, to, genotype, 'A', /, 'A'])].
[sujeto(['This', is, the, first, study, that]), verbo([reports]), complemento([the, genotypic, frequency, of, this, polymorphism, and, its, association, with, 'PCa', in, a, 'Brazilian', population, sample])].
[sujeto(['To', investigate, the, protective, effect, of, 'α-lipoic', acid, '(', 'a-LA)', on, the, hepatocarcinogenic, process]), verbo([promoted]), complemento([by, thioacetamide, '(', 'TAA),', we, used, a, 'two-stage', liver, carcinogenesis, model, in, 'N-diethylnitrosamine', '(', 'DEN)-initiated', and, 'TAA-promoted', rats])].
[sujeto(['We', examined, the, modifying, effect, of, 'co-administered', 'a-LA', on, the, liver, tissue, environment, surrounding, preneoplastic, hepatocellular, 'lesions,', with, particular, focus, on, hepatic, macrophages, and, the, mechanism, behind, the]), verbo([decrease]), complemento([in, apoptosis, of, cells, surrounding, preneoplastic, hepatocellular, lesions, during, the, early, stages, of, hepatocellular, tumor, promotion])].
[sujeto(['TAA']), verbo([increased]), complemento([the, number, and, area, of, glutathione, 'S-transferase', placental, form, '(', 'GST-P)(+)', liver, cell, foci, and, the, numbers, of, proliferating, and, apoptotic, cells, in, the, liver])].
[sujeto(['Co-administration', with, 'a-LA']), verbo([suppressed]), complemento([these, effects])].
[sujeto(['TAA', also]), verbo([increased]), complemento([the, numbers, of, 'ED2(+),', 'cyclooxygenase-2(+),', and, heme, 'oxygenase-1(+)', hepatic, macrophages, as, well, as, the, number, of, 'CD3(+)', lymphocytes])].
[sujeto(['These', effects, were, also]), verbo([suppressed]), complemento([by, 'a-LA'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, hepatic, macrophages, producing, proinflammatory, factors, may, be, activated, in, 'TAA-induced', tumor, promotion])].
[sujeto(['a-LA', may]), verbo([suppress]), complemento(['tumor-promoting', activity, by, suppressing, the, activation, of, these, macrophages, and, the, subsequent, inflammatory, responses])].
[sujeto(['Furthermore,', 'a-LA', may]), verbo([suppress]), complemento(['tumor-promoting', activity, by, suppressing, the, 'DR5-mediated', extrinsic, pathway, of, apoptosis, and, the, subsequent, regeneration, of, liver, cells, outside, 'GST-P(+)', foci])].
[sujeto(['Gastric', cancer, is, one, of, the, most, common, malignancies, and, remains, the, second]), verbo([leading]), complemento([cause, of, 'cancer-related', death, worldwide])].
[sujeto(['Disruption', of, epigenetic, processes, can]), verbo([lead]), complemento([to, altered, gene, function, and, malignant, cellular, transformation])].
[sujeto(['Recent', advancements, in, the, rapidly, evolving, field, of, cancer, epigenetics]), verbo([have]), complemento([shown, extensive, reprogramming, of, every, component, of, the, epigenetic, machinery, in, 'cancer,', including, 'DNA', 'methylation,', histone, 'modifications,', nucleosome, 'positioning,', noncoding, 'RNAs,', and, microRNAs])].
[sujeto(['Aberrant', 'DNA', methylation, in, the, promoter, regions, of, 'gene,', which]), verbo([leads]), complemento([to, inactivation, of, tumor, suppressor, and, other, 'cancer-related', genes, in, cancer, 'cells,', is, the, most, 'well-defined', epigenetic, hallmark, in, gastric, cancer])].
[sujeto(['The', advantages, of, gene, methylation, as, a]), verbo([target]), complemento([for, detection, and, diagnosis, of, cancer, in, biopsy, specimens, and, 'non-invasive', body, fluids, such, as, serum, and, gastric, washes, have, led, to, many, studies, of, application, in, gastric, cancer])].
[sujeto(['This', review, focuses, on, the, most, common, and, important, phenomenon, of, 'epigenetics,', 'DNA', 'methylation,', in, gastric, cancer, and, illustrates, the, impact, epigenetics]), verbo([has]), complemento([had, on, this, field])].
[sujeto(['The', aim, of, this, study, was, to]), verbo([find]), complemento([out, the, profile, of, cellular, glutathione, '(', 'GSH)', and, 'GSH', 'S-transferase', '(', 'GST)', in, hepatocytes, differentiated, from, adult, mesenchymal, stem, cells, '(', 'MSC)'])].
[sujeto(['For', this, 'purpose,', we]), verbo([have]), complemento([derived, functionally, active, 'hepatocyte-like', cells, from, normal, human, multipotent, adult, 'MSC'])].
[sujeto(['The', results, showed, that, there, is, more, than, threefold]), verbo([increase]), complemento([in, 'GST', catalytic, activity, in, hepatocytes, recovered, by, day, 14, of, differentiation])].
[sujeto(['Under', similar, 'conditions,', only, differentiated, 'hepatocyte-like', cells]), verbo([expressed]), complemento(['GST-A1-1', mRNA])].
[sujeto(['These', results, were, further, confirmed, by, showing, that, the, undifferentiated, cells]), verbo([expressed]), complemento([both, 'GST-A', and, 'GST-P', proteins])].
[sujeto(['These', data, may]), verbo([suggest]), complemento([that, hepatogenic, differentiation, of, human, bone, marrow, 'MSC', is, accompanied, with, the, regulation, of, factors, participating, in, 'GSH', conjugation, pathway])].
[sujeto(['Glutathione', 'S-transferase', '(', 'GST)', enzymes]), verbo([involved]), complemento([in, the, detoxification, of, reactive, metabolites, of, carcinogens, may, be, important, in, modulating, susceptibility, to, cancers])].
[sujeto(['In', 'summary,', this, is, the, first, study, to]), verbo([report]), complemento([associations, between, glutathione, 'S-transferase', 'T1,', 'M1,', 'P1', and, 'A1', gene, polymorphisms, and, breast, cancer, in, 'Thai', patients])].
[sujeto(['While', 'GST', genotypes, may, not, be]), verbo([associated]), complemento([with, 'susceptibility,', a, 'GSTP1', polymorphism, '(', 'Ile105Val)', may, be, related, to, progression, of, breast, cancer])].
[sujeto(['Kelch-like', 'ECH-associated', protein, 1, '(', 'Keap1),', a, 'BTB-Kelch', substrate, adaptor, protein, for, a, 'Cul3-dependent', ubiquitin, ligase, 'complex,']), verbo([regulates]), complemento([the, induction, of, the, phase, 2, 'enzymes,', such, as, glutathione, 'S-transferase', '(', 'GST),', by, repressing, the, transcription, factor, 'Nrf2'])].
[sujeto(['It', is, known, 'that,', in, the, human, gastrointestinal, 'tract,', both, 'GST', 'A1', and, 'P1', are, constitutively]), verbo([expressed]), complemento([as, the, major, 'GST', isozymes])].
[sujeto(['It', was, revealed, that, the, overexpression, of, 'Keap1', completely]), verbo([repressed]), complemento([the, constitutive, expression, of, 'GST', 'A1,', but, not, 'GST', 'P1'])].
[sujeto(['The', constitutive, 'GST', 'A1', expression, in, 'Caco-2', cells, was]), verbo([repressed]), complemento([by, disruption, of, 'E-cadherin-mediated', 'cell-cell', 'adhesion,', suggesting, the, correlation, between, epithelial, cell, polarization, and, induction, of, the, basal, 'GST', 'A1', expressions, during, 'Caco-2', differentiation])].
[sujeto(['Keap1', overexpression, indeed]), verbo([inhibited]), complemento([the, activation, of, the, small, guanosine, triphosphatase, 'Rac1', on, the, formation, of, 'E-cadherin-mediated', 'cell-cell', adhesion])].
[sujeto(['The', transfection, of, 'V12Rac1,', the, constitutively, active, 'Rac1', 'mutant,', into, 'Keap1-overexpressed', cells]), verbo([promoted]), complemento([the, basal, 'GST', 'A1', 'expression,', suggesting, that, 'Keap1', regulated, the, basal, 'GST', 'A1', expression, during, 'Caco-2', differentiation, via, 'Rac1', activation, on, the, formation, of, 'E-cadherin-mediated', 'cell-cell', adhesion])].
[sujeto(['The', results, of, this, study]), verbo([suggest]), complemento([the, involvement, of, a, novel, 'Keap1-dependent', signaling, pathway, for, the, induction, of, the, constitutive, 'GST', 'A1', expression, during, epithelial, cell, differentiation])].
[sujeto(['Type', 2, diabetes, is]), verbo([associated]), complemento([with, an, increased, production, of, reactive, oxygen, species, and, a, reduction, in, antioxidant, defenses])].
[sujeto(['The', risk, among, the, 'GSTA1*B', allele, carriers, was, significantly]), verbo([increased]), complemento([by, 'current-smoking', status, '(', adjusted, 'OR,', 3.7, ;, 95, '%', 'CI,', 1.1, -, 12.7, ;, vs])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([to, show, that, the, 'GSTA1*B', allele, is, a, potential, risk, factor, for, 'smoking-related', type, 2, diabetes])].
[sujeto(['Thus', amplicons, derived, from, unmethylated, 'DNA']), verbo([retain]), complemento([fewer, cytosines, and, their, lower, 'G', +, 'C', content, allows, for, their, amplification, at, the, lower, melting, 'temperatures,', while, limiting, amplification, of, the, corresponding, methylated, amplicons, '(', 'Bisulphite', 'Differential', 'Denaturation', 'PCR,', 'BDD-PCR)'])].
[sujeto(['BDD-PCR']), verbo([has]), complemento([the, potential, to, be, used, to, selectively, amplify, and, detect, aberrantly, demethylated, 'genes,', such, as, 'oncogenes,', in, cancers])].
[sujeto(['Additionally', 'BDD-PCR', can, be, effectively, utilized, in, improving, the, specificity, of, methylation, specific, 'PCR', '(', 'MSP)', by, limiting, amplification, of, 'DNA', that, is, not, fully, 'converted,', thus]), verbo([preventing]), complemento([misinterpretation, of, the, methylation, versus, 'non-conversion'])].
[sujeto(['Genotoxicity', of, tobacco, smoke]), verbo([has]), complemento([long, been, investigated, and, tobacco, smoke, is, considered, to, be, one, of, the, principal, human, carcinogens])].
[sujeto(['Although', its, role, in, 'DNA-damage', induction, and, cancer, development]), verbo([has]), complemento([been, 'documented,', the, mechanisms, by, which, this, happens, are, not, well, understood])].
[sujeto(['Many', chemical, constituents, of, tobacco, smoke, are, enzymatically, metabolized, by, 'phase-I', and, 'phase-II', 'enzymes,', but, modifications, in, coding, and]), verbo([regulating]), complemento([sequences, of, these, genes, could, influence, their, ability, to, detoxify, these, compounds])].
[sujeto(['In', this, 'work,', we, studied, several, enzymes]), verbo([involved]), complemento([in, the, metabolism, of, 'xenobiotics,', viz])].
[sujeto([the, glutathione, 'S-transferases', '(', 'GST)', 'M1,', 'T1,', 'P1', and, 'A1,', with, respect, to, their, influence, on, the, genotoxic, effects]), verbo([induced]), complemento([by, cigarette, smoking])].
[sujeto(['We']), verbo([found]), complemento([that, smoke, and, gender, are, the, two, variables, that, most, influence, the, 'DNA', damage])].
[sujeto(['Moreover,', a, significant]), verbo([increase]), complemento([in, frequency, of, micronuclei, in, 'bi-nucleated', cells, '(', 'BNMN)', was, found, in, 'smokers,', but, not, in, 'non-smokers'])].
[sujeto(['This']), verbo([increase]), complemento([seems, to, be, influenced, not, only, by, age, and, 'gender,', but, also, by, genetic, constitution])].
[sujeto(['Subjects', carrying, 'GSTM1-null', genotype, seemed, to]), verbo([have]), complemento([an, higher, susceptibility, to, 'DNA', damage, induced, by, tobacco, smoke, than, 'GSTM1-positive', ones])].
[sujeto(['When', considering, a, combination, of, 'GST', 'genotypes,', we]), verbo([found]), complemento([a, lower, 'BNMN', frequency, in, subjects, with, 'GSTP1', variant, allele, plus, 'GSTM1-positive', 'genotypes,', while, the, most, damaged, cells, are, found, in, subjects, bearing, 'GSTM1-null', plus, 'GSTP1-wild', type])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, investigation, of, the, association, between, several, gene, polymorphisms, and, important, endpoints, of, 'DNA', damage, could, contribute, to, better, understanding, the, role, of, 'gene-gene', interaction])].
[sujeto(['To', detect, some, candidate, marker, proteins, which, may]), verbo([confer]), complemento([resistance, to, the, anticancer, drug, camptothecin, '(', 'CPT;', 'DNA', topoisomerase, 1, 'inhibitor),', the, current, study, deals, with, the, comparative, proteomic, profiling, of, 'CPT-resistant', 'PC3', and, 'CPT-sensitive', 'LNCaP', human, prostate, cancer, cell, lines, which, have, been, widely, employed, as, a, useful, model, to, investigate, prostate, cancer, cells])].
[sujeto(['Four', proteins, -, annexin, 'A1,', 'glutathione-S-transferase', '(', 'GST)', 'pi,', galectin, '(', 'Gal)', 3, and, 'glucose-regulated', protein, 78, /, 'Bip', -, that, are]), verbo([suggested]), complemento([to, contribute, to, the, development, of, drug, resistance, were, found, to, be, preferentially, or, highly, expressed, in, 'PC3', 'cells,', whereas, 'LNCaP', cells, did, not, show, detectable, expression, of, annexin, 'A1,', 'GST-pi', and, 'Gal-3'])].
[sujeto(['High', consumption, was, slightly, positively]), verbo([associated]), complemento([with, colorectal, adenomas, '[', odds, ratio, '(', 'OR)', 1.15, ;, 95, '%', confidence, 'interval,', 0.92, -, 1.44, ']'])].
[sujeto(['The', 'GSTA1', polymorphism, may]), verbo([have]), complemento([a, modifying, role, as, 'well:', the, 'OR', for, higher, intake, compared, with, lower, intake, was, 1.57, '(', 0.93, -, 2.65, ')', for, individuals, homozygous, for, the, low, expression, variant, '(', 'TT', 'genotype)'])].
[sujeto(['In', 'conclusion,', 'GSTP1', and, 'GSTA1', genotypes, might]), verbo([modulate]), complemento([the, association, between, cruciferous, vegetable, intake, and, colorectal, adenomas])].
[sujeto(['Using', proteomic, 'means,', herein, we]), verbo([have]), complemento([systematically, studied, the, responses, of, protein, expression, in, 'BGC823', 'cells,', a, gastric, cancer, cell, 'line,', induced, by, diallyl, trisulfide, '(', 'DATS),', a, major, component, of, garlic, derivatives])].
[sujeto(['Interestingly,', approximately, 50, '%', of, 'DATS-sensitive', proteins, '(', 19, /, 41, ')', in, 'BGC823', are, tightly]), verbo([associated]), complemento([with, apoptotic, pathways])].
[sujeto(['These', proteomic, results, 'presented,', 'therefore,']), verbo([provide]), complemento([additional, support, to, the, hypothesis, that, garlic, is, a, strong, inducer, of, apoptosis, in, tumor, cells])].
[sujeto(['Elevated', levels, of, glutathione, 'S-transferases', '(', 'GSTs)', are, among, the, factors]), verbo([associated]), complemento([with, an, increased, resistance, of, tumors, to, a, variety, of, antineoplastic, drugs])].
[sujeto(['Two', such, agents]), verbo([have]), complemento([been, synthesized, and, tested, on, the, human, 'Alpha,', 'Mu', and, 'Pi', 'GST', 'classes,', which, are, the, most, representative, targets, for, inhibitor, design])].
[sujeto(['The', novel, fluorescent, glutathione, 'S-conjugate', 'L-gamma-glutamyl-(S-9-fluorenylmethyl)-L-cysteinyl-glycine', '(', 4, ')']), verbo([has]), complemento([been, found, to, be, a, highly, potent, inhibitor, of, human, 'GSTA1-1', in, vitro, '(', 'IC50=0'])].
[sujeto(['The', peptide, is, also, able, to]), verbo([inhibit]), complemento(['GSTP1-1', and, 'GSTM2-2', isoenzymes, efficiently])].
[sujeto(['The', 'backbone-modified', analog, 'L-gamma-(gamma-oxa)glutamyl-(S-9-fluorenylmethyl)-L-cysteinyl-glycine', '(', 6, ')', ',', containing, an, urethanic, junction, as, isosteric, replacement, of, the, 'gamma-glutamyl-cysteine', peptide, 'bond,']), verbo([has]), complemento([been, developed, as, 'gamma-glutamyl', 'transpeptidase-resistant', mimic, of, 4, and, evaluated, in, the, same, inhibition, tests])].
[sujeto(['The', pseudopeptide, 6, was, shown, to]), verbo([inhibit]), complemento([the, 'GSTA1-1', 'protein,', albeit, to, a, lesser, extent, than, the, lead, 'compound,', with, no, effect, on, the, activity, of, the, isoenzymes, belonging, to, the, 'Mu', and, 'Pi', classes])].
[sujeto(['The', comparative]), verbo([loss]), complemento([in, biological, activity, consequent, to, the, isosteric, change, confirms, that, the, 'gamma-glutamyl', moiety, plays, an, important, role, in, modulating, the, affinity, of, the, ligands, addressed, to, interact, with, 'GSH-dependent', proteins])].
[sujeto(['The', new, specific, inhibitors, may]), verbo([have]), complemento([a, potential, in, counteracting, 'tumor-protective', effects, depending, upon, 'GSTA1-1', activity])].
[sujeto(['As', there, is, evidence, for, genetic, susceptibility, to, 'alcohol-related', liver, disease, we]), verbo([have]), complemento([compared, the, frequency, of, polymorphisms, of, 'GSTM1,', 'M3,', 'P1,', 'T1', and, 'A1', by, polymerase, chain, reaction, '(', 'PCR)', on, leucocyte, 'DNA', in, patients, from, 'North', 'Staffordshire,', 'Birmingham', and, 'Liverpool', with, 'alcohol-related', chronic, liver, disease, heavy, drinking, and, normal, local, controls])].
[sujeto(['There', was, a, significant]), verbo([increase]), complemento([in, the, 'GSTT1', null, 'Liverpool', alcoholic, liver, disease, '(', 'ALD)', patients, compared, with, corresponding, 'non-drinking', controls, '(', 26.3, and, 14.6, '%', ',', 'respectively;', 'P', =, 0.044, ',', odds, ratio, '(', 'OR)', =, 2.1, ',', 95, '%', 'CI', =, 1.1, -, 4.7, ')', though, this, was, not, repeated, in, the, 'Birmingham', and, 'North', 'Staffordshire', cohorts])].
[sujeto(['For', 'GSTA1,', the, -, 69, 'CC', genotype, was]), verbo([associated]), complemento([with, increased, risk, of, 'ALD', in, the, 'Liverpool', 'group,', but, a, reduced, risk, in, the, 'North', 'Staffordshire', group])].
[sujeto(['We']), verbo([have]), complemento([failed, to, demonstrate, within, the, limitation, of, a, 'case-control', study, a, reproducible, significant, association, of, 'GST', polymorphisms, with, susceptibility, to, 'ALD', but, there, are, suggestions, that, 'GSTA1', and, 'GSTT1', warrant, further, study])].
[sujeto(['Nitrobenzoxadiazole', derivatives, '(', 'NBDs),', including, 'NBDHEX', and, the, recently, developed, 'MC3181,', are, promising, anticancer, agents, able, to]), verbo([target]), complemento([glutathione, transferase, and, inhibit, both, its, catalytic, activity, and, ability, to, sequester, 'TNF-receptor', associated, factor, 2, '(', 'TRAF2)', and, 'c-Jun', 'N-terminal', kinase, '(', 'JNK)'])].
[sujeto(['NBDs']), verbo([have]), complemento([been, shown, to, impair, the, growth, and, survival, of, a, 'broad-spectrum', of, tumor, 'types,', in, vitro, and, in, vivo])].
[sujeto(['The', role, of, 'JNK', in, the, reduction, of, autophagic, flux]), verbo([caused]), complemento([by, 'NBDs', was, investigated, using, 'JNK1', 'shRNA-transfected', cells])].
[sujeto(['Similar', to, 'NBDHEX,', 'MC3181', reduced, viability, and]), verbo([activated]), complemento(['TRAF2/JNK', signaling, in, 'U-2OS', cells])].
[sujeto(['Moreover,', 'NBDs']), verbo([induced]), complemento([the, accumulation, of, autophagic, vesicles, and, 'LC3-II', while, reducing, both, basal, and, nutritional, 'stress-induced', autophagic, flux])].
[sujeto(['Furthermore,']), verbo([increased]), complemento([levels, of, both, 'LC3-II', and, the, autophagy, selective, substrate, p62, were, observed, in, different, tumor, cell, lines, treated, with, 'NBDs,', the, concurrent, increase, of, these, markers, being, consistent, with, an, impairment, of, autophagosome, clearance])].
[sujeto(['Autophagy', inhibition, by, 'NBDs']), verbo([required]), complemento(['JNK', 'activity:', 'NBDs', caused, autophagy, inhibition, and, 'caspase-3', activation, in, 'JNK-positive', 'U-2OS,', but, no, autophagic, flux, inhibition, or, 'caspase-3', activation, in, 'JNK-silenced', cells])].
[sujeto(['Our', demonstration, that, 'NBDs', can]), verbo([act]), complemento([as, 'late-phase', autophagy, inhibitors, opens, new, opportunities, to, fully, exploit, their, therapeutic, potential])].
[sujeto(['This', may, not, rely, solely, on, their, effectiveness, in]), verbo([inducing]), complemento([cell, cycle, arrest, and, 'apoptosis,', but, also, on, their, ability, to, weaken, the, capacity, of, tumor, cells, to, endure, stress, conditions, via, autophagy])].
[sujeto(['In', 'addition,', this, study]), verbo([provides]), complemento([evidence, that, 'JNK', can, participate, in, impairing, autophagy])].
[sujeto(['The', mortality, pattern]), verbo([has]), complemento([changed, and, duodenal, cancer, now, is, one, of, the, main, 'cancer-related', causes, of, death, in, these, patients])].
[sujeto(['Duodenal', cancer, in, patients, with, 'FAP']), verbo([has]), complemento([a, poor, prognosis])].
[sujeto(['The', main, goal, of, this, study, is, to, identify, risk, markers, in, normal, duodenal, mucosa, of, patients, with, 'FAP,', that, could, help, identify, patients, at]), verbo([increased]), complemento([risk, for, malignant, transformation])].
[sujeto(['Messenger', 'RNA', '(', 'mRNA)', levels, of, glutathione, 'S-transferase', 'A1', '(', 'GSTA1),', glutathione, 'S-transferase', 'P1', '(', 'GSTP1),', 'KIAA1199,', 'E-cadherin,', peroxisome, proliferative]), verbo([activated]), complemento([receptor, δ, '(', 'PPARδ),', 'caspase-3,', cyclin, 'D1,', 'β-catenin,', and, 'cyclooxygenase-2', '(', 'COX-2)', were, measured, in, duodenal, 'mucosa,', using, the, 'QuantiGene', 2.0, 'Plex', assay])].
[sujeto(['COX-2', mRNA, levels, in, normal, duodenal, mucosa, of, patients, with, 'FAP', were]), verbo([found]), complemento([to, be, unexpectedly, low])].
[sujeto(['Protection', against, toxins, and, carcinogens, '(', 'GSTA1)', and, apoptosis, '(', 'caspase-3)', is, low, in, patients, with, 'FAP,', which, could, contribute, to]), verbo([increased]), complemento([susceptibility, for, malignant, transformation, of, duodenal, mucosa])].
[sujeto(['Nuclear', factor, '(', 'erythroid-derived', 2, ')', -, like, 2, '(', 'NRF2)', is, an, 'oxidant-responsive', transcription, factor]), verbo([involved]), complemento([in, induction, of, antioxidant, genes])].
[sujeto(['These', data]), verbo([suggest]), complemento([disturbances, in, 'SOD2', transcription, in, circulating, blood, leukocytes, of, males, with, bladder, cancer])].
[sujeto(['Moreover,', concomitant, constitutive, expression, of, 'NRF2', and, its]), verbo([target]), complemento([genes, may, suggest, important, role, of, 'NRF2', transcription, factor, in, positive, regulation, of, antioxidant, 'genes,', resulted, in, enhanced, cytoprotection, in, human, peripheral, blood, leukocytes])].
[sujeto(['Glutathione', 'S-transferases', '(', 'GST)', are]), verbo([involved]), complemento([in, the, detoxification, of, xenobiotics, and, protection, of, oxidative, damage])].
[sujeto(['We', hypothesized, that, genetic, polymorphism, in, antioxidant, enzymes, 'GSTA1,', 'GSTM1,', 'GSTP1', and, 'GSTT1', is, more, frequent, in, 'ESRD', and]), verbo([modulates]), complemento([the, degree, of, oxidative, stress, in, these, patients])].
[sujeto(['Furthermore,', a, strong, combined, effect, of, 'null/low-activity', 'GSTM1,', 'GSTT1,', 'GSTA1', and, 'GSTP1', genotypes, in, terms, of, susceptibility, towards, oxidative, and, carbonyl, stress, was]), verbo([found]), complemento([in, 'ESRD', patients])].
[sujeto(['Owing', to, the, presence, of, these, genetic, 'variants,', 'inter-individual', and, ethnic, differences, in, 'GSTs', detoxification, capacity]), verbo([have]), complemento([been, observed, in, various, populations])].
[sujeto(['The', combined, genotypes, distribution, of, 'GSTM1,', 'GSTT1,', 'GSTP1', and, 'GSTA1', polymorphisms, showed, that, thirty, one, of, the, 36, possible, genotypes, were, present, in, our, 'population;', eight, of, them]), verbo([have]), complemento([a, frequency, greater, than, 5, '%'])].
[sujeto(['To', the, best, of, our, 'knowledge,', this, is, the, first]), verbo([report]), complemento([of, 'GSTs', polymorphisms, in, 'South', 'Tunisian', population])].
[sujeto(['Our', findings, demonstrate, the, impact, of, ethnicity, and]), verbo([reveal]), complemento([a, characteristic, pattern, for, 'Tunisian', population])].
[sujeto(['The', molecular, studies, in, these, enzymes]), verbo([provide]), complemento([basis, for, further, epidemiological, investigations, in, the, population, where, these, functional, polymorphisms, alter, therapeutic, response, and, act, as, susceptibility, markers, for, various, clinical, conditions])].
[sujeto(['Genetic', polymorphisms, of, glutathione, 'S-transferase', '(', 'GST),', which, is]), verbo([involved]), complemento([in, the, metabolism, of, 'busulfan,', have, been, implicated, in, interindividual, variability, in, busulfan, pharmacokinetics])].
[sujeto(['Our', multiplex, system]), verbo([provides]), complemento([a, 'fast,', 'inexpensive,', and, accurate, method, of, detecting, multiple, 'GST', polymorphisms, '(', 'GSTA1,', 'GSTP1,', 'GSTM1,', and, 'GSTT1)'])].
[sujeto(['MC-LR', is, the, most, studied, 'MC', 'congener,', in, view, of, its, high, acute, hepatotoxicity, and, tumor]), verbo([promoting]), complemento([activity])].
[sujeto(['The', 'GSH', adduct, '(', 'GS-MCLR)', formation]), verbo([has]), complemento([been, shown, to, occur, spontaneously, and, 'enzymatically,', catalyzed, by, glutathione, transferases, '(', 'GSTs)'])].
[sujeto(['The', enzymatic, reaction]), verbo([has]), complemento([been, reported, but, not, characterized, both, in, vitro, and, in, vivo, in, animal, and, plant, species])].
[sujeto(['In', the, present, 'work,', the, 'MC-LR', conjugation, with, 'GSH', catalyzed, by, five, recombinant, human, 'GSTs', '(', 'A1-1,', 'A3-3,', 'M1-1,', 'P1-1,', and, 'T1-1)']), verbo([has]), complemento([been, characterized, for, the, first, time])].
[sujeto(['The', enzymes, mainly]), verbo([expressed]), complemento([in, the, liver, and, gastrointestinal, 'tract,', 'GSTA1-1,', 'T1-1,', and, 'M1-1,', seemed, to, be, mainly, involved, in, the, 'MC-LR', detoxification, after, oral, 'exposure,', whereas, 'P1-1', kinetics, and, location, in, the, skin, suggest, a, role, related, to, dermal, exposure])].
[sujeto(['Considering', the, high, frequency, of, some, 'GST', 'polymorphism,', especially, 'M1', and, 'T1', gene, 'deletion,', with, complete]), verbo([loss]), complemento([in, 'activity,', this, information, could, be, the, first, step, to, identify, groups, of, individual, at, higher, risk, associated, with, 'MC', exposure])].
[sujeto(['Busulfan', '(', 'BU),', often, used, in, high, dose, for, myeloablation, before, hematopoietic, stem, cell, transplantation, '(', 'HSCT),']), verbo([has]), complemento([been, implicated, in, certain, 'HSCT', 'toxicities,', including, the, occurrence, of, hepatic, 'veno-occlusive', disease, '(', 'HVOD)'])].
[sujeto(['In', addition, to, weight, and, 'age,', gene, polymorphisms, in, specific, members, of, the, 'glutathione-transferase', '(', 'GST)', gene, family, '(', 'A1,', 'P1,', 'M1,', and, 'T1),']), verbo([involved]), complemento([in, 'BU', 'metabolism,', may, play, a, role, in, the, wide, 'inter-patient', variability, in, systemic, 'BU', concentrations])].
[sujeto(['Six', 'SNPs', in, 'TGFB1,', 'SFTPA1,', 'SFTPA2', and, 'SFTPD', were, significantly]), verbo([associated]), complemento([with, 'FEV(1)/IVC', in, subjects, with, 'GOLD', stage, &, 'gt;or=1', 'COPD'])].
[sujeto(['By', the, end, of, the, eighth, 'week,', the, 'CD-fed']), verbo([induced]), complemento([fatty, liver, rats, showed, a, significant, decrease, in, the, activities, of, 'CYP1A2', and, 'UGT2B7', as, compared, to, the, standard, diet, group])].
[sujeto(['Although', the, only, notable, metabolite, is, 4, -, hydroxyvaleryl, metabolite, '(', 4, -, 'OH', 'valsartan),', the, responsible, enzyme]), verbo([has]), complemento([not, been, clarified, at, present])].
[sujeto(['The', current, in, vitro, studies, were, conducted, to, identify, the, cytochrome, 'P450', '(', 'CYP)', enzymes]), verbo([involved]), complemento([in, the, formation, of, 4, -, 'OH', valsartan])].
[sujeto(['For', the, specific, 'CYP', inhibitors, or, substrates, examined, '(', 'furafylline,', 'diclofenac,', 'S(+)-mephenytoin,', quinidine, and, 'troleandomycin),', only, diclofenac]), verbo([inhibited]), complemento([the, formation, of, 4, -, 'OH', valsartan])].
[sujeto(['Although', 'CYP2C9', is]), verbo([involved]), complemento([in, valsartan, 'metabolism,', 'CYP-mediated', 'drug-drug', interaction, between, valsartan, and, other, 'co-administered', drugs, would, be, negligible])].
[sujeto(['It', was]), verbo([found]), complemento(['that,', as, 'expected,', none, of, the, tested, species, was, similar, to, man, for, all, the, measured, 'P450', enzyme, 'activities,', but, that, in, each, species, only, some, of, the, 'P450', enzyme, activities, could, be, considered, as, similar, to, man])].
[sujeto(['When', it, is, known, which, human, cytochrome, 'P450', enzymes, are]), verbo([involved]), complemento([in, the, metabolism, of, a, 'compound,', the, comparative, data, presented, here, can, be, used, for, selecting, the, most, suitable, species, for, in, vitro, and, in, it, no, experiments])].
[sujeto(['Pretreatment', with, 'acetone,', dexamethasone, and, clofibrate, resulted, in]), verbo([enhanced]), complemento(['p-nitrophenol', hydroxylase, '(', 'CYP2E),', erythromycin, 'N-demethylase', '(', 'CYP3A)', and, lauric, acid, hydroxylase, '(', 'CYP4A)', activities, respectively, in, the, liver, of, the, lean, 'Zucker', rat, 'but,', in, 'contrast,', the, obese, 'Zucker', rat, was, refractive, to, such, 'treatment;', 'similarly,', hepatic, apoprotein, levels, of, the, 'CYP2E', and, 'CYP4A', subfamilies, were, increased, markedly, only, in, the, lean, 'Zucker', rat])].
[sujeto(['It', is, concluded, that, 'CYP2E,', 'CYP3A', and, 'CYP4A', subfamilies, are, poorly]), verbo([expressed]), complemento([in, the, obese, 'Zucker', 'rat,', and, this, rat, strain, may, serve, as, a, good, model, for, elucidating, the, molecular, mechanisms, of, induction, of, these, cytochrome, 'P450', proteins])].
[sujeto(['The', discovery, of, selective, lanosterol, 14, 'alpha-demethylase', inhibitors, may]), verbo([lead]), complemento([to, novel, hypolipidemic, drugs])].
[sujeto(['The', apparent, 'Ki', was, determined, to, be, 840, pM, and]), verbo([found]), complemento([to, be, similar, in, hepatic, microsomes, from, 'human,', 'rat,', and, hamster])].
[sujeto(['Doses', of, 3, -, 30, 'mg/kg', 'RS-21607', given, orally, to, hamsters]), verbo([caused]), complemento([a, 'dose-dependent', decrease, in, cholesterol, biosynthesis, with, a, corresponding, accumulation, of, 24, ',', 25, -, dihydrolanosterol])].
[sujeto(['RS-21607']), verbo([inhibited]), complemento([the, enzyme, and, cholesterol, biosynthesis, in, hamster, liver, by, 50, '%', at, 18, h, following, a, 30, 'mg/kg', oral, dose])].
[sujeto(['This', was, interpreted, to, indicate, that, 'RS-21607', is, able, to, distribute, to, the, site, of, action, in, hamsters, and]), verbo([inhibit]), complemento([the, target, enzyme])].
[sujeto(['In', the, same, dose, 'range,', the, plasma, concentrations, of, 'testosterone,', 'corticosterone,', and, 'progesterone,', the, endpoints, for, the, cytochromes, 'P450']), verbo([involved]), complemento([in, steroid, 'biosynthesis,', were, relatively, unaffected])].
[sujeto(['RS-21607']), verbo([interacted]), complemento([with, the, purified, enzyme, to, produce, a, type, 'II', binding, 'spectrum,', consistent, with, an, interaction, between, the, imidazole, moiety, and, the, heme])].
[sujeto(['The', electrostatic, contribution, of, the, imidazole]), verbo([binding]), complemento([was, investigated, using, the, desimidazole, analog, of, 'RS-21607'])].
[sujeto([',']), verbo([binding]), complemento([to, the, enzyme, with, similar, 'affinity,', and, that, the, coordination, of, the, imidazole, to, the, heme, provides, a, major, electrostatic, contribution, for, the, inhibition, of, lanosterol, 14, 'alpha-demethylase', by, 'RS-21607'])].
[sujeto(['RS-21607', was, also, observed, to]), verbo([increase]), complemento([the, accumulation, of, 3, 'beta-hydroxy-24,25-dihydrolanost-8-en-32-al,', the, second, intermediate, in, the, multistep, 'oxidation,', but, not, the, first, intermediate])].
[sujeto(['(', 'ABSTRACT', 'TRUNCATED', 'AT', 400, 'WORDS)', 'In', 'summary,', strain, difference, and, inhibition, studies, showed, that, an, 'enzyme(s)', converting, propranolol, to, a, reactive, metabolite, capable, of, irreversible]), verbo([binding]), complemento([to, microsomal, macromolecules, appeared, to, be, a, 'P450', 'isozyme(s)', which, catalyses, debrisoquine, 4, -, hydroxylation, in, rats])].
[sujeto(['It', seems, likely, that, cytochrome, 'P450', isozymes, responsible, for, debrisoquine, 4, -, hydroxylation]), verbo([activate]), complemento([propranolol, and, may, be, impaired, after, chronic, use, of, propranolol, also, in, human, subjects])].
[sujeto(['The', findings, obtained, in, the, present, study]), verbo([provide]), complemento([a, clue, for, the, elucidation, of, the, mechanism, of, 'propranolol-induced', impairment, of, the, drug, metabolizing, enzyme, system])].
[sujeto(['Further', studies, using, purified, debrisoquine, 4, -, hydroxylase, are]), verbo([required]), complemento([to, identify, a, 'P450', 'isozyme(s)', responsible, for, the, metabolic, activation, of, propranolol])].
[sujeto(['Previously,', we]), verbo([reported]), complemento([a, decrease, in, adenosine, 'A1', receptor, '(', 'A1AR)', protein, levels, in, sEH, knockout, '(', 'sEH(-/-))', and, an, increase, in, sEH, and, 'A1AR', protein, levels, in, 'A2AAR(-/-)', mice])].
[sujeto(['Additionally,', 'KATP', channels, are]), verbo([involved]), complemento([in, adenosine, receptor, '(', 'AR)-dependent', vascular, relaxation])].
[sujeto(['Thus,', we, hypothesize, that, a, potential, relationship, may, exist, among, sEH, 'over-expression,', 'A1AR', 'upregulation,', inactivation, of, 'KATP', 'channels,', and]), verbo([increased]), complemento([in, vascular, tone])].
[sujeto(['Our', data, revealed, that, 'NECA', '(', a, 'non-selective', adenosine, receptors, 'agonist)-induced', relaxation, was, significantly, reduced, in, 'Tie2-sEH', 'Tr', 'mice,', and, 'CCPA', '(', 'A1AR', 'agonist)-induced', contraction, was]), verbo([increased]), complemento([in, 'Tie2-sEH', 'Tr', mice])].
[sujeto(['Furthermore,', 'KATP', 'channel-dependent', relaxation, in, 'MAs', was]), verbo([enhanced]), complemento([by, inhibition, of, 'PKCα', and, 'ERK1/2', in, 'WT', but, not, 'Tie2-sEH', 'Tr', mice])].
[sujeto(['In', 'conclusion,', our, data]), verbo([suggest]), complemento([that, 'over-expression', of, sEH, enhances, 'A1AR-dependent', contraction, and, reduces, 'KATP', 'channel-dependent', relaxation, in, 'MAs'])].
[sujeto(['These', results]), verbo([suggest]), complemento([a, possible, interaction, between, 'sEH,', 'A1AR,', and, 'KATP', channels, in, regulating, vascular, tone])].
[sujeto(['Overproduction', of, reactive, oxygen, species, is]), verbo([associated]), complemento([with, the, development, of, alcoholic, liver, disease, '(', 'ALD)'])].
[sujeto(['Plant', polyphenols]), verbo([have]), complemento([been, used, as, dietary, interventions, for, multiple, diseases, including, 'ALD'])].
[sujeto(['Alcohol', feeding]), verbo([induced]), complemento([lipid, accumulation, in, the, liver, and, increased, plasma, alanine, aminotransferase, and, aspartate, aminotransferase, 'activities,', which, were, attenuated, by, fisetin, supplementation])].
[sujeto(['Although', fisetin, did, not, affect, the, protein, expression, of, alcohol, metabolism, 'enzymes,', the, aldehyde, dehydrogenase, activities, were, significantly]), verbo([increased]), complemento([by, fisetin, compared, to, the, alcohol, alone, group])].
[sujeto(['In', 'addition,', fisetin, supplementation, remarkably, reduced, hepatic, 'NADPH', oxidase, 4, levels, along, with]), verbo([decreased]), complemento([plasma, hydrogen, peroxide, and, hepatic, superoxide, and, 4, -, hydroxynonenal, levels, after, alcohol, exposure])].
[sujeto(['Alcohol-induced', apoptosis, and, 'up-regulation', of, 'Fas', and, cleaved, 'caspase-3', in, the, liver, were]), verbo([prevented]), complemento([by, fisetin])].
[sujeto(['Moreover,', fisetin, supplementation, attenuated, 'alcohol-induced', hepatic, steatosis, through]), verbo([increasing]), complemento([plasma, adiponectin, levels, and, hepatic, protein, levels, of, 'p-AMPK,', 'ACOX1,', 'CYP4A,', and, 'MTTP'])].
[sujeto(['The', data]), verbo([suggest]), complemento([that, fisetin, has, a, therapeutical, potential, for, treating, 'ALD'])].
[sujeto(['In', 'DETC-treated', 'SS-5(BN)', and, 'HS-fed', 'SS', 'rats:', 1, ')', 'DDMS', or, 'Tempol', ameliorated, vascular, dysfunction, 2, ')', 'DDMS', reduced, vascular, oxidative, stress, to, control, 'levels;', 3, ')', 'Chronic', 'Tempol', treatment, reduced, vascular, 'CYP4A', protein, 'expression;', and, 3, ')', combined, treatment, with, 'Tempol', and, 'L-NAME']), verbo([prevented]), complemento([the, reduction, in, 'CYP4A', protein, expression, in, 'MCA', of, 'HS-fed', 'SS', rats])].
[sujeto(['Serum', glucose, and, glycated, hemoglobin, levels, were]), verbo([increased]), complemento([in, 11, -, 'week-old', 'ZDF', 'rats,', but, not, in, 5, -, weekold, 'ZDF', rats])].
[sujeto(['Hepatic', levels, of, cytochrome, 'b5,', 'CYP2B1,', 'CYP2C11,', 'CYP2E1,', and, 'CYP3A2', were]), verbo([decreased]), complemento([in, 5, -, 'week-old', 'ZDF', 'rats,', but, not, in, 11, -, 'week-old', 'ZDF', rats])].
[sujeto(['Similarly,', pentoxyresorufin, 'O-depentylase,', testosterone, 2, 'α-', and, 16, 'α-hydroxylase,', chlorzoxazone, 6, -, 'hydroxylase,', and, midazolam, 1, '\'', -, and, 4, -, hydroxylase, activities, were]), verbo([decreased]), complemento([only, in, 5, -, weekold, 'ZDF', rats])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, hepatic, expression, of, 'CYP', enzymes, may, be, dysregulated, during, development, in, 'ZDF', rats])].
[sujeto(['With', the, exception, of, 'CYP2B1', and, 'CYP4A,', the, hepatic, levels, and, activities, of, 'CYP', were, comparable, between, 11, -, 'week-old', 'ZDF', and, control, 'rats,']), verbo([suggesting]), complemento([that, xenobiotic, metabolism, is, normally, regulated, in, the, early, diabetic, state])].
[sujeto(['Male', and, female, homozygous, 129, /, 'Sv', mice, carrying, four, copies, of, the, human, cytochrome, 'P450', 4, 'A11', gene, '(', 'CYP4A11)', under, control, of, its, native, promoter, '(', 'B-129/Sv-4A11(+/+))', develop, hypertension, '(', 142, ±, 8, versus, 113, ±, 7, mm, 'Hg', systolic, blood, pressure, '(', 'BP)),', and, exhibit]), verbo([increased]), complemento([20, -, hydroxyeicosatetraenoic, acid, '(', 20, -, 'HETE)', in, kidney, and, urine])].
[sujeto(['B-129/Sv-4A11(+/+)', mice, display, an, 18, '%']), verbo([increase]), complemento([of, plasma, potassium, '(', p, &, 'lt;', 0.02, ')', ',', but, plasma, 'aldosterone,', angiotensin, 'II', '(', 'ANGII),', and, renin, activities, are, unchanged])].
[sujeto(['This', phenotype, resembles, human, genetic, disorders, with, elevated, activity, of, the, sodium, chloride, 'co-transporter', '(', 'NCC)', 'and,', 'accordingly,', 'NCC', abundance, is]), verbo([increased]), complemento([by, 50, '%', in, transgenic, 'mice,', and, 'NCC', levels, are, normalized, by, 'HET0016'])].
[sujeto(['ANGII', is, known, to]), verbo([increase]), complemento(['NCC', 'abundance,', and, renal, mRNA, levels, of, its, precursor, angiotensinogen, are, increased, 2, -, fold, in, 'B-129/Sv-4A11(+/+),', and, blockade, of, the, 'ANGII', receptor, type, 1, with, losartan, normalizes, 'BP'])].
[sujeto(['A', 'pro-hypertensive', role, for, 20, -, 'HETE', was, implicated, by, normalization, of, 'BP', and, reversal, of, renal, angiotensin, mRNA]), verbo([increases]), complemento([by, administration, of, the, 20, -, 'HETE', antagonists, 2, -, '(', '(', 6, 'Z,15Z)-20-hydroxyicosa-6,15-dienamido)acetate', or, '(', 'S)-2-((6Z,15Z)-20-hydroxyicosa-6,15-dienamido)succinate'])].
[sujeto(['SGK1', expression, is, also]), verbo([increased]), complemento([in, 'B-129/Sv-4A11(+/+)', mice, and, paralleled, increases, seen, for, 'NCC'])].
[sujeto(['These', results, point, to, a, potential, 20, -, 'HETE', dependence, of, intrarenal, angiotensinogen, production, and, 'ANGII', receptor, type, 1, activation, that, are]), verbo([associated]), complemento([with, increases, in, 'NCC', and, 'SGK1', and, identify, elevated, 'P450', 4, 'A11', activity, and, 20, -, 'HETE', as, potential, risk, factors, for, 'salt-sensitive', human, hypertension, by, perturbation, of, the, renal, 'renin-angiotensin', axis])].
[sujeto(['In', the, 'vasculature,', 20, -, 'HETE', is, a, potent, 'vasoconstrictor,', the, 'up-regulation', of, which, contributes, to, 'inflammation,', oxidative, 'stress,', endothelial, dysfunction, and, an]), verbo([increase]), complemento([in, peripheral, vascular, resistance, in, models, of, 'obesity,', 'diabetes,', 'ischemia/reperfusion,', and, vascular, oxidative, stress])].
[sujeto(['Recent', studies]), verbo([have]), complemento([established, a, role, for, 20, -, 'HETE', in, normal, and, pathological, angiogenic, conditions])].
[sujeto(['We', discuss, in, this, review, the, synthesis, of, 20, -, 'HETE', and, how, it, and, various, 'autacoids,', especially, the, 'renin-angiotensin', 'system,']), verbo([interact]), complemento([to, promote, 'hypertension,', 'vasoconstriction,', and, vascular, dysfunction])].
[sujeto(['In', 'addition,', we, examine, the, molecular, mechanisms, through, which, 20, -, 'HETE']), verbo([induces]), complemento([these, actions, and, the, clinical, implication, of, inhibiting, 20, -, 'HETE', production, and, activity])].
[sujeto(['To', 'date,', the, role, of, sEH, in, the, modulation, of, 'pressure-induced', myogenic, 'response/constriction', in, coronary, 'arteries,', an, important, regulatory, mechanism, in, the, coronary, 'circulation,', and, the, issue, as, to, whether, the, disruption, of, the, sEH, gene, affects, the, myogenic, response, sex, differentially]), verbo([have]), complemento([never, been, addressed])].
[sujeto(['All', vessels, constricted, in, response, to]), verbo([increases]), complemento([in, intraluminal, pressure, from, 60, to, 120, mmHg])].
[sujeto(['Myogenic', vasoconstriction, was, significantly, 'attenuated,']), verbo([expressed]), complemento([as, an, upward, shift, in, the, 'pressure-diameter', curve, of, 'vessels,', associated, with, higher, cardiac, 'EETs', in, 'M-KO,', 'F-WT,', and, 'F-KO', mice, compared, with, 'M-WT', controls])].
[sujeto(['Blockade', of, 'EETs', via, exposure, of, vessels, to, 14, ',', 15, -, 'epoxyeicosa-5(Z)-enoic', acid, '(', 14, ',', 15, -, 'EEZE)']), verbo([prevented]), complemento([the, attenuated, myogenic, constriction, in, 'sEH-KO', mice])].
[sujeto(['Additional', administration, of, 'N(ω)-nitro-l-arginine', methyl, ester, eliminated, the, sex, difference, in, myogenic, 'responses,']), verbo([leading]), complemento([to, four, overlapped, 'pressure-diameter', curves])].
[sujeto(['In', 'summary,', in, combination, with, 'NO,', the]), verbo([increased]), complemento(['EET', bioavailability, as, a, function, of, genetic, deletion, 'and/or', downregulation, of, sEH, accounts, for, the, 'female-favorable', attenuation, of, 'pressure-induced', vasoconstriction])].
[sujeto(['Proteinuria', plays, an, essential, role, in, the, progression, of, tubulointerstitial, 'damage,', which]), verbo([causes]), complemento(['end-stage', renal, disease])].
[sujeto(['An']), verbo([increased]), complemento([load, of, fatty, acids, bound, to, albumin, reabsorbed, into, proximal, tubular, epithelial, cells, '(', 'PTECs)', contributes, to, tubulointerstitial, damage])].
[sujeto(['Fibrates,', agonists, of, peroxisome, 'proliferator-activated', receptor, α, '(', 'PPARα),']), verbo([have]), complemento([renoprotective, effects, against, proteinuria, whereas, the, effects, of, these, compounds, on, fatty, acid, metabolism, in, the, kidney, are, still, unknown])].
[sujeto(['Therefore,', the, present, study, examined, whether, the, renoprotective, effects, of, clofibrate, were]), verbo([associated]), complemento([with, improvement, of, fatty, acid, metabolism, in, puromycin, aminonucleoside, '(', 'PAN)-induced', nephrotic, rats])].
[sujeto(['PAN']), verbo([increased]), complemento(['proteinuria,', lipid, accumulation, in, 'PTECs,', excretions, of, 'N-acetyl-β-D-glucosaminidase', '(', 'NAG)', and, 8, -, hydroxydeoxyguanosine, '(', 8, 'OHdG)', and, the, area, of, caspase, 3, -, positive, tubular, cells])].
[sujeto(['It']), verbo([decreased]), complemento([renal, expressions, of, 'medium-chain', 'acyl-CoA', dehydrogenase, '(', 'MCAD),', cytochrome, 'P450', '(', 'CYP)4A,', peroxisome, 'proliferator-activated', receptor, γ, 'coactivator-1α', '(', 'PGC-1α)', and, 'estrogen-related', receptor, α, '(', 'ERRα)', without, change, of, the, expression, of, 'PPARα'])].
[sujeto(['Clofibrate', minimized, changes, in, 'MCAD,', 'CYP4A,', 'PGC-1α', and, 'ERRα', expressions, with]), verbo([increased]), complemento(['PPARα,', very, 'long-chain', 'acyl-CoA', dehydrogenase, '(', 'VLCAD)', and, 'long-chain', 'acyl-CoA', dehydrogenase, '(', 'LCAD)', expressions])].
[sujeto(['This', study, indicates, that, clofibrate]), verbo([has]), complemento([renoprotective, effects, through, maintaining, fatty, acid, metabolism, in, the, kidney, of, 'PAN-induced', nephrotic, rats])].
[sujeto(['The', 'SsuE', enzyme, is, an, 'NADPH-dependent', 'FMN', reductase, that]), verbo([provides]), complemento([reduced, flavin, to, the, 'SsuD', monooxygenase, enzyme])].
[sujeto(['Previous', studies]), verbo([have]), complemento([highlighted, the, presence, of, 'protein-protein', interactions, between, 'SsuE', and, 'SsuD', thought, to, be, important, in, the, flavin, transfer, 'event,', but, the, putative, interaction, sites, have, not, been, identified])].
[sujeto(['An', 'α-helix', on, 'SsuD', containing]), verbo([conserved]), complemento([charged, amino, acids, showed, a, decrease, in, percent, deuteration, in, the, presence, of, 'SsuE'])].
[sujeto(['A', 'SsuD', variant, containing, substitutions, of, the, charged, residues, showed, a, 4, -, fold]), verbo([decrease]), complemento([in, coupled, assays, that, included, 'SsuE', to, provide, reduced, 'FMN,', but, there, was, no, activity, observed, with, an, 'SsuD', variant, containing, a, deletion, of, the, 'α-helix', under, similar, conditions])].
[sujeto(['Desulfonation', by, the, 'SsuD', deletion, variant, was, only, observed, with, an]), verbo([increase]), complemento([in, enzyme, and, substrate, concentrations])].
[sujeto(['The', results, from, these, studies]), verbo([suggest]), complemento([that, optimal, transfer, of, reduced, flavin, from, 'SsuE', to, 'SsuD', requires, defined, 'protein-protein', 'interactions,', but, diffusion, can, occur, under, specified, conditions])].
[sujeto(['A', basis, is, established, for, further, studies, to, evaluate, the, structural, features, of, the, alkanesulfonate, monooxygenase, enzymes, that]), verbo([promote]), complemento([desulfonation])].
[sujeto(['VSL3']), verbo([increased]), complemento([each, bacterial, component, in, the, large, intestinal, content, of, the, 'CV', 'mice,', and, increased, these, bacteria, even, more, in, 'GF', 'mice,', likely, due, to, less, competition, for, growth, in, the, 'GF', environment])].
[sujeto(['VSL3', given, to, conventional, mice]), verbo([increased]), complemento([the, mRNAs, of, 'Cyp4v3,', alcohol, dehydrogenase, 1, ',', and, carboxyesterase, 2, 'a,', but, decreased, the, mRNAs, of, multiple, phase, 'II', 'glutathione-S-transferases'])].
[sujeto(['VSL3', given, to, 'germ-free', mice]), verbo([decreased]), complemento([the, mRNAs, of, 'UDP-glucuronosyltransferases', 1, a9, and, 2, a3])].
[sujeto(['In', 'conclusion,', conventionalization, and, 'VSL3', alter, the, expression, of, many, 'drug-metabolizing', enzyme, s, in, the, 'liver,']), verbo([suggesting]), complemento([the, importance, of, considering, &, 'quot;bacteria-drug&quot;', interactions, for, various, adverse, drug, reactions, in, patients])].
[sujeto(['Cisplatin', '(', 'CP)', is, a, major, antineoplastic, drug, for, the, treatment, of, solid, 'tumors,', but, it]), verbo([has]), complemento(['dose-dependent', renal, tubular, toxicity])].
[sujeto(['Previous', studies]), verbo([have]), complemento([shown, that, induction, of, cytochrome, 'P450', '(', 'CYP)', by, 'CP', may, play, a, role, in, the, renal, injury, of, 'CP'])].
[sujeto(['Results', showed, that, 20, -, 'HETE', '(', 1, ',', 10, ',', 50, 'μM),', a, 'CYP4A11', metabolite, of, arachidonic, 'acid,', significantly]), verbo([increased]), complemento([lactate, dehydrogenase, '(', 'LDH)', release, in, these, cells])].
[sujeto(['When', 'CP', '(', 10, '(', -, 4, ')', 'M)', and, 20, -, 'HETE', '(', 1, ',', 10, ',', 50, 'μM)', were, 'co-applied', to, these, 'cells,', 'CP-induced', 'LDH']), verbo([release]), complemento([was, significantly, exaggerated, by, 20, -, 'HETE'])].
[sujeto(['Furthermore,', 'clofibrate,', a, 'CYP4A', 'inducer,', also]), verbo([increased]), complemento(['LDH', release, in, 'CP-treated', cells])].
[sujeto(['In', 'contrast,', the, 'CYP4A', inhibitor, 'N-Hydrocy-N\'-(-4-butyl-2-methylphenyl)', formamidine, '(', 'HET-0016)']), verbo([decreased]), complemento(['LDH', release, in, 'CP-treated', cells])].
[sujeto(['The', 'AlkB', protein, was]), verbo([expressed]), complemento([by, diesel, oil, induction, and, detected, through, 'SDS-polyacrylamide', gel, electrophoresis])].
[sujeto([coli, 'DH5α)', with, the, oil, biodegradation, bacterial, consortium]), verbo([increased]), complemento([the, degradation, ratio, of, diesel, oil, at, 24, h, from, 31, '%', to, 50, '%', ',', and, the, facilitation, rates, were, increased, as, the, proportion, of, 'pCom8-GPo1', 'alkB/E'])].
[sujeto(['The', results]), verbo([suggested]), complemento([that, the, expression, of, the, 'GPo1', gene, in, 'E'])].
[sujeto([coli, 'DH5α', could]), verbo([enhance]), complemento([the, function, of, diesel, oil, degradation, by, the, bacterial, consortium])].
[sujeto([saline, significantly]), verbo([decreased]), complemento([brain, concentrations, of, 20, -, 'HETE', '(', -, 70.3, '%', ')', and, 15, -, 'epi-lipoxin', 'A4', '(', -, 60, '%', ')', in, adult, 'mice,', but, did, not, change, other, eicosanoid, concentrations])].
[sujeto(['Behavioral', changes, in, adult, mice, treated, postnatally, with, fluoxetine, may, be, related, to, reduced, brain, 'ARA', metabolism]), verbo([involving]), complemento(['CYP4A', and, 20, -, 'HETE', formation])].
[sujeto(['Many', clinically, used, drugs, or, some, alternative, medicine, compounds, are, also, known, to]), verbo([cause]), complemento(['drug-induced', liver, 'injury,', which, can, further, lead, to, fulminant, liver, failure, and, acute, deaths, in, extreme, cases])].
[sujeto(['During', liver, disease, 'process,', certain, cytochromes, 'P450', such, as, the, 'ethanol-inducible', cytochrome, 'P450-2E1', '(', 'CYP2E1)', and, 'CYP4A', isozymes, can, be]), verbo([induced]), complemento(['and/or', activated, by, alcohol, 'and/or', 'high-fat', diets, and, pathophysiological, conditions, such, as, 'fasting,', 'obesity,', and, diabetes])].
[sujeto(['Activation', of, these, 'P450', 'isozymes,']), verbo([involved]), complemento([in, the, metabolism, of, 'ethanol,', fatty, 'acids,', and, various, 'drugs,', can, produce, reactive, 'oxygen/nitrogen', species, directly, 'and/or', 'indirectly,', contributing, to, oxidative, modifications, of, 'DNA/RNA,', proteins, and, lipids])].
[sujeto(['These', highly, reactive, acetaldehyde, and, lipid, 'peroxides,', accumulated, due, to, 'ALDH2', 'suppression,', can]), verbo([interact]), complemento([with, cellular, macromolecules, 'DNA/RNA,', 'lipids,', and, 'proteins,', leading, to, suppression, of, their, normal, 'function,', contributing, to, 'DNA', 'mutations,', endoplasmic, reticulum, 'stress,', mitochondrial, 'dysfunction,', 'steatosis,', and, cell, death])].
[sujeto(['In', this, 'chapter,', we, specifically, review, the, roles, of, the, 'alcohol-metabolizing', enzymes, including, the, alcohol, 'dehydrogenase,', 'ALDH2,', 'CYP2E1,', and, other, enzymes, in]), verbo([promoting]), complemento([liver, disease])].
[sujeto(['We', also, discuss, translational, research, opportunities, with, natural, 'and/or', synthetic, 'antioxidants,', which, can]), verbo([prevent]), complemento([or, delay, the, onset, of, inflammation, and, liver, disease])].
[sujeto(['Human', 'CYP4', 'enzymes,', mainly, 'CYP4A11,', 'CYP4F2,', and, 'CYP4F3B,', hydroxylate, arachidonic, acid, at, the, omega, position, to, form, 20, -, 'HETE,', which]), verbo([has]), complemento([important, effects, in, tumor, progression, and, on, angiogenesis, and, blood, pressure, regulation, in, the, vasculature, and, kidney])].
[sujeto(['CYP2C', and, 'CYP2J', epoxygenases, convert, arachidonic, acid, to, 'anti-inflammatory', epoxyeicosatrienoic, 'acids,', which]), verbo([have]), complemento([protective, effects, in, a, variety, of, disorders, including, cardiovascular, disease, and, metabolic, syndrome])].
[sujeto(['CYP4A', and, 'CYP4F', hydroxylases]), verbo([have]), complemento([the, ability, to, metabolize, multiple, substrates, related, to, the, regulation, of, inflammation, and, lipid, 'homeostasis,', and, it, is, a, challenge, to, determine, which, substrates, are, physiologically, relevant, for, each, 'enzyme;', the, 'best-characterized', activities, include, generation, of, 20, -, hydroxyeicosatetraenoic, acid, and, inactivation, of, leukotriene, 'B4'])].
[sujeto(['The', expression, of, hepatic, 'drug-metabolizing', cytochrome, 'P450s', is]), verbo([modulated]), complemento([by, cytokines, during, 'inflammation,', resulting, in, changes, to, the, pharmacokinetics, of, prescribed, medications])].
[sujeto(['Cytochrome', 'P450s', are, therefore, the, focus, of, intersecting, challenges, in, the, pharmacology, of, 'inflammation:', not, only, do, they, represent]), verbo([targets]), complemento([for, development, of, new, 'anti-inflammatory', drugs, but, they, also, contribute, to, variability, in, drug, efficacy, or, toxicity, in, inflammatory, disease])].
[sujeto(['Animal', models, and, primary, hepatocytes]), verbo([have]), complemento([been, used, extensively, to, study, the, effects, of, cytokines, on, cytochrome, 'P450', expression, and, activity])].
[sujeto(['In', these, 'circumstances,', the, development, of, endogenous, markers, of, cytochrome, 'P450', metabolism, might]), verbo([provide]), complemento([a, useful, tool, to, reevaluate, drug, dosage, and, choice, of, therapy])].
[sujeto(['Stimulation', of, the, 'A1', adenosine, receptor, and, angiotensin, 'II', receptor, 'type-1', '(', 'AT1', 'receptor)']), verbo([causes]), complemento([vasoconstriction, through, activation, of, cytochrome, 'P450', 4, 'A', '(', 'CYP4A)', and, 'ERK1/2'])].
[sujeto(['Thus,', we, hypothesized, that, acute, angiotensin, 'II', activation, alters, the, vasomotor, response]), verbo([induced]), complemento([by, the, 'non-selective', adenosine, receptor, 'agonist,', 'NECA,', in, mouse, mesenteric, arteries, '(', 'MAs)'])].
[sujeto(['Acute', exposure, '(', 15, 'min)', to, angiotensin, 'II', attenuated, the, 'NECA-dependent', vasodilatation, and]), verbo([enhanced]), complemento([vasoconstriction])].
[sujeto(['Furthermore,', in, 'A2B', receptor, 'KO', 'mice,', the, expression, of, 'AT1', receptors, and, 'CYP4A', was]), verbo([increased]), complemento([and, the, angiotensin, 'II-induced', vasoconstriction, enhanced])].
[sujeto(['Acute', angiotensin, 'II', stimulation]), verbo([enhanced]), complemento(['A1', 'receptor-dependent', vasoconstriction, and, inhibited, 'A2B', 'receptor-dependent', 'vasodilatation,', leading, to, a, net, vasoconstriction, and, altered, vasomotor, response, to, 'NECA', in, 'MAs'])].
[sujeto(['The', objectives, of, this, study, were, to, uncover, 'Salix', 'purpurea-microbe', xenobiotic, degradation, systems, that, could, be, harnessed, in, 'rhizoremediation,', and, to, identify, microorganisms, that, are, likely]), verbo([involved]), complemento([in, these, partnerships])].
[sujeto(['purpurea\'s', ability, to]), verbo([stimulate]), complemento([the, expression, of, 10, marker, microbial, oxygenase, genes, in, a, soil, contaminated, with, hydrocarbons])].
[sujeto(['This', gene, expression, induction, is, consistent, with, 'willows\'', known, rhizoremediation, 'capabilities,', and]), verbo([suggests]), complemento([the, existence, of, 'S'])].
[sujeto(['purpurea-microbe', systems, that]), verbo([target]), complemento([many, organic, contaminants, of, interest, '(', i])].
[sujeto(['An']), verbo([enhanced]), complemento([expression, of, the, 4, genes, was, also, observed, within, the, bacterial, orders, 'Actinomycetales,', 'Rhodospirillales,', 'Burkholderiales,', 'Alteromonadales,', 'Solirubrobacterales,', 'Caulobacterales,', and, 'Rhizobiales,', which, suggest, that, members, of, these, taxa, are, active, participants, in, the, exposed, partnerships])].
[sujeto(['Although', the, expression, of, the, other, 6, marker, genes, did, not, appear, to, be]), verbo([stimulated]), complemento([by, the, plant, at, the, community, 'level,', signs, of, additional, systems, that, rest, on, their, expression, by, members, of, the, orders, 'Solirubrobacterales,', 'Sphingomonadales,', 'Actinomycetales,', and, 'Sphingobacteriales', were, observed])].
[sujeto(['Our', study, presents, the, first, 'transcriptomics-based', identification, of, microbes, whose, xenobiotic, degradation, activity, in, soil, appears]), verbo([stimulated]), complemento([by, a, plant])].
[sujeto(['An']), verbo([increasing]), complemento([number, of, studies, have, indicated, the, roles, of, 'CYP4', proteins, in, drug, 'metabolism;', 'however,', 'CYP4', expression, has, not, been, measured, in, cynomolgus, 'monkeys,', an, important, animal, species, for, drug, metabolism, studies])].
[sujeto(['Significant', correlations, were]), verbo([found]), complemento([in, liver, for, 'CYP4A11', with, lauric, acid, 11, -, /, 12, -, hydroxylation, and, for, 'CYP4F2/3', and, 'CYP4F11', with, astemizole, hydroxylation])].
[sujeto(['This', study, revealed, the, relatively, abundant, contents, of, cynomolgus, 'CYP2J2,', 'CYP4A11', and, 'CYP4Fs', in, liver, 'and/or', small, 'intestine,']), verbo([suggesting]), complemento([their, potential, roles, for, the, metabolism, of, xenobitotics, and, endogenous, substrates])].
[sujeto(['Immunofluorescence', staining, of, cryosections, of, 'perfusion-fixed', testes, showed, that, 'CYP1B1,', 'CYP2A1,', 'CYP17A1,', and, 'HSD3B', were]), verbo([expressed]), complemento([exclusively, or, mainly, in, interstitial, 'cells,', whereas, mEH, and, 'POR', protein, staining, was, detected, both, in, interstitial, cells, and, in, seminiferous, tubules])].
[sujeto(['Testicular', 'CYP1B1', and, 'CYP2A1', protein, levels, were]), verbo([decreased]), complemento([following, treatment, of, adult, rats, with, estradiol, benzoate, at, 0.004, ',', 0.04, ',', 0.4, ',', or, 4, 'μmol/kg/day', or, bisphenol, 'A', at, 400, or, 800, 'μmol/kg/day,', for, 14, 'days,', whereas, expression, of, 'HSD3B', was, unaffected])].
[sujeto(['Because', 'genome-scale', investigations]), verbo([have]), complemento([identified, many, novel, 'P450', 'isoforms,', it, is, critical, to, perform, a, systematic, characterization, of, these, 'P450s', during, liver, development])].
[sujeto(['More', than, half, of, the, mouse, 'P450s', are]), verbo([conserved]), complemento([in, 'humans,', but, there, are, more, isoforms, in, mice])].
[sujeto(['The', 'P450', mRNA, levels]), verbo([increased]), complemento([after, birth, in, mouse, 'liver,', forming, four, distinct, ontogenic, patterns])].
[sujeto(['In', 'conclusion,', the, present, study, revealed, four, patterns, of, ontogeny, for, 'P450s', in, liver, and, showed, that, many, 'P450s', within, a, genomic, cluster, exhibited, similar, ontogenic, 'patterns,', which]), verbo([suggests]), complemento([that, some, 'P450s', within, a, cluster, are, likely, regulated, by, a, common, pathway, during, liver, development])].
[sujeto(['We']), verbo([have]), complemento([used, 'maximum-likelihood', models, of, codon, substitution, to, investigate, the, role, of, adaptive, evolution, in, the, evolution, of, cytochrome, 'P450', '(', 'CYP)', sequences])].
[sujeto(['The', absence, of, signal, in, rat, 'CYP2B,', rat, 'CYP3A,', human, 'CYP2C', and, monkey, 'CYP2C']), verbo([suggests]), complemento([that, the, adaptive, evolution, did, not, operate, in, the, evolution, of, these, cytochromes])].
[sujeto(['The', absence, of, signal, for, adaptive, evolution, in, primate, 'CYP2C']), verbo([suggests]), complemento([that, the, identical, rat, and, rabbit, 'CYP2C', patterns, arose, in, the, last, common, ancestor, of, rodentia, and, lagomorpha])].
[sujeto(['Furthermore,', we]), verbo([have]), complemento([found, statistically, significant, association, of, sites, under, adaptive, evolution, and, 'Gotoh\'s', substrate, recognition, sites, in, rat, and, rabbit, 'CYP2C', '(', 5, '%', ')', ',', human, 'CYP3A', and, rat, 'CYP2D', '(', 10, '%', ')'])].
[sujeto(['From', these, 'correlations,', the, given, 'substrate-dependent', nature, of, differences, in, 'CYP', 'substrate-specificity', profiles, and, differences, in, cytochrome, 'active-site', 'residues,', we, hypothesize, that, the, most, likely, role, of, adaptive, evolution, in, the, evolution, of, cytochrome, 'P450', substrate, specificities, was, to, fix, mutations, that, permitted, an]), verbo([increased]), complemento([number, of, binding, modes, '(', thereby, expanding, the, substrate, 'repertoire)'])].
[sujeto(['The', immunochemical, data, seem, to]), verbo([suggest]), complemento([that, humans, and, wild, ruminants, share, some, similar, hepatic, 'CYP', enzymes, corresponding, to, members, of, subfamilies, 2, and, 3, ;, ruminant, liver, samples, also, contained, two, proteins, 'cross-reacting', with, 'anti-rat', 'CYP1A', antibodies])].
[sujeto(['High', activities, of, 'CYP1A', enzymes]), verbo([found]), complemento([in, liver, microsomes, of, male, fallow, deer, and, roe, deer, are, indicative, of, increased, susceptibility, of, these, species, towards, promutagens, that, are, metabolically, activated, by, these, 'CYPs'])].
[sujeto(['Oxidative', metabolism, of, testosterone, was, significantly, higher, in, wild, ruminants, than, the, values, previously]), verbo([reported]), complemento([from, bulls])].
[sujeto(['The', highest, 'CYP3A-dependent', testosterone, 6, 'beta-hydroxylase', activity, was]), verbo([found]), complemento([in, mouflons, and, fallow, deer])].
[sujeto(['A', different, pattern, of, 'CYP', activities, towards, testosterone, was]), verbo([found]), complemento([in, roe, 'deer,', which, showed, high, activities, of, testosterone, 2, 'beta-hydroxylase', and, lower, production, of, 'androstene-3,17-dione'])].
[sujeto(['An']), verbo([increased]), complemento([activity, of, 'CYP4A-dependent', laurate, 12, -, hydroxylase, found, in, roe, deer, and, mouflons, might, indicate, a, higher, metabolic, turnover, of, fatty, acids])].
[sujeto(['The', highest, hepatic, activities, specific, for, 'CYP3A,', 'CYP2C,', 'CYP2D,', and, 'CYP2E', enzymes, were]), verbo([found]), complemento([in, 'mouflon,', suggesting, that, this, species, has, the, highest, biotransformation, capacity])].
[sujeto(['The', proximal, tubule, is, a, frequent]), verbo([target]), complemento([for, nephrotoxic, compounds, due, to, 'it\'s', ability, to, transport, and, accumulate, xenobiotics, and, their, 'metabolites,', as, well, as, by, the, presence, of, an, 'organ-selective', set, of, biotransformation, enzymes])].
[sujeto(['Activities', of, the, 'CYP450', isoenzymes]), verbo([decreased]), complemento([considerably, during, culture, with, the, greatest, loss, in, activity, within, 24, h, of, culture])].
[sujeto(['Activity', of, the, phase, 'II', enzymes, remained, more, stable, 'and,', in, contrast, to, 'CYP450', 'activity,', significant, activity, was, still]), verbo([expressed]), complemento([after, 1, week, of, 'PT', cell, culture])].
[sujeto(['Thus,', despite, the, obvious, advantages, of, 'PT', cells, as, an, 'in-vitro', model, for, studies, of, biotransformation]), verbo([mediated]), complemento(['toxicity,', the, strong, time, dependency, of, especially, phase, 'I', 'and,', to, a, lesser, 'extent,', phase, 'II', biotransformation, activities, confers, limitations, to, their, application])].
[sujeto(['The', present, authors]), verbo([have]), complemento([previously, developed, a, transgenic, rat, carrying, a, chimeric, gene, of, the, mouse, whey, acidic, protein, promoter, and, the, structural, portion, of, human, growth, hormone, '(', 'GH)', gene])].
[sujeto(['Thus,', the]), verbo([loss]), complemento([of, 'male-specific', secretory, pattern, of, 'GH', results, in, feminization, of, the, pattern, of, expression, of, 'CYP', and, 'T5', 'alpha-reductase', activity, in, the, liver])].
[sujeto(['In', contrast, to, other, 'GH-deficient', models, so, far, 'studied,', an]), verbo([increase]), complemento([in, 'CYP4A1', and, a, decrease, in, 'CYP2E1', protein, expression, were, observed, in, the, low, 'GH', rat])].
[sujeto(['These', trends, are, consistent, with, the, characteristic, phenotype, of, obesity, in, the, transgenic, rat, because, 'CYP4A1', and, 'CYP2E1']), verbo([enhance]), complemento([fatty, acid, excretion, and, glyconeogenesis, from, fatty, acids, respectively])].
[sujeto(['At', least, five, 'PCP', metabolites, '(', 'c-PPC,', 't-PPC,', 'PCHP,', an, unknown, 'metabolite,', and, an, irreversibly]), verbo([bound]), complemento(['metabolite)', were, formed, by, the, various, human, liver, microsomes])].
[sujeto(['For', 'example,', the, irreversibly]), verbo([bound]), complemento([metabolite, was, formed, in, detectable, amounts, in, only, four, of, the, ten, samples])].
[sujeto(['c-PPC,', 't-PPC', and, the, irreversibly]), verbo([bound]), complemento(['PCP', metabolite, formation, rates, significantly, correlated, with, 'CYP3A', activity])].
[sujeto(['The', 'CYP3A', inhibitor, troleandomycin, was, used, to]), verbo([inhibit]), complemento([the, formation, of, 'PCP', metabolites])].
[sujeto(['Troleandomycin', inhibition, was, dose, dependent, with, the, highest, dose, producing, complete, inhibition, of, the, formation, of, 'c-PPC,', 't-PPC,', 'PCHP,', and, the, irreversibly]), verbo([bound]), complemento([metabolite])].
[sujeto(['In', 'addition,', 'PCP']), verbo([inhibited]), complemento(['CYP3A-mediated', testosterone, 6, 'beta-hydroxylation', by, 50, '%'])].
[sujeto(['These', studies]), verbo([suggest]), complemento([that, several, 'CYP', isoforms, contribute, to, 'PCP', metabolism, and, that, 'CYP3A', plays, a, major, role, in, 'PCP', biotransformation, in, human, liver, microsomes])].
[sujeto(['CYP2B1', content, was]), verbo([decreased]), complemento([to, 65, '%', of, control, during, the, acute, and, chronic, phases, of, inflammation])].
[sujeto(['Our', results, show, that, the, depletion, of, cytochrome, 'P-450']), verbo([induced]), complemento([by, inflammation, depends, on, the, severity, of, the, disease])].
[sujeto([to, regress, the, 'CL,', and, 2, controlled, internal, drug]), verbo([release]), complemento([devices, were, inserted, per, vaginum, on, d, 8, in, the, a])].
[sujeto(['Liver', biopsies, were, collected, on, d, 9, and, hepatic, mRNA, abundance, of, genes]), verbo([involved]), complemento([in, 'P4', catabolism, was, determined])].
[sujeto(['On', d, 10, ',', the, controlled, internal, drug]), verbo([release]), complemento([inserts, were, removed, and, frequent, blood, samples, were, collected, to, measure, the, rate, of, decline, in, circulating, 'P4'])].
[sujeto(['The', 'Fert+', cows, tended, to]), verbo([have]), complemento([greater, dry, matter, intake, compared, with, 'Fert-', cows, '(', +, 0.79, kg, of, dry, 'matter/d),', but, similar, milk, production, '(', 29.82, 'kg/d)'])].
[sujeto(['After', synchronized, 'ovulation,', the, rate, of]), verbo([increase]), complemento([in, circulating, 'P4', concentrations, was, greater, in, 'Fert+', cows, compared, with, 'Fert-', cows])].
[sujeto(['In', beef, 'cattle,', the, ability, to, conceive]), verbo([has]), complemento([been, associated, positively, with, size, of, the, preovulatory, follicle, '(', 'POF)'])].
[sujeto(['Proestrus', estradiol, and, subsequent, progesterone, concentrations, can]), verbo([regulate]), complemento([the, endometrium, to, affect, receptivity, and, fertility])].
[sujeto(['Endometrial', gene, expression, of, oxytocin, receptor, and, peptidase, inhibitor, 3, ',', 'skin-derived', was, 'reduced,', and, estrogen, receptor, alpha, 2, ',', 'aldo-keto', reductase, family, 1, ',', member, 'C4,', and, lipoprotein, lipase, expression, was]), verbo([increased]), complemento([in, 'LF-LCL', versus, 'SF-SCL'])].
[sujeto([',', proestrus, estradiol, and, diestrus, progesterone, 'concentrations)', and]), verbo([acts]), complemento([on, the, uterus, to, alter, endometrial, gene, expression])].
[sujeto(['Additionally,', it, is]), verbo([suggested]), complemento([that, increased, progesterone, secretion, of, cows, ovulating, larger, follicles, is, likely, due, to, increased, 'CL', size, rather, than, increased, luteal, expression, of, steroidogenic, genes])].
[sujeto(['Bile', acid, homeostasis, is, tightly]), verbo([regulated]), complemento([via, a, feedback, loop, operated, by, the, nuclear, receptors, farnesoid, 'X', receptor, '(', 'FXR)', and, small, heterodimer, partner, '(', 'SHP)'])].
[sujeto(['Contrary', to, current, 'models,', which, place, 'FXR', upstream, of, 'SHP', in, a, linear, regulatory, 'pathway,', here, we, show, that, the, phenotypic, consequences, in, mice, of, the, combined]), verbo([loss]), complemento([of, both, receptors, are, much, more, severe, than, the, relatively, modest, impact, of, the, loss, of, either, 'Fxr', or, 'Shp', alone])].
[sujeto(['Treatment', of, 'WT', mice, with, 17, -, 'OHP', was, sufficient, to]), verbo([induce]), complemento([liver, injury, that, reproduced, many, of, the, histopathological, features, observed, in, the, 'double-knockout', mice])].
[sujeto(['Therefore,', our, data, indicate, a, pathologic, role, for]), verbo([increased]), complemento([production, of, 17, -, hydroxy, steroid, metabolites, in, liver, injury, and, suggest, that, 'Fxr-/-Shp-/-', mice, could, provide, a, model, for, juvenile, onset, cholestasis])].
[sujeto(['Tumor', necrosis, factor, alpha, '(', 'TNF-alpha)']), verbo([has]), complemento([been, demonstrated, to, inhibit, steroidogenesis, in, 'Leydig', cells, at, the, transcriptional, level, of, steroidogenic, enzymes])].
[sujeto(['We', now, demonstrate, that]), verbo([nuclear]), complemento([factor, kappaB, '(', 'NF-kappaB)', activated, by, 'TNF-alpha', inhibits, the, transactivation, of, orphan, nuclear, 'receptors,', which, regulate, the, expression, of, 'steroidogenic-enzyme', genes])].
[sujeto(['TNF-alpha', treatment]), verbo([suppressed]), complemento([the, 'luteinizing-hormone-induced', or, 'Nur77/SF-1-stimulated', promoter, activity, of, 'steroidogenic-enzyme', genes, in, 'Leydig', cells])].
[sujeto(['In', 'addition,', overexpression, of, the, p65, '(', 'RelA)', subunit, of, 'NF-kappaB', showed, the, same, effect, as, 'TNF-alpha', and]), verbo([inhibited]), complemento(['Nur77', 'transactivation,', suggesting, the, involvement, of, 'NF-kappaB', activation, in, the, observed, gene, repression])].
[sujeto(['The', 'NF-kappaB', inhibition, of, 'Nur77', transactivation, was, likely, due, to, the, competition, of, p65, for, 'Nur77']), verbo([binding]), complemento([with, coactivators])].
[sujeto(['Finally,', chromatin, immunoprecipitation, assays, revealed, that, 'TNF-alpha', treatment]), verbo([caused]), complemento([the, recruitment, of, 'NF-kappaB', to, the, promoter, of, the, 'steroidogenic-enzyme', p450c17, 'gene,', supporting, the, hypothesis, that, the, 'TNF-alpha-mediated', gene, repression, involves, 'NF-kappaB', inhibition, of, the, transcriptional, activity, of, 'Nur77', and, other, orphan, nuclear, receptors])].
[sujeto(['These', findings]), verbo([provide]), complemento([a, molecular, mechanism, underlying, the, inhibition, of, testicular, steroidogenesis, by, proinflammatory, cytokines])].
[sujeto(['Steroid', profiling]), verbo([provides]), complemento([valuable, data, for, the, diagnostics, of, diseases, related, to, altered, steroidogenesis, in, the, fetal, and, maternal, compartments, and, placenta])].
[sujeto(['An']), verbo([increasing]), complemento([trend, was, demonstrated, with, advancing, gestation, toward, the, production, of, ketones, '(', and, 3, 'β-hydroxyl', groups, in, the, case, of, 3, 'α-hydroxy-steroids)', was, demonstrated, in, the, fetus, on, the, expense, of, 3, 'α-hydroxy-,', 17, 'β-hydroxy-,', and, 20, 'α-hydroxy-groups', weakening, in, the, sequence, 'C17,', 'C3,', and, 'C20'])].
[sujeto(['Previous', studies]), verbo([have]), complemento([shown, that, 'CYP3A', is, involved, in, the, metabolism, of, 17, -, 'OHPC'])].
[sujeto(['In', this, 'study,', we, evaluated, the, metabolism, of, 17, -, 'OHPC', in, adult, and, fetal, human, hepatocytes, and, in]), verbo([expressed]), complemento([cytochrome, 'P450', enzymes])].
[sujeto([17, -, 'OHPC', was, metabolized, by]), verbo([expressed]), complemento(['CYP3A7', and, by, fetal, hepatocytes])].
[sujeto(['The', metabolite, profile, was, qualitatively, different, between]), verbo([expressed]), complemento(['CYP3A4', and, 'CYP3A7'])].
[sujeto(['In', children, and, adolescents, treated, with, 'risperidone,', hyperprolactinemia, is, a, frequent, complication, that, may]), verbo([have]), complemento([clinical, repercussions])].
[sujeto(['Several', genes]), verbo([have]), complemento([been, associated, with, this, occurrence])].
[sujeto(['Among', 'patients,', hyperprolactinemia, was]), verbo([found]), complemento([in, 79, '(', 65.8, '%', ')', 'cases,', with, no, differences, regarding, 'sex,', skin, 'color,', or, being, in, monotherapy, with, risperidone, '(', 26.7, '%', of, total, 'patients)', or, not])].
[sujeto([microRNAs, '(', miRNAs, or, 'miRs)', are, small, 'non-coding', 'RNAs', that, are]), verbo([involved]), complemento([in, 'post-transcriptional', regulation, of, their, target, genes, in, a, 'sequence-specific', manner])].
[sujeto(['Dysregulation', of, miRNAs, disrupts, gene, regulatory, 'network,']), verbo([leading]), complemento([to, metabolic, syndrome, and, its, related, diseases])].
[sujeto(['We', emphasized, on, several, representative, miRNAs, that, are, functionally]), verbo([involved]), complemento([into, lipid, 'metabolism,', including, 'miR-33/33(⁎),', 'miR122,', 'miR27a/b,', 'miR378/378(⁎),', 'miR-34a', and, 'miR-21'])].
[sujeto(['Understanding', the, function, of, miRNAs, in, lipid, homeostasis, may]), verbo([provide]), complemento([potential, therapeutic, strategies, for, fatty, liver, disease])].
[sujeto(['In', mice, fed, normal, diets, and, given, injections, of, 1, ',', 25, '(', 'OH)2D3,', liver, and, plasma, concentrations, of, 1, ',', 25, '(', 'OH)2D3']), verbo([increased]), complemento([and, decreased, in, unison])].
[sujeto(['Changes', in, hepatic, 'Cyp7a1', messenger, 'RNA', '(', 'mRNA)', correlated, with, those, of, 'Cyp24a1', '(', 'a&nbsp;Vdr']), verbo([target]), complemento(['gene)', and, inversely, with, 'Shp', 'mRNA,', but, not, 'ileal&nbsp;Fgf15', mRNA])].
[sujeto(['Similarly,', incubation, with, 1, ',', 25, '(', 'OH)2D3']), verbo([increased]), complemento([levels, of, 'Cyp24a1/CYP24A1', and, 'Cyp7a1/CYP7A1', mRNA, in, mouse, and, human, 'hepatocytes,', and, reduced, levels, of, 'Shp', mRNA, in, mouse, hepatocytes])].
[sujeto(['In', 'Fxr(-/-)', and, 'wild-type', mice, with, 'hypercholesterolemia,', injection, of, 1, ',', 25, '(', 'OH)2D3', consistently, reduced, levels, of, plasma, and, liver, cholesterol, and, 'Shp', 'mRNA,', and]), verbo([increased]), complemento([hepatic, 'Cyp7a1', mRNA, and, 'protein;', these, changes, were, not, observed, in, 'Shp(-/-)', mice, given, 1, ',', 25, '(', 'OH)2D3', and, fed, 'Western', diets])].
[sujeto(['Truncation', of, the, human, small, heterodimer, partner, '(', 'SHP)', promoter, and, deletion, analyses, revealed, 'VDR-dependent', inhibition, of, 'SHP,', and, mobility, shift, assays, showed, direct]), verbo([binding]), complemento([of, 'VDR', to, enhancer, regions, of, 'SHP'])].
[sujeto(['In', 'addition,', chromatin, immunoprecipitation, analysis, of, livers, from, mice, showed, that, injection, of, 1, ',', 25, '(', 'OH)2D3']), verbo([increased]), complemento([recruitment, of, 'Vdr', and, rodent, retinoid, 'X', receptor, to, the, 'Shp', promoter])].
[sujeto(['Activation', of, the, 'VDR']), verbo([represses]), complemento([hepatic, 'SHP', to, increase, levels, of, mouse, and, human, 'CYP7A1', and, reduce, cholesterol])].
[sujeto(['Past', pharmacogenetic, research]), verbo([has]), complemento([not, explained, this, variation])].
[sujeto(['In', 'all,', 10, 'single-nucleotide', polymorphisms, '(', 'SNPs)', in, three, genes, were, potentially]), verbo([associated]), complemento([with, response, to, 'therapy:', peroxisome, 'proliferator-activated', 'receptor-delta', '(', 'PPAR-delta),', sulfotransferase, 'family,', 'cytosolic,', 1, 'C,', member, 2, '(', 'SULT1C2)', and, carbohydrate, '(', chondroitin, 6, ')', sulfotransferase, 3, '(', 'CHST3)'])].
[sujeto(['In', 'addition,', 11, 'SNPs', in, eight, genes, were]), verbo([associated]), complemento([with, toxicities, to, 'treatment:', spastic, paraplegia, 7, '(', pure, and, complicated, autosomal, 'recessive)', '(', 'SPG7),', 'CHST3,', cytochrome, 'P450,', family, 2, ',', subfamily, 'D,', polypeptide, 6, '(', 'CYP2D6),', 'N-acetyltransferase', 2, '(', arylamine, 'N-acetyltransferase)', '(', 'NAT2),', 'ATP-binding', 'cassette,', 'sub-family', 'C', '(', 'CFTR/MRP),', member, 6, '(', 'ABCC6),', 'ATPase,', 'Cu++', 'transporting,', alpha, polypeptide, '(', 'ATP7A),', cytochrome, 'P450,', family, 4, ',', subfamily, 'B,', polypeptide, 1, '(', 'CYP4B1)', and, solute, carrier, family, 10, '(', 'sodium/bile', acid, cotransporter, 'family),', member, 2, '(', 'SLC10A2)'])].
[sujeto(['These', findings, highlight, the, role, that, 'non-CYP450', metabolizing, enzymes, and, transporters, may]), verbo([have]), complemento([in, the, pharmacology, of, docetaxel, and, thalidomide])].
[sujeto(['Moreover,', etoricoxib, '(', 0.1, -, 100, 'microM)', was]), verbo([found]), complemento([to, be, a, relatively, weak, inhibitor, '(', 'IC(50)', &, 'gt;', 100, 'microM)', of, multiple, 'P450s', '(', 'CYP1A2,', 'CYP2D6,', 'CYP3A,', 'CYP2E1,', 'CYP2C9,', and, 'CYP2C19)', in, human, liver, microsomes])].
[sujeto(['In', this, 'study,', a, transgenic, mouse, model]), verbo([expressing]), complemento([human, 'PXR,', 'CAR,', 'CYP3A4/CYP3A7', and, 'CYP2D6', '(', 'Tg-Composite),', was, utilized, to, investigate, the, effect, of, induction, mediated, by, rifampin, on, the, pharmacokinetics, of, tamoxifen, and, its, metabolites])].
[sujeto(['In', 'human,', tamoxifen, is, metabolized, primarily, by, 'CYP3A4', and, 'CYP2D6,', and, 'multiple-day', treatment, with, rifampin]), verbo([decreased]), complemento([tamoxifen, exposure, by, 6.2, -, fold])].
[sujeto(['In', the, 'Tg-Composite', 'model,', 'pre-treatment', with, rifampin]), verbo([decreased]), complemento([tamoxifen, 'AUC0-8', from, 0.82, to, 0.2, 'µM*hr;', whereas, 'AUC0-8', of, 4, 'OHT,', 'NDM', and, endoxifen, decreased, by, 3.4, -, ',', 4.7, -, and, 1.3, -, 'fold,', 'respectively,', mirroring, the, clinic, observations])].
[sujeto(['In', the, humanized, 'PXR-CAR', '(', 'hPXR-CAR)', 'model,', rifampin]), verbo([decreased]), complemento(['AUC0-8', of, tamoxifen, and, its, metabolites, by, approximately, 2, -, fold])].
[sujeto(['In', vitro, kinetics, determined, in, microsomes, prepared, from, livers, of, the, 'Tg-Composite', animals, showed, that, although, 'Km', values, were, not, different, between, 'vehicle-', and, 'rifampin-treated', 'groups,', rifampin]), verbo([increased]), complemento([the, 'Vmax', for, the, 'CYP3A4-mediated', pathways])].
[sujeto(['Consequently,', 'Tg-Composite', model, may, be, a, suitable, tool, to, examine, the, extent, of, 'rifampin-mediated', induction, for, other, compounds, whose, metabolism, is]), verbo([mediated]), complemento([by, 'CYP3A4', 'and/or', 'CYP2D6'])].
[sujeto(['Protein', expression, levels, of, 'drug-metabolizing', enzymes, and, transporters, in, human, jejunal, tissues, excised, from, morbidly, obese, subjects, during, gastric, bypass, surgery, were, evaluated, using, quantitative]), verbo([targeted]), complemento([absolute, proteomics])].
[sujeto(['Smokers', showed]), verbo([increased]), complemento([levels, of, 'UGT1A1', and, 'UGT1A3'])].
[sujeto(['These', findings]), verbo([provide]), complemento([a, basis, for, understanding, the, changes, in, molecular, mechanisms, of, jejunal, metabolism, and, 'transport,', as, well, as, their, interindividual, 'variability,', in, morbidly, obese, patients])].
[sujeto(['Pain', clinicians]), verbo([have]), complemento([always, been, challenged, by, the, variability, of, response, to, pain, treatment])].
[sujeto(['Differences', in, the, degree, of, pain, stimulation, and, pain, 'sensitivity,', weight, and, age, 'differences,', prior, opioid, use, and, 'tolerance,', as, well, as, the, differences, in, bioavailability, of, various, opioid, formulations]), verbo([have]), complemento([been, cited, as, causes, for, the, wide, variability, in, analgesia, seen, with, opioids])].
[sujeto(['The', 'CYP450', enzymes]), verbo([involved]), complemento([in, the, metabolism, and, activity, of, opioids, and, adjuvant, analgesics, are, genetically, 'controlled,', as, are, the, opioid, receptors, and, a, variety, of, brain, chemistries])].
[sujeto(['Recent', research, findings]), verbo([suggest]), complemento([the, relationship, between, genetic, predisposition, and, clinical, 'behavior,', including, the, risk, of, opioid, misuse, and, addiction])].
[sujeto(['While', urine, drug, testing, may, hint, at, genetic, issues, regarding, opioid, 'metabolism,', cheek, swab, 'DNA', testing]), verbo([has]), complemento([become, economically, 'viable,', and, we, review, the, current, and, future, genetic, pain, issues, that, may, influence, the, decisions, that, pain, clinicians, make, every, day])].
[sujeto(['For', cytochrome, 'P450', enzymes, 1, '(', 'CYP1)', 'family,', the, expression, of, 'CYP1A2', was]), verbo([decreased]), complemento([90, '%', in, 'HCC,', 80, '%', in, alcoholic, 'cirrhosis,', and, 65, '%', in, severe, cirrhosis])].
[sujeto(['For', 'CYP2', 'family,', the, expression, of, 'CAR', was]), verbo([decreased]), complemento([50, '%', in, 'HCC,', but, increased, 50, '%', in, 'peri-HCC', tissues])].
[sujeto(['Similar']), verbo([decreases]), complemento(['(', about, 50, '%', ')', of, 'CYP2B6,', 'CYP2C9,', 'CYP2C19,', 'CYP2D6', and, 'CYP2E1', were, observed, in, 'HCC,', as, compared, to, 'peri-HCC', tissues, and, normal, livers])].
[sujeto(['CYP2C19', were]), verbo([decreased]), complemento([in, all, 'end-stage', liver, diseases, and, 'CYP2E1', also, decreased, in, alcoholic, cirrhosis, and, severe, cirrhosis])].
[sujeto(['For', 'CYP3', 'family,', the, expression, of, 'PXR', was]), verbo([decreased]), complemento([60, '%', in, 'HCC,', together, with, decreases, in, 'CYP3A4,', 'CYP3A5,', and, 'CYP3A7'])].
[sujeto(['In', 'contrast,', the, expression, of, 'CYP3A7', was, slightly]), verbo([increased]), complemento([in, 'HBV', cirrhosis])].
[sujeto(['The', expression, of, 'CYP4A11', was]), verbo([decreased]), complemento([85, '%', in, 'HCC,', 7, '%', in, alcoholic, cirrhosis, and, severe, liver, 'cirrhosis,', along, with, decreases, in, 'PPARα'])].
[sujeto(['The', expression, of, 'CYP', enzyme, genes, and, corresponding]), verbo([nuclear]), complemento([receptors, was, generally, decreased, in, 'end-stage', liver, 'diseases,', and, significant, differences, in, gene, expression, were, evident, between, 'peri-HCC', and, 'HCC'])].
[sujeto(['We']), verbo([found]), complemento([that, the, lyophilized, form, of, 'TL', in, 80, '%', ethanol, possessed, the, antioxidant, levels, within, the, range, 23, ',', 163.9, ±, 1457.4, 'Trolox', equivalents, 'mM/kg', dry, mass, and, 899.8, ±, 14.5, gallic, acid, equivalents, 'mM/kg', dry, mass, using, the, oxygen, radical, absorbance, capacity, assay, and, the, 'Folin', 'Ciocalteu', phenol, 'assay,', respectively])].
[sujeto(['TL', extract, '(', 'TLE)', at, a, high, dose, '(', 3000, 'mg/L)']), verbo([induced]), complemento([cytotoxicity, according, to, the, neutral, red, assay, and, the, 'MTT', assay])].
[sujeto(['TLE', significantly]), verbo([enhanced]), complemento([the, mRNA, expression, of, 'CYP1A1,', 'CYP1A2,', 'CYP2B6,', 'CYP3A4,', and, 'PPARg,', but, it, significantly, inhibited, the, mRNA, expression, of, 'CYP3A7,', 'CYP2D6,', and, 'CYP2E1', '(', 'P', &, 'lt;', 0.05, ')', by, reverse, 'transcription-polymerase', chain, reaction])].
[sujeto(['Moreover,', 'TLE', could]), verbo([increase]), complemento([the, activity, of, a, multidrug, 'transporter,', 'P-glycoprotein,', which, accelerated, the, excretion, of, toxic, substances, from, 'HepG2', cells])].
[sujeto(['It', is]), verbo([suggested]), complemento([that, 'TLE', may, be, beneficial, for, detoxification, by, reducing, oxidative, 'stress,', minimizing, toxicity, by, regulating, the, expression, 'CYP450', mRNAs, for, suitable, production, of, 'CYP450', 'isoenzymes,', and, increasing, 'PPARγ', mRNA, expression, and, 'P-glycoprotein', activity, in, 'HepG2', 'cells,', thereby, maintaining, xenobiotic, biotransformation, balance])].
[sujeto(['Cytochrome', 'P450', enzymes, '(', 'CYPs', or, 'P450s)', are, the, most, important, enzymes]), verbo([involved]), complemento([in, the, phase, 'I', metabolism, of, drugs, '(', and, other, 'xenobiotics)', in, 'humans,', and, the, corresponding, drug, metabolites, are, needed, as, reference, substances, for, their, structural, confirmation, and, for, pharmacological, or, toxicological, characterization])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, biotechnological, synthesis, of, such, metabolites, is, feasible, by, 'whole-cell', biotransformation, with, human, 'CYPs', recombinantly, expressed, in, the, fission, yeast, 'Schizosaccharomyces', pombe])].
[sujeto(['Risperidone', 'long-acting', injection, '(', 'RLAI)', avoids, the, 'first-pass', 'effect,', and, little, is, known, about, the, influence, of, gene, polymorphisms]), verbo([involved]), complemento([in, its, pharmacokinetics])].
[sujeto(['Furthermore,', 'high-density', lipoprotein, cholesterol, was, positively, correlated, with, 'CYP3A', activity, '(', 'P', =, 0.01, ')', ',', and, the, 'NR1/2', '(', 'rs2472677)', polymorphism, was]), verbo([associated]), complemento([with, different, adverse, effects, including, prolactin, plasma, levels, adjusted, for, age, and, sex])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([on, the, influence, of, 'NR1/2', polymorphisms, on, 'RLAI', exposure, and, on, 'drug-induced', adverse, effects])].
[sujeto(['The', demand, for, cryopreserved, hepatocytes, is]), verbo([increasing]), complemento([for, both, clinical, and, research, purposes])].
[sujeto(['We', first, compared, controlled, rate, freezing, to, polystyrene, box, freezing, and, did, not]), verbo([find]), complemento([any, significant, change, between, the, groups])].
[sujeto(['However,', the, highly]), verbo([expressed]), complemento(['P450', enzymes, were, 'CYP3A4,', 'CYP3A5,', 'CYP4F3,', 'CYP2C18,', 'CYP2C9,', 'CYP2D6,', 'CYP3A7,', 'CYP11B1', and, 'CYP2B6', in, the, human])].
[sujeto(['For', phase, 'II', 'enzymes,', glucuronosyltransferase, 'Ugt1a6,', glutathione, 'S-transferases', 'Gstp1,', 'Gstm3', and, 'Gsta2,', sulfotransferase, 'Sult1b1', and, acyltransferase, 'Dgat1', were, highly]), verbo([expressed]), complemento([in, the, mouse])].
[sujeto(['In', 'conclusion,', this, study]), verbo([has]), complemento([shown, for, the, first, time, a, significant, in, vivo, role, of, 'CYP2C19', and, the, 'P-gp', transporter, in, the, pharmacokinetics, of, clozapine])].
[sujeto(['CYP1A2', is, the, main, 'CYP', isoform]), verbo([involved]), complemento([in, clozapine, 'metabolism,', with, 'CYP2C19', contributing, 'moderately,', and, 'CYP3A4', contributing, only, in, patients, with, reduced, 'CYP1A2', activity])].
[sujeto(['In', 'mammals,', 'Cytochrome', 'P450', '(', 'CYP)', enzymes, are]), verbo([bound]), complemento([to, membranes, of, the, endoplasmic, reticulum, and, 'mitochondria,', where, they, are, responsible, for, the, oxidative, metabolism, of, many, xenobiotics, as, well, as, organic, endogenous, compounds])].
[sujeto(['The', data, from, surgical, human, liver, samples, establish, that, the, isoforms, 'CYP1A2,', 'CYP2A6,', 'CYP2B6,', 'CYP2E1,', 'CYP2C8,', 'CYP2D6,', 'CYP3A4,', 'CYP3A7,', and, 'CYP8B1', are]), verbo([phosphorylated]), complemento([in, vivo])].
[sujeto(['Although', most, of, 'P450', inhibitors]), verbo([decrease]), complemento([the, metabolic, activities, mediated, by, the, corresponding, 'P450', 'forms,', unexpected, 'phenomena,', which, are, called, as, activation, or, heterotropic, 'cooperativity,', have, been, often, observed])].
[sujeto(['We', summarize, 'Michaelis-Menten', constants, '(', 'K(m)),', maximal, velocities, '(', 'V(max)),', 'V(max)/K(m)', '(', intrinsic, 'clearance)', 'values,', 'and/or', metabolic, activities, for, 22, activators, and, 24, substrates, '(', 30, 'reactions)', mainly]), verbo([mediated]), complemento([by, 'CYP3A4', among, human, 'P450', forms])].
[sujeto(['Although', an, allosteric, mechanism]), verbo([has]), complemento([been, invoked, to, explain, the, 'cooperativity,', the, activation, patterns, or, phenomena, are, dependent, on, substrates, and, selected, enzyme, sources, in, vitro])].
[sujeto(['Interestingly,', recent, studies]), verbo([have]), complemento([been, shown, that, human, 'P450', forms, other, than, 'CYP3A4,', such, as, 'CYP1A2,', 'CYP2C8,', 'CYP2C9,', 'CYP2D6,', and, 'CYP3A7,', are, also, activated, by, some, 'compounds,', whereas, there, are, few, reports, on, 'CYP3A5'])].
[sujeto(['Several', models, describing, interaction, among, 'substrates,', 'effectors,', and, enzymes]), verbo([have]), complemento([been, 'proposed,', 'however,', the, detailed, mechanism, for, the, activation, is, still, generally, unknown, even, though, some, crystal, structures, have, been, shown])].
[sujeto(['A', few, cases, of, the, cooperativity, of, 'CYP3A', in, experimental, animals]), verbo([have]), complemento([been, 'presented,', whereas, the, clinical, significance, of, 'P450', cooperativity, is, still, unclear])].
[sujeto(['The', collective, findings]), verbo([provide]), complemento([fundamental, and, useful, information, for, the, activation, of, 'P450s', by, chemicals, despite, some, contradictive, kinetic, parameters, for, the, same, reactions, reported])].
[sujeto(['To', understand, causal, 'factor(s)', and, 'mechanism(s)', for, such, different]), verbo([reports]), complemento([summarized, here, is, still, one, of, the, hot, research, topics, to, be, solved, in, current, activation, reactions])].
[sujeto(['The', proliferation, and, viability, of, 'HFL', cells, were, evaluated, using, 3, -, '[', 4, ',', 5, -, 'dimethylthiazol-2-yl]-2,5-diphenyl', tetrazolium, bromide, 'assay,', and, the, cells]), verbo([increased]), complemento([by, more, than, 100, -, fold, by, culture, for, 15, d])].
[sujeto(['The', levels, of, expression, of, albumin, '(', 'ALB),', hepatocyte]), verbo([nuclear]), complemento([factor, 4, 'alpha,', hepatocyte, growth, 'factor,', 'CYP3A4,', 'CYP3A5,', and, 'CYP3A7', mRNAs, in, 'HFL', cells, increased, with, culture, 'period,', while, that, of, 'alpha-fetoprotein', '(', 'AFP)', mRNA, decreased, gradually])].
[sujeto(['In', 'HepG2', 'cells,', 'however,', the, expression, levels, of, 'ALB', and, 'AFP', mRNAs, were, not, 'changed,', and, the, levels, of, expression, of, 'CYP3A4,', 'CYP3A5,', and, 'CYP3A7', mRNAs]), verbo([decreased]), complemento([gradually])].
[sujeto(['With', the, exception, of, 'CYP1A2,', all, of, the, 'CYP', mRNAs]), verbo([expressed]), complemento([in, 'HepG2', cells, were, detected, in, 'HFL', cells])].
[sujeto(['CYP3A5', mRNA, expression, was]), verbo([increased]), complemento([to, a, level, 3, -, fold, greater, than, control, by, 'DEX'])].
[sujeto(['On', the, other, 'hand,', 'CYP3A4,', 'CYP3A5,', and, 'CYP3A7', mRNA, expression, levels, in, 'HepG2', cells, were]), verbo([increased]), complemento([from, 2, -, to, 3, -, fold, by, treatment, with, 'DEX', and, 'RIF'])].
[sujeto(['Pregnane', 'X', receptor, mRNA, was]), verbo([expressed]), complemento([in, 'HepG2', 'cells,', but, not, 'HFL', cells])].
[sujeto(['Mice']), verbo([expressing]), complemento([human, 'CYP1A1,', 'CYP1A2,', 'CYP2E1,', 'CYP2D6,', 'CYP3A4,', and, 'CYP3A7', were, generated, and, characterized])].
[sujeto(['With', this, mouse, 'line,', 'CYP3A4,', under, certain, 'circumstances,', was]), verbo([found]), complemento([to, alter, the, serum, levels, of, estrogen, resulting, in, deficient, lactation, and, low, pup, survival, as, a, result, of, underdeveloped, mammary, glands])].
[sujeto(['The', pregnane, 'X', receptor, '(', 'PXR)', is, also]), verbo([involved]), complemento([in, induction, of, drug, metabolism, through, its, target, genes, including, 'CYP3A4'])].
[sujeto(['Since', species, differences, exist, in, ligand, specificity, between, human, and, 'mice,', a, 'PXR-humanized', mouse, '(', 'hPXR)', was, produced, that]), verbo([responds]), complemento([to, human, 'PXR', activators, such, as, rifampicin, but, does, not, respond, to, the, rodent, activator, pregnenalone, 16, 'alpha-carbonitrile'])].
[sujeto(['This', study, was, designed, to, study, the, in, vitro, metabolism, of, 'indiplon,', a, novel, hypnotic, 'agent,', and, to, assess, its, potential, to]), verbo([cause]), complemento([drug, interactions])].
[sujeto(['The', 'N-deacetylation', reaction, did, not]), verbo([require]), complemento(['NADPH,', and, appeared, to, be, catalyzed, by, 'organophosphate-sensitive', microsomal, carboxylesterases])].
[sujeto(['The', 'N-demethylation', of, indiplon, was, catalyzed, by, 'CYP3A4/5', based, on, the, following, 'observations:', '(', 1, ')', the, 'sample-to-sample', variation, in, 'N-demethylation', of, indiplon, '(', '[', 'S]', =, 100, 'microM)', in, a, bank, of, human, liver, microsomes, was, strongly, correlated, with, testosterone, 6, 'beta-hydroxylase', '(', 'CYP3A4/5)', activity, '(', 'r(2)', =, 0.98, ')', ',', but, not, with, any, other, 'CYP', 'enzyme;', '(', 2, ')', recombinant, 'CYP1A1,', 'CYP1A2,', 'CYP3A4,', 'CYP3A5', and, 'CYP3A7', had, the, ability, to, catalyze, this, 'reaction;', '(', 3, ')', the, 'N-demethylation', of, indiplon, was]), verbo([inhibited]), complemento([by, 'CYP3A4/5', inhibitors, '(', ketoconazole, and, 'troleandomycin),', but, not, by, a, 'CYP1A2', inhibitor, '(', 'furafylline)'])].
[sujeto(['In', pooled, human, liver, 'microsomes,', indiplon, exhibited, a, weak, capacity, to]), verbo([inhibit]), complemento(['CYP1A2,', 'CYP2A6,', 'CYP2C8,', 'CYP2C9,', 'CYP2D6,', 'CYP2E1,', 'CYP3A4/5', and, carboxylesterase, '(', 'p-nitrophenylacetate', 'hydrolysis)', activities, '(', 'IC50', &, 'gt;/=', 20, 'microM)'])].
[sujeto(['In', 'addition,', we, comment, on, the, effects, on, 'CYP', expression, of, states]), verbo([associated]), complemento([with, profound, hormonal, 'changes,', such, as, 'pregnancy,', 'malnutrition,', 'obesity,', diabetes, 'mellitus,', systemic, 'inflammation,', and, conditions, of, altered, extracellular, fluid, volume, or, osmolality])].
[sujeto([to, mice, in, the, presence, and, absence, of, the, 'CYP3A', and, 'ABCG2', 'inhibitor,', 'ritonavir,', there, was, an]), verbo([increase]), complemento([in, 'BPU', plasma, exposure, and, decrease, in, metabolite, exposure, but, no, overall, change, in, cumulative, exposure, to, 'BPU', and, the, cytotoxic, metabolites])].
[sujeto(['Thus,', we, conclude, that, '(', 'a)', 'CYP3A4', and, 'CYP1A1', are, the, predominant, cytochrome, 'P450', enzymes, that, catalyze, 'BPU', 'metabolism,', '(', 'b)', 'BPU', is, metabolized, to, two, cytotoxic, and, four, noncytotoxic, 'metabolites,', and, '(', 'c)', ritonavir]), verbo([inhibits]), complemento(['BPU', metabolism, to, improve, the, systemic, exposure, to, 'BPU', without, altering, cumulative, exposure, to, 'BPU', and, the, cytotoxic, metabolites])].
[sujeto(['The', etiology, of, nasopharyngeal, carcinoma, '(', 'NPC)', is]), verbo([associated]), complemento([with, environmental, and, hereditary, factors])].
[sujeto(['Xenobiotics', from, environment, must, be]), verbo([activated]), complemento([to, derive, carcinogens])].
[sujeto(['Several', cytochrome, 'P450', '(', 'CYP450)', metabolic, enzymes]), verbo([participate]), complemento([to, the, activation, of, 'pre-carcinogens,', and, the, genetic, polymorphism, of, those, genes, is, associated, with, metabolic, polymorphism, and, susceptibility, to, cancer])].
[sujeto(['The', expression, of, a, great, number, of, 'CYP450', genes, was, detected, in, human, 'nasopharynx,', some, of, which, might]), verbo([participate]), complemento([to, the, activation, of, 'pre-carcinogen', in, human, nasopharynx])].
[sujeto(['Several', 'CYP', enzymes, metabolically]), verbo([activate]), complemento([procarcinogens, to, genotoxic, intermediates])].
[sujeto(['Controversial', findings]), verbo([suggest]), complemento([that, colorectal, and, prostate, cancers, may, be, associated, to, 'CYP', 'polymorphisms,', whereas, no, evidences, for, a, relevant, association, with, breast, or, bladder, cancers, were, reported])].
[sujeto(['This', review, discusses, on]), verbo([causes]), complemento([of, heterogeneity, in, the, proposed, 'associations,', controversial, findings, on, cancer, 'risk,', and, identifies, topics, that, require, further, investigation])].
[sujeto(['We', tested, the, inhibition, potency, of, azamulin, toward, 18, cytochromes, 'P450', using, human, liver, microsomes, or, microsomes, from, insect, cells]), verbo([expressing]), complemento([single, isoforms])].
[sujeto(['The', 'IC(50)', value, with, heterologously]), verbo([expressed]), complemento(['CYP3A4', was, 15, -, fold, and, 13, -, fold, less, than, those, of, 'CYP3A5', and, 'CYP3A7,', respectively])].
[sujeto(['Preincubation', of, 4.8, microM, azamulin, in, the, presence, of, 'NADPH', for, 10, min]), verbo([inhibited]), complemento([approximately, 95, '%', of, testosterone, 6, 'beta-hydroxylase', activity, compared, with, preincubation, in, the, absence, of, 'NADPH'])].
[sujeto(['Incubation', of, azamulin, with, heterologously]), verbo([expressed]), complemento(['CYP3A4', yielded, a, type, 'I', binding, spectrum, with, a, spectral, dissociation, constant, of, 3.5, 'microM,', whereas, no, interaction, was, found, with, 'CYP2D6'])].
[sujeto(['Aqueous', solubility, was]), verbo([found]), complemento([to, be, &, 'gt;300', microM])].
[sujeto(['β-Glucan,', a, soluble, fiber, with, viscous, 'property,']), verbo([has]), complemento([a, documented, 'cholesterol-lowering', effect])].
[sujeto(['Our', second, aim, was, to, determine, whether, any, 'gene-diet', interactions, are]), verbo([associated]), complemento([with, the, 'cholesterol-lowering', efficacy, of, 'β-glucan'])].
[sujeto(['This', effect, of, 'HMW', 'β-glucan', was]), verbo([associated]), complemento([with, 'gene-diet', 'interaction,', whereby, individuals, with, the, single, nucleotide, polymorphism, '(', 'SNP)', 'rs3808607-G', allele, '(', 'GG', or, 'GT)', of, the, cytochrome, 'P450', family, 7, subfamily, 'A', member, 1, gene, '(', 'CYP7A1)', had, greater, responses, to, 3, g, 'HMW', 'β-glucan/d', in, lowering, 'TC', than, 'TT', carriers, '(', 'P=', 0.0006, ')'])].
[sujeto(['Diabetic', patients]), verbo([have]), complemento([an, increased, risk, of, developing, cardiovascular, 'diseases,', which, are, the, leading, cause, of, death, in, developed, countries])].
[sujeto(['Although', multivitamin, products, are, widely, used, as, dietary, 'supplements,', the, effects, of, these, products]), verbo([have]), complemento([not, been, investigated, in, the, diabetic, heart, yet])].
[sujeto([100, 'mg/kg)', or, citrate, buffer, to]), verbo([induce]), complemento([diabetes])].
[sujeto([metallothionein, 1, 'a;', metallothionein, 2, 'a;', 'interleukin-6', 'receptor;', heme, oxygenase, '(', 'decycling)', 1, ;, and, glutathione, 'S-transferase,', theta, 3, ')', ',', and, hormones]), verbo([associated]), complemento([with, insulin, resistance, '(', e])].
[sujeto(['resistin;', 'FK506']), verbo([binding]), complemento([protein, 5, ;, 'galanin/GMAP', 'prepropeptide)'])].
[sujeto([similar, to, apolipoprotein, 'L2;', brain]), verbo([expressed]), complemento(['X-linked', 1, ;, prostaglandin, b2, synthase, '(', 'brain)'])].
[sujeto(['MVT-treatment', in, diabetic, rats, showed, opposite, gene, expression, changes, in, the, cases, of, 19, genes]), verbo([associated]), complemento([with, diabetic, cardiomyopathy])].
[sujeto(['While', it]), verbo([has]), complemento([long, been, recognized, that, bile, acids, are, essential, for, solubilizing, lipophilic, nutrients, in, the, small, 'intestine,', the, discovery, in, 1999, that, bile, acids, serve, as, ligands, for, the, nuclear, receptor, farnesoid, 'X', receptor, '(', 'FXR)', opened, the, floodgates, in, terms, of, characterizing, their, actions, as, selective, signaling, molecules])].
[sujeto(['Bile', acids]), verbo([act]), complemento([on, 'FXR', in, ileal, enterocytes, to, induce, the, expression, of, fibroblast, growth, factor, '(', 'FGF)15/19,', an, atypical, 'FGF', that, functions, as, a, hormone])].
[sujeto(['FGF15/19', subsequently]), verbo([acts]), complemento([on, a, cell, surface, receptor, complex, in, hepatocytes, to, repress, bile, acid, synthesis, and, 'gluconeogenesis,', and, to, stimulate, glycogen, and, protein, synthesis])].
[sujeto(['FGF15/19', also]), verbo([stimulates]), complemento([gallbladder, filling])].
[sujeto(['Thus,', the, bile, 'acid-FXR-FGF15/19', signaling, pathway]), verbo([regulates]), complemento([diverse, aspects, of, the, postprandial, enterohepatic, response])].
[sujeto(['Pharmacologically,', this, endocrine, pathway]), verbo([provides]), complemento([exciting, new, opportunities, for, treating, metabolic, disease, and, bile, 'acid-related', disorders, such, as, primary, biliary, cirrhosis, and, bile, acid, diarrhea])].
[sujeto(['Because', 'Se', status, affects, testosterone, synthesis, and, frequency, of, sperm, 'abnormalities,', and, the, form, of, 'Se', supplemented, to, cows, affects, 'tissue-specific', gene, 'expression,', the, objective, of, this, study, was, to, determine, whether, the, form, of, 'Se', consumed, by, cows, during, gestation, would, affect, the, expression, of, mRNAs, that]), verbo([regulate]), complemento([steroidogenesis, 'and/or', spermatogenesis, in, the, neonatal, calf, testis])].
[sujeto(['Twenty-four', predominantly, 'Angus', cows, were, assigned, randomly, to]), verbo([have]), complemento(['individual,', ad, 'libitum,', access, of, a, mineral, mix, containing, 35, &, 'nbsp;ppm', of, 'Se', in, 'free-choice', 'vitamin-mineral', mixes, as, either, inorganic, '(', 'ISe),', organic, '(', 'OSe),', or, a, 50, /, 50, mix, of, 'ISe', and, 'OSe', '(', 'MIX),', starting, 4, &, 'nbsp;months', prior, to, breeding, and, continuing, throughout, gestation])].
[sujeto(['Thirteen', male, calves, were, born, over, a, 3, -, month, period, '(', 'ISe,', n, =, 5, ;, 'OSe,', n, =, 4, ;, 'MIX,', n, =, 4, ')', ',', castrated, within, 2, &, 'nbsp;days', of, 'birth,', and, extracted, testis, 'RNA', subjected, to, transcriptomal, analysis, by, microarray, '(', 'Affymetrix', 'Bovine', 1.0, 'ST', 'arrays)', and]), verbo([targeted]), complemento([gene, expression, analysis, by, 'real-time', 'reverse-transcription', 'PCR', '(', 'RT-PCR)', of, mRNAs, encoding, proteins, known, to, affect, steroidogenesis, 'and/or', spermatogenesis])].
[sujeto(['The', form, of, dam, 'Se', affected, '(', 'P', &, 'lt;', 0.05, ')', the, expression, of, 853, annotated, 'genes,', including, 17, mRNAs, putatively]), verbo([regulating]), complemento([steroidogenesis, 'and/or', spermatogenesis])].
[sujeto(['If', these, profiles, are]), verbo([maintained]), complemento([throughout, 'maturation,', then, the, form, of, 'Se', fed, to, dams, may, impact, bull, fertility, and, the, development, of, 'Se', 'form-dependent', mineral, mixes, that, target, gestational, development, of, the, testis, are, warranted])].
[sujeto(['Recent', evidence]), verbo([suggests]), complemento([that, early, 'time-lapse', parameters, are, predictive, of, blastocyst, development])].
[sujeto(['Similarly,', a, number, of, candidate, genes, in, cumulus, cells]), verbo([have]), complemento([been, identified, as, potential, markers, of, embryo, viability])].
[sujeto(['Relationships', between, 'time-lapse', parameters, and, candidate, gene, expression, in, cumulus, cells]), verbo([have]), complemento([not, been, 'investigated,', and, a, combined, analysis, of, these, markers, has, not, been, attempted, in, relation, to, embryo, quality])].
[sujeto(['Expression', levels, of, 27, candidate, genes, for, embryo, viability, were, measured, in, 78]), verbo([associated]), complemento([cumulus, cell, masses, using, quantitative, 'real-time', 'PCR'])].
[sujeto(['Cumulus', cell, expression, of, 11, candidate, genes]), verbo([involved]), complemento([in, energy, metabolism, '(', 'ATPase,', 'H+', 'transporting,', lysosomal, 70, 'kDa,', 'V1', subunit, 'A', '(', 'ATP6V1A),', 'NADH', dehydrogenase, '(', 'ubiquinone)', 1, alpha, 'subcomplex,', 1, ',', 7.5, kDa, '(', 'NDUFA1),', lactate, dehydrogenase, 'A', '(', 'LDHA),', phosphofructokinase, platelet, '(', 'PFKP)', and, solute, carrier, family, 2, member, 4, '(', 'SLC2A4),', mitochondrial, biogenesis, '(', 'DNA', directed, 'RNA', 'polymerase,', mitochondrial, '(', 'POLRMT)', and, transcription, factor, 'A,', mitochondrial, '(', 'TFAM),', signalling, '(', 'prostaglandin-endoperoxide', synthase, 2, ')', ',', steroidogenesis, '(', cytochrome, 'P450,', family, 11, ',', subfamily, 'A,', polypeptide, 1, '(', 'CYP11A1)', and, cell, stress, '(', heat, shock, 70, kDa, protein, 5, '(', 'HSPA5)', and, peroxiredoxin, 3, '(', 'PRDX3))', correlated, to, 'time-lapse', parameters, of, the, developing, 'embryo,', largely, for, t3C, onwards, '(', all, 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['Results', presented, in, this, study]), verbo([suggest]), complemento([that, some, of, the, variation, of, 'time-lapse', parameters, may, be, related, to, cumulus, cell, gene, expression, and, thus, the, ovarian, microenvironment, in, which, the, oocyte, developed])].
[sujeto(['Funding', was]), verbo([provided]), complemento([by, 'Fertility', 'Associates', 'Ltd,', the, 'Auckland', 'Medical', 'Research', 'Foundation', and, the, 'University', of, 'Auckland'])].
[sujeto(['All', other, authors, of, this, manuscript]), verbo([have]), complemento([nothing, to, declare, and, no, conflict, of, interest, that, could, be, perceived, as, prejudicing, the, impartiality, of, the, research, reported])].
[sujeto(['Mice', deficient, in, the]), verbo([nuclear]), complemento([hormone, receptor, 'RORγt', have, defective, development, of, 'thymocytes,', lymphoid, 'organs,', 'Th17', 'cells,', and, type, 3, innate, lymphoid, cells])].
[sujeto(['RORγt']), verbo([binds]), complemento([to, oxysterols, derived, from, cholesterol, 'catabolism,', but, it, is, not, clear, whether, these, are, its, natural, ligands])].
[sujeto(['Analysis', of, lipids]), verbo([bound]), complemento([to, 'RORγ', identified, molecules, with, molecular, weights, consistent, with, 'CBIs'])].
[sujeto(['Furthermore,', 'CBIs', stabilized, the, 'RORγ', 'ligand-binding', domain, and]), verbo([induced]), complemento([coactivator, recruitment])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, 'CBIs', play, a, role, in, lymphocyte, development, potentially, through, regulation, of, 'RORγt'])].
[sujeto(['Consistent', with, disturbed, hepatic, clock, gene, expression, in, 'MLL4', mutant, 'mice,', we]), verbo([found]), complemento([that, rhythmic, fluctuation, of, hepatic, and, serum, bile, acid, '(', 'BA)', levels, over, the, circadian, cycle, is, abolished, in, 'MLL4', mutant, mice])].
[sujeto(['Together,', our, results]), verbo([provide]), complemento([strong, in, vivo, support, for, important, roles, of, both, 'MLL3', and, 'MLL4', in, similar, metabolic, pathways])].
[sujeto(['Both', 'MLL3', and, 'MLL4', complexes]), verbo([act]), complemento([as, major, epigenetic, regulators, of, diverse, metabolic, processes, '(', including, circadian, control, of, bile, acid, 'homeostasis)', and, as, critical, transcriptional, coactivators, of, the, circadian, 'TFs,', 'RORs'])].
[sujeto(['Bile', salts]), verbo([inhibit]), complemento([their, own, production, by, inducing, the, nuclear, receptor, small, heterodimer, partner, '(', 'SHP)', '(', encoded, by, 'NR0B2),', which, contributes, to, repression, of, the, gene, encoding, cholesterol, 7, 'α-hydroxylase', '(', 'CYP7A1),', a, key, enzyme, for, the, control, of, bile, salt, synthesis])].
[sujeto(['On', the, other, 'hand,', bile, salts]), verbo([stimulate]), complemento([hepatic, synthesis, of, nitric, oxide])].
[sujeto(['We', investigated, the, role, of, nitric, oxide, signaling, in, 'the&nbsp;control', of, 'CYP7A1', expression, and, the, involvement, in, 'this&nbsp;process', of, 'glyceraldehyde-3-phosphate', dehydrogenase, '(', 'GAPDH),', which]), verbo([participates]), complemento([in, intracellular, propagation, of, nitric, oxide, signals])].
[sujeto(['Rats', placed, on, 'cholate-rich', diets, and, given, 'L-NAME', had]), verbo([increased]), complemento([intrahepatic, and, biliary, levels, of, bile, 'salts,', and, deficiency, in, repression, of, 'CYP7A1', '(', at, the, messenger, 'RNA', and, protein, 'levels)', in, liver, 'tissue,', despite, preserved, induction, of, 'SHP'])].
[sujeto(['In', 'hepatocytes,', cholate]), verbo([promoted]), complemento(['S-nitrosylation', of, 'GAPDH', and, its, translocation, to, the, 'nucleus,', accompanied, by, 'S-nitrosylation', of, histone, deacetylase, 2, &, 'nbsp;(HDAC2)', and, 'Sirtuin', 1, '(', 'SIRT1),', deacetylases, that, 'participate,', 'respectively,', in, the, formation, of, 'Cyp7a1', and, 'Shp', repressor, complexes])].
[sujeto(['Knockdown', of, 'GAPDH']), verbo([prevented]), complemento([repression, of, 'CYP7A1', by, 'cholate,', and, blocking, nuclear, transport, of, nitrosylated, 'GAPDH', reduced, 'cholate-induced', nitrosylation, of, 'HDAC2', and, 'SIRT1;', this, effect, was, accompanied, by, abrogation, of, 'Cyp7a1', repression])].
[sujeto(['Cholate']), verbo([induced]), complemento([binding, of, 'SHP', to, 'HDAC2', and, its, recruitment, to, the, 'Cyp7a1', 'promoter;', these, processes, were, inhibited, by, blocking, nitric, oxide, synthesis])].
[sujeto(['Levels', of, nitrosylated, 'GAPDH', and, nitrosylated, 'HDAC2', were]), verbo([increased]), complemento([in, cholestatic, human, and, rat, livers, reflecting, increased, concentrations, of, bile, salts, in, these, conditions])].
[sujeto(['In', rat, 'liver,', excess, levels, of, bile, salts]), verbo([activate]), complemento([a, 'GAPDH-mediated', transnitrosylation, cascade, that, provides, feedback, inhibition, of, bile, salt, synthesis])].
[sujeto(['Intestinal', 'L-cells', secrete, 'glucagon-like', 'peptide-1', '(', 'GLP-1)', and, can, be]), verbo([activated]), complemento([by, bile, acids, '(', 'BA)', influencing, insulin, resistance, and, hepatic, steatosis, development, and, progression])].
[sujeto(['Administration', of, both, 'CA', and, 'UDCA', was]), verbo([associated]), complemento([to, decreased, hepatic, triglyceride, content, and, complete, reversion, of, histological, steatosis])].
[sujeto([')', significantly]), verbo([decreased]), complemento([the, plasma, levels, of, 'non-high-density', lipoprotein, '(', 'non-HDL)', cholesterol, and, apolipoprotein, 'B', in, a, 'dose-dependent', manner])].
[sujeto(['It', also]), verbo([decreased]), complemento([the, mRNA, levels, of, hepatic, small, heterodimer, 'partner-1,', induced, the, mRNA, expression, of, hepatic, cholesterol, 7, 'α-hydroxylase,', reduced, hepatic, cholesterol, and, triglyceride, 'levels,', increased, fecal, bile, acid, 'excretion,', and, upregulated, the, expression, of, hepatic, 'low-density', lipoprotein, '(', 'LDL)', receptor])].
[sujeto(['Furthermore,', 'compound-T3', significantly]), verbo([increased]), complemento([plasma, 'HDL', cholesterol, and, apolipoprotein, 'A-I', levels])].
[sujeto(['The', mRNA, expression, levels, of, hepatic, apolipoprotein, 'A-I', tended, to]), verbo([increase]), complemento([after, 'compound-T3', treatment])].
[sujeto(['Compound-T3', also]), verbo([induced]), complemento([accumulation, of, hepatic, bile, acids, and, decreased, the, mRNA, expression, levels, of, the, hepatic, bile, acid, export, pump])].
[sujeto([')', on, the, plasma, and, hepatic, lipid, parameters, were, similar, to, those, of, 'compound-T3,', and, it]), verbo([increased]), complemento([fecal, bile, acid, levels, without, causing, accumulation, of, hepatic, bile, acids])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'LDL', 'receptor-mediated', hepatic, 'LDL', incorporation, due, to, cholesterol, catabolism, catalyzed, by, cholesterol, 7, 'α-hydroxylase', decreases, plasma, 'non-HDL', cholesterol, levels])].
[sujeto(['Upregulation', of, hepatic, apolipoprotein, 'A-I', mRNA, expression, may, partially, contribute, to, the]), verbo([increase]), complemento([in, 'HDL', cholesterol, levels, mediated, by, 'compound-T3'])].
[sujeto(['The', solute, carrier, family, 7, '(', anionic, amino, acid, transporter, light, 'chain,', 'xc-system),', member, 11, '(', 'SLC7A11)', gene, in, the, interferon, 'pathway,']), verbo([reported]), complemento([to, be, involved, in, the, development, of, 'chemoresistance,', was, downregulated, by, 15, &, #, 8209, ;, fold])].
[sujeto(['The', caspase, 10, ',', 'apoptosis-related', cysteine, peptidase, '(', 'CASP10)', gene, was]), verbo([activated]), complemento([and, the, protein, tyrosine, 'phosphatase,', receptor, 'type,', 'R', '(', 'PTPRR)', and, myocyte, enhancer, factor, 2, 'C', '(', 'MEF2C)', genes, were, upregulated, in, the, classical, 'MAPK', and, p38, 'MAPK', pathways])].
[sujeto(['These', findings, indicate, that, thymquinone]), verbo([targets]), complemento([specific, genes, in, the, estrogen, metabolic, and, interferon, pathways])].
[sujeto(['Inflammation', is, a, major, contributor, to, the, development, of, atherosclerotic, 'plaque,', yet, the, involvement, of, liver, and, visceral, adipose, tissue, inflammatory, status, in, atherosclerotic, lesion, development]), verbo([has]), complemento([yet, to, be, fully, elucidated])].
[sujeto(['We', hypothesized, that, an, atherogenic, diet, would]), verbo([increase]), complemento([inflammatory, response, and, lipid, accumulation, in, the, liver, and, gonadal, adipose, tissue, '(', 'GAT)', and, would, correlate, with, systemic, inflammation, and, aortic, lesion, formation, in, 'low-density', lipoprotein, '(', 'LDL)', receptor, null, '(', 'LDLr-/-)', mice])].
[sujeto(['Compared', with, the, control, 'diet,', the, atherogenic, diet, significantly]), verbo([increased]), complemento([hepatic, triglyceride, and, total, cholesterol, '(', 'TC),', primarily, esterified, 'cholesterol,', and, 'GAT', triglyceride, content])].
[sujeto(['These', changes, were, accompanied, by]), verbo([increased]), complemento([expression, of, 'acyl-CoA', synthetase, 'long-chain', family, member, 5, ',', 'CD36,', 'ATP-binding', 'cassette,', subfamily, 'A,', member, 1, and, scavenger, receptor, 'B', class, 1, ',', and, they, decreased, the, expression, of, cytochrome, 'P450,', family, 7, and, subfamily, 'a,', polypeptide, 1, in, 'GAT'])].
[sujeto(['Aortic', 'TC', content, was, positively]), verbo([associated]), complemento([with, hepatic, 'TC,', 'triglyceride,', and, 'GAT', triglyceride, contents, as, well, as, plasma, interleukin, 6, and, monocyte, chemoattractant, 'protein-1', concentrations])].
[sujeto(['Although', when, compared, with, the, control, 'diet,', the, atherogenic, diet]), verbo([increased]), complemento([hepatic, tumor, necrosis, factor, α, 'production,', they, were, not, associated, with, aortic, 'TC', content])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, the, 'LDLr-/-', mice, responded, to, the, atherogenic, diet, by, increasing, lipid, accumulation, in, the, liver, and, 'GAT,', which, may, have, increased, inflammatory, response])].
[sujeto(['Aortic', 'TC', content, was, positively]), verbo([associated]), complemento([with, systemic, inflammation, but, not, hepatic, and, 'GAT', inflammatory, status])].
[sujeto(['Thyroid', hormone, '(', 'TH)']), verbo([increases]), complemento([biliary, cholesterol, secretion, and, hepatic, gene, expression, of, adenosine, triphosphate, '(', 'ATP)-binding', 'cassette,', subfamily, 'G', '(', 'WHITE),', member, 5, '(', 'ABCG5)', and, 'ATP-binding', 'cassette,', subfamily, 'G', '(', 'WHITE),', member, 8, '(', 'ABCG8),', two, 'half-transporters', that, act, as, a, heterodimeric, complex, promoting, sterol, secretion])].
[sujeto(['In', 'addition,']), verbo([nuclear]), complemento([liver, x, 'receptor-alpha', '(', 'LXRa),', also, regulated, by, 'TH,', induces, gene, expression, of, 'ABCG5/G8'])].
[sujeto(['We', here, investigated, if, the, 'TH-induced', stimulation, of, biliary, cholesterol, secretion, is]), verbo([mediated]), complemento([by, the, 'ABCG5/G8', complex, in, 'vivo,', and, if, 'so,', whether, 'LXRa', is, involved])].
[sujeto(['T3', treatment]), verbo([increased]), complemento([cholesterol, secretion, 3.1, -, fold, in, 'Abcg5(+/+)', 'mice,', whereas, this, response, was, severely, blunted, in, 'Abcg5(-/-)', mice])].
[sujeto(['In', 'contrast,', biliary, cholesterol, secretion, in, 'T3-treated', 'Lxra(+/+)', and, 'Lxra(-/-)', mice, was]), verbo([increased]), complemento([3.5, -, and, 2.6, -, 'fold,', 'respectively,', and, did, not, differ, significantly])].
[sujeto(['Ang', 'II']), verbo([increased]), complemento(['CYP11B2', 'activity,', mRNA, and, protein, with, a, concomitant, elevation, of, 6, -, 'Carboxy-', 2, '\'', ',', 7, '\'', -, dichlorodihydrofluorescein, diacetate, 'fluorescence,', malondialdehyde, and, protein, carbonyl, levels, '(', indices, of, 'ROS),', 'NADPH', oxidase, '(', 'Nox)', 'activity,', and, 'H(2)O(2)', levels, in, human, and, rat, adrenal, cortical, cells])].
[sujeto(['The', expression, of]), verbo([nuclear]), complemento([receptor, related, 1, 'protein,', a, transcription, factor, known, to, regulate, 'CYP11B2', 'expression,', was, also, augmented, by, 'Ang', 'II'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'Ang', 'II', facilitates, 'CYP11B2', activity, and, the, ensuing, aldosterone, production, via, activation, of, 'AT(1)R-Nox-H(2)O(2)', signaling, pathway])].
[sujeto(['Real', time, 'RCR', results, revealed, that, there, was, a, large]), verbo([increase]), complemento([in, 'CYP1C1', mRNA, in, liver, '(', 43.1, ')', ',', intestine, '(', 5.1, ')', and, muscle, '(', 2.4, ')'])].
[sujeto(['Patients', who, were, event, free, at, 1, &, 'nbsp;year', tended, to]), verbo([have]), complemento([higher, 'AUC0-6h', on, 'C1D1', compared, to, those, patients, who, 'progressed,', although, this, did, not, reach, significance, with, the, number, of, patients, studied, '(', 'P&nbsp;=&nbsp;0'])].
[sujeto(['Similarly,', patients, who, achieved, a, 13, -, cisRA, 'C', max, of, '≥2&nbsp;µM', on, 'C1D1', tended, to]), verbo([have]), complemento([higher, median, 'EFS', compared, to, those, who, did, not, '(', 17.0, vs])].
[sujeto(['UGT2B7,', 'CYP2C8*2/*3/*4', or, 'CYP3A5*3', genotype, did, not]), verbo([have]), complemento([any, effect, on, 13, -, cisRA, pharmacokinetics])].
[sujeto(['These', studies, show, that, two, 'acellular,', 'three-dimensional', culture, systems]), verbo([increase]), complemento([the, function, of, 'iPSC-derived', hepatocytes])].
[sujeto(['However,', scaffolds, derived, from, 'ECM', alone]), verbo([induced]), complemento([further, hepatocyte, maturation, compared, with, bioplotted, 'PLLA-collagen', scaffolds])].
[sujeto(['This', effect, is, likely]), verbo([mediated]), complemento([by, the, complex, composition, of, 'ECM', scaffolds, in, contrast, to, bioplotted, 'scaffolds,', suggesting, their, utility, for, in, vitro, hepatocyte, assays, or, drug, discovery])].
[sujeto(['Through', the, use, of, novel, technology, to, develop, 'three-dimensional', '(', 3, 'D)', 'scaffolds,', the, present, study, demonstrated, that, 'hepatocyte-like', cells, derived, via]), verbo([induced]), complemento([pluripotent, stem, cell, '(', 'iPSC)', technology, mature, on, 3, 'D', extracellular, matrix, scaffolds, as, a, result, of, 3, 'D', matrix, structure, and, scaffold, biology])].
[sujeto(['The', result, is, an, improved, hepatic, phenotype, with]), verbo([increased]), complemento([synthetic, and, catalytic, 'potency,', an, improvement, on, the, blunted, phenotype, of, 'iPSC-derived', 'hepatocytes,', a, critical, limitation, of, iPSC, technology])].
[sujeto(['These', findings]), verbo([provide]), complemento([insight, into, the, influence, of, 3, 'D', microenvironments, on, the, 'viability,', 'proliferation,', and, function, of, iPSC, hepatocytes, to, yield, a, more, mature, population, of, cells, for, cell, toxicity, studies, and, disease, modeling])].
[sujeto(['Sorafenib,', an, oral, tyrosine, kinase, inhibitor, that]), verbo([suppresses]), complemento([tumor, proliferation, and, 'angiogenesis,', emerged, as, the, first, effective, systemic, treatment, for, 'HCC', after, 30, years, of, 'research,', and, is, currently, the, 'standard-of-care', for, patients, with, advanced, 'HCC'])].
[sujeto(['The', 'CYP3A4', immunoreactivity, was, observed, in, surrounding, hepatocytes, in, 8, out, of, 11, 'cases;', while, the, 'CYP3A7', immunostaining, was]), verbo([found]), complemento([in, normal, liver, 'cells,', in, 7, out, of, 11, cases])].
[sujeto(['These', results]), verbo([suggest]), complemento([the, existence, of, a, marked, 'inter-individual', variability, regarding, the, presence, of, the, isoforms, of, 'CYP3A'])].
[sujeto(['In', 'addition,', since, sorafenib, is, metabolized, by, 'CYP3A4,', but, not, by, 'CYP3A7,', an, overexpression, of, 'CYP3A4', may]), verbo([lead]), complemento([to, an, increase, in, the, degradation, of, the, drug, and, then, to, clinical, ineffectiveness])].
[sujeto(['However,', these, drugs]), verbo([have]), complemento([the, poor, 'bioavailability,', which, may, be, caused, by, their, extensive, metabolism])].
[sujeto(['The', 21, -, and, 20, -, hydroxylation, metabolites]), verbo([inhibited]), complemento([the, expression, of, 'iNOS,', the, 'LPS-induced', activation, of, 'IkBα', and, p65, 'phosphorylation,', and, suppressed, p65, nuclear, translocation, in, 'RAW264'])].
[sujeto(['TGF-β', signalling, is]), verbo([involved]), complemento([in, pathogenesis, and, progress, of, hepatocellular, carcinoma, '(', 'HCC)'])].
[sujeto(['Differentially']), verbo([expressed]), complemento([genes, '(', 'DEGs)', were, screened, using, 'Limma', package, '(', false, discovery, rate, &, 'lt;', 0.05, and, '|', log2, fold, 'change|', &, 'gt;', 1.5, ')', ',', and, then, enrichment, analyses, of, 'function,', 'pathway,', and, disease, were, performed])].
[sujeto(['According', to, the, 'TF-DEG', regulatory, 'network,', the, two, hub, genes, were]), verbo([targeted]), complemento([by, 'SMAD2,', 'SMAD3,', and, 'HNF4A'])].
[sujeto(['Besides,', the, 11, pathways, in, 'TF-pathway-DEG', network, were, mainly, enriched, by, 'UGT1A', family, and, 'CYP3A7,', which, were, predicted, to, be]), verbo([regulated]), complemento([by, 'SMAD2,', 'SMAD3,', 'SOX2,', 'TP63,', and, 'HNF4A'])].
[sujeto(['CYP3A4', expression, varies, up, to, 100, -, fold, among, 'individuals,', 'and,', to, 'date,', genetic]), verbo([causes]), complemento([remain, elusive])].
[sujeto(['As', a, major, 'drug-metabolizing', 'enzyme,', elucidation, of, such, genetic]), verbo([causes]), complemento([would, increase, the, potential, for, introducing, personalized, dose, adjustment, of, therapies, involving, 'CYP3A4', drug, substrates])].
[sujeto(['The', foetal, 'CYP3A', 'isoform,', 'CYP3A7,', is]), verbo([reported]), complemento([to, be, expressed, in, '∼10%', of, 'European', adults, and, may, thus, contribute, towards, the, metabolism, of, endogenous, substances, and, 'CYP3A', drug, substrates])].
[sujeto(['However,', little, is, known, about, the, distribution, of, the, variant]), verbo([expressed]), complemento([in, the, adult])].
[sujeto(['We', also, conducted, the, first, extensive, geographic, survey, of, alleles]), verbo([associated]), complemento([with, adult, expression, of, 'CYP3A7', -, that, 'is,', 'CYP3A7*1B', and, 'CYP3A7*1C'])].
[sujeto(['No', nonsynonymous, mutation, was]), verbo([found]), complemento([in, the, homozygous, form, or, at, more, than, 2.8, '%', in, any, population])].
[sujeto(['CYP3A7*1C', was]), verbo([found]), complemento([at, up, to, 17.5, '%', in, 'North', 'African', populations, and, in, significant, linkage, disequilibrium, with, 'CYP3A5*3,', indicating, that, adult, expression, of, the, foetal, isoform, is, likely, to, be, accompanied, by, reduced, or, null, expression, of, 'CYP3A5'])].
[sujeto(['The', most, significantly]), verbo([associated]), complemento(['SNP', was, 'rs45446698,', an, 'SNP', that, tags, the, 'CYP3A7*1C', 'allele;', this, 'SNP', was, associated, with, a, 54, '%', decrease, in, urinary, 'E1G', levels])].
[sujeto(['Genotyping', this, 'SNP', in, 1, ',', 8, breast, 'cancer,', 1, ',', 128, lung, 'cancer,', and, 347, 'CLL', 'patients,', we]), verbo([found]), complemento([that, rs45446698, was, associated, with, breast, cancer, mortality, '(', 'HR,', 1.74, ;, 'P', =, 0.03, ')', ',', 'all-cause', mortality, in, lung, cancer, patients, '(', 'HR,', 1.43, ;, 'P', =, 0.009, ')', ',', and, 'CLL', progression, '(', 'HR,', 1.62, ;, 'P', =, 0.03, ')'])].
[sujeto(['We', also]), verbo([found]), complemento([borderline, evidence, of, a, statistical, interaction, between, the, 'CYP3A7*1C', 'allele,', treatment, of, patients, with, a, cytotoxic, agent, that, is, a, 'CYP3A', 'substrate,', and, clinical, outcome, '(', 'Pinteraction', =, 0.06, ')'])].
[sujeto(['Factors', linked, to, these, interindividual, differences, are, largely, 'unknown,', but, molecular, mechanisms]), verbo([regulating]), complemento([ontogeny, are, likely, involved])].
[sujeto(['Chromatin', structure, representing, a, poised, transcriptional, state, '(', bivalent, 'chromatin),', indicated, by, the, occupancy, by, modified, histones]), verbo([associated]), complemento([with, both, active, and, repressed, 'transcription,', was, observed, for, 'CYP3A4', and, most, 3, 'A7', regulatory, regions, in, both, postnatal, and, fetal, livers])].
[sujeto(['However,', the, 'CYP3A4', regulatory, regions, had, significantly, greater, occupancy, by, modified, histones]), verbo([associated]), complemento([with, repressed, transcription, in, the, fetal, liver])].
[sujeto(['Conversely,', some, modified, histones]), verbo([associated]), complemento([with, active, transcription, exhibited, greater, occupancy, in, the, postnatal, liver])].
[sujeto(['CYP3A7', regulatory, regions, also, had, significantly, greater, occupancy, by, modified, histones]), verbo([associated]), complemento([with, repressed, transcription, in, the, fetus])].
[sujeto(['Members', of, the, human, 'CYP3A', family, of, metabolizing, enzymes, exhibit, developmental, changes, in, expression, whereby, 'CYP3A7', is]), verbo([expressed]), complemento([in, fetal, 'tissues,', followed, by, a, transition, to, expression, of, 'CYP3A4', in, the, first, months, of, life])].
[sujeto(['Despite', knowledge, about, the, general, pattern, of, 'CYP3A', activity, in, human, 'development,', the, mechanisms, that]), verbo([regulate]), complemento([developmental, expression, remain, poorly, understood])].
[sujeto(['Epigenetic', 'changes,', including, cytosine, 'methylation,']), verbo([have]), complemento([been, suggested, to, play, a, role, in, the, regulation, of, 'CYP3A', expression])].
[sujeto(['Downregulated', genes, included, the, monooxygenase, 'CYP3A7,']), verbo([involved]), complemento([in, drug, and, lipid, metabolism])].
[sujeto(['Many', of, the, dysregulated, genes, play, important, roles, in, cellular, 'growth,', 'proliferation,', and, 'apoptosis,', and, may, be]), verbo([involved]), complemento([in, carcinogenesis])].
[sujeto(['However,', the, histopathological, findings, and, genes]), verbo([associated]), complemento([with, the, pathogenesis, of, melanosis, coli, remain, to, be, fully, elucidated])].
[sujeto(['The', present, study, aimed, to, examine, the, histopathological, features, and, differentially]), verbo([expressed]), complemento([genes, of, 'MC'])].
[sujeto(['This']), verbo([involved]), complemento([performing, hematoxylin, and, eosin, 'staining,', specific, staining, and, immunohistochemistry, on, tissues, 'sections,', which, were, isolated, from, patients, diagnosed, with, 'MC'])].
[sujeto(['DNA', expression, microarray, 'analysis,', western, blotting, and, immunofluorescence, assays, were, performed, to, analyze, the, differentially]), verbo([expressed]), complemento([genes, of, melanosis, coli])].
[sujeto(['The', results, of, the, present, study]), verbo([provided]), complemento([a, comprehensive, description, of, the, histopathological, characteristics, and, pathogenesis, of, 'MC', and, for, the, first, 'time,', to, the, best, of, our, 'knowledge,', demonstrated, that, the, cytochrome, 'P450&#8209;associated', genes, were, significantly, downregulated, in, melanosis, coli])].
[sujeto(['Despite', the, widespread, assumption, that, all, 'NHPs', are, 'safe,', they, contain, pharmacologically, active, substances, and, can, therefore]), verbo([have]), complemento([adverse, effects, 'and/or', interact, with, pharmaceuticals])].
[sujeto(['In', vitro, analysis]), verbo([involving]), complemento([several, melatonin, products, showed, 'product-dependent', inhibition, of, 'CYP1A2,', 'CYP2C19', and, 'CYP3A7'])].
[sujeto(['The', adverse, event, was, likely, due, to, a, primary, pharmacokinetic, interaction, between, melatonin, and, 'citalopram;', although, 'mechanistically,', interactions, affecting, cytochrome, 'P450-mediated', metabolism, may]), verbo([have]), complemento([occurred, with, all, of, these, health, products])].
[sujeto(['These', results, demonstrate, that, 'DHEA']), verbo([has]), complemento([the, highest, binding, 'affinity,', and, the, results, of, the, binding, free, energy, were, in, accordance, with, the, experimental, conclusion, that, estrone, is, better, than, estradiol])].
[sujeto(['In', 'addition,', a, cluster, of, 'Phe', residues]), verbo([provides]), complemento([a, hydrophobic, environment, to, stabilize, ligands])].
[sujeto(['This', study]), verbo([provides]), complemento([insights, into, the, structural, features, of, 'CYP3A7,', which, could, contribute, to, further, understanding, of, related, protein, structures, and, dynamics])].
[sujeto(['In', 'contrast,', the, developmental, expression, of, 'CYP3A5', is, less, well, understood, due, to, polymorphic, expression, of, the, enzyme, in, human, tissues, as, a, result, of, the, prevalence, of, the, 'CYP3A5*3', 'allele,', which]), verbo([leads]), complemento([to, alternative, splicing])].
[sujeto(['Formation', of, 4, -, 'OH', 'MDZ', was, significantly]), verbo([associated]), complemento([with, 1, '\'', -, 'OH', 'MDZ', '(', 'r(2)', =, 0.76, ',', 'P', &, 'lt;', 0.0001, ')', but, varied, '(', 36, -, 'fold)', independently, of, 'CYP3A5', genotype, or, expression])].
[sujeto(['The', substantial, interindividual, variability, that, remains, even, after, stratification, for, 'CYP3A5', genotype]), verbo([suggests]), complemento([that, factors, such, as, environmental, exposure, and, epigenetic, alterations, act, in, addition, to, genetic, variation, to, contribute, to, the, variability, of, 'CYP3A5', expression, in, human, prenatal, liver])].
[sujeto(['Data', from, the, clinical, absolute, bioavailability, '(', 'F)', study, with, cobimetinib]), verbo([suggested]), complemento([that, 'F', was, lower, than, predicted, based, on, its, low, hepatic, extraction, and, good, absorption])].
[sujeto(['The', approximately, 80, '%', lower, 'AUC', of, cobimetinib, in, transgenic, mice, when, intestinal, 'CYP3A4', was, present]), verbo([suggested]), complemento([that, the, intestinal, first, pass, contributed, to, the, oral, 'CL', of, cobimetinib])].
[sujeto(['In', 'drug-drug', interaction, '(', 'DDI)', studies, using, 'Cyp3a(-/-)Tg-3A4Hep/Int', 'mice,', 8, -, and, 4, -, fold]), verbo([increases]), complemento([in, oral, and, i])].
[sujeto(['In', 'PXR-CAR-CYP3A4/CYP3A7', 'mice,', rifampin, induction]), verbo([decreased]), complemento([cobimetinib, oral, exposure, by, approximately, 80, '%'])].
[sujeto(['Collectively,', these, data, support, the, conclusion, that, 'CYP3A4', intestinal, metabolism, contributes, to, the, oral, disposition, of, cobimetinib, and]), verbo([suggest]), complemento([that, under, certain, circumstances, the, transgenic, model, may, be, useful, in, predicting, clinical, 'DDIs'])].
[sujeto(['The', kinetics, of, desalkyl, metabolite, formation, of, the, two, drugs, were, well, fitted, to, the, 'Hill', 'equation;', 'however,', the, 'Hill', coefficients, '(', 'n)']), verbo([suggested]), complemento(['CYP3A-mediated', negative, cooperativity])].
[sujeto(['Next,', we, analyzed, the, kinetics, with, a, two]), verbo([binding]), complemento([sites, model, assuming, two, reaction, 'steps:', reaction, 1, with, 'high-affinity', and, 'low-capacity', metabolism, and, reaction, 2, with, 'low-affinity', and, 'high-capacity', metabolism])].
[sujeto(['The', kinetics, of, desalkyl, metabolite, formation, were, also, fitted, to, the, two]), verbo([binding]), complemento([sites, model])].
[sujeto(['These', results, may]), verbo([provide]), complemento([the, basis, not, only, for, understanding, the, metabolic, properties, of, the, two, 'PDE5', 'inhibitors,', but, also, for, one, possible, explanation, of, the, mechanisms, of, 'CYP3A-mediated', negative, cooperativity])].
[sujeto(['The', strongest, association, observed, was, with, 'rs7190447,', located, in, the, 'ATP-binding', cassette, subfamily, 'C', member, 6, '(', 'ABCC6)', gene, '[', 'discovery:', hazard, ratio, '(', 'HR)', =, 14.3, ',', 95, '%', confidence, interval, '(', 'CI)', =, 1.53, -, 134, ',', 'P', =, 0.02, ;, 'replication:', 'HR', =, 9.28, ',', 95, '%', 'CI', =, 2.2, -, 39.2, ',', 'P', =, 0.0024, ']', and, its, correlated, 'SNP', 'rs7192303,', which, was, predicted, to]), verbo([have]), complemento([a, plausible, regulatory, function])].
[sujeto(['We', also, replicated, associations, with, rs4148737, in, the, 'ATP-binding', cassette, subfamily, 'B', member, 1, '(', 'ABCB1)', gene, '(', 'discovery:', 'HR', =, 2.96, ',', 95, '%', 'CI', =, 1.08, -, 8.1, ',', 'P', =, 0.034, ;, 'replication:', 'HR', =, 1.6, ',', 95, '%', 'CI', =, 1.05, -, 2.44, ',', 'P', =, 0.029, ')', ',', which, we]), verbo([have]), complemento([previously, found, to, be, associated, with, poorer, 'OS', in, pediatric, osteosarcoma, 'patients,', and, rs11188147, in, cytochrome, 'P450', family, 2, subfamily, 'C', member, 8, gene, '(', 'CYP2C8)', '(', discovery, :, 'HR', =, 2.49, ',', 95, '%', 'CI', =, 1.06, -, 5.87, ',', 'P', =, 0.037, ;, 'replication:', 'HR', =, 1.77, ',', 95, '%', 'CI', =, 1.06, -, 2.96, ',', 'P', =, 0.03, ')', ',', an, enzyme, involved, in, the, oxidative, metabolism, of, the, 'ES', chemotherapeutic, agents, cyclophosphamide, and, ifosfamide])].
[sujeto(['Using', an, integrated, 'pathway-based', 'approach,', we, identified, polymorphisms, in, 'ABCC6,', 'ABCB1', and, 'CYP2C8']), verbo([associated]), complemento([with, 'OS'])].
[sujeto(['In', colon, 'cancer,', adenomatous, polyposis, coli, '(', 'APC)', inactivating, gene, mutations]), verbo([increase]), complemento([nuclear, 'β-catenin', levels, and, stimulate, proliferation])].
[sujeto(['In', 'vitro,', 1, ',', 25, dihydroxyvitamin, 'D', '(', 1, ',', 25, '(', 'OH)2D),']), verbo([suppresses]), complemento(['β-catenin-mediated', gene, transcription, by, inducing, vitamin, 'D', receptor, '(', 'VDR)-β-catenin', interactions])].
[sujeto(['We', examined, whether, acute, treatment, with, 1, ',', 25, '(', 'OH)2D', could]), verbo([suppress]), complemento(['β-catenin-mediated', gene, transcription, in, the, hyperplastic, colonic, lesions, of, mice, with, 'colon-specific', deletion, of, both, 'APC', gene, alleles, '(', 'CAC;', 'APC(Δ580/Δ580))'])].
[sujeto([mRNA, levels, of, 'β-catenin']), verbo([target]), complemento([genes, were, elevated, in, the, colon, of, 'CAC;', 'APC(Δ580/Δ580)', mice])].
[sujeto([1, ',', 25, '(', 'OH)2D']), verbo([increased]), complemento([25, hydroxyvitamin, 'D-24', hydroxylase, mRNA, levels, in, the, colon, of, 'CAC;', 'APC(Δ580/Δ580)', and, control, mice, indicating, the, treatments, activated, the, 'VDR'])].
[sujeto(['However,', 1, ',', 25, '(', 'OH)2D', had, no, effect, on, either, 'β-catenin']), verbo([target]), complemento([gene, mRNA, levels, or, the, proliferation, index, in, 'CAC;', 'APC(Δ580/Δ580)', or, control, mice])].
[sujeto(['VDR', mRNA, and, protein, levels, were, lower, '(', -, 65, '%', and, -, 90, '%', ')', in, the, colon, of, 'CAC;', 'APC(Δ580/Δ580)', mice, compared, to, control, 'mice,']), verbo([suggesting]), complemento([loss, of, colon, responsiveness, to, vitamin, 'D'])].
[sujeto(['Our', data, show, that, short, term, exposure, to, 1, ',', 25, '(', 'OH)2D', does, not]), verbo([suppress]), complemento([colonic, 'β-catenin', signaling, in, vivo])].
[sujeto(['Ovaries', exposed, to, 'DHT', showed, a, significant]), verbo([increase]), complemento([in, 17, 'β-estradiol', '(', 'E2)', production, while, 'FLUT', and, 'LIN', had, no, effect, on, 'E2'])].
[sujeto(['To', improve, understanding, of, androgen, receptor, signaling, in, the, 'ovary,', a, reciprocal, gene, expression, network, was, constructed, for, 'DHT', and, 'FLUT', using, pathway, analysis, and, these, data]), verbo([suggested]), complemento([that, steroid, 'metabolism,', 'translation,', and, 'DNA', replication, are, processes, regulated, through, 'AR', signaling, in, the, ovary])].
[sujeto(['Sub-network', enrichment, analysis, revealed, that, 'FLUT', and, 'LIN', shared, more]), verbo([regulated]), complemento([gene, networks, in, common, compared, to, 'DHT'])].
[sujeto(['This', study, advances, knowledge, regarding, molecular, signaling, cascades, in, the, ovary, that, are, responsive, to, androgens, and, 'anti-androgens', and]), verbo([provides]), complemento([proof, of, concept, that, gene, network, analysis, and, machine, learning, can, classify, priority, chemicals, using, experimental, transcriptomic, data, collected, from, different, fish, species])].
[sujeto(['The', vitamin, 'D', receptor, '(', 'VDR)']), verbo([maintains]), complemento([a, balance, of, plasma, calcium, and, 1, 'α,25-dihydroxyvitamin', 'D3', '[', 1, ',', 25, '(', 'OH)2D3],', its, natural, active, 'ligand,', by, directly, regulating, the, calcium, ion, channel, '(', 'TRPV6)', and, degradation, enzyme, '(', 'CYP24A1),', and, indirectly, regulating, the, parathyroid, hormone, '(', 'PTH)', for, feedback, regulation, of, the, synthetic, enzyme, 'CYP27B1'])].
[sujeto(['Studies', that, examined, the, intricate, relationships, between, plasma, and, tissue, 1, ',', 25, '(', 'OH)2D3', levels, and, changes, in, 'VDR']), verbo([target]), complemento([genes, and, plasma, calcium, and, 'PTH', are, virtually, nonexistent])].
[sujeto(['In', this, 'study,', we, investigated, temporal, correlations, between, tissue, 1, ',', 25, '(', 'OH)2D3', concentrations, and, 'VDR']), verbo([target]), complemento([genes, in, ileum, and, kidney, and, plasma, calcium, and, 'PTH', concentrations, in, response, to, 1, ',', 25, '(', 'OH)2D3', treatment, in, mice, '(', 2.5, 'μg/kg', 'ip,', singly, or, q2d, ×, 4, ')'])].
[sujeto(['Temporal', profiles, showed]), verbo([increased]), complemento([expressions, of, ileal, 'Cyp24a1', and, renal, 'Cyp24a1,', 'Mdr1/P-gp,', and, 'VDR', but, decreased, renal, 'Cyp27b1', mRNA, after, a, time, delay, in, 'VDR', activation])].
[sujeto(['Increased', plasma, calcium, and, attenuated, 'PTH', levels, and]), verbo([increased]), complemento([ileal, and, renal, 'Trpv6', expression, paralleled, the, changes, in, tissue, 1, ',', 25, '(', 'OH)2D3', concentrations])].
[sujeto(['The', data, revealed, that, 1, ',', 25, '(', 'OH)2D3', equilibrates, with, tissues, 'rapidly,', and, 'VDR']), verbo([target]), complemento([genes, respond, quickly, to, exogenously, administered, 1, ',', 25, '(', 'OH)2D3'])].
[sujeto(['Phorbol', 12, -, myristate, 13, -, acetate, '(', 'PMA)']), verbo([increased]), complemento([1, ',', 25, '(', 'OH)(2)D(3)-induced', human, 25, hydroxyvitamin, 'd-24', hydroxylase, '(', 'hCYP24A1)', gene, expression, and, vitamin, 'D', receptor, '(', 'VDR)', binding, to, the, hCYP24A1, promoter])].
[sujeto(['It', did, not, alter, transient, receptor, potential, cation, 'channel,', subfamily, 'V,', member, 6, '(', 'TRPV6)', 'expression,', 'VDR']), verbo([binding]), complemento([to, the, 'TRPV6', 'promoter,', or, 'VDR', binding, to, a, crude, chromatin, preparation])].
[sujeto(['PMA']), verbo([activated]), complemento(['Extracellular', 'signal-Regulated', 'Kinases', '(', 'ERK)', 1, /, 2, and, p38, mitogen, activated, protein, kinases, '(', 'MAPK)', and, inhibiting, these, kinases, reduced, 1, ',', 25, '(', 'OH)(2)D(3)-induced', and, 'PMA-enhanced', hCYP24A1, promoter, activity])].
[sujeto(['Mithramycin', 'A']), verbo([inhibits]), complemento(['Specific', 'Protein', '(', 'Sp)', family, member, binding, to, 'DNA', and, reduced, 1, ',', 25, '(', 'OH)(2)D(3)-induced', and, 'PMA-enhanced', hCYP24A1, promoter, activity])].
[sujeto(['PMA']), verbo([increased]), complemento(['MAPK-dependent', 'Sp3', 'phosphorylation,', 'Sp3-VDR', 'interactions,', and, 'Sp3', binding, to, the, hCYP24A1, promoter])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'MAPK', signaling, contributes, to, 1, ',', 25, '(', 'OH)(2)D(3)-induced', and, 'PMA-enhanced', 'CYP24A1', gene, transcription, by, modulating, 'Sp3', function])].
[sujeto(['ABCB1', 3435, 'C&gt;T', and, 'IL-10', -, 1082, 'G&gt;A', were, significantly]), verbo([associated]), complemento([with, log, 'C/D', '(', 'P=0'])].
[sujeto(['ABCB1', 3435, 'C&gt;T', and, 'IL-10', -, 1082, 'G&gt;A', were, significantly]), verbo([associated]), complemento([with, 'long-term', 'SRL', dose, requirements])].
[sujeto(['Most', rodent, developmental, toxicity, studies, of, dibutylphthalate, '(', 'DBP)']), verbo([have]), complemento([relied, on, bolus, gavage, dosing])].
[sujeto(['Maternal', exposure, to, 500, mg, 'DBP/kg/day']), verbo([induced]), complemento([a, significant, reduction, in, male, 'offspring\'s', anogenital, distance, indicating, in, utero, disruption, of, androgen, function])].
[sujeto(['Leydig', cell, 'aggregates,']), verbo([increased]), complemento([cord, 'diameters,', and, multinucleated, gonocytes, were, present, in, 'DBP-treated', rats])].
[sujeto(['Monobutyl', 'phthalate,', the, developmentally, toxic, metabolite, of, 'DBP,', and, its, glucuronide, conjugate, were]), verbo([found]), complemento([in, maternal, and, fetal, 'plasma,', amniotic, 'fluid,', and, maternal, urine])].
[sujeto(['We', examined, the, role, of, the, extracellular, signal]), verbo([regulated]), complemento([kinases, '(', 'ERK)', in, 1, ',', 25, -, dihydroxyvitamin, 'D', '(', 1, ',', 25, '(', 'OH)(2)D(3))-induced', gene, expression, in, the, differentiated, 'Caco-2', cells])].
[sujeto([1, ',', 25, '(', 'OH)(2)D(3)-regulated', expression, of, the, 25, -, hydroxyvitamin, 'D,', 24, -, hydroxylase, '(', 'CYP24)', gene, '(', both, natural, gene, and, promoter, 'construct)', was, strongly]), verbo([modulated]), complemento([by, altering, 'ERK', activity, '(', i])].
[sujeto([',', reduced, by, 'MEK', inhibitors, and, dominant, negative, '(', 'dn)', 'ERK1', and, 'ERK2,']), verbo([activated]), complemento([by, epidermal, growth, 'factor)', but, 'ERK', inhibition, had, no, effect, on, 1, ',', 25, '(', 'OH)(2)D(3)-regulated', expression, of, the, transient, receptor, potential, cation, 'channel,', subfamily, 'V,', member, 6, '(', 'TRPV6)'])].
[sujeto(['ERK5-mediated', phosphorylation, of, the, transcription, factor, 'Ets-1']), verbo([enhanced]), complemento([1, ',', 25, '(', 'OH)(2)D(3)-mediated', 'CYP24', gene, transcription, in, proliferating, but, not, differentiated, 'Caco-2', cells, due, to, reduced, levels, of, 'ERK5', and, 'Ets-1', '(', total, and, phosphoprotein, 'levels)', in, differentiated, cells])].
[sujeto(['MEK', inhibition, reduced, 1, ',', 25, '(', 'OH)(2)D(3)-induced', 3, 'X-VDRE', promoter, activity, but, had, no, impact, on, the, association, of, vitamin, 'D', receptor, '(', 'VDR)', with, chromatin]), verbo([suggesting]), complemento([a, role, for, 'co-activator', recruitment, in, 'ERK-modulation', of, vitamin, 'D-regulated', 'CYP24', gene, activation])].
[sujeto(['Chromatin', immunoprecipitation, assays, revealed, that, the, 'ERK1/2', 'target,', mediator, 1, '(', 'MED1),', is]), verbo([recruited]), complemento([to, the, 'CYP24,', but, not, the, 'TRPV6,', promoter, following, 1, ',', 25, '(', 'OH)(2)D(3)', treatment])].
[sujeto(['This']), verbo([suggests]), complemento(['ERK1/2', signaling, enhances, 1, ',', 25, '(', 'OH)(2)D(3)', effects, on, the, 'CYP24', promoter, by, 'MED1-mediated', events])].
[sujeto(['Polymorphisms', of, 'CYP2D6', in, particular]), verbo([have]), complemento([been, associated, with, effects, on, tamoxifen, disposition, and, clinical, 'efficacy,', with, interethnic, differences, in, distribution, of, functional, alleles, that, affect, metabolizer, phenotype])].
[sujeto(['Polymorphisms', of, 'CYP19A1', '(', aromatase, 'gene)']), verbo([have]), complemento([been, reported, to, correlate, with, clinical, outcomes, from, aromatase, inhibitors, in, small, studies, but, require, further, confirmation])].
[sujeto(['For', 'anthracyclines,', polymorphisms, in, genes, such, as, carbonyl, reductase, 3, '(', 'CBR3),', 'ATP-binding', cassette, subfamily, 'B,', member, 1, '(', 'ABCB1),', 'glutathione-related', transporter, 'genes,', and, oxidative, 'stress-related', genes]), verbo([have]), complemento([been, reported, to, correlate, with, clinical, outcomes])].
[sujeto(['The', pharmacogenetics, of, taxanes]), verbo([has]), complemento([been, extensively, 'investigated,', but, associations, of, genetic, polymorphisms, in, 'drug-metabolizing', enzymes, and, transporters, reported, in, earlier, small, studies, have, not, been, validated, in, a, recent, large, clinical, trial])].
[sujeto(['Allelic', variants]), verbo([associated]), complemento([with, 'gemcitabine,', 'capecitabine/5-fluorouracil,', 'vinorelbine,', and, platinum, disposition, are, reviewed])].
[sujeto(['No', pharmacogenetic, studies]), verbo([have]), complemento([been, published, for, targeted, agents, thus, 'far,', although, several, potential, candidate, genes, warrant, investigation])].
[sujeto(['The', present, study, systematically, explored, metabolic, pathways, and, altered, expressions, of, genes, speculatively]), verbo([participating]), complemento([in, colorectal, carcinogenesis, by, using, a, 'Microarray-Bioinformatic', analysis, methods])].
[sujeto(['The', analysis, of, 10, colorectal, cancer, tissue, specimens, demonstrated, that, genes]), verbo([involved]), complemento([in, fatty, acid, metabolic, pathways, had, high, rates, of, overexpression])].
[sujeto(['In', 'addition,', we]), verbo([stimulated]), complemento(['CRL-1790', cell, line, with, linoleic, acid, '(', a, polyunsaturated, fatty, 'acid)', for, 12, ',', 24, ',', 48, and, 72, h])].
[sujeto(['Further', analyses, revealed, that, the, genes, increasingly]), verbo([expressed]), complemento([in, the, cell, line, included, 'enoyl-Coenzyme', 'A,', 'hydratase/3-hydroxyacyl', 'Coenzyme', 'A', dehydrogenase, '(', 'EHHADH),', enoyl, 'Coenzyme', 'A', 'hydratase,', short, 'chain,', 1, ',', mitochondrial, '(', 'ECHS1);', 'glutaryl-Coenzyme', 'A', dehydrogenase, '(', 'GCDH),', 'acyl-Coenzyme', 'A', oxidase, 2, ',', branched, chain, '(', 'ACOX2);', 'acyl-Coenzyme', 'A', 'dehydrogenase,', 'C-2', to, 'C-3', short, chain, precursor, '(', 'ACADS);', carnitine, palmitoyltransferase, 1, 'B', '(', 'CPT1B),', 'acyl-CoA', synthetase, 'long-chain', family, member, 5, '(', 'ACSL5),', and, cytochrome, 'P450,', family, 4, ',', subfamily, 'A,', and, polypeptide, 11, '(', 'CYP4A11)', genes])].
[sujeto(['This', indicated, that, the]), verbo([stimulating]), complemento([effect, of, linoleic, acid, on, cell, proliferation, was, due, to, interference, with, the, metabolic, pathway, of, fatty, acid, metabolism])].
[sujeto(['In', 'conclusion,', genes, with, altered, expression, levels, in, 'CRC', were, mainly]), verbo([associated]), complemento([with, fatty, acid, metabolic, pathways, speculated, to, have, an, important, role, linked, to, carcinogenesis])].
[sujeto(['The', orphan, receptor, 'SHP']), verbo([interacts]), complemento([with, many, nuclear, receptors, and, inhibits, their, transcriptional, activities])].
[sujeto(['SHP', is, central, to, feedback, repression, of, cholesterol, 7, alpha, hydroxylase, gene, '(', 'CYP7A1)', expression, by, bile, 'acids,', which, is, critical, for]), verbo([maintaining]), complemento([cholesterol, homeostasis])].
[sujeto(['Chromatin', immunoprecipitation, studies, showed, that, mSin3A, and, a, 'Swi/Snf', complex, containing, 'Brm', as, a, central, 'ATPase', were]), verbo([recruited]), complemento([to, the, promoter])].
[sujeto(['This', recruitment, was]), verbo([associated]), complemento([with, chromatin, remodeling, after, bile, acid, treatment, that, was, blunted, by, inhibition, of, the, endogenous, 'Swi/Snf', function, by, 'dominant-negative', 'ATPase', mutants])].
[sujeto(['Biochemical', studies, indicated, that, 'SHP', was]), verbo([associated]), complemento([with, the, 'mSin3A-Swi/Snf', complex, by, direct, interaction, with, 'Brm', and, mSin3A, through, its, repression, domain])].
[sujeto(['Expression', of, 'Brm,', but, not, an, 'ATPase', 'mutant,']), verbo([inhibited]), complemento(['CYP7A1', promoter, activity, and, further, enhanced, 'SHP-mediated', repression])].
[sujeto(['Bile', 'acid-induced', recruitment, of, 'mSin3A/Brm,', chromatin, 'remodeling,', and, concomitant, repression, of, endogenous, 'CYP7A1', expression, were, impaired, when, 'SHP', expression, was]), verbo([inhibited]), complemento([by, 'SHP', small, interfering, 'RNA'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'SHP', mediates, recruitment, of, 'mSin3A-Swi/Snf', to, the, 'CYP7A1', 'promoter,', resulting, in, chromatin, remodeling, and, gene, 'repression,', which, may, also, be, a, mechanism, for, the, repression, by, 'SHP', of, genes, activated, by, many, nuclear, receptors])].
[sujeto(['Bile', acid, formation, and, messenger, 'RNA', '(', 'mRNA)', levels, of, key, enzymes, and, the]), verbo([nuclear]), complemento([receptor, short, heterodimer, partner, '(', 'SHP)', were, measured, after, 24, hours])].
[sujeto(['Glycochenodeoxycholic', acid, '(', 'GCDCA;', 100, 'micromol/L)', significantly]), verbo([decreased]), complemento([formation, of, cholic, acid, '(', 'CA)', to, 44, '%', +, /, -, 4, '%', of, controls, and, glycodeoxycholic, acid, '(', 'GDCA)', decreased, formation, of, 'CA', to, 67, '%', +, /, -, 11, '%', of, controls])].
[sujeto(['Addition', of, 'GCDCA,', 'GDCA,', and, 'GCA', '(', 100, 'micromol/L)', markedly]), verbo([decreased]), complemento([cholesterol, 7, 'alpha-hydroxylase', '(', 'CYP7A1)', mRNA, levels, to, 2, '%', +, /, -, 1, '%', ',', 2, '%', +, /, -, 1, '%', ',', and, 29, '%', +, /, -, 11, '%', of, 'controls,', 'respectively,', whereas, 'GUDCA', had, no, effect])].
[sujeto(['Addition', of, 'GDCA', and, 'GCDCA', '(', 100, 'micromol/L)', significantly]), verbo([decreased]), complemento([sterol, 12, 'alpha-hydroxylase', '(', 'CYP8B1)', mRNA, levels, to, 48, '%', +, /, -, 5, '%', and, 61, '%', +, /, -, 4, '%', of, 'controls,', 'respectively,', whereas, 'GCA', and, 'GUDCA', had, no, effect])].
[sujeto(['Addition', of, 'GCDCA', and, 'GDCA', '(', 100, 'micromol/L)', significantly]), verbo([decreased]), complemento([sterol, 27, -, hydroxylase, '(', 'CYP27A1)', mRNA, levels, to, 59, '%', +, /, -, 3, '%', and, 60, '%', +, /, -, 7, '%', of, 'controls,', 'respectively,', whereas, 'GUDCA', and, 'GCA', had, no, significant, effect])].
[sujeto(['Addition', of, both, 'GCDCA', and, 'GDCA', markedly]), verbo([increased]), complemento([the, mRNA, levels, of, 'SHP', to, 298, '%', +, /, -, 43, '%', and, 273, '%', +, /, -, 30, '%', of, 'controls,', respectively])].
[sujeto(['In', 'conclusion,', 'glycine-conjugated', and, free, bile, acids]), verbo([suppress]), complemento([bile, acid, synthesis, and, mRNA, levels, of, 'CYP7A1', in, the, order, 'CDCA', &, 'gt;', 'DCA', &, 'gt;', 'CA', &, 'gt;', 'UDCA'])].
[sujeto([mRNA, levels, of, 'CYP8B1', and, 'CYP27A1', are]), verbo([suppressed]), complemento([to, a, much, lower, degree, than, 'CYP7A1'])].
[sujeto([20, ')', was, cloned, with, a, tetrahistidine, tag, appended, to, the, 'C-terminus', and]), verbo([expressed]), complemento([in, 'Escherichia', coli])].
[sujeto(['Protein', purified, to, electrophoretic, homogeneity, was, observed, to]), verbo([bind]), complemento([the, 14, -, methylated, sterols, lanosterol, and, 24, -, 'methylene-24,25-dihydrolanosterol', '(', 24, -, 'MDL)'])].
[sujeto([coelicolor, 'A3(2)', mutant, containing, a, transposon, insertion, in, the, 'CYP51', 'gene,', which, will, abolish, synthesis, of, the, functional, 'haemoprotein,', was, isolated, as, a, viable, 'strain,', the, first, time, a, 'CYP51']), verbo([has]), complemento([been, identified, as, 'non-essential'])].
[sujeto([coelicolor, 'A3(2)', 'CYP51', contains, very, few, of, the]), verbo([conserved]), complemento(['CYP51', residues, 'and,', even, though, it, can, catalyse, 14, 'alpha-demethylation,', it, probably, has, another, function, in, 'Streptomyces'])].
[sujeto(['The', mechanisms, that]), verbo([lead]), complemento([to, the, steroidogenic, differences, in, the, human, fetal, adrenal, '(', 'HFA)', and, adult, adrenal, gland, are, not, known])].
[sujeto(['Sixty-nine', transcripts, were]), verbo([found]), complemento([to, have, a, greater, than, 2.5, -, fold, difference, in, expression, between, 'HFA', and, adult, adrenals])].
[sujeto(['Transcripts', concerned, with, cellular, immunity, and, signal, transduction, were, preferentially]), verbo([expressed]), complemento([in, the, adult, adrenal])].
[sujeto(['The', vast, majority, of, the, 69, transcripts]), verbo([have]), complemento([not, been, studied, with, regard, to, adrenal, function])].
[sujeto(['Thus,', these, gene, profiles]), verbo([provide]), complemento([valuable, information, that, could, help, define, the, mechanisms, that, control, adrenal, function])].
[sujeto(['A', set, of, 'inosine-containing', degenerate, primers, that, were]), verbo([targeted]), complemento([to, two, conserved, regions, of, known, cytochrome, 'P450', cDNAs, were, used])].
[sujeto(['One']), verbo([primer]), complemento([was, coded, for, the, 'well-described', and, conserved, 'heme-binding', region, of, 'P450', 'enzymes,', and, the, second, was, designed, based, upon, other, considerations, of, homology, among, 'P450', molecules])].
[sujeto(['One', of, the, four, 'PCR-amplified', cDNA, products, hybridized, to, two, major, 'RNA', 'bands,', 4.2, and, 5.3, 'kb,', that, were]), verbo([induced]), complemento([by, 'DMBA', or, 'BA'])].
[sujeto(['The', amino, acid, sequence, of, the, fragment, deduced, from, the, 'base-sequence', data, indicate, that, the, amplified, cDNA]), verbo([has]), complemento([a, 50, -, 55, '%', identity, with, the, cytochrome, 'P450', subfamily, 1, 'A'])].
[sujeto(['The', induction, of, 'P450CMEF', mRNA, preceded, the, induction, of, aryl, hydrocarbon, hydroxylase, activity, after, 'DMBA', or, 'BA', 'treatment,']), verbo([suggesting]), complemento([that, the, product, of, 'P450CMEF', is, involved, in, the, metabolism, of, these, polycyclic, aromatic, hydrocarbons, in, 10, 'T1/2', cells])].
[sujeto(['From', the, partial, sequence, of, the, cDNA, identified, by, this, 'procedure,', we, propose, that, 'P450CMEF', is, a, member, of, the, 'P450', 'superfamily,', possibly, in, a, subfamily, of, family, 1, ',', that, is]), verbo([induced]), complemento([in, 10, 'T1/2', cells, by, 'DMBA', and, 'BA'])].
[sujeto(['Due', to, their, consistent, correlation, with, each, other, in, each, 'species,', 'TRPV6,', 'calD9k/calD28k,', and, 'PMCA', appeared, to, be, the, main, pathways]), verbo([involved]), complemento([in, active, transepithelial, calcium, transport, in, the, kidney, of, 'sheep,', dogs, and, horses])].
[sujeto(['The', results, indicate, that, all, of, the, studied, genes, were]), verbo([expressed]), complemento([in, the, renal, tissue, of, studied, 'species,', although, the, expression, levels, and, correlation, of, transcripts, with, each, other, were, different, from, species, to, species])].
[sujeto(['The', findings]), verbo([suggest]), complemento([that, despite, low, serum, vitamin, 'D', 'concentrations,', vitamin, 'D', still, plays, a, significant, role, in, calcium, metabolism, in, 'horses,', especially, given, the, strong, correlations, between, 'VDR', and, vitamin, 'D', responsive, transcripts, in, these, animals])].
[sujeto(['Our', previous, studies]), verbo([found]), complemento([that, different, extracts, or, fractions, of, 'Fructus', ligustri, lucidi, '(', 'FLL)', played, different, roles, in, altering, the, regulation, of, bone, and, mineral, metabolism, in, different, animal, models])].
[sujeto(['However,', 'EE,', but, not, 'WE', 'treatment,', significantly]), verbo([increased]), complemento([serum, 1, ',', 25, '(', 'OH)2D3', levels, in, mature, 'OVX', rats])].
[sujeto(['An', in, vitro, study, using, human, proximal, tubule, '(', 'HKC-8)', cells, showed, that, 'EE,', but, not, 'WE,', significantly]), verbo([enhanced]), complemento([renal, 25, -, dihydroxyvitamin, 'D3-1[Formula:', see, 'text]-hydroxylase', '(', 1, -, 'OHase)', mRNA, expressions, and, simultaneously, repressed, renal, 25, -, dihydroxyvitamin, 'D3-24-hydroxylase', '(', 24, -, 'OHase)', mRNA, expressions])].
[sujeto(['Further', investigation, indicated, that, 'EE', could, significantly]), verbo([induce]), complemento([the, protein, expression, of, 1, -, 'OHase,', but, did, not, alter, 24, -, 'OHase', expression, in, 'HKC-8', cells])].
[sujeto(['Our', results, demonstrated, that, 'EE']), verbo([increased]), complemento([circulating, 1, ',', 25, '(', 'OH)2D3', levels, in, 'OVX', 'rats,', possibly, via, upregulation, of, renal, 1, -, 'OHase', expressions, in, renal, proximal, tubule, cells])].
[sujeto(['Our', study, indicates, that, 'FLL', is, a, natural, oral, agent, that, could, directly]), verbo([regulate]), complemento([renal, vitamin, 'D', metabolism, in, vivo, and, in, vitro])].
[sujeto(['Low', serum, 25, -, hydroxyvitamin, 'D', '(', 25, 'OHD)', is]), verbo([associated]), complemento([with, osteoporosis, and, osteoporotic, 'fracture,', but, it, remains, uncertain, whether, these, associations, are, causal])].
[sujeto(['In', observational, 'analyses,', total, serum, 25, 'OHD', was, positively]), verbo([associated]), complemento([with, 'BMD', at, lumbar, spine, '(', 'P', =, 0.003, ')', ',', femoral, neck, '(', 'P', =, 0.006, ')', and, total, hip, '(', 'P', =, 0.005, ')', ',', and, was, inversely, associated, with, intact, parathyroid, hormone, '(', 'PTH)', '(', 'P', =, 8.18e-9, ')', and, procollagen, type, 1, 'N-terminal', propeptide, '(', 'P1NP)', '(', 'P', =, 0.02, ')'])].
[sujeto(['The', use, of, four, single, nucleotide, 'polymorphisms,', 'GC-rs2282679,', 'NADSYN1-rs12785878,', 'CYP2R1-rs10741657', and, 'CYP24A1-rs6013897,', as, candidate, instrumental, variables, in, 'MR', analyses, showed, that, none, of, the, two, stage, least, squares, models]), verbo([provided]), complemento([evidence, for, associations, between, serum, 25, 'OHD', and, either, 'BMD', or, bone, metabolism, markers, '(', all, 'P', &, 'gt;', 0.05, ')'])].
[sujeto(['We']), verbo([suggest]), complemento([that, after, controlling, for, unidentified, confounding, factors, in, 'MR', 'analyses,', the, associations, between, genetically, low, serum, 25, 'OHD', and, 'BMD', and, bone, metabolism, markers, are, unlikely, to, be, causal])].
[sujeto(['Vitamin', 'D', deficiency, is]), verbo([associated]), complemento([with, many, inflammatory, respiratory, disease, states])].
[sujeto(['CRSsNP', and, 'CRSwNP', mucosa, exhibited]), verbo([decreased]), complemento(['CYP27B1', compared, with, controls, '(', 0.0437, '[', 'Interquartile', range, '(', 'IQR)', 0.0999, ']', vs, 0.326, '[', 'IQR', 2.9384, ']', vs, 0.6557, '[', 'IQR', 1.1005, ']', ',', p, =, 0.039, ')', ',', whereas, 'CYP24A1', was, upregulated, '(', 0.8522, '[', 'IQR', 1.317, ']', vs, 1.2239, '[', 'IQR', 4.4197, ']', vs, 0.1076, '[', 'IQR', 0.1791, ']', ',', p, =, 0.025, ')'])].
[sujeto(['Vitamin', 'D', may, be, dysregulated, at, multiple, 'levels,', with]), verbo([decreased]), complemento([transcription, of, the, metabolic, gene, 'CYP27B1', and, increased, transcription, of, the, catabolic, gene, 'CYP24A1', observed])].
[sujeto(['However,', the, levels, of, 'CYP24A1', in, 'ESRD', patients, were]), verbo([increased]), complemento([than, those, from, healthy, controls, '(', 50.18, '±21', vs, 7.78, '±1'])].
[sujeto(['VDR', levels, were, reduced, and, 'CYP24A1', levels, were]), verbo([increased]), complemento([in, patients, with, 'ESRD,', and, 'VDR', levels, were, negatively, correlated, with, 'CYP24A1'])].
[sujeto(['Vitamin', 'D', plays, a, critical, role, in, tissue, homeostasis, by]), verbo([regulating]), complemento([the, expression, of, genes, affecting, cell, 'proliferation,', 'differentiation,', and, apoptosis])].
[sujeto(['The', 'vitamin&nbsp;D', 24, -, hydroxylase, 'CYP24A1', functions, in, 'vitamin&nbsp;D']), verbo([target]), complemento([tissues, to, degrade, the, hormonal, form, of, 'vitamin&nbsp;D'])].
[sujeto(['Here,', we]), verbo([found]), complemento([that, the, suppression, of, constitutive, 'CYP24A1', expression, conferred, target, cells, with, increased, susceptibility, to, apoptosis, and, consequently, inhibited, 'anchorage-independent', growth, in, breast, carcinoma, cells])].
[sujeto(['These', data]), verbo([provide]), complemento([substantial, evidence, for, a, 'pro-survival', and, stimulatory, oncogenic, effect, of, 'CYP24A1', in, breast, carcinoma, cells])].
[sujeto(['The', ingestion, of, excessive, amounts, of, vitamin, 'D3', '(', or, vitamin, 'D2)', results, in, hypercalcemia, and, hypercalciuria, due, to, the, formation, of, 'supra-physiological', amounts, of, 25, -, hydroxyvitamin, 'D', '(', 25, '(', 'OH)D)', that]), verbo([bind]), complemento([to, the, vitamin, 'D', receptor, '(', 'VDR),', albeit, with, lower, affinity, than, active, form, of, the, 'vitamin,', 1, ',', 25, '(', 'OH)2D,', and, the, formation, of, 5, ',', 6, -, trans, 25, '(', 'OH)D', which, binds, to, the, 'VDR', more, tightly, than, 25, '(', 'OH)D'])].
[sujeto(['In', patients, with, granulomatous, disease, such, as, sarcoidosis, or, 'tuberculosis,', and, tumors, such, as, 'lymphomas,', hypercalcemia, occurs, as, a, result, of, the, activity, of, ectopic, 25, '(', 'OH)D-1-hydroxylase', '(', 'CYP27B1)']), verbo([expressed]), complemento([in, macrophages, or, tumor, cells, and, the, formation, of, excessive, amounts, of, 1, ',', 25, '(', 'OH)2D'])].
[sujeto(['Recent', work]), verbo([has]), complemento([identified, a, novel, cause, of, 'non-PTH', mediated, hypercalcemia, that, occurs, when, the, degradation, of, 1, ',', 25, '(', 'OH)2D', is, impaired, as, a, result, of, mutations, of, the, 1, ',', 25, '(', 'OH)2D-24-hydroxylase', cytochrome, 'P450', '(', 'CYP24A1)'])].
[sujeto(['Patients', with, 'bi-allelic,', and, in, some, 'instances,', 'mono-allelic', mutations, of, the, 'CYP24A1', gene]), verbo([have]), complemento([elevated, serum, calcium, concentrations, associated, with, elevated, serum, 1, ',', 25, '(', 'OH)2D,', suppressed, parathyroid, hormone, 'concentrations,', 'hypercalciuria,', 'nephrocalcinosis,', 'nephrolithiasis,', and, on, 'occasion,', reduced, bone, density])].
[sujeto(['Of', 'interest,', first, time, calcium, renal, stone, 'formers,']), verbo([have]), complemento([elevated, 1, ',', 25, '(', 'OH)2D', and, evidence, of, impaired, 24, -, 'hydroxylase-mediated', 1, ',', 25, '(', 'OH)2D', degradation])].
[sujeto(['We', will, describe, the, biochemical, processes]), verbo([associated]), complemento([with, the, synthesis, and, degradation, of, various, vitamin, 'D', 'metabolites,', the, clinical, features, of, the, vitamin, 'D-mediated', 'hypercalcemias,', their, biochemical, diagnosis, and, treatment])].
[sujeto(['In', this, 'disease,', the, thickened, epidermis, and, impaired, barrier, are]), verbo([associated]), complemento([with, altered, calcium, gradients])].
[sujeto(['Intracellular', calcium, is]), verbo([regulated]), complemento([by, 'calcium-sensing', 'receptor&nbsp;(CASR),', calcium, 'release-activated', calcium, 'modulator&nbsp;(ORAI)', and, stromal, interaction, 'molecule&nbsp;(STIM)'])].
[sujeto(['Other', proteins]), verbo([modulated]), complemento([by, 'vitamin&nbsp;D', play, important, roles, in, calcium, regulation, e])].
[sujeto(['We']), verbo([suggest]), complemento([an, altered, capacity, to, regulate, the, intracellular, 'Ca2+', 'concentration&nbsp;([Ca2+]i),', characterized, by, a, reduced, expression, of, 'CASR,', 'ORAI1,', 'ORAI3,', 'STIM1,', 'CALB1', and, 'TRPV6', associated, with, diminished, levels, of, 1, ',', 25, -, 'dihydroxyvitamin&nbsp;D3&nbsp;[1,25(OH)2D3],', which, may, be, associated, with, an, altered, balance, between, keratinocyte, proliferation, and, differentiation, in, the, psoriatic, epidermis])].
[sujeto(['The', transcriptional, coactivator, with, 'PDZ']), verbo([binding]), complemento([motif, '(', 'TAZ)', is, reported, as, one, of, the, nuclear, effectors, of, 'Hippo-related', pathways])].
[sujeto(['TAZ', is]), verbo([found]), complemento([overexpressed, in, many, primary, tumors, and, could, regulate, many, biological, processes])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, 'TAZ', is, expressed, more, in, 'ICC', tissues, than, in, peritumoral, 'tissue,', and, a, robust, expression, of, 'TAZ', is, correlated, with, a, lower, overall, survival, rate, of, 'ICC', patients, after, hepatectomy])].
[sujeto(['TAZ', knockdown, results, in, an]), verbo([increase]), complemento([in, cell, 'apoptosis,', a, promotion, of, 'cell-cycle', arrest, and, a, decrease, in, tumor, size, and, weight, in, vivo, through, an, increased, expression, of, p53])].
[sujeto(['Vitamin', 'D3', can, also]), verbo([inhibit]), complemento([cell, proliferation, by, promoting, p53, expression, in, 'ICC', cells])].
[sujeto(['A', reduction, in, 'TAZ', can, also]), verbo([enhance]), complemento([the, sensitivity, of, tumor, cells, to, vitamin, 'D', by, regulating, the, 'p53/CYP24A1', pathway])].
[sujeto(['In', 'conclusion,', 'TAZ', is]), verbo([associated]), complemento([with, the, proliferation, and, 'drug-resistance', of, 'ICC', 'cells,', and, could, be, a, novel, therapeutic, target, for, the, treatment, of, 'ICC'])].
[sujeto(['Vitamin', 'D,', a, hormone, once, thought, to]), verbo([have]), complemento([a, role, limited, to, calcium, homeostasis, and, bone, 'mineralization,', has, pleiotropic, effects, on, different, types, of, cells])].
[sujeto(['Vitamin', 'D', receptors, are]), verbo([reported]), complemento([in, vascular, smooth, muscle, 'cells,', endothelial, 'cells,', and, cardiomyocytes])].
[sujeto(['To', our, 'knowledge,', the, presence, of, vitamin, 'D', machinery, on, porcine, 'ADMSCs']), verbo([has]), complemento([not, yet, been, examined])].
[sujeto(['No', cytotoxicity, was, observed, when, 'MSCs', were]), verbo([stimulated]), complemento([with, 0.1, -, 10, nM, calcitriol])].
[sujeto(['A', significant]), verbo([increase]), complemento(['(', p, &, 'lt;0'])].
[sujeto(['The', levels, of, the, active, form, of, vitamin, 'D', were, significantly]), verbo([decreased]), complemento([once, the, 'CYP', enzymes, were, inhibited, '(', p, &, 'lt;0'])].
[sujeto(['Porcine', 'ADMSCs', possess, vitamin, 'D', hydrolases, and, 'VDR', to, metabolize, and]), verbo([respond]), complemento([to, vitamin, 'D'])].
[sujeto(['Hence,', in, vivo, circulating, 25, -, hydroxy, vitamin, 'D', levels, may]), verbo([have]), complemento([a, significant, role, in, regulating, the, differentiation, of, 'ADMSCs', into, different, 'lineages,', which, might, assist, in, stem, 'cell-based', therapy])].
[sujeto(['Cigarette', smoking, is]), verbo([associated]), complemento([with, increased, inflammation, and, defective, antibacterial, responses, in, the, airways])].
[sujeto(['Interestingly,', vitamin, 'D']), verbo([has]), complemento([been, shown, to, suppress, inflammation, and, to, improve, antibacterial, defense])].
[sujeto(['However,', it, is, currently, unknown, whether, vitamin, 'D', may]), verbo([modulate]), complemento([inflammation, and, antibacterial, defects, in, human, cigarette, smoke, '(', 'CS)-exposed', airways])].
[sujeto(['To', explore, these, unresolved, 'issues,', alveolar, macrophages, obtained, from, 'non-smoking', and, smoking, subjects, as, well, as, human, cigarette, smoke, extract, '(', 'CSE)-treated', 'THP-1', macrophages, were]), verbo([stimulated]), complemento([with, 1, ',', 25, -, dihydroxyvitamin, 'D', '(', 1, ',', 25, '(', 'OH)2D)', to, address, inflammatory, and, antibacterial, responses])].
[sujeto(['However,', 1, ',', 25, '(', 'OH)2D', significantly]), verbo([enhanced]), complemento([mRNA, expression, 'and/or', protein, levels, of, the, antimicrobial, peptide, cathelicidin, in, alveolar, macrophages, and, 'THP-1', 'macrophages,', independently, of, 'CS', exposure])].
[sujeto(['In', 'conclusion,', our, results]), verbo([provide]), complemento([the, first, evidence, that, vitamin, 'D', could, be, a, new, strategy, for, attenuating, airway, inflammation, and, improving, antibacterial, defense, in, 'CS-exposed', airways])].
[sujeto(['Bone', abnormalities, were, previously]), verbo([induced]), complemento([and, bone, mineral, density, '(', 'BMD)', reduced, in, offspring, from, sows, fed, diets, with, inadequate, vitamin, 'D3'])].
[sujeto(['Pigs', produced, by, +, 'D', or, +, +, 'D', sows, had]), verbo([increased]), complemento([gain, at, 3, weeks, '(', 'P&lt;0·05),', and, at, 8, weeks, had, increased, 'BMD', and, improved, femur, mechanical, properties])].
[sujeto(['Detection', of, a, maternal, and, nursery, diet, interaction, '(', 'P&lt;0·05)']), verbo([provided]), complemento([insights, into, the, 'long-term', effects, of, maternal, nutritional, inputs])].
[sujeto(['Characterising', early, stages, of, bone, abnormalities]), verbo([provided]), complemento([inferences, for, humans, and, animals, about, maternal, dietary, influence, on, offspring, skeletal, health])].
[sujeto(['Conventional', efforts, relying, on, 'high-throughput', physical, and, virtual, screening, of, large, compound, libraries]), verbo([have]), complemento([failed, to, yield, 'high-efficiency', chemical, probes, for, many, of, the, 48, human, nuclear, receptors])].
[sujeto(['Here,', we, investigated, whether, 'disulfide-trapping,', an, approach, new, to]), verbo([nuclear]), complemento(['receptors,', would, provide, effective, lead, compounds, targeting, human, liver, receptor, homolog, 1, '(', 'hLRH-1,', 'NR5A2)'])].
[sujeto(['Despite', the, fact, that, 'hLRH-1', contains, a, large, ligand]), verbo([binding]), complemento([pocket, and, binds, phospholipids, with, high, 'affinity,', existing, synthetic, 'hLRH-1', ligands, are, of, limited, utility, due, to, poor, 'solubility,', low, efficacy, or, significant, 'off-target', effects])].
[sujeto(['Using', 'disulfide-trapping,', we, identified, a]), verbo([lead]), complemento([compound, that, conjugates, with, remarkably, 'high-efficiency', to, a, native, cysteine, residue, '(', 'Cys346)', lining, the, hydrophobic, cavity, in, the, ligand, binding, domain, of, 'hLRH-1'])].
[sujeto(['Guided', by, computational, modeling, and, cellular, 'assays,', the]), verbo([lead]), complemento([compound, was, elaborated, into, ligands, 'PME8', and, 'PME9', that, bind, 'hLRH-1', reversibly, '(', no, cysteine, 'reactivity)', and, increase, 'hLRH-1', activity, in, cells])].
[sujeto(['When', compared, with, the, existing, 'hLRH-1', synthetic, agonist, 'RJW100,', both, 'PME8', and, 'PME9', showed, comparable, induction, of, the, 'LRH-1', dependent]), verbo([target]), complemento([gene, 'CYP24A1', in, human, 'HepG2', 'cells,', beginning, as, early, as, 3, h, after, drug, treatment])].
[sujeto(['These', data, show, that, 'PME8', and, 'PME9', are, potent, activators, of, 'hLRH-1', and]), verbo([suggest]), complemento([that, with, further, development, this, lead, series, may, yield, useful, chemical, probes, for, manipulating, 'LRH-1', activity, in, vivo])].
[sujeto(['The', fibroblasts]), verbo([expressed]), complemento([mRNA, for, cytochrome, 'P450', '(', 'CYP)', enzymes, catalysing, bioactivating, '(', 'CYP2R1,', 'CYP27A1', and, 'CYP27B1)', and, catabolic, reactions, '(', 'CYP24A1)'])].
[sujeto(['The', results, demonstrate, that, primary, dermal, fibroblasts]), verbo([have]), complemento([an, active, vitamin, 'D3', -, metabolizing, system])].
[sujeto(['Osteomalacia', and, severe, vitamin, 'D', deficiency]), verbo([have]), complemento([been, reported])].
[sujeto(['The', current, results, indicate, that, effects, on, gene, expression, may]), verbo([lead]), complemento([to, disturbed, vitamin, 'D', metabolism, and, decreased, cellular, levels, of, active, vitamin, 'D3'])].
[sujeto(['Specifically,', the, impact, of, liver, dysfunction, on, vitamin, 'D', status]), verbo([has]), complemento([not, been, well, addressed])].
[sujeto(['We']), verbo([recruited]), complemento([a, group, of, patients, '(', n, =, 345, ')', with, chronic, hepatitis, 'B', '(', n, =, 115, ')', ',', hepatitis, 'B', related, cirrhosis, '(', n, =, 115, ')', ',', and, 'age-', and, 'gender-matched', healthy, controls, '(', n, =, 115, ')'])].
[sujeto(['Furthermore,', 25, '(', 'OH)D3']), verbo([decreased]), complemento([stepwise, with, higher, 'Child-Pugh', classification])].
[sujeto(['Multiple', logistic, regression, analyses, confirmed, that, higher, 'Child-Pugh', score, was, independently]), verbo([associated]), complemento([with, 25, '(', 'OH)D3', deficiency, '(', &, 'lt;10', 'ng/mL)', with, an, odds, ratio, of, 1.2, '(', confidence, interval, 1.03, -, 1.39, ',', 'P', =, 0.016, ')'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, decreasing, vitamin, 'D', levels, are, likely, to, be, a, 'result,', rather, than, a, 'cause,', of, liver, dysfunction, and, irrespective, of, 'HBV', viral, load])].
[sujeto(['Loss-of-function', mutations, in, the, 'CYP24A1', 'gene,', which, encodes, the, vitamin, 'D-24', 'hydroxylase,']), verbo([have]), complemento([been, recognized, as, a, cause, of, elevated, 1, ',', 25, -, dihydroxyvitamin, 'D', 'concentrations,', 'hypercalcemia,', 'hypercalciuria,', nephrocalcinosis, and, nephrolithiasis, in, infants, and, adults])].
[sujeto(['As', only, a, case]), verbo([report]), complemento([describing, 2, adult, patients, has, been, reported, in, 'Italian', 'population,', we, report, here, the, mutation, analysis, of, 'CYP24A1', gene, in, an, 'Italian', cohort, of, 12, pediatric, and, adult, patients, with, idiopathic, infantile, hypercalcemia, '(', 'IIH)'])].
[sujeto(['CYP24A1', 'bi-allelic', mutations, were]), verbo([found]), complemento([in, 8, individuals, from, 7, 'Italian', families, '(', 7, /, 11, ;, 64, '%', ')'])].
[sujeto(['To', the, best, of, our, 'knowledge,', this, is, the, first]), verbo([report]), complemento([of, a, 'CYP24A1', molecular, analysis, performed, in, an, 'Italian', cohort, of, adult, and, pediatric, 'Italian', patients])].
[sujeto(['However,', when, 'combined,', complex, mixtures, may]), verbo([provoke]), complemento([unexpected, effects, even, at, low, amounts])].
[sujeto(['Fish', liver, is, a]), verbo([target]), complemento([organ, for, contaminants, due, to, its, crucial, role, in, detoxification, processes])].
[sujeto(['In', order, to, understand, the, effects, on, distinct, key, liver, metabolic, 'pathways,', transcription, levels, of, various, genes, were, 'measured,', including, cyp1a1, and, 'cyp3a,']), verbo([involved]), complemento([in, the, metabolism, of, organic, 'compounds,', including, toxic, 'ones,', and, the, catabolism, of, bile, acids, and, steroid, 'hormones;', 'cyp7a1,', fabp, and, 'hmg-CoA,', involved, in, lipid, and, cholesterol, 'homeostasis;', 'cyp24a1,', involved, in, vitamin, 'D', 'metabolism;', and, 'vtg,', a, key, gene, in, xenoestrogenic, response])].
[sujeto(['However,', when, exposed, in, 'combinations,', effects, not, detected, in, single, exposure, conditions, 'arose,']), verbo([suggesting]), complemento([complex, interactions, between, studied, pollutants, that, could, not, be, predicted, from, the, results, of, individual, exposure, scenarios])].
[sujeto(['CYP24A1', gene, mutations]), verbo([induce]), complemento([infantile, 'hypercalcemia,', with, high, 1, ',', 25, '(', 'OH)2D', contrasting, with, low, 'PTH', levels])].
[sujeto(['Two', unrelated, adult, patients, were, referred, for, 'nephrolithiasis,', 'hypertension,', 'hypercalcemia,', 'hypercalciuria,', normal, 25, -, 'OHD', 'levels,', and, inappropriate, 'PTH', levels, '(', 22, to, 92, 'pg/mL;N:', 15, -, 68, ')']), verbo([suggesting]), complemento([primary, 'hyperparathyroidism,', leading, to, surgery])].
[sujeto(['The', ratio, 25, -, 'OHD3/24-25-(OH)2D3&gt;100', '(', 'N&lt;25)']), verbo([suggested]), complemento([the, diagnosis, of, 'CYP24A1', mutations, which, were, confirmed, through, 'Sanger', sequencing])].
[sujeto(['In', 'conclusion,', the, adult, phenotype]), verbo([associated]), complemento([with, 'CYP24A1', mutations, can, evolve, over, time, from, hypercalcemia, with, suppressed, 'PTH', towards, hyperparathyroidism, with, moderately, increased, 'PTH', 'level,', adenoma, 'and/or', slightly, increased, parathyroid, glands])].
[sujeto(['Surgery']), verbo([decreased]), complemento([calciuria, and, improved, kidney, function])].
[sujeto(['Therefore,', it, is, of, topical, interest, to]), verbo([have]), complemento([reliable, and, efficient, in, vitro, screening, tools, for, the, identification, of, agonists, and, activators, of, human, 'VDR'])].
[sujeto(['Association', of, liver, calcitriol, '(', active, vitamin, 'D', 'metabolite)', catabolism, with, osteomalacia, during, prolonged, use, of, certain, drugs, was]), verbo([reported]), complemento([in, several, recent, studies])].
[sujeto(['To', examine, whether, the]), verbo([increased]), complemento([calcitriol, catabolism, could, be, a, potential, link, between, 'ageing/diabetes', mellitus, '(', 'DM)', and, bone, 'loss,', we, studied, the, dynamic, of, expression, of, 'CYP24,', the, main, calcitriol, catabolising, enzyme, in, the, liver, of, rats, during, ageing, and, a, 'long-term', experimental, 'DM1'])].
[sujeto(['DM1', model, was]), verbo([induced]), complemento([with, intraperitoneally, injected, streptozotocin, '(', 'STZ)', '(', 55, 'mg/kg)'])].
[sujeto(['We']), verbo([found]), complemento([that, ageing, and, 'long-term', 'DM1', resulted, in, a, significantly, increased, expression, of, 'CYP24', in, 'hepatocytes,', as, well, as, in, 'non-hepatocyte', liver, cells, '(', 'Kupffer', 'cells,', hepatic, stellate, cells, and, sinusoidal, endothelial, 'cells)'])].
[sujeto(['Ageing', and, 'long-term', 'DM1', resulted, in, an]), verbo([increased]), complemento([expression, of, 'TGF-β1', as, well])].
[sujeto(['We', concluded, that, liver]), verbo([has]), complemento([the, capacity, for, an, active, vitamin, 'D', catabolism, in, different, populations, of, liver, 'cells,', especially, in, sinusoidal, endothelial, 'cells,', through, an, expression, of, 'CYP24'])].
[sujeto(['That', capacity, is, substantially]), verbo([increased]), complemento([during, ageing, and, 'long-term', diabetes, mellitus])].
[sujeto(['Basal', renal, and, extrarenal, 'CYP24', is, usually, low, but, is, highly]), verbo([induced]), complemento([by, its, substrate, 1, ',', 25, -, dihydroxyvitamin, 'D'])].
[sujeto(['Unbalanced', high, 'and/or', 'long-lasting', 'CYP24', expression]), verbo([has]), complemento([been, proposed, to, underlie, diseases, like, chronic, kidney, 'disease,', 'cancers,', and, psoriasis, that, otherwise, should, favorably, respond, to, supplemental, vitamin, 'D'])].
[sujeto(['Using', genetically, modified, 'mice,', we]), verbo([have]), complemento([shown, that, renal, phosphate, wasting, hypophosphatemic, states, arising, from, high, levels, of, fibroblast, growth, factor, 23, '(', 'FGF23)', are, also, associated, with, increased, renal, 'Cyp24', 'expression,', suggesting, that, elevated, 'CYP24', activity, is, pivotal, to, the, pathophysiology, of, these, disorders])].
[sujeto(['Specifically,', we, evaluated, 'Cyp24', deficiency, in, 'Hyp', 'mice,', the, murine, homolog, of, 'X-linked', dominant, hypophosphatemic, 'rickets,', and, transgenic, mice, that, overexpress, a, mutant, 'FGF23', '(', 'FGF23R176Q)', that, is]), verbo([associated]), complemento([with, the, autosomal, dominant, form, of, hypophosphatemic, rickets])].
[sujeto(['Abnormal', 'up-regulation', of, 'CYP24', contributes, to, vitamin, 'D', insufficiency, and, resistance, to, vitamin, 'D', therapy, in, chronic, kidney, disease, '(', 'CKD),', because, human, 'CYP24', is, a, key, enzyme]), verbo([involved]), complemento([in, the, inactivation, of, 1, 'a,25-dihydroxyvitamin', 'D3', '(', 1, 'a,25(OH)2D3;', 'calcitriol)', and, 1, ',', 25, '(', 'OH)2D3'])].
[sujeto(['There', are, multiple, mechanisms]), verbo([regulating]), complemento(['CYP24', in, a, variety, of, types, of, tissues, and, diseases])].
[sujeto(['Increasing', body, of, evidence]), verbo([suggests]), complemento([that, 'microRNA-125b', '(', 'miR-125b)', plays, an, important, role, in, 'post-transcriptional', regulation, of, 'CYP24', mRNA])].
[sujeto(['We', sought, to, test, hypothesis, that, abnormal, elevation, of, 'CYP24', in, 'CKD', is, a, consequence, of]), verbo([loss]), complemento([of, 'miR-125b', in, 'CKD', in, a, uremia, rat, model])].
[sujeto(['We']), verbo([found]), complemento([that, expression, of, 'miR-125b', was, significantly, inhibited, in, uremic, rats, coupled, with, increased, 'CYP24', at, both, protein, and, mRNA, levels, compared, with, normal, controls])].
[sujeto(['In', 'NRK-52', kidney, 'cells,', we, further]), verbo([found]), complemento([that, 'miR-125b', antagomirs, increased, 'CYP24', but, 'miR-125b', mimics, decreased, 'CYP24,', and, luciferase, assay, confirmed, that, 'CYP24', is, a, direct, target, of, 'miR-125b'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, modulation, of, 'miR-125b', may, be, used, for, treatment, of, 'Vitamin', 'D', insufficiency, in, 'CKD'])].
[sujeto(['The', metabolite, 1, ',', 25, -, dihydroxyvitamin, 'D', '(', 1, ',', 25, '(', 'OH)2D)', is, synthesized, from, its, precursor, 25, -, hydroxyvitamin, 'D', '(', 25, '(', 'OH)D)', by, human, osteoblasts]), verbo([leading]), complemento([to, stimulation, of, osteoblast, differentiation, in, an, autocrine, or, paracrine, way])].
[sujeto(['Osteoblast', differentiation, is, also]), verbo([stimulated]), complemento([by, mechanical, loading, through, activation, of, various, responses, in, bone, cells, such, as, nitric, oxide, signaling])].
[sujeto(['Whether', mechanical, loading, affects, osteoblast, differentiation, through, an]), verbo([enhanced]), complemento([synthesis, of, 1, ',', 25, '(', 'OH)2D', by, human, osteoblasts, is, still, unknown])].
[sujeto(['We', hypothesized, that, mechanical, loading]), verbo([stimulates]), complemento([the, synthesis, of, 1, ',', 25, '(', 'OH)2D', from, 25, '(', 'OH)D', in, primary, human, osteoblasts])].
[sujeto([25, '(', 'OH)D3', did, not, significantly, alter, the, 'NO', response, of, primary, human, osteoblasts, to, 'PFF,', but, 25, '(', 'OH)D3']), verbo([increased]), complemento([osteocalcin, and, 'RANKL', mRNA, 'levels,', similar, to, 1, ',', 25, '(', 'OH)2D3'])].
[sujeto(['PFF', did, not]), verbo([increase]), complemento([1, ',', 25, '(', 'OH)2D3', amounts, in, our, 'model,', even, though, 'PFF', did, increase, 'CYP27B1', mRNA, levels, and, reduced, 'VDR', mRNA, levels])].
[sujeto(['CYP24', mRNA, levels, were, not, affected, by, 'PFF,', but, were, strongly]), verbo([increased]), complemento([by, both, 25, '(', 'OH)D3', and, 1, ',', 25, '(', 'OH)2D3'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 1, ',', 25, '(', 'OH)2D3', and, mechanical, 'loading,', both, stimuli, of, the, differentiation, of, 'osteoblasts,', interact, at, the, cellular, level])].
[sujeto(['Moreover,', both, vitamin, 'D', compounds]), verbo([increased]), complemento([the, anticancer, activity, of, 'GV;', 'however,', they, might, also, potentiate, some, adverse, effects])].
[sujeto(['Chronic', kidney, disease, '(', 'CKD)', is]), verbo([associated]), complemento([with, an, 'inflammation-mediated', 'process,', and, the, vitamin, 'D', '(', 3, ')', catabolizing, 'enzyme,', 'CYP24,', is, frequently, overexpressed, in, 'CKD,', where, it, may, play, a, crucial, role, in, kidney, disease])].
[sujeto(['Our', results, showed, that, 'IS', upregulates, proinflammatory, 'cytokine,', 'CYP24', and]), verbo([nuclear]), complemento(['factor-κB', '(', 'NF-κB)', expression, in, human, renal, proximal, tubule, epithelial, cells])].
[sujeto(['In', 'addition,', 'IS', treatment]), verbo([increased]), complemento(['ROS', production, and, simultaneously, upregulated, 'CYP24', expression, and, 'NF-κB', translocation])].
[sujeto(['Furthermore,', the, renal, cortex, of, 'DN', '(', 'Dahl', 'salt-resistant', 'normotensive)', +, 'IS,', 'DH', '(', 'Dahl', 'salt-sensitive', 'hypertensive),', and, 'DH', +, 'IS', rats, showed]), verbo([increased]), complemento([expression, of, 'NF-κB', 'p65,', 'CYP24,', 8, -, hydroxydeoxyguanosine, '(', 8, -, 'OHdG),', a, marker, of, 'ROS', and, macrophage, infiltration, compared, with, 'DN', rats])].
[sujeto(['These', results]), verbo([provide]), complemento([evidence, that, administration, of, 'IS', in, human, renal, tubular, epithelial, cells, upregulates, 'NF-κB,', which, leads, to, increase, 'CYP24', expression, and, 'ROS', production])].
[sujeto(['They', also]), verbo([suggest]), complemento([that, suppressing, 'NF-κB', signalling, is, promising, for, the, development, into, a, strategy, for, 'CKD', treatment])].
[sujeto(['Animal', models, show, that, vitamin, 'D', deficiency, may]), verbo([have]), complemento([severe, consequences, for, skeletal, health])].
[sujeto(['However,', most, studies]), verbo([have]), complemento([been, performed, in, young, rodents, for, a, relatively, short, 'period,', while, in, older, adult, rodents, the, effects, of, 'long-term', vitamin, 'D', deficiency, on, skeletal, health, have, not, been, extensively, studied])].
[sujeto(['The', second, aim, was, to, determine, the, effects, of, 'long-term', vitamin, 'D', deficiency, on, mRNA, levels, of, genes]), verbo([involved]), complemento([in, vitamin, 'D', metabolism, in, bones, from, older, adult, mice])].
[sujeto(['Micro-CT', and, histomorphometric, analysis, of, bone, mineral, 'density,', structure, and, remodeling, did, not]), verbo([reveal]), complemento([differences, between, control, and, vitamin, 'D', deficient, mice])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, mice, at, old, age, have, a, low, or, absent, response, to, vitamin, 'D', deficiency, probably, due, to, factors, such, as, a, decreased, bone, formation, rate, or, a, reduced, response, of, bone, cells, to, 25, '(', 'OH)D', and, 1, ',', 25, '(', 'OH)2D'])].
[sujeto(['Even', in, cells, that, are, resistant, to, the, differentiating, effects, of, vitamin, 'D,', the]), verbo([activated]), complemento([vitamin, 'D', receptor, '(', 'VDR)', can, downregulate, the, mitochondrial, respiratory, chain, and, sustain, cell, growth, through, enhancing, the, activity, of, biosynthetic, pathways])].
[sujeto(['The', aim, of, this, study, was, to, investigate, whether, vitamin, 'D', is, effective, also, in]), verbo([modulating]), complemento([mitochondria, and, biosynthetic, metabolism, of, differentiating, cells])].
[sujeto(['We', analysed, the]), verbo([nuclear]), complemento([translocation, and, features, of, 'VDR,', the, effects, of, vitamin, 'D', on, mitochondrial, transcription, and, the, consequences, on, lipid, biosynthetic, fate])].
[sujeto(['We']), verbo([found]), complemento([that, the, negative, modulation, of, respiratory, chain, is, a, general, mechanism, of, action, of, vitamin, 'D,', but, at, high, 'doses,', the, 'HaCaT', cells, became, resistant, to, mitochondrial, effects, by, upregulating, the, catabolic, enzyme, 'CYP24', hydroxylase])].
[sujeto(['In', differentiating, 'keratinocytes,', vitamin, 'D', treatment]), verbo([promoted]), complemento([intracellular, lipid, 'deposition,', likewise, the, inhibitor, of, respiratory, chain, 'stigmatellin,', whereas, in, proliferating, 'HaCaT,', this, biosynthetic, pathway, was, not, inducible, by, the, hormone])].
[sujeto(['By', linking, the, results, on, respiratory, chain, and, lipid, 'accumulation,', we, conclude, that, vitamin, 'D,', by]), verbo([suppressing]), complemento([respiratory, chain, transcription, in, all, 'keratinocytes,', is, able, to, support, both, the, proliferation, and, the, specialized, metabolism, of, differentiating, cells])].
[sujeto(['Through', mitochondrial, 'control,', vitamin, 'D', can]), verbo([have]), complemento([an, essential, role, in, all, the, metabolic, phenotypes, occurring, in, healthy, and, diseased, skin])].
[sujeto(['Low', serum, 25, '(', 'OH)D', concentrations]), verbo([have]), complemento([been, reported, in, obese, humans])].
[sujeto(['Inadequate', sun, exposure, and, impaired, hepatic, 25, -, hydroxylation]), verbo([have]), complemento([been, suggested, as, possible, reasons, for, 'obesity-associated', vitamin, 'D', 'deficiency;', 'however,', the, underlying, mechanism, has, not, been, elucidated])].
[sujeto(['Overall,', vitamin, 'D', metabolizing, enzyme, expression, was, influenced, by, high, fat, 'diet-induced', 'obesity,', which, might, partly, explain, the, mechanisms, of, the, altered, vitamin, 'D', endocrine, system]), verbo([associated]), complemento([with, obesity])].
[sujeto(['Higher', serum, 'PTH', and, 1, ',', 25, '(', 'OH)2', 'D', concentrations, in, obese, mice]), verbo([suggest]), complemento([abnormal, regulation, of, serum, 1, ',', 25, '(', 'OH)2', 'D', concentrations, due, to, 'hyperparathyroidism,', which, might, have, contributed, to, lower, hepatic, 25, -, hydroxylase, mRNA, levels])].
[sujeto(['Laboratory', studies]), verbo([suggest]), complemento([that, vitamin, 'D', '(', 'VD)', supplementation, inhibits, skin, carcinogenesis])].
[sujeto(['However,', epidemiologic, studies]), verbo([report]), complemento([mixed, findings, in, the, association, between, circulating, 'VD', levels, and, skin, cancer, risk])].
[sujeto(['CYP24', expression, in, 'PD-', and, 'PP-skin', was]), verbo([increased]), complemento([after, supplementation, by, 186, '%', ',', 'P', =, 0.08, ',', and, 134, '%', ',', 'P', =, 0.07, ',', respectively])].
[sujeto(['Caspase-14', expression, at, the, basal, layer, in, 'PD', skin, samples, was, the, only, epidermal, differentiation, marker, that, was, significantly]), verbo([increased]), complemento(['(', 49, '%', ',', 'P', &, 'lt;', 0.0001, ')'])].
[sujeto(['Vitamin', 'D3']), verbo([has]), complemento([emerged, as, an, important, regulator, of, the, immune, system])].
[sujeto(['We', examined, whether, 1, ',', 25, '(', 'OH)2D3', might, also]), verbo([enhance]), complemento([the, 'NLRP3-dependent', release, of, mature, 'IL-1β', from, macrophages])].
[sujeto(['PMA-differentiated', 'THP-1', cells, were]), verbo([stimulated]), complemento([with, vitamin, 'D3', metabolites, and, assessed, for, 'CYP27,', 'CYP24,', 'NLRP3,', 'ASC,', 'pro-caspase-1', expression, by, western, blot, and, 'real-time', qPCR, as, well, as, inflammasome, activation, with, 'pro-inflammatory', cytokine, 'IL-1β', release, measured, by, 'ELISA'])].
[sujeto(['Exposure', to, 1, ',', 25, '(', 'OH)2D3', had, no, effect, on, the, basal, expression, levels, of, 'VDR;', 'however,', 'CYP27A1', transcript, was]), verbo([suppressed]), complemento([and, 'CYP24A1', transcript, was, substantively, elevated])].
[sujeto(['Both', 1, ',', 25, '(', 'OH)2D3', -, and, 25, '(', 'OH)D3']), verbo([induced]), complemento(['IL-1β', release, from, 'THP-1', 'cells,', and, these, effects, were, blocked, with, application, of, the, 'caspase-1', inhibitor, 'YVAD', and, the, 'NLRP3', inhibitors, glyburide, and, 'Bay', 11, -, 7082])].
[sujeto(['The']), verbo([increase]), complemento([in, mature, 'IL-1β', elicited, by, 1, ',', 25, '(', 'OH)2D3', was, modest, compared, to, that, found, for, 'ATP', or, 'C'])].
[sujeto(['Vitamin', 'D', insufficiency, drives, secondary, hyperparathyroidism, '(', 'SHPT)', and, is]), verbo([associated]), complemento([with, increased, cardiovascular, mortality, in, patients, with, chronic, kidney, disease, '(', 'CKD)'])].
[sujeto(['Mean', plasma, iPTH]), verbo([decreased]), complemento([from, baseline, '(', 140.3, 'pg/ml)', by, 20.9, ±, 6.2, '%', '(', 'SE),', 32.8, ±, 5.7, and, 39.3, ±, 4.3, '%', in, the, 30, ',', 60, and, 90, µg, dose, 'groups,', 'respectively,', and, increased, 17.2, ±, 7.8, '%', in, the, pooled, placebo, group, '(', p, &, 'lt;', 0.005, ')'])].
[sujeto(['Oral', 'MR', calcifediol, appears, safe, and, highly, effective, in, treating, 'SHPT']), verbo([associated]), complemento([with, vitamin, 'D', insufficiency, in, 'CKD'])].
[sujeto(['The', most, biologically, active, metabolite, 1, ',', 25, -, dihydroxyvitamin, 'D3', '(', 1, ',', 25, '(', 'OH)2D3)']), verbo([has]), complemento([well, known, direct, effects, on, osteoblast, growth, and, differentiation, in, vitro])].
[sujeto(['Furthermore,', 25, '(', 'OH)D3', is, not, only, converted, to, 1, ',', 25, '(', 'OH)2D3,', but, also, to, 24, 'R,25-dihydroxyvitamin', 'D3', '(', 24, 'R,25(OH)2D3)', which, may]), verbo([have]), complemento([bioactivity, as, well])].
[sujeto(['We', showed, that, primary, human, osteoblasts]), verbo([responded]), complemento([to, both, 25, '(', 'OH)D3', and, 1, ',', 25, '(', 'OH)2D3', by, reducing, their, proliferation, and, enhancing, their, differentiation, by, the, increase, of, alkaline, 'phosphatase,', osteocalcin, and, osteopontin, expression])].
[sujeto(['Osteoblasts']), verbo([expressed]), complemento(['CYP27B1', and, 'CYP24', and, synthesized, 1, ',', 25, '(', 'OH)2D3', and, 24, 'R,25(OH)2D3', 'dose-dependently'])].
[sujeto(['We', demonstrated, that, 24, 'R,25(OH)2D3']), verbo([increased]), complemento([mRNA, levels, of, alkaline, 'phosphatase,', osteocalcin, and, osteopontin])].
[sujeto(['In', 'addition,', 24, 'R,25(OH)2D3', strongly]), verbo([increased]), complemento(['CYP24', mRNA])].
[sujeto(['We', showed, that, primary, human, osteoblasts, not, only]), verbo([respond]), complemento([to, 1, ',', 25, '(', 'OH)2D3,', but, also, to, 24, 'R,25(OH)2D3', by, enhancing, osteoblast, differentiation])].
[sujeto(['This']), verbo([suggests]), complemento([that, 25, '(', 'OH)D3', can, affect, osteoblast, differentiation, via, conversion, to, the, active, metabolite, 1, ',', 25, '(', 'OH)2D3,', but, also, via, conversion, to, 24, 'R,25(OH)2D3'])].
[sujeto(['Whether', 25, '(', 'OH)D3']), verbo([has]), complemento([direct, actions, on, osteoblast, function, needs, further, investigation])].
[sujeto(['A', novel, mutation, in, 'CYP24A1']), verbo([provides]), complemento([insight, into, idiopathic, infantile, hypercalcemia])].
[sujeto(['In', this]), verbo([report]), complemento([of, 3, 'brothers,', 'in&nbsp;twins', supplemented, with, vitamin, 'D', '(', 1900, 'IU/d),', only, the, twin, homozygous, for, 'CYP24A1', exhibited, idiopathic, infantile, hypercalcemia])].
[sujeto(['Vitamin', '(', 1, ',', 25, '(', 'OH)2D)']), verbo([has]), complemento(['anti-proliferative', effects, on, several, cancers])].
[sujeto(['Vitamin', 'D3', is, synthesized, by, the, 'enzyme,', 'CYP27B1,', and, signals, via, the]), verbo([nuclear]), complemento([vitamin, 'D3', receptor])].
[sujeto(['Cell', lines, were]), verbo([stimulated]), complemento([with, vehicle, or, vitamin, 'D3', from, 30, min, to, 48, h])].
[sujeto(['Vitamin', 'D3', 'receptor,', 'CYP24A1', and, 'CYP27B1', expression, was, measured, in, cholangiocarcinoma, cells]), verbo([stimulated]), complemento([with, vehicle, or, vitamin, 'D3'])].
[sujeto(['In', cholangiocarcinoma, lines, and, biopsy, 'samples,', vitamin, 'D3', receptor, and, 'CYP24A1', expression]), verbo([increased]), complemento([compared, to, 'controls,', whereas, 'CYP27B1', expression, was, decreased, or, unchanged])].
[sujeto(['Vitamin', 'D3']), verbo([induced]), complemento([nuclear, translocation, of, vitamin, 'D3', receptor, in, cholangiocarcinoma, and, decreased, cholangiocarcinoma, growth])].
[sujeto(['Treatment', with, vitamin, 'D3']), verbo([decreased]), complemento(['CYP24A1,', whereas, 'CYP27B1', expression, increased])].
[sujeto(['XPD', '(', 'ERCC2)', is, a, 'DNA', helicase]), verbo([involved]), complemento([in, nucleotide, excision, repair, and, in, transcription, as, a, structural, bridge, tying, the, transcription, factor, 'IIH', '(', 'TFIIH)', core, with, the, 'cdk-activating', kinase, 'complex,', which, phosphorylates, nuclear, receptors])].
[sujeto(['Mutations', in, 'XPD', are]), verbo([associated]), complemento([with, several, different, 'phenotypes,', including, trichothiodystrophy, '(', 'TTD),', with, 'sulfur-deficient', brittle, 'hair,', bone, 'defects,', and, developmental, abnormalities, without, skin, 'cancer,', xeroderma, pigmentosum, '(', 'XP),', with, pigmentary, abnormalities, and, increased, skin, 'cancer,', or, 'XP/TTD', with, combined, 'features,', including, skin, cancer])].
[sujeto(['We', studied, 'TFIIH-dependent', transactivation, by]), verbo([nuclear]), complemento([receptor, for, vitamin, 'D', '(', 'VDR)', and, thyroid, in, cells, from, these, patients])].
[sujeto(['The', vitamin, 'D', stimulation, ratio, of, 'CYP24', and, osteopontin, was]), verbo([associated]), complemento([with, specific, pairs, of, mutations, '(', reduced, in, 5, ',', elevated, in, 1, ')', but, not, correlated, with, distinct, clinical, phenotypes])].
[sujeto(['XPD', mutations, frequently, were]), verbo([associated]), complemento([with, abnormal, 'VDR', stimulation, in, compound, heterozygote, patients, with, 'TTD,', 'XP,', or, 'XP/TTD'])].
[sujeto([25, -, 'Hydroxyvitamin', 'D', '[', 25, '(', 'OH)D]', is, a, marker, of, nutritional, 'status;', 'however,', chronic, kidney, disease, '(', 'CKD)', results, in, alterations, in, vitamin, 'D', 'metabolism,', including, the]), verbo([loss]), complemento([of, vitamin, 'D-binding', proteins, and, alterations, in, 'CYP27B1', and, 'CYP24', enzymes, that, metabolize, 25, '(', 'OH)D'])].
[sujeto(['The', average, number, of, vitamin, 'D2', doses, was, 10.91, ±, 5.95, ;, the, average]), verbo([increase]), complemento([in, 25, '(', 'OH)D', level, was, 18, ±, 10.8, 'ng/mL'])].
[sujeto(['Patients', with, 'CKD']), verbo([required]), complemento([greater, amounts, of, vitamin, 'D2', to, achieve, similar, increases, in, 25, '(', 'OH)D', 'levels,', versus, 'non-CKD', patients])].
[sujeto(['The', presence, of, 'CKD', and, diabetes, mellitus, is]), verbo([associated]), complemento([with, resistance, to, correction, of, 25, '(', 'OH)D', deficiency, with, vitamin, 'D2', therapy])].
[sujeto(['We', previously, demonstrated, that, 'non-small', cell, lung, cancer, '(', 'NSCLC)', cells, and, primary, human, lung, tumors, aberrantly]), verbo([express]), complemento([the, vitamin, 'D3-catabolizing', 'enzyme,', 'CYP24,', and, that, 'CYP24', restricts, transcriptional, regulation, and, growth, control, by, 1, 'α,25-dihydroxyvitamin', 'D3', '(', 1, ',', 25, '(', 'OH)2D3)', in, 'NSCLC', cells])].
[sujeto(['Specifically,', 'K-ras', mutation, was]), verbo([associated]), complemento([with, a, median, 4.2, -, fold, increase, in, 'CYP24', mRNA, expression, '(', 'p=4'])].
[sujeto(['To', test, 'this,', we, measured, the, ability, of, 1, ',', 25, '(', 'OH)2D3', to]), verbo([increase]), complemento([reporter, gene, 'activity,', induce, transcription, of, endogenous, target, 'genes,', and, suppress, colony, formation])].
[sujeto(['These', data, are, the, first, to]), verbo([suggest]), complemento([that, 'EGFR', mutations, may, identify, a, lung, cancer, subset, which, remains, responsive, to, and, is, likely, to, benefit, from, 1, ',', 25, '(', 'OH)2D3', administration])].
[sujeto(['Its', 'dysfunction,']), verbo([caused]), complemento([by, mutations, in, either, the, enzyme, itself, or, 'AIPL1', '(', aryl, hydrocarbon, 'receptor-interacting', 'protein-like', 1, ')', ',', leads, to, retinal, diseases, culminating, in, blindness])].
[sujeto(['Progress', in, research, on, 'PDE6', and, 'AIPL1']), verbo([has]), complemento([been, severely, hampered, by, failure, to, express, functional, 'PDE6', in, a, heterologous, expression, system])].
[sujeto(['Mutations', in, the, 'primate-specific', 'proline-rich', domain, '(', 'PRD)', of, aryl, hydrocarbon, 'receptor-interacting', 'protein-like', 1, '(', 'AIPL1)', are, thought, to]), verbo([cause]), complemento(['Leber', congenital, amaurosis, or, dominant, 'cone-rod', dystrophy])].
[sujeto(['Here,', we]), verbo([have]), complemento([examined, properties, of, hAIPL1, and, effects, of, the, 'PRD', mutations, on, protein, structure, and, function])].
[sujeto(['Our', analysis]), verbo([suggests]), complemento([that, 'PRD', assumes, an, extended, conformation, and, does, not, interact, with, the, 'FK506-binding', and, tetratricopeptide, domains])].
[sujeto(['The', 'PRD', mutations]), verbo([caused]), complemento([little, or, no, changes, in, hAIPL1, binding, to, known, 'partners,', 'phosphodiesterase-6A', and, 'HSP90'])].
[sujeto(['Mutations', in, the, 'proline-rich', domain, '(', 'PRD)', of, human, 'AIPL1']), verbo([cause]), complemento([severe, retinal, 'diseases,', yet, the, role, of, 'PRD', and, the, mechanisms, of, 'PRD', mutations, are, unknown])].
[sujeto(['This', structure, and, functional, analyses]), verbo([provide]), complemento([a, framework, for, understanding, the, mechanisms, of, 'PRD', in, disease])].
[sujeto(['The', aim, of, this, study, was, to, investigate, the, interaction, and, 'co-localization', of, novel]), verbo([interacting]), complemento([proteins, with, the, 'Leber', congenital, amaurosis, '(', 'LCA)', associated, protein, aryl, hydrocarbon, receptor, interacting, 'protein-like', 1, '(', 'AIPL1)'])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'AIPL1', function, in, these, cells, is, not, related, to, the, role, of, 'EB', proteins, in, microtubule, dynamics, or, primary, 'ciliogenesis,', but, that, their, association, may, be, related, to, a, specific, role, in, the, specialized, cilia, apparatus, of, retinal, photoreceptors])].
[sujeto(['Defects', in, aryl, hydrocarbon, receptor]), verbo([interacting]), complemento(['protein-like1', '(', 'AIPL1)', are, associated, with, blinding, diseases, with, a, wide, range, of, severity, in, humans])].
[sujeto(['We', examined, the, mechanism, behind, autosomal, dominant, 'cone-rod', dystrophy, '(', 'adCORD)']), verbo([caused]), complemento([by, 12, base, pair, '(', 'bp)', deletion, at, proline, 351, of, hAIPL1, '(', 'P351Δ12)', mutation, in, the, 'primate-specific', region, of, human, 'AIPL1'])].
[sujeto(['Mutant', 'P351Δ12', human, 'isoform,', aryl, hydrocarbon, receptor]), verbo([interacting]), complemento(['protein-like', 1, '(', 'hAIPL1)', mice, demonstrated, a, 'CORD', phenotype, with, early, defects, in, 'cone-mediated', vision, and, subsequent, photoreceptor, degeneration])].
[sujeto(['A', dominant, 'CORD', phenotype, was, observed, in, double, transgenic, animals]), verbo([expressing]), complemento([both, mutant, 'P351Δ12', and, normal, 'hAIPL1,', but, not, with, 'co-expression', of, 'P351Δ12', hAIPL1, and, the, mouse, 'isoform,', aryl, hydrocarbon, receptor, interacting, 'protein-like', 1, '(', 'mAipl1)'])].
[sujeto(['Mutations', in, the, photoreceptor, 'cell-specific', gene, encoding, aryl, hydrocarbon, 'receptor-interacting', 'protein-like', 1, '(', 'AIPL1)']), verbo([lead]), complemento([to, 'Leber', congenital, amaurosis, '(', 'LCA4),', retinitis, 'pigmentosa,', and, 'cone-rod', dystrophy])].
[sujeto(['Gene', therapy, appears, to, be, promising, in, the, treatment, for, 'AIPL1-mediated', vision]), verbo([loss]), complemento([in, humans])].
[sujeto(['Müller', cell, processes, become, hypertrophic, and, form, a, dense, fibrotic, layer, outside, the, inner]), verbo([nuclear]), complemento([layer])].
[sujeto(['An', early, defect, in, photoreceptor, cells, in, the, 'AIPL1-LCA', mouse, model, affects, the, expression, of, postsynaptic, 'markers,']), verbo([suggesting]), complemento([abnormal, development, of, bipolar, synapses])].
[sujeto(['Mutations', in, 'Aryl', hydrocarbon, receptor]), verbo([interacting]), complemento([protein, 'like-1', '(', 'AIPL1)', are, linked, to, 'Leber', congenital, amaurosis, '(', 'LCA),', a, severe, blinding, disease, that, occurs, in, early, childhood])].
[sujeto(['Aipl1', is]), verbo([expressed]), complemento([very, early, during, retinal, development, in, both, rods, and, cones])].
[sujeto(['In', adult, 'primates,', robust, expression, of, 'Aipl1', is]), verbo([found]), complemento([in, rods, but, not, in, cones])].
[sujeto(['Aberrant', regulation, of, transcripts]), verbo([has]), complemento([been, implicated, in, many, types, of, cancers, including, 'NPC'])].
[sujeto(['We']), verbo([found]), complemento([2812, genes, and, 149, miRNAs, '(', human, and, 'EBV)', to, be, differentially, expressed, in, 'NP460,', 'HK1,', 'C666', and, 'X666', with, 'RNASeq;', 533, 'miRNA-mRNA', target, pairs, were, inversely, regulated, in, the, three, 'NPC', cell, lines, compared, to, 'NP460'])].
[sujeto(['Detection', of, three, previously]), verbo([reported]), complemento([novel, 'EBV-encoded', 'BART', miRNAs, and, their, isomiRs, were, also, observed])].
[sujeto(['This', comprehensive, characterization, of, mRNA, and, miRNA, transcriptomes, in, 'NPC', cell, lines, and, the, xenograft]), verbo([provides]), complemento([insights, on, miRNA, regulation, of, mRNA, and, valuable, resources, on, transcript, variation, and, regulation, in, 'NPC,', which, are, potentially, useful, for, mechanistic, and, preclinical, studies])].
[sujeto(['To', localize, and, identify, the, gene, and, mutations]), verbo([causing]), complemento([autosomal, recessive, retinal, dystrophy, in, two, consanguineous, 'Pakistani', families])].
[sujeto(['Genome-wide', linkage, scans, yielded, a, lod, score, of, 3.05, at, 'θ=0', for, 'D17S1832', and, 3.82, at, 'θ=0', for, 'D17S938,', localizing, the, disease, gene, to, a, 12.22, cM, '(', 6.64, 'Mb)', region, flanked, by, 'D17S1828', and, 'D17S1852', for, family, 61032, and, family, 61227, ',', which, contains, aryl, hydrocarbon, receptor]), verbo([interacting]), complemento(['protein-like', 1, '(', 'AIPL1),', a, gene, previously, implicated, in, recessive, 'Leber', congenital, amaurosis, and, autosomal, dominant, 'cone-rod', dystrophy])].
[sujeto(['The', results, strongly]), verbo([suggest]), complemento([that, the, c])].
[sujeto(['(', 'H93_Q155del))', mutations, in, 'AIPL1']), verbo([cause]), complemento([autosomal, recessive, retinal, degeneration, in, these, consanguineous, 'Pakistani', families])].
[sujeto(['Acromegaly', is, predominantly]), verbo([caused]), complemento([by, a, pituitary, 'adenoma,', which, secretes, an, excess, of, 'GH', resulting, in, increased, 'IGF1', levels])].
[sujeto(['In', 'theory,', the, diagnostic, sensitivity, may, be, lower, compared, with, the, previous, 'assays,', which]), verbo([have]), complemento([used, polyclonal, antibodies])].
[sujeto(['Hyperprolactinaemia', is]), verbo([found]), complemento([in, 30, -, 40, '%', of, patients, with, 'acromegaly,', and, hyperprolactinaemia, may, occasionally, be, diagnosed, before, acromegaly, is, apparent])].
[sujeto(['Pasireotide,', a, new, somatostatin, 'analogue,', may, be, more, efficacious, in, some, 'patients,', but, the, drug]), verbo([has]), complemento([not, yet, been, registered, for, acromegaly])].
[sujeto(['Papers', published, on, pasireotide]), verbo([have]), complemento([reported, an, increased, risk, of, diabetes, mellitus, due, to, a, reduction, in, insulin, levels])].
[sujeto(['Dopamine-D2-agonists', may, be, effective, as, monotherapy, in, a, few, 'patients,', but, it, may, prove, necessary, to, apply, combination, therapy]), verbo([involving]), complemento([a, somatostatin, analogue, 'and/or', pegvisomant])].
[sujeto(['Defects', in, the, 'photoreceptor-specific', gene, encoding, aryl, hydrocarbon, receptor]), verbo([interacting]), complemento([protein, 'like-1', '(', 'AIPL1)', are, linked, to, blinding, 'diseases,', including, 'Leber', congenital, amaurosis, '(', 'LCA)', and, cone, dystrophy])].
[sujeto(['A', defect, in, 'RetGC1', is, supported, by, our]), verbo([finding]), complemento([that, cones, lacking, 'Aipl1', exhibited, reduced, levels, of, cGMP])].
[sujeto(['These', findings, are, in, contrast, to, the, role, of, 'Aipl1', in, 'rods,', where, destabilization, of, rod, 'PDE6', results, in, an]), verbo([increase]), complemento([in, cGMP, 'levels,', which, drives, rapid, rod, degeneration])].
[sujeto(['Our', results, illustrate, mechanistic, differences, behind, the, death, of, rods, and, cones, in, retinal, degenerative, disease]), verbo([caused]), complemento([by, deficiencies, in, 'AIPL1'])].
[sujeto(['Somatostatin', is, a, peptide, with, a, potent, and, broad, antisecretory, 'action,', which, makes, it, an, invaluable, drug]), verbo([target]), complemento([for, the, pharmacological, management, of, pituitary, adenomas, and, neuroendocrine, tumors])].
[sujeto(['Somatostatin', receptors, '(', 'SSTR1,', 2, 'A', and, 'B,', 3, ',', 4, and, 5, ')', belong, to, the, 'G', protein, coupled, receptor, family, and]), verbo([have]), complemento([a, wide, expression, pattern, in, both, normal, tissues, and, solid, tumors])].
[sujeto(['Investigating', the, function, of, each, 'SSTR', in, several, tumor, types]), verbo([has]), complemento([provided, a, wealth, of, information, about, the, common, but, also, distinct, signaling, cascades, that, suppress, tumor, cell, 'proliferation,', survival, and, angiogenesis])].
[sujeto(['This']), verbo([provided]), complemento([the, rationale, for, developing, 'multireceptor-targeted', somatostatin, analogs, and, combination, therapies, with, 'signaling-targeted', agents, such, as, inhibitors, of, the, mammalian, '(', or, 'mechanistic)', target, of, rapamycin, '(', 'mTOR)'])].
[sujeto(['The', ability, of, 'SSTR', to, internalize, and, the, development, of, rabiolabeled, somatostatin, analogs]), verbo([have]), complemento([improved, the, diagnosis, and, treatment, of, neuroendocrine, tumors])].
[sujeto(['AIPL1']), verbo([has]), complemento([been, shown, to, bind, the, farnesylated, 'PDE6A', subunit])].
[sujeto(['Mutations', in, 'AIPL1', are, thought, to, destabilize, 'PDE6', and, thereby]), verbo([cause]), complemento(['Leber', congenital, amaurosis, type, 4, '(', 'LCA4),', a, severe, form, of, childhood, blindness])].
[sujeto(['Guided', by, the, 'model,', we, tested, the, hypothesis, that, 'AIPL1', directly]), verbo([binds]), complemento([the, farnesyl, moiety])].
[sujeto(['Our', studies, revealed, high, affinity]), verbo([binding]), complemento([of, the, 'farnesylated-Cys', probe, to, the, 'FKBP-like', domain, of, 'AIPL1,', thus, uncovering, a, novel, function, of, this, domain])].
[sujeto(['The', 'L147A', mutation, and, the, 'LCA-linked', 'C89R', mutation]), verbo([prevented]), complemento([the, binding, of, the, 'farnesyl-Cys', probe, to, 'AIPL1'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, the, binding, of, 'PDE6A', farnesyl, is, essential, to, normal, function, of, 'AIPL1', and, its, disruption, is, one, of, the, mechanisms, underlying, 'LCA'])].
[sujeto(['Human', aryl, hydrocarbon, receptor, '(', 'AHR)']), verbo([interacting]), complemento([protein, '(', 'AIP)', and, 'AIP', like, 1, '(', 'AIPL1)', are, cochaperones, of, 'Hsp90', which, share, 49, '%', sequence, identity])].
[sujeto(['AIPL1,', 'however,', exhibits, chaperone, activity, and]), verbo([prevents]), complemento([the, aggregation, of, 'non-native', proteins])].
[sujeto(['The', unique, 'proline-rich', domain, of, 'AIPL1', is, important, for, its, chaperone, function, as, its, truncation, severely, affects, the, ability, of, 'AIPL1', to]), verbo([bind]), complemento(['non-native', proteins])].
[sujeto(['Furthermore,', the, 'proline-rich', domain]), verbo([decreased]), complemento([the, affinity, of, 'AIPL1', for, 'Hsp90,', implying, that, this, domain, acts, as, a, negative, regulator, of, the, 'Hsp90', interaction, besides, being, necessary, for, efficient, binding, of, 'AIPL1', to, 'non-native', proteins])].
[sujeto(['Pituitary', adenomas]), verbo([have]), complemento([a, serious, disease, 'burden,', and, their, management, involves, 'neurosurgery,', biological, 'therapies,', and, radiotherapy])].
[sujeto(['Early', diagnosis, of, pituitary, tumors, while, they, are, smaller, may, help]), verbo([increase]), complemento([cure, rates])].
[sujeto(['Recent', years]), verbo([have]), complemento([seen, two, 'separate,', complimentary, advances, in, inherited, pituitary, tumor, research])].
[sujeto(['The', clinical, condition, of, familial, isolated, pituitary, adenomas, '(', 'FIPA)']), verbo([has]), complemento([been, 'described,', which, encompasses, the, familial, occurrence, of, isolated, pituitary, adenomas, outside, of, the, setting, of, syndromic, conditions, like, multiple, endocrine, neoplasia, type, 1, and, 'Carney', complex])].
[sujeto(['The', aryl, hydrocarbon, receptor]), verbo([interacting]), complemento([protein, '(', 'AIP)', gene, has, been, identified, as, causing, a, pituitary, adenoma, predisposition, of, variable, penetrance, that, accounts, for, 20, '%', of, 'FIPA', families])].
[sujeto(['Germline', 'AIP', mutations]), verbo([have]), complemento([been, shown, to, associate, with, the, occurrence, of, large, pituitary, adenomas, that, occur, at, a, young, 'age,', predominantly, in, 'children/adolescents', and, young, adults])].
[sujeto(['AIP', mutations, are, usually]), verbo([associated]), complemento([with, 'somatotropinomas,', but, 'prolactinomas,', nonfunctioning, pituitary, 'adenomas,', 'Cushing', 'disease,', and, other, infrequent, clinical, adenoma, types, can, also, occur])].
[sujeto(['Study', of, pituitary, adenoma, patients, with, 'AIP', mutations]), verbo([has]), complemento([demonstrated, that, these, cases, raise, clinical, challenges, to, successful, treatment])].
[sujeto(['Leber', congenital, amaurosis, '(', 'LCA)', is, an, autosomal, recessive, disorder, that]), verbo([causes]), complemento([visual, impairment, in, children, due, to, fifteen, different, gene, mutations])].
[sujeto(['Of', 'these,', mutations, in, 'Aryl-Hydrocarbon', 'Receptor', 'Interacting', 'Protein-like', 1, '(', 'AIPL1)']), verbo([cause]), complemento([the, most, severe, form, of, 'LCA', '(', 'LCA4)', leading, to, the, degeneration, of, photoreceptor, cells])].
[sujeto(['NEDD8', 'Ultimate', 'Buster', 1, '(', 'NUB1),', a, protein, that]), verbo([regulates]), complemento([cell, cycle, 'progression,', interacts, with, 'AIPL1', to, prevent, the, over, expression, of, 'NUB1'])].
[sujeto(['In', the, case, of, over, 'expression,', cell, cycle, progression, is, disrupted, and, may]), verbo([lead]), complemento([to, 'LCA'])].
[sujeto(['Thus,', other, genes, like, 'CDKN', and, 'AIP']), verbo([have]), complemento([been, showed, to, be, involved, in, 'MEN1-like', patients])].
[sujeto(['A', total, of, 79, different, sporadic, and, familial, cases, with, the, 'MEN1', phenotype]), verbo([have]), complemento([been, 'studied,', in, which, 34, of, them, '(', 48, '%', ')', present, a, mutation, in, 'MEN1', gene])].
[sujeto(['In', two, patients, without, a, detectable, mutation, in, 'MEN1', 'gene,', we]), verbo([have]), complemento([identified, a, novel, missense, mutation, '(', c])].
[sujeto(['Our', data, support, that, 'MEN1', gene, is, the, main]), verbo([target]), complemento([for, genetic, analysis, in, clinical, 'MEN1', syndrome])].
[sujeto(['Control', was, defined, as, when, 'insulin-like', growth, 'factor-1', '(', 'IGF-1)', levels, were, within, the, normal, range, for, the, 'patient\'s', age, at, 6, months, after, 'therapy,']), verbo([associated]), complemento([with, decreasing, tumour, volume])].
[sujeto(['Accelerated', growth, rate, was]), verbo([reported]), complemento([as, the, first, clinical, sign, in, four, patients])].
[sujeto(['Multiple', types, of, therapy, were, necessary, in, all, patients, with, an, identified, genetic, mutation, '(', 4, 'types:', n, =, 1, ;, 3, 'types:', n, =, 2, ;, 2, 'types:', n, =, 1, ')', ',', whereas, two, of, the, three, patients, with, sporadic, somatotropinoma]), verbo([required]), complemento([only, one, type, of, therapy])].
[sujeto(['We']), verbo([found]), complemento(['that,', in, 'children,', genetic, somatotropinomas, are, more, invasive, than, sporadic, somatotropinomas])].
[sujeto(['Defects', in, the, 'photoreceptor-specific', gene, aryl, hydrocarbon, receptor]), verbo([interacting]), complemento(['protein-like', 1, '(', 'Aipl1)', are, associated, with, 'Leber', congenital, amaurosis, '(', 'LCA),', a, childhood, blinding, disease, with, 'early-onset', retinal, degeneration, and, vision, loss])].
[sujeto(['The', rapid, photoreceptor, degeneration, and, vision]), verbo([loss]), complemento([observed, in, the, 'LCA', patient, population, are, mimicked, in, a, mouse, model, lacking, 'AIPL1'])].
[sujeto(['Using', this, 'model,', we, evaluated, if, gene, replacement, therapy, using, recent, advancements, in, 'adeno-associated', viral, vectors, '(', 'AAV)']), verbo([provides]), complemento([advantages, in, preventing, rapid, retinal, degeneration])].
[sujeto(['Specifically,', we, demonstrated, that, the, novel, 'self-complementary', 'Y733F', capsid, mutant, 'AAV2/8', '(', 'sc-Y733F-AAV)']), verbo([provided]), complemento([greater, preservation, of, photoreceptors, and, functional, vision, in, 'Aipl1', null, mice, compared, with, 'single-stranded', 'AAV2/8'])].
[sujeto(['Our', results]), verbo([provide]), complemento([important, considerations, for, viral, vectors, to, be, used, in, future, gene, therapy, clinical, trials, targeting, a, wider, severity, spectrum, of, inherited, retinal, dystrophies])].
[sujeto(['The', majority, of, pituitary, adenomas]), verbo([have]), complemento([a, sporadic, origin, with, recognized, genetic, mutations, seldom, being, 'found;', somatotropinomas, are, an, 'exception,', presenting, frequent, somatic, 'GNAS', mutations])].
[sujeto(['Genetic', 'changes,', such, as, allelic]), verbo([loss]), complemento([or, gene, 'amplification,', and, epigenetic, 'changes,', usually, by, promoter, 'methylation,', have, been, implicated, in, abnormal, gene, 'expression,', but, alternative, mechanisms, may, be, present])].
[sujeto(['MEN1', mutations]), verbo([cause]), complemento([multiple, endocrine, neoplasia, type, 1, '(', 'MEN1),', while, the, 'Carney', complex, '(', 'CNC)', is, characterized, by, mutations, in, the, protein, kinase, 'A', regulatory, 'subunit-1alpha', '(', 'PRKAR1A)', gene, or, changes, in, a, locus, at, 2, p16])].
[sujeto(['Recently,', a, 'MEN1-like', 'condition,', 'MEN4,', was]), verbo([found]), complemento([to, be, related, to, mutations, in, the, 'CDKN1B', gene])].
[sujeto(['The', clinical, entity, of, familial, isolated, pituitary, adenomas, '(', 'FIPA)', is, characterized, by, genetic, defects, in, the, aryl, hydrocarbon, receptor]), verbo([interacting]), complemento([protein, '(', 'AIP)', gene, in, about, 15, '%', of, all, kindreds, and, 50, '%', of, homogenous, somatotropinoma, families])].
[sujeto(['Mutations', in, the, 'AIPL1', '(', aryl, hydrocarbon, receptor]), verbo([interacting]), complemento(['protein-like', 1, ')', cause, the, blinding, disease, 'Leber\'s', congenital, amaurosis])].
[sujeto(['AIP', functions, as, part, of, a, chaperone, heterocomplex, to, facilitate, signalling, by, the, 'AhR', and, plays, an, important, role, in]), verbo([regulating]), complemento([the, nuclear, translocation, of, the, receptor])].
[sujeto(['We', review, the, evidence, for, the, role, of, 'AIP', in, protein, translocation, and, compare, the, potential, functions, of, 'AIPL1', in, the, translocation, of, its]), verbo([interacting]), complemento([partner, the, 'NEDD8', ultimate, buster, protein, 1])].
[sujeto(['Similar', to, certain, unliganded, steroid, hormone, receptor, 'complexes,', the, unliganded, aryl, hydrocarbon, receptor]), verbo([has]), complemento([been, shown, to, consist, of, a, multimeric, core, complex, that, includes, the, 90, -, kDa, heat, shock, protein, '(', 'hsp90)', and, the, 'immunophilin-like', hepatitis, 'B', 'X-associated', protein, 2, '(', 'XAP2)'])].
[sujeto(['Immunophilins', and, 'XAP2']), verbo([associated]), complemento([with, these, complexes, bind, to, the, 'carboxyl-terminal', end, of, hsp90, through, an, interaction, with, their, tetratricopeptide, repeat, '(', 'TPR)', domains])].
[sujeto(['The', consensus, 'TPR']), verbo([binding]), complemento([motif, contains, two, 'domains,', 'A', and, 'B'])].
[sujeto(['Recently,', the, carboxyl, terminus, of, 'XAP2']), verbo([has]), complemento([been, shown, to, contain, a, highly, conserved, 'TPR', domain, that, is, required, for, the, assembly, of, 'XAP2', with, both, hsp90, and, 'AhR'])].
[sujeto(['We', hypothesized, that, this]), verbo([conserved]), complemento([domain, 'B', region, may, be, involved, with, mediating, interactions, between, either, 'AhR-hsp90,', 'AhR-XAP2,', 'and/or', 'AhR-AhR', nuclear, translocator, protein])].
[sujeto(['Site-directed', mutagenesis, of, the, 'amino-terminal', alanine, residue, of, this, region, to, an, aspartic, acid, '(', 'A78D)', completely]), verbo([inhibited]), complemento([2, ',', 3, ',', 7, ',', 8, -, 'tetrachloro-p-dioxin', '(', 'TCDD)', -, dependent, activation, of, a, xenobiotic, response, element, '(', 'XRE)', driven, gene, expression, construct, in, transfected, 'COS-1', and, 'BP8', cells])].
[sujeto(['The', 'A82F', mutation]), verbo([caused]), complemento([a, 40, to, 50, '%', decrease, in, 'TCDD-dependent', activation])].
[sujeto(['The', inability, of, 'A78D', and, the, reduction, of, 'A82F', to, 'trans-activate', 'XRE-driven', reporter, activity, did, not, result, from, impaired, 'AhR-XAP2-hsp90', 'interactions,', 'TCDD-dependent', 'AhR', translocation, to, the, 'nucleus,', or, 'AhR-AhR']), verbo([nuclear]), complemento([translocator, protein, interactions])].
[sujeto(['In', vitro, 'DNA']), verbo([binding]), complemento([analysis, demonstrated, that, loss, of, 'trans-activation', potential, by, the, 'A78D', mutation, resulted, from, impaired, 'XRE', binding])].
[sujeto(['Transiently']), verbo([expressed]), complemento(['AhR'])].
[sujeto(['The', effect, of, 'XAP2', on, 'AhR', localization, was, specific]), verbo([involving]), complemento([a, nuclear, localization, 'signal-mediated', pathway])].
[sujeto(['Examination', of, the, ratio, of, 'AhR', to, 'XAP2', in, the, 'AhR', complex, revealed, that, approximately, 25, '%', of, transiently]), verbo([expressed]), complemento(['AhR', was, associated, with, 'XAP2,', in, contrast, with, approximately, 100, '%', when, the, 'AhR', and, 'XAP2', were, 'co-expressed'])].
[sujeto(['Strikingly,', 'TCDD', did, not, influence, these, 'ratios,']), verbo([suggesting]), complemento([that, ligand, binding, initiates, nuclear, translocation, prior, to, complex, dissociation])].
[sujeto(['Analysis', of, endogenous, 'AhR', in, 'Hepa-1', cells, revealed, that, approximately, 40, '%', of, the, 'AhR', complex, was]), verbo([associated]), complemento([with, 'XAP2,', predicting, observed, 'AhR', localization, to, cytoplasm, and, nuclei])].
[sujeto(['This', study]), verbo([reveals]), complemento([a, novel, functional, role, for, the, 'immunophilin-like', component, of, a, soluble, receptor, complex, and, provides, new, insight, into, the, mechanism, of, 'AhR-mediated', signal, 'transduction,', demonstrating, the, existence, of, two, structurally, distinct, and, possibly, functionally, unique, forms, of, the, 'AhR'])].
[sujeto(['The', aryl, hydrocarbon, receptor, '(', 'AhR)']), verbo([has]), complemento([been, shown, to, interact, with, an, 'immunophilin-like', molecule, known, as, 'AhR-interacting', protein, '(', 'AIP)', and, to, enhance, 'AhR', function])].
[sujeto(['We', show, here, that, 'AIP']), verbo([associates]), complemento([with, 'AhR', homologues, from, mouse, and, 'fish,', which, can, bind, ligands, such, as, 'dioxin,', but, nonligand, binding, homologues, from, 'Caenorhabditis', elegans, or, 'Drosophila', do, not, bind, to, 'AIP'])].
[sujeto(['However,', a, minimal, 'ligand-binding', domain, of, the, 'AhR', is, incapable, of]), verbo([binding]), complemento(['AIP'])].
[sujeto(['The']), verbo([binding]), complemento([of, 'AIP', to, 'AhR', in, reticulocyte, lysate, shows, several, of, the, characteristics, of, an, 'hsp90-dependent', 'process,', including, sensitivity, to, geldanamycin, and, temperature, and, a, requirement, for, 'ATP', or, nonhydrolyzable, analogues])].
[sujeto(['Purified', 'AIP']), verbo([binds]), complemento([to, the, 'C', terminus, of, 'hsp90,', and, mutation, of, a, conserved, basic, residue, in, the, tetratricopeptide, repeats, of, 'AIP', '(', 'K266A,', analogous, to, 'K97A', in, protein, phosphatase, 5, ')', abolishes, binding, to, hsp90])].
[sujeto(['Mutation', of, 'K266A', in, 'AIP', reduces]), verbo([binding]), complemento([to, 'AhR', by, 75, -, 80, '%', ;, the, geldanamycin, sensitivity, of, this, complex, shows, that, 'AhR', stabilizes, the, 'AIP-hsp90-AhR', complex])].
[sujeto(['The', 'alpha-helical', 'C', terminus, of, 'AIP,', which, is, outside, the, tetratricopeptide, repeat, 'domain,', is, absolutely]), verbo([required]), complemento([for, binding, to, 'AhR', as, shown, by, deletions, of, the, 'C-terminal', 5, amino, acids, or, 'alanine-scanning', 'mutagenesis,', but, it, is, not, required, for, binding, of, 'AIP', to, hsp90])].
[sujeto(['The', data, support, a, model, where, 1, ')', 'AIP']), verbo([binds]), complemento([to, both, hsp90, and, 'AhR;', 2, ')', hsp90, is, required, for, 'AhR-AIP', 'binding;', and, 3, ')', the, binding, of, 'AhR', to, 'AIP', stabilizes, the, 'AIP-hsp90-AhR', complex])].
[sujeto(['A', stop]), verbo([gain]), complemento([was, identified, at, position, c])].
[sujeto([5, 'A', &, 'gt;', 'G', variant]), verbo([causing]), complemento([a, p])].
[sujeto(['The', cat, 'AIPL1', variant, would]), verbo([have]), complemento([been, considered, a, high, priority, variant, for, 'evaluation,', regardless, of, a, priori, knowledge, from, previous, genetic, studies])].
[sujeto(['However,', as, the, feline, variant, database, 'improves,', development, of, cats, as, biomedical, models, for, human, disease, will, be, more, 'efficient,']), verbo([providing]), complemento([an, 'alternative,', large, animal, model, for, drug, and, gene, therapy, trials])].
[sujeto(['To', determine, the, human, retinal, phenotype]), verbo([caused]), complemento([by, mutations, in, the, gene, encoding, 'AIPL1', '(', 'Aryl', hydrocarbon, 'receptor-interacting', 'protein-like', 1, ')', now, that, there, are, 'proof-of-concept', results, for, gene, therapy, success, in, 'Aipl1-deficient', mice])].
[sujeto(['The', 'LCA', patients, had, severe, visual, acuity]), verbo([loss]), complemento([early, in, 'life,', nondetectable, electroretinograms, '(', 'ERGs),', and, little, or, no, detectable, visual, fields])].
[sujeto(['Cross-sectional', imaging, showed, foveal, cone, photoreceptor]), verbo([loss]), complemento([with, a, ring, of, minimally, preserved, paracentral, photoreceptor, nuclear, layer])].
[sujeto(['Full-field', sensitivity, was, reduced, by, at, least, 2, log, 'units,', and, chromatic, 'stimuli,', by, psychophysics, and, 'pupillometry,', revealed]), verbo([retained]), complemento([but, impaired, rod, function])].
[sujeto(['The', 'RD', 'patient,', examined, serially, over, two, decades, '(', 'ages,', 45, -, 67, 'years),']), verbo([retained]), complemento([an, 'ERG', in, the, fifth, decade, of, life, with, abnormal, rod, and, cone, 'signals;', and, there, was, progressive, loss, of, central, and, peripheral, function])].
[sujeto(['AIPL1-LCA,', unlike, some, other, forms, of, 'LCA', with, equally, severe, visual, 'disturbance,', shows, profound]), verbo([loss]), complemento([of, foveal, as, well, as, extrafoveal, photoreceptors])].
[sujeto(['Leber', congenital, amaurosis, '(', 'LCA)']), verbo([caused]), complemento([by, mutations, in, 'Aryl', hydrocarbon, receptor, interacting, protein, 'like-1', '(', 'Aipl1)', is, a, severe, form, of, childhood, blindness])].
[sujeto(['Cone', degeneration, observed, in, the, absence, of, 'AIPL1', could, be, due, to, an, indirect, '\'', bystander, 'effect\'']), verbo([caused]), complemento([by, rod, photoreceptor, death, or, a, direct, role, for, 'AIPL1', in, cones])].
[sujeto(['To', understand, the, importance, of, 'AIPL1', in, cone, photoreceptor, 'cells,', we, transgenically]), verbo([expressed]), complemento([hAIPL1, exclusively, in, the, rod, photoreceptors, of, the, 'Aipl1(-/-)', mouse])].
[sujeto(['However,', rod, photoreceptors, also]), verbo([provide]), complemento([support, that, partially, preserves, cone, photoreceptors, from, rapid, death, in, the, absence, of, 'AIPL1'])].
[sujeto(['To', test, patients, from, southern, 'India', for, the, presence, of, mutations, that, most, commonly]), verbo([cause]), complemento(['Leber', congenital, amaurosis, '(', 'LCA)', in, northern, 'America'])].
[sujeto(['A', review, of, the, literature, identified, 177, unique, 'LCA']), verbo([causing]), complemento([mutations, in, eight, different, 'genes:', aryl, hydrocarbon, receptor, interacting, 'protein-like', 1, '(', 'AIPL1),', crumbs, homolog, 1, '(', 'CRB1),', 'cone-rod', homeobox, '(', 'CRX),', guanylate, cyclase, 2, 'D', '(', 'GUCY2D),', nephronophthisis, 6, '(', 'NPHP6),', retinol, dehydrogenase, 12, '(', 'RDH12),', retinal, pigment, 'epithelium-specific', protein, 65, kDa, '(', 'RPE65),', and, retinitis, pigmentosa, 'GTPase', regulator, interacting, protein, 1, '(', 'RPGRIP1)'])].
[sujeto(['Only', one, participant, was]), verbo([found]), complemento([to, harbor, one, of, the, 104, mutations, in, the, 'allele-specific', assay, '(', homozygous, 'RPE65', 'Tyr368His)'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'LCA', in, 'India', is, caused, primarily, by, a, different, set, of, mutations, in, the, same, genes, associated, with, disease, in, northern, 'America,', or, by, mutations, in, other, genes, that, have, not, yet, been, discovered])].
[sujeto(['Aryl', hydrocarbon, 'receptor-interacting', 'protein-like', 1, '(', 'AIPL1)', is]), verbo([required]), complemento([for, the, biosynthesis, of, photoreceptor, phosphodiesterase, '(', 'PDE)'])].
[sujeto(['Gene', defects, in, 'AIPL1']), verbo([cause]), complemento([a, heterogeneous, set, of, conditions, ranging, from, 'Leber\'s', congenital, amaurosis, '(', 'LCA),', the, severest, form, of, 'early-onset', retinal, 'degeneration,', to, milder, forms, such, as, retinitis, pigmentosa, '(', 'RP)', and, 'cone-rod', dystrophy])].
[sujeto(['In', 'mice,', null, and, hypomorphic, alleles]), verbo([cause]), complemento([retinal, degeneration, similar, to, human, 'LCA', and, 'RP,', respectively])].
[sujeto(['Thus', these, mouse, models, represent, two, ends, of, the, disease, spectrum]), verbo([associated]), complemento([with, 'AIPL1', gene, defects, in, humans])].
[sujeto(['We']), verbo([found]), complemento([substantial, and, 'long-term', rescue, of, the, disease, phenotype, as, a, result, of, transgene, expression])].
[sujeto(['This', is, the, first, gene, therapy, study, in, which, both, rods, and, cones, were]), verbo([targeted]), complemento([successfully, with, a, single, 'photoreceptor-specific', promoter])].
[sujeto(['We', evaluate, whether, 'AAV-mediated', gene, replacement, therapy, is, able, to, improve, photoreceptor, function, and, survival, in, retinal, degeneration]), verbo([associated]), complemento([with, 'AIPL1', defects])].
[sujeto(['The', 'Aipl1', hypomorphic, '(', 'h/h)', mouse]), verbo([has]), complemento([reduced, 'Aipl1', levels, and, a, relatively, slow, degeneration])].
[sujeto(['Under', light, 'acceleration,', the, rate, of, degeneration, in, the, 'Aipl1', 'h/h', mouse, is]), verbo([increased]), complemento([by, 2, -, 3, -, fold])].
[sujeto(['The', 'Aipl1-/-', mouse]), verbo([has]), complemento([no, functional, 'Aipl1', and, has, a, very, rapid, retinal, degeneration])].
[sujeto(['We']), verbo([have]), complemento([thus, established, the, potential, of, gene, replacement, therapy, in, varying, rates, of, degeneration, that, reflect, the, clinical, spectrum, of, disease])].
[sujeto(['This', is, the, first, gene, replacement, study, to]), verbo([report]), complemento(['long-term', rescue, of, a, 'photoreceptor-specific', defect, and, to, demonstrate, effective, rescue, of, a, rapid, photoreceptor, degeneration])].
[sujeto(['Photoresponses', of, mouse, rods]), verbo([expressing]), complemento([lowered, amounts, of, 'AIPL1', were, studied, by, 'single-cell', and, electroretinogram, '(', 'ERG)', recordings])].
[sujeto(['Comparisons', were, made, to, rods]), verbo([expressing]), complemento([mutant, 'Y99C', guanylate, cyclase, activating, protein, '(', 'GCAP)-1,', to, understand, which, effects, arose, from, elevated, dark, levels, of, cGMP, and, 'Ca2+'])].
[sujeto(['Reduced', 'AIPL1', delayed, the, 'photoresponse,']), verbo([decreased]), complemento([its, amplification, 'constant,', slowed, a, 'rate-limiting', step, in, its, 'recovery,', and, limited, the, 'light-induced', decrease, in, 'Ca2+'])].
[sujeto(['Not', all, changes, were, attributable, to]), verbo([decreased]), complemento(['PDE', or, to, elevated, cGMP, and, 'Ca2+', in, darkness])].
[sujeto(['We']), verbo([find]), complemento([two, phases, associated, with, rod, differentiation])].
[sujeto(['By', 'Fwk', 11, -, 12, ',', these, rods, label, for, interphotoreceptor, retinoid]), verbo([binding]), complemento(['protein,', 'recoverin,', and, aryl, hydrocarbon, receptor, interacting, 'protein-like', 1])].
[sujeto(['TULP', is]), verbo([expressed]), complemento([relatively, late, at, 'Fwk', 18, -, 20, in, rods])].
[sujeto(['The', progression, of, rod, development, shown, here]), verbo([provides]), complemento([insight, into, the, possible, mechanisms, underlying, human, retinal, visual, dysfunction, when, there, are, mutations, affecting, key, 'rod-related', molecules])].
[sujeto(['Results', demonstrated, that, 'BaP', and, 'CHR', concentration, '(', 'BaP&lt;CHR)', in, tissues]), verbo([increased]), complemento([rapidly, in, a, time, and, dose, effect])].
[sujeto(['The', mRNA, expression, of, aryl, hydrocarbon, receptor, '(', 'AhR),', cytochrome, 'P450', 1, 'A1', '(', 'CYP1A1),', 'CYP1B1,', multidrug, resistance, protein, 1, '(', 'MRP1/ABCC1),', breast, cancer, resistance, protein, '(', 'BCRP/ABCG2)', and, 'P-glycoprotein', '(', 'P-gp)', were]), verbo([induced]), complemento([especially, in, the, mixtures, of, 'BaP', and, 'CHR'])].
[sujeto(['Heat', shock, protein, 90, '(', 'HSP90)', and, aryl, hydrocarbon, receptor]), verbo([nuclear]), complemento([translocator, '(', 'ARNT)', mRNA, expression, was, significantly, elevated, at, days, 1, ',', 10, and, 15])].
[sujeto(['Detoxification', enzymes, of, 7, -, ethoxyresorufin, 'O-deethylase', '(', 'EROD),', 'uridine-diphosphate-glucuronyl-transferase', '(', 'UGT)', and, sulfotransferase, '(', 'SULT)', were, significantly]), verbo([induced]), complemento([and, then, became, stable, gradually, while, 'glutathione-S-transferase', '(', 'GST)', was, inhibited, in, the, mixtures, of, 'BaP', and, 'CHR', at, days, 10, and, 15])].
[sujeto(['Superoxide', dismutase, '(', 'SOD),', glutathione, peroxidase, '(', 'GPx),', catalase, '(', 'CAT)', and, glutathione, '(', 'GSH)', were, all]), verbo([stimulated]), complemento([especially, in, the, mixtures, of, 'BaP', and, 'CHR'])].
[sujeto(['All', the, results, indicated, that, 'BaP', and, 'CHR']), verbo([have]), complemento([similar, induced, effect, and, a, majority, of, the, biomarkers, pointed, to, a, more, toxic, effect, when, 'BaP', and, 'CHR', were, mixed])].
[sujeto(['These', will]), verbo([provide]), complemento([a, solid, foundation, for, the, study, of, 'PAHs', detoxification, mechanism, in, bivalves, and, valuable, information, for, marine, pollution, monitoring])].
[sujeto(['The', aryl, hydrocarbon, receptor, '(', 'AHR)', shuttles, continuously, between, cytoplasm, and, 'nucleus,', unless, 'ligand-binding']), verbo([triggers]), complemento([association, with, the, 'AHR', nuclear, translocator, '(', 'ARNT)', and, subsequent, binding, to, cognate, 'DNA', motifs])].
[sujeto(['We']), verbo([have]), complemento([now, identified, 'Val', 647, as, mandatory, residue, for, export, from, the, nucleus, and, 'AHR-function'])].
[sujeto(['This', residue]), verbo([prevents]), complemento([inactivation, of, the, receptor, as, a, consequence, of, nuclear, sequestration, via, constitutive, import])].
[sujeto(['Although', ligands, accelerate]), verbo([nuclear]), complemento([import, 'transiently,', stable, nuclear, transition, depends, on, a, motif, adjacent, to, 'Val', 647, that, comprises, residues, 650, -, 661])].
[sujeto(['Together,', this, defined, region, within, the, 'Q-rich', domain]), verbo([regulates]), complemento([intracellular, trafficking, of, the, 'AHR', in, context, of, both, nucleocytoplasmic, shuttling, and, receptor, activation])].
[sujeto(['Nucleocytoplasmic', distribution, of, 'full-length', human, 'AHR', is, further, affected, by, a, section, of, the, 'PST', domain, that, shows, sequence, similarities, with]), verbo([nuclear]), complemento([export, signals])].
[sujeto(['In', 'concert,', these, motifs]), verbo([maintain]), complemento([a, predominant, cytoplasmic, 'compartmentalisation,', receptive, for, ligand, binding])].
[sujeto(['Those', able, to]), verbo([bind]), complemento([the, aryl, hydrocarbon, receptor, '(', 'AhR),', eliciting, a, plethora, of, toxic, 'responses,', are, defined, 'dioxin-like', '(', 'DL)', 'compounds,', while, the, remainders, are, called, 'non-DL', '(', 'NDL)'])].
[sujeto(['An', 'EFSA', opinion]), verbo([has]), complemento([highlighted, the, tendency, of, ovine, liver, to, specifically, accumulate, 'DL-compounds', to, a, greater, extent, than, any, other, farmed, ruminant, species])].
[sujeto(['To', examine, the, possible, role, in, such, an, accumulation, of, xenobiotic, metabolizing, enzymes, '(', 'XME)']), verbo([involved]), complemento([in, 'DL-compound', 'biotransformation,', liver, samples, were, collected, from, ewes, and, cows, reared, in, an, area, known, for, low, dioxin, contamination])].
[sujeto(['A', related, paper]), verbo([reported]), complemento([that, sheep, livers, had, about, 5, -, fold, higher, 'DL-compound', concentrations, than, cattle, 'livers,', while, the, content, of, the, six, marker, 'NDL-PCBs', did, not, differ, between, species])].
[sujeto(['Specimens', from, the, same, animals, were, subjected, to, gene, expression, analysis, for, 'AhR,', 'AhR']), verbo([nuclear]), complemento([translocator, '(', 'ARNT)', and, 'AhR-dependent', oxidative, and, conjugative, 'pathways;', 'XME', protein, expression, and, activities, were, also, investigated])].
[sujeto(['Both', 'AhR', and, 'ARNT', mRNA, levels, were, about, 2, -, fold, lower, in, ovine, samples, and, the, same, occurred, for, 'CYP1A1', and, 'CYP1A2,', being, approximately, 3, -, and, 9, -, fold, less]), verbo([expressed]), complemento([in, sheep, compared, to, 'cattle,', while, 'CYP1B1', could, be, detectable, in, cattle, only])].
[sujeto(['Oxygen-deprived', '(', 'hypoxic)', areas, are, commonly]), verbo([found]), complemento([within, neoplasms, caused, by, excessive, cell, proliferation])].
[sujeto(['The', transcription, factor, 'Aryl', hydrocarbon, receptor]), verbo([nuclear]), complemento([translocator, '(', 'ARNT)', is, part, of, the, 'hypoxia-inducible', factor, '(', 'HIF)', 'pathway,', which, mediates, adaptive, responses, to, ensure, cellular, survival, under, hypoxic, conditions])].
[sujeto(['HIF', signalling]), verbo([leads]), complemento([to, metabolic, 'alterations,', 'invasion/metastasis', and, the, induction, of, angiogenesis, in, addition, to, 'radio-chemoresistance', of, tumour, cells])].
[sujeto(['Activation', of, the, 'HIF', pathway, is, based, on, the, abundance, of, 'HIF-α', 'subunits,', which, are]), verbo([regulated]), complemento([in, an, 'oxygen-dependent', manner, and, form, transcriptional, active, complexes, with, 'ARNT', or, 'ARNT2', '(', also, referred, as, 'HIF-1β', and, 'HIF-2β,', 'respectively)'])].
[sujeto(['The', results, revealed, a, 'HIF-1α-dependent', mechanism]), verbo([leading]), complemento([to, 'ARNT', upregulation, in, hypoxia])].
[sujeto(['Forced', expression, of, 'ARNT']), verbo([increased]), complemento([reporter, activity, under, normoxic, and, hypoxic, conditions])].
[sujeto(['In', 'conclusion,', these, findings, indicate, a, novel, 'feed-forward', loop, and]), verbo([suggest]), complemento([that, 'ARNT', might, be, a, limiting, factor])].
[sujeto(['Augmented', 'HIF', signalling, in, terms, of, elevated]), verbo([target]), complemento([gene, expression, might, be, advantageous, for, tumour, cells])].
[sujeto(['Cellular', oxygen, sensors, measure, changes, in, tissue, oxygenation, and]), verbo([induce]), complemento([responses, aimed, at, restoring, sufficient, supply, with, oxygen])].
[sujeto(['Genetic', adaptation, to, hypoxia, is, under, control, of, 'hypoxia-inducible', factors, '(', 'HIFs),', of, which, two, highly, homologous, subunits, 'HIF-1α', and, 'HIF-2α', are]), verbo([regulated]), complemento([by, oxygen, tension])].
[sujeto(['Together', with, 'HIF-1β', '(', =, 'ARNT;', aryl, hydrocarbon, receptor]), verbo([nuclear]), complemento(['translocator)', they, form, transcriptionally, active, complexes, under, hypoxia, which, drive, the, expression, of, hypoxia, inducible, genes])].
[sujeto([',', 'HIF-1α/ARNT', versus, 'HIF-2α/ARNT', with, respect, to]), verbo([target]), complemento([gene, or, tissue, specificity, has, not, been, fully, resolved])].
[sujeto(['We']), verbo([found]), complemento([differences, both, in, nuclear, mobility, and, the, assembly, of, 'HIF-1', versus, 'HIF-2', which, might, help, to, better, understand, the, assembly, of, 'HIF', complexes])].
[sujeto(['The', 'Aryl', hydrocarbon, 'Receptor', '(', 'AhR)', is, a, transcription, factor, that]), verbo([mediates]), complemento([the, biochemical, response, to, xenobiotics, and, the, toxic, effects, of, a, number, of, environmental, 'contaminants,', including, dioxins])].
[sujeto(['Recently,', endogenous, regulatory, roles, for, the, 'AhR', in, normal, physiology, and, development]), verbo([have]), complemento([also, been, 'reported,', thus, extending, the, interest, in, understanding, its, molecular, mechanisms, of, activation])].
[sujeto(['Since', dimerization, with, the, 'AhR', 'Nuclear', 'Translocator', '(', 'ARNT)', 'protein,', occurring, through, the, 'Helix-Loop-Helix', '(', 'HLH)', and, 'PER-ARNT-SIM', '(', 'PAS)', 'domains,', is, needed, to, convert, the, 'AhR', into, its, transcriptionally, active, 'form,', deciphering, the, 'AhR:ARNT', dimerization, mode, would]), verbo([provide]), complemento([insights, into, the, mechanisms, of, 'AhR', transformation])].
[sujeto(['Both', 'well-established', hot, spot, prediction, methods, and, new, approaches, to, analyze, individual, residue, and, 'residue-pairwise', contributions, to, the, 'MM-GBSA']), verbo([binding]), complemento([free, energies, were, adopted, to, predict, residues, critical, for, dimer, stabilization])].
[sujeto(['On', this, 'basis,', a, mutagenesis, strategy, for, both, the, murine, 'AhR', and, 'ARNT', proteins, was, designed, and, 'ligand-dependent', 'DNA']), verbo([binding]), complemento([ability, of, the, 'AhR:ARNT', heterodimer, mutants, was, evaluated])].
[sujeto(['While', functional, analysis, disfavored, the, 'HIF2α:ARNT', 'heterodimer-based', 'PAS-B', 'model,', most, mutants, derived, from, the, 'CLOCK:BMAL1-based', 'AhR:ARNT', dimer, models, of, both, the, 'PAS-A', and, the, 'PAS-B', dramatically]), verbo([decreased]), complemento([the, levels, of, 'DNA', 'binding,', suggesting, this, latter, model, as, the, most, suitable, for, describing, 'AhR:ARNT', dimerization])].
[sujeto(['The', aryl, hydrocarbon, receptor, '(', 'AhR)', is, a, 'ligand-dependent', transcription, factor, that, can, be]), verbo([activated]), complemento([by, structurally, diverse, synthetic, and, natural, 'chemicals,', including, toxic, environmental, contaminant, 2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD)'])].
[sujeto(['In', the, present, 'study,', homology, models, of, the, porcine, 'AhR-ligand']), verbo([binding]), complemento([domain, '(', 'LBD)', and, the, porcine, aryl, hydrocarbon, receptor, nuclear, 'translocator-ligand', binding, domain, '(', 'ARNT-LBD)', were, created, on, the, basis, of, structures, of, closely, related, respective, proteins, i])].
[sujeto(['Molecular', docking, of, 'TCDD', to, the, porcine, 'AhR-LBD', model, revealed, high]), verbo([binding]), complemento([affinity, '(', -, 8.8, 'kcal/mol)', between, 'TCDD', and, the, receptor])].
[sujeto(['It', was]), verbo([found]), complemento([that, 'TCDD', '(', 10, 'nM,', 2, h, of, 'incubation)', not, only, bound, to, the, 'AhR', in, the, porcine, granulosa, cells, but, also, activated, the, receptor])].
[sujeto(['The', current, study]), verbo([provides]), complemento([a, framework, for, examining, the, key, events, involved, in, the, 'ligand-dependent', activation, of, the, 'AhR'])].
[sujeto(['Aryl', hydrocarbon, receptor, '(', 'AHR),', a, 'ligand-activated', transcription, 'factor,']), verbo([binds]), complemento([to, a, variety, of, chemical, compounds, including, various, environmental, contaminants, such, as, 2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin'])].
[sujeto(['This', receptor]), verbo([regulates]), complemento([expression, of, target, genes, through, dimerization, with, the, 'AHR', nuclear, translocator, '(', 'ARNT)'])].
[sujeto(['In', vitro, reporter, gene, assays, showed, that, all, complexes, of, alligator, 'AHR-ARNT', were, able, to]), verbo([activate]), complemento(['ligand-dependent', transcription, on, a, xenobiotic, response, element])].
[sujeto(['We']), verbo([found]), complemento([that, 'AHR-ARNT', complexes, had, higher, sensitivities, to, a, ligand, than, 'AHR-ARNT2', complexes])].
[sujeto(['Alligator', 'AHR1B', showed, the, highest, sensitivity, in, transcriptional, activation]), verbo([induced]), complemento([by, indigo, when, compared, with, 'AHR1A', and, 'AHR2'])].
[sujeto(['We', previously]), verbo([reported]), complemento([lifetime, exposure, to, cigarette, smoke, is, associated, with, 'adult-onset', 'AD'])].
[sujeto(['Aryl', hydrocarbon, receptor, '(', 'AhR)', is, important, in]), verbo([regulating]), complemento([environmental, exposure, to, 'xenobiotics,', including, benzopyrenes, '(', 'BP),', a, major, polycyclic, aromatic, hydrocarbon, '(', 'PAH)', present, in, cigarette, smoke])].
[sujeto(['However,', how, 'AhR']), verbo([regulates]), complemento([immune, responses, in, sensitization, phase, of, 'AD', remained, elusive])].
[sujeto(['We']), verbo([found]), complemento(['AhR', and, 'ARNT', '(', 'AhR', nuclear, 'translocator)', are, upregulated, in, 'AD', skin])].
[sujeto(['BP', exposure]), verbo([increases]), complemento(['Langerhans', cell, 'migration,', and, increases, 'IL-5,', 'IL-13,', and, 'IL-17', levels, when, lymph, node, cells, were, 're-challenged', with, 'Ova'])].
[sujeto(['The']), verbo([increased]), complemento([cytokine, levels, were, attenuated, in, 'AhR', defected, mice])].
[sujeto(['AhR', agonists, '(', 'BP', and, 'ITE)']), verbo([decreased]), complemento(['E-cadherin', 'expression,', while, 'AhR', antagonist, '(', 'CH223191)', increased, it, in, human, primary, keratinocytes])].
[sujeto(['These', results]), verbo([suggested]), complemento(['AhR', interacts, with, 'BP', to, polarize, 'T', cell, 'responses,', along, with, 'Langerhans', cell, migration])].
[sujeto(['Soy', consumption]), verbo([has]), complemento([been, associated, with, risk, reduction, for, chronic, diseases, such, as, cancer])].
[sujeto(['One', proposed, mechanism, for, cancer, prevention, by]), verbo([soy]), complemento([is, through, decreasing, cytochrome, 'P450', 1, 'A1', '(', 'Cyp1a1)', activity])].
[sujeto(['However,', it, is, not, known, with, certainty, which]), verbo([soy]), complemento([components, modulate, 'Cyp1a1,', or, the, characteristics, or, mechanisms, involved, in, the, responses, after, 'short-term', '(', &, 'lt;20', 'days)', dietary, treatment, without, concomitant, 'carcinogen-mediated', induction])].
[sujeto(['Therefore,', the, objective, was, to, test, the, hypothesis, that, physiologic, concentrations, of, dietary, genistein, 'and/or', daidzein, will]), verbo([decrease]), complemento([basal, hepatic, 'Cyp1a1', protein, expression, and, activity, in, male, and, female, 'Swiss', 'Webster', mice, via, inhibiting, the, bindings, of, aryl, hydrocarbon, receptor, '(', 'AhR)-AhR', nuclear, translocator, '(', 'ARNT)', and, estrogen, 'receptor-α', to, the, 'Cyp1a1', promoter, region, xenobiotic, response, element])].
[sujeto(['Genistein,', but, not, 'daidzein,', significantly]), verbo([decreased]), complemento([basal, hepatic, microsomal, 'Cyp1a1', protein, expression, and, activity])].
[sujeto(['This', study, demonstrated, that, genistein, consumption, reduced, constitutive, hepatic, 'Cyp1a1', protein, expression, and, 'activity,', thereby, contributing, to, the, understanding, of, how]), verbo([soy]), complemento([isoflavone, aglycones, modulate, cytochrome, 'P450', biotransformation, enzymes])].
[sujeto(['Aryl', hydrocarbon, receptor]), verbo([nuclear]), complemento([translocator, '(', 'ARNT)', 2, is, a, transcriptional, factor, related, to, adaptive, responses, against, cellular, stress, from, a, xenobiotic, substance])].
[sujeto(['Recent', evidence, indicates, 'ARNT', is]), verbo([involved]), complemento([in, carcinogenesis, and, cancer, 'progression;', 'however,', little, is, known, about, the, relevance, of, 'ARNT2', in, the, behavior, of, oral, squamous, cell, carcinoma, '(', 'OSCC)'])].
[sujeto(['In', addition, to, the, data, from, exogenous, experiments, that, 'ARNT2-overexpressed', cells, showed]), verbo([decreased]), complemento([cellular, 'proliferation,', 'ARNT2-positive', 'OSCC', cases, were, correlated, significantly, '(', 'P', &, 'lt;', 0.05, ')', with, tumoral, size])].
[sujeto(['Since', von, 'Hippel-Lindau', tumor, 'suppressor,', 'E3', ubiquitin, protein, 'ligase,', a, negative, regulator, of, 'hypoxia-inducible', factor, '(', 'HIF1)-α,', is, a, downstream, molecule, of, 'ARNT2,', we, speculated, that, 'HIF1-α', and, its, downstream, molecules, would]), verbo([have]), complemento([key, functions, in, cellular, growth])].
[sujeto(['Consistent', with, our, 'hypothesis,', overexpressed, 'ARNT2', cells, showed, 'down-regulation', of, 'HIF1-α,', which]), verbo([causes]), complemento([hypofunctioning, of, glucose, transporter, 1, ',', leading, to, decreased, cellular, growth])].
[sujeto(['Therefore,', 'ARNT2', may, be, a, potential, therapeutic]), verbo([target]), complemento([against, progression, of, 'OSCCs'])].
[sujeto(['The', 'HIF1', 'complex,', 'HIF1α', and, dimerization, partner, the, aryl, hydrocarbon, receptor]), verbo([nuclear]), complemento([translocator, '(', 'ARNT),', is, the, master, regulator, of, the, hypoxic, response])].
[sujeto(['Previously,', we, demonstrated, that, 'Rb']), verbo([represses]), complemento([the, transcriptional, response, to, hypoxia, by, virtue, of, its, association, with, 'HIF1'])].
[sujeto(['In', this, 'report,', we, further, characterized, the, role, 'Rb', plays, in]), verbo([mediating]), complemento(['hypoxia-regulated', genetic, programs, by, stably, ablating, 'Rb', expression, with, 'retrovirally-introduced', short, hairpin, 'RNA', in, 'LNCaP', and, 22, 'Rv1', human, prostate, cancer, cells])].
[sujeto(['DNA', microarray, analysis, revealed, that]), verbo([loss]), complemento([of, 'Rb', in, conjunction, with, hypoxia, leads, to, aberrant, expression, of, 'hypoxia-regulated', genetic, programs, that, increase, cell, invasion, and, promote, neuroendocrine, differentiation])].
[sujeto(['For', the, first, 'time,', we]), verbo([have]), complemento([established, a, direct, link, between, hypoxic, tumor, 'environments,', 'Rb', inactivation, and, progression, to, late, stage, metastatic, neuroendocrine, prostate, cancer])].
[sujeto(['The', aryl, hydrocarbon, receptor, '(', 'AHR)', is, a, 'ligand-activated', transcription, factor, that, is]), verbo([regulated]), complemento([by, environmental, toxicants, that, function, as, 'AHR', agonists, such, as, 2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD)'])].
[sujeto(['Overlapping', the, 'TCDD-RNA-Seq', dataset, obtained, in, this, study, with, a, published, 'TCDD-ChIP-seq', dataset, identified, 'LAT1', as, a, primary]), verbo([target]), complemento([of, 'AHR-dependent', 'TCDD', induction])].
[sujeto(['Short', interfering, 'RNA', '(', 'siRNA)-directed', knockdown, of, 'AHR', confirmed, that, 'TCDD-stimulated']), verbo([increases]), complemento([in, 'LAT1', mRNA, and, protein, required, 'AHR', expression])].
[sujeto(['TCDD-stimulated']), verbo([increases]), complemento([in, 'LAT1', mRNA, were, also, inhibited, by, the, 'AHR', antagonist, 'CH-223191'])].
[sujeto(['Upregulation', of, 'LAT1', by, 'TCDD', coincided, with]), verbo([increases]), complemento([in, leucine, uptake, by, 'MCF-7', cells, in, response, to, 'TCDD'])].
[sujeto(['Chromatin', 'immunoprecipitation-quantitative', 'PCR', '(', 'ChIP-qPCR)', assays, revealed]), verbo([increases]), complemento([in, 'AHR,', 'AHR', nuclear, translocator, '(', 'ARNT)', and, p300, binding, and, histone, 'H3', acetylation, at, an, 'AHR', binding, site, in, the, 'LAT1', gene, in, response, to, 'TCDD'])].
[sujeto(['Light-oxygen-voltage', sensitive, '(', 'LOV)', flavoproteins, are, ubiquitous, photoreceptors, that]), verbo([mediate]), complemento([responses, to, environmental, cues])].
[sujeto(['Photosensory', inputs, are, transduced, into, signaling, outputs, via, structural, rearrangements, in, sensor, domains, that, consequently]), verbo([modulate]), complemento([the, activity, of, an, effector, domain, or, multidomain, clusters])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, bioinformatics, identification, of, over, 6, ',', 700, candidate, 'LOV', domains, '(', including, over, 4, ',', 0, previously, unidentified, sequences, from, plants, and, 'protists),', and, insights, from, their, annotations, for, ontological, function, and, structural, arrangements])].
[sujeto(['Motif', analysis, identified, the, sensors, from, '∼42', million, 'ORFs,', with, strong, statistical, separation, from, other, flavoproteins, and, 'non-LOV', members, of, the, structurally, related, 'Per-aryl', hydrocarbon, receptor]), verbo([nuclear]), complemento([translocator, '(', 'ARNT)-Sim', family])].
[sujeto(['We']), verbo([found]), complemento([that, for, certain, 'effectors,', 'sensor-effector', linker, length, is, discretized, based, on, both, phylogeny, and, the, preservation, of, 'α-helical', heptad, repeats, within, an, extended, 'coiled-coil', linker, structure])].
[sujeto(['This']), verbo([finding]), complemento([suggests, that, preserving, 'sensor-effector', orientation, is, a, key, determinant, of, linker, 'length,', in, addition, to, 'ancestry,', in, 'LOV', signaling, 'structure-function'])].
[sujeto(['We']), verbo([found]), complemento([a, surprisingly, high, prevalence, of, effectors, with, functions, previously, thought, to, be, rare, among, 'LOV', 'proteins,', such, as, regulators, of, 'G', protein, 'signaling,', and, discovered, several, previously, unidentified, 'effectors,', such, as, lipases])].
[sujeto(['Recombinant', plasmid, 'CfAhR-pET32a', '(', designated, 'rCfAhR)', was, successfully]), verbo([expressed]), complemento([in, 'Escherichia', coli, 'BL21'])].
[sujeto(['To', investigate, the, molecular, detoxification, mechanism, of, 'benzo(a)pyrene', '(', 'BaP)', 'detoxification-related', genes, '(', 'AhR;', aryl, hydrocarbon, receptor]), verbo([nuclear]), complemento(['translocator,', 'ARNT;', heat, shock, protein, 90, ',', 'HSP90;', cytochrome, 'P450', 1, 'A1,', 'CYP1A1;', glutathione, 'S-transferase', 'pi,', 'GST-pi', and, 'P', 'glycoprotein,', 'Pgp)', in, 'C'])].
[sujeto([farreri, 'gill,', 'real-time', quantitative, 'PCR', analysis, revealed, that, the, mRNA, expression, level, of, 'CfAhR,', 'xenobiotic-metabolizing', enzymes, and, efflux, transporters, was]), verbo([induced]), complemento([by, 'BaP', and, was, sensitive, to, 'BaP', exposure, time, and, 'concentration,', suggesting, that, 'BaP', influenced, the, expression, of, a, putative, 'AhR/ARNT', signaling, pathway, in, scallops])].
[sujeto(['The', aryl, hydrocarbon, receptor, '(', 'AHR)', is, a, transcription, factor, which]), verbo([activates]), complemento([gene, transcription, by, binding, to, its, corresponding, enhancer, as, the, 'heterodimer,', which, is, consisted, of, 'AHR', and, the, aryl, hydrocarbon, receptor, nuclear, translocator, '(', 'ARNT)'])].
[sujeto(['Overexpression', of, human, 'AHR']), verbo([has]), complemento([been, limited, to, the, baculovirus, 'expression,', which, is, costly, and, tedious, due, to, the, need, of, repetitive, baculovirus, production])].
[sujeto(['We', observed, that, human, 'AHR', and, 'ARNT', can, be]), verbo([expressed]), complemento([in, 'Pichia', pastoris, with, yields, that, are, comparable, to, the, baculovirus, system, only, if, their, cDNAs, are, optimized, for, 'Pichia', expression])].
[sujeto(['Fusion', with, a, 'c-myc', tag, at, their, 'C-termini', seems, to]), verbo([increase]), complemento([the, expression, yield])].
[sujeto(['These', 'Pichia']), verbo([expressed]), complemento([proteins, can, effectively, heterodimerize, and, form, the, ternary, 'AHR/ARNT/enhancer', complex, in, the, presence, of, 'β-naphthoflavone', or, kynurenine])].
[sujeto(['The', aryl, hydrocarbon, receptor]), verbo([nuclear]), complemento([translocator, '(', 'ARNT)', is, involved, in, xenobiotic, and, hypoxic, 'responses,', and, we, previously, showed, that, 'ARNT', also, regulates, nuclear, 'factor-κB', '(', 'NF-κB)', signaling, by, altering, the, 'DNA', binding, activity, of, the, 'RelB', subunit])].
[sujeto(['We']), verbo([find]), complemento([here, that, while, normal, lymphocytes, harbor, equal, levels, of, isoform, 1, and, 3, ',', lymphoid, malignancies, exhibit, a, shift, to, higher, levels, of, 'ARNT', isoform, 1])].
[sujeto(['These', elevated, levels, of, 'ARNT', isoform, 1, are, critical, to, the, proliferation, of, these, cancerous, 'cells,', as, suppression, of, isoform, 1, in, a, human, multiple, myeloma, '(', 'MM)', cell, 'line,', and, an, anaplastic, large, cell, lymphoma, '(', 'ALCL)', cell, 'line,']), verbo([triggered]), complemento(['S-phase', cell, cycle, 'arrest,', spontaneous, 'apoptosis,', and, sensitized, cells, to, doxorubicin, treatment])].
[sujeto(['Furthermore,', 'co-suppression', of, 'RelB', or, p53, with, 'ARNT', isoform, 1]), verbo([prevented]), complemento([cell, cycle, arrest, and, blocked, doxorubicin, induced, apoptosis])].
[sujeto(['Together', our, findings]), verbo([reveal]), complemento([that, certain, blood, cancers, rely, on, 'ARNT', isoform, 1, to, potentiate, proliferation, by, antagonizing, 'RelB', and, 'p53-dependent', cell, cycle, arrest, and, apoptosis])].
[sujeto(['Significantly,', our, results, identify, 'ARNT', isoform, 1, as, a, potential]), verbo([target]), complemento([for, anticancer, therapies])].
[sujeto(['The', cellular, adaptations, to, sustained, hypoxia, are]), verbo([mediated]), complemento([by, 'hypoxia-inducible', factors, '(', 'HIFs)', to, regulate, downstream, target, gene, expression])].
[sujeto(['With', 'hypoxia,', the, stabilized, 'HIF-α', and, aryl, hydrocarbon, receptor]), verbo([nuclear]), complemento([translocator, '(', 'ARNT,', also, known, as, 'HIF-β)', heterodimer, bind, to, hypoxia, response, elements, '(', 'HREs)', and, regulate, expression, of, target, genes])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, 'WNT11', is, induced, by, hypoxia, in, many, cell, 'types,', and, that, transcription, of, 'WNT11', is, regulated, primarily, by, 'HIF-1α'])].
[sujeto(['We', observed]), verbo([induced]), complemento(['WNT11', expression, in, the, hypoxic, area, of, allograft, tumors])].
[sujeto(['In', 'addition,', in, mice, bearing, orthotopic, malignant, 'gliomas,', inhibition, with, bevacizumab, of, vascular, endothelial, growth, 'factor,', which, is, an, important, stimulus, for, 'angiogenesis,']), verbo([increased]), complemento([nuclear, 'HIF-1α', and, 'HIF-2α,', and, expression, of, 'WNT11'])].
[sujeto(['Gain-', and, 'loss-of-function', approaches, revealed, that, 'WNT11']), verbo([stimulates]), complemento(['proliferation,', migration, and, invasion, of, 'cancer-derived', 'cells,', and, increases, activity, of, matrix, metalloproteinase, '(', 'MMP)-2', and, 9])].
[sujeto(['Since', tumor, hypoxia]), verbo([has]), complemento([been, proposed, to, increase, tumor, 'aggressiveness,', these, data, suggest, 'WNT11', as, a, possible, target, for, cancer, 'therapies,', especially, for, tumors, treated, with, antiangiogenic, therapy])].
[sujeto(['AHR', agonists]), verbo([inhibit]), complemento(['pro-inflammatory', cytokine, expression, in, 'macrophages,', pivotal, cells, in, 'RA', 'aetiopathogenesis,', which, hints, at, specific, circuits, that, regulate, the, 'AHR', pathway, in, 'RA', macrophages])].
[sujeto(['Bioinformatics', predicted, the, 'AHR', regulator, 'ARNT', '(', 'AHR']), verbo([nuclear]), complemento(['translocator)', as, a, 'miR-223', target])].
[sujeto(['Pre-miR-223', overexpression, silenced, 'ARNT', 3, '\'', 'UTR-driven', reporter, 'expression,', reduced, 'ARNT', '(', but, not, 'AHR)', protein, levels, and]), verbo([prevented]), complemento(['AHR/ARNT-mediated', inhibition, of, 'pro-inflammatory', cytokine, expression])].
[sujeto(['Our', results]), verbo([associate]), complemento(['Notch', signalling, to, 'miR-223', downregulation, in, 'RA', 'macrophages,', and, identify, 'miR-223', as, a, negative, regulator, of, the, 'AHR/ARNT', pathway, through, 'ARNT', targeting])].
[sujeto([microRNAs, play, a, significant, role, in]), verbo([regulating]), complemento([proliferation, of, pulmonary, arterial, smooth, muscle, cells, '(', 'PASMCs)', in, pulmonary, hypertension])].
[sujeto(['Previous', studies]), verbo([have]), complemento([shown, that, 'HIF-1β', is, a, target, of, 'miR-103/107'])].
[sujeto(['In', this, present, 'study,', we, aimed, to, investigate, whether, 'miR-103/107']), verbo([regulate]), complemento([vascular, remodeling, in, 'HPH', via, 'HIF-1β'])].
[sujeto(['Hypoxia', exposure]), verbo([induced]), complemento([significant, proliferation, of, 'PASMCs,', overexpression, of, 'miR-103/107', inhibited, but, 'miR-103/107', inhibitors, exacerbated, 'PASMCs', proliferation])].
[sujeto(['Tumour', hypoxia]), verbo([promotes]), complemento([radioresistance, and, is, associated, with, poor, prognosis])].
[sujeto(['The', transcription, factor, 'Aryl', hydrocarbon, receptor]), verbo([nuclear]), complemento([translocator, '(', 'ARNT),', also, designated, as, 'Hypoxia-inducible', factor, '(', 'HIF)-1β,', is, part, of, the, 'HIF', pathway, which, mediates, cellular, adaptations, to, oxygen, deprivation, and, facilitates, tumour, progression])].
[sujeto(['HIF-1α', is]), verbo([regulated]), complemento([in, an, 'oxygen-dependent', manner, whereas, 'ARNT', is, considered, to, be, constitutively, expressed])].
[sujeto(['However,', there, is, mounting, evidence, that, certain, tumour, cells, are, capable, to, elevate, 'ARNT', in, hypoxia, which]), verbo([suggests]), complemento([a, survival, benefit])].
[sujeto(['The', results, of, this, study, indicate, that, 'ARNT', depletion, renders, tumour, cells, susceptible, to, radiation, whereas, overexpression, of, this, transcription, factor]), verbo([confers]), complemento([radioresistance])].
[sujeto(['These', findings]), verbo([provide]), complemento([evidence, to, consider, 'ARNT', as, a, drug, target, and, as, a, predictive, marker, in, clinical, applications, concerning, the, response, to, radiation])].
[sujeto(['The', 'hypoxia-inducible', factors, '(', 'HIFs)', coordinate, cellular, adaptations, to, low, oxygen, stress, by]), verbo([regulating]), complemento([transcriptional, programs, in, 'erythropoiesis,', angiogenesis, and, metabolism])].
[sujeto(['These', programs]), verbo([promote]), complemento([the, growth, and, progression, of, many, 'tumours,', making, 'HIFs', attractive, anticancer, targets])].
[sujeto(['Here', we, describe, crystal, structures, for, each, of, mouse, 'HIF-2α-ARNT', and, 'HIF-1α-ARNT', heterodimers, in, states, that, include]), verbo([bound]), complemento([small, molecules, and, their, hypoxia, response, element])].
[sujeto(['The', 'DNA-reading', head, 'rotates,', extends, and, cooperates, with, a, distal, 'PAS', domain, to]), verbo([bind]), complemento([hypoxia, response, elements])].
[sujeto(['HIF-α', mutations, linked, to, human, cancers, map, to, sensitive, sites, that, establish, 'DNA']), verbo([binding]), complemento([and, the, stability, of, 'PAS', domains, and, pockets])].
[sujeto(['Hypoxia-inducible', factors, '(', 'HIFs),', consisting, of, α, and, β, 'subunits,']), verbo([activate]), complemento([various, genes, to, adapt, to, low, oxygen, environments, through, their, heterodimeric, complex, formation, in, the, nucleus])].
[sujeto(['While', most, of, the, studies]), verbo([have]), complemento([been, extensively, focused, on, the, 'HIF-1α', 'isoform,', the, effect, of, 'HIF-α', isoforms, on, the, complex, formation, between, 'HIF-2α', and, 'HIF-1β', in, live, cells, has, not, been, reported, in, detail])].
[sujeto(['In', contrast, to, the, previous, results, showing, 'HIF-3α-mediated', blockage, of, 'HIF-1α', 'translocation,', the, presence, of, 'HIF-3α', did, not, affect, the, localization, of, 'HIF-2α,']), verbo([suggesting]), complemento([distinct, roles, of, 'HIF-3α', in, regulation, of, two, 'HIF-α', isoforms])].
[sujeto(['TNBC', is]), verbo([associated]), complemento([with, central, fibrosis, and, 'necrosis,', both, indicators, of, tumor, hypoxia])].
[sujeto(['Hypoxia', inducible, factor, 1, α, is, 'up-regulated', under, hypoxia, and, its, expression, is]), verbo([associated]), complemento([with, induction, of, angiogenesis, resulting, in, 'proliferation,', aggressive, tumor, phenotype, and, metastasis])].
[sujeto(['HIF-1α', protein, was]), verbo([expressed]), complemento([in, 35.5, '%', 'TNBC,', 45.3, '%', 'HER2+and', 25.0, '%', 'ER+/PR+', '(', p, =, 0.055, ;, χ2, 'test)'])].
[sujeto(['PCRanalysis', of, subgroup, of, breast, 'cancers,', 84.2, '%']), verbo([expressed]), complemento(['HIF-1α', protein, and, its, 'transcripts,', while, only, 66.7, '%', expressed, 'VEGF', transcripts, simultaneously, with, the, 'HIF-1α', protein, and, its, transcripts])].
[sujeto(['VEGFR3', was, highest, in, 'TNBC']), verbo([expressing]), complemento(['HIF-1α'])].
[sujeto(['HIF-1β', protein, was]), verbo([expressed]), complemento([in, 32.0, '%', of, 'HIF-1α(+),', and, in, '(', 44.3, '%', ')', of, 'HIF-1α(-)', breast, cancer, cases, '(', p, =, 0.033, ;, χ2, 'test)'])].
[sujeto(['A', proportion, of, 'TNBC']), verbo([express]), complemento(['HIF-1α', but, not, in, a, significantly, different, manner, from, other, breast, cancer, subtypes])].
[sujeto(['The', potential, of, 'anti-HIF-1α']), verbo([targeted]), complemento([therapy, is, therefore, not, a, candidate, for, exclusive, use, in, 'TNBC,', but, should, be, considered, in, all, breast, 'cancers,', especially, in, the, setting, of, clinically, aggressive, or, refractory, disease])].
[sujeto(['Both', type, 1, and, type, 2, diabetes, are]), verbo([associated]), complemento([with, insufficient, functional, 'β-cell', mass])].
[sujeto(['Understanding', intracellular, signaling, pathways]), verbo([associated]), complemento([with, this, decline, is, important, in, broadening, our, understanding, of, the, disease, and, potential, therapeutic, strategies])].
[sujeto(['Activation', of, this, pathway]), verbo([increases]), complemento([expression, of, numerous, genes, involved, in, multiple, cellular, processes, and, has, been, shown, to, impact, the, regulation, of, 'β-cell', function])].
[sujeto(['In', 'cells,', hypoxia]), verbo([activates]), complemento([a, major, transcriptional, program, coordinated, by, the, 'Hypoxia', 'Inducible', 'Factor', '(', 'HIF)', family])].
[sujeto(['HIF', can]), verbo([activate]), complemento([more, than, one, hundred, targets, but, not, all, of, them, are, activated, at, the, same, 'time,', and, there, is, considerable, cell, type, variability])].
[sujeto(['In', this]), verbo([report]), complemento([we, identified, the, 'paired-like', homeodomain, pituitary, transcription, factor, '(', 'PITX1),', as, a, transcription, factor, that, helps, promote, specificity, in, 'HIF-1α', dependent, target, gene, activation])].
[sujeto(['Mechanistically,', 'PITX1']), verbo([associates]), complemento([with, 'HIF-1β', and, it, is, important, for, the, induction, of, certain, 'HIF-1', dependent, genes, but, not, all])].
[sujeto(['Functionally,', 'PITX1', is]), verbo([required]), complemento([for, the, survival, and, proliferation, responses, in, 'hypoxia,', as, 'PITX1', depleted, cells, have, higher, levels, of, apoptotic, markers, and, reduced, proliferation])].
[sujeto(['Overall,', our, study, identified, 'PITX1', as, a, key, specificity, factor, in, 'HIF-1α', dependent, 'responses,']), verbo([suggesting]), complemento(['PITX1', as, a, protein, to, target, in, hypoxic, cancers])].
[sujeto(['Chronic', alcohol]), verbo([causes]), complemento([liver, hypoxia, and, 'steatosis,', which, eventually, develops, into, alcoholic, liver, disease, '(', 'ALD)'])].
[sujeto(['While', it]), verbo([has]), complemento([been, known, that, alcohol, consumption, activates, hepatic, hypoxia, inducing, 'factor-1α', '(', 'HIF-1α),', conflicting, results, regarding, the, role, of, 'HIF-1α', in, 'alcohol-induced', liver, injury, and, steatosis, in, mice, have, been, reported])].
[sujeto(['We']), verbo([found]), complemento([that, acute, alcohol, treatment, increased, 'BNIP3', and, 'BNIP3L/NIX', expression, in, primary, cultured, hepatocytes, and, in, mouse, 'livers,', suggesting, that, 'HIF', may, be, activated, in, these, models])].
[sujeto(['We', further]), verbo([found]), complemento([that, 'hepatocyte-specific', 'HIF-1β', knockout, mice, developed, less, steatosis, and, liver, injury, following, the, 'Gao-binge', model, or, acute, ethanol, treatment, compared, with, their, matched, wild, type, mice])].
[sujeto(['Mechanistically,', protection, against, 'Gao-binge', 'treatment-induced', steatosis, and, liver, injury, was, likely]), verbo([associated]), complemento([with, increased, 'FoxO3a', activation, and, subsequent, induction, of, autophagy, in, 'hepatocyte-specific', 'HIF-1β', knockout, mice])].
[sujeto(['After', 1, and, 3, 'weeks,', scaffolds, were, 'retrieved,', and, the, mRNA, expression, of, interleukin, 1, -, beta, '(', 'IL-1β),', 'IL-6,', 'IL-10,', 'hypoxia-inducible', factor, 1, -, alpha, '(', 'HIF-1α),', 'HIF-1β,', and, mammalian]), verbo([target]), complemento([of, rapamycin, was, examined, by, 'real-time', reverse, 'transcription-polymerase', chain, reaction])].
[sujeto(['Leukocyte', transmigration, genes, and, genes, in, 'Toll-like', receptor, 'pathways,']), verbo([expressed]), complemento([by, 'MSCs', cultured, in, vitro, with, or, without, 'ECs,', were, further, investigated, with, a, microarray, dataset])].
[sujeto(['In', 'vitro,', genes]), verbo([involved]), complemento([in, leukocyte, transmigration, and, 'Toll-like', receptor, pathways, were, clearly, influenced, by, the, addition, of, 'ECs'])].
[sujeto(['Platelet/endothelial', cell, adhesion, 'molecule-1', '(', 'PECAM-1)', and, 'cadherin-5', '(', 'CDH5),', both, genes]), verbo([involved]), complemento([in, leukocyte, 'transmigration,', were, expressed, significantly, higher, in, the, 'MSC/EC', group])].
[sujeto(['Dimerization', of, 'hypoxia-inducible', 'factor-1', beta, '(', 'HIF-1β)', '[', aryl, hydrocarbon, receptor]), verbo([nuclear]), complemento([translocator, '(', 'ARNT)]', with, 'HIF-1α', is, involved, in, various, aspects, of, cancer, 'biology,', including, proliferation, and, survival, under, hypoxic, conditions])].
[sujeto(['We', investigated, the, in, vitro, mechanism, by, which, silencing, of, 'HIF-1β']), verbo([leads]), complemento([to, the, suppression, of, tumor, cell, growth, and, cellular, functions])].
[sujeto(['Under', hypoxic, 'conditions,', silencing, of, 'HIF-1β', expression]), verbo([suppressed]), complemento([tumor, cell, growth, and, regulated, the, expression, of, tumor, 'growth-related', 'factors,', such, as, vascular, endothelial, growth, 'factor,', epidermal, growth, 'factor,', and, hepatocyte, growth, factor])].
[sujeto(['Silencing', of, 'HIF-1β', expression, may]), verbo([induce]), complemento(['anti-tumor', effects, under, hypoxic, conditions, in, 'HCC', cell, lines])].
[sujeto(['The', aryl, hydrocarbon, receptor]), verbo([nuclear]), complemento([translocator, '(', 'ARNT),', also, designated, as, 'hypoxia-inducible', factor, '(', 'HIF)-1β,', plays, a, pivotal, role, in, the, adaptive, responses, to, '(', 'micro-)environmental', stresses, such, as, dioxin, exposure, and, oxygen, deprivation, '(', 'hypoxia)'])].
[sujeto(['ARNT', belongs, to, the, group, of, basic, 'helix-loop-helix', '(', 'bHLH)-Per-ARNT-Sim', '(', 'PAS)', transcription, 'factors,', which]), verbo([act]), complemento([as, heterodimers])].
[sujeto(['ARNT', serves, as, a, common]), verbo([binding]), complemento([partner, for, the, aryl, hydrocarbon, receptor, '(', 'AhR)', as, well, as, 'HIF-α', subunits])].
[sujeto(['HIF-α', proteins, are]), verbo([regulated]), complemento([in, an, 'oxygen-dependent', 'manner,', whereas, 'ARNT', is, generally, regarded, as, constitutively, 'expressed,', meaning, that, neither, the, arnt, mRNA, nor, the, protein, level, is, influenced, by, hypoxia, '(', despite, the, name, 'HIF-1β)'])].
[sujeto(['Elucidating', the, mechanism, behind, this, rare, cellular, attribute, will, help, us, to]), verbo([gain]), complemento([new, insights, into, 'HIF', biology, and, might, provide, new, strategies, for, 'anti-cancer', therapeutics])].
[sujeto(['Hypoxia-Inducible', 'Factor', '(', 'HIF)', transcription, factors, are, heterodimeric, proteins]), verbo([involved]), complemento([in, the, regulation, of, oxygen, homeostatis])].
[sujeto(['Their', upregulation]), verbo([has]), complemento([been, related, to, several, tumors, with, a, remarkably, poor, clinical, outcome])].
[sujeto(['The', recent, discovery, of, a, druggable, cavity, in, the, 'HIF-2α', 'PAS-B', domain]), verbo([has]), complemento([opened, an, unprecedented, opportunity, for, targeting, the, 'HIF-2α', transcription, factor, in, view, of, pharmaceutical, strategies])].
[sujeto(['Coincidentally,', a, novel, compound, able, to, selectively, disrupt, the, 'HIF', heterodimerization, with, a, submicromolar, activity]), verbo([has]), complemento([been, reported])].
[sujeto(['While', 'long-term', '(', 24, 'h)', treatment, with, 'GS-HCl', strongly]), verbo([repressed]), complemento([the, expression, of, 'HIF-1α', and, 'HIF-1β', at, both, the, protein, and, mRNA, 'levels,', 'short-term', '(', 4, 'h)', 'GS-HCl', treatment, inhibited, 'HIF-1α', at, the, protein, level])].
[sujeto(['Short-term', 'GS-HCl', treatment, also]), verbo([decreased]), complemento([phosphorylation, of, p70S6K, and, 'S6,', 'translation-related', proteins])].
[sujeto(['However,', the, results, of, subsequent, pharmacological, inhibition, and, protein, stability, analyses, indicated, that, 'HIF-1α', protein, downregulation]), verbo([induced]), complemento([by, 'short-term', 'GS-HCl', treatment, was, not, through, modulation, of, the, 'mTOR/p70S6K/S6', signaling, 'pathways,', the, 26, 'S', proteasomal, and, lysosomal, activities, and, 'HIF-1α', protein, stability])].
[sujeto(['Importantly,', our, further, analyses, identified, that, 'HIF-1α', protein, downregulation]), verbo([induced]), complemento([by, 'short-term', 'GS-HCl', treatment, was, blunted, by, exogenous, administration, of, the, citric, acid, cycle, metabolites, citrate, and, 2, -, 'oxoglutarate,', but, not, the, glycolytic, end, byproducts, pyruvate, and, lactate])].
[sujeto(['Several', 'JMJDs', are]), verbo([induced]), complemento([by, hypoxic, stress, to, compensate, their, presumed, reduction, in, catalytic, activity, under, hypoxia])].
[sujeto(['In', this, 'study,', we, showed, that, an, 'H3K27me3', specific, histone, 'demethylase,', 'JMJD3', was]), verbo([induced]), complemento([by, 'hypoxia-inducible', factor, '(', 'HIF)-1α/β', under, hypoxia, and, that, treatment, with, 'Clioquinol,', a, 'HIF-1α', 'activator,', increased, 'JMJD3', expression, even, under, normoxia])].
[sujeto(['Chromatin', immunoprecipitation, '(', 'ChIP)', analyses, showed, that, both, 'HIF-1α', and, its, dimerization, partner, 'HIF-1β/Arnt', occupied, the, first, intron, region, of, the, mouse, 'JMJD3', 'gene,', whereas, the, 'HIF-1α/β', heterodimer]), verbo([bound]), complemento([to, the, upstream, region, of, the, human, 'JMJD3,', indicating, that, human, and, mouse, 'JMJD3', have, 'hypoxia-responsive', regulatory, regions, in, different, locations])].
[sujeto(['This', study, shows, that, both, mouse, and, human, 'JMJD3', are]), verbo([induced]), complemento([by, 'HIF-1'])].
[sujeto(['As', 'hypoxia-inducible', 'factor-1', '(', 'HIF-1)', is, a, critical, determinant, response, to, hypoxia, and, 'inflammation,', which]), verbo([has]), complemento([been, shown, to, be, deleterious, to, intestinal, barrier, 'function,', we, hypothesized, that, 'IFN-γ', induces, loss, of, barrier, function, through, the, regulation, of, 'HIF-1α', activation, and, function])].
[sujeto(['IFN-γ']), verbo([led]), complemento([to, an, increase, of, 'HIF-1α', expression, in, 'time-', and, 'dose-dependent', manners, but, did, not, change, the, expression, of, 'HIF-1β'])].
[sujeto(['The', 'IFN-γ-induced']), verbo([increase]), complemento([in, 'HIF-1α', was, associated, with, an, activation, of, 'NF-κB'])].
[sujeto(['Treatment', with, the, 'NF-κB', 'inhibitor,', pyrolidinedithiocarbamate, '(', 'PDTC),', significantly]), verbo([suppressed]), complemento([the, activation, of, 'NF-κB', and, the, expression, of, 'HIF-1α'])].
[sujeto(['In', 'addition,', 'IFN-γ', also]), verbo([increased]), complemento([intestinal, epithelial, permeability, and, depletion, of, tight, junction, 'proteins;', inhibition, of, 'NF-κB', or, 'HIF-1α', prevented, the, increase, in, intestinal, permeability, and, alteration, in, tight, junction, protein, expressions])].
[sujeto(['Interestingly,', we, demonstrated, that, a, significant, portion, of, 'IFN-γ', activation, 'NF-kB', and, modulation, tight, junction, expression, is]), verbo([mediated]), complemento([through, 'HIF-1α'])].
[sujeto(['Taken', 'together,', this, study]), verbo([suggested]), complemento([that, 'IFN-γ', induced, the, loss, of, epithelial, barrier, function, and, disruption, of, tight, junction, 'proteins,', by, upregulation, of, 'HIF-1α', expression, through, 'NF-κB', pathway])].
[sujeto(['Similar', to, other, 'species\'', 'HIF-1,', 'HdHIF-1']), verbo([has]), complemento([one, basic, 'helix-loop-helix', '(', 'bHLH)', domain, and, two, 'Per-Arnt-Sim', '(', 'PAS)', 'domains,', and, 'HdHIF-1α', has, a, 'oxygen-dependent', degradation, domain, '(', 'ODDD)', with, two, proline, hydroxylation, motifs, and, a, 'C-terminal', transactivation, domain, '(', 'C-TAD)', with, an, asparagine, hydroxylation, motif])].
[sujeto(['Under', thermal, stress, '(', 31, °, 'C),', 'HdHIF-1α', expression, was, significantly]), verbo([increased]), complemento([in, gills, at, 4, 'h,', and, hemocytes, at, 0, h, and, 4, 'h,', while, 'HdHIF-1β', expression, still, remained, relatively, constant])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, 'HIF-1α', may, play, an, important, role, in, adaption, to, poor, environment, in, 'H'])].
[sujeto(['Both', preclinical, and, clinical, studies]), verbo([suggest]), complemento([that, brief, cycles, of, ischemia, and, reperfusion, in, the, arm, or, leg, may, protect, the, heart, against, injury, following, prolonged, coronary, artery, occlusion, and, 'reperfusion,', a, phenomenon, known, as, remote, ischemic, preconditioning])].
[sujeto(['Recent', studies, in, mice, indicate, that]), verbo([increased]), complemento([plasma, 'interleukin-10', '(', 'IL-10)', levels, play, an, important, role, in, remote, ischemic, preconditioning, induced, by, clamping, the, femoral, artery, for, 5, min, followed, by, 5, min, of, reperfusion, for, a, total, of, three, cycles])].
[sujeto(['In', this, 'study,', we, demonstrate, that, remote, ischemic, preconditioning]), verbo([increases]), complemento([plasma, 'IL-10', levels, and, decreases, myocardial, infarct, size, in, 'wild-type', mice, but, not, in, littermates, that, are, heterozygous, for, a, knockout, allele, at, the, locus, encoding, 'hypoxia-inducible', factor, '(', 'HIF)', 1, α])].
[sujeto(['Injection', of, a, recombinant, adenovirus, encoding, a, constitutively, active, form, of, 'HIF-1α', into, mouse, hind, limb, muscle, was, sufficient, to]), verbo([increase]), complemento([plasma, 'IL-10', levels, and, decrease, myocardial, infarct, size])].
[sujeto(['Exposure', of, 'C2C12', mouse, myocytes, to, cyclic, hypoxia, and, reoxygenation, rapidly]), verbo([increased]), complemento([levels, of, 'IL-10', 'mRNA,', which, was, blocked, by, administration, of, the, 'HIF-1', inhibitor, acriflavine, or, by, expression, of, short, hairpin, 'RNA', targeting, 'HIF-1α', or, 'HIF-1β'])].
[sujeto(['Chromatin', immunoprecipitation, assays, demonstrated, that]), verbo([binding]), complemento([of, 'HIF-1', to, the, 'Il10', gene, was, induced, when, myocytes, were, subjected, to, cyclic, hypoxia, and, reoxygenation])].
[sujeto(['Taken', 'together,', these, data, indicate, that, 'HIF-1']), verbo([activates]), complemento(['Il10', gene, transcription, and, is, required, for, remote, ischemic, preconditioning])].
[sujeto(['Central', to, the, molecular, mechanisms, underlying, 'O2', homeostasis, are, 'hypoxia-inducible', factors, '(', 'HIFs),', heterodimeric, transcription, factors, composed, of, 'O2-regulated', α, subunits, '(', 'HIF1A/HIF-1α', or, 'EPAS1/HIF-2α),', and, a, constitutively]), verbo([expressed]), complemento(['ARNT/HIF-1β', 'subunit,', that, serve, as, master, regulators, of, the, adaptive, response, to, hypoxia])].
[sujeto(['HIF1A', and, 'EPAS1']), verbo([have]), complemento([both, unique, and, overlapping, functions, in, the, regulation, of, diverse, cellular, 'processes,', but, so, far, there, has, been, no, evidence, linking, 'HIF', signaling, to, peroxisomes])].
[sujeto(['Here', we, summarize, our, findings, and, discuss, potential, mechanisms, by, which, 'EPAS1', might]), verbo([trigger]), complemento([pexophagy])].
[sujeto(['ARNT', is, a, heterodimerisation, partner, of, the, xenobiotic, ligand]), verbo([activated]), complemento(['Aryl', 'Hydrocarbon', 'Receptor', '(', 'AhR),', the, 'Single', 'Minded', proteins, '(', 'SIM),', the, cardiovascular, 'helix-loop-helix', factor, 1, and, the, 'Hypoxia', 'Inducible', 'Factor', proteins, '(', 'HIF-α)'])].
[sujeto(['ARNT', is, obligatory, for, 'HIF-1,', 'HIF-2', and, 'HIF-3']), verbo([binding]), complemento([to, 'DNA'])].
[sujeto(['Whereas', degradation, of, the, 'HIF-α', subunits, is]), verbo([suppressed]), complemento([by, 'hypoxia,', 'ARNT', is, generally, regarded, as, constitutively, expressed, in, excess, within, the, 'cell,', and, stabilisation, is, commonly, thought, to, be, 'oxygen-independent'])].
[sujeto(['However,', we]), verbo([provide]), complemento([evidence, that, the, regulation, of, 'ARNT', is, far, more, complex])].
[sujeto(['We', demonstrate, that, this, effect, might, be]), verbo([triggered]), complemento([by, 'HIF-1α', which, plays, an, important, role, in, the, process, of, stabilizing, 'ARNT', in, hypoxia])].
[sujeto(['Lysophosphatidic', acid, '(', 'LPA)', is, a, lipid, growth, factor, with, multiple, biological, functions, and]), verbo([has]), complemento([been, shown, to, stimulate, cancer, cell, secretion, of, vascular, endothelial, growth, 'factor-A', '(', 'VEGF-A)', and, trigger, angiogenesis])].
[sujeto(['Hypoxia-inducible', 'factor-1', '(', 'HIF-1),', a, heterodimer, consisting, of, 'HIF-1α', and, 'HIF-1β', '(', also, known, as, aromatic, hydrocarbon, receptor]), verbo([nuclear]), complemento([translocator, '(', 'ARNT))', 'subunits,', is, an, important, regulator, of, angiogenesis, in, prostate, cancer, '(', 'PC)', through, the, enhancement, of, 'VEGF-A', expression])].
[sujeto(['In', this, 'study,', we, first, confirmed, the, ability, of, 'LPA', to]), verbo([induce]), complemento(['VEGF-A', expression, in, 'PC-3', cells, and, then, validated, that, 'LPA-induced', 'VEGF-A', expression, was, regulated, by, 'HIF-1α', and, 'ARNT', through, phosphatidylinositol, 3, -, kinase, activation])].
[sujeto(['Aromatic', hydrocarbon, receptor, '(', 'AHR),', a, receptor, for, 'dioxin-like', 'compounds,', functions, as, a, transcription, factor, through, dimerization, with, 'ARNT', and, was]), verbo([found]), complemento([to, inhibit, prostate, carcinogenesis, and, 'vanadate-induced', 'VEGF-A', production])].
[sujeto(['Since', 'ARNT', is, a, common, dimerization, partner, of, 'AHR', and, 'HIF-1α,', we, hypothesized, that, 'AHR', might]), verbo([suppress]), complemento(['LPA-induced', 'VEGF-A', expression, in, 'PC-3', cells, by, competing, with, 'HIF-1α', for, 'ARNT'])].
[sujeto(['Here', we, demonstrated, that, overexpression, and, ligand, activation, of, 'AHR']), verbo([inhibited]), complemento(['HIF-1-mediated', 'VEGF-A', induction, by, 'LPA', treatment, of, 'PC-3', cells])].
[sujeto(['In', 'conclusion,', our, results]), verbo([suggested]), complemento([that, 'AHR', activation, may, inhibit, 'LPA-induced', 'VEGF-A', expression, in, 'PC-3', cells, by, attenuating, 'HIF-1α', 'signaling,', and, 'subsequently,', suppressing, angiogenesis, and, metastasis, of, 'PC'])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, 'AHR', presents, a, potential, therapeutic, target, for, the, prevention, of, 'PC', metastasis])].
[sujeto(['Hypoxia']), verbo([stimulates]), complemento([a, variety, of, adaptive, 'responses,', many, mediated, via, the, hypoxia, inducible, factors, '(', 'HIF)', family, of, transcriptional, complexes])].
[sujeto(['The', balance, of, 'HIF-1,', -, 2, and, -, 3, controls, a, variety, of, 'genes,', directly, 'up-regulating', transcription, of, genes]), verbo([involved]), complemento([in, 'erythropoiesis,', 'angiogenesis,', vasomotor, 'tone,', metabolic, pathways, and, processes, related, to, cell, multiplication, and, 'survival,', and, indirectly, reducing, the, transcription, of, genes, with, other, effects])].
[sujeto(['HIF', transcription, factors, are, heterodimers, consisting, of, an, 'oxygen-regulated', alpha, chain]), verbo([bound]), complemento([to, the, constitutive, aryl, hydrocarbon, receptor, nuclear, translocator])].
[sujeto(['Hydroxylation', of, two, critical, prolyl, residues, by, the, 'HIF', prolyl, hydroxylases, '(', 'PHD1-3)']), verbo([leads]), complemento([to, recognition, by, the, von, 'Hippel-Lindau', 'E3', ubiquitin, ligase, 'complex,', polyubiquitylation, of, the, alpha, chain, and, its, consequent, destruction, by, the, proteasome])].
[sujeto(['Hydroxylation', of, an, asparaginyl, residue, by, 'Factor', 'Inhibiting', 'HIF']), verbo([prevents]), complemento([any, surviving, 'HIF', alpha, chains, from, recruiting, 'p300-CBP', 'proteins,', important, for, maximal, transcriptional, activation])].
[sujeto(['Under', conditions, of, acute, hypoxia, enzyme, activity, is, 'suppressed,', the, 'HIF', alpha, chains, are, allowed, to, exist, in, their, active, form, and]), verbo([target]), complemento([gene, transcription, is, enhanced])].
[sujeto(['In', sustained, 'hypoxia,', adaptive, responses]), verbo([mediated]), complemento([by, the, 'HIF', pathway, reduce, oxygen, demand, and, increase, oxygen, supply, and, thus, ultimately, 'down-regulate', the, pathway])].
[sujeto(['However,', a, number, of, other, processes, also]), verbo([modulate]), complemento(['HIF', signalling, and, the, balance, between, 'HIF-1', and, 'HIF-2', actions])].
[sujeto(['These', include, the, generation, of, antisense, 'HIF-1', and, micro, 'RNAs,', 'up-regulation', of, 'HIF-3', 'alpha,', antagonism, of, the, 'HIF-p300', interaction, by, 'CITED2,']), verbo([increased]), complemento(['PHD2', and, 'PHD3', levels, and, effects, on, the, pool, of, ankyrins, within, the, cell, which, compete, with, 'HIF', for, the, action, of, 'FIH'])].
[sujeto(['Additionally,', effects, on, intermediary, 'metabolism,', reactive, oxygen, 'species,', iron, 'availability,', nitric, oxide, levels, and, redox, status, within, the, cell, may]), verbo([modulate]), complemento(['HIF', activity])].
[sujeto(['Together,', these, effects]), verbo([lead]), complemento([to, a, reduction, in, the, magnitude, of, the, 'HIF', response, even, if, oxygenation, is, not, restored, and, are, predicted, to, alter, the, responsiveness, of, the, system, when, oxygenation, is, restored])].
[sujeto(['Circadian', misalignment]), verbo([induces]), complemento([insulin, resistance, in, both, human, and, animal, 'models,', and, skeletal, muscle, is, the, largest, organ, response, to, insulin])].
[sujeto(['However,', how, circadian, clock]), verbo([regulates]), complemento([muscle, insulin, sensitivity, and, the, underlying, molecular, mechanisms, are, still, largely, unknown])].
[sujeto(['Here', we, show, circadian, locomotor, output, cycles, kaput, '(', 'CLOCK)', and, brain, and, muscle, aryl, hydrocarbon, receptor]), verbo([nuclear]), complemento(['translocator-like', protein, '(', 'BMAL)-1,', two, core, circadian, transcription, 'factors,', are, 'down-regulated', in, 'insulin-resistant', 'C2C12', myotubes, and, mouse, skeletal, muscle])].
[sujeto(['Furthermore,', insulin, signaling, is, attenuated, in, the, skeletal, muscle, of, 'Clock(Δ19/Δ19)', 'mice,', and, knockdown, of, 'CLOCK', or, 'BMAL1', by, small, interfering, 'RNAs']), verbo([induces]), complemento([insulin, resistance, in, 'C2C12', myotubes])].
[sujeto(['Moreover,', 'CLOCK', and, 'BMAL1']), verbo([regulate]), complemento([the, expression, of, sirtuin, 1, '(', 'SIRT1),', an, important, regulator, of, insulin, 'sensitivity,', in, 'C2C12', myotubes, and, mouse, skeletal, 'muscle,', and, two, 'E-box', elements, in, 'Sirt1', promoter, are, responsible, for, its, 'CLOCK-', and, 'BMAL1-dependent', transcription, in, muscle, cells])].
[sujeto(['Further', studies, show, that, 'CLOCK', and, 'BMAL1']), verbo([regulate]), complemento([muscle, insulin, sensitivity, through, 'SIRT1'])].
[sujeto(['In', 'addition,', we]), verbo([find]), complemento([that, 'BMAL1', and, 'SIRT1', are, decreased, in, the, muscle, of, mice, maintained, in, constant, 'darkness,', and, resveratrol, supplementation, activates, 'SIRT1', and, improves, insulin, sensitivity])].
[sujeto(['All', these, data, demonstrate, that, 'CLOCK', and, 'BMAL1']), verbo([regulate]), complemento([muscle, insulin, sensitivity, via, 'SIRT1,', and, activation, of, 'SIRT1', might, be, a, potential, valuable, strategy, to, attenuate, muscle, insulin, resistance, related, to, circadian, misalignment])].
[sujeto(['Polymorphisms', in, aryl, hydrocarbon, receptor]), verbo([nuclear]), complemento(['translocator-like', '(', 'ARNTL)', 'gene,', the, key, component, of, circadian, clock, manifests, circadian, rhythm, abnormalities])].
[sujeto(['As', seasonal, affective, disorder, '(', 'SAD)', is]), verbo([associated]), complemento([with, disrupted, circadian, 'rhythms,', the, main, objective, of, this, study, was, to, screen, an, 'Indian', family, with, 'SAD', for, 'ARNTL', gene, polymorphisms])].
[sujeto(['Polymorphisms', in, 'ARNTL', gene, disrupt, circadian, rhythms]), verbo([causing]), complemento(['SAD', and, genetic, predisposition, becomes, more, deleterious, in, the, presence, of, adverse, environment])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, 'miR-27b-3p', exhibits, rhythmic, expression, in, the, metabolic, tissues, of, the, mice, subjected, to, constant, darkness])].
[sujeto(['MiR-27b-3p\'s', expression, is]), verbo([induced]), complemento([in, livers, of, unfed, and, 'ob/ob', mice])].
[sujeto(['In', 'addition,', the, oscillation, phases, of, 'miR-27b-3p', can, be, reversed, by, restricted, 'feeding,']), verbo([suggesting]), complemento([a, role, of, peripheral, clock, in, regulating, its, rhythmicity])].
[sujeto(['Bioinformatics', analysis, indicated, that, aryl, hydrocarbon, receptor]), verbo([nuclear]), complemento(['translocator-like', '(', also, known, as, 'Bmal1)', may, be, a, direct, target, of, 'miR-27b-3p'])].
[sujeto(['Luciferase', reporter, assay, showed, that, 'miR-27b-3p']), verbo([suppressed]), complemento(['Bmal1', 3, '\'', 'UTR', activity, in, a, 'dose-dependent', 'manner,', and, mutagenesis, of, their, binding, site, abolished, this, suppression])].
[sujeto(['Collectively,', our, results]), verbo([suggest]), complemento([that, 'miR-27b-3p', plays, an, important, role, in, the, posttranscriptional, regulation, of, 'BMAL1', protein, in, the, liver])].
[sujeto(['Rhythmic', expression, of, 'miR-27b-3p']), verbo([targets]), complemento([the, clock, gene, 'Bmal1', at, the, posttranscriptional, level, in, the, mouse, liver])].
[sujeto(['Hypoxia']), verbo([activates]), complemento(['hypoxia-inducible', factor, 1, ',', which, promotes, the, progression, of, malignancy, by, stimulating, angiogenesis, and, by, augmenting, the, ability, of, tumors, to, survive])].
[sujeto(['Thus,', 'HIF-1', is, one, of, the, most, compelling]), verbo([targets]), complemento([for, treating, cancers])].
[sujeto(['The', aim, of, this, study, was, to]), verbo([find]), complemento([a, small, molecule, that, inhibits, 'HIF-1', under, hypoxia, in, cancer, cells])].
[sujeto([7, ',', 280, compounds, in, a, chemical, library, were, tested, in, a, cancer, cell, line]), verbo([expressing]), complemento([luciferase, 'HIF-dependently'])].
[sujeto(['The', antibiotic, potently]), verbo([inhibited]), complemento(['HIF-1', expression, and, its, transcriptional, activity, in, cancer, cells, exposed, to, hypoxia])].
[sujeto(['Mechanistically,', diacetoxyscirpenol]), verbo([inhibits]), complemento([the, synthesis, of, 'HIF-1α', protein, and, also, interferes, with, the, dimerization, of, 'HIF-1α', and, 'ARNT'])].
[sujeto(['Recombinant', attenuated, 'Salmonella', enterica, serovar, 'Typhimurium', strains, are, believed, to]), verbo([act]), complemento([as, powerful, live, vaccine, carriers, that, are, able, to, elicit, protection, against, various, pathogens])].
[sujeto(['In', this, 'study,', we, describe, the, surprising]), verbo([finding]), complemento([that, deletion, of, aroA, dramatically, increased, the, virulence, of, attenuated, 'Salmonella', in, mouse, models])].
[sujeto(['Mutant', bacteria, lacking, aroA, elicited]), verbo([increased]), complemento([levels, of, the, proinflammatory, cytokine, tumor, necrosis, factor, alpha, '(', 'TNF-α)', after, systemic, application])].
[sujeto(['A', detailed, genetic, and, phenotypic, characterization, in, combination, with, transcriptomic, and, metabolic, profiling, demonstrated, that, 'ΔaroA', mutants, display, pleiotropic, alterations, in, cellular, physiology, and, lipid, and, amino, acid, 'metabolism,', as, well, as]), verbo([increased]), complemento([sensitivity, to, 'penicillin,', 'complement,', and, phagocytic, uptake])].
[sujeto(['Recombinant', attenuated, bacterial, vector, systems, based, on, genetically, engineered, 'Salmonella']), verbo([have]), complemento([been, developed, as, highly, potent, vaccines])].
[sujeto(['Due', to, the, pathogenic, properties, of, 'Salmonella,', efficient, attenuation, is]), verbo([required]), complemento([for, clinical, applications])].
[sujeto([1038, /, 291238, 'a0),', the, auxotrophic, 'ΔaroA', mutation]), verbo([has]), complemento([been, generally, considered, safe, and, universally, used, to, attenuate, bacterial, strains])].
[sujeto(['Here,', we, are, presenting, the, remarkable]), verbo([finding]), complemento([that, a, deletion, of, aroA, leads, to, pronounced, alterations, of, gene, 'expression,', 'metabolism,', and, cellular, 'physiology,', which, resulted, in, increased, 'immunogenicity,', 'virulence,', and, adjuvant, potential, of, 'Salmonella'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, enhanced, immunogenicity, of, 'aroA-deficient', 'Salmonella', strains, might, be, advantageous, for, optimizing, bacterial, vaccine, carriers, and, immunotherapy])].
[sujeto(['The', prevalence, of, metabolic, 'syndrome,', a, clustering, of, three, or, more, risk, factors, that, include, abdominal, 'obesity,']), verbo([increased]), complemento([blood, 'pressure,', and, high, levels, of, 'glucose,', 'triglycerides,', and, 'high-density', 'lipoproteins,', has, reached, dangerous, and, costly, levels, worldwide])].
[sujeto(['Increases', in, morbidity, and, mortality, result, from, a, combination, of, factors, that]), verbo([promote]), complemento([altered, glucose, 'metabolism,', insulin, 'resistance,', and, metabolic, dysfunction])].
[sujeto(['AhR']), verbo([binds]), complemento([a, range, of, 'ligands,', which, prompts, 'protein-protein', interactions, with, other, 'Per-Arnt-Sim', '(', 'PAS)-domain-containing', proteins, and, subsequent, transcriptional, activity])].
[sujeto(['This', review, focuses, on, the, reciprocal, crosstalk, between, the]), verbo([activated]), complemento(['AhR', and, the, molecular, circadian, clock])].
[sujeto(['This', review, highlights, the, state, of, knowledge, regarding, how, 'AhR', may]), verbo([act]), complemento([together, with, the, circadian, clock, to, influence, energy, metabolism])].
[sujeto(['Understanding', the, variety, of, 'AhR-dependent', 'mechanisms,', including, its, interactions, with, the, circadian, timing, system, that]), verbo([promote]), complemento([metabolic, 'dysfunction,', reveals, new, targets, of, interest, for, maintenance, of, healthy, metabolism])].
[sujeto(['To', overcome, these, 'shortages,', angiogenesis, is]), verbo([induced]), complemento([in, cancer, spheroids, in, vivo])].
[sujeto(['Vascular', endothelial, growth, factor, '(', 'VEGF)', is, an, important, molecule]), verbo([involved]), complemento([in, angiogenesis])].
[sujeto(['VEGF', expression, in, cancer, cells, is]), verbo([mediated]), complemento([by, 'hypoxia-inducible', factor, 1, α, '(', 'HIF1α),', which, accumulates, in, cancer, cells, during, hypoxia])].
[sujeto(['In', this, 'report,', we, show, that, 'VEGF', expression, is]), verbo([regulated]), complemento([by, 'HIF1α', and, that, 'VEGF', is, secreted, to, the, outside, of, the, spheroid, in, vitro])].
[sujeto(['Several', investigators]), verbo([have]), complemento([reported, that, 'HIF1α', forms, a, 'protein-protein', complex, with, aryl, hydrocarbon, receptor, translocator, '(', 'ARNT)'])].
[sujeto(['We']), verbo([report]), complemento([here, that, not, only, 'HIF1α', but, also, 'ARNT', regulates, 'VEGF', expression, in, 3, 'D', cancer, spheroids])].
[sujeto(['Our', results]), verbo([suggest]), complemento([the, utility, of, the, in, vitro, 3, 'D', cancer, spheroid, model, for, investigating, angiogenesis, in, cancerous, tissues])].
[sujeto(['Changes', in, hERG, channel, function, underlie, long, 'QT', syndrome, '(', 'LQTS)', and, are]), verbo([associated]), complemento([with, cardiac, arrhythmias, and, sudden, death])].
[sujeto(['In', other, 'proteins,', 'PAS', domains]), verbo([bind]), complemento([ligands, and, modulate, effector, domains])].
[sujeto(['We']), verbo([have]), complemento([uncovered, a, family, of, positive, modulators, of, hERG, that, specifically, bind, to, the, 'PAS', domain])].
[sujeto(['We', generated, two, 'single-chain', variable, fragments, '(', 'scFvs)', that]), verbo([recognize]), complemento([different, epitopes, on, the, 'PAS', domain])].
[sujeto(['Both', antibodies]), verbo([increase]), complemento([the, rate, of, deactivation, but, have, different, effects, on, channel, activation, and, inactivation])].
[sujeto(['Importantly,', we, show, that, both, 'antibodies,', on]), verbo([binding]), complemento([to, the, 'PAS', 'domain,', increase, the, total, amount, of, current, that, permeates, the, channel, during, a, ventricular, action, potential, and, significantly, reduce, the, action, potential, duration, recorded, in, human, cardiomyocytes])].
[sujeto(['Overall,', these, molecules, constitute, a, previously, unidentified, class, of, positive, modulators, and, establish, that, allosteric, modulation, of, hERG, channel, function, through, ligand]), verbo([binding]), complemento([to, the, 'PAS', domain, can, be, attained])].
[sujeto(['Mammalian', circadian, rhythms]), verbo([regulate]), complemento([many, metabolic, processes])].
[sujeto(['Recent', studies]), verbo([suggest]), complemento([that, brain, and, muscle, 'Arnt-like', 1, '(', 'BMAL1),', an, important, component, of, mammalian, circadian, 'rhythm,', is, associated, with, insulin, signaling])].
[sujeto(['Several', studies]), verbo([have]), complemento([shown, that, insulin, is, associated, with, bone, 'metabolism;', 'however,', the, relationship, between, 'BMAL1', and, osteoblasts, remains, unclear])].
[sujeto(['In', 'addition,', 'Bmal1', overexpression]), verbo([increased]), complemento([the, expression, of, osteogenic, genes, including, inhibitor, of, 'DNA', binding, '(', 'Id1),', 'Runt-related', transcription, factor, 2, '(', 'Runx2),', and, osteocalcin, '(', 'OC)'])].
[sujeto(['Interestingly,', expression, of, 'Bone', morphogenetic, 'protein-2', '(', 'BMP2),', an, important, upstream, factor, of, 'Id1,', 'Runx2,', and, 'OC,', was, markedly]), verbo([increased]), complemento([by, 'Bmal1'])].
[sujeto(['PCR', analysis, and, alizarin, red, 'S', staining, showed, that, 'insulin-mediated']), verbo([increases]), complemento([gene, expression, and, calcium, deposition, were, reduced, in, 'Bmal1', 'KO', cells, compared, to, 'wild-type', cells])].
[sujeto(['Taken', 'together,', these, results, demonstrate, that, 'Bmal1']), verbo([promotes]), complemento([osteoblast, differentiation, by, regulating, 'BMP2', expression, in, 'MC3T3-E1', cells])].
[sujeto(['The', adverse, effects, of, 'clozapine,', including, 'agranulocytosis,', make]), verbo([finding]), complemento([a, safe, 'clozapine-like', a, drug, a, goal, for, drug, developers])].
[sujeto(['The', drug, discrimination, paradigm, is, a, model, of, interoceptive, stimulus, that]), verbo([has]), complemento([been, used, in, an, effort, to, screen, experimental, drugs, for, 'clozapine-like', atypical, antipsychotic, effects])].
[sujeto(['The', present, findings]), verbo([suggest]), complemento([that, 5, -, 'HT2A', inverse, agonism, and, 'D4', receptor, antagonism, mediate, the, discriminative, stimulus, properties, of, 1.25, 'mg/kg', clozapine, in, 'rats,', and, further, confirm, that, clozapine, produces, a, complex, compound, discriminative, stimulus])].
[sujeto(['AhR']), verbo([has]), complemento([been, known, primarily, for, its, role, in, the, regulation, of, several, drug, and, xenobiotic, metabolizing, 'enzymes,', as, well, as, the, mediation, of, the, toxicity, of, certain, 'xenobiotics,', including, 2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD)'])].
[sujeto(['By', yeast, two, hybrid, 'system,', after, multiple, screening, with, the, high, screening, rate, 'medium,', rotary, 'verification,', sequencing, and, bioinformatics, 'analysis,', the, interactions, of, the, 'CfAhR', with, receptor, for]), verbo([activated]), complemento([protein, kinase, 'C', 1, '(', 'RACK1),', thyroid, 'peroxidase-like', protein, '(', 'TPO),', 'Toll-like', receptor, 4, '(', 'TLR', 4, ')', ',', 'androglobin-like,', 'store-operated', 'Ca(2+)', entry, '(', 'SocE),', 'ADP/ATP', carrier, 'protein,', cytochrome, 'b,', 'thioesterase,', 'actin,', ferritin, subunit, 1, ',', 'poly-ubiquitin,', 'short-chain', collagen, 'C4-like', and, one, hypothetical, protein, in, gill, cells, were, identified])].
[sujeto(['This', study]), verbo([suggests]), complemento([that, the, 'CfAhR', played, fundamental, roles, in, immune, system, 'homeostasis,', oxidative, stress, 'response,', and, in, grow, and, development, of, 'C'])].
[sujeto(['The', elucidation, of, these, protein, interactions, is, of, much, importance, both, in, understanding, the, normal, physiological, function, of, 'AhR,', and, as, potential]), verbo([targets]), complemento([for, further, research, on, protein, function, in, 'AhR', interactions])].
[sujeto(['Bmal1', '(', brain, and, muscle, 'ARNT-like', 'protein-1)', deficient, '(', 'Bmal1)', mice, prematurely, age, due, to, an]), verbo([increased]), complemento([reactive, oxygen, species, '(', 'ROS)', production])].
[sujeto(['Echocardiographic', analysis, revealed, that, 'TEMPOL', treatment, of, 'Bmal1', mice, normalized, cardiac, 'function,', as, evidenced, by, a]), verbo([decrease]), complemento([in, left, ventricular, diastolic, and, systolic, internal, 'diameters,', and, by, an, increase, in, fractional, shortening, and, ejection, fraction])].
[sujeto(['KCNH', 'voltage-gated', potassium, channels, play, critical, roles, in]), verbo([regulating]), complemento([cellular, functions])].
[sujeto(['PAS', domains, are]), verbo([conserved]), complemento([from, prokaryotes, to, eukaryotes, and, are, involved, in, sensing, signals, and, cellular, responses])].
[sujeto(['By', comparing, it, with, the, structures, of, the, 'Homo', sapiens, 'EAG-related', gene, '(', 'hERG)', channel, and, the, 'Drosophila', 'EAG-like', 'K(+)', '(', 'dELK)', channel, and, analyzing, the, structural, features, of, the, hEAG, 'channel,', it, was, identified, that, a, hydrophobic, patch, on, the, 'β-sheet', may]), verbo([mediate]), complemento([interaction, between, the, 'PAS', domain, and, other, regions, of, the, channel, to, regulate, its, functions])].
[sujeto(['Transcription', factors, of, the, basic, 'helix-loop-helix', '(', 'bHLH)', 'PER-ARNT-SIM', '(', 'PAS)', family, generally]), verbo([have]), complemento([critical, and, nonredundant, biological, 'roles,', but, some, bHLH, 'PAS', proteins, compete, for, common, cofactors, or, recognise, similar, 'DNA', elements])].
[sujeto(['Identifying', factors, that]), verbo([regulate]), complemento([function, of, bHLH, 'PAS', 'proteins,', particularly, in, cells, where, multiple, family, members, are, 'coexpressed,', is, important, for, understanding, bHLH, 'PAS', factor, biology])].
[sujeto(['MAGED1']), verbo([binds]), complemento([and, positively, regulates, the, transcriptional, activity, of, family, members, 'SIM1,', 'SIM2,', 'NPAS4', and, 'ARNT2,', but, does, not, interact, with, 'AhR,', 'HIF1α', and, 'ARNT'])].
[sujeto(['This', interaction, is]), verbo([mediated]), complemento([by, 'PAS', repeat, regions, which, also, form, the, interface, for, bHLH, 'PAS', 'dimerisation,', and, accordingly, 'MAGED1', is, not, found, in, complex, with, bHLH, 'PAS', dimers])].
[sujeto(['We', show, that, 'MAGED1', does, not, affect, bHLH, 'PAS', protein, levels, and, cannot, be]), verbo([acting]), complemento([as, a, coactivator, of, transcriptionally, active, 'heterodimers,', but, rather, appears, to, interact, with, nascent, bHLH, 'PAS', proteins, in, the, cytoplasm, to, enhance, their, function, prior, to, nuclear, import])].
[sujeto(['YycG,', a, key, 'two-component', histidine, kinase, in, 'Staphylococcus', 'aureus,', plays, an, essential, role, in, cell, viability, and]), verbo([regulates]), complemento([cell, wall, 'metabolism,', biofilm, 'formation,', 'virulence,', and, antibiotic, resistance])].
[sujeto(['For', these, 'reasons,', 'YycG', is, considered, a, compelling]), verbo([target]), complemento([for, the, development, of, novel, antibiotics])].
[sujeto(['From', these, 'results,', we, propose, that, signaling, through, 'YycG', is]), verbo([regulated]), complemento([by, multimerization, and, binding, of, 'YycH', and, 'YycI'])].
[sujeto(['These', structural, 'studies,', combined, with, biochemical, 'analyses,']), verbo([provide]), complemento([a, better, understanding, of, the, signaling, mechanism, of, 'YycG,', which, is, necessary, for, developing, novel, antibacterial, drugs, targeting, 'S'])].
[sujeto(['Recently,', methylation, in, a, 'non-CpG', context, was]), verbo([found]), complemento([to, occur, widely, on, genomic, 'DNA'])].
[sujeto(['To', study, 'non-CpG', methylation, effects, on, 'DNA/protein', 'interactions,', we]), verbo([have]), complemento([chosen, three, human, transcription, factors, '(', 'TFs):', glucocorticoid, receptor, '(', 'GR),', brain, and, muscle, 'ARNT-like', 1, '(', 'BMAL1)', -, circadian, locomotor, output, cycles, kaput, '(', 'CLOCK)', and, estrogen, receptor, '(', 'ER)', with, methylated, or, unmethylated, 'DNA', binding, 'sequences,', using, 'single-molecule', and, isothermal, titration, calorimetry, assays])].
[sujeto(['The', results, demonstrated, that, these, 'TFs']), verbo([interact]), complemento([with, methylated, 'DNA', with, different, effects, compared, with, their, cognate, 'DNA', sequences])].
[sujeto(['With', 'BisChIP-seq', assays, in, 'HEK-293T', 'cells,', we]), verbo([found]), complemento([that, 'GR', can, recognize, highly, methylated, sites, within, chromatin, in, cells])].
[sujeto(['Therefore,', we, conclude, that, 'non-CpG', methylation, of, 'DNA', can]), verbo([provide]), complemento([a, mechanism, for, regulating, gene, expression, through, directly, affecting, the, binding, of, 'TFs'])].
[sujeto(['The', 'AHR', is]), verbo([involved]), complemento([in, hematopoietic, stem, cell, '(', 'HSC)', functions, including, 'self-renewal,', 'proliferation,', 'quiescence,', and, differentiation])].
[sujeto(['We', hypothesize, that, 'AHR', impacts, 'HSC', functions, by, influencing, genes, that]), verbo([have]), complemento([roles, in, 'HSC', maintenance, and, function, and, that, this, may, occur, through, regulation, of, bone, marrow, '(', 'BM)', niche, cells])].
[sujeto(['We']), verbo([report]), complemento([changes, in, 'HSCs', and, peripheral, blood, cells, in, mice, lacking, 'AHR'])].
[sujeto(['Serial', transplantation, assays, revealed, a, significant]), verbo([increase]), complemento([in, long, term, 'HSCs'])].
[sujeto(['There', was, a, significant]), verbo([increase]), complemento([in, mesenchymal, stem, cells, constituting, the, endosteal, 'BM', niche])].
[sujeto(['Gene', expression, analyses, of, 'HSCs', revealed, an]), verbo([increase]), complemento([in, expression, of, genes, involved, in, proliferation, and, maintenance, of, quiescence])].
[sujeto(['Our', studies, infer, that]), verbo([loss]), complemento([of, 'AHR', results, in, increased, proliferation, and, 'self-renewal', of, long, term, 'HSCs,', in, 'part,', by, influencing, the, microenvironment, in, the, niche, regulating, the, balance, between, quiescence, and, proliferation, in, 'HSCs'])].
[sujeto(['Various', retinal, degenerative, diseases, including, dry, and, neovascular, 'age-related', macular, degeneration, '(', 'AMD),', retinitis, 'pigmentosa,', and, diabetic, retinopathy, are]), verbo([associated]), complemento([with, the, degeneration, of, the, retinal, pigmented, epithelial, '(', 'RPE)', layer, of, the, retina])].
[sujeto(['This', consequently, results, in, the, death, of, rod, and, cone, photoreceptors, that, they, 'support,', structurally, and, functionally]), verbo([leading]), complemento([to, legal, or, complete, blindness])].
[sujeto(['The', aryl, hydrocarbon, receptor, '(', 'AhR)', is, a, 'conserved,', environmental, 'ligand-dependent,', per, 'ARNT-sim', '(', 'PAS)', domain, containing, bHLH, transcription, factor, that]), verbo([mediates]), complemento([adaptive, response, to, stress, via, its, downstream, transcriptional, targets])].
[sujeto(['Using', in, 'silico,', in, vitro, and, in, vivo, 'assays,', we, identified, 2, ',', 2, '\'', -, aminophenyl, indole, '(', 2, 'AI)', as, a, potent, synthetic, ligand, of, 'AhR', that, protects, 'RPE', cells, in, vitro, from, lipid, peroxidation, cytotoxicity]), verbo([mediated]), complemento([by, 4, -, hydroxynonenal, '(', 4, 'HNE)', as, well, as, the, retina, in, vivo, from, 'light-damage'])].
[sujeto(['Additionally,', metabolic, characterization, of, this, molecule, by, 'LC-MS']), verbo([suggests]), complemento([that, 2, 'AI', alters, the, lipid, metabolism, of, 'RPE', 'cells,', enhancing, the, intracellular, levels, of, palmitoleic, acid])].
[sujeto(['Finally,', we, show, 'that,', as, a, downstream, effector, of, 2, 'AI-mediated', 'AhR', 'activation,', palmitoleic, acid, protects, 'RPE', cells, from, 4, 'HNE-mediated', 'stress,', and, light]), verbo([mediated]), complemento([retinal, degeneration, in, mice])].
[sujeto(['Cardiac', amyloid, load]), verbo([has]), complemento([not, been, analyzed, for, its, effect, on, mortality, in, patients, with, amyloid, 'light-chain', '(', 'AL)', cardiac, amyloidosis])].
[sujeto(['Patients', 'with&nbsp;&lt;20%', 'AL', amyloid, load, who]), verbo([responded]), complemento([to, chemotherapy, showed, significantly, better, survival, than, nonresponders])].
[sujeto(['Early', identification, of, subjects, with, 'AL', amyloid, is, essential, given, that, in, 'late-stage', disease, with, extensive, amyloid, 'load,', our, data]), verbo([suggested]), complemento([that, outcomes, are, not, affected, by, administration, of, chemotherapy])].
[sujeto(['The', 'hypoxia-inducible', factor, complex, '(', 'HIF-α·aryl', hydrocarbon, receptor]), verbo([nuclear]), complemento([translocator, '(', 'ARNT))', requires, association, with, several, transcription, coactivators, for, a, successful, cellular, response, to, hypoxic, stress])].
[sujeto(['In', addition, to, the, conventional, global, transcription, coactivator, 'CREB-binding', 'protein/p300', '(', 'CBP/p300)', that]), verbo([binds]), complemento([to, the, 'HIF-α', transactivation, 'domain,', a, new, group, of, transcription, coactivators, called, the, 'coiled-coil', coactivators, '(', 'CCCs)', interact, directly, with, the, second, 'PER-ARNT-SIM', '(', 'PAS)', domain, of, 'ARNT', '(', 'ARNT', 'PAS-B)'])].
[sujeto(['These', less, studied, transcription, coactivators, play, essential, roles, in, the, 'HIF-dependent', hypoxia, 'response,', and, 'CCC', misregulation, is]), verbo([associated]), complemento([with, several, forms, of, cancer])].
[sujeto(['We']), verbo([found]), complemento([that, the, 'HIF-2α', 'PAS-B', domain, also, directly, interacts, with, 'TACC3,', motivating, an, 'NMR', 'data-derived', model, suggesting, a, means, by, which, 'TACC3', could, form, a, ternary, complex, with, 'HIF-2α', 'PAS-B', and, 'ARNT', 'PAS-B', via, 'β-sheet/coiled-coil', interactions])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'TACC3', could, be, recruited, as, a, bridge, to, cooperatively, mediate, between, the, 'HIF-2α', 'PAS-B·ARNT', 'PAS-B', 'complex,', thereby, participating, more, directly, in, 'HIF-dependent', gene, transcription, than, previously, anticipated])].
[sujeto(['For', several, 'well-documented', 'reasons,', it]), verbo([has]), complemento([been, challenging, to, develop, artificial, small, molecule, inhibitors, of, 'protein/protein', complexes])].
[sujeto(['Here', we]), verbo([report]), complemento([parallel, approaches, to, identify, regulators, of, a, hypoxia, signaling, transcription, factor, 'complex,', involving, the, 'ARNT', subunit, of, the, 'HIF', '(', 'Hypoxia', 'Inducible', 'Factor)', activator, and, the, 'TACC3', '(', 'Transforming', 'Acidic', 'Coiled', 'Coil', 'Containing', 'Protein', 3, ')', coactivator])].
[sujeto(['In', one, 'route,', we, used, in, vitro, 'NMR', and, biochemical, screening, to, identify, small, molecules, that, selectively]), verbo([bind]), complemento([within, the, 'ARNT', 'PAS', '(', 'Per-ARNT-Sim)', domain, that, recruits, 'TACC3,', identifying, 'KG-548', as, an, 'ARNT/TACC3', disruptor])].
[sujeto(['Hypoxia-inducible', factor, '(', 'HIF)', is, the, key, transcriptional, effector, of, the, hypoxia, response, in, 'eukaryotes,', coordinating, the, expression, of, genes]), verbo([involved]), complemento([in, oxygen, 'transport,', 'glycolysis,', and, angiogenesis, to, promote, adaptation, to, low, oxygen, levels])].
[sujeto(['HIF', is, a, basic, 'helix-loop-helix', '(', 'bHLH)-PAS', '(', 'PER-ARNT-SIM)', heterodimer, composed, of, an, 'oxygen-labile', 'HIF-α', subunit, and, a, constitutively]), verbo([expressed]), complemento([aryl, hydrocarbon, receptor, nuclear, translocator, '(', 'ARNT)', 'subunit,', which, dimerize, via, basic, 'helix-loop-helix', and, 'PAS', 'domains,', and, recruit, coactivators, via, 'HIF-α', 'C-terminal', transactivation, domains])].
[sujeto(['Here', we, demonstrate, that, the, 'ARNT', 'PAS-B', domain]), verbo([provides]), complemento([an, additional, recruitment, site, by, binding, the, coactivator, transforming, acidic, 'coiled-coil', 3, '(', 'TACC3)', in, a, step, necessary, for, transcriptional, responses, to, hypoxia])].
[sujeto(['Structural', insights, from, 'NMR', spectroscopy, illustrate, how, this, 'PAS', domain, simultaneously]), verbo([mediates]), complemento([interactions, with, 'HIF-α', and, 'TACC3'])].
[sujeto(['Finally,', mutations, on, 'ARNT', 'PAS-B']), verbo([modulate]), complemento([coactivator, selectivity, and, target, gene, induction, by, 'HIF', in, 'vivo,', demonstrating, a, bifunctional, role, for, transcriptional, regulation, by, 'PAS', domains, within, 'bHLH-PAS', transcription, factors])].
[sujeto(['BpRc1', cells, are, a, hepa1c1c7, variant, defective, in, 'HIF-beta/aryl', hydrocarbon, receptor]), verbo([nuclear]), complemento([translocator, '(', 'Arnt),', and, are, therefore, unable, to, induce, 'HIF', target, genes, in, response, to, hypoxia])].
[sujeto(['By', comparing, hepa1c1c7, cells, with, 'BpRc1', 'cells,', we, were, able, to, investigate, 'hypoxia-regulated', gene, expression, as, well, as, the, role, played, by, 'HIF', in]), verbo([regulating]), complemento([the, 'hypoxic-dependent', response, of, gene, expression])].
[sujeto(['Only', two, of, the, four, confirmed, genes, were]), verbo([found]), complemento([to, be, repressed, in, an, 'Arnt-dependent', manner])].
[sujeto(['These', analyses, identified, novel, 'hypoxia-regulated', genes, and, confirmed, the, role, of, 'Arnt', and, 'HIF-1alpha', in]), verbo([regulating]), complemento([their, expression])].
[sujeto(['These', results, identify, additional, 'HIF']), verbo([target]), complemento([genes, and, provide, a, more, complete, understanding, of, hypoxia, signaling])].
[sujeto(['The', classical, 'AHR', pathway]), verbo([involves]), complemento([ligand, 'binding,', nuclear, 'translocation,', heterodimerization, with, the, 'AHR', nuclear, translocator, '(', 'ARNT),', and, binding, of, the, heterodimer, to, dioxin, response, elements, '(', 'DREs),', thereby, modulating, the, transcription, of, an, array, of, genes])].
[sujeto(['The', 'AHR']), verbo([has]), complemento([also, been, implicated, in, signaling, events, independent, of, nuclear, localization, and, 'DNA', 'binding,', and, it, has, been, suggested, that, such, pathways, may, play, important, roles, in, the, toxicity, of, 2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD)'])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, generation, of, a, mouse, model, that, expresses, an, 'AHR', protein, capable, of, ligand, 'binding,', interactions, with, chaperone, 'proteins,', functional, heterodimerization, with, 'ARNT,', and, nuclear, 'translocation,', but, is, unable, to, bind, 'DREs'])].
[sujeto(['Using', this, 'model,', we]), verbo([provide]), complemento([evidence, that, 'DNA', binding, is, required, 'AHR-mediated', liver, 'development,', as, 'Ahr(dbd/dbd)', mice, exhibit, a, patent, ductus, 'venosus,', similar, to, what, is, seen, in, 'Ahr(-/-)', mice])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'DNA', binding, is, necessary, for, 'AHR-mediated', developmental, and, toxic, signaling])].
[sujeto(['Aint', was, originally, identified, on, the, basis, of, its, interaction, in, vitro, with, the, aryl, hydrocarbon]), verbo([nuclear]), complemento([receptor, translocator, '(', 'Arnt)'])].
[sujeto(['Arnt', is, a, common, heterodimerization, partner, in, the, basic, 'helix-loop-helix', '(', 'bHLH)-PER-ARNT-SIM', '(', 'PAS)', protein, family, and, is]), verbo([involved]), complemento([in, diverse, biological, functions])].
[sujeto(['In', 'addition,', 'Arnt']), verbo([has]), complemento([a, crucial, role, during, development])].
[sujeto(['Here', we]), verbo([report]), complemento([the, spatiotemporal, expression, of, 'Tacc3', mRNA, and, protein, in, 'embryonic,', postnatally, 'developing,', and, adult, mouse, tissues, using, in, situ, hybridization, and, immunocytochemistry])].
[sujeto(['Tacc3', mRNA, was, highly]), verbo([expressed]), complemento([in, proliferating, cells, of, several, organs, during, murine, development])].
[sujeto(['However,', the, only, adult, tissues]), verbo([expressing]), complemento([high, levels, were, testis, and, ovary])].
[sujeto(['Immunocytochemistry', revealed, that, 'Tacc3', is, a]), verbo([nuclear]), complemento([protein])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'Tacc3', has, an, important, role, in, murine, 'development,', 'spermatogenesis,', and, oogenesis])].
[sujeto(['Basic', 'helix-loop-helix-PER-ARNT-SIM', '(', 'bHLH-PAS)', proteins, form, dimeric, transcription, factors, to]), verbo([mediate]), complemento([diverse, biological, functions, including, xenobiotic, 'metabolism,', hypoxic, 'response,', circadian, rhythm, and, central, nervous, system, midline, development])].
[sujeto(['The', 'Ah', receptor]), verbo([nuclear]), complemento([translocator, protein, '(', 'ARNT)', plays, a, central, role, as, a, common, heterodimerization, partner])].
[sujeto(['Herein,', we, describe, a, 'novel,', embryonically, 'expressed,', 'ARNT']), verbo([interacting]), complemento([protein, '(', 'AINT)', that, may, be, a, member, of, a, larger, 'coiled-coil', 'PAS', interacting, protein, family])].
[sujeto(['The', 'AINT', 'C-terminus']), verbo([mediates]), complemento([interaction, with, the, 'PAS', domain, of, 'ARNT', in, yeast, and, interacts, in, vitro, with, 'ARNT', and, 'ARNT2', specifically])].
[sujeto(['AINT', localizes, to, the, cytoplasm, and, overexpression]), verbo([leads]), complemento([to, 'non-nuclear', localization, of, 'ARNT'])].
[sujeto(['In', this, 'study,', a, 'three-generation', experiment, was, conducted, to, assess, the, reproductive, and, developmental, risks]), verbo([associated]), complemento([with, these, waters, in, 'C57BL/6J', female, 'mice,', including, female, 'reproduction,', pup, 'indices,', reproductive, hormone, 'levels,', and, levels, of, 'AhR,', 'ARNT,', and, 'CYP1A2', in, the, uterus])].
[sujeto(['A', striking]), verbo([finding]), complemento([is, the, 'TCDD', '(', 2, 'ng/l)', and, the, water, samples, significantly, reduced, 'Day', 4, pup, survival, rates, in, the, 'F2', and, 'F3'])].
[sujeto(['Both', 'TCDD', exposure, and, drinking, canal, water]), verbo([decreased]), complemento(['estradiol-17β', '(', 'E2)', levels, in, the, multiparous, females, and, decreased, 'follicle-stimulating', hormone, '(', 'FSH),', luteinizing, hormone, '(', 'LH)', and, 'E2', levels, in, the, virgin, females])].
[sujeto(['These', results, imply, that, the, canal, water, contains, 'AhR', ligands, that, could]), verbo([induce]), complemento([similar, toxic, effects, as, do, low, levels, of, 'TCDD'])].
[sujeto(['Considering', this, canals, are, open, directly, to, 'Pearl', 'River,', whether, these, effects, could, be]), verbo([caused]), complemento([in, human, reproduction, and, development, warrants, further, study])].
[sujeto(['Cyp1a1', induction]), verbo([requires]), complemento(['trans-activation', by, the, heterodimeric, transcriptional, complex, formed, by, the, liganded, 'Ah', receptor, '(', 'AHR)', and, its, 'partner,', 'ARNT'])].
[sujeto(['Previously,', we, showed, that, constitutively]), verbo([bound]), complemento(['HDAC1', dissociates, from, 'Cyp1a1', promoter, chromatin, after, 'ligand-mediated', 'induction,', concomitantly, with, the, recruitment, of, 'AHR/ARNT', complexes, and, p300])].
[sujeto(['Here,', we, investigated, the, hypothesis, that, 'HDAC1']), verbo([binding]), complemento([maintains, the, 'Cyp1a1', gene, in, a, silenced, state, in, uninduced, cells])].
[sujeto(['We']), verbo([find]), complemento([that, 'Cyp1a1', induction, by, the, 'AHR/ARNT', is, associated, with, modification, of, specific, chromatin, 'marks,', including, hyperacetylation, of, histone, 'H3K14', and, 'H4K16,', trimethylation, of, histone, 'H3K4,', and, phosphorylation, of, 'H3S10'])].
[sujeto(['HDAC1', and, 'DNMT1', form, complexes, on, the, 'Cyp1a1', promoter, of, uninduced, cells, but, 'HDAC1', inhibition, alone, is, not, sufficient, to]), verbo([induce]), complemento(['Cyp1a1', 'expression,', although, it, allows, for, the, hyperacetylation, of, 'H3K14', and, 'H4K16', to, levels, similar, to, those, found, in, 'B[a]P-induced', cells])].
[sujeto(['The', murine, homologue, of, 'TACC3,', murine, 'erythropoietin-induced', cDNA, '(', 'mERIC-1)', was, also]), verbo([found]), complemento([to, be, upregulated, by, 'Epo', in, the, 'Friend', virus, anaemia, '(', 'FVA)', model, by, differential, 'display-PCR'])].
[sujeto([3, ',']), verbo([has]), complemento([been, cloned, and, encodes, an, 838, -, amino, acid, protein, whose, 'N-', and, 'C-terminal', regions, are, highly, homologous, to, the, shorter, 558, -, amino, acid, murine, 'protein,', 'mERIC-1'])].
[sujeto(['ARNT']), verbo([interacting]), complemento([protein, '(', 'AINT),', a, protein, expressed, during, embryonic, development, in, the, 'mouse,', binds, through, its, coiled, coil, region, to, the, aryl, hydrocarbon, nuclear, translocator, protein, '(', 'ARNT)', and, has, a, central, portion, that, contains, seven, of, the, 24, amino, acid, repeats, found, in, 'mERIC-1'])].
[sujeto(['Thus', 'mERIC-1', and, 'AINT', appear, to, be, developmentally]), verbo([regulated]), complemento([alternative, transcripts, of, the, gene])].
[sujeto(['Maskin', contains, a, peptide, sequence]), verbo([conserved]), complemento([among, 'eIF-4E', binding, proteins, that, is, involved, in, oocyte, development])].
[sujeto(['D-TACC', cooperates, with, another]), verbo([conserved]), complemento(['microtubule-associated', protein, 'Msps', to, stabilise, spindle, poles, during, cell, division])].
[sujeto(['The', diversity, of, function, already, attributed, to, this, protein, 'family,', including, both, transforming, and, tumour, suppressor, 'properties,', should]), verbo([ensure]), complemento([that, a, new, and, interesting, narrative, is, about, to, unfold])].
[sujeto(['The']), verbo([nuclear]), complemento([receptors, '(', 'NR)-farnesoid', 'X', receptor, '(', 'FXR,', 'NR1H4)', and, pregnane, 'X', receptor, '(', 'PXR,', 'NR1I2)', have, important, effects, on, the, expression, of, genes, related, to, the, pharmacokinetics, '(', 'PKs)', of, rosuvastatin])].
[sujeto(['Innate', immune, responses, by, myeloid, cells, decisively, contribute, to, perpetuation, of, central, nervous, system, '(', 'CNS)', autoimmunity, and, their, pharmacologic, modulation, represents, a, promising, strategy, to]), verbo([prevent]), complemento([disease, progression, in, 'Multiple', 'Sclerosis', '(', 'MS)'])].
[sujeto(['Based', on, our, observation, that, peripheral, immune, cells, from, 'relapsing-remitting', and, primary, progressive, 'MS', patients, exhibited, strongly]), verbo([decreased]), complemento([levels, of, the, bile, acid, receptor, 'FXR', '(', 'farnesoid-X-receptor,', 'NR1H4),', we, evaluated, its, potential, relevance, as, therapeutic, target, for, control, of, established, 'CNS', autoimmunity])].
[sujeto(['Pharmacological', 'FXR', activation]), verbo([promoted]), complemento([generation, of, 'anti-inflammatory', macrophages, characterized, by, 'arginase-1,', increased, 'IL-10', 'production,', and, suppression, of, 'T&nbsp;cell', responses])].
[sujeto(['In', 'mice,', 'FXR', activation, ameliorated, 'CNS', autoimmunity, in, an, 'IL-10-dependent', fashion, and, even]), verbo([suppressed]), complemento([advanced, clinical, disease, upon, therapeutic, administration])].
[sujeto(['In', analogy, to, 'rodents,', pharmacological, 'FXR', activation, in, human, monocytes, from, healthy, controls, and, 'MS', patients]), verbo([induced]), complemento([an, 'anti-inflammatory', phenotype, with, suppressive, properties, including, control, of, effector, 'T', cell, proliferation])].
[sujeto(['We', 'therefore,', propose, an, important, role, of, 'FXR', in, control, of, 'T&nbsp;cell-mediated', autoimmunity, by]), verbo([promoting]), complemento(['anti-inflammatory', macrophage, responses])].
[sujeto(['Similar', to, 'FXR,', 'microRNA-192', '(', 'miR-192)', is, mainly]), verbo([expressed]), complemento([in, the, liver, and, colon, and, plays, an, important, role, in, the, pathogenesis, of, colon, carcinoma])].
[sujeto(['In', this, 'study,', we, investigated, the, extent, to, which, 'FXR', is]), verbo([regulated]), complemento([by, 'miR-192'])].
[sujeto(['Two', in, 'silico-predicted']), verbo([binding]), complemento([sites, for, 'miR-192-3p', within, the, 'NR1H4-3\'', untranslated, region, '(', 'UTR)', were, examined, in, vitro, by, luciferase, reporter, assays])].
[sujeto(['To', study, the, effects, of, 'miR-192', on, the, expression, of, 'FXR,', 'FXR']), verbo([target]), complemento([genes, and, cell, 'proliferation,', 'Huh-7', and, 'Caco-2', cells, were, transfected, with, 'miR-192-5p', and, -, 3, p, mimics, or, antagomirs])].
[sujeto(['MiR-192-3p']), verbo([bound]), complemento([specifically, to, the, 'NR1H4-3\'UTR', and, significantly, decreased, luciferase, activity])].
[sujeto(['Transfection', with, 'miR-192']), verbo([led]), complemento([to, significant, decreases, in, 'NR1H4', mRNA, and, protein, levels, as, well, as, the, mRNA, levels, of, the, 'FXR-inducible', bile, acid, transporters, 'OSTα-OSTβ', and, 'OATP1B3'])].
[sujeto(['In', 'summary,', 'microRNA-192']), verbo([suppresses]), complemento([the, expression, of, 'FXR', and, 'FXR', target, genes, in, vitro, and, in, vivo])].
[sujeto(['Neonatal', cholestasis, is, a, potentially, 'life-threatening', condition]), verbo([requiring]), complemento([prompt, diagnosis])].
[sujeto(['Mutations', in, several, different, genes, can]), verbo([cause]), complemento([progressive, familial, intrahepatic, 'cholestasis,', but, known, genes, cannot, account, for, all, familial, cases])].
[sujeto(['Here', we]), verbo([report]), complemento([four, individuals, from, two, unrelated, families, with, neonatal, cholestasis, and, mutations, in, 'NR1H4,', which, encodes, the, farnesoid, 'X', receptor, '(', 'FXR),', a, bile, 'acid-activated', nuclear, hormone, receptor, that, regulates, bile, acid, metabolism])].
[sujeto(['After', a, 'meal,', 'bile-acid', levels]), verbo([increase]), complemento([in, the, 'intestine,', 'liver,', and, also, in, the, systemic, circulation])].
[sujeto(['Recent', studies]), verbo([have]), complemento([described, bile, acids, as, versatile, signaling, molecules, endowed, with, systemic, endocrine, functions])].
[sujeto(['Bile', acids, are, ligands, for, 'G-protein', coupled, receptors, '(', 'GPCRs)', such, as, 'TGR5', '(', also, known, as, 'GPBAR1,', 'M-BAR,', and, 'BG37)', and]), verbo([nuclear]), complemento([hormone, receptors, including, farnesoid, 'X', receptor, '(', 'FXR;', also, known, as, 'NR1H4)'])].
[sujeto(['Acting', through, these, diverse, signaling, 'pathways,', bile, acids]), verbo([regulate]), complemento(['triglyceride,', 'cholesterol,', glucose, 'homeostasis,', and, energy, expenditure])].
[sujeto(['These', 'bile-acid-controlled', signaling, pathways]), verbo([have]), complemento([become, the, source, of, promising, novel, drug, targets, to, treat, common, metabolic, and, hepatic, diseases])].
[sujeto(['Understanding', of, molecular, mechanisms]), verbo([involved]), complemento([in, disease, pathogenesis, is, important, for, the, development, of, therapeutic, and, preventive, strategies])].
[sujeto(['This', result, was, confirmed, by]), verbo([decreased]), complemento(['high-density', lipoprotein, cholesterol, in, serum, of, infected, pigs])].
[sujeto(['Furthermore,', miRNA, analysis, of, ileum, at, 2, dpi, revealed, 62, miRNAs, potentially]), verbo([regulating]), complemento([target, genes, involved, in, this, inflammatory, process, '(', e])].
[sujeto(['In', 'colon,', genes]), verbo([involved]), complemento([in, epithelial, 'adherence,', proliferation, and, cellular, reorganization, were, 'down-regulated', at, 2, and, 6, dpi])].
[sujeto(['They', are, now, known, to, be]), verbo([involved]), complemento([in, the, regulation, of, multiple, functions, in, liver, 'cells,', mainly, hepatocytes, and, 'cholangiocytes,', and, also, in, extrahepatic, tissues])].
[sujeto(['The', identification, of]), verbo([nuclear]), complemento(['receptors,', such, as, farnesoid, 'X', receptor, '(', 'FXR', or, 'NR1H4),', and, plasma, membrane, 'receptors,', such, as, the, 'G', 'protein-coupled', bile, acid, receptor, '(', 'TGR5,', 'GPBAR1', or, 'MBAR),', which, are, able, to, trigger, specific, and, complex, responses, upon, activation, '(', with, dissimilar, 'sensitivities)', by, different, bile, acid, molecular, species, and, synthetic, 'agonists,', has, opened, a, new, and, promising, field, of, research, whose, implications, extend, to, 'physiology,', pathology, and, pharmacology])].
[sujeto(['In', 'addition,', pharmacological, development]), verbo([has]), complemento([taken, advantage, of, advances, in, the, understanding, of, the, chemistry, and, biology, of, bile, acids, and, the, biological, systems, that, interact, with, 'them,', which, in, addition, to, the, receptors, include, several, families, of, transporters, and, export, 'pumps,', to, generate, novel, bile, acid, derivatives, aimed, at, treating, different, liver, 'diseases,', such, as, 'cholestasis,', biliary, 'diseases,', metabolic, disorders, and, cancer])].
[sujeto(['Bile', acid, '(', 'BA)', is, de, novo, synthesized, exclusively, in, the, liver, and]), verbo([has]), complemento([direct, or, indirect, antimicrobial, effects])].
[sujeto(['On', the, other, 'hand,', the, composition, and, size, of, the, 'BA', pool, can, be, altered, by, intestinal, microbiota, via, the, biotransformation, of, primary, 'BAs', to, secondary, 'BAs,', and, subsequently]), verbo([regulate]), complemento([the, nuclear, farnesoid, 'X', receptor, '(', 'FXR;', 'NR1H4)'])].
[sujeto(['In', this, 'review,', we, mainly, discuss, the, interactions, between, 'BAs', and, intestinal, microbiota, and, their, roles, in]), verbo([regulating]), complemento([host, 'metabolism,', and, probably, the, autophagic, signaling, pathway])].
[sujeto(['The', lower, compartment, after, 'Caco2-transport', experiments, 'up-regulated', 'LDLR', and]), verbo([modulated]), complemento([several, other, 'lipid-related', genes, in, 'HepG2', cells])].
[sujeto(['In', 'mice,', 'SFE']), verbo([decreased]), complemento(['TC/HDL', ratio, and, reduced, hepatic, triglycerides, paralleled, with, 'down-regulation', of, 'Dgat1', 'expression,', while, 'EβG', did, it, without, transcriptional, changes])].
[sujeto(['Addition', of, 'SFE', or, ergosterol]), verbo([induced]), complemento([in, jejunum, a, similar, transcriptional, response, to, simvastatin, and, 'ezetimibe;', they, all, 'down-regulated', 'Srebf2', and, 'Nr1h4', '(', 'FXR)', genes])].
[sujeto(['These', extracts, may, be, useful, limiting, hepatic, steatosis, and, as, bioactive, ingredients, to, design, novel, functional, foods]), verbo([preventing]), complemento(['lifestyle-related', diseases, such, as, 'non-alcoholic', fatty, liver, disease])].
[sujeto(['LXR', '(', encoded, by, 'NR1H2', and, 3, ')', and, 'FXR', '(', known, as, bile, acid, 'receptor)', encoded, by, 'NR1H4', '(']), verbo([nuclear]), complemento([receptor, subfamily, 1, ',', group, 'H', and, member, 4, ')', are, nuclear, receptors, in, humans, and, are, important, regulators, of, bile, acid, 'production,', 'cholesterol,', fatty, acid, and, glucose, homeostasis, hence, responsible, for, liver, detoxification])].
[sujeto(['Several', strategies, for, drug, design, with, numerous, ligands, for, this]), verbo([target]), complemento([have, failed, owing, to, the, inability, of, the, ligand, to, access, the, 'target/receptor', or, their, early, metabolisation])].
[sujeto(['In', this, 'work,', we]), verbo([have]), complemento([evaluated, 'FXR', and, 'LXR', structure, bound, with, agonist, and, compared, the, binding, energy, affinity, of, active, ligands, present, in, live, 'green-real', veggies, with, reference, drugs, '(', 'ligands)', present, in, the, market])].
[sujeto(['A', high, throughput, screening, combined, with, molecular, 'docking,', 'absorption,', 'distribution,', 'metabolism,', excretion, and, toxicity, '(', 'ADMET)', 'predictions,', log, 'P', values, and, percentage, of, human, oral, absorption, value]), verbo([led]), complemento([to, the, identification, of, two, compounds, present, in, live, 'green-real', veggies, with, strong, potential, for, liver, detoxification])].
[sujeto(['The']), verbo([nuclear]), complemento([receptor, farnesoid, 'X', receptor, '(', 'FXR)', '(', nuclear, receptor, subfamily, 1, ',', group, 'H,', member, 4, ',', or, 'NR1H4)', is, highly, expressed, in, the, liver, and, intestine])].
[sujeto(['Previous']), verbo([reports]), complemento([have, suggested, beneficial, functions, of, 'FXR', in, the, homeostasis, of, bile, 'acids,', 'lipids,', and, 'glucose,', as, well, as, in, promoting, liver, regeneration, and, inhibiting, carcinogenesis])].
[sujeto(['To', investigate, the, effect, of, chronic, 'FXR', activation, in, 'vivo,', we, generated, transgenic, mice, that, conditionally, and, tissue, specifically]), verbo([express]), complemento([the, activated, form, of, 'FXR', in, the, liver, and, intestine])].
[sujeto(['The', perinatal, 'toxicity,', which, can, be, rescued, by, a, maternal, vitamin, 'supplement,', may]), verbo([have]), complemento([resulted, from, vitamin, deficiency, due, to, low, biliary, bile, acid, output, as, a, consequence, of, inhibition, of, bile, acid, formation])].
[sujeto(['Our', results, also]), verbo([suggested]), complemento([that, the, fibroblast, growth, 'factor-inducible', 'immediate-early', response, protein, 14, '(', 'Fn14),', a, member, of, the, proinflammatory, 'TNF', 'family,', is, a, 'FXR-responsive', gene])].
[sujeto(['Because', 'FXR', is, being, explored, as, a, therapeutic, 'target,', our, results]), verbo([suggested]), complemento([that, a, chronic, activation, of, this, nuclear, receptor, may, have, an, unintended, side, effect, especially, during, the, perinatal, stage])].
[sujeto(['Pigs', are, well]), verbo([recognized]), complemento([as, a, model, for, humans, in, research, studies, due, to, similarities, in, metabolism, and, physiology, between, the, two, species])].
[sujeto(['The', potential, for, pigs, to, model, humans, in, studying, metabolic, diseases, is, highly, dependent, on, similarities, in, hepatic, metabolism, between, the, two, 'species,', including, similarities, in, the, farnesoid, 'X', receptor, '(', 'FXR;', 'NR1H4)', which]), verbo([regulate]), complemento([bile, acid, homeostasis])].
[sujeto(['Treatment', with, the, tyrosine, phosphatase, inhibitor, sodium, orthovanadate, '(', 'Na3VO4)']), verbo([increased]), complemento([the, dominant, positive, effect, of, 'pFXR-SV1', by, about, 30, '%'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, dominant, positive, effect, may, be, dependent, on, the, phosphorylation, status, of, the, tyrosine, in, the, 'MYTG', insert])].
[sujeto(['The', human, variant, 'hFXRα+']), verbo([has]), complemento([the, same, 'MYTG', insert, as, 'pFXR-SV1,', but, did, not, cause, a, dominant, positive, effect, on, 'hFXR-WT', and, significantly, reduced, the, activity, of, 'hFXR-WT'])].
[sujeto(['Thus,', although, the, 'MYTG', insert, is]), verbo([conserved]), complemento([in, both, human, and, 'pig,', the, effects, of, this, insert, are, different, in, the, two, species])].
[sujeto(['Autophagy', is, an, evolutionarily]), verbo([conserved]), complemento([catabolic, process, that, recycles, nutrients, upon, starvation, and, maintains, cellular, energy, homeostasis])].
[sujeto(['The']), verbo([nuclear]), complemento([receptors, peroxisome, 'proliferator-activated', 'receptor-α', '(', 'PPARα)', and, farnesoid, 'X', receptor, '(', 'FXR)', are, activated, in, the, fasted, and, fed, 'liver,', respectively])].
[sujeto(['Here', we, show, that, both, 'PPARα', and, 'FXR']), verbo([regulate]), complemento([hepatic, autophagy, in, mice])].
[sujeto(['Pharmacological', activation, of, 'PPARα', reverses, the, normal, suppression, of, autophagy, in, the, fed, 'state,']), verbo([inducing]), complemento([autophagic, lipid, 'degradation,', or, lipophagy])].
[sujeto(['Pharmacological', activation, of, the, bile, acid, receptor, 'FXR', strongly]), verbo([suppresses]), complemento([the, induction, of, autophagy, in, the, fasting, 'state,', and, this, response, is, absent, in, 'FXR', knockout, '(', 'Fxr(-/-),', also, known, as, 'Nr1h4(-/-))', 'mice,', which, show, a, partial, defect, in, suppression, of, hepatic, autophagy, in, the, fed, state])].
[sujeto(['PPARα', and, 'FXR', compete, for]), verbo([binding]), complemento([to, shared, sites, in, autophagic, gene, 'promoters,', with, opposite, transcriptional, outputs])].
[sujeto(['These', results]), verbo([reveal]), complemento(['complementary,', interlocking, mechanisms, for, regulation, of, autophagy, by, nutrient, status])].
[sujeto(['Retinoic', acid, '(', 'RA)', and, bile, acids, share, common, roles, in]), verbo([regulating]), complemento([lipid, homeostasis, and, insulin, sensitivity])].
[sujeto(['Thus,', 'RA', can]), verbo([activate]), complemento([the, 'FXR-mediated', pathway, as, well])].
[sujeto(['Mice', were, fed, an, 'all-trans', 'RA-supplemented', diet, and, the, expression, of, 46, genes, that]), verbo([participate]), complemento([in, regulating, bile, acid, homeostasis, was, studied])].
[sujeto(['The', data, showed, that, 'all-trans', 'RA']), verbo([has]), complemento([a, profound, effect, in, regulating, genes, involved, in, synthesis, and, transport, of, bile, acids])].
[sujeto(['All-trans', 'RA', treatment, reduced, the, gene, expression, levels, of, 'Cyp7a1,', 'Cyp8b1,', and, 'Akr1d1,', which, are]), verbo([involved]), complemento([in, bile, acid, synthesis])].
[sujeto(['All-trans', 'RA', also]), verbo([decreased]), complemento([the, hepatic, mRNA, levels, of, 'Lrh-1', '(', 'Nr5a2)', and, 'Hnf4α', '(', 'Nr2a1),', which, positively, regulate, the, gene, expression, of, 'Cyp7a1', and, 'Cyp8b1'])].
[sujeto(['Moreover,', 'all-trans', 'RA']), verbo([induced]), complemento([the, gene, expression, levels, of, negative, regulators, of, bile, acid, synthesis, including, hepatic, 'Fgfr4,', 'Fxr,', and, 'Shp', '(', 'Nr0b2)', as, well, as, ileal, 'Fgf15'])].
[sujeto(['All-trans', 'RA', also]), verbo([decreased]), complemento([the, expression, of, 'Abcb11', and, 'Slc51b,', which, have, a, role, in, bile, acid, transport])].
[sujeto(['The', data]), verbo([suggest]), complemento([that, 'all-trans', 'RA-induced', 'SHP', may, contribute, to, the, inhibition, of, 'CYP7A1', and, 'CYP8B1,', which, in, turn, reduces, bile, acid, synthesis, and, affects, lipid, absorption, in, the, gastrointestinal, tract])].
[sujeto(['Farnesoid', 'X', receptor, '(', 'FXR,', 'NR1H4)', is, a, bile, 'acid-activated', transcription, factor, that, belongs, to, the]), verbo([nuclear]), complemento([receptor, superfamily])].
[sujeto(['It', is, highly]), verbo([expressed]), complemento([in, the, enterohepatic, 'system,', where, it, senses, bile, acid, levels, to, consequently, reduce, their, synthesis, while, inducing, their, detoxification])].
[sujeto(['Bile', acids, are, intestinal, tumor, promoters, and, their, concentrations]), verbo([have]), complemento([to, be, tightly, regulated])].
[sujeto(['Indeed,', reduced, expression, of, 'FXR', in, the, intestine]), verbo([increases]), complemento([colorectal, cancer, susceptibility, in, 'mice,', whereas, its, activation, can, promote, apoptosis, in, genetically, modified, cells])].
[sujeto(['Notably,', despite, the, broad, knowledge, of, the, 'FXR', enterohepatic, transcriptional, 'activity,', the, molecular, mechanisms]), verbo([regulating]), complemento(['FXR', expression, in, the, intestine, are, still, unknown])].
[sujeto(['Herein,', by, combining, both]), verbo([gain]), complemento([and, loss, of, function, approaches, and, 'FXR', promoter, activity, 'studies,', we, identified, 'caudal-related', homeobox, 2, '(', 'CDX2)', transcription, factor, as, a, positive, regulator, of, 'FXR', expression, in, the, enterocytes])].
[sujeto(['Our', results]), verbo([provide]), complemento([a, putative, novel, tool, for, modulating, 'FXR', expression, against, bile, 'acid-related', colorectal, cancer, progression])].
[sujeto(['Despite', the, mortality]), verbo([associated]), complemento([with, liver, disease, observed, in, patients, with, short, bowel, syndrome, '(', 'SBS),', mechanisms, underlying, the, development, of, 'SBS-associated', liver, disease, '(', 'SBS-ALD)', are, poorly, understood])].
[sujeto(['Gene', expression, of, intestinal, and, hepatic, 'FXR']), verbo([target]), complemento([genes, and, small, heterodimer, partner, '(', 'SHP)', transrepression, targets, were, assessed])].
[sujeto(['Microbiota', changes, included, a, 10, -, fold]), verbo([decrease]), complemento([in, 'Clostridium', and, a, 'two-fold', decrease, in, 'Bacteroides', in, 'SBS-ALD', piglets])].
[sujeto(['Intestinal', and, hepatic, regulation, of, 'BA', synthesis, was, characterised, by, a, blunted, intestinal, 'FXR', activation, response, and, a, failure, of, 'SHP', to]), verbo([repress]), complemento([key, hepatic, targets])].
[sujeto(['Furthermore', alterations, in, 'BA', composition, may]), verbo([have]), complemento([contributed, to, the, observed, disturbance, in, 'FXR-mediated', signalling, pathways])].
[sujeto(['These', findings]), verbo([provide]), complemento([an, insight, into, the, complex, mechanisms, mediating, the, development, of, liver, disease, in, patients, with, 'SBS'])].
[sujeto(['Bariatric', surgical, 'procedures,', such, as, vertical, sleeve, gastrectomy, '(', 'VSG),', are, at, present, the, most, effective, therapy, for, the, treatment, of, 'obesity,', and, are]), verbo([associated]), complemento([with, considerable, improvements, in, 'co-morbidities,', including, 'type-2', diabetes, mellitus])].
[sujeto(['The', underlying, molecular, mechanisms, contributing, to, these, benefits, remain, largely, 'undetermined,', despite, offering, the, potential, to]), verbo([reveal]), complemento([new, targets, for, therapeutic, intervention])].
[sujeto(['Moreover,', bile, acids, are, known, to]), verbo([regulate]), complemento([metabolism, by, binding, to, the, nuclear, receptor, 'FXR', '(', 'farsenoid-X', 'receptor,', also, known, as, 'NR1H4)'])].
[sujeto(['We', therefore, examined, the, results, of, 'VSG', surgery, applied, to, mice, with, 'diet-induced', obesity, and]), verbo([targeted]), complemento([genetic, disruption, of, 'FXR'])].
[sujeto(['Rather,', 'VSG', is]), verbo([associated]), complemento([with, increased, circulating, bile, 'acids,', and, associated, changes, to, gut, microbial, communities])].
[sujeto(['Prenatal', forms, of, autosomal, dominant, polycystic, kidney, disease, '(', 'ADPKD)', are, rare, but, can, be, recurrent, in, some, 'families,']), verbo([suggesting]), complemento([a, common, genetic, modifying, background])].
[sujeto(['Few', patients]), verbo([have]), complemento([been, reported, 'carrying,', in, addition, to, the, familial, 'mutation,', 'variation(s)', in, polycystic, kidney, disease, 1, '(', 'PKD1)', or, 'HNF1', homeobox, 'B', '(', 'HNF1B),', inherited, from, the, unaffected, 'parent,', or, biallelic, polycystic, kidney, and, hepatic, disease, 1, '(', 'PKHD1)', mutations])].
[sujeto(['To', assess, the, frequency, of, additional, variations, in, 'PKD1,', 'PKD2,', 'HNF1B,', and, 'PKHD1']), verbo([associated]), complemento([with, the, familial, 'PKD', mutation, in, early, 'ADPKD,', these, four, genes, were, screened, in, 42, patients, with, early, 'ADPKD', in, 41, families])].
[sujeto(['Two', patients, were]), verbo([associated]), complemento([with, de, novo, 'PKD1', mutations])].
[sujeto(['Forty', patients, occurred, in, 39, families, with, known, 'ADPKD', and, were]), verbo([associated]), complemento([with, 'PKD1', mutation, in, 36, families, and, with, 'PKD2', mutation, in, two, families, '(', no, mutation, identified, in, one, 'family)'])].
[sujeto(['These', results]), verbo([suggest]), complemento(['that,', at, least, in, some, 'patients,', the, severity, of, the, cystic, disease, is, inversely, correlated, with, the, level, of, polycystin, 1, function])].
[sujeto(['In', the, vast, majority, of, these, 'cases,', the, genomic, lesion, was, unsuspected, based, on, the, clinical, assessment, and, either, reclassified, the, disease, or]), verbo([provided]), complemento([information, that, might, have, triggered, additional, clinical, 'care,', such, as, evaluation, for, metabolic, or, neuropsychiatric, disease])].
[sujeto(['A', substantial, proportion, of, children, with, 'CKD']), verbo([have]), complemento([an, unsuspected, genomic, 'imbalance,', suggesting, genomic, disorders, as, a, risk, factor, for, common, forms, of, pediatric, nephropathy])].
[sujeto(['Detection', of, pathogenic, imbalances]), verbo([has]), complemento([practical, implications, for, personalized, diagnosis, and, health, monitoring, in, this, population])].
[sujeto(['Here,', we, demonstrate, that, 'HNFA', and, 'MIA2', are]), verbo([expressed]), complemento([in, a, subset, of, human, 'PDAC', tissues, and, that, 'HNF1A', induced, 'MIA2', in, vitro])].
[sujeto(['I141M)']), verbo([associated]), complemento([with, a, secretory, defect, of, the, 'MIA2', protein, in, 'PDAC', cells])].
[sujeto(['The', 'MIA2(I141M)', variant, was]), verbo([associated]), complemento([with, high, expression, of, 'ER', 'stress/UPR', 'genes--in', particular, those, of, the, 'ERN1/XBP', 'arm--in', human, 'PDAC', samples])].
[sujeto(['Accordingly,', 'PDAC', cell, lines]), verbo([expressing]), complemento([the, 'MIA2(I141M)', variant, expressed, high, levels, of, 'ERN1', and, were, more, sensitive, to, gemcitabine])].
[sujeto(['The', expression, of, 'HNF1', homeobox, 'B', '(', 'HNF1B)', is]), verbo([associated]), complemento([with, cancer, risk, in, several, 'tumors,', including, ovarian, 'cancer,', and, its, decreased, expression, play, roles, in, cancer, development])].
[sujeto(['However,', the, study, of, 'HNF1B', and, cancer, is, 'limited,', and, its, association, with, drug, resistance, in, cancer]), verbo([has]), complemento([never, been, reported])].
[sujeto(['On', the, basis, of, array, data, retrieved, from, 'Oncomine', and, 'Gene', 'Expression', 'Omnibus&nbsp;(GEO)', online, 'database,', we]), verbo([found]), complemento([that, the, mRNA, expression, of, 'HNF1B', in, 586, &, 'nbsp;ovarian', serous, cystadenocarcinomas, and, in, 'platinum-resistant', 'A2780', epithelial, ovarian, cancer, cells, was, significantly, 'decreased,', indicating, a, potential, role, of, 'HNF1B', in, drug, resistance, in, ovarian, cancer])].
[sujeto(['We']), verbo([found]), complemento([that, among, the, 'proteins/genes,', small, 'molecules/chemicals', and, microRNAs, which, directly, interacted, with, 'HNF1B,', the, majority, was, associated, with, drug, resistance, in, 'cancer,', particularly, in, ovarian, cancer])].
[sujeto(['Biological', process, annotation, revealed, that, 'HNF1B', closely, related, to, 24, biological, processes, which, were, all, notably]), verbo([associated]), complemento([with, ovarian, cancer, and, drug, resistance])].
[sujeto(['Fructooligosaccharides', '(', 'FOS)', are, indigestible, oligosaccharides, that]), verbo([increase]), complemento([the, expression, of, 'calbindin-D9k', and, consequently, increase, calcium, absorption, by, the, colon, in, rats])].
[sujeto(['The', molecular, mechanism, of, the]), verbo([increased]), complemento([expression, of, 'calbindin-D9k', resulting, from, 'FOS', ingestion, has, not, been, elucidated])].
[sujeto(['Short-chain', fatty, acids, '(', 'SCFAs),', 'namely,', fermentation, products, of, 'FOS', by, intestinal, bacteria]), verbo([have]), complemento([been, hypothesized, as, direct, effectors, of, 'calbindin-D9k', gene, expression])].
[sujeto(['To', test, this, 'hypothesis,', 'SCFAs', were, added, to, 'Caco-2', human, intestinal, epithelial, 'cells,', and, changes, in, the, levels, of, transcription, of, genes, for, 'calbindin-D9k,', and, transcription, factors, '(', vitamin, 'D', 'receptor:', 'VDR,', caudal, 'homeobox-2:', 'Cdx-2,', hepatocyte]), verbo([nuclear]), complemento([factor, 1, -, 'α:', 'HNF1-α)', were, determined, by, quantitative, reverse, transcription, polymerase, chain, reaction])].
[sujeto(['Addition', of, sodium, propionate, or, sodium, butyrate, to, cell, cultures]), verbo([increased]), complemento([levels, of, 'calbindin-D9k', mRNA, to, 731, '%', '(', 'p&lt;0'])].
[sujeto(['In', 'conclusion,', addition, of, 'SCFAs', to, cultured, 'Caco-2', cells, results, in, elevation, of, 'calbindin-D9k', 'mRNA,', consistent, with, the, expected, role, of, 'SCFAs', as, mediators, of, the]), verbo([increase]), complemento([of, calcium, absorption, in, rats, that, were, fed, with, 'FOS'])].
[sujeto(['The', positioning, of, the, first, molecular, boundary, within, the, hindbrain, '(', the, prospective, 'r4/r5', 'boundary)']), verbo([responds]), complemento([to, the, expression, of, an, 'Iroquois', '(', 'Irx)', gene, in, the, anterior, '(', 'r4)', and, the, gene, vHnf1, at, the, posterior, '(', 'r5)'])].
[sujeto(['However,', while, 'Irx3', is]), verbo([expressed]), complemento([anteriorly, in, 'amniotes,', a, novel, 'Irx', 'gene,', 'iro7,', acts, in, teleosts])].
[sujeto(['To', assess, the, evolutionary, history, of, the, genes, responsible, for, the, positioning, of, the, 'r4/r5', boundary, in, 'vertebrates,', we]), verbo([have]), complemento([stepped, outside, the, gnathostomes, to, investigate, these, genes, in, the, agnathans, 'Lethenteron', japonicum, and, 'Petromyzon', marinus])].
[sujeto(['We', propose, that, the, duplication, of, an, ancestral, hnf1, gene, present, in, the, common, ancestor, of, agnathans, and, gnathostomes, gave, rise, to, the, two, genes]), verbo([found]), complemento([in, gnathostomes])].
[sujeto(['We']), verbo([have]), complemento([also, amplified, 3, 'Irx', genes, in, 'L'])].
[sujeto(['We', hypothesized, that, serum, levels, of, 'high-sensitivity', 'C-reactive', protein, '(', 'hs-CRP)', could, represent, a, clinically, useful, biomarker, for, the, identification, of, 'HNF1A', mutations]), verbo([causing]), complemento(['maturity-onset', diabetes, of, the, young, '(', 'MODY)'])].
[sujeto(['hs-CRP']), verbo([has]), complemento([potential, as, a, widely, 'available,', 'cost-effective', screening, test, to, support, more, precise, targeting, of, 'MODY', diagnostic, testing])].
[sujeto(['We']), verbo([report]), complemento([on, a, patient, who, was, initially, suspected, to, have, 'Beckwith-Wiedemann', syndrome, because, of, recurrent, neonatal, 'hypoglycaemias,', macroglossia, and, 'overgrowth,', but, in, whom, no, 11, p15, abnormality, could, be, found])].
[sujeto(['Follow-up', showed, continued, overgrowth, and, disturbed, glucose, 'homeostasis,', a, marked, developmental, 'delay,', and, severe, behavioural, problems, especially]), verbo([caused]), complemento([by, anxieties])].
[sujeto(['The', deleted, region, contains, amongst, 'others:', 'HNF1', homeobox, 'A', '(', 'HNF1A)', which, is, important, for, the, regulation, of, gene, expression, in, the, liver, and]), verbo([involved]), complemento([in, 'maturity-onset', diabetes, of, the, young, type, 3, and, insulin, 'resistance;', 'acyl-CoA', dehydrogenase, short, chain, '(', 'ACADS)', which, encodes, an, enzyme, important, in, mitochondrial, fatty, acid, 'beta-oxidation', and, can, cause, 'short-chain', 'acyl-CoA', dehydrogenese, '(', 'SCAD)', 'deficiency,', and, purinergic, receptor, 'P2X7', '(', 'P2RX7)', which, encodes, a, 'ligand-gated', ion, 'channel,', and, of, which, polymorphisms, are, found, with, increased, frequency, in, patients, with, psychiatric, 'disorders,', especially, anxieties])].
[sujeto(['We', conclude, the, present, patient]), verbo([has]), complemento([a, hitherto, undescribed, contiguous, gene, 'syndrome,', which, can, initially, resemble, 'Beckwith-Wiedemann', syndrome])].
[sujeto(['Their', jejunal, activities, in, rodents, are]), verbo([induced]), complemento([by, a, 'high-starch/low-fat', '(', 'HS)-diet'])].
[sujeto(['However,', it, is, unknown, whether, jejunal, expression, of, the, 'maltase-glucoamylase', '(', 'Mgam)', gene, is]), verbo([enhanced]), complemento([by, the, 'HS-diet'])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, jejunal, 'Mgam', mRNA, was, increased, by, a, 'HS-diet', in, mice])].
[sujeto(['We', showed, that, the, 'HS-diet']), verbo([increased]), complemento([acetylation, of, 'histones,', bindings, of, a, 'coactivator,', 'Creb', binding, protein, '(', 'CREBBP),', and, the, transcriptional, factors, caudal, type, homeobox, 2, '(', 'CDX2)', and, 'HNF1', homeobox, '(', 'HNF1)', in, the, 'promoter/enhancer', and, transcriptional, regions, of, 'Mgam', gene])].
[sujeto(['This']), verbo([suggests]), complemento([that, the, increase, in, the, jejunal, activity, of, maltase, and, glucoamylase, caused, by, a, 'HS-diet', in, mice, is, regulated, at, the, mRNA, level, through, histone, acetylation, and, binding, of, 'CREBBP,', 'CDX2', and, 'HNF1', in, the, 'promoter/enhancer', and, transcriptional, regions, of, 'Mgam', gene])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factors, 1, alpha, and, beta, '(', 'HNF', 1, alpha, and, 'HNF', 1, 'beta)', activate, the, 'SGLT1', 'promoter,', whereas, 'GATA-binding', protein, 5, '(', 'GATA-5)', and, 'caudal-type', homeobox, protein, 2, '(', 'CDX2)', regulate, transcription, of, other, intestinal, genes])].
[sujeto(['HNF', 1, 'alpha,', 'GATA-5,', and, 'HNF', 1, beta, significantly]), verbo([activated]), complemento([the, 'SGLT1', promoter, '(', 'P', &, 'lt;'])].
[sujeto(['GATA-5', and, 'CDX2', also]), verbo([regulate]), complemento(['SGLT1', promoter, activity, and, show, cooperativity, with, the, 'HNF1s'])].
[sujeto(['We,', 'therefore,', propose, a, multifactorial, model, for, 'SGLT1', 'regulation,', with, interactions, between, 'HNF1,', 'GATA-5,', and, 'CDX2']), verbo([modulating]), complemento([intestinal, glucose, absorption])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento(['factor-6', '(', 'HNF6)', is, a, key, player, in, this, 'network,', because, it, controls, the, initiation, of, the, expression, of, pancreatic, and, duodenal, homeobox, 1, '(', 'Pdx1),', the, earliest, marker, of, pancreatic, precursor, cells])].
[sujeto(['To', further, characterize, this, 'network,', we]), verbo([have]), complemento([investigated, how, the, expression, of, 'HNF6', is, controlled, in, mouse, 'endoderm,', by, using, in, vitro, and, in, vivo, 'protein-DNA', interaction, techniques, combined, with, endoderm, 'electroporation,', 'transgenesis,', and, gene, inactivation, in, embryos])].
[sujeto(['We', delineated, 'Hnf6', regulatory, regions, that]), verbo([confer]), complemento([expression, of, a, reporter, gene, in, the, embryonic, endoderm, but, not, in, extraembryonic, visceral, endoderm])].
[sujeto(['HNF6', expression, in, the, embryonic, endoderm, was]), verbo([found]), complemento([to, depend, on, an, intronic, enhancer])].
[sujeto(['This', enhancer, contains, functional]), verbo([binding]), complemento([sites, for, the, 'tissue-specific', factors, of, the, forkhead, box, 'A', and, 'HNF1', families])].
[sujeto(['Among', the, 'latter,', variant, 'HNF1', '(', 'vHNF1)/TCF2,', which, is]), verbo([expressed]), complemento([before, 'HNF6', in, the, 'endoderm,', was, found, to, be, critical, for, 'HNF6', expression])].
[sujeto(['The', 'UDP', glucuronosyltransferases, '(', 'UGT)', are]), verbo([expressed]), complemento([predominantly, in, the, liver, and, gastrointestinal, tract, in, humans])].
[sujeto(['The', latter, differences, are, most, likely, the, result, of, polymorphisms, in, the, regulatory, elements, of, 'UGT', genes, and, in, the, transcription, factors, that]), verbo([bind]), complemento([to, these, elements])].
[sujeto(['Several', frequent, polymorphisms, in, the, promoters, of, 'UGT', genes]), verbo([have]), complemento([been, 'described;', 'however,', few, of, these, fall, within, critical, regulatory, elements, and, alter, 'UGT', expression])].
[sujeto(['Several', transcription, factors, that]), verbo([regulate]), complemento(['UGT', gene, expression, in, cells, of, hepatic, and, intestinal, origin, have, been, identified])].
[sujeto(['These', include, positive, regulators, of, 'UGT', gene, expression, such, as, hepatocyte]), verbo([nuclear]), complemento([factor, 1, alpha, '(', 'HNF1', 'alpha),', octamer, transcription, 'factor-1', '(', 'Oct-1)', and, the, 'intestine-specific', transcription, 'factor,', 'caudal-related', homeodomain, protein, 2, '(', 'Cdx2)'])].
[sujeto(['Negative', regulators, include, the, 'Pre', 'B', cell, homeobox, factor, '(', 'Pbx2)', and, its, dimerization, 'partner,', 'Pbx']), verbo([regulating]), complemento([protein, 1, '(', 'Prep1)'])].
[sujeto(['Polymorphisms', in, these, transcription, factors, may]), verbo([cause]), complemento([differences, in, their, interaction, and, binding, to, 'UGT', promoters])].
[sujeto(['Knowledge', of, 'UGT', promoter, elements, and, the, proteins, that]), verbo([bind]), complemento([to, these, 'elements,', as, well, as, knowledge, of, polymorphisms, that, alter, their, 'function,', may, aid, in, the, prediction, of, an, 'individual\'s', response, to, chemicals, and, in, the, prediction, of, chemical, toxicities])].
[sujeto(['Homeodomain', transcription, factors, are]), verbo([involved]), complemento([in, many, developmental, processes, and, have, been, intensely, studied, in, a, few, model, 'organisms,', such, as, 'mouse,', 'Drosophila', and, 'Caenorhabditis', elegans])].
[sujeto(['Eight', of, these, groups]), verbo([have]), complemento([been, found, only, in, 'vertebrates,', but, not, in, the, genome, of, the, tunicate, 'Ciona', intestinalis])].
[sujeto(['The', other, 81, groups, of, homeobox, gene, that]), verbo([have]), complemento([been, detected, in, vertebrates, so, far, probably, appeared, during, the, early, evolution, of, bilaterians, or, 'earlier,', as, they, are, also, present, outside, the, chordates])].
[sujeto(['How', the, homeobox, genes, evolved, during, and, after, the, main, radiation, of, the, bilaterians, remains, poorly, 'understood,', as, only, a, few, animal, genomes]), verbo([have]), complemento([been, sequenced, completely])].
[sujeto(['However,', drastic, changes]), verbo([have]), complemento([occurred, at, least, in, the, lineage, of, 'C'])].
[sujeto([elegans, ',', such, as]), verbo([loss]), complemento([of, several, 'Hox', genes, and, 'Hox', cluster, fragmentation])].
[sujeto(['Here', we]), verbo([report]), complemento([considerable, alterations, of, the, homeobox, gene, complement, in, the, tunicate, lineage])].
[sujeto(['In', the, present, 'study,', we]), verbo([found]), complemento([that, the, transcriptional, regulation, of, the, 'beta3Gal-T5', gene, is, controlled, by, 'homeoproteins,', i])].
[sujeto([members, of, 'caudal-related', homeobox, protein, '(', 'Cdx)', and, hepatocyte]), verbo([nuclear]), complemento([factor, '(', 'HNF)', families])].
[sujeto(['We']), verbo([found]), complemento([an, important, region, '(', -, 151, to, -, 121, from, the, transcription, initiation, 'site),', named, the, 'beta3Gal-T5', control, element, '(', 'GCE),', for, the, promoter, activity])].
[sujeto(['Four', 'factors,', 'Cdx1,', 'Cdx2,', 'HNF1alpha,', and, 'HNF1beta,', could]), verbo([bind]), complemento([to, 'GCE', and, transcriptionally, activate, the, 'beta3Gal-T5', gene])].
[sujeto([1, ')', 'During', in, vitro, differentiation, of, 'Caco-2', 'cells,', transcriptional, 'up-regulation', of, 'beta3Gal-T5', was, observed, in, correlation, with, the]), verbo([increase]), complemento([in, transcripts, for, 'Cdx2', and, 'HNF1alpha'])].
[sujeto(['This', 'down-regulation', was, correlated, with, the]), verbo([decrease]), complemento([of, 'Cdx1', and, 'HNF1beta', expression, in, cancer, tissue])].
[sujeto(['This', is, the, first]), verbo([finding]), complemento([that, a, glycosyltransferase, gene, is, transcriptionally, regulated, under, the, control, of, homeoproteins, in, a, 'tissue-specific', manner])].
[sujeto(['Of', the, 83, 'genes,', 76]), verbo([have]), complemento([possible, human, orthologues, and, 7, may, be, unique, to, 'Ciona'])].
[sujeto(['As', to, the, 'Hox', 'cluster,', the, 'Ciona', genome, contains, single, copies, of, each, of, the, paralogous, 'groups,']), verbo([suggesting]), complemento([that, there, is, a, single, 'Hox', 'cluster,', if, 'any,', but, genes, orthologous, to, 'Hox7,', 8, ',', 9, and, 11, were, not, found, in, the, genome])].
[sujeto(['In', 'addition,']), verbo([loss]), complemento([of, genes, had, occurred, independently, in, the, 'Ciona', lineage, and, was, noticed, in, 'Gbx', of, the, 'EHGbox', 'subclass,', 'Sax,', 'NK3,', 'Vax', and, vent, of, the, 'NK', 'class,', 'Cart,', 'Og9,', 'Anf', and, 'Mix', of, the, 'Paired', 'class,', 'POU-I,', 'III,', 'V', and, 'VI', of, the, 'POU', 'class,', 'Lhx6/7', of, the, 'LIM', 'class,', 'TGIF', of, the, 'TALE', 'class,', 'Cux', and, 'SATB', of, the, 'Cut', 'class,', and, 'ZFH1', of, the, 'ZFH', 'class,', which, might, have, reduced, the, number, of, 'Ciona', homeobox, genes])].
[sujeto(['Furthermore,', evidence, for, the, gene, structures, and, expression, of, 54, of, the, 83, homeobox, genes, was]), verbo([provided]), complemento([by, analysis, of, 'ESTs,', suggesting, that, cDNAs, for, these, 54, genes, are, available])].
[sujeto(['The', present, data, thus]), verbo([reveal]), complemento([the, repertoire, of, 'homeodomain-containing', transcription, factors, in, the, 'Ciona', 'genome,', which, will, be, useful, for, future, research, on, the, development, and, evolution, of, chordates])].
[sujeto(['UDP', glucuronosyltransferases, '(', 'UGT)', are]), verbo([expressed]), complemento([in, a, wide, range, of, tissues, in, which, their, levels, of, expression, and, distribution, are, dependent, on, 'cell-type', specific, regulatory, mechanisms])].
[sujeto(['The', presence, of, a, hepatocyte]), verbo([nuclear]), complemento([factor, '(', 'HNF)', 1, binding, site, in, the, proximal, promoters, of, several, 'UGT2B', genes, has, been, shown, to, contribute, to, their, expression, in, liver, cells, and, possibly, other, 'HNF1-containing', cell, types])].
[sujeto(['In', some, of, these, 'UGT2B', 'genes,', a, putative, 'pre-B', cell, homeobox, '(', 'Pbx)', transcription, factor]), verbo([binding]), complemento([site, is, found, directly, adjacent, to, the, functional, 'HNF1', site])].
[sujeto(['To', determine, whether, this, putative, 'Pbx', site, contributes, to, the, regulation, of, 'UGT2B', 'expression,', we, chose, the, 'UGT2B17', gene, and, investigated, the, capacity, of, its, 'Pbx', site, to]), verbo([bind]), complemento([specific, transcription, factors, and, alter, promoter, activity])].
[sujeto(['The', 'UGT2B17', 'Pbx', site, matches, a, consensus, 'Pbx', site, known, to]), verbo([bind]), complemento([members, of, the, 'Pbx,', 'Hox,', 'Meis,', and, 'Prep1', families, of, 'homeodomain-containing', proteins, and, has, previously, been, shown, to, bind, nuclear, proteins, in, 'DNaseI', footprint, assays])].
[sujeto(['In', this, 'study,', we, used, gel, shift, and, functional, assays, to, show, that, a, 'Pbx2-Prep1', heterodimer, can]), verbo([bind]), complemento([to, the, 'UGT2B17', 'Pbx', site, and, interfere, with, the, binding, of, 'HNF1alpha', to, its, site, adjacent, to, the, 'Pbx', site])].
[sujeto(['Modulation', of, transcription, by, restricting, the]), verbo([binding]), complemento([of, transcriptional, effectors, to, their, target, site, is, a, novel, role, for, 'Pbx2-Prep1', complexes])].
[sujeto(['Drosophila', enhancer, of, rudimentary, '[', 'e(r)]']), verbo([interacts]), complemento([genetically, with, the, rudimentary, 'gene,', which, encodes, a, protein, possessing, the, first, three, enzymatic, activities, of, the, pyrimidine, biosynthesis, pathway])].
[sujeto(['A', regulatory, or, enzymatic, activity, of, 'e(r)', in, pyrimidine, biosynthesis, and, the, cell, cycle]), verbo([has]), complemento([been, 'suggested,', but, nothing, is, known, about, its, molecular, function])].
[sujeto(['The', factor, is, evolutionarily, highly]), verbo([conserved]), complemento([since, homologues, exist, in, plants, and, mammals])].
[sujeto(['The', mRNA, is]), verbo([expressed]), complemento(['maternally,', enriched, in, ectodermal, derivatives, during, development, and, ubiquitously, detectable, in, the, adult])].
[sujeto(['Fused', to, the, 'DNA']), verbo([binding]), complemento([region, of, the, 'GAL4', transcription, factor, 'domain,', 'XERH', represses, the, activity, of, a, 'GAL4', responsive, reporter, in, 'HeLa,', but, not, in, 'NIH3T3', cells])].
[sujeto(['Furthermore,', the, 'DCoH/PCD', coactivation, of, a, 'HNF1', responsive, reporter, is]), verbo([inhibited]), complemento([by, 'XERH'])].
[sujeto(['TCF7L2', is, a, central, transcription, factor, in, the, canonical, 'wingless-type', 'MMTV', integration, site, '(', 'WNT)', signaling, 'pathway,', and, genetic, variants, in, 'TCF7L2']), verbo([have]), complemento([been, found, to, interact, with, dietary, fiber, intake, on, type, 2, diabetes, risk])].
[sujeto(['Here,', we, investigate, whether, other, type, 2, diabetes, genes, could, be]), verbo([involved]), complemento([in, the, 'WNT', signaling, pathway, and, whether, variants, in, such, genes, might, interact, with, dietary, fiber, on, type, 2, diabetes, incidence])].
[sujeto(['Seven', genes, '(', nine, single, nucleotide, polymorphisms, '(', 'SNPs))', were, annotated, as]), verbo([involved]), complemento([in, 'WNT', signaling, including, 'TCF7L2', '(', rs7903146, and, 'rs12255372),', 'HHEX', '(', 'rs1111875),', 'HNF1A', '(', 'rs7957197),', 'NOTCH2', '(', 'rs10923931),', 'TLE4', '(', 'rs13292136),', 'ZBED3', '(', 'rs4457053),', and, 'PPARG', '(', rs1801282, and, 'rs13081389)'])].
[sujeto(['The', magnitude, of, the, association, between, the, 'TCF7L2', risk, allele, and, incident, type, 2, diabetes]), verbo([increased]), complemento([from, the, lowest, to, the, highest, quintiles, of, fiber, intake])].
[sujeto(['Higher', fiber]), verbo([associated]), complemento([with, lower, type, 2, diabetes, risk, only, among, risk, allele, carriers, of, the, 'NOTCH2', variant, and, homozygotes, of, the, risk, allele, of, the, 'ZBED3', variant])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, several, type, 2, diabetes, susceptibility, 'SNPs', in, genes, involved, in, 'WNT', signaling, may, interact, with, dietary, fiber, intake, on, type, 2, diabetes, incidence])].
[sujeto(['However,', no, statistically, significant, differences, were]), verbo([found]), complemento([when, 'CRP,', 'HNF1A,', 'LEPR,', 'GCKR,', 'NLRP3,', 'IL1F10,', 'PPP1R3B,', 'ASCL1,', 'HNF4A', and, 'SALL1', were, evaluated, according, to, the, 'presence/absence', of, 'CV', 'events,', carotid, plaques, and, cIMT, after, adjustment])].
[sujeto(['We']), verbo([found]), complemento([molecular, 'subtypes,', but, not, clinicopathological, 'factors,', as, independent, predictors, of, survival])].
[sujeto(['Regulatory', network, analysis, predicted, that, 'HNF1A/B', are, among, thousand, 'TFs', the, top, enriched, master, regulators, of, the, genes]), verbo([expressed]), complemento([in, the, normal, pancreatic, tissue, compared, to, the, 'PDAC', regulatory, network])].
[sujeto(['HNF1A/B', seem, to, be, good, candidates, as, master, regulators, of, pancreatic, 'differentiation,', which, at, the, protein, level, loses, its, expression, in, malignant, ductal, cells, of, the, 'pancreas,']), verbo([suggesting]), complemento([its, putative, role, as, tumor, suppressor, in, pancreatic, cancer])].
[sujeto(['We']), verbo([report]), complemento([three, different, cases, of, 'MODY,', two, without, associated, abnormalities, and, one, with, renal, disorder])].
[sujeto(['Mutations', concern, genes, that, are, directly]), verbo([involved]), complemento([in, the, 'beta-cell', function])].
[sujeto(['In', patients, with, 'non-syndromic', 'diabetes,', more, than, 99, '%', of, 'MODY', result, from, mutations, in, hepatocyte]), verbo([nuclear]), complemento(['factor-1-alpha', '(', 'HNF-1-alpha', ;, formerly, 'MODY', 3, ')', ',', glucokinase, '(', 'MODY', 2, ')', ',', or, 'HNF-4-alpha', '(', 'MODY', 1, ')'])].
[sujeto(['Making', a, diagnosis, of, 'MODY', may]), verbo([have]), complemento([important, implications, for, the, guidance, of, appropriate, 'treatment,', prognosis, and, genetic, counselling])].
[sujeto(['Significant', heterogeneity, between, different, tumors]), verbo([prevents]), complemento([the, discovery, of, cancer, driver, 'genes,', especially, in, a, 'patient-specific', manner])].
[sujeto(['The', prioritized, 'mutation-driver', genes]), verbo([act]), complemento([as, tumor, suppressor, genes, and, inhibit, cell, proliferation, and, migration])].
[sujeto(['In', 'addition,', the, 'loss-of-function', effect, of, the, 'patient-specific', mutations]), verbo([promoted]), complemento([cell, proliferation, and, migration])].
[sujeto(['Of', 'note,', the, 'HNF1A', 'S247T', mutation, significantly, reduced, the, 'HNF1A', transcriptional, activity, for, hepatocyte]), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF4A)', but, did, not, disrupt, nuclear, localization, of, 'HNF1A'])].
[sujeto(['The', results]), verbo([provide]), complemento([evidence, for, supporting, the, validity, of, our, proposed, 'multi-omics', 'strategy,', which, supplies, a, new, avenue, for, prioritizing, 'mutation-drivers', towards, personalized, cancer, therapy])].
[sujeto(['Elevation', of, plasma, 'C-reactive', 'protein,', an, important, inflammatory, 'marker,', was, known, to]), verbo([associate]), complemento([with, increased, risk, of, ischemic, stroke])].
[sujeto(['Previous', studies]), verbo([reported]), complemento([association, between, genetic, variants, of, 'HNF1A', and, plasma, level, of, 'C-reactive', protein])].
[sujeto(['The', 'HNF1A', gene, encodes, a, hepatocyte, transcription, factor, which, might]), verbo([have]), complemento([regulatory, effects, on, 'C-reactive', protein, synthesis, in, liver])].
[sujeto(['Therefore,', the, 'C-reactive', protein]), verbo([associated]), complemento([gene, 'HNF1A', seems, to, be, a, promising, candidate, gene, for, ischemic, stroke])].
[sujeto(['Our', study]), verbo([provided]), complemento([additional, genetic, evidences, to, understand, the, role, of, 'HNF1A', gene, and, 'C-reactive', protein, underlying, ischemic, stroke])].
[sujeto(['Erdheim-Chester', disease, '(', 'ECD)', is, a, rare, form, of, 'non-Langerhans', cell, histiocytosis, characterized, by, xanthogranulomatous, infiltration, of, foamy, histiocytes, frequently]), verbo([involving]), complemento([bone, and, other, organ, systems])].
[sujeto(['We', herein]), verbo([report]), complemento([a, unique, case, of, 'ECD', discovered, incidentally, in, an, explanted, liver, in, a, 65, -, 'year-old', male, with, 'end-stage', liver, disease, secondary, to, hepatitis, 'C', cirrhosis])].
[sujeto(['Whole', body, 'PET', and, bone, scans, demonstrated]), verbo([increased]), complemento([heterogeneous, uptake, in, bilateral, humeral, and, femoral, 'diaphysis,', most, compatible, with, 'ECD'])].
[sujeto(['To', our, 'knowledge,', this, is, the, first, case]), verbo([report]), complemento([of, 'ECD', that, involves, mainly, bone, marrow, and, liver, with, novel, genomic, alterations])].
[sujeto(['This', study, investigated, the, associations, between, the, common, hepatocyte]), verbo([nuclear]), complemento(['factor-1A', '(', 'HNF1A)', variants, and, the, risk, of, diabetic, retinopathy, '(', 'DR)', in, relation, to, the, glycemic, control, and, weight, status])].
[sujeto(['It', is, increasingly, recognised, that, diabetes, in, young, adults]), verbo([has]), complemento([a, wide, differential, diagnosis])].
[sujeto(['Severe', insulin, resistance]), verbo([involves]), complemento([a, 'young-onset', metabolic, syndrome, often, with, a, disproportionately, low, 'BMI'])].
[sujeto(['Mutations', in, the, transcription, factors, 'HNF1A', and, 'HNF4A', and, in, the, 'β-cell', potassium, 'ATP', channel, components]), verbo([cause]), complemento([diabetes, which, responds, to, low, dose, and, high, dose, sulfonylurea, 'agents,', 'respectively,', while, glucokinase, mutations, require, no, treatment])].
[sujeto(['Monogenic', insulin, resistance, and, 'young-onset', type, 2, diabetes, are, both, challenging, to, 'treat,', but, first, line, management]), verbo([involves]), complemento([insulin, sensitisers, and, aggressive, management, of, cardiovascular, risk])].
[sujeto(['Diabetes', is]), verbo([increasing]), complemento([globally, and, 'Asia', is, the, epicenter])].
[sujeto(['Eighty-four', potential, 'probands,', identified, in, accordance, with, clinical, practice, 'guidelines,', were, subjected, to, 're-sequencing', of, 16, monogenic, diabetes, genes, and]), verbo([targeted]), complemento([genotyping, for, mitochondrial, 3243, 'A&gt;G', 'point-mutation'])].
[sujeto(['We', recently]), verbo([reported]), complemento([the, results, of, a, test, for, monogenic, forms, of, diabetes, in, 'Japanese', children, who, were, diagnosed, with, type, 1, 'B', diabetes, at, &, 'lt;5', years, of, age])].
[sujeto(['Thirty-two', 'Japanese', children, '(', eight, 'males,', 24, 'females)', with, type, 1, diabetes, negative, for, glutamate, decarboxylase, '(', 'GAD)', 65, 'and/or', 'IA-2A', autoantibodies, and, who, were, aged, &, 'gt;5', to, 15.1, years, at, diagnosis, were]), verbo([recruited]), complemento([from, 16, independent, hospitals, participating, in, the, 'Japanese', 'Study', 'Group', of, 'Insulin', 'Therapy', for, 'Childhood', and, 'Adolescent', 'Diabetes', '(', 'JSGIT)'])].
[sujeto(['We', performed, mutational, analyses, of, genes, with, a, high, frequency, of, mutation, '[', 'INS,', 'KCNJ11,', hepatocyte]), verbo([nuclear]), complemento([factor, 1, alpha, '(', 'HNF1α)', and, hepatocyte, nuclear, factor, 4, alpha, '(', 'HNF4α)]'])].
[sujeto(['We', identified, one, missense, mutation, '(', 'G32S)', in, the, 'INS', gene, and, two, mutations, '(', 'R131Q', and, 'R203S)', in, the, 'HNF1α', gene, that, could, be]), verbo([associated]), complemento([with, diabetes])].
[sujeto(['No', missense, change, was]), verbo([found]), complemento([in, the, 'KCNJ11', gene])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, although, mutations, in, the, 'INS', gene, can, be, detected, in, 'Japanese', patients, aged, &, 'gt;5', years, at, 'diagnosis,', the, frequency, of, mutations, decrease, in, older, age, groups])].
[sujeto(['Conversely,', the, frequency, of, the, mutation, in, the, 'HNF1α', gene]), verbo([increased]), complemento([in, patients, diagnosed, at, age, 5, or, older])].
[sujeto(['Here,', we, studied, 1, ',', 462, 'Mexican', children]), verbo([recruited]), complemento([from, 'Mexico', 'City'])].
[sujeto(['Six', genetic, variants, in, five, 'inflammation-related', genes, were, 'genotyped:', rs1137101, '(', leptin, receptor, '(', 'LEPR)),', rs7305618, '(', hepatocyte]), verbo([nuclear]), complemento([factor, 1, alpha, '(', 'HNF1A)),', rs1800629, '(', tumor, necrosis, factor, alpha, '(', 'TNFA)),', 'rs1800896,', rs1800871, '(', 'interleukin-10', '(', 'IL-10)),', rs1862513, '(', resistin, '(', 'RETN))'])].
[sujeto(['We']), verbo([found]), complemento([that, one, 'SNP', displayed, a, nominal, evidence, of, association, with, a, continuous, 'trait:', rs1800871, '(', 'IL-10)', with, 'LDL', '(', beta, =, -, 0.068, ±, 1.006, ',', 'P', =, 0.01, ')'])].
[sujeto(['Subsequently,', we]), verbo([found]), complemento([one, nominal, association, with, a, binary, 'trait:', rs7305618, '(', 'HNF1A)', with, family, history, of, hypertension, '(', 'odds-ratio', =, 1.389, '[', 1.054, -, 1.829, ']', ',', 'P', =, 0.02, ')'])].
[sujeto(['Our', data, in, a, 'Mexican', children, population, are, consistent, with, previous]), verbo([reports]), complemento([in, 'European', adults, in, failing, to, demonstrate, an, association, between, 'inflammation-associated', single, nucleotide, polymorphisms, '(', 'SNPs)', and, metabolic, traits])].
[sujeto(['Patients', are, selected, for, testing, according, to, clinical, 'criteria,', but, up, to, 80, '%', of, monogenic, diabetes, in, the, 'UK']), verbo([has]), complemento([not, been, correctly, diagnosed])].
[sujeto(['We', investigated, outcomes, of, genetic, testing, in, our, center, to, compare, methods, of, selecting, 'patients,', and, consider, avenues, to]), verbo([increase]), complemento([diagnostic, efficiency])].
[sujeto(['Cascade', testing, in, a, total, of, 16, relatives]), verbo([led]), complemento([to, diagnosis, of, a, further, 13, cases])].
[sujeto(['Further', evidence, is]), verbo([required]), complemento([to, inform, this, assessment])].
[sujeto(['Currently', 13, 'MODY', subtypes]), verbo([caused]), complemento([by, mutations, in, 13, 'genes,', are, known])].
[sujeto(['New', 'tools,', such, as, the, 'MODY', probability, 'calculator,', may, be, of, assistance, in]), verbo([finding]), complemento([those, patients, in, whom, further, genetic, testing, for, possible, 'MODY', is, warranted])].
[sujeto([pediatric, clinics, using, a, systematic, approach, of, biomarker, screening, and]), verbo([targeted]), complemento([genetic, testing])].
[sujeto([2, 'nmol/mmol)', underwent, islet, autoantibody, '(', 'GAD', and, 'IA2)', 'testing,', with, patients, who, were, autoantibody, negative, undergoing, genetic, testing, for, all, 29, identified]), verbo([causes]), complemento([of, monogenic, diabetes])].
[sujeto(['This', figure]), verbo([suggests]), complemento([that, '∼50%', of, the, estimated, 875, 'U'])].
[sujeto([pediatric, patients, with, monogenic, diabetes]), verbo([have]), complemento([still, not, received, a, genetic, diagnosis])].
[sujeto(['Congenital', hyperinsulinism, '(', 'CHI)', is, a, clinically, and, genetically, heterogeneous, disease, characterized, by, severe, hypoglycemia]), verbo([caused]), complemento([by, inappropriate, insulin, secretion, by, pancreatic, 'β-cells'])].
[sujeto(['Clinical', information, was]), verbo([provided]), complemento([by, the, referring, clinicians])].
[sujeto(['Most', mutations, were]), verbo([found]), complemento([in, 'ABCC8', '(', 20, /, 50, ')'])].
[sujeto(['Notably,', patients, with, 'ABCC8', mutations, were, diagnosed, 'earlier,', with, lower, blood, glucose, levels, and]), verbo([required]), complemento([higher, doses, of, diazoxide, than, those, without, a, genetic, diagnosis])].
[sujeto(['ABCC8', mutations, are, the, most, frequent]), verbo([cause]), complemento([of, 'CHI', in, 'Spain'])].
[sujeto(['We']), verbo([found]), complemento([ten, novel, mutations, in, the, 'KATP', channel, genes])].
[sujeto(['The', genetic, diagnosis, is, more, likely, to, be, achieved, in, patients, with, onset, within, the, first, week, of, life, and, in, those, who, fail, to]), verbo([respond]), complemento([to, diazoxide, treatment])].
[sujeto(['To', investigate, the, effect, of]), verbo([inhibiting]), complemento([and, activating, 'Wnt', signalling, pathway, on, monocyte, differentiation, of, 'HL-60', cells, induced, with, a, new, steroidal, drug, 'NSC67657', and, its, possible, mechamism])].
[sujeto(['Then', the, 'HL-60', cells, with]), verbo([inhibited]), complemento([and, activated, 'Wnt', pathway, were, treated, with, 'NSC67657', of, 10, 'µmol/L', for, 3, 'days;', the, expression, levels, of, 'CD14', and, 'down-stream', target, proteins, of, 'Wnt', signalling, pathway, in, blank, control, '(', culture, 'mediam)', 'group,', simple, 'NSC67657-treated', 'group,', 'NSC67657', combined, with, inhibitor, group, and, 'NSC67657', combined, activator, group, were, compared, and, analyzed])].
[sujeto([20, 'µmol/L', 'XAV-939', and, 20, 'mmol/L', 'LiCl', could, effectively]), verbo([inhibit]), complemento([and, activate, 'Wnt', signalling, pathway, of, 'HL-60', cells, 'respectively,', could, significantly, 'down-', and, 'up-regulate', the, expression, of, 'cyclinD1,', 'TCF1', and, 'c-Jun', genes, '(', 'P', &, 'lt;', 0.05, ')', and, proteins, '(', 'P', &, 'lt;', 0.05, ')', ;, 'moreover,', the, number, of, 'CD10(+)', 'HL-60', cells, in, these, conditions, was, below, 1, '%', ',', no, early, apoptosis, of, 'HL-60', cells, was, found])].
[sujeto(['In', the, simple, 'NSC67657-treated', 'groups,', the, expression, of, 'cyclinD1,', 'TCF1', and, 'c-Jun', proteins, was, 'down-regulated', '(', 'P', &, 'lt;', 0.05, ')', ',', and, the, percentage, of, 'CD14(+)', 'HL-60', cells, accounted, for, 62.13, ±, 9.44, ;, after, the, 'HL-60', cells, were, treated, with, 'XAV-939,', the, 'NSC67657', could, more, significantly, 'down-regulate', the, expression, of, 'cyclinD1,', 'TCF1', and, 'c-Jun', proteins, and, the, percentage, of, 'CD14(+)', 'HL-60', cell, accounted, for, 84.17, ±, 5.39, '%', ',', as, compared, with, simple, 'NSC67657-treated', 'group;', as, compared, with, blank, controls, 'group,', the, expression, of, 'cyclinD1,', 'TCF1', and, 'c-Jun', proteins, was, more, obviously, 'down-regulated', and, the, percentage, of, 'CD14(+)', 'HL-60', cells]), verbo([decreased]), complemento([to, 33.99, ±, 8.37, '%', in, 'NSC67657', combined, 'LiC1', streated, 'group,', but, which, were, higher, than, those, in, simple, 'NSC67657-treated', group, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto([20, 'µmol/L', 'XAV-939', and, 20, 'mmol/L', 'LiCl', as, effective, inhabitor, and, activator, of, 'Wnt', signalling, pathway, respectively, can, significantly, 'down-', and, 'up-regulate', the, expression, of, 'Wnt', 'down-stream', pathway]), verbo([target]), complemento([genes, and, proteins])].
[sujeto(['The', influence, of, 'XAV-939', and, 'LiC1', on, differentiation, of, 'HL-60', cells]), verbo([induced]), complemento([by, 'NSC67657', suggests, that, 'Wnt', signalling, pathway, plays, a, key, role, in, monocyte, differentiction, of, 'HL-60', cells, induced, by, 'NSC67657'])].
[sujeto(['Mutations', in, several, genes]), verbo([cause]), complemento([nonautoimmune, 'diabetes,', but, numerous, patients, still, have, unclear, genetic, 'defects,', hampering, our, understanding, of, the, development, of, the, disease, and, preventing, 'pathogenesis-oriented', treatment])].
[sujeto(['We', used, 'whole-genome', sequencing, with, linkage, analysis, to, study, a, consanguineous, family, with, 'early-onset', 'antibody-negative', diabetes, and, identified, a, novel, deletion, in, 'PCBD1', '(', 'pterin-4', 'α-carbinolamine', 'dehydratase/dimerization', cofactor, of, hepatocyte]), verbo([nuclear]), complemento([factor, 1, 'α),', a, gene, that, was, recently, proposed, as, a, likely, cause, of, diabetes])].
[sujeto(['We']), verbo([found]), complemento([that, 'Pcbd1', is, expressed, in, the, developing, pancreas, of, both, mouse, and, 'Xenopus', embryos, from, early, specification, onward, showing, colocalization, with, insulin])].
[sujeto(['Importantly,', a, 'morpholino-mediated', knockdown, in, 'Xenopus', revealed, that, pcbd1, activity, is]), verbo([required]), complemento([for, the, proper, establishment, of, early, pancreatic, fate, within, the, endoderm])].
[sujeto(['We']), verbo([provide]), complemento([the, first, genetic, evidence, that, 'PCBD1', mutations, can, cause, 'early-onset', nonautoimmune, diabetes, with, features, similar, to, dominantly, inherited, 'HNF1A-diabetes'])].
[sujeto(['This', condition]), verbo([responds]), complemento([to, and, can, be, treated, with, oral, drugs, instead, of, 'insulin,', which, is, important, clinical, information, for, these, patients])].
[sujeto(['Pterin-4a-carbinolamine', 'dehydratase/dimerization', cofactor, for, hepatocyte]), verbo([nuclear]), complemento(['factor-1', alpha, is, a, protein, with, two, different, functions])].
[sujeto(['We']), verbo([have]), complemento([overexpressed, and, purified, the, human, 'wild-type', 'protein,', and, its, 'Cys81Ser', and, 'Cys81Arg', mutants])].
[sujeto(['The', 'Cys81Arg', mutant]), verbo([has]), complemento([been, proposed, to, be, causative, in, a, hyperphenylalaninaemic, patient, '[', 'Citron,', 'B'])].
[sujeto(['Various', pterins]), verbo([bind]), complemento([and, quench, the, tryptophan, fluorescence, suggesting, the, presence, of, a, specific, binding, site])].
[sujeto(['Wild-type', and, the, 'Cys81Ser', protein]), verbo([enhance]), complemento([the, rate, of, the, phenylalanine, hydroxylase, assay, approximately, 10, -, 'fold,', a, value, similar, to, that, of, native, dehydratase, from, rat, 'liver;', the, 'Cys81Arg', 'mutant,', in, 'contrast,', has, significantly, lower, activity])].
[sujeto(['The', three, proteins]), verbo([enhance]), complemento([the, spontaneous, dehydration, of, the, synthetic, substrate, 6, ',', 6, -, 'dimethyl-7,8-dihydropterin-4a-carbinolamine', approximately, 50, -, 70, -, fold, at, 4, degrees, 'C', and, pH, 8.5])].
[sujeto(['The', 'bi-functional', protein, dimerization, cofactor, of, 'HNF1', '(', 'DCoH)/pterin-4', 'alpha-carbinolamine', dehydratase, '(', 'PCD)', is]), verbo([found]), complemento([in, liver, cell, nuclei, bound, to, the, transcription, factor, hepatocyte, nuclear, factor, 1, '(', 'HNF1)', as, well, as, in, the, cytoplasm, acting, as, an, enzyme, involved, in, the, phenylalanine, hydroxylation, system])].
[sujeto(['Deficiency', of, 'DCoH/PCD', activity, in, liver]), verbo([causes]), complemento([an, atypical, hyperphenylalaninemia, and, deficiency, in, human, epidermis, is, related, to, the, depigmentation, disorder, vitiligo])].
[sujeto(['DCoH/PCD', from, rat, 'liver,', which, is, identical, to, the, human, 'protein,', was]), verbo([expressed]), complemento([in, 'E'])].
[sujeto(['The', amino, acid, sequences, of, human, and, rat, 'PHS/PCD', were]), verbo([found]), complemento([to, be, identical])].
[sujeto(['Surprisingly,', the, primary, structure, of, 'PHS/PCD', is, also, essentially, identical, to, a, protein, of, the, cell, 'nucleus,', named, dimerization, cofactor, of, hepatocyte]), verbo([nuclear]), complemento([factor, 1, 'alpha,', recently, reported, to, be, involved, in, transcription, '(', 'Mendel,', 'D'])].
[sujeto(['Dimerization', 'co-factor', of, hepatocyte]), verbo([nuclear]), complemento([factor, 1, '(', 'HNF1)/pterin-4alpha-carbinolamine', dehydratase, '(', 'DCoH/PCD)', is, both, a, positive, 'co-factor', of, the, 'HNF1', homeobox, transcription, factors, and, thus, involved, in, gene, regulation, as, well, as, an, enzyme, catalyzing, the, regeneration, of, tetrahydrobiopterin])].
[sujeto(['Dysfunction', of, 'DCoH/PCD', is]), verbo([associated]), complemento([with, the, human, disorders, hyperphenylalaninemia, and, vitiligo])].
[sujeto(['In', 'Xenopus,', overexpression, of, the, protein, during, development]), verbo([induces]), complemento([ectopic, pigmentation])].
[sujeto(['In', this, study]), verbo([loss]), complemento([of, function, experiments, using, 'DCoH/PCD-specific', antibodies, demonstrated, that, the, protein, is, also, absolutely, necessary, for, pigment, cell, formation, in, 'Xenopus'])].
[sujeto(['In', normal, human, skin, 'DCoH/PCD', protein, is, weakly]), verbo([expressed]), complemento([in, the, basal, layer, of, the, epidermis, that, consists, of, keratinocytes, and, melanocytes])].
[sujeto(['The', comparison, with, the, commonly, used, melanoma, markers, 'S100', and, 'HMB45', demonstrated, that, 'DCoH/PCD']), verbo([has]), complemento([an, overlapping, but, distinct, expression, pattern, in, melanoma, lesions])].
[sujeto(['In', addition, to, human, colon, 'cancer,', this, is, the, second]), verbo([report]), complemento([about, the, overexpression, of, 'DCoH/PCD', in, human, tumor, cells, indicating, that, the, protein, might, be, involved, in, cancerogenesis])].
[sujeto(['The', 'tissue-specific', transcription, factors, 'LFB1', '(', 'HNF1)', and, 'LFB3', '(', 'vHNF1)', mainly]), verbo([expressed]), complemento([in, 'liver,', kidney, and, intestine, are, homeoproteins, that, interact, with, the, regulatory, element, 'HP1'])].
[sujeto(['The', 'HP1', sequence, constitutes, one, of, the, most, important, 'cis-acting', elements, in, 'liver-specifically']), verbo([expressed]), complemento(['genes,', while, its, function, in, other, cell, types, containing, 'LFB1', and, 'LFB3', is, not, fully, understood])].
[sujeto(['In', 'mammals,', 'LFB1', activity, is]), verbo([modulated]), complemento([by, 'DCoH,', a, cofactor, that, stimulates, the, 'LFB1', transactivation, significantly])].
[sujeto(['XDCoH']), verbo([enhances]), complemento([the, 'LFB1-dependent', transactivation, potential, in, transfection, experiments, and, interacts, in, vitro, directly, with, 'LFB1', and, its, variant, form, 'LFB3'])].
[sujeto(['The', protein, is, detectable, in, liver, and, kidney, extracts, of, adult, frogs, and, in, small, amounts, also, in, lung, and, 'stomach,', organs]), verbo([expressing]), complemento(['LFB1', 'and/or', 'LFB3', protein, as, well])].
[sujeto(['The', amount, of, 'XDCoH']), verbo([increases]), complemento([dramatically, following, 'neurulation,', when, the, formation, of, 'liver,', pronephros, and, other, organs, takes, place])].
[sujeto(['The', tissue, distribution, of, 'XDCoH', during, embryogenesis]), verbo([suggests]), complemento([that, 'XDCoH', is, involved, in, determination, and, differentiation, of, various, unrelated, cell, types])].
[sujeto(['The', two, disparate, functions, of, 'DCoH1', '(', dimerization, cofactor, of, 'HNF-1)/PCD', '(', 'pterin-4a-carbinolamine', 'dehydratase)', are]), verbo([associated]), complemento([with, a, change, in, oligomeric, state])].
[sujeto(['DCoH', dimers]), verbo([enhance]), complemento([the, activity, of, the, 'diabetes-associated', transcription, factor, 'HNF-1α', '(', hepatocyte, nuclear, 'factor-1α),', while, the, 'PCD', activity, of, 'DCoH1', homotetramers, aids, in, aromatic, amino, acid, metabolism])].
[sujeto(['Formation', of, the, 'DCoH1/HNF-1α', complex]), verbo([requires]), complemento([cofolding])].
[sujeto(['The', homotetramer, of, the, 'DCoH1', 'paralogue,', 'DCoH2,']), verbo([interacts]), complemento([with, 'HNF-1α', through, simple, mixing])].
[sujeto(['We', show, that, a, point, mutation, at, the, 'DCoH1', tetramer, 'interface,', 'Thr', 51, 'Ser,', overcomes, the, dissociation, barrier, of, the, homotetramer, and]), verbo([increases]), complemento([the, interaction, with, 'HNF-1α'])].
[sujeto(['For', 'wild-type', 'DCoH1', the, intermediates, changed, with, 'time,']), verbo([suggesting]), complemento([a, kinetic, origin, for, the, unfolding, barrier, of, the, homotetramer])].
[sujeto(['The', presence, of, albumin, in, the, human, epidermis]), verbo([has]), complemento([been, reported, more, than, a, decade, 'ago,', but, until, 'now,', it, was, assumed, that, this, protein, is, synthesized, in, the, liver, and, transported, to, the, avascular, skin])].
[sujeto(['An', inherited, form, of, 'diabetes,', 'maturity-onset', diabetes, of, the, young, type, 3, '(', 'MODY3),', results, from, mutations, in, the, transcriptional, 'activator,', hepatocyte]), verbo([nuclear]), complemento(['factor-1alpha', '(', 'HNF1alpha)'])].
[sujeto(['Transcription', by, 'HNF1alpha', is]), verbo([stimulated]), complemento([by, the, bifunctional, coactivator, 'DCoH', '(', dimerization, cofactor, of, 'HNF1)'])].
[sujeto(['Strikingly,', an, 'HNF1alpha', deletion, in, mice]), verbo([causes]), complemento([more, severe, phenotypes, than, a, 'DCoH', deletion])].
[sujeto(['It']), verbo([has]), complemento([been, hypothesized, that, a, 'DCoH', 'homolog,', 'DCoH2,', partially, complements, the, 'DCoH', deletion])].
[sujeto(['Like', 'DCoH,', 'DCoH2', forms, a, 'tetramer,', displays, 'pterin-4alpha-carbinolamine', dehydratase, 'activity,', and]), verbo([binds]), complemento(['HNF1alpha', in, vivo, and, in, vitro])].
[sujeto(['Phylogenetic', analysis]), verbo([reveals]), complemento([six, major, subfamilies, of, 'DCoH', 'proteins,', including, unique, 'DCoH', and, 'DCoH2', branches, in, metazoans])].
[sujeto(['These', results]), verbo([suggest]), complemento([distinct, roles, for, 'DCoH', and, 'DCoH2'])].
[sujeto(['Differences', in]), verbo([conserved]), complemento([surface, residues, could, mediate, binding, to, different, effectors])].
[sujeto(['We', propose, that, 'HNF1alpha']), verbo([binding]), complemento([kinetics, may, distinguish, regulation, by, 'DCoH2,', under, thermodynamic, 'control,', from, regulation, by, 'DCoH,', under, kinetic, control])].
[sujeto(['Earlier', studies]), verbo([have]), complemento([shown, that, the, abundance, of, hepatic, 'phenyl-alanine', hydroxylase, '(', 'PAH)', diminishes, to, 60, '%', of, control, values, in, rats, fed, with, a, diet, composed, of, 40, '%', '(', 'w/w)', glycerol, '[', 'Guerin,', 'Walsh,', 'Donlon', and, 'Kaufman', '(', 1998, ')', 'Int'])].
[sujeto(['In', this, experimental, 'model,', there, are, corresponding]), verbo([decreases]), complemento([in, the, hepatic, concentrations, of, both, the, hydroxylase, 'cofactor,', 'tetrahydrobiopterin,', and, the, nucleotide, guanosine, triphosphate])].
[sujeto(['PCD', also, functions, as, a, dimerization, cofactor, '(', 'DCoH)', for, the, hepatocyte]), verbo([nuclear]), complemento([factor, 1, alpha, '(', 'HNF1alpha)', and, the, relative, abundance, of, 'PCD/DCoH', in, the, nucleus, is, also, decreased])].
[sujeto(['HNF1alpha', is]), verbo([required]), complemento([for, the, expression, of, 'PAH', in, the, liver, and, our, results, support, a, role, for, 'PCD/DCoH,', through, its, interaction, with, 'HNF1alpha,', in, regulating, the, expression, of, 'PAH'])].
[sujeto(['Mutations', in, the, 'HNF1-alpha', gene]), verbo([cause]), complemento(['maturity-onset', diabetes, of, the, young, '(', 'MODY),', but, the, exact, mechanism, is, not, known])].
[sujeto(['Several', studies]), verbo([have]), complemento([highlighted, genes, 'down-regulated', in, 'beta-cells', lacking, this, 'gene,', but, it, is, not, clear, if, these, are, directly, regulated, by, 'HNF1-alpha'])].
[sujeto(['To', better, understand, 'this,', we, used, human, and, mouse, genome, data, to, examine, 29, genes]), verbo([expressed]), complemento([in, the, 'beta-cell'])].
[sujeto(['org)', we, examined, 2, kb, upstream, of, each, gene, for, possible, 'HNF1']), verbo([binding]), complemento([sequences])].
[sujeto(['In', five, genes, we, also, examined, 100, kb, upstream, of, each, 'gene,', but, only, the, portions, strongly]), verbo([conserved]), complemento([between, humans, and, mice])].
[sujeto(['We', identified, nine, putative, 'HNF1']), verbo([binding]), complemento([sites, upstream, of, seven, genes, '(', 'p&lt;0'])].
[sujeto(['In', 'conclusion,', our, computer, search, identified, some, known, 'HNF1', 'sites,', and]), verbo([suggested]), complemento([three, novel, sites, indicating, these, genes, are, very, likely, to, be, directly, activated, by, 'HNF1'])].
[sujeto(['Earlier', we]), verbo([have]), complemento([demonstrated, 'pterin-4a-carbinolamine', dehydratase, '(', 'PCD)', mRNA, and, enzyme, activities, in, epidermal, melanocytes, and, keratinocytes])].
[sujeto(['This', protein, dimerises, also, the, transcription, factor, hepatocyte]), verbo([nuclear]), complemento([factor, 1, '(', 'HNF-1),', leading, to, activation, of, multiple, genes])].
[sujeto(['Specific']), verbo([binding]), complemento([of, 'DCoH/HNF-1', complex, to, the, human, tyrosinase, promoter, was, confirmed, by, gel, shift, analysis])].
[sujeto(['These', results]), verbo([provide]), complemento([a, novel, mechanism, in, the, regulation, of, skin, pigmentation])].
[sujeto(['The', bifunctional, protein, 'DCoH', '(', 'Dimerizing', 'Cofactor', for, 'HNF1)']), verbo([acts]), complemento([as, an, enzyme, in, intermediary, metabolism, and, as, a, binding, partner, of, the, 'HNF1', family, of, transcriptional, activators])].
[sujeto(['DCoH']), verbo([acts]), complemento([as, a, cofactor, for, 'HNF1', that, stabilizes, the, dimeric, 'HNF1', complex])].
[sujeto(['To', examine, the, roles, of, 'DCoH,', a]), verbo([targeted]), complemento([deletion, allele, of, the, murine, 'DCoH', gene, was, created])].
[sujeto(['Mirk/Dyrk1B', is, an, 'arginine-directed', 'serine/threonine', protein, kinase, that, is]), verbo([expressed]), complemento([at, low, levels, in, most, normal, tissues, but, at, elevated, levels, in, many, tumor, cell, lines, and, in, normal, skeletal, muscle])].
[sujeto(['DCoHm', '(', dimerization, cofactor, of, hepatocyte]), verbo([nuclear]), complemento([factor, 1, alpha, '(', 'HNF1alpha)', from, 'muscle),', a, novel, gene, of, the, 'DCoH', family, with, 78, '%', amino, acid, identity, to, 'DCoH,', was, identified, as, a, 'Mirk-binding', protein, by, yeast, 'two-hybrid', analysis, and, cloned])].
[sujeto(['Mirk', 'co-immunoprecipitated', with, 'DCoHm', and]), verbo([bound]), complemento([to, 'DCoHm', in, glutathione, 'S-transferase', 'pull-down', assays])].
[sujeto(['DCoH', stabilizes, 'HNF1alpha', as, a, dimer, and]), verbo([enhances]), complemento([its, transcriptional, activity, on, the, 'beta-fibrinogen', promoter, 'reporter,', and, 'DCoHm', had, similar, activity])].
[sujeto(['Mirk']), verbo([enhanced]), complemento(['HNF1alpha', transcriptional, activity, in, a, 'dose-dependent', 'manner,', whereas, two, 'kinase-inactive', 'Mirk', mutants, and, a, 'Mirk', 'N-terminal', deletion, mutant, did, not])].
[sujeto(['Mirk']), verbo([bound]), complemento([to, a, specific, region, within, the, 'CREB-binding', 'protein-binding', region, of, 'HNF1alpha', and, phosphorylated, 'HNF1alpha', at, a, site, adjacent, to, the, 'Mirk-binding', region])].
[sujeto(['Conversely,', the, 'HNF1alpha']), verbo([binding]), complemento([domain, was, located, within, the, first, five, conserved, kinase, subdomains, of, 'Mirk'])].
[sujeto(['MKK3']), verbo([enhanced]), complemento(['Mirk', kinase, activity, and, the, transcriptional, activation, of, 'HNF1alpha', by, 'Mirk,', suggesting, that, 'Mirk,', like, 'p38,', is, activated, by, certain, environmental, stress, agents])].
[sujeto(['The', 'Mirk-binding', protein, 'DCoH']), verbo([has]), complemento([been, shown, to, be, selectively, expressed, in, colon, carcinomas, but, not, in, normal, tissue])].
[sujeto(['Maturity-onset', diabetes, mellitus, of, the, young, '(', 'MODY)', is, a, human, genetic, syndrome, most, commonly, due, to, mutations, in, hepatocyte]), verbo([nuclear]), complemento(['factor-1alpha', '(', 'HNF-1alpha)'])].
[sujeto(['The', 'crystal\'s', low, solvent, content, '(', 23, '%', ',', 'v/v)']), verbo([leads]), complemento([to, tight, packing, of, peptides, in, the, lattice])].
[sujeto(['Segmental', alignment, of, the, 'mini-zipper', '(', mean, pairwise, 'root-mean-square', difference, '(', 'rmsd)', in, 'C(alpha)', coordinates, of, 0.29, 'A)', is]), verbo([associated]), complemento([with, a, 2.1, 'A', mean, 'C(alpha)', rmsd, displacement, of, the, 'C-terminal', 'coiled-coil'])].
[sujeto(['Adjoining', 'H12', 'side-chains', in, a, 'native-like', dimer, are, predicted, to, alter, the, functional, surface, of, the, 'mini-zipper']), verbo([involved]), complemento([in, 'DCoH', recognition])].
[sujeto(['The', other, mutation, '(', 'G20R),', by, 'contrast,']), verbo([leads]), complemento([to, a, dimeric, molten, 'globule,', as, indicated, by, its, 1, 'H-NMR', features, and, fluorescent, binding, of, 1, -, 'anilino-8-naphthalene', sulfonate])].
[sujeto(['We']), verbo([have]), complemento([used, differential, display, 'PCR', to, study, altered, gene, expression, in, immortalized, chicken, embryo, fibroblasts, '(', 'CEFs)', that, have, been, established, in, our, laboratory])].
[sujeto(['This', technique, resulted, in, the, cloning, of, a, novel, counterpart, of, the, previously, cloned, chicken, dimerization, cofactor, of, hepatocyte]), verbo([nuclear]), complemento([factor, '(', 'HNF)-1', '(', 'cDcoH),', which, was, identified, as, cDcoHalpha])].
[sujeto(['Expression', of, cDcoHalpha]), verbo([increased]), complemento([in, the, late, 'G1', and, early, 'S', phases, of, the, cell, 'cycle,', while, cDcoH, mRNA, increased, in, the, late, 'S', and, 'G2/M', phases])].
[sujeto(['In', contrast, with, consistent, expression, of, both, genes, in, primary, quiescent, 'cells,', cDcoH, 'mRNA,', but, not, cDcoHalpha, 'mRNA,', was, dramatically]), verbo([decreased]), complemento([in, primary, senescent, cells])].
[sujeto(['The', highest, levels, of, cDcoHalpha, mRNA, were]), verbo([found]), complemento([in, the, 'kidney,', 'liver,', heart, and, ovarian, 'follicles,', while, the, major, tissues, expressing, cDcoH, were, 'hypothalamus,', kidney, and, liver])].
[sujeto(['When', transfected, into, human, 'HepG2', 'cells,', both, cDcoH, and, cDcoHalpha, showed, similar, functional, activity, as, measured, by]), verbo([increased]), complemento([expression, of, a, reporter, 'gene,', as, well, as, 'alpha-fetoprotein', and, albumin, genes, that, both, contain, 'HNF-1', binding, elements, in, their, promoters])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, the, novel, chicken, 'DcoHalpha', might, function, as, a, transcriptional, cofactor, for, 'HNF-1', in, specific, 'cellular-environmental', states])].
[sujeto(['The', 'N-terminal', dimerization, domain, of, the, transcriptional, activator, hepatocyte]), verbo([nuclear]), complemento(['factor-1alpha', '(', 'HNF-1alpha)', is, essential, for, 'DNA', binding, and, association, of, the, transcriptional, 'coactivator,', 'DCoH', '(', dimerization, cofactor, of, 'HNF-1)'])].
[sujeto(['In', all, three, crystal, 'forms,', the, 'HNF-p1', dimers, pair, through, an, exposed, hydrophobic, surface, that, also, forms, the]), verbo([binding]), complemento([site, for, 'DCoH'])].
[sujeto(['Mutations', in, 'HNF-1alpha', are]), verbo([associated]), complemento([with, 'maturity-onset', diabetes, of, the, young, type, 3, '(', 'MODY3),', and, the, structure, of, 'HNF-p1', provides, insights, into, the, effects, of, three, 'MODY3', mutations])].
[sujeto(['Maturity-onset', diabetes, of, the, young, type, 3, '(', 'MODY3)', results, from, mutations, in, the, transcriptional, activator, hepatocyte]), verbo([nuclear]), complemento(['factor-1alpha', '(', 'HNF-1alpha)'])].
[sujeto(['Several', 'MODY3', mutations]), verbo([target]), complemento([the, 'HNF-1alpha', dimerization, domain, '(', 'HNF-p1),', which, binds, the, 'coactivator,', dimerization, cofactor, of, 'HNF-1', '(', 'DCoH)'])].
[sujeto(['Through', rearrangements, of, interfacial, side, 'chains,', a, 'single,', bifunctional, interface, in, the, 'DCoH', dimer]), verbo([mediates]), complemento([both, 'HNF-1alpha', binding, and, formation, of, a, 'competing,', transcriptionally, inactive, 'DCoH', homotetramer])].
[sujeto(['DCoH,', the, dimerization, cofactor, of, the, 'HNF-1', homeodomain, proteins, '(', hepatocyte]), verbo([nuclear]), complemento(['factor-1alpha', and, 'beta),', is, involved, in, gene, expression, by, associating, with, these, transcription, factors])].
[sujeto(['DCoH/PCD', presumably, cooperates, with, other, 'partners,', because, it, is]), verbo([expressed]), complemento([earlier, than, 'HNF1', and, phenylalanine, hydroxylase, '(', 'PAH)', in, early, vertebrate, development])].
[sujeto(['It', is, also]), verbo([found]), complemento([in, cells, lacking, 'HNF1', and, 'PAH', like, 'skin,', brain, and, the, pigmented, epithelium, of, the, eye, suggesting, a, yet, unknown, function])].
[sujeto(['We', show, that, the, overexpression, of, 'DCoH/PCD', in, 'Xenopus']), verbo([induces]), complemento([the, formation, of, ectopic, pigment, cells, in, the, 'epidermis,', that, are, visible, earlier, than, the, endogenous, pigmentation, and, broader, distributed])].
[sujeto(['This', ectopic, pigmentation, is, accompanied, by, an]), verbo([increase]), complemento([in, tyrosinase, activity, and, the, amount, of, melanin])].
[sujeto(['Overexpression', of, 'DCoH/PCD']), verbo([induces]), complemento([the, appearance, of, pigment, cells, also, in, animal, cap, 'explants,', that, normally, differentiate, into, atypical, epidermis])].
[sujeto(['DCoH/PCD', mutants, with, impaired, carbinolamine, dehydratase, activity]), verbo([retain]), complemento([the, potential, to, induce, pigmentation, and, we, propose, therefore, that, 'DCoH/PCD', is, not, simply, an, essential, enzyme, for, melanin, 'biosynthesis,', but, also, a, regulator, for, the, differentiation, of, pigment, producing, cells])].
[sujeto(['Pterin', carbinolamine, 'dehydratase/dimerization', cofactor, of, 'HNF1', '(', 'PCD/DCoH)', is, a, protein, that]), verbo([has]), complemento([a, dual, function])].
[sujeto(['It', is, a, pterin, 4, 'alpha-carbinolamine', dehydratase, that, is]), verbo([involved]), complemento([in, the, regeneration, of, the, cofactor, tetrahydrobiopterin, during, the, phenylalanine, 'hydroxylase-', catalyzed, hydroxylation, of, phenylalanine])].
[sujeto(['In', 'addition,', it, is, the, dimerization, cofactor, of, 'HNF1', that, is, able, to]), verbo([activate]), complemento([the, transcriptional, activity, of, 'HNF1'])].
[sujeto(['Here', we]), verbo([report]), complemento([for, the, first, time, that, the, 'PCD/DCoH', mRNA, is, present, in, human, white, blood, cells, and, hair, follicles])].
[sujeto(['Taking', advantage, of, this, 'finding,', a, 'sensitive,', rapid, and, convenient, method, for, screening, mutations, occurring, in, the, coding, region, of, this, gene]), verbo([has]), complemento([been, described])].
[sujeto(['Phenylalanine', hydroxylase, stimulator, '(', 'PHS)', is, a, component, of, the, phenylalanine, hydroxylation, system, that, is]), verbo([involved]), complemento([in, the, regeneration, of, the, cofactor, tetrahydrobiopterin])].
[sujeto(['It', is, also, identical, to, the, dimerization, cofactor, of, hepatocyte]), verbo([nuclear]), complemento([factor, 1, '(', 'HNF1)', '(', 'DCoH)', that, is, able, to, enhance, the, transcriptional, activity, of, 'HNF1'])].
[sujeto(['Moreover,', it]), verbo([has]), complemento([the, structural, potential, for, binding, macromolecules, such, as, proteins, and, nucleic, 'acids,', consistent, with, its, involvement, in, gene, expression])].
[sujeto(['We', investigated, whether, 'PHS/DCoH', could]), verbo([enhance]), complemento([the, expression, of, phenylalanine, hydroxylase, '(', 'PAH)'])].
[sujeto(['The', 'HNF1']), verbo([binding]), complemento([sites, were, located, at, -, 3.5, kb, in, a, region, that, is, 77.5, '%', identical, to, the, mouse, 'liver-specific', 'hormone-inducible', 'PAH', gene, enhancer])].
[sujeto(['This', study]), verbo([suggests]), complemento([a, possible, dual, function, of, 'PHS', in, vivo, in, the, human, phenylalanine, hydroxylation, 'system:', it, is, involved, in, the, regeneration, of, the, cofactor, tetrahydrobiopterin, and, can, also, enhance, the, expression, of, the, human, 'PAH', gene])].
[sujeto(['We', review, our, knowledge, of, the, molecular, events]), verbo([involved]), complemento([in, the, activation, of, the, gene, encoding, the, 'tissue-specific', transcription, factor, 'HNF1', alpha, '(', 'LFB1)'])].
[sujeto(['The', available, data]), verbo([suggest]), complemento([that, the, maternal, factors, 'OZ-1,', 'HNF4', alpha, and, 'HNF4', beta, act, as, initial, activators, of, the, 'HNF1', alpha, promoter])].
[sujeto(['We', present, evidence]), verbo([suggesting]), complemento([that, the, 'mesoderm-inducing', factor, activin, 'A', plays, a, critical, role, by, acting, through, the, 'HNF4', binding, site, of, the, 'HNF1', alpha, promoter])].
[sujeto(['After', zygotic, gene, transcription, the, 'HNF1', 'alpha-related', transcription, factor, 'HNF1', beta, accumulates, faster, than, 'HNF1', alpha, itself, and, thus, is, likely, to, contribute, to, the, activation, of, the, 'HNF1', alpha, transcription, via, the, 'HNF1']), verbo([binding]), complemento([site])].
[sujeto(['Our', results]), verbo([provide]), complemento([a, detailed, description, of, setting, up, the, expression, pattern, of, a, 'tissue-specific', transcription, factor, during, embryogenesis])].
[sujeto(['HNF1', is, a, liver, enriched, atypical, homeoprotein, isolated, from, vertebrates, which, is]), verbo([involved]), complemento([in, the, transcriptional, activation, of, 'liver,', 'kidney,', intestine, and, pancreas, specific, genes])].
[sujeto(['Using', the, yeast, 'two-hybrid', system, we, searched, for, proteins]), verbo([interacting]), complemento([with, 'HNF1'])].
[sujeto(['We', repeatedly, obtained, cDNA, clones, encoding, 'DCOH/4-alpha-carbinolamine', 'dehydratase,', an, enzyme]), verbo([involved]), complemento([in, the, oxidation, of, aromatic, amino, acids, that, was, shown, to, bind, to, and, stabilise, 'HNF1', dimers])].
[sujeto(['Using', the, yeast, 'system,', we, show, that, the, enzymatic, activity, of, 'DCOH', is, not, essential, for, 'HNF1']), verbo([binding]), complemento([and, that, the, 'HNF1', dimerisation, domain, is, sufficient, for, 'DCOH', binding])].
[sujeto(['The', hepatocyte]), verbo([nuclear]), complemento(['factor-1', '(', 'HNF1)', is, a, homeodomain, transcription, factor, that, binds, 'DNA', as, a, dimer])].
[sujeto(['HNF1', dimers]), verbo([associate]), complemento([with, two, molecules, of, 'DCoH,', a, bifunctional, protein, that, also, has, an, enzymatic, function, in, the, tetrahydrobiopterin, 'regeneration,', to, form, stable, heterotetramers, also, capable, of, 'DNA', binding])].
[sujeto(['Although', we, detected, no, direct]), verbo([binding]), complemento([of, 'DCoH', to, 'DNA', or, 'RNA,', 'DCoH', stabilized, 'HNF1/DNA', complexes, and, promoted, interactions, with, 'sub-optimal', 'DNA', target, sequences, such, as, the, human, 'alpha1-antitrypsin', 'TATA', box, region])].
[sujeto(['Interestingly,', 'DCoH']), verbo([retains]), complemento([its, enzymatic, activity, while, complexed, with, 'HNF1'])].
[sujeto(['Our', results, document, intermolecular, regulation, of, 'HNF1']), verbo([binding]), complemento([to, nucleic, acids, by, 'DCoH'])].
[sujeto(['DCoH,', the, dimerization, cofactor, of, hepatocyte]), verbo([nuclear]), complemento([factor, 1, '(', 'HNF-1),', functions, as, both, a, transcriptional, coactivator, and, a, pterin, dehydratase])].
[sujeto(['The', ligand]), verbo([binds]), complemento([at, four, sites, per, tetrameric, 'enzyme,', with, little, apparent, conformational, change, in, the, protein])].
[sujeto(['Each', 'active-site', cleft, is, located, in, a, subunit, 'interface,', adjacent, to, a, prominent, saddle, motif, that]), verbo([has]), complemento([structural, similarities, to, the, 'TATA', binding, protein])].
[sujeto(['The', pterin]), verbo([binds]), complemento([within, an, arch, of, aromatic, residues, that, extends, across, one, dimer, interface])].
[sujeto(['The']), verbo([bound]), complemento([ligand, makes, contacts, to, three, conserved, 'histidines,', and, this, arrangement, restricts, proposals, for, the, enzymatic, mechanism, of, dehydration])].
[sujeto(['The', dihedral, symmetry, of, 'DCoH']), verbo([suggests]), complemento([that, binding, to, the, dimerization, domain, of, 'HNF-1', likely, involves, the, superposition, of, 'two-fold', rotation, axes, of, the, two, proteins])].
[sujeto(['The', bifunctional, protein, 'PCD/DCoH', is, both, an, enzyme]), verbo([involved]), complemento([in, the, phenylalanine, hydroxylation, system, and, a, transcription, coactivator, forming, a, 2, :, 2, heterotetrameric, complex, with, the, nuclear, transcription, factor, 'HNF1'])].
[sujeto(['The', discovery, of, a, bacterial, homologue, and, the, expression, pattern, during, 'Xenopus', embryogenesis]), verbo([suggest]), complemento([a, regulatory, function, not, only, restricted, to, 'HNF1'])].
[sujeto(['The', crystal, structures, of, the, tetrameric, rat, and, the, dimeric, bacterial, 'PCD/DCoH']), verbo([have]), complemento([led, to, the, proposal, of, substrate, and, 'HNF1', binding, sites])].
[sujeto(['The', 'saddle-shaped', 'beta-sheet', surfaces, of, the, 'DCoH', dimers, likely, represent]), verbo([binding]), complemento([sites, for, as, yet, unknown, macromolecular, interaction, partners])].
[sujeto(['The', bifunctional, protein, 'pterin-4a-carbinolamine', dehydratase, '(', 'PCD)/dimerization', cofactor, of, 'HNF1', '(', 'DCoH)', is, a, cytoplasmic, enzyme]), verbo([involved]), complemento([in, the, tetrahydrobiopterin, regeneration, and, is, found, in, complex, with, the, transcription, factor, 'HNF1', in, liver, cell, nuclei])].
[sujeto(['The', 'concave,', hydrophobic, surface, of, the, 'eight-stranded', 'beta-sheet', with, its, two, protruding, loops, at, either, end, is, reminiscent, of, the, 'saddle-like', shape, seen, in, the, 'TATA-box']), verbo([binding]), complemento([protein])].
[sujeto(['PCD/DCoH']), verbo([binds]), complemento([as, a, dimer, to, the, helical, dimerization, domain, of, dimeric, 'HNF1', forming, a, 'hetero-tetramer', possibly, through, a, mixed, four, helix, bundle])].
[sujeto(['The', 'F-domain', of, rat, 'HNF-4alpha1']), verbo([has]), complemento([a, crucial, impact, on, the, ligand, binding, 'affinity,', ligand, specificity, and, secondary, structure, of, 'HNF-4alpha'])].
[sujeto(['(', 'i)', 'Fluorescent']), verbo([binding]), complemento([assays, indicate, that, 'wild-type,', 'full-length', 'HNF-4alpha', '(', amino, acids, 1, -, 455, ')', has, high, affinity, '(', 'Kd=0'])].
[sujeto(['LCFA-CoA']), verbo([binding]), complemento([was, due, to, close, molecular, interaction, as, shown, by, fluorescence, resonance, energy, transfer, '(', 'FRET)', from, 'full-length', 'HNF-4alpha', tryptophan, '(', 'FRET', 'donor)', to, bound, 'cis-parinaroyl-CoA', '(', 'FRET', 'acceptor),', which, yielded, an, intermolecular, distance, of, 33, 'A,', although, no, 'FRET', to, 'cis-parinaric', acid, was, detected])].
[sujeto(['(', 'ii)', 'Deleting', the, 'N-terminal', 'A-D-domains,', comprising, the, 'AF1', and, 'DNA']), verbo([binding]), complemento(['functions,', only, slightly, affected, affinities, for, 'LCFA-CoAs', '(', 'Kd=0'])].
[sujeto(['No', 'FRET', from, 'HNF-4alpha-E', '(', amino, acids, 132, -, 370, ')', tryptophan, '(', 'FRET', 'donor)', to]), verbo([bound]), complemento(['cis-parinaroyl-CoA', '(', 'FRET', 'acceptor)', was, 'detected,', whereas, an, intermolecular, distance, of, 28, 'A', was, calculated, from, 'FRET', between, 'HNF-4alpha-E', and, 'cis-parinaric', acid])].
[sujeto(['(', 'v)', 'cis-Parinaric', acid]), verbo([bound]), complemento([to, 'HNF-4alpha', with, intact, 'F-domain', was, readily, displaceable, by, 'S-hexadecyl-CoA,', a, nonhydrolyzable, thioether, analogue, of, 'LCFA-CoAs'])].
[sujeto(['Truncation', of, the, 'F-domain', significantly]), verbo([decreased]), complemento(['cis-parinaric', acid, displacement])].
[sujeto(['Hence,', the, 'C-terminal', 'F-domain', of, 'HNF-4alpha']), verbo([regulated]), complemento([ligand, 'affinity,', ligand, 'specificity,', and, 'ligand-induced', conformational, change, of, 'HNF-4alpha'])].
[sujeto(['The', hepatic, differentiation, of, human]), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'hiPSC)', holds, great, potential, for, application, in, regenerative, 'medicine,', pharmacological, drug, 'screening,', and, toxicity, testing])].
[sujeto(['However,', full, maturation, of, hiPSC, into, functional, hepatocytes]), verbo([has]), complemento([not, yet, been, achieved])].
[sujeto(['Differentiation', into, definitive, endoderm, '(', 'DE)', was]), verbo([induced]), complemento([by, adding, activin, 'A,', 'Wnt3a,', and, sodium, butyrate, to, the, culture, medium])].
[sujeto(['The', same, differentiation, protocol, was, applied, to, hiPSC]), verbo([maintained]), complemento([in, 2, 'D', cultures])].
[sujeto(['Immunofluorescence', staining, showed, that, the, majority, of, cells, was, positive, for, 'albumin,', cytokeratin, 18, '(', 'CK18),', and, hepatocyte]), verbo([nuclear]), complemento([factor, 4, -, alpha, '(', 'HNF4A)', at, the, end, of, the, differentiation, process])].
[sujeto(['R63W', mutation, in, the, hepatocyte]), verbo([nuclear]), complemento(['factor-4', alpha, '(', 'HNF4A)', results, in, macrosomia, and, atypical, 'Fanconi', 'syndrome,', in, addition, to, hyperinsulinaemic, hypoglycaemia, '(', 'HI)'])].
[sujeto(['He']), verbo([responded]), complemento([to, 3, -, 10, 'mg/kg/day', of, diazoxide])].
[sujeto(['Raised', serum, creatinine]), verbo([led]), complemento([to, the, investigation, of, renal, tubular, 'function,', showing, leaking, of, electrolytes, and, protein])].
[sujeto(['Continuous', glucose, monitoring, was, performed, in, his, 'mother,']), verbo([revealed]), complemento([overnight, hypoglycaemia])].
[sujeto(['Our', cases]), verbo([suggest]), complemento([that, the, p])].
[sujeto(['We', hypothesize, that, the]), verbo([lead]), complemento(['genome-wide', association, study, 'single-nucleotide', polymorphism, 'rs9949617,', or, its, linkage, disequilibrium, 'proxies,', regulates, 1, of, the, 5, genes, in, the, 'triglyceride-associated', region])].
[sujeto(['We', performed, a, linkage, disequilibrium, analysis, and]), verbo([found]), complemento([9, additional, variants, in, linkage, disequilibrium, '(', 'r(2)&gt;0'])].
[sujeto([7, ')', with, the]), verbo([lead]), complemento(['single-nucleotide', polymorphism])].
[sujeto(['To', select, the, variants, for, functional, 'analyses,', we, annotated, the, 10, variants, using, 'DNase', 'I', hypersensitive, 'sites,', transcription, factor, and, chromatin, states, and, identified, rs17259126, as, the]), verbo([lead]), complemento([candidate, variant, for, functional, in, vitro, validation])].
[sujeto(['Using', luciferase, transcriptional, reporter, assay, in, liver, 'HepG2', 'cells,', we]), verbo([found]), complemento([that, the, 'G', allele, exhibits, a, significantly, lower, effect, on, transcription, '(', 'P&lt;0'])].
[sujeto(['The', electrophoretic, mobility, shift, and, 'ChIPqPCR', '(', chromatin, immunoprecipitation, coupled, with, quantitative, polymerase, chain, 'reaction)', assays, confirmed, that, the, minor, 'G', allele, of, rs17259126, disrupts, an, hepatocyte]), verbo([nuclear]), complemento([factor, 4, 'α-binding', site])].
[sujeto(['To']), verbo([find]), complemento([the, regional, candidate, 'gene,', we, performed, a, local, expression, quantitative, trait, locus, analysis, and, found, that, rs17259126, and, its, linkage, disequilibrium, proxies, alter, expression, of, the, regional, transmembrane, protein, 241, '(', 'TMEM241)', gene, in, 795, adipose, 'RNAs', from, the, 'Metabolic', 'Syndrome', 'In', 'Men', '(', 'METSIM)', cohort, '(', 'P=6'])].
[sujeto([2, harbors, a, regulatory, 'single-nucleotide', 'polymorphism,', 'rs17259126,', which, disrupts, normal, hepatocyte]), verbo([nuclear]), complemento([factor, 4, α, binding, and, decreases, the, expression, of, the, regional, 'TMEM241', gene])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, decreased, transcript, levels, of, 'TMEM241', contribute, to, increased, triglyceride, levels, in, 'Mexicans'])].
[sujeto(['It', is, logical, to, assume, that, buffalo, mammary, gland, will]), verbo([have]), complemento([mammary, 'stem/progenitor', cells])].
[sujeto(['Thus', 'far,', no]), verbo([report]), complemento([exists, on, identification, of, buffalo, mammary, stem, cells])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF4A)', is, a, candidate, marker, for, hepatic, progenitor, cells, and, has, recently, been, suggested, as, a, marker, of, bovine, mammary, 'stem/progenitor', cells])].
[sujeto(['We', hypothesized, that, '(', 1, ')', 'HNF4A', identifies, putative, buffalo, mammary, 'stem/progenitor', cells, and, '(', 2, ')', the, number, of, 'HNF4A-positive', cells]), verbo([increases]), complemento([during, mastitis])].
[sujeto([37.3, '%', ')', ',', which, was, likely, due, to]), verbo([loss]), complemento([of, 'MEC', in, mastitis])].
[sujeto(['Preliminary', study, showed, coexpression, of, 'HNF4A', with, 'MSI1', '(', a, mammary, stem, cell, marker, in, 'sheep),']), verbo([suggesting]), complemento(['HNF4A', was, likely, to, be, a, putative, mammary, 'stem/progenitor', cell, marker, in, buffalo])].
[sujeto(['The', first, hypothesis, that, 'HNF4A', identify, putative, mammary, 'stem/progenitor', cells, was, confirmed, but, the, second, hypothesis, that, the, number, of, mammary, 'stem/progenitor', cells]), verbo([decreases]), complemento([during, mastitis, was, unsupported])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([outlining, the, expression, of, 'HNF4A', and, identification, of, putative, mammary, 'stem/progenitor', cells, in, buffalo, mammary, gland])].
[sujeto(['In', an, adjusted, model, for, 'age,', 'sex,', 'BMI,', and, 'BMI', change, over, 12, &, 'nbsp;months,', five, out, of, the, studied, 37, single, nucleotide, polymorphisms, '(', 'SNPs)', were, significantly]), verbo([associated]), complemento([with, 'NODAT:', 'rs16936667:PRDM14', 'OR', 10.57, ;, 95, '%', 'CI', 1.8, -, 63.0, ;, 'p&nbsp;=&nbsp;0'])].
[sujeto(['This', study, represents, a, replication, study, of, candidate, 'SNPs']), verbo([associated]), complemento([with, developing, 'NODAT', and, implicates, mTOR, as, the, central, regulator, via, altered, insulin, 'sensitivity,', pancreatic, β, 'cell,', and, mitochondrial, survival, and, dysfunction, as, evidenced, by, the, five, 'SNPs'])].
[sujeto([3, ')', 'The', replication, study, generates, the, hypothesis, that, mTOR, signalling, pathway, may, be]), verbo([involved]), complemento([in, 'NODAT', development])].
[sujeto(['Berberine', '(', 'BBR)']), verbo([has]), complemento([been, shown, to, exhibit, protective, effects, against, diabetes, and, dyslipidemia])].
[sujeto(['Previous', studies]), verbo([have]), complemento([indicated, that, 'BBR', modulates, lipid, metabolism, and, inhibits, hepatic, gluconeogensis, by, decreasing, expression, of, 'Hepatocyte', 'Nuclear', 'Factor-4α', '(', 'HNF-4α)'])].
[sujeto(['However,', the, mechanism]), verbo([involved]), complemento([in, this, process, was, unknown])].
[sujeto(['Treatment', of, 'T2D', mice, for, 4, weeks, or, treatment, of, 'PA-incubated', 'HepG2', cells, for, 24, h, with, 'BBR']), verbo([decreased]), complemento([expression, of, 'HNF-4α', and, the, microRNA, 'miR122,', the, key, gluconeogenesis, enzymes, 'Phosphoenolpyruvate', carboxykinase, '(', 'PEPCK)', and, 'Glucose-6-phosphatase', '(', 'G6Pase)', and, the, key, lipid, metabolism, proteins, 'Sterol', response, element, binding, 'protein-1', '(', 'SREBP-1),', 'Fatty', acid, 'synthase-1', '(', 'FAS-1)', and, 'Acetyl-Coenzyme', 'A', carboxylase, '(', 'ACCα)', and, increased, 'Carnitine', 'palmitoyltransferase-1(CPT-1)', compared, to, 'T2D', mice, or, 'PA-incubated', 'HepG2', cells])].
[sujeto(['Expression', of, 'HNF-4α', in, 'HepG2', cells]), verbo([increased]), complemento([expression, of, gluconeogenic, and, lipid, metabolism, enzymes, and, 'BBR', treatment, or, knock, down, of, miR122, attenuated, the, effect, of, 'HNF-4α', expression])].
[sujeto(['In', 'addition,', miR122, mimic]), verbo([increased]), complemento([expression, of, gluconeogenic, and, lipid, metabolism, enzymes, in, 'HepG2', cells, with, knockdown, of, 'HNF-4α'])].
[sujeto(['The', effect, of, 'BBR', on, hepatic, gluconeogenesis, and, lipid, metabolism, is]), verbo([mediated]), complemento([through, 'HNF-4α', and, is, regulated, downstream, of, miR122])].
[sujeto(['Our', data]), verbo([provide]), complemento([new, evidence, to, support, 'HNF-4α', and, miR122, regulated, hepatic, gluconeogenesis, and, lipid, metabolism, as, promising, therapeutic, targets, for, the, treatment, of, 'T2D'])].
[sujeto(['The', diagnosis, of, the, monogenic, form, of, diabetes, may]), verbo([have]), complemento([substantial, influence, on, quality, of, 'life,', prognosis, and, the, choice, of, the, appropriate, treatment, of, affected, patients])].
[sujeto(['Later,', insulin, treatment]), verbo([has]), complemento([been, initiated, when, marked, hyperglycaemia, was, detected, during, an, episode, of, acute, pneumonia, at, age, of, 26])].
[sujeto(['R290H)', of, 'HNF4α', gene, was]), verbo([found]), complemento([and, 'MODY-1', was, diagnosed, in, both, cases])].
[sujeto(['No', further, positive, cases, were]), verbo([found]), complemento([during, screening, of, other, family, members])].
[sujeto(['Epithelial-to-mesenchymal', transition, '(', 'EMT)', is, a, complex, multistep, process, in, which, phenotype, switches, are]), verbo([mediated]), complemento([by, a, network, of, transcription, factors, '(', 'TFs)'])].
[sujeto(['Here,', we, performed, a, computational, analysis, that, integrated, 'time-course', 'EMT', transcriptomic, data, with, public, cistromic, data, and, identified, three, synergistic, master, 'TFs', '(', 'ETS2,', 'HNF4A', and, 'JUNB)', that]), verbo([regulate]), complemento([the, transition, through, the, 'partial-EMT', state])].
[sujeto(['Importantly,', these, factors, utilized, a, clique, 'motif,', physically]), verbo([interact]), complemento([and, their, cumulative, binding, generally, characterized, 'EMT-associated', genes])].
[sujeto(['Furthermore,', analyses, of, 'H3K27ac', 'ChIP-seq', data, revealed, that, 'ETS2,', 'HNF4A', and, 'JUNB', are]), verbo([associated]), complemento([with, 'super-enhancers', and, the, administration, of, 'BRD4', inhibitor, readily, abolished, 'TGF-β-induced', 'EMT'])].
[sujeto(['These', findings]), verbo([have]), complemento([implications, for, systematic, discovery, of, master, 'EMT', regulators, and, 'super-enhancers', as, novel, targets, for, controlling, metastasis])].
[sujeto(['Most']), verbo([have]), complemento([undergone, three, to, eight, cell, divisions, and, result, from, independent, events, '(', 'Luria-Delbrück', fluctuation, 'test);', we, calculate, that, they, arose, between, 'E8'])].
[sujeto(['Although', subtypes, of, pancreatic, ductal, adenocarcinoma, '(', 'PDAC)']), verbo([have]), complemento([been, 'described,', this, malignancy, is, clinically, still, treated, as, a, single, disease])].
[sujeto(['Whereas', hepatocyte]), verbo([nuclear]), complemento([factor, 4, ',', alpha, '(', 'HNF4A)', controls, basal, expression, of, 'CYP3A5,', 'drug-induced', 'CYP3A5', upregulation, is, mediated, by, the, nuclear, receptor, 'NR1I2'])].
[sujeto(['CYP3A5', also, contributes, to, acquired, drug, resistance, in, 'QM-PDA', and, classical, 'PDAC,', and, it, is, highly]), verbo([expressed]), complemento([in, several, additional, malignancies])].
[sujeto(['These', findings, designate, 'CYP3A5', as, a, predictor, of, therapy, response, and, as, a, tumor, 'cell-autonomous', detoxification, mechanism, that, must, be, overcome, to]), verbo([prevent]), complemento([drug, resistance])].
[sujeto(['We', show, here, that, 'Hepatocyte', 'Nuclear', 'Factor', 4, α, '(', 'HNF4α)', directly]), verbo([induces]), complemento(['XBP1', expression])].
[sujeto(['Mutations', in, 'HNF4α']), verbo([cause]), complemento(['Mature-Onset', 'Diabetes', of, the, 'Young', 'I', '(', 'MODYI),', a, subset, of, diabetes, characterized, by, diminished, 'GSIS'])].
[sujeto(['In', mouse, 'models,', cell, 'lines,', and, ex, vivo, 'islets,', using, dominant, negative, and, 'human-', 'disease-allele', point, mutants, or, 'knock-out', and, knockdown, 'models,', we, show, that, disruption, of, 'HNF4α']), verbo([caused]), complemento([decreased, expression, of, 'XBP1', and, reduced, cellular, 'ER', networks])].
[sujeto(['GSIS', depends, on, 'ER', 'Ca(2+)', 'signaling;', we, show, that, diminished, 'XBP1', 'and/or', 'HNF4α', in, 'β-cells']), verbo([led]), complemento([to, impaired, 'ER', 'Ca(2+)', homeostasis])].
[sujeto(['The']), verbo([nuclear]), complemento([factors, controlling, 'differentiation,', hepatocyte, nuclear, factor, '(', 'HNF)-4α,', 'HNF-1α,', 'HNF-6', and, upstream, stimulatory, 'factor-1', '(', 'USF-1),', and, the, oncogene, 'Myc', and, 'alpha-fetoprotein', '(', 'AFP)', were, measured])].
[sujeto(['The', 9, -, 11, -, days, chick, liver, extracts, and, 13.5, -, 14.5, -, days, mouse, 'hepatoblast-enriched', cells, could]), verbo([inhibit]), complemento([proliferation, and, induce, differentiation, of, 'HepG2', 'cells,', leading, to, either, death, or, maturation, to, hepatocytes])].
[sujeto(['The', maturation, of, surviving, 'HepG2', cells, was, confirmed, by]), verbo([increases]), complemento([in, the, expressions, of, 'HNF-4α,', 'HNF-1α,', 'HNF-6,', and, 'USF-1,', and, decreases, in, 'Myc', and, 'AFP'])].
[sujeto(['Furthermore,', the, 13.5, -, days, mouse, hepatoblast, culture, completely, eliminated, 'HepG2', tumors, with]), verbo([inhibited]), complemento(['Myc', and, induced, 'HNF-4α,', confirming, this, embryonic, induction, effect, in, vivo])].
[sujeto(['HCV', replication, in, persistently, infected, cell, culture, remains, resistant, to, 'IFN-α/RBV', combination, 'treatment,', whereas, 'IFN-λ1']), verbo([induces]), complemento([viral, clearance])].
[sujeto(['The', antiviral, mechanisms, by, which, 'IFN-λ1']), verbo([induces]), complemento([sustained, 'HCV', clearance, have, not, been, determined])].
[sujeto(['Activation', of, 'Jak-Stat', 'signaling,', interferon]), verbo([stimulated]), complemento([gene, '(', 'ISG)', 'expression,', and, 'miRNA-122', transcription, in, 'S3-GFP', and, 'R4-GFP', cells, were, examined])].
[sujeto(['We']), verbo([have]), complemento([shown, that, 'IFN-λ1', induces, 'HCV', clearance, in, 'IFN-α', resistant, and, sensitive, replicon, cell, lines, in, a, dose, dependent, manner, through, 'Jak-Stat', 'signaling,', and, induces, 'STAT', 1, and, 'STAT', 2, 'activation,', 'ISRE-luciferase', promoter, activation, and, 'ISG', expression])].
[sujeto(['Stat', 3, activation, is, also]), verbo([involved]), complemento([in, 'IFN-λ1', induced, antiviral, activity, in, 'HCV', cell, culture])].
[sujeto(['IFN-λ1']), verbo([induced]), complemento(['Stat', 3, phosphorylation, reduces, the, expression, of, hepatocyte, nuclear, factor, 4, alpha, '(', 'HNF4α)', through, 'miR-24', in, 'R4-GFP', cells])].
[sujeto(['Reduced', expression, of, 'HNF4α', is]), verbo([associated]), complemento([with, decreased, expression, of, 'miR-122', resulting, in, an, 'anti-HCV', effect])].
[sujeto(['Our', results, indicate, that, 'IFN-λ1']), verbo([activates]), complemento([the, 'Stat', 3, -, 'HNF4α', feedback, inflammatory, loop, to, inhibit, 'miR-122', transcription, in, 'HCV', cell, culture])].
[sujeto(['In', addition, to, the, classical, 'Jak-Stat', antiviral, signaling, 'pathway,', 'IFN-λ1']), verbo([inhibits]), complemento(['HCV', replication, through, the, suppression, of, 'miRNA-122', transcription, via, an, inflammatory, 'Stat', 3, -, 'HNF4α', feedback, loop])].
[sujeto(['Inflammatory', feedback, circuits]), verbo([activated]), complemento([by, 'IFNs', during, chronic, inflammation, expose, 'non-responders', to, the, risk, of, hepatocellular, carcinoma])].
[sujeto(['Determination', of, defined, roles, for, endogenous, homeobox, '(', 'Hox)', genes, in, adult, hematopoietic, stem, and, progenitor, cell, '(', 'HSPC)', activity]), verbo([has]), complemento([been, hampered, by, a, combination, of, embryonic, defects, and, functional, redundancy])].
[sujeto(['Notably,', the]), verbo([loss]), complemento([of, 'Hoxa', genes, had, little, impact, on, 'HSPC', differentiation])].
[sujeto(['Comparative', 'RNA', sequencing, analyses, of, 'Hoxa(-/-)', and, 'WT', hematopoietic, stem, cells, '(', 'CD150(+)/CD48(-)/Lineage(-)/c-kit(+)/Sca-1(+))', identified, a, large, number, of, differentially]), verbo([expressed]), complemento(['genes,', three, of, which, '(', 'Nr4a3,', 'Col1a1,', and, 'Hnf4a)', showed, &, 'gt;10-fold', reduced, levels])].
[sujeto(['Engineered', overexpression, of, 'Hoxa9', in, 'Hoxa(-/-)', 'HSPCs', resulted, in, partial, phenotypic, rescue, in, vivo, with]), verbo([associated]), complemento([recovery, in, expression, of, a, large, proportion, of, deregulated, genes])].
[sujeto(['Together,', these, results]), verbo([provide]), complemento([definitive, evidence, linking, 'Hoxa', gene, expression, to, proliferation, of, adult, 'HSPCs'])].
[sujeto(['Multiple', evidences]), verbo([suggest]), complemento([that, cccDNA, epigenetic, 'modifications,', such, as, histone, modifications, and, 'DNA', 'methylation,', participate, in, regulating, the, transcriptional, activity, of, the, 'HBV', cccDNA])].
[sujeto(['Inflammatory', cytokines, '(', 'TNFα,', 'LTβ)', and, the, pleiotropic, cytokine, 'interleukin-6', '(', 'IL6)']), verbo([inhibit]), complemento([hepatitis, 'B', virus, '(', 'HBV)', replication, and, transcription])].
[sujeto(['Here', we, 'show,', in, 'HepG2', cells, transfected, with, linear, 'HBV', monomers, and, 'HBV-infected', 'NTCP-HepG2', 'cells,', that, 'IL6', treatment]), verbo([leads]), complemento([to, a, reduction, of, 'cccDNA-bound', histone, acetylation, paralleled, by, a, rapid, decrease, in, 3.5, 'kb/pgRNA', and, subgenomic, 'HBV', 'RNAs', transcription, without, affecting, cccDNA, chromatinization, or, cccDNA, levels])].
[sujeto(['IL6', repressive, effect, on, 'HBV', replication, is]), verbo([mediated]), complemento([by, a, loss, of, 'HNF1α', and, 'HNF4α', binding, to, the, cccDNA, and, a, redistribution, of, 'STAT3', binding, from, the, cccDNA, to, 'IL6', cellular, target, genes])].
[sujeto(['While', the, experimental, analysis, is, often, time, consuming]), verbo([involving]), complemento([number, of, experiments, like, pulldown, 'assays,', they, are, not, necessarily, limiting, the, ability, to, detect, novel, protein, interactors])].
[sujeto(['In', this, 'work,', we, discuss, the, role, and, putative, interactors, of, 'SNAI2,', a, slug, protein, which, is]), verbo([involved]), complemento([in, the, development, of, cancer, progression])].
[sujeto(['The', protein, interactions]), verbo([have]), complemento([been, deciphered, by, domain, pair, exclusion, method, which, gives, confidence, to, already, precluded, interaction, pairs])].
[sujeto(['Additionally,', conservation, patterns, of, the, slug, protein]), verbo([have]), complemento([also, been, analysed, by, estimating, 'site-specific', evolutionary, rates, at, structural, level])].
[sujeto(['We', 'believe,', this, candidate, study, augmented, with, structural, conservation, will, definitely]), verbo([provide]), complemento([novel, insights, into, the, design, and, discovery, of, new, interactions, for, zinc, finger, class, of, proteins, besides, providing, possible, clues, for, discovery, of, various, cancer, types, associated, with, this, class, of, proteins])].
[sujeto(['During', 'renewal,', coordinated, expression, of, the, claudin, family, of, genes, is, vital, to]), verbo([maintain]), complemento([the, epithelial, barrier])].
[sujeto(['In', vitro, confirmatory, methods, identified, 2, pathways, that]), verbo([stimulate]), complemento([claudin, 'expression;', 'Hopx/Klf4', activation, of, 'Cldn4,', 7, and, 15, ',', and, 'Tcf7l2/Hnf4a', 'up-regulation', of, 'Cldn23'])].
[sujeto(['Furthermore,', 'Hnf4a', conditional, knockout, mice, fail, to]), verbo([induce]), complemento(['Cldn23', during, colonocyte, differentiation])].
[sujeto(['In', 'conclusion,', we]), verbo([report]), complemento([a, comprehensive, screen, of, colonic, claudin, gene, expression, and, discover, spatiotemporal, 'Hopx/Klf4', and, 'Tcf7l2/Hnf4a', signaling, as, stimulators, of, colonic, epithelial, barrier, differentiation])].
[sujeto(['The', genetic, architecture, of, diabetes, mellitus, in, general, and, in, pregnancy, is, 'complex,', owing, to, the, multiple, types, of, diabetes, that, comprise, both, 'complex/polygenic', forms, and, monogenic, '(', largely]), verbo([caused]), complemento([by, a, mutation, in, a, single, 'gene)', forms, such, as, 'maturity-onset', diabetes, of, the, young, '(', 'MODY)'])].
[sujeto(['Type', 1, diabetes, '(', 'T1D)', and, type, 2, diabetes, '(', 'T2D)']), verbo([have]), complemento([complex, genetic, 'etiologies,', with, over, 40, and, 90, 'genes/loci,', 'respectively,', implicated, that, interact, with, 'environmental/lifestyle', factors])].
[sujeto(['The', genetic, etiology, of, gestational, diabetes, mellitus]), verbo([has]), complemento([largely, been, found, to, overlap, that, of, 'T2D'])].
[sujeto(['Genetic', testing, for, complex, forms, of, diabetes, is, not, currently, useful, 'clinically,', but, genetic, testing, for, monogenic, 'forms,', particularly, 'MODY,']), verbo([has]), complemento([important, utility, for, determining, 'treatment,', managing, risk, in, family, 'members,', and, pregnancy, management])].
[sujeto(['In', 'particular,', diagnosing, 'MODY2,']), verbo([caused]), complemento([by, 'GCK', 'mutations,', indicates, that, insulin, should, not, be, 'used,', including, during, 'pregnancy,', with, the, possible, exception, of, an, unaffected, pregnancy, during, the, third, trimester, to, prevent, macrosomia])].
[sujeto(['A', relatively, simple, method, for, identifying, women, with, 'MODY2']), verbo([has]), complemento([been, piloted])].
[sujeto(['MODY1,']), verbo([caused]), complemento([by, 'HNF4A', 'mutations,', can, paradoxically, cause, neonatal, hyperinsulinemic, hypoglycemia, and, 'macrosomia,', indicating, that, detecting, these, cases, is, also, clinically, important])].
[sujeto(['Diagnosing', all, 'MODY', types]), verbo([provides]), complemento([opportunities, for, diagnosing, other, family, members])].
[sujeto(['The', aim, of, this, study, was, to, investigate, the, differentiation, potential, of]), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'iPSCs)', derived, from, human, foreskin, fibroblasts, '(', 'HFFs)', into, 'hepatocyte-like', cells, '(', 'HLCs)'])].
[sujeto(['The', iPSCs, were, firstly]), verbo([induced]), complemento([by, transduction, of, 'OCT4,', 'SOX2,', 'KLF4,', and, 'c-MYC', into, 'HFFs', using, retrovirus])].
[sujeto(['The', iPSCs, were, successfully]), verbo([induced]), complemento([by, 'HFFs,', which, exhibited, typical, embryonic, stem, cells, 'morphology,', positive, alkaline, phosphatase, 'staining,', normal, diploid, 'karyotype,', and, positive, expression, of, various, pluripotency, factors])].
[sujeto(['The', iPSCs, were, consecutively]), verbo([induced]), complemento([into, endoderm, 'cells,', hepatic, progenitor, cells, and, mature, 'HLCs,', and, the, differentiation, efficiency, was, 55.7, &, 'nbsp;±&nbsp;2'])].
[sujeto(['HFFs', were, successfully]), verbo([induced]), complemento([into, iPSCs, by, transduction, of, 'OCT4,', 'SOX2,', 'KLF4,', and, 'c-MYC'])].
[sujeto(['The', iPSCs, were, consecutively]), verbo([induced]), complemento([into, endoderm, 'cells,', hepatic, progenitor, 'cells,', and, mature, 'HLCs'])].
[sujeto(['Various', 'hepatocyte-specific', genes, were, highly]), verbo([expressed]), complemento([in, 'iPSC-induced', 'HLCs'])].
[sujeto(['HNF4A', is, an, established]), verbo([cause]), complemento([of, maturity, onset, diabetes, of, the, young, '(', 'MODY)'])].
[sujeto(['Congenital', hyperinsulinism, can, also, be]), verbo([associated]), complemento([with, mutations, in, the, 'HNF4A', gene])].
[sujeto(['HNF4A', mutations]), verbo([cause]), complemento([increased, birth, 'weight,', transient, neonatal, hypoglycaemia, and, maturity, onset, diabetes, of, the, young, '(', 'MODY)'])].
[sujeto(['The', most, frequently]), verbo([reported]), complemento(['HNF4A', mutation, is, p])].
[sujeto(['R127W)', but, functional, studies]), verbo([have]), complemento([shown, inconsistent, 'results,', there, is, lack, of, 'co-segregation', in, some, pedigrees, and, an, unexpectedly, high, frequency, in, public, variant, databases])].
[sujeto(['R114W', heterozygotes, do, not]), verbo([have]), complemento([the, increased, birth, weight, of, patients, with, other, 'HNF4A', mutations, '(', 3476, g, vs])].
[sujeto([4, ')', and, fewer, patients]), verbo([responded]), complemento([to, sulfonylurea, treatment, '(', 48, '%', vs])].
[sujeto(['R114W']), verbo([has]), complemento([reduced, 'penetrance;', only, 54, '%', of, heterozygotes, developed, diabetes, by, age, 30, compared, to, 71, '%', for, other, 'HNF4A', mutations])].
[sujeto(['R114W', as, a, pathogenic, mutation]), verbo([causing]), complemento([a, distinct, clinical, subtype, of, 'HNF4A', 'MODY', with, reduced, 'penetrance,', reduced, sensitivity, to, sulfonylurea, treatment, and, no, effect, on, birth, weight])].
[sujeto(['This']), verbo([has]), complemento([implications, for, diabetes, 'treatment,', management, of, pregnancy, and, predictive, testing, of, 'at-risk', relatives])].
[sujeto(['The']), verbo([increasing]), complemento([availability, of, 'large-scale', sequence, data, is, likely, to, reveal, similar, examples, of, 'rare,', 'low-penetrance', 'MODY', mutations])].
[sujeto(['SESN3']), verbo([has]), complemento([been, implicated, in, multiple, biological, processes, including, protection, against, oxidative, 'stress,', regulation, of, glucose, and, lipid, metabolism])].
[sujeto(['We', performed, in, silico, phylogenetic, footprinting, analysis, of, 5, kb, upstream, regions, of, a, diverse, set, of, human, 'SESN3', orthologs, for, the, identification, of, high, confidence]), verbo([conserved]), complemento([binding, motifs, '(', 'BMo)'])].
[sujeto(['We', further, analyzed, the, predicted, 'BMo', by, a, motif, comparison, tool, to, identify, the, 'TFs', likely, to]), verbo([bind]), complemento([these, discovered, motifs])].
[sujeto(['Our', study, revealed, high, confidence, set, of, 'BMos', '(', integrated, with, 'DNase', 'I', hypersensitivity, 'sites)', in, the, upstream, regulatory, regions, of, 'SESN3', that, could, be]), verbo([bound]), complemento([by, transcription, factors, from, multiple, families, including, 'FOXOs,', 'SMADs,', 'SOXs,', 'TCFs', and, 'HNF4A'])].
[sujeto(['We', show, using, 'ChIP-PCR', as, well, as, 'over-expression', and, knock, out, studies, that, 'FOXO3', and, 'SOX2', transcriptionally]), verbo([regulate]), complemento([the, expression, of, 'SESN3', gene])].
[sujeto(['Our', findings]), verbo([provide]), complemento([an, important, roadmap, to, further, our, understanding, on, the, regulation, of, 'SESN3'])].
[sujeto(['The', 'Cancer', 'Genome', 'Atlas', '(', 'TCGA)', offers, an, unprecedented, opportunity, to, identify, 'small-molecule']), verbo([binding]), complemento([sites, on, proteins, with, overexpressed, mRNA, levels, that, correlate, with, poor, survival])].
[sujeto(['Protein', products, of, these, genes, were, scanned, for]), verbo([binding]), complemento([sites, that, possess, shape, and, physicochemical, properties, that, can, accommodate, 'small-molecule', probes, or, therapeutic, agents, '(', 'druggable)'])].
[sujeto(['These']), verbo([binding]), complemento([sites, were, classified, as, enzyme, active, sites, '(', 'ENZ),', 'protein-protein', interaction, sites, '(', 'PPI),', or, other, sites, whose, function, is, unknown, '(', 'OTH)'])].
[sujeto(['Interestingly,', the, overwhelming, majority, of]), verbo([binding]), complemento([sites, were, classified, as, 'OTH'])].
[sujeto(['We']), verbo([find]), complemento([that, 'ENZ,', 'PPI,', and, 'OTH', binding, sites, often, occurred, on, the, same, structure, suggesting, that, many, of, these, 'OTH', cavities, can, be, used, for, allosteric, modulation, of, enzyme, activity, or, 'protein-protein', interactions, with, small, molecules])].
[sujeto(['We', discovered, several, 'ENZ', '(', 'PYCR1,', 'QPRT,', and, 'HSPA6)', and, 'PPI', '(', 'CASC5,', 'ZBTB32,', and, 'CSAD)']), verbo([binding]), complemento([sites, on, proteins, that, have, been, seldom, explored, in, cancer])].
[sujeto(['We', also]), verbo([found]), complemento([proteins, that, have, been, extensively, studied, in, cancer, that, have, not, been, previously, explored, with, small, molecules, that, harbor, 'ENZ', '(', 'PKMYT1,', 'STEAP3,', and, 'NNMT)', and, 'PPI', '(', 'HNF4A,', 'MEF2B,', and, 'CBX2)', binding, sites])].
[sujeto(['All']), verbo([binding]), complemento([sites, were, classified, by, the, signaling, pathways, to, which, the, protein, that, harbors, them, belongs, using, 'KEGG'])].
[sujeto(['In', 'addition,']), verbo([binding]), complemento([sites, were, mapped, onto, structural, 'protein-protein', interaction, networks, to, identify, promising, sites, for, drug, discovery])].
[sujeto(['The', occurrence, of, mutations, in, these]), verbo([binding]), complemento([sites, provides, new, opportunities, to, develop, 'small-molecule', probes, to, explore, their, function, in, cancer])].
[sujeto(['Research', on, bovine, embryonic, stem, cells, '(', 'bESCs)']), verbo([has]), complemento([been, hampered, because, bESCs, are, cultured, in, conditions, that, are, based, on, information, obtained, from, culturing, mouse, and, human, inner, cell, mass, '(', 'ICM)', cells])].
[sujeto(['Differentially']), verbo([expressed]), complemento([genes, '(', 'DEGs)', were, assessed, using, 'Gene', 'Ontology', '(', 'GO)', and, 'Kyoto', 'Encyclopaedia', of, 'Genes', and, 'Genomes', '(', 'KEGG)', databases])].
[sujeto(['We', validated, 27, genes, using, 'qRT-PCR', and]), verbo([found]), complemento([their, expression, patterns, were, mostly, similar, to, those, of, 'RNA-seq,', including, 12, novel, 'ICM-dominant', '(', 'HNF4A,', 'CCL24,', 'FGFR4,', 'IFITM3,', 'PTCHD2,', 'GJB5,', 'FN1,', 'KLK7,', 'PRDM14,', 'GRP,', 'FGF19', and, 'GCM1)', and, two, novel, 'TE-dominant', '(', 'SLC10A1', and, 'WNT4)', genes])].
[sujeto(['Bioinformatics', analysis, showed, that, these, 'DEGs', are]), verbo([involved]), complemento([in, many, important, 'pathways,', such, as, 'MAPK', and, cancer, cell, 'pathways,', and, these, pathways, have, been, shown, to, play, essential, roles, in, mouse, and, human, 'ESCs', in, the, 'self-renewal', and, pluripotent, maintenance])].
[sujeto(['FSH', coasting, appears, to]), verbo([modulate]), complemento([the, transcriptome, of, different, follicular, 'compartments,', which, cooperate, as, a, single, functional, unit])].
[sujeto(['Network', analysis, identified, 'HNF4A', '(']), verbo([involved]), complemento([in, metabolic, 'functions)', and, 'ELAVL1', '(', an, 'RNA-binding', 'protein)', as, hub, genes, regulated, respectively, upward, and, downward, in, the, clusters, enriched, at, the, optimal, coasting, 'time,', and, 'APP', '(', involved, in, mitochondrial, 'functions)', and, 'COPS5', '(', a, member, of, the, 'COP9', 'signalosome)', as, hub, genes, regulated, respectively, upwards, and, downwards, in, the, clusters, enriched, progressively, throughout, the, coasting, period])].
[sujeto(['We', confirmed, the, effects, on, 'HNF4A', downstream]), verbo([targets]), complemento(['(', 'TTR,', 'PPL)', and, other, hub, genes, '(', 'ELAVL1,', 'APP,', 'MYC,', and, 'PGR)', in, 30, cows, with, 'RT-quantitative', 'PCR'])].
[sujeto(['The', correlation, of, hub, gene, expression, levels, with, 'FSH', coasting, indicated, that, a, combination, of, these, genes, could, predict, oocyte, competence, with, 83, '%', 'sensitivity,']), verbo([suggesting]), complemento([that, they, are, potential, biomarkers, of, follicle, differentiation])].
[sujeto(['To', identify, coding, genetic, variants]), verbo([associated]), complemento([with, these, 'traits,', we, conducted, 'meta-analyses', of, seven, 'RBC', phenotypes, in, 130, ',', 273, 'multi-ethnic', individuals, 'from&nbsp;studies', genotyped, on, an, exome, array])].
[sujeto(['We']), verbo([found]), complemento(['low-frequency', missense, variants, in, 'MAP1A', '(', 'rs55707100,', minor, allele, frequency, '[', 'MAF]', =, 3.3, '%', ',', p, =, 2, &, 'nbsp;×&nbsp;10(-10)', for, hemoglobin, '[', 'HGB])', and, 'HNF4A', '(', 'rs1800961,', 'MAF', =, 2.4, '%', ',', p, &, 'lt;', 3, &, 'nbsp;×', 10, '(', -, 8, ')', for, hematocrit, '[', 'HCT]', and, 'HGB)'])].
[sujeto(['In', 'African', 'Americans,', we, identified, a, nonsense, variant, in, 'CD36']), verbo([associated]), complemento([with, higher, 'RBC', distribution, width, '(', 'rs3211938,', 'MAF', =, 8.7, '%', ',', p, =, 7, &, 'nbsp;×', 10, '(', -, 11, ')', ')', and, showed, that, it, is, associated, with, lower, 'CD36', expression, and, strong, allelic, imbalance, in, 'ex&nbsp;vivo', differentiated, human, erythroblasts])].
[sujeto(['We', also, identified, a, rare, missense, variant, in, 'ALAS2', '(', 'rs201062903,', 'MAF', =, 0.2, '%', ')']), verbo([associated]), complemento([with, lower, mean, corpuscular, volume, and, mean, corpuscular, hemoglobin, '(', p, &, 'lt;', 8, &, 'nbsp;×', 10, '(', -, 9, ')', ')'])].
[sujeto(['Mendelian', mutations, in, 'ALAS2', are, a]), verbo([cause]), complemento([of, sideroblastic, anemia, and, erythropoietic, protoporphyria])].
[sujeto(['Gene-based', testing, highlighted, three, rare, missense, variants, in, 'PKLR,', a, gene, mutated, in, 'Mendelian', 'non-spherocytic', hemolytic, 'anemia,']), verbo([associated]), complemento([with, 'HGB', and, 'HCT', '(', 'SKAT', p, &, 'lt;', 8, &, 'nbsp;×', 10, '(', -, 7, ')', ')'])].
[sujeto(['These', 'rare,', 'low-frequency,', and, common, 'RBC', variants, showed, 'pleiotropy,', being, also]), verbo([associated]), complemento([with, 'platelet,', white, blood, 'cell,', and, lipid, traits])].
[sujeto(['Our', association, results, and, functional, annotation]), verbo([suggest]), complemento([the, involvement, of, new, genes, in, human, erythropoiesis])].
[sujeto(['To', date, five, 'MODY', genes]), verbo([have]), complemento([been, 'identified:', hepatocyte, nuclear, 'factor-4', alpha, '(', 'HNF-4alpha/MODY1/TCF14)', on, chromosome, 20, 'q,', glucokinase, '(', 'GCK/MODY2)', on, chromosome, 7, 'p,', hepatocyte, nuclear, 'factor-1', alpha, '(', 'HNF-1alpha/MODY3/TCF1)', on, chromosome, 12, 'q,', insulin, promoter, 'factor-1', '(', 'IPF1/MODY4)', on, chromosome, 13, q, and, hepatocyte, nuclear, 'factor-1', beta, '(', 'HNF-1beta/MODY5/TCF2)', on, chromosome, 17, 'cen-q'])].
[sujeto(['We']), verbo([have]), complemento([screened, the, 'HNF-4alpha,', 'HNF-1alpha', and, 'HNF-1beta', genes, in, members, of, 18, 'MODY', kindreds, who, tested, negative, for, glucokinase, mutations])].
[sujeto(['Five', missense, '(', 'G31D,', 'R159W,', 'A161T,', 'R200W,', 'R271W),', one, substitution, at, the, splice, donor, site, of, intron, 5, '(', 'IVS5nt', +, 2, 'T--&gt;A)', and, one, deletion, mutation, '(', 'P379fsdelT)', were]), verbo([found]), complemento([in, the, 'HNF-1alpha', 'gene,', but, no, 'MODY-associated', mutations, were, found, in, the, 'HNF-4alpha', and, 'HNF-1beta', genes])].
[sujeto(['Of', 67, 'French', 'MODY', families, that, we]), verbo([have]), complemento([now, 'studied,', 42, '(', 63, '%', ')', have, mutations, in, the, glucokinase, 'gene,', 14, '(', 21, '%', ')', have, mutations, in, the, 'HNF-1alpha', 'gene,', and, 11, '(', 16, '%', ')', have, no, mutations, in, the, 'HNF-4alpha,', 'IPF1', and, 'HNF-1beta', genes])].
[sujeto(['Eleven', families, do, not]), verbo([have]), complemento([mutations, in, the, five, known, 'MODY', genes, suggesting, that, there, is, at, least, one, additional, locus, that, can, cause, 'MODY'])].
[sujeto(['It']), verbo([has]), complemento([been, estimated, that, 2, -, 5, '%', of, patients, with, 'NIDDM', may, have, this, form, of, diabetes, mellitus])].
[sujeto(['Clinical', studies]), verbo([have]), complemento([shown, that, prediabetic, 'MODY', subjects, have, normal, insulin, sensitivity, but, suffer, from, a, defect, in, 'glucose-stimulated', insulin, 'secretion,', suggesting, that, pancreatic, 'beta-cell', dysfunction, rather, than, insulin, resistance, is, the, primary, defect, in, this, disorder])].
[sujeto(['Linkage', studies]), verbo([have]), complemento([localized, the, genes, that, are, mutated, in, 'MODY', on, human, chromosomes, 20, '(', 'MODY1),', 7, '(', 'MODY2)', and, 12, '(', 'MODY3),', with, 'MODY2', and, 'MODY3', being, allelic, with, the, genes, encoding, 'glucokinase,', a, key, regulator, of, insulin, 'secretion,', and, hepatocyte, nuclear, 'factor-1alpha', '(', 'HNF-1alpha),', a, transcription, factor, involved, in, 'tissue-specific', regulation, of, liver, genes, but, also, expressed, in, pancreatic, 'islets,', insulinoma, cells, and, other, tissues])].
[sujeto(['Although', studies, in, mouse, models]), verbo([have]), complemento([defined, a, central, role, for, 'SIRT1', in, maintaining, metabolic, 'health,', the, molecular, mechanisms, remain, unclear])].
[sujeto(['Here', we, show, that]), verbo([loss]), complemento([of, the, 'Drosophila', 'SIRT1', homolog, sir2, leads, to, the, 'age-progressive', onset, of, 'hyperglycemia,', 'obesity,', glucose, 'intolerance,', and, insulin, resistance])].
[sujeto(['Tissue-specific', functional, studies, show, that, 'Sir2', is, both, necessary, and, sufficient, in, the, fat, body, '(', analogous, to, the, mammalian, 'liver)', to]), verbo([maintain]), complemento([glucose, homeostasis, and, peripheral, insulin, sensitivity])].
[sujeto(['Transcriptional', profiling, of, sir2, mutants, by, 'RNA-seq', revealed, a, major, overlap, with, genes]), verbo([regulated]), complemento([by, the, nuclear, receptor, 'Hepatocyte', 'Nuclear', 'Factor', 4, '(', 'HNF4)'])].
[sujeto(['Increasing', dHNF4, expression, in, sir2, mutants, is, sufficient, to, rescue, their, insulin, signaling, 'defects,', defining, this]), verbo([nuclear]), complemento([receptor, as, an, important, downstream, effector, of, 'Sir2', signaling])].
[sujeto(['This', study, demonstrates, that, the, key, metabolic, activities, of, 'SIRT1']), verbo([have]), complemento([been, conserved, through, 'evolution,', provides, a, genetic, model, for, functional, studies, of, phenotypes, related, to, type, 2, 'diabetes,', and, establishes, 'HNF4', as, a, critical, downstream, target, by, which, 'Sir2', maintains, metabolic, health])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF4α)', is, a, transcription, factor, involved, in, the, regulation, of, serum, glucose, and, lipid, levels])].
[sujeto(['Several', 'HNF4A', gene, variants]), verbo([have]), complemento([been, associated, with, the, risk, of, developing, type, 2, diabetes, mellitus])].
[sujeto(['However,', no, study]), verbo([has]), complemento([yet, explored, its, association, with, insulin, resistance, and, the, cardiometabolic, risk, in, children])].
[sujeto([25, ')', were]), verbo([associated]), complemento([with, the, risk, of, 'MetS'])].
[sujeto(['Additionally,', a, significant, association, was]), verbo([found]), complemento([between, rs3212172, and, apolipoprotein, 'B', levels, '(', 'coefficient:', -, 0.14, ±, 0.05, ;, 'P&lt;0'])].
[sujeto(['Our', study, demonstrates, that, 'HNF4α', genetic, variants, are]), verbo([associated]), complemento([with, the, 'MetS', and, metabolic, parameters, in, 'French', 'Canadian', children, and, adolescents])].
[sujeto(['This', 'study,', the, first, exploring, the, relation, between, 'HNF4A', genetic, variants, and, 'MetS', and, metabolic, variables, in, a, pediatric, 'cohort,']), verbo([suggests]), complemento([that, 'HNF4α', could, represent, an, early, marker, for, the, risk, of, developing, type, 2, diabetes, mellitus])].
[sujeto(['Fibroblast', growth, factors, 19, and, 21, '(', 'FGF19', and, 'FGF21)']), verbo([have]), complemento([been, 'implicated,', 'independently,', in, type, 2, diabetes, '(', 'T2D)', but, it, is, not, known, if, their, circulating, levels, correlate, with, each, other, or, whether, the, associated, hepatic, signaling, mechanisms, that, play, a, role, in, glucose, metabolism, are, dysregulated, in, diabetes])].
[sujeto(['We', used, a, 'cross-sectional,', 'case/control,', experimental, design]), verbo([involving]), complemento(['Class', 'III', obese, patients, undergoing, 'Roux-en-Y', bariatric, surgery, '(', 'RYGB),', and, measured, 'FGF19', and, 'FGF21', serum, levels, and, hepatic, gene, expression, '(', 'mRNA)', in, perioperative, liver, wedge, biopsies])].
[sujeto(['We']), verbo([found]), complemento([that, 'T2D', patients, had, lower, 'FGF19', and, higher, 'FGF21', serum, levels])].
[sujeto(['The', latter, was, corroborated, 'transcriptionally,', 'whereby,', 'FGF21,', as, well, as, 'CYP7A1,', 'β-Klotho,', 'FGFR4,', 'HNF4α,', and, glycogen, 'synthase,', but, not, of, 'SHP', or, 'FXR', mRNA, levels, in, liver, biopsies, were, higher, in, 'T2D', patients, that, did, not, remit, diabetes, after, 'RYGB', 'surgery,', compared, to, 'T2D', patients, that, remitted, diabetes, after, 'RYGB', surgery, or, did, not]), verbo([have]), complemento([diabetes])].
[sujeto(['In', a, 'Phenome-wide', association, analysis, using, 205, clinical, 'variables,', higher, 'FGF21', serum, levels, were]), verbo([associated]), complemento([with, higher, glucose, levels, and, various, cardiometabolic, disease, phenotypes])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'FGF19/FGF21', circulating, levels, and, hepatic, gene, expression, of, the, associated, signaling, pathway, are, significantly, dysregulated, in, type, 2, diabetes])].
[sujeto(['Sodium', 'meta-arsenite', '(', 'SA)', is, implicated, in, the, regulation, of, hepatic, 'gluconeogenesis-related', genes, in, 'vitro;', 'however,', the, effects, in, vivo]), verbo([have]), complemento([not, been, studied])].
[sujeto(['We', investigated, whether, 'SA']), verbo([has]), complemento([antidiabetic, effects, in, a, type, 2, diabetic, mouse, model])].
[sujeto(['In', primary, 'hepatocytes,', 'SA', treatment]), verbo([decreased]), complemento([glucose, production, and, the, expression, of, 'G6Pase,', 'PEPCK,', and, hepatocyte, nuclear, factor, 4, alpha, '(', 'HNF-4α)', mRNA])].
[sujeto(['Small', heterodimer, partner, '(', 'SHP)', mRNA, expression, was]), verbo([increased]), complemento([in, hepatocytes, dependent, upon, the, 'SA', concentration])].
[sujeto(['The', expression, of, 'Sirt1', mRNA, and, protein, was, 'reduced,', and, acetylated, forkhead, box, protein, 'O1', '(', 'FoxO1)', was]), verbo([induced]), complemento([by, 'SA', treatment, in, hepatocytes])].
[sujeto(['Oral', intubation, of, 'SA', ameliorates, hyperglycemia, in, 'db/db', mice, by, reducing, hepatic, gluconeogenesis, through, the]), verbo([decrease]), complemento([of, 'Sirt1', expression, and, increase, in, acetylated, 'FoxO1'])].
[sujeto(['MODY', is, a, rare]), verbo([cause]), complemento([of, diabetes, '(', 1, '%', of, all, 'cases)', and, is, frequently, misdiagnosed, as, 'Type', 1, diabetes, '(', 'T1DM)', or, 'Type', 2, diabetes, '(', 'T2DM)'])].
[sujeto(['A', precise, molecular, diagnosis, is, essential, because, it]), verbo([leads]), complemento([to, optimal, treatment, of, the, patients, and, allows, early, diagnosis, for, their, asymptomatic, family, members])].
[sujeto(['Mutations', in, the, glucokinase, '(', 'GCK)', '(', 'MODY', 2, ')', and, hepatocyte]), verbo([nuclear]), complemento([factor, '(', 'HNF)1A/4A', '(', 'MODY', 3, and, 'MODY', 1, ')', genes, are, the, most, common, causes, of, 'MODY'])].
[sujeto(['GCK', mutations]), verbo([cause]), complemento([a, 'mild,', 'asymptomatic,', and, stable, fasting, hyperglycemia, usually, requiring, no, specific, treatment])].
[sujeto(['However,', mutations, in, the, 'HNF1A', and, 'HNF4A']), verbo([cause]), complemento([a, progressive, pancreatic, 'β-cell', dysfunction, and, hyperglycemia, that, can, result, in, microvascular, complications])].
[sujeto(['Sulfonylureas', are, effective, in, these, patients, by]), verbo([acting]), complemento([on, adenosine, triphosphate, '(', 'ATP)-sensitive', potassium, 'channels,', although, insulin, therapy, may, be, required, later, in, life])].
[sujeto(['Mutations', in, the, 'HNF1B', '(', 'MODY', 5, ')', is]), verbo([associated]), complemento([with, pancreatic, 'agenesis,', renal, 'abnormalities,', genital, tract, 'malformations,', and, liver, dysfunction])].
[sujeto(['Compared', to, 'MODY', 1, ',', 2, ',', 3, ',', and, 5, ',', the, remaining, subtypes, of, 'MODY']), verbo([have]), complemento([a, much, lower, prevalence])].
[sujeto(['In', this, 'review,', we, summarize, the, main, clinical, and, laboratory, characteristics, of, the, common, and, rarer]), verbo([causes]), complemento([of, 'MODY'])].
[sujeto(['Controversy', remains, for, the, association, between, hepatocyte]), verbo([nuclear]), complemento([factor, 4, α, '(', 'HNF-4α)', 'P2', promoter, polymorphism, rs1884613, and, type, 2, diabetes, '(', 'T2D)'])].
[sujeto(['All', the, individuals, were]), verbo([recruited]), complemento([from, 16, community, health, service, centers, in, 'Nanshan', district, in, 'Shenzhen', province])].
[sujeto(['Polymorphism', rs1884613, was]), verbo([associated]), complemento([with, genetic, susceptibility, to, prediabetes, in, the, whole, samples, '(', 'OR', =, 1.4, ',', 95, '%', 'CI', =, 1.16, -, 1.68, ',', 'P', =, 0.0001, ')', and, the, female, subgrouped, samples, '(', 'OR', =, 1.48, ',', 95, '%', 'CI', =, 1.14, -, 1.92, ',', 'P', =, 0.003, ')', after, adjusting, for, age, and, body, mass, index, '(', 'BMI)'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, rs1884613, contributes, to, susceptibility, to, 'prediabetes,', whereas, this, polymorphism, may, not, play, an, important, role, in, the, development, of, 'T2D'])].
[sujeto(['Currently,', the, polymorphism, 'T130I', '(', 'rs1800961)', in, the, 'HNF4A', '(', hepatocyte]), verbo([nuclear]), complemento([factor, 4, 'A)', gene, has, been, described, as, a, risk, factor, to, type, 2, 'DM', and, shows, an, autosomal, dominant, inheritance, pattern, associated, to, 'β-cell', function, decrease])].
[sujeto(['Diabetes', diagnosed, in, 'T130I', mutation, carriers, was, related, to, stressful, situations, in, an, earlier, age, and, tightly]), verbo([associated]), complemento([with, gestational, diabetes])].
[sujeto(['Fasting', plasma, glucose, and, 'HbA(1c)', levels]), verbo([increased]), complemento([with, age, in, all, carriers, '(', r, =, 0.69, and, r, =, 0.66, ',', 'P', &, 'lt;', 0.01, ')', ',', respectively])].
[sujeto(['Our', study, supports, the, 'T130I', variant, in, 'HNF4A', as, a, major, susceptibility, genotype]), verbo([associated]), complemento([with, 'early-onset', type, 2, 'DM'])].
[sujeto(['Healthy', carriers, of, this, mutation]), verbo([require]), complemento([a, stricter, control, in, the, population, of, central, 'Spain'])].
[sujeto(['She']), verbo([responded]), complemento([well, to, subcutaneous, insulin])].
[sujeto(['In', view, of, this, strong, family, 'history,', the, possibility, of, monogenic, diabetes, was, 'raised,', and, the, 2, genes, consistent, with, this, 'phenotype,', hepatocyte]), verbo([nuclear]), complemento(['factor-1', alpha, '(', 'HNF1a)', and, hepatocyte, nuclear, 'factor-4', alpha, '(', 'HNF4a),', were, studied])].
[sujeto(['This', study, alerts, physicians, to, suspect, 'MODY', in, patients, who]), verbo([have]), complemento([a, strongly, positive, family, history, of, diabetes, over, a, few, generations, with, negative, pancreatic, antibodies, and, absence, of, ketoacidosis, and, obesity])].
[sujeto(['Pancreatic', β, cell, failure, in, type, 2, diabetes, is]), verbo([associated]), complemento([with, functional, abnormalities, of, insulin, secretion, and, deficits, of, β, cell, mass])].
[sujeto(['We']), verbo([have]), complemento([shown, that, loss, of, β, cell, mass, can, be, ascribed, to, impaired, 'FoxO1', function, in, different, models, of, diabetes])].
[sujeto(['The', present, findings, demonstrate, a, secretory, defect]), verbo([caused]), complemento([by, impaired, 'FoxO', activity, that, antedates, dedifferentiation])].
[sujeto(['The', plasma, level, of, sex, hormone]), verbo([binding]), complemento([globulin, '(', 'SHBG),', a, glycoprotein, produced, by, 'hepatocytes,', is, subject, to, 'genetic,', 'hormonal,', 'metabolic,', and, nutritional, 'regulation,', and, is, a, marker, for, the, development, of, the, metabolic, syndrome, and, diabetes])].
[sujeto(['Because', the, mechanism, for, these, associations, is, 'unclear,', and, no, studies, of, 'SHBG', gene, expression, in, humans]), verbo([have]), complemento([been, 'published,', 'SHBG', mRNA, was, measured, in, human, liver, samples, and, related, to, anthropometric, data])].
[sujeto(['A', strong, positive, correlation, was]), verbo([found]), complemento([between, the, level, of, the, mRNA, for, the, transcription, factor, 'HNF4α', and, 'SHBG', mRNA])].
[sujeto(['These', 'mRNAs,', as, well, as, serum, 'SHBG,', were, higher, when, the, hepatic, triglyceride, concentration, was, 'low,', and]), verbo([decreased]), complemento([with, increasing, body, mass, index, but, were, unrelated, to, age])].
[sujeto(['Fat', accumulation, in, liver, and, 'IR', are, important, determinants, of, 'SHBG', gene, expression, and, thereby, circulating, 'SHBG', levels, that, are, perhaps]), verbo([mediated]), complemento([through, effects, on, the, transcription, factor, 'HNF4α'])].
[sujeto(['These', findings]), verbo([provide]), complemento([a, potential, mechanism, to, explain, why, low, 'SHBG', predicts, the, development, of, type, 2, diabetes])].
[sujeto(['The', rapid, progress, of, genomic, technologies]), verbo([has]), complemento([been, providing, new, opportunities, to, address, the, need, of, 'maturity-onset', diabetes, of, the, young, '(', 'MODY)', molecular, diagnosis])].
[sujeto(['However,', whether, a, new, mutation]), verbo([causes]), complemento(['MODY', can, be, questionable])].
[sujeto(['A', number, of, in, silico, methods]), verbo([have]), complemento([been, developed, to, predict, functional, effects, of, rare, human, mutations])].
[sujeto(['The', purpose, of, this, study, is, to, compare, the, performance, of, different, bioinformatics, methods, in, the, functional, prediction, of, nonsynonymous, mutations, in, each, 'MODY', 'gene,', and]), verbo([provides]), complemento([reference, matrices, to, assist, the, molecular, diagnosis, of, 'MODY'])].
[sujeto(['Applying', 'gene-specific', thresholds, defined, by, this, study, may, be, able, to]), verbo([increase]), complemento([the, performance, of, in, silico, prediction, of, 'disease-causing', mutations])].
[sujeto(['One-third', of, type, 2, diabetes, patients, do, not]), verbo([respond]), complemento([to, metformin])].
[sujeto(['Genetic', variants, in, metformin, transporters]), verbo([have]), complemento([been, extensively, studied, as, a, likely, contributor, to, this, high, failure, rate])].
[sujeto(['Five', variants, in, specificity, protein, 1, '(', 'SP1),', a, transcription, factor, that]), verbo([modulates]), complemento([the, expression, of, metformin, 'transporters,', were, associated, with, changes, in, treatment, 'HbA1c', '(', 'P', &, 'lt;', 0.01, ')', and, metformin, secretory, clearance, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['Genetic', variants, in, other, transcription, 'factors,', peroxisome, 'proliferator-activated', 'receptor-α', and, hepatocyte]), verbo([nuclear]), complemento([factor, 4, -, 'α,', were, significantly, associated, with, 'HbA1c', change, only])].
[sujeto(['Mutations', in, the, genes, encoding, hepatocyte]), verbo([nuclear]), complemento([factor, '(', 'HNF)1α', and, 'HNF4α', cause, a, monogenic, form, of, diabetes, mellitus, known, as, 'maturity-onset', diabetes, of, the, young, '(', 'MODY)'])].
[sujeto(['The', primary]), verbo([cause]), complemento([of, 'MODY', is, an, impairment, of, 'glucose-stimulated', insulin, secretion, by, pancreatic, 'β-cells,', indicating, the, important, roles, of, 'HNF1α', and, 'HNF4α', in, 'β-cells'])].
[sujeto(['Large-scale', genetic, studies]), verbo([have]), complemento([clarified, that, the, common, variants, of, 'HNF1α', and, 'HNF4α', genes, are, also, associated, with, type, 2, 'diabetes,', suggesting, that, they, are, involved, in, the, pathogenesis, of, both, diseases])].
[sujeto(['Recent', experimental, studies, revealed, that, 'HNF1α', controls, both, 'β-cell', function, and, growth, by]), verbo([regulating]), complemento([target, genes, such, as, glucose, transporter, 2, ',', pyruvate, 'kinase,', 'collectrin,', hepatocyte, growth, factor, 'activator,', and, 'HNF4α'])].
[sujeto(['In', 'contrast,', 'HNF4α', mainly]), verbo([regulates]), complemento([the, function, of, 'β-cells'])].
[sujeto(['Although', direct]), verbo([target]), complemento([genes, of, 'HNF4α', in, 'β-cells', are, largely, 'unknown,', we, recently, identified, 'Anks4b', as, a, novel, target, of, 'HNF4α', that, regulates, 'β-cell', susceptibility, to, endoplasmic, reticulum, stress])].
[sujeto(['Studies', of, 'MODY']), verbo([have]), complemento([led, to, a, better, understanding, of, the, molecular, mechanism, of, 'glucose-stimulated', insulin, secretion, by, pancreatic, 'β-cells'])].
[sujeto(['T130I', was]), verbo([associated]), complemento([with, both, 'early-onset', and, 'late-onset', diabetes, and, caused, downregulated, 'HNF4A', 'expression,', whereas, 'HNF1A', polymorphisms, p])].
[sujeto(['S487N', were]), verbo([associated]), complemento([with, the, age, of, diagnosis, of, diabetes])].
[sujeto(['Until', now, only, a, few, families, with, early, onset, autosomal, diabetes, due, to, the, 'NEUROD1', gene, mutations]), verbo([have]), complemento([been, identified])].
[sujeto(['Next-generation', sequencing, '(', 'NGS)']), verbo([provides]), complemento([an, opportunity, to, detect, more, pathogenic, mutations, in, this, gene])].
[sujeto(['Genetic', testing, was, performed, by]), verbo([targeted]), complemento(['NGS', sequencing, using, a, panel, of, 28, monogenic, diabetes, genes])].
[sujeto(['As', detected, by, 'NGS,', one, patient, had, the, missense, 'Arg103Pro', '(', 'CGC/CCC)', mutation, in, the, gene, 'NEUROD1', changing, the, 'amino-acid', structure, of, the, 'DNA']), verbo([binding]), complemento([domain, of, this, transcription, factor])].
[sujeto(['We']), verbo([report]), complemento([a, family, with, autosomal, dominant, diabetes, related, to, a, new, 'NEUROD1', 'mutation,', one, of, very, few, meeting, 'MODY', criteria])].
[sujeto(['The', aim, of, this, study, is, to, investigate, both, novel, and, proven, mutations, of, 11, 'MODY', genes, in, 'Turkish', children, by, using]), verbo([targeted]), complemento([next, generation, sequencing])].
[sujeto(['Eighteen', patients]), verbo([have]), complemento(['GCK', 'mutations,', four, have, 'HNF1A,', one, has, 'HNF4A,', one, has, 'HNF1B,', two, have, 'NEUROD1,', one, has, 'PDX1', gene, variations, and, one, patient, has, both, 'HNF1A', and, 'HNF4A', heterozygote, mutations])].
[sujeto(['Very', high, frequency, of, novel, mutations, '(', 42, '%', ')', in, our, study, 'population,', supports, that, in, heterogenous, disorders, like, 'MODY', sequence, analysis]), verbo([provides]), complemento(['rapid,', cost, effective, and, accurate, genetic, diagnosis])].
[sujeto(['Our', aim, was, to, 're-evaluate', families]), verbo([participating]), complemento([in, the, 'Czech', 'T1D', 'Prediction', 'Programme', '(', 'PREDIA'])].
[sujeto(['MODY', families, were, more, likely, to]), verbo([have]), complemento([a, parent, with, diabetes, and, had, a, higher, proportion, of, females, than, 'non-MODY', 'families&lt;comment&gt;', 'Author:', 'Do', you, mean, '\'', had, a, higher, proportion, of, females, with, diabetes, than, 'non-MODY', 'families\'?', 'Please', clarify, &, 'lt;/comment&gt;'])].
[sujeto(['A', prediction, programme, for, 'Type&nbsp;1', diabetes, would]), verbo([provide]), complemento([a, useful, new, source, of, patients, with, 'MODY', most, likely, to, benefit, from, an, accurate, diagnosis])].
[sujeto(['This', identification]), verbo([has]), complemento([implications, for, patient, treatment, and, disease, prognosis])].
[sujeto(['Sulfonylurea', derivatives, are, widely, used, for, clinical, treatment, of, human, subjects, with, 'Maturity', 'Onset', 'Diabetes', of, the, 'Young', '(', 'MODY)']), verbo([caused]), complemento([by, mutations, in, 'HNF-1α', or, 'HNF-4α', despite, the, mechanism, leading, to, their, hypersensitivity, is, incompletely, understood])].
[sujeto(['We']), verbo([provide]), complemento([the, first, evidence, on, the, pharmacokinetics, and, pharmacodynamics, of, sulfonylurea, derivatives, in, human, 'MODY', subjects])].
[sujeto(['The', 'half-life', of, glibenclamide, was]), verbo([increased]), complemento([only, in, some, 'MODY', subjects, '(', 't1/2', 9.5, '±6'])].
[sujeto(['We', rejected, the, hypothesis, that, all, human, 'MODY-associated', mutations, in, 'HNF1A', /, 'HNF4A']), verbo([induce]), complemento([changes, in, the, pharmacokinetics, of, sulfonylureas, in, humans, analogically, to, the, 'Hnf1a(-/-)', mouse, model])].
[sujeto(['Among', 4, ',', 908, 'Chinese', 'T2D', patients, who, were, not, taking, 'lipid-lowering', 'medications,', single, nucleotide, polymorphisms, '(', 'SNPs)', in, seven, genes, previously]), verbo([found]), complemento([to, be, associated, with, lipid, traits, in, 'genome-wide', association, studies, conducted, in, populations, of, 'European', ancestry, '(', 'ABCA1,', 'GCKR,', 'BAZ1B,', 'TOMM40,', 'DOCK7,', 'HNF1A,', and, 'HNF4A)', were, genotyped])].
[sujeto(['After', adjusting, for, multiple, 'covariates,', 'SNPs', in, 'ABCA1,', 'GCKR,', 'BAZ1B,', 'TOMM40,', and, 'HNF1A', were, identified, as, significantly]), verbo([associated]), complemento([with, triglyceride, levels, in, 'T2D', patients, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['BAZ1B', '(', 'rs2240466)', also, was]), verbo([associated]), complemento([with, the, total, cholesterol, level, '(', 'P', =, 4.75, '×10(-2))'])].
[sujeto(['In', 'addition,', 'SNP', rs157580, in, 'TOMM40', was]), verbo([associated]), complemento([with, the, 'low-density', lipoprotein, cholesterol, level, '(', 'P', =, 6.94, '×10(-3))'])].
[sujeto(['Our', findings, confirm, that, 'lipid-related', genetic, loci, are]), verbo([associated]), complemento([with, lipid, profiles, in, 'Chinese', patients, with, type, 2, diabetes])].
[sujeto(['The', results, of, this, study, showed, that, mutations, in, the, 'GCK', gene, are, the]), verbo([leading]), complemento([cause, of, 'MODY', in, our, population])].
[sujeto(['Maturity', onset, diabetes, of, the, young, '(', 'MODY)', is, a, monogenic, form, of, diabetes]), verbo([caused]), complemento([by, a, mutation, in, a, single, 'gene,', often, not, requiring, insulin])].
[sujeto(['A', total, of, 22, subjects, '[', 20, '(', 21, '%', ')', when, excluding, two, 'siblings]', were]), verbo([found]), complemento([to, have, a, mutation, in, hepatocyte, nuclear, factor, 4, 'A', '(', n, =, 4, ')', ',', glucokinase, '(', n, =, 8, ')', ',', or, hepatocyte, nuclear, factor, 1, 'A', '(', n, =, 10, ')'])].
[sujeto(['In', 'summary,', this, study]), verbo([found]), complemento([a, high, frequency, of, 'MODY', mutations, with, the, majority, of, subjects, clinically, misdiagnosed])].
[sujeto(['Clinicians', should]), verbo([have]), complemento([a, high, index, of, suspicion, for, 'MODY', in, youth, with, 'antibody-negative', diabetes])].
[sujeto(['Maturity-onset', diabetes, of, the, young, '(', 'MODY)', is, a, subgroup, of, monogenic, diabetes, 'mellitus,', of, which, 'MODY1,']), verbo([caused]), complemento([by, 'HNF4A', 'mutations,', accounts, for, only, 5, '%', or, less, and, has, been, rarely, reported, in, 'East', 'Asian', countries])].
[sujeto(['Here', we]), verbo([report]), complemento([two, novel, 'HNF4A', mutations, in, two, 'Japanese', families, with, 'MODY1'])].
[sujeto(['Both', mutations, reside, in, the, 'HNF4α', dimerization, domain, and, the, corresponding, amino, acids, are, well]), verbo([conserved]), complemento([between, species])].
[sujeto(['These', two, mutations, are, most, likely, the]), verbo([cause]), complemento([of, 'MODY1', in, these, families])].
[sujeto(['The', hepatocyte]), verbo([nuclear]), complemento([factor, 4, α, '(', 'HNF-4α;', also, known, as, 'NR2A1)', is, a, member, of, the, nuclear, receptor, '(', 'NR)', family, of, transcription, 'factors,', which, have, conserved, 'DNA-binding', domains, and, 'ligand-binding', domains])].
[sujeto(['HNF-4α', is, the, most, abundant, 'DNA-binding', protein, in, the, 'liver,', where, some, 40, '%', of, the, actively]), verbo([transcribed]), complemento([genes, have, a, 'HNF-4α', response, element])].
[sujeto(['These']), verbo([regulated]), complemento([genes, are, largely, involved, in, the, hepatic, gluconeogenic, program, and, lipid, metabolism])].
[sujeto(['Previous', structural, analyses, of, 'NRs,', although, productive, in, elucidating, the, structure, of, individual, 'domains,']), verbo([have]), complemento([lagged, behind, in, revealing, the, connectivity, patterns, of, 'NR', domains])].
[sujeto(['Here', we, describe, the, 2.9, 'Å', crystal, structure, of, the, multidomain, human, 'HNF-4α', homodimer]), verbo([bound]), complemento([to, its, 'DNA', response, element, and, 'coactivator-derived', peptides])].
[sujeto(['An', arginine]), verbo([target]), complemento([of, 'PRMT1', methylation, protrudes, directly, into, this, convergence, zone, and, sustains, its, integrity])].
[sujeto(['A', serine]), verbo([target]), complemento([of, protein, kinase, 'C', is, also, responsible, for, maintaining, 'domain-domain', interactions])].
[sujeto(['These', 'post-translational', modifications]), verbo([lead]), complemento([to, changes, in, 'DNA', binding, by, communicating, through, the, tightly, connected, surfaces, of, the, quaternary, fold])].
[sujeto(['We']), verbo([find]), complemento([that, some, 'MODY1', 'mutations,', positioned, on, the, 'ligand-binding', domain, and, hinge, regions, of, the, 'receptor,', compromise, 'DNA', binding, at, a, distance, by, communicating, through, the, interjunctional, surfaces, of, the, complex])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, unique, quaternary, folds, and, interdomain, connections, in, 'NRs', could, be, exploited, by, 'small-molecule', allosteric, modulators, that, affect, distal, functions, in, these, polypeptides])].
[sujeto(['Mutations', in, the, gene, encoding, glucokinase, '(', 'GCK)']), verbo([cause]), complemento([a, mild, hereditary, form, of, diabetes, termed, 'maturity-onset', diabetes, of, the, young, '(', 'MODY)2', or, 'GCK-MODY'])].
[sujeto(['It']), verbo([has]), complemento([therefore, been, suggested, that, 'GCK-MODY', represents, a, metabolically, compensated, 'condition,', but, experimental, support, for, this, notion, is, lacking])].
[sujeto(['Here,', we, profiled, metabolites, in, serum, from, patients, with, 'MODY1', '(', 'HNF4A),', 'MODY2', '(', 'GCK),', 'MODY3', '(', 'HNF1A),', and, type, 2, diabetes, and, from, healthy, individuals, to, characterize, metabolic, perturbations]), verbo([caused]), complemento([by, specific, mutations])].
[sujeto(['Elevated', levels, of, fatty, acids, are, known, to]), verbo([associate]), complemento([with, 'β-cell', 'dysfunction,', insulin, 'resistance,', and, increased, incidence, of, late, complications])].
[sujeto(['Unique']), verbo([nuclear]), complemento([receptor, 'Hepatocyte', 'Nuclear', 'Factor', 4, α, '(', 'HNF4α)', is, an, essential, transcriptional, regulator, for, early, development, and, proper, function, of, pancreatic, 'ß-cells,', and, its, mutations, are, monogenic, causes, of, a, dominant, inherited, form, of, diabetes, referred, to, as, 'Maturity', 'Onset', 'Diabetes', of, the, 'Young', 1, '(', 'MODY1)'])].
[sujeto(['As', a, 'gene-specific', transcription, 'factor,', 'HNF4α', exerts, its, function, through, various, molecular, 'interactions,', but, its, protein]), verbo([recruiting]), complemento([network, has, not, been, fully, characterized])].
[sujeto(['Here', we]), verbo([report]), complemento([the, identification, of, 'MED25', as, one, of, the, 'HNF4α', binding, partners, in, pancreatic, 'ß-cells', leading, to, insulin, secretion, which, is, impaired, in, 'MODY', patients])].
[sujeto(['MED25', is, one, of, the, subunits, of, the, 'Mediator', complex, that, is]), verbo([required]), complemento([for, induction, of, 'RNA', polymerase, 'II', transcription, by, various, transcription, factors, including, nuclear, receptors])].
[sujeto(['This', 'HNF4α-MED25', interaction, was, initially, identified, by, a, 'yeast-two-hybrid', 'method,', confirmed, by, in, vivo, and, in, vitro, 'analyses,', and, proven, to, be]), verbo([mediated]), complemento([through, the, 'MED25-LXXLL', motif, in, a, 'ligand-independent', manner])].
[sujeto(['Reporter-gene', based, transcription, assays, and, 'siRNA/shRNA-based', gene, silencing, approaches, revealed, that, this, interaction, is, crucial, for, full, activation, of, 'HNF4α-mediated', 'transcription,', especially, expression, of]), verbo([target]), complemento([genes, implicated, in, 'glucose-stimulated', insulin, secretion])].
[sujeto(['Selected', 'MODY', mutations, at, the, 'LXXLL', motif]), verbo([binding]), complemento([pocket, disrupt, these, interactions, and, cause, impaired, insulin, secretion, through, a, '\'', 'loss-of-function\'', mechanism])].
[sujeto(['Inactivating', mutations, in, 'HNF1A', and, 'HNF4A']), verbo([cause]), complemento([the, 'maturity-onset', diabetes, of, youth, '(', 'MODY)-3', and, 'MODY1', forms, of, monogenic, 'diabetes,', respectively])].
[sujeto(['Our', objective, was, to, describe, three, novel, cases, of, hyperinsulinism]), verbo([associated]), complemento([with, 'MODY1', and, 'MODY3', mutations])].
[sujeto(['Case', 1, was, diagnosed, at, 20, months, with, persistent, hyperinsulinemic, hypoglycemia, and, was]), verbo([found]), complemento([to, have, a, novel, 'MODY3', 'HNF1A', 'mutation,', carried, by, her, father, who, had, diabetes])].
[sujeto(['She', was]), verbo([found]), complemento([to, have, a, novel, 'MODY3', 'HNF1A', missense, 'mutation,', also, carried, by, her, father])].
[sujeto(['Although', the, 'latter\'s', features]), verbo([suggested]), complemento(['Fanconi-Bickel', 'syndrome,', sequencing, of, the, 'SLC2A2', gene, was, normal])].
[sujeto(['The', patient, was]), verbo([found]), complemento([to, have, a, known, 'MODY1', mutation, in, 'HNF4A'])].
[sujeto(['The', first, two, cases, demonstrate, that, mutations, in, 'HNF1A', '(', 'MODY3)', can]), verbo([cause]), complemento([hyperinsulinism, early, in, life, and, diabetes, 'later,', similar, to, the, phenotype, recently, reported, for, 'HNF4A', '(', 'MODY1)', mutations])].
[sujeto(['Case', 3, indicates, that, the, effects, of, 'HNF4A', mutations, in, infancy, may, extend, beyond, pancreatic, 'β-cells', to, produce, a, disorder, similar, to, glucose, transporter, 2, deficiency]), verbo([involving]), complemento([both, liver, glycogen, metabolism, and, renal, tubular, transport])].
[sujeto(['Dysfunction', of, hepatocyte]), verbo([nuclear]), complemento([factor, 4, α, '(', 'HNF4α)', has, been, linked, to, maturity, onset, diabetes, of, the, young, '(', 'MODY1),', diabetes, type, 'II', and, possibly, to, renal, cell, carcinoma, '(', 'RCC)'])].
[sujeto(['Whereas', diabetes]), verbo([causing]), complemento([mutations, are, well, 'known,', there, are, no, 'HNF4A', mutations, found, in, 'RCC'])].
[sujeto(['Since', so, far, analyses]), verbo([have]), complemento([been, constricted, to, the, promoter, and, open, reading, frame, of, 'HNF4A,', we, performed, a, systematic, analysis, of, the, human, 'HNF4A', 3, '\'', 'UTR'])].
[sujeto(['We', identified, a, short, '(', 1724, 'nt)', and, long, '(', 3180, 'nt)', 3, '\'', 'UTR', that, are, much, longer, than, the, open, reading, frame, and]), verbo([conferred]), complemento([a, repressive, effect, in, luciferase, reporter, assays, in, 'HEK293', and, 'INS-1', cells])].
[sujeto(['By', dissecting, the, 3, '\'', 'UTR', into, several, 'pieces,', we, located, two, distinct, elements, of, about, 400, nt]), verbo([conferring]), complemento([a, highly, repressive, effect])].
[sujeto(['Dicer', 'knock-down', experiments, implied, that, the, 'HNF4A', 3, '\'', 'UTR', is]), verbo([regulated]), complemento([by, miRNAs])].
[sujeto(['One', of, the, identified, 'miR-34a']), verbo([binding]), complemento([sites, is, destroyed, by, 'SNP', rs11574744])].
[sujeto(['Markedly', reduced, levels, of, proinsulin, were]), verbo([found]), complemento([in, 'HNF4A', 'MODY', compared, to, 'T2D', and, that, tended, to, be, so, also, in, 'HNF1A', 'MODY', '(', 'HNF4A', 'MODY:', 3.7, ±, 1.2, ',', 'HNF1A', 'MODY:', 8.3, ±, 3.8, vs])].
[sujeto(['We', describe, a, 'maturity-onset', diabetes, of, the, young, '(', 'MODY)', case, with, mutations]), verbo([involving]), complemento([both, 'HNF4A', and, 'HNF1A', genes])].
[sujeto(['MODY1', and, 'MODY3', mutations, may]), verbo([interact]), complemento([by, chance, to, give, a, more, severe, form, of, diabetes, '(', younger, age, at, presentation, and, early, need, of, insulin, therapy, to, control, 'hyperglycemia)'])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF4alpha)', is, a, nuclear, receptor, involved, in, glucose, homeostasis, and, is, required, for, normal, beta, cell, function])].
[sujeto(['Mutations', in, the, 'HNF4alpha', gene, are]), verbo([associated]), complemento([with, maturity, onset, diabetes, of, the, young, type, 1, '(', 'MODY1)'])].
[sujeto(['This', known, mutation, was]), verbo([found]), complemento([in, 8, of, 30, patients, and, 3, of, 21, individuals, in, relatives])].
[sujeto(['This', mutation, was, present, in, 26.6, '%', of, our, 'patients,', but, nothing, was]), verbo([found]), complemento([in, control, group])].
[sujeto(['Thus,', we, hypothesized, that, 'MODY3', '(', 'HNF1alpha', gene, 'mutations)', and, possibly, 'MODY1', '(', 'HNF4alpha,', upstream, regulator, of, 'HNF1alpha,', gene, 'mutations)', subjects, may]), verbo([have]), complemento([lower, 'VLDL', esterified, cholesterol])].
[sujeto(['Mutagenesis', revealed, one, important, 'HNF4']), verbo([binding]), complemento([site, in, the, human, 'ACAT2', promoter])].
[sujeto(['ChIP', assays, and, 'protein-to-protein', interaction, studies, showed, that, 'HNF4alpha,', directly, or, indirectly, '(', via, 'HNF1alpha),', can]), verbo([bind]), complemento([to, the, 'ACAT2', promoter])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, the, lower, levels, of, esterified, cholesterol, in, 'VLDL-', and, 'LDL-particles', in, patients, with, 'MODY1', 'may-at', least, in, 'part-be', attributable, to, lower, 'ACAT2', activity, in, these, patients])].
[sujeto(['Orphan']), verbo([nuclear]), complemento([receptors, have, been, instrumental, in, identifying, novel, signaling, pathways, and, therapeutic, targets])].
[sujeto(['However,', identification, of, ligands, for, these, receptors]), verbo([has]), complemento([often, been, based, on, random, compound, screens, or, other, biased, approaches])].
[sujeto(['As', a, 'result,', it, remains, unclear, in, many, cases, if, the]), verbo([reported]), complemento([ligands, are, the, true, endogenous, 'ligands,--i'])].
[sujeto([',', the, ligand, that, is]), verbo([bound]), complemento([to, the, receptor, in, an, unperturbed, in, vivo, setting])].
[sujeto(['Technical', limitations]), verbo([have]), complemento([limited, our, ability, to, identify, ligands, based, on, this, rigorous, definition])].
[sujeto(['The', orphan, receptor, hepatocyte]), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF4alpha)', is, a, key, regulator, of, many, metabolic, pathways, and, linked, to, several, diseases, including, 'diabetes,', 'atherosclerosis,', hemophilia, and, cancer])].
[sujeto(['Interestingly,', 'however,', ligand, occupancy, does, not, appear, to]), verbo([have]), complemento([a, significant, effect, on, 'HNF4alpha', transcriptional, 'activity,', as, evidenced, by, 'genome-wide', expression, profiling, in, cells, derived, from, human, colon])].
[sujeto(['We', also, use, 'AIMS', to, show, that, 'LA']), verbo([binding]), complemento([is, reversible, in, intact, 'cells,', indicating, that, 'HNF4alpha', could, be, a, viable, drug, target])].
[sujeto(['This', study, establishes, a, general, method, to, identify, true, endogenous, ligands, for]), verbo([nuclear]), complemento([receptors, '(', and, other, lipid, binding, 'proteins),', independent, of, transcriptional, 'function,', and, to, track, in, vivo, receptor, occupancy, under, physiologically, relevant, conditions])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF4alpha)', is, a, critical, transcription, factor, for, pancreas, and, liver, development, and, functions, in, islet, beta, cells, to, maintain, glucose, homeostasis])].
[sujeto(['Mutations', in, the, human, 'HNF4A', gene]), verbo([lead]), complemento([to, maturity, onset, diabetes, of, the, young, '(', 'MODY1)', and, polymorphisms, are, associated, with, increased, risk, for, type, 2, diabetes, mellitus, '(', 'T2DM)'])].
[sujeto(['Expression', of, six, 'HNF4alpha', 'variants,', three, each, from, two, developmentally]), verbo([regulated]), complemento(['promoters,', has, been, firmly, established])].
[sujeto(['We']), verbo([have]), complemento([now, detected, a, new, set, of, 'HNF4alpha', variants, designated, 'HNF4alpha10-12', expressed, from, distal, promoter, 'P2'])].
[sujeto(['These', 'variants,', generated, by, inclusion, of, previously, undetected, exon, '1E', '(', 'human=222', 'nt,', 'rodent=136', 'nt)', following, exon, 1, 'D']), verbo([have]), complemento([an, altered, 'N-terminus', but, identical, remaining, reading, frame])].
[sujeto(['HNF4alpha10-alpha12', are]), verbo([expressed]), complemento([in, pancreatic, islets, '(', and, 'liver)', and, exhibit, transactivation, potentials, similar, to, the, corresponding, 'alpha7-alpha9', isoforms])].
[sujeto(['Our', results]), verbo([provide]), complemento([evidence, for, a, more, complex, expression, pattern, of, 'HNF4alpha', than, previously, appreciated])].
[sujeto(['Mutations', in, the, coding, region, of, hepatocyte]), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF4alpha),', and, its, upstream, promoter, '(', 'P2)', that, drives, expression, in, the, 'pancreas,', are, known, to, lead, to, 'maturity-onset', diabetes, of, the, young, 1, '(', 'MODY1)'])].
[sujeto(['We']), verbo([found]), complemento([that, the, level, of, 'HNF4alpha', protein, and, mRNA, was, decreased, in, the, liver, of, 'db/db', mice, but, increased, in, 'streptozotocin-treated', mice])].
[sujeto(['Because', insulin]), verbo([increases]), complemento([the, activity, of, sterol, regulatory, 'element-binding', proteins, '(', 'SREBP)-1c', and, -, 2, ',', we, also, examined, the, effect, of, 'SREBPs', on, hepatic, 'HNF4alpha', gene, expression, and, found, 'that,', like, 'insulin,', ectopic, expression, of, 'SREBPs', decreases, the, level, of, hepatic, 'HNF4alpha', protein, and, mRNA, both, in, vitro, in, primary, hepatocytes, and, in, vivo, in, the, liver, of, 'C57BL/6', mice])].
[sujeto(['Finally,', we, use, gel, 'shift,', chromatin, 'immunoprecipitation,', small, interfering, 'RNA,', and, reporter, gene, analysis, to, show, that, 'SREBP2']), verbo([binds]), complemento([the, human, 'HNF4alpha', 'P1', promoter, and, negatively, regulates, its, expression])].
[sujeto(['These', data, indicate, that, hyperinsulinemia, 'down-regulates', 'HNF4alpha', in, the, liver, through, the, 'up-regulation', of, 'SREBPs,', thereby, establishing, a, link, between, these, two, critical, transcription, factor, pathways, that]), verbo([regulate]), complemento([lipid, and, glucose, metabolism, in, the, liver])].
[sujeto(['These', findings, also]), verbo([provide]), complemento([new, insights, into, 'diabetes-associated', complications, such, as, fatty, liver, disease])].
[sujeto(['Heterozygous', mutations, of, the, hepatocyte]), verbo([nuclear]), complemento([factor, '(', 'HNF)-4alpha', gene, cause, a, particular, form, of, 'maturity-onset', diabetes, of, the, young, '(', 'MODY1)'])].
[sujeto(['Recent', genetic, studies]), verbo([have]), complemento([shown, that, single, nucleotide, polymorphisms, '(', 'SNPs)', of, the, 'beta-cell', type, 'P2', promoter, of, the, 'HNF-4alpha', gene, are, associated, with, type, 2, diabetes, in, some, populations])].
[sujeto(['In', the, 'Japanese', 'population,', a, haplotype, consisting, of, two, 'SNPs', '(', rs1884614, and, 'rs2144908)', in, the, 'P2', promoter, region, is]), verbo([reported]), complemento([to, show, a, significant, association, with, type, 2, diabetes])].
[sujeto(['However,', the, rs1884614, 'T/T', genotype, was, significantly]), verbo([associated]), complemento([with, a, smaller, area, under, the, plasma, insulin, curve, '(', 'AUC)', during, the, 'OGTT', in, 'non-obese', '(', 'BMI', &, 'lt;25', 'kg/m(2))', patients, '(', 'p=0'])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, '(', 'HNF4alpha)', is, a, nuclear, receptor, essential, for, endodermal, differentiation, and, cell, functions, in, the, adult, 'pancreas,', 'liver,', and, other, tissues])].
[sujeto(['Mutations', in, the, 'HNF4A', gene]), verbo([cause]), complemento(['MODY1'])].
[sujeto(['Up', to, nine, protein, variants, arise, from, two, developmentally]), verbo([regulated]), complemento([promoters])].
[sujeto(['Expression', of, 'HNF4alpha', variants, in, 'islets,', rat, 'Ins-1', insulinoma, 'cells,', and, human, 'Hep3B', hepatocellular, carcinoma, cells, was, assessed, using, a, 'long-range', reverse, 'transcription-polymerase', chain, reaction, '(', 'RT-PCR)', strategy, capable, of]), verbo([recognizing]), complemento([each, combination, of, mRNA, termini])].
[sujeto(['Mouse', islets, and, both, cell, lines]), verbo([express]), complemento(['HNF4alpha9,', which, lacks, both, 'AF-1', and, the, 'F', domain])].
[sujeto(['Islets', also]), verbo([expressed]), complemento([the, 'HNF4alpha', 'P1', promoter, variants, 'HNF4alpha1/alpha2,', and, 'Hep3B', cells, expressed, 'HNF4alpha3'])].
[sujeto(['When', ectopically]), verbo([expressed]), complemento([in, 'COS-7', 'cells,', 'HNF4alpha1,', 'alpha3,', 'alpha7,', and, alpha9, each, stimulated, an, 'HNF4alpha-dependent', promoter])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([of, 'HNF4alpha9', expression, in, any, tissue])].
[sujeto(['This', knowledge, may, be, useful, in, efforts, to, recover, or, establish]), verbo([regulated]), complemento([insulin, secretion])].
[sujeto(['Pancreatic', islet, beta, cell, differentiation, and, function, are, dependent, upon, a, group, of, transcription, factors, that]), verbo([maintain]), complemento([the, expression, of, key, genes, and, suppress, others])].
[sujeto(['Knockout', mice, with, the, heterozygous, deletion, of, the, gene, for, chicken, ovalbumin, upstream, 'promoter-transcription', factor, 'II', '(', 'COUP-TFII)', or, the, complete, disruption, of, the, gene, for, hepatocyte]), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF4alpha)', in, pancreatic, beta, cells, have, similar, insulin, secretion, 'defects,', leading, us, to, hypothesize, that, there, is, transcriptional, cross, talk, between, these, two, nuclear, receptors])].
[sujeto(['The', stable, association, of, the, endogenous, 'HNF4alpha', with, a, region, of, the, 'COUP-TFII', gene, promoter, that, contains, a, direct, repeat, 1, '(', 'DR-1)']), verbo([binding]), complemento([site, was, revealed, by, chromatin, immunoprecipitation])].
[sujeto(['The', dominant, negative, suppression, of, 'HNF4alpha', function]), verbo([decreased]), complemento([endogenous, 'COUP-TFII', 'expression,', and, the, specific, inactivation, of, 'COUP-TFII', by, small, interfering, 'RNA', caused, 'HNF4alpha', mRNA, levels, in, 832, /, 13, 'INS-1', cells, to, decrease])].
[sujeto(['This', positive, regulation, of, 'HNF4alpha', by, 'COUP-TFII', was, confirmed, by, the, 'adenovirus-mediated', overexpression, of, human, 'COUP-TFII', '(', 'hCOUP-TFII),', which]), verbo([increased]), complemento(['HNF4alpha', mRNA, levels, in, 832, /, 13, 'INS-1', cells, and, in, mouse, pancreatic, islets])].
[sujeto(['Finally,', 'hCOUP-TFII', overexpression, showed, that, there, is, direct, 'COUP-TFII', 'autorepression,', as, 'COUP-TFII', occupies, the, proximal, 'DR-1']), verbo([binding]), complemento([site, of, its, own, gene, in, vivo])].
[sujeto(['The', type, 1, ',', 3, ',', and, 5, forms, of, 'maturity-onset', diabetes, of, the, young, '(', 'MODY)', are]), verbo([caused]), complemento([by, mutations, of, the, genes, encoding, hepatocyte, nuclear, factor, '(', 'HNF)-4alpha,', 'HNF-1alpha,', and, 'HNF-1beta,', respectively, '[', 'Yamagata,', 'K'])].
[sujeto(['Mutations', in, the, hepatocyte]), verbo([nuclear]), complemento(['factor-1alpha', gene, in, 'maturity-onset', diabetes, of, the, young, '(', 'MODY3)'])].
[sujeto(['Mutations', in, the, hepatocyte]), verbo([nuclear]), complemento(['factor-4alpha', gene, in, 'maturity-onset', diabetes, of, the, young, '(', 'MODY1)'])].
[sujeto(['Mutation', in, hepatocyte]), verbo([nuclear]), complemento(['factor-1beta', gene, '(', 'TCF2)', associated, with, 'MODY'])].
[sujeto(['We']), verbo([found]), complemento([considerable, variation, in, the, level, of, 'HNF-4alpha', expression, by, the, individual, epithelial, cells, in, the, pancreatic, buds, on, 'E9'])].
[sujeto(['HNF-4alpha', and, 'HNF-1beta', were, initially]), verbo([expressed]), complemento([by, 'Pdx1(+)', common, progenitor, cells, and, 'neurogenin3(+)', '(', 'Ngn3(+))', endocrine, precursor, cells, during, the, first, 'transition,', but, expression, of, 'HNF-1beta', and, either, 'HNF-4alpha', or, 'HNF-1alpha', became, complementary, around, the, end, of, the, second, transition, '(', 'E15'])].
[sujeto(['In', the, mature, 'pancreas,', 'HNF-4alpha', was]), verbo([expressed]), complemento([by, 'glucagon-positive', 'alpha-cells,', 'insulin-positive', 'beta-cells,', 'somatostatin-positive', 'delta-cells,', and, pancreatic, 'polypeptide-positive', 'PP-cells,', as, well, as, by, pancreatic, exocrine, cells, and, ductal, cells])].
[sujeto(['These', results, indicate, that, the, expression, of, 'MODY', proteins, in, each, of, the, pancreatic, cell, types, is, strictly]), verbo([regulated]), complemento([in, accordance, with, the, status, of, differentiation, during, pancreatic, organogenesis])].
[sujeto(['Although', mutations, in, 'HNF4A', were, identified, as, the]), verbo([cause]), complemento([of, 'Maturity', 'Onset', 'Diabetes', of, the, 'Young', 1, '(', 'MODY1)', two, decades, 'ago,', the, mechanisms, by, which, this, nuclear, receptor, regulates, glucose, homeostasis, remain, unclear])].
[sujeto(['Here', we]), verbo([report]), complemento([that, loss, of, 'Drosophila', 'HNF4', recapitulates, hallmark, symptoms, of, 'MODY1,', including, 'adult-onset', 'hyperglycemia,', glucose, intolerance, and, impaired, 'glucose-stimulated', insulin, secretion, '(', 'GSIS)'])].
[sujeto(['These', defects, are, linked, to, a, role, for, dHNF4, in]), verbo([promoting]), complemento([mitochondrial, function, as, well, as, the, expression, of, 'Hex-C,', a, homolog, of, the, 'MODY2', gene, 'Glucokinase'])].
[sujeto([dHNF4, is]), verbo([required]), complemento([in, the, fat, body, and, 'insulin-producing', cells, to, maintain, glucose, homeostasis, by, supporting, a, developmental, switch, toward, oxidative, phosphorylation, and, 'GSIS', at, the, transition, to, adulthood])].
[sujeto(['Here', we, 'report,', for, the, first, 'time,', the, derivation, of, human]), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'hiPSCs)', from, patients, with, five, types, of, 'MODY:', 'MODY1', '(', 'HNF4A),', 'MODY2', '(', 'GCK),', 'MODY3', '(', 'HNF1A),', 'MODY5', '(', 'HNF1B),', and, 'MODY8', '(', 'CEL)', with, a, polycistronic, lentiviral, vector, expressing, a, 'Cre-excisable', human, &, 'quot;stem', cell, 'cassette&quot;', containing, the, four, reprogramming, factors, 'OCT4,', 'KLF4,', 'SOX2,', and, 'CMYC'])].
[sujeto(['These', 'MODY-hiPSCs', morphologically, resemble, human, pluripotent, stem, cells, '(', 'hPSCs),']), verbo([express]), complemento([pluripotency, markers, 'OCT4,', 'SOX2,', 'NANOG,', 'SSEA-4,', and, 'TRA-1-60,', give, rise, to, derivatives, of, the, three, germ, layers, in, a, teratoma, 'assay,', and, are, karyotypically, normal])].
[sujeto(['Overall,', our, 'MODY-hiPSCs', serve, as, invaluable, tools, to, dissect, the, role, of, 'MODY', genes, in, the, development, of, pancreas, and, islet, cells, and, to, evaluate, their, significance, in]), verbo([regulating]), complemento([beta, cell, function])].
[sujeto(['Mutations', of, the, 'HNF4A', gene]), verbo([cause]), complemento([a, form, of, 'maturity-onset', diabetes, of, the, young, '(', 'MODY1)', that, is, characterized, by, impairment, of, pancreatic, 'β-cell', function])].
[sujeto(['HNF4α', is, a, transcription, factor, belonging, to, the]), verbo([nuclear]), complemento([receptor, superfamily, '(', 'NR2A1),', but, its, target, genes, in, pancreatic, 'β-cells', are, largely, unknown])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, ankyrin, repeat, and, sterile, α, motif, domain, containing, 4, b, '(', 'Anks4b)', is, a, target, of, 'HNF4α', in, pancreatic, 'β-cells'])].
[sujeto(['Expression', of, 'Anks4b', was]), verbo([decreased]), complemento([in, both, βHNF4α, 'KO', islets, and, 'HNF4α', knockdown, 'MIN6', 'β-cells,', and, 'HNF4α', activated, 'Anks4b', promoter, activity])].
[sujeto(['Anks4b']), verbo([bound]), complemento([to, 'glucose-regulated', protein, 78, '(', 'GRP78),', a, major, endoplasmic, reticulum, '(', 'ER)', chaperone, 'protein,', and, overexpression, of, 'Anks4b', enhanced, the, 'ER', stress, response, and, 'ER', 'stress-associated', apoptosis, of, 'MIN6', cells])].
[sujeto(['These', results, indicate, that, 'Anks4b', is, a, 'HNF4α']), verbo([target]), complemento([gene, that, regulates, 'ER', stress, in, 'β-cells', by, interacting, with, 'GRP78,', thus, suggesting, that, 'HNF4α', is, involved, in, maintenance, of, the, 'ER'])].
[sujeto(['Effective', gene, therapy]), verbo([requires]), complemento([regulated, gene, expression, and, vector, safety])].
[sujeto(['We', developed, a, strategy, to, exponentially]), verbo([increase]), complemento([native, promoter, activity, while, retaining, inherent, regulation, by, inserting, 'multi-copy', response, elements, '(', 'REs)', into, 'non-adjacent', locations])].
[sujeto(['For', the, hepatocyte]), verbo([nuclear]), complemento([factor, '(', 'HNF)', 4, 'α-dependent', 'Hnf1a', '(', 'MODY3)', 'gene,', 'HNF4α', stimulation, increased, from, 5, -, to, 90, -, fold, by, inserting, 3, additional, 'HNF4α', 'REs', '(', 'H4REs)'])].
[sujeto(['Constructing', a, promoter, with, two, 4, xH4REs, 0.25, kb, apart, by, duplicating, the, 4, xH4RE, fragment]), verbo([increased]), complemento([stimulation, to, &, 'gt;1000-fold'])].
[sujeto(['Finally,', converting, the, 'HNF1α', 'RE', of, the, 'HNF4A', '(', 'MODY1)', 'P2', promoter, to, 4, xH1RE, and, adding, a, second, 4, xH1RE, 0.84, kb, upstream]), verbo([increased]), complemento(['HNF1α', stimulation, from, 26, -, to, &, 'gt;200-fold'])].
[sujeto(['Deleting', intervening, 'DNA', to, produce, 0.23, -, kb, spacing]), verbo([increased]), complemento([stimulation, to, &, 'gt;500-fold'])].
[sujeto(['Augmentation', of, three, promoters]), verbo([suggests]), complemento([that, this, approach, is, potentially, applicable, to, other, promoters, for, gene, therapy, and, might, obviate, the, need, for, viral, promoters])].
[sujeto(['It', forms, a, circuitry, of, molecular, 'cross-talk', with, other]), verbo([nuclear]), complemento([receptors, such, as, 'PXR', and, 'CAR', to, synergistically, initiate, transcription])].
[sujeto(['This', study]), verbo([reports]), complemento([on, the, 'frequency,', linkage, disequilibrium, pattern, and, 'tag-SNP', selection, of, 'NR2A1', polymorphisms, in, three, local, 'Asian', 'populations,', namely, 'Chinese,', 'Malays', and, 'Indians', '(', n, =, 56, subjects, 'each)'])].
[sujeto(['The', exonic, region, of, 'NR2A1', was, highly]), verbo([conserved]), complemento([with, only, 4, novel, and, 1, reported, 'SNPs', identified, at, low, allelic, frequencies, of, less, than, 0.02])].
[sujeto(['In-silico', predictions]), verbo([suggested]), complemento([that, some, of, these, polymorphic, variants, may, exert, functional, effects, through, affecting, the, binding, sites, of, transcription, and, splicing, factors])].
[sujeto(['Our', study]), verbo([provides]), complemento([valuable, information, on, the, genetic, variability, of, 'NR2A1', which, would, be, useful, for, pharmacogenetics, studies, in, the, local, 'Asian', populations])].
[sujeto(['The', constitutive, androstane, receptor, '(', 'CAR,', 'NR1I3)']), verbo([has]), complemento([a, central, role, in, detoxification, 'processes,', regulating, the, expression, of, a, set, of, genes, involved, in, metabolism])].
[sujeto(['The', dual, role, of, 'NR1I3', as, both, a, xenosensor, and, as, a, regulator, of, endogenous, energy, metabolism]), verbo([has]), complemento([recently, been, accepted])].
[sujeto(['It', was, shown, that, expression, of, the, gluconeogenic, genes, 'PEPCK', and, 'G6Pase', was]), verbo([repressed]), complemento([by, cisTPD, treatment, under, fasting, conditions])].
[sujeto(['Chromatin', immunoprecipitation, assays, demonstrated, that, cisTPD]), verbo([prevents]), complemento([the, binding, of, 'FOXO1', to, the, insulin, response, sequences, in, the, 'PEPCK', and, 'G6Pase', gene, promoters, in, rat, liver])].
[sujeto(['Moreover,', 'cisTPD-activated', 'NR1I3']), verbo([inhibited]), complemento(['NR2A1', '(', 'HNF-4)', transactivation, by, competing, with, 'NR2A1', for, binding, to, the, 'NR2A1-binding', element, '(', 'DR1-site)', in, the, gluconeogenic, gene, promoters])].
[sujeto(['Thus,', our, results, are, consistent, with, the, hypothesis, that, the, 'cisTPD-activated', 'NR1I3']), verbo([participates]), complemento([in, the, regulation, of, the, gluconeogenic, genes, 'PEPCK', and, 'G6Pase'])].
[sujeto(['Recent', 'studies,', 'however,']), verbo([suggest]), complemento([that, they, may, contain, transcription, factor, binding, sites, and, hence, possibly, play, a, role, in, regulating, gene, expression])].
[sujeto(['Here,', we, show, that]), verbo([binding]), complemento([sites, for, a, highly, conserved, member, of, the, nuclear, receptor, superfamily, of, 'ligand-dependent', transcription, 'factors,', hepatocyte, nuclear, factor, 4, alpha, '(', 'HNF4α,', 'NR2A1),', are, highly, prevalent, in, 'Alu', repeats])].
[sujeto(['We', employ, high, throughput, protein]), verbo([binding]), complemento([microarrays, '(', 'PBMs)', to, show, that, 'HNF4α', binds, &, 'gt;', 66, unique, sequences, in, 'Alu', repeats, that, are, present, in, '~1'])].
[sujeto(['We', use, chromatin, immunoprecipitation, '(', 'ChIP)', to, demonstrate, that, 'HNF4α']), verbo([binds]), complemento(['Alu', elements, in, the, promoters, of, target, genes, '(', 'ABCC3,', 'APOA4,', 'APOM,', 'ATPIF1,', 'CANX,', 'FEMT1A,', 'GSTM4,', 'IL32,', 'IP6K2,', 'PRLR,', 'PRODH2,', 'SOCS2,', 'TTR)', and, luciferase, assays, to, show, that, at, least, some, of, those, 'Alu', elements, can, modulate, 'HNF4α-mediated', transactivation, in, vivo, '(', 'APOM,', 'PRODH2,', 'TTR,', 'APOA4)'])].
[sujeto(['HNF4α-Alu', elements, are, enriched, in, promoters, of, genes]), verbo([involved]), complemento([in, 'RNA', processing, and, a, sizeable, fraction, are, in, regions, of, accessible, chromatin])].
[sujeto(['Comparative', genomics, analysis]), verbo([suggests]), complemento([that, there, may, have, been, a, gain, in, 'HNF4α', binding, sites, in, 'Alu', elements, during, evolution, and, that, non, 'Alu', 'repeats,', such, as, 'Tiggers,', also, contain, 'HNF4α', sites])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, 'HNF4α,', in, addition, to, regulating, gene, expression, via, high, affinity, binding, 'sites,', may, also, modulate, transcription, via, low, affinity, sites, in, 'Alu', repeats])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento(['factor-4α', '(', 'HNF4α,', 'NR2A1)', is, a, nuclear, receptor, that, has, a, critical, role, in, hepatocyte, differentiation, and, the, maintenance, of, homeostasis, in, the, adult, liver])].
[sujeto(['Here', we]), verbo([report]), complemento([the, native, 'HNF4α', 'isoform,', phosphorylation, 'status,', and, complexes, in, the, 'steady-state,', as, shown, by, shotgun, proteomics, in, 'HepG2', hepatocarcinoma, cells])].
[sujeto(['The']), verbo([associating]), complemento([complexes, identified, by, 'label-free', semiquantitative, proteomic, analysis, include, the, 'following:', the, 'DNA-dependent', protein, kinase, catalytic, 'subunit,', histone, acetyltransferase, 'complexes,', mRNA, splicing, 'complex,', other, nuclear, receptor, coactivator, 'complexes,', the, chromatin, remodeling, 'complex,', and, the, nucleosome, remodeling, and, histone, deacetylation, complex])].
[sujeto(['Among', the]), verbo([associating]), complemento(['proteins,', 'GRB10', interacting, 'GYF', protein, 2, '(', 'GIGYF2,', 'PERQ2)', is, a, new, candidate, cofactor, in, metabolic, regulation])].
[sujeto(['Moreover,', an, unexpected, heterodimerization, of, 'HNF4α', and, hepatocyte]), verbo([nuclear]), complemento(['factor-4γ', was, found])].
[sujeto(['A', biochemical, and, genomewide, analysis, of, transcriptional, regulation, showed, that, this, heterodimerization]), verbo([activates]), complemento([gene, transcription])].
[sujeto(['The', genes, thus]), verbo([transcribed]), complemento([include, the, cell, 'death-inducing', 'DEF45-like', effector, b, '(', 'CIDEB)', 'gene,', which, is, an, important, regulator, of, lipid, metabolism, in, the, liver])].
[sujeto(['This']), verbo([suggests]), complemento([that, the, analysis, of, the, distinctive, stoichiometric, balance, of, native, 'HNF4α', and, its, cofactor, complexes, described, here, are, important, for, an, accurate, understanding, of, transcriptional, regulation])].
[sujeto(['Nuclear', receptors, are, 'ligand-activated', transcription, factors]), verbo([involved]), complemento([in, all, major, physiological, functions, of, complex, organisms])].
[sujeto(['In', this, 'respect,', they, are, often, described, as, drugable]), verbo([targets]), complemento([for, a, number, of, pathological, states, including, hypercholesterolemia, and, atherosclerosis])].
[sujeto(['HNF4alpha', '(', 'NR2A1)', is, a, recently, '\'', 'deorphanized\'']), verbo([nuclear]), complemento([receptor, which, is, bound, in, vivo, by, linoleic, 'acid,', although, this, natural, ligand, does, not, seem, to, promote, transcriptional, activation])].
[sujeto(['In', 'mouse,', 'HNF4alpha', is, a, major, regulator, of, liver, development, and, hepatic, lipid, metabolism, and, mutations, in, human]), verbo([have]), complemento([been, linked, to, diabetes])].
[sujeto(['Here,', we]), verbo([have]), complemento([used, a, yeast, 'one-hybrid', system, to, identify, small, molecule, activators, of, 'HNF4alpha', in, a, library, of, synthetic, compounds, and, found, one, hit, bearing, a, methoxy, group, branched, on, a, nitronaphthofuran, backbone])].
[sujeto(['It', was]), verbo([found]), complemento([that, both, the, nitro, group, and, a, complete, naphthofuran, backbone, were, required, for, full, activity, of, the, compounds])].
[sujeto(['Furthermore,', adding, a, hydroxy, group, at, position, 7, of, the, minimal, backbone]), verbo([led]), complemento([to, the, most, active, compound, of, the, collection])].
[sujeto(['Accordingly,', a, direct, interaction, of, the, hydroxylated, compound, with, the, ligand]), verbo([binding]), complemento([domain, of, 'HNF4alpha', was, detected, by, 'NMR', and, thermal, denaturation, assays])].
[sujeto(['One', such, compound, was, able, to]), verbo([modulate]), complemento(['HNF4alpha-driven', transcription, in, transfected, 'HepG2C3A', cells])].
[sujeto(['These', data, indicate, that, 'HNF4alpha', activity, can, be]), verbo([modulated]), complemento([by, small, molecules, and, suggest, new, routes, for, targeting, the, receptor, in, humans])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 4, -, alpha, '(', 'HNF4alpha,', 'NR2A1)', is, a, nuclear, receptor, '(', 'NR)', required, for, liver, development, and, for, controlling, the, expression, of, many, 'hepatic-specific', genes, associated, with, important, metabolic, pathways])].
[sujeto(['Many', studies]), verbo([have]), complemento([also, identified, 'HNF4alpha', as, a, direct, transactivator, of, numerous, 'xenobiotic-metabolizing', cytochrome, 'P450', '(', 'CYP)', 'genes,', suggesting, that, this, factor, is, a, global, regulator, which, supports, 'CYP', transcription, in, the, liver])].
[sujeto(['In', the, last, few, 'years,', a, number, of, complex, interactions, and, 'cross-talks', between, 'HNF4alpha', and, other, transcription, factors, and, coregulators]), verbo([have]), complemento([also, 'surfaced,', and, the, impact, on, 'CYP', gene, expression, has, been, demonstrated])].
[sujeto(['Thus,', it, is, now, clear, that, 'HNF4alpha']), verbo([modulates]), complemento(['CYP', expression, in, the, liver, by, interacting, with, the, xenosensor, receptors, '(', 'PXR', and, 'CAR),', the, glucocorticoid, receptor, '(', 'GR),', the, 'feeding-fasting', cycle, target, 'PGC-1alpha,', the, 'sexual-dimorphism', factor, 'Stat5b,', and, other, 'liver-enriched', 'factors,', such, as, 'C/EBPs'])].
[sujeto(['In', addition, to]), verbo([regulating]), complemento([drug, elimination, 'pathways,', 'HNF4alpha', also, triggers, pleiotropic, effects, on, cholesterol, and, fatty, acid, 'metabolism,', glucose, homeostasis, and, inflammation])].
[sujeto(['The', host, cellular, factors, that]), verbo([promote]), complemento([persistent, viral, infections, in, vivo, 'are,', in, 'general,', poorly, understood])].
[sujeto(['Utilizing', the, hepatitis, 'B', virus, '(', 'HBV)', transgenic, mouse, model, of, chronic, 'infection,', we, demonstrate, that, the]), verbo([nuclear]), complemento(['receptor,', hepatocyte, nuclear, factor, 4, alpha, '(', 'HNF4alpha,', 'NR2A1),', is, essential, for, viral, biosynthesis, in, the, liver])].
[sujeto(['The', dependency, of, 'HBV', transcription, on, 'HNF4alpha', links, viral, biosynthesis, and, persistence, to, a, developmentally]), verbo([regulated]), complemento([transcription, factor, essential, for, host, viability])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF4alpha;', 'NR2A1)', is, an, orphan, member, of, the, nuclear, receptor, superfamily, expressed, in, liver, and, intestine])].
[sujeto(['Human', intestinal, biopsies, from, control, and, 'IBD', patients, were, examined, for, expression, of, mRNAs, encoding, 'HNF4alpha', and, other]), verbo([nuclear]), complemento([receptors])].
[sujeto(['In', human, intestinal, 'biopsies,', 'HNF4alpha', was, significantly]), verbo([decreased]), complemento([in, intestinal, tissues, from, 'Crohn\'s', disease, and, ulcerative, colitis, patients])].
[sujeto(['HNF4alpha', expression, was, also]), verbo([suppressed]), complemento([in, the, intestine, of, 'DSS-treated', mice])].
[sujeto(['In', the, 'DSS-induced', colitis, model, 'Hnf4alpha(DeltaIEpC)', mice, showed, markedly, more, severe, changes, in, clinical, symptoms, and, pathologies]), verbo([associated]), complemento([with, 'IBD', including, loss, of, body, 'weight,', colon, 'length,', and, histological, morphology, as, compared, with, 'Hnf4alpha(F/F)', mice])].
[sujeto(['Furthermore,', the, 'Hnf4alpha(DeltaIEpC)', mice, demonstrate, a, significant, alteration, of, 'mucin-associated', genes, and]), verbo([increased]), complemento([intestinal, 'permeability,', which, may, play, an, important, role, in, the, increased, susceptibility, to, acute, colitis, following, an, inflammatory, insult])].
[sujeto(['While', 'HNF4alpha', does, not]), verbo([have]), complemento([a, major, role, in, normal, function, of, the, 'intestine,', it, protects, the, gut, against, 'DSS-induced', colitis])].
[sujeto(['Pregnane', 'X', receptor, '(', 'PXR;', 'NR1I2),', a, key, transcriptional, factor, that]), verbo([regulates]), complemento([genes, encoding, 'drug-metabolizing', enzymes, and, drug, 'transporters,', is, abundantly, expressed, in, the, human, liver])].
[sujeto(['In', this, 'study,', we, examined, the, involvement, of, hepatocyte]), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF4alpha;', 'NR2A1)', in, the, transcriptional, regulation, of, the, human, 'PXR', gene, in, the, human, liver])].
[sujeto(['The', activities, of, the, human, 'PXR', promoter, containing, the, direct, repeat, 1, '(', 'DR1)', element, located, at, -, 88, /, -, 76, of, the, promoter, were, significantly]), verbo([increased]), complemento([by, 'co-expression', of, 'HNF4alpha', in, the, human, hepatocellular, carcinoma, cell, line])].
[sujeto(['The', results, of, gel, mobility, shift, assays, and, chromatin, immunoprecipitation, assays, showed, that, 'HNF4alpha', was]), verbo([bound]), complemento([to, the, promoter, region, containing, the, 'DR1', element])].
[sujeto(['A', 'knock-down', of, 'HNF4alpha', by, siRNA, significantly]), verbo([decreased]), complemento([expression, levels, of, endogenous, 'PXR', mRNA, in, 'HepG2', cells])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, 'HNF4alpha', transactivated, the, human, 'PXR', gene, by, binding, to, the, 'DR1', element, located, at, -, 88, /, -, 76, of, the, promoter, and, was, involved, in, the, expression, of, 'PXR', in, the, human, liver])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF4alpha,', 'NR2A1)', is, required, for, development, of, the, liver, and, for, controlling, the, expression, of, many, genes, specifically, expressed, in, the, liver, and, associated, with, a, number, of, critical, metabolic, pathways])].
[sujeto(['Among', the, genes]), verbo([regulated]), complemento([by, 'HNF4alpha', are, the, 'xenobiotic-metabolizing', cytochromes, 'P450,', 'UDP-glucuronosyltransferases', and, sulfotransferases, thus, making, this, transcription, factor, critical, in, the, control, of, drug, metabolism])].
[sujeto(['HNF4alpha,', a, member, of, the]), verbo([nuclear]), complemento([receptor, 'superfamily,', binds, as, a, homodimer, to, direct, repeat, elements, upstream, of, target, genes])].
[sujeto(['However,', in, contrast, to, many, other]), verbo([nuclear]), complemento(['receptors,', there, is, no, convincing, evidence, that, 'HNF4alpha', is, activated, by, exogenous, 'ligands,', at, least, in, the, classic, mechanism, used, by, other, steroid, and, metabolic, nuclear, receptors])].
[sujeto(['X-ray', crystallographic, studies, revealed, that, 'HNF4alpha']), verbo([has]), complemento([a, fatty, acid, embedded, in, its, putative, ligand, binding, site, that, may, not, be, easily, released, or, displaced, by, exogenous, ligands])].
[sujeto(['HNF4alpha,', as, a, general, 'rule,', controls, constitutive, expression, of, many, hepatic, genes, but, under, certain, circumstances, can, be, subjected, to, regulation, by, differential, 'co-activator', 'recruitment,', by, phosphorylation, and, by, interaction, with, other]), verbo([nuclear]), complemento([receptors])].
[sujeto(['The', ability, of, 'HNF4alpha', to, be]), verbo([regulated]), complemento([offers, hope, that, it, could, be, a, drug, target])].
[sujeto(['Animal', studies]), verbo([reveal]), complemento([that, fasting, and, caloric, restriction, produce, increased, activity, of, specific, metabolic, pathways, involved, in, resistance, to, weight, loss, in, liver])].
[sujeto(['Evidence']), verbo([suggests]), complemento([that, this, phenomenon, may, in, part, occur, through, the, action, of, the, constitutive, androstane, receptor, '(', 'CAR,', 'NR1I3)'])].
[sujeto(['Currently,', the, precise, molecular, mechanisms, that]), verbo([activate]), complemento(['CAR', during, fasting, are, unknown])].
[sujeto(['We', show, that, fasting, coordinately]), verbo([induces]), complemento([expression, of, genes, encoding, peroxisome, 'proliferator-activated', receptor, gamma, 'coactivator-1alpha', '(', 'PGC-1alpha),', 'CAR,', cytochrome, 'P-450', 2, b10, '(', 'Cyp2b10),', 'UDP-glucuronosyltransferase', 1, a1, '(', 'Ugt1a1),', sulfotransferase, 2, a1, '(', 'Sult2a1),', and, organic, 'anion-transporting', polypeptide, 2, '(', 'Oatp2)', in, liver, in, mice])].
[sujeto(['Treatments', that, elevate, intracellular, cAMP, levels, also, produce]), verbo([increased]), complemento([expression, of, these, genes, in, cultured, hepatocytes])].
[sujeto(['Our', data, show, that, 'PGC-1alpha', interaction, with, hepatocyte]), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF4alpha,', 'NR2A1)', directly, regulates, 'CAR', gene, expression, through, a, novel, and, evolutionarily, conserved, 'HNF4-response', element, '(', 'HNF4-RE)', located, in, its, proximal, promoter])].
[sujeto(['Expression', of, 'PGC-1alpha', in, cells]), verbo([increases]), complemento(['CAR', expression, and, 'ligand-independent', 'CAR', activity])].
[sujeto(['Genetic', studies]), verbo([reveal]), complemento([that, hepatic, expression, of, 'HNF4alpha', is, required, to, produce, 'fasting-inducible', 'CAR', expression, and, activity])].
[sujeto(['Taken', 'together,', our, data, show, that, fasting, produces]), verbo([increased]), complemento([expression, of, genes, encoding, key, metabolic, enzymes, and, an, uptake, transporter, protein, through, a, network, of, interactions, involving, 'cAMP,', 'PGC-1alpha,', 'HNF4alpha,', 'CAR,', and, 'CAR', target, genes, in, liver])].
[sujeto(['Given', the, recent]), verbo([finding]), complemento([that, mice, lacking, 'CAR', exhibit, a, profound, decrease, in, resistance, to, weight, loss, during, extended, periods, of, caloric, 'restriction,', our, findings, have, important, implications, in, the, development, of, drugs, for, the, treatment, of, obesity, and, related, diseases])].
[sujeto(['Phenobarbital', is, a, lipophilic, molecule, used, as, a, sedative, and, antiepileptic, drug, that, elicits, a, multitude, of, effects, in, the, 'liver,', including, gross, liver, 'enlargement,', hepatocyte, 'hypertrophy,', and]), verbo([induced]), complemento([expression, of, 'drug-metabolizing', enzymes, and, other, 'liver-specific', genes])].
[sujeto(['The', constitutive, androstane, receptor, '(', 'CAR;', 'NR1I3)', and, to, a, lesser, extent, the, pregnane, 'X', receptor, '(', 'PXR;', 'NR1I2)', are, responsible, for]), verbo([mediating]), complemento([induction, of, many, 'phenobarbital-responsive', genes])].
[sujeto(['However,', 'CAR-mediated', transcriptional, control, of, some, genes, is, critically, dependent, on, hepatocyte]), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF-4alpha;', 'NR2A1),', which, itself, regulates, multiple, 'liver-specific', genes, involved, in, hepatic, 'growth,', 'metabolism,', and, differentiation])].
[sujeto(['We', studied, the, effects, of, phenobarbital, on, 'HNF-4alpha', expression, in, hepatocytes, and]), verbo([provide]), complemento([evidence, that, 'HNF-4alpha', nuclear, expression, is, regulated, in, response, to, phenobarbital])].
[sujeto(['In', 'addition,']), verbo([nuclear]), complemento([expression, of, 'HNF-4alpha', protein, is, significantly, elevated, 3, hours, after, the, administration, of, phenobarbital, in, 'wild-type,', 'CAR-/-,', and, 'CAR-/-/PXR-/-', mice])].
[sujeto(['In', 'addition,', the, phosphatase, inhibitor, okadaic, acid, and, the, 'Ca2+/calmodulin-dependent', protein, kinase, 'II', inhibitor, 'KN62', block]), verbo([nuclear]), complemento([induction, of, 'HNF-4alpha', by, phenobarbital])].
[sujeto(['Furthermore,', 'HNF-4alpha']), verbo([nuclear]), complemento([expression, is, enhanced, by, inhibition, of, cyclic, 'AMP-dependent', protein, kinase, 'A'])].
[sujeto(['In', 'conclusion,']), verbo([induced]), complemento([nuclear, expression, of, 'HNF-4alpha', and, 'CAR', is, an, integral, part, of, the, phenobarbital, 'response,', aimed, at, coordinated, regulation, of, genes, involved, in, drug, metabolism, and, detoxification, as, well, as, maintenance, of, liver, function])].
[sujeto(['Bile', 'acids,', 'steroids,', and, drugs]), verbo([activate]), complemento([steroid, and, xenobiotic, receptor, pregnane, 'X', receptor, '(', 'PXR;', 'NR1I2),', which, induces, human, cytochrome, 'P4503A4', '(', 'CYP3A4)', in, drug, metabolism, and, cholesterol, 7, 'alpha-hydroxylase', '(', 'CYP7A1)', in, bile, acid, synthesis, in, the, liver])].
[sujeto(['Rifampicin,', a, human, 'PXR', 'agonist,']), verbo([inhibits]), complemento([bile, acid, synthesis, and, has, been, used, to, treat, cholestatic, diseases])].
[sujeto(['The', objective, of, this, study, is, to, elucidate, the, mechanism, by, which, 'PXR']), verbo([inhibits]), complemento(['CYP7A1', gene, transcription])].
[sujeto(['The', mRNA, expression, levels, of, 'CYP7A1', and, several]), verbo([nuclear]), complemento([receptors, known, to, regulate, the, 'CYP7A1', gene, were, assayed, in, human, primary, hepatocytes, by, quantitative, 'real-time', 'PCR', '(', 'Q-PCR)'])].
[sujeto(['Rifampicin', reduced, 'CYP7A1', and, small, heterodimer, partner, '(', 'SHP;', 'NR02B)', mRNA, expression]), verbo([suggesting]), complemento([that, 'SHP', was, not, involved, in, 'PXR', inhibition, of, 'CYP7A1'])].
[sujeto(['Rifampicin']), verbo([inhibited]), complemento(['CYP7A1', reporter, activity, and, a, 'PXR', binding, site, was, localized, to, the, bile, acid, response, 'element-I'])].
[sujeto(['Mammalian', 'two-hybrid', assays, revealed, that, 'PXR']), verbo([interacted]), complemento([with, hepatic, nuclear, factor, 4, alpha, '(', 'HNF4', 'alpha,', 'NR2A1)', and, rifampicin, was, required])].
[sujeto(['PXR', also]), verbo([interacted]), complemento([with, peroxisome, 'proliferator-activated', receptor, gamma, coactivator, '(', 'PGC-1', 'alpha),', which, interacted, with, 'HNF4', alpha, and, induced, 'CYP7A1', gene, transcription])].
[sujeto(['Rifampicin']), verbo([enhanced]), complemento(['PXR', interaction, with, 'HNF4', alpha, and, reduced, 'PGC-1', alpha, interaction, with, 'HNF4', alpha])].
[sujeto(['Chromatin', immunoprecipitation, assay, showed, that, 'PXR,', 'HNF4', 'alpha,', and, 'PGC-1', alpha]), verbo([bound]), complemento([to, 'CYP7A1', 'chromatin,', and, rifampicin, dissociated, 'PGC-1', alpha, from, chromatin])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, activation, of, 'PXR', by, rifampicin, promotes, 'PXR', interaction, with, 'HNF4', alpha, and, blocks, 'PGC-1', alpha, activation, with, 'HNF4', alpha, and, results, in, inhibition, of, 'CYP7A1', gene, transcription])].
[sujeto(['Along', with, retinoid, 'X', receptor, alpha, '(', 'RXRalpha),', 'HNF4alpha', belongs, to, the]), verbo([nuclear]), complemento([receptor, subfamily, 2, '(', 'NR2),', characterised, by, a, conserved, arginyl, residue, and, a, glutamate, residue, insert, in, helix, 7, '(', 'H7)', of, the, ligand, binding, domain, '(', 'LBD)'])].
[sujeto(['Crystallographic', studies, indicate, that, 'R348', and, 'E352', residues, in, 'RXRalpha', 'H7', are]), verbo([involved]), complemento([in, 'charge-driven', interactions, that, improve, dimerisation])].
[sujeto(['Moreover,', our, results]), verbo([provide]), complemento([a, new, concept, according, to, which, helices, of, the, 'HNF4alpha', 'LBD', dimerisation, interface, contribute, differently, to, dimerisation, required, for, 'DNA', 'binding;', unlike, 'H9', and, 'H10,', 'H7', is, not, involved, in, 'DNA', binding])].
[sujeto(['Substitutions', of, 'E262']), verbo([decreased]), complemento([the, repression, of, 'HNF4alpha', transcriptional, activity, by, a, 'dominant-negative', 'HNF4alpha', 'mutant,', highlighting, the, importance, of, this, residue, for, dimerisation, in, the, cell, context])].
[sujeto(['The', glutamate, residue, insert, and, the]), verbo([conserved]), complemento([arginyl, residue, in, 'H7', most, probably, represent, a, signature, of, the, 'NR2', subfamily, of, nuclear, receptors])].
[sujeto(['The']), verbo([nuclear]), complemento([receptor, '(', 'NR)', superfamily, is, a, large, group, of, 'related,', pharmacologically, important, 'receptors,', comprising, the, targets, for, over, 10, '%', of, commonly, prescribed, drugs])].
[sujeto(['Cross-genome', analysis, of, 'NR', 'sequence,', 'structure,', and, biological, 'function,']), verbo([provides]), complemento([an, important, source, of, information, on, the, function, of, human, 'NRs', and, thus, plays, a, role, in, 'NR', drug, discovery])].
[sujeto(['For', 'example,', research, on, the, pregnane, 'X', receptor, '(', 'PXR;', 'NR1I2),', constitutive, androstane, receptor, '(', 'CAR;', 'NR1I3),', hepatocyte]), verbo([nuclear]), complemento([factor, 4, '(', 'HNF4;', 'NR2A1),', and, farnesoid, 'X', receptor, '(', 'FXR)', illustrate, how, the, study, of, nonhuman, orthologs, has, provided, new, insights, into, 'NR', biology, and, has, increased, our, understanding, of, human, 'NRs', and, orphan, 'NR', function])].
[sujeto(['Understanding', differences, between, humans, and, pharmacological, model, species, may]), verbo([provide]), complemento([useful, tools, for, the, development, of, new, 'NR-binding', drugs])].
[sujeto(['For', most, 'ligand-dependent']), verbo([nuclear]), complemento(['receptors,', the, status, of, endogenous, ligand, modulates, the, relative, affinities, for, corepressor, and, coactivator, complexes])].
[sujeto(['It', is, less, clear, what, parameters]), verbo([modulate]), complemento([the, switch, between, corepressor, and, coactivator, for, the, orphan, receptors])].
[sujeto(['Our', previous, work, demonstrated, that, hepatocyte]), verbo([nuclear]), complemento([factor, 4, alpha1, '(', 'HNF4alpha1,', 'NR2A1)', interacts, with, the, p160, coactivator, 'GRIP1', and, the, cointegrators, 'CBP', and, p300, in, the, absence, of, exogenously, added, ligand, and, that, removal, of, the, 'F', domain, enhances, these, interactions])].
[sujeto(['Loss', of, the, 'F', domain, resulted, in, marked, reduction, of, the, ability, of, 'SMRT', to]), verbo([interact]), complemento([with, 'HNF4alpha1', in, vitro, and, repress, 'HNF4alpha1', activity, in, 'vivo,', although, the, isolated, 'F', domain, itself, failed, to, interact, with, 'SMRT'])].
[sujeto(['Surprisingly,']), verbo([loss]), complemento([of, both, the, 'A/B', and, 'F', domains, restored, full, repression, by, 'SMRT,', suggesting, involvement, of, both, domains, in, the, 'SMRT', interaction])].
[sujeto(['Collectively,', these, results]), verbo([suggest]), complemento([that, 'HNF4alpha', can, functionally, interact, with, both, a, coactivator, and, a, corepressor, without, altering, the, status, of, any, putative, ligand, and, that, the, presence, of, the, 'F', domain, may, play, a, role, in, discriminating, between, the, different, coregulators])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF4alpha)', '(', 'NR2A1),', an, orphan, member, of, the, nuclear, receptor, 'superfamily,', binds, 'DNA', exclusively, as, a, homodimer, even, though, it, is, very, similar, in, amino, acid, sequence, to, retinoid, 'X', receptor, alpha, '(', 'RXRalpha),', which, heterodimerizes, readily, with, other, receptors])].
[sujeto(['Here,', experimental, analysis, of, residues]), verbo([involved]), complemento([in, protein, dimerization, and, studies, on, a, reported, ligand, for, 'HNF4alpha', are, combined, with, a, structural, model, of, the, 'HNF4alpha', 'ligand-binding', domain, '(', 'LBD)', '(', residues, 137, to, 384, ')'])].
[sujeto(['When', 'K300', '(', in, helix, 9, ')', and, 'E327', '(', in, helix, 10, ')', of, 'HNF4alpha1', were, converted, to, the, analogous, residues, in, 'RXRalpha', '(', 'E390', and, 'K417,', 'respectively)', the, resulting, construct, did, not]), verbo([heterodimerize]), complemento([with, the, 'wild-type', 'HNF4alpha,', although, it, was, still, able, to, form, homodimers, and, bind, 'DNA'])].
[sujeto(['Furthermore,', the, double, mutant, did, not]), verbo([heterodimerize]), complemento([with, 'RXR', or, 'RAR', but, was, still, able, to, dimerize, in, solution, with, an, 'HNF4alpha', construct, truncated, at, amino, acid, residue, 268])].
[sujeto(['This']), verbo([suggests]), complemento([that, the, charge, compatibility, between, helices, 9, and, 10, is, 'necessary,', but, not, 'sufficient,', to, determine, dimerization, 'partners,', and, that, additional, residues, in, the, 'HNF4alpha', 'LBD', are, also, important, in, dimerization])].
[sujeto(['Finally,', these, results]), verbo([provide]), complemento([insight, into, the, mechanism, of, action, of, naturally, occurring, mutations, in, the, human, 'HNF4alpha', gene, found, in, patients, with, maturity, onset, diabetes, of, the, young, 1, '(', 'MODY1)'])].
[sujeto(['Transcription', 'factors,', such, as]), verbo([nuclear]), complemento(['receptors,', often, exist, in, various, forms, that, are, generated, by, highly, conserved, splicing, events])].
[sujeto(['Whereas', the, functional, significance, of, these, splicing, variants, is, often, not, 'known,', it, is, known, that]), verbo([nuclear]), complemento([receptors, activate, transcription, through, interaction, with, coactivators])].
[sujeto(['The', 'parameters,', other, than, 'ligands,', that, might]), verbo([modulate]), complemento([those, 'interactions,', 'however,', are, not, well, 'characterized,', nor, is, the, role, of, splicing, variants])].
[sujeto(['In', this, 'study,', transient, 'transfection,', yeast, 'two-hybrid,', and, 'GST', pulldown, assays, are, used, to, show, not, only, that]), verbo([nuclear]), complemento([receptor, hepatocyte, nuclear, factor, 4, alpha1, '(', 'HNF4alpha1,', 'NR2A1)', interacts, with, 'GRIP1,', and, other, 'coactivators,', in, the, absence, of, ligand, but, also, that, the, uncommonly, large, 'F', domain, in, the, 'C', terminus, of, the, receptor, inhibits, that, interaction])].
[sujeto(['In', 'vitro,', the, 'F', domain, was]), verbo([found]), complemento([to, obscure, an, 'AF-2-independent', binding, site, for, 'GRIP1', that, did, not, map, to, nuclear, receptor, boxes, 'II', or, 'III'])].
[sujeto(['A', series, of, protease, digestion, assays, indicates, that, there, may, be, structural, differences, between, 'HNF4alpha1', and, 'HNF4alpha2', in, the, 'F', domain, as, well, as, in, the, ligand]), verbo([binding]), complemento([domain, '(', 'LBD)'])].
[sujeto(['The', data, also]), verbo([suggest]), complemento([that, there, is, a, direct, physical, contact, between, the, 'F', domain, and, the, 'LBD', of, 'HNF4alpha1', and, -, alpha2, and, that, that, contact, is, different, in, the, 'HNF4alpha1', and, 'HNF4alpha2', isoforms])].
[sujeto(['Finally,', we, propose, a, model, in, which, the, 'F', domain, of, 'HNF4alpha1']), verbo([acts]), complemento([as, a, negative, regulatory, region, for, transactivation, and, in, which, the, alpha2, insert, ameliorates, the, negative, effect, of, the, 'F', domain])].
[sujeto(['A']), verbo([conserved]), complemento([repressor, sequence, in, the, 'F', domains, of, 'HNF4alpha1', and, -, alpha2, suggests, that, this, model, may, be, relevant, to, other, nuclear, receptors, as, well])].
[sujeto(['Nuclear', hormone, receptors, '(', 'NHRs)', are, transcription, factors, that]), verbo([regulate]), complemento([numerous, physiological, and, developmental, processes, and, represent, important, drug, targets])].
[sujeto(['NHR-49,', an, ortholog, of, 'Hepatocyte', 'Nuclear', 'Factor', 4, '(', 'HNF4),']), verbo([has]), complemento([emerged, as, a, key, regulator, of, lipid, metabolism, and, life, span, in, the, nematode, worm, 'Caenorhabditis', elegans])].
[sujeto(['However,', many, aspects, of, 'NHR-49', function, remain, poorly, 'understood,', including, whether, and, how, it]), verbo([regulates]), complemento([individual, sets, of, target, genes, and, whether, its, activity, is, modulated, by, a, ligand])].
[sujeto(['These', substitutions, all, affect, the, 'ligand-binding', domain, '(', 'LBD),', which, is, critical, for, ligand]), verbo([binding]), complemento([and, protein, interactions])].
[sujeto(['Thus,', these, alleles]), verbo([provide]), complemento([an, opportunity, to, test, how, three, specific, residues, contribute, to, 'NHR-49', dependent, gene, regulation])].
[sujeto(['We']), verbo([find]), complemento([that, despite, originating, from, a, screen, favoring, the, activation, of, specific, 'NHR-49', 'targets,', all, three, gof, alleles, cause, broad, upregulation, of, 'NHR-49', regulated, genes])].
[sujeto(['Interestingly,', 'nhr-49(et7)', and, 'nhr-49(et8)', exclusively, affect, 'nhr-49', dependent, 'activation,', whereas, the, 'nhr-49(et13)', surprisingly, affects, both, 'nhr-49']), verbo([mediated]), complemento([activation, and, 'repression,', implicating, the, affected, residue, as, dually, important])].
[sujeto(['We', also, observed, phenotypic, 'non-equivalence', of, these, 'alleles,', as, they, unexpectedly]), verbo([caused]), complemento([a, 'long,', 'short,', and, normal, life, 'span,', respectively])].
[sujeto(['However,', in, silico, structural, modeling, revealed, that, 'NHR-49', likely]), verbo([interacts]), complemento([with, small, molecule, ligands, and, that, the, missense, mutations, might, alter, ligand, 'binding,', providing, a, possible, explanation, for, increased, 'NHR-49', activity])].
[sujeto(['In', 'sum,', our, findings, indicate, that, the, three, 'nhr-49', gof, alleles, are, 'non-equivalent,', and, highlight, the]), verbo([conserved]), complemento(['V411', residue, affected, by, et13, as, critical, for, gene, activation, and, repression, alike])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 4, α, '(', 'HNF4α)', is, a, nuclear, receptor, that, regulates, the, expression, of, genes, involved, in, the, secretion, of, apolipoprotein, 'B', '(', 'apoB)-containing', lipoproteins, and, in, glucose, metabolism])].
[sujeto(['Luciferase', reporter, gene, assays, revealed, that, the, activity, of, the, 'MTP', gene, promoter, was]), verbo([suppressed]), complemento([by, luteolin, and, that, the, mutation, of, 'HNF4α-binding', element, abolished, luteolin, responsiveness])].
[sujeto(['Luteolin', treatment]), verbo([caused]), complemento([a, significant, decrease, in, the, mRNA, levels, of, 'HNF4α', target, genes, in, 'HepG2', cells, and, inhibited, 'apoB-containing', lipoprotein, secretion, in, 'HepG2', and, differentiated, 'Caco2', cells])].
[sujeto(['Luteolin', did, not, affect, the, 'DNA']), verbo([binding]), complemento([of, 'HNF4α', to, the, promoter, region, of, its, target, genes, but, suppressed, the, acetylation, level, of, histone, 'H3', in, the, promoter, region, of, certain, 'HNF4α', target, genes])].
[sujeto(['Short', term, treatment, of, mice, with, luteolin, significantly]), verbo([suppressed]), complemento([the, expression, of, 'HNF4α', target, genes, in, the, liver])].
[sujeto(['In', 'addition,', long, term, treatment, of, mice, with, luteolin, significantly]), verbo([suppressed]), complemento([their, 'diet-induced', obesity, and, improved, their, serum, glucose, and, lipid, parameters])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, flavonoid, luteolin, ameliorates, an, atherogenic, lipid, profile, in, vivo, that, is, likely, to, be, mediated, through, the, inactivation, of, 'HNF4α'])].
[sujeto(['This', mutation, is, located, in, the]), verbo([binding]), complemento([site, of, hepatocyte, nuclear, factor, 4, '(', 'HNF4),', and, a, number, of, 'liver&#8209;enriched', transcription, factors, are, involved, in, the, regulation, of, 'HBV', transcription, and, replication])].
[sujeto(['In', 'conclusion,', the, replication, capacity, of, 'HBV', with, the, 'TA', mutation, was, 'increased,', and, the, mutation, was]), verbo([associated]), complemento([with, a, reduction, in, serum, 'HBeAg', levels])].
[sujeto(['Nonalcoholic', fatty, liver, disease, '(', 'NAFLD)', is, a, risk, factor, for, 'Hepatocellular', carcinoma, '(', 'HCC),', but]), verbo([he]), complemento([transition, from, 'NAFLD', to, 'HCC', is, poorly, understood])].
[sujeto(['Our', findings, show, 'that:', '(', 'I)', 'HNF4', is, a, common, potential, transcription, factor]), verbo([mediating]), complemento([the, transcription, of, 'NAFLD', progression, genes, '(', 'II)', mice, 'HCC', derived, from, 'NAFLD', 'co-cluster', with, a, less, aggressive, human, 'HCC', subtype, of, differential, prognosis, and, mixed, etiology, '(', 'III)', the, 'HCC', survival, signature, is, able, to, correctly, classify, 95, '%', of, the, samples, and, gives, 'Fgf20', and, 'Tgfb1i1', as, the, most, robust, genes, for, prediction, '(', 'IV)', the, expression, values, of, genes, composing, the, signature, in, an, independent, human, 'HCC', dataset, revealed, different, 'HCC', subtypes, showing, differences, in, survival, time, by, a, 'Logrank', test])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, the, identification, of, a, novel, 'WD-domain', 'protein,', 'STRAP', that, plays, a, role, in, maintenance, of, mesenchymal, morphology, by, regulating, 'E-cadherin', and, that, enhances, tumorigenicity, partly, by, downregulating, 'CDK', inhibitor, 'p21(Cip1)'])].
[sujeto(['Here,', we]), verbo([have]), complemento([employed, 'STRAP', knock, out, and, knockdown, cell, models, '(', mouse, embryonic, 'fibroblast,', human, cancer, cell, 'lines)', to, show, how, 'STRAP', downregulates, 'E-cadherin', and, 'p21(Cip1)', by, abrogating, the, binding, of, 'Sp1', to, its, consensus, binding, sites])].
[sujeto(['Moreover,', 'ChIP', assays]), verbo([suggest]), complemento([that, 'STRAP', recruits, 'HDAC1', to, 'Sp1', binding, sites, in, 'p21(Cip1)', promoter])].
[sujeto(['Interestingly,']), verbo([loss]), complemento([of, 'STRAP', can, stabilize, 'Sp1', by, repressing, its, ubiquitination, in, 'G1', 'phase,', resulting, in, an, enhanced, expression, of, 'p21(Cip1)', by, &, 'gt;4'])].
[sujeto(['Using', 'Bioinformatics', and, 'Microarray', 'analyses,', we]), verbo([have]), complemento([observed, that, 87, '%', mouse, genes, downregulated, by, 'STRAP', have, conserved, 'Sp1', binding, sites])].
[sujeto(['These', results]), verbo([suggest]), complemento([a, novel, mechanism, of, regulation, of, 'E-cadherin', and, 'p21(Cip1)', by, 'STRAP', by, modulating, 'Sp1-dependent', 'transcription,', and, higher, expression, of, 'STRAP', in, lung, cancer, may, contribute, to, downregulation, of, 'E-cadherin', and, 'p21(Cip1)', and, to, tumor, progression])].
[sujeto(['Conversely,', metabolism, and, food, consumption]), verbo([regulate]), complemento([the, internal, 'clock,', pointing, the, existence, of, an, intricate, relationship, between, nutrient, state, and, circadian, homeostasis, that, is, far, from, being, understood])].
[sujeto(['To', systematically, understand, how, the, interplay, of, circadian, clock, and, 'nutrient-driven', rhythm]), verbo([regulates]), complemento(['SREBP1', 'activity,', we, evaluated, the, 'genome-wide', binding, of, 'SREBP1', to, its, targets, throughout, the, day, in, 'C57BL/6', mice])].
[sujeto(['However,', the, temporal, expression, of, 'SREBP1']), verbo([targets]), complemento([was, not, always, synchronized, with, its, binding, pattern])].
[sujeto(['In', 'particular,', different, expression, phases, were, observed, for, 'SREBP1']), verbo([target]), complemento([genes, depending, on, their, 'function,', suggesting, the, involvement, of, other, transcription, factors, in, their, regulation])].
[sujeto(['Interestingly,', the, proper, temporal, expression, profile, of, these, genes, was, dramatically, changed, in, 'Bmal1-/-', mice, upon, 'time-restricted', 'feeding,', for, which, a, 'rhythmic,', but, slightly, 'delayed,']), verbo([binding]), complemento([of, 'SREBP1', was, maintained])].
[sujeto(['Collectively,', our, results, show, that, besides, the, 'nutrient-driven', regulation, of, 'SREBP1']), verbo([nuclear]), complemento(['translocation,', a, second, layer, of, modulation, of, 'SREBP1', transcriptional, 'activity,', strongly, dependent, from, the, circadian, 'clock,', exists])].
[sujeto(['This', system, allows, us, to, fine, tune, the, expression, timing, of, 'SREBP1']), verbo([target]), complemento(['genes,', thus, helping, to, temporally, separate, the, different, physiological, processes, in, which, these, genes, are, involved])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 4, -, alpha, '(', 'HNF4-α)', is, a, nuclear, receptor, regulating, 'metabolism,', cell, 'junctions,', differentiation, and, proliferation, in, liver, and, intestinal, epithelial, cells])].
[sujeto(['Mutations', within, the, 'HNF4A', gene, are]), verbo([associated]), complemento([with, human, diseases, such, as, 'maturity-onset', diabetes, of, the, young])].
[sujeto(['Recently,', 'HNF4A']), verbo([has]), complemento([also, been, described, as, a, susceptibility, gene, for, ulcerative, colitis, in, 'genome-wide', association, studies])].
[sujeto(['In', 'addition,', specific, 'HNF4A', genetic, variants]), verbo([have]), complemento([been, identified, in, pediatric, cohorts, of, 'Crohn\'s', disease])].
[sujeto(['This', review, mainly, focuses, on, the, role, of, long, chain, fatty, acids, '(', 'LCFAs)', in]), verbo([regulating]), complemento([energy, metabolism, as, ligands, of, peroxisome, 'proliferator-activated', receptors, '(', 'PPARs)'])].
[sujeto(['PPAR-alpha']), verbo([expressed]), complemento([primarily, in, liver, is, essential, for, metabolic, adaptation, to, starvation, by, inducing, genes, for, 'beta-oxidation', and, ketogenesis, and, by, downregulating, energy, expenditure, through, fibroblast, growth, factor, 21])].
[sujeto(['PPAR-delta', is, highly]), verbo([expressed]), complemento([in, skeletal, muscle, and, induces, genes, for, 'LCFA', oxidation, during, fasting, and, endurance, exercise])].
[sujeto(['PPAR-delta', also]), verbo([regulates]), complemento([glucose, metabolism, and, mitochondrial, biogenesis, by, inducing, 'FOXO1', and, 'PGC1-alpha'])].
[sujeto(['Genes']), verbo([targeted]), complemento([by, 'PPAR-gamma', in, adipocytes, suggest, that, 'PPAR-gamma', senses, incoming, 'non-esterified', 'LCFAs', and, induces, the, pathways, to, store, 'LCFAs', as, triglycerides])].
[sujeto(['Adiponectin,', another, important]), verbo([target]), complemento([of, 'PPAR-gamma', may, act, as, a, spacer, between, adipocytes, to, maintain, their, metabolic, activity, and, insulin, sensitivity])].
[sujeto(['Specific', 'LCFAs', are]), verbo([required]), complemento([for, the, synthesis, of, skin, 'lipids,', which, are, essential, for, water, barrier, and, thermal, insulation, functions, of, the, skin])].
[sujeto(['Disturbance', of, skin, lipid, metabolism, often]), verbo([causes]), complemento([apparent, resistance, to, developing, obesity, at, the, expense, of, normal, skin, function])].
[sujeto(['Prenatal', ethanol, exposure, '(', 'PEE)']), verbo([induces]), complemento([dyslipidemia, and, hyperglycemia, in, fetus, and, adult, offspring])].
[sujeto(['However,', whether, 'PEE']), verbo([increases]), complemento([the, susceptibility, to, 'non-alcoholic', fatty, liver, disease, '(', 'NAFLD)', in, offspring, and, its, underlying, mechanism, remain, unknown])].
[sujeto(['This', study, aimed, to, demonstrate, an]), verbo([increased]), complemento([susceptibility, to, 'high-fat', diet, '(', 'HFD)-induced', 'NAFLD', and, its, intrauterine, programming, mechanisms, in, female, rat, offspring, with, 'PEE'])].
[sujeto(['The', results, showed, 'that,', in, 'PEE+ND', 'group,', serum, corticosterone, '(', 'CORT)', slightly]), verbo([decreased]), complemento([and, 'insulin-like', growth, 'factor-1', '(', 'IGF-1)', and, glucose, increased, with, partial, 'catch-up', 'growth;', 'In', 'PEE+HFD', 'group,', serum, 'CORT', 'decreased,', while, serum, 'IGF-1,', glucose, and, triglyceride, '(', 'TG)', 'increased,', with, notable, 'catch-up', 'growth,', higher, metabolic, status, and, 'NAFLD', formation])].
[sujeto(['In', 'PEE', 'fetus,', serum, 'CORT']), verbo([increased]), complemento([while, 'IGF-1', 'decreased,', with, low, body, 'weight,', 'hyperglycemia,', and, hepatocyte, ultrastructural, changes])].
[sujeto(['Based', on, these, 'findings,', we, propose, a, &, 'quot;two-programming&quot;', hypothesis, for, an]), verbo([increased]), complemento([susceptibility, to, 'HFD-induced', 'NAFLD', in, female, offspring, of, 'PEE'])].
[sujeto(['That', 'is,', the, intrauterine, programming, of, liver, glucose, and, lipid, metabolic, function, is, &, 'quot;the', first, 'programming&quot;,', and, postnatal, adaptive, 'catch-up', growth]), verbo([triggered]), complemento([by, intrauterine, programming, of, 'GC-IGF1', axis, acts, as, &, 'quot;the', second, 'programming&quot;'])].
[sujeto(['Rhesus', monkey, 'ESC', were]), verbo([induced]), complemento([towards, 'hepatocyte-like', cells, via, a, 'four-step', differentiation, 'process:', the, formation, of, embryoid, bodies, '(', 'EB),', 'EB', in, activin, 'A', and, 'insulin-transferrin-selenium', medium, for, 4, 'days,', in, fibroblast, growth, factor, '(', 'FGF)-4', and, bone, morphogenetic, 'protein-2', '(', 'BMP2)', medium, for, 8, 'days,', in, hepatocyte, culture, medium, containing, hepatocyte, growth, factor, for, 3, days, and, then, with, oncostatin, 'M', and, dexamethasone, for, another, 5, days])].
[sujeto(['The', expression, of, hepatocyte, markers, 'AFP,', 'ALB,', hepatocyte]), verbo([nuclear]), complemento([factor, 4, '(', 'HNF4),', cytokeratin, 8, '(', 'CK8),', 'CK19', and, cell, proliferation, 'marker,', 'Ki67,', in, the, differentiated, cells, were, determined, by, immunocytochemistry])].
[sujeto(['Hepatocyte-specific', genes, 'ALB,', 'glucose-6-phosphatase,', 'AFP', and, 'α1-AT', were]), verbo([expressed]), complemento([in, the, differentiated, cells])].
[sujeto(['The', differentiated, cells]), verbo([expressed]), complemento([hepatocyte, markers, 'AFP,', 'ALB,', 'HNF4,', 'CK8', and, 'CK19', at, the, protein, level])].
[sujeto(['The', cells, also]), verbo([expressed]), complemento([cell, proliferation, marker, 'Ki67'])].
[sujeto(['The', results, showed, that, the, chitin, content]), verbo([decreased]), complemento([in, prepupae, and, then, increased, in, pupae])].
[sujeto(['Over', 9000, unigenes, were, identified, to]), verbo([express]), complemento([differentially, during, the, transformation, process])].
[sujeto(['The', cytochrome, 'P450s,', 'VHDLs,', 'chitinase,', serine, protease, and, genes]), verbo([involved]), complemento([in, sex, pheromone, biosynthesis, changed, their, mRNA, levels, remarkably])].
[sujeto(['The', gene, expression, patterns]), verbo([suggest]), complemento([that, chitinase, and, 'β-N-acetylglucosaminidase', may, be, responsible, for, the, degradation, of, larval, 'cuticles,', whereas, chitin, deacetylase, may, help, to, degrade, the, pupal, counterparts])].
[sujeto(['The', '20E-induced']), verbo([nuclear]), complemento([receptors, seem, to, be, important, factors, regulating, chitin, metabolic, enzymes, during, the, cuticle, remodeling])].
[sujeto(['Our', data]), verbo([provide]), complemento([a, comprehensive, resource, for, exploring, the, molecular, mechanism, of, epidermal, metamorphosis, in, insects])].
[sujeto(['The', aberrant, regulation, of, many, related, genes, is]), verbo([involved]), complemento([in, the, development, and, progression, of, gastric, carcinoma])].
[sujeto(['Forced', overexpression, of, 'FOXO6']), verbo([promotes]), complemento([gastric, cancer, cell, 'proliferation,', while, knockdown, of, 'FOXO6', expression, inhibits, proliferation])].
[sujeto(['We', show, that, ectopic, 'FOXO6', expression]), verbo([induces]), complemento([the, expression, of, 'C-myc'])].
[sujeto(['Furthermore,', we]), verbo([found]), complemento([that, 'FOXO6', physically, interacts, with, the, transcription, factor, hepatic, nuclear, factor, 4, '(', 'HNF4)', in, gastric, cancer, cells])].
[sujeto(['FOXO6']), verbo([induces]), complemento(['C-myc', expression, by, associating, to, 'HNF4', and, mediating, histone, 'acetylation,', and, the, dissociation, of, 'HDAC3', from, the, promoter, of, the, 'C-myc', gene])].
[sujeto(['Therefore,', our, results]), verbo([suggest]), complemento([a, previously, unknown, 'FOXO6/HNF4/C-myc', molecular, network, controlling, gastric, cancer, development])].
[sujeto(['In', 'KYSE70', cells, '(', 'male),', 'UGT1A', gene, expression, was]), verbo([induced]), complemento([5, -, 10, 'fold,', and, inhibited, in, the, presence, of, 'ERα', by, 55, -, 77, '%'])].
[sujeto(['We', show, 'gender-specific', transcriptional, control, of, 'UGT1A', genes, in, jejunum, and, 'colon,', which, is]), verbo([repressed]), complemento([by, 'ERα', and, the, recruitment, of, 'HDCAs', to, the, 'UGT1A', promoter, sequence, in, females])].
[sujeto(['Here', we]), verbo([report]), complemento([that, the, proximal, promoter, of, the, murine, 'PC', gene, contains, three, binding, sites, for, hepatocyte, nuclear, factor, 4, α, '(', 'HNF4α)'])].
[sujeto(['These', sites, include, the, classical, direct, repeat, 1, '(', 'DR1)', '(', -, 386, /, -, 374, ')', ',', 'non-perfect', 'DR1', '(', -, 118, /, -, 106, ')', and, 'HNF4α-specific']), verbo([binding]), complemento([motif, '(', 'H4-SBM)', '(', -, 26, /, -, 14, ')'])].
[sujeto(['Under', basal, 'conditions,', mutation, of, the, 'non-perfect', 'DR1']), verbo([decreased]), complemento([promoter, activity, by, 50, '%', ',', whereas, mutation, of, neither, the, 'DR1', nor, the, 'H4-SBM', had, any, effect])].
[sujeto(['In', marked, 'contrast,', only, mutation, of, the, 'H4-SBM']), verbo([decreased]), complemento(['HNF4α-transactivation', of, the, promoter, activity, by, 65, '%'])].
[sujeto(['EMSA', revealed, that, 'HNF4α']), verbo([binds]), complemento([to, the, 'DR1site', and, 'H4-SBM', with, similar, affinity, while, it, binds, poorly, to, the, 'non-perfect', 'DR1'])].
[sujeto(['Mutation', of, the, 'non-perfect', 'DR1', together, with, the, nearby, 'E-box', reduced, 'USF1-', but, not, 'USF2-transactivation', of, promoter, 'activity,']), verbo([suggesting]), complemento([that, 'USF1', partly, contributes, to, the, basal, activity, of, the, promoter])].
[sujeto(['Substitution', of, the, 'H4-SBM', with, the, 'DR1', marginally, reduced, the, basal, promoter, activity, but, did, not, eliminate, 'HNF4α-transactivation,']), verbo([suggesting]), complemento([that, 'HNF4α', can, exert, its, effect, via, 'DR1', within, this, promoter, context])].
[sujeto(['ChIP-assay', confirmed, that, 'HNF4α', is]), verbo([associated]), complemento([with, the, 'H4-SBM'])].
[sujeto(['Suppression', of, 'HNF4α', expression, in, 'AML12', cells, 'down-regulated', 'PC', mRNA, and, 'PC', protein, by, 60, '%', and, 50, '%', ',', 'respectively,', confirming, that, 'PC', is, a]), verbo([target]), complemento([of, 'HNF4α'])].
[sujeto(['The', acute, liver, injury, was]), verbo([induced]), complemento([by, injecting, 'CCl4', intraperitoneally, in, 'C57/BL6', mice])].
[sujeto(['Hepatocytes', were, isolated, by, liver, 'perfusion,', cultured, in, a, defined, medium, to]), verbo([maintain]), complemento([their, differentiation, and, characterized, by, reverse, transcriptase, polymerase, chain, reaction, '(', 'RT-PCR)', using, the, hepatic, cell, specific, genes, 'albumin,', hepatocyte, nuclear, factor, 4, '(', 'HNF4)', and, cytokeratin, 18, '(', 'CK18)'])].
[sujeto(['In', the, 'CCl4-CM(MSC)', treated, 'hepatocytes,', 'interleukin-6', '(', 'IL-6)', was]), verbo([increased]), complemento([on, the, first, day, of, culture, compared, to, control, and, 'CCl4', and, was, followed, by, upregulation, of, 'fibroblast-like-protein', '(', 'FGL1)', expression, after, 48, hrs])].
[sujeto(['This', was]), verbo([associated]), complemento([with, a, significant, decrease, of, annexin, 'V', positive, 'CCl4-CM(MSC)', treated, hepatocytes, at, day, 3, post, plating])].
[sujeto(['Recombinant', 'IL-6', was]), verbo([induced]), complemento(['FGL1', expression, in, hepatocytes, derived, from, 'CCl4-treated', mice, suggesting, that, 'CM(MSC),', which, is, enriched, also, in, 'microparticles,', attenuates, 'CCl4-induced', early, apoptosis, in, hepatocytes, through, activation, of, 'FGL1'])].
[sujeto(['Complement', 'C3', is]), verbo([involved]), complemento([in, various, protective, and, regulatory, mechanisms, of, immune, system])].
[sujeto(['Recently', it, was, established, that, 'C3', expression, is]), verbo([regulated]), complemento([by, nuclear, receptors])].
[sujeto(['Hepatic']), verbo([nuclear]), complemento([factor, 4, α, '(', 'HNF4α)', is, a, nuclear, receptor, critical, for, hepatic, development, and, metabolism])].
[sujeto(['We']), verbo([have]), complemento([shown, that, 'HNF4α', is, a, positive, regulator, of, 'C3', gene, 'expression,', realizing, its, effects, through, binding, to, two, 'HNF4-response', elements, within, the, 'C3', promoter, in, 'HepG2', cells])].
[sujeto(['TNFα']), verbo([decreases]), complemento([the, amount, of, 'HNF4α', protein, in, 'HepG2', cells, through, 'NF-κB', and, 'MEK1/2', pathways, thereby, leading, to, a, decrease, in, 'HNF4α', bound, to, the, 'C3', promoter])].
[sujeto(['TNFα', and, 'HNF4α']), verbo([act]), complemento([in, a, synergetic, way, resulting, in, the, potent, activation, of, 'C3', transcription])].
[sujeto(['These', results]), verbo([suggest]), complemento([a, novel, mechanism, of, 'C3', regulation, during, acute, phase, response, in, 'HepG2', cells, and, display, the, mechanism, of, interaction, of, 'TNFα-induced', pathways, and, 'HNF4α', in, transcriptional, regulation, of, 'C3', gene])].
[sujeto(['Food', intake, elicits, major, physiological, 'changes,', which, are, counteracted, by, transient, systemic, responses, that]), verbo([maintain]), complemento([homeostasis, in, the, organism])].
[sujeto(['This', integration, of, external, information, occurs, through, cellular, sensory, 'elements,', such, as]), verbo([nuclear]), complemento(['receptors,', which, modulate, gene, expression, in, response, to, specific, cues, '[', 2, ']'])].
[sujeto(['To', our, 'knowledge,', 'however,', there, are, no, mechanisms]), verbo([reported]), complemento([that, protect, 'GSCs', from, harmful, dietary, metabolites])].
[sujeto(['Using', 'Caenorhabditis', elegans, as, a, 'model,', we]), verbo([report]), complemento([that, the, somatic, activity, of, the, conserved, nuclear, receptor, 'nhr-114/HNF4', protects, 'GSC', integrity, from, dietary, metabolites])].
[sujeto(['We']), verbo([found]), complemento(['that,', in, 'nhr-114(-)', 'animals,', the, induction, of, germline, defects, and, sterility, depend, on, bacterial, metabolic, 'status,', with, respect, to, the, essential, amino, acid, tryptophan])].
[sujeto(['This', illustrates, an, 'animal-microbe', interaction, in, which, somatic]), verbo([nuclear]), complemento([receptor, activity, preserves, the, germline, 'by&nbsp;buffering', against, dietary, 'metabolites,', most, likely, through, a, somatic, detoxifying, response])].
[sujeto(['Overall,', our, findings, uncover, an, 'unprecedented,', and, presumably, evolutionarily, 'conserved,', 'soma-to-germline', axis, of, communication, that]), verbo([maintains]), complemento([reproductive, robustness, on, variable, food, resources])].
[sujeto(['During', this, 'process,', 'Rho', 'GTPases', are, heavily]), verbo([involved]), complemento([in, 'neuritogenesis,', axon, formation, and, dendritic, 'development,', due, to, their, effects, on, the, cytoskeleton, through, downstream, effectors])].
[sujeto(['As', shown, in, our, previous, 'study,', these, are, also]), verbo([involved]), complemento([in, the, differentiation, of, 'NSCs;', 'however,', little, is, known, about, the, underlying, regulatory, mechanism])].
[sujeto(['Here,', we, describe, how, the, transcription, factors, hepatic]), verbo([nuclear]), complemento([factor, '(', 'HNF4-1)', and, 'myc-associated', zinc, finger, protein, '(', 'MAZ-1)', regulate, the, expression, of, 'Rho-GDIγ', in, the, stimulation, of, 'NSC', differentiation])].
[sujeto(['Our', results, show, that, 'HNF4-1', and, 'MAZ-1', decoy, 'ODNs', significantly, knock, down, 'Rho-GDIγ', gene, 'transcription,']), verbo([leading]), complemento([to, 'NSC', differentiation, towards, neurons])].
[sujeto(['We', observed, that, 'HNF4-1', and, 'MAZ-1', decoy, 'ODNs', are, able, enter, to, the, cell, nucleolus, and, specifically]), verbo([bind]), complemento([to, their, target, transcription, factors])].
[sujeto(['Furthermore,', the, expression, of, 'Rho-GDIγ-mediated', genes, was, 'identified,']), verbo([suggesting]), complemento([that, the, regulatory, mechanism, for, the, differentiation, of, 'NSCs', is, triggered, by, the, transcription, factors, 'MAZ-1', and, 'HNF4-1'])].
[sujeto(['These', findings, indicate, that, 'HNF4-1', and, 'MAZ-1']), verbo([regulate]), complemento([the, expression, of, 'Rho-GDIγ', and, contribute, to, the, differentiation, of, 'NSCs'])].
[sujeto(['Our', findings]), verbo([provide]), complemento([a, new, perspective, within, regulatory, mechanism, research, during, differentiation, of, 'NSCs,', especially, the, clinical, application, of, transcription, factor, decoys, in, 'vivo,', suggesting, potential, therapeutic, strategies, for, neurodegenerative, disease])].
[sujeto(['Nuclear', receptors, '(', 'NRs)']), verbo([regulate]), complemento([gene, expression, by, binding, specific, 'DNA', sequences, consisting, of, 'AG[G/T]TCA', or, 'AGAACA', half, site, motifs, in, a, variety, of, configurations])].
[sujeto(['Here,', a, systematic, examination, of, 'DNA']), verbo([binding]), complemento([specificity, by, 'protein-binding', microarrays, '(', 'PBMs)', of, three, closely, related, human, 'NRs--HNF4α,', retinoid, 'X', receptor, alpha, '(', 'RXRα)', and, 'COUPTF2--reveals', an, 'HNF4-specific', binding, motif, '(', 'H4-SBM),', 'xxxxCAAAGTCCA,', as, well, as, a, previously, unrecognized, polarity, in, the, classical, 'DR1', motif, '(', 'AGGTCAxAGGTCA)', for, 'HNF4α,', 'RXRα', and, 'COUPTF2', homodimers])].
[sujeto(['ChIP-seq', data, indicate, that, the, 'H4-SBM', is, uniquely]), verbo([bound]), complemento([by, 'HNF4α', but, not, 10, other, 'NRs', in, 'vivo,', while, 'NRs', 'PXR,', 'FXRα,', 'Rev-Erbα', appear, to, bind, adjacent, to, 'H4-SBMs'])].
[sujeto(['HNF4-specific', 'DNA', recognition, and, transactivation, are]), verbo([mediated]), complemento([by, residues, 'Asp69', and, 'Arg76', in, the, 'DNA-binding', 'domain;', this, combination, of, amino, acids, is, unique, to, 'HNF4', among, all, human, 'NRs'])].
[sujeto(['Expression', profiling, and, 'ChIP', data, predict, '≈', 100, new, human, 'HNF4α']), verbo([target]), complemento([genes, with, an, 'H4-SBM', 'site,', including, several, 'Co-enzyme', 'A-related', genes, and, genes, with, links, to, disease])].
[sujeto(['These', results]), verbo([provide]), complemento([important, new, insights, into, 'NR', 'DNA', binding])].
[sujeto(['This', study, investigated, the, association, of, hepatocyte]), verbo([nuclear]), complemento([factor, 4, '(', 'HNF4)', alpha, single, nucleotide, polymorphisms, '(', 'SNPs)', with, type, 2, diabetes, with, or, without, metabolic, syndrome, in, 'Malaysia'])].
[sujeto(['The', 'SNPs', 'rs4810424,', 'rs1884613,', and, rs2144908, were]), verbo([associated]), complemento([with, protection, against, type, 2, diabetes, without, metabolic, syndrome, '(', recessive, 'P', =, 0.018, ',', 'OR', 0.32, ;, 'P', =, 0.004, ',', 'OR', 0.25, ;, 'P', =, 0.005, ',', 'OR', 0.24, ',', 'respectively)'])].
[sujeto(['The', 6, -, 'SNP', haplotype2, 'CCCGTC', containing, the, risk, genotype, of, these, 'SNPs', was]), verbo([associated]), complemento([with, higher, risk, for, type, 2, diabetes, with, or, without, metabolic, syndrome, '(', 'P', =, 0.002, ',', 'OR', 2.2, ;, 'P', =, 0.004, ',', 'OR', 3.1, ')'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'HNF4', alpha, 'SNPs', and, haplotypes, contributed, to, increased, type, 2, diabetes, risk, in, the, 'Malaysian', population])].
[sujeto(['Maturity-onset', diabetes, of, the, young, '(', 'MODY)', as, a, result, of, mutations, in, hepatocyte]), verbo([nuclear]), complemento([factor, 1, -, α, '(', 'HNF1A)', is, often, misdiagnosed, as, type, 1, diabetes, or, type, 2, diabetes])].
[sujeto(['Recent', work]), verbo([has]), complemento([shown, that, 'high-sensitivity', 'C-reactive', protein, '(', 'hs-CRP)', levels, are, lower, in, 'HNF1A-MODY', than, type, 1, 'diabetes,', type, 2, 'diabetes,', or, glucokinase, '(', 'GCK)-MODY'])].
[sujeto(['In', recent, 'years,', simulated, 'microgravity,', a, physical, force]), verbo([has]), complemento([shown, to, differentially, regulate, the, differentiation, and, proliferation, of, stem, cells])].
[sujeto(['Microgravity', treatment, for, 2, h]), verbo([enhanced]), complemento([proliferation, of, stem, cells, by, twofold, without, inducing, apoptosis, and, compromising, cell, viability])].
[sujeto(['Analysis', of, hepatocyte]), verbo([nuclear]), complemento([factor, 4, -, α, '(', 'HNF4-α)', expression, after, 2, h, of, microgravity, treatment, revealed, that, microgravity, alone, can, induce, the, differentiation, of, stem, cells, within, 2, -, 3, days])].
[sujeto(['Further,', blocking, 'BMP4', using, dorsomorphin, and, chordin, conditioned, media, from, chordin, plasmid, transfected, cells, attenuated, microgravity]), verbo([mediated]), complemento([differentiation, of, liver, stem, cells])].
[sujeto(['In', 'conclusion,', microgravity, interplays, with, 'BMP4/Notch1', signaling, in, stem, cells, thus]), verbo([inducing]), complemento([differentiation, of, stem, cells, to, hepatocytes])].
[sujeto(['Present', findings, can, be, implicated, in, clinical, studies, where, microgravity]), verbo([activated]), complemento([stem, cells, can, regenerate, the, liver, efficiently, after, liver, injury])].
[sujeto(['The', concept, that, cellular, terminal, differentiation, is, stably]), verbo([maintained]), complemento([once, development, is, complete, has, been, questioned, by, numerous, observations, showing, that, differentiated, epithelium, may, undergo, an, 'epithelial-to-mesenchymal', transition, '(', 'EMT)', program])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 4, α, '(', 'HNF4α)', was, overexpressed, in, different, hepatocyte, cell, lines, and, the, resulting, gene, expression, profile, was, determined, by, 'real-time', quantitative, polymerase, chain, reaction])].
[sujeto(['Our', results, identified, key, 'EMT', regulators, and, mesenchymal, genes, as, new]), verbo([targets]), complemento([of, 'HNF4α'])].
[sujeto(['HNF4α,', in, cooperation, with, its]), verbo([target]), complemento(['HNF1α,', directly, inhibits, transcription, of, the, 'EMT', master, regulatory, genes, 'Snail,', 'Slug,', and, 'HMGA2', and, of, several, mesenchymal, markers])].
[sujeto(['HNF4α-mediated', repression, of, 'EMT', genes]), verbo([induces]), complemento(['MET', in, 'hepatomas,', and, its, silencing, triggers, the, mesenchymal, program, in, differentiated, hepatocytes, both, in, cell, culture, and, in, the, whole, liver])].
[sujeto(['The', pivotal, role, of, 'HNF4α', in, the, induction, and, maintenance, of, hepatocyte, differentiation, should, also, be, ascribed, to, its, capacity, to, continuously]), verbo([repress]), complemento([the, mesenchymal, 'program;', 'thus,', both, 'HNF4α', activator, and, repressor, functions, are, necessary, for, the, identity, of, hepatocytes])].
[sujeto(['miR-122', is, the, most, abundant, microRNA, in, the, liver, and]), verbo([regulates]), complemento([metabolic, pathways, including, cholesterol, 'biosynthesis,', fatty, acid, 'synthesis,', and, oxidation])].
[sujeto(['However,', little, is, known, about, mechanisms, that]), verbo([regulate]), complemento([the, expression, of, 'miR-122', in, the, liver])].
[sujeto(['Bioinformatics', 'analysis,', 'Northern', 'blotting,', 'RT-PCR,', and, 5, '\'', /, 3, '\'', 'RACE', were, performed, to, analyze, 'miR-122', primary, transcript, 'structure,', its, promoter, 'region,', and, potential, transacting, factor]), verbo([binding]), complemento([sites])].
[sujeto(['ChIP', and, 'EMSA', assays, were, performed, to, determine, 'HNF4α']), verbo([binding]), complemento([to, 'miR-122', promoter])].
[sujeto(['Here,', we, show, that, 'miR-122', is, processed, from, a, long, spliced, primary, transcript, directed, by, a, distal, upstream, promoter, region]), verbo([conserved]), complemento([across, species])].
[sujeto(['We', dissected, this, promoter, region, and, identified, putative]), verbo([binding]), complemento([sites, for, 'liver-enriched', transcriptional, factors, that, contribute, to, the, regulation, of, 'miR-122', 'expression,', including, a, putative, binding, site, for, hepatocyte, nuclear, factor, 4, α, '(', 'HNF4α)'])].
[sujeto(['We', demonstrate, that, 'HNF4α']), verbo([binds]), complemento([to, the, 'miR-122', promoter, region, through, the, conserved, 'DR-I', element])].
[sujeto(['We', observed, the, 'DR-1-element-dependent', activation, effect, of, 'HNF4α', on, the]), verbo([conserved]), complemento(['miR-122', promoter, and, the, activation, could, be, further, enhanced, by, the, addition, of, 'PGC1α'])].
[sujeto(['Using', overexpression, and, knockdown, 'strategies,', we, show, that, 'HNF4α', positively]), verbo([regulates]), complemento([miR122, expression, in, both, 'Huh7', cells, and, the, mouse, liver])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'HNF4α', is, a, key, regulator, of, 'miR-122', expression, in, the, liver])].
[sujeto(['Variants', in, hepatocyte]), verbo([nuclear]), complemento([factor, 4, 'A', '(', 'HNF4A)', cause, maturity, onset, diabetes, of, the, young, '(', 'MODY', 1, ')'])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([of, 'MODY', 1, mutations, from, 'India', and, shows, that, 3.4, '%', of, clinically, diagnosed, 'MODY', subjects, have, 'MODY', 1])].
[sujeto(['In', 'addition,', we]), verbo([report]), complemento(['SNPs', of, 'HNF4A', that, are, both, susceptible, 'to,', and, protective, 'against,', 'MODY', and, early, onset, 'T2DM'])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 4, -, alpha, '(', 'HNF4-alpha)', regulates, expression, of, a, number, of, genes, in, several, metabolic, organs])].
[sujeto(['The', 'HNF4-alpha', gene]), verbo([has]), complemento([two, promoters, and, encodes, at, least, nine, isoforms, through, differential, splicing])].
[sujeto(['Conversely,', the, adult, mouse, liver]), verbo([expressed]), complemento([significantly, higher, levels, of, 'P1-', than, 'P2-derived', mRNA])].
[sujeto(['Exposure', of, fetal, rats, to, the, synthetic, glucocorticoid, dexamethasone]), verbo([caused]), complemento([suppression, of, 'P2', while, enhancing, hepatic, expression, of, transcripts, from, 'P1'])].
[sujeto(['This', was]), verbo([associated]), complemento([with, increased, expression, of, erythropoietin, and, phosphoenolpyruvate, 'carboxykinase,', which, are, key, 'HNF4-alpha', targets, in, the, liver])].
[sujeto(['Unlike', 'liver,', the, kidney, and, stomach, used, promoters, more, 'selectively,', so, that, only, 'P1-derived', isoforms, were, detected, in, fetal, and, adult, kidneys, in, mice, or, 'rats,', whereas, the, stomach, in, both, species]), verbo([expressed]), complemento(['P2-derived', transcripts, exclusively])].
[sujeto(['These', data]), verbo([reveal]), complemento([striking, developmental, and, 'tissue-specific', variation, in, expression, of, 'HNF4-alpha,', and, indicate, that, this, can, be, influenced, by, environmental, factors, '(', such, as, exposure, to, glucocorticoid, 'excess),', with, potential, pathophysiological, consequences])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF4alpha),', a, member, of, the, nuclear, receptor, 'superfamily,', is, essential, for, liver, function, and, is, linked, to, several, diseases, including, 'diabetes,', 'hemophilia,', 'atherosclerosis,', and, hepatitis])].
[sujeto(['Although', many, 'DNA', response, elements, and]), verbo([target]), complemento([genes, have, been, identified, for, 'HNF4alpha,', the, complete, repertoire, of, binding, sites, and, target, genes, in, the, human, genome, is, unknown])].
[sujeto(['Here,', we, adapt, protein]), verbo([binding]), complemento([microarrays, '(', 'PBMs)', to, examine, the, 'DNA-binding', characteristics, of, two, 'HNF4alpha', species, '(', rat, and, 'human)', and, isoforms, '(', 'HNF4alpha2', and, 'HNF4alpha8)', in, a, 'high-throughput', fashion])].
[sujeto(['We', identified, approximately, 1400, new]), verbo([binding]), complemento([sequences, and, used, this, dataset, to, successfully, train, a, 'Support', 'Vector', 'Machine', '(', 'SVM)', model, that, predicts, an, additional, approximately, 10, ',', 0, unique, 'HNF4alpha-binding', 'sequences;', we, also, identify, new, rules, for, 'HNF4alpha', 'DNA', binding])].
[sujeto(['Using', this, integrated, 'approach,', we, identified, approximately, 240, new, direct, 'HNF4alpha', human]), verbo([target]), complemento(['genes,', including, new, functional, categories, of, genes, not, typically, associated, with, 'HNF4alpha,', such, as, cell, 'cycle,', immune, 'function,', 'apoptosis,', stress, 'response,', and, other, 'cancer-related', genes])].
[sujeto(['We']), verbo([report]), complemento([the, first, use, of, 'PBMs', with, a, 'full-length', 'liver-enriched', transcription, factor, and, greatly, expand, the, repertoire, of, 'HNF4alpha-binding', sequences, and, target, 'genes,', thereby, identifying, new, functions, for, 'HNF4alpha'])].
[sujeto(['A', previous]), verbo([report]), complemento([has, demonstrated, that, small, heterodimer, 'partner-interacting', leucine, zipper, protein, '(', 'SMILE)', regulates, the, nuclear, receptors, and, transcriptional, factors, that, control, hepatic, gluconeogenesis])].
[sujeto(['Here,', we, show, that, hepatic, 'SMILE', expression, was]), verbo([induced]), complemento([by, feeding, in, normal, mice, but, not, in, 'db/db', and, 'high-fat', diet, '(', 'HFD)-fed', mice])].
[sujeto(['Interestingly,', 'SMILE', expression, was]), verbo([induced]), complemento([by, insulin, in, mouse, primary, hepatocyte, and, liver])].
[sujeto(['At', the, molecular, 'level,', 'SMILE']), verbo([inhibited]), complemento([hepatocyte, nuclear, factor, 4, -, mediated, transcriptional, activity, via, direct, competition, with, 'PGC-1α'])].
[sujeto(['Moreover,', ablation, of, 'SMILE', augmented, gluconeogenesis, and]), verbo([increased]), complemento([blood, glucose, levels, in, mice])].
[sujeto(['Therefore,', 'SMILE', is, an, 'insulin-inducible', corepressor, that]), verbo([suppresses]), complemento([hepatic, gluconeogenesis])].
[sujeto(['Small', molecules, that]), verbo([enhance]), complemento(['SMILE', expression, would, have, potential, for, treating, hyperglycemia, in, diabetes])].
[sujeto(['High', intramuscular, fat, '(', 'IMF)', awards, price, premiums, to, beef, producers, and, is]), verbo([associated]), complemento([with, meat, quality, and, flavor])].
[sujeto(['Studying', gene, interactions, and, pathways, that, affect, 'IMF', might, unveil, causative, physiological, mechanisms, and, inform, genomic, 'selection,']), verbo([leading]), complemento([to, increased, accuracy, of, predictions, of, breeding, value])].
[sujeto(['To', study, gene, interactions, and, 'pathways,', a, gene, network, was, derived, from, genetic, markers]), verbo([associated]), complemento([with, direct, measures, of, 'IMF,', other, fat, 'phenotypes,', feedlot, 'performance,', and, a, number, of, meat, quality, traits, relating, to, body, 'conformation,', 'development,', and, metabolism, that, might, be, plausibly, expected, to, interact, with, 'IMF', biology])].
[sujeto(['Topological', network, parameters]), verbo([suggested]), complemento([a, highly, cohesive, 'network,', in, which, the, genes, are, strongly, functionally, interconnected])].
[sujeto(['Importantly,', none, of, these, genes, would]), verbo([have]), complemento([been, deemed, as, significantly, associated, with, 'IMF', from, the, 'GWAS'])].
[sujeto(['In', 'summary,', our, 'GWAS', and, network, predictions, are, supported, by, the, current, literature, and]), verbo([suggest]), complemento([a, cooperative, role, for, the, 3, 'TF', and, other, interacting, genes, including, 'CAPN6,', 'STC2,', 'MAP2K4,', 'EYA1,', 'COPS5,', 'XKR4,', 'NR2E1,', 'TOX,', 'ATF1,', 'ASPH,', 'TGS1,', and, 'TTPA', as, modulators, of, carcass, and, meat, quality, traits, in, beef, cattle])].
[sujeto(['Its', 'liver-specific', expression, in, hepatocytes, is, strongly, controlled, by, hepatocyte]), verbo([nuclear]), complemento(['factor-4α', '(', 'HNF4α)'])].
[sujeto(['HNF4α', expression, and, transcriptional, activity]), verbo([have]), complemento([been, demonstrated, to, be, augmented, by, glucocorticoid, receptor, '(', 'GR)', in, human, hepatocytes, and, rodent, livers])].
[sujeto(['It', was, examined, whether, 'GR', activation, indirectly]), verbo([induces]), complemento(['OCT1', gene, expression, via, 'HNF4α', 'up-regulation', in, primary, human, hepatocytes])].
[sujeto(['We', also, examined, which, other, transcription, factors, are]), verbo([involved]), complemento([in, 'OCT1', gene, expression, and, whether, they, are, regulated, by, dexamethasone, using, 'qRT-PCR', and, gene, reporter, assays])].
[sujeto(['We']), verbo([found]), complemento([that, dexamethasone, significantly, 'up-regulates', 'OCT1', mRNA, and, protein, in, normal, primary, human, 'hepatocytes,', but, not, in, 'hepatocyte-derived', tumor, cell, lines, 'HepG2', and, 'MZ-Hep1'])].
[sujeto(['Consistently,', we, observed, that, 'HNF4α', is]), verbo([induced]), complemento([by, dexamethasone, in, primary, human, 'hepatocytes,', but, not, in, hepatocyte, 'tumor-derived', cell, lines])].
[sujeto(['Viral', transduction, of, 'MZ-Hep1', cells, with, the, expression, constructs, for, 'HNF4α,', 'CCAAT/enhancer']), verbo([binding]), complemento([proteins, β, '(', 'C/EBPβ)', and, peroxisome, 'proliferator-activated', 'receptor-γ', coactivator, 1, α, '(', 'PGC1α)', demonstrated, significant, roles, of, the, transcription, factors, in, 'OCT1', gene, regulation])].
[sujeto(['We']), verbo([found]), complemento([that, expression, of, 'OCT1', mRNA, in, human, livers, significantly, correlates, with, 'C/EBPβ', and, 'HNF4α', mRNAs, expression, and, that, 'C/EBPβ', 'co-transfection', stimulates, 'OCT1', gene, reporter, construct, in, 'HepG2', cells])].
[sujeto(['Insulin', resistant, states, are, commonly]), verbo([associated]), complemento([with, excessive, hepatic, glucose, 'production,', which, contributes, to, both, fasting, hyperglycaemia, and, exaggerated, postprandial, hyperglycaemia])].
[sujeto(['In', this, 'regard,']), verbo([increased]), complemento([activity, of, phosphatases, may, contribute, to, the, dysregulation, of, gluconeogenesis])].
[sujeto(['Mitogen-activated', protein, kinase, 'phosphatase-3', '(', 'MKP-3)', is, a, key, protein]), verbo([involved]), complemento([in, the, control, of, gluconeogenesis])].
[sujeto(['MKP-3-mediated', dephosphorylation]), verbo([activates]), complemento(['FoxO1', '(', a, member, of, the, forkhead, family, of, transcription, 'factors)', and, subsequently, promotes, its, nuclear, translocation, and, binding, to, the, promoters, of, gluconeogenic, genes, such, as, phosphoenolpyruvate, carboxykinase, '(', 'PEPCK)', and, 'glucose-6-phosphatase', '(', 'G6Pase)'])].
[sujeto(['We']), verbo([found]), complemento([that, exercised, obese, mice, had, a, lower, expression, of, 'MKP-3', and, 'FoxO1/MKP-3', association, in, the, liver])].
[sujeto(['Further,', the, exercise, training]), verbo([decreased]), complemento(['FoxO1', phosphorylation, and, protein, levels, of, 'Peroxisome', 'proliferator-activated', receptor, gamma, coactivator, 1, -, alpha, '(', 'PGC-1α)', and, gluconeogenic, enzymes, '(', 'PEPCK', and, 'G6Pase)'])].
[sujeto(['These', molecular, results, were, accompanied, by, physiological, 'changes,', including]), verbo([increased]), complemento([insulin, sensitivity, and, reduced, 'hyperglycaemia,', which, were, not, caused, by, reductions, in, total, body, mass])].
[sujeto(['However,', our, results, showed, that, only, exercise, training, could, reduce, an, 'obesity-induced']), verbo([increase]), complemento([in, 'HNF-4α', protein, levels, while, 'ASO', treatment, alone, had, no, effect])].
[sujeto(['One', of, the, major, mechanisms]), verbo([involved]), complemento([in, acetaminophen, '(', 'APAP)-induced', hepatotoxicity, is, hepatocyte, nuclear, factor, 4, α, '(', 'HNF4α)-mediated', activation, of, pregnane, 'X', receptor, '(', 'PXR)', and, constitutive, androstane, receptor, '(', 'CAR)'])].
[sujeto(['In', the, present, 'study,', we, investigated, the, role, of, 'miR-561', and, its]), verbo([target]), complemento([gene, 'DAX-1', encoding, a, corepressor, of, 'HNF4α', in, the, process, of, 'APAP-induced', hepatotoxicity])].
[sujeto(['Our', bioinformatics, study]), verbo([suggests]), complemento([an, association, between, 'miR-561', and, 'DAX-1,', but, not, 'HNF4α'])].
[sujeto(['miR-561', was]), verbo([induced]), complemento([by, 'APAP', treatment, in, 'HepG2', cells])].
[sujeto(['HNF4α', is, physically]), verbo([associated]), complemento([with, 'DAX-1', in, 'HepG2', cells])].
[sujeto(['A']), verbo([decreased]), complemento([protein, level, of, 'DAX-1', by, 'APAP', treatment, was, also, enhanced, by, 'miR-561', mimic, transfection, in, 'HepG2', cells, and, primary, human, hepatocytes])].
[sujeto(['The', basal, and, 'APAP-induced', expression, of, 'PXR', and, 'CAR', was]), verbo([enhanced]), complemento([by, 'miR-561', mimic, 'transfection;', 'however,', transfection, of, 'HepG2', cells, or, primary, human, hepatocytes, with, a, 'miR-561', inhibitor, or, 'DAX-1', small, interfering, 'RNA', reversed, these, effects])].
[sujeto(['These', results, indicate, that, 'miR-561', worsens, 'APAP-induced', hepatotoxicity, via, inhibition, of, 'DAX-1', and, consequent, transactivation, of]), verbo([nuclear]), complemento([receptors])].
[sujeto(['Systemic', iron, homeostasis, is, finely]), verbo([regulated]), complemento([by, the, liver, through, synthesis, of, the, peptide, hormone, hepcidin, '(', 'HAMP),', which, plays, an, important, role, in, duodenal, iron, absorption, and, macrophage, iron, release])].
[sujeto(['Clinical', investigations]), verbo([have]), complemento([shown, that, chronic, and, 'low-grade', inflammation, leads, to, the, increase, of, serum, 'HAMP', levels, and, the, development, of, various, diseases, such, as, anemia, of, inflammation])].
[sujeto(['Here', we, show, that, although, inflammatory, stimuli]), verbo([increase]), complemento([hepatic, 'HAMP', expression, and, cause, systemic, iron, deficiency, in, 'mice,', they, inhibit, the, expression, of, peroxisome, 'proliferator-activated', receptor, γ, 'coactivator-1α', '(', 'PGC-1α),', a, transcriptional, coactivator, actively, involved, in, metabolic, regulation])].
[sujeto(['Consistently,', overexpression, of, 'PGC-1α', in, 'HepG2', or, 'HuH7', cells, also]), verbo([suppresses]), complemento(['HAMP', expression, and, reduces, iron, accumulation])].
[sujeto(['At', the, molecular, 'level,', 'PGC-1α']), verbo([suppresses]), complemento(['HAMP', transcription, via, the, interaction, with, hepatocyte, nuclear, factor, 4, α])].
[sujeto(['In', 'addition,', 'PGC-1α', is, present, near, hepatocyte]), verbo([nuclear]), complemento([factor, 4, 'α-binding', site, on, the, proximal, 'HAMP', promoter, and, turns, the, chromatin, structure, into, an, inactive, state])].
[sujeto(['Our', data]), verbo([suggest]), complemento([a, critical, role, for, 'PGC-1α', in, the, regulation, of, hepatic, 'HAMP', expression, and, iron, homeostasis, under, inflammatory, circumstances])].
[sujeto(['A', total, of, 52, tag, single, nucleotide, polymorphisms, '(', 'SNPs)', of, 11, candidate, genes]), verbo([involved]), complemento([in, regulating, bile, acid, synthesis, were, analyzed, by, polymerase, chain, reaction, '(', 'PCR)-restriction', fragment, length, 'polymorphism,', -, high, resolution, melting, curve, 'analysis,', or, -, direct, 'DNA', sequencing, in, 315, 'Japanese', patients, with, 'PBC'])].
[sujeto(['Specifically,', the, 'CYP7A1', promoter, carrying, the, risk, 'G', allele, for, 'PBC', progression]), verbo([induced]), complemento([higher, expression, of, 'CYP7A1', under, both, the, normal, and, cholestatic, conditions, in, vitro, as, compared, to, another, promoter, carrying, the, 'non-risk', 'T', allele])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, the, genetic, variants, of, 'CYP7A1', and, its, transcriptional, activators, '(', 'HNF4A', and, 'PPARGC1A)', may, activate, bile, acid, 'synthesis,', resulting, in, the, accumulation, of, bile, acids, in, hepatocytes, and, eventually, leading, to, the, predisposition, to, 'PBC', progression])].
[sujeto(['Thus,', the, regulation, of, 'CYP7A1', expression, may, represent, an, attractive, therapeutic]), verbo([target]), complemento([for, cholestatic, liver, diseases, including, 'PBC'])].
[sujeto(['Lipin', 1, is, a, bifunctional, protein, that, serves, as, a, metabolic, enzyme, in, the, triglyceride, synthesis, pathway, and]), verbo([regulates]), complemento([gene, expression, through, direct, 'protein-protein', interactions, with, 'DNA-bound', transcription, factors, in, liver])].
[sujeto(['Herein,', we, demonstrate, that, lipin, 1, is, a]), verbo([target]), complemento([gene, of, the, hepatocyte, nuclear, factor, 4, α, '(', 'HNF4α),', which, induces, lipin, 1, gene, expression, in, cooperation, with, peroxisome, 'proliferator-activated', receptor, γ, 'coactivator-1α', '(', 'PGC-1α)', through, a, nuclear, receptor, response, element, in, the, first, intron, of, the, lipin, 1, gene])].
[sujeto(['The', results, of, a, series, of, 'gain-of-function', and, 'loss-of-function', studies, demonstrate, that, lipin, 1, coactivates, 'HNF4α', to]), verbo([activate]), complemento([the, expression, of, a, variety, of, genes, encoding, enzymes, involved, in, fatty, acid, catabolism])].
[sujeto(['In', 'contrast,', lipin, 1, reduces, the, ability, of, 'HNF4α', to]), verbo([induce]), complemento([the, expression, of, genes, encoding, apoproteins, 'A4', and, 'C3'])].
[sujeto(['Although', the, ability, of, lipin, to, diminish, 'HNF4α', activity, on, these, promoters]), verbo([required]), complemento([a, direct, physical, interaction, between, the, two, 'proteins,', lipin, 1, did, not, occupy, the, promoters, of, the, repressed, genes, and, enhances, the, intrinsic, activity, of, 'HNF4α', in, a, 'promoter-independent', context])].
[sujeto(['The', aim, was, develop, stable, human, cell, line, stable, 'over-expressing', transcription, 'co-activator', peroxisome, 'proliferator-activated', receptor, gamma, 'co-activator', 1, α, '(', 'PGC-1α)', with, restored, hepatospecific, functions, and]), verbo([increased]), complemento([expression, of, major, xenobiotic, metabolizing, enzymes])].
[sujeto(['Expression', levels, of, protein, and, mRNA, of, hepatocyte]), verbo([nuclear]), complemento([factor, '(', 'HNF4α),', pregnane, 'X', receptor, '(', 'PXR)', and, aryl, hydrocarbon, receptor, '(', 'AhR)', were, determined])].
[sujeto(['Stably', transfected, cell, line, 'HepG2-PGC-1α', derived, from, 'HepG2', cells, 'over-expressing', 'PGC-1α', displayed]), verbo([increased]), complemento([secretion, of, 'fibrinogen,', but, not, albumin, or, 'alpha1-antitrypsin', compared, to, parent, 'HepG2', cells])].
[sujeto(['We']), verbo([found]), complemento([increased, levels, of, 'HNF4α,', 'PXR', and, 'AhR', proteins, but, not, their, mRNAs, in, 'HepG2-PGC1', cells])].
[sujeto(['Basal', expression, of, 'CYP3A4', protein, in, 'HepG2-PGC-1α', cells, was]), verbo([increased]), complemento([but, 'rifampicin-inducible', expression, of, 'CYP3A4', protein, was, lowered, in, comparison, with, parent, 'HepG2', cells])].
[sujeto(['Nuclear', receptors, '(', 'NRs)', play, crucial, roles, in, the, regulation, of, hepatic, cholesterol, 'synthesis,', 'metabolism,', and, conversion, to, bile, 'acids,', but, their, actions, in, cholangiocytes]), verbo([have]), complemento([not, been, examined])].
[sujeto(['We', examined, the, expression, of, 'NRs', and, other, genes]), verbo([involved]), complemento([in, cholesterol, homeostasis, in, freshly, isolated, and, cultured, murine, cholangiocytes, and, found, that, these, cells, express, a, specific, subset, of, 'NRs,', including, liver, 'X', receptor, '(', 'LXR)', β, and, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)', δ])].
[sujeto(['Activation', of, 'LXRβ', 'and/or', 'PPARδ', in, cholangiocytes]), verbo([induces]), complemento(['ATP-binding', cassette, cholesterol, transporter, 'A1', '(', 'ABCA1)', and, increases, cholesterol, export, at, the, basolateral, compartment, in, polarized, cultured, cholangiocytes])].
[sujeto(['In', 'addition,', 'PPARδ']), verbo([induces]), complemento(['Niemann-Pick', 'C1-like', 'L1', '(', 'NPC1L1),', which, imports, cholesterol, into, cholangiocytes, and, is, expressed, on, the, apical, cholangiocyte, membrane, via, specific, interaction, with, a, peroxisome, 'proliferator-activated', response, element, '(', 'PPRE)', within, the, 'NPC1L1', promoter])].
[sujeto(['In', this, 'study,', we, contrasted, the, hypothesis, that, maternal, diet, during, pregnancy]), verbo([has]), complemento([an, impact, on, fetal, metabolic, programming, through, changes, in, liver, mitochondrial, 'DNA', '(', 'mtDNA)', content, and, transcriptional, activity, of, 'Ppargc1a', and, that, these, effects, are, sex, specific])].
[sujeto(['Maternal', 'HFD', feeding, during, pregnancy, is]), verbo([associated]), complemento([with, a, decreased, liver, mtDNA, copy, number, '(', 'P&lt;'])].
[sujeto(['This', effect, was, independent, of, the, offspring, sex, or, 'diet,', and, was, significantly]), verbo([associated]), complemento([with, fatty, liver, when, dams, were, fed, 'HFD', '(', 'P&lt;'])].
[sujeto(['We', also]), verbo([found]), complemento([that, maternal, 'HFD', feeding, results, in, a, 'male-specific', significant, reduction, of, the, liver, abundance, of, 'Ppargc1a', mRNA, '(', 'P&lt;'])].
[sujeto(['Liver', abundance, of, 'Tfam,', 'Nrf1,', 'Hnf4a,', 'Pepck', and, 'Ppparg', mRNA, was, not]), verbo([associated]), complemento([with, maternal, programming])].
[sujeto(['The', deprived, rats, had, microvesicular, 'steatosis,', with]), verbo([increased]), complemento(['triglycerides,', decreased, methionine, synthase, 'activity,', 'S-adenosylmethionine,', and, 'S-adenosylmethionine/S-adenosylhomocysteine', ratio])].
[sujeto(['We', observed, no, change, in, apoptosis, 'markers,', oxidant, and, reticulum, 'stresses,', and, 'carnityl-palmitoyl', transferase, 1, 'activity,', and, a]), verbo([decreased]), complemento([expression, of, 'SREBP-1c'])].
[sujeto(['Impaired', 'beta-oxidation', of, fatty, acids, and, carnitine, deficit, were, the, predominant, 'changes,', with]), verbo([decreased]), complemento([free, and, total, 'carnitines,', increased, 'C14:1/C16', acylcarnitine, 'ratio,', decrease, of, oxidation, rate, of, 'palmitoyl-CoA', and, 'palmitoyl-L-carnitine', and, decrease, of, expression, of, novel, organic, cation, transporter, 1, ',', 'acylCoA-dehydrogenase', and, trifunctional, enzyme, subunit, alpha, and, decreased, activity, of, complexes, 'I', and, 'II'])].
[sujeto(['These', changes, were, related, to, lower, protein, expression, of, 'ER-α,', 'ERR-α', and, 'HNF-4α,', and, hypomethylation, of, 'PGC-1α', 'co-activator', that, reduced, its]), verbo([binding]), complemento([with, 'PPAR-α,', 'ERR-α,', and, 'HNF-4α'])].
[sujeto(['The', liver, steatosis, resulted, predominantly, from, hypomethylation, of, 'PGC1-α,']), verbo([decreased]), complemento([binding, with, its, partners, and, subsequent, impaired, mitochondrial, fatty, acid, oxidation])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 4, α, '(', 'HNF4α)', and, 'FOXO1', transcription, factors, have, implicated, in, this, process, through, transcriptional, regulation, of, 'glucose-6-phosphatase', '(', 'G6Pase)', and, phosphoenolpyruvate, carboxykinase, '(', 'PEPCK),', which, are, 'rate-limiting', enzymes, in, gluconeogenesis])].
[sujeto(['In', this, 'study,', we, demonstrate, that, glycogen, synthase, kinase, 3, β, '(', 'GSK3β)']), verbo([regulates]), complemento([the, expression, of, gluconeogenic, genes, through, 'HNF4α', and, 'FOXO1'])].
[sujeto(['Silencing', of, 'GSK3β']), verbo([leads]), complemento([to, reduction, in, the, expression, of, gluconeogenic, 'genes,', including, 'G6Pase,', 'PEPCK,', and, peroxisome, 'proliferator-activated', receptor, γ, 'coactivator-1α'])].
[sujeto(['We', show, that, 'GSK3β', directly]), verbo([binds]), complemento([to, both, 'HNF4α', and, 'FOXO1'])].
[sujeto(['We', also]), verbo([found]), complemento([that, overexpression, of, 'GSK3β', potentiates, 'G6Pase', promoter, activation, by, 'FOXO1', in, a, manner, dependent, on, its, kinase, activity])].
[sujeto(['Taken', 'together,', these, results]), verbo([reveal]), complemento([a, previously, unrecognized, mechanism, for, the, regulation, of, gluconeogenic, gene, expression])].
[sujeto(['CYP3A4', was]), verbo([induced]), complemento([by, rifampicin, '(', 'RIF),', mifepristone, '(', 'RU486),', clotrimazole, '(', 'CTZ),', and, dexamethasone, '(', 'DEX)', in, 'HepG2', 'cells,', while, these, 'PXR', ligands, with, the, exception, of, 'DEX', did, not, induce, 'CYP3A4', mRNA, expression, in, 'HFL', cells])].
[sujeto(['Ad-PXR', infection]), verbo([increased]), complemento([mRNA, levels, of, 'PXR', and, 'CYP3A4', in, both, cells, despite, the, absence, of, 'PXR', ligands])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, lower, expression, of, 'HNF4α', and, 'PGC1α', may, impair, 'RIF-mediated', 'CYP3A4', induction, under, conditions, of, 'PXR', overexpression, in, 'HFL', cells])].
[sujeto(['A', previous, study, revealed, that, 'ACAT2', gene, promoter, activity, was, upregulated, by, hepatocyte]), verbo([nuclear]), complemento([factor, 4, α, '(', 'HNF4α)', through, two, sites, around, -, 247, and, -, 311, of, 'ACAT2', gene, promoter])].
[sujeto(['In', 'HepG2', 'cells,', mutation, of, site, 'I']), verbo([decreased]), complemento(['ACAT2', gene, promoter, activity, to, 'one-fifth', of, that, of, the, wild, 'type,', while, mutation, of, site, 'II', reduced, promoter, activity, to, less, than, 'one-tenth', of, that, of, the, wild, type])].
[sujeto(['When', either, of, these, two, elements, was, inserted, into, 'pGL3-promoter,', 'HNF4α']), verbo([induced]), complemento([promoter, activity, through, the, inserted, 'element,', while, mutation, of, the, element, impaired, 'HNF4α', induction, effect])].
[sujeto(['In', electrophoretic, mobility, shift, assay, and, chromatin, immunoprecipitation, 'experiment,', 'HNF4α']), verbo([bound]), complemento([to, these, two, elements])].
[sujeto(['We', also, showed, that, 'HNF4α', positively]), verbo([regulates]), complemento(['ACAT2', gene, expression, at, mRNA, level])].
[sujeto(['Overexpression', of, 'HNF4α']), verbo([increased]), complemento(['ACAT2', 'expression,', whereas, knockdown, of, 'HNF4α', decreased, 'ACAT2', expression])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, gamma, coactivator, 1, α, '(', 'PCG1α),', a, coactivator, of, 'HNF4α,']), verbo([increased]), complemento(['ACAT2', 'expression,', while, small, heterodimer, partner, '(', 'SHP),', a, corepressor, of, 'HNF4α,', decreased, 'ACAT2', expression])].
[sujeto(['These', results]), verbo([provide]), complemento([more, insights, into, transcriptional, regulation, of, 'ACAT2', expression])].
[sujeto(['Liver-specific', insulin, 'receptor-deficient', mice, display, lower, hepatic, apoCIII, mRNA, levels, than, 'controls,']), verbo([suggesting]), complemento([that, factors, other, than, insulin, regulate, apoCIII, in, vivo])].
[sujeto(['Glucose']), verbo([induces]), complemento([apoCIII, transcription, in, primary, rat, hepatocytes, and, immortalized, human, hepatocytes, via, a, mechanism, involving, the, transcription, factors, carbohydrate, response, 'element-binding', protein, and, hepatocyte, nuclear, 'factor-4α'])].
[sujeto(['ApoCIII', induction, by, glucose, is, blunted, by, treatment, with, agonists, of, farnesoid, 'X', receptor, and, peroxisome, 'proliferator-activated', 'receptor-α', but, not, liver, 'X', 'receptor,', 'ie,']), verbo([nuclear]), complemento([receptors, controlling, triglyceride, metabolism])].
[sujeto(['Glucose']), verbo([induces]), complemento([apoCIII, 'transcription,', which, may, represent, a, mechanism, linking, 'hyperglycemia,', 'hypertriglyceridemia,', and, cardiovascular, disease, in, type, 2, diabetes])].
[sujeto(['Recent', studies]), verbo([have]), complemento([suggested, the, association, of, 'CYP3A', 'enzymes,', major, 'drug-metabolizing', 'enzymes,', with, cholesterol, metabolism])].
[sujeto(['In', the, present, 'study,', we]), verbo([have]), complemento([investigated, a, possible, involvement, of, 'SREBP-2', in, hepatic, 'Cyp3a11', expression])].
[sujeto(['Feeding', a, 'low-cholesterol', diet, '(', 'LCD)', to, mice]), verbo([activated]), complemento([hepatic, 'SREBP-2', whereas, it, attenuated, hepatic, 'Cyp3a11', expression])].
[sujeto(['This', region, contained, a, putative, hepatocyte]), verbo([nuclear]), complemento(['factor-4α', '(', 'HNF-4α)', binding, 'motif,', and, 'HNF-4α,', but, not, 'SREBP-2,', bound, to, the, motif, in, in, vitro, binding, assays])].
[sujeto(['In', 'pull-down', assays, and, coimmunoprecipitation, 'assays,', 'SREBP-2']), verbo([bound]), complemento([to, peroxisome, 'proliferator-activated', receptor, γ, 'coactivator-1α', '(', 'PGC-1α),', a, major, coactivator, for, 'HNF-4α,', via, its, transactivation, domain, and, inhibited, the, interaction, between, 'HNF-4α', and, 'PGC-1α', in, vitro])].
[sujeto(['Finally,', chromatin, immunoprecipitation, assays, demonstrated, that, the, extent, of, 'PGC-1α']), verbo([binding]), complemento([to, the, 'Cyp3a11', promoter, was, reduced, by, 'LCD-feeding', in, mouse, livers])].
[sujeto(['In', 'conclusion,']), verbo([activated]), complemento(['SREBP-2', interacts, with, 'PGC-1α', in, mouse, livers, at, reduced, cholesterol, intake])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento(['factor-4', alpha, '(', 'HNF-4alpha)', is, a, member, of, the, nuclear, receptor, superfamily, with, important, roles, in, hepatic, metabolism])].
[sujeto(['Fasting']), verbo([induces]), complemento([the, 'cAMP/protein', kinase, 'A', '(', 'PKA)-signaling', pathway])].
[sujeto(['The', mechanisms, whereby, cAMP]), verbo([regulates]), complemento(['HNF-4alpha', transcriptional, activity, are, incompletely, understood])].
[sujeto(['We']), verbo([have]), complemento([therefore, investigated, the, role, of, 'cAMP/PKA', in, regulation, of, 'HNF-4alpha', in, 'COS-1', cells, and, the, hepatoma, 'HepG2', cell, line])].
[sujeto(['cAMP/PKA']), verbo([inhibited]), complemento([the, transcriptional, activity, of, 'HNF-4alpha', in, 'COS-1', 'cells,', whereas, a, stimulatory, effect, was, observed, in, 'HepG2', cells])].
[sujeto(['The', 'cAMP-induced', inhibition, of, 'HNF-4alpha', in, 'COS-1', cells, was, counteracted, by, overexpression, of, the]), verbo([nuclear]), complemento([receptor, coactivator, 'PGC-1alpha,', and, 'cAMP/PKA-dependent', induction, of, the, 'PGC1A', gene, in, 'HepG2', cells, seems, to, explain, the, cell, specific, differences])].
[sujeto(['Similar', to, the, 'cAMP/PKA-mediated', regulation, of, 'HNF-4alpha,', overexpression, of, the, 'cAMP-response', element]), verbo([binding]), complemento([protein, '(', 'CREB)', inhibited, the, transcriptional, activity, of, 'HNF-4alpha', in, 'COS-1', 'cells,', regardless, of, 'cAMP/PKA', activation, and, 'CREB', phosphorylation])].
[sujeto(['Moreover,', activation, of, 'CREB', by, 'cAMP/PKA', further]), verbo([stimulated]), complemento(['HNF-4alpha', transactivation, in, 'HepG2', cells])].
[sujeto([cAMP]), verbo([induced]), complemento([the, expression, of, the, 'HNF-4alpha', target, genes, 'PCK1', and, 'G6Pase', in, these, cells])].
[sujeto(['In', 'conclusion,', our, results]), verbo([suggest]), complemento([that, the, level, of, 'PGC-1alpha', determines, whether, the, 'cAMP/PKA-pathway', overall, stimulates, or, inhibits, 'HNF-4alpha', transcriptional, activation])].
[sujeto(['Diabetes', is, the]), verbo([leading]), complemento([cause, of, 'end-stage', renal, disease, in, developed, countries])].
[sujeto(['Nuclear', hormone, receptors, are, transcription, factors, that]), verbo([regulate]), complemento([carbohydrate, 'metabolism,', lipid, 'metabolism,', the, immune, 'response,', and, inflammation])].
[sujeto(['These', receptors, also]), verbo([modulate]), complemento([the, development, of, fibrosis])].
[sujeto(['As', a, result, of, their, diverse, biological, 'effects,']), verbo([nuclear]), complemento([hormone, receptors, have, become, major, pharmaceutical, targets, for, the, treatment, of, a, host, of, diseases])].
[sujeto(['The']), verbo([increasing]), complemento([prevalence, of, diabetic, nephropathy, has, led, intense, investigation, into, the, role, that, nuclear, hormone, receptors, may, have, in, slowing, or, preventing, the, progression, of, renal, disease])].
[sujeto(['This', role, of]), verbo([nuclear]), complemento([hormone, receptors, would, be, associated, with, improvements, in, 'metabolism,', the, immune, 'response,', and, inflammation])].
[sujeto(['Eight']), verbo([nuclear]), complemento([receptors, have, shown, a, renoprotective, effect, in, the, context, of, diabetic, nephropathy])].
[sujeto(['This', 'Review', discusses, the, evidence, regarding, the, beneficial, effects, of, the, activation, of, these, receptors, in]), verbo([preventing]), complemento([the, progression, of, diabetic, nephropathy, and, describes, how, the, discovery, and, development, of, compounds, that, modulate, the, activity, of, nuclear, hormone, receptors, may, provide, potential, additional, therapeutic, approaches, in, the, management, of, diabetic, nephropathy])].
[sujeto(['We']), verbo([found]), complemento([evidence, of, pharmacogenetic, interactions, for, 'metformin,', 'sulfonylureas,', 'repaglinide,', 'thiazolidinediones,', and, acarbose, consistent, with, their, pharmacokinetics, and, pharmacodynamics])].
[sujeto(['Amongst', the, novel, associations]), verbo([found]), complemento([in, this, 'study,', selection, of, the, positive, marker, variants, of, genes, such, as, 'BCL3,', 'LPL,', 'PPARG,', 'SCAP,', and, 'SCD', will, improve, meat, organoleptic, characteristics, and, health, by, balancing, the, 'n-6', to, 'n-3', fatty, acid, ratio, in, meat])].
[sujeto(['Increased', variation, of, 'LINE1', sequence, methylation, was]), verbo([associated]), complemento([with, more, phenotypic, dissimilarity, measured, as, body, mass, index, '(', r, =, 0.77, ',', 'P', =, 0.007, ')', and, 2, -, hour, plasma, glucose, '(', r, =, 0.66, ',', 'P', =, 0.03, ')', whereas, the, variation, in, promoter, methylation, did, not, associate, with, phenotypic, differences])].
[sujeto([1, ')', which, had]), verbo([increased]), complemento([methylation, in, type, 2, diabetic, individuals])].
[sujeto(['Our', study]), verbo([suggests]), complemento([that, likely, acquired, 'DNA', methylation, changes, in, skeletal, muscle, or, adipose, tissue, gene, promoters, are, quantitatively, small, between, type, 2, diabetic, and, 'non-diabetic', twins])].
[sujeto(['Cholesterol', 7, 'alpha-hydroxylase', '(', 'Cyp7a1)', and, the, bile, acid, pool, size, are]), verbo([increased]), complemento([2, to, 3, -, fold, in, lactating, postpartum, rats])].
[sujeto(['We', investigated, the, interaction, of]), verbo([nuclear]), complemento([receptors, with, the, 'Cyp7a1', proximal, promoter, and, the, expression, of, regulatory, signaling, pathways, in, postpartum, rats, at, day, 10, '(', 'PPd10)', versus, female, controls, to, identify, the, mechanisms, of, increased, expression, of, 'Cyp7a1,', which, is, maximal, at, 16, hours])].
[sujeto(['Liver', 'X', receptor, '(', 'LXRalpha)', and, 'RNA', polymerase, 'II', '(', 'RNA', 'Pol', 'II)', recruitment, to, 'Cyp7a1', chromatin, were]), verbo([increased]), complemento([1.5, -, and, 2.5, -, 'fold,', 'respectively,', at, 16, hours, on, 'PPd10'])].
[sujeto(['Expression', of]), verbo([nuclear]), complemento([receptors, farnesoid, 'X', receptor, '(', 'FXR),', 'LXRalpha,', liver, receptor, homolog, '(', 'LRH-1),', hepatocyte, nuclear, factor, 4, alpha, '(', 'HNF4alpha),', and, short, heterodimer, partner, '(', 'SHP)', messenger, 'RNA', '(', 'mRNA)', and, coactivator, peroxisome, 'proliferators-activated', receptor, gamma, 'coactivator-1alpha', '(', 'PGC-1alpha)', mRNA, was, unchanged, in, 'PPd10', versus, controls, at, 16, 'hours,', whereas, chicken, ovalbumin, upstream, transcription, factor, 'II', '(', 'COUP-TFII)', was, decreased, 40, '%', at, 16, hours])].
[sujeto(['Investigation', of, a, repressive, signaling, 'pathway,', the, 'c-Jun-N-terminal', kinase, '(', 'JNK)', signaling, pathway, in, 'PPd10', versus, 'controls,', showed]), verbo([decreased]), complemento([mRNA, expression, of, hepatocyte, growth, factor, '(', 'HGF;', decreased, 60, '%', at, 16, 'hours)', and, tyrosine, kinase, receptor, 'c-Met', '(', decreased, 44, '%', -, 50, '%', at, 16, 'hours),', but, these, were, not, accompanied, by, decreased, expression, of, phosphorylated, 'c-Jun'])].
[sujeto(['Importantly,', expression, of, fibroblast, growth, factor, 15, '(', 'FGF15)', mRNA, in, the, ileum, was]), verbo([decreased]), complemento([70, '%', in, 'PPd10', versus, 'controls,', whereas, phosphorylated, 'mitogen-activated', protein, 'kinase/extracellular', 'signal-regulated', kinase, 1, /, 2, '(', 'Erk1/2)', protein, expression, in, liver, was, decreased, 88, '%', at, 16, hours])].
[sujeto(['The']), verbo([increased]), complemento([recruitment, of, 'LXRalpha,', a, 'Cyp7a1', stimulatory, 'pathway,', and, decreased, expression, of, 'FGF15', and, phosphorylated, 'Erk1/2,', a, 'Cyp7a1', repressive, 'pathway,', combined, to, increase, 'Cyp7a1', expression, during, lactation])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF4alpha)', is, a, novel, nuclear, receptor, that, participates, in, a, hierarchical, network, of, transcription, factors, regulating, the, development, and, physiology, of, such, vital, organs, as, the, 'liver,', 'pancreas,', and, kidney])].
[sujeto(['Among', the, various, transcriptional, coregulators, with, which, 'HNF4alpha', 'interacts,', peroxisome, 'proliferation-activated', receptor, gamma, '(', 'PPARgamma)', coactivator, 1, alpha, '(', 'PGC-1alpha)', represents, a, novel, coactivator, whose, activation, is, unusually, robust, and, whose]), verbo([binding]), complemento([mode, appears, to, be, distinct, from, that, of, canonical, coactivators, such, as, 'NCoA/SRC/p160', family, members])].
[sujeto(['To', elucidate, the, potentially, unique, molecular, mechanism, of, 'PGC-1alpha', 'recruitment,', we]), verbo([have]), complemento([determined, the, crystal, structure, of, 'HNF4alpha', in, complex, with, a, fragment, of, 'PGC-1alpha', containing, all, three, of, its, 'LXXLL', motifs])].
[sujeto(['Despite', the, presence, of, all, three, 'LXXLL', motifs, available, for, 'interactions,', only, one, is]), verbo([bound]), complemento([at, the, canonical, binding, 'site,', with, no, additional, contacts, observed, between, the, two, proteins])].
[sujeto(['However,', a, close, inspection, of, the, electron, density, map, indicates, that, the]), verbo([bound]), complemento(['LXXLL', motif, is, not, a, selected, one, but, an, averaged, structure, of, more, than, one, 'LXXLL', motif])].
[sujeto(['Further', biochemical, and, functional, studies, show, that, the, individual, 'LXXLL', motifs, can]), verbo([bind]), complemento([but, drive, only, minimal, transactivation])].
[sujeto(['Only', when, more, than, one, 'LXXLL', motif, is]), verbo([involved]), complemento([can, significant, transcriptional, activity, be, 'measured,', and, full, activation, requires, all, three, 'LXXLL', motifs])].
[sujeto(['These', findings]), verbo([led]), complemento([us, to, propose, a, model, wherein, each, 'LXXLL', motif, has, an, additive, 'effect,', and, the, multiple, binding, modes, by, 'HNF4alpha', toward, the, 'LXXLL', motifs, of, 'PGC-1alpha', could, account, for, the, apparent, robust, activation, by, providing, a, flexible, mechanism, for, combinatorial, recruitment, of, additional, coactivators, and, mediators])].
[sujeto(['The', transcriptional, coactivator, peroxisome, 'proliferator-activated', 'receptor-gamma', coactivator, '(', 'PGC)-1alpha', is]), verbo([involved]), complemento([in, the, coordinate, induction, of, changes, in, gene, expression, in, the, liver, that, enable, a, homeostatic, response, to, alterations, in, metabolic, 'state,', environmental, 'cues,', and, nutrient, availability])].
[sujeto(['In', exploring, the, specific, pathways, under, 'PGC-1alpha', regulation, in, the, 'liver,', we]), verbo([have]), complemento([made, the, surprising, observation, that, this, coactivator, can, induce, the, expression, of, 'CYP11A1', and, 'CYP17A1,', key, 'rate-limiting', enzymes, involved, in, the, initial, steps, of, steroidogenesis])].
[sujeto(['Estrogen-related', receptor, '(', 'ERR)-alpha']), verbo([mediates]), complemento(['PGC-1alpha\'s', induction, of, 'CYP11A1', and, binds, within, the, first, intron, of, the, 'CYP11A1', gene])].
[sujeto(['Both', 'ERR-alpha', and, hepatocyte]), verbo([nuclear]), complemento(['factor-4alpha', are, required, for, 'PGC-1alpha-mediated', induction, of, 'CYP17A1,', and, specific, binding, sites, for, these, receptors, have, been, identified, in, the, regulatory, regions, of, this, gene])].
[sujeto(['The', potential, physiological, significance, of, these, observations, was, highlighted, in, rats, where, fasting]), verbo([induced]), complemento([hepatic, expression, of, 'PGC-1alpha', and, 'CYP17A1', and, was, associated, with, an, increase, in, hepatic, levels, of, 'DHEA'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'DHEA', could, be, playing, a, role, as, an, intracellular, signaling, molecule, involved, in, modulating, hepatic, activity, in, response, to, fasting, conditions])].
[sujeto(['The', classical, functions, of, bile, acids, include]), verbo([acting]), complemento([as, detergents, to, facilitate, the, digestion, and, absorption, of, nutrients, in, the, gut])].
[sujeto(['In', 'addition,', bile, acids, also]), verbo([act]), complemento([as, signaling, molecules, to, regulate, glucose, 'homeostasis,', lipid, metabolism, and, energy, expenditure])].
[sujeto(['The', signaling, potential, of, bile, acids, in, compartments, such, as, the, systemic, circulation, is]), verbo([regulated]), complemento([in, part, by, an, efficient, enterohepatic, circulation, that, functions, to, conserve, and, channel, the, pool, of, bile, acids, within, the, intestinal, and, hepatobiliary, compartments])].
[sujeto(['These', alterations, in, turn, can]), verbo([have]), complemento([significant, effects, on, bile, acid, signaling, and, their, downstream, metabolic, targets])].
[sujeto(['This', review, discusses, recent, advances, in, our, understanding, of, the, 'inter-relationship', between, the, enterohepatic, cycling, of, bile, acids, and, the, metabolic, consequences, of, signaling, via, bile, 'acid-activated', 'receptors,', such, as, farnesoid, 'X']), verbo([nuclear]), complemento([receptor, '(', 'FXR)', and, the, 'G-protein-coupled', bile, acid, receptor, '(', 'TGR5)'])].
[sujeto(['Liver-enriched']), verbo([nuclear]), complemento([receptors, '(', 'NRs)', play, a, major, role, in, the, 'HBV', life, 'cycle,', operating, as, essential, transcription, factors, for, viral, gene, expression])].
[sujeto(['We', further, demonstrate, that, the, 'liver-enriched', 'NR', hepatocyte]), verbo([nuclear]), complemento([factor, 4, alpha, that, binds, 'HBV', plays, an, important, role, in, this, process])].
[sujeto(['Physiologically,', we, show, that, a, 'short-term', fast, that, turns, on, the, gluconeogenic, program, robustly]), verbo([induces]), complemento(['HBV', gene, expression, in, vivo])].
[sujeto(['We', conclude, that, 'HBV', is, tightly]), verbo([regulated]), complemento([by, changes, in, the, 'body\'s', nutritional, state, through, the, metabolic, regulator, 'PGC-1alpha'])].
[sujeto(['Our', data]), verbo([provide]), complemento([evidence, for, nutrition, signaling, to, control, viral, gene, expression, and, life, cycle, and, thus, ascribe, to, metabolism, an, important, role, in, 'virus-host', interaction])].
[sujeto(['Apolipoprotein', 'A-IV', '(', 'apoA-IV)', is, a, 46, kDa, glycoprotein, that]), verbo([associates]), complemento([with, 'triglyceride-rich', and, high, density, lipoproteins])].
[sujeto(['Blood', levels, of, 'apoA-IV', generally, correlate, with, triglyceride, levels, and, are]), verbo([increased]), complemento([in, diabetic, patients])].
[sujeto(['This', study, investigated, the, mechanisms]), verbo([regulating]), complemento([the, in, vivo, expression, of, 'apoA-IV', in, the, liver, and, intestine, of, mice, in, response, to, changes, in, nutritional, status])].
[sujeto(['Fasting', markedly]), verbo([increased]), complemento([liver, and, ileal, 'apoA-IV', mRNA, and, plasma, protein, concentrations])].
[sujeto(['This', induction, was]), verbo([associated]), complemento([with, increased, serum, glucocorticoid, levels, and, was, abolished, by, adrenalectomy])].
[sujeto(['Treatment', with, dexamethasone]), verbo([increased]), complemento(['apoA-IV', expression, in, adrenalectomized, mice])].
[sujeto(['Marked']), verbo([increases]), complemento([of, 'apoA-IV', expression, were, also, observed, in, two, murine, models, of, diabetes])].
[sujeto(['Reporter', gene, analysis, of, the, murine, and, human, 'apoA-IV/C-III', promoters, revealed, a]), verbo([conserved]), complemento([cooperative, activation, by, the, hepatic, nuclear, 'factor-4', alpha, '(', 'HNF-4', 'alpha)', and, the, peroxisome, 'proliferator-activated', receptor, gamma, 'coactivator-1', alpha, '(', 'PGC-1', 'alpha)', but, no, evidence, of, a, direct, regulatory, role, for, the, glucocorticoid, receptor])].
[sujeto(['Consistent', with, these, in, vitro, 'data,', induction, of, 'apoA-IV', in, response, to, fasting, was, accompanied, by]), verbo([increases]), complemento([in, 'HNF-4', alpha, and, 'PGC-1', alpha, expression, and, was, abolished, in, 'liver-specific', 'HNF-4', 'alpha-deficient', mice])].
[sujeto(['Together,', these, results, indicate, that, the, induction, of, 'apoA-IV', expression, in, fasting, and, diabetes, likely]), verbo([involves]), complemento(['PGC-1', 'alpha-mediated', coactivation, of, 'HNF-4', alpha, in, addition, to, 'glucocorticoid-dependent', actions])].
[sujeto(['The', aim, of, the, present, study, was, to, analyze, the, hepatic, expression, of, a, number, of]), verbo([nuclear]), complemento([receptors, involved, in, bile, acid, metabolism, in, human, cholesterol, gallstone, disease])].
[sujeto(['Surgical', liver, biopsies, were, obtained, from, 11, patients, with, untreated, cholesterol, cholelithiasis, and, nine, 'gallstone-free', 'subjects;', mRNA, levels, of, cholesterol, 7, 'alpha-hydroxylase', '(', 'CYP7A1)', and, related]), verbo([nuclear]), complemento([receptors, and, coactivators, were, assayed, by, quantitative, 'real-time', 'RT-PCR'])].
[sujeto(['No', differences, between, the, two, groups, were, detected, in, mRNA, levels, of, 'CYP7A1', and, related]), verbo([nuclear]), complemento(['receptors,', with, the, exception, of, peroxysome, 'proliferator-activated', 'receptor-gamma', coactivator, 1, '(', 'PGC-1),', which, was, significantly, '(', 'P', &, 'lt;', 0.01, ')', less, expressed, in, gallstone, subjects])].
[sujeto(['Expression', of, 'PGC-1', was, linearly, correlated, with, farnesoid, 'X', receptor, '(', 'FXR)', in, gallstone, patients, '(', r, =, 0.87, on, a, log, 'scale,', 'P', &, 'lt;', 0.01, ')', ',', but, not, in, control, 'subjects;', in, gallstone, patients, 'PGC-1', expression, was, also, correlated, with, hepatocyte]), verbo([nuclear]), complemento([factor, 4, '(', 'HNF-4)', '(', r, =, 0.78, ',', 'P', &, 'lt;', 0.01, ')'])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'PGC-1', can, play, a, role, in, the, prevention, of, cholesterol, gallstone, disease, in, 'humans;', this, might, take, place, via, interaction, with, the, bile, acid, receptor, 'FXR,', whose, protective, role, in, cholelithiasis, has, been, suggested, by, recent, evidence, in, animal, models, and, other, coactivators])].
[sujeto(['The', present, data, might, help, to, understand, the, pathophysiology, and, possibly, focus, on, new, therapeutical]), verbo([targets]), complemento([in, cholesterol, gallstone, disease])].
[sujeto(['The', role, of, the, constitutive, androstane, receptor, '(', 'CAR)', in, xenobiotic, metabolism, by]), verbo([inducing]), complemento([expression, of, cytochromes, 'P450', is, well, 'known,', but, 'CAR', has, also, been, implicated, in, the, 'down-regulation', of, key, genes, involved, in, bile, acid, 'synthesis,', 'gluconeogenesis,', and, fatty, acid, 'beta-oxidation', by, largely, unknown, mechanisms])].
[sujeto(['Because', a, key, hepatic, 'factor,', hepatic]), verbo([nuclear]), complemento(['factor-4', '(', 'HNF-4),', is, crucial, for, the, expression, of, many, of, these, 'genes,', we, examined, whether, 'CAR', could, suppress, 'HNF-4', transactivation])].
[sujeto(['Expression', of, 'CAR']), verbo([inhibited]), complemento(['HNF-4', transactivation, of, 'CYP7A1,', a, key, gene, in, bile, acid, 'synthesis,', in, 'HepG2', 'cells,', and, mutation, of, the, 'DNA', binding, domain, of, 'CAR', impaired, this, inhibition])].
[sujeto(['Gel', shift, assays, revealed, that, 'CAR', competes, with, 'HNF-4', for]), verbo([binding]), complemento([to, the, 'DR1', motif, in, the, 'CYP7A1', promoter])].
[sujeto(['TCPOBOP,', a, 'CAR', agonist, that]), verbo([increases]), complemento([the, interaction, of, 'CAR', with, 'coactivators,', potentiated, 'CAR', inhibition, of, 'HNF-4', transactivation])].
[sujeto(['Furthermore,', inhibition, by, 'CAR', was, reversed, by, expression, of]), verbo([increasing]), complemento([amounts, of, 'GRIP-1', or, 'PGC-1alpha,', indicating, that, 'CAR', competes, with, 'HNF-4', for, these, coactivators])].
[sujeto(['Treatment', of, mice, with, phenobarbital, or, 'TCPOBOP', resulted, in]), verbo([decreased]), complemento([hepatic, mRNA, levels, of, the, reported, genes, 'down-regulated', by, 'CAR,', including, 'Cyp7a1', and, 'Pepck'])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, 'CAR', inhibits, 'HNF-4', activity, by, competing, with, 'HNF-4', for, binding, to, the, 'DR1', motif, and, to, the, common, 'coactivators,', 'GRIP-1', and, 'PGC-1alpha,', which, may, be, a, general, mechanism, by, which, 'CAR', 'down-regulates', key, genes, in, hepatic, lipid, and, glucose, metabolism])].
[sujeto(['Increase', in, 'glucose-6-phosphatase', catalytic, subunit, '(', 'G6Pase,', 'G6pc)', transcription]), verbo([enhances]), complemento([hepatic, glucose, production, in, 'non-insulin-dependent', diabetes, mellitus, '(', 'NIDDM)'])].
[sujeto(['The', fact, that, carnivorous, fish, is, an, alternative, model, to, study, 'NIDDM']), verbo([led]), complemento([us, to, clone, and, characterise, the, first, 'G6pc', promoter, region, reported, for, fish, and, 'non-mammalian', animals])].
[sujeto(['The', 5, '\'', -, flanking, region, of, 'G6pc', from, gilthead]), verbo([sea]), complemento([bream, '(', 'Sparus', 'aurata)', was, isolated, by, chromosome, walking])].
[sujeto(['Transfection', experiments, in, 'HepG2', cells, showed, that, insulin]), verbo([repressed]), complemento(['S'])].
[sujeto(['Synergistic', activation, of, piscine, 'G6pc', promoter, was]), verbo([induced]), complemento([by, cotransfection, with, expression, plasmids, for, hepatocyte, nuclear, 'factor-4alpha', '(', 'HNF-4alpha)', and, peroxisome, 'proliferator-activated', 'receptor-gamma', 'coactivator-1', '(', 'PGC-1alpha)'])].
[sujeto(['No', direct, relationship, was]), verbo([found]), complemento([between, 'PGC-1alpha', coactivation, of, 'HNF-4alpha', transactivation, and, the, repressive, effect, of, insulin])].
[sujeto(['Interestingly,', insulin, hardly, affected, 'G6pc', promoter, activity, in, the, absence, of, 'glucose,']), verbo([suggesting]), complemento([that, a, reduced, capacity, of, 'insulin-dependent', repression, of, piscine, 'G6pc', may, lead, to, insulin, resistance, in, carnivorous, fish])].
[sujeto(['The', genes, coding, for, drug, and, bile, acid, transporters, and, 'CYP', enzymes, are]), verbo([regulated]), complemento([by, a, complex, network, of, transcriptional, 'cascades,', notably, by, the, 'ligand-activated', nuclear, receptors, 'FXR,', 'PXR,', and, 'CAR', and, by, the, 'ligand-independent', nuclear, receptor, 'HNF-4alpha'])].
[sujeto(['The', bile, acid, synthesizing, enzymes, 'CYP7A1,', 'CYP8B1,', and, 'CYP27A1', are, subject, to, negative, feedback, regulation, by, bile, 'acids,', which, is, partly]), verbo([mediated]), complemento([through, the, transcriptional, repressor, 'SHP'])].
[sujeto(['The', role, of, transcriptional, 'cofactors,', such, as, 'SRC-1', and, 'PGC-1,', in]), verbo([mediating]), complemento([the, 'gene-specific', effects, of, individual, nuclear, receptors, is, becoming, increasingly, evident])].
[sujeto(['Peroxisome', 'proliferator-activated', 'receptor-gamma', coactivator, 1, alpha, '(', 'PGC-1alpha)']), verbo([has]), complemento([been, shown, to, regulate, adaptive, thermogenesis, and, glucose, metabolism])].
[sujeto(['Here', we, show, that, 'PGC-1alpha']), verbo([regulates]), complemento([triglyceride, metabolism, through, both, farnesoid, 'X', receptor, '(', 'FXR)-dependent', and, -, independent, pathways])].
[sujeto(['PGC-1alpha']), verbo([increases]), complemento(['FXR', activity, through, two, 'pathways:', '(', 1, ')', it, increases, 'FXR', mRNA, levels, by, coactivation, of, 'PPARgamma', and, 'HNF4alpha', to, enhance, 'FXR', gene, 'transcription;', and, '(', 2, ')', it, interacts, with, the, 'DNA-binding', domain, of, 'FXR', to, enhance, the, transcription, of, 'FXR', target, genes])].
[sujeto(['Consistent', with, these, in, vitro, 'studies,', we, demonstrate, that, fasting]), verbo([induces]), complemento([hepatic, expression, of, 'PGC-1alpha', and, 'FXR', and, results, in, decreased, plasma, triglyceride, levels, in, 'wild-type', but, not, in, 'FXR-null', mice])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, 'PGC-1alpha', plays, an, important, physiological, role, in, maintaining, energy, homeostasis, during, fasting, by, decreasing, triglyceride, 'production/secretion', while, it, increases, fatty, acid, 'beta-oxidation', to, meet, energy, needs])].
[sujeto(['The', hepatocyte]), verbo([nuclear]), complemento(['factor-4alpha', '(', 'HNF-4alpha)/PGC-1', pathway, plays, a, crucial, role, in, the, transcriptional, regulation, of, hepatic, gluconeogenic, enzymes, such, as, phosphoenolpyruvate, carboxykinase, '(', 'PEPCK)', and, 'Glc-6-Pase,', genes, that, are, activated, at, fasting, and, suppressed, in, a, fed, state])].
[sujeto(['Here', we, show, the, mechanism, by, which, 'SREBP-1']), verbo([suppresses]), complemento([expression, of, gluconeogenic, genes])].
[sujeto(['A', series, of, luciferase, reporter, assays, demonstrated, that, 'SREBP-1a', and, -, 1, c, effectively]), verbo([inhibited]), complemento([the, 'PEPCK', promoter, activity, that, was, induced, by, 'HNF-4alpha'])].
[sujeto(['The', 'HNF-4alpha-binding', site, in, the, 'glucocorticoid-response', unit, was, responsible, for, the, 'SREBP-1', 'inhibition,', although, 'SREBP-1', did, not]), verbo([bind]), complemento([to, the, 'PEPCK', promoter, as, demonstrated, by, electrophoretic, mobility, shift, assays])].
[sujeto(['Coimmunoprecipitation', experiments, demonstrated, that, these, two, transcription, factors, directly]), verbo([interact]), complemento([through, the, transactivation, domain, of, 'SREBP-1', and, the, ligand, 'binding/AF2', domains, of, 'HNF-4alpha'])].
[sujeto(['Estimation', of, coactivator, recruitment, using, 'HNF-4alpha-Gal4DBD', fusion, assay, showed, that, 'SREBP-1', competitively]), verbo([inhibited]), complemento(['PGC-1', 'recruitment,', a, requirement, for, 'HNF-4alpha', activation])].
[sujeto(['Consistent', with, these, 'results,', hepatic, 'PEPCK', and, 'Glc-6-Pase', mRNA, levels, are]), verbo([suppressed]), complemento([by, overexpression, of, 'SREBP-1a', and, -, 1, c, in, the, transgenic, mice])].
[sujeto(['Our', data, indicate, that, 'SREBP-1']), verbo([has]), complemento([a, novel, role, as, negative, regulator, of, gluconeogenic, genes, through, a, 'cross-talk', with, 'HNF-4alpha', interference, with, 'PGC-1', recruitment])].
[sujeto(['However,', despite, the, recent, 'advances,', the, molecular, mechanisms, whereby, bile, acids]), verbo([regulate]), complemento([gene, transcription, and, cholesterol, homeostasis, in, mammals, still, need, further, investigations])].
[sujeto(['Here,', we, show, that, bile, acids]), verbo([suppress]), complemento([transcription, of, the, gene, '(', 'CYP7A1)', encoding, cholesterol, 7, 'alpha-hydroxylase,', the, 'rate-limiting', enzyme, in, bile, acid, 'biosynthesis,', also, through, an, unusual, mechanism, not, involving, the, bile, acid, nuclear, 'receptor,', farnesoid, 'X', receptor])].
[sujeto(['By', performing, 'cell-based', reporter, 'assays,', 'protein/protein', 'interaction,', and, chromatin, immunoprecipitation, 'assays,', we, demonstrate, that, bile, acids, impair, the, recruitment, of, peroxisome, 'proliferator-activated', 'receptor-gamma', 'coactivator-1alpha', and, cAMP, response, 'element-binding', 'protein-binding', protein, by, hepatocyte]), verbo([nuclear]), complemento(['factor-4alpha,', a, master, regulator, of, 'CYP7A1'])].
[sujeto(['We', also, show, for, the, first, time, that, bile, acids]), verbo([inhibit]), complemento([transcription, of, the, gene, '(', 'PEPCK)', encoding, phosphoenolpyruvate, 'carboxykinase,', the, 'rate-limiting', enzyme, in, 'gluconeogenesis,', through, the, same, farnesoid, 'X', 'receptor-independent', mechanism])].
[sujeto(['Chromatin', immunoprecipitation, assay, revealed, that, bile, 'acid-induced', dissociation, of, coactivators, from, hepatocyte]), verbo([nuclear]), complemento(['factor-4alpha', decreased, the, recruitment, of, 'RNA', polymerase, 'II', to, the, core, promoter, and, downstream, in, the, 3, '\'', -, untranslated, regions, of, these, two, 'genes,', reflecting, the, reduction, of, gene, transcription])].
[sujeto(['Finally,', we]), verbo([found]), complemento([that, 'Cyp7a1', expression, was, stimulated, in, fasted, mice, in, parallel, to, 'Pepck,', whereas, the, same, genes, were, repressed, by, bile, acids])].
[sujeto(['Collectively,', these, results]), verbo([reveal]), complemento([a, novel, regulatory, mechanism, that, controls, gene, transcription, in, response, to, extracellular, stimuli, and, argue, that, the, transcription, regulation, by, bile, acids, of, genes, central, to, cholesterol, and, glucose, metabolism, should, be, viewed, dynamically, in, the, context, of, the, 'fasted-to-fed', cycle])].
[sujeto(['We']), verbo([have]), complemento([shown, previously, that, the, transcriptional, coactivator, peroxisome, 'proliferator-activated', receptor, gamma, 'coactivator-1alpha', '(', 'PGC-1alpha)', is, induced, in, fasted, or, diabetic, liver, and, activates, the, entire, program, of, gluconeogenesis])].
[sujeto(['PGC-1alpha']), verbo([interacts]), complemento([with, several, nuclear, receptors, known, to, bind, gluconeogenic, promoters, including, the, glucocorticoid, 'receptor,', hepatocyte, nuclear, factor, 4, alpha, '(', 'HNF4alpha),', and, the, peroxisome, 'proliferator-activated', receptors])].
[sujeto(['However,', the, genetic, requirement, for, any, of, these, interactions]), verbo([has]), complemento([not, been, determined])].
[sujeto(['Using', hepatocytes, from, mice, lacking, 'HNF4alpha', in, the, 'liver,', we, show, here, that, 'PGC-1alpha', completely, loses, its, ability, to]), verbo([activate]), complemento([key, genes, of, gluconeogenesis, such, as, phosphoenolpyruvate, carboxykinase, and, 'glucose-6-phosphatase', when, 'HNF4alpha', is, absent])].
[sujeto(['It', is, also, shown, that, 'PGC-1alpha', can]), verbo([induce]), complemento([genes, of, 'beta-oxidation', and, ketogenesis, in, 'hepatocytes,', but, these, effects, do, not, require, 'HNF4alpha'])].
[sujeto(['It']), verbo([has]), complemento([recently, been, shown, that, 'adenoviral-mediated', expression, of, peroxisome, 'proliferator-activated', receptor, gamma, 'co-activator-1', alpha, '(', 'PGC-1', 'alpha)', in, hepatocytes, stimulates, 'glucose-6-phosphatase', catalytic, subunit, '(', 'G6Pase)', gene, expression])].
[sujeto(['A', combination, of, fusion, 'gene,', gel, retardation, and, chromatin, immunoprecipitation, assays, revealed, 'that,', in, 'H4IIE', 'cells,', 'PGC-1', alpha]), verbo([mediates]), complemento([this, stimulation, through, an, evolutionarily, conserved, region, of, the, 'G6Pase', promoter, that, binds, hepatocyte, nuclear, 'factor-4', alpha])].
[sujeto(['Expression', of, the, 'L-CPT', 'I', gene, is]), verbo([induced]), complemento([by, starvation, in, response, to, glucagon, secretion, from, the, 'pancreas,', an, effect, mediated, by, cAMP])].
[sujeto(['Our', data, strongly]), verbo([suggest]), complemento([that, the, coactivator, 'PGC-1', is, involved, in, the, regulation, of, this, gene, expression, by, cAMP, in, combination, with, 'HNF4', alpha, and, 'cAMP-response', 'element-binding', protein, '(', 'CREB)'])].
[sujeto(['Indeed,', '(', 'i)', cotransfection, of, 'CREB', or, 'HNF4', alpha, dominant, negative, mutants, completely, abolishes, the, effect, of, cAMP, on, the, 'L-CPT', 'I', 'promoter,', and, '(', 'ii)', the, 'cAMP-responsive', unit]), verbo([binds]), complemento(['HNF4', alpha, and, 'CREB', through, the, 'DR1', and, the, 'cAMP-response', element, 'sequences,', respectively])].
[sujeto(['Moreover,', cotransfection, of, 'PGC-1', strongly]), verbo([activates]), complemento([the, 'L-CPT', 'I', promoter, through, 'HNF4', alpha, bound, at, the, 'DR1', element])].
[sujeto(['Taken', together, these, observations]), verbo([suggest]), complemento([that, 'PGC-1', acts, to, coordinate, the, process, of, metabolic, adaptation, in, the, liver])].
[sujeto(['Blood', glucose, levels, are]), verbo([maintained]), complemento([by, the, balance, between, glucose, uptake, by, peripheral, tissues, and, glucose, secretion, by, the, liver])].
[sujeto(['Gluconeogenesis', is, strongly]), verbo([stimulated]), complemento([during, fasting, and, is, aberrantly, activated, in, diabetes, mellitus])].
[sujeto(['Here', we, show, that, the, transcriptional, coactivator, 'PGC-1', is, strongly]), verbo([induced]), complemento([in, liver, in, fasting, mice, and, in, three, mouse, models, of, insulin, action, 'deficiency:', 'streptozotocin-induced', 'diabetes,', 'ob/ob', genotype, and, liver, 'insulin-receptor', knockout])].
[sujeto(['PGC-1', is]), verbo([induced]), complemento([synergistically, in, primary, liver, cultures, by, cyclic, 'AMP', and, glucocorticoids])].
[sujeto(['Adenoviral-mediated', expression, of, 'PGC-1', in, hepatocytes, in, culture, or, in, vivo, strongly]), verbo([activates]), complemento([an, entire, programme, of, key, gluconeogenic, 'enzymes,', including, phosphoenolpyruvate, carboxykinase, '(', 'PEPCK)', and, 'glucose-6-phosphatase,', leading, to, increased, glucose, output])].
[sujeto(['Full', transcriptional, activation, of, the, 'PEPCK', promoter]), verbo([requires]), complemento([coactivation, of, the, glucocorticoid, receptor, and, the, 'liver-enriched', transcription, factor, 'HNF-4alpha', '(', hepatic, nuclear, 'factor-4alpha)', by, 'PGC-1'])].
[sujeto(['These', results, implicate, 'PGC-1', as, a, key, modulator, of, hepatic, gluconeogenesis, and, as, a, central]), verbo([target]), complemento([of, the, 'insulin-cAMP', axis, in, liver])].
[sujeto(['Prenatal', glucocorticoid, exposure]), verbo([causes]), complemento([lifelong, hyperglycaemia, in, rat, 'offspring,', associated, with, permanently, increased, hepatic, phosphoenolpyruvate, carboxykinase, 2, '(', 'PCK2),', the, 'rate-controlling', enzyme, of, gluconeogenesis])].
[sujeto(['To', elucidate, the, mechanisms, underlying, the, '\'', 'programming\'', of, 'PCK2,', this, study, examined, the, effect, of, prenatal, dexamethasone, treatment, on, expression, of, transcription, factors, that]), verbo([regulate]), complemento(['Pck2'])].
[sujeto(['Real-time', 'RT-PCR', and, in, situ, hybridisation, were, used, to, measure, and, localise, hepatic, mRNA]), verbo([transcribed]), complemento([from, the, genes, for, 'PCK2,', hepatocyte, nuclear, factor, 4, ',', alpha, '(', 'HNF4A),', transcription, factor, 1, '(', 'TCF1),', 'CCAAT/enhancer', binding, 'protein,', alpha, '(', 'CEBPA),', 'CEBPB,', the, glucocorticoid, receptor, '(', 'NR3C1)', and, peroxisome, proliferative, activated, 'receptor,', 'gamma,', coactivator, 1, alpha, '(', 'PPARGC1A)', in, foetal, and, adult, offspring, of, dams, treated, with, dexamethasone, or, vehicle, during, the, last, week, of, gestation])].
[sujeto(['This', resulted, from]), verbo([increased]), complemento([expression, of, isoforms, derived, from, the, '\'', 'adult\'', '(', 'P1)', 'Hnf4a', promoter])].
[sujeto(['In', 'contrast,', isoforms, from, the, '\'', 'foetal\'', '(', 'P2)', promoter, were, markedly]), verbo([suppressed]), complemento([by, dexamethasone])].
[sujeto(['Like', 'Pck2,', the]), verbo([increase]), complemento([in, hepatic, 'Hnf4a', mRNA, occurred, exclusively, in, the, periportal, zone])].
[sujeto(['Foetal', 'Tcf1', expression, was, also]), verbo([increased]), complemento([by, dexamethasone, 'treatment,', but, this, did, not, persist, into, adulthood])].
[sujeto(['Prenatal', dexamethasone, exposure]), verbo([caused]), complemento([a, permanent, increase, in, hepatic, 'Hnf4a', mRNA])].
[sujeto(['This', 'increase,', which, was]), verbo([associated]), complemento([with, a, premature, switch, from, foetal, to, adult, promoter, 'predominance,', was, congruent, with, changes, in, 'Pck2', expression])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'HNF4A', might, mediate, 'Pck2', overexpression, and, subsequent, hyperglycaemia])].
[sujeto(['The', initiation, of, hepatitis, 'B', virus, '(', 'HBV)', replication]), verbo([involves]), complemento([the, formation, of, covalently, closed, circular, 'DNA', '(', 'cccDNA)', and, its, transcription, into, pregenomic, 'RNA', '(', 'pgRNA)', in, hepatocyte, nuclei])].
[sujeto(['The', regulatory, mechanism, of, 'HBV', replication, by, acetyltransferase, is, thus, far, not, well, 'understood,', but, human, acetyltransferase]), verbo([has]), complemento([been, reported, as, being, involved, in, the, regulation, of, 'HBV', replication])].
[sujeto(['Consistent', with, these, 'observations,', 'HBV', replication, regulators, hepatocyte]), verbo([nuclear]), complemento(['factor-4-α', '(', 'HNF4α)', and, peroxisome, 'proliferator-activated', receptor, gamma, 'coactivator-', '(', 'PPARGC-)', 1, -, α, were, decreased, following, knockdown, of, 'HAT1', or, 'KAT8'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'KAT8', or, 'HAT1', regulate, 'HBV', replication, and, may, be, potential, drug, targets, of, 'anti-HBV', therapy])].
[sujeto(['Our', aim, was, to]), verbo([induce]), complemento([hepatic, transdifferentiation, of, 'ASCs', by, sequential, exposure, to, several, combinations, of, 'cytokines,', growth, 'factors,', and, hormones])].
[sujeto(['This', protocol]), verbo([activated]), complemento([transcription, factors, '[', 'GATA6,', 'Hex,', 'CCAAT/enhancer', binding, protein, alpha, and, beta, '(', 'CEBPalpha', and, 'beta),', peroxisome, 'proliferator-activated', 'receptor-gamma,', coactivator, 1, alpha, '(', 'PGC1alpha),', and, hepatocyte, nuclear, factor, 4, alpha, '(', 'HNF4alpha)],', which, promoted, a, characteristic, hepatic, 'phenotype,', as, assessed, by, new, informative, markers, for, the, 'step-by-step', hepatic, transdifferentiation, of, hMSC, '[', early, 'markers:', albumin, '(', 'ALB),', 'alpha-2-macroglobuline', '(', 'alpha2M),', complement, protein, 'C3', '(', 'C3),', and, selenoprotein, 'P1', '(', 'SEPP1);', late, 'markers:', cytochrome, 'P450', 3, 'A4', '(', 'CYP3A4),', apolipoprotein, 'E', '(', 'APOE),', 'acyl-CoA', synthetase, 'long-chain', family, member, 1, '(', 'ACSL1),', and, angiotensin, 'II', 'receptor,', type, 1, '(', 'AGTR1)]'])].
[sujeto(['The']), verbo([loss]), complemento([of, adipose, adult, stem, cell, phenotype, was, detected, by, losing, expression, of, 'Thy1', and, inhibitor, of, 'DNA', binding, 3, '(', 'Id3)'])].
[sujeto(['HNF-4alpha', '(', hepatocyte]), verbo([nuclear]), complemento(['factor-4alpha)', is, a, key, regulator, of, 'liver-specific', gene, expression])].
[sujeto(['We']), verbo([have]), complemento([shown, previously, that, the, 'HNF-4alpha-sensitive', 'APR', genes, 'ApoB', '(', apolipoprotein, 'B),', 'TTR', '(', 'transthyretin)', and, 'alpha1-AT', '(', 'alpha1-antitrypsin)', were, regulated, at, the, 'DNA', binding, and, transcriptional, levels, after, cytokine, stimulation])].
[sujeto(['We', now, show, that, 'co-activators']), verbo([have]), complemento([a, differential, impact, on, the, transactivation, of, 'HNF-4alpha-sensitive', genes, via, 'HNF-4alpha-binding', sites, in, 'ApoB,', 'TTR', or, 'alpha1-AT', promoters])].
[sujeto(['PGC-1alpha', strongly]), verbo([enhances]), complemento([the, transactivation, of, 'ApoB', and, 'alpha1-AT', 'and,', to, a, lesser, 'extent,', of, 'TTR,', whereas, 'SRC-1alpha', and, p300, only, have, a, weak, or, no, effect, on, these, three, genes])].
[sujeto(['More', 'importantly,', it, was]), verbo([found]), complemento([that, 'PGC-1alpha', has, a, novel, role, in, the, modulation, of, the, binding, ability, of, 'HNF-4alpha', in, response, to, cytokine, treatment])].
[sujeto(['Using', in, vitro, and, in, vivo, 'approaches,', electrophoretic, 'mobility-shift', and, chromatin, immunoprecipitation, 'assays,', we, demonstrate, that, the, reduced, 'HNF-4alpha-DNA']), verbo([binding]), complemento([ability, induced, by, cytokines, is, eliminated, by, overexpression, of, 'PGC-1alpha'])].
[sujeto(['Cytokine', treatment, does, not, significantly, alter, the, protein, levels, of, 'HNF-4alpha', and, 'PGC-1alpha,', but, it, does, reduce, the, recruitment, of, 'PGC-1alpha', to, 'HNF-4alpha-binding', sites, and, thereby]), verbo([decreases]), complemento([transcriptional, activity])].
[sujeto(['These', results, establish, the, importance, of, 'PGC-1alpha', for, 'HNF-4alpha', function, and, describe, a, new, 'HNF-4alpha-dependent', regulatory, mechanism, that, is]), verbo([involved]), complemento([in, the, response, to, injury])].
[sujeto(['Inborn', errors, of, mitochondrial, 'beta-oxidation']), verbo([cause]), complemento([ectopic, fat, 'accumulation,', particularly, in, the, liver])].
[sujeto(['Fatty', liver, is]), verbo([associated]), complemento([with, insulin, resistance, and, predisposes, to, hepatic, fibrosis])].
[sujeto(['The', factors, underlying, the, pathophysiological, consequences, of, hepatic, fat, accumulation]), verbo([have]), complemento([remained, poorly, defined])].
[sujeto(['Gene', expression, profiling, in, a, model, of, acute, fatty, liver, disease]), verbo([induced]), complemento([by, blocking, 'long-chain', fatty, acid, 'beta-oxidation', was, performed, to, study, the, early, effects, of, steatosis, on, the, transcriptome])].
[sujeto(['Tetradecylglycidic', acid, '(', 'TDGA)', was, used, to, irreversibly]), verbo([inhibit]), complemento([carnitine, palmitoyltransferase, 1, ',', a, key, enzyme, in, the, control, of, mitochondrial, 'beta-oxidation'])].
[sujeto(['TDGA', treatment]), verbo([induced]), complemento([massive, microvesicular, hepatic, steatosis, within, a, 12, -, h, time, frame, in, male, 'C57BL6/J', mice])].
[sujeto(['Increased', hepatic, 'long-chain', 'acyl-CoA', 'content,', particularly, of, 'C16:0,', 'C16:1', and, 'C18:1,', was]), verbo([associated]), complemento([with, profound, effects, on, the, transcriptome, as, revealed, by, unbiased, gene, expression, profiling, and, quantitative, 'real-time', 'PCR'])].
[sujeto(['The', results, indicate, drastic, changes, in, the, expression, of, genes, encoding, proteins]), verbo([involved]), complemento([in, 'lipid,', 'carbohydrate,', and, amino, acid, metabolism])].
[sujeto(['Pathway', analysis, identified, transcription, factors, and, coregulators, such, as, hepatocyte]), verbo([nuclear]), complemento([factor, 4, '(', 'HNF4),', peroxisome, 'proliferator-activated', 'receptor-alpha', '(', 'PPAR-alpha),', and, 'PPAR', gamma, coactivator, 1, alpha, '(', 'PGC-1alpha', ')', as, key, players, in, these, metabolic, adaptations])].
[sujeto(['Surprisingly,', a, strong, reduction, in, the, expression, of, genes]), verbo([involved]), complemento([in, hepatic, bile, salt, metabolism, and, transport, was, observed])].
[sujeto(['Insulin']), verbo([inhibits]), complemento([transcription, of, cholesterol, 7, 'alpha-hydroxylase', '(', 'Cyp7a1),', a, key, gene, in, bile, acid, 'synthesis,', and, the, hepatic, nuclear, 'factor-4', '(', 'HNF-4)', site, in, the, promoter, was, identified, as, a, negative, insulin, response, sequence])].
[sujeto(['Conversely,', 'HNF-4', interaction, with, 'SREBP-1c', was]), verbo([increased]), complemento([after, feeding])].
[sujeto(['In', vitro, studies]), verbo([suggested]), complemento([that, 'SREBP-1c', competed, with, 'PGC-1alpha', for, direct, interaction, with, the, 'AF2', domain, of, 'HNF-4'])].
[sujeto(['Reporter', assays, showed, that, 'SREBP-1c,', but, not, of, a, 'SREBP-1c', mutant, lacking, the, 'HNF-4']), verbo([interacting]), complemento(['domain,', inhibited, 'HNF-4/PGC-1alpha', transactivation, of, 'Cyp7a1'])].
[sujeto(['SREBP-1c', also]), verbo([inhibited]), complemento(['PGC-1alpha-coactivation', of, estrogen, 'receptor,', constitutive, androstane, 'receptor,', pregnane, 'X', 'receptor,', and, farnesoid, 'X', 'receptor,', implying, inhibition, of, 'HNF-4', by, 'SREBP-1c', could, extend, to, other, nuclear, receptors])].
[sujeto(['In', chromatin, immunoprecipitation, 'studies,', 'HNF-4']), verbo([binding]), complemento([to, the, promoter, was, not, 'altered,', but, 'PGC-1alpha', was, 'dissociated,', 'SREBP-1c', and, histone, 'deacetylase-2', '(', 'HDAC2)', were, 'recruited,', and, acetylation, of, histone, 'H3', was, decreased, upon, feeding])].
[sujeto(['This', mechanism, may, be, relevant, to, known, repression, of, many, other, 'HNF-4']), verbo([target]), complemento([genes, upon, feeding])].
[sujeto(['Interindividual', variability, in, the, 'CYP2A6', expression, level, in, human, liver, might, be]), verbo([caused]), complemento([by, an, inducible, 'property,', but, the, molecular, mechanism, of, induction, is, unclear])].
[sujeto(['Rifampicin,', 'phenobarbital,', and, 6, -, '(', 4, -, 'chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde', 'O-(3,4-dichlorobenzyl)oxime,', which, are, activators, of, pregnane, 'X', receptor, '(', 'PXR)', and, constitutive, androstane, receptor, '(', 'CAR),']), verbo([induced]), complemento(['CYP2A6', mRNA, in, human, hepatocytes])].
[sujeto(['We', identified, three, direct, repeat, separated, by, four, nucleotides, '(', 'DR4)-like', elements, at, -, 6698, ',', -, 5476, ',', and, -, 4618, in, the, 'CYP2A6', 'gene,', to, which, 'PXR', and, 'CAR', could]), verbo([bind]), complemento([after, dimerization, with, retinoid, 'X', receptor, '(', 'RXR)-alpha'])].
[sujeto(['In', luciferase, 'assays,', overexpression, of, 'PXR', or, 'CAR', could, not]), verbo([activate]), complemento([the, transcriptional, activity, of, 'CYP2A6', promoter, constructs, '(', -, 6754, to, -, 1, ')', in, 'HepG2', cells])].
[sujeto(['Cotransfection', of, hepatocyte]), verbo([nuclear]), complemento(['factor-4alpha', did, not, affect, the, transcriptional, activities, in, the, absence, or, presence, of, 'PXR', or, 'CAR'])].
[sujeto(['Interestingly,', cotransfection, of, peroxisome, 'proliferator-activated', 'receptor-gamma', coactivator, 1, alpha, '(', 'PGC-1alpha)', as, well, as, 'PXR', significantly]), verbo([enhanced]), complemento([the, transcriptional, activity, '(', 3.9, -, fold, of, 'control)'])].
[sujeto(['By', the, deletion, of, a, possible, suppresser, region, '(', -, 4533, to, -, 185, ')', ',', the, effects, of, 'PXR/PGC-1alpha', on, the, transcriptional, activity, were]), verbo([increased]), complemento(['(', 6.9, -, fold, of, 'control)'])].
[sujeto(['Chromatin', immunoprecipitation, assay, revealed, that, 'PXR', and, 'PGC-1alpha']), verbo([bind]), complemento([to, 'CYP2A6', chromatin])].
[sujeto(['In', 'conclusion,', we]), verbo([found]), complemento([that, 'CYP2A6', is, induced, via, 'PXR', and, 'PGC-1alpha', through, the, 'DR4-like', element, at, the, distal, response, region])].
[sujeto(['This', is, the, first, study, to]), verbo([report]), complemento([the, molecular, mechanism, of, the, induction, of, 'CYP2A6'])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento(['factor-4', '(', 'HNF-4alpha),', a, member, of, the, nuclear, receptor, 'superfamily,', binds, 'DNA', exclusively, as, a, homodimer])].
[sujeto(['Dimerization', controls, important, aspects, of, receptor, 'function,', such, as, 'DNA', 'binding,', protein, 'stability,', ligand]), verbo([binding]), complemento([and, interaction, with, coactivators])].
[sujeto(['Mutants', were, analysed, for, 'transactivation,', coactivator, 'interaction,', 'DNA']), verbo([binding]), complemento([and, dimerization])].
[sujeto(['EMSA', analysis, showed, that, the, mutants, are, able, to]), verbo([bind]), complemento(['DNA', as, dimers, and, coimmunoprecipitation, assays, confirmed, dimerization, in, solution])].
[sujeto(['Finally,', residue, 'R324,', located, in, the, 'H9/H10', 'loop,', which, was, suspected, to, be]), verbo([involved]), complemento([in, dimer, stabilization, via, an, ionic, interaction, with, residue, 'E276,', was, studied])].
[sujeto(['In', contrast, to, the, conservative, substitution, 'R324H', the, mutation, 'R324L', abolishes, 'HNF-4alpha', transcriptional, activity, and, coactivator, 'recruitment,']), verbo([revealed]), complemento([that, the, nature, of, substitution, may, play, an, important, role, in, 'HNF-4alpha', function])].
[sujeto(['Hepatic', lipase, '(', 'HL)', plays, a, key, role, in, the, metabolism, of, plasma, 'lipoproteins,', and, its, level, of, activity]), verbo([requires]), complemento([tight, 'regulation,', given, the, association, of, both, low, and, high, levels, with, atherosclerosis, and, coronary, artery, disease])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, the, human, hepatic, lipase, gene, '(', 'LIPC)', promoter, is, regulated, by, hepatocyte, nuclear, factor, 4, alpha, '(', 'HNF4alpha),', peroxisome, 'proliferator-activated', receptor, gamma, 'coactivator-1alpha', '(', 'PGC-1alpha),', apolipoprotein, 'A-I', regulatory, 'protein-1', '(', 'ARP-1),', and, hepatocyte, nuclear, factor, 1, alpha, '(', 'HNF1alpha)'])].
[sujeto(['Reporter', analysis, showed, that, 'HNF4alpha', directly]), verbo([regulates]), complemento([the, 'LIPC', promoter, via, two, newly, identified, direct, repeat, 'elements,', 'DR1', and, 'DR4'])].
[sujeto(['PGC-1alpha', is, capable, of]), verbo([stimulating]), complemento([the, 'HNF4alpha-dependent', transactivation, of, the, 'LIPC', promoter])].
[sujeto(['ARP-1', displaces, 'HNF4alpha', from, the, 'DR1', site, and, blocks, its, ability, to]), verbo([activate]), complemento([the, 'LIPC', promoter])].
[sujeto(['Induction', by, 'HNF1alpha']), verbo([requires]), complemento([the, 'HNF1', binding, site, and, upon, cotransfection, with, 'HNF4alpha', leads, to, an, additive, effect])].
[sujeto(['In', 'addition,', the, in, vivo, relevance, of, 'HNF4alpha', in, 'LIPC', expression, is, shown, by, the, ability, of, the, 'HNF4alpha', antagonist, 'Medica', 16, to]), verbo([repress]), complemento([endogenous, 'LIPC', mRNA, expression])].
[sujeto(['Furthermore,', disruption, of, 'Hnf4alpha', in, mice]), verbo([prevents]), complemento([the, expression, of, 'HL', mRNA, in, liver])].
[sujeto(['The', overall, effect, these, transcription, factors]), verbo([have]), complemento([on, 'HL', expression, will, ultimately, depend, on, the, interplay, between, these, various, factors, and, their, relative, intracellular, concentrations])].
[sujeto(['To']), verbo([maintain]), complemento([euglycemia, in, healthy, 'organisms,', hepatic, glucose, production, is, increased, during, fasting, and, decreased, during, the, postprandial, period])].
[sujeto(['These', responses, are]), verbo([associated]), complemento([with, the, insulin, signaling, pathway, and, the, reduction, in, the, activity, of, key, gluconeogenic, 'enzymes,', resulting, in, a, decrease, of, hepatic, glucose, production])].
[sujeto(['On', the, other, 'hand,', defects, in, the, liver, insulin, signaling, pathway, might]), verbo([promote]), complemento([inadequate, suppression, of, 'gluconeogenesis,', leading, to, hyperglycemia, during, fasting, and, after, meals])].
[sujeto(['The', hepatocyte]), verbo([nuclear]), complemento([factor, 4, ',', the, transcription, cofactor, 'PGC1-α,', and, the, transcription, factor, 'Foxo1', have, fundamental, roles, in, regulating, gluconeogenesis])].
[sujeto(['The']), verbo([loss]), complemento([of, insulin, action, is, associated, with, the, production, of, 'pro-inflammatory', biomolecules, in, obesity, conditions])].
[sujeto(['Among', the, molecular, mechanisms, 'involved,', we, emphasize, in, this, review, the, participation, of, 'TRB3', protein, '(', a, mammalian, homolog, of, 'Drosophila', 'tribbles),', which, is, able, to]), verbo([inhibit]), complemento(['Akt', activity, 'and,', 'thereby,', maintain, 'Foxo1', activity, in, the, nucleus, of, 'hepatocytes,', inducing, hyperglycemia])].
[sujeto(['In', 'contrast,', physical, exercise]), verbo([has]), complemento([been, shown, as, an, important, tool, to, reduce, insulin, resistance, in, the, liver, by, reducing, the, inflammatory, 'process,', including, the, inhibition, of, 'TRB3', 'and,', 'therefore,', suppressing, gluconeogenesis])].
[sujeto(['The', understanding, of, these, new, mechanisms, by, which, physical, exercise]), verbo([regulates]), complemento([glucose, homeostasis, has, critical, importance, for, the, understanding, and, prevention, of, diabetes])].
[sujeto(['Vanin-1', '(', 'VNN1)', is, a, 'liver-enriched', oxidative, stress, sensor, that]), verbo([has]), complemento([been, implicated, in, the, regulation, of, multiple, metabolic, pathways])].
[sujeto(['Clinical', investigations, indicated, that, the, levels, of, 'VNN1', were]), verbo([increased]), complemento([in, the, urine, and, blood, of, diabetic, 'patients,', but, the, physiological, significance, of, this, phenomenon, remains, unknown])].
[sujeto(['In', this, 'study,', we, demonstrated, that, the, hepatic, expression, of, 'VNN1', was]), verbo([induced]), complemento([in, fasted, mice, or, mice, with, insulin, resistance])].
[sujeto(['Gain-', and, 'loss-of-function', studies, indicated, that, 'VNN1']), verbo([increased]), complemento([the, expression, of, gluconeogenic, genes, and, hepatic, glucose, 'output,', which, led, to, hyperglycemia])].
[sujeto(['These', effects, of, 'VNN1', on, gluconeogenesis, were]), verbo([mediated]), complemento([by, the, regulation, of, the, 'Akt', signaling, pathway])].
[sujeto(['Mechanistically,', vnn1, transcription, was]), verbo([activated]), complemento([by, the, synergistic, interaction, of, peroxisome, 'proliferator-activated', receptor, γ, coactivator, 1, α, '(', 'PGC-1α)', and, hepatocyte, nuclear, 'factor-4α', '(', 'HNF-4α)'])].
[sujeto(['A', chromatin, immunoprecipitation, analysis, indicated, that, 'PGC-1α', was, present, near, the, 'HNF-4α']), verbo([binding]), complemento([site, on, the, proximal, vnn1, promoter, and, activated, the, chromatin, structure])].
[sujeto(['Taken', 'together,', our, results]), verbo([suggest]), complemento([an, important, role, for, 'VNN1', in, regulating, hepatic, gluconeogenesis])].
[sujeto(['Therefore,', 'VNN1', may, serve, as, a, potential, therapeutic]), verbo([target]), complemento([for, the, treatment, of, metabolic, diseases, caused, by, overactivated, gluconeogenesis])].
[sujeto(['HNF4α', '(', hepatocyte]), verbo([nuclear]), complemento([factor, 4, 'α)', is, a, culprit, gene, product, for, a, monogenic, and, dominantly, inherited, form, of, 'diabetes,', referred, to, as, 'MODY', '(', maturity, onset, diabetes, of, the, 'young)'])].
[sujeto(['As', a, member, of, the, 'NR', '(']), verbo([nuclear]), complemento(['receptor)', 'superfamily,', 'HNF4α', recruits, transcriptional, 'co-activators', such, as, 'SRC-1α', '(', steroid, receptor, 'co-activator-1α)', and, 'PGC-1α', '(', 'peroxisome-proliferator-activated', receptor, γ, 'co-activator-1α)', through, the, 'LXXLL-binding', motifs, for, its, 'transactivation,', and, our, recent, crystal, structures, of, the, complex, provided, the, molecular, details, and, the, mechanistic, insights, into, these, 'co-activator', recruitments])].
[sujeto(['Several', mutations]), verbo([have]), complemento([been, identified, from, the, 'MODY', patients, 'and,', among, 'these,', point, mutations, can, be, very, instructive, 'site-specific', measures, of, protein, function, and, structure])].
[sujeto(['Thus,', in, the, present, 'study,', we, probed, the, functional, effects, of, the, two, 'MODY', point, mutations, '(', 'D206Y', and, 'M364R)']), verbo([found]), complemento([directly, near, the, 'LXXLL', 'motif-binding', site, by, conducting, a, series, of, experiments, on, their, structural, integrity, and, specific, functional, roles, such, as, overall, 'transcription,', ligand, 'selectivity,', target, gene, recognition, and, 'co-activator', recruitment])].
[sujeto(['While', the, 'D206Y', mutation]), verbo([has]), complemento([a, subtle, 'effect,', the, 'M364R', mutation, significantly, impaired, the, overall, transactivation, by, 'HNF4α'])].
[sujeto(['These', functional, disruptions, are, mainly, due, to, their, reduced, ability, to]), verbo([recruit]), complemento(['co-activators', and, lowered, protein, stability, '(', only, with, 'M364R', 'mutation),', while, their, 'DNA-binding', activities, and, ligand, selectivities, are, preserved])].
[sujeto(['These', results, confirmed, our, structural, predictions, and, proved, that, 'MODY', mutations, are, 'loss-of-function', mutations]), verbo([leading]), complemento([to, impaired, 'β-cell', function])].
[sujeto(['These', findings, should, help]), verbo([target]), complemento([selective, residues, for, correcting, mutational, defects, or, modulating, the, overall, activity, of, 'HNF4α', as, a, means, of, therapeutic, intervention])].
[sujeto(['In', 'combination,', these, interventions]), verbo([have]), complemento([an, additive, effect, on, lifespan, in, 'Ames', 'DF', mice])].
[sujeto(['Therefore,', common, signaling, pathways]), verbo([regulated]), complemento([by, 'DF', and, 'CR', could, have, additive, effects, on, longevity])].
[sujeto(['Motif', analysis, of, the, upstream, sequences, of, those, genes, revealed, four, major, consensus, sequence, 'motifs,', which]), verbo([have]), complemento([been, named, dwarfism, and, calorie, 'restriction-responsive', elements, '(', 'DFCR-REs)'])].
[sujeto(['One', of, the, synthesized, sequences]), verbo([bound]), complemento([to, hepatocyte, nuclear, 'factor-4α', '(', 'HNF-4α),', an, important, transcription, factor, involved, in, liver, metabolism])].
[sujeto(['When', the, reporter, 'construct,', containing, an, element, upstream, of, a, secreted, alkaline, phosphatase, '(', 'SEAP)', 'gene,', was, 'co-transfected', with, 'HNF-4α', and, its, regulator, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)', γ, 'coactivator-1α', '(', 'PGC-1α),', 'SEAP', activity, was]), verbo([increased]), complemento([compared, with, untransfected, controls])].
[sujeto(['Moreover,', transient, transgenic, mice, established, using, this, construct, showed]), verbo([increased]), complemento(['SEAP', activity, in, 'CR', mice, compared, with, ad, 'libitum-fed', mice])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, because, of, its, 'rapidity,', ease, of, 'use,', and, 'specificity,', our, bioassay, will, be, more, useful, than, the, systems, currently, employed, to, screen, for, 'CR', 'mimetics,', which, mimic, the, beneficial, effects, of, 'CR'])].
[sujeto(['DAX-1', '(', 'dosage-sensitive', sex, reversal, adrenal, hypoplasia, congenital, critical, region, on, 'X', 'chromosome,', gene, 1, ')', is, an, atypical, member, of, the]), verbo([nuclear]), complemento([receptor, family, and, acts, as, a, corepressor, of, a, number, of, nuclear, receptors])].
[sujeto(['HNF4alpha', '(', hepatocyte]), verbo([nuclear]), complemento([factor, 4, 'alpha)', is, a, 'liver-enriched', transcription, factor, that, controls, the, expression, of, a, variety, of, genes, involved, in, 'cholesterol,', fatty, 'acid,', and, glucose, metabolism])].
[sujeto(['Here', we, show, that, 'DAX-1']), verbo([inhibits]), complemento([transcriptional, activity, of, 'HNF4alpha', and, modulates, hepatic, gluconeogenic, gene, expression])].
[sujeto(['Hepatic', 'DAX-1', expression, is]), verbo([increased]), complemento([by, insulin, and, 'SIK1', '(', 'salt-inducible', kinase, 1, ')', ',', whereas, it, is, decreased, in, high, fat, 'diet-fed', and, diabetic, mice])].
[sujeto(['Coimmunoprecipitation', assay, from, mouse, liver, samples, depicts, that, endogenous, 'DAX-1']), verbo([interacts]), complemento([with, 'HNF4alpha', in, vivo])].
[sujeto(['In', vivo, chromatin, immunoprecipitation, assay, affirms, that, the, recruitment, of, 'DAX-1', on, the, phosphoenolpyruvate, carboxykinase, '(', 'PEPCK)', gene, promoter, is, inversely, correlated, with, the, recruitment, of, 'PGC-1alpha', and, 'HNF4alpha', under, fasting, and, 'refeeding,', showing, that, 'DAX-1', could, compete, with, the, coactivator, 'PGC-1alpha', for]), verbo([binding]), complemento([to, 'HNF4alpha'])].
[sujeto(['Adenovirus-mediated', expression, of, 'DAX-1']), verbo([decreased]), complemento([both, 'HNF4alpha-', and, 'forskolin-mediated', gluconeogenic, gene, expressions])].
[sujeto(['Finally,', 'DAX-1']), verbo([inhibits]), complemento(['PEPCK', and, 'glucose-6-phosphatase', gene, expression, and, significantly, lowers, fasting, blood, glucose, level, in, high, fat, 'diet-fed', 'mice,', suggesting, that, 'DAX-1', can, modulate, hepatic, gluconeogenesis, in, vivo])].
[sujeto(['Overall,', this, study, demonstrates, that, 'DAX-1']), verbo([acts]), complemento([as, a, corepressor, of, 'HNF4alpha', to, negatively, regulate, hepatic, gluconeogenic, gene, expression, in, liver])].
[sujeto(['Hepatitis', 'B', virus, '(', 'HBV)', is, a, small, 'DNA', virus, that]), verbo([targets]), complemento([the, liver, and, infects, humans, worldwide])].
[sujeto(['Recently', we]), verbo([have]), complemento([shown, that, the, metabolic, regulator, 'PGC-1alpha', coactivates, 'HBV', transcription, thereby, rendering, the, virus, susceptible, to, fluctuations, in, the, nutritional, status, of, the, liver])].
[sujeto(['PGC-1alpha', coactivation, of, 'HBV', is]), verbo([mediated]), complemento([through, the, 'liver-enriched', nuclear, receptor, 'HNF4alpha', and, through, another, yet, unknown, transcription, 'factor(s)'])].
[sujeto(['Here', we, show, that, the, forkhead, transcription, factor, 'FOXO1,', a, known]), verbo([target]), complemento([for, 'PGC-1alpha', coactivation, and, a, central, mediator, of, glucose, metabolism, in, the, 'liver,', binds, 'HBV', core, promoter, and, activates, its, transcription])].
[sujeto(['This', activation, is, further]), verbo([enhanced]), complemento([in, the, presence, of, 'PGC-1alpha,', implying, that, 'FOXO1', is, a, target, for, 'PGC-1alpha', coactivation, of, 'HBV', transcription])].
[sujeto(['Thus,', our, results, identify, another, key, metabolic, regulator, as, an, activator, of, 'HBV', 'transcription,', thereby, supporting, the, principle, that, 'HBV', gene, expression, is]), verbo([regulated]), complemento([in, a, similar, way, to, key, hepatic, metabolic, genes])].
[sujeto(['Recently,', we]), verbo([reported]), complemento([stimulation, of, 'SeP', promoter, activity, by, the, forkhead, box, transcription, factor, 'FoxO1a', in, hepatoma, cells, and, its, attenuation, by, insulin])].
[sujeto(['Here,', we, demonstrate, that, this]), verbo([translates]), complemento([into, 'fine-tuning', of, 'SeP', production, and, secretion, by, insulin])].
[sujeto(['Overexpression', of, peroxisomal, proliferator]), verbo([activated]), complemento(['receptor-gamma', coactivator, 1, alpha, '(', 'PGC-1alpha)', enhanced, the, stimulatory, effect, of, 'FoxO1a', on, 'SeP', promoter, activity])].
[sujeto(['We', identified, a, novel, functional]), verbo([binding]), complemento([site, for, hepatocyte, nuclear, factor, '(', 'HNF)-4alpha,', termed, hepatocyte, nuclear, factor, binding, element, 1, ',', in, the, human, 'SeP', promoter, directly, upstream, of, the, 'FoxO-responsive', element, 'daf16-binding', element, 2, '(', 'DBE2)'])].
[sujeto(['Point', mutations, in, hepatocyte]), verbo([nuclear]), complemento([factor, binding, element, 1, alone, or, together, with, 'DBE2', decreased, basal, activity, and, responsiveness, of, the, 'SeP', promoter, to, 'PGC-1alpha'])].
[sujeto(['Moreover,', the, 'PGC-1alpha-inducing', glucocorticoid, dexamethasone, strongly]), verbo([enhanced]), complemento(['SeP', messenger, 'RNA', levels, and, protein, secretion, in, cultured, rat, 'hepatocytes,', whereas, insulin, suppressed, the, stimulation, of, both, 'PGC-1alpha', and, 'SeP', caused, by, dexamethasone, treatment])].
[sujeto(['In', a, 'brain-derived', neuroblastoma, cell, line, with, low, basal, 'SeP', 'expression,', 'SeP', transcription, was]), verbo([stimulated]), complemento([by, 'PGC-1alpha', together, with, 'FoxO1a,', and, overexpression, of, 'HNF-4alpha', potentiated, this, effect])].
[sujeto(['High-level', expression, of, 'SeP', in, liver, is]), verbo([ensured]), complemento([by, concerted, action, of, the, coactivator, 'PGC-1alpha', and, the, transcription, factors, 'FoxO1a', and, 'HNF-4alpha'])].
[sujeto(['Hence,', the, production, of, 'SeP', is]), verbo([regulated]), complemento([similarly, to, that, of, the, gluconeogenic, enzyme, 'glucose-6-phosphatase'])].
[sujeto(['The', nutritional, state, of, organisms, and, energy, balance, related, diseases, such, as, diabetes]), verbo([regulate]), complemento([the, metabolism, of, xenobiotics, such, as, 'drugs,', toxins, and, carcinogens])].
[sujeto(['The', 'xenobiotic-metabolizing', cytochrome, 'P450', '(', 'CYP)', 2, 'A5', enzyme]), verbo([has]), complemento([been, shown, to, be, induced, by, fasting, and, by, glucagon, and, cyclic, 'AMP', '(', 'cAMP),', which, mediate, numerous, fasting, responses])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, gamma, coactivator, '(', 'PGC)-1alpha']), verbo([triggers]), complemento([many, of, the, important, hepatic, fasting, effects, in, response, to, elevated, cAMP, levels])].
[sujeto(['In', the, present, 'study,', we, were, able, to, show, that, cAMP]), verbo([causes]), complemento([a, coordinated, induction, of, 'PGC-1alpha', and, 'CYP2A5', mRNAs, in, murine, primary, hepatocytes])].
[sujeto(['Furthermore,', the, elevation, of, the, 'PGC-1alpha', expression, level, by, adenovirus]), verbo([mediated]), complemento([gene, transfer, increased, 'CYP2A5', transcription])].
[sujeto(['Co-transfection', of, 'Cyp2a5', 5, '\'', promoter, constructs, with, the, 'PGC-1alpha', expression, vector, demonstrated, that, 'PGC-1alpha', is, able, to]), verbo([activate]), complemento(['Cyp2a5', transcription, through, the, hepatocyte, nuclear, factor, '(', 'HNF)-4alpha', response, element, in, the, proximal, promoter, of, the, 'Cyp2a5', gene])].
[sujeto(['In', 'conclusion,', 'PGC-1alpha']), verbo([mediates]), complemento([the, expression, of, 'Cyp2a5', induced, by, cAMP, in, mouse, hepatocytes, through, coactivation, of, transcription, factor, 'HNF-4alpha'])].
[sujeto(['This', strongly]), verbo([suggests]), complemento([that, 'PGC-1alpha', is, the, major, factor, mediating, the, fasting, response, of, 'CYP2A5'])].
[sujeto(['Fasting']), verbo([induces]), complemento([numerous, adaptive, changes, in, metabolism, by, several, central, signaling, 'pathways,', the, most, important, represented, by, the, 'HNF4alpha/PGC-1alpha-pathway'])].
[sujeto(['Because', 'HNF4alpha']), verbo([has]), complemento([been, identified, as, central, regulator, of, basolateral, bile, acid, transporters, and, a, previous, study, reports, increased, basolateral, bile, acid, uptake, into, the, liver, during, 'fasting,', we, hypothesized, that, 'HNF4alpha', is, involved, in, 'fasting-induced', bile, acid, uptake, via, upregulation, of, basolateral, bile, acid, transporters])].
[sujeto(['In', 'rats,', mRNA, of, 'Ntcp,', 'Oatp1,', and, 'Oatp2', were, significantly]), verbo([increased]), complemento([after, 48, h, of, fasting])].
[sujeto(['Protein', expression, as, determined, by, 'Western', blot, showed, significant]), verbo([increases]), complemento([for, all, three, transporters, 72, h, after, the, onset, of, fasting])].
[sujeto(['Whereas']), verbo([binding]), complemento([activity, of, 'HNF1alpha', in, electrophoretic, mobility, shift, assays, remained, 'unchanged,', 'HNF4alpha', binding, activity, to, the, 'Ntcp', promoter, was, increased, significantly])].
[sujeto(['In', line, with, this, 'result,', we]), verbo([found]), complemento([significantly, increased, mRNA, expression, of, 'HNF4alpha', and, 'PGC-1alpha'])].
[sujeto(['Functional', studies, in, 'HepG2', cells, revealed, an]), verbo([increased]), complemento([endogenous, 'NTCP', mRNA, expression, upon, cotransfection, with, either, 'HNF4alpha,', 'PGC-1alpha,', or, a, combination, of, both])].
[sujeto(['We', conclude, that, upregulation, of, the, basolateral, bile, acid, transporters, 'Ntcp,', 'Oatp1,', and, 'Oatp2', in, fasted, rats, is]), verbo([mediated]), complemento([via, the, 'HNF4alpha/PGC-1alpha', pathway])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, gamma, 'coactivator-1alpha', '(', 'PGC-1alpha)', is, a, transcriptional, coactivator]), verbo([involved]), complemento([in, several, aspects, of, energy, metabolism])].
[sujeto(['It', is]), verbo([induced]), complemento([or, activated, under, different, stimuli, in, a, highly, 'tissue-specific', manner, and, subsequently, partners, with, certain, transcription, factors, in, those, tissues, to, execute, various, biological, programs])].
[sujeto(['In', the, fasted, 'liver,', 'PGC-1alpha', is]), verbo([induced]), complemento([and, interacts, with, hepatocyte, nuclear, factor, 4, alpha, '(', 'HNF4alpha)', and, other, transcription, factors, to, activate, gluconeogenesis, and, increase, hepatic, glucose, output])].
[sujeto(['Given', the, broad, spectrum, of, liver, genes, responsive, to, 'HNF4alpha,', we, sought, to, determine, those, that, were, specifically]), verbo([targeted]), complemento([by, the, combination, of, 'PGC-1alpha', and, 'HNF4alpha'])].
[sujeto(['Coexpression', of, these, two, molecules, in, murine, stem, cells]), verbo([reveals]), complemento([a, high, induction, of, mRNA, for, apolipoproteins, 'A-IV', and, 'C-II'])].
[sujeto(['Forced', expression, of, 'PGC-1alpha', in, mouse, and, human, hepatoma, cells]), verbo([increases]), complemento([the, mRNA, of, a, subset, of, apolipoproteins, implicated, in, very, low, density, lipoprotein, and, triglyceride, 'metabolism,', including, apolipoproteins, 'A-IV,', 'C-II,', and, 'C-III'])].
[sujeto(['Coactivation', of, the, 'apoC-III/A-IV', promoter, region, by, 'PGC-1alpha', occurs, through, a, highly]), verbo([conserved]), complemento(['HNF4alpha', response, 'element,', the, loss, of, which, completely, abolishes, activation, by, 'PGC-1alpha', and, 'HNF4alpha'])].
[sujeto(['Adenoviral', infusion, of, 'PGC-1alpha', into, live, mice]), verbo([increases]), complemento([hepatic, expression, of, apolipoproteins, 'A-IV,', 'C-II,', and, 'C-III', and, increases, serum, and, very, low, density, lipoprotein, triglyceride, levels])].
[sujeto(['Conversely,', knock, down, of, 'PGC-1alpha', in, vivo]), verbo([causes]), complemento([a, decrease, in, both, apolipoprotein, expression, and, serum, triglyceride, levels])].
[sujeto(['During', the, third, trimester, of, 'pregnancy,', there, is, an]), verbo([increase]), complemento([in, serum, triglyceride, and, cholesterol, levels])].
[sujeto(['We', hypothesized, 'that,', during, 'pregnancy,', the, expression, of]), verbo([nuclear]), complemento([hormone, receptors, involved, in, regulating, lipid, metabolism, would, decrease])].
[sujeto(['In', 19, -, day, pregnant, 'mice,', serum, triglyceride, and, 'non-HDL', cholesterol, levels, were, significantly, 'increased,', whereas, total, cholesterol, was, slightly, 'decreased,', because, of, a]), verbo([decrease]), complemento([in, the, 'HDL', fraction])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, '(', 'PPAR)alpha,', 'PPARbeta/delta,', and, 'PPARgamma,', liver, 'X', receptor, '(', 'LXR)alpha', and, 'LXRbeta,', farnesoid, 'X', receptor, '(', 'FXR),', and, retinoid, 'X', receptor, '(', 'RXR)alpha,', 'RXRbeta,', and, 'RXRgamma', mRNA, levels, were, significantly]), verbo([decreased]), complemento([in, the, livers, of, 19, -, day, pregnant, mice])].
[sujeto(['Additionally,', the, expressions, of, thyroid, receptor, '(', 'TR)alpha,', pregnane, 'X', 'receptor,', sterol, regulatory, 'element-binding', proteins, '(', 'SREBP)-1a,', 'SREBP-1c,', 'SREBP-2,', and, liver, receptor, homolog, 1, were, also, 'decreased,', whereas, the, expression, of, 'TRbeta,', constitutive, androstane, 'receptor,', and, hepatic]), verbo([nuclear]), complemento([factor, 4, showed, no, significant, change])].
[sujeto([mRNA, levels, of, the, 'PPAR']), verbo([target]), complemento([genes, 'carnitine-palmitoyl', transferase, 1, alpha, and, 'acyl-CoA', 'oxidase,', the, 'LXR', target, genes, 'SREBP1c,', 'ATP-binding', cassettes, 'G5', and, 'G8,', the, 'FXR', target, gene, 'SHP,', and, the, 'TR', target, genes, malic, enzyme, and, 'Spot14', were, all, significantly, decreased])].
[sujeto(['Finally,', the, expressions, of, 'PPARgamma', coactivator, '(', 'PGC)-1alpha', and, 'PGC-1beta,', known, activators, of, a, number, of]), verbo([nuclear]), complemento([hormone, 'receptors,', were, also, significantly, decreased])].
[sujeto(['The']), verbo([decreases]), complemento([in, expression, of, 'RXRs,', 'PPARs,', 'LXRs,', 'FXR,', 'TRs,', 'SREBPs,', and, 'PGC-1s', could, contribute, to, the, alterations, in, lipid, metabolism, during, late, pregnancy])].
[sujeto(['The', gene, encoding, cholesterol, 7, 'alpha-hydroxylase', '(', 'CYP7A1)', is, tightly]), verbo([regulated]), complemento([to, control, bile, acid, synthesis, and, maintain, lipid, homeostasis])].
[sujeto(['Recent', studies, in, mice]), verbo([suggest]), complemento([that, bile, acid, synthesis, is, regulated, by, the, 'fasted-to-fed', 'cycle,', and, fasting, induces, 'CYP7A1', gene, expression, in, parallel, to, the, induction, of, peroxisome, 'proliferators-activated', receptor, gamma, 'co-activator', 1, alpha, '(', 'PGC-1alpha)', and, phosphoenolpyruvate, carboxykinase, '(', 'PEPCK)'])].
[sujeto(['How', glucagon]), verbo([regulates]), complemento(['CYP7A1', gene, expression, in, the, human, liver, is, not, clear])].
[sujeto(['Here', we, show, that, glucagon, and, cyclic, adenosine, monophosphate, '(', 'cAMP)', strongly]), verbo([repressed]), complemento(['CYP7A1', mRNA, expression, in, human, primary, hepatocytes])].
[sujeto(['Reporter', assays, confirmed, that, cAMP, and, protein, kinase, 'A', '(', 'PKA)']), verbo([inhibited]), complemento([human, 'CYP7A1', gene, 'transcription,', in, contrast, to, their, stimulation, of, the, 'PEPCK', gene])].
[sujeto(['Mutagenesis', analysis, identified, a, 'PKA-responsive', region, located, within, the, previously, identified, 'HNF4alpha']), verbo([binding]), complemento([site, in, the, human, 'CYP7A1', promoter])].
[sujeto(['Glucagon', and, cAMP]), verbo([increased]), complemento(['HNF4alpha', phosphorylation, and, reduced, the, amount, of, 'HNF4alpha', present, in, 'CYP7A1', chromatin])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, glucagon, inhibited, 'CYP7A1', gene, expression, via, 'PKA', phosphorylation, of, 'HNF4alpha,', which, lost, its, ability, to, bind, the, 'CYP7A1', gene, and, resulted, in, inhibition, of, human, 'CYP7A1', gene, transcription])].
[sujeto(['In', 'conclusion,', this, study, unveils, a, species, difference, in, nutrient, regulation, of, the, human, and, mouse, 'CYP7A1', gene, and]), verbo([suggests]), complemento([a, discordant, regulation, of, bile, acid, synthesis, and, gluconeogenesis, by, glucagon, in, human, livers, during, fasting])].
[sujeto(['BH3-interacting', domain, death, agonist, '(', 'Bid),', a, 'BH3-only', 'B', cell, lymphoma, 2, family, 'molecule,', is, generally, known, for, its, importance, in]), verbo([activating]), complemento([the, mitochondrial, apoptosis, pathway, after, death, receptor, 'engagement,', particularly, in, hepatocytes])].
[sujeto(['However,', 'Bid', also]), verbo([promotes]), complemento([hepatocyte, proliferation, during, liver, regeneration, and, carcinogenesis])].
[sujeto(['This', study, was, designed, to, examine, the, hypothesis, that, 'Bid']), verbo([regulates]), complemento([endoplasmic, reticulum, calcium, concentration, '(', '[', 'Ca(2+)](ER))', homeostasis, to, affect, hepatocyte, proliferation])].
[sujeto(['We']), verbo([found]), complemento([that, 'serum-stimulated', hepatocyte, proliferation, was, dependent, on, 'calcium,', and, the, depletion, of, calcium, with, thapsigargin, or, ethylene, glycol, tetraacetic, acid, '(', 'EGTA)', inhibited, the, proliferation])].
[sujeto(['Subcellular', fractionation, showed, that, a, portion, of, 'Bid', was, inserted, into, the, endoplasmic, reticulum, '(', 'ER)-enriched', 'membranes,', and, 'single-cell', calcium, imaging, indicated, that, 'Bid', was, important, for]), verbo([maintaining]), complemento([the, '[', 'Ca(2+)](ER)', level])].
[sujeto(['Finally,', 'B', cell, lymphoma, 2, -]), verbo([associated]), complemento(['X', protein, '(', 'Bax)', could, also, be, found, in, the, 'ER-enriched', 'membranes,', and, 'Bax', deficiency, caused, the, same, proliferation, defect])].
[sujeto(['However,', 'Bid/Bax', double, deletion, in, hepatocytes, did, not, further, augment, the, 'defect,', which]), verbo([suggested]), complemento([that, 'Bid', and, 'Bax', worked, by, the, same, regulatory, mechanism, in, '[', 'Ca(2+)](ER)', control])].
[sujeto(['Bid']), verbo([regulates]), complemento([hepatocyte, proliferation, by, positively, affecting, '[', 'Ca(2+)](ER)', 'homeostasis,', and, this, could, be, important, for, liver, regeneration, and, carcinogenesis])].
[sujeto(['On', 'average,', more, than, 700, differentially]), verbo([expressed]), complemento([genes, '(', 'DEGs)', were, identified, of, which, 146, are, mechanistically, linked, to, 'LD', formation])].
[sujeto(['We', identified, 51, 'LD-associated', 'DEGs', frequently]), verbo([regulated]), complemento([in, patient, samples, '(', range, '≥5', to, '≤102)', with, the, 'liver-receptor', 'homolog-1(NR5A2),', that, 'is,', a, key, regulator, of, cholesterol, metabolism, being, commonly, repressed, among, 100, patients, examined])].
[sujeto(['With', bland, 'steatosis,', notable, regulations]), verbo([involved]), complemento(['hypoxia-inducible', lipid, 'droplet-associated-protein', and, 'diacylglycerol-O-acyltransferase-2', renowned, for, their, role, in, 'LD-growth'])].
[sujeto(['Conversely,', nonalcoholic, 'steatohepatitis-associated', 'DEGs', coded, for, epidermal, growth, factor, receptor, and, 'TLR4', signaling, with]), verbo([decreased]), complemento([expression, of, the, 'GTPase', 'Rab5', and, the, lipid, phosphohydrolase, 'PPAP2B', thus, highlighting, adaptive, responses, to, 'inflammation,', 'LDL-mediated', endocytosis, and, 'lipogenesis,', respectively])].
[sujeto(['Studies', with, steatotic, primary, human, hepatocyte, cultures, demonstrated, induction, of, 'LD-associated', 'PLIN2,', 'CIDEC,', 'DNAAF1,', whereas]), verbo([repressed]), complemento([expression, of, 'CPT1A,', 'ANGPTL4,', and, 'PKLR', informed, on, burdened, mitochondrial, metabolism])].
[sujeto(['Equally,']), verbo([repressed]), complemento([expression, of, the, 'B-lymphocyte', chemoattractant, 'CXCL13', and, 'STAT4', as, well, as, induced, 'FGF21', evidenced, amelioration, of, 'steatosis-related', inflammation])].
[sujeto(['Lastly,', 'STRING', network, analysis, highlighted, potential, &, 'quot;druggable&quot;']), verbo([targets]), complemento([with, 'PLIN2,', 'CIDEC,', and, 'hypoxia-inducible', lipid, 'droplet-associated-protein', being, confirmed, by, immunofluorescence, microscopy])].
[sujeto(['In', 'conclusion,', steatosis, and, steatohepatitis, specific, gene, regulations, informed, on, the, pathogenesis, of, 'NAFLD', to, broaden, the, perspective, of]), verbo([targeted]), complemento([therapies])].
[sujeto(['The']), verbo([nuclear]), complemento([receptor, liver, receptor, homolog, 1, '(', 'LRH-1)', drives, expression, of, genes, regulating, 'RCT,', and, its, activity, can, be, modified, by, different, posttranslational, modifications])].
[sujeto(['The', mechanism, underlying, this, atheroprotection]), verbo([involves]), complemento([an, increase, in, 'RCT', and, its, associated, hepatic, genes, and, is, secondary, to, a, compromised, interaction, of, 'LRH-1', 'K289R', with, the, corepressor, prospero, homeobox, protein, 1, '(', 'PROX1)'])].
[sujeto(['Our', study]), verbo([reveals]), complemento([that, the, 'SUMOylation', status, of, a, single, nuclear, receptor, lysine, residue, can, impact, the, development, of, a, complex, metabolic, disease, such, as, atherosclerosis])].
[sujeto(['Genome-wide', association, studies, '(', 'GWAS)']), verbo([have]), complemento([identified, common, pancreatic, cancer, susceptibility, variants, at, 13, chromosomal, loci, in, individuals, of, 'European', descent])].
[sujeto(['To', identify, new, susceptibility, 'variants,', we, performed, imputation, based, on, 1000, 'Genomes', '(', 1000, 'G)', 'Project', data, and, association, analysis, using, 5, ',', 107, case, and, 8, ',', 845, control, subjects, from, 27, cohort, and, 'case-control', studies, that]), verbo([participated]), complemento([in, the, 'PanScan', 'I-III', 'GWAS'])].
[sujeto([33, '(', 'CLPTM1L-TERT)', as, per, analyses, conditioned, on, previously]), verbo([reported]), complemento([susceptibility, variants])].
[sujeto(['This']), verbo([finding]), complemento([was, validated, in, a, second, set, of, paired, '(', n, =, 20, ')', histologically, normal, and, tumor, derived, pancreatic, tissue, samples, '(', average, fold, change, for, three, 'NR5A2', isoforms, -, 31.3, to, -, 95.7, ',', 'P', =, 7.5, 'x10-4-2'])].
[sujeto(['Our', study]), verbo([has]), complemento([identified, new, susceptibility, variants, independently, conferring, pancreatic, cancer, risk, that, merit, functional, 'follow-up', to, identify, target, genes, and, explain, the, underlying, biology])].
[sujeto(['The', stepwise, progression, of, common, endoderm, progenitors, into, differentiated, liver, and, pancreas, organs, is]), verbo([regulated]), complemento([by, a, dynamic, array, of, signals, that, are, not, well, understood])].
[sujeto(['The']), verbo([nuclear]), complemento([receptor, subfamily, 5, ',', group, 'A,', member, 2, gene, 'nr5a2,', also, known, as, 'Liver', receptor, 'homolog-1', '(', 'Lrh-1)', is, expressed, in, several, tissues, including, the, developing, liver, and, pancreas])].
[sujeto(['Zygotic']), verbo([loss]), complemento([of, nr5a2, in, a, targeted, genetic, null, mutant, disrupted, the, development, of, the, exocrine, pancreas, and, 'liver,', while, leaving, the, endocrine, pancreas, intact])].
[sujeto(['Loss', of, nr5a2, abrogated, exocrine, pancreas, markers, such, as, 'trypsin,', while, pancreas, progenitors, marked, by, ptf1a, or, pdx1, remained, 'unaffected,']), verbo([suggesting]), complemento([a, role, for, 'Nr5a2', in, regulating, pancreatic, acinar, cell, differentiation])].
[sujeto(['In', the, developing, 'liver,', 'Nr5a2']), verbo([regulates]), complemento([hepatic, progenitor, outgrowth, and, 'differentiation,', as, nr5a2, mutants, exhibited, reduced, hepatoblast, markers, hnf4α, and, prox1, as, well, as, differentiated, hepatocyte, marker, fabp10a])].
[sujeto(['Through', the, first, in, vivo, use, of, 'Nr5a2', chemical, antagonist, 'Cpd3,', the, iterative, requirement, for, 'Nr5a2', for, exocrine, pancreas, and, liver, differentiation, was, temporally, 'elucidated:', chemical, inhibition, of, 'Nr5a2', function, during, hepatopancreas, progenitor, specification, was, sufficient, to, disrupt, exocrine, pancreas, formation, and]), verbo([enhance]), complemento([the, size, of, the, embryonic, 'liver,', suggesting, that, 'Nr5a2', regulates, hepatic, vs])].
[sujeto(['These', findings, define, critical, iterative, and, pleiotropic, roles, for, 'Nr5a2', at, distinct, stages, of, pancreas, and, liver, 'organogenesis,', and]), verbo([provide]), complemento([novel, perspectives, for, interpreting, the, role, of, 'Nr5a2', in, disease])].
[sujeto(['Here', we, identify]), verbo([nuclear]), complemento([receptor, 'NR5A2', as, a, central, node, in, these, regulatory, networks, and, key, player, in, neural, development])].
[sujeto(['Overexpression', and, 'loss-of-function', experiments, in, primary, 'NSCs', and, mouse, embryos]), verbo([suggest]), complemento([that, 'NR5A2', synchronizes, 'cell-cycle', exit, with, induction, of, neurogenesis, and, inhibition, of, astrogliogenesis, by, direct, regulatory, effects, on, 'Ink4/Arf', 'locus,', 'Prox1,', a, downstream, target, of, proneural, 'genes,', as, well, as, 'Notch1', and, 'JAK/STAT', signalling, pathways])].
[sujeto(['Collectively,', these, observations, render, 'NR5A2', a, critical, regulator, of, neural, development, and]), verbo([target]), complemento([gene, for, 'NSC-based', treatments, of, 'CNS-related', diseases])].
[sujeto(['Mouse', spermatogonial, stem, 'cells&nbsp;(mSSCs)', may, be, reprogrammed, to, become, pluripotent, stem, cells, 'under&nbsp;in&nbsp;vitro', culture, 'conditions,', due, to, epigenetic, 'modifications,', which, are, closely]), verbo([associated]), complemento([with, the, expression, of, transcription, factors, and, epigenetic, factors])].
[sujeto([2, ')', 'microbeads,', and, the, typical, morphological, characteristics, were]), verbo([maintained]), complemento(['under&nbsp;in&nbsp;vitro', culture, conditions, for, over, 5, months, to, form, 'long-term', propagated, 'mSSCs&nbsp;[mSSCs&nbsp;(l)]'])].
[sujeto(['These', 'mSSCs&nbsp;(l)']), verbo([expressed]), complemento(['pluripotency&#8209;associated', genes, and, were, induced, to, differentiate, into, sperm])].
[sujeto(['Our', findings, indicated, that, the, 'mSSCs&nbsp;(l)']), verbo([expressed]), complemento([high, levels, of, the, transcription, 'factors,', 'Lin28', and, 'Prmt5,', and, the, epigenetic, 'factors,', 'Tet3,', 'Parp1,', 'Max,', 'Tert', and, 'Trf1,', in, comparison, with, the, 'mESCs,', with, the, levels, of, 'Prmt5,', 'Tet3,', 'Parp1', and, 'Tert', significantly, higher, than, those, in, the, mESCs])].
[sujeto(['Collectively,', our, results]), verbo([suggest]), complemento([that, the, mSSCs, and, the, mESCs, displayed, differential, gene, expression, 'profiles,', and, the, mSSCs, possessed, the, potential, to, acquire, pluripotency, based, on, the, high, expression, of, transcription, factors, and, epigenetic, factors])].
[sujeto(['These', data, may]), verbo([provide]), complemento([novel, insights, into, the, reprogramming, mechanism, of, mSSCs])].
[sujeto(['Renal', fibrosis, is, a, common, histological]), verbo([finding]), complemento([present, in, many, 'pathologies;', 'however,', key, signaling, pathways, and, molecular, determinants, involved, in, the, development, of, fibrosis, are, not, fully, known, yet])].
[sujeto(['Previous', findings]), verbo([have]), complemento([established, a, causative, role, of, 'calreticulin\'s', 'up-regulation', during, the, development, of, renal, fibrosis, while, its, 'down-regulation', exhibited, a, protective, effect, against, fibrosis])].
[sujeto(['These', data, establish, for, the, first, time, a, role, for, 'NR5A2', and, its, 'SUMOylation', on, the, transcriptional, regulation, of, the, calreticulin, gene, in, a, rodent, model, of, renal, fibrosis, and, raise, the, possibility, that, 'NR5A2', might, be, a, novel]), verbo([target]), complemento([for, future, 'anti-fibrotic', interventions])].
[sujeto(['Here', we, identify, the]), verbo([nuclear]), complemento([receptor, liver, receptor, homolog, 1, '(', 'LRH-1)', as, a, key, regulator, in, the, process, of, hepatic, tumorigenesis, through, the, coordination, of, a, noncanonical, glutamine, pathway, that, is, reliant, on, the, mitochondrial, and, cytosolic, transaminases, glutamate, pyruvate, transaminase, 2, '(', 'GPT2)', and, glutamate, oxaloacetate, transaminase, 1, '(', 'GOT1),', which, fuel, anabolic, metabolism])].
[sujeto(['In', 'particular,', we, show, that]), verbo([gain]), complemento([and, loss, of, function, of, hepatic, 'LRH-1', modulate, the, expression, and, activity, of, mitochondrial, glutaminase, 2, '(', 'GLS2),', the, first, and, 'rate-limiting', step, of, this, pathway])].
[sujeto(['The', robust, reduction, in, glutaminolysis, and, the, limiting, availability, of, 'α-ketoglutarate', in, turn]), verbo([inhibit]), complemento([mTORC1, signaling, to, eventually, block, cell, growth, and, proliferation])].
[sujeto(['Collectively,', these, studies, highlight, the, importance, of, 'LRH-1', in, coordinating, 'glutamine-induced', metabolism, and, signaling, to]), verbo([promote]), complemento([hepatocellular, carcinogenesis])].
[sujeto(['Obesity', and, malnutrition, are]), verbo([associated]), complemento([with, decreased, fecundity, in, women])].
[sujeto(['However,', obese, women, with, ovulatory, cycles, also]), verbo([have]), complemento([reduced, 'fertility,', but, the, etiology, of, their, impaired, reproduction, is, only, partially, understood])].
[sujeto(['Accumulating', evidence]), verbo([suggests]), complemento([that, obesity, directly, impairs, oocyte, and, embryo, quality, as, well, as, endometrial, receptivity])].
[sujeto(['In', obese, 'women,', urinary, progesterone, metabolite, excretion, is, 'decreased,', but, in, excess, of, what, can, be, explained, by]), verbo([suppressed]), complemento([gonadotropin, 'secretion,', suggesting, that, apart, from, its, central, effect, obesity, may, directly, affect, progesterone, '(', 'P4)', production])].
[sujeto(['These', observations]), verbo([have]), complemento([led, to, the, novel, hypothesis, that, obesity, directly, affects, corpus, luteum, '(', 'CL)', function])].
[sujeto(['Similarly,', we, hypothesize, that, weight]), verbo([loss]), complemento([may, contribute, to, luteal, dysfunction])].
[sujeto(['Here,', we, propose, a, 'non-human', primate, 'model,', the, vervet, 'monkey,', to, examine, the, effect, of, weight]), verbo([gain]), complemento([and, loss, on, menstrual, cycle, parameters, and, 'CL', gene, expression])].
[sujeto(['In', this, 'model,', weight]), verbo([gain]), complemento([and, loss, did, not, significantly, alter, menstrual, 'cyclicity;', 'however,', both, induced, alterations, in, the, 'CL', transcriptome])].
[sujeto(['In', the, weight]), verbo([gain]), complemento(['monkey,', we, observed, that, impaired, 'mid-luteal', 'P4', secretion, was, associated, with, downregulation, of, steroidogenic, pathways, in, 'CL'])].
[sujeto(['Collectively,', these, preliminary, findings, support, our, hypothesis, that, weight]), verbo([gain]), complemento([and, loss, may, contribute, to, 'CL', dysfunction])].
[sujeto(['The', vervet, model, described, and, preliminary, observations]), verbo([provide]), complemento([a, basis, for, a, larger, study, to, address, this, important, question])].
[sujeto(['Understanding', the, mechanisms, by, which, weight]), verbo([gain]), complemento([and, loss, contribute, to, reproductive, dysfunction, can, assist, in, the, development, of, targeted, treatments, to, enhance, 'women\'s', reproductive, capability, when, it, is, desired])].
[sujeto(['CL:', corpus, 'luteum;', 'P4:', 'progesterone;', 'E2:', 'estradiol;', 'PDG:', pregnanediol, 3, -, 'glucoronide;', 'LH:', luteinizing, 'hormone;', 'FSH:', 'follicle-stimulating', 'hormone;', 'GnRH:', gonadotropin]), verbo([releasing]), complemento(['hormone;', 'BMI:', body, mass, 'index;', 'qrtPCR:', quantitative, 'real-time', 'PCR;', 'PGR:', progesterone, 'receptor;', 'ART:', assisted, reproductive, 'technology;', 'IVF:', in, vitro, 'fertilization;', 'HPO:', 'hypothalamic-pituitary-ovarian', 'axis;', 'MMPs:', matrix, metalloproteinases, 'Gene', 'symbols:', 'LH', receptor, '(', 'LHGCR);', cholesterol, 'side-chain', cleavage, enzyme, '(', 'CYP11A1);', 3, 'beta-hydroxysteroid', dehydrogenase, type, 'II', '(', 'HSD3B2);', steroidogenic, acute, regulatory, protein, '(', 'STAR);', 'LDL', receptor, '(', 'LDLR);', scavenger, receptor, 'B1', '(', 'SCARB1);', 'ATP-binding', cassette, 'sub-family', 'A', member, 1, '(', 'ABCA1);', 'ATP-binding', cassette, 'sub-family', 'G', member, 1, '(', 'ABCG1);', apolipoprotein, 'A', '(', 'APOA1);', 24, dehydrocholesterol, reductase, '(', 'DHCR24);', 3, -, 'hydroxy-3-methylglytaryl-CoA', reductase, '(', 'HMGCR);', vascular, endothelial, growth, factor, 'A', '(', 'VEGFA);', vascular, endothelial, growth, factor, 'C', '(', 'VEGFC);', vascular, endothelial, growth, factor, receptor, 1, '(', 'VEGFR1);', and, 'TIMP', metallopeptidase, inhibitor, 1, '(', 'TIMP1);', amphiregulin, '(', 'AREG);', epiregulin, '(', 'EREG);', 'CCAAT/enhancer', binding, protein, alpha, '(', 'CEBPBA);', cAMP, responsive, element, binding, protein, 3, -, like, 1, '(', 'CREB3L1);', 'ADAM', metallopeptidase, with, thrombospodin, type, 1, motif, 1, '(', 'ADAMTS1);', matrix, metallopeptidase, 9, '(', 'MMP9);', cytochrome, 'b-245', beta, polypeptide, '(', 'CYBB', or, 'NOX2);', 'NADH', oxidase, '(', 'NCF2', or, 'NOXA2);', 'Fc', fragment, of, 'IgG', receptor, 'IIb', '(', 'FCGR2B);', 'Fc', fragment, of, 'IgG', receptor, 'IIb', '(', 'FCGR2C);', ectonucleotide, 'pyrophosphatase/phosphodiesterase', 1, '(', 'ENPP1);', 'RAB27A', member, 'RAS', oncofamily, '(', 'RAB27A);', hydroxyprostaglandin, dehydrogenase, '(', 'HPGD);', 'prostaglandin-endoperoxidase', synthase, 1, '(', 'PTGS1);', integrin, 'B2', '(', 'ITGB2);', leukotriene, 'A4', hydrolase, '(', 'LTA4H);', radixin, '(', 'RDX);', ezrin, '(', 'EZR);', nuclear, receptor, subfamily, 5, group, 'A', member, 2, '(', 'NR5A2)'])].
[sujeto(['Pluripotent', 'self-renewing', embryonic, stem, cells, '(', 'ESCs)']), verbo([have]), complemento([been, the, focus, of, a, growing, number, of, 'high-throughput', 'experiments,', revealing, the, 'genome-wide', locations, of, hundreds, of, transcription, factors, and, histone, modifications])].
[sujeto(['By', comparing, 'genome-wide']), verbo([binding]), complemento([data, with, 'over-expression', and, knockdown, analysis, of, hundreds, of, 'genes,', we, discovered, that, the, 'pluripotency-related', factor, 'NR5A2', separates, mitochondrial, from, cytosolic, ribosomal, 'genes,', regulating, their, expression])].
[sujeto(['Our', approach, can, be, generalized, to]), verbo([reveal]), complemento([common, regulators, of, any, gene, 'group;', discover, novel, gene, 'families,', and, identify, common, genomic, elements, based, on, shared, chromatin, features])].
[sujeto(['Liver', receptor, homolog, 1, '(', 'Lrh1,', also, known, as, 'Nr5a2)', belongs, to, the, orphan]), verbo([nuclear]), complemento([receptor, superfamily, and, has, diverse, functions, in, 'development,', 'metabolism,', and, cell, differentiation, and, death])].
[sujeto(['Lrh1']), verbo([regulates]), complemento([the, expression, of, 'Oct4,', which, is, a, key, factor, of, early, embryonic, differentiation])].
[sujeto(['The', latter, effect, was, possibly, due, to, the]), verbo([decreased]), complemento([expression, of, 'hatching-related', genes, such, as, 'Fn1,', 'Itgα5,', and, 'Cox2', upon, the, inhibition, of, 'Lrh1'])].
[sujeto(['Incubation', with, the, 'LRH1', antagonist, also]), verbo([increased]), complemento([the, number, of, apoptotic, cells, among, the, blastocysts])].
[sujeto(['Moreover,', 'LRH1', inhibition]), verbo([enhanced]), complemento([the, expression, of, the, 'pro-apoptotic', genes, 'Bax', and, 'Casp3,', and, reduced, the, expression, of, the, 'anti-apoptotic', gene, 'Bcl2'])].
[sujeto(['Lrh1', inhibition, also]), verbo([led]), complemento([to, significant, decrease, in, the, expression, levels, of, 'Oct4', mRNA, and, 'octamer-binding', transcription, factor, 4, '(', 'OCT4)', protein, in, the, blastocysts])].
[sujeto(['Nuclear-Receptors', represent, ideal]), verbo([targets]), complemento([for, the, 'design/synthesis', of, pharmacological, ligands])].
[sujeto(['We']), verbo([provide]), complemento([an, overview, of, the, literature, available, on, the, expression, and, potential, role, played, by, 'Lipid-sensors,', 'Enigmatic-Orphans', and, 'Orphan-Receptors', in, 'breast-cancer'])].
[sujeto(['These', 'Nuclear-Receptors', represent, candidates, for, the, development, of, therapeutic, strategies, aimed, at]), verbo([increasing]), complemento([their, expression, or, activating, them, in, tumor, cells])].
[sujeto(['These', oncogenic, 'Nuclear-Receptors', should, be]), verbo([targeted]), complemento([with, selective, 'antagonists,', 'reverse-agonists', or, 'agents/strategies', capable, of, reducing, their, expression, in, 'breast-cancer', cells])].
[sujeto(['Preterm', birth, '(', 'PTB)', is, a, major]), verbo([cause]), complemento([of, neonatal, mortality, and, morbidity])].
[sujeto(['This', study]), verbo([suggests]), complemento([a, potential, association, between, intronic, 'SNPs', in, the, 'NR5A2', gene, and, 'PTB'])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'NR5A2', may, be, important, in, the, pathophysiology, of, 'PTB', and, exploring, noncoding, regulators, of, 'NR5A2', is, warranted])].
[sujeto(['Preeclampsia', '(', 'PE)', is, a, multisystem, disorder, unique, to, 'Homo', sapiens, that, is, known, to]), verbo([cause]), complemento([maternal, and, perinatal, mortality, and, morbidity])].
[sujeto(['NR5A1', and, 'NR5A2', are, orphan, members, of, the, 'Ftz-F1', subfamily, of]), verbo([nuclear]), complemento([receptors, and, are, involved, in, mammal, follicular, 'development,', female, 'reproduction,', 'steroidogenesis,', and, decidualization])].
[sujeto(['Disorders', of, the, endometrium, in, decidual, tissues, may, be]), verbo([associated]), complemento([with, the, abnormal, decidualization, thought, to, cause, 'PE'])].
[sujeto(['SUMO-modification', of]), verbo([nuclear]), complemento([proteins, has, profound, effects, on, gene, expression])].
[sujeto(['However,', 'non-toxic', chemical, tools, that]), verbo([modulate]), complemento([sumoylation, in, cells, are, lacking])].
[sujeto(['TA', also]), verbo([increased]), complemento(['hLRH-1', occupancy, on, 'SUMO-sensitive', transcripts])].
[sujeto(['Most', 'significantly,', when, tested, in, humanized, mouse, primary, 'hepatocytes,', 'TA']), verbo([inhibits]), complemento(['hLRH-1', sumoylation, and, induces, 'SUMO-sensitive', 'genes,', thereby, recapitulating, the, effects, of, expressing, 'SUMO-less', 'hLRH-1', in, mouse, liver])].
[sujeto(['Our', findings, underscore, the, benefits, of, phenotypic, screening, for]), verbo([targeting]), complemento(['post-translational', 'modifications,', and, illustrate, the, potential, utility, of, 'TA', for, probing, the, cellular, consequences, of, sumoylation])].
[sujeto(['Our', 'case-control', study]), verbo([found]), complemento([that, rs3790843, and, rs3790844, in, the, 'NR5A2', gene, are, associated, with, pancreatic, cancer, risk, in, 'Japanese', subjects])].
[sujeto(['Liver', receptor, homologue, 1, '(', 'LRH-1)', is, an, orphan]), verbo([nuclear]), complemento([receptor, that, has, been, implicated, in, the, progression, of, 'breast,', pancreatic, and, colorectal, cancer, '(', 'CRC)'])].
[sujeto(['To', determine, mechanisms, underlying, growth, promotion, by, 'LRH-1', in, 'CRC,', we, undertook, global, expression, profiling, following, 'siRNA-mediated', 'LRH-1', knockdown, in, 'HCT116', 'cells,', which]), verbo([require]), complemento(['LRH-1', for, growth, and, in, 'HT29', 'cells,', in, which, 'LRH-1', does, not, regulate, growth])].
[sujeto(['Interestingly,', expression, of, the, cell, cycle, inhibitor, p21, '(', 'CDKN1A)', was]), verbo([regulated]), complemento([by, 'LRH-1', in, 'HCT116', cells])].
[sujeto(['We', demonstrate, that, 'LRH-1-mediated', p21, regulation, in, 'HCT116', cells, does, not]), verbo([involve]), complemento([altered, p53, protein, or, 'phosphorylation,', and, we, show, that, 'LRH-1', inhibits, p53, recruitment, to, the, p21, 'promoter,', likely, through, a, mechanism, involving, chromatin, remodelling])].
[sujeto(['Our', study]), verbo([suggests]), complemento([an, important, role, for, 'LRH-1', in, the, growth, of, 'CRC', cells, that, retain, 'wild-type', p53])].
[sujeto(['Liver', receptor, 'homologue-1', '(', 'LRH1)', is, an, orphan]), verbo([nuclear]), complemento([receptor, that, has, been, shown, to, play, a, role, in, the, transcriptional, regulation, of, pathways, involved, in, cancer])].
[sujeto(['Nuclear', fractionation, protocol, was, essential, for, detection, of, 'LRH1', peptides, by, mass, spectrometry, '(', 'MS),', with, most, peptides, being, observed, in, the, insoluble, fraction, '(', receptor]), verbo([bound]), complemento([to, 'DNA)'])].
[sujeto(['SERBP1', and, 'ILF3', were, identified, as, 'LRH1']), verbo([interacting]), complemento([partners, by, both, 'Western', blot, and, 'MS/MS', analysis])].
[sujeto(['Receptor', knockdown, by, siRNA, showed, an]), verbo([increase]), complemento([in, 'SERBP1', 'expression,', while, 'ILF3', expression, was, unchanged])].
[sujeto(['In', 'contrast,', receptor, overexpression]), verbo([decreased]), complemento([only, 'SERBP1', mRNA, levels])].
[sujeto(['Consistent', with, these, 'data,', in, a, 'promoter:reporter', 'assay,']), verbo([binding]), complemento([of, 'LRH1', to, the, promoter, region, of, 'SERBP1', resulted, in, a, decrease, in, the, expression, level, of, the, reporter, 'gene,', subsequently, inhibiting, transcription])].
[sujeto(['Given', the, 'receptor\'s', role, in, cancer, 'progression,', the, study, here, elucidates, additional, transcriptional, machinery]), verbo([involved]), complemento([in, 'LRH1', signaling, and, potentially, provides, new, targets, for, therapeutics, development])].
[sujeto(['However,', the, role, of, 'LRH-1', in, osteosarcoma]), verbo([has]), complemento([not, been, well, investigated])].
[sujeto(['LRH-1', was, knocked, down, by, small, interfering, 'RNA', '(', 'siRNA),', and, this, phenomenon, significantly]), verbo([inhibited]), complemento([osteosarcoma, cell, proliferation])].
[sujeto(['Bioinformatics', analysis, results, showed, that, 'LRH-1', contained, putative]), verbo([binding]), complemento([sites, of, 'microRNA-451', '(', 'miR-451);', this, result, was, further, validated, through, a, 'dual-luciferase', activity, reporter, assay])].
[sujeto(['miR-451', was, overexpressed, in, osteosarcoma, cells, through, transfection, of, 'miR-451', 'mimics;', 'miR-451', overexpression, then, significantly]), verbo([inhibited]), complemento(['LRH-1', expression, and, cell, proliferation])].
[sujeto(['The']), verbo([loss]), complemento([of, 'LRH-1', by, siRNA, or, 'miR-451', mimics, significantly, impaired, 'Wnt/β-catenin', 'activity,', leading, to, 'G0/G1', cell, cycle, arrest])].
[sujeto(['The', orphan]), verbo([nuclear]), complemento([receptor, liver, receptor, homolog, 1, '(', 'LRH-1;', 'NR5A2)', is, a, potent, regulator, of, cholesterol, metabolism, and, bile, acid, homeostasis])].
[sujeto(['Recently,', 'LRH-1']), verbo([has]), complemento([been, shown, to, play, an, important, role, in, intestinal, inflammation, and, in, the, progression, of, estrogen, receptor, positive, and, negative, breast, cancers, and, pancreatic, cancer])].
[sujeto(['Structural', studies]), verbo([have]), complemento([revealed, that, 'LRH-1', can, bind, phospholipids, and, the, dietary, phospholipid, dilauroylphosphatidylcholine, activates, 'LRH-1', activity, in, rodents])].
[sujeto(['In', cotransfection, 'studies,', 'SR1848', reduced, 'LRH-1-dependent', expression, of, a, reporter, gene, and, in, cells, that, endogenously]), verbo([express]), complemento(['LRH-1', dose, dependently, reduced, the, expression, of, 'cyclin-D1', and, -, 'E1,', resulting, in, inhibition, of, cell, proliferation])].
[sujeto(['The', cellular, effects, of, 'SR1848', treatment, are, recapitulated, after, transfection, of, cells, with, 'small-interfering', 'RNA']), verbo([targeting]), complemento(['LRH-1'])].
[sujeto(['Immunocytochemistry', analysis, shows, that, 'SR1848']), verbo([induces]), complemento([rapid, translocation, of, nuclear, 'LRH-1', to, the, cytoplasm])].
[sujeto(['Combined,', these, results]), verbo([suggest]), complemento([that, 'SR1848', is, a, functional, repressor, of, 'LRH-1', that, impacts, expression, of, genes, involved, in, proliferation, in, 'LRH-1-expressing', cancers])].
[sujeto(['Thus,', 'SR1848', represents, a, novel, chemical, scaffold, for, the, development, of, therapies]), verbo([targeting]), complemento([malignancies, driven, by, 'LRH-1'])].
[sujeto(['The', transcriptional, factor, liver, receptor, homolog, 1, '(', 'LRH1)']), verbo([regulates]), complemento([pancreatic, 'development,', and, may, participate, in, pancreatic, oncogenesis, through, activation, of, growth, factor, signaling, transduction, cascades])].
[sujeto(['It', was]), verbo([found]), complemento([that, 'LRH1', enhanced, transcriptional, activity, of, 'β-catenin', and, the, expression, of, downstream, target, genes, '(', 'c-Myc,', 'MMP2/9),', as, well, as, promoted, 'migration,', wound, 'healing,', 'invasion,', and, sphere, formation, of, 'PC', cell, lines])].
[sujeto(['Specific', inhibition, of, 'LRH1', by, shRNAs, reduced, cell, 'migration,', 'invasion,', sphere, formation, and, expression, of, 'c-Myc', and, 'MMP2/9']), verbo([target]), complemento([genes])].
[sujeto(['Mice', injected, with, 'LRH1', overexpressing, stable, 'PC', cells, developed, tumors, with]), verbo([increased]), complemento([size, and, exhibited, striking, hepatic, metastatic, spread])].
[sujeto(['Our', findings, demonstrate, that, 'LRH1', overexpression, is]), verbo([associated]), complemento([with, increased, 'PC', growth, and, metastatic, 'spread,', indicating, that, 'LRH1-targeted', therapy, could, inhibit, tumor, progression])].
[sujeto(['Liver', receptor, 'homolog-1', '(', 'LRH-1)', is, an, orphan]), verbo([nuclear]), complemento([receptor, that, belongs, to, the, 'NR5A', subgroup, of, nuclear, receptors])].
[sujeto(['LRH-1']), verbo([induces]), complemento([key, genes, to, regulate, metabolic, 'process,', ovarian, 'function,', cancer, cell, 'proliferation,', and, steroidogenesis])].
[sujeto(['In', the, 'breast,', 'LRH-1']), verbo([modulates]), complemento([and, synergizes, with, endogenous, estrogen, signaling, to, promote, breast, cancer, cell, proliferation])].
[sujeto(['We', identified, key, genes]), verbo([involved]), complemento([in, 'TGF-β', signaling, to, be, highly, responsive, to, 'LRH-1', knockdown])].
[sujeto(['This', relationship, was, validated, in, 2, breast, cancer, cell, lines, overexpressing, 'LRH-1', in, vitro, and, in, a, novel, transgenic, mouse, with]), verbo([targeted]), complemento(['LRH-1', overexpression, in, mammary, epithelial, cells])].
[sujeto(['Notably,', 'TGF-β', signaling, was]), verbo([activated]), complemento([in, 'LRH-1-overexpressing', breast, cancer, cells, and, mouse, mammary, glands])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, altered, mammary, morphogenesis, in, 'LRH-1', transgenic, animals, is, mediated, via, enhanced, 'TGF-β', expression])].
[sujeto(['Collectively,', these, data, demonstrate, that, 'LRH-1']), verbo([regulates]), complemento(['TGF-β', expression, and, downstream, signaling, in, mouse, mammary, glands])].
[sujeto(['Ferredoxin', 1, '(', 'FDX1;', 'adrenodoxin)', is, an, 'iron-sulfur', protein, that, is]), verbo([involved]), complemento([in, various, metabolic, 'processes,', including, steroid, hormone, synthesis, in, mammalian, tissues])].
[sujeto(['Previously,', we]), verbo([reported]), complemento([that, the, 'NR5A', 'family,', including, steroidogenic, 'factor-1', '(', 'SF-1)', and, liver, receptor, 'homolog-1', could, induce, differentiation, of, human, mesenchymal, stem, cells, '(', 'hMSCs)', into, steroidogenic, cells])].
[sujeto(['A', 'ChIP', assay, showed, that, 'SF-1', could]), verbo([bind]), complemento([to, the, 'FDX1', promoter, in, differentiated, hMSCs])].
[sujeto(['Luciferase', reporter, assays, showed, that, transcription, of, 'FDX1', was, synergistically]), verbo([activated]), complemento([by, the, 'NR5A', family, and, 8, 'Br-cAMP', treatment, through, two, 'SF-1', binding, sites, and, a, 'CRE-like', sequence, in, a, human, ovarian, granulosa, cell, 'line,', 'KGN'])].
[sujeto(['These', results, indicate, transcription, of, 'FDX1', is]), verbo([regulated]), complemento([by, the, 'NR5A', family, and, cAMP, 'signaling,', and, participates, in, steroid, hormone, production, in, ovarian, granulosa, cells])].
[sujeto(['Liver', receptor, 'homologue-1', '(', 'LRH-1)', is, an, orphan]), verbo([nuclear]), complemento([receptor, that, has, been, implicated, in, steroid, hormone, biosynthesis, and, fertility])].
[sujeto(['Timed', ovarian, microarray, analysis, showed, 'that,', in, line, with, the, observed]), verbo([decrease]), complemento([in, plasma, progesterone, 'levels,', key, steroid, biosynthesis, 'genes,', namely, 'Star,', 'Cyp11a1,', 'Hsd3b', and, 'Scarb1,', were, downregulated, in, 'LRH-1-knockdown', ovaries])].
[sujeto(['In', contrast, with, what]), verbo([has]), complemento([been, described, 'previously,', no, clear, effect, was, observed, on, oestrogenic, activity, in, 'LRH-1-knockdown', mice])].
[sujeto(['Only', 'Sult1e1', 'and,', 'surprisingly,', 'Hsd17b7', expression, was]), verbo([modulated]), complemento([with, potentially, opposite, effects, on, oestradiol, bioavailability])].
[sujeto(['We', investigated, regulation, of, 'miR-200c', expression, by]), verbo([nuclear]), complemento([receptors])].
[sujeto(['Ectopic', expression, of, 'miR-200c']), verbo([inhibited]), complemento(['MHCC97H', cell, 'migration,', which, was, abrogated, by, the, synergistic, effects, of, 'PPARα', and, 'LRH-1', siRNAs])].
[sujeto(['The', expression, of, 'miR-200c', was]), verbo([decreased]), complemento([by, 'PPARα/LRH-1', siRNAs, and, increased, by, 'SHP', 'siRNAs,', and, overexpression, of, the, receptors, reversed, the, effects, of, their, respective, siRNAs])].
[sujeto(['SHP', siRNAs, also, drastically]), verbo([enhanced]), complemento([the, ability, of, the, 'LRH-1', agonist, 'RJW100', to, induce, 'miR-200c', and, downregulate, 'ZEB1', and, 'ZEB2', proteins])].
[sujeto(['Co-expression', of, 'PPARα', and, 'LRH-1', moderately, transactivated, the, 'miR-200c', 'promoter,', which, was]), verbo([repressed]), complemento([by, 'SHP', 'co-expression'])].
[sujeto(['RJW100']), verbo([caused]), complemento([strong, activation, of, the, 'miR-200c', promoter])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([to, demonstrate, that, 'miR-200c', expression, is, controlled, by, nuclear, receptors])].
[sujeto(['An', essential, regulator, of, gene, 'transcription,']), verbo([nuclear]), complemento([receptor, liver, receptor, homologue, 1, '(', 'LRH-1)', controls, cell, differentiation, in, the, developing, pancreas, and, maintains, cholesterol, homeostasis, in, adults])].
[sujeto(['In', this, 'work,', we, show, that, 'LRH-1', transcription, is]), verbo([activated]), complemento([up, to, 30, -, fold, in, human, pancreatic, cancer, cells, compared, to, normal, pancreatic, ductal, epithelium])].
[sujeto(['This', activation, correlates, with, markedly]), verbo([increased]), complemento(['LRH-1', protein, expression, in, human, pancreatic, ductal, adenocarcinomas, in, vivo])].
[sujeto(['Selective', blocking, of, 'LRH-1', by, receptor, specific, siRNA, significantly]), verbo([inhibits]), complemento([pancreatic, cancer, cell, proliferation, in, vitro])].
[sujeto(['The', inhibition, is, tracked, in, part, to, the, attenuation, of, the, 'receptor\'s', transcriptional]), verbo([targets]), complemento([controlling, cell, 'growth,', 'proliferation,', and, differentiation])].
[sujeto(['This', study, demonstrates, the, critical, involvement, of, 'LRH-1', in, development, and, progression, of, pancreatic, 'cancer,']), verbo([suggesting]), complemento([the, 'LRH-1', receptor, as, a, plausible, therapeutic, target, for, treatment, of, pancreatic, ductal, adenocarcinomas])].
[sujeto(['Small', heterodimer, partner, '(', 'SHP)', plays, important, roles, in, diverse, biological, processes, by, directly]), verbo([interacting]), complemento([with, transcription, factors, and, inhibiting, their, activities])].
[sujeto(['SHP']), verbo([has]), complemento([been, designated, an, orphan, nuclear, 'receptor,', but, whether, its, activity, can, be, modulated, by, ligands, has, been, a, 'long-standing', question])].
[sujeto(['Recently,', 'retinoid-related', 'molecules,', including, 4, -, '[', 3, -, '(', 1, -, 'adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic', acid, '(', 3, 'Cl-AHPC),', were, shown, to]), verbo([bind]), complemento([to, 'SHP', and, enhance, apoptosis])].
[sujeto(['We']), verbo([have]), complemento([examined, whether, 3, 'Cl-AHPC', acts, as, an, agonist, and, increases, 'SHP', activity, in, the, repression, of, bile, acid, biosynthetic, 'CYP7A1', and, 'CYP8B1', genes, and, delineated, the, underlying, mechanisms])].
[sujeto(['Contrary', to, this, 'expectation,', micromolar, concentrations, of, 3, 'Cl-AHPC']), verbo([increased]), complemento(['CYP7A1', expression, but, indirectly, via, p38, kinase, signaling])].
[sujeto(['Nanomolar', 'concentrations,', 'however,']), verbo([repressed]), complemento(['CYP7A1', expression, and, decreased, bile, acid, levels, in, 'HepG2', 'cells,', and, little, repression, was, observed, when, 'SHP', was, 'down-regulated', by, small, hairpin, 'RNA'])].
[sujeto(['Mechanistic', studies, revealed, that, 3, 'Cl-AHPC']), verbo([bound]), complemento([to, 'SHP,', increased, the, interaction, of, 'SHP', with, liver, receptor, homologue, '(', 'LRH)-1,', a, hepatic, activator, for, 'CYP7A1', and, 'CYP8B1', 'genes,', and, with, repressive, 'cofactors,', 'Brahma,', mammalian, 'Sin3a,', and, histone, 'deacetylase-1,', 'and,', 'subsequently,', increased, the, occupancy, of, 'SHP', and, these, cofactors, at, the, promoters])].
[sujeto(['Mutation', of, 'Leu-100,', predicted, to, contact, 3, 'Cl-AHPC', within, the, 'SHP', ligand]), verbo([binding]), complemento([pocket, by, molecular, 'modeling,', severely, impaired, the, increased, interaction, with, 'LRH-1,', and, repression, of, 'LRH-1', activity, mediated, by, 3, 'Cl-AHPC'])].
[sujeto([3, 'Cl-AHPC']), verbo([repressed]), complemento(['SHP', metabolic, target, genes, in, a, 'gene-specific', manner, in, human, primary, hepatocytes, and, 'HepG2', cells])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'SHP', may, act, as, a, 'ligand-regulated', receptor, in, metabolic, pathways])].
[sujeto(['LRH-1', '(', liver, receptor, 'homologue-1),', a, transcription, factor, and, member, of, the]), verbo([nuclear]), complemento([receptor, 'superfamily,', regulates, the, expression, of, its, target, 'genes,', which, are, involved, in, bile, acid, and, cholesterol, homoeostasis])].
[sujeto(['Previously,', we, identified, 'Ku80', and, 'Ku70', as, 'LRH-1-binding', proteins, and]), verbo([reported]), complemento([that, they, function, as, 'co-repressors'])].
[sujeto(['ILF3', formed, a, complex, with, 'LRH-1', and, the, other, two]), verbo([nuclear]), complemento([receptor, 'co-activators', 'PRMT1', '(', protein, arginine, methyltransferase, 1, ')', and, 'PGC-1α', '(', peroxisome, 'proliferator-activated', receptor, γ, 'co-activator-1α)'])].
[sujeto(['We', demonstrated, that, 'ILF3,', 'PRMT1', and, 'PGC-1α', were]), verbo([recruited]), complemento([to, the, promoter, region, of, the, 'LRH-1-regulated', 'SHP', '(', small, heterodimer, 'partner)', 'gene,', encoding, one, of, the, nuclear, receptors])].
[sujeto(['ILF3']), verbo([enhanced]), complemento(['SHP', gene, expression, in, 'co-operation', with, 'PRMT1', and, 'PGC-1α', through, the, 'C-terminal', region, of, 'ILF3'])].
[sujeto(['In', 'addition,', we]), verbo([found]), complemento([that, the, small, interfering, 'RNA-mediated', 'down-regulation', of, 'ILF3', expression, led, to, a, reduction, in, the, occupancy, of, 'PGC-1α', at, the, 'SHP', promoter, and, 'SHP', expression])].
[sujeto(['Taken', 'together,', our, results]), verbo([suggest]), complemento([that, 'ILF3', functions, as, a, novel, 'LRH-1', 'co-activator', by, acting, synergistically, with, 'PRMT1', and, 'PGC-1α,', thereby, promoting, 'LRH-1-dependent', gene, expression])].
[sujeto(['In', postmenopausal, breast, 'cancers,', the]), verbo([increase]), complemento([in, aromatase, expression, observed, in, tumour, associated, adipose, stromal, cells, is, mediated, via, the, upregulation, of, promoter, 'II', '(', 'PII)', transcription])].
[sujeto(['Factors', such, as, 'PGE₂', which, are, secreted, from, breast, carcinomas]), verbo([induce]), complemento(['PII', expression])].
[sujeto(['The', orphan]), verbo([nuclear]), complemento([receptor, 'LRH-1/NR5A2', is, one, of, the, critical, downstream, transcriptional, mediators, of, this, effect])].
[sujeto(['The', aim, of, the, current, study, was, to, determine, whether, 'LRH-1', could]), verbo([bind]), complemento([directly, to, 'PII', and, whether, the, suppression, of, 'LRH-1', expression, could, inhibit, aromatase, expression, in, human, adipose, stromal, fibroblasts])].
[sujeto(['To', assess, the, impact, of, 'LRH-1', knockdown, on, 'FSK/PMA']), verbo([mediated]), complemento(['PII', 'expression,', cells, were, transfected, with, shRNA, targeted, against, 'LRH-1', '(', 'shLRH-1)', and, treated, with, forskolin, and, 'PMA'])].
[sujeto(['A']), verbo([decrease]), complemento([in, 'LRH-1,', 'PII', and, total, aromatase, mRNA, transcripts, was, observed, in, 'shLRH-1', transfected, cells, compared, to, controls, under, basal, and, treatment, conditions])].
[sujeto(['Using', primary, rat, granulosa, 'cells,', we, demonstrated, that, in, the, absence, of, 'gonadotropins,', testosterone, '(', 'T)']), verbo([increases]), complemento([aromatase, '(', 'Cyp19)', and, 'P450', 'side-change', cleavage, 'expression,', two, enzymes, crucial, for, normal, ovarian, function])].
[sujeto(['However,', inhibition, of, 'Cyp19', 'and/or', 5, 'α-reductase', did, not]), verbo([prevent]), complemento([the, stimulatory, effects, of, 'T'])].
[sujeto(['Additionally,', 'T,', not, 5, 'α-dihydrotestosterone,']), verbo([stimulates]), complemento([liver, receptor, 'homolog-1', '(', 'LRH-1)', 'expression,', whereas, the, expression, of, steroidogenic, 'factor-1', '(', 'SF-1)', was, not, affected, by, either, steroid])].
[sujeto(['LRH-1', and, 'SF-1', are, transcription, factors, known, to, be]), verbo([involved]), complemento([in, the, regulation, of, 'Cyp19'])].
[sujeto(['Accordingly,', small, interference, 'RNA', against, 'LRH-1']), verbo([prevented]), complemento(['Cyp19', and, 'P450', 'side-change', cleavage, 'up-regulation', whereas, 'anti-SF-1', small, interference, 'RNA', had, no, effects])].
[sujeto(['Chromatin', immunoprecipitation, demonstrated, that, 'T', stimulation, of, 'LRH-1']), verbo([leads]), complemento([to, the, recruitment, of, 'LRH-1', to, the, native, 'Cyp19', 'promoter,', which, was, not, affected, by, cotreatment, with, 5, 'α-reductase', and, 'Cyp19', inhibitors])].
[sujeto(['Finally,', gel, shift, and, supershift, analysis, demonstrated, that, the, androgen, receptor]), verbo([binds]), complemento([to, an, androgen, response, element, located, within, the, 'LRH-1', promoter])].
[sujeto(['These', results]), verbo([provide]), complemento([novel, evidence, that, 'T', has, a, direct, effect, on, the, expression, of, genes, involved, in, granulosa, cell, differentiation])].
[sujeto(['Aberrant', hypermethylation, of, promoter, regions, in, 'cytosine-guanine', dinucleotides, '(', 'CpG)', islands]), verbo([has]), complemento([been, shown, to, be, associated, with, transcriptional, silencing, of, 'tumor-suppressor', genes, in, many, cancers])].
[sujeto(['In', vitro, methylation]), verbo([decreased]), complemento(['SHP', promoter, transactivation, and, nuclear, receptor, 'LRH-1', 'binding,', an, event, that, was, reversed, by, demethylation])].
[sujeto(['Overexpression', of, 'SHP']), verbo([inhibited]), complemento(['HCC', foci, 'formation,', arrested, 'HCC', tumor, growth, in, xenografted, nude, 'mice,', and, increased, the, sensitivity, of, 'HCC', cells, to, apoptotic, stimuli])].
[sujeto(['These', findings]), verbo([provide]), complemento([new, insight, into, the, molecular, mechanisms, leading, to, this, common, cancer, and, may, have, both, diagnostic, and, therapeutic, applications])].
[sujeto(['Liver', 'X', receptor, '(', 'LXR)']), verbo([activates]), complemento([fatty, acid, synthase, '(', 'FAS)', gene, expression, through, binding, to, a, 'DR-4', element, in, the, promoter])].
[sujeto(['We', show, that, a, distinct]), verbo([nuclear]), complemento([receptor, 'half-site', 21, bases, downstream, of, the, 'DR-4', element, is, also, critical, for, the, response, of, 'FAS', to, 'LXR', but, is, not, involved, in, 'LXR', binding, to, 'DNA'])].
[sujeto(['This', 'half-site', specifically]), verbo([binds]), complemento([liver, receptor, 'homologue-1', '(', 'LRH-1)', in, vitro, and, in, 'vivo,', and, we, show, 'LRH-1', is, required, for, maximal, 'LXR', responsiveness, of, the, endogenous, 'FAS', gene, as, well, as, from, promoter, reporter, constructs])].
[sujeto(['We', also, demonstrate, that, 'LRH-1', stimulation, of, the, 'FAS', 'LXR', response, is, blocked, by, the, addition, of, small, heterodimer, partner, '(', 'SHP)', and, that, 'FAS', mRNA, is, overexpressed, in, 'SHP', 'knock-out', 'animals,']), verbo([providing]), complemento([evidence, that, 'FAS', is, an, in, vivo, target, of, 'SHP', repression])].
[sujeto(['Taken', 'together,', these, findings, identify, the, first, direct, lipogenic, gene]), verbo([target]), complemento([of, 'LRH-1/SHP', repression, and, provide, a, mechanistic, explanation, for, bile, acid, repression, of, 'FAS', and, lipogenesis, recently, reported, by, others])].
[sujeto(['In', previous, studies, it, was, demonstrated, that, sterol, regulatory, 'element-binding', proteins, '(', 'SREBPs)', are, able, to]), verbo([interact]), complemento([with, one, of, the, nuclear, 'receptors,', hepatocyte, nuclear, receptor, '(', 'HNF)-4,', and, that, this, interaction, regulates, transcriptional, activities, of, these, proteins, '(', 'Misawa,', 'K'])].
[sujeto(['In', an, attempt, to, identify, other]), verbo([nuclear]), complemento([receptor, family, members, affecting, the, 'SREBP', transcriptional, 'activities,', we, found, that, the, liver, receptor, homolog, '(', 'LRH)-1', suppresses, them])].
[sujeto(['It', was, confirmed, that, suppression, in, endogenous, 'LRH-1', by, small, interference, 'RNA']), verbo([stimulates]), complemento([the, mRNA, levels, of, certain, 'SREBP', target, genes, and, that, elevation, in, active, 'SREBPs', in, the, nucleus, in, response, to, cholesterol, depletion, suppresses, the, 'LRH-1', activity])].
[sujeto(['In', 'vitro/in', vivo, glutathione, 'S-transferase', pulldown, experiments, demonstrated, that, the, basic, 'helix-loop-helix-leucine', zipper, domain, in, 'SREBP-2']), verbo([binds]), complemento([to, the, 'ligand-binding', domain, in, 'LRH-1'])].
[sujeto(['Furthermore,', we]), verbo([found]), complemento([that, 'SREBP-2', interferes, with, the, recruitment, of, a, coactivator, of, 'LRH-1,', the, peroxisome, 'proliferator-activated', receptor, gamma, 'coactivator-1alpha,', thereby, leading, to, the, inhibition, of, the, 'LRH-1', transcriptional, activity])].
[sujeto(['These', results, clearly, indicate, that, the, interaction, between, 'SREBPs', and, 'LRH-1', exerts, a, suppressive, influence, on, their]), verbo([target]), complemento([gene, expression, responsible, for, cholesterol, and, bile, acid, metabolism])].
[sujeto(['The', human, 'HSD3B2', gene, encodes, the, 3, 'beta-hydroxysteroid', 'dehydrogenase/delta5-delta4', isomerase, type, 2, '(', 3, 'beta-HSD2)', enzyme, that, is]), verbo([required]), complemento([for, steroid, hormone, biosynthesis])].
[sujeto(['Mutations', in, the, hHSD3B2, gene, are, responsible, for, a, form, of, congenital, adrenal, hyperplasia, and, male, pseudohermaphroditism, whereas, overexpression, of, hHSD3B2]), verbo([has]), complemento([been, recently, associated, with, polycystic, ovarian, syndrome])].
[sujeto(['Despite', the, importance, of, the, hHSD3B2, 'gene,', the, molecular, mechanisms, that]), verbo([regulate]), complemento([its, expression, remain, poorly, understood])].
[sujeto(['Indeed,', 'GATA-4', and, 'GATA-6', are, abundantly]), verbo([expressed]), complemento([in, steroidogenic, cells, of, the, gonads, and, adrenals])].
[sujeto(['We', now]), verbo([report]), complemento([that, the, human, 'HSD3B2', promoter, '(', 'hHSD3B2),', which, contains, four, consensus, 'GATA', 'elements,', constitutes, an, important, target, for, 'GATA', factors])].
[sujeto(['GATA-4', and, 'GATA-6', by, themselves, are, sufficient, to]), verbo([activate]), complemento([transcription, '(', up, to, 15, -, 'fold)', from, a, -, 1073, bp, hHSD3B2, promoter, fragment, and, blockade, of, endogenous, 'GATA', expression, 'and/or', activity, blunts, hHSD3B2, promoter, activity, in, steroidogenic, cells])].
[sujeto(['Deletion', studies, showed, that, the, proximal, 'GATA', element, located, at, -, 196, bp, is, sufficient, to]), verbo([confer]), complemento(['GATA', responsiveness, of, the, hHSD3B2, promoter, and, is, required, for, full, hHSD3B2, promoter, activity, in, steroidogenic, cells])].
[sujeto(['Moreover,', we]), verbo([report]), complemento([that, 'GATA-4', and, 'GATA-6', can, physically, interact, with, the, nuclear, 'receptors,', steroidogenic, factor, 1, and, liver, receptor, homolog, 1, ',', to, synergistically, activate, hHSD3B2, promoter, activity, in, both, homologous, and, heterologous, cells])].
[sujeto(['Aberrant', expression, of, transcription, factors, essential, for, hHSD3B2, expression, might, also, be]), verbo([involved]), complemento([in, some, 'pathologies/syndromes', associated, with, deregulated, hHSD3B2, expression])].
[sujeto(['The', liver, 'X', receptors, '(', 'LXRs,', 'NR1H2', and, 'NR1H3)', and, peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPARG,', 'NR1C3)']), verbo([nuclear]), complemento([receptor, transcription, factors, '(', 'TFs)', are, master, regulators, of, energy, homeostasis])].
[sujeto(['Intriguingly,', recent, studies]), verbo([suggest]), complemento([that, these, metabolic, regulators, also, impact, tumor, cell, proliferation])].
[sujeto(['To', better, define, the, underlying, molecular, processes, governing, the, genetic, control, of, cellular, growth, in, response, to, extracellular, metabolic, 'signals,', we, performed, a, 'comprehensive,', 'genome-wide', characterization, of, the, temporal, regulatory, cascades]), verbo([mediated]), complemento([by, 'LXR', and, 'PPARG', signaling, in, 'HT29', colorectal, cancer, cells])].
[sujeto(['For', this, 'analysis,', we, applied, a, 'multi-tiered', approach, that, incorporated, cellular, phenotypic, 'assays,', gene, expression, 'profiles,', chromatin, state, 'dynamics,', and]), verbo([nuclear]), complemento([receptor, binding, patterns])].
[sujeto(['Our', results, illustrate, that, the, activation, of, both]), verbo([nuclear]), complemento([receptors, inhibited, cell, proliferation, and, further, decreased, glutathione, 'levels,', consistent, with, increased, cellular, oxidative, stress])].
[sujeto(['Despite', a, common, metabolic, 'reprogramming,', the, gene, regulatory, network, programs, initiated, by, these]), verbo([nuclear]), complemento([receptors, were, widely, distinct])].
[sujeto(['PPARG', generated, a, rapid, and, 'short-term', response, while]), verbo([maintaining]), complemento([a, gene, activator, role])].
[sujeto(['By', 'contrast,', 'LXR', signaling, was, 'prolonged,', with, 'initial,', predominantly]), verbo([activating]), complemento([functions, that, transitioned, to, repressive, gene, regulatory, activities, at, late, time, points])].
[sujeto(['These', results, further]), verbo([provide]), complemento([a, detailed, molecular, map, of, metabolic, reprogramming, in, cancer, cells, through, 'LXR', and, 'PPARG', activation])].
[sujeto(['As', 'ligand-inducible', 'TFs,', these]), verbo([nuclear]), complemento([receptors, can, potentially, serve, as, attractive, therapeutic, targets, for, the, treatment, of, various, cancers])].
[sujeto(['An', important, step, towards, personalizing, cancer, treatment, is, to, integrate, heterogeneous, evidences, to, catalog, mutational, hotspots, that, are, biologically, and, therapeutically, relevant, and, thus, represent, where]), verbo([targeted]), complemento([therapy, would, likely, be, beneficial])].
[sujeto(['We']), verbo([found]), complemento([that, the, hotspot, mutations, nominated, by, our, approach, were, significantly, more, conserved, than, 'non-hotspot', mutations, in, the, corresponding, cancer, genes])].
[sujeto(['We', also, examined, the, biological, significance, and, pharmacogenomics, properties, of, these, hotspot, mutations, using, data, in, the, 'Cancer', 'Genome', 'Atlas', '(', 'TCGA)', and, the, 'Cancer', 'Cell-Line', 'Encyclopedia', '(', 'CCLE),', and]), verbo([found]), complemento([that, 53, hotspot, mutations, are, independently, associated, with, diverse, functional, evidences, in, 1, ')', mRNA, and, protein, 'expression,', 2, ')', pathway, 'activity,', or, 3, ')', drug, sensitivity, and, 82, were, highly, enriched, in, specific, tumor, types])].
[sujeto(['We', illustrated, the, common, and, distinct, mutational, signatures, of, hotspot, mutations, among, different, tumor, types, and, investigated, their, variable, functional, relevance, under, different, 'contexts,', which, could, potentially, serve, as, a, resource, for, explicitly, selecting]), verbo([targets]), complemento([for, 'diagnosis,', drug, 'development,', and, patient, management])].
[sujeto(['We', hypothesized, that, high, glucose]), verbo([suppresses]), complemento([aneurysm, by, inhibiting, macrophage, activation, via, activation, of, 'Nr1h2', '(', also, known, as, liver, 'X', receptor, 'β),', recently, characterized, as, a, 'glucose-sensing', nuclear, receptor])].
[sujeto(['Calcium', phosphate, '(', 'CaPO4)-induced', aneurysm, formation, was, significantly]), verbo([suppressed]), complemento([in, the, arterial, wall, in, type, 1, and, 2, diabetic, mice])].
[sujeto([7, ',', was, treated, with, tumor, necrosis, factor, α, '(', 'TNF-α)', plus, 'CaPO4', and, showed, a, significant]), verbo([increase]), complemento([in, matrix, metalloproteinase, 9, '(', 'Mmp9)', mRNA, and, secreted, protein, expression, compared, with, 'TNF-α', alone])].
[sujeto(['Elevated', 'Mmp9', expression, was, significantly]), verbo([suppressed]), complemento([by, hyperglycemic, conditions, '(', 15.5, &, 'nbsp;mmol/L', 'glucose)', compared, with, normoglycemic, conditions, '(', 5.5, &, 'nbsp;mmol/L', 'glucose)', or, normoglycemic, conditions, with, high, osmotic, pressure, '(', 5.5, &, 'nbsp;mmol/L', glucose, +, 10.0, &, 'nbsp;mmol/L', 'mannitol)'])].
[sujeto(['Nr1h2', mRNA, and, protein, expression, were]), verbo([suppressed]), complemento([by, treatment, with, 'TNF-α', plus, 'CaPO4', but, were, restored, by, hyperglycemic, conditions])].
[sujeto(['Activation', of, 'Nr1h2', by, the, antagonist, 'GW3965', during, stimulation, with, 'TNF-α', plus, 'CaPO4', mimicked, hyperglycemic, conditions, and]), verbo([inhibited]), complemento(['Mmp9', 'upregulation,', whereas, the, deactivation, of, 'Nr1h2', by, small, interfering, 'RNA', '(', 'siRNA)', under, hyperglycemic, conditions, canceled, the, suppressive, effect, and, restored, 'Mmp9', expression, induced, by, 'TNF-α', plus, 'CaPO4'])].
[sujeto(['Moreover,', 'Nr1h2', activation, with, 'GW3965', significantly]), verbo([suppressed]), complemento(['CaPO4-induced', aneurysm, in, mice, compared, with, 'vehicle-injected', control, mice])].
[sujeto(['Our', results, show, that, hyperglycemia]), verbo([suppresses]), complemento([macrophage, activation, and, aneurysmal, degeneration, through, the, activation, of, 'Nr1h2'])].
[sujeto(['Although', further, validation, of, the, underlying, pathway, is, 'necessary,']), verbo([targeting]), complemento(['Nr1h2', is, a, potential, therapeutic, approach, to, treating, aneurysm])].
[sujeto(['Liver', 'X', 'receptors,', 'LXRα', '(', 'NR1H3)', and, 'LXRβ', '(', 'NR1H2),', are, best, known, as]), verbo([nuclear]), complemento([oxysterol, receptors, and, physiological, master, regulators, of, lipid, and, cholesterol, metabolism])].
[sujeto(['Greater', myocyte, apoptosis, and, inflammation, within, the, infarcted, zones, were]), verbo([found]), complemento([in, 'LXRα(-/-)', group, at, 3, &, 'nbsp;days', after, 'MI'])].
[sujeto(['At', 4, weeks, 'post-MI,', 'LXRα(-/-)', 'MI', murine, hearts, demonstrated, significantly]), verbo([increased]), complemento([infarct, 'size,', reduced, ejection, fraction, '(', 'LXRα(-/-)', 29.4, &, 'nbsp;%', versus, 'WT', 34.4, &, 'nbsp;%),', aggravated, left, ventricular, '(', 'LV)', chamber, 'dilation,', enhanced, fibrosis, and, reduced, angiogenesis])].
[sujeto(['In', 'addition,', 'LXRα(-/-)', mice, had]), verbo([increased]), complemento([mortality, compared, with, 'WT', mice])].
[sujeto(['LXRα', deficiency]), verbo([increases]), complemento(['mortality,', aggravates, pathological, injury, and, 'LV', remodeling, induced, by, 'MI'])].
[sujeto(['Drugs', specifically]), verbo([targeting]), complemento(['LXRα', may, be, promising, in, the, treatment, of, 'MI'])].
[sujeto(['To', investigate, whether, the, ingestion, of, olive, oil, having, different, phenolic, contents, influences, the, expression, of, blood, 'pressure-related', 'genes,']), verbo([involved]), complemento([in, the, 'renin-angiotensin-aldosterone', 'system,', in, healthy, humans])].
[sujeto(['HPC']), verbo([decreased]), complemento([systolic, blood, pressure, compared, to, 'pre-intervention', values, and, to, 'LPC,', and, maintained, diastolic, blood, pressure, values, compared, to, 'LPC'])].
[sujeto(['HPC']), verbo([decreased]), complemento(['ACE', and, 'NR1H2', gene, expressions, compared, with, 'pre-intervention', 'values,', and, 'IL8RA', gene, expression, compared, with, 'LPC'])].
[sujeto(['The', introduction, to, the, diet, of, an, 'extra-virgin', olive, oil, rich, in, phenolic, compounds]), verbo([modulates]), complemento([the, expression, of, some, of, the, genes, related, to, the, 'renin-angiotensin-aldosterone', system])].
[sujeto(['These', changes, could, underlie, the]), verbo([decrease]), complemento([in, systolic, blood, pressure, observed])].
[sujeto(['In', nonprimate, 'species,', it]), verbo([has]), complemento([been, well, established, that, prostaglandin, 'F2', alpha, '(', 'PGF2alpha)', initiates, luteolysis])].
[sujeto(['Changes', in, intracellular, cholesterol, concentrations]), verbo([caused]), complemento([by, modulation, of, cholesterol, uptake, and, efflux, may, mediate, 'PGF2alpha-induced', luteolysis])].
[sujeto(['These', changes, in, cholesterol, efflux, and, uptake, are, 'controlled,', in, 'part,', by, the, liver, x, receptors, '(', 'LXR)', alpha, '(', 'NR1H3)', and, beta, '(', 'NR1H2),']), verbo([nuclear]), complemento([receptors, that, increase, expression, of, genes, necessary, for, cholesterol, efflux, or, limiting, cholesterol, uptake])].
[sujeto(['Therefore,', we, hypothesized, that, 'PGF2alpha', reduces, expression, of, cholesterol, uptake, and]), verbo([increases]), complemento([expression, of, cholesterol, efflux, 'genes,', mediated, in, part, by, enhanced, 'LXR', activity])].
[sujeto(['To', test, this, 'hypothesis,', an]), verbo([induced]), complemento([luteolysis, model, was, used, whereby, ewes, were, treated, during, their, midluteal, phase, with, saline, or, 'PGF2alpha', and, corpora, lutea, '(', 'CL)', collected, 12, ',', 24, ',', or, 48, h, later, for, determination, of, mRNA, and, protein, concentrations, by, quantitative, 'real-time', 'PCR', and, 'Western', blot, 'analysis,', respectively])].
[sujeto(['The', lipoprotein, receptors, responsible, for, cholesterol, uptake, were, significantly]), verbo([decreased]), complemento([in, both, luteolysis, models])].
[sujeto(['Expression', of, the, 'LXR']), verbo([target]), complemento([gene, 'ATP', binding, cassette, subfamily, 'A1', '(', 'ABCA1),', an, important, mediator, of, cholesterol, 'efflux,', was, significantly, increased, in, both, experimental, models])].
[sujeto(['Chromatin', immunoprecipitation, confirmed, that, 'PGF2alpha', treatment, resulted, in]), verbo([enhanced]), complemento(['NR1H3', and, 'NR1H2', binding, to, the, 'ABCA1', promoter])].
[sujeto(['These', data, support, the, hypothesis, that, reduced, cholesterol, uptake, and]), verbo([increased]), complemento([efflux, mediate, luteolysis, in, 'sheep,', which, is, partially, controlled, by, 'PGF2alpha', stimulation, of, 'LXR', activity])].
[sujeto(['Meat', intake, is]), verbo([associated]), complemento([with, the, risk, of, colorectal, cancer])].
[sujeto(['The', objective, of, this, systematic, review, was, to, evaluate, interactions, between, meat, intake, and, genetic, variation, in, order, to, identify, biological, pathways]), verbo([involved]), complemento([in, meat, carcinogenesis])].
[sujeto(['Interaction', between, a, polymorphism, in, 'XPC', and, meat, was]), verbo([found]), complemento([in, one, prospective, and, one, 'case-control', 'study;', 'however,', the, directions, of, the, risk, estimates, were, opposite])].
[sujeto(['The', results, from, this, systematic, review]), verbo([suggest]), complemento([that, genetic, variation, in, the, inflammatory, response, and, 'DNA', repair, pathway, is, involved, in, 'meat-related', colorectal, 'carcinogenesis,', whereas, no, support, for, the, involvement, of, heme, and, iron, from, meat, or, cooking, mutagens, was, found])].
[sujeto(['Liver-X-receptors,', 'LXRα', '(', 'NR1H3)', and, 'LXRβ', '(', 'NR1H2),', encode, 2, different, but, highly, homologous, isoforms, of, transcription, factors, belonging, to, the]), verbo([nuclear]), complemento([receptor, superfamily])].
[sujeto(['Whether', 'LXRα', and, 'LXRβ', subtypes]), verbo([have]), complemento([discrete, roles, in, the, regulation, of, cardiac, 'physiology/pathology', is, unknown])].
[sujeto(['Mechanistically,', 'LXR', activation]), verbo([inhibited]), complemento(['MI/R-induced', oxidative, stress, and, nitrative, 'stress,', attenuated, endoplasmic, reticulum, stress, and, mitochondrial, 'dysfunction,', and, reduced, cardiomyocyte, apoptosis, in, 'ischemic/reperfused', myocardium])].
[sujeto(['Moreover,', 'LXRα/β', 'double-knockout', and, 'LXRα-knockout', 'mice,', but, not, 'LXRβ-knockout', 'mice,']), verbo([increased]), complemento(['MI/R', 'injury,', exacerbated, 'MI/R-induced', 'oxidative/nitrative', 'stress,', and, aggravated, endoplasmic, reticulum, stress, and, mitochondrial, dysfunction])].
[sujeto(['Furthermore,', cardiac, 'LXRα,', not, 'LXRβ,', overexpression, via, adenoviral, transfection]), verbo([suppressed]), complemento(['MI/R', injury])].
[sujeto(['Our', study]), verbo([provides]), complemento([the, first, direct, evidence, that, the, 'LXRα,', but, not, 'LXRβ,', subtype, is, a, novel, endogenous, cardiac, protective, receptor, against, 'MI/R', injury])].
[sujeto(['Drug', development, strategies, specifically]), verbo([targeting]), complemento(['LXRα', may, be, beneficial, in, treating, ischemic, heart, disease])].
[sujeto(['Liver', 'X', receptors, '(', 'LXRs)', are, considered, to, be, potential, drug]), verbo([targets]), complemento([for, the, 'regulation,', 'treatment,', or, prevention, of, diabetes])].
[sujeto(['Sex', differences, in, 'CO', were]), verbo([found]), complemento([only, in, the, hypothalamus, for, 'LXRβ', expression, at, 35, 'D', and, 9, 'M', '(', 'P&lt;0'])].
[sujeto(['The']), verbo([nuclear]), complemento([receptor, liver, 'X', receptor, '[', 'LXR]', is, activated, by, endogenous, oxidized, derivatives, of, cholesterol])].
[sujeto(['Both', isoforms, of, 'LXR,', 'LXRα', '[', 'NR1H3]', and, 'LXRβ', '[', 'NR1H2],', form, heterodimers, with, the, isoforms, of, the, retinoid, 'X', receptor, '[', 'RXR],', which, then]), verbo([regulate]), complemento([the, gene, expression, by, binding, to, 'DNA', sequences, associated, with, target, genes])].
[sujeto(['LXR']), verbo([acts]), complemento([as, a, cholesterol, sensor, in, response, to, an, increased, concentration, of, cholesterol, in, cells, and, induces, the, transcription, of, genes, that, protect, cells, from, cholesterol, overload])].
[sujeto(['Therefore,', these, receptors, show, great, potential, as, pharmacological]), verbo([targets]), complemento([for, 'anti-atherosclerotic', activities])].
[sujeto(['Recent', discoveries]), verbo([have]), complemento([also, emphasized, the, important, involvement, of, 'LXRs', in, the, pathogenesis, of, 'diabetes,', 'Alzheimer\'s', 'disease,', 'inflammation,', adrenal, steroid, 'synthesis,', skin, aging, and, male, fertility])].
[sujeto(['However,', 'LXR', activation]), verbo([has]), complemento([also, been, shown, to, stimulate, lipogenesis, via, sterol, regulatory, element, binding, 'protein-1c,', leading, to, liver, steatosis, and, hypertriglyceridemia])].
[sujeto(['Liver', 'X', receptors, 'LXRα', '(', 'NR1H3)', and, 'LXRβ', '(', 'NR1H2)', are, transcription, factors, belonging, to, the]), verbo([nuclear]), complemento([receptor, 'superfamily,', activated, by, specific, 'oxysterols,', oxidized, derivatives, of, cholesterol])].
[sujeto(['These', receptors, are]), verbo([involved]), complemento([in, the, regulation, of, testis, physiology])].
[sujeto(['Lxr-deficient', mice, pointed, to, the, physiological, roles, of, these]), verbo([nuclear]), complemento([receptors, in, steroid, 'synthesis,', lipid, homeostasis, and, germ, cell, apoptosis, and, proliferation])].
[sujeto(['Various', lines, of, evidences]), verbo([have]), complemento([made, a, clear, link, between, 'estrogens,', their, nuclear, receptors, 'ERα', '(', 'NR3A1)', and, 'ERβ', '(', 'NR3A2),', and, 'Lxrα/β'])].
[sujeto(['As', 'LXR', activity, could, also, be]), verbo([regulated]), complemento([by, the, nuclear, receptor, small, heterodimer, partner, '(', 'SHP,', 'NR0A2)', and, 'DES', could, act, through, 'SHP,', we, wondered, whether, 'LXR', could, be, targeted, by, 'estrogen-like', endocrine, disruptors, such, as, 'DES'])].
[sujeto(['We', demonstrated, that, 'DES']), verbo([induced]), complemento([a, decrease, of, the, body, mass, at, 10, days, only, in, the, 'Lxr-deficient', mice, suggesting, a, protective, effect, of, 'Lxr'])].
[sujeto(['We', defined, three, categories, of, 'DES-target', genes, in, 'testis:', those, whose, accumulation, is, independent, of, 'Lxr;', those, whose, accumulation, is]), verbo([enhanced]), complemento([by, the, lack, of, both, 'Lxrα/β;', those, whose, accumulation, is, repressed, by, the, absence, of, 'Lxrα/β'])].
[sujeto(['Lxr-deficient', mice, present, different, lipid, 'profiles,', demonstrating, that, 'DES', could]), verbo([have]), complemento([its, effects, in, part, due, to, 'Lxrα/β'])].
[sujeto(['Altogether,', our, study, shows, that, both]), verbo([nuclear]), complemento([receptors, 'Lxrα', and, 'Lxrβ', are, not, only, basally, important, for, testicular, physiology, but, could, also, have, a, preventive, effect, against, 'estrogen-like', endocrine, disruptors])].
[sujeto(['Liver', 'X', receptors, '(', 'LXRs)', α, and, β, are]), verbo([nuclear]), complemento([hormone, receptors, that, are, widely, expressed, in, the, kidney])].
[sujeto(['They']), verbo([promote]), complemento([cholesterol, efflux, from, cells, and, inhibit, inflammatory, responses, by, regulating, gene, transcription])].
[sujeto(['Here,', we, hypothesised, '(', 1, ')', that, 'LXR', deficiency, would]), verbo([promote]), complemento([renal, decline, in, a, mouse, model, of, diabetes, by, accelerating, intraglomerular, cholesterol, accumulation, 'and,', 'conversely,', '(', 2, ')', that, 'LXR', agonism, would, attenuate, renal, decline, in, diabetes])].
[sujeto(['Diabetes', was]), verbo([induced]), complemento([with, streptozotocin, '(', 'STZ)', and, maintained, for, 14, &, 'nbsp;weeks', in, 'Lxrα/β', '(', +, /, +, ')', '(', 'Lxrα,', also, known, as, 'Nr1h3;', 'Lxrβ,', also, known, as, 'Nr1h2)', and, 'Lxrα/β', '(', -, /, -, ')', mice])].
[sujeto(['Even', in, the, absence, of, 'diabetes,', 'Lxrα/β', '(', -, /, -, ')', mice, exhibited, a, tenfold]), verbo([increase]), complemento([in, the, 'albumin:creatinine', ratio, and, a, 40, -, fold, increase, in, glomerular, lipid, accumulation, compared, with, 'Lxrα/β', '(', +, /, +, ')', mice])].
[sujeto(['In', the, 'DN-sensitive', 'STZ', 'DBA/2J', mouse, 'model,', 'DMHCA', treatment, significantly]), verbo([decreased]), complemento([albumin, and, nephrin, excretion, '(', by, 50, '%', 'each),', glomerular, lipids, and, plasma, triacylglycerol, '(', by, 70, '%', ')', and, cholesterol, '(', by, 48, '%', ')', ;, it, also, decreased, kidney, inflammatory, and, oxidative, stress, markers, compared, with, 'vehicle-treated', mice])].
[sujeto(['These', data, support, the, idea, that, 'LXR', plays, an, important, role, in, the, normal, and, diabetic, 'kidney,', while, showing, that, 'LXR,', through, its, inhibitory, effect, on, inflammation, and, cholesterol, accumulation, in, 'glomeruli,', could, also, be, a, novel, therapeutic]), verbo([target]), complemento([for, 'DN'])].
[sujeto(['The']), verbo([cause]), complemento([of, 'MetS', is, likely, to, be, due, to, a, complex, interaction, between, genetic, and, environmental, factors])].
[sujeto(['Although', 'The', 'NR1H2', polymorphism, rs2695121, was, nominally]), verbo([associated]), complemento([with, 'MetS', but, correction, for, 'multiple-testing', and, adjustment, for, 'age,', sex, and, number, of, 'MetS', 'criteria,', failed, to, identify, any, significant, interactions, associated, with, prevalence, of, 'MetS'])].
[sujeto(['However', in, the, haplotype, 'analysis,', a, 'LXRα', haplotype, 'AC,', was, more, common, in, controls, and, was]), verbo([associated]), complemento([with, a, significant, protective, effect, for, 'MetS', '(', 'OR', '[', 95, '%', 'CI]=0'])].
[sujeto(['In', 'conclusion,', this, study]), verbo([suggests]), complemento([that, the, 'above-named', variants, in, 'LXRα', and, 'LXRβ', genes, are, not, potential, contributors, to, the, risk, of, 'MetS', and, related, traits, in, an, 'Iranian', population])].
[sujeto(['For', 'instance,', the, accumulation, of, excess, cholesterol, by, macrophages, initiates, a, genetic, response]), verbo([mediated]), complemento([by, the, liver, 'X', receptors, '(', 'LXRs)-α', '(', 'NR1H3)', and, 'LXRβ', '(', 'NR1H2),', which, facilitates, the, transport, of, cholesterol, out, of, cells, to, 'high-density', lipoprotein, particles])].
[sujeto(['Studies', using, synthetic, 'LXR', agonists]), verbo([have]), complemento([also, demonstrated, that, macrophage, 'LXR', activation, simultaneously, induces, a, second, network, of, genes, that, promotes, fatty, acid, and, triglyceride, synthesis, that, may, support, the, detoxification, of, excess, free, cholesterol, by, storage, in, the, ester, form])].
[sujeto(['We', now, show, that, treatment, of, human, 'THP-1', macrophages, with, endogenous, or, synthetic, 'LXR', ligands]), verbo([stimulates]), complemento([both, transcriptional, and, posttranscriptional, pathways, that, result, in, the, selective, recruitment, of, the, 'LXRα', subtype, to, 'LXR-regulated', promoters])].
[sujeto(['Interestingly,', when, human, or, mouse, macrophages, are, loaded, with, cholesterol, under, conditions, that, mimic, the, development, of, atherogenic, macrophage, foam, 'cells,', a, selective, 'LXR', response, is, generated, that]), verbo([induces]), complemento([genes, mediating, cholesterol, transport, but, does, not, coordinately, regulate, genes, involved, in, fatty, acid, synthesis])].
[sujeto(['The', 'gene-selective', response, to, cholesterol, loading, 'occurs,', even, in, the, presence, of, 'LXRα']), verbo([binding]), complemento([to, the, promoter, of, the, gene, encoding, the, sterol, regulatory, 'element-binding', 'protein-1c,', the, master, transcriptional, regulator, of, fatty, acid, synthesis])].
[sujeto(['The', ability, of, promoter]), verbo([bound]), complemento(['LXRα', to, recruit, 'RNA', polymerase, to, the, sterol, regulatory, 'element-binding', 'protein-1c', 'promoter,', 'however,', appears, to, be, ligand, selective])].
[sujeto(['Concern']), verbo([has]), complemento([been, raised, over, chronic, exposure, effects, to, human, 'health,', especially, in, relation, to, cholesterol, metabolism])].
[sujeto(['Here,', we, explore, the, association, between, exposure, to, 'PFOA', and, 'PFOS', and, the, in, vivo, expression, of, genes]), verbo([involved]), complemento([in, cholesterol, metabolism])].
[sujeto(['Using', adjusted, linear, regression, 'models,', we]), verbo([found]), complemento([inverse, associations, between, serum, 'PFOA', levels, and, the, whole, blood, expression, level, of, genes, involved, in, cholesterol, transport, '(', 'NR1H2,', 'NPC1', and, 'ABCG1;', 'p=0'])].
[sujeto(['A', positive, association, was, seen, between, 'PFOS', and, a, transcript]), verbo([involved]), complemento([in, cholesterol, mobilisation, '(', 'NCEH1;', 'p=0'])].
[sujeto([18, ')', ',', and, a, negative, relationship, with, a, transcript]), verbo([involved]), complemento([in, cholesterol, transport, '(', 'NR1H3;', 'p=0'])].
[sujeto(['When', sexes, were, analysed, 'separately,', reductions, in, the, levels, of, mRNAs]), verbo([involved]), complemento([in, cholesterol, transport, were, seen, with, 'PFOA', in, men, '(', 'NPC1,', 'ABCG1,', and, 'PPARA;', 'p=0'])].
[sujeto([19, ')', ',', whereas, an]), verbo([increase]), complemento([in, the, levels, of, a, cholesterol, mobilisation, transcript, '(', 'NCEH1;', 'p=0'])].
[sujeto(['PFOS', was, positively]), verbo([associated]), complemento([with, expression, of, genes, involved, in, both, cholesterol, mobilisation, and, transport, in, women, '(', 'NCEH1', and, 'PPARA;', 'p=0'])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([of, associations, between, the, in, vivo, expression, of, genes, involved, in, cholesterol, metabolism, and, exposure, to, 'PFOA', or, 'PFOS,', suggested, that, exposure, to, these, compounds, may, promote, a, hypercholesterolaemic, 'environment,', with, wider, implications, for, human, disease])].
[sujeto(['The', constitutive, androstane, receptor, '(', 'CAR,', 'NR1I3),', initially, identified, as, a, 'xenobiotic-sensing', 'receptor,', may, also]), verbo([have]), complemento([roles, in, lipid, homeostasis])].
[sujeto(['The']), verbo([nuclear]), complemento([receptors, liver, 'X', receptors, '(', 'LXRs,', 'NR1H2/3)', and, peroxisome, 'proliferator-activated', receptors, '(', 'PPARs,', 'NR1C)', have, been, known, for, their, roles, in, lipid, metabolism])].
[sujeto(['LXR', is, a, sterol, sensor, that]), verbo([promotes]), complemento(['lipogenesis,', whereas, 'PPARα', controls, a, variety, of, genes, in, several, pathways, of, lipid, metabolism])].
[sujeto(['The', retinoic, acid, 'receptor-related', orphan, receptors, alpha, and, gamma, '(', 'RORalpha', '[', 'NR1F1]', and, 'RORgamma', '[', 'NR1F3])', are, members, of, the]), verbo([nuclear]), complemento([hormone, receptor, superfamily])].
[sujeto(['These', 2, receptors]), verbo([regulate]), complemento([many, physiological, processes, including, 'development,', metabolism, and, immunity])].
[sujeto(['We', recently]), verbo([found]), complemento([that, certain, 'oxysterols,', namely, the, 7, -, substituted, 'oxysterols,', bound, to, the, ligand, binding, domains, '(', 'LBDs)', of, 'RORalpha', and, 'RORgamma', with, high, 'affinity,', altered, the, 'LBD', conformation, and, reduced, coactivator, binding, resulting, in, suppression, of, the, constitutive, transcriptional, activity, of, these, two, receptors])].
[sujeto([24, 'S-OHC', functions, as, a, 'RORalpha/gamma', inverse, agonist]), verbo([suppressing]), complemento([the, constitutive, transcriptional, activity, of, these, receptors, in, cotransfection, assays])].
[sujeto(['Additionally,', 24, 'S-OHC']), verbo([suppressed]), complemento([the, expression, of, several, 'RORalpha', target, genes, including, 'BMAL1', and, 'REV-ERBalpha', in, a, 'ROR-dependent', manner])].
[sujeto(['We', also, demonstrate, that, 24, 'S-OHC']), verbo([decreases]), complemento([the, ability, of, 'RORalpha', to, recruit, the, coactivator, 'SRC-2', when, bound, to, the, 'BMAL1', promoter])].
[sujeto(['We', also, noted, that, 24, '(', 'S),', 25, -, epoxycholesterol, selectively]), verbo([suppressed]), complemento([the, activity, of, 'RORgamma'])].
[sujeto(['Thus,', 'RORalpha', and, 'RORgamma', display, an, overlapping, ligand, preference, with, another, class, of, oxysterol]), verbo([nuclear]), complemento(['receptors,', the, liver, 'X', receptors, '(', 'LXRalpha', '[', 'NR1H3]', and, 'LXRbeta', '[', 'NR1H2])'])].
[sujeto(['The', small, heterodimer, partner, 'SHP', '(', 'NR0B2)', is, an, unusual]), verbo([nuclear]), complemento([receptor, that, lacks, the, typical, 'DNA', binding, domain, common, to, most, nuclear, receptors])].
[sujeto(['SHP']), verbo([has]), complemento([been, reported, to, act, as, a, corepressor, for, several, nuclear, 'receptors,', but, its, exact, mechanism, of, action, is, still, elusive])].
[sujeto(['Here', we, show, that, 'SHP', can]), verbo([interact]), complemento([with, the, liver, 'X', receptors, 'LXRalpha', '(', 'NR1H3)', and, 'LXRbeta', '(', 'NR1H2),', as, demonstrated, by, 'glutathione-S-transferase', 'pull-down', 'assays,', mammalian, 'two-hybrid,', and, coimmunoprecipitation, experiments])].
[sujeto(['In', transfection, 'assays,', 'SHP']), verbo([inhibits]), complemento([the, expression, of, an, artificial, reporter, driven, by, an, 'LXR-response', element, and, represses, the, transcriptional, activation, by, 'LXR', of, the, human, 'ATP-binding', cassette, transporter, 1, '(', 'ABCA1)', promoter])].
[sujeto(['Treatment', of, 'Caco-2', cells, with, bile, 'acids,', which]), verbo([activate]), complemento([farnesoid, 'X', receptor, and, subsequently, induce, 'SHP,', leads, to, the, repression, of, the, human, 'ABCG1', 'gene,', an, established, 'LXR', target, gene])].
[sujeto(['These', results, demonstrate, that, 'SHP', is, able, to]), verbo([interact]), complemento([with, 'LXR', and, to, modulate, its, transcriptional, activity])].
[sujeto(['These', sites]), verbo([have]), complemento([not, been, reported, in, 'AN', methylation, 'analyses,', but, for, the, latter, comparison, 54, /, 81, sites, showed, directionally, consistent, differential, methylation, effects, in, the, 'AN-discordant', twins])].
[sujeto(['For', a, single, nucleotide, polymorphism, rs923768, in, 'CSGALNACT1', a, nearby, site, was, nominally]), verbo([associated]), complemento([with, 'AN'])].
[sujeto(['We']), verbo([found]), complemento([support, for, a, locus, at, 'NR1H3', in, the, 'AN', vs])].
[sujeto(['We', confirm, genes, like, 'TNXB', previously, described, to, comprise, differentially, methylated, 'sites,', and, highlight, further, sites, that, might, be, specifically]), verbo([involved]), complemento([in, 'AN', starvation, processes])].
[sujeto(['Multiple', sclerosis, '(', 'MS)', is, an, inflammatory, disease, characterized, by, myelin]), verbo([loss]), complemento([and, neuronal, dysfunction])].
[sujeto(['Despite', the, aggregation, observed, in, some, 'families,', pathogenic, mutations]), verbo([have]), complemento([remained, elusive])].
[sujeto(['Additionally,', association, analysis, of, common, variants, in, 'NR1H3', identified, rs2279238]), verbo([conferring]), complemento([a, 1.35, -, fold, increased, risk, of, developing, progressive, 'MS'])].
[sujeto(['Arg415Gln', position, is, highly]), verbo([conserved]), complemento([in, orthologs, and, 'paralogs,', and, disrupts, 'NR1H3', heterodimerization, and, transcriptional, activation, of, target, genes])].
[sujeto(['Protein', expression, analysis, revealed, that, mutant, 'NR1H3', '(', 'LXRA)', alters, gene, expression, 'profiles,']), verbo([suggesting]), complemento([a, disruption, in, transcriptional, regulation, as, one, of, the, mechanisms, underlying, 'MS', pathogenesis])].
[sujeto(['Our', study, indicates, that, pharmacological, activation, of, 'LXRA', or, its]), verbo([targets]), complemento([may, lead, to, effective, treatments, for, the, highly, debilitating, and, currently, untreatable, progressive, phase, of, 'MS'])].
[sujeto(['A', mutation, in, a]), verbo([nuclear]), complemento([receptor, '(', 'NR1H3)', gene, was, detected, in, a, 'familial,', progressive, form, of, multiple, sclerosis, '(', 'PPMS)'])].
[sujeto(['Further', analyses, showed, a, significant, association, between, a, common, 'NR1H3', variant, in, 'PPMS', patients, and]), verbo([loss]), complemento([of, function, for, the, encoded, protein])].
[sujeto(['Screening', of, bona, fide, ligands, for]), verbo([nuclear]), complemento([receptors, is, a, real, tour, de, force, as, the, identified, molecules, are, supposed, to, be, able, to, activate, the, targeted, proteins, in, cell, culture, as, well, as, in, vivo])].
[sujeto(['Indeed', orphan]), verbo([nuclear]), complemento([receptors, are, putative, pharmacologically, targets, for, various, diseases])].
[sujeto(['It', is, thus, necessary, to]), verbo([have]), complemento([quick, and, reproductive, systems, that, help, in, identifying, new, 'ligands,', agonist, or, 'antagonist,', before, using, them, in, vivo, in, animal, models, to, check, for, secondary, effects])].
[sujeto(['Nuclear', receptor, subfamily, 1, ',', group, 'H,', member, 3, '(', 'NR1H3,', an, alias, for, 'Liver', 'X', receptor, 'α,', 'LXRα)', is, a, member, of, the, 'LXR']), verbo([nuclear]), complemento([receptor, super, family, and, is, an, important, regulator, of, lipid, and, fatty, acid, accumulation, in, the, 'liver,', adipose, and, skeletal, muscle])].
[sujeto(['The', 'CC', genotype, was]), verbo([associated]), complemento([with, higher, backfat, thickness, than, the, 'AA', and, 'AC', genotypes, in, the, 'NYP'])].
[sujeto(['This']), verbo([increased]), complemento(['NR1H3', expression, might, be, associated, with, higher, lipid, deposition])].
[sujeto(['NR1H3', expression, in, the, backfat, of, 'YY', was, not, lower, than, that, in, 'DSP', or, 'TP,', which, might, because, 'NR1H3']), verbo([has]), complemento([an, alternative, regulatory, function, for, lipid, metabolism, in, the, subcutaneous, fat, of, pigs])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, allele, 'A', of, the, 'exon5-A201C', in, 'NR1H3', may, promote, a, reduction, in, backfat, 'thickness,', and, differences, in, 'NR1H3', expression, may, be, associated, with, differences, in, lipid, deposition, capacity, among, pigs])].
[sujeto(['However,', their, impact, on, biological, pathways]), verbo([involved]), complemento([in, the, atherosclerosis, development, was, not, investigated])].
[sujeto(['Although', 'PALM', 'INTER', did, not]), verbo([increase]), complemento([plasma, cholesterol, concentration, as, much, as, 'TRANS,', the, cholesterol, enrichment, in, the, 'LDL', particle, was, similar, in, both, groups])].
[sujeto(['Moreover,', 'PALM', 'INTER']), verbo([induced]), complemento([the, highest, 'IL-1β,', 'MCP-1', and, 'IL-6', secretion, from, peritoneal, macrophages, as, compared, to, others])].
[sujeto(['These', events, can, partially, be, attributed, to, a, macrophage, cholesterol, 'accumulation,']), verbo([promoted]), complemento([by, apoAI, and, 'HDL2-mediated', cholesterol, efflux, impairment, and, increased, 'Olr-1', and, decreased, 'Abca1', and, 'Nr1h3', expressions, in, the, arterial, wall])].
[sujeto(['Interesterified', fats, containing, palmitic, acid]), verbo([induce]), complemento([atherosclerosis, development, by, promoting, cholesterol, accumulation, in, 'LDL', particles, and, macrophagic, 'cells,', activating, the, inflammatory, process, in, 'LDLr-KO', mice])].
[sujeto(['Sequence', variants, affecting, blood, lipids, and, coronary, artery, disease, '(', 'CAD)', may]), verbo([enhance]), complemento([understanding, of, the, atherogenicity, of, lipid, fractions])].
[sujeto(['Five', variants, within, 'PCSK9,', 'APOA1,', 'ANGPTL4,', and, 'LDLR']), verbo([associate]), complemento([with, 'CAD', '(', 33, ',', 90, cases, and, 236, ',', 254, 'controls)'])].
[sujeto(['The', 'non-HDL', cholesterol, genetic, risk, score]), verbo([associates]), complemento([most, strongly, with, 'CAD', '(', 'P', =, 2.7, ×, 10, '(', -, 28, ')', ')', ',', and, no, other, genetic, risk, score, associates, with, 'CAD', after, accounting, for, 'non-HDL', cholesterol])].
[sujeto(['The', genetic, risk, score, for, 'non-HDL', cholesterol]), verbo([confers]), complemento(['CAD', risk, beyond, that, of, 'LDL', cholesterol, '(', 'P', =, 5.5, ×, 10, '(', -, 8, ')', ')', ',', suggesting, that, targeting, atherogenic, remnant, cholesterol, may, reduce, cardiovascular, risk])].
[sujeto(['Perfluorooctane', sulfonate, '(', 'PFOS),', one, persistent, organic, 'pollutant,']), verbo([has]), complemento([been, widely, detected, in, the, 'environment,', wildlife, and, human])].
[sujeto(['Currently', few, studies]), verbo([have]), complemento([documented, the, effects, of, chronic, 'PFOS', exposure, on, lipid, 'metabolism,', especially, in, aquatic, organisms])].
[sujeto(['The', underlying, mechanisms, of, hepatotoxicity]), verbo([induced]), complemento([by, chronic, 'PFOS', exposure, are, still, largely, unknown])].
[sujeto(['Quantitative', 'PCR', assay, further, indicated, that, 'PFOS', significantly]), verbo([increase]), complemento([the, transcriptional, expression, of, nuclear, receptors, '(', 'nr1h3,', 'rara,', 'rxrgb,', 'nr1l2)', and, the, genes, associated, with, fatty, acid, oxidation, '(', 'acox1,', 'acadm,', 'cpt1a)'])].
[sujeto(['In', 'addition,', chronic, 'PFOS', exposure, significantly]), verbo([decreased]), complemento([liver, 'ATP', content, and, serum, level, of, 'VLDL/LDL', lipoprotein, in, males])].
[sujeto(['Taken', 'together,', these, findings]), verbo([suggest]), complemento([that, chronic, 'PFOS', exposure, induces, hepatic, steatosis, in, zebrafish, via, disturbing, lipid, 'biosynthesis,', fatty, acid, 'β-oxidation', and, excretion, of, 'VLDL/LDL', 'lipoprotein,', and, also, demonstrate, the, validity, of, using, zebrafish, as, an, alternative, model, for, 'PFOS', chronic, toxicity, screening])].
[sujeto(['Diabetic', cardiomyopathy, is, a, myocardial, disease]), verbo([triggered]), complemento([by, impaired, insulin, 'signalling,', increased, fatty, acid, uptake, and, diminished, glucose, utilisation])].
[sujeto(['A', mouse, model, of, type, 2, diabetes, was]), verbo([induced]), complemento([by, a, 'high-fat', diet, '(', 'HFD,', 60, '%', energy, from, 'fat)', over, 16, &, 'nbsp;weeks', and, compared, with, a, 'low-fat', diet, '(', 10, '%', energy, from, 'fat)'])].
[sujeto(['A', mouse, model, of, type, 1, diabetes, was]), verbo([induced]), complemento([via, streptozotocin, injection, over, 12, &, 'nbsp;weeks'])].
[sujeto(['HFD', manifested, comparable]), verbo([increases]), complemento([in, body, 'weight,', plasma, triacylglycerol, and, insulin, resistance, per, 'OGTT', in, 'Lxrα-Tg', and, 'WT', mice])].
[sujeto(['HFD', significantly]), verbo([increased]), complemento([left, ventricular, weight, by, 21, '%', in, 'WT', 'hearts,', but, only, by, 5, '%', in, 'Lxrα-Tg'])].
[sujeto(['To', elucidate, metabolic, effects, in, the, 'heart,', microPET, '(', positron, emission, 'tomography)', imaging, revealed, that, cardiac, glucose, uptake, was]), verbo([increased]), complemento([by, 1.4, -, fold, in, 'WT', mice, on, an, 'HFD,', but, further, augmented, by, 1.7, -, fold, in, 'Lxrα-Tg', 'hearts,', in, part, through, 5, '\'', adenosine, 'monophosphate-activated', protein, kinase, '(', 'AMPK)', phosphorylation, and, restoration, of, glucose, transporter, 4, '(', 'GLUT4)'])].
[sujeto(['By', 'contrast,', 'streptozotocin-induced', ablation, of, insulin, signalling, diminished, cardiac, glucose, uptake, levels, and]), verbo([caused]), complemento([cardiac, 'dysfunction,', indicating, that, insulin, may, be, important, in, 'LXRα-mediated', glucose, uptake])].
[sujeto(['Chromatin', immunoprecipitation, assays, identified, natriuretic, 'peptides,', atrial, natriuretic, peptide, '(', 'ANP)', and, 'B-type', natriuretic, peptide, '(', 'BNP),', as, potential, direct]), verbo([targets]), complemento([of, cardiac, 'LXRα', overexpression])].
[sujeto(['Cardiac-specific', 'LXRα', overexpression, ameliorates, the, progression, of, 'HFD-induced', left, ventricular, hypertrophy, in, association, with]), verbo([increased]), complemento([glucose, reliance, and, natriuretic, peptide, signalling, during, the, early, phase, of, diabetic, cardiomyopathy])].
[sujeto(['These', findings, implicate, a, potential, protective, role, for, 'LXR', in]), verbo([targeting]), complemento([metabolic, disturbances, underlying, diabetes])].
[sujeto(['Sterol', regulatory, element]), verbo([binding]), complemento([protein, 1, '(', 'SREBP1;', gene, name, 'SREBF1)', is, known, to, be, the, master, regulator, of, lipid, homeostasis, in, 'mammals,', including, milk, fat, synthesis])].
[sujeto(['The', major, role, of, 'SREBP1', in, controlling, milk, fat, synthesis]), verbo([has]), complemento([been, demonstrated, in, bovine, mammary, epithelial, cells])].
[sujeto(['Except', for, a, demonstrated, role, in, controlling, the, expression, of, 'FASN,', a, regulatory, role, of, 'SREBP1', on, milk, fat, synthesis, is, very, 'likely,', but]), verbo([has]), complemento([not, yet, been, demonstrated, in, goat, mammary, epithelial, cells, '(', 'GMEC)'])].
[sujeto(['Expression', of, 'SREBF1', was, modest, in, mammary, compared, with, the, other, tissues, in, dairy, goats, but, its, expression]), verbo([increased]), complemento([approximately, 30, -, fold, from, pregnancy, to, lactation])].
[sujeto(['We', observed, no, changes, in, amount, of, the, precursor, form, of, 'SREBP1', protein, but, a, &, 'gt;10-fold']), verbo([increase]), complemento([of, the, mature, form, of, 'SREBP1', protein, with, 'Ad-nSREBP1'])].
[sujeto(['Compared', with, 'Ad-GFP', cells, '(', 'control),', 'Ad-nSREBP1', cells, had, a, significant]), verbo([increase]), complemento([in, expression, of, genes, related, to, 'long-chain', fatty, acid, activation, '(', 'ACSL1),', transport, '(', 'FABP3),', desaturation, '(', 'SCD1),', de, novo, synthesis, of, fatty, acids, '(', 'ACSS2,', 'ACLY,', 'IDH1,', 'ACACA,', 'FASN,', and, 'ELOVL6),', and, transcriptional, factors, '(', 'NR1H3', and, 'PPARG)'])].
[sujeto(['We', observed, a, &, 'gt;10-fold']), verbo([increase]), complemento([in, expression, of, 'INSIG1', but, 'SCAP', was, downregulated, by, 'Ad-nSREBP1'])].
[sujeto(['Compared', with, the, 'Ad-GFP,', the, cellular, triacylglycerol, content, was, higher, and, the, percentage, of, 'C16:0', and, 'C18:1', 'increased,', whereas, that, of, 'C16:1,', 'C18:0,', and, 'C18:2']), verbo([decreased]), complemento([in, 'Ad-nSREBP1', cells])].
[sujeto(['Overall,', the, data]), verbo([provide]), complemento([strong, support, for, a, central, role, of, 'SREBP1', in, the, regulation, of, milk, fat, synthesis, in, goat, mammary, cells])].
[sujeto(['The', mechanisms, by, which, genetic, 'variants,', such, as, single, nucleotide, polymorphisms, '(', 'SNPs),', identified, in, 'genome-wide', association, studies]), verbo([act]), complemento([to, influence, body, mass, remain, unknown, for, most, of, these, 'SNPs,', which, continue, to, puzzle, the, scientific, community])].
[sujeto(['We']), verbo([found]), complemento([that, alleles, at, 28, of, these, 'obesity-associated', 'SNPs', associate, with, methylation, levels, at, 107, proximal, 'CpG', sites])].
[sujeto(['Interestingly,', the]), verbo([associated]), complemento(['SNPs', are, in, known, eQTLs, for, some, of, these, genes])].
[sujeto(['We', also]), verbo([found]), complemento([that, the, 107, 'CpGs', are, enriched, in, enhancers, in, peripheral, blood, mononuclear, cells])].
[sujeto(['Our', results, strongly]), verbo([suggest]), complemento([that, many, 'obesity-associated', 'SNPs', are, associated, with, proximal, gene, 'regulation,', which, was, reflected, by, association, of, obesity, risk, allele, genotypes, with, differential, 'DNA', methylation])].
[sujeto(['This', study, highlights, the, importance, of, 'DNA', methylation, and, other, chromatin, marks, as, a, way, to, understand, the, molecular, basis, of, genetic, variants]), verbo([associated]), complemento([with, human, diseases, and, traits])].
[sujeto(['Existing', evidence]), verbo([suggests]), complemento([that, adverse, pregnancy, outcomes, are, closely, related, with, dietary, factors])].
[sujeto(['Previous', studies, in, mice]), verbo([have]), complemento([focused, on, the, harm, of, folate, deficiency, '(', 'FD)', on, development, of, 'embryo,', while, the, effect, of, low, maternal, folate, levels, on, maternal, intrauterine, environment, during, early, pregnancy, remains, unclear])].
[sujeto(['Since', our, previous, study]), verbo([found]), complemento([that, 'FD', treatment, of, mice, causes, no, apparent, defects, in, embryo, implantation, but, is, accompanied, by, female, 'subfertility,', we, next, chose, to, investigate, a, potential, role, of, 'FD', on, molecular, events, after, implantation])].
[sujeto(['The', results, of, functional, experiments, in, vivo, and, in, vitro, showed, that, 'FD']), verbo([inhibited]), complemento([the, process, of, endometrial, decidualization])].
[sujeto(['It']), verbo([has]), complemento([been, confirmed, that, 'DNA', methylation, participates, in, 'decidualization,', and, folate, as, a, methyl, donor, could, change, the, methylation, patterns, of, genes])].
[sujeto(['The', results, confirmed, that, 'FD', changes, the, methylation, patterns, of, 'genome,', and, 'GO', analysis, of, the, differentially, methylated, regions, revealed, that, the]), verbo([associated]), complemento([genes, mainly, participate, in, biological, 'adhesion,', biological, 'regulation,', cell, 'proliferation,', 'development,', metabolism, and, signalling])].
[sujeto(['In', 'addition,', we]), verbo([found]), complemento([some, candidates, for, regulators, of, decidual, 'transformation,', such, as, 'Nr1h3', and, 'Nr5a1'])].
[sujeto(['The', data, indicate, that, 'FD']), verbo([inhibits]), complemento(['decidualization,', possibly, by, altering, methylation, patterns, of, the, genome, in, mice])].
[sujeto(['The', protease, inhibitor, ritonavir, is]), verbo([associated]), complemento([with, the, development, of, lipodystrophy])].
[sujeto(['Quantifying', changes, in, adipogenic, gene, expression, in, the, presence, of, ritonavir, may, help, to, identify, therapeutic]), verbo([targets]), complemento([for, 'HIV', lipodystrophy])].
[sujeto(['PPAR-γ']), verbo([binding]), complemento([to, its, nuclear, consensus, 'site,', adiponectin, secretion, and, triglyceride, accumulation, were, all, reduced, by, ritonavir])].
[sujeto(['Ritonavir', had, a, significant, effect, on, expression, of, genes]), verbo([involved]), complemento([in, adipocyte, 'differentiation,', lipid, accumulation, and, glucose, metabolism])].
[sujeto(['Down-regulation', of, 'Pparg', may, be]), verbo([mediated]), complemento([by, changes, in, 'Cebpa,', 'Lcn2', and, 'Nr1h3'])].
[sujeto(['The', transformation, was, characterized, by, massively]), verbo([decreased]), complemento([mitochondrial, abundance, and, 'down-regulation', of, gene, expression, related, to, mitochondrial, function, and, oxidative, phosphorylation])].
[sujeto(['Between', the, brown, adipose, and, the, transition, phase, 170, genes, were, differentially, 'expressed,', and, 717, genes, were, differentially]), verbo([expressed]), complemento([between, the, transition, and, the, white, adipose, phase])].
[sujeto(['Thirty-eight', genes, were, shared, among, the, two, sets, of, differentially]), verbo([expressed]), complemento([genes])].
[sujeto(['We', identified, a, number, of]), verbo([regulated]), complemento([transcription, 'factors,', including, 'NR1H3,', 'MYC,', 'KLF4,', 'ESR1,', 'RELA', and, 'BCL6,', which, were, linked, to, the, overall, changes, in, gene, expression, during, the, adipose, tissue, remodeling])].
[sujeto(['Finally,', the, perirenal, adipose, tissue]), verbo([expressed]), complemento([both, brown, and, 'brite/beige', adipocyte, marker, genes, at, 'birth,', the, expression, of, which, changed, substantially, over, time])].
[sujeto(['Using', global, gene, expression, profiling, of, the, postnatal, 'BAT', to, 'WAT', transformation, in, 'sheep,', we]), verbo([provide]), complemento([novel, insight, into, adipose, tissue, plasticity, in, a, large, 'mammal,', including, identification, of, novel, transcriptional, components, linked, to, adipose, tissue, remodeling])].
[sujeto(['Moreover,', our, data, set]), verbo([provides]), complemento([a, useful, resource, for, further, studies, in, adipose, tissue, plasticity])].
[sujeto(['The']), verbo([nuclear]), complemento([receptor, liver, 'X', receptor, '(', 'LXR)', plays, an, important, role, in, the, metabolism, and, homeostasis, of, 'cholesterol,', 'lipids,', bile, 'acids,', and, steroid, hormones])].
[sujeto(['In', this, 'study,', we, uncovered, a, function, of, 'LXRα', '(', 'NR1H3)', in]), verbo([regulating]), complemento([the, human, hydroxysteroid, sulfotransferase, 'SULT2A1,', a, phase, 'II', conjugating, enzyme, known, to, sulfonate, bile, 'acids,', hydroxysteroid, 'dehydroepiandrosterone,', and, related, androgens])].
[sujeto(['We', showed, that, activation, of, 'LXR']), verbo([induced]), complemento([the, expression, of, 'SULT2A1', at, 'mRNA,', 'protein,', and, enzymatic, levels])].
[sujeto(['A', combination, of, promoter, reporter, gene, and, chromatin, immunoprecipitation, assays, showed, that, 'LXRα', transactivated, the, 'SULT2A1', gene, promoter, through, its, specific]), verbo([binding]), complemento([to, the, -, 500, -, to, -, 258, -, base, pair, region, of, the, 'SULT2A1', gene, promoter])].
[sujeto(['LXR', small, interfering, 'RNA', knockdown, experiments]), verbo([suggested]), complemento([that, 'LXRα,', but, not, 'LXRβ,', played, a, dominant, role, in, regulating, 'SULT2A1'])].
[sujeto(['In', primary, human, 'hepatocytes,', we]), verbo([found]), complemento([a, positive, correlation, between, the, expression, of, 'SULT2A1', and, 'LXRα,', which, further, supported, the, regulation, of, 'SULT2A1', by, 'LXRα'])].
[sujeto(['In', 'summary,', our, results, established, human, 'SULT2A1', as, a, novel, 'LXRα']), verbo([target]), complemento([gene])].
[sujeto(['Mammalian']), verbo([nuclear]), complemento([receptors, '(', 'NRs)', are, transcription, factors, regulating, the, expression, of, target, genes, that, play, an, important, role, in, drug, 'metabolism,', 'transport,', and, cellular, signaling, pathways])].
[sujeto(['The', orphan, and, structurally, unique, receptor, small, heterodimer, partner, 1, '(', syn, 'NR0B2)', is, not, only, known, for, its, modulation, of, drug, 'response,', but]), verbo([has]), complemento([also, been, reported, to, be, involved, in, hepatocellular, carcinogenesis])].
[sujeto(['Indeed,', previous, studies, show, that, 'NR0B2', is, downregulated, in, human, hepatocellular, 'carcinoma,']), verbo([suggesting]), complemento([that, 'NR0B2', acts, as, a, tumor, suppressor, via, inhibition, of, cellular, growth, and, activation, of, apoptosis, in, this, tumor, entity])].
[sujeto(['However,', there, was, a, significant]), verbo([decrease]), complemento([of, cellular, proliferation, in, cells, overexpressing, this, 'NR,', and, 'NR0B2', was, more, efficient, than, currently, used, antiproliferative, agents])].
[sujeto(['Taken', 'together,', our, data]), verbo([suggest]), complemento([that, downregulation, of, 'NR0B2', may, also, play, a, role, in, renal, cell, carcinoma, development, and, progression])].
[sujeto(['Residual', feed, intake, '(', 'RFI)', is, a, powerful, indicator, for, energy, utilization, efficiency, and]), verbo([responds]), complemento([to, selection])].
[sujeto(['Therefore,', a, 'genome-wide', association, study, '(', 'GWAS)', and, 'RNA', sequencing, were, performed, on, 'RFI', to, identify, genetic, variants, and, potential, candidate, genes]), verbo([associated]), complemento([with, energy, improvement])].
[sujeto(['A', lower, average, daily, feed, intake, was]), verbo([found]), complemento([in, 'low-RFI', birds, compared, to, 'high-RFI', birds])].
[sujeto(['GWAS', showed, that, 32, of, the, significant, single, nucleotide, polymorphisms, '(', 'SNPs)']), verbo([associated]), complemento([with, the, 'RFI', '(', 'P', &, 'lt;', 10, '(', -, 4, ')', ')', accounted, for, 53.01, &, 'nbsp;%', of, the, additive, genetic, variance])].
[sujeto(['One', hundred, and, sixteen, unique, genes, were, identified, as, differentially]), verbo([expressed]), complemento([genes, '(', 'DEGs)'])].
[sujeto(['The', 'GWAS', findings, showed, that, the, 1, &, 'nbsp;Mb', narrow, region, of, 'GGA12', should, be, important, because, it, contained, genes]), verbo([involved]), complemento([in, 'energy-consuming', 'processes,', such, as, 'lipogenesis,', social, 'behavior,', and, immunity])].
[sujeto(['Small', heterodimer, partner, '(', 'SHP,', 'NR0B2)', is, a]), verbo([nuclear]), complemento([orphan, receptor, without, endogenous, ligands])].
[sujeto(['As', 'such,', we, initiated, a, probe, discovery, effort, to, identify, compounds, capable, of]), verbo([modulating]), complemento(['SHP', function])].
[sujeto(['First,', we, performed]), verbo([binding]), complemento([assays, using, small, molecule, microarrays, '(', 'SMMs)', and, discovered, 5, -, '(', 'diethylsulfamoyl)-3-hydroxynaphthalene-2-carboxylic', acid, '(', 'DSHN)', as, a, novel, activator, of, 'SHP'])].
[sujeto(['DSHN', transcriptionally]), verbo([activated]), complemento(['Shp', 'mRNA,', but, also, stabilized, 'SHP', protein, by, preventing, its, ubiquitination, and, degradation])].
[sujeto(['Second,', we, identified, 'Ccl2', as, a, new, 'SHP']), verbo([target]), complemento([gene, by, 'RNA-seq'])].
[sujeto(['We', showed, that, activation, of, 'SHP', by, 'DSHN']), verbo([repressed]), complemento(['Ccl2', expression, and, secretion, by, inhibiting, p65, activation, of, 'CCL2', promoter, 'activity,', as, demonstrated, in, vivo, in, 'Shp-/-', mice, and, in, vitro, in, 'HCC', cells, with, 'SHP', overexpression, and, knockdown])].
[sujeto(['In', 'summary,', the, discovery, of, a, novel, small, molecule, activator, of, 'SHP']), verbo([provides]), complemento([a, therapeutic, perspective, for, future, translational, and, preclinical, studies, to, inhibit, 'HCC', metastasis, by, blocking, 'Ccl2', signaling])].
[sujeto(['Liver', 'X', receptors, '(', 'LXRs)']), verbo([suppress]), complemento([the, expression, of, inflammatory, genes, in, a, 'context-specific', manner])].
[sujeto(['In', 'astrocytes,', 'SUMOylation', of, 'LXRs']), verbo([promotes]), complemento([their, 'anti-inflammatory', effects])].
[sujeto(['We']), verbo([found]), complemento([that, small, heterodimer, partner, '(', 'SHP),', also, known, as, 'NR0B2', '(', nuclear, receptor, subfamily, 0, ',', group, 'B,', member, 2, ')', ',', facilitates, the, 'anti-inflammatory', actions, of, 'LXRs', by, promoting, their, 'SUMOylation'])].
[sujeto(['Knockdown', of, 'SHP', abrogated, 'SUMOylation', of, 'LXRs,']), verbo([preventing]), complemento([their, 'anti-inflammatory', 'effects,', in, primary, rat, astrocytes, but, not, macrophages])].
[sujeto(['SHP']), verbo([promoted]), complemento(['SUMO2', and, 'SUMO3', attachment, to, 'LXRα', by, interacting, directly, with, the, histone, deacetylase, and, 'E3', 'SUMO', ligase, 'HDAC4'])].
[sujeto(['In', 'contrast,', 'SHP']), verbo([promoted]), complemento(['SUMO1', attachment, to, 'LXRβ', by, stabilizing, the, 'E3', 'SUMO', ligase, 'PIAS1'])].
[sujeto(['SHP']), verbo([bound]), complemento(['PIAS1', and, disrupted, its, interaction, with, the, 'E3', ubiquitin, ligase, 'SIAH1'])].
[sujeto(['Our', data, collectively]), verbo([suggested]), complemento([that, 'SHP', mediates, the, 'anti-inflammatory', actions, of, 'LXRs', through, differential, regulation, of, receptor, 'SUMOylation', specifically, in, 'astrocytes,', thereby, revealing, potential, avenues, for, therapeutic, development, in, diseases, associated, with, brain, inflammation])].
[sujeto(['Circadian', rhythm]), verbo([regulates]), complemento([multiple, metabolic, processes, and, in, turn, is, readily, entrained, by, 'feeding-fasting', cycles])].
[sujeto(['Bile', acids, are, under, circadian, control, and, also]), verbo([increase]), complemento(['postprandially,', serving, as, regulators, of, the, fed, state, in, the, liver])].
[sujeto(['Here,', we, show, that]), verbo([nuclear]), complemento([receptor, 'Small', 'Heterodimer', 'Partner', '(', 'SHP),', a, regulator, of, bile, acid, 'metabolism,', impacts, the, endogenous, peripheral, clock, by, directly, regulating, 'Bmal1'])].
[sujeto(['Deficiency', of, the, orphan]), verbo([nuclear]), complemento([hormone, receptor, small, heterodimer, partner, '(', 'SHP,', 'NR0B2)', protects, mice, from, 'diet-induced', hepatic, 'steatosis,', in, 'part,', via, repression, of, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)-γ2', '(', 'Pparg2)', gene, expression])].
[sujeto(['The', ethanol, feeding]), verbo([induced]), complemento([liver, fat, accumulation, and, mRNA, expression, of, hepatic, 'Pparg2', in, 'WT', 'mice,', which, suggests, that, a, high, level, of, 'PPARγ2', is, a, common, driving, force, for, fat, accumulation, induced, by, ethanol, or, a, 'high-fat', diet])].
[sujeto(['The', current, data, show, faster, ethanol, catabolism, and, extra, fat, storage, through, conversion, of, acetate, to, 'acetyl-CoA', before, its]), verbo([release]), complemento([into, the, circulation, in, this, 'ethanol-feeding', model, in, 'SHP(-/-)', mice])].
[sujeto(['The', bile, 'acid-activated', farnesoid, 'X', receptor, '(', 'FXR)', is, a]), verbo([nuclear]), complemento([receptor, regulating, bile, 'acid,', glucose, and, cholesterol, homeostasis])].
[sujeto(['Obeticholic', acid, '(', 'OCA),', a, promising, drug, for, the, treatment, of, 'non-alcoholic', steatohepatitis, '(', 'NASH)', and, type, 2, 'diabetes,']), verbo([activates]), complemento(['FXR'])].
[sujeto(['Transcriptomic', analysis, showed, that, 'well-known', 'FXR']), verbo([target]), complemento(['genes,', including, 'NR0B2', '(', 'SHP),', 'ABCB11', '(', 'BSEP),', 'SLC51A', '(', 'OSTα)', and, 'SLC51B', '(', 'OSTβ),', and, 'ABCB4', '(', 'MDR3)', are, regulated, by, 'OCA', in, hPCLS])].
[sujeto(['ChIP-sequencing', in, mouse, liver, confirmed, 'FXR']), verbo([binding]), complemento([to, 'IR1', sequences, of, 'Akap13,', 'Cgnl1,', 'Dyrk3,', 'Pdia5,', 'Ppp1r3b', and, 'Tbx6'])].
[sujeto(['Our', study, shows, that, hPCLS]), verbo([respond]), complemento([to, 'OCA', treatment, by, upregulating, 'well-known', 'FXR', target, 'genes,', demonstrating, its, suitability, to, study, 'FXR-mediated', gene, regulation])].
[sujeto(['We', identified, six, novel, 'bona-fide', 'FXR']), verbo([target]), complemento([genes, in, both, mouse, and, human, liver])].
[sujeto(['Disrupted', bile, secretion]), verbo([leads]), complemento([to, liver, damage, characterized, by, 'inflammation,', 'fibrosis,', eventually, 'cirrhosis,', and, hepatocellular, cancer])].
[sujeto(['The', number, of, 'CTGF-positive', cells]), verbo([provided]), complemento([the, most, reliable, overall, measure, for, disease, progression, at, histological, 'level,', bilirubin, at, biochemical, 'level,', and, metalloproteinase, inhibitor, 1, '(', 'Timp1)', at, transcript, level])].
[sujeto(['Prominent', molecular, events, exhibited, by, strong, transcript, peaks, are]), verbo([found]), complemento([for, the, transcriptional, regulator, 'Nr0b2', '(', 'Shp)', and, 1, ',', 25, -, dihydroxyvitamin, 'D(3)', 24, -, hydroxylase, '(', 'Cyp24a1)', at, 6, &, 'nbsp;h'])].
[sujeto(['Small', heterodimer, partner, '(', 'SHP;', 'NR0B2)', is, a, unique, orphan]), verbo([nuclear]), complemento([receptor, '(', 'NR)', that, contains, a, putative, 'ligand-binding', domain, but, lacks, a, 'DNA-binding', domain])].
[sujeto(['In', this, 'review,', we, summarize, the, most, recent, findings, regarding, the, new, 'SHP', interaction, 'partners,', new, structural, insights, into, 'SHP\'s', gene]), verbo([repressing]), complemento(['activity,', and, 'SHP', protein, posttranslational, modifications, by, bile, acids])].
[sujeto(['We', also, discuss, the, pleiotropic, role, of, 'SHP', in]), verbo([regulating]), complemento([cell, 'proliferation,', 'apoptosis,', 'DNA', 'methylation,', and, inflammation, that, are, related, to, antitumor, role, of, 'SHP', in, 'HCC'])].
[sujeto(['Improving', our, understanding, of, 'SHP\'s', antitumor, role, in, the, development, of, liver, cancer, will]), verbo([provide]), complemento([new, insights, into, developing, novel, treatments, or, prevention, strategies])].
[sujeto(['Testosterone', production, by, 'Leydig', cells, is, a, tightly]), verbo([regulated]), complemento([process, requiring, synchronized, expression, of, several, steroidogenic, genes, by, numerous, transcription, factors])].
[sujeto(['So', far, in, the, 'testis,', 'MEF2', factors, were]), verbo([found]), complemento([to, regulate, 'Leydig', cell, steroidogenesis, by, controlling, 'Nr4a1', and, 'Star', gene, expression])].
[sujeto(['Several', genes, were, differentially]), verbo([expressed]), complemento([in, 'MEF2-depleted', 'Leydig', 'cells,', and, 16, were, validated, by, quantitative, 'RT-PCR'])].
[sujeto(['A', large, number, of, these, genes, are, known, to, be]), verbo([involved]), complemento([in, 'fertility,', gonad, 'morphology,', and, steroidogenesis])].
[sujeto(['In', silico, analyses, revealed, the, presence, of, 'MEF2-binding', sites, within, the, first, 2, kb, upstream, of, the, transcription, start, site, of, the, 'Por,', 'Bmal1,', and, 'Nr0b2', 'promoters,']), verbo([suggesting]), complemento([direct, regulation, by, 'MEF2'])].
[sujeto(['Using', transient, transfections, in, 'MA-10', 'Leydig', 'cells,', small, interfering, 'RNA', 'knockdown,', and, a, 'MEF2-Engrailed', dominant, 'negative,', we]), verbo([found]), complemento([that, 'MEF2', activates, the, 'Por,', 'Bmal1,', and, 'Nr0b2', promoters, and, that, this, requires, an, intact, 'MEF2', element])].
[sujeto(['Our', results, identify, novel]), verbo([target]), complemento([genes, for, 'MEF2', and, define, 'MEF2', as, an, important, regulator, of, 'Leydig', cell, function, and, male, reproduction])].
[sujeto(['The']), verbo([increasing]), complemento([incidence, of, male, reproductive, impairments, has, been, associated, with, 'di-(2-ethylhexyl)-phthalate', '(', 'DEHP)', exposure])].
[sujeto(['However,', mechanisms]), verbo([involved]), complemento([are, lacking])].
[sujeto(['Our', data, showed, that, pubertal, exposure, to, 'DEHP']), verbo([induces]), complemento([sperm, count, reduction, as, well, as, histological, abnormalities, in, seminiferous, epithelium, and, apoptosis, of, 'post-meiotic', germ, 'cells,', and, these, effects, are, concomitant, with, reduction, of, testosterone, levels, and, its, steroidogenic, gene, expression])].
[sujeto(['Moreover,', the, expressions, of, estrogen, receptor, 'ERβ', and]), verbo([nuclear]), complemento([receptors, 'Nr0b1,', 'Nr0b2', are, increased])].
[sujeto(['Furthermore,', spermatogonial, stem, cell, '(', 'SSC)', 'self-renewal,', differentiation, and, meiosis, were, significantly, 'impaired,', and, the, epigenetic, regulator, 'G9a-mediated', histone, methylation, was]), verbo([decreased]), complemento([following, 'DEHP', exposure])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, the, 'DEHP-induced', male, reproductive, impairments, may, depend, on, its, estrogenic, action, on, estrogen, receptor, and, nuclear, 'receptor,', and, involve, inhibition, of, 'steroidogenesis,', 'SSC', 'self-renewal', and, 'meiosis,', which, may, be, attributed, to, the, 'down-regulation', of, 'G9a-mediated', histone, methylation])].
[sujeto(['Small', heterodimer, partner, '(', 'SHP,', 'NR0B2)', is]), verbo([involved]), complemento([in, diverse, metabolic, 'pathways,', including, hepatic, bile, 'acid,', lipid, and, glucose, 'homeostasis,', and, has, been, implicated, in, effects, on, the, peroxisome, 'proliferator-activated', receptor, γ, '(', 'PPARγ),', a, master, regulator, of, adipogenesis, and, the, receptor, for, antidiabetic, drugs, thiazolidinediones, '(', 'TZDs)'])].
[sujeto(['Both', 'ob/ob', and, double, mutant, 'ob/ob;Shp(-/-)', mice, developed, 'hyperglycemia,', insulin, 'resistance,', and, 'hyperlipidemia,', but, hepatic, fat, accumulation, was]), verbo([decreased]), complemento([in, the, double, mutant, 'ob/ob;Shp(-/-)', mice])].
[sujeto(['PPARγ2', mRNA, levels, were, markedly, lower, in, 'ob/ob;Shp(-/-)', liver, and]), verbo([decreased]), complemento([to, a, lesser, extent, in, adipose, tissue])].
[sujeto(['Expression', of, the, 'adipocytokines,', such, as, adiponectin, and, 'resistin,', was, not]), verbo([stimulated]), complemento([by, troglitazone, treatment])].
[sujeto(['Moreover,', overexpression, of, 'SHP', by, adenovirus, infection]), verbo([increased]), complemento(['PPARγ2', mRNA, levels, in, mouse, primary, hepatocytes])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'SHP', is, required, for, both, antidiabetic, and, hypolipidemic, effects, of, 'TZDs', in, 'ob/ob', mice, through, regulation, of, 'PPARγ', expression])].
[sujeto(['Hyperhomocysteinemia', is, often]), verbo([associated]), complemento([with, liver, and, metabolic, diseases])].
[sujeto(['We', studied]), verbo([nuclear]), complemento([receptors, that, mediate, oscillatory, control, of, homocysteine, homeostasis, in, mice])].
[sujeto(['Hyperhomocysteinemia', was]), verbo([induced]), complemento([by, feeding, mice, alcohol, '(', 'National', 'Institute', on, 'Alcohol', 'Abuse', and, 'Alcoholism', binge, 'model)', or, chow, diets, along, with, water, containing, 0.18, '%', 'DL-homocysteine'])].
[sujeto(['SHP-null', mice, had, altered, timing, in, expression, of, genes, that]), verbo([regulate]), complemento([homocysteine, metabolism, compared, with, control, mice])].
[sujeto(['SHP']), verbo([inhibited]), complemento([transcriptional, activation, of, 'Bhmt', and, cystathionine, 'γ-lyase', by, 'FOXA1'])].
[sujeto(['Expression', of, 'Bhmt', and, cystathionine, 'γ-lyase', was]), verbo([decreased]), complemento([when, mice, were, fed, cholic, acid, but, increased, when, they, were, placed, on, diets, containing, cholestyramine, or, 'high-fat', content])].
[sujeto(['Diets', containing, ethanol, or, homocysteine]), verbo([induced]), complemento([hyperhomocysteinemia, and, glucose, intolerance, in, 'control,', but, not, 'SHP-null,', mice])].
[sujeto(['Ethanol', feeding]), verbo([induced]), complemento([accumulation, of, macrovesicular, lipid, vacuoles, to, the, greatest, extent, in, 'BHMT-null', and, 'BHMT-null/SHP-null', mice])].
[sujeto(['Disruption', of, 'Shp', in, mice, alters, timing, of, expression, of, genes, that]), verbo([regulate]), complemento([homocysteine, metabolism, and, the, liver, responses, to, ethanol, and, homocysteine])].
[sujeto(['SHP']), verbo([inhibits]), complemento([the, transcriptional, activation, of, 'Bhmt', and, cystathionine, 'γ-lyase', by, 'FOXA1'])].
[sujeto(['The', small, heterodimer, partner, '(', 'SHP)', '(', 'NR0B2)', is, an, atypical]), verbo([nuclear]), complemento([receptor, that, lacks, a, 'DNA-binding', domain])].
[sujeto(['It']), verbo([interacts]), complemento([with, and, inhibits, many, transcription, 'factors,', affecting, key, metabolic, 'processes,', including, bile, 'acid,', 'cholesterol,', fatty, 'acid,', and, drug, metabolism])].
[sujeto(['SHP', was]), verbo([found]), complemento([to, be, repressed, by, steatotic, drugs, '(', 'valproate,', 'doxycycline,', 'tetracycline,', and, cyclosporin, 'A)', in, cultured, hepatic, cells, and, the, livers, of, different, animal, models, of, 'NAFLD:', iatrogenic, '(', 'tetracycline-treated', 'rats),', genetic, '(', glycine, 'N-methyltransferase-deficient', 'mice),', and, nutritional, '(', mice, fed, a, 'methionine-', and, 'choline-deficient', 'diet)'])].
[sujeto(['Moreover,', inhibition, of, major, stress, signaling, pathways, demonstrated, that, the, 'mitogen-activated', protein, kinase, kinase, 1, /, 2, pathway, 'activates,', while, the, phosphatidylinositol, 3, kinase, pathway]), verbo([represses]), complemento(['SHP', in, a, 'C/EBP-dependent', manner])].
[sujeto(['These', conditions, can]), verbo([activate]), complemento([signals, that, target, 'C/EBPα', and, consequently, repress, 'SHP,', thus, favoring, the, progression, and, severity, of, 'NAFLD'])].
[sujeto(['The', small, heterodimer, partner, '(', 'SHP,']), verbo([nuclear]), complemento([receptor, subfamily, 0, ',', group, 'B,', member, 2, ;, 'NR0B2)', is, an, atypical, nuclear, receptor, known, mainly, for, its, role, in, bile, acid, homeostasis, in, the, enterohepatic, tract])].
[sujeto(['Moreover,', 'NR0B2']), verbo([mediates]), complemento([the, deleterious, testicular, effects, of, estrogenic, endocrine, disruptors, leading, to, infertility])].
[sujeto(['This', is, supported, by, a, large, number, of, studies, demonstrating, that, alterations, of, steroid, activity]), verbo([lead]), complemento([to, several, kinds, of, diseases, such, as, obesity, and, infertility])].
[sujeto(['Here,', we, show, that, 'LH/CG']), verbo([represses]), complemento(['Nr0b2', expression, through, the, protein, kinase, 'A-AMP', protein, kinase, pathway])].
[sujeto(['Moreover,', using, a, transgenic, mouse, model, invalidated, for, 'Nr0b2,', we, point, out, that, 'NR0B2']), verbo([mediates]), complemento([the, repression, of, testosterone, synthesis, and, subsequent, germ, cell, apoptosis, induced, by, exposure, to, 'anti-GnRH', compound])].
[sujeto(['This', review, focuses, on, a, number, of, new, data, on, biology, and, pathophysiology, of, the, metabolic, syndrome, '(', 'MetS)', and, the, involvement, of]), verbo([nuclear]), complemento([receptors, that, have, been, presented, during, the, last, 'Endocrine', 'Society', 'meeting,', held, in, 'Houston', in, 'June', 2012])].
[sujeto(['Several', studies]), verbo([have]), complemento([reported, beneficial, effects, of, various, orphan, nuclear, 'receptors,', including, 'SHP', '(', 'Small', 'Heterodimeric', 'Partner,', 'NR0B2)', and, 'LXR', '(', 'Liver', 'X', 'Receptor,', 'NR1H3', and, 'NR1H2),', on, various, components, of, 'MetS'])].
[sujeto(['By', using, an, inactivation, model, of, 'SHP,', 'David', 'Moore']), verbo([has]), complemento([shown, that, 'SHP', exerts, &, 'quot;antidiabetic&quot;', effects, but, associated, with, hepatic, steatosis, development])].
[sujeto(['He', also, showed, that, 'DLPC', '(', dilauroyl, 'phosphatidylcholine),', an, unconventional, 'phospholipid,', exhibited, 'anti-diabetic', properties, through, its]), verbo([binding]), complemento([to, 'LRH-1', '(', 'Liver', 'Receptor', 'Homolog-1,', 'NR5A2),', a, molecular, partner, of, 'SHP'])].
[sujeto(['Interestingly,', 'Carolyn', 'Cummins', investigated, 'LXR', α, and, β, isoforms, 'knock-out', mice, and]), verbo([provided]), complemento([experimental, evidence, for, the, detailed, mechanisms, involved, in, the, deleterious, metabolic, effects, of, 'glucocorticoids,', pointing, out, to, the, functional, interaction, between, 'LXRβ,', and, the, glucocorticoid, receptor])].
[sujeto(['Orphan']), verbo([nuclear]), complemento([receptor, 'Small', 'Heterodimer', 'Partner', '(', 'SHP;', 'NR0B2)', is, a, transcriptional, corepressor, of, a, wide, variety, of, nuclear, receptors, '(', 'NRs)'])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, 'SHP', recruits, 'SIRT1,', a, class, 'III', histone, 'deacetylase,', in, an, 'NR-specific', manner, to, inhibit, transcriptional, activity])].
[sujeto(['SHP']), verbo([interacts]), complemento([and, 'co-localizes', specifically, with, 'SIRT1', in, vivo, and, inhibition, of, 'SIRT1', activity, leads, to, a, recovery, from, the, intrinsic, repressive, activity, of, 'SHP', but, not, of, 'DAX1'])].
[sujeto(['LRH1-mediated', activation, of, 'CYP7A1', and, 'SHP', gene, transcription, was, significantly]), verbo([repressed]), complemento([by, both, 'SHP', and, 'SIRT1', whereas, inhibition, of, 'SIRT1', activity, by, inhibitors, or, dominant, negative, 'SIRT1', or, knockdown, of, 'SHP', led, to, a, significant, release, of, this, inhibitory, effect])].
[sujeto(['ChIP', assays, revealed, that, 'SHP']), verbo([recruits]), complemento(['SIRT1', on, 'LRH1', target, gene, promoters, and, 'SIRT1', deacetylated, 'template-dependent', histone, 'H3', and, 'H4', to, inhibit, transcription, of, 'LRH1', target, genes])].
[sujeto(['Finally,', we, demonstrated, that, inhibition, of, 'SIRT1', activity, significantly, reversed, 'SHP-mediated', inhibition, of, 'bile-acid', synthesis, by, 'LRH1', 'overexpression,', thereby]), verbo([suggesting]), complemento([a, novel, mechanism, of, 'SHP-mediated', inhibition, of, 'LRH1-dependent', 'bile-acid', homeostasis, via, recruitment, of, 'SIRT1', histone, deacetylase, protein])].
[sujeto(['The', liver, receptor, homologue, 1, '(', 'LRH-1', '(', 'NR5A2))', belongs, to, the, orphan]), verbo([nuclear]), complemento([receptor, 'family,', indicating, that, initially, no, ligand, was, known])].
[sujeto(['Although', recent, studies]), verbo([have]), complemento([shown, that, ligand, binding, can, be, 'obtained,', the, biological, relevance, remains, elusive])].
[sujeto(['The', peptide, +, 2, side, chain]), verbo([interacts]), complemento([with, a, charged, amino, acid, of, the, 'receptor,', in, 'hLRH-1', 'Asp372'])].
[sujeto(['Together', with, the, charge, clamp, residues, 'Arg361', and, 'Glu534,', 'Asp372', forms, a, triangle, shaped, charge, clamp, responsible, for, peptide, orientation, and]), verbo([increased]), complemento([affinity])].
[sujeto(['The']), verbo([binding]), complemento([of, the, 'PS', ligand, causes, no, overall, structural, changes, of, the, receptor, but, affects, the, interactions, with, cofactor, peptides])].
[sujeto(['The', cofactor, peptides, from, 'SHP']), verbo([decrease]), complemento([its, interaction, with, the, receptor, upon, ligand, binding, while, 'DAX-1', and, 'PROX1', are, unchanged, or, increase])].
[sujeto(['The', diverse, ligand]), verbo([binding]), complemento([response, of, the, cofactor, provides, an, opportunity, for, drug, design, with, the, possibility, to, create, agonist, ligands, to, modify, cofactor, interaction])].
[sujeto(['Small', heterodimer, partner, '(', 'SHP;', 'NR0B2)', is, an, orphan]), verbo([nuclear]), complemento([receptor, and, acts, as, a, repressor, for, wide, variety, of, nuclear, hormone, receptors])].
[sujeto(['Transient', transfection, of, the, mSHP, promoter, demonstrated, that, 'CLOCK-BMAL1,', core, circadian, clock, 'components,']), verbo([bound]), complemento([to, 'E-box', '(', 'CACGTG),', and, stimulated, the, promoter, activity, by, 4, -, fold])].
[sujeto(['Liver', receptor, 'homologue-1', '(', 'LRH-1;', 'NR5A2)']), verbo([stimulated]), complemento([the, mSHP, 'promoter,', and, 'CLOCK-BMAL1', synergistically, enhanced, the, 'LRH-1-mediated', transactivation])].
[sujeto(['Interestingly,', 'SHP', did, not, affect, the, 'CLOCK-BMAL1-mediated', promoter, 'activity,', but, strongly]), verbo([repressed]), complemento([the, synergistic, activation, of, 'CLOCK-BMAL1', and, 'LRH-1'])].
[sujeto(['In', 'summary,', this, study, shows, that, 'CLOCK-BMAL1,', 'LRH-1', and, 'SHP', coordinately]), verbo([regulate]), complemento([the, mSHP, gene, to, generate, the, circadian, oscillation])].
[sujeto(['The', cyclic, expression, of, mSHP, may, affect, daily, activity, of, other]), verbo([nuclear]), complemento([receptors, and, contribute, to, circadian, liver, functions])].
[sujeto(['The', orphan]), verbo([nuclear]), complemento([hormone, receptor, liver, receptor, homologous, 'protein-1', '(', 'LRH-1;', 'NR5A2,', also, known, as, 'FTF),', an, unusual, receptor, that, binds, 'DNA', as, a, 'monomer,', is, an, essential, regulator, of, expression, of, a, 'rate-limiting', enzyme, in, bile, acid, 'formation,', cholesterol, 7, -, 'alpha-hydroxylase'])].
[sujeto(['In', a, classic, negative, feedback, loop, that, is, a, crucial, component, of, the, complex, regulation, of, cholesterol, 'metabolism,', cholesterol, 7, -, 'alpha-hydroxylase', expression, is]), verbo([decreased]), complemento([when, bile, acid, levels, are, high])].
[sujeto(['This', repression, is, thought, to, be, based, on, the, bile, 'acid-dependent', induction, of, expression, of, the, orphan, receptor, small, heterodimer, partner, '(', 'SHP)', 'NR0B2,', which]), verbo([inhibits]), complemento([the, activity, of, 'LRH-1'])].
[sujeto(['We']), verbo([have]), complemento([explored, the, molecular, basis, for, this, important, regulatory, effect, by, characterizing, the, mechanisms, by, which, mouse, and, human, 'SHP', inhibit, 'LRH-1-mediated', transactivation])].
[sujeto(['Both', 'SHP', proteins, specifically]), verbo([interact]), complemento([with, the, 'AF-2', transactivation, domain, of, 'LRH-1', both, in, vivo, and, in, vitro])].
[sujeto(['This', domain, is, a, common]), verbo([target]), complemento([for, coactivator, 'interaction,', and, the, 'SHP', proteins, can, compete, with, p160, coactivators, for, binding, to, 'LRH-1'])].
[sujeto(['Neither', a, deletion, nor, a, point, mutation, specifically, affecting, this, domain, blocked, the, ability, to]), verbo([interact]), complemento([with, 'LRH-1', to, compete, for, coactivator, binding, or, to, repress, 'LRH-1', transactivation])].
[sujeto(['However,', the, relative, ability, of, these, mutants, to]), verbo([inhibit]), complemento(['LRH-1-mediated', transactivation, was, markedly, decreased])].
[sujeto(['The', orphan]), verbo([nuclear]), complemento([receptor, small, heterodimer, partner, '(', 'SHP;', 'NR0B2)', interacts, with, a, wide, array, of, nuclear, receptors, and, represses, their, transcriptional, activity])].
[sujeto(['SHP', expression, is]), verbo([regulated]), complemento([by, several, other, members, of, the, nuclear, receptor, 'superfamily,', including, the, orphan, receptors, 'SF-1', and, 'LRH-1,', and, the, bile, acid, receptor, 'FXR'])].
[sujeto(['We']), verbo([have]), complemento([found, that, the, 'SHP', promoter, is, also, activated, by, the, estrogen, 'receptor-related', receptor, gamma, '(', 'ERRgamma)', but, not, the, related, 'ERRalpha', and, 'ERRbeta', isoforms])].
[sujeto(['ERRgamma', transactivation, is, dependent, on, only, one, of, five, previously, characterized, 'DNA-binding', sites, for, 'SF-1,', and, this, element, differs, from, previously]), verbo([reported]), complemento(['ERR', response, elements])].
[sujeto(['However,', treatment, with, the, histone, deacetylase, inhibitor, trichostatin, 'A', significantly]), verbo([increased]), complemento(['ERRalpha', and, 'ERRbeta', activity, on, this, element, indicating, that, the, lack, of, activity, of, 'ERRalpha', and, -, beta, may, depend, on, their, association, with, 'co-repressor', in, vivo])].
[sujeto(['Furthermore,', using, protease, sensitivity, assays, on, 'DNA']), verbo([bound]), complemento([receptors, it, was, demonstrated, that, 'DNA', sequence, of, different, response, elements, may, cause, allosteric, modulation, of, 'ERR', 'proteins,', which, in, turn, may, be, responsible, for, the, differential, activities, of, these, receptors, on, different, response, elements])].
[sujeto(['SHP']), verbo([inhibits]), complemento(['ERRgamma', transactivation, and, physically, interacts, with, all, three, members, of, 'ERR', 'subfamily,', as, demonstrated, by, both, yeast, 'two-hybrid', and, biochemical, assays])].
[sujeto(['Several', recently, described, 'SHP', mutations]), verbo([associated]), complemento([with, moderate, obesity, in, humans, block, the, inhibition, of, 'ERRgamma', activity])].
[sujeto(['Small', heterodimer, partner, '(', 'SHP;', 'NR0B2)', is, an, atypical, orphan]), verbo([nuclear]), complemento([receptor, that, lacks, a, conventional, 'DNA-binding', domain])].
[sujeto(['Through', interactions, with, other, transcription, 'factors,', 'SHP']), verbo([regulates]), complemento([diverse, biological, 'events,', including, glucose, metabolism, in, liver])].
[sujeto(['However,', the, role, of, 'SHP', in, adult, heart, diseases]), verbo([has]), complemento([not, yet, been, demonstrated])].
[sujeto(['Hypertrophic', stresses]), verbo([repressed]), complemento([the, expression, of, 'SHP,', whereas, forced, expression, of, 'SHP', blocked, the, development, of, hypertrophy, in, cardiomyocytes])].
[sujeto(['SHP', reduced, the, protein, amount, of, 'Gata6', 'and,', by, direct, physical, interaction, with, 'Gata6,', interfered, with, the]), verbo([binding]), complemento([of, 'Gata6', to, 'GATA-binding', elements, in, the, promoter, regions, of, natriuretic, peptide, precursor, type, 'A'])].
[sujeto(['Metformin,', an, antidiabetic, 'agent,']), verbo([induced]), complemento(['SHP', and, suppressed, cardiac, hypertrophy])].
[sujeto(['These', results, establish, 'SHP', as, a, novel, antihypertrophic, regulator, that]), verbo([acts]), complemento([by, interfering, with, 'GATA6', signaling])].
[sujeto(['SHP', may]), verbo([participate]), complemento([in, the, 'metformin-induced', antihypertrophic, response])].
[sujeto(['This', study, unraveled, a, regulatory, cascade]), verbo([involving]), complemento(['E2F1,', early, growth, 'response-1', '(', 'Egr-1),', nuclear, receptor, small, heterodimer, partner, '(', 'SHP,', 'NR0B2),', and, 'EIA-like', inhibitor, of, differentiation, 1, '(', 'EID1)', in, cholestatic, liver, fibrosis])].
[sujeto(['E2F1', was, also, highly]), verbo([induced]), complemento([by, 3, ',', 5, -, 'diethoxycarbonyl-1,', 4, -, dihydrocollidine, '(', 'DDC)', feeding, and, 'bile-duct', ligation, '(', 'BDL)', in, mice])].
[sujeto(['E2F1-/-', mice, exhibited, reduced, biliary, fibrosis, by, 'DDC', as, determined, by, 'Masson', 'Trichrome', and, 'Picro', 'Sirius', red, 'staining,', and]), verbo([decreased]), complemento([serum, bile, acid, '(', 'BA),', 'BA', pool, 'size,', and, fecal, 'BA', excretion])].
[sujeto(['In', 'addition,', cholestatic, liver, fibrosis]), verbo([induced]), complemento([by, 'BDL,', as, determined, by, immunohistochemistry, analysis, of, a1, collagen, 'expression,', was, increased, in, 'SHP-/-', mice, but, attenuated, in, hepatocyte, 'SHP-overexpressed', transgenic, '(', 'STG)', mice])].
[sujeto(['Egr-1', promoter, was]), verbo([activated]), complemento([by, 'E2F1,', and, the, activation, was, abrogated, by, expression, of, 'SHP', and, its, 'co-repressor', 'EID1', in, hepatoma, cells, 'Huh7,', 'Hepa1,', and, stellate, cells, 'LX2'])].
[sujeto(['Interestingly,', 'E2F1']), verbo([activated]), complemento(['Egr-1', expression, in, a, biphasic, fashion, as, described, in, both, human, and, mouse, hepatocytes])].
[sujeto(['SHP', expression, is, diminished, in, human, cirrhotic, 'livers,']), verbo([suggesting]), complemento([a, regulatory, role, in, human, liver, diseases])].
[sujeto(['The', goal, of, this, study, was, to, identify, novel, 'SHP-regulated', genes, that, are]), verbo([involved]), complemento([in, the, development, and, progression, of, chronic, liver, disease])].
[sujeto(['This', approach, revealed, new, gene, signatures]), verbo([associated]), complemento([with, chronic, liver, disease, and, regulated, by, 'SHP'])].
[sujeto(['These', genes, include, peptidoglycan, recognition, protein, 2, ',', dual, specific, 'phosphatase-4,', tetraspanin, 4, ',', thrombospondin, 1, ',', and, 'SPARC-related']), verbo([modular]), complemento([calcium, binding, 'protein-2,', which, were, validated, by, qPCR, analysis, of, 126, human, liver, 'specimens,', including, 'steatosis,', 'fibrosis,', and, 'NASH,', alcohol, and, hepatitis, 'C', 'cirrhosis,', and, in, mouse, models, of, liver, inflammation, and, injury])].
[sujeto(['This', 'RNA-seq', analysis, identifies, new, genes, that, are]), verbo([regulated]), complemento([by, the, nuclear, receptor, 'SHP', and, implicated, in, the, molecular, pathogenesis, of, human, chronic, liver, diseases])].
[sujeto(['The', results]), verbo([provide]), complemento([valuable, transcriptome, information, for, characterizing, mechanisms, of, these, diseases])].
[sujeto(['Farnesoid', 'X', receptor, '(', 'FXR,', 'Nr1h4)', and, small, heterodimer, partner, '(', 'SHP,', 'Nr0b2)', are]), verbo([nuclear]), complemento([receptors, that, are, critical, to, liver, homeostasis])].
[sujeto(['Induction', of, 'SHP', serves, as, a, major, mechanism, of, 'FXR', in]), verbo([suppressing]), complemento([gene, expression])].
[sujeto(['SHP', is, one, of, the, most, strongly]), verbo([induced]), complemento([genes, by, 'FXR', in, the, liver, and, is, a, tumor, 'suppressor,', 'therefore,', we, hypothesized, that, deficiency, of, 'SHP', contributes, to, 'HCC', development, in, the, livers, of, 'FXR(-/-)', mice, and, 'therefore,', increased, 'SHP', expression, in, 'FXR(-/-)', mice, reduces, liver, tumorigenesis])].
[sujeto(['However,', 'SHP', overexpression]), verbo([led]), complemento([to, a, lower, grade, of, 'dysplasia,', reduced, indicator, cell, proliferation, and, increased, apoptosis])].
[sujeto(['All', 'tumor-bearing', mice, had]), verbo([increased]), complemento([serum, bile, acid, levels, and, 'IL-6', 'levels,', which, was, associated, with, activation, of, hepatic, 'STAT3'])].
[sujeto(['However,', disrupted, bile, acid, homeostasis, by, 'FXR', deficiency]), verbo([leads]), complemento([to, inflammation, and, 'injury,', which, ultimately, results, in, uncontrolled, cell, proliferation, and, tumorigenesis, in, the, liver])].
[sujeto(['The', small, heterodimer, partner, '(', 'SHP;', 'NR0B2)']), verbo([regulates]), complemento([the, transcription, of, a, variety, of, target, genes, and, controls, a, variety, of, physiological, functions, in, various, tissues])].
[sujeto(['However,', the, role, of, 'SHP', in, beta, cell]), verbo([has]), complemento([not, been, fully, determined, yet])].
[sujeto(['SHP', 'KO', mice, showed, significantly, lower, blood, 'glucose,', higher, insulin, 'levels,', and]), verbo([enhanced]), complemento([glucose, tolerance, compared, with, wild, type, '(', 'WT)', mice, after, 'MLDS', treatment])].
[sujeto(['Moreover,', beta, cell, mass, and, pancreatic, insulin, content, were, remarkably]), verbo([increased]), complemento([in, 'SHP', 'KO', mice])].
[sujeto(['In', the, response, to, glucose, 'stimulation,', islets, of, 'SHP', 'KO', showed]), verbo([increased]), complemento([insulin, secretion, via, 'up-regulation', of, beta, cell, enriched, transcription, factors, compared, to, 'WT', mice, after, streptozotocin, '(', 'STZ)', treatment])].
[sujeto(['In', quantification, for, beta, cell, apoptosis, at, day, 1, post, 'STZ', 'treatment,', the, 'SHP', 'KO', mice, showed, significantly]), verbo([increased]), complemento(['anti-apoptotic', gene, expression, and, decreased, release, of, apoptotic, markers, cytochrome, 'c,', 'smac/diablo,', and, only, a, few, apoptotic, beta, cells, were, found, in, 'SHP', 'KO', pancreas, through, inactivation, of, 'caspase-3,', compared, to, those, of, 'WT'])].
[sujeto(['These', data, demonstrate, that, 'SHP', deficiency, ameliorates, hyperglycemia, and, preserves, islet, function, by]), verbo([inhibiting]), complemento([apoptosis, of, pancreatic, beta, cells, and, 'up-regulating', of, their, enriched, transcriptional, factors])].
[sujeto(['Growth', hormone, '(', 'GH)', is, a, key, metabolic, regulator]), verbo([mediating]), complemento([glucose, and, lipid, metabolism])].
[sujeto(['Ataxia', telangiectasia, mutated, '(', 'ATM)', is, a, member, of, the, phosphatidylinositol, 3, -, kinase, superfamily, and]), verbo([regulates]), complemento([cell, cycle, progression])].
[sujeto(['The', orphan]), verbo([nuclear]), complemento([receptor, small, heterodimer, partner, '(', 'SHP:', 'NR0B2)', plays, a, pivotal, role, in, regulating, metabolic, processes])].
[sujeto(['GH']), verbo([induced]), complemento([phosphoenolpyruvate, carboxykinase, '(', 'PEPCK)', and, glucose, 6, -, phosphatase, gene, expression, in, primary, hepatocytes])].
[sujeto(['GH', treatment, and, 'adenovirus-mediated', 'STAT5', overexpression, in, hepatocytes]), verbo([increased]), complemento([glucose, 'production,', which, was, blocked, by, a, 'JAK2', 'inhibitor,', 'AG490,', dominant, negative, 'STAT5,', and, 'STAT5', knockdown])].
[sujeto(['We', identified, a, 'STAT5']), verbo([binding]), complemento([site, on, the, 'PEPCK', gene, promoter, using, reporter, assays, and, point, mutation, analysis])].
[sujeto(['Up-regulation', of, 'SHP', by, 'metformin-mediated', activation, of, the, 'ATM-AMP-activated', protein, kinase, pathway]), verbo([led]), complemento([to, inhibition, of, 'GH-mediated', induction, of, hepatic, 'gluconeogenesis,', which, was, abolished, by, an, 'ATM', 'inhibitor,', 'KU-55933'])].
[sujeto(['Immunoprecipitation', studies, showed, that, 'SHP', physically]), verbo([interacted]), complemento([with, 'STAT5', and, inhibited, 'STAT5', recruitment, on, the, 'PEPCK', gene, promoter])].
[sujeto(['GH-induced', hepatic, gluconeogenesis, was]), verbo([decreased]), complemento([by, either, metformin, or, 'Ad-SHP,', whereas, the, inhibition, by, metformin, was, abolished, by, 'SHP', knockdown])].
[sujeto(['Finally,', the]), verbo([increase]), complemento([of, hepatic, gluconeogenesis, following, 'GH', treatment, was, significantly, higher, in, the, liver, of, 'SHP', null, mice, compared, with, that, of, 'wild-type', mice])].
[sujeto(['Overall,', our, results]), verbo([suggest]), complemento([that, the, 'ATM-AMP-activated', protein, 'kinase-SHP', 'network,', as, a, novel, mechanism, for, regulating, hepatic, glucose, homeostasis, via, a, 'GH-dependent', 'pathway,', may, be, a, potential, therapeutic, target, for, insulin, resistance])].
[sujeto(['After', approximately, 30, mm, 'TL,', cyp19a1a, and, amh, displayed, a, gradual]), verbo([increase]), complemento([in, both, sexes])].
[sujeto(['No', 'apparent,', 'sex-dependent', expression, patterns, were]), verbo([found]), complemento([for, 'dax1,', shp, or, sox9b, transcripts])].
[sujeto(['However,', shp, levels, were, high, until, the, larvae, reached, around, 35, mm, 'TL', and, then, dropped, to, low, 'levels,', while, dax1, remained, low, until, 35, mm, 'TL,', and, then]), verbo([increased]), complemento([sharply])].
[sujeto(['This', pattern, was, corroborated, with, sexually, dimorphic, expression, patterns, of, cyp19a1a, from, 12, -, 13, mm, 'TL,', and, a, 'male-specific']), verbo([increase]), complemento([in, amh, from, 20, mm, 'TL'])].
[sujeto(['IL-6', is, a, proinflammatory, cytokine]), verbo([associated]), complemento([with, the, pathogenesis, of, hepatic, diseases])].
[sujeto(['Metformin', is, an, 'anti-diabetic', drug, used, for, the, treatment, of, type, 2, 'diabetes,', and, orphan]), verbo([nuclear]), complemento([receptor, small, heterodimer, partner, '(', 'SHP,', also, known, as, 'NR0B2),', a, transcriptional, 'co-repressor,', plays, an, important, role, in, maintaining, metabolic, homeostasis])].
[sujeto(['Here,', we, demonstrate, that, 'metformin-mediated', activation, of, 'AMP-activated', protein, kinase, '(', 'AMPK)']), verbo([increases]), complemento(['SHP', protein, production, and, regulates, 'IL-6-induced', hepatic, insulin, resistance])].
[sujeto(['We', investigated, 'metformin-mediated', 'SHP', production, improved, insulin, resistance, through, the, regulation, of, an, 'IL-6-dependent', pathway, '(']), verbo([involving]), complemento([signal, transducer, and, activator, of, transcription, 3, '[', 'STAT3]', and, suppressor, of, cytokine, signalling, 3, '[', 'SOCS3])', in, both, 'Shp', knockdown, and, 'Shp', null, mice])].
[sujeto(['IL-6-induced', 'STAT3', transactivation, and, 'SOCS3', production, were, significantly]), verbo([repressed]), complemento([by, 'metformin,', adenoviral, constitutively, active, 'AMPK', '(', 'Ad-CA-AMPK),', and, adenoviral, 'SHP', '(', 'Ad-SHP),', but, not, in, 'Shp', 'knockdown,', or, with, the, adenoviral, dominant, negative, form, of, 'AMPK', '(', 'Ad-DN-AMPK)'])].
[sujeto(['Chromatin', immunoprecipitation, '(', 'ChIP),', 'co-immunoprecipitation', '(', 'Co-IP)', and, protein, localisation, studies, showed, that, 'SHP']), verbo([inhibits]), complemento(['DNA', binding, of, 'STAT3', on, the, 'Socs3', gene, promoter, via, interaction, and, colocalisation, within, the, nucleus])].
[sujeto(['Finally,', chronic, 'IL-6', exposure]), verbo([caused]), complemento([hepatic, insulin, 'resistance,', leading, to, impaired, insulin, tolerance, and, elevated, 'gluconeogenesis,', and, these, phenomena, were, aggravated, in, 'Shp', null, mice])].
[sujeto(['Our', results, demonstrate, that, 'SHP', upregulation, by, metformin, may]), verbo([prevent]), complemento([hepatic, disorders, by, regulating, the, 'IL-6-dependent', 'pathway,', and, that, this, pathway, can, help, to, ameliorate, the, pathogenesis, of, 'cytokine-mediated', metabolic, dysfunction])].
[sujeto(['Genes']), verbo([involved]), complemento([in, the, physiological, control, of, energy, and, triglyceride, 'synthesis,', such, as, malic, enzyme, 1, ',', 'NADP(+)-dependent,', cytosolic, '(', 'ME1)', and, nuclear, receptor, subfamily, 0, ',', group, 'B,', member, 2, '(', 'NR0B2),', are, key, candidates, that, may, have, effects, on, meat, and, carcass, quality, traits])].
[sujeto(['The', majority, of, the, 'SNPs', were]), verbo([associated]), complemento([with, at, least, one, of, these, 'traits,', including, an, association, between, the, 'NR0B2', 'SNP', and, fat, 'class,', and, associations, between, at, least, one, of, the, 'ME1', 'SNPs', and, eye, muscle, 'area,', sirloin, weight, before, 'maturation,', sirloin, steak, tail, 'length,', and, juiciness])].
[sujeto(['Although', mice, after, 'DEN', exposure, are, among, the, most, widely, used, models, for, liver, 'tumorigenesis,', a, 'detailed,', mechanistic, characterization, of, the, longitudinal, changes, in, the, respective, tumor, genomes]), verbo([has]), complemento([never, been, performed])].
[sujeto(['Chromosomal']), verbo([gains]), complemento([and, losses, were, observed, in, tumors, by, week, 32, and, increased, significantly, by, week, 56])].
[sujeto(['Thus,', contrary, to, common, 'belief,', 'β-catenin', mutations, and, activation, of, the, 'Wnt/β-catenin', pathway, are, not]), verbo([involved]), complemento([in, tumor, initiation, in, this, model, of, chemical, hepatocarcinogenesis])].
[sujeto(['Our', study]), verbo([suggests]), complemento([that, the, majority, of, the, current, knowledge, about, genomic, changes, in, 'HCC', is, based, on, advanced, tumor, lesions, and, that, systematic, analyses, of, the, chronologic, order, including, early, lesions, may, reveal, 'new,', unexpected, findings])].
[sujeto(['Protein', deacetylase, 'Sirt1']), verbo([has]), complemento([been, implicated, in, the, regulation, of, hepatic, 'gluconeogenesis;', 'however,', the, mechanisms, are, not, fully, understood])].
[sujeto(['To', further, elucidate, how, 'Sirt1']), verbo([regulates]), complemento(['gluconeogenesis,', we, took, a, 'loss-of-function', approach, by, deleting, the, coding, 'DNA', sequence, for, the, catalytic, domain, of, the, 'Sirt1', gene, in, the, liver, of, a, 'wild-type', mouse, '(', 'LKO(Sirt)¹)', or, a, genetic, diabetic, mouse, in, which, hepatic, insulin, receptor, substrates, 1, and, 2, are, deleted, '(', 'DKO(Irs½))'])].
[sujeto(['Pyruvate', tolerance, was, also, significantly, improved, in, 'TKO(Irs½:Sirt)¹', 'mice,']), verbo([suggesting]), complemento([that, 'Sirt1', promotes, hepatic, gluconeogenesis, in, this, diabetic, mouse, model])].
[sujeto(['To', understand, why, inactivation, of, hepatic, 'Sirt1', does, not, alter, blood, glucose, levels, in, the, 'wild-type', 'background,', we, searched, for, a, potential]), verbo([cause]), complemento([and, found, that, expression, of, small, heterodimer, partner, '(', 'SHP,', encoded, by, the, 'Nr0b2', 'gene),', an, orphan, nuclear, 'receptor,', which, has, been, shown, to, suppress, the, activity, of, forkhead, transcription, factor, 'FoxO1,', was, decreased, in, the, liver, of, 'LKO(Sirt)¹', mice])].
[sujeto(['Furthermore,', our, luciferase, reporter, assays, and, chromatin, immunoprecipitation, analysis, revealed, that, the, 'Nr0b2', gene, is, a]), verbo([target]), complemento([of, 'FoxO1,', which, is, also, regulated, by, 'Sirt1'])].
[sujeto(['After', the, gene, is, 'upregulated,', 'Nr0b2', can, feed, back, and]), verbo([repress]), complemento(['FoxO1-', and, 'Sirt1-activated', 'G6pc', and, 'Pdk4', gene, expression])].
[sujeto(['Thus,', our, results]), verbo([suggest]), complemento([that, 'Sirt1', can, both, positively, and, negatively, regulate, hepatic, gluconeogenesis, through, 'FoxO1', and, 'Nr0b2', and, keep, this, physiological, process, in, control])].
[sujeto(['Small', heterodimer, partner, '(', 'SHP,', 'NR0B2)', is, a, unique, member, of, the]), verbo([nuclear]), complemento([receptor, '(', 'NR)', superfamily, that, contains, the, dimerization, and, 'ligand-binding', domain, found, in, other, family, 'members,', but, lacks, the, conserved, 'DNA-binding', domain])].
[sujeto(['The', ability, of, 'SHP', to]), verbo([bind]), complemento([directly, to, multiple, 'NRs', is, crucial, for, its, physiological, function, as, a, transcriptional, inhibitor, of, gene, expression])].
[sujeto(['A', wide, variety, of]), verbo([interacting]), complemento([partners, for, 'SHP', have, been, 'identified,', indicating, the, potential, for, 'SHP', to, regulate, an, array, of, genes, in, different, biological, pathways])].
[sujeto(['In', this, 'review,', we, summarize, studies, concerning, the, structure, and]), verbo([target]), complemento([genes, of, 'SHP', and, discuss, recent, progress, in, understanding, the, function, of, 'SHP', in, bile, 'acid,', 'cholesterol,', 'triglyceride,', 'glucose,', and, drug, metabolism])].
[sujeto(['The', fact, that, 'SHP', controls, a, complex, set, of, genes, in, multiple, metabolic, pathways]), verbo([suggests]), complemento([the, intriguing, possibility, of, developing, new, therapeutics, for, metabolic, 'diseases,', including, fatty, 'liver,', dyslipidemia, and, 'obesity,', by, regulating, 'SHP', with, small, molecules])].
[sujeto(['Besides', its, metabolic, regulatory, 'function,', studies, by, us, and, other, groups]), verbo([provide]), complemento([strong, evidence, that, 'SHP', plays, a, critical, role, in, the, development, of, 'cancer,', particularly, liver, and, breast, cancer])].
[sujeto(['An']), verbo([increased]), complemento([understanding, of, the, fundamental, mechanisms, by, which, 'SHP', regulates, the, development, of, cancers, will, be, critical, in, applying, knowledge, of, 'SHP', in, 'diagnostic,', therapeutic, or, preventive, strategies, for, specific, cancers])].
[sujeto(['This', article, is, part, of, a, 'Special', 'Issue', 'entitled:', 'Translating']), verbo([nuclear]), complemento([receptors, from, health, to, disease])].
[sujeto(['NR', gene, profiles]), verbo([reveal]), complemento([that, individual, 'NR', has, its, own, gene, expression, signature, depending, on, tissue, type])].
[sujeto(['Notably,', 'NR0B2/SHP', expression, level, was, significantly]), verbo([decreased]), complemento([in, human, liver, cancer, but, not, in, normal, liver])].
[sujeto(['In', 'addition,', expression, of, 'SHP', is, well]), verbo([associated]), complemento([with, good, prognosis])].
[sujeto(['SHP', gene, network, analysis, based, on, microarray, data, in, liver, cancer, shows, that, 'SHP']), verbo([regulates]), complemento([cell, proliferation, and, metabolism, related, gene, sets])].
[sujeto(['Our', systematic, approaches]), verbo([suggest]), complemento([that, loss, of, 'SHP', expression, in, liver, might, be, key, genetic, events, during, hepatocarcinogenesis])].
[sujeto(['DAX1', is, an, orphan]), verbo([nuclear]), complemento([receptor, with, actions, in, mammalian, sex, 'determination,', regulation, of, 'steroidogenesis,', embryonic, development, and, neural, differentiation])].
[sujeto(['Conserved', patterns, of, 'DAX1', gene, expression, from, mammals, to, fish]), verbo([have]), complemento([been, taken, to, suggest, conserved, function])].
[sujeto(['In', the, present, 'study,', the, 'European']), verbo([sea]), complemento(['bass,', 'Dicentrarchus', 'labrax,', 'DAX1', promoter, was, isolated, and, its, conserved, features, compared, to, other, fish, and, mammalian, 'DAX1', promoters, in, order, to, derive, common, regulators, and, functional, gene, networks])].
[sujeto(['Pathway', analysis, clustered, these, into, candidate, gene, networks]), verbo([associated]), complemento([with, the, fish, and, mammalian, 'DAX1'])].
[sujeto(['Experimental', evidence, is]), verbo([provided]), complemento([supporting, roles, for, 'DAX1', in, steroid, signalling, and, osmoregulation, in, fish])].
[sujeto(['The', approach]), verbo([reported]), complemento([can, be, applied, to, genes, from, model, and, 'non-model', species])].
[sujeto(['We']), verbo([found]), complemento([that, these, animals, were, 'hypermetabolic,', 'hyperphagic,', and, displayed, a, down, setting, of, the, core, body, temperature])].
[sujeto(['Our', 'study,', 'therefore,']), verbo([suggests]), complemento([a, complementarity, of, action, between, the, mitochondrial, receptor, and, other, proteins, encoded, by, the, 'Thra', gene, in, the, control, of, basal, 'metabolism,', facultative, 'thermogenesis,', and, determination, of, the, set, point, of, temperature, regulation])].
[sujeto(['In', the, past, 3, 'years,', 15, patients, with, resistance, to, thyroid, hormone, α, '(', 'RTHα),', nine, 'THRA', gene, mutations]), verbo([have]), complemento([been, 'reported,', reforming, classification, of, 'RTH'])].
[sujeto(['Since', 2012, ',', eight, different, abnormalities]), verbo([have]), complemento([been, described, in, the, 'THRA', gene, '(', encoding, the, 'TRα1', thyroid, hormone, 'receptor)', of, 14, patients, from, 9, families])].
[sujeto(['These', mutations]), verbo([induce]), complemento([a, clinical, phenotype, '(', resistance, to, thyroid, hormone, type, 'α)', associating, symptoms, of, untreated, mild, congenital, hypothyroidism, and, a, 'near-normal', range, of, free, and, total, thyroid, hormones, and, 'TSH', '(', the, 'T4/T3', ratio, is, nevertheless, usually, 'low)'])].
[sujeto(['It', is, well, documented, that, these, hormones]), verbo([act]), complemento([via, the, 'TR', nuclear, 'receptors,', which, are, 'hormone-modulated', transcription, factors])].
[sujeto(['Several', studies]), verbo([have]), complemento([shown, that, thyroid, hormones, regulate, the, expression, of, several, genes, in, the, 'Notch', signaling, 'pathway,', indicating, a, possible, means, by, which, they, participate, in, the, control, of, gut, physiology])].
[sujeto(['However,', the, mechanisms, and, biological, significance, of, this, control]), verbo([have]), complemento([remained, unexplored])].
[sujeto(['Using', multiple, in, vivo, and, in, vitro, 'approaches,', we, show, that, thyroid, hormones, positively]), verbo([regulate]), complemento(['Notch', activity, through, the, 'TRα1', receptor])].
[sujeto(['From', a, molecular, point, of, 'view,', 'TRα1', indirectly, controls, 'Notch1,', 'Dll1,', 'Dll4', and, 'Hes1', expression, but]), verbo([acts]), complemento([as, a, direct, transcriptional, regulator, of, the, 'Jag1', gene, by, binding, to, a, responsive, element, in, the, 'Jag1', promoter])].
[sujeto(['Our', findings, show, that, the, 'TRα1']), verbo([nuclear]), complemento([receptor, plays, a, key, role, in, intestinal, crypt, 'progenitor/stem', cell, biology, by, controlling, the, 'Notch', pathway, and, hence, the, balance, between, cell, proliferation, and, cell, differentiation])].
[sujeto(['It']), verbo([has]), complemento([been, described, in, a, few, patients, with, growth, 'retardation,', short, 'stature,', and, a, low, free, 'T4/free', 'T3', '(', 'FT4/FT3)', ratio])].
[sujeto(['Treatment', with, 'T3']), verbo([led]), complemento([to, heart, rate, 'acceleration,', worsening, of, 'diarrhea,', and, 'TSH', suppression])].
[sujeto(['The', mutant, 'TRα1', had, a]), verbo([decrease]), complemento([in, transcriptional, activity, related, to, decreased, 'T3', binding, and, a, 'dominant-negative', effect, on, the, 'wild-type', receptor])].
[sujeto(['This', case]), verbo([suggests]), complemento([that, patients, with, a, low, 'FT4/FT3', ratio, should, be, screened, for, 'THRA', 'mutations,', even, if, clinical, and, biological, features, differ, from, previous, reported, cases, of, 'RTHα'])].
[sujeto(['In', about, 85, '%', of, 'cases,', a, mutation, in, 'THRB,', the, gene, coding, for, thyroid, receptor, β, '(', 'TRβ),', is, the]), verbo([cause]), complemento([of, this, disorder])].
[sujeto(['Recently,', individual]), verbo([reports]), complemento([described, the, first, patients, with, thyroid, hormone, receptor, α, gene, '(', 'THRA)', defects])].
[sujeto(['Laboratory', investigations, revealed, anaemia, and, slightly, elevated, 'cholesterol,', while, the, thyroid, profile, showed, low, free, thyroxine, '(', 'fT4)', levels, coupled, with, high, free, 'T3', '(', 'fT3),']), verbo([leading]), complemento([to, an, altered, 'T4', :, 'T3', 'ratio,', along, with, normal, 'thyroid-stimulating', hormone, levels])].
[sujeto(['Our', previous, study, showed, that, postnatal, exposure, to, a, low, dose, of, decaBDE, '(', 0.025, 'mg/kg', body, 'weight/day)', by, subcutaneous, injection, on, postnatal, days, '(', 'PNDs)', 1, through, 5]), verbo([leads]), complemento([to, reductions, in, testicular, size, and, number, of, 'Sertoli', cells, and, 'sperm,', while, higher, dose, of, decaBDE, '(', 2.5, 'mg/kg', body, 'weight/day)', had, no, significant, differences, about, these])].
[sujeto([mossambicus, and, the, endocrine, system, by, assessing, the, expression, of, selected, genes]), verbo([associated]), complemento([with, the, thyroid, and, adrenal, endocrine, axes, as, well, as, peroxisome, 'proliferator-activated', receptor, gamma, '(', 'pparg)'])].
[sujeto([mossambicus, than, fish, from, another, 'population,']), verbo([suggesting]), complemento([a, degree, of, thyroid, disruption])].
[sujeto(['The', altered, gene, expression, may, be, a, 'consequence,', rather, than]), verbo([cause]), complemento([of, obesity])].
[sujeto([mossambicus, exposed, to, unfiltered, compared, to, filtered, lake, 'water,', and, our, data]), verbo([suggest]), complemento([fasting, as, causative, factor])].
[sujeto(['Pansteatitis', was, not, a, significant, source, of, variance, in, the, expression, of, any, of, the, genes, 'investigated,']), verbo([suggesting]), complemento([that, the, disease, is, not, associated, with, disrupted, endocrine, signalling])].
[sujeto(['Zebrafish', embryos, were, exposed, to, progesterone, '(', 'P4)', or, norgestrel, '(', 'NGT)', at, 5, ',', 50, and, 100, ng, 'L(-1)', for, 144, h, post, fertilization, '(', 'hpf),', and, the, transcriptional, levels, of]), verbo([target]), complemento([genes, along, the, 'hypothalamic-pituitary-thyroid', axis, were, determined, daily])].
[sujeto(['The', overall, results, showed, that, besides, 'Nis', no, effects, on, the, 'hypothalamic-pituitary-thyroid', '(', 'HPT)', axis, are, observed, following, exposure, to, 'P4', and, 'NGT,', which, imply, that, both, 'P4', and, 'NGT']), verbo([have]), complemento([potential, effects, on, the, thyroid, endocrine, system, by, inducing, transcript, of, 'Nis', gene, during, the, early, stage, of, zebrafish])].
[sujeto(['RTHβ', '(', formerly, only, 'RTH)', is]), verbo([caused]), complemento([by, mutations, in, the, thyroid, hormone, receptor, β, gene, '(', 'THRB)'])].
[sujeto(['The', clinical, phenotype, reflects, the, dysbalance, between, resistance, of, tissues, predominantly]), verbo([expressing]), complemento([the, thyroid, hormone, receptor, 'β-isoforms', 1, and, 2, and, the, overstimulation, of, tissues, mainly, expressing, the, thyroid, hormone, receptor, 'α-isoform', to, thyroid, hormones])].
[sujeto(['The', hallmark, of, 'RTHβ', is, 'goiter,', sinus, 'tachycardia,', attention, deficit, hyperactivity, disorder, in, the, context, of]), verbo([increased]), complemento([levels, of, 'triiodothyronine/free', thyroxine, and, nonsuppressed, 'thyroid-stimulating', hormone])].
[sujeto(['Only', recently]), verbo([have]), complemento([mutations, in, the, thyroid, hormone, receptor, α, gene, '(', 'THRA)', been, identified, causing, a, new, form, of, 'RTH,', 'RTHα'])].
[sujeto(['The', few, patients, described, so, far, suffered, from, mental, retardation, of, variable, 'degree,', short, stature, with]), verbo([decreased]), complemento([subischial, leg, 'length,', chronic, constipation, and, bradycardia])].
[sujeto(['This', review]), verbo([provides]), complemento([an, overview, of, 'clinical,', biochemical, and, genetic, aspects, of, 'RTHα', and, 'RTHβ', relevant, for, 'diagnosis,', treatment, and, counseling, of, affected, patients, and, families])].
[sujeto(['Thyroid', hormone, action, is, predominantly]), verbo([mediated]), complemento([by, thyroid, hormone, receptors, '(', 'THRs),', which, are, encoded, by, the, thyroid, hormone, receptor, α, '(', 'THRA)', and, thyroid, hormone, receptor, β, '(', 'THRB)', genes])].
[sujeto(['Mechanistic', insights, about, the, contributions, of, 'THRβ', to, various, 'processes,', including, colour, 'vision,', development, of, the, cochlea, and, the, 'cerebellum,', and, normal, functioning, of, the, adult, liver, and, 'heart,']), verbo([have]), complemento([been, obtained, by, either, introducing, human, 'THRB', mutations, into, mice, or, by, deletion, of, the, mouse, 'Thrb', gene])].
[sujeto(['The', introduction, of, the, same, mutations, that, mimic, human, 'THRβ', alterations, into, the, mouse, 'Thra', and, 'Thrb', genes, resulted, in, distinct, 'phenotypes,', which]), verbo([suggests]), complemento([that, 'THRA', and, 'THRB', might, have, 'non-overlapping', functions, in, human, physiology])].
[sujeto(['These', studies, also]), verbo([suggested]), complemento([that, 'THRA', mutations, might, not, be, lethal])].
[sujeto(['Seven', patients, with, mutations, in, 'THRα']), verbo([have]), complemento([since, been, described])].
[sujeto(['These', patients]), verbo([have]), complemento(['RTHα', and, presented, with, major, abnormalities, in, growth, and, gastrointestinal, function])].
[sujeto(['The', 'hypothalamic-pituitary-thyroid', axis, in, these, individuals, is, minimally, 'affected,', which]), verbo([suggests]), complemento([that, the, central, 'T3', feedback, loop, is, not, impaired, in, patients, with, 'RTHα,', in, stark, contrast, to, patients, with, 'RTHβ'])].
[sujeto(['Here,', we, describe, the, first, patients, identified, with, a, mutation, in, 'THRA', that, affects, both, 'TRα1', and, 'TRα2,', and, compare, them, with, patients, who]), verbo([have]), complemento([resistance, to, thyroid, hormone, owing, to, a, mutation, affecting, only, 'TRα1,', to, delineate, the, relative, roles, of, 'TRα1', and, 'TRα2'])].
[sujeto(['The', 'Ala263Val', mutant, 'TRα1']), verbo([inhibited]), complemento([the, transcriptional, function, of, normal, receptor, in, a, 'dominant-negative', fashion])].
[sujeto(['High', concentrations, of, 'T3', restored, expression, of, thyroid, 'hormone-responsive']), verbo([target]), complemento([genes, in, 'patient-derived', blood, cells])].
[sujeto(['A', new, genetic, disorder]), verbo([has]), complemento([been, identified, that, results, from, mutation, of, 'THRA,', encoding, thyroid, hormone, receptor, α1, '(', 'TRα1)'])].
[sujeto(['Affected', children]), verbo([have]), complemento([a, high, serum, 'T3:T4', ratio, and, variable, degrees, of, intellectual, deficit, and, constipation, but, exhibit, a, consistently, severe, skeletal, dysplasia])].
[sujeto(['In', an, attempt, to, improve, developmental, delay, and, alleviate, symptoms, of, 'hypothyroidism,', patients, are, receiving, varying, doses, and, durations, of, 'T4', 'treatment,', but, responses]), verbo([have]), complemento([been, inconsistent, so, far])].
[sujeto(['Thra1(PV/+)', mice]), verbo([express]), complemento([a, similar, potent, 'dominant-negative', mutant, 'TRα1', to, affected, 'individuals,', and, thus, represent, an, excellent, disease, model])].
[sujeto(['Although', 'T4', treatment]), verbo([suppressed]), complemento(['TSH', 'secretion,', it, had, no, effect, on, skeletal, 'maturation,', linear, 'growth,', or, bone, 'mineralization,', thus, demonstrating, profound, tissue, resistance, to, thyroid, hormone])].
[sujeto(['Despite', 'this,', prolonged, 'T4', treatment, abnormally]), verbo([increased]), complemento([bone, stiffness, and, 'strength,', suggesting, the, potential, for, detrimental, consequences, in, the, long, term])].
[sujeto(['Our', studies, establish, that, 'TRα1']), verbo([has]), complemento([an, essential, role, in, the, developing, and, adult, skeleton, and, predict, that, patients, with, different, 'THRA', mutations, will, display, variable, responses, to, 'T4', 'treatment,', which, depend, on, the, severity, of, the, causative, mutation])].
[sujeto(['These', patients, had, a, clinical, syndrome, of, resistance, to, 'TH']), verbo([associated]), complemento([with, high, serum, 'TH', and, nonsuppressed, 'thyroid-stimulating', hormone, levels])].
[sujeto(['In', an, attempt, to, predict, the, clinical, phenotype, of, such, 'patients,', different, 'TRα1', mutant, mouse, models]), verbo([have]), complemento([been, generated])].
[sujeto(['These', mice]), verbo([have]), complemento([a, variable, phenotype, depending, on, the, location, and, severity, of, the, mutation])].
[sujeto(['While,', in, 'retrospect,', certain, features, present, in, humans, can, also, be]), verbo([found]), complemento([in, mouse, 'models,', the, first, humans, carrying, a, defect, in, 'TRα1', were, not, suspected, of, having, a, 'THRA', gene, mutation, initially])].
[sujeto(['Adult', mice, with, disrupted, thyroid, hormone, action, in, bone, due, to, a, mutation, of, 'Thra', or, deletion, of, 'Dio2,', encoding, the, type, 2, 'deiodinase,']), verbo([have]), complemento([high, bone, mass, and, mineralisation, despite, essentially, euthyroid, status])].
[sujeto(['No', individuals, with, 'DIO2', mutations]), verbo([have]), complemento([been, described, and, the, adult, phenotype, of, patients, with, 'THRA', mutations, is, largely, unknown])].
[sujeto(['Mutations', affecting, 'THRA', or, 'DIO2', are, not, a, common]), verbo([cause]), complemento([of, high, 'BMD', in, healthy, euthyroid, 'post-menopausal', women])].
[sujeto(['Mutations', of, the, thyroid, hormone, receptor, α, gene, '(', 'THRA)']), verbo([cause]), complemento([hypothyroidism, in, patients, with, growth, and, developmental, 'retardation,', and, skeletal, dysplasia])].
[sujeto(['Using', a, mouse, model, of, hypothyroidism]), verbo([caused]), complemento([by, a, dominant, negative, 'TRα1PV', mutant, and, its, derived, mouse, model, harboring, a, mutated, nuclear, receptor, corepressor, '(', 'NCOR1ΔID)', '(', 'Thra1(PV/+)Ncor1(ΔID/ΔID)', 'mice),', we, recently, showed, that, aberrant, release, of, 'TRα1', mutants, from, the, 'NCOR1', repressor, complex, mediates, dominant, negative, actions, of, 'TRα1', mutants, in, vivo])].
[sujeto(['We', tested, the, hypothesis, that, deacetylation, of, nucleosomal, histones]), verbo([associated]), complemento([with, aberrant, recruitment, of, corepressors, by, 'TRα1', mutants, underlies, pathological, phenotypic, expression])].
[sujeto(['We', focused, our, molecular, analyses, on, how, 'SAHA', improved, the, impaired, adipogenesis]), verbo([leading]), complemento([to, the, lean, phenotype])].
[sujeto(['We']), verbo([found]), complemento([that, 'SAHA', reverted, the, impaired, adipogenesis, by, 'de-repressing', the, expression, of, the, two, master, regulators, of, 'adipogenesis,', 'C/ebpα', and, 'Pparγ,', as, well, as, other, adipogenic, genes, at, both, the, mRNA, and, protein, levels])].
[sujeto(['Chromatin', immunoprecipitation, analyses, indicated, 'SAHA']), verbo([increased]), complemento([the, extent, of, acetylation, of, nucleosomal, 'H4K5', and, 'H3', to, 're-activate', adipogenic, genes, to, reverting, adipogenesis])].
[sujeto(['Thus,', 'HDAC']), verbo([confers]), complemento([in, vivo, aberrant, actions, of, 'TRα1', mutants])].
[sujeto(['Using', 'CRE/loxP-mediated', conditional, expression, 'approach,', we]), verbo([found]), complemento([that, this, mutation, primarily, alters, the, differentiation, of, 'Purkinje', cells, and, 'Bergmann', 'glia,', two, 'cerebellum-specific', cell, types])].
[sujeto(['Therefore,', despite, the, broad, distribution, of, its, 'receptors,', thyroid, hormone]), verbo([targets]), complemento([few, cell, types, that, exert, a, predominant, role, in, the, network, of, cellular, interactions, that, govern, normal, cerebellum, maturation])].
[sujeto(['Tumor', necrosis, factor, '(', 'TNF)', is, a, powerful, 'pro-inflammatory', cytokine, and, 'immuno-regulatory', 'molecule,', and]), verbo([modulates]), complemento([susceptibility, to, musculoskeletal, diseases])].
[sujeto(['Several', 'meta-analyses', and, replicated, association, studies]), verbo([have]), complemento([implicated, the, minor, '\'', 'A\'', variant, within, the, 'TNF', promoter, single, nucleotide, polymorphism, '(', 'SNP)', rs361525, '(', -, 238, 'A/G)', as, a, risk, allele, in, joint, related, 'disorders,', including, psoriatic, and, juvenile, idiopathic, 'arthritis,', and, osteolysis, after, joint, arthroplasty])].
[sujeto(['A', transcriptional, 'reporter,', encoding, the, -, 238, 'A', variant, of, the, 'TNF', 'promoter,', resulted, in, 2.2, to, 2.8, times, greater, transcriptional, activation, versus, the, '\'', 'G\'', variant, in, murine, macrophages, when]), verbo([stimulated]), complemento([with, 'pro-inflammatory', stimuli])].
[sujeto(['Bioinformatic', analysis, predicted, a, putative]), verbo([binding]), complemento([site, for, thyroid, hormone, receptor, '(', 'TR)', for, the, -, 238, 'A', but, not, the, -, 238, 'G', allele])].
[sujeto(['Overexpression', of, 'TR-α']), verbo([induced]), complemento([promoter, expression, 1.8, -, fold, in, the, presence, of, the, '\'', 'A\'', allele, only])].
[sujeto(['This', effect, was, independent, of, 'receptor-ligand']), verbo([binding]), complemento([of, triiodothyronine])].
[sujeto(['The', '\'', 'A\'', allele, at, rs361525]), verbo([confers]), complemento([increased, transcriptional, activation, of, the, 'TNF', promoter, and, influences, susceptibility, to, several, arthritic, conditions])].
[sujeto(['This', effect, is, 'modulated,', at, least, in, 'part,', by]), verbo([binding]), complemento([of, 'TR,', which, both, sensitizes, and, potentiates, transcriptional, activation, of, the, '\'', 'A\'', variant, independent, of, its, endogenous, ligand])].
[sujeto(['The', first, human, cases, '(', 'female,', age, 6, 'y;', father, and, 'daughter,', ages, 47, and, 11, 'y,', 'respectively)', with, growth, 'retardation/short', 'stature,', skeletal, 'dysplasia,', 'constipation,', and, defective, thyroid, receptor, α, '(', 'TRα)']), verbo([have]), complemento([been, recently, described])].
[sujeto(['She', is, heterozygous, for, a, novel, 'frameshift/premature', stop, '(', 'Ala382ProfsX7)', 'THRA', 'mutation,', generating, a, mutant, 'TRα', with, constitutive, corepressor]), verbo([binding]), complemento([and, negligible, coactivator, 'recruitment,', which, inhibits, its, 'wild-type', counterpart, in, a, 'dominant-negative', 'manner-both', in, vitro, and, in, 'mutation-containing', patient, blood, mononuclear, cells, studied, ex, vivo])].
[sujeto(['Her', alertness, and, constipation]), verbo([responded]), complemento([to, 'T4', 'therapy,', which, readily, suppressed, 'TSH', 'levels,', raised, basal, metabolic, 'rate,', and, normalized, elevated, muscle, creatine, 'kinase,', but, cardiac, parameters, '(', heart, 'rate,', 'contractility)', remained, relatively, refractory])].
[sujeto(['Clinical', '(', short, 'stature,', 'macrocephaly,', 'constipation)', and, biochemical, '(', low, free, 'T4/free', 'T3', 'ratio,', subnormal, 'rT3)', findings, that, are, congruent, with, previous, cases, and, newly]), verbo([recognized]), complemento([features, '(', 'epilepsy)', in, this, adult, female, with, defective, 'TRα', define, a, shared, phenotype, in, 'TRα-mediated', resistance, to, thyroid, 'hormone,', with, differential, tissue, responses, to, 'T4', treatment])].
[sujeto(['We', tested, the, hypothesis, that, the, severe, hypothyroidism, in, patients, with, 'THRA', mutations, is, due, to, an, inability, of, 'TRα1', mutants, to, properly]), verbo([release]), complemento([the, nuclear, corepressors, '(', 'NCORs),', thereby, inhibiting, thyroid, 'hormone-mediated', transcription, activity])].
[sujeto(['We', crossed, 'Thra1(PV)', 'mice,']), verbo([expressing]), complemento([a, dominant, negative, 'TRα1', mutant, '(', 'TRα1PV),', with, mice, expressing, a, mutant, 'Ncor1', allele, '(', 'Ncor1(ΔID)', 'mice)', that, cannot, recruit, the, 'TR', or, 'PV', mutant])].
[sujeto(['The', severe, retarded, 'growth,', 'infertility,', and, delayed, bone, development, were, partially, reverted, in, 'Thra1(PV/+)', mice]), verbo([expressing]), complemento(['NCOR1ΔID'])].
[sujeto(['The', impaired, adipogenesis, was, partially, corrected, by, 'de-repression', of, 'peroxisome-proliferator']), verbo([activated]), complemento([receptor, γ, and, 'CCAAT/enhancer-binding', protein, α, 'gene,', due, to, the, inability, of, 'TRα1PV', to, recruit, 'NCOR1ΔID', to, form, a, repressor, complex])].
[sujeto(['Thus,', the, aberrant, recruitment, of, 'NCOR1', by, 'TRα1', mutants, could]), verbo([lead]), complemento([to, clinical, hypothyroidism, in, humans])].
[sujeto(['Therefore,', therapies, aimed, at, the, 'TRα1-NCOR1', interaction, or, its, downstream, actions, could, be, tested, as, potential]), verbo([targets]), complemento([in, treating, 'TRα1', 'mutant-mediated', hypothyroidism, in, patients])].
[sujeto(['Primary', myelofibrosis, '(', 'PMF)', is, a, 'Philadelphia-negative', '(', 'Ph-)', myeloproliferative, 'disorder,', showing, abnormal, 'CD34+', progenitor, cell, 'trafficking,', 'splenomegaly,', marrow, fibrosis]), verbo([leading]), complemento([to, extensive, extramedullary, 'haematopoiesis,', and, abnormal, neoangiogenesis, in, either, the, bone, marrow, or, the, spleen])].
[sujeto(['Monocytes']), verbo([expressing]), complemento([the, 'angiopoietin-2', receptor, '(', 'Tie2)', have, been, shown, to, support, abnormal, angiogenic, processes, in, solid, tumors, through, a, paracrine, action, that, takes, place, in, proximity, to, the, vessels])].
[sujeto(['In', this, study, we, investigated, the, frequency, of, 'Tie2']), verbo([expressing]), complemento([monocytes, in, the, spleen, tissue, samples, of, patients, with, 'PMF,', and, healthy, subjects, '(', 'CTRLs),', and, evaluated, their, possible, role, in, favouring, spleen, angiogenesis])].
[sujeto(['We', show, by, confocal, microscopy, that, in, the, spleen, tissue, of, patients, with, 'PMF,', but, not, of, 'CTRLs,', the, most, of, the, 'CD14+', cells, are, 'Tie2+', and, are, close, to, 'vessels;', by, flow, 'cytometry,', we]), verbo([found]), complemento([that, 'Tie2', expressing, monocytes, were, 'Tie2+CD14lowCD16brightCDL62-CCR2-', '(', 'TEMs)', and, their, frequency, was, higher, '(', p, =, 0.008, ')', in, spleen, 'tissue-derived', mononuclear, cells, '(', 'MNCs)', of, patients, with, 'PMF', than, in, spleen, 'tissue-derived', 'MNCs', from, 'CTRLs', undergoing, splenectomy, for, abdominal, trauma])].
[sujeto(['By', in, vitro, angiogenesis, assay, we, evidenced, that, conditioned, medium, of, immunomagnetically, selected, spleen, tissue, derived, 'CD14+', cells, of, patients, with, 'PMF']), verbo([induced]), complemento([a, denser, tube, like, net, than, that, of, 'CTRLs;', in, 'addition,', 'CD14+Tie2+', cells, sorted, from, spleen, tissue, derived, single, cell, suspension, of, patients, with, 'PMF', show, a, higher, expression, of, genes, involved, in, angiogenesis, than, that, found, in, 'CTRLs'])].
[sujeto(['Our', results, document, the, enrichment, of, 'Tie2+', monocytes]), verbo([expressing]), complemento([angiogenic, genes, in, the, spleen, of, patients, with, 'PMF,', suggesting, a, role, for, these, cells, in, 'starting/maintaining', the, pathological, angiogenesis, in, this, organ])].
[sujeto(['Identifying', factors, that, predict, response, to, therapy, may, help]), verbo([increase]), complemento([efficacy, and, avoid, toxicity])].
[sujeto(['The', phase, 'II', 'SWOG', 'S0703', study, investigated, the, use, of, hydroxyurea, and, azacitidine, with, gemtuzumab, ozogamicin, in, the, elderly, 'AML', population, and]), verbo([found]), complemento([survival, rates, similar, to, those, expected, with, standard, 'AML', 'regimens,', with, less, toxicity])].
[sujeto(['Global', 'DNA', methylation, was, not]), verbo([associated]), complemento([with, a, clinical, response])].
[sujeto(['Samples', after, 3, or, 4, days, of, treatment, with, azacitidine, showed, significantly]), verbo([decreased]), complemento(['CDKN2A', promoter, 'DNA', methylation, in, patients, achieving, complete, remission, '(', 'CR)', compared, to, those, who, did, not])].
[sujeto(['Samples', from, day, 7, of, treatment, showed, significantly]), verbo([decreased]), complemento(['RARB,', 'CDKN2B', and, 'CDH1', promoter, 'DNA', methylation, in, responders, compared, to, nonresponders])].
[sujeto(['The', candidate, 'Division', 'MSBL1', '(', 'Mediterranean', 'Sea', 'Brine', 'Lakes', 1, ')', comprises, a, monophyletic, group, of, uncultured, archaea]), verbo([found]), complemento([in, different, hypersaline, environments])].
[sujeto(['Phylogeny', based, on, rRNA, genes, as, well, as]), verbo([conserved]), complemento([single, copy, genes, delineates, the, group, as, a, putative, novel, lineage, of, archaea])].
[sujeto(['Therefore,', based, on, the, occurrence, of, genes, for, 'glycolysis,', absence, of, the, core, genes]), verbo([found]), complemento([in, genomes, of, all, sequenced, methanogens, and, the, phylogenetic, 'position,', we, hypothesize, that, the, 'MSBL1', are, not, 'methanogens,', but, probably, 'sugar-fermenting', organisms, capable, of, autotrophic, growth])].
[sujeto(['Such', a, mixotrophic, lifestyle, would]), verbo([confer]), complemento([survival, advantage, '(', or, possibly, provide, a, unique, narrow, 'niche)', when, glucose, and, other, fermentable, sugars, are, not, available])].
[sujeto(['Although', 'age-related', hypofunction, of, 'Leydig', cells, is, well, illustrated, across, 'species,', its, circadian, nature]), verbo([has]), complemento([not, been, analyzed])].
[sujeto(['Although', 'arrhythmic,', the, expression, of, 'Insl3,', another, secretory, product, of, 'Leydig', 'cells,', was]), verbo([decreased]), complemento([in, both, groups])].
[sujeto(['Altogether', circadian, amplitude, of, 'Leydig', 'cell\'s', endocrine, function]), verbo([decreased]), complemento([during, aging])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, clock, genes, are, more, resistant, to, aging, than, genes, involved, in, steroidogenesis, supporting, the, hypothesis, about, peripheral, clock, involvement, in, rhythm, maintenance, during, aging])].
[sujeto(['Pinealectomy']), verbo([increased]), complemento([24, -, 'h-oscillations', of, serum, testosterone, and, 'LC\'s', cAMP, 'levels,', expression, of, 'Insl3,', 'Per1,', 'Star/StAR,', 'Hsd3b1/2,', 'Nur77,', decreased, 'Arr19', and, canceled, 'Per2', oscillatory, expression, pattern])].
[sujeto(['At', 'hypothalamic-pituitary', 'level,', pinealectomy]), verbo([increased]), complemento([mesor, of, 'Gnrh,', 'Lhb', and, rhythm, robustness, of, 'Mntr1a', expression])].
[sujeto(['The', objective, of, the, present, study, was, to, determine, whether, 'Dioscorea', batatas, '(', 'DB)', extract, reduces, visceral, fat, accumulation, and, 'obesity-related', biomarkers, in, mice, fed, a, 'high-fat', diet, '(', 'HFD)', and, whether, genes]), verbo([associated]), complemento([with, adipogenesis, and, inflammation, could, be, modulated, by, a, diet, containing, 'DB', extract])].
[sujeto(['Supplementation', of, the, diet, with, 'DB', extract, for, 14, weeks, significantly]), verbo([prevented]), complemento(['HFD-induced', increases, in, body, 'weight,', visceral, adipose, 'tissue,', plasma, lipid, 'levels,', and, leptins])].
[sujeto(['Supplementation', with, 'DB', extract, resulted, in, the, downregulation, of, the, adipogenic, transcription, factor, '(', 'C/ERBa)', and, its]), verbo([target]), complemento([gene, '(', 'CD36)', in, epididymal, adipose, 'tissue,', compared, to, 'HFD', alone])].
[sujeto(['DB', extract]), verbo([decreased]), complemento([the, expression, of, proinflammatory, cytokines, '(', 'TNF-α,', 'MCP-1,', and, 'IL-6)', in, epididymal, adipose, tissue])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'DB', extract, may, prevent, 'HFD-induced', obesity, by, downregulating, the, expression, of, genes, related, to, adipogenesis, and, inflammation, in, visceral, adipose, tissue])].
[sujeto(['Drug', effects, on, the, human, sense, of, smell, attract]), verbo([increasing]), complemento(['interest,', yet, systematic, evidence, from, controlled, studies, is, sparse])].
[sujeto(['The', association, between, the, 'patients\'', sense, of, smell, and, the, administered, medications, was, based, '(', 'i)', on, the, active, pharmacological, substances, and, '(', 'ii)', on, the, molecular]), verbo([targets]), complemento([queried, from, the, publicly, accessible, 'DrugBank', database])].
[sujeto(['The', administration, of, levothyroxine, was]), verbo([associated]), complemento([with, a, higher, olfactory, score, '(', p, =, 0.033, ')'])].
[sujeto(['For', the, 168, 'drugs,', 323, different]), verbo([targets]), complemento([could, be, queried])].
[sujeto(['Besides', agonistic]), verbo([targeting]), complemento([of, thyroid, hormone, receptors, '(', genes, 'THRA1,', 'THRB1)', agreeing, with, the, above, 'result,', antagonistically, targeting, the, adrenoceptor, alpha, 1, 'A', '(', gene, 'ADRA1A)', by, several, unrelated, medications, was, associated, with, a, significantly, higher, olfactory, score, '(', p, =, 0.012, ')'])].
[sujeto(['The', novel, molecular, 'target-based', approach]), verbo([suggested]), complemento([clear, advantages, over, the, classical, drug, or, drug, 'class-based', approach])].
[sujeto(['It']), verbo([increased]), complemento([the, analyzable, data, volume, fivefold, and, provided, plausible, hypotheses, about, mechanistic, drug, effects, opening, possibilities, for, drug, discovery, and, repurposing])].
[sujeto(['Response', to, thyrotropin]), verbo([releasing]), complemento([hormone, '(', 'TRH)', test, was, normal, and, 'TSH', concentrations, were, not, suppressed, during, oral, administration, of, suprafisiologic, doses, of, levothyroxine, '(', 'L-T4)'])].
[sujeto(['Peripheral', blood, 'DNA', was, extracted, from, the, patient, and, a, mutation, was]), verbo([found]), complemento([localized, in, cluster, 'one,', at, codon, 346, of, the, ligand, binding, domain, of, the, 'THRB', gene])].
[sujeto(['The', 'patient\'s']), verbo([son]), complemento([underwent, thyroid, function, testing, '(', 'TFT)', and, genetic, 'study,', both, 'negative,', suggesting, a, sporadic, mutation])].
[sujeto(['Mutations', interfering, with, three, major, steps]), verbo([required]), complemento([for, 'TH', action, on, target, tissues, have, 'been,', so, 'far,', identified, '(', 'TR-β,', 'TR-α,', 'MCT8,', 'SPB2)'])].
[sujeto(['Each', mutation, is]), verbo([associated]), complemento([with, a, distinctive, syndrome])].
[sujeto(['Goal', of, management, is, to]), verbo([maintain]), complemento([a, normal, serum, 'TSH', level, and, a, eumetabolic, state, and, offer, appropriate, genetic, counselling, and, prenatal, diagnosis])].
[sujeto(['It', was, examined, the, involvement, of, 'PI3K', pathway, in]), verbo([mediating]), complemento(['T3', effects, by, treating, 3, 'T3-L1', adipocytes, with, physiological, '(', 'P=10nM)', or, supraphysiological, '(', 'SI', =, 100, 'nM)', 'T3', doses, during, one, hour, '(', short, 'time),', in, the, absence, or, the, presence, of, 'PI3K', inhibitor, '(', 'LY294002)'])].
[sujeto(['T3']), verbo([increased]), complemento(['TRα', mRNA, expression, in, 'P', '(', 1.91, '±0'])].
[sujeto(['This']), verbo([increase]), complemento([was, completely, abrogated, by, 'LY294002', in, 'P', '(', 0.53, '±0'])].
[sujeto(['To', examine, whether, 'TRα', is, directly]), verbo([induced]), complemento([by, 'T3,', we, used, the, translation, inhibitor, cycloheximide, '(', 'CHX)'])].
[sujeto([1, ')', ',']), verbo([induced]), complemento([by, 'T3'])].
[sujeto(['These', results, demonstrate, that, the, activation, of, the, 'PI3K', signaling, pathway]), verbo([has]), complemento([a, role, in, 'T3-mediated', indirect, 'TRα', gene, expression, in, 3, 'T3-L1', adipocytes])].
[sujeto(['Few', studies]), verbo([have]), complemento([been, conducted, to, investigate, bone, and, mineral, metabolism, in, 'RTH'])].
[sujeto(['The', same, pattern, was, observed, when, the, results, were]), verbo([expressed]), complemento([as, 'Z-scores', between, 'groups,', with, a, lower, value, in, 'RTHG', than, in, 'CG', for, the, lumbar, spine, of, adults, '(', 'P='])].
[sujeto(['Considering', that, the, 'TRα1', isoform, is, the, predominant, 'TR', in, the, 'skeleton,', we, hypothesize, that, probably, these, patients, may, exhibit]), verbo([enhanced]), complemento([calcium, flux, from, bone, to, circulation])].
[sujeto(['As', a, novel, approach, to, 'APL', 'treatment,', one, possible, the, action, of, 'RA,', 'A', consense, sequence, '(', 5, '\'', -, 'TCAGGTCATGACCTGA-3\')']), verbo([has]), complemento([been, postulated, for, the, thyroid, hormone, '(', 'TRE)', and, retinoic, acid, responsive, element, '(', 'RARE)', containing, half, 'palindromes,', which, located, in, the, promoter, region, of, target, genes])].
[sujeto(['High', dose, '(', 100, -, 'fold)', of, 'RA-RARE-PML/RARa', complex, in, intracellular, localization, appears, to, relieve, repressor, from, 'DNA', 'binding,', including, corepressors, 'N-CoR,', 'SMRT', and, 'HDACs,']), verbo([release]), complemento(['PML/RARa-', mediated, transcriptional, 'repression,', and, release, histone, deacetylase, activity, from, 'PMLRARa'])].
[sujeto(['PML', protein, relocalizes, into, the, 'wild-type']), verbo([nuclear]), complemento([body, '(', 'PML-NB)', configuration, 'or/and', 'wild-type', 'RARa', upregulated])].
[sujeto(['Here,', like, 'v-erbA,', 'PML/RARa', is, a, '(', 'strong)', transcriptional, repressor, of, the, 'RA', receptor, '(', 'RAR)', 'complex,', and, 'PML/RARa', fusion, receptor, gene]), verbo([act]), complemento([as, conditional, oncogenic, receptor, '(', translocated, chimeric, retinoic, acid, a, 'signaling)', or, oncogenic, 'PML/RARa', may, participate, in, leukemogenesis, of, 'APL', through, blocking, 'RA-mediated', promyelocytic, differentiation])].
[sujeto(['Pharmaceuticals', and, personal, care, products, '(', 'PPCPs)']), verbo([have]), complemento([been, detected, widely, in, aquatic, 'ecosystems,', but, little, is, known, about, their, mechanisms, of, toxicity])].
[sujeto(['The', group, treated, with, 'DEET', only, showed, a, significant]), verbo([decrease]), complemento([in, ar, in, females])].
[sujeto(['Nevirapine', '(', 'NVP)', is, an, 'anti-retroviral', drug, used, for, the, treatment, of, 'HIV', 'infection,', that, may]), verbo([cause]), complemento([several, severe, adverse, 'events,', including, 'Stevens', 'Johnsons', 'Syndrome/Toxic', 'Epidermal', 'Necrolysis', '(', 'SJS/TEN)'])].
[sujeto(['The', 'HCP5', rs3099844, variant, allele, was, significantly]), verbo([associated]), complemento([with, the, 'SJS/TEN', susceptibility, '(', 'OR', =, 2.03, and, 'P', =, 0.039, ')'])].
[sujeto(['The', clinical, relevance, of]), verbo([targeting]), complemento([the, 'RAS/RAF/MEK/ERK', 'pathway,', activated, in, 70, '%', to, 80, '%', of, patients, with, acute, myelogenous, leukemia, '(', 'AML),', is, unknown])].
[sujeto(['Selumetinib', is]), verbo([associated]), complemento([with, modest, 'single-agent', antileukemic, activity, in, advanced, 'AML'])].
[sujeto(['However,', given, its, favorable, toxicity, 'profile,', combination, with, drugs, that]), verbo([target]), complemento([other, signaling, pathways, in, 'AML', should, be, considered])].
[sujeto(['The', potential, association, of, 'SNP', rs3733542, in, exon, 18, of, the, 'KIT', gene, with, antileukemic, activity, of, selumetinib, is, 'intriguing,', but, will]), verbo([require]), complemento([validation, in, larger, trials])].
[sujeto(['felineus,', and, to, analyze, the, expression, of, possible]), verbo([target]), complemento([genes, in, response, to, treatment, with, exogenous, thyroid, hormones])].
[sujeto(['The', genes, were, differentially]), verbo([expressed]), complemento([through, the, life, cycle])].
[sujeto(['Treatment', of, the, worms, with, triiodothyronine, and, thyroxine, resulted, in, an]), verbo([increase]), complemento([in, glucose, 6, -, phosphatase, mRNA, expression, and, a, decrease, in, malate, dehydrogenase, mRNA, 'expression,', potential, gene, targets, of, thyroid, hormones])].
[sujeto(['Thyroid', hormone, receptors, '(', 'TRs)', are, 'ligand-dependent', transcription, factors, that]), verbo([mediate]), complemento([the, actions, of, the, thyroid, hormone, '(', 'T3)', in, 'development,', 'growth,', and, differentiation])].
[sujeto(['The', 'THRA', and, 'THRB', genes, encode, several, 'TR', isoforms, that]), verbo([express]), complemento([in, a, 'tissue-', and, 'development-dependent', manner])].
[sujeto(['In', the, past, 'decades,', a, significant, advance]), verbo([has]), complemento([been, made, in, the, understanding, of, 'TR', actions, in, maintaining, normal, cellular, functions])].
[sujeto(['The', reduced, expression, of, 'TRs', because, of, 'hypermethylation,', or, deletion, of, 'TR', genes]), verbo([found]), complemento([in, human, cancers, suggests, that, 'TRs', could, function, as, tumor, suppressors])].
[sujeto(['A', close, association, of, somatic, mutations, of, 'TRs', with, human, cancers, further, supports, the, notion, that, the]), verbo([loss]), complemento([of, normal, functions, of, 'TR', could, lead, to, uncontrolled, growth, and, loss, of, cell, differentiation])].
[sujeto(['In', line, with, the, findings, from, association, studies, in, human, 'cancers,', mice, deficient, in, total, functional, 'TRs', '(', 'Thra1(-/-)Thrb(-/-)', 'mice)', or, with, a]), verbo([targeted]), complemento([homozygous, mutation, of, the, 'Thrb', gene, '(', denoted, 'PV;', 'Thrb(PV/PV)', 'mice)', spontaneously, develop, metastatic, thyroid, carcinoma])].
[sujeto(['This', review, will, examine, the, evidence, learned, from, these, genetically, engineered, mice, that]), verbo([provided]), complemento([strong, evidence, to, support, the, critical, role, of, 'TRs', in, human, cancer])].
[sujeto(['Novel', mechanistic, insights, are, revealed, in, how, aberrant, 'TR', activities]), verbo([lead]), complemento([to, carcinogenesis])].
[sujeto(['Mouse', models, of, thyroid, cancer]), verbo([provide]), complemento([opportunities, to, identify, molecular, targets, as, potential, treatment, modalities])].
[sujeto(['Thyroid', hormone, is, critical, for, auditory, development, and]), verbo([has]), complemento(['well-known', actions, in, the, inner, ear])].
[sujeto(['During', the, later, stages, of, middle, ear, 'development,', prior, to, the, onset, of, 'hearing,', middle, ear, cavitation, 'occurs,']), verbo([involving]), complemento([clearance, of, mesenchyme, from, the, middle, ear, cavity, while, the, immature, cartilaginous, ossicles, attain, appropriate, size, and, ossify])].
[sujeto(['Thra(+/PV)', mice, that]), verbo([express]), complemento([a, 'dominant-negative', 'TRα1', protein, exhibited, deafness, with, elevated, auditory, thresholds, and, a, range, of, middle, ear, abnormalities, including, chronic, persistence, of, mesenchyme, in, the, middle, ear, into, 'adulthood,', markedly, enlarged, 'ossicles,', and, delayed, ossification, of, the, ossicles])].
[sujeto(['These', findings, demonstrate, that, middle, ear, maturation, is, 'TR', dependent, and]), verbo([suggest]), complemento([that, the, middle, ear, is, a, sensitive, target, for, thyroid, hormone, in, development])].
[sujeto(['The', present, article, reviews, the, evidence, that, 3, ',', 3, '\'', ',', 5, -, 'triiodo-L-thyronine']), verbo([regulates]), complemento([lipid, metabolism, via, thyroid, hormone, 'receptors,', focusing, particularly, on, 'in-vivo', findings, using, genetically, engineered, mice])].
[sujeto(['That', lipid, metabolism, is]), verbo([regulated]), complemento([via, thyroid, hormone, receptor, isoforms, in, a, 'tissue-dependent', manner, was, recently, uncovered, by, using, knockin, mutant, mice, harboring, an, identical, mutation, in, the, 'Thra', gene, '(', 'Thra1(PV)', 'mouse)', or, the, 'Thrb', gene, '(', 'Thrb(PV)', 'mouse)'])].
[sujeto(['The', mutation, in, the, 'Thra', gene, dramatically]), verbo([decreases]), complemento([the, mass, of, both, white, adipose, tissue, and, liver])].
[sujeto(['In', 'contrast,', the, mutation, in, the, 'Thrb', gene, markedly]), verbo([increases]), complemento([the, mass, of, liver, with, an, excess, depot, of, 'lipids,', but, no, significant, abnormality, is, observed, in, white, adipose, tissue])].
[sujeto(['Molecular', studies, show, that, the, expression, of, lipogenic, genes, is]), verbo([decreased]), complemento([in, white, adipose, tissue, of, 'Thra1(PV)', 'mice,', but, not, in, 'Thrb(PV)', mice])].
[sujeto(['Markedly']), verbo([increased]), complemento([lipogenic, enzyme, 'expression,', and, decreased, fatty, acid, 'beta-oxidation', activity, contribute, to, the, adipogenic, steatosis, and, lipid, accumulation, in, the, liver, of, 'Thrb(PV)', mice])].
[sujeto(['In', 'contrast,', reduced, expression, of, genes, critical, for, lipogenesis]), verbo([mediates]), complemento([decreased, liver, mass, with, lipid, scarcity, in, 'Thra1(PV)', mice])].
[sujeto(['Studies', using, 'Thra1(PV)', and, 'Thrb(PV)', mice, indicate, that, 'apo-thyroid', hormone, 'receptor-beta', and, 'apo-thyroid', hormone, 'receptor-alpha-1']), verbo([mediate]), complemento([distinct, deleterious, effects, on, lipid, metabolism])].
[sujeto(['Thus,', both, thyroid, hormone, receptor, isoforms, contribute, to, the, pathogenesis, of, lipid, abnormalities, in, 'hypothyroidism,', but, in, a]), verbo([target]), complemento(['tissue-dependent', manner])].
[sujeto(['These', studies]), verbo([suggest]), complemento([that, thyroid, hormone, receptor, 'isoform-specific', ligands, could, be, designed, as, therapeutic, targets, for, lipid, abnormalities])].
[sujeto(['Thyroid', hormone, '(', 'triiodothyronine,', 'T3)', is, a, pleiotropic, regulator, of, 'growth,', differentiation, and, tissue, homeostasis, in, higher, organisms, that]), verbo([acts]), complemento([through, the, control, of, target, gene, expression])].
[sujeto(['Most,', if, not, 'all,', major, 'T3', actions, are]), verbo([mediated]), complemento([by, specific, high, affinity, nuclear, receptors, '(', 'TR)', which, are, encoded, by, two, 'genes,', 'THRA', and, 'THRB'])].
[sujeto(['V-erbA']), verbo([causes]), complemento([erythroleukemias, and, sarcomas, in, 'birds,', and, hepatocellular, carcinomas, in, transgenic, mice])].
[sujeto(['In', recent, 'years,', many, studies]), verbo([have]), complemento([analyzed, the, presence, of, quantitative, '(', abnormal, 'levels)', or, qualitative, '(', 'mutations)', alterations, in, the, expression, of, 'THR', genes, in, different, types, of, human, neoplasias])].
[sujeto(['While', their, role, in, tumor, generation, or, progression, is, currently, 'unclear,', both, gross, chromosomal, and, minor, mutations, '(', 'deletions,', aberrant, 'splicing,', point, 'mutations)', and, changes, in, the, level, of, expression, of, 'THRA', and, 'THRB', genes]), verbo([have]), complemento([been, found])].
[sujeto(['Together', with, other, in, vitro, data, indicating, connections, between, 'TR', and, 'p53,', 'Rb,', cyclin, 'D', and, other, cell, cycle, regulators, and, 'oncogenes,', these, results]), verbo([suggest]), complemento([that, 'THRA', and, 'THRB', may, be, involved, in, human, cancer])].
[sujeto(['Allelic', imbalance, or]), verbo([loss]), complemento([of, heterozygosity, '(', 'LOH)', studies, have, been, used, extensively, to, identify, regions, on, chromosomes, that, may, contain, putative, tumour, suppressor, genes])].
[sujeto(['The', most, frequent, incidence, of, 'LOH', was]), verbo([found]), complemento([for, the, marker, 'THRA1', '(', 8, /, 33, ',', 24, '%', ')', indicating, that, thra, 'I', gene, becomes, a, strong, candidate, tumour, suppressor, 'gene,', whereas, of, 'MI', it, was, 'D10S109', '(', 3, /, 26, ',', 12, '%', ')'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'MI', may, be, an, early, event, in, mammary, tumorigenesis, whereas, 'LOH', occurs, at, a, late, stage])].
[sujeto(['The', thyroid, hormone, receptor, alpha, '(', 'THRA', or, 'c-erbA-1)', gene, belongs, to, a, family, of, genes, that, encode]), verbo([nuclear]), complemento([receptors, for, various, hydrophobic, ligands, such, as, 'steroids,', retinoic, acid, and, thyroid, hormones])].
[sujeto(['We']), verbo([have]), complemento([previously, described, the, genomic, organization, of, the, human, 'THRA', 'gene,', which, comprises, 10, exons, distributed, along, 27, kbp, of, genomic, 'DNA'])].
[sujeto(['The', activity, of, this, human, 'THRA', promoter, is]), verbo([enhanced]), complemento([by, the, synthetic, glucocorticoid, dexamethasone, but, seems, unaffected, by, thyroid, hormones])].
[sujeto(['The', 'thrA(1)1A(2)1', and, 'thrA(1)5A(2)5', mutations, of, 'threonine-excreting', strains, 'HNr21', and, 'TLr156,', which, result, in, the]), verbo([loss]), complemento([of, 'threonine-mediated', feedback, inhibition, of, both, 'AKI', activity, and, 'HDI', 'activity,', cause, single, amino, acid, substitutions, '(', 'Gly', to, 'Asp', at, position, 330, and, 'Ser', to, 'Phe', at, position, 352, ',', 'respectively)', in, the, central, region, of, the, 'AKI-HDI', protein])].
[sujeto(['The', 'thrA1+A(2)2', mutation, of, strain, 'HNr59,', which, results, in, a, 'threonine-sensitive', 'AKI', and, a, 'threonine-resistant', 'HDI,', also]), verbo([causes]), complemento([a, single, amino, acid, substitution, '(', 'Ala', to, 'Thr', at, position, 479, ')'])].
[sujeto(['The', thyroid, hormone, receptor, alpha, '(', 'THRA', or, 'c-erbA-1)', gene, belongs, to, a, family, of, genes, which, encode]), verbo([nuclear]), complemento([receptors, for, various, hydrophobic, ligands, such, as, 'steroids,', vitamin, 'D,', retinoic, acid, and, thyroid, hormones])].
[sujeto(['The', position, of, the, introns, in, human, 'THRA', is, highly]), verbo([conserved]), complemento([when, compared, to, the, chicken, gene, despite, their, differing, lengths])].
[sujeto(['In', 'addition,', we, confirm, that, another, 'gene,', belonging, to, the]), verbo([nuclear]), complemento([receptor, 'superfamily,', 'ear-1,', overlaps, with, the, 3, '\'', region, of, 'THRA', in, an, opposite, transcriptional, orientation])].
[sujeto(['However,', the, regulation, of, 'Bmal1']), verbo([has]), complemento([not, been, fully, understood])].
[sujeto(['A', series, of, 5, '\'', deletion, reporter, constructs, was, 'generated,', and]), verbo([binding]), complemento([site, mutations, of, mouse, 'Bmal1', promoter, fragments, were, cloned, into, 'pGL3-basic', and, 'pGL3(R2'])].
[sujeto(['DNA', affinity, precipitation, assay, was, used, to, detect, the, transcription, factors]), verbo([binding]), complemento([to, 'Bmal1', promoter])].
[sujeto(['Small', interfering, 'RNA', against]), verbo([nuclear]), complemento([factor, 'Y,', subunit, 'A', '(', 'NF-YA)', and, dominant, negative, 'NF-YA', were, employed, to, study, the, role, of, 'NF-Y', in, 'Bmal1', transcription, regulation])].
[sujeto(['Deletion', and, mutation, analyses, identified, two, clusters, of, 'CCAAT/GC-boxes', at, the, proximal, region, of, 'Bmal1', promoter, as, the]), verbo([activating]), complemento(['cis-elements'])].
[sujeto(['Bmal1', promoter, activity, was, 'up-regulated', by, 'NF-Y', 'and/or', 'Sp1', and]), verbo([repressed]), complemento([by, dominant, negative, 'NF-YA', or, siRNA, against, 'NF-YA'])].
[sujeto(['The', activation, of, 'Bmal1', promoter, activity, by, 'NF-Y', and, 'Sp1', was]), verbo([inhibited]), complemento([by, 'Rev-Erbα'])].
[sujeto(['DNA', affinity, precipitation, assay, showed, that, 'NF-Y', and, 'Sp1']), verbo([bound]), complemento([to, the, two, 'CCAAT/GC', clusters, of, 'Bmal1', promoter])].
[sujeto(['Our', aim, was, to, verify, whether, genetic, variability, in, 'NVP-metabolizing', cytochromes, or, in, transporter, genes, could, be]), verbo([involved]), complemento([in, susceptibility, to, 'SJS/TEN'])].
[sujeto(['CYP2B6', 'G516T', and, 'T983C', single, nucleotide, polymorphisms, '(', 'SNPs)', were]), verbo([found]), complemento([to, be, associated, with, 'SJS/TEN', susceptibility])].
[sujeto(['The', 983, 'C', allele, in, particular, was]), verbo([found]), complemento([to, be, highly, associated, with, a, higher, risk, to, develop, 'SJS/TEN', '[', odds, ratio, '(', 'OR)', 4.2, ',', 'P', =, 0.0047, ']'])].
[sujeto(['However,', to, 'date,', there, is, no, direct, evidence, of, circadian, clock, dysregulation, in, the, brains, of, patients, who]), verbo([have]), complemento(['MDD'])].
[sujeto(['Circadian', rhythmicity, of, gene, expression]), verbo([has]), complemento([been, observed, in, animals, and, peripheral, human, 'tissues,', but, its, presence, and, variability, in, the, human, brain, were, difficult, to, characterize])].
[sujeto(['The', description, of, its, breakdown, in, 'MDD']), verbo([suggests]), complemento([potentially, important, molecular, targets, for, treatment, of, mood, disorders])].
[sujeto(['To', identify, biologically, relevant, groupings, or, clusters, of]), verbo([nuclear]), complemento([receptors, '(', 'NR)', that, are, associated, with, breast, 'neoplasia,', with, potentially, 'diagnostic,', discriminant, or, prognostic, 'value,', we, quantitated, mRNA, expression, levels, of, all, 48, members, of, the, human, 'NR', superfamily, by, 'TaqMan', 'low-density', array, analysis, in, 116, curated, breast, tissue, 'samples,', including, 'pre-', and, postmenopausal, normal, breast, and, both, 'ERα(+)', and, 'ERα(-)', tumor, tissue])].
[sujeto(['In', 'addition,', we]), verbo([have]), complemento([determined, 'NR', levels, in, independent, cohorts, of, 'tamoxifen-treated', 'ERα(+)', and, 'ERα(-)', tissue, samples])].
[sujeto(['Third,', we]), verbo([find]), complemento([a, novel, negative, association, between, five, 'NR', '(', 'TRβ,', 'NUR77,', 'RORγ,', 'COUP-TFII,', and, 'LRH1)', and, histological, grade])].
[sujeto(['Cia5a', is, a, locus, on, rat, chromosome, 10, that]), verbo([regulates]), complemento([disease, severity, and, joint, damage, in, two, models, of, rheumatoid, 'arthritis,', 'collagen-', and, 'pristane-induced', arthritis, '(', 'PIA)'])].
[sujeto(['In', this, 'study,', we, aimed, to, identify, cellular, and, molecular, processes]), verbo([regulated]), complemento([by, 'Cia5a', using, 'microarray-based', gene, expression, analysis, of, synovial, tissues, from, 'MHC', identical, 'DA', '(', severe, erosive, 'disease)', and, 'DA'])].
[sujeto(['There', was, a, significantly]), verbo([increased]), complemento([expression, of, 'pro-inflammatory', mediators, such, as, 'Il1b', '(', 5, -, 'fold),', 'Il18', '(', 3.9, -, 'fold),', 'Cxcl1', '(', 10, -, 'fold),', 'Cxcl13', '(', 7.5, -, 'fold)', and, 'Ccl7', '(', 7.9, -, 'fold),', and, proteases, like, 'Mmp3', '(', 23, -, 'fold),', 'Mmp9', '(', 32, -, 'fold),', 'Mmp14', '(', 4.4, -, 'fold)', and, cathepsins, in, synovial, tissues, from, 'DA,', with, reciprocally, reduced, levels, in, congenics])].
[sujeto([mRNA, levels, of, 47, members, of, the, 'Spleen', 'Tyrosine', 'Kinase', '(', 'Syk)', pathway, were, significantly]), verbo([increased]), complemento([in, 'DA', synovial, tissues, compared, with, 'DA'])].
[sujeto(['F344(Cia5a),', and, included, 'Syk', '(', 5.4, -, 'fold),', 'Syk-activating', receptors, and]), verbo([interacting]), complemento(['proteins,', and, genes, regulated, by, 'Syk', such, as, 'NFkB,', and, 'NAPDH', oxidase, complex, genes])].
[sujeto(['Nuclear', receptors, '(', 'NR)', such, as, 'Rxrg,', 'Pparg', and, 'Rev-erba', were]), verbo([increased]), complemento([in, the, protected, 'congenics,', and, so, was, the, 'anti-inflammatory', 'NR-target', gene, 'Scd1', '(', 54, -, fold, 'increase)'])].
[sujeto(['Tnn', '(', 72, -, fold, 'decrease)', was, the, gene, most, significantly]), verbo([increased]), complemento([in, 'DA'])].
[sujeto(['Analyses', of, gene, expression, in, synovial, tissues, revealed, that, the, arthritis, severity, locus, 'Cia5a']), verbo([regulates]), complemento([the, expression, of, key, mediators, of, inflammation, and, joint, 'damage,', as, well, as, the, expression, of, members, of, the, 'Syk', pathway])].
[sujeto(['This', expression, pattern, correlates, with, disease, severity, and, joint, damage, and, along, with, the, gene, accounting, for, 'Cia5a', could, become, a, useful, biomarker, to, identify, patients, at]), verbo([increased]), complemento([risk, for, severe, and, erosive, disease])].
[sujeto(['The', identification, of, the, gene, accounting, for, 'Cia5a']), verbo([has]), complemento([the, potential, to, generate, a, new, and, important, target, for, therapy, and, prognosis])].
[sujeto(['Thyroxine', '(', 'T4)', injected, in, ovo, on, 'E9']), verbo([induces]), complemento([precocious, transparency, by, 'E12'])].
[sujeto(['The', present, study, was, conducted, to, determine, whether, corneal, cells, differentially]), verbo([express]), complemento([genes, for, 'T4', 'regulation,', keratan, sulfate, proteoglycan, '(', 'KSPG)', 'synthesis,', 'crystallins,', and, endothelial, cell, ion, transporters, during, transparency, development, and, whether, these, expressions, are, altered, when, 'E9', embryos, are, treated, with, 'T4'])].
[sujeto([mRNA, expressions, were, determined, by, 'real-time', 'PCR', using, cDNA, synthesized, from, 'whole-cell', 'RNA,', cells]), verbo([expressing]), complemento(['T4', receptor, mRNAs, assessed, by, in, situ, 'hybridization,', and, 'KS', disaccharide, sulfation, measured, by, electrospray, ionization, tandem, mass, spectrometry, '(', 'ESI-MS/MS)'])].
[sujeto(['All', corneal, layers]), verbo([expressed]), complemento(['T4', receptor, alpha, '(', 'THRA)', 'mRNA;', keratocytes, and, endothelial, cells, expressed, 'T4', receptor, beta, '(', 'THRB)', mRNA])].
[sujeto(['During', normal, 'development,', 'THRB', expression]), verbo([increased]), complemento([20, -, fold, from, 'E12', to, 'E20;', 'THRA', expression, remained, constant])].
[sujeto(['Expressions', of, most, genes]), verbo([involved]), complemento([in, 'KS', synthesis, increased, from, 'E9', to, 'E16,', and, then, decreased, from, 'E16', to, 'E20'])].
[sujeto(['From', 'E9', to, 'E20,', expressions, of, crystallin, genes, 'increased;', 'T4/3-deiodinase', 'DIII', '(', 'DIO3)']), verbo([increased]), complemento([10, -, 'fold;', and, 'sodium-potassium', 'ATPase', transporter, '(', 'ATP1A1),', 'sodium-bicarbonate', transporter, '(', 'NBC),', and, carbonic, anhydrase, 'II', '(', 'CA2)', increased, 5, -, to, 10, -, fold])].
[sujeto(['E9', 'T4', administration]), verbo([decreased]), complemento([corneal, thickness, by, 'E12;', increased, 'DIO3,', 'THRB,', and, 'CA2', expressions, 5, -, to, 20, -, 'fold;', decreased, 'KSPG', core, protein, genes, and, galactose, sulfotransferase, 'CHST1', expressions, 2, -, 'fold;', and, reduced, 'KS', 'disulfated/monosulfated', disaccharide, '(', 'DSD/MSD)', ratios])].
[sujeto(['Public', health, efforts, and, current, antiobesity, agents]), verbo([have]), complemento([not, controlled, the, increasing, epidemic, of, obesity])].
[sujeto(['Investigational', antiobesity, agents, consist, of, 1, ')', central, nervous, system, agents, that, affect, neurotransmitters, or, neural, ion, 'channels,', including, antidepressants, '(', 'bupropion),', selective, serotonin, 2, c, receptor, 'agonists,', antiseizure, agents, '(', 'topiramate,', 'zonisamide),', some, dopamine, 'antagonists,', and, 'cannabinoid-1', receptor, antagonists, '(', 'rimonabant);', 2, ')', 'leptin/insulin/central', nervous, system, pathway, 'agents,', including, leptin, 'analogues,', leptin, transport, 'and/or', leptin, receptor, 'promoters,', ciliary, neurotrophic, factor, '(', 'Axokine),', neuropeptide, 'Y', and, 'agouti-related', peptide, 'antagonists,', proopiomelanocortin, and, cocaine, and, amphetamine]), verbo([regulated]), complemento([transcript, 'promoters,', 'alpha-melanocyte-stimulating', hormone, 'analogues,', 'melanocortin-4', receptor, 'agonists,', and, agents, that, affect, insulin, 'metabolism/activity,', which, include, 'protein-tyrosine', 'phosphatase-1B', 'inhibitors,', peroxisome, proliferator, activated, 'receptor-gamma', receptor, 'antagonists,', 'short-acting', bromocriptine, '(', 'ergoset),', somatostatin, agonists, '(', 'octreotide),', and, 'adiponectin;', 3, ')', 'gastrointestinal-neural', pathway, 'agents,', including, those, that, increase, cholecystokinin, 'activity,', increase, 'glucagon-like', 'peptide-1', activity, '(', extendin, 4, ',', 'liraglutide,', dipeptidyl, peptidase, 'IV', 'inhibitors),', and, increase, protein, 'YY3-36', activity, and, those, that, decrease, ghrelin, 'activity,', as, well, as, amylin, analogues, '(', 'pramlintide);', 4, ')', agents, that, may, increase, resting, metabolic, rate, '(', &, 'quot;selective&quot;', 'beta-3', 'stimulators/agonist,', uncoupling, protein, 'homologues,', and, thyroid, receptor, 'agonists);', and, 5, ')', other, more, diverse, 'agents,', including, melanin, concentrating, hormone, 'antagonists,', phytostanol, 'analogues,', functional, 'oils,', 'P57,', amylase, 'inhibitors,', growth, hormone, 'fragments,', synthetic, analogues, of, dehydroepiandrosterone, 'sulfate,', antagonists, of, adipocyte, 11, 'B-hydroxysteroid', dehydrogenase, type, 1, 'activity,', 'corticotropin-releasing', hormone, 'agonists,', inhibitors, of, fatty, acid, 'synthesis,', carboxypeptidase, 'inhibitors,', 'indanones/indanols,', 'aminosterols,', and, other, gastrointestinal, lipase, inhibitors, '(', 'ATL962)'])].
[sujeto(['Thyroglobulin', '(', 'Tg),', the, thyroid, hormone, 'precursor,', is, a, major, protein, component, in, the, thyroid, gland, and, may]), verbo([have]), complemento([other, important, functions])].
[sujeto(['Here,', we, show, that, bovine, 'Tg']), verbo([inhibited]), complemento([125, 'I-labeled', transforming, growth, 'factor-beta1', '(', 125, 'I-TGF-beta1)', binding, to, 'cell-surface', 'TGF-beta', receptors, in, mink, lung, epithelial, cells, with, an, 'IC50', of, approximately, 300, nM])].
[sujeto([1, '%', 'SDS,', or, acidic, pH, '(', pH, 4, -, 5, ')', ',', 'Tg', exhibited, a, approximately, 5, -, 10, -, fold]), verbo([increase]), complemento([of, 125, 'I-TGF-beta1', binding, inhibitory, activity, with, 'IC50', of, approximately, 30, -, 60, nM])].
[sujeto(['After', 'DSS', 'activation,', 'Tg', possessed, 'TGF-beta', agonist, activity, and]), verbo([inhibited]), complemento(['DNA', synthesis, of, mink, lung, epithelial, cells, and, rat, thyroid, cells])].
[sujeto(['The']), verbo([activated]), complemento(['Tg', also, exerted, a, small, but, significant, 'TGF-beta', agonist, activity, in, transcriptional, activation, of, plasminogen, activator, 'inhibitor-1'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'Tg', possesses, an, authentic, 'TGF-beta', activity, which, can, be, induced, by, chemical, modifications, and, treatments, with, denaturing, agents, and, acidic, pH])].
[sujeto(['The', 'alpha-MHC', gene, is, under, positive, regulation, by, 3, ',', 5, ',', 3, '\'', -, 'triiodo-L-thyronine', '(', 'T3),', 'however,', the, mechanism, by, which, 'T3']), verbo([modulates]), complemento([its, transcription, is, not, clearly, understood])].
[sujeto(['We']), verbo([have]), complemento([used, an, 'avidin-biotin', complex, 'DNA', binding, assay, and, footprint, analysis, employing, dimethyl, sulfate, interference, and, hydroxyl, radical, protection, to, characterize, the, interaction, of, 'T3', receptors, with, target, sequences, located, in, the, 5, '\'', -, flanking, region, of, the, human, 'alpha-myosin', heavy, chain, '(', 'MHC)', gene])].
[sujeto(['The', results, indicate, that, liver, 'T3', receptors, and, in, vitro, 'transcribed-translated', beta, 'c-erbA']), verbo([bind]), complemento([with, high, affinity, to, a, site, '(', 'TRE1)', located, at, positions, -, 138, /, -, 158, base, pairs, upstream, from, the, 'CAP', site])].
[sujeto(['The', 'Kd', of, 'TRE1', for]), verbo([nuclear]), complemento([liver, 'T3', receptors, '(', 0.82, 'nM)', was, less, than, that, determined, for, the, rat, growth, hormone, gene, '(', 1.78, 'nM)'])].
[sujeto(['An', additional, site, '(', 'TRE2)', located, at, positions, -, 111, /, -, 129, was]), verbo([found]), complemento([which, bound, 'T3', receptors, with, considerably, lower, affinity, '(', 'Kd', =, 23, 'nM)'])].
[sujeto(['Methylation', interference, experiments, demonstrated, that, 'T3', receptors]), verbo([interact]), complemento([with, 'guanines,', in, 'TRE1', on, the, sense, and, antisense, 'strands,', within, two, octameric, imperfect, direct, repeats, '(', 'underlined)', 5, '\'', -, 'TCTGGAGGTGACAG-GAGGACA-3\'', '(', antisense, strand, 'sequence)', containing, the, consensus, sequence, 5, '\'', -, 'C(T/A)GGAGG(T/A)-3\''])].
[sujeto(['By', 'contrast,', methylation, interference, and, hydroxyl, radical, footprinting, demonstrate, that, the, 'T3']), verbo([binding]), complemento([element, of, 'TRE2', is, not, structurally, similar, to, 'TRE1', except, for, a, 'purine-rich', octameric, cluster, '(', 'underlined,', 5, '\'', -, 'ATCAAAGGAGGAGGAGCCA-3\')', containing, six, guanines, on, the, sense, strand])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, differences, in, nucleotide, sequences, involved, in, 'T3', 'receptor-DNA', complex, formation, determine, the, binding, affinities, of, 'TRE1', and, 'TRE2'])].
[sujeto(['Acute', promyelocytic, leukemia, '(', 'APL)', is, driven, by, the, promyelocytic, leukemia, '(', 'PML)-retinoic', acid, 'receptor-α', '(', 'PML-RARA)', fusion, 'protein,', which, interferes, with]), verbo([nuclear]), complemento([receptor, signaling, and, 'PML', nuclear, body, '(', 'NB)', assembly])].
[sujeto(['APL', is, the, only, malignancy, definitively, cured, by]), verbo([targeted]), complemento(['therapies:', retinoic, acid, '(', 'RA)', 'and/or', arsenic, 'trioxide,', which, both, trigger, 'PML-RARA', degradation, through, nonoverlapping, pathways])].
[sujeto(['We', demonstrate, that, a, functional, 'Pml-transformation-related', protein, 53, '(', 'Trp53)', axis, is]), verbo([required]), complemento([to, eradicate, 'leukemia-initiating', cells, in, a, mouse, model, of, 'APL'])].
[sujeto(['Upon', 'RA-induced', 'PML-RARA', 'degradation,', normal, 'Pml', elicits, 'NB', reformation, and]), verbo([induces]), complemento([a, 'Trp53', response, exhibiting, features, of, senescence, but, not, 'apoptosis,', ultimately, abrogating, 'APL-initiating', activity])].
[sujeto(['Apart', from]), verbo([triggering]), complemento(['PML-RARA', 'degradation,', arsenic, trioxide, also, targets, normal, 'PML', to, enhance, 'NB', 'reformation,', which, may, explain, its, clinical, 'potency,', alone, or, with, 'RA'])].
[sujeto(['Arsenic,', an, ancient, drug, used, in, traditional, 'Chinese', 'medicine,']), verbo([has]), complemento([attracted, worldwide, interest, because, it, shows, substantial, anticancer, activity, in, patients, with, acute, promyelocytic, leukemia, '(', 'APL)'])].
[sujeto(['Arsenic', trioxide, '(', 'As2O3)', exerts, its, therapeutic, effect, by]), verbo([promoting]), complemento([degradation, of, an, oncogenic, protein, that, drives, the, growth, of, 'APL', 'cells,', 'PML-RARalpha', '(', a, fusion, protein, containing, sequences, from, the, 'PML', zinc, finger, protein, and, retinoic, acid, receptor, 'alpha)'])].
[sujeto(['PML', and, 'PML-RARalpha', degradation, is]), verbo([triggered]), complemento([by, their, 'SUMOylation,', but, the, mechanism, by, which, 'As2O3', induces, this, posttranslational, modification, is, unclear])].
[sujeto(['Here', we, show, that, arsenic]), verbo([binds]), complemento([directly, to, cysteine, residues, in, zinc, fingers, located, within, the, 'RBCC', domain, of, 'PML-RARalpha', and, 'PML'])].
[sujeto(['Arsenic']), verbo([binding]), complemento([induces, 'PML', 'oligomerization,', which, increases, its, interaction, with, the, small, 'ubiquitin-like', protein, modifier, '(', 'SUMO)-conjugating', enzyme, 'UBC9,', resulting, in, enhanced, 'SUMOylation', and, degradation])].
[sujeto(['The', identification, of, 'PML', as, a, direct]), verbo([target]), complemento([of, 'As2O3', provides, new, insights, into, the, 'drug\'s', mechanism, of, action, and, its, specificity, for, 'APL'])].
[sujeto(['Patients', with, acute, promyelocytic, leukemia, '(', 'APML)', with, the, 't(11;17)', translocation, usually]), verbo([respond]), complemento([poorly, to, 'all-trans', retinoic, acid, '(', 'ATRA)', and, chemotherapy])].
[sujeto(['At', a, 'follow-up', of, 32, months, after, achieving, hematological, 'remission,']), verbo([he]), complemento([continues, to, remain, in, hematological, and, molecular, remission, with, normal, blood, parameters, and, negative, reverse, transcriptase, polymerase, chain, reaction, '(', 'RT-PCR)', results])].
[sujeto(['We']), verbo([have]), complemento([studied, the, interactions, of, the, 'v-Myb', and, retinoic, acid, receptor, proteins, which, have, opposing, effects, on, hematopoiesis])].
[sujeto(['While', 'v-myb']), verbo([acts]), complemento([as, a, transforming, oncogene, preventing, differentiation, of, monoblasts, to, 'macrophages,', 'RAR', alpha, functions, as, an, 'anti-oncogene', arresting, the, growth, of, 'v-myb-transformed', cells, and, allowing, their, final, myeloid, differentiation, steps, to, occur])].
[sujeto(['We']), verbo([found]), complemento([that, the, retinoic, acid, receptor, alpha, inhibits, 'v-Myb', transformation, by, suppressing, the, expression, of, 'v-Myb', target, genes, typified, by, the, 'mim-1', gene])].
[sujeto(['These', results, demonstrate, that, retinoic, acid, receptor, and, 'v-Myb', proteins]), verbo([act]), complemento([in, antagonistic, ways, and, reciprocally, modify, each, 'other\'s', functions])].
[sujeto(['In', 'APL', cells, with, 'PML/RARA', 'fusions,', arsenic, trioxide, and, 'all-trans', retinoic, acid, treatments, specifically]), verbo([target]), complemento([the, fusion, protein, for, 'proteasome-dependent', 'degradation,', thereby, promoting, cellular, differentiation, and, clinical, remission, of, disease])].
[sujeto(['In', 'contrast,', 'APL', cells]), verbo([expressing]), complemento(['PLZF/RARA', fusion, proteins, are, largely, resistant, to, similar, treatments, and, prognosis, for, patients, with, this, translocation, is, poor])].
[sujeto(['Understanding', the, molecular, mechanisms]), verbo([regulating]), complemento(['PLZF/RARA', protein, stability, would, provide, novel, therapeutic, targets, for, 'PLZF/RARA-associated', 'APL'])].
[sujeto(['Toward', this, 'end,', we]), verbo([have]), complemento([performed, an, 'RNAi-based', screen, to, identify, factors, affecting, 'PLZF/RARA', stability])].
[sujeto(['We', showed, that, 'USP37']), verbo([interacted]), complemento([with, 'PLZF/RARA', through, the, 'PLZF', moiety, and, sustained, 'PLZF/RARA', steady, state, levels])].
[sujeto(['Domain', mapping, study, revealed, that, 'N-terminal', domain, of, 'USP37', is]), verbo([required]), complemento([for, the, 'PLZF/RARA', interaction, and, protein, regulation])].
[sujeto(['Furthermore,', overexpression, or, depletion, of, 'USP37']), verbo([caused]), complemento([an, increase, or, decrease, of, 'PLZF/RARA', protein, 'half-life,', correlating, with, 'down-', or, upregulation, of, 'PLZF/RARA', 'poly-ubiquitination,', respectively])].
[sujeto(['By', 'PLZF/RARA-transduced', primary, mouse, hematopoietic, progenitor, 'cells,', we, demonstrated, that, 'Usp37', knockdown, alleviated, 'PLZF/RARA-mediated']), verbo([target]), complemento([gene, suppression, and, cell, transformation, potential])].
[sujeto(['Altogether,', our, findings, of, 'USP37-modulating', 'PLZF/RARA', stability, and, cell, transformation]), verbo([suggest]), complemento([that, 'USP37', is, a, potential, therapeutic, target, for, 'PLZF/RARA-associated', 'APL'])].
[sujeto(['Feeding', the, 'AIN93M', diet, to, adults]), verbo([increased]), complemento(['CA', frequency, over, 'NIH', 31, fed, mice])].
[sujeto(['Increased', follicular, dystrophy, was, seen, in, study, 1, and]), verbo([increased]), complemento([dermal, scars, in, study, 2, in, mice, fed, the, 28, 'IU', diet])].
[sujeto(['These', results, indicate, that, retinoid, metabolism, is, altered, in, 'CA', in, 'C57BL/6J', mice, that]), verbo([require]), complemento([precise, levels, of, dietary, vitamin, 'A'])].
[sujeto(['Many', retinoid, metabolism, proteins, were]), verbo([increased]), complemento([in, mild, 'CCCA,', but, were, undetectable, in, pseudopelade])].
[sujeto(['Studies', to, determine, whether, these, dietary, alterations, in, retinoid, metabolism, seen, in, 'C57BL/6J', mice, are, also]), verbo([involved]), complemento([in, different, types, of, human, 'CA', are, needed])].
[sujeto(['Although', the, skin, is]), verbo([involved]), complemento([in, half, of, the, reported, 'EMD', 'cases,', the, occurrence, of, cutaneous, promyelocytic, sarcoma, '(', 'PS)', has, been, described, very, rarely])].
[sujeto(['We']), verbo([report]), complemento([here, three, cases, of, 'PS', which, have, the, peculiarity, of, appearing, at, sites, of, punctures, for, arterial, and, venous, blood, and, marrow, samples, '(', sternal, 'manubrium,', antecubital, 'fossa,', wrist, over, the, radial, artery, 'pulse,', catheter, insertion, 'scar)'])].
[sujeto(['A', predilection, for, the, development, of, cutaneous, 'PS', at, sites, of, previous, vascular, damage]), verbo([has]), complemento([been, 'noted,', but, the, pathogenesis, remains, largely, unknown])].
[sujeto(['A', potential, role, for, 'all-trans', retinoic, acid]), verbo([has]), complemento([been, 'advocated,', although, one, of, the, three, patients, in, our, series, had, received, no, 'ATRA'])].
[sujeto(['A', review, of, the, literature, revealed, six, similar, cases, and, hyperleukocytosis, at, diagnosis, was, a, consistent]), verbo([finding]), complemento([in, all, of, them])].
[sujeto(['The']), verbo([nuclear]), complemento([retinoic, acid, '(', 'RA)', receptor, alpha, '(', 'RARalpha)', is, a, transcriptional, transregulator, that, controls, the, expression, of, specific, gene, subsets, through, binding, at, response, elements, and, dynamic, interactions, with, 'coregulators,', which, are, coordinated, by, the, ligand])].
[sujeto(['Here,', we, highlighted, a, novel, paradigm, in, which, the, transcription, of, 'RARalpha']), verbo([target]), complemento([genes, is, controlled, by, phosphorylation, cascades, initiated, by, the, rapid, 'RA', activation, of, the, 'p38MAPK/MSK1', pathway])].
[sujeto(['We', demonstrate, that, 'MSK1']), verbo([phosphorylates]), complemento(['RARalpha', at, 'S369', located, in, the, 'ligand-binding', 'domain,', allowing, the, binding, of, 'TFIIH', and, thereby, phosphorylation, of, the, 'N-terminal', domain, at, 'S77', by, 'cdk7/cyclin', 'H'])].
[sujeto(['MSK1', also]), verbo([phosphorylates]), complemento([histone, 'H3', at, 'S10'])].
[sujeto(['Finally,', the, phosphorylation, cascade, initiated, by, 'MSK1', controls, the, recruitment, of, 'RARalpha/TFIIH', complexes, to, response, elements, and, subsequently, 'RARalpha']), verbo([target]), complemento([gene, activation])].
[sujeto(['Cancer', cells, characterized, by, a, deregulated, 'p38MAPK/MSK1', 'pathway,', do, not]), verbo([respond]), complemento([to, 'RA,', outlining, the, essential, contribution, of, the, 'RA-triggered', phosphorylation, cascade, in, 'RA', signalling])].
[sujeto(['We']), verbo([provide]), complemento([evidence, of, a, 'cross-talk', between, nuclear, receptor, and, 'Ser/Thr', protein, phosphatases, and, show, that, vitamin, 'D', receptor, '(', 'VDR)', interacts, with, the, catalytic, subunit, of, protein, 'phosphatases,', 'PP1c', and, 'PP2Ac,', and, induces, their, enzymatic, activity, in, a, 'ligand-dependent', manner])].
[sujeto(['PP1c', specifically]), verbo([interacts]), complemento([with, 'VDR', but, not, retinoic, acid, receptor, alpha, and, retinoid, 'X', receptor, alpha, in, yeast])].
[sujeto(['Although', 'VDR-PP1c', and, 'VDR-PP2Ac', interaction, is, 'ligand-independent', in, 'vivo,', 1, 'alpha,25-dihydroxy-vitamin', 'D(3)']), verbo([induces]), complemento(['VDR-associated', phosphatase, activity])].
[sujeto(['Finally,', we, demonstrate, that, the, endogenous, 'VDR,', 'PP1c', or, 'PP2Ac,', and, 'p70(S6k)', are, present, in, a, ternary, complex, in, 'vivo,', and, the, interaction, of, 'p70(S6k)', with, the, 'VDR-PP', complex, is]), verbo([modulated]), complemento([by, the, phosphorylation, state, of, the, kinase])].
[sujeto(['Since', 'p70(S6k)', is, essential, for, 'G(1)-S', 'transition,', our, results]), verbo([provide]), complemento([a, molecular, basis, of, 1, 'alpha,25-dihydroxyvitamin', 'D(3)-induced', 'G(1)', block, in, colon, cancer, cells])].
[sujeto(['Differentiation', and, patterning, in, the, developing, nervous, system]), verbo([require]), complemento([the, vitamin, 'A', metabolite, 'all-trans-retinoic', acid, '(', 'atRA)'])].
[sujeto(['Recent', data]), verbo([suggest]), complemento([that, higher, cognitive, 'functions,', such, as, creation, of, hippocampal, 'memory,', also, require, atRA, and, its, 'receptors,', 'RAR,', through, affecting, synaptic, plasticity])].
[sujeto(['Here', we, show, that, within, 30, min, atRA]), verbo([increased]), complemento([dendritic, growth, approximately, 2, -, 'fold,', and, 'PSD-95', and, synaptophysin, puncta, intensity, approximately, 3, -, 'fold,', in, cultured, mouse, hippocampal, 'neurons,', suggesting, increased, synapse, formation])].
[sujeto([atRA, '(', 10, 'nM)']), verbo([increased]), complemento(['ERK1/2', phosphorylation, within, 10, min])].
[sujeto(['In', 'synaptoneurosomes,', atRA, rapidly]), verbo([increased]), complemento([phosphorylation, of, 'ERK1/2,', its, target, '4E-BP,', and, 'p70S6K,', and, its, 'substrate,', ribosome, protein, 'S6,', indicating, activation, of, 'MAPK', and, mammalian, target, of, rapamycin, '(', 'mTOR)'])].
[sujeto(['Prolonged', atRA, stimulation, reduced, 'surface/total', 'RARalpha', by, 43, '%', ',']), verbo([suggesting]), complemento(['internalization,', whereas, 'brain-derived', nerve, growth, factor, or, bicuculline, increased, the, ratio, by, approximately, 1.8, -, fold])].
[sujeto([atRA]), verbo([increased]), complemento([translation, in, the, somatodendritic, 'compartment,', similar, to, 'brain-derived', nerve, growth, factor])].
[sujeto([atRA, specifically]), verbo([increased]), complemento([dendritic, translation, and, surface, expression, of, the, 'alpha-amino-3-hydroxyl-5-methyl-4-isoxazole', propionate, receptor, '(', 'AMPAR)', subunit, 1, '(', 'GluR1),', without, affecting, 'GluR2'])].
[sujeto(['These', data]), verbo([provide]), complemento([mechanistic, insight, into, atRA, function, in, the, hippocampus, and, identify, a, unique, 'membrane-associated', 'RARalpha', that, mediates, rapid, induction, of, neuronal, translation, by, atRA])].
[sujeto(['In', the, present, study, epididymal, epithelium, was, immortalized, in, transgenic, mice, by]), verbo([expressing]), complemento([simian, virus, 40, 'T', antigen, under, a, 5.0, -, kb, mouse, glutathione, peroxidase, 5, promoter, '(', 'GPX5-Tag1)'])].
[sujeto(['Epididymal', tumorigenesis, was]), verbo([associated]), complemento([with, an, increase, in, 'c-Myc', 'expression,', and, a, marked, decrease, in, 'B-Myc', 'expression,', with, a, 500, -, fold, lower, level, in, the, 'GPX5-Tag1', caput, epididymis, compared, with, 'wild-type', caput])].
[sujeto(['Morphologically', different, epithelial, cell, lines, were, generated, from, the, immortalized, 'epididymides,', and, the, cells]), verbo([expressed]), complemento([several, genes, typical, for, epididymal, 'epithelium,', such, as, mouse, epididymal, 1, ',', mouse, epididymal, protein, 9, ',', androgen, and, estrogen, 'receptors,', anion, exchangers, 2, and, 4, ',', retinoic, acid, receptor, 'alpha,', and, polyoma, enhancer, activator, 3, '(', 'PEA3)'])].
[sujeto(['The', data, showed, that, 'PEA3', mRNA, expression, is]), verbo([regulated]), complemento([in, the, epididymis, via, protein, kinase, 'A', and, 'ERK', signaling, cascades])].
[sujeto(['Inhibiting', protein, kinase, 'A', resulted, in, 'up-regulation', and]), verbo([inhibiting]), complemento(['ERK', resulted, in, 'down-regulation', of, 'PEA3', 'mRNA,', whereas, no, significant, effect, on, 'PEA3', expression, was, found, by, modulating, the, protein, kinase, 'C,', 'stress-activated', 'p38,', phosphoinositol, 3, -, kinase, and, p70, 'S6', kinase, cascades])].
[sujeto(['MATERIAL', 'AND', 'METHODS', 'We', screened, a, 'kinase-specific', inhibitor, library, through, combining, it, with, 'α-Mangostin', in, 'NRAS', mutant, melanoma, cell, 'line,', and, verified, the]), verbo([enhancing]), complemento([effect, of, 'α-Mangostin', through, inhibition, of, the, tumorigenesis, pathway])].
[sujeto(['Colony', 'assay,', 'TUNEL', 'staining,', and, the, expressions, of, several, 'apoptosis-related', genes, revealed, that, 'a-Mangostin']), verbo([enhanced]), complemento([the, effect, of, retinoic, 'acid-induced', apoptosis])].
[sujeto(['Our', previous, studies]), verbo([have]), complemento([shown, that, vitamin, 'A', '(', 'VA)', status, is, associated, with, antiviral, immunity, and, pathogenic, conditions, in, enterovirus, 71, '(', 'EV71)-infected', children])].
[sujeto(['The', percentage, of, 'EV71-infected', cells, and, apoptosis]), verbo([induced]), complemento([by, 'EV71', were, determined, using, flow, cytometry])].
[sujeto(['Correspondingly,', 'ATRA']), verbo([increased]), complemento([the, production, of, 'IFN-α', one, of, the, most, important, antiviral, 'cytokines,', at, both, mRNA, and, protein, levels, in, 'EV71-infected', cells])].
[sujeto(['The', present, findings]), verbo([suggest]), complemento([that, 'ATRA', is, an, 'interferon-inducing', agent, with, antiviral, activity, against, 'EV71', in, vitro, and, that, its, actions, are, mediated, at, least, in, part, by, 'RAR-α', activity, and, the, 'RIG-I', signalling, pathway])].
[sujeto(['Vitamin', 'A', can, significantly]), verbo([decrease]), complemento(['measles-associated', morbidity, and, mortality])].
[sujeto(['Vitamin', 'A', can]), verbo([inhibit]), complemento([the, replication, of, measles, virus, '(', 'MeV)', in, vitro, through, an, 'RARα-', and, type, 'I', interferon, '(', 'IFN)-dependent', mechanism])].
[sujeto(['Retinoid-induced', gene, 'I', '(', 'RIG-I)', expression, is]), verbo([induced]), complemento([by, 'retinoids,', activated, by, 'MeV', 'RNA', and, is, important, for, 'IFN', signaling])].
[sujeto(['We', demonstrate, that, 'RIG-I', expression, is]), verbo([increased]), complemento([in, cells, treated, with, retinoids, and, infected, with, 'MeV'])].
[sujeto(['RAR-dependent', retinoid, signaling, was]), verbo([required]), complemento([for, the, induction, of, 'RIG-I', by, retinoids, and, 'MeV'])].
[sujeto(['Retinoid', signaling, was, also]), verbo([found]), complemento([to, act, in, combination, with, 'IFN', to, induce, high, levels, of, 'RIG-I', expression])].
[sujeto(['RIG-I', promoter, activation]), verbo([required]), complemento([both, retinoids, and, 'MeV,', as, indicated, by, markers, of, active, chromatin])].
[sujeto(['IRF-1', is, known, to, be]), verbo([regulated]), complemento([by, retinoids, and, 'MeV,', but, we, found, recruitment, of, 'IRF-1', to, the, 'RIG-I', promoter, by, retinoids, alone])].
[sujeto(['Using', luciferase, expression, 'constructs,', we, further, demonstrated, that, the, 'IRF-1', response, element, of, 'RIG-I', was]), verbo([required]), complemento([for, 'RIG-I', activation, by, retinoids, or, 'IFN'])].
[sujeto(['These', results]), verbo([reveal]), complemento([that, retinoid, treatment, and, 'MeV', infection, induces, significant, 'RIG-I'])].
[sujeto(['RIG-I', is]), verbo([required]), complemento([for, the, 'retinoid-MeV', antiviral, response])].
[sujeto(['All-trans', retinoic, acid, '(', 'ATRA)']), verbo([induces]), complemento([clinical, remission, in, patients, with, 't(15;17)', acute, promyelocytic, leukemia, '(', 'APL)', carrying, leukemogenic, promyelocytic, 'leukemia-retinoic', acid, receptor, alpha, '(', 'PML-RARalpha)', fusion, protein, by, overcoming, 'PML-RARalpha', transcriptional, repression, and, inducing, myeloid, differentiation])].
[sujeto(['In', the, absence, of, 'ATRA,', these, compounds, also]), verbo([induced]), complemento(['HL-60', and, murine, erythroleukemia, cells, to, undergo, partial, differentiation])].
[sujeto(['The', differentiation, effect, of, 'NSC656243', was]), verbo([associated]), complemento([with, enhanced, 'ATRA-mediated', 'up-regulation', of, cell, cycle, regulatory, proteins, p21waf1, and, 'p27kip1,', retinoblastoma, 'dephosphorylation,', expression, of, 'RIG-E', and, 'RIG-G,', and, myelomonocytic, 'differentiation-specific', 'down-regulation', of, the, myeloperoxidase, '(', 'MPO)', gene])].
[sujeto(['Moreover,', at, 2, -, to, 3, -, fold, higher, concentrations, than, those, used, to, synergize, with, 'ATRA,', 'NSC656243']), verbo([induced]), complemento([apoptosis, in, 'NB4-c', cells, by, reactive, oxygen, 'species-mediated', pathways])].
[sujeto(['Preferential']), verbo([binding]), complemento([to, the, lamina, rara, externa, '(', 'LRE)', was, documented, in, ultrastructure, by, preembedding, and, postembedding, assays, '(', 'HRP-coupled', antibody, and, protein, 'A-colloidal', 'gold,', 'respectively)'])].
[sujeto(['Non-cationized', 'Ig', aggregates, did, not]), verbo([bind]), complemento([to, the, glomerular, capillaries])].
[sujeto([after, 4, 'h)', produced, the, same, linear]), verbo([binding]), complemento([of, both, two, antigens, 'which,', 'however,', persisted, after, 10, days, and, assumed, a, granular, pattern])].
[sujeto([;, 4, days, before, 'cat-aggr', 'RIg)', the, early, linear, fixation, underwent, a, gradual, transformation, into, the, granular, pattern, and, deposits, of, 'mesangial,', rarely, of, epimembranous, type, were]), verbo([found]), complemento([1, week, after, 'cat-aggr', 'RIg', and, later])].
[sujeto(['The', antigen, load, did, not, produce, an, acute, glomerulonephritis, or, significant, 'proteinuria;', slight, focal, mesangial, sclerosis, and, a, discrete]), verbo([increase]), complemento([in, serum, creatinine, were, noted, after, 2, -, 3, months])].
[sujeto(['To', sum, 'up:', 'The', 'one-shot', charge, interaction, is, prompt, but, 'short-lived', whereas, the, local]), verbo([binding]), complemento([of, additional, 'proteins,', especially, after, a, specific, 'preimmunization,', significantly, prolongs, the, contamination, of, glomeruli, and, promotes, the, 'build-up', of, immune, 'complex-type', deposits, which, gradually, retreat, to, the, mesangial, stalk, and, vascular, pole])].
[sujeto(['During', follow, 'up,', the, patient, was]), verbo([found]), complemento([to, be, negative, for, the, 't(15;17)', transcript, after, 3, months, of, therapy, which, remained, 'undetectable,', thereafter])].
[sujeto(['All-trans-retinoic', acid, '(', 'ATRA)']), verbo([induces]), complemento([growth, 'inhibition,', 'differentiation,', and, apoptosis, in, cancer, 'cells,', including, acute, promyelocytic, leukemia, '(', 'APL)'])].
[sujeto(['In', 'APL,', expression, of, promyelocytic, leukemia, protein, retinoic, acid, 'receptor-alpha', '(', 'PML-RARalpha)', fusion, 'protein,', owing, to, the, 't(15;', 17, ')', reciprocal, 'translocation,']), verbo([leads]), complemento([to, a, block, in, the, promyelocytic, stage, of, differentiation])].
[sujeto(['Here,', we, studied, molecular, mechanisms]), verbo([involved]), complemento([in, 'ATRA-induced', growth, inhibition, and, myeloid, cell, differentiation, in, 'APL'])].
[sujeto(['By', employing, comprehensive, 'high-throughput', proteomic, methods, of, 2, -, dimensional, '(', 2, -, 'D)', gel, electrophoresis, and, amino, 'acid-coded', mass, tagging, coupled, with, electrospray, ionization, '(', 'ESI)', mass, 'spectrometry,', we, systematically, identified, a, total, of, 59, differentially]), verbo([expressed]), complemento([proteins, that, were, consistently, modulated, in, response, to, 'ATRA', treatment])].
[sujeto(['The', translational, inhibitor, 'DAP5/p97/NAT1', '(', 'death-associated', protein, 5, ')', and, 'PML', 'isoform-1', were]), verbo([found]), complemento([to, be, 'up-regulated', '(', 'P', &, 'lt;'])].
[sujeto(['Additionally,', the, 'down-regulation', of, heterogeneous]), verbo([nuclear]), complemento([ribonucleoproteins, '(', 'hnRNPs)', 'C1/C2,', 'UP2,', 'K,', and, 'F;', small, nuclear, 'RNPs', '(', 'snRNPs)', 'D3', and, 'E;', nucleoprotein, tumor, potentiating, region, '(', 'TPR);', and, protein, phosphatase, 2, 'A', '(', 'PP2A)', were, found, '(', 'P', &, 'lt;'])].
[sujeto([5, ')', ;, these, were]), verbo([found]), complemento([to, function, in, 'pre-mRNA', 'processing,', 'splicing,', and, export, events])].
[sujeto(['Our', data, in, comparison, with, previous, cDNA, microarray, studies, and, our, reverse, 'transcription-polymerase', chain, reaction, '(', 'RT-PCR)', experiments, demonstrate, that, broad, networks, of, posttranscriptional, suppressive, pathways, are]), verbo([activated]), complemento([during, 'ATRA-induced', growth, inhibition, processes, in, 'APL'])].
[sujeto(['In', gel, mobility, shift, 'assays,', heterodimers, of, retinoic, acid, receptor, alpha, '(', 'RARalpha)', and, retinoid, 'X', receptor, beta, '(', 'RXRbeta)']), verbo([bound]), complemento([specifically, to, this, element])].
[sujeto(['Neither', receptor, alone, was, able, to]), verbo([bind]), complemento([to, this, element, efficiently])].
[sujeto(['The', dissociation, constant, '(', 'Kd)', with, respect, to, 'RAR-RXR']), verbo([binding]), complemento([was, estimated, to, be, 8, nM])].
[sujeto(['The', 'IR0-containing', reporter, was]), verbo([induced]), complemento([by, 'RA', in, 'COS-1', cells, in, the, presence, of, exogenously, provided, 'RARalpha', and, 'RXRbeta'])].
[sujeto(['In', 'addition,', the, 'IR0', oligomers, could, be]), verbo([bound]), complemento([by, nuclear, extracts, isolated, from, 'COS-1', cells, harboring, the, expression, vectors, for, 'RARalpha', and, 'RXRbeta,', but, not, by, extracts, isolated, from, control, 'COS-1', cells])].
[sujeto(['RA', responsiveness, of, this, 'IR0', was, further, confirmed, in, 'P19', cells, that]), verbo([expressed]), complemento([endogenous, 'RARs', and, 'RXRs'])].
[sujeto(['Collectively,', these, data, 'demonstrated,', for, the, first, 'time,', the, presence, of, a, natural, 'RARE', of, the, 'IR0', 'type,', and]), verbo([suggested]), complemento([a, potential, 'cross-talk', between, nuclear, orphan, receptor, 'TR2-11', and, 'RAR-RXR', families])].
[sujeto(['HER2/neu', is]), verbo([associated]), complemento([with, poorer, clinical, outcome, in, breast, cancer])].
[sujeto(['GRB7', was, significantly, inversely]), verbo([associated]), complemento([with, improved, 'DFS', at, 60, months, '(', 'p=0'])].
[sujeto(['This', study, reaffirms, the, correlation, between, 'HER2/neu', and, the, 'co-localised', 'LASP1', and, 'GRB7;', the, latter]), verbo([target]), complemento([may, hold, additional, significance, in, addition, to, being, a, surrogate, marker, for, 'HER2/neu', expression])].
[sujeto(['The', relationship, identified, between, 'RARA', and, 'ER-positivity', may, herald, an, avenue, for]), verbo([targeted]), complemento([therapy, of, these, tumours])].
[sujeto(['The', growth]), verbo([arrest]), complemento([and, 'DNA', 'damage-inducible', 'protein,', 'GADD34,', associates, with, protein, phosphatase, 1, '(', 'PP1)', and, promotes, in, vitro, dephosphorylation, of, the, alpha, subunit, of, eukaryotic, translation, initiation, factor, 2, ',', '(', 'eIF-2', 'alpha)'])].
[sujeto(['In', this, 'report,', we, show, that, the, expression, of, human, 'GADD34', in, cultured, cells, reversed, 'eIF-2', alpha, phosphorylation]), verbo([induced]), complemento([by, thapsigargin, and, 'tunicamycin,', agents, that, promote, protein, unfolding, in, the, endoplasmic, reticulum, '(', 'ER)'])].
[sujeto(['GADD34', expression, also, reversed, 'eIF-2', alpha, phosphorylation]), verbo([induced]), complemento([by, okadaic, acid, but, not, that, induced, by, another, phosphatase, 'inhibitor,', calyculin, 'A', '(', 'CA),', which, is, a, result, consistent, with, 'PP1', being, a, component, of, the, 'GADD34-assembled', 'eIF-2', alpha, phosphatase])].
[sujeto(['Structure-function', studies, identified, a, bipartite, 'C-terminal', domain, in, 'GADD34', that, encompassed, a, canonical, 'PP1-binding', 'motif,', 'KVRF,', and, a, novel, 'RARA', 'sequence,', both, of, which, were]), verbo([required]), complemento([for, 'PP1', binding])].
[sujeto(['N-terminal', deletions, of, 'GADD34', established, that, while, 'PP1']), verbo([binding]), complemento([was, 'necessary,', it, was, not, sufficient, to, promote, 'eIF-2', alpha, dephosphorylation, in, cells])].
[sujeto(['Imaging', of, green, fluorescent, protein, '(', 'GFP)-GADD34', proteins, showed, that, the, 'N-terminal', 180, residues, directed, the, localization, of, 'GADD34', at, the, 'ER', and, that, 'GADD34']), verbo([targeted]), complemento([the, alpha, isoform, of, 'PP1', to, the, 'ER'])].
[sujeto(['These', data]), verbo([provide]), complemento([new, insights, into, the, mode, of, action, of, 'GADD34', in, assembling, an, 'ER-associated', 'eIF-2', alpha, phosphatase, that, regulates, protein, translation, in, mammalian, cells])].
[sujeto(['These', miRNAs]), verbo([have]), complemento([to, be, further, validated, and, the, role, of, these, miRNAs, in, the, molecular, function, level, of, thyroid, cancer, cell, lines, has, not, been, investigated])].
[sujeto(['Dual-luciferase', reporter, assay, was, used, to, determine, the, potential]), verbo([target]), complemento([of, 'miR-106a'])].
[sujeto(['The', results, of, 'dual-luciferase', reporter, assay, demonstrated, that, 'miR-106a', directly]), verbo([targeted]), complemento([retinoic, acid, receptor, beta, '(', 'RARB)', 3, '\'', -, 'UTR'])].
[sujeto(['miR-106a-RARB']), verbo([promoted]), complemento([viability, of, thyroid, cancer, cells, by, regulating, 'MEKK2-ERK1/2', and, 'MEKK2-ERK5', pathway])].
[sujeto(['miR-106a-RARB']), verbo([inhibited]), complemento([apoptosis, of, thyroid, cancer, cells, by, regulating, 'ASK1-p38', pathway])].
[sujeto(['Moreover,', 'miR-106a-RARB', could]), verbo([regulate]), complemento([the, expression, of, sodium, iodide, 'symporter,', 'TSH', receptor, and, alter, the, iodine, uptake, function, of, thyroid, cancer, cells])].
[sujeto(['miRNA-106a,', directly]), verbo([targeting]), complemento(['RARB,', associates, with, the, 'viability,', 'apoptosis,', differentiation, and, the, iodine, uptake, function, of, thyroid, cancer, cell, lines, by, regulating, 'MAPK', signaling, pathway, in, vitro])].
[sujeto(['These', findings, in, the, present, study, may]), verbo([provide]), complemento([new, strategies, for, the, diagnosis, and, treatment, in, 'radioiodine-refractory', differentiated, thyroid, carcinoma])].
[sujeto(['Retinoic', acid, is, a, promising, tool, in, adjuvant, cancer, 'therapies,', including, refractory, thyroid, 'cancer,', and, its, biological, role, is]), verbo([mediated]), complemento([by, the, retinoic, acid, receptor, beta, '(', 'RARβ)'])].
[sujeto(['The']), verbo([causes]), complemento([of, aberrant, 'RARB', expression, are, largely, unknown])].
[sujeto(['To', test, this, 'hypothesis,', we, assessed, the, expression, of, 'RARB', as, well, as, 'miR-146a-5p', and, 'miR-146b-5p', in, 48, 'PTC', 'tumor/normal', tissue, pairs, by, 'Taqman', assay, to]), verbo([reveal]), complemento([that, the, expression, of, 'RARB', was, 3.28, -, fold, 'decreased,', and, 'miR-146b-5p', was, 28.9, -, fold, increased, in, 'PTC', tumors])].
[sujeto(['Direct', interaction, between, miRs, and, 'RARB', was, determined, in, the, luciferase, assay, and, further, confirmed, in, cell, 'lines,', where, overexpression, of, 'miR-146a-5p', and, 'miR-146b-5p']), verbo([caused]), complemento([a, 31, '%', and, 33, '%', decrease, in, endogenous, 'RARB', mRNA, levels])].
[sujeto(['Inhibition', of, 'miR-146a', and, 'miR-146b', resulted, in, 62.5, '%', and, 45.4, '%']), verbo([increase]), complemento([of, 'RARB,', 'respectively,', and, a, concomitant, decrease, in, proliferation, rates, of, thyroid, cancer, cell, 'lines,', analyzed, in, xCELLigence, system])].
[sujeto(['We', showed, that, two, microRNAs, of, the, 'miR-146', family, directly]), verbo([regulate]), complemento(['RARB'])].
[sujeto(['Inhibition', of, miRs, resulted, in, restoration, of, 'RARB', expression, and]), verbo([decreased]), complemento([rates, of, proliferation, of, thyroid, cancer, cells])].
[sujeto(['In', 'Rarb(-/-)', 'knock-out', 'mice,', concomitant, reduction, of, 'Gad65,', dopamine, receptor, 'D1', '(', 'Drd1),', and, substance, 'P', expression, at, different, phases, of, prenatal, development, was]), verbo([associated]), complemento([with, reduced, number, of, 'Drd1-positive', cells, at, 'birth,', in, contrast, to, normal, numbers, of, striatopallidal, projection, neurons, expressing, dopamine, receptor, 'D2'])].
[sujeto(['Fate', mapping, using, 'BrdU', 'pulse-chase', experiments, revealed, that, such, deficits, may, originate, from, compromised, proliferation, of, 'late-born', striosomal, neurons, and]), verbo([lead]), complemento([to, decreased, number, of, 'Drd1-positive', cells, retaining, 'BrdU', in, postnatal, day, '(', 'P)', 0, 'Rarb(-/-)', striatum])].
[sujeto(['Reduced', expression, of, 'Fgf3', in, the, subventricular, zone, of, the, lateral, ganglionic, eminence, '(', 'LGE)', at, embryonic, day, 13.5, may, underlie, such, deficits, by]), verbo([inducing]), complemento([premature, differentiation, of, neuronal, 'progenitors,', as, illustrated, by, reduced, expression, of, the, proneural, gene, 'Ascl1', '(', 'Mash1)', and, increased, expression, of, 'Meis1,', a, marker, of, postmitotic, 'LGE', neurons])].
[sujeto(['In', agreement, with, a, critical, role, of, 'FGF3', in, this, 'control,', reduced, number, of, 'Ascl1-expressing', neural, 'progenitors,', and, a, concomitant]), verbo([increase]), complemento([of, 'Meis1-expressing', 'cells,', were, observed, in, primary, cell, cultures, of, 'Rarb(-/-)', 'LGE'])].
[sujeto(['Our', data, unveil, a, novel, mechanism, of, development, of, striatonigral, projection, neurons]), verbo([involving]), complemento([retinoic, acid, and, 'FGF,', two, signals, required, for, positioning, the, boundaries, of, 'Meis1-expressing', cells])].
[sujeto(['Previous', studies]), verbo([have]), complemento([shown, that, there, are, more, than, 1000, genes, likely, involved, in, 'ASD,', expressed, mainly, in, brain, and, highly, interconnected, among, them])].
[sujeto(['Two', missense, novel, 'SNVs', were]), verbo([found]), complemento([in, the, same, 'child:', 'ALDH1A3', '(', 'RefSeq', 'NM_000693:', c])].
[sujeto(['Gene', expression, studies]), verbo([reveal]), complemento([that, 'Aldh1a3', and, 'Foxn1', are, expressed, in, '~E13'])].
[sujeto(['Chromatin', immunoprecipitation, '(', 'ChIP)', assay, using, 'Retinoid', 'Acid', 'Receptor', 'B', '(', 'Rarb)', as, the, immunoprecipitation]), verbo([target]), complemento([suggests, 'RA', regulation, of, 'Aldh1a3', and, 'Foxn1', in, mice])].
[sujeto(['Our', results, frame, a, possible, link, of, 'RA', regulation, in, brain, to, 'ASD', 'etiology,', and, a, feasible, 'non-additive', effect, of, two, apparently, unrelated, variants, in, 'ALDH1A3', and, 'FOXN1']), verbo([recognizing]), complemento([that, every, result, given, by, next, generation, sequencing, should, be, cautiously, 'analyzed,', as, it, might, be, an, incidental, finding])].
[sujeto(['The', human, papillomavirus, type, 16, '(', 'HPV16)', 'E7', oncoprotein, alters, several, cellular, 'processes,']), verbo([regulating]), complemento([the, expression, of, many, genes, in, order, to, avoid, cell, cycle, control])].
[sujeto(['Retinoic', acid, receptor, beta, '(', 'RARB)', blocks, cell, 'growth,']), verbo([inducing]), complemento([differentiation, and, apoptosis])].
[sujeto(['We']), verbo([found]), complemento([that, 'HPV16', 'E7', increases, 'RARB', mRNA, and, 'RAR-beta', protein, expression, both, in, vitro, and, in, the, cervix, of, young, 'K14E7', transgenic, mice])].
[sujeto(['In', 'E7-expressing', 'cells,', 'RARB', overexpression, is, further]), verbo([increased]), complemento([in, the, presence, of, the, tumor, suppressor, p53, '(', 'TP53)', 'R273C', mutant])].
[sujeto(['This', effect, does, not, change, when, either, 'C33-A', or, 'E7-expressing', 'C33-A', cell, line, is, treated, with, 'Trichostatin', 'A,']), verbo([suggesting]), complemento([that, 'E7', enhances, 'RARB', expression, independently, of, histone, deacetylases, inhibition])].
[sujeto(['These', findings, indicate, that, 'RARB', overexpression, is, part, of, the, early, molecular, events]), verbo([induced]), complemento([by, the, 'E7', oncoprotein])].
[sujeto(['Microarray', expression, profiling, of, normal, versus, starved, 'H295R', cells, revealed, fourteen, differentially]), verbo([expressed]), complemento(['genes;', 'HSD3B2,', 'HSD3B1,', 'CYP21A2,', 'RARB,', 'ASS1,', 'CFI,', 'ASCL1', and, 'ENC1', play, a, role, in, steroid, and, energy, metabolism, and, 'ANGPTL1,', 'PLK2,', 'DUSP6,', 'DUSP10', and, 'FREM2', are, involved, in, signal, transduction])].
[sujeto(['We', discovered, two, new, gene, networks, around, 'RARB', and, 'ANGPTL1,', and, show, how, they]), verbo([regulate]), complemento([androgen, biosynthesis])].
[sujeto(['Transcription', factor, 'RARB']), verbo([stimulated]), complemento([the, promoters, of, genes, involved, in, androgen, production, '(', 'StAR,', 'CYP17A1', and, 'HSD3B2)', and, enhanced, androstenedione, production])].
[sujeto(['Secretory', protein, 'ANGPTL1']), verbo([modulated]), complemento(['CYP17A1', and, 'DUSP6', expression, by, inducing, 'ERK1/2', phosphorylation])].
[sujeto(['By', 'contrast,', our, studies, revealed, no, evidence, for, hormones, or, cell, cycle, involvement, in]), verbo([regulating]), complemento([androgen, biosynthesis])].
[sujeto(['Expression', levels, of, the, genes, were]), verbo([associated]), complemento([with, the, unmethylated, status, of, related, promoters, '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['The', crude, dietary, folate, and, adjusted, cobalamin, intakes, were, inversely]), verbo([associated]), complemento([with, methylated, 'RARB', and, 'BRCA1'])].
[sujeto(['Although', high, folate, intake]), verbo([increased]), complemento([the, chance, of, 'unmethylation-dependent', overexpression, of, 'BRCA1', 3, -, 'fold,', cobalamin, and, methionine, were, inversely, linked, to, 'methylation-mediated', expression])].
[sujeto(['These', findings]), verbo([provide]), complemento([new, insights, into, and, a, basic, understanding, of, the, selective, contributions, of, individual, 'B', vitamins, on, hypermethylation, and, 'methylation-related', expression, of, 'RARB', and, 'BRCA1', in, 'BC'])].
[sujeto(['Hypermethylation', at, promoters, of, 'RARB,', 'BRCA1,', and, 'RASSF1A', is]), verbo([associated]), complemento([with, reduced, transcript, levels, of, the, respective, gene, in, primary, breast, cancer, tissue, samples])].
[sujeto(['Dietary', folate, and, cobalamin, intake, is, inversely]), verbo([associated]), complemento([with, methylated, 'RARB', and, 'BRCA1'])].
[sujeto(['High', dietary, intake, of, riboflavin, and, pyridoxine, is]), verbo([associated]), complemento([with, increased, methylation, in, the, 'RARB', promoter])].
[sujeto(['Programmed', cell, death, during, chicken, ciliary, ganglion, '(', 'CG)', development, is, mostly, discussed, as, an, extrinsically]), verbo([regulated]), complemento(['process,', guided, either, by, the, establishment, of, a, functional, balance, between, preganglionic, and, postganglionic, activity, or, the, availability, of, 'target-derived', neurotrophic, factors])].
[sujeto(['We']), verbo([found]), complemento([that, the, expression, of, the, gene, coding, for, the, nuclear, retinoic, acid, receptor, β, '(', 'RARB)', is, transiently, upregulated, prior, to, and, during, the, execution, phase, of, cell, death, in, the, 'CG'])].
[sujeto(['The', knockdown]), verbo([led]), complemento([to, a, significant, increase, in, 'CG', neuron, number, after, the, cell, death, phase])].
[sujeto(['BrdU', injections, and, active, 'caspase-3', staining, revealed, that, this]), verbo([increase]), complemento([in, neuron, number, was, due, to, an, inhibition, of, apoptosis, during, the, normal, cell, death, phase])].
[sujeto(['Furthermore,', apoptotic, neuron, numbers, were, significantly]), verbo([increased]), complemento([at, a, stage, when, cell, death, is, normally, completed])].
[sujeto(['The', availability, of]), verbo([nuclear]), complemento([retinoic, acid, receptor, β, '(', 'RARβ)', and, 'RARβ-induced', transcription, of, genes, could, therefore, be, a, new, intrinsic, cue, for, the, maturation, of, 'CG', neurons, and, their, predisposition, to, undergo, cell, death])].
[sujeto(['Retinoic', acid, receptor, β, '(', 'RARβ)']), verbo([has]), complemento([been, proposed, to, act, as, a, tumor, suppressor, in, breast, cancer])].
[sujeto(['In', 'contrast,', recent, data]), verbo([have]), complemento([shown, that, 'RARβ', promotes, 'ERBB2-induced', mammary, gland, tumorigenesis, through, remodeling, of, the, stromal, compartment, and, activation, of, 'cancer-associated', fibroblasts])].
[sujeto(['We']), verbo([found]), complemento([that, compared, with, wild, type, 'mice,', inactivation, of, 'Rarb', resulted, in, a, lengthy, delay, in, 'Wnt1-induced', mammary, gland, tumorigenesis, and, in, a, significantly, slower, tumor, growth, rate])].
[sujeto(['Ablation', of, 'Rarb', altered, the, composition, of, the, 'stroma,']), verbo([repressed]), complemento([the, activation, of, 'cancer-associated', 'fibroblasts,', and, reduced, the, recruitment, of, inflammatory, cells, and, angiogenesis])].
[sujeto(['Our', results, show, 'that,', in, the, absence, of, retinoid, signaling, via, 'RARβ,', reduced, 'IGF-1', signaling, results, in, suppression, of, 'epithelial-mesenchymal', transition, and, delays, tumorigenesis]), verbo([induced]), complemento([by, the, 'Wnt1', oncogene])].
[sujeto(['Accordingly,', our, work, reinforces, the, concept, that, antagonizing, 'RARβ-dependent', retinoid, signaling, could]), verbo([provide]), complemento([a, therapeutic, avenue, to, treat, poor, outcome, breast, cancers])].
[sujeto(['DNA', hypermethylation, is, a, frequent, alteration, in, 'PCa,', but, interfocal, heterogeneity, of, these, changes]), verbo([has]), complemento([not, been, extensively, investigated])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, 'PCa', tissue, is, 'heterogeneous,', as, between, paired, foci, differences, in, 'DNA', methylation, status, were, found])].
[sujeto(['Therefore,', we, established, an, 'OSCC']), verbo([induced]), complemento([mouse, model, by, 4, -, 'nitroquinoline-1-oxide', '(', 4, -, 'NQO),', or, 'arecoline,', or, both, 'treatments,', respectively])].
[sujeto(['These', are, the, main, two, components, of, the, areca, nut, that, could]), verbo([increase]), complemento([the, occurrence, of, 'OSCC'])].
[sujeto(['We', examined, the, effects, with, the, noncommercial, 'MCGI', '(', mouse, 'CpG', 'islands)', microarray, for, 'genome-wide', screening, the, 'DNA', methylation, aberrant, in]), verbo([induced]), complemento(['OSCC', mice])].
[sujeto(['The', microarray, results, showed, 34, hypermethylated, genes, in, 4, -, 'NQO', plus, arecoline]), verbo([induced]), complemento(['OSCC', mice, tongue, tissues])].
[sujeto(['These', results, showed, that, retinoic, acid, receptor, β, '(', 'RARB)', was, indicated, in, hypermethylation, at, the, promoter, region, and, the]), verbo([loss]), complemento([of, expression, during, cancer, development])].
[sujeto(['According', to, the, results, of, 'real-time', 'PCR,', it, was, shown, that, de, novo, 'DNA', methyltransferases, were]), verbo([involved]), complemento([in, gene, epigenetic, alternations, of, 'OSCC'])].
[sujeto(['Collectively,', our, results, showed, that, 'RARB', hypermethylation, was]), verbo([involved]), complemento([in, the, 'areca-associated', oral, carcinogenesis])].
[sujeto([miRNAs, are, short, 'non-coding', 'RNAs', which, function, as, oncogenes, or, tumour, suppressor, gene, and]), verbo([regulate]), complemento([gene, expression, by, controlling, targets, that, play, role, in, cancer, development, and, progression])].
[sujeto(['Numerous', recent, studies]), verbo([have]), complemento([established, an, association, of, abnormal, expression, of, miRNA, with, cervical, cancer, progression])].
[sujeto(['Although', the, number, of]), verbo([reported]), complemento([deregulated, miRNA, in, cervical, cancer, is, 'increasing,', only, a, few, associations, between, miRNA, and, their, targets, have, been, studied, in, cervical, cancer])].
[sujeto(['Therefore,', we, performed, a, systematic, analysis, of, known, dysregulated, miRNAs]), verbo([involved]), complemento([in, cervical, cancer, so, as, to, identify, critical, miRNA, targets, that, could, pave, way, for, therapeutic, solutions])].
[sujeto(['In', this, 'study,', miRNAs]), verbo([reported]), complemento([to, be, dysregulated, in, cervical, cancer, were, collected, and, their, targets, predicted, using, 'TargetScan,', 'PicTar', and, miRanda])].
[sujeto(['These']), verbo([targets]), complemento([were, subsequently, compared, with, previously, curated, gene, dataset, involved, in, cervical, cancer, to, derive, the, putative, target, dataset])].
[sujeto(['Based', on, the, topological, properties, genes, were, ranked, and, observed, that, the, gene]), verbo([targets]), complemento(['BIRC5', '(', 'survivin),', 'HOXA1', and, 'RARB', presenting, with, high, 'Novoseek', score, of, 'Genecards', were, enriched, in, cervical, cancer])].
[sujeto(['BIRC5', is, an, 'anti-', apoptotic, protein, while, 'HOXA1', and, 'RARB', are, transcription, factors, which, play, critical, role, in, altering, the, level, of, cell, cycle, and, apoptosis]), verbo([associated]), complemento([proteins])].
[sujeto(['Also,', 'miRNA-mRNA', network, was, constructed, and, it, was]), verbo([found]), complemento([that, 'miR-203', and, 'miR-30b', could, target, these, genes])].
[sujeto(['The', analysis, indicates, that, the, genes, 'BIRC5,', 'HOXA1', and, 'RARB', are, critical]), verbo([targets]), complemento([that, play, an, important, regulatory, role, in, cervical, cancer, pathogenesis])].
[sujeto(['Prostate', cancer, '(', 'PCa)', is, the, most, frequently, diagnosed, 'non-cutaneous', cancer, that]), verbo([has]), complemento([become, the, sixth, leading, cause, of, mortality, in, both, the, developed, and, developing, countries])].
[sujeto(['Methylation', of, the, retinoic, acid, receptor, β, 'gene,', 'RARB,', and, that, of, the, checkpoint, with, forkhead, and, ring, finger, 'gene,', 'CHFR,', was]), verbo([associated]), complemento([with, tumour, stage, '(', 'RARB:', 51, '·9', per, cent, for, 'T1-2', versus, 33, '·9', per, cent, for, 'T3-4,', 'P', &, 'lt;', 0, '·001;', 'CHFR:', 5, '·5', per, cent, for, 'T1-2', versus, 12, '·6', per, cent, for, 'T3-4,', 'P', =, 0, '·005)'])].
[sujeto(['Gene', methylation]), verbo([associated]), complemento([with, nodal, metastasis, included, 'RARB', '(', 47, '·1', per, cent, for, 'N-', versus, 31, '·7', per, cent, for, 'N+;', 'P', =, 0, '·008),', chemokine, ligand, 12, ',', 'CXCL12', '(', 12, '·3', per, cent, for, 'N-', versus, 8, '·9', per, cent, for, 'N+;', 'P', =, 0, '·021),', and, 'death-associated', protein, kinase, 1, ',', 'DAPK1', '(', 19, '·3', per, cent, for, 'N-', versus, 12, '·3', per, cent, for, 'N+;', 'P', =, 0, '·022)'])].
[sujeto(['RARB', methylation, was, also]), verbo([associated]), complemento([with, 'LVI', '(', 45, '·1', per, cent, for, 'LVI-', versus, 31, '·7', per, cent, for, 'LVI+;', 'P', =, 0, '·038)'])].
[sujeto(['This', methylation, biomarker, panel]), verbo([provides]), complemento([a, step, towards, accurate, discrimination, of, indolent, and, aggressive, rectal, cancer, subtypes])].
[sujeto(['Our', results, indicate, that, multiple, 'SNPs', from, genes]), verbo([involved]), complemento([in, cell, 'adhesion,', viral, 'attachment,', and, viral, 'entry,', as, well, as, others, in, genes, involved, in, signaling, 'and/or', immune, response, 'regulation,', play, a, role, in, modulating, humoral, immune, responses, following, live, rubella, vaccination])].
[sujeto(['All', three, genes, were, previously]), verbo([reported]), complemento([as, the, most, promising, 'mRNA-based', markers, for, distinguishing, cancerous, lesions, from, benign, prostate, 'lesions;', 'however,', none, were, sufficiently, sensitive, and, specific, to, meet, the, criteria, for, a, 'PCa', diagnostic, biomarker])].
[sujeto(['Usually', described, as, mutually, 'exclusive,', this, statement, is, today, controversial, and, recent, in, vitro, studies]), verbo([suggest]), complemento([the, 'co-existence', of, both, repressor, systems])].
[sujeto(['We']), verbo([found]), complemento([that, the, 'RARβ', promoter, is, hypermethylated, in, all, studied, prostate, tumors, and, methylation, levels, are, positively, correlated, with, 'H3K27me3', enrichments])].
[sujeto(['We']), verbo([found]), complemento([this, repressive, association, in, 6, /, 6, patient, tumor, samples, of, different, 'Gleason', 'score,', suggesting, a, strong, interplay, of, 'DNA', methylation, and, 'EZH2', to, silence, 'RARβ', during, prostate, tumorigenesis])].
[sujeto(['Recently,', aside, from, 'PRNP,', single, nucleotide, polymorphisms, '(', 'SNPs)', of, two, candidate, genes, for, susceptibility, to, human, prion, diseases]), verbo([have]), complemento([been, identified, by, human, 'genome-wide', association, studies, '(', 'GWAS)', in, the, 'British', population])].
[sujeto(['One', 'SNP', of, retinoic, acid, receptor, beta, '(', 'RARB),', which, is, correlated, with, prion, disease, incubation, time, in, 'mice,', was]), verbo([associated]), complemento([with, human, prion, diseases, such, as, variant, and, iatrogenic, 'CJD', in, the, 'British', population])].
[sujeto(['The', other, 'SNP', of, the, gene, that, encodes, 'SCG10', '(', 'STMN2),', which, is, related, to, clinical, onset, of, sporadic, 'CJD,', was, also]), verbo([associated]), complemento([with, variant, 'CJD', and, kuru])].
[sujeto(['In', order, to, investigate, whether, two, polymorphisms, located, in, upstream, of, 'RARB', and, 'STMN2', are]), verbo([associated]), complemento([with, sporadic, 'CJD', in, the, 'Korean', 'population,', we, compared, genotype, and, allele, frequencies, of, these, polymorphisms, in, 217, sporadic, 'CJD', patients, and, 216, healthy, 'Koreans'])].
[sujeto(['This']), verbo([finding]), complemento([indicates, that, the, two, 'SNPs', are, not, correlated, with, genetic, susceptibility, to, sporadic, 'CJD', in, the, 'Korean', population])].
[sujeto(['Recent']), verbo([reports]), complemento([have, demonstrated, that, loss, of, 'RARβ', expression, may, be, 'responsible,', in, 'part,', for, the, drug, resistance, observed, in, clinical, trials])].
[sujeto(['However,', little, is, known, about, the, role, of, 'RARβ', in]), verbo([regulating]), complemento([drug, sensitivity, in, patients, with, cholangiocarcinoma, '(', 'CCA)', with, a, high, risk, of, mortality, and, poor, outcomes])].
[sujeto(['In', 'addition,', the, 'CCA', cell, line, 'QBC939,', which, exhibits, low, 'RARβ', 'expression,', was]), verbo([found]), complemento([to, be, significantly, resistant, to, chemotherapeutic, agents, compared, with, 'SK&#8209;ChA&#8209;1,', 'MZ&#8209;ChA&#8209;1', and, 'Hccc9810', 'CCA', cell, 'lines,', which, exhibit, high, 'RARβ', expression])].
[sujeto(['Furthermore,', upregulation, of, 'RARβ', significantly]), verbo([enhanced]), complemento([the, sensitivity, of, 'QBC939', cells, to, common, chemotherapeutic, agents, both, 'in&nbsp;vitro', and, 'in&nbsp;vivo'])].
[sujeto(['Upregulation', of, 'RARβ', was, shown, to]), verbo([increase]), complemento([the, expression, of, proapoptotic, genes, 'bax,', bak, and, 'bim,', in, addition, to, 'caspase&#8209;3', 'activity,', and, decrease, the, expression, of, antiapoptotic, genes, 'bcl&#8209;2,', 'bcl&#8209;xL', and, 'mcl&#8209;1'])].
[sujeto(['Taken', 'together,', these, data]), verbo([suggest]), complemento([that, 'RARβ', upregulation, rendered, 'CCA', cells, more, sensitive, to, chemotherapeutic, agents, by, increasing, the, susceptibility, of, cells, to, 'caspase-dependent', apoptosis])].
[sujeto(['These', results, support, the, hypothesis, that, 'RARβ', may, be, an, ideal, chemosensitization]), verbo([target]), complemento([for, the, treatment, of, patients, with, 'drug-resistant', 'CCA'])].
[sujeto(['Cervical', 'Cancer', '(', 'CC)']), verbo([has]), complemento([been, causally, linked, to, high, risk, human, papillomavirus, '(', 'HR-HPV)', infection])].
[sujeto(['Increasing', evidence]), verbo([suggests]), complemento([that, low, diet, in, vitamin, 'A', and, their, receptors, participate, in, the, development, of, 'CC'])].
[sujeto(['The', aim, of, this, study]), verbo([has]), complemento([been, to, investigate, the, effects, of, abated, 'RARβ', expression, in, the, development, of, cervical, premalignant, lesions, in, 4, 'month-old', conditional, mice, '(', 'RARβ(L-/L-))'])].
[sujeto(['Results', demonstrated, the, development, of, spontaneous, squamous, 'metaplasia,', inflammatory, 'infiltrate,']), verbo([enhanced]), complemento([mitotic, 'activity,', loss, of, cell, 'differentiation,', as, well, as, decreased, apoptosis, and, 'p16(INK4a)', protein, levels, in, 'RARβ(L-/L-)', mice, cervix])].
[sujeto(['Importantly,', our, results]), verbo([suggest]), complemento([that, the, low, expression, of, 'RARβ,', may, induce, the, down, regulation, of, 'p16(INK4a),', chronic, inflammation, and, decreased, apoptosis, and, may, be, involved, in, vulnerability, to, 'HR-HPV', and, early, stage, cervical, carcinogenesis])].
[sujeto(['Retinoic', acid]), verbo([binding]), complemento([protein, 'II', '(', 'CRABP-II)', is, a, cytoplasmic, receptor, that, critically, regulates, 'all-trans-retinoic', acid, '(', 'ATRA)', trafficking])].
[sujeto(['We', observed, earlier, and, more, diffuse, epidermal, 'dysplasia,', greater, incidence, and, severity, of, 'tumors,', reduced, expression, of, cytokeratin, 1, /, cytokeratin, 10, and, 'involucrin,']), verbo([increased]), complemento(['proliferation,', and, impaired, 'ATRA', inhibition, of, tumor, promotion, compared, with, 'wild-type', animals])].
[sujeto(['CRABP-II-transfected', 'HaCaT,', 'FaDu,', and, 'A431', cells, showed, expression, of, differentiation, 'markers,', retinoic, acid, 'receptor-β/-γ', 'signaling,', 'ATRA', 'sensitivity,', and, suppression, of, 'EGFR/v-akt', murine, thymoma, viral, oncogene, homolog, 1, '(', 'AKT)', pathways, in, a, fatty, acid]), verbo([binding]), complemento([protein, 5, /, peroxisome, 'proliferator-activated', 'receptor-β/-δ-independent', manner])].
[sujeto(['Finally,', 'CRABP-II', accumulation]), verbo([induced]), complemento(['ubiquitination-associated', reduction, of, 'EGFR'])].
[sujeto(['Our', results, showed, reduced, 'CRABP-II', expression, in, human, poorly, differentiated, squamous, cell, 'carcinomas,', and, its, gene, deletion, favored, experimental, skin, carcinogenesis, and, impaired, 'ATRA', antitumor, 'efficacy,', likely]), verbo([modulating]), complemento(['EGFR/AKT', pathways, and, retinoic, acid, 'receptor-β/-γ', signaling])].
[sujeto(['The', liver, is, the, main, storage, organ, of, vitamin, 'A,', but, activation, of, the, retinoic, acid, receptors, '(', 'RARs)', in, mouse, liver, and, in, human, liver, cell, lines]), verbo([has]), complemento([also, been, shown])].
[sujeto(['AlthoughatRA', treatment, improves, mitochondrial, function, in, skeletal, muscle, in, 'rodents,', its, role, in]), verbo([modulating]), complemento([mitochondrial, function, in, the, liver, is, 'controversial,', and, little, data, are, available, regarding, the, human, liver])].
[sujeto(['The', aim, of, this, study, was, to, determine, whetheratRA]), verbo([regulates]), complemento([hepatic, mitochondrial, activity])].
[sujeto([atRA, treatment]), verbo([increased]), complemento([the, mRNA, and, protein, expression, of, multiple, components, of, 'mitochondrialβ-oxidation,', tricarboxylic, acid, '(', 'TCA)', 'cycle,', and, respiratory, chain])].
[sujeto(['Additionally,atRA']), verbo([increased]), complemento([mitochondrial, biogenesis, in, human, hepatocytes, and, in, 'HepG2', cells, with, and, without, lipid, loading, based, on, peroxisome, proliferator, activated, receptor, gamma, coactivator, 1, αand, 1, βand, nuclear, respiratory, factor, 1, mRNA, and, mitochondrial, 'DNA', quantification])].
[sujeto(['Knockdown', studies, of, 'RARα,', 'RARβ,', and, 'PPARδrevealed', that, the, enhancement, of, mitochondrial, biogenesis, 'andβ-oxidation', byatRA]), verbo([requires]), complemento([peroxisome, proliferator, activated, receptor, delta])].
[sujeto(['In', vivo, in, 'mice,atRA', treatment]), verbo([increased]), complemento([mitochondrial, biogenesis, markers, after, an, overnight, fast])].
[sujeto(['Inhibition', ofatRA, metabolism, by, 'talarozole,', a, cytochrome, 'P450', '(', 'CYP)', 26, specific, 'inhibitor,']), verbo([increased]), complemento([the, effects, ofatRA, on, mitochondrial, biogenesis, markers, in, 'HepG2', cells, and, in, vivo, in, mice])].
[sujeto(['These', studies, show, thatatRA]), verbo([regulates]), complemento([mitochondrial, function, and, lipid, metabolism, and, that, increasingatRA, concentrations, in, human, liver, via, 'CYP26', inhibition, may, increase, mitochondrial, biogenesis, and, fatty, 'acidβ-oxidation', and, provide, therapeutic, benefit, in, diseases, associated, with, mitochondrial, dysfunction])].
[sujeto(['The', purpose, of, this, study, was, to, determine, methylation, status, at, 'APC', and, 'RAR-β', promoters, in, primary, 'NSCLC,', and, whether, they]), verbo([have]), complemento([any, relationship, with, survival])].
[sujeto(['APC', promoter, methylation, was]), verbo([found]), complemento([to, be, associated, with, 'T', stage, '(', 'P=0'])].
[sujeto(['RAR-β', promoter, methylation, was]), verbo([found]), complemento([associated, with, age, '(', 'P=0'])].
[sujeto(['Phosphatase', and, tensin, homolog, '(', 'PTEN)', is, a, major, negative, regulator, of, neuronal, regeneration, 'and,', as, 'such,']), verbo([inhibiting]), complemento([its, activity, has, been, considered, a, therapeutic, target, for, spinal, cord, '(', 'SC)', injuries, '(', 'SCIs)'])].
[sujeto(['Mechanism', studies, revealed, 'that,', in, 'RARβ-agonist-treated', 'neurons,', 'PTEN', activity, is]), verbo([decreased]), complemento([by, cytoplasmic, phosphorylation, and, increased, secretion, in, exosomes])].
[sujeto(['These', are, taken, up, by, 'astrocytes,', resulting, in, hampered, proliferation, and]), verbo([causing]), complemento([them, to, arrange, in, a, 'normal-appearing', scaffold, around, the, regenerating, axons])].
[sujeto(['Here,', we, identify, a, single, 'target,', neuronal, retinoic, acid, receptor, β, '(', 'RARβ),', which]), verbo([modulates]), complemento([these, two, aspects, of, the, postinjury, physiological, response])].
[sujeto(['Activation', of, 'RARβ', in, the, neuron, inactivates, phosphatase, and, tensin, homolog, and]), verbo([induces]), complemento([its, transfer, into, the, astrocytes, in, small, 'vesicles,', where, it, prevents, scar, formation])].
[sujeto(['Immunohistochemical', staining, for, 'β-catenin,', cellular, retinoic, acid]), verbo([binding]), complemento([protein, 1, '(', 'CRABP1),', cellular, retinoic, acid, binding, protein, 2, '(', 'CRABP2),', fatty, 'acid-binding', protein, 5, '(', 'FABP5),', retinoic, acid, receptors, '(', 'RAR-α,', -, 'β,', -, 'γ),', and, retinoid, 'X', receptors, '(', 'RXR-α,', -, 'β,', -, 'γ)', was, performed, on, tissue, samples, obtained, from, tumor, excision])].
[sujeto(['Of', these, 16, 'cases,', the, expression, of, 'β-catenin', was, significantly]), verbo([increased]), complemento([in, sebaceous, cell, carcinoma, cases])].
[sujeto(['CRABP1', was, similarly]), verbo([expressed]), complemento([in, the, sebaceous, cell, carcinoma, and, control, groups])].
[sujeto(['CRABP2', and, 'FABP5', were]), verbo([expressed]), complemento([in, hair, follicles, of, lid, skin, in, both, 'groups,', whereas, the, 'CRABP2', and, 'FABP5', were, aberrantly, expressed, in, the, tumor, cells, of, the, sebaceous, glands])].
[sujeto(['The', mRNA, and, protein, expression, levels, of]), verbo([nuclear]), complemento([retinoic, acid, receptor, β, '(', 'RARβ)', were, detected, with, 'RT-PCR', and, 'Western', blot, 'analysis,', respectively])].
[sujeto(['The', mean, survival, time, was, dramatically]), verbo([increased]), complemento([in, the, 'ATPR', treatment, 'groups,', in, a, 'dose-dependent', manner])].
[sujeto(['The', in, vivo, results, showed, 'that,', the, xenograft, tumor, growth, was, significantly]), verbo([inhibited]), complemento([by, the, 'ATPR', treatment])].
[sujeto(['The', serum, levels, of, 'ALP', and, 'LDH', were, both, dramatically]), verbo([decreased]), complemento([in, the, 'ATPR', treatment, groups])].
[sujeto(['Furthermore,', immunohistochemistry, showed, 'that,', the, expression, levels, of, 'COX-2', and, 'CEA', were, dramatically]), verbo([decreased]), complemento([in, the, 'ATPR', treatment, groups])].
[sujeto(['Importantly,', the, mRNA, and, protein, expression, levels, of, 'RARβ', in, xenograft, tumors, were, apparently]), verbo([increased]), complemento([by, the, 'ATPR', treatment])].
[sujeto(['ATPR', could]), verbo([inhibit]), complemento([proliferation, and, induce, differentiation, of, human, gastric, carcinoma, xenografts, via, 'up-regulating', 'RARβ', expression])].
[sujeto(['Oculo-auriculo-vertebral', spectrum, '(', 'OAVS)', is, a, developmental, disorder]), verbo([involving]), complemento([first, and, second, branchial, arches, 'derivatives,', mainly, characterised, by, asymmetric, ear, 'anomalies,', hemifacial, 'microsomia,', ocular, defects, and, vertebral, malformations])].
[sujeto(['Although', numerous, chromosomal, abnormalities]), verbo([have]), complemento([been, associated, with, 'OAVS,', no, causative, gene, has, been, identified, so, far])].
[sujeto(['As', sporadic, cases, are, mostly, described, in, 'Goldenhar', 'syndrome,', we]), verbo([have]), complemento([performed, whole, exome, sequencing, '(', 'WES)', on, selected, affected, individuals, and, their, unaffected, 'parents,', looking, for, de, novo, mutations])].
[sujeto(['Functional', studies, by, transient, knockdown, of, 'myt1a,', homologue, of, 'MYT1', in, 'zebrafish,']), verbo([led]), complemento([to, specific, craniofacial, cartilage, alterations])].
[sujeto(['Treatment', with, 'all-trans', retinoic, acid, '(', 'RA),', a, known, teratogenic, agent]), verbo([causing]), complemento(['OAVS,', led, to, an, upregulation, of, cellular, endogenous, 'MYT1', expression])].
[sujeto(['Additionally,', cellular, 'wild-type', 'MYT1', overexpression]), verbo([induced]), complemento([a, downregulation, of, 'RA', receptor, β, '(', 'RARB),', whereas, mutated, 'MYT1', did, not])].
[sujeto(['We']), verbo([report]), complemento(['MYT1', as, the, first, gene, implicated, in, 'OAVS,', within, the, 'RA', signalling, pathway])].
[sujeto(['Arg387Ser)', in, the, 'RA', 'Receptor', 'Beta', '(', 'RARB)', gene]), verbo([cause]), complemento([microphthalmia, and, diaphragmatic, hernia])].
[sujeto(['Here,', we, describe, nine, additional, subjects, with, microphthalmia, who]), verbo([have]), complemento([de, novo, mutations, in, 'RARB,', including, the, previously, described, p])].
[sujeto(['Moreover,', we, review, the, information, on, four, previously]), verbo([reported]), complemento([cases])].
[sujeto(['We', previously]), verbo([found]), complemento([that, p])].
[sujeto(['Arg387Ser']), verbo([induce]), complemento([a, 'gain-of-function'])].
[sujeto(['Leu213Pro', 'RARB', mutations, further]), verbo([promote]), complemento([the, 'RA', 'ligand-induced', transcriptional, activity, by, twofold, to, threefold, over, the, 'wild-type', 'receptor,', also, indicating, a, 'gain-of-function', mechanism])].
[sujeto(['These', observations]), verbo([suggest]), complemento([that, precise, regulation, of, 'RA', signaling, is, required, for, brain, development, 'and/or', function, in, humans])].
[sujeto(['The', development, and, progression, of, melanoma]), verbo([have]), complemento([been, attributed, to, independent, or, combined, genetic, and, epigenetic, events])].
[sujeto(['There']), verbo([has]), complemento([been, remarkable, progress, in, understanding, melanoma, pathogenesis, in, terms, of, genetic, alterations])].
[sujeto(['However,', recent, studies]), verbo([have]), complemento([revealed, a, complex, involvement, of, epigenetic, mechanisms, in, the, regulation, of, gene, 'expression,', including, 'methylation,', chromatin, modification, and, 'remodeling,', and, the, diverse, activities, of, 'non-coding', 'RNAs'])].
[sujeto(['The', roles, of, gene, methylation, and, miRNAs]), verbo([have]), complemento([been, relatively, well, studied, in, 'melanoma,', but, other, studies, have, shown, that, changes, in, chromatin, status, and, in, the, differential, expression, of, long, 'non-coding', 'RNAs', can, lead, to, altered, regulation, of, key, genes])].
[sujeto(['The', biological, action, of, retinoic, acid, is]), verbo([mediated]), complemento([by, three, nuclear, receptors, denoted, 'RARα,', β, and, γ])].
[sujeto(['However,', it]), verbo([has]), complemento([been, recently, reported, that, 'RARβ', could, also, play, a, role, in, mammary, gland, 'tumorigenesis,', thus, demonstrating, the, important, but, yet, incompletely, understood, function, of, this, receptor, in, cancer, development])].
[sujeto(['Here', we]), verbo([provide]), complemento([experimental, evidences, that, the, novel, synthetic, retinoid, 'BMS948', is, an, 'RARβ-selective', ligand, exhibiting, a, full, transcriptional, agonistic, activity, and, activating, 'RARβ', as, efficiently, as, the, reference, agonist, 'TTNPB'])].
[sujeto(['These', structures]), verbo([provided]), complemento([a, rationale, to, explain, how, a, single, retinoid, can, be, at, the, same, time, an, 'RARα', antagonist, and, an, 'RARβ', full, 'agonist,', and, revealed, the, structural, basis, of, partial, agonism])].
[sujeto(['Finally,', in, addition, to]), verbo([revealed]), complemento([that, a, flip, by, 180, °, of, the, amide, 'linker,', that, usually, confers, 'RARα', 'selectivity,', accounts, for, the, 'RARβ', selectivity, of, 'BMS948,', the, structural, analysis, uncovers, guidelines, for, the, rational, design, of, 'RARβ-selective', antagonists])].
[sujeto(['Epigenetic', silencing]), verbo([mediated]), complemento([by, 'CpG', island, methylation, is, a, common, feature, of, many, cancers])].
[sujeto(['Characterizing', aberrant, 'DNA', methylation, changes]), verbo([associated]), complemento([with, prostate, carcinogenesis, could, potentially, identify, a, 'tumour-specific', methylation, 'pattern,', facilitating, the, early, diagnosis, of, prostate, cancer])].
[sujeto(['The', progression, of, pleomorphic, adenoma, '(', 'PA)', to, carcinoma, 'ex-pleomorphic', adenoma, '(', 'CXPA)', encompasses, several, genomic, alterations]), verbo([involving]), complemento([complex, pathways])].
[sujeto(['Copy', number]), verbo([losses]), complemento([of, 'CASP8,', 'MLH1,', and, 'RARB', genes, were, associated, with, 'PA', and, 'CXPA,', while, 'KLK3', and, 'AI69125', copy, number, losses, were, exclusive, to, 'CXPA'])].
[sujeto(['Hypermethylation', of, 'RASSF1', was]), verbo([found]), complemento([mainly, in, 'PA', and, less, frequently, in, malignant, tumors])].
[sujeto(['CASP8,', 'MLH1,', and, 'RARB', tumor, suppressor, genes, were, altered, by, copy, number]), verbo([losses]), complemento([during, 'PA', progression, to, 'CXPA'])].
[sujeto(['Retinoic', acid, '(', 'RA)', repression, of, 'Fgf8', is]), verbo([required]), complemento([for, many, different, aspects, of, 'organogenesis,', however, relatively, little, is, known, about, how, endogenous, 'RA', controls, gene, repression, as, opposed, to, gene, activation])].
[sujeto(['Here,', we, show, that]), verbo([nuclear]), complemento([receptor, corepressors, 'NCOR1', and, 'NCOR2', '(', 'SMRT)', redundantly, mediate, the, ability, of, 'RA', to, repress, 'Fgf8'])].
[sujeto(['Ncor1;Ncor2', double, mutants, generated, by, 'CRISPR/Cas9', gene, editing, exhibited, a, small, somite, and, distended, heart, phenotype, similar, to, that, of, 'RA-deficient', 'Raldh2-/-', 'embryos,']), verbo([associated]), complemento([with, increased, 'Fgf8', expression, and, 'FGF', signaling, in, caudal, progenitors, and, heart, progenitors])].
[sujeto(['Embryo', chromatin, immunoprecipitation, studies, revealed, that, 'NCOR1/2', but, not, coactivators, are]), verbo([recruited]), complemento([to, the, 'Fgf8', 'RA', response, element, '(', 'RARE)', in, an, 'RA-dependent', 'manner,', whereas, coactivators, but, not, 'NCOR1/2', are, recruited, 'RA-dependently', to, a, 'RARE', near, 'Rarb', that, is, activated, by, 'RA'])].
[sujeto(['This']), verbo([suggests]), complemento([the, existence, of, another, 'DNA', element, whose, function, overlaps, with, the, 'Fgf8', 'RARE', to, mediate, 'Fgf8', repression, by, 'RA', and, 'NCOR1/2'])].
[sujeto(['Our', studies, support, a, model, in, which, 'NCOR1/2']), verbo([mediates]), complemento([direct, 'RA-dependent', repression, of, 'Fgf8', in, caudal, progenitors, in, order, to, control, somitogenesis])].
[sujeto(['To', conduct, a, comprehensive, mapping, of, the, genomic, 'DNA', methylation, in, 'CDKN2A,', which, codes, for, the, 'p16(INK4A)', and, 'p14(ARF)', 'proteins,', and, 14, of, the, most, promising, 'DNA', methylation, marker, candidates, previously]), verbo([reported]), complemento([to, be, associated, with, progression, of, 'low-grade', cervical, intraepithelial, neoplasia, '(', 'CIN1)', to, cervical, cancer])].
[sujeto(['Validation', was, performed, using, high, resolution, mapping, of, the]), verbo([target]), complemento([genes, with, 'HELP-tagging', for, 286, 'CpGs,', followed, by, fine, mapping, of, candidate, genes, with, targeted, bisulfite, sequencing])].
[sujeto(['Only', those, 'CpGs', in, the, gene, body, of, 'CDKN2A', showed, a, monotonic]), verbo([increase]), complemento([in, methylation, between, persistent, 'CIN1,', 'CIN2,', 'CIN3', and, cancers])].
[sujeto(['Our', data]), verbo([suggests]), complemento([a, novel, link, between, early, cervical, disease, progression, and, 'DNA', methylation, in, a, region, downstream, of, the, 'CDKN2A', transcription, start, site, that, may, lead, to, increased, 'p16(INK4A)/p14(ARF)', expression, prior, to, development, of, malignant, disease])].
[sujeto(['K-means', clustering, analysis, of, gene, expression, revealed, that, expression, levels, of, 'cartilage-associated', genes, such, as, 'COLXIA', and, 'ACAN']), verbo([increased]), complemento([from, the, anterior, to, the, posterior, part, of, the, sclera])].
[sujeto(['Among', several, 'Wnt-family', genes, 'examined,', 'WNT2B', was]), verbo([found]), complemento([to, be, expressed, at, a, significantly, higher, level, in, the, posterior, 'sclera,', and, the, reverse, order, was, observed, for, 'WNT2'])].
[sujeto(['The', results, of, luciferase, reporter, assays]), verbo([suggested]), complemento([that, a, 'GSK-3β', inhibitor, stimulated, 'Wnt/β-catenin', signaling, particularly, strongly, in, the, posterior, sclera])].
[sujeto(['Chondrogenic', potential, was, higher, and, 'Wnt/β-catenin', signaling, was, more, potently]), verbo([activated]), complemento([by, a, 'GSK-3β', inhibitor, in, the, posterior, than, in, the, anterior, part, of, the, human, infant, sclera])].
[sujeto(['Although', the, differences, in, the, gene, expression, profiles, between, the, anterior, and, posterior, sclera, might, be]), verbo([involved]), complemento([only, in, normal, growth, 'processes,', this, anteroposterior, hierarchy, in, the, sclera, might, contribute, to, disorders, involving, abnormal, elongation, and, deformity, of, the, 'eyeball,', including, myopia])].
[sujeto(['Estrogen', receptor, '(', 'ER)', and, progesterone, receptor, '(', 'PR)', positivity, were]), verbo([associated]), complemento([with, increased, 'SCGB3A1', methylation, among, 'pre-', and, 'post-menopausal', cases])].
[sujeto(['Among', premenopausal, 'women,', compared, with, 'Stage', 0, 'cases,', cases, of, invasive, cancer, were, more, likely, to]), verbo([have]), complemento([increased, methylation, of, 'RARB', '(', 'Stage', 'I', 'OR', =, 4.7, ',', 95, '%', 'CI:', 1.1, -, 19.0, ;, 'Stage', 'IIA/IIB', 'OR', =, 9.7, ',', 95, '%', 'CI:', 2.4, -, 39.9, ;, 'Stage', 'III/IV', 'OR', =, 5.6, ',', 95, '%', 'CI:', 1.1, -, 29.4, ')', and, lower, methylation, of, 'FHIT', '(', 'Stage', 'I', 'OR', =, 0.2, ',', 95, '%', 'CI:', 0.1, -, 0.9, ;, 'Stage', 'IIA/IIB', 'OR', =, 0.2, ',', 95, '%', 'CI:', 0.1, -, 0.8, ;, 'Stage', 'III/IV', 'OR', =, 0.6, ',', 95, '%', 'CI:', 0.1, -, 3.4, ')'])].
[sujeto(['Among', postmenopausal, 'women,', methylation, of, 'SYK', was]), verbo([associated]), complemento([with, increased, tumor, size, '(', 'OR', =, 1.7, ',', 95, '%', 'CI:', 1.0, -, 2.7, ')', and, higher, nuclear, grade, '(', 'OR', =, 2.0, ',', 95, '%', 'CI', 1.2, -, 3.6, ')'])].
[sujeto(['Methylation', of, 'SCGB3A1', was]), verbo([associated]), complemento([with, reduced, risk, of, death, from, breast, cancer, '(', 'HR', =, 0.41, ',', 95, '%', 'CI:', 0.17, -, 0.99, ')', as, was, 'BRCA1', '(', 'HR', =, 0.41, ',', 95, '%', 'CI:', 0.16, -, 0.97, ')'])].
[sujeto(['CCND2', methylation, was]), verbo([associated]), complemento([with, increased, risk, of, breast, cancer, mortality, '(', 'HR', =, 3.4, ',', 95, '%', 'CI:', 1.1, -, 10.5, ')'])].
[sujeto(['We', observed, differences, in, methylation]), verbo([associated]), complemento([with, tumor, 'characteristics;', methylation, of, these, genes, was, also, associated, with, breast, cancer, survival, among, premenopausal, cases])].
[sujeto(['Understanding', of, the, associations, of, 'DNA', methylation, with, other, clinicopathological, features, may]), verbo([have]), complemento([implications, for, prevention, and, treatment])].
[sujeto(['We']), verbo([found]), complemento([28, genes, significantly, hypermethylated, in, &, 'gt;20%', of, the, tumors, analyzed])].
[sujeto(['In', the, present, 'study,', we, analyzed, '(', 1, ')', the, type, of, 'HPV', infection, and, '(', 2, ')', the, frequency, of]), verbo([loss]), complemento([of, heterozygosity, and, microsatellite, imbalance, '(', 'LOH/MSI)', in, normal, cytology, and, cervical, intraepithelial, neoplasia, '(', 'CIN1-3)'])].
[sujeto(['Significant', differences, in, 'OFAL', were]), verbo([found]), complemento([between, samples, with, versus, without, 'HPV', infection])].
[sujeto(['In', 'HPV-positive', 'patients,', significant, differences, in, 'OFAL', were]), verbo([found]), complemento([between, normal, 'cytology,', 'CIN1', and, 'CIN2/CIN3'])].
[sujeto(['HPV', infection, influences, the]), verbo([increase]), complemento([in, 'LOH/MSI', 'frequency,', especially, in, tumor, suppressor, gene, loci])].
[sujeto(['It', remains, unclear, whether, methylation, patterns, in, benign, prostate, 'tissue--prior', to, malignant, 'transformation--may']), verbo([provide]), complemento([similar, prognostic, information])].
[sujeto(['Risk', of, disease, progression]), verbo([associated]), complemento([with, methylation, was, estimated, using, 'time-to-event', analyses])].
[sujeto(['In', 'White', 'men,', methylation, of, the, 'APC', gene, was]), verbo([associated]), complemento([with, increased, risk, of, 'BCR,', even, after, adjusting, for, standard, clinical, risk, factors, for, prostate, cancer, progression, '(', adjusted, hazard, ratio, '(', 'aHR)', =, 2.26, ;, 95, '%', 'CI', 1.23, -, 4.16, ')'])].
[sujeto(['APC', methylation, was, most, strongly]), verbo([associated]), complemento([with, a, significant, increased, risk, of, 'BCR', in, 'White', men, with, low, prostate, specific, antigen, at, cohort, entry, '(', 'HR', =, 3.66, ;, 95, '%', 'CI', 1.51, -, 8.85, ')'])].
[sujeto(['In', additional, stratified, 'analyses,', we]), verbo([found]), complemento([that, methylation, of, the, 'RARB', gene, significantly, increased, risk, of, 'BCR', in, 'African', 'American', cases, who, demonstrated, methylation, of, at, least, one, of, the, other, four, genes, under, study, '(', 'HR', =, 3.8, ;, 95, '%', 'CI', 1.07, -, 13.53, ')'])].
[sujeto(['These', findings, may]), verbo([have]), complemento([implications, in, the, early, identification, of, aggressive, prostate, cancer, as, well, as, reducing, unnecessary, medical, procedures, and, emotional, distress, for, men, who, present, with, markers, of, indolent, disease])].
[sujeto(['We']), verbo([found]), complemento([there, were, a, significant, positive, correlation, between, the, promoter, methylation, status, of, 'DAPK1', and, cervical, disease, grade, '(', 'P=0'])].
[sujeto(['The', methylation, status, of, each, 'CpG', island, was, compared, between, the, cancer, and, 'BPH', samples, to, screen, the, genes]), verbo([involved]), complemento([in, prostate, cancer, development])].
[sujeto(['Among', all, the, tested, 'CpG', 'islands,', 10245, '(', 37.2, '%', ')', in, prostate, cancer, and, 8658, '(', 30.3, '%', ')', in, 'BPH', samples, were]), verbo([found]), complemento([to, be, abnormally, 'methylated,', and, &, 'gt;60%', of, the, methylated, 'CpG', islands, were, in, the, promoter, region])].
[sujeto(['Seven', genes, '(', 'DPYS,', 'P16,', 'APC,', 'GSTP1,', 'TMEM122,', 'RARB,', and, 'ARHGAP20)', in, prostate, cancer, were, identified, to]), verbo([have]), complemento([distinct, methylations])].
[sujeto(['Bioinformatics', analysis]), verbo([suggested]), complemento([that, these, genes, were, associated, with, several, biomolecular, and, biological, 'processes,', and, among, them, 'DPYS', gene, was, involved, in, 13, 'GO', anotated, biologic, 'functions,', development, of, 50, diseases, and, 47, protein, interactions])].
[sujeto(['Pyrosequencing', of, 7, sites, of, the, 'CPG', island, in, 'DPYS', gene, showed, a, methylation, frequency, of, 32.7, '%', ',']), verbo([suggesting]), complemento([the, importance, of, 'DPYS', gene, in, the, carcinogenesis, and, progression, of, prostate, cancer])].
[sujeto(['Epigenetic', regulation, of, 'transcription,', particularly, by, 'CpG', 'methylation,', plays, an, important, role, in, tumor, 'progression,', mainly, by]), verbo([repressing]), complemento(['tumor-suppressor', genes])].
[sujeto(['To', clarify, the, clinical, importance, of, aberrant, 'DNA', 'methylation,', we, studied, the, hypermethylation, status, of, 16]), verbo([target]), complemento([genes, in, the, genomes, of, 92, patients, with, 'JMML', by, bisulfite, conversion, and, the, pryosequencing, technique])].
[sujeto(['Epigenetic', analysis]), verbo([provides]), complemento([helpful, information, for, clinicians, to, select, treatment, strategies, for, patients, with, 'JMML'])].
[sujeto(['This', study, attempts, to, identify, differentially]), verbo([expressed]), complemento([genes, '(', 'DEGs)', related, to, lung, adenocarcinoma, in, 'Xuanwei'])].
[sujeto(['These', 'DEGs', are]), verbo([involved]), complemento([in, a, wide, range, of, 'cancer-related', 'processes,', which, include, cell, 'division,', cell, 'adhesion,', cell, 'proliferation,', and, 'DNA', 'replication,', and, in, many, pathways, such, as, the, p53, signaling, 'pathway,', the, 'MAPK', 'pathway,', the, 'Jak-STAT', signaling, 'pathway,', the, hedgehog, signaling, 'pathway,', and, the, 'non-small-cell', lung, cancer, pathway])].
[sujeto(['Expression', of, 'PAK1', was, significantly]), verbo([increased]), complemento([in, the, low, differentiation, group, '(', 'P=0'])].
[sujeto([31, ')', ',', whereas, expression, of, 'HGF', was, significantly]), verbo([decreased]), complemento([in, the, low, differentiation, group, '(', 'P=0'])].
[sujeto(['RARB', and, 'MAPK11', were, significantly]), verbo([increased]), complemento([in, the, nonsmoker, group, '(', 'P=0'])].
[sujeto(['A', large, number, of, 'DEGs', in, lung, adenocarcinoma, in, 'Xuanwei']), verbo([have]), complemento([been, 'detected,', which, may, enable, us, to, understand, the, pathogenesis, and, lay, an, important, foundation, for, the, prevention, and, treatment, of, lung, adenocarcinoma, in, 'Xuanwei'])].
[sujeto(['The', methylation, of, promoter, 'CpG', islands, and, interactions, between, microRNAs, '(', 'miRNAs)', and, messenger, 'RNAs', '(', 'mRNAs)', of]), verbo([target]), complemento([genes, are, considered, two, crucial, epigenetic, mechanisms, for, inducing, gene, and, pathway, deregulation, in, tumors])].
[sujeto(['In', 'summary,', the, obtained, data, indicate, the, involvement, of, methylation, in, the, 'down-regulation', of, the, studied, coding, and, miRNA, genes, and]), verbo([suggest]), complemento([the, involvement, of, 'miR-129-2', in, the, deregulation, of, 'RASSF1(A)', via, a, direct, interaction, 'or/and', mediators, in, common, pathways, '(', according, to, 'KEGG,', 'Gene', 'Ontology', '(', 'FDR', &, 'lt;', 0.01, ')', ',', and, 'GeneCards', 'data)', in, the, examined, gynecological, tumors])].
[sujeto(['Consumption', of, the, 'long-chain', 'ω-3', '(', 'n-3)', polyunsaturated, fatty, acid, docosahexaenoic, acid, '(', 'DHA)', is]), verbo([associated]), complemento([with, a, reduced, risk, of, cardiovascular, disease, and, greater, chemoprevention])].
[sujeto(['Therefore,', we, aimed, to, determine, if, the, beneficial, effects, of, 'DHA', may, be]), verbo([modulated]), complemento([in, part, through, miRNAs])].
[sujeto(['Loss', of, dicer, 1, ribonuclease, type, 'III', '(', 'DICER)', in, enterocyte, 'Caco-2', cells, supplemented, with, 'DHA']), verbo([suggested]), complemento([that, several, lipid, metabolism, genes, are, modulated, by, miRNAs])].
[sujeto(['Analysis', of, miRNAs, predicted, to]), verbo([target]), complemento([these, genes, revealed, several, miRNA, candidates, that, are, differentially, modulated, by, fatty, acids])].
[sujeto(['Among', the, miRNAs]), verbo([modulated]), complemento([by, 'DHA', were, 'miR-192', and, 'miR-30c'])].
[sujeto(['Overexpression', of, either, 'miR-192', or, 'miR-30c', in, enterocyte, and, hepatocyte, cells]), verbo([suggested]), complemento([an, effect, on, the, expression, of, genes, related, to, lipid, 'metabolism,', some, of, which, were, confirmed, by, endogenous, inhibition, of, these, miRNAs])].
[sujeto(['Our', results, show, in, enterocytes, that, 'DHA', exerts, its, biologic, effect, in, part, by]), verbo([regulating]), complemento([genes, involved, in, lipid, metabolism, and, cancer])].
[sujeto(['Moreover,', this, response, is]), verbo([mediated]), complemento([through, miRNA, activity])].
[sujeto(['We', validate, novel]), verbo([targets]), complemento([of, 'miR-30c', and, 'miR-192', related, to, lipid, metabolism, and, cancer, including, nuclear, receptor, corepressor, 2, ',', isocitrate, dehydrogenase, 1, ',', 'DICER,', caveolin, 1, ',', 'ATP-binding', cassette, subfamily, 'G', '(', 'white)', member, 4, ',', retinoic, acid, receptor, 'β,', and, others])].
[sujeto(['We', also, present, evidence, that, in, enterocytes, 'DHA']), verbo([modulates]), complemento([the, expression, of, regulatory, factor, 'X6', through, these, miRNAs])].
[sujeto(['Acute', promyelocytic, leukemia, '(', 'APL)', is]), verbo([associated]), complemento([with, oncogenic, 'PML-RARalpha', that, acts, as, a, dominant, negative, transcriptional, repressor, of, retinoic, acid, '(', 'RA)', receptor, target, genes, by, recruiting, histone, deacetylase, '(', 'HDAC)'])].
[sujeto(['The', peroxisome, 'proliferator-activated', 'receptor-gamma', '(', 'PPARgamma)', is, a, member, of, the]), verbo([nuclear]), complemento([receptor, family, that, forms, heterodimers, with, retinoid, 'X', receptor, '(', 'RXR)'])].
[sujeto(['In', addition, to, 'RAR', 'targets,', 'PML-RARalpha', silence, a, wide, range, of]), verbo([nuclear]), complemento([receptor, target, genes, including, 'PPARgamma', targets])].
[sujeto(['All-trans-retinoic', acid, '(', 'ATRA),', a, ligand, for, the, 'RA', receptor, '(', 'RAR),', restores, normal, retinoid, signaling, and]), verbo([induces]), complemento([terminal, differentiation, of, 'APL', 'cells;', 'however,', 'APL', cells, can, develop, resistance, to, 'ATRA'])].
[sujeto(['Using', 'ATRA', sensitive, 'NB4', and, 'ATRA-resistant', derivative, 'MR2', cell, 'lines,', we, demonstrate, that, 'PPARgamma', ligand, 2, -, 'cyano-3,', 12, -, 'dioxooleana-1,', 9, -, 'dien-28-oic', acid, '(', 'CDDO)']), verbo([enhances]), complemento(['pro-apoptotic', and, differentiating, effects, of, 'ATRA', in, 'ATRA-sensitive', 'NB4', cells, and, partially, reverses, 'ATRA', resistance, in, 'MR2', cells])].
[sujeto(['The', 'CDDO/ATRA', combination, synergistically]), verbo([induces]), complemento(['RARbeta2', expression, both, in, 'ATRA-sensitive', and, -, resistant, 'APL', cells])].
[sujeto(['RARbeta2', 'MrNA', induction, by, 'CDDO/ATRA', was]), verbo([mediated]), complemento([in, part, by, enhanced, 'H3-Lys9', acetylation, in, the, 'RARbeta2', promoter, which, in, turn, increased, the, affinity, of, 'RARbeta', for, betaRARE])].
[sujeto(['In', an, in, vivo, mouse, model, of, 'APL,', 'CDDO', derivative, 'CDDO-methyl', ester, markedly]), verbo([enhanced]), complemento(['ATRA-induced', maturation, and, extended, the, survival, of, mice])].
[sujeto(['In', 'summary,', these, results]), verbo([provide]), complemento([rationale, for, the, combined, targeting, of, 'RAR', and, 'PPARgamma', nuclear, receptors, in, the, therapy, of, 'APL'])].
[sujeto(['The', use, of, retinoids, as, 'anti-cancer', agents]), verbo([has]), complemento([been, limited, due, to, resistance, and, low, efficacy])].
[sujeto(['The', dynamics, of]), verbo([nuclear]), complemento([receptor, coregulation, are, incompletely, understood])].
[sujeto(['Cell-and', 'context-specific', activities, of]), verbo([nuclear]), complemento([receptors, may, be, in, part, due, to, distinct, coregulator, complexes, recruited, to, distinct, subsets, of, target, genes])].
[sujeto(['We', had, previously, shown, that, 'RIP140', limits, 'RA']), verbo([induced]), complemento([tumor, cell, differentiation, of, embryonal, 'carcinoma;', the, pluriopotent, stem, cells, of, testicular, germ, cell, tumors])].
[sujeto(['This', implies, that, 'RIP140']), verbo([represses]), complemento([key, genes, required, for, 'RA-mediated', tumor, cell, differentiation])].
[sujeto(['To', begin, to, address, this, 'issue,', microarray, technology, was, employed, to, elucidate, in, a, de, novo, fashion, the, global, role, of, 'RIP140', in, 'RA']), verbo([target]), complemento([gene, regulation, of, embryonal, carcinoma])].
[sujeto(['Hence,', 'RIP140', appears, to, discriminate, between, different, classes, of, 'RA']), verbo([target]), complemento([genes])].
[sujeto(['Few', if, any, genes, were]), verbo([regulated]), complemento([in, a, manner, to, support, a, role, for, 'RIP140', in, &, 'quot;active', 'repression&quot;'])].
[sujeto(['Together', the, data, demonstrates, that, 'RIP140']), verbo([has]), complemento([profound, effects, on, 'RA-mediated', gene, expression, in, this, cancer, stem, cell, model])].
[sujeto(['The', 'RIP140-dependent', 'RA']), verbo([target]), complemento([genes, identified, here, may, be, particularly, important, in, mediating, 'RA-induced', tumor, cell, differentiation, and, the, findings, suggest, that, 'RIP140', may, be, an, attractive, target, to, sensitize, tumor, cells, to, 'retinoid-based', differentiation, therapy])].
[sujeto(['We', isolated, 'MED25,', which]), verbo([associates]), complemento([with, retinoic, acid, '(', 'RA)-bound', retinoic, acid, receptor, '(', 'RAR)', through, the, 'C-terminal', nuclear, hormone, receptor, '(', 'NR)', 'box/LxxLL', 'motif,', and, increases, 'RAR/RXR-mediated', transcription])].
[sujeto(['Stimulation', of, 'RAR', by, 'MED25', was, correlated, with]), verbo([enhanced]), complemento(['RA', cytotoxicity, in, vivo])].
[sujeto(['Time-course', 'ChIP', assays, indicated, that, 'CBP,', together, with, 'RAR', and, 'MED25,', is]), verbo([recruited]), complemento(['early,', whereas, 'TRAP220', is, recruited, later, to, the, promoter])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, 'MED25,', in, cooperation, with, 'CBP', and, 'Mediators', through, its, distinct, 'domains,', imposes, a, selective, advantage, on, 'RAR/RXR', activation])].
[sujeto(['Conventional', methods, for]), verbo([regulating]), complemento([the, differentiation, of, stem, cells, are, largely, based, on, the, use, of, biological, agents, such, as, growth, factors])].
[sujeto(['To', test, our, 'hypothesis,', we]), verbo([have]), complemento([determined, 'which,', if, 'any,', of, the, nuclear, receptor, superfamily, might, be, involved, in, chondrogenesis])].
[sujeto(['We', used, 'fluorescence-activated', cell, 'sorting,', as, well, as, quantitative, polymerase, chain, 'reaction,', to, study, expression, of, a, range, of]), verbo([nuclear]), complemento([receptors, in, the, undifferentiated, mesenchymal, population, and, after, growth, 'factor-driven', differentiation, of, these, cells, to, chondrocytes])].
[sujeto(['A', low, molecular, weight, synthetic, inhibitor, of, the, 'RAR', alpha, and, 'RAR', beta, receptors, was, able, to]), verbo([induce]), complemento([chondrogenic, differentiation, of, mesenchymal, stem, cells, derived, from, osteoarthritis, 'patients,', in, the, absence, of, serum, and, growth, factors])].
[sujeto(['Furthermore,', the, pathway, is, independent, of, 'SOX9', upregulation, and, does, not]), verbo([lead]), complemento([to, hypertrophy])].
[sujeto(['Disclosure', of, potential, conflicts, of, interest, is]), verbo([found]), complemento([at, the, end, of, this, article])].
[sujeto(['Activating', signal, 'cointegrator-2', '(', 'ASC-2),', a, coactivator, of, multiple, transcription, factors, that, include, retinoic, acid, receptor, '(', 'RAR),']), verbo([associates]), complemento([with, histone, 'H3-K4', methyltranferases, '(', 'H3K4MTs)', 'MLL3', and, 'MLL4', in, 'mixed-lineage', leukemia])].
[sujeto(['Here,', we, show, that, mice]), verbo([expressing]), complemento([a, 'SET', domain, mutant, of, 'MLL3', share, phenotypes, with, isogenic, 'ASC2+/-', mice, and, that, expression, and, 'H3-K4', trimethylation, of, 'RAR', target, gene, 'RAR-beta2', are, impaired, in, 'ASC-2-null', mouse, embryo, fibroblasts, '(', 'MEFs)', or, in, 'MEFs', expressing, siRNAs, against, both, 'MLL3', and, 'MLL4'])].
[sujeto(['We', also, show, that, 'MLL3', and, 'MLL4', are]), verbo([found]), complemento([in, distinct, 'ASC-2-containing', complexes, rather, than, in, a, common, 'ASC-2', 'complex,', and, they, are, recruited, to, 'RAR-beta2', by, 'ASC-2'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'ASC-2', confers, target, gene, specificity, to, 'MLL3', and, 'MLL4', 'H3K4MT', complexes, and, that, recruitment, of, 'H3K4MTs', to, their, target, genes, generally, involves, interactions, between, integral, components, of, 'H3K4MT', complexes, and, transcription, factors])].
[sujeto(['Retinoic', acid, '(', 'RA)']), verbo([induces]), complemento([growth, 'arrest,', cell, 'death,', and, differentiation, in, many, human, cancer, cells, in, vitro, and, has, entered, routine, clinical, use, for, the, treatment, of, several, human, cancer, types])].
[sujeto(['The', 'RA', response, element, beta, '(', 'betaRARE)', is, the, essential, 'DNA', sequence]), verbo([required]), complemento([for, 'retinoid-induced', 'RARbeta', transcription])].
[sujeto(['EBBP', undergoes, serine, threonine, phosphorylation, and]), verbo([enhanced]), complemento([protein, stability, after, 'RA', treatment])].
[sujeto(['Following', 'RA', 'treatment,', we, also, observed]), verbo([increased]), complemento([nuclear, 'EBBP', levels, in, aggregates, with, the, promyelocytic, leukemia, protein, at, promyelocytic, leukemia, nuclear, bodies])].
[sujeto(['EBBP']), verbo([enhanced]), complemento(['RA-responsive', 'RARbeta', transcription, in, 'RA-sensitive', and, -, resistant, cancer, 'cells,', which, were, resistant, to, both, a, histone, deacetylase, inhibitor, and, a, demethylating, agent])].
[sujeto(['EBBP']), verbo([increased]), complemento(['betaRARE-transactivating', function, through, its, 'coiled-coil', domain])].
[sujeto(['Taken', 'together,', our, work]), verbo([suggests]), complemento([that, 'EBBP', may, have, a, pivotal, role, in, the, retinoid, 'anti-cancer', signal])].
[sujeto(['Tazarotene,', a, member, of, the, new, class, of, acetylenic, 'retinoids,']), verbo([has]), complemento([been, shown, to, be, effective, in, the, treatment, of, several, hyperproliferative, skin, 'diseases,', including, 'non-melanoma', skin, cancer])].
[sujeto(['Its', effectiveness, is, thought, to, rely, on, the, ability, to]), verbo([activate]), complemento([retinoic, acid, receptors, beta, and, gamma, and, to, induce, a, number, of, downstream, 'anti-proliferative', genes])].
[sujeto(['Here,', we, show, that, the, 'p53-related', gene, p73, is, a]), verbo([target]), complemento([of, tazarotene])].
[sujeto(['Indeed,', tazarotene]), verbo([modulates]), complemento([the, expression, of, the, p73, gene, in, immortalized, keratinocyte, cell, lines, by, inducing, the, 'pro-apoptotic', and, 'anti-proliferative', 'TAp73', isoforms, and, by, repressing, the, 'anti-apoptotic', and, 'pro-proliferative', 'DeltaNp73', isoforms])].
[sujeto(['The', selective, downregulation, of, 'DeltaNp73', expression, by, small, interfering, 'RNA']), verbo([led]), complemento([to, an, enhancement, of, 'tazarotene-induced', bax, activation, and, 'apoptosis,', whereas, the, downregulation, of, both, 'TA', and, 'DeltaN', isoforms, impairs, 'tazarotene-mediated', apoptosis])].
[sujeto(['Nuclear', 'receptor-mediated', gene, expression, is, proposed, to, be]), verbo([regulated]), complemento([by, the, ordered, recruitment, of, large, protein, complexes, in, which, activity, depends, on, mutual, interactions, and, posttranslational, modifications])].
[sujeto(['In', 'contrast,', relatively, little, attention]), verbo([has]), complemento([been, given, to, mechanisms, regulating, the, expression, of, the, coregulator, proteins, themselves])].
[sujeto(['Previously', we]), verbo([have]), complemento([shown, that, the, 'ligand-dependent', 'corepressor,', 'RIP140,', is, a, direct, transcriptional, target, of, 'all-trans', retinoic, acid, '(', 'RA)'])].
[sujeto(['Silencing', of, the, 'RA', induction, of, 'RIP140', dramatically]), verbo([enhances]), complemento([and, accelerates, retinoid, receptor, 'transactivation,', endogenous, expression, of, other, 'RA', target, 'genes,', and, 'RA-induced', neuronal, differentiation, and, cell, cycle, arrest, in, human, embryonal, carcinoma, cells])].
[sujeto(['The', data]), verbo([suggest]), complemento([that, 'RA', induction, of, 'RIP140', constitutes, a, functional, negative, feedback, loop, that, limits, activation, of, retinoid, receptors, in, the, continued, presence, of, 'RA', and, that, acutely, regulated, expression, of, coregulators, may, be, a, general, regulatory, mechanism, in, hormonal, signaling])].
[sujeto(['The', biological, effects, of, retinoic, acid, '(', 'RA)', are]), verbo([mediated]), complemento([by, nuclear, retinoic, acid, receptors, '(', 'RARs)', that, function, as, 'ligand-activated', transcriptional, factors])].
[sujeto(['The', response, of, human, cancer, cells, to, 'RA', is, known, to, be]), verbo([associated]), complemento([with, the, expression, of, 'RARbeta'])].
[sujeto(['Recent', studies]), verbo([have]), complemento([demonstrated, that, the, loss, of, 'RARbeta', expression, is, involved, in, the, development, of, a, variety, of, human, malignancies])].
[sujeto(['We', show, that, recombinant, 'adenovirus-mediated', 'p21(sdi1)', gene, transfer]), verbo([enhances]), complemento(['RARbeta', mRNA, expression, as, well, as, protein, expression, and, induces, the, sensitivity, to, 'all-trans', 'RA', '(', 'ATRA)', in, human, cancer, cells])].
[sujeto(['Semi-quantitative', reverse, 'transcription-polymerase', chain, reaction, analysis, demonstrated, that, infection, with, adenovirus, carrying, human, 'p21(sdi1)', gene, '(', 'Ad5CMV-p21),', which, encodes, a, 'cyclin-dependent', kinase, 'inhibitor,']), verbo([induced]), complemento(['RARbeta', mRNA, and, protein, expression, in, 'H1299', human, 'non-small', cell, lung, cancer, cells, and, 'DLD-1', human, colorectal, cancer, cells])].
[sujeto(['We', also]), verbo([found]), complemento([that, exogenous, introduction, of, the, 'p21(sdi1)', gene, transcriptionally, activated, the, upstream, promoter, function, of, the, 'RARbeta', gene])].
[sujeto(['Treatment', with, 1, microM, of, 'ATRA', showed, no, significant, inhibitory, effects, on, the, growth, of, 'H1299', and, 'DLD-1', 'cells;', after, 'Ad5CMV-p21', 'infection,', 'however,', cells, underwent, apoptosis, with, 'ATRA', treatment, at, the, same, 'concentration,']), verbo([suggesting]), complemento([that, 'p21(sdi1)', gene, transfer, sensitized, 'H1299', and, 'DLD-1', 'cells,', 'presumably,', through, 'RARbeta', upregulation])].
[sujeto(['Exposure', of, aggregated, murine, 'P19', embryonal, carcinoma, cells, to, dimethylsulfoxide, '(', 'DMSO)']), verbo([induces]), complemento([mesoderm, and, both, embryonic, cardiac, and, skeletal, muscle, 'differentiation,', while, retinoic, acid, '(', 'RA)', is, an, inducer, of, neuroectodermal, differentiation])].
[sujeto(['P19', cells, constitutively]), verbo([express]), complemento([the, retinoic, acid, receptor, alpha, '(', 'RAR', 'alpha)', and, 'RAR', gamma, mRNAs, while, 'RAR', beta, expression, is, induced, by, 'RA', through, a, consensus, 'RA-response', element, in, the, 'RAR', beta, promoter])].
[sujeto(['In', the, present, study, we, show, that, the, 'RAR', beta, transcript, is, strongly]), verbo([expressed]), complemento([in, both, 'P19', cells, and, in, a, 'RA-nonresponsive', derivative, of, 'P19', 'cells,', called, 'RAC65,', during, 'DMSO-induced', mesoderm, and, muscle, differentiation])].
[sujeto(['Reverse', 'transcriptase-polymerase', chain, reaction, analysis, indicated, that, 'RAR', beta, 2, is, the, predominant, isoform]), verbo([expressed]), complemento([in, 'DMSO-differentiated', 'cells,', providing, the, first, evidence, for, 'RA-independent', regulation, of, 'RAR', beta, 2, transcript, levels])].
[sujeto(['Immunoblot', analysis, showed, a, 3, -, fold]), verbo([increase]), complemento([in, the, 'RAR', beta, protein, expression, over, basal, levels, in, differentiated, 'cells,', and, immunohistochemistry, indicated, that, all, cells, in, the, culture, including, muscle, reacted, positively, for, the, 'RAR', beta, protein])].
[sujeto(['Little', transcription, of, the, 'RAR', beta, gene, was, detected, in]), verbo([nuclear]), complemento(['run-off', assays, of, undifferentiated, 'P19', cells, and, only, a, small, increase, in, transcription, was, observed, in, nuclei, from, 'DMSO-treated', cells])].
[sujeto(['RA', treatment, of, 'P19', cells, stably, transfected, with, the, 'RA-responsive', element, from, the, 'RAR', beta, gene, showed, that, 'RAR', beta, 2, mRNA, expression, during, 'DMSO', differentiation, was]), verbo([associated]), complemento([with, increased, sensitivity, to, 'RA'])].
[sujeto(['Together', these, data, show, that, 'RAR', beta, 2, is]), verbo([expressed]), complemento([spontaneously, in, an, apparently, 'RA-independent', manner, in, differentiating, mesoderm, and, mesoderm, 'derivatives,', resulting, in, increased, sensitivity, to, 'RA', in, these, cells])].
[sujeto(['Retinoids', are, pivotal, in, the, growth, and, differentiation, of, certain, epithelial, 'tissues,']), verbo([interacting]), complemento([with, nuclear, retinoid, receptors, '(', the, retinoic, acid, receptors, '[', 'RARs]', and, retinoid, 'X', receptors, '[', 'RXRs]),', which, function, as, transcription, factors])].
[sujeto(['RAR-beta', may]), verbo([suppress]), complemento([tumorigenicity])].
[sujeto(['Therefore,', we, hypothesized, that]), verbo([loss]), complemento([of, expression, of, 'RAR-beta', gene, in, stage, 'I', 'NSCLC', is, a, prognostic, factor, of, a, poor, clinical, outcome])].
[sujeto(['Unexpectedly,', strong, 'RAR-beta', expression, was]), verbo([associated]), complemento([with, a, significantly, worse, outcome, of, 'early-stage', 'NSCLC'])].
[sujeto(['The', mechanisms, underlying, this, clinically, and, biologically, important]), verbo([finding]), complemento([should, be, further, explored])].
[sujeto(['The', biologic, activity, of, vitamin, 'A', 'depends,', in, 'part,', on, its, metabolism, to, active]), verbo([nuclear]), complemento([receptor, 'ligands,', chiefly, retinoic, acid])].
[sujeto(['The', cellular, 'retinol-binding', protein, '(', 'CRBP)']), verbo([binds]), complemento([vitamin, 'A', with, high, affinity, and, is, postulated, to, regulate, its, uptake, and, metabolism])].
[sujeto(['CRBP', was]), verbo([expressed]), complemento([in, all, 15, mammoplasty, specimens, '(', normal, breast, 'tissue)', and, in, 33, of, 35, available, specimens, of, normal, tissue, adjacent, to, carcinoma])].
[sujeto(['The']), verbo([loss]), complemento([of, 'CRBP', expression, was, as, frequent, in, ductal, carcinoma, in, situ, '(', six, '[', 27, '%', ']', of, 22, ')', as, in, invasive, lesions, '(', six, '[', 22, '%', ']', of, 27, ')', ',', suggesting, that, it, is, a, relatively, early, event, in, carcinogenesis, and, not, associated, with, patient, 'age,', tumor, 'grade,', and, expression, of, steroid, receptors, or, 'c-Myc'])].
[sujeto(['Preliminary', experiments, did, not]), verbo([find]), complemento([an, association, between, 'CRBP', and, retinoic, acid, receptor, beta, 'loss,', but, most, '(', four, of, 'five)', 'CRBP-negative', tumors, were, also, retinoic, acid, receptor, beta, negative])].
[sujeto(['We', hypothesize, that, the]), verbo([loss]), complemento([of, 'CRBP', restricts, the, effects, of, endogenous, vitamin, 'A', on, breast, epithelial, cells])].
[sujeto(['We']), verbo([found]), complemento([that, 'CA-OV3', cells, could, be, made, resistant, to, 'all-trans-RA', growth, inhibition, by, overexpressing, 'RAR-beta(R269Q),', an, efficient, dominant, negative, mutant, which, inhibits, the, function, of, all, 'RAR', subtypes])].
[sujeto(['Our', results, show, that, cell, lines]), verbo([expressing]), complemento([reduced, levels, of, either, 'RAR-alpha', alone, or, 'RXR-alpha', alone, exhibited, a, small, decrease, in, sensitivity, to, growth, inhibition, by, 'all-trans-RA'])].
[sujeto(['These', results, demonstrate, the, importance, of, both, retinoid]), verbo([nuclear]), complemento([receptors, and, 'retinoid-X', receptors, in, 'general,', and, 'RAR-alpha', and, 'RXR-alpha', in, 'particular,', as, mediators, of, ovarian, carcinoma, cell, growth, inhibition, by, retinoids])].
[sujeto(['Retinoids,', analogues, of, vitamin, 'A,', are]), verbo([required]), complemento([for, the, normal, growth, and, differentiation, of, human, bronchial, epithelium])].
[sujeto(['They', are, also, able, to, reverse, premalignant, lesions, and]), verbo([prevent]), complemento([second, primary, tumors, in, some, patients, with, 'non-small-cell', lung, cancer, '(', 'NSCLC)'])].
[sujeto([',', retinoic, acid, receptors, '[', 'RARs]', and, retinoid, 'X', receptors, '[', 'RXRs]),', which]), verbo([mediate]), complemento([most, retinoid, 'actions,', are, 'suppressed,', abnormal, activity, may, result, that, could, enhance, cancer, development])].
[sujeto(['Transcripts', of]), verbo([nuclear]), complemento([retinoid, receptors, were, detected, in, 'formalin-fixed,', 'paraffin-embedded', specimens, by, use, of, 'digoxigenin-labeled', riboprobes, specific, for, 'RAR', 'alpha,', 'RAR', 'beta,', 'RAR', 'gamma,', 'RXR', 'alpha,', 'RXR', 'beta,', and, 'RXR', gamma, for, in, situ, hybridization, to, histologic, specimens, from, 79, patients, with, 'NSCLC', and, as, control, from, 17, patients, with, 'non-lung', cancer])].
[sujeto(['The', quality, and, specificity, of, the, 'digoxigenin-labeled', probes, were, determined, by, northern, 'blotting,', and, the, specificity, of, the]), verbo([binding]), complemento([of, antisense, riboprobes, was, verified, by, use, of, sense, probes, as, controls])].
[sujeto(['All', receptors, were]), verbo([expressed]), complemento([in, at, least, 89, '%', of, control, normal, bronchial, tissue, specimens, from, 17, patients, without, a, primary, lung, cancer, and, in, distant, normal, bronchus, specimens, from, patients, with, 'NSCLC'])].
[sujeto(['RAR', 'alpha,', 'RXR', 'alpha,', and, 'RXR', gamma, were]), verbo([expressed]), complemento([in, more, than, 95, '%', of, the, 'NSCLC', specimens])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, the, expression, of, 'RAR', 'alpha,', 'RXR', 'alpha,', and, 'RXR', gamma, is, not, altered, in, 'NSCLC;', 'however,', expression, of, 'RAR', beta, and, possibly, also, of, 'RAR', gamma, and, 'RXR', beta, is, suppressed, in, a, large, percentage, of, patients, with, lung, cancer])].
[sujeto(['The']), verbo([loss]), complemento([of, expression, of, one, or, more, of, these, nuclear, retinoid, receptors, may, be, associated, with, lung, carcinogenesis])].
[sujeto(['Cellular', retinol]), verbo([binding]), complemento([protein, 'II', '(', 'CRBPII)', is, an, abundant, small, intestinal, protein, that, facilitates, vitamin, 'A', trafficking, and, metabolism])].
[sujeto(['All-trans-', or, 9, -, 'cis-retinoic', acid]), verbo([increased]), complemento(['CRBPII', mRNA, levels, 'two-', to, threefold])].
[sujeto(['This', was]), verbo([associated]), complemento([with, a, 50, '%', increase, in, retinol, absorption])].
[sujeto(['Retinoic', acid, receptor, beta, and, apolipoprotein, 'A1', regulatory, 'protein-1,', two]), verbo([nuclear]), complemento([receptors, that, bind, to, the, 'CRBPII', 'promoter,', were, also, 'induced,', whereas, other, retinoid, and, orphan, receptors, were, not])].
[sujeto(['Thus,', retinoic, acid, may]), verbo([regulate]), complemento(['CRBPII', expression, directly, or, by, selectively, changing, levels, of, nuclear, receptors, or, other, factors])].
[sujeto(['These', studies, are, the, first, to, demonstrate, that, retinoic, acid, can]), verbo([modulate]), complemento([endogenous, 'CRBPII', mRNA, levels, and, retinol, absorption, in, 'Caco-2', cells, and, suggest, that, human, intestinal, vitamin, 'A', absorption, may, be, regulated, by, retinoids])].
[sujeto(['The', 'L-myc', oncogene, is, commonly]), verbo([expressed]), complemento([in, small, cell, lung, cancer, '(', 'SCLC)', cells, and, is, associated, with, 'SCLC', cells, with, a, high, level, of, neuroendocrine, differentiation, and, a, relatively, low, proliferative, index])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, that, 'all-trans-retinoic', acid, '(', 'RA)', inhibits, the, growth, of, 'NCI-H82', 'SCLC', cells, in, association, with, increased, neuroendocrine, 'differentiation,', increased, 'L-myc', gene, expression, and, decreased, 'c-myc', gene, expression])].
[sujeto(['By']), verbo([nuclear]), complemento(['run-on', 'analysis,', there, was, a, clear, increase, in, 'L-myc', transcript, initiation, in, 'NCI-H82', cells, treated, with, 1, microM, 'RA,', but, no, alteration, was, noted, in, the, baseline, degree, of, transcript, attenuation, when, compared, to, control, cells])].
[sujeto(['A', marked, 'dose-dependent']), verbo([increase]), complemento([in, 'RARbeta', expression, was, also, demonstrated, in, 'RA-treated', 'NCI-H82', cells])].
[sujeto(['We', conclude, that, 'RA-mediated', 'up-regulation', of, 'L-myc', gene, expression, occurs, through, stimulation, of, transcript, initiation, and, that, the, biological, effects, of, 'RA', in, 'SCLC', cells, may, be]), verbo([mediated]), complemento([through, 'RARbeta-dependent', pathways])].
[sujeto(['Many', of, the, biological, effects, of, retinoic, acid, are]), verbo([mediated]), complemento([by, its, nuclear, receptors, '(', 'RAR-alpha,', 'RAR-beta,', and, 'RAR-gamma),', and, each, of, these, three, receptors, exist, in, multiple, isoforms])].
[sujeto(['As', a, first, step, to, identify, if, any, of, the, receptor, isoforms, are]), verbo([involved]), complemento([in, dysmorphogenesis, which, is, induced, in, mouse, embryos, after, treatment, with, retinoic, acid, '(', 'RA),', we, examined, the, levels, of, mRNA, of, several, isoforms, of, each, 'RAR', in, the, limb, buds, and, other, embryonic, regions, of, normal, and, 'RA-treated', embryos])].
[sujeto(['Within', 3, to, 6, hr, after, treatment, of, mice, on, day, 11, of, gestation, with, 'RA,', 'RAR-beta', 2, mRNA, levels, in, the, whole, embryo]), verbo([increased]), complemento([7, -, fold, while, both, 'RAR-alpha', 2, and, 'RAR-gamma', 1, mRNA, levels, were, elevated, only, 2, -, fold])].
[sujeto(['Retinol,', the, precursor, of, 'RA', in, the, 'embryo,', was, also, capable, of, elevating, 'RAR-beta', 2, mRNA, levels, in, the, limb, 'bud,', but, the]), verbo([increase]), complemento([was, 'delayed,', apparently, indicating, that, metabolic, conversion, of, retinol, to, 'RA', preceded, the, effect, on, mRNA, levels])].
[sujeto(['(', 'ABSTRACT', 'TRUNCATED', 'AT', 250, 'WORDS)', 'The', human]), verbo([nuclear]), complemento([receptor, of, retinoic, acid, hRARgamma, is, a, 'ligand-dependent', transcription, regulator])].
[sujeto(['The', 'non-ionic', detergent, is]), verbo([required]), complemento([for, stabilization, and, crystallization, of, the, hRARgamma, 'LBD', and, mediates, a, crystal, contact, in, the, region, where, coactivator, proteins, bind])].
[sujeto(['Candidate', gene, studies]), verbo([have]), complemento([reported, genetic, associations, with, 'ACT,', but, these, studies, have, in, general, lacked, robust, patient, 'numbers,', independent, replication, or, functional, validation])].
[sujeto(['Ser427Leu)', in, 'RARG', highly]), verbo([associated]), complemento([with, 'ACT', '(', 'P', =, 5.9, ×, 10, '(', -, 8, ')', ',', odds, ratio, '(', 95, '%', confidence, 'interval)', =, 4.7, '(', 2.7, -, 8.3, ')', ')'])].
[sujeto(['This', variant, alters, 'RARG', 'function,']), verbo([leading]), complemento([to, derepression, of, the, key, 'ACT', genetic, determinant, 'Top2b,', and, provides, new, insight, into, the, pathophysiology, of, this, severe, adverse, drug, reaction])].
[sujeto(['Stem', cells]), verbo([ensure]), complemento([tissue, homeostasis, through, the, production, of, differentiating, and, 'self-renewing', progeny])].
[sujeto(['Aundiff', include, glial, cell, 'line-derived', neurotrophic, factor, receptor, α1, '(', 'GFRα1)(+)', and, neurogenin, 3, '(', 'NGN3)(+)', 'subpopulations,', both, of, which]), verbo([retain]), complemento([the, ability, to, 'self-renew'])].
[sujeto(['In', the, present, 'study,', by, combining, fate, analysis, of, 'pulse-labeled', cells, and, a, model, of, vitamin, 'A', 'deficiency,', we, demonstrate, that, retinoic, acid, '(', 'RA),', which, may, periodically]), verbo([increase]), complemento([in, concentration, in, the, tubules, during, the, seminiferous, epithelial, 'cycle,', induced, only, 'NGN3(+)', cells, to, differentiate])].
[sujeto(['Comparison', of, gene, expression, revealed, that, retinoic, acid, receptor, γ, '(', 'Rarg)', was, predominantly]), verbo([expressed]), complemento([in, 'NGN3(+)', 'cells,', but, not, in, 'GFRα1(+)', 'cells,', whereas, the, expression, levels, of, many, other, 'RA', 'response-related', genes, were, similar, in, the, two, populations])].
[sujeto(['Ectopic', expression, of, 'RARγ', was, sufficient, to]), verbo([induce]), complemento(['GFRα1(+)', cells, to, directly, differentiate, to, 'KIT(+)', cells, without, transiting, the, 'NGN3(+)', state])].
[sujeto(['The', limitation, of, this, technology, is, that, these, 'genome-integration', viruses, may]), verbo([increase]), complemento([the, risk, of, gene, mutation, and, cause, insertional, mutagenesis])].
[sujeto(['We', recently]), verbo([found]), complemento([that, 'non-integration', adenovirus, carrying, neuronal, transcription, factors, can, induce, fibroblasts, to, neurons])].
[sujeto(['In', this, study, we, show, that, the, combination, of, 'Rarg', '(', retinoic, acid, receptor, 'γ)', and, 'Nr5a2', '(']), verbo([nuclear]), complemento([receptor, subfamily, 5, ',', group, 'A,', member, 2, ;, also, known, as, 'Lrh-1', '(', liver, receptor, homologue, 1, ')', ')', rapidly, promote, the, iN, cell, maturation, within, 1, week, and, greatly, facilitate, the, conversion, with, neuronal, purities, of, '∼50%', and, yields, of, &, 'gt;130%'])].
[sujeto(['Vitamin', 'A', and, its, derivatives, '(', 'retinoids)', are, important, regulators, of, 'haematopoiesis,']), verbo([acting]), complemento([via, retinoic, acid, receptors, '(', 'RARs)'])].
[sujeto(['Embryos', homozygous, for, the, dd, allele, possess, communicating, diaphragmatic, 'hernias,', central, tendon, patterning, 'defects,', and]), verbo([increased]), complemento([cell, proliferation, with, diaphragmatic, tissue, hyperplasia])].
[sujeto(['Because', the, patterning, of, the, central, tendon, is, 'undescribed,', we, analyzed, the, expression, of, genes]), verbo([regulating]), complemento([tendonogenesis, in, 'dd/dd', mutant, 'embryos,', and, we, determined, that, retinoic, acid, '(', 'RA)', signaling, was, misregulautted])].
[sujeto(['Knockdown', of, 'Kif7,', and, retinoic, acid, receptors, alpha, '(', 'Rara),', beta, '(', 'Rarb),', and, gamma, '(', 'Rarg)', indicated, that, 'RA', signaling, is, dependent, on, these, genes, to]), verbo([promote]), complemento([tendonogenesis, within, the, embryonic, diaphragm])].
[sujeto(['Taken', 'together,', our, results]), verbo([provide]), complemento([evidence, for, a, model, in, which, inhibition, of, 'RA', receptor, signaling, promotes, 'CDH', pathogenesis, through, a, complex, gene, network])].
[sujeto(['Embryonic', stem, cells, '(', 'ESCs)']), verbo([have]), complemento([the, capacity, to, differentiate, into, nearly, all, sorts, of, cell, 'types,', including, germ, 'cells,', which, were, regarded, as, one, type, of, highly, specialized, cells, in, 'mammals,', taking, the, responsibility, of, transferring, genetic, materials, to, the, next, generation])].
[sujeto(['In', this, 'study,', several, 'miRNAs,', which, might, be, related, to, 'spermatogenesis,', were, initially, selected, and, detected, in, the, mouse, tissues, by, 'semi-polymerase', chain, reaction, '(', 'PCR)', and, quantitative, real, time, '(', 'qRT)-PCR', to]), verbo([find]), complemento([a, 'testis-specific', miRNA])].
[sujeto(['The', results, showed, that, 'miR-34c']), verbo([promoted]), complemento([mESCs, differentiation, into, male, 'germ-like', 'cells,', to, some, extent])].
[sujeto(['Then', 'miR-34c']), verbo([targeted]), complemento([genes, were, predicted, by, 'bioinformatics;', 'Retinoic', acid, receptor, gamma, '(', 'RARg)', was, 'selected,', and, two, 'dual-luciferase', reporter, vectors, contained, the, normal, and, mutated, 3, '\'', untranslated, region, of, 'RARg', were, 'constructed,', respectively])].
[sujeto(['By', miRNA, mimics, and, vector, 'co-transfection', 'experiment,', the, predicted]), verbo([target]), complemento(['gene-RARg', was, confirmed])].
[sujeto(['In', 'conclusion,', we]), verbo([found]), complemento([a, mammalian, male, germ, cell, specific, 'miRNA--miR-34c,', and, it, might, be, pivotal, in, mESCs, differentiation, into, male, germ, cells, through, its, 'target--RARg'])].
[sujeto(['Understanding', molecular, changes, in, 'ESCC', should, improve, identification, of, risk, factors, with, different, molecular, subtypes, and]), verbo([provide]), complemento([potential, targets, for, early, detection, and, therapy])].
[sujeto(['Our', study, aimed, to, obtain, a, molecular, signature, of, 'ESCC', through, the, regulation, network, based, on, differentially]), verbo([expressed]), complemento([genes, '(', 'DEGs)'])].
[sujeto(['In', 'conclusion,', our, regulation, network]), verbo([provided]), complemento([information, on, important, genes, which, might, be, useful, in, investigating, the, complex, interacting, mechanisms, underlying, the, disease])].
[sujeto(['Its', 'metabolite,', retinoic, acid, '(', 'RA),']), verbo([acts]), complemento([in, a, 'hormone-like', manner, through, binding, to, and, activating, three, nuclear, receptor, 'isotypes,', 'RA', receptor, '(', 'RAR)α', '(', 'RARA),', 'RARβ,', and, 'RARγ', '(', 'RARG)'])].
[sujeto(['Here,', we, show, that, 1, ')', 'RARG', is]), verbo([expressed]), complemento([by, 'A', aligned, '(', 'A(al))', 'spermatogonia,', as, well, as, during, the, transition, from, 'A(al)', to, 'A(1)', 'spermatogonia,', which, is, known, to, require, 'RA;', and, 2, ')', ablation, of, 'Rarg,', either, in, the, whole, mouse, or, specifically, in, 'spermatogonia,', does, not, affect, meiosis, and, spermiogenesis, but, impairs, the, 'A(al)', to, 'A(1)', transition, in, the, course, of, some, of, the, seminiferous, epithelium, cycles])].
[sujeto(['During', the, prepubertal, spermatogenic, 'wave,', the]), verbo([loss]), complemento([of, 'RARG', function, can, however, be, compensated, by, 'RARA,', as, indicated, by, the, normal, timing, of, appearance, of, meiotic, cells, in, 'Rarg-null', testes])].
[sujeto(['Accordingly,', 'RARG-', and, 'RARA-selective', agonists, are, both, able, to]), verbo([stimulate]), complemento(['Stra8', expression, in, 'wild-type', prepubertal, testes])].
[sujeto(['This', latter, observation, supports, the, notion, that, the, 'RA-signaling', pathway, previously, shown, to, operate, in, 'Sertoli', cells, also]), verbo([participates]), complemento([in, spermatogonia, differentiation])].
[sujeto(['Somatic', cells, can, be, reprogrammed, to]), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'iPSCs)', by, expressing, four, transcription, 'factors:', 'Oct4,', 'Sox2,', 'Klf4,', and, 'c-Myc'])].
[sujeto(['Here', we]), verbo([report]), complemento([that, enhancing, 'RA', signaling, by, expressing, 'RA', receptors, '(', 'RARs)', or, by, 'RA', agonists, profoundly, promoted, 'reprogramming,', but, inhibiting, it, using, a, 'RAR-α', 'dominant-negative', form, completely, blocked, it])].
[sujeto(['Coexpressing', 'Rarg', '(', 'RAR-γ)', and, 'Lrh-1', '(', liver, receptor, homologue, 1, ;, 'Nr5a2)', with, the, four, factors, greatly, accelerated, reprogramming, so, that, reprogramming, of, mouse, embryonic, fibroblast, cells, to, 'ground-state', iPSCs]), verbo([requires]), complemento([only, 4, d, induction, of, these, six, factors])].
[sujeto(['Our', findings, demonstrate, that, signaling, through, 'RARs']), verbo([has]), complemento([critical, roles, in, molecular, reprogramming, and, that, the, synergistic, interaction, between, 'Rarg', and, 'Lrh1', directs, reprogramming, toward, 'ground-state', pluripotency])].
[sujeto(['There', is]), verbo([increasing]), complemento([evidence, that, dioxin, interferes, with, 'all-trans-retinoic', acid, '(', 'atRA),', a, 'hormone-like', signal, derived, from, vitamin, 'A,', which, plays, an, essential, role, during, embryonic, development])].
[sujeto(['Although', similarities]), verbo([have]), complemento([been, described, between, 'dioxin-induced', toxicity, and, the, outcome, of, altered, atRA, signaling, during, palate, 'development,', their, relationship, needs, to, be, clarified])].
[sujeto(['We', used, a, genetic, approach, to, understand, the, interaction, between, atRA, and, dioxin, and, to, identify, the, cell, type]), verbo([targeted]), complemento([by, dioxin, toxicity, during, secondary, palate, formation, in, mice])].
[sujeto(['We']), verbo([found]), complemento([that, an, intact, atRA, signal, was, required, to, enable, 'TCDD', to, induce, cleft, palate])].
[sujeto(['This', mechanism, is, likely]), verbo([conserved]), complemento([throughout, vertebrate, evolution, and, may, therefore, be, relevant, in, humans])].
[sujeto(['MM']), verbo([has]), complemento([been, induced, by, retinoic, acid, teratogenicity, in, rodent, models])].
[sujeto(['We', hypothesized, that, genetic, variants, influencing, retinoic, acid, '(', 'RA)', induction, via, retinoic, acid, receptors, '(', 'RARs)', may, be]), verbo([associated]), complemento([with, risk, for, 'MM'])].
[sujeto(['One', variant, in, the, 'RARA', gene, '(', 'rs12051734),', three, variants, in, the, 'RARB', gene, '(', 'rs6799734,', 'rs12630816,', 'rs17016462),', and, a, single, variant, in, the, 'RARG', gene, '(', 'rs3741434)', were]), verbo([found]), complemento([to, be, statistically, significant, at, p, &, 'lt;', 0.05])].
[sujeto(['RAR', genes, were]), verbo([associated]), complemento([with, risk, for, 'MM'])].
[sujeto(['For', all]), verbo([associated]), complemento(['SNPs,', the, rare, allele, conferred, a, protective, effect, for, 'MM', susceptibility])].
[sujeto(['We']), verbo([report]), complemento([a, case, of, acute, myeloid, leukemia, with, a, clonal, translocation, 't(11;12)(p15;q13)', displaying, morphologic, and, immunophenotypic, features, resembling, the, classical, hypergranular, subtype, of, acute, promyelocytic, leukemia])].
[sujeto(['The', involvement, of, 'RARG', in, a, chimeric, fusion, transcript]), verbo([has]), complemento([not, been, reported, previously, in, human, leukemia])].
[sujeto(['The', role, of, retinoic, acid, '(', 'RA)', in, limb, development, is, 'unclear,', although, it]), verbo([has]), complemento([been, suggested, to, be, a, proximalizing, factor, which, plays, a, morphogenetic, role, in, pattern, formation])].
[sujeto(['Exogenous', 'RA', produces, a, teratogenic, effect, on, limb, 'morphology;', 'similarly,', changes, in, the, endogenous, distribution, of, 'RA', following, genetic, ablation, of, the, 'RA-metabolizing', 'enzyme,', 'CYP26B1,', result, in, phocomelia, accompanied, by, changes, in, expression, of, 'proximo-distal', '(', 'P-D)', patterning, 'genes,']), verbo([increased]), complemento([cell, 'death,', and, delayed, chondrocyte, maturation])].
[sujeto(['This', model]), verbo([reveals]), complemento([two, genetically, separable, effects, of, 'RA', in, the, 'limb:', an, apoptotic, effect, mediated, by, 'RARgamma', in, the, presence, of, ectopic, 'RA,', and, a, 'P-D', patterning, defect, which, is, uncovered, following, the, loss, of, both, 'CYP26B1', and, 'RARgamma'])].
[sujeto(['These', data]), verbo([provide]), complemento([genetic, evidence, to, clarify, the, roles, of, both, 'RA', and, 'CYP26B1', in, limb, outgrowth, and, 'proximo-distal', patterning])].
[sujeto(['We', investigated, miRNA, expression, changes]), verbo([associated]), complemento([with, 'stress-induced', premature, senescence, '(', 'SIPS)', in, primary, cultures, of, human, diploid, fibroblast, '(', 'HDF)', and, human, trabecular, meshwork, '(', 'HTM)', cells])].
[sujeto(['SIPS', in, both, 'HTM', and, 'HDF', cell, types, was]), verbo([associated]), complemento([with, significant, 'down-regulation', of, four, members, of, the, 'miR-15', family, and, five, miRNAs, of, the, 'miR-106b', family, located, in, the, oncogenic, clusters, 'miR-17-92,', 'miR-106a-363,', and, 'miR-106b-25'])].
[sujeto(['SIPS', was, also]), verbo([associated]), complemento([with, 'up-regulation', of, two, miRNAs, '(', 182, and, 183, ')', from, the, 'miR-183-96-182', cluster])].
[sujeto(['Transfection', with, 'miR-106a', agomir]), verbo([inhibited]), complemento([the, 'up-regulation', of, 'p21(CDKN1A)', associated, with, 'SIPS', while, transfection, with, 'miR-106a', antagomir, led, to, increased, 'p21(CDKN1A)', expression, in, senescent, cells])].
[sujeto(['In', 'addition,', we, identified, retinoic, acid, receptor, gamma, '(', 'RARG)', as, a]), verbo([target]), complemento([of, 'miR-182', and, showed, that, this, protein, was, 'down-regulated', during, 'SIPS', in, 'HDF', and, 'HTM', cells])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, changes, in, miRNA, expression, might, contribute, to, phenotypic, alterations, of, senescent, cells, by, modulating, the, expression, of, key, regulatory, proteins, such, as, 'p21(CDKN1A)', as, well, as, by, targeting, genes, that, are, 'down-regulated', in, senescent, cells, such, as, 'RARG'])].
[sujeto(['We']), verbo([report]), complemento([a, case, of, adult, acute, myeloid, leukemia, with, a, new, 't(11;12)(p15;q13)', underlying, a, 'NUP98', rearrangement, without, 'HOXC', cluster, gene, involvement])].
[sujeto(['It', is, noteworthy, that, so, far, only, 'ESPL1']), verbo([has]), complemento([been, implicated, in, human, cancers])].
[sujeto(['The', molecular, events]), verbo([associated]), complemento([with, the, development, of, adenocarcinoma, of, the, oesophagus, are, not, well, understood])].
[sujeto(['Gene', expression]), verbo([associated]), complemento([with, oesophageal, adenocarcinoma, was, investigated, using, a, cDNA, array, containing, 1, ',', 176, human, 'cancer-associated', genes])].
[sujeto(['Approximately', 59, '%', of, the, genes, were]), verbo([expressed]), complemento([at, detectable, levels, with, 15, genes, '(', 1.3, '%', ')', exhibiting, differential, '(', &, 'gt;', 2.5, -, 'fold)', expression, in, either, normal, oesophagus, or, adenocarcinoma, tissue])].
[sujeto(['Many', of, these, differentially]), verbo([expressed]), complemento([genes, influence, 'cell-cell', 'adhesion,', 'cell-extracellular', matrix, and, 'composition,', transcriptional, activation, and, cell, cycle, progression, and, are, likely, to, contribute, to, development, of, oesophageal, adenocarcinoma])].
[sujeto(['Heterotopic', ossification, '(', 'HO)']), verbo([involves]), complemento([formation, of, endochondral, bone, at, 'non-skeletal', 'sites,', is, prevalent, in, severely, wounded, service, 'members,', and, causes, significant, complications, and, delayed, rehabilitation])].
[sujeto(['Previously,', we, showed, that, the, retinoic, acid, receptor, γ, agonist, 'Palovarotene']), verbo([inhibited]), complemento([subcutaneous, and, intramuscular, 'HO', in, 'mice,', but, those, models, do, not, mimic, complex, combat, injury])].
[sujeto(['Thus,', we, tested, 'Palovarotene', in, our, validated, rat, 'trauma-induced', 'HO', model, that]), verbo([involves]), complemento(['blast-related', limb, 'injury,', femoral, 'fracture,', quadriceps, crush, 'injury,', amputation, and, infection, with, 'methicillin-resistant', 'Staphylococcus', aureus, from, combat, wound, infections])].
[sujeto(['Compared', to, 'vehicle-control', 'animals,', 'Palovarotene', significantly]), verbo([decreased]), complemento(['HO', by, 50, to, 60, '%', regardless, of, when, the, treatment, started, and, if, infection, was, present])].
[sujeto(['Custom', gene, array, data, verified, that, while, expression, of, key, chondrogenic, and, osteogenic, genes, was]), verbo([decreased]), complemento([within, soft, tissues, of, residual, limb, in, 'Palovarotene-treated', 'rats,', expression, of, cartilage, catabolic, genes, was, 'increased,', including, matrix, 'metalloproteinase-9'])].
[sujeto(['Our', data, show, for, the, first, time, that, 'Palovarotene', significantly]), verbo([inhibits]), complemento(['HO', triggered, by, blast, injury, and, associated, 'complications,', strongly, indicating, that, it, may, prevent, 'HO', in, patients, at, high, risk, such, as, those, sustaining, combat, injuries, and, other, forms, of, blast, trauma])].
[sujeto(['The']), verbo([nuclear]), complemento([retinoic, acid, receptors, '(', 'RARs)', play, key, roles, in, skeletal, development, and, endochondral, ossification])].
[sujeto(['Previously,', we, showed, that, 'RARγ']), verbo([regulates]), complemento([chondrogenesis, and, that, pharmacological, activation, of, 'RARγ', blocked, heterotopic, ossification, '(', 'HO),', pathology, in, which, endochondral, bone, forms, in, soft, tissues])].
[sujeto(['Thus,', we, reasoned, that, pharmacological, inhibition, of, 'RARγ', should]), verbo([enhance]), complemento([endochondral, 'ossification,', leading, to, a, potential, therapeutic, strategy, for, bone, deficiencies])].
[sujeto(['Next,', we, implanted, a, mixture, of, 'Matrigel', and, rhBMP2, subdermally, to]), verbo([induce]), complemento([ectopic, endochondral, ossification])].
[sujeto(['Administration', of, 'RARγ', antagonists, significantly]), verbo([stimulated]), complemento([ectopic, bone, formation, in, wild, type, but, not, in, 'RARγ-null', mice])].
[sujeto(['The', 'antagonist-induced']), verbo([increases]), complemento([in, bone, formation, were, preceded, by, increases, in, cartilage, formation, and, were, accompanied, by, higher, levels, of, phosphorylated, 'Smad1/5/8', '(', 'pSmad1/5/8)', compared, to, 'vehicle-treated', control])].
[sujeto(['Higher', 'pSmad1/5/8', levels, were, also, observed, in, cartilaginous, tissues, forming, in, healing, bone, defects, in, 'RARγ-null', 'mice,', and]), verbo([increases]), complemento([in, 'pSmad1/5/8', levels, and, 'Id1-luc', activity, were, observed, in, 'RARγ', 'antagonist-treated', chondrogenic, cells, in, culture])].
[sujeto(['Our', data, show, that, genetic, or, pharmacological, interference, with, 'RARγ']), verbo([stimulates]), complemento([endochondral, bone, formation, and, does, so, at, least, in, part, by, stimulating, canonical, 'BMP', signaling])].
[sujeto(['This', pharmacologic, strategy, could, represent, a, new, tool, to]), verbo([enhance]), complemento([endochondral, bone, formation, in, the, setting, of, various, orthopedic, surgical, interventions, and, other, skeletal, deficiencies])].
[sujeto(['X-ray', crystallography, and, 'structure-based', drug, design, were, used, to, improve, selectivity, for, 'RARγ', by]), verbo([targeting]), complemento([residue, differences, in, the, ligand, binding, pockets, of, these, receptors])].
[sujeto(['This', resulted, in, the, discovery, of, novel, antagonists, which]), verbo([maintained]), complemento(['RARγ', potency, but, were, greater, than, 500, -, fold, selective, versus, 'RARα', and, 'RARβ'])].
[sujeto(['Epidemiological,', 'clinical,', biochemical, and, genetic, research]), verbo([has]), complemento([revealed, that, renal, cell, cancer, '(', 'RCC)', etiology, is, 'hormone-related'])].
[sujeto(['It', was, shown, that, hormone, receptors, are, abnormally]), verbo([expressed]), complemento([in, 'RCC', cells])].
[sujeto(['Cellular', 'proliferation,', 'migration,', 'angiogenesis,', and, drug, resistance, in, 'RCC', is]), verbo([modulated]), complemento([by, 'para-', and, autocrine, hormonal, stimulation])].
[sujeto(['On', the, 'contrary,', corticotropin]), verbo([releasing]), complemento([hormone, was, reported, to, inhibit, 'RCC', cell, proliferation, and, regulate, angiogenesis])].
[sujeto(['Overexpression', of, luteinizing, hormone, also]), verbo([promotes]), complemento(['RCC', tumor, angiogenesis])].
[sujeto(['Estrogen', receptor, α, overexpression]), verbo([increases]), complemento([the, transcriptional, factor, activity, of, hypoxia, inducible, factor, 'HIF-1α,', but, estrogen, receptor, β, has, a, cancer, suppressive, role])].
[sujeto(['In', 'RCC,', 'follicle-stimulating', hormone, receptor]), verbo([promotes]), complemento([angiogenesis, and, metastatic, formation, via, 'VEGF', release])].
[sujeto(['Mineralocorticoid', receptor, overexpression]), verbo([promotes]), complemento([cell, survival, and, increases, 'RCC', cell, proliferation])].
[sujeto(['RAR-β']), verbo([promotes]), complemento([tumorigenesis, but, retinoic, acid, receptor, γ, expression, correlates, negatively, with, the, 'TNM', stage, at, diagnosis])].
[sujeto(['Molecular', data, analysis, revealed, the, possibility, of, renal, cancer, cell, proliferation, induction, via, hormone]), verbo([activated]), complemento([pathways])].
[sujeto(['Fibrodysplasia', ossificans, progressiva, '(', 'FOP),', a, rare, and, as, yet, untreatable, genetic, disorder, of, progressive, extraskeletal, 'ossification,', is, the, most, disabling, form, of, heterotopic, ossification, '(', 'HO)', in, humans, and]), verbo([causes]), complemento([skeletal, 'deformities,', movement, 'impairment,', and, premature, death])].
[sujeto(['Most', 'FOP', patients, carry, an]), verbo([activating]), complemento([mutation, in, a, bone, morphogenetic, protein, '(', 'BMP)', type, 'I', receptor, 'gene,', 'ACVR1(R206H)', ',', that, promotes, ectopic, chondrogenesis, and, osteogenesis, 'and,', in, 'turn,', 'HO'])].
[sujeto(['We', showed, previously, that, the, retinoic, acid, receptor, γ, '(', 'RARγ)', agonist, palovarotene, effectively]), verbo([inhibited]), complemento(['HO', in, 'injury-induced', and, genetic, mouse, models, of, the, disease])].
[sujeto(['Here', we]), verbo([report]), complemento([that, the, drug, additionally, prevents, spontaneous, 'HO,', using, a, novel, 'conditional-on', 'knock-in', mouse, line, carrying, the, human, 'ACVR1(R206H)', mutation, for, classic, 'FOP'])].
[sujeto(['In', 'addition,', palovarotene, restored, long, bone, 'growth,']), verbo([maintained]), complemento([growth, plate, 'function,', and, protected, growing, mutant, neonates, when, given, to, lactating, mothers])].
[sujeto(['Importantly,', palovarotene]), verbo([maintained]), complemento(['joint,', 'limb,', and, body, 'motion,', providing, clear, evidence, for, its, encompassing, therapeutic, potential, as, a, treatment, for, 'FOP'])].
[sujeto(['Recent', mouse, studies, showed, that, 'HO', was, significantly]), verbo([inhibited]), complemento([by, systemic, treatment, with, a, corticosteroid, or, the, retinoic, acid, receptor, γ, agonist, 'Palovarotene'])].
[sujeto(['Because', these, drugs]), verbo([act]), complemento(['differently,', the, data, raised, intriguing, questions, including, whether, the, drugs, affected, 'HO', via, similar, 'means,', whether, a, combination, therapy, would, be, more, effective, or, whether, the, drugs, may, hamper, each, 'other\'s', action])].
[sujeto(['To', tackle, these, 'questions,', we, used, an, effective, 'HO', mouse, model]), verbo([involving]), complemento([subcutaneous, implantation, of, 'Matrigel', plus, 'rhBMP2,', and, compared, the, effectiveness, of, 'prednisone,', 'dexamathaosone,', 'Palovarotene', or, combination, of])].
[sujeto(['While', 'Palovarotene', had, effectively]), verbo([prevented]), complemento([the, initial, cartilaginous, phase, of, 'HO,', the, steroids, appeared, to, act, more, on, the, bony, phase])].
[sujeto(['In', reporter, 'assays,', dexamethasone, and, 'Palovarotene']), verbo([induced]), complemento([transcriptional, activity, of, their, respective, 'GRE', or, 'RARE', constructs, and, did, not, interfere, with, each, 'other\'s', pathway])].
[sujeto(['Interestingly,', both, drugs]), verbo([inhibited]), complemento([the, activity, of, a, reporter, construct, for, the, inflammatory, mediator, 'NF-κB,', particularly, in, combination])].
[sujeto(['Most', 'importantly,', they, directly, or, indirectly]), verbo([inhibit]), complemento([the, recruitment, of, immune, and, inflammatory, cells, present, at, the, affected, 'site,', thus, alleviating, the, effects, of, key, 'HO', instigators])].
[sujeto(['Vitamin', 'A']), verbo([has]), complemento([essential, but, largely, unexplained, roles, in, regulating, lymphopoiesis])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, retinoic, acid, receptor, '(', 'RAR)', 'γ-deficient', mice, have, hematopoietic, 'defects,', some, phenotypes, of, which, were, microenvironment, induced])].
[sujeto(['Bone', marrow, '(', 'BM)', microenvironment, cells, identified, by, either, their, expression, of, nestin, '(', 'Nes)', or, osterix, '(', 'Osx)']), verbo([have]), complemento([previously, been, shown, to, have, roles, in, regulating, lymphopoiesis])].
[sujeto(['In', the, 'thymus,', 'Nes', expression, was, restricted, to, thymic, stromal, cells, that]), verbo([expressed]), complemento([cerebellar, 'degeneration-related', 'Ag', 1, and, lacked, expression, of, epithelial, cell, adhesion, molecule])].
[sujeto(['These', cells]), verbo([expressed]), complemento(['platelet-derived', growth, factor, α, and, high, transcript, levels, of, 'Rars,', 'Cxcl12,', and, stem, cell, factor, '(', 'Scf)'])].
[sujeto(['Short-term', treatment, of, mice, with, 'all-trans', retinoic, acid, resulted, in]), verbo([increased]), complemento(['PreB', lymphopoiesis, in, 'BM', and, an, increase, in, thymic, 'double-negative', 4, 'T', 'cells,', inverse, to, that, observed, upon, 'Nes', 'cell-specific', deletion, of, 'Rarγ'])].
[sujeto(['Viral', infection, during, pregnancy]), verbo([has]), complemento([been, correlated, with, increased, frequency, of, autism, spectrum, disorder, '(', 'ASD)', in, offspring])].
[sujeto(['This', observation]), verbo([has]), complemento([been, modeled, in, rodents, subjected, to, maternal, immune, activation, '(', 'MIA)'])].
[sujeto(['The', immune, cell, populations, critical, in, the, 'MIA', model]), verbo([have]), complemento([not, been, identified])].
[sujeto(['Using', both, genetic, mutants, and, blocking, antibodies, in, 'mice,', we, show, that, retinoic, acid, 'receptor-related', orphan]), verbo([nuclear]), complemento([receptor, gamma, t, '(', 'RORγt)-dependent', effector, 'T', lymphocytes, '[', for, 'example,', 'T', helper, 17, '(', 'TH17)', 'cells]', and, the, effector, cytokine, 'interleukin-17a', '(', 'IL-17a)', are, required, in, mothers, for, 'MIA-induced', behavioral, abnormalities, in, offspring])].
[sujeto(['We']), verbo([find]), complemento([that, 'MIA', induces, an, abnormal, cortical, 'phenotype,', which, is, also, dependent, on, maternal, 'IL-17a,', in, the, fetal, brain])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, therapeutic, targeting, of, 'TH17', cells, in, susceptible, pregnant, mothers, may, reduce, the, likelihood, of, bearing, children, with, 'inflammation-induced', 'ASD-like', phenotypes])].
[sujeto(['The']), verbo([release]), complemento([of, matrix, metalloproteinases, '(', 'MMPs)', into, culture, supernatants, was, assessed, with, immunoblot, analysis, and, gelatin, zymography])].
[sujeto(['R667']), verbo([inhibited]), complemento([transforming, growth, 'factor-β1', '(', 'TGF-β1)-induced', collagen, gel, contraction, mediated, by, 'HTFs', in, a, 'concentration-', and, 'time-dependent', 'manner,', whereas, an, 'RARα', agonist, inhibited, this, process, to, a, lesser, extent, and, an, 'RARβ', agonist, had, no, effect])].
[sujeto(['R667']), verbo([inhibited]), complemento(['TGF-β1-induced', contraction, and, extracellular, matrix, synthesis, in, 'HTFs'])].
[sujeto(['Such', effects, might]), verbo([have]), complemento([contributed, to, the, lowering, of, 'IOP', by, 'R667', in, a, rat, model, of, glaucoma, filtration, surgery])].
[sujeto(['Restricted', availability, of, retinoic, acid, '(', 'RA)', in, the, testicular, milieu]), verbo([regulates]), complemento([transcriptional, activity, of, 'c-kit', '(', 'KIT,', 'CD117),', which, aids, in, the, determination, of, spermatogonial, 'stem-cell', differentiation])].
[sujeto(['The', effect, of, 'RA', on, 'c-kit']), verbo([has]), complemento([been, reported, 'previously,', but, its, mode, of, genomic, action, remains, unresolved])].
[sujeto(['A', novel, retinoic, acid, response, element, '(', 'RARE)', positioned, at, -, 989, nucleotides, upstream, of, the, transcription, start, site, '(', 'TSS)', was, 'identified,']), verbo([providing]), complemento([a, binding, site, for, a, dimeric, 'RA', receptor, '(', i])].
[sujeto([1, ')', ',', specificity, protein, 1, '(', 'SP1)', and, four, 'E26', 'transformation-specific', '(', 'ETS)', tandem]), verbo([binding]), complemento([sites, at, the, proximal, region])].
[sujeto(['Gel', retardation, and, chromatin, immunoprecipitation, '(', 'ChIP)', assays, showed]), verbo([binding]), complemento([for, 'RARγ,', 'PU'])].
[sujeto([1, and, 'SP1', to, the, predicted, consensus]), verbo([binding]), complemento(['sequences,', whereas, 'GABPα', occupied, only, two, out, of, four, 'ETS', binding, sites, within, the, 'c-kit', promoter, region])].
[sujeto(['We']), verbo([have]), complemento([previously, demonstrated, that, cigarette, smoke, is, associated, with, a, significant, reduction, of, retinoic, acid, in, rat, lungs, and, the, formation, of, tracheal, precancerous, lesions])].
[sujeto(['However,', the, underlying, mechanism, of, cancer, risk]), verbo([induced]), complemento([by, vitamin, 'A', deficiency, is, unclear])].
[sujeto(['Three', experimental, groups, were, exposed, to]), verbo([increasing]), complemento([doses, of, cigarette, smoke, from, 20, ',', 40, or, 60, commercial, 'cigarettes/day', for, 5, 'days/week'])].
[sujeto(['After', 6, 'weeks,', the, retinoic, acid, concentrations, in, the, lung, tissue, as, measured, via, high, performance, liquid, chromatography, '(', 'HPLC)', significantly]), verbo([decreased]), complemento(['(', 'P', &, 'lt;', 0.01, ')', in, cigarette, smoke, exposed, groups])].
[sujeto(['Western', 'Blot', analysis, revealed, that, cigarette, smoke, exposure]), verbo([increased]), complemento([lung, protein, expression, of, 'RAR', α, in, a, threshold, manner, and, decreased, 'RAR', β, and, 'RAR', γ, expression, in, a, 'dose-dependent', fashion])].
[sujeto(['Protein', expressions, of, cyclin, 'E', and, proliferating, cell]), verbo([nuclear]), complemento([antigen, '(', 'PCNA)', were, increased, significantly, in, a, 'dose-dependent', manner, in, cigarette, smoke, 'exposed-groups'])].
[sujeto(['Additionally,', there, was, a, significant]), verbo([increase]), complemento([in, protein, expression, of, cJun, and, cyclin, 'D1', demonstrating, a, threshold, effect, similar, to, that, exhibited, by, 'RARα,', suggesting, a, potential, independent, signaling, pathway, for, 'RARα', in, lung, carcinogenesis])].
[sujeto(['Findings', from, this, study]), verbo([suggest]), complemento([that, cigarette, 'smoke-induced', lung, retinoic, acid, depletion, may, involve, two, independent, 'pathways,', 'RARα-', and, 'RARβ-mediated,', responsible, for, the, increased, cancer, risk, associated, with, cigarette, 'smoke-induced', vitamin, 'A', deficiency])].
[sujeto(['The', commonly, used, inhalation, anesthetic, isoflurane, could, permeate, rapidly, through, the, placental, barrier, and]), verbo([induce]), complemento([toxicity, to, the, central, nervous, system, of, the, developing, fetus])].
[sujeto(['Pregnant', mice, were]), verbo([executed]), complemento([and, the, fetal, mice, were, weighed, and, observed])].
[sujeto(['Isoflurane']), verbo([decreased]), complemento(['self-renewal', and, the, expression, stemness, genes, '(', 'Nanog,', 'Oct4,', 'Sox2,', and, 'Lin28)', in, mESCs])].
[sujeto(['Vitamin', 'A', attenuated, the, effects, of, isoflurane]), verbo([inducing]), complemento(['self-renewal', inhibition])].
[sujeto(['Moreover,', isoflurane]), verbo([inhibits]), complemento([mESCs, 'self-renewal', through, retinoic, acid, receptor])].
[sujeto(['Retinoic', acid, signaling]), verbo([regulates]), complemento([several, biological, 'events,', including, myogenesis])].
[sujeto(['We', previously]), verbo([found]), complemento([that, retinoic, acid, receptor, γ, '(', 'RARγ)', agonist, blocks, heterotopic, 'ossification,', a, pathological, bone, formation, that, mostly, occurs, in, the, skeletal, muscle])].
[sujeto(['Interestingly,', 'RARγ', agonist, also, weakened, deterioration, of, muscle, architecture, adjacent, to, the, heterotopic, ossification, 'lesion,']), verbo([suggesting]), complemento([that, 'RARγ', agonist, may, oppose, skeletal, muscle, damage])].
[sujeto(['Furthermore,', we]), verbo([found]), complemento([a, rapid, increase, in, retinoid, signaling, in, lacerated, 'muscle,', as, monitored, by, retinoid, signaling, reporter, mice])].
[sujeto(['Together,', our, results, indicate, that, endogenous, 'RARγ', signaling, is]), verbo([involved]), complemento([in, muscle, repair, and, that, selective, 'RARγ', agonists, may, be, beneficial, to, promote, repair, in, various, types, of, muscle, injuries])].
[sujeto(['In', inflamed, intestinal, tissues, from, 'Crohn\'s', disease, 'patients,', numbers, of, 'CD127(+)', 'ILC1']), verbo([increased]), complemento([at, the, cost, of, 'ILC3'])].
[sujeto(['Here', we]), verbo([found]), complemento([that, differentiation, of, 'ILC3', to, 'CD127(+)', 'ILC1', is, reversible, in, vitro, and, in, vivo])].
[sujeto(['CD127(+)', 'ILC1', differentiated, to, 'ILC3', in, the, presence, of, 'interleukin-2', '(', 'IL-2),', 'IL-23,', and, 'IL-1β', dependent, on, the, transcription, factor, 'RORγt,', and, this, process, was]), verbo([enhanced]), complemento([in, the, presence, of, retinoic, acid])].
[sujeto(['Furthermore,', we, observed, in, resection, specimen, from, 'Crohn\'s', disease, patients, a, higher, proportion, of, 'CD14(+)', dendritic, cells, '(', 'DC),', which, in, vitro]), verbo([promoted]), complemento([polarization, from, 'ILC3', to, 'CD127(+)', 'ILC1'])].
[sujeto(['In', 'contrast,', 'CD14(-)', 'DCs']), verbo([promoted]), complemento([differentiation, from, 'CD127(+)', 'ILC1', toward, 'ILC3'])].
[sujeto(['These', observations]), verbo([suggest]), complemento([that, environmental, cues, determine, the, 'composition,', 'function,', and, phenotype, of, 'CD127(+)', 'ILC1', and, 'ILC3', in, the, gut])].
[sujeto(['Subretinal', fibrosis, contributes, to, the]), verbo([loss]), complemento([of, vision, associated, with, 'age-related', macular, degeneration, '(', 'AMD)'])].
[sujeto(['Transforming', growth, 'factor-β2', '(', 'TGF-β2)-induced', collagen, gel, contraction]), verbo([mediated]), complemento([by, the, 'RPE', cells, was, inhibited, by, the, 'RAR-γ', agonist, 'R667', in, a, 'concentration-', and, 'time-dependent', manner])].
[sujeto(['Expression', of, the, mesenchymal, markers, 'α-smooth', muscle, actin, and, 'fibronectin,', the]), verbo([release]), complemento([of, 'interleukin-6,', and, the, phosphorylation, of, 'paxillin,', 'mitogen-activated', protein, kinases, '(', 'ERK,', 'p38,', and, 'JNK),', 'Smad2,', and, 'AKT', induced, by, 'TGF-β2', were, also, suppressed, by, the, 'RAR-γ', agonist])].
[sujeto(['Furthermore,', gelatin, zymography, and, immunoblot, analysis, revealed, that, the, 'TGF-β2-induced']), verbo([release]), complemento([of, matrix, metalloproteinase, '(', 'MMP)-2,', 'MMP-3,', 'MMP-8,', and, 'MMP-9', from, 'RPE', cells, was, inhibited, by, 'R667,', and, the, 'MMP', inhibitor, 'GM6001', attenuated, 'TGF-β2-induced', 'RPE', cell, contraction])].
[sujeto(['Finally,', immunohistofluorescence, analysis, with, antibodies, to, glial, fibrillary, acidic, protein, showed, that, 'R667']), verbo([inhibited]), complemento([the, development, of, subretinal, fibrosis, in, a, mouse, model, in, vivo])].
[sujeto(['Our', results, thus]), verbo([suggest]), complemento([that, 'RAR-γ', agonists, may, prove, effective, for, the, treatment, of, subretinal, fibrosis, associated, with, 'AMD'])].
[sujeto(['RAR-γ', agonist, 'R667']), verbo([suppressed]), complemento([collagen, gel, contraction, mediated, by, 'RPE', cells])].
[sujeto(['Epithelial-mesenchymal', transition, '(', 'EMT)', in, 'RPE', cells, was]), verbo([inhibited]), complemento([by, 'RAR-γ', agonist, 'R667'])].
[sujeto(['RAR-γ', agonist, 'R667']), verbo([inhibited]), complemento(['fibrosis-related', processes, in, 'RPE', cells])].
[sujeto(['To', further, define, whether, retinoic, acid, receptor, α, '(', 'RARα)']), verbo([mediated]), complemento([the, induction, of, apelin, by, 'ATRA,', endogenous, 'RARα', was, down, regulated, by, transfection, of, siRNA, against, 'RARα', '(', 'si-RARα)', or, 'RARα', was, 'over-expressed', by, infection, of, the, adenovirus, vector, 'pAd-GFP-RARα', in, the, 'VSMCs'])].
[sujeto(['The', results, showed, that, 'ATRA', significantly]), verbo([induced]), complemento([apelin, expression, in, a, 'time-', and, 'dose-dependent', manner, in, the, 'VSMCs'])].
[sujeto(['Although', 'RARα', expression, was]), verbo([increased]), complemento([in, a, 'time-dependent', 'manner,', the, expressions, of, 'RARβ', and, 'RARγ', were, little, changed, by, the, 'ATRA', treatment])].
[sujeto(['When', 'VSMCs', were, treated, with, a, 'RARα', antagonist, 'Ro', 41, -, 5253, prior, to, the, addition, of, 'ATRA,', or, 'si-RARα', was, used, to, down]), verbo([regulate]), complemento([endogenous, 'RARα', 'expression,', the, blockade, of, 'RARα', signaling, partially, reduced, the, response, of, apelin, to, 'ATRA'])].
[sujeto(['Moreover,', 'RARα', 'over-expression,']), verbo([induced]), complemento([by, infection, of, 'pAd-GFP-RARα,', further, increased, the, induction, of, apelin, by, 'ATRA'])].
[sujeto(['Studies']), verbo([have]), complemento([reported, that, irbesartan, '(', 'Irbe),', an, angiotensin, 'II', receptor, blocker, '(', 'ARB)', widely, prescribed, for, 'CKD,', activates, hepatic, 'PPARα'])].
[sujeto(['The', results, were, compared, with, those, of, losartan, '(', 'Los),', another, 'ARB', that, does, not]), verbo([activate]), complemento(['PPARα'])].
[sujeto(['PPARα', and, its]), verbo([target]), complemento([gene, expression, were, significantly, increased, only, in, the, kidneys, of, 'Irbe-treated', 'WT', mice, and, not, in, 'KO', or, 'Los-treated', 'mice,', suggesting, that, the, renal, 'PPARα-activating', effect, was, 'Irbe-specific'])].
[sujeto(['Irbe-treated-PON-WT', mice, exhibited]), verbo([decreased]), complemento([urine, protein, 'excretion,', tubular, 'injury,', oxidative, 'stress,', and, 'pro-inflammatory', and, 'apoptosis-stimulating', 'responses,', and, they, exhibited, maintenance, of, fatty, acid, metabolism])].
[sujeto(['Furthermore,', the, expression, of, 'PPARα', and, that, of, its]), verbo([target]), complemento([mRNAs, encoding, proteins, involved, in, oxidative, 'stress,', 'pro-inflammatory', 'responses,', 'apoptosis,', and, fatty, acid, metabolism, was, maintained, upon, 'Irbe', treatment])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'Irbe', activates, renal, 'PPARα', and, that, the, resultant, increased, 'PPARα', signaling, mediates, its, renoprotective, effects])].
[sujeto(['Evidence']), verbo([suggests]), complemento([that, peroxisome, 'proliferator-activated', receptor, α, '(', 'PPARα)', represses, the, expression, of, several, amino, 'acid-catabolizing', 'enzymes,', but, for, 'Gls2', this, is, unknown])].
[sujeto(['The', aim, of, the, study, was, to, assess, whether, 'PPARα']), verbo([regulates]), complemento(['Gls2', expression])].
[sujeto(['Cotransfection', analyses, in, hepatocellular, carcinoma, cell, line, '(', 'HepG2)', cells, with, 'PPARα', and, hepatocyte]), verbo([nuclear]), complemento([factor, 4, α, '(', 'HNF4α)', expression, vectors, were, performed])].
[sujeto(['GLS2', protein, abundance, in, 'HepG2', cells, was, 78, '%', greater, than, that, in, the, controls, '(', 'P', &, 'lt;', 0.0001, ')', after, 'HNF4α', 'overexpression,', and, it, was, 99, '%', greater, after, transfection, with, a, short, hairpin]), verbo([targeting]), complemento(['PPARα'])].
[sujeto(['In', 'HepG2', cells, overexpressing, 'HNF4α,', 'Gls2', expression, 'increased,', an, effect]), verbo([repressed]), complemento([by, overexpression, of, 'PPARα'])].
[sujeto(['This']), verbo([suggests]), complemento([that, 'Gls2', depends, on, the, 'PPARα/HNF4α', counterregulatory, transcriptional, control])].
[sujeto(['UPLC-ESI-QTOFMS-based', metabolomics, was, used, to, explore, the, contributing, components, of, the, serum, metabolome, that]), verbo([led]), complemento([to, variation, between, 'wild-type', and, 'Pparα-null', mice])].
[sujeto(['The', serum, metabolome, in, 'wild-type', clustered, differently, from, that, in, 'Pparα-null,', featured, by, sharp]), verbo([increases]), complemento([in, bile, acid, components])].
[sujeto(['Increase', in, 'Il-10', and, activation, of, the, 'JNK', pathway, indicated, inflammation, was]), verbo([induced]), complemento([by, disruption, of, bile, acid, homeostasis, in, 'wild-type', mice])].
[sujeto(['These', data]), verbo([suggest]), complemento([disruptive, and, protective, role, of, 'PPARα', in, hepatic, responses, induced, by, 'PFDA'])].
[sujeto(['Although', sporadically, 'reported,', a, rational, basis, for, the, use, of, fibrates, for, the, treatment, of, dyslipidemia, with, concurrent, metabolic, syndrome]), verbo([has]), complemento([not, been, established])].
[sujeto(['Genes']), verbo([involved]), complemento([in, glucose, metabolism, were, determined, by, quantitative, polymerase, chain, reaction, analysis])].
[sujeto(['Gemfibrozil,', not, 'fenofibrate,', 'down-regulates', systemic, glucose, level, and, glycogen, storage, in, the, liver, dependent, on, 'PPARα,']), verbo([suggesting]), complemento([its, potential, value, for, treatment, of, dyslipidemia, with, concurrent, diabetes, or, high, glucose, levels])].
[sujeto(['A', 'meta-analysis', was, performed, with, the, aim, of, 're-evaluating', the, role, of, the, peroxisome, proliferator]), verbo([activated]), complemento([receptor, alpha, '(', 'PPARA)', gene, intron, 7, 'G/C', polymorphism, '(', 'rs4253778)', in, 'athletes\'', high, ability, in, endurance, sports])].
[sujeto(['Patients', with, 'NASH', resolution, after, receiving, elafibranor, 120, mg, had, reduced, liver, fibrosis, stages, compared, with, those, without, 'NASH', resolution, '(', mean, reduction, of, 0.65, ±, 0.61, in, responders, for, the, primary, outcome, vs, an]), verbo([increase]), complemento([of, 0.1, ±, 0.98, in, 'nonresponders;', 'P', &, 'lt;'])].
[sujeto(['Elafibranor', was, 'well&nbsp;tolerated', and, did, not]), verbo([cause]), complemento([weight, gain, or, cardiac, 'events,', but, did, produce, a, 'mild,', reversible, increase, in, serum, creatinine, '(', effect, size, vs, 'placebo:', increase, of, 4.31, ±, 1.19, 'μmol/L;', 'P', &, 'lt;'])].
[sujeto(['Here,', we]), verbo([report]), complemento([a, novel, observation, that, 'fenofibrate,', a, synthetic, peroxisome, 'proliferator-activated', receptor, alpha, '(', 'PPARa)', 'agonist,', induces, bHB, production, in, melanoma, and, glioblastoma, 'cells,', as, well, as, in, neurospheres, composed, of, 'non-transformed', cells])].
[sujeto(['The', 'fenofibrate-induced', ketogenesis, is, accompanied, by, growth]), verbo([arrest]), complemento([and, downregulation, of, 'transketolase,', but, the, 'NADP/NADPH', and, 'GSH/GSSG', ratios, remain, unaffected])].
[sujeto(['Our', results]), verbo([reveal]), complemento([a, 'new,', intriguing, aspect, of, cancer, cell, biology, and, highlight, the, benefits, of, fenofibrate, as, a, supplement, to, both, canonical, and, dietary, '(', 'ketogenic)', therapeutic, approaches, against, glioblastoma])].
[sujeto(['Gene', array, analysis, revealed, that, mice, receiving, clofibrate]), verbo([have]), complemento([enhanced, hepatic, 'Vanin-1', '(', 'Vnn1)', gene, 'expression,', a, response, that, is, also, 'PPARa', dependent])].
[sujeto(['Together,', these, data, strongly]), verbo([suggest]), complemento([that, the, susceptibility, of, 'Vnn1', knockout, mice, is, not, due, to, differences, in, 'APAP', metabolism])].
[sujeto(['Immunochemistry', revealed, a, lack, of, proliferating, cell]), verbo([nuclear]), complemento(['antigen-positive', hepatocytes, and, 'F4/80-positive', macrophages, in, and, around, areas, of, centrilobular, necrosis, in, 'APAP-treated', 'Vnn1', knockouts])].
[sujeto(['These', results, indicate, that, mice, lacking, 'Vnn1']), verbo([have]), complemento([deficiencies, in, compensatory, repair, and, immune, responses, following, toxic, 'APAP', exposure, and, that, these, mechanisms, may, contribute, to, the, enhanced, hepatotoxicity, seen])].
[sujeto(['It', was]), verbo([reported]), complemento([that, 2, ',', 4, -, dichlorophenoxyacetic, acid, '(', 2, ',', 4, -, 'D),', a, commonly, used, herbicide, and, a, possible, endocrine, 'disruptor,', can, disturb, 'spermatogenesis,', but, the, precise, mechanism, is, not, understood])].
[sujeto(['Since', 2, ',', 4, -, 'D', is, a, weak, peroxisome, proliferator, in, hepatocytes, and, peroxisome, 'proliferator-activated', receptor, α, '(', 'PPARα)', is, also]), verbo([expressed]), complemento([in, 'Leydig', 'cells,', this, study, aimed, to, investigate, the, link, between, 'PPARα', and, 2, ',', 4, -, 'D-mediated', testicular, dysfunction])].
[sujeto(['Treatment', with, 2, ',', 4, -, 'D', markedly]), verbo([decreased]), complemento([testicular, testosterone, in, 'wild-type', 'mice,', leading, to, degeneration, of, spermatocytes, and, 'Sertoli', cells])].
[sujeto(['The', 2, ',', 4, -, 'D']), verbo([decreased]), complemento([cholesterol, levels, in, 'Leydig', cells, of, 'wild-type', mice, through, 'down-regulating', the, expression, of, 3, -, 'hydroxy-3-methylglutaryl', coenzyme, 'A', synthase, 1, and, 'reductase,', involved, in, de, novo, cholesterogenesis])].
[sujeto(['However,', the, mRNAs, encoding, the, important, proteins]), verbo([involved]), complemento([in, testosterone, synthesis, were, unchanged, by, 2, ',', 4, -, 'D', except, for, 'CYP17A1,', indicating, that, exhausted, cholesterol, levels, in, the, cells, is, a, main, reason, for, reduced, testicular, testosterone])].
[sujeto(['Collectively,', these, results]), verbo([suggest]), complemento([a, critical, role, for, 'PPARα', in, 2, ',', 4, -, 'D-induced', testicular, toxicity, due, to, disruption, of, 'cholesterol/testosterone', homeostasis, in, 'Leydig', cells])].
[sujeto(['This', study, yields, novel, insights, into, the, possible, mechanism, of, testicular, dysfunction, and, male, infertility]), verbo([caused]), complemento([by, 2, ',', 4, -, 'D'])].
[sujeto(['Fish', currently, supplies, only, 40, '%', of, the, eicosapentaenoic, acid, '(', 'EPA)', and, docosahexaenoic, acid, '(', 'DHA)']), verbo([required]), complemento([to, allow, all, individuals, globally, to, meet, the, minimum, intake, recommendation, of, 500, 'mg/d'])].
[sujeto(['Six-week-old', male, 'C57BL/6J', mice, were, fed, for, 10, wk, either, a, palm, 'oil-containing', control, '(', 'C)', diet, or, diets, supplemented, with, 'EPA-CO', or, 'FO,', with, the, 'C,', 'low-EPA', 'CO', '(', 'COL),', 'high-EPA', 'CO', '(', 'COH),', 'low-EPA', 'FO', '(', 'FOL),', and, 'high-EPA', 'FO', '(', 'FOH)', diets]), verbo([providing]), complemento([0, ',', 0.4, ',', 3.4, ',', 0.3, ',', and, 2.9, g, 'EPA/kg', 'diet,', respectively])].
[sujeto(['The', expression, of, selected, hepatic, genes]), verbo([involved]), complemento([in, 'EPA', and, 'DHA', biosynthesis, and, in, modulating, their, cellular, impact, was, determined])].
[sujeto(['The', oils, were, well, 'tolerated,', with, significantly, greater, weight]), verbo([gain]), complemento([in, the, 'COH', and, 'FOH', groups, relative, to, the, 'C', group, '(', 'P', &, 'lt;', 0.001, ')'])].
[sujeto(['Higher', fatty, acid, desaturase, 2, '(', 'Fads2),', peroxisome, 'proliferator-activated', receptor, α, '(', 'Ppara),', and, peroxisome, 'proliferator-activated', receptor, γ, '(', 'Pparg)', '(', 'P', &, 'lt;', 0.005, ')', expressions, were]), verbo([induced]), complemento([by, 'CO'])].
[sujeto(['These', data]), verbo([provide]), complemento([support, for, the, future, assessment, of, this, oil, in, a, human, feeding, trial])].
[sujeto(['Peroxisome', 'proliferator-activated', 'receptor-α', null, '(', 'Ppara)', mice]), verbo([have]), complemento([greater, mortality, than, 'wild-type', mice, when, subjected, to, sepsis, by, cecal, ligation, and, puncture])].
[sujeto(['We', sought, to, characterize, the, role, of, peroxisome, 'proliferator-activated', 'receptor-α', in, sepsis, and, to, identify, the, mechanism, whereby, peroxisome, 'proliferator-activated', 'receptor-α']), verbo([confers]), complemento([a, survival, advantage])].
[sujeto(['Cardiac', injury, due, to, inadequate, energy, production, from, fatty, acid, substrate, is, a, probable, mechanism, of]), verbo([decreased]), complemento([survival, in, 'Ppara', mice])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, altered, peroxisome, 'proliferator-activated', 'receptor-α-mediated', cellular, metabolism, may, play, an, important, role, in, 'sepsis-related', 'end-organ', injury, and, 'dysfunction,', especially, in, the, heart])].
[sujeto(['The', latter, is, an, epigenetic, modification]), verbo([involved]), complemento([in, the, regulation, of, gene, 'expression,', 'hence,', tissue, function])].
[sujeto(['Several', 'PPARα']), verbo([target]), complemento([and, putative, target, genes, associated, with, carnitine, synthesis, and, 'uptake,', fatty, acid, 'metabolism,', 'hepatokines,', and, carbohydrate, metabolism, were, also, studied])].
[sujeto(['The', upregulation, of, 'PPARα']), verbo([target]), complemento([genes, indicates, that, supplemental, 'Met,', likely, through, the, synthesis, of, 'S-adenosylmethionine,', activated, 'PPARA-regulated', signaling, pathways])].
[sujeto(['Upregulation', of, hepatic, 'PPARA']), verbo([has]), complemento([been, associated, with, improved, lipid, metabolism, and, immune, 'function,', both, of, which, were, reported, in, companion, publications, from, this, study])].
[sujeto(['Recently', we, demonstrated, that, peroxisome, 'proliferator-activated', receptor, alpha, '(', 'PPARα),', a]), verbo([nuclear]), complemento([receptor, primarily, involved, in, control, of, lipid, and, energy, homeostasis, directly, regulates, the, transcription, of, 'CYP3A4'])].
[sujeto(['Two', linked, intronic, 'SNPs', in, 'PPARα', '(', 'rs4253728,', 'rs4823613)', previously]), verbo([associated]), complemento([with, hepatic, 'CYP3A4', status, showed, significant, association, with, 'CYP2C8', protein, level, in, human, liver, samples, '(', 'N', =, 150, ')'])].
[sujeto(['Furthermore,', 'siRNA-mediated', 'knock-down', of, 'PPARα', in, 'HepaRG', human, hepatocyte, cells, resulted, in, up, to, '∼60', and, '∼50%', downregulation, of, 'CYP2C8', mRNA, and, 'activity,', while, treatment, with, the, 'PPARα', agonist, 'WY14,643']), verbo([lead]), complemento([to, an, induction, by, &, 'gt;150', and, &, 'gt;100%,', respectively])].
[sujeto(['Electromobility', shift, assay, demonstrated, direct]), verbo([binding]), complemento([of, 'PPARα', to, a, 'DR-1', motif, located, at, positions, -, 2762, /, -, 2775, bp, upstream, of, the, 'CYP2C8', transcription, start, site])].
[sujeto(['Moreover,', based, on, our, previous, studies, we, demonstrated, that, 'WNT/β-catenin']), verbo([acts]), complemento([as, a, functional, inhibitor, of, 'PPARα-mediated', inducibility, of, 'CYP2C8', expression])].
[sujeto(['In', 'conclusion,', our, data]), verbo([suggest]), complemento([direct, involvement, of, 'PPARα', in, both, constitutive, and, inducible, regulation, of, 'CYP2C8', expression, in, human, 'liver,', which, is, further, modulated, by, 'WNT/β-catenin', pathway])].
[sujeto(['PPARA', gene, polymorphism, could]), verbo([have]), complemento([a, modest, influence, on, 'CYP2C8', phenotype])].
[sujeto(['Fatty', acid, oxidation, is, transcriptionally]), verbo([regulated]), complemento([by, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)α', and, under, normal, conditions, accounts, for, 70, '%', of, cardiac, 'ATP', content])].
[sujeto(['Reduced', 'Ppara', expression, during, sepsis, and, heart, failure]), verbo([leads]), complemento([to, reduced, fatty, acid, oxidation, and, myocardial, energy, deficiency])].
[sujeto(['We', discovered, that, 'KLF5']), verbo([activates]), complemento(['Ppara', gene, expression, via, direct, promoter, binding])].
[sujeto(['This', is, blocked, in, hearts, of, septic, mice, by, 'c-Jun,', which]), verbo([binds]), complemento([an, overlapping, site, on, the, 'Ppara', promoter, and, reduces, transcription])].
[sujeto(['These', changes, were]), verbo([associated]), complemento([with, reduced, cardiac, fatty, acid, 'oxidation,', 'ATP', 'levels,', increased, triglyceride, 'accumulation,', and, cardiac, dysfunction])].
[sujeto(['Compromised', cardiac, fatty, acid, oxidation, '(', 'FAO)']), verbo([induced]), complemento([energy, deprivation, is, a, critical, cause, of, cardiac, dysfunction, in, sepsis])].
[sujeto(['Acyl-CoA', thioesterase, 1, '(', 'ACOT1)', is]), verbo([involved]), complemento([in, regulating, cardiac, energy, production, via, altering, substrate, metabolism])].
[sujeto(['This', study, aims, to, clarify, whether, 'ACOT1']), verbo([has]), complemento([a, potency, to, ameliorate, septic, myocardial, dysfunction, via, enhancing, cardiac, 'FAO'])].
[sujeto(['αMHC-ACOT1', mice, exhibited, a, markedly]), verbo([increase]), complemento([in, glucose, utilization, and, cardiac, 'FAO', compared, with, 'LPS-treated', 'WT', mice])].
[sujeto(['Suppression', of, cardiac, peroxisome, proliferator]), verbo([activated]), complemento([receptor, alpha, '(', 'PPARa)', and, 'PPARγ-coactivator-1α', '(', 'PGC1a)', signaling, observed, in, 'LPS-challenged', 'WT', mice, was, activated, by, the, presence, of, 'ACOT1'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'ACOT1', has, potential, therapeutic, values, to, protect, heart, from, sepsis, mediated, 'dysfunction,', possibly, through, activating, 'PPARa/PGC1a', signaling])].
[sujeto(['The', 'n-3', 'PUFAs', are, essential, components]), verbo([required]), complemento([for, normal, cellular, function, and, have, preventive, and, therapeutic, effects, on, many, diseases])].
[sujeto(['Fatty', acid, analysis, showed, that, fat1, overexpression, significantly]), verbo([increased]), complemento([the, levels, of, total, 'n-3', 'PUFAs', and, decreased, the, levels, of, total, 'n-6', 'PUFAs', in, 'GEFCs'])].
[sujeto(['Overall,', 'fat1-overexpression', resulted, in, an]), verbo([increase]), complemento([in, the, 'n-3', fatty, acids, and, altered, expression, of, 'PUFA', synthesis, related, genes, in, 'GEFCs'])].
[sujeto(['What', is, the, topic, of, this, 'review?', 'Tibetans']), verbo([have]), complemento([genetic, adaptations, that, are, hypothesized, to, underlie, the, distinct, set, of, traits, they, exhibit, at, altitude])].
[sujeto(['What', advances, does, it, 'highlight?', 'Several', adaptive, signatures, in, the, same, genomic, regions]), verbo([have]), complemento([been, identified, among, 'Tibetan', populations, resident, throughout, the, 'Qinghai-Tibetan', 'Plateau'])].
[sujeto(['Many', highland, 'Tibetans', exhibit, a, haemoglobin, concentration, within, the, range, expected, at]), verbo([sea]), complemento(['level,', and, this, trait, is, associated, with, putatively, adaptive, regions, harbouring, the, 'hypoxia-inducible', factor, pathway, genes, 'EGLN1,', 'EPAS1', and, 'PPARA'])].
[sujeto(['Some', native, 'Tibetan,', 'Andean', and, 'Ethiopian', populations]), verbo([have]), complemento([lived, at, altitudes, ranging, from, 3000, to, &, 'gt;4000&nbsp;m', above, sea, level, for, hundreds, of, generations, and, exhibit, distinct, combinations, of, traits, at, altitude])].
[sujeto(['It', was, long, hypothesized, that, genetic, factors, contribute, to, adaptive, differences, in, these, 'populations,', and, recent, advances, in, genomics]), verbo([provide]), complemento([evidence, that, some, of, the, strongest, signatures, of, positive, selection, in, humans, are, those, identified, in, 'Tibetans'])].
[sujeto(['Putatively', adaptive, copies, of, three, 'hypoxia-inducible', factor, pathway, 'genes,', 'EPAS1,', 'EGLN1', and, 'PPARA,', are]), verbo([associated]), complemento([with, 'sea-level', 'range,', rather, than, 'elevated,', haemoglobin, concentration, observed, in, many, 'Tibetans', at, high, 'altitude,', and, recent, studies, provide, insight, into, some, of, the, precise, adaptive, 'variants,', timing, of, adaptive, events, and, functional, roles])].
[sujeto(['While', several, studies, in, highland, 'Tibetans']), verbo([have]), complemento([converged, on, a, few, 'hypoxia-inducible', factor, pathway, 'genes,', additional, candidates, have, been, reported, in, independent, studies, of, 'Tibetans', located, throughout, the, 'Qinghai-Tibetan', 'Plateau'])].
[sujeto(['Various', aspects, of, adaptive, significance]), verbo([have]), complemento([yet, to, be, 'identified,', 'integrated,', and, fully, explored])].
[sujeto(['Given', the, rapid, technological, advances, and, interdisciplinary, efforts, in, 'genomics,', physiology, and, molecular, 'biology,', careful, examination, of, 'Tibetans', and, comparisons, with, other, distinctively, adapted, highland, populations, will]), verbo([provide]), complemento([valuable, insight, into, evolutionary, processes, and, models, for, both, basic, and, clinical, research])].
[sujeto(['In', 'rodents,', fibroblast, growth, factor, 21, '(', 'FGF21)']), verbo([has]), complemento([emerged, as, a, key, metabolic, regulator, produced, by, liver])].
[sujeto(['In', experiment, 1, ',', induction, of, ketosis, through, feed, restriction, on, d, 5, postpartum, upregulated, 'FGF21,', its, 'co-receptor', 'KLB,', and, 'PPARA', but, only, elicited, a, numerical]), verbo([increase]), complemento([in, serum, 'FGF21', concentration])].
[sujeto(['In', experiment, 2, ',', cows, in, control, '(', 'CON)', or, receiving, 50, 'g/d', of, 'L-carnitine', '(', 'C50)', from, -, 14, through, 21, d, had]), verbo([increased]), complemento(['FGF21,', 'PPARA,', and, 'NFIL3', on, d, 10, compared, with, d, 2, postpartum])].
[sujeto(['For', 'FGF21', mRNA, expression, in, 'CON,', the, 'LPS', challenge, '(', 'CON:Y)']), verbo([prevented]), complemento([a, decrease, in, expression, between, d, 7, and, 14, postpartum, such, that, cows, in, 'CON:N', had, a, 4, -, fold, lower, expression, on, d, 14, compared, with, d, 7])].
[sujeto(['The', inflammatory, stimulus]), verbo([induced]), complemento([by, 'LPS', in, 'CON:Y', resulted, in, upregulation, of, 'PPARA', on, d, 14, to, a, similar, level, as, cows, in, 'OVE:N'])].
[sujeto(['On', d, 7, ',', 'LPS']), verbo([led]), complemento([to, a, 4, -, fold, greater, serum, 'FGF21', only, in, 'OVE', but, not, in, 'CON', cows])].
[sujeto(['In', 'fact,', 'OVE:Y', reached, the, same, serum, 'FGF21', concentration, as, 'CON:N,']), verbo([suggesting]), complemento([a, carryover, effect, of, dietary, energy, level, on, signaling, mechanisms, within, liver])].
[sujeto(['The', functional, outcome, of, these, changes, merits, further, 'study,', and, in, particular, the, mechanisms]), verbo([regulating]), complemento([transcription, in, response, to, changes, in, energy, balance, and, feed, intake])].
[sujeto(['Human', gene, datasets]), verbo([regulated]), complemento([by, glucose, were, compared, to, gene, datasets, either, dysregulated, in, 'HCC', or, regulated, by, other, signaling, pathways])].
[sujeto(['Significant', numbers, of, common, genes]), verbo([suggested]), complemento([putative, involvement, in, transcriptional, regulations, by, glucose])].
[sujeto(['High', glucose]), verbo([promoted]), complemento(['HuH7', cell, proliferation, but, not, that, of, 'HepG2', cell, line])].
[sujeto(['Gene', network, analyses]), verbo([suggest]), complemento([that, gene, transcription, by, glucose, could, be, mediated, at, 92, '%', through, 'ChREBP', in, 'HepG2', 'cells,', compared, to, 40, '%', in, either, other, human, cells, or, rodent, healthy, 'liver,', with, alteration, of, 'LKB1', '(', 'serine/threonine', kinase, 11, ')', and, 'NOX', '(', 'NADPH', 'oxidases)', signaling, pathways, and, loss, of, transcriptional, regulation, of, 'PPARGC1A', '(', 'peroxisome-proliferator', activated, receptors, gamma, coactivator, 1, ')', target, genes, by, high, glucose])].
[sujeto(['Both', 'PPARA', and, 'PPARGC1A']), verbo([regulate]), complemento([transcription, of, genes, commonly, regulated, by, 'glycolysis,', by, the, antidiabetic, agent, metformin, and, by, 'NOX,', suggesting, their, major, interplay, in, the, control, of, 'HCC', progression])].
[sujeto(['Fructose']), verbo([induces]), complemento([nonalcoholic, fatty, liver, disease, '(', 'NAFLD)'])].
[sujeto(['Compared', with, 'controls,', fructose]), verbo([led]), complemento([to, 'NAFLD', with, significantly, higher, visceral, fat, mass, '(', 128, '%', ')', ',', lower, lean, body, mass, '(', -, 7, '%', ')', ',', insulin, resistance, '(', 135, '%', ')', ',', increased, plasma, triglycerides, '(', 'TGs;', 67, '%', ')', ',', and, altered, plasma, amino, acid, concentrations, with, decreased, 'Arg', bioavailability, '(', -, 27, '%', ')'])].
[sujeto(['Fructose']), verbo([caused]), complemento([a, 2, -, fold, increase, in, the, gene, expression, of, fatty, acid, synthase, '(', 'Fas)', and, 70, '%', and, 90, '%', decreases, in, that, of, carnitine, 'palmitoyl-transferase', 1, a, and, microsomal, 'TG', transfer, protein, via, a, nearly, 10, -, fold, higher, gene, expression, of, sterol, regulatory, 'element-binding', 'protein-1c', '(', 'Srebp1c)', and, 'carbohydrate-responsive', 'element-binding', protein, '(', 'Chrebp),', and, a, 90, '%', lower, gene, expression, of, peroxisome, 'proliferator-activated', receptor, α, '(', 'Ppara)'])].
[sujeto(['NEAA', or, 'Cit', supplementation]), verbo([led]), complemento([to, a, 'Ppara', gene, expression, similar, to, controls, and, decreased, those, of, 'Srebp1c', and, 'Chrebp', in, the, liver, by, 50, -, 60, '%'])].
[sujeto(['Only', 'Cit']), verbo([led]), complemento([to, 'Fas', gene, expression, and, 'Arg', bioavailability, similar, to, controls])].
[sujeto(['In', our, rat, 'model,', 'Cit', and, 'NEAAs', effectively]), verbo([prevented]), complemento(['fructose-induced', 'NAFLD'])].
[sujeto(['On', the, basis, of, literature, data, and, our, 'findings,', we, propose, that, 'NEAAs', may, exert, their, effects, specifically, on, the, 'liver,', whereas, 'Cit', presumably]), verbo([acts]), complemento([at, both, the, hepatic, and, 'whole-body', 'level,', in, part, via, improved, peripheral, 'Arg', metabolism])].
[sujeto(['Peroxisome', proliferator]), verbo([activated]), complemento([receptor, '(', 'PPAR)', is, a, nuclear, receptor, that, is, one, of, the, transcription, factors, regulating, lipid, and, glucose, metabolism])].
[sujeto(['DNA', microarray, analysis, of, rat, liver, treated, with, 'FG', indicated, that, 'FG', affects, on, lipid, metabolism, are]), verbo([mediated]), complemento([by, 'PPAR-α'])].
[sujeto(['Our', study]), verbo([suggested]), complemento([that, metabolites, of, 'fermentation,', in, addition, to, 'ginsenosides,', contribute, to, the, health, benefits, of, 'FG'])].
[sujeto(['Oxidative', 'stress,', leukocyte, infiltration, and]), verbo([increased]), complemento([expression, of, intercellular, adhesion, molecule, 1, '(', 'ICAM-1)', in, the, colon, are, the, most, important, factors, in, inflammatory, bowel, disease])].
[sujeto([')', was, tested, in, a, mouse, experimental, model, of, colitis]), verbo([induced]), complemento([by, intracolonic, administration, of, dinitrobenzene, sulfonic, acid])].
[sujeto(['Nuclear', 'factor-κB', 'translocation,', 'cyclooxygenase-2', and, 'phospho-extracellular', 'signal-regulated', kinase, as, well, as, tumor, necrosis, 'factor-α', and, 'interleukin-1β', were, significantly]), verbo([increased]), complemento([in, colon, tissues, after, dinitrobenzene, sulfonic, acid, administration])].
[sujeto(['Treatment', with, adelmidrol]), verbo([decreased]), complemento(['diarrhea,', body, weight, loss, and, myeloperoxidase, activity])].
[sujeto(['Adelmidrol', 'treatment,', 'moreover,', reduced]), verbo([nuclear]), complemento(['factor-κB', 'translocation,', 'cyclooxygenase-2', and, 'phospho-extracellular', 'signal-regulated', kinase, 'expression,', 'pro-inflammatory', cytokine, 'release,', the, incidence, of, nitrotyrosine, and, 'poly(ADP)ribose', in, the, colon, and, decreased, the, 'up-regulation', of, 'ICAM-1', and, 'P-selectin'])].
[sujeto(['This', study, clearly, demonstrates, that, adelmidrol, exerts, important, 'anti-inflammatory', effects, that, are, partly, dependent, on, 'PPAR-γ,']), verbo([suggesting]), complemento([that, this, molecule, may, represent, a, new, pharmacological, approach, for, inflammatory, bowel, disease, treatment])].
[sujeto(['The', peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)-γ', 'coactivator-1α', '(', 'PGC-1α)', and, 'coactivator-1β', '(', 'PGC-1β)']), verbo([modulate]), complemento([members, of, the, 'PPARs,', which, regulate, mitochondrial, energy, metabolism, and, the, production, of, mitochondrial, reactive, oxygen, species, in, the, heart])].
[sujeto([5, ')', to, attenuate, mitochondrial, dysfunction, in, murine, cardiomyocytes]), verbo([stimulated]), complemento([with, serum, from, septic, shock, patients])].
[sujeto([5, treatment, attenuated, the, suppression, of, 'PPAR-α,', 'PPAR-γ', '(', 'P', =, 0.0004, and, 'P', =, 0.0001, ',', 'respectively)', and, 'PGC-1α/β', '(', 'P', =, 0.0008, and, 'P', =, 0.0147, ',', 'respectively)', in, cardiomyocytes]), verbo([stimulated]), complemento([with, serum, from, septic, shock, patients, compared, with, untreated, cells])].
[sujeto([5, treatment]), verbo([enhanced]), complemento([the, mitochondrial, maximum, respiration, '(', 'P', &, 'lt;', 0.0001, ')', ',', increased, cellular, 'ATP', levels, '(', 'P', &, 'lt;', 0.0001, ')', and, reduced, the, production, of, mitochondrial, reactive, oxygen, species])].
[sujeto([5, may]), verbo([have]), complemento([the, potential, as, a, promising, therapeutic, approach, in, septic, cardiomyopathy, by, attenuating, mitochondrial, dysfunction, in, the, septic, heart])].
[sujeto(['Cannabinoids']), verbo([modulate]), complemento([intestinal, permeability, through, 'CB1', 'The', 'endocannabinoid-like', compounds, oleoylethanolamine, '(', 'OEA)', and, palmitoylethanolamine, '(', 'PEA)', play, an, important, role, in, digestive, 'regulation,', and, we, hypothesized, they, would, also, modulate, intestinal, permeability])].
[sujeto(['OEA', '(', applied, 'apically,', logEC50, -, 5.4, ')', and, 'PEA', '(', 'basolaterally,', logEC50, -, 4.9, ;, apically, logEC50, -, 5.3, ')']), verbo([increased]), complemento(['Caco-2', resistance, by, 20, -, 30, '%', via, transient, receptor, potential, vanilloid, '(', 'TRPV)-1', and, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)-α'])].
[sujeto(['Preventing', their, degradation, '(', by]), verbo([inhibiting]), complemento([fatty, acid, amide, 'hydrolase)', enhanced, the, effects, of, 'OEA', and, 'PEA'])].
[sujeto(['OEA', and, 'PEA']), verbo([induced]), complemento([cytoskeletal, changes, and, activated, focal, adhesion, kinase, and, 'ERKs', 1, /, 2, ',', and, decreased, 'Src', kinases, and, aquaporins, 3, and, 4])].
[sujeto(['In', 'Caco-2', cells, treated, with, 'IFNγ', and, 'TNFα,', 'OEA', '(', via, 'TRPV1)', and, 'PEA', '(', via, 'PPARα)']), verbo([prevented]), complemento([or, reversed, the, 'cytokine-induced', increased, permeability, compared, to, vehicle, '(', 0.1, '%', 'ethanol)'])].
[sujeto(['PEA', '(', 'basolateral)', also, reversed]), verbo([increased]), complemento([permeability, when, added, 48, or, 72, h, after, cytokines, '(', 'P', &, 'lt;', 0.001, ',', via, 'PPARα)'])].
[sujeto(['Cellular', and, secreted, levels, of, 'OEA', and, 'PEA', '(', 'P', &, 'lt;', 0.001, -, 0.001, ')', were]), verbo([increased]), complemento([in, response, to, inflammatory, mediators])].
[sujeto(['OEA', and, 'PEA']), verbo([have]), complemento([endogenous, roles, and, potential, therapeutic, applications, in, conditions, of, intestinal, hyperpermeability, and, inflammation])].
[sujeto(['Oleoylethanolamine', and, palmitoylethanolamine]), verbo([modulate]), complemento([intestinal, permeability, in, vitro, via, 'TRPV1', and, 'PPARα'])].
[sujeto(['They', are, considered, as, therapeutic]), verbo([targets]), complemento([for, metabolic, diseases, such, as, dyslipidemia, and, type, 2, diabetes, mellitus])].
[sujeto(['Various', 'PPAR', agonists]), verbo([have]), complemento([been, 'developed,', but, most, of, them, contain, a, carboxylic, acid, '(', 'CA)', or, thiazolidinedione, '(', 'TZD)', 'moiety,', which, is, essential, for, the, activity])].
[sujeto(['Therefore,', here, we, evaluated, the, immunological, effects, of, the, abbreviated, 'GC', therapy, in, experimental, colitis]), verbo([induced]), complemento([by, 3, '%', 'Dextran', 'Sulfate', 'Sodium', '(', 'DSS)', in, 'C57BL/6', mice])].
[sujeto(['The', control, of, the, local, inflammatory, responses]), verbo([involved]), complemento([a, reduction, in, the, expression, of, 'IFN-γ', and, 'IL-1ß,', associated, to, augmented, mRNA, levels, of, peroxisome, 'proliferator-activated', receptors, 'PPAR', '(', α, and, 'γ)', in, intestine])].
[sujeto(['Furthermore,', there, was, a, reduction, of, 'CD4(+)', 'T', cells, producing, 'IFN-γ,', together, with, an]), verbo([increased]), complemento([frequency, of, the, putative, regulatory, population, of, 'T', cells, producing, 'IL-10,', in, spleen])].
[sujeto(['These', systemic, alterations, were, accompanied, by, a]), verbo([decrease]), complemento([in, the, proliferative, potential, of, splenocytes, of, mice, treated, in, vivo, with, 'GC'])].
[sujeto(['Notably,', treatment, with, 'GC', also]), verbo([led]), complemento([to, an, increase, in, the, frequency, of, the, regulatory, markers, 'GITR,', 'CTLA-4,', 'PD-1,', 'CD73', and, 'FoxP3,', more, prominently, in, spleen])].
[sujeto(['Finally,', this, is, the, first, time, that, 'GC-treatment', was]), verbo([associated]), complemento([to, the, modulation, of, a, broad, number, of, regulatory, markers, in, an, experimental, model, of, colitis])].
[sujeto(['Transcription', of, 'apoA-I']), verbo([involves]), complemento(['peroxisome-proliferator-activated-receptor-alpha', '(', 'PPARα)', 'activation,', but, endoplasmic, reticulum, '(', 'ER)', -, stress, and, inflammation, also, influence, 'apoA-I', production])].
[sujeto(['To', unravel, why, 'PPARα', agonist, 'GW7647']), verbo([increased]), complemento(['apoA-I', production, compared, to, 'PPARα', agonist, fenofibric, acid, '(', 'FeAc)', in, human, hepatocellular, carcinoma, '(', 'HepG2)', and, colorectal, adenocarcinoma, '(', 'CaCo-2)', 'cells,', gene, expression, profiles, were, compared])].
[sujeto(['Microarray', analyses]), verbo([suggested]), complemento(['CCAAT/enhancer-binding-protein-beta', '(', 'C/EBP-β)', involvement, in, the, 'FeAc', condition])].
[sujeto(['This', 'ER-stress', related, signature, was]), verbo([associated]), complemento([with, decreased, 'apoA-I', secretion])].
[sujeto(['Cytokine', addition]), verbo([increased]), complemento([intracellular, 'C/EBP-β', levels, and, lowered, 'apoA-I', concentrations])].
[sujeto(['Although', a, 'C/EBP']), verbo([binding]), complemento([place, is, present, in, the, 'apoA-I', 'promoter,', 'C/EBP-β', silencing, or, 'isoform-specific', overexpression, did, not, affect, 'apoA-I', production, in, 'inflammatory,', 'non-inflammatory', and, 'ER-stressed', conditions])].
[sujeto(['Therefore,', 'C/EBP-β', is, not, a]), verbo([target]), complemento([to, influence, hepatic, 'apoA-I', production])].
[sujeto(['Leucine', supplementation]), verbo([has]), complemento([been, reported, to, improve, lipid, metabolism])].
[sujeto(['However,', lipid, metabolism, in, adipose, tissues, and, liver]), verbo([has]), complemento([not, been, extensively, studied, for, leucine, supplementation, in, mice, fed, with, a, 'high-fat/cholesterol', diet, '(', 'HFCD)'])].
[sujeto(['In', 'addition,', expression, levels, of, proteins]), verbo([associated]), complemento([with, hepatic, 'lipogenesis,', adipocyte, 'lipolysis,', and, white, adipose, tissue, '(', 'WAT)', browning, were, determined])].
[sujeto(['Compared', with, 'HFCD,', leucine, supplementation, lowered, weight]), verbo([gain]), complemento([and, 'TC', levels, in, circulation, and, the, liver, without, changing, energy, intake])].
[sujeto(['The']), verbo([decrease]), complemento([in, body, fat, was, supported, by, histological, examination, in, the, 'WAT', and, liver])].
[sujeto(['Furthermore,', serum, levels, of, proinflammatory, 'adipokines,', such, as, 'leptin,', 'IL-6,', and, tumor, necrosis, 'factor-alpha,', were, significantly]), verbo([decreased]), complemento([by, supplemented, leucine])].
[sujeto(['At', the, protein, 'level,', leucine, potently]), verbo([decreased]), complemento([the, hepatic, lipogenic, enzymes, '(', fatty, acid, synthase, and, 'acetyl-coenzyme', 'A', 'carboxylase)', and, corresponding, upstream, proteins])].
[sujeto(['In', epididymal, 'WAT,', the, reduced, expression, levels, of, two, major, lipases, by, 'HFCD,', namely]), verbo([phosphorylated]), complemento(['hormone-sensitive', lipase, and, adipose, triglyceride, 'lipase,', were, reversed, when, leucine, was, supplemented])].
[sujeto(['Uncoupling', protein, 1, ',', β3, adrenergic, 'receptors,', peroxisome, 'proliferator-activated', receptor, g, 'coactivator-1α,', and, fibroblast, growth, factor, 21, were]), verbo([involved]), complemento([in, the, thermogenic, program, and, 'WAT', browning])].
[sujeto(['Several', pathogenetic, factors]), verbo([have]), complemento([been, involved, in, the, onset, and, progression, of, 'Parkinson\'s', disease, '(', 'PD),', including, 'inflammation,', oxidative, 'stress,', unfolded, protein, 'accumulation,', and, apoptosis])].
[sujeto(['Palmitoylethanolamide', '(', 'PEA),', an, endogenous, 'N-acylethanolamine,']), verbo([has]), complemento([been, shown, to, be, a, neuroprotective, and, 'anti-inflammatory', 'molecule,', acting, as, a, peroxisome, proliferator, activated, receptor, '(', 'PPAR)-α', agonist])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, 'PEA', '(', 3, -, 30, 'mg/kg/days'])].
[sujeto([')', improved, behavioral, impairments]), verbo([induced]), complemento([by, unilateral, intrastriatal, injection, of, 6, -, 'OHDA'])].
[sujeto(['This', effect, was, accompanied, by, a, significant]), verbo([increase]), complemento([in, tyrosine, hydroxylase, expression, at, striatal, 'level,', indicating, 'PEA', preserving, effect, on, dopaminergic, neurons])].
[sujeto(['Moreover,', we]), verbo([found]), complemento([a, reduction, in, the, expression, of, 'pro-inflammatory', 'enzymes,', i])].
[sujeto(['Similar', data, were]), verbo([found]), complemento([in, in, vitro, 'studies,', where, 'PEA', treatment, was, found, to, rescue, 'SH-SY5Y', neuroblastoma, cells, from, 6, -, 'OHDA-induced', damage, and, 'death,', partly, by, inhibiting, endoplasmic, reticulum, stress, detrimental, response])].
[sujeto(['Therefore,', 'PEA,', counteracting, the, pathogenetic, aspects]), verbo([involved]), complemento([in, the, development, of, 'PD,', showed, its, therapeutic, 'potential,', possibly, integrating, current, treatments, correcting, dopaminergic, deficits, and, motor, dysfunction])].
[sujeto(['Regulatory', 'T', '(', 'Treg)', cells, are, important, to]), verbo([induce]), complemento([and, maintain, immunological, 'self-tolerance'])].
[sujeto(['In', 'Treg', 'cells,', 'PPARα', gene, deletion, also]), verbo([induced]), complemento([a, decrease, of, migratory, 'abilities,', and, downregulated, the, expression, of, chemokine, receptors, '(', 'CCR-4,', 'CCR-8', and, 'CXCR-4)', and, 'p27(KIP1)', mRNA])].
[sujeto(['Since', low, 'Treg', 'activity,', as, observed, in, 'PPARα(-/-)', 'mice,', is, known, to, be]), verbo([associated]), complemento([with, the, inhibition, of, tumor, 'growth,', we, inoculated, these, mice, with, 'B16', melanoma, cells, and, assessed, tumor, proliferation])].
[sujeto(['Consistently,', adoptive, transfer, into, lymphopenic, 'RAG2(-/-)', mice, of, total, 'PPARα(-/-)splenic', 'T', cells]), verbo([inhibited]), complemento([more, the, growth, rate, of, 'B16', tumor, than, the, wild, type, splenic, 'T', cells])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, 'PPARα', 'deficiency,', by, diminishing, 'Treg', cell, functions, and, upregulating, 'pro-inflammatory', 'T', cell, 'phenotype,', exerts, an, 'in&nbsp;vivo', 'anti-cancer', properties])].
[sujeto(['Chemotherapy-induced', peripheral, neuropathy, '(', 'CIPN)', represents, a, serious, complication]), verbo([associated]), complemento([with, anticancer, drugs])].
[sujeto(['Although', there, are, no, medications, available, that, effectively]), verbo([prevent]), complemento(['CIPN,', many, classes, of, drugs, have, been, used, to, treat, this, 'condition,', including, 'anticonvulsants,', serotonin, and, noradrenaline, reuptake, 'inhibitors,', and, opioids])].
[sujeto([')', reversed, 'paclitaxel-induced', 'allodynia,']), verbo([suggesting]), complemento([that, it, may, act, at, multiple, sites, in, the, neuroaxis, and, periphery])].
[sujeto(['These', findings, taken, together]), verbo([suggest]), complemento([that, 'PEA', possesses, potential, to, treat, peripheral, neuropathy, in, cancer, patients, undergoing, chemotherapy])].
[sujeto(['Accumulating', evidence]), verbo([suggests]), complemento([that, loss, of, the, renal, tubular, epithelial, phenotype, plays, an, important, role, in, the, pathogenesis, of, renal, tubulointerstitial, fibrosis])].
[sujeto(['Systemic', activation, of, peroxisome, 'proliferator-activated', receptor, γ, '(', 'PPAR-γ)']), verbo([has]), complemento([been, shown, to, be, protective, against, renal, 'fibrosis,', although, the, mechanisms, are, poorly, understood])].
[sujeto(['In', response, to, 'TGF-β1', 'challenge,', 'PPAR-γ', expression, and, activity, in, the, renal, proximal, tubule, epithelial, cells, '(', 'RPTECs)', were, significantly, 'reduced,', and, the, reduction, was, accompanied, by]), verbo([decreased]), complemento(['E-cadherin', and, elevated, 'α-SMA,', indicating, a, loss, of, the, epithelial, phenotype])].
[sujeto(['Oxidative', stress]), verbo([induced]), complemento([by, 'TGF-β1', was, shown, to, be, attributed, to, the, alteration, of, the, epithelial, phenotype, and, 'PPAR-γ', inhibition])].
[sujeto(['Activation', of, 'PPAR-γ', by, its, agonists, of, rosiglitazone, and, 15, 'd-PGJ2', or, genetic, overexpression, of, 'PPAR-γ']), verbo([prevented]), complemento([the, loss, of, the, epithelial, phenotype, induced, by, 'TGF-β1', in, line, with, the, inhibition, of, oxidative, stress])].
[sujeto(['Taken', 'together,', these, findings, identified, an, important, role, of, renal, tubular, 'epithelium-targeted', 'PPAR-γ', in]), verbo([maintaining]), complemento([the, normal, epithelial, phenotype, and, opposing, 'fibrogenesis,', possibly, via, antagonizing, oxidative, stress])].
[sujeto(['The', 'ACTN3', '(', 'R577X)', polymorphism, is, not]), verbo([associated]), complemento([with, 'strength/power', athletic, status, in, two, cohorts, of, 'European', athletes])].
[sujeto(['We']), verbo([found]), complemento([that, the, 'PPARGC1A', '(', 'Gly482Ser)', polymorphism, is, associated, with, 'strength/power', athlete, status])].
[sujeto(['CAR']), verbo([induced]), complemento([paw, 'edema,', hyperalgesia, and, the, activation, of, 'pro-inflammatory', 'NF-κB', pathway, were, markedly, reduced, by, treatment, with, adelmidrol])].
[sujeto(['Thus,', in, this, 'study,', we]), verbo([report]), complemento([that, adelmidrol, reduces, the, development, of, acute, and, chronic, inflammation, and, could, represent, a, novel, therapeutic, approach, for, inflammation, and, pain])].
[sujeto(['Ethnomedical', applications, of, the, herb]), verbo([have]), complemento([been, identified, as, treatment, for, 'jaundice,', stomach, 'problems,', skin, 'disease,', 'fever,', and, kidney, 'stones,', reproductory, 'issues,', and, piles])].
[sujeto(['Evidence']), verbo([has]), complemento([been, demonstrated, through, scientific, studies, as, to, the, antidiabetic, effects, of, crude, extracts, of, 'S'])].
[sujeto(['The', primary, mechanisms, of, action, of, antidiabetic, activity, of, the, plant, and, its, bioactive, constituents, are, through, 'α-glucosidase', 'inhibition,', curbing, of, 'PPAR-γ', and]), verbo([increased]), complemento([secretion, of, insulin])].
[sujeto(['Scoparic', acid, 'A,', scoparic, acid, 'D,', 'scutellarein,', 'apigenin,', 'luteolin,', 'coixol,', and, glutinol, are, some, of, the, compounds, which]), verbo([have]), complemento([been, identified, as, responsible, for, these, mechanisms, of, action])].
[sujeto([dulcis]), verbo([has]), complemento([also, been, shown, to, exhibit, 'analgesic,', 'antimalarial,', 'hepatoprotective,', 'sedative,', 'hypnotic,', 'antiulcer,', 'antisickling,', and, antimicrobial, activities])].
[sujeto([dulcis, could, be]), verbo([promoted]), complemento([among, the, masses, as, an, alternative, and, complementary, therapy, for, 'diabetes,', provided, further, scientific, studies, on, the, toxicological, and, pharmacological, aspects, are, carried, out, through, either, in, vivo, or, clinical, means])].
[sujeto(['We', hypothesized, that, peroxisome, 'proliferator-activated', receptors, '(', 'PPARs)', might, be]), verbo([involved]), complemento([in, a, complex, protective, action, of, 'ACE', inhibitors, '(', 'ACEi)', in, 'anthracyclines-induced', cardiomyopathy])].
[sujeto(['In', severe, 'cardiomyopathy,', hemodynamic, dysfunction, remained, unaltered, upon, ramipril, although, it]), verbo([decreased]), complemento([the, significantly, 'up-regulated', cardiac, 'ANP', mRNA, expression])].
[sujeto(['Simultaneously,', while, 'high-dose', daunorubicin, significantly]), verbo([decreased]), complemento(['PPARbeta/delta', and, 'PPARgama', 'mRNA,', ramipril, normalized, these, abnormalities])].
[sujeto(['On', the, other, 'hand,', ramipril, was, unable, to, correct, both, the, significantly]), verbo([decreased]), complemento([relative, abundance, of, 'Myh6', and, increased, 'Myh7', mRNA, 'levels,', respectively])].
[sujeto(['Acetyl-CoA', carboxylases, '(', 'ACCs)', catalyze, a, critical, step, in, de, novo, 'lipogenesis,', and, are, considered, as, promising]), verbo([targets]), complemento([for, treatment, of, 'obesity,', dyslipidemia, and, type, 2, diabetes, mellitus])].
[sujeto(['On', the, other, 'hand,', peroxisome, 'proliferator-activated', receptors, '(', 'PPARs)', are, 'well-established', therapeutic]), verbo([targets]), complemento([for, these, metabolic, 'syndrome-related', diseases])].
[sujeto(['Subsequently,', 'AEA', facilitates, food, intake, via, activation, of, cannabinoid, 'type-1', receptors, '(', 'CB1Rs)', while, 'OEA']), verbo([decreases]), complemento([food, intake, via, activation, of, peroxisome, 'proliferator-activated', 'receptor-α', '(', 'PPARα)', 'and/or', 'G-protein-coupled', receptor, 119, '(', 'GPR119)'])].
[sujeto(['Neuronal', activity, in, the, gastrointestinal, region, of, the, autonomic, insula, '(', 'GI-Au-I)', that, rostrally, adjoins, the, gustatory, insula, '(', 'Gu-I)']), verbo([increases]), complemento([during, 'fasting,', enhancing, appetite, while, umami, and, sweet, taste, sensations, in, 'Gu-I', enhances, appetite, in, 'GI-Au-I,', strongly, suggesting, the, presence, of, a, neural, interaction, between, the, 'Gu-I', and, 'GI-Au-I', which, changes, depending, on, the, concentrations, of, 'AEA', and, 'OEA'])].
[sujeto(['However,', this, possibility]), verbo([has]), complemento([never, been, investigated])].
[sujeto(['In', rat, slice, 'preparations,', we, demonstrate, with, 'voltage-sensitive', dye, imaging, that, activation, of, 'CB1Rs', by, 'AEA']), verbo([induces]), complemento(['θ-rhythm', oscillatory, synchronization, in, the, 'Gu-I', which, propagates, into, the, 'GI-Au-I', but, stops, at, its, caudal, 'end,', displaying, an, oscillatory, coordination])].
[sujeto(['Our', results, demonstrate, that, the, neural, coordination, between, the, 'Gu-I', and, 'GI-Au-I', is, generated, or]), verbo([suppressed]), complemento([by, the, opposing, activities, between, 'CB1R', and, 'GPR119'])].
[sujeto(['This', mechanism, may, be]), verbo([involved]), complemento([in, the, feeding, behavior, based, on, taste, recognition])].
[sujeto(['Because', phthalates, are, not, chemically]), verbo([bound]), complemento([to, 'products,', they, can, easily, leak, out, to, enter, the, environment])].
[sujeto(['DBP']), verbo([stimulated]), complemento(['caspase-3', and, 'LDH', activities, as, well, as, 'ROS', formation, in, a, concentration, '(', 10, &, 'nbsp;nM-100&nbsp;µM)', and, 'time-dependent', '(', 3, -, 48, &, 'nbsp;h)', manner])].
[sujeto(['DBP']), verbo([induced]), complemento(['ROS', formation, at, nanomolar, 'concentrations,', while, it, activated, 'caspase-3', and, 'LDH', activities, at, micromolar, concentrations])].
[sujeto(['The', biochemical, effects, of, 'DBP', were, accompanied, by]), verbo([decreased]), complemento([cell, viability, and, induction, of, apoptotic, bodies])].
[sujeto(['Treatment', with, 'DBP']), verbo([enhanced]), complemento(['Ahr', mRNA, 'expression,', which, was, reflected, by, the, increased, 'AhR', protein, level, observed, at, 3, &, 'nbsp;h', after, exposure])].
[sujeto(['ERα,', 'ERβ,', and, 'PPARγ', antagonists]), verbo([stimulated]), complemento(['DBP-induced', 'caspase-3', and, 'LDH', activities])].
[sujeto(['AhR', silencing, demonstrated, that, 'DBP-induced', apoptosis, and, neurotoxicity, are]), verbo([mediated]), complemento([by, 'AhR,', which, is, consistent, with, the, results, from, 'DBP-induced', enhancement, of, 'AhR', mRNA, and, protein, expression])].
[sujeto(['Our', study, showed, that, 'AhR', is]), verbo([involved]), complemento([in, 'DBP-induced', apoptosis, and, 'neurotoxicity,', while, the, 'ERs', and, 'PPARγ', signaling, pathways, are, impaired, by, the, phthalate])].
[sujeto(['We']), verbo([have]), complemento([studied, the, effect, of, fenofibrate, on, 'b-oxidation', of, fatty, acids, and, related, 'free-radical', processes])].
[sujeto(['The', most, effective, concentration, of, fenofibrate, '(', 0.3, '%', ')', added, to, the, chow]), verbo([caused]), complemento([a, significant, decrease, of, the, body, weight, of, mice])].
[sujeto(['The', data, obtained, by, quantitative, 'PCR', demonstrated]), verbo([increased]), complemento([hepatic, gene, expression, responsible, for, 'b-oxidation', of, fatty, acids, in, peroxisomes, and, mitochondria])].
[sujeto(['Enhancement', of, oxidative, processes]), verbo([caused]), complemento([a, 2, -, fold, increase, in, the, rate, of, reactive, oxygen, species, '(', 'ROS)', 'production,', as, evidenced, by, determination, of, the, level, of, lipid, peroxidation, '(', 'LPO)', products, in, the, liver])].
[sujeto(['Mitochondrial', antioxidant, systems, are, more, sensitive, to, elevated, 'ROS', 'production,', as, they]), verbo([respond]), complemento([by, increased, expression, of, 'SOD2', and, 'PRDX3', 'genes,', than, cytoplasmic, and, peroxisomal, antioxidant, 'systems,', where, expression, of, 'CAT1,', 'SOD1,', 'PRDX5', genes, remained, unaltered])].
[sujeto(['Differentially']), verbo([expressed]), complemento([genes, in, the, left, atria, of, mitral, regurgitation, '(', 'MR)', pigs, have, been, linked, to, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)', signaling, pathway, in, the, 'KEGG', pathway])].
[sujeto(['However,', specific, genes, of, the, 'PPAR', signaling, pathway, in, the, left, atria, of, 'MR', patients]), verbo([have]), complemento([never, been, explored])].
[sujeto(['Gene', expression, profiling, analysis, through, 'PCR', assay, identified, 23, genes, to, be, differentially]), verbo([expressed]), complemento([in, the, left, atria, of, 'MR', patients, compared, to, normal, controls])].
[sujeto(['Notably,', only, 'ACADM,', 'FABP3,', 'ECH1,', 'ACAA2,', 'EHHADH,', 'CPT1A', and, 'PLTP', of, the, 'PPAR', pathway, were, significantly, differentially]), verbo([expressed]), complemento([in, the, 'MR', patients, compared, to, patients, with, aortic, valve, disease, and, normal, controls])].
[sujeto(['Differentially']), verbo([expressed]), complemento([genes, of, the, 'PPAR', pathway, have, been, identified, in, the, left, atria, of, 'MR', patients, compared, with, patients, with, aortic, valve, disease, and, normal, controls])].
[sujeto(['The', 'Peroxisome', 'Proliferator-Activated', 'Receptors', '(', 'PPARs)', 'PPARA', and, 'PPARD', are, regulators, of, lipid, metabolism, with, important, roles, in, energy]), verbo([release]), complemento([through, lipid, 'breakdown,', while, 'PPARG', plays, a, key, role, in, lipid, storage, and, adipogenesis])].
[sujeto(['Zebrafish', are, an, appropriate, model, to, study, human, 'diseases,', including, obesity, and, related, metabolic, 'diseases,', as, pathways, important, for, adipogenesis, and, lipid, metabolism, which, are]), verbo([conserved]), complemento([between, mammals, and, fish])].
[sujeto(['AMPK', activation, by, 'AICAR', was, confirmed, by]), verbo([increased]), complemento(['phospho-Thr(172)-AMPK', and, 'phospho-Ser(79)-ACC', protein, levels, in, 'HL-1', cardiomyocytes])].
[sujeto(['Treatment', with, 'AICAR']), verbo([induced]), complemento([gene, expression, of, all, three, 'PPARs,', but, only, the, 'Ppara', and, 'Pparg', regulation, were, dependent, on, 'AMPK'])].
[sujeto(['HP/HI']), verbo([induced]), complemento([insulin, resistance, and, lipid, storage, was, accompanied, by, increased, 'Cd36,', 'Acot1,', and, 'Ucp3', mRNA, levels])].
[sujeto(['AICAR', treatment]), verbo([induced]), complemento([the, expression, of, 'Acadvl', and, 'Glut4,', which, correlated, to, prevention, of, the, 'HP/HI-induced', intramyocellular, lipid, 'build-up,', and, attenuation, of, the, 'HP/HI-induced', impairment, of, glucose, uptake])].
[sujeto(['Ossification', defects]), verbo([leading]), complemento([to, craniofacial, dysmorphism, or, rhizomelia, are, typical, phenotypes, in, patients, and, corresponding, knockout, mouse, models, with, distinct, peroxisomal, disorders])].
[sujeto(['The', peroxisome, number, and, metabolism, strongly]), verbo([increased]), complemento([in, chondrocytes, during, endochondral, ossification, from, the, reserve, to, the, hypertrophic, 'zone,', whereas, in, 'bone,', metabolically, active, osteoblasts, contained, a, higher, numerical, abundance, of, this, organelle, than, osteocytes])].
[sujeto(['During', 'culture,', calvarial, 'pre-osteoblasts', differentiated, into, secretory, osteoblasts, accompanied, by, peroxisome, proliferation, and]), verbo([increased]), complemento([levels, of, peroxisomal, genes, and, proteins])].
[sujeto(['Since', many, peroxisomal, genes, contain, a, 'PPAR-responsive', 'element,', we, analyzed, the, gene, expression, of, 'PPARɑ/ß/ɣ', in, calvarial, osteoblasts, and, 'MC3T3-E1', 'cells,']), verbo([revealed]), complemento([higher, levels, for, 'PPARß', than, for, 'PPARɑ', and, 'PPARɣ'])].
[sujeto(['Treatment', with, different, 'PPAR', agonists, and, antagonists, not, only, changed, the, peroxisomal, compartment, and]), verbo([associated]), complemento([gene, 'expression,', but, also, induced, complex, alterations, of, the, gene, expression, patterns, of, the, other, 'PPAR', family, members])].
[sujeto(['Studies', in, 'M3CT3-E1', cells, showed, that, the, 'PPARß', agonist, 'GW0742']), verbo([activated]), complemento([the, 'PPRE-mediated', luciferase, expression, and, 'up-regulated', peroxisomal, gene, transcription, '(', 'Pex11,', 'Pex13,', 'Pex14,', 'Acox1', and, 'Cat),', whereas, the, 'PPARß', antagonist, 'GSK0660', led, to, repression, of, the, 'PPRE', and, a, decrease, of, the, corresponding, mRNA, levels])].
[sujeto(['In', the, same, 'way,', treatment, of, calvarial, osteoblasts, with, 'GW0742']), verbo([increased]), complemento([in, peroxisome, number, and, related, gene, expression, and, accelerated, osteoblast, differentiation])].
[sujeto(['Taken', 'together,', our, results]), verbo([suggest]), complemento([that, 'PPARß', regulates, the, numerical, abundance, and, metabolic, function, of, peroxisomes, via, 'Pex11ß', in, parallel, to, osteoblast, differentiation])].
[sujeto(['Administration', of, 'TZD']), verbo([increased]), complemento([blood, concentrations, of, 'glucose,', 'insulin,', and, 'beta-hydroxybutyrate', '(', 'BHBA)', at, 2, to, 4, weeks, after, diet, 'initiation,', while, the, concentration, of, 'NEFA', and, adiponectin, '(', 'ADIPOQ)', remained, unchanged, during, 'TZD'])].
[sujeto(['The', 'TZD', upregulated, the, mRNA, expression, of, 'PPARG', and, its]), verbo([targets]), complemento(['FASN', and, 'SREBF1', in, 'SAT,', but, also, 'SUMO1', and, 'UBC9', which, encode, sumoylation, proteins, known, to, 'down-regulate', 'PPARG', expression, and, curtail, adipogenesis])].
[sujeto(['In', skeletal, 'muscle,', where, 'PPARA', and, its]), verbo([targets]), complemento([orchestrate, carbohydrate, metabolism, and, fatty, acid, 'oxidation,', the, 'OVE', cows, had, greater, glyceroneogenesis, '(', higher, mRNA, expression, of, 'PC', and, 'PCK1),', whereas, 'CON', cows, had, greater, glucose, transport, '(', 'SLC2A4)'])].
[sujeto(['Administration', of, 'TZD']), verbo([increased]), complemento([triacylglycerol, concentration, and, altered, expression, of, 'carbohydrate-', and, fatty, acid, 'oxidation-related', genes, in, skeletal, muscle])].
[sujeto(['The', bovine, 'PPARG', receptor, appears, 'TZD-responsive,', with, its, activation, potentially]), verbo([leading]), complemento([to, greater, adipogenesis, and, lipogenesis, in, 'SAT,', while, differentially, regulating, glucose, homeostasis, and, fatty, acid, oxidation, in, skeletal, muscle])].
[sujeto(['Targeting', 'PPARG', via, dietary, nutraceuticals, while, avoiding, excessive, fat, deposition, might, improve, insulin, sensitivity, in, dairy, cows, during, times, such, as, the, peripartal, period, when, the, onset, of, lactation, naturally]), verbo([decreases]), complemento([systemic, insulin, release, and, sensitivity, in, tissues, such, as, 'AT'])].
[sujeto(['Maternal', nutrition, can, affect, 'development,']), verbo([leading]), complemento([to, 'long-term', effects, on, the, health, of, offspring])].
[sujeto(['All', four, models]), verbo([induced]), complemento([programmed, hypertension, in, adult, male, offspring])].
[sujeto(['The', identified, differential]), verbo([expressed]), complemento([genes, '(', 'DEGs)', that, are, related, to, the, regulation, of, blood, pressure, included, 'Adrb3,', 'Alb,', 'Apoe,', 'Calca,', 'Kng1,', 'Adm2,', 'Guca2b,', 'Hba2,', 'Hba-a2,', and, 'Ppara'])].
[sujeto(['Conclusively,', a, variety, of, maternal, nutritional, insults]), verbo([induced]), complemento([the, same, 'phenotype-programmed', hypertension, with, differential, alterations, of, renal, transcriptome, in, adult, male, offspring])].
[sujeto(['Hepatocellular', carcinoma, '(', 'HCC)', is, the, second]), verbo([leading]), complemento([cause, of, 'cancer-related', 'deaths,', reflecting, the, aggressiveness, of, this, type, of, cancer, and, the, absence, of, effective, therapeutic, regimens])].
[sujeto(['MicroRNAs']), verbo([have]), complemento([been, involved, in, the, pathogenesis, of, different, types, of, 'cancers,', including, liver, cancer])].
[sujeto(['Our', aim, was, to, identify, microRNAs, that]), verbo([have]), complemento([both, functional, and, clinical, relevance, in, 'HCC', and, examine, their, downstream, signaling, effectors])].
[sujeto(['MiR-9,', 'miR-21', and, 'miR-224', were, the, top, inducers, of, 'HCC', invasiveness, and, also, their, expression, was]), verbo([increased]), complemento([in, 'HCC', relative, to, control, liver, tissues])].
[sujeto(['MiR-9', levels, correlated, with, 'HCC', tumor, stage, and, 'miR-9', overexpression]), verbo([induced]), complemento(['SNU-449', and, 'HepG2', cell, 'growth,', invasiveness, and, their, ability, to, form, colonies, in, soft, agar])].
[sujeto(['Inhibition', of, 'PPARA']), verbo([suppressed]), complemento(['CDH1', mRNA, 'levels,', suggesting, that, 'miR-9', regulates, 'CDH1', expression, directly, through, binding, in, its, 3, '\'', 'UTR', and, indirectly, through, 'PPARA'])].
[sujeto(['On', the, other, 'hand,', 'miR-9', inhibition, of, overexpression]), verbo([suppressed]), complemento(['HCC', tumorigenicity, and, invasiveness])].
[sujeto(['PPARA', and, 'CDH1', mRNA, levels, were]), verbo([decreased]), complemento([in, 'HCC', relative, to, controls, and, were, inversely, correlated, with, 'miR-9', levels])].
[sujeto(['Increasing', evidence]), verbo([suggests]), complemento([that, the, source, of, dietary, protein, can, have, an, impact, on, weight, gain, and, fat, mass, during, 'high-fat', feeding, in, both, humans, and, rodents])].
[sujeto(['The', present, study, examined, whether, dietary, bovine, serum, albumin, '(', 'BSA)', as, the, dominant, source, of, protein, alters, energy, balance, and, adiposity]), verbo([associated]), complemento([with, 'high-fat', feeding])].
[sujeto(['The', 'HFD+BSA', diet, did, not, significantly, alter, daily, energy, 'expenditure,', locomotor, activity, and, 'RER,', but, did]), verbo([increase]), complemento([cumulative, energy, intake, and, percentage, of, lean, mass, while, reducing, feed, efficiency, and, percentage, of, fat, mass, when, compared, with, the, 'HFD', '(', 'P&lt;', 0, '·05)'])].
[sujeto(['In', subcutaneous, adipose, tissue, '(', 'SAT),', the, 'HFD+BSA', diet]), verbo([increased]), complemento([the, mRNA, levels, of, 'PPARα', '(', 'PPARA),', carnitine, palmitoyltransferase, 1, b, '(', 'CPT1b)', and, uncoupling, protein, 3, '(', 'UCP3),', but, reduced, the, mRNA, level, of, leptin, when, compared, with, the, 'HFD', '(', 'P&lt;', 0, '·05)'])].
[sujeto(['While', differences, in, leptin, levels, were]), verbo([associated]), complemento([with, the, percentage, of, fat, mass, '(', 'P&lt;', 0, '·01),', changes, in, corticosterone, concentrations, were, independent, of, the, percentage, of, fat, mass, '(', 'P&lt;', 0, '·05)'])].
[sujeto(['The', data]), verbo([suggest]), complemento([that, the, 'HFD+BSA', diet, influences, plasma, leptin, levels, via, 'SAT', mass, reduction, where, mRNA, levels, of, genes, linked, to, 'β-oxidation', were, 'increased,', whereas, differences, in, plasma, corticosterone, levels, were, not, related, to, fat, mass, reduction])].
[sujeto(['The', results, indicated, that, exposure, to, 'LCT', is, capable, of]), verbo([inducing]), complemento([an, 'up-regulation', in, the, mRNA, expression, levels, of, peroxisome, proliferative, activated, receptor, α, and, γ, '(', 'PPAR', α, and, 'PPAR', 'γ),', tumor, necrosis, factor, '(', 'TNF-α),', fatty, acid, synthase, '(', 'FAS)', and, sterol, regulatory, element, binding, 'protein-1c', '(', 'SREBP-1c)'])].
[sujeto(['Additionally,', our, study, revealed, a, significant]), verbo([increase]), complemento([in, serum, levels, of, 'ALT,', 'AST,', 'ALP,', γGT, as, well, as, the, inflammatory, cytokines, 'TNF-α', and, monocyte, chemoattractant, 'protein-1', '(', 'MCP-1)'])].
[sujeto(['A', significant, elevation, in, total, 'lipids,', total, 'cholesterol,', 'triacylglycerol,', 'LDL-c', and, leptin, with, a, corresponding, significant]), verbo([decrease]), complemento([in, 'HDL-c', was, also, noted])].
[sujeto(['Moreover,', our, results, depicted, that, 'LCT', treatment, exhibits, a, significant]), verbo([increase]), complemento([in, hepatic, 'MDA', levels, concurrent, with, a, significant, decrease, in, 'GSH', levels, and, the, activities, of, 'CAT,', 'SOD,', and, 'GPx'])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, alpha, '(', 'PPARα)', ligands]), verbo([have]), complemento([been, shown, to, modulate, recovery, after, brain, insults, such, as, ischemia, and, irradiation, by, enhancing, neurogenesis])].
[sujeto(['These', results, identify, 'PPARα', receptors, as, a, potential]), verbo([target]), complemento([to, counteract, the, naturally, observed, decline, in, adult, 'NPC', proliferation, associated, with, aging, and, impoverished, environments])].
[sujeto(['Oxadiazon', '(', 'OX)', is, a, protoporphyrinogen, 'oxidase-inhibiting', herbicide, that]), verbo([induces]), complemento([porphyria, and, liver, tumors, in, rodents])].
[sujeto(['Although', porphyria, is, generally, considered, to, be, a, risk, factor, for, liver, tumor, 'development,', the, mechanisms, through, which, 'OX']), verbo([mediates]), complemento([tumor, development, are, unclear])].
[sujeto(['After', 1, ',', 4, ',', or, 13, weeks, of, dietary, treatment, with, 1000, &, 'nbsp;ppm', 'OX,', hepatic, 'Cyp2b10', expression, was]), verbo([induced]), complemento([in, 'wild-type', '(', 'WT)', mice])].
[sujeto(['After', initiation, by, 'diethylnitrosamine,', 26, -, week, treatment, with, 'OX', resulted, in, an]), verbo([increase]), complemento([in, proliferative, 'lesions,', including, foci, and, 'adenomas,', in, both, 'genotypes,', and, the, incidence, and, multiplicity, of, proliferative, lesions, in, 'CARKO', mice, were, higher, than, those, in, control, mice, but, lower, than, those, in, 'WT', mice])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, 'CAR,', 'PPARα', 'activation,', and, cytotoxicity, were, involved, in, the, development, of, liver, tumors])].
[sujeto(['Moreover,', porphyrin, was, not, apparently]), verbo([involved]), complemento([in, 'OX-induced', tumor, development])].
[sujeto(['Inflammatory', bowel, disease, '(', 'IBD)', is, a, chronic, inflammatory, disease, with]), verbo([increasing]), complemento([incidence, and, prevalence, worldwide])].
[sujeto(['First,', to, test, whether, 'J11-Cl', can]), verbo([activate]), complemento([peroxisome, 'proliferator-activated', receptors, '(', 'PPARs),', we, performed, docking, simulations, because, 'J11-Cl', has, a, structural, similarity, with, 'anti-inflammatory', 15, -, 'deoxy-Δ(12,14)-prostaglandin', 'J2', '(', 15, 'd-PGJ2),', one, of, the, endogenous, ligands, of, 'PPARγ'])].
[sujeto(['J11-Cl']), verbo([bound]), complemento([to, the, ligand, binding, domain, of, 'PPARγ', in, the, same, manner, as, 15, 'd-PGJ2', and, 'rosiglitazone,', and, significantly, increased, transcriptional, activity, of, 'PPARγ'])].
[sujeto(['Moreover,', 'J11-Cl']), verbo([decreased]), complemento([production, of, 'pro-inflammatory', cytokines, including, 'IL-6,', 'IL-8,', and, 'G-CSF', as, well, as, chemokines, including, chemokine, '(', 'C-C', 'motif)', ligand, '(', 'CCL)20,', chemokine, '(', 'C-X-C', 'motif)', ligand, '(', 'CXCL)2,', 'CXCL3,', and, chemokine, '(', 'C-X3-C', 'motif)', ligand, 1, '(', 'CX3CL1)', in, colon, 'tissues,', and, 'LPS', or, 'TNF-α-stimulated', macrophages, and, epithelial, cells])].
[sujeto(['In', 'contrast,', production, of, 'anti-inflammatory', cytokines, including, 'IL-2', and, 'IL-4', as, well, as, the, proliferative, 'factor,', 'GM-CSF,', was]), verbo([increased]), complemento([by, 'J11-Cl'])].
[sujeto(['J11-Cl', reduced, intestinal, inflammation, by]), verbo([increasing]), complemento([the, transcriptional, activity, of, 'PPARγ', and, modulating, inflammatory, signaling, pathways])].
[sujeto(['Therefore,', our, study]), verbo([suggests]), complemento([that, 'J11-Cl', may, serve, as, a, novel, therapeutic, agent, against, 'IBD'])].
[sujeto(['The', truncated, splice, variant, 'PPARα-tr', was]), verbo([suggested]), complemento([to, exert, a, dominant, negative, function, despite, being, unable, to, bind, consensus, 'PPARα', 'DNA', response, elements])].
[sujeto(['Bioinformatic', analyses, of, 'genome-wide', liver, expression, profiling, data]), verbo([suggested]), complemento([a, possible, role, of, 'PPARα-tr', in, downregulating, proliferative, and, 'pro-inflammatory', genes])].
[sujeto(['Specific', gene, silencing, of, both, forms, in, primary, human, hepatocytes, showed, that, induction, of, metabolic, 'PPARα-target', genes, by, agonist, 'WY14,643', was]), verbo([prevented]), complemento([by, 'PPARα-wt', 'knock-down', but, neither, prevented, nor, augmented, by, 'PPARα-tr', 'knock-down'])].
[sujeto(['WY14,643', treatment, did, not]), verbo([induce]), complemento([proliferative, genes, including, 'MYC,', 'CDK1,', and, 'PCNA,', and, 'knock-down', of, 'PPARα-wt', had, no, 'effect,', while, 'PPARα-tr', 'knock-down', caused, up, to, 3, -, fold, induction, of, these, genes])].
[sujeto(['Pro-inflammatory', genes, including, 'IL-1β,', 'CCL2', and, 'TNFα', were]), verbo([induced]), complemento([by, 'WY14,643', in, mouse, and, human, cells, and, both, 'PPARα', forms, attenuated, induction])].
[sujeto(['As', potential, mechanism, of, 'PPARα-tr', inhibitory, action, we]), verbo([suggest]), complemento([crosstalk, with, 'WNT/β-catenin', pathway])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, the, truncated, 'PPARα', splice, variant, functions, as, an, endogenous, inhibitor, of, proliferative, and, 'pro-inflammatory', genes, in, human, cells, and, that, its, absence, in, mouse, may, explain, 'species-specific', differences, in, 'fibrate-induced', hepatocarcinogenesis])].
[sujeto(['Tumor-specific', metabolic, changes, can]), verbo([reveal]), complemento([new, therapeutic, targets])].
[sujeto(['NXT629']), verbo([inhibited]), complemento(['agonist-induced', transcription, of, 'PPARα-regulated', 'genes,', demonstrating, target, engagement, in, 'CLL', cells])].
[sujeto(['Furthermore,', 'NXT629']), verbo([induced]), complemento([apoptosis, of, 'CLL', cells, even, in, the, presence, of, a, protective, microenvironment])].
[sujeto(['To', mimic, the, proliferative, lymphoid, compartment, of, 'CLL,', we, examined, the, activity, of, 'NXT629', on, 'CLL', cells, that, were]), verbo([stimulated]), complemento([to, proliferate, in, vitro])].
[sujeto(['Overall,', these, results]), verbo([suggest]), complemento([that, fatty, acid, metabolism, promotes, survival, and, proliferation, of, primary, 'CLL', cells, and, that, inhibiting, 'PPARα', gene, regulation, could, be, a, new, therapeutic, approach, to, treating, 'CLL'])].
[sujeto(['The', mRNA, levels, of, 'PGC-1α', and, 'ERRγ', in, the, endometrial, adenocarcinomas]), verbo([increased]), complemento([with, clinical, 'staging,', depth, of, myometrial, 'invasion,', and, increases, in, the, number, of, metastatic, lymph, nodes])].
[sujeto(['The', mRNA, levels, of, 'PGC-1α', were, positively, correlated, with, the, concentrations, of, pyruvate, kinase, and, isocitrate, dehydrogenase, in, the, endometrial, carcinoma, 'tissues,', and, similar, results, were]), verbo([found]), complemento([for, 'ERRγ'])].
[sujeto(['Our', results]), verbo([suggested]), complemento([that, the, upregulation, of, 'PGC-1α', and, 'ERRγ', in, endometrial, cancer, might, be, a, requirement, for, cancer, cell, energy, 'metabolism,', which, contributes, to, the, development, of, endometrial, cancer])].
[sujeto(['The', cellular, mechanisms, that]), verbo([lead]), complemento([to, kidney, tissue, fibrosis, are, complex, and, 'include,', for, 'example,', increased, 'inflammation,', increased, oxidative, 'stress,', and, proximal, tubule, cell, death, in, the, form, of, apoptosis, or, senescence])].
[sujeto(['Recent', studies]), verbo([have]), complemento([identified, 'TWEAK,', a, tumor, necrosis, 'factor-like', weak, inducer, of, 'apoptosis,', as, a, novel, cytokine, that, mediates, kidney, inflammation, in, models, of, renal, fibrosis])].
[sujeto(['Inhibition', of, apoptosis, via, 'TWEAK', inhibition]), verbo([has]), complemento([been, shown, to, reduce, kidney, fibrosis])].
[sujeto(['Recent', studies, using, lineage, tracing]), verbo([suggest]), complemento([that, interstitial, 'pericytes/perivascular', fibroblasts, differentiate, into, myofibroblasts, and, undergo, proliferative, expansion, during, fibrosis])].
[sujeto(['Furthermore,']), verbo([increased]), complemento([expression, of, nuclear, peroxisome, 'proliferator-activated', 'receptor-α', in, proximal, tubules, can, directly, reduce, increased, expression, of, transforming, growth, 'factor-β1', and, interstitial, inflammation, in, models, of, renal, 'fibrosis,', which, suggests, preservation, of, proximal, tubule, cell, metabolism, and, integrity, represents, an, important, new, therapeutic, target])].
[sujeto(['In', this, 'review,', the, current, evidence, and, potential, molecular, mechanisms]), verbo([involved]), complemento([in, the, development, of, kidney, fibrosis, are, discussed])].
[sujeto(['The', molecular, basis, for, 'A20\'s', hepatoprotective, functions, were, partially, resolved, and, include, blockade, of, 'NF-kappaB', activation, in, support, of, its, 'anti-inflammatory', 'function,', inhibition, of, 'pro-caspase', 8, cleavage, in, support, of, its, 'anti-apoptotic', 'function,']), verbo([increasing]), complemento(['Peroxisome', 'Proliferator', 'Activated', 'Receptor', alpha, '(', 'PPARalpha)', expression, in, support, of, its, 'anti-oxidant', 'function,', and, decreasing, 'Cyclin', 'Dependent', 'Kinase', 'Inhibitor', p21, while, boosting, 'IL-6/STAT3', proliferative, signals, as, part, of, its, 'pro-regenerative', function])].
[sujeto(['Conversely,', partial]), verbo([loss]), complemento([of, 'A20,', as, in, 'A20', heterozygote, 'mice,', significantly, impairs, liver, regeneration, and, 'damage,', which, confers, high, lethality, to, an, otherwise, safe, procedure, i])].
[sujeto(['In', recent, 'work,', 'A20\'s', functions, in, the, liver]), verbo([have]), complemento([expanded, to, encompass, regulation, of, lipid, and, glucose, 'metabolism,', unlocking, a, whole, new, set, of, metabolic, diseases, that, could, be, affected, by, 'A20'])].
[sujeto(['Meridianin', 'C,', a, marine, 'alkaloid,', is, a, potent, protein, kinase, inhibitor, and]), verbo([has]), complemento(['anti-cancer', activity])].
[sujeto(['We']), verbo([have]), complemento([recently, developed, a, series, of, meridianin, 'C', derivatives, '(', compound, 7, 'a-7j)', and, reported, their, proviral, integration, 'Moloney', 'Murine', 'Leukemia', 'Virus', '(', 'pim)', 'kinases\'', inhibitory, and, 'anti-proliferative', effects, on, human, leukemia, cells])].
[sujeto(['Strikingly,', among, the, derivatives, 'tested,', compound, 7, b, most, strongly]), verbo([inhibited]), complemento([lipid, accumulation, during, the, differentiation, of, 3, 'T3-L1', preadipocytes, into, adipocytes])].
[sujeto(['Moreover,', compound, 7, b]), verbo([repressed]), complemento(['leptin,', but, not, 'adiponectin,', expression, during, adipocyte, differentiation])].
[sujeto(['Collectively,', these, findings, demonstrate, that, a, meridianin, 'C', derivative]), verbo([inhibits]), complemento([adipogenesis, by, 'down-regulating', expressions, 'and/or', phosphorylations, of, 'C/EBP-α,', 'PPAR-γ,', 'FAS,', 'STAT-3', and, 'STAT-5'])].
[sujeto(['Liver', regeneration, '(', 'LR)', is, a, valuable, model, for, studying, mechanisms]), verbo([modulating]), complemento([hepatocyte, proliferation])].
[sujeto(['To', validate, our, 'approach,', we, further, studied, 'PPARδ', role, in]), verbo([modulating]), complemento([hepatic, proliferation])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, 'NR', transcriptome, is, modulated, in, proliferating, liver, and, is, a, source, of, biomarkers, and, bona, fide, pharmacological, targets, for, the, management, of, liver, disease, affecting, hepatocyte, proliferation])].
[sujeto(['This', study, was, designed, to, determine, whether, 'fenofibrate,', a, 'PPARα', 'agonist,', can]), verbo([suppress]), complemento([4, -, nitroquinoline, 1, -, oxide, '(', 4, -, 'NQO)-induced', proliferative, lesions, in, the, lung, of, obese, hyperlipidemic, mice])].
[sujeto(['Male', 'Tsumura', 'Suzuki', 'Obese', 'Diabetic', mice, were, subcutaneously, injected, with, 4, -, 'NQO', to]), verbo([induce]), complemento([lung, proliferative, 'lesions,', including, adenocarcinomas])].
[sujeto(['Fenofibrate', also, significantly, reduced, the, serum, insulin, and, 'insulin-like', growth, factor, '(', 'IGF)-1', 'levels,', and]), verbo([decreased]), complemento([the, immunohistochemical, expression, of, 'IGF-1', receptor, '(', 'IGF-1R),', phosphorylated, 'Akt,', and, phosphorylated, 'Erk1/2', in, lung, adenocarcinomas])].
[sujeto(['Our', results, indicate, that, fenofibrate, can]), verbo([prevent]), complemento([the, development, of, 4, -, 'NQO-induced', proliferative, lesions, in, the, lung, by, modulating, the, 'insulin-IGF', axis])].
[sujeto(['Key', events, supported, a, peroxisome, 'proliferator-activated', receptor, alpha, '(', 'PPARα)', mode, of, action, for, 'DEHP,', with, secondary, cytotoxicity, at, the, high, 'dose,', whereas, 'DNOP']), verbo([induced]), complemento([modest, increases, in, 'PPARα', activity, without, proliferative, or, cytotoxic, effects])].
[sujeto(['Other']), verbo([target]), complemento([sites, included, testis, and, 'kidney,', which, showed, degenerative, changes, at, higher, doses, of, 'DEHP', but, not, 'DNOP'])].
[sujeto(['Recent', evidence]), verbo([has]), complemento([suggested, a, potential, role, in, various, cancers, including, glioblastoma])].
[sujeto(['Fenofibrate', exhibited, 'dose-dependent', 'p53-independent', 'anti-proliferative', effects, on, 'HGG', starting, at, 25, &, 'nbsp;μM', and, 'pro-apoptotic', effects, starting, at, 50, &, 'nbsp;μM,']), verbo([suggesting]), complemento([that, the, 'anti-proliferative', actions, are, present, only, at, 25, &, 'nbsp;μM'])].
[sujeto(['PPARα', was]), verbo([expressed]), complemento([in, all, 'HGG', cell, lines])].
[sujeto(['Inhibition', of, 'PPARα', with, specific, inhibitor, 'GW6471', did, not, affect, either, proliferation, or, apoptosis]), verbo([suggesting]), complemento([that, these, are, 'PPARα-independent', effects])].
[sujeto(['With', respect, to, 'GSC,', fenofibrate, treatment, at, 25, &, 'nbsp;μM', significantly]), verbo([decreased]), complemento([invasion, in, association, with, a, decrease, in, 'CD133', and, 'Oct4', expression])].
[sujeto(['Peroxisome', 'proliferative-activated', receptor, '(', 'PPAR)α']), verbo([has]), complemento([an, endothelial, protective, effect, related, to, activation, of, 'PPARγ', coactivator, '(', 'PGC)-1α', and, vascular, endothelial, growth, factor, '(', 'VEGF),', but, its, role, in, 'DPN', is, unknown])].
[sujeto(['We', investigated, whether, fenofibrate, would, improve, 'DPN']), verbo([associated]), complemento([with, endothelial, survival, through, 'AMPK-PGC-1α-eNOS', pathway])].
[sujeto(['The', 'db/db', mice, displayed, 'sensory-motor', 'impairment,', nerve, fibrosis, and, 'inflammation,']), verbo([increased]), complemento([apoptotic, 'cells,', disorganized, myelin, with, axonal, shrinkage, and, 'degeneration,', fewer, unmyelinated, 'fibers,', and, endoneural, vascular, rarefaction, in, the, sciatic, nerve, compared, to, 'db/m', mice])].
[sujeto(['In', 'contrast,', fenofibrate, treatment, ameliorated, neural, and, endothelial, damage, by]), verbo([activating]), complemento([the, 'PPARα-AMPK-PGC-1α-eNOS', pathway, in, 'db/db', 'mice,', 'HUVECs', and, 'HSCs'])].
[sujeto(['Fenofibrate', could, be, a, promising, therapy, to]), verbo([prevent]), complemento(['DPN', by, protecting, endothelial, cells, through, 'VEGF-independent', activation, of, the, 'PPARα-AMPK-PGC-1α-eNOS-NO', pathway])].
[sujeto(['Then', two, kinds, of, preadipocytes, were, cultured, or]), verbo([induced]), complemento([to, differentiation, with, different, doses, of, insulin, glargine])].
[sujeto(['(', 2, ')', 'MTT', results, showed, that, insulin, glargine, could]), verbo([inhibit]), complemento([the, proliferation, of, omental, preadipocytes, in, a, 'dose-dependent', fashion])].
[sujeto(['After', 72, h, 'incubation,', compared, with, negative, 'control,', the, absorbance, '(', 'A)', value, of, 1000, 'nmol/L', insulin, glargine, group]), verbo([decreased]), complemento([greatly, '(', 0.144, ±, 0.021, vs, 0.267, ±, 0.04, ',', 'P', &, 'lt;', 0.01, ')'])].
[sujeto(['(', 3, ')', 'Insulin', at, 500, 'nmol/L', was, a, suitable, concentration, for]), verbo([inducing]), complemento([differentiation])].
[sujeto(['RT-PCR', analysis, showed, 'that,', for, subcutaneous, 'adipocytes,', adipogenic, genes, such, as, peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPARγ)', '(', 'F', =, 31.31, ',', 'P', &, 'lt;', 0.01, ')', and, 'CCAAT', enhancer]), verbo([binding]), complemento([protein, α, '(', 'C/EBPα)', '(', 'F', =, 9.86, ',', 'P', &, 'lt;', 0.05, ')', had, the, highest, mRNA, expression, while, preadipocytes, gene, 'Pref-1', had, the, lowest, expression, at, this, concentration])].
[sujeto(['Insulin', glargine, could]), verbo([inhibit]), complemento([the, proliferation, of, omental, 'preadipocytes,', and, enhance, the, differentiation, of, subcutaneous, and, omental, preadipocytes])].
[sujeto(['It']), verbo([has]), complemento([special, interest, as, it, holds, anticancerous, properties])].
[sujeto(['This', study, aims, to, clarify, the, mechanisms]), verbo([involved]), complemento([in, quercetin, effects, during, the, occurrence, of, preneoplastic, lesions, in, rat, liver])].
[sujeto(['This', group, showed]), verbo([increased]), complemento([apoptosis, and, a, reduction, in, the, proliferative, index])].
[sujeto(['In', 'addition,', 'IPQ20', group, displayed, a, reduction, of, cell, percentages, in, 'G₁', and, 'S', 'phases,', accumulation, in, 'G₂,', and]), verbo([decrease]), complemento([in, 'M', 'phase,', with, reduced, expression, of, cyclin, 'D1,', cyclin, 'A,', cyclin, 'B,', and, 'cyclin-dependent', kinase, 1])].
[sujeto(['Interestingly,', peroxisome, proliferator]), verbo([activated]), complemento(['receptor-α', levels, were, reduced, in, 'IPQ20', group])].
[sujeto(['The', outcomes, of, this, study, represent, a, significant, contribution, to, the, current, understanding, on, the, preventive, mechanisms, of, quercetin, during, the, early, stages, of, liver, cancer, 'development,', demonstrating, that, in, addition, to, its, known, proapoptotic, 'characteristics,', the, flavonoid]), verbo([modulates]), complemento([the, expression, of, critical, cell, cycle, regulators, and, peroxisome, proliferator, activated, 'receptor-α', activity])].
[sujeto(['However,', expression, levels, of, key, regulators, of, 'metabolism,', 'AMP-activated', protein, kinase, '(', 'Ampk),', peroxisome, proliferative]), verbo([activated]), complemento([receptor, gamma, coactivator, 1, -, α, '(', 'Ppargc1a),', and, 'Ppara,', were, significantly, lower, than, those, in, controls, and, correlated, with, fibrosis, development])].
[sujeto(['Treatment', of, 'Lkb1-deficient', cells, with, an, 'AMP-activated', protein, kinase, '(', 'AMPK)', agonist, '(', 'A769662)', or, a, peroxisome, proliferative]), verbo([activated]), complemento([receptor, alpha, agonist, '(', 'fenofibrate)', restored, the, fatty, oxidation, defect, and, reduced, apoptosis])].
[sujeto(['In', 'conclusion,', we, show, that]), verbo([loss]), complemento([of, 'LKB1', in, renal, tubular, epithelial, cells, has, an, important, role, in, kidney, disease, development, by, influencing, intracellular, metabolism])].
[sujeto(['PP', treatment]), verbo([caused]), complemento([significant, decreases, in, the, weight, and, cell, numbers, of, thymus, and, spleen, and, proliferative, responsiveness, of, lymphocytes, to, 'ConA', and, 'LPS', in, 'wild-type', 'mice,', whereas, these, effects, were, significantly, weaker, in, 'PPARalpha-null', mice])].
[sujeto(['The', significant]), verbo([decreases]), complemento([of, the, 'CD4+', 'CD8+', population, existed, in, the, thymus, and, 'pro/pre-B', cells, and, total, 'B220+', cells, in, the, bone, marrow, of, 'wild-type', mice, with, 'PP', 'treatment,', but, not, in, 'PPARa-null', mice])].
[sujeto(['We', hypothesised, that, gene, expression, would, be, discordantly]), verbo([regulated]), complemento([when, comparing, the, two, groups])].
[sujeto(['The', mRNA, gene, expression, of, suppressor, of, cytokine, signalling, '(', 'SOCS)', 3, ',', peroxisome, proliferative]), verbo([activated]), complemento([receptor, '(', 'PPAR)', 'alpha/delta,', 'PPAR', 'gamma,', coactivator, 1, ',', alpha, '(', 'PPARGC1A),', carnitine, palmitoyltransferase, 1, 'B', and, solute, carrier, family, 2, '(', facilitated, glucose, 'transporter),', member, 4, '(', formerly, known, as, glucose, transporter, 4, /, 'GLUT4),', was, higher, in, adipose, 'tissue,', but, lower, in, skeletal, muscle, of, diabetic, patients, than, in, that, of, control, subjects])].
[sujeto(['The', following, genes, were]), verbo([increased]), complemento([by, infusion, of, recombinant, human, 'IL6', in, both, 'groups:', 'SOCS1/3,', 'resistin,', 'adiponectin,', 'AMP-activated', protein, 'kinase-alpha-1', and, 'PPARA'])].
[sujeto(['The', observation, that, 'PPARGC1A', and, the, 'PPARs', were, upregulated, in, the, adipose, tissue, of, type, 2, diabetic, 'patients,', along, with, the]), verbo([finding]), complemento([that, adipose, tissue, from, some, patients, with, type, 2, diabetes, can, express, 'UCP1', 'mRNA,', suggests, that, in, these, patients, white, adipose, tissue, may, move, towards, a, brown, adipose, tissue, phenotype])].
[sujeto(['Sleep', disturbances, are]), verbo([associated]), complemento([with, type, 2, 'diabetes;', 'therefore,', the, amelioration, of, sleep, may, improve, metabolic, disorders])].
[sujeto(['To', investigate, this, 'possibility,', we, herein, examined, the, effects, of, 'suvorexant,', an, 'anti-insomnia', drug]), verbo([targeting]), complemento([the, orexin, 'system,', on, sleep, and, glucose, metabolism, in, type, 2, diabetic, mice])].
[sujeto([',', the, beginning, of, the, resting, 'phase)']), verbo([increased]), complemento(['non-rapid', eye, movement, sleep, time, during, the, resting, phase, 'and,', as, a, 'consequence,', reduced, awake, time])].
[sujeto(['The', improving, effect, of, suvorexant, on, glucose, tolerance, was]), verbo([associated]), complemento([with, a, reduction, in, the, expression, levels, of, hepatic, gluconeogenic, 'factors,', including, 'PEPCK', and, peroxisome, 'proliferator-activated', receptor, γ, 'coactivator-1α', in, the, liver, in, the, resting, phase])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, 'suvorexant-induced', increase, of, sleep, time, at, the, resting, phase, improved, hepatic, glucose, metabolism, in, 'db/db', mice])].
[sujeto(['Our', results]), verbo([provide]), complemento([insight, into, the, development, of, novel, pharmacological, interventions, for, type, 2, diabetes, that, target, the, 'orexin-operated', 'sleep/wake', regulatory, system])].
[sujeto(['Previous', studies, demonstrated, that, 'endothelin-1', '(', 'ET-1)', can, significantly]), verbo([increase]), complemento([the, cell, size, and, stimulate, adiponectin, expression, in, cultured, human, cardiomyocytes, '(', 'HCM)'])].
[sujeto(['The', cultured, human, cardiomyocytes, '(', 'HCM)', were]), verbo([stimulated]), complemento([with, or, without, 'ET-1'])].
[sujeto(['ET-1', significantly]), verbo([increased]), complemento([the, cell, 'size,', 'dose-dependently', suppressed, the, expression, of, 'PPARα,', and, enhanced, the, expression, of, 'adiponectin;', 'whereas,', such, an, increase, of, cell, size, and, enhancement, of, adiponectin, expression, were, inhibited, by, the, 'pre-treatment', with, fenofibrate])].
[sujeto(['Moreover,', we]), verbo([found]), complemento([that, fenofibrate, treatment, can, significantly, improve, the, left, ventricular, function, and, reverse, the, myocardial, expression, of, adiponectin])].
[sujeto(['Our', study, shows, that, fenofibrate, may, protect, against, 'ET-1-induced', cardiomyocyte, hypertrophy, and]), verbo([enhanced]), complemento([adiponectin, expression, through, modulation, of, 'PPARα', expression, in, vitro, and, limitation, of, daunorubicin, cardiotoxicity, in, 'vivo,', suggesting, a, novel, mechanistic, insight, into, the, role, of, 'PPARα', and, adiponectin, in, cardiac, hypertrophy, and, heart, failure])].
[sujeto(['Given', evidence]), verbo([suggesting]), complemento([that, smoking, influences, the, severity, of, 'schizophrenia,', together, with, our, recent, data, linking, the, 'PPARα-L162V', polymorphism, to, clinical, manifestations, of, schizophrenia, '(', in, the, 'Croatian', 'population),', we, hypothesized, that, interactions, between, the, two, '(', smoking, and, the, 'PPARα-L162V', 'polymorphism)', might, contribute, to, disease, onset, and, scores, for, the, 'Positive', and, 'Negative', 'Syndrome', 'Scale'])].
[sujeto(['Exercise', '(', 'Ex)']), verbo([increases]), complemento([reactive, oxygen, species, and, impairs, antioxidant, defense, systems])].
[sujeto(['Recent', data]), verbo([suggest]), complemento([that, curcumin, '(', 'CW)', possesses, peroxisome, 'proliferator-activated', receptor, gamma, activity, and, 'anti-inflammatory', properties])].
[sujeto(['CW', was, administered, as, 100, 'mg/kg', 'CurcuWin(®),']), verbo([providing]), complemento([20, mg, of, curcuminoids, daily, for, 6, weeks])].
[sujeto(['Lactate', and, muscle, malondialdehyde, levels]), verbo([decreased]), complemento([in, the, 'CW-treated', groups, '(', 'P&lt;0'])].
[sujeto(['However,', activities, of, antioxidant, enzyme, levels]), verbo([increased]), complemento([in, the, 'CW-treated', groups])].
[sujeto(['Muscle']), verbo([nuclear]), complemento(['factor-κB', '(', 'P&lt;0'])].
[sujeto(['In', 'addition,', muscle, inhibitors, of, kappa, 'B,', peroxisome, 'proliferator-activated', receptor, gamma, coactivator, 1, -, 'alpha,', 'thioredoxin-1,', sirtuin, 1, ',']), verbo([nuclear]), complemento([factor, '(', 'erythroid-derived', 2, ')', -, like, 2, ',', and, glucose, transporter, 4, protein, levels, in, the, 'Ex', +, 'CW', group, were, higher, than, those, in, the, control, and, 'Ex', groups, '(', 'P&lt;0'])].
[sujeto(['This', study]), verbo([suggests]), complemento([that, novel, 'CW', has, the, potential, to, help, prevent, muscle, damage, by, regulating, the, nuclear, 'factor-κB', and, nuclear, factor, '(', 'erythroid-derived', 2, ')', -, like, 2, pathways, and, improve, the, performance, and, nutritional, values, of, 'CW'])].
[sujeto(['Overexpression', of, pFATP1, in, porcine, intramuscular, preadipocytes, significantly]), verbo([promoted]), complemento([the, proliferation, of, porcine, intramuscular, 'preadipocytes,', and, also, significantly, upregulated, the, expressions, of, peroxisome, 'proliferator-activated', receptor, 'γ,', 'CCAAT', enhancer, binding, protein, 'α,', lipoprotein, 'lipase,', fatty, acid, synthetase, and, perilipin, 1])].
[sujeto(['Moreover,', overexpression, of, pFATP1, in, porcine, intramuscular, preadipocytes, significantly]), verbo([increased]), complemento([fat, accumulation, and, downregulated, 'β-catenin', protein, expression])].
[sujeto(['Overall,', our, results, indicated, that, pFATP1, played, an, important, role, in, porcine, intramuscular, preadipocytes, proliferation, and, 'differentiation,', and, it, might]), verbo([promote]), complemento([adipogenesis, in, porcine, intramuscular, preadipocytes, by, repressing, 'Wnt/β-catenin', signaling, pathway])].
[sujeto(['Ethanol', exposure, resulted, in, the]), verbo([increase]), complemento([of, 'TG', 'level,', lipid, accumulation, and, 'ROS', 'generation,', and, the, decrease, of, mitochondrial, membrane, potential, and, 'ATP', production, in, the, cells])].
[sujeto(['Ginsenosides', could]), verbo([prevent]), complemento(['ethanol-induced', hepatocyte, steatosis, in, vitro, related, to, the, inhibition, of, oxidative, stress, and, the, improvement, of, mitochondrial, function])].
[sujeto(['The', peptide, reduced, weight]), verbo([gain]), complemento([in, juvenile, rats, to, one, fifth, of, that, of, controls, and, increased, the, weight, loss, in, older, animals, by, about, five, fold])].
[sujeto(['The', strong]), verbo([increase]), complemento([in, body, weight, in, young, rats, was, associated, with, a, low, mtDNA, copy, number, and, high, 'PPARγ', mRNA, levels, in, controls])].
[sujeto(['In', 'contrast,', 'α-MSH', treatment]), verbo([suppressed]), complemento(['OXPHOS', enzyme, and, citrate, synthase, activity])].
[sujeto(['In', 'addition,', administration, of, 'α-MSH']), verbo([suppressed]), complemento([citrate, synthase, and, 'OXPHOS', activities, independent, of, age])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'α-MSH', exposure, may, inhibit, mitochondrial, biogenesis])].
[sujeto(['The', present, study, revealed, that, 'RIP140']), verbo([repressed]), complemento(['Sirtuin', 3, '(', 'SIRT3),', a, mitochondrial, deacetylase, that, plays, an, important, role, in, regulating, cardiac, function])].
[sujeto(['Ad-RIP140']), verbo([enhanced]), complemento([the, expressions, of, the, cardiac, hypertrophic, markers, and, increased, cardiomyocyte, surface, 'area,', whereas, 'SIRT3', overexpression, prevented, the, effect, of, 'Ad-RIP140'])].
[sujeto(['Additionally,', 'SIRT3', overexpression, reversed, 'Ad-RIP140-induced', mitochondrial, dysfunction, and, energy, metabolic, 'dysfunction,', such, as]), verbo([increase]), complemento([in, oxidative, 'stress,', decrease, of, mitochondrial, membrane, potential, and, 'ATP', 'production,', as, well, as, downregulation, of, mitochondrial, 'DNA-encoded', genes, and, genes, related, to, mitochondrial, genome, replication, and, 'transcription,', mitochondrial, oxidative, phosphorylation, and, fatty, acid, oxidation])].
[sujeto(['RIP140', and, 'PGC-1α', might]), verbo([act]), complemento([as, functional, antagonists, on, the, regulation, of, 'SIRT3'])].
[sujeto(['Strategies']), verbo([targeting]), complemento([inhibition, of, 'RIP140', and, upregulation, of, 'SIRT3', might, improve, cardiac, energy, metabolism, and, suggest, therapeutic, potential, for, heart, diseases])].
[sujeto(['Sirt1,', a, 'NAD(+)-dependent', 'enzyme,', is, known, to, play, an, important, protective, role, through, deacetylation, of, many, substrates]), verbo([involved]), complemento([in, oxidative, phosphorylation, and, reactive, oxygen, species, '(', 'ROS)', generation])].
[sujeto(['Conditioned', medium, from, mesenchymal, stem, cells, '(', 'MSCs-CM)']), verbo([has]), complemento([emerged, as, a, promising, 'cell-free', therapy, due, to, the, trophic, actions, of, 'MSCs', secreted, molecules])].
[sujeto(['We']), verbo([found]), complemento([that, high, glucose, 'stimulated-MSCs-CM', attenuated, several, glucotoxicity, induced, 'processes,', oxidative, stress, and, apoptosis, of, human, umbilical, vein, endothelial, cells])].
[sujeto(['MSCs-CM']), verbo([activated]), complemento([the, phosphorylation, of, 'PI3K', and, 'AKT,', leading, to, direct, interaction, between, 'AKT', and, 'Sirt1,', and, subsequently, enhanced, 'Sirt1', expression])].
[sujeto(['Additionally,', both, 'MSCs-CM', and, 'Sirt1', activation, were, able, to]), verbo([increase]), complemento([the, expression, of, peroxisome, 'proliferator-activated', receptor, gamma, 'coactivator-1', α, '(', 'PGC-1α),', as, well, as, increase, the, mRNA, expression, of, its, downstream, mitochondrial, 'biogenesis-related', genes])].
[sujeto(['This', indirect, regulation, was]), verbo([mediated]), complemento([by, activation, of, 'AMP-activated', protein, kinase, '(', 'AMPK)'])].
[sujeto(['This', exhaustive, in, silico, study, looks, into, the, molecular, interactions, of, phthalates, and, their, metabolites, with, human, peroxisome, 'proliferator-activated', receptor, '(', 'hPPAR)', and, retinoid, 'X', receptor, '(', 'hRXR)', 'α,', β, and, γ, 'subtypes--the']), verbo([nuclear]), complemento([receptor, proteins, function, as, transcription, factors, by, regulating, the, expression, of, downstream, genes])].
[sujeto(['Apart', from, the, much, discussed, plasticizer, bisphenol, 'A,', we, examined, the]), verbo([binding]), complemento([affinities, of, 15, common, diphthalates, and, their, 'monophthalates,', natural, '(', linoleic, 'acid,', conjugated, linoleic, 'acid)', and, synthetic, '(', 'bezafibrate,', 'pioglitazone,', 'GW', 50156, ')', ligands, with, hPPARs])].
[sujeto(['In', 'general,', natural, ligands, of, hPPAR, showed, less]), verbo([binding]), complemento([efficiencies, than, phthalic, acid, esters, and, drugs])].
[sujeto(['Briefly,', this, study, gives, an, overview, on, the, preference, of, phthalic, acid, 'esters,', natural, and, synthetic, ligands, on, to, hPPAR, and, hRXR, 'subtypes,', which, would]), verbo([lead]), complemento([to, further, in, vitro, mechanistic, as, well, as, in, vivo, preclinical, and, clinical, studies])].
[sujeto(['Based', on, 'X-ray', crystallographic, analysis, of, a, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)', 'α/δ', dual, agonist, complexed, with, human, 'PPARs', ligand]), verbo([binding]), complemento([domain, '(', 'LBD),', we, previously, reported, the, design, and, synthesis, of, a, 'pyrene-based', fluorescent, 'PPARα/δ', 'co-agonist', 2])].
[sujeto(['Here,', we]), verbo([found]), complemento([that, the, fluorescence, intensity, of, 2, increased, upon, binding, to, 'hPPARα-LBD,', in, a, manner, dependent, upon, the, concentration, of, the, 'LBD'])].
[sujeto(['But,', 'surprisingly,', the, fluorescence, intensity, of, 2]), verbo([decreased]), complemento(['concentration-dependently', upon, binding, to, 'hPPRδ-LBD'])].
[sujeto(['Site-directed', mutagenesis, of, the, two, hPPAR, subtypes, clearly, indicated, that, 'Trp264', of, 'hPPARδ-LBD,', located, between, 'H2\'', helix, and, 'H3', helix, '(', omega, 'loop),', is, critical, for, the, 'concentration-dependent']), verbo([decrease]), complemento([in, fluorescence, 'intensity,', which, is, suggested, to, be, due, to, fluorescence, resonance, energy, transfer, '(', 'FRET)', from, the, pyrene, moiety, of, bound, 2, to, the, nearby, 'side-chain', indole, moiety, of, 'Trp264', in, the, 'hPPARδ-LBD'])].
[sujeto(['We']), verbo([report]), complemento([here, that, 'α-substituted', phenylpropanoic, 'acid-type', hPPAR, agonists, with, similar, structure, bind, to, the, hPPAR, ligand, binding, domain, '(', 'LBD)', in, different, 'conformations,', depending, on, the, receptor, subtype])].
[sujeto(['These', results, might, indicate, that, hPPAR, ligand]), verbo([binding]), complemento([pockets, have, multiple, binding, points, that, can, be, utilized, to, accommodate, structurally, flexible, hPPAR, ligands])].
[sujeto(['Following', oral, administration, of, '[', '¹⁴C]sipoglitazar', to, 'rats,', sipoglitazar, and, its, metabolites, were, distributed, to, the, rat, tissues, with, relatively, high, concentrations, in, the, liver, and, also, to, the]), verbo([target]), complemento(['tissue,', the, adipose, tissue])].
[sujeto(['The', peroxisome, 'proliferator-activated', receptors, '(', 'PPARs)', belong, to, the]), verbo([nuclear]), complemento([hormone, receptor, superfamily])].
[sujeto(['To', 'date,', three, different, 'PPAR', 'isotypes,', namely, 'PPAR-alpha,', -, 'delta,', and, -, 'gamma,']), verbo([have]), complemento([been, identified, in, vertebrates, and, have, distinct, patterns, of, tissue, distribution])].
[sujeto(['Like', all]), verbo([nuclear]), complemento(['receptors,', the, human, 'PPAR-gamma', '(', 'hPPAR-gamma)', is, characterized, by, a, modular, structure, composed, of, an, 'N-terminal', 'A/B', 'domain,', a, 'DNA-binding', domain, with, two, zinc, fingers, '(', 'C', 'domain),', a, 'D', 'domain,', and, a, 'C-terminal', 'ligand-binding', domain, '(', 'E/F', 'domain)'])].
[sujeto(['The', 'hPPAR-gamma(2)', isoform, is, predominantly]), verbo([expressed]), complemento([in, adipose, 'tissue,', whereas, 'hPPAR-gamma(1)', is, relatively, widely, expressed])].
[sujeto(['Its', transcriptional, activity, is]), verbo([induced]), complemento([by, the, binding, of, endogenous, and, synthetic, lipophilic, 'ligands,', which, has, led, to, the, determination, of, many, roles, for, 'PPAR-gamma', in, pathological, states, such, as, type, 2, 'diabetes,', 'atherosclerosis,', 'inflammation,', and, cancer])].
[sujeto(['Peroxisome', 'proliferator-activated', receptors, '(', 'PPARs)', are, important]), verbo([targets]), complemento([for, drugs, used, in, the, treatment, of, 'atherosclerosis,', 'dyslipidaemia,', 'obesity,', type, 2, 'diabetes,', and, other, diseases, caused, by, abnormal, regulation, of, the, glucose, and, lipid, metabolism])].
[sujeto(['From', the, resulting, 10, virtual, screening, 'hits,', five, tested, positive, in, human, 'PPAR', 'ligand-binding', domain, '(', 'hPPAR-LBD)', transactivation, assays, and, showed, affinities, for, 'PPAR', in, a, competitive]), verbo([binding]), complemento([assay])].
[sujeto(['To', determine, the, impact, of, the, species, difference, between, rodents, and, humans, in, response, to, peroxisome, proliferators, '(', 'PPs)']), verbo([mediated]), complemento([by, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)alpha,', 'PPAR', 'alpha-humanized', transgenic, mice, were, generated, using, a, 'P1', phage, artificial, chromosome, '(', 'PAC)', genomic, clone, bred, onto, a, ppar, 'alpha-null', mouse, 'background,', designated, hPPAR, alpha, 'PAC'])].
[sujeto(['In', hPPAR, alpha, 'PAC', 'mice,', the, human, 'PPAR', alpha, gene, is]), verbo([expressed]), complemento([in, tissues, with, high, fatty, acid, catabolism, and, induced, upon, 'fasting,', similar, to, mouse, 'PPAR', alpha, in, 'wild-type', '(', 'Wt)', mice])].
[sujeto(['Upon', treatment, with, the, 'PP', 'fenofibrate,', hPPAR, alpha, 'PAC', mice, exhibited, responses, similar, to, 'Wt', 'mice,', including, peroxisome, 'proliferation,', lowering, of, serum, 'triglycerides,', and, induction, of, 'PPAR', alpha]), verbo([target]), complemento([genes, encoding, enzymes, involved, in, fatty, acid, metabolism, in, 'liver,', 'kidney,', and, 'heart,', suggesting, that, human, 'PPAR', alpha, '(', hPPAR, 'alpha)', functions, in, the, same, manner, as, mouse, 'PPAR', alpha, in, regulating, fatty, acid, metabolism, and, lowering, serum, triglycerides])].
[sujeto(['However,', in, contrast, to, 'Wt', 'mice,', treatment, of, hPPAR, alpha, 'PAC', mice, with, fenofibrate, did, not]), verbo([cause]), complemento([significant, hepatomegaly, and, hepatocyte, 'proliferation,', thus, indicating, that, the, mechanisms, by, which, 'PPAR', alpha, affects, lipid, metabolism, are, distinct, from, the, hepatocyte, proliferation, 'response,', the, latter, of, which, is, only, induced, by, mouse, 'PPAR', alpha])].
[sujeto(['The', hPPAR, alpha, 'PAC', mouse, model]), verbo([provides]), complemento([an, in, vivo, platform, to, investigate, the, species, difference, mediated, by, 'PPAR', alpha, and, an, ideal, model, for, human, risk, assessment, 'PPs', exposure])].
[sujeto(['The', design, and, synthesis, of, the, dual, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)', 'gamma/delta', agonist, '(', 'R)-3-{4-[3-(4-chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl-phenyl}-propionic', acid, '(', 20, ')', for, the, treatment, of, type, 2, diabetes, and]), verbo([associated]), complemento([dyslipidemia, is, described])].
[sujeto(['In', preclinical, 'models,', the, compound, improves, insulin, sensitivity, and, reverses, diabetic, hyperglycemia, with, less, weight]), verbo([gain]), complemento([at, a, given, level, of, glucose, control, relative, to, rosiglitazone])].
[sujeto(['Dihydrotrichodimerol', '(', 2, ')', specifically]), verbo([activated]), complemento([peroxisome, 'proliferator-activated', receptor, gamma, with, an, 'ED50', value, of, 80, 'ng/ml', as, measured, by, a, transactivation, assay, using, a, chimeric, 'hPPAR/GAL4', system, without, affecting, peroxisome, 'proliferator-activated', receptors, alpha, and, sigma])].
[sujeto(['On', the, other, 'hand,', compounds, 1, and, 2]), verbo([suppressed]), complemento([the, production, of, tumor, necrosis, 'factor-alpha', and, nitric, oxide, in, 'LPS-stimulated', 'RAW264'])].
[sujeto(['The', design, and, synthesis, of, the, dual, peroxisome, proliferator]), verbo([activated]), complemento([receptor, '(', 'PPAR)', 'alpha/gamma', agonist, '(', 'S)-2-methyl-3-[4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]phenyl]-2-phenoxypropionic', acid, '(', 2, ')', for, the, treatment, of, type, 2, diabetes, and, associated, dyslipidemia, are, described])].
[sujeto(['We', investigated, the, role, of, 'hPPAR-alpha', in]), verbo([regulating]), complemento([muscle, lipid, utilization, by, studying, the, effects, of, a, highly, selective, 'PPAR-alpha', 'agonist,', 'GW7647,', on, '[', '(', 14, ')', 'C]oleate', metabolism, and, gene, expression, in, primary, human, skeletal, muscle, cells])].
[sujeto(['Robust', induction, of, 'PPAR-alpha', protein, expression, occurred, during, muscle, cell, differentiation, and, corresponded, with, 'differentiation-dependent']), verbo([increases]), complemento([in, oleate, oxidation])].
[sujeto(['In', mature, 'myotubes,', 48, -, h, treatment, with, 10, -, 1, ',', 0, 'nmol/l', 'GW7647']), verbo([increased]), complemento([oleate, oxidation, 'dose-dependently,', up, to, threefold])].
[sujeto(['Additionally,', 'GW7647']), verbo([decreased]), complemento([oleate, esterification, into, myotube, triacylglycerol, '(', 'TAG),', up, to, 45, '%'])].
[sujeto(['Consistent', with, its, metabolic, 'actions,', 'GW7647']), verbo([induced]), complemento([mRNA, expression, of, mitochondrial, enzymes, that, promote, fatty, acid, 'catabolism;', carnitine, palmityltransferase, 1, and, 'malonyl-CoA', decarboxylase, increased, approximately, 2, -, 'fold,', whereas, pyruvate, dehydrogenase, kinase, 4, increased, 45, -, fold])].
[sujeto(['Expression', of, several, genes, that]), verbo([regulate]), complemento([glycerolipid, synthesis, was, not, changed, by, 'GW7647', 'treatment,', implicating, involvement, of, other, targets, to, explain, the, 'TAG-depleting', effect, of, the, compound])].
[sujeto(['These', results, demonstrate, a, role, for, 'hPPAR-alpha', in]), verbo([regulating]), complemento([muscle, lipid, homeostasis])].
[sujeto(['In', contrast, human, hepatocytes, transfected, with, 'mPPAR(alpha)', and, 'mRXR(alpha)', display]), verbo([increased]), complemento([expression, of, 'PPAR(alpha),', and, increased, 'PPRE-reporter', activity, when, treated, with, 'WY-14,643,', 'TCA,', and, 'DCA'])].
[sujeto(['Tumor', necrosis, factor, '(', 'TNF)-alpha', is, one, of, the, candidate, mediators, of, insulin, resistance]), verbo([associated]), complemento([with, 'obesity,', a, major, risk, factor, for, the, development, of, type, 2, diabetes])].
[sujeto(['The', insulin, resistance]), verbo([induced]), complemento([by, 'TNF-alpha', is, antagonized, by, thiazolidinediones, '(', 'TZDs),', a, new, class, of, 'insulin-sensitizing', drugs])].
[sujeto(['Adenovirus-mediated', gene, transfer, of, either, 'wild-type', human, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)-gamma2', or, a, mutant, carrying, a, replacement, at, the, consensus, 'mitogen-activated', protein, kinase, phosphorylation, site, '(', 'hPPAR-gamma2-S112A)']), verbo([promoted]), complemento([adipogenesis, of, 3, 'T3-L1', fibroblasts, and, restored, 'TNF-alpha-induced', decrease, of, triglyceride, in, adipocytes, as, effectively, as, pioglitazone])].
[sujeto(['These', results, indicate, that, the, ability, of, pioglitazone, to, restore, 'insulin-stimulated', tyrosine, phosphorylation, of, 'IR/IRS-1,', which, is, necessary, for, amelioration, of, 'TNF-alpha-induced', insulin, 'resistance,', may, be, independent, of, the, adipogenic, activity, of, 'PPAR-gamma', that]), verbo([regulates]), complemento([protein, levels, of, 'IR/IRS-1'])].
[sujeto(['The', peroxisome, 'proliferator-activated', receptors, '(', 'PPARs)', are, members, of, the]), verbo([nuclear]), complemento([hormone, receptor, superfamily])].
[sujeto(['In', order, to]), verbo([bind]), complemento([to, 'DNA', and, activate, transcription, 'PPAR', requires, the, formation, of, heterodimers, with, the, retinoid, 'X', receptor, '(', 'RXR)'])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, that, replacement, of, a, single, leucine, by, an, arginine, at, position, 433, of, hPPAR, alpha, '(', 'L433R),', located, in, a, highly, conserved, region, of, the, ninth, heptad, repeat, of, a, 'leucine-zipper-like', motif, in, the, ligand, binding, 'domain,', abolished, heterodimerization, of, 'PPAR', with, 'RXR', and, hence, its, 'trans-activating', capacity])].
[sujeto(['The', aim, of, our, present, work, was, to, investigate, if, other]), verbo([conserved]), complemento([amino, acids, of, the, ligand, binding, domain, are, important, for, heterodimerization, of, 'PPAR', with, 'RXR'])].
[sujeto(['We']), verbo([found]), complemento([that, conserved, 'leucines,', 'L370', and, 'L391,', in, a, 'leucine-zipper-like', motif, of, hPPAR, 'alpha,', as, well, as, a, highly, conserved, aspartic, acid, '(', 'D304)', in, the, 'tau(i)', domain, are, necessary, for, heterodimerization, with, 'RXR'])].
[sujeto(['Surprisingly,', we]), verbo([found]), complemento([that, some, mutants, deficient, in, heterodimerization, with, 'RXR', '(', hPPAR, 'alpha-L370R', and, -, 'L391R)', were, still, functional, on, specific, peroxisome, 'proliferator-activator', response, elements, '(', 'PPREs)'])].
[sujeto(['Both', mutants, could, 'trans-activate', on, a, 'PPRE', from, the, 'P450', cytochrome, promoter, 'CYP4A1,', whereas, only, the, hPPAR, 'alpha-L391R', mutant, could, 'trans-activate', from, the, 'acyl-CoA', oxidase, 'PPRE', '(', 'ACOA)', 'and,', when]), verbo([stimulated]), complemento([with, the, peroxisome, proliferator, 'Wy14643,', also, from, the, bifunctional, enzyme, 'PPRE'])].
[sujeto(['We', therefore, hypothesize, either, 'that:', '(', 'i)', these, mutants, might, be, able, to]), verbo([heterodimerize]), complemento([with, a, protein, other, than, 'RXR', and, the, affinity, for, this, novel, partner, may, depend, on, the, nature, of, the, 'PPRE', and, to, some, degree, on, the, choice, of, the, 'activator,', or, 'alternatively;', '(', 'ii)', that, additional, nuclear, proteins, might, compensate, in, vivo, for, the, decreased, binding, of, 'RXR', to, these, mutant, 'PPARs', observed, in, vitro])].
[sujeto(['Peroxisome', proliferators, '(', 'PPs)', are, a, class, of, 'non-genotoxic', rodent, hepatocarcinogens, that]), verbo([act]), complemento([by, perturbing, liver, growth, regulation])].
[sujeto(['We']), verbo([have]), complemento([demonstrated, previously, that, 'PPs', suppress, both, spontaneous, rat, hepatocyte, apoptosis, and, that, induced, by, exogenous, stimuli, such, as, transforming, growth, 'factor-beta1', '(', 'TGF', 'beta1)'])].
[sujeto(['More', 'recently,', we]), verbo([have]), complemento([demonstrated, that, 'PPs', can, suppress, apoptosis, induced, by, more, diverse, stimuli, such, as, 'DNA', damage, or, ligation, of, 'Fas,', a, receptor, related, to, the, tumour, necrosis, factor, alpha, '(', 'TNF', 'alpha)', family, of, cell, surface, receptors])].
[sujeto(['PPs', transcriptionally]), verbo([activate]), complemento([the, peroxisome, proliferator, activated, 'receptor-alpha,', 'PPAR', 'alpha,', a, member, of, the, nuclear, hormone, receptor, superfamily])].
[sujeto(['We', investigated, whether, activation, of, 'PPAR', alpha]), verbo([mediates]), complemento([the, suppression, of, rat, hepatocyte, apoptosis, induced, by, 'PPs'])].
[sujeto([hPPAR, 'alpha-6/29', shared, the, ability, of, mPPAR, alpha, to]), verbo([bind]), complemento([to, 'DNA', 'but,', unlike, mPPAR, 'alpha,', could, not, be, activated, by, 'PPs'])].
[sujeto(['Furthermore,', hPPAR, 'alpha-6/29', could]), verbo([act]), complemento([as, a, dominant, negative, regulator, of, 'PPAR-mediated', gene, transcription])].
[sujeto(['When', introduced, into, primary, rat, liver, cell, cultures, by, transient, 'transfection,', hPPAR, 'alpha-6/29']), verbo([prevented]), complemento([the, suppression, of, hepatocyte, apoptosis, by, the, 'PP', 'nafenopin,', but, not, that, seen, in, response, to, phenobarbitone, '(', 'PB),', a, 'non-genotoxic', carcinogen, whose, action, does, not, involve, 'PPAR', alpha])].
[sujeto(['The', suppression, of, hepatocyte, apoptosis, was, abrogated, completely, even, though, only, 30, '%', of, hepatocytes, were, 'transfected,']), verbo([suggesting]), complemento([the, involvement, of, a, soluble, factor])].
[sujeto(['Recent', data]), verbo([have]), complemento([suggested, that, 'TNF', 'alpha,', perhaps, released, by, liver, 'Kupffer', cells, in, response, to, 'PPs,', may, play, a, key, role, in, mediating, the, effects, of, 'PPs', on, hepatocyte, growth, regulation])].
[sujeto(['Peroxisome', proliferators, '(', 'PPs)', are, a, group, of, compounds, which]), verbo([cause]), complemento([peroxisome, proliferation, and, hepatocellular, carcinomas, in, 'rodents,', and, form, a, class, of, 'non-genotoxic', carcinogens])].
[sujeto(['It', is, thought, that, 'PPs']), verbo([act]), complemento([via, a, receptor, similar, to, members, of, the, nuclear, hormone, superfamily, termed, the, peroxisome, proliferator, activated, receptor, '(', 'PPAR)'])].
[sujeto(['Multiple', subtypes, '(', 'alpha,', 'beta,', delta, and, 'gamma)', of, the, receptor, exist, and, are, differentially]), verbo([expressed]), complemento([between, tissues, and, species])].
[sujeto(['PPAR', alpha]), verbo([has]), complemento([been, shown, to, activate, transcription, by, binding, to, response, elements, upstream, of, peroxisome, proliferator, responsive, genes])].
[sujeto(['This', is, possibly, due, to, regulation, of, 'PPAR,', and, it]), verbo([has]), complemento([been, recently, reported, that, 'PPAR', alpha, is, a, phosphoprotein, in, vivo, and, insulin, regulates, its, phosphorylation])].
[sujeto(['A', system, employing, 'epitope-tagged', receptors]), verbo([has]), complemento([been, developed, to, study, this, 'further,', with, the, aim, of, establishing, stably, transfected, cell, lines, expressing, high, levels, of, 'epitope-tagged', mouse, and, human, 'PPAR', alpha])].
[sujeto(['Our', experiments, clearly, demonstrate, that, an, 'epitope-tagged', mPPAR, alpha, receptor]), verbo([has]), complemento([an, equal, ability, to, modulate, transcription, as, the, native, receptor, in, transactivation, assays, and, will, be, further, used, to, examine, the, molecular, mechanisms, of, peroxisome, proliferation])].
[sujeto(['We']), verbo([have]), complemento([demonstrated, previously, that, 'PPs', suppress, both, spontaneous, rat, hepatocyte, apoptosis, and, that, induced, by, exogenous, stimuli, such, as, transforming, growth, 'factor-beta1', '(', 'TGFbeta1)'])].
[sujeto(['PPs', transcriptionally]), verbo([activate]), complemento([the, peroxisome, proliferator, activated, 'receptor-alpha', '(', 'PPAR', 'alpha),', a, member, of, the, nuclear, hormone, receptor, superfamily])].
[sujeto(['Here,', we, investigate, whether, activation, of, 'PPAR', alpha]), verbo([mediates]), complemento([the, suppression, of, rat, hepatocyte, apoptosis, induced, by, 'PPs'])].
[sujeto(['Electrophoretic', mobility, shift, assays, '(', 'EMSA)', demonstrated, that, hPPAR, 'alpha-6/29', shared, the, ability, of, mPPAR, alpha, to, heterodimerise, with, the, retinoid, 'X', receptor, '(', 'RXR)', and]), verbo([bind]), complemento([to, 'DNA'])].
[sujeto(['When', hPPAR, 'alpha-6/29', was, transfected, into, 'Hepa1c1c7', cells, together, with, a, reporter, plasmid, containing, a, 'PPAR', response, element, '(', 'PPRE),', hPPAR, 'alpha-6/29,', unlike, mPPAR, 'alpha,', could, not, be]), verbo([activated]), complemento([by, 'PPs'])].
[sujeto(['Furthermore,', hPPAR, 'alpha-6/29', could]), verbo([act]), complemento([as, a, dominant, negative, regulator, of, 'PPAR-mediated', gene, transcription, since, increasing, concentrations, of, hPPAR, 'alpha-6/29', abrogated, the, activation, of, 'co-transfected', mPPAR, alpha])].
[sujeto(['When', introduced, into, primary, rat, liver, cell, cultures, by, transient, 'transfection,', hPPAR, 'alpha-6/29']), verbo([prevented]), complemento([the, suppression, of, hepatocyte, apoptosis, by, the, 'PP', 'nafenopin,', but, not, that, seen, in, response, to, phenobarbitone, '(', 'PB),', a, nongenotoxic, carcinogen, whose, action, does, not, involve, 'PPAR', alpha])].
[sujeto(['The', suppression, of, hepatocyte, apoptosis, was, abrogated, completely, even, though, only, 30, '%', of, hepatocytes, were, 'transfected,']), verbo([suggesting]), complemento([the, involvement, of, a, soluble, factor])].
[sujeto(['These', data, indicate, that, activation, of, rat, liver, 'PPAR', alpha]), verbo([provides]), complemento([a, survival, signal, for, 'hepatocytes,', preventing, their, death, in, response, to, apoptotic, stimuli])].
[sujeto(['We']), verbo([have]), complemento([been, attempting, to, elucidate, the, molecular, mechanisms, through, which, peroxisome, proliferators, exert, their, pleiotropic, 'effects,', with, particular, emphasis, on, understanding, why, humans, appear, unresponsive, to, these, compounds])].
[sujeto(['There', is, a, wealth, of, data, to, implicate, the, peroxisome, 'proliferator-activated', receptor, alpha, '(', 'PPAR', 'alpha)', in]), verbo([mediating]), complemento([these, effects, in, rodent, 'species;', 'PPAR', alpha, is, expressed, in, tissues, that, show, physiological, changes, in, response, to, 'PPs,', is, transcriptionally, activated, in, vitro, by, a, variety, of, 'PPs,', and, it, has, been, recently, demonstrated, that, mice, lacking, this, receptor, are, refractory, to, the, effects, of, clofibrate, and, 'Wy-14,643,', at, least, in, the, short, term])].
[sujeto(['It', is, conceivable, that, differences, in, 'PPAR', alpha, between, responsive, rodent, and, unresponsive, human, subjects, may]), verbo([provide]), complemento([the, key, to, understanding, the, basis, of, this, species, variation, in, 'response,', and, with, this, in, mind, we, have, been, studying, the, biology, of, 'PPAR', alpha, in, humans, and, looking, at, interindividual, variation])].
[sujeto(['We']), verbo([have]), complemento([extended, these, 'findings,', and, shown, 'that:', 'There', is, considerable, variation, in, hPPAR, alpha, cDNAs, obtained, from, different, 'individuals,', both, at, the, gross, structural, level, '(', lack, of, a, coding, 'exon)', and, of, a, more, subtle, nature, '(', single, base, changes, leading, to, amino, acid, 'substitutions)'])].
[sujeto(['The', degree, to, which, hPPAR, alpha, transcripts, are]), verbo([expressed]), complemento([in, human, livers, can, vary, by, up, to, an, order, of, magnitude, between, individuals])].
[sujeto(['In', 'particular,', the, human, liver, contains, generally, low, levels, of, 'PPAR', alpha, in, contrast, to, the, responsive, 'rodents,', in, which, potent, 'PPs']), verbo([cause]), complemento([liver, tumors])].
[sujeto(['Taken', 'together,', these, data]), verbo([suggest]), complemento([first, that, human, and, rodent, 'PPAR', alphas, differ, according, to, a, number, of, molecular, and, biochemical, 'criteria,', and, secondly, that, there, is, a, degree, of, interindividual, variation, in, 'PPAR', alpha, structure, and, function])].
[sujeto(['The', aromatic, fatty, acid, phenylacetate, and, its, analogs]), verbo([induce]), complemento([tumor, cytostasis, and, differentiation, in, experimental, models])].
[sujeto(['We']), verbo([have]), complemento([now, examined, whether, these, 'compounds,', structurally, similar, to, the, peroxisome, proliferator, 'clofibrate,', affect, the, human, peroxisome, 'proliferator-activated', receptor, '(', 'hPPAR),', a, homolog, of, the, rodent, 'PPAR', 'alpha,', a, transcriptional, factor, regulating, lipid, metabolism, and, cell, growth])].
[sujeto(['Gene', transfer, experiments, showed, activation, of, 'hPPAR,', evident, by, the]), verbo([increased]), complemento([expression, of, the, reporter, gene, chloramphenicol, acetyltransferase, linked, to, 'PPAR-response', element, from, either, the, rat, 'acyl-CoA', oxidase, or, rabbit, 'CYP4A6', genes])].
[sujeto(['The', ability, of, the, aromatic, fatty, acids, to]), verbo([activate]), complemento(['PPAR', was, confirmed, in, 'vivo,', as, 'CYP4A', mRNA, levels, increased, in, hepatocytes, of, treated, rats])].
[sujeto(['Further', studies, using, human, prostate, 'carcinoma,', 'melanoma,', and, glioblastoma, cell, lines, showed, a, tight, correlation, between, 'drug-induced', 'cytostasis,']), verbo([increased]), complemento([expression, of, the, endogenous, 'hPPAR,', and, receptor, activation, documented, in, the, 'gene-transfer', model])].
[sujeto(['These', results, identify, phenylacetate, and, its, analogs, as, a, new, class, of, aromatic, fatty, acids, capable, of]), verbo([activating]), complemento(['hPPAR,', and, suggest, that, this, nuclear, receptor, may, mediate, tumor, cytostasis, induced, by, these, drugs])].
[sujeto(['We']), verbo([have]), complemento([cloned, a, human, cognate, of, the, mouse, 'peroxisome-proliferator-activated', 'receptor-gamma', '(', hPPAR, 'gamma)', from, a, human, placenta, cDNA, library])].
[sujeto(['Sequence', analysis]), verbo([reveals]), complemento([a, high, degree, of, similarity, with, the, mouse, receptor, 'and,', like, other, 'PPAR,', hPPAR, gamma, forms, heterodimers, with, the, retinoid, 'X', receptor, alpha, '(', 'RXR', 'alpha)', and, binds, in, vitro, to, 'DNA', elements, containing, direct, repeats, of, the, sequence, 'TGACCT'])].
[sujeto(['In', common, with, mouse, 'PPAR', 'gamma,', hPPAR, gamma, is]), verbo([expressed]), complemento([strongly, in, adipose, 'tissue,', but, significant, levels, also, are, detectable, in, 'placenta,', lung, and, ovary])].
[sujeto(['In', vitro, 'trans-activation', data]), verbo([suggest]), complemento([hPPAR, gamma, is, only, poorly, activated, by, xenobiotic, peroxisome, 'proliferators,', although, certain, fatty, acids, and, eicosanoids, are, potent, activators, of, this, receptor])].
[sujeto(['Both', mouse, and, human, 'PPAR', gamma, are, capable, of, being]), verbo([activated]), complemento([by, thiazolidinedione, 'drugs,', although, the, two, receptors, appear, to, differ, in, their, sensitivity, to, these, compounds])].
[sujeto(['Taken', 'together,', these, data]), verbo([suggest]), complemento([a, high, degree, of, structural, and, functional, similarity, between, mouse, and, human, 'PPAR', 'gamma,', and, provide, evidence, for, variation, in, human, receptor, structure, which, may, result, in, differential, sensitivity, to, activators])].
[sujeto(['Fatty', acids, and, their, 'derivatives,', 'eicosanoids,', 'phosphoinositides,', 'sphingolipids,', some, 'cannabinoid-like', molecules]), verbo([bind]), complemento([and, activate, nuclear, 'receptors,', including, peroxisome, 'proliferator-activated', receptors, '(', 'PPARs)'])].
[sujeto(['This', subfamily, of, transcription, factors, comprises, three, isotypes, -, 'PPARα', '(', 'NR1C1),', 'PPAR', 'β/δ', '(', 'NR1C2),', 'PPARγ', '(', 'NR1C3)', -, which]), verbo([bind]), complemento([to, specific, 'DNA', response, 'elements,', as, heterodimers, with, retinoid, 'X', receptors])].
[sujeto(['PPAR', activity, is]), verbo([modulated]), complemento([by, 'post-translational', modifications, and, 'cofactors,', towards, which, they, show, differential, affinity])].
[sujeto(['The', three, 'PPARs', mutually, 'interact,', being, integrated, in, a, complex, 'system,']), verbo([leading]), complemento([to, the, concept, of, a, &, 'quot;PPAR', 'triad&quot;'])].
[sujeto(['Nevertheless,', the, isotypes, also, show, distinct, actions, on, cellular, physiology, and, partially, different, 'tissue,', ligand, and]), verbo([target]), complemento([gene, specificities])].
[sujeto(['PPARα', appears, especially, 'intriguing,', since, it, is, selectively]), verbo([expressed]), complemento([in, certain, brain, areas, and, 'neuronal/glial', 'populations,', and, modulates, antioxidant, 'responses,', 'neurotransmission,', 'neuroinflammation,', 'neurogenesis,', and, glial, cell, 'proliferation/differentiation'])].
[sujeto(['This', receptor, and, its, endogenous, 'ligands,', including, oleoylethanoloamide, '(', 'OEA)', and, palmitoylethanolamide, '(', 'PEA),', are]), verbo([involved]), complemento([in, physiological, and, pathological, 'responses,', such, as, 'satiety,', memory, 'consolidation,', and, modulation, of, pain, perception])].
[sujeto(['Adequate', production, of, nitric, oxide, '(', 'NO)', by, endothelial, nitric, oxide, synthase, '(', 'eNOS)']), verbo([requires]), complemento([eNOS, coupling, promoted, by, tetrahydrobiopterin, '(', 'BH(4))'])].
[sujeto(['Peroxisome', proliferator]), verbo([activated]), complemento([receptors, '(', 'NR1C)', are, a, family, of, nuclear, receptors, activated, by, ligand])].
[sujeto(['Clofibrate,', a, member, of, a, hypolipidemic, class, of, 'drugs,']), verbo([acts]), complemento([by, activating, the, alpha, isoform, of, 'NR1C'])].
[sujeto(['To', determine, the, participation, of, 'NR1C1', activation, in, 'BH(4)', and, dihydrobiopterin, '(', 'BH(2))', metabolism, and, its, implications, on, eNOS, coupling, in, 'hypertension,', we, performed, aortic, coarctation, '(', 'AoCo)', at, 'inter-renal', level, on, male, 'Wistar', rats, in, order, to]), verbo([have]), complemento([a, hypertensive, model])].
[sujeto(['Clofibrate', '(', 7, 'days)']), verbo([increased]), complemento([eNOS, coupling, in, the, 'AoCo-C', group, compared, with, 'AoCo-V'])].
[sujeto(['Clofibrate', also, recovered, the, 'BH(4):BH(2)', ratio, in, control, values, and]), verbo([prevented]), complemento([the, rise, in, superoxide, anion, 'production,', 'lipoperoxidation,', and, reactive, oxygen, species, production])].
[sujeto(['In', 'addition,', clofibrate]), verbo([increased]), complemento(['GTP', 'cyclohydrolase-1', '(', 'GTPCH-1)', protein, 'expression,', which, is, related, with, 'BH(4)', recovered, production])].
[sujeto(['The', peroxisome, 'proliferator-activated', receptor, alpha, '(', 'PPARalpha,', or, 'NR1C1)', is, a]), verbo([nuclear]), complemento([hormone, receptor, activated, by, a, structurally, diverse, array, of, synthetic, chemicals, known, as, peroxisome, proliferators])].
[sujeto(['Endogenous', activation, of, 'PPARalpha', in, liver]), verbo([has]), complemento([also, been, observed, in, certain, gene, knockout, mouse, models, of, lipid, 'metabolism,', implying, the, existence, of, enzymes, that, either, generate, '(', 'synthesize)', or, degrade, endogenous, 'PPARalpha', agonists])].
[sujeto(['For', 'example,', substrates]), verbo([involved]), complemento([in, fatty, acid, oxidation, can, function, as, 'PPARalpha', ligands])].
[sujeto(['PPARalpha', serves, as, a, xenobiotic, and, lipid, sensor, to]), verbo([regulate]), complemento([energy, 'combustion,', hepatic, 'steatosis,', lipoprotein, 'synthesis,', inflammation, and, liver, cancer])].
[sujeto(['Mainly,', 'PPARalpha']), verbo([modulates]), complemento([the, activities, of, all, three, fatty, acid, oxidation, 'systems,', namely, mitochondrial, and, peroxisomal, 'beta-oxidation', and, microsomal, 'omega-oxidation,', and, thus, plays, a, key, role, in, energy, expenditure])].
[sujeto(['Sustained', activation, of, 'PPARalpha', by, either, exogenous, or, endogenous, agonists]), verbo([leads]), complemento([to, the, development, of, hepatocellular, carcinoma, resulting, from, sustained, oxidative, and, possibly, endoplasmic, reticulum, stress, and, liver, cell, proliferation])].
[sujeto(['PPARalpha']), verbo([requires]), complemento([transcription, coactivator, 'PPAR-binding', protein, '(', 'PBP)/mediator', subunit, 1, '(', 'MED1)', for, its, transcriptional, activity])].
[sujeto(['Emerging', evidence, demonstrates, that, several]), verbo([nuclear]), complemento([receptor, '(', 'NR)', family, members, regulate, 'drug-inducible', expression, and, activity, of, several, important, carboxylesterase, '(', 'CES)', enzymes, in, mammalian, liver, and, intestine])].
[sujeto(['Moreover,', a, key, strategy, used, in, rational, drug, design, frequently, utilizes, an, ester, linkage, methodology, to, selectively]), verbo([target]), complemento([a, 'prodrug,', or, to, improve, the, water, solubility, of, a, novel, compound])].
[sujeto(['New', knowledge, regarding, the, transcriptional, regulation, of, 'CES', enzymes, by, 'NR', proteins, pregnane, x, receptor, '(', 'NR1I2)', and, constitutive, androstane, receptor, '(', 'NR1I3)']), verbo([has]), complemento([recently, come, to, light, through, the, use, of, knockout, and, transgenic, mouse, models])].
[sujeto(['Elucidation', of, the, role, of, 'NR-mediated', regulation, of, 'CES', enzymes, in, liver, and, intestine, will]), verbo([have]), complemento([a, significant, impact, on, rational, drug, design, and, the, development, of, novel, 'prodrugs,', especially, for, patients, on, combination, therapy])].
[sujeto(['The']), verbo([nuclear]), complemento([receptor, constitutive, androstane, receptor, '(', 'CAR)', '(', 'NR1I3)', regulates, hepatic, genes, involved, in, xenobiotic, detoxification, as, well, as, genes, involved, in, energy, homeostasis])].
[sujeto(['We']), verbo([provide]), complemento([data, that, extend, the, role, of, 'CAR', to, regulation, of, serum, triglyceride, levels, under, conditions, of, 'metabolic/nutritional', stress])].
[sujeto(['Moreover,']), verbo([increases]), complemento([in, serum, triglycerides, observed, after, a, 'high-fat', diet, '(', 'HFD)', regime, were, not, observed, in, 'Car(-/-)', animals])].
[sujeto(['Conversely,', pharmacological, induction, of, 'CAR', activity, using, the, selective, mouse, 'CAR', agonist, 'TCPOBOP', during, 'HFD', feeding, resulted, in, a, 'CAR-dependent']), verbo([increase]), complemento([in, serum, triglyceride, levels])].
[sujeto(['A', major, regulator, of, hepatic, fatty, oxidation, is, the]), verbo([nuclear]), complemento([receptor, 'PPARalpha', '(', 'NR1C1)'])].
[sujeto(['The', expression, of, peroxisome, 'proliferator-activated', receptor, alpha, '(', 'PPARalpha)']), verbo([target]), complemento([genes, was, inversely, related, to, the, activity, of, 'CAR'])].
[sujeto(['Consistent', with, these, 'observations,', 'Car(-/-)', animals, exhibited]), verbo([increased]), complemento([hepatic, fatty, acid, oxidation])].
[sujeto(['Treatment', of, mice, with, 1, ',', 4, -, 'bis[2-(3,5-dichloropyridyloxy)]benzene', '(', 'TCPOBOP)', significantly]), verbo([decreased]), complemento([expression, of, 'PPARalpha', mRNA, as, well, as, 'Cyp4a14,', 'CPT1alpha,', and, cytosolic, 'Acyl-CoA', thioesterase, '(', 'CTE)', in, the, liver])].
[sujeto(['These', data]), verbo([have]), complemento([implications, in, disease, therapy, such, as, for, diabetes, and, nonalcoholic, steatohepatitis, '(', 'NASH)'])].
[sujeto(['In', this, 'work,', the, nature, of, the, receptor]), verbo([involved]), complemento([in, this, neurotrophic, effect, was, investigated])].
[sujeto(['As', oleic, acid]), verbo([has]), complemento([been, reported, to, be, a, ligand, and, activator, of, the, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR),', we, focus, on, this, family, of, receptors])].
[sujeto(['Our', results, show, that, 'PPARalpha,', 'beta/delta,', and, gamma, are]), verbo([expressed]), complemento([in, neurons, in, culture])].
[sujeto(['However,', only, the, agonists, of, 'PPARalpha,', 'Wy14643,', 'GW7647', and, 'oleoylethanolamide,']), verbo([promoted]), complemento([neuronal, 'differentiation,', while, 'PPAR', 'beta/delta', and, gamma, agonists, did, not, modify, neuronal, differentiation])].
[sujeto(['Our', results, indicate, that, oleic, acid]), verbo([activates]), complemento(['PPARalpha', in, neurons])].
[sujeto(['In', 'addition,', the, effect, of, oleic, acid, on, neuronal, 'morphology,', 'growth-associated', protein, 43, and, 'microtubule-associated', protein, 2, expression]), verbo([decreases]), complemento([in, neurons, after, 'PPARalpha', has, been, silenced, by, small, interfering, 'RNA'])].
[sujeto(['Taken', 'together,', our, results]), verbo([suggest]), complemento([that, 'PPARalpha', could, be, the, receptor, for, oleic, acid, in, 'neurons,', further, broadening, the, range, of, functions, attributed, to, this, family, of, transcription, factors])].
[sujeto(['Although', several, works]), verbo([have]), complemento([reported, that, 'PPARalpha', could, be, involved, in, 'neuroprotection,', the, present, work, provides, the, first, evidence, suggesting, a, role, of, 'PPARalpha', in, neuronal, differentiation])].
[sujeto(['Peroxisome', 'proliferator-activated', receptors, '(', 'PPARs)', are]), verbo([nuclear]), complemento([hormone, receptors, that, are, activated, by, fatty, acids, and, their, derivatives])].
[sujeto(['Each', of, them, is, encoded, in, a, separate, gene, and]), verbo([binds]), complemento([fatty, acids, and, eicosanoids])].
[sujeto(['Although', each, isotype, fulfills, distinct, 'functions,', 'PPARs', function, not, only, as, an, important, fatty, acid, sensor, that]), verbo([regulate]), complemento(['lipid,', carbohydrate, and, amino, acid, metabolism, but, also, play, an, important, role, in, various, signaling, pathways, '(', 'immunity,', 'inflammation,', apoptosis, and, cell, 'differentiation)'])].
[sujeto(['Dysfunction', of, 'PPAR-mediated', signals]), verbo([leads]), complemento([to, various, diseases, such, as, 'diabetes,', 'obese,', 'hyperlipidemia,', inflammation, and, cancer])].
[sujeto(['Importantly,', magnesium, appears, to, play, a, pivotal, role, in]), verbo([regulating]), complemento([the, 'PPAR-mediated', signaling, pathways, as, a, key, cofactor, in, the, protein, phosphorylation])].
[sujeto(['Peroxisome', 'proliferator-activated', receptors, '(', 'PPARs)', are, 'ligand-activated', transcription, factors, which, form, a, subfamily, of, the]), verbo([nuclear]), complemento([receptor, gene, family])].
[sujeto(['PPARalpha', is]), verbo([expressed]), complemento([primarily, in, tissues, with, a, high, level, of, fatty, acid, catabolism, such, as, 'liver,', brown, 'fat,', 'kidney,', heart, and, skeletal, muscle])].
[sujeto(['PPARbeta', is, ubiquitously, 'expressed,', and, 'PPARgamma']), verbo([has]), complemento([a, restricted, pattern, of, 'expression,', mainly, in, white, and, brown, adipose, 'tissues,', whereas, other, tissues, such, as, skeletal, muscle, and, heart, contain, limited, amounts])].
[sujeto(['Furthermore,', 'PPARalpha', and, gamma, isotypes, are]), verbo([expressed]), complemento([in, vascular, cells, including, endothelial, and, smooth, muscle, cells, and, 'macrophages/foam', cells])].
[sujeto(['PPARs', are]), verbo([activated]), complemento([by, 'ligands,', such, as, naturally, occurring, fatty, 'acids,', which, are, activators, of, all, three, 'PPAR', isotypes])].
[sujeto(['In', addition, to, fatty, 'acids,', several, synthetic, 'compounds,', such, as, fibrates, and, 'thiazolidinediones,']), verbo([bind]), complemento([and, activate, 'PPARalpha', and, 'PPARgamma,', respectively])].
[sujeto(['In', order, to, be, transcriptionally, 'active,', 'PPARs', need, to]), verbo([heterodimerize]), complemento([with, the, 'retinoid-X-receptor', '(', 'RXR)'])].
[sujeto(['Upon', 'activation,', 'PPAR-RXR', heterodimers]), verbo([bind]), complemento([to, 'DNA', specific, sequences, called, peroxisome, 'proliferator-response', elements, '(', 'PPRE)', and, stimulate, transcription, of, target, genes])].
[sujeto(['PPARs', play, a, critical, role, in, lipid, and, glucose, 'homeostasis,', but, lately, they]), verbo([have]), complemento([been, implicated, as, regulators, of, inflammatory, responses])].
[sujeto(['A', role, for, 'PPARgamma', in, inflammation]), verbo([has]), complemento([also, been, reported, in, 'monocyte/macrophages,', where, ligands, of, this, receptor, inhibited, the, activation, of, macrophages, and, the, production, of, inflammatory, cytokines, '(', 'TNFalpha,', interleukin, 6, and, 1, 'beta),', although, part, of, the, 'anti-inflammatory', effects, of, these, ligands, seems, to, be, mediated, by, a, mechanism, not, involving, 'PPARgamma'])].
[sujeto(['All', these, findings]), verbo([suggest]), complemento([a, role, of, 'PPARs', in, the, control, of, the, inflammatory, response, with, potential, therapeutic, applications, in, 'inflammation-related', diseases])].
[sujeto(['Cholesterol', 7, 'alpha-hydroxylase', '(', 'cyp7a)']), verbo([mediates]), complemento([cholesterol, elimination, in, the, liver, by, catalyzing, the, first, and, 'rate-limiting', step, in, the, conversion, of, cholesterol, into, bile, acids])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, alpha, '(', 'PPARalpha;', 'NR1C1)', and, liver, 'X', receptor, alpha, '(', 'LXRalpha;', 'NR1H3)', are, two]), verbo([nuclear]), complemento([receptors, that, stimulate, the, murine, 'Cyp7a1', gene])].
[sujeto(['Here', we]), verbo([report]), complemento([that, 'co-expression', of, 'PPARalpha', and, 'LXRalpha', in, hepatoma, cells, abolishes, the, stimulation, of, 'Cyp7a1', gene, promoter, in, response, to, their, respective, agonists])].
[sujeto(['PPARalpha', and, 'LXRalpha', form, an, atypical, heterodimer, that]), verbo([binds]), complemento([to, two, directly, adjacent, hexameric, sequences, localized, within, overlapping, 'PPARalpha', and, 'LXRalpha', response, elements, '(', termed, 'Site', 'I),', antagonizing, the, interaction, of, 'PPARalpha:retinoid', 'X', receptor, alpha, '(', 'RXRalpha)', or, 'RXRalpha:LXRalpha', with, the, 'Cyp7a1', gene, promoter])].
[sujeto(['Mutations', within, either, hexameric, sequences, that, specifically, abolished, 'LXRalpha:PPARalpha', heterodimer]), verbo([binding]), complemento([to, the, murine, 'Cyp7a1', 'Site', 'I', also, relieved, promoter, inhibition])].
[sujeto(['The', 'LXRalpha:PPARalpha', heterodimer, may, be, important, in, coordinating, the, expression, of, genes, that, encode, proteins]), verbo([involved]), complemento([in, metabolism, of, fats, and, cholesterol])].
[sujeto(['We']), verbo([report]), complemento([the, 'x-ray', crystal, structure, of, the, ligand, binding, domain, of, 'PPAR', alpha, '(', 'NR1C1)', as, a, complex, with, the, agonist, ligand, 'GW409544', and, a, coactivator, motif, from, the, steroid, receptor, coactivator, 1])].
[sujeto(['Through', comparison, of, the, crystal, structures, of, the, ligand]), verbo([binding]), complemento([domains, of, the, three, human, 'PPARs,', we, have, identified, molecular, determinants, of, subtype, selectivity])].
[sujeto(['The', peroxisome, 'proliferator-activated', receptors, '(', 'PPARs)', are, dietary, lipid, sensors, that]), verbo([regulate]), complemento([fatty, acid, and, carbohydrate, metabolism])].
[sujeto(['We']), verbo([have]), complemento([used, combinatorial, chemistry, and, 'structure-based', drug, design, to, develop, a, potent, and, 'subtype-selective', 'PPARdelta', 'agonist,', 'GW501516'])].
[sujeto(['In', 'macrophages,', 'fibroblasts,', and, intestinal, 'cells,', 'GW501516']), verbo([increases]), complemento([expression, of, the, reverse, cholesterol, transporter, 'ATP-binding', cassette, 'A1', and, induces, apolipoprotein, 'A1-specific', cholesterol, efflux])].
[sujeto(['When', dosed, to, 'insulin-resistant', 'middle-aged', obese, rhesus, 'monkeys,', 'GW501516']), verbo([causes]), complemento([a, dramatic, 'dose-dependent', rise, in, serum, high, density, lipoprotein, cholesterol, while, lowering, the, levels, of, 'small-dense', low, density, 'lipoprotein,', fasting, 'triglycerides,', and, fasting, insulin])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'PPARdelta', agonists, may, be, effective, drugs, to, increase, reverse, cholesterol, transport, and, decrease, cardiovascular, disease, associated, with, the, metabolic, syndrome, 'X'])].
[sujeto(['Peroxisome', 'proliferator-activated', 'receptors,', 'PPARs,', '(', 'NR1C)', are]), verbo([nuclear]), complemento([hormone, receptors, implicated, in, energy, homeostasis])].
[sujeto(['Upon', 'activation,', these, 'ligand-inducible', transcription, factors]), verbo([stimulate]), complemento([gene, expression, by, binding, to, the, promoter, of, target, genes])].
[sujeto(['An', 'alpha-helical', configuration, was, predicted, for, this, 'region,', and, a, 'CD', spectrum, analysis, of, the, synthetic, peptides, showed, that, mutant, sequences, with, higher, 'AF-1', activity]), verbo([have]), complemento([higher, helical, contents, and, vice, versa])].
[sujeto(['Metformin', administration, is]), verbo([associated]), complemento([with, myocardial, protection, during, ischemia, 'and/or', 'reperfusion,', possibly, via, inhibition, of, inflammatory, responses, in, the, heart])].
[sujeto(['Exposure', to, 'pathogens,', in, addition, to, the, activation, of, the, immune, system, and, the]), verbo([associated]), complemento([metabolic, 'dysfunction,', often, results, in, compromised, myocardial, function])].
[sujeto(['We', examined, whether, metformin, administration, could]), verbo([maintain]), complemento([the, normal, myocardial, function, in, experimental, moderate, 'Gram', negative, 'infection,', induced, by, lipopolysaccharide, '(', 'LPS)', administration])].
[sujeto(['LPS', alone]), verbo([caused]), complemento([cardiac, 'dysfunction,', as, confirmed, by, 'echocardiography,', whereas, metformin, 'administration,', either, before, or, after, 'LPS,', rescued, myocardial, function])].
[sujeto(['LPS']), verbo([caused]), complemento([marked, reduction, of, the, cardiac, 'metabolism-related', genes, 'tested,', including, 'Prkaa2,', 'Cpt1b,', 'Ppargc1a', and, 'Ppargc1b;', reduction, of, fatty, acid, 'oxidation,', as, reflected, by, the, regulation, of, 'Ppara,', 'Acaca', and, 'Acacb;', increased, glucose, 'transport,', as, shown, by, 'Slc2a4', 'levels;', reduction, of, 'ATP', 'synthesis;', significant, increase, of, inflammatory, 'markers,', in, particular, 'IL6;', and, reduction, of, autophagy])].
[sujeto(['Genome-wide', association, studies, '(', 'GWAS)']), verbo([have]), complemento([identified, several, genetic, regions, involved, in, 'immune-regulatory', mechanisms, to, be, associated, with, celiac, disease])].
[sujeto(['Previous', 'GWAS', also, revealed, an, 'over-representation', of, genes]), verbo([involved]), complemento([in, type, 2, diabetes, and, anorexia, nervosa, associated, with, celiac, 'disease,', suggesting, involvement, of, common, metabolic, pathways, for, development, of, these, chronic, diseases])].
[sujeto(['Thirty', six]), verbo([target]), complemento([genes, involved, in, type, 2, diabetes, and, four, genes, associated, with, anorexia, nervosa, were, investigated, for, gene, expression, in, small, intestinal, biopsies, from, 144, children, with, celiac, disease, at, median, '(', 'range)', age, of, 7.4, years, '(', 1.6, -, 17.8, ')', and, from, 154, disease, controls, at, a, median, '(', 'range)', age, 11.4])].
[sujeto(['A', total, of, eleven, of, genes, were, differently]), verbo([expressed]), complemento([in, celiac, patients, compared, with, disease, controls, of, which, 'CD36,', 'CD38,', 'FOXP1,', 'SELL,', 'PPARA,', 'PPARG,', 'AGT', previously, associated, with, type, 2, diabetes, and, 'AKAP6,', 'NTNG1', with, anorexia, nervosa, remained, significant, after, correction, for, multiple, testing])].
[sujeto(['Shared', genetic, factors]), verbo([involved]), complemento([in, celiac, 'disease,', type, 2, diabetes, and, anorexia, nervosa, suggest, common, underlying, molecular, pathways, for, these, diseases])].
[sujeto(['The', objective, of, this, research, were, to, investigate, the, effect, of, a, conjugated, linoleic, acid, '(', 'CLA)-enriched', diet, on, 'Isa', 'Brown', laying, hen, health, status, and, to]), verbo([provide]), complemento([a, comprehensive, analysis, of, changes, in, blood, 'parameters,', liver, morphology, and, selected, hepatic, gene, expression])].
[sujeto(['The', 'CLA-enriched', diet, resulted, in, significant, changes, in, blood, and, serum, 'parameters;', 'specifically,', haematocrit, '(', 'HCT),', mean, corpuscular, volume, '(', 'MCV)', and, white, blood, cells, '(', 'WBC)', count, were]), verbo([decreased]), complemento([compare, to, the, control])].
[sujeto(['The', activity, of, alanine, aminotransferase, '(', 'ALT)', was, significantly]), verbo([increased]), complemento([in, the, 'CLA-supplemented', 'group,', while, aspartate, aminotransferase, '(', 'AST)', showed, an, increasing, tendency])].
[sujeto(['Additionally,', the, expression, of, hepatic, genes]), verbo([involved]), complemento([in, fatty, acids, synthesis, '(', 'ME1,', 'ACLY,', 'ACC,', 'FASN,', 'SCD1),', oxidation, '(', 'CPT1α,', 'PPARA),', detoxification, processes, '(', 'Cytochrome', 'P450,', 'CYP,', 'Flavin-containing', 'monooxygenase,', 'FMO3),', oxidative, stress, '(', 'NOX4,', 'XbP1)', and, inflammation, '(', 'IL6,', 'TNFα)', were, elevated])].
[sujeto(['The', results, of, this, study, indicate, that, dietary, 'CLA']), verbo([triggers]), complemento([an, integrated, stress, response, in, laying, hens, and, activates, mechanisms, involved, in, liver, detoxification])].
[sujeto(['We', aimed, to, investigate, the, protective, effects, of, fucoidan, on, dyslipidemia, and, atherosclerosis, in, apolipoprotein, 'E-deficient', mice, '(', 'ApoE(shl)', 'mice)', and, to, elucidate, its, molecular]), verbo([targets]), complemento([in, the, liver, by, using, a, transcriptomic, approach])].
[sujeto(['Fucoidan', supplementation, significantly, reduced, tissue, weight, '(', liver, and, white, adipose, 'tissue),', blood, 'lipid,', total, cholesterol, '(', 'TC),', triglyceride, '(', 'TG),', 'non-high-density', lipoprotein, cholesterol, '(', 'non-HDL-C)', and, glucose, levels, in, 'HFD-fed', 'ApoE(shl)', mice, but]), verbo([increased]), complemento([plasma, lipoprotein, lipase, '(', 'LPL)', activity, and, 'HDL-C', levels])].
[sujeto(['Fucoidan', also, reduced, hepatic, steatosis, levels, '(', liver, 'size,', 'TC', and, 'TG', 'levels,', and, lipid, 'peroxidation)', and]), verbo([increased]), complemento([white, adipose, tissue, 'LPL', activity])].
[sujeto(['DNA', microarray, analysis, and, quantitative, reverse, 'transcription-polymerase', chain, reaction, demonstrated, differential, expression, of, genes, encoding, proteins]), verbo([involved]), complemento([in, lipid, 'metabolism,', energy, homeostasis, and, insulin, 'sensitivity,', by, activating, 'Ppara', and, inactivating, 'Srebf1'])].
[sujeto(['Thus,', fucoidan, supplementation, appears, to]), verbo([have]), complemento(['anti-dyslipidemic', and, 'anti-atherosclerotic', effects, by, inducing, 'LPL', activity, and, inhibiting, the, effects, of, inflammation, and, oxidative, stress, in, 'HFD-fed', 'ApoE(shl)', mice])].
[sujeto(['Prior', to, this, 'work,', the, presence, of, 'NAA']), verbo([has]), complemento([not, been, described, in, adipocytes])].
[sujeto(['Here,', we, show, that, accumulation, of, 'NAA']), verbo([decreases]), complemento([the, brown, adipocyte, phenotype])].
[sujeto(['We']), verbo([increased]), complemento([intracellular, 'NAA', concentrations, in, brown, adipocytes, via, media, supplementation, or, 'knock-down', of, aspartoacylase, and, measured, reduced, 'lipolysis,', thermogenic, gene, 'expression,', and, oxygen, consumption])].
[sujeto(['Combinations', of, approaches, to]), verbo([increase]), complemento([intracellular, 'NAA', levels, showed, additive, effects, on, lipolysis, and, gene, 'repression,', nearly, abolishing, the, expression, of, 'Ucp1,', 'Cidea,', 'Prdm16,', and, 'Ppara'])].
[sujeto(['Further,']), verbo([activating]), complemento([histone, marks, '(', 'H3K27ac', and, 'H3K9ac)', in, 'promoters/enhancers', of, brown, marker, genes, showed, reduced, acetylation, status])].
[sujeto(['Thereby,', we, mechanistically, connect, the, 'NAA', pathway, to, the, epigenomic, regulation, of, gene, 'expression,']), verbo([modulating]), complemento([the, phenotype, of, brown, adipocytes])].
[sujeto(['The', liver, is, an, important, site, of, fat, 'oxidation,', which]), verbo([participates]), complemento([in, the, metabolic, regulation, of, food, intake])].
[sujeto(['This', phenotypic, eating, behavior]), verbo([suggests]), complemento([a, link, between, fat, oxidation, and, nutrient, choice, which, may, involve, an, energy, sensing, mechanism])].
[sujeto(['To', identify, hepatic, processes, that, could]), verbo([trigger]), complemento(['energy-related', 'signals,', we, have, now, performed, 'transcriptional,', metabolite, and, physiological, analyses, in, 'Acads-/-', mice, following, 'short-term', '(', 2, 'days)', exposure, to, either, 'high-', or, 'low-fat', diet])].
[sujeto(['Compared', to, 'wild-type', 'mice,']), verbo([phosphorylated]), complemento(['AMP-activated', protein, kinase, was, 40, '%', higher, in, 'Acads-/-', mice, after, 'short-term', 'high-fat', 'diet,', indicating, a, low, 'ATP/AMP', ratio])].
[sujeto([lowfat, diet, revealed]), verbo([increased]), complemento(['RXR/PPARA', 'signaling,', 'up-regulation', of, lipid, handling, pathways, '(', including, beta, and, omega, 'oxidation),', and, increased, mRNA, expression, of, 'Nfe2l2', target, genes])].
[sujeto(['Together,', these, results, point, to, an, oxidative, shortage, in, this, genetic, model, and, support, the, hypothesis, of, a, lower, hepatic, energy, state]), verbo([associated]), complemento([with, 'SCAD', deficiency, and, 'high-fat', diet])].
[sujeto(['Edaravone,', a, radical, 'scavenger,']), verbo([has]), complemento([been, recognized, as, a, potential, protective, agent, for, cardiovascular, diseases])].
[sujeto(['However,', little, is, known, about, the, effect, of, edaravone, in, cardiac, complications]), verbo([associated]), complemento([with, diabetes])].
[sujeto(['Here,', we]), verbo([have]), complemento([demonstrated, that, edaravone, prevents, cardiac, dysfunction, and, apoptosis, in, the, 'streptozotocin-induced', type, 1, diabetic, rat, heart])].
[sujeto(['In', 'addition,', treatment, of, diabetic, animals, by, edaravone]), verbo([increased]), complemento([protein, expressions, of, 'sirtuin-1', '(', 'SIRT-1),', peroxisome, proliferator, activated, receptor, γ, coactivator, α, '(', 'PGC-1α),', nuclear, factor, 'like-2', '(', 'NRF-2),', and, 'B', cell, lymphoma, 2, '(', 'Bcl-2),', and, reduced, protein, expressions, of, 'Bax', and, 'Caspase-3', compared, to, the, control, group])].
[sujeto(['In', 'addition,', the, treatment, of, 'high-glucose-incubated', 'H9c2', cells, by, edaravone]), verbo([increased]), complemento([the, activity, of, antioxidative, stress, by, increasing, 'SIRT-1,', 'PGC-1α,', and, 'NRF-2,', and, this, treatment, also, reduced, apoptosis, by, increasing, 'Bcl-2', expression, and, reducing, 'Bax', and, 'Caspase-3', expressions])].
[sujeto(['ATP']), verbo([binding]), complemento([cassette, transporter, 'A1', '(', 'ABCA1)', plays, a, key, role, in, atherogenesis])].
[sujeto(['Hydrogen', sulfide, '(', 'H₂S),', a, 'gasotransmitter,']), verbo([has]), complemento([been, reported, to, play, an, 'anti-atherosclerotic', role])].
[sujeto(['In', this, study, we, examined, whether, and, how, 'H₂S']), verbo([regulates]), complemento(['ABCA1', expression])].
[sujeto(['NaHS', '(', an, exogenous, 'H₂S', 'donor)', treatment, significantly]), verbo([increased]), complemento([the, expression, of, 'ABCA1,', 'ApoA1,', and, 'ApoA2', and, ameliorated, intracellular, lipid, accumulation, in, 'HepG2', cells])].
[sujeto(['Depletion', of, the, endogenous, 'H₂S', generator, cystathionine, 'γ-lyase', '(', 'CSE)', by, small, 'RNA', interference, '(', 'siRNA)', significantly]), verbo([decreased]), complemento([the, expression, of, 'ABCA1', and, resulted, in, the, accumulation, of, lipids, in, 'HepG2', cells])].
[sujeto(['In', vivo, 'NaHS', treatment, significantly, reduced, the, serum, levels, of, total, cholesterol, '(', 'TC),', triglycerides, '(', 'TG),', and, 'low-density', lipoproteins, '(', 'LDL),', diminished, atherosclerotic, plaque, 'size,', and]), verbo([increased]), complemento([hepatic, 'ABCA1', expression, in, 'fat-fed', 'ApoE(-/-)', mice])].
[sujeto(['Further', study, revealed, that, 'NaHS', upregulated, 'ABCA1', expression, by]), verbo([promoting]), complemento([peroxisome, 'proliferator-activated', receptor, α, '(', 'PPARα)', nuclear, translocation])].
[sujeto(['H₂S', 'up-regulates', the, expression, of, 'ABCA1', by]), verbo([promoting]), complemento([the, nuclear, translocation, of, 'PPARα,', providing, a, fundamental, mechanism, for, the, 'anti-atherogenic', activity, of, 'H₂S'])].
[sujeto(['Obesity', is, a, risk, factor, for, several, pain, syndromes, and, is]), verbo([associated]), complemento([with, increased, pain, sensitivity])].
[sujeto(['Evidence']), verbo([suggests]), complemento([that, obesity, causes, the, downregulation, of, peroxisome, 'proliferator&#8209;activated', receptor, '(', 'PPAR)α', in, the, spinal, 'cord,', contributing, to, augmented, peripheral, edema, and, inflammatory, hyperalgesia])].
[sujeto(['Ursolic', acid, '(', 'UA),', a, natural, pentacyclic, triterpenoid, carboxylic, 'acid,']), verbo([has]), complemento([been, shown, to, upregulate, 'PPARα', in, the, peripheral, tissues, of, obese, animals])].
[sujeto(['The', present, study, hypothesized, that, 'UA']), verbo([prevents]), complemento([augmented, peripheral, inflammation, and, inflammatory, hyperalgesia, in, obesity, by, restoring, downregulated, spinal, 'PPARα'])].
[sujeto(['Following', carrageenan, 'injection,', the, 'HFD', rats, exhibited]), verbo([increased]), complemento([thermal, hyperalgesia, and, paw, 'edema,', compared, with, the, rats, fed, a, 'low&#8209;fat', diet])].
[sujeto(['Molecular', investigations, revealed, that, the, 'HFD', rats, exhibited]), verbo([decreased]), complemento(['PPARα', 'activity,', and, exaggerated, expression, of, inflammatory, mediators, and, nuclear, 'factor&#8209;kB', activity, in, the, spinal, cord, in, response, to, carrageenan])].
[sujeto(['Oral', administration, of, 'UA', ameliorated, obesity, and, metabolic, 'disorder,', and]), verbo([prevented]), complemento([increased, thermal, hyperalgesia, and, paw, edema, in, the, 'HFD', rats])].
[sujeto(['Additionally,', 'UA', normalized, 'PPARα', activity, and]), verbo([inhibited]), complemento([the, exaggerated, spinal, cord, inflammatory, response, to, carrageenan])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, the, systemic, administration, of, 'UA', inhibited, the, exaggerated, spinal, cord, inflammatory, response, to, peripheral, inflammatory, stimulation, in, 'HFD&#8209;induced', obesity, by, restoring, downregulated, spinal, 'PPARα,', preventing, peripheral, inflammation, and, inflammatory, hyperalgesia])].
[sujeto(['UA', may, be, a, potential, therapeutic, option, for, the, prevention, of]), verbo([increased]), complemento([inflammatory, pain, in, obese, patients])].
[sujeto(['There', are, concerns, regarding, reproductive, toxicity, from, consumption, of]), verbo([soy]), complemento(['foods,', including, an, increased, risk, of, endometriosis, and, endometrial, 'cancer,', as, a, result, of, phytoestrogen, consumption])].
[sujeto(['In', this, 'study,', female, rats, were, fed, 'AIN-93G', diets, made, with, casein, '(', 'CAS)', or]), verbo([soy]), complemento([protein, isolate, '(', 'SPI)', from, postnatal, day, '(', 'PND)', 30, ',', ovariectomized, on, 'PND', 50, and, infused, with, 5, 'μg/kg/d', 17, 'β-estradiol', '(', 'E2)', or, vehicle])].
[sujeto(['E2']), verbo([increased]), complemento([uterine, wet, weight, '(', 'P&lt;0'])].
[sujeto(['The', major, 'E2', 'up-regulated', uterine, pathways, were, carcinogenesis, and, extracellular, matrix, 'organization,', whereas, 'SPI', feeding, 'up-regulated', uterine, peroxisome, proliferator]), verbo([activated]), complemento([receptor, '(', 'PPAR)', signaling, and, fatty, acid, metabolism])].
[sujeto(['The', ability, of, 'E2', to]), verbo([induce]), complemento([uterine, proliferation, in, response, to, the, carcinogen, 'dimethybenz(a)anthracene', '(', 'DMBA)', as, measured, by, expression, of, 'PCNA', and, 'Ki67', mRNA, was, suppressed, by, feeding, 'SPI', '(', 'P&lt;0'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'SPI', is, a, selective, estrogen, receptor, modulator, '(', 'SERM)', interacting, with, a, small, 'sub-set', of, 'E2-regulated', genes, and, is, 'anti-estrogenic', in, the, presence, of, endogenous, estrogens])].
[sujeto(['Our', previous, work]), verbo([suggested]), complemento([that, this, sex, disparity, is, a, consequence, of, higher, activity, of, the, 'androgen-induced', gene, peroxisome, 'proliferator-activated', receptor, α, '(', 'PPARα)', in, male, 'CD4(+)', 'T', cells])].
[sujeto(['The', objective, of, this, study, was, to, elucidate, the, cellular, and, molecular, mechanism, of, how, 'PPARα']), verbo([inhibits]), complemento(['Th1', responses, in, male, mice])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, 'PPARα', functions, within, 'CD4(+)', and, 'CD8(+)', 'T', lymphocytes, and, 'NKT', cells, to, negatively, regulate, 'IFN-γ', responses, in, male, mice, and, identified, 'Ifng', as, the, gene, target, of, 'PPARα', repression])].
[sujeto(['Treatment', of, male, 'CD4(+)', 'T', cells, with, the, 'PPARα', agonist, fenofibrate]), verbo([induced]), complemento([the, recruitment, of, 'PPARα', and, the, nuclear, 'receptor-interacting', 'protein,', nuclear, receptor, corepressor, 1, ',', to, specific, 'cis-regulatory', elements, in, the, 'Ifng', locus])].
[sujeto(['This', recruitment]), verbo([associated]), complemento([with, reduced, histone, acetylation, at, these, sites])].
[sujeto(['Knockdown', of]), verbo([nuclear]), complemento([receptor, corepressor, 1, in, primary, male, 'T', cells, abolished, the, effect, of, fenofibrate, in, reducing, 'IFN-γ', production])].
[sujeto(['In', 'contrast,', treatment, of, male, 'T', cells, with, 'IS001,', a, novel, antagonist, of, 'PPARα,']), verbo([increased]), complemento(['Ifng', gene, expression, and, histone, acetylation, across, the, 'Ifng', locus])].
[sujeto(['Finally,', we, investigated, the, effects, of, 'IS001', on, 'IFN-γ', responses, in, mice, during, infection, with, the, 'Th1-associated', pathogen, 'Listeria', monocytogenes, and, observed, that, 'IS001']), verbo([enhanced]), complemento(['IFN-γ', production, by, 'NKT,', 'CD4(+),', and, 'CD8(+)', 'T', cells, and, improved, the, survival, of, 'male,', but, not, 'female,', mice])].
[sujeto(['Our', findings]), verbo([provide]), complemento([a, novel, mechanism, of, why, 'IFN-γ', responses, are, more, robust, in, females, and, introduce, a, 'small-molecule', 'IS001', that, can, be, used, to, enhance, 'Th1', immunity, in, males])].
[sujeto(['To', determine, whether, the]), verbo([nuclear]), complemento([receptor, 'PPARδ', can, modulate, the, differentiation, of, human, dermal, fibroblasts, '(', 'HDFs)', into, myofibroblasts])].
[sujeto(['This', induction, was, significantly]), verbo([inhibited]), complemento([by, the, presence, of, siRNA, against, 'PPARδ,', indicating, that, 'PPARδ', is, involved, in, myofibroblast, transdifferentiation, of, 'HDFs'])].
[sujeto(['Ligand-activated', 'PPARδ']), verbo([increased]), complemento(['α-SMA', promoter, activity, in, a, dual, mode, by, directly, binding, a, direct, 'repeat-1', '(', 'DR1)', site, in, the, 'α-SMA', 'promoter,', and, by, inducing, expression, of, transforming, growth, factor, '(', 'TGF)-β,', whose, downstream, effector, 'Smad3', interacts, with, a, 'Smad-binding', element, '(', 'SBE)', in, another, region, of, the, promoter])].
[sujeto(['GW501516-activated', 'PPARδ', also]), verbo([increased]), complemento([the, migration, and, contractile, properties, of, 'HDFs,', as, demonstrated, by, 'Transwell', and, collagen, lattice, contraction, 'assays,', respectively])].
[sujeto(['PPARδ', plays, pivotal, roles, in, wound, healing, by]), verbo([promoting]), complemento(['fibroblast-to-myofibroblast', differentiation, via, 'TGF-β/Smad3', signaling])].
[sujeto(['Salusin-β']), verbo([has]), complemento([direct, effects, on, 'VSMCs'])].
[sujeto(['Western', blotting, 'analysis,', 'real-time', 'PCR', and, transient, transfection, approach, were, used, to, determine, expression, of]), verbo([target]), complemento([proteins])].
[sujeto(['Salusin-β', negatively]), verbo([regulated]), complemento(['PPARγ', gene, expression, at, 'protein,', mRNA, and, gene, promoter, level, in, 'VSMCs'])].
[sujeto(['IκBα-NF-κB', 'activation,', but, not, 'NF-κB', p50, or, 'p65,']), verbo([mediated]), complemento([the, 'salusin-β-induced', inhibition, of, 'PPARγ', gene, expression])].
[sujeto(['Salusin-β']), verbo([induced]), complemento([nuclear, translocation, of, histone, deacetylase, 3, '(', 'HDAC3)'])].
[sujeto(['HDAC3', siRNA]), verbo([prevented]), complemento(['salusin-β-induced', 'PPARγ', reduction])].
[sujeto(['Here,', we, investigated, the, role, of, 'LXRα', in, capsaicin]), verbo([mediated]), complemento(['anti-inflammatory', effects])].
[sujeto(['Results', revealed, that, capsaicin]), verbo([inhibits]), complemento(['LPS-induced', 'IL-1β,', 'IL-6', and, 'TNF-α', production, in, a, 'time-', and, 'dose-dependent', manner])].
[sujeto(['Moreover,', capsaicin]), verbo([increases]), complemento(['LXRα', expression, through, 'PPARγ', pathway])].
[sujeto(['Thus,', we, propose, that, the, 'anti-inflammatory', effects, of, capsaicin, are, 'LXRα', 'dependent,', and, 'LXRα', may, potentially, link, the, capsaicin]), verbo([mediated]), complemento(['PPARγ', activation, and, 'NF-κB', inhibition, in, 'LPS-induced', inflammatory, response])].
[sujeto(['FGF19']), verbo([regulates]), complemento([the, bile, acid, synthetic, pathway])].
[sujeto(['FGF19', expression, is]), verbo([induced]), complemento([by, farnesoid, 'X', receptor, '(', 'FXR),', a, nuclear, hormone, receptor, activated, by, bile, acids, in, the, small, intestine])].
[sujeto(['FGF21', expression, is]), verbo([stimulated]), complemento([by, the, nuclear, fatty, acid, receptor, peroxisome, 'proliferator-activated', receptor, α, '(', 'PPARα)', in, the, liver])].
[sujeto(['FGF19', and, 'FGF21', were, recently, identified, as]), verbo([targets]), complemento([of, activating, transcription, factor, 4, '(', 'ATF4),', which, is, activated, in, response, to, endoplasmic, reticulum, '(', 'ER)', stress])].
[sujeto(['ATF4', is, also]), verbo([activated]), complemento([by, oxidative, stress, and, amino, acid, deprivation])].
[sujeto(['We']), verbo([found]), complemento([that, 'FGF19', mRNA, is, induced, by, oxidative, stress, inducers, in, 'Caco-2', 'cells,', which, are, derived, from, the, human, intestinal, 'epithelium,', and, rat, intestinal, epithelial, 'IEC6', cells])].
[sujeto(['In', 'contrast,', ileal, 'FGF15', 'expression,', the, rodent, ortholog, of, human, 'FGF19,', is, not]), verbo([increased]), complemento([by, oxidative, stress])].
[sujeto(['In', 'contrast,', 'FGF21', expression, is]), verbo([induced]), complemento([by, oxidative, stress, and, amino, acid, deprivation, both, in, vitro, and, in, vivo])].
[sujeto(['The']), verbo([nuclear]), complemento([receptor, corepressor, '(', 'NCoR)', regulates, the, activities, of, gene, transcription])].
[sujeto(['The', results]), verbo([suggested]), complemento([that, rat, 'MSCs', could, differentiate, into, adipocytes, successfully, after, cultured, in, adipogenic, medium])].
[sujeto(['NCoR', protein, determined, by, 'Western', blot, showed, a, lower, expression, in, 'MSC-derived', 'adipocytes,', indicating, that, 'NCoR', was]), verbo([involved]), complemento([in, adipocyte, differentiation, of, rat, 'MSCs'])].
[sujeto(['It', further, proved, that, small, interfering, 'RNA', '(', 'siRNA)-mediated', knockdown, of, 'NCoR', could]), verbo([promote]), complemento([cell, viability, and, differentiation, and, enhance, messenger, 'RNA', '(', 'mRNA)', expression, of, lipoprotein, lipase, '(', 'LPL)', and, protein, expression, of, 'CCAAT/enhancer', binding, 'protein-α', '(', 'C/EBPα)', and, peroxisome, 'proliferator-activated', 'receptor-γ', '(', 'PPARγ)'])].
[sujeto(['It', indicated, that, 'NCoR', could, negatively]), verbo([regulate]), complemento([adipogenic, differentiation, of, rat, 'MSCs'])].
[sujeto(['Targeting', glycolysis, for, cancer, treatment]), verbo([has]), complemento([been, investigated, as, a, therapeutic, method, but, has, not, offered, a, feasible, chemotherapeutic, strategy])].
[sujeto(['Our', aim, was, to, examine, whether, 'AMP-activated', protein, kinase, '(', 'AMPK),', a, conditional, 'oncogene,', rescues, the, energetic, stress, and, cytotoxicity]), verbo([induced]), complemento([by, 2, -, deoxyglucose, '(', 2, -, 'DG),', a, glycolytic, 'inhibitor,', and, the, related, mechanisms])].
[sujeto([2, -, 'DG']), verbo([decreased]), complemento(['ATP', levels, and, subsequently, activated, 'AMPK,', which, contribute, to, intracellular, 'ATP', recovery, in, 'MCF-7', cells, thus, exhibiting, no, apparent, cytotoxicity])].
[sujeto(['Compound', 'C,', an, 'AMPK', 'inhibitor,', further, potentiates, 2, -, 'DG-induced']), verbo([decrease]), complemento([in, 'ATP', levels, and, inhibits, their, recovery])].
[sujeto([2, -, 'DG,', via, 'AMPK', 'activation,']), verbo([stimulated]), complemento([cAMP, response, 'element-binding', protein, '(', 'CREB)', phosphorylation, and, activity, and, promoted, nuclear, peroxisome, 'proliferator-activated', receptor, gamma, 'coactivator-1-beta', '(', 'PGC-1β)', and, 'estrogen-related', receptor, α, '(', 'ERRα)', protein, 'expression,', leading, to, augmented, mitochondrial, biogenesis, and, expression, of, fatty, acid, oxidation, '(', 'FAO)', genes, including, 'PPARα,', 'MCAD,', 'CPT1C,', and, 'ACO'])].
[sujeto(['However,', 2, -, 'DG', in, combination, with, 'AMPK', antagonists, or, small, interfering, 'RNA']), verbo([caused]), complemento([a, dramatic, increase, in, cytotoxicity, in, 'MCF-7', but, not, in, 'MCF-10A', cells])].
[sujeto(['Similarly,', when, combined, with, inhibition, of, 'CREB/PGC-1β/ERRα', 'pathway,', 2, -, 'DG', saliently]), verbo([suppressed]), complemento([mitochondrial, biogenesis, and, the, expression, of, 'FAO', 'genes,', depleted, 'ATP', 'production,', and, enhanced, cytotoxicity, in, cancer, cells])].
[sujeto(['Collectively,', the, combination, of, 2, -, 'DG', and, 'AMPK', inhibition, synergistically]), verbo([enhanced]), complemento([the, cytotoxic, potential, in, breast, cancer, cells, with, a, relative, nontoxicity, to, normal, cells, and, may, offer, a, 'promising,', 'safe,', and, effective, breast, cancer, therapeutic, strategy])].
[sujeto(['The', 'WNT/β-catenin', signaling, pathway]), verbo([has]), complemento([been, identified, as, an, important, endogenous, regulator, of, hepatic, cytochrome, 'P450', '(', 'P450)', expression, in, mouse, liver])].
[sujeto(['In', 'particular,', it, is]), verbo([involved]), complemento([in, the, regulation, of, 'P450', expression, in, response, to, exposure, to, xenobiotic, agonists, of, the, nuclear, receptors, constitutive, androstane, receptor, '(', 'CAR),', aryl, hydrocarbon, receptor, '(', 'AhR),', and, 'Nrf2'])].
[sujeto(['To', systematically, elucidate, the, effect, of, the, 'WNT/β-catenin', pathway, on, the, regulation, and, inducibility, of, major, human, 'P450', 'enzymes,', 'HepaRG', cells, were, treated, with, either, the, 'WNT/β-catenin', signaling, pathway, 'agonist,', 'WNT3a,', or, with, small, interfering, 'RNA', directed, against, 'β-catenin,', alone, or, in, combination, with, a, panel, of]), verbo([activating]), complemento([ligands, for, 'AhR', '[', 2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD)],', 'CAR', '[', 6, -, '(', 4, -, 'chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime', '(', 'CITCO)],', pregnane, 'X', receptor, '(', 'PXR)', '[', 'rifampicin],', and, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)', α, '[', 4, -, 'chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic', acid, '(', 'WY14,643)]'])].
[sujeto(['By', 'contrast,', activation, of, the, 'WNT/β-catenin', pathway]), verbo([prevented]), complemento(['PPARα-mediated', induction, of, 'CYP1A,', 'CYP2C8,', 'CYP3A4,', and, 'CYP4A11', 'genes,', suggesting, a, 'dominant-negative', role, of, 'β-catenin', in, 'PPARα-mediated', regulation, of, these, genes])].
[sujeto(['Our', data, indicate, a, significant, effect, of, the, 'WNT/β-catenin', pathway, on, the, regulation, of, 'P450', enzymes, in, human, hepatocytes, and]), verbo([reveal]), complemento([a, novel, crosstalk, between, 'β-catenin', and, 'PPARα', signaling, pathways, in, the, regulation, of, 'P450', expression])].
[sujeto(['Furthermore,', the, 'PRMT-dependent', induction, of, a, 'CAR', reporter, 'gene,', which, was, independent, of, methyltransferase, 'activity,', was]), verbo([enhanced]), complemento([in, the, presence, of, steroid, receptor, coactivator, 1, '(', 'SRC1),', peroxisome, 'proliferator-activated', 'receptor-gamma', coactivator, 1, alpha, '(', 'PGC-1α)', or, 'DEAD', box, 'DNA/RNA', helicase, 'DP97'])].
[sujeto(['Using', tetracycline, 'inducible-hCAR', system, in, 'HepG2', 'cells,', we, showed, that, knockdown, of, 'PRMT5', with, small, interfering, 'RNA']), verbo([suppressed]), complemento([tetracycline, -, induced, mRNA, expression, of, 'CYP2B6', but, not, of, 'CYP2C9', or, 'CYP3A4'])].
[sujeto(['PRMT5']), verbo([enhanced]), complemento(['phenobarbital-mediated', transactivation, of, a, 'phenobarbital-responsive', enhancer, module, '(', 'PBREM)-driven', reporter, gene, in, 'co-operation', with, 'PGC-1α', in, rat, primary, hepatocytes])].
[sujeto(['Based', on, these, 'findings,', we]), verbo([suggest]), complemento(['PRMT5', to, be, a, gene, '(', or, 'promoter)-selective', coactivator, of, 'CAR', by, mediating, the, formation, of, complexes, between, hCAR, and, appropriate, coactivators])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, γ, '(', 'PPARγ)', and, estrogen, receptor, '(', 'ER)', belong, to, a, family, of]), verbo([nuclear]), complemento([hormone, receptors, that, have, been, demonstrated, to, affect, each, 'other\'s', transcriptional, activity])].
[sujeto(['PPARγ', and, 'ERα', expression, levels, were, significantly]), verbo([associated]), complemento([with, pathological, grade, and, clinical, stage, in, endometrial, carcinoma, '(', 'P&lt;0'])].
[sujeto(['Moreover,', our, findings]), verbo([suggest]), complemento([that, 'PPARγ', activation, inhibited, the, 'migration,', invasion, and, proliferation, of, endometrial, carcinoma, 'cells;', 'ECC-1', cells, were, more, sensitive, to, this, inhibition])].
[sujeto(['The', present, study, demonstrated, that, 'PPARγ', activation]), verbo([inhibited]), complemento(['ERα', expression, in, 'ERα-positive', endometrial, carcinoma, cell, lines])].
[sujeto(['This', crosstalk, may, facilitate, the, development, of, novel, therapeutic, methods]), verbo([targeting]), complemento(['PPARγ', in, endometrial, carcinoma, 'treatment,', particularly, 'ERα-positive', carcinomas])].
[sujeto(['Dextran', sulphate, sodium, '(', 'DSS)-induced', colitis]), verbo([leads]), complemento([to, accumulation, of, bile, acids, in, inflamed, colon, tissues, via, activation, of, the, intestinal, peroxisome, 'PPARα-UGTs', pathway])].
[sujeto(['UGTs', accelerate, the, metabolic, elimination, of, bile, 'acids,', and, thereby]), verbo([decrease]), complemento([their, intracellular, levels, in, the, small, intestine])].
[sujeto(['Reduced', intracellular, bile, acids, results, in]), verbo([repressed]), complemento([farnesoid, 'X', receptor, '(', 'FXR)-FGF15', 'signalling,', leading, to, upregulation, of, hepatic, 'CYP7A1,', thus, promoting, the, de, novo, bile, acid, synthesis])].
[sujeto(['Obesity', is]), verbo([associated]), complemento([with, augmented, peripheral, inflammation, and, pain, sensitivity, in, response, to, inflammatory, 'stimulation,', but, the, underlying, mechanisms, remain, unclear])].
[sujeto(['Emerging', evidence]), verbo([has]), complemento([shown, that, activation, of, peroxisome, 'proliferator-activated', 'receptor-α', '(', 'PPARα)', in, the, central, nervous, system, controls, peripheral, inflammation, and, pain])].
[sujeto(['We', hypothesized, that, obesity, might, 'down-regulate', 'PPARα', in, the, spinal, 'cord,']), verbo([leading]), complemento([to, enhanced, peripheral, inflammation, and, inflammatory, hyperalgesia])].
[sujeto(['Sprague-Dawley', rats, fed, a, 'high-fat', diet, '(', 'HF)', for, 12, weeks, developed, metabolic, disorder, and, displayed, significantly]), verbo([decreased]), complemento([spinal, 'PPARα', expression, and, activity])].
[sujeto(['No', difference, in, the, expression, of, inflammatory, mediators, or]), verbo([nuclear]), complemento([factor, '(', 'NF)-κB', activity, was, observed, at, baseline, among, groups])].
[sujeto(['Carrageenan']), verbo([induced]), complemento([decreased, 'PPARα', expression, and, 'activity,', increased, spinal, cord, inflammatory, mediator, expression, and, 'NF-κB', activity, in, both, 'LF-and', 'HF-fed', rats])].
[sujeto(['However,', the]), verbo([increase]), complemento([was, more, pronounced, in, 'HF-fed', rats, and, corrected, by, 'PEA'])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'diet-induced', obesity, causes, 'down-regulation', of, spinal, 'PPARα,', which, facilitates, the, susceptibility, to, peripheral, inflammatory, challenge, by, increasing, inflammatory, response, in, the, spinal, 'cord,', contributing, to, augmented, peripheral, inflammation, and, inflammatory, hyperalgesia, in, obesity])].
[sujeto(['Modification', of, human, airway, smooth, muscle, '(', 'ASM)', function, by, proinflammatory, cytokines]), verbo([has]), complemento([been, regarded, as, a, potential, mechanism, underlying, bronchial, hyperresponsiveness, in, asthma])].
[sujeto(['Human', 'ASM', cells]), verbo([express]), complemento([intercellular, adhesion, molecule, '(', 'ICAM)-1', in, response, to, cytokines])].
[sujeto(['In', this, 'study,', we, examined, whether, 'ciglitazone,', a, synthetic, 'PPARγ', 'ligand,', can]), verbo([modulate]), complemento([the, basal, and, tumor, necrosis, factor, '(', 'TNF)α-induced', 'ICAM1', gene, expression, in, human, 'ASM', cells])].
[sujeto(['PPARγ', activity, was]), verbo([inhibited]), complemento([by, 'target-specific', small, interfering, '(', 'si)', 'RNA', targeting, 'PPARγ', and, 'GW9662,', a, 'PPARγ', antagonist])].
[sujeto(['Activity', of]), verbo([nuclear]), complemento([factor, '(', 'NF)-κB', was, assessed, by, using, immunoblot, 'analysis,', 'immune-confocal', 'images,', and, electrophoretic, mobility, shift, assay, '(', 'EMSA)'])].
[sujeto(['By', flow, 'cytometry,', ciglitazone, alone, had, no, effect, on, 'ICAM-1', expression, in, 'ASM', 'cells,', but]), verbo([inhibited]), complemento(['ICAM-1', expression, in, response, to, 'TNFα', '(', 10, 'ng/ml)', in, a, 'dose-dependent', manner, '(', 1, -, 10, 'μM)'])].
[sujeto(['It', also]), verbo([inhibited]), complemento(['TNFα-induced', 'ICAM1', gene, expression, by, 'RT-PCR', analysis])].
[sujeto(['Knockdown', of, 'PPARγ', gene, by, 'target-specific', siRNA]), verbo([targeting]), complemento(['PPARγ', enhanced, 'ICAM-1', expression, and, the, inhibitory, effect, of, ciglitazone, on, 'TNFα-induced', 'ICAM-1', expression, was, reversed, by, 'PPARγ', siRNA, and, 'GW9662'])].
[sujeto(['SN-50', '(', 10, 'μg/ml),', an, inhibitor, for]), verbo([nuclear]), complemento([translocation, of, 'NF-κB,', inhibited, 'TNFα-induced', 'ICAM-1', expression])].
[sujeto(['Ciglitazone', did, not]), verbo([prevent]), complemento(['TNFα-induced', degradation, of, the, cytosolic, inhibitor, of, 'NF-κB', '(', 'IκB),', but, inhibited, the, nuclear, translocation, of, p65, induced, by, 'TNFα', and, suppressed, the, 'NF-κB/DNA', binding, activity])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, ciglitazone, inhibits, 'TNFα-induced', 'ICAM1', gene, expression, in, human, 'ASM', cells, through, the, 'ligand-dependent', 'PPARγ', activation, and, 'NF-κB-dependent', pathway])].
[sujeto(['RNA', interference, '(', 'RNAi)']), verbo([has]), complemento([tremendous, potential, for, investigating, gene, function, and, for, developing, new, therapies])].
[sujeto(['However,', application, of, 'RNAi', in, 'PHH']), verbo([has]), complemento([some, technical, hurdles])].
[sujeto(['We', used, lentiviral, vectors, to, transduce, 'PHH', for, introduction, of, short, hairpin, 'RNAs', '(', 'shRNAs)']), verbo([targeting]), complemento([constitutive, androstane, receptor, '(', 'CAR),', peroxisome, proliferator, activated, receptor, alpha, '(', 'PPARα),', and, 'microRNA,', 'miR-143'])].
[sujeto(['We', demonstrated, the, feasibility, of, this, technique, in, studies, on]), verbo([targeting]), complemento([nuclear, 'receptors,', 'PPARα', and, 'CAR,', with, shRNAs, as, well, as, in, 'lentivirus-mediated', overexpression, and, 'knock-down', of, 'miRNA-143', experiments])].
[sujeto(['This', approach, should, be, useful, to, study, not, only, the, regulation, via]), verbo([nuclear]), complemento([receptors, but, also, other, 'biological,', 'pharmacological,', and, toxicological, aspects, of, drug, metabolism])].
[sujeto(['Sulfatides,', 3, -, 'O-sulfogalactosylceramides,', are, known, to]), verbo([have]), complemento([multifunctional, properties])].
[sujeto(['With', respect, to, this, 'issue,', we, previously]), verbo([found]), complemento([potential, sequences, of, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)', response, element, on, upstream, regions, of, the, mouse, 'CST', gene, and, presumed, the, possible, regulation, by, the, nuclear, receptor, 'PPARα'])].
[sujeto(['Fenofibrate', treatment]), verbo([increased]), complemento([sulfatides, and, 'CST', mRNA, levels, in, the, 'kidney,', 'heart,', 'liver,', and, small, intestine, in, a, 'PPARα-dependent', manner])].
[sujeto(['Analyses', of, the, 'DNA-binding', activity, and, conventional, gene, expression]), verbo([targets]), complemento([of, 'PPARα', has, demonstrated, that, fenofibrate, treatment, activated, 'PPARα', in, the, 'kidney,', 'heart,', 'liver,', and, small, intestine, but, did, not, affect, the, brain, or, colon])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'PPARα', activation, induces, 'CST', gene, expression, and, enhances, sulfatide, synthesis, in, 'mice,', which, suggests, that, 'PPARα', is, a, possible, transcriptional, regulator, for, the, mouse, 'CST', gene])].
[sujeto(['Interindividual', variability, in, cytochrome, 'P450', 3, 'A4', '(', 'CYP3A4)', is, believed, to, be, largely, 'heritable;', 'however,', predictive, genetic, factors]), verbo([have]), complemento([remained, scarce])].
[sujeto(['Using', a, 'candidate-gene', approach, in, a, human, liver, 'bank,', we, identified, 'single-nucleotide', polymorphisms, '(', 'SNPs)', in, the, 'Ah-receptor']), verbo([nuclear]), complemento([translocator, '(', 'ARNT),', glucocorticoid, receptor, '(', 'GR),', progesterone, receptor, membrane, component, 2, '(', 'PGRMC2),', and, peroxisome, 'proliferator-activated', 'receptor-α', '(', 'PPARA)', that, are, associated, with, 'CYP3A4', phenotype])].
[sujeto(['Validation', in, 'atorvastatin-treated', volunteers, confirmed, a]), verbo([decrease]), complemento([in, 'atorvastatin-2-hydroxylation', in, carriers, of, 'PPARA', 'SNP', rs4253728])].
[sujeto(['Homozygous', carriers]), verbo([expressed]), complemento([significantly, less, 'PPAR-α', protein, in, the, liver])].
[sujeto(['Moreover,', 'shRNA-mediated', 'PPARA', gene, knockdown, in, primary, human, hepatocytes]), verbo([decreased]), complemento([expression, levels, of, the, 'PPAR-α', target, 'ACOX1', and, of, 'CYP3A4', by, more, than, 50, '%'])].
[sujeto(['These', findings]), verbo([have]), complemento([implications, for, variability, in, response, to, drug, substrates, of, 'CYP3A4'])].
[sujeto(['Peroxisome', 'proliferator-activated', receptors, 'β/δ', '(', 'PPARβ/δ)']), verbo([have]), complemento([been, shown, to, suppress, 11, 'β-HSD2', expression, in, human, placental, cells])].
[sujeto(['Our', objectives, were, to, investigate, whether, the, reduced, 11, 'β-HSD2', expression, is]), verbo([associated]), complemento([with, the, changes, in, 'PPARs', in, 'PE', 'placentas,', and, whether, 'PPARα', and, 'PPARγ', affect, 11, 'β-HSD2', expression, in, placental, cells])].
[sujeto(['PPARα', and, 'PPARβ/δ', mRNA, and, protein, expression, was, 'increased,', whereas, 'PPARγ', mRNA, and, protein, expression, was]), verbo([decreased]), complemento([in, 'PE', placentas])].
[sujeto(['Knockdown', of, retinoid, 'X']), verbo([nuclear]), complemento([receptor, α, '(', 'RXRα)', resulted, in, a, loss, of, 'PPARγ', effect, but, not, 'PPARα', effect, 'on11β-HSD2'])].
[sujeto(['PPARγ', agonist, 'dose-dependently']), verbo([stimulated]), complemento([specificity, protein, 1, '(', 'Sp-1)', protein, expression])].
[sujeto(['Inhibition', or, knockdown, of, 'Sp-1', resulted, in, a]), verbo([loss]), complemento([of, the, effects, of, 'PPARα', and, 'PPARγ'])].
[sujeto(['Our', data, indicate, that, 11, 'β-HSD2', expression, can, be]), verbo([modulated]), complemento([by, 'PPARα', and, 'PPARγ', in, placental, trophoblasts, through, 'Sp-1'])].
[sujeto(['Decreased', 11, 'β-HSD2', expression, in, 'PE', placenta, might, be]), verbo([associated]), complemento([with, decreased, 'PPARγ', but, increased, 'PPARα', expression])].
[sujeto(['Many', epidemiological, studies]), verbo([have]), complemento([reported, the, link, between, magnesium, deficiency, and, metabolic, syndrome])].
[sujeto(['We', examined, whether, magnesium, deficiency, in, rats]), verbo([induces]), complemento([changes, in, glucocorticoid, metabolism])].
[sujeto(['We', observed, lower, expression, of, hepatic, 'PEPCK', 'mRNA,', in, the, 'magnesium-deficient', 'rats,', thus]), verbo([suggesting]), complemento([a, possible, compensatory, mechanism, to, diminish, glycogenesis])].
[sujeto(['A', 'low-magnesium', diet, alters, glucocorticoid, 'metabolism,', which]), verbo([leads]), complemento([to, endothelial, damage])].
[sujeto(['Higher', 'ADMA']), verbo([induces]), complemento([hypertension, and, insulin, resistance])].
[sujeto(['Hyperinsulinemia']), verbo([induces]), complemento([hepatic, 'down-regulation', of, 'PEPCK,', and, is, possibly, a, key, mechanism, inducing, the, metabolic, complications, of, magnesium, deficiency])].
[sujeto(['Many', epidemiologic, studies]), verbo([have]), complemento([reported, a, link, between, calcium, '(', 'Ca)', deficiency, and, metabolic, syndrome])].
[sujeto(['A', 'low-Ca', diet, alters, glucocorticoid, 'metabolism,', which]), verbo([leads]), complemento([to, hepatic, upregulation, of, 11, 'β-HSD1,', and, is, possibly, a, key, mechanism, inducing, the, metabolic, complications, of, 'Ca', deficiency])].
[sujeto(['Traditionally,', the, mineralocorticoid, receptor, was, thought, to, be]), verbo([activated]), complemento([by, the, mineralocorticoid, hormone, 'aldosterone,', and, to, exhibit, its, main, action, on, epithelia, by, promoting, renal, sodium, 'retention,', potassium, excretion, and, inducing, hypertension, upon, excessive, activation])].
[sujeto(['Recently,', evidence, appeared, that, mineralocorticoid, receptors, are]), verbo([expressed]), complemento([in, nonepithelial, cells, and, activated, by, endogenous, glucocorticoids, including, cortisol])].
[sujeto(['The', determination, of, the, intracellular, topology, of, 11, 'beta-HSD1,', facing, the, endoplasmic, reticulum, 'lumen,', and, 11, 'beta-HSD2,', facing, the, 'cytoplasm,']), verbo([suggests]), complemento([that, 11, 'beta-HSD1', acts, as, a, prereceptor, mechanism, in, the, local, activation, of, glucocorticoid, 'receptors,', whereas, 11, 'beta-HSD2', controls, mineralocorticoid, receptors, by, interacting, with, the, receptor, in, the, absence, of, aldosterone])].
[sujeto(['The', corresponding, signal, transcription, pathways, and, some, relevant, transcription, factors]), verbo([have]), complemento([been, identified])].
[sujeto(['Renal', sodium, retention, in, liver, 'cirrhosis,', nephrotic, syndrome, and, hypoxia]), verbo([have]), complemento([been, linked, to, 11, 'beta-HSD2', reduced, activity])].
[sujeto(['Overexpression', of, 11, 'beta-HSD1', specifically, in, adipose, tissue, in, mice]), verbo([caused]), complemento([central, 'obesity,', a, metabolic, syndrome, and, hypertension, due, to, increased, intracellular, cortisol, concentrations])].
[sujeto(['Recently,', mineralocorticoid, receptor, antagonists]), verbo([have]), complemento([been, used, in, the, randomized, aldactone, evaluation, study, '(', 'RALES)', with, 'spironolactone,', the, eplerenone, 'post-AMI', heart, failure, efficacy, and, survival, study, '(', 'EPHESUS),', and, in, severe, and, postmyocardial, infarct, heart, 'failure,', respectively])].
[sujeto(['Bile', acids, '(', 'BAs)', are, powerful, regulators, of, 'metabolism,', and, mice, treated, orally, with, cholic, acid, are, protected, from, 'diet-induced', 'obesity,', hepatic, lipid, 'accumulation,', and]), verbo([increased]), complemento([plasma, triacylglycerol, '(', 'TAG)', and, glucose, levels])].
[sujeto(['The', elevated, plasma, 'BA', concentration, was]), verbo([associated]), complemento([with, induction, of, genes, involved, in, energy, metabolism, and, 'uncoupling,', 'Dio2,', 'Pgc-1α,', and, 'Ucp1,', in, interscapular, brown, adipose, tissue])].
[sujeto(['Interestingly,', the, same, transcriptional, pattern, was]), verbo([found]), complemento([in, white, adipose, tissue, depots, of, both, abdominal, and, subcutaneous, origin])].
[sujeto(['Accordingly,', rats, fed, 'SPH-based', diet, exhibited]), verbo([increased]), complemento([whole, body, energy, expenditure, and, heat, dissipation])].
[sujeto(['In', skeletal, 'muscle,', expressions, of, the, peroxisome, 'proliferator-activated', receptor, 'β/δ']), verbo([target]), complemento([genes, '(', 'Cpt-1b,', 'Angptl4,', 'Adrp,', and, 'Ucp3)', were, induced])].
[sujeto(['Pharmacological', removal, of, 'BAs', by, inclusion, of, 0.5, weight, '%', cholestyramine, to, the, high, fat, 'SPH', diet, attenuated, the, reduction, in, abdominal, 'obesity,', the, reduction, in, liver, 'TAG,', and, the]), verbo([decrease]), complemento([in, nonfasted, plasma, 'TAG', and, glucose, levels])].
[sujeto(['Taken', 'together,', our, data]), verbo([provide]), complemento([evidence, that, bile, acid, metabolism, can, be, modulated, by, diet, and, that, such, modulation, may, 'prevent/ameliorate', the, characteristic, features, of, the, metabolic, syndrome])].
[sujeto(['Diet']), verbo([has]), complemento([a, great, impact, on, the, risk, of, developing, features, of, metabolic, syndrome, '(', 'MetS),', type, 2, diabetes, mellitus, '(', 'T2DM),', and, cardiovascular, diseases, '(', 'CVD)'])].
[sujeto(['PPARβ/δ']), verbo([interacts]), complemento([with, factors, such, as, nuclear, 'factor-kappa', 'B', '(', 'NF-κB)', and, regulates, the, expression, of, molecules, including, vascular, cell, adhesion, molecule, '(', 'VCAM)-1', and, intercellular, adhesion, molecule, '(', 'ICAM)-1'])].
[sujeto(['Modulation', of, 'PPARβ/δ', expression, in, hMSCs, either, using, 'GSK3787', or, hMSCs, from, different, origin]), verbo([reveals]), complemento([that, 'MSC', immunosuppressive, potential, is, inversely, correlated, with, 'Ppard', expression])].
[sujeto(['This', was, consistent, with, the, higher, capacity, of, 'PPARβ/δ(-/-)', 'MSCs', to]), verbo([inhibit]), complemento([both, the, proliferation, of, 'T', 'lymphocytes,', in, 'vitro,', and, arthritic, development, and, progression, in, 'CIA', compared, with, 'PPARβ/δ(+/+)', 'MSCs'])].
[sujeto(['When', primed, with, proinflammatory, cytokines, to, exhibit, an, immunoregulatory, 'phenotype,', 'PPARβ/δ(-/-)', 'MSCs']), verbo([expressed]), complemento([a, higher, level, of, mediators, of, 'MSC', immunosuppression, including, 'VCAM-1,', 'ICAM-1', and, nitric, oxide, '(', 'NO)', than, 'PPARβ/δ(+/+)', 'MSCs'])].
[sujeto(['The']), verbo([enhanced]), complemento(['NO2', production, by, 'PPARβ/δ(-/-)', 'MSCs', was, due, to, the, increased, retention, of, 'NF-κB', p65, subunit, on, the, κB, elements, of, the, inducible, nitric, oxide, synthase, promoter, resulting, from, 'PPARβ/δ', silencing])].
[sujeto(['Thus,', the, regulation, of, 'PPARβ/δ', expression]), verbo([provides]), complemento([a, new, strategy, to, generate, therapeutic, 'MSCs', with, a, stable, regulatory, phenotype])].
[sujeto(['Polymorphism', of, rs2016520, in, gene, 'PPARD']), verbo([has]), complemento([been, associated, with, lipid, 'metabolism,', 'obesity,', metabolic, syndrome, and, type, 2, diabetes, mellitus, '(', 'T2DM)'])].
[sujeto(['Moreover,', rs2016520, polymorphism, was]), verbo([associated]), complemento([with, 'FPG', '(', 'β=-0'])].
[sujeto([5, ')', ',', it, was, also]), verbo([associated]), complemento([with, indices, of, insulin, resistance, '(', 'HOMA-IR,', 'β=-0'])].
[sujeto(['In', 'addition,', we, observed, that, the, allele, 'G', was, also]), verbo([associated]), complemento([with, lower, 'SBP', '(', 'β=-1'])].
[sujeto(['However,', the, minor, allele, 'G', was, not]), verbo([associated]), complemento([with, risk, of, metabolic, disorders, including, 'prediabetes,', 'overweight,', hypertension, and, metabolic, syndrome])].
[sujeto(['Polymorphism', of, rs2016520, in, gene, 'PPARD', was]), verbo([associated]), complemento([with, benign, metabolic, traits, in, a, large, cohort, of, 'Chinese', adults])].
[sujeto(['The', 'G', allele, may]), verbo([confer]), complemento([protection, from, type, 2, diabetes, and, hypertension, in, 'Han', 'Chinese'])].
[sujeto(['Huntington\'s', disease, '(', 'HD)', is, a, progressive, neurodegenerative, disorder]), verbo([caused]), complemento([by, a, 'CAG', trinucleotide, repeat, expansion, in, the, huntingtin, '(', 'HTT)', 'gene,', which, encodes, a, polyglutamine, tract, in, the, 'HTT', protein])].
[sujeto(['We']), verbo([found]), complemento([that, peroxisome, 'proliferator-activated', receptor, delta, '(', 'PPAR-δ)', interacts, with, 'HTT', and, that, mutant, 'HTT', represses, 'PPAR-δ-mediated', transactivation])].
[sujeto(['Expression', of, 'dominant-negative', 'PPAR-δ', in, the, central, nervous, system, of, mice, was, sufficient, to]), verbo([induce]), complemento([motor, 'dysfunction,', 'neurodegeneration,', mitochondrial, abnormalities, and, transcriptional, alterations, that, recapitulated, 'HD-like', phenotypes])].
[sujeto(['In', mouse, models, of, 'HD,', pharmacologic, activation, of, 'PPAR-δ', using, the, agonist, 'KD3010', improved, motor, 'function,', reduced, neurodegeneration, and]), verbo([increased]), complemento([survival])].
[sujeto(['To', explore, the, effects, of, serum, from, patients, with, ankylosing, spondylitis, on, the, canonical, 'Wnt/β-catenin', pathway, and, to, assess, whether, the, serum]), verbo([has]), complemento([an, osteogenic, effect, in, 'MG63', cells])].
[sujeto(['No', associations, were]), verbo([found]), complemento([between, the, expression, of, the, five, genes, and, the, patient, demographics, and, clinical, assessments, '(', all, 'p&gt;0'])].
[sujeto(['Serum', from, ankylosing, spondylitis, patients]), verbo([increases]), complemento(['PPARD,', 'fra-1,', 'MMP7,', 'OPG', and, 'RANKL', expression, and, the, 'OPG/RANKL', ratio, in, 'MG63', 'cells;', these, effects, may, be, due, to, the, stimulatory, effect, of, the, serum, on, the, 'Wnt', pathway])].
[sujeto(['Functional', analysis, of, the, four, haplotypes, showed, that, the, transcriptional, activity, of, the, 'PPARD', promoter, fragment, carrying, haplotype, 'AC', was, significantly, lower, than, that, of, the, other, haplotypes, in, 3, 'T3-L1,', 'C2C12', and, 'PK-15', 'cells,', and, haplotype, 'AC', had, the, lowest]), verbo([binding]), complemento([capacities, to, the, nuclear, extracts])].
[sujeto(['Transcription', factor, 7, -, like, 2, '(', 'TCF7L2)']), verbo([enhanced]), complemento([the, transcription, activities, of, promoter, fragments, of, 'PPARD', gene, carrying, haplotypes, 'GT,', 'GC', and, 'AT', in, 'C2C12', and, 3, 'T3-L1', 'cells,', and, increased, the, protein, expression, of, 'PPARD', gene, in, 'C2C12', myoblasts])].
[sujeto(['TCF7L2', differentially]), verbo([bound]), complemento([to, the, four, 'haplotypes,', and, the, binding, capacity, of, 'TCF7L2', to, haplotype, 'AC', was, the, lowest])].
[sujeto(['These', results, strongly]), verbo([suggested]), complemento([that, the, 'SNPs', in, 5, '\'', regulatory, region, of, 'PPARD', genes, had, significant, impact, on, pig, fat, deposition, traits])].
[sujeto(['Gene', expression, profiling]), verbo([has]), complemento([offered, new, insights, into, postmortem, molecular, changes, associated, with, meat, quality])].
[sujeto([5, ')', ',']), verbo([suggesting]), complemento([no, altered, purity, of, total, 'RNA'])].
[sujeto(['Apart', from, a, slight]), verbo([decrease]), complemento([in, the, 28, 's:18s', ribosomal, 'RNA', ratio, in, 1.5, h, samples, '(', 'p&lt;0'])].
[sujeto(['Abundance', of, reference, genes, encoding, 'beta-actin', '(', 'ACTB),', glyceraldehyde, 3, -, phosphate, dehydrogenase, '(', 'GAPDH),', 'hypoxanthine-guanine', phosphoribosyltransferase, '(', 'HPRT),', peptidylprolylisomerase, 'A', '(', 'PPIA)', and, 'TATA', 'box-binding', protein, '(', 'TBP)', as, well, as, 'meat-quality']), verbo([associated]), complemento([genes, '(', 'insulin-like', growth, factor, 1, '(', 'IGF1),', pyruvate, dehydrogenase, kinase, isozyme, 4, '(', 'PDK4),', and, peroxisome, 'proliferator-activated', receptor, delta, '(', 'PPARD)', were, investigated, using, qPCR])].
[sujeto(['The', findings]), verbo([suggest]), complemento([an, adverse, effect, of, a, prolonged, postmortem, duration, on, reliability, of, transcript, quantification, in, chicken, skeletal, muscle])].
[sujeto(['PPARD', encodes, peroxisome, 'proliferator-activated', 're-ceptor', 'delta,', which]), verbo([has]), complemento([been, shown, to, play, an, important, role, in, 'control-ling', lipid, metabolism, and, atherosclerosis])].
[sujeto(['Analysis', by, age]), verbo([suggested]), complemento([that, the, 'G-allele', decreased, 'CHD', risk, by, 14.8, '%', in, ages, greater, than, 65, years, '(', 'χ(2)', =, 4.446, ',', 'P', =, 0.035, ',', 'OR', =, 0.852, ',', 95, '%', 'CI', =, 0.684, -, 1.06, ')'])].
[sujeto(['We']), verbo([found]), complemento([that, the, 'PPARD', 'rs2016520-GG', genotype, decreased, 'CHD', risk, in, a, 'Han', 'Chinese', population])].
[sujeto(['Moreover,', we]), verbo([found]), complemento([an, association, between, serum, 'high-density', lipoprotein, cholesterol, level, and, 'PPARD', rs2016520, in, senior, individuals, aged, '≥', 65, years])].
[sujeto(['The', 'meta-analysis', revealed, no, association, between, 'PPARD', rs2016520, and, 'CHD,']), verbo([suggesting]), complemento([ethnic, differences, in, the, association, between, the, 'PPARD', locus, and, 'CHD'])].
[sujeto(['We', explored, the, effects, of, 'β-aminoisobutyric', acid, '(', 'BAIBA)', on, 'hyperlipidaemic-condition-induced', insulin, resistance, and, inflammation, as]), verbo([mediated]), complemento([through, a, signalling, pathway, involving, 'AMP-activated', protein, kinase, '(', 'AMPK)', and, peroxisome, 'proliferator-activated', receptor, δ, '(', 'PPARδ)'])].
[sujeto(['Inflammation', and, the, expression, of, genes]), verbo([associated]), complemento([with, insulin, signalling, were, determined, by, western, blot, and, quantitative, 'real-time', 'PCR'])].
[sujeto(['In', 'addition,', 'BAIBA', treatment, reversed, 'HFD-induced']), verbo([increases]), complemento([in, body, weight, and, improved, impaired, glucose, tolerance, in, mice])].
[sujeto(['In', vitro, and, in, 'vivo,', inhibitory, κBα, '(', 'IκBα)', 'phosphorylation,']), verbo([nuclear]), complemento([factor, κB, '(', 'NFκB)', nuclear, translocation, and, downstream, inflammatory, cytokines, were, significantly, suppressed, by, 'BAIBA'])].
[sujeto(['Furthermore,', 'BAIBA', treatment, significantly]), verbo([induced]), complemento(['AMPK', phosphorylation, and, expression, of, 'PPARδ', in, 'C2C12', myocytes, and, in, skeletal, muscle, of, mice])].
[sujeto(['BAIBA', significantly]), verbo([induced]), complemento([the, expression, of, genes, associated, with, fatty, acid, 'oxidation,', such, as, carnitine, palmitoyltransferase, 1, '(', 'Cpt1),', 'acyl-CoA', oxidase, '(', 'Aco;', also, known, as, 'Acox1)', and, fatty, acid, binding, protein, 3, '(', 'Fabp3);', this, effect, of, 'BAIBA', was, significantly, reduced, by, compound, 'C', and, 'Pparδ', siRNA])].
[sujeto(['These', results, are, the, first, to, demonstrate, that, 'BAIBA', attenuates, insulin, 'resistance,']), verbo([suppresses]), complemento([inflammation, and, induces, fatty, acid, oxidation, via, the, 'AMPK-PPARδ', pathway, in, skeletal, muscle])].
[sujeto(['The', peroxisome, 'proliferator-activated', receptors, '(', 'PPARs)', are, a, group, of]), verbo([nuclear]), complemento([receptors, that, function, as, transcription, factors, regulating, the, expression, of, genes, involved, in, cellular, 'differentiation,', 'development,', metabolism, and, also, tumorigenesis])].
[sujeto(['Three', 'PPAR', isotypes, '(', 'α,', 'β/δ', and, 'γ)']), verbo([have]), complemento([been, 'identified,', among, which, 'PPARβ/δ', is, the, most, difficult, to, functionally, examine, due, to, its, 'tissue-specific', diversity, in, cell, fate, 'determination,', energy, metabolism, and, housekeeping, activities])].
[sujeto(['PPARβ/δ']), verbo([acts]), complemento([both, in, a, 'ligand-dependent', and, -, independent, manner])].
[sujeto(['Recently,', new, global, approaches, to, the, study, of]), verbo([nuclear]), complemento([receptors, have, made, it, possible, to, evaluate, their, molecular, activity, in, a, more, systemic, 'fashion,', rather, than, deeply, digging, into, a, single, 'pathway/function'])].
[sujeto(['The', +, 294, 'T/C', polymorphism, in, the, peroxisome, 'proliferator-activated', receptor, delta, '(', 'PPARD)', gene, is]), verbo([associated]), complemento([with, hyperlipidemia, in, several, younger, 'populations,', but, results, are, still, inconsistence, across, ethnic, groups, and, its, possible, impact, on, the, lipid, profiles, of, 'long-lived', individuals, remains, unexploited])].
[sujeto(['Genotyping', of, 'PPARD', +, 294, 'T/C', polymorphism, was, conducted, in, 505, 'long-lived', inhabitants, '(', aged, 90, and, 'above,', 'long-lived', 'group,', 'LG)', and, 468, healthy, controls, '(', aged, 60, -, 75, ',', 'non-long-lived', 'group,', 'non-LG)']), verbo([recruited]), complemento([from, 'Bama', area])].
[sujeto(['No', difference, in, allelic, and, genotypic, frequencies, was]), verbo([found]), complemento([between, the, two, groups, '(', 'P&gt;0'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, there, were, different, impact, patterns, of, 'PPARD', +, 294, 'T/C', polymorphism, on, lipid, profiles, between, 'long-lived', cohort, and, average, population, in, 'Bama', area, and, this, may, be, one, of, the, genetic, bases, of, its, longevity])].
[sujeto(['The', 'PPARD', polymorphisms, were, shown, to, be]), verbo([associated]), complemento([with, circulating, lipoprotein, metabolism, in, various, diseases])].
[sujeto(['Under', the, recessive, 'model,', 'PPARD', rs2016520, was, shown, to, be]), verbo([associated]), complemento([with, the, risk, of, 'ICH', '(', 'P=0'])].
[sujeto(['Additionally,', we, also]), verbo([found]), complemento([that, the, levels, of, 'TC', and, 'LDL-C', were, significantly, higher, in, participants, with, brain, diseases, than, in, the, controls, '(', 'TC:', 'P&lt;0'])].
[sujeto(['DG172', also]), verbo([inhibited]), complemento([the, expression, of, transcription, factors, driving, granulocytic, differentiation, '(', 'Cebpe,', 'Gfi1,', and, 'Klf5),', and, increased, the, levels, of, transcription, factors, promoting, 'macrophage/DC', differentiation, '(', 'Irf4,', 'Irf8,', 'Spib,', and, 'Spic)'])].
[sujeto(['DG172', exerted, these, effects, only, at, an, early, stage, of, 'BMC', differentiation]), verbo([induced]), complemento([by, 'GM-CSF,', did, not, affect, 'macrophage-colony-stimulating', 'factor-triggered', differentiation, to, macrophages, and, had, no, detectable, 'PPARβ/δ-independent', effect, on, other, cell, types, tested])].
[sujeto(['Structure-function', analyses, demonstrated, that, the, 4, -, methylpiperazine, moiety, in, 'DG172', is]), verbo([required]), complemento([for, its, effect, on, 'DC', 'differentiation,', but, is, dispensable, for, 'PPARβ/δ', binding])].
[sujeto(['Based', on, these, data, we, developed, a, new, 'compound,', '(', 'Z)-2-(4-chlorophenyl)-3-[4-(4-methylpiperazine-1-yl)phenyl]acrylonitrile', '(', 'DG228),', which]), verbo([enhances]), complemento(['DC', differentiation, in, the, absence, of, significant, 'PPARβ/δ', binding])].
[sujeto(['In', 'pig,', limb, bone, length, influences, ham, yield, and, body, height, to, a, great, extent, and]), verbo([has]), complemento([important, economic, implications, for, pig, industry])].
[sujeto(['The', aim, of, this, study, was, to, detect, potential, genetic, variants]), verbo([associated]), complemento([with, porcine, limb, bone, length])].
[sujeto(['A', 'genome-wide', association, study, was, performed, by, applying, the, previously]), verbo([reported]), complemento([approach, of, 'genome-wide', rapid, association, using, mixed, model, and, regression])].
[sujeto(['Analysis', of, the, 15, annotated, genes, that, were, identified, in, these, three, haplotype, blocks, indicated, that, 'HMGA1', and, 'PPARD,', which, are]), verbo([expressed]), complemento([in, limbs, and, influence, chondrocyte, cell, growth, and, 'differentiation,', could, be, considered, as, relevant, biological, candidates, for, limb, bone, length, in, 'pig,', with, potential, applications, in, breeding, programs])].
[sujeto(['Recent', studies]), verbo([have]), complemento([described, the, importance, of, 'PPARD', in, regulating, the, secretion, and, resistance, of, insulin])].
[sujeto(['No', significant, difference, was]), verbo([found]), complemento([in, either, allelic, frequency, '(', 'P&nbsp;=&nbsp;0'])].
[sujeto(['However,', 'T2DM', patients, carrying, genotype, 'TC', showed, a, significantly, lower]), verbo([increase]), complemento([in, postprandial, serum, insulin, '(', 'mU/L)', than, those, with, 'wild-type', 'TT', '(', 'P&nbsp;&lt;&nbsp;0'])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'PPARD', rs2016520, polymorphism, might, influence, the, therapeutic, effect, of, repaglinide, rather, than, 'T2DM', susceptibility, in, 'Chinese', 'Han', 'T2DM', patients])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, delta, '(', 'Ppard)', activation]), verbo([has]), complemento([been, implicated, in, regulating, a, multitude, of, biological, processes, in, placental, development])].
[sujeto(['Ingenuity', 'Pathway', 'Analysis', '(', 'IPA)', showed, that, phosphatidylethanolamine, biosynthesis, and, glycolysis, were, the, top, two, altered, metabolic, pathways]), verbo([involved]), complemento([in, carbohydrate, 'metabolism,', energy, 'production,', and, lipid, metabolism])].
[sujeto(['Subsequent', immunoblotting, experiments]), verbo([provided]), complemento([evidence, for, positive, correlation, of, 'PPARD', level, and, 'AKT', and, 'ERK', signaling, pathways, upon, 'GW501516', treatment])].
[sujeto(['Furthermore,', the, stimulation, of, 'GW501516']), verbo([increased]), complemento([trophoblast, cell, fusion, gene, 'syncytin-A', '(', 'Syna),', but, not, 'syncytin-B', '(', 'Synb),', 'expression,', suggesting, a, potential, role, of, 'Ppard', activation, in, promoting, cytotrophoblast, differentiation])].
[sujeto(['Our', results]), verbo([reveal]), complemento([that, 'Ppard', activation, elicits, dramatic, changes, of, the, metabolic, activities, in, 'placenta,', which, is, correlated, to, 'AKT', and, 'ERK', signaling])].
[sujeto(['Valproic', acid, '(', 'VPA)', is, a, widely, used, anticonvulsant, and, 'mood-stabilizing', drug, whose, use, is, often]), verbo([associated]), complemento([with, 'drug-induced', weight, gain])].
[sujeto(['Treatment', with, 'VPA']), verbo([has]), complemento([been, shown, to, upregulate, 'Wfs1', expression, in, vitro])].
[sujeto(['We', identified, 42, genes, affected, by, 'Wfs1', 'genotype,', 10, genes]), verbo([regulated]), complemento([by, 'VPA', 'treatment,', and, 9, genes, whose, regulation, by, 'VPA', was, dependent, on, genotype])].
[sujeto(['Among', the, genes, that, were]), verbo([regulated]), complemento([differentially, by, 'VPA', depending, on, genotype, was, peroxisome, 'proliferator-activated', receptor, delta, '(', 'Ppard),', whose, expression, was, upregulated, in, response, to, 'VPA', treatment, in, 'WT,', but, not, in, 'Wfs1', 'KO', mice])].
[sujeto(['Importantly,', 'PPARδ', is]), verbo([required]), complemento([for, dextran, sodium, sulfate, induction, of, proinflammatory, 'mediators,', including, 'chemokines,', 'cytokines,', 'COX-2,', and, prostaglandin, 'E2', '(', 'PGE2),', in, vivo])].
[sujeto(['We', further, show, that, activation, of, 'PPARδ']), verbo([induces]), complemento(['COX-2', expression, in, colonic, epithelial, cells])].
[sujeto(['COX-2-derived', 'PGE2']), verbo([stimulates]), complemento([macrophages, to, produce, proinflammatory, chemokines, and, cytokines, that, are, responsible, for, recruitment, of, leukocytes, from, the, circulation, to, local, sites, of, inflammation])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'PPARδ', promotes, colonic, inflammation, and, 'colitis-associated', tumor, growth, via, the, 'COX-2-derived', 'PGE2', signaling, axis, that, mediates, 'cross-talk', between, tumor, epithelial, cells, and, macrophages])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, '(', 'PPAR)', δ]), verbo([has]), complemento([been, implicated, in, the, vascular, pathophysiology])].
[sujeto(['GW501516-activated', 'PPARδ', significantly]), verbo([inhibited]), complemento([oxidized, 'low-density', lipoprotein, '(', 'oxLDL)-triggered', migration, and, proliferation, of, vascular, smooth, muscle, cells, '(', 'VSMCs)'])].
[sujeto(['These', 'GW501516-mediated', effects, were, significantly, reversed, by, 'PPARδ-targeting', 'siRNA,', indicating, that, 'PPARδ', is]), verbo([involved]), complemento([in, the, action, of, 'GW501516'])].
[sujeto(['Anti-proliferative', effect, of, 'GW501516', was, directly, linked, to, cell, cycle]), verbo([arrest]), complemento([at, the, 'G0/G1', to, 'S', phase, 'transition,', which, was, followed, by, the, 'down-regulation', of, 'cyclin-dependent', kinase, 4, along, with, increased, levels, of, p21, and, p53])].
[sujeto(['Finally,']), verbo([gain]), complemento([or, loss, of, 'SIRT1', function, imitated, the, action, of, 'PPARδ', on, 'oxLDL-triggered', migration, and, proliferation, of, 'VSMCs'])].
[sujeto(['Taken', 'together,', these, observations, indicate, that, 'PPARδ-dependent', upregulation, of, 'SIRT1', contributes, to, the, 'anti-atherogenic', activities, of, 'PPARδ', by]), verbo([suppressing]), complemento([the, migration, and, proliferation, of, 'VSMCs', linked, to, vascular, diseases, such, as, restenosis, and, atherosclerosis])].
[sujeto(['The', 'stearoyl-CoA', desaturase, 1, '(', 'SCD1),', also, known, as, 'Δ9-desaturase,', is, a, regulatory, enzyme, in, the, cellular, lipid, modification, process, that]), verbo([has]), complemento([been, linked, to, pancreatic, cancer, and, diabetes])].
[sujeto([1, ')']), verbo([decreased]), complemento([following, treatment, with, 'PPARδ', agonist, at, both, mRNA, and, protein, 'levels,', whereas, significant, increases, were, observed, after, treatment, with, 'MEK', or, 'EGFR', inhibitor])].
[sujeto(['It', was, also]), verbo([found]), complemento([that, the, activity, index, of, 'SCD1', were, lower, '(', 'p&lt;0'])].
[sujeto(['Furthermore,', the, aforementioned, kinase, signalling, pathways, were]), verbo([involved]), complemento([in, an, inhibitory, effect, on, the, expression, and, activity, of, 'SCD1', in, these, 'cells,', possibly, via, 'PPARδ', activation])].
[sujeto(['Telmisartan,', an, angiotensin, 'II', receptor, type, 1, blocker, '(', 'ARB),', was, recently]), verbo([reported]), complemento([to, promote, lipolysis, in, mice, by, acting, as, a, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)-δ', 'activator,', although, in, clinical, 'studies,', it, has, also, been, recognized, to, activate, 'PPAR-γ', as, a, major, cause, of, its, pleiotropic, actions])].
[sujeto(['The', aim, of, this, study, was, to, investigate, whether, telmisartan]), verbo([activates]), complemento([endogenous, 'PPAR-δ', and, thereby, exerts, 'anti-fibrotic', effects, in, human, mesangial, cells, '(', 'HMC)'])].
[sujeto(['In', the, 'HMC,', both, 'GW0742,', an, authentic, 'PPAR-δ', 'agonist,', and, telmisartan]), verbo([enhanced]), complemento(['PPAR', response, element, '(', 'PPRE)-luciferase', activity, dose, 'dependently,', and, these, increases, were, blunted, by, 'GSK0660,', a, specific, 'PPAR-δ', 'antagonist,', but, not, by, 'GW9662,', a, 'PPAR-γ', antagonist])].
[sujeto(['Telmisartan', also, upregulated, the, expression, of, 'PPAR-δ']), verbo([target]), complemento([genes, related, to, fatty, acid, 'oxidation;', that, 'is,', heart, 'type-fatty', 'acid-binding', protein, and, uncoupling, 'protein-2'])].
[sujeto(['These', effects, were]), verbo([inhibited]), complemento([by, both, 'PPAR-δ', antagonism, and, 'PPAR-δ', gene, silencing])].
[sujeto(['Transforming', growth, 'factor-β1', '(', 'TGF-β1)']), verbo([increased]), complemento([the, expression, of, plasminogen, activator, 'inhibitor-1', '(', 'PAI-1),', 'TGF-β1', and, collagen, 'IV'])].
[sujeto(['Telmisartan']), verbo([suppressed]), complemento(['TGF-β1-stimulated', 'PAI-1', and, collagen, 'IV', expression, and, 'ERK', 'phosphorylation,', and, these, effects, were, weakened, by, 'PPAR-δ', 'antagonism,', whereas, 'eprosartan,', a, 'non-PPAR', activating, 'ARB,', did, not, affect, 'TGF-β1-stimulated', 'PAI-1', expression])].
[sujeto(['These', results, indicate, that, in, 'HMC', telmisartan]), verbo([activates]), complemento([endogenous, 'PPAR-δ', and, may, prevent, 'TGF-β1-induced', fibrotic, changes, by, reducing, 'ERK', phosphorylation, in, a, 'PPAR-δ-dependent', 'manner,', and, 'thus,', might, be, useful, for, treating, hypertensive, patients, with, renal, and, metabolic, disorders])].
[sujeto(['The', 'Δ6-desaturase', '(', 'Δ6D),', also, known, as, fatty, acid, desaturase, 2, ',', is, a, regulatory, enzyme, in, de, novo, fatty, acid, 'synthesis,', which]), verbo([has]), complemento([been, linked, to, obesity, and, diabetes])].
[sujeto(['The', expression, of, 'Δ6D', '(', 'P', &, 'lt;', 0.01, ')']), verbo([increased]), complemento([following, treatment, with, 'PPAR', δ, agonist, both, at, mRNA, and, protein, 'levels,', whereas, no, significant, change, was, observed, after, treatment, with, 'MEK/ERK1/2', pathway, inhibitor])].
[sujeto(['It', was, also]), verbo([found]), complemento([that, the, increase, in, the, expression, of, 'Δ6D', in, response, to, 'GW0742', was, significantly, inhibited, by, 'PD98059', '(', &, 'gt;40%,', 'P', &, 'lt;', 0.05, ')', or, 'EGF', 'receptor-selective', inhibitor, 'AG1478', '(', &, 'gt;25%,', 'P', &, 'lt;', 0.05, ')', pretreatment])].
[sujeto(['The', peroxisome, 'proliferator-activated', 'receptor-δ', '(', 'PPARδ)']), verbo([regulates]), complemento([a, multitude, of, physiological, processes, associated, with, glucose, and, lipid, 'metabolism,', 'inflammation,', and, proliferation])].
[sujeto(['One', or, more, of, these, processes, are, potential, risk, factors, for, the, ability, of, 'PPARδ', agonists, to]), verbo([promote]), complemento([tumorigenesis, in, the, mammary, gland])].
[sujeto(['Histopathologic', changes, occurred, concurrently, with, an]), verbo([increase]), complemento([in, an, 'inflammatory,', 'invasive,', 'metabolic,', and, proliferative, gene, 'signature,', including, expression, of, the, trophoblast, 'gene,', 'Plac1,', beginning, 1, week, after, 'GW501516', 'treatment,', and, remained, elevated, throughout, tumorigenesis])].
[sujeto(['The', appearance, of, malignant, changes, correlated, with, a, pronounced]), verbo([increase]), complemento([in, phosphatidylcholine, and, lysophosphatidic, acid, 'metabolites,', which, coincided, with, activation, of, 'Akt', and, mTOR, signaling, that, were, attenuated, by, treatment, with, the, mTOR, inhibitor, everolimus])].
[sujeto(['Our', findings, are, the, first, to, show, a, direct, role, of, 'PPARδ', in, the, pathogenesis, of, mammary, 'tumorigenesis,', and]), verbo([suggest]), complemento([a, rationale, for, therapeutic, approaches, to, prevent, and, treat, this, disease])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, 'beta/delta', '(', 'PPARβ/δ)', is, highly]), verbo([expressed]), complemento([in, these, 'cells,', but, its, function, in, liver, repair, remains, incompletely, understood])].
[sujeto(['We']), verbo([found]), complemento([that, 'GW501516', treatment, enhanced, the, fibrotic, response])].
[sujeto(['Compared', to, the, other, experimental, 'groups,', 'CCl4/GW501516-treated', wild, type, mice, exhibited]), verbo([increased]), complemento([expression, of, various, profibrotic, and, 'pro-inflammatory', 'genes,', such, as, those, involved, in, extracellular, matrix, deposition, and, macrophage, recruitment])].
[sujeto(['Importantly,', compared, to, healthy, 'liver,', hepatic, fibrotic, tissues, from, alcoholic, patients, showed]), verbo([increased]), complemento([expression, of, several, 'PPAR', target, 'genes,', including, 'phosphoinositide-dependent', 'kinase-1,', transforming, growth, factor, 'beta-1,', and, monocyte, chemoattractant, 'protein-1'])].
[sujeto(['GW501516']), verbo([stimulated]), complemento(['HSC', proliferation, that, caused, enhanced, fibrotic, and, inflammatory, 'responses,', by, increasing, the, phosphorylation, of, p38, and, 'c-Jun', 'N-terminal', kinases, through, the, 'phosphoinositide-3', 'kinase/protein', 'kinase-C', 'alpha/beta', mixed, lineage, 'kinase-3', pathway])].
[sujeto(['This', study, clarified, the, mechanism, underlying, 'GW501516-dependent', promotion, of, hepatic, repair, by]), verbo([stimulating]), complemento([proliferation, of, 'HSCs', via, the, p38, and, 'JNK', 'MAPK', pathways])].
[sujeto(['Aldo-keto', reductase, '(', 'AKR)', 1, 'C3', '(', type, 5, 17, 'beta-hydroxysteroid', dehydrogenase, and, prostaglandin, 'F', 'synthase),', may]), verbo([stimulate]), complemento([proliferation, via, steroid, hormone, and, prostaglandin, '(', 'PG)', metabolism, in, the, breast])].
[sujeto(['We', established, 'MCF-7', cells, that, stably]), verbo([express]), complemento(['AKR1C3', '(', 'MCF-7-AKR1C3', 'cells)', to, model, its, 'over-expression', in, breast, cancer])].
[sujeto(['AKR1C3', expression]), verbo([increased]), complemento([steroid, conversion, by, 'MCF-7', 'cells,', leading, to, a, 'pro-estrogenic', state])].
[sujeto(['AKR1C3', therefore, represents, a, potential]), verbo([target]), complemento([for, attenuating, estrogen, receptor, alpha, induced, proliferation])].
[sujeto(['Expression', of, 'AKR1C3', reduced, the, 'anti-proliferative', effects, of, 'PGD(2)', on, 'MCF-7', 'cells,']), verbo([suggesting]), complemento([that, 'AKR1C3', limits, peroxisome, proliferator, activated, receptor, gamma, '(', 'PPARgamma)', signaling, by, reducing, formation, of, 15, -, 'deoxy-Delta(12,14)-PGJ(2)', '(', 15, 'dPGJ(2))'])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, gamma, '(', 'PPARgamma)', ligands]), verbo([have]), complemento([been, shown, to, possess, 'anti-proliferative', effects, in, many, types, of, cancer])].
[sujeto(['In', clear, cell, renal, cell, carcinoma, '(', 'CCRCC),', the]), verbo([targets]), complemento([involved, in, these, effects, are, not, known])].
[sujeto(['In', this, 'study,', we, demonstrated, 'that,', in, 'CCRCC', cell, 'lines,', the, endogenous, 'PPARgamma', ligand, 15, -, 'deoxy-Delta12,14-prostaglandin', 'J2', '(', 15, 'dPGJ2)']), verbo([induces]), complemento([the, 'expression,', both, at, the, mRNA, and, the, protein, 'levels,', of, the, 'HtrA3', gene])].
[sujeto(['This', gene, belongs, to, the, 'High-Temperature', 'Requirement', 'Factor', 'A', family, of, serine, proteases, that]), verbo([repress]), complemento([signaling, by, 'TGF-beta', family, members, and, inhibit, cell, migration])].
[sujeto(['Rosiglitazone', or, 'ciglitazone,', synthetic, 'PPARgamma', 'agonists,', did, not]), verbo([induce]), complemento(['HtrA3', 'expression,', and, the, 'PPARgamma', antagonist, 'GW9662', did, not, prevent, 15, dPGJ2, 'induction,', suggesting, that, the, 'up-regulation', of, 'HtrA3', by, 15, dPGJ2, is, independent, of, 'PPARgamma'])].
[sujeto(['The', 'MEK/ERK', inhibitor, 'PD98059', dramatically]), verbo([repressed]), complemento(['HtrA3', induction])].
[sujeto(['Altogether,', these, data, indicate, that, 15, dPGJ2, is, able, to]), verbo([stimulate]), complemento([the, expression, of, 'HtrA3', through, an, indirect, mechanism, involving, the, 'MEK/ERK', pathway, but, independent, of, 'PPARgamma'])].
[sujeto(['Our', results]), verbo([provide]), complemento([a, better, understanding, of, the, mechanisms, involved, in, the, regulation, of, 'HtrA3,', a, potential, tumor, suppressor, gene])].
[sujeto(['The', peroxisome, 'proliferator-activated', receptor, delta, '(', 'PPARdelta)', is, a, 'ligand-activated,']), verbo([nuclear]), complemento([receptor, transcription, factor, that, has, a, documented, role, in, glucose, and, lipid, homeostasis])].
[sujeto(['Recent', studies]), verbo([have]), complemento([implicated, this, nuclear, receptor, in, numerous, aspects, of, oncogenesis])].
[sujeto(['We']), verbo([report]), complemento([herein, the, characterization, of, a, novel, 'small-molecule', '(', 'SR13904)', that, inhibits, 'PPARdelta', 'agonist-induced', transactivation, and, functions, as, a, 'PPARdelta', antagonist])].
[sujeto(['These', inhibitory, effects, of, 'SR13904', on, tumor, cells, were, linked, to, a, 'G(1)/S', cell, cycle, block, and]), verbo([increased]), complemento([apoptosis])].
[sujeto(['The', antitumor, activities, of, 'SR13904']), verbo([suggest]), complemento([that, antagonism, of, 'PPARdelta-mediated', transactivation, may, inhibit, tumorigenesis, and, that, pharmacological, inhibition, of, 'PPARdelta', may, be, a, potential, strategy, for, treatment, or, prevention, of, cancer])].
[sujeto(['In', addition, to, their, ability, to, improve, glucose, 'homeostasis,', 'TZDs', possess, 'anti-inflammatory', properties, and]), verbo([inhibit]), complemento([growth, of, many, 'cells,', particularly, cancerous, airway, epithelial, cells])].
[sujeto(['However,', the, functional, effects, of, 'PPARgamma', ligands, on, nonmalignant, human, bronchial, epithelial, cells]), verbo([have]), complemento([never, been, investigated])].
[sujeto(['In', the, present, 'study,', we, questioned, whether, 'PPARgamma', ligands, may]), verbo([regulate]), complemento([proliferation, of, human, bronchial, epithelial, 'cells,', and, we, studied, their, potential, molecular, mechanisms])].
[sujeto(['We']), verbo([found]), complemento([that, synthetic, 'PPARgamma', 'agonists,', rosiglitazone, '(', 'RGZ)', and, troglitazone, '(', 'TGZ),', induced, proliferation, of, human, bronchial, epithelial, 'cells,', whereas, the, endogenous, 'PPARgamma', 'ligand,', 15, -, 'deoxy-Delta(12,14)-prostaglandin', 'J(2)', '(', 15, 'd-PGJ(2)),', inhibited, cell, growth])].
[sujeto(['RGZ', and, 'TGZ', '(', 10, 'microM)']), verbo([induced]), complemento([a, rapid, and, transient, intracellular, 'Ca(2+)', mobilization, from, 'thapsigargin-sensitive', intracellular, 'stores,', whereas, 15, 'd-PGJ(2)', '(', 5, 'microM)', did, not, induce, any, 'Ca(2+)', signal])].
[sujeto(['The', 'PPARgamma', antagonist, 'GW-9662', did, not]), verbo([inhibit]), complemento([any, biological, 'responses,', but, it, reversed, the, effect, of, 15, 'd-PGJ(2)', on, cell, growth])].
[sujeto(['Downregulation', of, 'GPR40', by, 'small-interfering', 'RNA']), verbo([led]), complemento([to, a, significant, inhibition, of, 'TZD-induced', 'Ca(2+)', mobilization, and, proliferation])].
[sujeto(['This', study]), verbo([provides]), complemento([evidence, for, the, proliferative, effect, of, 'anti-diabetic', drug, 'TZDs', in, nonmalignant, human, bronchial, epithelial, cells, through, 'GPR40', receptor, 'activation,', involving, an, intracellular, 'Ca(2+)', signaling, pathway])].
[sujeto(['Peroxisome', 'proliferator-activated', 'receptor-gamma', '(', 'PPAR-gamma)', is]), verbo([expressed]), complemento([in, certain, human, cancers])].
[sujeto(['Both', 15, 'd-PGJ2', and, troglitazone]), verbo([inhibited]), complemento([proliferation, and, 'DNA', synthesis, of, prostate, cancer, cell, lines, in, a, 'dose-dependent', 'manner,', and, slightly, increased, the, proportion, of, cells, with, 'S-phase', 'DNA', content])].
[sujeto(['Prostate', specific, antigen, '(', 'PSA)', promoter, reporter, assays, showed, that, troglitazone, and, 15, 'd-PGJ2', 'down-regulated', androgen]), verbo([stimulated]), complemento([reporter, gene, activity, in, prostate, cancer, cell, lines, 'LNCaP'])].
[sujeto(['Interestingly,', 'LNCaP', with, troglitazone, dramatically]), verbo([suppressed]), complemento(['PSA', protein, expression, without, suppressing, 'AR', expression])].
[sujeto(['Taken', 'together,', these, results]), verbo([suggest]), complemento([that, 'PPAR-gamma', ligands, may, be, a, useful, therapeutic, agent, for, the, treatment, of, prostate, cancer])].
[sujeto(['PPARbeta/delta', was]), verbo([expressed]), complemento([in, all, studied, human, 'non-small', cell, lung, 'cancers,', and, strong, 'PPARbeta/delta', immunoreactivity, was, observed, in, epithelial, cells, of, more, than, 75, '%', of, studied, lung, tumors])].
[sujeto(['We']), verbo([found]), complemento([that, 'ligand-binding', activation, of, 'PPARbeta/delta', stimulates, cell, proliferation, '(', an, effect, that, was, blocked, by, a, 'dominant-negative', construct, of, 'PPARbeta/delta),', stimulates, 'anchorage-independent', cell, 'growth,', and, inhibits, apoptosis, in, lung, cancer, cell, lines])].
[sujeto(['Importantly,', the, activation, of, 'PPARbeta/delta']), verbo([induces]), complemento(['Akt', phosphorylation, correlated, with, 'up-regulation', of, 'PDK1,', 'down-regulation', of, 'PTEN,', and, increased, expression, of, 'Bcl-xL', and, 'COX-2'])].
[sujeto(['In', 'conclusion,', 'PPARbeta/delta', is, strongly]), verbo([expressed]), complemento([in, the, majority, of, lung, 'cancers,', and, its, activation, induces, proliferative, and, survival, response, in, 'non-small', cell, lung, cancer])].
[sujeto(['Agonists', of, the, peroxisome, 'proliferator-activated', receptor, alpha, '(', 'PPARalpha)', and, gamma, '(', 'gamma)', exert, 'anti-proliferative', and, 'anti-inflammatory', effects, that]), verbo([led]), complemento([to, the, testing, of, these, drugs, in, experimental, cardiac, hypertrophy])].
[sujeto(['In', this, 'paper,', an, experiment, was, conducted, to, explore, whether, 'PPARbeta/delta', activation]), verbo([has]), complemento([an, effect, on, cardiac, hypertrophy])].
[sujeto(['An', in, vitro, cardiomyocyte, hypertrophy, from, neonatal, rats, was]), verbo([induced]), complemento([with, 'Angiotensin', 'II', '(', 'Ang', 'II1micromol', x, 'L(-1))', stimulation])].
[sujeto(['This', approach]), verbo([reveals]), complemento([a, global, network, pattern, for, vascular, homeostasis, connecting, known, 'angiogenesis-related', genes, with, previously, unknown, signaling, components])].
[sujeto(['In', pancreatic, cancer, 'patients,', we, validate, the, 'transcriptome-derived', switch, of, the, identified, &, 'quot;angiogenic', 'network:&quot;', 'The', angiogenic, state, in, chronic, pancreatitis, specimens, is, intermediate, between, the, normal, '(', angiogenesis, 'off)', and, neoplastic, '(', angiogenesis, 'on)', 'condition,']), verbo([suggesting]), complemento([that, aberrant, proangiogenic, environment, contributes, to, the, increased, cancer, risk, in, patients, with, chronic, pancreatitis])].
[sujeto(['In', knockout, experiments, in, 'mice,', we, show, that, the]), verbo([targeted]), complemento([removal, of, a, hub, node, '(', peroxisome, 'proliferative-activated', receptor, 'delta)', of, the, angiogenic, network, markedly, impairs, angiogenesis, and, tumor, growth])].
[sujeto(['Further,', in, tumor, 'patients,', we, show, that, peroxisome, 'proliferative-activated', receptor, delta, expression, levels, are, correlated, with, advanced, pathological, tumor, 'stage,']), verbo([increased]), complemento([risk, for, tumor, 'recurrence,', and, distant, metastasis])].
[sujeto(['Our', results, therefore, also, may, contribute, to, the, rational, design, of, antiangiogenic, cancer, 'agents;', whereas, &, 'quot;narrow&quot;']), verbo([targeted]), complemento([cancer, drugs, may, fail, to, shift, the, robust, angiogenic, regulatory, network, toward, 'antiangiogenesis,', the, network, may, be, more, vulnerable, to, multiple, or, 'broad-spectrum', inhibitors, or, to, the, targeted, removal, of, the, identified, angiogenic, &, 'quot;hub&quot;', nodes])].
[sujeto([15, -, 'Deoxy-Delta-prostaglandin', 'J2+docetaxel', showed, a, significant]), verbo([increase]), complemento([in, apoptosis, associated, with, inhibition, of, the, 'Bcl2', and, cyclin, 'D1', expression, and, overexpression, of, caspase, and, p53, pathway, genes])].
[sujeto(['Further,']), verbo([enhanced]), complemento([expression, of, caspase, 3, and, inhibition, of, cyclin, 'D1', by, 15, -, 'deoxy-Delta-prostaglandin', 'J2+docetaxel', was, not, reversed, by, 'GW9662,', thus, suggesting, a, possible, peroxisome, 'proliferator-activated', 'receptor-gamma-independent', mechanism])].
[sujeto(['In', 'conclusion,', 15, -, 'deoxy-Delta-prostaglandin', 'J2']), verbo([enhanced]), complemento([the, 'anti-tumor', action, of, docetaxel, by, peroxisome, 'proliferator-activated', 'receptor-gamma-dependent', and, -, independent, mechanisms, mediated, by, induction, of, apoptosis])].
[sujeto(['Peroxisome', 'proliferator-activated', 'receptor-gamma,', a]), verbo([nuclear]), complemento([receptor, and, transcription, 'factor,', and, its, natural, and, synthetic, ligands, have, become, a, focus, of, novel, approaches, to, induction, of, apoptosis, in, solid, tumors, and, hematologic, 'malignancies,', including, malignant, 'B-lineage', cells])].
[sujeto(['The', effect, on, mantle, cell, 'lymphoma,', a, subtype, with, dismal, 'prognosis,']), verbo([has]), complemento([not, yet, been, analyzed])].
[sujeto(['MTT', assays, revealed, 'anti-proliferative', effects]), verbo([induced]), complemento([by, both, 15, 'd-PGJ2,', the, natural, activator, of, 'Peroxisome', 'proliferator-activated', 'receptor-gamma,', and, 'PGZ', and, 'RGZ,', synthetic, 'Peroxisome', 'proliferator-activated', 'receptor-gamma', 'ligands,', in, a, 'dose-dependent', manner])].
[sujeto(['At', a, dose, of, 50, 'micromol/l,', 15, 'd-PGJ2']), verbo([induced]), complemento([growth, inhibition, in, all, cell, lines])].
[sujeto(['At', a, dose, of, 50, 'micromol/l,', 15, 'd-PGJ2']), verbo([led]), complemento([to, apoptosis, in, all, cell, lines, '(', 87, -, 99, '%', ')', after, 48, h, of, incubation])].
[sujeto(['Data', were, analyzed, from, 9, ',', 919, individuals, who]), verbo([participated]), complemento([in, two, large, 'community-based', cohort, studies, conducted, in, 'Washington', 'County,', 'Maryland', in, 1974, '(', 'CLUE', 'I)', and, 1989, '(', 'CLUE', 'II)'])].
[sujeto(['DNA', from, blood, collected, in, 1989, was, genotyped, for, 16, 'SNPs', in, 8, 'obesity-related', 'genes:', monoamine, oxidase, 'A', '(', 'MAOA),', lipoprotein, lipase, '(', 'LPL),', paraoxonase, 1, and, 2, '(', 'PON1', and, 'PON2),', leptin, receptor, '(', 'LEPR),', tumor, necrosis, 'factor-alpha', '(', 'TNFalpha),', and, peroxisome, proliferative]), verbo([activated]), complemento(['receptor-gamma', and, -, delta, '(', 'PPARG', and, 'PPARD)'])].
[sujeto(['Findings', from, this, cohort, study]), verbo([suggest]), complemento([that, the, selected, 'SNPs', are, not, associated, with, overall, or, 'cause-specific', 'death,', although, several, 'LEPR', 'SNPs', may, be, related, to, 'BMI', and, 'BMI', change, over, time])].
[sujeto(['The', existence, of, specific, 'melatonin-binding', sites, in, lymphoid, cells]), verbo([led]), complemento([to, the, discovery, of, signal, transduction, pathway, for, melatonin, in, human, lymphocytes, and, immunomodulatory, role, of, melatonin, in, immune, cells])].
[sujeto(['In', recent, 'years,', transcriptional, regulation, of, melatonin, on, various, transcription, factors]), verbo([has]), complemento([been, demonstrated])].
[sujeto(['Of', the, more, than, twofold, upregulated, transcription, factor, 'genes,', homeo, box, 'A4', '(', 'HOXA4),', forkhead, box, 'O1A', '(', 'FOXO1A),', transcription, elongation, factor, 'B', '(', 'SIII),', polypeptide, 3, '(', 'TCEB3),', and, peroxisome, proliferative]), verbo([activated]), complemento([receptor, delta, '(', 'PPARD)', were, identified])].
[sujeto(['In', 'summary,', identification, of, these, genes, by, cDNA, microarray, analysis, in, response, to, melatonin, administration, may]), verbo([provide]), complemento([a, foundation, for, further, studies, on, the, function, of, melatonin, in, human, 'PBMCs'])].
[sujeto(['The']), verbo([expressing]), complemento([of, 'glucagon-like', 'peptide-1', receptor, '(', 'GLP-1R)', in, 'INS-1', cells, was, assessed, by, 'Western', 'blotting,', quantification, of, 'PCR,', and, was, further, confirmed, by, immunofluorescence, staining])].
[sujeto(['The', potential, of, 'PPARdelta', to]), verbo([interact]), complemento([with, homologous, 'PPRE', in, the, 'GLP-1R', gene, was, determined, by, 'Chromatin', immunoprecipitation, '(', 'ChIP)'])].
[sujeto(['Our', results, showed, that, exposure, of, 'INS-1', cells, to, palmitate, for, 24, &, 'nbsp;h']), verbo([caused]), complemento([a, significant, increase, in, cell, 'apoptosis,', which, was, inhibited, by, 'GW501516'])].
[sujeto(['The', 'ChIP', assay, revealed, a, direct]), verbo([binding]), complemento([of, 'PPARdelta', to, a, noncanonical, 'PPRE', motif, of, the, 'GLP-1R', gene, in, 'INS-1', cells])].
[sujeto(['Our', study]), verbo([suggested]), complemento([that, the, 'anti-apoptotic', action, of, 'PPARdelta', may, involve, its, transcriptional, regulation, of, 'GLP-1R', and, 'PI3&nbsp;K/PKB/FoxO1', signaling])].
[sujeto(['GW501516', and, possible, other, 'GW-based', strategies, may]), verbo([confer]), complemento([additional, benefit, beyond, improved, glycemic, control])].
[sujeto(['Peroxisome', 'proliferator-activated', 'receptor-β/δ', '(', 'PPARβ/δ)', is, a]), verbo([nuclear]), complemento([receptor, that, regulates, 'differentiation,', 'inflammation,', lipid, 'metabolism,', extracellular, matrix, 'remodeling,', and, angiogenesis, in, multiple, tissues])].
[sujeto(['These', pathways, are, also, central, to, the, pathogenesis, of, 'age-related', macular, degeneration, '(', 'AMD),', the]), verbo([leading]), complemento([cause, of, vision, loss, globally])].
[sujeto(['PPARβ/δ', is]), verbo([expressed]), complemento([and, can, be, activated, in, 'AMD', vulnerable, 'cells,', including, retinal, pigment, epithelial, '(', 'RPE)', and, choroidal, endothelial, cells])].
[sujeto(['Further,', 'PPARβ/δ', knockdown]), verbo([modulates]), complemento(['AMD-related', pathways, selectively])].
[sujeto(['Specifically,', genetic, ablation, of, 'Pparβ/δ', in, aged, mice, resulted, in, exacerbation, of, several, phenotypic, features, of, early, dry, 'AMD,', but, attenuation, of, experimentally]), verbo([induced]), complemento([choroidal, neovascular, '(', 'CNV)', lesions])].
[sujeto(['Antagonizing', 'PPARβ/δ', in, both, in, vitro, angiogenesis, assays, and, in, the, in, vivo, experimentally]), verbo([induced]), complemento(['CNV', 'model,', inhibited, angiogenesis, and, angiogenic, 'pathways,', while, ligand, activation, of, 'PPARβ/δ,', in, 'vitro,', decreased, 'RPE', lipid, 'accumulation,', characteristic, of, dry, 'AMD'])].
[sujeto(['This', study, demonstrates, for, the, first, 'time,', selective, regulation, of, a]), verbo([nuclear]), complemento([receptor, in, the, eye, and, establishes, that, selective, targeting, of, 'PPARβ/δ', may, be, a, suitable, strategy, for, treatment, of, different, clinical, 'sub-types', of, 'AMD'])].
[sujeto(['Leucine']), verbo([modulates]), complemento([synthetic, and, degradative, pathways, in, 'muscle,', possibly, providing, metabolic, benefits, for, both, athletes, and, diseased, populations])].
[sujeto(['Leucine']), verbo([has]), complemento([become, popular, among, athletes, for, improving, performance, and, body, 'composition,', however, little, is, known, about, the, metabolic, effects, of, the, commonly, consumed, 'leucine-derived', metabolite, 'β-hydroxy-β-methyl', butyrate, '(', 'HMB)'])].
[sujeto(['Contrary', to, 'leucine\'s', stimulatory, effect, on, 'metabolism,', 'HMB-treated', cells, exhibited, significantly, reduced, regulators, of, lipid, oxidation, including, peroxisome, 'proliferator-activated', receptor, alpha, '(', 'PPARα)', and, 'PPARβ/δ,', as, well, as, downstream]), verbo([target]), complemento([carnitine, palmitoyl, 'transferase,', without, alterations, in, glucose, or, palmitate, oxidation])].
[sujeto(['Furthermore,', 'HMB', significantly]), verbo([inhibited]), complemento([activation, of, the, master, regulator, of, 'energetics,', 'AMP-activated', protein, kinase])].
[sujeto(['Additionally,', 'HMB', treatment, amplified, markers, of, lipid, biosynthesis, '(', 'PPARγ', and, fatty, acid, 'synthase)', as, well, as, consistently]), verbo([promoted]), complemento([elevated, total, lipid, content, versus, control, cells])].
[sujeto(['Collectively,', our, results, demonstrate, that, 'HMB', did, not, improve, mitochondrial, metabolism, or, 'content,', and, may]), verbo([promote]), complemento([elevated, cellular, lipid, content, possibly, through, heightened, 'PPARγ', expression])].
[sujeto(['These', observations]), verbo([suggest]), complemento([that, 'HMB', may, be, most, beneficial, for, populations, interested, in, stimulating, anabolic, cellular, processes])].
[sujeto(['Leptin,', an, 'adipocyte-derived', 'hormone,']), verbo([promotes]), complemento([liver, fibrogenesis, and, inhibits, the, expression, of, 'peroxisome-proliferator', activated, receptor, γ, '(', 'PPARγ),', a, key, transcription, factor, in, inhibition, of, hepatic, stellate, cell, '(', 'HSC)', 'activation,', in, 'HSCs'])].
[sujeto(['Results', demonstrated, that, 'sex-determining', region, 'Y-box', 9, '(', 'Sox9)', could]), verbo([bind]), complemento([to, a, site, around, -, 2275, within, leptin, response, region, of, 'PPARγ1', promoter, and, inhibited, 'PPARγ1', expression])].
[sujeto(['Leptin']), verbo([stimulated]), complemento(['Sox9', expression, and, 'Sox9', binding, to, 'PPARγ1', promoter])].
[sujeto(['The', signaling, pathways, of, 'NADPH', 'oxidase,', 'β-catenin,', and, 'delta-like', homolog1, '(', 'DLK1)']), verbo([mediated]), complemento([leptin, upregulation, of, 'Sox9', expression])].
[sujeto(['These', results, might, deepen, understanding, of, the, molecular, mechanisms, for, leptin, inhibition, of, 'PPARγ1', expression, in, 'HSCs', and, for, the, liver, fibrosis]), verbo([associated]), complemento([with, leptin])].
[sujeto(['The', 'PPAR']), verbo([nuclear]), complemento([receptor, family, has, acquired, great, relevance, in, the, last, 'decade,', which, is, formed, by, three, different, isoforms, '(', 'PPARα,', 'PPARβ/δ,', and, 'PPAR', 'ϒ)'])].
[sujeto(['Those']), verbo([nuclear]), complemento([receptors, are, members, of, the, steroid, receptor, superfamily, which, take, part, in, essential, metabolic, and, 'life-sustaining', actions])].
[sujeto(['Specifically,', 'PPARG']), verbo([has]), complemento([been, implicated, in, the, regulation, of, processes, concerning, 'metabolism,', 'inflammation,', 'atherosclerosis,', cell, 'differentiation,', and, proliferation])].
[sujeto(['Thus,', a, considerable, amount, of, literature]), verbo([has]), complemento([emerged, in, the, last, ten, years, linking, 'PPARG', signalling, with, metabolic, conditions, such, as, obesity, and, 'diabetes,', cardiovascular, 'disease,', 'and,', more, 'recently,', cancer])].
[sujeto(['PPAR', agonists]), verbo([have]), complemento([been, shown, to, control, inflammatory, 'processes,', in, part, by, inhibiting, the, expression, of, distinct, proinflammatory, genes, such, as, vascular, cell, adhesion, 'molecule-1', '(', 'VCAM-1),', 'IL-8,', and, intercellular, adhesion, 'molecule-1', '(', 'ICAM-1)'])].
[sujeto(['To', 'date,', the, influence, of, 'PPARα', and, δ, activators, on, the, expression, of, 'ICAM-1', in, 'non-induced,', quiescent, endothelial, cells]), verbo([has]), complemento([been, unclear])].
[sujeto(['We']), verbo([found]), complemento([that, 'PPARα', and, 'PPARδ', agonists, significantly, induced, 'ICAM-1', 'surface,', intracellular, 'protein,', and, mRNA, expression, in, a, time, and, 'concentration-dependent', manner])].
[sujeto(['The', 'PPARδ']), verbo([induced]), complemento(['ICAM-1', expression, could, be, paralleled, with, a, significantly, increased, 'T-cell', adherence, to, the, endothelial, cells, whereas, 'PPARα', failed, to, do, so])].
[sujeto(['Transcriptional', activity, studies, using, an, 'ICAM-1', reporter, gene, constructs, revealed, that, 'PPARδ,', but, not, 'PPARα', agonists]), verbo([induced]), complemento([gene, expression, by, stimulating, 'ICAM-1', promoter, activity, via, an, 'Sp1', transcription, factor, binding, site, and, inhibit, the, binding, of, the, transcription, factors, 'Sp1', and, 'Sp3'])].
[sujeto(['Furthermore,', we, performed, mRNA, stability, assays, and]), verbo([found]), complemento([that, 'PPARα', and, 'PPARδ', agonists, increased, 'ICAM-1', mRNA, stability])].
[sujeto(['Therefore,', our, data]), verbo([provide]), complemento([the, first, evidence, that, 'PPARα', and, 'PPARδ', agonists, induce, 'ICAM-1', expression, in, 'non-stimulated', endothelial, cells, via, transcriptional, and, posttranscriptional, mechanisms])].
[sujeto(['In', human, 'sebocytes,', 'TCDD', and, 'BaP', were]), verbo([found]), complemento([to, activate, the, expression, of, multiple, 'genes,', including, cytochrome, 'P450', 1, 'A1', '(', 'CYP1A1),', and, inhibit, lipid, synthesis, via, 'AhR,', while, little, is, known, about, endogenous, functions, of, the, 'AhR'])].
[sujeto(['In', order, to, expand, this, 'knowledge,', we, analyzed, the, impact, of, 'AhR', knockdown, on, lipid, synthesis, as, well, as, on, cell, differentiation, of, 'SZ95', sebocytes, 'in&nbsp;vitro', and, observed, that, lipid, synthesis, was, significantly]), verbo([induced]), complemento([in, 'AhR', silenced, 'SZ95', sebocytes])].
[sujeto(['In', line, with, this, 'result,', expression, of, 'lipogenesis-associated', 'genes,', such, as, peroxisome, proliferator]), verbo([activated]), complemento([receptor, '(', 'PPAR)', δ, and, 'PPARγ,', was, increased])].
[sujeto(['Morphological', changes, with, smaller, cells, in, size, but, more, abundant, cytoplasmic, lipids, were, observed, in, 'AhR', silenced, 'SZ95', sebocytes, compared, with, the, 'AhR']), verbo([activated]), complemento([cells])].
[sujeto(['To', the, best, of, our, 'knowledge,', we]), verbo([provide]), complemento([evidence, that, in, the, absence, of, exogenous, 'ligands,', the, 'AhR', inhibits, lipid, synthesis, and, involves, in, cell, differentiation, of, human, 'SZ95', 'sebocytes,', which, indicates, the, physiological, function, of, this, receptor, in, human, sebocytes])].
[sujeto(['Peroxisome', proliferator]), verbo([activated]), complemento([receptors, '(', 'PPARs)', are, transcription, factors, involved, in, the, regulation, of, key, metabolic, pathways])].
[sujeto(['Numerous', in, vivo, and, in, vitro, studies]), verbo([have]), complemento([established, their, important, roles, in, lipid, metabolism])].
[sujeto(['A', few, 'SNPs', in, 'PPAR', genes]), verbo([have]), complemento([been, reported, to, be, associated, with, lipid, levels])].
[sujeto(['The', present, study, showed, a, novel, 'SNP', ×, 'SNP', interaction, between, rs2267668, in, 'PPARδ', and, rs7191411, in, 'EMP2', that]), verbo([has]), complemento([significant, impact, on, circulating, 'HDL-C', levels, in, the, 'Singaporean', 'Chinese', population])].
[sujeto(['T3D-959', is, a, dual]), verbo([nuclear]), complemento([receptor, agonist, currently, in, a, 'Phase', 2, a, trial, in, 'mild-to-moderate', 'AD', patients, '(', 'ClinicalTrials'])].
[sujeto(['T3D-959\'s']), verbo([targeting]), complemento(['neuro-metabolic', dysfunctions, via, agonism, of, 'PPAR', delta, and, 'PPAR', gamma, nuclear, receptors, provides, potential, disease, modification, in, 'AD'])].
[sujeto(['Despite', the, known, risk, of, 'diabetes-induced', cardiac, 'fibrosis,', less, is, known, about, whether, diabetes]), verbo([causes]), complemento([an, altered, cardiac, phenotype, independent, of, coronary, atherosclerosis])].
[sujeto(['Herein', we, investigated, the, effectiveness, of, 'telmisartan,', a, unique, angiotensin, receptor, blocker, that]), verbo([increases]), complemento(['PPARδ', 'expression,', in, improving, left, ventricular, remodeling, in, diabetic, humans, and, rats])].
[sujeto(['Using', streptozotocin, to]), verbo([induce]), complemento([type, 1, diabetes, rat, 'model,', we, measured, 'PPARδ', expression, and, downstream, targets])].
[sujeto(['Compared', with, that, of, 'controls,', the, diabetic, rat, heart, developed, significant, 'fibrosis,', which, markedly]), verbo([decreased]), complemento([after, treatment, with, telmisartan, '(', 30, &, 'nbsp;mg/kg/day,', 'orally)', for, 7, &, 'nbsp;days'])].
[sujeto(['Interestingly,', the]), verbo([increased]), complemento([expression, of, 'fibrosis-associated', 'proteins,', including, signal, transducer, and, activator, of, transcription, 3, '(', 'STAT3)', was, attenuated, by, the, 'co-incubation', of, 'GW0742,', a, 'PPARδ', agonist])].
[sujeto(['By', knockdown, or, inhibition, of, 'STAT3,', the, hyperglycemia, related, high, expression, of, fibrosis]), verbo([associated]), complemento([targets, was, reversed])].
[sujeto(['Independent', from, the, hyperglycemic, 'incubation,', 'STAT3', 'over-expression']), verbo([led]), complemento([to, similar, results])].
[sujeto(['Risk', of, coronary, heart, disease, '(', 'CHD)']), verbo([has]), complemento([been, suggested, to, be, associated, with, polymorphisms, of, peroxisome, 'proliferator-activated', receptors, '(', 'PPARs),', while, the, results, were, controversial])].
[sujeto(['In', the, 'case-control', 'study,', 'T', allele, carriers, of, 'C161T', polymorphism, were, not, significantly]), verbo([associated]), complemento([with, 'CHD', risk, '(', 'Odds', ratio, '(', 'OR)', =, 0.74, ',', 95, '%', confidence, interval, '(', 'CI)', 0.47, -, 1.15, ',', 'P', =, 0.19, ')', ',', while, 'T', allele, carriers, showed, higher, risk, of, 'ACS', '(', 'OR', =, 1.63, ',', 95, '%', 'CI', 1.0, -, 2.65, ',', 'P', =, 0.048, ')'])].
[sujeto(['Three', other, polymorphisms, were, also]), verbo([found]), complemento([to, be, significantly, associated, with, 'CHD', risk, under, dominant, 'model:', 'PPAR-alpha', intron, 7, 'G/C', polymorphism, '(', 'CC+GC', vs, 'GG,', 'OR', 1.42, ',', 95, '%', 'CI', 1.13, -, 1.78, ',', 'P', =, 0.003, ')', ',', 'L162V', polymorphism, '(', 'VV+LV', vs, 'LL,', 'OR', 0.74, ',', 95, '%', 'CI', 0.56, -, 0.97, ',', 'P', =, 0.031, ')', ',', and, 'PPAR-delta', +, 294, 'T/C', polymorphism, '(', 'CC+TC', vs, 'TT,', 'OR', 1.51, ',', 95, '%', 'CI', 1.12, -, 2.05, ',', 'P', =, 0.007, ')'])].
[sujeto(['The', results]), verbo([suggested]), complemento([that, 'PPAR-alpha', intron, 7, 'G/C', and, 'L162V,', 'PPAR-delta', +, 294, 'T/C', and, 'PPAR-gamma', 'C161T', polymorphisms, could, affect, 'CHD', 'susceptibility,', and, 'C161T', polymorphism, might, have, different, effects, on, 'CHD', and, 'ACS'])].
[sujeto(['Despite', its]), verbo([increasing]), complemento(['popularity,', evaluation, methods, for, the, procedure, have, not, yet, been, fully, developed])].
[sujeto(['HIFU', treatment, effectively, reduced, abdominal, fat, in, a, porcine, 'model;', it, accurately, treated, the]), verbo([target]), complemento([subcutaneous, fat, layer, and, the, subcutaneous, fat, was, reduced, effectively, via, ultrasonic, measurement, after, 'HIFU', treatment])].
[sujeto(['On', histological, staining, '(', 'H&amp;E,', toluidine, 'blue,', oil, red, 'O', and, 'immunohistochemistry),', we]), verbo([found]), complemento([that, subcutaneous, fat, reduction, occurred, effectively, via, accurate, treatment, of, the, targeted, subcutaneous, fat, layer])].
[sujeto(['Via', carbon, tracer, 'test,', the, migration, of]), verbo([activated]), complemento([macrophages, was, identified, within, the, axillary, lymph, node, '(', 'LN)'])].
[sujeto(['PPAR-delta,', a, protein, defined, by, immunohistochemistry, 'staining,', was, overexpressed, in, the, early, stage, on, days, 1, and, 7, ',', but, a, gradual]), verbo([decreasing]), complemento([pattern, was, confirmed])].
[sujeto(['These', results]), verbo([provide]), complemento([that, the, essential, clues, toward, the, effective, 'evaluation,', guiding, selection, of, the, appropriate, diagnostic, investigations])].
[sujeto(['Exercise', training, with, 'PPARγ', agonist, is, expected, to]), verbo([increase]), complemento([glucose, uptake, and, improve, insulin, sensitivity, in, skeletal, muscle, of, patients, with, diabetes])].
[sujeto(['Glucose', uptake, and, insulin, sensitivity, was]), verbo([decreased]), complemento([in, diabetic, than, normal, animals])].
[sujeto(['Exercise', training, and, rosiglitazone, treatment, respectively]), verbo([increased]), complemento([the, expression, of, 'PPAR(peroxisome', 'proliferators-activated', 'receptor)-α,', -, 'β/δ,', -, 'γ,', 'PGC-1α(PPAR-γ', 'coactivator-1α),', 'adiponectin,', 'GLUT-4(glucose', 'transportor-4)', and, 'p-AMPK-α2(phospho-AMP', activated, protein, 'kinase-α2)', in, 'EDL', and, 'SOL', of, 'diabetic,', as, compared, to, normal, animals])].
[sujeto(['Interestingly,', training, combined, with, rosiglitazone, significantly]), verbo([increased]), complemento([glucose, uptake, and, insulin, 'sensitivity,', which, resulted, in, high, expression, of, all, molecules, in, diabetic, than, all, other, groups])].
[sujeto(['These', results, indicated, that, exercise, training, combined, with, rosiglitazone, might]), verbo([mediate]), complemento([regulation, of, glucose, uptake, and, insulin, sensitivity, in, skeletal, muscle])].
[sujeto(['β-alanine', is, a, common, component, of, numerous, sports, supplements, purported, to, improve, athletic, performance, through]), verbo([enhanced]), complemento([carnosine, biosynthesis, and, related, intracellular, buffering])].
[sujeto(['This', work, investigated, the, effects, of, 'β-alanine', on, the, expression, of, proteins, which]), verbo([regulate]), complemento([cellular, energetics])].
[sujeto(['β-alanine-treated', myotubes, displayed, significantly, elevated, markers, of, improved, oxidative, metabolism, including, elevated, peroxisome, 'proliferator-activated', receptor, 'β/δ', '(', 'PPARβ/δ)', and, mitochondrial, transcription, factor, a, '(', 'TFAM)', which]), verbo([led]), complemento([to, increased, mitochondrial, content, '(', evidenced, by, concurrent, increases, in, cytochrome, c, 'content)'])].
[sujeto(['Additionally,', 'β-alanine-treated', cells, exhibited, significantly]), verbo([increased]), complemento([oxygen, consumption, compared, to, control, in, a, 'PPARβ/δ-dependent', manner])].
[sujeto(['β-alanine', significantly]), verbo([enhanced]), complemento([expression, of, myocyte, enhancer, factor, 2, '(', 'MEF-2)', leading, to, increased, glucose, transporter, 4, '(', 'GLUT4)', content])].
[sujeto(['β-alanine', appears, to]), verbo([increase]), complemento([cellular, oxygen, consumption, as, well, as, the, expression, of, several, cellular, proteins, associated, with, improved, oxidative, 'metabolism,', suggesting, 'β-alanine', supplementation, may, provide, additional, metabolic, benefit, '(', although, these, observations, require, in, vivo, experimental, 'verification)'])].
[sujeto(['The', aim, of, this, study, was, to, examine, the, 'anti-obesity', effects, of, boiled, tuna, extract, in, 'C57BL/6N&nbsp;mice', with, obesity]), verbo([induced]), complemento([by, a, 'high-fat', 'diet&nbsp;(HFD)'])].
[sujeto(['Boiled', tuna, extract, also, attenuated, adipogenic, and, lipogenic, gene, 'expression,', namely, the, levels, of, fatty, acid, 'synthase&nbsp;(FAS),', lipoprotein, 'lipase&nbsp;(LPL),', 'acetyl-CoA', 'carboxylase&nbsp;(ACC),', glucose, transporter, 'type&nbsp;4&nbsp;(Glut4)', and]), verbo([phosphorylated]), complemento([adenosine, 'monophosphate-activated', protein, 'kinase&nbsp;α', 'and&nbsp;β&nbsp;(AMPKα,&nbsp;β)', in, a, 'dose-dependent', manner])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, boiled, tuna, extract, attenuates, the, progression, of, obesity, by, stimulating, fatty, acid, oxidation, through, the, upregulation, of, 'AMPK', 'genes,', as, well, as, by, inhibiting, the, synthesis, of, adipogenic, and, lipogenic, enzymes])].
[sujeto(['Fibroblast', growth, factor, 21, '(', 'FGF21),', a, peptide, hormone, with, pleiotropic, effects, on, carbohydrate, and, lipid, 'metabolism,', is, considered, a]), verbo([target]), complemento([for, the, treatment, of, diabetes])].
[sujeto(['Increased', 'Fgf21', was]), verbo([associated]), complemento([with, enhanced, protein, levels, in, the, 'heme-regulated', eukaryotic, translation, initiation, factor, 2, α, '(', 'eIF2α)', kinase, '(', 'HRI)'])].
[sujeto(['This']), verbo([increase]), complemento([caused, enhanced, levels, of, phosphorylated, eIF2α, and, activating, transcription, factor, '(', 'ATF)', 4, ',', which, is, essential, for, 'Fgf21-induced', expression])].
[sujeto([siRNA, analysis, demonstrated, that, 'HRI']), verbo([regulates]), complemento(['Fgf21', expression, in, primary, hepatocytes])].
[sujeto(['Interestingly,']), verbo([increased]), complemento(['Fgf21', expression, in, mice, fed, a, 'HFD', or, hepatocytes, exposed, to, palmitate, was, accompanied, by, reduced, 'PPARβ/δ', and, activation, of, the, 'HRI-eIF2α-ATF4', pathway])].
[sujeto(['Moreover,', pharmacological, activation, of, 'HRI']), verbo([increased]), complemento(['Fgf21', expression, and, reduced, 'lipid-induced', hepatic, steatosis, and, glucose, intolerance, and, these, effects, were, not, observed, in, 'Fgf21-null', mice])].
[sujeto(['Overall,', these, findings]), verbo([suggest]), complemento([that, 'HRI', is, a, potential, target, for, regulating, hepatic, 'FGF21', levels])].
[sujeto([83, b1, is, a, novel, quinoline, derivative, that]), verbo([has]), complemento([been, shown, to, inhibit, cancer, growth, in, human, esophageal, squamous, cell, carcinoma, '(', 'ESCC)'])].
[sujeto(['This', study, was, conducted, to, comprehensively, evaluate, the, cytotoxic, effects, of, 83, b1, on, a, series, of, 'ECSS', cell, lines, and, investigate, the, mechanisms, by, which, 83, b1]), verbo([suppresses]), complemento([cancer, growth, based, on, molecular, docking, analysis])].
[sujeto(['Prediction', of, the, molecular]), verbo([targets]), complemento([of, 83, b1, was, conducted, by, molecular, docking, analysis])].
[sujeto(['The', predicted, molecular]), verbo([target]), complemento([of, 83, b1, is, peroxisome, 'proliferator-activated', receptor, delta, '(', 'PPARδ),', which, is, a, widely, known, oncoprotein])].
[sujeto(['The', results, of, this, study]), verbo([suggest]), complemento([that, the, potential, 'anti-cancer', effects, of, 83, b1, on, human, esophageal, cancers, occur, through, the, possible, 'oncotarget,', 'PPARδ,', and, 'down-regulation', of, the, cancer, related, genes, and, molecules])].
[sujeto(['Peroxisome', 'proliferator-activated', receptors, '(', 'PPARs)']), verbo([regulate]), complemento([cardiac, glucose, and, lipid, homeostasis])].
[sujeto(['Histone', deacetylase, '(', 'HDAC)', inhibitor]), verbo([has]), complemento(['anti-inflammatory', effects, which, may, play, a, key, role, in, modulating, 'PPARs', and, fatty, acid, metabolism])].
[sujeto(['The', aim, of, this, study, was, to, investigate, whether, 'HDAC', 'inhibitor,', 'MPT0E014,', can]), verbo([modulate]), complemento([myocardial, 'PPARs,', 'inflammation,', and, fatty, acid, metabolism, in, diabetes, mellitus, '(', 'DM)', cardiomyopathy])].
[sujeto(['Moreover,', control, and, 'MPT0E014-treated', 'DM', rats, had, lower, concentrations, of, 5, '\'', adenosine, 'monophosphate-activated', protein, kinase, 2, 'α,', 'PPAR-γ', coactivator, 1, 'α,']), verbo([phosphorylated]), complemento([acetyl, 'CoA', 'carboxylase,', cluster, of, differentiation, 36, ',', diacylglycerol, acyltransferase, 1, '(', 'DGAT1),', 'DGAT2,', tumor, necrosis, 'factor-α,', and, 'interleukin-6', protein, than, 'DM', rats])].
[sujeto(['PPAR-alpha']), verbo([expressed]), complemento([primarily, in, liver, is, essential, for, metabolic, adaptation, to, starvation, by, inducing, genes, for, 'beta-oxidation', and, ketogenesis, to, increase, the, utility, of, 'LCFAs', and, fibroblast, growth, factor, 21])].
[sujeto(['PPAR-delta']), verbo([induces]), complemento([genes, for, 'LCFA', oxidation, during, fasting, and, endurance, exercise, in, skeletal, muscle])].
[sujeto(['PPAR-delta', also]), verbo([regulates]), complemento([glucose, metabolism, and, mitochondrial, biogenesis, by, inducing, 'FOXO1', and, 'PGC1-alpha'])].
[sujeto(['PPAR-gamma', can]), verbo([induces]), complemento([the, pathways, to, store, 'LCFAs', as, triglycerides, in, adipocytes])].
[sujeto(['Adiponectin,', another, important]), verbo([target]), complemento([of, 'PPAR-gamma', may, maintain, insulin, sensitivity, between, adipocytes])].
[sujeto(['The', present, review, summarize, that, 'PPARs']), verbo([mediate]), complemento([the, regulation, of, energy, metabolism, by, 'long-chain', fatty, acids])].
[sujeto(['Peroxisome', 'proliferator-activated', receptors, '(', 'PPARs)']), verbo([have]), complemento([demonstrated, a, lot, of, important, effects, in, the, regulation, of, glucose, and, lipid, metabolism, and, in, the, correct, functioning, of, adipose, tissue])].
[sujeto(['Recently,', many, studies]), verbo([have]), complemento([evaluated, a, possible, effect, of, 'PPARs', on, tumor, cells])].
[sujeto(['The', purpose, of, this, review, is, to, describe, the, effects, of, 'PPARs,', their, action, and, their, future, 'prospective;', 'Narrative', review, aimed, to, synthesize, 'cutting-edge', evidence, retrieved, from, searches, of, computerized, 'databases;', 'PPARs', play, a, key, role, in, metabolic, 'diseases,', which, include, several, cardiovascular, 'diseases,', insulin, 'resistance,', type, 2, 'diabetes,', metabolic, 'syndrome,', impaired, immunity, and, the]), verbo([increasing]), complemento([risk, of, 'cancer;', in, 'particular,', 'PPARα', and, 'PPARβ/δ', mainly, enable, energy, 'combustion,', while, 'PPARγ', contributes, to, energy, storage, by, enhancing, 'adipogenesis;', 'PPAR', agonists, could, represent, interesting, types, of, molecules, that, can, treat, not, only, metabolic, 'diseases,', but, also, inflammation, and, cancer])].
[sujeto(['Leucine']), verbo([stimulates]), complemento([anabolic, and, catabolic, processes, in, skeletal, 'muscle,', however, little, is, known, about, the, effects, of, leucine, on, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)', activity])].
[sujeto(['Leucine', significantly]), verbo([increased]), complemento(['PPARβ/δ', expression, as, well, as, markers, of, mitochondrial, 'biogenesis,', leading, to, significantly, increased, mitochondrial, content, and, oxidative, metabolism, in, a, 'PPARβ/δ-dependent', manner])].
[sujeto(['However,', 'leucine-treated', cells, did, not, display, significant, alterations, in, uncoupling, protein, expression, or, oxygen, consumed, per, relative, mitochondrial, content]), verbo([suggesting]), complemento(['leucine-mediated', increases, in, oxidative, metabolism, are, a, function, of, increased, mitochondrial, content, and, not, altered, mitochondrial, efficiency])].
[sujeto(['Leucine', treatment, also]), verbo([increased]), complemento(['GLUT4', content, and, glucose, uptake, as, well, as, 'PPARγ', and, 'FAS', expression, leading, to, increased, total, lipid, content])].
[sujeto(['Leucine', appears, to]), verbo([activate]), complemento(['PPAR', activity, leading, to, increased, mitochondrial, biogenesis, and, elevated, substrate, 'oxidation,', while, simultaneously, promoting, 'substrate/lipid', storage, and, protein, synthesis])].
[sujeto(['PPARs']), verbo([have]), complemento([been, reported, to, be, the, therapeutic, targets, of, metabolic, 'disorders,', such, as, 'obesity,', 'hypertension,', 'diabetes,', and, cardiovascular, disease])].
[sujeto(['In', recent, 'years,', 'multitarget-directed', 'PPAR', agonists, with, synergistic, reaction, as, well, as, fewer, 'side-effect']), verbo([have]), complemento([been, the, hot, topic, in, designing, promising, agents])].
[sujeto(['Among', these, 'molecules,', some, were, expected, to, be, promising, drugs, against, metabolic, 'disorders,', while, others, seemed, to]), verbo([provide]), complemento([new, insight, for, designing, novel, 'PPAR', agents])].
[sujeto(['The']), verbo([nuclear]), complemento([receptor, peroxisome, 'proliferator-activated', 'receptor-δ/β', '(', 'PPAR-d)', is, upregulated, in, human, colorectal, 'cancers,', but, its, role, in, colonic, tumorigenesis, remains, controversial])].
[sujeto(['We', generated, a, novel, mouse, model, of, intestinally]), verbo([targeted]), complemento(['PPAR-d', overexpression, to, simulate, 'PPAR-d', upregulation, in, human, colon, carcinogenesis])].
[sujeto(['Mice', with, and, without]), verbo([targeted]), complemento(['PPAR-d', overexpression, were, tested, for, azoxymethane, '(', 'AOM)-induced', colonic, tumorigenesis])].
[sujeto(['Mouse', 'whole-genome', transcriptome, microarray, analyses, were, performed, to, identify, 'PPAR-d']), verbo([target]), complemento([genes, to, promote, tumorigenesis])].
[sujeto(['Targeted', 'PPAR-d', overexpression, markedly]), verbo([increased]), complemento([colonic, tumor, incidence, '(', from, 0, of, 10, 'wild-type', '[', 'WT]', littermate, mice, to, 9, of, 10, mice, '[', 'P', &, 'lt;'])].
[sujeto([1, ']', in, 2, 'FVB/N', background, mouse, lines, '[', 'villin-PPAR-d-1', and, 'villin-PPAR-d-2]', at, a, 5, -, 'mg/kg', 'AOM', 'dose)', and, multiplicity, '(', number, of, tumors, per, mouse, per, 'mg/kg', dose, of, 'AOM']), verbo([increased]), complemento([from, 0.47, '[', 95, '%', confidence, interval, '[', 'CI]', =, 0.22, to, 0.72, ']', for, the, 'WT', littermates, to, 2.15, '[', 95, '%', 'CI', =, 1.9, to, 2.4, ']', '[', 'P', &, 'lt;'])].
[sujeto(['PPAR-d', overexpression]), verbo([modulated]), complemento([expression, of, several, novel, 'PPAR-d', target, genes, in, 'normal-appearing', colonic, epithelial, cells, of, mice, with, 'PPAR-d', overexpression, in, a, pattern, that, matched, the, changes, in, colonic, tumors])].
[sujeto(['Our']), verbo([finding]), complemento([that, 'PPAR-d', upregulation, profoundly, enhances, susceptibility, to, colonic, tumorigenesis, should, impact, the, development, of, strategies, of, molecularly, targeting, 'PPAR-d', in, cancer, and, noncancerous, diseases])].
[sujeto(['Interindividual', differences, in, response, to, weight]), verbo([loss]), complemento([and, maintenance, thereafter, are, ascribed, to, genetic, predisposition, and, behavioral, changes])].
[sujeto(['To', examine, whether, body, weight, and, short, and, 'long-term', body, weight]), verbo([loss]), complemento([were, affected, by, candidate, single, nucleotide, polymorphisms, '(', 'SNPs)', and, changes, in, eating, behavior, or, by, an, interaction, between, these, genetic, and, behavioral, factors])].
[sujeto(['A', high, genetic, predisposition, score, was]), verbo([associated]), complemento([with, a, high, body, weight, at, baseline, and, more, 'short-term', weight, loss])].
[sujeto(['From', the, six, selected, 'obesity-related', 'SNPs,', 'FTO', was]), verbo([associated]), complemento([with, increased, body, weight, at, 'baseline,', and, the, effect, allele, of, 'PPARGC1A', was, positively, associated, with, 'short-term', weight, 'loss,', when, assessed, for, each, 'SNP', separately])].
[sujeto(['Long-term', weight]), verbo([loss]), complemento([was, associated, with, a, larger, increase, in, dietary, restraint, and, larger, decrease, in, disinhibition])].
[sujeto(['Developmental', models, of, 'GH', deficiency, '(', 'GHD)', and, excess, indicate, that, 'GH', is, positively]), verbo([associated]), complemento([with, 'β-cell', mass])].
[sujeto(['Therefore,', the, reduction, in, 'GH', levels, observed, with, age, and, weight]), verbo([gain]), complemento([may, contribute, to, the, 'age-related', decline, in, 'β-cell', function])].
[sujeto(['However,', islets, from, older, 'LF-fed', 'AOiGHD', mice, exhibited, impaired, 'GSIS,']), verbo([associated]), complemento([with, reduced, expression, of, genes, important, to, maintain, glucose, 'sensing,', suggesting, that, factors, secondary, to, 'AOiGHD', can, alter, 'β-cell', function, with, age])].
[sujeto(['AOiGHD', mice, exhibited, postprandial, hypertriglyceridemia, and]), verbo([increased]), complemento([pancreatic, expression, of, 'lipid/inflammatory', stress, response, genes, '(', activating, transcription, factor, 3, and, peroxisome, proliferator, activator, receptor, 'β/δ)'])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, delta, '(', 'PPARD)', is]), verbo([nuclear]), complemento([hormone, receptor, involved, in, colorectal, cancer, '(', 'CRC)', differentiation, and, progression])].
[sujeto(['We']), verbo([found]), complemento([7, novel, variants, among, 22, inherited, or, acquired, 'PPARD', variants])].
[sujeto(['Food', intake]), verbo([increases]), complemento([the, activity, of, hepatic, de, novo, 'lipogenesis,', which, mediates, the, conversion, of, glucose, to, fats, for, storage, or, use])].
[sujeto(['In', 'mice,', this, program, follows, a, circadian, rhythm, that, peaks, with, nocturnal, feeding, and, is]), verbo([repressed]), complemento([by, 'Rev-erbα/β', and, an, 'HDAC3-containing', complex, during, the, day])].
[sujeto(['Disturbances', in, hepatic, lipogenesis, are, also]), verbo([associated]), complemento([with, systemic, metabolic, 'phenotypes,', suggesting, that, lipogenesis, in, the, liver, communicates, with, peripheral, tissues, to, control, energy, substrate, homeostasis])].
[sujeto(['Here', we, identify, a, 'PPARδ-dependent', de, novo, lipogenic, pathway, in, the, liver, that]), verbo([modulates]), complemento([fat, use, by, muscle, via, a, circulating, lipid])].
[sujeto(['The']), verbo([nuclear]), complemento([receptor, 'PPARδ', controls, diurnal, expression, of, lipogenic, genes, in, the, 'dark/feeding', cycle])].
[sujeto(['Unbiased', metabolite, profiling, identifies, phosphatidylcholine, 18, :, 0, /, 18, :, 1, '(', 'PC(18:0/18:1)', as, a, serum, lipid]), verbo([regulated]), complemento([by, diurnal, hepatic, 'PPARδ', activity])].
[sujeto(['PC(18:0/18:1)', reduces, postprandial, lipid, levels, and]), verbo([increases]), complemento([fatty, acid, use, through, muscle, 'PPARα'])].
[sujeto(['These', findings]), verbo([reveal]), complemento([an, integrated, regulatory, circuit, coupling, lipid, synthesis, in, the, liver, to, energy, use, in, muscle, by, coordinating, the, activity, of, two, closely, related, nuclear, receptors])].
[sujeto(['Recent']), verbo([reports]), complemento([have, shown, that, peroxisome, 'proliferator-activated', receptor, delta, '(', 'PPARD)', plays, an, important, role, in, different, vascular, processes, suggesting, that, 'PPARD', is, a, significant, modulator, of, cardiovascular, disease])].
[sujeto(['Mouse', studies]), verbo([suggest]), complemento([that, 'Ppard', is, an, important, metabolic, modulator, that, may, have, implications, for, cardiovascular, disease, '(', 'CVD)'])].
[sujeto(['During', recent, 'years,', development, of, specific, and, potent, 'PPARD', agonists]), verbo([has]), complemento([also, made, it, possible, to, study, the, effects, of, 'PPARD', activation, in, humans])].
[sujeto(['PPARD', agonists, seem, to, exert, beneficial, effects, on, dyslipidemia, and, 'insulin-resistant', syndromes, but, safety, issues]), verbo([have]), complemento([been, raised, due, to, the, role, that, 'PPARD', plays, in, cell, proliferation])].
[sujeto(['We', also, examined, whether, 'SNPs', that, were, shown, to]), verbo([associate]), complemento([with, obesity, affect, other, metabolic, abnormalities, such, as, blood, pressure, '(', 'BP),', 'glucose,', and, lipid, profile])].
[sujeto(['Average', dietary, energy, significantly]), verbo([associated]), complemento([with, increased, abdominal, circumference, '(', 'AC)', and, body, mass, index, '(', 'BMI)'])].
[sujeto(['The', major, allele, of, rs696217, significantly]), verbo([increased]), complemento(['BMI', and, an, increased, 'OR', with, 'obesity,', while, the, minor, allele, of, rs3782886, was, associated, with, significantly, decreased, 'AC', and, the, decreased, 'ORs', with, overweight, and, obesity])].
[sujeto(['The', minor, allele, of, rs3782886, was, also]), verbo([associated]), complemento([with, significantly, decreased, systolic, 'BP', '(', 'SBP),', triglyceride, '(', 'TG),', 'high-density', lipoprotein, '(', 'HDL),', and, fasting, blood, sugar, '(', 'FBS),', while, rs696217, was, not, associated, with, other, metabolic, abnormalities])].
[sujeto(['Average', dietary, energy, in, 'lunch,', 'rs3782886,', and, rs696217, were]), verbo([associated]), complemento([with, 'obesity,', and, rs3782886, was, associated, with, other, metabolic, abnormalities])].
[sujeto(['Immune', dysfunction, is, a, likely, contributor, to, the]), verbo([increased]), complemento([risk, of, disease, at, this, time])].
[sujeto(['Studies', using, 'high-yielding,', total, mixed, 'ration-fed', cows]), verbo([have]), complemento([indicated, that, neutrophil, function, is, perturbed, over, the, transition, 'period;', 'however,', this, reported, dysfunction, has, yet, to, be, investigated, in, 'moderate-yielding,', grazing, dairy, cows])].
[sujeto(['Therefore,', we, investigated, changes, in, the, expression, of, genes]), verbo([involved]), complemento([in, neutrophil, function])].
[sujeto(['Quantitative', reverse, transcriptase, 'PCR', with, 'custom-designed']), verbo([primer]), complemento([pairs, and, 'Roche', 'Universal', 'Probe', 'Library', '(', 'Roche,', 'Basel,', 'Switzerland)', 'chemistry,', combined, with, microfluidics, integrated, fluidic, circuit, chips, '(', 96.96, 'Dynamic', 'Array,', 'San', 'Francisco,', 'CA)', were, used, to, investigate, the, expression, of, 78, genes, involved, in, neutrophil, function, and, 18, endogenous, control, genes])].
[sujeto(['Genes', that, were, differentially]), verbo([expressed]), complemento([over, the, transition, period, included, those, involved, in, neutrophil, adhesion, '(', 'SELL,', 'ITGB2,', and, 'ITGBX),', mediation, of, the, immune, response, '(', 'TLR4,', 'HLA-DRA,', and, 'CXCR2),', 'maturation,', cell, cycle, 'progression,', apoptosis, '(', 'MCL1,', 'BCL2,', 'FASLG,', and, 'RIPK1),', and, control, of, gene, expression, '(', 'PPARG,', 'PPARD,', and, 'STAT3)'])].
[sujeto(['However,', their, performance]), verbo([requires]), complemento([different, proportions, of, 'power,', 'speed,', and, strength])].
[sujeto(['The', aim, of, the, current, study, was, to, examine, genetic, differences, between, subtypes, of, anaerobic, athletes, in, 3, genetic, 'variants:', 'ACTN3', 'R577X,', which, is]), verbo([associated]), complemento([with, muscle, 'contractions,', 'AGT', 'Met235Thr', which, is, associated, with, muscle, 'growth,', and, 'PPARD', 'T/C,', which, is, associated, with, aerobic, capacity])].
[sujeto([71, sprinters, and, jumpers, '(', 'S/J),', 54, weightlifters, '(', 'WL)', and, 86, controls]), verbo([participated]), complemento([in, the, study])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, there, may, be, a, specific, genetic, makeup, enabling, an, athlete, to, excel, in, 'speed-oriented', events, '(', 'sprints),', rather, than, in, 'strength-oriented', events, '(', 'weightlifting)'])].
[sujeto(['At', 24, and, 96, h, 'post-exposure', '(', 'hpe),', the, mRNA, expression, levels, of, the, genetic, markers]), verbo([involved]), complemento([in, general, stress, responses, '(', 'hsp70,', 'hsp47,', 'crh-a', and, 'ucn1),', oxidative, stress, '(', cat])].
[sujeto(['Similar', responses, were]), verbo([found]), complemento([for, genes, 'hsp70,', 'hsp47,', 'crh-a,', 'ucn1,', sod, and, ppard, at, 96, hpe])].
[sujeto(['While', a, distinct, set, of, processes, drive, metastasis, when, compared, to, 'tumorigenesis,', it, is, yet, unclear, if, genetic, alterations, in, metabolic, pathways, are]), verbo([associated]), complemento([with, metastatic, progression, of, human, cancers])].
[sujeto(['Here,', we, analyzed, the, 'mutation,', copy, number, variation, and, gene, expression, patterns, of, a, 'literature-derived', model, of, metabolic, genes]), verbo([associated]), complemento([with, glycolysis, '(', 'Warburg', 'effect),', fatty, acid, metabolism, '(', 'lipogenesis,', 'oxidation,', 'lipolysis,', 'esterification)', and, fatty, acid, uptake, in, &, 'gt;9000', primary, or, metastatic, tumor, samples, from, the, 'multi-cancer', 'TCGA', datasets])].
[sujeto(['Using', gene, expression, 'profiles,', we, established, a, 'gene-signature', '(', 'CAV1,', 'CD36,', 'MLXIPL,', 'CPT1C,', 'CYP2E1)', that, strongly]), verbo([associated]), complemento([with, 'epithelial-mesenchymal', program, across, multiple, cancers])].
[sujeto(['Genes', that]), verbo([have]), complemento([been, reported, to, be, correlated, with, 'SPN', were, used, as, the, clues, to, hunt, more, 'SPN-related', genes, in, the, network, according, to, a, shortest, path, approach])].
[sujeto([43, new, 'SPN-relevant', genes, were, 'discovered,', among, 'which,', we]), verbo([found]), complemento(['hsa-miR-194', and, 'hsa-miR-7', along, with, 7, transcription, factors, '(', 'TFs)', such, as, 'SOX11,', 'SMAD3', and, 'SOX4', etc])].
[sujeto(['This', study]), verbo([provides]), complemento([new, candidate, genes, related, to, 'SPN', and, the, potential, biomarkers, to, differentiate, 'SPN', from, 'PanNET', and, 'PDAC,', which, may, help, to, diagnose, patients, with, 'SPN', in, clinical, setting])].
[sujeto(['Furthermore,', candidate, biomarkers, such, as, 'SOX11', and, 'hsa-miR-204', which, could]), verbo([cause]), complemento([cell, proliferation, but, inhibit, invasion, or, metastasis, may, be, of, importance, in, understanding, the, molecular, mechanism, of, pancreatic, oncogenesis, and, could, be, possible, therapeutic, targets, for, malignant, pancreatic, tumors])].
[sujeto(['Epistasis', from, gene, set, based, on, the, 'function-related', genes, may]), verbo([confer]), complemento([to, the, susceptibility, of, type, 2, diabetes, '(', 'T2D)'])].
[sujeto(['The', 'Wnt', pathway]), verbo([has]), complemento([been, reported, to, play, an, important, role, in, the, pathogenesis, of, 'T2D'])].
[sujeto(['In', 'single-locus', 'analysis,', 'SNPs', in, four, genes, were, significantly]), verbo([associated]), complemento([with, 'T2D', adjusted, for, multiple, testing, '(', 'rs7903146(C)', in, 'TCF7L2,', p, =, 3.21, '∗10(-3),', 'OR', =, 1.39, ',', 95, '%', 'CI', '[', 1.31, -, 1.47, ']', ',', 'rs12904944(G)', in, 'SMAD3,', p, =, 2.51, '∗10(-3),', 'OR', =, 1.39, ',', 95, '%', 'CI', '[', 1.31, -, 1.47, ']', ',', 'rs2273368(C)', in, 'WNT2B,', p, =, 4.46, '∗10(-3),', 'OR', =, 1.23, ',', 95, '%', 'CI', '[', 1.11, -, 1.32, ']', ',', 'rs6902123(C)', in, 'PPARD,', p, =, 1.14, '∗10(-2),', 'OR', =, 1.4, ',', 95, '%', 'CI', '[', 1.32, -, 1.48, ']', ')'])].
[sujeto(['The', best, combination]), verbo([increased]), complemento([the, risk, of, 'T2D', by, 1.47, times, '(', 95, '%', 'CI', '[', 1.13, -, 1.91, ']', ',', p, =, 0.0039, ')'])].
[sujeto(['Epistasis', between, 'TCF7L2', and, 'WNT2B', is]), verbo([associated]), complemento([with, the, susceptibility, of, 'T2D', in, a, 'Han', 'Chinese', population])].
[sujeto(['Our', results, were, compatible, with, the, idea, of, the, complex, nature, of, 'T2D', that, would]), verbo([have]), complemento([been, missed, using, conventional, tools])].
[sujeto(['Little', is, known, about, inherited, factors]), verbo([associated]), complemento([with, the, risk, of, developing, chronic, myelogenous, leukemia, '(', 'CML)'])].
[sujeto(['Haplotype', analysis, showed, that, certain, combinations, of, rare, alleles, of, these, genes]), verbo([increased]), complemento([the, risk, of, developing, 'CML', by, more, than, two, or, 'three-fold'])].
[sujeto(['A', classification, tree, model, identified, five, 'SNPs', belonging, to, the, genes, 'PSMB10,', 'TNFRSF10D,', 'PSMB2,', 'PPARD', and, 'CYP26B1,', which, were]), verbo([associated]), complemento([with, 'CML', predisposition])].
[sujeto(['Interestingly,', the, score, was]), verbo([associated]), complemento([with, age, at, diagnosis, and, the, average, number, of, risk, alleles, was, significantly, higher, in, younger, patients])].
[sujeto(['The', 'risk-allele', score, showed, the, same, distribution, in, the, general, population, '(', 'HapMap', 'CEU', 'samples)', as, in, our, control, individuals, and, was]), verbo([associated]), complemento([with, differential, gene, expression, patterns, of, two, genes, '(', 'VAPA', and, 'TDRKH)'])].
[sujeto(['In', 'conclusion,', we, describe, haplotypes, and, a, genetic, score, that, are, significantly]), verbo([associated]), complemento([with, a, predisposition, to, develop, 'CML'])].
[sujeto(['Exposure', of, preadipocytes, to, long, chain, fatty, acids]), verbo([induces]), complemento([expression, of, several, gene, markers, of, adipocyte, differentiation])].
[sujeto(['This']), verbo([report]), complemento([describes, the, 'cloning,', from, a, preadipocyte, 'library,', of, a, cDNA, encoding, a, fatty, 'acid-activated', 'receptor,', 'FAAR'])].
[sujeto(['The', cDNA, had, the, characteristics, and, 'ligand-binding', domains, of]), verbo([nuclear]), complemento([hormone, receptors, and, encoded, a, 440, amino, acid, protein, related, to, peroxisome, 'proliferator-activated', 'receptors,', 'PPAR'])].
[sujeto(['The', mRNA, was, undetectable, in, growing, 'Ob1771', and, 3, 'T3-F442A', 'preadipocytes,', was, strongly]), verbo([induced]), complemento([early, during, 'differentiation,', and, was, increased, by, fatty, acid])].
[sujeto(['Transfection', of, 3, 'T3-C2', 'fibroblasts,', with, a, 'FAAR', expression, 'vector,']), verbo([conferred]), complemento([fatty, acid, inducibility, of, the, adipocyte, 'lipid-binding', protein, and, the, fatty, acid, transporter])].
[sujeto(['The']), verbo([nuclear]), complemento(['receptor,', 'NR1C2', or, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)-δ,', is, ubiquitously, expressed, and, important, for, placental, 'development,', fatty, acid, 'metabolism,', wound, 'healing,', 'inflammation,', and, tumour, development])].
[sujeto(['PPARδ']), verbo([has]), complemento([been, hypothesized, to, function, as, both, a, ligand, activated, transcription, factor, and, a, repressor, of, transcription, in, the, absence, of, agonist])].
[sujeto(['In', this, 'paper,', treatment, of, mice, conditionally]), verbo([expressing]), complemento([human, 'PPARδ', with, 'GW501516', resulted, in, a, marked, loss, in, body, weight, that, was, not, evident, in, nontransgenic, animals, or, animals, expressing, a, dominant, negative, derivative, of, 'PPARδ'])].
[sujeto(['Expression', of, either, functional, or, dominant, negative, hPPARδ, blocked, 'bezafibrate-induced', 'PPARα-dependent', hepatomegaly, and, blocked, the, effect, of, bezafibrate, on, the, transcription, of, 'PPARα']), verbo([target]), complemento([genes])].
[sujeto(['These', data, 'demonstrate,', for, the, first, 'time,', that, 'PPARδ', could]), verbo([inhibit]), complemento([the, activation, of, 'PPARα', in, vivo, and, provide, novel, models, for, the, investigation, of, the, role, of, 'PPARδ', in, pathophysiology])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, '(', 'PPAR)-beta/delta', is, a, member, of, the, 'PPAR']), verbo([nuclear]), complemento([hormone, receptor, family])].
[sujeto(['Recently,', there]), verbo([has]), complemento([been, a, great, deal, of, interest, in, the, involvement, of, 'PPARs', in, the, inflammatory, processes])].
[sujeto(['In', 'particular,', 'PPARalpha', and, 'PPARgamma']), verbo([inhibit]), complemento([the, activation, of, inflammatory, gene, expression, and, can, negatively, interfere, with, 'pro-inflammatory', transcription, factor, signalling, pathways, in, vascular, and, inflammatory, cells])].
[sujeto(['In', 'contrast,', the, roles, of, 'PPARbeta/delta']), verbo([regulating]), complemento([inflammation, and, immunity, are, only, just, emerging])].
[sujeto(['This', review, will, focus, on, these, emerging, roles, of, 'PPARbeta/delta', in]), verbo([regulating]), complemento([inflammatory, processes])].
[sujeto(['The', identification, of, small, molecule, agonists, for, the]), verbo([nuclear]), complemento([receptor, peroxisome, 'proliferator-activated', receptor, 'beta/delta', '(', 'PPAR-beta/delta,', 'NR1C2)', has, enabled, the, characterization, of, this, 'receptor\'s', functions, in, preclinical, models])].
[sujeto(['Subsequently,', a, number, of, small, molecule, agonists, of, 'PPAR-beta/delta']), verbo([have]), complemento([been, progressed, into, clinical, trials])].
[sujeto(['The', identification, of, small, molecule, ligands, for, the, peroxisome, 'proliferator-activated', receptors, '(', 'PPARs)']), verbo([has]), complemento([been, instrumental, in, elucidating, their, biological, roles])].
[sujeto(['In', 'particular,', agonists]), verbo([have]), complemento([been, the, focus, of, much, of, the, research, in, the, field, with, relatively, few, antagonists, being, described, and, all, of, those, being, selective, for, 'PPARalpha', or, 'PPARgamma'])].
[sujeto(['The', comparison, of, these, agonist, and, antagonist, ligands, in, cellular, and, animal, systems]), verbo([has]), complemento([often, led, to, surprising, results, and, new, insights, into, the, biology, of, the, 'PPARs'])].
[sujeto(['The', 'PPARbeta/delta', receptor, is, emerging, as, an, important, regulator, of, energy, 'metabolism,', 'inflammation,', and, cell, growth, and, 'differentiation;', 'however,', only, agonist, ligands]), verbo([have]), complemento([been, described, for, this, receptor, thus, far])].
[sujeto(['Here', we, describe, the, first]), verbo([report]), complemento([of, a, 'PPARbeta/delta', small, molecule, antagonist, ligand])].
[sujeto(['In', cultured, human, keratinocytes, or, murine, 'epidermis,', peroxisome, 'proliferator-activated', receptor, 'beta/delta', '(', 'PPARbeta/delta)', '(', 'NR1C2)', activators, '(', 1, ')']), verbo([stimulate]), complemento([keratinocyte, 'differentiation;', '(', 2, ')', decrease, keratinocyte, 'proliferation;', '(', 3, ')', accelerate, permeability, barrier, 'repair;', '(', 4, ')', increase, epidermal, lipid, 'synthesis;', and, '(', 5, ')', reduce, cutaneous, inflammation])].
[sujeto(['Since', these, results]), verbo([suggest]), complemento([that, 'PPARbeta/delta', could, play, an, important, role, in, cutaneous, 'homeostasis,', we, assessed, here, the, skin, phenotype, of, mice, deficient, in, 'PPARbeta/delta'])].
[sujeto(['However,', the, epidermis, was, thickened, and, proliferating, cell]), verbo([nuclear]), complemento([antigen, '(', 'PCNA)', staining, was, 'increased,', indicating, increased, cell, proliferation])].
[sujeto(['No', change, in, apoptosis, was, observed, but, the, expression, of, differentiation, 'markers,', such, as, 'filaggrin,', 'involucrin,', and, 'loricrin,', was, slightly]), verbo([increased]), complemento([in, 'PPARbeta/delta(-/-)', mice])].
[sujeto(['Delayed', barrier, recovery, correlated, with]), verbo([decreased]), complemento([production, and, secretion, of, lamellar, bodies, '(', 'LBs),', and, with, reduced, numbers, of, extracellular, lamellar, membranes, in, the, 'SC'])].
[sujeto(['Finally,', 'PPARbeta/delta', 'KO', mice, displayed]), verbo([increased]), complemento([inflammation, in, response, to, 12, -, 'O-tetradecanoylphorbol-13-acetate', '(', 'TPA)', treatment])].
[sujeto(['Together,', these, results, further, demonstrate, that, 'PPARbeta/delta', in, the, 'epidermis:', '(', 1, ')', is]), verbo([required]), complemento([for, permeability, barrier, 'homeostasis;', '(', 2, ')', regulates, keratinocyte, 'proliferation;', and, '(', 3, ')', modulates, cutaneous, inflammation])].
[sujeto(['The', peroxisome, 'proliferator-activated', receptors, '(', 'PPARs)']), verbo([regulate]), complemento([transcription, in, response, to, fatty, acids, 'and,', as, 'such,', are, potential, therapeutic, targets, for, these, diseases])].
[sujeto(['Euglycemic-hyperinsulinemic-clamp', experiments, further, demonstrate, that, a, 'PPARdelta-specific', agonist]), verbo([suppresses]), complemento([hepatic, glucose, 'output,', increases, glucose, 'disposal,', and, inhibits, free, fatty, acid, release, from, adipocytes])].
[sujeto(['Unexpectedly,', gene, array, and, functional, analyses]), verbo([suggest]), complemento([that, 'PPARdelta', ameliorates, hyperglycemia, by, increasing, glucose, flux, through, the, pentose, phosphate, pathway, and, enhancing, fatty, acid, synthesis])].
[sujeto(['Coupling']), verbo([increased]), complemento([hepatic, carbohydrate, catabolism, with, its, ability, to, promote, 'beta-oxidation', in, muscle, allows, 'PPARdelta', to, regulate, metabolic, homeostasis, and, enhance, insulin, action, by, complementary, effects, in, distinct, tissues])].
[sujeto(['The', combined, hepatic, and, peripheral, actions, of, 'PPARdelta']), verbo([suggest]), complemento([new, therapeutic, approaches, to, treat, type, 'II', diabetes])].
[sujeto(['Metabolism,', in, 'part,', is]), verbo([regulated]), complemento([by, the, peroxisome, 'proliferator-activated', receptors, '(', 'PPARs)'])].
[sujeto(['The', 'PPARs']), verbo([act]), complemento([as, nutritional, lipid, sensors, and, three, mammalian, 'PPAR', subtypes, designated, 'PPARalpha', '(', 'NR1C1),', 'PPARgamma', '(', 'NR1C3)', and, 'PPARdelta', '(', 'NR1C2)', have, been, identified])].
[sujeto(['This', subgroup, of]), verbo([nuclear]), complemento([hormone, receptors, binds, 'DNA', and, controls, gene, expression, at, the, nexus, of, pathways, that, regulate, lipid, and, glucose, 'homeostasis,', energy, storage, and, expenditure, in, an, 'organ-specific', manner])].
[sujeto(['Recent', evidence]), verbo([has]), complemento([demonstrated, activation, of, 'PPARdelta', in, the, major, mass, peripheral, tissue, '(', 'ie,', adipose, and, skeletal, 'muscle)'])].
[sujeto(['It']), verbo([enhances]), complemento([glucose, 'tolerance,', 'insulin-stimulated', glucose, 'disposal,', lipid, 'catabolism,', energy, 'expenditure,', cholesterol, efflux, and, oxygen, consumption])].
[sujeto(['Furthermore,', 'PPARdelta', activation, produces, a, predominant, type, 'I/slow', 'twitch/oxidative', muscle, fiber, phenotype, that]), verbo([leads]), complemento([to, increased, 'endurance,', insulin, sensitivity, and, resistance, to, obesity])].
[sujeto(['PPARdelta']), verbo([has]), complemento([rapidly, emerged, as, a, potential, target, in, the, battle, against, 'dyslipidemia,', insulin, 'insensitivity,', type, 'II', diabetes, and, 'obesity,', with, therapeutic, efficacy, in, the, treatment, of, cardiovascular, disease, risk, factors])].
[sujeto(['The', outcome, of, these, clinical, trials, are, eagerly, awaited, against, a, background, of, conflicting]), verbo([reports]), complemento([about, cancer, risks, in, genetically, predisposed, animal, models])].
[sujeto(['This', review, focuses, on, the, potential, pharmacological, utility, of, selective, 'PPARdelta', agonists, in, the, context, of, risk, factors]), verbo([associated]), complemento([with, metabolic, and, cardiovascular, disease])].
[sujeto(['Peroxisome', 'proliferator-activated', receptors, '(', 'PPARs)', are, members, of, the]), verbo([nuclear]), complemento([hormone, receptors, family])].
[sujeto(['PPARalpha,', -, 'beta/delta,', and, -, gamma, are, encoded, by, different, genes, but, show, substantial, amino, acid, 'similarity,', especially, within, the, 'DNA', and, ligand]), verbo([binding]), complemento([domains])].
[sujeto(['All', 'PPARs']), verbo([act]), complemento([as, heterodimers, with, the, 9, -, 'cis-retinoic', acid, receptors, '(', retinoid, 'X', 'receptor;', 'RXRs)', and, play, important, roles, in, the, regulation, of, metabolic, 'pathways,', including, those, of, lipid, of, biosynthesis, and, glucose, 'metabolism,', as, well, as, in, a, variety, of, cell, 'differentiation,', 'proliferation,', and, apoptosis, pathways])].
[sujeto(['Recently,', there]), verbo([has]), complemento([been, a, great, deal, of, interest, in, the, involvement, of, 'PPARs', in, inflammatory, processes])].
[sujeto(['PPAR', 'ligands,', in, particular, those, of, 'PPARalpha', and, 'PPARgamma,']), verbo([inhibit]), complemento([the, activation, of, inflammatory, gene, expression, and, can, negatively, interfere, with, 'pro-inflammatory', transcription, factor, signaling, pathways, in, vascular, and, inflammatory, cells])].
[sujeto(['Furthermore,', 'PPAR', levels, are, differentially]), verbo([regulated]), complemento([in, a, variety, of, inflammatory, disorders, in, 'man,', where, ligands, appear, to, be, promising, new, therapies])].
[sujeto(['The']), verbo([nuclear]), complemento([receptor, peroxisome, 'proliferator-activated', receptor, delta, '[', 'PPARdelta/beta', '(', 'NR1C2)]', has, been, implicated, in, colorectal, carcinogenesis, by, various, molecular, genetic, observations])].
[sujeto(['These', observations]), verbo([have]), complemento([recently, been, supported, by, studies, of, activation, of, 'PPARdelta', by, pharmacological, agents])].
[sujeto(['Here', we, present, the, first]), verbo([report]), complemento([of, the, stimulation, of, breast, and, prostate, cancer, cell, growth, using, 'PPARdelta', selective, agonists])].
[sujeto(['Activation', of, 'PPARdelta', with, compound, 'F']), verbo([stimulated]), complemento([proliferation, in, breast, '(', 'T47D,', 'MCF7)', and, prostate, '(', 'LNCaP,', 'PNT1A)', cell, 'lines,', which, are, responsive, to, sex, hormones])].
[sujeto(['Conversely,', we]), verbo([have]), complemento([found, that, several, 'steroid-independent', cell, 'lines,', including, colon, 'lines,', were, unresponsive, to, compound, 'F'])].
[sujeto(['Conditional', expression, of, 'PPARdelta', in, 'MCF7', 'Tet-On', cells, resulted, in, a, 'doxycycline-enhanced', response, to, 'GW501516,', thus]), verbo([providing]), complemento([direct, genetic, evidence, for, the, role, of, 'PPARdelta', in, the, proliferative, response, to, this, drug])].
[sujeto(['Activation', of, 'PPARdelta', in, 'T47D', cells, resulted, in]), verbo([increased]), complemento([expression, of, the, proliferation, marker, 'Cdk2', and, also, vascular, endothelial, growth, factor, alpha, '(', 'VEGFalpha)', and, its, 'receptor,', 'FLT-1,', 'thus,', suggesting, that, 'PPARdelta', may, initiate, an, autocrine, loop, for, cellular, proliferation, and, possibly, angiogenesis])].
[sujeto(['Consistent', with, this, 'hypothesis,', we, demonstrated, a, 'pro-proliferative', effect, of, 'GW501516', on, human, umbilical, vein, endothelial, cell, cultures, and]), verbo([found]), complemento([that, 'GW501516', also, regulated, the, expression, of, 'VEGFalpha', and, 'FLT-1', in, these, cells])].
[sujeto(['Our', observations]), verbo([provide]), complemento([the, first, evidence, that, activation, of, 'PPARdelta', can, result, in, increased, growth, in, breast, and, prostate, cancer, cell, lines, and, primary, endothelial, cells, and, supports, the, possibility, that, 'PPARdelta', antagonists, may, be, of, therapeutic, value, in, the, treatment, of, breast, and, prostate, cancer])].
[sujeto(['BACKGROUND:', 'PPARdelta', '(', 'NR1C2)']), verbo([promotes]), complemento([lipid, accumulation, in, human, macrophages, in, vitro, and, has, been, implicated, in, the, response, of, macrophages, to, vLDL])].
[sujeto(['We']), verbo([have]), complemento([investigated, the, role, of, 'PPARdelta', in, 'PMA-stimulated', macrophage, differentiation])].
[sujeto(['THP-1', 'sub-lines', that, either, 'over-expressed', 'PPARdelta', 'protein,', or]), verbo([expressed]), complemento(['PPARdelta', 'anti-sense', 'RNA', were, generated])].
[sujeto(['RESULTS:', 'The', 'PPARdelta', 'agonist,', compound, 'F,']), verbo([stimulated]), complemento([differentiation, in, the, presence, of, 'sub-nanomolar', concentrations, of, phorbol, ester])].
[sujeto(['Several', markers, of, differentiation, were]), verbo([induced]), complemento([by, compound, 'F', in, a, synergistic, fashion, with, phorbol, 'ester,', including, 'CD68', and, 'IL8'])].
[sujeto(['CONCLUSIONS:', 'These', data, collectively, demonstrate, that, 'PPARdelta', plays, a, fundamental, role, in]), verbo([mediating]), complemento([a, subset, of, cellular, effects, of, phorbol, ester, and, supports, observations, from, mouse, knockout, models, that, 'PPARdelta', is, involved, in, 'macrophage-mediated', inflammatory, responses])].
[sujeto(['PPARalpha', '(', 'NR1C1)', controls, lipid, oxidation, and, clearance, in, hepatocytes, and, 'PPARgamma', '(', 'NR1C3)']), verbo([promotes]), complemento([preadipocyte, differentiation, and, lipogenesis])].
[sujeto(['Drugs', that]), verbo([activate]), complemento(['PPARalpha', are, effective, in, lowering, plasma, levels, of, lipids, and, have, been, used, in, the, management, of, hyperlipidemia])].
[sujeto(['PPARgamma', agonists]), verbo([increase]), complemento([insulin, sensitivity, and, are, used, in, the, management, of, type, 2, diabetes])].
[sujeto(['In', 'contrast,', there, are, no, marketed, drugs, that, selectively]), verbo([target]), complemento(['PPARdelta', '(', 'NR1C2)', and, the, physiological, roles, of, 'PPARdelta', are, unclear])].
[sujeto(['In', this]), verbo([report]), complemento([we, demonstrate, that, the, expression, of, 'PPARdelta', is, increased, during, the, differentiation, of, human, macrophages, in, vitro])].
[sujeto(['In', 'addition,', a, highly, selective, agonist, of, 'PPARdelta', '(', compound, 'F)']), verbo([promotes]), complemento([lipid, accumulation, in, primary, human, macrophages, and, in, macrophages, derived, from, the, human, monocytic, cell, 'line,', 'THP-1'])].
[sujeto(['Compound', 'F']), verbo([increases]), complemento([the, expression, of, genes, involved, in, lipid, uptake, and, storage, such, as, the, class, 'A', and, 'B', scavenger, receptors, '(', 'SRA,', 'CD36)', and, adipophilin])].
[sujeto(['PPARdelta', activation, also]), verbo([represses]), complemento([key, genes, involved, in, lipid, metabolism, and, 'efflux,', i])].
[sujeto(['We']), verbo([have]), complemento([generated, 'THP-1', sublines, that, overexpress, 'PPARdelta', and, have, confirmed, that, 'PPARdelta', is, a, powerful, promoter, of, macrophage, lipid, accumulation])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'PPARdelta', may, play, a, role, in, the, pathology, of, diseases, associated, with, 'lipid-filled', 'macrophages,', such, as, 'atherosclerosis,', 'arthritis,', and, neurodegeneration])].
[sujeto(['The', peroxisome, 'proliferator-activated', receptors, '(', 'PPARalpha,', 'gamma,', 'delta)', are, members, of, the]), verbo([nuclear]), complemento([receptor, superfamily, of, 'ligand-activated', transcription, factors, that, have, central, roles, in, the, storage, and, catabolism, of, fatty, acids])].
[sujeto(['Although', the, three, 'PPAR', subtypes, are, closely, related, and]), verbo([bind]), complemento([to, similar, 'DNA', response, elements, as, heterodimers, with, the, 9, -, cis, retinoic, acid, receptor, 'RXR,', each, subserves, a, distinct, physiology])].
[sujeto(['In', 'rodents,', 'PPARalpha', agonists]), verbo([induce]), complemento([hepatomegaly, and, stimulate, a, dramatic, proliferation, of, peroxisomes, as, part, of, a, coordinated, physiological, response, to, lipid, overload])].
[sujeto(['In', contrast, to, 'PPARalpha', and, 'PPARgamma,', relatively, little, is, known, about, the, biology, of, 'PPARdelta', '(', 'NR1C2),', although, recent, findings]), verbo([suggest]), complemento([that, this, subtype, also, has, a, role, in, lipid, homeostasis])].
[sujeto(['All', three, 'PPARs', are]), verbo([activated]), complemento([by, naturally, occurring, fatty, acids, and, fatty, acid, 'metabolites,', indicating, that, they, function, as, the, 'body\'s', fatty, acid, sensors])].
[sujeto(['Three-dimensional', crystal, structures]), verbo([reveal]), complemento([that, the, 'ligand-binding', pockets, of, the, 'PPARs', are, much, larger, and, more, accessible, than, those, of, other, nuclear, 'receptors,', providing, a, molecular, basis, for, the, promiscuous, 'ligand-binding', properties, of, these, receptors])].
[sujeto(['Given', the, fundamental, roles, that, the, 'PPARs', play, in, energy, 'balance,', drugs, that]), verbo([modulate]), complemento(['PPAR', activity, are, likely, to, be, useful, for, treating, a, wide, range, of, metabolic, 'disorders,', including, 'atherosclerosis,', 'dyslipidemia,', 'obesity,', and, type, 2, diabetes])].
[sujeto(['Remodeling', of, quiescent, vessels, with]), verbo([increases]), complemento([in, 'permeability,', 'vasodilatation,', and, edema, are, hallmarks, of, inflammatory, disorders])].
[sujeto(['Factors']), verbo([involved]), complemento([in, this, type, of, remodeling, represent, potential, therapeutic, targets])].
[sujeto(['We', investigated, whether, the]), verbo([nuclear]), complemento([hormone, receptor, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)', 'β/δ,', a, regulator, of, 'metabolism,', 'fibrosis,', and, skin, 'homeostasis,', is, involved, in, regulation, of, this, type, of, remodeling])].
[sujeto(['AVH', and, dilatation, of, dermal, microvessels]), verbo([stimulated]), complemento([by, vascular, endothelial, growth, factor, 'A,', 'histamine,', and, thrombin, are, severely, compromised, in, 'PPARβ/δ-deficient', mice])].
[sujeto(['Selective', deletion, of, the, 'Pparb/d-encoding', gene, in, endothelial, cells, 'in&nbsp;vivo', similarly, limits, dermal, 'AVH', and, 'vasodilatation,']), verbo([providing]), complemento([evidence, that, endothelial, 'PPARβ/δ', is, the, major, player, in, regulating, acute, dermal, microvessel, remodeling])].
[sujeto(['Furthermore,', endothelial, 'PPARβ/δ', regulatory, functions, are, not, restricted, to, the, skin, vasculature, because, its, deletion, in, the, 'endothelium,', but, not, in, smooth, muscle, 'cells,', also]), verbo([leads]), complemento([to, reduced, systemic, 'anaphylaxis,', the, most, severe, form, of, allergic, 'reaction,', in, which, an, acute, vascular, response, plays, a, key, role])].
[sujeto(['PPARβ/δ-dependent', 'AVH', activation, likely]), verbo([involves]), complemento([the, activation, of, 'mitogen-activated', protein, kinase, and, 'Akt', pathways, and, leads, to, downstream, destabilization, of, endothelial, 'cell-cell', junctions])].
[sujeto(['These', results, unveil, not, only, a, novel, function, of, 'PPARβ/δ', as, a, direct, regulator, of, acute, vessel, permeability, 'and&nbsp;dilatation', but, also]), verbo([provide]), complemento([evidence, that, antagonizing, 'PPARβ/δ', represents, an, important, strategy, to, consider, for, moderating, diseases, with, altered, endothelial, 'integrity,', such, as, acute, inflammatory, and, allergic, disorders])].
[sujeto(['To']), verbo([gain]), complemento([insight, into, its, hypothesized, role, in, β, cell, 'function,', we, specifically, deleted, 'Pparb/d', in, the, epithelial, compartment, of, the, mouse, pancreas])].
[sujeto(['Mutant', animals, presented]), verbo([increased]), complemento([numbers, of, islets, 'and,', more, 'importantly,', enhanced, insulin, 'secretion,', causing, hyperinsulinemia])].
[sujeto(['Analyses', of, insulin]), verbo([release]), complemento([from, isolated, 'PPARβ/δ-deficient', islets, revealed, an, accelerated, second, phase, of, 'glucose-stimulated', insulin, secretion])].
[sujeto(['These', effects, in, 'PPARβ/δ-deficient', islets, correlated, with]), verbo([increased]), complemento([filamentous, actin, '(', 'F-actin)', disassembly, and, an, elevation, in, protein, kinase, 'D', activity, that, altered, 'Golgi', organization])].
[sujeto(['Taken', 'together,', these, results]), verbo([provide]), complemento([evidence, for, a, repressive, role, for, 'PPARβ/δ', in, β, cell, mass, and, insulin, 'exocytosis,', and, shed, a, new, light, on, 'PPARβ/δ', metabolic, action])].
[sujeto(['Peroxisome', 'proliferator-activated', receptordelta, '(', 'PPARdelta),', as, a, downstream]), verbo([target]), complemento([of, adenomatous, polyposis, coli, '(', 'APC)', signaling, 'pathway,', has, been, presumed, to, play, some, roles, in, colorectal, carcinogenesis])].
[sujeto(['An', 'HIV-1-based', lentivirus, packaging, system, was, used, for, the, construction, of, a, lentiviral, vector, '(', 'lentivector)']), verbo([mediating]), complemento(['RNA', interference, against, 'PPARB'])].
[sujeto(['The', direct, sequencing, demonstrated, that, the, resulting, lentivector, containing, the, 'short-hairpin', 'RNA', expression, cassette, specifically]), verbo([targeting]), complemento(['PPARdelta', '(', 'sh-PPARdelta)', was, successfully, 'constructed,', and, designated, as, pLVshPPARdelta])].
[sujeto(['The', results, demonstrated, that, the, lentivector]), verbo([mediating]), complemento(['RNAi', against, 'PPARdelta', was, successfully, 'constructed,', which, could, stably, knock, down, the, 'PPARdelta', expression, in, 'KM12C', cells])].
[sujeto(['This', study, finally]), verbo([provided]), complemento([a, new, cell, model, for, the, study, of, 'PPARdelta\'s', function, in, colorectal, cancer])].
[sujeto(['Peroxisome', 'proliferator-activated', receptors, '(', 'PPARs)', are, 'ligand-activated', transcription, factors, with, essential, functions, in]), verbo([regulating]), complemento([lipid, metabolism])].
[sujeto(['Both', the, 'PPARbeta', '(', also, referred, to, as, 'PPARdelta)', and, 'PPARgamma', subtype]), verbo([have]), complemento([been, reported, to, either, attenuate, or, potentiate, tumorigenesis, in, a, number, of, different, models, of, intestinal, and, skin, carcinogenesis])].
[sujeto(['In', the, present, 'study,', we]), verbo([have]), complemento([addressed, the, role, of, 'PPARbeta', and, 'PPARgamma', in, lung, tumorigenesis, in, a, transgenic, mouse, model, of, 'RAF-induced', lung, adenoma, using, two, different, 'strategies:', 'i)', crossing, with, 'PPARbeta', null, 'mice,', and, 'ii)', chronic, treatment, with, the, 'PPARgamma', agonist, rosiglitazone])].
[sujeto(['These', results, are, relevant, with, respect, to, the, clinical, application, of, drugs]), verbo([modulating]), complemento([the, activity, of, 'PPARbeta', or, 'PPARgamma'])].
[sujeto(['The', peroxisome, proliferator]), verbo([activated]), complemento(['receptor-beta', '(', 'PPARbeta)', plays, an, essential, role, in, lipid, 'metabolism,', immune, 'modulation,', differentiation, and, cell, proliferation])].
[sujeto(['In', the, present, 'study,', we]), verbo([have]), complemento([used, fibroblasts, derived, from, 'Pparb', 'wild-type', and, null, mice, to, determine, by, 2, -, 'DE', and, 'PMF', analysis, the, contribution, of, 'PPARbeta', to, the, protein, profile, of, fibroblasts])].
[sujeto(['Thirty-one', differentially]), verbo([expressed]), complemento([proteins, of, different, functional, categories, were, identified])].
[sujeto(['For', at, least, two, proteins, a, role, in, tumorigenesis, 'and/or', tumor, vascularization]), verbo([has]), complemento([previously, been, 'reported:', while, the, calcium, intracellular, 'channel-4', '(', 'CLIC4)', was, expressed, at, lower, levels, in, 'Pparb', null, 'cells,', expression, of, the, cellular, retinol, binding, protein, 1, '(', 'CRBP1)', was, enhanced])].
[sujeto(['There', is, considerable, debate, whether, peroxisome, 'proliferator-activated', receptor, 'beta/delta', '(', 'PPARbeta/delta)', ligands, potentiate, or]), verbo([suppress]), complemento([colon, carcinogenesis])].
[sujeto(['Whereas', administration, of, a, 'PPARbeta', ligand]), verbo([causes]), complemento([increased, small, intestinal, tumorigenesis, in, 'Apc(min/+)', 'mice,', 'PPARbeta-null', '(', 'Pparb-/-)', mice, exhibit, increased, colon, polyp, multiplicity, in, colon, cancer, 'bioassays,', suggesting, that, ligand, activation, of, this, receptor, will, inhibit, colon, carcinogenesis])].
[sujeto(['Ligand', activation, of, 'PPARbeta', in, 'Pparb+/+', mice]), verbo([caused]), complemento([an, increase, in, the, expression, of, mRNA, encoding, adipocyte, 'differentiation-related', 'protein,', fatty, 'acid-binding', 'protein,', and, cathepsin, 'E'])].
[sujeto(['No', 'PPARbeta-dependent', differences, in, replicative, 'DNA', synthesis, or, expression, of, phosphatase, and, tensin, 'homologue,', 'phosphoinositide-dependent', 'kinase,', 'integrin-linked', 'kinase,', or, 'phospho-Akt', were, detected, in, 'ligand-treated', mouse, colonic, epithelial, cells, although]), verbo([increased]), complemento([apoptosis, was, found, in, 'GW0742-treated', 'Pparb+/+', mice])].
[sujeto(['Consistent', with]), verbo([increased]), complemento([colonocyte, differentiation, and, 'apoptosis,', inhibition, of, colon, polyp, multiplicity, was, also, found, in, 'ligand-treated', 'Pparb+/+', 'mice,', and, all, of, these, effects, were, not, found, in, 'Pparb-/-', mice])].
[sujeto(['In', contrast, to, previous]), verbo([reports]), complemento([suggesting, that, activation, of, 'PPARbeta', potentiates, intestinal, 'tumorigenesis,', here, we, show, that, ligand, activation, of, 'PPARbeta', attenuates, chemically, induced, colon, carcinogenesis, and, that, 'PPARbeta-dependent', induction, of, cathepsin, 'E', could, explain, the, reported, disparity, in, the, literature, about, the, effect, of, ligand, activation, of, 'PPARbeta', in, the, intestine])].
[sujeto(['It', is, the, most, commonly]), verbo([reported]), complemento([fibrate, in, aquatic, environments, with, low, degradation, rate, and, potential, environmental, persistence])].
[sujeto(['Previous', fish, exposures, showed, that, 'CA', may, impact, 'spermatogenesis,', growth, and, the, expression, of, fat]), verbo([binding]), complemento([protein, genes])].
[sujeto(['In', order, to, study, the, potential, underlying, 'mechanisms,', the, transcription, levels, of, genes, coding, for, enzymes]), verbo([involved]), complemento([in, lipid, metabolism, pathways, were, determined])].
[sujeto(['The', results, show, that, chronic, 'life-cycle', exposure, to, 'CA']), verbo([induced]), complemento([a, significant, reduction, in, growth, of, 'F1', generation, and, lowered, triglyceride, muscle, content, '(', 10, 'mg/g', 'group)'])].
[sujeto(['Also,', an, impact, in, male, gonad, development, was, observed, together, with, a]), verbo([decrease]), complemento([in, the, fecundity, '(', 10, 'mg/g', 'group)', and, higher, frequency, of, embryo, abnormalities, in, the, offspring, of, fish, exposed, to, the, lowest, 'CA', dose])].
[sujeto(['The', profile, of, the]), verbo([target]), complemento([genes, was, 'sex-', and, 'tissue-dependent'])].
[sujeto(['In', 'F1', an, 'up-regulation', of, male, hepatic, 'pparaa,', pparb, and, acox, transcript, levels, was, 'observed,']), verbo([suggesting]), complemento([an, activation, of, the, fatty, acid, metabolism, '(', provided, that, transcript, level, change, indicates, also, a, protein, level, 'change)'])].
[sujeto(['Interestingly,', the, 'F2', 'generation,', raised, with, control, 'diet,', displayed, a, response, pattern, different, from, that, observed, in, 'F1,', showing, an]), verbo([increase]), complemento([in, weight, in, the, descendants, of, 'CA', exposed, 'fish,', in, comparison, with, control, 'animals,', which, points, to, a, multigenerational, effect])].
[sujeto(['Apolipoprotein', 'M', '(', 'APOM)']), verbo([has]), complemento([been, suggested, as, a, vasculoprotective, constituent, of, high, density, lipoprotein, '(', 'HDL),', which, plays, a, crucial, role, behind, the, mechanism, of, 'HDL-mediated', 'anti-atherosclerosis'])].
[sujeto(['Previous', studies, demonstrated, that, insulin, resistance, could]), verbo([associate]), complemento([with, decreased, 'APOM', expressions])].
[sujeto(['The', present, study, shows, that, 'Apom', expression, is, significantly, affected, by, either, rosiglitazone, or, hyperglycemia, alone, without, cross, interaction, with, each, 'other,', which, indicates, that, the, pathway, of, 'Apom', expression]), verbo([regulating]), complemento([by, hyperglycemia, might, be, differed, from, that, by, rosiglitazone])].
[sujeto(['Further', study, indicated, that, hyperglycemia, could, significantly]), verbo([inhibit]), complemento([mRNA, levels, of, 'Lxrb', '(', 'P=0'])].
[sujeto(['It', is, concluded, that, rosiglitazone, could]), verbo([increase]), complemento(['Apom', 'expression,', of, which, the, detailed, mechanism, needs, to, be, further, investigated])].
[sujeto(['The', downregulation, of, 'Apom', by, hyperglycemia, might, be, mainly, through]), verbo([decreasing]), complemento([expression, of, 'Pparg', and, followed, by, inhibiting, 'Lxrb', in, rats])].
[sujeto(['Myostatin', '(', 'Mstn)']), verbo([participates]), complemento([in, the, regulation, of, skeletal, muscle, size, and, has, emerged, as, a, regulator, of, muscle, metabolism])].
[sujeto(['Myostatin', deficiency, shifts, muscle, from, aerobic, toward, anaerobic, energy, 'metabolism,', as, evidenced, by]), verbo([decreased]), complemento([mitochondrial, 'respiration,', reduced, expression, of, 'PPAR', transcriptional, 'regulators,', increased, enolase, 'activity,', and, 'exercise-induced', lactic, acidosis])].
[sujeto(['As', a, 'consequence,', constitutively, reduced, myostatin, signaling, diminishes, exercise, 'capacity,', while, the, hypermuscular, state, of, 'Mstn(-/-)', mice]), verbo([increases]), complemento([oxygen, consumption, and, the, energy, cost, of, running])].
[sujeto(['Hence,', we, overexpressed, myostatin, propeptide, in, adult, 'mice,', which, did, not, affect, 'fiber-type', 'distribution,', while, nonetheless]), verbo([causing]), complemento([increased, muscle, 'fatigability,', diminished, exercise, 'capacity,', and, decreased, 'Pparb/d', and, 'Pgc1a', expression])].
[sujeto(['In', 'conclusion,', our, results]), verbo([suggest]), complemento([that, myostatin, endows, skeletal, muscle, with, high, oxidative, capacity, and, low, 'fatigability,', thus, regulating, the, delicate, balance, between, muscle, 'mass,', muscle, 'force,', energy, 'metabolism,', and, endurance, capacity])].
[sujeto(['Vitamin', 'A', '(', 'VA)']), verbo([has]), complemento([a, key, role, in, vertebrate, 'morphogenesis,', determining, body, patterning, and, growth, through, the, control, of, cell, proliferation, and, differentiation, processes])].
[sujeto(['VA']), verbo([regulates]), complemento([primary, molecular, pathways, of, those, processes, by, the, binding, of, its, active, metabolite, '(', retinoic, 'acid)', to, two, types, of, specific, nuclear, 'receptors:', retinoic, acid, receptors, '(', 'RARs)', and, retinoid, 'X', receptors, '(', 'RXRs),', which, promote, transcription, of, downstream, target, genes])].
[sujeto(['Therefore,', in, order, to]), verbo([gain]), complemento([further, knowledge, of, fish, larval, development, and, its, disruption, by, nutritional, 'VA', 'imbalance,', the, relative, expression, of, some, 'RARs', and, 'RXRs,', as, well, as, several, genes, involved, in, 'morpho-', and, skeletogenesis, such, as, peroxisome, 'proliferator-activated', receptors, '(', 'PPARA,', 'PPARB', and, 'PPARG);', 'retinol-binding', protein, '(', 'RBP);', 'insulin-like', growth, factors, 'I', and, 'II', '(', 'IGF1', and, 'IGF2,', 'respectively);', bone, morphogenetic, protein, 2, '(', 'Bmp2);', transforming, growth, factor, 'β-1', '(', 'TGFB1);', and, genes, encoding, different, extracellular, matrix, '(', 'ECM)', proteins, such, as, matrix, 'Gla', protein, '(', 'mgp),', osteocalcin, '(', 'bglap),', osteopontin, '(', 'SPP1),', secreted, protein, acidic, and, rich, in, cysteine, '(', 'SPARC)', and, type, 'I', collagen, α1, chain, '(', 'COL1A1)', have, been, studied, in, gilthead, sea, bream])].
[sujeto(['During', gilthead]), verbo([sea]), complemento([bream, larval, 'development,', specific, expression, profiles, for, each, gene, were, tightly, regulated, during, fish, morphogenesis, and, correlated, with, specific, morphogenetic, events, and, tissue, development])].
[sujeto(['Dietary', hypervitaminosis, 'A', during, early, larval, development, disrupted, the, normal, gene, expression, profile, for, genes]), verbo([involved]), complemento([in, 'RA', signalling, '(', 'RARA),', 'VA', homeostasis, '(', 'RBP)', and, several, genes, encoding, 'ECM', proteins, that, are, linked, to, 'skeletogenesis,', such, as, bglap, and, mgp])].
[sujeto(['Present', data, reflects, the, specific, gene, expression, patterns, of, several, genes]), verbo([involved]), complemento([in, larval, fish, 'RA', signalling, and, 'skeletogenesis;', and, how, specific, gene, disruption, induced, by, a, nutritional, 'VA', imbalance, underlie, the, skeletal, deformities])].
[sujeto(['Our', results, are, of, basic, interest, for, fish, 'VA', signalling, and, point, out, some, of, the, potential, molecular, players]), verbo([involved]), complemento([in, fish, skeletogenesis])].
[sujeto(['Increased', incidences, of, skeletal, deformities, in, gilthead]), verbo([sea]), complemento([bream, fed, with, hypervitaminosis, 'A', were, the, likely, ultimate, consequence, of, specific, gene, expression, disruption, at, critical, development, stages])].
[sujeto(['The', peroxisome, 'proliferator-activated', 'receptor-beta', '(', 'PPARbeta)']), verbo([has]), complemento([been, implicated, in, 'tumorigenesis,', but, its, precise, role, remains, unclear])].
[sujeto(['Matrigel', plugs, containing, 'pro-angiogenic', growth, factors, harbor]), verbo([increased]), complemento([numbers, of, morphologically, 'immature,', proliferating, endothelial, cells, in, 'Pparb(-/-)', 'mice,', and, retroviral, transduction, of, 'Pparb', triggers, microvessel, maturation])].
[sujeto(['We']), verbo([have]), complemento([identified, the, 'Cdkn1c', gene, encoding, the, cell, cycle, inhibitor, 'p57(Kip2)', as, a, 'PPARbeta', target, gene, and, a, mediator, of, the, 'PPARbeta-mediated', inhibition, of, cell, 'proliferation,', which, provides, a, possible, mechanistic, explanation, for, the, observed, tumor, endothelial, hyperplasia, and, deregulation, of, tumor, angiogenesis, in, 'Pparb(-/-)', mice])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, phytanic, acid, is, not, only, a, transactivator, of, 'PPARa,', but, it, also, acts, via, 'PPARb', and, 'PPARg', in, 'CV-1', cells, that, have, been, cotransfected, with, the, respective, 'full-length', receptor, and, an, 'acyl-CoA', 'oxidase-PPAR-responsive', 'element-luciferase', construct])].
[sujeto(['We', observed, 'that,', in, contrast, to, other, fatty, 'acids,', phytanic, acid, at, physiological, concentrations]), verbo([enhances]), complemento([uptake, of, 2, -, 'deoxy-D-glucose', in, rat, primary, hepatocytes])].
[sujeto(['This', result, could, be, explained, by, the]), verbo([increase]), complemento([in, mRNA, expression, of, glucose, 'transporters-1', and, -, 2, and, 'glucokinase,', as, determined, by, quantitative, 'real-time', reverse, 'transcriptase-polymerase', chain, reaction])].
[sujeto(['These', results, clearly, demonstrate, that, phytanic, acid]), verbo([acts]), complemento([via, different, 'PPAR', isoforms, to, modulate, expression, of, genes, involved, in, glucose, 'metabolism,', thus, suggesting, a, potential, role, of, phytanic, acid, in, the, management, of, insulin, resistance])].
[sujeto(['PPARB', was, identified, as, a]), verbo([target]), complemento([of, 'APC', through, the, analysis, of, global, gene, expression, profiles, in, human, colorectal, cancer, '(', 'CRC)', cells])].
[sujeto(['PPARdelta', expression, was, elevated, in, 'CRCs', and]), verbo([repressed]), complemento([by, 'APC', in, 'CRC', cells])].
[sujeto(['This', repression, was]), verbo([mediated]), complemento([by, 'beta-catenin/Tcf-4-responsive', elements, in, the, 'PPARdelta', promotor])].
[sujeto(['The', ability, of, 'PPARs', to]), verbo([bind]), complemento([eicosanoids, suggested, that, 'PPARdelta', might, be, a, target, of, chemopreventive, 'non-steroidal', 'anti-inflammatory', drugs, '(', 'NSAIDs)'])].
[sujeto(['Reporters', containing, 'PPARdelta-responsive', elements, were]), verbo([repressed]), complemento([by, the, 'NSAID', sulindac])].
[sujeto(['Furthermore,', sulindac, was, able, to, disrupt, the, ability, of, 'PPARdelta', to]), verbo([bind]), complemento([its, recognition, sequences])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'NSAIDs', inhibit, tumorigenesis, through, inhibition, of, 'PPARdelta,', the, gene, for, which, is, normally, regulated, by, 'APC'])].
[sujeto(['Peroxisome', 'proliferator-activated', 'receptor-gamma', '(', 'PPARg)', agonists]), verbo([have]), complemento([known, pleiotropic, cardiovascular, effects, with, favourable, properties, in, vascular, 'remodeling,', and, specifically, in, suppression, of, vascular, smooth, muscle, cell, proliferation])].
[sujeto(['EES', were, less, endothelialized, with, minimal, fibrin, 'deposition,', not]), verbo([found]), complemento([in, 'BMS', and, 'CCS', '(', '%', 'CD', 31, above, struts, after, 28, 'days,', 'BMS:', 100.0, '±0'])].
[sujeto(['pbPPARG-mediated', luciferase, activity, was]), verbo([suppressed]), complemento([by, synthetic, contaminant, mixtures, reflecting, levels, measured, in, polar, bear, adipose, 'tissue,', as, were, transcript, levels, of, 'PPARG', and, the, 'PPARG', target, gene, fatty, acid, binding, protein, 4, '(', 'FABP4)', in, pbASCs])].
[sujeto(['Contaminant', extracts, from, polar, bear, tissues]), verbo([enhanced]), complemento([triglyceride, accumulation, in, murine, 3, 'T3-L1', cells, and, 'pbASCs,', whereas, triglyceride, accumulation, was, not, affected, by, the, synthetic, mixtures])].
[sujeto(['Chemical', characterization, of, extracts, using, 'non-target', methods, revealed, presence, of, exogenous, compounds, that]), verbo([have]), complemento([previously, been, reported, to, induce, adipogenesis])].
[sujeto(['In', 'conclusion,', major, legacy, contaminants, in, polar, bear, adipose, tissue, exert, antagonistic, effects, on, 'PPARG,', but, adipogenesis, by, a, mixture, containing, emerging, compounds, may, be]), verbo([enhanced]), complemento([through, 'PPARG', or, other, pathways])].
[sujeto(['Infectious', diseases, are, more, frequent, in, diabetic, 'patients,']), verbo([leading]), complemento([to, increased, morbidity, and, mortality])].
[sujeto(['Quantitative', 'real-time', polymerase, chain, reaction, '(', 'PCR)', was, used, to, evaluate, the, expression, of, genes, in, white, adipose, tissue, '(', 'WAT)']), verbo([involved]), complemento(['in:', '(', 'i)', adipogenesis, '(', lipoprotein, lipase, '[', 'Lpl],', fatty, acid, binding, 'protein-4', '[', 'Ap2]', and, adiponectin, '[', 'Adipoq]);', '(', 'ii)', insulin, signaling, '(', peroxisome, 'proliferator-activated', receptor, gamma, '[', 'Pparg],', suppressor, of, cytokine, signaling, 3, '[', 'Socs3],', solute, carrier, family, 2, '[', facilitated, glucose, 'transporter],', member, 4, '[', 'Slc2a4]);', and, '(', 'iii)', inflammation, '(', tumor, necrosis, factor, '[', 'Tnf],', 'interleukin-6', '[', 'Il6],', monocyte, chemoattractant, 'protein-1', '[', 'Ccl2],', 'cyclo-oxygenase-2', '[', 'prostaglandin-endoperoxide', synthase, 2, ;, 'Ptgs2])'])].
[sujeto(['Pioglitazone', 'dose-dependently']), verbo([decreased]), complemento(['Tnf,', 'Il6,', 'Ccl2,', 'Ptgs2,', and, 'Socs3', expression, in, 'WAT,', in, association, with, upregulation, of, 'Lpl,', 'Ap2,', 'Slc2a4,', and, 'Adipoq', 'expression,', indicating, improvement, in, 'endotoxin-induced', 'IR'])].
[sujeto(['The', findings]), verbo([suggest]), complemento([that, 'LPS', challenge, exacerbates, 'IR', in, 'db/db', mice, by, altering, the, expression, of, genes, in, 'WAT', involved, in, adipogenesis, and, 'inflammation,', which, is, effectively, controlled, by, pioglitazone, treatment])].
[sujeto(['Prolonged', high, intakes, of, dietary, selenium]), verbo([have]), complemento([been, shown, to, induce, gestational, diabetes, in, rats, and, hyperinsulinemia, in, pigs])].
[sujeto([2, ',', the, 3, -, 'mg-Se/kg', 'diet,', compared, with, the, 0.3, -, 'mg-Se/kg', 'diet,']), verbo([increased]), complemento(['(', 'P', &, 'lt;', 0.05, ')', concentrations, of, plasma, insulin, '(', 0.2, compared, with, 0.4, 'ng/mL),', liver, and, adipose, lipids, '(', 41, '%', to, 2.4, -, 'fold),', and, liver, and, muscle, protein, '(', 10, -, 14, '%', ')'])].
[sujeto(['In', 'liver,', the, 3, -, 'mg-Se/kg', diet, upregulated, '(', 'P', &, 'lt;', 0.05, ')', the, 'expression,', 'activity,', or, both, of, key, factors, related, to, gluconeogenesis, '[', phosphoenolpyruvate, carboxykinase, '(', 'PEPCK);', 13, '%', ']', ',', lipogenesis, '[', sterol, regulatory, element]), verbo([binding]), complemento([protein, 1, '(', 'SREBP1),', 'acetyl-coenzyme', 'A', carboxylase, '(', 'ACC),', and, fatty, acid, synthase, '(', 'FASN);', 46, -, 90, '%', ']', ',', protein, synthesis, '[', insulin, receptor, '(', 'INSR),', 'P70', ribosomal, protein, 'S6', kinase, '(', 'P70),', and, phosphorylated, ribosomal, protein, 'S6', '(', 'P-S6);', 88, -, 105, '%', ']', ',', energy, metabolism, '[', 'AMP-activated', protein, kinase, '(', 'AMPK);', up, to, 2.8, -, 'fold],', and, selenoprotein, glutathione, peroxidase, 3, '(', 'GPX3;', 1.4, -, 'fold)', and, suppressed, '(', 'P', &, 'lt;', 0.05, ')', mRNA, levels, of, lipolysis, gene, cytochrome, 'P450,', family, 7, ',', subfamily, 'A,', polypeptide, 1, '(', 'CYP7A1;', 88, '%', ')', and, selenoprotein, gene, selenoprotein, 'W1', '(', 'SEPW1;', 46, '%', ')'])].
[sujeto(['In', 'muscle,', the, 3, -, 'mg-Se/kg', diet, exerted, no, effect, on, the, lipid, profiles, but]), verbo([enhanced]), complemento(['(', 'P', &, 'lt;', 0.05, ')', expression, of, 'P-S6', and, mammalian, target, of, rapamycin, '(', 'mTOR;', 42, -, 176, '%', ;, protein, 'synthesis);', selenoprotein, 'P', '(', 'SELP;', 40, -, 'fold);', and, tumor, suppressor, protein, 53, '(', 'P53)', and, peroxisome, 'proliferator-activated', receptor, γ, '(', 'PPARG;', 52, -, 58, '%', ;, 'lipogenesis)', and, suppressed, '(', 'P', &, 'lt;', 0.05, ')', expression, of, 'INSR', '(', 59, '%', ;, insulin, 'signaling);', selenoprotein, 'S', '(', 'SELS);', 'deiodinases,', 'iodothyronine,', type, 'I', '(', 'DIO1);', and, thioredoxin, reductase, 1, '(', 'TXNRD1;', 50, '%', ;, 'selenoproteins);', and, 'ACC1', and, 'FASN', '(', 35, -, 51, '%', ;, 'lipogenesis)'])].
[sujeto(['Our', research, showed, novel, 'roles,', to, our, best, 'knowledge,', and, mechanisms, of, high, selenium, intakes, in]), verbo([regulating]), complemento([the, metabolism, of, 'protein,', along, with, that, of, 'lipid,', in, a, 'tissue-specific', fashion, in, pigs])].
[sujeto(['MicroRNAs', '(', 'miRNAs)', are, noncoding, 'RNA', molecules, that]), verbo([regulate]), complemento([gene, expression, at, the, 'post-transcriptional', level, to, cause, translational, repression, or, degradation, of, targets])].
[sujeto(['A', total, of, 796]), verbo([conserved]), complemento(['miRNAs,', 263, new, 'miRNAs,', and, 821, 'pre-miRNAs', were, uncovered])].
[sujeto(['Further', studies, revealed, that, 'miR-145']), verbo([regulates]), complemento([metabolism, of, fatty, acids, in, goat, mammary, gland, epithelial, cells, '(', 'GMEC)'])].
[sujeto(['Compared', with, nonlactating, mammary, 'tissue,', lactating, mammary, gland, had, a, marked]), verbo([increase]), complemento([in, expression, of, 'miR-145'])].
[sujeto(['Overexpression', of, 'miR-145']), verbo([increased]), complemento([transcription, of, genes, associated, with, milk, fat, synthesis, resulting, in, greater, fat, droplet, 'formation,', triacylglycerol, 'accumulation,', and, proportion, of, unsaturated, fatty, acids])].
[sujeto(['Inhibition', of, 'miR-145']), verbo([increased]), complemento([methylation, levels, of, fatty, acid, synthase, '(', 'FASN),', 'stearoyl-CoA', desaturase, 1, '(', 'SCD1),', peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPARG),', and, sterol, regulatory, element, binding, transcription, factor, 1, '(', 'SREBF1)'])].
[sujeto(['Luciferase', reporter, assays, confirmed, that, insulin]), verbo([induced]), complemento([gene, 1, '(', 'INSIG1)', is, a, direct, target, of, 'miR-145'])].
[sujeto(['These', findings, underscore, the, need, for, further, studies, to, evaluate, the, potential, for]), verbo([targeting]), complemento(['miR-145', for, improving, beneficial, milk, components, in, ruminant, milk])].
[sujeto(['We', previously, generated, a, transgenic, mouse, model, of, 'PPFP', thyroid, carcinoma, and, showed, that, feeding, the, 'PPARγ', agonist, pioglitazone, greatly]), verbo([decreased]), complemento([the, size, of, the, primary, tumor, and, prevented, metastatic, disease, in, vivo, 'The', antitumor, effect, correlates, with, the, fact, that, pioglitazone, turns, 'PPFP', into, a, strongly, 'PPARγ-like', 'molecule,', resulting, in, 'trans-differentiation', of, the, thyroid, cancer, cells, into, 'adipocyte-like', cells, that, lose, malignant, character, as, they, become, more, differentiated])].
[sujeto(['Our', data, show, that, pioglitazone]), verbo([induced]), complemento([cellular, lipid, accumulation, and, the, expression, of, adipocyte, marker, genes, in, the, cultured, 'cells,', and, shRNA, knockdown, of, 'PPFP', eliminated, this, pioglitazone, effect])].
[sujeto(['In', 'addition,', we]), verbo([found]), complemento([that, 'PPFP', and, thyroid, transcription, factor, 1, '(', 'TTF-1)', physically, 'interact,', and, that, these, transcription, factors, bind, near, each, other, on, numerous, target, genes])].
[sujeto(['TTF-1', knockdown, and, overexpression, studies, showed, that, 'TTF-1']), verbo([inhibits]), complemento(['PPFP', target, gene, expression, and, impairs, adipogenic, 'trans-differentiation'])].
[sujeto(['Surprisingly,', pioglitazone]), verbo([repressed]), complemento(['TTF-1', expression, in, 'PPFP-expressing', thyrocytes])].
[sujeto(['Our', data, indicate, that, 'TTF-1']), verbo([interacts]), complemento([with, 'PPFP', to, inhibit, the, 'pro-adipogenic', response, to, 'pioglitazone,', and, that, the, ability, of, pioglitazone, to, decrease, 'TTF-1', expression, contributes, to, its, 'pro-adipogenic', action])].
[sujeto(['The', peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPARγ)']), verbo([regulates]), complemento([osteoblast, and, osteoclast, 'differentiation,', and, is, the, molecular, target, of, thiazolidinediones, '(', 'TZDs),', insulin, sensitizers, that, enhance, glucose, utilization, and, adipocyte, differentiation])].
[sujeto(['However,', clinical, use, of, 'TZDs']), verbo([has]), complemento([been, limited, by, side, effects, including, a, higher, risk, of, fractures, and, bone, loss])].
[sujeto(['Treatment', of, either, hyperglycemic, or, normoglycemic, animals, with, 'SR10171,', an, inverse, agonist, that, blocks, pS273, but, not, 'pS112,']), verbo([increased]), complemento([trabecular, and, cortical, bone, while, normalizing, metabolic, parameters])].
[sujeto(['Additionally,', 'SR10171', treatment]), verbo([modulated]), complemento(['osteocyte,', 'osteoblast,', and, osteoclast, 'activities,', and, decreased, marrow, adiposity])].
[sujeto(['These', data, demonstrate, that, regulation, of, bone, mass, and, energy, metabolism, shares, similar, mechanisms]), verbo([suggesting]), complemento([that, one, pharmacologic, agent, could, be, developed, to, treat, both, diabetes, and, metabolic, bone, disease])].
[sujeto(['The', paucity, of, biomarkers, to, predict, prostate, tumor, biology, makes, it, important, to, identify, key, pathways, that]), verbo([confer]), complemento([poor, prognosis, and, guide, potential, targeted, therapy])].
[sujeto(['Importantly,', inhibition, of, 'PPARG']), verbo([suppressed]), complemento([tumor, growth, in, 'vivo,', with, 'down-regulation', of, the, lipid, synthesis, program])].
[sujeto(['We', show, that, elevated, levels, of, 'PPARG', strongly, correlate, with, elevation, of, 'FASN', in, human, 'CaP', and, that, high, levels, of, 'PPARG/FASN', and, 'PI3K/pAKT', pathway, activation]), verbo([confer]), complemento([a, poor, prognosis])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'CaP', patients, could, be, stratified, in, terms, of, 'PPARG/FASN', and, 'PTEN', levels, to, identify, patients, with, aggressive, 'CaP', who, may, respond, favorably, to, 'PPARG/FASN', inhibition])].
[sujeto(['In', breeds, with, a, low, tendency, to, accumulate, 'IMF,', this, can]), verbo([lead]), complemento([to, compromised, meat, quality, because, of, the, contribution, of, fat, to, such, organoleptic, attributes, as, juiciness, and, taste])].
[sujeto(['This', study, considered, adiposity, and, gene, expression, of, some, of, the, main, markers]), verbo([involved]), complemento([in, adipogenesis, and, lipid, metabolism, in, the, subcutaneous, '(', 'SC)', adipose, tissue, '(', 'AT)', and, the, longissimus, thoracis, muscle, '(', 'LM)', and, investigated, differences, in, adipogenic, regulation, between, the, tissues, during, growth, and, fattening, under, different, conditions])].
[sujeto(['Backfat', thickness]), verbo([increased]), complemento([from, 6, to, 12, months, '(', 'P&lt;0'])].
[sujeto(['Although', age, and, diet, energy, density, did, not]), verbo([have]), complemento([a, significant, effect, on, increasing, the, amount, of, 'IMF,', these, factors, could, have, influenced, adipocyte, development, in, this, tissue, differently, than, in, the, 'SC', 'AT'])].
[sujeto(['This', was, evidenced, by, the, different, size, distributions, of, the, cells, in, the, two, 'tissues,', and, the, differing, expression, patterns, of, certain, markers, in, the, 'SC', 'AT', and, the, 'LM,', which, may, indicate, a, differential, role, of, 'PPARG', and, 'WNT10B', in]), verbo([triggering]), complemento([adipocyte, proliferation, and, fat, accumulation, capacity])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, gamma, '(', 'PPARG)', is, a, transcription, factor]), verbo([involved]), complemento([in, atherosclerosis, and, related, diseases])].
[sujeto(['In', this, 'study,', we, aimed, to, investigate, whether, 'PPARG', 'C161T', was]), verbo([associated]), complemento([with, lipid, levels, and, 'large-artery', atherosclerosis, '(', 'LAA)', ischemic, stroke, in, a, 'Han', 'Chinese', population, in, 'Guangdong', province])].
[sujeto(['The', frequency, of, 'CC', was, higher, than, that, of, 'CT&nbsp;+&nbsp;TT', and, was, significantly]), verbo([associated]), complemento([with, 'LAA', ischemic, stroke])].
[sujeto([29, ')', ;, the, 'PPARG', 'C161T', allele, was, not, independently]), verbo([associated]), complemento([with, an, increased, risk, of, 'LAA', ischemic, stroke, '(', 'OR&nbsp;=&nbsp;0'])].
[sujeto(['In', this, 'Han', 'population,', 'PPARG', 'C161T', 'CT/TT', was]), verbo([associated]), complemento([with, 'LAA', ischemic, stroke, and, lower, levels, of, blood, 'TC', and, 'LDL-C,', but, was, not, an, independent, risk, factor, for, 'LAA', ischemic, stroke])].
[sujeto(['Lambs', fed, 'L-A', diet, showed, lower, average, daily]), verbo([gain]), complemento([and, greater, slaughter, age, compared, to, 'Control', and, 'L', '(', 'P', &, 'lt;', 0.001, ')'])].
[sujeto(['Adding', either, linseed, or, linseed, and, algae]), verbo([increased]), complemento(['α-linolenic', acid, and, eicosapentaenoic, acid, contents, in, both, 'AT', '(', 'P', &, 'lt;', 0.001, ')', ;, 'however,', docosahexaenoic, acid, was, increased, by, 'L-A', '(', 'P', &, 'lt;', 0.001, ')'])].
[sujeto(['The', 'n-6/n-3', ratio]), verbo([decreased]), complemento([in, 'L', and, 'L-A', '(', 'P', &, 'lt;', 0.001, ')'])].
[sujeto(['In', the, subcutaneous, 'AT,', supplementing, either, 'L', or, 'L-A']), verbo([increased]), complemento([peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPARG)', and, 'CAAT-enhancer', binding, protein, alpha, '(', 'CEBPA)', '(', 'P', &, 'lt;', 0.05, ')', ',', although, it, had, no, effect, on, sterol, regulatory, 'element-binding', factor, 1, '(', 'SREBF1)'])].
[sujeto(['In', the, intramuscular, 'AT,', expression, of, 'ACACA,', 'SCD,', 'FADS1', and, 'FADS2']), verbo([decreased]), complemento([in, 'L', and, 'L-A', '(', 'P', &, 'lt;', 0.001, ')', and, 'LPL', in, 'L', '(', 'P', &, 'lt;', 0.01, ')', ',', but, 'PPARG,', 'CEBPA', and, 'SREBF1', were, unaffected])].
[sujeto(['The', aim, of, this, study, was, to, predict, the, key, genes, and, pathways]), verbo([associated]), complemento([with, papillary, thyroid, carcinoma, '(', 'PTC)'])].
[sujeto(['Based', on, the, microarray, data, of, 'GSE3467', from, 'Gene', 'Expression', 'Omnibus', 'database,', we, identified, the, differentially]), verbo([expressed]), complemento([genes, '(', 'DEGs)', between, 9, 'PTC', samples, and, 9, normal, controls])].
[sujeto(['The', 'down-regulated', 'DEGs,', including, paired, box, 8, '(', 'PAX8),', peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPARG),', and, cadherin, 1, ',', type, 1, were]), verbo([found]), complemento([enriched, in, 'hsa05216:Thyroid', cancer])].
[sujeto(['Disease-associated', network, analysis]), verbo([found]), complemento([that, 15, key, genes, such, as, 'JUN,', 'PPARG', and, matrix, metallopeptidase, 9, '(', 'MMP9)', were, involved, in, this, network])].
[sujeto(['DEGs', of, 'C3,', 'PPARG,', 'PAX8,', 'JUN', and, 'MMP9', were, differentially]), verbo([expressed]), complemento([in, 'PTC', samples, and, may, be, used, as, potential, biomarkers, in, the, diagnosis, and, treatment, of, 'PTC'])].
[sujeto(['Diabetes', and, obesity, are]), verbo([associated]), complemento([with, an, increased, risk, of, arrhythmia, and, sudden, cardiac, death])].
[sujeto(['A', transgenic, mouse, model, of, cardiac, lipid, 'overload,', the, peroxisome, 'proliferator-activated', 'receptor-γ', '(', 'PPARg)', cardiac, overexpression, 'mouse,']), verbo([has]), complemento([long, 'QT', and, increased, ventricular, ectopy])].
[sujeto(['The', purpose, of, this, study, was, to, evaluate, the, hypothesis, that, the]), verbo([increase]), complemento([in, ventricular, ectopy, during, cardiac, lipid, overload, is, caused, by, abnormalities, in, calcium, handling, due, to, increased, mitochondrial, oxidative, stress])].
[sujeto(['PPARg', cardiomyocytes]), verbo([have]), complemento([more, frequent, triggered, activity, and, increased, sparks, compared, to, control])].
[sujeto(['Sparks', and]), verbo([triggered]), complemento([activity, are, reduced, by, 'mitotempo,', a, 'mitochondrial-targeted', antioxidant])].
[sujeto(['This', is, explained, by, a, significant]), verbo([increase]), complemento([in, oxidation, of, 'RyR2'])].
[sujeto(['Calcium', transients, are]), verbo([increased]), complemento([in, 'amplitude,', and, sarcoplasmic, reticulum, '(', 'SR)', calcium, stores, are, increased, in, 'PPARg', cardiomyocytes])].
[sujeto(['Computer', modeling, of, the, cardiac, action, potential, demonstrates, that, long, 'QT', contributes, to]), verbo([increased]), complemento(['SR', calcium])].
[sujeto(['Mitotempo']), verbo([decreased]), complemento([ventricular, ectopy, in, vivo])].
[sujeto(['During', cardiac, lipid, 'overload,', mitochondrial, oxidative, stress]), verbo([causes]), complemento([increased, 'SR', calcium, leak, by, oxidizing, 'RyR2', channels])].
[sujeto(['This']), verbo([promotes]), complemento([ventricular, 'ectopy,', which, is, significantly, reduced, in, vivo, by, a, 'mitochondrial-targeted', antioxidant])].
[sujeto(['These', results]), verbo([suggest]), complemento([a, potential, role, for, 'mitochondrial-targeted', antioxidants, in, preventing, arrhythmia, and, sudden, cardiac, death, in, obese, and, diabetic, patients])].
[sujeto(['The', aim, of, the, present, study, was, to, investigate, the, effects, of, microRNA, '(', 'miR)-128', inhibition, on, the]), verbo([targeted]), complemento([activation, of, peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPARG)', and, on, cardiomyocyte, apoptosis, induced, by, myocardial, 'ischemia/reperfusion', '(', 'I/R)', injury])].
[sujeto(['Luciferase', reporter, assays, were, used, to, identify, whether, 'PPARG', is, a, direct]), verbo([target]), complemento([of, 'miR&#8209;128'])].
[sujeto(['Western', blotting, investigated, the, activation, of, 'Akt', '[']), verbo([phosphorylated]), complemento(['(', 'p)&#8209;Akt]', and, the, expression, of, 'total&#8209;Akt,', 'PPARG', and, myeloid, leukemia, cell, differentiation, 'protein&#8209;1', '(', 'Mcl&#8209;1)', in, the, myocardium])].
[sujeto(['Activation', of, 'Akt', '(', 'p&#8209;Akt),', 'Mcl&#8209;1', and, 'PPARG', expression, in, the, myocardium, were]), verbo([increased]), complemento([by, 'miR&#8209;128', inhibition])].
[sujeto(['In', 'conclusion,', 'miR&#8209;128', inhibition, attenuated, 'I/R', 'injury&#8209;induced', cardiomyocyte, apoptosis, by, the]), verbo([targeted]), complemento([activation, of, 'PPARG', signaling])].
[sujeto(['To', assess, whether, body, mass, index, '(', 'BMI)', in, pregnancy, is]), verbo([associated]), complemento([with, changes, in, the, methylation, of, the, peroxisome, 'proliferator-activated', receptor, γ, '(', 'PPAR)', promoter, region, '(', -, 359, to, -, 260, ')', in, maternal, and, neonatal, leukocytes])].
[sujeto(['Significant', differences, were]), verbo([found]), complemento([in, 'BMI,', pregestational, 'weight,', and, postdelivery, weight, between, groups, but, not, in, the, methylation, status, of, the, 'PPARγ', promoter, region, '(', -, 359, to, -, 260, ')'])].
[sujeto(['Alcohol', consumption, is]), verbo([associated]), complemento([with, increased, risk, of, breast, cancer, '(', 'BC),', and, the, underlying, mechanism, is, thought, to, be, 'sex-hormone', driven])].
[sujeto(['In', vitro, and, observational, studies]), verbo([suggest]), complemento([a, mechanism, involving, peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPARγ)', in, a, complex, with, peroxisome, 'proliferator-activated', receptor, gamma, coactivator, 1, -, α, '(', 'PGC-1α)', and, interaction, with, aromatase, '(', encoded, by, 'CYP19A1)'])].
[sujeto(['In', the, present, study, we, assessed, whether, genetic, variation, in, 'CYP19A1', is]), verbo([associated]), complemento([with, risk, of, 'BC', in, a, 'case-control', study, group, nested, within, the, 'Danish', &, 'quot;Diet,', 'Cancer', and, 'Health&quot;', cohort, '(', ncases, =, 687, and, ncontrols, =, 687, ')', and, searched, for, 'gene-gene', interaction, between, 'CYP19A1', and, 'PPARGC1A,', and, 'CYP19A1', and, 'PPARG,', and, 'gene-alcohol', and, 'gene-NSAID', interactions])].
[sujeto(['Genetic', variations, in, 'CYP19A1', were]), verbo([associated]), complemento([with, hormone, levels, '(', 'estrone:', 'P', rs11070844, =, 0.009, ',', estrone, 'sulphate:', 'P', rs11070844, =, 0.01, ',', 'P', rs749292, =, 0.004, ',', 'P', rs1062033, =, 0.007, and, 'P', rs10519297, =, 0.03, ',', and, sex, 'hormone-binding', globulin, '(', 'SHBG):', 'P', rs3751591, =, 0.03, ')', and, interacted, with, alcohol, intake, in, relation, to, hormone, levels, '(', estrone, 'sulphate:', 'P', 'interaction/rs2008691', =, 0.02, and, 'P', 'interaction/rs1062033=', 0.03, ',', and, 'SHBG:', 'P', 'interaction/rs11070844', =, 0.03, ')'])].
[sujeto(['CYP19A1/rs3751591', was, both]), verbo([associated]), complemento([with, 'SHBG', levels, '(', 'P', =, 0.03, ')', and, with, risk, of, 'BC', '(', 'Incidence', 'Rate', 'Ratio', =, 2.12, ;, 95, '%', 'Confidence', 'Interval:', 1.02, -, 4.43, ')', such, that, homozygous, variant, allele, carriers, had, increased, levels, of, serum, 'SHBG', and, were, at, increased, risk, of, 'BC'])].
[sujeto(['Acute', intake, of, alcohol]), verbo([decreased]), complemento([blood, estrone, '(', 'P', =, &, 'lt;0'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, genetically, determined, variation, in, 'CYP19A1', is, associated, with, differences, in, sex, hormone, levels])].
[sujeto(['However,', the, genetically, determined, differences, in, sex, hormone, levels, were, not, convincingly]), verbo([associated]), complemento([with, 'BC', risk])].
[sujeto(['Estrogen', deficiency, in, women, and, 'high-saturated', 'fat,', 'high-sucrose', '(', 'HFS)', diets]), verbo([have]), complemento([both, been, recognized, as, risk, factors, for, metabolic, syndrome])].
[sujeto(['Ovariectomy']), verbo([decreased]), complemento([bone, mineral, density, in, the, tibia, head, '(', 'TH)', by, 62, '%', and, the, femoral, end, '(', 'FE)', by, 49, '%', '(', 'P', &, 'lt;', 0.0001, ')'])].
[sujeto(['The', 'HFS', diet, aggravated, bone]), verbo([loss]), complemento([in, 'OVX', rats, by, an, additional, 41, '%', in, the, 'TH', and, 37, '%', in, the, 'FE', '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['Bone']), verbo([loss]), complemento([in, the, 'HFS-OVX', rats, was, accompanied, by, increased, urinary, deoxypyridinoline, concentrations, by, 28, '%', '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['The', 'HFS', diet]), verbo([induced]), complemento([cathepsin, 'K', by, 145, '%', but, reduced, osteoprotegerin, mRNA, expression, at, the, 'FE', of, the, 'HFS-sham', rats, by, 71, '%', '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['Ovariectomy', significantly]), verbo([increased]), complemento([peroxisome, 'proliferator-activated', receptor, γ, mRNA, expression, by, 136, '%', and, 170, '%', at, the, 'FE', of, the, 'LFS-', and, 'HFS-OVX', 'rats,', respectively, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['Our', previous, study, demonstrated, that, 14, -, 3, -, 3, γ, overexpression, was, able, to]), verbo([inhibit]), complemento([the, production, of, lipopolysaccharide, '(', 'LPS)-induced', cytokines, in, dairy, cow, mammary, epithelial, cells, '(', 'DCMECs)', by, inhibiting, the, activation, of, nuclear, 'factor-κB', '(', 'NF-κB)', signaling, pathways])].
[sujeto(['The', results, of, the, 'MTT', assay, and, lactate, dehydrogenase, activity, assay, demonstrated, that, 14, -, 3, -, 3, γ, overexpression, was, able, to, attenuate, 'LPS-induced', cytotoxicity, in, 'DCMECs,', and]), verbo([increase]), complemento([the, viability, of, the, cells])].
[sujeto(['In', 'addition,', the, results, of, reverse, 'transcription-quantitative', polymerase, chain, reaction]), verbo([suggested]), complemento([that, mRNA, expression, levels, of, genes, associated, with, milk, fat, 'synthesis,', including, sterol, regulatory, element, binding, protein, '(', 'SREBP1),', peroxisome, 'proliferator-activated', 'receptor-γ', '(', 'PPARG),', cluster, of, differentiation, 36, ',', 'acetyl-coA', carboxylase, '(', 'ACC),', fatty, acid, synthase, '(', 'FAS)', and, fatty, acid, binding, 'protein-3,', were, significantly, upregulated, in, cells, overexpressing, the, 14, -, 3, -, 3, γ, protein])].
[sujeto(['Furthermore,', western, blotting, demonstrated, that, 14, -, 3, -, 3, γ, overexpression]), verbo([enhanced]), complemento([the, protein, expression, levels, of, phosphorylated, 'SREBP1', and, 'PPARG'])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, high, levels, of, 14, -, 3, -, 3, γ, protein, were, able, to, attenuate, 'LPS-induced', cell, damage, and, promote, milk, fat, synthesis, in, 'LPS-induced', 'DCMECs', by, increasing, the, cell, viability, and, upregulating, the, expression, levels, of, transcription, factors, associated, with, milk, fat, synthesis])].
[sujeto(['Cellular', and, molecular, markers]), verbo([expressed]), complemento([during, osteoblastic, differentiation, were, assessed, by, cytochemical, 'analysis,', 'real-time', quantitative, 'PCR,', 'Western', 'blotting,', and, cDNA, microarray, analysis])].
[sujeto(['These', effects, were, blocked, by, 'ICI', 182, ',', 780, ',']), verbo([suggesting]), complemento([that, icariin, may, be, acting, via, the, estrogen, receptor, '(', 'ER)'])].
[sujeto(['In', 'total,', osteoblastic, gene, expression, profile, analysis]), verbo([suggested]), complemento([that, 33, genes, were, affected, by, 'icariin;', these, could, be, 'sub-divided', into, nine, functional, categories])].
[sujeto(['It', appears, that, icariin, could]), verbo([stimulate]), complemento([the, differentiation, and, mineralization, of, 'osteoblasts,', regulate, the, differentiation, of, 'osteoclasts,', and, inhibit, the, adipogenic, transdifferentiation, of, 'osteoblasts,', therefore, increasing, the, number, of, osteoblasts, undergoing, differentiation, to, mature, 'osteoblasts,', via, an, 'ER-mediated', pathway])].
[sujeto(['Pathogenesis', of, pulmonary, hypertension, is, complex, and]), verbo([involves]), complemento([activation, of, the, transcription, 'factor,', 'hypoxia-inducible', 'factor-1', '(', 'HIF-1)', that, shifts, cellular, metabolism, from, aerobic, respiration, to, 'glycolysis,', in, 'part,', by, increasing, the, expression, of, its, downstream, target, pyruvate, dehydrogenase, 'kinase-1', '(', 'PDK-1),', thereby, promoting, a, 'proliferative,', 'apoptosis-resistant', phenotype, in, pulmonary, vascular, cells])].
[sujeto(['Activation', of, the]), verbo([nuclear]), complemento([hormone, transcription, 'factor,', peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPARγ),', attenuates, pulmonary, hypertension, and, pulmonary, artery, smooth, muscle, cell, '(', 'PASMC)', proliferation])].
[sujeto(['In', the, current, 'study,', we, determined, whether, 'PPARγ']), verbo([inhibits]), complemento(['HIF-1α', and, 'PDK-1', expression, in, human, 'PASMCs'])].
[sujeto(['HIF-1α', protein, levels]), verbo([increased]), complemento([following, 4, and, 8, hours, of, hypoxia, and, returned, to, baseline, levels, by, 24, and, 72, hours])].
[sujeto(['PDK-1', protein, levels]), verbo([increased]), complemento([following, 24, hours, hypoxia, and, remained, elevated, by, 72, hours])].
[sujeto(['However,', 'RSG', treatment, during, final, 24, hours, of, 72, -, hour, 'hypoxia,', an, intervention, that]), verbo([inhibits]), complemento(['HPASMC', 'proliferation,', failed, to, prevent, 'hypoxia-induced', 'PDK-1', expression])].
[sujeto(['Hypoxia']), verbo([causes]), complemento([transient, activation, of, 'HPASMC', 'HIF-1α', that, is, attenuated, by, 'RSG', treatment, initiated, at, hypoxia, onset])].
[sujeto(['These', findings]), verbo([provide]), complemento([novel, evidence, that, 'PPARγ', modulates, fundamental, and, acute, cellular, responses, to, hypoxia, through, both, 'HIF-1-dependent', and, 'HIF-1-independent', mechanisms])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, gamma, '(', 'PPARγ)', is, a]), verbo([nuclear]), complemento([receptor, that, regulates, the, expression, of, many, genes, relevant, to, carcinogenesis])].
[sujeto(['Molecules', 3, 'c,', 3, 'm,', 4, c, and, 4, m, were]), verbo([found]), complemento([to, have, 'GI50', value, less, than, 50, μM])].
[sujeto(['These', molecules, were]), verbo([found]), complemento([to, block, 'G0/G1', phase, of, cell, cycle, in, dose, dependent, manner])].
[sujeto(['Western', blot, analysis, revealed, that, these, molecules]), verbo([inhibit]), complemento([proliferating, cell, nuclear, antigen, '(', 'PCNA)', and, cyclin, 'D1', expression])].
[sujeto(['Collectively,', these, results]), verbo([suggest]), complemento([that, these, molecules, could, play, a, role, as, a, novel, therapeutic, strategy, for, chronic, myeloid, leukemia])].
[sujeto(['Hypoxia']), verbo([stimulates]), complemento([pulmonary, hypertension, '(', 'PH),', in, part, by, increasing, the, proliferation, of, human, pulmonary, artery, smooth, muscle, cells, '(', 'HPASMCs)', via, sustained, activation, of, 'mitogen-activated', protein, 'kinase,', extracellular, 'signal-regulated', kinases, 1, and, 2, '(', 'ERK', 1, /, 2, ')', ',', and, nuclear, 'factor-kappa', 'B', '(', 'NF-κB);', elevated, expression, of, 'NADPH', oxidase, 4, '(', 'Nox4);', and, downregulation, of, peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPARγ)', levels])].
[sujeto(['Hypoxia']), verbo([activated]), complemento(['Pyk2', '(', detected, as, 'Tyr402', 'phosphorylation),', and, inhibition, of, 'Pyk2', with, small, interfering, 'RNA', '(', 'siRNA)', or, tyrphostin, 'A9', attenuated, 'hypoxia-induced', 'HPASMC', proliferation])].
[sujeto(['Pyk2', inhibition, attenuated, 'ERK', 1, /, 2, activation, as, early, as, 24, hours, after, the, onset, of, 'hypoxia,']), verbo([suggesting]), complemento([a, proximal, role, for, 'Pyk2', in, this, response])].
[sujeto(['Pyk2', inhibition, also, attenuated, 'hypoxia-induced', 'NF-κB', 'activation,', reduced, 'HPASMC', 'PPARγ', messenger, 'RNA', levels, and, 'activity,', and]), verbo([increased]), complemento(['NF-κB-mediated', 'Nox4', levels])].
[sujeto(['The', 'siRNA-mediated', 'PPARγ', knockdown]), verbo([enhanced]), complemento(['Pyk2', 'activation,', whereas, 'PPARγ', overexpression, reduced, 'Pyk2', activation, in, 'HPASMCs,', confirming, a, reciprocal, relationship, between, 'Pyk2', and, 'PPARγ'])].
[sujeto(['These', in, vitro, findings]), verbo([suggest]), complemento([that, 'Pyk2', plays, a, central, role, in, the, proliferative, phenotype, of, pulmonary, vascular, wall, cells, under, hypoxic, conditions])].
[sujeto(['Coupled', with, recent]), verbo([reports]), complemento([that, 'hypoxia-induced', 'PH', is, attenuated, in, 'Pyk2', knockout, 'mice,', these, findings, suggest, that, 'Pyk2', may, represent, a, novel, therapeutic, target, in, 'PH'])].
[sujeto(['Some', recent]), verbo([reports]), complemento([suggest, that, a, disproportionate, accumulation, of, 'DAT', is, related, to, 'obesity-associated', metabolic, complications])].
[sujeto(['This', is, consistent, with, the, findings, of, an, in, vitro, study, 'that,', compared, with, ccdPAs, in, 'DAT,', ccdPAs, in, 'SAT']), verbo([have]), complemento([higher, adipogenic, potential, and, lower, 'DNA', methylation, levels, of, 'PPAR-γ'])].
[sujeto(['The', senescence, effector, 'p16(Ink4a)', is]), verbo([expressed]), complemento([in, pancreatic, beta, cells, during, aging, and, limits, their, proliferative, 'potential;', 'however,', its, effects, on, beta, cell, function, are, poorly, characterized])].
[sujeto(['We']), verbo([found]), complemento([that, beta, 'cell-specific', activation, of, 'p16(Ink4a)', in, transgenic, mice, enhances, 'glucose-stimulated', insulin, secretion, '(', 'GSIS)'])].
[sujeto(['In', mice, with, 'diabetes,', this]), verbo([leads]), complemento([to, improved, glucose, 'homeostasis,', providing, an, unexpected, functional, benefit])].
[sujeto(['Expression', of, 'p16(Ink4a)', in, beta, cells]), verbo([induces]), complemento([hallmarks, of, 'senescence--including', cell, 'enlargement,', and, greater, glucose, uptake, and, mitochondrial, 'activity--which', promote, increased, insulin, secretion])].
[sujeto(['GSIS']), verbo([increases]), complemento([during, the, normal, aging, of, mice, and, is, driven, by, elevated, 'p16(Ink4a)', activity])].
[sujeto(['We']), verbo([found]), complemento([that, islets, from, human, adults, contain, 'p16(Ink4a)-expressing', senescent, beta, cells, and, that, senescence, induced, by, 'p16(Ink4a)', in, a, human, beta, cell, line, increases, insulin, secretion, in, a, manner, 'dependent,', in, 'part,', on, the, activity, of, the, mechanistic, target, of, rapamycin, '(', 'mTOR)', and, the, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)-γ', proteins])].
[sujeto(['Our', findings]), verbo([reveal]), complemento([a, novel, role, for, 'p16(Ink4a)', and, cellular, senescence, in, promoting, insulin, secretion, by, beta, cells, and, in, regulating, normal, functional, tissue, maturation, with, age])].
[sujeto(['Whether', combined, use, can]), verbo([enhance]), complemento([effect, is, unknown])].
[sujeto(['Concomitant', use, of, the, two, drugs]), verbo([inhibited]), complemento([the, proliferation, of, 'WT9-12', cells, significantly, through, a, superimposition, effect])].
[sujeto(['Rosiglitazone']), verbo([inhibited]), complemento([the, phosphorylation, of, mTOR, target, p70S6K])].
[sujeto(['Rosiglitazone', also]), verbo([inhibited]), complemento([the, phosphorylation, of, 'Akt', and, antagonize, the, activation, of, 'Akt', induced, by, rapamycin])].
[sujeto(['Concomitant', use, of, rosiglitazone, and, rapamycin, significantly, retarded, the, deterioration, of, renal, 'function,']), verbo([decreased]), complemento([cyst, cell, proliferation, and, interstitial, fibrosis, in, 'Han:', 'SPRD', rats])].
[sujeto(['Rapamycin', significantly]), verbo([increased]), complemento([cholesterol, levels, in, the, 'blood,', whereas, rosiglitazone, mitigated, 'rapamycin-induced', hyperlipidemia])].
[sujeto(['These', results, indicate, that, the, effects, of, concomitant, use, of, rosiglitazone, and, rapamycin, in]), verbo([inhibiting]), complemento([the, proliferation, of, 'WT9-12', cells, and, delaying, the, progression, of, 'ADPKD', in, 'Han:SPRD', rats, are, stronger, than, those, of, either, drug, alone])].
[sujeto(['The', present, study, may]), verbo([provide]), complemento([a, new, strategy, for, the, 'long-term', treatment, of, 'ADPKD'])].
[sujeto(['External', volume, expansion, by, suction, is, used, to, prepare, the, recipient, site, for, fat, grafting, by]), verbo([increasing]), complemento([its, compliance, and, vascularity])].
[sujeto(['Both', a, 2, -, hour, stimulation, and, cyclical, 2, -, hour, stimulation, for, 5, days]), verbo([induced]), complemento([1.5, -, and, 1.9, -, fold, increases, in, the, number, of, adipocytes, per, millimeter])].
[sujeto(['Peroxisome', 'proliferator-activated', 'receptor-γ', was]), verbo([increased]), complemento([at, the, end, of, stimulation])].
[sujeto(['Stretch', is, known, to]), verbo([stimulate]), complemento(['proliferation,', whereas, edema, and, inflammation, are, both, emerging, proadipogenic, factors])].
[sujeto(['The', 'anti-cancer', effects, of, 'TZDs', neither, correlate, well, with, their, ability, to]), verbo([activate]), complemento(['PPARγ', 'receptor,', nor, are, affected, by, the, presence, of, 'PPARγ', receptor, antagonists])].
[sujeto(['Accumulating', evidence]), verbo([suggests]), complemento([that, 'TZDs', act, as, selective, inhibitors, of, 'insulin-like', growth, 'factor-1', '(', 'IGF-1)', receptor, 'signaling,', and, 'IGF-1', signaling, is, known, to, be, aberrantly, regulated, in, various, cancers])].
[sujeto(['Structural', analysis, of, 'TZDs']), verbo([suggest]), complemento([that, the, presence, of, 5, -, exo, 'C-C', single, bond, of, the, 'thiazolidine-2,4-dione', ring, is, important, for, the, metabolic, effects, but, not, for, 'anti-cancer', 'effects,', as, inclusion, of, 'C=C', double, bond, at, this, position, promotes, antagonistic, properties, to, the, 'PPARγ', receptor, without, compromising, its, 'anti-proliferative', effects])].
[sujeto(['The', objectives, of, this, review, includes, summarization, of, the, relative, influence, of, 'TZDs', on, 'PPARγ', and, 'IGF-1', signaling, in]), verbo([mediating]), complemento([pharmacological, 'effects,', and, to, discuss, the, possibility, of, multiple, 'pharmacophores,', and, thereby, independent, regulation, of, 'PPARγ', and, 'IGF-1', signaling])].
[sujeto(['Male', 'Sprague', 'Dawley', rats, were, given, monocrotaline, '(', 'M,', 40, 'mg/kg)', or, subjected, to, hypobaric, hypoxia, '(', 'H)', to]), verbo([induce]), complemento(['PH'])].
[sujeto(['In', the, 4, wk, 'M+H', 'group,', several, arteries, with, reduced, 'caveolin-1', expression, in, endothelial, layer, coupled, with, an]), verbo([increased]), complemento([expression, in, smooth, muscle, cells, '(', 'SMC),', exhibited, neointimal, lesions])].
[sujeto(['Neointima', was, present, only, in, the, arteries, exhibiting]), verbo([enhanced]), complemento(['caveolin-1', expression, in, 'SMC'])].
[sujeto(['Lung', tissue, obtained, from, patients, with, 'PH', also, revealed, neointimal, lesions, only, in, the, arteries, exhibiting, endothelial, 'caveolin-1']), verbo([loss]), complemento([accompanied, by, an, increased, 'caveolin-1', expression, in, 'SMC'])].
[sujeto(['In', both, 'M', groups, and, in, the, 'M', +, 'H', group, at, 2, 'wk,', endothelial, 'caveolin-1']), verbo([loss]), complemento([was, accompanied, by, an, increase, in, 'PPARγ', expression])].
[sujeto(['In', the, 'M', +, 'H', group, at, 4, 'wk,']), verbo([increase]), complemento([in, 'caveolin-1', expression, was, accompanied, by, a, reduction, in, the, 'PPARγ', expression])].
[sujeto(['In', the, 'H', 'group,', there, was, neither, a]), verbo([loss]), complemento([of, endothelial, 'caveolin-1,', eNOS, or, 'HSP90,', nor, an, increase, in, 'SMC', 'caveolin-1', 'expression;', or, any, alteration, in, 'PPARγ', expression])].
[sujeto(['Proliferative', pathways, were]), verbo([activated]), complemento([in, all, experimental, groups])].
[sujeto(['Enhanced', 'caveolin-1', expression, in, 'SMC', follows, extensive, endothelial, 'caveolin-1']), verbo([loss]), complemento([with, subsequent, neointima, formation])].
[sujeto(['Estrogens', such, as, the, metabolite, 16, 'α-hydroxyestrone', '(', 16, 'αOHE)', may, contribute, to, 'PAH', 'pathogenesis,', and, alterations, in, cellular, energy, metabolism]), verbo([associate]), complemento([with, 'PAH'])].
[sujeto(['We', hypothesized, that, 16, αOHE]), verbo([promotes]), complemento([heritable, 'PAH', '(', 'HPAH)', via, 'microRNA-29', '(', 'miR-29)', family, upregulation, and, that, antagonism, of, 'miR-29', would, attenuate, pulmonary, hypertension, in, transgenic, mouse, models, of, 'Bmpr2', mutation])].
[sujeto(['MicroRNA', array, profiling, of, human, lung, tissue]), verbo([found]), complemento([elevation, of, microRNAs, associated, with, energy, 'metabolism,', including, the, 'miR-29', 'family,', among, 'HPAH', patients])].
[sujeto(['Pulmonary', artery, smooth, muscle, cells, derived, from, 'Bmpr2', murine, lungs, demonstrated, mitochondrial, 'abnormalities,', which, improved, with, 'anti-miR-29', transfection, in, 'vitro;', 'endothelial-like', cells, derived, from, 'HPAH', patient]), verbo([induced]), complemento([pluripotent, stem, cell, lines, were, similar, and, improved, with, 'anti-miR-29', treatment])].
[sujeto([16, αOHE]), verbo([promotes]), complemento([the, development, of, 'HPAH', via, upregulation, of, 'miR-29,', which, alters, molecular, and, functional, indexes, of, energy, metabolism])].
[sujeto(['Antagonism', of, 'miR-29', improves, in, vivo, and, in, vitro, features, of, 'HPAH', and]), verbo([reveals]), complemento([a, possible, novel, therapeutic, target])].
[sujeto(['The', seipin, gene, '(', 'BSCL2)', was, originally, identified, in, humans, as, a, 'loss-of-function', gene]), verbo([associated]), complemento([with, congenital, generalized, lipodystrophy, type, 2, '(', 'CGL2)'])].
[sujeto(['STAT3', phosphorylation, '(', 'Tyr705)', was]), verbo([enhanced]), complemento([in, 'seipin-nKO', 'mice,', and, was, further, elevated, by, rosi, treatment])].
[sujeto(['Although', human, pluripotent, stem, cells, '(', 'hPSCs)']), verbo([provide]), complemento([valuable, sources, for, regenerative, 'medicine,', their, applicability, is, dependent, on, obtaining, both, suitable, 'up-scaled', and, cost, effective, cultures])].
[sujeto(['Here', we]), verbo([have]), complemento([shown, that, 'pioglitazone,', a, selective, peroxisome, 'proliferative-activated', 'receptor-γ', 'agonist,', along, with, 'Y-27632', synergistically, diminished, 'dissociation-induced', apoptosis, and, increased, cloning, efficiency, '(', 2, -, 3, -, fold, versus, 'Y-27632)', without, affecting, pluripotency, of, hPSCs])].
[sujeto(['This', novel, setting]), verbo([provided]), complemento([a, step, toward, hPSC, manipulation, and, its, biomedical, applications])].
[sujeto(['Pulmonary', hypertension, '(', 'PH)', is, a, progressive, and, often, fatal, disorder, whose, pathogenesis]), verbo([involves]), complemento([pulmonary, artery, smooth, muscle, cell, '(', 'PASMC)', proliferation])].
[sujeto(['Although', modern, 'PH', therapies]), verbo([have]), complemento([significantly, improved, 'survival,', continued, progress, rests, on, the, discovery, of, novel, therapies, and, molecular, targets])].
[sujeto(['MicroRNA', '(', 'miR)-21']), verbo([has]), complemento([emerged, as, an, important, 'non-coding', 'RNA', that, contributes, to, 'PH', pathogenesis, by, enhancing, vascular, cell, 'proliferation,', however, little, is, known, about, available, therapies, that, modulate, its, expression])].
[sujeto(['PTEN', is, a, validated]), verbo([target]), complemento([of, 'miR-21'])].
[sujeto(['We', therefore, hypothesized, that, antiproliferative, effects]), verbo([conferred]), complemento([by, 'PPARγ', activation, are, mediated, through, inhibition, of, 'hypoxia-induced', 'miR-21', expression])].
[sujeto(['RSG', attenuated, hypoxic]), verbo([increases]), complemento([in, 'miR-21', expression, in, vitro, and, in, vivo, and, abrogated, reductions, in, 'PTEN', and, 'PASMC', proliferation])].
[sujeto(['Furthermore,', 'miR-21', mimic]), verbo([decreased]), complemento(['PTEN', and, stimulated, 'PASMC', 'proliferation,', whereas, 'miR-21', inhibition, increased, 'PTEN', and, attenuated, 'hypoxia-induced', 'HPASMC', proliferation])].
[sujeto(['Collectively,', these, results, demonstrate, that, 'PPARγ', ligands]), verbo([regulate]), complemento([proliferative, responses, to, hypoxia, by, preventing, hypoxic, increases, in, 'miR-21', and, reductions, in, 'PTEN'])].
[sujeto(['These', findings, further, clarify, molecular, mechanisms, that, support]), verbo([targeting]), complemento(['PPARγ', to, attenuate, pathogenic, derangements, in, 'PH'])].
[sujeto(['Astaxanthin', '(', 'ATX)', is, a, xanthophyll, carotenoid, which]), verbo([has]), complemento([been, approved, by, the, 'United', 'States', 'Food', and, 'Drug', 'Administration', '(', 'USFDA)', as, food, colorant, in, animal, and, fish, feed])].
[sujeto(['It', is, widely]), verbo([found]), complemento([in, algae, and, aquatic, animals, and, has, powerful, 'anti-oxidative', activity])].
[sujeto(['Previous', studies]), verbo([have]), complemento([revealed, that, 'ATX,', with, its, 'anti-oxidative', 'property,', is, beneficial, as, a, therapeutic, agent, for, various, diseases, without, any, side, effects, or, toxicity])].
[sujeto(['Several', researches]), verbo([have]), complemento([deciphered, that, 'ATX', exerts, its, 'anti-proliferative,', 'anti-apoptosis', and, 'anti-invasion', influence, via, different, molecules, and, pathways, including, signal, transducer, and, activator, of, transcription, 3, '(', 'STAT3),', nuclear, factor, 'kappa-light-chain-enhancer', of, activated, 'B', cells, '(', 'NF-κB)', and, peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPARγ)'])].
[sujeto(['Here,', we, review, the, rapidly, advancing, field, of, 'ATX', in, cancer, therapy, as, well, as, some, molecular]), verbo([targets]), complemento([of, 'ATX'])].
[sujeto(['Survival', from, traumatic, injury]), verbo([requires]), complemento([a, coordinated, and, controlled, inflammatory, and, immune, response])].
[sujeto(['Mitochondrial', and, metabolic, responses, to, stress]), verbo([have]), complemento([been, shown, to, play, a, role, in, these, inflammatory, and, immune, responses])].
[sujeto(['We', hypothesized, that]), verbo([increases]), complemento([in, mitochondrial, biogenesis, via, a, sirtuin, 1, agonist, would, decrease, tissue, injury, and, partially, ameliorate, the, immunosuppression, seen, following, trauma])].
[sujeto(['These', changes, in, mitochondrial, function, were]), verbo([associated]), complemento([with, altered, severity, of, hepatic, injury, with, significant, reductions, in, serum, alanine, aminotransferase, levels, seen, in, mice, treated, with, srt1720])].
[sujeto(['Treatment', with, 'Srt1720', minimized, the, 'trauma-induced']), verbo([decreases]), complemento([in, splenocyte, proliferation, '(', 'P', &, 'lt;', 0.05, ')', ',', whereas, treatment, with, 'PGC1α', siRNA, led, to, diminished, bacterial, clearance])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, gamma, '(', 'PPAR-γ),', a, 'ligand-activated', transcription, factor]), verbo([has]), complemento([been, investigated, as, the, target, for, cancer, treatment, as, well, as, metabolic, disorders])].
[sujeto(['Recent', studies]), verbo([have]), complemento([demonstrated, that, 'PPAR-γ', ligands, are, 'anti-tumorigenic', in, prostate, cancer, due, to, 'anti-proliferative', and, 'pro-differentiation', effects])].
[sujeto([10.7, '%', of, 'PCAs', '(', 78, /, 730, ')', showed, cytoplasmic, immunoreactivity, of, 'PPAR-γ', and, no]), verbo([nuclear]), complemento([immunoreactivity, was, noted, in, 'PCAs'])].
[sujeto(['The', 'GRX', line, is, an]), verbo([activated]), complemento(['HSC', model, that, can, be, induced, by, 'all-trans-retinol', to, accumulate, lipid, droplets])].
[sujeto(['Resveratrol', is, known, for]), verbo([activating]), complemento(['Sirtuin1', '(', 'SIRT1),', a, 'NAD(+)-dependent', deacetylase, that, suppresses, the, activity, of, peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPARγ),', an, important, adipogenic, transcription, factor, involved, in, the, quiescence, maintenance, of, 'HSC'])].
[sujeto(['Resveratrol-mediated', 'SIRT1', stimuli, did, not]), verbo([induce]), complemento([lipogenesis, and, reduced, the, 'retinol-mediated', 'fat-storing', capacity, in, 'GRX'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, 'PPARγ/SIRT1', ratio, plays, an, important, role, in, the, fate, of, 'HSC'])].
[sujeto(['To', investigate, the, characterizations, of, genetic, recombination, hotspots, and, linkage, disequilibrium, '(', 'LD)', patterns, in, peroxisome, proliferative]), verbo([activated]), complemento([receptor, gamma, '(', 'PPARG)', gene, in, 'Kirgiz', and, 'Uyghur', ethnic, groups])].
[sujeto(['The', last, 5, 'SNPs', within, the, 'PPARG', gene, were, shown, with, lower, recombination, rates, in, the, 'Kirgiz,', whereas, no, recombination, hotspot, was]), verbo([found]), complemento([in, the, 'Uyghur'])].
[sujeto(['Previously,', we, showed, that, mice, lacking, the, 'Wdr13', gene, had]), verbo([increased]), complemento([islet, mass, due, to, enhanced, beta, cell, proliferation])].
[sujeto(['Further,', we, analysed, the, histopathology, and, gene, expression, of, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)γ', 'and,', activator, protein, '(', 'AP)1']), verbo([targets]), complemento([in, various, metabolic, tissues])].
[sujeto(['Lepr(db/db)', mice, with, the, 'Wdr13', deletion, had, a, massively]), verbo([increased]), complemento([islet, 'mass,', hyperinsulinaemia, and, adipocyte, hypertrophy])].
[sujeto(['The']), verbo([increase]), complemento([in, beta, cell, mass, in, 'Wdr13(-/0)Lepr(db/db)', mice, was, due, to, an, increase, in, beta, cell, proliferation])].
[sujeto(['Hypertrophy', of, adipocytes, may, be, the, result, of]), verbo([increase]), complemento([in, transcription, of, 'Pparg', and, its, target, 'genes,', leading, in, turn, to, increased, expression, of, several, lipogenic, genes])].
[sujeto(['We', also, observed, a, significant]), verbo([decrease]), complemento([in, the, expression, of, 'AP1', and, nuclear, factor, κ, light, chain, enhancer, of, activated, 'B', cells, '(', 'NFκB)', target, genes, involved, in, inflammation])].
[sujeto(['This', study]), verbo([provides]), complemento([evidence, that, loss, of, 'WD', repeat, domain, 13, '(', 'WDR13)', protein, in, the, 'Lepr', '(', 'db/db)', mouse, model, of, diabetes, is, beneficial])].
[sujeto(['Based', on, these, 'findings,', we]), verbo([suggest]), complemento([that, 'WDR13', may, be, a, potential, drug, target, for, ameliorating, hyperglycaemia, and, inflammation, in, diabetic, conditions])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, gamma, '(', 'PPARG)', inactivation]), verbo([has]), complemento([been, identified, as, an, important, step, in, colorectal, cancer, '(', 'CRC)', 'progression,', although, the, events, involved, have, been, partially, clarified])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, 'UHRF1', negatively, regulates, 'PPARG', and, is, associated, with, a, higher, 'proliferative,', clonogenic, and, migration, potential])].
[sujeto(['Consistently,', 'UHRF1', ectopic, expression]), verbo([induces]), complemento(['PPARG', repression, through, its, recruitment, on, the, 'PPARG', promoter, fostering, 'DNA', methylation, and, histone, repressive, modifications])].
[sujeto(['In', 'addition,', the, inverse, relationship, with, 'PPARG']), verbo([found]), complemento([in, vitro, is, detected, in, vivo, and, 'UHRF1', prognostic, significance, appears, closely, related, to, 'PPARG', low, 'expression,', as, remarkably, validated, in, an, independent, dataset])].
[sujeto(['The', results, demonstrate, that, 'UHRF1']), verbo([regulates]), complemento(['PPARG', silencing, and, both, genes, appear, to, be, part, of, a, complex, regulatory, network])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, relationship, between, 'UHRF1', and, 'PPARG', may, have, a, relevant, role, in, 'CRC', progression])].
[sujeto(['We', investigated, whether, 'PPARG', is, epigenetically]), verbo([regulated]), complemento([in, colorectal, cancer, '(', 'CRC)', progression])].
[sujeto(['Remarkably,', the, same, methylation, pattern, is]), verbo([found]), complemento([in, 'PPARG-negative', 'CRC', cell, lines])].
[sujeto(['Transcriptional', silencing, is, due, to, the, recruitment, of, 'MeCP2,', 'HDAC1', and, 'EZH2', that, impart, repressive, chromatin, signatures, determining, an]), verbo([increased]), complemento([cell, proliferative, and, invasive, 'potential,', features, that, can, experimentally, be, reverted])].
[sujeto(['Our', findings]), verbo([provide]), complemento([a, novel, mechanistic, insight, into, epigenetic, silencing, of, 'PPARG', in, 'CRC', that, may, be, relevant, as, a, prognostic, marker, of, tumor, progression])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, gamma, polymorphisms]), verbo([have]), complemento([been, widely, associated, with, type, 2, 'diabetes,', although, their, role, in, the, pathogenesis, of, vascular, complications, is, not, yet, demonstrated])].
[sujeto(['A', significant, difference, was]), verbo([found]), complemento([for, -, 2819, 'G', frequency, when, patients, with, type, 2, 'diabetes-particularly', diabetic, women, with, the, proliferative, 'retinopathy-were', compared, with, healthy, control, individuals])].
[sujeto(['In', 'conclusion,', we, identified, a, novel, 'polymorphism,', 'A-2819G,', in, 'PPARG', 'gene,', and, we]), verbo([found]), complemento([it, to, be, associated, with, type, 2, diabetes, and, proliferative, retinopathy, in, diabetic, females])].
[sujeto(['Peroxisome', proliferator]), verbo([activated]), complemento([receptor, gamma, 2, '(', 'PPARg2)', is, the, nutritionally, regulated, isoform, of, 'PPARg'])].
[sujeto(['Ablation', of, 'PPARg2', in, the, 'ob/ob', 'background,', 'PPARg2(-/-)', 'Lep(ob)/Lep(ob)', '(', 'POKO', 'mouse),', resulted, in]), verbo([decreased]), complemento([fat, 'mass,', severe, insulin, 'resistance,', 'beta-cell', 'failure,', and, dyslipidaemia])].
[sujeto(['Our', results, indicate, that, the, 'PPARg2', isoform, plays, an, important, 'role,']), verbo([mediating]), complemento([adipose, tissue, expansion, in, response, to, positive, energy, balance])].
[sujeto(['Lipidomic', analyses]), verbo([suggest]), complemento([that, 'PPARg2', plays, an, important, antilipotoxic, role, when, induced, ectopically, in, liver, and, muscle, by, facilitating, deposition, of, fat, as, relatively, harmless, triacylglycerol, species, and, thus, preventing, accumulation, of, reactive, lipid, species])].
[sujeto(['Our', data, also, indicate, that, 'PPARg2', may, be]), verbo([required]), complemento([for, the, 'beta-cell', hypertrophic, adaptive, response, to, insulin, resistance])].
[sujeto(['In', 'summary,', the, 'PPARg2', isoform]), verbo([prevents]), complemento([lipotoxicity, by, '(', 'a)', promoting, adipose, tissue, 'expansion,', '(', 'b)', increasing, the, 'lipid-buffering', capacity, of, peripheral, 'organs,', and, '(', 'c)', facilitating, the, adaptive, proliferative, response, of, 'beta-cells', to, insulin, resistance])].
[sujeto(['Tendinosis', lesions, show, an]), verbo([increase]), complemento([of, glycosaminoglycan, 'amount,', 'calcifications,', and, lipid, accumulation])].
[sujeto(['In', adipogenic, 'medium,', intracellular, lipid, vacuoles, were, visible, and, 'tendon-derived', fibroblasts, showed, upregulation, of, adipogenic, markers, 'FABP4', '(', 'fatty-acid']), verbo([binding]), complemento([protein, 4, ')', and, 'PPARG', '(', peroxisome, proliferative, activated, receptor, 'gamma)'])].
[sujeto(['This', study]), verbo([suggests]), complemento([that, our, population, of, explanted, human, tendon, cells, has, an, intrinsic, differentiation, potential])].
[sujeto(['Postprandial', 'hypertriglyceridemia,', a, component, of, the, metabolic, 'syndrome,']), verbo([has]), complemento([varied, etiology, and, involves, many, genes, related, to, triglyceride, metabolism])].
[sujeto(['Patients', were, considered, to]), verbo([have]), complemento([postprandial, hypertriglyceridemia, if, the, difference, in, plasma, triglycerides, between, baseline, and, 3, h, after, the, test, was, 1.71, 'mmol/L', or, more])].
[sujeto(['We', also, measured, anthropometrical, variables, and, classified, the, patients, according, to, their, peroxisome, proliferative]), verbo([activated]), complemento(['receptor,', gamma, '(', 'PPARG)', gene, and, apolipoprotein, 'E', '(', 'APOE)', genotype])].
[sujeto(['Logistic', regression, analysis, showed, that, 'PPARG', and, 'APOE', sequence, variants, were]), verbo([associated]), complemento([with, the, presence, of, postprandial, hypertriglyceridemia])].
[sujeto(['The', 'Pro12Ala', 'PPARG', sequence, variant, together, with, a, 'non-E3/E3', 'APOE', genotype, is]), verbo([associated]), complemento([with, a, high, risk, for, postprandial, hypertriglyceridemia, in, patients, with, the, metabolic, 'syndrome,', indicating, a, close, association, between, these, genes, and, the, regulation, of, lipoproteinase, clearance])].
[sujeto(['It']), verbo([has]), complemento([been, demonstrated, that, mouse, satellite, cells, behave, as, multipotent, stem, cells])].
[sujeto(['We', studied, the, differentiation, capacities, of, human, satellite, cells, and, evaluated, the, effect, of, the, insulin, sensitiser, 'rosiglitazone,', a, well, known, peroxisome, proliferative]), verbo([activated]), complemento([receptor, gamma, '(', 'PPARG)', 'agonist,', on, their, adipogenic, conversion])].
[sujeto(['The', addition, of, rosiglitazone, to, the, adipogenic, medium, strongly]), verbo([activated]), complemento(['PPARG', expression, and, enhanced, adipogenesis, in, human, satellite, 'cells,', but, did, not, in, itself, trigger, the, complete, adipogenic, programme])].
[sujeto(['Moreover,', we, observed, a]), verbo([decrease]), complemento([in, 'wingless-type', 'MMTV', integration, site, family, member, 10, 'B', and, an, upregulation, of, growth, differentiation, factor, 8, 'expression,', both, being, independent, of, 'PPARG', activation])].
[sujeto(['Rosiglitazone', 'treatment,', while]), verbo([enhancing]), complemento(['adipogenesis,', induces, a, more, favourable, pattern, of, adipocytokine, expression, in, 'satellite-derived', fat, cells])].
[sujeto(['Mammalian']), verbo([target]), complemento([of, rapamycin, '(', 'mTOR)', is, a, key, regulator, of, 'metabolism,', cell, 'growth,', and, protein, synthesis])].
[sujeto(['Since']), verbo([decreased]), complemento([mTOR, activity, has, been, found, to, 'slow&nbsp;aging&nbsp;in&nbsp;many', 'species,', the, aim, of, this, study, was, to, examine, the, activity, of, mTOR, and, its, phosphorylated, form, in, in, vitro, and, in, vivo, models, mimicking, 'Alzheimer\'s', disease, '(', 'AD),', and, investigate, the, potential, pathway, of, 'PGC-1β', in, regulating, mTOR, expression])].
[sujeto(['Aβ25-35', treatment]), verbo([stimulated]), complemento([the, translocation, of, mTOR, from, cytoplasm, to, 'nucleus,', and, resulted, in, elevated, expression, of, mTOR, and, 'p-mTOR', '(', 'Ser2448)', and, reduced, 'PGC-1β', expression])].
[sujeto(['In', 'addition,', overexpression, of, 'PGC-1β', was]), verbo([found]), complemento([to, decrease, mTOR, expression])].
[sujeto(['The', results, of, this, study, demonstrate, that, 'Aβ']), verbo([increases]), complemento([the, expression, of, mTOR, and, 'p-mTOR', at, the, site, of, 'Ser2448,', and, the, stimulation, of, 'Aβ', is, likely, to, depend, on, sirtuin, 1, ',', 'PPARγ,', and, 'PGC-1β', pathway, in, regulating, mTOR, expression])].
[sujeto(['The', treatment, of, type, 2, diabetes, with, full, peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPARγ)', agonists, improves, insulin, 'sensitivity,', but, is]), verbo([associated]), complemento([with, weight, 'gain,', heart, 'failure,', peripheral, oedema, and, bone, loss])].
[sujeto(['Endotrophin,', the, 'C-terminal', fragment, of, the, α3, chain, of, procollagen, type, 'VI', '(', also, called, 'Pro-C6),', is]), verbo([involved]), complemento([in, both, adipose, tissue, matrix, remodelling, and, metabolic, control])].
[sujeto(['We', established, a, serum, assay, for, endotrophin, to, assess, if, this, novel, adipokine, could, identify, type, 2, diabetic, patients, who]), verbo([respond]), complemento([optimally, to, 'PPARγ', 'agonists,', improving, the, 'risk-to-benefit', ratio])].
[sujeto(['Endotrophin', was, significantly]), verbo([associated]), complemento([with, therapeutic, response, to, balaglitazone, and, pioglitazone])].
[sujeto(['Elevated', endotrophin, serum, levels, predict, response, to, two, insulin, sensitisers, and, reduce, the, risk, of]), verbo([associated]), complemento([adverse, 'effects,', 'thereby,', identifying, patients, with, type, 2, diabetes, who, may, profit, from, 'PPARγ', agonist, treatment])].
[sujeto(['In', this, 'study,', we, observed, that, grifolin]), verbo([inhibited]), complemento([tumor, cells, adhesion, and, migration])].
[sujeto(['Moreover,', grifolin, reduced, reactive, oxygen, species, '(', 'ROS)', production, and]), verbo([caused]), complemento([cellular, 'ATP', depletion, in, 'high-metastatic', tumor, cells])].
[sujeto(['PGC1α', '(', 'Peroxisome', 'proliferator-activated', receptor, 'γ,', coactivator, 1, 'α)', encodes, a, transcriptional, 'co-activator']), verbo([involved]), complemento([in, mitochondrial, biogenesis, and, respiration, and, play, a, critical, role, in, the, maintenance, of, energy, homeostasis])].
[sujeto(['Interestingly,', grifolin]), verbo([suppressed]), complemento([the, mRNA, as, well, as, protein, level, of, 'PGC1α'])].
[sujeto(['PGC1α', can]), verbo([bind]), complemento([with, 'metastatic-associated', transcription, 'factors:', 'Fra-1', and, 'LSF', and, the, 'protein-protein', interaction, was, attenuated, by, grifolin, treatment])].
[sujeto(['Overall,', these, findings]), verbo([suggest]), complemento([that, grifolin, decreased, 'ROS', generation, and, intracellular, 'ATP', to, suppress, tumor, cell, 'adhesion/migration', via, impeding, the, interplay, between, 'PGC1α', and, 'Fra-1', /, 'LSF-MMP2/CD44', axes])].
[sujeto(['Grifolin', may, develop, as, a, promising]), verbo([lead]), complemento([compound, for, antitumor, therapies, by, targeting, energy, metabolism, regulator, 'PGC1α', signaling])].
[sujeto(['International', diabetes, federation]), verbo([reported]), complemento([6.9, million, cases, of, diabetes, and, 87, ',', 548, deaths, due, to, diabetes, in, 'Pakistan', in, 2014])].
[sujeto(['Peroxisome', 'proliferators-activated', receptors, are, transcription, 'factors,']), verbo([regulating]), complemento([several, physiological, processes])].
[sujeto(['The', biochemical, and, anthropometric, parameters, were, analyzed, for, any, significant, association, with, the, 'SNP', showing, that, 'C1431T', variant]), verbo([has]), complemento([an, association, with, 'BMI,', 'weight,', fasting, glucose, and, 'LDLC'])].
[sujeto(['However,', no, significant, association, was]), verbo([found]), complemento([with, 'age,', 'gender,', 'height,', 'HDLC,', 'TC,', triglycerides, and, leptin])].
[sujeto(['In', 'conclusion,', the, presence, of, minor, allele, lowers, the, risk, of, diabetes, and, the, effect, may]), verbo([involve]), complemento([modulating, certain, serum, parameters])].
[sujeto(['The', level, of, 'CGRP', was]), verbo([decreased]), complemento([by, almost, 27, and, 17, &, 'nbsp;%', in, the, plasma, and, 'bone,', 'respectively,', in, 'OVX', rats, compared, with, sham, rats, '(', 'p&nbsp;&lt;&nbsp;0'])].
[sujeto(['Treatment', with, 'CGRP']), verbo([increased]), complemento([the, proliferation, and, mineralization, of, 'BMSCs,', and, significantly, decreased, the, lipid, accumulation, of, 'BMSCs', in, a, 'dose-dependent', manner])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, 'CGRP', played, a, role, in, adjusting, bone, mass, and, strength, by, promoting, the, proliferation, and, osteogenic, differentiation, of, 'BMSCs,', as, well, as, significantly, suppressing, the, adipogenic, differentiation, of, 'BMSCs'])].
[sujeto(['Recent', studies]), verbo([have]), complemento([implicated, a, role, for, peroxisome, 'proliferator-activated', receptor, γ, coactivator, 'protein-1α', '(', 'PGC-1α)', in, 'PD', and, in, animal, or, cellular, models, of, 'PD'])].
[sujeto(['Here', we]), verbo([find]), complemento([that, there, are, four, different, 'PGC-1α', isoforms, expressed, in, 'SH-SY5Y', 'cells,', and, these, four, isoforms, are, expressed, across, subregions, of, mouse, brain])].
[sujeto(['Adult', conditional, 'PGC-1α', 'knock-out', mice, show, a, significant]), verbo([loss]), complemento([of, dopaminergic, neurons, that, is, accompanied, by, a, reduction, of, dopamine, in, the, striatum])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, all, four, isoforms, of, 'PGC-1α', are, required, for, the, proper, expression, of, mitochondrial, proteins, in, 'SNpc', 'DA', neurons, and, that, 'PGC-1α', is, essential, for, 'SNpc', 'DA', neuronal, 'survival,', possibly, through, the, maintenance, of, mitochondrial, function])].
[sujeto(['MATERIAL', 'AND', 'METHODS', 'Intraperitoneal', injection, of, nitroglycerin, was, conducted, to]), verbo([induce]), complemento([trigeminovascular, activation, in, rats])].
[sujeto(['Our', study]), verbo([provides]), complemento([evidence, for, the, potential, use, of, valproate, in, the, treatment, of, migraine])].
[sujeto(['Aberrant', activation, of, the, epidermal, growth, factor, receptor, '(', 'EGFR)', signaling, is]), verbo([involved]), complemento([in, many, cancer, events])].
[sujeto(['Although', peroxisome, 'proliferator-activated', receptor, γ, '(', 'PPARγ)']), verbo([has]), complemento([been, implicated, in, inhibition, of, inflammation, and, 'cancer,', 'EGFR/MDM2', signaling, induces, 'PPARγ', phosphorylation, and, degradation])].
[sujeto(['Here', we]), verbo([found]), complemento([that, cancer, cells, in, response, to, 'EGF', reduced, 'PPARγ', protein, levels, by, inducing, its, 'phosphorylation,', ubiquitination, and, 'degradation,', but, 'PPARγ', agonist, pioglitazone, reversed, this, event])].
[sujeto(['More', 'importantly,', pioglitazone]), verbo([increased]), complemento([cancer, cell, sensitivity, to, chemotherapy, drugs])].
[sujeto(['Therefore,', our, study, revealed, a, novel, mechanism, that, pioglitazone]), verbo([inhibited]), complemento(['EGFR/MDM2-mediated', cancer, cell, 'chemoresistance,', which, provides, a, novel, strategy, for, cancer, treatment])].
[sujeto(['The', receptor]), verbo([interacting]), complemento(['protein-140', '(', 'RIP140)', is, a, cofactor, for, several, nuclear, receptors, and, has, been, involved, in, the, regulation, of, metabolic, and, inflammatory, genes])].
[sujeto(['We', hypothesize, that, 'RIP140', may, also, affect, 'Aβ', generation, because, it]), verbo([modulates]), complemento([the, activity, of, transcription, factors, previously, implicated, in, amyloid, precursor, protein, '(', 'APP)', 'processing,', such, as, peroxisome, 'proliferator-activated', 'receptor-γ', '(', 'PPARγ)'])].
[sujeto(['We']), verbo([found]), complemento([that, the, levels, of, 'RIP140', are, reduced, in, 'Alzheimer\'s', disease, '(', 'AD)', postmortem, brains, compared, with, healthy, controls])].
[sujeto(['In', 'addition,', in, situ, hybridization, experiments, revealed, that, 'RIP140', expression, is, enriched, in, the, same, brain, areas]), verbo([involved]), complemento([in, 'AD', 'pathology,', such, as, cortex, and, hippocampus])].
[sujeto(['Furthermore,', we]), verbo([provide]), complemento([evidence, using, cell, lines, and, genetically, modified, mice, that, 'RIP140', is, able, to, modulate, the, transcription, of, certain, genes, involved, in, 'AD', 'pathology,', such, as, 'β-APP', cleaving, enzyme, '(', 'BACE1)', and, 'GSK3'])].
[sujeto(['Consequently,', we]), verbo([found]), complemento([that, 'RIP140', overexpression, reduced, the, generation, of, 'Aβ', in, a, neuroblastoma, cell, line, by, decreasing, the, transcription, of, 'β-APP', cleaving, enzyme, via, a, 'PPARγ-dependent', mechanism])].
[sujeto(['The', results, of, this, study, therefore]), verbo([provide]), complemento([molecular, insights, into, common, signaling, pathways, linking, metabolic, disease, with, 'AD'])].
[sujeto(['Thiazolidinediones', are, insulin, sensitizers, that]), verbo([activate]), complemento([the, nuclear, receptor, 'PPAR-γ', and, have, been, shown, to, partially, ameliorate, autoimmune, type, 1, diabetes, in, humans, and, 'non-obese', diabetic, '(', 'NOD)', mice])].
[sujeto(['However,', treated, mice, showed, significantly, improved, glucose, tolerance, with]), verbo([enhanced]), complemento([serum, insulin, 'levels,', reduced, β, cell, 'death,', and, increased, β, cell, mass])].
[sujeto(['Isolated', islets, of, treated, mice, showed, a, more, robust, unfolded, protein, 'response,', with]), verbo([increases]), complemento([in, 'Bip', and, 'ATF4,', and, reductions, in, spliced, 'Xbp1', mRNA])].
[sujeto(['Our', results, demonstrate, that, 'PPAR-γ', activation, directly, improves, β, cell, function, and, survival, in, 'NOD', mice, by]), verbo([enhancing]), complemento([the, unfolded, protein, 'response,', and, suggest, that, blockade, of, 'PPAR-γ', '(', 'S273)', phosphorylation, may, prevent, type, 1, diabetes])].
[sujeto(['Electric', stimulation, significantly]), verbo([decreased]), complemento([cytoplasmic, lipid, 'content,', after, 'both&nbsp;2&nbsp;and&nbsp;9&nbsp;days', of, differentiation])].
[sujeto(['The', antiadipogenic, response, in, 'the&nbsp;9&nbsp;day', samples, was, accompanied, by, activation, of, 'mitogen&#8209;activated', protein, kinase, 'kinase&nbsp;1/2,']), verbo([decreased]), complemento([expression, and, partial, inactivation, of, peroxisome, 'proliferator&#8209;activated', receptor, '(', 'PPAR)&nbsp;γ,', which, was, translocated, from, the, nucleus, to, the, 'cytoplasm,', together, with, a, significant, decrease, in, the, expression, levels, of, the, 'PPARG1', 'gene,', 'perilipin,', 'angiopoietin&#8209;like', 'protein&nbsp;4', and, fatty, acid, synthase])].
[sujeto(['These', results, demonstrated, that, subthermal, stimulation, with, 'CRET', interferes, with, the, early, adipogenic, differentiation, in, 'ADSC,', indicating, that, the, electric, stimulus, itself, can]), verbo([modulate]), complemento([processes, controlling, the, synthesis, and, mobilization, of, 'fat,', even, in, the, absence, of, the, concomitant, thermal, and, mechanical, components, of, the, thermoelectric, therapy, 'CRET'])].
[sujeto(['Using', methylation, data, from, the, 'Infinium', 'HumanMethylation450', 'BeadChip', '(', n, =, 180, ')', ',', we]), verbo([found]), complemento([eight, 'CpG', sites, in, 'ADIPOR1', and, 'PPARG', where, methylation, level, was, associated, with, expression, by, 'RT-PCR', '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['Hypomethylation', of, 'PPARG', gene, body, site, cg10499651, was]), verbo([associated]), complemento([with, increased, expression, as, measured, by, both, 'RT-PCR', and, nCounter, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['We']), verbo([found]), complemento([no, statistically, significant, relationships, between, either, expression, or, methylation, of, 'ADIPOR1', and, 'PPARG', and, body, mass, index, or, waist, circumference])].
[sujeto(['However,', whether, it]), verbo([regulates]), complemento([the, stepwise, progression, of, adipogenesis, is, unknown])].
[sujeto(['Interestingly,', inhibition, of, adipogenesis, does, not]), verbo([require]), complemento([the, 'JmjC', demethylase, domain, of, 'FBXL10,', but, it, does, require, the, 'F-box', and, 'leucine-rich', repeat, 'domains,', which, we, show, recruit, a, noncanonical, polycomb, repressive, complex, 1, '(', 'PRC1)', containing, 'RING1B,', 'SKP1,', 'PCGF1,', and, 'BCOR'])].
[sujeto(['Knockdown', of, either, 'RING1B', or, 'SKP1']), verbo([prevented]), complemento(['FBXL10-mediated', repression, of, 3, 'T3-L1', preadipocyte, differentiation, indicating, that, 'PRC1', formation, mediates, the, inhibitory, effect, of, 'FBXL10', on, adipogenesis])].
[sujeto(['Using', 'ChIP-seq,', we, show, that, 'FBXL10']), verbo([recruits]), complemento(['RING1B', to, key, specific, genomic, loci, surrounding, the, key, cell, cycle, and, the, adipogenic, genes, 'Cdk1,', 'Uhrf1,', 'Pparg1,', and, 'Pparg2', to, repress, adipogenesis])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'FBXL10', represses, adipogenesis, by, targeting, a, noncanonical, 'PRC1', complex, to, repress, key, genes, '(', e])].
[sujeto(['Epigenetic', 'factors,', such, as, 'DNA', methylation, 'status,', may]), verbo([regulate]), complemento([adipogenesis, and, 'lipogenesis,', thus, affecting, intramuscular, fat, '(', 'IMF)', deposition, in, longissimus, dorsi, muscle, '(', 'LM)', of, beef, cattle])].
[sujeto(['Real-time', polymerase, chain, reaction, analysis, showed, that, the, mRNA, levels, of, both, adipogenic, peroxisome, 'proliferator-activated', receptor, gamma, isoform, 1, '(', 'PPARG1)', and, lipogenic, fatty, acid]), verbo([binding]), complemento([protein, 4, '(', 'FABP4)', were, higher, '(', 'p&lt;0'])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, 'DNA', methylation, status, regulates, 'tissue-specific', expression, of, adipogenic, and, lipogenic, genes, in, the, 'IMF', and, muscle, portions, of, 'LM', tissue, in, 'Korean', cattle])].
[sujeto(['Although', transcriptional, control, differences, between, isoforms]), verbo([have]), complemento([been, reported, in, human, adipose, 'tissue,', their, roles, in, ruminant, mammary, cells, are, not, well, known])].
[sujeto(['To', assess, which, of, these, isoforms, is, more, closely]), verbo([associated]), complemento([with, the, regulation, of, mammary, lipogenic, 'pathways,', their, tissue, distribution, was, analyzed, and, the, expression, of, key, genes, regulating, lipogenic, gene, networks, was, measured, after, overexpression, of, the, 2, isoforms, in, goat, mammary, epithelial, cells, '(', 'GMEC)'])].
[sujeto(['As', was]), verbo([reported]), complemento([in, previous, 'work,', 'PPARG1', upregulated, the, transcription, regulators, 'SREBF1', and, 'PPARG', and, the, lipogenic, genes, 'FASN,', 'ACACA,', and, 'SCD'])].
[sujeto(['Along', with, a, tendency, for, greater, expression, of, 'AGPAT6,', 'DGAT1,', and, 'PLIN2,', these, data]), verbo([suggest]), complemento([that, 'PPARG1', is, the, isoform, controlling, lipogenesis, in, mammary, cells])].
[sujeto(['Although', the, data]), verbo([suggest]), complemento([that, both, 'PPARG1', and, 'PPARG2', could, affect, mammary, lipogenesis, via, control, of, gene, expression, when, stimulated, '(', e])].
[sujeto([',', by, 'ROSI),', the, fact, that, 'PPARG1', is, more, abundant, in, mammary, tissue, and, that, its, overexpression, alone, upregulated, key, lipogenic, gene, networks]), verbo([suggest]), complemento([that, it, is, the, more, important, isoform, in, goat, mammary, cells])].
[sujeto(['However,', whether, or, how, 'PPARG']), verbo([regulates]), complemento([the, activity, of, mammary, 'SCD', in, ruminants, is, unknown])].
[sujeto(['This', study, explored, the, potential, role, of, 'PPARG', isoforms, in]), verbo([regulating]), complemento(['SCD', mRNA, expression, in, lactating, goat, mammary, epithelial, cells, '(', 'GMEC)'])].
[sujeto(['Overexpression', of, both, 'PPARG1', and, 'PPARG2', in, 'GMEC']), verbo([increased]), complemento([markedly, the, expression, of, 'SCD,', the, concentration, of, 16, :, 1, and, 18, :, 1, ',', and, the, desaturation, indices, of, 16, :, 1, and, 18, :, 1])].
[sujeto(['The', 'PPARG', ligand, rosiglitazone, further]), verbo([increased]), complemento(['SCD', expression, and, desaturation, indices, in, 'GMEC,', overexpressing, 'PPARG1', and, 'PPARG2'])].
[sujeto(['Incubation', with, rosiglitazone, alone]), verbo([increased]), complemento([the, expression, of, 'SCD,', but, did, not, alter, the, concentration, of, 16, -, to, 18, -, carbon, 'FA', or, their, desaturation, indices])].
[sujeto(['The', results]), verbo([provide]), complemento([evidence, that, 'PPARG', regulates, the, expression, and, activity, of, 'SCD', in, 'GMEC'])].
[sujeto(['The', objective, of, this, study, was, to, explore, whether, hyperandrogenism]), verbo([induces]), complemento([epigenetic, alterations, of, peroxisome, 'proliferator-activated', receptor, gamma, 1, '(', 'PPARG1),', nuclear, corepressor, 1, '(', 'NCOR1),', and, histone, deacetylase, 3, '(', 'HDAC3)', genes, in, granulosa, cells, '(', 'GCs)', of, polycystic, ovary, syndrome, '(', 'PCOS)', women, and, whether, these, alterations, are, involved, in, the, ovarian, dysfunction, induced, by, hyperandrogenism])].
[sujeto(['When', all, women, were, divided, into, successful, and, failed, pregnancy, subgroups, according, to, the, following, clinical, pregnancy, 'outcome,', we]), verbo([found]), complemento([lower, 'PPARG1', mRNA, levels, and, higher, 'NCOR1', and, 'HDAC3', mRNA, levels, in, the, failed, subgroup, of, 'HA', 'PCOS', '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['The', acetylation, levels, of, histone, 'H3', at, lysine, 9, and, p21, mRNA, expression, were]), verbo([decreased]), complemento([in, human, 'GCs', treated, with, dihydrotestosterone, in, vitro, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['Hyperandrogenism']), verbo([induces]), complemento([the, epigenetic, alterations, of, 'PPARG1,', 'NCOR1,', and, 'HDAC3', in, 'GCs,', which, are, involved, in, the, ovarian, dysfunction, of, 'HA', 'PCOS'])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, 'gamma-2', '(', 'PPARG2)', is, a, 'ligand-dependent', transcriptional, factor]), verbo([involved]), complemento([in, the, pathogenesis, of, insulin, resistance])].
[sujeto(['In', the, presence, of, a, 'ligand,', 'PPARG2']), verbo([associates]), complemento([with, 'co-activators,', while, it, recruits, 'co-repressors', '(', 'CoRs)', in, the, absence, of, a, ligand])].
[sujeto(['It']), verbo([has]), complemento([been, reported, that, the, interaction, of, liganded, 'PPARG2', with, 'co-activators', is, regulated, by, the, 'amino-terminal', 'A/B', domain, '(', 'NTD)', via, 'inter-domain', communication])].
[sujeto(['To', elucidate, 'this,', total, elimination, of, the, influence, of, ligands, is, 'required,', but, the, endogenous, ligands, of, 'PPARG2']), verbo([have]), complemento([not, been, fully, defined])].
[sujeto(['Reflecting', its, very, low, affinity, for, various, 'ligands,', this, mutant, does, not]), verbo([have]), complemento([transcriptional, activity, in, the, 'PPAR', response, 'element,', but, exhibits, dominant, negative, effects, '(', 'DNEs)', on, liganded, 'wild-type', 'PPARG2-mediated', transactivation])].
[sujeto(['Interestingly,', the, 'DNE', of, 'PPARG2-P495L', was]), verbo([increased]), complemento([by, the, truncation, of, its, 'NTD'])].
[sujeto(['NTD', deletion, also]), verbo([enhanced]), complemento([the, 'DNE', of, a, chimeric, 'receptor,', 'PT,', in, which, the, 'ligand-binding', domain, of, 'PPARG2', was, replaced, with, that, of, thyroid, hormone, receptor, 'beta-1'])].
[sujeto(['Moreover,', 'NTD', deletion, facilitated, the, in, vitro]), verbo([binding]), complemento([of, nuclear, receptor, 'CoR', with, 'wild-type', 'PPARG2,', mutant, 'P495L,', and, the, 'PT', chimera, '(', 'PPARG2-THRB)'])].
[sujeto(['Inter-domain', communication, in, 'PPARG2']), verbo([regulates]), complemento([not, only, 'ligand-dependent', transactivation, but, also, 'ligand-independent', silencing])].
[sujeto(['Aging']), verbo([involves]), complemento([a, progressive, physiological, remodeling, that, is, controlled, by, both, genetic, and, environmental, factors])].
[sujeto(['Many', of, these, factors, impact, also, on, white, adipose, tissue, '(', 'WAT),', which]), verbo([has]), complemento([been, shown, to, be, a, determinant, of, lifespan])].
[sujeto(['Within', this, 'subnetwork,', one, gene, was, 'Pparg', '(', 'Nr1c3),', an, 'adipose-enriched']), verbo([nuclear]), complemento([receptor, previously, not, associated, with, longevity])].
[sujeto(['These', results, establish, 'Ppargamma2', as, one, of, the, determinants, of, longevity, and]), verbo([suggest]), complemento([that, lifespan, may, be, rather, determined, by, a, purposeful, genetic, program, than, a, random, process])].
[sujeto(['We']), verbo([have]), complemento([examined, the, association, of, 14, tagging, single, nucleotide, polymorphisms, '(', 'tagSNPs)', in, peroxisome, proliferator, activated, 'receptor-gamma', transcripts, 1, and, 2, '(', 'PPARG1', and, 2, ')', and, 5, tagSNPs, in, adiponectin, '(', 'ADIPOQ)', genes, for, their, effect, on, type, 2, diabetes, mellitus, '(', 'T2D)', risk, in, 'Asian', 'Indian', 'Sikhs'])].
[sujeto(['Similarly,', none, of, the, tagSNPs, in, the, 'ADIPOQ', gene, was]), verbo([associated]), complemento([with, 'T2D', susceptibility, in, 'single-site', analysis])].
[sujeto(['However,', haplotype, analysis]), verbo([provided]), complemento([strong, evidence, of, association, of, these, loci, with, 'T2D'])].
[sujeto(['Three-site', haplotype, analysis, in, the, 'PPARG', locus, using, the, 2, marginally]), verbo([associated]), complemento(['SNPs', '(', 'P/rs11715073', and, 'P/rs3892175)', in, combination, with, 'Pro12', 'Ala', '(', 'P/rs1801282)', revealed, a, strong, association, of, 1, &, 'quot;risk&quot;', '(', 'CGC)', '(', 'P', =])].
[sujeto([5, ')', haplotype]), verbo([associated]), complemento([with, 'T2D'])].
[sujeto(['In', 'addition,', 2, -, site, haplotype, analysis, in, the, 'ADIPOQ', locus, using, only, 2, marginally]), verbo([associated]), complemento(['SNPs', '(', 'AD/rs182052', and, 'AD/rs7649121)', revealed, a, significant, protective, association, of, the, 'GA', haplotype, with, 'T2D', '(', 'P', =])].
[sujeto(['Our', new, findings, strongly]), verbo([suggest]), complemento([that, the, genetic, variation, in, 'PPARG', and, 'ADIPOQ', loci, could, contribute, to, the, risk, for, the, development, of, 'T2D', in, 'Indian', 'Sikhs'])].
[sujeto(['Lipodystrophies', are, syndromes, of, adipose, tissue, degeneration]), verbo([associated]), complemento([with, severe, defects, in, lipid, and, glucose, homeostasis])].
[sujeto(['We']), verbo([report]), complemento([here, the, generation, and, analysis, of, 'Pparg(ldi),', a, targeted, allele, that, confers, conditional, dominant, lipodystrophy, in, mice])].
[sujeto(['Doxycycline', can, both, completely]), verbo([prevent]), complemento([and, reverse, these, 'phenotypes,', providing, a, mouse, model, of, inducible, lipodystrophy])].
[sujeto(['Embryonic', fibroblasts, from, either, 'Pparg(ldi/+)', or, the, phenotypically, similar, 'aP2-nSrebp1c', '(', 'Sr)', transgenic, mice, undergo, robust, 'adipogenesis,']), verbo([suggesting]), complemento([that, neither, strain, develops, lipodystrophy, because, of, defective, adipocyte, differentiation])].
[sujeto(['In', 'addition,', 'Pparg(ldi/+)', adipose, tissue, shares, extensive, gene, expression, aberrations, with, that, of, 'Sr', 'mice,', authenticating, the, phenotype, at, the, molecular, level, and]), verbo([revealed]), complemento([a, common, expression, signature, of, lipodystrophic, fat])].
[sujeto(['Thus,', the, 'Pparg(ldi/+)', mouse]), verbo([provides]), complemento([a, conditional, animal, model, for, studying, lipodystrophy, and, its, associated, physiology, and, gene, expression])].
[sujeto(['DEHP']), verbo([decreased]), complemento(['%', fat, in, males, at, birth, from, 13.9, '%', '±0'])].
[sujeto([')', ',', representing, a, 15.1, '%']), verbo([decrease]), complemento([in, fat, by, 'DEHP,', and, these, males, caught, up, in, adiposity, to, controls, by, 'PND21'])].
[sujeto(['Adult', 'DEHP-exposed', males, had, a, 27.5, '%']), verbo([increase]), complemento([in, fat, '(', 12.5, '%', '±0'])].
[sujeto([5, '%', in, the, 'DEHP', 'group);', adipocyte, perimeter, was]), verbo([increased]), complemento([as, 'well,', with, fewer, 'small/medium-sized', 'adipocytes,', and, decreased, cell, number, compared, to, oil, controls])].
[sujeto(['HF', diet, intake, in, 'DEHP-exposed', males, further]), verbo([increased]), complemento([male, energy, intake, and, body, weight, and, led, to, glucose, intolerance])].
[sujeto(['In', 'PND21', 'males,', 'DEHP']), verbo([increased]), complemento([the, expression, of, adipogenic, markers, '(', 'Pparg1,', 'Cebpa,', 'Adipoq,', 'Ppard,', 'Fabp4,', 'Fasn,', 'Igf1),', decreased, 'Lep,', and, decreased, markers, of, mesenchymal, stem, cell, commitment, to, the, adipogenic, lineage, '(', 'Bmp2,', 'Bmp4,', 'Stat1,', 'Stat5a)', compared, to, oil, controls])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'DEHP', may, decrease, the, adipocyte, pool, at, 'birth,', which, initially, increases, adaptive, adipocyte, maturation, and, lipid, 'accumulation,', but, leads, to, adipose, tissue, dysfunction, in, 'adulthood,', decreasing, the, capacity, to, adapt, to, a, 'HF', 'diet,', and, leading, to, systemic, glucose, intolerance])].
[sujeto(['Four', different, subtypes, of, fatty, acid]), verbo([binding]), complemento([proteins, i])].
[sujeto(['liver-type', 'FABP1,', 'heart/muscle-type', 'FABP3,', 'adipocyte-type', 'FABP4', and, 'epithelial/epidermal-type', 'FABP5', are]), verbo([expressed]), complemento([in, adipose, tissue])].
[sujeto(['However,', only, the, regulatory, role, of, 'FABP4', in, adipogenesis]), verbo([has]), complemento([been, thoroughly, investigated])].
[sujeto(['To']), verbo([increase]), complemento([the, knowledge, on, possible, roles, of, these, 'FABP', subtypes, in, preadipocyte, 'differentiation,', gene, expression, patterns, were, examined, during, adipogenesis, in, pig, '(', 'Sus', 'scrofa)'])].
[sujeto(['FABP1', expression, was]), verbo([induced]), complemento([in, proliferating, 'cells,', whereas, 'FABP3,', 'FABP4', and, 'FABP5', expression, increased, throughout, preadipocyte, differentiation])].
[sujeto(['Interestingly,', the, 'FABP4', and, 'FABP5', expression]), verbo([increased]), complemento([early, in, the, 'differentiation,', followed, by, 'FABP3', later, in, the, differentiation, process])].
[sujeto(['This', indicates, a, role, of, 'FABP4', and, 'FABP5', in, intracellular, fatty, acid, transport, during, initiation, of, 'differentiation,', 'whereas,', 'FABP3', likely, is]), verbo([involved]), complemento([in, the, transport, of, fatty, acids, during, intermediate, stages, of, adipogenesis])].
[sujeto(['Altogether,', this]), verbo([suggests]), complemento([a, role, of, 'FABP1', during, cell, 'proliferation,', whereas, a, coordinated, expression, of, 'FABP3,', 'FABP4', and, 'FABP5', together, with, that, of, 'PPARA,', 'PPARG1', and, 'PPARG2', might, be, critical, for, the, metabolic, regulation, during, porcine, adipogenesis])].
[sujeto(['Thiazolidinediones', '(', 'TZDs),', which, are, synthetic, ligands, for, peroxisome, proliferator]), verbo([activated]), complemento([receptor, g, '(', 'PPARg)', 'activation,', have, been, introduced, in, clinical, medicine, to, improve, insulin, resistance, and, glycemic, control, in, patients, with, type, 2, diabetes])].
[sujeto(['The', metabolic, effects, of, 'TZDs', are]), verbo([mediated]), complemento([by, 'receptor-dependent', activation, of, the, 'PPARg-retinoid', 'X', receptor, '(', 'RXR)', complex, and, subsequent, transcriptional, activation, of, target, genes])].
[sujeto(['The', 'PPARg1', isoform, is, also]), verbo([expressed]), complemento([in, endothelial, 'cells,', vascular, smooth, muscle, 'cells,', and, 'monocytes/macrophages', in, the, vasculature])].
[sujeto(['TZDs']), verbo([have]), complemento([been, shown, to, have, 'anti-atherosclerotic', effects, on, these, cells, in, 'vitro,', which, appear, to, be, partially, independent, of, the, 'PPARg-RXR-mediated', transcriptional, effects])].
[sujeto(['Direct', 'anti-atherosclerotic', effects, of, 'TZDs', include]), verbo([increased]), complemento([nitric, oxide, 'bioavailability,', decreased, 'leukocyte/endothelial', cell, 'interaction,', reduced, vascular, smooth, muscle, cell, migration, and, 'proliferation,', and, cholesterol, efflux, from, macrophages])].
[sujeto(['So', 'far,', there, are, no, data, on, the, effects, of, 'TZDs', on, cardiovascular, 'events,', but, studies, using, surrogate, markers, of, vascular, disease]), verbo([provide]), complemento([preliminary, evidence, that, 'TZDs', delay, progression, of, atherosclerosis, in, different, patient, groups])].
[sujeto(['Reversal', of, fatty, infiltration, of, pennate, rotator, cuff, muscle, after, tendon]), verbo([release]), complemento([is, hitherto, impossible])].
[sujeto(['The', administration, of, nandrolone, starting, at, the, time, of, tendon]), verbo([release]), complemento([prevents, the, increase, in, fat, 'content,', but, does, not, revert, established, fatty, infiltration])].
[sujeto(['We', hypothesised, that, tendon]), verbo([release]), complemento([and, myotendinous, retraction, cause, alterations, in, lipid, related, gene, expression, leading, to, fatty, muscle, 'infiltration,', which, can, be, suppressed, by, nandrolone, through, its, genomic, actions, if, applied, immediately, after, tendon, release])].
[sujeto(['The', effects, of, infraspinatus, tendon]), verbo([release]), complemento([and, subsequent, tendon, repair, at, 16, weeks, were, studied, in, six, 'Swiss', 'Alpine', sheep])].
[sujeto(['In', the, interventional, 'groups,', 150, mg, nandrolone, was, administered, weekly, after, tendon]), verbo([release]), complemento([until, sacrifice, '(', 'N22W,', 'n=6)', or, starting, at, the, time, of, repair, '(', 'N6W,', 'n=6)'])].
[sujeto(['Infraspinatus', 'volume,', 'composition,']), verbo([expressed]), complemento(['transcripts,', 'lipids,', and, selected, proteins, were, analyzed, at, 'baseline,', 16, and, 22, weeks])].
[sujeto(['Tendon']), verbo([release]), complemento([reduced, infraspinatus, volume, by, 22, '%', and, increased, fat, content, from, 11, '%', to, 38, '%'])].
[sujeto(['Fatty', infiltration, was]), verbo([associated]), complemento([with, 'up-regulation', of, 227, lipid, 'species,', and, increased, levels, of, the, adipocyte, differentiation, marker, 'PPARG2', '(', peroxisome, 'proliferator-activated', receptor, gamma, 2, ')'])].
[sujeto(['Nandrolone', abrogated, lipid, 'accumulation,', halved, the]), verbo([loss]), complemento([in, fiber, area, 'percentage,', and, 'up-regulated', androgen, receptor, levels, and, transcript, expression, in, the, 'N22W', but, not, the, 'N6W', group])].
[sujeto(['The', results, document, that, nandrolone, mitigates, 'muscle-to-fat', transformation, after, tendon]), verbo([release]), complemento([via, a, general, 'down-regulation', of, lipid, accumulation, concomitantly, with, 'up-regulated', expression, of, its, nuclear, receptor, and, downstream, transcripts, in, skeletal, muscle])].
[sujeto(['We', developed, fluorescence]), verbo([nuclear]), complemento([cytometry, '(', 'FNC)', and, fluorescence, activated, nuclear, sorting, '(', 'FANS)', of, cellular, nuclei, from, visceral, adipose, tissue, '(', 'VAT)', using, the, levels, of, the, 'pan-adipocyte', 'protein,', peroxisome, 'proliferator-activated', receptor, 'gamma-2', '(', 'PPARg2),', to, distinguish, classes, of, 'PPARg2-Positive', '(', 'PPARg2-Pos)', adipocyte, nuclei, from, 'PPARg2-Negative', '(', 'PPARg2-Neg)', leukocyte, and, endothelial, cell, nuclei])].
[sujeto(['PPARg2-Pos', nuclei, showed, 2, -, to, 50, -, fold, higher, levels, of, transcripts, encoding, most, of, the, 'chromatin-remodeling', factors, 'assayed,', which]), verbo([regulate]), complemento([the, methylation, of, histones, and, 'DNA', cytosine, '(', e])].
[sujeto(['TAB-seq', demonstrated, 5, -, hydroxymethylcytosine, '(', 5, 'hmC)', levels, were, remarkably, dynamic, in, gene, bodies, of, various, classes, of, 'VAT', 'nuclei,', dropping, 3.8, -, fold, from, the, highest, quintile, of]), verbo([expressed]), complemento([genes, to, the, lowest])].
[sujeto(['Natural', phenols, may]), verbo([have]), complemento([beneficial, properties, against, oxidative, 'stress,', which, is, associated, with, aging, and, major, chronic, 'aging-related', 'diseases,', such, as, loss, of, bone, mineral, mass, '(', 'osteoporosis)', and, diabetes])].
[sujeto(['Such', cells, were]), verbo([induced]), complemento([to, differentiate, into, osteoblasts, or, adipocytes, in, the, presence, of, two, quercetin, concentrations, '(', 0.1, and, 10, 'μM)'])].
[sujeto(['Quercetin', '(', 10, 'μM)']), verbo([inhibited]), complemento([cell, 'proliferation,', alkaline, phosphatase, '(', 'ALPL)', activity, and, 'mineralization,', 'down-regulating', the, expression, of, 'ALPL,', collagen, type, 'I', alpha, 1, '(', 'COL1A1)', and, osteocalcin, '[', bone, 'gamma-carboxyglutamate', protein, '(', 'BGLAP)]', 'osteoblastogenesis-related', genes, in, 'MSC', differentiating, into, osteoblasts])].
[sujeto(['Quercetin', did, not, affect, 'proliferation,', but]), verbo([increased]), complemento(['adipogenesis,', mainly, at, 10, -, μM, concentration, in, 'MSC', induced, to, differentiate, to, adipocytes])].
[sujeto(['β-', and, 'γ-catenin', '(', 'plakoglobin)']), verbo([nuclear]), complemento([levels, were, reduced, and, 'increased,', 'respectively,', in, 'quercetin-treated', cultures])].
[sujeto(['This']), verbo([suggests]), complemento([that, the, effect, of, high, concentration, of, quercetin, on, 'MSC', osteoblastic, and, adipogenic, differentiation, is, mediated, via, 'Wnt/β-catenin', inhibition])].
[sujeto(['In', 'conclusion,', quercetin, supplementation]), verbo([inhibited]), complemento([osteoblastic, differentiation, and, promoted, adipogenesis, at, the, highest, tested, concentration])].
[sujeto(['The', innate, immune, cell, sensor, 'leucine-rich-containing', 'family,', pyrin, domain, containing, 3, '(', 'NLRP3)', inflammasome, controls, the, activation, of, 'caspase-1,', and, the]), verbo([release]), complemento([of, proinflammatory, cytokines, interleukin, '(', 'IL)-1β', and, 'IL-18'])].
[sujeto(['The']), verbo([increase]), complemento([in, inflammation, markers, was, paralleled, by, a, decrease, in, genes, related, to, insulin, sensitivity, '(', 'ADIPOQ,', 'GLUT4,', 'PPARG2,', and, 'SIRT1)', and, lipogenesis, '(', 'SREBP1c,', 'ACC,', 'LPL,', and, 'FASN)'])].
[sujeto(['Infiltration', of, macrophages, and, upregulation, of, the, 'NLRP3', inflammasome, together, with, the]), verbo([associated]), complemento([high, ceramide, content, in, the, plasma, and, 'SAT', of, obese, adolescents, with, a, high, 'VAT/VAT+SAT', may, contribute, to, the, limited, expansion, of, the, subcutaneous, abdominal, adipose, depot, and, the, development, of, insulin, resistance])].
[sujeto(['Evidence', is]), verbo([increasing]), complemento([for, the, adaptive, immune, 'system\'s', role, in, 'T2DM', and, suggests, the, presence, of, unidentified, autoantibodies])].
[sujeto(['While', 'high-density', protein, microarrays]), verbo([have]), complemento([emerged, as, a, useful, technology, to, identify, possible, novel, autoantigens, in, autoimmune, 'diseases,', its, application, in, 'T2DM', has, lagged])].
[sujeto(['In', 'Pima', 'Indians,', the, 'HLA', haplotype, '(', 'HLA-DRB1*02)', is, protective, against, 'T2DM', 'and,', when, studied, when, they]), verbo([have]), complemento([normal, glucose, 'tolerance,', subjects, with, this, 'HLA', haplotype, have, higher, insulin, secretion, compared, to, those, without, the, protective, haplotype])].
[sujeto(['A', subsequent, validation, phase]), verbo([involving]), complemento([45, cases, and, 45, 'controls,', matched, by, 'age,', sex, and, specimen, storage, 'time,', evaluated, 77, proteins])].
[sujeto(['A', 'multi-protein', classifier]), verbo([involving]), complemento([the, 11, autoantigens, had, 'sensitivity,', 'specificity,', and, area, under, the, receiver, operating, characteristics, curve, of, 0.73, ',', 0.8, ',', and, 0.83, '(', 95, '%', 'CI', 0.74, -, 0.91, ',', p, =, 3.4, 'x10-8),', respectively])].
[sujeto(['This', study, identified, 11, novel, autoantigens, which, were]), verbo([associated]), complemento([with, 'T2DM', and, an, 'HLA', background, associated, with, reduced, insulin, secretion])].
[sujeto(['While', further, studies, are, needed, to, distinguish, whether, these, antibodies, are]), verbo([associated]), complemento([with, insulin, secretion, via, the, 'HLA', 'background,', 'T2DM', more, 'broadly,', or, a, combination, of, the, 'two,', this, study, may, aid, the, search, for, autoantibody, biomarkers, by, narrowing, the, list, of, protein, targets])].
[sujeto(['We', observed, an, inverse, regulation, of, 'FFAR2', and, 'FFAR3', expression, over, time, and, both, receptors, also, showed, an, inverse, mRNA, abundance, as]), verbo([induced]), complemento([by, different, portions, of, concentrate])].
[sujeto(['Differentiated', 'hMSC-Tert', were, stably, transduced, with, or, without, siRNA]), verbo([targeting]), complemento(['APOE', while, murine, adipocytes, were, isolated, from, wild, type, and, 'Apoe', knockout, mice])].
[sujeto(['This', correlated, with, strongly]), verbo([decreased]), complemento([gene, expression, levels, of, adipocyte, markers, such, as, adiponectin, '(', 'ADIPOQ)', and, fatty, acid, binding, protein, 4, '(', 'FABP4)', as, well, as, the, key, transcription, factor, driving, adipocyte, 'differentiation,', peroxisome, proliferator, activator, receptor, gamma, '(', 'PPARG),', in, particular, the, 'PPARG2', isoform])].
[sujeto(['Interestingly,', incubation, of, 'APOE-deficient', 'hMSC-Tert', adipocytes, with, conditioned, media, from, 'APOE3-overexpressing', adipocytes, or, 'APOE-containing', 'Very', 'Low', 'Density', 'Lipoprotein', '(', 'VLDL)', partially, restored, triglyceride, 'accumulation,', but, were, unable, to]), verbo([induce]), complemento([adipocyte, 'differentiation,', as, judged, by, expression, of, adipocyte, markers])].
[sujeto(['Taken', 'together,', depletion, of, endogenous, 'APOE', in, human, adipocytes, severely, impairs, lipid, 'accumulation,', which, is]), verbo([associated]), complemento([with, an, inability, to, initiate, differentiation])].
[sujeto(['Among', obese, 'individuals,', carriers, of, genotype, 482, 'Gly/Gly', were, observed, to]), verbo([have]), complemento([decreased, body, 'fat,', 'BMI,', and, body, fat, ratio, versus, 482, 'Ser/Ser', carriers, and, increased, resistin, and, leptin, levels, in, carriers, 'Gly+', phenotype, versus, 'Gly-', phenotype])].
[sujeto(['Subjects', with, 'PPARG2', 'Ala-', phenotype, '(', genotype, 12, 'Pro/Pro)', showed, a]), verbo([decreased]), complemento(['HOMA-IR', index, versus, individuals, with, 'Ala+', phenotype, '(', genotypes, 12, 'Pro/Ala', plus, 12, 'Ala/Ala)'])].
[sujeto(['In', the, gastrocnemius, 'muscle,', 'diet-induced', obesity]), verbo([increased]), complemento([global, 'DNA', methylation])].
[sujeto(['Fish', oil]), verbo([prevented]), complemento([the, decrease, in, 'Pparg2', promoter, methylation, induced, by, obesity, in, the, gastrocnemius, muscle])].
[sujeto(['Regardless', of, the, diet, 'given,', fish, oil, supplementation]), verbo([increased]), complemento(['Pparg2', promoter, methylation, at, 'CpG-263', in, muscle, and, adipose, tissue])].
[sujeto(['Fish', oil, supplementation, attenuated, body, weight, 'gain,', abolished, the]), verbo([increase]), complemento([in, 'Pparg2', expression, in, the, liver, and, prevented, the, decrease, in, 'Pparg2', promoter, methylation, in, the, muscle, induced, by, the, 'HFD'])].
[sujeto(['Both', sedentary, time, and, 'MVPA', were, strongly]), verbo([associated]), complemento([with, 'HOMA-IS', and, 'Matsuda-ISI', after, adjustment, for, 'age,', 'sex,', 'ethnicity,', 'medication,', smoking, status, and, accelerometer, wear, time])].
[sujeto(['Every', 30, minute, difference, in, sedentary, time, was, inversely]), verbo([associated]), complemento([with, a, 4, '%', '(', 0, ',', 8, '%', ;, p, =, 0.043, ')', difference, in, 'Matsuda-ISI,', whereas, every, 30, minutes, in, 'MVPA', was, positively, associated, with, a, 13, '%', '(', 0, ',', 26, '%', ;, p, =, 0.048, ')', difference])].
[sujeto(['The', association, of, 'MVPA', with, 'Matsuda-ISI', was, modified, by, genotype, '(', p, =, 0.005, ')', and, only]), verbo([maintained]), complemento([in, 'Ala12', allele, carriers])].
[sujeto(['Conversely,', sedentary, time, was, not, modified, by, genotype, and, remained, inversely]), verbo([associated]), complemento([with, insulin, sensitivity, in, 'Pro12', allele, homozygotes])].
[sujeto(['Immune', function, was, assessed, by, ex, vivo, cytokine, production, in]), verbo([stimulated]), complemento([blood, and, plasma, immunoglobulin, 'E', '(', 'IgE)'])].
[sujeto(['Predominant', bacterial, fragments, were]), verbo([associated]), complemento([with, 18, months, 'IgE', in, all, infants, '(', 'P=0'])].
[sujeto(['PPARγ2', is]), verbo([expressed]), complemento([almost, exclusively, in, adipose, tissue, and, plays, a, central, role, in, adipogenesis])].
[sujeto(['Despite', intensive, studies, over, the, last, 2, 'decades,', the, mechanism]), verbo([regulating]), complemento([the, expression, of, the, 'Pparg2', 'gene,', especially, the, role, of, 'cis-regulatory', 'elements,', is, still, not, completely, understood])].
[sujeto(['Here,', we]), verbo([report]), complemento([a, comprehensive, investigation, of, the, enhancer, elements, within, the, murine, 'Pparg2', gene])].
[sujeto(['This', enhancer, element, was, first, identified, as, highly]), verbo([conserved]), complemento(['non-coding', sequence, 10, '(', 'CNS10)', and, was, later, shown, to, be, enriched, with, the, enhancer, marker, 'H3', 'K27', acetylation])].
[sujeto(['Further', studies, identified, a]), verbo([binding]), complemento([site, for, p300, as, the, essential, enhancer, element, in, 'CNS10'])].
[sujeto(['Moreover,', p300, physically]), verbo([binds]), complemento([to, 'CNS10', and, is, required, for, the, enhancer, activity, of, 'CNS10'])].
[sujeto(['In', 'summary,', our, study, identified, a, novel, enhancer, element, on, the, murine, 'Pparg2', gene, and]), verbo([suggested]), complemento([a, novel, mechanism, for, the, regulation, of, 'Pparg2', expression, by, p300, in, 3, 'T3-L1', adipogenesis])].
[sujeto(['The', fat, mass, and, 'obesity-associated', gene, '(', 'FTO)', rs9939609, and, peroxisome, 'proliferator-activated', receptor, gamma, 2, gene, '(', 'PPARG2)', rs1801282, polymorphisms, are, type, 2, diabetes, mellitus, susceptibility, gene, variants]), verbo([associated]), complemento([with, obesity])].
[sujeto(['This', study, examined, whether, these, variants, are]), verbo([associated]), complemento([with, anthropometry, at, birth, among, a, representative, 'multi-ethnic', sample, of, 'Trinidadian', neonates])].
[sujeto(['For', both, 'variants,', the, allelic, and, genotypic, frequencies, among, the, 'African', and, 'South', 'Asian', neonates, mirrored, those]), verbo([found]), complemento([elsewhere, for, similar, ethnic, groups])].
[sujeto(['Neonates', of, 'African', ethnicity, possess, the, highest, frequency, of, rs9939609, and, rs1801282, alleles, and, 'genotypes;', this, may, be]), verbo([associated]), complemento([with, ethnic, differences, in, the, risk, of, lifestyle, diseases])].
[sujeto(['The', free, fatty, acid, receptor, 'FFA1,', 'FFA2,', and, 'FFA3', and, 'hydroxy-carboxylic', acid, receptor, '(', 'HCA2)', are, 'G', 'protein-coupled', 'receptors,']), verbo([acting]), complemento([as, energy, and, metabolic, sensors])].
[sujeto(['In', view, of, the, metabolic, changes, occurring, during, the, different, phases, of, 'lactation,', in, 'particular,', the, altered, concentrations, of, 'non-esterified', fatty, acids, and, 'β-hydroxybutyrate']), verbo([acting]), complemento([as, receptor, 'ligands,', the, longitudinal, 'tissue-specific', characterization, provided, herein, allows, for, a, first, insight, into, the, regulation, of, these, receptors, at, the, gene, expression, level])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, 'n-3', 'LCPUFA', reduces, 'BP', and, plasma, triacylglycerol, '(', 'TAG)', in, infants])].
[sujeto(['Few', studies]), verbo([have]), complemento([found, effects, on, glucose, homeostasis, in, humans])].
[sujeto(['This', effect, was, modified, by, 'PPARG2-Pro12Ala,', as, 'TAG', only]), verbo([decreased]), complemento([among, heterozygotes])].
[sujeto(['FO', supplemented, 'PPARG2', 'Pro12Ala', heterozygotes, also, had]), verbo([decreased]), complemento([plasma, glucose, compared, with, the, 'SO', group, '(', 'p&nbsp;=&nbsp;0'])].
[sujeto(['In', 'conclusion,', our, results, confirm, that, 'FO', supplementation, in, late, infancy, reduces, 'TAG', and, 'BP', and, indicates, that, the, effects, are]), verbo([mediated]), complemento([via, peroxisome, 'proliferator-activated', 'receptor-γ', and, 'cyclooxygenase-2'])].
[sujeto(['Genome-wide', association, studies]), verbo([have]), complemento([revealed, numerous, risk, loci, associated, with, diverse, diseases])].
[sujeto(['We', show, that, integrative, computational, analysis, of, phylogenetic, conservation, with, a, complexity, assessment, of, 'co-occurring', transcription, factor]), verbo([binding]), complemento([sites, '(', 'TFBS)', can, identify, 'cis-regulatory', variants, and, elucidate, their, mechanistic, role, in, disease])].
[sujeto(['We', identified, the, 'PRRX1', homeobox, factor, as, a, repressor, of, 'PPARG2', expression, in, adipose, cells, and, demonstrate, its, adverse, effect, on, lipid, metabolism, and, systemic, insulin, 'sensitivity,', dependent, on, the, rs4684847, risk, allele, that]), verbo([triggers]), complemento(['PRRX1', binding])].
[sujeto(['Thus,', 'cross-species', conservation, analysis, at, the, level, of, 'co-occurring', 'TFBS']), verbo([provides]), complemento([a, valuable, contribution, to, the, translation, of, genetic, association, signals, to, 'disease-related', molecular, mechanisms])].
[sujeto(['Nuclear', receptors, '(', 'NR)']), verbo([regulate]), complemento([transcription, of, genes, involved, in, many, biological, processes, such, as, 'development,', cell, 'proliferation,', differentiation, and, cell, death])].
[sujeto(['The', presence, of, a, specific, 'DNA']), verbo([target]), complemento([was, required, to, induce, in, vitro, a, 'BRET', shift, reflecting, heterodimerization, of, 'RXR/PPARG2', or, 'RXR/THR'])].
[sujeto(['For', the]), verbo([nuclear]), complemento(['receptors,', we, found, by, mutagenesis, analysis, that, each, heterodimer, partner, must, harbor, an, intact, 'DNA', binding, domain, to, induce, 'BRET', and, heterodimerization, on, a, 'DNA', target])].
[sujeto(['Moreover', the, interaction, between, the, 'PPARG2', ligand]), verbo([binding]), complemento([domain, and, the, 'RXR', 'DNA', binding, domain, stabilized, the, heterodimer, on, its, 'DNA', target])].
[sujeto(['BRET', microscopy, in, living, cells, highlighted, the, heterodimerization, of, 'RXR/PPARG2', within, the, nucleus, clustered, in, discrete, foci, that, may, represent, active]), verbo([target]), complemento([gene, transcription, regulation, regions])].
[sujeto(['BRET', imaging, also]), verbo([suggested]), complemento([that, heterodimerization, between, 'RXR', and, 'PPARG2', required, the, 'DNA', binding, of, 'PPARG2'])].
[sujeto(['The', 'BRET', approach, described, here, allowed, us, to, study, the, dynamic, interactions, which, exist, between, 'NR', in, vitro, or, in, living, cells, and, can]), verbo([provide]), complemento([important, information, on, heterodimerization, 'modes,', affinity, with, a, given, 'RE', and, subcellular, localization, of, the, heterodimers])].
[sujeto(['This', method, could, be, used, to, study, real, time, changes, of, 'NR', heterodimers, occurring, on, 'DNA', depending, upon, cell, 'activation,', chromatin, state, and, help, to, define, the, mechanisms, of, ligands, or, drug, action, designed, to]), verbo([target]), complemento(['NRs'])].
[sujeto(['Concerning', the, genetic, factors, of, 'obesity,', no, consistent, association, between, populations]), verbo([has]), complemento([been, 'reported,', which, may, be, due, to, the, frequency, of, 'polymorphisms,', the, lifestyle, of, studied, populations, and, its, interaction, with, other, factors])].
[sujeto(['In', contrast, with, other, 'reports,', only, 'FTO', rs9939609, was]), verbo([associated]), complemento([with, obesity, 'related-traits,', including, 'BMI', '(', p, =, 0.03, ')', ',', waist, circumference, '(', p, =, 0.02, ')', ',', triceps, skinfold, '(', p, =, 0.03, ')', and, 'waist/height', ratio, '(', p, =, 0.01, ')', ',', and, also, with, cholesterol, levels, '(', p, =, 0.02, ')', and, 'LDL', '(', p, =, 0.009, ')'])].
[sujeto(['In', 'summary,', only, 'FTO', rs9939609, was]), verbo([associated]), complemento([with, obesity, 'related-traits,', while, 'PPARG2', rs1801282, and, 'ADIPOQ', rs4632532, were, involved, in, lipid, metabolism])].
[sujeto(['Human', and, animal, studies]), verbo([suggest]), complemento([an, interaction, between, the, 'Pro12Ala', polymorphism, of, 'PPARG', and, dietary, fat])].
[sujeto(['In', this, randomized, crossover, clinical, 'trial,', we, investigated, whether, subjects, with, the, 'Pro12Pro', and, 'Ala12Ala', genotypes, of, 'PPARG']), verbo([respond]), complemento([differently, to, a, diet, supplemented, with, high, saturated, '(', 'SAFA)', or, polyunsaturated, fatty, acid, '(', 'PUFA)'])].
[sujeto(['We']), verbo([recruited]), complemento(['non-diabetic', men, from, a, 'population-based', 'METSIM', study, '(', including, 10, ',', 197, 'men)', to, obtain, men, with, the, 'Ala12Ala', and, the, 'Pro12Pro', genotypes, matched, for, age, and, body, mass, index])].
[sujeto(['The', 'Ala12Ala', genotype, also]), verbo([associated]), complemento([with, higher, mRNA, expression, of, 'PPARG2,', 'LPIN1,', and, 'SREBP-1c', compared, to, participants, with, the, 'Pro12Pro', genotype, '(', 'FDR&nbsp;&lt;&nbsp;0'])].
[sujeto(['However,', the, beneficial, effects, of, dietary, 'PUFA', and, the, 'Ala12Ala', genotype, of, 'PPARG', on, serum, lipids, are]), verbo([mediated]), complemento([through, divergent, mechanisms])].
[sujeto(['PPARg2', 'Pro¹²Ala', polymorphism]), verbo([modulates]), complemento([expression, 'and/or', function, of, the, molecule, encoded, by, this, gene, and, is, a, promising, locus, of, 'GO'])].
[sujeto(['In', our, 'study,', the, 'Ala¹²', allele, and, 'Ala¹²', variant, '(', 'Ala¹²Ala', 'and/or', 'Pro¹²Ala', 'genotype)']), verbo([decreased]), complemento([the, risk, of, 'GO', '(', p, =, 1.2e-5, and, p, =, 0.00013, ')'])].
[sujeto(['The', opposite]), verbo([finding]), complemento([was, recorded, in, 'males,', in, whom, the, studied, polymorphism, was, related, to, 'activity,', but, not, to, the, 'development,', of, 'GO'])].
[sujeto(['A', multivariate, analysis, indicated, the, 'Pro¹²Ala', marker, as, an, independent, risk, factor, of, eye, symptoms, '(', p, =, 0.0001, ')', and, lack, of, 'Ala']), verbo([increases]), complemento([the, risk, of, 'GO', 3.24, -, fold])].
[sujeto(['In', 'conclusion,', the, 'gain-of-function', 'Ala¹²', variant, protects, against, 'GO', and]), verbo([modulates]), complemento([the, course, of, the, disease])].
[sujeto(['Both', genetic, factors, and, diabetogenic, environmental, 'factors,', such, as, a, 'high-sucrose', diet, '(', 'HSD),', are]), verbo([involved]), complemento([in, the, development, of, type, 2, diabetes])].
[sujeto(['In', this, 'study,', the, 'Nagoya-Shibata-Yasuda', '(', 'NSY)', 'mouse,', an, animal, model, of, type, 2, diabetes, and, 'C3H', mice, used, as, 'controls,', were, fed, a, 'HSD,', a, 'high-fat', diet, '(', 'HFD)', or, a]), verbo([regular]), complemento([diet, '(', 'RD)', from, weaning])].
[sujeto(['In', 'C3H', 'mice,', 'HFD', significantly]), verbo([increased]), complemento([body, weight, 'gain,', but, maintained, glucose, tolerance])].
[sujeto(['In', 'contrast,', in, 'NSY', 'mice,', 'HSD', resulted, in]), verbo([increased]), complemento([body, weight, gain, and, liver, steatosis, and, increased, glucose, intolerance, to, a, greater, extent, than, 'HFD'])].
[sujeto(['HSD-fed', 'NSY,', but, not, 'C3H', 'mice,', exhibited]), verbo([increased]), complemento([hepatic, expression, levels, of, 'Pparg2,', an, isoform, of, 'Pparg', as, well, as, 'G0s2,', a, target, of, 'Pparg,', which, are, known, to, be, 'adipocyte-specific', genes])].
[sujeto(['Compared', to, 'RD-fed', 'C3H', 'mice,', hepatic, expression, levels, of, 'Kat2b', '(', transcriptional, 'regulation),', 'Hsd3b5', '(', steroid, hormone, 'metabolism)', and, 'Cyp7b1', '(', bile, acid, 'metabolism)', were, initially, lower, in, 'RD-fed', 'NSY', 'mice,', and, were, further]), verbo([decreased]), complemento([in, 'HSD-fed', 'NSY', mice])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, elucidation, of, this, heterogeneity, in, response, to, 'HSD', might, contribute, to, further, understanding, of, the, 'gene-environment', interactions, leading, to, diabetes, in, humans])].
[sujeto(['DNA', polymerase, β, '(', 'Pol', 'β)']), verbo([participates]), complemento([in, 'BER', by, filling, 'DNA', gaps, that, result, from, excision, of, damaged, bases])].
[sujeto(['Approximately', 30, '%', of, human, tumours]), verbo([express]), complemento(['Pol', β, 'variants,', many, of, which, have, altered, fidelity, and, activity, in, vitro, and, when, 'expressed,', induce, cellular, transformation])].
[sujeto(['To', test, the, hypothesis, that, mutations]), verbo([induced]), complemento([in, vivo, by, 'Ile260Met', lead, to, cellular, 'transformation,', we, characterized, the, 'genome-wide', expression, profile, of, a, clone, expressing, 'Ile260Met', as, compared, with, its, 'non-induced', counterpart])].
[sujeto(['Gene', 'Ontology', '(', 'GO)', clusters, were, analyzed, using, 'Ingenuity', 'Pathways', 'Analysis', to, identify, altered, gene, networks, and]), verbo([associated]), complemento([nodes])].
[sujeto(['One', 'node,', peroxisome, 'proliferator-activated', protein, γ, '(', 'PPARG),', was, sequenced, and]), verbo([found]), complemento([to, contain, a, coding, region, mutation, in, 'PPARG2', only, in, transformed, cells])].
[sujeto(['Further', analysis]), verbo([suggests]), complemento([that, this, mutation, leads, to, dominant, negative, activity, of, 'PPARG2'])].
[sujeto(['PPARG', is, a, transcription, factor, implicated, to]), verbo([have]), complemento([tumour, suppressor, function])].
[sujeto(['This']), verbo([suggests]), complemento([that, the, 'PPARG2', mutant, may, have, played, a, role, in, driving, cellular, transformation])].
[sujeto(['We', conclude, that, 'PPARG']), verbo([induces]), complemento([cellular, transformation, by, a, mutational, mechanism])].
[sujeto(['Activation', of, the, peroxisome, 'proliferator-activated', receptor, g, '(', 'PPARg)', improves, insulin, sensitivity, and]), verbo([inhibits]), complemento([atherosclerosis])].
[sujeto(['We', conclude, that, 'PPARg2', 'Pro12Ala', polymorphisms, are]), verbo([associated]), complemento([with, increased, risk, for, myocardial, infarction, in, 'Han', 'Chinese', in, 'Hohhot'])].
[sujeto(['Type', 2, diabetes, risk, 'SNPs', in, or, near, 'KCNJ11', and, 'HHEX', were, significantly, '(', p, &, 'lt;', 0.0013, ')', ',', and, those, in, or, near, 'CDKN2B,', 'NOTCH2', and, 'MTNR1B', were, nominally, '(', p, &, 'lt;', 0.05, ')', ',']), verbo([associated]), complemento([with, decreased, liver, 'IR', index])].
[sujeto(['The', 'Pro12', allele, of, 'PPARG2', was, significantly]), verbo([associated]), complemento([with, a, high, adipocyte, 'IR', index, and, nominally, associated, with, high, liver, 'IR'])].
[sujeto(['The', 'Pro12', allele, of, 'PPARG2', seems, to, impair, 'insulin\'s', antilipolytic, 'effect,']), verbo([leading]), complemento([to, high, 'NEFA', release, in, the, fasting, state, and, 'IR'])].
[sujeto(['In', 'addition,', the, type, 2, diabetes, risk, alleles, of, 'KCNJ11', and, 'HHEX,', which, are, known, to, impair, insulin, 'secretion,', were]), verbo([associated]), complemento([with, increased, hepatic, insulin, sensitivity])].
[sujeto(['The', peroxisome, 'proliferator-activated', 'receptor-gamma', gene, '(', 'PPARG)']), verbo([has]), complemento([been, implicated, in, the, etiology, of, type, 2, diabetes, mellitus, and, has, been, investigated, in, numerous, epidemiologic, studies])].
[sujeto(['Population-based', 'cohort,', 'case-control,', 'cross-sectional,', or, 'genome-wide', association, studies]), verbo([reporting]), complemento([associations, between, the, 'PPARG', 'Pro12Ala', gene, variant, '(', 'rs1801282)', and, type, 2, diabetes, were, included])].
[sujeto(['An', updated, 'literature-based', 'meta-analysis']), verbo([involving]), complemento([32, ',', 849, type, 2, diabetes, cases, and, 47, ',', 456, controls, in, relation, to, the, 'PPARG', 'Pro12Ala', variant, was, conducted])].
[sujeto(['The', peroxisome, 'proliferator-activated', 'receptor-gamma2', '(', 'PPARG2)', 'Pro12Ala', polymorphism]), verbo([has]), complemento([been, associated, with, a, higher, 'BMI', and, a, lower, risk, of, type, 2, diabetes, in, adulthood])].
[sujeto(['The', objectives, of, this, study, were, to, assess, 1, ')', the, influence, of, the, 'PPARG2', 'Pro12Ala', polymorphism, on, adiposity, markers, in, adolescents, and, 2, ')', a, possible]), verbo([modulating]), complemento([effect, of, 'breast-feeding', on, these, associations])].
[sujeto(['Peroxisome', 'proliferator-activated', 'receptor-gamma2', '(', 'PPARG2)', is, a]), verbo([nuclear]), complemento([hormone, receptor, of, 'ligand-dependent', transcription, factor, involved, in, adipogenesis, and, a, molecular, target, of, the, insulin, sensitizers, thiazolidinediones])].
[sujeto(['We', addressed, the, question, of, whether, the, 3, variants, '(', -, 1279, 'G/A,', 'Pro12Ala,', and, 'His478His)', in, the, 'PPARG2', gene, are]), verbo([associated]), complemento([with, type, 2, diabetes, mellitus, and, its, related, traits, in, a, 'South', 'Indian', population])].
[sujeto(['The', -, 1279, 'G/A,', 'Pro12Ala,', and, 'His478His', variants, of, the, 'PPARG2', gene, were, not]), verbo([associated]), complemento([with, type, 2, diabetes, mellitus])].
[sujeto(['However,', the, 2, -, loci, analyses, showed, 'that,', in, the, presence, of, 'Pro/Pro', genotype, of, the, 'Pro12Ala', 'variant,', the, -, 1279, 'G/A', promoter, variant, showed]), verbo([increased]), complemento([susceptibility, to, type, 2, diabetes, mellitus, '(', odds, 'ratio,', 2.092, ;, 95, '%', confidence, 'interval,', 1.22, -, 3.59, ;, 'P', =])].
[sujeto(['The', 3, -, loci, haplotype, analysis, showed, that, the, 'A-Ala-T', '(', -, 1279, 'G/A-Pro12Ala-His478His)', haplotype, was]), verbo([associated]), complemento([with, a, reduced, risk, of, type, 2, diabetes, mellitus, '(', 'P', &, 'lt;'])].
[sujeto(['Although', our, data, indicate, that, the, 'PPARG2', gene, 'variants,', 'independently,']), verbo([have]), complemento([no, association, with, type, 2, diabetes, 'mellitus,', the, 2, -, loci, genotype, analysis, involving, -, 1279, 'G/A', and, 'Pro12Ala', variants, and, the, 3, -, loci, haplotype, analysis, have, shown, a, significant, association, with, type, 2, diabetes, mellitus, in, this, 'South', 'Indian', population])].
[sujeto(['CCAAT/Enhancer']), verbo([binding]), complemento([proteins, '(', 'C/EBPs)', and, peroxisome, 'proliferator-activated', receptors, gamma, '(', 'PPARG)', play, critical, roles, in, the, regulation, of, lipid, metabolism, genes])].
[sujeto(['Overexpression', of, 'CEBPdelta', '(', 'CEBPD)']), verbo([enhances]), complemento([lipid, accumulation, and, specifically, activates, 'PPARG2', transcription, in, 'HepG2', cells])].
[sujeto(['By', using, 5, '\'', -, serial, deletion, reporter, 'analysis,', we, show, that, the, region, comprising, the, -, 457, to, +, 129, base, pairs, is]), verbo([required]), complemento([for, 'CEBPD', response, of, the, 'PPARG2', promoter])].
[sujeto(['We', previously]), verbo([have]), complemento([shown, that, the, human, 'CEBPD', is, sumoylated, by, small, 'ubiquitin-related', 'modifier-1', '(', 'SUMO1)'])].
[sujeto(['We', further, demonstrated, that, the, sumoylation, of, 'CEBPD', lysine, 120, is, also, detectable, in, 'HepG2', 'cells,', and, this, modification, functions, for]), verbo([binding]), complemento([of, the, 'recruits,', 'HDAC1', and, 'HDAC3'])].
[sujeto(['Combining', that, the]), verbo([increasing]), complemento([amount, of, 'CEBPD', and, the, sumoylated, 'CEBPD', '(', 'suCEBPD)', consistently, responded, to, lipogenic, 'stimulation,', these, results, suggest, that, the, excess, 'non-sumoylated', 'CEBPD', could, be, a, critical, activator, which, reverses, 'suCEBPD/HDAC1/HDAC3-mediated', 'PPARG2', gene, inactivation, and, promotes, hepatic, lipogenesis])].
[sujeto(['Taken', 'together,', we]), verbo([suggest]), complemento([that, 'suCEBPD/HDAC1/HDAC3', complex, inactivates, 'PPARG2', 'transcription,', and, the, induction, of, 'CEBPD', expression, transiently, activates, 'PPARG2', transcription, which, is, involved, in, 'adipocyte-like', lipogenesis, in, 'HepG2', cells])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, protoporphyrin, diarginate, exerts, a, high, bactericidal, effect, against, 'methicillin-resistant', 'S'])].
[sujeto(['DNA', methylation, is, an, epigenetic, mechanism, that, can, be, influenced, by, 'genetic,', environmental, and, stochastic, events, and, may]), verbo([have]), complemento([an, important, impact, on, individual, variability])].
[sujeto(['A', mixture, approach, using, principal, component, analysis, '(', 'PCA)', and, 'Bayes', methods, allowed, to, combine, the, three, studies, and, to, leverage, the]), verbo([increased]), complemento([predictive, power, provided, by, the, larger, sample])].
[sujeto(['Network', analysis, revealed, gene, networks, centered, on, the, 'PPAR-γ', '(', 'NR1C3)', and, 'C-MYC', gene, hubs]), verbo([interacting]), complemento([through, the, 'AP-1', '(', 'c-Jun)', transcription, factor])].
[sujeto(['PPAR-γ', '(', 'NR1C3)', is, a, drug]), verbo([target]), complemento([for, 'pioglitazone,', which, has, been, shown, to, reduce, depression, symptoms, in, patients, with, 'MDD'])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, γ, '(', 'PPARγ,', 'NR1C3)', and, testicular, receptor, 4]), verbo([nuclear]), complemento([receptor, '(', 'TR4,', 'NR2C2)', are, two, members, of, the, nuclear, receptor, '(', 'NR)', superfamily, that, can, be, activated, by, several, similar, 'ligands/activators', including, polyunsaturated, fatty, acid, 'metabolites,', such, as, 13, -, hydroxyoctadecadienoic, acid, and, 15, -, hydroxyeicosatetraenoic, 'acid,', as, well, as, some, 'anti-diabetic', drugs, such, as, thiazolidinediones, '(', 'TZDs)'])].
[sujeto(['First,', activation, of, 'PPARγ']), verbo([increases]), complemento([insulin, sensitivity, yet, activation, of, 'TR4', decreases, insulin, sensitivity])].
[sujeto(['Second,', 'PPARγ', attenuates, atherosclerosis, but, 'TR4', might]), verbo([increase]), complemento([the, risk, of, atherosclerosis])].
[sujeto(['Third,', 'PPARγ']), verbo([suppresses]), complemento([prostate, cancer, '(', 'PCa)', development, and, 'TR4', suppresses, prostate, carcinogenesis, yet, promotes, 'PCa', metastasis])].
[sujeto(['Knocking', out, 'PPARγ', altered, the, ability, of, 'TR4', to]), verbo([promote]), complemento([prostate, carcinogenesis, and, knocking, down, 'TR4', also, resulted, in, 'TZD', treatment, promoting, 'PCa', 'development,', indicating, that, both, 'PPARγ', and, 'TR4', might, coordinate, with, each, other, to, regulate, 'PCa', 'initiation,', and, the, loss, of, either, one, of, them, might, switch, the, other, one, from, a, tumor, suppressor, to, a, tumor, promoter])].
[sujeto(['Over', the, past, 20, 'years,', the, prevalence, of, obesity]), verbo([has]), complemento([increased, rapidly, in, both, industrialized, and, developing, 'countries,', resulting, in, a, considerably, increased, risk, of, type, 2, diabetes, mellitus, '(', 'T2DM)', and, metabolic, syndrome])].
[sujeto(['Adipokines,', produced, and]), verbo([released]), complemento([by, adipose, 'tissue,', are, considered, as, factors, linking, 'obesity-induced', inflammation, with, insulin, 'resistance,', and, their, regulation, through, peroxisome, 'proliferator-activated', receptors, γ, '(', 'PPARγ', also, known, as, 'NR1C3)', is, essential, in, these, processes])].
[sujeto(['PPARγ', are, transcriptional, factors, belonging, to, the, 'ligand-activated']), verbo([nuclear]), complemento([receptor, superfamily, which, directly, regulate, the, expression, of, a, large, number, of, genes, involved, in, adipocyte, 'differentiation,', lipid, and, carbohydrate, metabolism, as, well, as, adipokine, 'synthesis;', thereby, they, are, implicated, in, various, metabolic, 'disorders,', including, 'obesity,', insulin, 'resistance,', 'dyslipidemia,', and, hypertension])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, '(', 'PPAR)', includes, the, family, of, 'ligand-activated', transcription, factors, which, belong, to, the, group, of]), verbo([nuclear]), complemento([hormone, receptors, and, are, connected, to, 'retinoid,', glucocorticoid, and, thyroid, hormone, receptors])].
[sujeto(['PPARgamma', and, 'PPARalpha', are, identified, as, important, immunomodulators, and, potentially, represent, an, 'anti-inflammatory']), verbo([target]), complemento([for, respiratory, diseases])].
[sujeto(['PPARgamma', deficiency, in, the, lungs]), verbo([has]), complemento([been, observed, in, the, inflammatory, diseases, such, as, 'asthma,', pulmonary, alveolar, 'proteinosis,', fibrosis, and, 'sarcoidosis,', as, well, as, in, the, animal, models, of, the, lung, inflammation])].
[sujeto(['At', the, same, 'time,', an]), verbo([increased]), complemento([activity, of, the, nuclear, factor, kappa, 'B', '(', 'NF-kappaB)', in, the, bronchoalveolar, lavage, has, been, recorded, in, patients, with, sarcoidosis])].
[sujeto(['The', reason, for, the]), verbo([decrease]), complemento([in, the, production, of, 'PPARgamma', in, sarcoidosis, remains, unknown])].
[sujeto(['Several', possible, mechanisms, are, 'mentioned:', genetic, defect, with, lowered, 'production,', 'down-regulation', due, to, the]), verbo([increased]), complemento([values, of, 'IFN-gamma', or, an, increased, decomposition, of, 'PPARgamma'])].
[sujeto(['Further', investigation, will, explain, the, mechanisms, regarding, the]), verbo([decreased]), complemento([production, of, 'PPARgamma', in, sarcoidosis])].
[sujeto(['Eicosapentaenoic', acid, '(', 'EPA)', and, docosahexaenoic, acid, '(', 'DHA)', are, 'n-3', fatty, acids]), verbo([found]), complemento([in, oily, fish, and, fish, oil, supplements])].
[sujeto(['These', fatty, acids, are, able, to]), verbo([inhibit]), complemento([partly, a, number, of, aspects, of, inflammation, including, leucocyte, 'chemotaxis,', adhesion, molecule, expression, and, 'leucocyte-endothelial', adhesive, 'interactions,', production, of, eicosanoids, like, prostaglandins, and, leukotrienes, from, the, 'n-6', fatty, acid, arachidonic, 'acid,', production, of, inflammatory, cytokines, and, 'T', cell, reactivity])].
[sujeto(['In', 'parallel,', 'EPA', gives, rise, to, eicosanoids, that, often]), verbo([have]), complemento([lower, biological, potency, than, those, produced, from, arachidonioc, acid, and, 'EPA', and, 'DHA', give, rise, to, 'anti-inflammatory', and, inflammation, resolving, resolvins, and, protectins])].
[sujeto(['Mechanisms', underlying, the, 'anti-inflammatory', actions, of, 'n-3', fatty, acids, include, altered, cell, membrane, phospholipid, fatty, acid, 'composition,', disruption, of, lipid, 'rafts,', inhibition, of, activation, of, the, 'pro-inflammatory', transcription, factor]), verbo([nuclear]), complemento([factor, kappa, 'B', so, reducing, expression, of, inflammatory, 'genes,', activation, of, the, 'anti-inflammatory', transcription, factor, 'NR1C3', '(', i])].
[sujeto([peroxisome, proliferator]), verbo([activated]), complemento([receptor, 'γ)', and, binding, to, the, 'G', protein, coupled, receptor, 'GPR120'])].
[sujeto(['In', adult, 'humans,', an, 'EPA', plus, 'DHA', intake, greater, than, 2, g, 'day⁻¹', seems, to, be]), verbo([required]), complemento([to, elicit, 'anti-inflammatory', 'actions,', but, few, dose, finding, studies, have, been, performed])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, γ, '(', 'PPARγ;', 'NR1C3)', is, known, as, a, key, regulator, of, adipocytogenesis, and, the, molecular]), verbo([target]), complemento([of, thiazolidinediones, '(', 'TZDs),', also, known, as, antidiabetic, agents])].
[sujeto(['Despite', the, clinical, benefits, of, 'TZDs,', their, use, is, often]), verbo([associated]), complemento([with, adverse, effects, including, peripheral, 'edema,', congestive, heart, 'failure,', and, weight, gain])].
[sujeto(['Here', we]), verbo([report]), complemento([the, identification, and, characterization, of, a, 'non-thiazolidinedione', 'PPARγ', partial, 'agonist,', 'Cerco-A,', which, is, a, derivative, of, the, natural, 'product,', '(', -, ')', -, cercosporamide])].
[sujeto(['Cerco-A', was]), verbo([found]), complemento([to, be, a, binder, of, the, 'PPARγ', 'ligand-binding', domain, in, a, ligand, competitive, binding, assay, and, showed, a, unique, cofactor, recruitment, profile, compared, to, rosiglitazone])].
[sujeto(['A', crystal, structure, analysis, revealed, that, 'Cerco-A']), verbo([binds]), complemento([to, 'PPARγ', without, direct, hydrogen, bonding, to, helix12])].
[sujeto(['After', a, 14, -, day, oral, 'administration,', once, per, day, of, 'Cerco-A', in, 'Zucker', diabetic, fatty, '(', 'ZDF)', 'rats,', an, apparent]), verbo([decrease]), complemento([of, plasma, glucose, and, triglyceride, was, 'observed,', as, with, pioglitazone])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, 'Cerco-A', offers, beneficial, effects, on, glycemic, control, with, attenuated, undesirable, side, effects])].
[sujeto(['The']), verbo([nuclear]), complemento([hormone, receptor, peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPAR', 'gamma;', 'NR1C3)', plays, a, central, role, in, adipogenesis, and, is, the, molecular, target, of, the, thiazolidinedione, class, of, antidiabetic, drugs])].
[sujeto(['To', overcome, the, 'well-known', shortcomings, of, 'thiazolidinediones,', we]), verbo([have]), complemento([identified, 'INT131', '(', formerly, 'T131', and, 'AMG131)', as, a, potent, selective, ligand, for, 'PPAR', gamma, that, is, structurally, and, pharmacologically, distinct, from, glitazone, agonists])].
[sujeto(['In', vitro, biochemical, and, 'cell-based', functional, assays, showed, that, 'INT131']), verbo([mediates]), complemento([a, distinct, pattern, of, coregulator, recruitment, to, 'PPAR', gamma])].
[sujeto(['In', 'adipocytes,', 'INT131', showed, minimal, stimulation, of, adipocyte, differentiation, and, partially]), verbo([activated]), complemento(['PPAR', gamma, target, genes, involved, in, adipogenesis, 'and,', at, the, same, 'time,', showed, more, agonistic, activity, on, another, set, of, target, genes, that, may, influence, insulin, sensitivity, directly])].
[sujeto(['These', unique, properties, of, 'INT131', may]), verbo([provide]), complemento([a, mechanistic, basis, for, its, distinct, pharmacological, profile])].
[sujeto(['In', 'vivo,']), verbo([increases]), complemento([in, glucose, tolerance, were, observed, in, 'Zucker', '(', 'fa/fa)', rats, following, a, 14, -, day, oral, treatment, with, 'INT131'])].
[sujeto(['Thus,', 'INT131', appears, to, selectively]), verbo([modulate]), complemento(['PPAR', gamma, responses, in, an, in, vivo, preclinical, 'model,', showing, antidiabetic, efficacy, while, exhibiting, an, improved, hemodynamic, and, cardiovascular, adverse, effect, profile, compared, to, the, full, agonist, rosiglitazone])].
[sujeto(['X-ray', crystallography, revealed, that, 'INT131']), verbo([interacts]), complemento([with, 'PPAR', gamma, through, a, distinct, binding, 'mode,', forming, primarily, hydrophobic, contacts, with, the, 'ligand-binding', pocket, without, direct, 'hydrogen-bonding', interactions, to, key, residues, in, helix, 12, that, are, characteristic, of, full, agonists])].
[sujeto(['Mutagenesis', studies, on, 'Tyr473', in, helix, 12, demonstrated, this, residue, as, essential, for, 'rosiglitazone-induced', receptor, 'activation,', but, nonessential, for, 'INT131', function, in, 'vitro,']), verbo([providing]), complemento([one, possible, molecular, determinant, for, 'INT131\'s', distinct, pharmacology])].
[sujeto(['The', peroxisome, 'proliferator-activated', 'receptor-gamma', '(', 'PPARgamma,', 'NR1C3)', in, complex, with, the, retinoid, 'X', receptor, '(', 'RXR)', plays, a, central, role, in, white, adipose, tissue, '(', 'WAT)', differentiation, and, 'function,']), verbo([regulating]), complemento([the, expression, of, key, 'WAT', proteins])].
[sujeto(['In', this]), verbo([report]), complemento([we, show, that, 'poly(ADP-ribose)', 'polymerase-2', '(', 'PARP-2),', also, known, as, an, enzyme, participating, in, the, surveillance, of, the, genome, 'integrity,', is, a, member, of, the, 'PPARgamma/RXR', transcription, machinery])].
[sujeto(['In', the, 'WAT', of, 'PARP-2(-/-)', mice, the, expression, of, a, number, of, 'PPARgamma']), verbo([target]), complemento([genes, is, reduced, despite, the, fact, that, 'PPARgamma1', and, -, gamma2, are, expressed, at, normal, levels])].
[sujeto(['In', transient, transfection, 'assays,', 'PARP-2', small, interference, 'RNA']), verbo([decreases]), complemento([basal, activity, and, 'ligand-dependent', activation, of, 'PPARgamma,', whereas, 'PARP-2', overexpression, enhances, the, basal, activity, of, 'PPARgamma,', although, it, does, not, change, the, maximal, 'ligand-dependent', activation])].
[sujeto(['In', 'combination,', our, results]), verbo([suggest]), complemento([that, 'PARP-2', is, a, novel, cofactor, of, 'PPARgamma', activity])].
[sujeto(['Lipid', and, carbohydrate, homeostasis, in, higher, organisms, is, governed, by, an, integrated, system, that]), verbo([has]), complemento([a, capacity, to, rapidly, respond, to, metabolic, changes])].
[sujeto(['Numerous', signals, reciprocally, convey, information, about, body, fat, status, from, the, periphery, to, central, nervous, system, in, the, attempt, to]), verbo([maintain]), complemento([body, weight, nearly, stable, throughout, life])].
[sujeto(['These', observations]), verbo([have]), complemento([spurred, interest, in, the, identification, of, the, transcriptional, and, other, regulatory, pathways, of, adipocyte, differentiation])].
[sujeto(['The']), verbo([nuclear]), complemento(['receptor,', peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPAR', 'gamma)', '(', 'NR1C3)', and, members, of, the, 'CCAAT', 'enhancer-binding', protein, '(', 'C/EBP)', family, are, central, mediators, controlling, adipocyte, differentiation, and, function])].
[sujeto(['Rev-erb', alpha, '(', 'NR1D1)', is, an, orphan]), verbo([nuclear]), complemento([receptor, encoded, on, the, opposite, strand, of, the, thyroid, receptor, alpha, gene])].
[sujeto(['Rev-erb', alpha]), verbo([acts]), complemento([as, a, negative, regulator, of, transcription, binding, to, the, same, response, element, than, another, orphan, nuclear, 'receptor,', 'ROR', alpha])].
[sujeto(['Rev-erb', alpha, is, highly]), verbo([expressed]), complemento([in, adipose, 'tissue,', skeletal, 'muscle,', 'heart,', liver, and, brain])].
[sujeto(['Rev-erb', alpha, expression]), verbo([increases]), complemento([during, adipocyte, differentiation, of, 3, 'T3-L1', cells, and, is, induced, by, 'PPAR', gamma, activation, in, both, 3, 'T3-L1', cells, in, vitro, and, in, rat, adipose, tissue, in, vivo, via, a, direct, repeat, '(', 'DR2)', in, the, 'Rev-erb', alpha, promoter])].
[sujeto(['Recent', results, in, vascular, smooth, muscle, cells, '(', 'VSMCs)', indicate, that, 'Rev-erb', alpha, also, controls, inflammation, by]), verbo([regulating]), complemento(['NF-kappa', 'B', responsive, 'genes,', such, as, 'IL-6', and, 'COX-2'])].
[sujeto(['Rev-Erbalpha', '(', 'NR1D1)', is, an, orphan]), verbo([nuclear]), complemento([receptor, encoded, on, the, opposite, strand, of, the, thyroid, receptor, alpha, gene])].
[sujeto(['Rev-Erbalpha', mRNA, is]), verbo([induced]), complemento([during, adipocyte, differentiation, of, 3, 'T3-L1', 'cells,', and, its, expression, is, abundant, in, rat, adipose, tissue])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, gamma, '(', 'PPARgamma)', '(', 'NR1C3)', is, a]), verbo([nuclear]), complemento([receptor, controlling, adipocyte, differentiation, and, insulin, sensitivity])].
[sujeto(['Here', we, show, that, 'Rev-Erbalpha', expression, is]), verbo([induced]), complemento([by, 'PPARgamma', activation, with, rosiglitazone, in, rat, epididymal, and, perirenal, adipose, tissues, in, vivo, as, well, as, in, 3, 'T3-L1', adipocytes, in, vitro])].
[sujeto(['Furthermore,']), verbo([activated]), complemento(['PPARgamma', induces, 'Rev-Erbalpha', promoter, activity, by, binding, to, the, direct, repeat, '(', 'DR)-2', response, element, 'Rev-DR2'])].
[sujeto(['Mutations', of, the, 5, '\'', or, 3, '\'', 'half-sites', of, the, response, element, totally, abrogated, 'PPARgamma']), verbo([binding]), complemento([and, transcriptional, 'activation,', identifying, this, site, as, a, novel, type, of, functional, 'PPARgamma', response, element])].
[sujeto(['Finally,', ectopic, expression, of, 'Rev-Erbalpha', in, 3, 'T3-L1', preadipocytes, potentiated, adipocyte, differentiation]), verbo([induced]), complemento([by, the, 'PPARgamma', ligand, rosiglitazone])].
[sujeto(['These', results, identify, 'Rev-Erbalpha', as, a]), verbo([target]), complemento([gene, of, 'PPARgamma', in, adipose, tissue, and, demonstrate, a, role, for, this, nuclear, receptor, as, a, promoter, of, adipocyte, differentiation])].
[sujeto(['The', activation, function, 2, '(', 'AF-2)-dependent', recruitment, of, coactivator, is, essential, for, gene, activation, by]), verbo([nuclear]), complemento([receptors])].
[sujeto(['We', show, that, the, peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPARgamma)', '(', 'NR1C3)', 'coactivator-1', '(', 'PGC-1)']), verbo([requires]), complemento([both, the, intact, 'AF-2', domain, of, 'PPARgamma', and, the, 'LXXLL', domain, of, 'PGC-1', for, 'ligand-dependent', and, 'ligand-independent', interaction, and, coactivation])].
[sujeto(['Although', the, 'AF-2', domain, of, 'PPARgamma', is, absolutely]), verbo([required]), complemento([for, 'PGC-1-mediated', 'coactivation,', this, coactivator, displayed, a, unique, lack, of, requirement, for, the, charge, clamp, of, the, 'ligand-binding', domain, of, the, receptor, that, is, thought, to, be, essential, for, 'LXXLL', motif, recognition])].
[sujeto(['The', mutation, of, a, single, serine, residue, adjacent, to, the, core, 'LXXLL', motif, of, 'PGC-1']), verbo([led]), complemento([to, restoration, of, the, typical, charge, clamp, requirement])].
[sujeto(['Thus,', the, unique, structural, features, of, the, 'PGC-1', 'LXXLL', motif, appear, to]), verbo([mediate]), complemento([an, atypical, mode, of, interaction, with, 'PPARgamma'])].
[sujeto(['Thus,', distinct, structural, 'determinants,', which, may, be, unique, for, a, particular, 'ligand,', are, utilized, by, the, receptor, to]), verbo([recognize]), complemento([the, coactivator])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, even, subtle, differences, in, ligand, structure, are, perceived, by, the, receptor, and, translated, into, a, unique, display, of, the, 'coactivator-binding', surface, of, the, 'ligand-binding', 'domain,', allowing, for, differential, recognition, of, coactivators, that, may, underlie, distinct, pharmacological, profiles, observed, for, ligands, of, a, particular, nuclear, receptor])].
[sujeto(['The']), verbo([nuclear]), complemento([hormone, receptor, peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPARgamma', '(', 'NR1C3))', plays, a, central, role, in, adipogenesis, and, is, the, molecular, target, for, the, thiazolidinedione, '(', 'TZD)', class, of, antidiabetic, drugs])].
[sujeto(['With', an, apparent]), verbo([binding]), complemento([affinity, '(', concentration, at, 50, '%', inhibition, of, '[', '(', 3, ')', 'H]rosiglitazone', binding, or, 'IC(50))', of, 1, 'nm,', 'T0070907', covalently, modifies, 'PPARgamma', on, cysteine, 313, in, helix, 3, of, human, 'PPARgamma2'])].
[sujeto(['Consistent', with, its, role, as, an, antagonist, of, 'PPARgamma,', 'T0070907', blocked, 'agonist-induced', recruitment, of, 'coactivator-derived', peptides, to, 'PPARgamma', in, a, homogeneous, 'time-resolved', 'fluorescence-based', assay, and]), verbo([promoted]), complemento([recruitment, of, the, transcriptional, corepressor, 'NCoR', to, 'PPARgamma', in, both, glutathione, 'S-transferase', 'pull-down', assays, and, a, 'PPARgamma/retinoid', 'X', receptor, '(', 'RXR)', 'alpha-dependent', gel, shift, assay])].
[sujeto(['Studies', with, mutant, receptors]), verbo([suggest]), complemento([that, 'T0070907', modulates, the, interaction, of, 'PPARgamma', with, these, cofactor, proteins, by, affecting, the, conformation, of, helix, 12, of, the, 'PPARgamma', 'ligand-binding', domain])].
[sujeto(['Interestingly,', whereas, the, 'T0070907-induced', 'NCoR', recruitment, to, 'PPARgamma/RXRalpha', heterodimer, can, be, almost, completely, reversed, by, the, simultaneous, treatment, with, 'RXRalpha', agonist, 'LGD1069,', 'T0070907', treatment]), verbo([has]), complemento([only, modest, effects, on, 'LGD1069-induced', coactivator, recruitment, to, the, 'PPARgamma/RXRalpha', heterodimer])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, activity, of, 'PPARgamma', antagonists, can, be, modulated, by, the, availability, and, concentration, of, 'RXR', agonists])].
[sujeto(['Human', lung, fibroblasts, '(', 'HLFs)']), verbo([act]), complemento([as, innate, immune, sentinel, cells, that, amplify, the, inflammatory, response, to, injurious, stimuli])].
[sujeto(['Here,', we, use]), verbo([targeted]), complemento([lipidomics, to, explore, the, hypothesis, that, 'HLFs', also, play, an, active, role, in, the, resolution, of, inflammation])].
[sujeto(['We', next, confirmed, the, ability, of, 'HLF', supernatants, to]), verbo([activate]), complemento(['PPARγ', using, a, 'cell-based', luciferase, 'reporter,', demonstrating, for, the, first, time, that, 'HLFs', activated, with, 'pro-inflammatory', 'IL-1β', or, cigarette, smoke, extract, '(', 'CSE)', produce, functional, 'PPARγ', 'ligands;', this, phenomenon, is, 'temporally-regulated,', 'COX-2-', and, 'lipocalin-type', 'PGD', 'synthase-dependent,', and, enhanced, by, arachidonic, acid, supplementation])].
[sujeto(['Finally,', we, used, luciferase, reporter, assays, to, show, that, several, of, the, 'PGs', in, the, lipidome, of]), verbo([activated]), complemento(['HLFs', independently, activate, 'PPARγ', 'and/or', inhibit, 'NFκB'])].
[sujeto(['These', results, indicate, that, 'HLFs,', as, immune, 'sentinels,']), verbo([regulate]), complemento([both, 'pro-inflammatory', and, 'pro-resolving', responses, to, injurious, stimuli])].
[sujeto(['This', novel, endogenous, resolution, pathway, represents, a, new, therapeutic]), verbo([target]), complemento([for, globally, important, inflammatory, diseases, like, chronic, obstructive, pulmonary, disease])].
[sujeto(['Pulmonary', hypertension, '(', 'PH),', a, serious, complication, of, sickle, cell, disease, '(', 'SCD),']), verbo([causes]), complemento([significant, morbidity, and, mortality])].
[sujeto(['While', recent, study, determined, that, hemin]), verbo([release]), complemento([during, hemolysis, triggers, endothelial, dysfunction, in, 'SCD,', the, pathogenesis, of, 'SCD-PH', remains, incompletely, defined])].
[sujeto(['SS', mice, developed, 'PH', and, 'RVH']), verbo([associated]), complemento([with, reduced, lung, levels, of, 'PPARγ', and, increased, levels, of, 'miR-27a,', 'v-ets', avian, erythroblastosis, virus, 'E26', oncogene, homolog, 1, '(', 'ETS1),', 'endothelin-1', '(', 'ET-1),', and, markers, of, endothelial, dysfunction, '(', 'platelet/endothelial', cell, adhesion, molecule, 1, ',', 'PECAM1', and, 'E', 'selectin,', 'E-SEL)'])].
[sujeto(['HPAEC', treated, with, hemin, had]), verbo([increased]), complemento(['ETS1,', 'miR-27a,', 'ET-1,', and, endothelial, dysfunction, and, decreased, 'PPARγ', levels])].
[sujeto(['In', 'SS', mouse, lung, or, in, 'hemin-treated', 'HPAECs,', activation, of, 'PPARγ', with, 'RSG', attenuated, reductions, in, 'PPARγ', and]), verbo([increases]), complemento([in, 'miR-27a,', 'ET-1,', and, markers, of, endothelial, dysfunction])].
[sujeto(['In', 'SCD-PH', 'pathogenesis,', 'ETS1']), verbo([stimulates]), complemento([increases, in, 'miR-27a', levels, that, reduce, 'PPARγ', and, increase, 'ET-1', and, endothelial, dysfunction])].
[sujeto(['PPARγ', activation, attenuated, 'SCD-associated', signaling, derangements]), verbo([suggesting]), complemento([a, novel, therapeutic, approach, to, attenuate, 'SCD-PH', pathogenesis])].
[sujeto(['In', this, 'study,', we, performed, high, throughput, 'RNA', sequencing, at, the, preadipocyte, '(', 'D0)', and, differentiated, adipocyte, '(', 'D7)', stages, of, primary, brown, preadipocyte, differentiation, in, order, to, characterize, the, transcriptional, events]), verbo([regulating]), complemento([differentiation, and, function])].
[sujeto(['Compared', to, the, preadipocyte, stage, '(', 'D0),', 6, ',', 668, genes, were, identified, as, differentially]), verbo([expressed]), complemento([genes, '(', 'DEGs)', with, a, fold, change, of, '≥', 2.0, at, the, differentiated, adipocyte, stage, '(', 'D7)'])].
[sujeto(['Several', adipogenic, genes, including, peroxisome, 'proliferator-activated', 'receptor-γ', '(', 'PPARγ)', and, 'CCAAT/enhancer-binding', 'protein-α', '(', 'C/EBPα),', and, 'Krüppel-like', factor, '(', 'KLF)', family, genes, were, differentially]), verbo([expressed]), complemento([at, 'D0', and, 'D7'])].
[sujeto(['Since', 'KLF16', gene, expression, was, downregulated, at, day, 7, and, its, adipogenic, function]), verbo([has]), complemento([not, been, 'characterized,', we, investigated, its, role, in, adipogenesis])].
[sujeto(['Knockdown', of, 'KLF16']), verbo([stimulated]), complemento([the, differentiation, of, both, brown, and, 3, 'T3-L1', 'preadipocytes,', and, led, to, increased, 'PPARγ', expression])].
[sujeto(['Furthermore,', 'KLF16', downregulated, 'PPARγ', expression, in, brown, adipocytes, and]), verbo([inhibited]), complemento([its, promoter, activity])].
[sujeto(['These', results, indicate, that, 'KLF16']), verbo([inhibits]), complemento([adipogenesis, through, downregulation, of, 'PPARγ', expression])].
[sujeto(['ZAG']), verbo([has]), complemento([recently, been, characterized, as, a, potent, metabolic, 'regulator,', but, the, effect, of, 'anti-diabetic', agents, on, 'ZAG', in, humans, remains, unknown])].
[sujeto(['After', 3, -, months, of, 'DAPA', 'therapy,', 'HbA1c,', 'FBG,', 2, 'h-PBG,', 'FFA,', 'TG,', blood, 'pressure,', 'BMI,', 'WHR,', body, 'weight,', 'FAT%,', 'FINS,', and, 'HOMA-IR', in, 'T2DM', patients]), verbo([decreased]), complemento(['significantly,', whereas, 'HDL-C', was, significantly, increased])].
[sujeto(['Importantly,', circulating, 'ZAG', and, 'ADI', levels, in, these, patients, were, also, significantly]), verbo([increased]), complemento([after, 'DAPA', therapy])].
[sujeto(['Basal', 'ZAG', levels, were]), verbo([associated]), complemento([with, changes, in, 'BMI,', 'FAT%,', 'TC,', 'HbA1c,', 'HDL-C', and, 'ADI', at, 'post-treatment,', whereas, basal, 'ADI', levels, were, associated, with, changes, in, 'FAT%,', 'TC,', 'HbA1c,', 'FFA', and, 'HDL-c'])].
[sujeto(['In', 'vitro,', 'DAPA', treatment, showed]), verbo([increased]), complemento(['ZAG', expression, and, secretion, in, 'HepG2', cells])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, circulating, 'ZAG', can, be, regulated, by, 'DAPA,', and, 'DAPA', promotes, the, expression, and, secretion, of, 'ZAG', in, the, liver, via, the, activation, of, 'PPAR-γ'])].
[sujeto(['The', changes, in, 'ZAG']), verbo([induced]), complemento([by, 'DAPA', may, play, a, physiologic, role, in, enhancing, insulin, sensitivity])].
[sujeto(['To', discover, new, genes]), verbo([involved]), complemento([in, adipocyte, 'differentiation,', preadipocytes, were, treated, with, three, newly, identified, 'pro-adipogenic', small, molecules, and, 'GW7845', '(', a, 'Pparγ', 'agonist)', for, 24, hours, and, transcriptional, profiling, was, analyzed])].
[sujeto(['Four', 'genes,', 'Peroxisome', 'proliferator-activated', receptor, γ, '(', 'Pparγ),', human, complement, factor, 'D', homolog, '(', 'Cfd),', 'Chemokine', '(', 'C-C', 'motif)', ligand, 9, '(', 'Ccl9),', and, 'GIPC', 'PDZ', 'Domain', 'Containing', 'Family', 'Member', 2, '(', 'Gipc2)', were]), verbo([induced]), complemento([by, at, least, two, different, small, molecules, but, not, by, 'GW7845'])].
[sujeto(['Small', hairpin, 'RNA', '(', 'shRNA)']), verbo([mediated]), complemento([knockdown, of, 'Cfd', in, preadipocytes, inhibited, lipid, accumulation, and, expression, of, adipocyte, markers, during, adipocyte, differentiation])].
[sujeto(['Overexpression', of, 'Cfd']), verbo([promoted]), complemento([adipocyte, 'differentiation,', increased, 'C3a', 'production,', and, led, to, induction, of, 'C3a', receptor, '(', 'C3aR)', target, gene, expression])].
[sujeto(['Similarly,', treatments, with, 'C3a', or, 'C3aR', agonist, '(', 'C4494)', also]), verbo([promoted]), complemento([adipogenesis])].
[sujeto(['C3aR', knockdown]), verbo([suppressed]), complemento([adipogenesis, and, impaired, the, 'pro-adipogenic', effects, of, 'Cfd,', further, suggesting, the, necessity, for, 'C3aR', signaling, in, 'Cfd-mediated', 'pro-adipogenic', axis])].
[sujeto(['Adaptor', protein, 'Lnk', '(', 'Src', homology, 2, 'B3', '[', 'SH2B3]),', which, belongs, to, a, family, of, 'SH2-containing', 'proteins,']), verbo([modulates]), complemento([the, bioactivities, of, different, stem, 'cells,', including, hematopoietic, stem, cells, and, endothelial, progenitor, cells])].
[sujeto(['In', this, 'study,', we, investigated, whether, an, interaction, between, 'insulin-like', growth, 'factor-1', receptor, '(', 'IGF-1R)', and, 'Lnk']), verbo([regulated]), complemento(['IGF-1-induced', adipogenic, differentiation, of, 'MSCs'])].
[sujeto(['We']), verbo([found]), complemento([that, 'wild-type', 'MSCs', showed, greater, adipogenic, differentiation, potential, than, 'Lnk', '(', -, /, -, ')', 'MSCs'])].
[sujeto(['An', ex, vivo, adipogenic, differentiation, assay, showed, that, 'Lnk', '(', -, /, -, ')', 'MSCs', had]), verbo([decreased]), complemento([adipogenic, differentiation, potential, compared, with, 'wild-type', 'MSCs'])].
[sujeto(['Interestingly,', we]), verbo([found]), complemento([that, 'Lnk', formed, a, complex, with, 'IGF-1R', and, that, 'IGF-1', induced, the, dissociation, of, this, complex])].
[sujeto(['In', 'addition,', we, observed, that, 'IGF-1-induced']), verbo([increase]), complemento([in, the, phosphorylation, of, 'Akt', and, mammalian, target, of, rapamycin, was, triggered, by, the, dissociation, of, the, 'IGF-1R-Lnk', complex])].
[sujeto(['Expression', levels, of, a, pivotal, transcription, factor, peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPAR-γ)', and, its, adipogenic]), verbo([target]), complemento([genes, '(', 'LPL', and, 'FABP4)', significantly, decreased, in, 'Lnk', '(', -, /, -, ')', 'MSCs'])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, 'Lnk', adaptor, protein, regulated, the, adipogenesis, of, 'MSCs', through, the, 'IGF-1/Akt/PPAR-γ', pathway])].
[sujeto(['Our', previous, data]), verbo([have]), complemento([shown, that, the, protein, level, of, 'PPARγ', is, increased, in, the, cortex, after, middle, cerebral, artery, occlusion, '(', 'MCAO);', 'PPARγ', 'up-regulation', contributes, to, 'PPARγ', activation, and, is, effective, in, reducing, ischemic, damage, to, brain])].
[sujeto(['Overexpression', of, 'miR-383', by, 'miR-383', agomir]), verbo([increased]), complemento([infarct, volume, and, aggravated, neurological, damage])].
[sujeto(['Furthermore,', we]), verbo([found]), complemento([that, 'PPARγ', protein, was, 'down-regulated', by, 'miR-383', 'overexpression,', and, 'up-regulated', by, 'miR-383', inhibition, both, in, rat, model, of, 'MCAO', and, in, primary, culture, cells])].
[sujeto(['Finally,', we]), verbo([found]), complemento([that, 'miR-383', suppressed, the, luciferase, activity, of, the, vector, carrying, the, 3, '\'', 'UTR', of, 'PPARγ,', whereas, mutation, of, the, binding, sites, relived, the, repressive, effect, of, 'miR-383'])].
[sujeto(['Our', study, demonstrated, that, 'miR-383', may, play, a, key, role, in, focal, cerebral, ischemia, by]), verbo([regulating]), complemento(['PPARγ', expression, at, the, 'post-transcriptional', 'level,', and, 'miR-383', may, be, a, potential, therapeutic, target, for, stroke])].
[sujeto(['In', this, 'study,', we, focused, on, the, role, of, peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPARγ)', as, a, potential, therapeutic]), verbo([target]), complemento([of, 'Cajanus', cajan, and, its, main, compounds, for, the, treatment, of, 'cancer,', inflammation, and, 'inflammation-related', disorders])].
[sujeto([cajan]), verbo([provides]), complemento([excellent, beneficial, medicinal, attributes, and, may, be, used, as, a, potential, food, or, a, pharmaceutical, supplement])].
[sujeto(['Terminal', differentiation, of, multipotent, stem, cells, is, achieved, through, a, coordinated, cascade, of]), verbo([activated]), complemento([transcription, factors, and, epigenetic, modifications, that, drive, gene, transcription, responsible, for, unique, cell, fate])].
[sujeto(['We', therefore, investigated, genomic]), verbo([binding]), complemento([of, transcription, factors, and, accompanying, epigenetic, modifications, that, occur, during, osteogenic, and, adipogenic, differentiation, of, mouse, bone, 'marrow-derived', mesenchymal, stem, cells, '(', 'MSCs)'])].
[sujeto(['As', assessed, by, 'ChIP-sequencing', and, 'RNA-sequencing', 'analyses,', we]), verbo([found]), complemento([that, genes, vital, for, osteogenic, identity, were, linked, to, 'RUNX2,', 'C/EBPβ,', retinoid, 'X', 'receptor,', and, vitamin, 'D', receptor, binding, 'sites,', whereas, adipocyte, differentiation, favored, 'PPARγ,', retinoid, 'X', 'receptor,', 'C/EBPα,', and, 'C/EBPβ', binding, sites])].
[sujeto(['These', 'marrow-derived', 'MSCs', displayed, an, epigenetic, pattern, that]), verbo([suggested]), complemento([a, default, preference, for, the, osteogenic, 'pathway;', 'however,', these, patterns, were, rapidly, altered, near, the, 'Adipoq,', 'Cidec,', 'Fabp4,', 'Lipe,', 'Plin1,', 'Pparg,', and, 'Cebpa', genes, during, adipogenic, differentiation])].
[sujeto(['Surprisingly,', we]), verbo([found]), complemento([that, these, cells, also, exhibited, an, epigenetic, plasticity, that, enabled, them, to, 'trans-differentiate', from, adipocytes, to, osteoblasts, '(', and, vice, 'versa)', after, 'commitment,', as, assessed, by, 'staining,', gene, 'expression,', and, 'ChIP-quantitative', 'PCR', analysis])].
[sujeto(['The', osteogenic, default, pathway, may, be, subverted, during, pathological, 'conditions,']), verbo([leading]), complemento([to, skeletal, fragility, and, increased, marrow, adiposity, during, 'aging,', estrogen, 'deficiency,', and, skeletal, unloading])].
[sujeto(['Taken', 'together,', our, data]), verbo([provide]), complemento([an, increased, mechanistic, understanding, of, the, epigenetic, programs, necessary, for, multipotent, differentiation, of, 'MSCs', that, may, prove, beneficial, in, the, development, of, therapeutic, strategies])].
[sujeto(['Elevated', systemic, 'IL-6', in, 'IR', individuals, was]), verbo([associated]), complemento([with, hyperplasia, of, adipose, 'tissue-derived', 'SVF', 'cells,', despite, higher, frequency, of, hypertrophied, adipocytes])].
[sujeto(['Impaired', adipogenesis, in, 'IR', individuals, was, further]), verbo([associated]), complemento([with, increased, adipose, secretion, of, 'IL-6'])].
[sujeto(['Understanding', the, molecular, mechanisms, underlying, reduced, adipogenic, capacity, in, 'IR', individuals, could, help]), verbo([target]), complemento([appropriate, therapeutic, strategies, aimed, at, those, at, greatest, risk, of, insulin, resistance, and, type, 2, diabetes, mellitus])].
[sujeto(['Although', substantial, studies, on, peroxisome, 'proliferator-activated', receptor, g, '(', 'PPARg)']), verbo([have]), complemento([focused, on, the, mechanisms, by, which, 'PPARg', regulates, glucose, and, lipid, 'metabolism,', recent, reports, have, suggested, that, 'PPARg', shows, tumorigenic, or, antitumorigenic, effects])].
[sujeto(['The', results, showed, that, 'RGZ']), verbo([suppressed]), complemento([proliferation, and, induced, apoptosis, of, esophageal, cancer, 'cells,', which, could, be, partly, restored, by, inactivation, of, 'PPARg'])].
[sujeto(['RGZ']), verbo([suppressed]), complemento([the, 'MAPK', and, 'TLR4', 'pathways,', and, the, inhibitory, effect, could, be, counteracted, by, 'PPARg', antagonist, or, specific, 'RNA', interference])].
[sujeto(['We', also]), verbo([suggested]), complemento([that, 'MAPK', activation, was, regulated, by, the, 'TLR4', pathway, and, that, blocking, the, 'TLR4', and, 'MAPK', pathways, significantly, suppressed, proliferation, and, induced, apoptosis, of, esophageal, cancer, cells])].
[sujeto(['In', 'conclusion,', our, data]), verbo([suggested]), complemento([that, activation, of, 'PPARg', suppressed, proliferation, and, induced, apoptosis, of, esophageal, cancer, cells, by, inhibiting, 'TLR4-dependent', 'MAPK', pathway])].
[sujeto(['PPARγ']), verbo([modulates]), complemento([energy, metabolism, and, inflammation])].
[sujeto(['However,', its, specific, functions, in, the, balance, of, immunity, in, vivo]), verbo([have]), complemento([been, explored, incompletely])].
[sujeto(['These', symptoms, were, preceded, by, splenomegaly, at, an, early, 'age,', which, was]), verbo([associated]), complemento([with, increases, in, splenocyte, accumulation, and, 'B-cell', activation, but, not, with, relocation, of, hematopoiesis, to, the, spleen])].
[sujeto(['The', mechanism, of, splenic, lymphocyte, accumulation]), verbo([involved]), complemento([reduced, 'sphingosine-1-phosphate', receptor, 1, '(', 'S1P1)', expression, and, diminished, migration, toward, 'S1P', in, the, 'Pparg(C/-)', 'splenocytes,', which, impeded, lymphocyte, egression])].
[sujeto(['Mechanistically,']), verbo([increased]), complemento(['Th17', polarization, and, 'IL-17', signaling, in, the, 'Pparg(C/-)', 'CD4(+)', 'T', cells, contributed, to, 'B-cell', hyperactivation, in, the, spleen])].
[sujeto(['Finally,', the, activation, of, the, remaining, 'PPARγ', in, 'Pparg(C/-)', mice, by, pioglitazone]), verbo([increased]), complemento(['S1P1', 'levels,', reduced, the, 'Th17', population, in, the, 'spleen,', and, ameliorated, splenomegaly])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, γ, '(', 'PPARγ)']), verbo([has]), complemento([been, shown, to, attenuate, 'AAA', through, inhibition, of, inflammation, and, proteolytic, degradation])].
[sujeto(['PPARγ', was, highly]), verbo([expressed]), complemento([in, human, 'AAA', within, all, vascular, 'cells,', including, inflammatory, cells, and, fibroblasts])].
[sujeto(['In', the, aortas, of, transgenic, mice]), verbo([expressing]), complemento(['PPARγ', at, 25, '%', normal, levels, '(', 'Pparg(C)', '(', /, -, ')', 'mice),', we, observed, the, fragmentation, of, elastic, fibers, and, reduced, expression, of, vital, elastic, fiber, components, of, elastin, and, 'fibulin-5'])].
[sujeto(['Infusion', of, a, moderate, dose, of, angiotensin, 'II', '(', 500, 'ng/kg', per, 'minute)', did, not]), verbo([induce]), complemento(['AAA', but, 'Pparg(+/-)', aorta, developed, flattened, elastic, 'lamellae,', whereas, 'Pparg(C/-)', aorta, showed, severe, destruction, of, elastic, fibers])].
[sujeto(['Chromatin', immunoprecipitation, assay, demonstrated, 'PPARγ']), verbo([binding]), complemento([in, the, genomic, sequence, of, 'fibulin-5', in, fibroblasts])].
[sujeto(['This', polymorphism, is, known, to, be]), verbo([associated]), complemento([with, increased, insulin, sensitivity])].
[sujeto(['Pioglitazone,', a, 'thiazolidinedione,', is, an, 'anti-diabetic', drug, which]), verbo([acts]), complemento([as, an, agonist, at, 'PPAR', γ, receptor])].
[sujeto(['Our', study]), verbo([suggests]), complemento([that, there, is, a, potential, association, between, 'Pro12Ala', polymorphism, and, glycaemic, response, to, pioglitazone])].
[sujeto(['The', transcription, repressor, 'BTB', and, 'CNC', homology, 1, '(', 'BACH1)']), verbo([represses]), complemento([genes, involved, in, heme, metabolism, and, oxidative, stress, response])].
[sujeto(['BACH1', also]), verbo([suppresses]), complemento([the, 'p53-dependent', cellar, senescence, in, primary, mouse, embryonic, fibroblasts, '(', 'MEFs)'])].
[sujeto(['To', investigate, the, role, of, 'BACH1', in, 'MEF', other, than, its, known, 'functions,', we, carried, out, a, genomewide, mapping, of]), verbo([binding]), complemento([site, for, 'BACH1', and, its, heterodimer, partner, 'MAFK', in, immortalized, 'MEFs', '(', 'iMEFs)', using, chromatin, immunoprecipitation, and, 'next-generation', sequencing, technology, '(', 'ChIP-sequence)'])].
[sujeto(['The', comparative, analysis, of, the, 'ChIP-sequence', data, and, 'DNA', microarray, data, from, 'Bach1-deficient', and, 'wild-type', '(', 'WT)', iMEF, showed, 35, novel, candidate]), verbo([target]), complemento([genes, of, 'BACH1'])].
[sujeto(['Bach1-deficient', iMEFs, showed]), verbo([increased]), complemento([expression, of, mRNA, and, protein, of, 'PPARγ,', which, is, the, key, factor, of, adipogenesis])].
[sujeto(['These', cells, also, showed, a, concomitant]), verbo([increase]), complemento([in, 'ligand-dependent', activation, of, 'PPARγ', target, genes, compared, with, 'wild-type', iMEFs])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'BACH1', regulates, expression, of, 'adipocyte-related', genes, including, 'Pparg', and, potentiates, adipocyte, differentiation, capacity])].
[sujeto(['Human', exposure, to, bisphenol, 'A']), verbo([has]), complemento([been, associated, with, negative, health, outcomes, in, humans, and, its, use, is, now, regulated, in, a, number, of, countries])].
[sujeto(['Bisphenol', 'S', '(', 'BPS)', is, increasingly, used, as, a, replacement, for, bisphenol, 'A;', 'however,', its, effects, on, cellular, metabolism, and, potential, role, as, an, endocrine, disruptor]), verbo([have]), complemento([not, been, fully, characterized])].
[sujeto(['Treatment', of, preadipocytes, with, 25, μM, 'BPS']), verbo([induced]), complemento([lipid, accumulation, and, increased, the, mRNA, and, protein, levels, of, several, adipogenic, markers, including, lipoprotein, lipase, and, adipocyte, protein, 2, '(', 'aP2)'])].
[sujeto(['Cotreatment', of, cells, with, the, estrogen, receptor, antagonist, 'ICI-182,780', significantly]), verbo([inhibited]), complemento(['BPS-induced', lipid, accumulation, and, affected, aP2, but, not, lipoprotein, lipase, protein, levels])].
[sujeto(['Furthermore,', reporter, gene, assays, using, a, synthetic, promoter, containing, peroxisome, 'proliferator-activated', 'receptor-γ', '(', 'PPARG)-response', elements, and, a, 'PPARG-responsive', human, aP2, promoter, region, showed, that, 'BPS', was, able, to]), verbo([activate]), complemento(['PPARG'])].
[sujeto(['To', our, 'knowledge,', this, study, is, the, first, to, show, that, 'BPS']), verbo([induces]), complemento([lipid, accumulation, and, differentiation, of, primary, human, 'preadipocytes,', and, this, effect, may, be, mediated, through, a, 'PPARG', pathway])].
[sujeto(['Logistic', regression, analysis, showed, an, association, between, genotypes, of, variants, in, rs1805192, and]), verbo([decreased]), complemento(['EH', 'risk,', 'EH', risk, was, significantly, lower, in, carriers, of, 'Ala', allele, of, the, rs1805192, polymorphism, than, those, with, 'Pro/Pro', '(', 'Pro/Ala+', 'Ala/Ala', versus, 'Pro/Pro,', adjusted, 'OR', '(', 95, '%', 'CI)', =, 0.65, '(', 0.53, -, 0.83, ')', ',', after, covariate, adjustment])].
[sujeto(['In', 'addition,', the, 'Ala', allele, of, the, rs1805192, polymorphism, was, also]), verbo([associated]), complemento([with, diastolic, blood, pressure, '(', 'DBP),', but, not, systolic, blood, pressure, '(', 'SBP),', we, also, 'found,', by, interaction, 'analysis,', combined, effect, of, rs1805192, and, 'HDL', on, 'EH', risk, after, covariate, adjustment])].
[sujeto(['Although', the, peroxisome, 'proliferator-activated', receptor, γ, '(', 'PPARγ)', pathway, is, central, in, 'adipogenesis,', it, remains, unknown, whether, it, influences, change, in, body, weight, '(', 'BW)', and, whether, dietary, fat]), verbo([has]), complemento([a, modifying, effect, on, the, association])].
[sujeto(['We', examined, whether, 27, single, nucleotide, polymorphisms, '(', 'SNPs)', within, 4, genes, in, the, 'PPARγ', pathway, are]), verbo([associated]), complemento([with, the, 'OR', of, being, a, 'BW', gainer, or, with, annual, changes, in, anthropometry, and, whether, intake, of, total, 'fat,', monounsaturated, 'fat,', polyunsaturated, 'fat,', or, saturated, fat, has, a, modifying, effect, on, these, associations])].
[sujeto(['A', 'case-noncase', study, included, 11, ',', 48, men, and, women, from, cohorts, in, the, 'European', 'Diet,', 'Obesity', and, 'Genes', 'study;', 5552, were, 'cases,', defined, as, individuals, with, the, greatest, 'BW']), verbo([gain]), complemento([during, 'follow-up,', and, 6548, were, randomly, 'selected,', including, 5496, noncases])].
[sujeto(['We', selected, 4, genes, '[', 'CCAAT/enhancer']), verbo([binding]), complemento([protein, β, '(', 'CEBPB),', phosphoenolpyruvate, carboxykinase, 2, ',', 'PPARγ', gene, '(', 'PPARG),', and, sterol, regulatory, element, binding, transcription, factor, 1, ']', according, to, evidence, about, biologic, plausibility, for, interactions, with, dietary, fat, in, weight, regulation])].
[sujeto(['The', 'OR', for, being, a, 'BW', gainer, for, each, additional, rs4253449, minor, allele, per, 100, kcal, higher, total, fat, intake, was, 1.07, '(', 95, '%', 'CI:', 1.02, ',', 1.12, ;, 'P', =, 0.008, ')', ',', and, similar, associations, were]), verbo([found]), complemento([for, subgroups, of, fat])].
[sujeto(['Tie2-promoter-mediated']), verbo([loss]), complemento([of, peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPARγ,', also, known, as, 'PPARG)', in, mice, leads, to, osteopetrosis, and, pulmonary, arterial, hypertension])].
[sujeto(['Vascular', disease, is]), verbo([associated]), complemento([with, loss, of, 'PPARγ', in, pulmonary, microvascular, endothelial, cells, '(', 'PMVEC);', we, evaluated, the, role, of, 'PPARγ', in, 'PMVEC', 'functions,', such, as, angiogenesis, and, migration])].
[sujeto(['RNA', sequencing, and, bioinformatic, approaches, were, utilized, to]), verbo([reveal]), complemento(['angiogenesis-associated', targets, for, 'PPARγ'])].
[sujeto(['Analysis', of, endothelial, 'progenitor-like', cells, using, bone, marrow, transplantation, combined, with, evaluation, of, isolated, 'PMVECs', revealed, that]), verbo([loss]), complemento([of, 'PPARγ', attenuates, the, migration, and, angiogenic, capacity, of, mature, 'PMVECs'])].
[sujeto(['Bioinformatic', and, experimental, analyses, newly, revealed, 'E2F1', as, a]), verbo([target]), complemento([of, 'PPARγ', in, the, regulation, of, 'PMVEC', migration])].
[sujeto(['Disruption', of, the, 'PPARγ-E2F1', axis, was]), verbo([associated]), complemento([with, a, dysregulated, 'Wnt', pathway, related, to, the, 'GSK3B', interacting, protein, '(', 'GSKIP)'])].
[sujeto(['We', further, outline, how, to, fractionate, the, cell, lysate, into, cytosolic, and]), verbo([nuclear]), complemento([fractions, to, enhance, the, sensitivity, of, the, measurements, and, to, investigate, the, dynamic, concentration, changes, in, those, compartments])].
[sujeto(['Impairment', of, myocardial, fatty, acid, substrate, metabolism, is, characteristic, of, 'late-stage', heart, failure, and]), verbo([has]), complemento([limited, treatment, options])].
[sujeto(['The']), verbo([increased]), complemento([fatty, acid, utilization, of, 'FASN', transgenic, neonatal, cardiomyocytes, rapidly, switched, to, a, heart, failure, phenotype, in, an, 'adult-like', lipogenic, milieu])].
[sujeto(['Cardioprotective', 'GRK2', inhibition]), verbo([required]), complemento([an, intact, 'ERK', 'axis,', which, blunted, the, induction, of, cardiotoxic, 'transcripts,', in, part, by, enhanced, serine, 273, phosphorylation, of, 'Pparg', '(', peroxisome, 'proliferator-activated', receptor, 'γ)'])].
[sujeto(['Conversely,', the, 'dual-specific', 'GRK2', and, 'ERK', cascade, 'inhibitor,', 'RKIP', '(', 'Raf', kinase, inhibitor, 'protein),']), verbo([triggered]), complemento([dysfunctional, cardiomyocyte, energetics, and, the, expression, of, heart, 'failure-promoting', 'Pparg-regulated', genes])].
[sujeto(['Thus,', 'GRK2', inhibition, is, a, novel, approach, that]), verbo([targets]), complemento([the, dysfunctional, substrate, metabolism, of, the, failing, heart])].
[sujeto(['We', show, that, a, major, phenotype, of, white, adipose, tissue, in, 'non-obese', individuals, with, type, 2, diabetes, is, adipocyte, 'hypertrophy,', which, may, be]), verbo([mediated]), complemento([by, an, impaired, adipogenic, capacity, in, progenitor, cells])].
[sujeto(['Consequently,', this, could]), verbo([have]), complemento([an, impact, on, adipose, tissue, 'inflammation,', release, of, fatty, 'acids,', ectopic, fat, deposition, and, insulin, sensitivity])].
[sujeto(['Recent', studies, demonstrating, a, higher, incidence, of, metabolic, disorders, after, calving]), verbo([have]), complemento([challenged, the, management, practice, of, increasing, dietary, energy, density, during, the, last, '~3', wk, prepartum])].
[sujeto(['Our', hypothesis, was, that, prepartum, body, condition, score, '(', 'BCS),', in, combination, with, feeding, 'management,', plays, a, central, role, in, the, peripartum, changes]), verbo([associated]), complemento([with, energy, balance, and, inflammatory, state])].
[sujeto(['Quantitative', polymerase, chain, reaction, was, used, to, measure, mRNA, and, microRNA, '(', 'miRNA)', expression, of]), verbo([targets]), complemento([related, to, fatty, acid, metabolism, '(', 'lipogenesis,', 'lipolysis),', adipokine, 'synthesis,', and, inflammation])].
[sujeto(['Overfed', 'BCS5', cows, had, the, greatest, prepartum, expression, of, fatty, acid, synthase, '(', 'FASN)', and, an, overall, greater, expression, of, leptin, '(', 'LEP);', 'BCS5', was, also]), verbo([associated]), complemento([with, greater, overall, adiponectin, '(', 'ADIPOQ)', and, peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPARG),', whereas, overfeeding, upregulated, expression, of, proadipogenic, miRNA])].
[sujeto(['The', dynamic, process, of, adipose, differentiation]), verbo([involves]), complemento([stepwise, expressions, of, transcription, factors, and, proteins, specific, to, the, mature, fat, cell, phenotype])].
[sujeto(['In', this, 'study,', it, was, revealed, that, expression, levels, of, 'IntS6', and, 'IntS11,', subunits, of, the, 'Integrator', 'complex,', were]), verbo([increased]), complemento([in, 3, 'T3-L1', cells, in, the, period, when, the, cells, reached, confluence, and, differentiated, into, 'adipocytes,', while, being, reduced, to, basal, levels, after, the, completion, of, differentiation])].
[sujeto(['Suppression', of, 'IntS6', or, 'IntS11', expression, using, siRNAs, in, 3, 'T3-L1', preadipocytes, markedly]), verbo([inhibited]), complemento([differentiation, into, mature, 'adipocytes,', based, on, morphological, findings, as, well, as, mRNA, analysis, of, 'adipocyte-specific', genes, such, as, 'Glut4,', perilipin, and, 'Fabp4'])].
[sujeto(['Although', 'Pparγ2', protein, expression, was]), verbo([suppressed]), complemento([in, 'IntS6', or, 'IntS11-siRNA', treated, 'cells,', adenoviral, forced, expression, of, 'Pparγ2', failed, to, restore, the, capacity, for, differentiation, into, mature, adipocytes])].
[sujeto(['Taken', 'together,', these, findings, demonstrate, that]), verbo([increased]), complemento([expression, of, 'Integrator', complex, subunits, is, an, indispensable, event, in, adipose, differentiation])].
[sujeto(['Although', further, study, is, necessary, to, elucidate, the, underlying, 'mechanism,', the, processing, of, 'U1,', 'U2', small]), verbo([nuclear]), complemento(['RNAs', may, be, involved, in, cell, differentiation, steps])].
[sujeto(['Gene', expression, in, the, liver, of, these, women]), verbo([has]), complemento([not, been, reported])].
[sujeto(['We', hypothesized, that, endometriosis, may, impact, hepatic, gene, expression, to]), verbo([promote]), complemento([a, low, 'BMI'])].
[sujeto(['To', determine, the, effect, of, endometriosis, on, liver, gene, 'expression,', we]), verbo([induced]), complemento([endometriosis, in, female, mice, by, suturing, donor, mouse, endometrium, into, the, peritoneal, cavity, and, measuring, the, weights, of, these, mice])].
[sujeto(['Microarray', analysis, identified, 26, genes, differentially]), verbo([regulated]), complemento([in, the, livers, of, mice, with, endometriosis])].
[sujeto(['Six', out, of, 26, genes, were]), verbo([involved]), complemento([in, metabolism])].
[sujeto(['Expression', of, 'Cyp2r1,', 'Fabp4,', 'Mrc1,', and, 'Rock2', was]), verbo([increased]), complemento([while, 'Igfbp1', and, 'Mmd2', expression, was, decreased])].
[sujeto(['Here', we, demonstrate, that, endometriosis]), verbo([causes]), complemento([reduced, body, weight, and, body, 'fat,', and, disrupts, liver, gene, expression])].
[sujeto(['We']), verbo([suggest]), complemento([that, altered, metabolism, mediated, by, the, liver, contributes, to, the, clinically, observed, low, 'BMI', that, is, characteristic, of, women, with, endometriosis])].
[sujeto(['These', findings]), verbo([reveal]), complemento([the, systemic, and, 'multi-organ', nature, of, endometriosis])].
[sujeto(['Low', birthweight, '(', 'LBW)', is]), verbo([associated]), complemento([with, dysfunctions, of, adipose, tissue, and, metabolic, disease, in, adult, life])].
[sujeto(['Indeed,', silencing, of, 'CCNT2', in, human, adipocytes]), verbo([decreased]), complemento([leptin, secretion, as, well, as, the, mRNA, expression, of, several, genes, involved, in, 'adipogenesis,', including, 'MGLL,', 'LIPE,', 'PPARG,', 'LEP', and, 'ADIPOQ'])].
[sujeto(['The', objective, was, to, elucidate, gene, expression, differences, in, 'uterus,', 'caruncle,', and, cotyledon, of, ewes, with, subclinical, pregnancy, toxemia, '(', 'SCPT)', and, healthy, 'ewes,', and, to, identify]), verbo([associated]), complemento([biological, functions, and, pathways, involved, in, pregnancy, toxemia])].
[sujeto(['The', mRNA, expressions, were, determined, by, quantitative, 'PCR', 'method,', and, prediction, of, miRNA, partners, and]), verbo([target]), complemento([genes, for, the, predicted, miRNA, were, identified, using, miRDB, '(', 'http://mirdb'])].
[sujeto(['Top', ranked]), verbo([target]), complemento([genes, were, used, to, identify, associated, biological, functions, and, pathways, in, response, to, 'SPCT', using, 'PANTHER'])].
[sujeto(['The', predicted, miRNA, and]), verbo([associated]), complemento([target, genes, contributed, to, several, biological, 'processes,', including, 'apoptosis,', biological, 'adhesion,', biological, 'regulation,', cellular, component, 'biogenesis,', cellular, 'process,', developmental, 'process,', immune, system, 'process,', 'localization,', metabolic, 'process,', multicellular, organismal, 'process,', 'reproduction,', and, response, to, stimulus])].
[sujeto(['The']), verbo([target]), complemento([genes, were, involved, in, several, pathways, including, 'angiogenesis,', cytoskeletal, 'regulation,', hypoxia, response, via, 'HIF', 'activation,', interleukin, 'signaling,', ubiquitin, 'proteasome,', and, 'VEGF', signaling, pathway])].
[sujeto(['In', 'conclusion,', genes]), verbo([associated]), complemento([with, blood, vessel, remodeling, were, lower, in, abundances, and, that, the, genes, associated, with, hypoxic, conditions, were, greater, in, abundances, in, the, uteroplacental, compartment, of, 'SCPT', ewes])].
[sujeto(['It', is, obvious, that, the, factors, that, influence, placental, vascular, development, and, angiogenesis, as, noted, in, this, study, set, the, course, for, hemodynamic, changes, and, hence]), verbo([have]), complemento([a, major, impact, on, the, rate, of, transplacental, nutrient, 'exchange,', fetal, 'growth,', and, health, of, the, dam])].
[sujeto(['Substantial', improvement, in, the, understanding, of, the, oncogenic, pathways, in, thyroid, cancer]), verbo([has]), complemento([led, to, identification, of, specific, molecular, 'alterations,', including, mutations, of, 'BRAF', and, 'RET', in, papillary, thyroid, 'cancer,', mutation, of, 'RAS', and, rearrangement, of, 'PPARG', in, follicular, thyroid, 'cancer,', mutation, of, 'RET', in, medullary, thyroid, 'cancer,', and, mutations, of, 'TP53', and, in, the, phosphatidylinositol, 3, '\'', -, kinase, '(', 'PI3K)/AKT1', pathway, in, anaplastic, thyroid, cancer])].
[sujeto(['Certain', 'mutations,', such, as, mutations, of, 'BRAF', in, papillary, thyroid, carcinoma, and, mutations, in, 'RET', codons, 883, ',', 918, ',', and, 928, ',', are]), verbo([associated]), complemento([with, an, aggressive, course, in, medullary, thyroid, 'carcinoma,', and, affected, patients, need, close, surveillance])].
[sujeto(['Currently,', 'Food', and, 'Drug', 'Administration-approved', molecularly]), verbo([targeted]), complemento([therapies, for, metastatic, 'RAI-refractory', thyroid, 'cancer,', including, 'sorafenib,', 'lenvatinib,', 'vandetanib,', and, 'cabozantinib,', target, the, vascular, endothelial, growth, factor, receptor, and, 'RET', kinases])].
[sujeto(['A', wide, spectrum, of, toxic, effects, is]), verbo([associated]), complemento([with, the, molecularly, targeted, therapies, used, in, thyroid, cancer, and, can, be, detected, at, restaging, scans])].
[sujeto(['Frequent', and]), verbo([regular]), complemento([physical, activity, has, significant, benefits, for, 'health,', including, improvement, of, body, composition, and, help, in, weight, control])].
[sujeto(['Consequently,']), verbo([promoting]), complemento([training, 'programmes,', particularly, in, those, who, are, genetically, 'predisposed,', is, a, significant, step, towards, controlling, the, presently, increasing, epidemic, of, obesity])].
[sujeto(['We', describe, the, most, reliable, candidate, genetic, markers, that, are]), verbo([involved]), complemento([in, energy, balance, pathways, and, body, composition, changes, in, response, to, training, 'programmes,', such, as, 'FTO,', 'MC4R,', 'ACE,', 'PPARG,', 'LEP,', 'LEPR,', 'ADRB2,', and, 'ADRB3'])].
[sujeto(['This', knowledge, can]), verbo([have]), complemento([an, enormous, impact, not, only, on, individualization, of, exercise, programmes, to, make, them, more, efficient, and, 'safer,', but, also, on, improved, 'recovery,', 'traumatology,', medical, 'care,', 'diet,', supplementation, and, many, other, areas])].
[sujeto(['Long', 'non-coding', 'RNAs', '(', 'lncRNAs)', play, an, important, role, in, gene, regulation, and, are]), verbo([involving]), complemento([in, diverse, cellular, processes])].
[sujeto(['We', showed, that, 'HoxA-AS3', is]), verbo([increased]), complemento([upon, adipogenic, induction, of, 'MSCs,', while, 'HoxA-AS3', remains, unaltered, during, osteogenic, induction])].
[sujeto(['Silencing', of, 'HoxA-AS3', in, 'MSCs', resulted, in]), verbo([decreased]), complemento([adipogenesis, and, expression, of, adipogenic, 'markers,', 'PPARG,', 'CEBPA,', 'FABP4', and, 'ADIPOQ'])].
[sujeto(['Conversely,', knockdown, of, 'HoxA-AS3', expression, in, 'MSCs', exhibited, an]), verbo([enhanced]), complemento([osteogenesis, and, osteogenic, markers, 'expression,', including, 'RUNX2,', 'SP7,', 'COL1A1,', 'IBSP,', 'BGLAP', and, 'SPP1'])].
[sujeto(['Mechanistically,', 'HoxA-AS3']), verbo([interacts]), complemento([with, 'Enhancer', 'Of', 'Zeste', 2, '(', 'EZH2)', and, is, required, for, 'H3', 'lysine-27', trimethylation, '(', 'H3K27me3)', of, key, osteogenic, transcription, factor, 'Runx2'])].
[sujeto(['Our', data]), verbo([reveal]), complemento([that, 'HoxA-AS3', acts, as, an, epigenetic, switch, that, determines, the, lineage, specification, of, 'MSC'])].
[sujeto(['Patients', suffering, from, osteoporosis, show, an]), verbo([increased]), complemento([number, of, adipocytes, in, their, bone, 'marrow,', concomitant, with, a, reduction, in, the, pool, of, human, mesenchymal, stem, cells, '(', 'hMSCs)', that, are, able, to, differentiate, into, 'osteoblasts,', thus, leading, to, suppressed, osteogenesis])].
[sujeto(['In', order, to, be, able, to, interfere, with, this, 'process,', we]), verbo([have]), complemento([investigated, 'in-vitro', culture, conditions, whereby, adipogenic, differentiation, of, hMSCs, is, impaired, and, osteogenic, differentiation, is, promoted])].
[sujeto(['By', means, of, gene, expression, microarray, 'analysis,', we]), verbo([have]), complemento([investigated, genes, which, are, potential, targets, for, prevention, of, fat, cell, differentiation])].
[sujeto(['Our', data, show, that, 'BMP2']), verbo([promotes]), complemento([both, adipogenic, and, osteogenic, differentiation, of, 'hMSCs,', while, transforming, growth, factor, beta, '(', 'TGFβ)', inhibits, differentiation, into, both, lineages])].
[sujeto(['However,', when, cells, are, cultured, under, adipogenic, differentiation, 'conditions,', which, contain, 'cAMP-enhancing', agents, such, as, 'IBMX', of, 'PGE2,', 'TGFβ']), verbo([promotes]), complemento([osteogenic, 'differentiation,', while, at, the, same, time, inhibiting, adipogenic, differentiation])].
[sujeto(['By', means, of, gene, expression, microarray, 'analysis,', we]), verbo([have]), complemento([investigated, genes, which, are, downregulated, by, 'TGFβ', under, adipogenic, differentiation, conditions, and, may, therefore, be, potential, targets, for, prevention, of, fat, cell, differentiation])].
[sujeto(['Our', results, show, that, drugs, directed, against, the]), verbo([nuclear]), complemento([hormone, receptor, 'PPARG,', the, metalloproteinase, 'ADAMTS5,', and, the, 'aldo-keto', reductase, 'AKR1B10', inhibit, adipogenic, differentiation, in, a, 'dose-dependent', 'manner,', although, in, contrast, to, 'TGFβ', they, do, not, appear, to, promote, osteogenic, differentiation])].
[sujeto(['The', approach, chosen, in, this, study]), verbo([has]), complemento([resulted, in, the, identification, of, new, targets, for, inhibition, of, fat, cell, 'differentiation,', which, may, not, only, be, relevant, for, prevention, of, 'osteoporosis,', but, also, of, obesity])].
[sujeto(['Concomitant', obesity, and, diabetes]), verbo([increase]), complemento([the, risk, of, 'HBV-related', hepatocellular, carcinoma, '(', 'HCC)', development])].
[sujeto(['Among', 270, 'HBV-infected', 'patients,', concurrent, fatty, liver, was]), verbo([found]), complemento([in, 107, patients, '(', 39.6, '%', ')', and, was, associated, with, metabolic, 'risks,', cirrhosis, '(', 'P', =, 0.016, ')', and, 'PNPLA3', rs738409, 'CG/GG', genotype, '(', 'P', =, 0.002, ')'])].
[sujeto(['APOC3', gene, polymorphism, also]), verbo([increases]), complemento([risk, of, 'HBV-related', 'HCC', and, its, role, requires, further, characterization])].
[sujeto(['Use', of, 'ART', containing, 'HIV', 'PIs']), verbo([has]), complemento([previously, been, associated, with, toxicity, in, subcutaneous, adipose, tissue, '(', 'SAT),', potentially, contributing, to, the, development, of, lipodystrophy, and, insulin, resistance])].
[sujeto(['Over', 24, 'weeks,', limb, fat]), verbo([increased]), complemento(['(', +, 416.4, 'g,', 'P', =, 0.023, ')', ',', coinciding, with, larger, adipocytes, as, indicated, by, decreased, adipocyte, density, in, biopsies, '(', -, 32.3, 'cells/mm(2),', 'P', =, 0.047, ')', and, increased, mRNA, expression, of, adipogenesis, regulator, 'PPARG', at, week, 2, '(', +, 58.1, '%', ',', 'P', =, 0.003, ')'])].
[sujeto(['Increases', in, mtDNA, over, 24, weeks, '(', +, 600, 'copies/cell,', 'P', =, 0.041, ')', ',']), verbo([decreased]), complemento(['NRF1', mRNA, expression, at, week, 2, '(', -, 33.7, '%', ',', 'P', &, 'lt;', 0.001, ')', and, increased, 'COX2/COX4', protein, ratio, at, week, 24, '(', +, 288, '%', ',', 'P', =, 0.038, ')', indicated, improved, mitochondrial, function])].
[sujeto(['Despite']), verbo([decreased]), complemento(['AKT2', mRNA, at, week, 2, '(', -, 28.6, '%', ',', 'P', =, 0.002, ')', and, increased, 'PTPN1', mRNA, at, week, 24, '(', +, 50.3, '%', ',', 'P', =, 0.016, ')', suggesting, insulin, 'resistance,', clinical, insulin, sensitivity, '[', by, homeostasis, model, assessment, '(', 'HOMA-IR)]', was, unchanged])].
[sujeto(['Here', we]), verbo([report]), complemento([the, first, 'RNA', sequencing, study, of, these, 'tumors,', with, data, for, 30, minimally, invasive, 'FTCs', '(', 'miFTCs)', and, 25, 'FAs'])].
[sujeto(['The', novel, molecular, 'subtype,', 'NBNR,', was]), verbo([associated]), complemento([with, 'DICER1,', 'EIF1AX,', 'IDH1,', 'PTEN,', 'SOS1,', 'SPOP,', and, 'PAX8-PPARG'])].
[sujeto(['The', transcriptome, of, miFTC, or, encapsulated, 'FVPTC', was, indistinguishable, from, that, of, 'FA,']), verbo([providing]), complemento([a, molecular, explanation, for, the, similarly, indolent, behavior, of, these, tumors])].
[sujeto(['These', results, expanded, the, current, molecular, understanding, of, thyroid, cancer, and, may]), verbo([lead]), complemento([to, new, diagnostic, and, therapeutic, approaches, to, the, disease])].
[sujeto(['Several', studies, in, dairy, cows]), verbo([have]), complemento([shown, a, relationship, between, milk, fat, depression, '(', 'MFD)', and, alterations, caused, in, lipogenic, gene, expression, by, dietary, nutrients])].
[sujeto(['Therefore,', this, experiment, was, conducted, in, dairy, ewes, to, study, the, effect, of, a, diet, known, to]), verbo([induce]), complemento(['MFD', on, milk, fatty, acid, '(', 'FA)', composition, and, mRNA, abundance, of, key, candidate, genes, involved, in, mammary, lipogenesis])].
[sujeto(['Twelve', lactating, 'Assaf', ewes, '(', on, average, 63, d, in, 'milk)', were, randomly, assigned, to, 2, treatments, consisting, of, a, total, mixed, ration, based, on, alfalfa]), verbo([hay]), complemento([and, concentrates, '(', 50, :, 50, ')', ',', supplemented, with, 0, '(', 'control)', or, 17, g, of, fish, 'oil/kg', of, diet, 'DM', '(', 'FO)'])].
[sujeto(['As', 'expected,', 'FO']), verbo([induced]), complemento(['MFD', and, modified, milk, 'FA', composition])].
[sujeto(['However,']), verbo([increases]), complemento([in, confirmed, or, putative, antilipogenic, 'FA', '(', 'trans-10,cis-12', and, 'trans-9,cis-11', 18, :, 2, ',', 'cis-9', 16, :, 1, ',', 'cis-11', 18, :, 1, ',', and, 'oxo-FA)', were, already, established, on, the, early, stage, of, the, treatment, and, lasted, until, the, end, of, the, feeding, period])].
[sujeto(['These', changes, were, accompanied, by]), verbo([decreases]), complemento([in, the, mRNA, abundance, of, genes, encoding, lipogenic, enzymes])].
[sujeto(['In', this, 'regard,', without, ruling, out, the, potential, contribution, of, 'PPARG,', our, results]), verbo([suggest]), complemento([that, 'SREBF1', would, have, a, relevant, role, in, the, 'MFD', syndrome, in, sheep, fed, 'FO'])].
[sujeto(['Among', the, other, studied, transcription, 'factors,', the, tendency, to, a, downregulation, of, 'INSIG1', was]), verbo([associated]), complemento([with, that, of, 'SREBF1,', whereas, no, variation, was, detected, for, 'SCAP', or, 'THRSP'])].
[sujeto(['Overall,', changes, in, potential, antilipogenic, 'FA', and, mRNA, abundance, of, candidate, lipogenic, genes, support, a, relationship, between, them, and]), verbo([suggest]), complemento([that, 'FO-induced', 'MFD', in, dairy, ewes, would, be, mediated, by, transcriptional, mechanisms])].
[sujeto(['Oxidative', stress]), verbo([mediates]), complemento([the, pathogenesis, of, neurodegenerative, disorders])].
[sujeto(['Glutamate', resulted, in, cell, death, in, a, 'dose-dependent', manner, and, supplementation, of, 1, -, 10, &, 'nbsp;µM', gartanin]), verbo([prevented]), complemento([the, detrimental, effects, of, glutamate, on, cell, survival])].
[sujeto(['Additional', investigations, on, the, underlying, mechanisms]), verbo([suggested]), complemento([that, gartanin, could, effectively, reduce, 'glutamate-induced', intracellular, 'ROS', generation, and, mitochondrial, depolarization])].
[sujeto(['We', further]), verbo([found]), complemento([that, gartanin, induced, 'HO-1', expression, independent, of, nuclear, factor, 'erythroid-derived', 2, -, like, 2, '(', 'Nrf2)'])].
[sujeto(['Finally,', the, protein, expression, of, phosphorylation, of, 'AMP-activated', protein, kinase, '(', 'AMPK)', and, its, downstream, signal, 'molecules,', 'Sirtuin', activator, '(', 'SIRT1)', and, peroxisome, 'proliferator-activated', 'receptor-γ', 'coactivator-1α', '(', 'PGC-1α),']), verbo([increased]), complemento([after, gartanin, treatment])].
[sujeto(['Taken', 'together,', these, findings]), verbo([suggest]), complemento([gartanin, is, a, potential, neuroprotective, agent, against, 'glutamate-induced', oxidative, injury, partially, through, increasing, 'Nrf-2-independed', 'HO-1', and, 'AMPK/SIRT1/PGC-1α', signaling, pathways])].
[sujeto(['Madecassoside']), verbo([has]), complemento([potent, 'anti-pulmonary', fibrosis, '(', 'PF)', effects, when, administered, p])].
[sujeto(['Madecassoside']), verbo([increased]), complemento([the, expression, of, hepatocyte, growth, factor, '(', 'HGF)', in, colon, 'tissues,', and, 'HGF', receptor, antagonists, attenuated, its, 'anti-PF', effect])].
[sujeto(['Madecassoside', facilitated, the, secretion, of, 'HGF', from, colonic, epithelial, cells, by]), verbo([activating]), complemento([the, 'PPAR-γ', 'pathway,', as, shown, by, an, 'up-regulation', of, 'PPAR-γ', mRNA, 'expression,', nuclear, translocation, and, 'DNA-binding', activity, both, in, vitro, and, in, vivo])].
[sujeto(['Also', 'GW9662,', a, selective, 'PPAR-γ', 'antagonist,', almost, completely]), verbo([prevented]), complemento([the, 'madecassoside-induced', increased, expression, of, 'HGF', and, amelioration, of, 'PF'])].
[sujeto(['The', potent, 'anti-PF', effects]), verbo([induced]), complemento([by, p])].
[sujeto([madecassoside, in, mice, are, not]), verbo([mediated]), complemento([by, its, metabolites, or, itself, after, absorption, into, blood])].
[sujeto(['Instead,', madecassoside]), verbo([increases]), complemento([the, activity, of, 'PPAR-γ,', which, subsequently, increases, 'HGF', expression, in, colonic, epithelial, cells])].
[sujeto(['Rapid', induction, of, 'Smaf1', protein, occurs, during, 'in&nbsp;vitro', adipogenesis, and, its, expression, in, 3, 'T3-L1', adipocytes, is, positively]), verbo([regulated]), complemento([by, insulin, and, glucose])].
[sujeto(['Moreover,', siRNA, studies]), verbo([reveal]), complemento([that, expression, of, 'Smaf1', in, adipocytes, is, wholly, dependent, on, 'PPARγ'])].
[sujeto(['On', the, other, 'hand,', use, of, siRNA, for, 'Smaf1', to, nearly, abolish, its, protein, expression, in, adipocytes, revealed, that, 'Smaf1', does, not]), verbo([have]), complemento([a, major, role, in, adipocyte, triglyceride, 'accumulation,', lipolysis, or, 'insulin-stimulated', pAkt, induction])].
[sujeto(['However,', immunolocalization, studies, using, 'HA-tagged', 'Smaf1']), verbo([reveal]), complemento([enrichment, at, adipocyte, lipid, droplets])].
[sujeto(['In', supporting, the, cross, talk, between, drug, metabolism, and, energy, 'metabolism,', activation, of, 'CAR']), verbo([has]), complemento([been, shown, to, suppress, hepatic, gluconeogenesis, and, ameliorate, hyperglycemia, in, 'vivo,', but, the, underlying, molecular, mechanism, remains, elusive])].
[sujeto(['In', this, 'study,', we, demonstrated, that, 'CAR']), verbo([suppressed]), complemento([hepatic, gluconeogenic, gene, expression, through, posttranslational, regulation, of, the, subcellular, localization, and, degradation, of, 'PGC1α'])].
[sujeto(['Activated', 'CAR', translocated, into, the, nucleus, and, served, as, an, adaptor, protein, to]), verbo([recruit]), complemento(['PGC1α', to, the, 'Cullin1', 'E3', ligase, complex, for, ubiquitination])].
[sujeto(['The', interaction, between, 'CAR', and, 'PGC1α', also]), verbo([led]), complemento([to, their, sequestration, within, the, promyelocytic, leukemia, 'protein-nuclear', 'bodies,', where, 'PGC1α', and, 'CAR', subsequently, underwent, proteasomal, degradation])].
[sujeto(['Taken', 'together,', our, findings, revealed, an, unexpected, function, of, 'CAR', in]), verbo([recruiting]), complemento([an, 'E3', ligase, and, targeting, the, gluconeogenic, activity, of, 'PGC1α'])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, gamma, '(', 'PPARγ)', is, a]), verbo([nuclear]), complemento([receptor, that, plays, a, major, regulatory, role, in, metabolic, function])].
[sujeto(['It', is, overexpressed, in, many, types, of, cancer, 'cells,']), verbo([suggesting]), complemento([that, regulation, of, 'PPARγ', may, also, affect, carcinogenesis])].
[sujeto(['Our', previous, study]), verbo([suggested]), complemento([that, 'PTB-associated', splicing, factor, '(', 'PSF)', is, a, 'PPARγ-interacting', protein, and, growth, regulator, of, colon, cancer, cells])].
[sujeto(['In', 'addition,', 'PSF']), verbo([has]), complemento([been, shown, to, be, involved, in, several, important, regulatory, steps, of, cancer, cell, proliferation])].
[sujeto(['PSF', expression, affected, the, expression, of, 'PPARγ,', and, knockdown, of, 'PSF', using, specific, 'small-interfering', 'RNA', '(', 'siRNA)', significantly]), verbo([suppressed]), complemento([the, proliferation, of, pancreatic, cancer, cells])].
[sujeto(['Furthermore,', 'PSF', knockdown]), verbo([induced]), complemento([cell, growth, inhibition, and, autophagosome, formation, through, inhibition, of, 'PPARγ'])].
[sujeto(['This', study, is, the, first, to, describe, the, effects, of, 'PSF', on, pancreatic, cancer, cell, growth, and, autophagy]), verbo([associated]), complemento([with, 'PPARγ'])].
[sujeto(['The']), verbo([nuclear]), complemento(['factor,', 'erythroid-derived', 2, ',', -, like, 1, '(', 'Nrf1)', is, a, member, of, the, cap, &, 'quot;n&quot;', collar, subfamily, of, basic, region, leucine, zipper, transcription, factors, and, plays, the, major, role, in, regulating, the, adaptive, response, to, oxidants, and, electrophiles, within, the, cell])].
[sujeto(['Here,', we, injected, small, interfering, 'RNA', '(', 'siRNA)']), verbo([targeting]), complemento(['Nrf1', in, dorsal, third, ventricle, of, adult, male, albino, 'Wistar', rats, and, subsequently, examined, the, effect, of, this, silencing, on, 'anxiety-related', behavior])].
[sujeto(['Caspase-3', did, not]), verbo([increase]), complemento([in, 'Nrf1-siRNA-injected', rats, even, though, 'Bax/Bcl2', ratio, markedly, elevated, in, 'Nrf1-knockdown', rats, in, all, three, mentioned, regions, compared, to, control, rats])].
[sujeto(['Besides', trapping, excess, glucose, and]), verbo([providing]), complemento([for, triglycerides, and, energy, 'storage,', endogenously, synthesized, lipids, can, function, as, potent, signaling, molecules])].
[sujeto(['Indeed,', several, specific, lipids, and, their, molecular]), verbo([targets]), complemento([that, mediate, insulin, sensitivity, have, been, recently, identified])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, 'carbohydrate-response', 'element-binding', protein, '(', 'ChREBP),', a, transcriptional, inducer, of, glucose, use, and, de, novo, 'lipogenesis,', controls, the, activity, of, the, adipogenic, master, regulator, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)γ'])].
[sujeto(['Expression', of, 'constitutive-active', 'ChREBP', in, precursor, cells]), verbo([activated]), complemento([endogenous, 'PPARγ', and, promoted, adipocyte, differentiation])].
[sujeto(['Intriguingly,', 'ChREBP-constitutive-active', 'ChREBP', expression]), verbo([induced]), complemento(['PPARγ', activity, in, a, fatty, acid, 'synthase-dependent', manner, and, by, 'trans-activating', the, 'PPARγ', 'ligand-binding', domain])].
[sujeto(['Reducing', endogenous, 'ChREBP', activity, by, either, small, interfering, 'RNA-mediated', 'depletion,', exposure, to, 'low-glucose', 'concentrations,', or]), verbo([expressing]), complemento([a, 'dominant-negative', 'ChREBP', impaired, differentiation])].
[sujeto(['In', 'adipocytes,', 'ChREBP']), verbo([regulated]), complemento([the, expression, of, 'PPARγ', target, 'genes,', in, particular, those, involved, in, 'thermogenesis,', similar, to, synthetic, 'PPARγ', ligands])].
[sujeto(['In', 'summary,', our, data]), verbo([suggest]), complemento([that, 'ChREBP', controls, the, generation, of, endogenous, fatty, acid, species, that, activate, 'PPARγ'])].
[sujeto(['Thus,']), verbo([increasing]), complemento(['ChREBP', activity, in, adipose, tissue, by, therapeutic, interventions, may, promote, insulin, sensitivity, through, 'PPARγ'])].
[sujeto(['Superinfection', with, 'HDV', in, chronic, hepatitis, 'B', is]), verbo([associated]), complemento([with, a, more, threatening, form, of, liver, disease, leading, to, rapid, progression, to, cirrhosis])].
[sujeto(['In', spite, of, some, controversy, in, the, epidemiological, 'studies,', 'HDV', infection, does]), verbo([increase]), complemento([the, risk, of, hepatocellular, carcinoma, '(', 'HCC)', compared, to, hepatitis, 'B', virus, '(', 'HBV)', monoinfection])].
[sujeto(['The', large, hepatitis, 'D', antigen, is, a, regulator, of, various, cellular, functions, and, an, activator, of, signal, transducer, and, activator, of, transcription, '(', 'STAT)3', and, the]), verbo([nuclear]), complemento([factor, kappa, 'B', pathway])].
[sujeto(['HDV', antigens]), verbo([have]), complemento([also, been, associated, with, increased, histone, 'H3', acetylation, of, the, clusterin, promoter])].
[sujeto(['This']), verbo([enhances]), complemento([the, expression, of, clusterin, in, infected, 'cells,', increasing, cell, survival, potential])].
[sujeto(['The']), verbo([targeted]), complemento([inhibition, of, 'STAT3', and, 'cyclophilin,', and, augmentation, of, peroxisome, 'proliferator-activated', receptor, γ, have, a, potential, therapeutic, role, in, 'HCC'])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, 'Astragaloside', 'IV', '(', 'ASIV),', a, major, active, constituent, of, 'Astragalus', membranaceus, '(', 'Fisch)', 'Bge', protects, against, cardiac, hypertrophy, in, rats, induced, by, isoproterenol, '(', 'Iso),', however, the, mechanism, underlying, the, protection, remains, unknown])].
[sujeto(['Dysfunction', of, cardiac, energy, biosynthesis, contributes, to, the, hypertrophy, and, 'Nuclear', 'Factor', κB, '(', 'NF-κB)/Peroxisome', 'Proliferator-Activated', 'Receptor-γ', 'Coactivator', 1, α, '(', 'PGC-1α)', signaling, gets]), verbo([involved]), complemento([in, the, dysfunction])].
[sujeto(['The', present, study, was, designed, to, investigate, the, mechanism, by, which, 'ASIV', improves, the, cardiac, hypertrophy, with, focuses, on, the, 'NF-κB/PGC-1α', signaling]), verbo([mediated]), complemento([energy, biosynthesis])].
[sujeto(['The', results, showed, that, combination, with, 'ASIV', significantly, attenuated, the, pathological, 'changes,', reduced, the, ratios, of, heart, 'weight/body', weight, and, 'Left', ventricular, 'weight/body', 'weight,', improved, the, cardiac, 'hemodynamics,', 'down-regulated', mRNA, expression, of, 'Atrial', 'Natriuretic', 'Peptide', '(', 'ANP)', and, 'Brain', 'Natriuretic', 'Peptide', '(', 'BNP),']), verbo([increased]), complemento([the, ratio, of, 'ATP/AMP,', and, decreased, the, content, of, 'Free', 'Fat', 'Acid', '(', 'FFA)', in, heart, tissue, of, rats, compared, with, 'Iso', alone])].
[sujeto(['In', 'addition,', pretreatment, with, 'ASIV', significantly]), verbo([decreased]), complemento([the, surface, area, and, protein, 'content,', 'down-regulated', mRNA, expression, of, 'ANP', and, 'BNP,', increased, the, ratio, of, 'ATP/AMP,', and, decreased, the, content, of, 'FFA', in, 'NRVMs', compared, with, 'Iso', alone])].
[sujeto(['Furthermore,', 'ASIV']), verbo([increased]), complemento([the, protein, expression, of, 'ATP5D,', subunit, of, 'ATP', synthase, and, 'PGC-1α,', inhibited, translocation, of, 'p65,', subunit, of, 'NF-κB', into, nuclear, fraction, in, both, rats, and, 'NRVMs', compared, with, 'Iso', alone])].
[sujeto(['Knockdown', of, p65, with, siRNA]), verbo([decreased]), complemento([the, surface, areas, and, increased, 'PGC-1α', expression, of, 'NRVMs', compared, with, 'Iso', alone])].
[sujeto(['The', results]), verbo([suggested]), complemento([that, 'ASIV', protects, against, 'Iso-induced', cardiac, hypertrophy, through, regulating, 'NF-κB/PGC-1α', signaling, mediated, energy, biosynthesis])].
[sujeto(['cAMP-response', 'element-binding', protein, '(', 'CREB)', is]), verbo([required]), complemento([for, the, induction, of, adipogenic, transcription, factors, such, as, 'CCAAT/enhancer-binding', proteins, '(', 'C/EBPs)'])].
[sujeto(['Interestingly,', it, is, known, from, studies, in, other, tissues, that, 'LKB1', and, its, substrates, 'AMP-activated', protein, kinase, '(', 'AMPK)', and, 'salt-inducible', kinases, '(', 'SIKs)', negatively]), verbo([regulate]), complemento([gene, expression, by, phosphorylating, the, 'CREB', 'co-activator', 'CRTC2', and, class, 'IIa', histone, deacetylases, '(', 'HDACs),', which, results, in, their, exclusion, from, the, nucleus, where, they, 'co-activate', or, inhibit, their, targets])].
[sujeto(['In', this, 'study,', we, show, that, 'AMPK/SIK', signalling, is, acutely, attenuated, during, adipogenic, differentiation, of, 3, 'T3-L1', 'preadipocytes,', which, coincides, with, the, dephosphorylation, and]), verbo([nuclear]), complemento([translocation, of, 'CRTC2', and, 'HDAC4'])].
[sujeto(['In', 'addition,', the, phosphorylation, of, 'CRTC2', and, 'HDAC4', was, 'reduced,', and, the, mRNA, expression, of, adipogenic, transcription, factors, 'Cebpa,', peroxisome, 'proliferator-activated', receptor, γ, '(', 'Pparg)', and, 'adipocyte-specific', proteins, such, as, 'hormone-sensitive', lipase, '(', 'HSL),', fatty, acid, synthase, '(', 'FAS),', 'aP2,', 'GLUT4', and, adiponectin, was]), verbo([increased]), complemento([in, the, absence, of, 'LKB1'])].
[sujeto(['The', mRNA, and, protein, expression, of, 'Ddit3/CHOP10,', a, 'dominant-negative', member, of, the, 'C/EBP', 'family,', was, reduced, in, 'Lkb1-shRNA-expressing', 'cells,']), verbo([providing]), complemento([a, potential, mechanism, for, the, 'up-regulation', of, 'Pparg', and, 'Cebpa', expression])].
[sujeto(['The', majority, of, human, pancreatic, cancers]), verbo([have]), complemento([activating, mutations, in, the, 'KRAS', 'proto-oncogene'])].
[sujeto(['These', mutations, result, in]), verbo([increased]), complemento([activity, of, the, 'NF-κB', pathway, and, the, subsequent, constitutive, production, of, proinflammatory, cytokines])].
[sujeto(['Here,', we, show, that, inhibitor, of, κB, kinase, 2, '(', 'Ikk2),', a, component, of, the, canonical, 'NF-κB', signaling, 'pathway,', synergizes, with, basal, 'Notch', signaling, to, upregulate, transcription, of, primary, 'Notch']), verbo([target]), complemento(['genes,', resulting, in, suppression, of, antiinflammatory, protein, expression, and, promotion, of, pancreatic, carcinogenesis, in, mice])].
[sujeto(['We']), verbo([found]), complemento([that, in, the, 'Kras(G12D)Pdx1-cre', mouse, model, of, pancreatic, 'cancer,', genetic, deletion, of, 'Ikk2', in, initiated, 'pre-malignant', epithelial, cells, substantially, delayed, pancreatic, oncogenesis, and, resulted, in, downregulation, of, the, classical, 'Notch', target, genes, 'Hes1', and, 'Hey1'])].
[sujeto(['Tnf-α']), verbo([stimulated]), complemento([canonical, 'NF-κB', signaling, 'and,', in, collaboration, with, basal, 'Notch', 'signals,', induced, optimal, expression, of, 'Notch', targets])].
[sujeto(['Hes1']), verbo([suppresses]), complemento([expression, of, 'Pparg,', which, encodes, the, antiinflammatory, nuclear, receptor, 'Pparγ'])].
[sujeto(['These', findings]), verbo([reveal]), complemento([what, we, believe, to, be, a, novel, interaction, between, oncogenic, inflammation, and, a, major, cell, fate, pathway, and, show, how, these, pathways, can, cooperate, to, promote, cancer, progression])].
[sujeto(['Various', factors, related, to, androgen, biosynthesis, are]), verbo([expressed]), complemento([in, human, sebaceous, glands])].
[sujeto(['In', 'addition,', the, overexpression, of, 17, 'β-HSD2', in, 'SZ95', significantly]), verbo([increased]), complemento([the, androstenedione, production, and, markedly, decreased, the, amounts, of, testosterone, and, dihydrotestosterone, when, 'DHEA', was, added, externally])].
[sujeto(['On', the, other, 'hand,', the, phosphorylation, of, mammalian]), verbo([target]), complemento([of, 'rapamycin,', which, is, well, known, to, induce, sebum, secretion, and, the, onset, 'and/or', aggravation, of, 'acne,', was, increased, by, the, addition, of, testosterone, in, the, presence, of, 'IGF1', in, hamster, sebocytes])].
[sujeto(['There', is, evidence, that, placental, 11, 'beta-HSD2', is, reduced, in, pregnancies, complicated, with, intrauterine, growth, restriction, '(', 'IUGR),', but, the, relationship, between, the, two, is, uncertain, owing, to, other, maternal, complications, often]), verbo([associated]), complemento([with, this, pathological, condition, of, pregnancy])].
[sujeto(['To']), verbo([gain]), complemento([insight, into, the, role, of, placental, 11, 'beta-HSD2', in, the, pathogenesis, of, 'IUGR,', we, studied, variations, in, the, activity, and, expression, of, this, important, enzyme, as, well, as, its, functional, 'indicator,', the, ratio, of, cortisone, to, cortisol, in, umbilical, cord, 'blood,', in, a, cohort, of, 12, term, deliveries, complicated, with, idiopathic, 'IUGR', and, 12, term, controls])].
[sujeto(['This', was, accompanied, by, a]), verbo([decrease]), complemento([in, the, ratio, of, cortisone, to, cortisol, in, the, umbilical, 'artery,', suggesting, that, not, only, placental, but, also, fetal, 11, 'beta-HSD2', activity, may, be, compromised, in, idiopathic, 'IUGR'])].
[sujeto(['Given', that, we, previously, identified, the]), verbo([nuclear]), complemento([receptor, 'PPARdelta', as, a, potent, suppressor, of, placental, 11, 'beta-HSD2,', we, also, tested, but, found, no, evidence, to, support, the, hypothesis, that, placental, 'PPARdelta', expression, is, increased, in, 'IUGR', thereby, contributing, to, the, molecular, mechanisms, that, underlie, the, attenuated, placental, 11, 'beta-HSD2'])].
[sujeto(['Taken', 'together,', our, present, findings]), verbo([provide]), complemento([evidence, suggesting, a, role, for, an, attenuated, placental, as, well, as, fetal, 11, 'beta-HSD2', in, the, pathogenesis, of, 'IUGR'])].
[sujeto(['Accumulating', evidence]), verbo([suggests]), complemento([that, the, human, placental, enzyme, 11, 'beta-hydroxysteroid', dehydrogenase, type, 2, '(', 11, 'beta-HSD2)', plays, a, key, role, in, fetal, development, by, controlling, fetal, exposure, to, maternal, glucocorticoids])].
[sujeto(['Recently,', the]), verbo([nuclear]), complemento([peroxisome, 'proliferator-activated', receptor, delta, '(', 'PPAR', 'delta)', has, been, found, to, be, the, most, abundantly, expressed, 'PPAR', subtype, in, the, human, 'placenta,', but, its, function, in, this, organ, is, unknown])].
[sujeto(['Given', that, 'PPAR', 'delta-null', mice, exhibited, placental, defects, and, consequent, intrauterine, growth, 'restriction,', the, present, study, was, undertaken, to, examine, the, hypothesis, that, 'PPAR', delta]), verbo([regulates]), complemento([human, placental, function, in, part, by, targeting, 11, 'beta-HSD2'])].
[sujeto(['Using', cultured, human, trophoblast, cells, as, a, model, 'system,', we, demonstrated, that, 1, ')', the, putative, 'PPAR', delta, agonist, carbaprostacyclin, '(', 'cPGI2)', reduced, 11, 'beta-HSD2', activity, as, well, as, 11, 'beta-HSD2', expression, at, both, protein, and, mRNA, 'levels;', 2, ')', 'GW610742', '(', a, selective, 'PPAR', delta, 'agonist)', mimicked, the, effect, of, 'cPGI2,', whereas, indomethacin, '(', a, known, ligand, for, 'PPARalpha', and, 'PPAR', 'gamma)', had, no, 'effect;', 3, ')', the, 'cPGI2-induced', 'down-regulation', of, 11, 'beta-HSD2', mRNA, did, not]), verbo([require]), complemento([de, novo, protein, 'synthesis;', 4, ')', cPGI2, suppressed, 'HSD11B2', promoter, 'activity,', but, did, not, alter, the, 'half-life', of, 11, 'beta-HSD2', 'mRNA;', and, 5, ')', the, inhibitory, effect, of, cPGI2, on, 'HSD11B2', promoter, activity, was, abrogated, in, trophoblast, cells, cotransfected, with, a, dominant, negative, 'PPAR', delta, mutant])].
[sujeto(['Taken', 'together,', these, findings]), verbo([suggest]), complemento([that, activation, of, 'PPAR', delta, 'down-regulates', 'HSD11B2', gene, expression, in, human, trophoblast, 'cells,', and, that, this, effect, is, mediated, primarily, at, the, transcriptional, level])].
[sujeto(['Thus,', the, present, study]), verbo([reveals]), complemento([11, 'beta-HSD2', as, an, additional, target, for, 'PPAR', delta, and, identifies, a, molecular, mechanism, by, which, this, nuclear, receptor, may, regulate, human, placental, function])].
[sujeto(['Inter-individual', differences, in, toxic, symptoms, and, pharmacokinetics, of, 'high-dose', methotrexate, '(', 'MTX)', treatment, may, be]), verbo([caused]), complemento([by, genetic, variants, in, the, 'MTX', pathway])].
[sujeto(['The', risk, of, toxicity, was]), verbo([associated]), complemento([with, five, 'SNPs', in, the, 'ABCC2', and, 'NR1I2', genes])].
[sujeto(['Pharmacokinetic', parameters, were]), verbo([associated]), complemento([with, four, 'SNPs', of, the, 'ABCB1,', 'ABCC3,', 'NR1I2,', and, 'GGH', 'genes,', and, toxicity, was, shown, to, be, associated, with, 'ABCC1', rs246219, and, 'ABCC2', rs717620, using, the, univariate, and, 'BN-BMLA', method])].
[sujeto(['Colorectal', cancer, lethality, usually, results, from, 'post-treatment', relapse, in, the, majority, of, stage, 'II-IV', 'patients,', due, to, the]), verbo([enhanced]), complemento([resistance, of, 'Cancer', 'Stem', 'Cells', '(', 'CSCs)'])].
[sujeto(['Here,', we, show, that, the]), verbo([nuclear]), complemento([receptor, 'Pregnane', 'X', 'Receptor', '(', 'PXR,', 'NR1I2),', behaves, as, a, key, driver, of, 'CSC-mediated', tumor, recurrence])].
[sujeto(['First,', 'PXR', is, specifically]), verbo([expressed]), complemento([in, 'CSCs,', where, it, drives, the, expression, of, genes, involved, in, 'self-renewal', and, chemoresistance])].
[sujeto(['Clinically,', high, levels, of, 'PXR', correlate, with, poor, 'recurrence-free', survival, in, a, cohort, of, &, 'gt;200', stage, 'II/III', colorectal, cancer, patients, treated, with, 'chemotherapy,', for, whom]), verbo([finding]), complemento([biomarkers, of, treatment, outcome, is, an, urgent, clinical, need])].
[sujeto([shRNA, silencing, of, 'PXR']), verbo([increased]), complemento([the, 'chemo-sensitivity', of, human, colon, 'CSCs,', reduced, their, 'self-renewal', and, 'tumor-initiating', 'potential,', and, drastically, delayed, tumor, recurrence, in, mice, following, chemotherapy])].
[sujeto(['This', study, uncovers, 'PXR', as, a, key, factor, for, 'CSC', 'self-renewal', and, chemoresistance, and]), verbo([targeting]), complemento(['PXR', thus, represents, a, promising, strategy, to, minimize, colorectal, cancer, relapse, by, selectively, sensitizing, 'CSCs', to, chemotherapy])].
[sujeto(['Recently,', the, pregnane, 'X', receptor, '(', 'PXR)', was, identified, as, a, sensor, for, microbial, 'metabolites,', whose, activation, can]), verbo([regulate]), complemento([the, intestinal, epithelial, barrier])].
[sujeto(['Mutations', in, 'NR1I2,', the, gene, that, encodes, the, 'PXR,']), verbo([have]), complemento([been, linked, to, 'IBD,', and, in, animal, 'models,', 'PXR', deletion, leads, to, barrier, dysfunction])].
[sujeto(['In', the, current, 'study,', we, sought, to, assess, the, 'mechanism(s)', through, which, the, 'PXR']), verbo([regulates]), complemento([barrier, function, during, inflammation])].
[sujeto(['In', 'Caco-2', intestinal, epithelial, cell, 'monolayers,', tumor, necrosis, 'factor-α/interferon-γ', exposure, disrupted, the, barrier, and]), verbo([triggered]), complemento([zonula, 'occludens-1', 'relocalization,', increased, expression, of, myosin, 'light-chain', kinase, '(', 'MLCK),', and, activation, of, 'c-Jun', 'N-terminal', kinase, 1, /, 2, '(', 'JNK1/2)'])].
[sujeto(['Activation', of, the, 'PXR', '[', rifaximin, and, '[', '[', 3, ',', 5, -, 'Bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenylidene]bis-phosphonic', acid, tetraethyl, ester, '(', 'SR12813);', 10, 'μM]', protected, the, 'barrier,', an, effect, that, was]), verbo([associated]), complemento([with, attenuated, 'MLCK', expression, and, 'JNK1/2', activation])].
[sujeto(['In', 'vivo,', activation, of, the, 'PXR', '[', pregnenolone, 16, 'α-carbonitrile', '(', 'PCN)]', attenuated, barrier, disruption]), verbo([induced]), complemento([by, 'toll-like', receptor, 4, activation, in, 'wild-type,', but, not, 'Pxr-/-,', mice])].
[sujeto(['Furthermore,', 'PCN', treatment, protected, the, barrier, in, the, 'dextran-sulfate', sodium, model, of, experimental, 'colitis,', an, effect, that, was]), verbo([associated]), complemento([with, reduced, expression, of, mucosal, 'MLCK', and, phosphorylated, 'JNK1/2'])].
[sujeto(['Together,', our, data]), verbo([suggest]), complemento([that, the, 'PXR', regulates, the, intestinal, epithelial, barrier, during, inflammation, by, modulating, 'cytokine-induced', 'MLCK', expression, and, 'JNK1/2', activation])].
[sujeto(['Thus,']), verbo([targeting]), complemento([the, 'PXR', may, prove, beneficial, for, the, treatment, of, 'inflammation-associated', barrier, disruption, in, the, context, of, 'IBD'])].
[sujeto(['Pharmacogenetic', factors, were, not]), verbo([associated]), complemento([with, risk, for, 'DGF,', 'AR', or, 'SCR'])].
[sujeto(['In', a, 'sub-analysis', of, the, patients, with, 'AR,', those, treated, with, rejection, treatment, including, 'ATG,', significantly, less, frequent, 'SCR', was]), verbo([found]), complemento([in, the, 6, -, month, biopsy, '(', 13, '%', vs])].
[sujeto(['Furthermore,', rejection, treatment, with, depleting, antibodies, effectively]), verbo([prevented]), complemento(['SCR', in, 6, -, month, surveillance, biopsies])].
[sujeto(['STAT5A', and, 'STAT5B', are, important, transcription, factors, that, play, a, key, role, in, regulation, of, several, important, physiological, processes, including, 'proliferation,', 'survival,', mediation, of, responses, to, cytokines, and, in]), verbo([regulating]), complemento([gender, differences, in, drug, response, genes, such, as, the, hepatic, cytochrome, 'P450s', '(', 'CYPs)', that, are, responsible, for, a, large, majority, of, drug, metabolism, reactions, in, the, human, body])].
[sujeto(['STAT5A', and, 'STAT5b']), verbo([have]), complemento([a, high, degree, of, sequence, homology, and, have, been, reported, to, have, largely, similar, functions])].
[sujeto(['Recent', studies, 'have,', 'however,', indicated, that, they, can, also, often]), verbo([have]), complemento([distinct, and, unique, roles, in, regulating, gene, expression])].
[sujeto(['In', this, 'study,', we, evaluated, the, association, of, 'STAT5A', and, 'STAT5B', mRNA, expression, levels, with, those, of, several, key, hepatic, cytochrome, 'P450s', '(', 'CYPs)', and, hepatic, transcription, factors, '(', 'TFs)', and, evaluated, the, potential, roles, of, 'STAT5A', and, 5, b, in]), verbo([mediating]), complemento([gender, differences, in, these, 'CYPs', and, 'TFs'])].
[sujeto(['As', 'STAT5A', and, 'STAT5B']), verbo([have]), complemento([been, shown, to, be, important, in, regulation, of, gender, differences, in, 'CYPs,', we, also, analyzed, 'STAT5A', and, 5, b, associations, with, 'CYPs', and, 'TFs', separately, in, males, and, females, and, observed, gender, dependent, differential, associations, of, 'STATs', with, several, 'CYPs', and, 'TFs'])].
[sujeto(['CYP3A4,', 'CYP2C19),', 'STAT5B', expression, was, observed, to, demonstrate, positive, association, with, most, of, the, 'CYPs/TFs', analyzed]), verbo([suggesting]), complemento([that, 'STAT5A', and, 'STAT5b', have, potentially, different, and, distinct, roles, in, regulating, expression, of, hepatic, drug, response, genes])].
[sujeto(['Because', clopidogrel, is, a, 'prodrug,', polymorphisms, of, genes, encoding, the, enzymes]), verbo([involved]), complemento([in, its, biotransformation, may, be, the, primary, influential, factors])].
[sujeto(['The', 'NR1I2', '(', 'rs13059232)', polymorphism, was, moderately]), verbo([associated]), complemento([with, 'CR', '(', 'CC', vs, 'TT+TC,', 'OR:', 0.533, ',', 95, '%', 'CI:', 0.286, -, 0.991, ',', 'P=0'])].
[sujeto(['In', 'addition,', an, association, was]), verbo([found]), complemento([between, hypertension, and, 'CR', '(', 'P=0'])].
[sujeto(['The']), verbo([associated]), complemento(['SNPs', studied, may, be, useful, to, predict, clopidogrel, resistance, in, 'Chinese', patients, with, ischemic, stroke])].
[sujeto(['Recent', epidemiological, studies]), verbo([have]), complemento([found, a, correlation, between, circulating, phthalate, levels, and, type, 2, 'diabetes,', whereas, animal, studies, indicate, that, phthalates, are, capable, of, disrupting, endocrine, signaling])].
[sujeto(['Here,', we, show, that, feeding, 'Drosophila', males, the, xenobiotic, dibutyl, phthalate, '(', 'DBP)', affects]), verbo([conserved]), complemento(['insulin-', and, 'glucagon-like', signaling])].
[sujeto(['We']), verbo([report]), complemento([that, raising, flies, on, food, containing, 'DBP', leads, to, starvation, 'resistance,', increased, lipid, 'storage,', 'hyperglycemia,', and, hyperphagia])].
[sujeto(['We', establish, that, raising, flies, on, 'DBP-containing', food, or, feeding, adults, 'DBP', food, affects, the, expression, of, homologous, genes]), verbo([involved]), complemento([in, xenobiotic, and, lipid, metabolism, '(', 'AHR', '[', 'Drosophila', 'ss],', 'NR1I2', '[', 'Hr96],', 'ABCB1', '[', 'MDR50],', 'ABCC3', '[', 'MRP],', and, 'CYP3A4', '[', 'Cyp9f2])'])].
[sujeto(['Our', results]), verbo([provide]), complemento([comprehensive, evidence, that, 'DBP', can, disrupt, metabolism, in, 'Drosophila', 'males,', by, regulating, genes, involved, in, 'glucose,', 'lipid,', and, xenobiotic, metabolism])].
[sujeto(['Small', molecular, weight, proteins, less, than, 25, kDa, and, phospholipids, were, analyzed, with, 'MALDI-TOF', 'MS/MS', in, order, to, compare, expression, 'patterns,']), verbo([revealed]), complemento([that, some, peaks, were, dramatically, altered, after, 'CHL', treatment])].
[sujeto(['In', an, angiogenesis, test, on, larvae, of, transgenic, 'zebrafish,', 'CHL', did, not]), verbo([have]), complemento([an, inhibitory, effect])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, the, 'up-regulation', of, metabolic, enzymes, including, 'CYP450', and, 'MDR1', may, be, involved, in, 'CHL', resistance, in, zebrafish])].
[sujeto(['The', multinational, 'PEARLS', '(', 'ACTG', 'A5175)', 'study,', conducted, mainly, in, 'resource-limited', 'settings,', identified, an]), verbo([increased]), complemento([treatment, failure, rate, among, 'HIV-infected', individuals, randomized, to, 'once-daily', unboosted, 'atazanavir,', 'didanosine-EC,', and, emtricitabine, compared, with, 'efavirenz-based', regimens])].
[sujeto(['Expression', of, 'CYP3A5', appears, to, be]), verbo([associated]), complemento([with, increased, 'M1', and, 'M2', atazanavir, metabolite, 'formation,', without, significantly, affecting, parent, compound, pharmacokinetics])].
[sujeto(['Post-translational', modification, '(', 'PTM)', of]), verbo([nuclear]), complemento([receptor, superfamily, members, regulates, various, aspects, of, their, biology, to, include, 'sub-cellular', 'localization,', the, repertoire, of, 'protein-binding', 'partners,', as, well, as, their, stability, and, mode, of, degradation])].
[sujeto(['The']), verbo([nuclear]), complemento([receptor, pregnane, 'X', receptor, '(', 'PXR,', 'NR1I2)', is, a, 'master-regulator', of, the, 'drug-inducible', gene, expression, in, liver, and, intestine])].
[sujeto(['The', 'PXR-mediated', gene, activation, program, is, primarily]), verbo([recognized]), complemento([to, increase, drug, 'metabolism,', drug, 'transport,', and, drug, efflux, pathways, in, these, tissues])].
[sujeto(['The', activation, of, 'PXR', also]), verbo([has]), complemento([important, implications, in, significant, human, diseases, including, inflammatory, bowel, disease, and, cancer])].
[sujeto(['Our', recent, investigations]), verbo([reveal]), complemento([that, 'PXR', is, modified, by, multiple, 'PTMs', to, include, 'phosphorylation,', 'SUMOylation,', and, ubiquitination])].
[sujeto(['Further,', we, show, that]), verbo([increased]), complemento([acetylation, of, 'PXR', stimulates, its, increased, 'SUMO-modification', to, support, active, transcriptional, suppression])].
[sujeto(['Pharmacologic', inhibition, of, lysine, 'de-acetylation', using, trichostatin, 'A', '(', 'TSA)', alters, the, 'sub-cellular', localization, of, 'PXR', in, cultured, 'hepatocytes,', and, also]), verbo([has]), complemento([a, profound, impact, upon, 'PXR', transactivation, capacity])].
[sujeto(['Both', the, acetylation, and, 'SUMOylation', status, of, the, 'PXR', protein, is, affected, by, its, ability, to]), verbo([associate]), complemento([with, the, lysine, 'de-acetylating', enzyme, histone, 'de-acetylase', '(', 'HDAC)3', in, a, complex, with, silencing, mediator, of, retinoic, acid, and, thyroid, hormone, receptor, '(', 'SMRT)'])].
[sujeto(['Taken', 'together,', our, data, support, a, model, in, which, a, 'SUMO-acetyl', '\'', 'switch\'', occurs, such, that, acetylation, of, 'PXR', likely]), verbo([stimulates]), complemento(['SUMO-modification', of, 'PXR', to, promote, the, active, repression, of, 'PXR-target', gene, expression])].
[sujeto(['This', article, is, part, of, a, 'Special', 'Issue', 'entitled:', 'Xenobiotic']), verbo([nuclear]), complemento(['receptors:', 'New', 'Tricks', for, 'An', 'Old', 'Dog,', edited, by, 'Dr'])].
[sujeto(['Genetic', association, studies, on, the, pharmacokinetics, of, tacrolimus]), verbo([have]), complemento([reported, conflicting, 'results,', except, for, the, role, of, the, 'CYP3A5*3', polymorphism])].
[sujeto(['Aside', from, 'CYP3A5*3,', the, rs3814055, polymorphism, in, the, 'NR1I2', gene, was]), verbo([associated]), complemento([with, the, tacrolimus, pharmacokinetics, based, on, false, discovery, 'rate-corrected', multiple, tests, and, the, least, absolute, shrinkage, and, selection, operator, analysis])].
[sujeto(['An', in, vitro, luciferase, reporter, assay, indicated, that, downregulation, of, 'PXR', expression, is, the, likely, molecular, mechanism, responsible, for, the]), verbo([increased]), complemento([exposure, to, tacrolimus, in, subjects, carrying, the, rs3814055, 'C&gt;T', variant])].
[sujeto(['The', aim, of, this, study, was, to, identify, related, genes, for, total, cholesterol, '(', 'TC)', and, evaluate, the, functional, relevance, to]), verbo([provide]), complemento([evidences, for, prioritizing, these, genes])].
[sujeto(['A', total, of, 22, ',', 98, genes, were, analyzed, for, 'TC', levels, in, 'gene-based', association, analysis, and, 433, of, them, were]), verbo([found]), complemento([to, be, significant, after, 'Bonferroni', correction, '(', p, &, 'lt;', 2.3, ×, 10, '(', -, 6, ')', ')'])].
[sujeto(['The', findings, might]), verbo([provide]), complemento([more, insights, into, the, genetic, basis, of, lipid, metabolism])].
[sujeto(['Despite', administration, of, fixed, doses, of, 'EFV,', 'inter-individual', variability, in, plasma, concentrations]), verbo([has]), complemento([been, reported])].
[sujeto(['Poor', treatment, outcomes, such, as, development, of, adverse, drug, reactions, or, treatment, failure]), verbo([have]), complemento([been, linked, to, 'EFV', plasma, concentrations, outside, the, therapeutic, range, '(', 1, -, 4, 'μg/mL)', in, some, studies])].
[sujeto(['DME', coding, genes, are, also]), verbo([regulated]), complemento([by, microRNAs, through, targeting, the, 3, '\'', -, untranslated, region])].
[sujeto(['This', study, is, a, continuation, of, earlier, pharmacogenetics, studies, emphasizing, the, role, of, genetic, variation, in, the, 3, '\'', -, 'UTR', of, genes, which, products, are, either, pharmacokinetic, or, pharmacodynamic]), verbo([targets]), complemento([of, 'EFV'])].
[sujeto(['We']), verbo([have]), complemento([shown, that, 'CYP2B6', c])].
[sujeto(['One', key, protein]), verbo([involved]), complemento([in, transcellular, transport, of, sulfate, is, the, 'sodium-sulfate', cotransporter, 'NaSi-1,', and, previous, studies, suggest, that, vitamin, 'D', modulates, sulfate, homeostasis, by, regulating, 'NaSi-1', expression])].
[sujeto(['In', the, present, 'study,', we]), verbo([found]), complemento(['that,', in, mice, lacking, the, vitamin, 'D', receptor, '(', 'VDR),', 'NaSi-1', expression, in, the, kidney, was, reduced, by, 72, '%', but, intestinal, 'NaSi-1', levels, remained, unchanged])].
[sujeto(['In', connection, with, these, 'findings,', urinary, sulfate, excretion, was]), verbo([increased]), complemento([by, 42, '%', whereas, serum, sulfate, concentration, was, reduced, by, 50, '%', in, 'VDR', knockout, mice])].
[sujeto(['Treatment', of, 'wild-type', mice, with, 1, ',', 25, -, dihydroxyvitamin, 'D3', or, vitamin, 'D', analog, markedly]), verbo([stimulated]), complemento([renal, 'NaSi-1', mRNA, expression])].
[sujeto(['These', data]), verbo([provide]), complemento([strong, in, vivo, evidence, that, vitamin, 'D', plays, a, critical, role, in, sulfate, homeostasis])].
[sujeto(['However,', the, observation, that, serum, sulfate, and, skeletal, proteoglycan, levels, in, normocalcemic, 'VDR', knockout, mice, remained, low, in, the, absence, of, rickets, and, osteomalacia]), verbo([suggests]), complemento([that, the, contribution, of, sulfate, deficiency, to, development, of, rickets, and, osteomalacia, is, minimal])].
[sujeto([1, 'alpha,25(OH)(2)D(3)']), verbo([regulates]), complemento([rat, growth, plate, chondrocytes, via, nuclear, vitamin, 'D', receptor, '(', 1, ',', 25, -, 'nVDR)', and, membrane, 'VDR', '(', 1, ',', 25, -, 'mVDR)', mechanisms])].
[sujeto([1, 'alpha,25(OH)(2)D(3)', had, no, effect, on, '[', '(', 3, ')', 'H]-thymidine', incorporation, in, 'VDR(-/-)', 'GC', 'cells,', but, it]), verbo([increased]), complemento(['[', '(', 3, ')', 'H]-thymidine', incorporation, in, 'VDR(+/+)', cells])].
[sujeto(['Proteoglycan', production, was]), verbo([increased]), complemento([in, cultures, of, both, 'VDR(-/-)', and, 'VDR(+/+)', 'cells,', based, on, '[', '(', 35, ')', 'S]-sulfate', incorporation])].
[sujeto([1, 'alpha,25(OH)(2)D(3)']), verbo([caused]), complemento([a, 10, -, fold, increase, in, 'PKC', specific, activity, in, 'VDR(-/-),', and, 'VDR(+/+)', 'GC', cells, as, early, as, 1, 'min,', supporting, this, hypothesis])].
[sujeto(['Phospholipase', 'C', '(', 'PLC)', activity, was, also]), verbo([increased]), complemento([within, 1, min, in, 'GC', chondrocyte, cultures, treated, with, 1, 'alpha,25(OH)(2)D(3)'])].
[sujeto(['As', noted, previously, for, rat, growth, plate, 'chondrocytes,', 1, 'alpha,25(OH)(2)D(3)']), verbo([mediated]), complemento([its, increases, in, 'PKC', and, 'PLC', activities, in, the, 'VDR(-/-)', 'GC', cells, through, activation, of, phospholipase, 'A(2)', '(', 'PLA(2))'])].
[sujeto(['These', responses, to, 1, 'alpha,25(OH)(2)D(3)', were, blocked, by, antibodies, to, 1, ',', 25, -, 'MARRS,', which, is, a, '[', '(', 3, ')', 'H]-1,25(OH)(2)D(3)']), verbo([binding]), complemento([protein, identified, in, chick, enterocytes])].
[sujeto([24, 'R,25(OH)(2)D(3)']), verbo([regulated]), complemento(['PKC', in, 'VDR(-/-)', and, 'VDR(+/+)', 'RC', cells])].
[sujeto(['Wild', type, 'RC', cells]), verbo([responded]), complemento([to, 24, 'R,25(OH)(2)D(3)', with, an, increase, in, 'PKC,', whereas, treatment, of, 'RC', cells, from, mice, lacking, a, functional, 1, ',', 25, -, nVDR, caused, a, 'time-dependent', decrease, in, 'PKC', between, 6, and, 9, min])].
[sujeto([24, 'R,25(OH)(2)D(3)', dependent, 'PKC', was]), verbo([mediated]), complemento([by, phospholipase, 'D,', but, not, by, 'PLC,', as, noted, previously, for, rat, 'RC', cells, treated, with, 24, 'R,25(OH)(2)D(3)'])].
[sujeto(['These', results]), verbo([provide]), complemento([definitive, evidence, that, there, are, two, distinct, receptors, to, 1, 'alpha,25(OH)(2)D(3)'])].
[sujeto([1, 'alpha,25(OH)(2)D(3)-dependent', regulation, of, 'DNA', synthesis, in, 'GC', cells]), verbo([requires]), complemento([the, 1, ',', 25, -, 'nVDR,', although, other, physiological, responses, to, the, vitamin, 'D', 'metabolite,', such, as, proteoglycan, 'sulfation,', involve, regulation, via, the, 1, ',', 25, -, mVDR])].
[sujeto(['Acute', administration, of, dihydroxycholecalciferol, '[', 1, ',', 25, '(', 'OH)(2)D(3)]', blunts, phosphaturia, and]), verbo([increases]), complemento([urinary, cAMP, excretion, in, parathyroid, hormone, '(', 'PTH)-infused', parathyroidectomized, '(', 'PTX)', rats])].
[sujeto(['Because', chronic, administration, of, 1, ',', 25, '(', 'OH)(2)D(3)']), verbo([enhances]), complemento([the, phosphaturic, response, to, exogenous, parathyroid, hormone, despite, blunting, of, urinary, cAMP, 'excretion,', we, have, examined, the, expression, of, the, renal, cortex, type, 'II', 'Na-P(i)', cotransporter, '(', 'NaPi-2)', mRNA, and, protein, in, 1, ')', chronic, 'PTX', 'Sabra', 'rats,', 2, ')', 'PTX', rats, receiving, a, physiological, dose, of, 1, ',', 25, '(', 'OH)-2-D(3),', 3, ')', 'PTX', rats, receiving, 35, 'ng/h', of, 'PTH,', and, 4, ')', rats, receiving, both, 'PTH', and, 1, ',', 25, '(', 'OH)(2)D(3),', for, 7, days, via, osmotic, minipumps])].
[sujeto(['Our', results, confirm, that, there, is]), verbo([increased]), complemento([phosphaturia, in, the, 'PTH+1,25(OH)(2)D(3)-infused', animals, despite, blunting, of, urinary, cAMP, 'excretion,', a, reduced, filtered, load, of, 'phosphate,', and, lack, of, a, phosphaturic, effect, by, 1, ',', 25, '(', 'OH)(2)D(3)', alone])].
[sujeto(['Both', 'PTH', and, 1, ',', 25, '(', 'OH)(2)D(3)', significantly, reduced, expression, of, renal, cortex, 'NaPi-2', mRNA, and, 'NaPi-2', 'protein,', and, the, administration, of, 'PTH', together, with, 1, ',', 25, '(', 'OH)(2)D(3)', had, additive, effects, in, further]), verbo([decreasing]), complemento(['NaPi-2', mRNA, and, 'NaPi-2', protein, levels])].
[sujeto(['Expression', of, two, other, epithelial, 'transporters,', type, 1, 'Na-sulfate', and, type, 1, 'Na-glucose', 'cotransporters,', were, not, different, between, the, 'groups,']), verbo([suggesting]), complemento([specificity, of, the, effects, of, 'PTH', and, 1, ',', 25, '(', 'OH)(2)D(3)', on, phosphate, transport])].
[sujeto(['The', effect, of, chronic, administration, of, 1, ',', 25, '(', 'OH)(2)D(3)']), verbo([has]), complemento([not, been, noted, 'previously,', and, the, cellular, mechanisms, and, signaling, processes, that, mediate, the, decrease, in, 'NaPi-2', remain, to, be, determined])].
[sujeto(['Topical', treatment, of, normal, skin, with, 1, ',', 25, -, dihydroxyvitamin, 'D3', '[', 1, ',', 25, -, '(', 'OH)2D3]', or, its, synthetic, analogs, results, in]), verbo([enhanced]), complemento([keratinocyte, proliferation])].
[sujeto([1, ',', 25, -, '(', 'OH)2D3']), verbo([enhanced]), complemento([the, autonomous, proliferation, of, 'HaCaT', human, keratinocytes, in, the, absence, of, exogenous, growth, factors])].
[sujeto(['Autonomous', and, 1, ',', 25, -, '(', 'OH)2D3-stimulated', proliferations, were]), verbo([inhibited]), complemento([by, a, specific, inhibitor, of, 'EGF', receptor, '(', 'EGFR)', tyrosine, 'kinase,', an, 'EGFR-neutralizing', 'antibody,', 'heparin,', the, heparin, antagonist, 'hexadimethrine,', and, the, proteoglycan, sulfation, inhibitor, chlorate])].
[sujeto([1, ',', 25, -, '(', 'OH)2D3']), verbo([caused]), complemento([a, marked, increase, in, the, cellular, contents, of, 'ErbB1,', 'ErbB2,', and, 'ErbB3', proteins])].
[sujeto(['The']), verbo([increase]), complemento([in, 'ErbB', proteins, that, mediates, signal, transduction, by, 'EGFR', ligands, can, account, for, the, stimulatory, effect, of, 1, ',', 25, -, '(', 'OH)2D3', on, autonomous, keratinocyte, proliferation])].
[sujeto(['The', human, 1, ',', 25, -, dihydroxyvitamin, 'D3', receptor, '(', 'hVDR)']), verbo([has]), complemento([been, recently, shown, to, be, phosphorylated, in, vitro, by, casein, 'kinase-II'])].
[sujeto(['Most', of, the, residues]), verbo([phosphorylated]), complemento([by, this, enzyme, were, shown, to, reside, between, 'Asn160', and, 'Asp232,', a, region, near, the, 'N-terminal', boundary, of, the, 'hormone-binding', domain])].
[sujeto(['We']), verbo([report]), complemento([here, that, the, hVDR, is, also, phosphorylated, in, vivo, after, transfection, into, 'ROS', 17, /, 2.8, cells])].
[sujeto(['Therefore,', we]), verbo([have]), complemento([localized, the, major, site, of, phosphorylation, of, hVDR, to, residues, in, the, 'N-terminal', region, of, the, 'hormone-binding', domain])].
[sujeto(['The', boundaries, of, this, region, fall, within, the, amino, acid, segment, defined, for, phosphorylation, of, hVDR, by, casein, 'kinase-II', in, 'vitro,']), verbo([suggesting]), complemento([that, 'VDR', is, an, in, vivo, substrate, for, casein, 'kinase-II', or, a, related, protein, kinase])].
[sujeto(['It']), verbo([has]), complemento([been, reported, that, serum, 1, ',', 25, '(', 'OH)2D3', were, lower, in, 'ITP', patients])].
[sujeto(['We']), verbo([found]), complemento([that, 1, ',', 25, '(', 'OH)2D3/VDR', levels, were, decreased, in, active, 'ITP', 'patients,', and, 1, ',', 25, '(', 'OH)2D3', had, significant, 'anti-inflammatory', effects, on, 'ITP', 'patients,', including, both, 'anti-proliferation', of, peripheral, blood, mononuclear, cells, '(', 'PBMCs)', and, reversing, the, abnormal, 'T', cells, polarization])].
[sujeto([1, ',', 25, '(', 'OH)2D3']), verbo([inhibited]), complemento([the, differentiation, of, 'T', helper, '(', 'Th)1', and, 'Tc1', cells, but, induced, the, differentiation, of, 'Th2,', 'Tc2', and, 'T', regulatory, '(', 'Treg)', cells, in, 'ITP', patients])].
[sujeto(['In', 'addition,', 1, ',', 25, '(', 'OH)2D3', also]), verbo([suppressed]), complemento(['pro-inflammatory', cytokines, '(', 'INF-γ', and, 'IL-17A)', but, promoted, 'anti-inflammatory', cytokine, '(', 'IL-10)', secretion, in, 'ITP', patients])].
[sujeto(['In', 'conclusion,']), verbo([decreased]), complemento([1, ',', 25, '(', 'OH)2D3/VDR', might, participate, in, the, pathogenesis, of, 'ITP,', and, appropriate, supplement, of, 1, ',', 25, '(', 'OH)2D3', may, be, a, promising, treatment])].
[sujeto(['CCCTC-binding', factor, '(', 'CTCF)', is, a, transcription, factor, being]), verbo([involved]), complemento([in, 3, 'D', chromatin, organization, and, displays, a, highly, conserved, 'genome-wide', binding, pattern])].
[sujeto(['In', this, 'study,', we]), verbo([report]), complemento([the, cistrome, of, 'CTCF', in, 'THP-1', human, monocytes, and, confirm, that, from, the, 40, ',', 78, 'CTCF', binding, sites, nearly, 85, '%', are, identical, with, those, found, in, 'K562', monocytes])].
[sujeto([5, ')']), verbo([modulated]), complemento([by, stimulation, with, the, natural, vitamin, 'D', receptor, '(', 'VDR)', ligand, 1, 'α,25-dihydroxyvitamin', 'D3', '(', 1, ',', 25, '(', 'OH)2D3)'])].
[sujeto(['Some', 55, '%', of, these, 'CTCF', sites, contribute, to, 'DNA', looping, and, mark, the, anchors, of, 587, putative, topologically]), verbo([associating]), complemento([domains, '(', 'TADs)', containing, at, least, one, 'VDR', binding, site, and, one, 1, ',', 25, '(', 'OH)2D3', target, gene])].
[sujeto(['These', 'TADs', can, explain, the, regulatory, scenarios, of, up, to, 70, '%', of, all, 1, ',', 25, '(', 'OH)2D3']), verbo([target]), complemento([genes])].
[sujeto(['A', 'self-organizing', map, approach, subdivided, the, vitamin, 'D-sensitive', 'CTCF', sites, into, seven, classes, that, can, be, distinguished, by, participation, in, 'DNA', loop, 'formation,']), verbo([binding]), complemento([to, open, 'chromatin,', carrying, binding, motifs, for, 'CTCF', or, its, relative, 'BORIS,', overlap, with, transcription, start, site, '(', 'TSS)', regions, and, binding, of, 'VDR'])].
[sujeto(['These', variant, molecular, profiles]), verbo([suggest]), complemento([different, mechanisms, of, the, 1, ',', 25, '(', 'OH)2D3-dependent', action, of, 'CTCF'])].
[sujeto(['The', 'co-location', of, 'VDR', and, 1, ',', 25, '(', 'OH)2D3-dependent', 'CTCF', sites]), verbo([increases]), complemento([in, the, context, of, accessible, chromatin, and, 'TSS', regions, but, does, not, show, any, significant, correlation, with, classical, 'DNA', binding, mechanisms, of, 'CTCF'])].
[sujeto(['In', 'conclusion,', vitamin, 'D-sensitive', 'CTCF', sites]), verbo([provide]), complemento([further, mechanistic, details, to, the, 'epigenome-wide', understanding, of, 1, ',', 25, '(', 'OH)2D3-mediated', gene, regulation])].
[sujeto(['The', regulation, of, transcellular, calcium, transport, by, 1, ',', 25, -, dihydroxyvitamin, 'D3', '(', 1, ',', 25, -, '(', 'OH)2D3,', the, active, form, of, vitamin, 'D)']), verbo([has]), complemento([been, confirmed, in, humans, and, 'rodents,', and, 'regulators,', including, vitamin, 'D', receptor, '(', 'VDR),', calcium, binding, protein, 'D9k', '(', 'calbindin-D9k),', plasma, membrane, 'Ca(2+)-ATPase', 1, b, '(', 'PMCA1b),', 'PMAC2b', and, 'Orai1,', are, involved, in, this, process])].
[sujeto(['However,', it, is, still, unclear, whether, 1, ',', 25, -, '(', 'OH)2D3', could]), verbo([stimulate]), complemento([calcium, transport, in, the, ruminant, mammary, gland])].
[sujeto(['Cell', proliferation, 'ratios,', glucose, consumption, and, enzyme, activities, were, measured, with, commercial, 'kits,', and, 'real-time', quantitative, polymerase, chain, reaction, '(', 'RT-qPCR),', and, western, blots, were, used, to, determine, the, expression, of, genes, and, proteins]), verbo([associated]), complemento([with, mammary, calcium, transport, in, dairy, 'goats,', respectively])].
[sujeto([1, ',', 25, -, '(', 'OH)2D3']), verbo([promoted]), complemento([cell, proliferation, and, the, expression, of, genes, involved, in, calcium, transport, in, a, 'dose-dependent', manner, when, the, concentration, did, not, exceed, 10.0, &, 'nbsp;nmol/L'])].
[sujeto(['In', 'addition,', 100.0, &, 'nbsp;nmol/L', 1, ',', 25, -, '(', 'OH)2D3']), verbo([inhibited]), complemento([cell, proliferation, and, the, expression, of, associated, genes, compared, with, the, 10.0, &, 'nbsp;nmol/L', treatment])].
[sujeto(['The', inhibition, of, hexokinase, 2, '(', 'HK2),', a, 'rate-limiting', enzyme, in, glucose, 'metabolism,']), verbo([decreased]), complemento([the, expression, of, 'PMCA1b', and, 'PMCA2b', at, the, mRNA, and, protein, levels, as, well, as, the, transcription, of, 'Orai1,', indicating, that, glucose, availability, was, required, for, goat, mammary, calcium, transport])].
[sujeto(['Supplementation', with, 1, ',', 25, -, '(', 'OH)2D3', influenced, cell, proliferation, and]), verbo([regulated]), complemento([the, expression, of, calcium, transport, modulators, in, a, 'dose-', and, 'energy-dependent', 'manner,', thereby, highlighting, the, role, of, 1, ',', 25, -, '(', 'OH)2D3', as, an, efficacious, regulatory, agent, that, produces, 'calcium-enriched', milk, in, ruminants, when, a, suitable, energy, status, was, guaranteed])].
[sujeto(['While', up, to, 10, -, 20, &, 'nbsp;%', of, the, human, 'organism\'s', requirements, in, vitamin, 'D', can, be, obtained, by, the, diet, '(', under, most, living, conditions, in, the, 'USA', and, 'Europe),', approximately, 90, &, 'nbsp;%', of, all, needed, vitamin, 'D']), verbo([has]), complemento([to, be, photosynthesized, in, the, skin, through, the, action, of, the, sun, '(', 'ultraviolet-B', '(', 'UV-B))'])].
[sujeto(['The', skin, represents, a, key, organ, of, the, human, 'body\'s', vitamin, 'D', endocrine, system, '(', 'VDES),', being, both, the, site, of, vitamin, 'D', synthesis, and, a]), verbo([target]), complemento([tissue, for, biologically, active, vitamin, 'D', metabolites])].
[sujeto(['Many', skin, cells, '(', including, 'keratinocytes,', 'sebocytes,', 'fibroblasts,', 'melanocytes,', and, skin, immune, 'cells)']), verbo([express]), complemento([the, vitamin, 'D', receptor, '(', 'VDR),', an, absolute, 'pre-requisite', for, the, mediation, of, genomic, effects, of, 1, ',', 25, '(', 'OH)2D3', and, analogs])].
[sujeto(['Numerous', 'studies,', including, cDNA, microarray, analyses, of, messenger, 'RNAs', '(', 'mRNAs),', indicate, that, as, many, as, 500, -, 1000, genes, may, be]), verbo([regulated]), complemento([by, 'VDR', ligands, that, control, various, cellular, functions, including, 'growth,', 'differentiation,', and, apoptosis])].
[sujeto(['The', observation, that, 1, ',', 25, '(', 'OH)2D3', is, extremely, effective, in]), verbo([inducing]), complemento([the, terminal, differentiation, and, in, inhibiting, the, proliferation, of, cultured, human, keratinocytes, has, resulted, in, the, use, of, vitamin, 'D', analogs, for, the, treatment, of, psoriasis])].
[sujeto(['Vitamin', 'D', receptor, '(', 'VDR)', genetic, polymorphisms, are, considered, to, be]), verbo([associated]), complemento([with, type, 2, diabetes, mellitus, '(', 'T2DM),', but, this, is, inconclusive])].
[sujeto(['The', subgroup, analysis, showed, that, this, association, was, only]), verbo([found]), complemento([in, the, studies, with, a, small, sample, size, '(', &, 'lt;200)'])].
[sujeto(['Deficiency', in, methyl, donor, '(', folate, and, vitamin, 'B12)', and, in, vitamin, 'D', is, independently]), verbo([associated]), complemento([with, altered, bone, development])].
[sujeto(['Previously,', methyl, donor, deficiency, '(', 'MDD)', was, shown, to, weaken, the, activity, of]), verbo([nuclear]), complemento([receptor, 'coactivator,', peroxisome, 'proliferator-activated', 'receptor-γ', 'coactivator-1α', '(', 'PGC1α),', for, nuclear, signaling, in, rat, 'pups,', including, estrogen, 'receptor-α', and, 'estrogen-related', 'receptor-α;', its, effect, on, vitamin, 'D', receptor, '(', 'VDR)', 'signaling,', 'however,', is, unknown])].
[sujeto(['We', studied, bone, development, under, 'MDD', in, rat, pups, and, used, human, 'MG-63', preosteoblast, cells, to, better, understand, the]), verbo([associated]), complemento([molecular, mechanism])].
[sujeto(['In', young, 'rats,', 'MDD']), verbo([decreased]), complemento([total, body, bone, mineral, 'density,', reduced, tibia, 'length,', and, impaired, growth, plate, 'maturation,', and, in, 'preosteoblasts,', 'MDD', slowed, cellular, proliferation])].
[sujeto(['Mechanistic', studies, revealed]), verbo([decreased]), complemento([expression, of, 'VDR,', estrogen, 'receptor-α,', 'PGC1α,', arginine, methyltransferase, 1, ',', and, sirtuin, 1, in, both, rat, proximal, diaphysis, of, femur, and, in, 'MG-63,', as, well, as, decreased, nuclear, 'VDR-PGC1α', interaction, in, 'MG-63', cells])].
[sujeto(['The', weaker, 'VDR-PGC1α', interaction, could, be, attributed, to, the, reduced, protein, 'expression,', imbalanced, 'PGC1α', 'methylation/acetylation,', and]), verbo([nuclear]), complemento(['VDR', sequestration, by, heat, shock, protein, 90, '(', 'HSP90)'])].
[sujeto(['These', together, compromised, bone, 'development,', which, is, reflected, by, lowered, bone, alkaline, phosphatase, and]), verbo([increased]), complemento([proadipogenic, peroxisome, 'proliferator-activated', 'receptor-γ,', 'adiponectin,', and, 'estrogen-related', 'receptor-α', expression])].
[sujeto(['In', 'conclusion,', 'MDD', inactivates, vitamin, 'D', signaling, via, both, disruption, of, 'VDR-PGC1α', interaction, and, sequestration, of]), verbo([nuclear]), complemento(['VDR', attributable, to, 'HSP90', overexpression])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, vitamin, 'D', treatment, may, be, ineffective, under, 'MDD'])].
[sujeto(['This', disorder, is]), verbo([caused]), complemento([by, homogeneous, or, heterogeneous, mutations, affecting, the, function, of, the, vitamin, 'D', receptor, '(', 'VDR),', which, lead, to, complete, or, partial, target, organ, resistance, to, the, action, of, 1, ',', 25, -, dihydroxy, vitamin, 'D'])].
[sujeto(['Both', parents, had, a, normal, phenotype, and, were]), verbo([found]), complemento([to, be, heterozygous, for, this, mutation])].
[sujeto(['We']), verbo([report]), complemento([a, 'Chinese', 'Han', family, with, one, individual, affected, with, 'HVDRR'])].
[sujeto(['C41Y)', in, the, 'VDR', gene, was]), verbo([found]), complemento([to, be, responsible, for, the, 'patient\'s', syndrome])].
[sujeto(['In', contrast, to, the, results, of, treatment, of, 'HVDRR', in, other, 'patients,', our, patient]), verbo([responded]), complemento([well, to, a, supplement, of, oral, calcium, and, a, low, dose, of, calcitriol])].
[sujeto(['The', primary, function, of, vitamin, 'D', is, to]), verbo([regulate]), complemento([calcium, 'homeostasis,', which, is, essential, for, bone, formation, and, resorption])].
[sujeto(['Vitamin', 'D', is, also, manufactured, in, the, skin, through, a, photolysis, 'process,']), verbo([leading]), complemento([to, a, process, called, the, &, 'quot;sunshine', vitamin])].
[sujeto(['It']), verbo([has]), complemento([been, found, that, several, immune, cells, express, the, vitamin, 'D', receptor, '(', 'VDR)', and, 'CYP27B1;', of, the, 'latter,', synthesis, is, determined, by, several, 'immune-specific', signals])].
[sujeto(['The', realisation, that, vitamin, 'D', employs, several, molecular, mechanisms, to]), verbo([regulate]), complemento([innate, immune, responses, is, more, recent])].
[sujeto(['This', review, considers, the, current, knowledge, of, how, immune, signals]), verbo([regulate]), complemento([vitamin, 'D', metabolism, and, how, innate, immune, system, function, is, modulated, by, 'ligand-bound', 'VDR'])].
[sujeto(['The', 'VDR', gene, polymorphisms, appeared, to, be]), verbo([associated]), complemento([with, 'HOMA', index, in, prediabetes])].
[sujeto(['Low', concentrations, of, vitamin, 'D3', are]), verbo([associated]), complemento([with, 'AAA', 'development;', 'however,', the, potential, direct, effect, of, vitamin, 'D3', on, 'AAA', remains, unknown])].
[sujeto(['This', study, evaluates, the, effect, of, oral, treatment, with, the, vitamin, 'D3', receptor, '(', 'VDR)', 'ligand,', 'calcitriol,', on, dissecting, 'AAA']), verbo([induced]), complemento([by, 'angiotensin-II', '(', 'Ang-II)', infusion, in, 'apoE(-/-)', mice])].
[sujeto(['Immunohistochemistry', and, 'reverse-transcription', polymerase, chain, reaction, analysis, demonstrated, a, significant]), verbo([increase]), complemento([in, macrophage, 'infiltration,', neovessel, 'formation,', matrix, 'metalloproteinase-2', and, matrix, 'metalloproteinase-9,', chemokine, '(', 'CCL2', '[', '(', 'C-C', 'motif)', ligand, 2, ']', ',', 'CCL5', '[', '(', 'C-C', 'motif)', ligand, 5, ']', ',', and, 'CXCL1', '[', '(', 'C-X-C', 'motif)', ligand, 1, ']', ')', and, vascular, endothelial, growth, factor, expression, in, suprarenal, aortic, walls, of, 'apoE(-/-)', mice, infused, with, 'Ang-II,', and, all, were, significantly, reduced, by, cotreatment, with, calcitriol])].
[sujeto(['Phosphorylation', of, extracellular, 'signal-regulated', kinases, 1, /, 2, ',', p38, 'mitogen-activated', protein, 'kinase,', and]), verbo([nuclear]), complemento(['factor-κB', was, also, decreased, in, the, suprarenal, aortas, of, 'apoE(-/-)', mice, cotreated, with, calcitriol])].
[sujeto(['These', effects, were, accompanied, by, a, marked]), verbo([increase]), complemento([in, 'VDR-retinoid', 'X', receptor, '(', 'RXR)', interaction, in, the, aortas, of, 'calcitriol-treated', mice])].
[sujeto(['In', 'vitro,', 'VDR', activation, by, calcitriol, in, human, endothelial, cells]), verbo([inhibited]), complemento(['Ang-II-induced', 'leukocyte-endothelial', cell, 'interactions,', 'morphogenesis,', and, production, of, endothelial, proinflammatory, and, angiogenic, chemokines, through, 'VDR-RXR', 'interactions,', and, knockdown, of, 'VDR', or, 'RXR', abolished, the, inhibitory, effects, of, calcitriol])].
[sujeto(['VDR', activation, reduces, dissecting, 'AAA', formation]), verbo([induced]), complemento([by, 'Ang-II', in, 'apoE(-/-)', mice, and, may, constitute, a, novel, therapeutic, strategy, to, prevent, 'AAA', progression])].
[sujeto(['Fibromyalgia', '(', 'FM)', is, a, chronic, syndrome, with, an]), verbo([increasing]), complemento(['prevalence,', characterized, by, widespread, musculoskeletal, pain, in, combination, with, a, variety, of, cognitive, symptoms, and, fatigue])].
[sujeto(['A', plethora, of, scientific, evidence, that]), verbo([has]), complemento([accumulated, during, the, last, 'decades,', resulted, in, a, significant, improvement, of, the, understanding, of, the, pathophysiology, of, the, disease])].
[sujeto(['Vitamin', 'D,', a, 'fat-soluble', vitamin, derived, mainly, from, skin, synthesis, through, ultraviolet, 'radiation,']), verbo([has]), complemento([been, recognized, to, manifest, a, plethora, of, extraskeletal, 'actions,', apart, from, its, fundamental, role, in, skeletal, and, calcium, 'homeostasis,', including, modulation, of, cell, 'growth,', neuromuscular, 'actions,', and, potential, 'anti-inflammatory', properties])].
[sujeto(['Vitamin', 'D', receptor, gene, 'Bsm', 'I', polymorphism, may, be]), verbo([associated]), complemento([with, the, therapeutic, response, to, antiviral, therapy, with, pegylated, interferon, plus, ribavirin, in, chronic, hepatitis, 'C', patients])].
[sujeto(['In', many, cells, throughout, the, 'body,', vitamin, 'D', is, converted, into, its, active, form, calcitriol, and]), verbo([binds]), complemento([to, the, vitamin, 'D', receptor, '(', 'VDR),', which, functions, as, a, transcription, factor, to, regulate, various, biological, processes, including, cellular, differentiation, and, immune, response])].
[sujeto(['Vitamin', 'D-metabolising', enzymes, '(', including, 'CYP24A1', and, 'CYP27B1)', and, 'VDR', play, major, roles, in, exerting, and]), verbo([regulating]), complemento([the, effects, of, vitamin, 'D'])].
[sujeto(['Preclinical', and, epidemiological, studies]), verbo([have]), complemento([provided, evidence, for, 'anti-cancer', effects, of, vitamin, 'D', '(', particularly, against, colorectal, 'cancer),', although, clinical, trials, have, yet, to, prove, its, benefit])].
[sujeto(['In', 'addition,', molecular, pathological, epidemiology, research, can]), verbo([provide]), complemento([insights, into, the, interaction, of, vitamin, 'D', with, tumour, molecular, and, immunity, status])].
[sujeto(['Several', studies]), verbo([have]), complemento([shown, an, association, between, low, levels, of, vitamin, 'D', and, autoimmune, 'disorders,', including, multiple, 'sclerosis,', rheumatoid, 'arthritis,', type, 1, 'diabetes,', autoimmune, thyroid, 'diseases,', celiac, 'disease,', and, systemic, lupus, erythematosus, '(', 'SLE)'])].
[sujeto(['Vitamin', 'D', receptor, ligands, can]), verbo([mediate]), complemento([immunosuppressive, effects])].
[sujeto(['It']), verbo([has]), complemento([been, suggested, that, low, levels, of, this, hormone, contribute, to, the, immune, activation, in, lupus, and, other, autoimmune, diseases])].
[sujeto(['Although', emerging, evidence]), verbo([suggests]), complemento([that, vitamin, 'D', has, beneficial, effects, in, the, cardiovascular, 'health,', the, underlying, mechanisms, are, far, from, fully, elucidated])].
[sujeto(['We', examined, the, protein, expression, of, 'NRG1,', 'ErbB', receptors, '(', 'ErbB2', and, 'ErbB4)', and, their]), verbo([phosphorylated]), complemento([forms, in, the, myocardium, of, rats, following, 6, -, week, administration, of, calcitriol, '(', 50, 'ng/kg/day', or, 100, 'ng/kg/day)'])].
[sujeto(['Generally,', calcitriol]), verbo([enhanced]), complemento([myocardial, 'VDR', expression, and, 'NRG1/ErbB', signaling])].
[sujeto(['Calcitriol']), verbo([increased]), complemento(['NRG1', protein, level, at, the, higher, 'dose,', while, both, doses, promoted, 'ErbB2', and, phosphorylated, 'ErbB2', expression])].
[sujeto(['Although', calcitriol]), verbo([has]), complemento([no, significant, influence, on, 'ErbB4', 'expression,', phosphorylated, 'ErbB4', receptors, were, enhanced, at, the, higher, dose])].
[sujeto(['Furthermore,', the, serum, 'neuregulin-1', concentration, was]), verbo([increased]), complemento([at, both, doses])].
[sujeto(['Overall,', our, data, firstly, showed, that, chronic, calcitriol, administration]), verbo([enhanced]), complemento(['NRG1/ErbB', signaling, in, the, 'heart,', indicating, a, novel, mechanism, underlying, the, cardiac, effects, of, vitamin, 'D'])].
[sujeto(['Chronic', hepatitis, 'C', infection, is, a, major]), verbo([cause]), complemento([of, 'end-stage', liver, disease])].
[sujeto(['A', total, of, 155, chronic, hepatitis, 'C', patients, were]), verbo([recruited]), complemento([from, the, 'Swiss', 'Hepatitis', 'C', 'Cohort', 'Study', for, 'NR1I1', genotyping, and, plasma, 25, -, 'OH', vitamin, 'D', level, measurement])].
[sujeto(['Decreased', vitamin, 'D', levels]), verbo([have]), complemento([been, described, in, various, forms, of, chronic, liver, disease, and, associated, with, advanced, fibrosis])].
[sujeto(['Whether', this, association, is, a]), verbo([cause]), complemento([or, consequence, of, advanced, fibrosis, remains, unclear, to, date])].
[sujeto(['The', 'VDR', haplotype, and, genotypes, as, well, as, plasma, 25, -, 'OH', vitamin, 'D', levels, were]), verbo([associated]), complemento([with, fibrosis, progression])].
[sujeto(['The', 'bAt[CCA]-haplotype', was, significantly]), verbo([associated]), complemento([with, fibrosis, progression, &, 'gt;0'])].
[sujeto(['Likewise,', 'ApaI', rs7975232, 'CC', genotype, was, significantly]), verbo([associated]), complemento([with, fibrosis, progression, and, cirrhosis])].
[sujeto(['Lower', plasma, 25, -, 'OH', vitamin, 'D', levels, were, significantly]), verbo([associated]), complemento([with, fibrosis, progression, &, 'gt;0'])].
[sujeto(['Low', 25, -, 'OH', vitamin, 'D', plasma, levels, and, the, unfavourable, 'VDR', 'bAt[CCA]-haplotype', are]), verbo([associated]), complemento([with, rapid, fibrosis, progression, in, chronic, 'HCV', patients])].
[sujeto(['In', 'non-malignant', 'RWPE-1', prostate, epithelial, cells, signaling, by, the]), verbo([nuclear]), complemento([receptor, 'Vitamin', 'D', 'Receptor', '(', 'VDR,', 'NR1I1)', induces, cell, cycle, arrest, through, targets, including, 'CDKN1A', '(', encodes, 'p21((waf1/cip1)))'])].
[sujeto(['VDR', dynamically]), verbo([induced]), complemento([individual, histone, modification, patterns, at, three, 'VDR', binding, sites, '(', 'R1,', 2, ',', 3, ')', on, the, 'CDKN1A', promoter])].
[sujeto(['The', epigenetic, events, appeared, to, allow, 'VDR', actions, to, combine, with, p53, to]), verbo([enhance]), complemento(['p21((waf1/cip1))', activation, further])].
[sujeto(['In', 'parallel,', 'VDR']), verbo([binding]), complemento([to, the, 'MCM7', gene, induced, 'H3K9ac', enrichment, associated, with, rapid, mRNA, 'up-regulation', to, generate, 'miR-106b', and, consequently, regulate, 'p21((waf1/cip1))', expression])].
[sujeto(['We', conclude, that, 'VDR']), verbo([binding]), complemento(['site-', and, 'promoter-specific', patterns, of, histone, modifications, combine, with, miRNA, 'co-regulation', to, form, a, 'VDR-regulated', 'feed-forward', loop, to, control, 'p21((waf1/cip1))', expression, and, cell, cycle, arrest])].
[sujeto(['Nuclear', hormone, receptors, '(', 'NHRs)', are, transcription, factors, that, work, in, concert, with, 'co-activators', and, 'co-repressors', to]), verbo([regulate]), complemento([gene, expression])].
[sujeto(['These', 'NHRs']), verbo([participate]), complemento([in, 'complex,', overlapping, transcriptional, regulation, networks, involving, cholesterol, homeostasis, and, energy, metabolism])].
[sujeto(['Some', of, these, 'receptors,', particularly, 'PXR', and, 'CAR,', are, promiscuous, with, respect, to, the, structurally, wide, range, of, ligands, that]), verbo([act]), complemento([as, agonists])].
[sujeto(['A', combination, of, functional, and, computational, analyses]), verbo([has]), complemento([shed, light, on, the, evolutionary, changes, of, 'NR1H', and, 'NR1I', receptors, across, 'vertebrates,', and, how, these, receptors, may, have, diverged, from, ancestral, receptors, that, first, appeared, in, invertebrates])].
[sujeto([1, 'alpha,25-dihydroxyvitamin', 'D(3)', '(', 1, 'alpha,25(OH)(2)D(3)),', the, active, metabolite, of, vitamin, 'D,']), verbo([mediates]), complemento([many, of, its, effects, through, the, intranuclear, vitamin, 'D', receptor, '(', 'VDR,', 'NR1I1),', that, belongs, to, the, large, superfamily, of, nuclear, receptors])].
[sujeto(['Vitamin', 'D', receptor, can, directly]), verbo([regulate]), complemento([gene, expression, by, binding, to, vitamin, 'D', response, elements, '(', 'VDREs)', located, in, promoter, or, enhancer, regions, of, various, genes])].
[sujeto(['Although', numerous, synthetic, analogs, of, 1, 'alpha,25(OH)(2)D(3)']), verbo([have]), complemento([been, analysed, for, 'VDR', binding, and, transactivation, of, 'VDRE-driven', gene, 'expression,', the, biologic, activity, of, many, naturally, occurring, metabolites, has, not, yet, been, analyzed, in, detail])].
[sujeto(['The', metabolites, that, were, active, in, the, reporter, gene, assay, also]), verbo([induced]), complemento([expression, of, 'CYP24', mRNA, in, the, human, keratinocyte, cell, line, 'HaCaT,', although, with, less, potency, than, the, parent, hormone])].
[sujeto(['A', 'ligand-binding', assay, based, on]), verbo([nuclear]), complemento([extracts, from, 'COS-1', cells, overexpressing, human, 'VDR', demonstrated, that, the, 'metabolites,', although, active, in, the, reporter, gene, 'assay,', were, much, less, effective, in, displacing, '[', '(', 3, ')', 'H]-labeled', 1, 'alpha,25(OH)(2)D(3)', from, 'VDR', than, the, parent, hormone])].
[sujeto(['Thus,', we]), verbo([report]), complemento([that, several, natural, metabolites, of, 1, 'alpha,25(OH)(2)D(3)', retain, significant, biologic, activity, mediated, through, 'VDR', despite, their, apparent, low, affinity, for, 'VDR'])].
[sujeto(['Although', transcriptional, regulation, of, 'CYP3A4', is, known, to, be, tightly, controlled, by, some]), verbo([nuclear]), complemento([receptors, '(', 'NR)', including, vitamin, 'D', receptor, '(', 'VDR/NR1I1),', posttranscriptional, regulation, of, 'CYP3A4', remains, elusive])].
[sujeto(['In', this, 'study,', we, show, that, noncoding, microRNAs, '(', 'miRNAs)', may, control, posttranscriptional, and, transcriptional, regulation, of, 'CYP3A4', by, directly]), verbo([targeting]), complemento([the, 3, '\'', -, untranslated, region, '(', 3, '\'', 'UTR)', of, 'CYP3A4', and, indirectly, targeting, the, 3, '\'', 'UTR', of, 'VDR,', respectively])].
[sujeto(['Luciferase', reporter, assays, showed, that, 'CYP3A4', 3, '\'', 'UTR-luciferase', activity, was, significantly]), verbo([decreased]), complemento([in, human, embryonic, kidney, 293, cells, transfected, with, plasmid, that, expressed, 'microRNA-27b', '(', 'miR-27b)', or, mouse, 'microRNA-298', '(', 'mmu-miR-298),', whereas, the, activity, was, unchanged, in, cells, transfected, with, plasmid, that, expressed, 'microRNA-122a', or, 'microRNA-328'])].
[sujeto(['Disruption', of, the, corresponding, miRNA, response, element, '(', 'MRE)', within, 'CYP3A4', 3, '\'', 'UTR']), verbo([led]), complemento([to, a, 2, -, to, 3, -, fold, increase, in, luciferase, activity])].
[sujeto(['The']), verbo([decrease]), complemento([in, 'CYP3A4', protein, expression, was, associated, with, significantly, decreased, 'CYP3A4', mRNA, 'levels,', as, determined, by, quantitative, 'real-time', 'PCR', '(', 'qPCR)', analyses])].
[sujeto(['The', 'mmu-miR-298', 'MRE', site, is, well]), verbo([conserved]), complemento([within, the, 3, '\'', 'UTR', of, 'mouse,', 'rat,', and, human, 'VDR'])].
[sujeto(['Furthermore,', overexpression, of, 'miR-27b', or, 'mmu-miR-298', in, 'PANC1', cells]), verbo([led]), complemento([to, a, lower, sensitivity, to, cyclophosphamide])].
[sujeto(['Together,', these, findings]), verbo([suggest]), complemento([that, 'CYP3A4', gene, expression, may, be, regulated, by, miRNAs, at, both, the, transcriptional, and, posttranscriptional, level])].
[sujeto(['The']), verbo([nuclear]), complemento([hormone, receptor, '(', 'NR)', superfamily, complement, in, humans, is, composed, of, 48, genes, with, diverse, roles, in, metabolic, 'homeostasis,', 'development,', and, detoxification])].
[sujeto(['In', 'general,', 'NRs', are, strongly]), verbo([conserved]), complemento([between, vertebrate, 'species,', and, few, examples, of, molecular, adaptation, '(', positive, 'selection)', within, this, superfamily, have, been, demonstrated])].
[sujeto(['Previous', studies, utilizing, 'two-species', comparisons]), verbo([reveal]), complemento([strong, purifying, '(', 'negative)', selection, of, most, 'NR', 'genes,', with, two, possible, exceptions, being, the, 'ligand-binding', domains, '(', 'LBDs)', of, the, pregnane, 'X', receptor, '(', 'PXR,', 'NR1I2)', and, the, constitutive, androstane, receptor, '(', 'CAR,', 'NR1I3),', two, proteins, involved, in, the, regulation, of, toxic, compound, metabolism, and, elimination])].
[sujeto(['Additional', functional, data, is, also]), verbo([reported]), complemento([for, activation, of, 'PXR', and, the, vitamin, 'D', receptor, '(', 'VDR;', 'NR1I1)', to, gain, further, insight, into, the, evolution, of, the, 'NR1I', subfamily])].
[sujeto(['CAR', was, also, unusual, in, showing, high, relative, omega, ratios, in, both, the, 'DBD', and, 'LBD,', a]), verbo([finding]), complemento([that, may, relate, to, the, recent, appearance, of, the, 'CAR', gene, '(', presumably, by, duplication, of, a, 'pre-mammalian', 'PXR', 'gene)', just, prior, to, the, evolution, of, mammals])].
[sujeto(['Functional', analyses, of, the, 'NR1I', subfamily, show, that, human, and, zebrafish, 'PXRs', show, similar, activation, by, steroid, hormones, and, early, bile, 'salts,', properties, not, shared, by]), verbo([sea]), complemento(['lamprey,', 'mouse,', or, human, 'VDRs,', or, by, 'Xenopus', laevis, 'PXRs'])].
[sujeto(['The', main, exceptions, are, 'PXR', and, 'CAR,', genes, that, may]), verbo([have]), complemento([adapted, to, 'cross-species', differences, in, toxic, compound, exposure])].
[sujeto(['Chitinase', 3, -, like, 1, ',', otherwise, known, as, 'YKL-40,', is, a, secreted, glycoprotein, purported, to]), verbo([have]), complemento([a, role, in, extracellular, matrix, metabolism])].
[sujeto(['The', first, mammalian, cell, type]), verbo([found]), complemento([to, express, 'YKL-40', was, the, human, 'osteosarcoma-derived', 'osteoblast,', 'MG63'])].
[sujeto(['In', that, first, study, the, active, vitamin, 'D3', 'metabolite,', 1, ',', 25, -, dihydroxycholecalciferol, '(', 1, ',', 25, 'D),']), verbo([stimulated]), complemento(['YKL-40', 'expression,', thereby, indicating, that, a, vital, factor, for, skeletal, health, promoted, 'YKL-40', synthesis, by, bone, forming, cells])].
[sujeto(['Given', that, 1, ',', 25, 'D', is, now, known, to, 'co-operate', with, selected, growth, 'factors,', including, 'LPA,', to, influence, human, osteoblast, differentiation, we, hypothesised, that, 1, ',', 25, 'D', and, 'LPA', may, work, together, to]), verbo([stimulate]), complemento([osteoblast, 'YKL-40', expression])].
[sujeto(['Herein', we]), verbo([report]), complemento([that, 1, ',', 25, 'D', and, 'LPA', synergistically, promote, 'YKL-40', expression, by, 'MG63&nbsp;cells'])].
[sujeto(['Inhibitors']), verbo([targeting]), complemento(['AP1,', 'MEK,', 'Sp1', and, 'STAT3', blunted, the, expression, of, both, alkaline, phosphatase, and, 'YKL-40', by, 'MG63&nbsp;cells', in, response, to, 'co-stimulation', with, 1, ',', 25, 'D', and, 'LPA'])].
[sujeto(['Circulating', levels, of, fibroblast, growth, factor, 23, '(', 'FGF23)']), verbo([increase]), complemento([during, the, early, stages, of, kidney, 'disease,', but, the, underlying, mechanism, remains, incompletely, characterized])].
[sujeto(['We', investigated, the, role, of, vitamin, 'D', metabolites, in]), verbo([regulating]), complemento([intact, 'FGF23', production, in, genetically, modified, mice, without, and, with, 'adenine-induced', uremia])].
[sujeto(['Exogenous', calcitriol, '(', 1, ',', 25, -, dihydroxyvitamin, 'D)', and, high, circulating, levels, of, calcidiol, '(', 25, -, hydroxyvitamin, 'D)', each]), verbo([increased]), complemento([serum, 'FGF23', levels, in, 'wild-type', mice, and, in, mice, with, global, deficiency, of, the, 'Cyp27b1', gene, encoding, 25, -, hydroxyvitamin, 'D', 1, -, 'α-hydroxylase,', which, produces, 1, ',', 25, -, hydroxyvitamin, 'D'])].
[sujeto(['Compared', with, 'wild-type', 'mice,', 'normal,', or, uremic, mice, lacking, 'Cyp27b1', had, lower, levels, of, serum, 'FGF23,', despite, having, high, concentrations, of, parathyroid, 'hormone,', but, administration, of, exogenous, 1, ',', 25, -, dihydroxyvitamin, 'D']), verbo([increased]), complemento(['FGF23', levels])].
[sujeto(['Furthermore,', raising, serum, calcium, levels, in, 'Cyp27b1-depleted', mice, directly]), verbo([increased]), complemento(['FGF23', levels, and, indirectly, enhanced, the, action, of, ambient, vitamin, 'D', metabolites, via, the, vitamin, 'D', receptor])].
[sujeto(['In', chromatin, immunoprecipitation, 'assays,', 25, -, hydroxyvitamin, 'D']), verbo([promoted]), complemento([binding, of, the, vitamin, 'D', receptor, and, retinoid, 'X', receptor, to, the, promoters, of, osteoblastic, target, genes])].
[sujeto(['Conditional', osteoblastic, deletion, of, 'Cyp27b1']), verbo([caused]), complemento([lower, serum, 'FGF23', 'levels,', despite, normal, circulating, levels, of, vitamin, 'D', metabolites])].
[sujeto(['In', 'adenine-induced', 'uremia,', only, a, modest]), verbo([increase]), complemento([in, serum, 'FGF23', levels, occurred, in, mice, with, osteoblastic, deletion, of, 'Cyp27b1', '(', 12, -, 'fold)', compared, with, a, large, increase, '(', 58, -, 'fold)', in, 'wild-type', mice])].
[sujeto(['Although', the, 'anti-HIV-1', effects, of, 'Vitamin', 'D', '(', 'VitD)']), verbo([have]), complemento([been, 'reported,', mechanisms, behind, such, protection, remain, largely, unexplored])].
[sujeto(['We', quantified, levels, of]), verbo([released]), complemento([p24, by, 'ELISA,', of, intracellular, p24, and, 'cell-surface', expression, of, 'CD38', and, 'HLA-DR', by, flow, 'cytometry,', and, mRNA, expression, of, antiviral, and, immunoregulatory, genes, by, 'qRT-PCR'])].
[sujeto(['Calcitriol']), verbo([decreased]), complemento([the, frequency, of, 'HIV-1-infected', p24CD4, 'T-cells', and, levels, of, p24, in, supernatants, in, a, 'dose-dependent', manner])].
[sujeto(['Moreover,', the, 'CD4CD38HLA-DR', and, 'CD4CD38HLA-DR', subpopulations, were, more, susceptible, to, 'infection,', but, displayed, the, greatest, 'calcitriol-induced']), verbo([decreases]), complemento([in, infection, rate, by, an, 'X4-tropic', strain])].
[sujeto(['Likewise,', calcitriol, at, its, highest, concentration]), verbo([decreased]), complemento([the, frequency, of, 'CD38HLA-DR', but, not, of, 'CD38HLA-DR', 'T-cell', subsets])].
[sujeto(['In', 'addition,', an]), verbo([increase]), complemento([in, mRNA, expression, of, 'APOBEC3G', and, 'PI3,', and, a, reduction, of, 'TRIM22', and, 'CCR5', 'expression,', this, latter, positively, correlated, with, p24, 'levels,', was, noted])].
[sujeto(['VitD', reduces, 'HIV-1', infection, in, 'T', cells, possibly, by]), verbo([inducing]), complemento([antiviral, gene, 'expression,', reducing, the, viral, 'co-receptor', 'CCR5', 'and,', at, least, at, the, highest, calcitriol, 'concentration,', by, promoting, an, 'HIV-1-restrictive', 'CD38HLA-DR', 'immuno-phenotype'])].
[sujeto(['The', active, hormonal, form, of, vitamin, 'D,', 1, ',', 25, -, dihydroxyvitamin, 'D', '(', 1, ',', 25, 'D)', is, an, important, modulator, of, the, immune, 'system,']), verbo([inhibiting]), complemento([cellular, proliferation, and, regulating, transcription, of, immune, response, genes])].
[sujeto(['We', carried, out, a, 'genome-wide', association, scan, of, percent, inhibition, of, cell, proliferation, '(', 'Imax)']), verbo([induced]), complemento([by, 1, ',', 25, 'D', treatment, of, peripheral, blood, mononuclear, cells, from, 88, healthy, 'African-American', individuals])].
[sujeto(['Two', 'genome-wide', significant, variants, were, 'identified:', rs1893662, in, a, gene, desert, on, chromosome, 18, '(', p, =, 2.32, x, 10, -, 8, ')', and, rs6451692, on, chromosome, 5, '(', p, =, 2.55, x, 10, -, 8, ')', ',', which, may, influence, the, 'anti-proliferative', activity, of, 1, ',', 25, 'D', by]), verbo([regulating]), complemento([the, expression, of, nearby, genes, such, as, the, chemokine, 'gene,', 'CCL28,', and, the, translation, initiation, 'gene,', 'PAIP1'])].
[sujeto(['In', 'addition,', we, identified, response, eQTLs, in, vitamin, 'D', receptor]), verbo([binding]), complemento([sites, near, genes, differentially, expressed, in, response, to, 1, ',', 25, 'D,', such, as, 'FERM', 'Domain', 'Containing', 6, '(', 'FRMD6),', which, plays, a, critical, role, in, regulating, both, cell, proliferation, and, apoptosis])].
[sujeto([1, ',', 25, -, dihydroxyvitamin, 'D3', '[', 1, ',', 25, '(', 'OH)2D3]', is, a, powerful, 'immuno-modulator,', which]), verbo([enhances]), complemento([expression, of, antimicrobial, peptides, and, induces, autophagy, in, 'monocytes/macrophages'])].
[sujeto(['Since', 1, ',', 25, '(', 'OH)2D3']), verbo([increases]), complemento([the, phagocytic, potential, of, 'monocytes/macrophages,', we, have, explored, the, effect, of, 1, ',', 25, '(', 'OH)2D3', on, the, expression, of, receptors, such, as, mannose, receptor, '(', 'CD206)', and, 'DC-SIGN', '(', 'CD209)', as, well, as, autophagy, genes, such, as, 'ATG5', and, 'Beclin-1', '(', 'BECN1)', in, 'monocytes/macrophages', of, healthy, controls, '(', 'HCs)', and, pulmonary, tuberculosis, '(', 'PTB)', patients, with, and, without, cavitary, disease])].
[sujeto([1, ',', 25, '(', 'OH)2D3', significantly, upregulated, the, expression, of, mannose, 'receptor,', 'ATG5', and, 'BECN1;', whereas, 'DC-SIGN', expression, was]), verbo([suppressed]), complemento([in, 'Mtb', infected, cells, of, both, study, groups, '(', 'p&nbsp;&lt;&nbsp;0'])].
[sujeto(['Our', study, results]), verbo([suggest]), complemento([that, vitamin, 'D', supplementation, in, 'PTB', patients, without, cavitary, disease, could, enhance, innate, immune, functions, and, may, help, to, control, intracellular, growth, of, mycobacteria, in, macrophages])].
[sujeto(['Inhibition', of, 'pro-inflammatory', functions, of, microglia]), verbo([has]), complemento([been, considered, a, promising, strategy, to, prevent, pathogenic, events, in, the, central, nervous, system, under, neurodegenerative, conditions])].
[sujeto(['Here', we, examined, potential, inhibitory, effects, of]), verbo([nuclear]), complemento([receptor, ligands, on, lipopolysaccharide, '(', 'LPS)-induced', inflammatory, responses, in, microglial, 'BV-2', cells])].
[sujeto(['Specifically,', both, 'VD3', and, 'HX630']), verbo([inhibited]), complemento([expression, of, mRNAs, encoding, inducible, nitric, oxide, synthase, '(', 'iNOS)', and, 'IL-6,', whereas, expression, of, 'IL-1β', mRNA, was, inhibited, only, by, 'VD3'])].
[sujeto(['Moreover,', 'VD3', and, 'HX630']), verbo([inhibited]), complemento(['LPS-induced', activation, of, extracellular, 'signal-regulated', kinase, '(', 'ERK)', and, nuclear, translocation, of, nuclear, factor, κB, '(', 'NF-κB)'])].
[sujeto(['PD98059,', an, inhibitor, of, 'ERK', 'kinase,', attenuated, 'LPS-induced']), verbo([nuclear]), complemento([translocation, of, 'NF-κB', and, induction, of, mRNAs, for, 'iNOS,', 'IL-1β', and, 'IL-6'])].
[sujeto(['These', results, indicate, that, 'VD3', can]), verbo([inhibit]), complemento([production, of, several, 'pro-inflammatory', molecules, from, 'microglia,', and, that, suppression, of, 'ERK', activation, is, at, least, in, part, involved, in, the, 'anti-inflammatory', effect, of, 'VD3'])].
[sujeto(['We', investigated, whether, 1, ',', 25, -, 'dihydroxy-vitamin', 'D3', '(', 1, ',', 25, '(', 'OH)2D3)', could, improve, early, diabetic, nephropathy, through, the, 'DNA-damage-inducible', transcript, 4, /, tuberous, sclerosis, 2, /, mammalian]), verbo([target]), complemento([of, rapamycin, pathway])].
[sujeto(['The', expressions, of, vitamin, 'D', 'receptor,', 'DNA-damage-inducible', transcript, 4, ',', and, mammalian]), verbo([target]), complemento([of, rapamycin, were, measured])].
[sujeto([1, ',', 25, '(', 'OH)2D3']), verbo([inhibited]), complemento([the, proliferation, of, mesangial, cells, induced, by, hyperglycemia])].
[sujeto(['The', phosphorylation, of, mammalian]), verbo([target]), complemento([of, rapamycin, was, reduced, by, 1, ',', 25, '(', 'OH)2D3', treatment])].
[sujeto(['The', current, study, demonstrates, that, 1, ',', 25, '(', 'OH)2D3', can, effectively]), verbo([inhibit]), complemento([mesangial, cells, proliferation, induced, by, 'hyperglycemia,', thus, suppressing, the, development, of, diabetic, nephropathy])].
[sujeto(['To', 'date,', such, images]), verbo([have]), complemento([been, quantified, primarily, based, on, ventilation, defects])].
[sujeto(['Older', healthy, volunteers, exhibited, a, significantly, 'right-skewed', distribution, '(', 0.46, ±, 0.2, ',', 'P', =, 0.034, ')', ',', resulting, in, significantly]), verbo([increased]), complemento(['VDR', '(', 7.0, ±, 4.8, '%', ',', 'P', =, 0.008, ')', and, 'LVR', '(', 24.5, ±, 11.5, '%', ',', 'P', =, 0.025, ')'])].
[sujeto(['In', the, 'asthmatics,', 'VDR', and, 'LVR']), verbo([increased]), complemento([in, the, older, 'population,', and, 'HVR', was, significantly, reduced, '(', 13.5, ±, 4.6, '%', vs, 18.9, ±, 4.5, '%', ',', 'P', =, 0.009, ')'])].
[sujeto(['Quantitative', '(', 129, ')', 'Xe', 'MRI']), verbo([provides]), complemento([a, robust, and, objective, means, to, display, and, quantify, the, pulmonary, ventilation, 'distribution,', even, in, subjects, who, have, airway, function, impairment, not, appreciated, by, spirometry])].
[sujeto(['For', stratified, analyses, by, ethnicity, and, study, 'design,', no, significant, associations, were]), verbo([found]), complemento([in, 'Caucasian', population, and, 'Asian', 'population,', as, well, as, the, 'population-based', studies, and, 'hospital-based', studies, under, all, genetic, models])].
[sujeto(['TaqI,', 'FokI,', and, 'ApaI', polymorphisms, of, 'VDR', gene, were, not, significantly]), verbo([associated]), complemento([with, the, predisposition, of, 'LDD'])].
[sujeto(['Vitamin', 'D', receptor, '(', 'VDR)', polymorphisms, are]), verbo([found]), complemento([more, commonly, in, some, tumor, types, than, in, healthy, 'individuals,', suggesting, that, some, polymorphisms, '(', 'Cdx2,', 'Fok1,', 'Bsm1,', 'Apa1,', 'Taq1)', contribute, to, tumor, development])].
[sujeto(['There', is, no, previous]), verbo([report]), complemento([on, 'VDR', polymorphism, in, 'Hodgkin\'s', lymphoma, '(', 'HL)', patients])].
[sujeto(['No', statistically, significant, difference, was]), verbo([found]), complemento([between, the, patient, group, and, control, group, in, terms, of, 'Cdx2,', 'Fok1,', 'Bsm1,', 'Apa1,', and, 'Taq1', polymorphisms, '(', 'P&gt;0'])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, 'VDR', polymorphisms, may, not, play, a, role, in, 'HL', development])].
[sujeto(['We']), verbo([have]), complemento([previously, demonstrated, that, 'Salmonella', infection, promotes, the, degradation, and, plasma, sequestration, of, 'Axin1,', leading, to, bacterial, invasiveness, and, inflammatory, responses])].
[sujeto(['Although', 'VDR', and, 'Axin1', are, all]), verbo([involved]), complemento([in, intestinal, 'inflammation,', it, remains, unclear, whether, these, processes, are, related, or, function, independently])].
[sujeto(['Candidate', genomic, 'VDR']), verbo([binding]), complemento([sites, for, 'Axin1', were, tested, by, chromatin, immunoprecipitation, '(', 'ChIP)', assay])].
[sujeto(['We']), verbo([found]), complemento([that, 'VDR', deletion, led, to, lower, protein, and, mRNA, levels, of, 'Axin1,', whereas, knockdown, of, 'Axin1', did, not, change, the, expression, level, of, 'VDR', protein])].
[sujeto(['The', 'VDR', regulation, of, 'Axin1', was, through, a, 'VDR', genomic]), verbo([binding]), complemento([site, for, 'Axin1', gene, on, the, regulatory, region])].
[sujeto(['Fractionation', data, showed, that, cytosolic, 'Axin1', was, significantly, reduced, due, to, 'VDR', 'deletion,', leaving, the]), verbo([nuclear]), complemento([fraction, unchanged])].
[sujeto(['The', discovery, of, 'Axin1', as, a, 'VDR']), verbo([target]), complemento([gene, provides, novel, and, fundamental, insights, into, the, interactions, between, the, 'VDR', and, 'β-catenin', signaling, pathways])].
[sujeto(['The', vitamin, 'D', receptor, '(', 'VDR)']), verbo([mediates]), complemento([the, immunological, function, of, vitamin, 'D3,', which, activates, 'macrophages,', and, vitamin, 'D', deficiency, has, been, linked, to, tuberculosis, risk])].
[sujeto(['We', observed, the, allele, &, 'quot;A&quot;', of, rs11574143, and, rs11168287]), verbo([increased]), complemento([the, 'PTB', risk, and, the, allele, &, 'quot;A&quot;', of, rs11574079, provided, a, protective, effect, against, 'PTB'])].
[sujeto(['SHPT', occurs, during, the, early, course, of, progressive, renal, 'insufficiency,', and, is]), verbo([associated]), complemento([with, mortality, and, cardiovascular, events])].
[sujeto(['CKD', was]), verbo([induced]), complemento([through, 'two-step', 5, /, 6, 'nephrectomy,', and, then, 'CKD', rats, and, 'sham-operated', rats, were, maintained, for, 8, &, 'nbsp;weeks', on, diets, containing, 0.7, &, 'nbsp;%', phosphorus, '(', normal, 'phosphate)', or, 1.2, &, 'nbsp;%', phosphorus, '(', high, 'phosphate)'])].
[sujeto(['Consequently,', our, data]), verbo([suggest]), complemento([that, 'mechanisms,', other, than, 'DNA', 'hypermethylation,', were, responsible, for, the, reduction, in, mRNA, and, protein, levels, of, 'CaSR', and, 'VDR', in, 'PTGs', of, 'CKD', 'HP', rats])].
[sujeto(['Despite', similarities, in, upfront, treatment, of, childhood, 'cancer,', not, every, adult, survivor, of, childhood, cancer, '(', 'CCS)']), verbo([has]), complemento([an, impaired, bone, mineral, density, '(', 'BMD)'])].
[sujeto(['Multivariate', analyses, revealed, that, lower, 'BMD', was]), verbo([associated]), complemento([with, lower, weight, and, height, at, 'follow-up,', male, 'sex,', and, previously, administered, radiotherapy])].
[sujeto(['CCSs', who, are, carriers, of, candidate, 'SNPs', in, the, 'ESR1', or, 'LRP5', genes, seem, to]), verbo([have]), complemento([an, impaired, bone, mass, at, an, early, adult, age])].
[sujeto(['Then,', we, coupled, it, with, 'A-ring', fragments, using, 'Sonogashira', or, 'Wittig-Horner', 'protocol,']), verbo([providing]), complemento([the, targeted, analogs, of, 'D-seco', analogs, of, 1, 'α,25-dihydroxyvitamin', 'D3', and, 1, 'α,25-dihydroxy-19-norvitamin', 'D3', possessing, a, vinyl, substituent, at, 'C-14', and, a, double, bond, between, 'C-17', and, 'C-20'])].
[sujeto(['Animal', studies]), verbo([suggest]), complemento([a, role, of, vitamin, 'D', in, fetal, lung, development, although, not, studied, in, preterm, animals])].
[sujeto(['In', 'conclusion,', 'Vitamin', 'D', depletion]), verbo([led]), complemento([to, lower, oxygenation, and, reduced, survival, time, in, the, preterm, 'offspring,', associated, with, reduced, lung, weight, and, birth, weight])].
[sujeto([&, 'nbsp;', 'Vitamin', 'D', deficiency, was]), verbo([found]), complemento([in, 87.6, '%', and, insufficiency, in, 7.7, '%'])].
[sujeto(['The', carries, of, 'GG', allele, was]), verbo([associated]), complemento([with, increased, risks, of, vitamin, 'D', insufficiency, '(', p, less, 'than&nbsp;0'])].
[sujeto(['The', presence, of, 'GG', allele, of, the, 'SNP', rs2228570, of, 'VDR', 'gene,', 'SNPs', rs4588, of, 'GC', gene, and, 'CYP2R1', rs10741657, gene, was]), verbo([associated]), complemento([with, vitamin, 'D', deficiency])].
[sujeto(['The']), verbo([nuclear]), complemento([receptor, 'REV-ERBα', links, circadian, rhythms, and, numerous, physiological, 'processes,', but, its, physiological, role, in, ovaries, remains, largely, unknown])].
[sujeto(['The', aim, of, this, study, was, to, determine, the, potential, role, of, 'REV-ERBα', in, the, regulation, of, the, transcription, of, its, putative]), verbo([target]), complemento([genes, in, granulosa, cells, '(', 'GCs)', prepared, from, 'Per2-destablized', luciferase, '(', 'dLuc)', reporter, gene, transgenic, rats])].
[sujeto(['Two', agonists, '(', 'GSK4112,', 'heme)', and, an, antagonist, '(', 'SR8278)', of, 'REV-ERBα', as, well, as, 'Rev-erbα', siRNA, knockdown, were, used, to, identify, its]), verbo([target]), complemento([genes])].
[sujeto(['GSK4112', treatment, lengthened, and, 'SR8278', treatment, shortened, the, period, of, circadian, oscillations, in, matured, 'GCs']), verbo([stimulated]), complemento([with, or, without, luteinizing, hormone, '(', 'LH)'])].
[sujeto(['GSK4112', showed, an, inhibitory, effect, on, the, amplitude, of, circadian, oscillations, and]), verbo([caused]), complemento([an, arrhythmic, expression, of, canonical, clock, genes])].
[sujeto(['Heme', treatment, also]), verbo([repressed]), complemento([the, expressions, of, clock, 'genes,', 'Alas1,', 'Il6,', and, 'Ppargc1a'])].
[sujeto(['Collectively,', these, data, extend, the, recent]), verbo([finding]), complemento([to, rat, 'GCs', and, demonstrate, that, 'REV-ERBα', represses, the, expressions, of, 'Alas1,', 'Ppargc1a,', and, 'Il6,', providing, novel, insights, into, the, physiological, significance, of, 'REV-ERBα', in, ovarian, circadian, oscillators])].
[sujeto(['Similar']), verbo([decreases]), complemento([were, observed, for, blood, hemoglobin, '(', 11.4, +, /, -, 0.2, vs])].
[sujeto(['An', 'iron-deficient', diet]), verbo([decreased]), complemento([body, and, skeletal, muscle, growth, by, 15, '(', 'P', less, than, 0.005, ')', and, 10, '%', '(', 'P', less, than, 0.05, ')', ',', 'respectively,', whereas, concentrations, of, 'protein,', 'RNA,', 'ALAS', 'mRNA,', and, citrate, synthase, activity, in, muscle, were, not, different, from, control])].
[sujeto(['One', mechanism, by, which, heme, biosynthesis, may, be, slowed, in, muscle, of, young, anemic, rats, is, a]), verbo([decrease]), complemento([in, 'ALAS', activity])].
[sujeto(['At', a, time, when, enzyme, activity, was, 'decreased,', 'ALAS', mRNA, expression, was, not, affected, by, an, 'iron-deficient', 'diet,']), verbo([suggesting]), complemento([that, steps, after, transcription, of, the, 'ALAS', gene, may, regulate, the, decrease, in, activity])].
[sujeto(['Maximal', enzyme, activity, was]), verbo([increased]), complemento([2.5, -, and, 4.0, -, fold, after, 3, and, 7, days, of, overload])].
[sujeto(['The', content, of, 'ALV', synthase, mRNA, '(', 'ng/mg', total, 'RNA)', was, not, changed, after, 3, days, but]), verbo([increased]), complemento(['(', 20, '%', ;, 'P', less, than, 0.05, ')', after, 7, days, of, overload])].
[sujeto(['Normalizing', the, content, of, 'ALV', synthase, mRNA, relative, to, the]), verbo([increase]), complemento([in, total, 'RNA', indicated, that, 'ALV', synthase, mRNA, increased, by, 1.6, -, and, 2.0, -, fold, at, 3, and, 7, 'days,', respectively])].
[sujeto(['On', this, 'basis,', the]), verbo([increase]), complemento([in, enzyme, activity, per, gram, protein, exceeded, the, increase, in, mRNA, content, per, gram, protein, by, 60, -, 70, '%'])].
[sujeto(['During', 'overload,', the, activity, of, cytochrome, oxidase, was, unchanged, after, 3, days, but]), verbo([increased]), complemento([by, 1.5, -, fold, '(', 'P', less, than, 0.05, ')', after, 7, days, of, overload])].
[sujeto(['The', data, indicate, that, 1, ')', the, initial, rise, in, 'ALV', synthase, mRNA, and, activity, due, to, overload, occurs, in, the, absence, of, a, prior, change, in, the, level, of, cytochrome, 'oxidase,', an, enzyme, that]), verbo([requires]), complemento([heme, for, its, 'assembly,', and, 2, ')', induction, of, 'ALV', synthase, activity, is, regulated, largely, by, processes, at, the, translational, or, posttranslational, steps])].
[sujeto(['Real-time', reverse, transcription, quantitative, 'PCR', '(', 'RT-qPCR)']), verbo([has]), complemento([become, the, method, of, choice, for, quantification, of, gene, expression, changes])].
[sujeto(['Pituitary', adenomas, are, common, 'tumours,', and, the, appropriate, interpretation, of, increasingly, published, data, within, this, field, is]), verbo([prevented]), complemento([by, the, lack, of, a, proper, selection, and, validation, of, stably, expressed, reference, genes])].
[sujeto(['To']), verbo([find]), complemento([and, validate, the, optimal, reference, gene, or, gene, combination, for, reliable, 'RT-qPCR', gene, expression, in, both, 'non-functioning', '(', 'NFPA)', and, hormone, secreting, '(', 'GH', and, 'ACTH)', pituitary, adenomas])].
[sujeto(['Several', of, the, reference, genes]), verbo([expressed]), complemento([good, stability, yielding, several, candidate, genes])].
[sujeto(['PSMC4', and, 'ALAS1', were, overall, the, most, stably]), verbo([expressed]), complemento([genes, in, pituitary, adenoma, merely, differing, in, ranking, order])].
[sujeto(['PSMC4', and, 'ALAS1']), verbo([have]), complemento([so, far, not, been, reported, as, reference, genes, in, pituitary, adenomas])].
[sujeto(['The', various, reference, gene, algorithms, showed, a, mixed, selection, of, top, ranked, 'genes,', thus]), verbo([suggesting]), complemento([a, need, for, an, individualised, and, rational, choice, of, reference, genes])].
[sujeto(['In', the, current, 'study,', we]), verbo([provide]), complemento([evidence, that, the, mitochondrial, 'ATP-dependent', protease, 'ClpXP,', which, is, a, 'hetero-multimer', of, 'CLPX', and, 'CLPP,', is, involved, in, the, 'heme-dependent', degradation, of, 'ALAS1', in, mitochondria])].
[sujeto(['We']), verbo([found]), complemento([that, 'ALAS1', forms, a, complex, with, 'ClpXP', in, a, 'heme-dependent', manner, and, that, 'siRNA-mediated', suppression, of, either, 'CLPX', or, 'CLPP', expression, induced, 'ALAS1', accumulation, in, the, 'HepG2', human, hepatic, cell, line])].
[sujeto(['We', also]), verbo([found]), complemento([that, a, specific, 'heme-binding', motif, on, 'ALAS1,', located, at, the, 'N-terminal', end, of, the, mature, 'protein,', is, required, for, the, 'heme-dependent', formation, of, this, protein, complex])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'ALAS1', undergoes, a, conformational, change, following, the, association, of, heme, to, the, 'heme-binding', motif, on, this, protein])].
[sujeto(['This', change, in, the, structure, of, 'ALAS1', may]), verbo([enhance]), complemento([the, formation, of, complexes, between, 'ALAS1', and, 'ATP-dependent', proteases, in, the, 'mitochondria,', thereby, accelerating, the, degradation, of, 'ALAS1', protein, to, maintain, appropriate, intracellular, heme, levels])].
[sujeto(['Isoniazid', '(', 'INH)', can]), verbo([cause]), complemento([hepatotoxicity])].
[sujeto(['Our', metabolomic, analysis, revealed, that, chronic, treatment, with, 'INH', in, mice]), verbo([causes]), complemento([a, hepatic, accumulation, of, protoporphyrin, 'IX', '(', 'PPIX)'])].
[sujeto(['We', further]), verbo([found]), complemento([that, 'INH', induces, 'delta-aminolevulinate', synthase, 1, '(', 'ALAS1),', the, 'rate-limiting', enzyme, in, heme, biosynthesis])].
[sujeto(['We', also]), verbo([found]), complemento([that, 'INH', downregulates, ferrochelatase, '(', 'FECH),', the, enzyme, that, converts, 'PPIX', to, heme])].
[sujeto(['In', 'summary,', this, study, illustrated, that, chronic, treatment, with, 'INH']), verbo([causes]), complemento(['PPIX', accumulation, in, mouse, liver, in, part, through, 'ALAS1', induction, and, 'FECH', downregulation])].
[sujeto(['This', study, also, highlights, that, drugs, can, disrupt, the, metabolic, pathways, of, endobiotics, and]), verbo([increase]), complemento([the, risk, of, liver, damage])].
[sujeto(['Real-time', reverse, transcription, quantitative, polymerase, chain, reaction, '(', 'RT-qPCR)']), verbo([has]), complemento([become, the, most, common, technique, to, investigate, mRNA, expression, levels, of, target, genes])].
[sujeto(['Human', retinal, endothelial, cells, '(', 'HREC)', cultured, in, a, hypoxic, and, hyperglycemic, environment, is, a, potential, cell, model, to, study, diabetic, retinopathy, '(', 'DR),', but, the, proper, reference, genes, for, 'RNA', analysis]), verbo([have]), complemento([not, yet, been, determined])].
[sujeto(['The', 'RT-qPCR', analysis, showed, that, there, was, a, significant]), verbo([increase]), complemento([in, 'Robo4', expression, under, hyperglycemic, 'conditions,', while, there, was, a, decrease, in, expression, under, hypoxic, and, combined, hypoxic, and, hyperglycemic, 'conditions,', suggesting, that, 'Robo4', might, play, different, roles, in, various, stages, of, 'DR'])].
[sujeto(['Physical', exercise, training, '(', 'ET)']), verbo([has]), complemento([been, shown, to, promote, 'anti-diabetic', and, 'anti-atherogenic', responses, in, skeletal, muscle, of, these, 'patients,', but, the, role, of, the, circadian, 'clock-machinery', remains, unknown])].
[sujeto(['A', selection, of, clock, genes, and]), verbo([associated]), complemento([components, '(', circadian, locomoter, output, cycle, kaput, protein, '(', 'CLOCK),', period, '(', 'PER)', 1, ',', cryptochrome, '(', 'CRY)', 2, and, 'aminolevulinate-deltA-synthase-1', '(', 'ALAS1))', was, reliably, measured, and, used, for, further, analysis])].
[sujeto(['This', is, the, first, study, to, analyse, clock, gene, expression, in, skeletal, muscles, of, patients, with, 'CAD', and, 'T2DM']), verbo([participating]), complemento([in, a, 'long-lasting', exercise, intervention])].
[sujeto(['Therefore,', the, 'ALAS1', gene, was, significantly]), verbo([associated]), complemento([with, litter, size, in, two, populations, and, could, be, a, useful, molecular, marker, for, the, selection, of, increasing, litter, size, in, pigs])].
[sujeto(['Their', osteogenic, capacity]), verbo([has]), complemento([been, validated, in, vitro, and, may, be, transferred, to, human, cell, therapy, for, maxillary, large, bone, 'defects,', as, they, share, a, neural, crest, cell, origin, with, jaw, bone, cells])].
[sujeto(['The', acute, hepatic, porphyrias, are]), verbo([caused]), complemento([by, inherited, enzymatic, deficiencies, in, the, heme, biosynthesis, pathway])].
[sujeto(['Induction', of, the, first, enzyme, 5, -, aminolevulinic, acid, synthase, 1, '(', 'ALAS1)', by]), verbo([triggers]), complemento([such, as, fasting, or, drug, exposure, can, lead, to, accumulation, of, neurotoxic, heme, intermediates, that, cause, disease, symptoms])].
[sujeto(['We']), verbo([have]), complemento([demonstrated, that, hepatic, 'ALAS1', silencing, using, siRNA, in, a, lipid, nanoparticle, effectively, prevents, and, treats, induced, attacks, in, a, mouse, model, of, acute, intermittent, porphyria])].
[sujeto(['Herein,', we]), verbo([report]), complemento([the, development, of, 'ALN-AS1,', an, investigational, 'GalNAc-conjugated', 'RNAi', therapeutic, targeting, 'ALAS1'])].
[sujeto(['Moreover,', in, 'donor-matched', human, urine, and, 'serum,', we, demonstrate, a, notable, correspondence, in, 'ALAS1', 'levels,', minimal, interday, assay, 'variability,', low, interpatient, variability, from, serial, sample, 'collections,', and, the, ability, to, distinguish, between, healthy, volunteers, and, porphyria, patients, with]), verbo([induced]), complemento(['ALAS1', levels])].
[sujeto(['Recently,', sequence, polymorphisms, at, the, 'genome-wide', level]), verbo([have]), complemento([been, investigated, in, a, wide, range, of, animals])].
[sujeto(['A', common, approach, to, detect, selection, signatures, is, to, compare, breeds, that]), verbo([have]), complemento([been, selected, for, different, breeding, goals, '(', i])].
[sujeto(['This', study]), verbo([provided]), complemento([evidence, on, the, different, selection, histories, of, two, cattle, breeds, and, the, usefulness, of, genomic, scans, to, detect, selective, sweeps, even, in, cattle, breeds, that, are, bred, for, similar, production, aptitudes])].
[sujeto(['Acute', intermittent, porphyria, '(', 'AIP)', is, an, 'autosomal-dominant', hepatic, disorder]), verbo([caused]), complemento([by, the, 'half-normal', activity, of, hydroxymethylbilane, '(', 'HMB)', synthase])].
[sujeto(['Symptomatic', individuals, experience, 'life-threatening', acute, neurovisceral, attacks, that, are, precipitated, by, factors, that]), verbo([induce]), complemento([the, hepatic, expression, of, 5, -, aminolevulinic, acid, synthase, 1, '(', 'ALAS1),', resulting, in, the, marked, accumulation, of, the, putative, neurotoxic, porphyrin, precursors, 5, -, aminolevulinic, acid, '(', 'ALA)', and, porphobilinogen, '(', 'PBG)'])].
[sujeto(['Here,', we]), verbo([provide]), complemento([the, first, detailed, description, of, the, biochemical, and, pathologic, alterations, in, the, explanted, liver, of, an, 'AIP', patient, who, underwent, orthotopic, liver, transplantation, '(', 'OLT)', due, to, untreatable, and, debilitating, chronic, attacks])].
[sujeto(['In', the, explanted, 'liver,', '(', 'a)', 'ALAS1', mRNA, and, activity, were, elevated, approximately, '~3-', and, 5, -, 'fold,', and, 'ALA', and, 'PBG', concentrations, were]), verbo([increased]), complemento(['~3-', and, 1, ',', 760, -, 'fold,', 'respectively;', '(', 'b)', uroporphyrin, 'III', concentration, was, 'elevated;', '(', 'c)', microsomal, heme, content, was, 'sufficient,', and, representative, cytochrome, 'P450', activities, were, essentially, 'normal;', '(', 'd)', 'HMB', synthase, activity, was, approximately, 'half-normal', '(', '~42%);', '(', 'e)', iron, concentration, was, slightly, 'elevated;', and, '(', 'f)', heme, oxygenase, 'I', mRNA, was, increased, approximately, 'three-fold'])].
[sujeto(['Notable', pathologic, findings, included, nodular, regenerative, 'hyperplasia,', previously, not]), verbo([reported]), complemento([in, 'AIP', 'livers,', and, minimal, iron, 'deposition,', despite, the, large, number, of, hemin, infusions, received, before, 'OLT'])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, neurovisceral, symptoms, of, 'AIP', are, not, associated, with, generalized, hepatic, heme, deficiency, and, support, the, neurotoxicity, of, 'ALA', 'and/or', 'PBG'])].
[sujeto(['Research', in, rodents]), verbo([has]), complemento([revealed, changes, in, the, clock, circadian, regulator, '(', 'CLOCK)', gene, network, expression, around, parturition])].
[sujeto(['In', 'general,', the, expression, of, 'NPAS2,', 'NR1D1,', 'NR2F2,', 'ALAS1,', 'FECH,', 'FBXW11,', 'CCRN4L,', 'PPARA,', 'PPARGC1A,', and, 'FGF21', was, lower, at, -, 10, d, but]), verbo([increased]), complemento([postpartum, in, all, tissues])].
[sujeto(['The', interaction, detected, for, 'CSNK1D', was]), verbo([associated]), complemento([with, increased, expression, postpartum, in, 'AT', and, 'MG', but, not, 'LIV'])].
[sujeto(['Leptin', was, barely, detectable, in, 'LIV,', but, there, was, an, interaction, effect, in, 'AT', and, 'MG']), verbo([associated]), complemento([with, upregulation, postpartum, in, 'MG', and, downregulation, in, 'AT'])].
[sujeto(['Together,', these, results]), verbo([suggest]), complemento([that, the, control, of, metabolic, adaptations, in, 'LIV,', 'MG,', and, 'AT', around, parturition, might, be, partly, regulated, through, the, 'CLOCK', gene, network])].
[sujeto(['Although', the, present, study, did, not, specifically, address, rhythmic, control, of, tissue, metabolism, via, the, 'CLOCK', gene, 'network,', the, difference, in, expression, of, genes, studied, among, tissues, confirms, that, the, behavior, of, 'circadian-controlled', metabolic, genes, around, parturition, differs, by, tissue, 'and,', as, 'such,', is, closely]), verbo([associated]), complemento([with, the, metabolic, function, of, the, organ])].
[sujeto(['Inorganic', arsenic, species, are, potent, environmental, toxins, and]), verbo([causes]), complemento([of, numerous, health, problems])].
[sujeto(['Most', studies]), verbo([have]), complemento([assumed, that, 'arsenic-induced', changes, in, mRNA, levels, result, from, effects, on, gene, transcription])].
[sujeto(['In', 'arsenite-exposed', 'cells,', 186, probe, 'set-identified', transcripts, were, significantly]), verbo([increased]), complemento([and, 167, were, significantly, decreased])].
[sujeto(['This', change, presumably, accounted, for, at, least, part, of, the, 2.7, -, fold]), verbo([increase]), complemento([in, 'steady-state', 'ALAS1', mRNA, levels, seen, after, arsenite, treatment])].
[sujeto(['This', could, reflect]), verbo([decreases]), complemento([in, cellular, heme, caused, by, the, massive, induction, by, arsenite, of, heme, oxygenase, mRNA, '(', 'HMOX1;', 68, -, fold, 'increase),', the, 'rate-limiting', enzyme, in, heme, catabolism])].
[sujeto(['Reverse', transcription, quantitative, polymerase, chain, reaction, '(', 'RT&#8209;qPCR)']), verbo([has]), complemento([become, a, frequently, used, strategy, in, gene, expression, studies])].
[sujeto(['In', the, present, 'study,', screening, was, performed, using, 12, common, reference, 'genes,', which, were, selected, in, order, to]), verbo([provide]), complemento([an, experimental, basis, for, the, investigation, of, gene, expression, in, gallbladder, carcinoma])].
[sujeto(['Following', comparison, of, the, results, of, the, three, software, 'programs,', 'HPRT1', was, identified, as, the, most, stably]), verbo([expressed]), complemento([reference, gene])].
[sujeto(['In', the, normal, gallbladder, 'group,', the, relative, stably]), verbo([expressed]), complemento([reference, gene, was, 'PPIA', and, in, the, entire, sample, 'group,', the, relatively, stably, expressed, reference, gene, was, 'PPIA'])].
[sujeto(['The', circadian, rhythm, of, the, liver]), verbo([maintains]), complemento([glucose, 'homeostasis,', and, disruption, of, this, rhythm, is, associated, with, type, 2, diabetes])].
[sujeto(['Dietary', iron, affects, circadian, glucose, metabolism, through, 'heme-mediated', regulation, of, the, interaction, of]), verbo([nuclear]), complemento([receptor, subfamily, 1, group, d, member, 1, '(', 'Rev-Erbα)', with, its, cosuppressor, nuclear, receptor, corepressor, 1, '(', 'NCOR)'])].
[sujeto(['Loss', of]), verbo([regulated]), complemento([heme, synthesis, was, achieved, by, aminolevulinic, acid, '(', 'ALA)', treatment, of, mice, or, cultured, cells, to, bypass, the, 'rate-limiting', enzyme, in, hepatic, heme, 'synthesis,', 'ALA', synthase, 1, '(', 'ALAS1)'])].
[sujeto(['Dietary', iron]), verbo([modulates]), complemento([levels, of, peroxisome, 'proliferator-activated', receptor, γ, coactivator, 1, α, '(', 'PGC-1α),', a, transcriptional, activator, of, 'ALAS1,', to, affect, hepatic, heme])].
[sujeto(['Treatment', of, mice, with, the, antioxidant, 'N-acetylcysteine', diminishes, 'PGC-1α', variation, observed, among, the, iron, 'diets,']), verbo([suggesting]), complemento([that, iron, is, acting, through, reactive, oxygen, species, signaling])].
[sujeto(['Factors', that]), verbo([induce]), complemento([the, expression, of, hepatic, 5, -, aminolevulinic, acid, synthase, 1, '(', 'ALAS1)', result, in, the, accumulation, of, the, neurotoxic, porphyrin, precursors, 5, -, aminolevulinic, acid, '(', 'ALA)', and, porphobilinogen, '(', 'PBG),', which, recent, studies, indicate, are, primarily, responsible, for, the, acute, attacks])].
[sujeto(['Current', treatment, of, these, attacks]), verbo([involves]), complemento([i])].
[sujeto(['Here,', we, describe, preclinical, studies, of, 'liver-directed', small, interfering, 'RNAs', '(', 'siRNAs)']), verbo([targeting]), complemento(['Alas1', '(', 'Alas1-siRNAs)', in, a, mouse, model, of, acute, intermittent, 'porphyria,', the, most, common, acute, hepatic, porphyria])].
[sujeto([dose, of, 'Alas1-siRNA']), verbo([prevented]), complemento([the, 'phenobarbital-induced', biochemical, acute, attacks, for, approximately, 2, wk])].
[sujeto(['Injection', of, 'Alas1-siRNA', during, an]), verbo([induced]), complemento([acute, attack, significantly, decreased, plasma, 'ALA', and, 'PBG', levels, within, 8, 'h,', more, rapidly, and, effectively, than, a, single, hemin, infusion])].
[sujeto(['Alas1-siRNA', was, well, tolerated, and, a, therapeutic, dose, did, not]), verbo([cause]), complemento([hepatic, heme, deficiency])].
[sujeto(['These', studies]), verbo([provide]), complemento(['proof-of-concept', for, the, clinical, development, of, 'RNA', interference, therapy, for, the, prevention, and, treatment, of, the, acute, attacks, of, the, acute, hepatic, porphyrias])].
[sujeto(['Ideal', housekeeping, genes, must]), verbo([have]), complemento([stable, expression, patterns, regardless, of, the, sample, type, and, menstrual, cycle, phase])].
[sujeto(['Bach1', is, an, oxidative, 'stress-responsive', transcription, factor, that]), verbo([represses]), complemento([heme, oxygenase, 1, '(', 'HO-1),', the, 'rate-limiting', enzyme, in, the, catabolism, of, 'heme,', a, potent, 'pro-oxidant'])].
[sujeto(['We', previously, demonstrated, that, carbon, tetrachloride, '(', 'CCl4)']), verbo([causes]), complemento([oxidative, hepatic, injury, in, 'rats,', exacerbated, by, free, 'heme,', suggesting, that, 'CCl4', may, affect, 'Bach1', gene, expression])].
[sujeto(['In', the, present, 'study,', we, used, northern, blot, analysis, to, measure, 'Bach1,', 'HO-1', and, 'δ-aminolevulinate', synthase, '(', 'ALAS1;', a, heme, biosynthesis, 'enzyme)', mRNA, expression, levels, during, acute, hepatic, injury]), verbo([induced]), complemento([by, 'CCl4', '(', at, doses, of, 0.1, ',', 1.0, and, 2.0, 'ml/kg', body, 'weight)'])].
[sujeto(['Treatment', with, 'CCl4']), verbo([induced]), complemento([a, significant, 'dose-dependent', increase, in, 'Bach1', mRNA, 1, -, 3, h, after, administration])].
[sujeto(['Bach1', mRNA, peaked, at, 6, h, after, 'CCl4', treatment, '(', 1, 'ml/kg),', followed, by, a, rapid]), verbo([decrease]), complemento([and, gradual, return, to, baseline, by, 12, h, after, treatment])].
[sujeto(['Serum', 'ALT', levels, and, hepatic, 'MDA', concentration, were, significantly]), verbo([increased]), complemento([at, 24, h, after, 'CCl4', 'treatment,', while, the, hepatic, 'GSH', content, was, significantly, reduced, within, 3, h, of, treatment])].
[sujeto(['These', findings, indicate, that, 'Bach1', mRNA, is, transiently]), verbo([induced]), complemento([in, rat, liver, by, 'CCl4,', possibly, as, a, regulatory, mechanism, to, restore, 'HO-1', to, baseline, following, free, heme, catabolism])].
[sujeto(['Our', findings, also]), verbo([suggest]), complemento([that, 'Bach1', mRNA, expression, may, be, a, novel, indicator, of, the, extent, of, oxidative, hepatic, injury, caused, by, free, heme])].
[sujeto(['Acute', intermittent, porphyria, '(', 'AIP),', an, inherited, hepatic, 'disorder,', is, due, to, a, defect, of, hydroxymethylbilane, synthase, '(', 'HMBS),', an, enzyme]), verbo([involved]), complemento([in, heme, biosynthesis])].
[sujeto(['AIP', is, characterized, by, 'recurrent,', 'life-threatening', attacks, at, least, partly, due, to, the]), verbo([increased]), complemento([hepatic, production, of, 5, -, aminolaevulinic, acid, '(', 'ALA)'])].
[sujeto(['Both', the, mitochondrial, 'enzyme,', 'ALA', synthase, '(', 'ALAS)', 1, ',']), verbo([involved]), complemento([in, the, first, step, of, heme, 'biosynthesis,', which, is, closely, linked, to, mitochondrial, bioenergetic, 'pathways,', and, the, promise, of, an, 'ALAS1', siRNA, hepatic, therapy, in, 'humans,', led, us, to, investigate, hepatic, energetic, metabolism, in, 'Hmbs', 'KO', mice, treated, with, phenobarbital])].
[sujeto(['RC', and, 'TCA', cycle, were, significantly, affected, in, comparison, to, controls, in, mice, treated, with, phenobarbital, with]), verbo([decreased]), complemento([activities, of, 'RC', complexes, 'I', '(', -, 52, '%', ',', '(', *, *, ')', 'p&lt;0'])].
[sujeto([5, ')', ',', and]), verbo([decreased]), complemento([activity, of, 'α-ketoglutarate', dehydrogenase, '(', -, 64, '%', ',', '(', *, ')', 'p&lt;0'])].
[sujeto(['Most', of, these, metabolic, alterations, were, at, least, partially, restored, after, the, phenobarbital]), verbo([arrest]), complemento([and, heme, arginate, administration])].
[sujeto(['These', results]), verbo([suggest]), complemento([a, cataplerosis, of, the, 'TCA', cycle, induced, by, 'phenobarbital,', caused, by, the, massive, withdrawal, of, 'succinyl-CoA', by, 'ALAS', 'induction,', such, that, the, 'TCA', cycle, is, unable, to, supply, the, reduced, cofactors, to, the, 'RC'])].
[sujeto(['MicroRNAs', '(', 'miRNAs)', can]), verbo([provide]), complemento([useful, biomarkers, of, tissue, function])].
[sujeto(['The', aim, of, the, present, study, was, to, 'determine,', in, bovine, follicles, '(', n, =, 66, ;, diameter, 4, -, 22, 'mm),', the, relationship, among, several, indices, of, steroidogenesis, and, levels, of, 15, miRNAs, previously, identified, to, be]), verbo([associated]), complemento([with, follicle, development])].
[sujeto(['When', considering, all, follicle, 'end-points', 'together,', we]), verbo([found]), complemento([that, using, a, 'cut-off', value, of, 'E', :, 'P', =, 1, overestimated, the, number, of, 'oestrogen-inactive', 'follicles,', whereas, using, 'CYP19A1', as, a, classifier, provided, a, clearer, separation, of, follicle, samples, based, on, oestrogen, 'activity,', in, agreement, with, the, 'E', :, 'P', 'ratio,', 'LHCGR', expression, and, levels, of, 'miR-873', and, 'miR-202'])].
[sujeto(['Bile', acids, are, primarily, synthesized, from, cholesterol, in, the, liver, and]), verbo([have]), complemento([important, roles, in, dietary, lipid, absorption, and, cholesterol, homoeostasis])].
[sujeto(['Detailed', roles, of, the, orphan]), verbo([nuclear]), complemento([receptors, regulating, cholesterol, 7, 'α-hydroxylase', '(', 'CYP7A1),', the, 'rate-limiting', enzyme, in, bile, acid, 'synthesis,', have, not, yet, been, fully, elucidated])].
[sujeto(['In', the, present, 'study,', we]), verbo([report]), complemento([that, 'oestrogen-related', receptor, γ, '(', 'ERRγ)', is, a, novel, transcriptional, regulator, of, 'CYP7A1', expression])].
[sujeto(['Activation', of, cannabinoid, receptor, type, 1, '(', 'CB1', 'receptor)', signalling]), verbo([induced]), complemento(['ERRγ-mediated', transcription, of, the, 'CYP7A1', gene])].
[sujeto(['Overexpression', of, 'ERRγ']), verbo([increased]), complemento(['CYP7A1', expression, in, vitro, and, in, 'vivo,', whereas, knockdown, of, 'ERRγ', attenuated, 'CYP7A1', expression])].
[sujeto(['Small', heterodimer, partner, '(', 'SHP)']), verbo([inhibited]), complemento([the, transcriptional, activity, of, 'ERRγ', and, thus, regulated, 'CYP7A1', expression])].
[sujeto(['Overexpression', of, 'ERRγ']), verbo([led]), complemento([to, increased, bile, acid, 'levels,', whereas, an, inverse, agonist, of, 'ERRγ,', 'GSK5182,', reduced, 'CYP7A1', expression, and, bile, acid, synthesis])].
[sujeto(['These', results]), verbo([provide]), complemento([the, molecular, mechanism, linking, 'ERRγ', and, bile, acid, metabolism])].
[sujeto(['Small', heterodimer, partner, '(', 'SHP)', is]), verbo([involved]), complemento([in, 'bile,', 'lipid,', and, glucose, metabolism])].
[sujeto(['Loss', of, 'SHP', in, 'ApoE-/-', mice]), verbo([decreased]), complemento([the, size, of, adipocytes, in, white, adipose, tissue, and, reduced, lipid, accumulation, in, the, liver])].
[sujeto(['There', was, no, statistical, difference, in, 'non-high', density, lipoprotein, cholesterol, levels, between, 'ApoE-/-SHP-/-', mice, and, 'ApoE-/-', mice, despite, an]), verbo([increase]), complemento([of, cholesterol, 7, 'α-hydroxylase', expression, in, the, liver])].
[sujeto(['In', 'conclusion,']), verbo([loss]), complemento([of, 'SHP', function, can, prevent, 'atherosclerosis,', and, resistance, to, 'diet-induced', obesity, is, the, primary, factor, contributing, to, this, protective, effect])].
[sujeto(['Treatment', with, antihyperglycemic, agents, is, initially, successful, in, type, 2, 'diabetes,', but, it, is, often]), verbo([associated]), complemento([with, a, high, secondary, failure, 'rate,', and, the, addition, of, insulin, is, eventually, necessary, for, many, 'patients,', in, order, to, restore, acceptable, glycemic, control, and, to, reduce, the, risk, of, development, and, progression, of, disease, complications])].
[sujeto(['Notably,', even, patients, who, appear, to]), verbo([have]), complemento([similar, requirements, of, antidiabetic, regimens, show, great, variability, in, drug, 'disposition,', glycemic, 'response,', 'tolerability,', and, incidence, of, adverse, effects, during, treatment])].
[sujeto(['Pharmacogenomics', is, a, promising, area, of, investigation, and]), verbo([involves]), complemento([the, search, for, genetic, polymorphisms, that, may, explain, the, interindividual, variability, in, antidiabetic, therapy, response])].
[sujeto(['These', genes, belong, to, three, major, 'classes:', genes]), verbo([involved]), complemento([in, drug, metabolism, and, transporters, that, influence, pharmacokinetics, '(', including, the, cytochrome, 'P450', '[', 'CYP]', 'superfamily,', the, organic, anion, transporting, polypeptide, '[', 'OATP]', 'family,', and, the, polyspecific, organic, cation, transporter, '[', 'OCT]', 'family);', genes, encoding, drug, targets, and, receptors, '(', including, peroxisome, 'proliferator-activated', receptor, gamma, '[', 'PPARG],', the, adenosine, triphosphate, '[', 'ATP]-sensitive', potassium, channel, '[', 'K(ATP)],', and, incretin, 'receptors);', and, genes, involved, in, the, causal, pathway, of, 'T2DM', that, are, able, to, modify, the, effects, of, drugs, '(', including, 'adipokines,', transcription, factor, 7, -, like, 2, '(', 'T', cell, 'specific,', 'HMG-box)', '[', 'TCF7L2],', insulin, receptor, substrate, 1, '[', 'IRS1],', nitric, oxide, synthase, 1, '(', 'neuronal)', adaptor, protein, '[', 'NOS1AP],', and, solute, carrier, family, 30, '(', zinc, 'transporter),', member, 8, '[', 'SLC30A8])'])].
[sujeto(['In', addition, to, these, three, major, 'classes,', we, also, review, the, available, evidence, on, novel, genes, '(', 'CDK5', regulatory, subunit]), verbo([associated]), complemento([protein, 1, -, like, 1, '[', 'CDKAL1],', 'insulin-like', growth, factor, 2, mRNA, binding, protein, 2, '[', 'IGF2BP2],', potassium, 'voltage-gated', 'channel,', 'KQT-like', 'subfamily,', member, 1, '[', 'KCNQ1],', paired, box, 4, '[', 'PAX4]', and, neuronal, differentiation, 1, '[', 'NEUROD1]', transcription, 'factors,', ataxia, telangiectasia, mutated, '[', 'ATM],', and, serine, racemase, '[', 'SRR])', that, have, recently, been, proposed, as, possible, modulators, of, therapeutic, response, in, subjects, with, 'T2DM'])].
[sujeto(['The', number, of, 'GST-P-positive', foci]), verbo([promoted]), complemento([by, 'OX', was, significantly, inhibited, by, the, combined, antioxidant, 'EMIQ', or, 'MLT', 'administration,', and, the, area, of, 'GST-P-positive', foci, was, inhibited, by, the, administration, of, 'MLT'])].
[sujeto(['Real-time', 'RT-PCR', analysis, revealed]), verbo([decreases]), complemento([in, mRNA, expression, levels, of, cytochrome, 'P450,', family, 2, ',', subfamily, 'b,', polypeptide, 2, '(', 'Cyp2b2)', and, malic, enzyme, 1, '(', 'Me1)', in, the, 'DEN-OX-EMIQ', and, 'DEN-OX-MLT', groups, and, decreases, in, mRNA, expression, levels, of, 'Cyp1a1', and, 'aldo-keto', reductase, family, 7, ',', member, 'A3', '(', 'Akr7a3)', in, the, 'DEN-OX-MLT', group, compared, to, those, in, the, 'DEN-OX', group])].
[sujeto(['In', in, vitro, 'ROS', production, 'assay,']), verbo([inhibited]), complemento([production, of, 'NADPH-dependent', 'ROS', was, observed, by, the, treatment, with, 'EMIQ', or, 'MLT'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, coadministration, of, 'EMIQ', or, 'MLT', suppresses, the, hepatocellular, 'tumor-promoting', activity, of, 'OX', in, rats, through, the, decrease, in, 'ROS', production, by, the, activation, of, 'CYPs'])].
[sujeto(['SHP', '(', short, heterodimer, 'partner)', is, an, orphan]), verbo([nuclear]), complemento([receptor, lacking, a, 'DNA', binding, domain, that, interacts, with, nuclear, receptors, '(', 'NR)', including, thyroid, receptor, '(', 'TR),', retinoic, acid, receptors, '(', 'RAR', and, 'RXR),', and, estrogen, receptors, alpha, and, beta, '(', 'ERalpha', and, 'ERbeta)'])].
[sujeto(['SHP']), verbo([acts]), complemento([as, a, negative, regulator, of, these, receptors, by, inhibiting, 'DNA', binding, and, transcriptional, activation])].
[sujeto([2, ',', 3, ',', 7, ',', 8, -, 'Tetrachlorodibenzo-p-dioxin', '(', 'TCDD)']), verbo([binds]), complemento([to, arylhydrocarbon, receptor, '(', 'AHR),', activating, the, 'AHR/AHR', nuclear, translocator, '(', 'ARNT)', heterodimer])].
[sujeto(['In', 'RL95-2', human, endometrial, carcinoma, 'cells,', 'SHP']), verbo([inhibited]), complemento(['TCDD-stimulated', reporter, activity, from, the, 'AHR-responsive', 'CYP1A1', and, 'UGT1A6', gene, promoters, in, a, 'concentration-dependent', manner])].
[sujeto(['In', 'GST', 'pull-down', 'assays,', 'ARNT']), verbo([interacted]), complemento([directly, with, 'SHP', in, 'vitro,', but, 'AHR', did, not, interact, with, 'GST-SHP'])].
[sujeto(['SHP']), verbo([inhibited]), complemento(['AHR/ARNT-DNA', binding, in, vitro])].
[sujeto(['A', novel, 'benz[a]anthracene', and, 2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD)-inducible', cytochrome, 'P-450', '(', 'P450EF),', which, is, very, active, in, polycyclic, aromatic, hydrocarbon, 'metabolism,']), verbo([has]), complemento([been, purified, from, 'C3H10T1/2', mouse, embryo, fibroblasts, '(', 'Pottenger,', 'L'])].
[sujeto(['A', 4.9, -, kilobase, '(', 'kb)', cDNA, encoding, 'P450EF']), verbo([has]), complemento([been, isolated, from, a, lambda, 'ZAP', cDNA, expression, library, generated, from, mRNA, of, 'TCDD-induced', 'C3H10T1/2', cells])].
[sujeto(['A', 'SmaI', fragment, of, the, 4.9, -, kb, cDNA, hybridized, to, a, 5.2, -, kb, mRNA, species, equally]), verbo([induced]), complemento([by, 'benz[a]anthracene', '(', 10, 'microM)', and, 'TCDD', '(', 10, 'nM)', in, 'C3H10T1/2', 'cells,', consistent, with, the, involvement, of, the, 'Ah', receptor, in, this, induction, process])].
[sujeto(['These', sequence, relationships]), verbo([suggest]), complemento([that, 'P450EF', is, a, member, of, a, new, 'CYP1B', subfamily, '(', mouse, 'CYP1B1)'])].
[sujeto(['Compared', with, the, 'beta-NF-induced', 'uterus,', polycyclic, aromatic, 'hydrocarbon-induced', uterine, fibroblasts, exhibited, 10, -, 20, -, fold, higher, levels, of, 'CYP1B1,']), verbo([suggesting]), complemento([that, stromal, fibroblasts, are, a, major, source, of, the, protein])].
[sujeto(['Long-term', parenteral, nutrition, '(', 'PN)', administration, can]), verbo([lead]), complemento([to, 'PN-associated', liver, diseases, '(', 'PNALD)'])].
[sujeto(['Although', multiple, risk, factors]), verbo([have]), complemento([been, identified, for, 'PNALD,', to, 'date,', the, roles, of, bile, acids, '(', 'BAs)', and, the, pathways, involved, in, 'BA', homeostasis, in, the, development, and, progression, of, 'PNALD', are, still, unclear])].
[sujeto(['We']), verbo([have]), complemento([established, a, mouse, 'PN', model, with, 'IV', infusion, of, 'PN', solution, containing, soybean, 'oil-based', lipid, emulsion, '(', 'SOLE)'])].
[sujeto(['Our', results, showed, that, 'PN', altered, the, expression, of, genes]), verbo([involved]), complemento([in, a, variety, of, liver, functions, at, the, mRNA, levels])].
[sujeto(['PN']), verbo([increased]), complemento([liver, gene, expression, of, 'Cyp7a1', and, markedly, decreased, that, of, 'Cyp8b1,', 'Cyp7b1,', 'Bsep,', and, 'Shp'])].
[sujeto(['CYP7A1', and, 'CYP8B1', are, important, for, synthesizing, the, total, amount, of, 'BAs', and]), verbo([regulating]), complemento([the, hydrophobicity, of, 'BAs,', respectively])].
[sujeto(['Consistently,', both, the, levels, and, the, percentages, of, primary, 'BAs', as, well, as, total, 'non-12α-OH', 'BAs']), verbo([increased]), complemento([significantly, in, the, serum, of, 'PN', mice, compared, with, saline, 'controls,', whereas, liver, 'BA', profiles, were, largely, similar])].
[sujeto(['The', expression, of, several, key, 'liver-X', 'receptor-α', '(', 'LXRα)']), verbo([target]), complemento([genes, involved, in, lipid, synthesis, was, also, increased, in, 'PN', mouse, livers])].
[sujeto(['Retinoid', 'acid-related', orphan, 'receptor-α', '(', 'RORα)']), verbo([has]), complemento([been, shown, to, induce, the, expression, of, 'Cyp8b1', and, 'Cyp7b1,', as, well, as, to, suppress, 'LXRα', function])].
[sujeto(['Western', blot, showed, significantly, reduced]), verbo([nuclear]), complemento([migration, of, 'RORα', protein, in, 'PN', mouse, livers])].
[sujeto(['This', study, shows, that, continuous, 'PN', infusion, with, 'SOLE', in, mice]), verbo([leads]), complemento([to, dysregulation, of, 'BA', homeostasis])].
[sujeto(['Licorice', '(', 'LE)']), verbo([has]), complemento([been, commonly, used, in, traditional, 'Chinese', medicine, '(', 'TCM)', for, over, 4000, years, to, reconcile, various, drugs, and, for, hepatic, disorders])].
[sujeto(['Treatment', of, 'HepG2', cells, with, glycyrrhizin, resulted, in, marked]), verbo([increase]), complemento([in, both, 'CYP3A4', mRNA, and, protein, levels])].
[sujeto(['Glycyrrhizin']), verbo([activates]), complemento([the, 'DNA-binding', capacity, of, the, 'PXR', for, the, 'CYP3A4', element, responding, to, xenobiotic, 'signals,', as, measured, by, the, 'electrophoretic-mobility', shift, assay, '(', 'EMSA)'])].
[sujeto(['These', results, indicate, that, the, induction, of, the, hepatic, 'CYP3A4', by, glycyrrhizin, is]), verbo([mediated]), complemento([through, the, activation, of, 'PXR'])].
[sujeto(['The', next, aim, of, the, current, study, was, to, determine, whether, the, activation, of, 'PXR', and, induction, of, 'CYP3A', by, glycyrrhizin]), verbo([prevents]), complemento([hepatotoxicity, during, cholestasis, as, a, mechanism, of, hepatoprotection])].
[sujeto(['Pre-treatment', with, 'glycyrrhizin,', as, well, as, the, 'PXR', activator, pregnenolone, 16, 'α-carbontrile', '(', 'PCN),']), verbo([prevents]), complemento([the, increase, in, plasma, 'ALT', and, 'AST', 'activity,', multifocal, necrosis, and, prevents, an, increase, in, a, level, of, serum, 'LCA', level, in, 'mice,', as, compared, with, the, results, in, the, mice, treated, with, 'LCA', alone])].
[sujeto(['Activation', of, the, 'PXR', by, glycyrrhizin, results, in, induction, of, 'CYP3A11', '(', 'CYP3A4', for, 'human)', expression, and, inhibition, of, 'CYP7A1', through, an]), verbo([increase]), complemento([in, small, heterodimer, partner, '(', 'SHP)', expression])].
[sujeto(['Glycyrrhizin']), verbo([regulates]), complemento([the, expression, of, the, gene, mentioned, above, to, prevent, toxic, accumulation, of, bile, acids, in, the, liver, and, it, also, protects, mouse, livers, from, the, harmful, effects, of, 'LCA'])].
[sujeto(['Our', previous, study, using, 'interleukin-1α/β-knockout', '(', 'IL-1-KO)', and, 'wild-type', '(', 'WT)', mice, demonstrated, that, 'IL-1']), verbo([acts]), complemento([as, a, positive, factor, for, constitutive, gene, expression, of, hepatic, cytochrome, 'P4507a1', '(', 'Cyp7a1)'])].
[sujeto(['In', this, 'study,', to, clarify, the, role, of, 'IL-1', in, the, expression, of, the, hepatic, 'Cyp7a1', 'gene,', we, focused, on, 'Cyp7a1', transcriptional, regulators, such, as, 'α-fetoprotein', transcription, factor, '(', 'FTF),', liver, 'X', receptor, α, '(', 'LXRα),', hepatocyte]), verbo([nuclear]), complemento([factor, 4, α, '(', 'HNF4α)', and, small, heterodimer, partner, '(', 'SHP)', and, examined, the, effects, of, 'IL-1', on, their, gene, expression, by, 'real-time', 'reverse-transcription', polymerase, chain, reaction, using, 'IL-1-KO', and, 'WT', mice])].
[sujeto(['These', findings, demonstrate, 'that,', like, 'TNF-α,', 'IL-1', positively, controls, the, gene, expression, of, 'Cyp7a1', transcriptional, upregulators, 'but,', in, contrast, to, the, previously]), verbo([reported]), complemento([action, of, 'TNF-α,', 'IL-1', also, acts, to, downregulate, 'SHP', gene, expression])].
[sujeto(['Bile', acid, sequestrants]), verbo([have]), complemento([been, shown, to, lower, glucose, levels, in, patients, with, type, 2, diabetes])].
[sujeto(['The', rats, were, fed, 'HE;', 'HE', +, 2, '%', 'CL;', 'HE', +, 0.02, '%', 'SC-435', '(', 'SC),', an, apical, 'sodium-dependent', bile, acid, transporter, 'inhibitor;', and]), verbo([regular]), complemento([chow, '(', 'controls)'])].
[sujeto(['CL']), verbo([induced]), complemento([release, of, 'glucagon-like', 'peptide-1', '(', 'GLP-1)', because, the, area, under, the, curve, of, plasma, total, 'GLP-1', in, the, 'CL', +, 'HE', group, was, significantly, greater, than, in, the, 'HE', group, during, the, 'OGTT'])].
[sujeto(['Bile', acid, concentrations, in, the, portal, blood, did, not]), verbo([decrease]), complemento([in, the, 'HE', group, but, declined, significantly, both, in, the, 'CL', +, 'HE', and, 'SC', +, 'HE', groups, with, reduced, farnesoid, 'X', receptor, activation, compared, with, controls])].
[sujeto(['It', is, unlikely, that, the, improvement, is, attributable, to]), verbo([decreased]), complemento([bile, acid, flux, to, the, liver, but, is, likely, secondary, to, induced, 'GLP-1', 'secretion,', which, improves, insulin, release])].
[sujeto(['Bile', acid, homeostasis, is, critical, in]), verbo([maintaining]), complemento([health, and, is, primarily, regulated, by, the, nuclear, receptors, farnesoid, 'X', receptor, '(', 'FXR)', and, small, heterodimer, partner, '(', 'SHP)'])].
[sujeto(['Bile', 'acid-activated', 'FXR', indirectly]), verbo([inhibits]), complemento([expression, of, cholesterol, 7, alpha, hydroxylase, '(', 'CYP7A1),', a, key, enzyme, in, conversion, of, cholesterol, to, bile, 'acids,', by, induction, of, 'SHP'])].
[sujeto(['We', recently, demonstrated, that, 'SHP']), verbo([inhibits]), complemento(['CYP7A1', transcription, by, recruiting, 'chromatin-modifying', 'cofactors,', including, 'Brm-Swi/Snf'])].
[sujeto(['Swi/Snf', complexes, contain, either, 'Brm', or, 'Brg-1', 'ATPases,', and, whether, these, subunits]), verbo([have]), complemento([distinct, functions, remains, unclear])].
[sujeto(['We']), verbo([have]), complemento([examined, the, role, of, these, subunits, in, regulation, of, bile, acid, metabolism, under, physiological, conditions, by, 'FXR', and, 'SHP'])].
[sujeto(['Brg-1']), verbo([interacted]), complemento([with, 'FXR', and, enhanced, 'FXR-mediated', transactivation, of, 'SHP,', whereas, 'Brm', interacted, with, 'SHP', and, enhanced, 'SHP-mediated', repression, of, 'CYP7A1', 'and,', 'interestingly,', 'auto-repression', of, 'SHP'])].
[sujeto(['Chromatin', immunoprecipitation, and, remodeling, studies, revealed, that, after, treatment, with, 'FXR', 'agonists,', 'Brg-1', was]), verbo([recruited]), complemento([to, the, 'SHP', 'promoter,', resulting, in, transcriptionally, active, accessible, 'chromatin,', whereas, 'Brm', was, recruited, to, both, 'CYP7A1', and, 'SHP', 'promoters,', resulting, in, inactive, inaccessible, chromatin])].
[sujeto(['Our', studies, demonstrate, that, 'Brm', and, 'Brg-1']), verbo([have]), complemento([distinct, functions, in, the, regulation, of, two, key, 'genes,', 'CYP7A1', and, 'SHP,', within, a, single, physiological, 'pathway,', feedback, inhibition, of, bile, acid, 'biosynthesis,', by, differentially, targeting, 'SHP', and, 'FXR'])].
[sujeto(['To']), verbo([gain]), complemento([insight, into, clock, output, functions, of, 'REV-ERBalpha,', we, carried, out, 'genome-wide', transcriptome, profiling, experiments, with, liver, 'RNA', from, 'wild-type', 'mice,', 'Rev-erbalpha', 'knock-out', 'mice,', or, 'REV-ERBalpha', overexpressing, mice])].
[sujeto(['On', the, basis, of, these, genetic, 'loss-', and, 'gain-of-function', 'experiments,', we, concluded, that, 'REV-ERBalpha']), verbo([participates]), complemento([in, the, circadian, modulation, of, sterol, regulatory, 'element-binding', protein, '(', 'SREBP)', 'activity,', and, thereby, in, the, daily, expression, of, 'SREBP', target, genes, involved, in, cholesterol, and, lipid, metabolism])].
[sujeto(['REV-ERBalpha', also]), verbo([participates]), complemento([in, the, cyclic, expression, of, 'cholesterol-7alpha-hydroxylase', '(', 'CYP7A1),', the, 'rate-limiting', enzyme, in, converting, cholesterol, to, bile, acids])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, this, control, acts, via, the, stimulation, of, 'LXR', nuclear, receptors, by, cyclically, produced, oxysterols])].
[sujeto(['In', 'conclusion,', our, study]), verbo([suggests]), complemento([that, rhythmic, cholesterol, and, bile, acid, metabolism, is, not, just, driven, by, alternating, 'feeding-fasting', 'cycles,', but, also, by, 'REV-ERBalpha,', a, component, of, the, circadian, clockwork, circuitry])].
[sujeto(['Intraluminal', concentrations, of, bile, acids, are, low, in, newborn, infants, and]), verbo([increase]), complemento([rapidly, after, 'birth,', at, least, partly, owing, to, increased, bile, acid, synthesis, rates])].
[sujeto(['The', expansion, of, the, bile, acid, pool, is, critical, since, bile, acids, are]), verbo([required]), complemento([to, stimulate, bile, flow, and, absorb, 'lipids,', a, major, component, of, newborn, diets])].
[sujeto(['The', purpose, of, the, present, studies, was, to, determine, the, mechanism, responsible, for, the]), verbo([increase]), complemento([in, bile, acid, synthesis, rates, and, the, subsequent, enlargement, of, bile, acid, pool, sizes, '(', 'BAPS)', during, the, neonatal, 'period,', and, how, changes, in, circulating, hormone, levels, might, affect, 'BAPS'])].
[sujeto(['In', the, 'hamster,', pool, size, was, low, just, after, birth, and]), verbo([increased]), complemento([modestly, until, 10.5, days, postpartum, '(', 'dpp)'])].
[sujeto(['BAPS']), verbo([increased]), complemento([more, significantly, '(', approximately, 3, -, 'fold)', between, 10.5, and, 15.5, dpp])].
[sujeto(['An']), verbo([increase]), complemento([in, mRNA, and, protein, levels, of, cholesterol, 7, 'alpha-hydroxylase', '(', 'Cyp7a1),', the, 'rate-limiting', step, in, classical, bile, acid, 'synthesis,', immediately, preceded, an, increase, in, 'BAPS'])].
[sujeto(['Finally,', although, simultaneous]), verbo([increases]), complemento([in, circulating, cortisol, and, 'Cyp7a1', levels, 'occurred,', precocious, expression, of, 'Cyp7a1', could, not, be, induced, in, neonatal, hamsters, with, dexamethasone])].
[sujeto(['Thus', the, significant]), verbo([increase]), complemento([in, 'Cyp7a1', levels, in, neonatal, hamsters, is, due, to, mechanisms, independent, of, the, 'FXR', and, 'SHP', pathway, and, cortisol])].
[sujeto(['Peroxisome', 'proliferators,', such, as, the, 'lipid-lowering', fibrates, that, function, as, agonists, for, peroxisome, 'proliferator-activated', receptor, alpha, '(', 'PPARalpha),']), verbo([induce]), complemento([liver, tumors, in, rodents, and, may, produce, cholestasis, in, humans])].
[sujeto(['Considerable', attention]), verbo([has]), complemento([focused, on, peroxisome, 'proliferator-induced', hepatocellular, 'carcinoma,', a, phenomenon, not, noted, in, 'man,', whereas, limited, studies, examine, fibrates, and, other, therapeutic, drugs, that, induce, 'cholestasis,', a, common, finding, in, humans])].
[sujeto(['Moreover,', the, mechanisms, by, which, fibrates]), verbo([induce]), complemento([hepatocyte, proliferation, and, cholestasis, are, still, not, fully, understood])].
[sujeto(['We']), verbo([have]), complemento([examined, the, role, of, hepatocyte, retinoid, 'X', receptor, alpha, '(', 'RXRalpha),', an, essential, partner, of, 'PPARalpha,', in, modulating, 'WY-14,643-induced', hepatocyte, proliferation, and, cholestasis])].
[sujeto(['WY-14,643', treatment]), verbo([induced]), complemento([hepatomegaly, in, wild, type, '(', 'WT)', mice, that, was, also, accompanied, by, induction, of, the, expression, of, cyclins, 'D1,', 'D3,', 'A2,', and, 'B1', and, 'Cdc2', as, well, as, inhibition, of, 'Wee', 1])].
[sujeto(['Furthermore,', neither, 'WY-14,643', treatment, nor, 'RXRalpha', deficiency, affected, 'apoptosis,', indicating, the, importance, of, 'PPARalpha/RXRalpha', in]), verbo([regulating]), complemento(['Wee', 1, -, mediated, 'Cdc2/cyclin', 'B1', expression, for, cells, to, enter, into, mitosis])].
[sujeto(['WY-14,643', treatment, also]), verbo([induced]), complemento([cholestasis, and, liver, 'injury,', which, is, evidenced, by, induction, of, alanine, 'aminotransferase,', alkaline, 'phosphatase,', and, hepatic, bile, acid, levels, in, 'WT', mice])].
[sujeto(['WY-14,643-mediated', induction, of, the, small, heterodimer, 'partner,', 'Mrp3,', and, 'Cyp3a11', levels, was, greater, in, hepatocyte, 'RXRalpha-null', than, in, 'WT', mouse, livers]), verbo([suggesting]), complemento([enhanced, repression, of, bile, acid, synthesis, and, increased, efflux, of, bile, acids, into, blood, for, renal, excretion, as, well, as, hydroxylation, of, bile, acids, because, of, hepatocyte, 'RXRalpha', deficiency])].
[sujeto(['These', data, establish, a, crucial, role, of, hepatocyte, 'RXRalpha', in]), verbo([regulating]), complemento(['WY-14,643-mediated', cell, cycle, progression, as, well, as, bile, acid, homeostasis])].
[sujeto(['TCDD']), verbo([caused]), complemento([an, increase, in, the, fecal, chenodeoxycholic, acid, and, taurocholic, acid, content, and, in, urinary, adrenaline, and, 17, 'β-estradiol,', while, the, urinary, melatonin, level, was, reduced, by, 'TCDD'])].
[sujeto(['In', 'addition,', 'CYP7A1,', a, 'rate-limiting', enzyme, for, bile, acid, 'biosynthesis,', was, attenuated, by, 'TCDD', 'treatment,', although, 'TCDD']), verbo([induced]), complemento([hepatic, 'CYP8B1,', an, enzyme, essential, for, cholic, acid, synthesis])].
[sujeto(['These', results]), verbo([suggest]), complemento(['that:', 1, ')', 'TCDD', alters, the, circulating, levels, of, bile, acids, and, hormones, via, a, mechanism, distinct, from, an, attenuation, in, dietary, 'intake,', although, the, majority, of, 'TCDD-induced', changes, in, nutrient, contents, in, the, excrement, is, due, to, a, reduction, in, food, 'intake;', and, 2, ')', 'TCDD', facilitates, the, excretion, of, bile, acids, and, disrupts, their, 'biosynthesis,', resulting, in, the, disturbance, of, lipid, homeostasis])].
[sujeto(['This', study, aimed, to, examine, sex, differences, in, the, circadian, variation, of, hepatic, cytochrome, 'P450', '(', 'Cyp)', genes, and, corresponding]), verbo([nuclear]), complemento([receptors])].
[sujeto(['Circadian', variation, of, hepatic, clock, genes, such, as]), verbo([nuclear]), complemento([receptor, 'Rev-erbα,', cryptochrome, 1, '(', 'Cry1),', and, brain, muscle, 'ARNT-like', protein, 1, '(', 'Bmal1)', showed, distinct, patterns])].
[sujeto(['Sex', differences, and, circadian, rhythmicity, of, 'Cyp', genes, and, corresponding]), verbo([nuclear]), complemento([receptors, exist, in, mouse, liver, that, could, impact, xenobiotic, metabolism, and, toxicity, at, different, times, of, the, day])].
[sujeto(['Cholesterol', 7, 'α-hydroxylase', '(', 'CYP7A1)']), verbo([regulates]), complemento([the, balance, between, cholesterol, supply, and, metabolism, by, catalyzing, the, 'rate-limiting', step, of, bile, acid, biosynthesis])].
[sujeto(['The', transcriptional, activity, of, 'CYP7A1', is, tightly, controlled, by, various]), verbo([nuclear]), complemento([receptors])].
[sujeto(['A', forkhead, transcription, factor, 'O1', '(', 'FOXO1)', plays, a, critical, role, in, 'metabolism,', and, insulin, inactivates, 'FOXO1', through, 'Akt-dependent', phosphorylation, and]), verbo([nuclear]), complemento([exclusion])].
[sujeto(['We', investigated, the, role, of, 'insulin-', 'Akt-FOXO1', signaling, pathway, in, 'CYP7A1', transcriptional, regulation, since, we]), verbo([found]), complemento([putative, 'insulin-response', 'elements,', 'FOXO1', binding, 'sequences,', in, both, rat, and, human, 'CYP7A1', promoters])].
[sujeto(['However,', ectopic, expression, of, 'FOXO1']), verbo([increased]), complemento([the, rat, 'CYP7A1-,', but, mildly, reduced, human, 'CYP7A1-promoter', activities, in, a, 'dose-dependent', manner])].
[sujeto(['Similarly', to, bile, 'acids,', insulin, treatment]), verbo([increased]), complemento([small, heterodimer, partner, '(', 'SHP)', mRNA, rapidly, and, 'transiently,', leading, to, the, suppression, of, 'CYP7A1', transcription, in, both, human, and, rodents])].
[sujeto(['Chromatin', immunoprecipitation, showed, that, 'FOXO1', directly]), verbo([bound]), complemento([to, rat, 'CYP1A1', promoter, in, the, absence, of, insulin])].
[sujeto(['FOXO1']), verbo([binding]), complemento([to, the, rat, promoter, was, diminished, by, insulin, treatment, as, well, as, by, expression, of, 'SHP'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, the, stimulation, of, 'insulin-', signaling, pathway, of, 'Akt-FOXO1', and, 'SHP', expression, may, regulate, 'cholesterol/bile', acid, metabolisms, in, 'liver,', linking, carbohydrate, and, cholesterol, metabolic, pathways])].
[sujeto(['A', prolonged, exposure, of, insulin, in, hyperinsulinemic, insulin, resistance, or, diabetic, status]), verbo([represses]), complemento(['CYP7A1', transcription, and, bile, acid, biosynthesis, through, 'SHP', induction, and, 'FOXO1', 'inactivation,', leading, to, impairment, of, the, hepatic, 'cholesterol/bile', acid, metabolisms])].
[sujeto(['To', understand, the, exact, mechanism, of, 'cold-stress', in, broilers, depends, heavily, on, identification, of, differentially]), verbo([expressed]), complemento(['genes,', rarely, conducted, so, 'far,', in, the, pituitary, of, 1, &, 'nbsp;day', 'pre-', and, 'post-cold-stress'])].
[sujeto(['The', results, showed, that, the, expression, of, 15, genes, were, 'up-regulated', and, 15, 'down-regulated', in, the, pituitary, of, cold, stressed, broilers, compared, with, normal, 'ones;', and, these, differentially]), verbo([expressed]), complemento([genes, belong, to, groups, involved, with, catalytic, 'activity,', enzyme, regulatory, 'activity,', signal, transducer, activity, and, transporter, activity])].
[sujeto(['Functional', analysis, revealed, that, cytochrome, 'P450', '(', 'CYP)', gene, 'group,', such, as, 'CYP7A1,', 'CYP1A1,', which, are, highly, related, to, fat, 'metabolism,']), verbo([involved]), complemento([in, those, biological, activities])].
[sujeto(['Furthermore,', blood, lipid, levels, of, 'triglyceride,', total, 'cholesterol,', 'low-density-lipoprotein', and, 'high-density-lipoprotein', were, 'measured,', and, the]), verbo([decreased]), complemento([level, of, blood, lipid, after, cold, stress, suggested, that, lipid, could, positively, affect, 'CYP7A1', gene, expression, in, broilers])].
[sujeto(['However,', future, study, is]), verbo([required]), complemento([to, quantify, the, 'CYP', gene, expression, during, cold, stress])].
[sujeto(['In', 'conclusion,', our, findings, will, not, only, offer, basic, genetic, information, to, identify, candidate, genes, for, chicken, breeding, of, 'anti-cold', stress, 'broilers,', but, also]), verbo([provide]), complemento([new, clues, for, deciphering, mechanisms, underlining, cold, stress, in, vertebrates])].
[sujeto(['Cytochrome', 'P450', enzymes, '(', 'CYPs)', belong, to, hemeproteins]), verbo([found]), complemento([in, all, living, organisms])].
[sujeto(['CYP1A1', and, 'CYP3A8', mRNAs, were, significantly]), verbo([induced]), complemento([by, 3, -, methylcholanthrene, and, 'rifampicin,', respectively])].
[sujeto(['However,', 'CYP2C43', and, 'CYP2D17', were, not]), verbo([induced]), complemento([by, these, compounds])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, the, differentiation, into, hepatocytes, is, affected, by, the, incubation, period, for, 'EB', 'formation,', and, that, 'Matrigel', successfully, promoted, in, vitro, differentiation, of, cmES, cells, to, hepatocytes])].
[sujeto(['Hepatocyte', differentiation, markers, were]), verbo([expressed]), complemento([in, the, cells, differentiated, from, mouse, embryonic, stem, '(', 'ES)', cells])].
[sujeto(['In', the, differentiating, 'ES', 'cells,', 'Cyp1a1', mRNA, was, highly]), verbo([expressed]), complemento([during, the, early, to, middle, 'stage;', 'Cyp2c29,', 'Cyp2e1,', 'Cyp3a11', and, 'Cyp7a1', mRNAs, were, expressed, only, at, the, late, 'stage;', 'Cyp7b1', mRNA, was, expressed, throughout, all, stages])].
[sujeto(['Aryl', hydrocarbon, 'receptor,', aryl, hydrocarbon, receptor]), verbo([nuclear]), complemento([translocator, and, glucocorticoid, receptor, mRNAs, were, detected, in, differentiating, 'ES', cells, throughout, the, culture, period])].
[sujeto(['The', expression, levels, of, 'Cyp2c29,', 'Cyp3a11', and, 'Cyp7a1', and, 'G6p', mRNAs, were]), verbo([increased]), complemento([in, embryoid, bodies, that, were, cultured, with, culture, medium, containing, acid, fibroblast, growth, 'factor,', hepatocyte, growth, factor, '(', 'HGF)', and, oncostatin, 'M', for, 12, or, 18, 'days,', then, the, medium, was, replaced, by, that, without, 'HGF'])].
[sujeto(['These', findings]), verbo([suggested]), complemento([that, the, expression, levels, of, 'Cyp', genes, in, hepatocytes, differentiated, from, 'ES', cells, were, markedly, changed, in, individual, enzymes, during, the, course, of, 'differentiation,', and, that, the, duration, of, incubation, with, the, addition, of, 'HGF', affected, the, expression, of, 'Cyps', and, hepatocytes, marker, proteins])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF4alpha)', is, a, key, transcription, factor, for, the, constitutive, expression, of, cytochromes, 'P450', '(', 'P450s)', in, the, liver])].
[sujeto(['However,', human, hepatoma, 'HepG2', cells, show, a, high, level, of, 'HNF4alpha', but]), verbo([express]), complemento([only, marginal, 'P450', levels])].
[sujeto(['We']), verbo([found]), complemento([that, the, 'HNF4alpha-mediated', 'P450', transcription, in, 'HepG2', is, impaired, by, the, low, level, of, coactivators, peroxisomal, proliferator, activated, 'receptor-gamma', coactivator, 1, alpha, '(', 'PGC1alpha)', and, steroid, receptor, coactivator, 1, '(', 'SRC1)'])].
[sujeto(['Reporter', assays, with, a, chimeric, 'CYP2C9-LUC', construct, demonstrated, that, the, sole, transfection, of, coactivators]), verbo([induced]), complemento([luciferase, activity, in, 'HepG2', cells])].
[sujeto(['In', 'HeLa', cells, 'however,', 'CYP2C9-LUC', activity, only, significantly]), verbo([increased]), complemento([when, coactivators, were, cotransfected, with, 'HNF4alpha'])].
[sujeto(['A', deletion, mutant, lacking, the, two, proximal, 'HNF4alpha']), verbo([binding]), complemento([sites, in, the, 'CYP2C9', promoter, did, not, respond, to, 'PGC1alpha', or, 'SRC1,', demonstrating, that, coactivators, were, acting, through, 'HNF4alpha', response, elements])].
[sujeto(['Adenovirus-mediated', transfection, of, 'PGC1alpha', in, human, hepatoma, cells]), verbo([caused]), complemento([a, significant, 'dose-dependent', increase, in, 'CYP2C9,', 'CYP1A1,', and, 'CYP1A2', and, in, the, positive, control, 'CYP7A1'])].
[sujeto(['PGC1alpha', also, showed, a, moderate]), verbo([activating]), complemento([effect, on, 'CYP3A4,', 'CYP3A5,', and, 'CYP2D6'])].
[sujeto(['Chromatin', immunoprecipitation, assay, demonstrated, in, vivo]), verbo([binding]), complemento([of, 'HNF4alpha', and, 'PGC1alpha', to, 'HNF4alpha', response, sequences, in, the, 'CYP2C9', promoter, and, to, three, new, regulatory, regions, in, the, common, 23.3, kilobase, spacer, sequence, of, the, 'CYP1A1/2', cluster])].
[sujeto(['Insulin', treatment, of, 'HepG2', and, human, hepatocytes]), verbo([caused]), complemento([repression, of, 'PGC1alpha', and, a, concomitant, 'down-regulation', of, 'P450s'])].
[sujeto(['Small', 'Heterodimer', 'Partner', '(', 'SHP)']), verbo([inhibits]), complemento([numerous, transcription, factors, that, are, involved, in, diverse, biological, 'processes,', including, lipid, and, glucose, metabolism])].
[sujeto(['In', response, to]), verbo([increased]), complemento([hepatic, bile, 'acids,', 'SHP', gene, expression, is, induced, and, the, 'SHP', protein, is, stabilized])].
[sujeto(['We', now, show, that, the, activity, of, 'SHP', is, also]), verbo([increased]), complemento([by, posttranslational, methylation, at, 'Arg-57', by, protein, arginine, methyltransferase, 5, '(', 'PRMT5)'])].
[sujeto(['Adenovirus-mediated', hepatic, depletion, of, 'PRMT5']), verbo([decreased]), complemento(['SHP', methylation, and, reversed, the, suppression, of, metabolic, genes, by, 'SHP'])].
[sujeto(['Mutation', of, 'Arg-57']), verbo([decreased]), complemento(['SHP', interaction, with, its, known, 'cofactors,', 'Brm,', 'mSin3A,', and, histone, deacetylase, 1, '(', 'HDAC1),', but, not, with, 'G9a,', and, decreased, their, recruitment, to, 'SHP', target, genes, in, mice])].
[sujeto(['Hepatic', overexpression, of, 'SHP']), verbo([inhibited]), complemento([metabolic, target, 'genes,', decreased, bile, acid, and, hepatic, triglyceride, 'levels,', and, increased, glucose, tolerance])].
[sujeto(['In', 'contrast,', mutation, of, 'Arg-57', selectively, reversed, the, inhibition, of, 'SHP']), verbo([target]), complemento([genes, and, metabolic, outcomes])].
[sujeto(['The', importance, of, 'Arg-57', methylation, for, the, repression, activity, of, 'SHP']), verbo([provides]), complemento([a, molecular, basis, for, the, observation, that, a, natural, mutation, of, 'Arg-57', in, humans, is, associated, with, the, metabolic, syndrome])].
[sujeto(['A', cytochrome, 'P-450', '(', 'P-450),', designated, 'P-450HK', 'omega,']), verbo([has]), complemento([been, isolated, and, purified, from, human, kidney, microsomes, to, a, specific, content, of, 13, nmoles, of, 'P-450/mg', of, protein])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, 'P-450HK', omega, is, a, member, of, the, same, 'P-450', gene, family, '(', 'IVA', 'subfamily)', as, the, rabbit, enzymes])].
[sujeto(['To', our, 'knowledge,', this, is, the, first, time, that, a, 'P-450', specific, for, fatty, acid, 'omega-hydroxylase', activity]), verbo([has]), complemento([been, isolated, to, homogeneity, from, human, tissues])].
[sujeto(['We']), verbo([have]), complemento([isolated, a, cDNA, clone, for, a, 'P-450,', designated, 'P-450ib', '(', 'Ichihara,', 'K'])].
[sujeto(['As', the, 'NH2-terminal', methionine, was, not]), verbo([found]), complemento([in, the, sequence, from, the, purified, 'protein,', the, apoprotein, of, 'P-450ib', is, composed, of, 500, amino, acids, with, a, molecular, weight, of, 57, ',', 193])].
[sujeto(['P-450ib', shows, 35, -, 41, '%', sequence, similarity, with, several, members, of, 8, subfamilies, in, the, 'P-450', 'II', 'family,', whereas, it]), verbo([has]), complemento([a, less, than, 30, '%', sequence, similarity, with, other, 'P-450', 'families,', suggesting, that, this, 'P-450', is, the, first, member, of, a, novel, subfamily, within, the, 'P-450', 'II', family])].
[sujeto(['RNA', blot, analysis, shows, that, mRNA, hybridized, to, the, cDNA, is]), verbo([expressed]), complemento([in, the, small, 'intestine,', but, not, significantly, in, other, tissues, including, 'liver,', 'colon,', 'kidney,', 'lung,', 'spleen,', 'brain,', 'stomach,', and, 'cecum,', indicating, that, 'P-450ib', is, a, 'P-450', specific, to, the, small, intestine])].
[sujeto(['The', protein]), verbo([expressed]), complemento([in, 'COS-7', cells, using, the, cDNA, in, an, expression, 'vector,', 'pKCRH2,', shows, benzphetamine, 'N-demethylase', activity, and, gives, a, band, identical, with, that, of, 'P-450ib', in, its, mobility, on, sodium, dodecyl, 'sulfate-polyacrylamide', gel, electrophoresis])].
[sujeto(['While', the, pathogenesis, of, 'TCDD-induced', toxicity, is, poorly, 'understood,', it]), verbo([has]), complemento([been, shown, that, the, aryl, hydrocarbon, receptor, '(', 'AHR)', is, required])].
[sujeto(['However,', the, specific, transcriptomic, changes, that]), verbo([lead]), complemento([to, toxic, outcomes, have, not, yet, been, identified])].
[sujeto(['We', previously, identified, a, panel, of, 33, genes, that]), verbo([respond]), complemento([to, 'TCDD', treatment, in, two, 'TCDD-sensitive', rodent, species])].
[sujeto(['To', identify, genes]), verbo([involved]), complemento([in, the, onset, of, hepatic, 'toxicity,', we, explored, 25, of, these, 'in-depth', using, liver, from, two, rat, 'strains:', the, 'TCDD-resistant', 'Han/Wistar', '(', 'H/W)', and, the, 'TCDD-sensitive', 'Long-Evans', '(', 'L-E)'])].
[sujeto(['Time', course, and, 'dose-response', analyses, of, mRNA, abundance, following, 'TCDD', insult, indicate, that, eight, genes, are, similarly]), verbo([regulated]), complemento([in, livers, of, both, strains, of, 'rat,', suggesting, that, they, are, not, central, to, the, severe, 'L-E-specific', 'TCDD-induced', toxicities])].
[sujeto(['Four', genes, showed, an, early, 'inter-strain', difference, that, was, sustained, throughout, most, of, the, time, course, '(', atypical, chemokine, receptor, 3, '(', 'Ackr3),', 'collagen,', type, 'XVIII,', alpha, 1, '(', 'Col18a1),', 'Cyb5a', and, glutamate, dehydrogenase, 1, '(', 'Glud1)),', and, of, those, genes, examined, in, this, 'study,', are, most, likely, to, represent, genes]), verbo([involved]), complemento([in, the, pathogenesis, of, 'TCDD-induced', hepatotoxicity, in, 'L-E', rats])].
[sujeto(['Lansoprazole', is, a, potent, 'anti-gastric', ulcer, drug, that]), verbo([inhibits]), complemento([gastric, proton, pump, activity])].
[sujeto(['Gastric', administration, of, lansoprazole, '(', 10, -, 100, 'mg/kg)', to, male, 'Wistar', rats, produced, a, 'dose-dependent']), verbo([increase]), complemento([in, hepatic, mRNA, levels, of, nuclear, 'factor,', 'erythroid-derived', 2, ',', -, like, 2, '(', 'Nrf2),', a, 'redox-sensitive', transcription, 'factor,', at, 3, h, and, 'Nrf2', immunoreactivity, '(', 'IR)', in, whole, hepatic, lysates, at, 6, h])].
[sujeto(['Furthermore,', the, levels, of, 'HO-1', 'IR', were, 'dose-dependently']), verbo([increased]), complemento([in, hepatocytes, at, 6, h])].
[sujeto(['Subcutaneous', administration, of, lansoprazole, '(', 30, 'mg/kg/day)', for, 7, successive, days, resulted, in, 'up-regulation', and]), verbo([nuclear]), complemento([translocation, of, 'Nrf2', 'IR', in, hepatocytes, and, 'up-regulation', of, 'HO-1', 'IR', in, the, liver])].
[sujeto(['Up-regulation', of, the, aryl, hydrocarbon, receptor, '(', 'AhR)-cytochrome', 'P450,', family, 1, ',', subfamily, 'a,', polypeptide, 1, '(', 'Cyp1a1)', pathway, was]), verbo([associated]), complemento([with, 'up-regulation', of, 'Nrf2', mRNA])].
[sujeto(['In', 'conclusion,', lansoprazole, might]), verbo([have]), complemento([an, alternative, indication, in, the, prevention, and, treatment, of, oxidative, hepatic, damage, through, the, induction, of, both, phase, 'I', and, phase, 'II', 'drug-metabolizing', 'systems,', i])].
[sujeto(['The', aryl, hydrocarbon, receptor, '(', 'AHR)', is, a, 'ligand-activated', transcription, factor, which, plays, a, role, in, the, development, of, multiple, tissues, and, is]), verbo([activated]), complemento([by, a, large, number, of, 'ligands,', including, 2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD)'])].
[sujeto(['AHR-KO', rats, were, also, insensitive, to, thymic, 'involution,']), verbo([increased]), complemento([hepatic, weight, and, the, induction, of, 'AHR-responsive', genes, '(', 'Cyp1a1,', 'Cyp1a2,', 'Cyp1b1,', 'Ahrr)', following, acute, exposure, to, 25, 'μg/kg', 'TCDD'])].
[sujeto(['Western', 'Blot', analysis, using, the, antibody, 'anti-CYP1A']), verbo([recognized]), complemento([the, presence, of, a, band, of, about, 60, kDa, in, the, liver, of, males, and, females])].
[sujeto(['The', present, data]), verbo([suggest]), complemento([that, pollutants, are, 'bio-available', as, demonstrated, by, our, biomarker, analyses, and, may, have, a, harmful, effect, on, aquatic, organisms, such, as, 'Z'])].
[sujeto(['We']), verbo([report]), complemento([that, the, highest, levels, of, hepatic, 8, -, 'OHdG', and, 'CYP1A', expression, were, detected, in, 'males,', showing, clear, gender, specificity])].
[sujeto(['We', determined, whether, different, blood, dioxin, concentrations, are]), verbo([associated]), complemento([with, polymorphisms, in, 'AHR', '(', dbSNP, 'ID:', 'rs2066853),', 'AHR', repressor, '(', 'AHRR;', 'rs2292596),', 'CYP1', subfamily, 'A', polypeptide, 1, '(', 'CYP1A1;', rs4646903, and, 'rs1048963),', 'CYP1', subfamily, 'A', polypeptide, 2, '(', 'CYP1A2;', 'rs762551),', and, 'CYP1', subfamily, 'B', polypeptide, 1, '(', 'CYP1B1;', 'rs1056836)', in, pregnant, 'Japanese', women])].
[sujeto(['Second,', we]), verbo([found]), complemento([a, significant, association, with, the, dominant, genotype, model, '(', '[', 'TT+TC]', vs])].
[sujeto(['No', significant, differences, were]), verbo([found]), complemento([among, blood, dioxin, concentrations, and, polymorphisms, in, 'AHRR,', 'CYP1A1', '(', 'rs1048963),', 'CYP1A2,', and, 'CYP1B1'])].
[sujeto(['Thus,', polymorphisms, in, 'AHR', and, 'CYP1A1', '(', 'rs4646903)', were]), verbo([associated]), complemento([with, maternal, dioxin, concentrations])].
[sujeto(['Among', the, differentially]), verbo([expressed]), complemento([genes, in, both, cell, 'lines,', cytochrome, 'P450,', family, 1, ',', subfamily, 'A,', polypeptide, 1, '(', 'CYP1A1)', was, chosen, for, further, study])].
[sujeto(['CYP1A1', mRNA, and, protein, levels, and, enzymatic, activity]), verbo([increased]), complemento([upon, 'PCE', incubation])].
[sujeto(['CYP1A1', transcriptional, activation, by, 'PCE', was]), verbo([mediated]), complemento([through, 'AhR', binding, to, 'XRE', elements, within, the, 'CYP1A1', promoter, in, 'MCF-7', cells])].
[sujeto(['The', combination, of, 'PCE', with, tamoxifen]), verbo([caused]), complemento([a, synergistic, cytotoxicity, in, both, cell, lines, and, was, due, to, an, increase, in, apoptosis, in, 'MCF-7', cells])].
[sujeto(['The', interaction, between, 'ERα', and, 'AhR', upon, incubation, with, 'PCE']), verbo([leads]), complemento([to, 'CYP1A1', induction, in, breast, cancer, cells])].
[sujeto(['The', synergy, between, 'PCE', and, 'non-cytotoxic', tamoxifen, concentrations, opens, the, possibility, for, a, combination, therapy, based, on, polyphenols, from, cocoa, that]), verbo([increased]), complemento([tamoxifen, efficacy])].
[sujeto(['An', inherited, profile, of, genes, related, to, the, response, to, aggressive, environmental, factors, such, as, viruses, and, chemicals, may, be, related, to, an]), verbo([increased]), complemento([susceptibility, to, 'Graves\'', disease, '(', 'GD)'])].
[sujeto([1, ')', ',', and, it]), verbo([increased]), complemento([the, risk, for, 'GD', more, than, three, times, '(', 'OR=3'])].
[sujeto(['The', inheritance, of, less, efficient, 'Pro/Pro', 'TP53', gene, variants, significantly]), verbo([increased]), complemento([the, risk, of, 'GD', development, '(', 'OR=5'])].
[sujeto(['We']), verbo([suggest]), complemento([that, an, inherited, genetic, profile, involving, 'TP53', may, favor, 'HHV-7', infection, and, 'maintenance,', 'which,', in, 'turn,', may, initiate, and, perpetuate, 'GD', autoimmune, process])].
[sujeto(['Lung', cancer, remains, a]), verbo([leading]), complemento([cause, of, disease, 'globally,', with, smoking, being, the, largest, single, cause])].
[sujeto(['Phase', 'I', 'enzymes,', including, cytochrome, 'P(450),', family, 1, ',', subfamily, 'A,', polypeptide, 1, '(', 'CYP1A1),', are]), verbo([involved]), complemento([in, the, activation, of, 'carcinogens,', such, as, polycyclic, aromatic, 'hydrocarbons,', to, reactive, intermediates, that, are, capable, of, binding, covalently, to, 'DNA', to, form, 'DNA', 'adducts,', potentially, initiating, the, carcinogenic, process])].
[sujeto(['CYP1A1', haplotypes, '(', in, allele, order, 'CYP1A1*4,', 'CYP1A1*2C,', 'CYP1A1*2A)', 'CGC', and, 'CGT', were]), verbo([associated]), complemento([with, an, increased, risk, of, lung, 'cancer,', whereas, 'AAT', was, associated, with, decreased, lung, cancer, risk, in, this, population])].
[sujeto(['The', present, study]), verbo([has]), complemento([identified, risk, haplotypes, for, 'CYP1A1', in, 'NSCLC', and, confirmed, that, 'CYP1A1', polymorphisms, are, a, minor, risk, factor, for, 'NSCLC'])].
[sujeto(['Polycystic', ovary, syndrome, '(', 'PCOS)', is, a, complex, 'multi-factorial', disorder]), verbo([involving]), complemento([a, number, of, genetic, and, environmental, factors])].
[sujeto(['CYP1A1', '(', 'Cytochrome', 'P450,', family, 1, ',', subfamily, 'A,', polypeptide, 1, ')', 'gene,', which, belongs, to, 'Cytochrome', 'P450', '(', 'CYP)', super, 'family,', encodes, a, phase, 'I', cytochrome, 'P450', 'enzyme,']), verbo([involved]), complemento([in, the, oxidative, metabolism, of, estrogens])].
[sujeto(['A', recent, study]), verbo([suggested]), complemento([that, a, common, polymorphism, 'Ile462Val', of, the, 'CYP1A1', gene, might, be, associated, with, 'PCOS', development, in, 'Turkish', women])].
[sujeto(['We']), verbo([have]), complemento([analyzed, the, effects, of, 'low-dose', transplacental, and, lactational, exposure, of, 2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD)', on, gene, expression, relating, to, the, dioxin, and, sexual, hormone, 'cascade,', and, demonstrated, the, effects, on, testicular, growth, and, sexual, maturation, in, male, offspring, rats])].
[sujeto(['Gene', expression, of, cytochrome, 'P450', family, 1, subfamily, 'A', polypeptide, 1, '(', 'CYP1A1)', in, the, liver, of, 17, -, 'day-old', rats, was, significantly]), verbo([increased]), complemento([compared, with, controls])].
[sujeto(['Furthermore,', expression, of, estrogen, receptors, '(', 'ER)alpha', and, 'ERbeta', was, significantly]), verbo([increased]), complemento([at, 17, and, 42, days, 'old,', respectively, in, the, testis, of, 'TCDD-administered', rats, compared, with, controls])].
[sujeto(['Although', testicular, weight, and, the, seminiferous, tubule, diameter, were]), verbo([increased]), complemento([in, 17, -, 'day-old', 'rats,', there, was, no, difference, in, the, number, of, germ, cells, between, 'TCDD-treated', and, control, animals])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'low-dose', exposure, of, 'TCDD', leads, to, unusual, development, of, the, testis, by, perturbation, of, steroid, hormone, homeostasis])].
[sujeto(['The', inhibitory, effect, of, a, series, of, these, compounds, on, 'high-affinity', phenacetin, 'O-deethylase', activity, in, the, human, liver, microsomal, 'fraction,', a, measure, of, 'CYP1A2', 'activity,']), verbo([has]), complemento([been, evaluated])].
[sujeto([1, -, 'Methylxanthine,', 'caffeine,', 'theophylline,', 8, -, 'methylxanthine,', pentoxyfylline, and, 3, 'isobutyl-1-methylxanthine']), verbo([caused]), complemento([moderate, inhibition, with, 'IC50', =, 260, ',', 140, ',', 120, ',', 100, ',', 62, and, 36, microM, respectively])].
[sujeto(['Cadmium', uptake]), verbo([increased]), complemento([during, a, 24, -, h, period])].
[sujeto(['Cadmium', effects, were, reduced, in, preexposed, 'cells,', indicating, adaptive, tolerance, or]), verbo([increased]), complemento([resistance, had, occurred])].
[sujeto(['Twenty-four-hour', 'LC50,', dose]), verbo([causing]), complemento([death, of, 50, '%', of, the, test, 'subjects,', values, were, 0.97, ',', 0.69, ',', and, 0.8, ppm, '(', 8.7, ',', 6.2, ',', and, 7.2, 'microM)', for, naive, cells, and, 1.45, ',', 1.21, ',', and, 1.39, ppm, '(', 12.9, ',', 10.7, ',', and, 12.3, 'microM)', for, preexposed, cells, based, on, the, 'NR,', 'MTT,', and, 'L/D', 'assays,', respectively])].
[sujeto(['Introduction', of, an, isopropyl, group, at, the, 2, -, position, and, a, methoxy, group, at, the, 5, -, position, of, the, benzimidazole, ring, of]), verbo([lead]), complemento([compound, 1, resulted, in, the, identification, of, 2, -, '{', '[', '(', 2, -, 'isopropyl-5-methoxy-1-phenyl-1H-benzimidazol-6-yl)oxy]methyl}quinoline', '(', 25, 'b),', which, exhibited, potent, 'PDE10A', inhibitory, activity, with, reduced, 'CYP1A2', inhibitory, activity, compared, to, compound, 1])].
[sujeto(['Cholestasis']), verbo([activates]), complemento([bile, acid, receptor, farnesoid, 'X', receptor, '(', 'FXR)', and, subsequently, enhances, hepatic, expression, of, small, heterodimer, partner, '(', 'SHP)'])].
[sujeto(['We', previously, demonstrated, that, 'SHP']), verbo([represses]), complemento([the, transactivation, of, cytochrome, 'P450', 2, 'D6', '(', 'CYP2D6)', promoter, by, hepatocyte, nuclear, factor, '(', 'HNF)', 4, α])].
[sujeto(['In', 'CYP2D6-humanized', transgenic, '(', 'Tg-CYP2D6)', 'mice,', cholestasis]), verbo([triggered]), complemento([by, administration, of, 17, 'α-ethinylestradiol', '(', 'EE2)', at, a, high, dose, led, to, 2, -, to, 3, -, fold, decreases, in, 'CYP2D6', expression])].
[sujeto(['This', was, accompanied, by]), verbo([increased]), complemento([hepatic, 'SHP', expression, and, subsequent, decreases, in, the, recruitment, of, 'HNF4α', to, 'CYP2D6', promoter])].
[sujeto(['Interestingly,', 'estrogen-induced', cholestasis, also]), verbo([led]), complemento([to, increased, recruitment, of, estrogen, receptor, '(', 'ER)', 'α,', but, not, that, of, 'FXR,', to, 'Shp', 'promoter,', suggesting, a, predominant, role, of, 'ERα', in, transcriptional, regulation, of, 'SHP', in, 'estrogen-induced', cholestasis])].
[sujeto(['EE2', at, a, low, dose, '(', that, does, not]), verbo([cause]), complemento(['cholestasis)', also, increased, 'SHP', '(', by, '∼', 50, '%', ')', and, decreased, 'CYP2D6', expression, '(', by, 1.5, -, 'fold)', in, 'Tg-CYP2D6', 'mice,', the, magnitude, of, differences, being, much, smaller, than, that, shown, in, 'EE2-induced', cholestasis])].
[sujeto(['Taken', 'together,', our, data, indicate, that, 'EE2-induced', cholestasis]), verbo([increases]), complemento(['SHP', and, represses, 'CYP2D6', expression, in, 'Tg-CYP2D6', mice, in, part, through, 'ERα', transactivation, of, 'Shp', promoter])].
[sujeto(['We']), verbo([have]), complemento([recently, reported, that, transactivation, of, cytochrome, 'P450', '(', 'CYP)', 2, 'D6', promoter, by, hepatocyte, nuclear, factor, '(', 'HNF)', 4, α, is, enhanced, during, 'pregnancy,', and, this, is, triggered, in, part, by, altered, expression, of, small, heterodimer, partner, '(', 'SHP)', and, 'Krüppel-like', factor, 9, '(', 'KLF9)'])].
[sujeto(['The', objective, of, this, study, is, to, determine, whether, this, is]), verbo([conserved]), complemento([for, mouse, endogenous, 'Cyp2d', 'gene(s)'])].
[sujeto(['Among', the, eight, 'Cyp2d', homologs, of, mouse, we, 'examined,', only, 'Cyp2d40', expression, was]), verbo([found]), complemento([induced, '(', by, 6, -, 'fold)', at, term, pregnancy, as, compared, to, 'pre-pregnancy', level])].
[sujeto(['In', mice, where, hepatic, 'Hnf4α', was, 'knocked-down,', the, 'pregnancy-mediated']), verbo([increase]), complemento([in, 'Cyp2d40', expression, was, abrogated])].
[sujeto(['Results', from, transient, 'transfection,', promoter, reporter, 'assays,', and, electrophoretic, mobility, shift, assays, indicated, that, 'HNF4α', transactivates, 'Cyp2d40', promoter, via, direct]), verbo([binding]), complemento([to, -, 117, /, -, 105, of, the, gene])].
[sujeto(['Chromatin', immunoprecipitation, assay, showed, a, 2.3, -, fold]), verbo([increase]), complemento([in, 'HNF4α', recruitment, to, 'Cyp2d40', promoter, during, pregnancy])].
[sujeto([',', 'GW4064)', and, 'HepG2', cells, 'co-transfected', with, 'KLF9']), verbo([suggest]), complemento([that, neither, 'SHP', nor, 'KLF9', is, involved, in, the, increased, 'HNF4α', transactivation, of, 'Cyp2d40', promoter, during, pregnancy])].
[sujeto(['Together,', our, results, indicate, that, while, the, underlying, molecular, mechanism, is, different, from, that, for, 'CYP2D6,', 'Cyp2d40', is]), verbo([induced]), complemento([during, pregnancy, through, enhanced, transactivation, by, 'HNF4α'])].
[sujeto(['However,', there]), verbo([have]), complemento([been, no, consistent, results, reported, regarding, the, relationship, between, cytochrome, 'P450', '(', 'CYP)', 2, 'D6', or, adenosine, 'triphosphate-binding', cassette, subfamily, 'B', member, 1, '(', 'ABCB1)', variant, alleles, and, 9, -, 'OH-RIS', or, total, active, moiety, plasma, levels])].
[sujeto(['A', description, of, weighing, the, available, dibutyl, phthalate, data, set, for, utility, in, risk, assessment]), verbo([provides]), complemento([an, example, for, considering, genomic, data, for, future, chemical, assessments])].
[sujeto(['The', use, of, selective, 5, -, hydroxytryptamine, type, 3, receptor, antagonists]), verbo([has]), complemento([improved, the, management, of, postoperative, nausea, and, 'vomiting,', but, has, not, completely, eliminated, it])].
[sujeto(['Dolasetron,', 'granisetron,', 'ondansetron,', 'palonosetron,', and, tropisetron]), verbo([have]), complemento([similar, mechanisms, of, action, but, different, pharmacokinetic, and, pharmacodynamic, properties])].
[sujeto(['This', study, aimed, to, summarize, the, available, data, on, genetic, polymorphisms]), verbo([associated]), complemento([with, cytochrome, enzymes, conducted, in, 'Roma', populations])].
[sujeto(['Differences', between, 'Roma', and, 'Hungarian', samples, are]), verbo([reported]), complemento([for, 7, variant, genotypes])].
[sujeto(['Apart', from, their, role, in, the, deactivation, of, most, endogenous, compounds, and, 'xenobiotics,', they, also]), verbo([mediate]), complemento([most, procarcinogens, oxidation, to, ultimate, carcinogens])].
[sujeto([1, ')', 'Formation', of, epoxide, and, 'diol-epoxides', 'intermediates,', such, as, 'CYP1A1', and, 'CYP1B1']), verbo([mediates]), complemento(['PAHs', oxidation, to, epoxide, 'intermediates;', 2, ')', 'Formation', of, diazonium, 'ions,', such, as, 'CYP2A6,', 'CYP2A13', and, 'CYP2E1', mediates, activation, of, most, nitrosamines, to, unstable, 'metabolites,', which, can, rearrange, to, give, diazonium, ions])].
[sujeto([5, ')', 'Formation', of, free, 'radical,', such, as, 'CYP2E1', is]), verbo([involved]), complemento([in, activation, tetrachloromethane, to, free, radicals])].
[sujeto(['While', for, 'CYP2B6', and, 'CYP2D6,', only, a, minor, role]), verbo([has]), complemento([been, found, in, procarcinogens, activation])].
[sujeto(['In', 'addition,', as, the, gene, polymorphisms, 'reflected,', the, polymorphisms, of, 'CYP1A1', '(', -, 3801, 'T/C', and, -, 4889, 'A/G),', 'CYP1A2', '(', -, 163, 'C/A', and, -, 2467, 'T/delT),', 'CYP1B1', '(', -, 48, 'G/C,', -, 119, 'G/T', and, -, 432, 'G/C),', 'CYP2E1', '(', -, 1293, 'G/C', and, -, 1053, 'C/T)']), verbo([have]), complemento([been, associated, with, an, increased, risk, of, lung, cancer])].
[sujeto(['The', polymorphisms, 'CYP1A1', '(', -, 3801, 'T/C', and, -, 4889, 'A/G),', and, 'CYP2E1', '(', 'PstI/Rsa', and, 9, -, bp, 'insertion)']), verbo([have]), complemento([an, association, with, higher, risk, colon, 'cancers,', whereas, 'CYP1A2', '(', -, 163, 'C/A', and, -, 3860, 'G/A)', polymorphism, is, found, to, be, among, the, protective, factors])].
[sujeto(['The', polymorphisms, 'CYP1A1', '(', -, 3801, 'T/C', and, -, 4889, 'A/G),', 'CYP1B1', -, 432, 'G/C,', 'CYP2B6', '(', -, 516, 'G/T', and, -, 785, 'A/G)', may]), verbo([increase]), complemento([the, risk, of, breast, cancer])].
[sujeto(['In', 'conclusion,', 'CYP1A1,', 'CYP1A2,', 'CYP1B1,', 'CYP2A6,', and, 'CYP2E1', are, responsible, for, most, of, the, procarcinogens, 'activation,', and, their, gene, polymorphisms, are]), verbo([associated]), complemento([with, the, risk, of, cancers])].
[sujeto(['Associations', of, cytochrome, 'P450', '(', 'CYP)', polymorphisms, with, risk, of, disease, development]), verbo([have]), complemento([been, reported, widely])].
[sujeto(['For', lung, 'cancer,', a, large, number, of, studies, on, 'CYP1A1,', 'CYP2D6,', and, 'CYP2A6', polymorphisms]), verbo([have]), complemento([been, performed])].
[sujeto(['However,', recent, 'studies,', including, 'meta-analyses', and, 'genome-wide', association, 'studies,']), verbo([suggest]), complemento([that, only, the, 'CYP2A6', 'association,', where, genotypes, associated, with, low, activity, decrease, susceptibility, possibly, due, to, slower, nicotine, 'metabolism,', appears, significant])].
[sujeto(['Associations', with, lung, cancer, susceptibility]), verbo([have]), complemento([also, been, reported, for, 'CYP1A2,', 'CYP1B1,', and, 'CYP2E1', polymorphisms, but, 'these,', though, biologically, 'plausible,', have, not, been, well, replicated])].
[sujeto(['Examples', include, 'CYP3A', for, hepatocellular, carcinoma, due, to, aflatoxin, 'exposure,', 'CYP1A2', for, colon, cancer]), verbo([associated]), complemento([with, heterocyclic, arylamine, exposure, and, 'CYP2E1', for, 'nitrosamine-related', nasopharyngeal, cancer])].
[sujeto(['CYP2C', isoforms, and, 'CYP2J2', contribute, to, extrahepatic, metabolism, of, arachidonic, acid, to, epoxyeicosanoic, acids, which]), verbo([have]), complemento([effects, in, the, cardiovascular, system])].
[sujeto(['CYP2C19', poor, metabolizers, may, be, at]), verbo([increased]), complemento([risk, of, 'endometriosis,', and, 'CYP2E1', genotype, may, modulate, risk, of, development, of, alcoholic, liver, disease])].
[sujeto(['In', 'conclusion,', 'CYP', polymorphisms, are, relevant, to, risk, for, some, diseases, but, this, may]), verbo([have]), complemento([been, overstated, in, earlier, studies])].
[sujeto(['Human', pluripotent, stem, 'cell-derived', hepatocytes]), verbo([have]), complemento([the, potential, to, provide, in, vitro, model, systems, for, drug, discovery, and, hepatotoxicity, testing])].
[sujeto(['Inhibition', of, 'DNA', methyltransferases, '(', 'DNMTs)', during, hepatic, maturation]), verbo([induced]), complemento([demethylation, of, the, 'CpG', sites, of, 'CYP1A1', and, 'CYP1A2,', leading, to, the, 'up-regulation', of, their, transcription])].
[sujeto(['Combinatorial', inhibition, of, 'DNMTs', and, histone, deacetylases, '(', 'HDACs)']), verbo([increased]), complemento([the, transcript, levels, of, 'CYP1A1,', 'CYP1A2,', 'CYP1B1,', and, 'CYP2D6'])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, limited, expression, of, 'CYP', genes, in, 'hESC-Hep', is, modulated, by, epigenetic, regulatory, factors, such, as, 'DNMTs', and, 'HDACs'])].
[sujeto(['Amygdala', '(', 'AMG)', and, prefrontal, cortex, '(', 'PFC)', are, brain, regions, that]), verbo([modulate]), complemento([the, effects, of, alcohol, and, 'smoking,', yet, little, is, known, about, the, expression, of, cytochrome, 'P450', enzymes, '(', 'P450s)', and, 'ATP-binding', cassette, '(', 'ABC)', transporters, in, these, tissues])].
[sujeto(['CYP2A6,', 'CYP2C9,', 'CYP2C19,', 'CYP3A4,', 'CYP3A5,', adrenodoxin, reductase, and, the]), verbo([nuclear]), complemento([receptors, pregnane, 'X', receptor, and, constitutive, androstane, receptor, were, detected, but, below, the, limit, of, quantification])].
[sujeto(['Our', study, shows, that, most, 'xenobiotic-metabolizing', 'P450s', and]), verbo([associated]), complemento([redox, 'partners,', transporters, and, transcription, factors, are, expressed, in, human, 'AMG', and, 'PFC'])].
[sujeto(['The', cytochrome, 'P450', '(', 'CYP)', genes, are, oxygenases]), verbo([involved]), complemento([in, estrogen, biosynthesis, and, 'metabolism,', generation, of, 'DNA', damaging, 'procarcinogens,', and, response, to, 'anti-estrogen', therapies])].
[sujeto(['Since', lifetime, estrogen, exposure, is, an, established, risk, factor, for, breast, 'cancer,', determining, the, role, of, 'CYP', genes, in, breast, cancer, etiology, may]), verbo([provide]), complemento([critical, information, for, understanding, tumorigenesis, and, response, to, treatment])].
[sujeto(['Associations', between, single, nucleotide, polymorphism, in, 'CYP1B1', and, 'DNA', damage]), verbo([caused]), complemento([by, procarcinogenic, estrogen, metabolites, were, ambiguous])].
[sujeto(['Variants', in, 'CYP2D6', are]), verbo([associated]), complemento([with, altered, metabolism, 'tamoxifen;', 'however,', current, data, do, not, support, widespread, clinical, testing])].
[sujeto(['Evaluation', of, 'DNA', variants, in, 'CYP', genes]), verbo([involved]), complemento([with, estrogen, metabolism, or, treatment, response, has, been, 'inconclusive,', reflecting, small, samples, 'sizes,', tumor, 'heterogeneity,', and, differences, between, populations])].
[sujeto(['The', relative, role, of, genetic, and, environmental, factors, in, the, pathogenesis, of, 'Parkinson\'s', disease, '(', 'PD)']), verbo([has]), complemento([been, the, matter, of, investigation, and, 'debate,', especially, in, the, last, 30, years])].
[sujeto(['The', possible, interaction, between, genetic, and, environmental, factors]), verbo([led]), complemento([to, a, great, number, of, association, studies, between, single, nucleotide, polymorphisms, '(', 'SNPs)', of, many, candidate, genes, and, 'PD', risk])].
[sujeto(['In', this, study, we, summarized, and, critically, reviewed, the, results, of, studies, published, on, this, 'issue,', with, especial, reference, to, those]), verbo([reported]), complemento([in, the, last, 5, years])].
[sujeto(['Many', studies]), verbo([provided]), complemento([conflicting, findings, 'and,', when, positive, associations, were, 'identified,', associations, were, weak])].
[sujeto(['Polymorphisms', related, with, activation, or, detoxification, of, drugs, and, 'xenobiotics,', such, as, 'CYP1A1,', 'CYP1A2,', 'CYP19A1,', 'CYP1B1,', 'CYP2C9,', 'CYP2C19,', 'CYP2E1,', 'CYP2D6,', 'NAT2,', 'GSTM1,', 'GSTM3,', 'GSTO1,', 'GSTP1,', 'PON1,', 'PON2,', 'ABCB1', and, 'ADH', genes]), verbo([have]), complemento([not, been, demonstrated, convincingly, a, definitive, association, with, the, risk, of, developing, 'PD'])].
[sujeto(['In', addition, we, analyzed, other, putative, relations, and, genes]), verbo([associated]), complemento([with, monogenic, familial, 'PD'])].
[sujeto(['Taking', together, the, results, of, candidate, gene, association, studies, and, genome, wide, association, 'studies,', only, some, 'SNPs', of, the, 'MAPT,', 'SNCA,', 'HLA', and, 'GBA', genes, seem, to, be, the, most, likely]), verbo([associated]), complemento([with, 'PD', risk])].
[sujeto(['The', occurrence, of, head, and, neck, cancer, '(', 'HNC)', is]), verbo([associated]), complemento([with, smoking, and, alcohol, drinking])].
[sujeto(['Genetic', polymorphisms, are]), verbo([associated]), complemento([with, a, number, of, enzymes, involved, in, the, metabolism, of, carcinogens, important, in, the, induction, of, 'HNC'])].
[sujeto(['It']), verbo([has]), complemento([been, suggested, that, such, polymorphisms, may, be, linked, to, cancer, susceptibility])].
[sujeto(['Extracts', from, the, marine, algae, 'Cymopolia', barbata]), verbo([have]), complemento([previously, shown, promising, pharmacological, activity, including, 'antifungal,', 'antitumor,', 'antimicrobial,', and, antimutagenic, properties])].
[sujeto(['Even', though, extracts]), verbo([have]), complemento([demonstrated, such, 'bioactivity,', isolated, ingredients, responsible, for, such, bioactivity, remain, unspecified])].
[sujeto(['In', 'addition,', their, inhibitory, impact, on, the, activities, of, heterologously]), verbo([expressed]), complemento([cytochrome, 'P450', '(', 'CYP)', enzymes, '(', 'CYP1A1,', 'CYP1A2,', 'CYP1B1,', 'CYP2C19,', 'CYP2D6,', and, 'CYP3A4)', was, evaluated, using, a, fluorescent, assay])].
[sujeto(['Both', 'PBQs', had, potent, inhibition, against, the, activities, of, 'CYP1A1', and, 'CYP1B1,', the, latter, which, is, known, to, be, a, universal, marker, for, cancer, and, a]), verbo([target]), complemento([for, drug, discovery])].
[sujeto(['Inhibitors', of, 'CYP1', enzymes, by, virtue, of, the, prevention, of, activation, of, carcinogens, such, as, 'benzo-a-pyrene']), verbo([have]), complemento([drawn, attention, as, potential, chemopreventors])].
[sujeto(['PBQ2', potently]), verbo([inhibited]), complemento([the, activity, of, 'CYP1B1', '(', 'IC50', 0.14, ±, 0.04, 'μM),', while, both, 'PBQ1', and, 'PBQ2', potently, inhibited, the, activity, of, 'CYP1A1', '(', 'IC50s', of, 0.39, ±, 0.05, μM, and, 0.93, ±, 0.26, 'μM,', 'respectively)'])].
[sujeto(['We']), verbo([report]), complemento([for, the, first, 'time,', two, isolated, ingredients, from, 'C'])].
[sujeto(['PBQs', also, show, potency, against, the, activities, of, 'CYP1', enzyme, which, may, be, a]), verbo([lead]), complemento([in, chemoprevention])].
[sujeto(['Potent', inhibition, was]), verbo([found]), complemento([against, 'CYP1A1', with, 'IC(50)', and, 'K(i)', for, 'CA1', '(', 'acetamide),', being, the, lowest, at, 1.547, ±, 1.0, μM, and, 0.37, μM, 'respectively,', displaying, 'non-competitive', kinetics])].
[sujeto(['The', selectivity, for, 'CYP1A1', was]), verbo([increased]), complemento([in, 'CA3', '(', 'butanamide),', which, also, exhibited, cytotoxicity, against, breast, cancer, 'cells,', 'MCF7', with, an, 'IC(50)', of, 47.46, ±, 1.62, μM])].
[sujeto(['Structure-activity', relationship, studies]), verbo([provide]), complemento([insight, at, a, molecular, level, for, 'CAs', with, implications, in, chemoprevention, and, chemotherapy])].
[sujeto(['We']), verbo([recruited]), complemento([767, cases, of, 'PD', and, 1989, 'age-matched', and, 'gender-matched', controls])].
[sujeto(['The', polymorphisms, of, genes]), verbo([involved]), complemento([either, in, metabolism, of, compounds, contained, in, tobacco, smoke, '(', 'CYP2D6,', 'CYP1B1,', 'GSTM1,', 'GSTT1,', 'GSTM3,', 'GSTP1,', 'NQO1,', 'SOD2,', 'EPHX', and, 'NAT2)', or, in, dopaminergic, neurotransmission, '(', 'MAOA,', 'MAOB,', 'DAT1', and, 'DRD2)', were, characterized, by, 'PCR', based, methods, on, genomic, 'DNA'])].
[sujeto(['We']), verbo([found]), complemento([evidence, of, statistically, significant, 'gene-tobacco', interaction, for, 'GSTM1,', 'NAT2,', and, 'GSTP1,', the, negative, association, between, tobacco, smoking, and, 'PD', being, significantly, enhanced, in, subjects, expressing, 'GSTM1-1', 'activity,', in, 'NAT2', fast, 'acetylators,', and, in, those, with, the, 'GSTP1*B*C', haplotype])].
[sujeto(['Owing', to, the, retrospective, design, of, the, 'study,', these, results]), verbo([require]), complemento([confirmation])].
[sujeto(['The', beneficial, effects, of, tamoxifen, in, the, prevention, and, treatment, of, breast, cancer, are, compromised, by, an]), verbo([increased]), complemento([risk, of, endometrial, 'polyps,', 'hyperplasia,', and, cancer])].
[sujeto(['The', aim, of, this, study, was, to, investigate, cellular, '[', '(', 3, ')', 'H]tamoxifen', adduct, formation, by, light, microscopic, autoradiography, and, cell, stress, by, immunohistochemical, analysis, of, 'glucose-regulating', protein, 78, '(', 'GRP78),']), verbo([nuclear]), complemento([factor, kappaB, '(', 'NF-kappaB),', and, caspase, 3, in, human, endometrial, explants, after, 'short-term', incubation, with, tamoxifen])].
[sujeto(['There', was, also, a, selective, expression, of, the, endoplasmic, reticulum, stress, chaperone, 'GRP78', and]), verbo([activated]), complemento([caspase, 3, at, these, sites, after, incubation, with, cytotoxic, concentrations, of, tamoxifen, '(', 10, -, 100, 'microM)'])].
[sujeto(['The', colocalization, of, '[', '(', 3, ')', 'H]tamoxifen', 'adducts,', expression, of, 'GRP78,', caspase, 3, ',', and, 'tamoxifen-metabolizing', enzymes, in, human, glandular, and, surface, epithelia]), verbo([suggest]), complemento([a, local, bioactivation, of, tamoxifen, at, these, sites, and, that, epithelial, cells, are, early, target, sites, for, 'tamoxifen-induced', cell, stress])].
[sujeto(['The', polymorphic, 'P450', '(', 'CYP)', enzyme, superfamily, is, the, most, important, system]), verbo([involved]), complemento([in, the, biotransformation, of, many, endogenous, and, exogenous, substances, including, 'drugs,', 'toxins,', and, carcinogens])].
[sujeto(['Genotyping', for, 'CYP', polymorphisms]), verbo([provides]), complemento([important, genetic, information, that, help, to, understand, the, effects, of, xenobiotics, on, human, body])].
[sujeto(['Pathways', of, carcinogen, metabolism, are, 'complex,', and, are]), verbo([mediated]), complemento([by, activities, of, multiple, 'genes,', while, single, genes, have, a, limited, impact, on, cancer, risk])].
[sujeto(['We']), verbo([have]), complemento([genotyped, 25, polymorphic, variants, of, 18, key, 'XME', genes, in, 429, 'Russians,', including, 215, asthmatics, and, 214, healthy, controls, by, a, polymerase, chain, 'reaction,', followed, by, restriction, fragment, length, polymorphism, analyses])].
[sujeto(['We']), verbo([found]), complemento([for, the, first, time, significant, associations, of, 'CYP1B1', 'V432L', '(', 'P=0'])].
[sujeto(['The', 'multifactor-dimensionality', reduction, method]), verbo([has]), complemento([obtained, the, best, 'three-locus', model, for, 'gene-gene', interactions, between, three, 'loci,', 'EPHX1', 'Y113H,', 'CYP1B1', 'V432L', and, 'CYP2D6', 'G1934A,', in, asthma, at, a, maximum, 'cross-validation', consistency, of, 100, '%', '(', 'P=0'])].
[sujeto(['A', specific, pattern, of, gametic, correlations, between, alleles, of, 'XME', genes, was]), verbo([found]), complemento([in, asthmatics, in, comparison, with, healthy, individuals])].
[sujeto(['The', study, results, point, to, the, potential, relevance, of, toxicogenomic, mechanisms, of, bronchial, asthma, in, the, modern, 'world,', and, may, thereby]), verbo([provide]), complemento([a, novel, direction, in, the, genetic, research, of, the, respiratory, disease, in, the, future])].
[sujeto(['When', 'ranked,', the, lowest, 'IC(50)', '(', concentration, of, inhibitor]), verbo([required]), complemento([to, decrease, activity, by, 50, '%', ')', values, were, obtained, with, recombinant, 'CYP1A1', '(', 'rCYP1A1)', '[', 'IC(50(total))', =, 'IC(50(free))', =, 2.7, 'microM]', and, 'CYP2C19', activity, in, human, liver, microsomes, '(', 'HLM)', '[', 'IC(50(total))', =, 4.4, 'microM;', 'IC(50(free))', =, 2.8, 'microM]'])].
[sujeto(['Overall,', it, is, very, difficult, to, rationalize, drug, interactions]), verbo([involving]), complemento(['EE', based, on, direct, inhibition, of, 'CYP2B6', '(', e])].
[sujeto(['Cytochrome', 'P450', '(', 'P450)', enzymes, and, 'ATP-binding', cassette, '(', 'ABC)', transporters]), verbo([modulate]), complemento([the, transport, and, metabolism, of, both, endogenous, and, exogenous, substrates, and, could, play, crucial, roles, in, the, human, brain])].
[sujeto(['In', this, 'study,', we]), verbo([report]), complemento([the, transcript, expression, profile, of, seven, 'ABC', transporters, '(', 'ABCB1,', 'ABCC1-C5,', and, 'ABCG2),', 24, 'P450s', '(', 'CYP1,', 'CYP2,', and, 'CYP3', families, and, 'CYP46A1),', and, 14, related, transcription, factors, '[', aryl, hydrocarbon, 'receptor,', nuclear, receptor, '(', 'NR)1I2/pregnane', 'X', 'receptor,', 'NR1I3/constitutive', androstane, receptor, and, 'NR1C/peroxisome', 'proliferator-activated', 'receptor,', 'NR1H/liver', 'X', 'receptor,', 'NR2B/retinoid', 'X', 'receptor,', and, 'NR3A/estrogen', receptor, 'subfamilies]', in, the, whole, 'brain,', the, dura, 'mater,', and, 17, different, encephalic, areas])].
[sujeto(['The', most, abundant, transporters, were, 'ABCC5', and, 'ABCG2,', 'which,', 'interestingly,', had, a, higher, mRNA, expression, in, the, brain, compared, with, that]), verbo([found]), complemento([in, the, liver])].
[sujeto(['Thus,', our, study, shows, key, enzymes, of, cholesterol, and, fatty, acid, metabolism, to, be, present, in, the, human, brain, and]), verbo([provides]), complemento([novel, information, of, importance, for, elucidation, of, enzymes, responsible, for, normal, and, pathological, processes, in, the, human, brain])].
[sujeto(['However,', mutations, in, the, 'CYP1B1', gene]), verbo([have]), complemento([been, linked, to, congenital, glaucoma])].
[sujeto(['Expression', of, mRNAs, for, major, xenobiotic, metabolizing, 'CYPs', in, families, 1, -, 3, and, regulatory, factors]), verbo([involved]), complemento([in, the, induction, of, 'CYPs', was, studied, using, reverse, 'transcriptase-polymerase', chain, reaction])].
[sujeto([mRNAs, of, 'CYP1A1,', 'CYP1B1,', and, 'CYP2D6', and, of, the, regulatory, factors, aryl, hydrocarbon, receptor, '(', 'AHR),', aryl, hydrocarbon, receptor]), verbo([nuclear]), complemento(['translocator,', and, glucocorticoid, receptor, were, expressed, in, the, human, nonpigmented, ciliary, epithelial, cell, line])].
[sujeto(['CYP1B1', mRNA, was, strongly, and, dose, dependently]), verbo([induced]), complemento([by, 'TCDD'])].
[sujeto(['CYP1B1', promoter, was]), verbo([activated]), complemento([by, 'TCDD'])].
[sujeto(['TCDD', potently]), verbo([induces]), complemento(['CYP1B1', mRNA, in, human, nonpigmented, ciliary, epithelial, 'cells,', suggesting, the, involvement, of, an, 'AHR-mediated', pathway, in, the, regulation, of, ciliary, 'CYP1B1', expression])].
[sujeto(['The']), verbo([increasing]), complemento([number, of, transgenic, or, gene, knockout, mouse, models, generated, for, use, in, drug, metabolism, studies, has, meant, that, a, greater, understanding, of, the, function, and, substrate, specificities, of, murine, cytochromes, 'P450', '(', 'P450s)', has, become, 'essential,', particularly, with, the, recent, advances, in, &, 'quot;humanized&quot;', mouse, models])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([heterologously, expressed, nine, murine, 'P450s--Cyp1a1,', 'Cyp1a2,', 'Cyp1b1,', 'Cyp2a4,', 'Cyp2b20,', 'Cyp2c29,', 'Cyp2d22,', 'Cyp2e1,', and, 'Cyp3a11--individually', with, human, 'P450', oxidoreductase, to, generate, functional, monooxygenase, systems, in, 'Escherichia', coli])].
[sujeto(['We']), verbo([have]), complemento([identified, a, suitable, fluorogenic, probe, for, each, 'P450', and, determined, the, apparent, kinetic, parameters])].
[sujeto(['These', probes]), verbo([have]), complemento([enabled, the, screening, of, a, panel, of, 31, test, compounds, classified, as, &, 'quot;drugs,&quot;', &, 'quot;natural', 'compounds,&quot;', &, 'quot;endogenous', 'compounds,&quot;', and, &, 'quot;pesticides&quot;', by, measurement, of, 'IC(50),', thus, allowing, the, comparison, of, binding, affinities])].
[sujeto(['Although', there, were, general, similarities, between, human, and, mouse, 'P450s,', perhaps, the, most, significant]), verbo([finding]), complemento([in, this, study, was, the, observation, 'that,', despite, 77, '%', amino, acid, 'identity,', 'Cyp2d22', and, 'CYP2D6', were, remarkably, dissimilar, in, a, range, of, enzymatic, 'properties,', with, potentially, serious, implications, for, pharmacokinetic, studies, using, 'CYP2D', substrates])].
[sujeto(['The', data, presented, in, this, study]), verbo([provide]), complemento([a, solid, foundation, with, which, to, assess, the, degree, of, similarity, '(', or, 'difference)', between, mouse, and, human, 'P450s', involved, in, xenobiotic, metabolism, and, can, be, used, as, a, basis, for, further, studies])].
[sujeto(['Steroidogenic', 'factor-1', '(', 'Sf-1)', '(', officially, designated]), verbo([nuclear]), complemento([receptor, subfamily, 5, group, 'A', member, 1, '[', 'NR5A1])', is, a, master, regulator, of, steroidogenesis, and, reproduction, in, mammals])].
[sujeto(['Clustered', regularly, interspaced, short, palindromic, 'repeats/CRISPR']), verbo([associated]), complemento([protein, 9, '(', 'Cas9)', cleavage, of, 'sf-1', resulted, in, a, high, mutation, rate, in, the, 'F0', generation, and, a, phenotype, of, gonadal, dysgenesis, and, reduced, steroidogenic, cells, in, 'XX', and, 'XY', fish])].
[sujeto(['Sf-1', deficiency, also, resulted, in]), verbo([decreased]), complemento([cytochrome, 'P450,', family, 19, ',', subfamily, 'A,', polypeptide, 1, 'a,', forkhead, box, 'L2', 'expression,', and, serum, 'estradiol-17β', in, 'XX', fish])].
[sujeto(['In', 'XY', 'fish,', 'Sf-1', deficiency]), verbo([increased]), complemento([cytochrome, 'P450,', family, 19, ',', subfamily, 'A,', polypeptide, 1, a, and, forkhead, box, 'L2', expression, but, decreased, cytochrome, 'P450,', family, 11, ',', subfamily, 'B,', polypeptide, 2, expression, and, serum, 11, -, ketotestosterone, levels])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, 'Sf-1', is, a, major, regulator, of, steroidogenesis, and, reproduction, in, 'fish,', as, it, is, in, mammals])].
[sujeto(['Members', of, the]), verbo([nuclear]), complemento([receptor, 5, 'A', '(', 'NR5A)', family, '(', steroidogenic, factor, 1, and, liver, receptor, homolog, 1, ')', play, a, crucial, role, in, the, transcriptional, regulation, of, these, genes])].
[sujeto(['The', 'NR5A', family]), verbo([activates]), complemento([these, genes, by, binding, to, 'NR5A', responsive, elements, present, within, their, promoter, 'regions,', as, well, as, to, the, elements, far, from, their, promoters])].
[sujeto(['In', 'addition,', various, 'NR5A-interacting', proteins, including, peroxisome, 'proliferator-activated', 'receptor-γ', 'coactivator-1α', '(', 'PGC-1α),']), verbo([nuclear]), complemento([receptor, subfamily, 0, ',', group, 'B,', member, 1, '(', 'DAX-1),', and, 'CCAAT/enhancer-binding', proteins, '(', 'C/EBP)', are, involved, in, the, transcription, of, 'NR5A', target, genes, and, regulate, the, transcription, either, positively, or, negatively, under, both, basal, and, tropic, 'hormone-stimulated', conditions])].
[sujeto(['Pollution,', including, polycyclic, aromatic, hydrocarbons, '(', 'PAH),', may, contribute, to]), verbo([increased]), complemento([prevalence, of, asthma])].
[sujeto(['PAH', can]), verbo([bind]), complemento([to, the, 'Aryl', hydrocarbon, 'Receptor', '(', 'AhR),', a, transcription, factor, involved, in, 'Th17/Th22', type, polarization])].
[sujeto(['Increased', 'IL-17', and, 'IL-22', productions]), verbo([have]), complemento([been, associated, with, asthma])].
[sujeto(['At', 'baseline,']), verbo([activated]), complemento(['PBMCs', from, 'AA', exhibited, an, increased, 'IL-17/IL-22', profile, compared, with, 'NA', subjects])].
[sujeto(['Diesel', exhaust, particle, '(', 'DEP)-PAH', and, 'Benzo[a]Pyrene', '(', 'B[a]P)', stimulation, further]), verbo([increased]), complemento(['IL-22', but, decreased, 'IL-17A', production, in, both, groups])].
[sujeto(['Among', 'PBMCs,', 'PAH-induced', 'IL-22', expression, originated, principally, from, single, 'IL-22-', but, not, from, 'IL-17-']), verbo([expressing]), complemento(['CD4', 'T', cells])].
[sujeto(['The', 'Th17', transcription, factors, 'RORA', and, 'RORC', were, down, 'regulated,', whereas, 'AhR']), verbo([target]), complemento([gene, 'CYP1A1', was, upregulated])].
[sujeto(['Altogether,', these, data]), verbo([suggest]), complemento([that, 'DEP-PAH', and, 'B[a]P', may, contribute, to, increased, 'IL22', production, in, both, healthy, and, asthmatic, subjects, through, mechanisms, involving, both, 'AhR', -, dependent, and, -, independent, pathways])].
[sujeto(['Extracellular', matrix, proteins, of, the, tenascin, family, resemble, each, other, in, their, domain, 'structure,', and, also, share, functions, in]), verbo([modulating]), complemento([cell, adhesion, and, cellular, responses, to, growth, factors])].
[sujeto(['In', accordance, with, their, highly]), verbo([regulated]), complemento(['expression,', the, promoters, of, the, 'tenascin-C', and, -, 'W', genes, contain, 'TATA', 'boxes,', whereas, those, of, the, other, 2, tenascins, do, not])].
[sujeto(['Predicting', whether, candidate, compounds]), verbo([induce]), complemento(['CYP3A4', and, 'P-gp', is, a, crucial, stage, in, the, drug, development, 'process,', as, 'drug-drug', interactions, may, result, in, the, induction, of, intestinal, 'CYP3A4', and, 'P-gp'])].
[sujeto(['To', address, this, urgent, 'requirement,', 'LS174T', cells, were, used, to, create, two, stable, cell, lines]), verbo([expressing]), complemento([the, 'CYP3A4', or, 'ATP-binding', cassette, subfamily, 'B', member, 1, '(', 'ABCB1,', encoding, 'P-gp)', reporter, genes])].
[sujeto(['First,', these, stable, cells, were, tested, by, treatment, with, 1, 'α,25-dihydroxyvitamin', 'D3', '(', 1, ',', 25, '(', 'OH)2D3),', 'all-trans-retinoic', acid, '(', 'ATRA)', and, 9, -, 'cis-retinoic', acid, '(', 9, -, cis, 'RA)', that]), verbo([induce]), complemento(['CYP3A4', and, 'P-gp', in, the, intestines])].
[sujeto(['All', these, compounds, significantly]), verbo([increased]), complemento([both, 'CYP3A4', and, 'ABCB1', reporter, activities, in, the, stable, cell, lines])].
[sujeto(['The', mixed, cells, showed, a, significant]), verbo([increase]), complemento([in, the, 'CYP3A4', and, 'ABCB1', reporter, activities, following, treatment, with, 1, ',', 25, '(', 'OH)2', 'D3,', 'ATRA,', and, 9, -, cis, 'RA'])].
[sujeto(['These', activity, levels, were]), verbo([maintained]), complemento([after, passaging, more, than, 20, times, and, following, multiple, 'freeze-thaw', cycles])].
[sujeto(['These', results, demonstrate, that, our, established, cell, lines, can, be, used, to, evaluate, simultaneously, 'CYP3A4', and, 'ABCB1', induction, in, the, 'intestines,']), verbo([providing]), complemento([a, valuable, in, vitro, model, for, the, evaluation, of, future, drug, candidates])].
[sujeto(['Metals', are, a, threat, to, human, health, by]), verbo([increasing]), complemento([disease, risk])].
[sujeto(['Experimental', data]), verbo([have]), complemento([linked, altered, miRNA, expression, with, exposure, to, some, metals])].
[sujeto(['MiRNAs', comprise, a, large, family, of, 'non-coding', 'single-stranded', molecules, that, primarily, function, to, negatively]), verbo([regulate]), complemento([gene, expression, 'post-transcriptionally'])].
[sujeto(['Thus,', this, study, aims, to, evaluate, global, miRNA, and, mRNA, expression, changes]), verbo([induced]), complemento([by, a, metal, mixture, containing, 'NaAsO2,', 'CdCl2,', 'Pb(C2H3O2)2·3H2O', and, to, predict, possible, 'metal-associated', disease, development, under, these, conditions])].
[sujeto(['Our', results, show, that, this, metal, mixture, results, in, a, miRNA, expression, profile, that, may, be, responsible, for, the, mRNA, expression, changes, observed, under, experimental, conditions, in, which, coding, proteins, are]), verbo([involved]), complemento([in, cellular, 'processes,', including, cell, 'death,', growth, and, proliferation, related, to, the, 'metal-associated', inflammatory, response, and, cancer])].
[sujeto(['It']), verbo([has]), complemento([been, shown, previously, that, differential, enzyme, expression, among, human, and, 'rodent/non-rodent', species, can, be, a, roadblock, in, drug, discovery, and, development, process])].
[sujeto(['We']), verbo([found]), complemento([equal, expression, of, 'CYP1B1,', 2, 'J2,', 3, 'A4,', 3, 'A5,', 'UGT1A9,', 'SULT2A1', and, 'GSTA,', higher, expression, of, 2, 'B6,', 2, 'D6,', 4, 'A11,', 4, 'F2,', 4, 'F8,', 4, 'F11,', 'UGT2B7,', 'SULT1E1', in, 'RPTEC/TERT1', and, absence, of, 'GSTT', in, 'RPTEC/TERT1', compared, to, 'HK-2', at, mRNA, level])].
[sujeto(['The', significant]), verbo([increases]), complemento([in, expression, of, 'GSTK1,', 'GSTM1,', and, 'GSTT1', in, psoriasis, may, reflect, the, increased, activation, of, 'GST', in, response, to, excessive, free, radical, formation, from, activated, neutrophils, or, ultraviolet, exposure, to, maintain, antioxidant, capacity, in, psoriasis])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, psoriasis, is, an, oxidative, stress, 'condition,', although, phototherapy, does, not, affect, these, enzymatic, systems])].
[sujeto(['The', zebrafish, embryo]), verbo([has]), complemento([been, proposed, as, a, '\'', bridge, 'model\'', to, study, the, effects, of, cigarette, smoke, on, early, development])].
[sujeto(['Previous', studies, showed, that, exposure, to, total, particulate, matter, '(', 'TPM)']), verbo([led]), complemento([to, adverse, effects, in, developing, 'zebrafish,', and, suggested, that, the, antioxidant, and, aryl, hydrocarbon, receptor, '(', 'AHR)', pathways, play, important, roles])].
[sujeto(['This', study, investigated, the, roles, of, these, two, pathways, in]), verbo([mediating]), complemento(['TPM', toxicity])].
[sujeto(['In', experiment, 'II,', 'TPM', exposures, were, performed, in, embryos, that, were, microinjected, with]), verbo([nuclear]), complemento([factor, erythroid, 2, -, related, factor, 2, '(', 'Nrf2),', 'AHR2,', cytochrome, 'P450', 1, 'A', '(', 'CYP1A),', or, 'CYP1B1', 'morpholinos,', and, deformities, were, assessed])].
[sujeto(['In', experiment, 'III,', embryos, were, exposed, to, 'TPM,', and, 'embryos/larvae', were, collected, at, 24, ',', 48, ',', 72, ',', and, 96, hpf, to, assess, several, genes]), verbo([associated]), complemento([with, the, antioxidant, and, 'AHR', pathways])].
[sujeto(['Moreover,', as, shown, by, gene, expression, the, 'AHR', 'pathway,', but, not, the, antioxidant, 'pathway,', was]), verbo([induced]), complemento([in, response, to, 'TPM', 'exposure,', providing, further, evidence, for, its, importance, in, mediating, 'TPM', toxicity])].
[sujeto(['Bulky', 'DNA', adducts, were]), verbo([induced]), complemento([after, both, treatment, 'periods;', the, effect, of, 1, -, 'NP', was, weak])].
[sujeto([3, -, 'NBA']), verbo([induced]), complemento([high, levels, of, bulky, 'DNA', adducts, even, after, 4, -, h, 'treatment,', suggesting, rapid, metabolic, activation])].
[sujeto([1, -, 'NP']), verbo([caused]), complemento([protein, oxidation, and, weak, induction, of, lipid, peroxidation, after, 4, -, h, incubation])].
[sujeto([3, -, 'NBA']), verbo([induced]), complemento([lipid, peroxidation, after, 24, -, h, treatment])].
[sujeto(['All', test, compounds]), verbo([induced]), complemento([mRNA, expression, of, 'NQO1,', 'POR,', and, 'AKR1C2', after, 24, -, h, treatment])].
[sujeto(['AKR1C2', expression, indicates, involvement, of, processes]), verbo([associated]), complemento([with, reactive, oxygen, species, generation])].
[sujeto(['This', was, supported, further, by, 'COX2', expression]), verbo([induced]), complemento([by, 24, -, h, treatment, with, 1, -, 'NP'])].
[sujeto(['We', selected, eight, common, variants, in, maternal, and, newborn, candidate, genes, related, to, 'B[a]P', 'metabolism,', 'detoxification,', and, repair, for, our, 'analyses:', 'CYP1A1,', 'CYP1A2,', 'CYP1B1,', 'GSTM1,', 'GSTT2,', 'NQO1,', and, 'XRCC1', 'We', observed, significant, interactions, between, maternal, 'PAH', exposure, and, 'SNPs', on, cord, 'B[a]P-DNA', adducts, in, the, following, 'genes:', maternal, 'CYP1A1', and, 'GSTT2,', and, newborn, 'CYP1A1', and, 'CYP1B1', 'These', novel, findings, highlight, differences, in, maternal, and, newborn, genetic, contributions, to, 'B[a]P-DNA', adduct, formation, and]), verbo([have]), complemento([the, potential, to, identify, 'at-risk', subpopulations, who, are, susceptible, to, the, carcinogenic, potential, of, 'B[a]P'])].
[sujeto(['To']), verbo([induce]), complemento([liver, 'insufficiency,', animals, were, treated, with, nitrosodiethylamine, '(', 'DEN)', at, 50, &, 'nbsp;mg/kg', of, body, weight, twice, a, week, for, 7, weeks])].
[sujeto(['To']), verbo([induce]), complemento([serotonergic, system, 'dysfunction,', the, animals, were, fed, a, 'tryptophan-free', diet, for, 3, days])].
[sujeto(['Serotonergic', system, dysfunction, during, liver, insufficiency, generated, the, aryl, hydrocarbon, receptor, '(', 'AhR)', activation, and, the, &, 'quot;superinduction&quot;', of, the, 'AhR']), verbo([target]), complemento(['genes:', 'CYP1A1,', 'CYP1B1', and, 'UGT1A,', with, a, concomitant, increase, in, 'CYP1A1', protein, and, activity])].
[sujeto(['CYP1A2', gene, expression, was, simultaneously, 'down-regulated,', with, a, concomitant]), verbo([decrease]), complemento([in, 'CYP1A2', protein, and, activity])].
[sujeto(['A', significant, reduction, in, 'TRβ', receptor, 'levels,', together, with, a, simultaneous]), verbo([increase]), complemento([of, 'TRα', receptor, gene, and, protein, level, '(', mainly, 'TRα2', 'isoform)', after, serotonergic, system, 'dysfunction,', suggests, that, the, serotoninergic, system, is, involved, in, the, regulation, of, 'CYP1A', isoforms, without, influence, from, thyroid, hormones, during, liver, insufficiency])].
[sujeto(['The', interplay, between, the, serotonergic, system, and, the, regulation, of, 'CYP1A', 'isoforms,', which, are, downstream]), verbo([targets]), complemento([of, 'AhR', 'activation,', is, dependent, on, hepatic, function, and, can, be, observed, without, influence, from, thyroid, hormones])].
[sujeto(['Although', glucose, transporter, 1, ',', 'claudin-3,', and, plasmalemma, 'vesicular-associated', protein]), verbo([have]), complemento([been, identified, as, 'Wnt/β-catenin', targets, in, brain, endothelial, 'cells,', further, downstream, targets, relevant, to, 'BBB', formation, and, function, are, incompletely, explored])].
[sujeto(['By', 'Affymetrix', expression, 'analysis,', we, show, that, the, cytochrome, 'P450', enzyme, 'Cyp1b1', was, significantly]), verbo([decreased]), complemento([in, 'β-catenin-deficient', mouse, endothelial, 'cells,', whereas, its, close, homolog, 'Cyp1a1', was, upregulated, in, an, aryl, hydrocarbon, 'receptor-dependent', 'manner,', hence, indicating, that, 'β-catenin', is, indispensable, for, 'Cyp1b1', but, not, for, 'Cyp1a1', expression])].
[sujeto(['Functionally,', 'Cyp1b1', could, generate, retinoic, acid, from, retinol]), verbo([leading]), complemento([to, 'cell-autonomous', induction, of, the, 'barrier-related', 'ATP-binding', cassette, transporter, 'P-glycoprotein'])].
[sujeto(['Cyp1b1', could, also, generate, 20, -, hydroxyeicosatetraenoic, acid, from, arachidonic, 'acid,']), verbo([decreasing]), complemento([endothelial, barrier, function, in, vitro, 'In', mice, in, vivo, pharmacological, inhibition, of, 'Cyp1b1', increased, 'BBB', permeability, for, small, molecular, 'tracers,', and, 'Cyp1b1', was, downregulated, in, glioma, vessels, in, which, 'BBB', function, is, lost])].
[sujeto(['Hence,', we, propose, 'Cyp1b1', as, a]), verbo([target]), complemento([of, 'β-catenin', indirectly, influencing, 'BBB', properties, via, its, metabolic, 'activity,', and, as, a, potential, target, for, modulating, barrier, function, in, endothelial, cells])].
[sujeto(['Wnt/β-catenin', signaling, is, crucial, for, 'blood-brain', barrier, '(', 'BBB)', development, and, 'maintenance;', 'however,', its, role, in]), verbo([regulating]), complemento([metabolic, characteristics, of, endothelial, cells, is, unclear])].
[sujeto(['We']), verbo([provide]), complemento([evidence, that, 'β-catenin', influences, endothelial, metabolism, by, transcriptionally, regulating, the, cytochrome, 'P450', enzyme, 'Cyp1b1', 'Furthermore,', expression, of, its, close, homolog, 'Cyp1a1', was, inhibited, by, 'β-catenin'])].
[sujeto(['Functionally,', 'Cyp1b1', generated, retinoic, acid, as, well, as, 20, -, hydroxyeicosatetraenoic, acid, that]), verbo([regulated]), complemento(['P-glycoprotein', and, junction, 'proteins,', 'respectively,', thereby, modulating, 'BBB', properties])].
[sujeto(['Inhibition', of, 'Cyp1b1', in, vivo]), verbo([increased]), complemento(['BBB', permeability, being, in, line, with, its, downregulation, in, glioma, 'endothelia,', potentially, implicating, 'Cyp1b1', in, other, brain, pathologies])].
[sujeto(['In', 'conclusion,', 'Wnt/β-catenin', signaling]), verbo([regulates]), complemento([endothelial, metabolic, barrier, function, through, 'Cyp1b1', transcription])].
[sujeto(['The', human, cytochrome, 'P450', family, 1, enzymes, consist, of, three, 'members,', 'CYP1A1,', 'CYP1A2', and, 'CYP1B1,', which, are, predominantly]), verbo([involved]), complemento([in, the, phase, 'I', metabolism, of, xenobiotics])].
[sujeto(['Because', they]), verbo([have]), complemento([been, implicated, in, 'carcinogenesis,', cancer, 'progression,', and, drug, 'resistance,', the, inhibition, of, these, enzymes, has, been, widely, considered, an, effective, oncological, therapeutic, strategy])].
[sujeto(['Some', natural, and, synthetic, flavonoids, and, naphthoflavonoids]), verbo([have]), complemento([been, extensively, documented, to, exert, pronounced, influence, in, the, modulation, of, 'CYP1s,', including, functioning, as, 'inhibitors,', 'substrates,', and, aryl, hydrocarbon, receptor, '(', 'AhR)', ligands])].
[sujeto(['This', review, summarizes, the, structural, features, responsible, for, the, 'CYP1', inhibitory, effects, of, the]), verbo([reported]), complemento([flavonoids, and, naphthoflavonoids])].
[sujeto(['We', hope, this, review]), verbo([provides]), complemento([a, useful, foundation, for, the, rational, design, of, potent, and, selective, 'CYP1', isozyme, 'inhibitors,', thereby, accelerating, the, drug, discovery, process])].
[sujeto(['The', primary, hypothesis, was, that, patients, carrying, the, 'low-activity', 'CYP3A4*22', '(', 'rs35599367)', 'single-nucleotide', polymorphism, '(', 'SNP)', would]), verbo([have]), complemento([greater, exemestane, concentration])].
[sujeto(['CYP3A4*22', was]), verbo([associated]), complemento([with, a, 54, '%', greater, exemestane, concentration, '(', 'P&lt;0'])].
[sujeto(['Concentration', was, greater, in, patients, who]), verbo([reported]), complemento(['White', 'race,', had, elevated, 'aminotransferases,', renal, 'insufficiency,', lower, body, mass, index, and, had, not, received, chemotherapy, '(', all, 'P&lt;0'])].
[sujeto([5, ')', ',', and, 'CYP3A4*22']), verbo([maintained]), complemento([significance, after, adjustment, for, covariates, '(', 'P&lt;0'])].
[sujeto(['Botanical', estrogen, '(', 'BE)', dietary, supplements, are, consumed, by, women, as, substitutes, for]), verbo([loss]), complemento([of, endogenous, estrogens, at, menopause])].
[sujeto(['BEs', and, estradiol, '(', 'E2),']), verbo([acting]), complemento([through, 'ERα,', stimulated, 'proliferation,', 'ERα', chromatin, binding, and, 'target-gene', expression])].
[sujeto(['BEs', but, not, 'E2,']), verbo([acting]), complemento([through, 'AhR,', bound, to, xenobiotic, response, 'element-containing', chromatin, sites, and, enhanced, 'AhR', 'target-gene', expression, '(', 'CYP1A1,', 'CYP1B1)'])].
[sujeto(['While', 'E2', and, 'TCDD']), verbo([acted]), complemento([quite, selectively, through, their, respective, 'receptors,', 'BEs', acted, via, both, 'receptors,', with, their, 'AhR', activity, moderated, by, negative, crosstalk, through, 'ERα'])].
[sujeto(['Previous', studies]), verbo([have]), complemento([demonstrated, that, most, of, the, intraspecies, variation, in, sensitivity, to, the, toxic, effects, of, 2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD),', including, suppression, of, antibody, 'responses,', in, murine, models, is, due, to, single, nucleotide, polymorphisms, '(', 'SNPs)', within, the, aryl, hydrocarbon, receptor, '(', 'AhR)', gene])].
[sujeto(['The', underlying, reason, for, variation, in, sensitivity, to, 'TCDD-induced', suppression, of, 'IgM', responses, among, humans, is, not, well, 'understood,', but, is, 'thought,', in, 'part,', to, be, a, result, of, different, polymorphic, forms, of, the, 'AhR']), verbo([expressed]), complemento([by, different, individuals])].
[sujeto(['Furthermore,', all, 'AhR', variants, were, able, to]), verbo([mediate]), complemento(['TCDD-induced', suppression, of, the, 'IgM', 'response;', 'however,', a, combined, 'P517S+R554K+V570I', variant, partially, reduced, sensitivity, to, 'TCDD-mediated', suppression, of, 'IgM', secretion])].
[sujeto(['By', 'contrast,', attenuation, of, 'TCDD-induced', 'IgM', suppression]), verbo([required]), complemento([a, combination, of, all, three, 'SNPs', 'P517S,', 'R554K,', and, 'V570I'])].
[sujeto(['Selected', genes, were]), verbo([involved]), complemento([in, 'FAC', chemotherapy, drugs, transport, '(', 'ABCB1,', 'ABCC2,', 'ABCG2,', 'SLC22A16),', metabolism, '(', 'CYP1B1,', 'CYP2C19,', 'GSTT1,', 'GSTM1,', 'GSTP1,', 'TYMS,', 'MTHFR,', 'DPYD),', 'drug-induced', damage, repair, '(', 'ERCC1,', 'ERCC2,', 'XRCC1)', and, involved, in, regulation, of, 'DNA', damage, response, and, cell, cycle, control, '(', 'ATM,', 'TP53)'])].
[sujeto(['Furthermore,', the, growing, number, of, 'high-risk', genotypes, was, reflected, in, gradual]), verbo([increase]), complemento([in, risk, of, the, 'non-responsiveness', to, 'treatment-', from, 'OR', 2.68, for, presence, of, two, genotypes, to, 'OR', 9.93, for, carriers, of, all, three, negative, genotypes, in, the, group, of, all, patients])].
[sujeto(['Also,', 'TFFS', significantly, shortened, with, the]), verbo([increasing]), complemento([number, of, 'high-risk', 'genotypes,', with, median, of, 54.4, months, for, carriers, of, one, 'variant,', to, 51.5, and, 34.9, months, for, the, carriers, of, two, and, three, 'genotypes,', respectively])].
[sujeto(['This']), verbo([finding]), complemento([contributes, to, the, elucidation, of, the, mechanisms, of, drug, resistance, in, this, subgroup, of, breast, cancer, patients])].
[sujeto(['The', results, revealed, that, 'I3C', significantly]), verbo([inhibited]), complemento([triglyceride, accumulation, in, mature, adipocytes, in, association, with, significantly, increased, expression, of, 'AhR', and, 'CYP1B1', proteins, as, well, as, slightly, decreased, nuclear, factor, 'erythroid-derived', factor, 2, -, related, factor, 2, ',', 'hormone-sensitive', 'lipase,', and, 'glycerol-3-phosphate', dehydrogenase, expression, by, mature, adipocytes])].
[sujeto(['Furthermore,', 'I3C']), verbo([inhibited]), complemento(['CM-stimulated', endothelial, tube, 'formation,', which, was, accompanied, by, the, modulated, secretion, of, angiogenic, factors, in, 'adipocytes,', including, vascular, endothelial, growth, 'factor,', 'interleukin-6,', matrix, 'metalloproteinases,', and, nitric, oxide])].
[sujeto(['In', 'conclusion,', 'I3C', reduced, lipid, droplet, accumulation, in, adipocytes, and]), verbo([suppressed]), complemento(['adipocyte-stimulated', angiogenesis, in, 'ECs,', suggesting, that, 'I3C', is, a, potential, therapeutic, agent, for, treating, obesity, and, 'obesity-associated', disorders])].
[sujeto(['The', aryl, hydrocarbon, receptor, '(', 'AhR)', is, an, important]), verbo([nuclear]), complemento([transcription, factor, that, is, best, known, for, mediating, toxic, responses, by, adjusting, numbers, of, 'metabolism-related', 'enzymes,', including, 'CYP1A1', and, 'CYP1B1'])].
[sujeto(['Previous', findings]), verbo([have]), complemento([revealed, 'that,', in, addition, to, negatively, regulating, cell, proliferation, and, 'survival,', 'AhR', may, also, positively, regulate, these, pathways])].
[sujeto(['Here,', we, review, these, findings, and, summarize, distinct, mechanisms, by, which, 'AhR']), verbo([promotes]), complemento([cell, proliferation, and, 'survival,', including, modulation, of, receptor, 'expression,', growth, factor, signalling, and, 'apoptosis,', regulating, the, cell, cycle, and, promoting, cytokine, expression])].
[sujeto(['The', 8, /, 9, and, the, 7, /, 12, genotypes, of, '(', 'TTTA)n', in, 'CYP19', showed, suggestive, evidence, for, association, with]), verbo([decreased]), complemento([prostate, cancer, risk, and, the, risk, for, aggressive, 'disease,', respectively])].
[sujeto(['The', haplotype, analysis, revealed, 2, 'CYP1B1', haplotypes]), verbo([associated]), complemento([with, 'PC', risk, reduction])].
[sujeto(['Some', 'CYP1B1', haplotypes, and, genotypes, of, the, 'CYP19', '(', 'TTTA)n', repeat, appeared, to, be]), verbo([associated]), complemento([with, disease, risk, or, aggressiveness, in, 'Bulgarian', 'PC', patients])].
[sujeto(['Glaucoma', is, the, second]), verbo([leading]), complemento([cause, of, 'blindness,', affecting, '~65', million, people, worldwide])].
[sujeto(['Exclusion', analysis]), verbo([suggested]), complemento([linkage, to, the, 'CYP1B1', 'locus,', with, positive, 'two-point', logarithm, of, odds, scores, in, 23, 'families,', while, 'Sanger', sequencing, identified, a, total, of, 11, 'variants,', including, two, novel, 'mutations,', in, 23, families])].
[sujeto(['The', gene, 'CYP2D6']), verbo([has]), complemento([an, extremely, important, role, in, drug, metabolism])].
[sujeto(['The', cytochrome, 'P450', proteins, are, monooxygenases, that, are, heavily]), verbo([involved]), complemento([in, drug, metabolism, '(', 'Genetics', 'Home', 'Reference,', 2013, ')', ',', and, many, drugs, are, activated, into, their, biologically, active, compounds])].
[sujeto(['Because', of, numerous, 'polymorphisms,', the, gene, also]), verbo([has]), complemento([significant, 'person-to-person', variability])].
[sujeto(['To', 'date,', more, than, 80, distinct, 'CYP2D6', alleles, and, specific, types, and, frequencies]), verbo([have]), complemento([been, associated, with, different, ethnic, groups])].
[sujeto(['CYP2D6*4', is, the, most, common, variant, allele, in, 'Caucasians', 'and,', in, that, 'population,']), verbo([has]), complemento([a, frequency, of, about, 25, '%'])].
[sujeto(['A', major, pathway, for, 'Ca(2+)', entry, in, 'non-excitable', cells, is]), verbo([activated]), complemento([following, depletion, of, intracellular, 'Ca(2+)', stores])].
[sujeto(['A', de, novo, conformational, coupling, between, elements, in, the, plasma, membrane, '(', 'PM)', and, 'Ca(2+)', stores]), verbo([has]), complemento([been, proposed, as, the, most, likely, mechanism, to, activate, this, capacitative, 'Ca(2+)', entry, '(', 'CCE)', in, several, cell, 'types,', including, platelets])].
[sujeto(['Here', we]), verbo([report]), complemento([that, a, cytochrome, 'P450', 'metabolite,', 5, ',', 6, -, 'EET,', might, be, a, component, of, the, de, novo, conformational, coupling, in, human, platelets])].
[sujeto(['In', these, 'cells,', 5, ',', 6, -, 'EET']), verbo([induces]), complemento([divalent, cation, entry, without, having, any, detectable, effect, on, 'Ca(2+)', store, depletion])].
[sujeto(['Ca(2+)', entry]), verbo([stimulated]), complemento([by, low, concentrations, of, 'thapsigargin,', which, selectively, depletes, the, dense, tubular, system, and, induces, 'EET', 'production,', was, impaired, by, the, cytochrome, 'P450', inhibitor, 17, -, 'ODYA,', which, has, no, effect, on, 'CCE', mediated, by, depletion, of, the, acidic, stores, using, 2, ',', 5, -, 'di-(tert-butyl)-1,4-hydroquinone'])].
[sujeto(['We']), verbo([have]), complemento([found, that, 5, ',', 6, -, 'EET-induced', 'Ca(2+)', entry, requires, basal, levels, of, 'H(2)O(2),', which, might, maintain, a, redox, state, favourable, for, this, event])].
[sujeto(['Finally,', our, results, indicate, that, 5, ',', 6, -, 'EET']), verbo([induces]), complemento([the, activation, of, tyrosine, kinase, proteins, and, the, reorganization, of, the, actin, 'cytoskeleton,', which, might, provide, a, support, for, the, transport, of, portions, of, the, 'Ca(2+)', store, towards, the, 'PM', to, facilitate, de, novo, coupling, between, 'IP(3)R', type, 'II', and, hTRPC1, detected, by, coimmunoprecipitation])].
[sujeto(['Substrates', of, a, major, 'drug-metabolizing', enzyme, 'CYP2D6', display]), verbo([increased]), complemento([elimination, during, 'pregnancy,', but, the, underlying, mechanisms, are, unknown, in, part, due, to, a, lack, of, experimental, models])].
[sujeto(['Here,', we, introduce, 'CYP2D6-humanized', '(', 'Tg-CYP2D6)', mice, as, an, animal, model, where, hepatic, 'CYP2D6', expression, is]), verbo([increased]), complemento([during, pregnancy])].
[sujeto(['In', the, mouse, 'livers,', expression, of, a, known, positive, regulator, of, 'CYP2D6,', hepatocyte]), verbo([nuclear]), complemento([factor, 4, α, '(', 'HNF4α),', did, not, change, during, pregnancy])].
[sujeto(['However,', 'HNF4α', recruitment, to, 'CYP2D6', promoter]), verbo([increased]), complemento([at, term, 'pregnancy,', accompanied, by, repressed, expression, of, small, heterodimer, partner, '(', 'SHP)'])].
[sujeto(['In', 'HepG2', 'cells,', 'SHP']), verbo([repressed]), complemento(['HNF4α', transactivation, of, 'CYP2D6', promoter])].
[sujeto(['In', transgenic, '(', 'Tg)-CYP2D6', 'mice,', 'SHP', knockdown]), verbo([led]), complemento([to, a, significant, increase, in, 'CYP2D6', expression])].
[sujeto(['Retinoic', 'acid,', an, endogenous, compound, that]), verbo([induces]), complemento(['SHP,', exhibited, decreased, hepatic, levels, during, pregnancy, in, 'Tg-CYP2D6', mice])].
[sujeto(['Administration', of, 'all-trans-retinoic', acid]), verbo([led]), complemento([to, a, significant, decrease, in, the, expression, and, activity, of, hepatic, 'CYP2D6', in, 'Tg-CYP2D6', mice])].
[sujeto(['This', study]), verbo([provides]), complemento([key, insights, into, mechanisms, underlying, altered, 'CYP2D6-mediated', drug, metabolism, during, 'pregnancy,', laying, a, foundation, for, improved, drug, therapy, in, pregnant, women])].
[sujeto(['Human', 'CYP2D6', is, present, in, 'brain,', metabolizes, many, drugs, and]), verbo([has]), complemento([been, implicated, in, 'Parkinson\'s', and, 'Alzheimer\'s', diseases, and, some, cancers])].
[sujeto(['These', data, strongly]), verbo([suggest]), complemento([that, 'CYP2D1', and, not, 'CYP2D5', mediates, 'DOD', activity, in, rat, 'brain,', and, may, be, the, rat, homologue, of, human, 'CYP2D6'])].
[sujeto(['Polyclonal', antibody, was, produced, 'and,', in, conjunction, with, 'immunoblots,', was, used, to, identify, and, purify, a, second, immunorelated, 'P450', '(', 'P450db2)', that, does, not]), verbo([have]), complemento([debrisoquine, hydroxylating, activity])].
[sujeto(['The', cDNA, clones, to, db1, and, db2, were, isolated, from, a, lambda, gt11, expression, 'library,', 'sequenced,', and]), verbo([found]), complemento([to, share, 78, '%', nucleotide, and, 73, '%', deduced, amino, acid, similarities])].
[sujeto(['Southern', blot, analysis, and, preliminary, genomic, cloning]), verbo([suggest]), complemento([that, at, least, four, genes, exist, in, the, 'subfamily,', although, the, present, evidence, suggests, that, only, db1, and, db2, are, expressed, in, rat, liver])].
[sujeto(['A', polymorphism]), verbo([has]), complemento([been, described, for, debrisoquine, metabolism, in, the, 'DA', rat, 'strain,', adult, females, having, markedly, decreased, debrisoquine, 4, -, hydroxylase, activity])].
[sujeto(['Our', immunoblot, analysis, and, mRNA, analysis]), verbo([suggest]), complemento([that, debrisoquine, 4, -, hydroxylase, deficiency, in, the, female, 'DA', rat, is, not, due, to, a, decrease, in, db1, protein, or, mRNA])].
[sujeto(['The', db1, and, db2, proteins, are, differentially, 'regulated:', during, development, db2, is, present, at, birth, while, db1, is, 'absent,', and, db1]), verbo([increases]), complemento([by, 1, week, of, 'age;', in, 'addition,', db1, is, slightly, induced, by, 'phenobarbital,', 3, -, 'methyl-cholanthrene,', and, dexamethasone, whereas, db2, is, marginally, increased, by, these, latter, two, agents])].
[sujeto(['These', results, demonstrate, that, debrisoquine, 4, -, hydroxylase, is, a, member, of, a, new, constitutively]), verbo([expressed]), complemento(['P450II', 'sub-family', containing, two, or, more, genes, in, the, rat, and, establish, that, the, debrisoquine, polymorphism, in, the, 'DA', rat, is, probably, due, to, a, structurally, altered, db1, protein])].
[sujeto(['Fusidic', 'Acid', '(', 'FA)', is, widely, used, for, the, treatment, of, infections, of, sensitive, osteomyelitis, or, skin, and, soft, tissue]), verbo([caused]), complemento([by, bacteria])].
[sujeto(['FA', metabolism, rate, was]), verbo([inhibited]), complemento([by, 49.8, '%', and, 83.1, '%', under, 'CYP2D6,', 'CYP3A4', selective, inhibitors, in, 'HLMs'])].
[sujeto(['Although', propolis, is, one, of, the, most, popular, functional, foods, for, human, 'health,', there]), verbo([have]), complemento([been, no, comprehensive, studies, of, 'herb-drug', interactions, through, cytochrome, 'P450', '(', 'CYP)', inhibition])].
[sujeto(['Propolis']), verbo([inhibited]), complemento(['CYP1A2,', 'CYP2E1', and, 'CYP2C19', with, an, 'IC50', value, of, 6.9, ',', 16.8, ',', and, 43.1, 'μg/mL,', 'respectively,', whereas, 'CYP2A6,', 2, 'B6,', 2, 'C9,', 2, 'D6,', and, 3, 'A4', were, unaffected])].
[sujeto(['CYP1A2', and, 'CYP2D6', are]), verbo([involved]), complemento([in, hydroxylation, of, duloxetine, to, 4, -, hydroxy, 'duloxetine,', the, major, 'metabolite,', which, was, decreased, following, propolis, addition, in, 'HLMs'])].
[sujeto(['Compared', with, their, respective, wild, 'type,', 'Km,', 'Vmax,', and, 'CLint']), verbo([decreased]), complemento([by, 51.6, '%', ',', 88.7, '%', and, 70.7, '%', in, 'CYP2A6*1/*4', 'genotype,', 'Vmax', and, 'CLint', decreased, by, 32.8, '%', and, 60.2, '%', in, 'CYP2C9*1/*3', 'genotype,', 'Km', increased, by, 118.4, '%', and, 'CLint', decreased, by, 65.2, '%', in, 'CYP2D6', 100, 'TT', 'genotype,', respectively])].
[sujeto(['In', 'conclusions,', the, genotypes, and, contents, of, some, 'CYPs']), verbo([have]), complemento([only, limited, effects, on, metabolic, 'activities,', which, imply, that, there, are, other, more, important, factors, to, influence, 'inter-individual', variations])].
[sujeto(['The', most, potent, inhibitors, were, genistein, and, daidzein]), verbo([inhibiting]), complemento([noncompetitively, the, 'CYP2C9', with, 'Ki', of, 35.95, ±, 6.96, and, 60.56, ±, 3.53, 'μmol/l', and, 'CYP3A4', '(', inhibited, by, genistein, with, 'Ki', of, 23.25, ±, 5.85, 'μmol/l', also, by, a, noncompetitive, 'mechanism)'])].
[sujeto(['Genistein', and, daidzein]), verbo([inhibit]), complemento([noncompetitively, 'CYP3A4', and, 'CYP2C9'])].
[sujeto(['We']), verbo([found]), complemento([that, 'CYP', activity, values, expressed, as, intrinsic, clearance, '(', 'CLint)', differed, between, 'HCC', patients, and, control, subjects])].
[sujeto(['HCC', patient, samples, showed]), verbo([increased]), complemento(['CLint', for, 'CYP2C9,', 'CYP2D6,', and, 'CYP2E1', compared, to, controls])].
[sujeto(['Meanwhile,', 'CYP1A2,', 'CYP2C8,', and, 'CYP2C19', 'CLint', values]), verbo([decreased]), complemento([and, 'CYP2A6,', 'CYP2B6,', and, 'CYP3A4/5', activity, was, unchanged, relative, to, controls])].
[sujeto(['In', the, 'HCC', 'group,', the, 'CLint', of, 'CYP2D6*10', mutant, homozygote, was]), verbo([decreased]), complemento([by, 95, '%', compared, to, 'wild-type', 'samples,', and, the, frequency, of, this, homozygote, was, 2.8, -, fold, lower, than, the, controls])].
[sujeto(['We']), verbo([found]), complemento([that, there, were, large, variations, in, protein, 'content,', mRNA, 'levels,', and, intrinsic, activities, of, the, 10, 'P450s', in, 100, human, liver, 'samples,', in, which, 'CYP2E1', and, 'CYP2C9', showed, the, highest, expression, levels])].
[sujeto(['P450', gene, polymorphisms, had, different, effects, on, activity, at, two, 'levels:', 'CYP3A5*3', and, 'CYP2A6*9', alleles]), verbo([conferred]), complemento([increased, activity, at, the, isoform, level, but, decreased, activity, at, the, microsomal, 'level;', 'CYP2C9*3', had, no, effect, at, the, isoform, level, but, decreased, activity, at, the, microsomal, level])].
[sujeto(['In', 'conclusion,', we, first, offered, the, physiologic, data, of, 10, 'P450', isoform, contents, and]), verbo([found]), complemento([that, some, single, nucleotide, polymorphisms, had, obvious, effects, on, 'P450', expression, in, human, normal, livers])].
[sujeto(['Aschantin', is, a, bioactive, neolignan]), verbo([found]), complemento([in, 'Magnolia', flos, with, 'antiplasmodial,', 'Ca(2+)-antagonistic,', platelet, activating, 'factor-antagonistic,', and, chemopreventive, activities])].
[sujeto(['Aschantin', potently]), verbo([inhibited]), complemento(['CYP2C8-mediated', amodiaquine, 'N-de-ethylation,', 'CYP2C9-mediated', diclofenac, 4, '\'', -, 'hydroxylation,', 'CYP2C19-mediated', '[', 'S]-mephenytoin', 4, '\'', -, 'hydroxylation,', and, 'CYP3A4-mediated', midazolam, 1, '\'', -, 'hydroxylation,', with, 'Ki', values, of, 10.2, ',', 3.7, ',', 5.8, ',', and, 12.6, 'µM,', respectively])].
[sujeto(['Aschantin', at, 100, µM, negligibly]), verbo([inhibited]), complemento(['CYP1A2-mediated', phenacetin, 'O-de-ethylation,', 'CYP2A6-mediated', coumarin, 7, -, 'hydroxylation,', 'CYP2B6-mediated', bupropion, 'hydroxylation,', and, 'CYP2D6-mediated', bufuralol, 1, '\'', -, hydroxylation])].
[sujeto(['At', 200, 'µM,', it, weakly]), verbo([inhibited]), complemento(['UGT1A1-catalyzed', 'SN-38', 'glucuronidation,', 'UGT1A6-catalyzed', 'N-acetylserotonin', 'glucuronidation,', and, 'UGT1A9-catalyzed', mycophenolic, acid, 'glucuronidation,', with, 'IC50', values, of, 131.7, ',', 144.1, ',', and, 71.0, 'µM,', 'respectively,', but, did, not, show, inhibition, against, 'UGT1A3,', 'UGT1A4,', or, 'UGT2B7', up, to, 200, µM])].
[sujeto(['The', roles, of, cytochrome, 'P450', enzymes, '(', 'CYPs)', in, the, metabolism, of, 'STS']), verbo([have]), complemento([remained, unclear])].
[sujeto(['Sodium', tanshinone, 'IIA', sulfonate]), verbo([inhibited]), complemento([the, activity, of, 'CYP3A4', in, a, 'dose-dependent', manner, by, the, 'HLMs', and, 'CYP3A4', isoform])].
[sujeto(['This', in, vitro, study, showed, that, 'STS', mainly]), verbo([inhibited]), complemento([the, activities, of, 'CYP3A4'])].
[sujeto(['STS']), verbo([inhibited]), complemento([the, activity, of, 'CYP3A4', in, a, 'dose-dependent', manner, in, the, 'HLMs', and, 'CYP3A4', isoform])].
[sujeto(['The', results]), verbo([suggested]), complemento([that, 'STS', primarily, inhibits, the, activities, of, 'CYP3A4', in, 'vitro,', and, 'STS', has, the, potential, to, perpetrate, 'drug-drug', interactions, with, other, 'CYP3A4', substrates])].
[sujeto(['Ginsenoside', compound, 'K', '(', 'CK),', a, rare, ginsenoside, originating, from, 'Panax', 'Ginseng,']), verbo([has]), complemento([been, found, to, possess, unique, pharmacological, activities, specifically, as, 'anti-cancers'])].
[sujeto(['The', results, showed, that, 'CK']), verbo([inhibited]), complemento([the, enzyme, activities, of, 'CYP2C9', and, 'CYP3A4', in, the, 'HLMs'])].
[sujeto(['The', results]), verbo([suggested]), complemento([that, 'CK', was, a, substrate, and, also, inhibitors, for, both, 'CYP2C9', and, 'CYP3A4'])].
[sujeto(['Patients', using, 'CK', in, combination, with, therapeutic, drugs, that, are, substrates, of, 'CYP2C9', and, 'CYP3A4', for, different, reasons, should, be, 'careful,', although, the]), verbo([inhibiting]), complemento([potency, of, 'CK', is, much, poorer, than, that, of, 'enzyme-specific', inhibitors])].
[sujeto(['The', 'Escherichia', naturally, contain, no, 'CYPs', and, no, 'NADPH:CYP', 'oxidoreductase,', however, it, was]), verbo([reported]), complemento([that, some, 'CYPs', heterologously, expressed, in, 'E'])].
[sujeto(['The', reduction, state, of, several, human, 'CYPs']), verbo([expressed]), complemento([in, the, intact, living, 'E'])].
[sujeto(['We', determined, the, reduction, state, of, five, human, 'CYPs', heterologously]), verbo([expressed]), complemento([in, 'E'])].
[sujeto(['Depending', on, the, resting, 'state,', the, 'CYPs', heterologously]), verbo([expressed]), complemento([in, 'E'])].
[sujeto([coli, present, mainly, in, the, oxidized, 'form;', while, 'CYP1A1,', 1, 'A2,', 2, 'A6,', 2, 'A13,', 2, 'B6,', 2, 'D6', are]), verbo([found]), complemento([predominantly, in, the, reduced, form])].
[sujeto(['We']), verbo([found]), complemento([a, significant, correlation, between, the, stability, of, 'CYP-flavodoxin', complexes, and, the, percentage, of, reduced, 'CYPs', in, bacteria])].
[sujeto(['Hence,', the, naturally]), verbo([expressed]), complemento([flavodoxin, is, probably, responsible, for, reduction, of, a, larger, group, of, human, 'CYPs', in, bacterial, cells])].
[sujeto(['Glycyrrhetinic', acid, '(', 'GA)']), verbo([has]), complemento([been, used, clinically, in, the, treatment, of, patients, with, chronic, hepatitis])].
[sujeto(['With', midazolam, as, the, probe, 'substrate,', 'GA', greatly]), verbo([decreased]), complemento(['CYP3A4', activity, with, 'IC50', values, of, 8.195, μM, in, 'HLMs', and, 7.498, μM, in, the, recombinant, 'cDNA-expressed', 'CYP3A4', enzyme, 'system,', respectively])].
[sujeto(['It', significantly]), verbo([decreased]), complemento(['CYP3A4', activity, in, a, 'dose-', but, not, 'time-dependent', manner])].
[sujeto(['Results', from, 'Lineweaver-Burk', plots, showed, that, 'GA', could]), verbo([inhibit]), complemento(['CYP3A4', activity, 'competitively,', with, a, 'Ki', value, of, 1.57, μM, in, 'HLMs'])].
[sujeto(['Moreover,', 'CYP2C9', and, 'CYP2C19', could, also, be]), verbo([inhibited]), complemento([significantly, by, 'GA', with, 'IC50', of, 42.89, and, 40.26, μM, in, 'HLMs,', respectively])].
[sujeto(['In', 'addition,', it, was, observed, that, mRNA, expressions, of, the, 'Cyps2c', and, 3, a, family]), verbo([decreased]), complemento([significantly, in, the, livers, of, mice, treated, with, 'GA'])].
[sujeto(['In', 'conclusion,', this, study, indicates, that, 'GA', may, exert, 'herb-drug', interactions, by, competitively]), verbo([inhibiting]), complemento(['CYP3A4'])].
[sujeto(['Sal', 'B']), verbo([has]), complemento(['anti-oxidative,', 'anti-inflammatory,', 'anti-hypoxic,', 'anti-arteriosclerotic', and, 'anti-apoptotic', properties])].
[sujeto(['The', listed, drug, 'Salvianolate,', which, contains, a, substantial, amount, of, 'Sal', 'B,']), verbo([has]), complemento([been, used, for, the, treatment, of, coronary, heart, disease])].
[sujeto(['Salvianolate']), verbo([have]), complemento([a, potent, inhibitory, effect, on, 'CYP3A4', activity, with, 'IC50', values, of, 1.438, '(', 'HLMs)', and, 3.582, '(', recombinant, 'cDNA-expressed', 'CYP3A4)', 'mg/L,', respectively])].
[sujeto(['Salvianolate', strongly, 'dose,', but, not, 'time-dependently']), verbo([decreased]), complemento(['CYP3A4', activity, in, 'HLMs'])].
[sujeto(['The', typical, 'Lineweaver-Burk', plots, showed, that, 'Salvianolate']), verbo([inhibited]), complemento(['CYP3A4', activity, 'noncompetitively,', with, a, 'Ki', value, of, 2.27, 'mg/L', in, 'HLMs'])].
[sujeto(['These', findings, indicate, that, salvianolate, may, be]), verbo([involved]), complemento([in, potential, drug, interactions, when, 'co-administrated', with, 'CYP3A4', substrates])].
[sujeto(['To', address, this, 'need,', the, 'Centers', for, 'Disease', 'Control', and, 'Prevention-based', 'Genetic', 'Testing', 'Reference', 'Material', 'Coordination', 'Program,', in, collaboration, with, members, of, the, pharmacogenetic, testing, community, and, the, 'Coriell', 'Cell', 'Repositories,']), verbo([has]), complemento([characterized, 137, genomic, 'DNA', samples, for, 28, genes, commonly, genotyped, by, pharmacogenetic, testing, assays, '(', 'CYP1A1,', 'CYP1A2,', 'CYP2A6,', 'CYP2B6,', 'CYP2C8,', 'CYP2C9,', 'CYP2C19,', 'CYP2D6,', 'CYP2E1,', 'CYP3A4,', 'CYP3A5,', 'CYP4F2,', 'DPYD,', 'GSTM1,', 'GSTP1,', 'GSTT1,', 'NAT1,', 'NAT2,', 'SLC15A2,', 'SLC22A2,', 'SLCO1B1,', 'SLCO2B1,', 'TPMT,', 'UGT1A1,', 'UGT2B7,', 'UGT2B15,', 'UGT2B17,', and, 'VKORC1)'])].
[sujeto(['DNA', samples, were, coded, and, distributed, to, volunteer, testing, laboratories, for]), verbo([targeted]), complemento([genotyping, using, a, number, of, commercially, available, and, laboratory, developed, tests])].
[sujeto(['These', samples, are, also, being, characterized, by, other, pharmacogenetic, 'assays,', including, 'next-generation', 'sequencing,', which, will, be]), verbo([reported]), complemento([separately])].
[sujeto(['Genotyping', results, were, consistent, among, 'laboratories,', with, most, differences, in, allele, assignments, attributed, to, assay, design, and, variability, in]), verbo([reported]), complemento([allele, 'nomenclature,', particularly, for, 'CYP2D6,', 'UGT1A1,', and, 'VKORC1'])].
[sujeto(['These', publicly, 'available&nbsp;samples', will, help]), verbo([ensure]), complemento([the, accuracy, of, pharmacogenetic, testing])].
[sujeto(['All', tested, 'TDNPS', with, the, exception, of, 'DMT']), verbo([inhibited]), complemento(['CYP2D6', activity, with, 'IC50', values, below, 100, μM])].
[sujeto(['DALTs']), verbo([inhibited]), complemento(['CYP2D6', activity, similar, to, paroxetine, and, quinidine, and, 'CYP1A2', activity, comparable, to, fluvoxamine])].
[sujeto(['Five', of, the, 'AMTs', also]), verbo([inhibited]), complemento(['CYP1A2', activity, comparable, to, amiodarone])].
[sujeto(['AMT', and, 6, -, 'F-AMT']), verbo([inhibited]), complemento(['CYP2A6', activity, in, the, range, of, the, test, inhibitor, tranylcypromine])].
[sujeto(['CYP2B6', activity, was]), verbo([inhibited]), complemento([by, 19, 'tryptamines,', but, weakly, compared, to, efavirenz])].
[sujeto(['CYP2C8', activity, was]), verbo([inhibited]), complemento([by, five, of, the, tested, 'TDNPS', and, three, showed, values, comparable, to, trimethoprim, and, gemfibrozil])].
[sujeto(['Six', tryptamines]), verbo([inhibited]), complemento(['CYP2C9', and, seven, 'CYP2C19', activities, comparable, to, fluconazole, and, 'chloramphenicol,', respectively])].
[sujeto(['Gene', copy, number, variants, '(', 'CNVs)', of, 'CYP2E1']), verbo([have]), complemento([been, described, but, not, functionally, characterized])].
[sujeto(['CYP2E1', 'mRNA,', protein, and, enzyme, activity, '(', 'chlorzoxazone-6-hydroxylation)', phenotypes, of, 'CYP2E1', were, not]), verbo([associated]), complemento([with, gene, copy, number])].
[sujeto(['Analysis', of, gene, expression, in, lymphoblastoid, cell, lines, in, relation, to, 'CNV', confirmed, this]), verbo([finding]), complemento([in, an, extrahepatic, tissue, and, for, other, ethnicities])].
[sujeto(['In', 'summary,', our, data]), verbo([suggest]), complemento([a, 'homeostatic,', gene, 'dosage-insensitive', regulation, of, 'CYP2E1', expression, by, unknown, gene, dosage, compensation, mechanisms])].
[sujeto(['This', is, in, striking, contrast, to, 'well-known', structural, variations, of, 'CYP2A6', and, 'CYP2D6', that]), verbo([have]), complemento([a, strong, impact, on, expression, and, activity])].
[sujeto(['We', examined, 1936, single, nucleotide, polymorphisms, '(', 'SNPs)', of, 225, genes, that]), verbo([have]), complemento([documented, functional, and, clinical, significances, in, phase, 'I', and, phase, 'II', drug, metabolism, 'enzymes,', drug, transporters, and, other, genes, involved, in, 'ADME', processes])].
[sujeto(['Tamsulosin', '(', 'TAM)', and, tolterodine, '(', 'TOL)']), verbo([inhibited]), complemento(['CYP3A4', activity, with, an, enantiospecific, pattern])].
[sujeto(['Although', enantiospecific, interactions, were]), verbo([found]), complemento(['(', 'TAM,', 'TOL,', 'KET),', they, are, probably, not, clinically, relevant, as, the, plasma, levels, are, generally, lower, than, the, drug, concentration, needed, for, prominent, inhibition, '(', at, least, 50, '%', of, 'CYP', 'activity)'])].
[sujeto([p53]), verbo([has]), complemento([been, reported, to, coregulate, the, induction, of, 'PANK1', and, miR107])].
[sujeto(['Here,', we, examine, the, possible, downregulation, of, 'CYP2C8', by, drugs, capable, of]), verbo([inducing]), complemento([miR107])].
[sujeto(['Hypolipidemic', 'drugs,', such, as, 'bezafibrate,', known, activators, of, the, peroxisome, 'proliferator-activated', receptor, α, '(', 'PPARα),']), verbo([induce]), complemento([both, the, 'PANK1', gene, and, miR107, '(', '∼2'])].
[sujeto(['Surprisingly,', 'CYP2C8', mRNA, and, protein, levels, were]), verbo([induced]), complemento([by, bezafibrate])].
[sujeto(['CYP2C8', promoter, activity, was]), verbo([increased]), complemento([by, ectopic, expression, of, 'PPARα', in, 'HepG2', 'cells,', with, a, further, increase, after, bezafibrate, '(', '∼18-fold),', 4, -, 'chloro-6-(2,3-xylidino)-2-pyrimidinylthio', acetic, acid, '(', '∼10-fold)', 'treatment,', or, the, antidiabetic, drug, 'rosiglitazone,', all, known, 'PPAR', activators])].
[sujeto(['Thus,', we, show, for, the, first, time, that, 'CYP2C8', is, transcriptionally]), verbo([regulated]), complemento([by, 'PPARα,', suggesting, the, potential, for, 'drug-drug', interactions, due, to, upregulation, of, 'CYP2C8', by, 'PPAR', activators])].
[sujeto(['Australian', marsupials, are, unique, fauna, that]), verbo([have]), complemento([evolved, and, adapted, to, unique, environments, and, thus, it, is, likely, that, their, detoxification, systems, differ, considerably, from, those, of, 'well-studied', eutherian, mammals])].
[sujeto(['In', this, study, we]), verbo([have]), complemento([cloned, and, characterized, 'CYP3A70,', the, first, identified, member, of, the, 'CYP3A', gene, subfamily, from, 'Eastern', gray, kangaroo, '(', 'Macropus', 'giganteus)'])].
[sujeto(['Transfection', of, the, 'CYP3A70', cDNAs, into, 293, 'T', cells, resulted, in, stable, cell, lines]), verbo([expressing]), complemento([a, 'CYP3A', 'immuno-reactive', protein, that, was, recognized, by, a, goat, 'anti-human', 'CYP3A4', polyclonal, antibody])].
[sujeto(['Collectively,', this, study]), verbo([provides]), complemento([primary, molecular, data, regarding, the, 'Eastern', kangaroo, hepatic, 'CYP3A70', gene, and, enables, further, functional, analyses, of, 'CYP3A', enzymes, in, marsupials])].
[sujeto([2, ',', 5, ',', 2, '\'', ',', 5, '\'', -, 'Tetrachlorobiphenyl', '(', 'TCB)']), verbo([induced]), complemento(['Type', 'I', binding, spectra, with, cytochrome, 'P450', '(', 'P450', or, 'CYP)', 2, 'A6', and, 2, 'A13,', having, 'Ks', values, of, 9.4, and, 0.51, 'μM,', respectively])].
[sujeto(['Molecular', docking, analysis]), verbo([suggested]), complemento([that, there, are, different, orientations, of, interaction, of, 2, ',', 5, ',', 2, '\'', ',', 5, '\'', -, 'TCB', with, the, active, sites, '(', over, the, 'heme)', of, human, and, monkey, 'CYP2A', enzymes, and, that, ligand, interaction, energies, '(', 'U', 'values)', of, bound, 'protein-ligand', complexes, show, structural, relationships, of, interaction, of, 'TCBs', and, other, ligands, with, active, sites, of, 'CYP2A', enzymes])].
[sujeto(['Catalytic', differences, in, human, and, monkey, 'CYP2A', enzymes, in, the, oxidation, of, 2, ',', 5, ',', 2, '\'', ',', 5, '\'', -, 'TCB', are]), verbo([suggested]), complemento([to, be, due, to, amino, acid, changes, at, substrate, recognition, 'sites,', i])].
[sujeto(['Interventions', aimed, at, smoking, cessation, in, the, 'Roma', population, should, preferentially]), verbo([target]), complemento([cultural, and, environmental, factors])].
[sujeto([',', the, ratio, 3, -, 'hydroxycotinine/cotinine,', is, used, to, assess, the, nicotine, metabolic, status, and]), verbo([has]), complemento([been, proven, to, predict, the, response, to, smoking, cessation, treatments, in, randomized, clinical, trials])].
[sujeto(['Efavirenz', frequently]), verbo([causes]), complemento([central, nervous, system, '(', 'CNS)', symptoms])].
[sujeto(['Slow', metabolizer, genotypes, were]), verbo([associated]), complemento([significantly, with, efavirenz, discontinuation, for, reported, 'CNS', symptoms])].
[sujeto(['We', identified, 248, 'CYP2A6', variants]), verbo([associated]), complemento([with, 'CYP2A6', activity, '(', 'p&lt;5x10-8)'])].
[sujeto(['When', we, examined, the, effect, of, these, variants, on, lung, cancer, risk, in, the, 'Transdisciplinary', 'Research', in, 'Cancer', of, the, 'Lung', '(', 'TRICL)', consortium, 'GWAS', dataset, '(', 13, ',', 479, 'cases,', 43, ',', 218, 'controls),', we]), verbo([found]), complemento([that, the, vast, majority, of, these, individual, effects, were, directionally, consistent, and, associated, with, an, increased, lung, cancer, risk])].
[sujeto([226, of, the, 248, variants]), verbo([associated]), complemento([with, 'CYP2A6', activity, in, the, 'MEC', were, available, in, 'TRICL'])].
[sujeto(['Of', 'them,', 81, '%', had, directionally, consistent, risk, estimates, and, six, were, globally, significantly]), verbo([associated]), complemento([with, lung, cancer])].
[sujeto(['When', conditioning, on, nine, known, functional, variants, and, two, 'deletions,', the, top, two, 'SNPs', '(', rs56113850, in, 'MEC', and, rs35755165, in, 'TRICL)', remained, significantly]), verbo([associated]), complemento([with, 'CYP2A6', activity, in, 'MEC', and, lung, cancer, in, 'TRICL'])].
[sujeto(['The', present, data, support, the, hypothesis, that, a, greater, 'CYP2A6', activity]), verbo([causes]), complemento([smokers, to, smoke, more, extensively, and, be, exposed, to, higher, levels, of, 'carcinogens,', resulting, in, an, increased, risk, for, lung, cancer])].
[sujeto(['The', 'CYP', superfamily]), verbo([has]), complemento([been, shown, to, expand, itself, through, gene, 'duplication,', and, some, of, them, become, pseudogenes, due, to, gene, mutations])].
[sujeto(['We']), verbo([have]), complemento([used, a, panel, of, online, databases, to, identify, the, orthologs, of, human, 'CYP', 'genes:', 'NCBI,', 'Ensembl', 'Compara,', 'GeneCards,', 'OMA', '(', &, 'quot;Orthologous', 'MAtrix&quot;)', 'Browser,', 'PATHER,', 'TreeFam,', 'EggNOG,', and, 'Roundup'])].
[sujeto(['The', results, show, that, each, human, 'CYP']), verbo([has]), complemento([various, numbers, of, paralogs, and, orthologs, using, 'GeneCards', and, 'Ensembl'])].
[sujeto(['For', 'example,', the, paralogs, of, 'CYP2A6', include, 'CYP2A7,', 2, 'A13,', 2, 'B6,', 2, 'C8,', 2, 'C9,', 2, 'C18,', 2, 'C19,', 2, 'D6,', 20.0, ',', 2, 'F1,', 2, 'J2,', 2, 'R1,', 2, 'S1,', 2, 'U1,', and, 2, 'W1;', 'CYP11A1']), verbo([has]), complemento([6, paralogs, including, 'CYP11B1,', 11, 'B2,', 24, 'A1,', 27, 'A1,', 27, 'B1,', and, 27, 'C1;', 'CYP51A1', has, only, three, 'paralogs:', 'CYP26A1,', 26, 'B1,', and, 26, 'C1;', while, 'CYP20A1', has, no, paralog])].
[sujeto(['The', majority, of, human, 'CYPs', are, well]), verbo([conserved]), complemento([from, 'plants,', 'amphibians,', 'fishes,', or, mammals, to, humans, due, to, their, important, functions, in, physiology, and, xenobiotic, disposition])].
[sujeto(['Substance', abuse, disorders]), verbo([have]), complemento([a, strong, genetic, component])].
[sujeto(['Genetic', risk, factors]), verbo([associated]), complemento([with, alcohol, abuse, include, common, variants, in, genes, coding, for, 'alcohol-metabolizing', enzymes, and, 'gamma-aminobutyric', acid, 'A', receptors])].
[sujeto(['Nicotine', use, disorders, are]), verbo([associated]), complemento([with, polymorphisms, in, a, cluster, of, nicotinic, acetylcholine, receptors, on, chromosome, 15, 'q24,', and, mutations, that, reduce, the, enzymatic, activity, of, 'CYP2A6'])].
[sujeto(['Genetic', risk, factors, for, other, illicit, drug, use]), verbo([have]), complemento([not, been, 'well-studied'])].
[sujeto(['Kinsenoside,', the, 'herb-derived', medicine, isolated, from, the, plant, 'Anoect', 'chilus,']), verbo([has]), complemento([diverse, pharmacological, 'actions,', and, it, is, considered, to, be, a, promising, antihyperlipidemic, drug, candidate])].
[sujeto(['The', effect, of, kinsenoside, was, negligible, on, the, enzyme, activity, of, all, the, 'CYP', isozymes, tested, even, though, 'CYP2A6', was, slightly]), verbo([inhibited]), complemento([at, higher, concentrations])].
[sujeto(['The', 'drug-drug', interaction, assay, also, showed, that, the, concomitant, use, of, kinsenoside]), verbo([has]), complemento([a, 'non-significant', effect, on, the, concentration, of, lovastatin, or, 'amlodipine,', and, their, major, metabolites])].
[sujeto(['Rate', of, nicotine, metabolism]), verbo([has]), complemento([been, identified, as, an, important, factor, influencing, nicotine, intake, and, can, be, estimated, using, the, nicotine, metabolite, ratio, '(', 'NMR),', a, validated, biomarker, of, 'CYP2A6', enzyme, activity])].
[sujeto(['Individuals', who, metabolize, nicotine, faster, '(', higher, 'NMR)', may, alter, their, smoking, behavior, to, titrate, their, nicotine, intake, in, order, to]), verbo([maintain]), complemento([similar, levels, of, nicotine, in, the, body, compared, to, slower, nicotine, metabolizers])].
[sujeto(['However,', this, relationship, was, not]), verbo([found]), complemento([in, 'African', 'Americans'])].
[sujeto(['The', sedative, clomethiazole, '(', 'CMZ)']), verbo([has]), complemento([been, used, in, 'Europe', since, the, 'mid-1960s', to, treat, insomnia, and, alcoholism])].
[sujeto(['It']), verbo([has]), complemento([been, previously, demonstrated, in, clinical, studies, to, reversibly, inhibit, human, 'CYP2E1', in, vitro, and, decrease, 'CYP2E1-mediated', elimination, of, chlorzoxazone])].
[sujeto(['We']), verbo([have]), complemento([investigated, the, selectivity, of, 'CMZ', inhibition, of, 'CYP2E1', in, pooled, human, liver, microsomes, '(', 'HLMs)'])].
[sujeto(['The', substantial]), verbo([increase]), complemento([in, potency, of, 'CYP2E1', inhibition, upon, preincubation, enables, the, use, of, 'CMZ', to, investigate, the, role, of, human, 'CYP2E1', in, xenobiotic, metabolism, and, provides, advantages, over, other, chemical, inhibitors, of, 'CYP2E1'])].
[sujeto(['The', 'KI', and, kinact, 'values,', along, with, other, 'parameters,', were, used, in, a, mechanistic, static, model, to, explain, earlier, observations, of, a, profound]), verbo([decrease]), complemento([in, the, rate, of, chlorzoxazone, elimination, in, volunteers, despite, the, absence, of, detectable, 'CMZ', in, blood])].
[sujeto(['Most', '(', 34, /, 36, ')', 'genome-wide', significant, variants]), verbo([suggested]), complemento([reduced, 'CYP2A6', 'activity;', functional, mechanisms, were, identified, and, tested, in, 'knowledge-bases'])].
[sujeto(['This', 'meta-GWAS', of, the, 'NMR', identifies, 'CYP2A6', 'variants,', replicates, the, 'top-ranked', single, nucleotide, polymorphism, from, a, recent, 'Finnish', 'meta-GWAS', of, the, 'NMR,', identifies, functional, 'mechanisms,', and]), verbo([provides]), complemento(['pan-continental', population, biomarkers, for, nicotine, metabolism])].
[sujeto(['This', multiple, ancestry, 'meta-GWAS', of, the, laboratory, 'study-based', 'NMR']), verbo([provides]), complemento([novel, evidence, and, replication, for, 'genome-wide', association, of, 'CYP2A6', single, nucleotide, and, 'insertion-deletion', polymorphisms])].
[sujeto(['We', replicate, the, 'top-ranking', single, nucleotide, polymorphism, from, a, recent, 'GWAS', of, the, 'NMR', in, 'Finnish', 'smokers,', identify, a, functional, mechanism, for, this, intronic, variant, from, in, silico, analyses, of, 'RNA-seq', data, that, is, consistent, with, 'CYP2A6', expression, measured, in, postmortem, lung, and, 'liver,', and]), verbo([provide]), complemento([additional, support, for, the, intergenic, region, between, 'CYP2A6', and, 'CYP2A7'])].
[sujeto(['There', was, a, significant]), verbo([decrease]), complemento([in, urine, 'NMR', over, the, 7, weeks, after, alcohol, abstinence, '(', 'F(2,42)=18'])].
[sujeto([1, ')', ',', indicating, a]), verbo([decrease]), complemento([in, rate, of, nicotine, metabolism])].
[sujeto(['On', average, 'NMR']), verbo([decreased]), complemento([50.0, '%', from, baseline, to, week, 7, '(', 9.6, '±1'])].
[sujeto(['The', results, support, the, idea, that, chronic, alcohol, abuse, may]), verbo([increase]), complemento([the, rate, of, nicotine, 'metabolism,', which, then, decreases, over, time, after, alcohol, cessation])].
[sujeto(['The', cytochrome, 'P450', '(', 'P450)', family, of, enzymes, is, a, major, player, in, the, metabolism, of, therapeutic, drugs, available, on, the, 'market,', and, the, development, of, novel, drugs]), verbo([has]), complemento([to, take, into, account, these, enzymes, in, the, fate, of, new, drugs])].
[sujeto(['Porcine', 'CYP2A19']), verbo([has]), complemento([the, highest, sequence, homology, to, human, 'CYP2A6', and, 'CYP2A13,', and, pig, 'CYP2C33v4', and, 'CYP2C49', are, the, porcine, equivalent, of, human, 'CYP2C9', and, 'CYP2C18,', respectively])].
[sujeto(['CYP2C76', catalysed, typical, 'CYP2C', substrates, with, low, 'activities,', and]), verbo([has]), complemento([not, been, found, in, humans])].
[sujeto(['These', results, indicate, that, cynomolgus, monkeys]), verbo([express]), complemento(['CYPs', similar, to, human, 'CYPs', that, are, important, in, drug, metabolism])].
[sujeto(['We']), verbo([have]), complemento([previously, found, that, for, acetaminophen, kinetic, differences, exist, between, the, hepatic, microsomal, catalyzed, protein, binding, and, cysteine, conjugation])].
[sujeto(['We']), verbo([have]), complemento([also, observed, that, the, protein, binding, of, acetaminophen, is, only, to, intralumenal, proteins])].
[sujeto(['Together', these, data]), verbo([suggested]), complemento([that, two, pools, of, the, reactive, 'metabolite,', 'N-acetyl-p-benzoquinone', imine, '(', 'NABQI),', are, formed, during, the, oxidative, metabolism, of, 'acetaminophen:', one, on, the, cytosolic, surface, and, the, other, within, the, lumen, of, the, microsomes])].
[sujeto(['This', would, indicate, that, some, of, forms, of, cytochrome, 'P450', '(', 'CYP)', catalyzing, 'NABQI', formation]), verbo([have]), complemento([their, active, site, on, the, cytosolic, surface, and, others, on, the, lumenal, surface])].
[sujeto(['We']), verbo([have]), complemento([examined, this, question, by, comparing, the, rates, of, cysteine, conjugation, and, protein, binding, of, acetaminophen, by, microsomes, from, lymphoblasts, transfected, with, the, cDNAs, for, human, 'CYPs'])].
[sujeto(['We']), verbo([found]), complemento([that, 'CYP2D6', catalyzed, only, cysteine, 'conjugation;', 'CYP1A2', and, 3, 'A4', catalyzed, only, protein, 'binding;', 'CYP2E1', catalyzed, 'both;', and, 'CYP1A1,', 'CYP2A6', and, 'CYP2B6', catalyzed, neither])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'CYP2D6', has, its, active, site, only, on, the, cytosolic, 'surface;', 'CYP1A2', and, 'CYP3A4', only, on, the, lumenal, 'surface;', and, 'CYP2E1', has, catalytic, sites, on, both, the, lumenal, and, cytosolic, surfaces, of, the, membrane])].
[sujeto(['In', mouse, studies, we]), verbo([have]), complemento([found, that, ethanol, administration, increased, acetaminophen, protein, binding, by, 265, '%', but, cysteine, conjugation, by, only, 61, '%'])].
[sujeto(['CYP2E1', and, 'CYP2B', 'increased,', whereas, 'CYP3A']), verbo([decreased]), complemento([and, the, others, did, not, change])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, in, control, mice, 'CYP2E1', catalyzes, the, bulk, of, protein, 'binding,', whereas, 'CYP2D', catalyzes, slightly, more, cysteine, conjugation, than, does, 'CYP2E1'])].
[sujeto(['The', cumene, hydroperoxide, '(', 'CuOOH)-mediated', metabolism, of, '(', +, ')', -, bufuralol]), verbo([suggested]), complemento([that, at, least, two, enzymes, were, responsible, for, bufuralol, 1, '\'', -, hydroxylation, in, both, human, and, monkey, intestinal, microsomes])].
[sujeto(['Bufuralol', metabolism]), verbo([mediated]), complemento([by, 'NADPH', exhibited, biphasic, kinetics, and, was, less, efficient, than, that, observed, in, the, presence, of, 'CuOOH', in, both, human, and, monkey, 'intestines,', in, agreement, with, the, observations, in, the, livers])].
[sujeto(['The', hepatic, metabolism, of, '(', +, ')', -, bufuralol, in, humans, and, monkeys, was, only]), verbo([inhibited]), complemento(['(', 75, '%', ')', by, 'anti-CYP2D6,', but, not, by, 'anti-CYP3A1'])].
[sujeto(['Overall,', the, results]), verbo([suggest]), complemento([that, '(', 1, ')', tissue, and, species, differences, exist, in, the, catalysis, of, '(', +, ')', -, bufuralol, 1, '\'', -, 'hydroxylation,', and, '(', 2, ')', 'CYP2D6-related', enzymes, are, partially, or, primarily, responsible, for, the, bufuralol, hydroxylase, activity, in, human, and, monkey, intestines, or, monkey, liver])].
[sujeto(['The', furanocoumarins, bergapten, '(', 5, -, 'methoxypsoralen),', isopimpinellin, '(', 5, ',', 8, -, 'dimethoxypsoralen),', imperatorin, and, sphondin, also, effectively]), verbo([inhibited]), complemento([mouse, 'COH', activity, '(', 'IC50', values, 19, -, 40, 'microM)'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, '(', 'i)', the, 'coumarin-type', compounds, in, particular, interact, with, the, active, sites, of, 'Cyp2a-5', and, 'CYP2A6,', and, '(', 'ii)', the, active, sites, of, 'Cyp2a-5', and, 'CYP2A6', are, structurally, 'different,', since, a, number, of, compounds, inhibited, 'mouse,', but, not, human, 'COH', activity])].
[sujeto([',']), verbo([has]), complemento([drawn, a, lot, of, attention, for, its, plenty, of, pharmacological, properties, including, antidiabetes, and, 'anti-cancer'])].
[sujeto(['In', 'general,', the, relatively, low, 'Ki', values, of, plumbagin, in, humans, would]), verbo([have]), complemento([a, high, potential, to, cause, the, toxicity, and, drug, interactions, involving, 'CYP', enzymes])].
[sujeto(['MGCD0103,', an, 'isotype-selective', histone, deacetylase, inhibitor, '(', 'HDACi),']), verbo([has]), complemento([been, clinically, evaluated, for, the, treatment, of, hematologic, malignancies, and, advanced, solid, 'tumors,', alone, and, in, combination, with, 'standard-of-care', agents])].
[sujeto(['Continuous', 7, -, day, intragastric, administration, of, 'MGCD0103', slightly]), verbo([induces]), complemento([the, activities, of, 'CYP2C11', of, rats])].
[sujeto(['Cytochrome', 'P450', '(', 'CYP)', enzymes, in, the, brain, may]), verbo([have]), complemento([a, role, in, the, activation, or, inactivation, of, centrally, acting, 'drugs,', in, the, metabolism, of, endogenous, 'compounds,', and, in, the, generation, of, damaging, toxic, metabolites, 'and/or', oxygen, stress])].
[sujeto(['CYPs', are, distributed, unevenly, among, brain, 'regions,', and, are]), verbo([found]), complemento([in, 'neurons,', glial, cells, and, at, the, 'blood-brain', interface])].
[sujeto(['They']), verbo([have]), complemento([been, observed, in, mitochondrial, 'membranes,', in, neuronal, processes, and, in, the, plasma, 'membrane,', as, well, as, in, endoplastic, reticulum])].
[sujeto(['Brain', 'CYPs', are, inducible, by, many, common, hepatic, 'inducers,', however, many, compounds, affect, liver, and, brain, 'CYP', expression, 'differently,', and, some, 'CYPs', which, are, constitutively]), verbo([expressed]), complemento([in, liver, are, inducible, in, brain])].
[sujeto(['While', it, is, unlikely, that, brain, 'CYPs', contribute, to, overall, clearance, of, 'xenobiotics,', their, 'punctate,', 'region-', and, 'cell-specific', expression]), verbo([suggests]), complemento([that, 'CNS', 'CYPs', may, create, 'micro-environments', in, the, brain, with, differing, drug, and, metabolite, levels, '(', not, detected, or, predicted, by, plasma, drug, 'monitoring)'])].
[sujeto(['Coupled', with, the, sensitivity, of, 'CNS', 'CYPs', to, 'induction,', this, may, in, part, account, for, 'inter-individual', variation, in, response, to, centrally]), verbo([acting]), complemento([drugs, and, 'neurotoxins,', and, may, have, implications, for, individual, variation, in, receptor, adaptation, and, 'cross-tolerance', to, different, drugs])].
[sujeto(['It', holds, promise, for, furthering, our, undestanding, of, 'inter-individual', variability, in, response, to, centrally]), verbo([acting]), complemento([drugs, as, well, as, risk, for, neurological, diseases, and, pathogies])].
[sujeto(['We']), verbo([report]), complemento([quantitative, estimates, of, the, parameters, for, metabolism, of, bromodichloromethane, '(', 'BDCM)', by, recombinant, preparations, of, hepatic, cytochrome, 'P450s', '(', 'CYPs)', from, rat, and, human])].
[sujeto(['Earlier', work, identified, 'CYP2E1,', 'CYP2B1/2', and, 'CYP1A2', as]), verbo([activating]), complemento([enzymes, necessary, for, hepatotoxicity, in, rat])].
[sujeto(['We']), verbo([have]), complemento([conducted, in, vitro, experiments, using, recombinant, preparations, of, the, three, rat, 'CYP', isoenzymes, mentioned, above, and, for, 'CYP2C11', and, 'CYP3A1', as, well])].
[sujeto(['Similar', experiments]), verbo([have]), complemento([been, performed, with, human, recombinant, isoenzymes, for, 'CYP2E1,', 'CYP1A2,', 'CYP2A6,', 'CYP2B6,', 'CYP2D6', and, 'CYP3A4'])].
[sujeto(['CYP3A1', may, also]), verbo([have]), complemento([some, activity])].
[sujeto(['Oxidative', metabolism, of, carbamazepine, results, in, covalent]), verbo([binding]), complemento([of, its, reactive, metabolite, to, liver, microsomal, 'proteins,', which, has, been, proposed, as, an, important, event, in, pathogenesis, of, the, hypersensitivity, reactions, to, this, drug])].
[sujeto(['Although', the, proposed, reactive, metabolites, are, produced, by, cytochrome, 'P450', enzymes, '(', 'P450', or, 'CYP),', the, impact, of, the, formation, of, unstable, metabolites, on, the, enzyme, itself]), verbo([has]), complemento([not, been, elucidated])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'CYP2D', 'enzyme(s)', in, rats, and, 'CYP1A2', in, humans, biotransform, carbamazepine, into, reactive, 'metabolites,', resulting, in, inactivation, of, the, enzyme, 'themselves,', and, raise, the, possibility, that, the, 'P450', isoforms, participate, in, toxicity, induced, by, the, drug, in, both, animal, species])].
[sujeto(['Northern', blot, analysis, showed, that, mRNAs, hybridizable, with, cDNAs, for, rat, 'CYP1A2,', human, 'CYP2A6,', rat, 'CYP2B1,', human, 'CYP2C8,', human, 'CYP2D6,', rat, 'CYP2E1,', human, 'CYP3A4', and, rat, 'CYP4A1', were]), verbo([expressed]), complemento([in, various, tissues, from, 'Suncus'])].
[sujeto(['Furthermore,', it, was]), verbo([found]), complemento([that, the, level, of, 'CYP2A', mRNA, in, the, 'Suncus', lung, was, higher, compared, to, the, 'Suncus', liver])].
[sujeto(['These', results, indicate, that, the, 'Suncus', is, a, unique, animal, species, in, that, mRNAs, for, 'CYP3A', and, 'FMO', are]), verbo([expressed]), complemento([at, very, low, levels])].
[sujeto(['The', 7, -, 'ethoxy-4-(trifluoromethyl)coumarin', 'O-deethylation', activity, of, purified, rat, liver, 'P450', 2, 'B1', and]), verbo([expressed]), complemento([human, 'P450', 2, 'B6', was, inactivated, by, 'PPP', in, a, reconstituted, system, containing, 'NADPH-cytochrome', 'P450', reductase, and, lipid])].
[sujeto(['In', the, presence, of, 'NADPH,', the]), verbo([loss]), complemento([of, activity, was, 'time-', and, 'concentration-dependent,', and, followed, pseudo, first, order, kinetics])].
[sujeto(['The', rate, of, inactivation, for, 'P450', 2, 'B1', was, 0.3, 'min(-1),', and, the, concentration, of, 'PPP']), verbo([required]), complemento([to, achieve, 'half-maximal', inactivation, was, 12, microM])].
[sujeto(['The', inactivated, 'P450s', 2, 'B1', and, 2, 'B6', lost, about, 25, and, 15, '%', ',', 'respectively,', of, their, ability, to, form, a, 'CO-reduced', 'complex,']), verbo([suggesting]), complemento([that, the, loss, of, activity, was, caused, by, a, 'PPP', modification, of, the, apoprotein, rather, than, the, heme])].
[sujeto(['PPP-inactivated', 'P450s', 2, 'B1', and, 2, 'B6', were]), verbo([recognized]), complemento([on, 'Western', blots, by, an, antibody, generated, to, phencyclidine, that, had, been, conjugated, to, 'BSA'])].
[sujeto(['Stoichiometries', of, 1.4, :, 1, and, 0.7, :, 1, were, determined, for, the]), verbo([binding]), complemento([of, a, '[', 3, 'H]PPP', metabolite, to, 'P450', 2, 'B1', and, 2, 'B6,', respectively])].
[sujeto(['A', series, of, methylenedioxyphenyl, compounds, were, evaluated, for, their, inhibitory, and, inactivation, effects, on, nine, human, cytochrome, 'P450', '(', 'CYP)', activities, using, microsomes, from, human, 'B-lymphoblast', cells]), verbo([expressing]), complemento([specific, human, 'CYP', isoforms])].
[sujeto(['Ethoxyresorufin', 'O-deethylation', by, 'CYP1A2,', coumarin, 7, -, hydroxylation, by, 'CYP2A6,', and, chlorzoxazone, 6, -, hydroxylation, by, 'CYP2E1', were, not]), verbo([inhibited]), complemento([by, almost, any, of, the, methylenedioxyphenyl, compounds])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, the, methylenedioxyphenyl, compounds, investigated, in, this, study, would, be, potent, 'mechanism-based', inactivators, of, these, human, 'CYP', isoforms])].
[sujeto(['The', present, study]), verbo([suggested]), complemento([that, the, selectivity, of, inhibition, or, inactivation, of, human, 'CYP', isoforms, by, methylenedioxyphenyl, compounds, may, vary, according, to, the, structure, of, the, side, chain])].
[sujeto(['While', 'African', green, monkey, showed, 'Km', and, 'Vmax', values, of, 2.7, microM, and, 0.52, 'nmol/mg/min,', which, were, similar, to, 'human,', higher, 'Km', and, 'Vmax', values, were]), verbo([found]), complemento([in, cynomolgus, monkey])].
[sujeto(['Coumarin', 7, -, hydroxylation, in, human, and, 'African', green, monkey, was, selectively]), verbo([inhibited]), complemento([by, methoxsalen, and, pilocarpine, '(', 'CYP2A6', 'inhibitors)', but, not, by, other, 'inhibitors,', i])].
[sujeto(['Immunoinhibition', results, supported, 'CYP2A6', involvement, in, human, and, its, homolog, in, monkey, in, coumarin, 7, -, 'hydroxylation,', as, only, 'anti-CYP2A6,', but, not, 'CYP2B1,', 'CYP2C13,', 'CYP2D6,', 'CYP2E1', or, 'CYP3A', 'antibodies,']), verbo([inhibited]), complemento([this, conversion])].
[sujeto(['African', green, monkey, was]), verbo([found]), complemento([to, be, similar, to, human, in, catalytic, activity, of, coumarin, 7, -, hydroxylation, and, response, to, 'CYP2A6', inhibitors, or, antibody, inhibition])].
[sujeto(['However,', the, monkey, 'CYP2A6', is, not, identical, to, the, human, in, that, 'Ki', values, were, 'different,', and, differences, were, observed, with, some, 'CYP2A6', 'inhibitors,', such, as, nicotine, and, 'methoxsalen,']), verbo([suggesting]), complemento(['that,', under, some, 'circumstances,', studies, of, nicotine, kinetics, and, drug, taking, behavior, in, monkey, may, not, be, comparable, to, human])].
[sujeto(['The', ability, of, 'CYP2B6', to]), verbo([activate]), complemento([prodrugs, and, procarcinogens, was, examined, using, gene, locus, mutation, assays, in, 'CYP2B6-expressing', human, lymphoblast, cells])].
[sujeto(['CYP2B6-expressing', cells, were]), verbo([found]), complemento([to, be, more, sensitive, than, control, cells, to, the, cytotoxicity, and, mutagenicity, of, 'cyclophosphamide,', aflatoxin, 'B1,', and, 4, -, '(', 'methylnitrosamino)-1-(3-pyridyl)-1-butanone'])].
[sujeto(['CYP2B6', is, thus, a, widely]), verbo([expressed]), complemento([human, liver, microsomal, 'CYP', that, can, contribute, to, a, broad, range, of, drug, metabolism, and, procarcinogen, activation, reactions])].
[sujeto(['Formation', of, 'o-cresol', was, elevated, in, microsomes, from, human, livers, derived, from, cigarette, 'smokers,', but, the]), verbo([induced]), complemento(['CYP', isoforms, were, not, clear])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, structure, of, 'CYP2B1', at, the, site, of, 'Leu', 58, rather, than, 'Ile-114', and, 'Glu-282', plays, an, important, role, in, the, formation, of, toluene, ring, 'products,', whereas, in, 'CYP2B1', 'Ile-114', plays, an, important, role, in, the, formation, of, benzyl, alcohol])].
[sujeto(['These', results, may, 'explain,', in, 'part,', the, lower, activity, of, 'CYP2B6,', which]), verbo([has]), complemento(['Phe', at, position, 58, of, the, 'protein,', for, toluene, ring, oxidations, than, that, of, 'CYP2B1'])].
[sujeto(['Because', 'YM17E', '(', 1, ',', 3, -, 'bis[[1-cycloheptyl-3-(p-dimethylaminophenyl)', 'ureido]methyl]benzene', 'dihydrochloride)']), verbo([inhibits]), complemento([acyl, coenzyme, 'A:cholesterol', acyltransferase, '(', 'ACAT)', it, has, potential, application, in, the, treatment, of, hypercholesterolaemia])].
[sujeto(['This', reaction, was]), verbo([inhibited]), complemento([by, metabolites, 'M2-a,', 'M2-b,', 'M3', and, 'M4'])].
[sujeto(['Further,', 'N-demethylation', of, '[', 14, 'C]-YM17E', was, also]), verbo([inhibited]), complemento([by, its, 'product,', 'M1'])].
[sujeto(['These', results, showed, that, primary, metabolism, of, 'YM17E', was]), verbo([inhibited]), complemento([by, its, 'products,', and, supported, the, finding, that, the, 'non-linear', increase, in, plasma, concentration, of, the, parent, drug, and, metabolites, observed, in, an, 'in-vivo', study, was, due, to, inhibition, by, these, products])].
[sujeto(['When', cytochrome, 'P450', 'isozyme-specific', substrates, and, chemical, inhibitors, were, used, to]), verbo([inhibit]), complemento(['YM17E', 'N-demethylase', 'activity,', 'CYP3A-specific', substrate, and, inhibitors, such, as, 'nifedipine,', ketoconazole, and, triacetyloleandomycin, strongly, inhibited, this, 'activity,', whereas, 'CYP1A-specific', substrate, or, 'inhibitor,', ethoxyresorufin, and, 'alpha-naphthoflavone,', inhibited, weakly])].
[sujeto(['An', inhibition, study, using, 'anti-rat', 'CYP1A1,', 'CYP2B1,', 'CYP2C11,', 'CYP2E1', and, 'CYP3A2', antibodies, demonstrated, that, only, 'anti-rat', 'CYP3A2', antibody]), verbo([inhibited]), complemento(['YM17E', 'metabolism,', to, 40, '%', of, control, 'level,', with, no, other, antibodies, showing, an, inhibitory, effect])].
[sujeto(['DETC-Me', sulfoxidation, by, microsomes, from, male, and, female, rats, treated, with, various, cytochrome, 'P450-enzyme', inducers]), verbo([suggested]), complemento([that, multiple, enzymes, can, catalyze, this, 'reaction,', and, these, 'include,', 'CYP1A1/2,', 'CYP2B1/2,', and, 'CYP3A1/2'])].
[sujeto([90, ')', ',']), verbo([suggesting]), complemento([that, 'CYP2A6', and, 'CYP3A4/5', contribute, to, the, sulfoxidation, of, 'DETC-Me', by, human, liver, microsomes])].
[sujeto(['Similarly,', when, 'DETC-Me', sulfoxidation, was, studied, in, the, presence, of, diethyldithiocarbamate, '(', 'DDTC),', the]), verbo([inhibited]), complemento(['DETC-Me', sulfoxidase, activity, correlated, better, '(', 'r=0'])].
[sujeto(['Polyclonal', antibodies, against, 'CYP2E1']), verbo([caused]), complemento([a, modest, inhibition, '(', 30, '%', ')', of, 'DETC-Me', sulfoxidation, by, human, liver, microsomes])].
[sujeto(['Anti-CYP3A1', antibodies, completely]), verbo([inhibited]), complemento(['DETC-Me', sulfoxidation, by, 'cDNA-expressed', 'CYP3A4'])].
[sujeto(['Under', similar, 'conditions,', 'DETC-Me', sulfoxidation, by, human, liver, microsomes, was, only, partially]), verbo([inhibited]), complemento([by, 'anti-CYP3A1', antibodies])].
[sujeto(['Although', studies, with, the, rat, and, 'cDNA-expressed', cytochrome, 'P450', enzymes]), verbo([suggested]), complemento([that, 'CYP1A2', contributed, to, 'DETC-Me', 'sulfoxidation,', this, reaction, was, not, inhibited, by, either, furafylline, '(', a, 'mechanism-based', inhibitor, of, 'CYP1A2)', or, antibodies, against, 'CYP1A1/2'])].
[sujeto(['A', significant, role, for, 'CYP2C9', was, excluded, by, the, inability, of, sulfaphenazole, to]), verbo([inhibit]), complemento([the, sulfoxidation, of, 'DETC-Me', by, human, liver, microsomes])].
[sujeto(['Collectively,', these, data]), verbo([suggest]), complemento([that, multiple, cytochrome, 'P450', enzymes, can, catalyze, the, sulfoxidation, of, 'DETC-Me'])].
[sujeto(['It', is, interesting, to, note, that, 'DDTC,', the, reduced, metabolite, of, 'disulfiram,', is, known, to]), verbo([inhibit]), complemento([these, same, enzymes])].
[sujeto(['The', ability, of, 'DDTC', to, block, the, formation, of, 'DETC-Me', sulfoxide, may, explain, why, the, dose, of, disulfiram]), verbo([required]), complemento([to, produce, a, 'disulfiram-ethanol', reaction, in, alcoholics, is, so, variable, and, often, inadequate])].
[sujeto(['Repetitive', oral, administration, of, imipramine, '(', 100, 'mg/kg/day', for, 5, 'days)']), verbo([caused]), complemento([a, decrease, in, rat, liver, microsomal, debrisoquine, 4, -, hydroxylase, 'activity,', a, characteristic, reaction, catalyzed, by, cytochrome, 'P450', '(', 'CYP)', 2, 'D1'])].
[sujeto(['Imipramine', pretreatment, did, not, change, the, immunochemically, determined, content, of, the, 'CYP2D', 'protein,']), verbo([suggesting]), complemento([that, 'CYP2D', is, inactivated])].
[sujeto(['Imipramine', pretreatment, also, resulted, in, an]), verbo([increase]), complemento([in, total, 'CYP', content, and, in, formation, of, a, ferrous, 'CYP', metabolic, intermediate, '(', 'MI)-complex', absorbing, at, 454, nm])].
[sujeto(['Although', the, total, 'CYP', content, was]), verbo([increased]), complemento([by, the, treatment, of, these, microsomes, with, ferricyanide, to, dissociate, the, 'MI-complex,', the, 'CYP2D-dependent', activities, were, not, 'restored,', suggesting, that, the, 'MI-complex', was, not, the, primary, cause, of, 'CYP2D', inhibition])].
[sujeto(['This', pretreatment, regimen]), verbo([caused]), complemento([marked, increases, in, immunochemically, determined, levels, of, 'CYP2A1,', 'CYP2B1,', 'CYP2B2,', 'CYP2C6,', and, 'CYP3A2,', and, in, the, activities, of, 2, 'alpha-,', 2, 'beta-,', 6, 'beta-,', 7, 'alpha-,', 16, 'alpha-,', and, 16, 'beta-hydroxylation', and, 17, -, oxidation, of, testosterone])].
[sujeto(['These', results, indicate, that, imipramine]), verbo([has]), complemento([two, actions, on, the, liver, 'CYP', system, '(', i])].
[sujeto(['P450', isozyme, specificity, in, this, effect, is]), verbo([suggested]), complemento([by, the, fact, that, the, interaction, is, pronounced, in, microsomes, from, rats, treated, with, 'phenobarbital,', but, does, not, occur, in, microsomes, of, 'isoniazid-', or, 'beta-naphthoflavone-treated', animals])].
[sujeto(['Three', of, the, samples, exhibited, 'isoflurane-stimulated']), verbo([increases]), complemento(['(', 24, ',', 32, ',', and, 41, '%', ')', in, 'CDE', 'defluorination;', isoflurane, either, inhibited, or, had, no, effect, on, 'CDE', metabolism, in, the, other, seven, samples])].
[sujeto(['In', microsomes, from, cells, transfected, with, cDNAs, coding, for, individual, human, 'P450s,', 'CDE', metabolism, by, 'CYP2B6', was]), verbo([stimulated]), complemento(['(', 216, '%', ')', by, 'isoflurane,', whereas, isoflurane, did, not, stimulate, 'CDE', metabolism, by, human, 'CYP2A6,', 'CYP3A4,', 'CYP2D6,', or, 'CYP2E1'])].
[sujeto(['Isoflurane', highly]), verbo([increased]), complemento(['CDE', defluorination, in, purified, rat, 'CYP2B1', '(', 470, '%', ')'])].
[sujeto(['At', a, low, styrene, concentration, '(', 0.085, 'mM),', the, rates]), verbo([decreased]), complemento([in, the, 'order,', mouse, &, 'gt;', rat, &, 'gt;', 'human;', at, a, high, concentration, '(', 1.85, 'mM),', the, order, was, rat, &, 'gt;', mouse, &, 'gt;', human])].
[sujeto(['We']), verbo([found]), complemento([no, significant, influence, in, the, mRNA, expression, of, hepatic, 'CYP1A2,', 2, 'C11,', 20.0, ',', 3, 'A1,', 3, 'A2,', and, 4, 'A1', after, repeated, administration, of, 'SCRT', for, 13, weeks])].
[sujeto(['By', 'contrast,', the, mRNA, and, protein, expression, of, hepatic, 'CYP1A1', was]), verbo([increased]), complemento([by, repeated, 'SCRT', treatment, in, male, 'rats,', but, not, in, female, rats])].
[sujeto(['The', mRNA, and, protein, expression, of, hepatic, 'CYP2B1/2', in, both, genders, was]), verbo([increased]), complemento([by, administration, of, 'SCRT'])].
[sujeto(['In', case, of, 'male,', an, attention, is, also]), verbo([required]), complemento([when, 'SCRT', and, drugs, metabolized, by, 'CYP1A1', are, taken, together])].
[sujeto(['Our', findings]), verbo([provide]), complemento([information, regarding, the, safety, and, effectiveness, of, 'SCRT', when, combined, with, conventional, drugs])].
[sujeto(['Oral', administration, of, 'Socheongryong-tang', for, 13, weeks, did, not, affect, the, mRNA, expression, of, hepatic, 'CYP1A2,', 2, 'C11,', 20.0, ',', 3, 'A1,', 3, 'A2,', and, 4, 'A1In', male, 'rats,', oral, administration, of, 'Socheongryong-tang', for, 13, weeks]), verbo([induced]), complemento([the, mRNA, and, protein, expression, of, hepatic, 'CYP1A1', and, 'CYP2B1/2In', female, 'rats,', oral, administration, of, 'Socheongryong-tang', for, 13, weeks, induced, the, mRNA, and, protein, expression, of, hepatic, 'CYP2B1/2'])].
[sujeto(['These', results, strongly]), verbo([suggest]), complemento([that, marked, gender, differences, exist, in, the, expression, profiles, of, some, 'CYP', subtypes, in, rat, brain])].
[sujeto(['Concern', about, potential, susceptibilities, of, infants, and, children, to, chemicals]), verbo([has]), complemento([led, to, the, consideration, of, immature, rodents, as, potential, test, surrogates])].
[sujeto(['Maturation', of, some, hepatic, microsomal, cytochrome, 'P450s', '(', 'CYPs),', that]), verbo([participate]), complemento([in, metabolic, activation, of, organic, solvents, and, polycyclic, aromatic, hydrocarbons, '(', 'PAHs),', may, differ, significantly, between, humans, and, rodents])].
[sujeto(['The', same, ontogenic, profiles, were, manifested, when, the, enzyme, activities, were]), verbo([expressed]), complemento([per, entire, liver, or, liver, normalized, to, body, weight])].
[sujeto(['These', patterns, are, in, contrast, to, human, 'CYP1A2', and, 'CYP2E1,', which, are]), verbo([reported]), complemento([to, progressively, increase, in, liver, during, the, first, few, months, to, years, of, life])].
[sujeto(['The', immature, rat, does, not, appear, to, be, a, suitable, model, for, assessing, risks, posed, to, infants, and, children, by, chemicals, metabolically]), verbo([activated]), complemento([by, 'CYP2E1,', based, on, the, findings, of, greater, carbon, tetrachloride, hepatotoxicity, in, preweanlings, and, weanlings, than, in, adult, animals])].
[sujeto(['Additional', studies, are]), verbo([required]), complemento([to, determine, whether, immature, 'S-D', rats, may, be, used, as, an, animal, model, for, substrates, of, other, 'CYPs,', as, total, 'CYP450', levels, in, the, liver, progressively, rose, during, 'maturation,', similarly, to, humans])].
[sujeto(['Sprague-Dawley', rats, were, given, a, 'methionine/choline-deficient', '(', 'MCD)', or, 'high-fat', '(', 'HF)', diet, to]), verbo([induce]), complemento(['NASH', and, 'SFL,', respectively])].
[sujeto(['These', results, may]), verbo([promote]), complemento([a, better, understanding, of, the, influence, of, 'NAFLD', on, 'CYP2B1-mediated', 'metabolism,', which, could, have, important, implications, for, the, safety, and, pharmacokinetics, of, drug, substrates, for, the, 'CYP2B', subfamily, in, patients, with, 'NAFLD'])].
[sujeto(['These', agents]), verbo([modulate]), complemento([liver, 'P450', content, through, increased, synthesis, or, reduction, via, inactivation, 'and/or', proteolytic, 'degradation,', resulting, in, clinically, significant, 'drug-drug', interactions])].
[sujeto(['P450', proteolytic, degradation, occurs, via, 'ER-associated', degradation, '(', 'ERAD)']), verbo([involving]), complemento([either, of, two, distinct, 'routes:', 'Ubiquitin', '(', 'Ub)-dependent', 26, 'S', proteasomal, degradation, '(', 'ERAD/UPD)', or, autophagic, lysosomal, degradation, '(', 'ERAD/ALD)'])].
[sujeto(['We', are]), verbo([gained]), complemento([insight, into, the, nature, of, the, structural, determinants, involved, in, 'CYP3A4', and, 'CYP2E1', molecular, recognition, in, 'ERAD/UPD', '[', i])].
[sujeto(['K48-linked', polyUb, chains, and, linear, 'and/or', &, 'quot;conformational&quot;', phosphodegrons, consisting, either, of, consecutive, sequences, on, surface, loops, 'and/or', disordered, 'regions,', or, 'structurally-assembled', surface, clusters, of, negatively, charged, acidic, '(', 'Asp/Glu)', and]), verbo([phosphorylated]), complemento(['(', 'Ser/Thr)', 'residues,', within, or, vicinal, to, 'which,', 'Lys-residues', are, targeted, for, 'ubiquitination]'])].
[sujeto(['Structural', inspection, of, select, human, liver, 'P450s']), verbo([reveals]), complemento([that, such, linear, or, conformational, phosphodegrons, may, indeed, be, a, common, 'P450-ERAD/UPD', feature])].
[sujeto(['In', this, study, we, aimed, to, compare, hepatocyte, monocultures, with, 'hepatocyte-KC', 'co-cultures', regarding, some, basic, liver, functions]), verbo([associated]), complemento([with, the, chemical, defense, system])].
[sujeto(['These', pathways]), verbo([involve]), complemento([transporters, and, enzymes, the, function, of, which, is, highly, sensitive, towards, hepatotoxic, events])].
[sujeto(['KCs']), verbo([decreased]), complemento([phenobarbital, inducibility, of, 'CYP2B1/2', in, a, cell, ratio, dependent, manner, and, activation, of, 'KCs', by, lipopolisacharide, '(', 'LPS)', amplified, this, effect])].
[sujeto(['Similarly,', 'KCs']), verbo([decreased]), complemento([the, transport, of, 'B', and, its, glucuronides, '(', 'BG)', in, both, sinusoidal, and, canalicular, directions, resulting, in, its, intracellular, accumulation])].
[sujeto(['Immuno-labelling', of, 'sodium-dependent', taurocholate, transporter, '(', 'Ntcp)', revealed]), verbo([increased]), complemento([expression, of, the, transporter, in, the, presence, of, 'KCs'])].
[sujeto(['Here', we, presented, that, 'KCs']), verbo([have]), complemento([a, direct, impact, on, some, hepatocyte, functions, suggesting, that, the, 'co-culture', model, may, be, more, suitable, for, drug, related, hepatotoxicity, studies, than, hepatocyte, monocultures])].
[sujeto(['One', of, the, 209, 'PCB', 'congeners,', 2, ',', 3, '\'', ',', 4, ',', 4, '\'', ',', 5, -, pentachlorobiphenyl, '(', 'CB118),', is, abundantly]), verbo([found]), complemento([in, the, environment, and, in, mammals])].
[sujeto(['Understanding', the, metabolic, fate, of, 'CB118', can]), verbo([provide]), complemento([important, information, toward, evaluating, its, toxicity])].
[sujeto(['Docking', models, of, 'CYP2Bs', with, 'CB118', revealed, a, short, distance, between, the, 3, -, position, of, 'CB118', and, the, heme, iron]), verbo([caused]), complemento([by, polarization, of, the, 'substrate-binding', 'cavity,', and, maintenance, of, this, pose, through, interaction, with, the, peripheral, amino, acids, determines, the, activity, and, position, of, hydroxylation])].
[sujeto(['The', metabolites, 3, -, 'OH-CB118', and, 4, -, 'OH-CB107']), verbo([decreased]), complemento([potential, for, activating, the, aryl, hydrocarbon, receptor, compared, with, that, of, 'CB118,', thereby, leading, to, a, decrease, in, 'dioxin-like', 'toxicity;', 'however,', the, neurodevelopmental, toxicity, of, 4, -, 'OH-CB107', has, been, previously, reported])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, these, 3, 'P450', isoforms, play, an, important, role, in, determining, the, extent, of, 'CB118', toxicity])].
[sujeto(['Accumulating', data]), verbo([suggest]), complemento([that, epoxyeicosatrienoic, acids, '(', 'EETs)', and, 20, -, hydroxyeicosatetraenoic, 'acid,', both, cytochrome, 'P450', '(', 'P450)', enzyme, metabolites, of, arachidonic, acid, '(', 'AA),', play, important, roles, in, cardiovascular, diseases])].
[sujeto(['For', many, 'years,', the, cardiotonic, pill, '(', 'CP),', an, herbal, preparation, derived, from, 'Salviae', 'Miltiorrhizae', 'Radix', et, 'Rhizoma,', 'Notoginseng', 'Radix', et, 'Rhizoma,', and, 'Borneolum', 'Syntheticum,']), verbo([has]), complemento([been, widely, used, in, 'China', for, the, treatment, of, coronary, artery, disease])].
[sujeto(['However,', its, pharmacological, mechanism]), verbo([has]), complemento([not, been, well, elucidated])].
[sujeto(['Cardiac', 'Cyp1b1,', 'Cyp2b1,', 'Cyp2e1,', 'Cyp2j3,', and, 'Cyp4f6', were, significantly]), verbo([induced]), complemento(['(', 'P', &, 'lt;', 0.05, ')', ;, 'CYP2J', and, 'CYP2C11', proteins, were, upregulated, '(', 'P', &, 'lt;', 0.05, ')', ;, and, 'AA-epoxygenases', activity, was, significantly, increased, '(', 'P', &, 'lt;', 0.05, ')', after, 'CP', '(', 40, 'mg/kg/d;', 7, 'days)', administration, in, rats])].
[sujeto(['In', 'H9c2', 'cells,', the, 'CP', also]), verbo([increased]), complemento(['(', 'P', &, 'lt;', 0.05, ')', the, 'EET', concentrations, and, showed, protection, in, 'hypoxia-reoxygenation', '(', 'H/R)', cells])].
[sujeto(['Using', bioinformatics, analysis, we, selected, microRNAs, which, could]), verbo([bind]), complemento([3, '\'', -, 'UTR-region', of, cytochrome, 'P450', '(', 'CYP)', genes])].
[sujeto(['Three', microRNA, 'miR-21,', -, 221, ',', -, 222, ',', their, potential]), verbo([targets]), complemento([might, be, mRNA, for, 'CYP1A1,', and, two, microRNA, 'miR-143,', 'miR-152', for, 'CYP2B1', accordingly, were, selected, for, experimental, verification])].
[sujeto(['The']), verbo([decrease]), complemento([in, miR, expression, was, accompanied, by, a, considerable, '(', 5.5, -, 8.7, -, 'fold)', increase, in, the, 'CYP1A1-mediated', 'EROD', activity])].
[sujeto(['The', expression, of, 'miR-143', remained, unchanged, after, the, 'PB', 'treatment,', while, the, expression, of, 'miR-152']), verbo([increased]), complemento([by, 2, 'times,', 'however,', the, '(', 10.5, -, 'fold)', increase, in, 'PROD', activity, of, 'CYP2B', was, much, higher])].
[sujeto(['In', the, 'DDT-treated', liver, 'PROD', activity]), verbo([increased]), complemento([by, 20, 'times,', the, expression, of, 'miR-152', 'didn\'t', 'change,', and, the, expression, of, 'miR-143', increased, by, 2, times])].
[sujeto(['The', bioinformatics, analysis, of, interactions, between, microRNAs, and]), verbo([targets]), complemento([showed, that, the, studied, miRs, can, potentially, bind, 3, '\'', -, end, of, 'AhR,', 'ESR1,', 'GR,', 'CCND1,', 'PTEN', mRNA])].
[sujeto(['In', silico, analysis, 'confirmed,', that, microRNAs]), verbo([target]), complemento([not, only, cytochrome, 'P450', mRNA, but, also, other, 'genes,', including, those, involved, in, hormonal, 'carcinogenesis,', they, also, can, be, regulated, with, studied, miRs])].
[sujeto(['Modification', of, 'CYP450', expression, may]), verbo([have]), complemento([important, influences, on, drug, metabolism, and, lead, to, untoward, effects, on, those, with, narrow, therapeutic, windows])].
[sujeto(['However,', the, impact, of, 'blast-induced', 'TBI', '(', 'bTBI)', on, the, expression, of, 'CYP450']), verbo([has]), complemento([received, little, attention])].
[sujeto(['The', results, showed, that, bTBI, could, significantly, reduce, mRNA, expressions, of, 'CYP1A2,', 'CYP2D1,', and, 'CYP3A2', at, the, early, stage, and]), verbo([induce]), complemento([the, expressions, from, 48, &, 'nbsp;h', to, 1, &, 'nbsp;week', after, injury])].
[sujeto(['The', 'cytokines,', 'IL-1β,', 'IL-2,', 'IL-6,', and, 'TNF-α,']), verbo([increased]), complemento([significantly, in, the, early, 'phase,', and, began, to, reduce, at, the, delayed, phase, of, bTBI])].
[sujeto(['In', 'conclusion,', our, work, 'has,', for, the, first, 'time,', indicated, that, bTBI]), verbo([has]), complemento([significant, impact, on, the, expressions, of, 'CYP1A2,', 'CYP2B1,', 'CYP2D1,', and, 'CYP3A2,', which, may, be, related, to, the, cytokines, induced, by, the, injury])].
[sujeto(['The', purpose, of, this, study, was, to, introduce, an, experimental, distal, phalanx, amputation, model, in, mice, '(', which, are, higher, 'vertebrates)', in, which, nAG, and, 'Prod-1', are]), verbo([expressed]), complemento([in, the, amputation, stumps])].
[sujeto([nAG, and, 'Prod-1', were]), verbo([expressed]), complemento([in, experimental, stumps, only])].
[sujeto(['Finally,', quantitative, mRNA, showed, a, 21, -, fold]), verbo([increase]), complemento([of, osteocalcin, in, experimental, stumps, compared, with, control, 'stumps,', and, this, was, statistically, significant])].
[sujeto(['Injection', of, nAG, and, 'Prod-1', into, the, footpad, will, result, in, their, expression, in, the, distal, amputation, 'stumps,', and, this, will]), verbo([enhance]), complemento([bone, regeneration, in, the, model, described])].
[sujeto(['In', 'addition,', the, observation, of, multiple, -, 'Cl', and, -, 'NH-π', interactions, of, 4, -, 'CPI', with, the, aromatic, side, chains, in, the, 'CYP2B35', and, 'CYP2B37', structures]), verbo([provides]), complemento([insight, into, the, influence, of, such, functional, groups, on, 'CYP2B', ligand, binding, affinity, and, specificity])].
[sujeto(['Rat', cytochrome, 'P450', '(', 'CYP)', exhibits, 'inter-strain', 'differences,', but, their, analysis]), verbo([has]), complemento([been, scattered, across, studies, under, different, conditions])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, strain, differences, in, 'CYP3A2', enzymatic, activity, are, caused, by, differences, in, mRNA, expression])].
[sujeto(['This']), verbo([suggests]), complemento([that, the, strain, differences, in, enzymatic, activity, are, not, related, to, 'Cyp2b1', mRNA, expression])].
[sujeto(['In', 'conclusion,', 'WI', rats, tended, to]), verbo([have]), complemento([the, lowest, 'CYP1A1,', 2, 'B1', and, 3, 'A2', mRNA, 'expression,', protein, expression, and, enzymatic, activity, among, the, strains])].
[sujeto(['Our', laboratory, previously]), verbo([reported]), complemento([that, accumulation, of, nonsterol, isoprenoids, following, treatment, with, the, squalene, synthase, 'inhibitor,', squalestatin, 1, '(', 'SQ1)', markedly, induced, cytochrome, 'P450', '(', 'CYP)2B1', mRNA, and, reporter, activity, in, primary, cultured, rat, 'hepatocytes,', which, was, dependent, on, activation, of, the, constitutive, androstane, receptor, '(', 'CAR)'])].
[sujeto(['The', objective, of, the, current, study, was, to, evaluate, whether, isoprenoids, likewise]), verbo([activate]), complemento([murine, 'CAR', '(', 'mCAR)', or, one, or, more, isoforms, of, human, 'CAR', '(', 'hCAR)', produced, by, alternative, splicing, '(', 'SPTV,', 'hCAR2;', 'APYLT,', 'hCAR3)'])].
[sujeto(['We']), verbo([found]), complemento([that, 'SQ1', significantly, induced, 'Cyp2b10', mRNA, '(', '∼3'])].
[sujeto(['Cotransfection', with, an, expression, plasmid, for, 'hCAR1,', but, not, hCAR2, or, 'hCAR3,']), verbo([mediated]), complemento(['SQ1-induced', 'CYP2B1', and, 'CYP2B6', reporter, activation, in, hepatocytes, isolated, from, 'CAR-knockout', mice])].
[sujeto(['The', direct, agonist, 'CITCO']), verbo([increased]), complemento([interaction, of, 'hCAR1,', 'hCAR2,', and, hCAR3, with, steroid, receptor, 'coactivator-1'])].
[sujeto(['However,', no, significant, effect, on, coactivator, recruitment, was, observed, with, 'SQ1,']), verbo([suggesting]), complemento([an, indirect, activation, mechanism])].
[sujeto(['Further', results, from, an, in, vitro, ligand]), verbo([binding]), complemento([assay, demonstrated, that, neither, farnesol, nor, other, isoprenoids, are, direct, ligands, for, hCAR1])].
[sujeto(['Collectively,', our, findings, demonstrate, that, 'SQ1']), verbo([activates]), complemento(['CYP2B', transcriptional, responses, through, farnesol, metabolism, in, an, 'hCAR1-dependent', manner])].
[sujeto(['Dihydromyricetin', '(', 'DHM)', is, a, 'flavonoid,', which]), verbo([has]), complemento([been, shown, to, antagonize, effects, of, ethanol, intoxication])].
[sujeto(['On', the, 'contrary,', 'real-time', 'PCR', revealed, elevated, expression, of, 'CYP1A1', and, 'CYP1A2', mRNA, in, proximal, part, of, the, small, intestine, while]), verbo([decreased]), complemento([in, the, middle, part])].
[sujeto(['The', activity, and, gene, expression, of, 'HO-1', and, its, transcription, factor, '(', 'Nrf2)', level]), verbo([increased]), complemento([significantly, after, 5, h, of, reperfusion, in, 'CD-fed', rats, but, not, in, 'ED-fed', rats])].
[sujeto(['The']), verbo([decrease]), complemento([in, 'CYP2B1', activity, and, the, increase, in, 'CYP2E1', activity, were, augmented, after, hepatic, 'IR', in, 'ED-fed', animals])].
[sujeto(['Finally,', 'CHOP', expression, and, 'PERK', 'phosphorylation,', microsomal, lipid, 'peroxidation,', and, levels, of, proinflammatory, mediators]), verbo([increased]), complemento([in, 'ED-fed', rats, compared, to, 'CD-fed', rats, after, reperfusion])].
[sujeto(['These']), verbo([increases]), complemento([were, attenuated, by, hemin])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'AFL', exacerbates, hepatic, drug, metabolizing, dysfunction, during, hepatic, 'IR', via, endoplasmic, reticulum, stress, and, lipid, peroxidation, and, this, is, associated, with, impaired, 'HO-1', induction])].
[sujeto(['Treatment', with, the, squalene, synthase, inhibitor, squalestatin, 1, '(', 'SQ1)']), verbo([causes]), complemento([accumulation, of, 'FPP,', its, dephosphorylated, metabolite, 'farnesol,', and, several, oxidized, 'farnesol-derived', metabolites])].
[sujeto(['In', 'addition,', 'SQ1', treatment, of, primary, cultured, rat, hepatocytes]), verbo([increases]), complemento(['CYP2B', expression, through, a, mechanism, that, requires, 'FPP', synthesis, and, activation, of, the, constitutive, androstane, receptor, '(', 'CAR)'])].
[sujeto(['Because', direct, farnesol, treatment, also]), verbo([increases]), complemento(['CYP2B', 'expression,', it, seems, likely, that, 'SQ1-mediated', 'CAR', activation, requires, 'FPP', dephosphorylation, to, farnesol])].
[sujeto(['The', lipid, 'phosphatase,', phosphatidic, acid, phosphatase, domain, containing, 2, '(', 'PPAPDC2),', was, recently]), verbo([reported]), complemento([to, catalyze, 'FPP', dephosphorylation])].
[sujeto(['Cotransfection', of, rat, hepatocytes, with, a, plasmid]), verbo([expressing]), complemento([rat, or, human, 'PPAPDC2', enhanced, 'SQ1-mediated', activation, of, a, 'CAR-responsive', reporter, by, 1.7, -, or, 2.4, -, fold, over, the, 'SQ1-mediated', activation, that, was, produced, when, hepatocytes, were, cotransfected, with, empty, expression, plasmid])].
[sujeto(['Similarly,', transduction, of, rat, hepatocytes, with, a, recombinant, adenovirus]), verbo([expressing]), complemento(['PPAPDC2', enhanced, 'SQ1-mediated', 'CYP2B1', mRNA, induction, by, 1.4, -, fold, over, the, induction, that, was, seen, in, hepatocytes, transduced, with, control, adenovirus])].
[sujeto(['Cotransfection', with, a, short, hairpin, 'RNA']), verbo([targeting]), complemento(['PPAPDC2', reduced, 'SQ1-mediated', 'CAR', activation, by, approximately, 80, '%', relative, to, the, activation, that, occurred, in, hepatocytes, transfected, with, nontargeting, short, hairpin, 'RNA'])].
[sujeto(['The', present, study, was, undertaken, to, determine, the, in, vivo, effects, of, 'EH', on, hepatic, 'CYP2B,', 'CYP2C,', 'CYP2D,', and, 'CYP3A', enzymes, that, are, primarily]), verbo([involved]), complemento([in, drug, metabolism])].
[sujeto(['Erythromycin', 'N-demethylase', activity, was]), verbo([inhibited]), complemento([by, 53, and, 21, &, 'nbsp;%', in, 'EHWE-', and, 'EA-treated', 'rats,', respectively])].
[sujeto(['Benzphetamine', 'N-demethylase', and, 7, -, 'benzyloxyresorufin-O-debenzylase', activities, were]), verbo([decreased]), complemento([by, 53, and, 43, &, 'nbsp;%,', and, 57, and, 57, &, 'nbsp;%', in, 'EHWE-and', 'EA-treated', 'rats,', respectively])].
[sujeto(['Moreover,', protein, levels, of, 'CYP2B1,', 'CYP2C6,', 'CYP2D2,', and, 'CYP3A1', also]), verbo([decreased]), complemento([by, 55, ',', 15, ',', 33, ',', and, 82, &, 'nbsp;%', as, a, result, of, 'EHWE', treatment, of, 'rats,', respectively])].
[sujeto(['Similarly,', 'CYP2B1,', 'CYP2C6,', 'CYP2D2,', and, 'CYP3A1', protein, levels]), verbo([decreased]), complemento([by, 62, ',', 63, ',', 49, ',', and, 37, &, 'nbsp;%', with, 'EA', 'treatment,', respectively])].
[sujeto(['qRT-PCR', analyses, also, showed, that, mRNA, levels, of, these, enzymes, were, significantly]), verbo([inhibited]), complemento([with, bothEHWE, and, 'EA', treatments])].
[sujeto(['In', 'conclusion,', inhibition, of, drug, clearances]), verbo([leading]), complemento([to, drug, toxicity, because, of, the, lowered, activity, and, expression, of, 'drug-metabolizing', enzymes, might, be, observed, in, the, people, who, used, 'EH', as, complementary, herbal, remedy, that, might, be, contributed, by, its, 'EA', content])].
[sujeto(['This', study, was, performed, to]), verbo([find]), complemento([which, types, of, hepatic, 'CYP', isoforms, are, responsible, for, the, metabolism, of, mirodenafil, '(', a, new, 'erectogenic)', and, one, of, its, 'metabolite,', 'SK3541,', using, various, hepatic, 'CYP', inducers, and, inhibitors, in, rats])].
[sujeto(['The', above, data]), verbo([suggest]), complemento([that, hepatic, 'CYP1A1/2,', 2, 'B1/2,', 2, 'D', 'subfamily,', and, 3, 'A1/2', are, involved, in, the, metabolism, of, both, mirodenafil, and, 'SK3541', in, rats])].
[sujeto(['The', area, under, the, curve, '(', 'AUC)', of, mirodenafil, after, intravenous, administration, in, diabetes, mellitus]), verbo([induced]), complemento([by, streptozotocin, '(', 'DMIS)', rats, was, significantly, smaller, '(', by, 28.0, '%', ')', than, the, control, 'value,', and, the, 'AUC(SK3541)/AUC(mirodenafil)', ratio, was, significantly, greater, '(', by, 130, '%', ')', in, 'DMIS', rats])].
[sujeto(['This', may, be, explained, by, the, significantly, faster, hepatic, 'CL(int)', of, 'mirodenafil,', owing, to]), verbo([increased]), complemento([hepatic, 'CYP1A,', 'CYP2B1/2,', 'CYP2D,', and, 'CYP3A', 'expression,', and, a, faster, hepatic, blood, flow, 'rate,', compared, with, control, values])].
[sujeto(['The', 'AUC', of, mirodenafil, after, oral, administration, was, comparable, between, 'DMIS', and, control, 'rats,', possibly, because, of, the, comparable, intestinal, 'CL(int),', which, may, be, attributable, to]), verbo([increased]), complemento(['CYP1A2', expression, and, decreased, 'CYP2D', expression, in, the, intestines, of, 'DMIS', rats])].
[sujeto(['Males', had, higher, metabolism, than, corresponding, females, for, phenacetin, 'O-deethylation', '(', human, marker, for, 'CYP1A2', 'activity),', and, a, high, correlation, was]), verbo([found]), complemento([between, phenacetin, activity, and, immunoreactivity, in, 'Western', blots, produced, with, rat, 'CYP1A2', antibodies])].
[sujeto(['Ring', hydroxylation, of, nonselective, 'beta-adrenergic', blocking, agent, propranolol, is]), verbo([mediated]), complemento([mainly, by, cytochrome, 'P450', '(', 'CYP)', 2, 'D6', and, 'N-desisopropylation', by, 'CYP1A2', in, human, and, rat, liver, microsomes])].
[sujeto(['In', this, 'study,', the, repeated, administration, of, propranolol, resulted, in, a, marked, inhibition, of, hepatic, metabolism, and, an]), verbo([increase]), complemento([in, its, systemic, 'availability,', due, to, covalent, binding, of, reactive, metabolites, '(', formed, from, 4, -, 'OH-propranolol)', to, liver, microsomal, 'P4502D', enzymes])].
[sujeto(['The', absence, of, 'CYP1A2', and, the, presence, of, 'CYP2D', in, the, lung]), verbo([suggest]), complemento([a, different, pulmonary, metabolism, of, propranolol, in, comparison, with, those, in, the, liver])].
[sujeto([')']), verbo([decreased]), complemento(['NADPH', cytochrome, c, reductase, activity, and, cytochrome, 'P-450-dependent', dealkylation, of, 7, -, benzyloxyresorufin, '(', 'BROD)', '(', 'CYP1A1,', 2, 'A1,', 3, 'A1)', and, 7, -, ethoxyresorufin, '(', 'EROD)', '(', 'CYP1A1)', in, 'RTII,', while, 'glutathione-S-transferase', '(', 'GST),', 'DT-diaphorase', '(', 'QR),', 'gamma-glutamyl', transferase, '(', 'gamma-GT)', 'activities,', intracellular, reduced, glutathione, level, and, dealkylation, of, 7, -, pentoxyresorufin, '(', 'PROD)', '(', 'CYP2B1)', were, not, changed])].
[sujeto(['It', was]), verbo([found]), complemento([that, propranolol, significantly, increased, 'NADPH', cytochrome, c, reductase, and, 'BROD', activities, in, 'RAM'])].
[sujeto(['The', results]), verbo([suggest]), complemento([a, different, susceptibility, of, 'RTII', and, 'RAM', to, propranolol, and, its, contrary, effects, on, lung, 'xenobiotic-metabolizing', enzyme, activities, in, both, types, of, cells])].
[sujeto(['A', slight, decline, was, observed, in, the, hepatic, microsomal, content, of, 'CYP2D', 'apoprotein,', whereas, a, substantial]), verbo([decrease]), complemento([occurred, in, 'CYP2C11', content, during, liver, regeneration])].
[sujeto(['Since', imipramine, 2, -, hydroxylation, and, 'N-demethylation', are]), verbo([mediated]), complemento([by, 'CYP2D', and, 2, 'C11', 'respectively,', metabolic, 'pathway-specific', alterations, in, the, activities, of, imipramine, metabolism, are, explained, by, the, isozyme, selective, alteration, in, the, levels, of, 'CYPs', in, regenerating, liver])].
[sujeto(['CYP3A2', 'apoprotein,', one, of, the, 'male-specific', 'CYP', 'isoforms,', was, significantly]), verbo([suppressed]), complemento([in, regenerating, liver, showing, a, similar, pattern, of, alteration, to, the, levels, of, 'CYP2C11'])].
[sujeto(['In', the, partially, hepatectomized, male, 'rate,', no, significant]), verbo([increase]), complemento([in, androstenedione, 5, -, alpha, reductase, 'activity,', an, activity, predominant, in, the, female, 'rat,', was, detected])].
[sujeto(['Human', 'P450s', '(', 'CYP1A2,', 2, 'A6,', 2, 'B6,', 2, 'C8,', 2, 'C9,', 2, 'C18,', 2, 'D6,', 20.0, ',', and, 3, 'A4)', were]), verbo([expressed]), complemento([in, 'Saccharomyces', cerevisiae, and, purified])].
[sujeto(['The', stereoselectivity, '[', '(', +, ')', -, isomer, versus, '(', -, ')', -, 'isomer]', varied, from, 0.78, to, 1.94, after, pretreatment, of, the, rats, with, 'phenobarbital,', 3, -, 'methylcholanthrene,', 'pregnenolone-16', 'alpha-carbonitrile,', or, 'pyrazole,']), verbo([suggesting]), complemento([that, different, isozymes, participate, in, the, reaction])].
[sujeto(['The', 'low-Km', demethylenation, was, not]), verbo([induced]), complemento([by, these, compounds, and, was, not, inhibited, by, antibodies, raised, against, 'CYP2C11'])].
[sujeto(['The', 'low-Km', demethylenation, was, also]), verbo([inhibited]), complemento([by, 'CYP2D', substrates, such, as, 'sparteine,', 'bufuralol,', or, desipramine, and, was, almost, completely, inhibited, by, antibodies, against, 'P450', 'BTL,', which, belongs, to, the, 'CYP2D', family])].
[sujeto(['The', 'higg-Km', demethylation, activity, was]), verbo([induced]), complemento([by, phenobarbital, and, 'pregnenolone-16', 'alpha-carbonitrile', and, the, activity, in, both, untreated, and, 'phenobarbital-induced', microsomes, was, suppressed, by, 'anti-CYP2B1', 'IgG'])].
[sujeto(['Experiments', with, 'IgG', raised, against, cytochrome, b5]), verbo([suggested]), complemento([that, the, hemoprotein, contributed, to, the, 'low-Km', activity, but, not, the, 'high-Km', activity])].
[sujeto(['These', results, indicate, that, cytochrome, 'P450', isozymes, belonging, to, the, 'CYP2D', subfamily, catalyze, demethylenation, with, low, 'Km', values, and, that, the, reaction, occurring, with, high, 'Km', values, is, likely, to, be]), verbo([mediated]), complemento([by, members, of, the, 'CYP2B', 'family,', but, with, the, possible, participation, of, other, 'phenobarbital-inducible', isoforms])].
[sujeto(['Tamoxifen', is, used, in, clinical, practice, for, breast, cancer, patients, and, to]), verbo([prevent]), complemento([osteoporosis])].
[sujeto(['Tamoxifen', metabolism, is, primarily]), verbo([mediated]), complemento([by, 'CYP2D6,', 'CYP3A4', with, minor, contribution, from, 'CYP2C9,', 'CYP2E1', and, 'CYP1A2', isoforms])].
[sujeto(['Although,', red, clover, 'pre-treatment', significantly, '(', p, &, 'lt;', 0.05, ')']), verbo([decreased]), complemento([the, mRNA, expression, and, activity, of, 'CYP3a2,', no, effect, on, 'CYP2d4', and, increased, expression, and, activity, of, 'CYP2c11', could, be, the, plausible, reasons, for, lack, of, effect, on, tamoxifen, and, its, metabolite, pharmacokinetics, in, rats])].
[sujeto(['Similar']), verbo([finding]), complemento([were, observed, in, the, human, liver, preparations, as, in, rats])].
[sujeto(['BDE-47']), verbo([decreased]), complemento(['CYP2B1/2', activity, and, expression, but, had, no, effect, on, 'SULT1A', or, 'COMT'])].
[sujeto([5, -, 'OH-BDE-47', and, 6, -, 'OH-BDE-47']), verbo([decreased]), complemento(['progesterone,', but, had, no, effect, on, estrogen, secretion])].
[sujeto(['The', inhibitory, effect, of, 'BDE-47', on, 'CYP2B1/2']), verbo([suggests]), complemento([the, possibility, of, 'BDE-47', accumulation, in, the, corpus, 'luteum;', by, affecting, steroid, secretion, and, steroidogenesis, 'enzymes,', 'BDE-47', and, its, metabolites, can, be, responsible, for, shortening, luteal, phase])].
[sujeto(['The', 'AEtLP', treated, rats, showed, an]), verbo([increase]), complemento([in, the, number, of, 'stools,', mucosa, 'thickness,', flat, luminal, surface, 'thickness,', mucin, 'secretion,', and, crypt, number])].
[sujeto(['Overall,', compared, to, the, 'controls,', 581, genes, were, 'up-regulated', and, 216, genes, were, 'down-regulated', by, the, constipation]), verbo([induced]), complemento([by, loperamide, in, the, constipated, rats])].
[sujeto(['These', results, indicate, that, several, gene, functional, groups, and, individual, genes, as, constipation, biomarkers]), verbo([respond]), complemento([to, an, 'AEtLP', treatment, in, constipated, model, rats])].
[sujeto(['Propofol,', an, intravenous, anesthetic, 'agent,', is, widely, used, for]), verbo([inducing]), complemento([and, maintaining, anesthesia, during, surgical, procedures, and, for, sedating, intensive, care, unit, patients])].
[sujeto(['Administration', of, phenobarbital, to, male, 'Wistar', rats, significantly]), verbo([increased]), complemento([levels, of, hepatic, cytochrome, 'P450', '(', 'CYP)', 2, 'B1/2', and, microsomal, pentoxyresorufin, 'O-dealkylase', '(', 'PROD)', activity])].
[sujeto(['In', 'comparison,', 'PROD', activity, and, 4, -, 'hydroxy-propofol', production, from, propofol, metabolism, were]), verbo([suppressed]), complemento([by, 'orphenodrine,', an, inhibitor, of, 'CYP2B1/2,', and, a, polyclonal, antibody, against, rat, 'CYP2B1/2', protein])].
[sujeto(['Meanwhile,', propofol]), verbo([decreased]), complemento([the, dealkylation, of, pentoxyresorufin, by, 'phenobarbital-treated', rat, liver, microsomes, in, a, 'concentration-dependent', manner])].
[sujeto(['Taken', 'together,', this, study, shows, that, rat, hepatic, 'CYP2B1/2', plays, a, critical, role, in, the, 'ring-oxidative', metabolism, of, propofol, into, 4, -, 'hydroxypropofol,', and, this, anesthetic, agent, can]), verbo([inhibit]), complemento(['CYP2B1/2', activity, without, affecting, protein, synthesis])].
[sujeto(['Peroxisome', proliferator]), verbo([activated]), complemento([receptor, α, '(', 'PPARα)', 'ligands,', fibrates, used, to, control, hyperlipidemia])].
[sujeto(['Luciferase', assays, showed, that, 'CFA']), verbo([increased]), complemento(['CYP2B1', transcription, to, the, same, level, as, 'PB,', or, 'TCPOBOP', in, 'HepG2', transfected, with, mouse, 'CAR', 'But', failed, to, induce, it, in, 'PPARα', transfected, cells])].
[sujeto(['CYP2B', expressions, were]), verbo([increased]), complemento([with, 'PB', or, 'CFA', in, 'Wistar', female, rats, '(', having, normal, levels, of, 'CAR)', but, not, in, 'Wistar', 'Kyoto', female, rats, '(', having, low, levels, of, 'CAR)'])].
[sujeto(['The', induction, of, 'CYP2B', by, 'PB', or, 'CFA', was, comparable, to]), verbo([nuclear]), complemento(['CAR', levels])].
[sujeto(['CAR']), verbo([nuclear]), complemento([translocation, was, induced, by, 'CFA', in, both, rat, strains])].
[sujeto(['This', indicates, that, fibrates, can]), verbo([activate]), complemento(['CAR', and, that, 'fibrates-insulin', sensitization, effect, may, occur, through, 'CAR,', while, hypolipidemic, effect, may, operate, through, 'PPARα'])].
[sujeto(['The', mechanisms, underlying, the]), verbo([decrease]), complemento([in, hepatic, cytochrome, 'P-450', '(', 'CYP)', content, in, ascorbic, acid, deficiency, was, investigated, in, 'scurvy-prone', 'ODS', rats])].
[sujeto(['Ascorbic', acid, deficiency]), verbo([decreased]), complemento([hepatic, microsomal, total, 'CYP', 'content,', 'CYP2B1/2B2', 'protein,', and, mitochondrial, cytochrome, oxidase, '(', 'COX)', complex, 'IV', subunit, 'I', 'protein,', and, simultaneously, increased, heme, 'oxygenase-1', protein, in, microsomes, and, mitochondria])].
[sujeto(['The', administration, of, these, inducers]), verbo([decreased]), complemento([hepatic, microsomal, total, 'CYP', 'content,', 'CYP2B1/2B2', 'protein,', and, mitochondrial, 'COX', complex, 'IV', subunit, 'I', protein])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, the, stimulation, of, hepatic, heme, 'oxygenase-1', expression, by, ascorbic, acid, deficiency, caused, the, decrease, in, 'CYP', content, in, liver])].
[sujeto(['DBDPE']), verbo([induced]), complemento([oxidative, 'stress,', elevated, blood, glucose, 'levels,', increased, 'CYP2B2', 'mRNA,', 'CYP2B1/2', 'protein,', 7, -, pentoxyresorufin, 'O-depentylase', '(', 'PROD)', 'activity,', and, induced, 'CYP3A2', 'mRNA,', 'CYP3A2', 'protein,', and, luciferin, benzylether, debenzylase, '(', 'LBD)', activity])].
[sujeto(['UDPGT', activity]), verbo([increased]), complemento([with, its, increasing, exposure, 'levels,', suggesting, that, oral, 'DBDPE', exposure, induces, 'drug-metabolizing', enzymes, in, rats, via, the, 'CAR/PXR', signaling, pathway])].
[sujeto(['Pressure', overload, cardiac, hypertrophy, was]), verbo([induced]), complemento([in, 'Sprague', 'Dawley', rats, using, the, descending, aortic, constriction, procedure])].
[sujeto(['Our', results, showed, that, 5, ',', 6, -, ',', 8, ',', 9, -, ',', 11, ',', 12, -, ',', and, 14, ',', 15, -, epoxyeicosatrienoic, acids, '(', 'EETs),', and, 5, -, ',', 12, -, ',', 15, -, ',', and, 20, -, hydroxyeicosatetraenoic, acids, '(', 'HETEs)', levels, were, 'increased,', 'whereas,', 19, -, 'HETE', formation, was]), verbo([decreased]), complemento([in, hypertrophied, hearts])].
[sujeto(['The']), verbo([increase]), complemento([in, 'EETs', was, linked, to, 'CYP2B2'])].
[sujeto(['On', the, other, 'hand,', 'CYP1B1', and, 'CYP2J3', were]), verbo([involved]), complemento([in, 'mid-chain', 'HETE', 'metabolism,', 'whereas,', 'CYP4A2/3', inhibition, was, involved, in, the, decrease, in, 19, -, 'HETE', formation, in, hypertrophied, hearts])].
[sujeto(['These', 'CYP', can, be, valid]), verbo([targets]), complemento([for, the, development, of, drugs, to, treat, and, prevent, cardiac, hypertrophy, and, heart, failure])].
[sujeto(['It']), verbo([has]), complemento([been, previously, shown, that, the, cytochrome, 'P450', '(', 'P450)', 'modulator,', 'fenofibrate,', protects, against, cardiovascular, diseases])].
[sujeto(['P450', and, their, 'metabolites,', epoxyeicosatrienoic, acids, '(', 'EETs)', and, 20, -, hydroxyeicosatetraenoic, acid, '(', 20, -, 'HETE)', were]), verbo([found]), complemento([to, play, an, important, role, in, cardiovascular, diseases])].
[sujeto(['Therefore,', it, is, important, to, examine, whether, fenofibrate, would]), verbo([modulate]), complemento([the, cardiac, 'P450', and, its, associated, arachidonic, acid, metabolites, and, whether, this, modulation, protects, against, 'isoproterenol-induced', cardiac, hypertrophy])].
[sujeto(['Our', results, showed, that, fenofibrate, significantly]), verbo([induced]), complemento([the, cardiac, 'P450', 'epoxygenases,', such, as, 'CYP2B1,', 'CYP2B2,', 'CYP2C11,', and, 'CYP2C23,', whereas, it, decreased, the, cardiac, 'ω-hydroxylase,', 'CYP4A3'])].
[sujeto(['Moreover,', fenofibrate, significantly]), verbo([increased]), complemento([the, formation, of, 14, ',', 15, -, 'EET,', 11, ',', 12, -, 'EET,', and, 8, ',', 9, -, 'EET,', whereas, it, decreased, the, formation, of, 20, -, 'HETE', in, the, heart])].
[sujeto(['Furthermore,', fenofibrate, significantly]), verbo([decreased]), complemento([the, hypertrophic, markers, and, the, increase, in, 'heart-to-body', weight, ratio, induced, by, isoproterenol])].
[sujeto(['Natamycin', is, a, polyene, macrolide, antibiotic, widely, used, in, the, food, industry, as, a, feed, additive, to]), verbo([prevent]), complemento([mold, contamination, of, foods])].
[sujeto(['There', are, many, contradictory, results, on, the, genotoxic, effects, of, macrolides, which, could]), verbo([suggest]), complemento([a, potential, risk, for, humans])].
[sujeto(['The', activities, of, 'CYP2E1,', 'CYP1A1/2', 'CYP2B1/2', and, 'CYP4A1/2', enzymes, significantly]), verbo([decreased]), complemento([after, treatment, with, 1, ',', 3, and, 10, 'mg/kg', 'bw/day,', in, a, 'dose-dependent', manner, as, compared, to, control])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, natamycin, may, not, potentiate, the, toxicity, of, many, xenobiotics, via, metabolic, activation, 'and/or', accumulation, of, reactive, metabolites, but, also, might, affect, the, clearance, of, other, xenobiotics, detoxified, by, the, studied, 'CYP', enzymes])].
[sujeto(['Based', on, the, hypothesis, that, this, results, from, a, perturbation, of, hepatic, thyroid, hormone, 'metabolism,', our, goal, was, to, investigate, the, pathways]), verbo([involved]), complemento([in, 'fipronil-induced', liver, gene, expression, regulations])].
[sujeto(['Fipronil', treatment]), verbo([led]), complemento([to, the, upregulation, of, several, genes, involved, in, the, metabolism, of, 'xenobiotics,', including, the, cytochrome, 'P450', 'Cyp2b1,', 'Cyp2b2', and, 'Cyp3a1,', the, carboxylesterases, 'Ces2', and, 'Ces6,', the, phase, 'II', enzymes, 'Ugt1a1,', 'Sult1b1', and, 'Gsta2,', and, the, membrane, transporters, 'Abcc2,', 'Abcc3,', 'Abcg5,', 'Abcg8,', 'Slco1a1', and, 'Slco1a4'])].
[sujeto(['Based', on, a, large, overlap, with, the]), verbo([target]), complemento([genes, of, constitutive, androstane, receptor, '(', 'CAR)', and, pregnane, 'X', receptor, '(', 'PXR),', we, postulated, that, these, two, nuclear, receptors, are, involved, in, mediating, the, effects, of, fipronil, on, liver, gene, expression, in, rodents])].
[sujeto(['We', controlled, that, liver, gene, expression, changes]), verbo([induced]), complemento([by, fipronil, were, generally, reproduced, in, 'mice,', and, then, studied, the, effects, of, fipronil, in, 'wild-type,', 'CAR-', and, 'PXR-deficient', mice])].
[sujeto(['However,', 'CAR', and, 'PXR', activation, in, mouse, liver, was, not]), verbo([associated]), complemento([with, a, marked, increase, of, thyroid, hormone, 'clearance,', as, observed, in, rat])].
[sujeto(['Nevertheless,', our, data, clearly, indicate, that, 'PXR', and, 'CAR', are, key, modulators, of, the, hepatic, gene, expression, profile, following, fipronil, treatment, 'which,', in, 'rats,', may, contribute, to]), verbo([increase]), complemento([thyroid, hormone, clearance])].
[sujeto(['wt)', supplemented, groups, and]), verbo([maintained]), complemento([for, 30, days])].
[sujeto(['There', was, a, significant]), verbo([increase]), complemento([in, the, activities, of, alanine, 'aminotransferase,', aspartate, 'aminotransferase,', and, 'γ-glutamyl', transpeptidase, in, the, serum, of, the, ethanol, group])].
[sujeto(['The', intracellular, reactive, oxygen, species, '(', 'ROS)', and, expressions, of, cytochrome, 'P4502E1', and]), verbo([nuclear]), complemento([factor, 'κB1,', tumor, necrosis, 'factor-α,', and, transforming, growth, 'factor-β(1)', in, hepatocytes, were, significantly, increased, in, ethanol, group])].
[sujeto(['The', fibrotic, markers, 'α-smooth', muscle, actin, and, 'α(1)(I)', collagen, and, activity, of, cytotoxicity, marker, 'caspase-3', were, significantly]), verbo([increased]), complemento([and, 'AA', content, was, significantly, reduced, in, hepatocytes, of, 'alcohol-treated', guinea, pigs])].
[sujeto(['AA', could]), verbo([induce]), complemento([greater, reduction, of, inflammatory, and, fibrotic, markers, in, hepatocytes, than, silymarin])].
[sujeto(['This', indicates, that, 'AA', is, superior, to, silymarin, in]), verbo([inhibiting]), complemento([intracellular, 'ROS', generation, and, thereby, reducing, the, 'ethanol-induced', inflammation, in, hepatocytes])].
[sujeto(['This', may, be, partly, due, to, the, absence, of, physiological, parameters, that]), verbo([maintain]), complemento([metabolic, phenotype, in, vivo])].
[sujeto(['Hepatocytes', in, the, devices, exhibited, polarized, 'morphology,', retention, of, differentiation, markers, '[', 'E-cadherin', and, hepatocyte]), verbo([nuclear]), complemento(['factor-4α', '(', 'HNF-4α)],', the, canalicular, transporter, '[', 'multidrug-resistant', 'protein-2', '(', 'Mrp-2)],', and, significantly, higher, levels, of, liver, function, compared, with, nonflow, cultures, over, 2, wk, '(', albumin, '~4-fold', and, urea, '~5-fold)'])].
[sujeto(['Gene', expression, of, cytochrome, 'P450', '(', 'CYP)', enzymes, was, significantly, higher, '(', fold]), verbo([increase]), complemento([over, 'nonflow:', 'CYP1A1:', 53.5, ±, 10.3, ;, 'CYP1A2:', 64.0, ±, 15.1, ;, 'CYP2B1:', 15.2, ±, 2.9, ;, 'CYP2B2:', 2.7, ±, 0.8, ;, 'CYP3A2:', 4.0, ±, 1.4, ')', and, translated, to, significantly, higher, basal, enzyme, activity, '(', device, vs])].
[sujeto([2.43, ±, 0.56, ')', while]), verbo([retaining]), complemento([inducibility, by, 3, -, methylcholanthrene, and, dexamethasone, '(', fold, increase, over, 'DMSO:', 'CYP1A', =, 27.33, and, 'CYP3A', =, 4.94, ')'])].
[sujeto(['Many', transporters, and, 'DMEs', are]), verbo([regulated]), complemento([by, xenobiotic, receptors, '[', 'XRs;', e])].
[sujeto(['Microarray,', quantitative, 'real-time', polymerase, chain, reaction, and, immunoblotting, analyses, were, used, to, identify, significantly]), verbo([regulated]), complemento([genes])].
[sujeto([',', 'CYP2B2', and, 'CYP3A1)', were]), verbo([regulated]), complemento(['(', 'P', &, 'lt;', 0.05, ')', with, fold, changes, ranging, from, -, 46.3, to, 17.1])].
[sujeto(['Therefore,', a, series, of, 'transactivation/translocation', assays, were, conducted, to, determine, whether, the, observed, changes, of, 'transporters/DMEs', are]), verbo([mediated]), complemento([by, direct, activation, of, 'PXR,', 'CAR,', or, 'AhR', by, oxycodone, or, its, major, metabolites, '(', noroxycodone, and, 'oxymorphone)'])].
[sujeto(['Neither', oxycodone, nor, its, metabolites]), verbo([activated]), complemento(['PXR,', 'CAR,', or, 'AhR'])].
[sujeto(['Taken', 'together,', these, findings, identify, a, signature, hepatic, 'gene-network']), verbo([associated]), complemento([with, repeated, oxycodone, administration, in, rats, and, demonstrate, that, oxycodone, alters, the, expression, of, many, transporters, and, 'DMEs', '(', without, direct, activation, of, 'PXR,', 'CAR,', and, 'AhR),', which, could, lead, to, undesirable, 'DDIs', after, coadministration, of, substrates, of, these, 'transporters/DMEs', with, oxycodone])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, 'isoprenaline-induced', cardiac, hypertrophy, causes, significant, changes, in, the, expression, of, cytochromes, 'P450', '(', 'CYP)', and, soluble, epoxide, hydrolase, '(', 'sEH)', genes])].
[sujeto(['Isoprenaline', significantly]), verbo([induced]), complemento([the, 'hypertrophic,', fibrotic, markers, as, well, as, the, heart, to, body, weight, 'ratio,', which, was, significantly, reversed, by, 'TUPS'])].
[sujeto(['Isoprenaline', also]), verbo([caused]), complemento([an, induction, of, 'CYP1A1,', 'CYP1B1,', 'CYP2B1,', 'CYP2B2,', 'CYP4A3', and, 'CYP4F4', gene, expression, and, 'TUPS', significantly, inhibited, this, 'isoprenaline-mediated', effect])].
[sujeto(['Moreover,', isoprenaline, significantly, reduced, 5, ',', 6, -, ',', 8, ',', 9, -, ',', 11, ',', 12, -, and, 14, ',', 15, -, 'EET', and]), verbo([increased]), complemento([their, corresponding, 8, ',', 9, -, ',', 11, ',', 12, -, and, 14, ',', 15, -, dihydroxyeicosatrienoic, acid, '(', 'DHET)', and, the, 20, -, 'HETE', metabolites])].
[sujeto(['In', 'H9c2', 'cells,', isoprenaline]), verbo([caused]), complemento([a, significant, induction, of, 'ANP,', 'BNP', and, 'EPHX2', mRNA, levels])].
[sujeto(['Both', 'TUPS', and, 11, ',', 12, -, 'EET', significantly]), verbo([decreased]), complemento([this, 'isoprenaline-mediated', induction, of, 'ANP,', 'BNP', and, 'EPHX2'])].
[sujeto(['We', analyzed, the, activity, and, expression, of, enzymes]), verbo([involved]), complemento([in, phase, 'I', '(', 'CYP1A1', and, 'CYP2B1/2)', and, phase, 'II', '(', 'SULT1A', and, 'COMT)', of, 'BDE-47', metabolism])].
[sujeto(['Basal', 'CYP1A1', and, 'CYP2B1/2', activity]), verbo([increased]), complemento([during, culture])].
[sujeto(['BDE-47', had, no, effect, on, 'CYP1A1,', however]), verbo([increased]), complemento(['CYP2B1/2', activity, after, exposure, for, 6, h])].
[sujeto(['BDE-47']), verbo([increased]), complemento(['SULT1A', after, exposure, for, 6, 'h,', and, 'COMT', activity, after, exposure, for, 24, and, 48, h])].
[sujeto(['In', the, present, study, we]), verbo([found]), complemento([that, 'down-regulation', of, 'CYP2B', proteins, by, the, 'NO', donor, 'NOC-18', is, accelerated, by, pretreatment, of, the, hepatocytes, with, 'IL-1', '(', 'interleukin-1β)', in, the, presence, of, an, 'NO', synthase, 'inhibitor,', suggesting, that, an, 'NO-independent', action, of, 'IL-1', contributes, to, the, lability, of, 'CYP2B', proteins])].
[sujeto(['The', immunoproteasome, subunit, 'LMP2', '(', large, multifunctional, peptidase, 2, ')', was, significantly]), verbo([expressed]), complemento([in, hepatocytes, under, basal, 'conditions,', and, 'IL-1', induced, 'LMP2', within, 6, -, 12, h, of, treatment])].
[sujeto(['The', results, show, that, 'LMP2', contributes, to, the, 'NO-dependent', degradation, of, 'CYP2B', 'proteins,', and]), verbo([suggest]), complemento([that, induction, of, 'LMP2', may, be, involved, in, the, potentiation, of, this, degradation, by, 'IL-1'])].
[sujeto(['In', 'rats,', the, widely, used, insecticide, fipronil]), verbo([increases]), complemento([the, clearance, of, thyroxine, '(', 'T(4))'])].
[sujeto(['This', effect, is]), verbo([associated]), complemento([with, a, high, plasma, concentration, of, fipronil, 'sulfone,', the, fipronil, main, metabolite, in, several, species, including, rats, and, humans])].
[sujeto(['We', postulated, that, fipronil, biotransformation, into, fipronil, sulfone, by, hepatic, cytochromes, 'P450', '(', 'CYP)', could]), verbo([act]), complemento([as, a, potential, thyroid, disruptor])].
[sujeto(['Fipronil', and, fipronil, sulfone, treatments, '(', 3.4, 'μmol/kg/day', per, 'os,', 14, 'days)']), verbo([increased]), complemento([total, and, free, 'T(4)', clearances, to, the, same, extent, in, 'THX', +, 'T(3),', 'euthyroid-like', rats])].
[sujeto(['Both', treatments]), verbo([induced]), complemento([a, 2.5, -, fold, increase, in, 'Ugt1a1', and, 'Sult1b1', messenger, 'RNA', '(', 'mRNA)', expressions, and, a, twofold, increase, in, 'UGT1A', activity, suggesting, that, 'T(4)', elimination, was, 'mediated,', at, least, in, 'part,', by, hepatic, uridine, 5, '\'', -, 'diphospho-glucuronosyltransferases', '(', 'UGT)', 'and/or', sulfotransferases, '(', 'SULT)', induction])].
[sujeto(['Both', treatments]), verbo([induced]), complemento([a, 10, -, fold, increase, in, 'Cyp3a1', and, 'Cyp2b2', mRNA, expressions, concomitant, with, a, threefold, increase, in, 'CYP3A', immunoreactivity, and, a, 1.7, -, fold, increase, in, antipyrine, 'clearance,', a, biomarker, of, 'CYP3A', activity])].
[sujeto(['The', potential, of, fipronil, sulfone, to]), verbo([act]), complemento([as, a, thyroid, disruptor, is, all, the, more, critical, because, it, persists, much, longer, in, the, organism, than, fipronil, itself])].
[sujeto(['Studies', of, cancer, chemoprevention, with, caffeic, acid, phenethyl, ester, '(', 'CAPE)', in, the, resistant, hepatocyte, model, of, hepatocarcinogenesis]), verbo([have]), complemento([shown, the, participation, of, 'CYP', drug, metabolizing, enzymes])].
[sujeto(['To']), verbo([prevent]), complemento([neoplastic, and, preneoplasic, 'lesions,', we, must, specifically, identify, which, 'CYP', activities, are, modified, in, the, mechanism, of, action, of, 'CAPE'])].
[sujeto(['The', inhibition, of, 'CYP2B1/2']), verbo([prevented]), complemento([the, appearance, of, preneoplastic, lesions])].
[sujeto(['Microsomal', assays, demonstrated, that, 'CAPE', interfered, with, 'DEN', activation, diminishing, nitrites, similar, to, 'SKF525A', and, probably]), verbo([mediated]), complemento([by, 'CYP2B1/2', inhibition])].
[sujeto(['These', results, confirmed, that, 'CAPE', is, a, promising, agent, to]), verbo([confer]), complemento([chemoprotection, in, liver, cancer, and, should, be, considered, for, human, therapies])].
[sujeto(['We']), verbo([report]), complemento([the, role, of, dietary, glycine, and, the, type, of, oil, used, as, a, vehicle, in, the, hepatotoxicity, of, control, rats, and, rats, treated, with, 2, ',', 2, '\'', ',', 4, ',', 4, '\'', ',', 5, ',', 5, '\'', -, hexachlorobiphenyl, '(', 'PCB-153)'])].
[sujeto(['In', our, first, 'experiment,', glycine, or, valine, '(', as, 'control)', was, fed, in, an, unrefined, diet, at, 5, '%', for, the, entire, study, duration, '(', 5, 'days)', to]), verbo([inhibit]), complemento(['Kupffer', cell, activity])].
[sujeto(['MCT', oil]), verbo([decreased]), complemento([cell, proliferation, by, approximately, 50, '%'])].
[sujeto(['PCB-153', slightly]), verbo([increased]), complemento([hepatic, cell, 'proliferation,', but, dietary, glycine, did, not, reduce, cell, proliferation])].
[sujeto(['Because', of, the, inhibition, of, cell, proliferation, in, rats, receiving, 'MCT', oil, compared, with, rats, receiving, no, 'injection,', we, hypothesized, that, 'MCT', oil, may]), verbo([have]), complemento([been, inhibiting, the, hepatocyte, proliferation, in, 'PCB-153-treated', rats])].
[sujeto(['MCT', oil, again]), verbo([decreased]), complemento([the, hepatocyte, proliferation, by, approximately, 50, '%'])].
[sujeto(['Modest']), verbo([increases]), complemento([in, catalytic, efficiency, of, 7, -, 'EFC', 'O-deethylation', by, the, mutants, were, magnified, considerably, by, chlorination, or, bromination, of, the, substrate, ethoxy, chain])].
[sujeto(['Analysis', of, available, 'CYP2B', structures]), verbo([suggest]), complemento([that, the, effect, of, the, amino, acid, substitutions, within, the, peripheral, pocket, derive, from, altered, interactions, between, the, 'F', and, 'G', helices])].
[sujeto(['X-ray', crystal, structures, of, complexes, of, cytochromes, 'CYP2B6', and, 'CYP2A6', with, the, monoterpene, sabinene, revealed, two, distinct]), verbo([binding]), complemento([modes, in, the, active, sites])].
[sujeto(['In', 'contrast,', sabinene, was]), verbo([found]), complemento([in, an, alternate, conformation, in, the, more, compact, 'CYP2A6,', where, the, larger, hydrophobic, side, chains, resulted, in, a, significantly, reduced, 'active-site', cavity])].
[sujeto(['Furthermore,', results, from, isothermal, titration, calorimetry, indicated, a, much, more, substantial, contribution, of, favorable, enthalpy, to, sabinene]), verbo([binding]), complemento([to, 'CYP2B6', as, opposed, to, 'CYP2A6,', consistent, with, the, previous, observations, with, '(', +, ')', -, 'α-pinene'])].
[sujeto(['Structural', analysis, of, 'CYP2B6', complexes, with, sabinene, and, the, structurally, similar, '(', 3, ')', -, carene, and, comparison, with, previously, solved, structures, revealed, how, the, movement, of, the, 'F206', side, chain, influences, the, volume, of, the]), verbo([binding]), complemento([pocket])].
[sujeto(['This']), verbo([binding]), complemento([mode, may, reflect, the, formation, of, 'Cl-π', or, 'NH-π', bonds, with, aromatic, rings, in, the, active, 'site,', which, serve, as, important, contributors, to, 'protein-ligand', binding, affinity, and, specificity])].
[sujeto(['Overall,', the, findings, from, multiple, techniques, illustrate, how, drugs, metabolizing, 'CYP2B6', and, 'CYP2A6', handle, a, common, hydrocarbon]), verbo([found]), complemento([in, the, environment])].
[sujeto(['The', study, also]), verbo([provides]), complemento([insight, into, the, role, of, specific, functional, groups, of, the, ligand, that, may, influence, the, binding, to, 'CYP2B6'])].
[sujeto(['Despite', recent, advances, in, 'atomic-level', understanding, of, drug, and, inhibitor, interactions, with, human, cytochromes, 'P450,', the, 'decades-old', questions, of, chemical, and, structural, determinants, of, hydrocarbon]), verbo([binding]), complemento([are, still, unanswered])].
[sujeto(['Thermodynamics', of, ligand]), verbo([binding]), complemento([were, explored, using, isothermal, titration, calorimetry, and, compared, to, those, of, 'P450', 2, 'A6,', which, is, much, less, flexible, than, 2, 'B6', based, on, comparison, of, multiple, 'X-ray', crystal, structures])].
[sujeto(['Consistent', with, 'expectation,', entropy, is, the, major, driving, force, for, hydrocarbon]), verbo([binding]), complemento([to, 'P450', 2, 'A6,', as, evidenced, by, the, calorimetric, results])].
[sujeto(['However,', formation, of, the, 2, 'B6-(+)-α-pinene', complex]), verbo([has]), complemento([a, significant, enthalpic, component])].
[sujeto(['A', 2.0, 'Å', resolution, crystal, structure, of, this, 'enzyme-ligand', complex]), verbo([reveals]), complemento([that, the, highly, plastic, 2, 'B6', utilizes, previously, unrecognized, rearrangements, of, protein, motifs])].
[sujeto(['The', results, indicate, that, the, specific, components, of, enthalpic, contribution, to, ligand]), verbo([binding]), complemento([are, closely, tied, to, the, degree, of, enzyme, flexibility])].
[sujeto(['The', sulfate, conjugation, by, 'SULT2A1', also, contributed, to, the, metabolism, of, 'TAK-438', to, form, 'TAK-438', 'N-sulfate,', and, 'CYP2C9']), verbo([mediated]), complemento([the, formation, of, 'M-IV-Sul', from, 'TAK-438', 'N-sulfate'])].
[sujeto(['Standard', hepatocyte, suspension, intrinsic, clearance, '(', 'CLint)', methods, can, only]), verbo([provide]), complemento([reliable, 'CLint', values, above, 2.5, 'μL/min/million', cells])].
[sujeto(['A', method, that, permits, extended, incubation, time, with]), verbo([maintained]), complemento([performance, and, metabolic, activity, of, the, in, vitro, system, is, warranted, to, allow, in, vivo, clearance, predictions, and, metabolite, identification, of, slowly, metabolized, drugs])].
[sujeto(['Further,', both, phase, 'I', and, phase, 'II', metabolites, were, detected, and, an]), verbo([increased]), complemento([number, of, metabolites, were, observed, in, the, 'HμREL', coculture, compared, to, hepatocyte, suspension])].
[sujeto(['Infection', by, hepatitis, 'C', virus, '(', 'HCV)', and, its, subsequent, complications, are, a, major]), verbo([cause]), complemento([of, mortality, worldwide])].
[sujeto(['The', current, pilot, clinical, trial, revealed, that, the, water, extract, of, a, 'WEA', plant]), verbo([decreased]), complemento([the, 'HCV', viral, load, below, the, detection, level, in, 12, out, of, 15, patients])].
[sujeto(['The', total, 'WEA', extract]), verbo([inhibited]), complemento(['CYP2B6', '(', 'OH-BUP)', and, 'CYP2C19', '(', 5, -, 'OH-OME)', with, high, 'affinity,', 'IC50', '∼', 20, μg, 'ml(-1),', while, moderate, inhibitory, interactions, were, observed, for, 'CYP1A2,', 'CYP2D6,', 'CYP2E1', and, 'CYP3A4'])].
[sujeto(['Results', presented, herein]), verbo([suggest]), complemento([that, the, 'WEA', exhibits, strong, antiviral, activity, against, 'HCV', and, may, be, useful, for, its, treatment])].
[sujeto(['Compared', to, the, artichoke, product, &, 'quot;Hepar', 'SL', 'Forte(®)&quot;,', 'WEA', was]), verbo([found]), complemento([to, be, more, enriched, in, sesquiterpenes, versus, the, abundance, of, phenolic, 'compounds,', especially, flavonoids, in, 'Hepar', 'SL', 'Forte(®)', as, revealed, via, 'UPLC-MS', analysis, coupled, to, chemometrics])].
[sujeto(['This']), verbo([report]), complemento([describes, phase, 1, clinical, trials, performed, to, assess, interactions, of, oral, isavuconazole, at, the, clinically, targeted, dose, '(', 200, 'mg,', administered, as, isavuconazonium, sulfate, 372, 'mg,', 3, times, a, day, for, 2, 'days;', 200, mg, once, daily, '[', 'QD]', 'thereafter)', with, single, oral, doses, of, the, cytochrome, 'P450', '(', 'CYP)', 'substrates:', bupropion, hydrochloride, '(', 'CYP2B6;', 100, &, 'nbsp;mg;', n, =, 24, ')', ',', repaglinide, '(', 'CYP2C8/CYP3A4;', 0.5, 'mg;', n, =, 24, ')', ',', caffeine, '(', 'CYP1A2;', 200, 'mg;', n, =, 24, ')', ',', dextromethorphan, hydrobromide, '(', 'CYP2D6/CYP3A4;', 30, 'mg;', n, =, 24, ')', ',', and, methadone, '(', 'CYP2B6/CYP2C19/CYP3A4;', 10, 'mg;', n, =, 23, ')'])].
[sujeto(['Compared', with, each, drug, 'alone,', coadministration, with, isavuconazole, changed, the, area, under, the, 'concentration-time', curves, '(', 'AUC∞', ')', and, maximum, concentrations, '(', 'Cmax', ')', as, 'follows:', 'bupropion,', 'AUC∞', reduced, 42, '%', ',', 'Cmax', reduced, 31, '%', ;, 'repaglinide,', 'AUC∞', reduced, 8, '%', ',', 'Cmax', reduced, 14, '%', ;, 'caffeine,', 'AUC∞']), verbo([increased]), complemento([4, '%', ',', 'Cmax', reduced, 1, '%', ;, 'dextromethorphan,', 'AUC∞', increased, 18, '%', ',', 'Cmax', increased, 17, '%', ;, 'R-methadone,', 'AUC∞', reduced, 10, '%', ',', 'Cmax', increased, 3, '%', ;, 'S-methadone,', 'AUC∞', reduced, 35, '%', ',', 'Cmax', increased, 1, '%'])].
[sujeto(['In', all, 'studies,', there, were, no, 'deaths,', 1, serious, adverse, event, '(', dextromethorphan, 'study;', perioral, 'numbness,', numbness, of, right, arm, and, 'leg),', and, adverse, events]), verbo([leading]), complemento([to, study, discontinuation, were, rare])].
[sujeto(['Further', elucidation, of, bupropion, and, metabolite, disposition]), verbo([suggests]), complemento([that, bupropion, is, not, a, reliable, in, vivo, marker, of, 'CYP2B6', activity])].
[sujeto(['In', 'summary,', to, our, 'knowledge,', this, is, the, first, comprehensive]), verbo([report]), complemento([to, provide, novel, insight, into, mechanisms, underlying, bupropion, disposition, by, detailing, the, stereoselective, pharmacokinetics, of, individual, bupropion, 'metabolites,', which, will, enhance, clinical, understanding, of, 'bupropion\'s', effects, and, 'DDIs', with, 'CYP2D6'])].
[sujeto(['To', examine, whether, certain, genotypes, were]), verbo([associated]), complemento([with, 'this,', we, examined, the, frequencies, of, 29, 'SNPs', located, in, candidate, genes, related, to, opioid, 'pharmacology:', 'ABCB1,', 'OPRM1,', 'UGT2B7,', 'CYP3A5,', 'CYP2B6,', 'CYP2C19,', 'CYP2D6,', 'COMT,', 'KCNJ6', and, 'SCN9A', in, 274, deceased, patients, with, 'OA', '(', 'DOA),', 309, living, patients, with, 'OA', '(', 'LOA)', and, in, 394, healthy, volunteers, '(', 'HV)'])].
[sujeto(['However,', for, another, 'ABCB1', 'variant,', 'rs9282564,', we]), verbo([found]), complemento([that, the, frequencies, of, the, 'AG', and, 'TT', genotypes, were, 13, ',', 21, and, 25, '%', in, 'DOA,', 'LOA', and, 'HV,', 'respectively,', and, after, correcting, for, 'age,', sex, and, multiple, 'testing,', the, differences, between, 'DOA', and, 'LOA', were, statistically, significantly, different, '(', p, =, 0.027, ')'])].
[sujeto(['In', 'conclusion,', this, study, generated, two, hypotheses]), verbo([suggesting]), complemento([possible, associations, of, a, reduced, risk, of, death, and, 'carrying,', 'respectively,', the, 'ABCB1', rs9282564, 'AG', and, 'TT', genotypes, and, the, 'COMT', rs4680, 'AA', genotype, among, patients, with, 'OA'])].
[sujeto(['Inconsistent', therapeutic, efficacy]), verbo([has]), complemento([been, reported, with, 'ATX,', which, may, be, related, to, variable, 'CYP2D6-mediated', drug, clearance])].
[sujeto(['Competing', pathways, of, 'ATX', metabolism, '[', 'N-desmethylatomoxetine', '(', 'NDM-ATX)', and, 2, -, 'CH2OH-ATX', 'formation]', had]), verbo([increasing]), complemento([importance, in, livers, with, lesser, 'CYP2D6', 'activity,', 'but,', overall, 'ATX', clearance, was, still, compromised])].
[sujeto(['Modeling', 'ATX', exposure, to, individualize, therapy, would]), verbo([require]), complemento([comprehensive, knowledge, of, factors, that, affect, 'CYP2D6', activity, as, well, as, an, understanding, of, competing, 'pathways,', particularly, for, individuals, with, lower, 'CYP2D6', activity])].
[sujeto([mRNA, kinetics, in, biochips, showed, an]), verbo([increase]), complemento([in, the, levels, of, 'CYP2B6,', 'CYP2C19,', 'CYP2C8,', 'CYP3A4,', 'CYP1A2,', 'CYP2D6,', 'HNF4a,', 'SULT1A1,', 'UGT1A1', mRNA, related, genes, when, compared, with, post, extraction, levels])].
[sujeto(['The', 'CYP3A4', midazolam, metabolism, was]), verbo([maintained]), complemento([in, biochips, after, 13, days, of, 'culture,', whereas, it, was, almost, undetectable, in, 'Petri', dishes])].
[sujeto(['This']), verbo([led]), complemento([to, a, 5000, -, fold, higher, value, of, the, metabolic, ratio, in, the, biochips])].
[sujeto(['CYP1A2', phenacetin, metabolism, was]), verbo([found]), complemento([to, be, higher, in, biochips, after, 5, ',', 9, and, 13, days, of, culture])].
[sujeto(['Recently,', we]), verbo([have]), complemento([developed, a, cocktail, '(', 'Geneva', 'cocktail)', which, combines, the, use, of, 'low-dose', probes, with, a, 'low-invasiveness', dried, blood, spots, '(', 'DBS)', sampling, technique, and, a, single, analytical, method, for, the, phenotyping, of, six, major, 'CYP', isoforms])].
[sujeto(['We']), verbo([have]), complemento([previously, demonstrated, that, modulation, of, 'CYP', activity, after, 'pre-treatment', with, 'CYP', 'inhibitors/inducer', could, be, reliably, predicted, using, 'Geneva', cocktail])].
[sujeto(['To', further, validate, this, 'cocktail,', in, this, 'study,', we]), verbo([have]), complemento([verified, whether, probe, drugs, contained, in, the, latter, cause, mutual, 'drug-drug', interactions])].
[sujeto(['Individually,', 'CYP2D6', and, 'CYP3A', activities, were, shown, to]), verbo([have]), complemento([moderate, contribution, on, clearance, of, tramadol, enantiomers, '(', 11, -, 16, '%', and, 11, -, 18, '%', ',', 'respectively)'])].
[sujeto(['In', 'conclusion,', factors, affecting, fraction, unbound, of, drugs, '(', such, as, hyperglycemia, or, 'co-administration', of, drugs, highly]), verbo([bound]), complemento([to, plasma, 'proteins)', should, be, 'monitored,', because, this, parameter, dominates, the, elimination, of, tramadol, enantiomers])].
[sujeto(['Flos', 'Daturae,', known, as, &, 'quot;baimantuoluo&quot;', or, &, 'quot;yangjinhua&quot;', in, 'China,']), verbo([has]), complemento([been, used, for, centuries, in, 'Traditional', 'Chinese', 'Medicine', for, the, treatment, of, 'asthma,', 'convulsions,', 'pain,', and, rheumatism])].
[sujeto(['The', results, from, the, present, in, vivo, study, showed, that, 'Flos', 'Daturae']), verbo([induce]), complemento([the, activity, of, 'CYP2D6', enzyme, with, the, decreased, 'Cmax,', 'AUC(0-∞)', '(', 'P', &, 'lt;', 0.05, ')', and, the, increased, 'CL', '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['Therefore,', the, resulting, data]), verbo([suggested]), complemento([that, caution, was, needed, when, 'Flos', 'Daturae', was, 'co-administered', with, 'CYP2D6', 'substrates,', which, may, result, in, treatment, failure, and, 'herb-drug', interactions])].
[sujeto(['It', indicated, that, the, 'Radix', 'Sophorae', 'Flavescentis', may]), verbo([induce]), complemento([the, activities, of, 'CYP2D6,', and, inhibit, of, 'CYP2C19,', 'CYP1A2', and, 'CYP2C9', of, rats])].
[sujeto(['Case']), verbo([reports]), complemento([from, 'Sweden', and, 'Japan', demonstrate, its, current, use, and, the, necessity, of, applying, analytical, procedures, in, clinical, and, forensic, toxicology])].
[sujeto(['As', compared, to, most, 'pesticides,', paraquat, is, extremely, toxic, to, humans, and, the, lack, of, strategies, to, manage, paraquat, poisoning]), verbo([has]), complemento([resulted, in, high, fatality, rates])].
[sujeto(['The', influence, of, acute, paraquat, poisoning, on, the, activities, of, 'CYP450', isoforms, 'CYP2B6,', 'CYP1A2,', 'CYP2C9,', 'CYP2D6,', 'CYP3A4', and, 'CYP2C19', were, evaluated, by, cocktail, 'method,', they, were]), verbo([responded]), complemento([by, the, changes, of, pharmacokinetic, parameters, of, 'bupropion,', 'phenacetin,', 'tolbutamide,', 'metoprolol,', midazolam, and, omeprazole])].
[sujeto(['Acute', paraquat, poisoning, may]), verbo([induce]), complemento([the, activities, of, 'CYP2C19,', and, inhibit, of, 'CYP2B6,', 'CYP2C9,', 'CYP2D6', and, 'CYP3A4', in, rats])].
[sujeto(['Several', enzymes, are]), verbo([involved]), complemento([in, this, steroidogenic, process, including, the, steroidogenic, acute, regulatory, protein, '(', 'StAR),', 'P450', side, chain, cleavage, enzyme, '(', 'Cyp11a1),', and, aldosterone, synthase, '(', 'Cyp11b2)', which, has, been, demonstrated, to, be, transcriptionally, regulated, by, the, nuclear, transcription, factors, 'NGF1-B', and, 'Nurr1'])].
[sujeto(['Using', 'real-time', 'PCR', a, fast, upregulation, of, adrenal, 'Cyp11b2', expression, '(', 53, +, /, -, 5, '%']), verbo([increase]), complemento([over, 'baseline)', could, be, observed, 10, min, after, sham, injection, which, was, accompanied, by, a, transient, increase, in, aldosterone, secretion, while, 'StAR', and, 'Cyp11a1', upregulation, was, delayed, and, more, sustained])].
[sujeto(['ANGII']), verbo([caused]), complemento([an, increase, of, 'StAR', and, 'Cyp11a1', expression, similar, to, that, observed, after, sham, injection, while, 'Cyp11b2', upregulation, was, more, pronounced, '(', 10, 'min,', 236, +, /, -, 39, '%', ')', and, reflected, 'ANGII', induced, stimulation, of, aldosterone, output])].
[sujeto(['While']), verbo([increases]), complemento([in, 'NGF1-B', mRNA, levels, were, similar, between, the, treatment, 'groups,', 'Nurr1', expression, levels, were, induced, only, upon, 'ANGII', administration])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, acute, regulation, of, aldosterone, synthesis, is, accompanied, by, fast, transcriptional, modulation, of, steroidogenic, enzymes, and, transcription, factors, that, are, likely, to, be, involved, in, aldosterone, secretion])].
[sujeto(['The', role, of, farnesoid, 'X', receptor, '(', 'FXR)', in, the, development, of, atherosclerosis]), verbo([has]), complemento([been, unclear])].
[sujeto(['WAY-362450', also]), verbo([induced]), complemento([small, heterodimer, partner, '(', 'SHP)', expression, and, repressed, cholesterol, 7, 'alpha-hydroxylase', '(', 'CYP7A1)', and, sterol, 12, 'alpha-hydroxylase', '(', 'CYP8B1)', expression])].
[sujeto(['In', male, 'LDLR(-/-)SHP(-/-)', or, 'apoE(-/-)SHP(-/-)', 'mice,', 'WAY-362450', still]), verbo([repressed]), complemento(['CYP7A1', and, 'CYP8B1', expression, by, 10, -, fold, and, still, strongly, reduced, 'non-HDL', cholesterol, levels, and, aortic, lesion, area])].
[sujeto(['In', 'contrast,', in, the, female, 'LDLR(-/-)SHP(-/-)', or, 'apoE(-/-)SHP(-/-)', 'mice,', 'WAY-362450', only, slightly]), verbo([repressed]), complemento(['CYP7A1', and, 'CYP8B1', expression, and, did, not, reduce, 'non-HDL', cholesterol, or, aortic, lesion, size])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, activation, of, 'FXR', protects, against, atherosclerosis, in, the, 'mouse,', and, this, protective, effect, correlates, with, repression, of, bile, acid, synthetic, 'genes,', with, mechanistic, differences, between, male, and, female, mice])].
[sujeto(['Th17', cell, differentiation, is, dependent, on, interleukin, '(', 'IL)-6', and, transforming, growth, factor, '(', 'TGF)-beta,', and, it, is]), verbo([modulated]), complemento([by, activation, of, the, aryl, hydrocarbon, receptor, '(', 'AhR)'])].
[sujeto(['In', this, 'study,', we, show, that, differentiation, of, 'Th17', 'cells,', but, not, 'Th1', or]), verbo([induced]), complemento([regulatory, 'T', '(', iT, 'reg)', 'cells,', is, increased, by, endogenous, 'AhR', agonists, present, in, culture, medium])].
[sujeto(['The', presence, of, natural, 'AhR', agonists, in, culture, medium, is, also, revealed, by, the, induction, of, 'CYP1A1,', a, downstream]), verbo([target]), complemento([of, 'AhR', activation])].
[sujeto(['The', relative, paucity, of, 'AhR', agonists, in, 'RPMI', 'medium,', coupled, with, the, presence, of, factors, conducive, to, 'IL-2', activation, and]), verbo([enhanced]), complemento(['Stat5', 'phosphorylation,', conspire, against, optimal, 'Th17', differentiation])].
[sujeto(['Our', data, emphasize, that, 'AhR', activation, plays, an, essential, part, in, the, development, of, 'Th17', cells, and]), verbo([provide]), complemento([a, rational, explanation, for, the, poor, in, vitro, polarization, of, 'Th17', cells, that, is, reported, in, the, majority, of, publications, for, both, mouse, and, human, cells])].
[sujeto(['To', investigate, the, expressions, of, small, heterodimer, partner, '(', 'SHP)', and]), verbo([target]), complemento([gene, 'cholesterol-7-hydroxylase', '(', 'CYP7A1)', in, livers, of, rats, with, intrahepatic, cholestasis, of, pregnancy, '(', 'ICP),', and, to, study, the, mechanism, of, 'ICP'])].
[sujeto(['(', 1, ')', 'In', the, 'EB', 'group,', the, serum, levels, of, 'ALT,', 'AST,', 'ALP,', 'TBA,', 'TBil,', and, 'DBil', after, 'EB', administration]), verbo([increased]), complemento([significantly, '(', 'P', less, than, 0.01, ')', ',', but, there, were, no, significant, changes, in, the, 'NS', group, '(', 'P', more, than, 0.05, ')', ;, '(', 2, ')', 'Intrahepatic', cholestasis, appeared, in, the, 'EB', 'group,', but, not, in, the, 'NS', 'group;', '(', 3, ')', 'The', mRNA, expressions, of, 'SHP', and, 'CYP7A1', were, significantly, higher, in, the, 'EB', group, than, in, the, 'NS', group, '[', '(', 'SHPmRNA:', 'NS', 0.365, +, /, -, 0.0317, vs, 'EB', 0.4865, +, /, -, 0.0237, ',', 'P', less, than, 0.01, ')', ',', '(', 'CYP7A1', 'mRNA:', 'NS', 0.357, +, /, -, 0.0175, vs, 'EB', 0.4802, +, /, -, 0.0217, ',', 'P', less, than, 0.01, ')', ']', ;, '(', 4, ')', 'The', protein, expressions, of, 'SHP', and, 'CYP7A1', were, also, higher, in, the, 'EB', group, than, that, in, the, 'NS', group, '[', '(', 'SHP:', 'NS', 0.3762, +, /, -, 0.0284, vs, 'EB', 0.5033, +, /, -, 0.0274, ',', 'P', less, than, 0.01, ')', ',', '(', 'CYP7A1:', 'NS', 0.357, +, /, -, 0.0175, vs, 'EB', 0.4802, +, /, -, 0.0217, ',', 'P', less, than, 0.01, ')', ']'])].
[sujeto(['Estrogen']), verbo([induces]), complemento(['ICP', in, rats])].
[sujeto(['The', mRNA, and, protein, expressions, of, 'SHP', and, 'CYP7A1', in, livers, of, the, 'ICP', rats, were, 'increased,', which]), verbo([causes]), complemento([more, bile, acids, to, be, synthesized])].
[sujeto(['Ontogenic', changes, in, the, rat, bile, acid, '(', 'BA)', 'pool,', measured, enzymatically, and, by, 'GC-MS,', and, expression, of, enzymes, '(', 5, 'alpha-reductase,', 5, 'beta-reductase,', and, cytochrome, 'P450', enzymes, 'Cyp7a1,', 'Cyp8b1,', 'Cyp27', and, 'Cyp3a11),', transporters, '[', bile, salt, export, 'pump,', sodium, 'taurocholate-cotransporting', 'polypeptide,', apical, 'sodium-dependent', bile, acid, 'transporter,', and, organic, solute, transporter, 'alpha/beta', '(', 'Ostalpha/Ostbeta)],', and]), verbo([nuclear]), complemento([receptors, '[', fetoprotein, transcription, factor, '(', 'Ftf),', farnesoid, 'X', receptor, '(', 'Fxr),', small, heterodimer, partner, '(', 'Shp),', and, hepatic, nuclear, factor, 4, alpha, '(', 'HNF-4alpha)],', determined, by, quantitative, 'PCR,', were, investigated])].
[sujeto(['The', absolute, size, of, the, 'BA', pool]), verbo([increased]), complemento([progressively, up, to, 'adulthood,', whereas, the, complexity, of, its, composition, was, high, in, 'fetuses,', decreased, after, 'birth,', increased, again, progressively, up, to, 'adulthood,', and, decreased, in, aged, animals])].
[sujeto(['The', relative, size, of, the, 'BA', 'pool,', corrected, by, liver, 'weight,', was]), verbo([maintained]), complemento([from, 1, week, after, 'birth,', except, at, 'weaning,', when, a, transient, peak, accompanied, by, 'Shp', downregulation, and, 'Cyp7a1', upregulation, was, observed])].
[sujeto(['An', imposed, weaning, delay, of, 1, week, had, no, effect, on, the, time, course, of, the, 'BA', pool, size, but]), verbo([decreased]), complemento([the, proportion, of, chenodeoxycholic, and, 'alpha-muricholic', 'acids,', whereas, the, proportion, of, cholic, acid, was, 'increased,', probably, as, a, result, of, 'Cyp8b1', upregulation])].
[sujeto(['In', 'conclusion,', changes, in, the, expression, of, genes]), verbo([involved]), complemento([in, 'BA', homeostasis, may, play, a, role, in, physiological, adaptations, to, digestive, functions, during, the, rat, life, span])].
[sujeto(['In', humans, and, 'mice,', low, plasma, levels, of, 'PON1']), verbo([have]), complemento([also, been, linked, to, the, development, of, atherosclerosis])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, hepatic, 'Pon1', expression, was, decreased, when, 'C57BL/6J', mice, were, fed, a, 'high-fat,', 'high-cholesterol', diet, supplemented, with, cholic, acid, '(', 'CA)'])].
[sujeto(['PON1', mRNA, levels, were, also]), verbo([repressed]), complemento([when, 'HepG2', 'cells,', derived, from, a, human, 'hepatoma,', were, incubated, with, natural, or, highly, specific, synthetic, 'FXR', agonists])].
[sujeto(['In', 'contrast,', fibroblast, growth, 'factor-19', '(', 'FGF-19)', mRNA, levels, were, greatly]), verbo([induced]), complemento([by, these, same, 'FXR', agonists])].
[sujeto(['Furthermore,', treatment, of, 'HepG2', cells, with, recombinant, human, 'FGF-19', significantly]), verbo([decreased]), complemento(['PON1', mRNA, levels])].
[sujeto(['These', data, demonstrate, that, human, 'PON1', expression, is]), verbo([repressed]), complemento([by, bile, acids, through, the, actions, of, 'FXR', and, 'FGF-19'])].
[sujeto(['CYP2C8', is, the, most, strongly, inducible, member, of, the, 'CYP2C', subfamily, in, human, 'hepatocytes,', but, the, mechanism, of, induction, by, xenobiotics]), verbo([has]), complemento([not, been, delineated])].
[sujeto(['To', determine, the, mechanisms, controlling, the, regulation, of, this, important, 'P450,', we, cloned, the, 5, '\'', -, flanking, region, of, 'CYP2C8', and, investigated, its, transcriptional, regulation, by]), verbo([nuclear]), complemento([factors, such, as, the, pregnane, 'X', receptor, '(', 'PXR),', constitutive, androstane, receptor, '(', 'CAR),', glucocorticoid, receptor, '(', 'GR),', and, hepatic, nuclear, factor, 4, '(', 'HNF4alpha)', that, are, known, to, be, involved, in, the, induction, of, other, 'P450', enzymes, using, both, cell, lines, and, primary, hepatocyte, models])].
[sujeto(['We', initially, identified, a, distal, 'PXR/CAR-binding', site, in, the, 'CYP2C8', promoter, that]), verbo([confers]), complemento([inducibility, of, 'CYP2C8', via, the, 'PXR', 'agonist/ligand', rifampicin, and, the, 'CAR', 'agonist/ligand', 'CITCO', '[', 6, -, '(', 4, -, 'chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde', 'O-(3,4-dichlorobenzyl)oxime]'])].
[sujeto(['A', 'glucocorticoid-responsive', element, was, identified, that]), verbo([mediates]), complemento([dexamethasone, induction, via, the, 'GR'])].
[sujeto(['In', 'summary,', the, present, studies, show, that, 'CAR,', 'PXR,', 'GR,', and, 'HNF4alpha', can]), verbo([regulate]), complemento(['CYP2C8', expression, and, identify, specific, 'cis-elements', within, the, promoter, that, control, these, regulatory, pathways])].
[sujeto(['Cerebrotendinous', xanthomatosis, '(', 'CTX),', sterol, 27, -, hydroxylase, '(', 'CYP27A1)', 'deficiency,', is]), verbo([associated]), complemento([with, markedly, reduced, chenodeoxycholic, acid, '(', 'CDCA),', the, most, powerful, activating, ligand, for, farnesoid, 'X', receptor, '(', 'FXR)'])].
[sujeto(['We', investigated, the, effects, of, reduced, 'CDCA', on, 'FXR']), verbo([target]), complemento([genes, in, humans])].
[sujeto(['However,', another]), verbo([nuclear]), complemento(['receptor,', hepatocyte, nuclear, factor, 4, alpha, '(', 'HNF4alpha),', was, induced, 2.9, -, fold, in, 'CTX,', which, was, associated, with, enhanced, mRNA, levels, of, 'HNF4alpha', target, 'genes,', 'CYP7A1,', 7, 'alpha-hydroxy-4-cholesten-3-one', 12, 'alpha-hydroxylase,', 'CYP27A1,', and, 'NTCP'])].
[sujeto(['In', 'conclusion,', the, coordinate, regulation, of, 'FXR']), verbo([target]), complemento([genes, was, lost, in, 'CTX'])].
[sujeto(['The', mechanism, of, the, disruption, may, be, explained, by, a, normally]), verbo([stimulated]), complemento(['FXR', pathway, attributable, to, markedly, increased, bile, alcohols, with, activation, of, 'HNF4alpha', caused, by, reduced, bile, acids, in, 'CTX', liver])].
[sujeto(['The', metabolism, of, the, norisoprenoid, 'β-ionone', was, investigated, in, vitro, using, human, liver, microsomes, and, 11, different, recombinant, cytochrome, 'P450', enzymes]), verbo([expressed]), complemento([in, 'Trichoplusia', ni, cells])].
[sujeto(['β-Ionone', was]), verbo([found]), complemento([to, be, oxidized, via, 4, 'S-hydroxylation', by, 'CYP2B6', in, human, liver, microsomes])].
[sujeto(['The', reaction, rates, observed, using, human, liver, microsomes, and, recombinant, 'CYP2B6', were, very, high, compared, with, those, of, other, 'CYP2B6', substrates]), verbo([reported]), complemento([thus, far])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'β-ionone,', a, norisoprenoid, present, in, 'nature,', is, one, of, the, effective, substrates, for, 'CYP2B', enzymes, in, human, liver, microsomes])].
[sujeto(['To', the, best, of, our, 'knowledge,', this, is, the, first, time, that, 4, -, hydroxy, 'β-ionone']), verbo([has]), complemento([been, described, as, a, human, metabolite, of, 'β-ionone'])].
[sujeto(['Eleven', polymorphisms, were]), verbo([associated]), complemento([with, increased, risk, of, developing, 'HGOS', '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['In', the, survival, cohort, '(', n, =, 126, ',', median, 'follow-up', =, 126, 'months),', genotypes, of, 'ABCC2_1249A/G,', 'GGH_452T/C,', 'TP53_IVS2+38G/C', and, 'CYP2B6*6', were]), verbo([associated]), complemento([with, 'EFS', '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['In', the, toxicity, cohort, '(', n, =, 57, ')', ',', genotypes, of, 'ABCB1_1236T/C,', 'ABCC2_1249A/G,', 'ABCC2_3972A/G,', 'ERCC1_8092T/G,', 'XPD_23591A/G,', 'XRCC3_18067T/C,', 'MTHFR_1298A/C', and, 'GGH_16T/C', were]), verbo([associated]), complemento([with, elevated, risk, for, toxicity, development, '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['MSCs', were, genetically, engineered, 'ex-vivo', to, stably]), verbo([express]), complemento(['CYP2B6TM-RED'])].
[sujeto(['Ex', vivo, and, in, vivo, investigations, showed, that, 'MSCs']), verbo([expressing]), complemento(['CYP2B6TM-RED', were, able, 1, ')', to, bioactivate, 'CPA', and, produce, local, cytotoxic, metabolites, in, tumor, sites, and, 2, ')', to, destroy, neighboring, tumor, cells, through, a, bystander, effect])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'MSCs', expressing, 'CYP2B6TM-RED', with, 'CPA', could, represent, a, promising, treatment, for, solid, tumors, to, test, in, future, clinical, trials])].
[sujeto(['Cytochrome', 'P450', '(', 'CYP)', enzymes, are]), verbo([induced]), complemento([by, some, therapeutic, 'drugs,', leading, to, interactions, reducing, drug, plasma, concentrations])].
[sujeto(['Recently,', an, assessment, of, 'CYP', induction, using, messenger, 'RNA', '(', 'mRNA)', levels]), verbo([has]), complemento([shown, advantages, over, measurement, of, enzymatic, 'activity;', it, has, a, larger, dynamic, range, of, induction, and, enables, us, to, measure, the, intrinsic, induction, potential, of, 'time-dependent', 'CYP', inhibitors])].
[sujeto(['Compared', with, the, evaluation, of, 'CYP', induction, in, human, 'hepatocytes,', the, response, at, 'R10', in, 'HepaRG', cells]), verbo([suggested]), complemento([the, possibility, of, exhibiting, induction, potency, for, corresponding, 'CYPs'])].
[sujeto(['Interestingly,', the, results, with, our, 'in-house', 109, compounds, showed, that, several, compounds]), verbo([induced]), complemento(['CYP1A2', or, 'CYP2B6', expression, without, upregulation, of, 'CYP3A4,', suggesting, that, 'R10', is, valuable, in, examining, the, induction, potential, of, these, 'CYP', isoforms])].
[sujeto(['The', crystal, structures, of, human, 'P450', 2, 'B6', '(', 'CYP2B6)', indicate, that, 'Phe206', and, 'Val367', are, in, close, proximity, to, the, substrate]), verbo([binding]), complemento([site, and, suggest, that, both, residues, may, play, important, roles, in, substrate, metabolism, and, inhibitor, binding])].
[sujeto(['For', 'Testo', 'metabolism,', 16, 'β-OH-Testo', formation, by, 'F206A', was, &, 'lt;5%', of, wild, type, '(', 'WT),', whereas, the, 'V367A', mutant, exhibited, a, doubling, of, 16, 'α-OH-Testo', formation, with, a, 50, '%']), verbo([decrease]), complemento([in, 16, 'β-OH-Testo', formation, compared, to, 'WT'])].
[sujeto(['Although', the, rates, of, inactivation, of, both, mutants, by, 'BG', were, not, significantly]), verbo([decreased]), complemento([compared, to, 'WT,', the, efficiency, of, inactivation, by, 'BPA', of, both, mutants, was, more, than, an, order, of, magnitude, lower])].
[sujeto(['Our', results, demonstrate, that, 'Phe206', plays, a, crucial, role, in, determining, the, specificity, of, 2, 'B6', for, the, 16, 'β-hydroxylation', of, 'Testo', and, 'Andro', and, that, it, also, plays, an, important, role, in, 'BG']), verbo([binding]), complemento([and, 'mechanism-based', inactivation, by, 'BPA'])].
[sujeto(['In', 'addition,', 'Val367', dramatically]), verbo([enhances]), complemento([the, catalytic, activity, of, 'CYP2B6', toward, 'Andro', and, plays, an, important, role, in, 'mechanism-based', inactivation, by, 'BPA'])].
[sujeto(['Bupropion', sustained]), verbo([release]), complemento(['(', 'SR)', is, used, to, promote, smoking, cessation, in, males, and, 'non-pregnant', females])].
[sujeto(['The', present, study]), verbo([reports]), complemento([that, the, 'isoform-specific', effect, of, pregnancy, on, 'bupropion-metabolizing', enzymes, along, with, the, increase, of, renal, elimination, of, the, drug, could, collectively, result, in, a, slight, decrease, in, exposure, to, bupropion, in, pregnancy])].
[sujeto(['On', the, other, 'hand,', 'pregnancy-induced']), verbo([increase]), complemento([in, 'CYP2B6-catalyzed', bupropion, hydroxylation, did, not, impact, the, plasma, levels, of, 'OHBUP,', probably, due, to, a, higher, rate, of, 'OHBUP', glucuronidation, and, renal, elimination, associated, with, pregnancy])].
[sujeto([120, males, were]), verbo([recruited]), complemento([for, this, study])].
[sujeto(['C64T', and, 'G15631T', in, 'CYP2B6and', 'G31A,', 'G691C,', and, 'A118G', in, 'OPRM1', were]), verbo([found]), complemento([to, be, 'polymorphic,', and, the, allelic, frequencies, of, each, were, calculated])].
[sujeto(['C64T', and, 'G15631T', in, 'CYP2B6and', 'G31A,', 'G691C,', and, 'A118G', in, 'OPRM1were']), verbo([found]), complemento([to, be, polymorphic])].
[sujeto(['Bupropion', is, a, widely, used, 'antidepressant,', smoking, cessation, aid, and, weight]), verbo([loss]), complemento([therapy])].
[sujeto(['Yet', the, stereoselective, metabolism, in, vitro, and, the, enzymes, contributing, to, the, stereoselective, disposition, of, bupropion]), verbo([have]), complemento([not, been, characterized])].
[sujeto(['In', humans, the, fraction, of, bupropion, metabolized, '(', 'fm)', to, the, 'CYP2B6', probe, metabolite, 'OH-bupropion', is, 5, -, 16, '%', ',', but, ticlopidine]), verbo([increases]), complemento([bupropion, 'AUC', by, 61, '%', ',', suggesting, a, 40, '%', 'CYP2B6', 'and/or', 'CYP2C19', fm, for, bupropion])].
[sujeto(['Yet,', the, 'CYP2C19', contribution, to, bupropion, clearance]), verbo([has]), complemento([not, been, 'defined,', and, the, enzymes, contributing, to, overall, bupropion, metabolite, formation, are, not, fully, characterized])].
[sujeto(['Importantly,', ticlopidine, was]), verbo([found]), complemento([to, inhibit, all, metabolic, pathways, of, bupropion, in, vitro, including, 'threohydrobupropion,', erythrohydrobupropion, and, 4, '\'', 'OH-bupropion', 'formation,', explaining, the, in, vivo, 'DDI'])].
[sujeto(['The', current, study, determined, if, known, single, nucleotide, polymorphisms, '(', 'SNPs)', for, 'Fc', gamma, receptors, '(', 'FcγRs)', or, cytochrome, p450, '(', 'CYP450)', enzymes, were]), verbo([associated]), complemento([with, the, response, to, rituximab, and, cyclophosphamide, 'treatment,', respectively])].
[sujeto(['However,', when, the, treatment, groups, were, 'combined,', an, association, was]), verbo([found]), complemento([between, the, 519, 'AA', genotype, of, 'FcγRIIA', and, complete, remission, '(', 'P', =, 0.01, ')'])].
[sujeto(['The']), verbo([finding]), complemento([that, the, homozygous, 'FcγRIIA', 519, 'AA', variant, was, associated, with, complete, response, and, a, shorter, time, to, complete, response, in, the, 'RAVE', 'trial,', independent, of, treatment, 'type,', implies, 'FcγRIIA', may, be, broadly, involved, in, disease, pathogenesis, and, response, to, therapy])].
[sujeto(['The', formation, of, 'drug-protein', adducts, via, metabolic, activation, and, covalent]), verbo([binding]), complemento([may, stimulate, an, immune, response, or, may, result, in, direct, cell, toxicity])].
[sujeto(['Protein', covalent]), verbo([binding]), complemento([is, a, potentially, pivotal, step, in, the, development, of, idiosyncratic, adverse, drug, reactions, '(', 'IADRs)'])].
[sujeto(['Trimethoprim', '(', 'TMP)-sulfamethoxazole', '(', 'SMX)', is, a, combination, antibiotic, that, commonly]), verbo([causes]), complemento(['IADRs'])].
[sujeto(['Recent', data]), verbo([suggest]), complemento([that, the, contribution, of, the, 'TMP', component, of, 'TMP-SMX', to, 'IADRs', may, be, underappreciated])].
[sujeto(['We', previously, demonstrated, that, 'TMP', is, bioactivated, to, chemically, reactive, intermediates, that, can, be, trapped, in, vitro, by, 'N-acetyl', cysteine, '(', 'NAC),', and, we]), verbo([have]), complemento([detected, 'TMP-NAC', adducts, '(', i])].
[sujeto(['However,', the, occurrence, and, extent, of, 'TMP', covalent]), verbo([binding]), complemento([to, proteins, was, unknown])].
[sujeto(['We', observed, protein, covalent]), verbo([binding]), complemento([that, was, 'NADPH', dependent, and, increased, with, incubation, time, and, concentration, of, both, protein, and, 'TMP'])].
[sujeto(['The', estimated, covalent]), verbo([binding]), complemento([was, 0.8, nmol, 'Eq', 'TMP/mg', 'protein,', which, is, comparable, to, the, level, of, covalent, binding, for, several, other, drugs, that, have, been, associated, with, covalent, 'binding-induced', toxicity, 'and/or', 'IADRs'])].
[sujeto(['These', results, demonstrate, for, the, first, time, that, 'TMP', bioactivation, can]), verbo([lead]), complemento([directly, to, protein, adduct, 'formation,', suggesting, that, 'TMP', has, been, overlooked, as, a, potential, contributor, of, 'TMP-SMX', 'IADRs'])].
[sujeto(['Genetic', differences, in, the]), verbo([target]), complemento(['proteins,', metabolizing, enzymes, and, transporters, that, contribute, to, 'inter-individual', differences, in, drug, response, are, not, integrated, in, contemporary, drug, development, programs])].
[sujeto(['Ayurveda,', that]), verbo([has]), complemento([propelled, many, drug, discovery, programs, albeit, for, the, search, of, new, chemical, entities, incorporates, 'inter-individual', variability, &, 'quot;Prakriti&quot;', in, development, and, administration, of, drug, in, an, individualized, manner])].
[sujeto(['Prakriti']), verbo([has]), complemento([also, been, shown, to, have, molecular, and, genomic, correlates])].
[sujeto(['Five', aspects, that]), verbo([have]), complemento([been, carried, out, are, '(', 1, ')', analysis, of, variability, in, 'FDA', approved, pharmacogenomics, 'genes/SNPs', in, exomes, of, 72, healthy, individuals, including, predominant, 'Prakriti', types, and, matched, controls, from, a, 'North', 'Indian', 'Indo-European', cohort, '(', 2, ')', establishment, of, a, consortium, network, and, development, of, five, genetically, homogeneous, cohorts, from, diverse, ethnic, and, 'geo-climatic', background, '(', 3, ')', identification, of, parameters, and, development, of, uniform, standard, protocols, for, objective, assessment, of, 'Prakriti', types, '(', 4, ')', development, of, protocols, for, 'Prakriti', evaluation, and, its, application, in, more, than, 7500, individuals, in, the, five, cohorts, '(', 5, ')', 'Development', of, data, and, sample, repository, and, integrative, omics, pipelines, for, identification, of, genomic, correlates])].
[sujeto(['(', 3, ')', 'Comparison', of, 'Prakriti', phenotypes, across, different, 'ethnic,', age, and, gender, groups]), verbo([led]), complemento([to, identification, of, invariant, features, as, well, as, some, that, require, weighted, considerations, across, the, cohorts])].
[sujeto(['CKD']), verbo([leads]), complemento([to, accumulation, of, uremic, 'toxins,', including, 'indoxyl-3-sulfate', '(', 3, -, 'INDS)', and, 'indole-3-acetic', acid, '(', 3, -, 'IAA)'])].
[sujeto(['In', this, 'study,', we, evaluated, the, potential, of, 3, -, 'INDS', and, 3, -, 'IAA', '(', 10, ',', 30, and, 100, 'μM)', to]), verbo([induce]), complemento([liver, cytochrome, 'P450', '(', 'CYP)', enzymes, 'CYP1A2,', 2, 'B6', and, 3, 'A4/5', using, cultured, primary, human, hepatocytes, following, once, daily, treatment, for, 3, days])].
[sujeto([3, -, 'INDS', potently]), verbo([induced]), complemento(['CYP1A2', mRNA, and, enzyme, activity, in, a, 'dose-dependent', manner, but, did, not, induce, 'CYP2B6', or, 3, 'A4'])].
[sujeto(['At', 100, 'μM,', a, concentration, observed, in, humans, under, uremic, 'conditions,', 3, -, 'INDS']), verbo([increased]), complemento(['CYP1A2', mRNA, and, activity, by, 93, '%', and, 292, '%', respectively, when, compared, with, prototypical, inducer, omeprazole])].
[sujeto(['However,', 3, -, 'IAA', did, not]), verbo([induce]), complemento(['CYP1A2,', 2, 'B6', or, 3, 'A4'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, uremic, 'toxin,', 3, -, 'INDS,', is, a, potent, 'CYP1A2', inducer, and, lends, valuable, mechanistic, basis, for, how, kidney, disease, can, affect, hepatic, metabolism])].
[sujeto(['Accidental', or, intentional, exposures, to, 'parathion,', an, organophosphorus, '(', 'OP)', 'pesticide,', can]), verbo([cause]), complemento([severe, poisoning, in, humans])].
[sujeto(['We']), verbo([have]), complemento([been, investigating, inhibitors, of, 'CYP-mediated', bioactivation, of, 'OPs', as, a, method, of, preventing, or, reversing, progressive, parathion, toxicity])].
[sujeto(['It', is, well]), verbo([recognized]), complemento([that, 'NADPH-cytochrome', 'P450', 'reductase,', an, enzyme, required, for, the, transfer, of, electrons, to, 'CYPs,', mediates, chemical, redox, cycling])].
[sujeto(['Menadione']), verbo([has]), complemento([relatively, low, toxicity, and, is, approved, by, the, 'Food', and, 'Drug', 'Administration', for, other, indications])].
[sujeto(['Tamoxifen']), verbo([requires]), complemento([enzymatic, activation, by, cytochrome, 'P450', '(', 'CYP)', enzymes, for, the, formation, of, active, metabolites, 4, -, hydroxytamoxifen, and, endoxifen])].
[sujeto(['As', compared, with, the, parent, 'drug,', both, metabolites]), verbo([have]), complemento([an, approximately, 100, -, fold, greater, affinity, for, the, estrogen, receptor, and, the, ability, to, inhibit, cell, proliferation])].
[sujeto(['The', polymorphic, 'CYP2D6', is, the, key, enzyme, in, this, 'biotransformation,', and, recent, 'mechanistic,', 'pharmacologic,', and, clinical, evidence]), verbo([suggests]), complemento([that, genetic, variants, and, drug, interaction, by, 'CYP2D6', inhibitors, influence, the, plasma, concentrations, of, active, tamoxifen, metabolites, and, the, outcomes, of, 'tamoxifen-treated', patients])].
[sujeto(['In', 'particular,', nonfunctional, '(', poor, 'metabolizer)', and, severely, impaired, '(', intermediate, 'metabolizer)', 'CYP2D6', alleles, are]), verbo([associated]), complemento([with, higher, recurrence, rates])].
[sujeto(['The', expression, of, small, intestinal, cytochromes, 'P450', '(', 'P450s)']), verbo([has]), complemento([not, been, systematically, measured, in, cynomolgus, 'monkeys,', which, are, widely, used, in, preclinical, drug, studies, to, predict, pharmacokinetics, and, toxicity, in, 'humans:', 'therefore,', 'P450', content, of, small, intestine, was, quantified, in, 35, cynomolgus, monkeys, by, immunoblotting, using, 11, selective, antibodies])].
[sujeto(['These', findings, should, help, to]), verbo([increase]), complemento([the, understanding, of, drug, 'metabolism,', especially, the, 'first-pass', 'effect,', in, cynomolgus, monkey, small, intestines])].
[sujeto(['Sulfaphenazole', strongly]), verbo([inhibits]), complemento(['DFOH', in, human, liver, 'microsomes,', but, does, not, effectively, inhibit, 'DFOH', in, monkey, liver, and, intestinal, microsomes])].
[sujeto(['On', the, other, 'hand,', cynomolgus, 'CYP2C76', orthologue, is, not]), verbo([expressed]), complemento([in, humans, and, shows, 70, -, 72, '%', identity, in, amino, acid, sequences, of, human, 'CYP2C', subfamilies])].
[sujeto(['Despite', their, importance, in, drug, 'metabolism,', the, content, of, each, cytochrome, 'P450', '(', 'P450)', enzyme]), verbo([has]), complemento([not, been, systematically, determined, in, cynomolgus, monkey, livers])].
[sujeto(['No', apparent, sex, differences, were]), verbo([found]), complemento([for, any, 'P450'])].
[sujeto(['The', results, presented, in, this, study]), verbo([provide]), complemento([useful, information, for, drug, metabolism, studies, using, cynomolgus, monkeys])].
[sujeto(['Some', of, the, 'P450', enzymes]), verbo([have]), complemento([been, characterized, in, the, pig, regarding, substrate, 'specificity,', inhibition, and, regulation])].
[sujeto(['Some', of, the, porcine, enzymes]), verbo([have]), complemento([been, sequenced, i])].
[sujeto(['Until', now, chemical, inhibitors]), verbo([have]), complemento([been, 'used,', but, they, are, rarely, 100, '%', specific])].
[sujeto(['Anti-human', inhibitory, antibodies]), verbo([have]), complemento([also, been, 'used,', but, they, may, not, recognize, the, porcine, enzyme, and, therefore, will, not, inhibit, the, reaction])].
[sujeto(['From', what, is, known, about, the, porcine, 'P450,', it, can, be, concluded, that, the, pig, seems, to, be, a, good, test, species, if, 'CYP1A,', 'CYP2A', or, 'CYP3A', are]), verbo([involved]), complemento([in, the, metabolism, of, the, test, 'compound,', depending, on, the, contribution, of, other, enzymes, in, competing, pathways])].
[sujeto(['In', this, 'study,', the, human, hepatic, 'CYPs']), verbo([involved]), complemento([in, 'FP', dealkylation, were, identified, using, recombinant, 'CYPs', and, human, liver, microsomes, '(', 'HLM)'])].
[sujeto(['The', in, vivo, studies]), verbo([suggested]), complemento([that, 'CYP2D6', is, not, crucial, to, the, 'N-dealkylation', but, to, another, metabolic, 'step,', most, probably, to, the, ring, hydroxylation])].
[sujeto(['At', a, low, styrene, concentration, '(', 0.085, 'mM),', the, rates]), verbo([decreased]), complemento([in, the, 'order,', mouse, '(', 2.43, +, /, -, 0.29, 'nmol/(mg', of, protein])].
[sujeto(['CYP1A2,', 'CYP2B6,', 'CYP2C8,', 'CYP2E1,', and, 'CYP3A4/3A3', were]), verbo([expressed]), complemento([in, human, liver, 'microsomes,', and, 'CYP2C8', was, expressed, in, human, lung, 'microsomes,', although, the, expression, of, 'CYP2F1', and, 'CYP4B1', could, not, be, investigated])].
[sujeto(['We', investigated, the, impact, of, candidate, genetic, variations, on, cholesterol, response, to, 'PSs', in, a, trial, that]), verbo([recruited]), complemento([individuals, with, high, or, low, endogenous, cholesterol, 'synthesis,', estimated, by, lathosterol, to, cholesterol, '(', 'L:C)', ratio])].
[sujeto(['Low-density', lipoprotein, '(', 'LDL)', cholesterol, lowering, in, response, to, 'PSs', was]), verbo([associated]), complemento([with, 'individuals\'', genotypes])].
[sujeto(['Cholesterol', 7, 'alpha-hydroxylase', '(', 'CYP7A1-rs3808607)', 'T/T', homozygotes, showed, no, 'LDL', cholesterol, lowering, '(', mean, ±, 'SEM:', -, 0.05, ±, 0.07, 'mmol/L,', 'P', =, 0.9999, ',', n, =, 20, ')', ',', whereas, the, presence, of, the, 'G-allele']), verbo([associated]), complemento([with, 'LDL', cholesterol, response, in, a, 'dose-dependent', fashion, '(', mean, ±, 'SEM', 'G/T:', -, 0.22, ±, 0.06, 'mmol/L,', 'P', =, 0.0006, ',', n, =, 35, ;, 'G/G:', -, 0.46, ±, 0.12, 'mmol/L,', 'P', =, 0.0009, ',', n, =, 8, ')'])].
[sujeto(['Similarly,', 'APOE', ɛ3, carriers, '(', mean, ±, 'SEM:', -, 0.13, ±, 0.05, 'mmol/L,', 'P', =, 0.037, ',', n, =, 40, ')']), verbo([responded]), complemento([less, than, 'APOE', ɛ4, carriers, '(', mean, ±, 'SEM:', -, 0.31, ±, 0.07, 'mmol/L,', 'P', &, 'lt;', 0.0001, ',', n, =, 23, ')'])].
[sujeto(['Moreover,', genoset, 'CYP7A1-rs3808607', 'T/T/APOE', ɛ3, was]), verbo([associated]), complemento([with, nonresponsiveness, '(', mean, ±, 'SEM:', +, 0.09, ±, 0.08, 'mmol/L,', 'P', =, 0.9999, ',', n, =, 14, ')'])].
[sujeto([rs5882, in, cholesteryl, ester, transfer, protein, '(', 'CETP)', and, rs4148217, in, 'ATP-binding', cassette, subfamily, 'G', member, 8, '(', 'ABCG8)', did, not]), verbo([associate]), complemento([with, 'LDL', cholesterol, lowering])].
[sujeto(['Cholesterol', absorption]), verbo([decreased]), complemento([as, a, result, of, 'PS', 'consumption,', but, this, decrease, was, not, related, to, circulating, 'LDL', cholesterol, 'concentrations,', cholesterol, synthesis, 'phenotype,', or, genotypes])].
[sujeto(['CYP7A1-rs3808607', and, 'APOE', isoform, are]), verbo([associated]), complemento([with, the, extent, of, reduction, in, circulating, 'LDL', cholesterol, in, response, to, 'PS', consumption, and, could, serve, as, potential, predictive, genetic, markers, to, identify, individuals, who, would, derive, maximum, 'LDL', cholesterol, lowering, with, 'PS', consumption])].
[sujeto(['In', female, 'mice,', 'Etv5', was, previously, shown, to, be]), verbo([expressed]), complemento([in, the, mouse, ovary])].
[sujeto(['Adult', 'Etv5-/-', female, mice, show]), verbo([decreased]), complemento([ovulation, and, no, interest, in, mating, even, after, gonadotrophin, treatment])].
[sujeto(['Injection', of, 17, 'β-estradiol', to, 'gonadotrophin-treated', 'Etv5-/-', mice, significantly]), verbo([increased]), complemento(['ovulation,', mating, and, fertilization, rates])].
[sujeto(['However,', 2, -, cell, embryos, of, 'Etv5-/-', females, show, compromised, 'development,']), verbo([suggesting]), complemento([a, role, for, 'Etv5', in, the, developmental, competence, of, embryos])].
[sujeto(['Collectively,', our, results]), verbo([suggest]), complemento([that, 'Etv5', is, important, for, the, developmental, competence, of, germ, cells, and, the, regulation, of, responses, to, steroid, hormones, in, female, mice])].
[sujeto(['Using', 'ddPCR,', differentially]), verbo([expressed]), complemento([bands, '(', n, =, 282, ')', were, excised, from, gels, and, 107, were, 'sequenced,', yielding, 84, unique, porcine, follicle, expressed, sequence, tags])].
[sujeto(['Expression', differences, between, lines, for, two, 'genes,', follistatin, and]), verbo([nuclear]), complemento([receptor, subfamily, 4, ',', group, 'A,', member, 1, ',', were, confirmed, using, 'Northern', hybridization])].
[sujeto(['These', results, demonstrate, changes, in, follicular, gene, expression, as, the, result, of, 'long-term', selection, for]), verbo([enhanced]), complemento([reproduction])].
[sujeto([',', quantitative, trait, 'loci),', or, more, 'likely,', transcriptional, changes, in, other, genes, that]), verbo([interact]), complemento([with, reproductive, 'QTL'])].
[sujeto(['Using', differential, display, polymerase, chain, 'reaction,', early, growth, response, gene, alpha, '(', 'EGR', 'alpha)', was, first, isolated, as, a, 291, -, base, pair, 3, '\'', -, cDNA, 'clone,', which, was, highly]), verbo([expressed]), complemento([in, the, 'androgen-independent', prostate, carcinoma, cell, lines, 'PC3', and, 'DU145,', as, compared, with, the, 'androgen-responsive', prostate, carcinoma, cell, line, 'LNCaP'])].
[sujeto(['Full', length, cloning, of, the, 'EGR', alpha, coding, region, revealed, that, 'EGR', alpha, was, a, new, member, of, an, important, subfamily, of]), verbo([nuclear]), complemento([zinc, finger, transcription, factors, '(', others, members, e])].
[sujeto(['Moreover,', it, was, observed, that, 'EGR', 'alpha,', as, with, most, 'Sp1', subfamily, 'members,', was]), verbo([conserved]), complemento([between, mammalian, species, ranging, from, human, to, rabbit])].
[sujeto(['Two', hormones, important, for, prostate, development, and, differentiation, were]), verbo([found]), complemento([to, be, potent, regulators, of, 'EGR', alpha, mRNA, expression])].
[sujeto(['Androgens', were, observed, to]), verbo([induce]), complemento([a, 'down-regulation', of, 'EGR', alpha, mRNA, expression, '(', 70, '%', in, 72, 'h),', while, epidermal, growth, factor, induced, a, rapid, transient, 'up-regulation', '(', 6, -, fold, in, 100, 'min)'])].
[sujeto(['The', 'up-regulation', was, controlled, at, the, transcriptional, level, and, effectively, blocked, by, staurosporine, '(', which]), verbo([suggests]), complemento([the, involvement, of, the, protein, kinase, 'C', 'pathway)'])].
[sujeto(['Functional', analysis, demonstrated, that, 'EGR', alpha, could]), verbo([bind]), complemento(['to,', and, stimulate, transcription, 'from,', a, basic, transcription, element, '(', 'BTE)', consensus, sequence, on, 'DNA', '(', 'BTE', is, a, 'transcription-modulating', sequence, in, the, promoter, region, of, some, cytochrome, 'P450', family, 'members)'])].
[sujeto(['Furthermore,', in, 'stage-synchronized', prostate, 'cells,', 'EGR', alpha, mRNA, was, highly]), verbo([expressed]), complemento([in, the, early, 'G1', phase, of, the, cell, 'cycle,', similar, to, 'c-fos', mRNA, expression])].
[sujeto(['We', genotyped, 12, single, nucleotide, polymorphisms, in, genes, '(', 'CYP2C9,', 'VKORC1,', 'CYP4F2,', 'GGCX,', 'EPHX1,', 'CALU)']), verbo([associated]), complemento([with, altered, warfarin, dose, requirements, and, tested, their, associations, with, international, normalized, ratio, variability, '(', 'INRVAR)', and, percent, time, in, therapeutic, range, in, 'European-Americans', and, 'African-Americans'])].
[sujeto(['One', allele, copy, of, rs2108622, in, 'CYP4F2', was]), verbo([associated]), complemento([with, a, 15, '%', '[', 95, '%', confidence, interval, '(', 'CI):', 1, -, 26, ',', 'P=0'])].
[sujeto([3, ']']), verbo([decrease]), complemento([in, the, median, 'INRVAR', in, 'European-Americans'])].
[sujeto(['In', 'African-Americans,', 'GGCX', variants, rs11676382, and, rs699664, were]), verbo([associated]), complemento([with, 4.16, -, fold, '(', 95, '%', 'CI:', 1.45, -, 11.97, ',', 'P=0'])].
[sujeto([2, ')', changes, in, the, median, 'INRVAR', per, variant, allele, 'copy,', 'respectively;', rs11676382, was, also, significantly]), verbo([associated]), complemento([with, a, 23.19, '%', '(', 95, '%', 'CI:', 5.89, -, 40.48, ',', 'P=0'])].
[sujeto([1, ')']), verbo([decrease]), complemento([in, time, in, therapeutic, range])].
[sujeto([taraxacifolia]), verbo([have]), complemento([been, 'suggested,', but, little, is, known, about, putative, molecular, mechanisms, or, potential, for, 'herb-drug', interactions, through, inhibition, or, induction, of, 'drug-metabolizing', enzymes])].
[sujeto(['Antiproliferative', and, apoptotic, effects, were, evaluated, using, the, 'MTT', '[', 3, -, '(', 4, ',', 5, -, 'dimethylthiazol-2-yl)-2,5-diphenyltetrazolium', 'bromide]', assay, and, flow, 'cytometry,', while, 'examining,', in, 'parallel,', the, genes]), verbo([regulating]), complemento([apoptosis, and, cell, cycle, in, this, cell, culture, model])].
[sujeto(['Cell', cycle, analysis, showed, a, 'G0-G1', cell, cycle]), verbo([arrest]), complemento([in, 'WHC01', cells, in, the, presence, of, 'L'])].
[sujeto([taraxacifolia, extract]), verbo([caused]), complemento([reversible, and, 'time-dependent', inhibition, of, the, recombinant, 'CYP1A2,', 'CYP2C9,', and, 'CYP2C19'])].
[sujeto(['This', study]), verbo([provides]), complemento([new, insights, on, possible, anticancer, effects, of, 'L'])].
[sujeto(['Further', mechanistic, studies, expanding, on, these, observations, would, be, timely, and, contribute, to, the, field, of, global, precision, medicine, that]), verbo([requires]), complemento([solid, understanding, of, drug, and, herb, molecular, mechanisms, of, action, and, 'drug-herb', interaction, 'potentials,', given, the, worldwide, use, of, medicinal, plants])].
[sujeto(['The', incidence, of, cardiovascular, diseases, '(', 'CVDs)', in, 'African', populations, residing, in, the, 'African', continent, is, on, the, rise, fueled, by, both, a, steady]), verbo([increase]), complemento([in, 'CVD', risk, factors, and, comorbidities, such, as, human, immunodeficiency, 'virus/acquired', immune, deficiency, syndrome, '(', 'HIV/AIDS),', 'tuberculosis,', and, parasitic, diseases, such, as, bilharzia])].
[sujeto(['We']), verbo([report]), complemento([on, qualitative, and, quantitative, differences, in, the, distribution, of, genetic, variants, that, affect, efficacy, and, toxicity, of, rosuvastatin])].
[sujeto(['Finally,', we, advocate, for, extensive, pharmacogenetic, studies, in, 'African', populations, that, take, into, account, the, genetic, diversity, of, 'intra-African', ethnic, groups, and, the, genetic, differences, between, 'African', populations, and, other, global, 'populations,', with, a, collaborative, and, collective, aim, to]), verbo([provide]), complemento([effective, and, safe, use, of, rosuvastatin, in, management, of, 'CVD', in, 'Africa'])].
[sujeto(['In', the, search, to]), verbo([prevent]), complemento([hemorrhages, associated, with, anticoagulant, 'therapy,', a, major, goal, is, to, validate, predictors, of, sensitivity, to, warfarin])].
[sujeto(['However,', previous, studies, in, 'Colombia', that, included, polymorphisms, in, the, 'VKORC1', and, 'CYP2C9', genes, as, predictors]), verbo([reported]), complemento([different, algorithm, performances, to, explain, dose, 'variations,', and, did, not, evaluate, the, prediction, of, sensitivity, to, warfarin])].
[sujeto(['Polymorphisms', in, the, 'CYP2C9', and, 'CYP2C19', genes]), verbo([confer]), complemento([potential, risk, for, specific, adverse, drug, reactions, and, therapeutic, effect, failure])].
[sujeto(['This', study, was, aimed, to, describe, the, distribution, of, 'CYP2C9', and, 'CYP2C19', alleles, and, haplotypes, in, four, 'Mestizo', populations, from, 'Western', 'Mexico', and, their, comparison, with, the]), verbo([reported]), complemento([data, from, other, ethnic, groups])].
[sujeto(['Our', findings]), verbo([increase]), complemento([the, evidence, for, genetic, variability, at, relevant, pharmacogenetic, loci, and, could, be, useful, in, association, studies, involving, drugs, that, are, substrates, for, 'CYP2C', enzymes, in, the, 'Western', 'Mexican', population])].
[sujeto(['CYP4F2', 'TT,', 'CT', and, 'T', carriers]), verbo([required]), complemento([a, 18, '%', '(', 7.0, '%', -, 30.0, '%', ')', ',', 7, '%', '(', 7.0, '%', -, 7.0, '%', ')', and, 11, '%', '(', 7.0, '%', -, 14.0, '%', ')', higher, 'MDWD,', 'respectively,', than, 'CYP4F2', 'CC', carriers])].
[sujeto(['VKORC1', 1173, 'CC,', 'CT', and, 'C', carriers]), verbo([required]), complemento([a, 98, '%', '(', 78.0, '%', -, 118.0, '%', ')', ',', 49, '%', '(', 37.0, '%', -, 62.0, '%', ')', and, 56, '%', '(', 44.0, '%', -, 67.0, '%', ')', higher, 'MDWD,', 'respectively,', than, 'VKORC1', 1173, 'TT', carriers])].
[sujeto(['This', 'meta-analysis', is, the, first, to]), verbo([report]), complemento([the, relationship, between, genotypes, and, 'MDWD', among, 'Han-Chinese', patients])].
[sujeto(['Warfarin', oral, anticoagulant, therapy, '(', 'OAT)']), verbo([requires]), complemento([regular, and, frequent, drug, adjustment, monitored, by, 'INR'])].
[sujeto(['HPLC', assessment, of, 'warfarin/enantiomers', was]), verbo([suggested]), complemento([as, a, valid, 'monitoring-tool', along, with, 'INR,', but, definite, results, are, still, lacking])].
[sujeto([133, 'OAT', patients, were]), verbo([recruited]), complemento([and, assessed, for, 'warfarin/3\'-hydroxywarfarin', serum, levels, '(', 'HPLC),', 'INR,', and, 'VKORC1', and, 'CYP2C9', genotypes])].
[sujeto(['A', subgroup, of, 52, patients, were, monitored, in, detail, '(', 5, consecutive, 'controls;', 'c0-c4)', till, the]), verbo([target]), complemento(['INR', was, reached])].
[sujeto(['Conversely,', warfarin, weekly, dosage, better, correlates, with, warfarin, than, with, 3, '\'', -, hydroxywarfarin, '(', r2, =, 0.0975, and, r2, =, 0.0381, 'respectively),', but, considering, together, warfarin, plus, 3, '\'', -, hydroxywarfarin, the, correlation, strongly]), verbo([increased]), complemento(['(', r2, =, 0.1114, ;, 'p&lt;0'])].
[sujeto(['The', pharmacogenetics, studies, confirmed, that, patients, carrying, the, 'VKORC1', 'variant-allele']), verbo([required]), complemento([lower, warfarin, maintenance, dosage, and, that, the, combination, of, 'VKORC1', and, 'CYP2C9', yielded, a, warfarin, responsive, index, '(', 'WRI)', inversely, related, to, the, number, variant, alleles])].
[sujeto(['Our', results, overall]), verbo([suggest]), complemento([that, 3, '\'', -, hydroxywarfarin, monitoring, could, be, of, great, advantage, in, 'INR', monitoring, respect, to, classical, warfarin, assessment, showing, significant, contribution, also, in, multivariate, analysis])].
[sujeto(['Therefore,', additional, active, metabolites, should, be]), verbo([recognized]), complemento([and, investigated, as, novel, useful, indicators])].
[sujeto(['Several', studies]), verbo([have]), complemento([demonstrated, an, association, between, body, mass, index, '(', 'BMI)', and, warfarin, therapeutic, 'dose,', but, none, evaluated, the, association, of, 'BMI', with, the, clinically, important, outcome, of, major, bleeding, in, a, community, setting])].
[sujeto(['In', exploratory, 'analyses,', we, evaluated, the, interaction, between, genetic, variants, potentially]), verbo([associated]), complemento([with, warfarin, bleeding, '(', 'CYP2C9,', 'VKORC1,', and, 'CYP4F2)', and, obesity, on, the, risk, of, major, bleeding])].
[sujeto([49, ')', ',']), verbo([suggesting]), complemento([a, protective, effect, of, obesity, on, the, risk, of, major, bleeding, among, those, wild, type, for, 'CYP4F2*3,', but, not, among, variants])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, 'BMI', is, an, important, clinical, factor, in, assessing, and, managing, warfarin, therapy])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, a, 'high-fat', and, 'high-cholesterol', '(', 'HFHC)', diet, for, 12, weeks, induced, 'non-alcoholic', steatohepatitis, '(', 'NASH)', and, influenced, major, 'CYP', subtype, gene, expression, levels, and, activities, in, a, mouse, model])].
[sujeto(['The', plasma, 'glucose-lowering', effects, of, tolbutamide, were, attenuated, in, the, 'HFHC', group, even, though, 'luciferin-H', hydroxylation, activity, was]), verbo([suppressed]), complemento([in, this, group])].
[sujeto(['The', reason, for, this, discrepancy, was, attributed, to, the, mRNA, expression, levels, of, 'Cyp2c44', being, lower, and, those, of, 'Cyp2c29', and, 'Cyp2c66,', which, are]), verbo([involved]), complemento([in, the, metabolism, of, 'tolbutamide,', being, higher, in, the, 'HFHC', group, than, in, the, 'Control', group])].
[sujeto(['A', total, of, 552, warfarin, treated, patients, who]), verbo([maintained]), complemento([on, a, target, 'INR', level, of, 2.0, -, 3.5, for, at, least, three, consecutive, intervals, were, enrolled, from, those, attended, our, anticoagulation, clinics])].
[sujeto(['Those', who, were, carriers, of, 'CYP2C9', 'one-variant', haplotypes, '(', *, 1, /, *, 2, or, *, 1, /, *, 3, ')', were, also]), verbo([found]), complemento([to, be, associated, with, the, higher, risk, of, bleeding, events])].
[sujeto(['Compared', to, reference, group, '(', *, 1, /, *, 1, ')', ',', the, odds, of, bleeding]), verbo([increased]), complemento([for, carriers, of, one, variant, allele, '(', *, 1, /, *, 2, or, *, 1, /, *, 3, ')', '(', adjusted, 'OR:', 1.75, ',', 95, '%', 'CI:', 1.03, to, 2.97, ',', 'P=0'])].
[sujeto(['Variant', 'VKORC1,', 'Factor', 'VII,', and, 'EPHX1', genotypes, were, not, significantly]), verbo([associated]), complemento([with, the, risk, of, bleeding, events])].
[sujeto(['The', 'SNP', 'C609T', within, 'NQO1', and, haplotypes, of, 'CYP2C9', '(', 1, *, 2, or, 1, *, 3, ')', are, independently]), verbo([associated]), complemento([to, bleeding, complications, of, warfarin, at, normal, 'INR'])].
[sujeto(['Further', studies, are]), verbo([required]), complemento([to, confirm, such, associations, in, diverse, racial, and, ethnic, populations])].
[sujeto(['No', studies]), verbo([have]), complemento([reported, 'Gb', pharmacokinetics, in, children])].
[sujeto(['Patients', carrying, these, allelic, variants, had, a, clearance]), verbo([decreased]), complemento([by, 45, &, 'nbsp;%'])].
[sujeto(['We']), verbo([report]), complemento([on, metabolite, exposure, from, a, clinical, excretion, 'balance,', on, in, vitro, studies, performed, to, determine, the, likelihood, of, a, 'metabolite-dependent', 'drug-drug', interaction, '(', 'DDI)', and, on, a, clinical, warfarin, 'DDI', study])].
[sujeto(['Clinically,', 'S-warfarin', 'AUC']), verbo([increased]), complemento([on, average, 1.4, -, fold, '(', 95, '%', confidence, 'interval:', 1.22, to, 1.5, ')', and, 2.4, -, fold, '(', 95, '%', confidence, 'interval:', 2.11, to, 2.64, ')', after, 100, mg, '(', n, =, 13, ')', and, 400, mg, 'AZD1981', '(', n, =, 11, ')', administration, respectively])].
[sujeto(['N-deacetylated', 'AZD1981', is, added, to, the, small, list, of, drug, metabolites]), verbo([reported]), complemento([as, sole, contributors, to, clinical, 'drug-drug', 'interactions,', with, weak, time, dependent, inhibition, exacerbated, by, efficient, hepatic, uptake, being, the, cause])].
[sujeto(['Throughout', our, 'NAMPT', inhibitor, 'program,', we]), verbo([found]), complemento([that, exposed, pyridines, or, related, heterocyclic, systems, in, the, 'left-hand', portion, of, the, inhibitors, are, necessary, pharmacophores, for, potent, cellular, 'NAMPT', inhibition])].
[sujeto(['However,', when, combined, with, a, benzyl, group, in, the, center, of, the, 'inhibitors,', such, 'pyridine-like', moieties, also]), verbo([led]), complemento([to, consistent, and, potent, inhibition, of, 'CYP2C9'])].
[sujeto(['In', an, attempt, to, reduce, 'CYP2C9', 'inhibition,', a, parallel, synthesis, approach, was, used, to, identify, central, benzyl, group, replacements, with]), verbo([increased]), complemento(['Fsp3'])].
[sujeto(['A', spirocyclic, central, motif, was, thus, discovered, that, was, combined, with, 'left-hand', pyridines, '(', or, 'pyridine-like', 'systems)', to]), verbo([provide]), complemento([cellularly, potent, 'NAMPT', inhibitors, with, minimal, 'CYP2C9', inhibition])].
[sujeto(['Further', optimization, of, potency, and, 'ADME', properties]), verbo([led]), complemento([to, the, discovery, of, compound, 68, ',', a, highly, potent, 'NAMPT', inhibitor, with, outstanding, efficacy, in, a, mouse, tumor, xenograft, model, and, lacking, measurable, 'CYP2C9', inhibition, at, the, concentrations, tested])].
[sujeto(['Compared', to, individuals, with, the, wild, type, 'allele,', 'CYP2C9*1,', carriers, of, the, common, *, 3, variant]), verbo([have]), complemento([significantly, impaired, 'CYP2C9', metabolism])].
[sujeto(['Plasma', clearance, of, 'S-warfarin,', but, not, 'R-warfarin,']), verbo([decreased]), complemento(['multi-exponentially', and, in, a, 'CYP2C9', 'gene-dependent', 'manner:', 56, ',', 70, and, 75, '%', for, 'CYP2C9*1/*3,', 'CYP2C9*2/*3,', 'CYP2C9*3/*3', 'genotypes,', 'respectively,', compared, to, 'CYP2C9*1/*1,', resulting, in, pronounced, differences, in, the, 'S:R', ratio, that, identified, 'warfarin-sensitive', genotypes])].
[sujeto(['The', 10, -, hydroxywarfarin, 'metabolites,', whose, detailed, pharmacokinetics, are]), verbo([reported]), complemento([for, the, first, 'time,', exhibit, a, prolonged, 'half-life', with, no, evidence, of, renal, excretion, and, display, elimination, 'rate-limited', kinetics])].
[sujeto(['Green', tea, is, a, traditional, beverage, that]), verbo([has]), complemento([been, enjoyed, by, the, 'Japanese', to, this, day])].
[sujeto(['Recently,', there]), verbo([has]), complemento([been, an, increase, in, the, consumption, of, green, tea, beverage, having, high, concentrations, of, 'catechins,', such, as, '(', -, ')', -, 'epigallocatechin-3-O-gallate', '(', 'EGCG)'])].
[sujeto(['Many', people, tend, to, ingest, large, amounts, of, catechins, through, the, frequent, consumption, of, green, tea, 'beverage,', and, this, dietary, habit, may]), verbo([lead]), complemento([to, unwanted, interactions, between, the, catechins, in, green, tea, and, medicinal, drug])].
[sujeto(['From', a, comparison, of, the, fifty, percent, inhibitory, concentration, '(', 'IC50)', values, of, the, eight, green, tea, 'catechins,', it, was]), verbo([found]), complemento([that, 'non-gallated', catechins, did, not, inhibit, 'CYPs,', whereas, gallated, catechins, inhibited, all, 'CYPs', except, 'CYP2D6'])].
[sujeto(['Among', 'them,', 'CYP2C9', was, most, strongly]), verbo([inhibited]), complemento([by, '(', -, ')', -, 'catechin-3-O-gallate', '(', 'CG)', '(', 7.6, 'µM),', and, 'CYP1A2', was, most, strongly, inhibited, by, 'EGCG', '(', 8.93, 'µM)'])].
[sujeto(['The', present, study, is, the, first, to]), verbo([report]), complemento([the, inhibitory, effect, of, 'CG', on, 'CYP2C9'])].
[sujeto(['Previous']), verbo([reports]), complemento([had, predicted, that, plasma, 'EGCG', concentration, reached, 7.4, µM, after, ingesting, green, tea, having, high, concentrations, of, catechins])].
[sujeto(['Warfarin', dosage, estimation, using, the, pharmacogenetic, algorithms]), verbo([has]), complemento([been, shown, to, improve, the, quality, of, anticoagulation, control, in, patients, with, atrial, fibrillation])].
[sujeto(['The', quality, of, anticoagulation, within, the, first, 3, months, since, surgery, was]), verbo([expressed]), complemento([as, the, time, of, international, normalized, ratio, '(', 'INR)', in, the, therapeutic, range, '(', 'TTR)'])].
[sujeto(['Coronary', artery, disease, '(', n, =, 84, ',', 42, '%', ')', and, previous, stroke, '(', n, =, 5, ',', 2.5, '%', ')', predicted, higher, 'TTR,', while, possession, of, 'CYP2C9*2', variant, allele, '(', n, =, 49, ',', 25, '%', ')', was]), verbo([associated]), complemento([with, lower, 'TTR', '(', 'P', =, 0.01, ')'])].
[sujeto([-, 1639, 'A,', 'CYP2C9*2', and, *, 3, variants, were, independently]), verbo([associated]), complemento([with, actual, warfarin, dose, '(', 'P', &, 'lt;', 0.0001, ')'])].
[sujeto(['Possession', of, 'CYP2C9*2', 'and/or', 'CYP2C9*3', allele, variants, is]), verbo([associated]), complemento([with, lower, 'TTR', values, and, warfarin, dose, variations, in, 'AVR', 'patients,', the, latter, affected, also, by, 'VKORC1', c])].
[sujeto(['The', plasma, 'S-warfarin', '(', 'Cp(S))', time, courses, following, the, 'genotype-based', dosing, algorithms, simulated, using, the, 'PPK', estimates, showed, 'African', 'Americans', with, 'CYP2C9*1/*1', and, any, of, the, 'VKORC1', genotypes, would]), verbo([have]), complemento([an, average, 'Cp(S)', at, steady, state, 1.5, -, 1.8, times, higher, than, in, 'Asians', and, whites])].
[sujeto(['The', results]), verbo([have]), complemento([been, included, in, the, software, application, &, 'quot;Lekgen&quot;', that, we, developed, for, the, interpretation, of, pharmacogenetic, testing])].
[sujeto(['To', achieve, efficient, 'CYP-oxidation', and, prodrug, 'bioconversion,', 1, ',', 3, -, cyclic, propyl, ester, of, phosphate, was, designed, to]), verbo([have]), complemento([a, 'C4-aryl', substituent, and, synthesized, using, 'phosphorus(III)', chemistry])].
[sujeto(['The', free, phosphate, was, further, dephosphorylated, by, microsomal, 'phosphatases,']), verbo([releasing]), complemento([the, parent, molecule, with, a, free, hydroxyl, group])].
[sujeto(['This', method, was, suitable, for, use, in, pharmacokinetic, studies, in, human, 'volunteers,', and]), verbo([provides]), complemento([a, useful, tool, for, measuring, 'CYP2C19', activity])].
[sujeto(['In', hepatic, microsomes, of, cynomolgus, 'monkeys,', both, antibodies]), verbo([recognized]), complemento([two, proteins, showing, different, mobilities, on, 'SDS-PAGE', '(', 50, and, 53, 'kDa)'])].
[sujeto(['Anti-P450', 2, 'C9', antibody]), verbo([inhibited]), complemento([the, activity, of, 'S-mephenytoin', 4, '\'', -, 'hydroxylase,', but, not, the, activities, of, 'R-mephenytoin', 4, '\'', -, hydroxylase, and, 'R-', and, 'S-mephenytoin', 'N-demethylases', in, liver, microsomes, from, cynomolgus, monkeys])].
[sujeto(['From', these, lines, of, evidence, we, conclude, that, 'P450', 'CMLd', is, classified, into, the, 'P450', 2, 'C', subfamily, and]), verbo([acts]), complemento([as, one, of, the, 'S-mephenytoin', 4, '\'', -, hydroxylases, in, hepatic, microsomes, of, cynomolgus, monkeys])].
[sujeto(['In', this, 'study,', we, aimed, to, investigate, the, association, between, genetic, polymorphisms, in, 'CYP2C19,', 'CYP3A4', and, 'MDR1', and, pharmacokinetics, of, pantoprazole, and, therapeutic, outcomes, in, patients, with, either, 'Helicobacter', pylori]), verbo([associated]), complemento(['[', 'H'])].
[sujeto(['Despite', the, undoubted, benefit, of, proton, pump, inhibitors, '(', 'PPIs),', they]), verbo([have]), complemento([several, 'shortcomings,', such, as, a, slow, onset, of, action, and, a, remarkable, 'inter-individual', 'variability,', that, limit, the, complete, success, of, these, drugs])].
[sujeto(['Recently,', a, new, 'PPI,', 'ilaprazole,']), verbo([has]), complemento([been, developed, and, used, in, 'GERD', patients])].
[sujeto(['The', present, review]), verbo([provides]), complemento([an, update, on, the, following, 'points:', current, knowledge, of, 'GERD', 'mechanisms;', limitations, of, actual, 'therapies;', pharmacokinetic, profile, and, metabolism, of, 'ilaprazole;', initial, studies, on, the, therapeutic, efficacy, of, ilaprazole, in, 'GERD'])].
[sujeto(['Compared', with, all, other, approved, 'PPIs,', ilaprazole]), verbo([has]), complemento([shown, an, extended, plasma, 'half-life,', a, metabolism, not, significantly, influenced, by, 'CYP2C19', genetic, polymorphism, and, similar, safety])].
[sujeto(['The', results, of, pharmacokinetic, analysis, showed, that, the, oral, bioavailability, of, clopidogrel, thiolactone, converted, from, 'PLD-301', was, 4, -, to, 5, -, fold, higher, than, that, of, the, one, converted, from, 'clopidogrel,']), verbo([suggesting]), complemento([that, in, comparison, with, 'clopidogrel,', lower, doses, of, 'PLD-301', could, be, used, clinically])].
[sujeto(['In', 'summary,', 'PLD-301', presents, a, potent, and, orally, bioavailable, antiplatelet, agent, that, might]), verbo([have]), complemento([some, advantages, over, 'clopidogrel,', such, as, overcoming, clopidogrel, resistance, for, 'CYP2C19-allele', 'loss-of-function', 'carriers,', and, lowering, 'dose-related', toxicity, due, to, a, much, lower, effective, dose])].
[sujeto(['Helicobacter', pylori, is, a, gastric, pathogen, that]), verbo([causes]), complemento([several, gastroduodenal, disorders, such, as, peptic, ulcer, disease, and, gastric, cancer])].
[sujeto([&, 'nbsp;', 'The', majority, of, the, clarithromycin, resistant, isolates, '(', 135, of, 165, 'subjects)']), verbo([have]), complemento(['MICs', ranging, from, 2, 'μg/mL', to, 16, 'μg/mL'])].
[sujeto([&, 'nbsp;', 'Therefore,', the, present, study]), verbo([suggests]), complemento([that, providing, susceptibility, testing, prior, to, treatment, or, alternative, screening, strategies, for, antimicrobial, resistance, is, important, for, future, clinical, practice])].
[sujeto(['Mutations', in, 'CYP2C19', cDNA, were, introduced, by, 'site-directed', 'mutagenesis,', and, the, 'CYP2C19', wild, type, '(', 'WT)', as, well, as, variants, proteins, were, subsequently]), verbo([expressed]), complemento([using, 'Escherichia', coli, cells])].
[sujeto([2, &, 'nbsp;μM)']), verbo([increased]), complemento([significantly, as, compared, to, 'CYP2C19', 'WT', '(', 123.0, &, 'nbsp;±&nbsp;19'])].
[sujeto(['These', findings]), verbo([suggested]), complemento([that, catalytic, activity, of, 'CYP2C19', was, not, affected, by, the, corresponding, amino, acid, substitutions, in, 'CYP2C19*23', 'protein;', and, the, reverse, was, true, for, 'CYP2C19*24', protein])].
[sujeto(['This', study]), verbo([provides]), complemento([evidence, that, for, 'CYP2C19-related', poor, metabolisers, prasugrel, may, be, more, effective, than, clopidogrel, to, prevent, major, adverse, cardiovascular, events, after, 'PCI', and, this, approach, could, be, 'cost-effective'])].
[sujeto(['CYP2C19', 'polymorphisms,', 'obesity,', older, 'age,', diabetes, and, 'drug-drug', interactions]), verbo([have]), complemento([been, identified, as, risk, factors, for, adverse, events, and, treatment, failure])].
[sujeto(['When', considering, the, combined, impact, of, these, 'covariates,', our, analysis, results, indicate, that, higher, maintenance, doses, are]), verbo([required]), complemento([for, 'CYP2C19', 'IMs', and, 'PMs', compared, to, 'EMs', and, that, respective, maintenance, doses, have, to, be, further, increased, for, obese, subjects, for, each, of, these, 'CYP2C19', phenotypes])].
[sujeto(['Clopidogrel', resistance, from, 'CYP2C19', polymorphism]), verbo([has]), complemento([been, associated, with, stent, thrombosis, in, patients, undergoing, percutaneous, coronary, intervention, with, 'drug-eluting', stents])].
[sujeto(['Although']), verbo([he]), complemento([was, compliant, with, his, dual, antiplatelet, 'therapy,', he, developed, stent, 'thrombosis,', which, was, confirmed, as, clopidogrel, resistance, from, homozygous, 'CYP2C19', polymorphism])].
[sujeto(['Interindividual', variability, in, drug, response, and, adverse, effects]), verbo([have]), complemento([been, described, for, proton, pump, 'inhibitors,', 'anticonvulsants,', selective, serotonin, reuptake, 'inhibitors,', tricyclic, 'antidepressants,', and, 'anti-infectives,', but, little, is, known, about, the, safety, and, efficacy, of, these, medications, in, patients, with, sickle, cell, disease, '(', 'SCD)'])].
[sujeto(['We', genotyped, the, 'CYP2C19', gene, which]), verbo([has]), complemento([been, implicated, in, the, metabolism, of, these, drugs, in, a, 'SCD', patient, cohort, to, determine, the, frequencies, of, reduced, 'function,', increased, 'function,', or, complete, 'loss-of-function', variants])].
[sujeto(['However,', the, main, challenge, to, implementing, 'genetics-guided', prescribing, practice, is]), verbo([ensuring]), complemento([concordance, between, 'CYP2C19', genotypes, and, metabolic, phenotypes, in, 'SCD', patients])].
[sujeto(['The', concomitant, use, of, 'PPIs', and, clopidogrel, in, patients, with, 'IS', may, not, be]), verbo([associated]), complemento([with, an, increased, risk, of, 'RIS,', 'MI,', or, vascular, death])].
[sujeto(['We']), verbo([report]), complemento([a, simple, method, for, fluorescence, detection, of, 'single-nucleotide', alterations, in, a, long, target, 'DNA,', which, is, based, on, the, formation, of, a, 'three-way-junction-structured', 'cholic-acid-binding', 'DNA', aptamer, by, the, hybridization, of, the, target, with, binary, 'DNA', probes])].
[sujeto(['Rare', deletions, possibly, contributing, to, genetic, predisposition, to, 'SAM', were]), verbo([found]), complemento([in, two, 'patients:', one, removed, 'EYS', associated, previously, with, 'SAM,', the, other, was, present, in, 'LARGE', associated, with, congenital, muscular, dystrophy])].
[sujeto(['We']), verbo([found]), complemento([no, common, large, 'CNVs', potentially, associated, with, 'SAM', and, no, 'CNVs', in, the, 'SLCO1B', locus])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, large, 'CNVs', do, not, play, a, substantial, role, in, the, aetiology, of, 'SAM'])].
[sujeto([pylori, infection, was, correlated, with, the, fastest]), verbo([increase]), complemento([in, intragastric, 'pH,', especially, in, the, 'OME', 'IV', infusion, group])].
[sujeto(['In', patients, with, 'NVUGIB,', 'OME', 'IV', bolus, followed, by, continuous, infusion, was, more, effective, than, 'OME', 'IV', bolus, bid, in]), verbo([maintaining]), complemento([higher, intragastric, 'pH,', regardless, of, 'CYP2C19', genetic, polymorphisms])].
[sujeto(['In', this, 'study,', benzydamine, 'N-oxygenation', and, 'N-demethylation']), verbo([mediated]), complemento([by, liver, microsomes, from, 'rats,', 'dogs,', 'monkeys,', and, humans, were, characterized, comprehensively])].
[sujeto(['Benzydamine', 'N-oxygenation', by, liver, microsomes, was, extensively]), verbo([suppressed]), complemento([by, preheating, liver, microsomes, at, 45, °, 'C', for, 5, min, or, at, 37, °, 'C', for, 5, -, 10, min, without, 'NADPH,', and, benzydamine, 'N-demethylation', was, strongly, inhibited, by, 1, -, aminbobenztriazole])].
[sujeto(['Liver', microsomal, benzydamine, 'N-oxygenation', was]), verbo([inhibited]), complemento([by, dimethyl, sulfoxide, and, 'methimazole,', whereas, 'N-demethylation', was, inhibited, by, quinidine])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, benzydamine, 'N-oxygenation', and, 'N-demethylation', are, mediated, by, 'FMO1/3', and, 'P450s,', 'respectively,', and, that, the, contribution, of, 'FMO', to, metabolic, eliminations, of, new, drug, candidates, might, be, underestimated, under, certain, experimental, conditions, suitable, for, 'P450', enzymes])].
[sujeto(['Lu', 'AA21004', was]), verbo([found]), complemento([in, vitro, to, be, oxidized, to, a, 4, -, 'hydroxy-phenyl', 'metabolite,', a, 'sulfoxide,', an, 'N-hydroxylated', 'piperazine,', and, a, benzylic, 'alcohol,', which, was, further, oxidized, to, the, corresponding, benzoic, acid, '[', 3, -, 'methyl-4-(2-piperazin-1-yl-phenysulfanyl)-benzoic', acid, '(', 'Lu', 'AA34443)]'])].
[sujeto(['The', formation, of, the, 4, -, 'hydroxy-phenyl', metabolite, was, catalyzed, by, 'CYP2D6', with, some, contribution, from, 'CYP2C9,', whereas, the, formation, of, the, sulfoxide, was]), verbo([mediated]), complemento([by, 'CYP3A4/5', and, 'CYP2A6'])].
[sujeto(['The', expression, of, 'P450s', generally]), verbo([decreased]), complemento([when, 'DMSO', was, removed, from, the, 'medium,', whereas, transporters, and, 'liver-specific', factors, were, unaffected])].
[sujeto(['The', 'P450', probe, substrates, indicate, a]), verbo([decrease]), complemento([in, 'CYP1A2,', 'CYP2B6,', 'CYP2C9,', and, 'CYP3A4', activities, in, 'HepaRG', cells, 1, day, after, removal, of, 'DMSO', from, the, medium])].
[sujeto(['Based', on, the, stable, expression, of, 'liver-specific', functions, over, a, long, period, in, 'culture,', the, relative, mRNA, content, of, 'drug-metabolizing', 'P450s,', and, metabolic, 'properties,', 'HepaRG', cells]), verbo([provide]), complemento([a, valuable, in, vitro, model, for, human, drug, metabolism, studies])].
[sujeto(['HepG2', 'cells,', a, human, hepatoma, cell, 'line,', stably]), verbo([expressing]), complemento(['NADPH-cytochrome', 'P450', reductase, '(', 'OR)', 'and/or', cytochrome, 'P450', 2, 'D6', 'wild-type', '(', 'CYP2D6-WT)', or, its, variants, '(', 'Pro34Ser,', 'Gly42Arg,', 'Arg296Cys', and, 'Ser486Thr)', were, established, in, the, present, study])].
[sujeto(['The', cultivation, of, 'HepG2', cells]), verbo([expressing]), complemento(['CYP2D6-WT', in, the, culture, medium, containing, dimethyl, sulfoxide, '(', 'DMSO,', 0.1, '%', of, final, 'concentration)', markedly, increased, the, bufuralol, '(', 'BF)', 1, '\'', '\'', -, hydroxylase, activity, compared, with, that, of, control, cells, when, cultivated, without, 'DMSO'])].
[sujeto(['A', similar, effect, was, also, observed, in, 'HepG2', cells, stably]), verbo([expressing]), complemento(['CYP2D6', and, 'OR'])].
[sujeto(['The', addition, of, hemin, in, place, of, 'DMSO', to, the, culture, medium, resulted, in, no]), verbo([increase]), complemento([in, the, enzyme, activity])].
[sujeto(['Spectrophotometric', analysis, of, reduced, carbon, 'monoxide-difference', spectra, of, 'HepG2', cells]), verbo([expressing]), complemento(['CYP2D6-WT', 'and/or', 'OR', demonstrated, that, the, addition, of, 'DMSO', increased, the, peak, height, of, functional, 'CYP2D6', at, 450, nm])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, increase, in, 'CYP2D6', activity, is, attributable, to, the, 'radical-scavenging', effect, of, 'DMSO'])].
[sujeto(['The', 'HepG2', cell, lines, stably]), verbo([expressing]), complemento(['OR', and, 'CYP2D6', or, its, variants, in, combination, with, 'DMSO', treatment, may, be, useful, for, screening, the, cytotoxicity, of, chemical, compounds, which, undergo, oxidation, by, 'CYP2D6'])].
[sujeto(['The', identification, of, a, large, number, of, biologically, active, chemical, entities, during, high, throughput, screening, '(', 'HTS)', necessitates, the, incorporation, of, new, strategies, to, identify, compounds, with, druglike, properties, early, during, the]), verbo([lead]), complemento([prioritization, and, development, process])].
[sujeto(['One', of, the, major, steps, in]), verbo([lead]), complemento([prioritization, is, the, assessment, of, drug, metabolism, mediated, by, the, cytochrome, 'P(450)', '(', 'CYP)', enzymes, to, evaluate, the, potential, 'drug-drug', interactions])].
[sujeto(['CYP2D6', and, 'CYP3A4', comprise, the, main, human, 'CYP', enzymes]), verbo([involved]), complemento([in, drug, metabolism])].
[sujeto(['The', recent, availability, of, specific, 'CYP', cDNA, expression, systems, and, the, development, of, specific, fluorescent, probes]), verbo([have]), complemento([accelerated, the, ability, to, develop, robust, in, vitro, assays, in, 'HTS', format])].
[sujeto(['Thus', the, assay, optimization]), verbo([involved]), complemento([the, comparison, of, different, substrates, to, identify, those, most, suitable, for, use, in, a, miniaturized, format])].
[sujeto(['Because', of, current, technical, limitations, in, liquid, dispensing, of, nanoliter, 'volumes,', assay, sensitivity, to, organic, solvents, also]), verbo([provides]), complemento([a, main, concern, during, assay, miniaturization])].
[sujeto(['Previous', studies, demonstrated, that, 'CPR']), verbo([regulates]), complemento([the, levels, of, various, 'P450', isoforms, in, vitro])].
[sujeto(['By', transfection, of, 'Chinese', hamster, ovary, 'DUKXB11', cells, we, obtained, the, cell, line, 'DUKX/2D6,', which]), verbo([expressed]), complemento([human, 'CYP2D6,', a, 'P450', isoform])].
[sujeto(['Expression', of, recombinant, 'CPR']), verbo([decreased]), complemento([the, level, of, spectrally, detectable, 'CYP2D6', holoprotein, in, 'DUKX/2D6/CPR-3', cells, by, 70, '%', ',', whereas, the, level, of, immunodetectable, apoprotein, remained, unchanged])].
[sujeto(['Addition', of, the, radical, scavenger, 'DMSO']), verbo([increased]), complemento([levels, of, 'CYP2D6', holoenzyme, in, 'DUKX/2D6/CPR-3', cells, but, not, in, 'DUKX/2D6', cells])].
[sujeto(['Importantly,', combined, treatment, with, 'DMSO', and, hemin]), verbo([increased]), complemento([levels, of, 'CYP2D6', holoenzyme, in, 'DUKX/2D6/CPR-3', but, not, in, 'DUKX/2D6', cells, even, further, than, either, treatment, alone])].
[sujeto(['This', demonstrates, that, expression, of, 'CPR']), verbo([increases]), complemento([production, of, damaging, radicals, but, also, that, 'CPR', may, alter, haem, homoeostasis])].
[sujeto(['In', agreement, with, 'this,', the, activity, of, haem, 'oxygenase,', a, 'rate-limiting', enzyme, in, haem, 'metabolism,', was, compared, with, that, in, 'DUKX/DHFR', control, cells, '(']), verbo([expressing]), complemento([dihydrofolate, 'reductase),', and, was, 3, -, fold, higher, in, 'DUKX/2D6/CPR-3', but, similar, in, 'DUKX/2D6', cells])].
[sujeto(['Furthermore,', treatment, of, cells, with, sodium, arsenite]), verbo([increased]), complemento([levels, of, haem, oxygenase, concomitant, with, a, marked, decrease, of, spectrally, detectable, 'CYP2D6', and, a, rise, in, levels, of, 'ferritin,', which, sequesters, free, iron, released, from, the, destruction, of, haem])].
[sujeto(['These', data, demonstrate, that, 'CPR']), verbo([regulates]), complemento(['P450', activity, by, supplying, electrons, and, also, by, altering, 'P450', levels, via, 'radical-and', haem, 'oxygenase-mediated', pathways])].
[sujeto(['DMSO', was]), verbo([found]), complemento([to, inhibit, 'CYP2C9', and, 'CYP2C19,', 'CYP2E1,', and, 'CYP3A4', in, a, 'concentration-dependent', manner])].
[sujeto(['Methanol', was]), verbo([found]), complemento([to, inhibit, 'CYP2C9', and, 'CYP2E1', 'activities,', but, to, a, lesser, extent, than, 'DMSO'])].
[sujeto(['Cetirizine,', 'terfenadine,', 'loratadine,', astemizole, and, mizolastine, were, compared, for, their, ability, to]), verbo([inhibit]), complemento([marker, activities, for, 'CYP1A2,', 'CYP2C9,', 'CYP2C19,', 'CYP2D6,', 'CYP3A4', and, for, some, glucuronidation, isoenzymes, in, human, liver, microsomes])].
[sujeto(['The', most, pronounced, effects, were, observed, with, 'terfenadine,', astemizole, and, loratadine, which]), verbo([inhibited]), complemento(['CYP3A4-mediated', testosterone, 6, 'beta-hydroxylation', '(', 'IC50', of, 23, ',', 21, and, 32, 'microM,', 'respectively)', and, 'CYP2D6-mediated', dextromethorphan, 'O-demethylation', '(', 'IC50', of, 18, ',', 36, and, 15, 'microM,', 'respectively)'])].
[sujeto(['In', 'addition,', loratadine, markedly]), verbo([inhibited]), complemento([the, 'CYP2C19', marker, 'activity,', '(', 'S)-mephenytoin', 4, -, hydroxylation, '(', 'Ki', of, 0.17, 'microM)'])].
[sujeto(['Furthermore,', loratadine]), verbo([activated]), complemento([the, 'CYP2C9-catalyzed', tolbutamide, hydroxylation, '(', ca])].
[sujeto([3, -, fold]), verbo([increase]), complemento([at, 30, 'microM)', and, inhibited, some, glucuronidation, enzymes])].
[sujeto(['A', comparison, of, the, inhibitory, potencies, of, 'cetirizine,', 'terfenadine,', 'loratidine,', astemizole, and, mizolastine, with, their, corresponding, plasma, concentrations, in, humans]), verbo([suggests]), complemento([that, these, antihistamines, are, not, likely, to, interfere, with, the, metabolic, clearance, of, coadministered, 'drugs,', with, the, exception, of, 'loratidine,', which, appears, to, inhibit, 'CYP2C19', with, sufficient, potency, to, warrant, additional, investigation])].
[sujeto(['These', data, show, that, specific, solvents]), verbo([have]), complemento(['enzyme-selective', effects, on, 'P-450', activities])].
[sujeto(['Methanol', did, not, substantially]), verbo([inhibit]), complemento(['(', &, 'lt;/=10%)', any, of, the, activities, at, 0.3, '%', ',', but, did, inhibit, 'CYP1A1,', 'CYP2B6,', 'CYP2C9,', and, 'CYP2D6', by, 12, to, 26, '%', at, 1, '%'])].
[sujeto(['In', 'contrast,', 0.1, '%', ethanol]), verbo([inhibited]), complemento(['CYP1A1,', 'CYP2B6,', and, 'CYP2C19', by, 20, to, 30, '%'])].
[sujeto(['Ethanol', at, 1, '%', did, not]), verbo([inhibit]), complemento(['CYP1A2,', 'CYP3A4,', 'CYP2C8,', and, 'CYP2C9'])].
[sujeto(['DMSO']), verbo([inhibited]), complemento(['CYP3A4,', 'CYP2C19,', and, 'CYP2D6', by, 15, to, 25, '%', at, 0.1, '%'])].
[sujeto(['Acetonitrile,', like, 'methanol,', did, not]), verbo([inhibit]), complemento([any, 'P-450', activity, at, 0.3, '%', solvent, except, for, 'CYP1A1', '(', 26, '%', ')', and, 'CYP2B6', '(', 13, '%', ')'])].
[sujeto(['At', 1, '%', ',', acetonitrile]), verbo([decreased]), complemento([activities, of, 'CYP1A1', and, 'CYP2B6', by, 40, to, 60, '%', ',', and, inhibited, 'CYP2A6,', 'CYP3A4,', 'CYP2C19,', and, 'CYP2D6', activity, by, 10, to, 20, '%'])].
[sujeto(['Acetonitrile', also]), verbo([increased]), complemento(['CYP2C9', activity, by, 10, to, 15, '%', above, control, values, at, 1, to, 3, '%', solvent])].
[sujeto(['Hormone-sensitive', lipase, '(', 'HSL)', is, an, intracellular, enzyme, that]), verbo([has]), complemento([a, central, role, in, the, regulation, of, fatty, acid, metabolism])].
[sujeto(['The', 'enzyme,', 'therefore,', is, a, potentially, interesting, pharmacological]), verbo([target]), complemento([for, the, treatment, of, insulin, resistance, and, dyslipidemic, disorders])].
[sujeto(['Both', inhibitors, were, active, in, acute, antilipolytic, experiments, in, vivo, and, none, of, the, inhibitors]), verbo([inhibited]), complemento([the, cytochrome, 'P450', '(', 'CYP)', isoforms, 2, 'D6,', 3, 'A4,', and, 1, 'A2'])].
[sujeto(['Introduction', of, the, spirocyclic, pyranochromene, scaffold, yielded, several, advantages, over, previous, generation, 'cores,', including]), verbo([increased]), complemento(['potency,', reduced, 'efflux,', and, reduced, 'CYP2D6', inhibition])].
[sujeto(['Further', profiling]), verbo([suggested]), complemento([that, a, high, fraction, of, the, metabolism, '(', &, 'gt;95%)', was, due, to, 'CYP2D6,', increasing, the, potential, risk, for, 'victim-based', 'drug-drug', interactions, '(', 'DDI)', and, variable, exposure, in, the, clinic, due, to, the, polymorphic, nature, of, this, enzyme])].
[sujeto(['To', guide, future, 'design,', we, solved, crystal, structures, of, 'CYP2D6', complexes, with, substrate, 5, and, its, corresponding, metabolic, product, pyrazole, 6, ',', which]), verbo([provided]), complemento([insight, into, the, binding, mode, and, movements, between, 'substrate/inhibitor', complexes])].
[sujeto(['Androstenone,', a, steroid, produced, in, testis, and]), verbo([acting]), complemento([as, a, sex, pheromone, regulating, reproductive, function, in, female, 'pigs,', is, one, of, the, main, compounds, responsible, for, boar, taint])].
[sujeto(['The', genes, 'Cytochrome', 'P450', c17, '(', 'CYP17A1),', 'Steroidogenic', acute, regulatory, protein, '(', 'STAR),', 'Aldo-keto', reductase, family, 1, member, 'C4', '(', 'AKR1C4),', 'Short-chain', 'dehydrogenase/reductase', family, member, 4, '(', 'DHRS4),', 'Ferritin', light, polypeptide, '(', 'FTL),', 'Sulfotransferase', family, 2, 'A,', 'dehydroepiandrosterone-preferring', member, 1, '(', 'SULT2A1),', 'Cytochrome', 'P450', subfamily, 'XIA', polypeptide, 1, '(', 'CYP11A1),', 'Cytochrome', b5, '(', 'CYB5A),', and, 17, -, 'beta-Hydroxysteroid', dehydrogenase, 'IV', '(', 'HSD17B4)', were, all]), verbo([found]), complemento([to, be, significantly, '(', 'P', &, 'lt;', 0.05, ')', 'up-regulated', in, high, androstenone, boars, in, both, 'Duroc', and, 'Landrace'])].
[sujeto(['The', genes, 'Nuclear', 'Receptor', 'co-activator', 4, '(', 'NCOA4),', 'Sphingomyrlin', phosphodiesterase, 1, '(', 'SMPD1)', and, 3, 'beta-hydroxysteroid', dehydrogenase, '(', 'HSD3B)', were, not, significantly, differentially]), verbo([expressed]), complemento([in, any, breeds])].
[sujeto(['Association', between, 'SNP', and, androstenone, level, was, observed, in, 'CYB5A', 'only,']), verbo([suggesting]), complemento(['cis-regulation', of, the, differential, transcription, in, this, gene])].
[sujeto(['The', current, study, contributes, to, the, knowledge, about, which, genes, that, is, differentially]), verbo([expressed]), complemento([regard, to, the, levels, of, androstenone, in, pigs])].
[sujeto(['Results', in, this, paper]), verbo([suggest]), complemento([that, several, genes, are, important, in, the, regulation, of, androstenone, level, in, boars, and, warrant, further, evaluation, of, the, above, mentioned, candidate, 'genes,', including, analyses, in, different, 'breeds,', identification, of, causal, mutations, and, possible, gene, interactions])].
[sujeto(['Orphan']), verbo([nuclear]), complemento([receptor, 'NR4A1,', a, member, of, the, nuclear, receptor, 'superfamily,', is, widely, expressed, in, different, cell, types, and, mediates, diverse, biological, processes])].
[sujeto(['Recent', emerging, evidence]), verbo([suggests]), complemento([that, 'NR4A1', is, involved, in, the, transcriptional, regulation, of, several, steroidogenic, enzyme, genes, in, gonads, and, adrenals])].
[sujeto(['In', the, present, 'study,', immunohistochemical, staining, of, 'NR4A1', in, healthy, human, ovaries, indicate, that, it, is]), verbo([expressed]), complemento([in, theca, cells, and, granulosa, cells])].
[sujeto(['In', an, effort, to, explore, the, function, of, 'NR4A1', in, the, transcript, regulation, of, steroidogenic, enzyme, genes, responsible, for, ovarian, theca, cell, 'steroidogenesis,', we, constructed, recombinant, adenovirus, 'AdCMV-NR4A1', and, 'AdH1-NR4A1', to]), verbo([enhance]), complemento([or, knockdown, the, expression, of, 'NR4A1', in, theca, 'cells,', respectively])].
[sujeto(['Our', results, show, that, overexpression, of, 'NR4A1', in, theca, cells]), verbo([stimulates]), complemento([the, expression, of, 'StAR,', 'CYP11A1,', 'CYP17', and, 'HSD3B2,', leading, to, increased, testosterone, production])].
[sujeto(['Conversely,', knockdown, of, the, endogenous, 'NR4A1', exhibits, a, significant]), verbo([decrease]), complemento([in, 'StAR,', 'CYP11A1,', 'CYP17', and, 'HSD3B2', expression, and, testosterone, production])].
[sujeto(['Since', expression, of, 'NR4A1', in, the, endocrine, organs, is, known, to, be]), verbo([regulated]), complemento([by, both, 'cAMP/PKA', mediated, 'hormones,', 'ACTH', and, 'LH,', forskolin, '(', 'FSK),', an, activator, of, 'cAMP/PKA', 'pathway,', was, applied, to, the, cultured, follicles])].
[sujeto(['FSK', rapidly]), verbo([increases]), complemento([the, 'NR4A1', mRNA, levels, followed, by, an, increase, in, 'StAR,', 'CYP11A1,', 'CYP17', and, 'HSD3B2'])].
[sujeto(['Aldosterone', is, principally, synthesized, in, the, zona, glomerulosa, of, the, adrenal, by, a, series, of, enzymatic, reactions]), verbo([leading]), complemento([to, the, conversion, of, cholesterol, to, aldosterone])].
[sujeto(['Angiotensin', 'II', '(', 'Ang', 'II)', is, the, major, physiological, regulator, of, aldosterone, production]), verbo([acting]), complemento([acutely, to, stimulate, aldosterone, biosynthesis, and, chronically, to, increase, the, capacity, of, the, adrenals, to, produce, aldosterone])].
[sujeto(['We', previously, defined, eight, transcription, factors, that, are, rapidly]), verbo([induced]), complemento([following, 'Ang', 'II', treatment, using, three, in, vitro, adrenocortical, cell, models])].
[sujeto(['NGFI-B', family, members]), verbo([induced]), complemento([promoter, activity, of, 3, -, 'beta-hydroxysteroid-dehydrogenase', type, 2, '(', 'HSD3B2),', 21, -, hydroxylase, '(', 'CYP21A2),', and, aldosterone, synthase, '(', 'CYP11B2)'])].
[sujeto(['A', pharmacological, approach, was, used, to, characterize, the, 'Ang', 'II', pathways]), verbo([regulating]), complemento([transcription, of, 'NGFI-B', family, genes])].
[sujeto(['Transcription', of, 'NGFI-B', members, were]), verbo([decreased]), complemento([following, inhibition, of, 'Ang', 'II', type, 1, receptor, '(', 'AT1R),', protein, kinase, 'C', '(', 'PKC),', 'calcium/calmodulin-dependent', kinases, '(', 'CaMK),', and, 'Src', tyrosine, kinase, '(', 'SRC)'])].
[sujeto(['Taken', 'together,', these, results]), verbo([suggest]), complemento([that, 'Ang', 'II', binding, to, the, 'AT1R', increases, activity, of, 'PKC,', 'CaMK,', and, 'SRC,', which, act, to, increase, expression, of, the, family, of, 'NGFI-B', genes, as, well, as, 'CYP11B2'])].
[sujeto(['Ang', 'II', induction, of, the, 'NGFI-B', family, members, represents, an, important, pathway, to]), verbo([increase]), complemento([the, capacity, of, adrenal, cells, to, produce, aldosterone])].
[sujeto(['Endometrial', cancer, cells]), verbo([express]), complemento([the, genes, encoding, the, steroidogenic, enzymes, involved, in, estradiol, synthesis])].
[sujeto(['Here', we, used, 'RT-PCR', and, 'Western', blot, to, show, that, the]), verbo([nuclear]), complemento([receptors, 'SF1', and, 'LRH1,', two, 'well-known', regulators, of, steroidogenic, gene, expression, in, gonadal, and, adrenal, 'cells,', are, also, expressed, in, endometrial, cancer, cell, lines])].
[sujeto(['By', transient, 'transfections,', we]), verbo([found]), complemento([that, 'SF1', and, 'LRH1,', but, not, the, related, nuclear, receptor, 'NUR77,', can, activate, the, promoters, of, three, human, steroidogenic, 'genes:', 'STAR,', 'HSD3B2,', and, 'CYP19A1', 'PII'])].
[sujeto(['Similarly,', forskolin, but, not, 'PMA,', could]), verbo([activate]), complemento([all, three, promoters])].
[sujeto(['In', 'addition,', we]), verbo([found]), complemento([that, both, 'SF1', and, 'LRH1', can, transcriptionally, cooperate, with, the, 'AP-1', family, members, 'c-JUN', and, 'c-FOS,', known, to, be, associated, with, enhanced, proliferation, of, endometrial, carcinoma, 'cells,', to, further, enhance, activation, of, the, 'STAR,', 'HSD3B2,', and, 'CYP19A1', 'PII', promoters])].
[sujeto(['All', 'together,', our, data]), verbo([provide]), complemento([novel, insights, into, the, mechanisms, of, steroidogenic, gene, expression, in, endometrial, cancer, cells, and, thus, in, the, regulation, of, estradiol, biosynthesis, by, tumour, cells])].
[sujeto(['Recent', study, of, 'Leydig', cell, function]), verbo([has]), complemento([focused, on, the, mechanisms, regulating, 'steroidogenesis;', 'however,', few, investigations, have, examined, the, importance, of, mitochondria, in, this, process])].
[sujeto([cAMP, treatment, of, 'MA-10', cells, resulted, in, significant]), verbo([increases]), complemento([in, both, cellular, respiration, and, 'Deltapsim'])].
[sujeto(['Preventing', electron, transport, in, mitochondria, with, antimycin, 'A', significantly, reduced, cellular, 'ATP,', potently]), verbo([inhibited]), complemento(['steroidogenesis,', and, reduced, 'StAR', protein, levels])].
[sujeto(['Inhibiting', mitochondrial, 'ATP', synthesis, with, oligomycin, reduced, cellular, 'ATP,']), verbo([inhibited]), complemento([progesterone, synthesis, and, 'StAR', 'protein,', but, had, no, effect, on, 'Deltapsim'])].
[sujeto([22, '(', 'R)-hydroxycholesterol-stimulated', progesterone, synthesis, was, not]), verbo([inhibited]), complemento([by, any, of, the, mitochondrial, 'reagents,', indicating, that, neither, 'P450', 'side-chain', cleavage, nor, 3, 'beta-hydroxysteroid', dehydrogenase, activity, was, inhibited])].
[sujeto(['These', results, indicate, that, 'Deltapsim,', mitochondrial, 'ATP', 'synthesis,', and, mitochondrial, pH, are, all]), verbo([required]), complemento([for, acute, steroid, biosynthesis])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, mitochondria, must, be, 'energized,', 'polarized,', and, actively, respiring, to, support, 'Leydig', cell, 'steroidogenesis,', and, alterations, in, the, state, of, mitochondria, may, be, involved, in, regulating, steroid, biosynthesis])].
[sujeto(['Cytomegalic', adrenal, hypoplasia, congenita, '(', 'AHC)', is, an, 'X-linked', disease]), verbo([caused]), complemento([by, mutations, in, 'DAX1-encoding', gene, 'NR0B1,', previously, thought, to, function, primarily, in, steroidogenesis])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, murine, 'Dax1', is, a, unique, marker, in, early, embryonic, 'development,', distinguishing, the, extraembryonic, '(', 'proximal)', endoderm, from, the, remainder, of, the, developing, embryo])].
[sujeto(['We', showed, that, 'Wilms', tumor, 1, ',', steroidogenic, factor, 1, ',', and, estrogen, receptor, beta, were]), verbo([expressed]), complemento([throughout, the, 'embryo,', but, the, 'progesterone,', estrogen, alpha, and, androgen, 'receptors,', cytochrome, 'P450', '(', 'Cyp11a1)', and, 'Nur77', were, not, observed, in, any, of, the, embryonic, layers])].
[sujeto(['Nr0b1', conditional, knockout, in, 'ES', cells]), verbo([led]), complemento([to, 'differentiation,', confirming, our, knockdown, results])].
[sujeto(['Our', investigations]), verbo([suggest]), complemento([that, 'Nr0b1', functions, in, a, novel, role, in, the, maintenance, of, a, relatively, undifferentiated, state])].
[sujeto(['Our', results, further]), verbo([suggest]), complemento([that, the, failure, of, conventional, murine, 'Nr0b1', knockout, attempts, may, be, due, to, disregulated, differentiation])].
[sujeto(['We', 'co-crystallized', human, cytochrome, 'P450', 3, 'A4', '(', 'CYP3A4)', with, progesterone, '(', 'PRG)', under, two, different, 'conditions,', but, the, resulting, complexes, contained, only, one, 'PRG', molecule]), verbo([bound]), complemento([to, the, previously, identified, peripheral, site])].
[sujeto(['Citrate', was]), verbo([found]), complemento([to, affect, the, properties, of, both, redox, partners, and, stimulated, their, catalytic, activities, in, a, 'concentration-dependent', manner, via, a, complex, mechanism])].
[sujeto(['Comparative', analysis, of, various, negatively, charged, organic, compounds, indicated, 'that,', in, addition, to, alterations]), verbo([caused]), complemento([by, changes, in, ionic, 'strength,', anions, modulate, the, properties, of, 'CYP3A4', and, 'CPR', through, specific, 'anion-protein', interactions])].
[sujeto(['Our', results, help, to, better, understand, previous, observations, and]), verbo([provide]), complemento([new, mechanistic, insights, into, 'CYP3A4', function])].
[sujeto(['Pharmacology', studies]), verbo([have]), complemento([shown, that, 'Cistanche', possesses, an, 'androgen-like', 'effect;', 'however,', the, exact, mechanism, is, unclear])].
[sujeto(['The', study, illustrates, that, the, administration, of, 'CTE', '(', 0.4, and, 0.8, 'g/kg)']), verbo([increased]), complemento([sperm, count, '(', 2.3, -, and, 2.7, -, 'folds)', and, sperm, motility, '(', 1.3, -, and, 1.4, -, 'folds)', and, decreased, the, abnormal, sperm, '(', 0.76, -, and, 0.6, -, 'folds)'])].
[sujeto(['The', serum, level, of, progesterone, and, testosterone, in, rats, was, also]), verbo([increased]), complemento([by, 'CTE', administration, '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['Results', of, immunohistochemistry, and, western, blot, analysis, confirmed, that, the, expression, of, 'CYP11A1,', 'CYP17A1,', and, 'CYP3A4', was]), verbo([enhanced]), complemento([by, 'CTE', '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['It', was, also]), verbo([found]), complemento([that, 'high-dose', of, 'CTE', can, cause, mild, hepatic, edema])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, the, increase, in, sex, hormone, levels, could, be, mediated, by, the, induction, of, testicular, steroidogenic, enzymes])].
[sujeto(['In', pregnant, 'women,', 'CYP3A', activity]), verbo([increases]), complemento([by, 100, '%', during, the, third, trimester, '(', 'T3)'])].
[sujeto(['Our', laboratory]), verbo([has]), complemento([shown, that, 'sandwich-cultured', human, hepatocytes, '(', 'SCHH)', and, 'HepaRG', cells, have, the, potential, to, predict, the, magnitude, of, in, vivo, induction, of, 'CYP3A', activity, likely, to, be, observed, in, 'T1', and, 'T2'])].
[sujeto(['In', all, three, 'trimesters,', only, cortisol, '(', 'C)', consistently, and, significantly]), verbo([induced]), complemento(['CYP3A', 'activity,', while, other, individual, hormones, '(', 'progesterone,', 'estradiol,', or, growth, 'hormones)', failed, to, induce, 'CYP3A', activity])].
[sujeto(['Moreover,', we, predict, that, the, magnitude, of, 'CYP3A', induction, during, 'T1', and, 'T2', will, be, similar, to, that, observed, during, 'T3', '(', '∼100%']), verbo([increase]), complemento([versus, 'postpartum)'])].
[sujeto(['This', prediction, is, consistent, with, the, observation, of, similar]), verbo([increases]), complemento([in, 'T2', and, 'T3', oral, clearance, of, indinavir, '(', a, 'CYP3A', cleared, 'drug)', versus, postpartum])].
[sujeto(['Using', 'Nanodiscs,', we, quantitate, the, heterotropic, interaction, between, two, different, drugs]), verbo([mediated]), complemento([by, monomeric, 'CYP3A4', incorporated, into, a, nativelike, membrane, environment])].
[sujeto(['Preferred']), verbo([binding]), complemento([of, 'PGS', at, the, allosteric, site, and, a, stronger, preference, for, 'CBZ', binding, at, the, productive, site, give, rise, to, a, nontrivial, 'drug-drug', interaction])].
[sujeto(['Molecular', dynamics, simulations, indicate, functionally, important, conformational, changes]), verbo([caused]), complemento([by, 'PGS', binding, at, the, allosteric, site, and, by, two, 'CBZ', molecules, positioned, inside, the, substrate, binding, pocket])].
[sujeto(['Structural', changes]), verbo([involving]), complemento(['Phe-213,', 'Phe-219,', and, 'Phe-241', are, thought, to, be, responsible, for, the, observed, synergetic, effects, and, positive, allosteric, interactions, between, these, two, substrates])].
[sujeto(['Such', a, mechanism, is, likely, of, general, relevance, to, the, mutual, heterotropic, effects]), verbo([caused]), complemento([by, biologically, active, compounds, that, exhibit, different, patterns, of, interaction, with, the, distinct, allosteric, and, productive, sites, of, 'CYP3A4,', as, well, as, other, xenobiotic, metabolizing, cytochromes, 'P450', that, are, also, involved, in, 'drug-drug', interactions])].
[sujeto(['To', distinguish, the, direct, effects, of, 'HS', from]), verbo([decreased]), complemento([dry, matter, 'intake,', cohorts, were, pair, fed, '(', 'PF)', in, thermoneutral, conditions, to, match, the, intake, of, the, 'HS', cows, during, both, experiments])].
[sujeto(['Heat', stress]), verbo([decreased]), complemento([hepatic, 'CYP2C', expression, during, both, experiments])].
[sujeto(['Interestingly,', during, experiment, 2, ',', hepatic, 'CYP3A', expression, also]), verbo([decreased]), complemento([during, 'PF'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'HS', reduces, the, capacity, of, the, liver, to, metabolize, progesterone, through, distinct, effects, on, 'CYP2C', and, 'CYP3A,', and, that, the, effects, appear, to, vary, based, upon, stage, of, lactation])].
[sujeto(['Some', metabolic, activities, of, 'CYP3A4,', including, dehydroepiandrosterone, 7, 'β-/16α-hydroxylation,', estrone, 2, -, hydroxylation, and, testosterone, 6, 'β-hydroxylation,', were, higher, than, those, for, polymorphically]), verbo([expressed]), complemento(['CYP3A5'])].
[sujeto(['Further', research, is]), verbo([required]), complemento([on, the, metabolism, of, steroid, hormones, by, various, 'P450s', and, on, prediction, of, their, relative, contributions, to, in, vivo, metabolism])].
[sujeto(['The', findings, collected, here]), verbo([provide]), complemento([fundamental, and, useful, information, on, the, metabolism, of, steroid, compounds])].
[sujeto(['The', clinical, pharmacology, profile, of, a, drug, critically, determines, its, 'therapeutics,', and, this, review, summarizes, the, characteristics]), verbo([associated]), complemento([with, the, antiepileptic, drug, '(', 'AED)', perampanel])].
[sujeto(['Congress', abstract, data, are, included, where, necessary, and, 'Eisai', 'Ltd']), verbo([provided]), complemento([access, to, unpublished, data, on, file])].
[sujeto(['These', 'half-life', values, allow, for, 'once-daily', 'dosing,', which, will, aid, patient, compliance, and, in, the, event, of, a, missed, 'dose,', will]), verbo([have]), complemento([minimal, impact, on, seizure, control])].
[sujeto(['In', healthy, volunteers, prescribed, 'carbamazepine,', 'half-life']), verbo([decreases]), complemento([to, 25, &, 'nbsp;h'])].
[sujeto(['Perampanel']), verbo([has]), complemento([minimal, propensity, to, cause, pharmacokinetic, interactions])].
[sujeto(['However,', it, is, the]), verbo([target]), complemento([of, such, interactions, and, 'CYP3A4-inducing', 'AEDs', enhance, its, 'clearance;', this, can, be, used, to, advantage, because, dose, titration, can, be, faster, and, thus, optimum, therapeutic, outcome, can, be, achieved, sooner])].
[sujeto(['Perampanel', 12, &, 'nbsp;mg,', but, not, 4, or, 8, &, 'nbsp;mg,']), verbo([enhances]), complemento([the, metabolism, of, the, progesterone, component, of, the, oral, contraceptive, 'pill,', necessitating, the, need, for, an, additional, reliable, contraceptive, method])].
[sujeto(['Overall,', perampanel]), verbo([has]), complemento([a, favorable, clinical, pharmacology, 'profile,', which, should, aid, its, clinical, use])].
[sujeto(['EE2']), verbo([acts]), complemento([as, a, reversible, inhibitor, of, 'CYP3A-mediated', progesterone, 6, 'β-hydroxylation', and, inactivates, 'CYP3A-', and, 'CYP2C-catalyzed', testosterone, 6, 'β-hydroxylation', and, progesterone, 21, -, or, 16, 'α-hydroxylation,', 'respectively,', in, a, 'mechanism-based', manner])].
[sujeto(['The', objective, of, this, experiment, was, to, determine, if, frequency, of, protein, supplementation, impacts, physiological, responses]), verbo([associated]), complemento([with, reproduction, in, beef, cows])].
[sujeto(['Within', each, 'period,', cows, were, assigned, to, an, estrus, synchronization, 'protocol:', 100, μg, of, 'GnRH', +, controlled, internal, drug]), verbo([release]), complemento([device, '(', 'CIDR)', containing, 1.38, g, of, progesterone, '(', 'P4)', on, d, 1, ',', 25, mg, of, 'PGF2α', on, d, 8, ',', and, 'CIDR', removal, +, 100, μg, of, 'GnRH', on, d, 11])].
[sujeto(['Hence,']), verbo([decreasing]), complemento([frequency, of, protein, supplementation, did, not, reduce, uterine, flushing, pH, or, plasma, 'P4', 'concentrations,', which, are, known, to, impact, reproduction, in, beef, cows])].
[sujeto(['A', series, of, in, vitro, experiments, conducted, early, in, the, development, of, ivacaftor, indicated, ivacaftor, and, metabolites, may]), verbo([have]), complemento([the, potential, to, inhibit, cytochrome, 'P450', '(', 'CYP)', 2, 'C8,', 'CYP2C9,', 'CYP3A,', and, 'CYP2D6,', as, well, as, 'P-glycoprotein', '(', 'P-gp)'])].
[sujeto(['The', results, indicate, ivacaftor, is, a, weak, inhibitor, of, 'CYP3A', and, 'P-gp,', but]), verbo([has]), complemento([no, effect, on, 'CYP2C8', or, 'CYP2D6'])].
[sujeto(['Ivacaftor']), verbo([caused]), complemento(['non-clinically', significant, increases, in, ethinyl, estradiol, and, norethisterone, exposure])].
[sujeto(['The', average, 'CLm(6β)', levels, that, were]), verbo([suppressed]), complemento([by, the, 'OC', in, four, women, were, extremely, low, '(', 0.6, -, 1.23, 'mL/min)', compared, with, the, normal, 'CLm(6β)', range, '(', 1.5, -, 3.5, 'mL/min)', that, was, obtained, from, 49, healthy, subjects, in, our, previous, study])].
[sujeto(['The', in, vivo, inhibitory, potencies, '(', 43, -, 64, '%', ')', obtained, in, this, study, were, stronger, than, expected, from]), verbo([reported]), complemento([in, vitro, studies, '(', '∼20%)'])].
[sujeto(['The', results, presented, here, should]), verbo([provide]), complemento([important, information, on, the, inhibitory, effect, of, 'OC', on, the, 'CYP3A', activities, in, 'women,', which, are, involved, in, the, metabolism, of, a, number, of, drugs, with, a, narrow, therapeutic, range])].
[sujeto(['In', 'Mexico,', breast, cancer, '(', 'BCa)', is, the]), verbo([leading]), complemento([type, of, cancer, in, women])].
[sujeto(['In', 'addition,', these, enzymes]), verbo([have]), complemento([influence, on, tumor, development, and, tumor, response, to, therapy])].
[sujeto(['We']), verbo([found]), complemento([a, significant, 'CYP3A4', overexpression, in, 'BCa', stroma, and, gland, regions, in, comparison, with, healthy, tissue])].
[sujeto(['We']), verbo([suggest]), complemento([that, 'CYP3A4', expression, promotes, 'BCa', development, and, can, be, used, in, the, prediction, of, tumor, response, to, different, treatments])].
[sujeto(['However,', 17, 'OHP-C', at, 1, 'μmol/L']), verbo([increased]), complemento(['CYP2C19', activity, by, 2.8, -, fold, '(', 'P', &, 'lt;'])].
[sujeto(['The', activity, and, expression, of, hepatic, 'CYP2C19', was, significantly]), verbo([increased]), complemento([by, 17, 'OHP-C', in, primary, cultures, of, human, hepatocytes])].
[sujeto(['This']), verbo([suggests]), complemento([that, exposure, to, medications, that, are, metabolized, by, 'CYP2C19', may, be, decreased, in, pregnant, patients, receiving, 17, 'OHP-C'])].
[sujeto(['The', cytochrome, b5, domain, containing, 2, '(', 'CYB5D2;', 'Neuferricin)', protein]), verbo([has]), complemento([been, reported, to, bind, 'heme,', 'however,', the, critical, residues, responsible, for, 'heme-binding', are, undefined])].
[sujeto(['Previous', studies, examining, 'heme-binding', in, two, cytochrome, b5, 'heme-binding', 'domain-containing', 'proteins,', 'damage-associated', protein, 1, '(', 'Dap1;', 'Saccharomyces', 'cerevisiae)', and, human, progesterone, receptor, membrane, component, 1, '(', 'PGRMC1),']), verbo([have]), complemento([revealed, that, conserved, tyrosine, '(', 'Y)', 73, ',', 'Y79,', aspartic, acid, '(', 'D)', 86, ',', and, 'Y127', residues, present, in, human, 'CYB5D2', may, be, involved, in, 'heme-binding'])].
[sujeto(['CYB5D2']), verbo([binds]), complemento([to, type, b, 'heme,', 'however,', only, the, substitution, of, glycine, '(', 'G)', at, 'D86', '(', 'D86G)', within, its, cytochrome, b5, 'heme-binding', '(', 'cyt-b5)', domain, abolished, its, 'heme-binding', ability])].
[sujeto(['Ectopic', 'CYB5D2', expression]), verbo([inhibited]), complemento([cell, proliferation, and, 'anchorage-independent', colony, growth, of, 'HeLa', cells])].
[sujeto(['Conversely,', 'CYB5D2', knockdown, and, ectopic, 'CYB5D2(D86G)', expression]), verbo([increased]), complemento([cell, proliferation, and, colony, growth])].
[sujeto(['As', 'PGRMC1']), verbo([has]), complemento([been, reported, to, regulate, the, expression, and, activities, of, cytochrome, 'P450', proteins, '(', 'CYPs),', we, examined, the, role, of, 'CYB5D2', in, regulating, the, activities, of, 'CYPs', involved, in, sterol, synthesis, '(', 'CYP51A1)', and, drug, metabolism, '(', 'CYP3A4)'])].
[sujeto(['Lastly,', 'CYB5D2', expression]), verbo([conferred]), complemento(['HeLa', cell, survival, from, chemotherapeutic, agents, '(', 'paclitaxel,', cisplatin, and, 'doxorubicin),', with, its, ability, to, promote, survival, being, dependent, on, its, 'heme-binding', ability])].
[sujeto(['Taken', 'together,', this, study]), verbo([provides]), complemento([evidence, that, 'heme-binding', is, critical, for, 'CYB5D2', in, regulating, 'HeLa', cell, growth, and, 'survival,', with, endogenous, 'CYB5D2', being, required, to, modulate, 'CYP', activities])].
[sujeto(['These', enzymes, are]), verbo([modulated]), complemento([by, estrogen, and, progesterone, which, regulate, the, menstrual, cycle])].
[sujeto(['The', variations, in, the, pharmacokinetics, '(', 'PK)', of, many, drugs, like, 'amphetamine,', benzodiazepines, and, caffeine]), verbo([have]), complemento([been, reported, during, menstrual, cycle])].
[sujeto(['The', present, study]), verbo([suggests]), complemento([that, high, estrogen, levels, of, follicular, phase, may, result, in, increased, absorption, of, omeprazole])].
[sujeto(['The', lower, 'MR', for, 5, -, hydroxy, omeprazole, and, omeprazole, sulphone, in, follicular, phase, as, compared, to, luteal, phase]), verbo([suggests]), complemento([that, metabolism, of, omeprazole, is, low, in, follicular, phase, as, compared, to, luteal, 'phase,', which, is, 'progesterone-dominant', phase])].
[sujeto(['We', examined, whether, variants, in, genes, related, to, sex, hormone, biosynthesis, and, metabolism, were]), verbo([associated]), complemento([with, hypospadias, in, humans])].
[sujeto(['Our', study, indicates, that, several, genes, that, contribute, to, sex, hormone, biosynthesis, and, metabolism, are]), verbo([associated]), complemento([with, hypospadias, risk])].
[sujeto(['Conserved', human, cytochrome, b5, '(', 'b5)', residues, 'D58', and, 'D65', are, critical, for, interactions, with, 'CYP2E1', and, 'CYP2C19,', whereas, 'E48', and, 'E49', are, essential, for]), verbo([stimulating]), complemento([the, 17, ',', 20, -, lyase, activity, of, 'CYP17A1'])].
[sujeto(['Here,', we, show, that, b5, mutations, 'E48G,', 'E49G,', 'D58G,', and, 'D65G']), verbo([have]), complemento([reduced, capacity, to, stimulate, 'CYP3A4-catalyzed', progesterone, and, testosterone, 6, 'β-hydroxylation', or, nifedipine, oxidation])].
[sujeto(['The', b5, double, mutation, 'D58G/D65G', fails, to]), verbo([stimulate]), complemento([these, 'reactions,', similar, to, 'CYP2E1', and, 'CYP2C19,', whereas, mutation, 'E48G/E49G', retains, 23, -, 42, '%', of, 'wild-type', stimulation])].
[sujeto(['Cross-linking', of, 'CYP3A4', and, b5]), verbo([decreased]), complemento([in, the, order, 'wild-type&gt;E48G/E49G&gt;D58G/D65G', and, varied, with, phospholipid])].
[sujeto(['We', conclude, that, two, b5, acidic, 'surfaces,', primarily, the, domain, including, residues, 'D58-D65,']), verbo([participate]), complemento([in, the, stimulation, of, 'CYP3A4', activities])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, a, minor, population, of, 'CYP3A4', molecules, remains, sensitive, to, b5, mutation, 'E48G/E49G,', consistent, with, 'phospholipid-dependent', conformational, heterogeneity, of, 'CYP3A4'])].
[sujeto(['Erythromycin,', a, macrolide, 'antibiotic,']), verbo([has]), complemento([been, shown, to, be, a, moderate, 'CYP3A4', inhibitor])].
[sujeto(['Geometric', mean, 'Cmax', and, 'AUCs', of, 'UPA', were]), verbo([increased]), complemento([by, 24, '%', '[', geometric, mean, ratio, point, estimate, '(', 90, '%', 'CI):', 1, '·24', '(', 1, '·01-1·52)]', and, +, 224, '%', and, +, 227, '%', '[', geometric, mean, ratio, point, estimates, '(', 90, '%', 'CI):', 'AUC0-t', 3, '·24', '(', 2, '·75-3·83)', and, 'AUC0-∞', '(', 3, '·27', '(', 2, '·79-3·83)],', 'respectively,', with, no, effect, on, median, tmax, or, 't1/2'])].
[sujeto(['Geometric', mean, 'Cmax', of, 'PGL4002', was]), verbo([decreased]), complemento([by, 47, '%', '[', geometric, mean, ratio, point, estimate, '(', 90, '%', 'CI):', 0, '·523', '(', 0, '·44-0·62)],', but, 'AUCs', were, increased, by, +, 62, '%', and, +, 66, '%', '[', geometric, mean, ratio, point, estimates, '(', 90, '%', 'CI):', 'AUC0-t', 1, '·62', '(', 1, '·43-1·85)', and, 'AUC0-∞', by, 1, '·66', '(', 1, '·47-1·88)],', 'respectively,', with, no, effect, on, median, tmax])].
[sujeto(['Concomitant', use, of, ulipristal, acetate, with, erythromycin, at, therapeutic, concentrations]), verbo([led]), complemento([to, a, limited, increase, in, 'Cmax', and, a, 3, -, fold, increase, in, 'AUCs', for, 'UPA', and, to, a, decrease, in, 'Cmax', and, an, increase, in, 'AUCs', and, prolonged, elimination, for, 'PGL4002'])].
[sujeto(['Previously', we]), verbo([reported]), complemento([decreased, circulating, progesterone, and, fertility, in, one, and, two, year, old, ewes, born, to, undernourished, mothers])].
[sujeto(['Female', offspring, '(', 4, per, treatment, 'group)', were]), verbo([maintained]), complemento([as, a, group, and, fed, to, requirements, from, weaning, until, assigned, to, this, study, at, 6, years, of, age])].
[sujeto(['There', appears, to, be, no, difference, in, hepatic, steroid, catabolism, that, could]), verbo([have]), complemento([led, to, the, decreased, serum, progesterone])].
[sujeto(['However,', these, data, are, consistent, with, the, programming, of]), verbo([decreased]), complemento([steroidogenic, enzyme, expression, in, 'CL', of, 'NR', 'offspring,', leading, to, reduced, synthesis, and, secretion, of, progesterone])].
[sujeto(['Recent', studies]), verbo([have]), complemento([revealed, potent, 'CYP', inhibition, by, 'R'])].
[sujeto([rosea, product, quality]), verbo([have]), complemento([also, been, published])].
[sujeto(['CYP3A4', was, significantly, more]), verbo([inhibited]), complemento([by, the, different, products, than, 'CYP1A2', '(', p, &, 'lt;'])].
[sujeto(['Several', of, the, products, demonstrate, similar, inhibition, levels, as, the, product, 'Arctic', 'Root', already, proven, to]), verbo([inhibit]), complemento(['CYP', enzyme, activity, in, man])].
[sujeto(['The', use, of, fermented, red, ginseng]), verbo([requires]), complemento([close, attention, due, to, the, potential, for, increased, systemic, exposure, when, it, is, used, in, combination, with, 'P-gp', substrate, drugs])].
[sujeto(['Reuterin']), verbo([has]), complemento([a, high, potential, as, a, food, preservative, due, to, both, its, chemical, characteristics, and, its, antimicrobial, activity, against, 'food-borne', pathogens, and, spoilage, bacteria])].
[sujeto(['However,', there, is, a, lack, of, information, about, its, toxicity, and, its, capacity, to, interfere, with, the, metabolism, of, drugs, by]), verbo([inhibiting]), complemento([cytochrome, 'P450', '(', 'CYP)', activity])].
[sujeto(['Reuterin', was, much, less, toxic, than, acrolein, and, only, four, times, more, toxic, than, 'diacetyl,', a, generally]), verbo([recognized]), complemento([as, safe, flavoring, compound])].
[sujeto(['Genotyping', was, performed]), verbo([revealed]), complemento(['CYP2D6*6/*6,', 'CYP3A4*1/*1,', and, 'UGT2B7', -, 161, 'C/T', 'genotypes,', implicating, 'poor,', extensive, and, intermediate, 'metabolism,', respectively])].
[sujeto(['It', was, the, introduction, of, ciprofloxacin, which, was, a]), verbo([trigger]), complemento([for, the, development, of, adverse, drug, reaction, due, to, inhibition, of, 'CYP3A4,', which, was, in, presented, patient, main, metabolic, pathway, for, haloperidol, since, he, was, 'CYP2D6', poor, metabolizer])].
[sujeto(['Presented', case]), verbo([report]), complemento([highlights, the, importance, of, genotyping])].
[sujeto(['We', sought, to, unravel, the, influence, of, body, weight, and, body, mass, index, '(', 'BMI),', both, consistently]), verbo([reported]), complemento([as, pharmacokinetic, relevant, 'parameters,', on, metabolism, of, risperidone, in, a, naturalistic, sample])].
[sujeto(['We']), verbo([suggest]), complemento([changes, in, 'CYP2D6', or, 'CYP3A4', activity, or, differences, in, 'P-glycoprotein', function, in, obese, patients, with, greater, 'BMI', as, a, plausible, mechanism, underlying, these, alterations])].
[sujeto(['Cariprazine', is, also, a, partial, agonist, at, the, serotonin, 5, -, 'HT1A', receptor, and]), verbo([acts]), complemento([as, an, antagonist, at, 5, -, 'HT2B', and, 5, -, 'HT2A', receptors])].
[sujeto(['Pooled']), verbo([responder]), complemento([rates, were, 31, '%', for, cariprazine, 1.5, -, 6, 'mg/d', vs])].
[sujeto(['Short-term', weight]), verbo([gain]), complemento([appears, small, '(', approximately, 8, '%', of, patients, receiving, cariprazine, 1.5, -, 6, 'mg/d', gained, '≥7%', body, weight, from, 'baseline,', compared, with, 5, '%', for, those, randomized, to, 'placebo,', resulting, in, an, 'NNH', of, 34, ')'])].
[sujeto(['Cariprazine', is]), verbo([associated]), complemento([with, no, clinically, meaningful, alterations, in, metabolic, 'variables,', 'prolactin,', or, the, 'ECG', 'QT', interval])].
[sujeto(['Cariprazine', is, also, approved, for, the, acute, treatment, of, manic, or, mixed, episodes]), verbo([associated]), complemento([with, bipolar, 'I', disorder])].
[sujeto(['Cytochrome', 'P450', 17, 'A1', '(', 'CYP17A1)', is, an, important]), verbo([target]), complemento([in, the, treatment, of, prostate, cancer, because, it, produces, androgens, required, for, tumour, growth])].
[sujeto(['The', 'FDA']), verbo([has]), complemento([approved, only, one, 'CYP17A1', 'inhibitor,', 'abiraterone,', which, contains, a, steroidal, scaffold, similar, to, the, endogenous, 'CYP17A1', substrates])].
[sujeto(['Abiraterone', is, structurally, similar, to, the, substrates, of, other, cytochrome, 'P450', enzymes]), verbo([involved]), complemento([in, 'steroidogenesis,', and, interference, can, pose, a, liability, in, terms, of, side, effects])].
[sujeto(['Using', 'non-steroidal', scaffolds, is, expected, to, enable, the, design, of, compounds, that]), verbo([interact]), complemento([more, selectively, with, 'CYP17A1'])].
[sujeto(['Therefore,', we, combined, a, 'structure-based', virtual, screening, approach, with, density, functional, theory, '(', 'DFT)', calculations, to]), verbo([suggest]), complemento(['non-steroidal', compounds, selective, for, 'CYP17A1'])].
[sujeto(['In', vitro, assays, demonstrated, that, two, such, compounds, selectively]), verbo([inhibited]), complemento(['CYP17A1', 17, 'α-hydroxylase', and, 17, ',', 20, -, lyase, activities, with, 'IC50', values, in, the, nanomolar, 'range,', without, affinity, for, the, major, 'drug-metabolizing', 'CYP2D6', and, 'CYP3A4', enzymes, and, 'CYP21A2,', with, the, latter, result, confirmed, in, human, 'H295R', cells])].
[sujeto(['The', 'dimethoxyphenyl-N-((2-methoxyphenyl)methyl)ethanamine', '(', 'NBOMe)', compounds, are, potent, serotonin, 5, -, 'HT2A', receptor, agonists, and]), verbo([have]), complemento([recently, been, subject, to, recreational, use, due, to, their, hallucinogenic, effects])].
[sujeto(['Use', of, 'NBOMe', compounds]), verbo([has]), complemento([been, known, since, 2011, ',', and, several, 'non-fatal', and, fatal, intoxication, cases, have, been, reported, in, the, scientific, literature])].
[sujeto(['The', aim, of, this, study, was, to, determine, the, importance, of, the, different, cytochrome, 'P450', enzymes, '(', 'CYP)']), verbo([involved]), complemento([in, the, metabolism, of, 2, -, '(', 4, -, 'iodo-2,5-dimethoxyphenyl)-N-(2methoxybenzyl)ethanamine', '(', 25, 'I-NBOMe)', and, 2, -, '[', '[', 2, -, '(', 4, -, 'iodo-2,5dimethoxyphenyl)ethylamino]methyl]phenol', '(', 25, 'I-NBOH)', and, to, characterize, the, metabolites])].
[sujeto(['The', following, approaches, were, used, to, identify, the, main, enzymes]), verbo([involved]), complemento([in, primary, 'metabolism:', incubation, with, a, panel, of, 'CYP', and, monoamine, oxidase, '(', 'MAO)', enzymes, and, incubation, in, pooled, human, liver, microsomes, '(', 'HLM)', with, and, without, specific, 'CYP', chemical, inhibitors])].
[sujeto(['The', major, 'CYP', enzymes]), verbo([involved]), complemento([in, the, metabolism, of, 25, 'I-NBOMe', and, 25, 'INBOH', were, identified, as, 'CYP3A4', and, 'CYP2D6,', respectively])].
[sujeto(['Many', adverse, drug, reactions, are]), verbo([caused]), complemento([by, the, cytochrome, 'P450', '(', 'CYP)-dependent', activation, of, drugs, into, reactive, metabolites])].
[sujeto(['We', screened, a, series, of, drugs, to, explore, structural, motifs, that, may, be, responsible, for, 'CYP450-dependent', activation]), verbo([caused]), complemento([by, reactive, metabolite, 'formation,', which, highlighted, specific, liabilities, regarding, certain, phenols, and, anilines])].
[sujeto(['One', of, the, primary, factors]), verbo([leading]), complemento([to, these, pharmacokinetic, changes, is, altered, activity, of, 'drug-metabolizing', enzymes])].
[sujeto(['We', evaluated, the, pharmacokinetics, of, ondansetron, at, three, different, gestational, time, points, in, a, 26, -, 'year-old,', 'pregnant,', 'Caucasian', woman, with, normal, liver, and, kidney, 'function,', who, was]), verbo([maintained]), complemento([on, ondansetron, 8, mg, administered, orally, 3, 'times/day', throughout, her, pregnancy])].
[sujeto(['Ondansetron', area, under, the, plasma, 'concentration-time', curve]), verbo([decreased]), complemento([progressively, across, gestation, '(', 634, ng, 'hr/ml', in, early, 'pregnancy,', 553, ng, 'hr/ml', in, 'mid-pregnancy,', and, 387, ng, 'hr/ml', in, late, 'pregnancy),', with, a, corresponding, increase, in, apparent, oral, clearance, '(', 12.6, 'L/hr', in, 'early-pregnancy,', 14.5, 'L/hr', in, 'mid-pregnancy,', and, 20.7, 'L/hr', in, 'late-pregnancy)'])].
[sujeto(['The']), verbo([decreased]), complemento([area, under, the, plasma, 'concentration-time', curve, and, exposure, to, ondansetron, across, gestation, is, likely, due, to, increased, activity, of, 'CYP3A4', and, 'CYP2D6', during, pregnancy])].
[sujeto(['To', our, 'knowledge,', this, is, the, first]), verbo([report]), complemento([to, describe, ondansetron, pharmacokinetics, across, gestation])].
[sujeto(['Goji', berry, '(', 'Lycium', 'barbarum)']), verbo([has]), complemento([been, used, as, traditional, 'Chinese', medicine, and, a, functional, food, in, 'China'])].
[sujeto(['Goji', tea, may]), verbo([interact]), complemento([with, drugs, such, as, warfarin, by, inhibiting, the, cytochrome, 'P450', '(', 'CYP)', 2, 'C9,', and, this, study, was, undertaken, to, characterize, the, effect, of, 'Goji', products, on, 'CYP2C9/19-,', 'CYP2D6', *, 1, /, *, 10, -, ',', 'CYP3A4/5/7-,', 'CYP19-,', and, 'flavin-containing', monooxygenase, '(', 'FMO)', 3, -, mediated, metabolism])].
[sujeto(['Data', indicates, that, both, fresh, juice, and, commercially, available, juice]), verbo([caused]), complemento([strong, inhibition, '(', over, 75, '%', ')', of, most, of, the, major, 'CYP450', enzymes, and, moderate, inhibition, of, 'FMO3', '(', 30, -, 60, '%', ')'])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'Goji', products, '(', 'berries,', 'tea,', 'tincture,', and, 'juice)', can, inhibit, phase, 'I', drug, metabolism, enzymes, and, have, the, potential, to, affect, the, safety, and, efficacy, of, therapeutic, products])].
[sujeto(['All', the, tested, herbal, formulae]), verbo([inhibited]), complemento(['CYP2C19', activity, '(', 'IC50:', 'SJZD,', 83.28, 'μg/mL;', 'SWD,', 235.54, 'μg/mL;', 'BWD,', 166.82, 'μg/mL;', 'SDD,', 178.19, 'μg/mL);', 'SJZD', '(', 'IC50', =, 196.46, 'μg/mL),', 'SWD', '(', 'IC50', =, 333.42, 'μg/mL)', and, 'SDD', '(', 'IC50', =, 163.42, 'μg/mL)', inhibited, 'CYP2E1-mediated', 'metabolism;', whereas, 'BWD', exhibited, comparatively, weak, inhibition, of, 'CYP2E1', '(', 'IC50', =, 501.78, 'μg/mL)'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'SJZD,', 'SWD,', 'BWD', and, 'SDD', could, potentially, inhibit, the, metabolism, of, 'co-administered', synthetic, drugs, whose, primary, route, of, elimination, is, via, 'CYP2C19'])].
[sujeto(['Our', fifi, ndings]), verbo([provide]), complemento([information, for, the, safety, and, effective, clinical, use, of, these, four, classic, herbal, formulas])].
[sujeto(['The', functions, of, genes]), verbo([involved]), complemento([in, idiopathic, portal, hypertension, '(', 'IPH)', remain, unidentified])].
[sujeto(['The', present, study, was, undertaken, to, identify, the, functions, of, genes]), verbo([expressed]), complemento([in, blood, samples, from, patients, with, 'IPH', through, comprehensive, analysis, of, gene, expression, using, 'DNA', microarrays])].
[sujeto(['The', data, were, compared, with, data, from, healthy, individuals, to, explore, the, functions, of, genes, showing]), verbo([increased]), complemento([or, decreased, expression, in, patients, with, 'IPH'])].
[sujeto(['In', functional, annotation, analysis, using, the, 'Database', for, 'Annotation', 'Visualization', and, 'Integrated', 'Discovery', 'tool,', clusters, showing, dysfunction, in, patients, with, 'IPH']), verbo([involved]), complemento([gene, terms, related, to, the, immune, system])].
[sujeto(['Analysis', using, 'network-based', pathways, revealed]), verbo([decreased]), complemento([expression, of, adenosine, 'deaminase,', ectonucleoside, triphosphate, diphosphohydrolase, 4, ',', 'ATP-binding', 'cassette,', subfamily, 'C,', member, 1, ',', transforming, growth, 'factor-β,', and, prostaglandin, 'E', receptor, 2, ;, increased, expression, of, cytochrome, 'P450,', family, 4, ',', subfamily, 'F,', polypeptide, 3, ',', and, glutathione, peroxidase, 3, ;, and, abnormalities, in, the, immune, 'system,', nucleic, acid, 'metabolism,', arachidonic, 'acid/leukotriene', 'pathways,', and, biological, processes])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, 'IPH', involved, compromised, function, of, immunocompetent, cells, and, that, such, dysfunction, may, be, associated, with, abnormalities, in, nucleic, acid, metabolism, and, arachidonic, 'acid/leukotriene-related', 'synthesis/metabolism'])].
[sujeto(['Transforming', growth, 'factor-', β1, '(', 'TGF-β1)']), verbo([has]), complemento([been, reported, to, inhibit, luteinizing, hormone, '(', 'LH)', 'mediated-steroidogenesis', in, testicular, 'Leydig', cells])].
[sujeto(['Here,', we, investigated, the, possibility, that, 'TGF-β1']), verbo([represses]), complemento([steroidogenesis, through, 'cross-talk', with, the, orphan, nuclear, receptor, 'Nur77'])].
[sujeto(['Nur77,', which, is]), verbo([induced]), complemento([by, 'LH/cAMP', 'signaling,', is, one, of, major, transcription, factors, that, regulate, the, expression, of, steroidogenic, genes, in, 'Leydig', cells])].
[sujeto(['TGF-β1', signaling]), verbo([inhibited]), complemento(['cAMP-induced', testosterone, production, and, the, expression, of, steroidogenic, genes, such, as, 'P450c17,', 'StAR', and, 3, 'β-HSD', in, mouse, 'Leydig', cells])].
[sujeto(['Further,', 'TGF-β1/ALK5', signaling]), verbo([repressed]), complemento(['cAMP-induced', and, 'Nur77-activated', promoter, activity, of, steroidogenic, genes])].
[sujeto(['In', 'addition,', 'TGF-β1/ALK5-activated', 'Smad3']), verbo([repressed]), complemento(['Nur77', transactivation, of, steroidogenic, gene, promoters, by, interfering, with, 'Nur77', binding, to, 'DNA'])].
[sujeto(['Taken', 'together,', these, results]), verbo([suggest]), complemento([that, 'TGF-β1/ALK5/Smad3', signaling, represses, the, expression, of, steroidogenic, genes, via, the, suppression, of, 'Nur77', transactivation, in, testicular, 'Leydig', cells])].
[sujeto(['These', findings, may]), verbo([provide]), complemento([a, molecular, mechanism, involved, in, the, 'TGF-β1-mediated', repression, of, testicular, steroidogenesis])].
[sujeto(['The', mean, maximum, 'QTcF']), verbo([increase]), complemento([from, baseline, was, 407, ',', 487, ',', and, 437, milliseconds, for, 'AZD1305,', alone, and, in, combination, with, verapamil, or, 'ketoconazole,', respectively])].
[sujeto(['Both', the, in, vivo, study, and, the, 'Simcyp', predictions]), verbo([suggest]), complemento([a, contraindication, for, strong, 'CYP3A4', inhibitors, and, 'AZD1305', when, given, in, combination])].
[sujeto(['The', results]), verbo([reported]), complemento([in, this, work, are, significant, for, personalized, medicine, and, 'point-of-care', chemical, 'treatment,', especially, to, improve, the, life, expectancy, and, quality, of, life, of, patients, with, 'prostate-cancer'])].
[sujeto(['Nonenzymatic', biosensors, were, functionalized, with, 'MWCNTs', as, catalyst, for, signal, 'en-hancement,', while, enzymatic, biosensors]), verbo([have]), complemento([been, obtained, with, 'CYP3A4', protein, immobilized, on, 'MWCNTs', as, recognition, biomolecule])].
[sujeto(['This', study, aimed, to, investigate, 'atorvastatin-induced', hepatotoxicity, in, diabetic, rats]), verbo([induced]), complemento([by, 'high-fat', diet, combined, with, streptozotocin])].
[sujeto(['Expressions', and, activities, of, hepatic, 'Cyp3a', and, 'SLCO1B1', were]), verbo([increased]), complemento([in, diabetic, 'rats,', which, were, highly, correlated, with, hepatotoxicity])].
[sujeto(['Antioxidants', '(', glutathione, and, 'N-Acetylcysteine),', 'Cyp3a', inhibitor, ketoconazole, and, 'SLCO1B1', inhibitor, gemfibrozil]), verbo([suppressed]), complemento([cytotoxicity, and, 'ROS', formation, in, primary, hepatocytes, of, diabetic, rats])].
[sujeto(['Phenobarbital', pretreatment, was, used, to]), verbo([induce]), complemento([hepatic, 'Cyp3a', and, 'SLCO1B1', in, rats])].
[sujeto(['Phenobarbital', aggravated, 'atorvastatin-induced', 'hepatotoxicity,', while]), verbo([decreased]), complemento([plasma, exposure, of, atorvastatin])].
[sujeto(['All', these, findings, demonstrated, that, the, upregulations, of, hepatic, 'Cyp3a', and, 'SLCO1B1', in, diabetic, rats, potentiated, 'atorvastatin-induced', hepatotoxicity, via]), verbo([increasing]), complemento(['ROS', formation])].
[sujeto(['Direct', 'IL-6', stimulation, that, mimics, an, inflammatory, state]), verbo([induced]), complemento([a, 'dose-dependent', suppression, of, 'CYP3A4', 'activity,', an, increase, in, 'C-reactive', protein, '(', 'CRP)', 'secretion,', and, a, decrease, in, shed, soluble, 'IL-6R', 'levels,', indicating, expected, hepatic, 'IL-6', bioactivity])].
[sujeto(['Tocilizumab,', an, 'anti-IL-6R', monoclonal, antibody, used, to, treat, rheumatoid, 'arthritis,']), verbo([has]), complemento([been, demonstrated, clinically, to, impact, small, molecule, drug, pharmacokinetics, by, modulating, cytochrome, 'P450', enzyme, 'activities,', an, effect, not, observed, in, traditional, hepatic, cultures])].
[sujeto(['We']), verbo([have]), complemento([now, recapitulated, the, clinical, observation, in, a, 3, 'D', bioreactor, system])].
[sujeto(['This', change, in, 'CYP3A4', activity]), verbo([decreased]), complemento([the, 'half-life', and, 'AUClast', of, the, small, molecule, 'CYP3A4', substrate, simvastatin, hydroxy, 'acid,', measured, before, and, after, tocilizumab, treatment])].
[sujeto(['Many', factors, influence, the, fentanyl, pharmacokinetics]), verbo([leading]), complemento([to, a, wide, 'inter-', and, 'intra-patient', variability])].
[sujeto(['In', elderly, 'patients,', current, data]), verbo([suggest]), complemento([that, we, should, carefully, dose, fentanyl, due, to, alterations, in, absorption, and, metabolism])].
[sujeto(['Several', other, factors]), verbo([have]), complemento([been, studied, but, did, not, show, significant, and, clinically, relevant, effects, on, fentanyl, pharmacokinetics])].
[sujeto(['To', handle, fentanyl, treatment, in, a, population, of, cancer, 'patients,', it, is, essential, that, physicians]), verbo([recognize]), complemento([factors, that, influence, fentanyl, 'pharmacokinetics,', thereby, preventing, potential, 'side-effects', and, increase, its, efficacy])].
[sujeto(['Oncology', therapy, typically]), verbo([involves]), complemento([drug, combinations, since, monotherapy, seldom, provides, the, desired, outcome])].
[sujeto(['Physiologically', based, pharmacokinetic, '(', 'PBPK)', modeling, can, be, effectively, used, for, predicting, 'DDIs', and, guiding, 'dose-selection,', but]), verbo([requires]), complemento([development, of, 'PBPK', models, of, cancer, drugs])].
[sujeto(['AUC,', 'Cmax', and, 'half-life', were, within, 1.5, -, fold, of, observed, results, obtained, from, two]), verbo([reported]), complemento(['studies,', supporting, verification, of, the, 'PBPK', model])].
[sujeto(['However,', nothing, is, known, about, their, effects, in, metabolic, and, transporter, 'proteins,', which, could, potentially]), verbo([lead]), complemento([to, 'herb-drug', interactions, '(', 'HDI)'])].
[sujeto(['In', this, 'work,', we, assess, 'non-toxic', concentrations, '(', 100, 'μg/mL)', of, the, plant, infusions, for, their, in, vitro, ability, to]), verbo([modulate]), complemento(['CYP3A4', mRNA, gene, expression, and, intracellular, glutathione, levels, in, 'HepG2', 'cells,', as, well, as, 'P-glycoprotein', '(', 'P-gp)', activity, in, 'vincristine-resistant', 'Caco-2', cells, '(', 'Caco-2', 'VCR)'])].
[sujeto(['The', latter, plant, extract, was, able, to]), verbo([decrease]), complemento(['GGT', activity, '(', -, 48, '%', ',', p, &, 'lt;', 0.01, ')'])].
[sujeto(['In', 'conclusion,', this, preclinical, study, shows, that, the, administration, of, some, of, these, herbal, medicines, may, be, able, to]), verbo([cause]), complemento([disturbances, to, metabolic, mechanisms, in, vitro])].
[sujeto([3, 'D', cultures, of, human, stem, 'cell-derived', 'hepatocyte-like', cells, '(', 'HLCs)']), verbo([have]), complemento([emerged, as, promising, models, for, 'short-', and, 'long-term', maintenance, of, hepatocyte, phenotype, in, vitro, cultures, by, better, resembling, the, in, vivo, environment, of, the, liver, and, consequently, increase, the, translational, value, of, the, resulting, data])].
[sujeto(['The', second, stage, was, performed, by, either]), verbo([maintaining]), complemento([cells, in, 2, 'D', cultures, for, an, extra, 10, &, 'nbsp;days,', as, 'control,', or, alternatively, cultured, in, 3, 'D', as, 'self-assembled', spheroids, or, in, multicompartment, membrane, bioreactor, system])].
[sujeto(['However,', 'EROD', activity, and, urea, production, were]), verbo([increased]), complemento([in, both, 3, 'D', systems])].
[sujeto(['Moreover,', the, spheroids, revealed, higher, bupropion, 'conversion,', whereas, bioreactor, showed]), verbo([increased]), complemento([albumin, production, and, capacity, to, biotransform, diclofenac])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, the, 3, 'D', models, tested, improved, 'HLC', maturation, showing, a, relevant, biotransformation, capacity, and, thus, provide, more, appropriate, reliable, models, for, mechanistic, studies, and, more, predictive, systems, for, in, vitro, toxicology, applications])].
[sujeto(['No', clinically, relevant, interaction]), verbo([has]), complemento([been, found, with, drugs, used, for, migraine, prophylactic, treatment, or, other, acute, 'drugs,', with, the, exception, of, ergot, derivatives, that, should, not, be, 'co-administered', with, eletriptan])].
[sujeto(['Opioid-induced', constipation, '(', 'OIC)', and, other, gastrointestinal, '(', 'GI)', symptoms, of, 'opioid-induced', bowel, dysfunction, '(', 'OIBD)', significantly, deteriorate, 'patients\'', quality, of, life, and, may]), verbo([lead]), complemento([to, noncompliance, with, opioid, schedule, and, undertreatment, of, pain])].
[sujeto(['Targeted', management, of, 'OIBD', comprises, the, use, of, purely, peripherally]), verbo([acting]), complemento(['μ-opioid', receptor, antagonists, '(', 'PAMORA):', naloxegol, and, methylnaltrexone])].
[sujeto(['The', central, nervous, system, penetration, of, naloxegol, is, negligible, due, to, reduced, permeability, and, its]), verbo([increased]), complemento([efflux, across, the, 'BBB,', related, to, 'P-gp', transporter])].
[sujeto(['Naloxegol', antagonizes, 'μ-', and, 'κ-opioid', receptors, and, displays, low, affinity, to, 'δ-opioid', receptors, in, the, 'GI', 'tract,', thereby]), verbo([decreasing]), complemento(['OIBD', symptoms, without, reversing, central, analgesic, effects])].
[sujeto(['Mild', or, moderate, hepatic, impairment]), verbo([has]), complemento([no, impact, on, naloxegol, 'dosing;', naloxegol, was, not, studied, and, is, not, recommended, in, patients, with, hepatic, failure])].
[sujeto(['It', is, thought, that, eating, habits]), verbo([induces]), complemento([individual, variation, in, intestinal, absorption, and, metabolism, of, drugs])].
[sujeto(['The', metabolisms, to, 6, 'β-hydroxytestosterone', by, recombinant, 'CYP3A4', were, significantly]), verbo([inhibited]), complemento([by, 'VJ-o,', 'VJ-g,', and, 'VJ-y', in, a, preincubation, 'time-dependent', 'manner,', and, 'CYP3A4', activity, in, 'LS180', cells, were, significantly, inhibited, by, 'VJ-o', and, 'VJ-y'])].
[sujeto(['These', results, show, that, the, difference, in, ingestion, volume, of, vegetable, juices, and, vegetables, might, partially]), verbo([induce]), complemento([individual, difference, in, intestinal, drug, metabolism])].
[sujeto(['We', could, not]), verbo([find]), complemento([any, other, association, of, other, genotypes, with, neurotoxicity, grades])].
[sujeto(['Pregnane', 'X', receptor, '(', 'PXR)', is, a]), verbo([nuclear]), complemento([receptor, that, affects, drug, 'metabolism/efflux', and, 'drug-drug', interaction, through, control, of, multiple, drug, resistance, 1, '(', 'MDR1),', which, implies, a, major, role, in, multidrug, 'resistance,', and, other, genes])].
[sujeto(['PXR', 'agonists,', phthalate, and, pregnenolone, had, significant, positive, effects, on, 'cytochrome&nbsp;P450', '(', 'CYP)', 3, 'A4', expression, and, 'PXR-mediated', transcription, through, the, 'CYP3A4', 'promoter,', whereas, 'MDR1', expression, and, 'PXR-mediated', transcription, though, the, 'MDR1', promoter, were, significantly]), verbo([increased]), complemento([in, the, presence, of, paclitaxel, or, cisplatin])].
[sujeto(['Downregulation', of, 'PXR']), verbo([suppressed]), complemento([the, augmented, 'MDR1', expression, and, 'PXR-mediated', transcription, by, 'PXR', 'ligands,', and, significantly, enhanced, cell, growth, inhibition, and, apoptosis, in, the, presence, of, paclitaxel, or, cisplatin])].
[sujeto(['Additionally,', 'ketoconazole,', a, 'PXR', 'antagonist,']), verbo([suppressed]), complemento([the, augmented, 'MDR1', expression, and, 'PXR-mediated', transactivation, by, paclitaxel, and, 'cisplatin,', and, enhanced, cell, growth, inhibition, and, apoptosis, in, their, presence])].
[sujeto(['Our', results, showed, that, orally, administered, 'DDPH', '(', 12.5, -, 50, 'mg/kg/d)', for, 7, days, significantly]), verbo([inhibited]), complemento(['CYP2D1', and, 'CYP3A1', activity, and, mRNA, and, protein, expression, but, weakly, increased, 'CYP1A2', activity, and, expression, in, rats])].
[sujeto(['Further', in, vivo, study, showed, that, oral, administration, of, 'DDPH', '(', 12.5, -, 50, 'mg/kg/d)', for, 7, days, in, rats, significantly]), verbo([increased]), complemento([the, area, under, the, plasma, 'concentration-time', curve, '(', 'AUC)', of, propafenone, by, 25.4, '%', -, 63.9, '%', ',', with, a, concomitant, decrease, in, the, plasma, clearance])].
[sujeto(['In', 'conclusion,', the, results, indicated, that, 'DDPH']), verbo([inhibited]), complemento(['CYP2D', and, 'CYP3A', activities, and, 'down-regulated', their, protein, expression, and, mRNA, transcription])].
[sujeto(['DDPH', might]), verbo([cause]), complemento([metabolic, 'drug-drug', interactions, through, modulation, of, the, activity, and, expression, of, 'CYP2D', and, 'CYP3A'])].
[sujeto(['The', model]), verbo([has]), complemento([been, improved, through, additional, humanization, for, the, nuclear, receptors, constitutive, androgen, receptor, and, pregnane, 'X', receptor, that, control, the, expression, of, key, drug, metabolizing, enzymes, and, transporters])].
[sujeto(['In', this, most, complex, humanized, mouse, model]), verbo([reported]), complemento([to, 'date,', the, cytochromes, 'P450', function, as, predicted, and, we, illustrate, how, these, mice, can, be, applied, to, predict, 'drug-drug', interactions, in, humans])].
[sujeto([5, 'fold),', reduces, the, 'AUC(0-∞)', of, '(', +, ')', -, '(', 'S)-IBU', '(', approximately, 2, 'fold)', and]), verbo([inhibits]), complemento([preferentially, the, metabolism, of, '(', -, ')', -, '(', 'R)-FLU'])].
[sujeto(['In', 'conclusion,', inhalation, exposure, of, ethanol, at, a, concentration, of, 2, 'TLV-STEL', '(', 6, 'h/day', for, 6, 'weeks)']), verbo([induces]), complemento(['CYP3A', and, 'CYP2C', but, inhibits, 'CYP2D', in, rats])].
[sujeto(['Cytochrome', 'P450', monooxygenases, '(', 'P450s),', which, are, 'well-known', 'drug-metabolizing', 'enzymes,', are, thought, to, play, a, signal, transduction, role, in, µ, opioid, analgesia, and, may, serve, as, 'high-affinity', '(', 3, ')', 'H-cimetidine', '(', '(', 3, ')', 'HCIM)']), verbo([binding]), complemento([sites, in, the, brain])].
[sujeto(['(', 3, ')', 'HCIM']), verbo([binding]), complemento([sites, may, also, be, related, to, opioid, or, nonopioid, analgesia])].
[sujeto(['However,', of, the, more, than, 100, murine, 'P450', 'enzymes,', the, specific, 'isoform(s)', responsible, for, either, function]), verbo([have]), complemento([not, been, identified])].
[sujeto(['Presently,', three, lines, of, constitutive, 'P450', gene, cluster, knockout, '(', 'KO)', mice, with, 'full-length', deletions, of, 14, 'Cyp2c,', 9, 'Cyp2d,', and, 7, 'Cyp3a', genes, were, studied, for, deficiencies, in, '(', 3, ')', 'HCIM']), verbo([binding]), complemento([and, for, opioid, analgesia])].
[sujeto(['Liver', and, brain, homogenates, from, all, three, genotypes, showed, normal, '(', 3, ')', 'HCIM']), verbo([binding]), complemento(['values,', indicating, that, gene, products, of, 'Cyp2d,', 'Cyp3a,', and, 'Cyp2c', are, not, '(', 3, ')', 'HCIM-binding', proteins])].
[sujeto(['A', possible, role, for, 'Cyp2c', gene, products, in, opioid, analgesia]), verbo([requires]), complemento([further, consideration])].
[sujeto(['Compared', with, the, inhibition, effect, of, 'RA', decoctions, on, 'CYP450', 'isoforms,', their, 'co-decoctions', of, 'RA', and, 'RPA', with, different, proportions, can]), verbo([decrease]), complemento(['RA\'', inhibition, on, 'CYP3A,', 'CYP2D,', 'CYP2C', and, 'CYP1A2,', but, can, not, reduce, 'RA\'', effect, on, 'CYP2E1'])].
[sujeto(['Compared', with, the, metabolic, fingerprints, of, 'RA', 'decoction,', the, intensity, of, 'diester-diterpenoid', aconitum, alkaloids]), verbo([decreased]), complemento(['significantly,', while, the, intensity, of, 'monoester-diterpenoid', alkaloids, significantly, increased, in, the, metabolic, fingerprints, of, 'co-decoctions', of, 'RA', and, 'RPA'])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, 'RA', coadministration, with, 'RPA', increased, the, degradation, of, toxic, alkaloid, and, show, the, effect, of, toxicity, reducing, and, efficacy, enhancing])].
[sujeto(['Interestingly,', it, also, possesses, a, number, of, 'drug-metabolizing', enzymes]), verbo([found]), complemento([in, 'humans,', such, as, 'CYP1A,', 'CYP2D', and, 'CYP3A'])].
[sujeto(['To', evaluate, the, hypothesis, that, the, 'guinea-pig', also]), verbo([expresses]), complemento([a, functional, 'CYP2C', 'drug-metabolizing', enzyme, and, the, 'P-glycoprotein', '(', 'P-gp)', drug, transporter, in, various, tissues])].
[sujeto(['The', 'guinea-pig']), verbo([expresses]), complemento([functional, 'CYP2C', and, 'P-gp,', thus, suggesting, its, usefulness, for, further, validating, data, obtained, with, other, animal, models, in, drug, 'biotransformation/transport', studies])].
[sujeto(['In', the, in, vitro, cytochrome, 'P450', inhibition, 'study,', the, rate, of, disappearance, of, testosterone, was, significantly, reduced, in, the, presence, of, 10, µM, 'PU,', while, that, of, other, cytochrome, 'P450', substrates, was, not, significantly, affected, in, both, human, and, rat, liver, 'microsomes,']), verbo([suggesting]), complemento([that, puerarin, inhibits, the, in, vitro, hepatic, 'CYP3A-mediated', metabolism, in, the, human, and, rat, systems, '(', 'IC50', =, 15.5, ±, 3.9, 'µM)'])].
[sujeto(['After', intravenous, administration, of, buspirone, with, single, simultaneous, coadministration, of, intravenous, puerarin, at, a, dose, of, 10, 'mg/kg', in, 'rats,', the, total, area, under, the, plasma, 'concentration-time', curve, from, time, zero, to, time, infinity, was]), verbo([increased]), complemento([while, 'time-averaged', total, body, clearance, decreased])].
[sujeto(['Therefore,', results, of, the, in, vitro, microsomal, and, in, vivo, pharmacokinetic, studies]), verbo([suggest]), complemento([the, possible, inhibition, of, hepatic, 'CYP3A-mediated', drug, metabolism, by, puerarin, 'administration,', potentially, leading, to, 'metabolism-mediated', 'herb-drug', interactions, with, clinical, significance])].
[sujeto(['To', establish, the, role, of, the, hepatic, and, extrahepatic, 'P450', system, in, drug, and, foreign, chemical, 'disposition,', drug, 'efficacy,', and, 'toxicity,', we, created, a, unique, mouse, model, in, which, 30, cytochrome, 'P450', genes, from, the, 'Cyp2c,', 'Cyp2d,', and, 'Cyp3a', gene, clusters]), verbo([have]), complemento([been, deleted])].
[sujeto(['Remarkably,', despite, a, wide, range, of, putative, important, endogenous, 'functions,', 'Cyp2c/2d/3a', 'KO', mice, were, viable, and, 'fertile,', demonstrating, that, these, genes]), verbo([have]), complemento([evolved, primarily, as, detoxification, enzymes])].
[sujeto(['Changes', in, hepatic, morphology, and, a]), verbo([decreased]), complemento([blood, glucose, '(', 30, '%', ')', were, also, noted])].
[sujeto(['Thus,', 'Cyp2c/2d/3a', 'KO', mice]), verbo([provide]), complemento([a, powerful, model, to, study, the, in, vivo, role, of, the, 'P450', system, in, drug, metabolism, and, 'efficacy,', as, well, as, in, chemical, toxicity])].
[sujeto(['Ulcerative', colitis, '(', 'UC)', patients, may]), verbo([have]), complemento([increased, concentrations, of, drugs, in, their, blood])].
[sujeto(['We', hypothesized, that, this, response, is, mainly, due, to, a]), verbo([decrease]), complemento([in, the, expression, and, activity, of, the, 'drug-metabolizing', 'enzyme,', cytochrome, 'P450', '(', 'CYP),', in, the, liver])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([tried, to, demonstrate, the, hypothesis])].
[sujeto(['UC', was]), verbo([induced]), complemento([in, mice, by, treatment, with, dextran, sulfate, sodium, '(', 'DSS)', solution])].
[sujeto(['The']), verbo([nuclear]), complemento([translocations, of, nuclear, factor, kappa, 'B', '(', 'NF-κB),', pregnane, 'X', receptor, '(', 'PXR),', and, constitutive, androstane, receptor, '(', 'CAR)', were, analyzed])].
[sujeto(['The', levels, of, hepatic, inflammatory, cytokines]), verbo([increased]), complemento([in, the, 'DSS-treated', group])].
[sujeto(['The', hepatic, mRNA, and, protein, expression, of, 'CYP', '(', 'CYP1A,', 'CYP2C,', 'CYP2D,', 'CYP2E,', and, 'CYP3A)', and, the, 'CYP3A', metabolic, activity, significantly]), verbo([decreased]), complemento([compared, to, the, control, group])].
[sujeto(['Hepatic', 'NF-κB']), verbo([nuclear]), complemento([translocation, significantly, increased, in, the, 'DSS-treated', group])].
[sujeto(['In', 'contrast,', the]), verbo([nuclear]), complemento([translocations, of, 'PXR', and, 'CAR', were, decreased])].
[sujeto(['Lipopolysaccharides', from, inflammatory, sites, in, the, colon]), verbo([induce]), complemento([hepatic, inflammation, in, 'DSS-induced', murine, colitis])].
[sujeto(['This', inflammation, then]), verbo([causes]), complemento([an, increase, in, the, nuclear, translocation, of, hepatic, 'NF-κB', and, a, decrease, in, the, nuclear, translocation, of, 'PXR', and, 'CAR,', resulting, in, the, decreased, expression, and, activities, of, 'CYP'])].
[sujeto(['The', results, of, this, study, indicated, that, at, the, onset, of, 'UC,', the]), verbo([decreased]), complemento([activity, of, hepatic, 'CYP', causes, an, increase, in, the, concentrations, of, drugs, in, the, 'blood,', leading, to, an, increase, in, the, incidence, of, adverse, reactions])].
[sujeto(['In', 'addition,', mechanism, of, inhibition, experimental, results, showed, that, the]), verbo([inhibiting]), complemento([abilities, of, 'Folium', 'Crataegi', extract, and, 'Radix', 'Puerariae', extract, on, each, 'CYP450', isozyme, increased, with, the, increasing, of, the, preincubation, 'time,', 'therefore,', the, inhibitory, effects, were, a, 'mechanism-based', inhibition])].
[sujeto(['In', patients, with, 'gastrectomy,', it, is, possible, that, drug, effectiveness, is, reduced, compared, to, healthy, subjects, due, to, the]), verbo([increased]), complemento([of, the, 'drug-metabolizing', 'enzyme,', 'Cytochrome', 'P450', '(', 'CYP)'])].
[sujeto(['On', the, other, 'hand,', significant]), verbo([increases]), complemento([in, the, protein, expression, levels, of, any, 'CYPs', were, observed, in, the, gastrectomy, group, compared, to, the, sham, operation, group, from, 12, weeks, after, the, gastrectomy, onward])].
[sujeto(['These']), verbo([increases]), complemento([in, expression, levels, were, maintained, until, 24, weeks, after, the, gastrectomy])].
[sujeto(['The', examination, of, metabolic, activity, in, the, liver, in, the, gastrectomy, group, using, triazolam, revealed, that, the, metabolic, activity, at, 12, weeks, after, the, gastrectomy, was, significantly]), verbo([increased]), complemento([in, the, gastrectomy, group])].
[sujeto(['The', administration, of, the, anticancer, drug, 'imatinib,', which, is, a, substrate, of, 'CYP3A,', to, mice, at, 12, weeks, after, gastrectomy, resulted, in, an]), verbo([increase]), complemento([in, the, metabolic, 'rate,', suggesting, a, possible, decrease, in, drug, effectiveness])].
[sujeto(['It']), verbo([has]), complemento([been, revealed, that, drug, effectiveness, may, be, reduced, after, gastrectomy, because, the, expression, levels, of, various, 'CYPs', in, the, liver, were, increased, over, a, prolonged, period])].
[sujeto(['Cytochrome', 'P450', '(', 'CYP450)', isoforms, are]), verbo([involved]), complemento([in, the, metabolism, of, a, majority, of, drugs, in, clinical, use, and, plays, a, significant, role, in, reducing, possible, drug, interactions])].
[sujeto(['The', other, isoforms]), verbo([involved]), complemento([in, the, metabolism, included, 'CYP3A,', 'CYP2D,', 'CYP1A', and, 'CYP2E'])].
[sujeto(['But', the, metabolism, of, gliquidone, in, the, human, liver, microsomes, was, mainly]), verbo([mediated]), complemento([by, 'CYP3A4'])].
[sujeto(['The', other, isoforms]), verbo([involved]), complemento([in, this, process, were, 'CYP2C9,', 'CYP2C19', and, 'CYP2D6'])].
[sujeto(['Simultaneously,', significant]), verbo([decreases]), complemento([in, the, serum, concentration, of, the, growth, 'hormone,', testosterone, and, the, thyroid, hormone, 'thyroxine,', as, well, as, an, increase, in, corticosterone, level, were, observed])].
[sujeto(['Significant']), verbo([decreases]), complemento([in, the, activity, of, liver, 'CYP2C11', '(', measured, as, a, rate, of, the, 2, 'α-', and, 16, 'α-hydroxylation', of, 'testosterone)', and, 'CYP3A', '(', measured, as, a, rate, of, the, 2, 'β-', and, 6, 'β-hydroxylation', of, 'testosterone)', were, found])].
[sujeto(['The', obtained, results, indicate, an, important, role, of, the, brain, noradrenergic, system, in, the, neuroendocrine, regulation, of, liver, cytochrome, 'P450', 'expression,', which, may, be, of, significance, in, pathological, states]), verbo([involving]), complemento([this, 'system,', or, during, pharmacotherapy, with, drugs, affecting, noradrenergic, transmission])].
[sujeto(['Baicalin']), verbo([has]), complemento([been, shown, to, possess, many, pharmacological, 'effects,', including, 'antiviral,', 'antioxidant,', 'anti-cancer', and, 'anti-inflammatory', properties])].
[sujeto(['In', the, current, 'study,', we]), verbo([reveal]), complemento([the, inhibitory, effects, of, baicalin, on, the, metabolism, of, dextromethorphan, '(', 'DXM),', a, dual, probe, substrate, of, 'CYP2D', and, 'CYP3A,', in, rats])].
[sujeto(['Lineweaver-Burk', plots, demonstrated, that, baicalin]), verbo([inhibited]), complemento([the, activities, of, 'CYP2D', and, 'CYP3A', in, a, 'non-competitive', manner, in, rat, liver, microsomes, '(', 'RLMs)'])].
[sujeto([')']), verbo([increased]), complemento([the, maximum, drug, concentration, '(', 'C(max))', '(', 37, '%', ')', and, the, area, under, 'concentration-time', curve, '(', 'AUC)', '(', 42, '%', ')', and, decreased, the, clearance, '(', 'CL)', '(', 27, '%', ')', of, 'DXM', in, a, 'randomised,', crossover, study, in, rats, '(', 'P', &, 'lt;', 0.01, ')'])].
[sujeto(['The', activity, of, 'CYP3A', in, excised, liver, samples, from, rats, following, multiple, baicalin, treatment, was, significantly]), verbo([decreased]), complemento([compared, to, that, of, the, control, group, '(', 'P', &, 'lt;', 0.05, ')', ',', whereas, multiple, doses, of, baicalin, had, no, obvious, effect, on, the, activity, of, 'CYP2D'])].
[sujeto(['Taken', 'together,', these, data, demonstrate, that, baicalin]), verbo([inhibits]), complemento([the, metabolism, of, 'DXM', in, a, 'concentration-dependent', manner, in, 'rats,', possibly, through, inhibiting, hepatic, 'CYP2D', and, 'CYP3A', activities])].
[sujeto(['Tamoxifen', '(', 'TAM)', is, used, in, breast, cancer, 'treatment,', but, interindividual, variabilities, in, 'TAM-metabolizing', enzymes, exist, and]), verbo([have]), complemento([been, linked, to, single, nucleotide, polymorphisms, in, the, respective, encoding, genes])].
[sujeto(['The', different, alleles, and, genotypes, of, these, genes]), verbo([have]), complemento([been, presented, for, 'Caucasians', and, 'Asians'])].
[sujeto(['This', research, indicates, the, high, prevalence, of, these, defective, alleles, that, are]), verbo([involved]), complemento([in, 'TAM-metabolic', pathways, that, might, further, affect, 'TAM', treatment])].
[sujeto(['Estrogens']), verbo([have]), complemento([important, roles, in, the, pathogenesis, of, endometrial, cancer])].
[sujeto(['They', can]), verbo([have]), complemento([carcinogenic, effects, through, stimulation, of, cell, proliferation, or, formation, of, 'DNA-damaging', species])].
[sujeto(['HIEEC', and, 'Ishikawa']), verbo([expressed]), complemento([all, 'ERs', to, different, 'extents,', while, 'HEC-1A', cells, lacked, expression, of, 'ESR1'])].
[sujeto(['This', study]), verbo([reveals]), complemento([that, 'HIEEC,', 'Ishikawa,', and, 'HEC-1A', cells, can, all, form, estrogens, only, via, the, sulfatase, pathway])].
[sujeto(['HIEEC,', 'Ishikawa,', and, 'HEC-1A', cells]), verbo([expressed]), complemento([all, the, major, genes, in, the, production, of, hydroxyestrogens, and, estrogen, 'quinones,', and, in, their, conjugation])].
[sujeto(['This', study]), verbo([provides]), complemento([further, characterization, of, 'HIEEC,', 'Ishikawa,', and, 'HEC-1A', 'cells,', and, shows, that, they, differ, greatly, in, expression, of, the, genes, investigated, and, in, their, capacity, for, 'E2', 'formation,', and, thus, they, represent, different, in, vitro, models])].
[sujeto(['This', study, investigates, the, metabolism, and, mode, of, action, of, galaxolide, '(', 'HHCB)', in, the, 'European']), verbo([sea]), complemento([bass, -, 'Dicentrarchus', 'labrax-', following, a, single, intraperitoneal, injection, of, 50, &, 'nbsp;mg', 'HHCB/kg', body, weight])].
[sujeto(['HHCB', was, actively, metabolised, by]), verbo([sea]), complemento([bass, and, acted, as, a, weak, inhibitor, of, the, synthesis, of, oxyandrogens, in, gonads, of, male, fish])].
[sujeto(['Eight', 'Gir', ×, 'Holstein', cows, were]), verbo([maintained]), complemento([on, a, 'low-quality', 'Brachiaria', brizantha, pasture, with, reduced, forage, 'availability,', but, they, individually, 'received,', on, 'average,', 3, 'kg/cow', daily, '(', as, 'fed)', of, a, 'corn-based', concentrate, from, d, -, 28, to, 0, of, the, experiment])].
[sujeto(['In', 'conclusion,', hepatic, 'CYP3A4', and, 'CYP2C19', mRNA, expression, can, be, promptly]), verbo([modulated]), complemento([by, glucose, infusion, followed, by, acute, increases, in, circulating, 'insulin,', which, provides, novel, insight, into, the, physiological, mechanisms, associating, nutrition, and, reproductive, function, in, dairy, cows])].
[sujeto(['CYP3A', activity, is]), verbo([induced]), complemento([by, approximately, 2, -, fold, during, the, third, trimester, of, human, pregnancy])].
[sujeto(['Placental', growth, hormone, '(', 'PGH),', estrogens, '(', primarily, 17, 'β-estradiol),', 'cortisol,', and, progesterone]), verbo([have]), complemento([the, potential, to, modulate, 'CYP3A', activity])].
[sujeto(['Therefore,', we, determined, whether, the, elevated, plasma, concentrations, of, these, hormones, during, pregnancy]), verbo([induce]), complemento([hepatic, 'CYP3A', expression])].
[sujeto(['The', combination, of, 'PGH/growth', hormone, and, cortisol]), verbo([induced]), complemento(['CYP3A', activity, and, expression, significantly, more, than, did, cortisol, alone])].
[sujeto(['When', incubated, with, the, unbound, or, total, plasma, concentration, of, all, the, 'hormones,', 'CYP3A', activity, in, 'SCHH', was]), verbo([induced]), complemento([to, an, extent, comparable, to, that, observed, in, vivo, during, the, third, trimester])].
[sujeto(['Tamoxifen', is, metabolically]), verbo([activated]), complemento([to, 4, -, hydroxytamoxifen, and, endoxifen, by, cytochrome, 'P450', '(', 'CYP)'])].
[sujeto(['CYP', phenotypes]), verbo([have]), complemento([been, correlated, to, tamoxifen, 'outcomes,', but, few, have, considered, drug, interactions, or, combinations, of, genes])].
[sujeto(['Fewer', still]), verbo([have]), complemento([considered, 'ABCB1,', which, encodes, 'P-glycoprotein', and, transports, active, tamoxifen, metabolites])].
[sujeto(['No', significant, relationships, were]), verbo([found]), complemento([for, other, genes, unless, patients, were, subgrouped, according, to, 'CYP2D6', phenotypes, or, 'ABCB1', genotypes])].
[sujeto(['When', 'CYP2D6', was, 'impaired,', 'ABCB1', 3435, 'CC', '(', 'rs1045642)', was]), verbo([associated]), complemento([with, significantly, higher, endoxifen, '(', p, =, 0.03, ')'])].
[sujeto(['Pharmacogenomic', '(', 'PGx)', testing]), verbo([has]), complemento([been, increasingly, used, to, optimize, drug, 'regimens;', 'however,', its, potential, in, older, adults, with, polypharmacy, has, not, been, systematically, studied])].
[sujeto(['Both', patients, with, significant, 'drug-gene', interactions, had, a, history, of, frequent, hospitalizations, '(', six, and, 23, ',', 'respectively),', whereas, the, person, without, impaired, cytochrome, 'P450', enzyme, activity, had, only, two, acute, episodes, in, the, last, 5, 'years,', although]), verbo([he]), complemento([was, older, and, had, multiple, comorbidities])].
[sujeto(['For', practical, implementation, of, pharmacogenomics, in, routine, clinical, 'care,', besides]), verbo([providing]), complemento([convincing, evidence, of, its, clinical, 'effectiveness,', multiple, barriers, must, be, addressed])].
[sujeto(['Introduction', of, intelligent, clinical, decision, support, in, electronic, medical, record, systems, is]), verbo([required]), complemento([to, address, complexities, of, simultaneous, 'drug-gene', and, 'drug-drug', interactions, in, older, adults, with, polypharmacy])].
[sujeto(['Genetic', polymorphisms, of, 'drug-metabolizing', enzymes, and, transporters]), verbo([have]), complemento([been, extensively, studied, with, regard, to, tamoxifen, treatment, outcomes])].
[sujeto(['Analysis', of, 'organ-specific', metastasis, may]), verbo([reveal]), complemento([the, association, of, these, pharmacogenetic, factors])].
[sujeto(['In', the, univariate, 'analysis,', primary, tumor, size, &, 'gt;5', cm, was, significantly]), verbo([associated]), complemento([with, increased, risk, of, distant, metastasis, '(', 'P=0'])].
[sujeto(['ABCC2', -, 24, 'CC', were, shown, to, be]), verbo([associated]), complemento([with, increased, risk, of, distant, metastasis, '(', 'P=0'])].
[sujeto(['The', combined, genotype, of, 'ABCC2', -, 24, 'CC', -, 'ABCB1', 3435, 'CT+TT', was]), verbo([associated]), complemento([with, increased, risk, of, distant, and, bone, metastasis, '(', 'P=0'])].
[sujeto(['This', study, indicates, that, polymorphisms, of, 'ABCC2', and, 'ABCB1', are, independently]), verbo([associated]), complemento([with, bone, metastasis])].
[sujeto(['Many', clinically, relevant, 'SNPs,', including, 'CYP2C19*2,', 'CYP2D6*10,', 'CYP3A5*3,', and, 'SLCO1B1*5,', were]), verbo([found]), complemento([to, have, frequencies, similar, to, those, in, the, 'Chinese', population])].
[sujeto(['Metabolism', by, the, polymorphic, cytochrome, 'P450', '(', 'CYP)', 2, 'D6', enzyme, to, the, psychoactive, metabolite, 4, -, hydroxymethamphetamine, '(', 'OH-MA),', and, possibly, by, additional, 'enzymes,', is]), verbo([suggested]), complemento([to, be, involved, in, its, toxicity])].
[sujeto(['Our', study, demonstrated, that, the, 'CYP2D6', enzyme, and, genotype, are, important, in, the, metabolism, of, 'PMMA', to, 'OH-MA', in, 'humans,', but, that, other, enzymes, are, also]), verbo([involved]), complemento([in, this, biotransformation])].
[sujeto(['The', overrepresentation, of, the, 'CYP2D6', poor, metabolizer, '(', 'PM)', genotype]), verbo([found]), complemento([in, the, nonfatal, 'PMMA', abuse, controls, warrants, further, investigations])].
[sujeto(['The', pharmacokinetics, and, pharmacogenomics, were, not]), verbo([associated]), complemento([with, significantly, different, 'toxicities,', response, 'rates,', or, survival, times, with, gefitinib])].
[sujeto(['Elevated', gefitinib, exposure, might, be]), verbo([associated]), complemento([with, 'drug-induced', 'ILD'])].
[sujeto(['There', are, conflicting]), verbo([reports]), complemento([regarding, the, effects, of, cytochrome, 'P450', '(', 'P450,', 'CYP)', genotypes, on, the, plasma, concentrations, of, risperidone, and, its, pharmacologically, active, 'metabolite,', 9, -, hydroxyrisperidone, '(', 'paliperidone),', in, clinical, patients])].
[sujeto(['Conventional', mass, spectrometry, '(', 'MS)', analyses, of, tamoxifen, and, its, metabolites]), verbo([require]), complemento([isotopic, internal, standards, '(', 'ISs)'])].
[sujeto(['Furthermore,', this, reductive, 'amination-based', method, may]), verbo([enhance]), complemento([the, signal, intensities, of, 'D2-methyl', modified, 'N-desmethyltamoxifen', and, 'endoxifen,', thus, facilitating, the, 'MS', detection])].
[sujeto(['The', microarray, results, showed, to]), verbo([have]), complemento([high, call, rate, and, accuracy, according, to, concordance, with, genotypes, identified, by, independent, bidirectional, sequencing])].
[sujeto(['Furthermore,', we]), verbo([found]), complemento([that, the, major, 'CYP2C9,', 'CYP2C19,', 'CYP2D6', and, 'CYP3A5', alleles, in, 'Chinese', 'Han', population, were, 'CYP2C9*3', '(', allelic, frequency, of, 10.7, '%', ')', ',', 'CYP2C9*2', '(', 20.31, '%', ')', ',', 'CYP2C19*2', '(', 5.68, '%', ')', ',', 'CYP2D6*10', '(', 58.52, '%', ')', ',', 'CYP2D6*2', '(', 13.76, ')', and, 'CYP3A5*3', '(', 70.69, '%', ')'])].
[sujeto(['With', flexible, 'DNA', 'preparation,', the, microarray, can, significantly, facilitates, the, process, of, detecting, genetics, variations, in, 'CYP2C9,', 'CYP2C19,', 'CYP2D6', and, 'CYP3A5', gene, and]), verbo([provide]), complemento([safe, and, effective, therapy, for, individual, patients])].
[sujeto(['Metabolic', activities, of, 'P450s']), verbo([expressed]), complemento([in, recombinant, 'Escherichia', coli, at, substrate, concentrations, around, the, 'Michaelis', constant, were, compared, in, the, presence, or, absence, of, the, antibiotics])].
[sujeto(['Amoxicillin,', 'ampicillin,', and, piperacillin, at, 0.5, or, 1, mM, concentrations, neither]), verbo([inhibited]), complemento([nor, stimulated, 'CYP2C9-mediated', tolbutamide, 'methylhydroxylation,', 'CYP2D6-mediated', dopamine, formation, from, 'p-tyramine,', or, 'CYP3A4-', or, 'CYP3A5-mediated', testosterone, 6, 'β-hydroxylation'])].
[sujeto(['However,', amoxicillin, and, piperacillin]), verbo([inhibited]), complemento(['CYP2C8-mediated', aminopyrine, 'N-demethylation', at, 50, '%', inhibitory, concentration, of, 0.83, and, 1.14, 'mM,', respectively])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, piperacillin, might, inhibit, 'CYP2C8', 'clinically,', although, the, interactions, between, these, three, 'penicillin-based', antibiotics, and, other, drugs, that, are, metabolized, by, 'P450s', investigated, would, not, be, clinically, significant])].
[sujeto(['This', study, was, undertaken, to, determine, the, association, of, clinical, 'markers,', cytochrome, 'P450,', family, 3, ',', subfamily, 'A,', polypeptide, 5, '(', 'CYP3A5)', and]), verbo([nuclear]), complemento([receptor, subfamily, 1, ',', group, 'I,', member, 3, '(', 'NR1I3)', gene, polymorphisms, with, tacrolimus, pharmacokinetics])].
[sujeto(['In', single, variable, 'analysis,', hemoglobin, '(', 'Hb),', hematocrit, '(', 'Hct),', donor, 'CYP3A5,', 'NR1I3', gene, polymorphisms, and, recipient, 'CYP3A5', gene, polymorphisms, were]), verbo([associated]), complemento([with, 'log-transformed', tacrolimus, 'C/D', ratios])].
[sujeto(['Donor', 'CYP3A5', polymorphisms, were, the, most, important, 'variant,', accounting, for, 14.3, '%', of, total, variation]), verbo([involved]), complemento([in, tacrolimus, pharmacokinetics])].
[sujeto(['Hepatotoxicity', is, a, major]), verbo([cause]), complemento([of, the, withdrawal, of, epidermal, growth, factor, receptor, tyrosine, kinase, inhibitors, '(', 'EGFR-TKIs)', when, treating, 'EGFR', 'mutation-positive', 'non-small', cell, lung, cancer, '(', 'NSCLC)'])].
[sujeto(['We']), verbo([report]), complemento([a, case, in, which, 'gefitinib-', and, 'elrotinib-induced', severe, hepatotoxicity, arose, in, a, patient, with, the, uridine, diphosphate, glucuronosyltransferase, isoform, 1, 'A1', '(', 'UGT1A1)', and, cytochrome, p450, 3, 'A5', '(', 'CYP3A5)', poor, metabolizer, phenotypes])].
[sujeto(['Evaluation', of, single, nucleotide, polymorphisms, '(', 'SNPs)', in, metabolic, enzymes, might, be, useful, to, predict, severe, hepatotoxicity]), verbo([induced]), complemento([by, 'EGFR-TKIs'])].
[sujeto(['We', analyzed, the, effect, of, single, nucleotide, polymorphisms, '(', 'SNPs)', in, genes]), verbo([involved]), complemento([in, sunitinib, pharmacokinetics, on, clinical, outcomes, in, 'Japanese', patients, with, mRCC])].
[sujeto(['We', analyzed, the, effect, of, 'SNPs', in, genes]), verbo([involved]), complemento([in, sunitinib, pharmacokinetics, on, the, clinical, outcome, in, mRCC, patients, in, a, 'Japanese', population])].
[sujeto(['In', 'conclusion,', our, data, showed, that, the, 'ABCB1', rs2032582, 'GG', genotype, was]), verbo([associated]), complemento([with, individual, adverse, 'events\'', susceptibility, among, 'Japanese', patients, treated, with, sunitinib, in, routine, clinical, settings])].
[sujeto(['To', investigate, whether, plasma, miRNAs]), verbo([targeting]), complemento(['CYP3A4/5', have, an, impact, on, the, variance, of, pharmacokinetics, of, clopidogrel])].
[sujeto(['The', association, between, plasma, miRNAs]), verbo([targeting]), complemento(['CYP3A4/5', mRNA, and, clopidogrel, pharmacokinetics, was, analyzed, in, 31, patients, with, coronary, heart, disease, who, received, 300, mg, loading, dose, of, clopidogrel])].
[sujeto(['Plasma', 'miR-142', was, negatively]), verbo([associated]), complemento([with, 'H4', 'Cmax', '(', r, =, -, 0.5269, ;, p, =, 0.004, ')', and, associated, with, 'H4', 'AUC0-4h', '(', r, =, -, 0.4986, ;, p, =, 0.0069, ')', after, 300, mg, loading, dose, of, clopidogrel, in, coronary, heart, disease, patients])].
[sujeto(['Due', to, unavoidable, confounding, variables, in, the, direct, study, of, human, 'subjects,', it]), verbo([has]), complemento([been, difficult, to, unravel, the, effects, of, prenatal, cocaine, exposure, on, the, human, fetal, 'brain,', as, well, as, the, cellular, and, biochemical, mechanisms, involved])].
[sujeto(['This', model]), verbo([retains]), complemento([essential, features, of, human, neocortical, development, by, encompassing, a, single, 'self-organized', neocortical, 'structure,', without, including, an, 'animal-derived', gelatinous, matrix])].
[sujeto(['We']), verbo([reported]), complemento([previously, that, prenatal, cocaine, exposure, to, rats, during, the, most, active, period, of, neural, progenitor, proliferation, induces, cytoarchitectural, changes, in, the, embryonic, neocortex])].
[sujeto(['Using', hPSC, 3, 'D', neocortical, 'organoids,', we, demonstrate, that, the, effects, of, cocaine, are]), verbo([mediated]), complemento([through, 'CYP3A5-induced', generation, of, reactive, oxygen, 'species,', inhibition, of, neocortical, progenitor, cell, 'proliferation,', induction, of, premature, neuronal, 'differentiation,', and, interruption, of, neural, tissue, development])].
[sujeto(['Furthermore,', knockdown, of, 'CYP3A5', reversed, these, 'cocaine-induced', pathological, 'phenotypes,']), verbo([suggesting]), complemento(['CYP3A5', as, a, therapeutic, target, to, mitigate, the, deleterious, neurodevelopmental, effects, of, prenatal, cocaine, exposure, in, humans])].
[sujeto(['Moreover,', 3, 'D', organoid, methodology]), verbo([provides]), complemento([an, innovative, platform, for, identifying, adverse, effects, of, abused, psychostimulants, and, pharmaceutical, 'agents,', and, can, be, adapted, for, use, in, neurodevelopmental, disorders, with, genetic, etiologies])].
[sujeto(['Being', a, substrate, of, the, cytochrome, 'P450', 3, 'A4', '(', 'CYP3A4)', 'isoenzyme,', sirolimus, metabolism, is]), verbo([decreased]), complemento([when, posaconazole, is, administered, concomitantly])].
[sujeto(['We', were, able, to, describe, well, the, 'interaction,', and]), verbo([found]), complemento([a, value, of, 'IC50', of, posaconazole, towards, sirolimus, clearance, of, 0.68, &, 'nbsp;μg/mL'])].
[sujeto(['The', simulations, showed, that, even, a, 80, '%']), verbo([decrease]), complemento([of, the, daily, dose, of, sirolimus, is, unsuitable, in, many, cases, with, trough, concentrations, of, posaconazole, of, 2, &, 'nbsp;μg/mL'])].
[sujeto(['A']), verbo([decrease]), complemento([of, 40, '%', of, the, dose, with, spacing, administrations, of, 3, days, may, be, considered])].
[sujeto(['However,', diplotype, analysis]), verbo([suggested]), complemento([that, 'CYP3A5', expressers, with, the, 'CYP3A4*1/*1G', genotype, '(', n, =, 3, ')', had, significantly, lower, midazolam, 'AUC0-∞', values, '(', 210, '·0', ±, 33, '·5', vs])].
[sujeto(['There', were, no, significant, associations, between, midazolam, pharmacokinetic, parameters, and, urinary, ratios, of, 6, 'β-OHF/F', and, the, two, 'CYP3A', polymorphisms, were, not]), verbo([associated]), complemento([with, the, urinary, ratios, of, 6, 'β-OHF/F', or, midazolam, pharmacokinetic, parameters])].
[sujeto(['The', possible, association, of, 'CYP3A5*3', and, 'CYP3A4*1G', polymorphisms, on, 'CYP3A', activity, and, their, potential, interaction]), verbo([require]), complemento([confirmation, in, a, larger, study])].
[sujeto(['The', administered, doses]), verbo([required]), complemento([to, achieve, the, target, trough, level, were, significantly, higher, on, day, 7, than, on, day, 1, among, all, 'groups,', regardless, of, the, differences, in, the, 'SNPs,', especially, among, those, with, donor, 'CYP3A5', *, 1, allele])].
[sujeto(['The', tacrolimus, concentration, was, kept, within, the]), verbo([targeted]), complemento([level, all, through, the, study, regardless, of, 'SNPs'])].
[sujeto(['Cytochrome', 'P450', oxidoreductase, '(', 'POR)', is, the, only, flavoprotein, that, donates, electrons, to, all, microsomal, 'P450', enzymes, '(', 'CYP),', and, several, 'POR', 'SNPs']), verbo([have]), complemento([been, shown, to, be, important, contributors, to, altered, 'CYP', activity, or, 'CYP-mediated', drug, metabolism])].
[sujeto(['Of', 'CYP3A5*3/*3/', 'POR', 'rs1057868-rs2868177GC-GT', diplotype, 'carriers,', 85.71, '%', exceeded, the, upper, limit, of, the]), verbo([target]), complemento([range, '(', 8, 'ng/mL),', which, was, also, significantly, higher, compared, with, the, latter, two, groups, '(', 14.29, '%', and, 0.0, '%', ',', 'respectively,', 'P&lt;0'])].
[sujeto(['Genotyping', of, 'POR', 'rs1057868-rs2868177', diplotypes, would, help, to, differentiate, initial, tacrolimus, dose, requirements, and, to, achieve, early]), verbo([target]), complemento(['C0', ranges, in, 'Chinese', renal, transplant, recipients])].
[sujeto(['Understanding', of, the, pharmacogenetic]), verbo([causes]), complemento([is, critical, to, predict, drug, response, hence, providing, a, basis, for, personalized, medications])].
[sujeto(['Genetic', alteration, in, activity, of, drug]), verbo([target]), complemento([and, drug, metabolizing, proteins, could, explain, the, development, of, pharmacoresistant, epilepsy])].
[sujeto(['CYP3A5*3', variants]), verbo([have]), complemento([no, contributing, effect, on, pharmacoresistance, among, 'Egyptian', epileptic, children])].
[sujeto(['The', optimal, dose, of, angiotensin, receptor, blocker, is, not, 'known,', and, no, data, are, available, about, losartan, pharmacogenetic, profile, in, 'Marfan', 'syndrome;', we]), verbo([have]), complemento([proposed, a, strategy, to, tackle, this, issue, based, on, evaluating, the, major, genetic, polymorphisms, involved, in, the, losartan, conversion, into, active, carboxylic, acid, metabolite])].
[sujeto(['Scarce', data]), verbo([have]), complemento([been, compiled, for, these, samples, despite, the, rich, genetic, background, of, north, 'African', populations])].
[sujeto(['North', 'African', populations, are, 'heterogeneous,', genetically, diverse, and, show, a, considerable, 'sub-Saharan', 'African', contribution, for, markers]), verbo([associated]), complemento([with, increased, risk, of, prostate, cancer, and, with, differential, drug, metabolism])].
[sujeto(['Metabolic', activation, of, the, 'dual-tyrosine', kinase, inhibitor, lapatinib, by, cytochromes, 'CYP3A4', and, 'CYP3A5']), verbo([has]), complemento([been, implicated, in, 'lapatinib-induced', idiosyncratic, 'hepatotoxicity;', 'however,', the, relative, enzyme, contributions, have, not, been, established])].
[sujeto(['The', objective, of, this, study, was, to, examine, the, roles, of, 'CYP3A4', and, 'CYP3A5', in, lapatinib, bioactivation]), verbo([leading]), complemento([to, a, 'reactive,', potentially, toxic, quinoneimine])].
[sujeto(['Limited', sampling, strategies, '(', 'LSS)']), verbo([have]), complemento([been, proposed, as, an, alternative, method, for, estimating, area, under, 'concentration-time', curve, '(', 'AUC)', of, immunosuppressive, agent, tacrolimus, '(', 'TAC)'])].
[sujeto(['We', also]), verbo([found]), complemento([that, 'ABCB1', genotype, may, be, a, reason, of, variation, in, the, prediction, performance])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, 'S'])].
[sujeto([nigrum]), verbo([has]), complemento([hepatoprotective, effects, against, 'ethanol-induced', injury, both, 'in&nbsp;vitro', and, 'in&nbsp;vivo,', and, can, protect, the, integrity, of, hepatocytes, and, thus, reduce, the, release, of, liver, 'GSTA1,', which, contributes, to, improved, liver, detoxification])].
[sujeto(['MEF2-deficient', 'MA-10', 'Leydig', cells, exhibit, a, significant]), verbo([decrease]), complemento([in, steroidogenesis, concomitant, with, a, reduction, in, glutathione, 'S-transferase', '(', 'GST)', activity, and, in, the, expression, of, the, 4, 'Gsta', members, '(', 'GST)', that, encode, 'ROS', inactivating, enzymes])].
[sujeto(['Here,', we]), verbo([report]), complemento([a, novel, role, for, 'MEF2', in, 'ROS', detoxification, by, directly, regulating, 'Gsta', expression, in, 'Leydig', cells])].
[sujeto(['Endogenous', 'Gsta1-4', mRNA, levels, were]), verbo([decreased]), complemento([in, 'MEF2-deficient', 'MA-10', 'Leydig', cells])].
[sujeto(['Conversely,', overexpression, of, 'MEF2']), verbo([increased]), complemento([endogenous, 'Gsta1', levels])].
[sujeto(['MEF2', recruitment, to, the, proximal, 'Gsta1', promoter, and, direct]), verbo([binding]), complemento([on, the, -, 506, -, bp, 'MEF2', element, were, confirmed, by, chromatin, immunoprecipitation, and, 'DNA', precipitation, assays])].
[sujeto(['In', 'MA-10', 'Leydig', 'cells,', 'MEF2']), verbo([activates]), complemento([the, 'Gsta1', promoter, and, cooperates, with, 'Ca(2+)/calmodulin-dependent', kinases, 'I', to, further, enhance, 'Gsta1', promoter, activity])].
[sujeto(['Similar', results, were, obtained, on, the, 'Gsta2,', 'Gsta3,', and, 'Gsta4', 'promoters,']), verbo([suggesting]), complemento([a, global, role, for, 'MEF2', factors, in, the, regulation, of, all, 4, 'Gsta', genes])].
[sujeto(['Altogether,', our, results, identify, a, novel, role, for, 'MEF2', in, the, expression, of, genes]), verbo([involved]), complemento([in, 'ROS', 'detoxification,', a, process, essential, for, adequate, testosterone, production, in, 'Leydig', cells])].
[sujeto(['Arsenic', is, a, worldwide, environmental, pollutant, that, is]), verbo([associated]), complemento([with, skin, and, several, types, of, internal, cancers])].
[sujeto(['Recent']), verbo([reports]), complemento([revealed, that, arsenic, biomethylation, could, activate, the, toxic, and, carcinogenic, potential, of, arsenic])].
[sujeto(['Our', in, vivo, results, demonstrated, 'that,', 'TMAO', alone]), verbo([increased]), complemento(['Cyp1a1,', 'Cyp1a2,', 'Cyp1b1,', 'Nqo1,', 'Gsta1,', and, 'Ho-1', at, mRNA, level])].
[sujeto(['Western', blotting, revealed, 'that,', 'TMAO', alone]), verbo([increased]), complemento(['Cyp1a1,', 'Cyp1a2,', 'Nqo1,', 'Gsta1/2,', and, 'Ho-1', protein, 'levels,', and, potentiated, the, 'TCDD-mediated', induction, of, 'Cyp1a1', and, 'Cyp1b1', protein, level])].
[sujeto(['In', 'addition,', 'TMAO', alone, significantly]), verbo([increased]), complemento(['Cyp1a1,', 'Cyp1a2,', 'Nqo1,', 'Gst,', and, 'Ho-1', activities, and, significantly, potentiated, the, 'TCDD-mediated', induction, of, 'Cyp1a1', activity])].
[sujeto(['At', the, in, vitro, 'level,', 'TMAO']), verbo([induced]), complemento(['Cyp1a1', and, potentiated, the, 'TCDD-mediated', induction, of, 'Cyp1a1', at, 'mRNA,', protein, and, activity, levels])].
[sujeto(['In', 'addition,', 'TMAO']), verbo([increased]), complemento([the, nuclear, localization, of, 'AhR', and, 'AhR-dependent', 'XRE-driven', luciferase, activity])].
[sujeto(['Our', results, demonstrate, that, the, 'TMAO,']), verbo([modulates]), complemento(['AhR-regulated', genes, which, could, potentially, 'participate,', at, least, in, 'part,', in, arsenic, induced, toxicity, and, carcinogenicity])].
[sujeto(['To', identify]), verbo([involved]), complemento(['factors,', we, evaluated, the, effect, on, gene, expression, of, direct, addition, of, dyslipidemic, human, serum, samples, to, cultured, human, hepatoma, cells, '(', 'HepG2)'])].
[sujeto(['Cells', were, treated, with, 32, sera, from, hypercholesterolemic, and, normocholesterolemic, subjects, to, identify, differentially]), verbo([regulated]), complemento([mRNAs, using, 'DNA', microarray, analysis])].
[sujeto(['Four', genes, resulted, both, affected, by, serum, composition, and, 'PUFAs:', 3, -, 'hydroxy-3-methylglutaryl-CoenzymeA', synthase, 2, '(', 'HMGCS2),', glutathione, 'S-transferase', alpha, 1, '(', 'GSTA1),', liver]), verbo([expressed]), complemento([antimicrobial, peptide, 2, '(', 'LEAP2)', and, apolipoprotein, 'M', '(', 'ApoM)'])].
[sujeto(['HMGCS2', expression, appears, the, most, relevant, and, was, also]), verbo([found]), complemento([modulated, via, transcription, factors, peroxysome, proliferator, activated, receptor, α, '(', 'PPARα)', and, forkhead, box, 'O1', '(', 'FoxO1)'])].
[sujeto(['The', 'MDR-involved', human, 'GSTA1-1,', an, important, isoenzyme, overexpressed, in, several, tumors]), verbo([leading]), complemento([to, 'chemotherapeutic-resistant', tumour, 'cells,', has, been, targeted, by, 2, ',', 2, '\'', -, dihydroxybenzophenones, and, some, of, their, carbonyl, 'N-analogues,', as, its, potential, inhibitors])].
[sujeto(['Screening', against, 'hGSTA1-1']), verbo([led]), complemento([to, benzophenones, 6, and, 8, ',', and, hydrazones, 14, and, 16, ',', having, the, highest, inhibition, potency, '(', 'IC₅₀', values, in, the, range, 0.18, ±, 0.02, to, 1.77, ±, 0.1, 'μM)'])].
[sujeto(['Enzyme', inhibition, 'kinetics,', molecular, modeling, and, docking, studies, showed, that, they]), verbo([interact]), complemento([primarily, at, the, 'CDNB-binding', catalytic, site, of, the, enzyme])].
[sujeto(['These', structures, may, serve, as]), verbo([leads]), complemento([for, the, design, of, new, potent, 'mono-', and, 'bi-functional', inhibitors, and, 'pro-drugs', against, human, 'GTSs'])].
[sujeto(['The', hepatic, toxic, 'effects,', including, carcinogenicity, and, oxidative, 'stress,', of, polycyclic, aromatic, hydrocarbons, '(', 'PAHs)']), verbo([have]), complemento([been, extensively, studied, in, recent, years])].
[sujeto(['Previous']), verbo([reports]), complemento([have, demonstrated, that, 3, -, methylcholanthrene, '(', 3, 'MC)', is, capable, of, altering, the, expression, of, aryl, hydrocarbon, receptor, '(', 'AHR)-regulated', genes, and, antioxidant, genes, in, 'liver,', but, little, is, known, about, the, expression, patterns, in, other, tissues])].
[sujeto(['Moreover,', acute, 3, 'MC', exposure, significantly]), verbo([increased]), complemento([the, mRNA, levels, of, 'Cyp1a1', and, 'Cyp1b1', in, all, the, 'lung,', kidney, and, heart])].
[sujeto(['As', to, antioxidant, 'genes,', 3, 'MC']), verbo([induced]), complemento([the, transcription, of, glutathione, reductase, '(', 'Gr)', in, the, lung, and, kidney, at, 24, h, and, the, transcription, of, glutathione, peroxidase, 1, '(', 'Gpx1)', in, the, lung, and, kidney, at, 6, and, 24, h])].
[sujeto(['The', mRNA, levels, of, quinone, oxidoreductase, 1, '(', 'Nqo1)', were]), verbo([induced]), complemento([by, 3, 'MC', in, all, the, 'lung,', kidney, and, heart])].
[sujeto(['Although', the, constitutive, expression, of, catalase, '(', 'Cat)', is, very, low, in, the, 'heart,', the, transcription, of, 'Cat', was, significantly]), verbo([induced]), complemento([both, at, 6, and, 24, h])].
[sujeto(['Taken', 'together,', ours, findings]), verbo([suggested]), complemento([that, the, expression, of, 'AHR-', and, 'antioxidant-related', genes, in, a, 'tissue-specific', manner, with, or, without, treatment, of, a, 'PAH'])].
[sujeto(['Brostallicin', is, a, 'DNA', minor, groove, binder, that]), verbo([has]), complemento([shown, activity, in, patients, with, soft, tissue, sarcoma, '(', 'STS)', failing, 'first-line', therapy])].
[sujeto(['Only', 'GSTA1', genotype, was, significantly]), verbo([associated]), complemento([with, success, rate, of, doxorubicin, treatment])].
[sujeto(['The', present, study, was, designed, to, evaluate, the, influence, of, 'long-term', environmental, human, exposure, to, three, heavy, 'metals,']), verbo([lead]), complemento(['(', 'Pb),', cadmium, '(', 'Cd),', and, mercury, '(', 'Hg),', on, the, expression, of, 'detoxifying,', xenobiotic, 'metabolizing,', and, 'DNA', repair, genes, in, 'Mahd', 'Ad-Dahab', city])].
[sujeto(['The', mRNA, expression, levels, of, 'detoxifying,', 'NQO1,', 'HO-1,', 'GSTA1,', 'MT-1,', and, 'HSP70,', were, significantly]), verbo([decreased]), complemento([in, all, heavy, 'metal-exposed', group, as, compared, to, control, group])].
[sujeto(['This', was, accompanied, with, a, proportional]), verbo([decrease]), complemento([in, the, expression, of, xenobiotic, metabolizing, 'gene,', cytochrome, 'P4501A1'])].
[sujeto(['On', the, other, 'hand,', the, 'DNA', repair, gene, 'OGG1', and, the, 8, -, 'OHdG', level, were, dramatically]), verbo([inhibited]), complemento([in, 'Cd-exposed', group, only])].
[sujeto(['In', this, 'study,', we, identified, novel, 'SF-1']), verbo([target]), complemento([genes, using, a, 'genome-wide', promoter, tiling, array, and, a, 'DNA', microarray])].
[sujeto(['SF-1', was]), verbo([found]), complemento([to, regulate, human, glutathione, 'S-transferase', 'A', '(', 'GSTA)', family, genes, '(', 'hGSTA1-hGSTA4),', a, superfamily, of, detoxification, enzymes, clustered, on, chromosome, 6, p12])].
[sujeto(['Chromatin', immunoprecipitation, 'assays,', 'however,', revealed, that, 'SF-1']), verbo([bound]), complemento([directly, to, the, promoters, of, hGSTA3, and, weakly, of, hGSTA4])].
[sujeto(['Chromosome', conformation, capture, assays, revealed, that, the, coordinated, expression, of, the, genes, was, based, on, changes, in, 'higher-order', chromatin, structure]), verbo([triggered]), complemento([by, 'SF-1,', which, enables, the, formation, of, 'long-range', 'interactions,', at, least, between, hGSTA1, and, hGSTA3, gene, promoters])].
[sujeto(['We']), verbo([have]), complemento([demonstrated, that, such, susceptibility, is, associated, with, the, inability, of, hepatic, glutathione, 'S-transferases', '(', 'GSTs)', to, detoxify, the, reactive, electrophilic, metabolite, 'exo-AFB1-8,9-epoxide', '(', 'AFBO)'])].
[sujeto(['Alpha-class', identity, was, affirmed, by]), verbo([conserved]), complemento(['GST', domains, and, four, signature, motifs])].
[sujeto(['As', predicted, by, their, relative, 'resistance,', livers, from, domestic, turkeys, lacked, detectable, 'GST-mediated', 'AFBO', detoxification, 'activity,', whereas, those, from, wild, and, heritage, birds, possessed, this, critical, 'activity,']), verbo([suggesting]), complemento([that, intensive, breeding, and, selection, resulted, in, loss, of, 'AFB1-protective', alleles, during, domestication])].
[sujeto(['These', data, may, inform, of, possible, molecular, mechanisms, of, resistance, to, 'AFB1,', and, may, also]), verbo([have]), complemento([the, benefit, of, identifying, genetic, markers, which, could, be, used, to, enhance, 'AFB1', resistance, in, modern, domestic, strains])].
[sujeto(['Using', a, luciferase, reporter, assay, 'system,', we, previously, showed, that, 'MMA']), verbo([activates]), complemento([the, glutathione, 'S-transferase', alpha, 1, gene, '(', 'Gsta1)', promoter, through, the, 'anti-oxidant', responsive, element, '(', 'ARE)'])].
[sujeto(['However,', it, is, not, known, whether, 'HEMA']), verbo([induces]), complemento(['ARE-mediated', transcription])].
[sujeto(['In', this, 'system,', 'MMA']), verbo([increased]), complemento(['ARE', activity, by, 244, -, fold, at, 30, 'mM;', 'HEMA', augmented, 'ARE', activity, at, 3, mM, more, intensely, than, 'MMA', '(', 36, -, fold, versus, 11, -, 'fold)', and, was, equipotent, as, 'MMA', at, 10, mM, '(', 56, -, fold, 'activation);', 'however,', 'HEMA', failed, to, increase, 'ARE', activity, at, 30, mM])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, 'low-concentration', effect, of, 'HEMA', on, 'ARE', activity, reflects, its, cytotoxicity])].
[sujeto(['We', assessed, whether, variants, in, 22, oxidative, 'stress-related', genes, are]), verbo([associated]), complemento([with, mortality, of, breast, cancer, patients, and, whether, the, associations, differ, according, to, radiotherapy])].
[sujeto(['Eleven', 'SNPs', in, 'MT2A,', 'NFE2L2,', 'NQO1,', 'PRDX1,', and, 'PRDX6', were, significantly]), verbo([associated]), complemento([with, overall, mortality, after, a, median, 'follow-up', of, 5.7, years])].
[sujeto(['Three', 'SNPs', in, 'NQO1', '(', 'rs2917667)', and, in, 'PRDX6', '(', 'rs7314,', 'rs4916362)', were, consistently]), verbo([associated]), complemento([with, increased, risk, of, dying, across, all, three, study, populations, '(', 'pooled:', 'HRNQO1_rs2917667', 1.2, ',', 95, '%', 'CI', 1.0, -, 1.44, ',', p, =, 0.051, ;, 'HRPRDX6_rs7314', 1.16, ',', 95, '%', 'CI', 1.0, -, 1.35, ',', p, =, 0.056, ',', 'HRPRDX6_rs4916362', 1.14, 95, '%', 'CI', 1.0, -, 1.32, ',', p, =, 0.062, ')'])].
[sujeto(['Potential', effect, modification, by, radiotherapy, was]), verbo([found]), complemento([for, 'CAT_rs769218'])].
[sujeto(['Human', colonic, adenocarcinoma, '(', 'Caco-2)', cells, in, culture, undergo, spontaneous, differentiation, into, mature, enterocytes, in, association, with, progressive]), verbo([increases]), complemento([in, expression, of, glutathione, 'S-transferase', 'alpha-1', '(', 'GSTA1)'])].
[sujeto(['We', demonstrate]), verbo([increased]), complemento(['GSTA1', levels, associated, with, decreased, proliferation, and, increased, expression, of, differentiation, markers, alkaline, 'phosphatase,', 'villin,', dipeptidyl, 'peptidase-4', and, 'E-cadherin', in, postconfluent, 'Caco-2', cells])].
[sujeto(['Results', of, 'MTS', 'assays,', 'BrdU', incorporation, and, flow, cytometry, indicate, that, forced, expression, of, 'GSTA1', significantly, reduces, cellular, proliferation, and, 'siRNA-mediated', 'down-regulation', of, 'GSTA1', significantly]), verbo([increases]), complemento([cells, in, 'S-phase', and, associated, cell, proliferation])].
[sujeto(['Sodium', butyrate, '(', 'NaB)', at, a, concentration, of, 1, mM, reduces, 'Caco-2', cell, 'proliferation,']), verbo([increases]), complemento([differentiation, and, increases, 'GSTA1', activity, 4, -, fold, by, 72, hours])].
[sujeto(['In', 'contrast,', 10, mM, 'NaB']), verbo([causes]), complemento([significant, toxicity, in, preconfluent, cells, via, apoptosis, through, 'caspase-3', activation, with, reduced, 'GSTA1', activity])].
[sujeto(['While', 10, mM, 'NaB']), verbo([causes]), complemento(['GSTA1-JNK', complex, 'dissociation,', phosphorylation, of, 'JNK', is, not, altered])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'GSTA1', levels, may, play, a, role, in, modulating, enterocyte, proliferation, but, do, not, influence, differentiation, or, apoptosis])].
[sujeto(['Oxidative', damage, in, brain, cells, is, one, of, the, factors, hypothesized, to, be]), verbo([involved]), complemento([in, the, pathogenesis, of, schizophrenia])].
[sujeto(['Glutathione', 'S-transferase', '(', 'GST)', 'A1*B', 'polymorphism,', a, genotype]), verbo([associated]), complemento([with, a, higher, risk, of, oxidative, 'damage,', is, associated, with, increased, frequency, of, schizophrenia, diagnosis])].
[sujeto(['Results', confirmed, that, patients, with, schizophrenia, who, were, carriers, of, the, 'GSTA1', *, 'B', risk, allele, had, an]), verbo([increased]), complemento(['MD', in, bilateral, thalami, and, increased, severity, of, auditory, and, global, hallucinations, in, comparison, with, 'non-B', carriers])].
[sujeto(['Thus,', oxidative, stress]), verbo([associated]), complemento([factors, may, be, implicated, in, specific, mechanisms, of, schizophrenia, such, as, altered, microstructure, of, the, thalami, and, specific, psychopathological, features, of, auditory, hallucinations])].
[sujeto(['We']), verbo([report]), complemento([on, the, synthesis, of, 11, pyrrole, derivatives, as, 'hGSTA1-1', inhibitors, starting, from, 1, -, 'methyl-2-[(2-nitrobenzylsulfanyl]-1H-pyrrole'])].
[sujeto(['Molecular', modeling, revealed, two, locations, in, the, enzyme, 'H']), verbo([binding]), complemento(['site:', the, catalytic, primary, one, accommodating, shorter, and, longer, derivatives, and, the, secondary, 'one,', where, shorter, derivatives, can, occupy])].
[sujeto(['Derivative', 9]), verbo([binds]), complemento(['(', 'K(i(9))', =, 71, ±, 4, 'μM)', at, the, primary, site, competitively, vs, 'CDNB'])].
[sujeto(['Derivative', 4]), verbo([binds]), complemento(['(', 'K(i(4))', =, 135, ±, 27, 'μM)', at, the, primary, and, secondary, 'sites,', allowing, the, binding, of, a, second, molecule, '(', 4, or, 'CDNB)', leading, to, formation, of, unreactive, and, reactive, 'complexes,', respectively])].
[sujeto(['The', arylmethylsulfonylpyrrole, core, structure, is, a, new, pharmacophore, for, 'hGSTA1-1,', whereas, its, derivative, 9, may, serve, as, a]), verbo([lead]), complemento([structure])].
[sujeto(['We', recently]), verbo([reported]), complemento([that, vanadium, '(', 'V(5+)', ')', was, able, to, decrease, the, 2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD)-mediated', induction, of, 'Cyp1a1', and, 'Nqo1', at, 'mRNA,', protein, and, catalytic, activity, levels, in, mouse, hepatoma, 'Hepa', 1, c1c7, and, human, hepatoma, 'HepG2', cells])].
[sujeto(['Our', results, demonstrated, that, 'V(5+)', alone, significantly]), verbo([decreased]), complemento(['Cyp1b1', protein, and, catalytic, activity, levels, in, kidney, at, 24, h])].
[sujeto(['Upon', 'co-exposure,', we]), verbo([found]), complemento([that, 'V(5+)', significantly, inhibited, the, 'TCDD-mediated', induction, of, 'Cyp1a1,', 'Cyp1a2', and, 'Cyp1b1', 'mRNA,', protein, and, catalytic, activity, levels, in, the, kidney, at, 24, h])].
[sujeto(['Interestingly,', all, tested, genes, in, the, heart, were, significantly]), verbo([decreased]), complemento([at, 6, h, with, the, exception, of, 'Gsta1', mRNA])].
[sujeto(['The', present, study, demonstrates, that, 'V(5+)']), verbo([modulates]), complemento(['TCDD-induced', 'AhR-regulated', genes])].
[sujeto(['Therefore,', we, examined, the, ability, of, camel, milk, to]), verbo([modulate]), complemento([the, expression, of, a, 'well-known', 'cancer-activating', 'gene,', 'Cytochrome', 'P450', 1, a1, '(', 'Cyp1a1),', and, 'cancer-protective', 'genes,', 'NAD(P)H:quinone', oxidoreductase, 1, '(', 'Nqo1)', and, glutathione, 'S-transferase', a1, '(', 'Gsta1),', in, murine, hepatoma, 'Hepa', 1, c1c7, cell, line])].
[sujeto(['Our', results, showed, that, camel, milk, significantly]), verbo([inhibited]), complemento([the, induction, of, 'Cyp1a1', gene, expression, by, 2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD),', the, most, potent, 'Cyp1a1', inducer, and, known, carcinogenic, 'chemical,', at, 'mRNA,', 'protein,', and, activity, levels, in, a, 'concentration-dependent', manner])].
[sujeto(['In', 'addition,', camel, milk, significantly]), verbo([decreased]), complemento([the, xenobiotic, responsive, element, '(', 'XRE)-dependent', luciferase, 'activity,', suggesting, a, transcriptional, mechanism, is, involved])].
[sujeto(['Furthermore,', this, inhibitory, effect, of, camel, milk, was]), verbo([associated]), complemento([with, a, proportional, increase, in, heme, oxygenase, 1])].
[sujeto(['On', the, other, 'hand,', camel, milk, significantly]), verbo([induced]), complemento(['Nqo1', and, 'Gsta1', mRNA, expression, level, in, a, 'concentration-dependent', fashion])].
[sujeto(['The', 'RNA', synthesis, 'inhibitor,', actinomycin, 'D,', completely, blocked, the, induction, of, 'Nqo1', mRNA, by, camel, milk]), verbo([suggesting]), complemento([the, requirement, of, de, novo, 'RNA', synthesis, through, a, transcriptional, mechanism])].
[sujeto(['In', 'conclusion,', camel, milk]), verbo([modulates]), complemento([the, expression, of, 'Cyp1a1,', 'Nqo1,', and, 'Gsta1', at, the, transcriptional, and, posttranscriptional, levels])].
[sujeto(['This', study, aimed, to]), verbo([enhance]), complemento([the, drug, metabolism, function, of, the, human, hepatoma, cell, line, 'C3A', and, to, explore, the, related, significance, for, patients, with, severe, liver, disease])].
[sujeto(['Furthermore,', in, order, to]), verbo([increase]), complemento([the, expression, of, 'CYP', 3, 'A4', and, 'GST', 'A1,', they, were, optimized, according, to, human, optimal, codons])].
[sujeto(['Atherosclerosis', and]), verbo([associated]), complemento([cardiovascular, complications, such, as, stroke, and, myocardial, infarction, are, major, causes, of, morbidity, and, mortality])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, a, significant, increase, in, mRNA, levels, of, the, scavenger, receptor, 'CD36', in, aortae, of, 'cholesterol-fed', rabbits, and, shown, that, vitamin, 'E', treatment, attenuated, increased, 'CD36', mRNA, expression])].
[sujeto(['In', the, present, 'study,', we, further, investigated, the, redox, signaling, pathways]), verbo([associated]), complemento([with, protection, against, atherogenesis, induced, by, high, dietary, cholesterol, and, correlated, these, with, 'CD36', expression, and, the, effects, of, vitamin, 'E', supplementation, in, a, rabbit, model])].
[sujeto(['To', elucidate, the, mechanisms, by, which, vitamin, 'E', supplementation, alters, the, effects, of, hypercholesterolemia, in, rabbit, 'aortae,', we, measured, peroxisome, 'proliferator-activated', receptor, γ, '(', 'PPARγ),', 'ATP-binding', cassette, transporter, 'A1', '(', 'ABCA1),', and, matrix, 'metalloproteinase-1', '(', 'MMP-1)', mRNA, levels, by, quantitative, 'RT-PCR', and, the, expression, of, 'MMP-1,']), verbo([nuclear]), complemento(['factor-erythroid', 2, -, related, factor, 2, '(', 'Nrf2),', and, glutathione, 'S-transferase', α, '(', 'GSTα)', protein, by, immunoblotting])].
[sujeto(['The']), verbo([increased]), complemento(['MMP-1', and, decreased, 'GSTα', expression, observed, suggests, that, a, 'cholesterol-rich', diet, contributes, to, the, development, of, 'atherosclerosis,', whereas, vitamin, 'E', supplementation, affords, protection, by, decreasing, 'MMP-1', and, increasing, 'PPARγ,', 'GSTα,', and, 'ABCA1', levels, in, aortae, of, rabbits, fed, a, 'cholesterol-rich', diet])].
[sujeto(['Notably,', protein, expression, of, 'Nrf2,', the, antioxidant, transcription, 'factor,', was]), verbo([increased]), complemento([in, both, the, 'cholesterol-fed', and, the, vitamin, 'E-supplemented', groups])].
[sujeto(['Although', 'Nrf2', activation, can]), verbo([promote]), complemento(['CD36-mediated', cholesterol, uptake, by, 'macrophages,', the, increased, induction, of, 'Nrf2-mediated', antioxidant, genes, is, likely, to, contribute, to, decreased, lesion, progression])].
[sujeto(['Thus,', our, study, demonstrates, that, 'Nrf2', can]), verbo([mediate]), complemento([both, 'pro-', and, antiatherosclerotic, effects])].
[sujeto(['Phase', 'II', metabolising, enzymes, enable, the, metabolism, and, excretion, of, potentially, harmful, substances, in, 'adults,', but, to, date, it, is, unclear, whether, dietary, phytochemicals, can]), verbo([induce]), complemento([phase, 'II', enzymes, differently, between, adults, and, infants])].
[sujeto(['Following', phytochemical, 'treatment,', a, significant]), verbo([increase]), complemento([in, mRNA, of, glutathione, 'S-transferase', 'A1', '(', 'GSTA1)', and, 'NAD(P)H:quinone', oxidoreductase, 1, '(', 'NQO1)', was, 'observed,', with, the, most, marked, increases, seen, in, response, to, sulphoraphane, '(', 3, -, 10, -, fold, for, 'GSTA1,', 'P&nbsp;=&nbsp;0·001,', and, 6, -, 35, -, fold, for, 'NQO1,', 'P&nbsp;=&nbsp;0·001-0·017)'])].
[sujeto(['Catechin', also]), verbo([induced]), complemento([3, -, 5, -, fold, changes, in, 'NQO1', 'transcription,', whereas, quercetin, had, less, effect, on, 'NQO1', mRNA, induction, in, infant, cells])].
[sujeto(['Moreover,', 'NQO1', protein, levels, were, significantly]), verbo([increased]), complemento([in, 2, -, 'year-old', and, adult, cell, models, in, response, to, sulphoraphane, treatment])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, metabolic, plasticity, and, response, to, xenobiotics, may, be, different, in, infants, and, 'adults;', and, therefore, the, inclusion, of, phytochemicals, in, the, infant, diet, may, modulate, their, induction, of, phase, 'II', 'metabolism,', thereby, providing, increased, protection, from, potentially, harmful, xenobiotics, in, later, life])].
[sujeto(['In', this, 'study,', isothermal, titration, calorimetry, was, used, to, probe, the]), verbo([binding]), complemento([energetics, of, 'G-site', '(', glutathione, and, glutathione, 'sulfonate)', and, 'H-site', '(', ethacrynic, 'acid)', ligands, to, 'wild-type', and, a, 'Y9F', mutant, of, human, glutathione, transferase, 'A1-1'])].
[sujeto(['Although', previous, studies]), verbo([have]), complemento([reported, a, favourable, entropic, component, to, the, binding, of, conjugates, occupying, both, 'sites,', our, data, reveal, that, ligand, binding, is, enthalpically, driven, when, either, the, 'G-', or, 'H-site', is, occupied, independently])].
[sujeto(['The', 'Tyr-9', hydroxyl, group, contributes, significantly, to, ligand]), verbo([binding]), complemento(['energetics,', although, the, effect, differs, between, the, two, binding, sites])].
[sujeto(['G-site']), verbo([binding]), complemento([is, made, slightly, enthalpically, more, favourable, and, entropically, less, favourable, by, the, 'Y9F', mutation])].
[sujeto(['Binding', to, the, 'H-site', is, more, dramatically, 'affected,', with, the, 'K(d)', for, ethacrynic, acid]), verbo([increasing]), complemento([5, fold, despite, a, more, favourable, 'ΔS'])].
[sujeto(['The', heat, capacity, change, is, more, negative, for, 'G-site']), verbo([binding]), complemento([in, the, absence, of, the, 'Tyr-9', hydroxyl, '(', 'ΔΔC(p)=-0'])].
[sujeto([73, kJ, 'mol(-1)', 'K(-1)),', but, less, negative, for, 'H-site']), verbo([binding]), complemento([to, the, 'Y9F', mutant, '(', 'ΔΔC(p)=0'])].
[sujeto(['This']), verbo([suggests]), complemento([that, the, relationship, between, 'Tyr-9', and, α9, is, not, independent, of, the, ligand])].
[sujeto(['An', 'alpha-class', glutathione, transferase, '(', 'GST)']), verbo([has]), complemento([been, cloned, from, pig, gonads])].
[sujeto(['Porcine', 'GST', 'A1-1', was]), verbo([expressed]), complemento([in, 'Escherichia', coli, and, its, kinetic, properties, were, determined, using, alternative, substrates])].
[sujeto(['In', vitro, maturation, of, oocytes, is, a, crucial, step, in, assisted, reproductive, technologies, in, 'cattle;', 'however,', the, molecular, mechanisms, of, cumulus, contribution, to, oocyte, developmental, potential]), verbo([require]), complemento([more, investigation])].
[sujeto(['Based', on, transcriptomic, 'data,', we, studied, by, using, 'real-time', 'RT-PCR', and, western, blot, in, bovine, cumulus, 'cells,', the, kinetics, of, expression, of, several, candidate, genes]), verbo([involved]), complemento([in, oxidative, stress, 'response,', 'apoptosis,', steroid, metabolism, and, signal, transmission, throughout, 'IVM'])].
[sujeto(['Glutathione-S-transferase', 'A1', '(', 'GSTA1)', transcript, and, protein, abundance, significantly]), verbo([decreased]), complemento([throughout, 'IVM', progression])].
[sujeto(['Similarly,', transcript, levels, of, 'FSH', receptor, and, aromatase, '(', 'CYP19A1)', and, protein, levels, of, three, steroidogenic, enzymes, '(', steroidogenic, acute, regulatory, 'protein,', cytochrome, 'P450scc', and, 3, -, 'beta-hydroxysteroid', 'dehydrogenase)']), verbo([decreased]), complemento([along, with, progression, of, maturation, and, especially, since, 10, hours, of, 'IVM'])].
[sujeto(['Expression', of, progesterone, receptor, '(', 'PGR)', and, clusterin, '(', 'CLU)', mRNA, and, phosphorylations, of, protein, kinases, 'AKT,', 'MAPK', 'P38', and, 'SMAD2', were, particularly]), verbo([increased]), complemento([at, 10, hours, of, 'IVM'])].
[sujeto(['These', factors, and, signaling, pathways, in, cumulus, cells, are, potentially]), verbo([involved]), complemento([in, controlling, different, stages, of, oocyte, nuclear, maturation, and, acquirement, of, its, developmental, potential])].
[sujeto(['Each', subunit]), verbo([has]), complemento([two, distinct, domains, and, an, active, site, consisting, of, a, 'G-site', for, binding, 'GSH', and, an, 'H-site', for, an, electrophilic, substrate])].
[sujeto(['Domain', 1, of, class, alpha, 'GSTs']), verbo([has]), complemento([a, conserved, tryptophan, '(', 'Trp21)', in, helix, 1, that, forms, a, major, interdomain, contact, with, helices, 6, and, 8, in, domain, 2])].
[sujeto(['The', study, demonstrates, that, the, stability, of, the, 'domain-domain', interface, plays, a, role, in]), verbo([mediating]), complemento([the, catalytic, functionality, of, the, active, 'site,', particularly, the, 'H-site,', of, class, alpha, 'GSTs'])].
[sujeto(['Arg15,']), verbo([conserved]), complemento([in, class, 'Alpha', 'GSTs', '(', glutathione, 'transferases),', is, located, at, the, interface, between, the, 'G-', and, 'H-sites', of, the, active, site, where, its, cationic, guanidinium, group, might, play, a, role, in, catalysis, and, ligand, binding])].
[sujeto(['Arg15', in, human, 'GSTA1-1', was, replaced, with, a, leucine, and, 'crystallographic,', 'spectroscopic,', thermodynamic, and, molecular, docking, methods, were, used, to, investigate, the, contribution, made, by, 'Arg15', towards, '(', 'i)', the]), verbo([binding]), complemento([of, glutathione, '(', 'GSH)', to, the, 'G-site,', '(', 'ii)', the, 'pK(a)', of, the, thiol, group, of, 'GSH,', '(', 'iii)', the, stabilization, of, an, analog, of, the, anionic, transition, state, of, the, 'S(N)Ar', reaction, between, 1, -, 'chloro-2,4-dinitrobenzene', '(', 'CDNB)', and, 'GSH,', 'and,', '(', 'iv)', the, binding, of, the, anionic, 'non-substrate', ligand, 8, -, 'anilino-1-naphthalene', sulphonate, '(', 'ANS)', to, the, 'H-site'])].
[sujeto(['While', the, 'R15L', mutation, substantially, diminishes, the, 'CDNB-GSH', conjugating, activity, of, the, 'enzyme,', it]), verbo([has]), complemento([little, effect, on, protein, structure, and, stability])].
[sujeto(['The', anionic, 'sigma-complex', formed, between, 'GSH', and, 1, ',', 3, ',', 5, -, trinitrobenzene, is, stabilized, by, 'Arg15,']), verbo([suggesting]), complemento([that, it, also, stabilizes, the, transition, state, formed, in, the, 'S(N)Ar', reaction, between, 'GSH', and, 'CDNB'])].
[sujeto(['The', trinitrocyclohexadienate, moiety, of, the, 'sigma-complex']), verbo([binds]), complemento([the, 'H-site', where, the, catalytic, 'residue,', 'Tyr9,', was, identified, to, hydrogen, bond, to, an, 'o-nitro', group, of, the, 'sigma-complex'])].
[sujeto(['The', affinity, for, 'ANS', at, the, 'H-site', is]), verbo([decreased]), complemento([about, 3, -, fold, by, the, 'R15L', mutation, implicating, the, positive, electrostatic, potential, of, 'Arg15', in, securing, the, organic, anion, at, this, site])].
[sujeto(['Herein', we]), verbo([report]), complemento([the, first, crystal, structures, of, 'GIMFhelix,', both, in, complex, with, 'GSH', and, in, apo, form, at, 1.98, and, 2.38, 'A', resolution])].
[sujeto(['In', contrast, to, the, preorganized, hydrophobic]), verbo([binding]), complemento([pocket, that, accommodates, alkenals, in, 'GSTA4-4,', 'GSTA1-1', includes, a, dynamic, alpha9, helix, that, undergoes, a, 'ligand-dependent', localization, to, complete, the, active, site])].
[sujeto(['Comparisons', of, the, 'GIMFhelix', structures, with, previously]), verbo([reported]), complemento([structures, show, a, striking, similarity, with, the, 'GSTA4-4', active, site, obtained, within, an, essentially, 'GSTA1-1', scaffold, and, reveal, the, alpha9, helix, assumes, a, similar, localized, structure, regardless, of, active, site, occupancy, in, a, manner, resembling, that, of, 'GSTA4-4'])].
[sujeto(['The', contribution, of, 'Phe10', to, the, 'Tyr212-Phe10-Phe220', network]), verbo([prevents]), complemento([complete, 'C-terminal', closure, and, demonstrates, that, the, presence, of, 'Phe10', within, the, context, of, a, 'GSTA4-4-like', active, site, may, ultimately, hinder, 'Phe220,', a, key, 'C-terminal', 'residue,', from, effectively, contributing, to, the, active, site])].
[sujeto(['In', 'total,', these, results, illustrate, the, remaining, structural, differences, presumably, reflected, in, the, previously]), verbo([reported]), complemento([catalytic, efficiencies, of, 'GIMFhelix', and, 'GSTA4-4', and, emphasize, the, 'F10P', mutation, as, being, necessary, to, completely, accomplish, the, transformation, to, a, highly, specific, 'GST', from, the, more, promiscuous, 'GSTA1-1', enzyme])].
[sujeto(['We']), verbo([have]), complemento([previously, developed, a, labeling, scheme, that, can, be, used, to, 'site-specifically', link, human, glutathione, transferases, '(', 'hGSTs)', from, the, alpha, class, to, chemical, entities, such, as, fluorophores, and, aldehydes])].
[sujeto(['We']), verbo([have]), complemento([focused, on, a, lysine, mutant, of, hGST, 'A1:A216K'])].
[sujeto(['We']), verbo([have]), complemento([used, random, mutagenesis, to, scramble, the, hydrophobic, binding, site, of, 'A216K', through, mutations, at, position, 'M208', and, isolated, a, library, of, 11, 'A216K/M208X', mutants])].
[sujeto(['All', mutants, were, easily]), verbo([expressed]), complemento([and, purified, and, retained, all, or, parts, of, the, catalytic, properties, of, the, parent, 'GST'])].
[sujeto(['Labeling', with, coumarin, results, in, a, fluorescent, 'protein-conjugate', that, can]), verbo([bind]), complemento([glutathione, '(', 'GSH)', derivatives, for, subsequent, affinity, purification])].
[sujeto(['Analysis', of, the, 'GSTD4', structure, showed, subtle, conformational, changes, in, the, 'GSH-binding', site, and, in, 'electron-sharing', network, that, may, contribute, to, the]), verbo([increased]), complemento(['GSH', affinity])].
[sujeto(['The', 'Cys112Ser', mutation]), verbo([confers]), complemento([optimal, oxidative, stability, and, kinetic, properties, in, the, 'GSTD4', enzyme])].
[sujeto(['The']), verbo([release]), complemento([of, 'GSTA1', was, demonstrated, to, be, an, earlier, and, more, sensitive, indicator, of, hepatocytes, injury, than, other, indicators])].
[sujeto(['Significant']), verbo([increases]), complemento([in, 'GSTA1', were, detected, at, 2, h, after, ethanol, 'exposure,', while, other, indicators, were, undetected, at, this, time])].
[sujeto(['The']), verbo([release]), complemento([of, 'GSTA1', was, significantly, increased, at, a, concentration, of, 50, 'mmol/L', 'ethanol,', the, lowest, exposure, concentration, than, that, in, other, indicators])].
[sujeto(['In', 'contrast,', other, indicators]), verbo([release]), complemento([was, not, statistically, significant, until, concentrations, of, 75, 'mmol/L', and, 100, 'mmol/L', ethanol])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'GSTA1', can, be, detected, at, the, early, stage, of, low, concentration, ethanol, exposure, and, that, 'GSTA1', is, more, sensitive, and, reliable, marker, in, 'ethanol-induced', hepatic, injury])].
[sujeto(['Glutathion', '(', 'GSH)', metabolism, is, the, most]), verbo([reported]), complemento([pathway, involved, in, hepatotoxicity, mechanism, of, 'PAs'])].
[sujeto(['Firstly,', the, potential]), verbo([targets]), complemento([of, 22, 'PAs', '(', from, three, major, 'PA', 'types)', in, 'GSH', metabolism, were, identified, by, reverse, 'docking;', 'Secondly,', glutathione, 'S-transferase', 'A1', '(', 'GSTA1)', and, glutathione, peroxidase, 1, '(', 'GPX1)', targets, pattern, was, found, to, be, a, special, characteristic, of, toxic, 'PAs', with, stepwise, multiple, linear, 'regressions;', 'Furthermore,', the, molecular, mechanism, underlying, the, interactions, within, toxic, 'PAs', and, these, two, targets, was, demonstrated, with, the, 'ligand-protein', interaction, 'analysis;', 'Finally,', 'GSTA1', and, 'GPX1', were, proved, to, be, significant, nodes, in, 'GSH', metabolism])].
[sujeto(['Overall,', toxic, 'PAs', could, be, identified, by, 'GSTA1', and, 'GPX1']), verbo([targets]), complemento(['pattern,', which, suggests, their, common, hepatotoxicity, 'mechanism:', the, interfering, of, detoxication, in, 'GSH', metabolism])].
[sujeto(['Also', included, are, mass, spectra, of, peptides, from, 'Grx\'s', or, 'GSTA1-1', that]), verbo([have]), complemento([cys, residues, that, do, not, react, with, 'EdAG'])].
[sujeto(['Clearance']), verbo([decreased]), complemento([by, 15, '%', and, area, under, the, 'concentration-time', curves, '(', 'AUCs)', increased, with, 'GSTA1', variants, compared, with, 'wild-type', '(', both, p, &, 'lt;', 0.05, ')'])].
[sujeto(['To', our, 'knowledge,', this, is, the, first, 'PPK', study, to]), verbo([suggest]), complemento([that, 'GSTA1', polymorphisms, in, adults, are, associated, with, busulfan, 'PK'])].
[sujeto(['EdAG', contains, the, electrophilic, 'dehydroalanine,', which, is, expected, to, react, with, protein, 'nucleophiles,', particularly, proteins, with, 'GSH']), verbo([binding]), complemento([sites, such, as, glutaredoxins, '(', 'Grx\'s)'])].
[sujeto(['In', 'contrast,', the, glutathione, transferase, 'A1-1', includes, a, 'GSH']), verbo([binding]), complemento([site, with, a, potentially, reactive, tyrosinate, '(', 'Tyr-9)', but, it, does, not, react, with, 'EdAG'])].
[sujeto(['The', results]), verbo([provide]), complemento([the, first, demonstration, of, the, reactivity, of, any, busulfan, metabolites, with, intact, 'proteins,', and, they, suggest, that, 'GSH-binding', sites, containing, thiolates, are, most, susceptible])].
[sujeto(['The', adduction, of, 'Grx\'s', by, 'EdAG']), verbo([suggests]), complemento([the, possible, alteration, of, proteins, that, are, normally, regulated, via, 'Grx-dependent', reversible, glutathionylation, or, deglutathionylation])].
[sujeto(['Glutathione', 'S-transferase', 'A1', '(', 'GSTA1)', appears, to, be, primarily]), verbo([involved]), complemento([in, detoxification, 'processes,', but, possible, roles, in, lung, cancer, remain, unclear])].
[sujeto(['Transfection', into, 'A549', cells, demonstrated, that, 'down-regulated', expression, could]), verbo([inhibit]), complemento([cell, viability])].
[sujeto(['Our', data, indicated, that, 'GSTA1', expression, may, be, a]), verbo([target]), complemento([molecule, in, early, diagnosis, and, treatment, of, lung, cancer])].
[sujeto(['Studies', in, 'hamsters,', mice, and, rats]), verbo([have]), complemento([demonstrated, that, estradiol, '(', 'E2),', its, interconvertible, metabolite, estrone, '(', 'E1)', and, their, catechol, 'metabolites,', in, particular, 4, -, hydroxy, 'E2/E1,', are, carcinogenic, in, the, 'kidney,', uterus, and, mammary, gland])].
[sujeto(['Observational', studies, and, clinical, trials, consistently, show, that, sustained, exposure, to, 'E2/E1', is]), verbo([associated]), complemento([with, the, development, of, sporadic, breast, cancer])].
[sujeto(['One', pathway]), verbo([involves]), complemento([activation, of, nuclear, and, cytoplasmic, signaling, pathways, through, the, binding, of, estrogen, to, nuclear, and, 'membrane-bound', estrogen, receptors, leading, to, increased, cell, proliferation])].
[sujeto(['The', other, pathway]), verbo([involves]), complemento([the, oxidative, metabolism, of, 'E2/E1', to, catechols, and, then, reactive, quinones, that, can, contribute, to, oxidative, 'DNA', damage, and, form, 'specific,', mutagenic, depurinating, adducts, with, adenine, and, guanine, which, then, in, turn, can, serve, as, biomarkers, for, the, occurrence, of, these, processes])].
[sujeto(['Various', chemopreventive, agents, such, as, sulforaphane, '(', 'SFN)', and, resveratrol]), verbo([have]), complemento([been, shown, in, cell, culture, to, block, oxidative, metabolism, of, 'E2/E1', and, thus, prevent, 'DNA', damage])].
[sujeto(['Pretreatment', of, 'MCF-7', and, 'MCF-10F', cells, with, and, inhibitor, of, 'catechol-O-methyltransferase', '(', 'COMT)', followed, by, treatment, with, 'E2', or, 4, -, 'OH', 'E2']), verbo([caused]), complemento([increased, oxidative, 'DNA', damage, '(', 8, -, 'oxo-dG)', and, depurinating, 'DNA', adducts, showing, the, importance, of, 'E2-catechol', 'O-methylation', by, 'COMT', as, a, protective, pathway])].
[sujeto(['E2', treatment, of, 'MCF-10A', cells, with, 'E2', or, 4, -, 'OH', 'E2']), verbo([caused]), complemento([an, increase, in, 'E2-adenine', and, guanine, adducts])].
[sujeto(['Treatment', with, sulforaphane]), verbo([increased]), complemento([quinone, oxidoreductase, 1, '(', 'NQO1)', and, 'glutathione-S-transferase', 'A1', '(', 'GSTA1)', expression, without, affecting, expression, of, 'catechol-O-methyltransferase', '(', 'COMT)', or, cytochrome, 'P450', 1, 'B1'])].
[sujeto(['Pretreatment', with, 'SFN']), verbo([decreased]), complemento([depurinating, 'DNA', adducts, while, increasing, levels, of, 4, -, 'OCH3E1/2', and, 4, -, 'OHE1/2-glutathione', conjugates])].
[sujeto(['Treatment', of, 'MCF-10F', cells, with, 'E2', or, 4, -, 'OH-E2', also]), verbo([caused]), complemento([increased, depurinating, 'DNA', adducts, and, neoplastic, transformation, while, pretreatment, with, resveratrol, caused, a, reduction, in, adduct, levels, and, neoplastic, transformation])].
[sujeto(['Increased', levels, of, 'estrogen-quinone', conjugates, and, 'DNA', adducts]), verbo([have]), complemento([also, been, detected, in, urine, of, women, at, increased, risk, for, and, with, breast, cancer])].
[sujeto(['These', observations, support, the, notion, that]), verbo([targeting]), complemento([the, 'estrogen/estrone', metabolism, pathway, may, be, another, way, to, reduce, breast, cancer, risk])].
[sujeto(['GSTA1']), verbo([release]), complemento([was, demonstrated, to, be, an, earlier, and, more, sensitive, indicator, of, hepatotoxicity, than, was, 'ALT'])].
[sujeto(['Significant']), verbo([increases]), complemento([in, 'GSTA1', were, detected, at, 2, h, after, 'CCl4', 'exposure,', while, 'ALT', was, undetected, at, this, time])].
[sujeto(['In', the, 'APAP', and, ethanol, 'models,', 'GSTA1', was, markedly]), verbo([increased]), complemento([earlier, than, 'ALT,', at, 2, h, post, exposure])].
[sujeto(['The']), verbo([release]), complemento([of, 'GSTA1', was, significantly, increased, at, a, dose, of, 12.5, 'mg/kg', '(', 'CCl4', 'model),', 100, 'mg/kg', '(', 'APAP', 'model)', and, 10, 'ml/kg', '(', ethanol, 'model),', the, lowest, exposure, concentration, for, each, model])].
[sujeto(['In', 'contrast,', 'AST']), verbo([release]), complemento([was, not, statistically, significant])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'GSTA1', can, be, detected, at, low, concentrations, during, the, early, stages, of, acute, hepatic, injury, and, that, 'GSTA1', is, a, more, sensitive, and, more, accurate, indicator, than, 'ALT'])].
[sujeto(['There', are, still, approximately, half, of, the, 'RSA', patients, with]), verbo([cause]), complemento([not, being, identified, to, date])].
[sujeto(['Accumulating', studies]), verbo([have]), complemento([confirmed, that, genetic, polymorphisms, in, glutathione, 'S-transferases', '(', 'GSTs)', were, associated, with, the, risk, of, recurrent, spontaneous, abortion])].
[sujeto(['We']), verbo([found]), complemento([that, the, frequencies, of, genotypes, between, cases, and, controls, have, no, significant, difference, '(', 'P', =, 0.908, ')', and, 'GSTA1', mutant, allele, 'GSTA1', -, 69, 'T', was, present, at, a, frequency, of, 0.122, in, case, 'group,', while, in, controls, the, frequency, was, 0.125, '(', 'P', =, 0.922, ')'])].
[sujeto(['The', polymorphism, of, 'GSTA1', '(', 'rs3957357)', may, not, be]), verbo([associated]), complemento([with, the, risk, of, recurrent, spontaneous, abortion, in, 'Chinese', 'Han', population])].
[sujeto(['Glutathione', transferases, '(', 'GSTs)', are, cell, detoxifiers]), verbo([involved]), complemento([in, multiple, drug, resistance, '(', 'MDR),', hampering, the, effectiveness, of, certain, anticancer, drugs])].
[sujeto(['To', our, 'knowledge,', this, is, the, first]), verbo([report]), complemento([on, 'well-defined', synthetic, xanthones, as, 'GST', inhibitors])].
[sujeto(['Of', 'them,', derivative, 17, readily]), verbo([inhibited]), complemento(['hGSTA1-1', in, colon, cancer, cell, lysate, '(', 'IC(50)', =, 10.54, ±, 2.41, 'µM)'])].
[sujeto(['We', subsequently, identified, the, oxidoreductase, 'NAD(P)H', 'dehydrogenase,', quinone, 1, '(', 'NQO1)', as, the, major]), verbo([target]), complemento([of, dimeric, naphthoquinones, and, proposed, a, mechanism, of, action, that, entailed, induction, of, a, futile, redox, cycling])].
[sujeto(['Moreover,', our, studies]), verbo([reveal]), complemento([an, extensive, binding, interface, between, 'E6a', and, the, isoalloxazine, ring, of, the, flavin, adenine, dinucleotide, '(', 'FAD)', cofactor, of, 'NQO1', in, addition, to, interactions, with, protein, side, chains, in, the, active, site])].
[sujeto(['Comparison', of, the, mode, of]), verbo([binding]), complemento([of, 'E6a', with, those, of, other, chemotherapeutics, reveals, unique, characteristics, of, the, interaction, that, can, be, leveraged, in, future, drug, optimization, efforts])].
[sujeto(['The', first, structure, of, a, dimeric, 'naphthoquinone-NQO1', complex, was, 'reported,', which, can, be, used, for, design, and, synthesis, of, more, potent, next, generation, dimeric, naphthoquinones, to]), verbo([target]), complemento(['NQO1', with, higher, affinity, and, specificity])].
[sujeto(['Bond', 'lengths,', intramolecular, 'distances,', and, the, pattern, of, 'hydrogen-bond', donors, and, acceptors]), verbo([suggest]), complemento([the, cofactor, may, interact, with, 'Met10'])].
[sujeto(['Iron', '(', 'Fe)', homeostasis, is, essential, for, life, and]), verbo([has]), complemento([been, intensively, investigated, for, 'dicots,', while, our, knowledge, for, species, in, the, 'Poaceae', is, fragmentary])].
[sujeto(['The', response, to, 'Fe', deficiency, includes, proteins]), verbo([involved]), complemento([in, 'development,', whereas, membrane, remodeling, and, assembly, 'and/or', repair, of, 'Fe-S', clusters, is, discussed, for, 'Fe', toxicity])].
[sujeto(['The', general, stress, response, appears, to]), verbo([involve]), complemento([proteins, related, to, oxidative, 'stress,', growth, 'regulation,', an, increased, rigidity, and, synthesis, of, cell, walls, and, adaption, of, nutrient, uptake, 'and/or', translocation])].
[sujeto(['Jadomycin', 'B', is, a, member, of, atypical, angucycline, antibiotics, whose, biosynthesis]), verbo([involves]), complemento([a, unique, ring, opening, 'C-C', bond, cleavage, reaction])].
[sujeto(['In', vitro, analysis, of, the, 'JadG', catalyzed, reaction, revealed, that, it]), verbo([requires]), complemento(['FMNH(2)', or, 'FADH(2)', as, cofactors, in, the, conversion, of, dehydrorabelomycin, to, jadomycin, 'A'])].
[sujeto(['NQO1']), verbo([has]), complemento([been, also, shown, to, rescue, proteins, containing, intrinsically, unstructured, 'domains,', such, as, p53, and, 'p73,', from, degradation, by, the, 20, 'S', proteasome, through, an, unknown, mechanism])].
[sujeto(['Our', study, revealed, a, double, negative, feedback, loop, between, 'NQO1', and, the, 20, 'S', 'proteasome,', whereby, 'NQO1']), verbo([prevents]), complemento([the, proteolytic, activity, of, the, 20, 'S', proteasome, and, the, 20, 'S', proteasome, degrades, the, apo, form, of, 'NQO1'])].
[sujeto(['These', observations]), verbo([suggest]), complemento([a, link, between, 20, 'S', proteolysis, and, the, metabolic, cellular, state])].
[sujeto(['More', 'generally,', the, results, may, represent, a, regulatory, mechanism, by, which]), verbo([associated]), complemento([cofactors, dictate, the, stability, of, 'proteins,', thus, coordinating, protein, levels, with, the, metabolic, status])].
[sujeto(['Germline', mutations, in, phosphatase, and, tensin, homolog, '(', 'PTEN)']), verbo([have]), complemento([been, recently, reported, in, 23, '%', of, a, large, series, of, classic, 'CS'])].
[sujeto(['None', of, these, 'SDHx', variants, was]), verbo([found]), complemento([in, 700, population, controls, '(', 'P', &, 'lt;', 0.0001, ')'])].
[sujeto(['We', then]), verbo([found]), complemento([that, 'SDHx', variants, also, occur, in, 6, '%', '(', 26, /, 444, ')', of, 'PTEN', 'mutation-positive', '(', 'PTEN(mut+))', 'CS/CSL', individuals, '(', 'PTEN(mut+)/SDH(var+))'])].
[sujeto(['Most', 'interestingly,', we, also, observed, the]), verbo([loss]), complemento([of, 'steady-state', p53, in, the, majority, of, 'SDH(var+)', cells])].
[sujeto(['This']), verbo([loss]), complemento([of, p53, was, regulated, by, 'MDM2-independent', 'NADH', quinone, oxidoreductase, 1, -, mediated, protein, 'degradation,', likely, due, to, the, imbalance, of, flavin, adenine, 'dinucleotide/nicotinamide', adenine, dinucleotide, in, 'SDH(var+)', cells])].
[sujeto(['Our', data]), verbo([suggest]), complemento([the, potential, regulation, of, 'HIF1α,', p53, and, 'PTEN', signaling, by, mitochondrial, metabolism, in, 'CS/CSL', tumorigenesis])].
[sujeto(['Together,', our, findings]), verbo([suggest]), complemento([the, importance, of, considering, 'SDHx', as, candidate, predisposing, and, modifier, genes, for, 'CS/CSL-related', malignancy, 'risks,', and, a, mechanism, which, suggests, ways, of, therapeutic, reversal, or, prevention])].
[sujeto(['In', those, 'processes,', 'TftC']), verbo([provides]), complemento([all, the, required, 'FADH(2)'])].
[sujeto(['We']), verbo([have]), complemento([determined, the, crystal, structures, of, dimeric, 'TftC', and, tetrameric, 'TftD', at, 2.0, and, 2.5, 'A', 'resolution,', respectively])].
[sujeto(['The', stacked, 'nicotinamide:isoalloxazine', rings, in, 'TftC', and, sequential, reaction, kinetics]), verbo([suggest]), complemento([that, the, reduced, 'FAD', leaves, 'TftC', after, 'NADH', oxidation])].
[sujeto(['An', 'H289A', mutation, resulted, in, the, complete]), verbo([loss]), complemento([of, activity, toward, 2, ',', 5, -, 'DiCHQ', and, a, significant, decrease, in, catalytic, efficiency, toward, 2, ',', 4, ',', 5, -, 'TCP'])].
[sujeto(['EcWrbA', and, 'AfWrbA', are, oligomeric, flavoproteins]), verbo([binding]), complemento([one, flavin, mononucleotide, '(', 'FMN)', per, monomer, and, belonging, to, a, new, family, of, 'NAD(P)H:quinone', oxidoreductases, '(', 'NQOs)'])].
[sujeto(['By', blending, the, 'Os', redox, polymer, with, 'SWCNTs,', the, electrocatalytic, current, could, be]), verbo([increased]), complemento([up, to, a, factor, of, 5])].
[sujeto(['Pyruvate-dependent', reduction, of, 'NADP']), verbo([has]), complemento([been, demonstrated, in, cell, extracts, of, the, human, gastric, pathogen, 'Helicobacter', pylori])].
[sujeto(['However,', 'NADP', is, not, a, substrate, of, purified, 'pyruvate:ferredoxin', oxidoreductase, '(', 'PFOR),']), verbo([suggesting]), complemento([that, other, redox, active, enzymes, mediate, this, reaction])].
[sujeto(['Here', we, show, that, fqrB, '(', 'HP1164),', which, is, essential, and, highly]), verbo([conserved]), complemento([among, the, 'epsilonproteobacteria,', exhibits, 'NADPH', oxidoreductase, activity])].
[sujeto([pylori, and, 'Campylobacter', 'jejuni,', also]), verbo([inhibited]), complemento(['NADP', reduction, in, 'cell-free', lysates])].
[sujeto(['Thus,', 'FqrB']), verbo([provides]), complemento([a, novel, function, in, pyruvate, metabolism, 'and,', together, with, production, of, superoxide, anions, via, quinone, reduction, under, high, oxygen, 'tensions,', contributes, to, the, unique, microaerobic, lifestyle, that, defines, the, epsilonproteobacterial, group])].
[sujeto(['The', activities, of, 'NADH:ubiquinone-1', and, 'NADH:menadione', oxidoreductase, were]), verbo([enhanced]), complemento([approximately, 8, -, fold, and, 4, -, 'fold,', 'respectively,', from, the, 'Triton', 'X-100', extracted, membranes])].
[sujeto(['Based', on, these, 'results,', we]), verbo([suggest]), complemento([that, the, aerobic, respiratory, 'chain-linked', 'NADH', oxidase, system, of, 'B'])].
[sujeto(['While', there]), verbo([have]), complemento([been, extensive, investigations, of, mammalian, 'homologues,', putative, prokaryotic, members, of, this, enzyme, family, have, received, little, attention])].
[sujeto(['The', 'three-dimensional', crystal, structure, of, 'apo-MdaB']), verbo([reported]), complemento([herein, exhibits, significant, structural, similarity, to, a, number, of, 'flavoproteins,', including, the, mammalian, 'DT-diaphorases'])].
[sujeto(['We']), verbo([have]), complemento([shown, by, mass, spectrometry, that, the, endogenously, associated, cofactor, is, flavin, adenine, dinucleotide, and, we, present, here, the, structure, of, 'MdaB', in, complex, with, this, compound])].
[sujeto(['However,', 'over-expression', of, recombinant, quinol, monooxygenase]), verbo([conferred]), complemento([a, state, of, resistance, against, both, tetracycline, and, adriamycin])].
[sujeto(['This', work]), verbo([suggests]), complemento([that, the, redox, cycle, formed, by, these, proteins, protects, 'E'])].
[sujeto(['The', recombinant, expression, of, one, of, the, homologues, in, 'Escherichia', coli]), verbo([led]), complemento([to, a, distinct, change, in, the, quinone, profile, of, the, host, 'cells,', although, the, homologue, is, the, most, distantly, related, to, the, geranylgeranyl, reductase])].
[sujeto(['The', new, compounds]), verbo([found]), complemento([in, the, profile, had, successively, longer, elution, times, than, those, of, ordinary, quinones, from, 'E'])].
[sujeto(['Structural', analyses, of, the, new, compounds, by, electron, 'impact-mass', spectrometry, indicated, that, their, molecular, masses, progressively]), verbo([increase]), complemento([relative, to, the, ordinary, quinones, at, a, rate, of, 2, 'U', but, that, they, still, contain, quinone, head, 'structures,', strongly, suggesting, that, the, compounds, are, quinones, with, partially, saturated, prenyl, side, chains])].
[sujeto(['This', novel, enzyme, noncovalently]), verbo([binds]), complemento([flavin, adenine, 'dinucleotide,', similar, to, geranylgeranyl, 'reductase,', but, was, not, able, to, utilize, 'NAD(P)H', as, the, electron, 'donor,', unlike, the, plant, homologue])].
[sujeto(['The', effects, of]), verbo([increasing]), complemento([mitochondrial, oxidative, phosphorylation, '(', 'OXPHOS),', by, enhancing, electron, transport, chain, 'components,', were, evaluated, on, 1, -, 'methyl-4-phenylpyridinium', '(', 'MPP+)', toxicity, in, brain, neuroblastoma, cells])].
[sujeto(['In', 'contrast,', 'MOC', in, whole, cells, is, highly]), verbo([regulated]), complemento([by, the, supply, of, 'flavins:', 'riboflavin,', flavin, adenine, dinucleotide, '(', 'FAD)', and, flavin, mononucleotide, '(', 'FMN),', where, cell, respiration, reached, up, to, 410, '%', of, controls])].
[sujeto(['In', isolated, 'mitochondria,', 'FAD', and, 'FMN', drastically]), verbo([increased]), complemento([complex, 'I', rate, of, reaction, '(', 1300, '%', ')', and, '(', 450, '%', ')', ',', 'respectively,', having, no, effects, on, complex, 'II', or, 'III'])].
[sujeto(['The', nicotinamides, and, glucose]), verbo([prevented]), complemento(['MPP+', toxicity, by, fueling, anaerobic, 'glycolysis,', evident, by, accumulation, of, lactate, in, the, absence, of, 'MOC'])].
[sujeto(['An']), verbo([increase]), complemento([in, 'CO(2),', 'CO(2)/O(2)', 'ratio,', mitochondrial, inhibition, or, 'O(2)', deprivation, was, not, directly, 'toxic,', but, activated, metabolism, through, glycolysis, prompting, depletion, of, glucose, and, starvation])].
[sujeto(['In', 'conclusion,', the, results, of, this, study, indicate, that, the, mechanism, of, action, for, 'MPP+,']), verbo([involves]), complemento([the, inhibition, of, complex, 'I', and, and, more, specifically, complex, 'IV,', leading, to, impaired, 'OXPHOS', and, 'MOC'])].
[sujeto(['It', contains, two, redox, 'centers:', a, 'tightly,', but, 'noncovalently,']), verbo([bound]), complemento(['FAD', and, an, enzymic, 'disulfide,', each, of, which, can, accommodate, two, electrons])].
[sujeto(['Comparison', of, the, rates, of, reduction, of, the, above, substrates, by, 'EH(2)', and, 'EH(4)', with, their, corresponding, 'steady-state', kinetic, parameters, for, kinetic, competence]), verbo([leads]), complemento([to, the, conclusion, that, reduction, of, lipoyl, substrates, occurs, with, 'EH(2)', while, reduction, of, diaphorase, substrates, occurs, with, 'EH(4)'])].
[sujeto(['NADH', readily]), verbo([provides]), complemento([reducing, equivalents, to, 'membrane-bound', methane, monooxygenase, '(', 'pMMO)', from, 'Methylococcus', capsulatus, '(', 'Bath)', in, isolated, membrane, 'fractions,', but, detergent, solubilization, disrupts, this, 'electron-transfer', process])].
[sujeto(['The', purified, 'NDH-2']), verbo([has]), complemento([a, subunit, molecular, weight, of, 36, kDa, and, exists, as, a, monomer, in, solution])].
[sujeto(['Rotenone', and, flavone, did, not]), verbo([inhibit]), complemento([the, 'NDH-2,', whereas, amytal, caused, partial, inhibition, but, only, at, high, concentrations])].
[sujeto(['The', gene, encoding, dihydrolipoamide, dehydrogenase, from, 'Mycobacterium', 'tuberculosis,', 'Rv0462,', was]), verbo([expressed]), complemento([in, 'Escherichia', coli, and, the, protein, purified, to, homogeneity])].
[sujeto(['The', 49, kDa, polypeptide, forms, a, homodimer, containing, one, tightly]), verbo([bound]), complemento([molecule, of, 'FAD/monomer'])].
[sujeto(['Solvent', deuterium, kinetic, isotope, effects, with, 4, ',', 4, -, dithiopyridine, '(', 'DTP),', the, 4, -, thiopyridone, product, of, which]), verbo([requires]), complemento([no, 'protonation,', are, also, inverse, with, '(', 'D)(V/K)(APADH)', =, 0.75, +, /, -, 0.06, ',', '(', 'D)(V/K)(DTP)', =, 0.71, +, /, -, 0.02, ',', and, '(', 'D)V(app)', =, 0.56, +, /, -, 0.15])].
[sujeto(['Taken', 'together,', these, results]), verbo([suggest]), complemento([that, '(', 1, ')', the, reductive, 'half-reaction', '(', hydride, transfer, from, 'NADH', to, 'FAD)', is, rate, limiting, when, a, quinone, is, the, 'oxidant,', and, '(', 2, ')', deprotonation, of, enzymic, 'thiols,', most, likely, 'Cys(46)', and, 'Cys(41),', limits, the, reductive, and, oxidative, 'half-reactions,', 'respectively,', when, 'D,L-lipoamide', is, the, oxidant])].
[sujeto(['Alternatively,', in, tumor, cells, 'QR', can]), verbo([activate]), complemento([a, number, of, cancer, chemotherapeutic, agents, such, as, mitomycins, and, aziridylbenzoquinones])].
[sujeto(['Thus,', the, same, enzyme, that, protects, the, organism, from, the, deleterious, effects, of, quinones, can]), verbo([activate]), complemento([cytotoxic, chemotherapeutic, prodrugs, and, cause, cancer, cell, death])].
[sujeto(['Here', we]), verbo([report]), complemento([ab, initio, quantum, mechanical, calculations, in, and, around, the, active, site, of, the, enzyme, that, provide, information, about, the, fine, details, of, the, contribution, of, the, protein, to, the, stabilization, of, the, reduced, flavin])].
[sujeto(['The', results, show, that, '(', 1, ')', protein, interactions]), verbo([provide]), complemento([approximately, 2, 'kcal/mol', to, stabilize, the, planar, conformation, of, the, reduced, flavin, isoalloxazine, ring, observed, in, the, 'X-ray', 'structure;', '(', 2, ')', the, charge, separation, present, in, the, reduced, planar, form, of, the, flavin, is, stabilized, by, interactions, with, groups, of, the, 'protein;', '(', 3, ')', even, after, 'stabilization,', the, reduction, potential, of, the, cofactor, remains, more, negative, than, that, of, the, free, 'flavin,', making, it, a, better, reductant, for, a, larger, variety, of, 'quinones;', and, '(', 4, ')', the, more, negative, reduction, potential, may, also, result, in, faster, kinetics, for, the, quinone, reduction, step])].
[sujeto([lamblia, was]), verbo([expressed]), complemento([in, 'Escherichia', coli])].
[sujeto(['Most', amino, acid, residues, of, the, mammalian, enzymes, that]), verbo([participate]), complemento([in, substrate, binding, or, catalysis, are, conserved])].
[sujeto(['Complex', 'I', '(', 'NADH-quinone', 'oxidoreductase)', is, an, enzyme, that, catalyzes, the, initial, electron, transfer, from, nicotinamide, adenine, dinucleotide, '(', 'NADH)', to, flavin, mononucleotide, '(', 'FMN)']), verbo([bound]), complemento([at, the, tip, of, the, hydrophilic, domain, of, complex, 'I'])].
[sujeto(['However,', 'Helicobacter', pylori]), verbo([has]), complemento([an, unusual, complex, 'I', that, lacks, typical, 'NQO1', and, 'NQO2', 'subunits,', both, of, which, are, generally, included, in, the, 'NADH', dehydrogenase, domain, of, complex, 'I'])].
[sujeto(['pylori,', which, is, located, in, place, of, 'NQO2,', by, 'three-dimensional']), verbo([nuclear]), complemento([magnetic, resonance, '(', 'NMR)', spectroscopy, and, revealed, that, 'HP1264', can, bind, to, 'FMN', through, 'UV-visible,', 'fluorescence,', and, 'NMR', titration, experiments])].
[sujeto(['This', result]), verbo([suggests]), complemento([that, 'FMN-bound', 'HP1264', could, be, involved, in, the, initial, electron, transfer, step, of, complex, 'I'])].
[sujeto(['Notably,', these, residues, are, not]), verbo([conserved]), complemento([in, the, 'FMN', binding, site, of, any, other, flavoproteins, with, known, structure])].
[sujeto(['This', study, of, the, relationship, between, the, structure, and, 'FMN']), verbo([binding]), complemento([property, of, 'HP1264', will, contribute, to, improving, our, understanding, of, flavoprotein, structure, and, the, electron, transfer, mechanism, of, complex, 'I'])].
[sujeto(['These', in, silico, 'absorption,', 'distribution,', metabolism, and, excretion, models, are, helpful, in, making, quantitative, prediction, of, their, metabolic, rates, for, new]), verbo([lead]), complemento([compounds, before, resorting, in, vitro, and, in, vivo, experimentation])].
[sujeto(['Both', compounds]), verbo([increased]), complemento([mRNAs, of, the, drug, metabolizing, enzymes, 'CYP3A4,', 'CYP1A1,', 'CYP1A2', and, the, flavin, containing, monooxygenase, 'FMO5,', and, of, the, multidrug, resistance, protein, 'MRP2'])].
[sujeto(['Expression', of, genes]), verbo([mediating]), complemento([cholesterol, biosynthesis, was, 'decreased,', while, facilitated, glucose, transporters, and, glycolysis, genes, were, 'induced,', indicating, increased, glucose, metabolism])].
[sujeto(['Changes', of, a, considerable, number, of, additional, transcripts, corresponded, to]), verbo([reports]), complemento([on, gene, regulation, by, hypoxia])].
[sujeto(['Endoplasmic', reticulum, 'stress-regulated', genes]), verbo([involved]), complemento([in, unfolded, protein, response, and, in, protection, of, cells, from, apoptosis, were, downregulated])].
[sujeto(['Other', calcium]), verbo([binding]), complemento([proteins, were, affected, by, both, 'treatments,', suggesting, an, increase, in, intracellular, calcium])].
[sujeto(['John\'s', wort, and, hyperforin, concordantly, affected, expression, of, genes, not, only]), verbo([mediating]), complemento([metabolism, and, transport, of, exogenous, and, endogenous, 'compounds,', but, also, involved, in, energy, 'metabolism,', intracellular, calcium, 'regulation,', cell, proliferation, and, apoptosis])].
[sujeto(['The', expression, and, partial, characterization, of, the, 'NQO7', 'subunit,', one, of, the, seven, subunits, that, constitute, the, hydrophobic, sector, of, the, enzyme, 'complex,']), verbo([have]), complemento([been, performed, and, are, reported, here])].
[sujeto(['The', 'GST-fused', 'NQO7', subunit, was]), verbo([expressed]), complemento([in, the, membrane, fraction, of, the, host, cells, and, was, extracted, from, the, membranes, by, nonionic, detergents, '(', 'Triton', 'X-100,', dodecyl, 'maltoside)'])].
[sujeto(['The', isolated, 'GST-fused', 'NQO7', subunit, '(', but, not, the, 'GST', 'alone)', was, determined, to]), verbo([interact]), complemento([with, phospholipid, vesicles, and, suppress, the, membrane, fluidity])].
[sujeto(['By', use, of, immunochemical, and, cysteine, residue, modification, 'techniques,', the, topology, of, the, 'Paracoccus', 'NQO7', subunit, in, the, membranes]), verbo([has]), complemento([been, examined])].
[sujeto(['The', data]), verbo([suggest]), complemento([that, the, 'Paracoccus', 'NQO7', subunit, contains, three, transmembrane, segments, and, that, its, 'N-', and, 'C-terminal', regions, are, directed, toward, the, cytoplasmic, and, periplasmic, phases, of, the, 'membrane,', respectively])].
[sujeto(['The', proposed, topology, of, the, 'GST-fused', 'NQO7', subunit]), verbo([expressed]), complemento([in, 'E'])].
[sujeto(['Reports', document, that, they]), verbo([have]), complemento([antioxidant, and, 'anti-inflammatory', 'activities;', 'nonetheless,', the, molecular, mechanisms, involved, in, their, 'anti-inflammatory', actions, have, not, yet, been, elucidated])].
[sujeto(['The', effects, of, 'CR', and, 'ET', on, mitogen]), verbo([activated]), complemento([protein, kinases, '(', 'MAPKs)', and, nuclear, factor, '(', 'NF)-κB', signaling, pathways, were, examined, using, 'Western', blotting, and, specific, inhibitors])].
[sujeto(['CR', and, 'ET']), verbo([suppressed]), complemento(['BV2', 'activation,', 'down-regulated', iNOS, and, 'COX-2', expression, and, inhibited, nitric, oxide, '(', 'NO)', overproduction, without, affecting, cell, viability])].
[sujeto(['They', also]), verbo([inhibited]), complemento([p65, 'NF-κB', phosphorylation, and, modulated, 'Jun-N', terminal, kinase, '(', 'JNK)', activation, in, 'BV2', cells])].
[sujeto(['NF-κB', 'inhibitor,', 'Bay', 11, -, 7082, ',']), verbo([enhanced]), complemento([the, 'anti-IL-6', effects, of, both, 'CR', and, 'ET'])].
[sujeto(['Our', results, show, that, 'CR', and, 'ET', exhibit, 'anti-neuroinflammatory', activities, by]), verbo([inhibiting]), complemento(['pro-inflammatory', mediator, expression, and, 'production,', upregulating, 'HO-1,', 'GCLM', and, 'NQO1,', blocking, 'NF-κB', and, modulating, 'JNK', signaling, pathways])].
[sujeto(['They', may, offer, therapeutic, potential, for]), verbo([suppressing]), complemento([overactivated, microglia, and, alleviating, neurodegeneration])].
[sujeto(['Ruminal', genes, differentially]), verbo([expressed]), complemento([in, crossbred, beef, steers, from, 'USMARC', with, variation, in, gain, and, feed, intake, were, identified, in, a, previous, study])].
[sujeto(['Of', the, 17, genes, 'tested,', two, were, differentially]), verbo([expressed]), complemento([by, 'RFI', class, in, the, 'Angus&nbsp;×&nbsp;Hereford', animals])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, some, of, the, genes, identified, in, a, previous, rumen, transcriptome, discovery, study, may, have, utility, for, identifying, or, selecting, for, animals, with, superior, feed, efficiency, phenotypes, across, cattle, breeds, and, populations])].
[sujeto(['Maintenance', of, muscle, performance, by]), verbo([involving]), complemento([in, physical, activities, is, essential, to, increase, independence, and, quality, of, life, among, elderly])].
[sujeto(['The', use, of, natural, compounds, with, ergogenic, activity, in, old, people, would]), verbo([increase]), complemento([the, effect, of, moderate, exercises, in, the, maintenance, of, physiological, muscle, capacity])].
[sujeto(['Resveratrol', '(', 'RSV),', a, polyphenol]), verbo([found]), complemento([in, 'walnuts,', berries, and, 'grapes,', shows, this, ergogenic, activity])].
[sujeto(['By', using, 'young,', mature, and, old, mice, as, 'models,', we]), verbo([have]), complemento([found, that, 'RSV', improves, muscle, performance, in, mature, and, old, animals, but, not, in, young, animals])].
[sujeto(['Without', showing, significant, effect, by, 'itself,', 'RSV', primed, the, effect, of, exercise, by]), verbo([increasing]), complemento(['endurance,', coordination, and, strength, in, old, animals])].
[sujeto(['This', effect, was, accompanied, by, a, higher, protection, against, oxidative, damage, and, an]), verbo([increase]), complemento([in, mitochondrial, mass])].
[sujeto(['RSV']), verbo([increased]), complemento([catalase, and, superoxide, dismutase, protein, levels, in, muscle, and, primed, exercise, to, reverse, the, decrease, in, their, activities, during, ageing])].
[sujeto(['Furthermore,', 'RSV']), verbo([increased]), complemento([the, level, of, mitochondrial, mass, markers, such, as, cytochrome, 'C,', mitochondrial, transcription, factor, 'A', and, nuclear, respiratory, 'factor-1', in, muscle, in, exercised, animals])].
[sujeto(['Our', results, indicate, that, 'RSV', can, be, considered, an, ergogenic, compound, that, helps]), verbo([maintain]), complemento([muscle, performance, during, ageing, and, subsequently, reduces, frailty, and, increases, muscle, performance, in, old, individuals, practising, moderate, exercise])].
[sujeto(['To', construct, the, malignant, transformation, model, of, human, bronchial, epithelial, '(', 'HBE)', cell, line, by, exposing, to, low, level, of, sodium, arsenite, and, determine, if, the]), verbo([nuclear]), complemento([factor, 'E2', related, factor, 2, '(', 'Nrf2)', signaling, pathway, is, involved, in, this, process])].
[sujeto(['MTT', assay, demonstrated, that, the, proliferation, of, 'HBE', cells, was, out, of, control, with]), verbo([increasing]), complemento([passages, of, sodium, arsenite, exposure])].
[sujeto(['Also,', the, expresion, of, 'QO1', and, 'HO-1,', downstream, of, 'Nrf2']), verbo([target]), complemento(['proteins,', were, also, decreased, with, the, expression, of, 'Nrf2'])].
[sujeto(['The', transformation, of, 'HBE', cells]), verbo([induced]), complemento([by, chronic, exposure, to, sodium, arsenite, is, mediated, by, decreased, 'Nrf2', level, and, its, downstream, 'NQO1', and, 'HO-1', 'protein,', which, subsequently, promote, the, malignant, proliferation])].
[sujeto(['To', explore, a, new, method, of, establishing, 'HepG2', cell, model, of, steatosis, and, observe, the, expression, and, significance, of]), verbo([nuclear]), complemento([factor, 'erythroid-2p45-related', factor, 2, '(', 'Nrf2)/antioxidative', response, element, '(', 'ARE)', pathway, related, factors, in, 'HepG2', cells, of, steatosis])].
[sujeto(['HepG2', cells, were]), verbo([induced]), complemento([with, 'DMEM', containing, 25, '%', fetal, bovine, 'serum,', 0.1, '%', 'MCT/LCT', 'Fat', 'Emulsion', and, 0.1, 'mmol/L', free, fatty, acid, '(', 'FFA)', at, different, stages, and, the, control, group, cells, were, cultured, with, normal, 'DMEM', medium])].
[sujeto(['Nitric', oxide, '(', 'NO),', superoxide, 'dismutase(SOD),', 'malonyldialdehyde(MDA)', and, glutathione, 'peroxidase(GSH-Px)', were, tested, by, biological, reagent, 'kit,', while, the, protein, expression, of]), verbo([nuclear]), complemento([factor, 'erythroid-2p45-related', factor, 2, '(', 'Nrf2),', heme, 'oxygenase-1', '(', 'HO-1)', and, quinone, 'oxidoreductase-1(NQO1)', were, analyzed, by, 'Western', blot])].
[sujeto(['Nuclear', factor, erythroid, 2, '(', 'NF-E2)-related', factor, 2, '(', 'Nrf2)']), verbo([regulates]), complemento([multiple, 'anti-oxidative', enzymes, and, has, neuroprotective, effects])].
[sujeto(['Pterostilbene', '(', 'PTE)', is, a, natural, 'anti-oxidant']), verbo([found]), complemento([in, blueberries])].
[sujeto(['PTE', was, nontoxic, and]), verbo([induced]), complemento([the, nuclear, translocation, of, 'Nrf2', when, 'HT22', cell, cultures, were, incubated, with, different, concentrations, of, 'PTE'])].
[sujeto(['Further,', 'PTE', displayed, a, 'dose-dependent', neuroprotective, 'effect,', as, indicated, by]), verbo([increased]), complemento([cell, viability, and, a, reduction, in, lactate, dehydrogenase, '(', 'LDH)', release, after, glutamate, treatment])].
[sujeto(['Nrf2', siRNA, treatment]), verbo([inhibited]), complemento(['PTE-induced', neuroprotective, effects])].
[sujeto(['Moreover,', the, levels, of]), verbo([nuclear]), complemento(['Nrf2', and, downstream, heme, 'oxygenase-1', '(', 'HO-1)', and, quinone, oxidoreductase, 1, '(', 'NQO1)', were, elevated, after, 'PTE', treatment])].
[sujeto(['The', 'PTE-induced', elevation, of]), verbo([nuclear]), complemento(['Nrf2,', as, well, as, the, increases, in, 'HO-1', and, 'NQO1', 'levels,', was, abolished, by, 'Nrf2', siRNA])].
[sujeto(['PTE', treatment, reduced, the, production, of, reactive, oxygen, species, '(', 'ROS)', and, significantly]), verbo([enhanced]), complemento([the, activities, of, the, cellular, 'anti-oxidants', glutathione, '(', 'GSH)', and, superoxide, dismutase, '(', 'SOD),', indicating, an, attenuation, of, 'glutamate-induced', oxidative, stress])].
[sujeto(['The', 'KEAP1-NRF2', pathway]), verbo([regulates]), complemento([cellular, redox, homeostasis, by, transcriptional, induction, of, genes, associated, with, antioxidant, synthesis, and, detoxification, in, response, to, oxidative, stress])].
[sujeto(['Previously,', we]), verbo([reported]), complemento([that, 'KEAP1', mutation, elicits, constitutive, 'NRF2', activation, and, resistance, to, cisplatin, '(', 'CDDP)', and, dacarbazine, '(', 'DTIC)', in, human, melanomas])].
[sujeto(['The', present, study, was, conducted, to, clarify, whether, an, 'HSP90', 'inhibitor,', 17, -, 'AAG,', efficiently, eliminates, melanoma, with, 'KEAP1', 'mutation,', as, the, 'NRF2']), verbo([target]), complemento(['gene,', 'NQO1,', is, a, key, enzyme, in, 17, -, 'AAG', bioactivation])].
[sujeto(['NQO1', is, highly]), verbo([expressed]), complemento([in, normal, melanocytes, and, in, several, melanoma, cell, lines, despite, the, presence, of, 'wild-type', 'KEAP1,', and, the, 'NQO1', expression, is, dependent, on, 'NRF2', activation])].
[sujeto(['Because', either, 'CDDP', or, 'DTIC', produces, reactive, oxygen, species, that]), verbo([activate]), complemento(['NRF2,', we, determined, whether, these, agents, would, sensitize, 'NQO1-low', melanoma, cells, to, 17, -, 'AAG'])].
[sujeto(['Perinatal', hypoxic, ischaemic, encephalopathy, '(', 'HIE)']), verbo([has]), complemento([a, high, mortality, rate, with, neuropsychological, impairment])].
[sujeto(['In', 'vitro,', argon, treatment, of, cortical, neuronal, cultures, resulted, in, a, significant]), verbo([increase]), complemento([of, 'p-mTOR', and, 'Nuclear', factor, '(', 'erythroid-derived', 2, ')', -, like, 2, '(', 'Nrf2)', and, protection, against, 'OGD', challenge])].
[sujeto(['In', 'vivo,', argon, exposure, significantly]), verbo([enhanced]), complemento(['Nrf2', and, its, 'down-stream', effector, 'NAD(P)H', 'Dehydrogenase,', 'Quinone', 1, '(', 'NQO1)', and, superoxide, dismutase, 1, '(', 'SOD1)'])].
[sujeto(['Oxidative', 'stress,', neuroinflammation, and, neuronal, cell, death, were, significantly]), verbo([decreased]), complemento([and, brain, infarction, was, markedly, reduced])].
[sujeto(['These', data]), verbo([provide]), complemento([a, new, molecular, mechanism, for, the, potential, application, of, 'Argon', as, a, neuroprotectant, in, 'HIE'])].
[sujeto(['The', 'constitutively-expressed', cyclooxygenase, 1, '(', 'COX-1)', and, the, inducible, 'COX-2', are, both]), verbo([involved]), complemento([in, the, conversion, of, arachidonic, acid, '(', 'AA)', to, prostaglandins, '(', 'PGs)'])].
[sujeto(['COX-1(-/-)', or, 'COX-2(-/-)', cells, shared, about, 50, '%', of, the]), verbo([induced]), complemento([transcripts, with, 'WT', cells, treated, with, 'IL-1β,', respectively])].
[sujeto(['The', augmented, 'COX-1', mRNA, '(', in, 'COX-2(-/-)', 'cells)', was]), verbo([associated]), complemento([with, the, upregulation, of, mRNAs, for, glutathione, 'S-transferase', '(', 'GST),', superoxide, dismutase, '(', 'SOD),', 'NAD(P)H', dehydrogenase, quinone, 1, '(', 'NQO1),', aryl, hydrocarbon, receptor, '(', 'AhR),', 'peroxiredoxin,', 'phospholipase,', prostacyclin, 'synthase,', and, prostaglandin, 'E', 'synthase,', resulting, in, a, significant, increase, in, the, levels, of, 'PGE2,', 'PGD2,', leukotriene, 'B4', '(', 'LTB4),', 'PGF1α,', thromboxane, 'B2', '(', 'TXB2),', and, 'PGF2α'])].
[sujeto(['The', genomic, characteristics, of, 'COX-2(-/-)', is, similar, to, that, of, proinflammatory, cells, as, observed, in, 'IL-1β']), verbo([induced]), complemento(['WT', cells])].
[sujeto(['We']), verbo([have]), complemento([examined, how, forced, expression, of, the, 'NAD(P)H', quinone, 'dehydrogenase,', quinone, 1, '(', 'NQO1),', a, major, 'quinone-reducing', enzyme, in, 'cytosol,', affects, the, survival, of, 'RD-treated', cells])].
[sujeto(['We']), verbo([found]), complemento([that, treatment, of, the, mouse, melanoma, cell, line, 'B16BL6', or, normal, human, melanocytes, with, carnosic, 'acid,', a, transcriptional, inducer, of, the, 'NQO1', 'gene,', notably, suppressed, the, cell, killing, effect, of, 'RD'])].
[sujeto(['Moreover,', conditional, overexpression, of, the, human, 'NQO1', transgene, in, 'B16BL6']), verbo([led]), complemento([to, an, 'expression-dependent', increase, of, cell, survival, after, 'RD', treatment])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'NQO1', attenuates, the, cytotoxicity, of, 'RD', 'and/or', its, metabolites])].
[sujeto(['Safflower', yellow, 'B', '(', 'SYB)']), verbo([has]), complemento([been, reported, to, protect, the, brain, against, damage, induced, by, oxidative, 'stress;', 'however,', whether, 'SYB', can, also, protect, hepatocytes, from, oxidative, stress, remains, unknown])].
[sujeto(['H2O2']), verbo([induced]), complemento([pronounced, injury, to, the, 'HepG2', 'cells,', as, evidenced, by, increased, levels, of, malondialdehyde, '(', 'MDA)', and, 'ROS,', the, decreased, activity, of, 'SOD', and, 'GSH-Px,', the, increased, activitation, of, 'caspase-3', and, cell, 'apoptosis,', and, the, loss, of, mitochondrial, membrane, potential])].
[sujeto(['SYB', significantly]), verbo([inhibited]), complemento([the, damaging, effects, of, 'H2O2,', indicating, that, it, protected, the, cells, against, 'H2O2-induced', oxidative, damage])].
[sujeto(['Moreover,', 'pre-treatment', with, 'SYB']), verbo([increased]), complemento([the, expression, of, nuclear, factor, erythroid, 2, -, related, factor, 2, '(', 'Nrf2),', heme, oxygenase, 1, '(', 'HO-1)', and, 'NAD(P)H', 'dehydrogenase,', quinone, 1, '(', 'NQO1)', which, are, peroxiredoxins])].
[sujeto(['SYB', also, significantly]), verbo([increased]), complemento([the, phosphorylation, of, 'AKT'])].
[sujeto(['The', findings, of, our, study]), verbo([suggest]), complemento([that, the, activation, of, the, 'AKT/Nrf2', pathway, is, involved, in, the, cytoprotective, effects, of, 'SYB', against, oxidative, stress])].
[sujeto(['Our', findings]), verbo([provide]), complemento([new, insight, into, the, cytoprotective, effects, of, 'SYB', and, the, possible, mechanisms, underlying, these, effects])].
[sujeto(['To']), verbo([provide]), complemento([insight, into, their, genetic, 'composition,', we, sequenced, and, analyzed, the, entire, genome, of, 'TK6', 'cells,', as, well, as, the, normalized, transcriptomes, of, 'TK6,', 'WTK1,', and, 'NH32', cells])].
[sujeto(['Normalized', 'mRNA-seq', analysis, identified, the, expression, of, transcripts, bearing, 'SNPs', or, mutations, for, 'TK6,', 'WTK1,', and, 'NH32', as, 2.88, '%', ',', 2.04, '%', ',', and, 1.71, '%', ',', 'respectively,', and, several, of, the, variant, transcripts, identified, appear, to]), verbo([have]), complemento([important, implications, in, genetic, toxicology])].
[sujeto(['SNPs', in, the, thiopurine, 'S-methyltransferase', '(', 'TPMT)', gene, '(', 'TPMT*3A', 'SNP),', and, in, the, xenobiotic, metabolizing, 'enzyme,', 'NADPH', quinine, oxidoreductase, 1, '(', 'NQO1)', gene, '(', 'NQO1*2', 'SNP),', are, both]), verbo([associated]), complemento([with, decreased, enzyme, activity])].
[sujeto(['The', clinically, relevant, 'TPMT*3A', and, 'NQO1*2', 'SNPs', can, make, these, cell, lines, useful, in, pharmacogenetic, studies, aimed, at, improving, or, tailoring, drug, treatment, regimens, that, minimize, toxicity, and]), verbo([enhance]), complemento([efficacy])].
[sujeto(['Diet-induced', nonalcoholic, fatty, liver, disease, '(', 'NAFLD)', is, characterized, by, profound, lipid, accumulation, and]), verbo([associated]), complemento([with, an, inflammatory, 'response,', oxidative, stress, and, hepatic, mitochondrial, dysfunction])].
[sujeto(['Molecular', hydrogen, in, 'hydrogen-rich', liquid, or, inhaling, 'gas,', which]), verbo([has]), complemento([been, confirmed, in, scavenging, reactive, oxygen, species, and, preventing, mitochondrial, 'decay,', improved, metabolic, syndrome, in, patients, and, animal, models])].
[sujeto(['We']), verbo([found]), complemento([that, 'CCH', durably, generated, hydrogen, in, vivo, and, in, vitro])].
[sujeto(['Moreover,', 'CCH', effectively, improved, 'HFD-induced', hepatic, mitochondrial, 'dysfunction,', reduced, oxidative, 'stress,', and]), verbo([activated]), complemento([phase, 'II', enzymes])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'CCH', is, an, efficient, 'hydrogen-rich', 'agent,', which, could, prevent, 'HFD-induced', 'NAFLD', via, activating, phase, 'II', enzymes, and, improving, mitochondrial, function])].
[sujeto(['The', 'Mre11,', 'Rad50,', and, 'Nbs1', '(', 'MRN)', complex, is, a, 'DNA', 'double-strand', break, sensor]), verbo([involved]), complemento([in, 'DNA', damage, repair])].
[sujeto(['In', 'vitro,', cisplatin]), verbo([increased]), complemento([the, expression, of, 'MRN', complex, proteins, and, 'NQO1', in, 'NQO1-expressing', 'ACHN', cells, in, a, 'time-', and, 'concentration-dependent', manner])].
[sujeto(['The', expression, of, 'MRN', complex, proteins, was, relatively]), verbo([inhibited]), complemento([in, 'NQO1-knockdown', cells])].
[sujeto(['In', 'vivo,']), verbo([increased]), complemento([expression, of, renal, 'MRN', complex, proteins, was, accompanied, by, upregulation, of, 'γ-H2A', histone, member, 'X,', a, 'DNA', damage, 'marker,', in, 'cisplatin-treated', 'wild-type', mice])].
[sujeto(['Although', the, 'NQO1-knockout', '(', 'NQO1(-/-))', mice, showed, more, severe, 'cisplatin-induced', renal, 'damage,', the, renal, expression, of, 'MRN', complex, proteins, was, lower, than, in, 'NQO1-expressing', 'mice;', expression, of, 'poly[ADP-ribose]', polymerase, 1, ',', which]), verbo([promotes]), complemento(['MRN', complex, 'accumulation,', was, also, lower, in, these, animals])].
[sujeto(['In', 'addition,', 'cisplatin-induced', expression, of, 'DNA', damage, 'repair-related', 'proteins,', ataxia, telangiectasia, mutated, and, 'sirtuin1,', markedly]), verbo([decreased]), complemento([in, the, 'NQO1(-/-)', 'group,', relative, to, the, 'NQO1-expressing', mice])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'NQO1', deletion, might, be, associated, with, decreased, 'MRN', complex, 'expression,', which, might, be, partially, responsible, for, the, exacerbation, of, 'cisplatin-induced', 'AKI', in, the, absence, of, 'NQO1'])].
[sujeto(['The', multitarget, approach]), verbo([has]), complemento([gained, increasing, acceptance, as, a, useful, tool, to, address, complex, and, multifactorial, maladies, such, as, 'Alzheimer\'s', disease, '(', 'AD)'])].
[sujeto(['The', concurrent, inhibition, of, the, validated, 'AD']), verbo([targets]), complemento(['β-secretase', '(', 'BACE-1)', and, glycogen, synthase, 'kinase-3β', '(', 'GSK-3β)', by, attacking, both, 'β-amyloid', and, tau, protein, cascades, has, been, identified, as, a, promising, 'AD', therapeutic, strategy])].
[sujeto(['In', our, 'study,', curcumin, was, identified, as, a]), verbo([lead]), complemento([compound, for, the, simultaneous, inhibition, of, both, 'targets;', 'therefore,', synthetic, efforts, were, dedicated, to, obtaining, a, small, library, of, novel, 'curcumin-based', 'analogues,', and, a, number, of, potent, and, balanced, 'dual-target', inhibitors, were, obtained])].
[sujeto(['Notably,', for, some, new, compounds, the, symmetrical, diketo, and, the, 'β-keto-enol', tautomeric, forms, were, purposely, isolated, and, tested, in, 'vitro,', allowing, us, to]), verbo([gain]), complemento([insight, into, the, key, requirements, for, 'BACE-1', and, 'GSK-3β', inhibition])].
[sujeto(['Alterations', in, the, expression, of, antioxidant, enzymes, are]), verbo([associated]), complemento([with, changes, in, cancer, cell, sensitivity, to, chemotherapeutic, drugs, '(', menadione, and, 'β-lapachone)'])].
[sujeto(['Finally,', the, importance, of, 'NQO1', overexpression, in, the, putative, acquisition, of, either, drug, resistance, or, an]), verbo([increased]), complemento([sensitivity, to, quinones, by, cancer, cells, was, investigated, by, immunoblotting, and, cytotoxicity, assays])].
[sujeto(['Genomic']), verbo([gain]), complemento([of, the, chromosomal, band, 16, q22, was, detected, in, 'Resox', cells, compared, to, parental, breast, cancer, 'MCF-7', cells, and, normal, human, mammary, epithelial, 250, 'MK', cells])].
[sujeto(['This', genomic]), verbo([gain]), complemento([was, associated, with, amplification, of, the, 'NQO1', gene, in, one, tumor, biopsy, as, well, as, in, breast, cancer, cell, lines])].
[sujeto(['Using', different, breast, cell, 'models,', we]), verbo([found]), complemento([that, 'NQO1', overexpression, was, a, main, determinant, for, a, potential, chemotherapy, resistance, or, an, increased, sensitivity, to, 'quinone-bearing', compounds])].
[sujeto(['Ketones']), verbo([decrease]), complemento([oxidative, 'stress,', increase, antioxidants, and, scavenge, free, radicals])].
[sujeto(['It', is, hypothesized, that, ketogenic, diet, '(', 'KD)', will]), verbo([decrease]), complemento(['post-TBI', oxidative, stress, and, improve, mitochondria])].
[sujeto(['Oxidative', stress, was, significantly]), verbo([increased]), complemento([at, 6, and, 24, h, 'post-injury', and, attenuated, by, 'KD', while, inducing, protein, expression, of, 'antioxidants,', 'NAD(P)H', dehydrogenase, quinone, 1, '(', 'NQO1)', and, superoxide, dismutase, '(', 'SOD1/2)'])].
[sujeto(['Complex', 'I', activity, was]), verbo([inhibited]), complemento([in, 'STD', and, 'KD', groups, at, 6, h, and, normalized, by, 24, h])].
[sujeto(['These', results, strongly]), verbo([suggest]), complemento([that, ketones, improve, 'post-TBI', cerebral, metabolism, by, providing, alternative, substrates, and, through, antioxidant, 'properties,', preventing, oxidative, 'stress-mediated', mitochondrial, dysfunction])].
[sujeto(['Compelling', evidences]), verbo([have]), complemento([shown, that, diverse, environmental, insults, arising, during, early, life, can, either, directly, lead, to, a, reduction, in, the, number, of, dopaminergic, neurons, or, cause, an, increased, susceptibility, to, neurons, degeneration, with, subsequent, environmental, insults, or, with, aging, alone])].
[sujeto(['We', show, that, 'PQ', can]), verbo([decrease]), complemento([the, activity, of, 'SOD', and, 'CAT', but, increase, 'MDA', and, 'LDH', level])].
[sujeto(['Furthermore,', the, activities, of, 'Cyc', and, 'caspase-9', were]), verbo([found]), complemento([increased, significantly, at, 10, μM, of, 'PQ', treatment])].
[sujeto(['The']), verbo([nuclear]), complemento(['Nrf2', protein, expressions, were, upregulated, as, well, as, the, downstream, mRNA, expressions, of, 'HO-1', and, 'NQO1', in, a, 'dose-dependent', manner])].
[sujeto(['In', 'addition,', the, proteins, expression, of, 'PKC', and, 'CKII', was, also]), verbo([increased]), complemento([significantly, even, at, 1, μM])].
[sujeto(['The', results]), verbo([suggested]), complemento([that, 'Nrf2/ARE', pathway, is, involved, in, mild, to, moderate, 'PQ-induced', oxidative, stress, which, is, evident, from, dampened, 'Nrf2', activity, and, low, expression, of, antioxidant, genes, in, 'PQ', induced, oxidative, damage])].
[sujeto(['Lead', '(', 'Pb)', is, an, environmental, pollutant, that, can, get, entry, into, human, body, through, contaminated, 'foods,', 'drinks,', and, inhaled, air]), verbo([leading]), complemento([to, severe, biological, 'consequences,', and, has, been, responsible, for, many, deaths, worldwide])].
[sujeto(['Additionally,', these, 'Pb', concentrations]), verbo([induced]), complemento([oxidative, stress, in, 'HepG2', cells, in, terms, of, production, of, reactive, oxygen, species, '(', 'ROS)', and, induced, heme, 'oxygenase-1', mRNA, expression, in, a, 'concentration-dependent', phenomenon])].
[sujeto(['Thus,', consumption, of, foods, rich, in, these, micronutrients, may, help, to, reduce, the, adverse, effects, of]), verbo([lead]), complemento([in, areas, with, high, levels, of, pollution])].
[sujeto(['It']), verbo([has]), complemento([been, proposed, that, this, enzyme, may, have, a, protective, effect, against, cancer, caused, by, quinones, and, their, metabolic, precursors])].
[sujeto(['The', corresponding, human, 'NMOR1', mRNA]), verbo([has]), complemento([an, unusually, long, 3, '\'', -, untranslated, region, '(', 1679, base, 'pairs)', with, four, potential, polyadenylation, signals, '(', 'I-IV)', at, positions, 986, ',', 1460, ',', 1838, ',', and, 2419, and, a, single, copy, of, human, 'Alu', repetitive, sequence, between, polyadenylation, sites, 'II', and, 'III'])].
[sujeto(['Southern', blot, analysis, of, human, genomic, 'DNA']), verbo([suggests]), complemento([the, presence, of, a, single, 'NMOR1', gene, approximately, 10, kilobases, '(', 'KB)', in, length])].
[sujeto(['Interestingly,', the, longest, '(', 2.7, 'kb)', mRNA, species, was]), verbo([induced]), complemento([severalfold, by, 'TCDD,', whereas, the, other, two, mRNAs, '(', 1.7, and, 1.2, 'kb)', were, induced, to, a, much, lesser, extent, by, 'TCDD', treatment])].
[sujeto(['Recently', two]), verbo([reports]), complemento(['[', 'J'])].
[sujeto([262, ',', 572, -, 575, ']']), verbo([have]), complemento([appeared, concerning, the, nucleotide, sequence, of, quinone, reductase, cDNA, clones])].
[sujeto(['In', order, to, clarify, the, sequence, of, this, 'region,', we]), verbo([have]), complemento([isolated, quinone, reductase, clones, from, a, rat, genomic, library, using, a, cDNA, 'clone,', 'pDTD55,', isolated, and, characterized, by, our, laboratory])].
[sujeto(['We']), verbo([have]), complemento([determined, the, sequence, of, exons, 1, and, 2, of, the, structural, gene, by, 'double-stranded', sequencing, using, oligonucleotide, primers])].
[sujeto(['These', data, agree, with, the, published, sequence, of, lambda, 'NMOR1']), verbo([reported]), complemento([by, 'Robertson', et, al])].
[sujeto(['On', 'Western', '(', 'immuno)', blot, 'analysis,', large]), verbo([increases]), complemento([in, this, hepatic, menadione, reductase, protein, '(', 'NMOR1)', of, 3, -, 'methylcholanthrene-treated', 'C57BL/6N', but, not, 'DBA/2N', mice, confirmed, that, induction, of, this, enzyme, by, 3, -, 'methyl-cholanthrene', is, regulated, by, the, 'Ah', receptor])].
[sujeto(['Positive', cDNA, clones, were, plaque, purified, and, further, characterized, by, showing]), verbo([enhanced]), complemento([hybridization, to, 3, -, 'methylcholanthrene-induced', 'poly(A+)', 'RNA', from, 'rats;', the, longest, cDNA, clone, '(', 1, ',', 501, base, 'pairs)', has, an, open, reading, frame, '(', bases, 75, -, 899, ')', and, a, nucleotide, sequence, consistent, with, a, new, gene, family])].
[sujeto(['Recent', genome, screening, studies]), verbo([have]), complemento([identified, novel, regions, of, possible, interest, for, susceptibility, to, type, 1, diabetes])].
[sujeto(['Data']), verbo([has]), complemento([suggested, association, of, a, polymorphism, '(', 'P187S)', in, the, 'NQO1', gene, and, type, 1, diabetes])].
[sujeto(['NQO1', is]), verbo([involved]), complemento([in, protection, against, oxidative, 'stress,', which, is, likely, to, be, involved, in, 'beta-cell', destruction])].
[sujeto(['By', use, of, the, transmission, disequilibrium, test, '(', 'TDT),', we, analyzed, the, 'P187S', polymorphism, for, association, to, type, 1, diabetes, in, a, 'population-based', sample, of, 247, 'Danish']), verbo([nuclear]), complemento([type, 1, diabetic, families])].
[sujeto(['Hence,', the, 'NQO1', polymorphism, is, not, likely, to, be, an, etiological, mutation, underlying, the]), verbo([reported]), complemento([linkage, of, the, 16, 'q22-q24', region])].
[sujeto(['Atherosclerosis,', the, underlying]), verbo([cause]), complemento([of, ischemic, heart, disease, and, 'stroke,', is, an, inflammatory, disease, of, arteries, in, a, hyperlipidemic, milieu])].
[sujeto(['The', dietary, 'flavonoid,', 'quercetin,']), verbo([has]), complemento([been, reported, to, inhibit, expression, of, cellular, adhesion, 'molecules,', but, the, underlying, mechanisms, are, incompletely, understood])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, quercetin, 'dose-dependently', '(', 5, -, 20, 'µM)', inhibits, lipopolysaccharide, '(', 'LPS)-induced', mRNA, and, protein, expression, of, 'E-selectin', and, 'ICAM-1', in, human, aortic, endothelial, cells, '(', 'HAEC)'])].
[sujeto(['Incubation', of, 'HAEC', with, quercetin, also, significantly, reduced, 'LPS-induced', oxidant, 'production,', but, did, not]), verbo([inhibit]), complemento([activation, of, the, nuclear, 'factor-kappaB', '(', 'NF-κB)'])].
[sujeto(['Furthermore,', quercetin]), verbo([induced]), complemento([activation, of, the, nuclear, factor, erythroid, 2, -, related, factor, 2, '(', 'Nrf2)', and, subsequent, mRNA, and, protein, expression, of, the, antioxidant, 'enzymes,', heme, 'oxygenase-1', '(', 'HO-1),', 'NAD(P)H', 'dehydrogenase,', quinone, 1, ',', and, 'glutamate-cysteine', ligase])].
[sujeto(['The', induction, of, 'Nrf2', and, antioxidant, enzymes, was, partly]), verbo([inhibited]), complemento([by, the, p38, 'mitogen-activated', protein, kinase, '(', 'p38)', 'inhibitor,', 'SB203580'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, quercetin, suppresses, 'LPS-induced', oxidant, production, and, adhesion, molecule, expression, by, inducing, 'Nrf2', activation, and, antioxidant, enzyme, 'expression,', which, is, partially, mediated, by, 'p38;', and, the, inhibitory, effect, of, quercetin, on, adhesion, molecule, expression, is, not, due, to, inhibition, of, 'NF-κB', 'activation,', but, instead, due, to, 'antioxidant-independent', effects, of, 'HO-1'])].
[sujeto(['Nuclear', factor, 'E2-related', factor, 2, '(', 'Nrf2)', is, considered, a, promising]), verbo([target]), complemento([against, diabetic, complications, such, as, cardiovascular, diseases, and, diabetic, nephropathy])].
[sujeto(['Our', results, showed, that, 'SAA', significantly]), verbo([increased]), complemento([the, macrovascular, relaxation, response, to, acetylcholine, '(', 'ACh)', and, sodium, nitroprusside, '(', 'SNP)', in, diabetic, mice])].
[sujeto(['Interestingly,', treatment, with, 'SAA', alone, only]), verbo([provided]), complemento([a, minor, protection, against, renal, 'injury,', as, reflected, by, minor, improvements, in, impaired, renal, function, and, 'structure,', despite, significantly, reduced, oxidative, stress, observed, in, the, diabetic, kidney])].
[sujeto(['We', demonstrated, that]), verbo([decreased]), complemento([oxidative, stress, and, 'NF-κB', p65, expression, was, associated, with, 'SAA-induced', expression, of, 'Nrf2', responsive, antioxidant, enzymes, heme, 'oxygenase-1', '(', 'HO-1),', 'NAD(P)H', dehydrogenase, '(', 'quinone)', 1, '(', 'NQO-1),', and, glutathione, 'peroxidase-1', '(', 'GPx-1)', in, vivo, or, in, 'vitro,', which, suggested, that, 'SAA', was, a, potential, 'Nrf2', modulator])].
[sujeto(['More', 'significantly,', we]), verbo([found]), complemento(['that,', compared, to, treatment, with, either, 'SAA', or, 'MET', 'alone,', their, combination, provided, further, protection, against, the, macrovascular, and, renal, 'injury,', which, was, at, least, partly, due, to, therapeutic, activation, of, both, 'MET-mediated', 'AMP-activated', protein, kinase, '(', 'AMPK)', and, 'SAA-mediated', 'Nrf2/', antioxidant, response, elements, '(', 'ARE)', pathways])].
[sujeto(['These', findings]), verbo([suggested]), complemento([that, polyphenol, 'Nrf2', 'modulators,', especially, combined, with, drugs, activating, 'AMPK', including, hypoglycemic, 'drugs,', are, worthy, of, further, investigation, to, combat, diabetic, complications])].
[sujeto(['Environmental', arsenic, '(', 'As)-containing', pesticide, use, correlates, with]), verbo([increased]), complemento([incidence, of, 'PD'])].
[sujeto(['Moreover,', because, 'As', exposure, can]), verbo([lead]), complemento([to, inhibition, of, autophagic, flux, we, hypothesize, that, 'As', can, facilitate, the, accumulation, of, toxic, 'SYN', 'oligomers/aggregates', and, subsequent, increases, in, markers, of, autophagy])].
[sujeto(['Chronic', exposure, of, 'SH-SY5Y', cells, overexpressing, 'SYN', to, 'As']), verbo([caused]), complemento([a, 'dose-dependent', oligomerization, of, 'SYN,', with, concomitant, increases, in, protein, ubiquitination, and, expression, of, other, stress, markers, '(', protein, glutathione, 'binding,', 'γ-GCS,', light, chain, 3, '(', 'LC3)-I/II,', 'P62,', and, 'NAD(P)H', dehydrogenase, quinone, 1, ')', ',', indicative, of, an, increased, proteotoxic, stress])].
[sujeto(['Because', 'SYN', can]), verbo([inhibit]), complemento(['TH', 'function,', and, 'As', can, decrease, monoamine, 'levels,', 'As', exposure, possibly, leads, to, compensatory, mechanisms, leading, to, an, increase, in, 'TH', expression])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, susceptible, individuals, may, be, at, higher, risk, of, developing, synucleinopathies, 'and/or', neurodegeneration, due, to, environmental, 'As', exposure])].
[sujeto(['Light', chain, amyloidosis, '(', 'AL)', is]), verbo([associated]), complemento([with, high, 'mortality,', especially, in, patients, with, advanced, cardiovascular, involvement])].
[sujeto(['It', is]), verbo([caused]), complemento([by, toxicity, of, misfolded, light, chain, proteins, '(', 'LC)', in, 'vascular,', 'cardiac,', and, other, tissues])].
[sujeto(['LC']), verbo([decreased]), complemento([endothelial, cell, nitric, oxide, production, and, cell, viability, while, increasing, superoxide, and, 'peroxynitrite;', these, adverse, effects, were, reversed, by, 'NLGM1'])].
[sujeto(['NLGM1']), verbo([increased]), complemento([endothelial, cell, protein, expression, of, antioxidant, enzymes, heme, oxygenase, 1, and, 'NAD(P)H', quinone, dehydrogenase, 1, and, increased, nuclear, 'factor,', erythroid, 2, like, 2, '(', 'Nrf-2)', protein])].
[sujeto(['NLGM1', protects, against, 'LC-induced', human, microvascular, endothelial, dysfunction, through]), verbo([increased]), complemento([nitric, oxide, bioavailability, and, reduced, oxidative, and, nitrative, stress, mediated, by, 'Nrf-2-dependent', antioxidant, stress, response])].
[sujeto(['Obesity']), verbo([has]), complemento([become, a, common, public, health, problem, in, the, world, and, raises, the, risk, of, various, cardiovascular, diseases])].
[sujeto(['The', present, study, investigated, the, effects, of, high, fat, diet, '(', 'HFD)']), verbo([induced]), complemento([obesity, on, the, aorta, in, 'mice,', and, evaluated, whether, it, can, be, affected, by, zinc, deficiency, or, supplementation])].
[sujeto(['Results', showed, that, 'HFD', feeding]), verbo([induced]), complemento([a, 'time-dependent', aortic, 'remodeling,', demonstrated, by, increased, vessel, wall, 'thickness,', tunica, cell, proliferation, and, fibrotic, 'responses,', and, inflammatory, 'response,', reflected, by, increased, expression, of, inflammatory, cytokines, '(', tumor, necrosis, 'factor-α', and, vascular, cell, adhesion, molecule, 1, ')'])].
[sujeto(['HFD', feeding, also]), verbo([caused]), complemento([aortic, oxidative, 'damage,', reflected, by, 3, -, nitrotyrosine, and, 4, -, 'hydroxy-2-nonenal', 'accumulation,', and, 'down-regulated', nuclear, factor, '(', 'erythroid-derived', 2, ')', -, like, 2, '(', 'Nrf2)', expression, and, 'function,', shown, by, 'down-regulation', of, its, downstream, 'antioxidants,', 'catalase,', 'NAD(P)H', dehydrogenase, '(', quinone, 1, ')', ',', and, metallothionein, expression])].
[sujeto(['In', 'addition,', 'down-regulation', of, 'Nrf2', function, and]), verbo([associated]), complemento([antioxidants, expression, were, also, worsened, by, zinc, deficiency, but, improved, by, zinc, supplementation])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'HFD', induces, aortic, 'remodeling,', which, can, be, exacerbated, by, zinc, deficiency, and, improved, by, zinc, supplementation])].
[sujeto(['Breast', cancer, cells]), verbo([responded]), complemento([to, 'tamoxifen-induced', oxidation, by, increasing, 'Nrf2', expression, and, subsequent, activation, of, the, 'anti-oxidant', response, element, '(', 'ARE)'])].
[sujeto(['This']), verbo([increased]), complemento([the, transcription, of, 'anti-oxidant', genes, and, multidrug, resistance, transporters])].
[sujeto(['As', a, 'result,', breast, cancer, cells, are, able, to, destroy, or, export, toxic, oxidation, products]), verbo([leading]), complemento([to, increased, survival, from, 'tamoxifen-induced', oxidative, damage])].
[sujeto(['Therefore,', overcoming, 'tamoxifen-induced', activation, of, the, 'ARE', could]), verbo([increase]), complemento([the, efficacy, of, tamoxifen, in, treating, breast, cancer])].
[sujeto(['Aristolochic', acid, 'I', '(', 'AAI)', is, a, natural, plant, alkaloid]), verbo([causing]), complemento([aristolochic, acid, 'nephropathy,', 'Balkan', endemic, nephropathy, and, their, associated, urothelial, malignancies])].
[sujeto(['One', of, the, most, efficient, enzymes, reductively]), verbo([activating]), complemento(['AAI', to, species, forming, 'AAI-DNA', adducts, is, cytosolic, quinone, oxidoreductase, 1])].
[sujeto(['AAI', is, also, either, reductively]), verbo([activated]), complemento([or, oxidatively, detoxified, to, 8, -, hydroxyaristolochic, acid, '(', 'AAIa)', by, microsomal, cytochrome, 'P450', '(', 'CYP)', 1, 'A1', and, 1, 'A2'])].
[sujeto(['The', induction, of, 'CYP1A1/2', by, 'Sudan', 'I']), verbo([increased]), complemento(['AAI', detoxification, to, its, 'O-demethylated', metabolite, 'AAIa,', thereby, reducing, the, actual, amount, of, 'AAI', available, for, reductive, activation])].
[sujeto(['Our', results, demonstrate, that, 'CYP1A1/2-mediated', oxidative, detoxification, of, 'AAI', is, the, predominant, role, of, these, enzymes, in, rats, in, 'vivo,', thereby]), verbo([suppressing]), complemento([levels, of, 'AAI-DNA', adducts])].
[sujeto(['TQ', and, 'NSE']), verbo([regulated]), complemento(['NAD(P)H/NAD(P)(+)', ratios, via, a, 'quinone-dependent', redox, cycling, mechanism])].
[sujeto(['TQ', content, was, positively, correlated, with, the, degree, of, redox, cycling, activity, of, 'NSE', 'extracts,']), verbo([suggesting]), complemento([that, 'TQ', is, a, major, component, engaged, in, mediating, 'NSE-dependent', redox, cycling])].
[sujeto(['Both', acute, and, chronic, exposure, to, 'TQ', and, 'NSE']), verbo([enhanced]), complemento(['GSIS', and, were, associated, with, the, ability, of, 'TQ', and, 'NSE', to, increase, the, 'ATP/ADP', ratio])].
[sujeto(['This', protective, action, was]), verbo([associated]), complemento([with, the, 'TQ-dependent', normalization, of, chronic, accumulation, of, 'malonyl-CoA,', elevation, of, 'acetyl-CoA', carboxylase, '(', 'ACC),', fatty, acid, 'synthase,', and, fatty, 'acid-binding', proteins, following, chronic, glucose, overload])].
[sujeto(['Together,', these, data]), verbo([suggest]), complemento([that, 'TQ', modulates, the, 'β-cell', redox, circuitry, and, enhances, the, sensitivity, of, 'β-cell', metabolic, pathways, to, glucose, and, 'GSIS', under, normal, conditions, as, well, as, under, hyperglycemia])].
[sujeto(['This', action, is]), verbo([associated]), complemento([with, the, ability, of, 'TQ', to, regulate, 'carbohydrate-to-lipid', flux, via, downregulation, of, 'ACC', and, 'malonyl-CoA'])].
[sujeto(['We']), verbo([found]), complemento([that, salidroside, pretreatment, upregulated, 'Nrf2', translocation, to, the, nucleus, and, transcription, activity, in, 'HaCaT', 'cells,', as, reflected, by, the, increased, nuclear, accumulation, of, 'Nrf2', as, well, as, the, gene, and, protein, expression, of, downstream, 'Nrf2', 'antioxidants,', including, 'NQO1', and, 'HO-1'])].
[sujeto(['In', 'addition,', we, also]), verbo([found]), complemento([that, pretreatment, with, salidroside, reactive, oxygen, species, '(', 'ROS)', in, irradiated, 'HaCaT', cells])].
[sujeto(['The', oral, administration, of, salidroside, '(', 0.1, '%', 'w/w)', to, guinea, pigs]), verbo([inhibited]), complemento([the, 'UVB-mediated', formation, of, apoptotic, 'SBCs', and, 8, -, 'OHdG-positive', epidermal, cells, in, the, skin, of, guinea, pigs])].
[sujeto(['Our', results, show, that, 'UVB-induced', oxidative, damage, can, be]), verbo([prevented]), complemento([by, salidroside, with, upregulation, of, nuclear, 'Nrf2', expression])].
[sujeto([2, ',', 3, ',', 4, '\'', ',', 5, -, 'Tetrahydroxystilbene-2-O-β-d-glucoside', '(', 'THSG)', affects, 'neuroinflammation-related', neurodegenerative, diseases, and]), verbo([inhibits]), complemento([neuroinflammatory, mediators])].
[sujeto(['Furthermore,', it, was, observed, that, activation, of, 'IκBα', and, 'NF-κB', was, significantly]), verbo([increased]), complemento([upon, 'LPS', 'stimulation,', and, suppressed, by, 'THSG', treatment, in, a, 'dose-dependent', manner])].
[sujeto(['The', expression, of, 'HO-1', and, 'NQO1,', as, well, as, 'Nrf2', 'activation,', was]), verbo([induced]), complemento([by, 'THSG', in, microglia])].
[sujeto(['The', promoter, activity, of, 'ARE', and, 'HO-1', also]), verbo([increased]), complemento([in, a, 'dose-dependent', manner, following, 'THSG', treatment])].
[sujeto(['Nrf2/HO-1/NQO1']), verbo([has]), complemento(['anti-inflammatory', 'properties;', the, 'knock-down', of, 'Nrf2/HO-1/NQO1', by, specific, siRNA, prevented, the, 'THSG-mediated', inhibition, of, iNOS, and, 'COX-2', promoter, activity])].
[sujeto(['The', blockade, of, 'AMPK', by, a, pharmacological, inhibitor]), verbo([prevented]), complemento(['THSG-induced', 'HO-1', and, 'NQO1', expression])].
[sujeto(['In', 'conclusion,', we, demonstrated, that, 'THSG', attenuates, the, 'LPS-induced', neuroinflammatory, response]), verbo([mediated]), complemento([by, 'AMPK/Nrf2', signaling, pathways])].
[sujeto(['In', 'contrast,', quinones, can]), verbo([induce]), complemento([cytoprotection, through, induction, of, detoxification, 'enzymes,', 'anti-inflammatory', 'activities,', and, modification, of, redox, status])].
[sujeto(['The', mechanisms, by, which, quinones]), verbo([cause]), complemento([these, effects, can, be, quite, complex])].
[sujeto(['The', various, biological]), verbo([targets]), complemento([of, quinones, depend, on, their, rate, and, site, of, formation, and, their, reactivity])].
[sujeto(['Quinones', are, formed, through, a, variety, of, mechanisms, from, simple, oxidation, of, 'catechols/hydroquinones', catalyzed, by, a, variety, of, oxidative, enzymes, and, metal, ions, to, more, complex, mechanisms]), verbo([involving]), complemento([initial, 'P450-catalyzed', hydroxylation, reactions, followed, by, 'two-electron', oxidation])].
[sujeto(['Alternatively,', quinones, are, highly, redox, active, molecules, which, can, redox, cycle, with, their, semiquinone, radical, anions]), verbo([leading]), complemento([to, formation, of, reactive, oxygen, species, '(', 'ROS)', including, 'superoxide,', hydrogen, 'peroxide,', and, ultimately, the, hydroxyl, radical])].
[sujeto(['This', perspective, explores, the, varied, biological]), verbo([targets]), complemento([of, quinones, including, 'GSH,', 'NADPH,', protein, sulfhydryls, '[', heat, shock, 'proteins,', 'P450,', 'cyclooxygenase-2', '(', 'COX-2),', glutathione, 'S-transferase', '(', 'GST),', 'NAD(P)H:quinone', oxidoreductase, 1, ',', '(', 'NQO1),', 'kelch-like', 'ECH-associated', protein, 1, '(', 'Keap1),', 'IB', kinase, '(', 'IKK),', arylhydrocarbon, receptor, '(', 'AhR)],', and, 'DNA'])].
[sujeto(['The', evidence, strongly]), verbo([suggests]), complemento([that, the, numerous, mechanisms, of, quinone, modulations, '(', i])].
[sujeto(['Oxidative', stress, is, closely]), verbo([associated]), complemento([with, various, diseases, and, is, considered, to, be, a, major, factor, in, ischemia])].
[sujeto(['Tat-NQO1', protein, transduced, into, 'HT-22', cells, and, significantly]), verbo([inhibited]), complemento([against, hydrogen, peroxide, '(', 'H2O2)-induced', cell, death, and, cellular, toxicities])].
[sujeto(['Tat-NQO1', protein]), verbo([inhibited]), complemento(['Akt', and, mitogen, activated, protein, kinases, '(', 'MAPK)', activation, as, well, as, 'caspase-3', expression, levels, in, 'H2O2', exposed, 'HT-22', cells])].
[sujeto(['Our', results, indicate, that, 'Tat-NQO1', protein, exerts, protection, against, neuronal, cell, death]), verbo([induced]), complemento([by, oxidative, 'stress,', suggesting, that, 'Tat-NQO1', protein, may, potentially, provide, a, therapeutic, agent, for, neuronal, diseases])].
[sujeto(['Human']), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'hiPSCs)', are, considered, as, a, powerful, tool, for, drug, and, chemical, screening, and, development, of, new, in, vitro, testing, strategies, in, the, field, of, 'toxicology,', including, neurotoxicity, evaluation])].
[sujeto(['These', human, 'cells-based', neuronal, models, serve, as, test, systems, for, mechanistic, studies, on, different, pathways]), verbo([involved]), complemento([in, neurotoxicity])].
[sujeto(['One', of, the, 'well-known', mechanisms, that, are]), verbo([activated]), complemento([by, 'chemically-induced', oxidative, stress, is, the, 'Nrf2', signalling, pathway])].
[sujeto(['Therefore,', in, the, current, 'study,', we, evaluated, whether, 'Nrf2', signalling, machinery, is]), verbo([expressed]), complemento([in, human, induced, pluripotent, stem, cells, '(', 'hiPSCs)-derived', mixed, 'neuronal/glial', culture, and, if, so, whether, it, becomes, activated, by, 'rotenone-induced', oxidative, stress, mediated, by, complex, 'I', inhibition, of, mitochondrial, respiration])].
[sujeto(['Rotenone', was]), verbo([found]), complemento([to, induce, the, activation, of, 'Nrf2', signaling, particularly, at, the, highest, tested, concentration, '(', 100, &, 'nbsp;nM),', as, shown, by, 'Nrf2', nuclear, translocation, and, the, 'up-regulation', of, the, 'Nrf2-downstream', antioxidant, 'enzymes,', 'NQO1', and, 'SRXN1'])].
[sujeto(['Interestingly,', exposure, to, rotenone, also]), verbo([increased]), complemento([the, number, of, astroglial, cells, in, which, 'Nrf2', activation, may, play, an, important, role, in, neuroprotection])].
[sujeto(['Moreover,', rotenone]), verbo([caused]), complemento([cell, death, of, dopaminergic, neurons, since, a, decreased, percentage, of, tyrosine, hydroxylase, '(', 'TH(+))', cells, was, observed])].
[sujeto(['The', obtained, results]), verbo([suggest]), complemento([that, 'hiPSC-derived', mixed, 'neuronal/glial', culture, could, be, a, valuable, in, vitro, human, model, for, the, establishment, of, neuronal, specific, assays, in, order, to, link, 'Nrf2', pathway, activation, '(', biomarker, of, oxidative, 'stress)', with, additional, neuronal, specific, readouts, that, could, be, applied, to, in, vitro, neurotoxicity, evaluation])].
[sujeto(['Nicotinamide', phosphoribosyltransferase, '(', 'NAMPT)', catalyzes, the, first, 'rate-limiting', step, in, converting, nicotinamide, to, 'NAD(+),', essential, for, a, number, of, enzymes, and, regulatory, proteins]), verbo([involved]), complemento([in, a, variety, of, cellular, 'processes,', including, deacetylation, enzyme, 'SIRT1', which, modulates, several, tumor, suppressors, such, as, p53, and, 'FOXO'])].
[sujeto(['Herein', we]), verbo([report]), complemento([that, 'NQO1', substrates, 'Tanshione', 'IIA', '(', 'TSA)', and, 'β-lapachone', '(', 'β-lap)', induced, a, rapid, depletion, of, 'NAD(+)', pool, but, adaptively, a, significant, upregulation, of, 'NAMPT'])].
[sujeto(['NAMPT', inhibition, by, 'FK866', at, a, nontoxic, dose, significantly]), verbo([enhanced]), complemento(['NQO1-targeting', 'agent-induced', apoptotic, cell, death])].
[sujeto(['Compared', with, 'TSA', or, 'β-lap', treatment, 'alone,', 'co-treatment', with, 'FK866']), verbo([induced]), complemento([a, more, dramatic, depletion, of, 'NAD(+),', repression, of, 'SIRT1', 'activity,', and, thereby, the, increased, accumulation, of, acetylated, 'FOXO1', and, the, activation, of, apoptotic, pathway])].
[sujeto(['In', 'conclusion,', the, results, from, the, present, study, support, that, 'NAMPT', inhibition, can, synergize, with, 'NQO1', activation, to]), verbo([induce]), complemento([apoptotic, cell, 'death,', thereby, providing, a, new, rationale, for, the, development, of, combinative, therapeutic, drugs, in, combating, 'non-small', lung, cancer])].
[sujeto(['Small', interfering, 'RNA', and, shuttle, plasmids, were, used, to]), verbo([modulate]), complemento([the, expression, of, 'NRF2,', 'wild-type', 'KEAP1,', and, mutant, 'KEAP1'])].
[sujeto(['We']), verbo([found]), complemento([that, 'platinum-based', therapies, modified, the, 'NRF2', signaling, pathway, differently, in, 'KEAP1-mutated', 'non-small', cell, lung, cancer, '(', 'NSCLC)', cell, lines, compared, with, 'wild-type', 'KEAP1', cell, lines])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, 'NRF2', signaling, plays, an, indispensable, role, in, 'NSCLC', cell, sensitivity, to, 'platinum-based', treatments, and, provides, a, rationale, for, using, 'NRF2', as, a, specific, biomarker, for, predicting, which, patients, will, be, most, likely, to, benefit, from, 'platinum-based', treatment])].
[sujeto(['Resveratrol', can, modify, cardiac, stem, cells, to]), verbo([enhance]), complemento([their, survival, and, 'differentiation,', 'however,', its, effect, and, the, mechanism, underlying, its, neuroprotective, effect, on, 'NSCs', following, stroke, remain, to, be, fully, elucidated])].
[sujeto(['Nuclear', factor, erythroid, 2, &, #, 8209, ;, related, factor, 2, '(', 'Nrf&#8209;2)', signaling, is, important, in, antioxidative, 'stress,', and, the, role, of, 'Nrf&#8209;2', signaling, in, the]), verbo([enhanced]), complemento([neuroprotection, of, 'NSCs', by, resveratrol, following, stroke, also, remains, to, be, elucidated])].
[sujeto(['It', was]), verbo([found]), complemento([that, resveratrol, markedly, enhanced, 'NSC', survival, and, 'proliferation,', decreased, apoptosis, and, the, levels, of, 'MDA,', and, increased, the, activity, of, 'SOD', and, content, of, 'GSH', in, a, 'concentration&#8209;dependent', manner, following, 'OGD/R', injury, 'in&nbsp;vitro'])].
[sujeto(['These', findings]), verbo([suggested]), complemento([that, resveratrol, attenuated, injury, and, promoted, proliferation, of, the, 'NSCs,', at, least, in, 'part,', by, upregulating, the, expression, of, 'Nrf2,', 'HO&#8209;1', and, 'NQO1', following, 'OGD/R', injury, 'in&nbsp;vitro'])].
[sujeto(['Tryptophan', metabolism, is, essential, in, diverse, kinds, of, tumors, via]), verbo([regulating]), complemento([tumor, immunology])].
[sujeto(['Here,', we, establish, a, mechanistic, link, from, 'L-type', amino, acid, transporter, 1, '(', 'LAT1)']), verbo([mediated]), complemento([transport, of, tryptophan, and, the, subsequent, 'de-novo', 'NAD+', synthesis, to, 'SIRT1-FOXO1', regulated, apoptotic, signaling, in, 'A549', cells, in, response, to, 'NQO1', activation])].
[sujeto(['In', response, to, 'NQO1', 'activation,', 'SIRT1', is]), verbo([repressed]), complemento([leading, to, the, increased, cellular, accumulation, of, acetylated, 'FOXO1', that, transcriptionally, activates, apoptotic, signaling])].
[sujeto(['Decreased', uptake, of, tryptophan, due, to, the, downregulation, of, 'LAT1', coordinates, with, 'PARP-1', hyperactivation, to]), verbo([induce]), complemento([rapid, depletion, of, 'NAD+', pool])].
[sujeto(['Particularly,', the, 'LAT1-NAD+-SIRT1', signaling, is]), verbo([activated]), complemento([in, tumor, tissues, of, patients, with, 'non-small', cell, lung, cancer])].
[sujeto(['Because', 'NQO1', activation, is, characterized, with, oxidative, challenge]), verbo([induced]), complemento(['DNA', 'damage,', these, results, suggest, that, 'LAT1', and, 'de-novo', 'NAD+', synthesis, in, 'NSCLC', cells, may, play, essential, roles, in, sensing, excessive, oxidative, stress])].
[sujeto(['In', 'contrast,', 'NADPH', cytochrome, 'P450', oxidoreductase, '(', 'CYP450OR),', catalyzes, the, 1, -, electron, reduction, of, quinones, and, 'xenobiotics,', resulting, in]), verbo([enhanced]), complemento([superoxide, formation])].
[sujeto(['However,', to, 'date,', the, roles, of, 'NQO1', and, 'CYP450OR', in, pancreatic, 'β-cell', metabolism, under, basal, conditions, and, oxidant, challenge]), verbo([have]), complemento([not, been, characterized])].
[sujeto(['Using', 'NQO1', 'inhibition,', 'over-expression', and, knock, 'out,', we]), verbo([have]), complemento([demonstrated, 'that,', in, addition, to, protection, of, 'β-cells', from, toxic, concentrations, of, the, redox, cycling, quinone, 'menadione,', 'NQO1', also, regulates, the, basal, level, of, 'reduced-to-oxidized', 'nucleotides,', suggesting, other, 'role(s)', beside, that, of, an, antioxidant, enzyme])].
[sujeto(['In', 'contrast,', 'over-expression', of, 'NADPH', cytochrome, 'P450', oxidoreductase, '(', 'CYP450OR)', resulted, in]), verbo([enhanced]), complemento([redox, cycling, activity, and, decreased, cellular, 'viability,', consistent, with, the, enhanced, generation, of, superoxide, and, 'H2O2'])].
[sujeto(['However,', 'NQO1,', but, not, 'CYP450OR,', was, strongly]), verbo([induced]), complemento([in, 'β-cells', exposed, to, menadione])].
[sujeto(['Together,', these, results, demonstrate, that, 'NQO1', and, 'CYP450OR', reciprocally]), verbo([regulate]), complemento([oxidant, metabolism, in, pancreatic, 'β-cells'])].
[sujeto(['Sulforaphane,', a, naturally, occurring, compound]), verbo([found]), complemento([in, cruciferous, 'vegetables,', has, been, shown, to, be, neuroprotective, in, several, neurological, disorders])].
[sujeto(['In', this, 'study,', we, sought, to, investigate, the, potential, protective, effects, and]), verbo([associated]), complemento([molecular, mechanisms, of, sulforaphane, in, an, in, vivo, 'Parkinson\'s', disease, '(', 'PD)', 'model,', based, on, 'rotenone-mediated', neurotoxicity])].
[sujeto(['Our', results, showed, that, sulforaphane]), verbo([inhibited]), complemento(['rotenone-induced', locomotor, activity, deficiency, and, dopaminergic, neuronal, loss])].
[sujeto(['Additionally,', sulforaphane, treatment]), verbo([inhibited]), complemento([the, 'rotenone-induced', reactive, oxygen, species, 'production,', malondialdehyde, '(', 'MDA)', 'accumulation,', and, resulted, in, an, increased, level, of, total, glutathione, and, reduced, glutathione, '(', 'GSH):', oxidized, glutathione, '(', 'GSSG)', in, the, brain])].
[sujeto(['Western', blot, analysis, illustrated, that, sulforaphane]), verbo([increased]), complemento([the, expression, of, nuclear, factor, '(', 'erythroid-derived', 2, ')', -, like, 2, '(', 'Nrf2),', heme, 'oxygenase-1', '(', 'HO-1),', and, 'NAD(P)H', quinone, oxidoreductase, '(', 'NQO1),', the, latter, two, of, which, are, 'anti-oxidative', enzymes])].
[sujeto(['Collectively,', these, findings, demonstrated, that, sulforaphane, exert, neuroprotective, effect]), verbo([involving]), complemento(['Nrf2-dependent', reductions, in, oxidative, 'stress,', 'mTOR-dependent', inhibition, of, neuronal, 'apoptosis,', and, the, restoration, of, normal, autophagy])].
[sujeto(['Sulforaphane', appears, to, be, a, promising, compound, with, neuroprotective, properties, that, may, play, an, important, role, in]), verbo([preventing]), complemento(['PD'])].
[sujeto(['Polygonum', multiflorum, extracts, are, known, to, improve, memory, and, learning, 'ability,', and]), verbo([have]), complemento([neuroprotective, and, 'anti-aging', activity])].
[sujeto(['multiflorum,', and]), verbo([found]), complemento([a, novel, 'compound,', 'CRPE55IB'])].
[sujeto(['CRPE55IB', also, reduced, the, production, of, 'pro-inflammatory', cytokines, '(', 'TNF-α', and, 'IL-6)']), verbo([induced]), complemento([by, 'LPS'])].
[sujeto(['Furthermore,', investigation, of, the, molecular, mechanism, indicated, that, 'CRPE55IB']), verbo([inhibited]), complemento(['LPS-induced', 'NF-κB', activation, by, inactivating, phosphorylation, of, 'IKKα/β,', and, phosphorylation, and, degradation, of, 'IκBα'])].
[sujeto(['We', further]), verbo([found]), complemento([that, 'CRPE55IB', inhibited, the, phosphorylation, of, 'ERK', and, 'JNK', at, a, lower, concentration, than, that, for, p38, 'MAPK'])].
[sujeto(['Further', experiments, revealed, that, 'CRPE55IB', treatment, considerably]), verbo([increased]), complemento([the, activation, of, 'Nrf2/ARE,', and, the, expression, of, its, target, 'genes,', including, 'HO-1', and, 'NQO1'])].
[sujeto(['CRPE55IB', also]), verbo([induced]), complemento([phosphorylation, of, 'AMPK/LKB/CaMKII', in, microglia])].
[sujeto(['Analysis', using, a, specific, inhibitor, of, 'AMPK', demonstrated, that, 'AMPK', activation, was]), verbo([involved]), complemento([in, 'CRPE55IB-induced', 'HO-1', and, 'NQO1', expression])].
[sujeto(['The', 'Kelch-like', 'ECH-associated', protein, 1, '(', 'Keap1)/nuclear', factor, erythroid, 2, -, related, factor, 2, '(', 'Nrf2)/antioxidant', response, elements, pathway, enables, cells, to, survive, oxidative, stress, conditions, through]), verbo([regulating]), complemento([the, expression, of, cytoprotective, enzymes, such, as, quinone, oxidoreductase, 1, '(', 'NQO1)'])].
[sujeto(['Molecular', docking, of, the, new, compounds, was, performed, to, assess, their, ability, to]), verbo([inhibit]), complemento(['Keap1-Nrf2', 'protein-protein', interaction, through, occupying, the, 'Keap1-Nrf2-binding', 'domain,', which, leads, to, 'Nrf2', accumulation, and, enhanced, gene, expression, of, 'NQO1'])].
[sujeto(['Docking', results, showed, that, all, compounds, can, potentially]), verbo([interact]), complemento([with, 'Keap1;', 'however,', 1, ',', 5, -, 'dimethyl-2-phenyl-4-(2-phenylquinazolin-4-ylamino)-1,2-dihydropyrazol-3-one', '(', 9, ')', ',', the, most, potent, 'inducer,', showed, the, largest, number, of, interactions, with, key, amino, acids, in, the, binding, pocket, '(', 'Arg483,', 'Tyr525,', and, 'Phe478)', compared, to, the, native, ligand, or, any, other, compound, in, this, series])].
[sujeto(['These', compounds, and, some, previously, described, analogs, were, evaluated, as, antioxidant, agents, with, three, chemical, model, 'systems,', and, cancer, chemopreventive, potential, was, examined, by, inhibition, of, 'NO', 'production,', 'TNF-α']), verbo([activated]), complemento(['NFκB', 'activity,', and, aromatase, 'activity,', as, well, as, induction, of, 'QR1', and, 'RXRE', binding])].
[sujeto(['Two', of, the, test, 'compounds,', 9, and, 12, ',', displayed, promising, activity, by]), verbo([inhibiting]), complemento(['iNOS,', 'NFκB', and, aromatase, in, 'dose-dependent', 'manner,', with, 'IC50', values, in, low, micromolar, range])].
[sujeto(['The', same, compounds]), verbo([activated]), complemento(['QR1', in, a, bifunctional, manner])].
[sujeto(['When', incubated, with, human, liver, 'microsomes,', the, active, compounds, were, further, hydroxylated, on, the, parent, ring, 'system,']), verbo([suggesting]), complemento([the, next, logical, step, in, the, development, of, these, promising, leads, will, entail, synthetic, production, of, metabolites, followed, by, additional, assessment, of, biological, activity])].
[sujeto(['It', exhibits, its, cancer, protective, activity, mainly, by]), verbo([inhibiting]), complemento([the, formation, of, intracellular, semiquinone, 'radicals,', and, by, generating, 'α-tocopherolhydroquinone,', which, acts, as, a, free, radical, scavenger])].
[sujeto(['It', is, therefore, believed, that, 'QR1', inducers, can]), verbo([act]), complemento([as, cancer, chemopreventive, agents])].
[sujeto(['Resveratrol', '(', 1, ')', is, a, naturally, occurring, stilbene, derivative, that]), verbo([requires]), complemento([a, concentration, of, 21, μM, to, double, 'QR1', activity, '(', 'CD', =, 21, 'μM)'])].
[sujeto(['The', stilbene, double, bond, of, resveratrol, was, replaced, with, a, thiadiazole, ring, and, the, phenols, were, eliminated, to]), verbo([provide]), complemento([a, more, potent, and, selective, derivative, 2, '(', 'CD', =, 2.1, 'μM)'])].
[sujeto(['Optimizing', the, substitution, pattern, of, the, two, phenyl, rings, and, the, central, heterocyclic, linker]), verbo([led]), complemento([to, a, highly, potent, and, selective, 'QR1', inducer, 9, o, with, a, 'CD', value, of, 0.087, μM])].
[sujeto(['Chemoprevention', is, an, approach, to]), verbo([decrease]), complemento([cancer, morbidity, and, mortality, through, inhibition, of, carcinogenesis, and, prevention, of, disease, progression])].
[sujeto(['Although', the, trans, stilbene, derivative, resveratrol]), verbo([has]), complemento([chemopreventive, 'properties,', its, action, is, compromised, by, weak, 'non-specific', effects, on, many, biological, targets])].
[sujeto(['Replacement', of, the, stilbene, ethylenic, bridge, of, resveratrol, with, a, 1, ',', 2, ',', 4, -, thiadiazole, heterocycle, and, modification, of, the, substituents, on, the, two, aromatic, rings, afforded, potential, chemopreventive, agents, with]), verbo([enhanced]), complemento([potencies, and, selectivities, when, evaluated, as, inhibitors, of, aromatase, and, 'NF-κB', and, inducers, of, quinone, reductase, 1, '(', 'QR1)'])].
[sujeto(['Callophycin', 'A', was, originally, isolated, from, the, red, algae, 'Callophycus', oppositifolius, and, shown, to]), verbo([mediate]), complemento([anticancer, and, cytotoxic, effects])].
[sujeto(['In', our, collaborative, effort, to, identify, potential, chemopreventive, and, anticancer, agents, with]), verbo([enhanced]), complemento([potency, and, 'selectivity,', we, employed, a, 'tetrahydro-β-carboline-based', template, inspired, by, callophycin, 'A', for, production, of, a, chemical, library])].
[sujeto(['Quinone', reductase, 2, '(', 'QR2)', is, one, of, two, members, comprising, the, mammalian, quinone, reductase, family, of, enzymes, responsible, for, performing, 'FAD']), verbo([mediated]), complemento([reductions, of, quinone, substrates])].
[sujeto(['Several', studies]), verbo([have]), complemento([linked, 'QR2', to, the, generation, of, quinone, free, 'radicals,', several, neuronal, degenerative, 'diseases,', and, cancer])].
[sujeto(['QR2']), verbo([has]), complemento([been, also, identified, as, the, third, melatonin, receptor, '(', 'MT3)', through, in, cellulo, and, in, vitro, inhibition, of, 'QR2', by, traditional, 'MT3', 'ligands,', and, through, recent, 'X-ray', structures, of, human, 'QR2', '(', 'hQR2)', in, complex, with, melatonin, and, 2, -, iodomelatonin])].
[sujeto(['Several', 'MT3', specific, ligands]), verbo([have]), complemento([been, developed, that, exhibit, both, potent, in, cellulo, inhibition, of, hQR2, 'nanomolar,', affinity, for, 'MT3'])].
[sujeto(['The', potency, of, these, ligands]), verbo([suggest]), complemento([their, use, as, molecular, probes, for, hQR2])].
[sujeto(['Furthermore,', 'X-ray', structures, for, each, of, these, ligands, in, complex, with, hQR2, were, determined, allowing, for, a, structural, evaluation, of, the]), verbo([binding]), complemento([modes, of, these, ligands, in, relation, to, the, potency, of, 'MT3', ligands])].
[sujeto(['In', the, search, for, agents, with, cancer, chemopreventive, 'potential,', 14, -, 'chloromethyl-12H-5,11a-diazadibenzo[b,h]fluoren-11-one', '(', compound, 1, ')', ',', originally, synthesized, as, a, potential, topoisomerase, 'I', 'inhibitor,', and, 2, ',', 4, -, 'dibromo-1-hydroxyphenazine', '(', compound, 2, ')', ',', an, analog, of, a, substance]), verbo([found]), complemento([in, the, marine, bacteria, 'Streptomyces', 'CNS284,', were, found, to, significantly, enhance, 'NADP(H):quinone', oxidoreductase, 1, '(', 'QR1),', glutathione, 'S-transferase', '(', 'GST),', and, glutathione, '(', 'GSH)', levels, in, cell, culture])].
[sujeto(['However,', following, a, 'short-term', absorption, 'study,', analyses, of, livers, from, the, treatment, groups, did, not]), verbo([reveal]), complemento([a, significant, increase, in, 'QR1', or, 'GST', 'activity,', or, 'GSH', levels])].
[sujeto(['The', compounds, were, 'absorbed,', as, judged, by, 'LC/MS', analyses, of, serum, and, tissue, 'samples,', although, levels, were, well, below, the, concentrations]), verbo([required]), complemento([to, mediate, in, vitro, responses])].
[sujeto(['Five', resveratrol, sulfate, metabolites, were, synthesized, and, assessed, for, activities, known, to, be]), verbo([mediated]), complemento([by, 'resveratrol:', inhibition, of, tumor, necrosis, factor, '(', 'TNF)', alpha, induced, 'NFkappaB', 'activity,', cylcooxygenases, '(', 'COX-1', and, 'COX-2),', 'aromatase,', nitric, oxide, production, in, 'endotoxin-stimulated', 'macrophages,', proliferation, of, 'KB', or, 'MCF7', 'cells,', induction, of, quinone, reductase, 1, '(', 'QR1),', accumulation, in, the, 'sub-G(1)', phase, of, the, cell, 'cycle,', and, quenching, of, 2, ',', 2, -, 'diphenyl-1-picrylhydrazyl', '(', 'DPPH)', free, radical])].
[sujeto(['Two', metabolites, showed, activity, in, these, 'assays;', the, 3, -, sulfate, exhibited, 'QR1', 'induction,', 'DPPH', free, radical, 'scavenging,', and, 'COX-1', and, 'COX-2', inhibitory, activities, and, the, 4, '\'', -, sulfate]), verbo([inhibited]), complemento(['NFkappaB', 'induction,', as, well, as, 'COX-1', and, 'COX-2', activities])].
[sujeto(['Resveratrol', and, its, 3, '\'', -, sulfate, and, 4, -, sulfate]), verbo([inhibit]), complemento(['NO', production, by, 'NO', scavenging, and, 'down-regulation', of, iNOS, expression, in, 'RAW', 264.7, cells])].
[sujeto(['The', same, pattern, was, also, observed, with, quinone, reductase, '(', 'QR)', 'activity:', fijiolide, 'A', was]), verbo([found]), complemento([to, induce, quinone, 'reductase-1', '(', 'QR1)', with, an, induction, ratio, of, 3.5, at, a, concentration, of, 20, 'microg/mL', '(', 28.4, 'microM)'])].
[sujeto(['The', concentration]), verbo([required]), complemento([to, double, the, activity, was, 1.8, microM])].
[sujeto(['On', the, basis, of, these, 'data,', fijiolide, 'A', is, viewed, as, a, promising]), verbo([lead]), complemento([for, more, advanced, anticancer, testing])].
[sujeto(['Despite', a, relatively, close, 'sequence-based', resemblance, to, 'NAD(P)H:quinone', oxidoreductase, 1, '(', 'QR1),', it]), verbo([has]), complemento([many, different, features])].
[sujeto(['QR2', is, the, third, melatonin]), verbo([binding]), complemento([site, '(', 'MT3)'])].
[sujeto(['It', is]), verbo([inhibited]), complemento([in, the, micromolar, range, by, 'melatonin,', and, does, not, accept, conventional, phosphorylated, nicotinamides, as, hydride, donors])].
[sujeto(['QR2']), verbo([has]), complemento([a, powerful, capacity, to, activate, quinones, leading, to, unexpected, toxicity, situations])].
[sujeto(['In', the, present, 'paper,', we]), verbo([report]), complemento([the, characterization, of, three, 'QR2', 'modulators:', 'melatonin,', resveratrol, and, 'S29434'])].
[sujeto(['The', latter, compound]), verbo([inhibits]), complemento(['QR2', activity, with, an, 'IC(50)', in, the, low, nanomolar, range])].
[sujeto(['These', molecular, tools, might, permit, to, explore, and, better, understand, the, relationship, existing, between, 'QR2', catalytic, activity, and, the, various, pathological, situations, in, which, 'QR2']), verbo([has]), complemento([a, key, role])].
[sujeto(['Quinone', reductases, type, 1, '(', 'QR1)', are, 'FAD-containing', enzymes, that, catalyze, the, reduction, of, many, 'quinones,', including, menadione, '(', 'Vit', 'K3),', to, hydroquinones, using, reducing, equivalents]), verbo([provided]), complemento([by, 'NAD(P)H'])].
[sujeto(['The', reaction, proceeds, with, a, 'ping-pong', mechanism, in, which, the, 'NAD(P)H', and, the, substrate, occupy, alternatively, overlapping, regions, of, the, same]), verbo([binding]), complemento([site, and, participate, in, a, double, hydride, 'transfer:', one, from, 'NAD(P)H', to, the, 'FAD', of, the, 'enzyme,', and, one, from, the, 'FADH(2)', of, the, enzyme, to, the, quinone, substrate])].
[sujeto(['In', 'addition,', the, same, reaction, that, 'QR1', uses, in, the, detoxification, of, 'quinones,']), verbo([activates]), complemento([some, compounds, making, them, cytotoxic])].
[sujeto(['Since', 'QR1', is, elevated, in, many, 'tumors,', this, property]), verbo([has]), complemento([encouraged, the, development, of, chemotherapeutic, compounds, that, become, cytotoxic, after, reduction, by, 'QR1'])].
[sujeto(['The', structures, of, 'QR1', 'alone,', and, in, complexes, with, 'substrates,', 'inhibitors,', and, chemotherapeutic, 'prodrugs,', combined, with, biochemical, and, mechanistic, studies]), verbo([have]), complemento([provided, invaluable, insight, into, the, mechanism, of, the, enzyme, as, well, as, suggestions, for, the, improvements, of, the, chemotherapeutic, prodrugs])].
[sujeto(['Parkinson\'s', disease, '(', 'PD)', is, a, progressive, neurodegenerative, disorder, with, a, selective]), verbo([loss]), complemento([of, dopaminergic, neurons, in, the, substantia, nigra])].
[sujeto(['Evidence']), verbo([suggests]), complemento([oxidation, of, dopamine, '(', 'DA)', to, 'DA', quinone, and, consequent, oxidative, stress, as, a, major, factor, contributing, to, this, vulnerability])].
[sujeto(['We']), verbo([have]), complemento([previously, observed, that, exposure, to, or, induction, of, 'NAD(P)H:quinone', reductase, '(', 'QR1),', the, enzyme, that, catalyzes, the, reduction, of, 'quinone,', effectively, protects, 'DA', cells])].
[sujeto(['In', the, present, 'study,', we, show, that, 'SF', protects, against, compounds, known, to]), verbo([induce]), complemento(['DA', quinone, production, '(', 6, -, hydroxydopamine, and, 'tetrahydrobiopterin)', in, 'DAergic', cell, lines, 'CATH'])].
[sujeto(['SF']), verbo([leads]), complemento([to, attenuation, of, the, increase, in, 'protein-bound', quinone, in, 'tetrahydrobiopterin-treated', 'cells,', but, this, does, not, occur, in, cells, that, have, been, depleted, of, 'DA,', suggesting, involvement, of, 'DA', quinone])].
[sujeto(['SF', pretreatment]), verbo([prevents]), complemento([membrane, 'damage,', 'DNA', 'fragmentation,', and, accumulation, of, reactive, oxygen, species])].
[sujeto(['SF']), verbo([causes]), complemento([increases, in, mRNA, levels, and, enzymatic, activity, of, 'QR1', in, a, 'dose-dependent', manner])].
[sujeto(['Taken', 'together,', these, results, indicate, that, 'SF']), verbo([causes]), complemento([induction, of, 'QR1', gene, 'expression,', removal, of, intracellular, 'DA', 'quinone,', and, protection, against, toxicity, in, 'DAergic', cells])].
[sujeto(['Thus,', this, major, isothiocyanate]), verbo([found]), complemento([in, cruciferous, vegetables, may, serve, as, a, potential, candidate, for, development, of, treatment, 'and/or', prevention, of, 'PD'])].
[sujeto(['Kinetic', 'experiments,', 'docking,', and]), verbo([binding]), complemento([affinity, calculations, were, performed, on, a, series, of, structurally, varied, quinone, substrates])].
[sujeto(['A', good, correlation, between, calculated, and, measured]), verbo([binding]), complemento([affinities, from, kinetic, determinations, was, obtained])].
[sujeto(['The', experimental, and, theoretical, studies, independently, support, a, model, in, which, quinones, '(', with, one, to, three, fused, aromatic, 'rings)']), verbo([bind]), complemento([in, the, 'QR1', active, site, utilizing, a, 'pi-stacking', interaction, with, the, isoalloxazine, ring, of, the, 'FAD', cofactor])].
[sujeto(['Remarkably,', the, same, enzyme]), verbo([activates]), complemento([cancer, prodrugs, that, become, cytotoxic, only, after, 'two-electron', reduction])].
[sujeto(['QR1\'s', ability, to, bioactivate, quinones, and, its, elevated, expression, in, many, human, solid, tumors, makes, this, protein, an, excellent]), verbo([target]), complemento([for, 'enzyme-directed', drug, development])].
[sujeto(['Until', 'now,', structural, analysis, of, the, mode, of]), verbo([binding]), complemento([of, chemotherapeutic, compounds, to, 'QR1', was, based, on, model, building, using, the, structures, of, complexes, with, simple, 'substrates;', no, structure, of, complexes, of, 'QR1', with, chemotherapeutic, prodrugs, had, been, reported])].
[sujeto(['Here', we]), verbo([report]), complemento([the, 'high-resolution', crystal, structures, of, complexes, of, 'QR1', with, three, chemotherapeutic, 'prodrugs:', 'RH1,', a, 'water-soluble', homolog, of, 'dimethylaziridinylbenzoquinone;', 'EO9,', an, 'aziridinylindolequinone;', and, 'ARH019,', another, aziridinylindolequinone])].
[sujeto(['The', structures, show, that, compounds, can]), verbo([bind]), complemento([to, 'QR1', in, more, than, one, orientation])].
[sujeto(['Surprisingly,', the, two, aziridinylindolequinones]), verbo([bind]), complemento([to, the, enzyme, in, different, orientations])].
[sujeto(['The', results, presented, here]), verbo([reveal]), complemento([two, new, factors, that, must, be, taken, into, account, in, the, design, of, prodrugs, targeted, for, activation, by, 'QR1:', the, enzyme, binding, site, is, highly, plastic, and, changes, to, accommodate, binding, of, different, 'substrates,', and, homologous, drugs, with, different, substituents, may, bind, to, 'QR1', in, different, orientations])].
[sujeto(['These', structural, insights]), verbo([provide]), complemento([important, clues, for, the, optimization, of, chemotherapeutic, compounds, that, utilize, this, reductive, bioactivation, pathway])].
[sujeto(['QR1', is]), verbo([expressed]), complemento([in, the, cytoplasm, of, many, 'tissues,', and, is, highly, inducible])].
[sujeto(['A', closely, related, 'homologue,', quinone, reductase, type, 2, '(', 'QR2),']), verbo([has]), complemento([been, identified, in, several, mammalian, species])].
[sujeto(['X-ray', crystallographic, studies, of, 'QR1', and, 'QR2', illustrate, that, despite, their, different, biochemical, 'properties,', these, enzymes]), verbo([have]), complemento([very, similar, 'three-dimensional', structures])].
[sujeto(['In', 'particular,']), verbo([conserved]), complemento([features, of, the, active, sites, point, to, the, close, relationship, between, these, two, enzymes])].
[sujeto(['Measurement', of, 'QR1', activity, in, murine, hepatoma, cells, grown, in, 96, -, well, microtiter, plates]), verbo([has]), complemento([provided, a, rapid, and, quantitative, method, for, detecting, inducer, activity, and, determining, inducer, potency])].
[sujeto(['In', this, paper, we]), verbo([report]), complemento([the, apoenzyme, structures, of, human, '(', at, 1.7, -, 'A', 'resolution)', and, mouse, '(', 2.8, 'A)', 'QR1', and, the, complex, of, the, human, enzyme, with, the, substrate, duroquinone, '(', 2.5, 'A)', '(', 2, ',', 3, ',', 5, ',', 6, -, 'tetramethyl-p-benzoquinone)'])].
[sujeto(['In', addition, to]), verbo([providing]), complemento([a, description, and, rationale, of, the, structural, and, catalytic, differences, among, several, 'species,', these, structures, reveal, the, changes, that, accompany, substrate, or, cofactor, '(', 'NAD)', binding, and, release])].
[sujeto(['Tyrosine-128', and, the, loop, spanning, residues, 232, -, 236, close, the]), verbo([binding]), complemento(['site,', partially, occupying, the, space, left, vacant, by, the, departing, molecule, '(', substrate, or, 'cofactor)'])].
[sujeto(['These', changes, highlight, the, exquisite, control, of, access, to, the, catalytic, site, that, is]), verbo([required]), complemento([by, the, 'ping-pong', mechanism, in, 'which,', after, reducing, the, 'flavin,', 'NAD(P)(+)', leaves, the, catalytic, site, and, allows, substrate, to, bind, at, the, vacated, position])].
[sujeto(['In', the, human, 'QR1-duroquinone', structure, one, ring, carbon, is, significantly, closer, to, the, flavin, 'N5,']), verbo([suggesting]), complemento([a, direct, hydride, transfer, to, this, atom])].
[sujeto(['In', 'mammals,', two, separate, but, homologous, cytosolic, quinone, reductases]), verbo([have]), complemento([been, 'identified:', 'NAD(P)H:quinone', oxidoreductase, type, 1, '(', 'QR1)', '(', 'EC', 1.6])].
[sujeto(['We']), verbo([report]), complemento([here, two, crystal, structures, of, 'QR2:', in, its, native, form, and, bound, to, menadione, '(', vitamin, 'K(3)),', a, physiological, substrate])].
[sujeto(['The', 'FAD']), verbo([binding]), complemento([sites, of, 'QR1', and, 'QR2', are, very, 'similar,', but, their, hydride, donor, binding, sites, are, considerably, different])].
[sujeto(['Unexpectedly,', we]), verbo([found]), complemento([that, 'QR2', contains, a, specific, metal, binding, 'site,', which, is, not, present, in, 'QR1'])].
[sujeto(['Two', histidine, 'nitrogens,', one, cysteine, 'thiol,', and, a, main, chain, carbonyl, group, are]), verbo([involved]), complemento([in, metal, coordination])].
[sujeto(['The', metal]), verbo([binding]), complemento([site, is, 'solvent-accessible,', and, is, separated, from, the, 'FAD', cofactor, by, a, distance, of, about, 13, 'A'])].
[sujeto(['Recombinant', human, 'QR2:', '(', 'i)', reacts, with, 'N-ribosyl-', and, 'N-alkyldihydronicotinamides,', but, not, with, 'NADH,', 'NADPH,', or, 'NMNH;', '(', 'ii)', is, very, weakly]), verbo([inhibited]), complemento([by, dicumarol, or, 'Cibacron', 'blue;', '(', 'iii)', is, very, potently, inhibited, by, 'benzo[a]pyrene'])].
[sujeto(['The', 'x-ray', crystal, structure, of, rat, 'QR1', shows, that, the, 43, amino, acid, 'C-terminal', tail, of, 'QR1']), verbo([provides]), complemento([the, binding, site, for, the, hydrophilic, portions, of, 'NADH', and, 'NADPH'])].
[sujeto(['In', the, absence, of, this]), verbo([binding]), complemento([site, in, 'QR2,', the, enzyme, retains, the, essential, catalytic, 'machinery,', including, affinity, for, 'FAD,', but, cannot, bind, phosphorylated, hydride, donors])].
[sujeto(['One-electron', reduction, of, quinones, or, their, derivatives, by, enzymes, such, as, cytochrome, 'P450', reductase, or, other, flavoproteins, generates, unstable, 'semiquinones,', which, undergo, redox, cycling, in, the, presence, of, molecular, oxygen]), verbo([leading]), complemento([to, the, formation, of, highly, reactive, oxygen, species])].
[sujeto(['This', characteristic]), verbo([confers]), complemento([a, detoxifying, enzyme, role, to, 'QR1', and, 'QR2,', even, if, this, character, is, strongly, linked, to, the, excretion, capacity, of, the, cell])].
[sujeto(['Indeed,', whereas, the, amount, of, 'ROS', produced, in, the, cell, was, strongly]), verbo([decreased]), complemento([with, 'para-quinones', such, as, menadione, in, the, presence, of, quinone, reductase, 1, or, 2, ',', a, strong, increase, in, 'ROS', was, recorded, with, 'ortho-quinones', such, as, 'adrenochrome,', 'aminochrome,', 'dopachrome,', or, 3, ',', 5, -, 'di-tert-butyl-o-benzoquinone', in, cells, overexpressing, 'QR,', especially, 'QR2'])].
[sujeto(['The', reactions, for, the, detection, of, glucose, proceed, as, 'follows:', glucose, dehydrogenase, oxidizes, glucose, to, gluconolactone, with, 'NAD(+)', as, the, electron, acceptor, to, yield, 'NADH,', and, 'NADH', can, be, utilized, by, 'DTD', to, further, react, with, the, probe]), verbo([releasing]), complemento([resorufin])].
[sujeto(['The', method, showed, high, selectivity, for, glucose, with, a, detection, limit, of, 0.2, 'µM,', which, may]), verbo([provide]), complemento([a, potential, way, for, fluorescence, detection, of, glucose, through, 'enzyme-coupling', reactions])].
[sujeto(['Furthermore,', the, applicability, of, the, method]), verbo([has]), complemento([been, demonstrated, by, detecting, glucose, in, human, urine, samples])].
[sujeto([max, were]), verbo([provided]), complemento([to, animals, in, feed])].
[sujeto(['The', test, diet, also, elevated, the, content, of, reduced, glutathione, whereas, it]), verbo([decreased]), complemento([the, level, of, the, peroxidative, damage, along, with, the, specific, activity, of, lactate, dehydrogenase])].
[sujeto([max, seeds]), verbo([provided]), complemento([chemoprevention, against, skin, and, cervical, papillomagenesis, probably, by, modulating, the, detoxifying, and, antioxidative, enzymes])].
[sujeto(['This', trial, describes, a, 'first-in-man', evaluation, of, 'RH1,', a, novel, bioreductive, drug]), verbo([activated]), complemento([by, 'DT-diaphorase', '(', 'DTD),', an, enzyme, overexpressed, in, many, tumours])].
[sujeto(['Plasma', pharmacokinetic, analysis, showed, 'RH1', is, rapidly, cleared, from, blood, '(', 't(1/2)', =, 12.3, 'min),', with, 'AUC']), verbo([increasing]), complemento([proportionately, with, dose])].
[sujeto(['The', 'comet-X', assay, demonstrated, 'dose-related']), verbo([increases]), complemento([in, 'DNA', cross, linking, in, 'PBMCs'])].
[sujeto(['The', biomarkers, of, 'DNA', cross, 'linking,', 'DTD', activity, and, 'NQO1', status]), verbo([have]), complemento([been, validated, and, clinically, developed])].
[sujeto(['The', novel, cytotoxic, 'RH1', '(', 2, ',', 5, -, 'diaziridinyl-3-[hydroxymethyl]-6-methyl-1,4-benzoquinone)', is]), verbo([activated]), complemento([by, the, obligate, 'two-electron', reductase, 'DT-diaphorase', '(', 'DTD,', widely, expressed, in, adult, tumour, 'cells)', to, a, potent, 'DNA', interstrand, 'cross-linker'])].
[sujeto(['However,', synergy, between, 'RH1', and, cisplatin, or, doxorubicin, was, only, seen, in, low, 'DTD']), verbo([expressing]), complemento([cell, lines])].
[sujeto(['In', 'A673', 'Ewing\'s', sarcoma, and, 791, 'T', osteosarcoma, tumour, xenografts, in, mice, 'RH1']), verbo([induced]), complemento([apoptosis, 24, h, after, a, single, bolus, injection, '(', 0.4, 'mg/kg)', and, daily, dosing, for, 5, days, delayed, tumour, growth, relative, to, control])].
[sujeto(['The', demonstration, of, 'RH1', efficacy, against, paediatric, tumour, cell, 'lines,', which, was, performed, concurrently, with, the, adult, 'Phase', 1, 'Trial,']), verbo([suggests]), complemento([that, this, agent, may, have, clinical, usefulness, in, childhood, cancer])].
[sujeto(['The', fluorogenic, chemical, transformation, of, 'BQC']), verbo([triggered]), complemento([by, 'DTD', in, the, presence, of, 'NADH', is, through, a, series, of, tandem, 'reactions,', 'DTD-catalyzed', benzoquinone, 'reduction,', 'trimethyl-locks', cyclization, and, intramolecular, urea, 'formation,', which, are, spontaneous, and, irreversible, at, physiological, temperature, in, aqueous, media])].
[sujeto(['The', fluorescence, signal, revealed, by, this, process, is, specific, and, exhibited, in, the, near, red, spectrum, region, with, emission, maxima, at, 595, 'nm,', and, it, could, be, competitively]), verbo([inhibited]), complemento([by, menadione])].
[sujeto(['Drugs', can]), verbo([modulate]), complemento([the, expression, of, drug, metabolizing, enzymes, and, are, useful, in, chemoprevention, as, well, as, therapy, in, cancer])].
[sujeto([4, -, 'Nitroquinoline', 1, -, oxide, '(', 4, -, 'NQO)', is, used, to]), verbo([induce]), complemento([oral, cancer, in, the, present, study])].
[sujeto(['In']), verbo([induced]), complemento(['rats,', there, was, a, decrease, in, the, activity, of, 'Phase', 'II', enzymes, and, an, increase, in, the, activity, of, 'Phase', 'I', enzymes])].
[sujeto(['On', supplementation, of, 'GTP', by, both, simultaneous, and, post, treatment, mode, '(', 200, 'mg/kg)', there, was, a, significant]), verbo([increase]), complemento([in, the, activity, of, 'GST', and, 'UDP-GT', and, a, significant, decrease, in, the, activity, of, 'Phase', 'I', enzymes])].
[sujeto(['There', was, a, significant, decline, in, the, number, of, 'tumors,', tumor, volume, and, oral, squamous, cell, carcinoma, in, both, simultaneous, and, post, 'GTP', treated, animals, relative, to, 4, -, 'NQO']), verbo([induced]), complemento(['animals;', on, comparing, simultaneous, and, post, 'GTP', treated, animals, the, number, of, 'tumors,', tumor, volume, and, oral, squamous, cell, carcinoma, was, significantly, reduced, in, post, treated, animals])].
[sujeto(['Thus', inhibition, of, 'Phase', 'I', enzymes, could, be, attributed, to, the, protective, efficacy, of, 'GTP', which, deactivates, carcinogen, and, 'GTP']), verbo([induced]), complemento([the, expression, of, 'Phase', 'II', enzymes, that, detoxifies, the, 4, -, 'NQO'])].
[sujeto(['It', can, be, proposed, that, 'GTP', plays, role, as, a, detoxifying, agent, by, which, its]), verbo([modulating]), complemento([role, 'prevented/inhibited', the, formation, of, tumor])].
[sujeto(['According', to, our, previous, 'data,', hematoporphyrin, dimethyl, ether, '(', 'HPde)', at, concentrations, useful, for, photodynamic, therapy, can, radiosensitize, aggressive, 'Ehrlich', ascite, carcinoma, '(', 'EAT)', to, 2, 'Gy', irradiation]), verbo([inducing]), complemento([total, tumour, growth, inhibition])].
[sujeto(['Our', results]), verbo([reveal]), complemento([that, 'HPde', is, inducing, several, rearrangements, in, the, 'EAT', 'cells:', 1.2, x, 10, -, 6, 'M', of, the, photosensitizer, diminishes, the, number, of, cells, in, mitosis, by, a, factor, of, 3, ',', increases, the, number, of, cells, in, the, 'S', phase, of, the, cell, 'cycle,', modifies, the, activities, of, antioxidant, enzymes, glutation, 'S-transferase', '(', 'GST)', and, 'DT-diaphorase', '(', 'DTD),', and, eventually, induces, slight, apoptosis])].
[sujeto(['Named', &, 'quot;house', 'keeper,&quot;', 'PBR', is, usually, responsible, for, all, these, 'perturbations,', 'which,', in, our, 'case,']), verbo([act]), complemento([in, concert, with, the, following, ionizing, 'radiation,', producing, the, interaction, of, two, 'antiproliferative/destructive', factors])].
[sujeto(['The', specific, activities, of, catalase, '(', 'CAT),', 'DT-diaphorase', '(', 'DTD)', and, 'glutathione-S-transferase', '(', 'GST)', were]), verbo([found]), complemento(['decreased,', and, the, level, of, reduced, glutathione, '(', 'GSH)', and, the, specific, activity, of, lactate, dehydrogenase, '(', 'LDH)', increased, in, the, 'tumour-bearing', 'fore-stomach;', 'however,', no, change, was, observed, in, superoxide, dismutase, '(', 'SOD)', activity])].
[sujeto(['In', 'addition,', the, contents, of, cyt, 'P450', and, cyt, 'b5,', and, the, activity, of, 'NADPH', cyt, 'P450', reductase, were, significantly]), verbo([decreased]), complemento([in, the, liver])].
[sujeto(['The', results]), verbo([suggest]), complemento([increased, oxidative, stress, in, the, 'tumour,', and, disturbance, in, the, cooperative, antioxidant, functions, in, the, distant, normal, organs])].
[sujeto(['Since,', the, antioxidant, potential, and, the, drug, metabolism, function, were, 'altered,', the, findings, may]), verbo([have]), complemento([relevance, to, the, radiation, and, chemotherapy, of, cancer])].
[sujeto(['Doxorubicin', '(', 'DOX),', a, standard, chemotherapeutic, anthracycline, 'agent,']), verbo([causes]), complemento([a, positive, inotropic, effect, in, 'guinea-pig', isolated, atria, in, a, 'concentration-dependent', manner, with, an, 'ED(50)', of, 3.6, 'micromol/L'])].
[sujeto(['This']), verbo([increase]), complemento([in, contractility, is, strictly, related, to, the, generation, of, reactive, oxygen, species, '(', 'ROS)', as, a, consequence, of, quinone, metabolism])].
[sujeto(['The', 'ED(50)', of, 'DOX', is, significantly]), verbo([increased]), complemento(['(', 'P', &, 'lt;', 0.05, ')', in, the, presence, of, 150, 'U', superoxide, dismutase, '(', 'SOD)'])].
[sujeto(['Whether', 'DOX', will, be]), verbo([activated]), complemento([or, detoxified, by, 'two-electron', reduction, is, important, for, the, understanding, of, the, mechanism, of, both, the, toxic, and, antitumour, actions, of, 'DOX'])].
[sujeto(['In', 'guinea-pig', isolated, left, 'atria,', 4, 'micromol/L', dicoumarol, significantly]), verbo([enhanced]), complemento([the, positive, inotropic, effect, of, 'DOX,', especially, at, lower, concentrations, of, 'DOX'])].
[sujeto([for, 4, 'days),', 'DTD', activity, was]), verbo([enhanced]), complemento(['(', approximately, twice, that, of, the, 'control;', 'P', &, 'lt;', 0.01, ')', ',', whereas, the, activity, of, glutathione, 'S-transferase', '(', 'GST)', was, not, significantly, altered])].
[sujeto(['In', these, 'preparations,', 'DOX']), verbo([caused]), complemento([a, significantly, lower, increase, in, force, of, contraction, than, in, atria, isolated, from, untreated, animals])].
[sujeto(['Pretreatment', with, 'DMF', significantly]), verbo([increased]), complemento([cytotoxicity, of, 'MMC', and, 'SN', in, glioblastoma, cell, lines, and, the, 'NCI-H1299', lung, cancer, cell, 'line,', but, had, no, effect, on, 'BCNU', cytotoxicity])].
[sujeto(['DMF', significantly]), verbo([increased]), complemento(['DTD', and, cytochrome, b5, reductase, 'activity,', and, decreased, 'GST', in, three, of, four, glioblastoma, cell, lines])].
[sujeto(['Addition', of, the, 'DTD', 'inhibitor,', 'dicumarol,', significantly]), verbo([inhibited]), complemento([cytotoxicity, of, 'MMC', and, 'SN,', and, reversed, the, increased, cytotoxicity, seen, when, 'DMF', was, combined, with, either, 'MMC', or, 'SN', in, all, glioblastoma, cell, lines])].
[sujeto(['The', differential, in, 'DTD', between, tumour, and, normal, tissue, should, allow]), verbo([targeted]), complemento([activation, of, chemotherapeutic, quinones, in, the, tumour, whilst, minimising, normal, tissue, toxicity])].
[sujeto(['Other', bioreductive, drugs]), verbo([have]), complemento([failed, because, of, poor, solubility, and, inability, to, surpass, other, agents, in, use])].
[sujeto(['It']), verbo([has]), complemento([been, demonstrated, to, have, 'anti-tumour', effects, both, in, vitro, and, in, vivo, and, demonstrates, a, relationship, between, 'DTD', expression, levels, and, drug, response])].
[sujeto(['RH1']), verbo([has]), complemento([recently, entered, a, phase, 'I', clinical, trial, in, solid, tumours, under, the, auspices, of, 'Cancer', 'Research', 'UK'])].
[sujeto(['Recent', work]), verbo([has]), complemento([demonstrated, that, 'DTD', is, present, in, the, nucleus, and, is, associated, with, both, p53, and, the, heat, shock, 'protein,', 'HSP-70'])].
[sujeto(['Furthermore,', 'DTD', is, inducible, by, several, 'non-toxic', compounds, and, therefore, much, interest]), verbo([has]), complemento([focussed, on, increasing, the, differential, in, 'DTD', levels, between, tumour, and, normal, tissues])].
[sujeto(['The', drug, was, originally, designed, as, a, substrate, for, the, enzyme, 'DT-diaphorase', '(', 'DTD)', such, that, metabolic, activation, of, the, drug, would]), verbo([lead]), complemento([to, toxicity])].
[sujeto(['To', evaluate, 'this,', we]), verbo([have]), complemento([measured, the, toxicity, of, 'RH1', in, a, pair, of, 'non-small', cell, lung, cancer, '(', 'NSCLC)', cell, lines, of, widely, differing, levels, of, 'DTD', and, in, 'MDA231', breast, cancer, cells, which, have, been, engineered, to, overexpress, 'DTD'])].
[sujeto(['In', 'addition,', we]), verbo([have]), complemento([explored, the, importance, of, the, putative, 'one-electron', 'reductase,', 'P450', 'reductase,', by, assessing, the, toxicity, of, 'RH1', in, 'MDA231', cells, engineered, to, overexpress, the, enzyme])].
[sujeto(['D7', versus, 'MDA231', wt, and, 'H460', versus, 'H596,', are, substantially, more, sensitive, to, 'RH1', than, the, cell, lines]), verbo([expressing]), complemento([low, 'DTD', activity])].
[sujeto([comparing, 'MDA231', wt, with, 'R4,']), verbo([has]), complemento(['little,', if, 'any,', impact, on, the, toxicity, of, 'RH1', under, hypoxic, or, aerobic, conditions])].
[sujeto(['In', 'summary,', 'RH1', can, be, effective, in, killing, cells, containing, high, levels, of, 'DTD', and, may, be, useful, in, treating, tumors]), verbo([expressing]), complemento([this, enzyme])].
[sujeto(['RH1', is, a, new, bioreductive, agent, that, was, developed, as, a, cytotoxic, agent, with, selectivity, for, tumour, cells]), verbo([expressing]), complemento([high, levels, of, the, enzyme, 'DT-diaphorase', '(', 'DTD)'])].
[sujeto(['To', determine, 'DNA', interstrand, crosslinks, or, 'single-strand', 'breaks,', linearized, or, supercoiled, plasmid, 'DNA,', 'respectively,', were, incubated, with, purified, human, 'DTD', and]), verbo([increasing]), complemento([concentrations, of, each, 'BM', analog])].
[sujeto(['After', reduction, by, 'DTD,', the, 'BM', analogs, produced, a, 'concentration-dependent']), verbo([increase]), complemento([in, 'DNA', crosslink, and, 'DNA', strand, break, formation])].
[sujeto(['Furthermore,', the, 'D(10)', values, '(', concentration, of, 'BM', analog, that]), verbo([decreased]), complemento([the, surviving, cell, fraction, to, 0.1, ')', for, cytotoxic, activity, of, the, 'BM', analogs, correlated, with, the, maximum, levels, of, 'DNA', crosslinks, formed, with, each, 'BM', 'analog,', with, 'r(s)', values, of, -, 0.85, '(', 'P&lt;0'])].
[sujeto(['Electron-donating', groups]), verbo([increased]), complemento(['DNA', 'damage,', whereas, 'electron-withdrawing', groups, and, sterically, bulky, groups, at, the, 'C6', position, had, no, effect, or, decreased, the, ability, of, the, compounds, to, produce, 'DNA', damage, compared, to, 'BM'])].
[sujeto(['Moreover,', both, 'DNA', crosslink, and, strand, break, formation, appear, to]), verbo([have]), complemento([an, important, impact, on, the, cytotoxicity, of, the, 'BM', analogs])].
[sujeto(['These', results, may]), verbo([have]), complemento([significance, for, optimal, use, of, 'BM-based', antitumor, agents, and, for, rationalization, of, the, development, of, novel, therapeutic, compounds, that, require, bioactivation, by, 'DTD'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'DTD', is, not, involved, in, the, initial, steps, of, the, bioreductive, metabolism, of, 'NLCQ-1,', although, it, could, be, involved, with, metabolites, of, 'NLCQ-1,', and, that, cytochrome, 'P450', and, cytochrome, b5, reductases, play, a, significant, role, in, the, bioreductive, metabolism, of, 'NLCQ-1'])].
[sujeto(['H460', and, 'HT29', are, rich, in, 'DT-diaphorase', '(', 'DTD),', and, 'H596', and, 'BE', cells]), verbo([have]), complemento([negligible, amounts, of, functional, 'DTD'])].
[sujeto(['Compound', 10, ',', which]), verbo([has]), complemento([a, propyl, linker, 'group,', was, subjected, to, in, vivo, studies])].
[sujeto(['The', observation, that, 'DT-diaphorase', is, highly]), verbo([expressed]), complemento([in, many, cancerous, tissues, compared, to, normal, tissues, has, provided, us, with, a, potentially, selective, target, that, can, be, exploited, in, the, design, of, novel, anticancer, agents])].
[sujeto(['We']), verbo([found]), complemento([a, specific, high, expression, of, 'DT-diaphorase', in, glomerular, visceral, epithelial, cells, '(', 'podocytes)'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, a, high, expression, of, 'DT-diaphorase', in, podocytes, could, play, a, major, role, in, the, pathogenesis, of, renal, toxicity, and, mitomycin, 'C-induced', hemolytic, uremic, 'syndrome,', in, which, injury, to, the, glomerular, filtration, mechanism, is, the, primary, 'damage,', leading, to, a, cascade, of, deleterious, events, including, microangiopathic, hemolytic, anemia, and, thrombocytopenia])].
[sujeto(['This', observation]), verbo([has]), complemento([potential, therapeutic, implications, because, the, 'DT-diaphorase', metabolic, pathway, is, influenced, by, many, 'agents,', including, 'drugs,', 'diet,', and, environmental, cell, factors, such, as, pH, and, oxygen, tension])].
[sujeto(['A', series, of, 2, -, and, 3, -, substituted, indolequinone, phosphoramidate, prodrugs]), verbo([targeted]), complemento([to, 'DT-diaphorase', '(', 'DTD)', have, been, synthesized, and, evaluated])].
[sujeto(['Chemical', reduction, of, the, phosphoramidate, prodrugs]), verbo([led]), complemento([to, rapid, expulsion, of, the, corresponding, phosphoramidate, anions, in, both, series, of, compounds])].
[sujeto(['Compounds', substituted, at, the, 2, -, position, are, excellent, substrates, for, human, 'DTD', '(', 'k(cat)/K(M)', =, '(', 2, -, 5, ')', x, 10, '(', 6, ')', 'M(-1)', 's(-1));', 'however,', compounds, substituted, at, the, 3, -, position, are, potent, inhibitors, of, the]), verbo([target]), complemento([enzyme])].
[sujeto(['There', was, a, correlation]), verbo([found]), complemento([between, cytotoxicity, and, 'DTD', activity, for, the, 2, -, series, of, 'phosphoramidates;', 'however,', there, was, no, correlation, between, cytotoxicity, and, 'DTD', activity, in, the, 3, -, series, of, compounds])].
[sujeto(['This']), verbo([finding]), complemento([suggests, the, presence, of, an, alternative, mechanism, for, the, activation, of, these, compounds])].
[sujeto(['As', there, is]), verbo([increasing]), complemento([evidence, that, 17, -, 'beta-estradiol', interferes, with, certain, pathways, of, xenobiotic, 'biotransformation,', we, additionally, tested, the, effects, of, different, concentrations, of, 17, -, 'beta-estradiol', '(', 0.2, -, 10, 'microM)', alone, and, 17, -, 'beta-estradiol', '(', 1, 'microM)', in, combination, with, 100, microM, 'B[a]p'])].
[sujeto(['The', observation, that, 'DTD', is, overexpressed, in, many, cancerous, tissues, compared, to, normal, tissues]), verbo([has]), complemento([provided, us, with, a, potentially, selective, target, that, can, be, exploited, in, the, design, of, novel, anticancer, agents])].
[sujeto(['We']), verbo([found]), complemento([strong, expression, of, this, enzyme, in, testicular, stromal, cells, '(', 'Leydig', 'cells)', and, in, the, epithelium, of, 'epididymis,', ductuli, 'efferentes,', and, 'Fallopian', tube])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'DTD-bioactivated', quinones, could, be, responsible, for, a, selective, toxicity, on, these, components, of, the, reproductive, system, and, cause, clinical, problems, due, to, testosterone, deficiency, and, infertility])].
[sujeto(['(', 'J', 'Histochem', 'Cytochem', 49, :, 1187, -, 1188, ',', 2001, ')', 'RH1', '(', 2, ',', 5, -, 'diaziridinyl-3-(hydroxylmethyl)-6-methyl-1,4-benzoquinone)']), verbo([has]), complemento([shown, preferential, activity, against, human, tumour, cell, lines, which, express, high, levels, of, 'DTD', '(', 'EC', 1.6])].
[sujeto(['The', two, 'DTD', substrates, 'RH1', and, 'EO9', are, clearly, metabolised, 'differently,']), verbo([suggesting]), complemento([that, 'RH1', may, have, different, pharmacological, properties, to, those, of, 'EO9', in, the, clinic])].
[sujeto(['A', network, composed, of, activation, and, inactivation, pathways, to]), verbo([regulate]), complemento([mitomycin, 'C', '(', 'MMC)', action, is, suggested, to, exist, in, human, cancer, cells])].
[sujeto(['Northern', analysis, revealed, that, expression, of, the, 'NADPH:cytochrome', 'P450', reductase, '(', 'P450', 'reductase)', gene, was]), verbo([decreased]), complemento([in, the, 'transfectant,', 'COLO201/NQO1,', associated, with, the, increase, of, 'NQO1', expression])].
[sujeto(['Biochemical', characterization, of, the, cells, showed, a, significant]), verbo([increase]), complemento([of, the, glutathione, '(', 'GSH)', content, concomitantly, with, the, decrease, of, the, 'P450', reductase, activity])].
[sujeto(['As', a, result, of, these, coordinated, 'modulations,', sensitivity, of, 'COLO201/NQO1', to, 'MMC', was, not]), verbo([increased]), complemento([as, compared, to, the, parent, cells])].
[sujeto(['In', 'contrast,', 'GST', appeared, to]), verbo([participate]), complemento([in, 'MMC', inactivation, in, cells, with, a, high, level, of, 'GST', activity])].
[sujeto(['These', results, indicated, that, 'DTD,', 'P450', 'reductase,', 'GSH', and, 'GST', may]), verbo([act]), complemento([together, compensatively, or, 'competitively,', depending, on, their, levels, in, 'cells,', to, determine, the, cellular, sensitivity, to, 'MMC'])].
[sujeto(['Anti-tumor', 'quinone,', including, mitomycin, 'C', '(', 'MMC),', needs, to, be]), verbo([activated]), complemento([by, bioreduction, to, exert, its, cytotoxic, activities])].
[sujeto(['The', enzymes, underlying, this, bioreductive, activation]), verbo([have]), complemento([been, the, subject, of, extensive, research, on, 'Mitomycin', 'C'])].
[sujeto(['Cytochrome', 'P450', 'reductase,', cytochrome, b5, 'reductase,', xanthine, 'oxidase,', xanthine, dehydrogenase, and, 'DT-diaphorase', '(', 'DTD)']), verbo([have]), complemento([been, shown, to, be, involved, in, the, reduction, of, 'MMC'])].
[sujeto(['The', relationship, between, bioreductive, enzymes, and, the, cytotoxicity, of, 'quinone,', 'however,']), verbo([has]), complemento([not, been, analyzed, yet])].
[sujeto(['II)', 'We']), verbo([have]), complemento([examined, the, bioreductive, enzyme, activities, of, 'DTD', and, cytochrome, 'P450', reductase, and, 'IC50\'s', of, 'MMC', in, 13, colon, and, gastric, carcinoma, cell, lines])].
[sujeto(['A', positive, correlation, was, not]), verbo([found]), complemento([between, the, enzyme, activities, and, 'MMC', 'sensitivities,', but, the, cells, with, little, or, no, 'DTD', activity, showed, higher, 'IC50', values, compared, to, the, other, cell, lines])].
[sujeto(['NQO1', gene, encodes, 'DTD', and, 'St-4', cells]), verbo([have]), complemento([no, 'DTD', activity])].
[sujeto(['In', 10, human, cancer, cell, 'lines,', the, activity, of, mitomycin, 'C', '(', 'MMC)', was]), verbo([found]), complemento([to, be, determined, by, an, interplay, between, activation, by, 'DT-diaphorase', '(', 'DTD)', and, inactivation, by, glutathione, 'S-transferase', '(', 'GST)'])].
[sujeto(['In', cell, lines, in, which, 'DTD', action, was, 'predominant,', tumor, selectivity, was, achieved, by]), verbo([enhancing]), complemento(['DTD-mediated', activation, with, 'm-iodobenzylguanidine', and, 'hyperglycemia,', which, reduced, the, 'intra-tumoral', pH])].
[sujeto(['KW2149,', a, novel, 'MMC', analogue]), verbo([activated]), complemento([by, 'glutathione,', was, most, active, against, tumors, in, which, 'GSTpi', predominated])].
[sujeto(['Such', 'MMC', treatment, based, on, cell, enzymology, may]), verbo([enhance]), complemento([significantly, 'MMC', 'efficacy,', helping, to, overcome, multidrug, resistance])].
[sujeto(['Mitomycin', 'C', '(', 'MMC),', a, known, cytotoxic, 'agent,']), verbo([requires]), complemento([cellular, 'enzyme-mediated', activation, for, effective, antitumor, activity])].
[sujeto(['We']), verbo([found]), complemento([that, cell, lines, with, nonexistent, or, marginal, 'DTD', 'activity,', such, as, 'St-4', and, 'MKN7,', showed, resistance, to, 'MMC,', in, comparison, to, cell, lines, with, 'DTD', activity, ranging, from, 210, to, 1420, 'nmol/min/mg', protein])].
[sujeto(['No', correlation, was]), verbo([found]), complemento([between, 'NADPH:cytochrome', 'P-450', reductase, activity, and, 'MMC', sensitivity, in, these, cell, lines])].
[sujeto(['To', confirm, the, role, of, 'DTD', in, cellular, 'MMC', 'sensitivity,', we, constructed, an, expression, vector, containing, 'NQO1,', a, gene, that, codes, for, 'DTD,', and, transfected, the, vector, into, 'St-4', cells]), verbo([expressing]), complemento([no, 'DTD', activity])].
[sujeto(['Consistent', with, the, 'MMC', 'sensitivity,', we, also]), verbo([found]), complemento([that, 'MMC-DNA', adduct, was, formed, more, extensively, in, the, 'NQO1', transfectants, than, in, the, 'St-4', cells])].
[sujeto(['These', results, indicate, that, 'DTD', activity, is]), verbo([required]), complemento([for, effective, cytotoxicity, of, 'MMC', in, colon, and, gastric, carcinoma, cells])].
[sujeto(['HT-29', 'cells,', which]), verbo([have]), complemento([intermediate, 'DTD', activity, '(', 769, +, /, -, 144, 'nmol/min/mg', 'protein,', mean, +, /, -, 'SD)', and, are, sensitive, to, 'MMC,', showed, high, 'NQO1', expression, relative, to, 'beta-actin', '(', taken, as, 100, '%', here, for, comparative, 'purposes)'])].
[sujeto(['BE', cells, which]), verbo([have]), complemento([no, detectable, 'DTD', activity, and, are, resistant, to, 'MMC', showed, moderate, 'NQO1', expression, '(', 91, '%', of, 'HT-29)'])].
[sujeto(['This']), verbo([confers]), complemento([a, proline, to, serine, substitution, in, the, amino, acid, sequence, of, the, protein])].
[sujeto(['Adrenal', production, of, dehydroepiandrosterone, sulfate, '(', 'DHEA-S)']), verbo([increases]), complemento([throughout, childhood, owing, to, expansion, of, the, zona, reticularis, '(', 'ZR)'])].
[sujeto(['ZR', features, cells, with, a, steroidogenic, phenotype, distinct, from, that, of, the, adjacent, zona, fasciculata, '(', 'ZF),', with, higher, expression, of, cytochrome, b5, type, 'A', '(', 'CYB5A)', and, steroid, sulfotransferase, type, 2, 'A1', '(', 'SULT2A1)', but]), verbo([decreased]), complemento([3, 'β-hydroxysteroid', dehydrogenase, type, 2, '(', 'HSD3B2)'])].
[sujeto(['In', addition, to, 'DHEA-S,', three, adrenal, 'Δ5-steroid', sulfates, could]), verbo([provide]), complemento([additional, tools, to, define, adrenal, maturation])].
[sujeto(['Finally,', 'HAC15', adrenocortical, cells, were, transduced, with, lentiviral, short, hairpin, 'RNA', '(', 'shRNA)', to]), verbo([suppress]), complemento(['CYB5A', expression])].
[sujeto(['Adiol-S']), verbo([increased]), complemento([in, parallel, with, 'DHEA-S'])].
[sujeto(['Steroid', ratios, '(', 17, 'OHPreg-S/DHEA-S)']), verbo([suggested]), complemento([increases, in, 17, ',', 20, -, lyase, activity, during, childhood])].
[sujeto(['Immunofluorescence', analysis, showed, 'age-related']), verbo([increases]), complemento([in, 'ZR', 'CYB5A', immunoreactivity])].
[sujeto(['Adiol-S', shows, a, similar, 'age-related']), verbo([increase]), complemento([to, that, of, 'DHEA-S'])].
[sujeto(['This', likely, results, from, the, childhood, expansion, of, 'CYB5A-expressing', 'ZR,', which]), verbo([enhances]), complemento([17, ',', 20, -, lyase, activity, and, the, production, of, 'DHEA-S', and, 'Adiol-S'])].
[sujeto(['To', explore, the, metabolism, of, steroids, in, the, pig, 'species,', a, qualitative, 'PCR', analysis, was, performed, for, the, main, transcript, of, 27, genes]), verbo([involved]), complemento([in, steroid, metabolism])].
[sujeto(['Some', genes, were, shown, to]), verbo([have]), complemento([a, 'tissue-specific', expression])].
[sujeto(['Two', of, them, were]), verbo([expressed]), complemento([only, in, 'testes,', ovaries, and, 'adrenals:', 'CYP11A1', and, 'CYP11B'])].
[sujeto(['The', 'CYP21', and, 'HSD17B3', 'genes,', were]), verbo([expressed]), complemento([respectively, only, in, adrenals, and, only, in, testes])].
[sujeto(['However,', the, expression, of, genes]), verbo([involved]), complemento([in, the, sulfonation, of, steroids, was, higher, in, testes, than, in, adrenals, from, males])].
[sujeto(['The', present, study, shows, that, the, 'SRD5A2', and, 'CYP21', genes, were, not]), verbo([involved]), complemento([in, the, testicular, biosynthesis, of, androstenone])].
[sujeto(['In', 'humans,', palbociclib, undergoes, metabolism]), verbo([mediated]), complemento([primarily, by, 'CYP3A', and, 'SULT2A1,', and, it, is, also, a, weak, 'time-dependent', 'CYP3A', inhibitor])].
[sujeto(['Using', this, final, 'PBPK', 'model,', it, was, predicted, that, weak, 'CYP3A', inhibitors, '(', fluoxetine, and, 'fluvoxamine)', are, anticipated, to]), verbo([have]), complemento([negligible, 'DDI', risk, with, 'palbociclib,', whereas, moderate, 'CYP3A', inhibitors, '(', diltiazem, and, 'verapamil)', may, increase, plasma, palbociclib, 'AUC', by, '∼40%'])].
[sujeto(['A', moderate, 'CYP3A', inducer, '(', 'efavirenz)', may]), verbo([decrease]), complemento([plasma, palbociclib, 'AUC', by, '∼40%'])].
[sujeto(['In', this, 'work,', tunnels, that, facilitate, the, transport, of, substrates, in, the, enzyme, were, 'studied,', with, and, without]), verbo([bound]), complemento(['cofactor,', using, extensive, molecular, dynamics, simulations])].
[sujeto(['We']), verbo([found]), complemento([that, binding, of, cofactor, could, significantly, narrow, the, tunnel, based, on, the, closing, of, the, 'active-site', cap, to, the, enzyme])].
[sujeto(['The', human, cytosolic, sulfotransferases, '(', 'SULTs)', comprise, a, 13, -, member, enzyme, family, that]), verbo([regulates]), complemento([the, activities, of, 'hundreds,', perhaps, 'thousands,', of, signaling, small, molecules, via, regiospecific, transfer, of, the, sulfuryl, moiety, '(', -, 'SO3)', from, 'PAPS', '(', 3, '\'', -, phosphoadenosine, 5, '\'', -, 'phosphosulfate)', to, the, hydroxyls, and, amines, of, acceptors])].
[sujeto(['Signaling', molecules]), verbo([regulated]), complemento([by, sulfonation, include, numerous, steroid, and, thyroid, 'hormones,', 'epinephrine,', 'serotonin,', and, dopamine])].
[sujeto(['SULT1A1,', a, major, phase, 'II', metabolism, 'SULT', 'isoform,', is]), verbo([found]), complemento([at, a, high, concentration, in, liver, and, has, recently, been, show, to, harbor, two, allosteric, binding, 'sites,', each, of, which, binds, a, separate, and, complex, class, of, 'compounds:', the, catechins, '(', naturally, occurring, 'polyphenols)', and, nonsteroidal, 'anti-inflammatory', drugs])].
[sujeto(['The', allosteric, network]), verbo([associated]), complemento([with, either, site, has, yet, to, be, defined])].
[sujeto(['Here,', using, equilibrium]), verbo([binding]), complemento([and, 'pre-steady', state, 'studies,', the, network, is, shown, to, involve, 14, distinct, complexes])].
[sujeto(['ECGG']), verbo([binds]), complemento([both, the, allosteric, site, 'and,', relatively, 'weakly,', the, active, site, of, 'SULT1A1'])].
[sujeto(['EGCG']), verbo([binds]), complemento([17, -, fold, more, tightly, when, the, 'active-site', cap, of, the, enzyme, is, closed, by, the, binding, of, the, nucleotide])].
[sujeto(['When', nucleotide, is, 'saturating,', 'EGCG']), verbo([binds]), complemento([in, two, phases])].
[sujeto(['In', the, 'first,', it]), verbo([binds]), complemento([to, the, 'cap-open', 'conformer;', in, the, 'second,', it, traps, the, cap, in, the, closed, configuration])].
[sujeto(['Cap', closure, encapsulates, the, 'nucleotide,']), verbo([preventing]), complemento([its, 'release;', 'hence,', the, 'EGCG-induced', cap, stabilization, slows, nucleotide, 'release,', inhibiting, turnover])].
[sujeto(['It', was]), verbo([found]), complemento([that, androsterone, '(', 'ADT)', is, able, to, form, hydrogen, bonds, with, residues, 'Ser80,', 'Ile82,', and, 'His99', of, the, active, site])].
[sujeto(['Results', revealed, that, 'ADT']), verbo([interacts]), complemento([with, the, other, residues, through, electrostatic, and, 'Van', der, 'Waals', interactions])].
[sujeto(['Combining', the, brain, and, body, should]), verbo([provide]), complemento([a, comprehensive, understanding, of, the, etiology, of, 'MDD'])].
[sujeto(['As', the, largest, internal, organ, of, the, human, 'body,', the, liver]), verbo([has]), complemento([an, important, 'function,', yet, no, proteomic, study, has, assessed, liver, protein, expression, in, a, preclinical, model, of, depression])].
[sujeto(['According', to, the, ingenuity, pathway, analysis, '(', 'IPA),', we]), verbo([found]), complemento([that, proteins, related, to, the, inflammation, 'response,', immune, 'regulation,', lipid, metabolism, and, 'NFκB', signaling, network, were, altered, by, 'CUMS'])].
[sujeto(['Moreover,', four, proteins, closely]), verbo([associated]), complemento([with, these, 'processes,', 'hemopexin,', 'haptoglobin,', cytochrome, 'P450', 2, 'A4', '(', 'CYP2A4)', and, bile, salt, sulfotransferase, 1, '(', 'SULT2A1),', were, validated, by, western, blotting])].
[sujeto(['Our', findings]), verbo([provide]), complemento([novel, insight, '(', 'liver-brain', 'axis)', into, the, multifaceted, mechanisms, of, major, depressive, disorder])].
[sujeto(['The', microminipig, is, one, of, the, smallest, minipigs, that]), verbo([has]), complemento([emerged, as, a, possible, experimental, animal, 'model,', because, it, shares, many, anatomical, 'and/or', physiological, similarities, with, 'humans,', including, the, coronary, artery, distribution, in, the, 'heart,', the, digestive, 'physiology,', the, kidney, size, and, its, 'structure,', and, so, on])].
[sujeto(['Liver', carboxylesterase, '(', 'CES)', 'precursor,', liver, 'CES-like,', 'UDP-glucuronosyltransferase', '(', 'UGT)', 2, 'C1-like,', amine, sulfotransferase, '(', 'SULT)-like,', 'N-acetyltransferases', '(', 'NAT8)', and, glutathione, 'S-transferase', '(', 'GST)', 'A2', 'genes,', which, are, relatively, unknown, genes, in, pigs, 'and/or', 'humans,', were]), verbo([expressed]), complemento([strongly])].
[sujeto(['These', results]), verbo([provide]), complemento([a, foundation, for, mechanistic, studies, and, the, use, of, microminipigs, as, model, animals, for, drug, development, in, the, future])].
[sujeto(['A', 'genome-wide', association, study, '(', 'GWAS)', of, 280, cases, identified, the, hepatic, cholesterol, transporter, 'ABCG8', as, a, locus]), verbo([associated]), complemento([with, risk, for, gallstone, 'disease,', but, findings, have, not, been, reported, from, any, other, 'GWAS', of, this, phenotype])].
[sujeto(['We', performed, an, inverse, variance, 'weighted,', 'fixed-effects', 'meta-analysis', of, 'study-specific', estimates, to, identify, 'single-nucleotide', polymorphisms, that, were]), verbo([associated]), complemento([independently, with, gallstone, disease])].
[sujeto(['We', also, identified, 'and/or', replicated, associations, for, rs9843304, in, 'TM4SF4', '(', 'OR,', 1.12, ;, 95, '%', 'CI,', 1.08, -, 1.16, ;, 'P&nbsp;=', 6.09, &, 'nbsp;×', 10, '(', -, 11, ')', ')', ',', rs2547231, in, 'SULT2A1', '(', encodes, a, sulfoconjugation, enzyme, that]), verbo([acts]), complemento([on, hydroxysteroids, and, 'cholesterol-derived', sterol, bile, 'acids)', '(', 'OR,', 1.17, ;, 95, '%', 'CI,', 1.12, -, 1.21, ;, 'P&nbsp;=', 2.24, &, 'nbsp;×', 10, '(', -, 10, ')', ')', ',', rs1260326, in, glucokinase, regulatory, protein, '(', 'OR,', 1.12, ;, 95, '%', 'CI,', 1.07, -, 1.17, ;, 'P&nbsp;=&nbsp;2'])].
[sujeto(['Among', individuals, of, 'African', 'American', and, 'Hispanic', 'American', 'ancestry,', rs11887534, and, rs4245791, were]), verbo([associated]), complemento([positively, with, gallstone, disease, 'risk,', whereas, 'the&nbsp;association', for, the, rs1260326, variant, was, inverse])].
[sujeto(['In', this, 'large-scale', 'GWAS', of, gallstone, 'disease,', we, identified, 4, loci, in, genes, that]), verbo([have]), complemento([putative, functions, in, cholesterol, metabolism, and, 'transport,', and, sulfonylation, of, bile, acids, or, hydroxysteroids])].
[sujeto(['Although', childhood, adrenocortical, carcinomas, '(', 'c-ACCs)', with, a, 'TP53', mutation, are, known, to, produce, 'androgens,', detailed, steroidogenic, characters]), verbo([have]), complemento([not, been, clarified])].
[sujeto(['Furthermore,', the, 'c-ACC', was]), verbo([associated]), complemento([with, elevated, expressions, of, 'CYP11A1,', 'CYP17A1,', 'POR,', 'HSD17B3,', and, 'SULT2A1,', a, low, but, similar, expression, of, 'CYB5A,', and, reduced, expressions, of, 'AKR1C3', '(', 'HSD17B5)', and, 'HSD3B2'])].
[sujeto(['Notably,', a, 'Leydig', cell, marker, 'INSL3', was]), verbo([expressed]), complemento([at, a, low, but, detectable, level, in, the, 'c-ACC'])].
[sujeto(['Furthermore,', molecular, studies, revealed, a, maternally, inherited, heterozygous, germline, 'TP53', 'mutation,', and, several, 'post-zygotic', genetic, aberrations, in, the, 'c-ACC', including]), verbo([loss]), complemento([of, paternally, derived, chromosome, 17, with, a, wildtype, 'TP53', and, loss, of, maternally, inherited, chromosome, 11, and, resultant, marked, hyperexpression, of, paternally, expressed, growth, promoting, gene, 'IGF2', and, drastic, hypoexpression, of, maternally, expressed, growth, suppressing, gene, 'CDKN1C'])].
[sujeto(['Even', 'though,', levels, of, 'EtG', and, 'EtS', in, blood, and, urine]), verbo([increase]), complemento([with, increasing, doses, of, 'alcohol,', a, high, 'inter-individual', variability, in, their, production, has, been, noticed])].
[sujeto(['All', enzymes, investigated, were]), verbo([involved]), complemento([in, the, conjugation, of, ethanol])].
[sujeto(['Findings', for, quercetin, with, regard, to, 'UGT2B7', and, 'SULT2A1', and, for, kaempferol, with, regard, to, 'SULT1E1', and, 'SULT2A1']), verbo([suggested]), complemento([a, mechanism, based, inhibition])].
[sujeto(['Beside', the, known, polymorphisms, of, the, transferases]), verbo([involved]), complemento([in, 'EtG', and, 'EtS', 'formation,', prediction, of, the, inhibitory, potential, indicates, that, polyphenols, may, contribute, to, the, variable, formation, rate, of, 'EtG', and, 'EtS'])].
[sujeto(['Lorcaserin', is, primarily, cleared, by, 'metabolism,', which]), verbo([involves]), complemento([multiple, enzyme, systems, with, various, metabolic, pathways, in, humans])].
[sujeto(['Human', sulfotransferases, '(', 'SULTs)', 'SULT1A1,', 'SULT1A2,', 'SULT1E1,', and, 'SULT2A1', are]), verbo([involved]), complemento([in, the, formation, of, lorcaserin, 'N-sulfamate'])].
[sujeto(['Lorcaserin', 'N-sulfamate']), verbo([binds]), complemento([to, human, plasma, protein, with, high, affinity, '(', i])].
[sujeto(['Thus,', despite, being, the, major, circulating, 'metabolite,', the, level, of, free, lorcaserin, 'N-sulfamate', would, be, minimal, at, a, lorcaserin, therapeutic, dose, and, unlikely, be, sufficient, to]), verbo([cause]), complemento(['drug-drug', interactions])].
[sujeto(['Considering', its, formation, kinetic, 'parameters,', high, plasma, protein]), verbo([binding]), complemento(['affinity,', minimal, 'P450', inhibition, or, induction, 'potential,', and, 'stability,', the, potential, for, metabolic, 'drug-drug', interaction, or, toxicological, effects, of, lorcaserin, 'N-sulfamate', is, remote, in, a, normal, patient, population])].
[sujeto(['Various', factors, including, altered, steroid, biosynthesis, may]), verbo([participate]), complemento([in, its, pathophysiology])].
[sujeto(['The', steroid, levels, '(', 47, steroids, and, steroid, polar, 'conjugates)', and, their, ratios, in, 'AD', female, patients, indicated]), verbo([increased]), complemento(['CYP11A1', 'activity,', weakened, activity, of, the, 'CYP17A1C17,20', lyase, metabolic, step, and, attenuated, sulfotransferase, 'SULT2A1', activity, at, higher, activity, of, the, 'CYP17A1', 17, -, hydroxylase, step])].
[sujeto(['The', women, with, 'AD', had, also, attenuated, steroid, 7, 'α-hydroxylation', forming, immunoprotective, 'Δ(5)-C19', 'steroids,', attenuated, aromatase, activity, forming, estradiol, that]), verbo([induces]), complemento([autoimmunity, and, a, shift, from, the, 3, 'β-hydroxy-5α/β-reduced', 'C19', steroids, to, their, neuroinhibitory, and, antiinflammatory, 'GABAergic', 3, 'α-hydroxy-', counterparts, and, showed, higher, levels, of, the, 3, 'α-hydroxy-5α/β-reduced', 'C21', steroids, and, pregnenolone, sulfate, '(', improves, cognitive, abilities, but, may, be, both, protective, and, 'excitotoxic)'])].
[sujeto(['Our', study]), verbo([suggested]), complemento([relationships, between, 'AD', status, in, women, based, on, the, age, of, subjects, and, levels, of, 10, steroids, measured, by, 'GC-MS'])].
[sujeto(['Although', their, role]), verbo([has]), complemento([been, 'studied,', the, corresponding, metabolomic, data, is, limited])].
[sujeto(['Tolvaptan,', a, vasopressin, receptor, 2, antagonist, used, to, treat, 'hyponatremia,']), verbo([has]), complemento([recently, been, reported, to, be, associated, with, liver, injury])].
[sujeto(['Sulfotransferases', '(', 'SULTs)']), verbo([have]), complemento([been, implicated, as, important, detoxifying, 'and/or', activating, enzymes, for, numerous, 'xenobiotics,', 'drugs,', and, endogenous, compounds])].
[sujeto(['Moreover,', exposing, cells, to, tolvaptan, in, the, presence, of, cyclosporine, 'A,', an, inhibitor, of, the, drug, efflux, 'transporters,', significantly]), verbo([increased]), complemento([the, intracellular, levels, of, tolvaptan, sulfate, and, decreased, the, cell, viability, in, 'HEK293/SULT1C3', cells])].
[sujeto(['These', data, indicate, that, sulfation]), verbo([increased]), complemento([the, cytotoxicity, of, tolvaptan])].
[sujeto(['The', human, sulfotransferases, '(', 'SULTs)']), verbo([regulate]), complemento([the, activities, of, 'hundreds,', if, not, 'thousands,', of, small, molecule, metabolites, via, transfer, of, the, 'sulfuryl-moiety', '(', -, 'SO3)', from, the, nucleotide, 'donor,', 3, '\'', -, phosphoadenosine, 5, '\'', -, phosphosulfate, '(', 'PAPS)', to, the, hydroxyls, and, amines, of, the, recipients])].
[sujeto(['Our', understanding, of, the, molecular, basis, of, 'SULT', catalysis]), verbo([has]), complemento([expanded, considerably, in, recent, years])].
[sujeto(['The', basic, kinetic, mechanism, of, these, 'enzymes,', previously, thought, to, be, 'ordered,']), verbo([has]), complemento([been, redefined, as, random, for, 'SULT2A1,', a, representative, member, of, the, superfamily])].
[sujeto(['More', recent, work]), verbo([has]), complemento([revealed, that, the, caps, of, the, 'SULT1A1', are, controlled, by, homotropic, allosteric, interactions, between, 'PAPS', molecules, bound, at, the, 'dimer\'s', active, sites])].
[sujeto(['These', interactions]), verbo([cause]), complemento([the, catalytic, efficiency, of, 'SULT1A1', to, vary, in, a, 'substrate-dependent', fashion, by, as, much, as, two, orders, of, magnitude, over, a, range, of, 'PAPS', concentrations, that, spans, those, found, in, human, tissues])].
[sujeto(['SULT', catalysis, is, further, complicated, by, the, fact, that, these, enzymes, are, frequently]), verbo([inhibited]), complemento([by, their, substrates])].
[sujeto(['This', review]), verbo([provides]), complemento([an, overview, of, the, mechanistic, features, of, 'SULT1A1', that, are, important, for, the, design, and, interpretation, of, 'SULT1A1', assays])].
[sujeto(['To', investigate, protective, effects, of, alisol, 'B', 23, -, acetate, '(', 'AB23A)', against, hepatotoxity, and, cholestasis]), verbo([induced]), complemento([by, 17, 'α-ethinylestradiol', '(', 'EE)', in, association, with, farnesoid, 'X', receptor, '(', 'FXR)', activation, in, vivo, and, in, vitro])].
[sujeto(['AB23A', treatment, protected, against, liver, injury]), verbo([induced]), complemento([by, 'EE', through, increasing, hepatic, efflux, and, reducing, uptake, of, bile, acid, via, an, induction, in, efflux, transporters, '(', 'Bsep', and, 'Mrp2)', and, an, inhibition, in, hepatic, uptake, transporter, '(', 'Ntcp)', expression])].
[sujeto(['AB23A', also, reduced, bile, acid, synthesis, through]), verbo([repressing]), complemento(['Cyp7a1', and, 'Cyp8b1,', and, increased, bile, acid, metabolism, through, an, induction, in, gene, expression, of, 'Sult2a1'])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF4alpha)', is, an, important, transcription, factor, in, hepatic, gene, expression])].
[sujeto(['Here,', we]), verbo([have]), complemento([investigated, the, role, of, 'HNF4alpha', in, the, expression, of, 'drug-metabolizing', enzymes, and, transporters, in, human, hepatocytes, using, an, adenovirus, expressing, human, 'HNF4alpha-small', interfering, 'RNA', '(', 'hHNF4alpha-siRNA)'])].
[sujeto(['The', 'hHNF4alpha-siRNA', effectively, reduced, the, mRNA, and]), verbo([nuclear]), complemento([protein, levels, of, hHNF4alpha, in, a, 'concentration-dependent', manner])].
[sujeto(['The', 'hHNF4alpha-siRNA', also]), verbo([decreased]), complemento([the, mRNA, levels, of, 'CYP2A6,', 'CYP2B6,', 'CYP2C8,', 'CYP2C9,', 'CYP2C19,', 'CYP2D6,', 'CYP3A4,', 'UGT1A1,', 'UGT1A9,', 'SULT2A1,', 'ABCB1,', 'ABCB11,', 'ABCC2,', 'OATP1B1', and, 'OCT1,', as, well, as, those, of, 'PXR', and, 'CAR'])].
[sujeto(['To', discern, the, role, of, these]), verbo([nuclear]), complemento(['receptors,', we, 'co-infected', hepatocytes, with, 'hHNF4alpha-siRNA', and, 'PXR-', or, 'CAR-expressing', adenovirus])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'HNF4alpha', plays, a, dominant, role, in, the, expression, of, 'drug-metabolizing', enzymes, and, transporters, in, human, 'hepatocytes,', and, that, 'HNF4alpha', expression, levels, is, a, possible, determinant, for, 'inter-individual', variations, in, the, expression, of, these, enzymes, and, transporters])].
[sujeto(['Normal', rats, and, bile, 'duct-ligated', '(', 'BDL)', rats, were, given, oleanolic, acid, and, serum, 'biochemistry,', bile, 'salts,', and, 'pro-inflammatory', factors, were, 'measured,', as, well, as, the, expression, levels, of, liver, bile, acid, synthesis, and, detoxification, 'enzymes,', membrane, 'transporters,']), verbo([nuclear]), complemento(['receptors,', and, transcriptional, factors])].
[sujeto(['Oral', administration, of, oleanolic, acid, at, 100, 'mg/kg', did, not]), verbo([cause]), complemento([rat, liver, injury])].
[sujeto(['In', 'addition,', the, expression, levels, of, detoxification, enzymes, 'Cyp3a,', 'Ugt2b,', 'Sult2a1,', 'Gsta1-2,', and, 'Gstm1-3,', membrane, transporters, 'Mrp3,', 'Mrp4,', 'Ostβ,', 'Mdr1,', 'Mdr2,', and, 'Bsep,']), verbo([nuclear]), complemento([receptors, 'Pxr,', 'Vdr,', 'Hnf4α,', 'Rxrα,', 'Rarα,', 'Lxr,', and, 'Lrh-1,', and, transcriptional, factors, 'Nrf2,', 'Hnf3β,', and, 'Ahr', were, significantly, increased, in, oleanolic, 'acid-treated', rats])].
[sujeto(['The', 'anti-cholestatic', effect, may, be]), verbo([associated]), complemento([with, the, induction, of, hepatic, detoxification, enzymes, and, efflux, transporters, mediated, by, nuclear, receptors, and, transcriptional, factors])].
[sujeto(['Sirtuin1', '(', 'SIRT1)']), verbo([regulates]), complemento([central, metabolic, functions, such, as, 'lipogenesis,', protein, 'synthesis,', 'gluconeogenesis,', and, bile, acid, '(', 'BA)', homeostasis, through, deacetylation])].
[sujeto(['SIRT', mice, showed]), verbo([increased]), complemento(['mortality,', impaired, hepatocyte, 'proliferation,', 'BA', 'accumulation,', and, profuse, liver, injury, after, surgery])].
[sujeto(['The', damaging, phenotype, in, 'SIRT', mice, correlated, with, impaired, farnesoid, 'X', receptor, '(', 'FXR)', activity, due, to, persistent, deacetylation, and, lower, protein, expression, that]), verbo([led]), complemento([to, decreased, 'FXR-target', gene, 'expression;', small, heterodimer, partner, '(', 'SHP),', bile, salt, export, pump, '(', 'BSEP),', and, increased, 'Cyp7A1'])].
[sujeto(['Next,', we, show, that, 24, -, norUrsodeoxycholic, acid, '(', 'NorUDCA)', attenuates, 'SIRT', protein, 'expression,']), verbo([increases]), complemento([the, acetylation, of, 'FXR', and, neighboring, 'histones,', restores, trimethylation, of, 'H3K4', and, 'H3K9,', and, increases, miR34a, 'expression,', thus, reestablishing, 'BA', homeostasis])].
[sujeto(['Consequently,', 'NorUDCA', restored, liver, regeneration, in, 'SIRT', 'mice,', which, showed]), verbo([increased]), complemento([survival, and, hepatocyte, proliferation])].
[sujeto(['Furthermore,', a, 'leucine-enriched', diet, restored, mammalian]), verbo([target]), complemento([of, rapamycin, '(', 'mTOR)', 'activation,', acetylation, of, 'FXR', and, 'histones,', leading, to, an, overall, lower, 'BA', production, through, 'SHP-inhibition', of, 'Cyp7A1', and, higher, transport, '(', 'BSEP)', and, detoxification, '(', 'Sult2a1)', leading, to, an, improved, liver, regeneration])].
[sujeto(['Finally,', we]), verbo([found]), complemento([that, human, hepatocellular, carcinoma, '(', 'HCC)', samples, have, increased, presence, of, 'SIRT1,', which, correlated, with, the, absence, of, 'FXR,', suggesting, its, oncogenic, potential])].
[sujeto(['We', define, 'SIRT1', as, a, key, regulator, of, the, regenerative, response, in, the, liver, through, posttranscriptional, modifications, that]), verbo([regulate]), complemento([the, activity, of, 'FXR,', 'histones,', and, mTOR])].
[sujeto(['Moreover,', our, data]), verbo([suggest]), complemento([that, 'SIRT1', contributes, to, liver, tumorigenesis, through, dysregulation, of, 'BA', homeostasis, by, persistent, 'FXR', deacetylation])].
[sujeto(['In', sexually, mature, male]), verbo([sea]), complemento([lamprey, '(', 'Petromyzon', marinus, 'L'])].
[sujeto([')', a, bile, salt, is]), verbo([released]), complemento([in, large, amounts, across, gill, epithelia, into, water, where, it, functions, as, a, pheromone])].
[sujeto(['We', postulate, that, the]), verbo([release]), complemento([of, this, pheromone, is, associated, with, a, dramatic, increase, in, its, biosynthesis, and, transport, to, the, gills, upon, sexual, maturation])].
[sujeto(['We', show, an, 8000, -, fold]), verbo([increase]), complemento([in, transcription, of, 'cyp7a1,', a, 'three-fold', increase, in, transcription, of, 'cyp27a1,', and, a, 'six-fold', increase, in, transcription, of, cyp8b1, in, the, liver, of, mature, male, sea, lamprey, over, immature, male, adults])].
[sujeto(['LC-MS/MS', data, on, 'tissue-specific', distribution, and]), verbo([release]), complemento([rates, of, bile, salts, from, mature, males, show, a, high, concentration, of, petromyzonol, sulfate, '(', 'PZS)', in, the, liver, and, gills, of, mature, males])].
[sujeto([3, -, keto, petromyzonol, sulfate, '(', 3, 'kPZS,', known, as, a, male, sex, 'pheromone)', is, the, primary, compound]), verbo([released]), complemento([from, 'gills,', suggesting, a, conversion, of, 'PZS', to, 3, kPZS, in, the, gill, epithelium])].
[sujeto(['High', expression, of, sult2b1, and, sult2a1, in, gill, epithelia, of, mature, 'males,', and, 'tissue-specific', expression, of, bile, salt, transporters, such, as, 'bsep,', 'slc10a1,', and, 'slc10a2,']), verbo([suggest]), complemento([additional, sulfation, and, transport, of, bile, salts, that, are, dependent, upon, maturation, state])].
[sujeto(['This']), verbo([report]), complemento([presents, a, rare, example, where, specific, genes, associated, with, biosynthesis, and, release, of, a, sexual, pheromone, are, dramatically, upregulated, upon, sexual, maturation, in, a, vertebrate])].
[sujeto(['We']), verbo([provide]), complemento([a, well, characterized, example, of, a, complex, mechanism, of, bile, salt, biosynthesis, and, excretion, that, has, likely, evolved, for, an, additional, function, of, bile, salts, as, a, mating, pheromone])].
[sujeto(['AOPs', are, designed, to]), verbo([provide]), complemento([a, 'clear-cut', mechanistic, representation, of, critical, toxicological, effects, that, span, over, different, layers, of, biological, organization])].
[sujeto(['Elaborate', 'AOP', frameworks]), verbo([have]), complemento([yet, been, proposed, for, 'chemical-induced', skin, 'sensitization,', 'cholestasis,', liver, fibrosis, and, liver, steatosis])].
[sujeto(['In', the, past, 'decade,', important, new, insights]), verbo([have]), complemento([been, made, relating, to, the, regulatory, mechanisms, governing, the, expression, of, 'drug-metabolizing', enzymes, and, transporters, by, 'ligand-activated', nuclear, receptors])].
[sujeto(['Specifically,', there, is, compelling, evidence, to, demonstrate, that, 'PXR,', 'CAR,', 'FXR,', 'LXR,', 'VDR,', 'HNF4alpha,', and, 'AhR', form, a, battery, of]), verbo([nuclear]), complemento([receptors, that, regulate, the, expression, of, many, important, 'drug-metabolizing', enzyme, and, transporters])].
[sujeto(['In', this, 'review,', the, authors, focus, on, clinically, important, 'drug-metabolizing', enzymes, such, as, 'CYP3A4,', 'CYP2B6,', 'CYP2C9,', 'CYP2C19,', 'UGT1A1,', 'SULT2A1,', and, glutathione, 'S-transferases', and, their, regulation, by]), verbo([nuclear]), complemento([receptors])].
[sujeto(['They', also, review, the]), verbo([nuclear]), complemento(['receptor-mediated', regulation, of, drug, transporters, such, as, 'MDR1,', 'MRP2,', 'MRP4,', 'BSEP,', 'BCRP,', 'NTCP,', 'OATP1B3,', and, 'OATP1A2'])].
[sujeto(['Finally,', they, outline, how, the, drug, development, process]), verbo([has]), complemento([been, affected, by, the, current, understanding, of, the, involvement, of, nuclear, receptors, in, the, regulation, of, drug, disposition, genes])].
[sujeto(['Because', the]), verbo([nuclear]), complemento([xenobiotic, receptors, constitutive, androstane, receptor, '(', 'CAR)', and, pregnane, 'X', receptor, '(', 'PXR)', regulate, involved, enzymes, and, 'transporters,', we, aimed, to, induce, adaptive, alternative, pathways, with, different, 'CAR', and, 'PXR', agonists, in, vivo])].
[sujeto(['Hepatic', bile, acid, and, 'bilirubin-metabolizing/detoxifying', enzymes, '(', 'Cyp2b10,', 'Cyp3a11,', 'Ugt1a1,', 'Sult2a1),', their, regulatory]), verbo([nuclear]), complemento([receptors, '(', 'CAR,', 'PXR,', farnesoid, 'X', 'receptor),', and, bile, 'acid/organic', anion, and, lipid, transporters, '(', 'Ntcp,', 'Oatp1,2,4,', 'Bsep,', 'Mrp2-4,', 'Mdr2,', 'Abcg5/8,', 'Asbt)', in, the, liver, and, kidney, were, analyzed, via, 'reverse-transcriptase', polymerase, chain, reaction, and, 'Western', blotting])].
[sujeto(['CAR', agonists]), verbo([induced]), complemento(['Mrp2-4', and, 'Oatp2;', 'PXR', agonists, induced, only, 'Mrp3', and, 'Oatp2'])].
[sujeto(['Both', 'PXR', and, 'CAR', agonists, profoundly]), verbo([stimulated]), complemento([bile, 'acid-hydroxylating/detoxifying', enzymes, 'Cyp3a11', and, 'Cyp2b10'])].
[sujeto(['These', changes, were, accompanied, by, reduced, serum, levels, of, bilirubin, and, bile, acids, in, healthy, and, 'CBDL', mice, and, by]), verbo([increased]), complemento([levels, of, polyhydroxylated, bile, acids, in, serum, and, urine, of, cholestatic, mice])].
[sujeto(['Atorvastatin', significantly]), verbo([increased]), complemento(['Oatp2,', 'Mdr2,', and, 'Asbt,', while, other, transporters, and, enzymes, were, moderately, affected])].
[sujeto(['Oleanolic', acid, '(', 'OA)', is, a, natural, triterpenoid, and]), verbo([has]), complemento([been, demonstrated, to, protect, against, varieties, of, hepatotoxicants])].
[sujeto(['Recently,', 'however,', 'OA', at, high, doses, was]), verbo([reported]), complemento([to, produce, apparent, cholestasis, in, mice])].
[sujeto([')', significantly, improved, mouse, survival, 'rate,', attenuated, liver, 'necrosis,', and]), verbo([decreased]), complemento([serum, alanine, 'aminotransferase,', aspartate, 'aminotransferase,', and, alkaline, 'phosphatase;', more, 'importantly,', serum, total, bile, acids, and, 'bilirubin,', as, well, as, hepatic, total, bile, acids, were, also, remarkably, reduced])].
[sujeto(['Gene', and, protein, expression, analysis, showed, that, hepatic, expression, of, multidrug, 'resistance-associated', protein, 2, '(', 'Mrp2),', 'Mrp3,', and, 'Mrp4', was, significantly]), verbo([increased]), complemento([by, 'OA', 'cotreatment,', whereas, other, bile, acid, 'metabolism-', and, 'transport-related', 'genes,', including, 'Na+/taurocholate', 'cotransporter,', organic, anion, transporter, 1, 'b2,', bile, salt, export, 'pump,', multidrug, resistance, protein, 3, ',', 'Cyp3a11,', 'Cyp2b10,', 'Sulfotransferase', 2, a1, '(', 'Sult2a1),', and, 'UDP-glucuronosyltransferase', 1, a1, '(', 'Ugt1a1),', were, only, slightly, changed])].
[sujeto(['OA', also]), verbo([caused]), complemento([increased, nuclear, 'factor-E2-related', factor, '(', 'Nrf2)', mRNA, expression, and, nuclear, protein, 'accumulation,', whereas, nuclear, receptors, farnesoid, 'X', receptor, '(', 'FXR),', pregnane, 'X', receptor, '(', 'PXR),', and, constitutive, androstane, receptor, were, not, significantly, influenced, by, 'OA'])].
[sujeto(['Finally,', in, mouse, primary, cultured, 'hepatocytes,', 'OA', 'dose-', and, 'time-dependently']), verbo([induced]), complemento([expression, of, 'Mrp2,', 'Mrp3,', and, 'Mrp4;', 'however,', this, upregulation, was, abrogated, when, 'Nrf2', was, silenced])].
[sujeto(['We', therefore, investigated, expression, of, genes, for, bile, acid, 'synthesis,', detoxification, and, alternative, basolateral, export, and, regulatory]), verbo([nuclear]), complemento([factors, in, primary, biliary, cirrhosis, '(', 'PBC)'])].
[sujeto(['Hepatic', 'CYP7A1,', 'CYP27A1,', 'CYP8B1', '(', bile, acid, 'synthesis),', 'CYP3A4', '(', 'hydroxylation),', 'SULT2A1', '(', 'sulphation),', 'UGT2B4/2B7', '(', 'glucuronidation),', 'MRP4', '(', basolateral, 'export),', farnesoid, 'X', receptor, '(', 'FXR),', retinoid, 'X', receptor, '(', 'RXR),', short, heterodimer, partner, '(', 'SHP),', hepatocyte]), verbo([nuclear]), complemento([factor, 1, alpha, '(', 'HNF1alpha)', and, 'HNF4alpha', expression, was, determined, in, 11, patients, with, 'late-stage', 'PBC', and, this, was, compared, with, 'non-cholestatic', controls])].
[sujeto(['CYP7A1', mRNA, was]), verbo([repressed]), complemento([in, 'PBC', to, 10, -, 20, '%', of, 'controls,', while, 'CYP27', and, 'CYP8B1', mRNA, remained, unchanged])].
[sujeto(['MRP4', protein, levels, were]), verbo([induced]), complemento(['three-fold', in, 'PBC,', whereas, mRNA, levels, remained, unchanged])].
[sujeto(['Patients', with, 'STSL', '(', 5, 'males,', 3, 'females,', 16, -, 56, years, of, 'age)', receiving, 'EZE', intervention, as, part, of, their, routine, care]), verbo([participated]), complemento([in, this, study])].
[sujeto(['EZE']), verbo([increased]), complemento(['PLT', count, '(', 23, '%', ±, 9, '%', ')', and, decreased, mean, 'PLT', volume, '(', 'MPV;', 10, '%', ±, 3, '%', ',', all, 'P', &, 'lt;'])].
[sujeto(['EZE', reduces, plasma, and, 'RBC', 'PS', 'levels,', while]), verbo([increasing]), complemento(['PLT', count, and, decreasing, 'MPV,', and, thereby, may, reduce, the, risk, for, bleeding, in, 'STSL'])].
[sujeto(['To']), verbo([provide]), complemento([an, update, on, recent, advances, made, in, our, mechanistic, and, pathophysiological, understanding, of, the, rare, human, disease, 'Sitosterolemia,', the, role, of, 'ABCG5/ABCG8', in, sterol, trafficking, and, how, newer, data, implicate, a, more, wider, role, in, the, body])].
[sujeto(['Sitosterolemia', is]), verbo([caused]), complemento([by, a, genetic, defect, of, sterolins, '(', 'ABCG5/ABCG8)', mapped, to, the, 'STSL', locus])].
[sujeto(['Polymorphic', variations, in, 'STSL']), verbo([have]), complemento([been, linked, to, lipid, levels, and, gallstone, disease, in, whites])].
[sujeto(['Although', the, '\'', 'promoter\'', region, of, the, 'STSL', is, 'minimal,', regulatory, regions, responsive, to, liver, 'X', receptor]), verbo([have]), complemento([remained, 'elusive,', but, no, 'longer;', two, intronic, regions, in, 'ABCG8', have, now, been, identified])].
[sujeto(['Xenosterol', accumulation]), verbo([leads]), complemento([to, loss, of, abdominal, 'fat,', 'infertility,', and, premature, death])].
[sujeto(['Xenosterol', accumulation, in, mouse, platelet, membranes]), verbo([leads]), complemento([to, platelet, 'hyperactivation,', increased, microparticle, 'formation,', and, reduced, αIIbβ3, surface, expression])].
[sujeto(['In', 'humans,', phytosterols, may]), verbo([promote]), complemento([liver, injury, in, parenteral, 'nutrition-associated', liver, disease])].
[sujeto(['Progress', in, understanding, sterolin, function, is, beginning, to, show, that, xenosterols, can, be, toxic, and, are]), verbo([involved]), complemento([on, 'pathogenesis,', and, the, role, of, 'ABCG5/ABCG8', may, extend, into, other, metabolic, processes, by, altering, intracellular, sterol, metabolism])].
[sujeto(['Sitosterolemia', '(', 'STSL)', is, a, rare, autosomal, recessive, 'disease,', manifested, by, extremely, elevated, plant, sterols, '(', 'PS)', in, plasma, and, 'tissue,']), verbo([leading]), complemento([to, xanthoma, and, premature, atherosclerotic, disease])].
[sujeto(['Therapeutic', approaches, include, limiting, 'PS', 'intake,', interrupting, enterohepatic, circulation, of, bile, acid, using, bile, acid]), verbo([binding]), complemento([resins, such, as, 'cholestyramine,', 'and/or', ileal, 'bypass,', and, inhibiting, intestinal, sterol, absorption, by, ezetimibe, '(', 'EZE)'])].
[sujeto(['Blocking', sterols, absorption, with, 'EZE']), verbo([has]), complemento([revolutionized, 'STSL', patient, treatment, as, it, reduces, circulating, levels, of, 'non-cholesterol', sterols, in, 'STSL'])].
[sujeto(['However,', none, of, the, available, treatments, including, 'EZE']), verbo([have]), complemento([normalized, plasma, 'PS', concentrations])].
[sujeto(['Sitosterolaemia', is, an, extremely, rare, autosomal, recessive, 'disease,', the, key, feature, of, which, is, the, impairment, of, pathways, that, normally]), verbo([prevent]), complemento([absorption, and, retention, of, 'non-cholesterol', 'sterols,', for, example, plant, sterols, and, shellfish, sterols])].
[sujeto(['The', 'gene(s)']), verbo([causing]), complemento([sitosterolaemia, was, mapped, to, the, 'STSL', locus, on, human, chromosome, 2, 'p21,', and, mutations, in, either, of, the, two, genes, that, comprise, this, 'locus,', 'ABCG5', or, 'ABCG8,', cause, this, disease])].
[sujeto(['This', rare, disease]), verbo([has]), complemento([shed, light, into, the, molecular, mechanisms, that, control, sterol, trafficking, in, the, enterocyte, and, 'hepatocyte;', 'ABCG5', and, 'ABCG8', heterodimerise, to, form, a, sterol, efflux, transporter, in, the, liver, and, intestine])].
[sujeto(['Two', 'genes,', 'ABCG5', and, 'ABCG8,', comprise, the, 'STSL', and, mutations, in, either]), verbo([cause]), complemento([sitosterolemia])].
[sujeto(['ABCG5', and, 'ABCG8', are, thought, to]), verbo([have]), complemento([evolved, by, gene, duplication, event, and, are, arranged, in, a, 'head-to-head', configuration])].
[sujeto(['We']), verbo([report]), complemento([here, a, detailed, characterization, of, the, 'STSL', in, 'Caucasian', and, 'African-American', cohorts])].
[sujeto(['Sitosterolemia', '(', 'MIM', 210250, ')', is, a, rare, genetic, disorder]), verbo([caused]), complemento([by, disruption, of, the, normal, mechanisms, that, regulate, dietary, cholesterol, absorption, and, prevent, the, accumulation, of, noncholesterol, sterols])].
[sujeto(['It', is, not, clear, which, 'organ,', liver, or, 'intestine,', is, of, greater, importance, in]), verbo([maintaining]), complemento([sterol, balance, with, respect, to, noncholesterol, sterols])].
[sujeto(['We']), verbo([report]), complemento([here, a, case, of, a, patient, who, presented, with, &, 'quot;chronic', active, liver, 'disease&quot;', and, was, found, to, have, sitosterolemia, by, chance, and, subsequently, underwent, orthotopic, liver, transplantation])].
[sujeto(['Following', 'transplantation,', the, grossly, elevated, pretransplantation, serum, plant, sterol, levels]), verbo([decreased]), complemento([to, values, only, slightly, higher, than, those, of, the, 'patient\'s', heterozygous, father])].
[sujeto(['This', case, highlights, 2, important, 'features:', '(', 1, ')', 'The', liver, functions, as, the, predominant, organ, for]), verbo([maintaining]), complemento([noncholesterol, sterol, balance, '(', because, the, intestinal, defect, was, not, 'altered),', and, '(', 2, ')', a, new, clinical, feature, of, undiagnosed, sitosterolemia, may, be, &, 'quot;idiopathic&quot;', liver, disease])].
[sujeto(['Sitosterolemia', is, a, recessively, inherited, disorder, in, humans, that, is]), verbo([associated]), complemento([with, premature, atherosclerotic, disease])].
[sujeto(['Mutations', in, 'ABCG5', or, 'ABCG8,', comprising, the, sitosterolemia, 'locus,', 'STSL,', are, now, known, to]), verbo([cause]), complemento([this, disease])].
[sujeto(['Three', 'in-bred', strains, of, 'rats,', 'WKY,', 'SHR', and, 'SHRSP,', are, known, to, be, 'sitosterolemic,', hypertensive, and, they, carry, a, missense, '\'', 'mutation\'', in, a]), verbo([conserved]), complemento([residue, of, 'Abcg5,', 'Gly583Cys'])].
[sujeto(['Additionally,', we, measured, 'tail-cuff', blood, pressure, and, measured, intestinal, lipid, transport, to, identify, possible, mechanisms, whereby, this, mutation]), verbo([causes]), complemento([sitosterolemia])].
[sujeto(['Tail-cuff', monitoring, of, blood, pressure, in, conscious, animals, showed, no, significant, differences, between, 'wild-type,', heterozygous, and, homozygous, mutant, 'F2', 'rats,']), verbo([suggesting]), complemento([that, this, alteration, may, not, be, a, significant, determinant, of, hypertension, in, these, rats, on, a, chow, diet])].
[sujeto(['A', defect, in, the, 'ABCG5', or, 'ABCG8', 'co-transporter', gene, locus, '(', 'STSL)']), verbo([causes]), complemento([an, increased, intestinal, absorption, and, a, decreased, biliary, elimination, of, all, 'sterols,', plant, sterols, as, well, as, 'cholesterol,', leading, to, a, 50, to, 200, -, fold, increase, in, plasma, plant, sterol, concentrations])].
[sujeto(['A', few, recent, publications, indicate, that, even, moderately, elevated, plasma, plant, sterol, levels, might, be]), verbo([associated]), complemento([with, an, increased, risk, of, atherosclerosis])].
[sujeto(['This', raises, the, question, whether, plant, sterols, themselves, might, be, atherogenic, or, whether, elevated, plasma, levels, are, a, marker, for, a]), verbo([decreased]), complemento(['ABCG5/G8', transporter, activity, which, itself, causes, an, increased, risk, for, atherosclerosis])].
[sujeto(['The', molecular, mechanisms, that]), verbo([regulate]), complemento([the, entry, of, dietary, sterols, into, the, body, and, their, removal, via, hepatobiliary, secretion, are, now, beginning, to, be, defined])].
[sujeto(['Mutations', in, 'either,', but, not, 'both,', of, two, genes, 'ABCG5', or, 'ABCG8,', comprising, the, 'STSL', 'locus,', are, now, known, to]), verbo([cause]), complemento([this, disease, and, their, protein, products, are, proposed, to, function, as, heterodimers])].
[sujeto(['Based', upon, the, defects, in, 'sitosterolemia,', 'ABCG5', and, 'ABCG8', serve, specifically, to, exclude, 'non-cholesterol', sterol, entry, at, the, intestinal, level, and, are]), verbo([involved]), complemento([in, sterol, excretion, at, the, hepatobiliary, level])].
[sujeto(['Here', we]), verbo([report]), complemento([the, biochemical, and, 'immuno-localization', of, 'ABCG5', and, 'ABCG8', in, human, 'liver,', gallbladder, and, intestine, using, cell, fractionation, and, immunohistochemical, analyses])].
[sujeto(['Using', human, liver, 'samples,', cell, fractionation, studies, showed, both, proteins, are]), verbo([found]), complemento([in, membrane, 'fractions,', but, they, did, not, 'co-localize', with, 'caveolin-rafts,', 'ER,', 'Golgi', or, mitochondrial, markers])].
[sujeto(['Immunohistochemical', analyses, showed, that, while, both, proteins, were, readily, detectable, in, the, 'liver,', 'ABCG5', was]), verbo([found]), complemento([predominately, lining, canalicular, 'membranes,', whereas, 'ABCG8', was, found, in, association, with, bile, duct, epithelia])].
[sujeto(['Using', standard, deglycosylation, 'methods,', 'ABCG5', and, 'ABCG8', do, not, appear, to, be, 'glycosylated,']), verbo([suggesting]), complemento([a, difference, between, human, and, mouse, proteins])].
[sujeto(['We']), verbo([report]), complemento([the, distribution, patterns, of, 'ABCG5', and, 'ABCG8', in, human, tissues])].
[sujeto(['Cell', fractionation, studies, showed, that, both, proteins, 'co-fractionated', in, 'general,', but, could, also, be]), verbo([found]), complemento([independent, of, each, other])].
[sujeto(['As', 'predicted,', they, are]), verbo([expressed]), complemento([apically, in, both, intestine, and, 'liver,', although, their, intracellular, expression, patterns, are, not, completely, congruent])].
[sujeto(['These', studies, support, the, concept, of, heterodimerization, of, 'ABCG5', and, 'ABCG8,', but, also, support, the, notion, that, these, proteins, may]), verbo([have]), complemento([an, independent, function])].
[sujeto(['Mutations', in, either, of, two, genes, comprising, the, 'STSL', 'locus,', 'ATP-binding', cassette, '(', 'ABC)-transporters', 'ABCG5', '(', encoding, 'sterolin-1)', and, 'ABCG8', '(', encoding, 'sterolin-2),', result, in, 'sitosterolemia,', a, rare, autosomal, recessive, disorder, of, sterol, trafficking, characterized, by]), verbo([increased]), complemento([plasma, plant, sterol, levels])].
[sujeto(['No', phenotypic, difference]), verbo([has]), complemento([yet, been, described, in, humans, with, complete, defects, in, either, 'ABCG5', or, 'ABCG8'])].
[sujeto(['These', 'proteins,', based, upon, the, defects, in, 'humans,', are, responsible, for]), verbo([regulating]), complemento([dietary, sterol, entry, and, biliary, sterol, secretion])].
[sujeto(['In', order, to, mimic, the, human, 'disease,', we, 'created,', by, a]), verbo([targeted]), complemento(['disruption,', a, mouse, model, of, sitosterolemia, resulting, in, 'Abcg8/sterolin-2', deficiency, alone])].
[sujeto(['Mice', deficient, in, 'Abcg8']), verbo([have]), complemento([significantly, increased, plasma, and, tissue, plant, sterol, levels, '(', sitosterol, and, 'campesterol)', consistent, with, sitosterolemia])].
[sujeto(['Interestingly,', 'Abcg5/sterolin-1', was]), verbo([expressed]), complemento([in, both, liver, and, intestine, in, 'Abcg8/sterolin-2', deficient, mice, and, continued, to, show, an, apical, expression])].
[sujeto(['Remarkably,', 'Abcg8', deficient, mice, had, an, impaired, ability, to, secrete, cholesterol, into, 'bile,', but, still]), verbo([maintained]), complemento([the, ability, to, secrete, sitosterol])].
[sujeto(['We', also]), verbo([report]), complemento([an, intermediate, phenotype, in, the, heterozygous, 'Abcg8+/-', mice, that, are, not, 'sitosterolemic,', but, have, a, decreased, level, of, biliary, sterol, secretion, relative, to, 'wild-type', mice])].
[sujeto(['These', data, indicate, that, 'Abcg8/sterolin-2', is, necessary, for, biliary, sterol, secretion, and, that]), verbo([loss]), complemento([of, 'Abcg8/sterolin-2', has, a, more, profound, effect, upon, biliary, cholesterol, secretion, than, sitosterol])].
[sujeto(['Since', biliary, sitosterol, secretion, is, 'preserved,', although, not, elevated, in, the, sitosterolemic, 'mice,', this, observation]), verbo([suggests]), complemento([that, mechanisms, other, than, by, 'Abcg8/sterolin-2', may, be, responsible, for, its, secretion, into, bile])].
[sujeto(['Elevated', plant, sterol, accumulation]), verbo([has]), complemento([been, reported, in, the, spontaneously, hypertensive, rat, '(', 'SHR),', the, 'stroke-prone', spontaneously, hypertensive, rat, '(', 'SHRSP)', and, the, 'Wistar-Kyoto', '(', 'WKY)', rat])].
[sujeto(['Additionally,', a, blood, pressure, quantitative, trait, locus, '(', 'QTL)']), verbo([has]), complemento([been, mapped, to, rat, chromosome, 6, in, a, 'New', 'Zealand', genetically, hypertensive, rat, strain, '(', 'GH', 'rat)'])].
[sujeto(['ABCG5', and, 'ABCG8', '(', encoding, 'sterolin-1', and, 'sterolin-2', 'respectively)']), verbo([have]), complemento([been, shown, to, be, responsible, for, causing, sitosterolemia, in, humans])].
[sujeto(['Both', 'Abcg5', and, 'Abcg8', were]), verbo([expressed]), complemento([only, in, liver, and, intestine])].
[sujeto(['GH', 'rat)', do, not]), verbo([have]), complemento([mutations, in, 'Abcg5', or, 'Abcg8'])].
[sujeto(['This', mutation, allows, for, expression, and, apparent, apical]), verbo([targeting]), complemento([of, 'Abcg5', protein, in, the, intestine])].
[sujeto(['These', rat, strains, may, therefore, allow, us, to, study, the, pathophysiological, mechanisms]), verbo([involved]), complemento([in, the, human, disease, of, sitosterolemia])].
[sujeto(['Patients', with, this, disease]), verbo([have]), complemento([expanded, body, pools, of, cholesterol, and, very, elevated, plasma, 'plant-sterol', species, and, frequently, develop, tendon, and, tuberous, 'xanthomas,', accelerated, 'atherosclerosis,', and, premature, coronary, artery, disease])].
[sujeto(['In', previous, 'studies,', we]), verbo([have]), complemento([mapped, the, 'STSL', locus, to, human, chromosome, 2, p21])].
[sujeto(['Recently,', we]), verbo([reported]), complemento([that, a, novel, member, of, the, 'ABC-transporter', 'family,', named, &, 'quot;sterolin-1&quot;', and, encoded, by, 'ABCG5,', is, mutated, in, 9, unrelated, families, with, 'sitosterolemia;', in, the, remaining, 25, 'families,', no, mutations, in, 'sterolin-1', could, be, identified])].
[sujeto(['Thus,', two, highly, homologous, 'genes,', located, in, a, 'head-to-head', configuration, on, chromosome, 2, 'p21,', are]), verbo([involved]), complemento([as, causes, of, sitosterolemia])].
[sujeto(['The', molecular, mechanisms]), verbo([regulating]), complemento([the, amount, of, dietary, cholesterol, retained, by, the, 'body,', as, well, as, the, 'body\'s', ability, to, exclude, other, dietary, sterols, 'selectively,', are, poorly, understood])].
[sujeto(['Approximately', 50, -, 60, '%', of, dietary, cholesterol, is, absorbed, and]), verbo([retained]), complemento([by, the, normal, human, 'body,', but, less, than, 1, '%', of, the, 'non-cholesterol', sterols, are, retained])].
[sujeto(['In', 'sitosterolemia,', a, rare, autosomal, recessive, 'disorder,', affected, individuals, hyperabsorb, and]), verbo([retain]), complemento([not, only, cholesterol, but, also, all, other, 'sterols,', including, plant, and, shellfish, sterols, from, the, intestine])].
[sujeto(['Consequently,', patients, with, this, disease]), verbo([have]), complemento([very, high, levels, of, plant, sterols, in, the, 'plasma,', and, develop, tendon, and, tuberous, 'xanthomas,', accelerated, 'atherosclerosis,', and, premature, coronary, artery, disease])].
[sujeto(['The', 'STSL', locus]), verbo([has]), complemento([been, mapped, to, human, chromosome, 2, p21])].
[sujeto(['The', identification, of, these, genes, should, now]), verbo([lead]), complemento([to, a, better, understanding, of, the, molecular, 'mechanism(s)', governing, the, highly, selective, absorption, and, retention, of, cholesterol, by, the, body])].
[sujeto(['Indeed,', it, is, the, very, existence, of, this, disease, that]), verbo([has]), complemento([given, credence, to, the, hypothesis, that, there, is, a, molecular, pathway, that, regulates, dietary, cholesterol, absorption, and, sterol, excretion, by, the, body])].
[sujeto(['The', molecular, mechanisms]), verbo([regulating]), complemento([the, amount, of, dietary, cholesterol, retained, in, the, 'body,', as, well, as, the, 'body\'s', ability, to, exclude, selectively, other, dietary, 'sterols,', are, poorly, understood])].
[sujeto(['About', 50, -, 60, '%', of, the, dietary, cholesterol, is, absorbed, and]), verbo([retained]), complemento([by, the, normal, human, 'body,', but, less, than, 1, '%', of, the, 'non-cholesterol', sterols, are, retained])].
[sujeto(['Consequently,', patients, with, this, disease]), verbo([have]), complemento([very, high, levels, of, plant, sterols, in, the, plasma, and, develop, tendon, and, tuberous, 'xanthomas,', accelerated, 'atherosclerosis,', and, premature, coronary, artery, disease])].
[sujeto(['We', now]), verbo([report]), complemento([that, a, new, member, of, the, 'ABC', transporter, 'family,', 'ABCG5,', is, mutant, in, nine, unrelated, sitosterolemia, patients])].
[sujeto(['Here', we, evaluate, the, effect, of, 'SERMs', on, the, 'macrophage-specific', reverse, cholesterol, transport, '(', 'M-RCT)', 'pathway,', which, is]), verbo([mediated]), complemento([by, 'HDL'])].
[sujeto(['Treatment', of, human, and, mouse, macrophages, with, 'tamoxifen,', raloxifene, or, toremifene]), verbo([induced]), complemento([the, accumulation, of, cytoplasmic, vesicles, of, 'acetyl-LDL-derived', free, cholesterol])].
[sujeto(['When', '[', '(', 3, ')', 'H]cholesterol-loaded', macrophages, were, injected, into, mice, 'intraperitoneally,', 'tamoxifen,', but, not, 'raloxifene,']), verbo([decreased]), complemento([the, '[', '(', 3, ')', 'H]cholesterol', levels, in, 'serum,', liver, and, feces])].
[sujeto(['Both', 'SERMs', downregulated, liver, 'ABCG5', and, 'ABCG8', protein, 'expression,', but, tamoxifen, reduced, the, capacity, of, 'HDL', and, plasma, to]), verbo([promote]), complemento([macrophage, cholesterol, efflux, to, a, greater, extent, than, raloxifene])].
[sujeto(['This', effect, is, primarily, attributable, to, the, 'tamoxifen-mediated', reduction, of, the, capacity, of, 'HDL', to]), verbo([promote]), complemento([cholesterol, mobilization, from, macrophages])].
[sujeto(['However,', strains, of, 'Ganoderma', lucidum, of, 'Mexican', origin]), verbo([have]), complemento([not, yet, been, studied])].
[sujeto(['Acetylsalicylic', acid, '(', 10, 'mM)', added, to, the, cultivation, substrate]), verbo([modulated]), complemento([properties, of, 'Gl', extracts, obtained, from, mature, basidiomata])].
[sujeto(['These', effects, were]), verbo([associated]), complemento([with, a, significant, reduction, in, the, expression, of, lipogenic, genes, '(', 'Hmgcr,', 'Srebp1c,', 'Fasn,', and, 'Acaca)', and, genes, involved, in, reverse, cholesterol, transport, '(', 'Abcg5', and, 'Abcg8),', as, well, as, an, increase, in, 'Ldlr', gene, expression, in, the, liver])].
[sujeto(['A', proposed, mechanism, of, action, for, the, reduction, in, cholesterol, levels, is]), verbo([mediated]), complemento([by, 'α-glucans', and, 'β-glucans', from, 'Gl,', which, promoted, decreased, absorption, of, cholesterol, in, the, 'gut,', as, well, as, greater, excretion, of, fecal, bile, acids, and, cholesterol])].
[sujeto(['The', prebiotic, effects, of, 'Gl-1', and, 'Gl-2', extracts]), verbo([modulated]), complemento([the, composition, of, gut, microbiota, and, produced, an, increase, in, the, 'Lactobacillaceae', family, and, 'Lactobacillus', genus, level, compared, to, the, control, 'group,', 'high-cholesterol', diet, group, and, group, supplemented, with, simvastatin])].
[sujeto(['Sitosterolemia', is, a, very, rare, autosomal, recessive, lipoprotein, metabolic, disorder]), verbo([caused]), complemento([by, homozygous, or, compound, heterozygous, mutations, in, one, of, the, two, adenosine, 'triphosphate-binding', cassette, transporter, 'genes,', 'ABCG5', and, 'ABCG8'])].
[sujeto(['Diagnosis', of, sitosterolemia, was, confirmed, by, 'DNA', sequencing, showing, compound, heterozygosity, for, previously]), verbo([reported]), complemento([missense, mutations, in, exon, 9, of, 'ABCG5'])].
[sujeto(['Inherited', macrothrombocytopenia, represents, a, heterogeneous, group, of, disorders, which, are, characterized, by, the, presence, of, a, reduced, number, of, abnormally, large, platelets, in, the, 'circulation,', which, may, or, may, not, be]), verbo([associated]), complemento([with, a, bleeding, tendency])].
[sujeto(['Agonist']), verbo([induced]), complemento([platelet, aggregation, and, platelet, 'GP1b/IX/V', receptor, expression, were, investigated, to, assess, 'GP1b/IX/V', receptor, expression, and, the, 'GP1BA,', 'GP1BB,', 'GP9,', 'ABCG5,', 'ABCG8,', 'TUBB1', and, 'MYH9', genes, were, analysed, to, identify, candidate, gene, defects])].
[sujeto(['This', study]), verbo([increases]), complemento([the, understanding, of, the, molecular, basis, of, an, isolated, giant, platelet, 'disorder,', a, common, heterogeneous, condition, prevalent, in, north, and, eastern, 'India'])].
[sujeto(['The', reconstructed, ratios, of, six, mdr1a, substrates, '(', 'dexamethasone,', 'digoxin,', 'loperamide,', 'quinidine,', 'verapamil,', 'vinblastine)', and, one, nonsubstrate, '(', 'diazepam)', were, consistent, with, the, observed, values]), verbo([reported]), complemento([by, 'Adachi', et, al])].
[sujeto(['Sixteen', '(', 'mdr1a,', 'mrp4,', 'bcrp,', 'abcg5,', 'abcg8,', 'glut1,', 4, 'f2hc,', 'sglt1,', 'lat2,', 'pept1,', 'mct1,', 'slc22a18,', 'ostβ,', 'villin1,', 'Na(+)/K(+)-ATPase,', 'γ-gtp)', out, of, 46]), verbo([target]), complemento([molecules, were, detected, by, employing, our, established, quantitative, targeted, absolute, proteomics, technique])].
[sujeto(['The', protein, expression, amounts, of, mdr1a, and, bcrp]), verbo([increased]), complemento([progressively, from, duodenum, to, ileum])].
[sujeto(['Sglt1,', 'lat2,', and, 4, f2hc, were, highly]), verbo([expressed]), complemento([in, jejunum, and, ileum])].
[sujeto(['Mct1', and, ostβ, were, highly]), verbo([expressed]), complemento([in, ileum])].
[sujeto(['ATP']), verbo([binding]), complemento([cassette, '(', 'ABC)', transporters, play, critical, roles, in, maintaining, sterol, balance, in, higher, eukaryotes])].
[sujeto(['The', 'ABCG5/ABCG8', heterodimer, '(', 'G5G8)']), verbo([mediates]), complemento([excretion, of, neutral, sterols, in, liver, and, intestines])].
[sujeto(['Mutations', disrupting, 'G5G8']), verbo([cause]), complemento(['sitosterolaemia,', a, disorder, characterized, by, sterol, accumulation, and, premature, atherosclerosis])].
[sujeto(['The', structure]), verbo([reveals]), complemento([a, new, transmembrane, fold, that, is, present, in, a, large, and, functionally, diverse, superfamily, of, 'ABC', transporters])].
[sujeto(['The', 'G5G8', structure]), verbo([provides]), complemento([a, mechanistic, framework, for, understanding, sterol, transport, and, the, disruptive, effects, of, mutations, causing, sitosterolaemia])].
[sujeto(['Sitosterolemia', is, an, autosomal, recessive, disorder, characterized, by]), verbo([increased]), complemento([plant, sterol, 'levels,', 'xanthomas,', and, accelerated, atherosclerosis])].
[sujeto(['Although', it, was, originally]), verbo([reported]), complemento([in, patients, with, normolipemic, 'xanthomas,', severe, hypercholesterolemia, have, been, reported, in, patients, with, 'sitosterolemia,', especially, in, children])].
[sujeto(['Sitosterolemia', is]), verbo([caused]), complemento([by, increased, intestinal, absorption, and, decreased, biliary, excretion, of, sterols, resulting, from, biallelic, mutations, in, either, 'ABCG5', or, 'ABCG8,', which, encode, the, sterol, efflux, transporter, 'ABCG5', and, 'ABCG8'])].
[sujeto(['Patients', with, sitosterolemia, show, extreme, phenotypic, 'heterogeneity,', ranging, from, almost, asymptomatic, individuals, to, those, with, severe, hypercholesterolemia]), verbo([leading]), complemento([to, accelerated, atherosclerosis, and, premature, cardiac, death])].
[sujeto(['Because', prognosis, can, be, improved, by, proper, 'management,', it, is, important, to]), verbo([find]), complemento([these, patients, out, and, diagnose, correctly])].
[sujeto(['This', review, article, aimed, to, summarize, recent, publications, on, 'sitosterolemia,', and, to]), verbo([suggest]), complemento([clinical, indications, for, plant, sterol, assay])].
[sujeto(['The', adenosine, 'triphosphate-binding', cassette, '(', 'ABC)', sterol, 'transporter,', 'Abcg5/g8,', is, 'Lith9', in, 'mice,', and, two, 'gallstone-associated', variants, in, 'ABCG5/G8']), verbo([have]), complemento([been, identified, in, humans])].
[sujeto(['We', hypothesize, that, in, the, defect, of, 'ABCG5/G8,', an, 'ABCG5/G8-independent', pathway, is, essential, for]), verbo([regulating]), complemento([hepatic, secretion, of, biliary, 'sterols,', which, is, independent, of, the, lithogenic, mechanism, of, the, 'ABCG5/G8', pathway])].
[sujeto(['We']), verbo([found]), complemento([that, 'ABCG5(-/-)/G8(-/-)', and, 'ABCG8', '(', -, /, -, ')', mice, displayed, the, same, biliary, and, gallstone, phenotypes])].
[sujeto(['The', 'LXR', agonist, significantly]), verbo([increased]), complemento([biliary, cholesterol, secretion, and, gallstones, in, 'WT,', but, not, 'ABCG5(-/-)/G8(-/-)', or, 'ABCG8', '(', -, /, -, ')', ',', mice])].
[sujeto(['The', 'ABCG5/G8-independent', pathway, plays, an, important, role, in]), verbo([regulating]), complemento([biliary, cholesterol, 'secretion,', the, transport, of, 'HDL-derived', cholesterol, from, plasma, to, 'bile,', and, gallstone, 'formation,', which, works, independently, of, the, 'ABCG5/G8', pathway])].
[sujeto(['Affected', individuals]), verbo([have]), complemento([mutations, in, both, alleles, of, either, 'ABCG5', or, 'ABCG8', 'genes,', leading, to, a, total, loss, of, one, of, the, proteins, and, subsequent, functional, deficiency])].
[sujeto(['We', here]), verbo([report]), complemento([a, 'Mexican', family, with, clinical, and, biochemical, features, of, sitosterolemia, carrying, 2, new, mutations, of, the, 'ABCG5', gene])].
[sujeto(['Concentrations', of, 'sitosterol,', 'campesterol,', and, cholesterol, were]), verbo([found]), complemento([to, be, higher, for, the, index, case, '(', a, 10, -, 'year-old', 'girl)', than, for, her, also, affected, sibling, '(', 64.1, vs, 19, 'mg/dL,', 32, vs, 12.1, 'mg/dL,', and, cholesterol, 295, vs, 235, 'mg/dL,', 'respectively)'])].
[sujeto([1523, 'delC,', which, occurred, in, exon, 11, ',']), verbo([causing]), complemento([an, amino, acid, change, at, codon, 510, '(', p])].
[sujeto(['In', 'conclusion,', we, here]), verbo([report]), complemento([the, first, case, of, a, 'Mexican', family, with, sitosterolemia, carrying, two, new, 'ABCG5', gene, mutations])].
[sujeto(['Emerging', evidence]), verbo([suggested]), complemento([phytosterol, esters, '(', 'PE)', exhibited, an, advantage, over, naturally, occurring, phytosterols, in, reducing, atherosclerosis, risk, factors, due, to, improved, fat, solubility, and, compatibility])].
[sujeto(['ALA-PE', 'dose-dependently', lowered, plasma, total, cholesterol, '(', 'TC),', triglyceride, '(', 'TG)', and, 'low-density', lipoprotein, cholesterol, '(', 'LDL-C)', concentrations, with, a, maximal]), verbo([decrease]), complemento([of, 42, '%', ',', 59, '%', and, 73, '%', ',', respectively, '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['The', contents, of, hepatic, 'α-linolenic', '(', 'ALA),', docosapentaenoic, '(', 'DPA)', and, docosahexaenoic, '(', 'DHA)', acids, were, 'dose-dependently']), verbo([increased]), complemento([in, different, 'ALA-PE', groups, compared, to, those, in, 'HFD', group])].
[sujeto(['ALA-PE', 'dose-dependently', improved, lipid, profile, in, hamsters, fed, 'HFD', independent, of, intestinal, 'ABCG5,', 'ABCG8', and, 'NPC1L1,', accompanying, by]), verbo([increased]), complemento([conversion, of, 'ALA', to, 'DPA', and, 'DHA', in, liver])].
[sujeto(['This', study, was, to]), verbo([gain]), complemento([further, understanding, of, the, potential, mechanisms, of, the, protective, effects, of, fish, oil, against, 'NAFLD'])].
[sujeto(['Fish', oil, consumption, also, corrected, the, expression, levels, of, genes]), verbo([involved]), complemento([in, fatty, acid, and, cholesterol, 'metabolism,', such, as, 'Srebf1,', 'Fasn,', 'Scd1,', 'Insig2,', 'Cd36,', 'Cyp7a1,', 'Abcg5,', 'Abcg8', and, 'Pcsk9'])].
[sujeto(['Genetic', variation, in, 'NPC1L1']), verbo([has]), complemento([been, widely, studied, in, recent, years])].
[sujeto(['Our', study]), verbo([suggests]), complemento([that, the, 'G', allele, of, the, 'NPC1L1', polymorphism, 'g1679C&gt;G', may, be, a, positive, marker, of, gallstone, formation, risk])].
[sujeto(['Recent', evidence]), verbo([suggests]), complemento([that, the, essential, amino, acid, leucine, may, be, involved, in, systemic, cholesterol, metabolism])].
[sujeto(['Leucine', supplementation, resulted, in, 57.6, '%', reduction, of, aortic, atherosclerotic, lesion, area, in, apoE, null, 'mice,', accompanied, by, 41.2, '%']), verbo([decrease]), complemento([of, serum, 'LDL-C', levels, and, 40.2, '%', increase, of, serum, 'HDL-C', levels])].
[sujeto(['Furthermore,', leucine, supplementation]), verbo([increased]), complemento([the, expression, of, 'Abcg5', and, 'Abcg8', '(', that, were, involved, in, hepatic, cholesterol, 'efflux)', by, 1.28, -, and, 0.86, -, 'fold,', 'respectively,', and, significantly, increased, their, protein, levels])].
[sujeto(['Leucine', supplementation, also]), verbo([increased]), complemento([the, expression, of, 'Srebf1,', 'Scd1', and, 'Pgc1b', '(', that, were, involved, in, hepatic, triglyceride, 'metabolism)', by, 3.73, -, ',', 1.35, -, and, 1.71, -, 'fold,', respectively])].
[sujeto(['Consequently,', leucine, supplementation, resulted, in, 51.77, '%', reduction, of, liver, cholesterol, content, and, 2.2, -, fold]), verbo([increase]), complemento([of, liver, triglyceride, content])].
[sujeto(['Additionally,', leucine, supplementation, did, not, affect, the, serum, levels, of, 'IL-6,', 'IFN-γ,', 'TNF-α,', 'IL-10', and, 'IL-12,', but, markedly]), verbo([decreased]), complemento([the, serum, level, of, 'MCP-1'])].
[sujeto(['Niemann-Pick', 'C1-like', 1, '(', 'NPC1L1),', 'ATP-binding', cassette, '(', 'ABC)G5,', and, 'ABCG8']), verbo([mediate]), complemento([intestinal, cholesterol, absorption])].
[sujeto(['Significant']), verbo([decreases]), complemento([in, 'NPC1L1,', 'ABCG5,', and, 'ABCG8', mRNA, expression, were, observed, in, the, 'duodenum,', but, not, jejunum, and, 'ileum,', of, mice, 24, h, after, treatment, with, 'PR,', but, not, 'EZ'])].
[sujeto(['In', 'HepG2', 'cells,', 'PR', but, not, 'EZ', treatment, for, 24, h, also, significantly]), verbo([decreased]), complemento(['NPC1L1', protein, and, 'ABCG5,', and, 'ABCG8', mRNA, 'expression,', while, increasing, 'LXRa', mRNA, levels])].
[sujeto(['PR-induced']), verbo([increases]), complemento([in, 'LXRa', mRNA, levels, may, be, involved, in, attenuation, of, 'NPC1L1', 'expression,', subsequently, decreasing, intestinal, cholesterol, absorption])].
[sujeto(['ASE', reduced, body, weight, 'gain,', food, 'intake,', glucose, 'levels,', accumulation, of, cholesterol, and, 'TG', in, the, 'liver,', which, was]), verbo([associated]), complemento([with, a, reduction, of, hepatic, steatosis])].
[sujeto(['The']), verbo([increased]), complemento([expressions, of, 'SREBP-1c', and, 'HMG-CoA', reductase, and, reduced, expressions, of, pAMPK, and, 'pACC/ACC', in, 'HF', group, were, antagonized, by, 'ASE'])].
[sujeto(['The', 'ABCG5', and, 'ABCG8', transporters, expressions, were]), verbo([increased]), complemento([by, the, extract])].
[sujeto(['The', antioxidant, effect, of, 'ASE', was, demonstrated, in, liver, of, 'HF', mice, by, restoration, of, 'SOD,', 'CAT', and, 'GPx', activities, and, reduction, of, the]), verbo([increased]), complemento([levels, of, malondialdehyde, and, protein, carbonylation])].
[sujeto(['In', 'conclusion,', 'ASE', substantially, reduced, the, obesity, and, hepatic, steatosis]), verbo([induced]), complemento([by, 'HF', diet, by, reducing, 'lipogenesis,', increasing, cholesterol, excretion, and, improving, oxidative, stress, in, the, 'liver,', providing, a, nutritional, resource, for, prevention, of, 'obesity-related', adiposity, and, hepatic, steatosis])].
[sujeto(['As', compared, to, the, 'HFLD', fed, 'mice,', despite, the, similar, final, body, 'weights,', 'HCLD', 'feeding:', '(', 1, ')']), verbo([induced]), complemento([more, severe, hepatic, 'steatosis;', '(', 2, ')', 'up-regulated', hepatic, expression, of, 'miR-34a', accompanied, with, significant, decrease, of, 'SIRT1', and, nicotinamide, phosphoribosyltransferase, '(', 'NAMPT),', 'SIRT1', activity, and, phosphorylation, of, 'AMPK;', '(', 3, ')', 'up-regulated', de, novo, lipogenesis, '(', 'DNL)', related, proteins, expression, '(', 'ACC,', 'SCD1),', and, 'down-regulated', expressions, of, 'miR-122,', 'miR-370', and, 'miR-33;', '(', 4, ')', decreased, mRNA, expressions, of, genes, 'Cpt1,', 'Pparα', and, 'Pgc1α', related, to, fatty, acid, 'oxidation;', '(', 5, ')', increased, hepatic, total, cholesterol, concentration, and, decreased, expression, of, cholesterol, metabolism, related, genes, 'Abcg5,', 'Abcg8,', 'Abcg11,', 'Cyp7a1', and, 'Cyp8b1;', and, '(', 6, ')', induced, higher, hepatic, inflammatory, response, accompanied, with, significant, increased, mRNA, expressions, of, 'Il1β,', 'Tnfα', and, 'Mcp1'])].
[sujeto(['Thus,', isocaloric, 'HCLD', feeding]), verbo([induced]), complemento([greater, severity, in, hepatic, steatosis, and, inflammatory, response, than, 'HFLD', 'feeding,', potentially, through, 'miR-34a/SIRT1', axis, mediated, promotion, of, 'DNL,', inhibition, of, fatty, acid, oxidation, and, cholesterol, metabolism])].
[sujeto(['In', 'Abcg8', 'knockouts,', biliary, cholesterol, secretion, was]), verbo([decreased]), complemento([by, 75, '%', '(', 'p&nbsp;&lt;&nbsp;0'])].
[sujeto(['Hepatic', reinstitution, of, 'Abcg8']), verbo([increased]), complemento([biliary, cholesterol, secretion, 5, -, fold, '(', 'p&nbsp;&lt;&nbsp;0'])].
[sujeto(['ABCG5/G8']), verbo([mediate]), complemento([mass, biliary, cholesterol, secretion, but, not, from, a, 'RCT-relevant', pool])].
[sujeto(['Intervention', strategies, aiming, at]), verbo([increasing]), complemento([hepatic, 'Abcg5/g8', expression, for, enhancing, 'RCT', are, not, likely, to, be, successful])].
[sujeto(['Mice', lacking, leptin, '(', 'ob/ob)', or, its, receptor, '(', 'db/db)', are, 'obese,', insulin, 'resistant,', and]), verbo([have]), complemento([reduced, levels, of, biliary, cholesterol, 'due,', in, 'part,', to, reduced, levels, of, hepatic, 'G5G8'])].
[sujeto(['Chronic', leptin, replacement, restores, 'G5G8', abundance, and]), verbo([increases]), complemento([biliary, cholesterol, 'concentrations,', but, the, molecular, mechanisms, responsible, for, 'G5G8', regulation, remain, unclear])].
[sujeto(['Alternatively,', 'G5G8', may, be]), verbo([decreased]), complemento([in, 'ob/ob', and, 'db/db', mice, due, to, 'ER', 'dysfunction,', the, site, of, 'G5G8', complex, assembly])].
[sujeto(['Both', 'G5', and, 'G8', protein, levels]), verbo([increased]), complemento([as, did, total, biliary, 'cholesterol,', but, in, the, absence, of, changes, in, 'G5', or, 'G8', mRNAs])].
[sujeto(['The']), verbo([increase]), complemento([in, 'G5G8', was, associated, with, increases, in, a, number, of, 'proteins,', including, the, 'ER', lectin, 'chaperone,', 'calnexin,', a, key, regulator, of, 'G5G8', complex, assembly])].
[sujeto(['Leptin', signaling, does, not, directly]), verbo([regulate]), complemento(['G5G8', abundance])].
[sujeto(['The']), verbo([loss]), complemento([of, 'G5G8', in, mice, harboring, defects, in, the, leptin, axis, is, likely, associated, with, compromised, 'ER', function])].
[sujeto(['The', formation, of, cholesterol, gallstones]), verbo([involves]), complemento([very, complex, 'imbalances,', such, as, alterations, in, the, secretion, of, biliary, lipids, '(', which, involves, the, 'ABCG5,', 'ABCG8,', 'ABCB4', and, 'ABCB11', 'transporters),', biochemical, and, immunological, reactions, in, the, gallbladder, that, produce, biliary, sludge, '(', 'mucins),', physicochemical, changes, in, the, structure, of, cholesterol, '(', 'crystallization),', alterations, in, gallbladder, 'motility,', changes, in, the, intestinal, absorption, of, cholesterol, '(', 'ABCG5/8', transporters, and, 'Niemann-Pick', 'C1L1', 'protein)', and, alterations, in, small, intestine, motility])].
[sujeto(['Some', of, these, proteins]), verbo([have]), complemento([been, studied, at, the, clinical, and, experimental, 'levels,', but, more, research, is, required])].
[sujeto(['In', this, 'review,', we, discuss, the, results, of, studies, on, some, molecules]), verbo([involved]), complemento([in, the, pathophysiology, of, gallstones, that, may, be, future, therapeutic, targets, to, prevent, the, development, of, this, 'disease,', and, possible, sites, for, treatment, based, mainly, on, the, absorption, of, intestinal, cholesterol, '(', 'Niemann-Pick', 'C1L1', and, 'ABCG5/8', 'proteins)'])].
[sujeto(['It']), verbo([has]), complemento([two, transmembrane, domains, '(', 'TMDs)', comprising, of, six, transmembrane, helices, '(', 'TMH)', that, envisage, and, confer, the, substrate, specificity, and, two, nucleotide, binding, domains, '(', 'NBDs),', interconnected, by, extracellular, loops, '(', 'ECLs)', and, intracellular, loops, '(', 'ICLs)', 'Cdr1p'])].
[sujeto(['The', localization, of, 'substrate-susceptible', mutants, in, an, 'ABCG5/G8', homology, model, highlights, the, common, and, specific]), verbo([binding]), complemento([pockets, inside, the, membrane, 'domain,', where, rhodamines, and, tetrazoliums, mainly, engage, the, 'N-moiety', of, 'Cdr1p,', binding, between, 'TMH', 2, ',', 11, and, surrounded, by, 'TMH', 1, ',', 5])].
[sujeto(['Whereas,', tin, chlorides]), verbo([involve]), complemento([both, 'N', and, 'C', moieties, located, at, the, interface, of, 'TMH', 2, ',', 11, ',', 1, and, 5])].
[sujeto(['In', silico, localization]), verbo([reveals]), complemento([a, binding, site, at, the, 'TMH', 12, ',', 9, and, 10, 'interface,', which, is, widely, exposed, to, the, lipid, interface])].
[sujeto(['Together,', for, the, first, 'time,', our, study, shows, the, molecular, localization, of, 'Cdr1p', 'substrates-binding', sites, and, demonstrates, the, participation, of, 'TMH12', in, a, peripheral, drug]), verbo([binding]), complemento([site])].
[sujeto(['Intestinal', absorption, of, dietary, lipids]), verbo([involves]), complemento([their, hydrolysis, in, the, lumen, of, proximal, intestine, as, well, as, 'uptake,', intracellular, transport, and, 're-assembly', of, hydrolyzed, lipids, in, 'enterocytes,', leading, to, the, formation, and, secretion, of, the, lipoproteins, chylomicrons, and, 'HDL'])].
[sujeto(['We', isolated, three, populations, of, 'CLD', '(', ranging, from, 15, to, 1000, &, 'nbsp;nm)', which, showed, differential, expression, of, the, major, lipid, transporters, scavenger, receptor, 'BI', '(', 'SR-BI),', cluster, of, differentiation, 36, '(', 'CD-36),', 'Niemann', 'Pick', 'C-like', 1, '(', 'NPC1L1),', and, the, 'ATP-binding', cassette, transporters, 'ABCG5/G8', but, also, caveolin, 2, and, fatty, acid]), verbo([binding]), complemento([proteins])].
[sujeto(['The', enzyme, monoacylglycerol, acyltransferase, 2, '(', 'MGAT2)', was, identified, in, the, brush, border, membrane, '(', 'BBM)', in, addition, to, the, endoplasmic, 'reticulum,']), verbo([suggesting]), complemento([local, synthesis, of, triglycerides, and, 'CLD', at, both, places])].
[sujeto(['We', show, a, very, fast, production, of, 'CLD', by, enterocytes]), verbo([associated]), complemento([with, a, transfer, of, apical, constituents, as, lipid, transporters])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, following, their, uptake, by, 'enterocytes,', lipids, can, be, partially, metabolized, at, the, 'BBM', and, packaged, into, 'CLD', for, their, transportation, to, the, 'ER'])].
[sujeto(['In', atherosclerosis, 'patients,', plasma, levels, of, 'N-acetylneuraminic', acid, '(', 'NANA)', are, 'increased;', 'however,', the, underlying, mechanisms]), verbo([have]), complemento([not, yet, been, clarified])].
[sujeto(['We', assume, the]), verbo([increased]), complemento(['NANA', level, may, be, a, compensatory, mechanism, due, to, oxidative, stress, 'and/or', inflammation])].
[sujeto([1, ')', 'NANA', administration]), verbo([decreased]), complemento([18.9, '%', of, the, atherosclerotic, plaque, formation, in, the, aorta, and, 26.7, '%', of, the, lipid, deposition, in, the, liver, of, 'high-fat', diet, 'apoE(-/-)', 'mice;', 2, ')', 'notably,', 'NANA', treatment, reduced, 62.6, '%', of, the, triglyceride, by, improving, lipoprotein, lipase, 'activity;', 3, ')', 'NANA', lowered, 17.5, '%', of, the, plasma, total, cholesterol, by, 'up-regulating', reverse, cholesterol, transport, '(', 'RCT)-related', protein, expression, such, as, 'ATP-binding', cassette, transporter, '(', 'ABC)', 'G1', and, 'ABCG5', in, liver, or, small, 'intestine;', 4, ')', 'NANA', administration, notably, decreased, oxidative, stress, by, increasing, antioxidant, enzymes, activity, and, protein, expression, of, paraoxonase, 1, and, 2, ;, 5, ')', 'NANA', markedly, reduced, tumour, necrosis, 'factor-α', and, intercellular, adhesion, 'molecule-1', expression, in, aorta, and, liver])].
[sujeto(['NANA', exhibited, triglyceride, 'lowering,', 'anti-oxidation,', and, 'RCT']), verbo([promoting]), complemento(['activities,', and, therefore, 'NANA', supplementation, may, be, a, new, strategy, for, prevention, and, treatment, of, atherosclerosis])].
[sujeto(['Although', they, are]), verbo([reported]), complemento([to, be, associated, with, metabolic, 'disorders,', the, underlying, mechanism, is, unclear])].
[sujeto(['Differences', of, gene, expression]), verbo([involved]), complemento([in, hepatic, lipid, metabolism, and, hepatic, lipids, content, were, compared, in, liver, biopsies, between, groups, with, high, and, low, level, of, 'OCPs'])].
[sujeto(['Furthermore,', higher, 'OCPs', in, adipose, tissue]), verbo([led]), complemento([to, increase, in, the, expression, of, hepatic, cholesterol, transporters, 'ABCG5', and, 'G8', '(', +, 34, '%', and, +, 27, '%', ',', 'P&lt;', 0.01, ')', and, higher, cholesterol, saturation, index, in, gallbladder, 'bile,', and, induced, hepatic, fatty, acids, 'synthesis,', which, was, further, confirmed, in, 'HepG2', cells])].
[sujeto(['OCPs', might]), verbo([enhance]), complemento([hepatic, secretion, of, cholesterol, into, bile, via, 'ABCG5/G8', which, promoting, gallstone, disease, as, well, as, lipogenesis])].
[sujeto(['Whole', exome, sequencing, '(', 'WES)', technologies]), verbo([have]), complemento([accelerated, genetic, studies, of, 'Mendelian', 'disorders,', yielding, approximately, 30, '%', diagnostic, success])].
[sujeto(['Among', 206, ',', 430, variants]), verbo([found]), complemento([in, this, 'individual,', we, found, 18, ',', 220, 'nonsense,', 'missense,', or, splice, site, 'variants,', of, which, 3, ',', 87, were, rare, '(', minor, allele, frequency, '≤', 0.01, or, not, 'reported)', in, 1000, 'Genome', '(', 'Asian', 'population)'])].
[sujeto(['Mushrooms', typically]), verbo([act]), complemento([as, 'lipid-lowering', 'agents;', 'however,', little, is, known, about, the, mechanisms, of, action, of, 'A'])].
[sujeto(['This', study, aimed, to, determine, the, underlying, mechanism]), verbo([involved]), complemento([in, the, 'cholesterol-lowering', effect, of, 'A'])].
[sujeto([brasiliensis, through, the, assessment, of, fecal, and, serum, lipid, profiles, in, addition, to, gene, expression, analysis, of, specific, transcription, 'factors,', 'enzymes,', and, transporters]), verbo([involved]), complemento([in, cholesterol, homeostasis])].
[sujeto([brasiliensis, dietary, supplementation, markedly]), verbo([promoted]), complemento([fecal, cholesterol, excretion])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, consumption, of, 'A'])].
[sujeto([brasiliensis, improves, the, serum, lipid, profile, in, hypercholesterolemic, rats, by]), verbo([modulating]), complemento([the, expression, of, key, genes, involved, in, hepatic, cholesterol, metabolism])].
[sujeto(['It', could, be, shown, that, 'oxyphytosterols,']), verbo([found]), complemento([in, atherosclerotic, 'tissue,', are, most, likely, of, in, situ, oxidation, '(', 'Schött', et, al])].
[sujeto(['Here,', we]), verbo([provide]), complemento([further, information, about, the, oxidation, of, sitosterol, and, the, transport, of, its, oxidation, products, out, of, tissue])].
[sujeto(['This']), verbo([finding]), complemento([indicates, that, sitosterol, is, oxidized, to, a, higher, amount, than, campesterol, and, that, a, selective, oxidative, mechanism, might, exist, which, can, differentiate, between, certain, phytosterols])].
[sujeto(['Secondly,', the, concentrations, of, oxyphytosterols]), verbo([found]), complemento([in, plasma, and, tissue, support, the, idea, that, oxysitosterols, are, preferably, transported, out, of, individual, tissues])].
[sujeto(['Hypercholesterolaemia', is, a, risk, factor, for, 'CVD,', which, is, a]), verbo([leading]), complemento([cause, of, death, in, industrialised, societies])].
[sujeto(['The', present, study, aimed, to]), verbo([gain]), complemento([more, comprehensive, understanding, of, the, relationship, between, circulating, cholesterol, levels, and, molecular, effects, in, target, tissues, using, the, hamster, model])].
[sujeto(['The', 'high-fat', diet]), verbo([increased]), complemento([circulating, cholesterol, and, 'down-regulated', 'CYP51,', but, not, 'HMG-CoA', reductase])].
[sujeto(['The', 'CA', diet]), verbo([decreased]), complemento([cholesterol, and, increased, 'CYP51', 'expression,', but, 'HMG-CoA', reductase, expression, was, not, affected])].
[sujeto(['Correlation', analysis, also, showed, that, circulating, cholesterol, levels, were]), verbo([regulated]), complemento([by, 'LXR/retinoid', 'X', receptor, and, 'PPAR', pathways, in, the, liver])].
[sujeto(['Using', the, hamster, 'model,', the, present, study]), verbo([provided]), complemento([additional, molecular, insights, into, the, influence, of, circulating, cholesterol, on, hepatic, cholesterol, metabolism, pathways, during, hypercholesterolaemia])].
[sujeto(['Dairy', intake]), verbo([has]), complemento([been, associated, with, varying, impacts, on, circulating, cholesterol, concentrations, across, nutritional, epidemiology, and, intervention, 'studies,', with, findings, attributed, mainly, to, differences, in, the, nature, of, dairy, products, consumed, or, study, designs])].
[sujeto(['The', contribution, of, the, genomic, architecture, to, such, observations]), verbo([has]), complemento([yet, to, be, revealed])].
[sujeto(['In', a, 'multicenter,', randomized, crossover, 'design,', 101, normolipidemic, adults, '(', n, =, 29, men, and, 72, 'women),', with, a, mean, ±, 'SD', age, of, 41.7, ±, 16.7, y, and, a, body, mass, index, '(', 'BMI,', in, 'kg/m(2))', of, 25.9, ±, 4.3, consumed, 3, 'servings/d', of, dairy, '[', 375, mL, 1, '%', 'milk-fat', '(', 'MF)', 'milk,', 175, g, 1.5, '%', 'MF', 'yogurt,', and, 30, g, of, 34, '%', 'MF', 'cheese]', or, 'energy-matched', control, products, '(', 'juice,', 'cashews,', and, 'cookies)']), verbo([provided]), complemento([within, a, prudent, background, diet, for, 4, wk, 'each,', separated, by, a, 4, -, to, 8, -, wk, washout, period])].
[sujeto(['The', responsiveness, of, serum, total, cholesterol, '(', 'TC)', and, 'LDL', cholesterol, to, the, dairy, compared, with, the, control, diet, was]), verbo([associated]), complemento([with, 'individuals\'', genotypes])].
[sujeto(['Previously,', we]), verbo([found]), complemento([that, 'Celastrus', orbiculatus, 'Thunb'])].
[sujeto(['(', 'COT)']), verbo([decreases]), complemento(['athero-susceptibility', in, lipoproteins, and, the, aorta, of, guinea, pigs, fed, a, 'high-fat', 'diet,', and, increases, 'high-density', lipoprotein, '(', 'HDL)'])].
[sujeto(['In', the, present, 'study,', we, investigated, the, effect, of, 'COT', in, reducing, lipid, accumulation, and]), verbo([promoting]), complemento([reverse, cholesterol, transport, '(', 'RCT)', in, vivo, and, vitro])].
[sujeto(['The', expression, of, hepatic, genes, and, protein]), verbo([associated]), complemento([with, 'RCT', were, analyzed])].
[sujeto(['COT', administration, reduced, lipid, accumulation, in, the, 'liver,', ameliorated, the, pathological, 'changes,', and, lessened, liver, 'injury,', the, levels, of, 'TG,', 'TC,', and, 'non-HDL-C', in, plasma, were]), verbo([decreased]), complemento(['significantly,', and, 'COT', led, to, a, significant, increase, in, plasma, 'HDL-C', and, 'apolipoprotein&nbsp;A', '(', 'apoA1)'])].
[sujeto(['(', 3, ')', 'H-cholesterol', in, 'plasma,', 'liver,', 'bile,', and, feces, was, also, significantly]), verbo([increased]), complemento([in, 'COT-treated', mice, compared, to, controls])].
[sujeto(['An', in, vitro, isotope, tracing, experiment, showed, that, 'COT', and, its, bioactive, 'ingredients,', such, as, 'celastrol,', ursolic, 'acid,', oleanolic, 'acid,', and, 'quercetin,', significantly]), verbo([increased]), complemento([the, efflux, of, '(', 3, ')', 'H-cholesterol'])].
[sujeto(['They', also]), verbo([increased]), complemento([the, expression, of, 'SRB1,', 'ABCA1,', and, 'ABCG1', significantly, in, macrophages])].
[sujeto(['Our', findings]), verbo([provided]), complemento([a, positive, role, of, 'COT', in, reducing, lipid, accumulation, by, promoting, 'RCT'])].
[sujeto(['These', effects, may, be, achieved, by]), verbo([activating]), complemento([the, 'SRB1', and, 'ABC', transporter, pathway, and, promoting, cholesterol, metabolism, via, the, 'CYP7A1', pathway, in, vivo])].
[sujeto(['Changes', in, nutritional, status, during, gestation, and, lactation]), verbo([have]), complemento([detrimental, effects, on, offspring, metabolism])].
[sujeto(['Several', animal, studies]), verbo([have]), complemento([shown, that, maternal, 'high-fat', diet, '(', 'HFD)', can, predispose, the, offspring, to, development, of, obesity, and, metabolic, 'diseases,', however, the, mechanisms, underlying, these, transgenerational, effects, are, poorly, understood])].
[sujeto(['Therefore,', we, examined, the, effect, of, maternal, 'HFD', consumption, on, metabolic, phenotype, and, hepatic, expression, of]), verbo([involved]), complemento([genes, in, dams, to, determine, whether, any, of, these, parameters, were, associated, with, the, metabolic, outcomes, in, the, offspring])].
[sujeto(['Hepatic', lipid, levels, and, mRNA, levels, of, genes]), verbo([involved]), complemento([in, lipid, 'metabolism,', including, 'LXRα,', 'SREBP-2,', 'FXR,', 'LDLR,', and, 'ABCG8', were, significantly, changed, by, maternal, 'HFD', intake])].
[sujeto(['HFD', feeding, also]), verbo([induced]), complemento([significant, oxidative, stress, in, serum, and, liver, of, dams])].
[sujeto(['Maternal', 'HFD', consumption]), verbo([induced]), complemento([metabolic, 'dysfunction,', including, altered, liver, growth, and, oxidative, stress, in, 'dams,', which, may, contribute, to, the, disturbed, cholesterol, homeostasis, in, the, early, life, of, male, mice, offspring])].
[sujeto(['Maternal', 'high-fat', diet, '(', 'HFD)']), verbo([promotes]), complemento([obesity, and, metabolic, disturbances, in, offspring, at, weaning, and, adult, life])].
[sujeto(['Liver', of, 'HFD', offspring, groups, showed]), verbo([increased]), complemento([free, cholesterol, and, 'FO-treated', 'HFD', group, showed, lower, expression, of, 'Abcg8,', suggesting, decreased, cholesterol, biliary, excretion])].
[sujeto(['Serum', 'n-3', 'PUFA', were]), verbo([decreased]), complemento([in, 'FO-treated', 'HFD', compared, to, 'FO-treated', 'STD', 'offspring,', which, may, explain, the, reduced, hypolipidemic, 'FO', effect])].
[sujeto(['Maternal', 'HFD', impaired, the, ability, of, 'FO', to, reduce, adiposity, and, serum, lipids, in, adolescent, 'offspring,']), verbo([suggesting]), complemento([a, potential, predisposition, to, future, development, of, metabolic, disorders])].
[sujeto(['ATP', 'Binding', 'Cassette', 'Transporter', 'A4', '(', 'ABCB4)', is, a, sterol, export, pump, that]), verbo([regulates]), complemento([excretion, of, biliary, cholesterol])].
[sujeto(['In', a, 'cross-sectional', 'study,', 296, subjects, were]), verbo([recruited]), complemento([from, a, 'hospital-based', population])].
[sujeto([1, ')', and, of, 'ABCB4', rs2230028, '(', 'OR', =, 0.12, ',', 95, '%', 'CI:', 0.06, -, 0.22, ',', 'P', =, 0.001, ')', were]), verbo([associated]), complemento([with, an, increased, risk, for, gallstone, disease, in, 'Europeans'])].
[sujeto(['Funnel', plot, and, 'Egger\'s', test]), verbo([suggested]), complemento([absence, of, publication, bias])].
[sujeto([1, ')', ',', rs2230028, '(', heterozygote, 'CT)', '(', 'P', =, 0.023, ')', and, 'ABCG8', rs11887534, '(', heterozygote, 'CG)', '(', 'P', =, 0.006, ')', were, significantly]), verbo([associated]), complemento([with, gallstone, disease, in, 'Chinese', population])].
[sujeto(['Genetic', risk]), verbo([associated]), complemento([with, 'ABCB4', rs2230028, '(', homozygote, 'GG)', polymorphism, was, dominated, in, asymptomatic, gallstone, disease, '(', 95, '%', 'C'])].
[sujeto(['In', 'conclusion,', carriers, of, 'ABCB4', 'rs1202283,', rs2230028, are, at, an]), verbo([increased]), complemento([risk, for, gallstone, 'disease,', while, 'ABCB4', rs2230028, is, associated, with, asymptomatic, gallstone, disease])].
[sujeto(['Black', pigment, stones, can, be]), verbo([caused]), complemento([by, chronic, 'haemolysis;', brown, pigment, stones, typically, develop, in, obstructed, and, infected, bile, ducts])].
[sujeto(['Factors']), verbo([involved]), complemento([in, metabolic, syndrome, increase, the, risk, of, developing, gallstones, and, form, the, basis, of, primary, prevention, by, lifestyle, changes])].
[sujeto(['Common', mutations, in, the, hepatic, cholesterol, transporter, 'ABCG8']), verbo([confer]), complemento([most, of, the, genetic, risk, of, developing, 'gallstones,', which, accounts, for, '∼25%', of, the, total, risk])].
[sujeto(['Although', our, knowledge, on, the, genetics, and, pathophysiology, of, gallstones]), verbo([has]), complemento([expanded, 'recently,', current, treatment, algorithms, remain, predominantly, invasive, and, are, based, on, surgery])].
[sujeto(['The', pathogen, was]), verbo([inhibited]), complemento([by, both, strains, in, 'vitro,', whereas, 'C'])].
[sujeto(['This', study, demonstrates, the, potential, for, combining, different, biocontrol, agents, and]), verbo([suggests]), complemento([an, involvement, of, 'ABC', transporters, in, secondary, metabolite, tolerance, in, 'C'])].
[sujeto(['Here', we, utilized, male, mice, with]), verbo([increased]), complemento([levels, of, 27, 'OH', either, due, to, increased, production, '(', 'CYP27A1', transgenic, 'mice)', or, reduced, metabolism, '(', 'Cyp7b1-/-', 'mice)'])].
[sujeto(['In', the, liver, of, 'CYP27tg', mice, we]), verbo([found]), complemento([a, modest, increase, of, the, mRNA, levels, corresponding, to, the, 'LXR', target, genes, 'Cyp7b1', and, 'Abca1'])].
[sujeto(['In', the, liver, of, the, 'Cyp27-/-', mice, treated, with, 0.025, '%', cholic, acid, there, was, no, significant, effect, of, the, knockout, on, the, 'LXR']), verbo([target]), complemento([genes])].
[sujeto(['In', a, previous, work, 'triple-knockout', mice, deficient, in, the, biosynthesis, of, 24, 'S-hydroxycholesterol,', 25, -, hydroxycholesterol, and, 27, 'OH', were, shown, to]), verbo([have]), complemento([impaired, response, to, dietary, 'cholesterol,', suggesting, 'side-chain', oxidized, oxysterols, to, be, mediators, in, 'cholesterol-induced', effects, on, 'LXR', target, genes, at, a, transcriptional, level, '(', 'Chen', 'W'])].
[sujeto(['We', show, here, that, treatment, of, wildtype, mice, with, dietary, cholesterol, under, the, same, conditions, as, in, the, above, study]), verbo([induced]), complemento([the, 'LXR', target, genes, 'Lpl,', 'Abcg8', and, 'Srebp1c', in, wild, type, mice, but, failed, to, activate, the, same, genes, in, mice, lacking, 27, -, hydroxycholesterol, due, to, a, knockout, of, 'Cyp27'])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, 27, 'OH', is, not, an, important, regulator, of, 'Srebp-', or, 'LXR', regulated, genes, under, basal, conditions, in, mouse, liver])].
[sujeto(['On', the, other, hand, 27, 'OH', appears, to]), verbo([mediate]), complemento(['cholesterol-induced', effects, on, some, 'LXR', target, genes, at, a, transcriptional, level, under, some, in, vivo, conditions])].
[sujeto(['Dietary', patterns, with, cardiovascular, benefits]), verbo([have]), complemento([been, 'recommended,', but, the, relative, contributions, of, individual, foods, and, food, 'components,', alone, or, in, 'combination,', remain, undefined])].
[sujeto(['Male', 'ApoE(-/-)', mice, were, fed, either, a, purified, 'AIN-93G', control, 'diet,', a, 'Western', diet, '(', 'WD),', or, a, 'WD', with, 10, '%', tomato, powder, '(', 'TP),', 2, '%']), verbo([soy]), complemento([germ, '(', 'SG),', or, the, 'combination,', for, 4, wk, '(', n, =, 10, per, 'group)'])].
[sujeto(['TP', and, 'SG', did, not]), verbo([decrease]), complemento([atherosclerosis, as, measured, by, 'H&amp;E-stained', sections, of, the, aortic, 'root,', aortic, 'arch,', and, descending, aorta])].
[sujeto(['The', 'TP', diets, further]), verbo([increased]), complemento([plasma, 'cholesterol,', but, also, led, to, increased, expression, of, the, 'Abcg5/8', transporters, involved, in, cholesterol, efflux])].
[sujeto(['Addition', of, 'SG', alone, to, the, 'WD', attenuated, 'WD-induced']), verbo([increases]), complemento([in, plasma, 'cholesterol,', liver, 'lipids,', and, gonadal, adipose, weight])].
[sujeto(['The', results, of, this, study, do, not, support, the, use, of, either, 'TP', or, 'SG', for, reduction, of, 'atherosclerosis,', but]), verbo([suggest]), complemento([some, beneficial, effects, of, 'SG', on, lipid, metabolism, in, this, model, of, cardiovascular, disease])].
[sujeto(['IMB-170', significantly]), verbo([activated]), complemento(['LXRα,', with, an, 'EC50', value, of, 0.27, μM])].
[sujeto(['Interestingly,', 'IMB-170', not, only]), verbo([increased]), complemento([the, expression, of, 'ATP-binding', cassette, transporter, 'A1', '(', 'ABCA1)', and, 'G1', '(', 'ABCG1),', which, are, related, to, the, reverse, cholesterol, transport, '(', 'RCT)', 'process,', but, also, influenced, the, expression, levels, of, other, genes, involved, in, the, cholesterol, metabolism, pathway, in, many, cell, lines])].
[sujeto(['Moreover,', 'IMB-170', significantly, reduced, cellular, lipid, accumulation, and]), verbo([increased]), complemento([cholesterol, efflux, from, 'RAW264'])].
[sujeto(['Interestingly,', compared, with, 'TO901317,', 'IMB-170', only, slightly]), verbo([increased]), complemento([protein, expression, levels, of, 'lipogenesis-related', genes, in, 'HepG2', 'cells,', indicating, that, 'IMB-170', may, have, a, lower, lipogenesis, side, effect, in, vivo])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'IMB-170', showed, the, selective, agonistic, activity, for, 'LXRα'])].
[sujeto(['Moreover,', compared, with, full, 'LXR-agonists,', 'IMB-170', possesses, a, differential, ability, to]), verbo([recruit]), complemento([coregulators])].
[sujeto(['This']), verbo([suggests]), complemento([that, 'IMB-170', has, distinct, interactions, with, the, active, sites, in, the, 'LXRα', 'ligand-binding', domain])].
[sujeto(['In', 'summary,', 'IMB-170', is, a, novel, partial, 'LXRα', agonist, without, the, classical, lipogenesis, side, 'effects,', which, could, be, used, as, a, potential, 'anti-atherosclerotic']), verbo([leading]), complemento([compound, in, the, future])].
[sujeto([',', 'ABCA1,', 'ABCA7,', 'ABCG1,', 'ABCG2,', and, 'ABCG5;']), verbo([associated]), complemento([transcription, factors, viz])].
[sujeto(['Additionally,', the, expression, of, 'LXRα', 'SREBF1,', and, 'PPARA', which, are, known, to]), verbo([regulate]), complemento([some, of, the, 'ABC', tranporters, were, also, analyzed])].
[sujeto(['Among', the, several, 'SLC', transporters, 'studied,', 'SLC2A1,', 'SLC2A4,', and, 'SLC2A8', showed, significant, '(', p, &, 'lt;', 0.05, ')', higher, expression, during, lactation, 'stage,', whereas, 'SLC2A12', expression, was, greater, during, heifer, stage]), verbo([suggesting]), complemento(['SLC2A1,', 'SLC2A4,', and, 'SLC2A8', to, be, the, major, transporters, associated, with, glucose, uptake, in, buffalo, mammary, gland])].
[sujeto(['The', expression, profile, of, '(', 'lactoferrin)', 'LTF,', known, to, be]), verbo([expressed]), complemento([at, high, level, in, mammary, gland, during, involution, was, also, studied])].
[sujeto(['The', inclusion, of, 'LTF', as, a, control, gene, further]), verbo([provided]), complemento([the, confidence, in, the, buffalo, mammary, gland, expression, data, generated, in, the, present, study])].
[sujeto(['This', study, thus, helped, to]), verbo([provide]), complemento([information, about, the, distinct, expression, pattern, of, various, transporters, and, their, regulators, in, buffalo, mammary, gland, during, different, physiological, states])].
[sujeto(['Thus,', cellular, cholesterol, homeostasis, is, tightly]), verbo([regulated]), complemento([by, 'uptake,', de, novo, 'synthesis,', and, efflux])].
[sujeto(['Any', surplus, of, cholesterol, must, either, be, stored, in, the, cytosol, in, the, form, of, esters, or]), verbo([released]), complemento([from, the, cell])].
[sujeto(['Recently,', several, 'ATP-binding', cassette, '(', 'ABC)', 'transporters,', such, as, 'ABCA1,', 'ABCG1,', 'ABCG5,', and, 'ABCG8']), verbo([have]), complemento([been, shown, to, play, important, roles, in, the, regulation, of, cellular, cholesterol, homeostasis, by, mediating, cholesterol, efflux])].
[sujeto(['Mutations', in, 'ABC', transporters, are]), verbo([associated]), complemento([with, several, human, diseases])].
[sujeto(['In', this, 'review,', we, discuss, the, physiological, roles, of, 'ABC', transporters, and, the, underlying, mechanisms, by, which, they]), verbo([mediate]), complemento([cholesterol, translocation])].
[sujeto(['Atherosclerosis', is, a, chronic, inflammatory, disease, and, represents, the, major]), verbo([cause]), complemento([of, cardiovascular, morbidity, and, mortality])].
[sujeto(['We', demonstrated, that, cellular, cholesterol, content, was, significantly]), verbo([decreased]), complemento([while, 'apoA1-mediated', cholesterol, efflux, was, significantly, increased, following, treatment, with, 'DHC', in, 'THP-1', 'macrophage-derived', foam, cells])].
[sujeto(['We', also, observed, that, plasma, levels, of, 'TG,', 'LDL-C,', 'VLDL-C,', 'IL-1β,', 'IL-6,', 'TNF-α', and, 'CRP', were, markedly]), verbo([decreased]), complemento([while, plasma, levels, of, apoA1, and, 'HDL-C', were, significantly, 'increased,', and, consistent, with, 'this,', atherosclerotic, lesion, development, was, significantly, inhibited, by, 'DHC', treatment, of, 'apoE(-/-)', mice, fed, a, 'high-fat/high-cholesterol', diet])].
[sujeto(['These', observations]), verbo([provide]), complemento([direct, evidence, that, 'DHC', can, significantly, decrease, atherosclerotic, plaque, formation, involving, in, a, 'PPARγ/LXRα', pathway, and, thus, 'DHC', may, represent, a, promising, candidate, for, a, therapeutic, agent, for, the, treatment, or, prevention, of, atherosclerosis])].
[sujeto(['Thus,', cellular, cholesterol, homeostasis, is, tightly]), verbo([regulated]), complemento([by, 'uptake,', de, novo, 'synthesis,', and, efflux])].
[sujeto(['Any', surplus, of, cholesterol, must, either, be, stored, in, the, cytosol, in, the, form, of, esters, or]), verbo([released]), complemento([from, the, cell])].
[sujeto(['Recently,', several, 'ATP-binding', cassette, '(', 'ABC)', 'transporters,', such, as, 'ABCA1,', 'ABCG1,', 'ABCG5,', and, 'ABCG8']), verbo([have]), complemento([been, shown, to, play, important, roles, in, the, regulation, of, cellular, cholesterol, homeostasis, by, mediating, cholesterol, efflux])].
[sujeto(['Mutations', in, 'ABC', transporters, are]), verbo([associated]), complemento([with, several, human, diseases])].
[sujeto(['In', this, 'review,', we, discuss, the, physiological, roles, of, 'ABC', transporters, and, the, underlying, mechanisms, by, which, they]), verbo([mediate]), complemento([cholesterol, translocation])].
[sujeto([5, ')']), verbo([increase]), complemento([in, body, 'weight,', plasma, 'TG', '(', 'p&lt;0'])].
[sujeto([1, ')', with, an]), verbo([increase]), complemento([in, 'VLDL', 'TG', and, in, 'VLDL', and, 'LDL', cholesterol, '(', 'p&lt;0'])].
[sujeto(['Compared', to, 'HF,', 'HFω3', presented, significant]), verbo([decrease]), complemento([in, body, weight])].
[sujeto([1, ')', related, to, a]), verbo([decrease]), complemento([in, 'VLDL', 'TG', and, 'HDL', cholesterol, respectively, and, higher, 'LCAT', activity, '(', 'p&lt;0'])].
[sujeto(['This']), verbo([increase]), complemento([was, related, to, higher, gene, expression, of, 'ABCG5,', 'ABCA1', and, 'SR-B1', in, 'HFω3', compared, to, 'Control', and, 'HF', groups, '(', &, 'lt;0'])].
[sujeto(['This', change, was, related, to, the, higher, cholesterol, and, fecal, bile, acids, excretion, and, to, the, activation, of, major, genes]), verbo([involved]), complemento([in, 'RCT'])].
[sujeto(['Significant', associations, of, intratumoral, levels, of, 'ABCC1', and, 'ABCC8', with, grade, and, expression, of, hormonal, receptors, were]), verbo([found]), complemento([in, both, sets, of, patients])].
[sujeto(['ABCA12,', 'ABCA13', and, 'ABCD2', levels, were, significantly]), verbo([associated]), complemento([with, the, response, to, neoadjuvant, chemotherapy, in, 'post-treatment', patients])].
[sujeto(['Pharmacological', 'LXR', activation]), verbo([has]), complemento(['anti-atherosclerotic', actions, in, animal, models])].
[sujeto(['Mechanisms', underlying, these, 'LXR-mediated', effects]), verbo([have]), complemento([not, been, fully, elucidated])].
[sujeto(['HDL', cholesterol, was, maximally, 60, '%']), verbo([increased]), complemento([in, a, 'time-dependent', fashion, due, to, appearance, of, more, and, larger, 'HDL', particles])].
[sujeto(['Fecal', neutral, sterol, secretion, was, maximally]), verbo([induced]), complemento([after, 1, week, treatment])].
[sujeto(['T0901317', treatment]), verbo([induced]), complemento([fecal, neutral, sterol, secretion, by, '~300%', in, 'wild-type', but, not, in, 'Lxrα', deficient, mice])].
[sujeto(['Surprisingly,', 'LXR', activation, reduced, 'SR-B1', protein, amount, in, hepatic, 'membranes,']), verbo([suggesting]), complemento([that, this, might, contribute, to, elevated, 'HDL', cholesterol])].
[sujeto(['However,', 'T0901317', still, elevated, plasma, 'HDL', cholesterol, in, 'Sr-b1', deficient, 'mice,']), verbo([suggesting]), complemento([that, 'SR-B1', is, not, the, only, step, involved, in, 'LXR-mediated', induction, of, plasma, 'HDL', cholesterol])].
[sujeto(['SR-B1', is, not]), verbo([required]), complemento([to, enhance, fecal, neutral, sterol, secretion])].
[sujeto(['Of', the, 49, hum, an, 'ABC', 'proteins,', a, significant, number, are, known, to]), verbo([mediate]), complemento([the, extrusion, of, lipids, from, membranes, or, the, flipping, of, membrane, lipids, across, the, bilayer, to, generate, and, maintain, membrane, lipid, asymmetry])].
[sujeto(['The', importance, of, these, 'ABC', lipid, transporters, in, cell, physiology, is, evident, from, the]), verbo([finding]), complemento([that, mutations, in, the, genes, encoding, many, of, these, proteins, are, responsible, for, severe, inherited, diseases])].
[sujeto(['For', 'example,', mutations, in, 'ABCA1']), verbo([cause]), complemento(['Tangier', disease, associated, with, defective, efflux, of, cholesterol, and, phosphatidylcholine, from, the, plasma, membrane, to, the, lipid, acceptor, protein, apoA1, '(', apolipoprotein, 'AI),', mutations, in, 'ABCA3', cause, neonatal, surfactant, deficiency, associated, with, a, loss, in, secretion, of, the, lipid, pulmonary, surfactants, from, lungs, of, 'newborns,', mutations, in, 'ABCA4', cause, 'Stargardt', macular, 'degeneration,', a, retinal, degenerative, disease, linked, to, the, reduced, clearance, of, retinoid, compounds, from, photoreceptor, 'cells,', mutations, in, 'ABCA12', cause, harlequin, and, lamellar, 'ichthyosis,', skin, diseases, associated, with, defective, lipid, trafficking, in, 'keratinocytes,', and, mutations, in, 'ABCB4', and, 'ABCG5/ABCG8', are, responsible, for, progressive, intrafamilial, hepatic, disease, and, sitosterolaemia, associated, with, defective, phospholipid, and, sterol, transport, respectively])].
[sujeto(['ATP']), verbo([binding]), complemento([cassette, '(', 'ABC)', transporters, represent, a, large, and, diverse, family, of, proteins, that, transport, specific, substrates, across, a, membrane])].
[sujeto(['The', importance, of, these, transporters, is, illustrated, by, the]), verbo([finding]), complemento([that, inactivating, mutations, within, 17, different, family, members, are, known, to, lead, to, specific, human, diseases])].
[sujeto(['Clinical', data, from, humans, 'and/or', studies, with, mice, lacking, functional, transporters, indicate, that, 'ABCA1,', 'ABCG1,', 'ABCG4,', 'ABCG5', and, 'ABCG8', are]), verbo([involved]), complemento([in, cholesterol, 'and/or', phospholipid, transport])].
[sujeto(['This', review, discusses, the, multiple, mechanisms, that, control, cellular, sterol, 'homeostasis,', including, the, roles, of, 'microRNAs,']), verbo([nuclear]), complemento([and, cell, surface, receptors, and, 'ABC', 'transporters,', with, particular, emphasis, on, recent, findings, that, have, provided, insights, into, the, 'role(s)', of, 'ABCG1'])].
[sujeto([2, 'D-DIGE', analysis, of, serum, proteins, showed, that, 'T(3)', treated, rats, had]), verbo([increased]), complemento(['ApoA-I,', 'ApoA-IV', and, fetuin, 'A', levels, with, decreased, 'Apo', 'E', levels])].
[sujeto(['Microarray', and, 'real-time', 'RT-PCR', analysis, of, rat, liver, revealed, large]), verbo([increases]), complemento([in, 'ApoA-I,', 'ApoA-IV,', 'ABCG5,', and, 'ABCG8', in, response, to, 'T(3)'])].
[sujeto(['J774', 'macrophages,', 'BHK', 'cells,', and, 'Fu5AH', rat, hepatoma, cells, were, used, to, measure, cholesterol, efflux]), verbo([mediated]), complemento([by, 'ABCA1,', 'ABCG1', transporters, or, 'SR-BI'])].
[sujeto(['Sera', from, 'T(3)-treated', rats]), verbo([stimulated]), complemento([efflux, via, 'ABCA1', but, not, by, 'ABCG1', or, 'SR-BI'])].
[sujeto(['Gel', filtration, chromatography, revealed, that, 'T(3)', treatment]), verbo([caused]), complemento([a, decrease, in, 'HDL', particle, size, accompanied, by, higher, levels, of, 'lipid-poor', 'ApoA-I'])].
[sujeto(['Thyroid', hormone]), verbo([enhances]), complemento([the, ability, of, serum, to, accept, cellular, cholesterol, via, the, 'ABCA1', transporter])].
[sujeto(['This', effect, is, most, likely, attributable, to]), verbo([increases]), complemento([in, small, 'HDL', and, lipid, poor, 'ApoA-I', in, response, to, 'T(3)'])].
[sujeto(['Potent', synthetic, nonsteroidal, liver, 'X', receptor, '(', 'LXR)', agonists, like, 'T0901317']), verbo([induce]), complemento([triglyceridaemia, and, fatty, 'liver,', effects, not, observed, with, some, natural, and, synthetic, 'steroidal,', relatively, weak, agonists, of, 'LXR'])].
[sujeto(['Eight', week, old, male, 'LDLR(-/-)', mice, fed, an, atherogenic, diet, were, orally, treated, with, vehicle, or, 'ATI-111', at, 3, and, 5, 'mg·kg(-1)', '·day(-1)', for, 8, 'weeks,', and, effects, on, plasma, and, liver, lipid, 'levels,', expression, of, genes]), verbo([involved]), complemento([in, lipid, metabolism, and, on, atherogenesis, were, analysed])].
[sujeto(['ATI-111']), verbo([increased]), complemento([the, expression, of, genes, involved, in, lipid, 'transport,', such, as, 'ABCA1,', 'ABCG1', and, 'ABCG5/G8,', in, intestine, and, 'macrophages;', decreased, 'ABCG1,', 'apoE;', and, slightly, increased, 'ABCA1', and, 'ABCG5/G8', expression, in, liver])].
[sujeto(['ATI-111', markedly]), verbo([increased]), complemento([sterol, regulatory, 'element-binding', protein, '(', 'SREBP)-1c', mRNA, in, some, 'tissues,', whereas, 'acetyl-coenzyme', 'A', carboxylase, and, fatty, acid, synthase, expression, was, unaffected, or, only, slightly, increased, in, intestine, and, liver])].
[sujeto(['ATI-111']), verbo([inhibited]), complemento([the, conversion, of, 'SREBP-1c', precursor, form, to, its, active, form])].
[sujeto(['Compared', with, 'vehicle-treated', 'mice,', the, levels, of, hepatic, lipids, and, 'liver-secreted', nascent, lipoproteins, were, not, 'altered,', while, a, significant]), verbo([decrease]), complemento([in, plasma, cholesterol, and, triglyceride, levels, was, observed, in, 'ATI-111-treated', mice])].
[sujeto(['ATI-111', significantly]), verbo([inhibited]), complemento([atherogenesis, in, three, separate, vascular, sites])].
[sujeto(['ATI-111', is, a, promising, candidate, for, further, development, as, a, treatment, of, certain, vascular, diseases, as, it, lacks, the, significant, side, effects]), verbo([associated]), complemento([with, nonsteroidal, 'LXR', 'agonists,', the, induction, of, fatty, liver, and, hypertriglyceridaemia])].
[sujeto(['Exogenous', cholesterol, uptake]), verbo([involves]), complemento([a, complex, process, in, the, intestines, for, the, absorption, of, cholesterol, and, bile, acids])].
[sujeto(['This', process, is]), verbo([regulated]), complemento([by, intestinal, nuclear, transcription, factors, such, as, 'LXR', that, affect, sterol, transporters, 'NPC1L1,', 'ABCG5/G8,', and, 'ABCG1,', and, enzymes, such, as, 'ACAT-2'])].
[sujeto(['Plant', 'sterol/stanols,', 'ezetimibe,', and, bile, acid, sequestrants]), verbo([have]), complemento([a, variety, of, effects, on, these, various, 'transporters,', and, new, insights, into, their, 'mechanism(s)', of, action, have, provided, a, plethora, of, exciting, targets, for, metabolic, 'diseases,', 'dyslipidemia,', and, atherosclerosis])].
[sujeto(['Along', with, many, other, mammalian, 'ATP-binding', cassette, '(', 'ABC)', 'transporters,', members, of, the, 'ABCG', group, are]), verbo([involved]), complemento([in, the, regulated, transport, of, hydrophobic, compounds, across, cellular, membranes])].
[sujeto(['In', 'humans,', five, 'ABCG', family, members]), verbo([have]), complemento([been, 'identified,', encoding, proteins, ranging, from, 638, to, 678, amino, acids, in, length])].
[sujeto(['All', five]), verbo([have]), complemento([been, the, subject, of, intensive, investigation, to, better, understand, their, physiological, 'roles,', expression, 'patterns,', interactions, with, substrates, and, 'inhibitors,', and, regulation, at, both, the, transcript, and, protein, level])].
[sujeto(['ABCG2']), verbo([has]), complemento([a, much, broader, substrate, specificity, and, its, ability, to, transport, numerous, diverse, pharmaceuticals, has, implications, for, the, 'absorption,', 'distribution,', 'metabolism,', excretion, and, toxicity, '(', 'ADMETOx)', profile, of, these, compounds])].
[sujeto(['ABCG2', is, one, of, at, least, three, 'so-called', multidrug, resistant, 'ABC', transporters]), verbo([expressed]), complemento([in, 'humans,', and, its, activity, is, associated, with, decreased, efficacy, of, 'anti-cancer', agents, in, several, carcinomas])].
[sujeto(['We', summarize, here, data, on, all, five, human, 'ABCG', transporters, and]), verbo([provide]), complemento([a, current, perspective, on, their, roles, in, human, health, and, disease])].
[sujeto(['Glucose', and, lipids, are, essential, to, the, 'body,', but, excess, glucose, or, lipids]), verbo([lead]), complemento([to, metabolic, syndrome])].
[sujeto(['ATP-binding', cassette, '(', 'ABC)', proteins, are]), verbo([involved]), complemento([in, the, homeostasis, of, glucose, and, lipid, in, that, they, regulate, insulin, secretion, and, remove, excess, cholesterol, from, the, body])].
[sujeto(['Sulfonylurea', receptor, '(', 'SUR)', is, a, subunit, of, the, 'ATP-sensitive', potassium, 'channels,', which]), verbo([regulate]), complemento([insulin, secretion, from, pancreatic, 'beta-cells', by, sensing, cellular, metabolic, levels])].
[sujeto(['ABCG5', and, 'ABCG8']), verbo([suppress]), complemento([the, absorption, of, cholesterol, in, the, intestine, and, exclude, cholesterol, from, the, liver, to, the, bile, duct])].
[sujeto(['ABCG1', and, 'ABCG4,']), verbo([expressed]), complemento([in, the, central, nervous, 'system,', play, roles, in, lipid, metabolism, in, the, brain])].
[sujeto(['These', 'ABC', proteins, are]), verbo([targets]), complemento([of, drugs, and, functional, foods, to, cure, and, prevent, 'diabetes,', 'hyperlipidemia,', and, neurodegenerative, diseases])].
[sujeto(['In', 'men,', subjects, with, the, 'AA', genotype, of, the, 'ABCA1', rs2230806, '(', 'R219K)', polymorphism, were]), verbo([associated]), complemento([with, increased, plasma, 'LDLc', 'levels,', while, the, 'ABCA1', 'haplotype,', which, included, the, rs2230806, 'A', 'allele,', was, associated, with, higher, 'TC', and, 'LDLc', plasma, concentrations])].
[sujeto(['In', 'women,', significant, relationships, were]), verbo([found]), complemento([between, rs1893590, polymorphisms, '(', 'ABCG1', 'gene)', and, 'HDLc', plasma, concentrations, '(', subjects, with, the, 'AA', genotype, had, lower, 'HDLc', 'levels)'])].
[sujeto(['For', the, 'ABCG8', 'gene,', the, rs4148211, polymorphism, was]), verbo([associated]), complemento([with, higher, plasma, 'TC', and, 'LDLc', concentrations, in, the, total, population])].
[sujeto(['Moreover,', an, 'ABCG5-G8', 'haplotype,', which, included, the, rs6544718, 'T', 'allele,', was]), verbo([associated]), complemento([with, higher, 'HDLc', plasma, concentrations, in, women])].
[sujeto(['Activation', of, 'Receptors', for, 'Advanced', 'Glycation', 'End', products, '(', 'RAGE)', is]), verbo([involved]), complemento([in, the, pathogenesis, of, 'diabetes,', and, its, complications])].
[sujeto(['S100B']), verbo([mediated]), complemento([regulation, of, 'LXR', target, genes, like, 'ABCA1,', 'ABCG1,', 'ABCG8,', 'LXR-α', and, 'LXR-β', in, 'THP-1', cells, was, analyzed, by, 'real-time', 'PCR,', 'RT-PCR', and, western, blots])].
[sujeto(['Effect', of, 'LXR', ligand, on, 'S100B']), verbo([induced]), complemento([changes, in, 'LXR', target, genes, was, also, studied])].
[sujeto(['Luciferase', reporter, assay, was, used, for, 'S100B']), verbo([induced]), complemento(['ABCA1', promoter, regulation])].
[sujeto([1, ')']), verbo([decrease]), complemento([in, 'T1317', induced, 'ABCA1', promoter, activation])].
[sujeto(['Atherosclerosis,', driven, by, inflamed, 'lipid-laden', 'lesions,', can, occlude, the, coronary, arteries, and]), verbo([lead]), complemento([to, myocardial, infarction])].
[sujeto(['However,', the, body, is, able, to, mobilize, and, excrete, cholesterol, and, other, 'lipids,', thus]), verbo([preventing]), complemento([atherosclerosis, by, a, process, termed, reverse, cholesterol, transport, '(', 'RCT)'])].
[sujeto(['Insight', into, the, mechanism, of, 'RCT']), verbo([has]), complemento([been, gained, by, the, study, of, two, rare, syndromes, caused, by, the, mutation, of, 'ABC', transporter, loci])].
[sujeto(['In', 'Tangier', 'disease,']), verbo([loss]), complemento([of, 'ABCA1', prevents, cells, from, exporting, cholesterol, and, 'phospholipid,', thus, resulting, in, the, 'build-up', of, cholesterol, in, the, peripheral, tissues, and, a, loss, of, circulating, 'HDL'])].
[sujeto(['Likewise,', sitosterolemia, is, another, inherited, syndrome]), verbo([associated]), complemento([with, premature, atherosclerosis])].
[sujeto(['Here', mutations, in, either, the, 'ABCG5', or, 'G8', 'loci,']), verbo([prevents]), complemento([hepatocytes, and, enterocytes, from, excreting, cholesterol, and, plant, 'sterols,', including, 'sitosterol,', into, the, bile, and, intestinal, lumen])].
[sujeto(['Interestingly,', a, third, 'protein,', 'ABCG1,', that]), verbo([has]), complemento([been, shown, to, have, 'anti-atherosclerotic', activity, in, 'mice,', may, also, act, to, transfer, cholesterol, to, mature, 'HDL', particles])].
[sujeto(['Of', particular, interest, are, recent]), verbo([reports]), complemento([that, indicate, both, 'ABCA1', and, 'ABCG1', modulate, cell, surface, cholesterol, levels, and, inhibit, its, partitioning, into, lipid, rafts])].
[sujeto(['Given', lipid, rafts, may]), verbo([provide]), complemento([platforms, for, innate, immune, receptors, to, respond, to, inflammatory, 'signals,', it, follows, that, loss, of, 'ABCA1', and, 'ABCG1', by, increasing, raft, content, will, increase, signaling, through, these, 'receptors,', as, has, been, experimentally, demonstrated])].
[sujeto(['Moreover,', additional]), verbo([reports]), complemento([indicate, 'ABCA1,', and, possibly, 'SR-BI,', another, 'HDL', 'receptor,', may, directly, act, as, 'anti-inflammatory', receptors, independent, of, their, lipid, transport, activities])].
[sujeto(['Finally,', we, give, an, update, on, the, progress, and, pitfalls, of, therapeutic, approaches, that, seek, to]), verbo([stimulate]), complemento([the, flux, of, lipids, through, the, 'RCT', pathway])].
[sujeto(['HDL', cholesterol, levels, are]), verbo([decreased]), complemento([in, 'Crohn\'s', 'disease,', a, tumor, necrosis, 'factor-alpha', '(', 'TNF-alpha)-driven', chronic, inflammatory, condition, involving, the, gastrointestinal, tract])].
[sujeto(['ATP-binding', cassette, transporter, 'A1', '(', 'ABCA1),', one, of, several, liver, 'X', receptor, '(', 'LXR)']), verbo([target]), complemento(['genes,', is, a, cell, surface, transporter, that, mediates, the, 'rate-controlling', step, in, 'HDL', synthesis])].
[sujeto(['In', response, to, cholesterol, micelles, or, 'T0901317,', an, 'LXR', nonsterol, 'agonist,', 'TNF-alpha']), verbo([decreased]), complemento([the, basolateral, efflux, of, cholesterol, to, apolipoprotein, 'A1', '(', 'apoA1)'])].
[sujeto(['TNF-alpha,', by, attenuating, 'ABCA1', promoter, 'activity,', markedly]), verbo([decreased]), complemento(['ABCA1', gene, expression, without, attenuating, the, expression, of, 'LXR-alpha,', 'LXR-beta,', and, most, other, 'LXR', target, 'genes,', such, as, 'ABCG1,', 'FAS,', 'ABCG8,', scavenger, 'receptor-B1', '(', 'SR-B1),', and, apoC1])].
[sujeto(['TNF-alpha', also]), verbo([decreased]), complemento(['ABCA1', mass, by, markedly, enhancing, the, rate, of, 'ABCA1', degradation, and, modestly, inhibiting, its, rate, of, synthesis])].
[sujeto(['Inhibitors', of, the]), verbo([nuclear]), complemento(['factor-kappaB', '(', 'NF-kappaB)', 'pathway,', which, is, activated, by, 'TNF-alpha,', partially, reverse, the, effect, of, 'TNF-alpha', on, 'ABCA1', protein, expression])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, 'TNF-alpha,', the, major, cytokine, implicated, in, the, inflammation, of, 'Crohn\'s', 'disease,', decreases, 'HDL', cholesterol, levels, by, attenuating, the, expression, of, intestinal, 'ABCA1', and, cholesterol, efflux, to, apoA1])].
[sujeto(['Survival', depends, on, the]), verbo([regulated]), complemento([and, selective, transport, of, 'nutrients,', waste, products, and, regulatory, molecules, across, these, 'membranes,', a, process, that, is, often, mediated, by, integral, membrane, proteins])].
[sujeto(['The', largest, and, most, diverse, of, these, membrane, transport, systems, is, the, 'ATP']), verbo([binding]), complemento([cassette, '(', 'ABC)', family, of, membrane, transport, proteins])].
[sujeto(['The', 'ABC', family, is, a, large, evolutionary]), verbo([conserved]), complemento([family, of, transmembrane, proteins, '(', &, 'gt;250', 'members)', present, in, all, 'phyla,', from, bacteria, to, 'Homo', 'sapiens,', which, require, energy, in, the, form, of, 'ATP', hydrolysis, to, transport, substrates, against, concentration, gradients])].
[sujeto(['In', prokaryotes, the, majority, of, 'ABC', transporters, are]), verbo([involved]), complemento([in, the, transport, of, nutrients, and, other, macromolecules, into, the, cell])].
[sujeto(['This', review, focuses, on, the, members, of, the, 'ABCG', subfamily, of, 'transporters,', which, are]), verbo([conserved]), complemento([through, evolution, in, multiple, taxa])].
[sujeto(['As', discussed, 'below,', these, proteins]), verbo([participate]), complemento([in, multiple, cellular, homeostatic, 'processes,', and, functional, mutations, in, some, of, them, have, clinical, relevance, in, humans])].
[sujeto(['In', 'contrast,', 'ABCG5', and, 'ABCG8', function, as, heterodimers, on, the, plasma, 'membrane,', and, the, homodimer, of, either, 'ABCG5', or, 'ABCG8', is]), verbo([retained]), complemento([in, the, endoplasmic, reticulum, '(', 'ER)'])].
[sujeto(['To', examine, the, molecular, mechanisms, of, the]), verbo([regulated]), complemento([trafficking, of, 'ABCG5', and, 'ABCG8,', the, subcellular, localizations, of, chimeric, 'proteins,', fused, with, 'ABCG1', or, 'ABCG2,', were, analyzed])].
[sujeto(['This']), verbo([suggests]), complemento([that, the, 'N-terminal', cytosolic, domains, of, 'ABCG5', and, 'ABCG8', are, involved, in, 'ER', retention, of, their, 'homodimers,', and, that, novel, 'ER-retention', or, -, retrieval, motifs, exist, within, these, domains])].
[sujeto(['The', fetus]), verbo([has]), complemento([a, high, requirement, for, cholesterol, and, synthesizes, cholesterol, at, elevated, rates])].
[sujeto(['Recent', studies]), verbo([suggest]), complemento([that, fetal, cholesterol, also, can, be, obtained, from, exogenous, sources])].
[sujeto(['Cholesterol', feeding, resulted, in, a, 3.1, -, fold]), verbo([increase]), complemento([in, the, amount, of, 'LDL-cholesterol', taken, up, by, the, fetus, and, a, 2.4, -, fold, increase, in, the, amount, of, 'HDL-cholesterol', taken, up])].
[sujeto(['Several', proteins]), verbo([associated]), complemento([with, sterol, transport, and, 'efflux,', including, those, induced, by, activated, liver, 'X', 'receptor,', were, expressed, in, hamster, and, human, 'placentas:', 'NPC1,', 'NPC1L1,', 'ABCA2,', 'SCP-x,', and, 'ABCG1,', but, not, 'ABCG8'])].
[sujeto(['NPC1L1', was, the, only, protein]), verbo([increased]), complemento([in, hypercholesterolemic, placentas])].
[sujeto(['Thus,']), verbo([increasing]), complemento([maternal, 'lipoprotein-cholesterol', concentrations, can, enhance, transport, of, maternal, cholesterol, to, the, 'fetus,', leading, to, 1, ')', increased, movement, of, cholesterol, down, a, concentration, gradient, in, the, 'placenta,', 2, ')', increased, lipoprotein, secretion, from, the, yolk, sac, '(', shown, 'previously),', and, possibly, 3, ')', increased, placental, 'NPC1L1', expression])].
[sujeto(['Mammalian', cells]), verbo([have]), complemento([developed, various, responses, to, minimize, accumulation, of, unesterified, 'cholesterol,', as, the, latter, can, result, in, cell, toxicity, and, death, '[', reviewed, in, this, edition, by, 'Björkhem', '(', 'Björkhem,', 'I'])].
[sujeto(['These', responses, include, esterification, to, sequester, excess, sterol, in, intracellular, lipid, 'droplets,', repression, of, both, cholesterol, synthesis, and, 'LDL', receptor, expression, '(', thus, reducing, endocytosis, of, 'LDL),', and, induction, of, a, panoply, of, genes, that]), verbo([promote]), complemento([sterol, efflux, and, affect, lipid, metabolism])].
[sujeto(['The']), verbo([nuclear]), complemento([receptor, 'liver-X-receptor', '(', 'LXR)', functions, as, a, cellular, &, 'quot;sterol', 'sensor&quot;', and, plays, a, critical, role, in, these, latter, transcriptional, changes, '[', reviewed, in, this, edition, by, 'Glass', '(', 'Shibata,', 'N'])].
[sujeto(['Activation', of, 'LXR', by, either, endogenous, oxysterols, or, synthetic, agonists]), verbo([induces]), complemento([the, expression, of, many, 'genes,', including, those, encoding, 'ATP-binding', cassette, '(', 'ABC)', transporters, 'ABCA1,', 'ABCG1,', 'ABCG5,', and, 'ABCG8'])].
[sujeto(['As', discussed, 'below,', these, four, proteins, function, to]), verbo([promote]), complemento([sterol, efflux, from, cells])].
[sujeto(['Human', 'ATP-binding', cassette, '(', 'ABC)', transporters, comprise, a, family, of, 48, 'membrane-spanning', transport, 'proteins,', many, of, which, are]), verbo([associated]), complemento([with, genetic, diseases, or, multidrug, resistance, of, cancers])].
[sujeto(['We', analyzed, the, expression, of, 25, proteins, and, demonstrate, that, 11, 'transporters,', including, 'ABCC3,', 'ABCB6,', 'ABCD1,', 'ABCG1,', 'ABCG4,', 'ABCG5,', 'ABCG8,', 'ABCE1,', 'ABCF1,', 'ABCF2,', and, 'ABCF3,', were]), verbo([expressed]), complemento([at, high, levels, comparable, to, that, of, 'ABCB1', '(', 'P-glycoprotein)'])].
[sujeto(['As', an, example, of, the, purification, strategy, via, tandem, affinity, 'chromatography,', we, purified, 'ABCC3', '(', 'MRP3)', whose, role, in, the, transport, of, anticancer, 'drugs,', bile, 'acids,', and, glucuronides]), verbo([has]), complemento([been, controversial])].
[sujeto(['Purified', 'ABCC3,']), verbo([activated]), complemento([with, 'PC', 'lipids,', exhibited, significant, 'ATPase', activity, with, a, 'Vmax', of, 82, +, /, -, 32, nmol, 'min-1', 'mg-1'])].
[sujeto(['The', 'ATPase', activity, was]), verbo([stimulated]), complemento([by, bile, acids, and, glucuronide, 'conjugates,', reaching, 170, +, /, -, 28, nmol, 'min-1', 'mg-1,', but, was, not, stimulated, by, a, variety, of, anticancer, drugs])].
[sujeto(['The', glucuronide, conjugates, 'ethinylestradiol-3-glucuronide', and, 17, 'beta-estradiol-17-glucuronide']), verbo([stimulated]), complemento([the, 'ATPase', with, relatively, high, affinities, '(', apparent, 'Km', values, of, 2, and, 3, 'microM,', 'respectively)', in, contrast, to, bile, acids, '(', apparent, 'Km', values, of, &, 'gt;130', 'microM),', suggesting, that, glucuronides, are, the, preferred, substrates, for, this, transporter])].
[sujeto(['In', the, 'blood,', 'HCV', virions, are]), verbo([associated]), complemento([with, 'lipoproteins,', forming, lipoviroparticles, '(', 'LVPs),', which, are, the, most, infectious, form, of, the, virus])].
[sujeto(['ApoE', is, also, a, cell, host, factor]), verbo([involved]), complemento([in, lipoprotein, homeostasis])].
[sujeto(['Although', the, majority, of, apoE, is]), verbo([associated]), complemento([with, 'lipoproteins,', a, 'lipid-free', '(', 'LF)', form, exists, in, blood])].
[sujeto(['A', 'dose-dependent']), verbo([decrease]), complemento([in, 'HCV', replication, was, observed, when, 'Huh7'])].
[sujeto([5.1, cells, and, 'PHH', were, treated, with]), verbo([increasing]), complemento([amounts, of, 'LF-apoE'])].
[sujeto(['We', showed, that, 'LF-apoE']), verbo([acts]), complemento([on, 'HCV', replication, independently, of, previously, described, apoE, receptors])].
[sujeto(['We', observed, that, 'LF-apoE']), verbo([induced]), complemento([a, marked, hepatic, cholesterol, efflux, via, the, 'ATP-binding', cassette, subfamily, 'G', member, 1, '(', 'ABCG1)', protein, that, in, turn, inhibits, 'HCV', replication])].
[sujeto(['LF-apoE', also]), verbo([increases]), complemento([both, apolipoprotein, 'AI', and, 'high-density', lipoprotein, production])].
[sujeto(['To', understand, the, mechanisms, underlying, of, 'resistance,', previous, studies]), verbo([have]), complemento([driven, the, acquisition, of, 'Tam', resistance, by, exposing, cells, to, varying, concentration, of, drug, for, varying, lengths, of, time])].
[sujeto(['ABC', proteins]), verbo([participate]), complemento([in, various, biological, processes, and, insecticide, resistance, in, 'insects,', and, are, divided, into, eight, subfamilies, '(', 'A-H)'])].
[sujeto(['The', three, mosquitoes]), verbo([have]), complemento([55, ',', 69, ',', and, 70, 'ABC', 'genes,', respectively])].
[sujeto(['The', 'ABCB,', 'ABCD,', 'ABCE,', and, 'ABCF', subfamilies, were]), verbo([conserved]), complemento([in, the, three, mosquito, species])].
[sujeto([quinquefasciatus, transcriptomes, during, development, showed, that, the, 'ABCG', and, 'ABCC', genes, were, mainly, highly]), verbo([expressed]), complemento([at, the, egg, and, pupal, stages])].
[sujeto(['The', 'pigment-transport', relative, 'brown,', 'white,', and, 'scarlet,', as, well, as, the, 'ABCF', 'subfamily,', were, highly]), verbo([expressed]), complemento([at, the, egg, stage])].
[sujeto(['The', highly]), verbo([expressed]), complemento([genes, in, larvae, included, three, 'ABCA3', genes])].
[sujeto(['The', majority, of, the, highly]), verbo([expressed]), complemento([genes, in, adults, were, 'ABCG1/4', genes])].
[sujeto(['These', results]), verbo([provided]), complemento([insights, into, the, evolution, of, the, 'ABC', transporter, family, in, mosquitoes])].
[sujeto(['Contemporary', research]), verbo([suggests]), complemento([that, macrophage, foam, cell, and, cholesterol, efflux, defect, play, pivotal, role, in, atherogenesis])].
[sujeto(['We']), verbo([reported]), complemento([on, the, heretofore, unknown, therapeutic, effect, of, 'Danshensu', '(', 'DSS)', in, reducing, intracellular, cholesterol, level, and, unraveled, the, mechanism, of, 'DSS', promotes, cholesterol, efflux])].
[sujeto(['In', 'addition,', 'DSS']), verbo([stimulated]), complemento([the, upregulation, of, cellular, cholesterol, exporters, 'ABCA1', and, 'ABCG1', to, reduce, intracellular, lipid, accumulation])].
[sujeto(['Oxidized', 'low-density', lipoprotein, '(', 'oxLDL)', can]), verbo([bind]), complemento([to, 'β2-glycoprotein&nbsp;I', '(', 'β2GPI)', and, 'C-reactive', protein, '(', 'CRP)', to, form, stable, 'complexes,', which, exert, certain, effects, in, diabetic, cardiovascular, disease])].
[sujeto(['A', previous, study, by, our, group]), verbo([has]), complemento([confirmed, that, the, resulting, complexes, promote, atherosclerosis, in, diabetic, 'BALB/c', mice])].
[sujeto(['Compared', with, 'oxLDL,', the, three, complexes]), verbo([induced]), complemento([less, lipid, accumulation, '(', 'P&lt;0'])].
[sujeto([5, ')', through]), verbo([inhibiting]), complemento([the, expression, of, 'CD36', mRNA, and, promoting, the, expression, of, and, 'ABCG1', mRNA, '(', 'P&lt;0'])].
[sujeto(['oxLDL),', and, obvious, effects, on, 'p38/mitogen&#8209;activated', protein, kinase, and]), verbo([nuclear]), complemento([factor, '(', 'NF)&#8209;κB', phosphorylation, were, also, observed, in, these, groups, '(', 'P&lt;0'])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, 'CRP/oxLDL/βG2P1', complexes, may, induce, lipid, accumulation, and, inflammation, in, macrophages, via, the, 'p38/MAPK', and, 'NF&#8209;κB', signaling, pathways])].
[sujeto(['ATP-binding', cassette, transporter, 'G1', '(', 'ABCG1)']), verbo([promotes]), complemento([cholesterol, accumulation, and, alters, 'T', cell, 'homeostasis,', which, may, contribute, to, progression, of, atherosclerosis])].
[sujeto(['Here,', we, investigated, how, the, selective]), verbo([loss]), complemento([of, 'ABCG1', in, 'T', cells, impacts, atherosclerosis, in, 'LDL', 'receptor-deficient', '(', 'LDLR-deficient)', 'mice,', a, model, of, the, disease])].
[sujeto(['Furthermore,', 'T', 'cell-specific', 'ABCG1', deficiency]), verbo([led]), complemento([to, a, 30, '%', increase, in, 'Treg', percentages, in, aorta, and, 'aorta-draining', lymph, nodes, '(', 'LNs)', of, these, mice, compared, with, animals, with, only, 'LDLR', deficiency])].
[sujeto(['When', 'Abcg1', was, selectively, deleted, in, 'Tregs', of, 'LDLR-deficient', 'mice,', we, observed, a, 30, '%']), verbo([increase]), complemento([in, 'Treg', percentages, in, aorta, and, 'aorta-draining', 'LNs', and, reduced, atherosclerosis])].
[sujeto(['In', the, absence, of, 'ABCG1,', intracellular, cholesterol, accumulation]), verbo([led]), complemento([to, downregulation, of, the, mTOR, 'pathway,', which, increased, the, differentiation, of, naive, 'CD4', 'T', cells, into, 'Tregs'])].
[sujeto(['The']), verbo([increase]), complemento([in, 'Tregs', resulted, in, reduced, 'T', cell, activation, and, increased, 'IL-10', production, by, 'T', cells])].
[sujeto(['Last,', we]), verbo([found]), complemento([that, higher, 'ABCG1', expression, in, 'Tregs', was, associated, with, a, higher, frequency, of, these, cells, in, human, blood, samples])].
[sujeto(['Our', study, indicates, that, 'ABCG1']), verbo([regulates]), complemento(['T', cell, differentiation, into, 'Tregs,', highlighting, a, pathway, by, which, cholesterol, accumulation, can, influence, 'T', cell, homeostasis, in, atherosclerosis])].
[sujeto(['MicroRNAs', '(', 'miRNAs)', are, short, 'non-coding', 'RNAs', that]), verbo([regulate]), complemento([gene, expression, by, promoting, degradation, 'and/or', repressing, translation, of, specific, target, mRNAs])].
[sujeto(['Several', miRNAs]), verbo([have]), complemento([been, identified, that, regulate, the, amplitude, of, the, innate, immune, response, by, directly, targeting, 'Toll-like', receptor, '(', 'TLR)', pathway, members, 'and/or', cytokines])].
[sujeto(['These', miRNAs]), verbo([regulate]), complemento([macrophage, cholesterol, by, targeting, the, lipid, efflux, transporters, 'ATP', binding, cassette, '(', 'ABC)A1', and, 'ABCG1'])].
[sujeto(['We', and, others]), verbo([have]), complemento([previously, reported, that, 'Abca1(-/-)', and, 'Abcg1(-/-)', macrophages, have, increased, 'TLR', proinflammatory, responses, due, to, augmented, lipid, raft, cholesterol])].
[sujeto(['Herein,', we]), verbo([report]), complemento([that, multiple, 'TLR', ligands, 'down-regulate', 'miR-33', in, murine, macrophages])].
[sujeto(['miR-33', augments, macrophage, lipid, rafts, and]), verbo([enhances]), complemento([proinflammatory, cytokine, induction, and, 'NF-κB', activation, by, 'LPS'])].
[sujeto(['Taken', 'together,', these, findings, extend, the, purview, of, 'miR-33,', identifying, it, as, an, indirect, regulator, of, innate, immunity, that]), verbo([mediates]), complemento([bidirectional, 'cross-talk', between, lipid, homeostasis, and, inflammation])].
[sujeto(['Atherosclerosis', is, the, most, common]), verbo([cause]), complemento([of, cardiovascular, 'diseases,', such, as, myocardial, infarction, and, stroke])].
[sujeto(['We', hypothesized, that, nagilactone, 'B', '(', 'NLB),', a, small, molecule, extracted, from, the, root, bark, of, 'Podocarpus', nagi, '(', 'Podocarpaceae),']), verbo([suppresses]), complemento([atherosclerosis, in, an, atherosclerotic, mouse, model])].
[sujeto([7, 'cells,', 'NLB', significantly, ameliorated, cholesterol, accumulation, in, macrophages, via]), verbo([enhancing]), complemento([apolipoprotein, 'A-I', and, 'HDL-mediated', cholesterol, efflux])].
[sujeto(['Mechanistically,', 'NLB']), verbo([induced]), complemento([messenger, 'RNA', and, protein, expression, of, the, 'ATP-binding', cassette, transporter, 'A1', '(', 'ABCA1)', and, 'G1', '(', 'ABCG1)', in, 'RAW264'])].
[sujeto(['LXRα', and, 'LXRβ', small, interfering, 'RNA']), verbo([suppressed]), complemento(['NLB-mediated', induction, of, 'ABCA1', expression])].
[sujeto(['Consistent', with, in, vitro, 'results,', 'NLB']), verbo([induced]), complemento(['ABCA1', expression, and, suppressed, macrophage, areas, in, the, aortic, sinus])].
[sujeto(['Moreover,', 'NLB', treatment, did, not]), verbo([induce]), complemento([the, protein, expression, of, 'LXR', in, liver])].
[sujeto(['Selective', 'LXR', activation, in, macrophages, with, 'NLB']), verbo([induces]), complemento(['ABCA1-', and, 'ABCG1-mediated', cholesterol, efflux, while, exerting, minimal, effects, on, lipogenesis, and, lipid, accumulation, in, 'liver,', resulting, in, regression, of, 'atherosclerosis,', and, therefore, might, be, a, promising, strategy, for, therapeutics])].
[sujeto(['Tissue', specific, expression, of, genes, encoding, cholesterol, transporters, 'ABCA1', and, 'ABCG1', as, well, as, genes, encoding, the, most, important, transcriptional, regulators, of, adipogenesis, -, 'LXRa,', 'LXRb,', 'PPARg', and, 'RORa']), verbo([has]), complemento([been, investigated, in, intraabdominal, adipose, tissue, '(', 'IAT)', samples])].
[sujeto([5, ',', 'respectively)']), verbo([suggests]), complemento([the, role, of, the, transcription, factor, 'RORa', in, the, regulation, of, 'IAT', 'ABCA1', and, 'ABCG1', protein, levels])].
[sujeto(['The', development, of, obesity, is]), verbo([associated]), complemento([with, decreased, 'IAT', levels, of, 'RORa', and, 'LXRb', mRNA, '(', 'p=0'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, the, nuclear, factor, 'RORa', can, play, a, significant, role, in, the, regulation, of, cholesterol, metabolism, and, control, 'IAT', expression, of, 'ABCA1', and, 'ABCG1,', while, the, level, of, 'IAT', 'LXRb', gene, expression, may, be, an, important, factor, associated, with, the, development, of, obesity])].
[sujeto(['Atherosclerosis', '(', 'AS)', is]), verbo([associated]), complemento([with, severe, cardiovascular, disease])].
[sujeto(['The', 'anti-inflammatory,', 'anti-oxidation,', and, lipid]), verbo([regulating]), complemento([properties, of, baicalin, suggest, potential, as, an, 'anti-atherosclerotic', agent])].
[sujeto(['In', 'vivo,', treatment, with, baicalin, markedly]), verbo([decreased]), complemento([atherosclerotic, lesion, sizes, and, lipid, accumulation, in, 'AS', rabbit, carotid, arteries])].
[sujeto(['Molecular', data, showed, that, baicalin, significantly]), verbo([increased]), complemento([the, expression, levels, of, 'PPARγ,', 'LXRα,', 'ATP', binding, cassette, transporters, '(', 'ABC)', 'A1', and, 'ABCG1'])].
[sujeto(['Cell', transfection, experiments, '(', including, 'PPARγ', and, 'LXRα', 'siRNAs)']), verbo([suggested]), complemento([that, the, effects, of, baicalin, are, mediated, by, the, 'PPARγ-LXRα', signalling, 'pathway,', which, stimulates, the, expression, of, 'ABCA1', and, 'ABCG1'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, baicalin, potentially, exerts, 'anti-atherosclerosis', 'effects,', possibly, through, the, 'PPARγ-LXRα-ABCA1/ABCG1', 'pathway,', by, promoting, efflux, of, cholesterol, from, macrophages, and, delaying, the, formation, of, foam, cells])].
[sujeto([7, 'cells,', betulin, '(', 0.1, -, 2.5, 'μg/mL)', 'dose-dependently', ameliorated, 'oxLDL-induced', cholesterol, accumulation, and]), verbo([enhanced]), complemento([cholesterol, efflux])].
[sujeto([7, and, 'THP-1', 'cells,', betulin]), verbo([increased]), complemento([the, expression, of, 'ABCA1', and, 'ABCG1', via, suppressing, the, transcriptional, repressors, 'sterol-responsive', 'element-binding', proteins, '(', 'SREBPs)', that, bound, to, 'E-box', motifs, in, 'ABCA1', 'promoter,', whereas, 'E-box', binding, site, mutation, markedly, attenuated, 'betulin-induced', 'ABCA1', promoter, activity])].
[sujeto(['Furthermore,', betulin, administration, significantly]), verbo([increased]), complemento(['ABCA1', expression, and, suppressed, macrophage, positive, areas, in, the, aortic, sinuses])].
[sujeto(['Moreover,', betulin, administration, improved, plasma, lipid, profiles, and]), verbo([enhanced]), complemento([fecal, cholesterol, excretion, in, the, mice])].
[sujeto(['Betulin', attenuates, atherosclerosis, in, 'apoE(-/-)', mice, by]), verbo([promoting]), complemento([cholesterol, efflux, in, macrophages])].
[sujeto(['Expression', of, 'ATP-binding', cassette, transporter, 'G1', '(', 'ABCG1),', a, molecule, facilitating, cholesterol, efflux, to, 'HDL,', is]), verbo([activated]), complemento([by, liver, 'X', receptor, '(', 'LXR)'])].
[sujeto(['In', this, 'study,', we, investigated, if, inhibition, of, 'ERK1/2', can]), verbo([activate]), complemento([macrophage, 'ABCG1', expression, and, functions])].
[sujeto(['MEK1/2', 'inhibitors,', 'PD98059', and, 'U0126,']), verbo([increased]), complemento(['ABCG1', mRNA, and, protein, 'expression,', and, activated, the, natural, 'ABCG1', promoter, but, not, the, promoter, with, the, 'LXR', responsive, element, '(', 'LXRE)', deletion])].
[sujeto(['Inhibition', of, 'ABCG1', expression, by, 'ABCG1', siRNA, did]), verbo([enhance]), complemento([the, formation, of, 'macrophage/foam', cells, and, it, attenuated, the, inhibitory, effect, of, 'MEK1/2', inhibitors, on, foam, cell, formation])].
[sujeto(['MEK1/2', inhibitors]), verbo([activated]), complemento([macrophage, cholesterol, efflux, to, 'HDL', in, 'vitro,', and, they, enhanced, reverse, cholesterol, transport, '(', 'RCT)', in, vivo])].
[sujeto(['ApoE', deficient, '(', 'apoE(-/-))', mice, receiving, 'U0126', treatment, had, reduced, sinus, lesions, in, the, aortic, root, which, was]), verbo([associated]), complemento([with, activated, macrophage, 'ABCG1', expression, in, the, lesion, areas])].
[sujeto(['MEK1/2', inhibitors, coordinated, the, 'RXR', 'agonist,', but, not, the, 'LXR', 'agonist,', to]), verbo([induce]), complemento(['ABCG1', expression])].
[sujeto(['Furthermore,', induction, of, 'ABCG1', expression, by, 'MEK1/2', inhibitors, was]), verbo([associated]), complemento([with, activation, of, 'SIRT1,', a, positive, regulator, of, 'LXR', 'activity,', and, inactivation, of, 'SULT2B1', and, 'RIP140,', two, negative, regulators, of, 'LXR', activity])].
[sujeto(['Taken', 'together,', our, study]), verbo([suggests]), complemento([that, 'MEK1/2', inhibitors, activate, macrophage, 'ABCG1', 'expression/RCT,', and, inhibit, foam, cell, formation, and, lesion, development, by, multiple, 'mechanisms,', supporting, the, concept, that, 'ERK1/2', inhibition, is, 'anti-atherogenic'])].
[sujeto(['Liver', 'X', receptors, '(', 'LXRs)', are, 'ligand-activated']), verbo([nuclear]), complemento([receptors, involved, mainly, in, the, regulation, of, cholesterol, metabolism, in, many, 'organs,', including, liver, and, 'intestine,', as, well, as, in, macrophages, and, neutrophils])].
[sujeto(['Besides,', both, 'anti-inflammatory', and, 'pro-inflammatory', properties]), verbo([have]), complemento([been, ascribed, to, 'LXRs'])].
[sujeto(['The', effect, of, the, inflammatory, condition, on, the, expression, of, 'LXRα', and, its]), verbo([target]), complemento([genes, has, not, been, previously, addressed, in, human, neutrophils])].
[sujeto(['We']), verbo([have]), complemento([described, that, 'platelet-activating', factor, '(', 'PAF)', and, hydrogen, peroxide, '(', 'H2O2)', are, potent, 'pro-inflammatory', mediators, that, link, the, haemostatic, and, innate, immune, systems])].
[sujeto(['In', this, work, we]), verbo([report]), complemento([that, 'H2O2', at, low, doses, '(', 1, 'pM-1μM)', exerts, an, inhibitory, effect, on, 'TO901317-induced', mRNA, expression, of, 'LXRα', and, of, its, target, genes, encoding, the, 'ATP-binding', cassette, '(', 'ABC)', transporters, 'ABCA1', and, 'ABCG1,', and, the, sterol, regulatory, 'element-binding', protein, 1, c, '(', 'SREBP1c)'])].
[sujeto([',', a, 'transcription-enhancing', 'effect,', was]), verbo([found]), complemento([at, higher, 'H2O2', doses, '(', 100, -, 500, 'μM)', on, most, of, these, genes])].
[sujeto(['On', the, other, 'hand,', low, doses, of, 'PAF', or, 'H2O2']), verbo([induced]), complemento([phosphorylation, of, extracellular, 'signal-regulated', kinases, 1, and, 2, '(', 'ERK', 1, /, 2, ')', and, 'NF-κB', 'activation,', 'However,', 'PAF', or, 'H2O2', at, high, doses, did, not, produce, changes, in, 'NF-κB', activation, levels])].
[sujeto(['In', 'summary,', our, results, show, that, 'H2O2,', either, exogenous, or, 'PAF-induced,', exerts, a, dual, regulation, on, mRNA, expression, of, 'LXRα', and, its]), verbo([target]), complemento([genes])].
[sujeto(['Using', 'RNA-seq', data, available, for, a, large, subset, of, individuals, '(', 'N', =, 2044, ')', ',', 'DNA', methylation, of, these, six, 'CpGs', is]), verbo([associated]), complemento([with, the, expression, of, 'CPT1A', and, 'SREBF1', '(', for, 'triglycerides),', 'DHCR24', '(', for, 'LDL', 'cholesterol)', and, 'ABCG1', '(', for, 'HDL', 'cholesterol),', which, are, all, key, regulators, of, lipid, metabolism])].
[sujeto(['Our', analysis]), verbo([suggests]), complemento([a, role, for, epigenetic, priming, in, 'end-product', feedback, control, of, lipid, metabolism, and, highlights, 'Mendelian', randomization, as, an, effective, tool, to, infer, causal, relationships, in, integrative, genomics, data])].
[sujeto(['Many', plant, polyphenols]), verbo([have]), complemento([been, shown, to, inhibit, macrophage, foam, cell, formation, and, the, development, of, atherosclerotic, lesions])].
[sujeto([7, 'macrophages,', which, may, be, due, to]), verbo([decreasing]), complemento([the, macrophage, 'CD36', protein, expression, and, not, 'SR-A'])].
[sujeto(['In', 'addition,', pomegranate, peel, polyphenols]), verbo([promoted]), complemento(['apoA-1-mediated', macrophage, cholesterol, efflux, by, 'up-regulating', 'ABCA1', and, 'LXRα', at, the, mRNA, and, protein, 'levels,', independently, of, 'ABCG1', and, 'PPARγ'])].
[sujeto(['The', evaluation, of, the, inhibitory, effect, of, hBSEP, transport, activity]), verbo([provides]), complemento([significant, information, for, predicting, toxic, potential, in, the, early, phase, of, drug, development])].
[sujeto(['The', role, and, function, of, hBSEP]), verbo([have]), complemento([been, investigated, by, the, examination, of, the, 'ATP-dependent', transport, of, radioactive, isotopically, '(', 'RI)-labeled', bile, acid, such, as, a, tritium, labeled, taurocholic, 'acid,', in, membrane, vesicles, obtained, from, 'hBSEP-expressing', cells])].
[sujeto(['Identification', of, the, mechanisms, directing, bile, canalicular, transport, of, these, agents, will]), verbo([provide]), complemento([insights, into, the, basis, of, their, hepatic, handling, for, assessing, perturbations])].
[sujeto(['Among', these, 'transporters,']), verbo([decreased]), complemento([expression, of, 'Abcc2', was, most, 'prominent,', and, this, decline, persisted, for, 4, wk])].
[sujeto(['In', healthy, 'HsdRccHan:WIST', 'rats,', only, 23, '%', +, /, -, 3, '%', of, the, peak, '(', 99, 'm)Tc-mebrofenin', activity, was]), verbo([retained]), complemento([after, 60, min])].
[sujeto(['By', 'contrast,', in, 'HsdAMC:TR-Abcc2', mutant, 'rats,', 73, '%', +, /, -, 5, '%', of, the, peak, '(', 99, 'm)Tc-mebrofenin', activity, was]), verbo([retained]), complemento(['(', 'P', &, 'lt;', 0.001, ')'])].
[sujeto(['Moreover,', the, administration, of, cyclosporin, 'A', markedly]), verbo([inhibited]), complemento(['(', 99, 'm)Tc-mebrofenin', excretion, in, healthy, 'rats,', with, no, further, effect, on, already, impaired, '(', 99, 'm)Tc-mebrofenin', excretion, in, 'HsdAMC:TR-Abcc2', mutant, rats])].
[sujeto(['Although', there]), verbo([has]), complemento([been, considerable, research, on, liver, regeneration, after, 'two-thirds', partial, hepatectomy, '(', 'PHx),', little, is, known, about, how, the, liver, protects, itself, against, 'BA', toxicity, during, regeneration])].
[sujeto(['PHx', did, not, influence, the, hepatic, concentrations, of, 'taurine-conjugated', 'BAs', '(', 'T-BA)', but]), verbo([increased]), complemento([the, concentration, of, 'glycine-conjugated', '(', 'G-BA)', and, unconjugated, 'BAs'])].
[sujeto(['Total', 'BA', excretion, '(', microg, x, 'min(-1)', x, g, liver, 'wt(-1))']), verbo([increased]), complemento([2.4, -, fold, and, was, accompanied, by, a, 55, '%', increase, in, bile, flow, after, 'PHx'])].
[sujeto(['The', mRNA, and, protein, levels, of, the, 'BA', uptake, transporter, 'Ntcp', were, unchanged, after, 'PHx,', whereas, the, canalicular, 'Bsep', protein]), verbo([increased]), complemento([twofold, at, 48, h])].
[sujeto(['The', basolateral, efflux, transporter, 'Mrp3', was]), verbo([induced]), complemento([at, the, mRNA, '(', 2.6, -, 'fold)', and, protein, '(', 3.1, -, 'fold)', levels, after, 'PHx,', which, may, contribute, to, elevated, plasma, 'BA', and, bilirubin, levels])].
[sujeto(['Biliary', phospholipid, excretion, was, nearly, doubled, in, 'PHx', 'mice,', most, likely, owing, to]), verbo([increased]), complemento([mRNA, expression, of, the, phospholipid, 'transporter,', 'Mdr2'])].
[sujeto(['The', multidrug, resistance, protein, 'ABCC4', '(', 'MRP4),', a, member, of, the, 'ATP-binding', cassette, 'superfamily,']), verbo([mediates]), complemento(['ATP-dependent', unidirectional, efflux, of, organic, anions, out, of, cells])].
[sujeto(['In', the, present, 'study,', using, 'inside-out', membrane, 'vesicles,', we, demonstrated, that, human, 'ABCC4', in, the, presence, of, physiological, concentrations, of, 'GSH']), verbo([has]), complemento([a, high, affinity, for, the, taurine, and, glycine, conjugates, of, the, common, natural, bile, acids, as, well, as, the, unconjugated, bile, acid, cholate])].
[sujeto(['K(m)', values, of, the, bile, acids, for, 'ABCC4', were, in, a, range, similar, to, those]), verbo([reported]), complemento([for, the, canalicular, bile, salt, export, pump, 'ABCB11'])].
[sujeto(['Progressive', familial, intrahepatic, cholestasis, type, 2, '(', 'PFIC2)', is]), verbo([caused]), complemento([by, a, mutation, in, the, bile, salt, export, pump, '(', 'BSEP/ABCB11)', gene])].
[sujeto(['However,', the, mechanisms, for, the, deficiency, in, the, function, of, two, mutations, '(', 'E297G', and, 'D482G),', which, are, frequently]), verbo([found]), complemento([in, 'European', 'patients,', have, not, yet, been, identified])].
[sujeto(['Introduction', of, 'E297G', and, 'D482G', mutations, into, the, human, 'BSEP', gene, by, 'site-directed', mutagenesis, resulted, in, a, significant, reduction, in, the, 'BSEP', expression, 'level,', which, was]), verbo([associated]), complemento([with, impaired, membrane, trafficking])].
[sujeto(['Progressive', familial, intrahepatic, cholestasis, type, 2, '(', 'PFIC-2)', patients]), verbo([have]), complemento([a, defect, in, the, hepatocanalicular, bile, salt, secretion])].
[sujeto(['The', disease, is]), verbo([caused]), complemento([by, mutations, in, the, bile, salt, export, pump, '(', 'BSEP)'])].
[sujeto(['Ten', different, missense, mutations]), verbo([have]), complemento([been, described])].
[sujeto(['The', effect, on, expression, and, subcellular, sorting, was, studied, in, 'HepG2', 'cells,', stably]), verbo([expressing]), complemento([enhanced, green, fluorescent, protein, '(', 'EGFP)-tagged', mBsep, proteins])].
[sujeto(['At', 30, degrees, 'C,', the, mutant, mRNA, and, protein, levels, were, strongly, 'increased,', and, the, protein, was, predominantly, glycosylated, and, efficiently]), verbo([targeted]), complemento([to, the, canalicular, membrane])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'PFIC-2', patients, with, the, 'D482G', mutation, express, a, 'functional,', but, highly, 'unstable,', 'temperature-sensitive', bile, salt, export, pump])].
[sujeto(['The', bile, salt, export, pump, '(', 'Bsep),', a, member, of, the, 'ATP-binding', cassette, superfamily, of, 'transporters,']), verbo([mediates]), complemento([the, 'ATP-dependent', canalicular, secretion, of, bile, salts])].
[sujeto(['We']), verbo([have]), complemento([cloned, and, expressed, the, mouse, 'Bsep', '(', 'mBsep)', protein, in, 'Sf9', insect, 'cells,', and, characterized, its, transport, and, 'ATPase', properties])].
[sujeto(['Because', its, deduced, amino, acid, sequence, predicts, multiple, phosphorylation, sites, for, protein, kinase, 'A,', protein, kinase, 'C', '(', 'PKC)', and, 'Ca(2+)-calmodulin', dependent, kinase, 'II,', we]), verbo([have]), complemento([also, tested, whether, mBsep, undergoes, phosphorylation])].
[sujeto(['Sf9', cell, membranes, that]), verbo([express]), complemento([mBsep, exhibit, higher, basal, 'ATPase', activity, than, control, 'membranes,', and, this, is, further, stimulated, by, bile, salts, and, inhibited, by, vanadate])].
[sujeto(['MBsep', exists, as, a, 'phospho-protein', when]), verbo([expressed]), complemento([in, 'Sf9', cells, and, the, immunoprecipitated, mBsep, complex, is, a, substrate, for, the, catalytic, subunit, of, 'PKC'])].
[sujeto(['This', is, further]), verbo([increased]), complemento([to, 18, -, fold, after, activation, by, phorbol, ester])].
[sujeto(['Given', that, bile, salts]), verbo([activate]), complemento([selected, 'PKC', isoforms, in, 'hepatocytes,', including, the, alpha, 'isoform,', the, phosphorylation, of, mBsep, by, 'PKCalpha', may, represent, a, point, of, regulation, for, this, transporter, that, is, mediated, by, its, own, substrate])].
[sujeto(['In', concert, with, 'ABCG5/G8,', these, two, transporters, are, responsible, for, the, formation, of, bile, and, mutations, within, these, transporters, can]), verbo([lead]), complemento([to, severe, hereditary, diseases])].
[sujeto(['In', this, 'study,', we]), verbo([report]), complemento([the, heterologous, overexpression, and, purification, of, human, 'BSEP', and, 'MDR3', as, well, as, the, expression, of, the, corresponding, 'C-terminal', 'GFP-fusion', proteins, in, the, yeast, 'Pichia', pastoris])].
[sujeto(['By', screening, over, 100, detergents, using, a, dot, blot, 'technique,', we]), verbo([found]), complemento([that, only, 'zwitterionic,', 'lipid-like', detergents, such, as, 'Fos-cholines', or, 'Cyclofos', were, able, to, extract, both, transporters, in, sufficient, amounts, for, subsequent, functional, analysis])].
[sujeto(['For', 'MDR3,', 'fluorescence-detection', size, exclusion, chromatography, '(', 'FSEC)', screens, revealed, that]), verbo([increasing]), complemento([the, acyl, chain, length, of, 'Fos-Cholines', improved, monodispersity])].
[sujeto([pastoris, membranes, showed]), verbo([binding]), complemento([to, 'ATP-agarose'])].
[sujeto(['Patients', with, 'non-small', cell, lung, cancer, '(', 'NSCLC)', 'EGFR', mutations]), verbo([have]), complemento([shown, a, dramatic, response, to, 'EGFR', inhibitors, '(', 'EGFR-TKI)'])].
[sujeto(['EGFR', 'T790M', mutation, and, 'MET', amplification]), verbo([have]), complemento([been, recognized, as, major, mechanisms, of, acquired, resistance, to, 'EGFR-TKI'])].
[sujeto(['Therefore,', 'MET', inhibitors]), verbo([have]), complemento([recently, been, used, in, 'NSCLC', patients, in, clinical, trials])].
[sujeto(['The', level, of, 'miR-138', that]), verbo([targeted]), complemento(['ABCB1', was, decreased, in, 'EBC-1R', cells])].
[sujeto(['ABCB1', siRNA, and, the, 'ABCB1', inhibitor, elacridar, could, reduce, sphere, numbers, and]), verbo([suppress]), complemento(['EMT'])].
[sujeto(['Our', study, demonstrated, that, 'ABCB1', 'overexpression,', which, was]), verbo([associated]), complemento([with, 'CSC', properties, and, 'EMT,', was, involved, in, the, acquired, resistance, to, 'MET', inhibitors])].
[sujeto(['Research']), verbo([reports]), complemento([discussing, correlations, between, the, 'ABCB1', 'C3435T', polymorphism, and, patient, responses, to, 'anti-epileptic', drug, '(', 'AED)', therapy, were, collected])].
[sujeto(['Subgroup', analyses]), verbo([suggested]), complemento([that, in, 'Caucasian', population, there, are, significant, differences, between, resistance, group, '(', 'RN)', and, control, group, '(', 'N)', in, both, allele, model, '(', 'C', 'vsT:', 'OR', =, 1.13, ;, 95, '%', 'CI:', 1.03, -, 1.25, ')', and, genotype, model, '(', 'CC', 'vsCT+TT:', 'OR', =, 1.27, ;, 95, '%', 'CI:', 1.08, -, 1.5, ')'])].
[sujeto(['The', 'ABCB1', 'C3435T', polymorphism, is]), verbo([associated]), complemento([with, drug, resistance, in, epilepsy, in, 'Caucasian', population])].
[sujeto(['To', investigate, the, mechanism, underlying, the, effects, of, matrine, in]), verbo([enhancing]), complemento([the, cytotoxic, sensitivity, of, 'CNE2/DDP', cells, highly, expressing, 'ATP-binding', cassette, superfamily, 'G', member, 2, '(', 'ABCG(2)(High))', to, allogenic, natural, killer, '(', 'Allo-NK)', cells])].
[sujeto(['ABCG(2)(High)', 'CNE2/DDP', cells, and, 'Allo-NK', cells, were, isolated, by, magnetic]), verbo([activated]), complemento([cell, sorting, '(', 'MACS)'])].
[sujeto(['Flow', cytometry, was, used, to, evaluate, the, purity, of, the, isolated, cells, and, the, expression, of, 'NKG2D', ligands, on, the]), verbo([target]), complemento([cells, before, and, after, incubation, with, matrine])].
[sujeto(['The', cytotoxic, sensitivity, of, the, treated, and, 'non-treated', 'ABCG(2)(High)', 'CNE2/DDP', cells, to, 'Allo-NK', cells, was, measured, by, 'LDH']), verbo([releasing]), complemento([assay])].
[sujeto(['The', expression, rates, of, 'MICA,', 'MICB,', 'ULBP1,', 'ULBP2,', and, 'ULBP3', on, the]), verbo([target]), complemento([cells, incubated, with, matrine, increased, from, '(', 2.92, -, /, +, 0.33, ')', '%', ',', '(', 4.27, -, /, +, 0.33, ')', '%', ',', '(', 5.8, -, /, +, 0.62, ')', '%', ',', '(', 11.1, -, /, +, 3.15, ')', '%', ',', and, '(', 7.75, -, /, +, 1.14, ')', '%', to, '(', 11.3, -, /, +, 0.89, ')', '%', ',', '(', 14.29, -, /, +, 2.61, ')', '%', ',', '(', 12.56, -, /, +, 1.06, ')', '%', ',', '(', 43.24, -, /, +, 4.43, ')', '%', ',', and, '(', 12.77, -, /, +, 1.06, ')', '%', ',', respectively])].
[sujeto(['At', the, 'E:', 'T', ratio, of, 10, :, 1, and, 20, :, 1, ',', the, cytotoxic, sensitivity, of, 'ABCG(2)(High)', cells, to, 'Allo-NK', cells]), verbo([increased]), complemento([from, '(', 15.32, -, /, +, 1.34, ')', '%', and, '(', 27.26, -, /, +, 6.81, ')', '%', in, 'un-treated', cells, to, '(', 28.53, -, /, +, 1.37, ')', '%', and, '(', 42.72, -, /, +, 2.8, ')', '%', in, 'matrine-treated', 'cells,', 'respectively,', showing, significant, differences, in, the, cytotoxic, sensitivity, of, the, target, cells, in, both, groups, produced, by, matrine, treatment, '(', 'F=29'])].
[sujeto(['Matrine', can, 'up-regulate', the, expressions, of, 'NKG2D', ligands, '(', 'MICA/B', and, 'ULBP1-3)', in, 'ABCG(2)(High)', nasopharyngeal, carcinoma, 'cells,', which, results, in]), verbo([increased]), complemento([cytotoxic, sensitivity, of, the, cells, to, 'Allo-NK', cells])].
[sujeto(['An', association, was, also]), verbo([found]), complemento([between, allele, 'T', of, the, c])].
[sujeto(['Identifying', the, genetic, variants, that]), verbo([regulate]), complemento([fasting, glucose, concentrations, may, further, our, understanding, of, the, pathogenesis, of, diabetes])].
[sujeto(['We']), verbo([found]), complemento([a, significant, association, between, the, 'SNP', rs563694, and, fasting, glucose, concentrations, '(', 'P', =, 3.5, x, 10, '(', -, 7, ')', ')'])].
[sujeto(['Across', these, 'studies,', fasting, glucose, concentrations]), verbo([increased]), complemento([0.01, -, 0.16, mM, with, each, copy, of, the, major, 'allele,', accounting, for, approximately, 1, '%', of, the, total, variation, in, fasting, glucose])].
[sujeto(['Our', results, in, combination, with, data]), verbo([reported]), complemento([in, the, literature, suggest, that, 'G6PC2,', a, 'glucose-6-phosphatase', almost, exclusively, expressed, in, pancreatic, islet, 'cells,', may, underlie, variation, in, fasting, 'glucose,', though, it, is, possible, that, 'ABCB11,', which, is, expressed, primarily, in, 'liver,', may, also, contribute, to, such, variation])].
[sujeto(['To', identify, regions, of, the, genome]), verbo([associated]), complemento([with, acquired, resistance, to, therapeutic, 'drugs,', we, conducted, molecular, cytogenetic, analyses, of, 23, 'cancer-cell', 'lines,', each, resistant, to, either, 'camptothecin,', 'cisplatin,', etoposide, '(', 'VP-16),', 'Adriamycin,', or, 1, -, 'beta-D-arabinofuranosylcytosine,', although, the, parental, tumor, lines, were, not])].
[sujeto(['Subtractive', comparative, genomic, hybridization, studies, revealed, regions, of]), verbo([gain]), complemento([or, loss, in, 'DNA-copy', numbers, that, were, characteristic, of, 'drug-resistant', cell, 'lines;', i])].
[sujeto(['A']), verbo([decrease]), complemento([in, copy, numbers, of, genes, encoding, deoxycytidine, 'kinase,', 'DNA', topoisomerase, 'I,', and, 'DNA', topoisomerase, 'II', alpha, reduced, their, expression, levels, in, one, cytosine, 'arabinoside-resistant', 'line,', two, of, three, 'camptothecin-resistant', 'lines,', and, two, of, five, 'VP-16-resistant', cell, 'lines,', respectively])].
[sujeto(['Our', results, indicated, that, changes, in, 'DNA-copy', numbers, of, the, genes, mentioned, can]), verbo([activate]), complemento([or, 'down-regulate', them, in, 'drug-resistant', cell, 'lines,', and, that, such, genomic, alterations, might, be, implicated, in, acquired, chemoresistance])].
[sujeto([a, custom, 'oligonucleotide-based', microarray, was, constructed, to]), verbo([provide]), complemento(['high-density', coverage, of, an, initial, set, of, 130, nuclear, genes, involved, in, the, pathogenesis, of, metabolic, and, mitochondrial, disorders])].
[sujeto(['In', 2, females, with, 'OTC', 'deficiency,', we, also]), verbo([found]), complemento([2, large, heterozygous, deletions, of, approximately, 7.4, 'Mb', and, 9, 'Mb', on, the, short, arm, of, the, 'X', chromosome, extending, from, sequences, telomeric, to, the, 'DMD', gene, '[', dystrophin, '(', muscular, 'dystrophy,', 'Duchenne', and, 'Becker', 'types)]', to, sequences, within, or, centromeric, to, the, 'OTC', gene, '(', ornithine, 'carbamoyltransferase)'])].
[sujeto(['This', technology, may, be, particularly, useful, as, a, complementary, diagnostic, test, in, the, context, of, a, recessive, disease, when, only, one, mutant, allele, is]), verbo([found]), complemento([by, sequencing])].
[sujeto(['The', lithogenic, diet]), verbo([induced]), complemento([ductular, proliferation, in, 'C57L', mice])].
[sujeto(['These', alterations, in, transporter, expressions, were, not]), verbo([associated]), complemento([with, changes, in, taurocholate, uptake])].
[sujeto(['The', lithogenic, diet]), verbo([induced]), complemento([biliary, hyperplasia, and, reduced, bile, salt, transporter, expressions, in, 'C57L', mice])].
[sujeto(['Although', bile, salt, uptake, was, not]), verbo([increased]), complemento([in, the, bile, duct, 'unit,', we, speculate, that, the, biliary, hyperplasia, on, the, lithogenic, diet, may, lead, to, an, increase, in, intrahepatic, bile, salt, recycling, during, cholesterol, cholelithogenesis])].
[sujeto(['Bile', acids]), verbo([have]), complemento([emerged, as, important, biological, molecules, that, support, the, solubilization, of, various, lipids, and, 'lipid-soluble', compounds, in, the, 'gut,', and, the, regulation, of, gene, expression, and, cellular, function])].
[sujeto(['Bile', acids, are, synthesized, from, cholesterol, in, the, liver, and, eventually]), verbo([released]), complemento([into, the, small, intestine])].
[sujeto(['The', components, of, the, mechanism, responsible, for, the, recycling, of, bile, acids, within, the, enterohepatic, circulation]), verbo([have]), complemento([been, identified, whereas, the, mechanism, for, intracellular, transport, is, less, understood])].
[sujeto(['Recently,', the, ileal, lipid]), verbo([binding]), complemento([protein, '(', 'ILBP;', human, gene, symbol, 'FABP6)', was, shown, to, be, needed, for, the, efficient, transport, of, bile, acids, from, the, apical, side, to, the, basolateral, side, of, enterocytes, in, the, distal, intestine])].
[sujeto(['A', variety, of, pathologies, is]), verbo([associated]), complemento([with, the, malfunction, of, the, bile, acid, transport, system])].
[sujeto(['The', 'LH', surge]), verbo([promotes]), complemento([terminal, differentiation, of, follicular, cells, to, become, luteal, cells])].
[sujeto(['RUNX2']), verbo([has]), complemento([been, shown, to, play, an, important, role, in, cell, 'differentiation,', but, the, regulation, of, 'Runx2', expression, and, its, function, in, the, ovary, remain, to, be, determined])].
[sujeto(['Runx2', expression, was]), verbo([induced]), complemento([in, periovulatory, granulosa, cells, of, human, and, rodent, ovaries])].
[sujeto(['RUNX2', and, core]), verbo([binding]), complemento(['factor-beta', '(', 'CBFbeta)', proteins, in, nuclear, extracts, and, 'RUNX2', binding, to, a, consensus, binding, sequence, increased, after, human, chorionic, gonadotropin, '(', 'hCG)', administration])].
[sujeto(['We', also]), verbo([found]), complemento([that, in, the, 'C/EBPbeta', knockout, mouse, 'ovary,', 'Runx2', expression, was, 'reduced,', indicating, 'C/EBPbeta-mediated', expression])].
[sujeto(['Next,', the, function, of, 'RUNX2', was, investigated, by]), verbo([suppressing]), complemento(['Runx2', expression, by, small, interfering, 'RNA', in, vitro])].
[sujeto(['Chromatin', immunoprecipitation, analysis, demonstrated, the]), verbo([binding]), complemento([of, 'RUNX2', in, the, promoter, region, of, these, 'genes,', suggesting, that, these, genes, are, direct, downstream, targets, of, 'RUNX2'])].
[sujeto(['Collectively,', the, present, data, indicate, that, the, 'LH', 'surge-induced', 'RUNX2', is]), verbo([involved]), complemento([in, various, aspects, of, luteal, function, by, directly, regulating, the, expression, of, diverse, luteal, genes])].
[sujeto(['The', ileal, fatty, acid]), verbo([binding]), complemento([protein, '(', 'FABP6)', is, known, to, be, involved, in, enterohepatic, bile, acid, metabolism])].
[sujeto(['We']), verbo([have]), complemento([previously, found, a, significant, association, between, the, rare, allele, of, the, 'FABP6', 'Thr79Met', polymorphism, and, lower, type, 2, diabetes, risk, in, a, small, 'case-control', study, '(', 192, cases, and, 384, 'controls)', embedded, in, the, large, 'EPIC-Potsdam', cohort])].
[sujeto(['Homozygosity', for, the, 'Met-allele', was]), verbo([associated]), complemento([with, lower, risk, of, type, 2, diabetes, '(', 'EPIC-Potsdam:', 0.7, ',', 'P=0'])].
[sujeto(['In', 'summary,', we]), verbo([found]), complemento([evidence, that, 'the-putative', 'functional-Thr79Met', substitution, of, 'FABP6', confers, a, protective, effect, on, type, 2, diabetes, in, obese, individuals])].
[sujeto(['We']), verbo([have]), complemento([determined, the, structure, of, the, fatty, 'acid-binding', protein, 6, '(', 'fabp6)', gene, and, the, 'tissue-specific', distribution, of, its, transcripts, in, 'embryos,', larvae, and, adult, zebrafish, '(', 'Danio', 'rerio)'])].
[sujeto(['The', coding, region, of, the, gene, and]), verbo([expressed]), complemento([sequence, tags, code, for, a, polypeptide, of, 131, amino, acids, '(', 14, 'kDa,', pI, 6.59, ')'])].
[sujeto(['Transcripts', of, 'ASBT', and, 'IBABP,', but, not, 'OSTalpha', and, 'OSTbeta,', were]), verbo([expressed]), complemento([at, higher, levels, in, ileum, than, duodenum])].
[sujeto(['No', significant, differences, in, mean, or, median, values, were]), verbo([found]), complemento([between, the, groups, for, any, of, these, transcripts])].
[sujeto(['However,', findings, on, regression, analysis]), verbo([suggested]), complemento([that, these, transporters, differ, in, their, 'regulation,', particularly, in, the, relationships, of, 'CDX2,', 'LRH-1', and, 'FXR', with, 'OSTalpha'])].
[sujeto(['Most', cases, of, 'IBAM', are, unlikely, to, be]), verbo([caused]), complemento([by, genetic, variation, in, 'FABP6', or, by, major, differences, in, transporter, transcript, expression])].
[sujeto(['To', search, for, common, variants, etiological, for, type, 2, 'diabetes,', we, screened, 15, genes]), verbo([involved]), complemento([in, fat, assimilation, for, sequence, variants])].
[sujeto(['Evidence', for, an, association, with, disease, status, was, also]), verbo([found]), complemento([for, a, novel, 'Arg109Cys', '(', g])].
[sujeto(['The', results, presented, here]), verbo([provide]), complemento([preliminary, evidence, for, the, association, of, common, variants, in, genes, involved, in, fat, assimilation, with, the, genetic, susceptibility, of, type, 2, diabetes])].
[sujeto(['Fatty', acid]), verbo([binding]), complemento([protein, 6, '(', 'FABP6)', is, a, 'cancer-related', protein, that, acts, as, an, intracellular, transporter, of, bile, acid, in, the, ileal, epithelium])].
[sujeto(['The', expression, of, mRNA, was]), verbo([increased]), complemento([in, cancer, compared, with, 'adenoma,', but, was, dramatically, decreased, in, node, metastases])].
[sujeto(['The', expression, of, 'FABP6', was, higher, in, primary, colorectal, cancers, and, adenomas, than, in, normal, 'epithelium,', but, was, dramatically]), verbo([decreased]), complemento([in, lymph, node, 'metastases,', suggesting, that, 'FABP6', may, play, an, important, role, in, early, carcinogenesis])].
[sujeto(['The', fatty, acid]), verbo([binding]), complemento([protein, 6, gene, '(', 'Fabp6)', codes, for, ileal, lipid, binding, protein])].
[sujeto(['An', intronless, 'Fabp6', segment, was]), verbo([found]), complemento([in, four, related, rat, inbred, strains, '(', 'SHR;', 'SHRSP;', 'WKY;', and, 'OKA),', but, not, in, 62, other, rat, inbred, strains])].
[sujeto(['Human', ileal, bile, 'acid-binding', protein, '(', 'I-BABP),', a, member, of, the, family, of, intracellular, lipid]), verbo([binding]), complemento([proteins, plays, a, key, role, in, the, cellular, trafficking, and, metabolic, regulation, of, bile, salts])].
[sujeto(['The', protein]), verbo([has]), complemento([two, internal, 'and,', according, to, a, recent, 'study,', an, additional, superficial, binding, site, and, binds, 'di-', and, trihydroxy, bile, salts, with, positive, cooperativity, and, a, high, degree, of, 'site-selectivity'])].
[sujeto(['Previously,', in, the, apo, 'form,', we]), verbo([have]), complemento([identified, an, extensive, network, of, conformational, fluctuations, on, the, millisecond, time, 'scale,', which, cease, upon, ligation])].
[sujeto(['Additionally,', ligand]), verbo([binding]), complemento([at, room, temperature, was, found, to, be, accompanied, by, a, slight, rigidification, of, 'picosecond-nanosecond', '(', 'ps-ns)', backbone, flexibility])].
[sujeto(['In', the, current, 'study,', 'temperature-dependent', '(', 15, ')', 'N', 'NMR', spin, relaxation, measurements, were, used, to]), verbo([gain]), complemento([more, insight, into, the, role, of, dynamics, in, human, 'I-BABP-bile', salt, recognition])].
[sujeto(['The', 'entropy-enthalpy', compensation, observed, for, both, clusters]), verbo([suggests]), complemento([a, 'disorder-order', transition, between, a, ground, and, a, sparsely, populated, higher, energy, state, in, the, absence, of, ligands])].
[sujeto(['Intriguingly,', while, bile, salt]), verbo([binding]), complemento([results, in, a, more, uniform, response, to, temperature, change, throughout, the, 'protein,', the, temperature, derivative, of, the, generalized, order, parameter, shows, different, responses, to, temperature, increase, for, the, two, forms, of, the, protein, in, the, investigated, temperature, range])].
[sujeto(['Analysis', of, both, slow, and, fast, motions, in, human, 'I-BABP', indicates, largely, different, energy, landscapes, for, the, apo, and, holo, states]), verbo([suggesting]), complemento([that, optimization, of, binding, interactions, might, be, achieved, by, altering, the, dynamic, behavior, of, specific, segments, in, the, protein])].
[sujeto(['Ileal', bile, 'acid-binding', proteins, '(', 'I-BABP),', belonging, to, the, family, of, intracellular, 'lipid-binding', 'proteins,', control, bile, acid, trafficking, in, enterocytes, and]), verbo([participate]), complemento([in, regulating, the, homeostasis, of, these, 'cholesterol-derived', metabolites])].
[sujeto(['However', variations, in, the, primary, sequences, determine, differences, in]), verbo([binding]), complemento([properties, such, as, the, degree, of, binding, cooperativity])].
[sujeto(['A', comparative, structural, analysis, with, closely, related, members, of, the, same, protein, family]), verbo([provided]), complemento([the, basis, to, design, a, double, mutant, '(', 'H99Q/A101S', 'cI-BABP)', capable, of, establishing, a, cooperative, binding, mechanism])].
[sujeto(['Molecular', dynamics, simulation, studies, of, the, wild, type, and, mutant, complexes, and, essential, dynamics, analysis, of, the, trajectories, supported, the, role, of, the, identified, amino, acid, residues, as, hot, spot, mediators, of, communication, between]), verbo([binding]), complemento([sites])].
[sujeto(['The', emerging, picture, is, consistent, with, a]), verbo([binding]), complemento([mechanism, that, can, be, described, as, an, extended, conformational, selection, model])].
[sujeto(['This', study, aims, at, improving, diagnosis, of, intestinal, 'ischemia,', by, measuring, plasma, and, urinary, fatty, acid]), verbo([binding]), complemento([protein, '(', 'FABP)', levels])].
[sujeto(['Plasma', and, urinary, concentrations, of, intestinal, 'FABP', '(', 'I-FABP),', liver, 'FABP', '(', 'L-FABP)', and, ileal, bile, acid]), verbo([binding]), complemento([protein, '(', 'I-BABP)', were, measured, using, 'enzyme-linked', immunosorbent, assays])].
[sujeto(['Positive', and, negative, likelihood, ratios, significantly]), verbo([increased]), complemento([positive, posttest, probability, and, decreased, negative, posttest, probability, on, intestinal, ischemia])].
[sujeto(['In', patients, with, intestinal, ischemia, a, trend, to, higher, plasma, 'I-BABP', levels, was, observed, when, the, ileum, was]), verbo([involved]), complemento(['(', 18.4, 'ng/mL', vs])].
[sujeto(['Cholelithiasis', is, a, multifactorial, 'process,', and, several, mechanisms]), verbo([have]), complemento([been, postulated])].
[sujeto(['A']), verbo([decreased]), complemento([expression, of, the, ileal, apical, 'sodium-dependent', bile, acid, transporter, '(', 'ASBT)', and, of, the, cytosolic, ileal, lipid, binding, protein, '(', 'ILBP)', was, recently, described, in, female, 'non-obese', patients])].
[sujeto(['In', 'conclusion,', an, impaired, function, of, all, three, ileal, bile, acid, transporters, may]), verbo([lead]), complemento([to, low, ileal, bile, acid, reabsorption, and, an, altered, bile, acid, pool, composition, and, therefore, may, contribute, to, the, formation, of, gallstones, in, 'non-obese', patients])].
[sujeto(['We']), verbo([have]), complemento([isolated, a, cDNA, encoding, a, human, intestinal, 15, -, kDa, protein, '(', 'I-15P)', from, a, human, ileal, lambda, gt, 11, cDNA, 'library,', using, a, 'full-length', rat, 'I-15P', cDNA])].
[sujeto(['In', vitro]), verbo([binding]), complemento([studies, revealed, that, the, bacterially, expressed, recombinant, 'I-15P', showed, much, lower, affinities, for, palmitate, and, oleate, than, 'L-FABP'])].
[sujeto(['Comparison', of, the, structural, features, of, human, 'I-15P', and, human, 'L-FABP']), verbo([suggested]), complemento([that, loss, of, a, long, 'alpha-helix', region, and, hydrophobic, profile, of, 'I-15P', may, be, attributable, to, a, unique, 'ligand-binding', specificity, of, 'I-15P'])].
[sujeto(['Immuno-electron', microscopy, further, demonstrated, that, 'I-15P', is, localized, in, both, the, cytoplasmic, and]), verbo([nuclear]), complemento([matrix, regions, of, these, cells])].
[sujeto(['The', present, results]), verbo([suggest]), complemento([roles, of, 'I-15P', not, only, in, the, transport, of, bile, salts, but, also, in, the, metabolisms, of, certain, steroid, hormones])].
[sujeto(['This', cDNA, was]), verbo([found]), complemento([to, contain, an, open, reading, frame, of, 384, nucleotides, as, well, as, 5, '\'', '(', 27, 'nucleotides)', and, 3, '\'', '(', 46, 'nucleotides)', 'non-coding', regions])].
[sujeto(['Northern', blot, analysis, indicated, that, the, same, size, of, transcript, as, that, of, the, ileum, was, detected, in, the, 'ovary,']), verbo([suggesting]), complemento([that, 'I-15P', or, a, homologous, protein, might, be, involved, in, the, metabolism, of, steroids, in, steroid, 'hormone-producing', tissues])].
[sujeto(['The', 14, kDa, bile, acid]), verbo([binding]), complemento([protein, of, rat, ileal, cytosol, '(', 'I-BABP),', previously, shown, to, be, the, major, intracellular, transporter, of, bile, acids, in, 'enterocytes,', was, purified, by, affinity, chromatography, and, gel, electrophoresis])].
[sujeto(['Enzymatic', digestion, of, 'I-BABP', which, had, been, electroblotted, to, nitrocellulose]), verbo([led]), complemento([to, the, recovery, and, sequence, analysis, of, four, peptides, representing, 47, residues, of, sequence, '(', approximately, 35, '%', of, the, full, 'sequence)'])].
[sujeto(['Gastrotropin,', a, peptide, initially, isolated, from, porcine, intestinal, 'extracts,']), verbo([has]), complemento([been, proposed, to, be, an, enterooxyntin])].
[sujeto(['We']), verbo([have]), complemento([isolated, a, full, length, gastrotropin, cDNA, from, a, hog, small, intestinal, lambda, gt11, library])].
[sujeto(['Analysis', of, the, distribution, of, gastrotropin, in, nine, adult, 'Sprague-Dawley', rat, tissues, revealed, that, the, gene, is]), verbo([expressed]), complemento([in, small, intestine, but, not, in, 'stomach,', 'liver,', 'heart,', skeletal, 'muscle,', 'lung,', 'kidney,', 'adrenals,', or, brain])].
[sujeto(['Together', these, data]), verbo([suggest]), complemento([that, gastrotropin, is, not, likely, to, be, secreted, as, a, hormone, or, to, function, as, an, enterooxyntin])].
[sujeto(['Moreover,', it, appears, that, gastrotropin, represents, one, of, several, members, of, the, family, of, hydrophobic, ligand]), verbo([binding]), complemento([proteins, that, are, expressed, in, the, small, intestine])].
[sujeto(['Previous', studies]), verbo([have]), complemento([indicated, that, 'GT', is, a, potent, 'enterooxyntin,', and, to, further, characterize, these, observations, we, have, investigated, the, actions, of, both, porcine, and, canine, 'GT', on, isolated, enriched, preparations, of, guinea, pig, and, dog, parietal, and, chief, cells])].
[sujeto(['The', efficacies, of, canine, and, porcine, 'GT', preparations, in]), verbo([stimulating]), complemento([pepsinogen, secretion, and, '[', 14, 'C]aminopyrine', uptake, were, identical, and, equal, to, those, of, cholecystokinin, octapeptide, '(', 'CCK8)', and, pentagastrin])].
[sujeto(['Maximal', '[', 14, 'C]aminopyrine', accumulation, was, observed, with, 10, '(', -, 8, ')', 'M', 'GT,', with, an, 'ED50', of, 2, x, 10, '(', -, 9, ')', 'M', compared, to, 'pentagastrin,', which]), verbo([caused]), complemento([maximal, accumulation, at, 10, '(', -, 6, ')', 'M', and, had, an, 'ED50', of, 5, x, 10, '(', -, 8, ')', 'M'])].
[sujeto(['The', maximal, chief, cell, response, to, 'GT', was, unaffected, by, the, addition, of, 'CCK8', or, 'carbachol,', but]), verbo([responded]), complemento([additively, with, 'forskolin,', indicating, that, 'GT', uses, the, same, transduction, mechanism, as, 'CCK8', and, carbachol, and, does, not, involve, the, activation, of, adenylate, cyclase])].
[sujeto(['The', stomach, is]), verbo([stimulated]), complemento([by, an, enterooxyntin, factor, in, a, delayed, response, to, 'feeding,', resulting, in, an, increase, in, both, gastric, acid, and, pepsinogen, secretion])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, on, the, identity, of, such, a, factor, from, the, porcine, ileum, '(', 'Wider,', 'M'])].
[sujeto(['We']), verbo([have]), complemento([completed, the, primary, structure, of, porcine, gastrotropin, by, 'Edman', degradation, and, mass, spectrometry])].
[sujeto(['Gastrotropin', '(', 'Mr', =, 14, ',', 54, ')', contains, 127, amino, acid, residues, and]), verbo([has]), complemento([a, blocked, '(', 'acetylated)', alanine, at, its, 'NH2', terminus])].
[sujeto(['The', sequences, of, the, 'NH2-terminal', regions, of, these, proteins, account, for, virtually, all, of, the, 'homology;', there, are, 9]), verbo([conserved]), complemento([residues, common, to, all, five, proteins])].
[sujeto(['Gastrotropin', represents, the, first, member, of, the, 'FABP', family, which]), verbo([has]), complemento([an, extracellular, function])].
[sujeto(['In', preliminary, studies, we]), verbo([found]), complemento([that, circulating, 'HEX', activity, became, elevated, following, 3, to, 4, hr, of, vessel, occlusion, followed, by, reperfusion])].
[sujeto(['(', 'ABSTRACT', 'TRUNCATED', 'AT', 250, 'WORDS)', 'Porcine', ileal, 'polypeptide,', an, enterooxyntin, isolated, from, distal, small, intestinal, mucosal, 'epithelium,']), verbo([has]), complemento([been, observed, to, stimulate, gastric, acid, secretion, in, vivo, as, well, as, in, vitro, '(', 'Wider,', 'M'])].
[sujeto(['We']), verbo([report]), complemento([here, that, porcine, ileal, polypeptide, stimulates, both, acid, '(', aminopyrine, 'accumulation)', and, pepsinogen, secretion, in, 'isolated,', enriched, populations, of, guinea, pig, parietal, and, chief, cells, in, a, 'dose-dependent', manner])].
[sujeto(['Further,', 10, '(', -, 9, ')', 'M', porcine, ileal, polypeptide]), verbo([caused]), complemento([an, increase, in, cytoplasmic, 'Ca2+', concentration, in, both, parietal, and, chief, cells, similar, in, magnitude, to, that, observed, with, 'gastrin-17', '(', 10, '(', -, 8, ')', 'M)', '(', as, measured, by, both, 'fura-2', and, 'aequorin)', and, cholecystokinin, octapeptide, '(', 'CCK-OP)', '(', 10, '(', -, 8, ')', 'M),', respectively])].
[sujeto(['Porcine', ileal, polypeptide]), verbo([has]), complemento([been, observed, to, cause, no, stimulation, of, cAMP, production, in, gastric, glands, from, guinea, pigs, '(', 'Gespach,', 'C'])].
[sujeto(['It', is, concluded, that, porcine, ileal, 'polypeptide,', at, concentrations, similar, to, circulating, levels, observed, in, plasma, of, normal, pigs, '(', 5, x, 10, '(', -, 9, ')', 'M),']), verbo([acts]), complemento([directly, on, the, parietal, and, chief, cells, to, cause, the, mobilization, of, intracellular, 'Ca2+', from, the, stores, resulting, in, acid, and, pepsinogen, secretion])].
[sujeto(['These', experiments, demonstrate, that, this, peptide, is, a, potent, enterooxyntin, and, chief, cell, secretagogue, which]), verbo([acts]), complemento([via, the, same, signal, transduction, mechanisms, as, gastrin, and, cholecystokinin])].
[sujeto(['[', 125, 'I]PIP', was, prepared, by, the, lactoperoxidase, 'method,', and]), verbo([bound]), complemento([and, free, were, separated, by, the, addition, of, a, second, 'antibody,', goat, 'anti-rabbit', immunoglobulin, 'G'])].
[sujeto(['The', assay, is, sensitive, to, 0.5, 'ng/ml', and]), verbo([has]), complemento([a, detection, limit, of, 0.1, 'ng/ml'])].
[sujeto(['Plasma', was, diluted, 1, :, 10, for, assay, and, was]), verbo([found]), complemento([to, have, 32.5, +, /, -, 5.5, and, 50.6, +, /, -, 6.6, 'ng/ml', immunoreactive, 'PIP,', respectively])].
[sujeto(['Intramuscular', injection, of, 1, microgram, 'PIP', every, hour, for, 3, h, in, conscious, rats, with, a, ligated, pylorus]), verbo([stimulated]), complemento([both, volume, and, acid, secretion, by, the, stomach, '(', 'P', less, than, 0.0005, ')', :, 'PIP', '(', n, =, 25, ')', 286, +, /, -, 23, mumol, 'H+,', and, 3.23, +, /, -, 0.23, ml, fluid, vs])].
[sujeto(['It', is, concluded, that, 'PIP', is, secreted, into, the, circulation, in, normal, pigs, and]), verbo([causes]), complemento([an, increase, in, gastric, secretion, of, acid, and, fluid, volume, in, vivo, as, well, as, the, previously, observed, action, on, the, gastric, mucosa, in, vitro])].
[sujeto(['Asynchronous', replication, patterns, of, the, analysed, genes, were, observed, in, both, amniotic, cell, cultures, but, the, percentage, of, interphase, nuclei, presenting, with, asynchronous, replication, was, significantly]), verbo([increased]), complemento([in, the, cultures, with, synchronisation, '(', 40, -, 51, '%', ')', ',', as, compared, to, those, without, synchronisation, '(', 20, -, 23, '%', ')'])].
[sujeto(['In', 'contrast,', the, percentage, of, cells, with, asynchronous, replication, in, the, case, with, 'i(15p)', was, significantly]), verbo([decreased]), complemento(['(', 3, -, 6, '%', ')', ',', as, compared, to, the, control, 'value,', and, it, may, be, indicated, by, uniparental, disomy, of, chromosome, 15, '(', 'UPD15)'])].
[sujeto(['In', 'addition,', those, results]), verbo([have]), complemento([been, confirmed, by, molecular, 'evaluation,', using, the, methylation, diagnostic, test, for, diagnosis, of, the, 'Prader-Willi', 'Syndrome'])].
[sujeto(['A', 'lipid-binding', protein, identical, to, the, rat, intestinal, bile, 'acid-binding', 'protein,', termed, 'I-15P,', was]), verbo([expressed]), complemento([in, steroid, 'hormone-producing', tissues, such, as, ovary, and, adrenal, 'gland,', but, not, testis])].
[sujeto(['In', immature, 'rats,', 'I-15P', was]), verbo([expressed]), complemento([in, intestine, but, not, in, ovaries])].
[sujeto(['The', expression, of, 'I-15P', in, the, ovaries, of, immature, rats, was]), verbo([induced]), complemento([to, the, level, in, immature, rats, by, gonadotropin, treatment])].
[sujeto(['This']), verbo([suggests]), complemento([that, the, expression, of, 'I-15P', in, the, ovaries, is, controlled, by, the, ovarian, cycle])].
[sujeto(['Our', colleagues, and, we]), verbo([have]), complemento([determined, the, complete, primary, structure, of, a, low, molecular, weight, cytoplasmic, 'FABP', '(', also, known, as, 'z-protein)', that, binds, to, 'LCFAs', with, high, 'affinities,', obtained, from, rat, liver])].
[sujeto(['Since', 'then,', extensive, investigation, of, 'structures,', functions, and, expressions]), verbo([has]), complemento([been, carried, out, on, a, whole, family, of, 'FABPs'])].
[sujeto(['Analyses', of, rat, heart, 'FABP;', 'FABP1,', 'FABP3', and, 'alpha(2U)-globulin']), verbo([expressed]), complemento([in, rat, 'kidney;', discovery, of, ileal, 'FABP6', '(', 'I-15P);', and, first, application, of, 'FABP2', as, a, diagnostic, marker, also, stand, out, in, particular])].
[sujeto(['Substitution', of, the, 'helix-turn-helix', capping, motif, '(', residues, 9, -, 35, ')', of, rabbit, 'I-BABP', with, a, flexible, 'Gly-Gly-Ser-Gly', linker, results, in, the]), verbo([loss]), complemento([of, stabilizing, hydrophobic, contacts, and, renders, the, 'beta-clamshell', structure, of, this, steroidal, bile, acid, transport, protein, unfolded])].
[sujeto(['However,', in, the, presence, of, a, bile, acid, 'ligand,', we, observe, strong, coupling, between]), verbo([binding]), complemento([and, 'folding,', resulting, in, an, 'enthalpy-driven', 'high-affinity', interaction, '(', 'K(A)', approximately, 4, x, 10, '(', 5, ')', 'M(-1))', that, &, 'quot;rescues&quot;', the, native, state])].
[sujeto(['We', investigate, the, mechanism, of]), verbo([induced]), complemento([folding, using, fluorescence, 'stopped-flow', kinetic, measurements, to, distinguish, between, conformational, selection, and, 'induced-fit', models])].
[sujeto(['We', observe, both, 'ligand-dependent', and, -, independent, kinetic, phases, 'which,', together, with, their, relative, 'amplitudes,', we, attribute, to, an, 'induced-fit', &, 'quot;fly', 'casting&quot;', type, of, model, in, which, transient, encounter, complexes, between, the, ligand, and, the, extended, polypeptide, chain, may]), verbo([act]), complemento([as, nucleation, sites, for, folding])].
[sujeto(['We', show, that, the, intermediate, forms, at, a, rate, 1000, times, slower, than, the, rate, of, ligand, association, with, 'wild-type', 'I-BABP,', reflecting, the, large, configurational, entropic, barrier, to, the, coupled]), verbo([binding]), complemento([and, folding, steps, of, 'Deltaalpha-I-BABP'])].
[sujeto(['We']), verbo([have]), complemento([provided, mechanistic, insights, into, how, natively, disordered, 'states,', now, commonly, identified, in, 'biology,', may, fold, on, binding, a, target, substrate, or, ligand])].
[sujeto(['The', ileal, lipid]), verbo([binding]), complemento([protein, '(', 'ilbp)', is, a, cytoplasmic, protein, that, binds, bile, acids, with, high, affinity])].
[sujeto(['Elimination', of, ilbp]), verbo([increased]), complemento([fecal, bile, acid, excretion, '(', 54.2, '%', ',', 'P&lt;0'])].
[sujeto(['The', activity, of, cholesterol, 7, 'α-hydroxylase', '(', 'cyp7a1),', the, 'rate-controlling', enzyme, of, the, classical, bile, acid, biosynthetic, 'pathway,', was, significantly]), verbo([increased]), complemento([in, female, '(', 63.5, '%', ',', 'P&lt;0'])].
[sujeto(['The']), verbo([retained]), complemento([fraction, of, the, '[', '(', 3, ')', 'H]TCA', localized, in, the, small, and, large, intestines, was, increased, by, 22, '%', '(', 'P&lt;0'])].
[sujeto([2, ')', and]), verbo([decreased]), complemento([by, 62.7, '%', '(', 'P&lt;0'])].
[sujeto(['Mucosal', to, serosal, bile, acid, transport, using, everted, distal, gut, sacs, was]), verbo([decreased]), complemento([by, 74, '%', '(', 'P&lt;0'])].
[sujeto(['The', results, demonstrate, that, ilbp, is]), verbo([involved]), complemento([in, the, apical, to, basolateral, transport, of, bile, acids, in, ileal, 'enterocytes,', and, is, vital, for, the, maintenance, of, bile, acid, homeostasis, in, the, enterohepatic, circulation, '(', 'EHC)', in, mice])].
[sujeto(['Recently,', interest]), verbo([has]), complemento([been, shown, in, 'drug-drug', interactions, in, the, intestine])].
[sujeto(['It', is, now]), verbo([recognized]), complemento([that, changes, in, the, functions, of, drug, transporters, substantially, influence, the, absorption, of, administered, drugs, from, the, intestine])].
[sujeto(['AMD', significantly, and, rapidly]), verbo([increased]), complemento([the, uptake, of, '[', '(', 3, ')', 'H]estrone-3-sulfate', '(', 'E-3-S)', for, 5, min])].
[sujeto(['The', 'apical-to-basal', transport, of, '[', '(', 3, ')', 'H]E-3-S', was, significantly]), verbo([increased]), complemento([by, 'AMD'])].
[sujeto(['The', 'AMD-stimulated', '[', '(', 3, ')', 'H]E-3-S', uptake, was]), verbo([inhibited]), complemento([by, organic, anion, transporting, polypeptide, '(', 'OATP)', substrates])].
[sujeto(['Caco-2', cells, treated, with, 'AMD', showed]), verbo([increased]), complemento(['OATP2B1', expression, on, the, cell, surface])].
[sujeto(['AMD', also]), verbo([increased]), complemento([the, absorption, of, sulfobromophthalein, '(', 'BSP),', which, is, a, typical, organic, anion, 'compound,', and, the, expression, level, of, 'Oatp2b1', at, the, membrane, in, in, vivo, experiments])].
[sujeto(['The', results, indicate, that, 'AMD']), verbo([induces]), complemento(['OATP2B1/Oatp2b1', expression, at, the, membrane, in, the, intestine, and, enhances, absorption, of, organic, anion, compounds])].
[sujeto(['Cooperative']), verbo([binding]), complemento([pervades, 'Nature'])].
[sujeto(['ITC']), verbo([has]), complemento([broad, scope, in, the, analysis, of, cooperativity, as, it, determines, binding, 'stiochiometries,', affinities, and, thermodynamic, 'parameters,', including, enthalpy, and, entropy, in, a, single, experiment])].
[sujeto(['Allergies']), verbo([involve]), complemento([a, state, of, immediate, hypersensitivity, to, 'antigens,', including, food, proteins])].
[sujeto(['The', mechanism, underlying, the, initiation, and, development, of, allergic, responses]), verbo([involves]), complemento(['IL-4', that, directly, induces, the, differentiation, of, committed, effector, 'Th2', lymphocytes])].
[sujeto(['Although', it, is, clear, that, 'Th2', responses, play, a, pivotal, role, in, the, development, of, allergic, 'responses,', it, remains, unclear, which, mechanisms, are]), verbo([involved]), complemento([in, the, development, of, the, intestinal, damages, observed, in, food, allergy])].
[sujeto(['Results', demonstrated, that, exposure, to, peanut, seeds]), verbo([led]), complemento([to, weight, loss, in, 'WT', but, not, in, 'IL-4-/-', mice, that, preserved, gut, integrity, with, no, signs, of, mucosal, inflammation])].
[sujeto(['These', animals, presented]), verbo([increased]), complemento([levels, of, 'IgG2a', in, 'sera,', suggesting, a, role, for, allergic, antibodies, in, the, pathogenesis, of, 'WT', animals])].
[sujeto(['Most', 'importantly,', results, also, showed, that, lack, of, 'IL-4']), verbo([modulated]), complemento([gut, mucosal, response, in, food, allergy, through, diminished, expression, of, 'TNF-alpha', 'mRNA,', increased, 'Th1', 'IFN-gamma,', 'IL-12p40,', regulatory, 'cytokines,', and, 'Foxp3,', demonstrating, their, relevance, in, the, control, of, allergic, inflammatory, 'processes,', especially, in, the, intestine])].
[sujeto(['Finally,', this, study, highlighted, some, of, the, complex, mechanisms]), verbo([involved]), complemento([in, the, pathogenesis, of, allergic, responses, to, food, antigens, in, the, 'gut,', thereby, providing, valuable, tools, for, directing, novel, therapeutic, or, preventive, strategies, to, the, control, of, allergic, enteropathy])].
[sujeto(['Fatty', acid]), verbo([binding]), complemento([protein, 6, '(', 'FABP6)', is, a, potential, drug, discovery, 'target,', 'which,', if, 'inhibited,', may, have, a, therapeutic, benefit, for, the, treatment, of, diabetes])].
[sujeto(['Currently,', there, are, no, published, inhibitors, of, 'FABP6,', and, with, the]), verbo([target]), complemento([believed, to, be, amenable, to, 'fragment-based', drug, 'discovery,', a, structurally, enabled, program, was, initiated])].
[sujeto(['Several', hits, were, validated, with, 'SAR', and, were]), verbo([found]), complemento([to, be, displaced, by, the, natural, ligand, taurocholate])].
[sujeto(['We']), verbo([report]), complemento([the, first, crystal, structure, of, human, 'FABP6', in, the, unbound, 'form,', in, complex, with, 'cholate,', and, with, one, of, the, key, fragments])].
[sujeto(['In', order, to]), verbo([provide]), complemento([better, understanding, of, the, molecular, biology, of, ccRCC, and, to, identify, potential, 'diagnostic/prognostic', biomarker, and, therapeutic, 'targets,', we, utilized, a, microarray, to, profile, mRNA, expression, of, corresponding, normal, and, malignant, renal, tissues])].
[sujeto([ccRCC, cell, lines, were, treated, with, sertraline, to]), verbo([inhibit]), complemento([the, dopamine, transporter, 'SLC6A3'])].
[sujeto(['Immunohistochemistry', indicated, that, this]), verbo([decrease]), complemento([was, due, to, higher, concentrations, of, 'SLC6A3', in, the, proximal, tubules])].
[sujeto(['Treatment', of, ccRCC, cells, with, the, 'SLC6A3', inhibitor, sertraline]), verbo([induced]), complemento(['dose-dependent', 'cell-death'])].
[sujeto(['Protein', levels, of, endotoxin, and, 'α1-acid', glycoprotein, '(', 'AGP)', in, 'serum,', as, well, as, mRNA, levels, of, interleukin, '(', 'IL)-8,', 'IL-1β,', transforming, growth, factor, '(', 'TGF)-β4,', and, fatty, 'acid-binding', protein, '(', 'FABP)', 6, were]), verbo([increased]), complemento(['(', 'P', &, 'lt;', 0.05, ')', in, 'GBF', birds, compared, to, 'CON', 'birds;', 'however,', mRNA, levels, of, 'FABP2,', 'occludin,', and, mucin, 2, '(', 'MUC2)', were, reduced, by, 34, '%', '(', 'P', &, 'lt;', 0.05, ')', ',', 24, '%', '(', 'P', =, 0.107, ')', ',', and, 29, '%', '(', 'P', =, 0.088, ')', ',', 'respectively,', in, 'GBF', birds, compared, to, 'CON', birds])].
[sujeto(['The', results, from, the, present, study]), verbo([suggest]), complemento([that, serum, endotoxin, and, 'AGP,', as, well, 'as,', gene, expression, of, 'FABP2,', 'FABP6,', 'IL-8,', 'IL-1β,', 'TGF-β4,', 'occludin,', and, 'MUC2', in, mucosa, may, work, as, potential, biomarkers, for, gut, barrier, health, in, chickens])].
[sujeto(['In', 'colon,', 184, proteins, were, detected, in, the, infected, samples, of, which, 46, resulted, differentially]), verbo([expressed]), complemento([with, respect, to, the, controls])].
[sujeto(['Further', biological, interpretation, of, proteomics, data, using, bioinformatics, tools, demonstrated, that, the, expression, changes, in, colon, were]), verbo([found]), complemento([in, proteins, involved, in, cell, death, and, 'survival,', tissue, morphology, or, molecular, transport, at, the, early, stages, and, tissue, regeneration, at, 6, dpi])].
[sujeto([iTRAQ]), verbo([has]), complemento([proved, to, be, a, proteomic, robust, approach, allowing, us, to, identify, ileum, as, the, earliest, response, focus, upon, 'S'])].
[sujeto(['In', 'addition,', new, functions]), verbo([involved]), complemento([in, the, response, to, bacteria, such, as, eIF2, 'signaling,', free, radical, scavengers, or, antimicrobial, peptides, '(', 'AMP)', expression, have, been, identified])].
[sujeto(['Finally,', the, impairment, at, of, the, enterohepatic, circulation, of, bile, acids, and, lipid, metabolism, by, means, the, under, regulation, of, 'FABP6', protein, and, 'FXR/RXR', and, 'LXR/RXR', signaling, pathway, in, ileum]), verbo([has]), complemento([been, established, for, the, first, time, in, pigs])].
[sujeto(['Taken', 'together,', our, results]), verbo([provide]), complemento([a, better, understanding, of, the, porcine, response, to, 'Salmonella', infection, and, the, molecular, mechanisms, underlying, 'Salmonella-host', interactions])].
[sujeto(['The', fatty, acid]), verbo([binding]), complemento([protein, 6, '(', 'Fabp6)', is, commonly, regarded, as, a, bile, acid, binding, protein, found, in, the, distal, portion, of, the, small, intestine, and, has, been, shown, to, be, important, in, maintaining, bile, acid, homeostasis])].
[sujeto(['Previous', studies]), verbo([have]), complemento([also, reported, the, presence, of, 'Fabp6', in, 'human,', rat, and, fish, 'ovaries,', but, the, significance, of, 'Fabp6', in, this, organ, is, largely, unknown])].
[sujeto(['Here', we, show, that, the, 'Fabp6', gene, is]), verbo([expressed]), complemento([in, granulosa, and, luteal, cells, of, the, mouse, ovary])].
[sujeto(['Treatment', with, gonadotropins]), verbo([stimulated]), complemento(['Fabp6', gene, expression, in, large, antral, follicles])].
[sujeto(['The', ovulation, rate, in, response, to, superovulatory, treatment, in, 'Fabp6-deficient', mice, was, markedly]), verbo([decreased]), complemento([compared, to, wildtype, '(', 'C57BL/6)', mice])].
[sujeto(['The', results, of, this, study]), verbo([suggest]), complemento([that, expression, of, 'Fabp6', gene, in, granulosa, cells, serves, an, important, and, previously, unrecognized, function, in, fertility])].
[sujeto(['The']), verbo([increased]), complemento([use, of, plant, oil, as, a, dietary, supplement, with, the, resultant, high, dietary, lipid, loads, challenges, the, lipid, 'transport,', metabolism, and, storage, mechanisms, in, economically, important, aquaculture, 'species,', such, as, rainbow, trout])].
[sujeto(['Fatty', 'acid-binding', proteins, '(', 'Fabp),', ubiquitous, in, tissues, highly, active, in, fatty, acid, 'metabolism,']), verbo([participate]), complemento([in, lipid, uptake, and, 'transport,', and, overall, lipid, homeostasis])].
[sujeto(['Phylogenetic', analyses]), verbo([suggest]), complemento([that, many, of, these, extant, fabp, genes, in, rainbow, trout, exist, as, 'duplicates,', which, putatively, arose, owing, to, the, 'teleost-specific', whole, genome, duplication, '(', 'WGD);', three, pairs, of, duplicated, fabp, genes, '(', fabp2a])].
[sujeto(['The', suite, of, fabp, genes, described, here]), verbo([provides]), complemento([the, foundation, to, investigate, the, 'role(s)', of, fatty, 'acid-binding', proteins, in, the, 'uptake,', mobilization, and, storage, of, fatty, acids, in, cultured, fish, fed, diets, differing, in, lipid, 'content,', especially, the, use, of, plant, oil, as, a, dietary, supplement])].
[sujeto(['These', nutritional, dietary, supplements, may, well]), verbo([lead]), complemento([to, high, lipid, loads, with, the, resultant, challenges, to, lipid, homeostasis, 'and,', 'thus,', health, of, cultivated, fish, which, may, be, mediated, by, appropriate, transcriptional, control, of, fabp, genes])].
[sujeto(['The', 'enucleation-induced', '(', 'EI)', rapid, proliferation, of, adrenocortical, cells, is, followed, by, their, 'differentiation,', the, degree, of, which, may, be, characterized, by, the, expression, of, genes, directly, and, indirectly]), verbo([involved]), complemento([in, steroid, hormone, biosynthesis])].
[sujeto(['In', this, 'study,', out, of, 30, ',', 0, transcripts, of, genes, identified, by, means, of, 'Affymetrix', 'Rat', 'Gene', 1.1, 'ST', 'Array,', we, aimed, to, select, genes, '(', either, 'up-', or, 'downregulated)']), verbo([involved]), complemento([in, steroidogenesis, in, the, course, of, 'enucleation-induced', adrenal, regeneration])].
[sujeto(['On', day, 1, ',', we]), verbo([found]), complemento([32, genes, with, altered, expression, 'levels,', 15, were, upregulated, and, 17, were, downregulated, '[', i])].
[sujeto([',', 3, 'β-hydroxysteroid', dehydrogenase, '(', 'Hsd3β),']), verbo([nuclear]), complemento([receptor, subfamily, 0, ',', group, 'B,', member, 1, '(', 'Nr0b1),', cytochrome, 'P450', aldosterone, synthase, '(', 'Cyp11b2)', and, sterol, 'O-acyltransferase', 1, '(', 'Soat1)]'])].
[sujeto(['On', day, 15, ',', the, expression, of, only, 2, genes, was]), verbo([increased]), complemento([and, that, of, 3, was, decreased])].
[sujeto(['Fatty', acid]), verbo([binding]), complemento([protein, 6, '(', 'Fabp6)', was, markedly, 'upregulated,', whereas, 'hormone-sensitive', lipase, '(', 'Lipe)', was, downregulated])].
[sujeto(['The', expression, of, 'Soat1', was, lowest, on, regeneration, day, 1, 'and,', 'subsequently,', its, expression]), verbo([increased]), complemento([from, there, 'on,', reaching, levels, higher, than, the, control])].
[sujeto(['After', the, initial]), verbo([decrease]), complemento([in, steroidogenic, factor, 1, '(', 'Sf-1)', mRNA, levels, observed, on, the, 1, st, day, of, the, 'experiment,', a, marked, upregulation, in, its, expression, was, observed, from, there, on])].
[sujeto(['Data', from, the, current, study, strongly]), verbo([suggest]), complemento([the, role, of, 'Fabp6,', 'Lipe', and, 'Soat1', in, supplying, substrates, of, regenerating, adrenocortical, cells, for, steroid, synthesis])].
[sujeto(['Moreover,', our, data, demonstrated, that, in, 'enucleation-induced', 'regeneration,', the, restoration, of, genes]), verbo([involved]), complemento([in, glucocorticoid, synthesis, is, notably, shorter, than, that, of, those, involved, in, aldosterone, synthesis])].
[sujeto(['In', order, to, identify, genetic, variants]), verbo([associated]), complemento([with, 'fatness,', we, used, a, selective, genomic, approach, sampling, 'DNA', from, animals, at, the, extreme, ends, of, the, fat, and, lean, spectrum, using, estimated, breeding, values, derived, from, a, total, population, size, of, over, 70, ',', 0, animals])].
[sujeto(['Quantitative', analysis, of, the, data, identified, putative, 'CNV', regions, containing, genes, whose, ontology]), verbo([suggested]), complemento([fatness, related, functions, '(', 'MCHR1,', 'PPARα,', 'SLC5A1', and, 'SLC5A4)'])].
[sujeto(['Selective', genotyping, of, 'EBVs', at, either, end, of, the, phenotypic, spectrum, proved, to, be, a, cost, effective, means, of, identifying, 'SNPs', and, 'CNVs']), verbo([associated]), complemento([with, fatness, and, with, estimated, major, effects, in, a, large, population, of, animals])].
[sujeto(['The', study, objectives, 'were:', to, mine, the, complete, exome, to, identify, putative, rare, single, nucleotide, variants, '(', 'SNVs)']), verbo([associated]), complemento([with, irritable, bowel, syndrome, '(', 'IBS)-diarrhea', '(', 'IBS-D)', 'phenotype,', to, assess, genes, that, regulate, bile, acids, in, 'IBS-D,', and, to, explore, univariate, associations, of, 'SNVs', with, symptom, phenotype, and, quantitative, traits, in, an, independent, 'IBS', cohort])].
[sujeto(['Using', principal, components, 'analysis,', we, identified, two, groups, of, 'IBS-D', '(', n, =, 16, ')', with]), verbo([increased]), complemento([fecal, bile, 'acids:', rapid, colonic, transit, or, high, bile, acids, synthesis])].
[sujeto(['Mining', the, complete, exome, did, not]), verbo([reveal]), complemento([significant, associations, with, 'IBS-D', over, controls])].
[sujeto(['Variations', in, 'KLB', '(', 'rs1015450,', 'downstream)', and, 'FGFR4', '[', rs434434, '(', 'intronic),', 'rs1966265,', and, rs351855, '(', 'nonsynonymous)]', were]), verbo([associated]), complemento([with, colonic, transit, '(', 'rs1966265;', 'P', =, 0.043, ')', ',', fecal, bile, acids, '(', 'rs1015450;', 'P', =, 0.064, ')', ',', and, principal, components, analysis, groups, '(', all, 3, 'FGFR4', 'SNVs;', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['In', the, 633, -, person, 'cohort,', 'FGFR4', rs434434, was]), verbo([associated]), complemento([with, symptom, phenotype, '(', 'P', =, 0.027, ')', and, rs1966265, with, 24, -, h, colonic, transit, '(', 'P', =, 0.066, ')'])].
[sujeto(['Thus', exome, sequencing, identified, additional, variants, in, 'KLB', and, 'FGFR4']), verbo([associated]), complemento([with, bile, acids, or, colonic, transit, in, 'IBS-D'])].
[sujeto(['Consistent', with, the, microarray, and, quantitative, 'RT-PCR', 'experiments,', immunohistochemical, expression, of, 'ANXA10', was, markedly]), verbo([increased]), complemento([in, 'SSA/Ps', compared, to, 'MVHPs', '(', p, &, 'lt;', 0.0001, ')'])].
[sujeto(['An', 'ANXA10', score, '≥', 3]), verbo([has]), complemento([a, sensitivity, of, 73, '%', and, a, specificity, of, 95, '%', in, the, diagnosis, of, an, 'SSA/P'])].
[sujeto(['In', 'conclusion,', we, show, that, 'SSA/Ps', and, 'MVHPs']), verbo([have]), complemento([significant, overlap, in, gene, 'expression,', but, also, important, 'differences,', particularly, in, 'cancer-related', pathways])].
[sujeto(['Transcription', of, some, duplicated, fabp, genes, is]), verbo([modulated]), complemento([by, fatty, acids, '(', 'FAs)', 'and/or', 'clofibrate,', a, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)', agonist])].
[sujeto([acox1, transcripts, were, not]), verbo([induced]), complemento([in, the, brain, of, fish, fed, 'clofibrate,', which, suggests, this, drug, may, not, cross, the, blood, brain, barrier])].
[sujeto(['The', 'steady-state', level, of, fabp2, transcripts]), verbo([increased]), complemento([in, 'intestine,', while, fabp3, mRNA, increased, in, liver, of, fish, fed, diets, differing, in, 'FA', content])].
[sujeto(['All', 'Fabp6a', and, 'Fabp6b', from, different, species, cluster, together, in, a, distinct, clade, in, phylogenetic, analysis, and, the, topology, of, the, tree]), verbo([suggests]), complemento([that, fabp6a, and, fabp6b, from, medaka, and, 'three-spined', stickleback, are, most, likely, duplicated, genes, of, an, ancestral, 'FABP6', owing, to, 'teleost-specific', 'whole-genome', duplication])].
[sujeto(['The', 'tissue-specific', distribution, of, fabp6a, transcripts]), verbo([suggests]), complemento([the, retention, of, ancestral, 'function(s)', of, the, fabp6a, gene, in, medaka, and, 'three-spined', stickleback, with, acquisition, of, new, 'function(s)', in, different, tissues])].
[sujeto(['However,', the, 'tissue-specific', regulation, of, the, fabp6b, gene]), verbo([has]), complemento([diverged, markedly, in, medaka, and, 'three-spined', stickleback, since, the, duplication, of, the, fabp6, gene])].
[sujeto(['Phylogenetic', analysis, of, avian, and, other, vertebrate, fatty, acid]), verbo([binding]), complemento([proteins, '(', 'FABPs)', supported, the, hypothesis, that, several, gene, duplications, within, this, family, occurred, prior, to, the, most, recent, common, ancestor, '(', 'MRCA)', of, tetrapods, and, bony, fishes])].
[sujeto(['Since', these, clusters, corresponded, to, major, clusters, in, the, phylogenetic, tree, as, 'well,', it, seems, a, plausible, hypothesis, that, the, earliest, duplication, in, the, vertebrate, 'FABP', family]), verbo([led]), complemento([to, the, divergence, of, a, 'gut-specialized', gene, from, a, gene, expressed, mainly, in, nervous, and, muscular, systems])].
[sujeto(['Numerous', studies]), verbo([have]), complemento([suggested, that, hyperlipidemia, is, closely, linked, to, cardiovascular, disease])].
[sujeto(['For', the, male, 'rats,', compared, with, the, hyperlipidemia, 'group,', the, middle, dosage, 'HU', had, the, most, pronounced, effect, on]), verbo([increasing]), complemento([the, mRNA, levels, of, 'FXR', '(', p, &, 'lt;', 0.01, ')', ;, 'low-', and, 'high-dosage', 'HU', showed, a, significant, inhibition, of, the, mRNA, levels, of, 'LXR', '(', p, &, 'lt;', 0.01, ')'])].
[sujeto(['The', heteromeric, organic, solute, transporter, 'alpha-beta', '(', 'Ostα-Ostβ)', is]), verbo([expressed]), complemento([at, relatively, high, levels, on, the, basolateral, membrane, of, 'enterocytes,', where, it, plays, a, critical, role, in, the, intestinal, absorption, of, bile, acids, and, the, enterohepatic, circulation])].
[sujeto(['However,', this, transporter, is, also]), verbo([expressed]), complemento([in, nearly, all, human, 'tissues,', including, those, that, are, not, normally, thought, to, be, involved, in, bile, acid, 'homeostasis,', indicating, that, 'Ostα-Ostβ', may, have, additional, roles, beyond, bile, acid, transport, in, these, other, 'tissues,', or, that, bile, acids, and, their, derivatives, are, more, pervasive, than, currently, envisioned])].
[sujeto(['Emerging', data, from, different, laboratories]), verbo([provide]), complemento([support, for, both, of, these, hypotheses])].
[sujeto(['In', 'particular,', recent, studies, indicate, that, tissues, such, as, brain, and, ovary]), verbo([have]), complemento([the, capacity, to, synthesize, bile, acids, or, bile, acid, precursors])].
[sujeto(['In', 'addition,', studies, examining, 'Ostα-Ostβ', substrate, specificity]), verbo([have]), complemento([revealed, that, this, transporter, can, also, accept, conjugated, 'steroids,', including, some, 'neurosteroids,', and, that, the, transporter, is, selectively, expressed, in, steroidogenic, cells, of, the, brain, and, adrenal, 'gland,', suggesting, a, novel, function, for, 'Ostα-Ostβ'])].
[sujeto(['The', broad, tissue, expression, of, 'Ostα-Ostβ', is, also, consistent, with, the, emerging, concept, that, bile, acids, and, their, derivatives]), verbo([act]), complemento([as, signaling, molecules, in, diverse, tissues])].
[sujeto(['Bile', acids]), verbo([activate]), complemento([nuclear, receptors, such, as, the, farnesoid, 'X', receptor, '(', 'FXR/NR1H4),', the, pregnane, 'X', receptor, and, the, vitamin, 'D', 'receptor,', are, ligands, for, a, 'G-protein-coupled', bile, acid, receptor, '(', 'GPBAR1/TGR5),', and, can, also, activate, protein, kinases, 'A', and, 'C', as, well, as, 'mitogen-activated', protein, kinase, pathways])].
[sujeto(['These', signaling, pathways, are, present, in, many, tissues, and]), verbo([regulate]), complemento([processes, such, as, 'triglyceride,', glucose, and, energy, homeostasis])].
[sujeto(['Note', that, although, 'FXR', and, 'TGR5', are, thought, to, function, primarily, as, bile, acid, 'receptors,', they, are]), verbo([modulated]), complemento([by, some, other, sterols, and, select, lipid, 'metabolites,', and, are, also, widely, expressed, in, 'tissues,', indicating, a, complex, interplay, among, diverse, regulatory, networks, that, impact, critical, cell, and, organ, functions])].
[sujeto(['The', present]), verbo([report]), complemento([summarizes, the, evidence, for, a, pleiotropic, role, of, 'Ostα-Ostβ', in, different, tissues])].
[sujeto(['Besides', their, 'well-established', roles, in, dietary, lipid, absorption, and, cholesterol, 'homeostasis,', bile, acids, '(', 'BA)', also]), verbo([act]), complemento([as, metabolically, active, signaling, molecules])].
[sujeto(['glucose,', 'lipids),']), verbo([provides]), complemento([a, signal, that, coordinates, hepatic, triglyceride, '(', 'TG),', glucose, and, energy, homeostasis])].
[sujeto(['As', signaling, molecules, with, systemic, endocrine, 'functions,', 'BA', can]), verbo([activate]), complemento([protein, kinases, 'A', and, 'C', as, well, as, 'mitogen-activated', protein, kinase, pathways])].
[sujeto(['Additionally,', they, are, ligands, for, a, 'G-protein-coupled', 'BA', receptor, '(', 'TGR5/Gpbar-1)', and]), verbo([activate]), complemento([nuclear, receptors, such, as, farnesoid, 'X', receptor, '(', 'FXR;', 'NR1H4)'])].
[sujeto(['FXR', and, its, downstream]), verbo([targets]), complemento([play, a, key, role, in, the, control, of, hepatic, de, novo, 'lipogenesis,', 'very-low-density', 'lipoprotein-TG', export, and, plasma, 'TG', turnover])].
[sujeto(['BA-activated', 'FXR', and, signal, transduction, pathways, are, also]), verbo([involved]), complemento([in, the, regulation, of, hepatic, 'gluconeogenesis,', glycogen, synthesis, and, insulin, sensitivity])].
[sujeto(['Via', 'TGR5,', 'BA', are, able, to]), verbo([stimulate]), complemento(['glucagon-like', 'peptide-1', secretion, in, the, small, intestine, and, energy, expenditure, in, brown, adipose, tissue, and, skeletal, muscle])].
[sujeto(['Thus,', 'BA', transport, and, 'BA-controlled']), verbo([nuclear]), complemento([receptors, and, signaling, pathways, are, promising, drug, targets, for, treatment, of, 'NAFLD'])].
[sujeto(['As', 'such,', 'FXR', 'and/or', 'TGR5', ligands]), verbo([have]), complemento([shown, promising, results, in, animal, models, of, 'NAFLD', and, clinical, pilot, studies])].
[sujeto(['Collectively,', these, findings]), verbo([suggest]), complemento([that, 'BA', and, targeting, their, 'receptor/signaling', pathways, may, represent, a, promising, approach, to, treat, 'NAFLD', and, closely, linked, disorders, such, as, 'obesity,', 'diabetes,', dyslipidemia, and, arteriosclerosis])].
[sujeto(['While', bile, acids, '(', 'BAs)']), verbo([have]), complemento([long, been, known, to, be, essential, in, dietary, lipid, absorption, and, cholesterol, 'catabolism,', in, recent, years, an, important, role, for, 'BAs', as, signalling, molecules, has, emerged])].
[sujeto(['BAs']), verbo([activate]), complemento(['mitogen-activated', protein, kinase, 'pathways,', are, ligands, for, the, 'G-protein-coupled', receptor, '(', 'GPCR)', 'TGR5', and, activate, nuclear, hormone, receptors, such, as, farnesoid, 'X', receptor, alpha, '(', 'FXR-alpha;', 'NR1H4)'])].
[sujeto(['FXR-alpha']), verbo([regulates]), complemento([the, enterohepatic, recycling, and, biosynthesis, of, 'BAs', by, controlling, the, expression, of, genes, such, as, the, short, heterodimer, partner, '(', 'SHP;', 'NR0B2)', that, inhibits, the, activity, of, other, nuclear, receptors])].
[sujeto(['The', 'FXR-alpha-mediated', 'SHP', induction, also, underlies, the, downregulation, of, the, hepatic, fatty, acid, and, triglyceride, biosynthesis, and, 'very-low-density', lipoprotein, production]), verbo([mediated]), complemento([by, 'sterol-regulatory-element-binding', protein, 1, c])].
[sujeto(['Here', we, show, that, the, administration, of, 'BAs', to, mice]), verbo([increases]), complemento([energy, expenditure, in, brown, adipose, 'tissue,', preventing, obesity, and, resistance, to, insulin])].
[sujeto(['This', novel, metabolic, effect, of, 'BAs', is, critically, dependent, on, induction, of, the, 'cyclic-AMP-dependent', thyroid, hormone]), verbo([activating]), complemento([enzyme, type, 2, iodothyronine, deiodinase, '(', 'D2)', because, it, is, lost, in, 'D2-/-', mice])].
[sujeto(['Treatment', of, brown, adipocytes, and, human, skeletal, myocytes, with, 'BA']), verbo([increases]), complemento(['D2', activity, and, oxygen, consumption])].
[sujeto(['These', effects, are, independent, of, 'FXR-alpha,', and, instead, are]), verbo([mediated]), complemento([by, increased, cAMP, production, that, stems, from, the, binding, of, 'BAs', with, the, 'G-protein-coupled', receptor, 'TGR5'])].
[sujeto(['In', both, rodents, and, 'humans,', the, most, thermogenically, important, tissues, are, specifically]), verbo([targeted]), complemento([by, this, mechanism, because, they, coexpress, 'D2', and, 'TGR5'])].
[sujeto(['The', 'BA-TGR5-cAMP-D2', signalling, pathway, is, therefore, a, crucial, mechanism, for, 'fine-tuning', energy, homeostasis, that, can, be]), verbo([targeted]), complemento([to, improve, metabolic, control])].
[sujeto(['Cirrhosis', is, a, 'end-stage', disease, of, the, liver, in, which, 'fibrogenesis,', angiogenesis, and, distortion, of, intrahepatic, microcirculation]), verbo([lead]), complemento([to, increased, intrahepatic, resistance, to, portal, blood, 'flow,', a, condition, known, as, portal, hypertension])].
[sujeto(['Portal', hypertension, is]), verbo([maintained]), complemento([by, a, variety, of, molecular, mechanisms, including, sinusoidal, endothelial, cells, '(', 'LSECs)', 'hyporeactivity,', activation, of, hepatic, stellate, cells, '(', 'HSCs),', reduction, in, hepatic, endothelial, nitric, oxide, synthase, '(', 'eNOS)', activity, along, with, increased, 'eNOS-derived', 'NO', generation, in, the, splanchnic, and, systemic, circulations])].
[sujeto(['A', reduction, of, the, 'expression/function', of, the, two, major, hydrogen, sulfide, '(', 'H2S)-producing', 'enzymes,', cystathionine, 'γ-lyase', '(', 'CSE)', and, cystathionine, 'β-synthase', '(', 'CBS),']), verbo([has]), complemento([also, been, demonstrated])].
[sujeto(['A', deficit, in, the, transsulfuration, pathway]), verbo([leading]), complemento([to, the, accumulation, of, homocysteine, might, contribute, to, defective, generation, of, 'H2S', and, endothelial, hyporeactivity])].
[sujeto(['Bile', acids, are, ligands, for]), verbo([nuclear]), complemento(['receptors,', such, as, farnesoid, 'X', receptor, '(', 'FXR),', and, 'G-protein-coupled', receptors, '(', 'GPCRs),', such, as, the, 'G-protein', bile, acid, receptor, 1, '(', 'GPBAR1)'])].
[sujeto(['FXR', and, 'GPBAR1', ligands]), verbo([regulate]), complemento([the, 'expression/activity', of, 'CSE', by, both, genomic, and, 'non-genomic', effects, and, have, been, proved, effective, in, protecting, against, endothelial, dysfunction, observed, in, rodent, models, of, cirrhosis])].
[sujeto(['GPBAR1,', a, receptor, for, secondary, bile, 'acids,', is, selectively]), verbo([expressed]), complemento([by, 'LSECs', and, its, activation, increases, the, expression, of, 'CSE', and, attenuates, the, production, of, 'endotelin-1,', a, potent, vasoconstrictor, agent])].
[sujeto(['In', vivo, 'GPBAR1', ligand, attenuates, the, imbalance, between, vasodilatory, and, 'vaso-constricting', 'agents,', making, 'GPBAR1', a, promising]), verbo([target]), complemento([in, the, treatment, of, portal, hypertension])].
[sujeto(['GPBAR1', '(', also, known, as, 'TGR5)', is, a, bile, acid]), verbo([activated]), complemento([receptor, expressed, in, several, adenocarcinomas, and, its, activation, by, secondary, bile, acids, increases, intestinal, cell, proliferation])].
[sujeto(['Here,', we]), verbo([have]), complemento([examined, the, expression, of, 'GPBAR1', in, human, gastric, adenocarcinomas, and, investigated, whether, its, activation, promotes, the, acquisition, of, a, 'pro-metastatic', phenotype])].
[sujeto(['By', immunohistochemistry, and, 'RT-PCR', analysis, we]), verbo([found]), complemento([that, expression, of, 'GPBAR1', associates, with, advanced, gastric, cancers, '(', 'Stage', 'III-IV)'])].
[sujeto(['Exposure', of, 'MKN45', cells, to, 'GPBAR1', 'ligands,', 'TLCA,', oleanolic, acid, or, 6, -, 'ECDCA', '(', a, dual, 'FXR', and, 'GPBAR1', 'ligand)']), verbo([increased]), complemento([the, expression, of, genes, associated, with, 'EMT', including, 'KDKN2A,', 'HRAS,', 'IGB3,', 'MMP10', and, 'MMP13', and, downregulated, the, expression, of, 'CD44', and, 'FAT1', '(', 'P&lt;0'])].
[sujeto(['GPBAR1', activation, in, 'MKN45', cells]), verbo([associated]), complemento([with, 'EGF-R', and, 'ERK1', phosphorylation])].
[sujeto(['These', effects, were]), verbo([inhibited]), complemento([by, 'DFN406,', a, 'GPBAR1', 'antagonist,', and, cetuximab])].
[sujeto(['GPBAR1', ligands]), verbo([increase]), complemento(['MKN45', 'migration,', adhesion, to, peritoneum, and, wound, healing])].
[sujeto(['Pretreating', 'MKN45', cells, with, 'TLCA']), verbo([increased]), complemento([propensity, toward, peritoneal, dissemination, in, vivo])].
[sujeto(['In', 'summary,', we]), verbo([report]), complemento([that, 'GPBAR1', is, expressed, in, advanced, gastric, cancers, and, its, expression, correlates, with, markers, of, 'EMT'])].
[sujeto(['GPBAR1', activation, in, 'MKN45', cells]), verbo([promotes]), complemento(['EMT'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'GPBAR1', antagonist, might, have, utility, in, the, treatment, of, gastric, cancers])].
[sujeto(['Bile', acids, are, signaling, molecules]), verbo([interacting]), complemento([with, nuclear, receptors, and, membrane, 'G-protein-coupled', receptors])].
[sujeto(['Among', these, 'receptors,', the, farnesoid, 'X', receptor, '(', 'FXR)', and, the, membrane, 'G-coupled', receptor, '(', 'GPBAR1)']), verbo([have]), complemento([gained, increasing, consideration, as, druggable, receptors, and, their, exogenous, dual, regulation, represents, an, attractive, strategy, in, the, treatment, of, enterohepatic, and, metabolic, disorders])].
[sujeto(['However,', the, therapeutic, use, of, dual, modulators, could, be]), verbo([associated]), complemento([to, severe, side, effects, and, therefore, the, discovery, of, selective, 'GPBAR1', and, 'FXR', agonists, is, an, essential, step, in, the, medicinal, chemistry, optimization, of, bile, acid, scaffold])].
[sujeto(['In', this, 'study,', a, new, series, of, 6, -, ethylcholane, derivatives, modified, on, the, tetracyclic, core, and, on, the, side, chain]), verbo([has]), complemento([been, designed, and, synthesized, and, their, in, vitro, activities, on, 'FXR', and, 'GPBAR1', were, assayed])].
[sujeto(['Bile', acids, are, the, endogenous, modulators, of, the]), verbo([nuclear]), complemento([receptor, 'FXR', and, the, membrane, receptor, 'GPBAR1'])].
[sujeto(['FXR', represents, a, promising, pharmacological]), verbo([target]), complemento([for, the, treatment, of, cholestatic, liver, disorders])].
[sujeto(['Currently', available, semisynthetic, bile, acid, derivatives, cover, the, same, chemical, space, of, bile, acids, and, therefore, they, are, poorly, selective, toward, 'BA', 'receptors,']), verbo([increasing]), complemento([patient, risk, for, adverse, side, effects])].
[sujeto(['In', this, 'report,', we]), verbo([have]), complemento([investigated, around, the, structure, of, 'CDCA', describing, the, synthesis, and, the, in, vitro, and, in, vivo, pharmacological, characterization, of, a, novel, family, of, compounds, modified, on, the, steroidal, tetracyclic, core, and, on, the, side, chain])].
[sujeto(['Bile', 'acids,', the, end, products, of, cholesterol, 'metabolism,']), verbo([activate]), complemento([multiple, mechanisms, through, the, interaction, with, membrane, 'G-protein', coupled, receptors, including, the, bile, acid, receptor, 'GPBAR1', and, nuclear, receptors, such, as, the, bile, acid, 'sensor,', farnesoid, 'X', receptor, '(', 'FXR)'])].
[sujeto(['Even', if, dual, 'FXR/GPBAR1', agonists, are, largely, considered, a, novel, opportunity, in, the, treatment, of, several, liver, and, metabolic, 'diseases,', selective]), verbo([targeting]), complemento([of, one, of, these, receptors, represents, an, attractive, therapeutic, approach, for, a, wide, range, of, disorders, in, which, dual, modulation, is, associated, to, severe, side, effects])].
[sujeto(['In', the, present, study, we]), verbo([have]), complemento([investigated, around, the, structure, of, 'LCA', generating, a, small, library, of, cholane, 'derivatives,', endowed, with, dual, 'FXR', 'agonism/GPBAR1', antagonism])].
[sujeto(['To', the, best, of, our, 'knowledge,', this, is, the, first]), verbo([report]), complemento([of, bile, acid, derivatives, able, to, antagonize, 'GPBAR1'])].
[sujeto(['Thus,', adjusting, the, membrane, cholesterol, composition, is, essential, for]), verbo([maintaining]), complemento([cellular, homeostasis])].
[sujeto(['Cholesterol', biosynthesis, and, uptake, by, 'LDL', receptors, are, tightly]), verbo([regulated]), complemento([at, the, transcriptional, level, through, negative, feedback, 'control,', which, is, mediated, by, sterol, regulatory, 'element-binding', proteins, '(', 'SREBPs)'])].
[sujeto(['In', 'particular,', 'SREBP-2', is]), verbo([activated]), complemento([in, a, 'cholesterol-dependent', manner, 'and,', 'thus,', is, significantly, involved, in, regulating, the, expression, of, those, genes, associated, with, cholesterol, metabolism])].
[sujeto(['Cholesterol', metabolites, such, as, oxysterols, are]), verbo([involved]), complemento([in, regulating, sterol, metabolism, by, binding, to, the, nuclear, 'receptor,', liver, 'X', receptor, '(', 'LXR)'])].
[sujeto([',', bile, 'acids,', are, agonists, for, another]), verbo([nuclear]), complemento(['receptor,', farnesoid, 'X', receptor, '(', 'FXR),', and, a, bile, acid, 'receptor,', 'TGR5'])].
[sujeto(['Activated', 'FXR']), verbo([regulates]), complemento([bile, acid, metabolism, and, 'TGR5', improves, glucose, metabolism, through, the, actions, of, 'glucagon-like', 'peptide-1', '(', 'GLP-1)'])].
[sujeto(['The', underlying, molecular, mechanisms, of, liver, regeneration]), verbo([have]), complemento([been, extensively, studied, in, the, past, using, the, partial, hepatectomy, '(', 'PH)', model, in, 'rodents,', where, 2, /, 3, 'PH', is, carried, out, by, removing, two, lobes])].
[sujeto(['The', whole, process, of, liver, regeneration, is, 'complicated,', orchestrated, event]), verbo([involving]), complemento([a, network, of, connected, 'interactions,', which, still, remain, fully, elusive])].
[sujeto(['Bile', acids, '(', 'BAs)', are, ligands, of, farnesoid, 'X', receptor, '(', 'FXR),', a]), verbo([nuclear]), complemento([receptor, of, 'ligand-activated', transcription, factor])].
[sujeto(['FXR']), verbo([has]), complemento([been, shown, to, be, highly, involved, in, liver, regeneration])].
[sujeto(['BAs', and, 'FXR', not, only]), verbo([interact]), complemento([with, each, other, but, also, regulate, various, downstream, targets, independently, during, liver, regeneration])].
[sujeto(['Moreover,', recent, findings]), verbo([suggest]), complemento([that, 'tissue-specific', 'FXR', also, contributes, to, liver, regeneration, significantly])].
[sujeto(['These', novel, findings]), verbo([suggest]), complemento([that, 'FXR', has, much, broader, role, than, regulating, 'BA,', 'cholesterol,', lipid, and, glucose, metabolism])].
[sujeto(['Therefore,', these, researches, highlight, 'FXR', as, an, important, pharmaceutical]), verbo([target]), complemento([for, potential, use, of, 'FXR', ligands, to, regulate, liver, regeneration, in, clinic])].
[sujeto(['Bile', acids, can]), verbo([regulate]), complemento([nutrient, metabolism, through, the, activation, of, the, cell, membrane, receptor, 'GPBAR1', and, the, nuclear, receptor, 'FXR'])].
[sujeto(['Here,', taking, advantage, of, our, knowledge, of, the, two, 'targets,', we]), verbo([have]), complemento([identified, through, a, rational, drug, design, study, a, series, of, amine, lithocholic, acid, derivatives, as, selective, 'GPBAR1', agonists])].
[sujeto(['GPBAR1', is, a, bile, acids]), verbo([activated]), complemento([receptor, expressed, in, 'entero-hepatic', tissues])].
[sujeto(['In', the, systemic, circulation, vasodilation]), verbo([caused]), complemento([by, 'GPBAR1', agonists, is, abrogated, by, inhibition, of, 'cystathione-γ-liase', '(', 'CSE),', an, enzyme, essential, to, the, generation, of, hydrogen, sulfide, '(', 'H2S),', a, vasodilatory, agent])].
[sujeto(['Cirrhosis', was]), verbo([induced]), complemento([in, mice, by, carbon, tetrachloride, '(', 'CCL4)', administration, for, 9, weeks])].
[sujeto(['Liver', endothelial, dysfunction, was]), verbo([induced]), complemento([by, feeding, wild, type, and, 'Gpbar1-/-', mice, with, methionine, for, 4, weeks])].
[sujeto(['In', the, 'CCl4', 'model,', 9, weeks, treatment, with, 'BAR501', effectively, protected, against, development, of, endothelial, dysfunction, by]), verbo([increasing]), complemento([liver, 'CSE', expression, and, activity, and, by, reducing, endothelin, '(', 'ET)-1', gene, expression])].
[sujeto(['In', mice, feed, 'methionine,', treatment, with, 'BAR501', attenuated, endothelial, dysfunction, and]), verbo([caused]), complemento([a, 'GPBAR1-dependent', regulation, of, 'CSE'])].
[sujeto(['Using', human, liver, sinusoidal, 'cells,', we]), verbo([found]), complemento([that, modulation, of, 'CSE', 'expression/activity', is, mediated, by, both, genomic, '(', recruitment, of, 'CREB', to, 'CRE', in, the, 'CSE', 'promoter)', and, 'non-genomic', 'effects,', involving, a, 'Akt-dependent', phosporylation, of, 'CSE', and, endothelial, nitric, oxide, '(', 'NO)', synthase, '(', 'eNOS)'])].
[sujeto(['BAR501,']), verbo([phosphorylates]), complemento(['FOXO1', and, inhibits, 'ET-1', transcription, in, liver, sinusoidal, cells])].
[sujeto(['Perturbations', of, the, microbiota, shape, the, bile, acid, pool, and]), verbo([modulate]), complemento([the, activity, of, bile, 'acid-activated', receptors, '(', 'BARs)', even, beyond, the, gastrointestinal, 'tract,', triggering, various, metabolic, axes, and, altering, host, metabolism])].
[sujeto(['Bile', 'acids,', in, 'turn,', can, also]), verbo([regulate]), complemento([the, composition, of, the, gut, microbiome, at, the, highest, taxonomic, levels])].
[sujeto(['Since', the, discovery, of, bile, acid, 'receptors,', of, which, there, are, farnesoid, 'X', receptor, '(', 'FXR),', a]), verbo([nuclear]), complemento(['receptor,', and, the, plasma, membrane, 'G-protein', 'receptor,', as, well, as, 'Takeda', 'G-protein', coupled, receptor, clone, 5, ',', further, roles, have, been, elucidated, for, bile, acids, including, glucose, and, lipid, metabolism, as, well, as, inflammation])].
[sujeto(['Additionally,', treatment, with, bile, acid, receptor, agonists]), verbo([has]), complemento([shown, a, decrease, in, the, amount, of, atherosclerosis, plaque, formation, and, decreased, portal, vascular, resistance, and, portal, hypotension, in, animal, models])].
[sujeto(['Furthermore,', rodent, models]), verbo([have]), complemento([demonstrated, antifibrotic, activity, using, bile, acid, receptor, agonists])].
[sujeto(['Early', human, data, using, a, 'FXR', 'agonist,', obeticholic, 'acid,']), verbo([have]), complemento([shown, promising, results, with, improvement, of, histological, activity, and, even, a, reduction, of, fibrosis])].
[sujeto(['Human', studies, are, ongoing, and, will]), verbo([provide]), complemento([further, information, on, bile, acid, receptor, agonist, therapies])].
[sujeto(['Thus,', bile, acids, and, their, derivatives]), verbo([have]), complemento([the, potential, for, management, of, liver, diseases, and, potentially, other, disease, states, including, diabetes, and, the, metabolic, syndrome])].
[sujeto(['In', cholestatic, 'syndromes,', body, accumulation, of, bile, acids, is, thought, to]), verbo([cause]), complemento([itching])].
[sujeto(['Recently,', 'GPBAR1', '(', 'TGR5)', a, 'G-protein', coupled, receptor]), verbo([has]), complemento([been, shown, to, mediate, itching, caused, by, intradermal, administration, of, 'DCA', and, 'LCA'])].
[sujeto(['Cholestasis', was]), verbo([induced]), complemento([in, wild, type, and, 'GPBAR1-/-', mice, by, administration, of, 'α-naphthyl-isothiocyanate', '(', 'ANIT)', or, 17, 'α-ethynylestradiol'])].
[sujeto(['In', naïve, mice, skin, application, of, 'DCA,', 'TLCA,', 6, -, 'ECDCA,', oleanolic, and, betulinic, acid]), verbo([induces]), complemento([a, 'GPBAR1', dependent, pruritogenic, response, that, could, be, desensitized, by, 're-challenging', the, mice, with, the, same, 'GPBAR1', agonist])].
[sujeto(['In', wild, type, and, 'GPBAR1-/-', mice, cholestasis]), verbo([induced]), complemento([by, 'ANIT', fails, to, induce, spontaneous, itching, and, abrogates, scratching, behavior, caused, by, intradermal, administration, of, 'DCA'])].
[sujeto(['In', this, 'model,', 'co-treatment', with, 'BAR502']), verbo([increases]), complemento(['survival,', attenuates, serum, alkaline, phosphatase, levels, and, robustly, modulates, the, liver, expression, of, canonical, 'FXR', target, genes, including, 'OSTα,', 'BSEP,', 'SHP', and, 'MDR1,', without, inducing, pruritus])].
[sujeto(['Betulinic', 'acid,', a, selective, 'GPBAR1', 'ligand,', failed, to, rescue, wild, type, and, 'GPBAR1-/-', mice, from, 'ANIT', cholestasis, but, did, not]), verbo([induced]), complemento([itching])].
[sujeto(['In', the, 17, 'α-ethynylestradiol', model, 'BAR502', attenuates, cholestasis, and, reshapes, bile, acid, pool, without]), verbo([inducing]), complemento([itching])].
[sujeto(['In', models, of, 'non-obstructive', 'cholestasis,', 'BAR502', attenuates, liver, injury, without]), verbo([causing]), complemento([itching])].
[sujeto(['Bile', acids, are, signalling, 'molecules,', which]), verbo([activate]), complemento([the, transmembrane, receptor, 'TGR5', and, the, nuclear, receptor, 'FXR'])].
[sujeto(['BA', sequestrants, '(', 'BAS)', complex, bile, acids, in, the, intestinal, lumen, and]), verbo([decrease]), complemento([intestinal, 'FXR', activity])].
[sujeto(['The', 'BAS-BA', complex, also]), verbo([induces]), complemento(['glucagon-like', 'peptide-1', '(', 'GLP-1)', production, by, 'L', cells, which, potentiates, 'β-cell', 'glucose-induced', insulin, secretion])].
[sujeto(['Whether', 'FXR', is]), verbo([expressed]), complemento([in, 'L', cells, and, controls, 'GLP-1', production, is, unknown])].
[sujeto(['Here,', we, show, that, 'FXR', activation, in, 'L', cells]), verbo([decreases]), complemento([proglucagon, expression, by, interfering, with, the, 'glucose-responsive', factor, 'Carbohydrate-Responsive', 'Element', 'Binding', 'Protein', '(', 'ChREBP)', and, 'GLP-1', secretion, by, inhibiting, glycolysis])].
[sujeto(['In', 'vivo,', 'FXR', deficiency]), verbo([increases]), complemento(['GLP-1', gene, expression, and, secretion, in, response, to, glucose, hence, improving, glucose, metabolism])].
[sujeto(['Moreover,', treatment, of, 'ob/ob', mice, with, the, 'BAS', colesevelam]), verbo([increases]), complemento([intestinal, proglucagon, gene, expression, and, improves, glycaemia, in, a, 'FXR-dependent', manner])].
[sujeto(['These', findings, identify, the, 'FXR/GLP-1', pathway, as, a, new, mechanism, of, 'BA', control, of, glucose, metabolism, and, a, pharmacological]), verbo([target]), complemento([for, type, 2, diabetes])].
[sujeto(['Next', to, their, ancestral, roles, in, lipid, digestion, and, 'solubilization,', 'BAs', are, today]), verbo([recognized]), complemento([signaling, molecules, involved, in, many, physiological, functions])].
[sujeto(['These', signaling, pathways]), verbo([involve]), complemento([the, activation, of, metabolic, nuclear, 'receptors,', mainly, the, 'BA', sensor, 'FXR,', and, the, dedicated, membrane, 'G', 'protein-coupled', 'receptor,', 'GPBAR1', '(', 'TGR5)'])].
[sujeto(['Targeted', oriented, discovery, of, natural, compounds, and, medicinal, chemistry, manipulation]), verbo([have]), complemento([allowed, the, development, of, promising, drug, candidates])].
[sujeto(['In', many, 'cells,', bile, acids, '(', 'BAs)']), verbo([have]), complemento([a, multitude, of, 'effects,', some, of, which, may, be, mediated, by, specific, receptors, such, the, 'TGR5', or, 'FXR', receptors])].
[sujeto(['Here', we, show, that, 'CDCA', '(', chenodeoxycholic, 'acid)']), verbo([caused]), complemento([fast, and, 'concentration-dependent', 'ATP', release, from, acini, '(', 'AR42J)', and, duct, cells, '(', 'Capan-1)'])].
[sujeto(['Taurine', and, glycine, conjugated, forms, of, 'CDCA', had, smaller, effects, on, 'ATP']), verbo([release]), complemento([in, 'Capan-1', cells])].
[sujeto(['In', duct, 'monolayers,', 'CDCA']), verbo([stimulated]), complemento(['ATP', release, mainly, from, the, luminal, 'membrane;', the, releasing, mechanisms, involved, both, vesicular, and, 'non-vesicular', secretion, pathways])].
[sujeto(['In', duct, 'cells,', 'CDCA']), verbo([caused]), complemento([reversible, increase, in, the, intracellular, 'Ca(2+)', concentration, '[', 'Ca(2', +, ')', ']', 'i,', which, could, be, significantly, inhibited, by, antagonists, of, purinergic, receptors])].
[sujeto(['The', 'TGR5', 'receptor,']), verbo([expressed]), complemento([on, the, luminal, side, of, pancreatic, 'ducts,', was, not, involved, in, 'ATP', release, and, 'Ca(2+)', 'signals,', but, could, stimulate, 'Na(+)/Ca(2+)', exchange, in, some, conditions])].
[sujeto(['CDCA', evokes, significant, 'ATP']), verbo([release]), complemento([that, can, stimulate, purinergic, 'receptors,', which, in, turn, increase, '[', 'Ca(2+)]i'])].
[sujeto(['The', 'TGR5', receptor, is, not]), verbo([involved]), complemento([in, these, processes, but, can, play, a, protective, role, at, high, intracellular, 'Ca(2+)', conditions])].
[sujeto(['GPBAR1', is, a, bile, 'acid-activated', receptor, '(', 'BAR)', for, secondary, bile, 'acids,', lithocholic, '(', 'LCA)', and, deoxycholic, acid, '(', 'DCA),']), verbo([expressed]), complemento([in, the, enterohepatic, tissues, and, in, the, vasculature, by, endothelial, and, smooth, muscle, cells])].
[sujeto(['Despite', that, bile, acids]), verbo([cause]), complemento(['vasodilation,', it, is, unclear, why, these, effects, involve, 'GPBAR1,', and, the, vascular, phenotype, of, 'GPBAR1', deficient, mice, remains, poorly, defined])].
[sujeto(['Previous', studies]), verbo([have]), complemento([suggested, a, role, for, nitric, oxide, '(', 'NO)', in, regulatory, activity, exerted, by, 'GPBAR1', in, liver, endothelial, cells])].
[sujeto(['Here', we, demonstrate, that, 'GPBAR1', null, mice, had]), verbo([increased]), complemento([levels, of, primary, and, secondary, bile, acids, and, impaired, vasoconstriction, to, phenylephrine])].
[sujeto(['In', aortic, ring, 'preparations,', vasodilation]), verbo([caused]), complemento([by, chenodeoxycholic, acid, '(', 'CDCA),', a, weak, 'GPBAR1', ligand, and, 'farnesoid-x-receptor', agonist, '(', 'FXR),', was, 'iberiotoxin-dependent', and, 'GPBAR1-independent'])].
[sujeto(['In', 'contrast,', vasodilation]), verbo([caused]), complemento([by, 'LCA', was, 'GPBAR1', dependent, and, abrogated, by, 'propargyl-glycine,', a, 'CSE', 'inhibitor,', and, by, 5, 'β-cholanic', 'acid,', a, 'GPBAR1', 'antagonist,', but, not, by, 'N(5)-(1-iminoethyl)-l-ornithine', '(', 'l-NIO),', an, endothelial, 'NO', synthase, 'inhibitor,', or, 'iberiotoxin,', a, 'large-conductance', 'calcium-activated', potassium, '(', 'BKCa)', channels, antagonist])].
[sujeto(['In', venular, and, aortic, endothelial, '(', 'HUVEC', and, 'HAEC)', cells, 'GPBAR1', activation]), verbo([increases]), complemento(['CSE', 'expression/activity', and, 'H2S', production])].
[sujeto(['Two', cAMP, response, element]), verbo([binding]), complemento([protein, '(', 'CREB)', sites, '(', 'CREs)', were, identified, in, the, 'CSE', promoter])].
[sujeto(['In', 'addition,', 'TLCA']), verbo([stimulates]), complemento(['CSE', phosphorylation, on, serine, residues])].
[sujeto(['In', conclusion, we, demonstrate, that, 'GPBAR1']), verbo([mediates]), complemento([the, vasodilatory, activity, of, 'LCA', and, regulates, the, 'expression/activity', of, 'CSE'])].
[sujeto(['Vasodilation']), verbo([caused]), complemento([by, 'CDCA', involves, 'BKCa', channels])].
[sujeto(['These', include]), verbo([nuclear]), complemento([and, membrane, receptor, agonists, and, 'BA', derivatives])].
[sujeto(['The']), verbo([nuclear]), complemento([receptors, farnesoid, 'X', receptor, '(', 'FXR),', retinoid, 'X', receptor, '(', 'RXR),', peroxisome, 'proliferator-activated', receptor, α, '(', 'PPARα),', and, pregnane, 'X', receptor, '(', 'PXR)', are, transcriptional, modifiers, of, bile, formation, and, at, present, are, under, investigation, as, promising, targets, for, therapeutic, interventions, in, cholestatic, disorders])].
[sujeto(['Here,', we]), verbo([provide]), complemento([an, overview, on, established, and, future, promising, therapeutic, agents, and, their, potential, molecular, mechanisms, and, sites, of, action, in, cholestatic, diseases])].
[sujeto(['Farnesoid', 'X', receptor, and, 'Takeda', 'G-protein-coupled', 'receptor-5', are, well, known, bile, acid, receptors, and]), verbo([act]), complemento([as, promising, targets, for, the, drug, development, and, treatment, of, diabetes])].
[sujeto(['Agonists', of, both, the, bile, acid, receptors]), verbo([increase]), complemento([insulin, sensitivity, and, control, 'glucose,', lipids, and, bile, acid, homeostasis])].
[sujeto(['Initially,', an, experimentally, proven, 'well-known', dual, agonist, of, 'FXR', and, 'TGR5,', namely, 'INT-767,', was, docked, into, the]), verbo([binding]), complemento([sites, of, 'FXR', and, 'TGR5', to, determine, the, protein, residues, important, for, ligand, binding])].
[sujeto(['Further,', 'structure-based', virtual, screening, was, performed, with, screened, hits, to]), verbo([find]), complemento([potential, agonists, of, 'FXR', and, 'TGR5'])].
[sujeto(['The']), verbo([binding]), complemento([mode, of, these, compounds, with, both, receptors, was, analyzed, in, detail])].
[sujeto(['Furthermore,', molecular, 'dynamics,', 'ADME', toxicity, 'prediction,', density, functional, theory, and]), verbo([binding]), complemento([free, energy, calculations, were, carried, out, to, rank, the, compounds])].
[sujeto(['The', results, of, in, vitro, assays]), verbo([suggested]), complemento([that, 'ChemBridge_9149693', is, a, potent, and, promising, drug, for, the, treatment, of, type, 'II', diabetes])].
[sujeto(['In', addition, to, their, role, in, nutrient, 'absorption,', bile, acids, are, signaling, molecules, that, exert, genomic, and, 'non-genomic', effects, by]), verbo([activating]), complemento(['TGR5', '(', 'M-BAR,', 'GP-BAR1', or, 'BG37)', a, 'G-protein-coupled', 'receptor,', and, farnesoid, 'X', receptor, '(', 'FXR),', a, member, of, the, nuclear, hormone, receptor, superfamily])].
[sujeto(['TGR5', ligands]), verbo([decrease]), complemento([blood, glucose, levels, and, increase, energy, expenditure, by, promoting, intracellular, thyroid, hormone, activation, in, thermogenically, competent, tissues])].
[sujeto(['FXR', agonists]), verbo([repress]), complemento([the, synthesis, of, endogenous, bile, acids, and, reduce, 'triglyceride,', cholesterol, and, glucose, plasma, levels, and, are, currently, being, tested, in, nonalcoholic, steatohepatitis])].
[sujeto(['FXR', modulators, are, being, developed, to]), verbo([target]), complemento([selective, gene, clusters, and, avoid, the, negative, impact, of, 'FXR', on, 'HDL', biosynthesis])].
[sujeto(['The', development, of, dual, 'FXR', and, 'TGR5', ligands, could]), verbo([provide]), complemento([new, opportunities, for, the, treatment, of, lipid, and, glucose, disorders])].
[sujeto(['They', function, as, nutrient, signaling, hormones, by]), verbo([activating]), complemento([specific, nuclear, receptors, '(', 'FXR,', 'PXR,', 'Vitamin', 'D)', and, 'G-protein', coupled, receptors, '[', 'TGR5,', 'sphingosine-1', phosphate, receptor, 2, '(', 'S1PR2),', muscarinic, 'receptors]'])].
[sujeto(['Bile', acids, and, insulin, appear, to, collaborate, in]), verbo([regulating]), complemento([the, metabolism, of, nutrients, in, the, liver])].
[sujeto(['They', both]), verbo([activate]), complemento([the, 'AKT', and, 'ERK1/2', signaling, pathways])].
[sujeto(['Bile', acid, induction, of, the, 'FXR-α']), verbo([target]), complemento(['gene,', small, heterodimer, partner, '(', 'SHP),', is, highly, dependent, on, the, activation, 'PKCζ,', a, branch, of, the, insulin, signaling, pathway])].
[sujeto(['One', might, hypothesize, that, chronic, low, grade, inflammation, which, is]), verbo([associated]), complemento([with, insulin, 'resistance,', may, inhibit, bile, acid, signaling, and, disrupt, lipid, metabolism])].
[sujeto(['The', disruption, of, these, signaling, pathways, may]), verbo([increase]), complemento([the, risk, of, fatty, liver, and, 'non-alcoholic', fatty, liver, disease, '(', 'NAFLD)'])].
[sujeto(['Finally,', conjugated, bile, acids, appear, to]), verbo([promote]), complemento([cholangiocarcinoma, growth, via, the, activation, of, 'S1PR2'])].
[sujeto(['In', addition, to, their, role, in, dietary, lipid, absorption, bile, acids, are, signaling, modules]), verbo([activating]), complemento([nuclear, receptors, and, at, least, one, 'G-protein', coupled, receptors, named, the, 'TGR5'])].
[sujeto(['With', a, different, rank, of, potency, primary, and, secondary, bile, acids]), verbo([activates]), complemento([a, subset, of, nuclear, receptors, including, the, 'farnesoid-X-receptor', '(', 'FXR,', 'NR1H4);', the, constitutive, androstane, receptor, '(', 'CAR,', 'NR1H3),', the, 'pregnane-x-', receptor, '(', 'PXR,', 'NR1H2),', the, vitamin, 'D', receptor, '(', 'VDR,', 'NR1H1)'])].
[sujeto(['In', this, 'review,', we, will, spotlight, the, molecular, mechanisms, of, 'receptor/ligand', function, and, how, bile, 'acid-activated', receptors]), verbo([regulate]), complemento([the, innate, immunity, in, the, gastrointestinal, tract, and, liver])].
[sujeto(['The', ability, of, these, receptors, to, integrate, metabolic, and, inflammatory, signaling, makes, them, particularly, attractive]), verbo([targets]), complemento([for, intervention, in, 'immune-mediated', diseases])].
[sujeto(['Of', the, known, bile, 'acids,', only, the, dihydroxy, 'species,', deoxycholic, acid, and, chenodeoxycholic, acid, '(', 'CDCA),', and, their, 'conjugates,']), verbo([activate]), complemento([processes, that, stimulate, epithelial, 'Cl(-)', secretion])].
[sujeto(['We']), verbo([have]), complemento([previously, published, that, 'CDCA', acts, in, a, rapid, manner, to, stimulate, colonic, ion, secretion, via, protein, kinase, 'A', '(', 'PKA)-mediated', activation, of, the, dominant, 'Cl(-)', 'channel,', the, cystic, fibrosis, transmembrane, conductance, regulator, '(', 'CFTR)', '(', 'AJP', 305, :, 'C447-56,', 2013, ')', ;, 'however,', 'PKA', signaling, did, not, account, for, the, entire, 'CDCA', response])].
[sujeto(['Here', we, show, that, in, human, colonic, 'T84', 'cells,', 'CDCA\'s', induction, of, 'CFTR', 'activity,', measured, as, changes, in, 'short-circuit', current, '(', 'Isc),', is, dependent, on, epidermal, growth, factor, receptor, '(', 'EGFR)', 'activation,', and, does, not]), verbo([involve]), complemento([the, bile, acid, receptors, 'TGR5', or, 'FXR'])].
[sujeto(['CDCA', activation, of, 'Cl(-)', secretion, does, not]), verbo([require]), complemento(['Src,', mitogen, activated, protein, 'kinases,', or, 'phosphoinositide-3', kinase, downstream, of, 'EGFR,', but, does, require, an, increase, in, cytosolic, 'Ca(2+)', 'In', addition, to, 'PKA', 'signaling,', we, found, that, the, 'CDCA', response, requires, a, novel, involvement, of, the, exchange, protein, directly, activated, by, cAMP, '(', 'EPAC)'])].
[sujeto(['Downstream', of, 'EPAC,', 'CDCA']), verbo([activates]), complemento(['Rap2,', and, changes, in, '[', 'Ca(2+)]i', were, dependent, on, both, 'EPAC', and, 'EGFR', activation])].
[sujeto(['Bile', acids]), verbo([activate]), complemento([farnesoid, 'X', receptor, '(', 'FXR)', and, 'G', 'protein-coupled', bile, acid, receptor, 1, '(', 'TGR5)', to, regulate, 'lipid,', glucose, and, energy, metabolism])].
[sujeto(['In', this, 'study,', we, showed, that, 'adenovirus-mediated', overexpression, of, 'Cyp7a1', ameliorated, lipopolysaccharide, '(', 'LPS)-induced', inflammatory, cell, infiltration, and, 'pro-inflammatory', cytokine, production, in, 'WT', and, 'Tgr5-/-', 'mice,', but, not, in, 'Fxr-/-', 'mice,']), verbo([suggesting]), complemento([that, bile, acid, signaling, through, 'FXR', protects, against, hepatic, inflammation])].
[sujeto(['NF-κB-luciferase', reporter, assay, showed, that, 'FXR', agonists, significantly]), verbo([inhibited]), complemento(['TNFα-induced', 'NF-κB', activity])].
[sujeto(['Furthermore,', chromatin, immunoprecipitation, and, mammalian, 'two-hybrid', assays, showed, that, 'ligand-activated', 'FXR']), verbo([interacted]), complemento([with, 'NF-κB', and, blocked, recruitment, of, steroid, receptor, 'coactivator-1', '(', 'SRC-1)', to, cytokine, promoter, and, resulted, in, inhibition, of, 'NF-κB', activity])].
[sujeto(['Methionine/choline-deficient', '(', 'MCD)', diet]), verbo([increased]), complemento([hepatic, 'inflammation,', free, 'cholesterol,', oxidative, 'stress,', 'apoptosis,', and, fibrosis, in, 'Cyp7a1-/-', mice, compared, to, 'WT', mice])].
[sujeto(['Current', studies]), verbo([suggest]), complemento([that, increased, 'Cyp7a1', expression, and, bile, acid, synthesis, ameliorated, hepatic, inflammation, through, activation, of, 'FXR,', whereas, reduced, bile, acid, synthesis, aggravated, 'MCD', 'diet-induced', hepatic, inflammation, and, fibrosis])].
[sujeto(['Two', bile, acid, '(', 'BA)', 'receptors,', farnesoid, 'X', receptor, '(', 'FXR)', and, 'G-protein-coupled', receptor, 'TGR5,']), verbo([have]), complemento([emerged, as, putative, therapeutic, targets, for, obesity, and, 'NAFLD'])].
[sujeto(['OVX', mice, had, significantly, higher, bodyweight]), verbo([gain]), complemento([than, 'SHAM', 'mice,', which, was, attenuated, by, 'INT747-', or, 'INT777-treatment'])].
[sujeto(['Liver', triglyceride, and, cholesterol, content, was, significantly]), verbo([increased]), complemento([in, 'OVX', compared, to, 'SHAM', 'mice,', which, was, normalized, by, 'INT747-', or, 'INT777-treatment'])].
[sujeto(['Significant', changes, in, metabolic, gene, expression, were]), verbo([found]), complemento([in, liver, '(', 'Cpt1,', 'Acox1),', muscle, '(', 'Ucp3,', 'Pdk4,', 'Cpt1,', 'Acox1,', 'Fasn,', 'Fgf21),', brown, adipocytes, '(', 'Dio2)', and, white, adipocytes, '(', 'c/EBPα,', 'Pparγ,', 'Adipoq)'])].
[sujeto(['For', the, first, 'time,', expression, of, 'FXR', and, induction, of, its]), verbo([target]), complemento([gene, 'Pltp1', was, shown, in, skeletal, muscle])].
[sujeto(['Potential', mechanisms, include]), verbo([increased]), complemento([energy, expenditure, and, changes, in, expression, patterns, of, key, metabolic, genes, in, 'liver,', muscle, and, adipose, tissues])].
[sujeto(['Bile', acids, are, synthesized, from, cholesterol, and, are, known, to, be]), verbo([involved]), complemento([with, the, emulsification, and, digestion, of, dietary, lipids, and, 'fat-soluble', vitamins])].
[sujeto(['Outside', of, this, 'role,', bile, acids, can]), verbo([act]), complemento([as, cell, signaling, effectors, through, binding, and, activating, receptors, on, both, the, cell, membrane, and, nucleus])].
[sujeto(['Numerous']), verbo([reports]), complemento([have, investigated, these, signaling, pathways, in, conditions, where, the, liver, is, damaged])].
[sujeto(['More', 'recently,', effort]), verbo([has]), complemento([been, made, to, investigate, the, role, of, bile, acids, in, diseases, outside, of, those, associated, with, liver, damage])].
[sujeto(['The', intracellular]), verbo([nuclear]), complemento([receptor, farnesoid, 'X', receptor, '(', 'FXR)', and, the, transmembrane, 'G', 'protein-coupled', receptor, 5, '(', 'TGR5)', respond, to, bile, acids, '(', 'BAs)', by, activating, transcriptional, networks, 'and/or', signaling, cascades])].
[sujeto(['These', cascades, affect, the, expression, of, a, great, number, of]), verbo([target]), complemento([genes, relevant, for, 'BA,', 'cholesterol,', lipid, and, carbohydrate, 'metabolism,', as, well, as, genes, involved, in, 'inflammation,', fibrosis, and, carcinogenesis])].
[sujeto(['This', review, discusses, the, relevant, 'BA', 'receptors,', the, new, drugs, that]), verbo([target]), complemento(['BA', transport, and, signaling, and, their, possible, applications])].
[sujeto(['It', is, hypothesized, that, 'Rhizoma', 'Coptidis', '(', 'RC)', alkaloids, exert, their, hypolipidemic, effects, primarily, by]), verbo([targeting]), complemento([the, gastrointestinal, tract, and, liver])].
[sujeto(['Thus,', this, study, was, conducted, to, evaluate, the, antihyperlipidemic, mechanisms, of, 'RC', alkaloids, '(', at, a, daily, dose, of, 140, 'mg/kg', for, 35, 'days)', in, 'high-fat', and, 'high-cholesterol']), verbo([induced]), complemento([hyperlipidemic, 'B6', mice])].
[sujeto(['After', 'treatment,', serum, lipid, parameters, were, 'determined,', the, expression, of, lipid, metabolism, related, genes, and, pathways, such, as, the, sterol, regulatory, element]), verbo([binding]), complemento([proteins, '(', 'SREBPs)', and, bile, acid, signaling, in, mice, were, also, investigated])].
[sujeto(['The', results, indicated, that, 'RC', alkaloids, reduced, the, body, weight]), verbo([gain]), complemento([and, serum, total, cholesterol, '(', 'TC),', triglyceride, '(', 'TG),', 'low-density', lipoprotein, cholesterol, '(', 'LDL-C),', total, bile, acids, '(', 'TBA)', and, lipopolysaccharide, of, 'B6', mice])].
[sujeto(['RC', alkaloids, feeding, significantly]), verbo([promoted]), complemento([the, abundance, of, 'Sporobacter', 'termitidis,', 'Alcaligenes', 'faecalis,', 'Akkermansia', muciniphila, in, the, gut, of, 'mice,', 'whereas,', the, abundance, of, 'Escherichia', 'coli,', 'Desulfovibrio', 'C21_c20,', 'Parabacteroides', distasonis, was, suppressed])].
[sujeto(['The', prevalence, of, 'obesity-related', glomerulopathy, is]), verbo([increasing]), complemento([in, parallel, with, the, worldwide, obesity, epidemic])].
[sujeto(['The', glomerulus, enlarges, in, response, to, 'obesity-induced']), verbo([increases]), complemento([in, glomerular, filtration, 'rate,', renal, plasma, 'flow,', filtration, fraction, and, tubular, sodium, reabsorption])].
[sujeto(['Adipokines', and, ectopic, lipid, accumulation, in, the, kidney]), verbo([promote]), complemento([insulin, resistance, of, podocytes, and, maladaptive, responses, to, cope, with, the, mechanical, forces, of, renal, hyperfiltration])].
[sujeto(['Although', most, patients]), verbo([have]), complemento([stable, or, slowly, progressive, 'proteinuria,', up, to, 'one-third', develop, progressive, renal, failure, and, 'end-stage', renal, disease])].
[sujeto(['Renin-angiotensin-aldosterone', blockade, is, effective, in, the, 'short-term', but, weight]), verbo([loss]), complemento([by, hypocaloric, diet, or, bariatric, surgery, has, induced, more, consistent, and, dramatic, antiproteinuric, effects, and, reversal, of, hyperfiltration])].
[sujeto(['Altered', fatty, acid, and, cholesterol, metabolism, are, increasingly]), verbo([recognized]), complemento([as, key, mediators, of, renal, lipid, 'accumulation,', 'inflammation,', oxidative, stress, and, fibrosis])].
[sujeto(['Novel', tools, for, monitoring, primary, biliary, cirrhosis, '(', 'PBC)', and, primary, sclerosing, cholangitis, '(', 'PSC)', patients]), verbo([have]), complemento([been, recently, proposed])].
[sujeto(['In', 'addition,', major, insight]), verbo([has]), complemento([been, gained, into, bile, acid, '(', 'BA)', physiology, during, the, last, decade, including, the, role, of, 'BAs', as, metabolic, modulators, and, the, 'gut-liver', axis])].
[sujeto(['As', a, 'consequence,', alongside, drugs]), verbo([targeting]), complemento([immune, response, or, fibrotic, 'processes,', a, number, of, novel, 'anti-cholestatic', agents, have, undergone, 'pre-clinical', and, clinical, evaluation, and, have, shown, promising, results, although, none, has, been, approved, yet])].
[sujeto(['Novel', therapeutic, approaches, include, '(', 'i)', agonists, of]), verbo([nuclear]), complemento(['receptors,', especially, farnesoid, 'X', receptor, '(', 'FXR),', pregnane, 'X', receptor, '(', 'PXR),', glucocorticoid, receptor, '(', 'GR)', and, peroxisome, 'proliferator-activated', receptor, α, '(', 'PPARα)', that, are, transcriptional, modifiers, of, bile, 'formation;', '(', 'ii)', agonists, of, 'TGR5,', a, 'BA', membrane, receptor, expressed, in, various, 'tissues;', '(', 'iii)', inhibitors, of, the, ileal, apical, sodium, 'BA', 'transporter;', '(', 'iv)', derivatives, of, the, 'FXR-induced', fibroblast, growth, factor, 19, from, the, ileum, that, suppresses, hepatic, 'BA', synthesis, and, '(', 'v)', 'norUDCA,', a, side, chain, shortened, 'UDCA', derivative, with, specific, physicochemical, and, therapeutic, properties])].
[sujeto(['Overweight', and, obesity]), verbo([increase]), complemento([the, risk, for, a, number, of, 'diseases,', 'namely,', cardiovascular, 'diseases,', type, 2, 'diabetes,', 'dyslipidemia,', premature, 'death,', 'non-alcoholic', fatty, liver, disease, as, well, as, different, types, of, cancer])].
[sujeto(['Current', research, efforts]), verbo([have]), complemento([focused, on, host, and, environmental, factors, that, may, affect, energy, balance])].
[sujeto(['It', was, hypothesized, that, a, microbiota, profile, specific, to, an, obese, host, with]), verbo([increased]), complemento(['energy-yielding', behavior, may, exist])].
[sujeto(['Alteration', of, microbiota, composition, may]), verbo([stimulate]), complemento([development, of, obesity, and, other, metabolic, diseases, via, several, 'mechanisms:', increasing, gut, permeability, with, subsequent, metabolic, 'inflammation;', increasing, energy, harvest, from, the, 'diet;', impairing, 'short-chain', fatty, acids, 'synthesis;', and, altering, bile, acids, metabolism, and, 'FXR/TGR5', signaling])].
[sujeto(['Prebiotics', and, probiotics]), verbo([have]), complemento([physiologic, functions, that, contribute, to, the, health, of, gut, 'microbiota,', maintenance, of, a, healthy, body, weight, and, control, of, factors, associated, with, obesity, through, their, effects, on, mechanisms, that, control, food, 'intake,', body, 'weight,', gut, microbiota, and, inflammatory, processes])].
[sujeto(['A', growing, body, of, evidence]), verbo([has]), complemento([demonstrated, that, bile, salts, are, important, for, liver, regeneration, following, partial, hepatectomy])].
[sujeto(['The', relative, bile, salt, overload, after, partial, liver, resection]), verbo([causes]), complemento([activation, of, bile, salt, receptors, in, 'non-parenchymal', '(', viz])].
[sujeto([the, intracellular, receptor, 'FXR)', cells, in, the, 'liver,', 'thus,']), verbo([providing]), complemento([signals, to, the, regenerative, process])].
[sujeto(['Conversely,', compensatory, liver, 're-growth', in, hepatectomized, mice, can, be]), verbo([stimulated]), complemento([by, feeding, of, bile, salts, or, alisol, 'B', 23, -, 'acetate,', a, natural, triterpenoid, agonist, of, 'Fxr'])].
[sujeto(['Both', ileal, and, hepatic, 'Fxr', play, a, key, role, in, regulation, of, bile, salt, homeostasis, 'and,', 'thus,']), verbo([preventing]), complemento([hepatotoxicity, caused, by, excessive, levels, of, bile, salts])].
[sujeto(['Agents', that]), verbo([target]), complemento([bile, salt, receptors, hold, promise, as, drugs, to, stimulate, liver, regeneration, in, selected, patients])].
[sujeto(['Hydrophobic', bile, acids, '(', 'BAs)', are, thought, to]), verbo([inhibit]), complemento([smooth, muscle, contractility, in, several, organs])].
[sujeto(['Lithocholic', acid, '(', 'LCA)', treatment]), verbo([increased]), complemento([the, micturition, interval, and, induced, a, 'concentration-dependent', relaxation, of, bladder, detrusor, strips])].
[sujeto(['In', 'addition,', 'LCA', reduced, the, concentration, of, intracellular, free, 'Ca(2+)([Ca(2+)]i)', and]), verbo([inhibited]), complemento([both, the, outward, and, inward, 'Na(+)/Ca(2+)', exchanger, '(', 'NCX)', current, '(', 'INCX)', in, primary, isolated, smooth, muscle, cells, '(', 'SMCs)'])].
[sujeto(['We']), verbo([found]), complemento([that, the, 'NCX', inhibitor, 3, '\'', ',', 4, '\'', -, 'Dichlorobenzamil', '(', 'DCB)', can, significantly, inhibit, the, relaxation, of, detrusor, strips, and, a, reduction, of, the, '[', 'Ca(2+)]i', induced, by, 'LCA,', while, the, antagonist, of, muscarinic, receptor, and, the, agonist, of, the, 'G', 'protein-coupled', bile, acid, receptor, '(', 'TGR5)', and, the, farnesoid, 'X', receptor, '(', 'FXR)', had, no, effect])].
[sujeto(['In', 'conclusion,', these, data]), verbo([suggest]), complemento([that, the, relaxation, of, rat, detrusor, induced, by, hydrophobic, 'BAs', is, mediated, by, 'NCX'])].
[sujeto(['Further', research, is, needed, to, carry, out, to, demonstrate, the, possible, pathway, and]), verbo([provide]), complemento([a, potential, new, strategy, to, investigation, for, the, treatment, of, the, low, urinary, tract, syndromes])].
[sujeto(['BAS']), verbo([decrease]), complemento(['low-density', 'lipoprotein-cholesterol', by, stimulating, de, novo, hepatic, bile, acid, synthesis, and, lowering, intestinal, lipid, 'absorption,', and, improve, glucose, homeostasis, in, type, 2, diabetes, 'mellitus,', at, least, in, part, by, increasing, 'GLP-1', 'production,', via, intestinal, 'TGR5-', and, 'FXR-dependent', mechanisms])].
[sujeto(['Bile', acids, are, regulators, of, metabolism]), verbo([acting]), complemento([in, an, integrated, interorgan, manner, via, 'FXR', and, 'TGR5'])].
[sujeto(['Modulation', of, the, bile, acid, pool, size, and, 'composition,', and, selective, interference, with, their, receptors, 'could,', 'therefore,', be, a, therapeutic, approach, to]), verbo([decrease]), complemento(['CVRFs'])].
[sujeto(['Bile', acids, can, serve, as, signaling, molecules, by]), verbo([activating]), complemento([the, nuclear, receptor, 'FXR', and, the, 'G-protein-coupled', receptor, 'TGR5', and, both, bile, acid, receptors, are, prominent, experimental, drug, targets])].
[sujeto(['Bile', acids]), verbo([have]), complemento([emerged, as, important, signaling, molecules, in, the, 'host,', as, they, interact, either, locally, or, systemically, with, specific, cellular, 'receptors,', in, particular, the, farnesoid, 'X', receptor, '(', 'FXR)', and, 'TGR5'])].
[sujeto(['Through', defined, enzymatic, 'activities,', the, gut, microbiota, can, significantly, modify, the, signaling, properties, of, bile, acids, and, therefore, can]), verbo([have]), complemento([an, impact, upon, host, health])].
[sujeto(['Alterations', to, the, gut, microbiota, that, influence, bile, acid, metabolism, are]), verbo([associated]), complemento([with, metabolic, 'disease,', 'obesity,', 'diarrhea,', inflammatory, bowel, disease, '(', 'IBD),', 'Clostridium', difficile, 'infection,', colorectal, 'cancer,', and, hepatocellular, carcinoma])].
[sujeto(['Here,', we, examine, the, regulation, of, this, 'gut-microbiota-liver', axis, in, the, context, of, bile, acid, metabolism, and, indicate, how, this, pathway, represents, an, important]), verbo([target]), complemento([for, the, development, of, new, nutraceutical, '(', diet, 'and/or', 'probiotics)', and, targeted, pharmaceutical, interventions])].
[sujeto(['It']), verbo([has]), complemento([become, clear, that, bile, acids, are, no, longer, labeled, as, simple, 'detergent-like', 'molecules,', but, also, represent, complex, hormonal, metabolic, regulators])].
[sujeto(['ICP']), verbo([has]), complemento([also, been, associated, with, increased, incidence, rates, of, gestational, diabetes, mellitus])].
[sujeto(['Irisin', is, a, newly, discovered, myokine, that, is, able, to]), verbo([regulate]), complemento([glucose, and, lipid, 'levels,', thus, improving, insulin, sensitivity])].
[sujeto(['In', this, 'study,', maternal, serum, irisin, levels, were, analyzed, in, order, to]), verbo([provide]), complemento([a, new, perspective, on, the, pathogenesis, of, 'ICP'])].
[sujeto(['However,', it, is, difficult, to, infer, whether, high, irisin, level, is, a]), verbo([cause]), complemento([or, effect, of, 'ICP'])].
[sujeto(['With', the, high, prevalence, of, 'obesity,', 'diabetes,', and, other, features, of, the, metabolic, syndrome, in, 'United', 'States,', nonalcoholic, fatty, liver, disease, '(', 'NAFLD)']), verbo([has]), complemento([inevitably, become, a, very, prevalent, chronic, liver, disease, and, is, now, emerging, as, one, of, the, leading, indications, for, liver, transplantation])].
[sujeto(['Recent', advances, in, the, functional, characterization, of, bile, acid, 'receptors,', such, as, farnesoid, 'X', receptor, '(', 'FXR)', and, transmembrane, 'G', 'protein-coupled', receptor, '(', 'TGR)', 5, ',']), verbo([have]), complemento([provided, further, insight, in, the, pathophysiology, of, 'NASH', and, have, led, to, the, development, of, potential, therapeutic, targets, for, 'NAFLD', and, 'NASH'])].
[sujeto(['Beyond']), verbo([maintaining]), complemento([bile, acid, 'metabolism,', 'FXR', and, 'TGR5', also, regulate, lipid, 'metabolism,', maintain, glucose, 'homeostasis,', increase, energy, 'expenditure,', and, ameliorate, hepatic, inflammation])].
[sujeto(['These', intriguing, features]), verbo([have]), complemento([been, exploited, to, develop, bile, acid, analogues, to, target, pathways, in, 'NAFLD', and, 'NASH', pathogenesis])].
[sujeto(['This', review]), verbo([provides]), complemento([a, brief, overview, of, the, pathogenesis, of, 'NAFLD', and, 'NASH,', and, then, delves, into, the, biological, functions, of, bile, acid, 'receptors,', particularly, with, respect, to, 'NASH', 'pathogenesis,', with, a, description, of, the, associated, experimental, 'data,', 'and,', 'finally,', we, discuss, the, prospects, of, bile, acid, analogues, in, the, treatment, of, 'NAFLD', and, 'NASH'])].
[sujeto(['Zebrafish', phenotypic, assays]), verbo([have]), complemento([shown, promise, to, assess, human, 'hepatotoxicity,', though, scoring, of, liver, morphology, remains, subjective, and, difficult, to, standardize])].
[sujeto(['The', hepatotoxic, compounds]), verbo([induced]), complemento([the, expected, zebrafish, liver, degeneration, or, changes, in, 'size,', whereas, saccharin, did, not, have, any, phenotypic, adverse, effect])].
[sujeto(['Experiments', showed]), verbo([decreased]), complemento([expression, of, all, markers])].
[sujeto(['We', had, previously, demonstrated, that, a, 'Chinese', 2, -, herb, formula, '(', 'NF3)', significantly]), verbo([stimulated]), complemento([angiogenesis, of, 'HUVEC', in, wound, healing])].
[sujeto(['However,', the, molecular, mechanism]), verbo([has]), complemento([not, yet, been, elucidated])].
[sujeto(['In', line, with, 'this,', global, expression, profiling, of, 'NF3-treated', 'HUVEC', was, performed, so, as, to, assess, the, regulatory, role, of, 'NF3']), verbo([involved]), complemento([in, the, underlying, signaling, pathways, in, wound, healing, angiogenesis])].
[sujeto(['The', microarray, results, illustrated, that, different, panels, of, differentially]), verbo([expressed]), complemento([genes, were, strictly, governed, in, 'NF3-treated', 'HUVEC', in, a, 'time-regulated', manner])].
[sujeto(['This', study]), verbo([provided]), complemento([concrete, scientific, evidence, in, support, of, the, regulatory, role, of, 'NF3', on, endothelial, cells, involved, in, wound, healing, angiogenesis])].
[sujeto(['The', density, of, cells, immunoreactive, for, 'GLP-1,', 'CCK', and, 'GIP']), verbo([increased]), complemento([in, patients, after, 'RYGB', and, the, density, of, those, immunoreactive, for, 'GLP-1,', 'PYY,', 'CCK', and, 'PC2', increased, in, controls])].
[sujeto(['Numerous', alterations, in, the, distribution, of, enteroendocrine, cells, and, their, expression, of, hormonal, genes, are, seen, after, 'RYGB', and, include]), verbo([increased]), complemento([density, of, 'GLP-1-,', 'PYY-,', 'CCK-,', 'GIP-', and, 'PC2-positive', 'cells,', reduced, gene, expression, of, 'GHRL,', 'SCT', and, 'GIP', and, increased, expression, of, 'GCG'])].
[sujeto(['Increased', consumption, of, folic, acid, is, 'prevalent,']), verbo([leading]), complemento([to, concerns, about, negative, consequences])].
[sujeto(['Methylenetetrahydrofolate', reductase, '(', 'MTHFR)']), verbo([provides]), complemento([methyl, donors, for, 'S-adenosylmethionine', '(', 'SAM)', synthesis, and, methylation, reactions])].
[sujeto(['High', folic, acid]), verbo([inhibited]), complemento(['MTHFR', activity, in, 'vitro,', and, 'MTHFR', protein, was, reduced, in, 'FASD-fed', mice])].
[sujeto(['The', latter, 'changes,', which, included, higher]), verbo([nuclear]), complemento([sterol, regulatory, 'element-binding', protein, 1, ',', higher, 'Srepb2', messenger, 'RNA', '(', 'mRNA),', lower, farnesoid, 'X', receptor, '(', 'Nr1h4)', 'mRNA,', and, lower, 'Cyp7a1', 'mRNA,', would, lead, to, greater, lipogenesis, and, reduced, cholesterol, catabolism, into, bile])].
[sujeto(['We']), verbo([suggest]), complemento([that, high, folic, acid, consumption, reduces, 'MTHFR', protein, and, activity, 'levels,', creating, a, 'pseudo-MTHFR', deficiency])].
[sujeto(['This', deficiency, results, in, hepatocyte, 'degeneration,']), verbo([suggesting]), complemento([a, 2, -, hit, mechanism, whereby, mutant, hepatocytes, cannot, accommodate, the, lipid, disturbances, and, altered, membrane, integrity, arising, from, changes, in, 'phospholipid/lipid', metabolism])].
[sujeto(['These', preliminary, findings, may]), verbo([have]), complemento([clinical, implications, for, individuals, consuming, 'high-dose', folic, acid, 'supplements,', particularly, those, who, are, 'MTHFR', deficient])].
[sujeto(['To', identify, relevant, pharmacokinetic, mechanisms, in, the, bladder, 'urothelium,', mRNA, expression, of, multidrug, 'transporters,', drug, metabolizing, 'enzymes,', and]), verbo([nuclear]), complemento(['receptors,', and, the, uptake, of, 'TC', into, primary, human, bladder, urothelium, '(', 'HBU)', cells, were, measured])].
[sujeto(['Drug', metabolizing, enzymes, 'CYP3A5,', -, 2, 'B6,', -, 2, 'B7', -, 20.0, ',', 'SULT1A1-4,', 'UGT1A1-10,', and, 'UGT2B15,', and]), verbo([nuclear]), complemento([receptors, 'NR1H3', and, 'NR1H4', were, also, expressed, on, mRNA, level])].
[sujeto(['TC', was, taken, up, into, 'HBU', cells, '(', 'Km', =, 18.5, ±, 4.8, 'μmol/L;', 'Vmax', =, 106, ±, 11.3, 'pmol/mg·min)', by, mechanisms, that, could, be, synergistically]), verbo([inhibited]), complemento([by, naringin, '(', 'IC50', =, 10.8, '(', 8.4, ;, 13.8, ')', 'μmol/L)', and, verapamil, '(', 'IC50', =, 4.6, '(', 2.8, ;, 7.5, ')', 'μmol/L),', inhibitors, of, 'OATP1A2', and, 'OCT1,', respectively])].
[sujeto(['The', human, urothelium]), verbo([expresses]), complemento([many, drug, transporters, and, drug, metabolizing, enzymes, that, may, interact, with, 'TC', and, other, drugs, eliminated, into, the, urine])].
[sujeto(['Cholestasis', is, a, clinically, significant, symptom, and, widely]), verbo([associated]), complemento([with, liver, 'diseases,', 'however,', there, are, very, few, effective, therapies, for, cholestasis])].
[sujeto(['Danning', tablet, '(', 'DNT,', a, 'Chinese', patent, medicine, 'preparation)']), verbo([has]), complemento([been, clinically, used, to, treat, human, liver, and, gallbladder, diseases, for, more, than, 20, years, in, 'China'])].
[sujeto(['However,', which, ingredients, of, 'DNT', contributed, to, this, beneficial, effect, and, their, mechanistic, underpinnings]), verbo([have]), complemento([been, largely, unknown])].
[sujeto(['Curcumin,', one, major, compound, derived, from, 'DNT,', exerted, the, protective, effect, against, cholestasis, through, farnesoid, 'X', receptor, '(', 'FXR),', which]), verbo([has]), complemento([been, focused, as, potential, therapeutic, targets, for, treating, cholestasis])].
[sujeto(['Bile', acid, sequestrants, are, synthetic, polymers, that]), verbo([bind]), complemento([bile, acids, in, the, gut, and, are, used, to, treat, dyslipidemia, and, hyperphosphatemia])].
[sujeto(['Recently,', these, agents]), verbo([have]), complemento([been, reported, to, lower, blood, glucose, and, increase, insulin, sensitivity, by, altering, bile, acid, signaling, pathways])].
[sujeto(['At', the, end, of, 'treatment,', disease, severity, was, 'assessed,', hepatic, leukocyte, populations, were, 'examined,', and, expression, of, genes]), verbo([involved]), complemento([in, farnesoid, 'X', receptor, '(', 'FXR)', signaling, in, the, liver, and, intestine, was, analyzed])].
[sujeto(['Sevelamer-treated', 'NAFLD', livers, had, notably, fewer, 'pro-inflammatory', infiltrating, macrophages, and, a, significantly, greater, fraction, of, alternatively]), verbo([activated]), complemento(['Kupffer', cells, compared, to, controls])].
[sujeto(['Expression', of, genes]), verbo([involved]), complemento([in, 'FXR', signaling, in, the, liver, and, intestine, were, significantly, altered, in, mice, with, 'NAFLD', as, well, as, those, treated, with, sevelamer])].
[sujeto(['We']), verbo([report]), complemento([on, the, molecular, interactions, of, the, 'Farnesoid', 'X', 'Receptor', '(', 'FXR)', with, 'prenylflavonoids,', an, emerging, class, of, 'FXR', modulators])].
[sujeto(['FXR', is, an, attractive, therapeutic]), verbo([target]), complemento([for, mitigating, metabolic, syndromes, '(', 'MetS)', because, 'FXR', activates, the, inhibitory, nuclear, 'receptor,', small, heterodimer, partner, '(', 'SHP),', thereby, inhibiting, both, gluconeogenesis, and, de, novo, lipogenesis])].
[sujeto(['We', and, others]), verbo([have]), complemento([shown, that, xanthohumol, '(', 'XN),', the, principal, prenylflavonoid, of, the, hop, plant, '(', 'Humulus', lupulus, 'L'])].
[sujeto([')', ',', is, a, 'FXR', agonist, based, on, its, ability, to, affect, lipid, and, glucose, metabolism, in, vivo, and, to]), verbo([induces]), complemento(['FXR', target, genes, in, biliary, carcinoma, cells, and, 'HEK293', cells])].
[sujeto(['We', addressed, this, deficiency, and]), verbo([report]), complemento([the, first, systematic, study, of, 'FXR', prenylflavonoid, interactions])].
[sujeto(['We', combined, 'Hydrogen', 'Deuterium', 'Exchange', 'Mass', 'Spectrometry', '(', 'HDX-MS)', with, computational, studies, for, dissecting, molecular, recognition, and, conformational, impact, of, prenylflavonoid, interactions, on, the, ligand]), verbo([binding]), complemento([domain, '(', 'LBD)', of, human, 'FXR'])].
[sujeto(['Enhancement', of, the, 'HDX', protection, profile, data, by, in, silico, predicted, models, of, 'FXR', prenylflavonoid, complexes, resulted, in, mapping, of, the, prenylflavonoid, interactions, within, the, canonical, ligand]), verbo([binding]), complemento([pocket])].
[sujeto(['Our', findings]), verbo([provide]), complemento([a, foundation, for, the, exploration, of, the, chemical, scaffolds, of, prenylated, chalcones, and, flavanones, as, leads, for, future, structure, activity, studies, of, this, important, nuclear, receptor, with, potential, relevance, for, ameliorating, lipid, metabolic, disorders, associated, with, obesity, and, 'MetS'])].
[sujeto(['There', is, significant, unmet, need, in, 'Primary', 'Biliary', 'Cholangitis', '(', 'PBC)', in, patients, 'under-responsive', to, the, only, approved, therapy, 'Ursodeoxycholic', 'Acid', '(', 'UDCA)', who, are, at]), verbo([increased]), complemento([risk, of, progressing, to, 'end-stage', liver, disease])].
[sujeto(['Obeticholic', 'Acid', '(', 'OCA)', is, a, farnesoid, 'X', receptor, '(', 'FXR)', agonist, which]), verbo([has]), complemento([been, evaluated, as, a, second, line, therapy, in, 'PBC', and, has, recently, been, licenced, by, the, 'FDA'])].
[sujeto(['It', significantly, improves, liver, biochemical, parameters, strongly]), verbo([associated]), complemento([with, risk, of, disease, progression, in, 'UDCA', 'under-responsive', patients, and, the, key, 'side-effect', of, pruritus, can, be, reduced, by, optimised, dosing])].
[sujeto(['In', 'contrast,', 'IL10', mice, with, ileitis, had, a, trend, toward]), verbo([decreased]), complemento(['Fgf15', serum, levels, compared, with, controls, and, increased, expression, of, 'Asbt', as, a, negative, 'Fxr-target', gene])].
[sujeto(['Consequently,', our, studies, were, designed, primarily, to, determine, if, 'ER-/PR-/Her2-', breast, cancer, cells]), verbo([have]), complemento([the, potential, to, produce, endogenous, 'AHR', ligands, 'and,', if, 'so,', how, production, of, these, ligands, is, controlled])].
[sujeto(['We', postulated, 'that:', 1, ')', malignant, cells, produce, 'tryptophan-derived', 'AHR', 'ligand(s)', through, the, kynurenine, 'pathway,', 2, ')', these, metabolites]), verbo([have]), complemento([the, potential, to, drive, 'AHR-dependent', breast, cancer, 'migration,', 3, ')', the, 'AHR', controls, expression, of, a, 'rate-limiting', kynurenine, pathway, 'enzyme(s)', in, a, closed, amplification, 'loop,', and, 4, ')', environmental, 'AHR', ligands, mimic, the, effects, of, endogenous, ligands])].
[sujeto(['Data', presented, here, indicate, that, primary, human, breast, 'cancers,', and, their, 'metastases,']), verbo([express]), complemento([high, levels, of, 'AHR', and, 'TDO;', representative, 'ER-/PR-/Her2-', cell, lines, express, 'TDO', and, produce, sufficient, intracellular, kynurenine, and, xanthurenic, acid, concentrations, to, chronically, activate, the, 'AHR'])].
[sujeto(['The', net, biologic, effect, of, 'AHR', activation, by, endogenous, 'ligands,', which, can, be, mimicked, by, environmental, 'ligands,', is, an]), verbo([increase]), complemento([in, tumor, cell, 'migration,', a, measure, of, tumor, aggressiveness])].
[sujeto(['Comparison', of, eleven, human]), verbo([nuclear]), complemento([receptor, amino, acid, sequences, revealed, a, conserved, phosphorylation, motif, within, their, 'DNA', binding, domains, as, an, 'intra-molecular', signal, that, regulates, proteolytic, degradation])].
[sujeto(['A', phosphomimetic, farnesoid, 'X', receptor, '(', 'FXR)', 'S154D', mutant, neither]), verbo([bound]), complemento([to, nor, 'trans-activated', an, 'FXR', response, 'element-driven', reporter, 'gene,', and, was, rapidly, degraded, in, 'COS-1', cells])].
[sujeto(['Ectopically-expressed', 'FXR', had]), verbo([increased]), complemento(['Ser154', phosphorylation, in, 'COS-1', cells, after, ligand, 'treatment,', and, 'knock-down', of, the, nuclear, kinase, 'VRK1', greatly, reduced, this, phosphorylation])].
[sujeto(['FXR', was]), verbo([phosphorylated]), complemento([at, 'Ser154', in, the, nucleus, of, centrilobular, hepatocytes, only, in, 'ligand-treated', mice])].
[sujeto(['BA', synthesis, is]), verbo([inhibited]), complemento([through, intestinal, farnesoid, 'X', receptor, '(', 'FXR)', activity])].
[sujeto(['Animal', data]), verbo([has]), complemento([demonstrated, a, regulatory, role, for, the, 'FXR', in, triglyceride, metabolism])].
[sujeto(['FXR']), verbo([inhibits]), complemento([hepatic, lipogenesis, by, inhibiting, the, expression, of, sterol, regulatory, element, binding, protein, 1, c, via, small, heterodimer, primer, activity])].
[sujeto(['Conversely,', 'FXR']), verbo([promotes]), complemento([free, fatty, acids, oxidation, by, inducing, the, expression, of, peroxisome, 'proliferator-activated', receptor, α])].
[sujeto(['FXR', can, reduce, the, expression, of, microsomal, triglyceride, transfer, 'protein,', which]), verbo([regulates]), complemento([the, assembly, of, very, 'low-density', lipoproteins, '(', 'VLDL)'])].
[sujeto(['FXR', activation, in, turn]), verbo([promotes]), complemento([the, clearance, of, circulating, triglycerides, by, inducing, apolipoprotein, 'C-II,', very, 'low-density', lipoproteins, receptor, '(', 'VLDL-R)', and, the, expression, of, 'Syndecan-1', together, with, the, repression, of, apolipoprotein, 'C-III,', which, increases, lipoprotein, lipase, activity])].
[sujeto(['Emerging', data]), verbo([suggests]), complemento([that, a, third, of, patients, with, 'BAD', have, hypertriglyceridemia])].
[sujeto(['Further', research, is]), verbo([required]), complemento([to, establish, the, risk, of, hypertriglyceridaemia, in, patients, with, 'BAD', and, elicit, the, mechanisms, behind, 'this,', allowing, for, targeted, treatment])].
[sujeto(['Originally', identified, as, an, orphan, 'SULT', by, computational, analysis, of, the, human, 'genome,', we, recently]), verbo([reported]), complemento([that, 'SULT1C3', is, expressed, in, human, intestine, and, 'LS180', colorectal, adenocarcinoma, cells, and, is, 'up-regulated', by, agonists, of, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)', α, and, γ])].
[sujeto(['Transfection', analysis, in, 'LS180', cells, demonstrated, that, 'PPARα,', 'σ,', and, γ, agonist, treatments]), verbo([induced]), complemento([luciferase, expression, from, a, reporter, plasmid, containing, the, 2.8, 'Kb', but, not, the, 1.9, 'Kb', fragment])].
[sujeto(['The', 'PPAR', agonists, also]), verbo([activated]), complemento([a, 1, 'Kb', reporter, containing, the, 863, nt, deletion, region])].
[sujeto(['Although', agonists, of, all, three, 'PPARs', could]), verbo([activate]), complemento(['SULT1C3', 'transcription,', 'RNA', interference, analysis, indicated, the, predominance, of, 'PPARγ'])].
[sujeto(['Farnesoid', 'X', receptor, '(', 'FXR)']), verbo([has]), complemento([been, confirmed, to, sense, bile, acids, in, various, tissues])].
[sujeto(['In']), verbo([nuclear]), complemento(['compartments,', the, neuronal, 'FXR', exhibited, a, punctate, distribution])].
[sujeto(['Activation', of, 'FXR']), verbo([increased]), complemento([the, small, heterodimer, partner, '(', 'SHP)', mRNA, and, protein, expression, levels, in, cultured, neurons, and, in, brain, tissues])].
[sujeto(['The', farnesoid, 'X', receptor, '(', 'FXR)', is, a]), verbo([nuclear]), complemento([receptor, responsible, for, homeostasis, of, bile, 'acids,', 'lipids,', and, glucose])].
[sujeto(['Therefore,', there, is, an]), verbo([increasing]), complemento([need, for, 'high-throughput', screening, assays, of, 'FXR', activity, to, profile, large, numbers, of, environmental, chemicals, and, drugs])].
[sujeto(['To', identify, compounds, that]), verbo([modulate]), complemento(['FXR', transactivation, at, the, cellular, 'level,', we, first, screen, compounds, from, the, 'Tox21', 10, 'K', compound, library, in, an, 'FXR-driven', 'beta-lactamase', reporter, gene, assay, multiplexed, with, a, cell, viability, assay, in, the, same, well, of, the, 1536, -, well, plates])].
[sujeto(['The', selected, compounds, are, then, tested, biochemically, for, their, ability, to]), verbo([modulate]), complemento(['FXR-coactivator', binding, interactions, using, a, 'time-resolved', fluorescence, resonance, energy, transfer, '(', 'TR-FRET)', coactivator, assay])].
[sujeto(['Ocaliva,', a, synthetic, bile, acid, analog, with, high, affinity, for, the]), verbo([nuclear]), complemento([bile, acid, receptor, 'FXR,', is, effective, in, treating, primary, biliary, 'cholangitis,', an, autoimmune, liver, disease])].
[sujeto(['It', works, in, patients, who, fail, to]), verbo([respond]), complemento([to, or, cannot, tolerate, conventional, treatment, with, the, natural, bile, acid, ursodeoxycholic, acid, '(', 'UDCA)'])].
[sujeto(['There', exists, a, close, link, between, energy, metabolism, and, cell, 'survival,', which, are, coordinately]), verbo([regulated]), complemento([by, common, signaling, pathways])].
[sujeto(['Farnesoid', 'X', receptor, '(', 'FXR)', serves, as, a, 'ligand-mediated', transcription, factor, to]), verbo([regulate]), complemento([diverse, genes, involved, in, bile, 'acid,', 'lipid,', and, glucose, 'metabolism,', controlling, cellular, and, systemic, energy, metabolism])].
[sujeto(['FXR', exerts, antioxidative, and, cytoprotective, 'effect,', which, is, closely]), verbo([associated]), complemento([with, the, ability, of, 'FXR', to, regulate, mitochondrial, function])].
[sujeto(['To']), verbo([maintain]), complemento([complex, biological, processes, under, 'homeostasis,', 'FXR', activity, needs, to, be, dynamically, and, tightly, controlled, by, different, signaling, pathways, and, modifications])].
[sujeto(['This', single, 'RNA', molecule, needs, to, become]), verbo([involved]), complemento([in, replication, process, before, it, is, recognized, and, degraded, by, cellular, machinery])].
[sujeto(['In', this, 'study,', we, show, that, distantly, related, 'New', 'World', and, 'Old', 'World', alphaviruses]), verbo([have]), complemento([independently, evolved, to, utilize, different, cellular, stress, 'granule-related', proteins, for, assembly, of, 'complexes,', which, recruit, viral, genomic, 'RNA', and, facilitate, formation, of, viral, replication, complexes, '(', 'vRCs)'])].
[sujeto(['Both', 'FXR', and, 'G3BP', proteins]), verbo([interact]), complemento([with, 'virus-specific,', repeating, amino, acid, sequences, located, in, the, 'C-termini', of, 'hypervariable,', intrinsically, disordered, domains, '(', 'HVDs)', of, viral, nonstructural, protein, nsP3])].
[sujeto(['The', use, of, multiple, homologous, proteins, with, redundant, functions]), verbo([mediates]), complemento([highly, efficient, recruitment, of, viral, 'RNA', into, the, replication, process])].
[sujeto(['This', independently, evolved, acquisition, of, different, families, of, cellular, proteins, by, the, disordered, protein, fragment, to, support, alphavirus, replication]), verbo([suggests]), complemento([that, other, 'RNA', viruses, may, utilize, a, similar, mechanism, of, host, factor, recruitment, for, vRC, assembly])].
[sujeto(['Hepatocytes', cultured, on, 'EHS', matrigel, produced, more, bile, acids, and]), verbo([expressed]), complemento([higher, levels, of, cholesterol, 7, 'α-hydroxylase', '(', 'CYP7A1)', than, cells, cultured, on, rat, tail, collagen])].
[sujeto(['Supplementation', with, dexamethasone]), verbo([increased]), complemento([the, formation, of, cholic, acid, '(', 'CA)', and, decreased, chenodeoxycholic, acid, formation])].
[sujeto(['In', line, with, these, 'results,', the, mRNA, expression, of, sterol, 12, 'α-hydroxylase', '(', 'CYP8B1)']), verbo([increased]), complemento([following, dexamethasone, treatment])].
[sujeto(['Surprisingly,', the, mRNA, expression, of, 'CYP7A1', and, 'CYP27A1', was, not]), verbo([increased]), complemento([to, the, same, extent])].
[sujeto(['By', using, the, 'GR', antagonist, 'RU486,', we, concluded, that, 'CYP8B1', induction, is]), verbo([mediated]), complemento([via, a, 'GR-independent', pathway])].
[sujeto(['An', altered, expression, of, 'retinoid-related', orphan, receptor, '(', 'ROR)', α, and, 'ROR', α]), verbo([target]), complemento([gene, 'Glucose-6-phosphatase', '(', 'G6Pase)', suggests, that, 'ROR', α, signaling, may, regulate, 'CYP8B1', expression])].
[sujeto(['Primary', human, hepatocytes]), verbo([have]), complemento([an, increased, bile, acid, synthesis, rate, when, cultured, on, matrigel, as, compared, to, collagen])].
[sujeto(['Exposure', to, glucocorticoid, hormones]), verbo([stimulates]), complemento([the, expression, of, 'CYP8B1,', leading, to, an, increased, formation, of, 'CA', and, alteration, of, the, bile, acid, composition])].
[sujeto(['The', effect, is, most, likely]), verbo([mediated]), complemento([through, a, 'GR-independent', 'pathway,', possibly, through, 'ROR', α])].
[sujeto(['The', farnesoid, 'X', receptor, '(', 'FXR,', 'NR1H4)']), verbo([regulates]), complemento([bile, acid, and, lipid, homeostasis, by, acting, as, an, intracellular, bile, 'acid-sensing', transcription, 'factor,', resulting, in, altered, expression, of, enzymes, and, transporters, involved, in, bile, acid, synthesis, and, transport])].
[sujeto(['Cholic', acid, feeding]), verbo([led]), complemento([to, significantly, decreased, levels, of, expression, of, oatp1, and, oct1, and, an, increased, level, of, expression, of, oatp2, in, 'wild-type', mouse, liver])].
[sujeto(['Our', results]), verbo([suggested]), complemento([that, 'FXR', is, involved, in, the, transcriptional, regulation, of, oatp, and, other, transporters, in, a, 'tissue-specific', manner])].
[sujeto(['Pairs', of, forward, and, reverse, primers, and, 'TaqMan', probes, specific, to, each, human]), verbo([nuclear]), complemento([receptor, were, prepared])].
[sujeto(['Analysis', of, the, mRNA, expression, level, of, each]), verbo([target]), complemento([of, 43, nuclear, receptors, in, total, 'RNA', from, single, and, pooled, specimens, of, various, human, organs, '(', 'liver,', 'kidney,', adrenal, 'gland,', 'lung,', 'heart,', 'brain,', 'cerebellum,', skeletal, 'muscle,', 'spleen,', 'thymus,', thyroid, 'gland,', 'prostate,', 'testis,', 'uterus,', 'placenta,', bone, 'marrow,', 'trachea,', and, salivary, 'gland)', was, performed, by, 'real-time', reverse, transcription, 'PCR', using, an, 'ABI', 'PRISM', 7700, sequence, detector, system])].
[sujeto(['The', mRNA, expression, of, 33]), verbo([nuclear]), complemento([receptors, '(', 'NR1A1,', 1, 'A2,', 1, 'B1,', 1, 'B2,', 1, 'B3,', 1, 'C1,', 1, 'C2,', 1, 'C3,', 1, 'D1,', 1, 'D2,', 1, 'F1,', 1, 'F2,', 1, 'F3,', 1, 'H2,', 1, 'H3,', 1, 'I1,', 1, 'I2,', 2, 'B1,', 2, 'B2,', 2, 'B3,', 2, 'C1,', 2, 'C2,', 2, 'F1,', 2, 'F2,', 3, 'A2,', 3, 'B1,', 3, 'C1,', 3, 'C2,', 3, 'C4,', 4, 'A1,', 4, 'A2,', 4, 'A3,', and, 6, 'A1)', was, successfully, detected, in, all, of, the, tissues, by, this, method])].
[sujeto(['This', study]), verbo([provides]), complemento([information, concerning, the, tissue, distribution, of, the, mRNA, expression, of, 43, human, nuclear, receptors])].
[sujeto(['These', results, are, valuable, for, establishing, a]), verbo([nuclear]), complemento(['receptor-mediated', screening, system, for, new, chemical, entities, in, new, drug, development])].
[sujeto(['We', identified, significant, loci]), verbo([associated]), complemento([with, gallstone, weight, on, chromosomes, 10, and, 4, ',', named, 'Lith7', and, 'Lith8,', respectively, '(', both, susceptibility, alleles, conferred, by, strain, 'I/LnJ)'])].
[sujeto(['Positional', candidate, genes, with, higher, expression, in, 'I/LnJ', mice, are, 'Fxr', '(', official, 'symbol,', 'Nr1h4),', encoding, the]), verbo([nuclear]), complemento([bile, salt, 'receptor,', on, chromosome, 10, and, 'Shp1', '(', official, 'symbol,', 'Nr0b2),', encoding, the, small, heterodimer, partner, 1, ',', on, chromosome, 4])].
[sujeto(['A', significant, locus]), verbo([associated]), complemento([with, gallstone, score, on, chromosome, 17, ',', named, 'Lith9', '(', susceptibility, allele, conferred, by, strain, 'PERA/Ei),', colocalizes, with, the, genes, 'Abcg5', and, 'Abcg8', that, encode, the, canalicular, cholesterol, transporter])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([a, primary, role, of, the, nuclear, bile, salt, receptor, 'FXR', and, the, canalicular, cholesterol, transporter, 'ABCG5/ABCG8', in, the, genetic, susceptibility, and, pathogenesis, of, cholesterol, cholelithiasis, in, these, strains, of, inbred, mice])].
[sujeto(['The', farnesoid, 'X', receptor, '(', 'FXR)']), verbo([regulates]), complemento([bile, acid, '(', 'BA)', metabolism, and, possesses, tumor, suppressor, functions])].
[sujeto(['Identifying', the, mechanisms, responsible, for, this, reduction, may, offer, new, molecular]), verbo([targets]), complemento([for, colon, cancer, prevention])].
[sujeto(['We', hypothesized, that, 'APC', inactivation, would, epigenetically]), verbo([repress]), complemento([nuclear, receptor, subfamily, 1, ',', group, 'H,', member, 4, '(', 'FXR', gene, 'name)', expression, through, increased, 'CpG', methylation])].
[sujeto(['In', 'Apc(Min)', '(', /, +, ')', 'mice,', constitutive, 'CpG', methylation, of, the, 'Fxrα3/4', promoter, was, linked, to, reduced, '(', 60, -, 90, '%', ')', baseline, 'Fxr,', 'Ibabp,', and, 'Shp', and]), verbo([increased]), complemento(['Cox-2', expression, in, apparently, normal, adjacent, mucosa, and, colon, tumors])].
[sujeto(['Apc', knockdown, in, 'HCT-116', cells]), verbo([increased]), complemento([cellular, myelocytomatosis, '(', 'c-MYC)', and, lowered, '(', '∼50%)', 'FXR', 'expression,', which, was, further, reduced, '(', '∼80%)', by, 'DCA'])].
[sujeto(['In', human, 'HCT-116', but, not, 'HT-29', colon, cancer, 'cells,', 'DCA']), verbo([induced]), complemento(['FXR', expression, and, lowered, 'CpG', methylation, of, 'FXR'])].
[sujeto(['We', conclude, that, the]), verbo([loss]), complemento([of, 'APC', function, favors, the, silencing, of, 'FXR', expression, through, 'CpG', hypermethylation, in, mouse, colonic, mucosa, and, human, colon, 'cells,', leading, to, reduced, expression, of, downstream, targets, '(', 'SHP,', 'IBABP)', involved, in, 'BA', homeostasis, while, increasing, the, expression, of, factors, '(', 'COX-2,', 'c-MYC)', that, contribute, to, inflammation, and, colon, cancer])].
[sujeto(['Identification', of, substances, with, specific, toxicity, for, carcinoma, cells, promises, to, facilitate, the, development, of, cancer, chemotherapeutics, that]), verbo([cause]), complemento([minimal, side, effects])].
[sujeto(['Here,', we, show, that, knockdown, of, the, farnesoid, 'X', receptor, '(', 'FXR)', effectively]), verbo([suppresses]), complemento([the, proliferation, of, human, hepatocellular, carcinoma, cell, lines, 'HepG2', and, 'HLE', accompanied, by, elevated, expression, of, 'cyclin-dependent', kinase, '(', 'CDK)', inhibitor, 'p16/INK4a', and, 'p21/Cip1', proteins])].
[sujeto(['On', the, other, 'hand,', the, growth, of, the, primary, human, 'hepatocyte-derived', cell, line, 'Fa2N-4', is, not, affected, by, the, treatment, with, 'FXR', siRNA, irrespective, of, marked]), verbo([increases]), complemento([in, the, mRNAs, of, 'p16/INK4a', and, 'p21/Cip1'])].
[sujeto(['Since', the, expression, levels, of, these, 'CDK', inhibitor, proteins, in, 'FXR-knockdown', 'Fa2N-4', cells, were, elevated, in, the, presence, of, proteasomal, inhibitor, 'MG132,', these, 'CDK', inhibitors, may, be, subjected, to, the, proteasomal, 'degradation,', thereby, counteracting, the]), verbo([increased]), complemento([expression, of, their, cognate, 'mRNAs,', therefore, similar, levels, of, p16, and, p21, proteins, were, observed, in, control, and, 'FXR-knockdown', 'Fa2N-4', cells])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'FXR-knockdown', is, effective, for, inhibiting, the, proliferation, of, hepatocellular, carcinoma, 'cells,', not, interfering, with, the, regulatory, mechanism, of, normal, hepatocyte, growth])].
[sujeto(['Acetylation', of, transcriptional, regulators, is, normally, dynamically]), verbo([regulated]), complemento([by, nutrient, status, but, is, often, persistently, elevated, in, 'nutrient-excessive', obesity, conditions])].
[sujeto(['We', investigated, the, functional, consequences, of, such, aberrantly, elevated, acetylation, of, the]), verbo([nuclear]), complemento([receptor, 'FXR', as, a, model])].
[sujeto(['In', vivo, studies, utilizing, 'acetylation-mimic', and, 'acetylation-defective', 'K217', mutants, and, gene, expression, profiling, revealed, that, 'FXR', acetylation]), verbo([increased]), complemento([proinflammatory, gene, 'expression,', macrophage, 'infiltration,', and, liver, cytokine, and, triglyceride, 'levels,', impaired, insulin, 'signaling,', and, increased, glucose, intolerance])].
[sujeto(['Mechanistically,', acetylation, of, 'FXR', blocked, its, interaction, with, the, 'SUMO', ligase, 'PIASy', and]), verbo([inhibited]), complemento(['SUMO2', modification, at, 'K277,', resulting, in, activation, of, inflammatory, genes])].
[sujeto(['SUMOylation', of, 'agonist-activated', 'FXR']), verbo([increased]), complemento([its, interaction, with, 'NF-κB', but, blocked, that, with, 'RXRα,', so, that, 'SUMO2-modified', 'FXR', was, selectively, recruited, to, and, 'trans-repressed', inflammatory, genes, without, affecting, 'FXR/RXRα', target, genes])].
[sujeto(['A', dysregulated, 'acetyl/SUMO', switch, of, 'FXR', in, obesity, may, serve, as, a, general, mechanism, for, diminished, 'anti-inflammatory', response, of, other, transcriptional, regulators, and]), verbo([provide]), complemento([potential, therapeutic, and, diagnostic, targets, for, 'obesity-related', metabolic, disorders])].
[sujeto(['Atorvastatin']), verbo([decreased]), complemento(['BA', pool, 'size,', mainly, due, to, less, 'BA', in, the, intestine])].
[sujeto(['Atorvastatin']), verbo([increased]), complemento([the, ratio, of, 12, 'α-OH/non12α-OH', 'BAs'])].
[sujeto(['Atorvastatin']), verbo([increased]), complemento([the, mRNAs, of, the, 'BA-synthetic', enzymes, cholesterol, 7, 'α-hydroxylase', '(', 'Cyp7a1)', '(', over, 10, -, 'fold)', and, cytochrome, 'P450', 27, 'a1,', the, 'BA', uptake, transporters, 'Na⁺/taurocholate', cotransporting, polypeptide, and, organic, anion, transporting, polypeptide, 1, 'b2,', and, the, efflux, transporter, multidrug, 'resistance-associated', protein, 2, in, the, liver])].
[sujeto(['Noticeably,', atorvastatin]), verbo([suppressed]), complemento([the, expression, of, 'BA', nuclear, receptor, farnesoid, 'X', receptor, '(', 'FXR)', target, 'genes,', namely, small, heterodimer, partner, '(', 'liver)', and, fibroblast, growth, factor, 15, '(', 'ileum)'])].
[sujeto(['Furthermore,', atorvastatin]), verbo([increased]), complemento([the, mRNAs, of, the, organic, cation, uptake, transporter, 1, and, cholesterol, efflux, transporters, 'Abcg5', and, 'Abcg8', in, the, liver])].
[sujeto(['The']), verbo([increased]), complemento([expression, of, 'BA-synthetic', enzymes, and, 'BA', transporters, appear, to, be, a, compensatory, response, to, maintain, 'BA', homeostasis, after, atorvastatin, treatment])].
[sujeto(['The', 'Cyp7a1', induction, by, atorvastatin, appears, to, be, due, to]), verbo([suppressed]), complemento(['FXR', signaling, in, both, the, liver, and, intestine])].
[sujeto(['MicroRNAs', '(', 'miRNAs),', a, class, of, small, noncoding, 'RNAs,', play, critical, roles, in, human, carcinogenesis, through, downregulation, of, various]), verbo([target]), complemento([genes])].
[sujeto(['In', the, present, 'study,', we]), verbo([found]), complemento([that, 'miR-92', is, upregulated, in, gastric, cancer, tissues, compared, with, adjacent, normal, tissues])].
[sujeto(['Interestingly,', 'miR-92', expression, is, significantly]), verbo([associated]), complemento([with, clinical, characteristics, of, patients])].
[sujeto(['Gain', or, 'loss-of-function', in, vitro, experiments, further, show, that, 'miR-92', mimics, significantly, 'promoted,', while, its, antisense, oligos]), verbo([inhibited]), complemento([gastric, cancer, cell, proliferation, and, invasion])].
[sujeto(['Moreover,', luciferase, reporter, assays, and, western, blot, indicated, that, farnesoid, 'X', receptor, '(', 'FXR),', is, a, direct]), verbo([target]), complemento([of, 'miR-92'])].
[sujeto(['Therefore,', our, data]), verbo([suggest]), complemento([that, upregulation, of, 'miR-92', may, represent, an, important, mechanism, for, the, development, of, gastric, cancer])].
[sujeto(['The', farnesoid, 'X', receptor, '(', 'FXR)', is, mainly]), verbo([expressed]), complemento([in, 'liver,', intestine, and, kidney])].
[sujeto(['We', investigated, whether, 6, -, ethyl, chenodeoxycholic, acid, '(', '6ECDCA),', a, semisynthetic, derivative, of, chenodeoxycholic, aicd, '(', 'CDCA,', an, 'FXR', 'ligand),', protects, against, kidney, injury, and]), verbo([modulates]), complemento([small, heterodimer, partner, '(', 'SHP)', in, 'cisplatin-induced', kidney, injury])].
[sujeto(['Cisplatin']), verbo([inhibited]), complemento(['SHP', protein, expression, in, the, kidney, of, 'cisplatin-treated', mice, and, human, proximal, tubular, '(', 'HK2)', 'cells;', this, effect, was, counteracted, by, 'FXR', ligand])].
[sujeto(['Cisplatin']), verbo([induced]), complemento(['NF-κB', activation, in, 'HK2', 'cell;', this, effect, was, attenuated, by, pretreatment, with, 'FXR', ligand])].
[sujeto(['In', 'SHP', knockdown, by, small, interfering, 'RNA,', 'cisplatin-induced', activation, of, 'TGF-β1,', 'p-JNK', and, 'Bax/Bcl-2', ratio, was, not, 'attenuated,', while, 'SHP', overexpression, and, 'FXR', ligand]), verbo([inhibited]), complemento([expression, of, these, proteins, in, 'cisplatin-pretreated', 'HK2', cells])].
[sujeto(['In', 'conclusion,', 'FXR', 'ligand,', '6ECDCA']), verbo([prevents]), complemento(['cisplatin-induced', kidney, 'injury,', the, underlying, mechanism, of, which, may, be, associated, with, 'anti-fibrotic,', 'anti-inflammatory,', and, 'anti-apoptotic', effects, through, 'SHP', induction])].
[sujeto(['To', investigate, the, effect, of, bile, acid, on, the, expression, of, histidine, decarboxylase, '(', 'HDC),', which, is, a, major, enzyme]), verbo([involved]), complemento([in, histamine, 'production,', and, gene, expression, of, gastric, transcription, factors, upon, cooperative, activation])].
[sujeto(['The', relationship, between, gastric, precancerous, state, and, 'HDC', expression]), verbo([induced]), complemento([by, bile, acid, was, determined])].
[sujeto(['Here,', we, show, that, bile, acid]), verbo([increased]), complemento([the, expression, of, 'HDC,', which, is, a, 'rate-limiting', enzyme, of, the, histamine, production, pathway])].
[sujeto(['FXR', was]), verbo([found]), complemento([to, be, a, primary, regulatory, transcription, factor, for, bile, 'acid-induced', 'HDC', expression])].
[sujeto(['In', 'addition,', the, transcription, factors, 'CDX1', and, 'SHP', synergistically]), verbo([enhanced]), complemento([bile, 'acid-induced', elevation, of, 'HDC', gene, expression])].
[sujeto(['HDC', production, in, the, stomach, is]), verbo([associated]), complemento([with, bile, acid, exposure, and, its, related, transcriptional, regulation, network, of, 'FXR,', 'SHP,', and, 'CDX1'])].
[sujeto(['Liver', 'X', 'receptor-α', '(', 'LXRα),', a, member, of, the]), verbo([nuclear]), complemento([receptor, superfamily, of, 'ligand-activated', transcription, 'factors,', regulates, de, novo, fatty, acid, synthesis, that, leads, to, stimulate, hepatic, steatosis])].
[sujeto(['Although,', resveratrol]), verbo([has]), complemento([beneficial, effects, on, metabolic, 'disease,', it, is, not, known, whether, resveratrol, affects, 'LXRα-dependent', lipogenic, gene, expression])].
[sujeto(['Resveratrol']), verbo([inhibited]), complemento([the, ability, of, 'LXRα', to, activate, sterol, regulatory, element, binding, 'protein-1c', '(', 'SREBP-1c)', and, thereby, inhibited, target, gene, expression, in, hepatocytes])].
[sujeto(['Moreover,', resveratrol]), verbo([decreased]), complemento(['LXRα-RXRα', 'DNA', binding, activity, and, 'LXRE-luciferase', transactivation])].
[sujeto(['Resveratrol', is, known, to]), verbo([activate]), complemento(['Sirtuin', 1, '(', 'Sirt1)', and, 'AMP-activated', protein, kinase, '(', 'AMPK),', although, its, precise, mechanism, of, action, remains, controversial])].
[sujeto(['We']), verbo([found]), complemento([that, the, ability, of, resveratrol, to, repress, 'T0901317-induced', 'SREBP-1c', expression, was, not, dependent, on, 'AMPK', and, 'Sirt1'])].
[sujeto(['It', is, well, established, that, hepatic, steatosis, is]), verbo([associated]), complemento([with, antioxidant, and, redox, signaling])].
[sujeto(['Sesn2', overexpression]), verbo([repressed]), complemento(['LXRα-activated', 'SREBP-1c', expression, and, 'LXRE-luciferase', activity])].
[sujeto(['Heterozygous', mutations, in, hepatocyte]), verbo([nuclear]), complemento([factor, 1, α, '(', 'HNF1α)', cause, maturity, onset, diabetes, of, the, young, 3, '(', 'MODY3),', an, autosomal, dominant, form, of, diabetes])].
[sujeto(['Deficiency', of, 'HNF1α', in, mice, results, in, 'diabetes,', hypercholesterolaemia, and]), verbo([increased]), complemento([bile, acid, '(', 'BA)', and, cholesterol, synthesis])].
[sujeto(['The', aim, of, this, study, was, to, investigate, whether, patients, with, 'MODY3']), verbo([have]), complemento([altered, cholesterol, and, 'BA', synthesis, and, intestinal, cholesterol, absorption])].
[sujeto(['Cotransfection', experiments, were, performed, with, several, promoters]), verbo([involved]), complemento([in, 'BA', metabolism, along, with, expression, vectors, carrying, the, mutations, found, in, these, patients])].
[sujeto(['Cotransfection', experiments, showed, that, one, of, the, mutations, '(', 'P379A)']), verbo([increased]), complemento([the, induction, of, the, cholesterol, 7, 'α-hydroxylase', promoter, compared, with, 'HNF1α,', without, further, differences, in, other, studied, promoters])].
[sujeto(['BA', synthesis, is]), verbo([increased]), complemento([in, patients, with, 'MODY3', compared, with, control, subjects])].
[sujeto(['Mutations', in, 'HNF1α', affect, promoters]), verbo([involved]), complemento([in, 'BA', metabolism])].
[sujeto(['We']), verbo([have]), complemento([shown, a, hepatoprotective, effect, of, adiponectin, in, steatotic, livers, of, hepatitis, 'C', virus, '(', 'HCV)', patients, and, recent, data, links, bile, acid, '(', 'BA)', metabolism, to, the, pathogenesis, of, 'NAFLD'])].
[sujeto(['Serum', 'FFA,', 'BA,', and, 'M30', were]), verbo([increased]), complemento([in, 'NASH', versus, simple, 'steatosis,', while, adiponectin, was, significantly, decreased])].
[sujeto(['Up-regulation', of, 'NTCP', and, 'CYP7A1', indicate, failure, to]), verbo([activate]), complemento([small, heterodimer, partner, '(', 'SHP)', upon, farnesoid, 'X', receptor, '(', 'FXR)', stimulation, by, increasing, 'BA', concentrations])].
[sujeto(['FFA', exposure]), verbo([prevented]), complemento(['SHP-mediated', repression, of, 'NTCP', and, 'Cyp7A1', 'expression,', which, lead, to, increased, 'BA', synthesis, and, uptake])].
[sujeto(['In', 'NASH,', 'BA', accumulation]), verbo([induced]), complemento([hepatocyte, cell, death, and, late, 'FXR', activation, failed, to, prevent, hepatocyte, injury, due, to, decreased, adiponectin, levels])].
[sujeto(['Early', treatment, with, 'FXR', ligands, 'and/or', 'adiponectin-receptor', agonists, might]), verbo([prevent]), complemento(['NASH'])].
[sujeto(['Multidrug', resistance, is, a, serious, barrier, to, successful, treatment, of, many, human, 'diseases,', including, 'cancer,', wherein, chemotherapeutics, are, exported, from]), verbo([target]), complemento([cells, by, 'membrane-embedded', pumps])].
[sujeto(['The', transmembrane, region, encapsulates, a, hydrophobic, 'cavity,', accessed, by, portals, in, the, 'membrane,', that]), verbo([binds]), complemento([cytotoxic, compounds, as, well, as, lipids, and, peptides])].
[sujeto(['Activation', in, the, gas, phase]), verbo([leads]), complemento([to, formation, of, 'ions,', largely, devoid, of, 'detergent,', yet, retaining, drug, molecules, as, well, as, charged, or, zwitterionic, lipids])].
[sujeto(['Measuring', the, rates, of, lipid]), verbo([binding]), complemento([and, calculating, apparent, 'KD', values, shows, that, up, to, six, negatively, charged, diacylglycerides, bind, more, favorably, than, zwitterionic, lipids])].
[sujeto(['Similar', experiments, confirm]), verbo([binding]), complemento([of, cardiolipins, and, show, that, prior, binding, of, the, immunosuppressant, and, antifungal, antibiotic, cyclosporin, 'A', enhances, subsequent, binding, of, cardiolipin])].
[sujeto(['Ion', mobility, 'MS']), verbo([reveals]), complemento([that, 'P-gp', exists, in, an, equilibrium, between, different, 'states,', readily, interconverted, by, ligand, binding])].
[sujeto(['Overall', these, 'MS', results, show, how, concerted, small, molecule]), verbo([binding]), complemento([leads, to, synergistic, effects, on, binding, affinities, and, conformations, of, a, multidrug, efflux, pump])].
[sujeto(['While', cellular, accumulations, in, culture, of, 'oligomers,', such, as, interfering, 'RNA', and, antisense, 'DNA,', are]), verbo([reported]), complemento([to, benefit, from, the, addition, of, transmembrane, transfectors, '(', 'TFs),', the, extent, to, which, individual, 'TFs', improve, cellular, delivery, is, usually, inferred, and, rarely, measured])].
[sujeto(['The', goal, of, this, investigation, was, to, use, radioactivity, to, measure, in, cells, in, culture, the, degree, to, which, accumulations, of, 'DNA']), verbo([increased]), complemento([when, complexed, with, 'TFs', and, without, 'DNA', entrapment, in, vesicles])].
[sujeto(['The', antisense, '(', 'AS)', 'DNA']), verbo([targeting]), complemento([mdr1, mRNA, coding, for, 'P-glycoprotein', '(', 'Pgp)', and, its, sense, '(', 'S)', complement, 'DNA', were, radiolabeled, with, 99, mTc, and, mixed, with, 'jetPEI,', 'Chariot,', or, 'Neophectin', over, a, range, of, 'TF/DNA', ratios])].
[sujeto(['Cellular', accumulations, were]), verbo([increased]), complemento([under, most, incubation, conditions, and, by, as, much, as, threefold, with, jetPEI, and, eightfold, with, 'Neophectin'])].
[sujeto(['In', 'conclusion,', by, using, radiolabeled, 'DNAs,', definitive, evidence, was, obtained, showing, that, the, addition, of, 'Neophectin', and, jet, 'PEI']), verbo([increased]), complemento([cellular, accumulations, of, both, 'AS', and, 'S', 'DNA', without, evidence, of, vesicle, entrapment])].
[sujeto(['We', studied, the, capacity, of, doxorubicin, encapsulation, in, liposomes, of, various, lipid, compositions, to, circumvent, multidrug, resistance, in, several, variants, of, the, 'C6', rat, glioblastoma, cell, line, in, 'culture,', and, to]), verbo([inhibit]), complemento([azidopine, binding, to, membranes, isolated, from, these, cells])].
[sujeto(['Free', doxorubicin, was, able, to]), verbo([decrease]), complemento([50, '%', of, '[', 3, 'H]azidopine', photolabelling, to, 'P-glycoprotein', at, a, concentration, of, 40, 'microM;', doxorubicin, encapsulated, in, 'PC/CL/cho', or, 'PC/PS/cho', liposomes, was, able, to, inhibit, '[', 3, 'H]azidopine', binding, similarly, as, free, 'drug,', whereas, doxorubicin, encapsulated, in, 'DPPC/cho', liposomes, had, no, significant, effect, on, this, parameter])].
[sujeto(['Together', with, physical, studies, performed, in, parallel, on, doxorubicin, trapping, in, liposomes, '(', 'J', 'Liposome', 'Res', 1993, ',', 3, ',', 753, -, 766, ')', ',', these, results]), verbo([suggest]), complemento([that, doxorubicin, leaked, out, of, fluid, liposomes, '(', 'PC/PS/cho', or, 'PC/CL/cho),', whereas, rigid, liposomes, '(', 'DPPC/cho)', were, able, to, sequester, the, drug, more, efficiently])].
[sujeto(['In', 'conclusion,', no, reversal, of, doxorubicin, resistance, was]), verbo([found]), complemento([to, occur, through, liposomal, encapsulation, of, the, drug])].
[sujeto(['Recent', data, from, the, literature, together, with, personal, results, strongly]), verbo([suggest]), complemento([that, multidrug, resistance, phenotype, is, overwhelming, the, sole, expression, of, 'P170', glycoprotein, efflux, pump])].
[sujeto(['Morphological', alterations]), verbo([have]), complemento([been, put, in, evidence, in, 'MDR', cells, after, transmission, and, scanning, electron, microscopy])].
[sujeto(['They', include, presence, of, osmiophilic, vesicles, and, modifications, of]), verbo([nuclear]), complemento([and, nucleolar, chromatin])].
[sujeto(['Such', a, fact, could, be, more, or, less, related, to, the]), verbo([increased]), complemento([occurrence, of, mdr1, 'RNA', in, 'metastasis,', especially, in, breast, 'cancers,', compared, to, primary, tumors])].
[sujeto(['If', the, 'P170-mediated', efflux, is, one, of, the, key, mechanism, of, 'MDR,', a]), verbo([decreased]), complemento([influx, of, anticancer, drugs, cannot, be, excluded])].
[sujeto(['Liposomes,', for, instance, made, of, 'cardiolipin,', are, thus, able, to]), verbo([increase]), complemento([the, intracellular, drug, uptake, of, vinblastine, without, any, action, upon, efflux, mechanism])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([confirmed, the, ability, of, 'liposome-encapsulated', doxorubicin, to, modulate, drug, 'resistance,', as, previously, observed, in, 'CH', 'LZ', cells, '(', 'Thierry', et, al])].
[sujeto(['This', effect, was, specific, to, 'MDR', 'cells,', as, liposomally, encapsulated, doxorubicin, did, not]), verbo([enhance]), complemento([cell, sensitivity, to, the, drug, in, the, parental, cell, lines])].
[sujeto(['This', effect, seems, to, be, due, to, the, high, affinity, of, 'Dox', for, 'cardiolipin,', one, of, the, liposome, 'components,', which]), verbo([leads]), complemento([to, the, association, of, the, drug, and, the, 'cardiolipin-containing', liposomes, in, the, culture, medium, before, entry, into, the, cells])].
[sujeto(['Neither', pretreatment, of, empty, liposomes, before, drug, treatment, nor, combined, incubation, of, vincristine, and, empty, liposomes, alter, 'MDR', in, 'CH', 'LZ', 'cells,']), verbo([suggesting]), complemento([that, the, drug, must, be, encapsulated, or, complexed, to, the, liposomes, to, overcome, 'MDR'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, enhancement, of, sensitivity, of, 'MDR', cells, using, 'Dox', encapsulated, in, liposomes, or, complexed, with, liposomes, may, be, explained, by, an, increase, in, cell, drug, incorporation, and, by, an, intracellular, drug, redistribution])].
[sujeto(['In', 'addition,', presentation, of, 'Dox', in, liposomes, modifies, the, drug, distribution, pattern, in, 'MDR', cells, by, partially, shifting, the, drug, to]), verbo([nuclear]), complemento([compartments])].
[sujeto(['d-Serine', is, a, 'co-agonist', of, 'NMDA', receptors, '(', 'NMDARs)', whose, activity, is, potentially]), verbo([regulated]), complemento([by, 'Asc-1', '(', 'SLC7A10),', a, transporter, that, displays, high, affinity, for, 'd-serine', and, glycine])].
[sujeto(['We', developed, a, selective, 'Asc-1', 'blocker,', 'Lu', 'AE00527,', that, blocks, 'd-serine']), verbo([release]), complemento([mediated, by, all, the, transport, modes, of, 'Asc-1', in, primary, cultures, and, neocortical, slices])].
[sujeto(['Furthermore,', 'd-serine']), verbo([release]), complemento([is, reduced, in, slices, from, 'Asc-1', knockout, '(', 'KO)', 'mice,', indicating, that, 'd-serine', efflux, is, the, preferred, direction, of, 'Asc-1'])].
[sujeto(['In', 'slices,', 'Lu', 'AE00527']), verbo([decreases]), complemento([the, 'long-term', potentiation, at, the, 'Schaffer', 'collateral-CA1', 'synapses,', but, does, not, affect, the, 'long-term', depression])].
[sujeto(['Our', data, demonstrate, that, 'Asc-1']), verbo([mediates]), complemento([tonic, 'co-agonist', 'release,', which, is, required, for, optimal, 'NMDAR', activation, and, synaptic, plasticity])].
[sujeto(['Human', kinesin, 'CENP-E', is, an, attractive]), verbo([target]), complemento([for, cancer, chemotherapy])].
[sujeto(['In', our, 'work,', we]), verbo([have]), complemento([analyzed, the, influence, of, the, 'Pgp', efflux, pump, on, the, cytostatic, effect, of, 'GSK923295'])].
[sujeto(['We']), verbo([have]), complemento([demonstrated, that, multidrug, resistant, 'MESSA', 'Dx5', cells, overexpressing, 'Pgp', are, 70, -, 80, times, more, resistant, to, 'GSK923295', than, their, parental, counterpart, 'MESSA', cells])].
[sujeto(['Our', results, demonstrate, that, tumors, possessing, 'Pgp', could, be, more, resistant, to, 'GSK923295,', and, that, overexpression, of, 'Pgp', can]), verbo([decrease]), complemento([the, therapeutic, effect, of, this, drug])].
[sujeto(['As', a, member, of, the, 'multidrug-resistance']), verbo([associated]), complemento([protein, '(', 'MRP)', 'family,', 'MRP2', affects, the, brain, entry, of, different, endogenous, and, exogenous, compounds])].
[sujeto(['However,', there, is, limited, knowledge, regarding, the, factors, that]), verbo([regulate]), complemento(['MRP2', in, neurologic, disease, states])].
[sujeto(['The', involvement, of, the, 'NMDA', receptor, was, further]), verbo([suggested]), complemento([by, the, fact, that, the, 'NMDA', receptor, antagonist, 'MK-801', '[', '(', 5, 'S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine],', as, well, as, the, 'NMDA', receptor, glycine, binding, site, antagonist, 'L-701,324', '[', 7, -, 'chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(1H)-quinolinone],', prevented, the, impact, of, glutamate])].
[sujeto(['Taken', together, the, findings]), verbo([provide]), complemento([first, evidence, for, a, role, of, a, 'glutamate-induced', 'NMDA', 'receptor/cyclooxygenase-2', signaling, pathway, in, the, regulation, of, 'MRP2', expression, and, function])].
[sujeto(['The', response, to, excessive, glutamate, concentrations, might, contribute, to, overexpression, of, 'MRP2,', which]), verbo([has]), complemento([been, reported, in, neurologic, diseases, including, epilepsy])].
[sujeto(['The', overexpression, might]), verbo([have]), complemento([implications, for, brain, access, of, various, compounds, including, therapeutic, drugs])].
[sujeto(['UPLC/scheduled', 'MRM-MS', with, negative, ion, electrospray, ionization, enabled]), verbo([targeted]), complemento([quantitation, of, 43, and, 44, 'BAs,', 'respectively,', in, serum, samples, from, seven, individuals, with, and, without, 'fasting,', as, well, as, in, plasma, samples, from, six, cholestatic, gene, knockout, mice, and, six, 'age-', and, 'gender-matched', 'wild-type', '(', 'FVB/NJ)', animals])].
[sujeto(['To', profile, other, potential, 'BAs', not, included, in, the, 50, known]), verbo([targets]), complemento([from, the, knockout, versus, 'wild-type', mouse, 'plasma,', 'class-specific', 'precursor/fragment', ion, transitions, were, used, to, perform, 'UPLC-MRM-MS', for, untargeted, detection, of, the, structural, isomers, of, 'glycine-', and, 'taurine-conjugated', 'BAs', and, unconjugated, 'tetra-hydroxy', 'BAs'])].
[sujeto(['In', 'summary,', this, 'UPLC-MRM-MS', method]), verbo([has]), complemento([enabled, the, quantitation, of, the, largest, number, of, 'BAs', in, the, blood, thus, 'far,', and, the, results, presented, have, revealed, an, unexpectedly, complex, 'BA', profile, in, mouse, plasma])].
[sujeto(['We', demonstrated, a, significant]), verbo([increase]), complemento([of, 'CYP1A1', mRNA, level, '(', by, 89, '%', ',', p, =, 0.002, and, 125, '%', ',', p, =, 0.004, ')', as, compared, with, the, control, group])].
[sujeto(['An']), verbo([increase]), complemento([of, 'AHR', and, 'CAR', expression, after, 10, days, was, also, observed, '(', by, 60, '%', ',', p, &, 'lt;', 0.001, and, 52, '%', ',', p, &, 'gt;', 0.05, ',', 'respectively)'])].
[sujeto(['A', significant]), verbo([decrease]), complemento([of, mRNA, level, was, observed, for, 'CYP3A1', '(', human, 'CYP3A4)', in, the, liver, and, 'Mdr1b', in, the, intestinal, epithelium])].
[sujeto(['Moreove,', we, also, showed, a, slight]), verbo([decrease]), complemento([in, the, amount, of, mRNA, for, 'CAR,', 'PXR', and, 'ARNT', after, 3, days])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'Glycine', max, may, change, the, expression, level, of, 'CYPs,', especially, 'CYP3A4', and, 'CYP1A', 7, ',', involved, in, biotransformation, of, xenobiotics, '(', 'drugs,', 'procarcinogens)', and, may, participate, in, clinically, significant, interactions, with, drugs, metabolized, by, these, enzymes])].
[sujeto(['Moreover', an]), verbo([increase]), complemento([of, 'CYP1A1', '(', homologue, to, human, 'CYPIA', 1, ')', mRNA, level, may, not, only, reduce, the, carcinogenicity, of, foreign, 'compounds,', but, may, also, activate, some, compounds, to, their, carcinogenicity, 'In', case, of, 'transporters,', it, is, considered, that, an, increase, of, their, expression, in, the, body, may, lead, to, increased, fetoprotection])].
[sujeto(['Hence,', the, search, for, a, safe, substance, that, could, effectively]), verbo([modulate]), complemento([transporter, activity, especially, in, the, treatment, of, certain, hormone, -, dependent, 'disorders,', e])].
[sujeto(['Collateral', sensitivity, '(', 'CS),', a, phenomenon, of, drug, 'hypersensitivity,', is, defined, as, the, ability, of, certain, compounds, to, selectively]), verbo([target]), complemento(['MDR', 'cells,', but, not, the, 'drug-sensitive', parent, cells, from, which, they, were, derived])].
[sujeto(['The', drug, tiopronin]), verbo([has]), complemento([been, previously, shown, to, elicit, 'CS'])].
[sujeto(['We']), verbo([have]), complemento([determined, that, the, 'CS', activity, of, tiopronin, is, mediated, by, the, generation, of, reactive, oxygen, species, '(', 'ROS)', and, that, 'CS', can, be, reversed, by, a, variety, of, 'ROS-scavenging', compounds])].
[sujeto(['Pgp', '(', 'P-glycoprotein)', is, a, prototype, 'ABC', '(', 'ATP-binding-cassette)', transporter]), verbo([involved]), complemento([in, multidrug, resistance, of, cancer])].
[sujeto(['Cys1121', in, 'NBD2', showed, a, clear, preference, for, positively, charged, arginine, '(', 38, '%', ')']), verbo([suggesting]), complemento([a, salt, bridge, with, 'Glu269', in, the, 'ICL2', '(', intracellular, loop, 2, ')', may, stabilize, domain, interactions])].
[sujeto(['Overall,', directed, evolution, identified, 'site-specific,', 'non-conservative', 'Cys', substitutions, that, allowed, building, of, a, robust, 'CL', 'Pgp,', an, invaluable, new, tool, for, future, functional, and, structural, 'studies,', and, that, may, guide, the, construction, of, other, 'CL', proteins, where, alanine, and, serine]), verbo([have]), complemento([proven, unsuccessful])].
[sujeto(['Statins,', 3, -, 'hydroxy-3-methyl-glutaryl-coenzyme', 'A', reductase, 'inhibitors,']), verbo([have]), complemento([proven, efficacy, in, both, lowering, 'low-density-lipoprotein', levels, and, preventing, major, coronary, 'events,', making, them, one, of, the, most, commonly, prescribed, drugs, in, the, 'United', 'States'])].
[sujeto(['Statins', exhibit, a, 'class-wide', side, effect, of, muscle, toxicity, and, 'weakness,', which]), verbo([has]), complemento([led, regulators, to, impose, both, dosage, limitations, and, a, recall])].
[sujeto(['This', review, focuses, on, the, 'best-characterized', genetic, factors]), verbo([associated]), complemento([with, increased, statin, muscle, 'concentrations,', including, the, genes, encoding, cytochrome, 'P450', enzymes, '(', 'CYP2D6,', 'CYP3A4,', and, 'CYP3A5),', a, mitochondrial, enzyme, '(', 'GATM),', an, influx, transporter, '(', 'SLCO1B1),', and, efflux, transporters, '(', 'ABCB1', and, 'ABCG2)'])].
[sujeto(['Studies', eligible, for, inclusion, must]), verbo([have]), complemento([incorporated, genotype, information, and, must, have, associated, it, with, some, measure, of, 'myopathy,', either, creatine, kinase, levels, or, 'self-reported', muscle, aches, and, pains])].
[sujeto(['After', an, initial, 'review,', focus, was, placed, on, seven, genes, that, were, adequately, characterized, to]), verbo([provide]), complemento([a, substantive, 'review:', 'CYP2D6,', 'CYP3A4,', 'CYP3A5,', 'GATM,', 'SLCO1B1,', 'ABCB1,', and, 'ABCG2'])].
[sujeto(['Among', the, genetic, factors, 'evaluated,', 'statin-related', myopathy, appears, to, be, most, strongly]), verbo([associated]), complemento([with, variants, in, 'SLCO1B1'])].
[sujeto(['The', glycine, 'co-agonist']), verbo([binding]), complemento([site, of, the, 'N-methyl-D-aspartat', '(', 'NMDA)', receptor, is, discussed, as, an, interesting, target, for, different, central, nervous, system, diseases])].
[sujeto(['Antagonism', at, this, 'co-agonist', site]), verbo([has]), complemento([been, suggested, as, an, alternative, to, the, use, of, 'non-competitive', or, competitive, 'NMDA', receptor, 'antagonists,', which, are, associated, with, a, pronounced, adverse, effect, profile, in, chronic, epilepsy, models, and, epilepsy, patients])].
[sujeto(['A', low, dosage, of, phenobarbital]), verbo([caused]), complemento([a, significant, increase, of, the, generalized, seizure, threshold, in, the, 'L-701,324', 'pre-treated', 'group,', whereas, it, did, not, exert, a, comparable, effect, in, animals, that, received, vehicle, during, the, massive, kindling, phase])].
[sujeto(['In', 'conclusion,', the, data, indicate, that]), verbo([targeting]), complemento([of, the, 'NMDA', receptor, 'glycine-binding', site, does, not, result, in, anticonvulsant, or, 'disease-modifying', effects])].
[sujeto(['Thus,']), verbo([targeting]), complemento([regulatory, signaling, cascades, might, render, a, basis, for, novel, therapeutic, approaches])].
[sujeto(['Both', inhibition, of, 'cyclooxygenase-2', and, antagonism, at, the, 'glycine-binding', site, of, the, 'NMDA', receptor]), verbo([prevented]), complemento([the, 'glutamate-mediated', induction, of, 'P-glycoprotein', transport, function, in, human, capillaries])].
[sujeto(['In', 'conclusion,', the, data, argue, against, species, differences, in, the, signaling, factors]), verbo([increasing]), complemento([endothelial, 'P-glycoprotein', transport, function, in, response, to, glutamate, exposure])].
[sujeto(['Failure', of, conventional, chemotherapy]), verbo([has]), complemento([resulted, in, recurrence, and, development, of, virulent, multi, drug, resistant, '(', 'MDR)', phenotypes, adding, to, the, complexity, and, diversity, of, this, deadly, disease])].
[sujeto(['In', this, 'regard,', multifunctional, nanoparticles, that, can, integrate, various, key, components, such, as, 'drugs,', 'genes,', imaging, agents, and]), verbo([targeting]), complemento([ligands, using, unique, delivery, platforms, would, be, more, efficient, in, treating, 'MDR', cancers])].
[sujeto(['This', review, presents, some, of, the, important, principles]), verbo([involved]), complemento([in, development, of, 'MDR', and, novel, methods, of, treating, cancers, using, 'multifunctional-targeted', nanoparticles])].
[sujeto(['We']), verbo([found]), complemento([that, neutral, net, charge, was, critical, to, favour, the, liposome, uptake, and, decrease, the, 'Vmax', of, doxorubicin, efflux])].
[sujeto(['PEG-coating', was, necessary, to]), verbo([increase]), complemento([the, 'Km', of, doxorubicin, for, 'Pgp'])].
[sujeto(['PEGylated', 'distearoyl-phosphatidylethanolamine', '(', 'DSPE-PEG),', was, a, 'Pgp', allosteric, 'inhibitor,']), verbo([increased]), complemento([doxorubicin, 'Km', and, inhibited, 'Pgp', 'ATPase', activity])].
[sujeto(['Site-directed', mutagenesis, experiments]), verbo([suggested]), complemento([that, the, domain, centred, around, glycine, 185, of, 'Pgp', was, necessary, for, these, inhibitory, properties, of, 'DSPE-PEG', and, 'PEGylated', neutral, liposomes])].
[sujeto(['Na,', 'Estybon)', is, a, 'novel,', anticancer, agent, undergoing, phase, 3, clinical, trials, for, a]), verbo([lead]), complemento([indication, against, myelodysplastic, syndromes, '(', 'MDS)'])].
[sujeto(['The', compound, displayed, nonlinear, absorption, in, the, 'IPRI', 'model,']), verbo([suggesting]), complemento([a, saturable, transport, process])].
[sujeto(['MnNG']), verbo([induced]), complemento([apoptosis, significantly, in, 'CEM/ADR', 5000, cells, probably, through, generation, of, reactive, oxygen, species])].
[sujeto([')', application, of, 'MnNG', at, 'non-toxic', doses]), verbo([caused]), complemento([significant, increase, in, the, 'life-span', of, 'Swiss', albino, mice, bearing, sensitive, and, doxorubicin, resistant, subline, of, 'Ehrlich', ascites, carcinoma, cells])].
[sujeto(['Multidrug', resistance, is, a, major]), verbo([cause]), complemento([of, chemotherapy, failure])].
[sujeto(['Recent', studies, indicate, that, drug, resistance, can, be, rapidly]), verbo([induced]), complemento([by, some, soluble, 'factors,', such, as, 'cytokines,', 'chemokines,', growth, 'factors,', and, cell, adhesion, factors, in, the, tumor, microenvironment])].
[sujeto(['Osteopontin', '(', 'OPN),', an, extracellular, matrix, 'protein,']), verbo([has]), complemento([a, functional, 'arginine-glycine-aspartic', acid, '(', 'RGD)', domain, for, binding, to, integrin])].
[sujeto(['Here', we]), verbo([found]), complemento(['OPN', expression, to, be, upregulated, by, hypoxic, condition, in, 'PC-3', prostate, tumor, cells])].
[sujeto(['OPN']), verbo([increased]), complemento([the, mRNA, and, protein, expression, of, 'p-glycoprotein', '(', 'P-gp),', a, subfamily, of, 'ATP-binding', cassette, transporter, in, a, 'concentration-', and, 'time-dependent', manner])].
[sujeto(['The']), verbo([increase]), complemento([in, 'P-gp', transporter, by, 'OPN', was, mediated, by, binding, to, αvβ3, integrin])].
[sujeto(['Daunomycin', '(', 'DUN),', a, chemotherapeutic, agent, with, 'autofluorescence,', was, used, to, evaluate, the, pump, 'activity,', and, 'OPN']), verbo([increased]), complemento([the, drug, 'pumping-out', activity])].
[sujeto(['OPN']), verbo([inhibited]), complemento(['DUN-induced', cell, 'death,', which, was, antagonized, by, αvβ3, monoclonal, antibody])].
[sujeto(['Long-term', treatment, with, 'DUN', further]), verbo([enhanced]), complemento([the, expression, of, 'OPN'])].
[sujeto(['Furthermore,', knockdown, of, 'OPN']), verbo([enhanced]), complemento([cell, death, caused, by, other, 'drugs,', including, 'paclitaxel,', 'doxorubicin,', 'actinomycin-D,', and, 'rapamycin,', which, are, also, 'P-gp', substrates])].
[sujeto(['The', animal, studies, also, showed, that, 'OPN', knockdown]), verbo([enhanced]), complemento([the, cytotoxic, action, of, 'DUN'])].
[sujeto(['These', results, indicate, that, 'OPN', is, a, potential, therapeutic]), verbo([target]), complemento([for, cancer, therapy, to, reduce, drug, resistance, in, sensitive, tumors])].
[sujeto(['Glycine', transporter, 1, '(', 'GlyT-1)', is, one, of, the, most, attractive, therapeutic]), verbo([targets]), complemento([for, schizophrenia])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, properties, of, three, novel, 'non-sarcosine-based', radioligands, '[', '(', 11, ')', 'C]CHIBA-3007,', '[', '(', 11, ')', 'C]CHIBA-3009,', and, '[', '(', 11, ')', 'C]CHIBA-3011,', for, 'GlyT-1', imaging, in, the, mouse, brain, in, vivo])].
[sujeto(['However,', pretreatment, with, 'CHIBA-3007', '(', 1, 'mg/kg)', or, the, 'GlyT-1', selective, inhibitor, 'ALX5407', '(', 'N-[(3R)-3-([1,1\'-Biphenyl]-4-yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine)', '(', 30, 'mg/kg)', did, not, significantly]), verbo([decrease]), complemento([brain, uptake, of, '[', '(', 11, ')', 'C]CHIBA-3007,', suggesting, low, specific, binding, to, 'GlyT-1'])].
[sujeto(['Pretreatment', with, cyclosporin, 'A', significantly]), verbo([increased]), complemento([brain, uptake, of, '[', '(', 11, ')', 'C]CHIBA-3009', and, '[', '(', 11, ')', 'C]CHIBA-3011,', suggesting, a, role, for, 'P-glycoprotein', in, the, brain, uptake, of, these, ligands])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, these, three, radioligands, are, not, suitable, for, in, vivo, imaging, of, 'GlyT-1', in, the, brain, because, of, low, brain, uptake, and, rapid, metabolism])].
[sujeto(['Further', structural, refinement, is, necessary, to]), verbo([enhance]), complemento([brain, uptake])].
[sujeto(['BCRP', inhibitor, 'Ko143', '(', 50, μM, and, 100, 'μM)', significantly]), verbo([increased]), complemento([the, intestinal, absorption, amount, in, 'jejunum,', ileum, and, colon, '(', 'p&lt;0'])].
[sujeto(['Furthermore,', the, plasma, concentration, 'MED-5', and, 'tolmetin,', metabolites, of, 'MED-15,']), verbo([increased]), complemento([2, -, fold, and, 4, -, 'fold,', 'respectively,', in, 'Bcrp1', knockout, mice, compared, with, 'wild-type', mice, after, the, 'single-pass', perfusion, of, small, intestine, with, 'MED-15'])].
[sujeto(['UDCA']), verbo([induced]), complemento([duodenal, expression, of, key, export, 'pumps,', 'BCRP', and, 'P-glycoprotein'])].
[sujeto(['In', a, 'cell-based', assay, system, with, human, 'MDR1', cDNA, overexpressed, mouse, fibroblast, 'NIH', 'MDR1-G185', cell, 'line,', we, demonstrated, that, this, metal, complex, can, directly]), verbo([interact]), complemento([with, this, transporter])].
[sujeto(['As', 'CuNG']), verbo([increased]), complemento([cellular, accumulation, of, doxorubicin, in, 'P-gp-expressing', 'cells,', we, presumed, that, of, 'CuNG', may, be, potential, to, reverse, 'P-gp-mediated', drug, resistance, probably, by, lowering, the, 'P-gp', expression, at, the, protein, as, well, as, mRNA, level])].
[sujeto(['Interestingly,', our, studies, on, 'UIC2', '(', a, conformation, sensitive, monoclonal, 'antibody)']), verbo([binding]), complemento([assay, indicated, the, direct, interaction, of, 'CuNG', with, 'P-gp'])].
[sujeto(['However,', 'CuNG', did, not, compete, for, the, substrate]), verbo([binding]), complemento([as, photoaffinity, labeling, of, 'P-gp', with, a, substrate, analog, '[', '(', 125, ')', 'I]', iodoarylazidoprazosin, '(', '[', '(', 125, ')', 'I]', 'IAAP)', showed, approximately, twofold, increase, in, '[', '(', 125, ')', 'I]', 'IAAP', binding, in, presence, of, 'CuNG'])].
[sujeto(['In', vitro, study, showed, that, 'CuNG', significantly]), verbo([stimulated]), complemento(['P-gp-specific', 'ATPase', activity, in, isolated, membrane, preparations, from, 'NIH', 'MDR1-G185', cells])].
[sujeto(['This', study, also, demonstrated, that, 'CuNG']), verbo([has]), complemento([a, drug, interaction, site, different, from, 'verapamil-,', 'vinblastine-', and, 'progesterone-binding', sites, on, 'P-gp'])].
[sujeto(['Taken', 'together,', this, is, the, first]), verbo([report]), complemento([of, molecular, interaction, of, any, 'Schiff\'s', base, metal, chelate, 'CuNG', with, human, 'P-gp'])].
[sujeto(['Resistance', to, etoposide]), verbo([has]), complemento([been, associated, with, the, overexpression, of, 'P-glycoprotein', and, 'MRP1', in, human, tumor, cells])].
[sujeto(['However,', the, role, of, 'BCRP', in, resistance, to, etoposide]), verbo([has]), complemento([not, been, clearly, 'established,', especially, the, significance, of, arginine, 482, mutations, in, drug, transport, '(', cellular, uptake, and, 'efflux)'])].
[sujeto(['Different', levels, of, resistance, to, etoposide]), verbo([have]), complemento([been, recently, observed, in, cells, expressing, 'BCRP', in, terms, of, cytotoxicity])].
[sujeto(['Drug', efflux, measurements, showed, that, 'fumitremorgin&nbsp;C', was, able, to]), verbo([increase]), complemento([the, residual, cellular, '[', 3, 'H]-etoposide', uptake, in, 'BCRP-transfected', cells, and, especially, in, 'HEK/R482G', ones])].
[sujeto(['Our', data, show, that, the, 'R482G', mutation, in, 'BCRP', is, able, to]), verbo([increase]), complemento([efflux, of, etoposide, and, that, mutation, analysis, at, codon, 482, may, be, of, clinical, importance, in, cancers, treated, with, etoposide])].
[sujeto(['Together', with, 'P-glycoprotein', '(', 'ABCB1)', and, the, breast, cancer, resistance, protein, '(', 'BCRP/ABCG2),', hMRP1]), verbo([confers]), complemento([resistance, to, a, large, number, of, structurally, diverse, drugs])].
[sujeto(['Mutagenesis', and, labeling, studies]), verbo([have]), complemento([shown, 'TM16', and, 'TM17', to, be, important, for, function])].
[sujeto(['We', synthesized, 'TM16', and, 'TM17,', with, the, 'Trp', 'residues,', 'W1198', in, 'TM16', and, 'W1246', in, 'TM17,']), verbo([acting]), complemento([as, an, intrinsic, fluorescent, 'probe,', and, 'TM16', and, 'TM17', 'Trp', 'variants,', to, probe, different, positions, in, the, peptide, sequence])].
[sujeto(['We', assessed, the, interaction, of, peptides, with, membrane, mimics, by, evaluating, the]), verbo([increase]), complemento([in, fluorescence, intensity, resulting, from, such, interactions])].
[sujeto(['Tryptophan', fluorescence, lifetimes, were]), verbo([found]), complemento([to, depend, on, the, position, of, the, tryptophan, residue, in, the, various, 'peptides,', probably, reflecting, differences, in, local, structures])].
[sujeto(['Together', with, the, high, 'Trp', correlation, 'times,', the, presence, of, these, structures]), verbo([suggests]), complemento([that, 'TM16', 'self-association', may, occur, at, the, interface])].
[sujeto(['In', 'conclusion,', this, experimental, study]), verbo([suggests]), complemento([an, interfacial, location, for, both, 'TM16', and, 'TM17', in, membrane, mimics])].
[sujeto(['In', terms, of, overall, hMRP1, 'structure,', the, experimentally, demonstrated, amphipathic, properties, of, these, 'TM', are, consistent, with, a, role, in, the, lining, of, an, at, least, partly, hydrophilic, transport, 'pore,', as]), verbo([suggested]), complemento([by, the, currently, accepted, structural, 'model,', the, final, structure, being, modified, by, interaction, with, other, 'TM', helices])].
[sujeto(['Alkyl', gallates]), verbo([increased]), complemento([the, cellular, accumulation, of, these, 'P-gp', substrates, dependent, on, their, alkyl, chain, lengths, by, inhibiting, the, efflux, of, the, substrates])].
[sujeto(['n-Dodecylresorcinol', also]), verbo([increased]), complemento([the, 'accumulation,', but, its, effect, was, less, than, that, of, 'n-dodecyl', gallate])].
[sujeto(['However,', either, lauric, acid, or, 'n-dodecyl-beta-d-maltoside,', which, does, not]), verbo([have]), complemento([a, phenol, 'group,', did, not, increase, the, accumulation])].
[sujeto(['A', new, member, of, the, 'ATP-binding', cassette, '(', 'ABC)', 'family,', known, in, 'Bacillus', subtilis, as, 'YvcC', and, homologous, to, each, half, of, mammalian, 'P-glycoprotein', and, to, 'LmrA', of, 'Lactococcus', 'lactis,']), verbo([has]), complemento([been, studied, here])].
[sujeto(['The', yvcC, gene, was, constitutively]), verbo([expressed]), complemento([in, 'B'])].
[sujeto(['After', solubilization, with, 'n-dodecyl', 'beta-D-maltoside,', the, 'hexahistidine-tagged', 'YvcC', was, purified, by, a, 'one-step', affinity, 'chromatography,', and, its, ability, to]), verbo([bind]), complemento([many, 'P-glycoprotein', effectors, was, evidenced, by, fluorescence, spectroscopy, experiments])].
[sujeto(['Besides,', reconstitution, of, 'YvcC', into, liposomes]), verbo([led]), complemento([to, the, 'highest,', 'vanadate-sensitive,', 'ATPase', activity, reported, so, far, for, an, 'ABC', transporter])].
[sujeto(['Interestingly,', such, a, high, 'ATP', hydrolysis, proceeds, with, a, positive, cooperativity, 'mechanism,', a, property, only]), verbo([found]), complemento([so, far, with, 'ABC', importers])].
[sujeto(['Dodecyl', maltoside, proved, to, be, the, most, effective, detergent, for, the, membrane, solubilization, of, 'MDR-TCBD,', and, various, salts, were]), verbo([found]), complemento([to, significantly, affect, reconstitution, into, 'PLs'])].
[sujeto(['After', extensive, 'analysis,', we]), verbo([find]), complemento([that, purified, reconstituted, 'MDR-TCBD', protein, does, not, catalyze, measurable, 'H(+)', pumping, in, the, presence, of, 'ATP'])].
[sujeto(['However,', in, the, absence, of, 'ATP,', although, control, 'PLs', still]), verbo([maintain]), complemento([easily, measurable, 'K(+)/Na(+)', diffusion, potentials, upon, addition, of, 'valinomycin,', 'MDR-TCBD', 'PLs', do, not])].
[sujeto(['P-glycoprotein', '(', 'P-gp),', a, plasma, membrane, glycoprotein]), verbo([associated]), complemento([with, the, multidrug, resistance, 'phenotype,', is, responsible, for, the, 'ATP-dependent', efflux, of, various, amphiphilic, drugs])].
[sujeto([in, the, absence, of, 'drug)', and, 'verapamil-dependent', 'P-gp', 'ATPase', activities]), verbo([induced]), complemento([by, various, 'detergents,', at, 'non-solubilizing,', as, well, as, at, 'solubilizing,', concentrations])].
[sujeto(['The', progressive, membrane, solubilization, with]), verbo([increasing]), complemento([detergent, concentration, was, monitored, by, light, scattering, and, centrifugation, experiments])].
[sujeto(['For', 'non-solubilizing', detergent, 'concentrations,', all, tested, detergents, except, 'DOC']), verbo([induced]), complemento([a, partial, inhibition, of, 'P-gp', 'ATPase', 'activity,', which, was, not, correlated, with, the, amount, of, the, various, tested, detergents, incorporated, in, the, membranes])].
[sujeto(['Analysis', of, the, 'verapamil-induced', 'P-gp', activation]), verbo([reveals]), complemento([that, 'P-gp', 'ATPase', activity, is, differently, modulated, by, the, various, detergents, at, 'non-solubilizing', concentrations])].
[sujeto(['P-glycoprotein', '(', 'Pgp)', is, a, plasma, membrane, protein, known, as, an, 'ATP-dependent', 'drug-efflux', pump, that]), verbo([confers]), complemento([multidrug, resistance, to, tumor, cells])].
[sujeto(['These', 'data,', which, constitute, the, first]), verbo([report]), complemento([of, 'Pgp', structure, analysis, by, circular, 'dichroism,', are, consistent, with, the, 48, '%', 'alpha-helix', and, 16, '%', 'beta-sheets', global, contents, predicted, by, using, recently, reported, efficient, secondary, structure, prediction, methods])].
[sujeto(['This']), verbo([provides]), complemento([a, good, framework, for, precise, 3, 'D', structure, modeling, of, 'Pgp', by, homology, with, proteins, of, known, 3, 'D', 'structure,', as, it, is, illustrated, here, for, the, 'A', motifs, of, the, 'ATP-binding', domains, of, 'Pgp'])].
[sujeto(['P-Glycoprotein', '(', 'P-gp)', is, a, 180, -, kDa, 'membrane-bound', transporter, which, can]), verbo([confer]), complemento([the, 'multi-drug', resistance, phenotype, on, tumor, cells])].
[sujeto(['We']), verbo([have]), complemento([examined, the, factors, required, to, preserve, activity, of, 'P-gp', during, its, purification])].
[sujeto(['These', membranes, displayed, drug]), verbo([stimulated]), complemento(['ATPase', activity, '(', 'Vm', =, 897, +, /, -, 55, nmol, 'min(-1)', 'mg(-1);', 'Km', =, 1.8, +, /, -, 0.4, 'mM)', and, high, affinity, binding, of, '[', 3, 'H]vinblastine', '(', 'Kd', =, 36, +, /, -, 5, 'nM;', 'Bm', =, 161, +, /, -, 11, 'pmol/mg)'])].
[sujeto(['Several', 'non-ionic', detergents, which, readily, solubilized, 'P-glycoprotein', significantly]), verbo([inhibited]), complemento(['ATPase', activity, and, drug, binding, at, concentrations, well, below, their, respective, 'CMC', values])].
[sujeto(['This', inactivation, was]), verbo([prevented]), complemento([by, excess, crude, lipid, 'mixtures,', with, the, greatest, protection, afforded, against, 'dodecyl-maltoside'])].
[sujeto(['Furthermore,', the, significantly, reduced]), verbo([binding]), complemento([affinity, and, capacity, of, solubilized, 'P-gp', was, partly, reversed, by, the, addition, of, lipids])].
[sujeto(['The', 'purified,', reconstituted, 'P-gp', displayed, high, 'ATPase', activity, '(', 'Vm', =, 2137, +, /, -, 309, ;, 'Km', =, 2.9, +, /, -, 0.9, 'mM)', which, was]), verbo([stimulated]), complemento([by, verapamil, '(', 'EC50', =, 3.8, +, /, -, 0.6, 'microM)', and, inhibited, by, orthovanadate, '(', 3.1, +, /, -, 0.8, 'microM)'])].
[sujeto(['Pure', 'P-gp', also, displayed, high, affinity, vinblastine]), verbo([binding]), complemento(['(', 'Kd', =, 64, +, /, -, 9, 'nM)', with, a, capacity, of, 2320, +, /, -, 192, 'pmol/mg'])].
[sujeto(['This', purification, scheme, yields, the, highest, 'P-gp', activity]), verbo([reported]), complemento([to, 'date,', and, indicates, a, dependence, of, function, on, maintaining, a, 'lipid-protein', interface])].
[sujeto(['A', general, procedure, using, ceramic, hydroxyapatite, '(', 'HAP)', chromatography, was, developed, for, the, complete, removal, of, 'SDS']), verbo([bound]), complemento([to, soluble, or, membrane, proteins])].
[sujeto(['This', procedure]), verbo([involves]), complemento(['(', 'i)', the, binding, of, the, 'SDS-protein', complexes, onto, the, ceramic, hydroxyapatite, 'column,', '(', 'ii)', extensive, washing, of, bound, proteins, with, phosphate, buffer, containing, a, mild, detergent, to, exchange, 'SDS,', '(', 'iii)', elution, of, the, retained, protein, by, increasing, the, phosphate, concentration])].
[sujeto(['The', efficiency, of, 'protein-bound', 'SDS', removal, is, very, likely, due, to, the, combined, effect, of, phosphate, ions, and, the, hydrophobic, tail, of, nonionic, 'detergent:']), verbo([acting]), complemento(['together,', they, are, able, to, displace, 'SDS', molecules, from, their, 'protein-binding', sites])].
[sujeto(['This', demonstrates, that, reactivation, of, 'SDS-treated', protein, can, be, 'achieved,']), verbo([provided]), complemento([that, 'SDS', is, completely, removed, under, mild, conditions])].
[sujeto(['Plasma', membrane, 'P-glycoprotein', is, known, as, an, 'ATP-dependent', drug, efflux, pump, that]), verbo([confers]), complemento([multidrug, resistance, to, tumor, cells])].
[sujeto(['None', of, the]), verbo([reported]), complemento([purification, procedures, worked, properly, for, our, 'P-glycoprotein-overproducing', cell, 'lines,', i])].
[sujeto(['We']), verbo([have]), complemento([thus, developed, a, general, procedure, for, efficient, purification, of, 'P-glycoprotein', by, combining, solubilization, with, sodium, dodecyl, sulfate, and, chromatography, on, ceramic, hydroxyapatite])].
[sujeto(['This', 'ATPase', activity, was, sensitive, to, orthovanadate, inhibition, and]), verbo([stimulated]), complemento([by, verapamil, and, other, drugs])].
[sujeto(['Raltegravir', shows, marked, pharmacokinetic, variability, in, 'patients,', with, gastrointestinal, pH, and, 'divalent-metal']), verbo([binding]), complemento([being, potential, factors])].
[sujeto(['We', investigated, raltegravir, 'solubility,', 'lipophilicity,', 'pK(a),', and, permeativity, in, vitro, to, elucidate, known, interactions, with, 'omeprazole,', 'antacids,', and, 'food,', all, of, which]), verbo([increase]), complemento([gastric, pH])].
[sujeto(['Raltegravir', lipophilicity, was, pH, dependent, and, was, reduced, as, pH, was]), verbo([increased]), complemento([from, 5, to, 9])].
[sujeto(['Raltegravir', cellular, permeativity, was, heavily, influenced, by, changes, in, extracellular, 'pH,', where, 'apical-to-basolateral', permeativity, was, reduced, 9, -, fold, '(', 'P', &, 'lt;', 0.05, ')', when, apical, pH, was]), verbo([increased]), complemento([from, 5, to, 8.5])].
[sujeto(['Cellular', accumulation, of, raltegravir, was]), verbo([increased]), complemento([independently, by, inhibiting, 'ABCB1', and, by, lowering, extracellular, pH, from, pH, 8, to, 5])].
[sujeto(['Gastrointestinal', pH, and, polyvalent, metals, can, potentially, alter, the, pharmacokinetic, properties, of, 'raltegravir,', and, these, data]), verbo([provide]), complemento([an, explanation, for, the, variability, in, raltegravir, exposure, in, patients])].
[sujeto(['In', this, study, we, characterize, 'ATP', hydrolysis, by, human, 'MRP4']), verbo([expressed]), complemento([in, insect, cells])].
[sujeto(['MRP4', hydrolyzes, 'ATP', '(', 'Km,', 0.62, 'mm),', which, is]), verbo([inhibited]), complemento([by, orthovanadate, and, beryllium, fluoride])].
[sujeto([8, -, 'Azido[alpha-32P]ATP']), verbo([binds]), complemento([to, 'MRP4', '(', concentration, for, 'half-maximal', binding, approximately, 3, 'microm)', and, is, displaced, by, 'ATP', or, by, its, 'non-hydrolyzable', analog, 'AMPPNP', '(', concentrations, for, 'half-maximal', inhibition, of, 13.3, and, 308, 'microm)'])].
[sujeto(['MRP4', 'substrates,', the, prostaglandins, 'E1', and, 'E2,']), verbo([stimulate]), complemento(['ATP', hydrolysis, 2, -, to, 3, -, fold, but, do, not, affect, the, 'Km', for, 'ATP'])].
[sujeto(['Several', other, 'substrates,', 'azidothymidine,', 9, -, '(', 2, -, 'phosphonylmethoxyethyl)adenine,', and, methotrexate, do, not]), verbo([stimulate]), complemento(['ATP', hydrolysis, but, inhibit, prostaglandin, 'E2-stimulated', 'ATP', hydrolysis])].
[sujeto(['However,', 'Co2+']), verbo([increases]), complemento([8, -, 'azido[alpha-32P]ATP', binding, and, beryllium, 'fluoride-induced', 8, -, 'azido[alpha-32P]ADP', trapping, but, does, not, support, 'steady-state', 'ATP', hydrolysis])].
[sujeto(['ADP']), verbo([inhibits]), complemento([basal, and, prostaglandin, 'E2-stimulated', 'ATP', hydrolysis, '(', concentrations, for, 'half-maximal', inhibition, 0.19, and, 0.25, 'mm,', 'respectively)', and, beryllium, 'fluoride-induced', 8, -, 'azido[alpha-32P]ADP', 'trapping,', whereas, 'Pi', has, no, effect, up, to, 20, mm])].
[sujeto(['In', 'aggregate,', our, results, demonstrate, that, 'MRP4', exhibits, 'substrate-stimulated', 'ATP', 'hydrolysis,', and, we, propose, a, kinetic, scheme]), verbo([suggesting]), complemento([that, 'ADP', release, from, the, 'post-hydrolysis', transition, state, may, be, the, 'rate-limiting', step, during, the, catalytic, cycle])].
[sujeto(['MDR1', is, clinically, important, because, it, is]), verbo([involved]), complemento([in, multidrug, resistance, of, cancer, cells, and, affects, the, pharmacokinetics, of, various, drugs])].
[sujeto(['Here', we]), verbo([report]), complemento([a, novel, method, to, measure, 'ATPase', activity, of, 'MDR1', using, 'high-performance', liquid, chromatography, equipped, with, a, titanium, dioxide, column])].
[sujeto(['This', method, made, it, possible, to, reduce, the, amount, of, purified, 'MDR1']), verbo([required]), complemento([for, a, reaction, to, 0.5, 'ng,', about, 1, /, 20, th, of, the, conventional, colorimetric, inorganic, phosphate, detection, assay])].
[sujeto(['This', method, is, sensitive, enough, to, detect, any, subtle, changes, in, 'ATPase', activity, of, 'MDR1']), verbo([induced]), complemento([by, drugs, and, can, be, applied, to, measure, 'ATPase', activity, of, any, protein])].
[sujeto(['Determination', of, the, details, of, the, catalytic, cycle, of, 'P-glycoprotein', is, critical, if, we, are, to, understand, the, mechanism, of, drug, transport, and, design, ways, to]), verbo([inhibit]), complemento([it])].
[sujeto(['It']), verbo([has]), complemento([been, proposed, that, the, 'vanadate-trapped', transition, state, of, 'P-glycoprotein', '(', 'Pgp', x, 'ADP', x, 'V(i)', x, 'M(2+),', where, 'M(2+)', is, a, divalent, metal, 'ion)', has, a, very, low, affinity, for, drugs, compared, to, resting, state, 'protein,', thus, leading, to, binding, of, substrate, on, the, cytoplasmic, side, of, the, membrane, and, release, of, substrate, to, the, extracellular, medium, '(', or, the, extracellular, membrane, 'leaflet)'])].
[sujeto(['We']), verbo([have]), complemento([used, several, different, fluorescence, spectroscopic, approaches, to, show, that, isolated, purified, 'P-glycoprotein,', when, trapped, in, a, stable, transition, state, with, vanadate, and, either, 'Co(2+)or', 'Mg(2+),', binds, drugs, with, high, affinity])].
[sujeto(['For', 'vinblastine,', 'colchicine,', rhodamine, 123, ',', and, 'doxorubicin,', the, affinity, of, the, 'vanadate-trapped', transition, state, for, drugs, was, only, very, slightly, '(', less, than, 2, -, 'fold)', lower, than, the]), verbo([binding]), complemento([affinity, of, resting, state, 'Pgp,', whereas, for, the, modulators, cyclosporin, 'A', and, verapamil, and, the, substrate, 'Hoechst', 33342, ',', the, binding, affinity, was, very, similar, for, the, two, states])].
[sujeto(['The', drug]), verbo([binding]), complemento([affinity, of, the, 'ADP-bound', form, of, the, transporter, was, also, comparable, to, that, of, the, unoccupied, transporter])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, release, of, drug, from, the, transporter, during, the, catalytic, cycle, precedes, formation, of, the, transition, state])].
[sujeto(['Magnesium']), verbo([has]), complemento([the, property, to, suppress, hippocampal, 'kindling,', to, reduce, the, release, of, adrenocorticotrophic, hormone, '(', 'ACTH)', and, to, affect, adrenocortical, sensitivity, to, 'ACTH'])].
[sujeto(['The', role, of, magnesium, in, the, central, nervous, system, could, be]), verbo([mediated]), complemento([via, the, 'N-methyl-D-aspartate-antagonistic,', 'gamma-aminobutyric', 'acidA-agonistic', or, a, angiotensin, 'II-antagonistic', property, of, this, ion])].
[sujeto(['A', direct, impact, of, magnesium, on, the, function, of, the, transport, protein, 'p-glycoprotein', at, the, level, of, the, 'blood-brain', barrier]), verbo([has]), complemento([also, been, 'demonstrated,', possibly, influencing, the, access, of, corticosteroids, to, the, brain])].
[sujeto(['Furthermore,', magnesium, dampens, the, 'calciumion-proteinkinase', 'C', related, neurotransmission, and]), verbo([stimulates]), complemento([the, 'Na-K-ATPase'])].
[sujeto(['All', these, systems]), verbo([have]), complemento([been, reported, to, be, involved, in, the, pathophysiology, of, depression])].
[sujeto(['Substantial', evidence, indicates, that, the, two, catalytic, sites, of, the, nucleotide]), verbo([binding]), complemento([domains, function, in, a, highly, 'cooperative,', alternating, sites, 'mode,', which, suggests, the, possibility, that, they, interact, with, each, other, physically])].
[sujeto(['In', this, 'study,', fluorescence, energy, transfer, experiments, were, used, to, estimate, the, distance, between, two, 'fluors,', each, covalently, linked, to, a, highly]), verbo([conserved]), complemento(['Cys', residue, '(', 'Cys428', and, 'Cys1071)', within, the, 'Walker', 'A', motif, of, the, catalytic, site])].
[sujeto(['Following']), verbo([loss]), complemento([of, the, trapped, vanadate, 'complex,', the, newly, vacant, site, was, then, labeled, with, 'NBD-Cl', '(', 7, -, 'chloro-4-nitrobenzo-2-oxa-1,3-diazole)'])].
[sujeto(['On', the, other, 'hand,', the, fluorescence, emission, of, the, 'MIANS', group, in, doubly, labeled, 'P-glycoprotein', was, highly, quenched, as, a, result, of, energy, transfer, to, 'NBD,']), verbo([leading]), complemento([to, an, estimate, of, a, 'donor-acceptor', separation, distance, of, approximately, 16, 'A', for, 'P-glycoprotein', labeled, in, the, native, plasma, membrane, and, approximately, 22, 'A', for, 'P-glycoprotein', labeled, in, detergent, solution])].
[sujeto(['The', separation, of, the, two, fluorophores, is, compatible, with, the, recently]), verbo([reported]), complemento([crystal, structure, of, the, 'Rad50cd', 'dimer,', but, not, with, that, of, the, 'HisP', dimer])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, two, catalytic, sites, of, the, 'P-glycoprotein', nucleotide, binding, domains, are, relatively, close, 'together,', which, would, facilitate, cooperation, between, them, during, the, catalytic, cycle])].
[sujeto(['It', is, a, paradigm, for, understanding, the, 'structure-function', of, the, nucleotide]), verbo([binding]), complemento([domains, '(', 'NBD)', of, medically, important, efflux, 'pumps,', such, as, 'P-glycoprotein,', because, it, has, two, 'sequence-related,', interacting, 'NBD,', for, which, the, structure, is, known])].
[sujeto(['On', the, basis, of, a, rigorous, analysis, of, the, 'pre-steady-state', kinetics, of, nucleotide]), verbo([binding]), complemento([and, 'hydrolysis,', we, propose, a, model, in, which, 'ArsA', alternates, between, two, mutually, exclusive, conformations, as, 'follows:', the, 'ArsA(1)', conformation, in, which, the, 'A1', site, is, closed, but, the, 'A2', site, 'open;', and, the, 'ArsA(2)', 'conformation,', in, which, the, 'A1', and, 'A2', sites, are, open, and, 'closed,', respectively])].
[sujeto(['Antimonite', elicits, its, effects, by, sequestering, 'ArsA', in, the, 'ArsA(1)', 'conformation,', which, catalyzes, rapid, 'ATP', hydrolysis, at, the, 'A2', site, to, drive, 'ArsA', between, conformations, that]), verbo([have]), complemento([high, '(', 'nucleotide-bound', 'ArsA)', and, low, affinity, '(', 'nucleotide-free', 'ArsA)', for, 'Sb(III)'])].
[sujeto(['Glutamine-471', and, the, corresponding, 'glutamine-1114', in, the, two, catalytic, sites, of, 'P-glycoprotein', are]), verbo([conserved]), complemento([in, 'ABC', transporters])].
[sujeto(['X-ray', structures, show, that, they, lie, close, to, the]), verbo([bound]), complemento([nucleotide])].
[sujeto(['We']), verbo([found]), complemento([that, equivalent, mutations, '(', 'Ala', or, 'Glu)', in, either, of, the, two, 'P-glycoprotein', catalytic, sites, produced, the, same, 'effects,', implying, functional, symmetry, of, the, two, sites])].
[sujeto(['P-glycoprotein', mutants, 'S430A/T', and, 'S1073A/T,', affecting]), verbo([conserved]), complemento(['Walker', 'A', 'Ser', 'residues,', were, characterized, to, elucidate, molecular, roles, of, the, 'Ser', and, functioning, of, the, two, 'P-glycoprotein', catalytic, sites])].
[sujeto(['Thus,', congruent, with, previous, 'work,', both, sites, must, be, intact, and, must]), verbo([interact]), complemento([for, catalysis])].
[sujeto(['Initial', substrate]), verbo([binding]), complemento([is, apparently, to, an, &, 'quot;open&quot;', catalytic, site, 'conformation,', where, the, 'Ser-OH', is, dispensable])].
[sujeto(['This', changes, to, a, &, 'quot;closed&quot;', conformation]), verbo([required]), complemento([to, attain, the, transition, 'state,', in, which, the, 'Ser-OH', is, a, critical, ligand])].
[sujeto(['Formation', of, the, latter, conformation]), verbo([requires]), complemento([both, 'sites;', both, sites, may, provide, direct, ligands, to, the, transition, state])].
[sujeto(['Limited', trypsin, digestion, was, used, to, monitor, 'nucleotide-induced', conformational, changes, in, 'wild-type', 'P-glycoprotein', '(', 'Pgp)', as, well, as, in, nucleotide]), verbo([binding]), complemento([domain, '(', 'NBD)', 'Pgp', mutants])].
[sujeto(['The', 'Pgp', tryptic, digestion, products, were, separated, by, 'SDS-PAGE', followed, by, immunodetection, with, the, mouse, monoclonal, 'anti-Pgp', antibody, 'C219,', which]), verbo([recognizes]), complemento([a, conserved, epitope, '(', 'VVQE/AALD)', in, each, half, of, the, protein])].
[sujeto(['A', unique, trypsin, digestion, profile, suggestive, of]), verbo([enhanced]), complemento([resistance, to, trypsin, was, observed, under, conditions, of, 'vanadate-induced', trapping, of, nucleotides, '(', 'MgATP', +, 'vanadate)'])].
[sujeto(['This', is, consistent, with, the, absence, of, 'ATP', hydrolysis, and, of, 'vanadate-induced', trapping, of, 8, -, 'azido-ADP', previously]), verbo([reported]), complemento([for, these, mutants, '[', 'Urbatsch', et, al])].
[sujeto(['The', different, sensitivity, profiles, of, 'Pgp', mutants, bearing, mutations, at, the, homologous, residue, in, 'NBD1', '(', 'D551N)', and, 'NBD2', '(', 'D1196N)']), verbo([suggest]), complemento([possible, structural, and, functional, differences, between, the, two, sites])].
[sujeto(['P-glycoprotein', '(', 'Pgp)']), verbo([mediates]), complemento([drug, transport, utilizing, the, energy, released, from, 'ATP', hydrolysis])].
[sujeto(['The', present, work, is, undertaken, to, describe, kinetically, the, first, 'step,', which, is, the, interdependence, of, nucleotide, and, drug]), verbo([binding]), complemento([to, the, 'Pgp', by, the, use, of, vanadate])].
[sujeto(['Preincubation', of, human, 'Pgp']), verbo([expressed]), complemento([in, 'Sf9', insect, cells, with, vanadate, in, the, presence, of, 'Mg2+,', 'ATP,', and, verapamil, resulted, in, nearly, complete, and, stable, inhibition, of, the, 'drug-stimulated', 'ATPase', function])].
[sujeto(['Inhibition', was, highly, specific, for, divalent, cations, that, support, 'ATP', 'hydrolysis,', for, nucleotides, that, serve, as, substrates, of, 'hydrolysis,', and, for, those, 'drugs/compounds', that]), verbo([interact]), complemento([with, the, 'drug-binding/transport', sites, of, the, 'Pgp'])].
[sujeto(['Kinetic', analysis, indicated, that, vanadate, inhibition, was, 'MgATP', 'concentration-dependent', with, an, apparent, 'Ki', value, similar, to, the, apparent, 'Km,']), verbo([suggesting]), complemento([that, 'MgATP', was, bound, to, a, similar, 'ATP-binding', site, in, both, the, 'ATPase', inhibition, and, activation, reactions])].
[sujeto(['In', support, of, this, 'conclusion,', 'vanadate,', in, the, presence, of, 'Mg2+', and, 'verapamil,']), verbo([caused]), complemento([selective, trapping, of, 8, -, azido, '[', 'alpha-32P]', 'ATP', and, covalent, labeling, of, 'ATP-binding', site, in, the, 'Pgp'])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, the, affinity, of, the, interacting, 'drug/compound', is, a, constant, and, influences, the, overall, stability, of, the, inhibited, 'Pgp', species])].
[sujeto(['Expression', of, the, cystic, fibrosis, transmembrane, conductance, regulator, '(', 'CFTR),', and, of, at, least, one, other, member, of, the, 'ATP-binding', cassette, family, of, transport, 'proteins,', 'P-glycoprotein,', is]), verbo([associated]), complemento([with, the, electrodiffusional, movement, of, the, nucleotide, 'ATP'])].
[sujeto(['Here', it, is]), verbo([reported]), complemento([that, reconstitution, into, a, lipid, bilayer, of, highly, purified, 'CFTR', of, human, epithelial, origin, enables, the, permeation, of, both, 'Cl-', and, 'ATP'])].
[sujeto(['Similar', to, previously]), verbo([reported]), complemento([data, for, in, vivo, 'ATP', current, of, 'CFTR-expressing', 'cells,', the, reconstituted, channels, displayed, competition, between, 'Cl-', and, 'ATP', and, had, multiple, conductance, states, in, the, presence, of, 'Cl-', and, 'ATP'])].
[sujeto(['Purified', 'CFTR-mediated', 'ATP', currents, were]), verbo([activated]), complemento([by, protein, kinase, 'A', and, 'ATP', '(', 1, 'mM)', from, the, &, 'quot;intracellular&quot;', side, of, the, molecule, and, were, inhibited, by, 'diphenylamine-2-carboxylate,', 'glibenclamide,', and, 'anti-CFTR', antibodies])].
[sujeto(['P-glycoprotein', '(', 'Pgp)', is, a, membrane, protein, that, transports, chemotherapeutic, 'drugs,']), verbo([causing]), complemento([multidrug, resistance, in, human, cancer, cells])].
[sujeto(['It']), verbo([has]), complemento([been, suggested, that, the, conformation, of, 'Pgp', changes, in, the, catalytic, cycle])].
[sujeto(['In', this, 'study,', we, tested, this, hypothesis, by, using, limited, proteolysis, as, a, tool, to, detect, different, conformational, states, trapped, by]), verbo([binding]), complemento([of, nucleotide, ligands, and, inhibitors])].
[sujeto(['Pgp']), verbo([has]), complemento([high, basal, 'ATPase', 'activity;', that, 'is,', 'ATP', hydrolysis, by, 'Pgp', is, not, rigidly, associated, with, drug, transport])].
[sujeto(['This', activity]), verbo([provides]), complemento([a, convenient, method, for, studying, the, conformational, change, of, 'Pgp', induced, by, nucleotide, 'ligands,', in, the, absence, of, drug, substrates, which, may, generate, complications, due, to, their, own, binding])].
[sujeto(['Changes', in, the, proteolysis, profile, of, 'Pgp', owing, to]), verbo([binding]), complemento([of, nucleotides, were, used, to, indicate, the, conformational, changes, in, 'Pgp'])].
[sujeto(['We']), verbo([found]), complemento([that, generation, of, tryptic, 'fragments,', including, the, loop, linking, transmembrane, '(', 'TM)', regions, 'TM8', and, 'TM9', of, 'Pgp,', were, stimulated, by, the, binding, of, 'Mg-p[NH]ppA,', 'MgATP', and, 'MgADP,', indicating, that, the, 'Pgp', conformation, was, changed, by, the, binding, of, these, nucleotides])].
[sujeto(['The', effects, of, nucleotides, on, 'Pgp', conformation, are, directly]), verbo([associated]), complemento([with, the, binding, 'and/or', hydrolysis, of, these, ligands])].
[sujeto(['Recently,', several, studies, on, 'P-glycoprotein', '(', 'Pgp)']), verbo([suggested]), complemento([that, the, topogenesis, of, polytopic, membrane, proteins, is, likely, more, complicated, than, anticipated])].
[sujeto(['While', studying, the, mechanism, by, which, 'Pgp', topogenesis, is, 'determined,', we, unexpectedly]), verbo([found]), complemento([that, ribosomes, or, proteins, associated, with, ribosomes, are, involved, in, regulating, the, membrane, insertion, and, folding, of, 'Pgp', during, its, translation])].
[sujeto(['We', discovered, that, when, 'Pgp', was]), verbo([translated]), complemento([by, wheat, germ, ribosomes, in, 'vitro,', 'TM3', could, not, reinitiate, the, insertion, of, the, protein, into, microsomal, membranes, following, the, membrane, insertion, of, 'TM1', and, 'TM2'])].
[sujeto(['In', 'contrast,', 'TM3', could, reinitiate, membrane, insertion, when, the, protein, was]), verbo([translated]), complemento([by, rabbit, reticulocyte, ribosomes])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, ribosomes, or, proteins, associated, with, ribosomes, play, an, important, role, in, membrane, insertion, and, folding, of, 'TM', segments, of, 'Pgp', and, that, rabbit, reticulocyte, and, wheat, germ, ribosomes, may, use, different, mechanisms, to, control, the, membrane, insertion, of, the, same, nascent, peptide])].
[sujeto(['We', propose, that, ribosomes, or, proteins]), verbo([associated]), complemento([with, ribosomes, help, reinitiate, insertion, of, internal, 'TM', segments, into, the, membrane, by, dissociation, and, reassociation, with, the, 'protein-conducting', channel, in, 'ER', membranes])].
[sujeto(['To', understand, the, roles, of, the, two, 'nucleotide-binding', folds, '(', 'NBFs)', of, 'SUR1', in, the, regulation, of, 'KATP', channel, 'activity,', we, introduced, point, mutations, into, the, core, consensus, sequence, of, the, 'Walker', 'A', or, 'B', motif, of, each, 'NBF', of, 'SUR1', and, characterized, 'ATP']), verbo([binding]), complemento([and, 'ADP', or, 'MgADP', antagonism, to, it])].
[sujeto(['These', results, show, that, 'SUR1,', unlike, other, 'ABC', 'proteins,', strongly]), verbo([binds]), complemento(['ATP', at, 'NBF1', even, in, the, absence, of, 'Mg2+', and, that, 'MgADP,', through, binding, at, 'NBF2,', antagonizes, the, 'Mg2+-independent', high, affinity, 'ATP', binding, at, 'NBF1'])].
[sujeto(['Vanadate', trapping, of, 'Mg-', or, 'Co-8-azido-nucleotide', '(', 1, 'mol/mol', of, 'Pgp)']), verbo([caused]), complemento([complete, inhibition, of, 'Pgp', 'ATPase', 'activity,', with, reactivation, rates, at, 37, degrees, 'C', of, 1.4, x, 10, '(', -, 3, ')', 's-1', '(', 't1/2', =, 8, 'min)', or, 3.3, x, 10, '(', -, 4, ')', 's-1', '(', 't1/2', =, 35, 'min),', respectively])].
[sujeto(['UV', irradiation, of, the]), verbo([inhibited]), complemento(['Pgp', yielded, permanent, inactivation, of, 'ATPase', activity, and, specific, photolabeling, of, 'Pgp'])].
[sujeto(['The', results, show, that, both, nucleotide, sites, in, 'Pgp', are, capable, of, nucleotide, 'hydrolysis,', that, vanadate, trapping, of, nucleotide, at, either, site, completely]), verbo([prevents]), complemento([hydrolysis, at, both, 'sites,', and, that, vanadate, trapping, of, nucleotide, in, the, 'N-', or, 'C-terminal', nucleotide, sites, occurs, 'non-selectively'])].
[sujeto(['The']), verbo([inhibited]), complemento(['Pgp-Mg-nucleotide'])].
[sujeto([vanadate, complex, is, probably, an, analog, of, the, catalytic, transition, 'state,', implying, that, when, one, nucleotide, site, assumes, the, catalytic, transition, state, conformation, the, other, site, cannot, do, so, and]), verbo([suggesting]), complemento([that, the, two, sites, may, alternate, in, catalysis])].
[sujeto(['Using', plasma, membranes, from, a, 'multidrug-resistant', 'Chinese', hamster, ovary, cell, 'line,', which, are, highly, enriched, in, 'Pgp,', we, show, that, 'vanadate-induced', trapping, of, nucleotide, at, a, single, catalytic, site, produces, stably]), verbo([inhibited]), complemento(['Pgp,', with, t, 1, /, 2, for, reactivation, of, 'ATPase', activity, of, 84, min, at, 37, degrees, 'C', and, &, 'gt;30', h, at, 4, degrees, 'C'])].
[sujeto(['Reactivation', of, 'ATPase', correlated, with]), verbo([release]), complemento([of, trapped, nucleotide])].
[sujeto(['Concentrations', of, 'MgATP', and, 'MgADP']), verbo([required]), complemento([to, produce, 50, '%', inhibition, were, 9, and, 15, 'microM,', 'respectively,', thus, the, apparent, affinity, for, nucleotide, is, greatly, increased, by, 'vanadate-trapping'])].
[sujeto(['Divalent', 'Cation', was, 'required,', with, 'magnesium,', 'manganese,', and, cobalt, all, 'effective:', cobalt, yielded, a, very, stable]), verbo([inhibited]), complemento(['species,', 't1/2', at, 37, degrees, 'C', =, 18, h])].
[sujeto(['Vanadate-trapping', with, 8, -, 'azido-ATP', followed, by, 'UV', irradiation]), verbo([caused]), complemento([permanent, inactivation, and, specific, labeling, of, 'Pgp'])].
[sujeto(['The']), verbo([finding]), complemento([that, vanadate, trapping, of, nucleotide, at, just, one, 'site/Pgp', is, sufficient, to, give, full, inhibition, at, 'ATPase', activity, shows, that, the, two, predicted, nucleotide, sites, can, not, function, independently, as, catalytic, sites])].
[sujeto(['A', range, of, other, compounds, known, to]), verbo([interact]), complemento([with, 'Pgp', in, whole, cells, also, stimulated, the, 'MgATPase', activity])].
[sujeto(['Predominantly,', the, catalytic, features, seen, resembled, those]), verbo([reported]), complemento([previously, for, the, plasma, 'membrane-bound', form, of, 'Pgp'])].
[sujeto(['In', this]), verbo([report]), complemento([we, show, that, the, expression, of, the, human, 'MDR1', gene, in, cultured, 'Sf9', insect, cells, via, a, baculovirus, vector, generates, a, high, activity, 'vanadate-sensitive', membrane, 'ATPase'])].
[sujeto(['This', 'ATPase', is, markedly]), verbo([stimulated]), complemento([by, drugs, known, to, interact, with, the, 'P-glycoprotein,', such, as, vinblastine, and, 'verapamil,', and, the, ability, of, the, various, drugs, to, stimulate, the, 'ATPase', corresponds, to, their, previously, observed, affinity, for, this, transporter])].
[sujeto(['The', 'drug-induced', 'ATPase']), verbo([requires]), complemento([magnesium, 'ions,', does, not, utilize, 'ADP', or, 'AMP', as, 'substrates,', exhibits, a, 'half-maximal', activation, at, about, 0.5, mM, 'MgATP,', and, its, maximal, activity, '(', about, 3, -, 5, 'mumol/mg', 'MDR', 'protein/min)', approaches, that, of, the, well, characterized, ion, transport, 'ATPases'])].
[sujeto(['These', results]), verbo([provide]), complemento([the, first, direct, demonstration, of, a, high, capacity, 'drug-stimulated', 'ATPase', activity, of, the, human, multidrug, resistance, protein, and, offer, a, new, and, simple, assay, for, the, investigation, of, functional, interactions, of, various, drugs, with, this, clinically, important, enzyme])].
[sujeto(['The', 'Mr', 170, ',', 0, to, 180, ',', 0, membrane, glycoprotein]), verbo([associated]), complemento([with, multidrug, resistance, '(', 'P-glycoprotein)', is, involved, in, drug, transport, mechanisms, across, the, plasma, membrane, of, 'multidrug-resistant', cells])].
[sujeto(['We']), verbo([have]), complemento([recently, reported, the, purification, of, 'P-glycoprotein'])].
[sujeto(['The', purified, 'P-glycoprotein', was]), verbo([found]), complemento([to, have, an, 'ATPase', 'activity,', which, might, be, coupled, with, the, active, efflux, of, anticancer, drugs])].
[sujeto(['In', the, present, 'study,', we]), verbo([have]), complemento([further, studied, the, properties, of, the, 'P-glycoprotein', 'ATPase', activity, by, an, immobilized, enzyme, assay, procedure, using, a, 'P-glycoprotein-antibody-Protein', 'A-Sepharose', complex])].
[sujeto(['Maximum', activity, was, obtained, when, 0.1, -, 0.2, '%', 3, -, '[', '(', 3, -, 'cholamidopropyl)dimethyl-ammonio]-propane', sulfonate, was, 'used,', while, higher, concentrations, markedly]), verbo([inhibited]), complemento([the, 'ATPase', activity])].
[sujeto(['Divalent', cations, such, as, 'Ca2+,', 'Zn2+,', 'Ni2+,', 'Cd2+,', and, 'Cu2+']), verbo([inhibited]), complemento([the, 'Mg2+-catalyzed', 'ATP', hydrolysis])].
[sujeto(['N-Ethylmaleimide', and, vanadate]), verbo([inhibited]), complemento([the, 'ATPase', 'activity,', while, sodium, azide, or, ouabain, had, no, effect])].
[sujeto(['In', 'contrast,', verapamil, and, 'trifluoperazine,', agents, which]), verbo([inhibit]), complemento([active, drug, efflux, and, restore, drug, sensitivity, in, resistant, 'cells,', caused, an, increase, in, the, 'P-glycoprotein', 'ATPase', activity, suggesting, that, 'P-glycoprotein', might, be, the, target, molecule, of, these, agents])].
[sujeto(['The', deletion, was, assessed, in, a, large, data, set, '(', 531, cases, and, 527, 'controls)', 'and,', after, adjustments, for, 'age,', 'sex,', and, 'APOE', 'status,', was, significantly]), verbo([associated]), complemento([with, disease, '(', p, =, 0.0002, ',', odds, ratio, '[', 'OR]', =, 2.13, '[', 95, '%', confidence, interval, '(', 'CI):', 1.42, -, 3.2, ']', ')'])].
[sujeto(['An', independent, data, set, replicated, the, association, '(', 447, cases, and, 880, 'controls,', p, =, 0.0117, ',', 'OR', =, 1.65, '[', 95, '%', 'CI:', 1.12, -, 2.44, ']', ')', ',', and, joint, analysis]), verbo([increased]), complemento([the, significance, '(', p, =, 1.414, ×, 10, '(', -, 5, ')', ',', 'OR', =, 1.81, '[', 95, '%', 'CI:', 1.38, -, 2.37, ']', ')'])].
[sujeto(['According', to, the, cancer, stem, cell, 'theory,', a, small, subpopulation, of, cancer, 'cells,', known, as, cancer, stem, cells, '(', 'CSCs),', exist, that, are, 'self-renewing', and, are]), verbo([involved]), complemento([in, tumor, 'invasion,', metastasis, and, recurrence])].
[sujeto(['A', number, of, studies]), verbo([have]), complemento([reported, that, certain, cancer, cells, are, able, to, efflux, the, 'Hoechst', 33342, dye])].
[sujeto(['The', immunofluorescence, and, reverse, transcription, polymerase, chain, reaction, analysis, revealed, that, 'SP', cells]), verbo([have]), complemento([an, enhanced, expression, of, the, 'ATP-binding', cassette, '(', 'ABC)', transporter, protein, 'ABC', subfamily, 'G,', member, 2, '(', 'ABCG2),', which, has, been, identified, to, be, actively, involved, in, drug, exclusion])].
[sujeto(['Similarly,', the, mRNA, level, of, the, oncogene, 'B', lymphoma, 'Mo-MLV', insertion, 'region-1', and, the, stem, cell, surface, proteins, nestin, and, 'octamer-binding', transcription, 'factor-4', were, highly]), verbo([expressed]), complemento([in, the, 'SP', cells, compared, with, the, 'non-SP', cells])].
[sujeto(['In', 'addition,', it, was, demonstrated, that, 'HNSCC', 'SP', cells, exhibited]), verbo([increased]), complemento([proliferation, and, were, highly, resistant, to, multiple, drugs])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, presence, of, 'CSCs,', such, as, 'SP', 'cells,', may, be, responsible, for, chemotherapy, failure, and, tumor, relapse, in, patients, with, 'HNSCC'])].
[sujeto(['Therefore,', the, identification, of, a, novel, therapeutic, drug, that, could, effectively]), verbo([target]), complemento(['CSCs', may, help, to, eradicate, refractory, tumors])].
[sujeto(['The', 'meta-analysis', study, results, revealed, that, the, 'VEGF', rs2010963, 'G&gt;C', polymorphism]), verbo([increased]), complemento([the, risk, of, 'ONFH,', while, the, 'VEGF', rs2010963, 'G&gt;C', and, 'ABCB1', rs1045642, 'C&gt;T', polymorphisms, increased, the, risk, of, 'ONFH', under, the, allele, model])].
[sujeto(['Moreover,', cabazitaxel, had, low, 'efficacy,', whereas, paclitaxel, had, high, efficacy, in]), verbo([stimulating]), complemento([the, 'ATPase', activity, of, 'ABCB1,', indicating, a, direct, interaction, of, both, drugs, with, the, transporter])].
[sujeto(['ABCB1', and, 'ABCC10', are, not, primary, resistance, factors, for, cabazitaxel, compared, with, 'paclitaxel,']), verbo([suggesting]), complemento([that, cabazitaxel, may, have, a, low, affinity, for, these, efflux, transporters])].
[sujeto(['In', 'addition,', 'ABCB1', polymorphisms, were, connected, with]), verbo([increased]), complemento([risk, of, liver, dysfunction, and, infection, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['ABCB1', 3435, 'C', &, 'gt;', 'T', polymorphisms, may, be]), verbo([associated]), complemento([with, susceptibility, to, acute, 'leukemia,', and, 'ABCB1', polymorphisms, might, be, a, sensitive, indicator, for, predicting, efficacy, of, 'MTX', therapy, in, the, treatment, of, acute, leukemia])].
[sujeto(['Various', alterations, underlying, acquired, resistance, to, epidermal, growth, factor, 'receptor-tyrosine', kinase, inhibitors, '(', 'EGFR-TKIs)']), verbo([have]), complemento([been, described])].
[sujeto(['However,', we, describe, that, two, different, molecular, alterations]), verbo([confer]), complemento([acquired, resistance, to, 'EGFR-TKIs', and, cytotoxic, 'agents,', respectively])].
[sujeto(['The', objective, of, this, study, was, to, determine, the, effect, of, the, 'CYP3A5', and, 'ATP']), verbo([binding]), complemento([cassette, subfamily, 'B', member, 1, '(', 'ABCB1)', 'single-nucleotide', polymorphisms, on, the, disposition, of, sunitinib, and, 'SU12662,', on, clinical, 'response,', and, on, the, manifestation, of, toxicities, in, 'Asian', metastatic, renal, cell, carcinoma, patients])].
[sujeto(['The', 'CC', genotype, for, 'ABCB1', was]), verbo([associated]), complemento([with, a, higher, sunitinib, exposure, '(', 76.81, vs, 56.55, ng, 'ml(-1),', 'P=0'])].
[sujeto(['The', polymorphism, of, 'ABCB1', '(', 'C3435T)']), verbo([has]), complemento([an, important, role, in, the, manifestation, of, toxicities, and, drug, 'exposure,', but, not, polymorphism, of, 'CYP3A5'])].
[sujeto(['Familial', 'Mediterranean', fever, '(', 'FMF)', is, considered, an, autosomal, recessive, 'disorder,']), verbo([associated]), complemento([with, a, single, gene, named, 'Mediterranean', fever, '(', 'MEFV)'])].
[sujeto(['The', 'CT-GG', binary, genotype, and, 'C-T', and, 'T-G', haplotypes, for, 'C1236T-G2677T/A', polymorphisms, may]), verbo([have]), complemento([a, high, degree, of, protective, effect, against, 'FMF', '(', p, =, 0.0005, ',', 0.002, and, 0.0, ',', 'respectively)'])].
[sujeto(['ABCC10']), verbo([mediates]), complemento([multidrug, resistance, '(', 'MDR)', in, cancer, cells, by, preventing, the, intracellular, accumulation, of, certain, antitumor, drugs])].
[sujeto(['In', recent, 'years,', 'ABCC10', 'inhibitors,', including, 'cepharanthine,', 'lapatinib,', 'erlotinib,', 'nilotinib,', 'imatinib,', 'sildenafil,', and, 'vardenafil,']), verbo([have]), complemento([been, reported, to, overcome, 'ABCC10-mediated', 'MDR'])].
[sujeto(['High', 'Abcg2', '(', 'ATP-Binding', 'Cassette', 'Transporter', 'Subfamily', 'G,', 'Member-2)', levels]), verbo([have]), complemento([been, found, in, reproductive, 'tissues,', such, as, the, placenta, and, uterus])].
[sujeto(['Nifedipine,', commonly, used, in, acute, tocolytic, 'therapy,', exerts, a, greater, tocolytic, effect, and]), verbo([has]), complemento([fewer, 'side-effects', than, 'β2-adrenergic', receptor, agonists])].
[sujeto(['Low', levels, of, 'Abcg2', were]), verbo([found]), complemento([in, 'non-pregnant', animals, and, 'early-pregnancy', '(', days, 6, ',', 8, and, 10, ')', ',', but, on, day, 15, of, 'gestation,', a, sharp, increase, in, 'Abcg2', levels, was, 'observed,', which, reached, its, maximum, on, day, 18, and, later, decreased, until, the, end, of, gestation])].
[sujeto(['The', in, vivo, contractility, studies, revealed, that, nifedipine, had, a, strong, 'uterus-relaxant', effect, on, spontaneous, 'contractions,', and, that, this, effect, was, significantly, and, 'dose-dependently']), verbo([increased]), complemento([by, the, 'Abcg2', blocker, 'KO134'])].
[sujeto(['Substrate-induced', upregulation, of, 'ATP-binding', cassette, subfamily, 'G', member, 2, '(', 'ABCG2)']), verbo([has]), complemento([been, well, studied, in, cancer, 'cells,', but, it, is, also, important, to, understand, whether, 'ABCG2', is, upregulated, by, its, substrates, in, tissues, in, which, it, is, constitutively, expressed])].
[sujeto(['On', the, 'contrary,', mitoxantrone, markedly]), verbo([increased]), complemento([the, expression, of, estrogen, receptor, '(', 'ER)', α, and, progesterone, receptor, '(', 'PR)', 'B'])].
[sujeto(['Fulvestrant,', an, 'ER', 'antagonist,', attenuated, the, 'mitoxantrone-induced']), verbo([increase]), complemento([of, 'Abcg2', mRNA, 'expression,', whereas, 'mifepristone,', a, 'PR', 'antagonist,', had, little, effect])].
[sujeto([17, 'β-estradiol,', an, 'ER', 'ligand,', positively]), verbo([regulated]), complemento([the, 'mitoxantrone-induced', increase, of, 'Abcg2', expression])].
[sujeto(['DNA', demethylation, by, 5, -, 'aza-2-deoxycytidine', treatment]), verbo([increased]), complemento(['ERα', 'expression,', but, mitoxantrone, failed, to, facilitate, the, demethylation, of, 'ERα', promoter, in, 'TR-TBT', 18, 'd-1', cells])].
[sujeto(['In', 'conclusion,', 'Abcg2', expression, is]), verbo([induced]), complemento([by, mitoxantrone, via, the, induction, of, 'ERα', in, 'TR-TBT', 18, 'd-1', cells])].
[sujeto(['Apolipoprotein', 'M', '(', 'apoM)', may]), verbo([have]), complemento([potential, antiatherosclerotic, properties])].
[sujeto(['It']), verbo([has]), complemento([been, reported, that, apoM, expression, could, be, regulated, by, many, intracellar, and, extracellar, factors])].
[sujeto(['In', the, present, study, we, further, investigated, regulation, of, apoM, expression, in, 'Caco-2', cells]), verbo([stimulated]), complemento([by, a, liver, 'X', receptor, '(', 'LXR)', 'agonist,', 'TO901317'])].
[sujeto(['When', 'Caco-2', cell, cultured, with, 'TO901317', 'alone,', the, mRNA, levels, of, 'ABCA1,', 'apoA1,', 'apoM,', 'LRH-1', and, 'SHP1', were, significantly]), verbo([increased]), complemento([with, 'dose-dependent', manners, '(', p, &, 'lt;', 0.05, ')', ',', whereas, when, the, cells, cultured, with, guggulsterone, 'alone,', the, mRNA, levels, of, 'apoM,', 'SHP1', and, 'LRH-1', '(', p, &, 'lt;', 0.05, ')', were, strongly, inhibited])].
[sujeto(['Moreover,', guggulsterone, could, abolish, the, 'TO901317']), verbo([enhanced]), complemento([mRNA, levels, of, apoA1, 'apoM,', 'SHP1', and, 'LRH-1'])].
[sujeto(['The', present, study, demonstrated, that, 'LXR', agonist, 'TO901317']), verbo([induced]), complemento([apoM, expression, in, 'Caco-2', cells, might, be, mediated, via, the, 'LXR/FXR', pathway])].
[sujeto(['The', recent, discovery, that, several, proteins, are]), verbo([involved]), complemento([in, carotenoid, metabolism, in, humans, has, prompted, a, possible, explanation, for, this, 'phenomenon:', genetic, variants, in, genes, encoding, for, these, proteins, may, affect, their, expression, or, 'activity,', and, in, turn, carotenoid, metabolism, and, carotenoid, status])].
[sujeto(['The', proteins, clearly, identified, so, far, are, '(', 'i)', the, carotene, oxygenases, 'β,β-carotene-15,15\'-monooxygenase', '(', 'BCMO1)', and, 'β,β-carotene-9\',10\'-oxygenase', '(', 'BCDO2),', which, are]), verbo([involved]), complemento([in, carotenoid, 'cleavage,', '(', 'ii)', scavenger, receptor, class, 'B', type, 'I', '(', 'SR-BI),', cluster, determinant, 36, '(', 'CD36),', and, 'Niemann', 'Pick', 'C1-like', 1, '(', 'NPC1L1),', which, are, involved, in, carotenoid, uptake, by, 'cells,', and, '(', 'iii)', glutathione, 'S-transferase', 'Pi', 1, '(', 'GSTP1)', and, human, retinal, 'lutein-binding', protein, '(', 'HR-LBP),', which, are, involved, in, the, transport, of, xanthophylls, in, the, retina])].
[sujeto(['Other', 'proteins,', such, as, 'ATP-binding', cassette, subfamily, 'G', member, 5, '(', 'ABCG5)', and, the, fatty, 'acid-binding', proteins, '(', 'FABPs)', are, also, apparently]), verbo([involved]), complemento([although, firmer, evidence, is, still, required])].
[sujeto(['A', 'genome-wide', association, 'study,', as, well, as, several, candidate, gene, association, 'studies,']), verbo([has]), complemento([shown, that, groups, of, subjects, bearing, different, alleles, in, single, nucleotide, polymorphisms, located, in, or, near, several, of, the, 'above-mentioned', genes, display, different, blood, 'and/or', tissue, concentrations, of, carotenoids])].
[sujeto(['Further', studies, are, needed, to, identify, all, the, proteins]), verbo([involved]), complemento([in, carotenoid, metabolism, and, assess, whether, other, types, of, genetic, 'variation,', e])].
[sujeto([copy, number, variants, and, epigenetic, 'modifications,', can]), verbo([modulate]), complemento([carotenoid, status])].
[sujeto(['Thirty-four', patients, with, advanced, ovarian, and, primary, peritoneal, cancer, were, administered, docetaxel, at, 75, &, 'nbsp;mg/m(2)', as, a, 1, -, h, infusion, in, combination, with, carboplatin, 'IV', over, 30, &, 'nbsp;min', at, a]), verbo([target]), complemento(['AUC', of, 5, &, 'nbsp;mg/ml&nbsp;min'])].
[sujeto(['There', was, an, inverse, relationship, between, midazolam, clearance, '(', 'CL)', and, 'CA-125', level, after, cycle, 6, where, a, higher, midazolam, 'CL', was]), verbo([associated]), complemento([with, a, 'CA-125&nbsp;&lt;10&nbsp;U/ml', '(', 'P&nbsp;=&nbsp;0'])].
[sujeto(['The', 'CA-125', categories, were]), verbo([associated]), complemento([with, response, achieved, '(', complete, 'response/partial', 'response)', '(', 'CR/PR),', stable, disease, '(', 'SD),', and, progressive, disease, '(', 'PD)', at, the, end, of, therapy, '(', 'P&nbsp;=&nbsp;0'])].
[sujeto(['To', this, 'end,', we, implemented, a, quantitative, mass, spectrometry, approach, based, on, the, selective]), verbo([decrease]), complemento([in, the, buoyant, density, of, liver, lysosomes, that, occurs, when, animals, are, treated, with, 'Triton-WR1339'])].
[sujeto(['This', analysis]), verbo([suggests]), complemento([that, several, proteins, assigned, to, the, lysosome, in, other, proteomics, studies, are, not, true, lysosomal, residents])].
[sujeto(['Its', clinical, 'use,', 'however,', is, complicated, by, side, effects, '(', mainly, 'nephrotoxicity),', narrow, therapeutic, index, and, pharmacokinetic, variability, which, can, result, in, an]), verbo([increased]), complemento([risk, of, treatment, failure, or, toxicity])].
[sujeto(['Studies', examining, interindividual, differences, in, the, expression, of, the, 'ABCB1', '(', 'ATP-binding', 'cassette,', subfamily, 'B,', member, 1, ')', gene, '(', which, encodes, the, drug, 'transporter,', 'P-gp)', and, its, genetic, polymorphisms]), verbo([have]), complemento([attempted, to, elucidate, variations, in, tacrolimus, response, and, disposition, in, children])].
[sujeto(['Large', prospective, studies, 'are,', 'however,']), verbo([required]), complemento([to, further, explore, the, potential, of, genetic, testing, in, identifying, children, who, are, at, risk, of, toxicity, and, to, better, individualise, tacrolimus, therapy])].
[sujeto(['Ticks', are, among, the, most, important, vectors, of, pathogens]), verbo([causing]), complemento([human, and, animal, disease])].
[sujeto(['Acaricides', are, used, to, control, tick, 'infestation,', although, there, are]), verbo([increasing]), complemento([reports, of, resistance])].
[sujeto(['Recently,', 'over-expression', of, 'ATP-binding', cassette, '(', 'ABC)', transporter, proteins, '(', 'P-glycoproteins,', 'PgP)']), verbo([has]), complemento([been, implicated, in, resistance, to, the, acaricide, ivermectin, in, the, ticks, 'Rhipicephalus', '(', 'Boophilus)', microplus, and, 'Rhipicephalus', sanguineus, sensu, lato])].
[sujeto(['Ixodid', tick, cell, lines]), verbo([have]), complemento([been, used, to, investigate, drug, resistance, mechanisms])].
[sujeto(['qRT-PCR', showed, that, 'ABC', pump, expression, was, not, significantly]), verbo([modulated]), complemento([by, ivermectin, treatment])].
[sujeto(['ABCB6', and, 'ABCB10', gene, expression, was, not]), verbo([modulated]), complemento([by, ivermectin, treatment, and, 'ABCB1', expression, was, not, detected])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([of, 'PgP', expression, in, an, 'I'])].
[sujeto(['Here', we]), verbo([report]), complemento([the, identification, and, functional, characterization, of, a, novel, 'ATPase', 'protein,', protein, associated, with, 'ABC', transporters, '(', 'PAAT),', in, humans])].
[sujeto(['We', showed, that, 'PAAT', is, localized, in, both, the, cytoplasm, and, the, mitochondria, and]), verbo([has]), complemento([an, intrinsic, 'ATPase', activity])].
[sujeto(['PAAT', physically]), verbo([interacts]), complemento([with, the, 3, known, mitochondrial, inner, membrane, 'ABC', 'proteins,', 'ABCB7,', 'ABCB8,', and, 'ABCB10,', but, not, 'ABCB1,', 'ABCB6,', or, 'ABCG2,', and, functionally, regulates, the, transport, of, ferric, nutrients, and, heme, biosynthesis])].
[sujeto(['Significantly,', 'PAAT', deficiency]), verbo([promotes]), complemento([cell, 'death,', reduces, mitochondrial, 'potential,', and, sensitizes, mitochondria, to, oxidative, 'stress-induced', 'DNA', damages])].
[sujeto(['The', human, transporter]), verbo([associated]), complemento([with, antigen, processing, '(', 'TAP)', is, a, member, of, the, 'ATP', binding, cassette, '(', 'ABC)', transporter, superfamily])].
[sujeto(['TAP', is, a, heterodimer, formed, by, the, association, of, two, 'half-transporters,', 'TAP1', and, 'TAP2,', with, a, typical, 'ABC', transporter, core, that, consists, of, two, nucleotide]), verbo([binding]), complemento([domains, and, two, transmembrane, domains])].
[sujeto(['We', described]), verbo([conserved]), complemento([regions, in, the, endoplasmic, 'reticulum-facing', loops, with, a, role, in, the, opening, and, closing, of, the, cavity])].
[sujeto(['We', also, identified]), verbo([conserved]), complemento(['π-stacking', interactions, in, the, cytosolic, part, of, the, transmembrane, domains, that, could, explain, the, experimental, data, available, for, 'TAP1-Phe-265'])].
[sujeto(['Electrostatic', potential, calculations, gave, structural, insights, into, the, role, of, residues]), verbo([involved]), complemento([in, peptide, 'binding,', such, as, 'TAP1-Val-288,', 'TAP2-Cys-213,', 'TAP2-Met-218'])].
[sujeto(['Moreover,', these, calculations, identified, additional, residues, potentially]), verbo([involved]), complemento([in, peptide, 'binding,', in, turn, verified, with, replica, exchange, simulations, performed, on, a, peptide, bound, to, the, 'inward-facing', models])].
[sujeto(['While', 'P-glycoprotein', '(', 'PGP,', 'ABCB1)', is, known, to, play, an, important, role, in, drug, exclusion, at, the, blood, brain, barrier, '(', 'BBB),', less, is, known, about, the, contribution, of, other, members, in, the, 'ATP-binding', cassette, '(', 'ABC)', transporter, family, to, 'BBB', drug, 'efflux,', or, whether, these, transporters, are]), verbo([expressed]), complemento([differently, in, humans, and, in, mammalian, species, of, pharmacological, interest])].
[sujeto(['After', treatment, of, 'EGCG,', 210, differentially]), verbo([expressed]), complemento([genes, were, identified, in, 'BEL7404/ADM', 'cells:', 38, were, 'up-regulated', and, 172, were, 'down-regulated;', the, potential, 'MDR-related', genes, included, the, 'up-regulated', 'ABCB10', '(', 'MDR/TAP),', 'TOP2A,', 'TOP2B,', 'CCNG1,', and, 'down-regulated', 'ABCB1,', 'MVP,', 'ARHD,', 'HDAC5,', 'GSS,', 'GSTPI,', 'HSPA1B,', 'HSPB7,', 'CDKN1A,', 'RAB11B,', 'RAB9P40'])].
[sujeto(['After', treatment, of, 'EGCG,', 179, differentially]), verbo([expressed]), complemento([genes, were, identified, in, 'BEL7402/5-FU', 'cells:', 31, were, 'up-regulated', and, 148, were, 'down-regulated;', the, potential, 'MDR-related', genes, included, the, 'up-regulated', 'ABCG', '(', 'BCRP),', 'CCNG2,', 'GADD34,', 'RB1,', 'RBBP4,', and, 'down-regulated', 'DTYMK,', 'GPX1,', 'USP5,', 'BAX,', 'BAK1,', 'HSPA1L'])].
[sujeto([',', 'ABCB1', '(', 'MDR1)', 3435, 'C&gt;T]', that, was, previously]), verbo([reported]), complemento([to, be, linked, to, 'CYP3A4', mRNA, levels, was, unrelated, to, any, of, the, studied, phenotypic, measures, '(', 'P', &, 'gt;', or, =, 0.49, ')'])].
[sujeto(['The', studied, genetic, variants, in, 'CYP3A4', and, 'CYP3A5', are, unlikely, to]), verbo([have]), complemento([an, important, functional, significance, to, phenotypic, 'CYP3A', activity, in, patients, with, cancer])].
[sujeto(['ATP']), verbo([binding]), complemento([cassette, '(', 'ABC)-transporters', like, 'P-glycoprotein', '(', multidrug, resistance, '(', 'MDR)1/ABCB1),', the, multidrug, resistance, associated, proteins, 1, and, 2, '(', 'MRP1/ABCC1', and, 'MRP2/ABCC2),', and, the, breast, cancer, resistance, protein, '(', 'BCRP/ABCG2)', have, a, large, impact, on, the, pharmacokinetics, of, numerous, drugs, and, may, also, modulate, the, effectiveness, of, drug, therapy])].
[sujeto(['In', 'conclusion,', the, study]), verbo([suggests]), complemento([that, basal, expression, levels, of, the, transporters, are, directly, influenced, by, 'PXR', expression, in, liver, and, 'PBMCs', and, demonstrates, that, 'PBMCs', do, not, qualify, as, surrogate, tissue, for, the, expression, of, the, four, 'ABC-transporters', in, small, intestine, and, liver])].
[sujeto(['Metastatic', renal, cell, carcinomas, '(', 'mRCC)', are, highly, vascularized, tumors, that, are, a, paradigm, for, the, treatment, with, antiangiogenesis, drugs]), verbo([targeting]), complemento([the, vascular, endothelial, growth, factor, '(', 'VEGF)', pathway])].
[sujeto(['The', available, drugs]), verbo([increase]), complemento([the, time, to, progression, but, are, not, curative, and, the, patients, eventually, relapse])].
[sujeto(['In', this, study, we]), verbo([have]), complemento([focused, our, attention, on, the, molecular, mechanisms, leading, to, resistance, to, 'sunitinib,', the, first, line, treatment, of, mRCC])].
[sujeto(['At', these, 'concentrations,', sunitinib, accumulated, in, 'lysosomes,', which, downregulated, the, activity, of, the, lysosomal, protease, 'CTSB', '(', cathepsin, 'B)', and]), verbo([led]), complemento([to, incomplete, autophagic, flux])].
[sujeto(['Amino', acid, deprivation, initiates, autophagy]), verbo([enhanced]), complemento([sunitinib, resistance, through, the, amplification, of, autolysosome, formation])].
[sujeto(['Sunitinib']), verbo([stimulated]), complemento([the, expression, of, 'ABCB1', '(', 'ATP-binding', 'cassette,', 'sub-family', 'B', '[', 'MDR/TAP],', member, 1, ')', ',', which, participates, in, the, accumulation, of, the, drug, in, autolysosomes, and, favor, its, cellular, efflux])].
[sujeto(['Proteasome', inhibitors, also]), verbo([induced]), complemento([the, death, of, resistant, cells, suggesting, that, the, 'ubiquitin-proteasome', system, compensates, inhibition, of, autophagy, to, maintain, a, cellular, homeostasis])].
[sujeto(['Based', on, our, results, we, propose, a, new, therapeutic, approach, combining, sunitinib, with, molecules, that]), verbo([prevent]), complemento([lysosomal, accumulation, or, inhibit, the, proteasome])].
[sujeto(['Phenothiazines']), verbo([have]), complemento([anticancer, properties, and, are, able, to, reverse, the, multidrug, resistance, of, neoplastic, cells, by, inhibiting, the, 'ATP-binding', 'cassette,', 'sub-family', 'B', '(', 'MDR/TAP),', member, 1, protein, '(', 'ABCB1', or, 'P-glycoprotein)', activity])].
[sujeto(['Although', chronic, myeloid, leukemia, '(', 'CML)', treatment]), verbo([has]), complemento([improved, since, the, introduction, of, imatinib, mesylate, '(', 'IM),', cases, of, resistance, have, been, reported])].
[sujeto(['This', resistance]), verbo([has]), complemento([been, associated, with, the, emergence, of, multidrug, resistance, '(', 'MDR)', 'phenotype,', as, a, 'BCR-ABL', independent, mechanism])].
[sujeto(['The', use, of, 2, -, 'DE', coupled, with, a, 'MS', approach, resulted, in, the, identification, of, 36, differentially]), verbo([expressed]), complemento([proteins])].
[sujeto(['In', 'addition,', our, proteomic, approach, identified, candidate, actors]), verbo([involved]), complemento([in, 'resistance,', which, could, lead, to, additional, information, on, 'BCR-ABL-independent', molecular, mechanisms])].
[sujeto(['Their', roles, as]), verbo([targets]), complemento([for, potential, therapies, for, cholangiopathies, are, also, explored])].
[sujeto(['While', many, factors, are]), verbo([involved]), complemento([in, these, complex, signaling, 'pathways,', this, review, emphasizes, the, roles, of, transmembrane, 'G', protein, coupled, receptor, '(', 'TGR5),', farnesoid, 'X', receptor, '(', 'FXR),', ursodeoxycholic, acid, '(', 'UDCA)', and, the, bicarbonate, umbrella])].
[sujeto(['These', findings, all, demonstrate, that, bile, acids, influence, biliary, functions, which, 'can,', in, 'turn,']), verbo([regulate]), complemento([the, cholangiocyte, response, during, pathological, events])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, characterization, of, wild, type, 'MDR3', and, the, 'Q1174E', 'mutant,', which, was, identified, previously, in, a, patient, with, progressive, familial, intrahepatic, cholestasis, type, 3, '(', 'PFIC-3)'])].
[sujeto(['We']), verbo([expressed]), complemento([different, variants, of, 'MDR3', in, the, yeast, 'Pichia', 'pastoris,', purified, the, proteins, via, tandem, affinity, 'chromatography,', and, determined, 'MDR3-specific', 'ATPase', activity, in, the, presence, or, absence, of, phospholipids])].
[sujeto(['The', 'ATPase', activity, of, wild, type, 'MDR3', was]), verbo([stimulated]), complemento([2, -, fold, by, liver, 'PC', or, 1, ',', 2, -, 'dioleoyl-sn-glycero-3-phosphatidylethanolamine', lipids])].
[sujeto(['Similarly,', 'phosphatidylethanolamine,', 'phosphatidylserine,', and, sphingomyelin, lipids, did, not]), verbo([induce]), complemento([an, increase, of, wild, type, 'MDR3', 'ATPase', activity])].
[sujeto(['The', phosphate, analogues, beryllium, fluoride, and, aluminum, fluoride]), verbo([led]), complemento([to, complete, inhibition, of, 'ATPase', 'activity,', whereas, orthovanadate, inhibited, exclusively, the, 'PC-stimulated', 'ATPase', activity, of, 'MDR3'])].
[sujeto(['The', 'Q1174E', mutation, is, located, in, the, 'nucleotide-binding', domain, in, direct, proximity, of, the, leucine, of, the, 'ABC', signature, motif, and, extended, the, 'X', 'loop,', which, is]), verbo([found]), complemento([in, 'ABC', exporters])].
[sujeto(['Our', data, on, the, 'Q1174E', mutant, demonstrated, basal, 'ATPase', 'activity,', but, 'PC', lipids, were, incapable, of]), verbo([stimulating]), complemento(['ATPase', activity, highlighting, the, role, of, the, extended, 'X', loop, in, the, 'cross-talk', of, the, 'nucleotide-binding', domain, and, the, transmembrane, domain])].
[sujeto(['LAN', '(', 'Langereis)', was, officially]), verbo([recognized]), complemento([by, the, 'International', 'Society', of, 'Blood', 'Transfusion', in, 2012, as, being, the, 33, rd, human, blood, group, system])].
[sujeto(['The', exceptional, 'Lan-', people, do, not]), verbo([express]), complemento(['ABCB6', '(', 'Lan', null, 'phenotype),', owing, to, several, different, molecular, mechanisms, affecting, 'ABCB6:', frameshift, leading, to, a, premature, stop, 'codon(deletion,', 'insertion,', or, nonsense, mutation, of, 'nucleotides);missense', 'mutation;', or, intronic, mutation, responsible, for, 'RNA', splicing, defect])].
[sujeto(['Despite', the, 'Lan', 'antigen\'s', being]), verbo([reported]), complemento([to, play, a, key, role, in, erythropoiesis, and, detoxification, of, 'cells,', 'Lan', people, do, not, appear, to, demonstrate, susceptibility, to, any, disease, or, seemingly, physiologic, disorder])].
[sujeto(['Anti-Lan']), verbo([has]), complemento([been, described, as, having, variable, clinical, 'significance,', either, for, hemolytic, transfusion, reactions, '(', none, to, 'severe)', or, hemolytic, disease, of, the, fetus, and, newborn, '(', none, to, 'mild)'])].
[sujeto(['Despite', challenging, conditions]), verbo([caused]), complemento([by, the, scarcity, of, 'Lan-', donors, 'worldwide,', 'Lan-', blood, should, ideally, be, given, to, patients, with, 'anti-Lan,', especially, those, with, a, 'high-titer', antibody])].
[sujeto(['Transcript', levels, of, 'ABCA12,', 'ABCC7', and, 'ABCC8']), verbo([increased]), complemento([in, direction, from, colon, to, rectum])].
[sujeto([a]), verbo([decrease]), complemento([in, direction, from, colon, to, rectum])].
[sujeto(['ATP-binding', cassette, '(', 'ABC)', transporters]), verbo([regulate]), complemento([the, transport, of, a, variety, of, physiologic, substrates])].
[sujeto(['Moreover,', several, human, 'ABC', proteins, are, responsible, for, drug, exclusion, in, 'compound-treated', tumor, 'cells,']), verbo([providing]), complemento([cellular, mechanisms, for, the, development, of, multidrug, resistance, 'and,', 'therefore,', playing, an, important, role, in, malignant, transformation])].
[sujeto(['In', relation, to, normal, 'melanocytes,', 'ABCB3,', 'ABCB6,', 'ABCC2,', 'ABCC4,', 'ABCE1', and, 'ABCF2', were, significantly]), verbo([increased]), complemento([in, melanoma, cell, 'lines,', whereas, 'ABCA7,', 'ABCA12,', 'ABCB2,', 'ABCB4,', 'ABCB5', and, 'ABCD1', showed, lower, expression, levels])].
[sujeto(['The', differentially]), verbo([regulated]), complemento(['ABC', transporters, detected, by, our, approach, may, be, candidate, genes, involved, in, melanoma, 'tumorigenesis,', progression, and, therapy, resistance, and, could, therefore, be, of, great, importance, to, identify, novel, options, for, melanoma, therapy])].
[sujeto(['Mutations', in, the, gene, encoding, the, 'ABCB4', '[', adenosine, triphosphate, '(', 'ATP)-binding', 'cassette,', 'sub-family', 'B', '(', 'MDR/TAP),', member, 4, ']', transporter, lower, phosphatidylcholine, output, into, bile, and, contribute, to, cholesterol, gallstone, formation, by]), verbo([decreasing]), complemento([the, solubility, of, cholesterol, in, bile])].
[sujeto(['Mutations', in, 'ABCB4']), verbo([have]), complemento([been, identified, in, patients, with, low, 'phospholipid-associated', cholelithiasis])].
[sujeto(['The', frequency, of, missense, mutations]), verbo([found]), complemento([in, the, patient, material, was, measured, in, 95, healthy, controls])].
[sujeto(['In', 'addition,', six, missense, mutations, were]), verbo([found]), complemento([in, the, 'ABCB4', 'gene,', and, three, of, these, were, only, present, in, patients])].
[sujeto(['In', our, 'study,', &, 'lt;2%', of, young, gallstone, patients, were]), verbo([found]), complemento([to, be, heterozygous, for, detrimental, 'ABCB4', mutations])].
[sujeto(['Thus,', mutations, in, the, 'ABCB4', gene, are, a, rare]), verbo([cause]), complemento([of, gallstone, disease])].
[sujeto(['Progressive', familial, intrahepatic, cholestasis, type, 3, '(', 'PFIC3)', is, a, rare, hepatic, disease]), verbo([caused]), complemento([by, genetic, mutations, of, 'ABCB4'])].
[sujeto(['In', this, 'study,', we, characterized, 8, 'ABCB4', mutations]), verbo([found]), complemento([in, 'PFIC3', 'patients,', using, in, vitro, molecular, assays])].
[sujeto(['Among', these, 'mutants,', one, mutation, 'A364V,', located, in, intracellular, 'domains,', markedly]), verbo([decreased]), complemento(['MDR3', expression, on, the, plasma, 'membrane,', while, the, others, did, not, affect, the, expression])].
[sujeto(['Our', study]), verbo([provides]), complemento([the, molecular, mechanisms, of, 'ABCB4', mutations, and, may, contribute, to, the, understanding, of, 'PFIC3', pathogenesis, and, the, development, of, a, 'mutation-specific', targeted, treatment, for, 'PFIC3'])].
[sujeto(['Nonsyndromic', cleft, lip, with, or, without, cleft, palate, '(', 'NSCL/P)', is, a, common, craniofacial, birth, defect, that]), verbo([has]), complemento([a, complex, etiology])].
[sujeto(['Genome-wide', association, studies]), verbo([have]), complemento([recently, identified, new, loci, associated, with, 'NSCL/P,', but, these, loci, have, not, been, analyzed, in, a, 'Mexican', 'Mestizo', population])].
[sujeto(['A', complex, etiology, implies, the, presence, of, genetic, 'interactions,', but, there, is, little, available, information, regarding, this, in, 'NSCL/P,', and, no, signaling, pathway]), verbo([has]), complemento([been, clearly, implicated, in, humans])].
[sujeto(['Six', 'SNPs', located, in, paired, box, 7, ',', ventral, anterior, homeobox, 1, ',', sprouty, 'RTK', signaling, antagonist, 2, ',', bone, morphogenetic, protein, 4, ',', and, tropomyosin, 1, genes, were]), verbo([associated]), complemento([with, higher, risks, of, 'NSCL/P', '(', 'P', =, 0.0001, to, 0.04, ')', ;, 2, 'SNPs,', 1, each, in, netrin, 1, and, 'V-maf', avian, musculoaponeurotic, fibrosarcoma, oncogene, homolog, 'B,', were, associated, with, a, lower, risk, of, 'NSCL/P', '(', 'P', =, 0.013, to, 0.03, ')', ;, and, 2, 'SNPs,', 1, each, in, 'ATP', binding, cassette, subfamily, 'A', member, 4, '(', 'ABCA4)', and, 'noggin,', showed, associations, with, 'NSCL/P', that, approached, the, threshold, of, significance, '(', 'P', =, 0.056, to, 0.07, ')'])].
[sujeto(['The', 'SMF', slightly, reduced, cell, viability, and, proliferation, and]), verbo([inhibited]), complemento([the, expression, of, 'CD49d,', 'CD54,', and, 'CD73', but, did, not, damage, 'DNA', integrity])].
[sujeto(['Exposure', to, 0.5, 'T', 'SMF', for, seven, days]), verbo([inhibited]), complemento(['viability,', 'proliferation,', surface, antigen, 'expression,', cytokine, 'secretion,', stem, cell, genetic, marker, 'expression,', and, adipogenic, and, osteogenic, differentiation, but, did, not, affect, the, 'DNA', integrity, in, 'ASCs', with, or, without, 'SPIO', labeling])].
[sujeto(['Total', plasma, cholesterol, '(', 75.9, -, 127.9, 'mg/dL),', 'LDL-', '(', 3.2, -, 12.2, 'mg/dL),', and, 'HDL-', '(', 53.8, -, 98.9, 'mg/dL)', cholesterols]), verbo([increased]), complemento([over, the, 24, wk, study])].
[sujeto(['Aortic', total, cholesterol]), verbo([increased]), complemento([from, 9.72, to, 12.2, 'μg/mg', 'protein,', whereas, aortic, cholesteryl, 'ester,', a, measure, of, atherosclerosis, 'development,', was, less, than, 0.18, 'μg/mg', protein, throughout, the, study])].
[sujeto(['The', mRNA, expression, of, 'ATP-binding', 'cassette,', subfamily, 'B', member, 11]), verbo([increased]), complemento([between, wk, 0, and, 8, but, then, remained, 'unchanged,', suggesting, increased, requirements, for, cholesterol, in, early, growth])].
[sujeto(['These', results, indicate, that, the, consumption, of, a, 'STD', does, not]), verbo([increase]), complemento([atherosclerotic, disease, risk, factors, in, golden, 'Syrian', hamsters, through, 31, wk, of, age])].
[sujeto(['In', one, cell, line, with, acquired, resistance, to, gemcitabine, '(', 'TCC-SUP(r)GEMCI(20)),', 'cross-resistance', seemed, to, be]), verbo([mediated]), complemento([by, 'ABCB1', expression])].
[sujeto(['Non-alcoholic', fatty, liver, disease, '(', 'NAFLD)', is, the, most, common]), verbo([cause]), complemento([of, chronic, liver, disease])].
[sujeto(['Patients', with, 'non-alcoholic', steatohepatitis, '(', 'NASH)']), verbo([have]), complemento([increased, plasmatic, and, hepatic, concentrations, of, bile, acids, '(', 'BA),', suggesting, that, they, can, be, associated, with, the, progression, of, the, disease])].
[sujeto(['Hepatic']), verbo([nuclear]), complemento([receptors, are, known, to, modulate, genes, controlling, 'BA', 'metabolism;', 'thus,', in, this, work, we, aimed, to, compare, the, expression, of, liver, nuclear, receptors, -, farnesoid, 'X', '(', 'FXR),', small, heterodimer, partner, '(', 'SHP)', and, liver, 'X', alpha, '(', 'LXRα)', 'receptors-', and, 'BA', transporters, -, 'sodium+/taurocholate', cotransporting, polypeptide, '(', 'NTCP)', and, bile, salt, export, pump, '(', 'BSEP)-', in, liver, biopsy, samples, of, patients, with, simple, steatosis, '(', 'SS)', and, 'NASH'])].
[sujeto(['Gene', expression, of]), verbo([nuclear]), complemento(['FXR,', 'LXRα,', 'SHP,', 'NTCP', and, 'BSEP', was, analyzed, by, 'real-time', reverse, transcription, polymerase, chain, reaction, and, protein, level, was, quantified, by, western, blot])].
[sujeto(['In', 'contrast,', protein, level, for, 'FXR,', 'SHP', and, 'NTCP', was]), verbo([decreased]), complemento([in, the, 'NASH', patients, vs])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, liver, nuclear, receptors, '(', 'FXR', and, 'SHP)', and, 'BA', transporters, '(', 'NTCP', and, 'BSEP)', are, associated, with, the, progression, of, 'NAFLD'])].
[sujeto(['Single-marker', analyses, revealed, a, significant, association, solely, for, the, rs1045642, polymorphism, '(', 'C/C', genotype, carriers, had]), verbo([increased]), complemento([risk, for, 'AD),', which, remains, significant, after, correction, for, multiple, testing])].
[sujeto(['In', the, past, decade, the, presence, of, 'psychopharmaceuticals,', including, fluoxetine, '(', 'FLU),', in, the, aquatic, environment]), verbo([has]), complemento([been, associated, with, the, increasing, trend, in, human, consumption, of, these, substances])].
[sujeto(['Embryo', development, was, disrupted, at, the, lowest, 'FLU', concentration, tested, '(', 0.0015, 'μM),', which, is, in, the, range, of, concentrations]), verbo([found]), complemento([in, 'WWTP', effluents])].
[sujeto(['Embryos', exposed, to, higher, concentrations, of, 'FLU']), verbo([decreased]), complemento(['Cu/Zn', 'SOD,', and, increased, 'CAT', '(', 0.0015, and, 0.5, 'μM)', enzymatic, activity])].
[sujeto(['Exposure', to, higher, concentrations, of, 'FLU']), verbo([decreased]), complemento([the, expression, of, most, genes, belonging, to, the, detoxification, system, and, upregulated, cat, at, 0.0015, μM, of, 'FLU'])].
[sujeto(['Most', of, the, tested, concentrations, downregulated, 'pparα,', 'pparβ,', 'pparγ,', and, 'raraa,', 'rxraa,', 'rxrab,', rxrbb, rxrgb, and, ahr, gene, expression, while, pxr, was, significantly, up]), verbo([regulated]), complemento([at, all, tested, concentrations])].
[sujeto(['In', 'conclusion,', this, study, shows, that, 'FLU', can, impact, zebrafish, embryo, 'development,', at, concentrations]), verbo([found]), complemento([in, effluents, of, 'WWTPs,', concomitantly, with, changes, in, antioxidant, 'enzymes,', and, the, transcription, of, key, genes, involved, in, detoxification, and, development])].
[sujeto(['These']), verbo([finding]), complemento([raises, additional, concerns, supporting, the, need, to, monitor, the, presence, of, this, compound, in, aquatic, reservoirs])].
[sujeto(['Recently', it]), verbo([has]), complemento([been, shown, that, 'HCC', promotion, depends, on, 'Toll-like', receptor, '(', 'TLR)', 4])].
[sujeto(['After', 'DEN', 'challenge,', 'apoptosis,', proliferation, and, inflammatory, markers, are]), verbo([decreased]), complemento([in, 'TLR4-deficient', in, comparison, to, 'TLR4-sufficient', mice])].
[sujeto(['Consistent', with, these, 'effects,', selective, digestive, tract, decontamination, in, 'ABCB4-/-', mice, also]), verbo([led]), complemento([to, reduced, tumor, size, and, number, after, 'DEN'])].
[sujeto(['Resistance', to, 'taxane-based', therapy, in, breast, cancer, patients, is, a, major, clinical, problem, that, may, be, addressed, through, insight, of, the, genomic, alterations]), verbo([leading]), complemento([to, taxane, resistance, in, breast, cancer, cells])].
[sujeto(['Two', human, breast, cancer, in, vitro, models, '(', 'MCF-7', and, 'MDA-MB-231)', of, the, 'step-wise', acquisition, of, docetaxel, resistance, were, developed, by, exposing, cells, to, 18, gradually]), verbo([increasing]), complemento([concentrations, of, docetaxel])].
[sujeto(['Whole', exome, sequencing, performed, at, five, successive, stages, during, this, process, was, used, to, identify, single, point, mutational, 'events,', 'insertions/deletions', and, copy, number, alterations]), verbo([associated]), complemento([with, the, acquisition, of, docetaxel, resistance])].
[sujeto(['A', number, of, genomic, changes, were]), verbo([found]), complemento([to, be, undergoing, evolutionary, 'selection,', some, of, which, were, likely, to, be, functional])].
[sujeto(['MCF-7', cell, acquired, several, copy, number]), verbo([gains]), complemento([on, chromosome, 7, ',', including, 'ABC', transporter, 'genes,', including, 'ABCB1', and, 'ABCB4,', as, well, as, 'DMTF1,', 'CLDN12,', 'CROT,', and, 'SRI'])].
[sujeto(['For', 'MDA-MB-231', numerous, copy, number]), verbo([losses]), complemento([on, chromosome, 'X', involving, more, than, 30, genes, was, observed])].
[sujeto(['At', higher, docetaxel, concentration, 'MCF-7', subclones, exhibited, a, copy, number]), verbo([loss]), complemento([in, 'E2F4,', and, the, gene, encoding, this, important, transcription, factor, was, 'down-regulated', in, 'MCF-7', resistant, cells])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, no, single, genomic, event, sufficiently, predicts, resistance, to, 'docetaxel,', but, require, genomic, alterations, affecting, multiple, pathways, that, in, concert, establish, the, final, resistance, stage])].
[sujeto(['To']), verbo([gain]), complemento([insight, into, the, protein, molecules, associated, with, 'Cd', toxicity, in, placenta, and, explore, their, roles, in, 'Cd', 'transportation,', a, reproductive, animal, experiment, was, carried, out, using, 'Sprague-Dawley', rats])].
[sujeto(['The', 'DIGE', assay, identified, 15, protein, spots, that, were, differentially]), verbo([expressed]), complemento([with, a, greater, than, 1.5, -, fold, change, in, placenta, of, 'Cd-treated', rats, compared, to, the, control, rats])].
[sujeto(['These', results, indicated, that, 'down-regulation', of, 'ABCG2', and, 'ABCB4', transporters, may]), verbo([regulate]), complemento(['Cd', across, through, placenta, and, thus, affect, the, in, vivo, toxic, effect, of, 'Cd', to, fetus])].
[sujeto(['In', various, genetic, association, 'studies,', potential, genetic, risk, markers, for, 'ACT']), verbo([have]), complemento([been, identified])].
[sujeto(['RARG', 'rs2229774,', 'SLC28A3', rs7853758, and, 'UGT1A6', rs17863783, variants, currently]), verbo([have]), complemento([the, strongest, and, the, most, consistent, evidence, for, association, with, 'ACT'])].
[sujeto(['Genetic', variants, in, 'ABCC1,', 'ABCC2,', 'ABCC5,', 'ABCB1,', 'ABCB4,', 'CBR3,', 'RAC2,', 'NCF4,', 'CYBA,', 'GSTP1,', 'CAT,', 'SULT2B1,', 'POR,', 'HAS3,', 'SLC22A7,', 'SCL22A17,', 'HFE', and, 'NOS3']), verbo([have]), complemento([also, been, associated, with, 'ACT,', but, require, additional, validation])].
[sujeto(['Based', on, an, overall, risk, 'stratification,', taking, into, account, genetic, and, clinical, risk, 'factors,', we, recommend, a, number, of, management, options, including]), verbo([increased]), complemento([frequency, of, echocardiogram, 'monitoring,', 'follow-up,', as, well, as, therapeutic, options, within, the, current, standard, of, clinical, practice])].
[sujeto(['Existing', evidence, demonstrates, that, genetic, factors]), verbo([have]), complemento([the, potential, to, improve, the, discrimination, between, individuals, at, higher, and, lower, risk, of, 'ACT'])].
[sujeto(['To', estimate, the, frequency, of, mutations]), verbo([involving]), complemento([exons, 6, ',', 8, and, 9, of, 'Adenosine', 'triphosphate-binding', 'cassette,', subfamily, 'B,', member, 4, '(', 'ABCB4)', gene, among, children, with, progressive, intrahepatic, cholestasis, with, high, 'γ-GT', activity, '(', 'PFIC3)'])].
[sujeto(['WISH', showed, that, abcb4, gene, was]), verbo([expressed]), complemento([in, the, guts, of, zebrafish, embryos])].
[sujeto(['Doxorubicin']), verbo([increases]), complemento([the, expression, of, abcb4, gene, in, zebrafish, embryos])].
[sujeto(['In', a, first, 'approach,', constitutive, transcription, of, key, genes]), verbo([involved]), complemento([in, detoxification, was, determined])].
[sujeto(['Simvastatin']), verbo([acted]), complemento([as, a, weak, inhibitor, of, 'ABC', proteins, and, increased, 'EROD', and, 'GST', 'activity,', whereas, 'Cu/ZnSOD', and, 'CAT', activity, were, decreased])].
[sujeto(['To', study, the, 'interleukin-1', '(', 'IL-1)', pathway, as, a, therapeutic]), verbo([target]), complemento([for, liver, fibrosis, in, vitro, and, in, vivo, using, the, 'ATP-binding', cassette, transporter, 'b4(-/-)', '(', 'Abcb4(-/-))', mouse, model])].
[sujeto(['Murine', 'HSCs', were]), verbo([stimulated]), complemento([with, up, to, 1, 'ng/mL', 'IL-1β', with, or, without, 2.5, 'μg/mL', 'Anakinra,', an, 'IL-1', receptor, 'antagonist,', respectively])].
[sujeto(['Reduced', liver, fibrosis, was]), verbo([associated]), complemento([with, significantly, lower, levels, of, 'F4/80', mRNA, expression, '(', 1, ±, 0.28, vs, 0.71, ±, 0.41, 'fold,', 'respectively;', n, =, 12, -, 15, ;, 'P', &, 'lt;', 0.05, ;, 'Mann-Whitney', 'U-test)', and, significantly, lower, 'IL-1β', mRNA, expression, levels, '(', 1, ±, 0.38, vs, 0.44, ±, 0.26, 'fold,', 'respectively;', n, =, 13, -, 15, ;, 'P', &, 'lt;', 0.001, ;, 'Mann-Whitney', 'U-test)'])].
[sujeto(['In', 'vitro,', the, administration, of, 'IL-1β', resulted, in, a, significant]), verbo([increase]), complemento([in, 'HSC', proliferation, '[', 0.94, ±, 0.72, arbitrary, units, '(', 'A'])].
[sujeto([at, an, 'IL-1β', concentration, of, 1, 'ng/mL;', in, samples, from, n, =, 6, donor, 'animals;', 'P', &, 'lt;', 0.001, ;, 'ANOVA)']), verbo([suggesting]), complemento([an, 'anti-proliferative', effect, of, this, clinically, approved, 'IL-1', receptor, antagonist])].
[sujeto(['IL-1β', expression, is]), verbo([associated]), complemento([with, the, degree, of, liver, fibrosis, in, 'Abcb4(-/-)', mice, and, promotes, 'HSC', proliferation])].
[sujeto(['Multidrug', resistance, protein, 3, '(', 'MDR3,', 'ABCB4)', is, a, hepatocellular, membrane, protein, that]), verbo([mediates]), complemento([biliary, secretion, of, phosphatidylcholine])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, the, 'disease-associated', mutations, p])].
[sujeto(['A934T', resulted, in, retention, of, 'ABCB4', in, the, endoplasmic, 'reticulum,', thus, failing, to]), verbo([target]), complemento([the, plasma, membrane])].
[sujeto(['The', delivery, of, these, mutants, to, the, plasma, membrane, was, accompanied, by, a, switch, in, the, ratio, of, mature, to, inmature, protein, 'forms,']), verbo([leading]), complemento([to, a, predominant, expression, of, the, mature, protein])].
[sujeto(['Collectively,', these, data, indicate, that, the, functionality, of, selected, 'trafficking-defective', 'ABCB4', mutants, can, be, recovered, by, chemical, chaperones, through, restoration, of, membrane, 'localization,']), verbo([suggesting]), complemento([a, potential, treatment, for, patients, carrying, such, mutations])].
[sujeto(['Earlier', studies]), verbo([have]), complemento([shown, that, perfluorooctane, sulfonate, '(', 'PFOS)', increases, the, toxicity, of, other, chemicals, by, enhancing, their, uptake, by, cells, and, tissues])].
[sujeto(['The', present, study, aimed, at, testing, whether, the, underlying, mechanism, of]), verbo([enhanced]), complemento([uptake, of, chemicals, by, zebrafish, '(', 'Danio', 'rerio)', embryos, in, the, presence, of, 'PFOS', is, by, interference, of, this, compound, with, the, cellular, efflux, transporter, 'Abcb4'])].
[sujeto(['Upon', 90, min, exposure, of, 24, hpf, embryos, to, 1, μM, 'RhB', and, different, 'PFOS', concentrations, '(', 3, -, 300, 'μM)', accumulation, of, 'RhB', in, zebrafish, was]), verbo([increased]), complemento([by, up, to, 11.9, -, fold, compared, to, 'controls,', whereas, 'RhB', increases, in, verapamil, treatments, were, 1.7, -, fold])].
[sujeto(['Co-administration', of, 'PFOS', and, vinblastine, in, exposures, from, 0, to, 48, hpf, resulted, in, higher, 'vinblastine-caused', mortalities, in, zebrafish, embryos, indicating]), verbo([increased]), complemento([uptake, of, this, compound])].
[sujeto(['PFOS']), verbo([lead]), complemento([to, a, 'concentration-dependent', decrease, of, the, 'verapamil-stimulated', 'Abcb4', 'ATPase', 'activity;', at, higher, 'PFOS', concentrations, '(', 250, ',', 500, 'μM),', also, the, basal, 'ATPase', activity, was, lowered, indicating, 'PFOS', to, be, an, 'Abcb4', inhibitor])].
[sujeto(['In', exposures, of, 48, hpf, embryos, to, a, very, high, 'RhB', concentration, '(', 200, 'μM),', accumulation, of, 'RhB', in, embryo, tissue, and, adsorption, to, the, chorion, were]), verbo([increased]), complemento([in, the, presence, of, 50, or, 100, μM, 'PFOS'])].
[sujeto(['In', 'conclusion,', the, results, indicate, that, 'PFOS']), verbo([acts]), complemento([as, inhibitor, of, zebrafish, 'Abcb4;', 'however,', the, exceptionally, large, 'PFOS-caused', effect, amplitude, of, 'RhB', accumulation, in, the, 1, μM, 'RhB', experiments, and, the, clear, 'PFOS', effects, in, the, experiments, with, 200, μM, 'RhB', suggest, that, an, additional, mechanism, appears, to, be, responsible, for, the, potential, of, 'PFOS', to, enhance, uptake, of, 'Abcb4', substrates])].
[sujeto(['ABCB4/MDR3,', a, member, of, the, 'ABC', 'superfamily,', is, an, 'ATP-dependent', phosphatidylcholine, translocator]), verbo([expressed]), complemento([at, the, canalicular, membrane, of, hepatocytes])].
[sujeto(['Defects', in, the, 'ABCB4', gene, are]), verbo([associated]), complemento([with, rare, biliary, diseases])].
[sujeto(['The', stability, of, several, 'ABC', transporters, is]), verbo([regulated]), complemento([through, their, binding, to, 'PDZ', '(', 'PSD95/DglA/ZO-1)', 'domain-containing', proteins])].
[sujeto(['We']), verbo([found]), complemento([that, truncation, of, the, 'QNL', motif, decreased, the, stability, of, 'ABCB4', in, 'HepG2-transfected', cells])].
[sujeto(['EBP50,', a, 'PDZ', protein, highly]), verbo([expressed]), complemento([in, the, 'liver,', strongly, colocalized, and, coimmunoprecipitated, with, 'ABCB4,', and, this, interaction, required, the, 'QNL', motif])].
[sujeto(['Down-regulation', of, 'EBP50', by, siRNA, or, by, expression, of, an, 'EBP50', 'dominant-negative', mutant]), verbo([caused]), complemento([a, significant, decrease, in, the, level, of, 'ABCB4', protein, 'expression,', and, in, the, amount, of, 'ABCB4', localized, at, the, canalicular, membrane])].
[sujeto(['Choline', kinase, α, '(', 'CHKα)', plays, a, crucial, role, in, the, regulation, of, membrane, phospholipid, synthesis, and]), verbo([has]), complemento([oncogenic, properties, in, vitro])].
[sujeto(['We']), verbo([have]), complemento([analyzed, the, expression, of, 'CHKα', in, cell, lines, derived, from, pancreatic, ductal, adenocarcinoma, '(', 'PDAC)', and, have, found, increased, 'CHKα', 'expression,', associated, with, differentiation])].
[sujeto(['Accordingly,', 'CHKα', knockdown]), verbo([led]), complemento([to, reduced, drug, sensitivity])].
[sujeto(['In', 'addition,', we]), verbo([found]), complemento([that, 'gemcitabine-resistant', 'PDAC', cells, displayed, enhanced, sensitivity, to, 'CHKα', inhibition, 'and,', in, 'vitro,', 'MN58b', had, additive, or, synergistic, effects, with, 'gemcitabine,', 5, -, 'fluorouracil,', and, 'oxaliplatin,', three, active, drugs, in, the, treatment, of, 'PDAC'])].
[sujeto(['Using', tissue, 'microarrays,', 'CHKα', was]), verbo([found]), complemento([to, be, overexpressed, in, 90, '%', of, pancreatic, tumors])].
[sujeto(['While', cytoplasmic, 'CHKα', did, not, relate, to, 'survival,']), verbo([nuclear]), complemento(['CHKα', distribution, was, observed, in, 43, '%', of, samples, and, was, associated, with, longer, 'survival,', especially, among, patients, with, 'well/moderately', differentiated, tumors])].
[sujeto(['To', identify, the, mechanisms]), verbo([involved]), complemento([in, resistance, to, 'CHKα', 'inhibitors,', we, cultured, 'IMIM-PC-2', cells, with, increasingly, higher, concentrations, of, 'MN58b', and, isolated, a, subline, with, a, 30, -, fold, higher, 'IC50'])].
[sujeto(['RNA-Seq', analysis, identified, upregulation, of, 'ABCB1', and, 'ABCB4', multidrug, resistance, 'transporters,', and, functional, studies, confirmed, that, their, upregulation, is, the, main, mechanism]), verbo([involved]), complemento([in, resistance])].
[sujeto(['Common']), verbo([causes]), complemento([of, cholestasis, were, excluded, and, liver, histologies, were, nonspecific])].
[sujeto(['Disease', and, mechanisms, that, determine, cholestasis, are, complex, and, their, understanding, may]), verbo([provide]), complemento([new, therapeutics])].
[sujeto(['Administration', of, 'HSD', to, 'HHTg', rats]), verbo([led]), complemento([to, increased, triglyceride, deposition, in, the, liver])].
[sujeto(['HSD', reduced, 'BF', as, a, consequence, of]), verbo([decreased]), complemento([biliary, secretion, of, bile, acids, '(', 'BA)', and, glutathione])].
[sujeto(['Boldine', partially, attenuated, cholestatic, effect, of, 'HSD', by, promotion, of, biliary, secretion, of, 'BA', through, 'up-regulation', of, 'Bsep', and, 'Ntcp,', and, by]), verbo([increase]), complemento([in, biliary, secretion, of, glutathione, as, a, consequence, of, its, increased, hepatic, disposition])].
[sujeto(['This', study, demonstrates, mechanisms, of, impaired, 'BF', during, nonalcoholic, fatty, liver, disease]), verbo([induced]), complemento([by, 'HSD'])].
[sujeto(['Altered', function, of, responsible, transporters]), verbo([suggests]), complemento([also, potential, for, changes, in, kinetics, of, 'drugs,', which, may, complicate, pharmacotherapy, in, subjects, with, high, intake, of, 'sucrose,', and, with, fatty, liver, disease])].
[sujeto(['Sucrose']), verbo([induced]), complemento([alterations, in, 'BF', may, be, alleviated, by, administration, of, boldine])].
[sujeto(['Three', distinct, forms, are, 'described:', 'FIC1', and, 'FIC2,']), verbo([associated]), complemento([with, 'low/normal', 'GGT', level, in, 'serum,', which, are, caused, by, impaired, bile, salt, secretion, due, to, defects, in, 'ATP8B1', encoding, the, 'FIC1', protein, and, defects, in, 'ABCB11', encoding, bile, salt, export, pump, 'protein,', 'respectively;', 'FIC3,', linked, to, high, 'GGT', 'level,', involves, impaired, biliary, phospholipid, secretion, due, to, defects, in, 'ABCB4,', encoding, multidrug, resistance, 3, protein])].
[sujeto(['Different', mutations, in, these, genes, may]), verbo([cause]), complemento([either, a, progressive, familial, intrahepatic, cholestasis, '(', 'PFIC)', or, a, benign, recurrent, intrahepatic, cholestasis, '(', 'BRIC)'])].
[sujeto(['Thirty-four', different, mutations, were]), verbo([found]), complemento([of, which, 11, were, novel])].
[sujeto(['Estrogen', sulfotransferase, '(', 'EST)', is, responsible, for, the, sulfoconjugation, of, 'estrogens,', thereby, changing, their, physical, properties, and]), verbo([preventing]), complemento([their, action, via, the, estrogen, receptors])].
[sujeto(['In', granulosa, 'cells,', a, significant]), verbo([increase]), complemento([in, 'EST', transcript, was, observed, 30, -, 39, h, after, hCG])].
[sujeto(['Similarly,', 'ABCC1', transcript, levels, were]), verbo([induced]), complemento([in, granulosa, cells, 12, -, 39, h, after, hCG])].
[sujeto(['The']), verbo([increase]), complemento([in, 'EST', and, 'ABCC1', transcripts, observed, in, granulosa, cells, was, reflected, in, preparations, of, intact, follicle, 'walls,', suggesting, that, the, granulosa, cell, layer, contributes, the, majority, of, 'EST', and, 'ABCC1', expression, in, preovulatory, follicles])].
[sujeto(['The', present, study, demonstrates, that, follicular, luteinization, is, accompanied, not, only, by, a]), verbo([decrease]), complemento([in, 17, 'beta-estradiol', biosynthesis, but, also, by, an, increase, in, expression, of, genes, responsible, for, estrogen, inactivation, and, elimination, from, granulosa, 'cells,', such, as, 'EST', and, 'ABCC1,', respectively])].
[sujeto(['The', 190, -, kDa, 'ATP-binding', cassette, '(', 'ABC)', multidrug, resistance, protein, 1, '(', 'MRP1)', encoded, by, the, 'MRP1/ABCC1', gene]), verbo([mediates]), complemento([the, active, cellular, efflux, of, 'glucuronide,', glutathione, and, sulfate, conjugates])].
[sujeto(['It', can, also]), verbo([confer]), complemento([resistance, to, a, diverse, spectrum, of, chemotherapeutic, agents, and, transport, a, variety, of, toxicants])].
[sujeto(['Immunoblotting', experiments, showed, that, all, mutant, proteins, were]), verbo([expressed]), complemento([at, levels, comparable, to, 'wild-type', 'MRP1'])].
[sujeto(['Vesicular', transport, assays, revealed, that, the, 'Ala989Thr', mutation]), verbo([caused]), complemento([a, significant, decrease, in, estradiol, 17, 'beta-glucuronide', transport, due, to, a, decrease, in, apparent, affinity, '(', 'Km)', for, this, organic, anion])].
[sujeto(['In', 'conclusion,', our, data]), verbo([suggest]), complemento([that, none, of, the, 'MRP1/ABCC1', variants, studied, are, likely, by, themselves, to, have, major, deleterious, effects, in, healthy, 'individuals,', and, the, 'SIFT', and, 'PolyPhen', algorithms, appear, to, be, poor, predictors, of, the, phenotypic, consequences, of, these, 'MRP1', mutations, at, least, in, vitro])].
[sujeto(['In', addition, to, being, 'substrates,', many, 'glucuronide,', glutathione, and, sulfate, conjugates, can, also]), verbo([inhibit]), complemento([the, transport, activities, of, these, 'MRP-related', 'proteins,', sometimes, in, a, glutathione, '(', 'GSH)-dependent', manner])].
[sujeto(['Three', glucuronide, metabolites, of, this, compound]), verbo([have]), complemento([been, identified, in, 'vivo:', 'nicotine-N-glucuronide,', 'cotinine-N-glucuronide', and, 'trans-hydroxycotinine-O-glucuronide'])].
[sujeto(['In', this, 'study,', we, first, chemically, synthesized, 'trans-hydroxycotinine-O-glucuronide', and, then, tested, the, ability, of, this, 'compound,', 'nicotine-N-glucuronide', and, 'cotinine-N-glucuronide', to]), verbo([modulate]), complemento([the, vesicular, transport, of, several, organic, anions, by, 'MRP1,', 'MRP2', and, 'MRP3'])].
[sujeto(['MRP3-mediated', transport, of, 17, 'beta-estradiol', 17, -, '(', 'beta-d-glucuronide)', and, methotrexate, were, partially]), verbo([inhibited]), complemento([by, 'trans-hydroxycotinine-O-glucuronide', '(', 300, 'microM)', '(', by, 70, '%', and, 50, '%', ',', 'respectively),', whereas, 'nicotine-N-glucuronide', and, 'cotinine-N-glucuronide', had, no, effect])].
[sujeto(['Multidrug', resistance, proteins, '(', 'MRPs)', are, 'ATP-dependent', export, pumps, that]), verbo([mediate]), complemento([the, export, of, organic, anions])].
[sujeto(['Bimane-glutathione', efflux]), verbo([increased]), complemento([with, time, and, &, 'gt;85%', of, the, conjugate, was, exported, after, 15, min])].
[sujeto(['The', determination, that, 'ABCC4', can]), verbo([mediate]), complemento([the, transport, of, glucuronide, and, glutathione, conjugates, indicates, that, 'ABCC4', may, play, a, role, in, the, cellular, extrusion, of, 'Phase', 'II', detoxification, metabolites])].
[sujeto(['The', multidrug, resistance, 'protein,', 'MRP1', '(', 'ABCC1),', is, an, 'ATP-binding', cassette, transporter, that]), verbo([confers]), complemento([resistance, to, chemotherapeutic, agents])].
[sujeto(['MRP1', also]), verbo([mediates]), complemento([transport, of, organic, anions, such, as, leukotriene, 'C(4)', '(', 'LTC(4)),', 17, 'beta-estradiol', 17, -, '(', 'beta-d-glucuronide)', '(', 'E(2)17betaG),', estrone, 3, -, 'sulfate,', methotrexate, '(', 'MTX),', and, 'GSH'])].
[sujeto(['All', mutants, were]), verbo([expressed]), complemento([in, transfected, human, embryonic, kidney, cells, at, levels, comparable, with, 'wild-type', 'MRP1,', and, confocal, microscopy, showed, that, they, were, correctly, routed, to, the, plasma, membrane])].
[sujeto(['E(2)17betaG', transport, was, not]), verbo([inhibited]), complemento([by, 'LTC(4)', and, could, not, be, photolabeled, with, '[', '(', 3, ')', 'H]LTC(4),', indicating, that, the, 'MRP1-Lys(332)', mutants, no, longer, bound, this, substrate])].
[sujeto(['Kinetic', analyses, showed, that, 'V(max)', '(', 'LTC(4))', of, these, mutants, was]), verbo([decreased]), complemento([but, 'K(m)', was, unchanged])].
[sujeto(['In', contrast, to, the, selective]), verbo([loss]), complemento([of, 'LTC(4)', transport, in, the, 'Lys(332)', and, 'His(335)', 'mutants,', the, 'MRP1-Asp(336)', mutants, no, longer, transported, 'LTC(4),', 'E(2)17betaG,', estrone, 3, -, 'sulfate,', or, 'GSH,', and, transport, of, 'MTX', was, reduced, by, &, 'gt;50%'])].
[sujeto(['The', importance, of, 'Lys(332)', and, 'His(335)', in, determining, substrate, specificity, and, of, 'Asp(336)', in, overall, transport, activity]), verbo([suggests]), complemento([that, such, interactions, are, critical, for, the, binding, and, transport, of, 'LTC(4)', and, other, substrates, of, 'MRP1'])].
[sujeto([',', 'Cry', and, 'Cyt', 'toxins)', derived, from, 'Bacillus', thuringiensis, '(', 'Bt)']), verbo([have]), complemento([been, useful, alternatives, to, chemical, insecticides, for, the, control, of, 'P'])].
[sujeto([xylostella]), verbo([has]), complemento([already, been, reported])].
[sujeto([xylostella, larvae, revealed, 31, differentially]), verbo([expressed]), complemento(['proteins,', 21, of, which, were, identified, by, mass, spectrometry])].
[sujeto(['Of', these, identified, 'proteins,', the, following, fell, into, diverse, eukaryotic, orthologous, group, '(', 'KOG)', subcategories, may, be]), verbo([involved]), complemento([in, 'Cry1Ac', resistance, in, 'P'])].
[sujeto(['Collectively,', these, proteomic, results]), verbo([increase]), complemento([our, understanding, of, the, molecular, resistance, mechanisms, to, 'Bt', 'Cry1Ac', toxin, in, 'P'])].
[sujeto(['In', this, study, we, investigated, the, effect, of, linsitinib, on, the, reversal, of, multidrug, resistance, '(', 'MDR)']), verbo([mediated]), complemento([by, the, overexpression, of, the, 'ATP-binding', cassette, '(', 'ABC)', subfamily, members, 'ABCB1,', 'ABCG2,', 'ABCC1', and, 'ABCC10'])].
[sujeto(['Linsitinib', moderately]), verbo([enhanced]), complemento([the, cytotoxicity, of, vincristine, in, cell, lines, overexpressing, 'ABCB1,', whereas, it, did, not, alter, the, cytotoxicity, of, substrates, of, 'ABCC1'])].
[sujeto(['Furthermore,', linsitinib, significantly]), verbo([increased]), complemento([the, intracellular, accumulation, and, decreased, the, efflux, of, '[', '(', 3, ')', 'H]-MX', in, 'ABCG2-overexpressing', cells, and, '[', '(', 3, ')', 'H]-paclitaxel', in, 'ABCC10-overexpressing', cells])].
[sujeto(['Moreover,', linsitinib]), verbo([stimulated]), complemento([the, 'ATPase', activity, of, 'ABCG2', in, a, 'concentration-dependent', manner])].
[sujeto(['Overall,', our, study]), verbo([suggests]), complemento([that, linsitinib, attenuates, 'ABCG2-', and, 'ABCC10-mediated', 'MDR', by, directly, inhibiting, their, function, as, opposed, to, altering, 'ABCG2', or, 'ABCC10', protein, expression])].
[sujeto(['When']), verbo([interacting]), complemento([with, estrogen, 'receptors,', 'ZEN', leads, to, animal, fertility, disturbances, and, other, reproductive, pathologies])].
[sujeto(['We', focused, on, the, expression, and, cellular, localization, of, major, 'ABC', transporters]), verbo([expressed]), complemento([in, adult, rat, 'testis,', comparing, 'ZEN', effects, with, those, of, 'Estradiol', 'Benzoate', '(', 'EB)', neonatal, exposure])].
[sujeto(['ZEN', and, 'EB', effects, were]), verbo([inhibited]), complemento([by, in, vitro, addition, of, the, pure, 'anti-estrogen', 'ICI', 182.78, ',', suggesting, the, at, least, partial, implication, of, 'ZEN', estrogenic, activity, in, these, modulations])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, 'ZEN', neonatal, exposure, could, affect, the, exposure, of, testis, to, 'ABC', transporter, 'substrates,', and, negatively, influence, spermatogenesis, and, male, fertility])].
[sujeto(['Stemlike', cells]), verbo([have]), complemento([been, isolated, by, their, ability, to, efflux, 'Hoechst', 33342, dye, and, are, called, the, side, population, '(', 'SP)'])].
[sujeto(['We', evaluated, the, effect, of, axitinib, on]), verbo([targeting]), complemento([cancer, stemlike, cells, and, enhancing, the, efficacy, of, chemotherapeutical, agents])].
[sujeto(['We']), verbo([found]), complemento([that, axitinib, enhanced, the, cytotoxicity, of, topotecan, and, mitoxantrone, in, 'SP', cells, sorted, from, human, lung, cancer, 'A549', cells, and, increased, cell, apoptosis, induced, by, chemotherapeutical, agents])].
[sujeto(['Moreover,', axitinib, particularly]), verbo([inhibited]), complemento([the, function, of, adenosine, triphosphate, '(', 'ATP)-binding', cassette, subfamily, 'G', member, 2, '(', 'ABCG2)', and, reversed, 'ABCG2-mediated', multidrug, resistance, '(', 'MDR)', in, vitro])].
[sujeto(['In', nude, mice, bearing, 'ABCG2-overexpressing', 'S1-M1-80', 'xenografts,', axitinib, significantly]), verbo([enhanced]), complemento([the, antitumor, activity, of, topotecan, without, causing, additional, toxicity])].
[sujeto(['Taken', 'together,', these, data]), verbo([suggest]), complemento([that, axitinib, particularly, targets, cancer, stemlike, cells, and, reverses, 'ABCG2-mediated', drug, resistance, by, inhibiting, the, transporter, activity, of, 'ABCG2'])].
[sujeto(['To']), verbo([gain]), complemento([insight, into, the, disease, 'mechanism,', serum, metabolite, changes, were, assessed, using, metabolomics, with, ultraperformance, liquid, 'chromatography-electrospray', 'ionization-quadrupole', 'time-of-flight', mass, spectrometry, and, a, conventional, mouse, 'NASH', model, induced, by, a, 'methionine-', and, 'choline-deficient', '(', 'MCD)', diet])].
[sujeto(['Significant']), verbo([decreases]), complemento([in, serum, 'palmitoyl-,', 'stearoyl-,', and, 'oleoyl-lysophosphatidylcholine', '(', 'LPC)', and, marked, increases, in, 'tauro-β-muricholate,', taurocholate, and, 12, -, hydroxyeicosatetraenoic, acid, '(', 12, -, 'HETE)', were, detected, in, mice, with, 'NASH'])].
[sujeto(['In', agreement, with, these, metabolite, 'changes,', hepatic, mRNAs, encoding, enzymes, and, proteins]), verbo([involved]), complemento([in, 'LPC', degradation, '(', lysophosphatidylcholine, acyltransferase, '[', 'Lpcat]', 1, -, 4, ')', ',', basolateral, bile, acid, excretion, '(', 'ATP-binding', cassette, subfamily, 'C', member, '[', 'Abcc]', 1, /, 4, /, 5, and, organic, solute, transporter, 'β),', and, 12, -, 'HETE', synthesis, '(', arachidonate, 12, -, 'lipoxygenase)', were, significantly, 'up-regulated'])].
[sujeto(['Furthermore,', tumor, necrosis, 'factor-α', and, transforming, growth, 'factor-β1']), verbo([induced]), complemento([the, expression, of, 'Lpcat2/4', and, 'Abcc1/4', and, 'down-regulated', 'Slc10a1', and, 'Slco1a1', in, primary, 'hepatocytes,', suggesting, an, association, between, the, changes, in, serum, 'LPC', and, bile, acids, and, proinflammatory, cytokines])].
[sujeto(['Finally,', induction, of, hepatitis, in, 'ob/ob', mice, by, 'D-galactosamine', injection]), verbo([led]), complemento([to, similar, changes, in, serum, metabolites, and, related, gene, expression])].
[sujeto(['Phospholipid', and, bile, acid, metabolism, is, disrupted, in, 'NASH,', likely, due, to]), verbo([enhanced]), complemento([hepatic, inflammatory, signaling])].
[sujeto(['This', study, was, designed, to, test, the, hypothesis, that, 'single-nucleotide', polymorphisms, '(', 'SNPs)', in, methotrexate, transmembrane, transporters, and, adenosine, receptors, are]), verbo([associated]), complemento([with, efficacy, 'and/or', toxicity, of, the, drug])].
[sujeto(['SNPs', within, the, efflux, transporter, genes, 'ABCC1', '(', 'ATP-binding', 'cassette,', subfamily, 'C,', member, 1, ')', and, 'ABCG2', '(', 'ATP-binding', 'cassette,', subfamily, 'G,', member, 2, ')', are]), verbo([associated]), complemento([with, good, response, to, methotrexate, therapy, in, patients, with, 'psoriasis;', the, former, gene, was, also, associated, with, the, onset, of, toxicity])].
[sujeto(['KCNJ11', '(', potassium, inwardly, rectifying, 'channel,', subfamily, 'J,', member, 11, ')', and, 'ABCC8', '(', 'ATP-binding', 'cassette,', subfamily, 'C', '(', 'CFTR/MRP),', member, 8, ')']), verbo([have]), complemento([been, studied, for, association, with, type, 2, diabetes, in, various, ethnic, populations, with, contradictory, results])].
[sujeto(['However,', rs5219, was, not]), verbo([associated]), complemento([with, type, 2, diabetes, in, the, 'Chinese', 'Han', population])].
[sujeto(['Our', 'meta-analysis', demonstrated, that, 'KCNJ11', and, 'ABCC8', polymorphisms, are]), verbo([associated]), complemento([with, risk, for, type, 2, diabetes, in, the, global, population])].
[sujeto(['Comparative', genomics, and, bioinformatics, analyses, revealed, that, rs5210, is, located, within, a]), verbo([conserved]), complemento([3, '\'', -, 'UTR,', and, that, allele, 'A', may, abolish, the, binding, site, of, 'hsa-miR-1910', that, the, risk, allele, 'G', possesses])].
[sujeto(['The', 'PDX1-transduced', hepatocytes]), verbo([expressed]), complemento([several, pancreatic, transcription, factors, related, to, early, pancreatic, endocrine, development, '(', endogenous, 'Pdx1,', neurogenic, differentiation, factor, 1, '[', 'Neurod1],', and, 'NK6', transcription, factor, 'related,', locus, 1, '[', 'Nkx6-1])', as, well, as, the, 'late-stage', pancreatic, transcription, factors, '(', paired, box, gene, 4, '[', 'Pax4],', paired, box, gene, 6, '[', 'Pax6],', and, 'v-maf', musculoaponeurotic, fibrosarcoma, oncogene, homolog, 'A', '[', 'Mafa])'])].
[sujeto(['Active', efflux, of, both, drugs, and, organic, anion, metabolites, is]), verbo([mediated]), complemento([by, the, multidrug, resistance, proteins, '(', 'MRPs)'])].
[sujeto(['MRP1', '(', 'ABCC1),', 'MRP2', '(', 'ABCC2),', 'MRP3', '(', 'ABCC3),', and, 'MRP4', '(', 'ABCC4)']), verbo([have]), complemento([partially, overlapping, substrate, specificities, and, all, transport, 17, 'β-estradiol', 17, -, '(', 'β-d-glucuronide)', '(', 'E217βG)'])].
[sujeto(['The', cysteinyl, leukotriene, receptor, 1, '(', 'CysLT1R)', antagonist, 'MK-571']), verbo([inhibits]), complemento([all, four, 'MRP', 'homologs,', but, little, is, known, about, the, modulatory, effects, of, newer, leukotriene, modifiers, '(', 'LTMs)'])].
[sujeto(['Three', of, four, 'CysLT1R-selective', 'LTMs', also]), verbo([stimulated]), complemento(['MRP2', '(', but, not, 'MRP3)', transport, and, thus, exerted, a, 'concentration-dependent', biphasic, effect, on, 'MRP2'])].
[sujeto(['The', fourth, 'CysLT1R', 'antagonist,', 'LY171883,', only]), verbo([stimulated]), complemento(['MRP2', '(', and, 'MRP3)', transport, but, none, of, the, 'MRPs', were, stimulated, by, either, 'CysLT2R-selective', 'LTM'])].
[sujeto(['Sea', urchins, occupy, an, important, phylogenetic, position, for, understanding, the, evolution, of, vertebrate, proteins, and]), verbo([have]), complemento([been, an, important, invertebrate, model, system, for, study, of, 'ABC', transporters])].
[sujeto(['We', used, phylogenetic, analyses, to, examine, the, evolution, of, 'MRP', transporters, and, functional, approaches, to, identify, functional, forms, of]), verbo([sea]), complemento([urchin, 'MRP1', '(', also, known, as, 'SpABCC1)'])].
[sujeto(['SpABCC1,', the, only, 'MRP', homolog, in]), verbo([sea]), complemento(['urchins,', is, 'co-orthologous', to, human, 'MRP1,', 'MRP3,', and, 'MRP6', '(', 'ABCC1,', 'ABCC3,', and, 'ABCC6)', transporters])].
[sujeto(['However,', efflux, assays, revealed, that, alternative, splicing, of, exon, 22, ',', a, region, critical, for, substrate, 'interactions,', could, diversify, functions, of]), verbo([sea]), complemento([urchin, 'MRP1'])].
[sujeto(['Phylogenetic', comparisons, also, indicate, that, while, 'MRP1,', 'MRP3,', and, 'MRP6', transporters, potentially, arose, from, a, single, transporter, in, basal, 'deuterostomes,', alternative, splicing, appears, to]), verbo([have]), complemento([been, the, major, mode, of, functional, diversification, in, 'invertebrates,', while, duplication, may, have, served, a, more, important, role, in, vertebrates])].
[sujeto(['These', results]), verbo([provide]), complemento([a, deeper, understanding, of, the, evolutionary, origins, of, 'MRP', transporters, and, the, potential, mechanisms, used, to, diversify, their, functions, in, different, groups, of, animals])].
[sujeto(['Treatment', with, 'As(V)']), verbo([caused]), complemento([a, moderate, decrease, in, intracellular, pH, and, a, strong, increase, in, the, concentration, of, free, thiols, '(', 'GSH)'])].
[sujeto(['Passive', surface, adsorption, was]), verbo([found]), complemento([to, be, negligible, for, living, cells, exposed, to, 'DMA', and, 'As(V)'])].
[sujeto(['The']), verbo([increase]), complemento([of, bound, 'As-GS/PC', complexes, was, found, to, be, strongly, related, to, an, increase, in, concentration, of, 'As(III)', in, media])].
[sujeto(['As(III)']), verbo([triggers]), complemento([the, formation, of, arsenic, complexes, with, 'PC', and, homophytochelatins, '(', 'hPC)', and, their, compartmentalisation, to, vacuoles])].
[sujeto(['A', conceptual, model, was, devised, to, explain, the, mechanisms]), verbo([involving]), complemento(['ABCC1/2', transport])].
[sujeto(['Aquatic', 'organisms,', such, as, 'bivalves,', employ, 'ATP']), verbo([binding]), complemento([cassette, '(', 'ABC)', transporters, for, efflux, of, potentially, toxic, chemicals])].
[sujeto(['Applying', rapid, amplification, of, cDNA, ends, '(', 'RACE)', 'PCR', we, identified, complete, cDNAs, encoding, 'ABCB1-', and, 'ABCC1-type', transporter, homologs, from, zebra, mussel]), verbo([providing]), complemento([the, molecular, basis, for, expression, of, both, transporter, types, in, zebra, mussel, gills])].
[sujeto(['The', assumption, that, different, inhibitors]), verbo([targeted]), complemento([different, efflux, pump, types, was, confirmed, when, comparing, measured, effects, of, binary, inhibitor, compound, mixtures, in, dye, accumulation, assays, with, predictions, from, mixture, effect, models])].
[sujeto(['The', binary, mixture, approach, was, further, applied, to, identify, the, efflux, pump, type]), verbo([targeted]), complemento([by, environmentally, relevant, chemosensitizing, compounds])].
[sujeto(['Pentachlorophenol', and, musk, 'ketone,', which, were, selected, after, a, 'pre-screen', of, twelve, compounds, that, previously, had, been, identified, as, 'chemosensitizers,', showed, mixture, effects, that, corresponded, better, with, concentration, addition, when, combined, with, reversine, 205, but, with, independent, action, predictions, when, combined, with, 'MK571', indicating]), verbo([targeting]), complemento([of, an, 'ABCB1-type', efflux, pump, by, these, compounds])].
[sujeto(['Studies', of, human, gene, polymorphisms]), verbo([have]), complemento([identified, a, potential, role, for, the, multidrug, 'resistance-like', protein, '(', 'MRP/ABCC)', 'family,', 'ATP-dependent', 'transporters,', in, 'MeHg', susceptibility])].
[sujeto(['MRP', transporters]), verbo([have]), complemento([been, shown, to, be, important, for, 'MeHg', excretion, in, adult, mouse, 'models,', but, their, role, in, moderating, 'MeHg', toxicity, during, development, has, not, been, explored])].
[sujeto(['Furthermore,']), verbo([targeted]), complemento([knockdown, of, dMRP, expression, using, 'GAL4&gt;UAS', 'RNAi', methods, demonstrates, a, 'tissue-specific', function, for, dMRP, in, 'gut,', 'Malpighian', 'tubules,', and, the, nervous, system, in, moderating, developmental, susceptibility, to, 'MeHg'])].
[sujeto(['In', 'sum,', these, data, demonstrate, that, dMRP, 'expression,', both, globally, and, within, 'Hg-targeted', 'organs,']), verbo([has]), complemento([a, profound, effect, on, susceptibility, to, 'MeHg', in, developing, flies])].
[sujeto(['Finally,', this, experimental, system]), verbo([provides]), complemento([a, tractable, model, to, evaluate, human, polymorphic, variants, of, 'MRP', and, other, gene, variants, relevant, to, genetic, studies, of, 'mercury-exposed', populations])].
[sujeto(['Over', the, 'years,', several, strategies]), verbo([have]), complemento([been, evaluated, to, overcome, 'MDR,', based, not, only, on, the, use, of, 'low-molecular-weight', 'MDR', 'modulators,', but, also, on, the, implementation, of, 1, -, 100, '(', 0, ')', 'nm-sized', drug, delivery, systems])].
[sujeto(['While', certain, challenges, still, need, to, be, overcome, before, such, constructs, and, concepts, can, be, widely, applied, in, the, 'clinic,', the, insights, obtained, and, the, progress, made, strongly]), verbo([suggest]), complemento([that, nanomedicine, formulations, hold, significant, potential, for, improving, the, treatment, of, 'multidrug-resistant', malignancies])].
[sujeto(['Ovarian', cancer, is, the, main]), verbo([cause]), complemento([of, death, from, gynaecological, malignancies])].
[sujeto(['In', spite, of, the, efficacy, of, 'platinum-paclitaxel', treatment, in, patients, with, primary, epithelial, ovarian, 'carcinoma,', 'platinum-based', chemotherapy, is, not, curative, and, resistance, remains, one, of, the, most, important]), verbo([causes]), complemento([of, treatment, failure])].
[sujeto(['Although', 'ABC', transporters]), verbo([have]), complemento([been, implicated, in, cellular, resistance, to, multiple, 'drugs,', the, clinical, relevance, of, these, efflux, pumps, is, still, poorly, understood])].
[sujeto([',', 'ABCC1/MRP1,', 'ABCC4/MRP4)', to]), verbo([gain]), complemento([insights, into, their, clinical, impacts])].
[sujeto(['We']), verbo([found]), complemento([an, association, between, 'MRP1', expression, and, 'grading,', and, we, observed, that, 'MRP4', displayed, an, unfavourable, impact, on, disease, relapse, in, multivariate, analysis, '(', 'HR', =, 2.05, ',', 95, '%', 'CI:', 1.01, -, 4.11, ;, 'P', =, 0.045, ')'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, in, epithelial, ovarian, 'cancer,', 'MRP1', may, be, a, marker, for, aggressiveness, because, its, expression, was, associated, with, tumor, grade, and, support, that, 'MRP4', may, play, an, unfavourable, role, in, disease, outcome])].
[sujeto(['Multidrug', resistance, '(', 'MDR)', is, considered, the, main]), verbo([cause]), complemento([of, cancer, chemotherapy, failure, and, patient, relapse])].
[sujeto(['The', active, drug, efflux]), verbo([mediated]), complemento([by, transporter, proteins, of, the, 'ABC', '(', 'ATP-binding', 'cassette)', family, is, the, most, investigated, mechanism, leading, to, 'MDR'])].
[sujeto(['With', the, aim, of]), verbo([inhibiting]), complemento([this, transport, and, circumventing, 'MDR,', a, great, amount, of, work, has, been, dedicated, to, identifying, pharmacological, inhibitors, of, specific, 'ABC', transporters])].
[sujeto(['Herein,', we, show, that, 3, 'ATA', strongly]), verbo([inhibited]), complemento([the, activity, of, 'MRP1/ABCC1'])].
[sujeto(['Nevertheless,', the, low, inhibitory, effect, of, 3, 'ATA', on, 'A549,', a, cell, line, that]), verbo([expresses]), complemento(['MRP1-5,', suggests, that, it, may, not, inhibit, other, 'MRPs'])].
[sujeto(['The', use, of, cells, transfected, with, 'ABCC2,', 'ABCC3', or, 'ABCC4', showed, that, 3, 'ATA', was, also, able, to]), verbo([modulate]), complemento([these, 'transporters,', though, with, an, inhibition, ratio, lower, than, that, observed, for, 'MRP1/ABCC1'])].
[sujeto(['Cancer', stem, cells, '(', 'CSCs)', in, gliomas, are]), verbo([associated]), complemento([with, resistance, to, 'radio-', and, 'chemotherapy,', based, on, 'O(6)-methylguanine-DNA', methyltransferase, '(', 'MGMT)', hypermethylation, and, the, 'Multidrug', resistance, '(', 'MDR)', system, activation])].
[sujeto(['ABCC1', expression, was, variably, positive, in, tumor, cells, and, positive, in, 'neurospheres,', and, less]), verbo([expressed]), complemento([in, adherent, cells])].
[sujeto(['The', mechanisms, by, which, β1, integrins]), verbo([regulate]), complemento([chemoresistance, of, cancer, cells, are, still, poorly, understood])].
[sujeto(['In', this, 'study,', we]), verbo([report]), complemento([that, 'collagen/β1', integrin, signaling, inhibits, 'doxorubicin-induced', apoptosis, of, 'Jurkat', and, 'HSB2', leukemic, 'T-cells', by, 'up-regulating', the, expression, and, function, of, the, 'ATP-binding', cassette, 'C', 1, '(', 'ABCC1)', 'transporter,', also, known, as, multidrug, 'resistance-associated', protein, 1])].
[sujeto(['We']), verbo([find]), complemento([that, collagen, but, not, fibronectin, reduces, intracellular, doxorubicin, content, and, 'up-regulates', the, expression, levels, of, 'ABCC1'])].
[sujeto(['We', also, demonstrate, that, activation, of, the, extracellular, 'signal-regulated', kinase, '(', 'ERK)/mitogen-activated', protein, kinase, signaling, pathway, is]), verbo([involved]), complemento([in, 'collagen-induced', reduction, of, intracellular, doxorubicin, 'accumulation,', 'collagen-induced', 'up-regulation', of, 'ABCC1', expression, 'levels,', and, 'collagen-mediated', cell, survival])].
[sujeto(['Finally,', 'collagen-mediated', 'up-regulation', of, 'ABCC1', expression, and, function, also]), verbo([requires]), complemento([actin, polymerization])].
[sujeto(['Taken', 'together,', our, results, indicate, for, the, first, time, that, 'collagen/β1', 'integrin/ERK', signaling, 'up-regulates', the, expression, and, function, of, 'ABCC1', and]), verbo([suggest]), complemento([that, its, activation, could, represent, an, important, pathway, in, cancer, chemoresistance])].
[sujeto(['Thus', simultaneous]), verbo([targeting]), complemento([of, 'collagen/β1', integrin, and, 'ABCC1', may, be, more, efficient, in, preventing, drug, resistance, than, targeting, each, pathway, alone])].
[sujeto(['Up-regulation', of, abcc2, was, more, 'pronounced,', with, up, to, 8, -, fold]), verbo([increase]), complemento([in, expression])].
[sujeto(['All', metals]), verbo([caused]), complemento([a, significant, inhibition, of, both, 'P-gp', '(', 2.9, -, to, 4, -, fold, vs])].
[sujeto(['Modulation', of, 'ABC', genes, and, transport, activities, was, further, investigated, in, 'PLHC-1/wt', cells, exposed, to, 1, μM, 'HgCl(2)', for, 72, h, and, in, 'Hg', resistant, cells, selected, by, long, term, cultivation, of, 'PLHC-1/wt', cells, in]), verbo([increasing]), complemento([concentrations, of, 'HgCl(2)'])].
[sujeto(['Exposure', to, 'HgCl(2)', for, 72, h]), verbo([induced]), complemento(['MRP', genes, expression, and, efflux, activity])].
[sujeto(['The', long, term, cultivation, of, 'PLHC-1/wt', cells, in, 'HgCl(2),', did, not]), verbo([cause]), complemento([prolonged, 'up-regulation', of, the, tested, abc, genes, but, resulted, in, higher, 'MRP', transport, activities, as, determined, by, the, increased, sensitivity, of, these, cells, to, 'MK571', '(', 'MRP', specific, 'inhibitor)'])].
[sujeto(['If', 'JIA', patients, are, unresponsive, to, 'MTX,', early, and, effective, combination, treatment, with, biologicals, is]), verbo([required]), complemento([to, prevent, joint, damage])].
[sujeto(['The', authors, developed, a, prediction, model, to, identify, 'JIA', patients, not]), verbo([responding]), complemento([to, 'MTX'])].
[sujeto(['In', a, cohort, of, 183, 'JIA', 'patients,', clinical, variables, and, single, nucleotide, polymorphisms, '(', 'SNPs)', in, genes]), verbo([involved]), complemento([in, the, mechanism, of, action, of, 'MTX', were, determined, at, the, start, of, 'MTX', treatment])].
[sujeto(['The', prediction, model, that, we, developed, and, validated, combines, clinical, and, genetic, variables, to, identify, 'JIA', patients, not]), verbo([responding]), complemento([to, 'MTX', treatment])].
[sujeto(['Oxidative', stress]), verbo([has]), complemento([been, linked, to, the, 'podocytopathy,', mesangial, expansion, and, progression, of, diabetic, nephropathy])].
[sujeto(['Some', 'ABC', transporters]), verbo([have]), complemento([been, shown, to, extrude, 'GSH,', oxidised, glutathione, or, their, conjugates, out, of, the, 'cell,', thus, implying, a, role, for, these, transporters, in, 'GSH', homeostasis])].
[sujeto(['We']), verbo([found]), complemento([a, remarkable, expression, of, mRNA, for, multidrug, 'resistance-associated', proteins, '(', 'MRP/ABCC)', 1, ',', 3, ',', 4, and, 5, in, rat, glomeruli])].
[sujeto(['Three', weeks, after, induction, of, diabetes, in, glomeruli, of, 'streptozotocin-treated', 'rats,', we, observed, a, decline, in, reduced, 'GSH', levels, and, an]), verbo([increase]), complemento([in, the, expression, and, activity, of, 'MRP1', '(', 'ABCC1)'])].
[sujeto(['We', conclude, that]), verbo([increased]), complemento([activity, of, 'MRP1', in, diabetic, glomeruli, is, correlated, with, an, inadequate, adaptive, response, to, oxidative, stress])].
[sujeto(['Macrophages', represent, major, cellular]), verbo([targets]), complemento([of, various, 'drugs,', especially, antibiotics, and, 'anti-viral', drugs])].
[sujeto(['Using', quantitative, polymerase, chain, reaction, 'assays,', these, cells, were]), verbo([found]), complemento([to, exhibit, very, high, or, high, levels, of, mRNA, expression, of, concentrative, nucleoside, transporter, '(', 'CNT)', 3, ',', equilibrative, nucleoside, transporter, 3, ',', monocarboxylate, transporter, '(', 'MCT)', 1, ',', 'MCT4,', 'peptide/histidine', transporter, '(', 'PHT)', 1, ',', 'PHT2,', organic, anion, transporting, polypeptide, transporter, 2, 'B1', and, 'ABC', pumps, multidrug, resistance, protein, '(', 'MRP)', 1, /, 'ABCC1', and, 'MRP3/ABCC3'])].
[sujeto(['By', 'contrast,', other, 'transporters,', including, the, efflux, pump, 'ABCB1/P-glycoprotein,', were]), verbo([found]), complemento([at, lower, levels, or, were, not, expressed])].
[sujeto(['Such', a, functional, expression, of, these, transporters]), verbo([has]), complemento([likely, to, be, considered, with, respect, to, cellular, pharmacokinetics, of, drugs, targeting, macrophages])].
[sujeto(['Gemcitabine-resistant', pancreatic, cancer, cell, line, 'SW1990/GZ', was, obtained, by, treating, parental, cell, line, 'SW1990', in, vitro, with]), verbo([increasing]), complemento([dosage, of, gemcitabine, in, culture, medium, intermittently, for, 24, weeks])].
[sujeto(['Stable', cultures, were, obtained, which, were, 77.2, -, fold]), verbo([increased]), complemento([in, resistance, relative, to, parental, cells])].
[sujeto(['Gemcitabine-resistant', cell, line, 'SW1990/GZ']), verbo([has]), complemento([a, higher, proportion, of, pancreatic, cancer, stem, cells, compared, to, its, parental, cell, line, 'SW1990'])].
[sujeto(['CD44', is, mainly, responsible, for, acquired, drug, 'resistance,', which, can, be, a, potential]), verbo([target]), complemento([to, overcome, acquired, drug, resistance, in, pancreatic, cancer])].
[sujeto(['MRP1-5', can, collectively]), verbo([confer]), complemento([resistance, to, natural, product, anticancer, drugs, and, their, conjugated, 'metabolites,', platinum, 'compounds,', folate, 'antimetabolites,', nucleoside, and, nucleotide, 'analogs,', and, alkylating, agents])].
[sujeto(['MRP1-3', are, often]), verbo([associated]), complemento([with, tumor, resistance, which, is, often, caused, by, an, increased, efflux, and, decreased, intracellular, accumulation, of, natural, product, anticancer, drugs, and, other, anticancer, agents])].
[sujeto(['Experimental', studies, in, 'Abcc1-difficient', mice]), verbo([have]), complemento([demonstrated, a, role, of, 'MRP1', in, inflammation, process, in, vivo])].
[sujeto(['Abcc3-difficient', mice]), verbo([have]), complemento([normal, bile, salt, 'transport,', however, they, have, decreased, blood, bilirubin, glucuronide, levels])].
[sujeto(['Drug']), verbo([targeting]), complemento([of, these, transporters, to, overcome, 'MRP/ABCC-mediated', multidrug, resistance, may, play, a, role, in, cancer, and, infection, '(', e])].
[sujeto(['Some', modulators, of, 'MRPs']), verbo([have]), complemento([shown, reversing, effects, on, 'MDR', phenotype, in, preliminary, clinical, studies, and, some, modulators, of, 'MRPs', may, modify, the, inflammatory, process, and, consequently, ameliorate, the, inflammatory, symptoms])].
[sujeto(['A', better, understanding, of, the, interactions, of, these, modulators, with, 'MRPs']), verbo([has]), complemento([important, implications, in, development, of, novel, drugs, for, treatment, of, 'cancer,', infection, and, inflammation])].
[sujeto(['Puromycin']), verbo([induced]), complemento(['ABCC1/MRP1,', whereas, 'G418', suppressed, 'ABCB1/Pgp,', at, the, messenger, 'RNA', '(', 'mRNA)', level])].
[sujeto(['Based', on, sequence, 'relatedness,', mammalian, 'ABC', proteins]), verbo([have]), complemento([been, divided, into, seven, 'subfamilies,', 'ABC', subfamily, 'A', '(', 'ABCA)', to, 'ABCG'])].
[sujeto(['Ycf1p', is, located, in, the, vacuolar, membrane, in, yeast, and, functions, in, a, manner, analogous, to, that, of, the, human, multidrug, 'resistance-related', protein, '(', 'MRP1,', also, called, 'ABCC1),']), verbo([mediating]), complemento([the, transport, of, 'glutathione-conjugated', toxic, compounds])].
[sujeto([iMYTH, technology]), verbo([has]), complemento([successfully, identified, novel, interactors, of, 'Ycf1p', and, promises, to, be, an, invaluable, tool, in, future, efforts, to, comprehensively, define, the, yeast, 'ABC', interactome])].
[sujeto(['The', differentially]), verbo([expressed]), complemento([genes, were, classified, according, to, their, level, of, 'expression,', calculated, as, the, ratio, of, the, value, obtained, after, each, treatment, relative, to, control, 'cells,', with, a, statistical, significance, of, 'P', &, 'lt;', 0.05, '(', 'upregulated:', ratio, &, 'gt;', 1.5, ;, 'downregulated:', ratio, &, 'lt;', 0.6, ')'])].
[sujeto(['Treatment', with, epicatechin]), verbo([decreased]), complemento([the, expression, of, 21, genes, and, upregulated, 24, genes])].
[sujeto(['The', changes, in, expression, for, ferritin, heavy, polypeptide, 1, '(', 'FTH1),', 'mitogen-activated', protein, kinase, kinase, 1, '(', 'MAPKK1),', signal, transducer, and, activator, of, transcription, 1, '(', 'STAT1),', and, topoisomerase, 1, upon, incubation, with, 'epicatechin,', and, for, myeloid, leukemia, factor, 2, '(', 'MLF2),', 'CCAAT/enhancer']), verbo([binding]), complemento([protein, gamma, '(', 'C/EBPG),', 'MAPKK1,', 'ATP-binding', 'cassette,', subfamily, c, member, 1, '(', 'MRP1),', 'STAT1,', topoisomerase, 1, ',', and, 'x-ray', repair, complementing, defective, repair, 1, '(', 'XRCC1)', upon, incubation, with, the, cocoa, polyphenolic, extract, were, validated, by, 'RT-PCR'])].
[sujeto(['The', changes, in, the, expression, of, 'STAT1,', 'MAPKK1,', 'MRP1,', and, 'FTH1', 'genes,', which, are]), verbo([involved]), complemento([in, the, cellular, response, to, oxidative, 'stress,', are, in, agreement, with, the, antioxidant, properties, of, cocoa, flavonoids])].
[sujeto(['In', 'addition,', the, changes, in, the, expression, of, 'C/EBPG,', topoisomerase, 1, ',', 'MLF2,', and, 'XRCC1']), verbo([suggest]), complemento([novel, mechanisms, of, action, of, flavonoids, at, the, molecular, level])].
[sujeto(['Mutant', 'MRP1', lacking, 'N-linked', glycosylation, '[', 'Asn19/23/1006Gln;', 'sugar-free', '(', 'SF)-MRP1]']), verbo([expressed]), complemento([in, either, 'HEK293', or, 'HeLa', cells, had, low, 'Km', and, 'Vmax', values, for, 'As(GS)3,', similar, to, 'HeLa', 'wild-type', '(', 'WT)', 'MRP1'])].
[sujeto(['Together,', these, results]), verbo([suggest]), complemento([that, 'Asn19/Asn23', glycosylation, and, 'Tyr920/Ser921', phosphorylation, are, responsible, for, altering, the, kinetics, of, 'MRP1-mediated', 'As(GS)3', transport])].
[sujeto(['Overall,', these, data]), verbo([suggest]), complemento([that, 'cross-talk', between, 'MRP1', glycosylation, and, phosphorylation, occurs, and, that, phosphorylation, of, 'Tyr920', and, 'Ser921', can, switch, 'MRP1', to, a, 'lower-affinity,', 'higher-capacity', 'As(GS)3', 'transporter,', allowing, arsenic, detoxification, over, a, broad, concentration, range])].
[sujeto(['ATP-binding', cassette, '(', 'ABC)', transporters]), verbo([have]), complemento([been, associated, with, methylmercury, '(', 'MeHg)', toxicity, in, experimental, animal, models])].
[sujeto(['Nutrition', 'Cohort', 2, '(', 'NC2)', is, an, observational, 'mother-child', cohort]), verbo([recruited]), complemento([in, the, 'Republic', of, 'Seychelles', from, 2008, -, 2011])].
[sujeto(['Seven', of, fifteen, 'ABC', 'SNPs', '(', 'ABCC1', 'rs11075290,', 'rs212093,', and, 'rs215088;', 'ABCC2', 'rs717620;', 'ABCB1', 'rs10276499,', 'rs1202169,', and, 'rs2032582)', were]), verbo([associated]), complemento([with, concentrations, of, maternal, hair, 'Hg', '(', 'p&lt;0'])].
[sujeto(['One', 'SNP', '(', 'ABCC1', 'rs11075290)', was, also, significantly]), verbo([associated]), complemento([with, 'neurodevelopment;', children, born, to, mothers, with, rs11075290, 'CC', genotype, '(', mean, hair, 'Hg', 3.6, 'ppm)', scored, on, average, 2, points, lower, on, the, 'Mental', 'Development', 'Index', '(', 'MDI)', and, 3, points, lower, on, the, 'Psychomotor', 'Development', 'Index', '(', 'PDI)', than, children, born, to, mothers, with, 'TT', genotype, '(', mean, hair, 'Hg', 4.7, 'ppm)', while, children, with, the, 'CT', genotype, '(', mean, hair, 'Hg', 4.0, 'ppm)', had, intermediate, 'BSID', scores])].
[sujeto(['Genetic', variation, in, 'ABC', transporter, genes, was]), verbo([associated]), complemento([with, maternal, hair, 'Hg', concentrations])].
[sujeto(['We']), verbo([report]), complemento([the, 'design,', synthesis, and, biological, characterisation, of, a, novel, hybrid, drug, by, conjugation, of, two, tubulin, 'inhibitors,', a, hemiasterlin, derivative, 'A', '(', 'H-Mpa-Tle-Aha-OH),', obtained, by, condensation, of, three, 'non-natural', amino, 'acids,', and, 'cis-3,4\',5-trimethoxy-3\'aminostilbene', '(', 'B)'])].
[sujeto(['As', we]), verbo([have]), complemento([previously, demonstrated, synergy, between, 'A', and, 'B,', we, used, a, monocarbonyl, derivative, of, triethylene, glycol, as, linker, '(', 'L)', to, synthesise, compounds, 'A-L', and, 'A-L-B;', via, 'HPLC', we, analysed, the, release, of, its, potential, hydrolysis, products, 'A,', 'A-L,', 'B', and, 'B-L', in, physiological, 'fluids:', the, hybrid, 'A-L-B', undergo, hydrolysis, in, rat, whole, blood, of, the, ester, bond, between, 'A', and, 'L', '(', 'half-life=118'])].
[sujeto(['Via', permeation, studies, across, 'NCM460', monolayers, we, demonstrate, the, poor, aptitude, of, 'A', to]), verbo([interact]), complemento([with, active, efflux, transporters, '(', 'AET):', 'indeed,', the, ratio, between, its, permeability, coefficients, for, the, basolateral, '(', 'B)→apical', '(', 'A)', and, 'B→A', transport, was, 1.5, '±0'])].
[sujeto(['Elevated', expression, of, drug, efflux, pumps, such, as, multidrug, resistant, 'protein-1', '(', 'MDR1/ABCB1)', and, multidrug, resistance]), verbo([associated]), complemento(['protein-1', '(', 'MRP1/ABCC1)', in, cancer, stem, cells, '(', 'CSCs)', among, a, bulky, tumor, cell, population, was, attributed, to, drug, resistance])].
[sujeto(['For', the, first, 'time,', we]), verbo([have]), complemento([quantitatively, evaluated, the, cytotoxic, profile, of, camptothecin, '(', 'CPT)', against, the, 'CSC'])].
[sujeto(['In', the, present, 'study,', a, 'Qdot', based, total, internal, reflection, fluorescence, '(', 'TIRF)', detection, system, effectively, interpreted, that, drug, resistance, to, 'CPT', was, reduced, in, the, 'CSC', under, 'ABCB1']), verbo([inhibited]), complemento([conditions])].
[sujeto(['This', study, revealed, that, quantitative]), verbo([finding]), complemento([of, the, 'EC50', value, for, apoptosis, and, necrosis, in, correlation, with, the, 'ABC', inhibitor, and, 'CSC', population, using, 'TIRF', could, provide, more, details, of, the, 'anti-cancer', efficacy, of, chemotherapeutic, agents])].
[sujeto(['The', majority, of, 'ABC', proteins, are, primary, active, transporters, that]), verbo([bind]), complemento([and, hydrolyze, 'ATP', to, mediate, the, efflux, of, a, diverse, range, of, substrates, across, lipid, membranes])].
[sujeto(['In', this, 'study,', we, cloned, and, characterized, a, putative, multidrug, resistance]), verbo([associated]), complemento([protein, 1, '(', 'MRP1)', from, 'Rhopalosiphum', padi, encoded, by, 'ABCC1'])].
[sujeto(['Structural', analysis, showed, that, this, protein]), verbo([has]), complemento([structural, features, typical, of, the, 'ABC', transporter, family])].
[sujeto(['Real-time', quantitative, polymerase, chain, reaction, '(', 'PCR)', analysis, showed, that, 'ABCC1', was]), verbo([expressed]), complemento([throughout, all, 'R'])].
[sujeto(['We', also, examined, 'ABCC1', expression, in, four, different, tissue, types, and]), verbo([found]), complemento([that, it, was, most, highly, expressed, in, the, midgut])].
[sujeto([padi, to, imidacloprid, and, chlorpyrifos]), verbo([increased]), complemento(['ABCC1', expression])].
[sujeto([padi, to, verapamil, in, combination, with, insecticides, significantly]), verbo([increased]), complemento([the, toxicity, of, the, insecticides])].
[sujeto(['padi,', particularly, its, role, in, insecticide, 'resistance,', and]), verbo([suggest]), complemento([novel, strategies, for, pest, management, that, use, 'ABC', transporter, inhibitors, to, increase, the, effectiveness, of, insecticides])].
[sujeto(['Breast', cancer, is, a, serious, threat, to, 'women\'s', 'health,', because, multidrug, resistance, '(', 'MDR)']), verbo([has]), complemento([hampered, treatment, and, prognosis])].
[sujeto(['Drugs', can, be, delivered, to, tumor, tissue, by, passive, and, active, tumor]), verbo([targeting]), complemento(['strategies,', which, may, reduce, or, reverse, drug, resistance])].
[sujeto(['Several', generations, of, 'ABC', efflux, transporter, inhibitors]), verbo([have]), complemento([been, 'developed,', 'however,', none, of, them, could, provide, better, clinical, outcome, due, to, systemic, toxicities, and, significant, 'drug-drug', interactions])].
[sujeto(['Therefore,', the, present, study, focused, on, identifying, the, effect, of, the, natural, carotenoid, on, 'ABC', transporters, and, may]), verbo([provide]), complemento([a, safer, choice, to, defeat, 'MDR', cancer])].
[sujeto(['Among', the, tested, 'ABC', efflux, 'transporters,', 'β-carotene', significantly]), verbo([inhibited]), complemento([human, 'P-gp', efflux, function, without, altering, 'ABCB1', mRNA, expression])].
[sujeto(['Furthermore,', 'β-carotene']), verbo([stimulated]), complemento([both, 'P-gp', basal, 'ATPase', activity, and, the, 'verapamil-stimulated', 'P-gp', 'ATPase', activity])].
[sujeto(['The', combination, of, 'β-carotene', and, chemotherapeutic, agents, significantly, potentiated, their, cytotoxicity, in, both, cell, stably]), verbo([expressed]), complemento([human, 'P-gp', '(', 'ABCB1/Flp-In(TM)-293)', and, 'MDR', cancer, cells, '(', 'KB-vin', and, 'NCI-H460/MX20)'])].
[sujeto(['This', transport, protein, is, a, major]), verbo([target]), complemento([to, overcome, multidrug, resistance, in, cancer, patients])].
[sujeto(['Its', replacement, by, an, amino, group]), verbo([led]), complemento([to, decreased, activity])].
[sujeto(['Doxorubicin', '(', 'DOX)']), verbo([induces]), complemento(['dose-dependent', cardiotoxicity, in, part, due, to, its, ability, to, induce, oxidative, stress])].
[sujeto(['We', showed, that]), verbo([loss]), complemento([of, multidrug, 'resistance-associated', protein, 1, '(', 'Abcc1/Mrp1)', potentiates, 'DOX-induced', cardiac, dysfunction, in, mice, in, vivo, 'Here,', we, characterized, 'DOX', toxicity, in, cultured, cardiomyocytes, '(', 'CM)', and, cardiac, fibroblasts, '(', 'CF)', derived, from, 'C57BL', wild, type, '(', 'WT)', and, 'Mrp1', null, '(', 'Mrp1-/-)', neonatal, mice])].
[sujeto(['Following', 'DOX', '(', 0.3, -, 4, 'μM),', 'Mrp1-/-', 'CM,', and, 'CF,', especially, 'CM,', showed, a, greater]), verbo([decrease]), complemento([in, viability, and, increased, apoptosis, and, 'DNA', 'damage,', demonstrated, by, higher, caspase, 3, 'cleavage,', poly, '(', 'ADP-ribose)', polymerase, 1, '(', 'PARP)', cleavage, and, phosphorylated, histone, 'H2AX', '(', 'γH2AX)', levels, versus, 'WT', cells])].
[sujeto([5, ')', ',', but, the, redox, potential, '(', 'Eh)', of, the, 'GSH/GSSG', pool, did, not, differ, between, genotypes, in, 'CM', and, 'CF,', indicating, that, 'Mrp1-/-', cells]), verbo([maintain]), complemento([this, major, redox, couple])].
[sujeto(['DOX']), verbo([increased]), complemento([expression, of, the, 'rate-limiting', 'GSH', synthesis, enzyme, 'glutamate-cysteine', ligase, catalytic, '(', 'GCLc)', and, regulatory, subunits, '(', 'GCLm)', to, a, significantly, greater, extent, in, 'Mrp1-/-', versus, 'WT', 'cells,', suggesting, adaptive, responses, to, oxidative, stress, in, 'Mrp1-/-', cells, that, were, inadequate, to, afford, protection])].
[sujeto(['Thus,', 'Mrp1', protects, 'CM', in, particular, and, 'CF', against, 'DOX-induced', 'toxicity,', potentially, by]), verbo([regulating]), complemento([extracellular, redox, states])].
[sujeto(['To', evaluate, the, correlation, of, resistance, proteins, 'Pgp', '(', 'P-glycoprotein),', 'MRP1', '(', 'Multidrug', 'Related', 'Protein,', 'Multidrug', 'Resistance-Associated', 'Protein)', and, 'MRP3', with, clinical, -, pathological, factors, and, to]), verbo([find]), complemento([the, clinical, outcome, of, these, data, in, ovarian, cancer, patients])].
[sujeto(['We']), verbo([found]), complemento([prognostic, significance, of, 'Pgp,', 'MRP1', and, 'MRP3', expression, in, ovarian, cancer, patients])].
[sujeto(['MRP1']), verbo([have]), complemento([some, additional, prognostic, value, for, the, clinical, outcome, of, patients, with, ovarian, carcinoma])].
[sujeto(['The', onset, of, drug, resistance, is, a, major]), verbo([cause]), complemento([of, treatment, failure, in, multiple, myeloma])].
[sujeto(['Although']), verbo([increasing]), complemento([evidence, is, defining, the, role, of, miRNAs, in, mediating, drug, 'resistance,', their, potential, activity, as, 'drug-sensitizing', agents, has, not, yet, been, investigated, in, multiple, myeloma])].
[sujeto(['Inhibition', of, 'miR-221/222', overcame, melphalan, resistance, and]), verbo([triggered]), complemento([apoptosis, of, multiple, myeloma, cells, in, 'vitro,', in, the, presence, or, absence, of, human, bone, marrow, '(', 'BM)', stromal, cells])].
[sujeto(['Decreased', multiple, myeloma, cell, growth]), verbo([induced]), complemento([by, inhibition, of, 'miR-221/222', plus, melphalan, was, associated, with, a, marked, upregulation, of, 'pro-apoptotic', 'BBC3/PUMA', 'protein,', a, 'miR-221/222', 'target,', as, well, as, with, modulation, of, drug, 'influx-efflux', transporters, 'SLC7A5/LAT1', and, the, 'ABC', transporter, 'ABCC1/MRP1'])].
[sujeto(['Taken', 'together,', our, findings]), verbo([provide]), complemento([the, proof, of, concept, that, 'LNA-i-miR-221', can, reverse, melphalan, resistance, in, preclinical, models, of, multiple, 'myeloma,', providing, the, framework, for, clinical, trials, to, overcome, drug, 'resistance,', and, improve, patient, outcome, in, multiple, myeloma])].
[sujeto(['The', umbilical, cord, is, a, direct, conduit, to, the, fetus, hence, transporters, could]), verbo([have]), complemento([roles, in, partitioning, substances, between, the, 'maternal-placental-fetal', units])].
[sujeto(['RALBP1),', an, 'ATP-dependent', transporter, of, 'electrophile-glutathione', 'conjugates,']), verbo([modulates]), complemento(['BBB', permeability, through, the, regulation, of, tight, junction, 'function,', cell, 'adhesion,', and, exocytosis])].
[sujeto(['Genes', and, pathways]), verbo([regulated]), complemento([by, 'RLIP76', are, transcriptional, targets, of, tumor, necrosis, factor, alpha, '(', 'TNF-α)', 'pro-inflammatory', 'molecule,', suggesting, that, 'RLIP76', may, also, be, an, inflammation, target])].
[sujeto(['We']), verbo([find]), complemento([most, to, be, 'modulated,', and, analysis, of, several, inflammation, datasets, as, well, as, a, metaanalysis, of, more, than, 5000, human, tissue, samples, encompassing, more, than, 300, cell, types, and, diseases, show, that, no, single, housekeeping, gene, may, be, used, as, a, reference, gene])].
[sujeto(['Using', three, different, 'algorithms,', 'however,', we, uncovered, a, reference, geneset, impervious, to, 'TNF-α,', and, show, for, the, first, time, that, 'RLIP76', expression, is]), verbo([induced]), complemento([by, 'TNF-α', and, follows, the, induction, kinetics, of, inflammation, 'markers,', suggesting, that, inflammation, can, influence, 'RLIP76', expression, at, the, 'BBB'])].
[sujeto(['ABCC1),', another, 'electrophile-glutathione', 'transporter,', is, not]), verbo([modulated]), complemento([in, the, same, cells, and, 'conditions,', indicating, that, 'RLIP76', regulation, by, 'TNF-α', is, not, a, general, property, of, glutathione, transporters])].
[sujeto(['Multidrug', 'resistance-associated', protein, 1, '(', 'MRP1),', encoded, by, the, 'ABCC1', 'gene,', is, an, 'ATP-binding', cassette, transporter]), verbo([mediating]), complemento([efflux, of, organic, anions, and, 'xenobiotics;', its, overexpression, leads, to, multidrug, resistance])].
[sujeto(['An', additional]), verbo([targeted]), complemento(['SNP', verification, study, for, ten, variants, was, performed, to, verify, sensitivity, of, the, scanning, method])].
[sujeto(['Ethnic', differences, were]), verbo([found]), complemento([for, frequency, of, some, variants, in, the, 'Polish', population, compared, to, others])].
[sujeto(['GA-13315', is, a, gibberellin, derivative, that]), verbo([reveals]), complemento([antitumor, and, antineoplastic, effects, both, in, vitro, and, in, vivo])].
[sujeto(['In', combination, with, conventional, chemotherapeutic, 'agents,', 'GA-13315', at, 'sub-toxic', concentrations, reversed, the, multidrug, resistance]), verbo([mediated]), complemento([by, 'ABCB1', but, exacerbated, the, resistance, conferred, by, multidrug, 'resistance-associated', protein, 1, '(', 'ABCC1)'])].
[sujeto(['GA-13315']), verbo([increased]), complemento([intracellular, accumulation, of, doxorubicin, and, rhodamine, 123, in, 'MCF-7/adr', cells, and, in, 'ABCB1-transfected', 'HEK293', cells, but, facilitated, drug, 'flush-out', from, cells, that, overexpress, 'ABCC1'])].
[sujeto(['GA-13315']), verbo([inhibited]), complemento([the, 'ATPase', activity, of, 'ABCB1', while, stimulated, that, of, 'ABCC1'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'GA-13315', sensitizes, 'multidrug-resistant', cells, at, least, partially, by, impeding, the, efflux, function, of, 'ABCB1'])].
[sujeto(['The', opposite, effects, of, 'GA-13315', on, different, 'ATP-binding', cassette, transporters, and, their, implications, in, overcoming, drug, resistance]), verbo([require]), complemento([further, investigation])].
[sujeto(['Also,', multidrug, resistance, '(', 'MDR)', is, generally]), verbo([associated]), complemento([with, tumor, chemoresistance, in, pancreatic, cancer])].
[sujeto(['We', demonstrated, that, cell, signaling, of, 'TM4SF1']), verbo([mediated]), complemento([chemoresistance, in, cancer, cells, by, assessing, the, expression, of, multidrug, resistance, '(', 'MDR)', genes, using, quantitative, 'RT-PCR'])].
[sujeto(['We', evaluated, that, 'TM4SF1', was, a, putative]), verbo([target]), complemento([for, gemcitabine, resistance, in, pancreatic, cancer, cells])].
[sujeto(['Using', 'AsPC-1,', 'MIA', 'PaCa-2', and, 'PANC-1,', we, investigated, that, 'TM4SF1', silencing, affected, cell, proliferation, and]), verbo([increased]), complemento([the, percentages, of, cell, apoptosis, mediated, by, treatment, with, gemcitabine, compared, with, cells, which, were, treated, with, negative, control])].
[sujeto(['This', resistance, was]), verbo([associated]), complemento([with, the, expression, of, multidrug, resistance, genes, including, 'ABCB1', and, 'ABCC1'])].
[sujeto(['In', 'vivo,', silencing, of, 'TM4SF1', in, 'MIA', 'PaCa-2', cell, lines]), verbo([increased]), complemento([the, effectiveness, of, 'gemcitabine-based', treatment, in, orthotopic, pancreatic, tumor, models, evaluated, using, noninvasive, bioluminescent, imaging])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'TM4SF1', is, a, surface, membrane, antigen, that, is, highly, expressed, in, pancreatic, cancer, cells, and, increases, the, chemoresistance, to, gemcitabine])].
[sujeto(['Thus,', 'TM4SF1', may, be, a, promising]), verbo([target]), complemento([to, overcome, the, chemoresistance, of, pancreatic, cancer])].
[sujeto(['A', natural, compound, oleanolic, acid, '(', 'OA)', was]), verbo([found]), complemento([to, be, active, against, many, types, of, neoplastic, cells])].
[sujeto(['Viability', 'inhibition,', proapoptotic, 'activity,', as, well, as, influence, on, the, 'ABCC1', gene, expression, 'level,', ability, to]), verbo([inhibit]), complemento([the, transport, function, of, multidrug, resistance, associated, protein, 1, '(', 'ABCC1)', and, to, alter, its, level, by, the, tested, 'compounds,', were, evaluated])].
[sujeto(['DIOXOL', was, most, efficient, in]), verbo([inducing]), complemento([apoptosis, of, 'HL-60', cells])].
[sujeto(['It']), verbo([activated]), complemento([both, intrinsic, and, extrinsic, pathways, of, apoptotic, cell, death])].
[sujeto(['Proapoptotic', properties, of, 'DIOXOL', were, probably, related, to, the, significant]), verbo([decrease]), complemento([of, p65, 'NFκB', level, and, inhibition, of, its, translocation, to, the, nucleus])].
[sujeto(['It']), verbo([inhibited]), complemento(['ABCC1', transport, function, '(', short, time, 'response)', and, decreased, the, level, of, 'ABCC1', protein, '(', long, time, 'response)', as, a, result, of, reduction, of, 'ABCC1', expression])].
[sujeto(['Cardiotoxicity', is, a, major, 'dose-limiting', adverse, effect, of, doxorubicin, '(', 'DOX),']), verbo([mediated]), complemento([in, part, by, overproduction, of, reactive, oxygen, species, and, oxidative, stress])].
[sujeto(['Abcc1', '(', 'Mrp1)']), verbo([mediates]), complemento([the, efflux, of, reduced, and, oxidized, glutathione, '(', 'GSH,', 'GSSG)', and, is, also, a, major, transporter, that, effluxes, the, 'GSH', conjugate, of, 4, -, 'hydroxy-2-nonenal', '(', 'HNE;', 'GS-HNE),', a, toxic, product, of, lipid, peroxidation, formed, during, oxidative, stress])].
[sujeto(['GSH', and, the, 'GSH/GSSG', ratio, were, significantly]), verbo([increased]), complemento([in, 'treatment-naïve', 'Mrp1(-/-)', versus, 'WT', 'mice;', 'GSH', remained, significantly, higher, in, 'Mrp1(-/-)', versus, 'WT', mice, after, saline, and, 'DOX', 'treatment,', with, no, changes, in, 'GSSG', or, 'GSH/GSSG'])].
[sujeto(['DOX', treatment]), verbo([decreased]), complemento(['GS-HNE', in, 'WT', but, not, 'Mrp1(-/-)', 'mice,', so, that, 'GS-HNE', was, modestly, but, significantly, higher, in, 'Mrp1(-/-)', versus, 'WT', hearts, after, 'DOX'])].
[sujeto(['Expression', of, enzymes]), verbo([mediating]), complemento(['GSH', synthesis, and, antioxidant, proteins, did, not, differ, between, genotypes])].
[sujeto(['Thus,', despite, elevated, 'GSH', levels, in, 'Mrp1(-/-)', 'hearts,', 'DOX']), verbo([induced]), complemento([significantly, more, injury, in, the, nuclei, of, 'Mrp1(-/-)', versus, 'WT', hearts])].
[sujeto(['Doxorubicin', '(', 'DOX),', an, effective, cancer, chemotherapeutic, 'agent,']), verbo([induces]), complemento(['dose-dependent', 'cardiotoxicity,', in, part, due, to, its, ability, to, cause, oxidative, stress])].
[sujeto(['Chronic', 'DOX']), verbo([induced]), complemento([body, weight, loss, and, 'hemotoxicity,', adverse, effects, significantly, exacerbated, in, 'Mrp1(-/-)', versus, 'WT', mice])].
[sujeto(['In', the, 'heart,', significantly, higher, basal, levels, of, glutathione, '(', 1.41, -, fold, ±, 0.27, -, 'fold)', and, glutathione, disulfide, '(', 1.35, -, fold, ±, 0.16, -, 'fold)', were, detected, in, 'Mrp1(-/-)', versus, 'WT', 'mice,', and, there, were, comparable]), verbo([decreases]), complemento([in, the, 'glutathione/glutathione', disulfide, ratio, in, 'WT', and, 'Mrp1(-/-)', mice, after, 'DOX', administration])].
[sujeto(['Surprisingly,', 'DOX']), verbo([induced]), complemento([comparable, increases, in, 4, -, hydroxynonenal, glutathione, conjugate, concentration, in, hearts, from, 'WT', and, 'Mrp1(-/-)', mice])].
[sujeto(['However,', more, 'DOX-induced', apoptosis, was, detected, in, 'Mrp1(-/-)', versus, 'WT', hearts, '(', 'P', &, 'lt;', 0.05, ')', '(', protocol, 'A),', and, cardiac, 'function,', assessed, by, measurement, of, fractional, shortening, and, ejection, fraction, with, 'echocardiography,', was, significantly]), verbo([decreased]), complemento([by, 'DOX', in, 'Mrp1(-/-)', versus, 'WT', mice, '(', 'P', &, 'lt;', 0.05, ;, 95, '%', confidence, intervals, of, 20.0, '%', -, 24.3, '%', versus, 23.7, '%', -, 29.5, '%', for, fractional, 'shortening,', and, 41.5, '%', -, 48.4, '%', versus, 47.7, '%', -, 56.7, '%', for, ejection, 'fraction;', protocol, 'B)'])].
[sujeto(['Transfection', of, 'miR-134', mimics]), verbo([induced]), complemento(['MCF-7/ADR', cell, apoptosis])].
[sujeto(['Over-expression', of, 'miR-134']), verbo([decreased]), complemento([the, expression, of, 'ABCC1', at, the, protein, level])].
[sujeto(['MicroRNA-134']), verbo([modulates]), complemento([resistance, to, doxorubicin, in, breast, cancer, cells, by, downregulating, the, expression, of, 'ABCC1', which, is, known, to, encode, the, multidrug, 'resistance-associated', protein, 1])].
[sujeto(['Inhibitors', and, substrates, of, these, transporters, may]), verbo([participate]), complemento([in, pharmacokinetic, 'drug-drug', interactions, '(', 'DDIs)', that, alter, drug, disposition, during, pharmacotherapy])].
[sujeto(['To', assess, such, risks]), verbo([associated]), complemento([with, dinaciclib, we, evaluated, its, possible, effects, on, efflux, activities, of, 'ABCB1,', 'ABCC1', and, 'ABCG2', transporters, in, vitro])].
[sujeto(['In', 'addition,', overexpression, of, 'ABCB1,', 'ABCG2', and, 'ABCC1']), verbo([conferred]), complemento([resistance, to, dinaciclib, in, 'MDCKII', cells])].
[sujeto(['In', 'ATPase', 'assays,', dinaciclib]), verbo([decreased]), complemento([stimulated, 'ATPase', activity, of, 'ABCB1,', 'ABCG2', and, 'ABCC1,', confirming, it, has, interactive, potential, toward, all, three, transporters])].
[sujeto(['Moreover,', dinaciclib, significantly]), verbo([inhibited]), complemento(['ABCC1-mediated', efflux, of, daunorubicin, '(', 'EC50=18', 'μM)'])].
[sujeto(['The', inhibition, of, 'ABCC1', further]), verbo([led]), complemento([to, a, synergistic, effect, of, dinaciclib, in, both, 'MDCKII-ABCC1', and, human, cancer, 'T47D', 'cells,', when, applied, in, combination, with, anticancer, drugs])].
[sujeto(['Taken', 'together,', our, results]), verbo([suggest]), complemento([that, 'ABC', transporters, can, substantially, affect, dinaciclib, transport, across, cellular, 'membranes,', leading, to, 'DDIs'])].
[sujeto(['Hepatocellular', carcinoma, is, the, third, most, common]), verbo([cause]), complemento([of, 'cancer-related', deaths, worldwide])].
[sujeto(['Hispidulin', '(', 6, -, 'methoxy-5,7,4\'-trihydroxyflavone)', is, a, flavonoid]), verbo([found]), complemento([in, various, medicinal, herbs, that, present, antineoplastic, properties])].
[sujeto(['Here', we, evaluated, how, modulation, of, reactive, oxygen, species, '(', 'ROS)', and, alterations, of, antioxidant, defenses, could, be]), verbo([associated]), complemento([to, the, antiproliferative, effects, of, hispidulin, in, 'HepG2', cells])].
[sujeto(['In', 'addition,', we, studied, the, inhibitory, activity, of, hispidulin, on, the, efflux, of, drugs]), verbo([mediated]), complemento([by, 'ABC', transporters, involved, in, multidrug, resistance])].
[sujeto(['In', order, to, understand, the]), verbo([increase]), complemento([of, intracellular, 'ROS', promoted, by, 'hispidulin,', we, investigated, the, mRNA, expression, levels, and, activities, of, antioxidant, 'enzymes,', and, the, 'GSH/GSSG', ratio])].
[sujeto(['We', showed, that, hispidulin, significantly, 'down-regulated', the, transcription, levels, of, 'catalase,']), verbo([leading]), complemento([to, reduction, of, enzyme, activity, and, decrease, of, the, 'GSH', content])].
[sujeto(['These', data, clearly, indicate, a, strong, involvement, of, intracellular, 'ROS', levels, for]), verbo([triggering]), complemento([the, antiproliferative, effects])].
[sujeto(['Furthermore,', 'HepG2', cells, were, more, sensitive, to, 'hispidulin-mediated', cell, death, than, immortalized, 'L929', 'fibroblasts,']), verbo([suggesting]), complemento([a, differential, toxicity, of, this, compound, between, tumor, and, 'non-tumor', cell, lines])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, hispidulin, constitutes, a, promising, candidate, to, sensitize, chemoresistant, cancer, cells, overexpressing, 'ABCG2'])].
[sujeto(['Glutathione', '(', 'GSH),', the, major, antioxidant, in, the, central, nervous, 'system,', is, primarily, synthesized, and]), verbo([released]), complemento([by, astrocytes])].
[sujeto(['We', determined, if, 'β-amyloid', '(', 'Aβ42),', crucially]), verbo([involved]), complemento([in, 'Alzheimer\'s', 'disease,', affected, 'GSH', release])].
[sujeto(['Monomeric', 'Aβ', '(', 'mAβ)']), verbo([stimulated]), complemento(['GSH', release, from, cultured, cortical, astrocytes, more, effectively, than, oligomeric, 'Aβ', '(', 'oAβ)', or, fibrillary, 'Aβ', '(', 'fAβ)'])].
[sujeto(['Monomeric', 'Aβ']), verbo([increased]), complemento([the, expression, of, the, transporter, 'ABCC1', '(', also, referred, to, as, 'MRP1)', that, is, the, main, pathway, for, 'GSH', release])].
[sujeto(['GSH']), verbo([release]), complemento([from, 'astrocytes,', with, or, without, mAβ, 'stimulation,', was, reduced, by, pharmacological, inhibition, of, 'ABCC1'])].
[sujeto(['Astrocytes', robustly]), verbo([express]), complemento([connexin, 'proteins,', especially, connexin43, '(', 'Cx43),', and, mAβ, also, stimulated, 'Cx43', 'hemichannel-mediated', glutamate, and, 'GSH', release])].
[sujeto(['Using', a, mouse, model, of, 'AD', with, early, onset, 'Aβ', deposition, '(', 5, 'xFAD),', we]), verbo([found]), complemento([that, cortical, 'ABCC1', was, significantly, increased, in, temporal, register, with, the, surge, of, 'Aβ', levels, in, these, mice])].
[sujeto(['These', results, support, the, hypothesis, that, in, the, early, stage, of, 'AD', 'pathogenesis,', less, aggregated, 'Aβ']), verbo([increases]), complemento(['GSH', release, from, astrocytes, '(', via, 'ABCC1', transporters, and, 'Cx43', 'hemichannels)', providing, temporary, protection, from, oxidative, stress, which, promotes, 'AD', development])].
[sujeto(['MicroRNAs', '(', 'miRNAs)', represent, a, class, of, small, 'non-coding', 'RNAs', and]), verbo([have]), complemento([been, shown, to, play, important, roles, in, various, biological, processes, including, cell, 'growth,', differentiation, and, apoptosis, by, regulating, the, target, genes])].
[sujeto(['miR-7']), verbo([has]), complemento([been, described, not, only, as, a, tumour, suppressor, gene, but, also, as, an, oncogene, in, human, cancers])].
[sujeto(['By', using, a, bioinformatic, 'assay,', we]), verbo([found]), complemento([that, 'MRP1/ABCC1', was, a, potential, target, gene, of, 'miR-7'])].
[sujeto(['Low-level', expression, of, 'miR-7', was]), verbo([associated]), complemento([significantly, with, drug, responsiveness, and, overall, survival, rate, of, patients, with, 'SCLC,', but, not, with, 'gender,', age, and, stage])].
[sujeto(['A', 'dual-luciferase', reporter, assay, confirmed, that, 'miR-7']), verbo([targeted]), complemento([predicted, sites, in, the, 3, '\'', -, untranslated, region, '(', 3, '\'', -, 'UTR)', of, the, 'MRP1/ABCC1', gene])].
[sujeto(['Our', data]), verbo([suggested]), complemento([that, 'miR-7', mediated, 'SCLC', chemoresistance, by, repressing, 'MRP1/ABCC1', and, may, be, a, prognostic, predictor, and, potential, therapeutic, target, in, human, 'SCLC'])].
[sujeto(['Increased', risk, for, 'non-response', was]), verbo([associated]), complemento([to, 'SLC22A11', rs11231809, 'T', 'carriers;', 'ABCC1', rs246240, 'G', 'carriers;', 'ABCC1', rs3784864, 'G', 'carriers;', 'CGG', haplotype, for, 'ABCC1', 'rs35592,', rs2074087, and, 'rs3784864;', and, 'CGG', haplotype, for, 'ABCC1', 'rs35592,', rs246240, and, rs3784864])].
[sujeto(['This', study, revealed, that, 'SLC22A11', and, 'ABCC1', may, be, important, to, identify, those, patients, who, will, not, benefit, from, 'MTX', 'treatment,', highlighting, the, relevance, in]), verbo([translating]), complemento([these, results, to, clinical, practice])].
[sujeto(['Amyloidosis', mouse, models, of, 'Alzheimer\'s', disease, are, generally, established, by, transgenic, approaches]), verbo([leading]), complemento([to, an, overexpression, of, mutated, human, genes, that, are, known, to, be, involved, in, the, generation, of, 'amyloid-β', in, 'Alzheimer\'s', families])].
[sujeto(['Using', behavioural, 'tests,', electrophysiology, and, morphological, 'analyses,', we, compared, different, 'ABC', 'transporter-deficient', animals, and]), verbo([found]), complemento([that, alterations, are, most, prominent, in, neprilysin, ×, 'ABCC1', 'double-deficient', mice])].
[sujeto(['We', show, that, these, mice]), verbo([have]), complemento([a, reduced, probability, to, 'survive,', show, increased, anxiety, in, new, 'environments,', and, have, a, reduced, working, memory, performance])].
[sujeto([astrogliosis, and, reduced, numbers, of, 'synapses,']), verbo([leading]), complemento([to, defective, 'long-term', potentiation, in, functional, measurements])].
[sujeto(['SNS-032', also]), verbo([decreased]), complemento(['ABCG2-mediated', 'efflux,', while, 'AT-7519', failed, to, inhibit, 'ABCB1,', 'ABCG2', or, 'ABCC1'])].
[sujeto(['ABCB1', was]), verbo([found]), complemento([to, confer, significant, resistance, to, 'AT-7519', and, 'SNS-032,', but, not, to, flavopiridol])].
[sujeto(['In', 'contrast,', 'ABCG2', and, 'ABCC1']), verbo([conferred]), complemento([resistance, to, 'flavopiridol,', but, not, to, 'AT-7519', and, 'SNS-032'])].
[sujeto(['Our', data]), verbo([provide]), complemento([detailed, information, on, interactions, of, 'flavopiridol,', 'SNS-032', and, 'AT-7519', with, 'ABC', 'transporters,', which, may, help, elucidate, the, pharmacokinetic, behavior, and, toxicity, of, these, compounds])].
[sujeto(['Human', 'ATP-binding', cassette, '(', 'ABC)', transporter, 'ABCG2', '(', 'BCRP)', is, critically]), verbo([involved]), complemento([in, multidrug, resistance, of, human, cancer])].
[sujeto(['To']), verbo([gain]), complemento([insight, into, the, relationship, between, the, molecular, structure, of, compounds, and, the, 'ABCG2-mediated', transport, 'activity,', we, have, developed, a, 'high-speed', screening, method, to, analyze, the, substrate, specificity, of, 'ABCG2'])].
[sujeto(['In', 'addition,', we]), verbo([have]), complemento([developed, an, algorithm, that, analyzes, 'QSAR', to, evaluate, 'ABCG2-drug', interactions])].
[sujeto(['Remarkable', advances]), verbo([have]), complemento([been, made, in, cancer, chemotherapy, by, developing, new, anticancer, drugs, and, pharmacogenomics, strategies])].
[sujeto(['Several', 'ATP-binding', cassette, '(', 'ABC)', transporters]), verbo([cause]), complemento([multidrug, resistance, in, cancer, cells, by, actively, extruding, the, clinically, administered, chemotherapeutic, drugs])].
[sujeto(['P-glycoprotein', '(', 'ABCB1/MDR1/P-gp)', and, 'MRP1', '(', 'ABCC1/GS-X', 'pump)']), verbo([have]), complemento([been, well, characterized, in, terms, of, their, molecular, structure, and, function])].
[sujeto(['In', 'addition,', 'ABCG2/breast', cancer, resistance, protein, '(', 'BCRP)', is, the, most, recently, 'identified/ABC', 'transporter,', and, is, also, reportedly]), verbo([associated]), complemento([with, cellular, resistance, against, chemotherapeutic, 'agents,', such, as, 'DNA', topoisomerase, 'I,', 'II', inhibitor])].
[sujeto(['It', is, important, to, note, that, these, 'ABC', transporters, are]), verbo([expressed]), complemento([not, only, in, cancer, cells, but, also, in, normal, tissues, to, play, a, pivotal, role, in, the, 'absorption,', 'distribution,', and, excretion, of, endogenous, substances, as, well, as, xenobiotics])].
[sujeto(['Recent', studies]), verbo([have]), complemento([revealed, that, many, single, nucleotide, polymorphisms, '(', 'SNPs)', reside, in, these, 'ABC', transporter, genes])].
[sujeto(['Four', important, transporter, genes, are]), verbo([expressed]), complemento([in, the, 'kidney,', including, organic, cation, transporter, 2, '(', 'OCT2),', multidrug, and, toxin, extrusion, 1, '(', 'MATE1),', 'ATP-binding', cassette, subfamily, 'B', member, 1, '(', 'ABCB1),', and, 'ATP-binding', cassette, subfamily, 'C', member, 2, '(', 'ABCC2),', and, genetic, polymorphisms, in, these, genes, may, alter, the, efficacy, and, adverse, effects, of, platinum, drugs])].
[sujeto(['A', total, of, 403, 'Chinese', 'NSCLC', patients, were]), verbo([recruited]), complemento([for, this, study])].
[sujeto(['OCT2', rs316019, was]), verbo([associated]), complemento([with, hepatotoxicity, '(', 'P&nbsp;=&nbsp;0'])].
[sujeto([39, ')', ',', and, 'MATE1', rs2289669, was]), verbo([associated]), complemento([with, hematological, toxicity, induced, by, platinum, '(', 'P&nbsp;=&nbsp;0'])].
[sujeto(['In', 'addition,', 'ABCC2', rs717620, was, significantly]), verbo([associated]), complemento([with, the, 'platinum-based', chemotherapy, response, '(', 'P&nbsp;=&nbsp;0'])].
[sujeto(['ABCB1', polymorphisms, were]), verbo([associated]), complemento([with, neither, response, nor, toxicity])].
[sujeto(['OCT2', 'rs316019,', 'MATE1', 'rs2289669,', and, 'ABCC2', rs717620, might, be, potential, clinical, markers, for, predicting, chemotherapy, toxicity, and, response]), verbo([induced]), complemento([by, 'platinum-based', treatment, in, 'NSCLC', patients])].
[sujeto(['CDDP', 'cross-resistance']), verbo([has]), complemento([been, suggested, to, develop, with, 'PTX,', thus, hindering, successful, 'UCUB', treatment])].
[sujeto(['Therefore,', elucidating, the, mechanisms, underlying, 'CDDP-induced', anticancer, drug, resistance, is, imperative, and, may]), verbo([provide]), complemento([an, insight, in, developing, novel, therapeutic, strategy])].
[sujeto(['Reporter', and, in, vivo, 'DNA-binding', assays, were, employed, to, determine, whether, 'CEBPD', directly]), verbo([regulates]), complemento(['ATP', binding, cassette, subfamily, 'B', member, 1, '(', 'ABCB1)', and, 'ATP', binding, cassette, subfamily, 'C', member, 2, '(', 'ABCC2)', activation])].
[sujeto(['CEBPD', expression, was]), verbo([maintained]), complemento([in, postoperative, chemotherapy, 'patients,', and, this, expression, was, induced, by, 'CDDP', even, in, 'CDDP-resistant', 'UCUB', cells])].
[sujeto(['Upon', 'CDDP', 'treatment,', 'CEBPD']), verbo([activated]), complemento(['ABCB1', and, 'ABCC2'])].
[sujeto(['Gefitinib', and, 'S3I-201', treatment, significantly, reduced, the, expression, of, 'CEBPD', and]), verbo([enhanced]), complemento([the, sensitivity, of, 'CDDP-resistant', 'UCUB', cells, to, 'CDDP', and, 'PTX'])].
[sujeto(['Our', results, revealed, the, risk, of, 'CEBPD', activation, in, 'CDDP-resistant', 'UCUB', cells, and]), verbo([suggested]), complemento([a, therapeutic, strategy, for, patients, with, 'UCUB', or, 'UCUB', resisted, to, 'CDDP', and, 'PTX', by, combination, with, either, gefitinib, or, 'S3I-201'])].
[sujeto(['However,', its, precise, role, in, various, cancer, types]), verbo([has]), complemento([been, 'controversial,', and, the, aim, of, this, study, was, to, investigate, the, expression, of, 'ABCG2', in, hepacellular, carcinoma, '(', 'HCC)', and, relate, the, results, to, established, prognostic, factors])].
[sujeto(['Additionally,']), verbo([increased]), complemento([expression, of, 'ABCG2', in, 'HCC', and, its, statistically, significant, correlation, with, hepatitis, 'B', surface, antigen, was, found, in, elderly, '(', 'p=0'])].
[sujeto(['Importantly,', by, using, 'Kaplan-Meier', and, 'Cox', regression, 'analysis,', overall, survival, in, patients, with, high, expression, of, 'ABCG2', was]), verbo([found]), complemento([reduced, in, elderly, patients, '(', 'p=0'])].
[sujeto(['ABCG2', can, be, used, as, a]), verbo([target]), complemento([for, the, development, of, novel, therapies, in, 'HCC'])].
[sujeto(['DNA', methylation, is, influenced, by, diet, and, single, nucleotide, polymorphisms, '(', 'SNPs),', and, methylation]), verbo([modulates]), complemento([gene, expression])].
[sujeto(['We', aimed, to, explore, whether, the, 'gene-by-diet', interactions, on, blood, lipids]), verbo([act]), complemento([through, 'DNA', methylation])].
[sujeto(['On', the, basis, of, the, 'meta-analysis', of, 7, cohorts, in, the, 'CHARGE', 'consortium,', higher, plasma, 'HDL', cholesterol, was]), verbo([associated]), complemento([with, fewer, 'C', alleles, at, 'ATP-binding', cassette, subfamily, 'A', member, 1, '(', 'ABCA1)', rs2246293, '(', β, =, -, 0.6, 'mg/dL,', 'P', =, 0.015, ')', and, higher, circulating, eicosapentaenoic, acid, '(', 'EPA)', '(', β, =, 3.87, 'mg/dL,', 'P', =, 5.62, ×, 10, '(', 21, ')', ')'])].
[sujeto(['The', difference, in, 'HDL', cholesterol]), verbo([associated]), complemento([with, higher, circulating, 'EPA', was, dependent, on, genotypes, at, 'rs2246293,', and, it, was, greater, for, each, additional, 'C', allele, '(', β, =, 1.69, 'mg/dL,', 'P', =, 0.006, ')'])].
[sujeto(['In', the, 'GOLDN', '(', 'Genetics', of, 'Lipid', 'Lowering', 'Drugs', and, 'Diet', 'Network)', 'study,', higher, 'ABCA1', promoter, cg14019050, methylation, was]), verbo([associated]), complemento([with, more, 'C', alleles, at, rs2246293, '(', β, =, 8.84, '%', ',', 'P', =, 3.51, ×, 10, '(', 18, ')', ')', and, lower, circulating, 'EPA', '(', β, =, -, 1.46, '%', ',', 'P', =, 0.009, ')', ',', and, the, mean, difference, in, methylation, of, cg14019050, that, was, associated, with, higher, 'EPA', was, smaller, with, each, additional, 'C', allele, of, rs2246293, '(', β, =, -, 2.83, '%', ',', 'P', =, 0.007, ')'])].
[sujeto(['Compared', with, the, model, without, the, adjustment, of, cg14019050, 'methylation,', the, model, with, such, adjustment]), verbo([provided]), complemento([smaller, estimates, of, the, mean, plasma, 'HDL', cholesterol, concentration, in, association, with, both, the, rs2246293, 'C', allele, and, 'EPA', and, a, smaller, difference, by, rs2246293, genotypes, in, the, 'EPA-associated', 'HDL', cholesterol])].
[sujeto(['We', obtained, little, evidence, that, the, 'gene-by-fatty', acid, interactions, on, blood, lipids]), verbo([act]), complemento([through, 'DNA', methylation])].
[sujeto(['MRP4']), verbo([mediates]), complemento([the, 'ATP-dependent', efflux, of, many, endogenous, and, exogenous, solutes, across, the, plasma, 'membrane,', and, in, polarized, 'cells,', it, localizes, to, the, apical, or, basolateral, plasma, membrane, depending, on, the, tissue, type])].
[sujeto(['Together', these, data, indicate, that, 'N-glycosylation', at, 'Asn746', and, 'Asn754', is, not, essential, for, plasma, membrane, localization, of, 'MRP4', but]), verbo([cause]), complemento(['substrate-selective', effects, on, its, transport, activity])].
[sujeto(['After', 'CO2', 'asphyxiation,', several, immediate, early, genes, were]), verbo([expressed]), complemento([at, lower, levels, in, 'Abcc5(-/-)', brains, than, in, wild, type, 'brains,', suggesting, altered, glutamate, signaling])].
[sujeto(['Current', evidence]), verbo([suggests]), complemento([that, heredity, contributes, to, the, progression, of, gout])].
[sujeto(['Previous', studies]), verbo([have]), complemento([shown, that, regulation, of, the, 'ATP-binding', cassette, subfamily, 'G', member, 2, '(', 'ABCG2)', pathways, plays, a, role, in, gout, occurrence])].
[sujeto(['We', identified, that, four, susceptibility, 'SNPs', were, potentially]), verbo([associated]), complemento([with, occurrence, of, gout])].
[sujeto(['Rs2622621', and, rs3114018, in, 'ABCG2', can, actually]), verbo([increase]), complemento([the, risk, of, gout, in, 'log-additive', model, '(', 'rs2622621,', odds, ratio, '(', 'OR)', =, 1.9, ',', 95, '%', confidence, interval, '(', 'CI)', 1.39, -, 2.61, ',', p, &, 'lt;', 0.001, ;, 'rs3114018,', 'OR', =, 1.55, ',', 95, '%', 'CI', 1.13, -, 2.13, ',', p, =, 0.006, ')'])].
[sujeto(['We']), verbo([found]), complemento([that, 'rs17731799G/T-G/G', and, rs3114020, 'T/C-T/T', in, 'ABCG2', can, actually, increase, the, risk, of, gout, in, dominant, model, '(', 'rs17731799,', 'OR', =, 1.67, ',', 95, '%', 'CI', 1.05, -, 2.66, ',', p, =, 0.028, ;, 'rs3114020,', 'OR', =, 1.58, ',', 95, '%', 'CI', 1.0, -, 2.51, ',', p, =, 0.048, ')'])].
[sujeto(['The', 'ABCG2', haplotype, &, 'quot;GGCTCTC&quot;', '(', 'OR', =, 0.46, ',', 95, '%', 'CI', 0.28, -, 0.75, ',', p, =, 0.0019, ')']), verbo([decreased]), complemento([the, gout, risk])].
[sujeto(['Our', 'results,', combined, with, those, from, previous, 'studies,']), verbo([suggest]), complemento([that, genetic, variation, in, 'ABCG2', may, influence, gout, susceptibility, in, the, 'Han', population])].
[sujeto(['Vitamin', 'D', 'deficiency,', a, major, 'public-health', 'worldwide,', is]), verbo([associated]), complemento([with, hyperuricemia, but, casual, association, is, questioned])].
[sujeto(['A', potential, causal, effect, of, 'C', allele, on, 'UA', through, 25, '(', 'OH)D', was, -, 0.0236, '(', 95, '%', 'CI:', -, 0.0411, ',', -, 0.0058, ')', ',', indicating, every, minor, 'C', allele, resulted, in]), verbo([decreasing]), complemento([the, 25, '(', 'OH)D', and, then, significantly, decreased, the, 'UA', by, 0.0236, unit])].
[sujeto(['For', the, second, 'pathway,', the, mediation, effect, was, 0.0806, '(', 95, '%', 'CI:', 0.0107, ',', 0.1628, ')', ;, every, 'T', allele, copy, for, rs2231142]), verbo([increased]), complemento(['UA', and, thus, increased, 25, '(', 'OH)D', by, 0.0806, unit])].
[sujeto(['Our', study]), verbo([suggested]), complemento([potential, causal, associations, between, the, 'GC', gene, and, 'UA', through, the, 25, '(', 'OH)D', 'mediator,', and, the, 'ABCG2', and, the, 25, '(', 'OH)D', through, the, 'UA', mediator, but, the, absolute, effects, are, very, clinically, small])].
[sujeto(['Using', parallel, protein, fractionation, in, conjunction, with, shotgun, proteomics, on, fractions, containing, 'N-lactoyl-Phe-forming', 'activity,', we, unexpectedly]), verbo([found]), complemento([that, a, 'protease,', cytosolic, nonspecific, dipeptidase, 2, '(', 'CNDP2),', catalyzes, their, formation])].
[sujeto(['The', plasma, levels, of, these, metabolites, strongly, correlate, with, plasma, levels, of, lactate, and, amino, 'acid,', as, shown, by]), verbo([increased]), complemento([levels, after, physical, exercise, and, in, patients, with, phenylketonuria, who, suffer, from, elevated, 'Phe', levels])].
[sujeto(['Our', approach, to, identify, unknown, metabolites, and, their, biosynthesis]), verbo([has]), complemento([general, applicability, in, the, further, exploration, of, the, human, metabolome])].
[sujeto(['We', present, evidence, that, despite, structural, 'differences,', carbamazepine, and, glibenclamide, compete, for]), verbo([binding]), complemento([to, 'KATP', 'channels,', and, both, drugs, share, a, binding, pocket, in, 'SUR1', to, exert, their, effects])].
[sujeto([2, ',', which, is]), verbo([involved]), complemento([in, normal, channel, 'biogenesis,', for, their, chaperoning, effects, on, 'SUR1', mutants])].
[sujeto(['Conversely,', both, drugs, can, correct, channel, biogenesis, defects]), verbo([caused]), complemento([by, 'Kir6'])].
[sujeto([2, ',', we, demonstrate, in, living, cells, that, both, drugs]), verbo([promote]), complemento([interactions, between, the, distal, 'N', terminus, of, 'Kir6'])].
[sujeto(['These', findings]), verbo([reveal]), complemento([a, converging, pharmacological, chaperoning, mechanism, wherein, glibenclamide, and, carbamazepine, stabilize, the, heteromeric, subunit, interface, critical, for, channel, biogenesis, to, overcome, defective, biogenesis, caused, by, mutations, in, individual, subunits])].
[sujeto(['The', 'ATP-binding', 'cassette,', subfamily, 'C', '[', 'CFTR/MRP],', member, 2, '(', 'ABCC2)', gene, is, a, member, of, the, 'ATP-binding', cassette, transporters, and, is]), verbo([involved]), complemento([in, the, transport, of, molecules, across, cellular, membranes])].
[sujeto([4544, 'G&gt;A,', and, a, third, 'variant,']), verbo([suggesting]), complemento([that, c])].
[sujeto(['Here,', we]), verbo([report]), complemento([a, new, haplotype, in, 'ABCC2'])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, the, polymorphisms, of, 'OCT1', rs628031, and, 'ABCG2', rs2231142, may, affect, 'LTG', metabolism, in, 'Chinese', patients, with, epilepsy])].
[sujeto(['The', 'UGT1A1', '(', 'rs8175347)', polymorphism, was]), verbo([associated]), complemento([with, hyperbilirubinemia, and, treatment, interruption])].
[sujeto(['Polymorphisms', in, 'SLCO1B1', '(', 'rs2306283,', 'rs4149056)', were]), verbo([associated]), complemento([with, diarrhea, and, 'thrombocytopenia,', respectively])].
[sujeto(['None', of, the, investigated, polymorphisms, was]), verbo([associated]), complemento([with, overall, or, 'progression-free', survival, in, hepatocellular, cancer, patients])].
[sujeto(['Polymorphisms', in, 'SLCO1B1', and, 'UGT1A1', are]), verbo([associated]), complemento([with, several, different, sorafenib, side, effects])].
[sujeto(['Several', studies]), verbo([have]), complemento([evaluated, the, efficacy, of, neoadjuvant, treatment, using, oxaliplatin, and, fluoropyrimidines, in, advanced, gastric, cancer, '(', 'GC)'])].
[sujeto(['The', 'ABCC2-24C', &, 'gt;', 'T', '(', 'rs717620)', genotype, was]), verbo([associated]), complemento([with, pathologic, response, to, neoadjuvant, chemotherapy])].
[sujeto(['Patients', with, the, 'TT', and, 'TC', genotypes]), verbo([responded]), complemento([to, neoadjuvant, chemotherapy, 3.8, times, more, often, than, those, with, the, 'CC', genotype, '(', 95, '%', 'CI:', 1.27, -, 11.32, ')'])].
[sujeto(['We', investigated, their, interaction, using, stably]), verbo([expressing]), complemento(['non-lytic', clonal, 'Sf9', cell, lines, expressing, either, protein, or, both, together])].
[sujeto(['Untransfected', 'Sf9', cells, are, innately, sensitive, to, 'Cry1Ca', 'toxin,', but, not, to, 'Cry1A', 'toxins;', and, quantitative, 'PCR', revealed, negligible, expression, of, genes]), verbo([involved]), complemento([in, 'Cry1A', toxicity, such, as, 'cadherin,', 'ABCC2,', alkaline, phosphatase, '(', 'ALP)', and, aminopeptidase, 'N', '(', 'APN)'])].
[sujeto(['Cry1Aa,', 'Cry1Ab', or, 'Cry1Ac']), verbo([caused]), complemento([swelling, of, 'Sf9', cells, expressing, 'HevABCC2,', and, caused, faster, 'swelling,', lysis, and, up, to, 86, '%', mortality, in, cells, expressing, both, proteins])].
[sujeto(['No', such, effect, was, observed, in, control, 'Sf9', cells, or, in, cells]), verbo([expressing]), complemento([only, 'HevCaLP'])].
[sujeto(['The', results, of, a, mixing, experiment, demonstrated, that, both, proteins, need, to, be]), verbo([expressed]), complemento([within, the, same, cell, for, high, 'cytotoxicity,', and, suggest, a, novel, role, for, 'HevCaLP'])].
[sujeto(['Our', findings, confirm, that, 'HevABCC2', is, the, central]), verbo([target]), complemento([in, 'Cry1A', toxin, mode, of, 'action,', and, that, 'HevCaLP', plays, a, supporting, role, in, increasing, 'Cry1A', toxicity])].
[sujeto(['The', use, of, combination, antiretroviral, therapy, '(', 'cART)', and, cytotoxic, chemotherapy, for, 'HIV-associated', lymphoma, runs, the, risks, of]), verbo([inducing]), complemento(['HIV', drug, resistance])].
[sujeto(['In', 'conclusion,', concomitant, administration, of, cytotoxic, chemotherapy, and, cART, does, not]), verbo([induce]), complemento([expression, of, 'MTP'])].
[sujeto(['Furthermore,', no, significant, changes, in, viral, resistance, were, observed, 'pre-', and, 'post-chemotherapy,']), verbo([suggesting]), complemento([mutagenic, cytotoxic, chemotherapy, seems, not, to, induce, mutations, in, 'HIV', 'pro-viral', 'DNA'])].
[sujeto(['To', 'conclude,', placental, transport, of, lamivudine, does, not, seem, to, be, affected, by, 'P-gp,', 'MRP2,', or, 'BCRP,', but, a, 'pH-dependent', mechanism]), verbo([mediates]), complemento([transport, of, lamivudine, in, the, 'fetal-to-maternal', direction])].
[sujeto(['We']), verbo([suggest]), complemento([that, 'MATE1', might, 'be,', at, least, 'partly,', responsible, for, this, transport])].
[sujeto(['They']), verbo([prevent]), complemento([intracellular, accumulation, of, toxic, 'compounds,', rendering, them, a, major, defense, mechanism, against, harmful, substances])].
[sujeto(['To']), verbo([gain]), complemento([insight, in, the, function, of, this, crucial, 'protein,', we, have, investigated, and, developed, the, first, effective, inhibitors, of, this, pump])].
[sujeto(['We']), verbo([found]), complemento([that, 2, -, indolylmethylenebenzofuranone, derivatives, as, promising, candidates])].
[sujeto(['Optimization', of, the, hits]), verbo([provided]), complemento([new, compounds, that, inhibit, 'ABCC2', in, the, micromolar, 'range,', making, them, the, first, potent, 'ABCC2', inhibitors, reported, so, far])].
[sujeto(['Transcription', factor, 'Nrf2']), verbo([induces]), complemento([a, number, of, detoxifying, enzymes, and, antioxidant, proteins, to, confer, protection, against, the, toxic, effects, of, a, diverse, range, of, chemicals, including, inorganic, arsenicals])].
[sujeto(['Although', a, number, of, studies, using, cultured, cells]), verbo([have]), complemento([demonstrated, that, 'Nrf2', has, a, 'cell-protective', function, against, acute, and, 'high-dose', arsenic, 'toxicity,', there, is, no, clear, in, vivo, evidence, of, this, effect])].
[sujeto(['After', treatment, with, 1, mM, sodium, 'arsenite,', the, survival, of, 'nrf2a(fh318)', larvae, was, significantly, shorter, than, that, of, 'wild-type', 'siblings,']), verbo([suggesting]), complemento([that, 'Nrf2', protected, the, zebrafish, larvae, against, 'high-dose', arsenite, exposure])].
[sujeto(['To', understand, the, molecular, basis, of, the, 'Nrf2-dependent', 'protection,', we, analyzed, the, gene, expression, profiles, after, arsenite, 'exposure,', and]), verbo([found]), complemento([that, the, genes, involved, in, the, antioxidative, function, '(', prdx1, and, 'gclc),', arsenic, metabolism, '(', 'gstp1)', and, xenobiotic, elimination, '(', 'abcc2)', were, induced, in, an, 'Nrf2-dependent', manner])].
[sujeto(['Based', on, these, 'results,', we, concluded, that, 'Nrf2', plays, a, fundamental, and]), verbo([conserved]), complemento([role, in, protection, against, acute, sodium, arsenite, toxicity])].
[sujeto(['In', the, setting, of, chronic, kidney, disease, '(', 'CKD),', altered, 'extra-renal', urate, handling, may, be, necessary, to]), verbo([regulate]), complemento([plasma, uric, acid])].
[sujeto(['What', do, drug, transporters, really, 'do?', 'Nat', 'Rev', 'Drug', 'Discov', 2015, ;, 14, :, 29, -, 44, ')']), verbo([suggests]), complemento([that, multispecific, solute, carrier, '(', 'SLC)', and, 'ATP-binding', cassette, '(', 'ABC)', drug, transporters, in, different, tissues, are, part, of, an, 'inter-organ', communication, system, that, maintains, levels, of, urate, and, other, metabolites, after, organ, injury])].
[sujeto(['In', 'CRIC,', weaker, associations, were, also]), verbo([found]), complemento([for, 'SLC17A3', '(', 'NPT4)', and, 'gender-specific', associations, found, for, 'SLC22A8', '(', 'OAT3),', 'SLC22A11', '(', 'OAT4),', and, 'ABCC4', '(', 'MRP4)'])].
[sujeto(['In', patients, of, 'EA', with, 'CKD', '(', 'CRIC', 'cohort),', we]), verbo([found]), complemento([striking, associations, between, uric, acid, and, 'SNPs', on, 'ABCG2,', a, key, transporter, of, uric, acid, by, intestine])].
[sujeto(['Therapies', focused, on]), verbo([enhancing]), complemento(['ABCG2', urate, handling, may, be, helpful, in, the, setting, of, 'CKD', and, hyperuricemia])].
[sujeto(['With', studies]), verbo([revealed]), complemento([an, association, between, interindividual, patient, 'ADR', variation, and, efflux, transporter, 'variants,', we, carried, out, a, 'meta-analysis', and, systemic, 'review,', in, order, to, highlight, current, knowledge, regarding, the, strength, of, association, between, efflux, transporter, 'SNPs', variants, and, 'chemotherapeutic-drug', induced, 'ADRs'])].
[sujeto(['Of', the, known, efflux, drug, 'transporters,', we]), verbo([report]), complemento([findings, on, the, 'ABC', members, 'ABCB1,', 'ABCC1,', 'ABCC2,', 'ABCG2,', 'ABCA1,', 'ABCC4', and, 'ABCC5'])].
[sujeto(['Meta-analysis', showed, an]), verbo([decreased]), complemento([risk, of, 'irinotecan-induced', neutropenia, in, patients, expressing, 'ABCB1', 2677, 'G&gt;T/G', '(', odds, ratio, '[', 'OR]:', 0.24, ;, 95, '%', 'CI:', 0.1, -, 0.59, ;, p, =, 0.002, ')', but, increased, risk, for, 'ABCC2', 3972, 'T&gt;T', '(', 'OR:', 1.67, ;, 95, '%', 'CI:', 1.01, -, 2.74, ;, p, =, 0.04, ')'])].
[sujeto(['ABCG2', 34, 'G&gt;A', was]), verbo([associated]), complemento([with, a, threefold, increased, risk, of, 'irinotecan-induced', diarrhea, '(', 95, '%', 'CI:', 1.0, -, 6.24, ;, p, =, 0.05, ')'])].
[sujeto(['The', majority, of, studies]), verbo([have]), complemento([identified, a, role, for, variants, in, effluxdrug, transporters, in, contributing, to, lung, cancer, 'treatment-associated', 'ADRs'])].
[sujeto(['This', study, hypothesized, that, 'obesity-induced', inflammation, impedes, 'RCT', and, alters, 'HDL', 'composition,', and, investigated, if, dietary, replacement, of, saturated, '(', 'SFA)', for, monounsaturated, '(', 'MUFA)', fatty, acids]), verbo([modulates]), complemento(['RCT'])].
[sujeto(['Both', 'HFDs']), verbo([increased]), complemento([plasma, '(', 3, ')', 'H-cholesterol', counts, during, 'RCT', in, vivo, and, 'ATP-binding', 'cassette,', subfamily, 'A,', member, 1, -, independent, efflux, to, plasma, ex, 'vivo,', effects, that, were, attributable, to, elevated, 'HDL', cholesterol])].
[sujeto(['SFA-HFD', impaired, 'liver-to-feces', 'RCT,']), verbo([increased]), complemento([hepatic, 'inflammation,', and, reduced, 'ABC', subfamily, 'G', member, 5, /, 8, and, 'ABC', subfamily, 'B', member, 11, transporter, expression, in, comparison, with, 'low-fat', 'diet,', whereas, 'liver-to-feces', 'RCT', was, preserved, after, 'MUFA-HFD'])].
[sujeto(['Ex', vivo, efflux, assays, validated]), verbo([increased]), complemento(['macrophage-to-plasma', 'RCT', in, vivo, after, both, 'HFDs', but, failed, to, capture, differential, modulation, of, hepatic, cholesterol, trafficking])].
[sujeto(['This', excretory, function, of, 'ABCC3', becomes, very, apparent, particularly, under, cholestatic, 'conditions,', since, 'ABCC3', is]), verbo([induced]), complemento([when, the, biliary, excretion, pathway, is, impaired])].
[sujeto(['In', this, 'study,', we, analyzed, the, functional, properties, of, 11, nonsynonymous, single, nucleotide, polymorphisms, '(', 'SNPs)', in, the, 'ABCC3', gene]), verbo([found]), complemento([in, the, public, 'SNP', database])].
[sujeto(['After', transient, transfection, of, cDNA, into, 'HeLa', 'cells,', it, was]), verbo([found]), complemento([that, 'R1381S', 'ABCC3', exhibits, intracellular, accumulation, of, immature, 'protein,', the, localization, of, which, was, mostly, merged, with, a, marker, for, the, endoplasmic, reticulum])].
[sujeto(['The', results, of, this, study]), verbo([suggest]), complemento([that, the, possession, of, 'R1381S,', 'S346F,', and, 'S607N', types, of, 'ABCC3', sequences, may, be, a, possible, risk, factor, for, the, acquisition, of, 'hepatotoxicity,', due, to, their, poor, ability, to, transport, toxic, compounds, across, the, sinusoidal, membrane])].
[sujeto(['The', specificity, of, bacterial, nutrient, importers, of, the, 'ATP-binding', cassette, '(', 'ABC)', type, depends, on, external, receptor, proteins, that, not, only]), verbo([bind]), complemento([the, solute, to, be, 'transported,', but, also, initiate, the, transport, process, by, inducing, 'ATP', hydrolysis, in, the, cytoplasmic, 'nucleotide-binding', domains])].
[sujeto(['Here', we, propose, a, mode, of, ligand]), verbo([binding]), complemento([to, the, 'solute-binding', protein, 'AatJ', that, is, required, for, glutamate, uptake, by, the, 'AatJMQP', transporter, in, 'Pseudomonas', putida, 'KT2440'])].
[sujeto(['The', general, validity, of, the, model, was, then, confirmed, by, alanine, scanning, mutagenesis, of, several, residues, predicted, to]), verbo([interact]), complemento([with, the, ligand, and, by, 'semi-quantitative', binding, studies, with, '[', '(', 14, ')', 'C]-Glu', and, '[', '(', 14, ')', 'C]-Asp'])].
[sujeto(['The', 'ALD', gene, 'product,', 'so-called', 'ALDP', '(', 'ABCD1),', is, thought, to, be]), verbo([involved]), complemento([in, the, transport, of, 'VLCFA', or, 'VLCFA-CoA', into, the, peroxisomes])].
[sujeto(['ALDP', is, a, 'half-sized', peroxisomal, 'ABC', protein, and, it]), verbo([has]), complemento([745, amino, acids, in, humans])].
[sujeto(['During', this, 'process,', 'ALDP']), verbo([interacts]), complemento([with, 'Pex19p,', a, 'chaperone-like', protein, for, intracellular, trafficking, of, peroxisomal, membrane, protein, '(', 'PMP),', the, complex, targets, 'Pex3p', on, the, peroxisomal, 'membranes,', and, 'ALDP', is, inserted, into, the, membranes])].
[sujeto(['We']), verbo([found]), complemento([that, mutant, 'ALDP', '(', 'S606L,', 'R617H,', and, 'H667D)', was, degraded, together, with, 'wild-type', 'ALDP', by, proteasomes])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, complex, of, mutant, and, 'wild-type', 'ALDP', is, recognized, as, misfolded, proteins, and, degraded, by, the, protein, quality, control, system, associated, with, proteasomes])].
[sujeto(['Further,', we]), verbo([found]), complemento([fragmentation, of, mutant, 'ALDP', '(', 'R104C)', on, peroxisomes, and, it, was, not, inhibited, by, proteasomes, 'inhibitors,', suggesting, that, an, additional, 'protease(s)', is, also, involved, in, the, quality, control, of, mutant, 'ALDP'])].
[sujeto(['In', 'addition,', mutation, of, 'ALDP', '(', 'Y174C)']), verbo([suggests]), complemento([that, a, loop, between, transmembrane, domains, 2, and, 3, is, important, for, the, targeting, of, 'ALDP', to, peroxisomes])].
[sujeto(['Membrane', transporters, '(', such, as, 'ABCs,', 'SLCs', and, 'ATPases)']), verbo([act]), complemento([in, carcinogenesis, and, chemoresistance, 'development,', but, their, relevance, for, prognosis, of, epithelial, ovarian, cancer, '(', 'EOC)', remains, poorly, understood])].
[sujeto(['ABCA2', gene, expression, significantly]), verbo([associated]), complemento([with, 'EOC', grade, in, both, sets, of, patients])].
[sujeto(['Notably,', expression, level, of, 'ABCA9,', 'ABCA10,', 'ABCC9', and, 'SLC16A14', significantly]), verbo([associated]), complemento([with, 'progression-free', survival, '(', 'PFS)', of, the, disease, in, either, pilot, or, validation, sets])].
[sujeto(['ABCG2', level]), verbo([associated]), complemento([with, 'PFS', in, the, pooled, set, of, patients])].
[sujeto(['To', determine, the, basic, expression, of, 'ABC', transporters, in, an, epithelial, ovarian, cancer, cell, 'line,', and, to, investigate, whether, low, concentrations, of, acetaminophen, and, ibuprofen]), verbo([inhibited]), complemento([the, growth, of, this, cell, line, in, vitro])].
[sujeto(['We', observed, a, significant]), verbo([decrease]), complemento([in, 'TOV-21', 'G', cell, growth, after, exposure, to, 15, 'μg/mL', of, acetaminophen, for, 24, '(', 'p=0'])].
[sujeto(['Assessing', the, morphology, of, 'TOV-21', 'G', cells, did, not]), verbo([reveal]), complemento([evidence, of, extensive, apoptosis])].
[sujeto(['This', study]), verbo([provides]), complemento([in, vitro, evidence, of, inhibitory, effects, of, growth, in, therapeutic, concentrations, of, acetaminophen, and, ibuprofen, on, 'TOV-21', 'G', cells])].
[sujeto(['One', of, the, most, common]), verbo([causes]), complemento([of, worldwide, cancer, premature, death, is, 'non-small', cell, lung, carcinoma, '(', 'NSCLC)', with, a, very, low, survival, rate, of, 8, '%', -, 15, '%'])].
[sujeto(['Since', patients, with, an, early, stage, diagnosis, can]), verbo([have]), complemento([up, to, four, times, the, survival, 'rate,', discovering, 'cost-effective', biological, markers, that, can, be, used, to, improve, the, diagnosis, and, prognosis, of, the, disease, is, an, important, clinical, challenge])].
[sujeto(['In', the, last, few, 'years,', significant, progress]), verbo([has]), complemento([been, made, to, address, this, challenge, with, identified, biomarkers, ranging, from, 5, -, gene, signatures, to, 133, -, gene, signatures])].
[sujeto(['However,', 'A', typical, molecular, 'sub-classification', method, for, lung, carcinomas, would]), verbo([have]), complemento([a, low, predictive, accuracy, of, 68, '%', -, 71, '%', because, datasets, of, 'gene-expression', profiles, typically, have, tens, of, thousands, of, genes, for, just, few, hundreds, of, patients])].
[sujeto(['We', discovered, that, a, small, set, of, nine, 'gene-signatures', '(', 'JAG1,', 'MET,', 'CDH5,', 'ABCC3,', 'DSP,', 'ABCD3,', 'PECAM1,', 'MAPRE2', and, 'PDF5)', from, the, dataset, of, 12, ',', 600, 'gene-expression', profiles, of, 'NSCLC']), verbo([acts]), complemento([like, an, inference, basis, for, 'NSCLC', lung, carcinoma, and, hence, can, be, used, as, genetic, markers])].
[sujeto(['Furthermore,', we, present, a, novel, method, that]), verbo([finds]), complemento([genetic, markers, for, 'sub-classification', of, 'NSCLC'])].
[sujeto([',', 'JAG1', and, 'MAPRE2)']), verbo([have]), complemento([been, showed, to, involve, in, the, signal, transduction, of, cells, and, proliferation, control, of, normal, 'cells,', specific, functions, of, proteins, encoded, by, other, 'gene-signatures', have, not, yet, been, determined])].
[sujeto(['The', 'EGFR', over]), verbo([expressing]), complemento(['DU-145', 'WT', cell, line, exhibited, a, 4, -, fold, increase, in, expression, relative, to, non, transfected, 'DU-145', prostate, cell, lines])].
[sujeto(['Furthermore,', 'Ingenuity', 'Network', analysis, implicated, our, 'AA', prostate, candidate, genes, are]), verbo([involved]), complemento([in, three, network, 'hubs,', 'ERK,', 'MapK', and, 'NFkB', pathways])].
[sujeto(['Taken', 'together,', these, findings, are, intriguing, because, other, members, of, the, 'ABC', gene, 'family,', 'namely,', 'ABCC3,', 'ABCD1,', and, 'ABCD2']), verbo([have]), complemento([been, shown, to, confer, chemoresistance, in, certain, cancer, types])].
[sujeto(['Equally', 'important,', is, the, fact, that, activation, of, the, 'MapK/ERK', pathway, via, 'EGFR', stimulation, is, vital, for]), verbo([increased]), complemento([transcription, of, numerous, cancer, related, genes])].
[sujeto(['It', is, especially, noteworthy, that, overexpression, of, 'EGFR']), verbo([has]), complemento([been, widely, observed, in, 'AA', prostate, tumors])].
[sujeto(['Collectively', our, findings]), verbo([lead]), complemento([us, to, think, that, a, novel, signaling, 'cascade,', through, which, increased, aggressiveness, and, chemoresistance, is, 'achieved,', may, explain, prostate, cancer, health, disparity, in, 'AA', males, and, the, nature, of, aggressive, 'CaP', tumors, in, general])].
[sujeto(['Among', the, few, molecularly, defined, 'entities,', mutations, in, the, gene, encoding, the, 'ATP-binding', cassette, '(', 'ABC),', subfamily, 'A,', member, 3, '(', 'ABCA3)', lipid, transporter, represent, the, main]), verbo([cause]), complemento([of, inherited, surfactant, dysfunction, 'disorders,', a, subgroup, of, 'ILD'])].
[sujeto(['We']), verbo([found]), complemento([that, presence, of, the, 'K1388N', mutation, did, not, affect, protein, 'expression,', but, resulted, in, an, altered, protein, processing, and, a, functional, impairment, of, 'ABCA3'])].
[sujeto(['This', was, demonstrated, by]), verbo([decreased]), complemento(['dipalmitoyl-phosphatidylcholine', '(', 'PC', 32, :, 0, ')', content, and, malformed, lamellar, bodies, in, cells, transfected, with, the, 'K1388N', variant, as, compared, to, controls])].
[sujeto(['Knowledge', of, the, molecular, defects, and, close, correlation, of, in, vitro, and, ex, vivo, data, will, allow, us, to, define, groups, of, mutations, that, can, be]), verbo([targeted]), complemento([by, small, molecule, correctors, for, restoring, impaired, 'ABCA3', transporter, in, the, future])].
[sujeto(['Pulmonary', congenital, anomalies]), verbo([require]), complemento([a, high, index, of, suspicion])].
[sujeto(['Surfactant', protein, 'B', deficiency, is, clinically, progressive, and, fatal, in, the, majority, of, the, 'cases,', similar, to, that, of, 'ATP']), verbo([binding]), complemento([cassette, subfamily, 'A', member, 3, '(', 'ABCA3)', deficiency])].
[sujeto(['Due', to, the, similarity, in, the, histological, 'pattern,', genetic, studies, help, to, achieve, greater, certainty, in, the, prognosis, and, the, possibility, of]), verbo([providing]), complemento([adequate, genetic, counselling])].
[sujeto(['In', the, 'study,', we]), verbo([found]), complemento([that, the, frequency, of, 'C3435T', 'TT', genotype, was, much, lower, in, case, 'group,', compared, with, that, of, controls, '(', 17.7, '%', vs])].
[sujeto(['Based', on, the, 'results,', 'ABCB1', polymorphisms, were]), verbo([associated]), complemento([with, the, risk, for, 'ONFH'])].
[sujeto(['ATP-binding', 'cassette,', subfamily, 'C,', member, 3, '(', 'ABCC3),', a, member, of, the, 'ABC', transporter, 'family,', is, highly]), verbo([expressed]), complemento([in, tumor, 'cells,', where, it, actively, effluxes, a, broad, spectrum, of, metabolites])].
[sujeto(['We']), verbo([found]), complemento([that, both, mRNA, and, protein, levels, of, 'ABCC3', were, significantly, higher, in, 'UBC', tissues, than, normal, tissues])].
[sujeto(['ABCC3-knockdown', cells, showed, a, significant]), verbo([decrease]), complemento([in, cell, growth, and, drug, resistance])].
[sujeto(['RNA', interference, of, 'ABCC3', also]), verbo([caused]), complemento([downregulation, of, lactate, dehydrogenase, 'A', '(', 'LDHA),', which, positively, correlated, with, 'ABCC3', expression, in, 'UBC', specimens])].
[sujeto(['In', 'addition,', cancer, cell, glycolytic, ability, was]), verbo([decreased]), complemento([upon, 'ABCC3', knockdown])].
[sujeto(['The', activity, of, 'LDHA', was, also, abrogated, in, 'ABCC3-deficient', 'UBC', 'cells,', and, the, blockade, of, 'LDHA']), verbo([increased]), complemento(['UBC', cells, sensitivity, to, 'Cis-diamine', dichloroplatinum, '(', 'CDDP)'])].
[sujeto(['In', 'summary,', our, study]), verbo([suggests]), complemento(['ABCC3', is, an, important, oncoprotein, involved, in, glycolysis, and, drug, resistance])].
[sujeto(['These', data, also, indicates, that, 'ABCC3', could, be, a, potential, prognostic, marker, and, promising, therapeutic]), verbo([target]), complemento([in, 'UBC'])].
[sujeto(['PXE', is, considered, a, prototype, of, multisystem, ectopic, mineralization, disorders, and, it, is, characterized, by, aberrant, mineralization, of, soft, connective, tissue, with, degeneration, of, the, elastic, 'fibers,']), verbo([involving]), complemento([primarily, the, 'eyes,', the, cardiovascular, 'system,', and, the, skin])].
[sujeto(['PXE', is]), verbo([caused]), complemento([by, mutations, in, the, 'ABCC6', '(', 'ATP-binding', cassette, subfamily, 'C', member, 6, ')', gene, that, encodes, a, transmembrane, 'ATP', binding, efflux, 'transporter,', normally, expressed, in, the, liver, and, the, 'kidney;', 'however,', the, exact, mechanism, of, ectopic, mineralization, remains, largely, unknown])].
[sujeto(['The', histological, examination, of, cutaneous, 'lesions,']), verbo([revealed]), complemento([accumulation, of, pleomorphic, elastic, structures, in, 'middermis,', is, essential, for, the, definitive, diagnosis, of, 'PXE,', excluding, 'PXE-like', conditions])].
[sujeto(['PXE', is, currently, an, intractable, 'disease;', although, the, cutaneous, findings, primarily, present, a, cosmetic, 'problem,', they, signify, the, risk, for, development, of, ocular, and, cardiovascular, complications]), verbo([associated]), complemento([with, considerable, morbidity, and, mortality])].
[sujeto(['Combining', paclitaxel, and, afatinib]), verbo([caused]), complemento([tumor, regressions, and, tumor, necrosis, in, 'A2780T', xenografts, in, vivo])].
[sujeto(['Afatinib', not, only]), verbo([inhibited]), complemento([the, efflux, function, of, 'ABCB1,', but, also, attenuated, its, expression, transcriptionally, via, 'down-regulation', of, 'PI3K/AKT', and, 'MAPK/p38-dependent', activation, of, 'NF-κB'])].
[sujeto(['Furthermore,', apart, from, a, substrate]), verbo([binding]), complemento(['domain,', afatinib, could, also, bind, to, an, 'ATP', binding, domain, of, 'ABCB1', through, forming, hydrogen, bonds, with, 'Gly533,', 'Gly534,', 'Lys536', and, 'Ala560', sites])].
[sujeto(['Importantly,', mutations, in, these, four]), verbo([binding]), complemento([sites, of, 'ABCB1', and, the, tyrosine, kinase, domain, of, 'EGFR', were, not, correlated, with, the, reversal, activity, of, afatinib, on, 'MDR'])].
[sujeto(['Given', that, afatinib, is, a, clinically, approved, 'drug,', our, results]), verbo([suggest]), complemento([combining, afatinib, with, chemotherapeutic, drugs, in, ovarian, cancer])].
[sujeto(['This', study, can, facilitate, the, rediscovery, of, superior, 'MDR', reversal, agents, from, molecular]), verbo([targeted]), complemento([drugs, to, provide, a, more, effective, and, safer, way, of, resensitizing, 'MDR'])].
[sujeto(['Oysters', are, considered, 'hyper-accumulators', of, 'Cu,', but, the, molecular, mechanism, by, which, they]), verbo([maintain]), complemento(['Cu', cell, homeostasis, is, still, unclear])].
[sujeto(['In', this, 'study,', to]), verbo([provide]), complemento([insight, into, the, roles, of, 'ABCB1', in, resistance, against, 'Cu', in, 'oysters,', complete, cDNA, of, abcb1, gene, in, 'Crassostrea', angulata, was, cloned, and, analyzed])].
[sujeto(['Abcb1', was, mainly]), verbo([expressed]), complemento([in, the, apical, epithelial, cell, of, gills, and, epithelia, of, mantles])].
[sujeto(['Epithelial-mesenchymal', transition, '(', 'EMT),', a, process, implicated, in, cancer, 'metastasis,', is]), verbo([associated]), complemento([with, the, transcriptional, regulation, of, members, of, the, 'ATP-binding', cassette, superfamily, of, efflux, 'pumps,', and, drug, resistance, in, breast, cancer, cells])].
[sujeto(['In', this, study, induction, of, 'EMT', was, shown, to, result, in, the, transcriptional, 'up-regulation', of, 'ATP-binding', 'cassette,', subfamily, 'C,', member, 3, '(', 'ABCC3),', a, member, of, the, 'ABC', transporter, 'superfamily,', which]), verbo([has]), complemento([a, recognized, role, in, multidrug, resistance])].
[sujeto(['Buffering', of, cytosolic, free, calcium]), verbo([inhibited]), complemento(['EGF-mediated', 'ABCC3', 'increases,', indicating, a, 'calcium-dependent', mode, of, regulation])].
[sujeto(['Silencing', of, 'TRPM7', '(', an, ion, channel]), verbo([involved]), complemento([in, 'EMT', associated, vimentin, 'induction)', did, not, inhibit, 'ABCC3', 'up-regulation'])].
[sujeto(['Improved', understanding, of, the, relationship, between, calcium, 'signaling,', 'EMT', and, the, regulation, of, genes, important, in, therapeutic, resistance, may, help, identify, novel, therapeutic]), verbo([targets]), complemento([for, breast, cancer])].
[sujeto(['Resistance', of, the, patient, to, clopidogrel, '(', an, inactive, 'prodrug)']), verbo([has]), complemento([been, recently, reported, to, be, associated, with, increased, mRNA, expression, of, 'ABCC3', that, encodes, 'MRP3', '(', multidrug, 'resistance-associated', protein, 3, ')'])].
[sujeto(['Results', indicated, that, 'Abcc3', 'KO', mice, exhibited]), verbo([increased]), complemento([formation, of, 'CAM', and, greater, systemic, exposure, to, clopidogrel, as, well, as, enhanced, inhibition, of, 'ADP-induced', platelet, aggregation, ex, vivo, by, clopidogrel, when, compared, with, 'well-matched', 'WT', mice])].
[sujeto(['We', conclude, that, 'Abcc3', 'KO', mice]), verbo([have]), complemento([enhanced, platelet, response, to, clopidogrel, due, to, increased, formation, of, 'CAM'])].
[sujeto(['Here,', we]), verbo([found]), complemento([that, 'Abcc3', is, highly, expressed, in, 'blood-derived', 'NK', cells, but, not, in, 'CD8(+)', 'T', cells])].
[sujeto(['In', 'GL261', 'glioma-bearing', mice, treated, with, the, alkylating, agent, temozolomide, '(', 'TMZ)', for, 5, 'd,', an, early]), verbo([increased]), complemento([frequency, of, 'NK', cells, was, observed])].
[sujeto(['We', also]), verbo([found]), complemento([that, 'Abcc3', is, strongly, upregulated, and, functionally, active, in, 'NK', cells, from, mice, treated, with, 'TMZ', compared, to, controls])].
[sujeto(['We', demonstrate, that, 'Abcc3', is, critical, for, 'NK', cell, survival, during, 'TMZ', 'administration;', more, 'importantly,', 'Akt,']), verbo([involved]), complemento([in, lymphocyte, 'survival,', is, phosphorylated, only, in, 'NK', cells, expressing, 'Abcc3'])].
[sujeto(['The', resistance, of, 'NK', cells, to, chemotherapy, was, accompanied, by]), verbo([increased]), complemento([migration, and, homing, in, the, brain, at, early, time, points])].
[sujeto(['Cytotoxicity,', evaluated, by, 'IFNγ', production, and, specific, lytic, activity, against, 'GL261', 'cells,']), verbo([increased]), complemento([peripherally, in, the, later, 'phases,', after, conclusion, of, 'TMZ', treatment])].
[sujeto(['Intra-tumor']), verbo([increase]), complemento([of, the, 'NK', effector, subset, as, well, as, in, 'IFNγ,', granzymes, and, 'perforin-1', 'expression,', were, found, early, and, persisted, over, 'time,', correlating, with, a, profound, modulation, on, glioma, microenvironment, induced, by, 'TMZ'])].
[sujeto(['Our', findings]), verbo([reveal]), complemento([an, important, involvement, of, 'Abcc3', in, 'NK', cell, resistance, to, chemotherapy, and, have, important, clinical, implications, for, patients, treated, with, 'chemo-immunotherapy'])].
[sujeto(['For', 'example,', the, expressions, of, 'ABCC2,', 'ABCB1,', and, 'ABCC3', were]), verbo([increased]), complemento([1.9, -, ',', 1.7, -, ',', and, 1.2, -, 'fold,', respectively])].
[sujeto(['PXR', expression, was, very, low, in, the, kidney, 'cells;', this, may, explain, why, rifampin]), verbo([induces]), complemento([gene, expression, in, a, 'tissue-specific', manner])].
[sujeto(['Rifampin', alters, the, expression, of, many, of, the, clinically, relevant, hepatic, drug, 'transporters,', which, may]), verbo([provide]), complemento([a, rational, basis, for, understanding, 'rifampin-induced', 'drug-drug', interactions, reported, in, vivo])].
[sujeto(['Increased', expression, of, 'ABC-family', of, transporters, is]), verbo([associated]), complemento([with, chemotherapy, failure])].
[sujeto(['Although', the, drug, transporters, 'ABCG2,', 'ABCB1', and, 'ABCC1']), verbo([have]), complemento([been, majorly, implicated, in, cancer, drug, 'resistance,', recent, studies, have, associated, 'ABCC3', with, multi, drug, resistance, and, poor, clinical, response])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([examined, the, expression, of, 'ABCC3', in, breast, cancers, and, studied, its, role, in, drug, resistance, and, stemness, of, breast, cancer, cells, in, comparison, with, the, more, studied, 'ABCC1'])].
[sujeto(['Importantly,', expression, of, both, transporters, was, further]), verbo([increased]), complemento([in, chemotherapy, treated, patient, samples])].
[sujeto(['Consistent', with, 'this,', we, observed, that, treatment, of, breast, cancer, cell, lines, with, 'anti-cancer', agents]), verbo([increased]), complemento([their, mRNA, levels, of, both, 'ABCC1', and, 'ABCC3'])].
[sujeto(['Further,', similar, to, knockdown, of, 'ABCC1,', knockdown, of, 'ABCC3', also, significantly]), verbo([increased]), complemento([the, retention, of, chemotherapeutic, drugs, in, breast, cancer, cells, and, rendered, them, more, 'chemo-sensitive'])].
[sujeto(['Interestingly,', 'ABCC1', and, 'ABCC3', knockdown, cells, also, showed, reduction, in, the, expression, of, stemness, 'genes,', while, 'ABCC3', knockdown, additionally]), verbo([led]), complemento([to, a, reduction, in, the, 'CD44high/CD24low', breast, cancer, 'stem-like', subpopulation])].
[sujeto(['Further,', these, results]), verbo([suggest]), complemento([that, combinatorial, inhibition, of, these, transporters, together, with, standard, chemotherapy, can, reduce, 'therapy-induced', resistance, in, breast, cancer])].
[sujeto(['Human', hepatic, 'membrane-embedded', transporter, proteins, are]), verbo([involved]), complemento([in, trafficking, endogenous, and, exogenous, substrates])].
[sujeto(['Correlating', age, within, the, 'fetal/infant', age, group]), verbo([suggested]), complemento([four, specific, protein, expression, 'patterns,', as, 'follows:', 'stable,', low, to, 'high,', high, to, 'low,', and, 'low-high-low'])].
[sujeto(['The']), verbo([suggested]), complemento(['age-related', differences, in, transporter, protein, expression, may, aid, our, understanding, of, normal, growth, and, 'development,', and, also, may, impact, the, disposition, of, substrate, drugs, in, neonates, and, young, infants])].
[sujeto(['Translation', of, the, mouse, model, to, humans, for, the, purpose, of, explaining, exceptionally, high, human, pharmacokinetic, variability, and, its, relationship, with, 'exposure-dependent', 'dose-limiting', toxicities, will]), verbo([require]), complemento([delineation, of, the, importance, of, these, processes, on, disposition])].
[sujeto(['Embryos', of, oviparous, 'fish,', in, contrast, to, '(', 'ovo)', viviparous, 'species,', develop, in, the, aquatic, 'environment,', and, therefore, need, solute, transport, systems, at, their, body, surfaces, for]), verbo([maintaining]), complemento([internal, homeostasis, and, defending, against, potentially, harmful, substances])].
[sujeto(['While', clofibric, acid, had, no, 'effect,', clotrimazole]), verbo([lead]), complemento([to, an, increased, rhodamine, 'B', accumulation])].
[sujeto(['The', results]), verbo([provide]), complemento([evidence, that, the, transition, from, the, 'eleuthero-embryo', to, the, larval, stage, is, accompanied, by, a, major, alteration, in, tissue, expression, of, 'ABC', transporters])].
[sujeto(['Metabolic', syndrome, is, a, multifactorial, disease]), verbo([associated]), complemento([with, 'obesity,', insulin, 'resistance,', 'diabetes,', and, the, alteration, of, multiple, metabolic, hormones])].
[sujeto(['Obesity', rates]), verbo([have]), complemento([been, rising, 'worldwide,', which, increases, our, need, to, understand, how, this, population, will, respond, to, drugs, and, exposure, to, other, chemicals])].
[sujeto(['The', purpose, of, this, study, was, to, determine, in, lean, and, obese, mice, the, ontogeny, of, clinical, biomarkers, such, as, serum, hormone, and, blood, glucose, levels, as, well, as, the, physiologic, markers, that, correlate, with]), verbo([nuclear]), complemento(['receptor-', and, 'transporter-related', pathways])].
[sujeto(['Overall,', the, correlation, between, physiologic, changes, and, gene, expression, indicate, that, 'metabolism-related', hormones, may, play, a, role, in]), verbo([regulating]), complemento([the, genes, involved, in, drug, metabolism, and, transport])].
[sujeto(['Here', we, show, that, 'ATP-binding', cassette, member, 'B5', '(', 'ABCB5)']), verbo([confers]), complemento([resistance, to, 'standard-of-care', 'MCC', chemotherapeutic, agents, and, provide, 'proof-of-principle', that, 'ABCB5', blockade, can, inhibit, human, 'MCC', tumor, growth, through, sensitization, to, 'drug-induced', cell, cytotoxicity])].
[sujeto(['Carboplatin-', and, 'etoposide-resistant', 'MCC', cell, lines, exhibited]), verbo([increased]), complemento([expression, of, 'ABCB5,', along, with, enhanced, 'ABCB1', and, 'ABCC3', transcript, expression])].
[sujeto(['Moreover,', patients, with, 'MCC', also, exhibited]), verbo([enhanced]), complemento(['ABCB5', positivity, after, 'carboplatin-', and, 'etoposide-based', 'chemotherapy,', pointing, to, clinical, significance, of, this, chemoresistance, mechanism])].
[sujeto(['Our', results, establish, 'ABCB5', as, a, chemoresistance, mechanism, in, 'MCC', and]), verbo([suggest]), complemento([utility, of, this, molecular, target, for, improved, 'MCC', therapy])].
[sujeto(['We']), verbo([reported]), complemento([that, variants, of, the, 'ATP', binding, cassette, gene, 'ABCC3', '(', facilitates, hepatic, morphine, metabolite, 'efflux)', affect, morphine, metabolite, clearance])].
[sujeto(['In', this, study, of, 316, children, undergoing, 'tonsillectomy,', we]), verbo([found]), complemento([significant, association, between, 'ABCC3', variants, and, 'RD', leading, to, prolonged, postoperative, care, unit, stay, '(', prolonged, 'RD)'])].
[sujeto(['Allele', 'A', at, rs4148412, and, allele, 'G', at, rs729923]), verbo([caused]), complemento([a, 2.36, '(', 95, '%', 'CI=1'])].
[sujeto([50, ')', times]), verbo([increase]), complemento([in, odds, of, prolonged, 'RD,', respectively])].
[sujeto(['These', clinical, associations, were, supported, by]), verbo([increased]), complemento([formation, clearance, of, morphine, glucuronides, in, children, with, rs4148412, 'AA', and, rs4973665, 'CC', genotypes, in, this, 'cohort,', as, well, as, an, independent, spine, surgical, cohort, of, 67, adolescents])].
[sujeto(['This', is, the, first, study, to]), verbo([report]), complemento([association, of, 'ABCC3', variants, with, 'opioid-related', 'RD,', and, morphine, metabolite, formation, '(', in, two, independent, surgical, 'cohorts)'])].
[sujeto(['The', aim, of, this, study, was, to, understand, the, contribution, of, host, constitutive, 'DNA', polymorphisms, in, discriminating, between]), verbo([responder]), complemento([and, nonresponder, patients])].
[sujeto(['Sixteen', single, nucleotide, polymorphisms, '(', 'SNPs)', of, the, 'DMET', array, resulted, significantly]), verbo([associated]), complemento([with, either, good, or, poor, 'response;', no, association, was, found, for, the, 4, variants, mapping, in, 'DNA', repair, genes])].
[sujeto(['Interestingly,', their, combination, with, the, clinical, variables, significantly]), verbo([increased]), complemento([the, predictivity, of, the, model, '(', 'AUC', =, 0.78, vs, 0.62, ',', 'P', =, 0.0016, ')'])].
[sujeto(['Hepatic', fibrosis, was]), verbo([induced]), complemento([by, repetitive, intraperitoneal, 'CCl4', treatment, of, 'BALB/c', mice, or, developed, spontaneously, in, 'BALB/c-ATP-binding', 'cassette,', subfamily, 'B,', member, 4, '(', 'Abcb4)', knock, out, mice])].
[sujeto(['In', 'CCl4-induced', fibrosis, 20, out, of, 40, and, in, 'BALB/c-Abcb4(-/-)', mice, 8, out, of, 28, differentially]), verbo([expressed]), complemento([proteins, were, identified, utilizing, 'DIGE'])].
[sujeto(['Only', two, 'proteins,', 'selenium-binding', protein, '(', 'Sbp2)', and, carbonic, anhydrase, 3, ',']), verbo([have]), complemento([been, unidirectionally, expressed, '(', i])].
[sujeto(['Relevant', differences, in, the, pathogenesis, of, toxically]), verbo([induced]), complemento([liver, fibrosis, and, sclerosing, cholangitis, exist])].
[sujeto(['Ko143', '(', a, selective, 'BCRP', 'inhibitor)', did, not, show, inhibitory, effects, on, sulfate, 'disposition,', whereas, the, 'pan-MRP', inhibitor, 'MK-571']), verbo([caused]), complemento([significant, reductions, '(', 38.5, -, 64.3, '%', ',', 'p&lt;0'])].
[sujeto(['Further,', two, efflux, transporters, '(', 'BCRP', and, 'MRP4)']), verbo([expressed]), complemento([in, the, cells, were, 'knocked-down', by, 'shRNA-mediated', silencing])].
[sujeto(['By', 'contrast,', 'MRP4', 'knock-down']), verbo([led]), complemento([to, moderate, decreases, '(', 17.1, -, 20.6, '%', ',', 'p&lt;0'])].
[sujeto([5, ')', in, sulfate, excretion, and]), verbo([increases]), complemento(['(', 125, -, 135, '%', ',', 'p&lt;0'])].
[sujeto(['In', 'addition,', knockdown, of, 'MRP4']), verbo([led]), complemento([to, a, substantial, reduction, '(', &, 'gt;47'])].
[sujeto(['Although', glucuronide, and, sulfate, conjugates, of, many, drugs, and, endogenous, compounds, undergo, appreciable, hepatic, basolateral, excretion, into, sinusoidal, 'blood,', the, mechanisms, that, govern, basolateral, translocation, of, these, hydrophilic, metabolites]), verbo([have]), complemento([not, been, completely, elucidated])].
[sujeto(['In', the, livers, of, 'Abcc3(-/-)', and, 'Abcc4(-/-)', 'mice,', the, basolateral, excretory, clearance, of, acetaminophen, sulfate, was, reduced, approximately, 20, and, approximately, 20, '%', ',', 4, -, methylumbelliferyl, sulfate, was, reduced, approximately, 50, and, approximately, 65, '%', ',', and, harmol, sulfate, was]), verbo([decreased]), complemento([approximately, 30, and, approximately, 45, '%', ',', respectively])].
[sujeto(['These', results]), verbo([provide]), complemento([the, first, direct, evidence, that, 'Mrp3', and, 'Mrp4', participate, in, the, hepatic, basolateral, excretion, of, sulfate, 'conjugates,', although, additional, 'mechanism(s)', are, likely, involved])].
[sujeto(['In', 'addition,', they]), verbo([reveal]), complemento([that, 'Mrp3', mediates, the, hepatic, basolateral, excretion, of, diverse, glucuronide, conjugates])].
[sujeto(['Early', studies]), verbo([have]), complemento([suggested, that, esophageal, eosinophilia, occurs, in, association, with, 'T(H)2', allergic, 'responses,', yet, the, local, and, systemic, expression, of, relevant, cytokines, has, not, been, well, characterized])].
[sujeto(['Esophageal', transcripts, of, numerous, chemokines, '(', 'eg,', chemokine, '[', 'C-C', 'motif]', ligand, '[', 'CCL]', 1, ',', 'CCL1,', 'CCL23,', 'CCL26', '[', 'eotaxin-3],', chemokine, '[', 'C-X-C', 'motif]', ligand, '[', 'CXCL]', 1, ',', and, 'CXCL2),', cytokines, '(', 'eg,', 'IL13', and, 'ATP-binding', 'cassette,', subfamily, 'F,', member, 1, ')', ',', and, cytokine, receptors, '(', 'eg,', 'IL5', 'receptor,', 'alpha)', were]), verbo([induced]), complemento([at, least, 4, -, fold, in, individuals, with, 'EE'])].
[sujeto(['The', presence, of, allergy, was]), verbo([associated]), complemento([with, significantly, increased, esophageal, expression, of, 'IL4', and, 'IL5', mRNA, in, patients, with, active, 'EE'])].
[sujeto(['When', applied, to, a, 'blind,', prospectively]), verbo([recruited]), complemento([group, of, 36, 'patients,', the, cytokine, panel, scoring, system, had, a, 79, '%', positive, predictive, 'value,', 68, '%', negative, predictive, 'value,', 61, '%', 'sensitivity,', and, 83, '%', specificity, for, identifying, 'EE'])].
[sujeto(['Evidence', is, presented, that, 'IL13', and, 'IL5']), verbo([associate]), complemento([with, eosinophil, and, 'eotaxin-3', 'levels,', indicating, the, key, role, of, adaptive, 'T(H)2', immunity, in, regulating, 'eotaxin-3-driven', esophageal, eosinophilia, in, the, absence, of, a, consistent, systemic, change, in, cytokines])].
[sujeto(['Elucidation', of, the, biochemical, pathways]), verbo([involved]), complemento([in, activation, of, preterm, and, term, human, labour, would, facilitate, the, development, of, effective, management, and, inform, judgements, regarding, the, necessity, for, preterm, tocolysis, and, 'post-term', induction])].
[sujeto(['Prostaglandins']), verbo([act]), complemento([at, all, stages, of, human, 'reproduction,', and, are, potentially, activators, of, labour])].
[sujeto(['Expression', of, 15, genes]), verbo([involved]), complemento([in, prostaglandin, 'synthesis,', transport, and, degradation, was, measured, by, qPCR, using, tissue, samples, from, human, 'placenta,', amnion, and, choriodecidua, at, preterm, and, 'full-term', vaginal, and, caesarean, delivery])].
[sujeto(['Chorioamnionitis/deciduitis', was]), verbo([associated]), complemento([with, upregulation, of, 'PTGS2', '(', 'prostaglandin-endoperoxide', synthase, 2, '(', prostaglandin, 'G/H', synthase, and, 'cyclooxygenase)),', along, with, the, inflammatory, genes, 'IL8', '(', interleukin, 8, ')', ',', 'S100A8', '(', 'S100', calcium, binding, protein, 'A8)', and, 'TLR2', '(', 'toll-like', receptor, 2, ')', ',', in, amnion, and, 'choriodecidua,', and, with, downregulation, of, 'CBR1', '(', carbonyl, reductase, 1, ')', and, 'HPGD', '(', hydroxyprostaglandin, dehydrogenase, 15, -, '(', 'NAD))', in, choriodecidua])].
[sujeto(['Preterm', and, term, labour, are]), verbo([associated]), complemento([with, distinct, prostaglandin, pathway, expression, 'profiles;', inflammation, provokes, specific, 'changes,', unrelated, to, the, presence, of, 'labour;', spontaneous, and, induced, term, labour, are, indistinguishable])].
[sujeto(['We', aimed, to, determine, whether, genes]), verbo([expressed]), complemento([in, whole, blood, early, following, initiation, of, intravenous, corticosteroid, treatment, can, be, associated, with, response])].
[sujeto(['A', total, of, 41, genes, differentially]), verbo([expressed]), complemento([between, responders, and, 'non-responders', were, detected, with, statistical, significance])].
[sujeto(['Two', of, these, 'genes,', 'CEACAM1', and, 'MMP8,', possibly]), verbo([inhibited]), complemento([by, methylprednisolone, through, 'IL8,', were, both, found, to, be, 'over-expressed', in, 'non-responsive', patients])].
[sujeto(['Elevated', expression, of, several, genes]), verbo([involved]), complemento([in, inflammatory, pathways, was, associated, with, resistance, to, intravenous, corticosteroid, therapy, early, in, the, course, of, treatment])].
[sujeto(['The', identification, of, genes]), verbo([associated]), complemento([with, recurrent, drug, resistance, in, gastric, cancer, and, the, elucidation, of, the, underlying, molecular, mechanisms, associated, with, recurrent, drug, resistance, in, gastric, cancer, are, important, for, the, effective, treatment, and, prognosis, of, this, cancer])].
[sujeto(['In', the, present, 'study,', we, demonstrated, that, the, 'ABCC4', gene, was, highly]), verbo([expressed]), complemento([in, multiple, types, of, gastric, cancer, 'cells,', and, 'ABCC4', expression, was, even, more, prominent, in, the, 'drug-resistant', gastric, cancer, cells])].
[sujeto(['We', used, 'RNA', interference, to]), verbo([decrease]), complemento([the, expression, of, 'ABCC4', in, 'drug-resistant', gastric, cancer, 'cells,', which, resulted, in, an, increase, in, apoptosis, and, cell, cycle, arrest, in, the, 'G1', phase])].
[sujeto(['In', 'addition,', we]), verbo([found]), complemento([that, 'ABCC4', knockdown, in, 5, -, fluorouracil, '(', 5, -, 'FU)-resistant', cancer, cells, restored, 5, -, 'FU', 'sensitivity,', resulting, in, the, inhibition, of, cell, proliferation, and, tumour, growth, in, nude, mice])].
[sujeto(['Our', results, showed, that, inhibition, of, 'ABCC4', gene, expression, can]), verbo([inhibit]), complemento([the, proliferation, of, 'multidrug-resistant', gastric, cancer, cells, and, can, enhance, gastric, cancer, cell, sensitivity, to, chemotherapeutic, drugs])].
[sujeto(['ATP-binding', 'cassette,', subfamily, 'G,', member, 2, '(', 'ABCG2)', overexpression]), verbo([has]), complemento([been, associated, with, multidrug, resistance, and, cancer, progression, by, promoting, proliferation, 'and/or', suppressing, 'apoptosis,', but, how, this, process, happens, remains, to, be, determined])].
[sujeto(['We']), verbo([found]), complemento([that, introduction, of, 'ABCG2', siRNA, into, 'Hep-2', and, 'Hep-2T', cells, significantly, enhanced, the, intracellular, accumulation, of, mitoxantrone, '(', 'MX)'])].
[sujeto(['Down-regulation', of, 'ABCG2', by, transient, 'RNAi']), verbo([inhibited]), complemento([cell, proliferation, and, blocked, cell, cycle, progression, by, regulating, the, expression, of, cyclin, 'D3', and, p21, 'Cip1'])].
[sujeto(['ABCG2', silence, also]), verbo([induced]), complemento([cell, apoptosis, by, regulating, the, expression, of, 'surviving,', 'bcl-2', and, the, cleavage, of, poly, '(', 'ADP-ribose)', polymerase, '(', 'PARP)', in, 'Hep-2', and, 'Hep-2T', cells])].
[sujeto(['ABCG2-specific', 'inhibitor,', fumitremorgin, 'C', '(', 'FTC),', and, 'mitogen-activated', protein, kinase, '(', 'MAPK)', pathway, 'inhibitor,', 'U0126,']), verbo([inhibited]), complemento([cell, proliferation, and, promoted, cell, apoptosis, by, degrading, endogenous, 'ABCG2', in, 'Hep-2T', cells])].
[sujeto(['Furthermore,', inhibition, of, 'MAPK', pathway, by, 'U0126']), verbo([enhanced]), complemento(['anti-cancer', effects, of, 'MX', in, vivo])].
[sujeto(['In', 'conclusion,', suppression, of, 'ABCG2']), verbo([inhibits]), complemento([the, procession, of, 'LSCC', tumor, growth, by, regulating, cell, proliferation, and, apoptosis])].
[sujeto(['Our', data, also]), verbo([provide]), complemento([more, evidence, for, the, importance, of, the, 'MAPK', pathway, as, a, suitable, therapeutic, target, for, 'LSCC'])].
[sujeto(['MRP4', '(', multidrug, 'resistance-associated', protein, 4, ')', is, a, member, of, the, 'MRP/ABCC', subfamily, of, 'ATP-binding', cassette, '(', 'ABC)', transporters, that, are, essential, for, many, cellular, processes]), verbo([requiring]), complemento([the, transport, of, substrates, across, cell, membranes])].
[sujeto(['Although', 'MRP4']), verbo([has]), complemento([been, implicated, as, a, detoxification, protein, by, transport, of, structurally, diverse, endogenous, and, xenobiotic, 'compounds,', including, antivirus, and, anticancer, 'drugs,', that, usually, induce, oxidative, stress, in, 'cells,', its, in, vivo, biological, function, remains, unknown])].
[sujeto(['Flies', lacking, dMRP4]), verbo([have]), complemento([a, shortened, lifespan, under, both, oxidative, and, normal, conditions])].
[sujeto(['Overexpression', of, 'dMRP4,', on, the, other, 'hand,', is, sufficient, to]), verbo([increase]), complemento([oxidative, stress, resistance, and, extend, lifespan])].
[sujeto(['By', genetic, 'manipulations,', we, demonstrate, that, dMRP4, is]), verbo([required]), complemento([for, 'JNK', '(', 'c-Jun', 'NH2-terminal', 'kinase)', activation, during, paraquat, challenge, and, for, basal, transcription, of, some, 'JNK', target, genes, under, normal, condition])].
[sujeto(['We', show, that, impaired, 'JNK', signaling, is, an, important]), verbo([cause]), complemento([for, major, defects, associated, with, dMRP4, 'mutations,', suggesting, that, dMRP4, regulates, lifespan, by, modulating, the, expression, of, a, set, of, genes, related, to, both, oxidative, resistance, and, 'aging,', at, least, in, 'part,', through, 'JNK', signaling])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, 'afatinib,', a, small, molecule, tyrosine, kinase, inhibitor, '(', 'TKI)', targeting, 'EGFR,', 'HER-2', and, 'HER-4,', reversed, the, chemoresistance, mediated, by, 'ABCG2', in, 'vitro,', but, had, no, effect, on, that, mediated, by, multidrug, resistance, protein, 'ABCB1', and, 'ABCC1'])].
[sujeto(['In', 'addition,', 'afatinib,', in, combination, with, 'topotecan,', significantly]), verbo([inhibited]), complemento([the, growth, of, 'ABCG2-', overexpressing, cell, xenograft, tumors, in, vivo])].
[sujeto(['Mechanistic', investigations, exhibited, that, afatinib, significantly]), verbo([inhibited]), complemento(['ATPase', activity, of, 'ABCG2', and, downregulated, expression, level, of, 'ABCG2,', which, resulted, in, the, suppression, of, efflux, activity, of, 'ABCG2', in, parallel, to, the, increase, of, intracellular, accumulation, of, 'ABCG2', substrate, anticancer, agents])].
[sujeto(['Taken', 'together,', our, findings, may]), verbo([provide]), complemento([a, new, and, useful, combinational, therapeutic, strategy, of, afatinib, with, chemotherapeutical, drug, for, the, patients, with, 'ABCG2', overexpressing, cancer, cells])].
[sujeto(['GalNAc', transferase, 7, '(', 'GALNT7),', 'ATP-Binding', 'Cassette,', 'Sub-Family', 'G', '(', 'WHITE),', 'Member', 1, '(', 'ABCG1),', and, an, intergenic, region, on, chromosome, 9, were]), verbo([associated]), complemento([with, 'NP', 'score;', and, 'Potassium', 'Large', 'Conductance', 'Calcium-Activated', 'Channel,', 'Subfamily', 'M,', 'Beta', 'Member', 2, '(', 'KCNMB2)', was, strongly, associated, with, 'HS'])].
[sujeto(['However,', whether, 'MRP4', directly]), verbo([involves]), complemento([platelet, activation, remains, unclear])].
[sujeto(['Our', results, revealed, that, the, 'MRP4', inhibitor, 'MK571']), verbo([inhibited]), complemento(['collagen-induced', platelet, aggregation, which, was, partially, reversed, by, the, 'PKA', inhibitor, 'H89,', but, not, by, the, adenylyl, cyclase, '(', 'AC)', inhibitor, 'SQ22536', and, the, guanylyl, cyclase, '(', 'GC)', inhibitor, 'ODQ,', suggesting, that, 'MK571', can, prevent, 'collagen-induced', aggregation, via, a, route, independent, of, cyclic, nucleotide, production])].
[sujeto(['In', the, present, 'study,', we]), verbo([found]), complemento([that, 'MK571', inhibited, 'collagen-induced', 'ATP', release, and, calcium, mobilization])].
[sujeto(['The', phosphorylation, of, protein, kinase, 'C,', 'JNK,', and, 'Akt', was, also]), verbo([inhibited]), complemento([by, 'MK571,', and, electron, spin, resonance, experiment, showed, that, 'MK571', significantly, reduced, hydroxyl, radical, formation])].
[sujeto(['However,', previous, studies]), verbo([have]), complemento([reported, that, 'MK571', also, blocks, 'MRP1', and, leukotriene, 'D4', '(', 'LTD4)', receptor])].
[sujeto(['Therefore,', whether, 'MK571']), verbo([inhibits]), complemento([platelet, activation, through, 'MRP1', or, 'LTD4', receptor, needs, to, be, considered, and, further, defined])].
[sujeto(['In', 'conclusion,', in, addition, to, blocking, the, transport, of, cyclic, 'nucleotides,', 'MRP4', inhibition, may]), verbo([prevent]), complemento([thrombus, formation, in, vitro, and, in, vivo])].
[sujeto(['Our', findings, also, support, the, idea, that, 'MRP4', may, represent, a, potential]), verbo([target]), complemento([for, the, development, of, novel, therapeutic, interventions, for, the, treatment, of, thromboembolic, disorders])].
[sujeto(['Deregulation', of, prostaglandin, 'E2', '(', 'PGE2)', levels]), verbo([reported]), complemento([in, colorectal, carcinogenesis, contributes, to, key, steps, of, cancer, development])].
[sujeto(['The', best, 'four-locus', 'gene-gene', interaction, model, included, the, 'rs1346271,', rs1863642, and, rs12500316, single, nucleotide, polymorphisms, in, 'HPGD', and, rs1678405, in, 'ABCC4', genes, and, was]), verbo([associated]), complemento([with, a, 13, -, fold, increased, susceptibility, '(', 95, '%', 'CI:', 3.84, -, 46.3, ',', 'P&lt;0'])].
[sujeto(['Interesting,', in, 'low-risk', patients, the, 'ABCC4', rs9524821AA, genotype, was]), verbo([associated]), complemento([not, only, with, a, higher, hazard, ratio, '(', 'HR=2'])].
[sujeto(['Abcc4', gene, codes, for, a, protein, '(', 'ABCC4)']), verbo([involved]), complemento([in, the, transportation, of, different, classes, of, drugs, outside, the, cells])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([identified, a, novel, transcript, of, mouse, 'Abcc4', gene, using, a, combination, of, bioinformatics, and, molecular, biology, techniques])].
[sujeto(['This', transcript, was]), verbo([found]), complemento([to, be, different, from, the, reported, transcript, in, having, a, different, first, exon, that, was, found, to, be, located, on, previously, identified, first, intron])].
[sujeto(['Newly', identified, transcript, was]), verbo([found]), complemento([to, be, expressed, across, different, tissues, we, studied, and, in, different, developmental, stages])].
[sujeto(['Expression', level, of, novel, and]), verbo([reported]), complemento([transcripts, was, studied, using, quantitative, real, time, 'PCR'])].
[sujeto(['After', conceptually]), verbo([translating]), complemento([the, novel, 'transcript,', various, 'post-translational', modifications, were, studied])].
[sujeto(['Flutamide', '(', 'FLU),', an, 'oral,', nonsteroidal, antiandrogen, drug, used, in, the, treatment, of, prostate, 'cancer,', is]), verbo([associated]), complemento([with, idiosyncratic, hepatotoxicity, that, sometimes, causes, severe, liver, 'damage,', including, 'cholestasis,', 'jaundice,', and, liver, necrosis])].
[sujeto(['A', significant]), verbo([increase]), complemento([of, liver, 'weights,', and, liver, and, serum, bile, acid, levels, was, observed, after, 'FLU', 'treatment,', indicating, hepatomegaly, and, disrupted, bile, acid, homeostasis])].
[sujeto(['Expression', of, the, 'AhR', gene, battery, was, markedly]), verbo([increased]), complemento([in, livers, of, 'wild-type', mice, 'Ahr(+/+)', treated, with, 'FLU,', while, no, change, was, noted, in, 'Ahr(-/-)', mice])].
[sujeto(['Messenger', 'RNAs', encoded, by, 'AhR']), verbo([target]), complemento([genes, were, induced, in, primary, mouse, hepatocytes, cultured, with, 'FLU,', which, confirmed, the, in, vivo, results])].
[sujeto(['Expression', of, mRNA, encoding, the, bile, acid, transporter, 'ABCC4', was]), verbo([increased]), complemento([and, farnesoid, 'X', receptor, signaling, was, inhibited, in, the, livers, of, 'Ahr(+/+)', 'mice,', but, not, in, 'Ahr(-/-)', mice, treated, with, 'FLU,', in, agreement, with, the, observed, downstream, metabolic, alterations])].
[sujeto(['These', findings]), verbo([provide]), complemento([new, insights, into, the, mechanism, of, liver, injury, caused, by, 'FLU', treatment, involving, activation, of, 'AhR', and, the, alterations, of, bile, acid, 'homeostasis,', which, could, guide, clinical, application])].
[sujeto(['It', is]), verbo([associated]), complemento([with, problematic, adverse, hematological, effects, in, this, population, of, immunosuppressed, 'patients,', which, may, lead, to, dose, reduction, thus, favoring, resistance])].
[sujeto(['GCV', crosses, the, membranes, of, 'cells,', is]), verbo([activated]), complemento([by, 'phosphorylation,', and, then, stops, the, replication, of, viral, 'DNA'])].
[sujeto(['In', both, 'cohorts,', we]), verbo([found]), complemento([a, variant, in, 'ABCC4', '(', 'rs11568658)', associated, with, decreased, neutrophil, counts, following, valganciclovir, '(', 'GCV', 'prodrug)', administration, '(', exploratory, 'cohort:', 'β±SD=-0'])].
[sujeto(['MRP4-expressing', cells, showed]), verbo([decreased]), complemento(['GCV', accumulation, as, compared, to, negative, control, cells, '(', transfected, with, an, empty, 'vector)', '(', -, 61, '%', ;, 'p&lt;0'])].
[sujeto(['The', efflux, process, was, almost, abolished, in, cells]), verbo([expressing]), complemento(['MRP4', rs11568658, variant, protein])].
[sujeto(['Multivariate', analysis, showed, that, the, rs37751333GG, genotype, was, significantly]), verbo([associated]), complemento([with, responses, at, 6, and, 12, months, '(', odds, ratio, 2.63, ',', 95, '%', confidence, interval, 1.391, -, 4.974, ',', 'P=0'])].
[sujeto(['The', 'Multi-drug', 'Resistance', 'Protein', 4, variant, was, significantly]), verbo([associated]), complemento([with, 'HBV', 'DNA', level, suppression, in, chronic, hepatitis, 'B', patients, treated, with, 'entecavir,', and, 'therefore,', patients, with, the, rs3751333GG, genotype, might, respond, better, to, entecavir, in, the, 'Chinese', 'Han', population])].
[sujeto(['Respiratory', syncytial, virus, '(', 'RSV)', is, a, major]), verbo([cause]), complemento([of, lower, respiratory, tract, infections, in, 'children,', 'elderly,', and, immunocompromised, individuals])].
[sujeto(['However,', the, evolution, of, statistical, methods, and, functional, analysis, together, with, the, large, amount, of, expression, data]), verbo([provide]), complemento([opportunities, to, uncover, novel, biomarkers, of, inflammation, and, infections])].
[sujeto(['The', results, from, those, analyses, argue, for, the, reevaluation, of, previously]), verbo([reported]), complemento([transcription, patterns, and, biological, pathways, in, 'BEAS-2B', cell, lines, infected, with, 'RSV'])].
[sujeto(['However,', response, is, 'variable,', and, no, predictive, markers]), verbo([have]), complemento([been, validated])].
[sujeto(['The', 'miR-17-92a-1', cluster, host, gene, '(', 'MIR17HG),', which, is]), verbo([involved]), complemento([in, the, 'development,', 'progression,', and, aggressiveness, of, colorectal, 'cancer,', and, the, 'ABCC4', 'gene,', an, 'ATP-binding', cassette, 'transporter,', are, located, at, this, region])].
[sujeto(['We']), verbo([report]), complemento([the, first, combined, analysis, of, 'whole-genome', 'sequence,', detailed, clinical, 'history,', and, transcriptome, sequence, of, multiple, prostate, cancer, metastases, in, a, single, patient, '(', 'A21)'])].
[sujeto(['Whole-genome', and, transcriptome, sequence, was, obtained, from, nine, anatomically, separate, 'metastases,', and]), verbo([targeted]), complemento(['DNA', sequencing, was, performed, in, cancerous, and, noncancerous, foci, within, the, primary, tumor, specimen, removed, 5, yr, before, death])].
[sujeto(['Transcriptome', analysis, revealed]), verbo([increased]), complemento([expression, of, androgen, receptor, '(', 'AR)-regulated', genes, in, liver, metastases, that, harbored, an, 'AR', p])].
[sujeto(['L702H', 'mutation,']), verbo([suggesting]), complemento([a, dominant, effect, by, the, mutation, despite, being, present, in, only, one, of, an, estimated, 16, copies, per, cell])].
[sujeto(['If', the, patient, were, treated, 'today,', given, this, 'knowledge,', the, use, of, 'second-generation', 'androgen-directed', 'therapies,', cessation, of, glucocorticoid, 'administration,', and, therapeutic, inhibition, of, the, 'PI3K/AKT', pathway, or, 'FGFR1', receptor, could]), verbo([provide]), complemento([personalized, benefit])].
[sujeto(['P75R)', were]), verbo([expressed]), complemento([at, the, 'RNA', level, and, assessed, as, druggable])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, a, large, set, of, deeply, analyzed, cases, could, serve, as, a, powerful, guide, to, more, effective, prostate, cancer, basic, science, and, personalized, cancer, medicine, clinical, trials])].
[sujeto(['This', review, focuses, on, multidrug, resistance, protein, 4, '(', 'MRP4', or, 'ABCC4)', that]), verbo([has]), complemento([recently, been, shown, to, play, a, role, in, cAMP, 'homeostasis,', a, 'key-pathway', in, vascular, biology, and, in, platelet, functions])].
[sujeto(['In', vascular, 'system,', recent, data]), verbo([provide]), complemento([evidence, that, inhibition, of, 'MRP4', prevents, human, coronary, artery, smooth, muscle, cell, proliferation, in, vitro, and, in, 'vivo,', as, well, as, human, pulmonary, artery, smooth, muscle, cell, proliferation, in, vitro, and, pulmonary, hypertension, in, mice, in, vivo])].
[sujeto(['In', the, 'heart,', 'MRP4', silencing, in, adult, rat, ventricular, myocytes, results, in, an]), verbo([increase]), complemento([in, intracellular, cAMP, levels, leading, to, enhanced, cardiomyocyte, contractility])].
[sujeto(['However,', a, prolonged, inhibition, of, 'MRP4', can]), verbo([promote]), complemento([cardiac, hypertrophy])].
[sujeto(['In', 'addition,', secreted, 'cAMP,', through, its, metabolite, 'adenosine,']), verbo([prevents]), complemento([adrenergically, induced, cardiac, hypertrophy, and, fibrosis])].
[sujeto(['Finally,', 'MRP4', inhibition, in, platelets]), verbo([induces]), complemento([a, moderate, thrombopathy])].
[sujeto([cAMP, storage, in, platelet, dense, granules, might, limit, the, cAMP, cytosolic, concentration, upon, adenylate, cyclase, 'activation,', a, necessary, step, to]), verbo([induce]), complemento([platelet, activation])].
[sujeto(['Additional', sample, sets, were, assessed, for]), verbo([targeted]), complemento([and, in, silico, replication])].
[sujeto(['Break-point', mapping, of, the, deleted, region]), verbo([suggested]), complemento(['non-allelic', homologous, recombination, as, the, mechanism, underlying, its, formation])].
[sujeto(['We', conducted, a, 'meta-analysis', of, pharmacogenomic, substudies, of, three, randomized, trials, conducted, in, patients, with, decompensated, heart, failure, '(', 'HF)', that, were]), verbo([led]), complemento([by, 'National', 'Heart', 'Lung', and, 'Blood', 'Institute', '(', 'NHLBI)-funded', 'HF', 'Network', to, test, the, hypothesis, that, candidate, genes, modulate, net, fluid, loss, and, weight, change, in, patients, with, decompensated, 'HF', treated, with, a, 'furosemide-based', diuretic, regimen])].
[sujeto(['Although', none, of, the, genetic, variants, previously, shown, to]), verbo([modulate]), complemento([the, effects, of, loop, diuretics, in, healthy, individuals, were, associated, with, net, fluid, loss, after, 72, h, of, 'treatment,', a, set, of, rare, variants, in, the, 'APOL1', 'gene,', which, codes, for, apolipoprotein, 'L1', '(', 'P=0'])].
[sujeto([5, in, the, random, effects, 'model),', was]), verbo([associated]), complemento([with, this, end, point])].
[sujeto(['Moreover,', a, common, variant, in, the, multidrug, resistance, 'protein-4', coding, gene, '(', 'ABCC4,', 'rs17268282)', was]), verbo([associated]), complemento([with, weight, loss, with, furosemide, use, '(', 'P=0'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, both, common, and, rare, genetic, variants, modulate, the, response, to, a, 'furosemide-based', diuretic, regimen, in, patients, with, decompensated, 'HF'])].
[sujeto(['Based', on, previous, studies, implicating, 'ABCC4/MRP4', in, the, transport, of, 'nucleosides,', we, hypothesized, that, cytarabine, is, sensitive, to, 'ABCC4-mediated', 'efflux,', thereby]), verbo([decreasing]), complemento([its, cytotoxic, response, against, 'AML', blasts])].
[sujeto(['The', uptake, of, cytarabine, and, its, monophosphate, metabolite, was]), verbo([found]), complemento([to, be, facilitated, in, 'ABCC4-expressing', vesicles, and, intracellular, retention, was, significantly, impaired, by, overexpression, of, human, 'ABCC4', or, mouse, 'Abcc4', '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['ABCC4', was]), verbo([expressed]), complemento([highly, in, 'AML', primary, blasts, and, cell, 'lines,', and, cytotoxicity, of, cytarabine, in, cells, was, increased, in, the, presence, of, the, 'ABCC4', inhibitors, 'MK571', or, 'sorafenib,', as, well, as, after, 'ABCC4', siRNA])].
[sujeto(['In', 'Abcc4-null', 'mice,', 'cytarabine-induced', hematological, toxicity, was]), verbo([enhanced]), complemento([and, ex, vivo, 'colony-forming', assays, showed, that, 'Abcc4-deficiency', sensitized, myeloid, progenitors, to, cytarabine])].
[sujeto(['ABCA3', '(', 'ATP-binding', cassette, subfamily, 'A,', member, 3, ')', is]), verbo([expressed]), complemento([in, the, lamellar, bodies, of, alveolar, type, 'II', cells, and, is, crucial, to, pulmonary, surfactant, storage, and, homeostasis])].
[sujeto(['ABCA3', gene, mutations]), verbo([have]), complemento([been, associated, with, neonatal, respiratory, distress, '(', 'NRD)', and, pediatric, interstitial, lung, disease, '(', 'ILD)'])].
[sujeto(['T1173R']), verbo([induced]), complemento([abnormal, lamellar, bodies])].
[sujeto(['T1173R']), verbo([increased]), complemento(['IL-8', secretion, in, vitro])].
[sujeto(['Two', mutations]), verbo([associated]), complemento([with, 'ILD', acted, via, different, pathophysiological, mechanisms, despite, similar, clinical, phenotypes])].
[sujeto([miRNAs]), verbo([have]), complemento([been, widely, investigated, in, terms, of, cell, proliferation, and, differentiation])].
[sujeto(['Here', we, characterized, the, promoter, of, 'miR-206', in, chicken, and]), verbo([found]), complemento([that, the, preferable, promoter, was, located, in, 1200, bp, upstream, of, 'pri-miR-206'])].
[sujeto(['In', this, 'region,', many, key, transcription, 'factors,', including, 'MyoD,', 'c-Myb,', 'CEBPα/β,', 'AP-4,', 'RAP1,', 'Brn2,', 'GATA-1/2/3,', 'E47,', 'Sn,', upstream, stimulatory, factor, '(', 'USF)', and, 'CdxA,', were, predicted, to]), verbo([bind]), complemento([and, interact, with, 'miR-206', promoter])].
[sujeto(['Overexpression', of, 'MyoD', sharply]), verbo([increased]), complemento(['miR-206', expression, in, both, fibroblast, and, myoblast, 'cells,', and, also, the, regulation, in, the, myoblast, cells, was, much, 'stronger,', indicating, that, 'miR-206', was, regulated, by, 'MyoD', combined, with, other, muscle, specific, transcriptional, factors])].
[sujeto(['Interestingly,', the, motif]), verbo([bound]), complemento([by, 'MyoD', was, individually, destroyed, by, 'G-to-C', mutation, located, at, 419, bp, upstream, of, 'miR-206', precursor])].
[sujeto(['Thus,', this, mutation]), verbo([caused]), complemento([low, expression, of, 'miR-206'])].
[sujeto(['Additionally,', the, regulation, of, 'miR-206', on, embryo, muscle, mass, mainly, by]), verbo([increasing]), complemento(['MyoG', and, muscle, creatine, kinase, '(', 'MCK)', expression, '(', p, &, 'lt;', 0.05, ')', with, little, change, in, 'MyoD,', 'TMEM8C', and, myosin, heavy, chain, '(', 'MHC)'])].
[sujeto(['In', 'conclusion,', our, findings]), verbo([provide]), complemento([a, novel, mutation, destroying, the, promoter, activity, of, 'miR-206', in, birds, and, shed, new, light, to, understand, the, regulation, mechanism, of, 'miR-206', on, the, embryonic, muscle, growth])].
[sujeto(['Previously,', we, identified, five, 'POs,', designated, 'As-pro-PO', 'I-V,', from, the, mosquito, 'Armigeres', subalbatus, and, demonstrated, that, the, functions, of, 'As-pro-PO', 'I,', 'II', and, 'III,', were]), verbo([associated]), complemento([with, filarial, parasite, 'melanization,', blood, feeding, and, cuticle, 'formation,', respectively])].
[sujeto(['We']), verbo([found]), complemento([that, the, level, of, 'As-pro-PO', 'V', mRNA, in, mosquitoes, was, significantly, increased, after, microfilaria, challenge, or, blood, 'feeding,', and, decreased, to, normal, level, after, oviposition])].
[sujeto(['Knockdown', of, 'As-pro-PO', 'V', by, dsRNA, resulted, in, significant]), verbo([decreases]), complemento([in, the, degree, of, microfilaria, 'melanization,', egg, chronic, melanization, rates, and, egg, hatching, rates, in, 'Ar'])].
[sujeto(['Further', transfection, and, electrophoretic, 'mobility-shift', assays, verified, the, 'As-pro-PO', 'V', gene, might]), verbo([regulated]), complemento([by, both, 'AP-1,', a, putative, 'immune-related', regulatory, element, and, 'CdxA,', a, developmental, regulatory, element])].
[sujeto(['The']), verbo([binding]), complemento([of, 'AP-1', and, 'CdxA', motif, with, mosquito, nuclear, extracts, was, significantly, enhanced, after, microfilaria, challenge, and, 'blood-feeding', in, 'Ar'])].
[sujeto(['These', results, indicate, that, 'As-pro-PO', 'V', is, a, critical, enzyme, that, is]), verbo([required]), complemento([for, both, an, effective, melanization, immune, response, and, egg, chorion, melanization, in, this, mosquito])].
[sujeto(['Our', recent, 'genome-wide', association, study, '(', 'GWAS)', had, discovered, a, new, locus, at, 8, p23, '(', 'rs2738048)']), verbo([associated]), complemento([with, 'IgA', nephropathy, '(', 'IgAN)', in, 'Chinese', 'Han', 'patients,', implicating, the, 'DEFA', gene, family, within, this, locus, as, susceptibility, genes])].
[sujeto(['However,', it, is, still, unknown, whether, there, are, additional, variations, within, these, genes]), verbo([associated]), complemento([with, the, disease, susceptibility])].
[sujeto(['We']), verbo([found]), complemento([seven, 'SNPs', within, 'DEFA', genes, that, were, significantly, associated, with, 'IgAN,', including, rs2738048, discovered, in, our, previous, 'GWAS', '(', 'p&nbsp;=&nbsp;0'])].
[sujeto(['Electrophoretic', mobility, shift, assays, and, luciferase, assays, demonstrated, that, fragments, containing, 'rs2738048,', rs2738081, and, rs6984215, were, transcription, factor]), verbo([binding]), complemento([sites, for, 'CTF,', 'SP1', and, 'CdxA,', 'respectively,', and, the, allele, status, of, rs2738048, and, rs6984215, could, significantly, change, the, luciferase, activity])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, polymorphisms, within, 'DEFA', genes, are, involved, in, gene, transcriptional, 'regulation,', and, this, may, have, some, effect, in, mediating, susceptibility, to, 'IgAN', in, southern, 'Chinese'])].
[sujeto(['Children', '(', 'n=488;', age, 'range:', 1.8, -, 6.0, 'y)', were, randomly]), verbo([recruited]), complemento([from, 'Montreal'])].
[sujeto([1, ')', were, positively]), verbo([associated]), complemento([with, 'BMC', and, aBMD, in, all, regression, 'models,', whereas, male, sex, contributed, positively, to, forearm, 'BMC', and, aBMD])].
[sujeto(['Having', a, 25, '(', 'OH)D', concentration, of, &, 'gt;75', 'nmol/L', positively]), verbo([associated]), complemento([with, forearm, and, whole, body, 'BMC', and, aBMD, '(', 'p&lt;0'])].
[sujeto(['Helicobacter', pylori, encoded, 'CagA', is, presently, the, only, known, virulence, factor, that, is, injected, into, gastric, epithelial, cells, where, it, destroys, apical, junctional, complexes, and]), verbo([induces]), complemento([dedifferentiation, of, gastric, epithelial, 'cells,', leading, to, 'H'])].
[sujeto(['However,', little, is, known, about, the, molecular, mechanisms, by, which, 'CagA']), verbo([mediates]), complemento([these, changes])].
[sujeto(['Caudal-related', homeobox, 2, '(', 'Cdx2)', is, an, 'intestine-specific', transcription, factor, highly]), verbo([expressed]), complemento([in, multistage, tissues, of, dysplasia, and, cancer])].
[sujeto(['One', specific]), verbo([target]), complemento([of, 'Cdx2,', 'Claudin-2,', is, involved, in, the, regulation, of, tight, junction, '(', 'TJ)', permeability])].
[sujeto(['In', this, 'study,', our, findings, showed, that, the, activity, of, 'Cdx2']), verbo([binding]), complemento([to, 'Cdx', binding, sites, of, 'CdxA', '(', 'GTTTATG)', and, 'CdxB', '(', 'TTTTAGG)', of, probes, corresponding, to, 'claudin-2', flanking, region, increased, in, 'AGS', 'cells,', infected, with, 'CagA', positive, 'wild-type', strain, of, 'H'])].
[sujeto(['In', the, 'meantime,', we]), verbo([found]), complemento([that, 'TJs', of, 'AGS', 'cells,', infected, with, 'CagA', positive, 'wild-type', strain, of, 'H'])].
[sujeto(['pylori,', compared, to, 'CagA', negative, isogenic, 'mutant-type', 'strain,', were, more, severely, 'destroyed,']), verbo([leading]), complemento([to, wider, cell, 'gap,', interference, of, 'contact,', scattering, and, highly, elevated, migration, of, cells])].
[sujeto(['pylori-encoded', 'CagA', disrupts, 'TJs', and]), verbo([induces]), complemento([invasiveness, of, 'AGS', gastric, carcinoma, cells, via, 'Cdx2-dependent', targeting, of, 'Claudin-2'])].
[sujeto(['This']), verbo([provides]), complemento([a, new, mechanism, whereby, 'CagA', induced, dedifferentiation, of, 'AGS', 'cells,', leading, to, malignant, behavior, of, biology])].
[sujeto(['In', this, 'study,', 'real-time', polymerase, chain, reactions, and, 'Western', blot, assays, indicated, that, 'HMGB1', transcriptional, activity, and, protein, level, are]), verbo([increased]), complemento([in, 'Tax+-T', cells, '(', 'TaxP)'])].
[sujeto(['We']), verbo([found]), complemento([that, promoter, activity, in, 'Tax+-T', cells, to, be, higher, than, that, in, 'Tax--T', 'cells,', indicating, a, significant, increase, in, pHLuc6])].
[sujeto(['Bay11-7082', '(', 'NF-κB', 'inhibitor)', treatment, did, not, block, the]), verbo([enhancing]), complemento([effect])].
[sujeto(['Chromatin', immunoprecipitation, assays, revealed, that, 'Tax', was]), verbo([retained]), complemento([on, a, 'HMGB1', promoter, fragment, encompassing, -, 1163, to, -, 975])].
[sujeto(['Mutation', of, 'cis-', elements, for, 'C/EBP', reduced, significant, 'HMGB1', promoter, activity]), verbo([induced]), complemento([by, 'Tax'])].
[sujeto(['These', findings, indicate, that, 'Tax']), verbo([enhances]), complemento([the, expression, of, 'HMGB1', gene, at, the, transcriptional, 'level,', possibly, by, interacting, with, 'C/EBP'])].
[sujeto(['Interferon', regulatory, factor, 2, '(', 'IRF-2)', is, a, 'multi-functional', transcription, factor, in, the, 'IRF', family, exhibiting, both, transcriptional]), verbo([activating]), complemento([and, repressing, activities])].
[sujeto(['The', amino, acid, sequence, had, a, highly]), verbo([conserved]), complemento(['N-terminal', 'DBD', 'structure,', containing, characteristic, repeats, of, six, tryptophan, residues])].
[sujeto(['Only&nbsp;+2365T/C', 'SNP', was, significantly]), verbo([associated]), complemento([with, 'resistance/susceptibility', of, 'H'])].
[sujeto(['Among', 'them,', three, 'SNPs', including, 'A-99G,', 'A-86C,', and, 'A-49C', in, 'GPX', promoter, and, five, 'SNPs', including, 'A2841T,', 'C2847T,', 'G3146C,', 'A3150G,', and, 'G4645T', in, 'GPX', introns, were]), verbo([associated]), complemento([with, 'resistance/susceptibility', of, 'H'])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, the, polymorphic, loci, in, the, 'GPX', gene, could, be, potential, genetic, markers, for, future, molecular, selection, of, strains, resistant, to, diseases])].
[sujeto(['However,', these, approaches]), verbo([require]), complemento([the, use, of, sophisticated, and, expensive, 'serum-free', medium, supplemented, with, epithelial, growth, factor, '(', 'EGF),', 'Wnt', agonist, '(', 'R-spondin', 1, ')', ',', and, bone, morphogenetic, protein, inhibitor, '(', 'Noggin)', in, high, concentrations])].
[sujeto(['They']), verbo([have]), complemento([the, appearance, of, empty, spheres, and, comprise, cells, expressing, cytokeratin, '(', an, epithelial, cell, 'marker),', villin, '(', a, marker, of, 'enterocytes),', and, 'Sox-9', '(', a, transcription, factor, characteristic, of, progenitors, and, stem, cells, of, intestinal, 'crypts)'])].
[sujeto(['With', chicken, embryonic, tissue, as, a, source, of, 'organoids,', prostaglandin, 'E2', is, as, effective, as, 'R-spondin', 1, and, 'Noggin', in]), verbo([promoting]), complemento([sustained, growth, and, survival, of, epithelial, spheroids])].
[sujeto(['Specifically,', 'β-casein', is, a, major, component, of, 'cow,', goat, and, sheep, 'milk,', and, its, promoter]), verbo([has]), complemento([been, used, to, regulate, the, expression, of, transgenic, genes, in, the, mammary, gland, of, transgenic, animals])].
[sujeto(['We', estimated, the, transcriptional, activity, for, the, 5, '\'', -, proximal, region, with, or, without, intron, 1, of, the, porcine, 'β-casein', gene, in, 'HC11', cells]), verbo([stimulated]), complemento([with, lactogenic, hormones])].
[sujeto(['Taken', 'together,', these, findings]), verbo([suggest]), complemento([that, the, transcription, of, porcine, 'β-casein', gene, is, regulated, by, lactogenic, hormone, via, intron, 1, and, promoter, containing, a, mutant, 'TATA', box, '(', 'CATAAAA)', has, poor, porcine, 'β-casein', gene, activity])].
[sujeto(['To', examine, whether, 'PARK16,', which, was, recently, identified, as, a, protective, locus, for, 'Parkinson', disease, '(', 'PD)', in, 'Asian,', 'white,', and, 'South', 'American', 'populations,', is, also]), verbo([associated]), complemento([with, 'PD', in, the, genetically, homogeneous, 'Ashkenazi', 'Jewish', population])].
[sujeto(['Bioinformatic', analysis, defined, the, putative, promoter, region, of, 'RAB7L1', and, the, transcription, factor]), verbo([binding]), complemento([sites, that, are, potentially, affected, by, 2, of, the, tested, 'SNPs'])].
[sujeto(['All', tested, 'SNPs', were, significantly]), verbo([associated]), complemento([with, 'PD', '(', odds, 'ratios&nbsp;=&nbsp;0'])].
[sujeto(['Two', of, 'them,', rs1572931, and, 'rs823144,', were, localized, to, the, putative, promoter, region, of, 'RAB7L1', and, their, sequence, variations, altered, the, predicted, transcription, factor]), verbo([binding]), complemento([sites, of, 'CdxA,', 'p300,', 'GATA-1,', 'Sp1,', and, 'c-Ets-1'])].
[sujeto(['Our', data, demonstrate, that, specific, 'SNP', variations, and, haplotypes, in, the, 'PARK16', locus, are]), verbo([associated]), complemento([with, reduced, risk, for, 'PD', in, 'Ashkenazim'])].
[sujeto(['Although', it, is, possible, that, alterations, in, the, putative, promoter, of, 'RAB7L1', are]), verbo([associated]), complemento([with, this, 'effect,', the, role, of, other, genes, in, this, locus, cannot, be, ruled, out])].
[sujeto(['It', is]), verbo([involved]), complemento([in, the, regulation, of, the, 'G1-phase', of, the, cell, cycle, and, is, considered, to, be, an, important, candidate, gene, for, selection, of, body, measurement, traits, through, 'marker-assisted', selection])].
[sujeto(['We', cloned, the, promoter, sequence, of, this, gene, in, bovines, and]), verbo([found]), complemento([it, to, share, high, similarity, with, that, of, the, human, 'CDK6', promoter])].
[sujeto(['A', 2271, -, bp, sequence, upstream, of, the, start, codon, in, the, bovine, 'CDK6', 5, '\'', -, flanking, sequence, is, rich, in, 'GC;', it, lacks, consensus, 'TATA', or, 'CAAT', 'box,', but, it, contains, several, 'MZF1']), verbo([binding]), complemento([sites])].
[sujeto(['Other', potential, 'cis-regulatory', elements, were]), verbo([found]), complemento([in, the, 5, '\'', -, flanking, 'region,', including, 'CdxA,', 'SRY,', 'p300,', 'GATA-1,', and, deltaE])].
[sujeto(['The', 'T-1075C', 'SNP', in, the, promoter, was]), verbo([found]), complemento([to, be, significantly, associated, with, body, length, and, heart, girth])].
[sujeto(['This', 'SNP', marker, was]), verbo([found]), complemento([to, be, significantly, associated, with, body, length, and, the, heart, girth, in, 737, individuals])].
[sujeto(['We', conclude, that, this, 'SNP', of, the, 'CDK6', gene]), verbo([has]), complemento([potential, as, a, genetic, marker, for, important, body, traits, in, bovine, reproduction, and, breeding])].
[sujeto(['The', aim, of, this, study]), verbo([has]), complemento([been, to, analyze, whether, 33, '%', radius, should, be, considered, the, recommended, area, to, assess, 'BMD', in, prostate, cancer, patients])].
[sujeto(['Normal', 'BMD', was]), verbo([found]), complemento([in, 17.7, '%', at, 33, '%', radius, and, 34.8, '%', at, cDXA])].
[sujeto(['The', 33, '%', radius, was, the, only, site, where, a, significant]), verbo([increase]), complemento([in, the, osteoporosis, rate, was, detected, in, patients, subjected, to, 'AS', compared, to, those, hormone, naïve, '(', 33, and, 13.8, '%', ')'])].
[sujeto(['The', 33, '%', radius, seems, more, sensible, than, the, central, skeleton, areas, to, detect, bone, mass]), verbo([loss]), complemento([in, patients, with, prostate, cancer])].
[sujeto(['Alkaline', phosphatases, are, ubiquitous, enzymes]), verbo([involved]), complemento([in, many, important, biological, processes])].
[sujeto(['Mammalian', 'tissue-nonspecific', alkaline, phosphatase]), verbo([has]), complemento([long, been, thought, to, feature, in, embryonic, development, and, bone, formation])].
[sujeto(['An', analysis, of, its, secondary, and, tertiary, structure, revealed, that, the, 'POALP', was]), verbo([conserved]), complemento([in, different, 'species,', but, one, disulfide, linkage, made, it, possible, to, adapt, to, 'low-temperature', environment])].
[sujeto(['The', 'ALP', activity, was]), verbo([found]), complemento([to, be, first, detectable, in, the, embryo, before, hatching])].
[sujeto(['These', findings]), verbo([suggest]), complemento([the, potential, role, of, 'POALP', in, nutrient, absorption, and, transportation])].
[sujeto(['To', evaluate, whether, these, genes, encode, enzymes, with, redundant, biological, 'functions,', each, gene, was, cloned, and]), verbo([expressed]), complemento([in, 'Escherichia', coli])].
[sujeto(['To', identify, the, amino, acid, residues, that, contribute, to, catalysis, and, substrate, specificity, within, this, family, of, 'enzymes,', the, roles, of]), verbo([conserved]), complemento([residues, '(', 'R177,', 'K214,', 'H215,', 'M251,', and, 'D286)', in, 'Xyl3B', were, probed, by, 'site-directed', mutagenesis])].
[sujeto(['Each', mutation]), verbo([led]), complemento([to, a, severely, decreased, catalytic, efficiency, without, a, change, in, the, overall, structure, of, the, mutant, enzymes])].
[sujeto(['Through', amino, acid, sequence, 'alignments,', an, amino, acid, residue, '(', 'E115)', 'that,', when, mutated, to, aspartic, 'acid,', resulted, in, a, 14, -, fold]), verbo([decrease]), complemento([in, the, 'k(cat)/K(m)', for, 'pNP-beta-d-xylopyranoside', '(', 'pNPX)', with, a, concurrent, 1.1, -, fold, increase, in, the, 'k(cat)/K(m)', for, 'pNP-beta-d-glucopyranoside', '(', 'pNPG)', was, identified])].
[sujeto(['Our', results, demonstrate, that, each, of, the, four, 'GH3', enzymes]), verbo([has]), complemento([evolved, to, perform, a, specific, role, in, lignopolysaccharide, hydrolysis, and, provide, insight, into, the, role, of, 'active-site', residues, in, catalysis, and, substrate, specificity, for, 'GH3', enzymes])].
[sujeto(['More', than, ten, 'bradykinin-related', peptides, and, their, cDNAs]), verbo([have]), complemento([been, identified, from, 'amphibians,', but, their, genes, are, unknown])].
[sujeto(['The', promoter, region, of, the, bradykinin, gene, contains, several, putative, recognition, sites, for]), verbo([nuclear]), complemento(['factors,', such, as, 'SRY,', 'GATA-1,', 'LYF-1,', 'DeltaE,', 'CDXA,', 'NKX-2'])].
[sujeto(['Interferon', regulatory, factor, 3, '(', 'IRF-3),', an, essential, transcriptional, regulator, of, the, interferon, 'genes,']), verbo([has]), complemento([been, implicated, in, virus, and, 'double-stranded', 'RNA', mediated, induction, of, 'IFN-α,', 'IFN-β', and, 'RANTES,', in, 'virus-induced', apoptosis, and, in, tumor, suppression])].
[sujeto(['Promoter', plays, an, important, role, in, the, regulation, of, gene, 'expression,', but, the, characterization, of, the, human, 'IRF-3', promoter]), verbo([has]), complemento([not, been, systematically, analyzed, in, 'HEK', 293, cells])].
[sujeto(['To', characterize, the, human, 'IRF-3', 'promoter,', we]), verbo([have]), complemento([isolated, a, genomic, clone, of, the, human, 'IRF-3', gene, promoter, region, containing, 1, ',', 0, nucleotides, of, the, 5, '\'', -, flanking, region])].
[sujeto(['This', region, contains, 'HSF,', 'E2F,', 'CdxA', and, 'c-Myb', transcription, factor]), verbo([binding]), complemento([sites])].
[sujeto(['The', 'E2F', sites, are, highly]), verbo([conserved]), complemento([among, 'IRF-3', promoter, regions, of, 'mouse,', rat, and, human])].
[sujeto(['Therefore,', it, was]), verbo([suggested]), complemento([that, this, 'E2F', site, may, be, essential, for, basal, promoter, activity])].
[sujeto(['Surprisingly,', mutation, of, this, 'E2F', site]), verbo([increased]), complemento([the, promoter, activity, by, 2, -, fold])].
[sujeto(['E2F1', transcription, factor, negatively]), verbo([regulates]), complemento([human, 'IRF-3', gene, promoter])].
[sujeto(['Although', the, requirement, for, 'RA', signaling, for, the, development, of, a, few, individual, endoderm, organs]), verbo([has]), complemento([been, established, a, systematic, assessment, of, its, activity, along, the, entire, 'antero-posterior', axis, has, not, been, performed, in, this, germ, layer])].
[sujeto(['These', results, imply, that, 'RA']), verbo([acts]), complemento([as, a, caudalizing, factor, in, a, graded, manner, in, pharyngeal, endoderm])].
[sujeto(['Posterior', foregut, and, midgut, organ, primordia, also]), verbo([require]), complemento(['RA,', but, exposing, endoderm, to, additional, 'RA', is, not, sufficient, to, expand, these, primordia, anteriorly])].
[sujeto(['Our', results, show, that, the, induction, of, 'CdxA,', a, midgut, 'marker,', and, pancreas, induction]), verbo([require]), complemento([direct, 'RA', signaling, in, endoderm])].
[sujeto(['Moreover,', communication, between, 'CdxA(+)', cells, is, necessary, to]), verbo([maintain]), complemento(['CdxA', 'expression,', therefore, synchronizing, the, cells, of, the, midgut, primordium])].
[sujeto(['We', further, show, that, the, 'RA', pathway]), verbo([acts]), complemento([synergistically, with, 'FGF4', in, endoderm, patterning, rather, than, mediating, 'FGF4', activity])].
[sujeto(['Gene', regulation, during, development, is, an, important, biological, activity, that]), verbo([leads]), complemento([to, synthesis, of, biomolecules, at, specific, locations, and, specific, times])].
[sujeto(['We', investigated, the, internal, promoter, of, tropomyosin, to, identify, sequences, that]), verbo([regulate]), complemento([expression, of, 'tmy-1', in, the, pharynx, and, intestine])].
[sujeto(['By', promoter, deletion, of, 'tmy-1', reporters, as, well, as, by, database, 'analyses,', a, 100, -, bp, fragment, that, contained]), verbo([binding]), complemento([sequences, for, a, 'GATA', 'factor,', for, a, chicken, 'CdxA', 'homolog,', and, for, a, forkhead, factor, was, identified])].
[sujeto(['Both', the, forkhead, and, 'CdxA']), verbo([binding]), complemento([sequences, contributed, to, pharyngeal, and, intestinal, expression])].
[sujeto(['We', showed, that, 'ELT-2', and, 'PHA-4', proteins]), verbo([interact]), complemento([directly, with, the, 'GATA', and, forkhead, binding, 'sequences,', 'respectively,', in, gel, mobility, shift, assays])].
[sujeto(['We']), verbo([found]), complemento([no, indication, of, a, synergistic, relation, between, 'ELT-2', and, 'PHA-4'])].
[sujeto(['The', immunoglobulin, 'enhancer-binding', 'proteins,', 'E12', and, 'E47,', encoded, by, the, 'E2A', gene, belong, to, the, basic, 'helix-loop-helix', '(', 'bHLH)', family, of, regulatory, proteins, and]), verbo([act]), complemento([as, transcriptional, activators])].
[sujeto(['In', addition, to, their, critical, role, in, 'B-lymphocyte', 'development,', the, 'E12', and, 'E47', proteins]), verbo([have]), complemento([been, implicated, in, the, induction, of, myogenesis, as, heterodimeric, partners, of, myogenic, bHLH, 'proteins,', 'MyoD', and, myogenin])].
[sujeto(['Here', we, demonstrate, that, the, 'E2A', proteins, form, heterodimers, with, the, bHLH, oncoprotein, 'tal-1', in, myeloid, and, erythroid, cells, and, that, these, heterodimers, specifically]), verbo([bind]), complemento([to, the, 'CANNTG', 'DNA', motif])].
[sujeto(['Heterodimerization', with, 'tal-1']), verbo([represses]), complemento([transactivation, by, 'E47', and, could, function, to, prevent, the, expression, of, immunoglobulin, genes, in, cells, other, than, 'B', lymphocytes])].
[sujeto(['DNA']), verbo([binding]), complemento([by, 'E2A-tal-1', heterodimers, in, the, 'M1', mouse, myeloid, cell, line, is, abrogated, upon, terminal, macrophage, differentiation, induced, by, the, cytokine, interleukin, 6])].
[sujeto(['The']), verbo([loss]), complemento([of, 'E2A-tal-1', 'DNA', binding, is, correlated, with, elevated, expression, of, mRNA, encoding, the, dominant, negative, 'HLH', 'proteins,', 'Id1', and, particularly, 'Id2'])].
[sujeto(['Moreover,', recombinant, 'Id', proteins]), verbo([inhibit]), complemento([the, 'E2A-tal-1-specific', 'DNA', binding, activity, from, undifferentiated, 'M1', cells])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'E2A-tal-1', heterodimers, may, play, a, role, in, preventing, terminal, differentiation, in, the, myeloid, lineage, and, provide, a, possible, explanation, for, oncogenic, transformation, induced, by, ectopic, 'tal-1', expression, in, acute, 'T-cell', lymphoblastic, leukemias])].
[sujeto(['In', the, present, study, four, 'genes,', 'H-FABP', '(', heart, fatty, 'acid-binding', 'protein),', 'MASTR', '(', 'MEF2']), verbo([activating]), complemento([motif, and, 'SAP', domain, containing, transcriptional, 'regulator),', 'UCP3', '(', uncoupling, protein, 3, ')', and, 'MYOD1', '(', myogenic, differentiation, 1, ')', were, researched, in, 'Large', 'White', pigs])].
[sujeto([187, 'C&gt;T']), verbo([have]), complemento([been, reported, to, be, associated, with, meat, quality, traits, in, pigs])].
[sujeto(['The', single, marker, association, analysis, showed, that, the, 'H-FABP', and, 'MASTR', genes, were]), verbo([associated]), complemento([with, 'IMF', '(', intramuscular, fat, 'content)', '(', 'P', &, 'lt;', 0.05, ')', ',', and, that, the, g])].
[sujeto(['Thus,', our, study, results]), verbo([suggested]), complemento([that, 'H-FABP', and, 'MASTR', polymorphisms, could, be, used, as, genetic, markers, in, the, 'marker-assisted', selection, towards, the, improvement, of, 'IMF', in, 'Large', 'White', pigs])].
[sujeto(['It', dorsalized, 'Xenopus', embryos, and, was]), verbo([expressed]), complemento([in, the, 'Spemann', organizer, during, early, gastrulation])].
[sujeto(['Frzb', was, secretable, and, could]), verbo([act]), complemento([across, cell, boundaries])].
[sujeto(['Furthermore,', 'Frzb', blocked, induction, of, 'MyoD,', an, action]), verbo([reported]), complemento([recently, for, a, 'dominant-negative', 'Xwnt-8'])].
[sujeto(['Frzb', coimmunoprecipitated, with, 'Wnt', 'proteins,']), verbo([providing]), complemento([direct, biochemical, evidence, for, 'Frzb-Wnt', interactions])].
[sujeto(['These', observations, implicate, 'Frzb', in, axial, patterning, and, support, the, concept, that, 'Frzb']), verbo([binds]), complemento([and, inactivates, 'Xwnt-8', during, 'gastrulation,', preventing, inappropriate, ventral, signaling, in, developing, dorsal, tissues])].
[sujeto(['Transcription', factors, containing, a, basic, 'helix-loop-helix', '(', 'bHLH)', motif]), verbo([regulate]), complemento([the, expression, of, 'tissue-specific', genes, in, a, number, of, mammalian, and, insect, systems])].
[sujeto(['Consequently,', 'Id', proteins]), verbo([inhibit]), complemento([binding, to, 'DNA', and, transcriptional, transactivation, by, heterodimerization, with, bHLH, proteins])].
[sujeto(['We']), verbo([report]), complemento([here, the, cDNA, sequence, of, a, novel, human, 'HLH', gene, '(', 'HGMW-approved', symbol, 'ID4)', that, lacks, the, basic, domain])].
[sujeto(['ID4', is, differentially]), verbo([expressed]), complemento([in, adult, organs, in, four, mRNA, 'molecules,', which, are, presumably, a, result, of, differential, splicing, 'and/or', alternative, usage, of, the, polyadenylation, sites])].
[sujeto(['Transfection', experiments, indicated, that, enforced, expression, of, 'Id-4H', protein]), verbo([inhibits]), complemento([the, 'trans-activation', of, the, muscle, creatine, kinase, 'E-box', enhancer, by, 'MyoD'])].
[sujeto(['The', three, ternary, complex, factors, '(', 'TCFs),', 'Net', '(', 'ERP/', 'SAP-2),', 'ELK-1', and, 'SAP-1,', are, highly, related, ets, oncogene, family, members, that]), verbo([participate]), complemento([in, the, response, of, the, cell, to, 'Ras', and, growth, signals])].
[sujeto(['Understanding', the, different, roles, of, these, factors, will]), verbo([provide]), complemento([insights, into, how, the, signals, result, in, coordinate, regulation, of, the, cell])].
[sujeto(['We', show, that, 'Net']), verbo([inhibits]), complemento([transcription, under, basal, 'conditions,', in, which, 'SAP-1a', is, inactive, and, 'ELK-1', stimulates])].
[sujeto(['Repression', is]), verbo([mediated]), complemento([by, the, 'NID,', the, 'Net', 'Inhibitory', 'Domain', of, about, 50, amino, 'acids,', which, autoregulates, the, 'Net', protein, and, also, inhibits, when, it, is, isolated, in, a, heterologous, fusion, protein])].
[sujeto(['Ras']), verbo([activates]), complemento(['Net', through, the, 'C-domain,', which, is, conserved, between, the, three, 'TCFs,', and, the, 'NID', is, an, efficient, inhibitor, of, 'Ras', activation])].
[sujeto(['The', 'NID,', as, well, as, more, 'C-terminal', 'sequences,']), verbo([inhibit]), complemento(['DNA', binding])].
[sujeto(['Net', is, more, refractory, to, 'DNA']), verbo([binding]), complemento([than, the, other, 'TCFs,', possibly, due, to, the, presence, of, multiple, inhibitory, elements])].
[sujeto(['The', sequence, resemblance, with, myogenic, factors]), verbo([suggested]), complemento([that, 'Net', may, form, complexes, with, the, same, partners])].
[sujeto(['Indeed,', we]), verbo([found]), complemento([that, 'Net', can, interact, in, vivo, with, the, basic, 'HLH', 'factor,', 'E47'])].
[sujeto(['We', propose, that, 'Net', is]), verbo([regulated]), complemento([at, the, level, of, its, latent, 'DNA-binding', activity, by, protein, interactions, 'and/or', phosphorylation])].
[sujeto(['The', identification, of, the, novel, inhibitory, domain]), verbo([provides]), complemento([a, new, inroad, into, exploring, the, different, roles, of, the, ternary, complex, factors, in, growth, control, and, transformation])].
[sujeto(['I-mfa', '(', inhibitor, of, the, 'MyoD', family, 'a)', is, a, transcription, modulator, that]), verbo([binds]), complemento([to, 'MyoD', family, members, and, inhibits, their, transcriptional, activities])].
[sujeto(['It', is, highly]), verbo([expressed]), complemento([in, the, sclerotome, and, plays, an, important, role, in, the, patterning, of, the, somite, early, in, development])].
[sujeto(['The', statistical, analyses, indicated, that, the, three, 'SNPs,', are]), verbo([associated]), complemento([with, the, phenotypic, traits, in, 'Luxi', '(', 'LX),', 'Qinchuan', '(', 'QC),', and, 'Jiaxian', '(', 'JX)', cattle, population, '(', 'P&nbsp;&lt;&nbsp;0'])].
[sujeto(['The', 'mutant-type', variants, were, superior, for, growth, 'traits;', the, heterozygote, diplotype, was]), verbo([associated]), complemento([with, higher, growth, traits, compared, to, 'wild-type', homozygote])].
[sujeto(['Our', results]), verbo([provide]), complemento([evidence, that, polymorphisms, in, the, 'I-mfa', gene, are, associated, with, growth, traits, and, may, be, used, for, 'marker-assisted', selection, in, beef, cattle, breeding, program])].
[sujeto(['Accumulating', evidence]), verbo([suggests]), complemento([that, 'Sirtuin', '(', 'Sirt)1', serves, a, significant, role, in, proliferation, and, differentiation, of, myoblast, 'cells;', however, the, signaling, mechanisms, involved, remain, to, be, established])].
[sujeto(['To', determine, if, 'MSTN', is]), verbo([involved]), complemento([in, the, regulation, of, myoblast, cell, proliferation, by, 'Sirt1,', the, present, study, administrated, the, 'Sirt1&nbsp;activator', 'resveratrol,', inhibitor, nicotinamide, '(', 'NAM)', and, 'MSTN', inhibitor, 'SB431542&nbsp;to', 'C2C12&nbsp;myoblast', cells])].
[sujeto(['It', was, demonstrated, that, the, 'Sirt1&nbsp;activator,', 'resveratrol,', 'repressed,', whereas, the, 'Sirt1&nbsp;inhibitor,', 'NAM,']), verbo([enhanced]), complemento(['C2C12&nbsp;myoblast', cells, proliferation, in, a, 'Sirt1&#8209;dependent', manner])].
[sujeto(['Additionally,', resveratrol, upregulated, the, mRNA, expression, of, 'MyoD,', but]), verbo([inhibited]), complemento([the, expression, of, 'MSTN'])].
[sujeto(['Additionally,', 'NAM', significantly]), verbo([repressed]), complemento([the, expression, of, 'MyoD', and, the, phosphorylation, of, 'P107', '(', 'p&#8209;P107),', but, enhanced, the, expression, of, 'MSTN', and, the, protein, expression, of, 'P107'])].
[sujeto(['Marek\'s', disease, '(', 'MD)', is, an, infectious, disease, of, chickens]), verbo([caused]), complemento([by, 'MD', virus, '(', 'MDV),', which, is, a, herpesvirus, that, initiates, tumor, formation])].
[sujeto(['Studies']), verbo([have]), complemento([indicated, that, microRNAs, '(', 'miRNAs)', are, linked, with, the, development, of, cancers, or, tumors])].
[sujeto(['The']), verbo([target]), complemento([genes, of, 'gga-miR-130a', were, predicted, using, 'TargetScan', and, miRDB, and, clustered, through, 'Gene', 'Ontology', analysis])].
[sujeto(['The']), verbo([target]), complemento([genes, were, validated, by, western, 'blot,', 'qRT-PCR,', and, a, dual, luciferase, reporter, assay])].
[sujeto(['Two']), verbo([target]), complemento(['genes,', homeobox, 'A3', '(', 'HOXA3)', and, 'MyoD', family, inhibitor, domain, containing, '(', 'MDFIC),', were, predicted, and, clustered, to, cell, proliferation])].
[sujeto(['Results', indicate, that, 'gga-miR-130a']), verbo([regulates]), complemento(['HOXA3', and, 'MDFIC', at, the, protein, level, but, not, at, the, mRNA, level])].
[sujeto(['Moreover,', the, 'gga-miR-130a']), verbo([binding]), complemento([sites, of, two, target, genes, have, been, confirmed])].
[sujeto(['We', conclude, that, 'gga-miR-130a', can]), verbo([arrest]), complemento(['MSB1', cell, proliferation, and, 'migration,', and, target, 'HOXA3', and, 'MDFIC,', which, are, both, involved, in, the, regulation, of, cell, proliferation])].
[sujeto(['Collectively,', 'gga-miR-130a', plays, a, critical, role, in, the, tumorigenesis]), verbo([associated]), complemento([with, chicken, 'MD'])].
[sujeto(['Extracellular', stimuli]), verbo([induce]), complemento([gene, expression, responses, through, intracellular, signaling, mediators])].
[sujeto(['To', investigate, the, global, gene, transcription, program]), verbo([regulated]), complemento([by, p38α, during, satellite, cell, differentiation, '(', 'myogenesis),', and, to, specifically, address, whether, this, regulation, occurs, through, direct, action, of, p38α, on, gene, 'promoters,', we, performed, a, combination, of, microarray, gene, expression, and, 'genome-wide', binding, analyses])].
[sujeto(['For', experimental, 'robustness,', two, myogenic, cellular, systems, with, genetic, and, chemical]), verbo([loss]), complemento([of, p38α, function, were, 'used:', '(', 1, ')', satellite, cells, derived, from, mice, with, 'muscle-specific', deletion, of, 'p38α,', and, '(', 2, ')', the, 'C2C12', murine, myoblast, cell, line, cultured, in, the, absence, or, presence, of, the, 'p38α/β', inhibitor, 'SB203580'])].
[sujeto(['We', show, that, p38α]), verbo([binds]), complemento([to, a, large, set, of, active, promoters, during, the, transition, of, myoblasts, from, proliferation, to, differentiation, stages])].
[sujeto(['p38α-bound', promoters, are, enriched, with]), verbo([binding]), complemento([motifs, for, several, transcription, 'factors,', with, 'Sp1,', 'Tcf3/E47,', 'Lef1,', 'FoxO4,', 'MyoD,', and, 'NFATc', standing, out, in, all, experimental, conditions])].
[sujeto(['Interestingly,', p38α, also]), verbo([associates]), complemento([with, genes, repressed, at, the, onset, of, 'differentiation,', thus, highlighting, the, relevance, of, 'p38-dependent', chromatin, regulation, for, transcriptional, activation, and, repression, during, myogenesis])].
[sujeto(['These', results, uncover, p38α, association, and, function, on, chromatin, at, novel, classes, of]), verbo([target]), complemento([genes, during, skeletal, muscle, cell, differentiation])].
[sujeto(['Acute', muscle, injury, and, physiological, stress, from, chronic, muscle, diseases, and, aging]), verbo([lead]), complemento([to, impairment, of, skeletal, muscle, function])].
[sujeto(['This', raises, the, question, of, whether, 'p53,', a, cellular, stress, 'sensor,']), verbo([regulates]), complemento([muscle, tissue, repair, under, stress, conditions])].
[sujeto(['By', investigating, muscle, differentiation, in, the, presence, of, genotoxic, 'stress,', we, discovered, that, p53]), verbo([binds]), complemento([directly, to, the, myogenin, promoter, and, represses, transcription, of, 'myogenin,', a, member, of, the, 'MyoD', family, of, transcription, factors, that, plays, a, critical, role, in, driving, terminal, muscle, differentiation])].
[sujeto(['This', reduction, of, myogenin, protein, is, observed, in, 'G1-arrested', cells, and]), verbo([leads]), complemento([to, decreased, expression, of, late, but, not, early, differentiation, markers])].
[sujeto(['In', response, to, acute, genotoxic, 'stress,', 'p53-mediated', repression, of, myogenin, reduces, 'post-mitotic']), verbo([nuclear]), complemento([abnormalities, in, terminally, differentiated, cells])].
[sujeto(['This', study]), verbo([reveals]), complemento([a, mechanistic, link, previously, unknown, between, p53, and, muscle, 'differentiation,', and, suggests, new, avenues, for, managing, 'p53-mediated', stress, responses, in, chronic, muscle, diseases, or, during, muscle, aging])].
[sujeto(['In', the, present, 'study,', we, performed, a, genome, wide, survey, of, candidate, genes, and, pathways]), verbo([associated]), complemento([with, individual, birth, weight, '(', 'IBW)', using, the, 'Illumina', 'PorcineSNP60', 'BeadChip', on, 24, high, '(', 'HEBV)', and, 24, low, estimated, breeding, value, '(', 'LEBV)', animals])].
[sujeto(['A', 'DSR', with, the, most, number, of, significant, 'SNPs', '(', including, 7, top, 0.1, '%', and, 31, top, 5, '%', 'SNPs)', was, located, on, 'SSC6,', while, another, 'DSR', with, the, largest, genetic, differences, in, 'F', 'ST', was]), verbo([found]), complemento([on, 'SSC18'])].
[sujeto(['These', regions, harbor, known, functionally, important, genes]), verbo([involved]), complemento([in, growth, and, 'development,', such, as, 'TNFRSF9', '(', tumor, necrosis, factor, receptor, superfamily, member, 9, ')', ',', 'CA6', '(', carbonic, anhydrase, 'VI)', and, 'MDFIC', '(', 'MyoD', family, inhibitor, domain, 'containing)'])].
[sujeto(['A', 'DSR', rich, in, imprinting, genes, appeared, on, 'SSC9,', which, included, 'PEG10', '(', paternally]), verbo([expressed]), complemento([10, ')', ',', 'SGCE', '(', 'sarcoglycan,', 'epsilon),', 'PPP1R9A', '(', protein, phosphatase, 1, ',', regulatory, subunit, 9, 'A)', and, 'ASB4', '(', ankyrin, repeat, and, 'SOCS', box, containing, 4, ')'])].
[sujeto(['More', 'importantly,', our, present, study]), verbo([provided]), complemento([evidence, to, support, six, quantitative, trait, loci, '(', 'QTL)', regions, for, pig, birth, 'weight,', six, 'QTL', regions, for, average, birth, weight, '(', 'ABW)', and, three, 'QTL', regions, for, litter, birth, weight, '(', 'LBW)', reported, previously, by, other, groups])].
[sujeto(['Furthermore,', gene, ontology, analysis, with, 183, genes, harbored, in, these, 27, 'DSRs']), verbo([suggested]), complemento([that, 'protein,', 'metal,', ion, and, 'ATP', 'binding,', viral, process, and, innate, immune, response, present, important, pathways, for, deciphering, their, roles, in, fetal, growth, or, development])].
[sujeto(['Overall,', our, study]), verbo([provides]), complemento([useful, information, on, candidate, genes, and, pathways, for, regulating, birth, weight, in, 'piglets,', thus, improving, our, understanding, of, the, genetic, mechanisms, involved, in, porcine, embryonic, or, fetal, development])].
[sujeto(['We']), verbo([have]), complemento([discovered, that, a, 'T-box', family, 'member,', 'TBX2,', is, highly, upregulated, in, tumor, cells, of, both, major, 'RMS', subtypes])].
[sujeto(['The', cell, cycle, regulator, p21, is]), verbo([required]), complemento([for, the, terminal, differentiation, of, skeletal, muscle, cells, and, is, silenced, in, 'RMS', cells])].
[sujeto(['We']), verbo([have]), complemento([found, that, 'TBX2', interacts, with, the, myogenic, regulatory, factors, 'MyoD', and, myogenin, and, inhibits, the, activity, of, these, factors])].
[sujeto(['TBX2', is]), verbo([expressed]), complemento([in, primary, myoblasts, and, 'C2C12', 'cells,', but, is, strongly, downregulated, upon, differentiation])].
[sujeto(['TBX2']), verbo([recruits]), complemento([the, histone, deacetylase, 'HDAC1', and, is, a, potent, inhibitor, of, the, expression, of, 'muscle-specific', genes, and, the, cell, cycle, 'regulators,', p21, and, p14])].
[sujeto(['TBX2']), verbo([promotes]), complemento([the, proliferation, of, 'RMS', cells, and, either, depletions, of, 'TBX2', or, dominant, negative, 'TBX2', upregulate, 'p21-', and, 'muscle-specific', genes])].
[sujeto(['Significantly,', depletion, or, interference, with, 'TBX2', completely]), verbo([inhibits]), complemento([tumor, growth, in, a, xenograft, 'assay,', highlighting, the, oncogenic, role, of, 'TBX2', in, 'RMS', cells])].
[sujeto(['Thus,', the, data, demonstrate, that, elevated, expression, of, 'TBX2', contributes, to, the, pathology, of, 'RMS', cells, by]), verbo([promoting]), complemento([proliferation, and, repressing, 'differentiation-specific', gene, expression])].
[sujeto(['These', results, show, that, deregulated, 'TBX2', serves, as, an, oncogene, in, 'RMS,']), verbo([suggesting]), complemento([that, 'TBX2', may, serve, as, a, new, diagnostic, marker, or, therapeutic, target, for, 'RMS', tumors])].
[sujeto(['I-mfa', null, mice]), verbo([have]), complemento([an, osteopenic, phenotype, characterized, by, increased, osteoclast, numbers, and, 'surface,', which, are, normalized, in, mice, lacking, both, 'Trpc1', and, 'I-mfa'])].
[sujeto(['In', vitro, differentiation, of, 'pre-osteoclasts', derived, from, 'I-mfa-deficient', mice]), verbo([leads]), complemento([to, an, increased, number, of, mature, osteoclasts, and, higher, bone, resorption, per, osteoclast])].
[sujeto(['Consistently,', whole, cell, currents]), verbo([activated]), complemento([in, response, to, the, depletion, of, intracellular, 'Ca(2+)', stores, are, larger, in, 'pre-osteoclasts', derived, from, 'I-mfa', 'knock-out', mice, compared, with, currents, in, wild, type, mice, and, normalized, in, cells, derived, from, double, mutant, 'mice,', suggesting, a, 'cell-autonomous', effect, of, 'I-mfa', on, 'TRPC1', in, these, cells])].
[sujeto(['Heterologous', expression, of, 'TRPC1ε', in, 'HEK293', cells, revealed, that, it, is, unique, among, all, known, 'TRPC1', isoforms, in, its, ability, to, amplify, the, activity, of, the, 'Ca(2+)', 'release-activated', 'Ca(2+)', '(', 'CRAC)', 'channel,']), verbo([mediating]), complemento(['store-operated', currents])].
[sujeto(['TRPC1ε', physically]), verbo([interacts]), complemento([with, 'Orai1,', the, 'pore-forming', subunit, of, the, 'CRAC', 'channel,', and, 'I-mfa', is, recruited, to, the, 'TRPC1ε-Orai1', complex, through, 'TRPC1ε', suppressing, 'CRAC', channel, activity])].
[sujeto(['We', propose, that, the, positive, and, negative, modulation, of, the, 'CRAC', channel, by, 'TRPC1ε', and, 'I-mfa,', 'respectively,', 'fine-tunes', the, dynamic, range, of, the, 'CRAC', channel]), verbo([regulating]), complemento([osteoclastogenesis])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, a, natural, compound, of, the, hydroxybenzoquinone, 'class,', 'embelin,', specifically, inhibits, 'H3Lys9', acetylation, in, mice, and, inhibits, recombinant, 'PCAF-mediated', acetylation, with, near, complete, specificity, in, vitro])].
[sujeto(['Furthermore,', using, 'embelin,', we]), verbo([have]), complemento([identified, the, gene, networks, that, are, regulated, by, 'PCAF', during, muscle, 'differentiation,', further, highlighting, the, broader, regulatory, functions, of, 'PCAF', in, muscle, differentiation, in, addition, to, the, regulation, via, 'MyoD', acetylation])].
[sujeto(['Ephrin-A5', is, a, chemotactic, molecule, that]), verbo([participates]), complemento([in, the, correct, positioning, and, formation, of, the, 'NMJ'])].
[sujeto(['Treatment', of, the, 'BSC', with, 'ephrin-A5']), verbo([causes]), complemento([a, reduction, '(', 'P', &, 'lt;', 0.05, ')', in, velocity, with, a, concomitant, increase, '(', 'P', &, 'lt;', 0.05, ')', in, directed, migration])].
[sujeto(['Ephrin-A5']), verbo([induced]), complemento([migration, appears, to, require, components, of, the, 'Ras', homolog, gene, family, member, 'A', '(', 'RhoA)', and, 'Rho-associated', protein, kinase, '(', 'ROCK)', signaling, machinery])].
[sujeto(['Supplementation', of, culture, media, with, a, chemical, 'ROCK', inhibitor]), verbo([suppressed]), complemento(['(', 'P', &, 'lt;', 0.05, ')', 'ephrin-A5', initiated, 'BSC', migration])].
[sujeto(['Twenty-four', hours, after, culture, 'establishment,', 'BSC', demonstrated, an]), verbo([increase]), complemento(['(', 'P', &, 'lt;', 0.05, ')', in, transwell, migration, toward, 'HGF'])].
[sujeto(['These', results, document, that, temporal, and, spatial, gradients, of, chemokines, and, growth, factors]), verbo([participate]), complemento([in, the, localization, of, 'BSC', within, the, niche])].
[sujeto(['The', class, 'IIa', histone, deacetylases, '(', 'HDACs)']), verbo([act]), complemento([as, transcriptional, repressors, by, altering, chromatin, structure, through, histone, deacetylation])].
[sujeto(['This', family, of, enzymes]), verbo([regulates]), complemento([muscle, development, and, 'phenotype,', through, regulation, of, 'muscle-specific', genes, including, myogenin, and, 'MyoD', '(', 'MYOD1)'])].
[sujeto(['More', 'recently,', class, 'IIa', 'HDACs']), verbo([have]), complemento([been, implicated, in, regulation, of, genes, involved, in, glucose, metabolism])].
[sujeto(['However,', the, effects, of, 'HDAC5', on, glucose, metabolism, and, insulin, action]), verbo([have]), complemento([not, been, directly, assessed])].
[sujeto(['Knockdown', of, 'HDAC5', in, human, primary, muscle, cells]), verbo([increased]), complemento([glucose, uptake, and, was, associated, with, increased, 'GLUT4', '(', 'SLC2A4)', expression, and, promoter, activity, but, was, associated, with, reduced, 'GLUT1', '(', 'SLC2A1)', expression])].
[sujeto(['The', effects, of, 'HDAC5', knockdown, on, glucose, metabolism, were, not, due, to, alterations, in, the, initiation, of, 'differentiation,', as, knockdown, of, 'HDAC5', after, the, onset, of, differentiation, also, resulted, in]), verbo([increased]), complemento([glucose, uptake, and, 'insulin-stimulated', glycogen, synthesis])].
[sujeto(['These', data, show, that, inhibition, of, 'HDAC5']), verbo([enhances]), complemento([metabolism, and, insulin, action, in, muscle, cells])].
[sujeto(['In', 'myotubes,', 'Scriptaid']), verbo([increased]), complemento([histone, 3, 'acetylation,', 'GLUT4', 'expression,', glucose, uptake, and, both, oxidative, and, 'non-oxidative', metabolic, flux])].
[sujeto(['Together,', these, data]), verbo([suggest]), complemento([that, 'HDAC5', regulates, muscle, glucose, metabolism, and, insulin, action, and, that, 'HDAC', inhibitors, can, be, used, to, modulate, these, parameters, in, muscle, cells])].
[sujeto(['Skeletal', muscle, differentiation, is]), verbo([regulated]), complemento([by, transcription, 'factors,', including, members, of, the, myogenic, regulatory, factor, '(', 'MRF)', family, and, many, signaling, pathways])].
[sujeto(['The', 'JAK1', and, 'JAK2', pathways, are, known, to, each]), verbo([have]), complemento([different, effects, on, myoblast, proliferation, and, 'differentiation;', 'however,', the, role, of, 'JAK3', in, myoblast, differentiation, remains, unclear])].
[sujeto(['During', myogenic, 'differentiation,', treatment, with, the, 'JAK3', inhibitor, 'WHIp154', significantly]), verbo([increased]), complemento([the, number, of, 'MHC-positive', multinucleated, myotubes, and, the, expressions, of, myosin, heavy, chain, '(', 'MHC),', myogenin, '(', 'MGN),', 'MyoD,', and, myogenic, enhancer, factor, 2, '(', 'MEF2)'])].
[sujeto(['Knockdown', of, the, 'JAK3', gene, using, siJAK3, also, significantly]), verbo([increased]), complemento(['MHC,', 'MGN', and, 'MyoD', mRNA, expressions, as, well, as, 'insulin-like', growth, 'factor-II', '(', 'IGF-II)', gene, expression])].
[sujeto(['During', 'differentiation,', 'JAK3', was, initially]), verbo([activated]), complemento([and, later, decreased])].
[sujeto(['Differentiation']), verbo([decreased]), complemento(['STAT1,', which, was, further, decreased, by, 'WHIp154'])].
[sujeto(['In', 'contrast,', 'STAT3', gradually, was, elevated, during, 'differentiation,', and, was]), verbo([increased]), complemento([by, 'JAK3', inhibition])].
[sujeto(['Moreover,', we]), verbo([found]), complemento([that, 'up-regulation', of, 'AKT', activity, and, 'down-regulation', of, 'ERK', activity, cooperated, to, accelerate, myogenic, differentiation])].
[sujeto(['Additionally,', 'JAK3', inhibition]), verbo([induced]), complemento([precocious, differentiation, and, played, important, roles, for, terminal, 'differentiation,', including, 'fusion,', which, is, involved, with, regulation, of, 'AKT', and, 'ERK', pathways])].
[sujeto(['Expression', of]), verbo([phosphorylated]), complemento(['Smad1/5/8,', which, is, an, indicator, of, 'BMP', 'activity,', was, higher, before, 'differentiation,', and, rapidly, decreased, after, differentiation, stimulation])].
[sujeto(['Treatment', with, inhibitors, of, 'BMP', type, 'I', receptors, or, noggin, in, 'C2C12', myoblasts, 'down-regulated', the, expression, of, myogenic, regulatory, 'factors,', such, as, 'Myf5', and, 'MyoD,']), verbo([leading]), complemento([to, impaired, myotube, formation])].
[sujeto(['Addition', of, 'BMP-2', during, the, myoblast, phase, also]), verbo([inhibited]), complemento([myotube, differentiation, through, the, 'down-regulation', of, 'Myf5', and, 'MyoD'])].
[sujeto(['A-83-01,', an, inhibitor, of, 'TGF-β', type, 'I', 'receptor,']), verbo([increased]), complemento([the, expression, of, 'Myf5', and, 'MyoD,', and, enhanced, myotube, formation])].
[sujeto(['The', present, results]), verbo([reveal]), complemento([that, endogenous, activities, of, the, 'TGF-β', family, are, changed, during, myogenesis, in, a, 'pathway-specific', 'manner,', and, that, the, activities, are, required, for, myogenesis])].
[sujeto(['Differentiation', often]), verbo([requires]), complemento([conversion, of, analogue, signals, to, a, stable, binary, output, through, positive, feedback])].
[sujeto(['Hedgehog', '(', 'Hh)', signalling]), verbo([promotes]), complemento([myogenesis, in, the, vertebrate, 'somite,', in, part, by, raising, the, activity, of, muscle, regulatory, factors, '(', 'MRFs)', of, the, 'Myod', family, above, a, threshold])].
[sujeto(['Hh', is, known, to]), verbo([enhance]), complemento(['MRF', expression])].
[sujeto(['Here', we, show, that, 'Hh', is, also, essential, at, a, second, step, that]), verbo([increases]), complemento(['Myod', protein, 'activity,', permitting, it, to, promote, 'Myogenin', expression])].
[sujeto(['Hh']), verbo([acts]), complemento([by, inducing, expression, of, cdkn1c, '(', 'p57(Kip2))', in, slow, muscle, precursor, 'cells,', but, neither, 'Hh', nor, 'Cdkn1c', is, required, for, their, cell, cycle, exit])].
[sujeto(['Myod', in, turn, 'up-regulates', 'cdkn1c,', thereby]), verbo([providing]), complemento([a, positive, feedback, loop, that, switches, myogenic, cells, to, terminal, differentiation])].
[sujeto(['We', show, here, that, 'OSM', potently]), verbo([inhibited]), complemento([myoblast, differentiation, mainly, by, activating, the, 'JAK1/STAT1/STAT3', pathway])].
[sujeto(['OSM', downregulated, myocyte, 'enhancer-binding', factor, 2, 'A', '(', 'MEF2A),', upregulated, the, expression, of, 'Id1', and, 'Id2,', and]), verbo([inhibited]), complemento([the, transcriptional, activity, of, 'MyoD', and, 'MEF2'])].
[sujeto(['In', 'addition,', 'OSM', also]), verbo([enhanced]), complemento([the, expression, of, 'STAT3', and, 'OSM', 'receptor,', which, constituted, a, positive, feedback, loop, to, further, amplify, 'OSM-induced', signaling])].
[sujeto(['Moreover,', we]), verbo([found]), complemento([that, 'STAT1', physically, associated, with, 'MEF2', and, repressed, its, transcriptional, 'activity,', which, could, account, for, the, 'OSM-mediated', repression, of, 'MEF2'])].
[sujeto(['Although', undetectable, in, normal, muscles, in, 'vivo,', 'OSM', was, rapidly]), verbo([induced]), complemento([on, muscle, injury, and, then, promptly, downregulated, just, before, the, majority, of, myoblasts, differentiate])].
[sujeto(['Prolonged', expression, of, 'OSM', in, muscles, compromised, the, regeneration, process, without, affecting, myoblast, 'proliferation,']), verbo([suggesting]), complemento([that, 'OSM', functions, to, prevent, proliferating, myoblasts, from, premature, differentiation, during, the, early, phase, of, muscle, regeneration])].
[sujeto(['Splitting', 'Fluc', into, 'N-', and, 'C-terminal', fragments, destroys, its, enzymatic, 'activity,', resulting, in, a, complete]), verbo([loss]), complemento([of, bioluminescence])].
[sujeto(['This']), verbo([led]), complemento([to, the, development, of, a, novel, labeling, strategy, for, imaging, 'protein–protein', interactions, in, 'vivo,', the, split, reporter, '(', 4, ')'])].
[sujeto(['In', this, 'method,', reporters, like, 'Fluc', are, dissected, into, two, fragments, and, fused, to, a, pair, of, proteins, '(', 'A', and, 'B)', that, strongly]), verbo([interact]), complemento([with, each, other])].
[sujeto(['The', interaction, between, protein, 'A', and, 'B', brings, the, 'N-', and, 'C-inteins', 'together,', resulting, in, the, joining, of, 'N-', and, 'C-terminal', fragments, of, 'Fluc', by, a, peptide, bond, and, a]), verbo([release]), complemento([of, a, fully, reconstituted, protein, 'Fluc'])].
[sujeto(['MyoD']), verbo([activates]), complemento([myogenesis, by, binding, directly, to, the, control, region, of, 'muscle-specific', 'genes,', and, it, converts, fibroblasts, into, skeletal, muscle])].
[sujeto(['The', helices, in, 'MyoD']), verbo([bind]), complemento([tightly, with, other, 'HLH', factors, such, as, 'Id', to, form, a, heterodimer])].
[sujeto(['Id,', also, known, as, an, inhibitor, of, differentiation, or, inhibitor, of, 'DNA', 'binding,', lacks, the, basic, domain, for, 'DNA']), verbo([binding]), complemento([and, acts, as, dominant, negative, regulator, in, myogenesis, or, other, cell, proliferations, '(', 6, ')'])].
[sujeto(['Id', 'protein-firefly', luciferase, 'N-fragment', &, 'amp;', firefly, luciferase, 'C-fragment-MyoD', protein, '(', 'Id-NFluc', &, 'amp;', 'CFluc-MyoD)', make, up, a, pair, of]), verbo([interacting]), complemento([proteins, attached, to, the, split, 'Fluc', fragments, '(', 7, ')'])].
[sujeto(['Kaposi\'s', 'sarcoma-associated', herpes, virus, '(', 'KSHV)-encoded', 'latency-associated']), verbo([nuclear]), complemento([antigen, '(', 'LANA)', protein, has, been, reported, to, interact, with, glycogen, synthase, kinase, 3, beta, '(', 'GSK-3beta)', and, to, negatively, regulate, its, 'activity,', leading, to, stimulation, of, 'GSK-3beta-dependent', 'beta-catenin', degradation])].
[sujeto(['We', show, here, that, the, 'I-mfa', domain, 'proteins,', 'HIC', '(', human, 'I-mfa', 'domain-containing', 'protein)', and, 'I-mfa', '(', inhibitor, of, 'MyoD', family, 'a),']), verbo([interacted]), complemento([in, vivo, with, 'LANA', through, their, 'C-terminal', 'I-mfa', domains])].
[sujeto(['This', interaction, affected, the, intracellular, localization, of, 'HIC,']), verbo([inhibited]), complemento([the, 'LANA-dependent', transactivation, of, a, 'beta-catenin-regulated', reporter, 'construct,', and, decreased, the, level, of, the, 'LANA'])].
[sujeto(['These', data]), verbo([reveal]), complemento([for, the, first, time, that, 'I-mfa', domain, proteins, interact, with, 'LANA', and, negatively, regulate, 'LANA-mediated', activation, of, 'Wnt', 'signaling-dependent', transcription, by, inhibiting, the, formation, of, the, 'LANA'])].
[sujeto(['MyoD', is, a, 'DNA-binding', protein, capable, of, specific, interactions, that]), verbo([involve]), complemento([the, 'helix-loop-helix', '(', 'HLH)', domain])].
[sujeto(['The', 'Id', family, consists, of, four, related, proteins, that, contain, a, highly]), verbo([conserved]), complemento([dimerization, motif, known, as, the, 'HLH', domain])].
[sujeto(['In', signaling, 'pathways,', 'Id', proteins]), verbo([act]), complemento([as, dominant, negative, antagonists, of, the, basic, 'helix-loop-helix', '(', 'bHLH)', family, of, transcription, factors, which, play, important, roles, in, cellular, 'development,', 'proliferation,', and, differentiation])].
[sujeto(['The', mechanism, of, 'Id', proteins, is, to, antagonize, bHLH, proteins, by]), verbo([binding]), complemento([as, dominant, negative, 'HLH', proteins, to, form, 'high-affinity', heterodimers, with, other, bHLH, 'proteins,', thereby, preventing, them, from, binding, to, 'DNA', and, inhibiting, transcription, of, 'differentiation-associated', genes])].
[sujeto(['The', goal, of, this, study, is, to, design, and, synthesize, peptide, fragments, of, 'MyoD', with, high, affinity, for, 'Id1', to, interrupt, the, interactions, among, 'Id1,', 'MyoD,', and, other, bHLH, 'DNA-binding', proteins, and, to]), verbo([inhibit]), complemento([the, proliferation, of, cancer, cells])].
[sujeto(['The', percentage, of, 'sub-G1', in, the, cell, cycle, of, the, cancer, cells, treated, with, 5, microM, of, 3, 'C', was, 'increased,', indicating, the]), verbo([induced]), complemento([apoptosis, of, cancer, cells, by, 3, 'C'])].
[sujeto(['Taken', 'together,', the, peptide, 3, 'C', is, a, promising]), verbo([lead]), complemento([compound, for, the, development, of, antiproliferative, agents])].
[sujeto(['Most', growth, factors]), verbo([stimulate]), complemento([myoblast, proliferation, and, prevent, 'differentiation,', whereas, 'insulin-like', growth, factors, '(', 'IGFs)', promote, myoblast, differentiation, through, the, phosphatidylinositol, 3, -, kinase, '(', 'PI3K)', pathway])].
[sujeto(['Subtilisin-like', proprotein, convertases, '(', 'SPCs)', are]), verbo([involved]), complemento([in, cell, growth, and, differentiation, via, activation, of, 'pro-growth', factors])].
[sujeto(['PACE4', mRNA, levels]), verbo([increased]), complemento([markedly, during, 'myogenesis,', whereas, the, expression, of, other, member, of, 'SPC', 'family,', furin, and, 'PC6,', remained, unchanged])].
[sujeto(['The', expression, of, shRNA]), verbo([targeting]), complemento(['PACE4,', but, not, 'furin,', suppressed, the, expression, of, the, 'muscle-specific', myosin, light, chain, '(', 'MLC)'])].
[sujeto(['Finally,', we, demonstrated, that, the, 'PI3K', inhibitor, 'LY294002', blocked, the, induction, of, 'PACE4', 'mRNA,', a, result, not, observed, when, another, myogenic, differentiation, 'inhibitor,', 'SB203580', '(', p38, 'MAP', kinase, 'inhibitor),', was, 'employed,', indicating, the, presence, of, a, positive, feedback, loop]), verbo([regulating]), complemento(['PACE4', expression])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'PACE4', plays, an, important, role, in, myogenic, differentiation, through, its, association, with, the, 'IGF-II', pathway])].
[sujeto(['Nuclear', localization, of, 'N', is, 'non-essential', for, 'PRRSV', replication, in, cultured, cells, but]), verbo([has]), complemento([been, shown, to, modulate, the, pathogenesis, of, virus, in, 'pigs,', suggesting, that, 'N', plays, an, accessory, role, in, the, nucleus, during, infection])].
[sujeto(['The', porcine, homolog, of, 'HIC', is, universally]), verbo([expressed]), complemento([in, pig, tissues, including, alveolar, macrophages])].
[sujeto(['The', 'I-mfa', domain, proteins, 'HIC', '(', also, known, as, 'MDFIC)', and, 'I-mfa', '(', also, known, as, 'MDFI)', are, candidate, tumor, suppressor, genes, that, are]), verbo([involved]), complemento([in, cellular, and, viral, transcriptional, regulation])].
[sujeto(['Here,', we, show, that, 'HIC', and, 'I-mfa', directly]), verbo([interact]), complemento([with, human, 'T-cell', leukemia, virus, 'type-1', '(', 'HTLV-1)', 'Tax', protein, in, vitro])].
[sujeto(['In', 'addition,', 'HIC', and, 'I-mfa']), verbo([repress]), complemento(['Tax-dependent', transactivation, of, an, 'HTLV-1', long, terminal, repeat, '(', 'LTR)', reporter, construct, in, 'COS-1,', 'Jurkat', and, 'high-Tax-producing', 'HTLV-1-infected', 'T', cells])].
[sujeto(['HIC', also]), verbo([interacts]), complemento([with, 'Tax', through, its, 'I-mfa', domain, in, vivo, and, represses, 'Tax-dependent', transactivation, of, 'HTLV-1', 'LTR', and, 'NF-κB', reporter, constructs, in, an, 'interaction-dependent', manner])].
[sujeto(['Furthermore,', we, show, that, 'HIC']), verbo([decreases]), complemento([the, nuclear, distribution, and, stimulates, the, proteasomal, degradation, of, 'Tax'])].
[sujeto(['These', data]), verbo([reveal]), complemento([that, 'HIC', specifically, interacts, with, 'HTLV-1', 'Tax', and, negatively, regulates, 'Tax', transactivational, activity, by, altering, its, subcellular, distribution, and, stability])].
[sujeto(['Furthermore,', 'genome-wide', 'DNA']), verbo([binding]), complemento([of, p53, was, analyzed, by, 'chromatin-immunoprecipitation', '(', 'ChIP-Seq)'])].
[sujeto(['Thereby,', we, identified, differentially]), verbo([regulated]), complemento([proteins, '(', 542, 'up,', 569, 'down),', mRNAs, '(', 1258, 'up,', 415, 'down),', miRNAs, '(', 111, 'up,', 95, 'down)', and, lncRNAs, '(', 270, 'up,', 123, 'down)'])].
[sujeto(['In', 'total,', we, detected, 133, direct, p53]), verbo([target]), complemento([genes, that, were, differentially, expressed, and, displayed, p53, occupancy, in, the, vicinity, of, their, promoter])].
[sujeto(['More', transcriptionally]), verbo([induced]), complemento([genes, displayed, occupied, p53, binding, sites, '(', 4.3, '%', 'mRNAs,', 7.2, '%', 'miRNAs,', 6.3, '%', 'lncRNAs,', 5.9, '%', 'proteins)', than, repressed, genes, '(', 2.4, '%', 'mRNAs,', 3.2, '%', 'miRNAs,', 0.8, '%', 'lncRNAs,', 1.9, '%', 'proteins),', suggesting, indirect, mechanisms, of, repression])].
[sujeto(['Moreover,', proteins]), verbo([repressed]), complemento([by, p53, significantly, overlapped, with, those, previously, shown, to, be, repressed, by, 'miR-34a'])].
[sujeto(['We', confirmed, 'up-regulation', of, the, novel, direct, p53]), verbo([target]), complemento([genes, 'LINC01021,', 'MDFI,', 'ST14', and, 'miR-486', and, showed, that, ectopic, 'LINC01021', expression, inhibits, proliferation, in, 'SW480', cells])].
[sujeto(['Furthermore,', 'KLF12,', 'HMGB1', and, 'CIT', mRNAs, were, confirmed, as, direct]), verbo([targets]), complemento([of, the, 'p53-induced', 'miR-34a,', 'miR-205', and, 'miR-486-5p,', respectively])].
[sujeto(['In', line, with, the]), verbo([loss]), complemento([of, p53, function, during, tumor, 'progression,', elevated, expression, of, 'KLF12,', 'HMGB1', and, 'CIT', was, detected, in, advanced, stages, of, cancer])].
[sujeto(['In', 'conclusion,', the, integration, of, multiple, omics, methods, allowed, the, comprehensive, identification, of, direct, and, indirect, effectors, of, p53, that]), verbo([provide]), complemento([new, insights, and, leads, into, the, mechanisms, of, 'p53-mediated', tumor, suppression])].
[sujeto(['However,', certain, patients, develop, drug, resistance, following, 'chemotherapy,', which, can]), verbo([lead]), complemento([to, disease, relapse, and, death])].
[sujeto(['Subgroups,', personalized, 'biomarkers,', and, therapy]), verbo([targets]), complemento([were, identified, using, cluster, analysis, of, differentially, expressed, genes])].
[sujeto(['We']), verbo([found]), complemento([that, 'basal-like', breast, cancer, could, be, further, divided, into, at, least, four, distinct, 'subgroups,', including, two, groups, at, risk, for, drug, resistance, and, two, groups, characterized, by, sensitivity, to, pharmacotherapy])].
[sujeto(['Therefore,', these, nine, differentially]), verbo([expressed]), complemento([genes, and, their, associated, functional, pathways, should, provide, the, basis, for, novel, personalized, clinical, treatments, of, 'basal-like', breast, cancer])].
[sujeto(['The', identified, hypermethylation, markers, in, 'CRC', patients, may]), verbo([have]), complemento([good, sensitivity, in, different, 'CRC', stages])].
[sujeto(['Whole', human, genome, oligo, microarray, was, applied, to, detect, the, differentially]), verbo([expressed]), complemento([genes, in, invasive, cells])].
[sujeto(['For', primary, cultured, invasive, 'cells,', differential, expressions, of, several, groups, of, common, genes, are, known, to]), verbo([have]), complemento([capacities, to, promote, proliferation, '(', 'CAV1,', 'IL6,', 'PLAT,', 'RRAD,', 'SRPX),', remodeling, of, extracellular, matrix, '(', 'COL1A1,', 'COL1A2,', 'NID2,', 'TNC,', 'RELN,', 'SPARC),', migration, '(', 'ACTG2,', 'CAV1,', 'CCL2,', 'CCL26,', 'CDC42EP3,', 'CNN1,', 'PHLDB2,', 'PLAT,', 'RRAD,', 'SRPX),', implantation, '(', 'IL6),', immune, escape, '(', 'CD70)', and, angiogenesis, '(', 'CCL2,', 'IL6,', 'IL18,', 'PLAT,', 'SLIT3)'])].
[sujeto(['In', 'conclusion,', the, characteristics, of, invasive, phenotype, 'HCC', cells, are, originated, from, differential, expressions, of, several, groups, of, genes, rather, than, few]), verbo([target]), complemento([genes])].
[sujeto(['Analysis', of, the, results, from, a, purchased, cell, line, may]), verbo([have]), complemento([bias, due, to, 'long-term', repeated, in, vitro, cultures])].
[sujeto(['Many', 'QTLs', for, fatness, traits]), verbo([have]), complemento([been, mapped, on, pig, chromosome, 7, q1])].
[sujeto(['Eight', novel, 'markers,', including, seven, 'SNPs', and, one, insertion, or, deletion, within, 'BTNL1,', 'COL21A1,', 'PPARD,', 'GLP1R,', 'MDFI,', 'GNMT,', 'ABCC10,', and, 'PLA2G7', 'genes,', as, well, as, two, previously]), verbo([reported]), complemento(['SNPs', in, 'SLC39A7', and, 'HMGA1', 'genes,', were, genotyped, in, 'Large', 'White', and, 'Meishan', pig, breeds])].
[sujeto(['Nine']), verbo([target]), complemento([genes, were, assayed, by, 'real-time', 'methylation-specific', polymerase, chain, reaction, '(', 'MSP)', in, 'bisulfite-treated', 'DNA', from, microdissected, frozen, specimens, of, 24, 'PanC', cases, and, 30, normal, colon, controls])].
[sujeto(['Combining', methylated, 'BMP3', and, mutant, 'KRAS']), verbo([increased]), complemento([stool, detection, over, either, marker, alone])].
[sujeto(['In', an, alkaline, 'medium,', the, chemiluminescence, '(', 'CL)', reaction, of, imidazole, derivatives, with, 'H(2)O(2)']), verbo([has]), complemento([been, investigated])].
[sujeto(['It', was, also]), verbo([found]), complemento([that, 'MDFI/H(2)O(2)', and, 't-BDFI/H(2)O(2)', systems, gave, strong, 'CL'])].
[sujeto(['Migraine', is]), verbo([associated]), complemento([with, an, increased, risk, for, cardiovascular, disease, '(', 'CVD)'])].
[sujeto(['We', performed, a, 'genome-wide', association, study, for, incident, 'CVD', events, during, 12, years, of, 'follow-up', among, 5, ',', 122, migraineurs]), verbo([participating]), complemento([in, the, 'population-based', 'Women\'s', 'Genome', 'Health', 'Study'])].
[sujeto(['No', 'SNP', was]), verbo([associated]), complemento([with, major, 'CVD,', ischemic, 'stroke,', myocardial, 'infarction,', or, 'CVD', death, at, the, 'genome-wide', 'level;', 'however,', five, 'SNPs', showed, association, with, 'p&lt;5×10(-6)'])].
[sujeto(['Among', migraineurs, with, aura, rs7698623, in, 'MEPE', '(', 'OR', =, 6.37, ;, 95, '%', 'CI', 3.15, -, 12.9, ;, p, =, 2.7, '×10(-7))', and, rs4975709, in, 'IRX4', '(', 'OR', =, 5.06, ;, 95, '%', 'CI', 2.66, -, 9.62, ;, p, =, 7.7, '×10(-7))', appeared, to, be]), verbo([associated]), complemento([with, ischemic, 'stroke,', rs2143678, located, close, to, 'MDF1', with, major, 'CVD', '(', 'OR', =, 3.05, ;, 95, '%', 'CI', 1.98, -, 4.69, ;, p, =, 4.3, '×10(-7)),', and, the, intergenic, rs1406961, with, 'CVD', death, '(', 'OR', =, 12.33, ;, 95, '%', 'CI', 4.62, -, 32.87, ;, p, =, 5.2, '×10(-7))'])].
[sujeto(['Further,', rs1047964, in, 'BACE1', appeared, to, be]), verbo([associated]), complemento([with, 'CVD', death, among, women, with, any, migraine, '(', 'OR', =, 4.67, ;, 95, '%', 'CI', 2.53, -, 8.62, ;, p, =, 8.0, '×10(-7))'])].
[sujeto(['Our', results]), verbo([provide]), complemento([some, suggestion, for, an, association, of, five, 'SNPs', with, 'CVD', events, among, women, with, 'migraine;', none, of, the, results, was, 'genome-wide', significant])].
[sujeto(['The', 'I-mfa', domain, proteins, 'I-mfa', and, 'HIC', are, considered, to, be, candidate, tumor, suppressor, genes, and]), verbo([have]), complemento([been, shown, to, be, involved, in, transcriptional, regulation])].
[sujeto(['We', show, here, that, 'I-mfa', and, 'HIC', specifically]), verbo([interact]), complemento([with, 'SEI-1', through, their, 'C-terminal', 'I-mfa', domains, 'in&nbsp;vivo'])].
[sujeto(['This', interaction, affects, the, intracellular, localization, of, 'I-mfa', and]), verbo([requires]), complemento([the, region, of, 'SEI-1', between, 30, and, 90, amino, 'acids,', which, includes, its, 'SERTA', 'domain,', and, results, in, repression, of, its, intrinsic, transcriptional, activity])].
[sujeto(['I-mfa', also]), verbo([decreases]), complemento([the, levels, of, the, 'SEI-1·DP-1', complex, and, endogenous, 'Fbxw7', 'mRNA,', the, expression, of, which, is, coregulated, by, 'E2F·DP-1', and, 'SEI-1', in, an, 'interaction-dependent', manner, 'in&nbsp;vitro'])].
[sujeto(['In', 'addition,', 'I-mfa', also, specifically]), verbo([interacts]), complemento([with, other, 'SERTA', 'domain-containing', 'proteins,', including, 'SEI-2,', 'SEI-3,', 'SERTAD3', and, 'SERTAD4,', through, its, 'I-mfa', domain, 'in&nbsp;vivo'])].
[sujeto(['This', interaction, also, affects, the, intracellular, localization, of, 'I-mfa', and]), verbo([represses]), complemento([the, intrinsic, transcriptional, activities, of, 'SEI-2', and, 'SERTAD3,', which, are, also, involved, in, the, 'E2F-dependent', transcription])].
[sujeto(['These', data]), verbo([reveal]), complemento([for, the, first, time, that, 'I-mfa', domain, proteins, interact, with, 'SERTA', domain, proteins, and, negatively, regulate, their, transcriptional, activity])].
[sujeto(['Because', 'SEI-1,', 'SEI-2', and, 'SERTAD3,', whose, intrinsic, transcriptional, activities, are]), verbo([repressed]), complemento([by, 'I-mfa,', are, suggested, to, be, 'oncogenes,', 'I-mfa', domain, proteins, may, be, involved, in, their, oncogenic, functions, by, negatively, regulating, their, transcriptional, activities])].
[sujeto(['The', phenotypes, of, the, 'Scnm1Delta3-5', mutant, confirm, the, role, of, this, splice, factor, in, processing, the, 'Scn8a(medJ)', transcript, and]), verbo([provide]), complemento([a, new, allele, of, greater, severity, for, future, studies])].
[sujeto(['More', than, 1, /, 2, of, the, genes, aberrantly, hypermethylated, in, 'Panc-1', were, not]), verbo([expressed]), complemento([in, the, pancreatic, duct, '(', 'HPDE)', by, expression, array, analysis])].
[sujeto(['Promoter', and, 'CpG', island, array, analysis]), verbo([finds]), complemento([aberrant, methylation, of, hundreds, of, promoters, and, 'CpG', islands, in, pancreatic, cancer, cells])].
[sujeto(['A', commercial, chromogenic, agar, medium, '(', 'DFI)', was, supplemented, with, glucose, '(', 'mDFI)', to]), verbo([enhance]), complemento([the, specificity, of, 'Enterobacter', sakazakii, '(', 'E'])].
[sujeto(['In', these, patients, the, discriminatory, function, index, '(', 'DFI)', &, 'gt;', 32, ',']), verbo([has]), complemento([been, associated, with, a, mortality, rate, of, up, to, 50, '%'])].
[sujeto(['MELD', is, a, scale, that]), verbo([has]), complemento([been, recently, validated, as, independent, risk, factors, for, death, in, patients, who, are, candidates, for, liver, transplantation])].
[sujeto(['Wnt', regulation, of, muscle, development, is, thought, to, be]), verbo([mediated]), complemento([by, the, 'beta-catenin-TCF/LEF-dependent', canonical, pathway])].
[sujeto(['Here', we, demonstrate, that, 'beta-catenin,', not, 'TCF/LEF,', is]), verbo([required]), complemento([for, muscle, differentiation])].
[sujeto(['We', showed, that, 'beta-catenin']), verbo([interacts]), complemento([directly, with, 'MyoD,', a, basic, 'helix-loop-helix', transcription, factor, essential, for, muscle, differentiation, and, enhances, its, binding, to, 'E', box, elements, and, transcriptional, activity])].
[sujeto(['MyoD-mediated', transactivation, is]), verbo([inhibited]), complemento([in, muscle, cells, when, 'beta-catenin', is, deficient, or, the, interaction, between, 'MyoD', and, 'beta-catenin', is, disrupted])].
[sujeto(['We', identify, a, novel, interaction, of, 'Hand1', with, a, protein, that, contains, an, 'I-mfa', '(', inhibitor, of, myogenic, 'factor)', domain, that, anchors, 'Hand1', in, the, nucleolus, where, it, negatively]), verbo([regulates]), complemento(['Hand1', activity])].
[sujeto(['In', the, trophoblast, 'stem-cell', line, 'Rcho-1,', nucleolar, sequestration, of, 'Hand1', accompanies, sustained, cell, proliferation, and, 'renewal,', whereas]), verbo([release]), complemento([of, 'Hand1', into, the, nucleus, leads, to, its, 'activation,', thus, committing, cells, to, a, differentiated, 'giant-cell', fate])].
[sujeto(['Site-specific', phosphorylation, is]), verbo([required]), complemento([for, nucleolar, release, of, 'Hand1,', for, its, dimerization, and, biological, 'function,', and, this, is, mediated, by, the, 'non-canonical', 'polo-like', kinase, 'Plk4', '(', 'Sak)'])].
[sujeto(['Sak', is, 'co-expressed', in, 'Rcho-1', 'cells,', localizes, to, the, nucleolus, during, 'G2', and]), verbo([phosphorylates]), complemento(['Hand1', as, a, requirement, for, trophoblast, 'stem-cell', commitment, to, a, 'giant-cell', fate])].
[sujeto(['This', study, defines, a, novel, cellular, mechanism, for]), verbo([regulating]), complemento(['Hand1', that, is, a, crucial, step, in, the, 'stem-cell', differentiation, pathway])].
[sujeto(['Positive', transcription, elongation, factor, b, '(', 'P-TEFb)', 'complexes,', composed, of, 'cyclin-dependent', kinase, 9, '(', 'CDK9)', and, cyclin, 'T1', or, 'T2,', are, engaged, by, many, cellular, transcription, regulators, that]), verbo([activate]), complemento([or, inhibit, transcription, from, specific, promoters])].
[sujeto(['The', related, 'I-mfa', '(', inhibitor, of, 'MyoD', family, 'a)', and, 'HIC', '(', human, 'I-mfa-domain-containing)', proteins, function, in, myogenic, differentiation, and, embryonic, development, by]), verbo([participating]), complemento([in, the, 'Wnt', signaling, pathway])].
[sujeto(['We']), verbo([report]), complemento([that, 'I-mfa', is, a, novel, regulator, of, 'P-TEFb'])].
[sujeto(['Both', 'HIC', and, 'I-mfa']), verbo([interact]), complemento([through, their, homologous, 'I-mfa', domains, with, cyclin, 'T1', and, 'T2', at, two, binding, sites])].
[sujeto(['One', site, is, the, regulatory, 'histidine-rich', domain, that]), verbo([interacts]), complemento([with, 'CDK9', substrates, including, 'RNA', polymerase, 'II'])].
[sujeto(['The', second, site, contains, a, lysine, and, 'arginine-rich', motif, that, is, highly]), verbo([conserved]), complemento([between, the, two, 'T', cyclins])].
[sujeto(['This', site, overlaps, and, includes, the, previously, identified, 'Tat/TAR', recognition, motif, of, cyclin, 'T1']), verbo([required]), complemento([for, activation, of, human, immunodeficiency, virus, type, 1, '(', 'HIV-1)', transcription])].
[sujeto(['Their', 'I-mfa', domains, also]), verbo([bind]), complemento([the, activation, domain, of, 'HIV-1', 'Tat', and, inhibit, 'Tat-', and, 'P-TEFb-dependent', transcription, from, the, 'HIV-1', promoter])].
[sujeto(['Our', findings, link, 'I-mfa', and, 'HIC', to, viral, 'replication,', and]), verbo([suggest]), complemento([that, 'P-TEFb', is, modulated, in, the, 'Wnt', signaling, pathway])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, 'beta-catenin', interacts, with, a, transcription, suppressor, 'I-mfa', 'and,', through, this, 'interaction,', canonical, 'Wnt', signaling, could, relieve, 'I-mfa-mediated', suppression, of, myogenic, regulatory, factors, '(', 'MRFs)'])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento(['that,', based, on, this, 'interaction,', 'I-mfa-mediated', suppression, of, the, 'Wnt', transcription, factor, 'T-cell', 'factor/lymphoid', enhancing, 'factor-1', '(', 'TCF/LEF-1)', can, also, be, relieved])].
[sujeto(['Our', work, showed, that, knocking, down, endogenous, 'I-mfa', expression, mimics, canonical, 'Wnt', treatment, by]), verbo([inducing]), complemento([myogenesis, and, increasing, 'Wnt', reporter, gene, 'activity,', endogenous, 'Wnt', target, gene, expression, and, expression, of, 'MRFs', in, 'P19', cells])].
[sujeto(['In', 'addition,', we]), verbo([found]), complemento([that, 'beta-catenin', could, compete, with, 'I-mfa', for, binding, to, 'LEF-1', and, relieve, the, inhibitory, effects, of, 'I-mfa', in, overexpression, systems])].
[sujeto(['Furthermore,', canonical, 'Wnt', was, able, to, reduce, the, levels, of, endogenous, 'I-mfa']), verbo([associated]), complemento([with, 'LEF-1,', while, increasing, that, of, 'I-mfa', associated, with, 'beta-catenin'])].
[sujeto(['All', of, the, evidence, supports, a, conclusion, that, 'I-mfa', can]), verbo([suppress]), complemento([myogenesis, by, inhibiting, 'TCF/LEF-1', and, that, canonical, 'Wnt', signaling, may, relieve, the, suppression, through, elevating, 'beta-catenin', 'levels,', which, in, turn, relieve, 'I-mfa-mediated', suppression])].
[sujeto(['Moreover,', we]), verbo([suggest]), complemento([that, the, modified, gene, expression, in, fetal, skeletal, muscle, can, be, viewed, as, the, origin, of, developmental, muscular, plasticity, involved, in, the, concept, of, fetal, programming])].
[sujeto(['Here,', we, demonstrate, that, fusion, of, 'Tet1', or, 'Dnmt3a', with, a, catalytically, inactive, 'Cas9', '(', 'dCas9)', enables]), verbo([targeted]), complemento(['DNA', methylation, editing])].
[sujeto(['Targeting', of, the, 'dCas9-Tet1', or, -, 'Dnmt3a', fusion, protein, to, methylated, or, unmethylated, promoter, sequences]), verbo([caused]), complemento([activation, or, 'silencing,', 'respectively,', of, an, endogenous, reporter])].
[sujeto(['Targeted', demethylation, of, the, 'BDNF', promoter, 'IV', or, the, 'MyoD', distal, enhancer, by, 'dCas9-Tet1']), verbo([induced]), complemento(['BDNF', expression, in, 'post-mitotic', neurons, or, activated, 'MyoD', facilitating, reprogramming, of, fibroblasts, into, 'myoblasts,', respectively])].
[sujeto(['Targeted', de, novo, methylation, of, a, 'CTCF', loop, anchor, site, by, 'dCas9-Dnmt3a', blocked, 'CTCF']), verbo([binding]), complemento([and, interfered, with, 'DNA', 'looping,', causing, altered, gene, expression, in, the, neighboring, loop])].
[sujeto(['PAS', domain, containing, protein, kinase, '(', 'Pask)', is, an, evolutionarily]), verbo([conserved]), complemento([protein, kinase, implicated, in, energy, homeostasis, and, metabolic, regulation, across, eukaryotic, species])].
[sujeto(['We', now, describe, an, unexpected, role, of, 'Pask', in]), verbo([promoting]), complemento([the, differentiation, of, myogenic, progenitor, 'cells,', embryonic, stem, cells, and, adipogenic, progenitor, cells])].
[sujeto(['This', function, of, 'Pask', is, dependent, upon, its, ability, to]), verbo([phosphorylate]), complemento(['Wdr5,', a, member, of, several, protein, complexes, including, those, that, catalyze, histone, 'H3', 'Lysine', 4, trimethylation, '(', 'H3K4me3)', during, transcriptional, activation])].
[sujeto(['Our', findings]), verbo([suggest]), complemento(['that,', during, myoblast, 'differentiation,', 'Pask', stimulates, the, conversion, of, repressive, 'H3K4me1', to, activating, 'H3K4me3', marks, on, the, promoter, of, the, differentiation, gene, myogenin, '(', 'Myog)', via, 'Wdr5', phosphorylation])].
[sujeto(['This']), verbo([enhances]), complemento([accessibility, of, the, 'MyoD', transcription, factor, and, enables, transcriptional, activation, of, the, 'Myog', promoter, to, initiate, muscle, differentiation])].
[sujeto(['Thus,', as, an, upstream, kinase, of, 'Wdr5,', 'Pask', integrates, signaling, cues, with, the, transcriptional, network, to]), verbo([regulate]), complemento([the, differentiation, of, progenitor, cells])].
[sujeto(['A', subset, of, microRNAs, '(', 'miRNAs)']), verbo([have]), complemento([been, identified, as, critical, regulators, of, myogenesis])].
[sujeto(['Recently,', 'miR-378a', was]), verbo([found]), complemento([to, be, involved, in, 'myogenesis,', but, the, mechanism, of, how, 'miR-378a', regulates, the, proliferation, and, differentiation, of, myoblasts, has, not, been, determined])].
[sujeto(['We']), verbo([found]), complemento([that, 'miR-378a-3p', expression, in, muscle, was, significantly, higher, than, in, other, 'tissues,', suggesting, an, important, effect, on, muscle, development])].
[sujeto(['Overexpression', of, 'miR-378a-3p']), verbo([increased]), complemento([the, expression, of, 'MyoD', and, 'MHC', in, 'C2C12', myoblasts, both, at, the, level, of, mRNA, and, 'protein,', confirming, that, 'miR-378a-3p', promoted, muscle, cell, differentiation])].
[sujeto(['The', forced, expression, of, 'miR-378a-3p']), verbo([promoted]), complemento([apoptosis, of, 'C2C12', cells, as, evidenced, by, 'CCK-8', assay, and, 'Annexin', 'V-FITC/PI', staining, results])].
[sujeto(['Through', 'TargetScan,', histone, acetylation, enzyme, 4, '(', 'HDAC4)', was, identified, as, a, potential]), verbo([target]), complemento([of, 'miR-378a-3p'])].
[sujeto(['We', confirmed]), verbo([targeting]), complemento([of, 'HDAC4', by, 'miR-378a-3p', using, a, dual, luciferase, assay, and, western, blotting])].
[sujeto(['Our', 'RNAi', analysis, results, also, showed, that, 'HDAC4', significantly]), verbo([promoted]), complemento([differentiation, of, 'C2C12', cells, and, inhibited, cell, survival, through, 'Bcl-2'])].
[sujeto(['Therefore,', we, conclude, that, 'miR-378a-3p']), verbo([regulates]), complemento([skeletal, muscle, growth, and, promotes, the, differentiation, of, myoblasts, through, the, 'post-transcriptional', 'down-regulation', of, 'HDAC4'])].
[sujeto(['Cellular', models, of, muscle, disease, are, taking, on]), verbo([increasing]), complemento([importance, with, the, large, number, of, genes, and, mutations, implicated, in, causing, myopathies, and, the, concomitant, need, to, test, personalized, therapies])].
[sujeto(['Fibroblasts', are, a, human, cell, source, that, works, well, for, the, generation, of]), verbo([induced]), complemento([pluripotent, stem, 'cells,', which, can, then, be, differentiated, into, cardiomyocyte, 'lineages,', and, with, less, 'efficiency,', skeletal, 'muscle-like', lineages])].
[sujeto(['Alternatively,', direct, reprogramming, with, the, transcription, factor, 'MyoD']), verbo([has]), complemento([been, used, to, generate, myotubes, from, cultured, human, fibroblasts])].
[sujeto(['Although', 'useful,', fibroblasts]), verbo([require]), complemento([a, skin, biopsy, to, obtain, and, this, can, limit, their, 'access,', especially, from, pediatric, populations])].
[sujeto(['Recent', evidence]), verbo([suggests]), complemento([that, autophagy, and, bone, morphogenetic, protein, signaling, pathway, regulate, skeletal, muscle, growth, and, bone, formation, in, aged, rats])].
[sujeto(['Downhill', and, uphill, training]), verbo([increased]), complemento([the, 'autophagy-related', proteins, 5, '(', 'ATG5),', 'microtubule-associated', protein, light, chain, '(', 'LC3-Ⅱ),', 'Beclin-1,', and, p62, proteins, in, aged, rats])].
[sujeto(['Phosphorylation', of, mammalian]), verbo([target]), complemento([of, rapamycin, '(', 'p-mTOR)', and, myogenic, differentiation, '(', 'MyoD)', were, increased, significantly, in, 'LMD', and, 'LMU', groups])].
[sujeto(['Consequently', in, the, 'femur,', 'BMP-2,', -, 7, and, autophagy, molecules, were]), verbo([expressed]), complemento([highly, in, 'LMD', and, 'LMU', groups])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, both, of, the, downhill, and, uphill, training, appeared, to, positively, affect, autophagy, molecules, and, 'BMPs', 'expression,', respectively])].
[sujeto(['Particularly,', these, physiological, adaptations, from, gradual, downhill, training]), verbo([have]), complemento([an, effect, on, bone, morphological, changes, and, muscle, quality, similar, to, gradual, uphill, training, interventions, in, aging])].
[sujeto(['Biomedical', scaffolds, must, be, used, in, tissue, engineering, to]), verbo([provide]), complemento([physical, stability, and, 'topological/biochemical', properties, that, directly, affect, tissue, regeneration])].
[sujeto(['In', this, 'study,', a, new, 'cell-laden', scaffold, was, developed, that, supplies, 'micro/nano-topological', cues, and]), verbo([promotes]), complemento([efficient, release, of, cells])].
[sujeto(['Importantly,', the, printed, myoblasts, were, fully, safe, and, were, efficiently]), verbo([released]), complemento([from, the, 'cell-laden', struts, to, neighboring, nanofiber, networks])].
[sujeto(['Postnatal', skeletal, muscle, growth, results, from, the, activation, of, satellite, cells, 'and/or', an]), verbo([increase]), complemento([in, protein, synthesis])].
[sujeto(['The', 'Notch', signalling, pathway]), verbo([maintains]), complemento([satellite, cells, in, a, quiescent, 'state,', and, once, 'activated,', sustains, their, proliferation, and, commitment, towards, differentiation])].
[sujeto(['In', 'mammals,', 'POFUT1-mediated', 'O-fucosylation']), verbo([regulates]), complemento([the, interactions, between, 'NOTCH', receptors, and, ligands, of, the, 'DELTA/JAGGED', 'family,', thus, initiating, the, activation, of, canonical, 'Notch', signalling])].
[sujeto(['Pofut1(cax/cax)', mice, exhibited, muscle, 'hypertrophy,', no, hyperplasia, and, a]), verbo([decrease]), complemento([in, satellite, cell, numbers, compared, with, 'wild-type', 'C3H', mice])].
[sujeto(['In', agreement, with, these, 'observations,', 'Pofut1(cax/cax)', 'SCDMs', differentiated, earlier, concomitant, with, reduced, 'Pax7', expression, and]), verbo([decrease]), complemento([in, 'PAX7(+)/MYOD(-)', progenitor, cells])].
[sujeto(['In', vitro]), verbo([binding]), complemento([assays, showed, a, reduced, interaction, of, 'DELTA-LIKE', 1, ligand, '(', 'DLL1)', with, 'NOTCH', receptors, expressed, at, the, cell, surface, of, 'SCDMs,', leading, to, a, decreased, 'Notch', signalling, as, seen, by, the, quantification, of, cleaved, 'NICD', and, 'Notch', target, genes])].
[sujeto(['These', results, demonstrated, that, 'POFUT1-mediated', 'O-fucosylation', of, 'NOTCH', receptors]), verbo([regulates]), complemento([myogenic, cell, differentiation, and, affects, postnatal, muscle, growth, in, mice])].
[sujeto(['Cdkn1c', protein, levels, are, carefully]), verbo([regulated]), complemento([via, imprinting, and, other, epigenetic, mechanisms, affecting, both, the, promoter, and, distant, regulatory, 'elements,', which, restrict, its, expression, to, particular, developmental, phases, or, specific, cell, types])].
[sujeto(['Inappropriate', activation, of, these, regulatory, mechanisms]), verbo([leads]), complemento([to, 'Cdkn1c', 'silencing,', causing, growth, disorders, and, cancer])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, 'that,', in, skeletal, muscle, 'cells,', induction, of, 'Cdkn1c', expression, requires, the, binding, of, the, bHLH, myogenic, factor, 'MyoD', to, a, 'long-distance', regulatory, element, within, the, imprinting, control, region, 'KvDMR1'])].
[sujeto(['Interestingly,', 'MyoD']), verbo([binding]), complemento([to, 'KvDMR1', is, prevented, in, myogenic, cell, types, refractory, to, the, induction, of, 'Cdkn1c'])].
[sujeto(['We', show, that, treatment, with, the, 'DNA', demethylating, agent, 5, -, azacytidine, restores, the]), verbo([binding]), complemento([of, 'MyoD', to, 'KvDMR1', in, cells, refractory, to, 'Cdkn1c', induction])].
[sujeto(['This,', in, 'turn,']), verbo([promotes]), complemento([the, release, of, a, repressive, chromatin, loop, between, 'KvDMR1', and, 'Cdkn1c', promoter, 'and,', 'thus,', the, upregulation, of, the, gene])].
[sujeto(['Analysis', of, the, chromatin, status, of, 'Cdkn1c', promoter, and, 'KvDMR1', in, two, cell, types, showed, that, their, differential, responsiveness, to, the, 'MyoD-dependent', induction, of, the, gene, does, not]), verbo([involve]), complemento([just, their, methylation, status, 'but,', 'rather,', the, differential, 'H3', lysine, 9, dimethylation, at, 'KvDMR1'])].
[sujeto(['Finally,', we]), verbo([report]), complemento([that, the, same, histone, modification, also, marks, the, 'KvDMR1', region, of, human, cancer, cells, in, which, 'Cdkn1c', is, silenced])].
[sujeto(['On', the, basis, of, these, 'results,', we]), verbo([suggest]), complemento([that, the, epigenetic, status, of, 'KvDMR1', represents, a, critical, determinant, of, the, cell, 'type-restricted', expression, of, 'Cdkn1c', 'and,', 'possibly,', of, its, aberrant, silencing, in, some, pathological, conditions])].
[sujeto(['The', purpose, of, this, paper, was, to, study, the, effect, of, transforming, growth, factor, beta, '(', 'TGFβ)', signaling, pathway, on, 'reloading-mediated', restoration, of, disuse, muscle]), verbo([loss]), complemento([induced, by, hind, limb, suspension, in, rats])].
[sujeto(['Reloading']), verbo([increased]), complemento(['MyoD', mRNA, and, restored, the, decreased, gastrocnemius, 'weight/body', weight, 'ratio,', protein, concentration, of, 'gastrocnemius,', 'phospho-ERK2,', 'Pax7', and, the, increased, 'TGFβ1,', 'MSTN,', 'phospho-smad2/3,', 'phospho-p38,', 'phospho-JNK1/2,', and, p21, induced, by, hind, limb, suspension])].
[sujeto(['Disuse', muscle]), verbo([loss]), complemento([can, be, recovered, by, reloading, in, an, 'intensity-dependent', manner, through, canonical, and, noncanonical, 'TGFβ', signaling, pathways])].
[sujeto(['Pax7', and, 'MyoD', might, be, the, effectors, of, 'TGFβ', pathway, in]), verbo([mediating]), complemento([the, recovery, effect, of, reloading])].
[sujeto(['Transfection', with, 'in&nbsp;vitro']), verbo([transcribed]), complemento([mRNAs, is, a, safe, and, effective, tool, to, convert, somatic, cells, to, any, cell, type, of, interest])].
[sujeto(['One', caveat, of, mRNA, transfection, is, that, mRNAs, are]), verbo([recognized]), complemento([by, multiple, 'RNA-sensing', toll, like, receptors, '(', 'TLRs)'])].
[sujeto(['These', 'TLRs', can, both]), verbo([promote]), complemento([and, inhibit, cellular, reprogramming])].
[sujeto(['We', demonstrated, that, mRNA, transfection]), verbo([stimulated]), complemento(['TLR3', and, 'TLR7', and, induced, cytotoxicity, and, 'IFN-β', expression, in, human, and, mouse, fibroblasts])].
[sujeto(['Furthermore,', mRNA, transfection]), verbo([induced]), complemento([paracrine, inhibition, of, repeated, mRNA, transfection, through, type, 'I', 'IFNs'])].
[sujeto(['Repeated', liposomal, transfection, with, 'MyoD', mmRNAs, significantly]), verbo([enhanced]), complemento([myogenic, conversion, of, human, and, mouse, fibroblasts, compared, with, repeated, transfection, with, 'MyoD', mRNAs])].
[sujeto(['At', a, low, 'concentration,', 'TLR7/8', agonist, 'R848']), verbo([enhanced]), complemento(['MyoD', 'mmRNA-driven', conversion, of, human, fibroblasts, into, skeletal, muscle, 'cells,', whereas, high, concentrations, of, 'R848', inhibited, myogenic, conversion, of, fibroblasts])].
[sujeto(['Our', study]), verbo([suggests]), complemento([that, deliberate, control, of, 'TLR', signaling, is, a, key, factor, in, the, success, of, 'mRNA-driven', cellular, reprogramming])].
[sujeto(['Quercetin']), verbo([inhibited]), complemento([myeloperoxidase, '(', 'MPO)', and, 'N-acetyl-β-D-', glucosaminidase, '(', 'NAG)', 'activities,', cytokine, 'production,', oxidative, 'stress,', 'cyclooxygenase-2', '(', 'COX-2)', and, gp91phox, mRNA, expression, and, muscle, injury, '(', creatinine, kinase, '[', 'CK]', blood, levels, and, myoblast, determination, protein, '[', 'MyoD]', mRNA, 'expression)', as, well, as, inhibited, 'NFκB', activation, and, induced, 'Nrf2', and, 'HO-1', mRNA, expression, in, the, soleus, muscle])].
[sujeto(['Beyond']), verbo([inhibiting]), complemento([those, peripheral, 'effects,', quercetin, also, inhibited, spinal, cord, cytokine, 'production,', oxidative, stress, and, glial, cells, activation, '(', glial, fibrillary, acidic, protein, '[', 'GFAP]', and, ionized, 'calcium-binding', adapter, molecule, 1, '[', 'Iba-1]', mRNA, 'expression)'])].
[sujeto(['Muscle', regeneration, is, a, coordinated, process, that]), verbo([involves]), complemento([proliferation, and, differentiation, of, muscle, progenitor, cells])].
[sujeto(['Activation', of, 'MyoD', is, a, key, event, in, myogenic, 'differentiation,', which, is]), verbo([regulated]), complemento([by, 'p38&nbsp;mitogen&#8209;activated', protein, kinases, '(', 'MAPK)'])].
[sujeto(['Treatment', of, 'C2C12', myoblasts, with, 'DHC']), verbo([increased]), complemento([the, expression, levels, of, 'muscle&#8209;specific', 'proteins,', including, 'MyoD,', myogenin, and, myosin, heavy, chain])].
[sujeto(['In', 'addition,', 'C2C12', myoblasts, exhibited]), verbo([enhanced]), complemento([multinucleated, myotube, formation, without, any, cytotoxicity])].
[sujeto(['Furthermore,', defects, in, 'differentiation&#8209;induced', 'p38&nbsp;MAPK', activation, and, myoblast, differentiation]), verbo([induced]), complemento([by, depletion, of, the, promyogenic, receptor, protein, 'Cdo', in, 'C2C12', myoblasts, were, restored, by, 'DHC', treatment])].
[sujeto(['In', 'conclusion,', these, results, indicated, that, 'DHC']), verbo([stimulates]), complemento(['p38&nbsp;MAPK', 'activation,', which, can, enhance, heterodimerization, of, 'MyoD', and, 'E&nbsp;proteins,', thus, resulting, in, 'MyoD', activation, and, myoblast, differentiation])].
[sujeto(['These', findings]), verbo([suggested]), complemento([that, 'DHC', may, be, considered, a, potential, therapeutic, compound, for, the, improvement, of, muscle, stem, cell, regenerative, capacity, in, injured, muscle])].
[sujeto(['Skeletal', muscle, is, capable, of, robust, 'self-repair', following, mild, 'trauma,', yet, in, cases, of, traumatic, volumetric, muscle]), verbo([loss]), complemento(['(', 'VML),', where, more, than, 20, '%', of, a, 'muscle\'s', mass, is, 'lost,', this, capacity, is, overwhelmed])].
[sujeto(['Current', autogenic, whole, muscle, transfer, techniques, are, 'imperfect,', which]), verbo([has]), complemento([motivated, the, exploration, of, implantable, scaffolding, strategies])].
[sujeto(['We']), verbo([found]), complemento([that, the, repair, of, 'VML', injuries, using, 'DSM', +, 'MM', scaffolds, significantly, increased, recovery, of, peak, contractile, force, '(', 81, ±, 3, '%', of, normal, contralateral, 'muscle)', compared, to, unrepaired, 'VML', controls, '(', 62, ±, 4, '%', ')'])].
[sujeto(['Histological', findings, revealed, a, marked]), verbo([decrease]), complemento([in, collagen, dense, repair, tissue, formation, both, at, and, away, from, the, implant, site, for, 'DSM', +, 'MM', repaired, muscles])].
[sujeto(['The', addition, of, 'MM', to, 'DSM', significantly]), verbo([increased]), complemento(['MyoD', 'expression,', compared, to, isolated, 'DSM', treatment, '(', 21, -, fold, 'increase)', and, unrepaired, 'VML', '(', 37, -, 'fold)', controls])].
[sujeto(['Current', therapeutic, options, for, the, pediatric, cancer, rhabdomyosarcoma, '(', 'RMS)']), verbo([have]), complemento([not, improved, 'significantly,', especially, for, metastatic, 'RMS'])].
[sujeto(['The', signature, we, determined, could, discriminate, 'RMS', from, 'muscle,']), verbo([revealed]), complemento([a, subset, of, 'muscle-enriched', microRNA, '(', 'myomiR),', including, 'miR-22', which, was, strongly, underexpressed, in, tumors])].
[sujeto(['miR-22', was, physiologically]), verbo([induced]), complemento([during, normal, myogenic, differentiation, and, was, transcriptionally, regulated, by, 'MyoD,', confirming, its, identity, as, a, myomiR])].
[sujeto(['Once', introduced, into, 'RMS', 'cells,', 'miR-22']), verbo([decreased]), complemento([cell, 'proliferation,', 'anchorage-independent', 'growth,', invasiveness, and, promoted, apoptosis])].
[sujeto(['Moreover,', restoring, 'miR-22', expression, blocked, tumor, growth, and]), verbo([prevented]), complemento([tumor, dissemination, in, vivo])].
[sujeto(['Gene', expression, profiling, analysis, of, 'miR-22-expressing', cells]), verbo([suggested]), complemento(['TACC1', and, 'RAB5B', as, possible, direct, 'miR-22', targets])].
[sujeto(['Accordingly,']), verbo([loss]), complemento([and, gain, of, function, experiments, defined, the, biological, relevance, of, these, genes, in, 'RMS', pathogenesis])].
[sujeto(['In', previous, 'studies,', we]), verbo([have]), complemento([reported, that, phospholipase, 'C', '(', 'PLC)-β1', plays, a, crucial, role, in, myogenic, differentiation, and, we, determined, the, importance, of, its, catalytic, activity, for, the, initiation, of, this, process])].
[sujeto(['We', show, that, the, 'Inositol', 'Polyphosphate', 'Multikinase', '(', 'IPMK)', is, able, to]), verbo([promote]), complemento([myogenic, differentiation, since, its, overexpression, determines, the, 'up-regulation', of, several, myogenic, markers])].
[sujeto(['Moreover,', we, demonstrate, that, 'IPMK']), verbo([activates]), complemento([the, same, cyclin, 'D3', promoter, region, targeted, by, 'PLC-β1', and, that, 'IPMK-induced', promoter, activation, relies, upon, 'c-jun', binding, to, the, 'promoter,', as, we, have, shown, previously, for, 'PLC-β1'])].
[sujeto(['Furthermore,', our, data, shows, that, 'IPMK', overexpression]), verbo([causes]), complemento([an, increase, in, 'β-catenin', translocation, and, accumulation, to, the, nuclei, of, differentiating, myoblasts, resulting, in, higher, 'MyoD', activation])].
[sujeto(['Finally,', we, describe, that, 'PLC-β1', overexpression, determines, too, an]), verbo([increase]), complemento([in, 'β-catenin', translocation, and, that, 'PLC-β1,', 'IPMK', and, 'β-catenin', are, mediators, of, the, same, signaling, pathway, since, their, overexpression, results, in, cyclin, 'D3', and, myosin, heavy, chain, '(', 'MYH)', induction])].
[sujeto(['Pompe', disease, '(', 'PD)', is, a, lysosomal, disorder]), verbo([caused]), complemento([by, acid, 'α-glucosidase', '(', 'GAA)', deficiency])].
[sujeto(['We', previously, used, lentiviral, 'vector-mediated', 'GAA', gene, transfer, in, 'PD', 'patient-specific']), verbo([induced]), complemento([pluripotent, stem, cells])].
[sujeto(['Transcription', factor, 'EB', is, a, master, regulator, of, lysosomal, biogenesis, and, autophagy, that]), verbo([has]), complemento([recently, been, associated, with, muscular, 'pathology,', and, is, now, a, potential, therapeutic, target, in, 'PD', model, mice])].
[sujeto(['Here,', we, differentiated, skeletal, muscle, from, 'PD', 'patient-specific']), verbo([induced]), complemento([pluripotent, stem, cells, by, forced, 'MyoD', expression])].
[sujeto(['Thus,', our, findings, show, that, abnormal, lysosomal, biogenesis, is]), verbo([associated]), complemento([with, the, muscular, pathology, of, 'PD,', and, transcription, factor, 'EB', gene, transfer, is, effective, as, an, 'add-on', strategy, to, 'GAA', gene, transfer])].
[sujeto(['We', previously, demonstrated, that, histone, methyltransferase, 'KMT1A']), verbo([associates]), complemento([with, and, inhibits, 'MyoD', in, proliferating, 'myoblasts,', and, must, be, removed, to, allow, differentiation, to, proceed])].
[sujeto(['Conversely,', forced, activation, of, p38α, was, sufficient, to]), verbo([activate]), complemento(['MyoD', and, overcome, the, differentiation, blockade, in, 'KMT1A-overexpressing', 'C2C12', cells])].
[sujeto(['This', phosphorylation, was]), verbo([prevented]), complemento([by, the, inhibition, of, p38α])].
[sujeto(['A', ready, source, of, autologous, myogenic, cells, is, of, vital, importance, for, drug, screening, and, functional, genetic, studies, in, 'Duchenne', 'Muscular', 'Dystrophy', '(', 'DMD),', a, rare, disease]), verbo([caused]), complemento([by, a, variety, of, dystrophin, gene, mutations])].
[sujeto(['We', demonstrated, that, native, 'urine-derived', stem, cells]), verbo([express]), complemento([the, 'full-length', dystrophin, 'transcript,', and, that, the, dystrophin, mutation, was, retained, in, 'DMD', patient, 'cells,', although, the, dystrophin, protein, was, detected, solely, in, control, cells, following, myogenic, transformation, according, to, the, phenotype])].
[sujeto(['Notably,', we, also, showed, that, treatment, with, antisense, oligoribonucleotide, against, dystrophin, exon, 44]), verbo([induced]), complemento([skipping, in, both, native, and, 'MyoD-transformed', 'urine-derived', stem, cells, in, 'DMD,', with, a, therapeutic, 'transcript-reframing', 'effect,', as, well, as, visible, protein, restoration, in, the, latter])].
[sujeto([2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin;', 'TCDD)']), verbo([cause]), complemento([cleft, palate, at, a, high, rate])].
[sujeto(['Runx2', and, osteopontin, immunoreactivity]), verbo([decreased]), complemento([in, the, 'TCDD-treated', palatal, 'bone,', and, 'MyoD', and, desmin, decreased, in, the, 'TCDD-treated', palatal, muscle])].
[sujeto(['TCDD', may]), verbo([suppress]), complemento([palatal, osteogenesis, and, myogenesis, via, 'AhR,', and, cause, cleft, palates, via, a, 'post-fusional', split, 'mechanism,', in, addition, to, a, failure, of, palatal, fusion])].
[sujeto(['Aryl', hydrocarbon, receptor, '(', 'AhR)']), verbo([nuclear]), complemento([translocator, '(', 'Arnt)', gene, has, been, isolated, and, characterized, from, a, mouse, genomic, 'DNA', library])].
[sujeto(['An', unusual, 'exon/intron', junctional, sequence, was]), verbo([found]), complemento([in, the, 11, th, intron, of, the, gene, that, begins, with, 'GC', at, its, 5, '\'', -, end])].
[sujeto(['The', gene, is, 'TATA-less', and]), verbo([has]), complemento([several, transcription, start, sites])].
[sujeto(['Of', 'all,', two, 'GC-boxes', displayed, the, most, dominant]), verbo([enhancing]), complemento([effects])].
[sujeto(['It', was, demonstrated, that, there, exist, specific, factors]), verbo([binding]), complemento([to, these, 'DNA', elements, in, the, nuclear, extracts, of, 'HeLa', cells])].
[sujeto(['Among', 'them,', 'Sp1', and, 'Sp3,', and, 'CAAT-box']), verbo([binding]), complemento(['factor-A', were, identified, to, bind, the, 'GC-boxes', and, 'CAAT-box,', respectively])].
[sujeto(['Expression', of, 'MyoD', in, 'HeLa', cells]), verbo([stimulated]), complemento([the, 'Arnt', promoter, activity, by, binding, to, the, 'E-box'])].
[sujeto(['The', 'AH-receptor', is, a, 'ligand-activated', transcription, factor, that]), verbo([regulates]), complemento([a, number, of, biological, responses, to, planar, aromatic, hydrocarbons])].
[sujeto(['Interest', in, this, receptor, is, related, to, its, role, in, the, toxic, action, of, a, variety, of, environmental, 'chemicals,', the, simplicity, and, elegance, of, the, murine, genetics, that]), verbo([led]), complemento([to, its, characterization, and, the, distinctive, mechanism, by, which, this, receptor, activates, gene, expression])].
[sujeto(['Recent', cloning, experiments]), verbo([have]), complemento([demonstrated, that, the, 'AH-receptor', is, structurally, related, to, the, 'Per,', 'ARNT', and, 'Sim', proteins])].
[sujeto(['In', the, 'AH-receptor,', this, domain, harbours, sequences]), verbo([involved]), complemento([in, the, formation, of, a, hydrophobic, pocket, that, bind, receptor, agonists])].
[sujeto(['Adjacent', to, the, 'PAS', domain, in, the, 'AH-receptor,', 'ARNT', and, 'Sim', proteins, is, a, 'basic/helix-loop-helix', '(', 'bHLH)', domain, that, appears, to]), verbo([mediate]), complemento([heterodimerization, and, sequence, specific, 'DNA', binding, properties])].
[sujeto(['The', observation, that, the, bHLH, domain, is, present, in, the, 'AH-receptor', and, the, 'ARNT', 'protein,', a, factor]), verbo([required]), complemento([for, proper, 'AH-receptor', 'function,', suggests, that, these, proteins, are, heterodimeric, partners, that, activate, gene, expression, in, a, manner, similar, to, 'Myc/Max', and, 'MyoD/E2A'])].
[sujeto(['The', objectives, of, this, review, are, to, describe, recent, experimental, results, in, this, field, and, to, use, this, information, to, develop, a, molecular, model, of, 'AH-receptor']), verbo([mediated]), complemento([signal, transduction])].
[sujeto(['A', cDNA, encoding, the, murine, 'Ah', receptor, '(', 'Ahb-1', allele, for, aromatic, hydrocarbon, 'responsiveness)']), verbo([has]), complemento([been, isolated, and, characterized])].
[sujeto(['Analysis', of, the, deduced, protein, sequence, revealed, a, region, with, similarity, to, the, basic, 'region/helix-loop-helix', '(', 'BR/HLH)', motif]), verbo([found]), complemento([in, many, transcription, factors, that, undergo, dimerization, for, function])].
[sujeto(['In', addition, to, the, 'BR/HLH', 'domain,', the, 'N-terminal', domain, of, the, 'Ah', receptor]), verbo([has]), complemento([extensive, sequence, similarity, to, the, human, 'ARNT', '(', aryl, hydrocarbon, receptor, nuclear, 'translocator)', protein, and, two, regulatory, proteins, of, 'Drosophila,', 'Sim', and, 'Per'])].
[sujeto(['Photoaffinity', labeling, and, peptide, mapping, studies, indicate, that, the, 'Ah', receptor]), verbo([binds]), complemento([agonist, at, a, domain, that, lies, within, this, conserved, 'N-terminal', domain])].
[sujeto(['The', 'Ah', receptor, appears, to, be, a, 'ligand-activated', transcription, factor, with, a, 'helix-loop-helix', motif, similar, to, those]), verbo([found]), complemento([in, a, variety, of, 'DNA-binding', 'proteins,', including, 'Myc', and, 'MyoD'])].
[sujeto(['The', protein, chaperone, heat, shock, protein, 90, '(', 'Hsp90)', is, a, major, regulator, of, different, transcription, factors, such, as, 'MyoD,', a, basic, helix, loop, helix, '(', 'bHLH)', 'protein,', and, the, 'bHLH-Per-aryl', hydrocarbon]), verbo([nuclear]), complemento([translocator, '(', 'ARNT)-Sim', '(', 'PAS)', factors, 'Sim', and, aryl, hydrocarbon, receptor, '(', 'Ahr)'])].
[sujeto(['The', transcription, factor, 'hypoxia-inducible', 'factor-1alpha', '(', 'HIF-1alpha),']), verbo([involved]), complemento([in, the, response, to, 'hypoxia,', also, belongs, to, the, 'bHLH-PAS', family])].
[sujeto(['Using', a, 'EGFP-HIF-1alpha', fusion, 'protein,', 'co-immunoprecipitation', experiments, evidenced, that, the, chimeric, protein]), verbo([expressed]), complemento([in, 'COS-7', cells, interacts, with, 'Hsp90', in, normoxia, but, not, in, hypoxia])].
[sujeto(['We', also, demonstrated, that, 'Hsp90']), verbo([interacts]), complemento([with, the, 'bHLH-PAS', domain, of, 'HIF-1alpha'])].
[sujeto(['At', 'last,', we, showed, that, 'Hsp90', activity, is, essential, for, 'HIF-1', activation, in, hypoxia, since, it, is]), verbo([inhibited]), complemento([in, the, presence, of, geldanamycin])].
[sujeto([1384, 'G&gt;A', 'SNP', was]), verbo([associated]), complemento([with, litter, size, in, the, 'GZ', goats, '(', 'P&lt;0'])].
[sujeto(['Luciferase', assay, analysis]), verbo([suggested]), complemento([that, the, 1384, 'A', allele, increased, luciferase, activity, when, compared, to, the, 1384, 'G', allele])].
[sujeto(['Functional', analysis]), verbo([suggested]), complemento([that, this, g])].
[sujeto([1384, 'G&gt;A', 'SNP', may, be, an, important, genetic, regulator, of, 'KISS1', gene, expression, with, effects, on, downstream, processes, that, are]), verbo([modulated]), complemento([by, 'KISS1', gene, because, of, the, changes, of, methylation, and, transcription, 'factor-binding', sites])].
[sujeto(['Therefore,', the, current, study]), verbo([provides]), complemento([evidence, in, goats, for, genetic, markers, that, might, be, used, in, breeding, programs])].
[sujeto(['Doxorubicin', '(', 'Dox,', 'Adriamicin),', a, potent, broad, spectrum, anthracycline, anticancer, 'drug,', selectively]), verbo([inhibits]), complemento([muscle, specific, gene, expression, in, cardiac, cells, in, vivo, and, prevents, terminal, differentiation, of, skeletal, muscle, cells, in, vitro])].
[sujeto(['By']), verbo([inducing]), complemento([the, expression, of, the, 'helix-loop-helix', '(', 'HLH)', transcriptional, inhibitor, 'ld2,', 'Dox', represses, the, myogenic, function, of, the, 'MyoD', family, of, muscle, regulatory, factors, '(', 'MRFs)'])].
[sujeto(['In', many, cell, 'types,', terminal, differentiation, is, coupled, to, an, irreversible, exit, from, the, cell, cycle, and, 'MyoD', plays, a, critical, role, in, the, permanent, cell, cycle]), verbo([arrest]), complemento([of, differentiating, myocytes, by, upregulating, the, cyclin, dependent, kinase, inhibitor, '(', 'cdki)', p21])].
[sujeto(['In', 'Dox-treated', quiescent, 'myoblasts,', which, fail, to, differentiate, into, myotubes, under, permissive, culture, 'conditions,', serum, 're-stimulation']), verbo([induces]), complemento(['cyclin/cdk', 're-association', on, the, 'E2F/DP', complexes, and, this, correlates, with, an, evident, increase, in, 'E2F/DP', driven, transcription, and, 're-entry', of, myoblasts, into, the, cell, cycle])].
[sujeto(['Despite', 'Dox', ability, to]), verbo([activate]), complemento([the, 'DNA-damage', dependent, 'p53/p21', 'pathway,', when, induced, in, the, absence, of, 'MyoD', or, other, 'MRFs,', p21, fails, to, maintain, the, postmitotic, state, in, 'Dox-treated', myocytes, induced, to, differentiate])].
[sujeto(['Thus,', uncoupling, p21, induction, and, 'MyoD', activity, results, in, a, 'serum-reversible', cell, cycle, 'arrest,', indicating, that, 'MRF', specific, activation, of, 'cdki(s)', is]), verbo([required]), complemento([for, permanent, cell, cycle, arrest, in, differentiating, muscle, cells])].
[sujeto(['Duchenne', muscular, dystrophy, '(', 'DMD)', is, a, progressive, and, fatal, muscle, degenerating, disease]), verbo([caused]), complemento([by, a, dystrophin, deficiency])].
[sujeto(['Patient-derived', human]), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'hiPSCs)', are, a, promising, tool, for, drug, discovery])].
[sujeto(['Here,', we]), verbo([report]), complemento([an, in, vitro, evaluation, system, for, a, 'DMD', therapy, using, hiPSCs, that, recapitulate, the, primary, pathology, and, can, be, used, for, 'DMD', drug, screening])].
[sujeto(['However,', electric, stimulation, of, these, myotubes, for, in, vitro, contraction]), verbo([caused]), complemento([pronounced, calcium, ion, '(', 'Ca(2+))', influx, only, in, 'DMD', myocytes])].
[sujeto(['Restoration', of, dystrophin, by, the, 'exon-skipping', technique]), verbo([suppressed]), complemento([this, 'Ca(2+)', overflow, and, reduced, the, secretion, of, creatine, kinase, '(', 'CK)', in, 'DMD', myotubes])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, early, pathogenesis, of, 'DMD', can, be, effectively, modelled, in, skeletal, myotubes, induced, from, 'patient-derived', 'iPSCs,', thereby, enabling, the, development, and, evaluation, of, novel, drugs])].
[sujeto(['Patient-derived']), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'iPSCs)', have, opened, the, door, to, recreating, pathological, conditions, in, vitro, using, differentiation, into, diseased, cells, corresponding, to, each, target, tissue])].
[sujeto(['Yet', for, muscular, 'diseases,', a, method, for, reproducible, and, efficient, myogenic, differentiation, from, human, iPSCs, is]), verbo([required]), complemento([for, in, vitro, modeling])].
[sujeto(['Here,', we, introduce, a, myogenic, differentiation, protocol]), verbo([mediated]), complemento([by, inducible, transcription, factor, expression, that, reproducibly, and, efficiently, drives, human, iPSCs, into, myocytes])].
[sujeto(['This', differentiation, protocol, can, be, applied, widely, in, various, types, of, 'patient-derived', human, iPSCs, and]), verbo([has]), complemento([great, prospects, in, disease, modeling, particularly, with, inherited, diseases, that, require, studies, of, early, pathogenesis, and, drug, screening])].
[sujeto(['Overexpression', of, 'SIRT1', is, frequently, observed, in, various, types, of, 'cancers,']), verbo([suggesting]), complemento([its, potential, role, in, malignancies])].
[sujeto(['This']), verbo([suggests]), complemento([aberrant, 'CpG', 'DNA', methylation, as, the, mechanistic, background, for, malignant, 'SIRT1', elevation])].
[sujeto(['Our', work, also]), verbo([provides]), complemento([an, example, where, epigenetic, mechanisms, cause, the, 'group-wide', regulation, of, miRNAs, sharing, a, common, key, target])].
[sujeto(['The', 'ZHTc6-MyoD', embryonic, stem, cell, line]), verbo([expresses]), complemento([the, myogenic, transcriptional, factor, 'MyoD', under, the, control, of, a, 'tetracycline-inducible', promoter])].
[sujeto(['However,', a, small, fraction, does, not, 'differentiate,', instead, forming, colonies, that]), verbo([retain]), complemento([the, potential, for, myocyte, differentiation])].
[sujeto(['In', our, current, 'study,', we]), verbo([found]), complemento([that, parathyroid, hormone, type, 1, receptor, '(', 'PTH1R)', expression, in, 'colony-forming', cells, at, 13, days, after, differentiation, was, higher, than, that, in, the, undifferentiated, 'ZHTc6-MyoD', cells])].
[sujeto(['We', also]), verbo([found]), complemento([that, 'PTH1R', expression, was, required, for, myocyte, 'differentiation,', and, that, parathyroid, hormone, accelerated, the, differentiation])].
[sujeto(['Our', analysis, of, human, and, mouse, skeletal, muscle, tissues, showed, that, most, cells]), verbo([expressing]), complemento(['PTH1R', also, expressed, 'Pax7', and, 'CD34,', which, are, biomarkers, of, satellite, cells])].
[sujeto(['Furthermore,', we]), verbo([found]), complemento([that, parathyroid, hormone, treatment, significantly, improved, muscle, weakness, in, 'dystrophin-deficient', mdx, mice])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([indicating, that, 'PTH1R', and, 'PTH', accelerate, myocyte, differentiation])].
[sujeto([3, -, 'Methylcholanthrene', '(', 3, 'MC)']), verbo([induces]), complemento([tumor, formation, at, the, site, of, injection, in, the, hind, leg, of, mice, within, 110, days])].
[sujeto(['Recent']), verbo([reports]), complemento([reveal, that, the, transformation, of, normal, muscle, cells, to, atypical, cells, is, one, of, the, causes, for, tumor, 'formation,', however, the, molecular, mechanism, behind, this, process, is, not, well, understood])].
[sujeto(['Here,', we, show, in, an, in, vitro, study, that, 3, 'MC']), verbo([induces]), complemento([fragmentation, of, multinucleate, myotubes, into, viable, mononucleates])].
[sujeto(['Immunoblot', analysis]), verbo([reveals]), complemento([that, phosphorylation, of, myosin, regulatory, light, chain, '(', 'RLC20)', is, 5.6, '±0'])].
[sujeto(['Interestingly,', addition, of, the, myosin, light, chain, kinase, 'inhibitor,', 'ML-7,']), verbo([enhances]), complemento([the, 'fragmentation,', whereas, phosphatase, inhibitor, perturbs, the, 3, 'MC', induced, fragmentation, of, myotubes])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, decrease, in, 'RLC20', phosphorylation, may, be, associated, with, the, fragmentation, step, of, dedifferentiation])].
[sujeto(['The', establishment, of, human]), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'hiPSCs)', has, enabled, the, production, of, in, 'vitro,', 'patient-specific', cell, models, of, human, disease])].
[sujeto(['However,', myogenic, differentiation, of, hiPSCs]), verbo([has]), complemento([faced, 'obstacles,', 'namely,', low, efficiency, 'and/or', poor, reproducibility])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, 'rapid,', 'efficient,', and, reproducible, differentiation, of, hiPSCs, into, mature, myocytes])].
[sujeto(['Myocytes']), verbo([induced]), complemento([in, this, manner, reach, maturity, within, 2, weeks, of, differentiation, as, assessed, by, marker, gene, expression, and, functional, 'properties,', including, in, vitro, and, in, vivo, cell, fusion, and, twitching, in, response, to, electrical, stimulation])].
[sujeto(['Miyoshi', 'Myopathy', '(', 'MM)', is, a, congenital, distal, myopathy]), verbo([caused]), complemento([by, defective, muscle, membrane, repair, due, to, mutations, in, 'DYSFERLIN'])].
[sujeto(['Using', our]), verbo([induced]), complemento([differentiation, 'technique,', we, successfully, recreated, the, pathological, condition, of, 'MM', in, 'vitro,', demonstrating, defective, membrane, repair, in, 'hiPSC-derived', myotubes, from, an, 'MM', patient, and, phenotypic, rescue, by, expression, of, 'full-length', 'DYSFERLIN', '(', 'DYSF)'])].
[sujeto(['We']), verbo([target]), complemento([this, inducible, cassette, exchange, '(', 'ICE)', allele, to, the, '(', 'HPRT)', locus, and, demonstrate, recombination, in, murine, embryonic, stem, cells, '(', 'ESCs)', and, primary, cells, from, derivative, 'ICE', mice])].
[sujeto(['In', the, present, 'study,', methods, were, developed, to, expand, cultures, of, 'MSCs', and, to]), verbo([promote]), complemento([the, myogenic, differentiation, of, these, 'cells,', which, were, then, used, in, a, new, approach, for, the, treatment, of, 'DMD'])].
[sujeto(['The', transduction, of, 'CD271(+)', 'MSCs', with, 'MyoD']), verbo([caused]), complemento([myogenic, differentiation, in, vitro, and, the, formation, of, myotubes, expressing, late, myogenic, markers])].
[sujeto(['Despite', having, distinct, expression, patterns, and, phenotypes, in, mutant, 'mice,', the, myogenic, regulatory, factors, 'Myf5', and, 'MyoD']), verbo([have]), complemento([been, considered, to, be, functionally, equivalent])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, these, factors, have, a, different, response, to, 'DNA', 'damage,', due, to, the, presence, in, 'MyoD', and, absence, in, 'Myf5', of, a, consensus, site, for, 'Abl-mediated', tyrosine, phosphorylation, that, inhibits, 'MyoD', activity, in, response, to, 'DNA', damage])].
[sujeto(['Genotoxins', failed, to]), verbo([repress]), complemento([skeletal, myogenesis, in, 'MyoD-null', 'embryos;', reintroduction, of, 'wild-type', 'MyoD,', but, not, mutant, 'Abl', 'phosphorylation-resistant', 'MyoD,', restored, the, 'DNA-damage-dependent', inhibition, of, muscle, differentiation])].
[sujeto(['The', presence, of, a, 'DNA-damage-responsive', phosphorylation, motif, in, 'vertebrate,', but, not, in, invertebrate, 'MyoD']), verbo([suggests]), complemento([an, evolved, response, to, environmental, 'stress,', originated, from, basic, 'helix-loop-helix', gene, duplication, in, vertebrate, myogenesis])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, that, the, level, of, 'MyoD', expression, correlates, with, the, level, of, apoptosis, that, occurs, in, a, subpopulation, of, skeletal, myoblasts, induced, to, differentiate, by, serum, withdrawal])].
[sujeto(['Further,', using, a, fibroblast, cell, line]), verbo([expressing]), complemento([an, estrogen, 'receptor:MyoD', fusion, 'protein,', we, have, determined, that, addition, of, estrogen, sensitizes, these, fibroblasts, to, apoptosis, induced, by, serum, 'withdrawal,', or, by, treatment, with, etoposide, or, thapsigargin])].
[sujeto(['RNAi']), verbo([mediated]), complemento([silencing, of, 'MyoD', in, either, 23, 'A2', or, 'C2C12', myoblasts, renders, these, cells, resistant, to, apoptosis, induced, by, serum, 'withdrawal,', or, by, treatment, with, etoposide, or, thapsigargin])].
[sujeto(['Finally,', 'MyoD']), verbo([mediated]), complemento([regulation, of, the, apoptotic, response, to, these, various, 'stimuli,', in, both, myoblasts, and, 'fibroblasts,', correlates, with, the, level, of, induction, of, the, 'pro-apoptotic', 'Bcl2', family, member, 'PUMA'])].
[sujeto(['We', used, external, fixation, '(', 'EF),', as, a, clinically, relevant, 'model,', to]), verbo([gain]), complemento([insights, into, the, relationships, between, muscle, degenerative, and, regenerative, conditions, to, the, myogenic, properties, and, abundance, of, bona, fide, satellite, cells])].
[sujeto(['EF']), verbo([induced]), complemento([muscle, mass, 'loss;', declined, expression, of, the, muscle, specific, regulatory, factors, '(', 'MRFs)', 'Myf5,', 'MyoD,', 'myogenin,', and, also, of, satellite, cell, numbers, and, myogenic, differentiation, aptitude])].
[sujeto(['Tet']), verbo([enhanced]), complemento([the, expression, of, 'MRFs,', but, did, not, prevent, the, decline, of, the, satellite, cell, pool])].
[sujeto(['Together,', our, results, point, to, 'Tet', and, exercise, running, as, promising, and, relevant, approaches, for]), verbo([enhancing]), complemento([muscle, recovery, after, atrophy])].
[sujeto(['In', our, present, proof, of, principle, 'studies,', we]), verbo([have]), complemento([successfully, constructed, a, multilayered, culture, of, skeletal, muscle, 'cells,', derived, from, neonatal, satellite, 'cells,', that, are, distributed, in, a, 3, 'D', pattern, of, organization, that, mimics, many, of, the, features, of, intact, tissue])].
[sujeto(['In', myogenic, 'C(2)C(12)', 'cells,', 5, mM, creatine]), verbo([increased]), complemento([the, incorporation, of, labeled, '[', '(', 35, ')', 'S]methionine', into, sarcoplasmic, '(', +, 20, '%', ',', 'P', &, 'lt;', 0.05, ')', and, myofibrillar, proteins, '(', +, 50, '%', ',', 'P', &, 'lt;', 0.01, ')'])].
[sujeto(['Creatine', also]), verbo([promoted]), complemento([the, fusion, of, myoblasts, assessed, by, an, increased, number, of, nuclei, incorporated, within, myotubes, '(', +, 40, '%', ',', 'P', &, 'lt;', 0.001, ')'])].
[sujeto(['Expression', of, myosin, heavy, chain, type, 'II', '(', +, 1, ',', 300, '%', ',', 'P', &, 'lt;', 0.001, ')', ',', troponin, 'T', '(', +, 65, '%', ',', 'P', &, 'lt;', 0.01, ')', ',', and, titin, '(', +, 40, '%', ',', 'P', &, 'lt;', 0.05, ')', was]), verbo([enhanced]), complemento([by, creatine])].
[sujeto(['The', addition, of, 'rapamycin,', the, inhibitor, of, mammalian]), verbo([target]), complemento([of, 'rapamycin/70-kDa', ribosomal, 'S6', protein, kinase, '(', 'mTOR/p70(s6k))', 'pathway,', and, 'SB', 202190, ',', the, inhibitor, of, 'p38,', completely, blocked, differentiation, in, control, 'cells,', and, creatine, did, not, reverse, this, 'inhibition,', suggesting, that, the, 'mTOR/p70(s6k)', and, p38, pathways, could, be, potentially, involved, in, the, effect, induced, by, creatine, on, differentiation])].
[sujeto(['Creatine', also, affected, the, phosphorylation, state, of, p38, '(', -, 50, '%', at, 24, h, and, +, 70, '%', at, 96, 'h,', 'P', &, 'lt;', 0.05, ')', as, well, as, the]), verbo([nuclear]), complemento([content, of, its, downstream, targets, myocyte, enhancer, 'factor-2', '(', -, 55, '%', at, 48, h, and, +, 170, '%', at, 96, 'h,', 'P', &, 'lt;', 0.05, ')', and, 'MyoD', '(', +, 60, '%', ',', 'P', &, 'lt;', 0.01, ')'])].
[sujeto(['In', 'conclusion,', this, study, points, out, the, involvement, of, the, p38, and, the, 'Akt/PKB-p70(s6k)', pathways, in, the]), verbo([enhanced]), complemento([differentiation, induced, by, creatine, in, 'C(2)C(12)', cells])].
[sujeto(['The', hindlimbs, of, some, animals, in, each, group, were, irradiated, before, injury, to]), verbo([prevent]), complemento([proliferation, of, myogenic, cells, during, recovery])].
[sujeto(['Inhibiting', myogenesis]), verbo([prevented]), complemento([the, recovery, of, contractile, function, after, 'MR,', but, not, after, 1, 'R'])].
[sujeto(['Both', protocols]), verbo([caused]), complemento(['Evans', blue, dye, uptake, immediately, after, 'injury,', but, 'Evans', blue, dye, was, only, retained, in, fibers, for, several, days, after, 1, 'R'])].
[sujeto(['This']), verbo([suggests]), complemento([that, membranes, reseal, after, 1, 'R,', but, not, after, 'MR'])].
[sujeto(['The', mechanisms, that, underlie, recovery, after, injuries]), verbo([caused]), complemento([by, repeated, lengthening, contractions, and, injuries, caused, by, a, single, lengthening, contraction, are, different])].
[sujeto(['The', differences, may, be, important, when, planning]), verbo([targeted]), complemento([rehabilitation, strategies, for, each, type, of, injury])].
[sujeto(['Advanced', gene, 'therapy,', tissue, engineering, and, biopharmaceutical, manufacturing]), verbo([require]), complemento([sophisticated, and, 'well-balanced', multiregulated, multigene, interventions, to, reprogram, desired, mammalian, cell, phenotypes])].
[sujeto(['We']), verbo([have]), complemento([combined, the, streptogramin, '(', 'PIP)-', and, tetracycline, '(', 'TET)-responsive', gene, regulation, systems, for, independent, expression, control, of, the, differentiation, determinants, myoD, and, msx1, in, 'C2C12-derived', cells])].
[sujeto(['Different', 'dual-regulated', expression, scenarios, which]), verbo([induce]), complemento([either, 'both,', only, one, or, none, of, the, lineage, control, genes, triggered, differential, differentiation, and, precise, control, of, 'myogenic,', osteogenic, or, adipogenic, cell, phenotypes])].
[sujeto(['We']), verbo([reported]), complemento([previously, that, transcription, factor, nuclear, factor, '(', 'NF)-kappaB', is, constitutively, activated, in, human, and, murine, squamous, cell, carcinomas, '(', 'SCCs)'])].
[sujeto(['Remarkably,', 'NF-kappaB']), verbo([modulated]), complemento([the, expression, of, &, 'gt;60%', of, the, 308, genes, differentially, expressed, between, normal, keratinocytes, and, metastatic, 'SCCs'])].
[sujeto(['NF-kappaB', directly, or, indirectly]), verbo([modulated]), complemento([expression, of, programs, of, genes, functionally, linked, to, 'proliferation,', 'apoptosis,', 'adhesion,', and, angiogenesis])].
[sujeto(['NF-kappaB', 'DNA']), verbo([binding]), complemento([motifs, were, detected, in, the, promoter, of, approximately, 63, '%', of, genes, showing, increased, expression, and, 33, '%', of, the, genes, showing, decreased, expression])].
[sujeto(['The', 'ACTACAG', motif, implicated, in, the, 'NF-kappaB-dependent', 'down-regulation', of, mRNA, expression, of, 'MyoD', and, 'Sox9', was, detected, in, the, coding, portion, of, about, 15, '%', of, genes, showing]), verbo([increased]), complemento([or, decreased, expression])].
[sujeto(['Inactivation', of, 'NF-kappaB']), verbo([inhibited]), complemento([malignant, phenotypic, features, including, 'proliferation,', cell, 'survival,', 'migration,', 'angiogenesis,', and, tumorigenesis])].
[sujeto(['These', results]), verbo([provide]), complemento([evidence, that, 'NF-kappaB', is, an, important, modulator, of, gene, expression, programs, that, contribute, to, the, malignant, phenotype, of, 'SCC'])].
[sujeto(['In', the, present, study, optimized, 'HIV-1-based', vector, systems, that, display, efficient, doxycycline, '(', 'Dox)-dependent', transgene, expression, in, vitro, and, in, vivo]), verbo([have]), complemento([been, developed, through, the, modification, of, factors, that, contribute, to, basal, activity, levels])].
[sujeto(['Dissection', of, 'HIV-1', vectors, harboring, a, 'tTA-dependent', transgene, expression, cassette, revealed, several, mechanisms, that, account, for, 'Dox-independent', transgene, 'expression,', including, those]), verbo([mediated]), complemento([by, an, internal, 'CMV', 'promoter,', as, well, as, a, potential, contribution, from, fusion, proteins, generated, by, translational, readthrough])].
[sujeto(['Cell-substratum', interactions]), verbo([trigger]), complemento([key, signaling, pathways, that, modulate, growth, control, and, 'tissue-specific', gene, expression])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, abolishing, adhesive, interactions, by, suspension, culture, results, in, 'G(0)', arrest, of, myoblasts])].
[sujeto(['We']), verbo([report]), complemento([that, blocking, intracellular, transmission, of, 'adhesion-dependent', signals, in, adherent, cells, mimics, the, absence, of, adhesive, contacts])].
[sujeto(['Furthermore,', both, 'ML7', and, 'BDM']), verbo([suppressed]), complemento([expression, of, 'MyoD', and, 'myogenin,', induced, 'p27(kip1)', but, not, 'p21(cip1),', and, inhibited, differentiation])].
[sujeto(['Thus,', as, with, 'suspension-arrest,', inhibition, of, 'acto-myosin', contractility, in, adherent, cells]), verbo([led]), complemento([to, arrest, uncoupled, from, differentiation])].
[sujeto(['By', 'contrast,', 'wild-type', 'RhoA']), verbo([induced]), complemento(['arrest,', maintained, 'MyoD', and, activated, myogenin, and, p21, expression])].
[sujeto(['The', 'Rho', effector, kinase, 'ROCK', did, not, appear, to]), verbo([mediate]), complemento(['Rho\'s', effects, on, 'MyoD'])].
[sujeto(['Signals']), verbo([regulated]), complemento([by, 'MLCK', are, 'critical,', since, inhibition, of, 'MLCK', suppressed, 'MyoD', expression, but, inhibition, of, 'ROCK', did, not])].
[sujeto(['Inhibition', of, contractility]), verbo([suppressed]), complemento(['MyoD', but, did, not, reduce, actin, polymer, levels])].
[sujeto(['However,', actin, depolymerization, with, latrunculin, 'B']), verbo([inhibited]), complemento(['MyoD', expression])].
[sujeto(['Taken', 'together,', our, observations, indicate, that, actin, polymer, status, and, contractility]), verbo([regulate]), complemento(['MyoD', expression])].
[sujeto(['We']), verbo([suggest]), complemento([that, in, 'myoblasts,', the, 'Rho', pathway, and, regulation, of, 'acto-myosin', contractility, may, define, a, control, point, for, conditional, uncoupling, of, differentiation, and, the, cell, cycle])].
[sujeto(['Several', studies]), verbo([have]), complemento([already, demonstrated, that, 'micro-', and, 'milli-calpains', '(', 'CAPN', 1, -, 'CAPN', 2, ')', ',', 'calcium-dependent', intracellular, 'cysteine-proteases', are, involved, in, many, biological, phenomenon, including, muscle, growth, and, development])].
[sujeto(['More', 'particularly,', recent, studies]), verbo([have]), complemento([demonstrated, that, 'milli-calpain', is, implicated, in, myoblast, fusion])].
[sujeto(['Because', 'micro-', and, 'milli-calpains', do, not]), verbo([have]), complemento([the, same, intracellular, 'localization,', it, appears, likely, that, these, two, 'calcium-dependent', proteases, have, different, biological, roles, during, muscle, cell, differentiation])].
[sujeto(['We', 'therefore,']), verbo([have]), complemento([developed, a, muscle, cell, line, in, which, 'micro-calpain', is, 'over-expressed,', using, the, inducible, 'Tet', 'Regulated', 'Expression', 'System'])].
[sujeto(['The', present, study, shows, important]), verbo([decreases]), complemento([in, the, expression, level, of, ezrin, '(', 68, '%', ')', ',', vimentin, '(', 64, '%', ')', and, caveolin, 3, '(', 76, '%', ')', whereas, many, other, cytoskeletal, proteins, remain, remarkably, stable])].
[sujeto(['Concerning', the, myogenic, transcription, 'factors,', only, the, level, of, myogenin]), verbo([decreased]), complemento(['(', 59, '%', ')', after, the, 'over-expression', of, 'micro-calpain'])].
[sujeto(['Ultra', structural, studies]), verbo([have]), complemento([shown, that, the, myofibrils, formed, near, the, cell, periphery, are, normally, 'oriented,', lying, along, the, longitudinal, axis])].
[sujeto(['This', regularity, is, lost, progressively, towards, the, cell, center, where, the, cytoskeleton, presented, an]), verbo([increasing]), complemento([disorganization])].
[sujeto(['All', these, results, indicate, that, 'micro-calpain', is]), verbo([involved]), complemento([in, regulation, pathway, of, myogenesis, via, at, least, its, action, on, 'ezrin,', 'vimentin,', caveolin, 3, and, 'myogenin,', a, muscle, transcription, factor])].
[sujeto(['Skeletal', muscle, contractile, activity]), verbo([has]), complemento([been, implicated, in, many, aspects, of, muscle, cell, differentiation, and, maturation])].
[sujeto(['Much', of, the, research, in, this, area]), verbo([has]), complemento([depended, upon, costly, and, 'labor-intensive', cultures, of, isolated, primary, muscle, cells, because, widely, available, immortalized, muscle, cell, lines, often, do, not, display, a, high, level, of, either, spontaneous, or, stimulated, contractile, activity])].
[sujeto(['We', sought, to, develop, 'conditionally-immortalized', skeletal, muscle, cell, lines, that, would]), verbo([provide]), complemento([a, source, of, myofibers, that, exhibit, robust, spontaneous, contractile, activity, similar, to, primary, muscle, cultures])].
[sujeto(['Using', a, 'tetracycline-regulated', retroviral, vector]), verbo([expressing]), complemento([a, 'temperature-sensitive', 'T-antigen', to, infect, primary, 'myoblasts,', we, isolated, individual, clonal, muscle, precursor, cell, lines, that, have, characteristics, of, activated, satellite, cells, during, growth, and, rapidly, differentiate, into, mature, myotubes, with, spontaneous, contractile, activity, after, culture, in, 'non-transformation-permissive', conditions])].
[sujeto(['Nutrition', plays, a, key, role, in, the, maintenance, of, muscle, and, bone, 'mass,', and, dietary, protein, deficiency]), verbo([has]), complemento([in, particular, been, associated, with, catabolism, of, both, muscle, and, bone, tissue])].
[sujeto(['One', mechanism, thought, to, link, protein, deficiency, with]), verbo([loss]), complemento([of, muscle, mass, is, deficiency, in, specific, amino, acids, that, play, a, role, in, muscle, metabolism])].
[sujeto(['Adult', mice, '(', 12, 'mo)', were, fed, a, normal, diet, '(', 18, '%', 'protein),', as, well, as, diets, with, low, protein, '(', 8, '%', ')', supplemented, with]), verbo([increasing]), complemento([concentrations, '(', 50, ',', 100, ',', and, 200, 'uM)', of, kynurenine, '(', 'Kyn)', or, with, tryptophan, '(', 'Trp;', 1.5, 'mM)', for, 8, weeks])].
[sujeto(['Enzyme-linked', immunosorbent, assays, showed, significant]), verbo([increases]), complemento([in, skeletal, muscle, 'insulin-like', growth, 'factor-1,', 'leptin,', and, the, myostatin, antagonist, follistatin, with, 'Trp', supplementation])].
[sujeto(['In', 'vitro,', neither, amino, acid, affected, proliferation, of, 'myoprogenitors,', but, 'Trp']), verbo([increased]), complemento([the, expression, of, the, myogenic, markers, 'MyoD,', 'myogenin,', and, myosin, heavy, chain])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, dietary, amino, acids, can, directly, affect, molecular, signaling, in, skeletal, 'muscle,', further, indicating, that, dietary, manipulation, with, specific, amino, acids, could, potentially, attenuate, muscle, loss, with, dietary, protein, deficiency])].
[sujeto(['The', cytokine, interleukin, 12, '(', 'IL-12)']), verbo([has]), complemento([been, implicated, as, a, potent, stimulator, of, tissue, degradation, in, the, pathogenesis, of, several, inflammatory, 'diseases,', including, periodontitis])].
[sujeto(['In', patients, with, 'periodontitis,', an]), verbo([increased]), complemento([level, of, 'IL-12', is, found, in, serum, and, gingival, crevicular, fluid])].
[sujeto(['As', inflammatory, cytokines]), verbo([have]), complemento([been, demonstrated, to, induce, activation, of, the, immunomodulatory, properties, of, mesenchymal, stem, cells, '(', 'MSCs),', this, study, aimed, to, investigate, the, influence, of, 'IL-12', on, these, properties, in, human, periodontal, ligament, '(', 'hPDL)', cells])].
[sujeto(['Moreover,', 'IL-12']), verbo([induced]), complemento([the, expression, of, the, immunomodulatory, proteins, 'IDO', and, 'HLA-G', via, an, 'IFN-γ-dependent', 'pathway,', as, indicated, by, experiments, using, an, 'IFN-γ', neutralizing, antibody])].
[sujeto(['Finally,', 'IL-12']), verbo([inhibited]), complemento([osteogenic, differentiation, of, the, hPDL, cells, and, preserved, the, 'self-clonal', expansion, property, of, these, 'cells,', as, assessed, by, 'Alizarin', 'Red', 'S', staining, and, the, 'colony-forming', unit, assay])].
[sujeto(['MR', hypointensities]), verbo([caused]), complemento([by, 'MPIOs', were, observed, on, 'T2(⁎)-weighted', images, at, all, time, points, after, 'MSCs', injection])].
[sujeto(['Real-time', 'PCR', for, rat, 'SRY', gene, showed, the, number, of, survival, 'MSCs', considerably]), verbo([decreased]), complemento([after, transplantation])].
[sujeto(['MSC-treated', hearts, had, significantly]), verbo([increased]), complemento([capillary, density, in, 'peri-infarct', region, and, lower, cardiomyocytes, apoptosis, and, fibrosis, formation])].
[sujeto(['The', internal, gonad, sexing, method, was]), verbo([found]), complemento([to, be, highly, 'accurate,', while, the, peritoneal, pigmentation, method, was, slightly, less, accurate])].
[sujeto(['In', 'Algeria,', the, data, on, infertility, and, its, various]), verbo([causes]), complemento([are, rare])].
[sujeto(['Recently,', the, introduction, of, assisted, reproduction]), verbo([has]), complemento([allowed, expecting, that, 300000, 'couples,', which, represent, 7, '%', of, couples, of, reproductive, 'age,', face, difficulty, conceiving, a, child])].
[sujeto(['Follicle']), verbo([stimulating]), complemento([hormone, '(', 'FSH)', and, luteinizing, hormone, '(', 'LH)', levels, were, evaluated, by, immunoradiometric, method])].
[sujeto(['Fetuses', with, lissencephaly]), verbo([have]), complemento([an, abnormal, smooth, brain, with, fewer, folds, and, grooves, which, will, be, detected, by, ultrasounds, or, fetal, magnetic, resonance, imaging, '(', 'MRI)', after, 30, weeks, of, gestation])].
[sujeto(['We']), verbo([report]), complemento([a, fetus, with, lissencephaly, diagnosed, as, 'Miller-Dieker', syndrome, postnatally])].
[sujeto(['However,', only, a, few, genetic, studies]), verbo([have]), complemento([explored, the, macaques, in, this, region])].
[sujeto([fascicularis, into, five, subclades, '(', 'Insular', 'Indonesia,', 'Sundaic', 'Thai', 'Gulf,', 'Vietnam,', 'Sundaic', 'Andaman']), verbo([sea]), complemento(['coast,', and, 'Indochina)', and, revealed, genetic, differentiation, between, the, two, sides, of, the, 'Thai', 'peninsula,', which, had, previously, been, reported, as, a, single, group, of, 'Malay', peninsular, macaques])].
[sujeto(['From', the, estimated, divergence, time, of, the, 'Sundaic', 'Andaman']), verbo([sea]), complemento([coast, 'subclade,', it, is, proposed, that, after, 'M'])].
[sujeto(['Then,', some, of, them, migrated, north, and, south, to, colonize, the, 'Thai', 'Andaman']), verbo([sea]), complemento([coast, and, northern, 'Sumatra,', respectively])].
[sujeto(['The', 'SRY-TSPY', phylogenetic, analysis]), verbo([suggested]), complemento([that, 'male-mediated', gene, flow, from, 'M'])].
[sujeto(['The', aim, of, the, present, study, was, to, prove, that, primary, cells, enriched, with, stem, cells, are, more, easily, reprogrammed, to, generate]), verbo([induced]), complemento([pluripotent, stem, '(', 'iPS)', cells, than, those, with, scarce, numbers, of, stem, cells])].
[sujeto(['The', number, of, cells, with, the, stemness, property, of, 'HDDPC', differs, among, 'individuals,', which]), verbo([suggests]), complemento([that, 'HDDPC', showing, an, increased, expression, of, both, 'ALP', and, 'OCT-3/4', can, be, more, easily, reprogrammed, to, generate, iPS, cells, after, the, forced, expression, of, reprogramming, factors])].
[sujeto(['Histone', acetylation]), verbo([regulated]), complemento([by, class, 'I', histone, deacetylases, '(', 'HDACs)', plays, a, pivotal, role, in, 'matrix-specific', gene, transcription, and, cartilage, development])].
[sujeto(['While', we, previously, demonstrated, that, microRNA, '(', 'miR)-455-3p', is, upregulated, during, chondrogenesis, and, can]), verbo([enhance]), complemento([early, 'chondrogenesis,', the, mechanism, underlying, this, process, remains, largely, unclear])].
[sujeto(['We', observed, that, 'miR-455-3p', was, highly]), verbo([expressed]), complemento([in, proliferating, and, 'pre-hypertrophic', 'chondrocytes,', while, 'HDAC2', and, 'HDAC8', were, primarily, expressed, in, hypertrophic, chondrocytes])].
[sujeto(['Meanwhile,', 'miR-455-3p']), verbo([suppressed]), complemento([the, activity, of, reporter, constructs, containing, the, 3, '\'', -, untranslated, regions, of, 'HDAC2/8,', inhibited, 'HDAC2/8', expression, and, promoted, histone, 'H3', acetylation, at, the, collagen, 2, '(', 'COL2A1)', promoter, in, human, 'SW1353', 'chondrocyte-like', cells])].
[sujeto(['Treatment', with, the, 'HDAC', inhibitor, trichostatin, 'A', '(', 'TSA)', resulted, in]), verbo([increased]), complemento([expression, of, 'cartilage-specific', genes, and, promoted, glycosaminoglycan, deposition])].
[sujeto(['Moreover,', 'TSA']), verbo([inhibited]), complemento([matrix, metalloproteinase, 13, '(', 'Mmp13)', expression, and, promoted, nuclear, translocation, of, 'SOX9', in, 'interleukin-1-treated', primary, mouse, chondrocytes])].
[sujeto(['Lastly,', knockdown, of, 'HDAC2/3/8']), verbo([increased]), complemento(['SRY', '(', 'sex-determining', region, 'Y)-box', 9, '(', 'SOX9)', and, decreased, 'Runt-related', transcription, factor, 2, '(', 'RUNX2)', expression])].
[sujeto(['Taken', 'together,', these, findings]), verbo([suggest]), complemento([that, 'miR-455-3p', plays, a, critical, role, during, chondrogenesis, by, directly, targeting, 'HDAC2/8', and, promoting, histone, 'H3', 'acetylation,', which, raises, possibilities, of, using, 'miR-455-3p', to, influence, chondrogenesis, and, cartilage, degeneration])].
[sujeto(['To', investigate, whether, high, 'glucose-induced', oxidative, stress, is, implicated, in, apoptosis, of, rat, nucleus, pulposus, cells, '(', 'NPCs)', and, abnormal, expression, of, critical, genes]), verbo([involved]), complemento([in, the, metabolic, balance, of, extracellular, matrix, '(', 'ECM)'])].
[sujeto(['High', glucose, reduced, viability, of, 'NPCs', and]), verbo([induced]), complemento([apoptosis])].
[sujeto(['High', glucose, resulted, in]), verbo([increased]), complemento(['ROS', generation, and, p38, 'MAPK', activation])].
[sujeto(['In', 'addition,', it, negatively]), verbo([regulated]), complemento([the, expression, of, type, 'II', 'collagen,', 'aggrecan,', 'Sox-9,', and, 'TIMP-1', and, positively, regulated, 'MMP-3', expression])].
[sujeto(['High', glucose, might]), verbo([promote]), complemento([apoptosis, of, 'NPCs,', trigger, 'ECM', catabolic, 'pathways,', and, inhibit, its, anabolic, 'activities,', possibly, through, a, p38, 'MAPK-dependent', oxidative, stress, mechanism])].
[sujeto(['In', this, 'study,', we, identified, the, transcriptional, factor, 'ZNF606', as, an]), verbo([interacting]), complemento([partner, for, 'Sox9', in, cells])].
[sujeto(['We', further, demonstrated, that, overexpression, of, 'ZNF606']), verbo([inhibited]), complemento([the, transcriptional, activity, of, 'Sox9,', while, knockdown, of, 'ZNF606', increased, 'Sox9-mediated', transcription])].
[sujeto(['Chromatin', immunoprecipitation, analysis, revealed, that, 'ZNF606']), verbo([prevents]), complemento(['Sox9', binding, to, the, enhancers, of, its, target, gene, col2a1])].
[sujeto(['Importantly,', the, interaction, between, 'ZNF606', and, 'Sox9', was]), verbo([decreased]), complemento([during, chondrocyte, differentiation])].
[sujeto(['Consistent', with, these, 'findings,', 'ZNF606']), verbo([inhibited]), complemento([chondrocyte, differentiation])].
[sujeto(['Thus,', our, results, demonstrate, that, 'ZNF606']), verbo([acts]), complemento([as, a, novel, 'Sox9', 'co-regulator', that, inhibits, 'Sox9-mediated', chondrocyte, differentiation])].
[sujeto(['To', establish, a, rabbit, model, for, investigating, the, effects, of, intermittent, cyclic, mechanical, tension, '(', 'ICMT)', on]), verbo([promoting]), complemento([degeneration, of, endplate, cartilage])].
[sujeto(['Multiple', strategies, were, employed, to, examine, degeneration, of, endplate, cartilage, and]), verbo([nuclear]), complemento([factor, '(', 'NF)-κB', signaling, pathway, activation])].
[sujeto(['Examination', of, hematoxylin, and, eosin, staining, of, sections, of, endplate, cartilage, showed, significant, damage, as, the, load, duration]), verbo([increased]), complemento([in, the, 'ICMT', loading, group])].
[sujeto(['Additionally,', 'ICMT', loading, can]), verbo([lead]), complemento([to, 'NF-κB', signaling, pathway, activation, as, well, as, degeneration, of, endplate, cartilage])].
[sujeto(['These', experiments, indicate, that, 'ICMT', contributes, to, the, activation, of, 'NF-κB', signaling, pathway, in, vivo, and, that, the, 'NF-κB', signaling, pathway, further, 'up-regulates', 'MMP13,']), verbo([leading]), complemento([to, degeneration, of, endplate, cartilage])].
[sujeto(['Although', oxidative, stress, is, implicated, in, 'SeMet', 'toxicity,', knowledge, gaps, remain, in, how, 'SeMet']), verbo([causes]), complemento([characteristic, spinal, deformities])].
[sujeto(['Gene', expression, studies, for, the, 'UPR']), verbo([suggest]), complemento([a, potential, role, for, 'CHOP', '(', 'c/ebp', homologous, 'protein)', induced, apoptosis, deformed, embryos, after, 5, μM, 'SeMet,', accompanied, by, a, significant, decrease, in, 'PDIA4', '(', protein, disulfide, isomerase, 'A4)', and, no, change, in, 'Dnajb9', '(', 'ER', 'DNA', 'J', 'Domain-Containing', 'Protein', 4, ')'])].
[sujeto(['This', expression, was, distinct, from, the, 'UPR']), verbo([induced]), complemento([by, 'well-studied', 'ER', stress, 'inducer,', 'tunicamycin,', which, robustly, activated, 'CHOP,', 'PDIA4', and, 'Dnajb9'])].
[sujeto(['Finally,', 'SeMet', treatment, significantly]), verbo([decreased]), complemento([transcripts, of, cartilage, 'development,', 'Sox9', '(', 'SRY', box, 9, ')', ',', while, increasing, 'Runx2', in, deformed, 'embryos,', without, altering, 'Twist', or, 'Collagen', 2, a1])].
[sujeto(['Results']), verbo([suggest]), complemento([that, oxidative, 'stress,', the, 'UPR', and, cell, death, play, key, roles, in, 'SeMet', induced, deformities, and, altered, skeletal, development, factors])].
[sujeto(['The', 'sex-determining', gene, 'SRY']), verbo([induces]), complemento(['SOX9', expression, in, the, testes, of, eutherian, mammals, via, two, pathways])].
[sujeto(['SRY']), verbo([binds]), complemento([to, 'testis-specific', enhancer, of, 'Sox9', '(', 'TESCO)', with, 'SF1', to, activate, 'SOX9', transcription])].
[sujeto(['SRY', also, 'up-regulates', 'ER71', 'expression,', and, 'ER71']), verbo([activates]), complemento(['Sox9', transcription])].
[sujeto(['After', the, initiation, of, testis, 'differentiation,', 'SOX9']), verbo([enhances]), complemento(['Amh', expression, by, binding, to, its, promoter, with, 'SF1'])].
[sujeto(['SOX8,', 'SOX9', and, 'SOX10,', members, of, the, 'SOXE', gene, 'family,', also]), verbo([enhance]), complemento([the, activities, of, the, 'Amh', promoter, and, 'TESCO'])].
[sujeto(['The', activity, of, the, 'AMH', promoter, was]), verbo([stimulated]), complemento([by, 'SOXE', genes, and, 'SF1'])].
[sujeto(['Mutant', 'AMH', 'promoters,', with, mutations, in, its, 'SOX', and, 'SF1']), verbo([binding]), complemento(['sites,', did, not, show, significant, activity, by, 'SOX9', and, 'SF1'])].
[sujeto(['These', results, indicate, that, 'AMH', expression, was]), verbo([regulated]), complemento([by, the, binding, of, 'SOX9', and, 'SF1'])].
[sujeto(['By', 'contrast,', 'SOXE', genes, could, not]), verbo([enhance]), complemento(['TESCO', activity])].
[sujeto(['Furthermore,', the, activity, of, the, 'SOX9', promoter, was]), verbo([enhanced]), complemento([by, 'ER71,', indicating, that, 'ER71', may, play, an, important, role, in, the, 'testis-specific', expression, of, 'SOX9'])].
[sujeto(['In', a, 46, ',', 'XY', 'individual,', the, presence, of, the, 'Y', chromosome, harboring, the, 'testis-determining', factor, '(', 'SRY)']), verbo([triggers]), complemento([testis, determination, and, differentiation])].
[sujeto(['In', a, 46, ',', 'XX', 'individual,', the, absence, of, 'SRY', along, with, the, activation, of, genes]), verbo([associated]), complemento([with, the, female, pathway, leads, to, ovarian, development])].
[sujeto(['The', latter, process]), verbo([has]), complemento([long, been, considered, as, a, default, pathway])].
[sujeto(['However,', recent, studies]), verbo([have]), complemento([cast, doubts, on, this, dogma])].
[sujeto(['Especial', attention, is, paid, to, 'FOXL2', whose, mutations, are, responsible, for, the, blepharophimosis, 'syndrome,', often]), verbo([associated]), complemento([with, female, 'infertility,', and, for, cancer])].
[sujeto(['We', highlight, the, cooperation, of, 'WNT4,', 'RSPO1', and, 'FOXL2', within, a, regulatory, network, and, the, need, for, further, research, to, better, understand, their, role, in, defining, and]), verbo([maintaining]), complemento([ovarian, identity])].
[sujeto(['Here,', we]), verbo([report]), complemento([a, rare, congenital, chromosomal, 'aberration,', 46, ',', 'X,dic(X;Y)(p22'])].
[sujeto(['A', cytogenetic, examination, of]), verbo([stimulated]), complemento([peripheral, blood, cells, revealed, the, constitutional, karyotype, 46, ',', 'X,dic(X;Y)(p22'])].
[sujeto(['A', 'CGH/SNP', array, '(', 'Illumina)', revealed, a]), verbo([gain]), complemento([of, 153, ',', 7, 'Mbp', of, the, 'X', chromosome, and, a, 803, -, kbp, microdeletion, '(', including, the, 'SHOX', 'gene),', which, were, also, confirmed, with, 'FISH'])].
[sujeto(['SHOX', encodes, a, transcriptional, factor, that]), verbo([regulates]), complemento([the, growth, of, the, long, bones])].
[sujeto(['The', deletion, of, the, 'SHOX', gene, together, with, the, 'Madelung', deformity, of, the, forearm, and, the, short, stature, of, the, proband]), verbo([led]), complemento([to, a, diagnosis, of, 'Léri-Weill', dyschondrosteosis, '(', 'LWD)'])].
[sujeto(['The']), verbo([gain]), complemento([of, almost, the, whole, 'X', chromosome, '(', 153, ',', 7, 'Mbp)', was, considered, a, variant, of, 'Klinefelter', syndrome, '(', 'KS)'])].
[sujeto(['We']), verbo([have]), complemento([reported, a, structural, aberration, of, the, sex, 'chromosomes,', 'dic(X;Y)(p22'])].
[sujeto(['The', related, genomic, imbalance, is]), verbo([associated]), complemento([with, two, known, hereditary, 'syndromes,', 'LWD', and, a, 'KS', 'variant,', identified, in, our, proband, at, an, advanced, age])].
[sujeto(['Because', the, breakpoints, did, not]), verbo([involve]), complemento([cancer, 'genes,', we, inferred, that, the, two, malignancies, in, the, proband, were, not, caused, by, this, abnormality])].
[sujeto(['The', addition, of, fibrin, protein, was, typically]), verbo([required]), complemento([to, achieve, a, similar, effect, on, 'M-ECM-adherent', monolayered, fibroblasts])].
[sujeto(['The', spheroid, fusion, process, was, followed, by, an]), verbo([increase]), complemento([in, cell, density, and, the, formation, of, tight, clusters])].
[sujeto(['The', fused, spheroids, continued, to]), verbo([maintain]), complemento([their, intracellular, 'ECM', turnover, and, proliferation, capacities])].
[sujeto(['A', model, is]), verbo([provided]), complemento([by, testis, determination, in, therian, mammals])].
[sujeto(['Mutations', in, human, 'SRY']), verbo([cause]), complemento([gonadal, dysgenesis, leading, to, 'XY', female, development, '(', 'Swyer', 'syndrome)'])].
[sujeto(['Here,', we]), verbo([have]), complemento([characterized, an, inherited, mutation, compatible, with, either, male, or, female, somatic, phenotypes, as, respectively, observed, in, an, 'XY', father, and, 'XY', daughter])].
[sujeto(['The', mutation, '(', a, 'crevice-forming', substitution, at, a]), verbo([conserved]), complemento([back, surface, of, the, 'SRY', 'high-mobility-group', 'box)', markedly, destabilizes, the, domain, but, preserves, specific, 'DNA', affinity, and, induced, 'DNA', bend, angle])].
[sujeto(['On', transient, transfection, of, diverse, human, and, rodent, cell, 'lines,', the, variant, 'SRY', exhibited, accelerated, proteasomal, degradation, '(', relative, to, 'wild-type)']), verbo([associated]), complemento([with, increased, 'ubiquitination;', in, vitro, susceptibility, to, 'ubiquitin-independent', '(', '″default″)', cleavage, by, the, 20, 'S', core, proteasome, was, unchanged])].
[sujeto(['Our', findings, define, a, novel, mechanism, of, impaired, 'organogenesis:', accelerated, 'ubiquitin-directed', proteasomal, degradation, of, a, master, transcription, factor]), verbo([leading]), complemento([to, a, developmental, decision, poised, at, the, edge, of, ambiguity])].
[sujeto(['In', this, commentary, we, briefly, summarize, early, work, on, circular, 'RNAs', derived, from, spliceosome]), verbo([mediated]), complemento([circularization])].
[sujeto(['We', highlight, how, this, early, work, inspired, work, on, the, basic, mechanisms, of]), verbo([nuclear]), complemento(['RNA', 'splicing,', the, possible, function, of, circular, 'RNAs', and, the, potential, uses, of, circular, 'RNAs', as, tools, in, biomedicine])].
[sujeto(['Recent', developments, in, the, study, of, circular, 'RNAs,', summarized, in, this, 'volume,']), verbo([have]), complemento([brought, these, questions, back, to, the, foreground])].
[sujeto(['SRY-related', 'HMG', box, '(', 'Sox)', genes, are, characterized, by, the, presence, of, a, 'DNA-binding', 'HMG', domain, and]), verbo([involved]), complemento([in, a, diverse, range, of, developmental, processes])].
[sujeto(['Two', core, promoters, in, 5, '\'', flanking, region, were, demonstrated, to, be, essential, for]), verbo([inducing]), complemento([transcriptional, regulatory, activity])].
[sujeto(['Interestingly,', 'EsSOXB2-1', protein, was, exclusively, localized, in, the, nucleus, of, spermatid, and, spermatozoa, even, at, the, end, of, acrosome, 'reaction,', and, was]), verbo([bound]), complemento([to, the, uncondensed, chromatin, in, nucleoplasm, of, mature, spermatozoa])].
[sujeto(['Knockdown', of, 'EsSoxB2-1', by, 'RNAi']), verbo([leads]), complemento([to, abnormal, transformation, of, the, nucleus, during, spermiogenesis])].
[sujeto(['Together,', these, findings, demonstrated, the, requirement, of, 'EsSoxB2-1', for, the, spermatozoa, nucleus, maturation, and, also]), verbo([suggested]), complemento([that, 'EsSoxB2-1', would, be, delivered, into, fertilized, eggs, along, with, chromatins, as, a, paternal, transcription, factor, for, regulating, early, embryonic, development])].
[sujeto(['The', 'SRY', gene, '(', 'SRY)']), verbo([provides]), complemento([instructions, for, making, a, transcription, factor, called, the, 'sex-determining', region, 'Y', protein])].
[sujeto(['The', 'sex-determining', region, 'Y', protein]), verbo([causes]), complemento([a, fetus, to, develop, as, a, male])].
[sujeto(['The', multiple, sequence, alignment, results, indicated, that, 'SRY', protein, sequences, from, 'Orcinus', orca, '(', killer, 'whale)', and, 'Tursiopsaduncus', '(', 'dolphin)']), verbo([have]), complemento([least, genetic, distance, of, 0.33, in, these, 15, species, and, are, 99.67, '%', identical, at, the, amino, acid, level])].
[sujeto(['Homosapiens', and, 'Pantroglodytes', '(', 'chimpanzee)']), verbo([have]), complemento([the, next, lowest, genetic, distance, of, 1.35, and, are, 98.65, '%', identical, at, the, amino, acid, level])].
[sujeto(['These', findings, indicate, that, the, 'SRY', proteins, are]), verbo([conserved]), complemento([in, the, 15, 'species,', and, their, evolutionary, relationships, are, similar])].
[sujeto(['No', mutation, was]), verbo([found]), complemento([in, the, 'SRY', gene])].
[sujeto(['The', karyotype, of, patients, carrying, 'idic(Y)(p)', seems, 'unstable,', and, female, patients]), verbo([have]), complemento([the, characteristics, of, short, stature, and, secondary, sexual, hypoplasia])].
[sujeto(['Here,', we, replaced, 'Sry', by, transgenic, activation, of, its, downstream]), verbo([target]), complemento(['Sox9,', and, 'Eif2s3y,', by, transgenic, overexpression, of, its, 'X', 'chromosome-encoded', homolog, 'Eif2s3x'])].
[sujeto(['During', its, final, 'phase,', 'spermiogenesis,', haploid, round, spermatids, undergo, cellular, differentiation, into, 'spermatozoa,', which]), verbo([involves]), complemento([extensive, restructuring, of, cell, 'morphology,', 'DNA,', and, epigenome])].
[sujeto(['Compared', with, the, 'Control', 'group,', 'CD47', +, 'MSC', +, 'BiAb', +, 'MB,', 'CD47', +, 'MSC', +, 'BiAb,', 'CD47', +, 'MSC', and, 'MSC', groups, had]), verbo([decreased]), complemento([levels, of, 'MMP-9,', 'TIMP-1,', 'STAT', 1, and, collagen, 'deposition,', and, increased, levels, of, 'STAT', 3])].
[sujeto(['Up']), verbo([regulated]), complemento(['STAT', 3, and, down, regulated, 'TIMP-1', were, significantly, different, in, 'CD47', +, 'MSC', +, 'BiAb', +, 'MB', compared, with, 'CD47', +, 'MSC', or, 'CD47', +, 'MSC', +, 'BiAb'])].
[sujeto(['CD47', can]), verbo([enhance]), complemento([the, homing, rate, and, repairing, efficacy, of, 'MSC'])].
[sujeto(['An', analytical, evaluation, using, blood, samples, from, patients, with, leukemia, showed, that, the, while, blood, cell, '(', 'WBC)', depletion, and, 'NRBC']), verbo([loss]), complemento([rates, of, the, positive, enrichment, process, were, 93.98, &, 'nbsp;%', and, 6.02, &, 'nbsp;%,', respectively])].
[sujeto(['Gonadoblastoma', '(', 'GB),', a, rare, in, situ, germ, cell, tumor, derived, from, sex, cord, and, germ, 'cells,', is, closely]), verbo([associated]), complemento([with, gonadal, dysgenesis])].
[sujeto(['Increasing', studies, show, that, the, formation, of, 'GB', is, closely, related, to, genes]), verbo([regulating]), complemento([sexual, differentiation, and, determination, '(', e])].
[sujeto(['Here', we, describe, the, clinical, and, pathological, 'features,', diagnosis, and, treatment, of, 'GB,', and, also, summarize, the, molecular, genetic, and, epigenetic, mechanisms, underlying, the, gonadal, abnormalities, that]), verbo([lead]), complemento([to, 'GB'])].
[sujeto(['We', analyze, and, construct, the, common, gene, regulatory, networks, related, to, the, development, of, 'GB,', and, describe, some, obstacles, and, deficiencies, in, current, studies, to]), verbo([provide]), complemento([innovative, perspectives, on, further, studying, the, pathological, and, molecular, mechanisms, of, 'GB'])].
[sujeto(['Sex', determination, in, mammals]), verbo([requires]), complemento([expression, of, the, 'Y-linked', gene, 'Sry', in, the, bipotential, genital, ridges, of, the, 'XY', embryo])].
[sujeto(['Here,', we, analysed, 'Sry', flanking, sequences, across, many, 'species,', using, newly, available, genome, sequences, and, computational, 'tools,', to, better, understand, 'Sry\'s', genomic, context, and, to, identify]), verbo([conserved]), complemento([regions, predictive, of, functional, roles])].
[sujeto(['We', identified, 'position-specific', conservation, of]), verbo([binding]), complemento([motifs, for, multiple, transcription, factor, 'families,', including, 'GATA', binding, factors, and, 'Oct/Sox', dimers])].
[sujeto(['In', contrast, with, the, landscape, of, extremely, low, sequence, conservation, around, the, 'Sry', coding, 'region,', our, analysis, highlighted, a, strongly]), verbo([conserved]), complemento([interval, of, '~106&nbsp;bp', within, the, 'Sry', promoter, '(', which, we, term, the, 'Sry', 'Proximal', 'Conserved', 'Interval,', 'SPCI)'])].
[sujeto(['We', further]), verbo([report]), complemento([that, inverted, repeats, flanking, murine, 'Sry', are, much, larger, than, previously, recognised])].
[sujeto(['The', unusually, fast, pace, of, sequence, drift, on, the, 'Y', chromosome, sharpens, the, likely, functional, significance, of, both, the, 'SPCI', and, the, identified]), verbo([binding]), complemento(['motifs,', providing, a, basis, for, future, studies, of, the, 'role(s)', of, these, elements, in, 'Sry', regulation])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([in, the, scientific, literature, of, an, 'SRY-positive', hermaphrodite, 'Holstein', cattle, with, continuous, ovarian, cycles])].
[sujeto(['In', mouse, 'XY', 'gonads,', 'SRY']), verbo([induces]), complemento(['SOX9', upregulation, and, subsequent, 'FGF9', expression, by, embryonic, day, 11.5, '(', 'E11'])].
[sujeto([5, ')', ',']), verbo([leading]), complemento([to, the, differentiation, of, 'Sertoli', cells])].
[sujeto(['These', 2, ovarian, 'factors,', together, with, retinoic, acid, '(', 'RA)', 'action,']), verbo([promote]), complemento([feminization, partially, through, the, repression, of, the, masculinizing, activities, of, 'SOX9,', 'FGF9', and, 'DMRT1'])].
[sujeto(['At', 'birth,', the, oocyte, nests, break, down, into, single, oocytes, surrounded, by, granulosa, 'cells,']), verbo([leading]), complemento([to, the, assembly, of, primordial, follicles])].
[sujeto(['Animal', researches, and, clinical, studies]), verbo([have]), complemento([supported, the, relevance, between, phthalates, exposure, and, testicular, dysgenesis, syndrome, '(', 'TDS)'])].
[sujeto(['DEHP', exposure, resulted, in, significant, reduction, in, mRNA, of, 'Sry', during, sex, determination, from, gestation, day, '(', 'GD)', 11.0, to, 11.5, in, male, fetal, 'mice,', and, the]), verbo([increasing]), complemento([of, 'Sry', expression, to, threshold, level, on, 'GD', 11.5, was, delayed])].
[sujeto(['Taken', 'together,', the, results]), verbo([suggest]), complemento([that, the, potential, mechanism, of, gonadal, development, disorder, by, 'DEHP', may, origin, from, repression, of, important, male, sex, determination, signaling, 'pathway,', involving, 'Gadd45g', '→', 'Gata4', '→', 'Sry', '→', 'Sox9'])].
[sujeto(['The', results, would]), verbo([promote]), complemento([a, better, understanding, of, the, association, between, phthalate, esters, '(', 'PAEs)', exposure, and, the, reductive, disorder])].
[sujeto(['The', 'SOX9', gene]), verbo([has]), complemento([been, identified, as, a, major, factor, in, testis, development, in, mammals, after, it, is, activated, by, the, 'SRY', gene])].
[sujeto(['However,', duplication, of, the, gene, itself, in, some, mammalian, 'species,', or, of, a, 'well-delimited', upstream, '\'', 'RevSex\'', region, in, 'humans,']), verbo([has]), complemento([been, shown, to, result, in, testis, development, in, the, absence, of, the, 'SRY', gene])].
[sujeto(['Contrary', to, what, is, observed, in, the, current, dog, genome, 'assembly,', we]), verbo([found]), complemento([that, the, genomic, organization, is, quite, similar, to, that, reported, in, humans, and, other, mammalian, 'species,', including, the, position, of, the, 'RevSex', region, in, respect, to, 'SOX9'])].
[sujeto(['The', analysis, of, the]), verbo([conserved]), complemento([sequences, within, this, region, in, 7, mammalian, species, facilitated, the, highlighting, of, a, consensus, sequence, for, 'SRY', binding])].
[sujeto(['This', new, information, could, help, in, the, identification, of, evolutionarily]), verbo([conserved]), complemento([elements, relevant, for, 'SOX9', gene, 'regulation,', and, could, provide, valid, targets, for, mutation, analysis, in, 'XY', 'DSD', patients])].
[sujeto(['Diagnosis', of, fetal, gender, early, in, pregnancy, is, very, useful, as, it, would]), verbo([prevent]), complemento([invasive, fetal, sampling, in, almost, half, the, cases, at, risk, of, inheriting, 'X-linked', disorders, or, those, affecting, sexual, differentiation])].
[sujeto(['Noninvasive', prenatal, diagnosis, '(', 'NIPD)', using, circulating, 'cell-free', fetal, '(', 'cff)', 'DNA', from, maternal, circulation]), verbo([has]), complemento([emerged, as, a, useful, alternative, to, existing, methods, for, prenatal, diagnosis, of, gender])].
[sujeto(['Sex-reversal', cases, in, humans, and, genetic, models, in, mice]), verbo([have]), complemento([revealed, that, the, fate, of, the, bipotential, gonad, hinges, upon, the, balance, between, 'pro-testis', 'SOX9', and, 'pro-ovary', 'beta-catenin', pathways])].
[sujeto(['In', the, absence, of, 'Sox9', and, 'beta-catenin,', both, 'XX', and, 'XY', gonads, progressively, lean, toward, the, testis, 'fate,', indicating, that, expression, of, certain, 'pro-testis', genes]), verbo([requires]), complemento([the, repression, of, the, 'beta-catenin', 'pathway,', rather, than, a, direct, activation, by, 'SOX9'])].
[sujeto(['XY)', affects, this, 'process,', we, compared, the, transcriptomes, of, 'Sox9/beta-catenin', mutant, gonads, and]), verbo([found]), complemento([that, early, molecular, changes, underlying, the, 'XY-specific', masculinization, involve, the, expression, of, 'Sry', and, 21, 'SRY', direct, target, 'genes,', such, as, 'Sox8', and, 'Cyp26b1'])].
[sujeto(['These', results, imply, that, when, both, 'Sox9', and, 'beta-catenin', are, 'absent,', 'Sry', is, capable, of]), verbo([activating]), complemento([other, 'pro-testis', genes, and, drive, testis, differentiation])].
[sujeto(['Our', findings, not, only]), verbo([provide]), complemento([insight, into, the, mechanism, of, sex, 'determination,', but, also, identify, candidate, genes, that, are, potentially, involved, in, disorders, of, sex, development])].
[sujeto(['This']), verbo([report]), complemento([describes, a, disorder, of, the, sexual, development, in, a, beagle, dog, resulting, in, an, intersex, condition])].
[sujeto(['Testosterone', levels, that, were, within, the, male, reference, ranges, before, surgery]), verbo([decreased]), complemento([to, basal, levels, postsurgically])].
[sujeto(['The', stem, cell, marker, 'OCT4', is, frequently]), verbo([expressed]), complemento([in, 'HCCs,', and, its, expression, correlates, with, those, of, putative, cancer, stem, cell, '(', 'CSC)', markers, and, 'CSC', properties])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, 'Sry', is, involved, in, tumor, malignancy, in, rodent, 'HCCs'])].
[sujeto(['Ectopic', expression, of, 'SRY']), verbo([increased]), complemento([multiple, stem, cell, 'factors,', including, 'OCT4', and, 'CD13'])].
[sujeto(['The', 'OCT4', promoter, contained, 'SRY-binding', sites, that, were, directly]), verbo([activated]), complemento([by, 'SRY'])].
[sujeto(['In', 'HCC-derived', 'cells,', 'SRY', knockdown]), verbo([decreased]), complemento(['OCT4', expression, and, cancer, 'stem-like', phenotypes, such, as, 'self-renewal,', 'chemoresistance,', and, tumorigenicity])].
[sujeto(['Conversely,', 'OCT4', and, 'SRY', overexpression]), verbo([promoted]), complemento([cancer, 'stem-like', phenotypes])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'SRY', is, involved, in, the, maintenance, of, cancer, 'stem-like', characteristics, through, 'OCT4'])].
[sujeto(['Noteworthily,', 'SRY', was, highly]), verbo([expressed]), complemento([in, some, hHCC, patients])].
[sujeto(['Gender', role, and, gender, identity, are]), verbo([reported]), complemento([as, male])].
[sujeto(['SRY,', the, gene, that, encodes, the, 'sex-determining', region, 'Y', 'protein,', is, the, principal, gene, known, to, be]), verbo([associated]), complemento([with, 46, ',', 'XX', testicular, 'DSD'])].
[sujeto(['Rearrangements', in, or, around, 'SOX9', and, 'SOX3', detected, by, 'CMA,', or, rarely, 'karyotype,']), verbo([have]), complemento([recently, been, reported, in, a, few, 'cases;', at, least, one, more, 'as-yet-unknown', gene, at, another, locus, is, implicated])].
[sujeto(['Treatment', of, 'manifestations:', 'Similar', to, that, for, other]), verbo([causes]), complemento([of, testosterone, deficiency])].
[sujeto(['After', age, 14, 'years,', 'low-dose', testosterone, therapy, is, initiated, and, gradually]), verbo([increased]), complemento([to, reach, adult, levels])].
[sujeto(['Surveillance:', 'Monitor', for, testosterone, effects, during, testosterone, replacement, 'therapy,', including, prostate, size, and, 'prostate-specific', antigen, '(', 'PSA)', in, 'adults;', routine, monitoring, of, 'hematocrit,', lipid, 'profile,', and, liver, function, 'tests;', bone, mineral, density, determination, by, bone, densitometry, '(', 'DEXA)', 'annually,', if, osteopenia]), verbo([has]), complemento([been, diagnosed])].
[sujeto(['Autosomal', dominant, inheritance]), verbo([has]), complemento([been, documented, for, familial, cases, thought, to, be, caused, by, 'CNV', in, or, around, 'SOX9'])].
[sujeto(['The', mode, of, inheritance, of, other, 'SRY-negative', 46, ',', 'XX', testicular, 'DSD', is, not, 'known,', but, autosomal, recessive, inheritance]), verbo([has]), complemento([been, postulated])].
[sujeto(['Mixed', gonadal, dysgenesis, '(', 'MGD)', is, a, disorder, of, sexual, development, that, typically]), verbo([has]), complemento([a, mosaic, 45, ',', 'X/46,XY', karyotype])].
[sujeto(['The', 'RNA']), verbo([binding]), complemento([motif, protein, 38, '(', 'RBM38,', also, known, as, 'RNPC1)', plays, a, pivotal, role, in, regulating, a, wide, range, of, biological, 'processes,', from, cell, proliferation, and, cell, cycle, arrest, to, cell, myogenic, differentiation])].
[sujeto(['It', was, originally]), verbo([recognized]), complemento([as, an, 'oncogene,', and, was, frequently, found, to, be, amplified, in, 'prostate,', ovarian, and, colorectal, 'cancer,', chronic, lymphocytic, 'leukemia,', colon, 'carcinoma,', esophageal, 'cancer,', dog, lymphomas, and, breast, cancer])].
[sujeto(['In', the, present, 'study,', the, complete, 'RNPC1', gene, was, identified, in, a, number, of, vertebrate, 'genomes,']), verbo([suggesting]), complemento([that, 'RNPC1', exists, in, all, types, of, 'vertebrates,', including, 'fish,', 'amphibians,', birds, and, mammals])].
[sujeto(['A', total, of, 34, functionally, relevant, single, nucleotide, polymorphisms, '(', 'SNPs),', including, 14, 'SNPs']), verbo([causing]), complemento([missense, 'mutations,', 8, exonic, splicing, enhancer, 'SNPs', and, 12, 'SNPs', causing, nonsense, 'mutations,', were, identified, in, the, human, 'RNPC1', gene])].
[sujeto(['RNPC1', was]), verbo([found]), complemento([to, be, expressed, in, 'bladder,', 'blood,', 'brain,', 'breast,', 'colorectal,', 'eye,', head, and, 'neck,', 'lung,', 'ovarian,', skin, and, soft, tissue, cancer])].
[sujeto(['We']), verbo([found]), complemento([that, the, association, between, the, expression, of, 'RNPC1', and, prognosis, varied, in, different, types, of, 'cancer,', and, even, in, the, same, type, of, cancer, from, the, different, databases, used])].
[sujeto(['This']), verbo([suggests]), complemento([that, the, function, of, 'RNPC1', in, these, tumors, may, be, multidimensional])].
[sujeto(['The', sex, determining, region, 'Y', '(', 'SRY)-box', 5, '(', 'Sox5),', 'runt-related', transcription, factor, 3, '(', 'RUNX3),', 'CCAAT', displacement, protein, 1, '(', 'CUTL1),', 'v-rel', avian, reticuloendotheliosis, viral, oncogene, homolog, '(', 'Rel)A,', peroxisome, 'proliferator-activated', receptor, γ, isoform, 2, '(', 'PPARγ2)', and]), verbo([activating]), complemento([transcription, factor, 6, '(', 'ATF6)', regulatory, transcription, factor, binding, sites, were, identified, in, the, upstream, '(', 'promoter)', region, of, the, 'RNPC1', 'gene,', and, may, thus, be, involved, in, the, effects, of, 'RNPC1', in, tumors])].
[sujeto(['The', upstream, region, of, the, 'XFGF8', gene, contains, two, putative]), verbo([binding]), complemento([sites, for, the, 'SRY', '(', 'sex-determining', region, 'Y)-box', 2, '(', 'SOX2)', transcription, factor])].
[sujeto(['Furthermore,', 'Xenopus', 'SOX2', '(', 'XSOX2)', physically]), verbo([interacted]), complemento([with, the, 'SOX2-binding', motif, within, the, upstream, region, of, the, 'XFGF8', gene, in, vitro, and, in, vivo])].
[sujeto(['Depletion', of, endogenous, 'XSOX2', resulted, in]), verbo([loss]), complemento([of, 'XFGF8', gene, expression, in, 'midbrain-hindbrain', 'junction,', auditory, 'placode,', lens, placode, and, forebrain, in, developing, 'Xenopus', embryos])].
[sujeto(['Collectively,', our, results]), verbo([suggest]), complemento([that, 'XSOX2', directly, upregulates, 'XFGF8', gene, expression, in, the, early, embryonic, development, of, 'Xenopus'])].
[sujeto(['Nuclear', receptor, subfamily, 5, ',', group, 'A,', member, 1, '(', 'NR5A1', previously, known, as, 'SF-1/AD4BP)', is, a, transcription, factor]), verbo([involved]), complemento([in, the, development, of, 'adrenal/gonadal', tissues, and, steroidogenic, lineage, cell, differentiation, in, adult, somatic, stem, cells])].
[sujeto(['To', understand, the, cellular, signaling, network, that]), verbo([regulates]), complemento(['NR5A1', gene, 'expression,', loss, of, function, screening, with, an, siRNA, kinome, 'library,', and, gain, of, function, screening, with, an, addressable, 'full-length', cDNA, library, representing, one, quarter, of, the, human, genome, was, carried, out])].
[sujeto(['The', 'NR5A1', gene, expression, was]), verbo([activated]), complemento([in, mesenchymal, stem, cells, by, siRNA, directed, against, protein, kinase, 'C', '(', 'PKC)-delta,', 'erb-B3,', 'RhoGAP', '(', 'ARHGAP26),', and, hexokinase, 2, ',', none, of, which, were, previously, known, to, be, involved, in, the, 'NR5A1', gene, expression])].
[sujeto(['In', 'addition,', the]), verbo([gain]), complemento([of, function, studies, indicated, that, 'sex-determining', region, 'Y', '(', 'SRY)-box', 15, '(', 'SOX15),', 'TEA', domain, family, member, 4, ',', 'KIAA1257', '(', a, gene, of, unknown, 'function),', 'ADAM', metallopeptidase, with, thrombospondin, type, 1, motif, 6, ',', 'Josephin', domain, containing, 1, ',', centromere, 'protein,', 'TATA', 'box-binding', 'protein-associated', factor, 5, -, like, 'RNA', 'polymerase,', and, inducible, 'T-cell', 'co-stimulator', activate, 'NR5A1', gene, expression])].
[sujeto(['These', results]), verbo([provide]), complemento([new, insights, into, the, molecular, mechanisms, of, 'NR5A1', gene, expression])].
[sujeto(['Seven', different, sets, of, oligonucleotide, 'primers,', sex, determining, region, 'Y', '(', 'SRY),', zinc, finger, gene, on, the, 'Y', chromosome, '(', 'ZFY),', testis, specific, protein, 'Y', '(', 'TSPY),', 'DYZ3,', 'DYF49S1,', 'RNA']), verbo([binding]), complemento([motif, protein, '(', 'RBM),', and, 'DYZ1,', spanning, on, centromeres, and, short, and, long, arms, of, the, 'Y', chromosome, were, used, for, 'PCR'])].
[sujeto(['The', 'leucine-zipper', and, 'HMG-box', motif, were, almost, completely]), verbo([conserved]), complemento([between, these, homologues])].
[sujeto([rSox6, '(', rat, 'Sox6)', was, specifically]), verbo([expressed]), complemento([in, the, neonatal, brain, and, adult, testis, with, 'Northern', blotting])].
[sujeto(['The', rSox6, was]), verbo([expressed]), complemento([in, the, neonatal, brain, and, adult, testis, as, well, as, by, 'Northern', blotting, and, also, expressed, in, the, adult, eyeball, and, slightly, in, the, ovary])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([identified, a, new, human, 'SOX', 'gene,', 'SOX13,', as, encoding, the, type, 1, diabetes, 'autoantigen,', islet, cell, antigen, 12, '(', 'ICA12)'])].
[sujeto(['Deletion', mapping, of, the, antibody, epitopes, showed, that, the, autoantibodies, were, primarily, directed, against, an, epitope]), verbo([requiring]), complemento([the, majority, of, the, protein])].
[sujeto(['Recombinant', 'SOX13', protein]), verbo([bound]), complemento([to, the, 'SOX', consensus, 'DNA', motif, 'AACAAT,', and, binding, was, inhibited, by, homodimer, formation])].
[sujeto(['These', 'observations-along', with, the, known, molecular, interactions, of, the, closely, related, 'protein,', rainbow, trout, 'Sox23-suggest', that, 'SOX13', may, be]), verbo([activated]), complemento([for, nuclear, import, and, 'DNA', binding, through, heterodimer, formation])].
[sujeto(['In', 'conclusion,', we]), verbo([have]), complemento([identified, 'ICA12', as, the, putative, transcription, factor, 'SOX13', and, demonstrated, an, increased, frequency, of, autoantibody, reactivity, in, sera, from, type, 1, diabetic, subjects, compared, with, type, 2, diabetic, and, healthy, control, subjects])].
[sujeto(['Leydig', cells, and, 'Sertoli', cells, of, the, testes, produce, hormones, that]), verbo([cause]), complemento([male, 'differentiation,', if, receptors, are, present])].
[sujeto(['The', 'Y', chromosomal, 'SRY', gene, '(', sex, determining, 'Region', 'Y', 'gene)']), verbo([acts]), complemento([as, 'TDF', and, is, required, for, regular, male, sex, determination])].
[sujeto(['SRY', represents, a, transcription, factor, belonging, to, the, superfamily, of, genes, sharing, the, 'HMG-box', 'motif(high-mobility', 'group-box),', which]), verbo([acts]), complemento([as, 'DNA', binding, region])].
[sujeto(['The', glycine, at, codon, 95, is, highly]), verbo([conserved]), complemento([between, the, family, of, 'HMG-box', proteins, and, between, species])].
[sujeto(['This', point, mutation]), verbo([has]), complemento([not, been, described, earlier, and, brings, the, total, number, of, 'SRY', mutations, described, so, far, to, 36, ',', each, mutation, being, unique])].
[sujeto(['The', present, data]), verbo([provide]), complemento([further, evidence, to, support, the, functional, importance, of, the, putative, 'DNA', binding, activity, of, the, 'SRY', 'HMG-box', domain])].
[sujeto(['In', vertebrates, several, proteins, containing, a, covalently]), verbo([bound]), complemento([selenocysteine, residue, have, been, identified])].
[sujeto(['The', protein, was, traced, in, rat, 'plasma,', but, its, role]), verbo([has]), complemento([not, been, worked, out, so, far])].
[sujeto(['Selenoprotein', 'P', was, also]), verbo([found]), complemento([to, be, expressed, in, 'testis,', 'brain,', 'gut,', and, hematopoietic, cells])].
[sujeto(['One', 'TATA', motif, 38, bp, upstream, to, exon, 1]), verbo([suggests]), complemento([transcription, of, selp, by, 'RNA', polymerase, 'II'])].
[sujeto(['Within', the, 1116, bp, upstream, of, exon, 1, four, hepatic]), verbo([nuclear]), complemento([factor, 3, beta, '(', 'HNF3beta)', binding, motifs, were, 'found,', which, is, in, line, with, 'liver-specific', expression, of, selenoprotein, 'P'])].
[sujeto(['Two', 'BRN-2', motifs, suitable, for, the]), verbo([binding]), complemento([of, 'brain-specific', regulatory, factors, correlated, to, the, selenoprotein, 'P', expression, in, the, cerebellum])].
[sujeto(['Selenoprotein', 'P', was, also]), verbo([expressed]), complemento([in, 'Leydig', cells, which, could, be, regulated, by, binding, proteins, docking, to, the, 'SRY', motifs, present, in, the, promoter, region])].
[sujeto(['The', methodology]), verbo([involved]), complemento([a, combination, of, polymerase, chain, reaction, '(', 'PCR)', and, nested, 'PCR', followed, by, 'Southern', blot, analysis, of, three, genes, the, sex, determining, region, 'Y', '(', 'SRY),', testis, specific, protein, 'Y', encoded, '(', 'TSPY)', and, 'RNA', binding, motif, protein, '(', 'RBM)', '(', previously, designated, as, 'YRRM)', and, nine, additional, 'STSs', spanning, all, seven, intervals, of, the, 'Y', chromosome])].
[sujeto(['The', methodology]), verbo([has]), complemento([a, high, sensitivity, as, it, detects, one, 46, ',', 'XY', cell, among, 10, '(', 5, ')', 46, ',', 'XX', cells])].
[sujeto(['Reliability', was]), verbo([ensured]), complemento([by, taking, several, precautions, to, avoid, false, positive, results])].
[sujeto(['We']), verbo([report]), complemento([the, results, of, screening, 50, 'TS', patients, and, the, identification, of, cryptic, 'Y', chromosome, material, in, 12, '(', 24, '%', ')', of, them])].
[sujeto(['Karyotypes', were, divided, in, four, 'groups:', 5, '(', 23.8, '%', ')', patients, out, of, the, 21, 'TS', patients, which]), verbo([have]), complemento([the, 45, ',', 'X', karyotype, '(', group, 'A)', also, have, cryptic, 'Y', 'sequences;', none, '(', 0, '%', ')', of, the, 7, patients, who, have, karyotypes, with, anomalies, on, one, of, the, 'X', chromosomes, have, 'Y', mosaicism, '(', group, 'B);', 1, '(', 6.3, '%', ')', of, the, 16, patients, with, a, mosaic, karyotype, have, 'Y', material, '(', group, 'C);', and, 6, '(', 100, '%', ')', out, of, 6, patients, with, a, supernumerary, marker, chromosome, '(', 'SMC)', have, 'Y', chromosome, sequences, '(', group, 'D)'])].
[sujeto(['This', study, used, a, reliable, and, sensitive, methodology, to, identify, the, presence, of, 'Y', chromosome, material, in, 'TS', patients, thus]), verbo([providing]), complemento([not, only, a, better, estimate, of, a, 'patient\'s', risk, in, developing, either, gonadoblastoma, or, another, form, of, gonadal, tumor, but, also, the, overall, incidence, of, cryptic, 'Y', mosaicism])].
[sujeto(['Regrowing', neurites, grew, atop, this, 'layer,', forming, 'non-uniform', patterns, that, were, similar, to, those, formed, by, endogenously]), verbo([expressed]), complemento(['laminin-1,', entactin, and, integrin, 'beta4,', but, not, fibronectin, or, tenascin])].
[sujeto(['In', cultures, grown, for, 42, h, and]), verbo([maintained]), complemento([in, three, different, growth, 'media,', all, regrowing, neurites, were, preferentially, associated, with, 'spindle-shaped', nonneural, cells])].
[sujeto(['The', spontaneous, and, preferential, association, of, neurites, in, culture, with, mitotic, 'Schwann', cells, highlights, the, potential, contribution, 'neurite-Schwann', cell, interactions, may]), verbo([have]), complemento([in, promoting, the, growth, and, regrowth, of, damaged, spiral, ganglion, neurons, in, the, cochlea])].
[sujeto(['Although', the, miRNAs, are]), verbo([involved]), complemento([in, breast, cancer, 'development,', their, axis, with, the, transcription, factors, that, show, therapeutic, potential, in, breast, cancer, is, largely, unknown])].
[sujeto(['Recently,', we, demonstrated, that, 'agonist-activated', 'Ahr']), verbo([induced]), complemento([a, highly, conserved, miRNA, 'cluster,', named, 'miR-212/132,', in, murine, cellular, immune, compartment])].
[sujeto(['Therefore,', current, study, was, performed, to, examine, if, this, miRNA, cluster]), verbo([mediates]), complemento([the, 'anti-metastatic', properties, of, 'Ahr', agonists])].
[sujeto(['The', 2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD)', and, 3, ',', 3, '\'', -, diindolylmethane, '(', 'DIM)', were, used, to]), verbo([activate]), complemento(['Ahr', in, 'MDA-MB-231', and, 'T47D', breast, cancer, cells])].
[sujeto(['Chromatin', immunoprecipitation, '(', 'ChIP)', assay, was, used, to, identify, the]), verbo([binding]), complemento(['site(s)', for, 'Ahr', on, 'miR-212/132', promoter])].
[sujeto(['For', prediction, of, potentially]), verbo([target]), complemento([gene, of, the, miRNA, 'cluster,', bioinformatics, analysis, was, carried, 'out,', and, to, test, 'targeting,', luciferase, activity, was, quantified])].
[sujeto(['The', 'miR-212/132', cluster, was, transcriptionally]), verbo([activated]), complemento([in, 'MDA-MB-231', and, 'T47D', cells, by, 'TCDD', and, 'DIM,', and, this, activation, was, regulated, by, 'Ahr'])].
[sujeto(['A', reciprocal, correlation, was, identified, between, 'Ahr', 'agonists-induced', 'miR-212/132', and, the, 'pro-metastatic', 'SRY-related', 'HMG-box4', '(', 'SOX4),', and, a, new, specific]), verbo([binding]), complemento([sites, for, 'miR-212/132', were, identified, on, the, untranslated, region, '(', 3, '\'', 'UTR)', of, 'SOX4'])].
[sujeto(['Further', in, vivo, studies, demonstrated, that, the, 'Ahr-miR-212/132-SOX4', module, was]), verbo([induced]), complemento([by, 'Ahr', activation])].
[sujeto(['Taken', 'together,', the, findings]), verbo([provide]), complemento([the, first, evidences, of, the, synergistic, 'anti-metastatic', properties, of, 'miR-212/132', cluster, through, suppression, of, 'SOX4'])].
[sujeto(['Also,', current, study]), verbo([suggest]), complemento([a, new, 'miRNA-based', mechanism, elucidating, the, 'anti-metastatic', properties, of, 'Ahr', 'agonists,', suggesting, possibility, of, using, 'miR-212/132', to, control, metastasis, in, breast, cancer, patients])].
[sujeto(['Goldfish', '(', 'Carassius', 'auratus)', and, zebrafish, '(', 'Danio', 'rerio)']), verbo([have]), complemento([utility, as, complementary, models, for, understanding, the, molecular, basis, and, functional, significance, of, exaggerated, neural, estrogen, biosynthesis])].
[sujeto(['Multiple', cytochrome, 'P450', aromatase, '(', 'P450arom)', cDNAs, that, derive, from, separate, gene, loci, '(', cyp19a, and, 'cyp19b)', are, differentially]), verbo([expressed]), complemento([in, brain, '(', 'P450aromB&gt;A)', and, ovary, '(', 'P450aromA&gt;B)', and, have, a, different, developmental, program, '(', 'B&gt;A)', and, response, to, estrogen, upregulation, '(', 'B', 'only)'])].
[sujeto(['As', measured, by]), verbo([increased]), complemento(['P450aromB', 'mRNA,', a, functional, estrogen, response, system, is, first, detected, 24, -, 48, h, 'post-fertilization', '(', 'hpf),', consistent, with, the, onset, of, estrogen, receptor, '(', 'ER)', expression, '(', 'alpha,', 'beta,', and, 'gamma)'])].
[sujeto(['The', 5, '\'', -, flanking, region, of, the, cyp19b, gene]), verbo([has]), complemento([a, 'TATA', 'box,', two, estrogen, response, elements, '(', 'EREs),', an, 'ERE', 'half-site', '(', 'ERE1/2),', a, nerve, growth, factor, 'inducible-B', protein, '(', 'NGFI-B)/Nur77', responsive, element, '(', 'NBRE)', binding, 'site,', and, a, sequence, identical, to, the, zebrafish, 'GATA-2', gene, neural, specific, enhancer])].
[sujeto(['The', cyp19a, promoter, region]), verbo([has]), complemento(['TATA', and, 'CAAT', 'boxes,', a, steroidogenic, 'factor-1', '(', 'SF-1)', binding, 'site,', and, two, aryl, hydrocarbon, receptor, '(', 'AhR)/AhR', nuclear, translocator, factor, '(', 'ARNT)', binding, motifs])].
[sujeto(['Both', genes]), verbo([have]), complemento([multiple, potential, 'SRY/SOX', binding, sites, '(', 16, and, 8, in, cyp19b, and, 'cyp19a,', 'respectively)'])].
[sujeto(['Luciferase', reporters]), verbo([have]), complemento([basal, promoter, activity, in, 'GH3', 'cells,', but, differences, '(', 'a&gt;b)', are, opposite, to, fish, pituitary, '(', 'b&gt;a)'])].
[sujeto(['When', microinjected, into, fertilized, zebrafish, 'eggs,', a, cyp19b, 'promoter-driven', green, fluorescent, protein, '(', 'GFP)', reporter, '(', but, not, 'cyp19a)', is]), verbo([expressed]), complemento([in, neurons, of, 30, -, 48, hpf, 'embryos,', most, prominently, in, retinal, ganglion, cells, '(', 'RGCs)', and, their, projections, to, optic, tectum])].
[sujeto(['Further', studies, are]), verbo([required]), complemento([to, identify, functionally, relevant, 'cis-elements', and, cellular, 'factors,', and, to, determine, the, regulatory, role, of, estrogen, in, neurodevelopment])].
[sujeto(['Diet', and, microbiome, derived, indole, derivatives, are, known, to]), verbo([activate]), complemento([the, ligand, induced, transcription, 'factor,', the, 'Aryl', hydrocarbon, 'Receptor', '(', 'AhR)'])].
[sujeto(['While', the, current, understanding, of, 'AhR', biology]), verbo([has]), complemento([confirmed, its, role, in, mucosal, 'lymphocytes,', its, function, in, intestinal, antigen, presenting, cells, '(', 'APCs)', is, poorly, understood])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, 'Cre-mediated', deletion, of, 'AhR', in, 'CD11c-expressing', cells, in, 'C57/BL6', mice, is, associated, with, altered, intestinal, epithelial, morphogenesis, in, vivo])].
[sujeto(['Moreover,', when, 'co-cultured', with, 'AhR-deficient', 'DCs', ex, 'vivo,', intestinal, organoids, showed, reduced, 'SRY', '(', sex, determining, region, 'Y)-box', 9, and]), verbo([increased]), complemento(['Mucin', 2, 'expression,', which, correlates, with, reduced, 'Paneth', cells, and, increased, goblet, cell, 'differentiation,', similar, to, the, data, obtained, in, vivo])].
[sujeto(['Further,', characterization, of, intestinal, 'APC', 'subsets,', devoid, of, 'AhR,', revealed, an, expression, pattern]), verbo([associated]), complemento([with, aberrant, intrinsic, 'Wnt', pathway, regulation])].
[sujeto(['At', a, functional, 'level,', the]), verbo([loss]), complemento([of, 'AhR', in, 'APCs', resulted, in, a, dysfunctional, epithelial, 'barrier,', associated, with, a, more, aggressive, chemically, induced, colitis, compared, to, wild, type, animals])].
[sujeto(['Our', results, are, consistent, with, a, model, whereby, the, 'AhR', signalling, pathway, may]), verbo([participate]), complemento([in, the, regulation, of, innate, immunity, through, intestinal, epithelium, development, and, mucosal, immunity])].
[sujeto(['In', the, 'male,', testosterone, '(', 'T)', secreted, by, the, developing, testes, defeminizes, 'LH']), verbo([release]), complemento(['mechanisms;', 'conversely,', perinatal, 'AhR', activation, by, 2, ',', 3, ',', 7, ',', 8, ',', -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD)', blocks, defeminization])].
[sujeto(['To', better, understand, developmental, mechanisms, altered, by, 'TCDD', 'exposure,', we, first, verified, that, neonatal, 'TCDD', exposure, in, male, rats]), verbo([prevented]), complemento([the, loss, of, 'AVPV', 'GABA/glutamate', neurons, that, are, critical, for, 'female-typical', 'LH', surge, release])].
[sujeto(['In', 'addition,', upstream, regulatory, analysis]), verbo([suggests]), complemento([that, both, estrogen, receptors, '(', 'ER)', and, androgen, receptors, '(', 'AR)', regulate, genes, targeted, by, 'TCDD'])].
[sujeto(['Of', the, 23, mRNAs]), verbo([found]), complemento([to, be, changed, by, 'TCDD', at, least, 2, -, fold, '(', 'p&lt;0'])].
[sujeto([5, ')', ',', most]), verbo([participate]), complemento([in, the, functions, identified, in, our, bioinformatics, analyses])].
[sujeto(['Several,', including, matrix, metallopeptidase, 9, and, 'SRY-box', 11, '(', 'Sox11),', are, known]), verbo([targets]), complemento([of, 'E2'])].
[sujeto(['CUG', triplet, 'repeat,', 'RNA']), verbo([binding]), complemento([protein, 2, '(', 'cugbp2)', is, particularly, interesting, because, it, is, 'sex-specific,', oppositely, regulated, by, estradiol, '(', 'E2)', and, 'TCDD'])].
[sujeto(['Moreover,', it]), verbo([regulates]), complemento([the, 'post-transcriptional', processing, of, molecules, previously, linked, to, sexual, differentiation, of, the, brain])].
[sujeto(['These', findings]), verbo([provide]), complemento([new, insights, into, how, 'TCDD', may, interfere, with, defeminization, of, 'LH', release, patterns])].
[sujeto(['Two', 'P450arom', mRNAs, which, derive, from, separate, gene, loci, '(', cyp19a, and, 'cyp19b)', are, differentially]), verbo([expressed]), complemento([in, brain, '(', 'b&gt;a)', and, ovary, '(', 'a&gt;b)', and, have, a, different, developmental, program, '(', 'b&gt;a)', and, estrogen, upregulation, '(', b, 'only)'])].
[sujeto(['Sequence', analysis, of, the, cyp19b, gene, approximately, 1.8, kb, upstream, of, the, transcription, start, site, revealed, a, 'TATA', box, at, nucleotide, '(', 'nt)', -, 30, ',', two, estrogen, responsive, elements, '(', 'EREs;', nt, -, 351, and, -, 211, ')', and, a, consensus]), verbo([binding]), complemento([site, '(', 'NBRE)', for, nerve, growth, factor, 'inducible-B', protein, '(', 'NGFI-B/Nur77)', at, -, 286, ',', which, includes, another, 'ERE', 'half-site'])].
[sujeto(['Also', present, were, a, sequence, at, nt, -, 399, '(', 'CCCTCCT)']), verbo([required]), complemento([for, neural, specificity, of, the, zebrafish, 'GATA-2', 'gene,', and, 16, copies, of, an, 'SRY/SOX', binding, motif])].
[sujeto(['The', 5, '\'', -, flanking, region, '(', approximately, 1.0, 'kb)', of, the, cyp19a, gene, had, 'TATA', '(', nt, -, 48, ')', and, 'CAAT', '(', nt, -, 71, ')', 'boxes,', a, steroidogenic, 'factor-1', '(', 'SF-1)']), verbo([binding]), complemento([site, '(', nt, -, 265, ')', ',', eight, copies, of, the, 'SRY/SOX', 'motif,', and, two, copies, of, a, recognition, site, for, binding, the, arylhydrocarbon, receptor, '(', 'AhR)/AhR', nuclear, translocator, factor, '(', 'ARNT)', heterodimer])].
[sujeto(['Tandem', analysis, of, cyp19a, and, cyp19b, promoters, in, living, zebrafish, embryos, can, be, a, useful, approach, for, identifying, 'cis-elements', and, cellular, factors]), verbo([involved]), complemento([in, the, correct, 'tissue-specific,', 'spatial,', temporal, and, estrogen, regulated, expression, of, aromatase, genes, during, 'CNS', and, gonadal, development])].
[sujeto(['ELISA', and, 'RT-PCR', were, used, to, measure, protein, and, mRNA, 'levels,', 'respectively,', of]), verbo([nuclear]), complemento([factor, '(', 'NF)-κB,', 'IL-1β,', 'IL-6', and, 'TNF-α'])].
[sujeto(['Donor', cell, numbers]), verbo([decreased]), complemento([over, time])].
[sujeto(['Pretreatment', with, triptolide, improved, graft, survival, both, 24, '(', 29.3, ±, 0.9, '%', ')', and, 72, h, '(', 17.5, ±, 1.2, '%', ')', after, transplantation, of, 'MSCs', and, resulted, in, a, 2.5, -, fold]), verbo([increase]), complemento([in, the, total, cell, number, 72, h, after, cell, transplantation])].
[sujeto(['The', mechanism, underlying, this, effect]), verbo([involves]), complemento([attenuating, the, inflammatory, response, via, inhibition, of, the, 'NF-κB', signaling, pathway])].
[sujeto(['Many', papers]), verbo([have]), complemento([shown, that, 'SRY', '(', 'sex-determining', region, 'Y)-box', '(', 'SOX)', family, genes, serve, as, either, tumor, suppressor, genes, '(', 'TSGs)', or, oncogenes, by, regulating, the, 'Wnt', signaling, pathway, in, different, cancers])].
[sujeto(['We']), verbo([have]), complemento([demonstrated, recently, that, epigenetic, silencing, of, 'SOX1', gene, occurs, frequently, in, cervical, cancer])].
[sujeto(['Overexpression', of, 'SOX1']), verbo([inhibited]), complemento([cell, 'proliferation,', anchorage, 'independency,', and, invasion, in, vitro])].
[sujeto(['SOX1']), verbo([suppressed]), complemento([tumor, growth, in, nonobese, 'diabetic/severe', combined, immunodeficiency, mice])].
[sujeto(['After', induction, of, 'SOX1', by, doxycycline, '(', 'DOX),', 'SOX1']), verbo([inhibited]), complemento([cell, growth, and, invasion, in, the, inducible, system])].
[sujeto(['SOX1']), verbo([inhibited]), complemento(['TCF-dependent', transcriptional, activity, and, the, 'Wnt', target, genes])].
[sujeto(['SOX1', also]), verbo([repressed]), complemento([the, invasive, phenotype, by, regulating, the, expression, of, 'invasion-related', genes])].
[sujeto(['Taken', 'together,', these, data]), verbo([suggest]), complemento([that, 'SOX1', can, function, as, a, tumor, suppressor, partly, by, interfering, with, 'Wnt/β-catenin', signaling, in, cervical, cancer])].
[sujeto(['BM-derived', 'MSCs', were, detected, by, 'RT-PCR', of, 'CD29', and, were, then, infused, into, the, tail, vein, of, female, rats, that, received, 'CCl4', injection, to]), verbo([induce]), complemento([liver, fibrosis])].
[sujeto(['MSCs', and, 'SIMV']), verbo([decreased]), complemento([liver, procollagens, 'I', and, 'III,', 'TIMP-1', and, endoglin, gene, 'expressions,', 'TGF-β1', 'immunostaining,', and, serum, liver, function, tests, compared, with, the, 'CCl4', group])].
[sujeto(['MMP-1', expression, was]), verbo([increased]), complemento([in, the, 'CCl4/MSCs', group])].
[sujeto(['Our', recent, studies]), verbo([have]), complemento([demonstrated, that, 'SRY', '(', sex, determining, region, 'Y)-box', 1, '(', 'SOX1)', and, secreted, 'frizzled-related', proteins, are, concomitantly, 'promoter-hypermethylated,', and, this, might, lead, to, abnormal, activation, of, the, 'Wnt', signaling, pathway, in, 'HCC'])].
[sujeto(['SOX1', encodes, a, transcription, factor]), verbo([involved]), complemento([in, the, regulation, of, embryonic, development, and, cell, fate, determination])].
[sujeto(['Overexpression', of, 'SOX1', by, a, constitutive, or, inducible, approach, could]), verbo([suppress]), complemento([cell, 'proliferation,', colony, 'formation,', and, invasion, ability, in, 'HCC', cell, 'lines,', as, well, as, tumor, growth, in, nonobese, 'diabetic/severe', combined, immunodeficiency, mice])].
[sujeto(['We', used, a, 'T', cell, factor, '(', 'TCF)-responsive', luciferase, reporter, assay, and, western, blot, analysis, to, prove, that, 'SOX1', could]), verbo([regulate]), complemento(['TCF-responsive', transcriptional, activity, and, inhibit, the, expression, of, 'Wnt', downstream, genes])].
[sujeto(['Furthermore,', we, used, glutathione, 'S-transferase', 'pull-down,', 'co-immunoprecipitation,', and, confocal, microscopy, to, demonstrate, that, 'SOX1', could]), verbo([interact]), complemento([with, 'β-catenin', but, not, with, the, 'β-catenin/TCF', complex])].
[sujeto(['Moreover,', restoration, of, the, expression, of, 'SOX1']), verbo([induces]), complemento([significant, cellular, senescence, in, 'Hep3B', cells])].
[sujeto(['MSCs', were, mainly, distributed, in, the, glomerular, capillaries, at, the, time, points, of, 6, h, and, 48, 'h,', but, the, number, of, 'MSCs', in, glomerular, capillaries]), verbo([decreased]), complemento([and, those, in, renal, mesenchyma, increased, at, the, time, points, from, 10, d, to, 60, d, 'gradually,', then, tended, to, a, steady, 'state,', meanwhile, it, showed, a, stable, increasing, trend, in, renal, tubule])].
[sujeto(['Cell', colony, of, 'MSCs', could, be]), verbo([found]), complemento([in, mesenchyma, with, a, slowed, down, increasing, between, 30, d, to, 60, 'd,', but, the, increasing, in, tubule, was, still, steady])].
[sujeto(['MSCs', transplantation]), verbo([has]), complemento([beneficial, effects, on, 'CAAN,', which, is, possibly, related, with, the, reduction, of, 'PTC'])].
[sujeto(['The', results, indicate, that, 'X-', or, 'Y-linked', genes]), verbo([have]), complemento([direct, 'effects,', not, mediated, by, gonadal, 'secretions,', on, sex, differences, in, two, different, types, of, acute, nociception])].
[sujeto(['Recent', studies]), verbo([have]), complemento([shown, that, hematopoietic, bone, marrow, '(', 'BM)', 'stem/progenitor', cells, can, give, rise, to, hepatocytes, in, 'diseased/damaged', liver])].
[sujeto(['One', study]), verbo([has]), complemento([reported, that, 'BM', cells, can, transdifferentiate, into, liver, 'progenitor/oval', 'cells,', but, it, has, not, been, proven, that, the, latter, can, repopulate, the, liver])].
[sujeto(['To', answer, this, 'question,', we]), verbo([have]), complemento([lethally, irradiated, female, 'DPP4(-)', mutant, 'F344', rats, and, transplanted, them, with, 50, million, 'wild-type', male, 'F344', 'BM', cells])].
[sujeto(['A', 'real-time', 'PCR-based', gene, expression, survey, was, performed, on, isolated, 'European']), verbo([sea]), complemento([bass, follicles, from, primary, growth, to, late, vitellogenesis])].
[sujeto([',', the, beginning, of, the, secondary, growth, 'phase)', showed, elevated, mRNA, amounts, of, follicle]), verbo([stimulating]), complemento([hormone, receptor, '(', 'fshr)', and, 'anti-Mullerian', hormone])].
[sujeto(['Early-to-mid', vitellogenic, follicles, showed, high, mRNA, levels, of, fshr, and, cytochrome, 'P450,', family, 19, ',', subfamily, 'A,', polypeptide, 1, a, while, 'mid-to-late', vitellogenic, follicles]), verbo([expressed]), complemento([increasing, transcript, amounts, of, luteinizing, 'hormone/choriogonadotropin', 'receptor,', steroidogenic, acute, regulatory, 'protein,', and, estrogen, receptors, 1, and, 2, a])].
[sujeto(['Fetoprotein', transcription, factor, '(', 'FTF)', is, an, orphan]), verbo([nuclear]), complemento([receptor, that, activates, the, 'alpha(1)-fetoprotein', gene, during, early, liver, developmental, growth])].
[sujeto(['Here', we, sought, to, define, better, the, position, of, 'FTF', in, transcriptional, cascades]), verbo([leading]), complemento([to, hepatic, differentiation])].
[sujeto(['The', mFTF, transcription, initiation, site, was, located, in, adult, liver, at, 238, nucleotides, from, the, first, translation, initiator, 'codon,', with, six, canonical, 'GATA,', 'E', 'box,', and, 'Nkx', motifs, clustered, between, -, 50, /, -, 140, base, pairs, '(', 'bp)', from, the, cap, 'site;', 'DNA/protein']), verbo([binding]), complemento([assays, also, pinpointed, an, 'HNF4-binding', element, at, +, 36, bp, and, an, 'FTF-binding', element, at, -, 257, bp])].
[sujeto(['Transfection', assays, and, point, mutations, showed, that, the, mFTF, promoter, is]), verbo([activated]), complemento([by, 'GATA,', 'HNF4alpha,', 'FTF,', 'Nkx,', and, basic, 'helix-loop-helix', 'factors,', with, marked, cooperativity, between, 'GATA', and, 'HNF4alpha'])].
[sujeto(['Three', genes, encoding, transcription, factors, critical, to, early, hepatic, 'differentiation,', 'Hnf3beta,', 'Hnf4alpha,', and, 'Hnf1alpha,', each, contain, dual, 'FTF-binding', elements, in, their, proximal, 'promoters,', and, all, three, promoters, are]), verbo([activated]), complemento([by, 'FTF', in, transfection, assays])].
[sujeto(['Direct', 'DNA']), verbo([binding]), complemento([action, and, cooperativity, was, demonstrated, between, 'FTF', and, 'HNF3beta', on, the, 'Hnf3beta', promoter, and, between, 'FTF', and, 'HNF4alpha', on, the, 'Hnf1alpha', promoter])].
[sujeto(['These', combined, results]), verbo([suggest]), complemento([that, 'FTF', is, an, early, intermediary, between, endodermal, specification, signals, and, downstream, genes, that, establish, and, amplify, the, hepatic, phenotype])].
[sujeto(['The', definitive, endoderm, 'marker,', 'FoxA2', is, the, key, transcriptional, factor, that]), verbo([regulates]), complemento([cell, differentiation, and, tissue, regeneration])].
[sujeto(['We', demonstrated, that, 'FoxA2', was, notably]), verbo([enhanced]), complemento([in, murine, liver, progenitor, cells, and, 'SMCCs,', and, was, silenced, in, human, 'PSC', and, 'PBC', liver, tissues, relative, to, respective, controls, that, are, correlated, with, the, epigenetic, methylation, enzymes, 'DNMT1', and, 'DNMT3B'])].
[sujeto(['Furthermore,', activation, of, fibrosis, signaling, pathways, were, observed, in, 'BDL/MDR2(-/-)', mouse, liver, as, well, as, in, isolated, hepatic, stellate, cells, by, laser, capture, 'microdissection,', and, these, signals, were, recovered, along, with, reduced, hepatic, senescence, and]), verbo([enhanced]), complemento([hepatic, stellate, cellular, senescence, after, 'SMCC', engraft])].
[sujeto(['The', definitive, endoderm, marker, and, the, positive, regulator, of, biliary, 'development,', 'FoxA2,']), verbo([mediates]), complemento([the, therapeutic, effect, of, 'biliary-committed', progenitor, cells, during, cholestatic, liver, injury])].
[sujeto(['The', majority, of, mutations, were, 'novel,']), verbo([loss]), complemento([of, function, '(', 'LOF)', '(', 78.4, '%', ')', 'mutations,', and, most, disrupted, the, 'DNA-binding', domain, '(', 58.8, '%', ')'])].
[sujeto(['Mutation', status, was]), verbo([associated]), complemento([with, tumor, grade, and, not, associated, with, survival, outcomes])].
[sujeto(['Most', tumors]), verbo([expressed]), complemento(['FOXA2', at, both, the, mRNA, and, protein, level])].
[sujeto(['In', those, tumors, with, 'mutations,', the, majority, of, cases]), verbo([expressed]), complemento([both, alleles])].
[sujeto(['The', pattern, of, 'FOXA2', mutations, and, expression, in, tumors]), verbo([suggests]), complemento([complex, regulation, and, a, haploinsufficient, or, 'dominant-negative', tumor, suppressor, function])].
[sujeto(['Insulin', is, a, crucial, mediator, of, the, glucose, and, lipid, metabolism, that]), verbo([has]), complemento([been, implicated, in, atherosclerotic, and, inflammatory, processes])].
[sujeto(['Important', mediators, of, insulin, signaling, such, as, 'Liver', 'X', 'Receptors', '(', 'LXRs)', and, 'Forkhead', 'Box', 'A2', '(', 'FOXA2)', are, known, to]), verbo([regulate]), complemento(['apoA-I', expression, in, liver])].
[sujeto(['Forkhead', 'Box', 'O1', '(', 'FOXO1)', is, a, 'well-known']), verbo([target]), complemento([of, insulin, signaling, and, a, key, mediator, of, oxidative, stress, response])].
[sujeto(['Low', doses, of, insulin, were, shown, to]), verbo([activate]), complemento(['apoA-I', expression, in, human, hepatoma, 'HepG2', cells])].
[sujeto(['Treatment', of, 'HepG2', cells, with, high, doses, of, insulin, '(', 48, 'hours,', 100, 'nM)']), verbo([suppresses]), complemento(['apoA-I', gene, expression])].
[sujeto(['FOXO1', forms, a, complex, with, 'LXRβ', and, insulin, treatment, impairs, 'FOXO1/LXRβ', complex]), verbo([binding]), complemento([to, hepatic, enhancer, and, triggers, its, nuclear, export])].
[sujeto(['Insulin', as, well, as, 'LXR', ligand, 'TO901317']), verbo([enhance]), complemento([the, interaction, between, 'FOXA2,', 'LXRα', and, hepatic, enhancer])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, high, doses, of, insulin, downregulate, 'apoA-I', gene, expression, in, 'HepG2', cells, through, redistribution, of, 'FOXO1/LXRβ', 'complex,', 'FOXA2', and, 'LXRα', on, hepatic, enhancer, of, 'apoA-I', gene])].
[sujeto(['Genes', significantly]), verbo([associated]), complemento([with, baseline, seizure, frequency, on, likelihood, ratio, test, were, identified, based, on, &, 'gt;0'])].
[sujeto(['Expression', levels, of, forty, genes, were, significantly]), verbo([associated]), complemento([with, baseline, seizure, frequency])].
[sujeto(['Of', the, seven, most, 'significant,', four]), verbo([have]), complemento([been, linked, to, other, neurologic, diseases])].
[sujeto(['Expression', levels]), verbo([associated]), complemento([with, high, seizure, frequency, included, low, expression, of, 'Homeobox', 'A10,', 'Forkhead', box, 'A2,', 'Lymphoblastic', leukemia, derived, sequence, 1, ',', 'HGF', 'activator,', 'Kelch', repeat, and, 'BTB', '(', 'POZ)', domain, containing, 11, ',', 'Thanatos-associated', protein, domain, containing, 8, and, 'Heparin', sulfate, '(', 'glucosamine)', 3, -, 'O-sulfotransferase', 3, 'A1'])].
[sujeto(['Four', of, the, seven, discussed]), verbo([have]), complemento([been, previously, related, to, other, neurologic, diseases])].
[sujeto(['Future', investigation, of, these, genes, could, establish, new, biomarkers, for, predicting, 'epileptogenicity,', and, could]), verbo([have]), complemento([significant, implications, for, diagnosis, and, management, of, temporal, lobe, 'epilepsy,', as, well, as, epilepsy, pathogenesis])].
[sujeto(['Pancreatic', cancer, is, the, fourth]), verbo([leading]), complemento([cause, of, cancer, death, in, the, 'United', 'States'])].
[sujeto(['Restoration', of, 'miR-1291', expression]), verbo([inhibited]), complemento([pancreatic, cancer, cell, 'proliferation,', which, was, associated, with, cell, cycle, arrest, and, enhanced, apoptosis])].
[sujeto(['Furthermore,', 'miR-1291', sharply]), verbo([suppressed]), complemento([the, tumorigenicity, of, 'PANC-1', cells, in, mouse, models])].
[sujeto(['Through', computational, and, experimental, studies, we, further, identified, that, forkhead, box, protein, 'A2', '(', 'FOXA2),', a, transcription, factor, governing, 'AGR2', 'expression,', was, a, direct]), verbo([target]), complemento([of, 'miR-1291'])].
[sujeto(['These', results, connect, 'miR-1291', to, the, 'FOXA2-AGR2', regulatory, pathway, in, the, suppression, of, pancreatic, cancer, cell, proliferation, and, 'tumorigenesis,']), verbo([providing]), complemento([new, insight, into, the, development, of, 'miRNA-based', therapy, to, combat, pancreatic, cancer])].
[sujeto(['Since', 'LAL-deficient', '(', 'Lal', '(', -, /, -, ')', ')', mice, suffer, from, progressive]), verbo([loss]), complemento([of, adipose, tissue, and, severe, accumulation, of, lipids, in, hepatic, 'lysosomes,', we, hypothesised, that, 'LAL', deficiency, triggers, alternative, energy, 'pathway(s)'])].
[sujeto(['Despite']), verbo([loss]), complemento([of, adipose, 'tissue,', 'Lal', '(', -, /, -, ')', mice, show, enhanced, glucose, clearance, during, insulin, and, glucose, tolerance, tests, and, have, increased, uptake, of, '[', '(', 3, ')', 'H]2-deoxy-D-glucose', into, skeletal, muscle, compared, with, 'wild-type', mice])].
[sujeto(['We', observed, 84, '%']), verbo([decreased]), complemento([plasma, leptin, levels, and, significantly, reduced, hepatic, 'ATP,', 'glucose,', glycogen, and, glutamine, concentrations, in, fed, 'Lal', '(', -, /, -, ')', mice])].
[sujeto(['Markedly', reduced, hepatic, 'acyl-CoA', concentrations]), verbo([decrease]), complemento([the, expression, of, peroxisome, 'proliferator-activated', receptor, α, '(', 'PPARα)', target, genes])].
[sujeto(['However,', treatment, of, 'Lal', '(', -, /, -, ')', mice, with, the, 'PPARα', agonist, fenofibrate, further]), verbo([decreased]), complemento([plasma, 'TG', '(', and, hepatic, glucose, and, 'glycogen)', concentrations, in, 'Lal', '(', -, /, -, ')', mice])].
[sujeto(['Depletion', of, hepatic]), verbo([nuclear]), complemento([factor, 4, α, and, forkhead, box, protein, a2, in, fasted, 'Lal', '(', -, /, -, ')', mice, might, be, responsible, for, reduced, expression, of, microsomal, 'TG', transfer, 'protein,', defective, 'VLDL', synthesis, and, drastically, reduced, plasma, 'TG', levels])].
[sujeto(['We', conclude, that]), verbo([decreased]), complemento([plasma, 'VLDL', production, enhances, glucose, uptake, into, skeletal, muscle, to, compensate, for, the, lack, of, energy, supply])].
[sujeto(['Genome-wide', association, studies, '(', 'GWAS)', of, type, 2, diabetes, '(', 'T2D)']), verbo([have]), complemento([discovered, a, number, of, loci, that, contribute, to, susceptibility, to, the, disease])].
[sujeto(['Future', challenges, include, elucidation, of, functional, mechanisms, through, which, these, 'GWAS-identified', loci]), verbo([modulate]), complemento(['T2D', disease, risk])].
[sujeto(['The', aim, of, the, present, study, was, to, comprehensively, characterize, 'T2D']), verbo([associated]), complemento([single, nucleotide, polymorphisms, '(', 'SNPs)', and, genes, through, computational, approaches])].
[sujeto(['Computational', biology, approaches, used, in, the, present, study, included, comparative, genomic, analyses, and, functional, annotation, using, 'GWAS3D', and, 'RegulomeDB,', investigation, of, the, effects, of, 'T2D-associated', 'SNPs', on, miRNA]), verbo([binding]), complemento([and, protein, 'phosphorylation,', and, gene, 'ontology,', pathway, 'enrichment,', 'protein-protein', interaction, '(', 'PPI)', networks, and, functional, module, analysis, of, 'T2D-associated', genes, from, previously, published, 'GWAS'])].
[sujeto(['Computational', analysis, identified, a, number, of, 'T2D', 'GWAS-associated', 'SNPs', that, were, located, at, protein]), verbo([binding]), complemento(['sites,', including, 'CCCTC-binding', factor, '(', 'CTCF),', 'E1A', binding, protein, p300, '(', 'EP300),', hepatocyte, nuclear, factor, 4, alpha, '(', 'HNF4A),', transcription, factor, 7, like, 2, '(', 'TCF7L2),', forkhead, box, 'A1', '(', 'FOXA1)', and, 'A2', '(', 'FOXA2),', and, potentially, affected, the, binding, of, miRNAs, and, protein, phosphorylation])].
[sujeto(['The', results]), verbo([provide]), complemento([objectives, and, clues, for, future, experimental, studies, and, further, insights, into, the, molecular, pathogenesis, of, 'T2D'])].
[sujeto(['Mutations', in, hepatocyte]), verbo([nuclear]), complemento([factor, 1, transcription, factors, '(', 'HNF1α/β)', are, associated, with, diabetes])].
[sujeto(['However,', they, also]), verbo([have]), complemento([an, important, role, in, the, biology, of, many, other, 'tissues,', including, the, intestine])].
[sujeto(['We', used, chromatin, immunoprecipitation, followed, by, direct, sequencing, '(', 'ChIP-seq)', to, identify, 'HNF1']), verbo([binding]), complemento([sites, 'genome-wide'])].
[sujeto(['Direct']), verbo([targets]), complemento([of, 'HNF1', were, validated, using, conventional, 'ChIP', assays, and, confirmed, by, 'siRNA-mediated', depletion, of, 'HNF1,', followed, by, 'RT-qPCR'])].
[sujeto(['Gene', ontology, process, enrichment, analysis, of, the, 'HNF1']), verbo([targets]), complemento([identified, multiple, processes, with, a, role, in, intestinal, epithelial, cell, 'function,', including, properties, of, the, cell, 'membrane,', cellular, response, to, 'hormones,', and, regulation, of, biosynthetic, processes])].
[sujeto(['Approximately', 50, '%', of, 'HNF1']), verbo([binding]), complemento([sites, were, also, occupied, by, other, members, of, the, intestinal, transcriptional, 'network,', including, hepatocyte, nuclear, factor, 4, 'A', '(', 'HNF4A),', caudal, type, homeobox, 2, '(', 'CDX2),', and, forkhead, box, 'A2', '(', 'FOXA2)'])].
[sujeto(['Depletion', of, 'HNF1', in, 'Caco2', cells]), verbo([increases]), complemento(['FOXA2', abundance, and, decreases, levels, of, 'CDX2,', illustrating, the, coordinated, activities, of, the, network])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'HNF1', plays, an, important, role, in, regulating, intestinal, epithelial, cell, 'function,', both, directly, and, through, interactions, with, other, intestinal, transcription, factors])].
[sujeto(['The', transcription, factor, forkhead, box, protein, 'A2', '(', 'FOXA2,', also, known, as, hepatocyte]), verbo([nuclear]), complemento([factor, 3, β, or, transcription, factor, 3, 'β),', has, been, found, to, play, pivotal, roles, in, multiple, phases, of, mammalian, 'life,', from, the, early, development, to, the, 'organofaction,', and, subsequently, in, homeostasis, and, metabolism, in, the, adult])].
[sujeto(['In', the, embryonic, development, 'period,', 'FOXA2', is]), verbo([require]), complemento([d, for, the, formation, of, the, primitive, node, and, 'notochord,', and, its, absence, results, in, embryonic, lethality])].
[sujeto(['Leukotriene', pathway, and, signal, transducers, and, activators, of, transcription, 6, pathway, may]), verbo([mediate]), complemento([this, inflammation, through, recruitment, and, activation, of, denditric, cell, during, lung, developments])].
[sujeto(['FOXA2', is, a, potential, treatment]), verbo([target]), complemento([for, lung, diseases, with, 'Th2', inflammation, and, goblet, cell, 'hyperplasia,', such, as, asthma, and, chronic, obstructive, pulmonary, disease])].
[sujeto(['In', this, 'study,', by, using, a, combination, of, chemical, inhibition, and, genetic, approaches, in, zebrafish, and, murine, 'cells,', we, identify, a, mechanism, by, which, cPLA2α]), verbo([promotes]), complemento([cell, proliferation])].
[sujeto(['We', identified, 2, cpla2α, genes, in, 'zebrafish,', cpla2αa, and, 'cpla2αb,', with]), verbo([conserved]), complemento([phospholipase, activity])].
[sujeto(['In', 'zebrafish,']), verbo([loss]), complemento([of, cpla2α, expression, or, inhibition, of, cpla2α, activity, diminished, 'G1', progression, through, the, cell, cycle])].
[sujeto(['We', further, show, that, 'PGE2,', through, 'PI3K/AKT', 'activation,']), verbo([promoted]), complemento(['Forkhead', box, protein, 'O1', '(', 'FOXO1)', phosphorylation, and, 'FOXO1', nuclear, export])].
[sujeto(['This']), verbo([led]), complemento([to, 'up-regulation', of, cyclin, 'D1', and, 'down-regulation', of, 'p27(Kip1),', thus, promoting, 'G1', progression])].
[sujeto(['Finally,', using, pharmacologic, 'inhibitors,', we, show, that, 'cPLA2α,', rapidly, accelerated, fibrosarcoma, '(', 'RAF)/MEK/ERK,', and, 'PI3K/AKT', signaling, pathways, cooperatively]), verbo([regulate]), complemento(['G1', progression, in, response, to, 'platelet-derived', growth, factor, stimulation])].
[sujeto(['In', 'summary,', these, data, indicate, that, 'cPLA2α,', through, its, phospholipase, 'activity,', is, a, critical, effector, of, 'G1', phase, progression, through, the, cell, cycle, and]), verbo([suggest]), complemento([that, pharmacological, targeting, of, this, enzyme, may, have, important, therapeutic, benefits, in, disease, mechanisms, that, involve, excessive, cell, 'proliferation,', in, 'particular,', cancer, and, proliferative, glomerulopathies])].
[sujeto(['The']), verbo([nuclear]), complemento(['receptor,', pregnane, 'X', receptor, '(', 'PXR),', is, a, key, transcription, factor, for, the, 'xenobiotic-induced', expression, of, genes, associated, with, various, liver, functions])].
[sujeto(['Recently,', we]), verbo([reported]), complemento([that, 'PXR', activation, stimulates, 'xenobiotic-induced', hepatocyte, proliferation])].
[sujeto(['In', the, present, 'study,', we, investigated, whether, 'PXR', activation, also]), verbo([stimulates]), complemento([growth, 'factor-mediated', hepatocyte, proliferation])].
[sujeto(['In', 'G0', 'phase-synchronized,', immortalized, mouse, 'hepatocytes,', serum, or, epidermal, growth, factor, treatment]), verbo([increased]), complemento([cell, growth, and, this, growth, was, augmented, by, the, expression, of, mouse, 'PXR', and, 'co-treatment', with, pregnenolone, 16, 'α-carbonitrile', '(', 'PCN),', a, 'PXR', ligand])].
[sujeto(['In', a, liver, regeneration, model, using, carbon, 'tetrachloride,', 'PCN', treatment]), verbo([enhanced]), complemento([the, 'injury-induced', increase, in, the, number, of, 'Ki-67-positive', nuclei, as, well, as, 'Ccna2', and, 'Ccnb1', mRNA, levels, in, 'wild-type', '(', 'WT)', but, not, 'Pxr-null', mice])].
[sujeto(['Chronological', analysis, of, this, model, demonstrated, that, 'PCN', treatment, shifted, the, maximum, cell, proliferation, to, an, earlier, time, point, and]), verbo([increased]), complemento([the, number, of, 'M-phase', cells, at, those, time, points])].
[sujeto(['In', 'WT', but, not, 'Pxr-null', 'mice,', 'PCN', treatment, reduced, hepatic, mRNA, levels, of, genes]), verbo([involved]), complemento([in, the, suppression, of, 'G0/G1-', and, 'G1/S-phase', 'transition,', e])].
[sujeto(['Analysis', of, the, 'Rbl2', promoter, revealed, that, 'PXR', activation]), verbo([inhibited]), complemento([its, 'Forkhead', box, 'O3', '(', 'FOXO3)-mediated', transcription])].
[sujeto(['Finally,', the, 'PXR-mediated', enhancement, of, hepatocyte, proliferation, was]), verbo([inhibited]), complemento([by, the, expression, of, dominant, active, 'FOXO3', 'in&nbsp;vitro'])].
[sujeto(['The', results, of, the, present, study]), verbo([suggest]), complemento([that, 'PXR', activation, stimulates, growth, 'factor-mediated', hepatocyte, proliferation, in, 'mice,', at, least, in, 'part,', through, inhibiting, 'FOXO3', from, accelerating, 'cell-cycle', progression])].
[sujeto(['The']), verbo([binding]), complemento([activity, of, 'H3/H4', histone, on, the, 'Ets-1', 'promoter,', and, that, of, forkhead, box, '(', 'FOX)A2,', 'FOXO1', and, 'Ets-1', on, the, 'Pdx-1', promoter, was, measured, by, chromatin, immunoprecipitation, and, quantitative, 'real-time', 'PCR', assay])].
[sujeto(['High', glucose]), verbo([induced]), complemento([upregulation, of, 'Ets-1', expression, and, hyperacetylation, of, histone, 'H3', and, 'H4', at, the, 'Ets-1', gene, promoter, in, beta, cells])].
[sujeto(['Ets-1', overexpression, dramatically]), verbo([suppressed]), complemento([insulin, secretion, and, biosynthesis, both, in, vivo, and, in, vitro])].
[sujeto(['Besides,', 'Ets-1', overexpression]), verbo([increased]), complemento([the, activity, of, 'FOXO1', but, decreased, that, of, 'FOXA2', binding, to, the, pancreatic, and, duodenal, homeobox, 1, '(', 'PDX-1)', homology, region, 2, '(', 'PH2),', resulting, in, inhibition, of, 'Pdx-1', promoter, activity, and, downregulation, of, 'PDX-1', expression, and, activity])].
[sujeto(['In', 'addition,', high, glucose]), verbo([promoted]), complemento([the, interaction, of, 'Ets-1', and, 'FOXO1,', and, the, activity, of, 'Ets-1', binding, to, the, 'Pdx-1', promoter])].
[sujeto(['Importantly,', 'PDX-1', overexpression, reversed, the, defect, in, pancreatic, beta, cells]), verbo([induced]), complemento([by, 'Ets-1', 'excess,', while, knockdown, of, 'Ets-1', prevented, 'hyperglycaemia-induced', dysfunction, of, pancreatic, beta, cells])].
[sujeto(['Our', observations]), verbo([suggest]), complemento([that, 'Ets-1', links, glucotoxicity, to, pancreatic, beta, cell, dysfunction, through, inhibiting, 'PDX-1', expression, in, type, 2, diabetes])].
[sujeto(['Cellular', metabolism, is, increasingly]), verbo([recognized]), complemento([as, a, controller, of, immune, cell, fate, and, function])].
[sujeto(['MicroRNA-33', '(', 'miR-33)']), verbo([regulates]), complemento([cellular, lipid, metabolism, and, represses, genes, involved, in, cholesterol, 'efflux,', 'HDL', 'biogenesis,', and, fatty, acid, oxidation])].
[sujeto(['Macrophage-specific', 'Mir33', deletion]), verbo([increased]), complemento([oxidative, 'respiration,', enhanced, spare, respiratory, 'capacity,', and, induced, an, 'M2', macrophage, 'polarization-associated', gene, profile])].
[sujeto(['Furthermore,', 'miR-33-mediated', 'M2', polarization]), verbo([required]), complemento(['miR-33', targeting, of, the, energy, sensor, 'AMP-activated', protein, kinase, '(', 'AMPK),', but, not, cholesterol, efflux])].
[sujeto(['Notably,', 'miR-33', inhibition]), verbo([increased]), complemento([macrophage, expression, of, the, retinoic, 'acid-producing', enzyme, aldehyde, dehydrogenase, family, 1, ',', subfamily, 'A2', '(', 'ALDH1A2)', and, retinal, dehydrogenase, activity, both, in, vitro, and, in, a, mouse, model])].
[sujeto(['Consistent', with, the, ability, of, retinoic, acid, to, foster, inducible, 'Tregs,', 'miR-33-depleted', macrophages, had, an]), verbo([enhanced]), complemento([capacity, to, induce, forkhead, box, 'P3', '(', 'FOXP3)', expression, in, naive, 'CD4(+)', 'T', cells])].
[sujeto(['Collectively,', these, results]), verbo([reveal]), complemento([that, 'miR-33', regulates, macrophage, inflammation, and, demonstrate, that, 'miR-33', antagonism, is, 'atheroprotective,', in, 'part,', by, reducing, plaque, inflammation, by, promoting, 'M2', macrophage, polarization, and, 'Treg', induction])].
[sujeto(['IL-13']), verbo([increases]), complemento([mucin, '(', 'MUC)', 5, 'AC,', the, major, component, of, airway, 'mucus,', in, airway, epithelial, cells])].
[sujeto(['According', to, the, 'literature,', 'IL-13', receptor, activation]), verbo([leads]), complemento([to, 'STAT6', activation, and, consequent, induction, of, chloride, channel, accessory, 1, '(', 'CLCA1)', gene, 'expression,', associated, with, the, induction, of, 'MUC5AC'])].
[sujeto(['Heme', 'oxygenase-1', '(', 'HO-1)', is, an, enzyme, that, catalyzes, oxidation, of, heme, to, 'biliverdin,', and]), verbo([has]), complemento(['anti-inflammatory', and, 'anti-oxidant', properties])].
[sujeto(['We', examined, the, effects, of, 'HO-1', on, mucin, production, and, goblet, cell, hyperplasia]), verbo([induced]), complemento([by, 'IL-13'])].
[sujeto(['Hemin', '(', 4, 'μM)', significantly]), verbo([increased]), complemento(['HO-1', protein, expression, '(', p, b, 0.01, ')', and, 'HO-1', mRNA, expression, '(', p, b, 0.001, ')'])].
[sujeto(['IL-13', significantly]), verbo([increased]), complemento([goblet, 'cells,', 'MUC5AC', protein, secretion, '(', p, b, 0.01, ')', and, 'MUC5AC', mRNA, '(', p, b, 0.001, ')', ',', and, these, were, decreased, by, hemin, by, way, of, 'HO-1'])].
[sujeto(['Hemin']), verbo([decreased]), complemento([the, expression, of, 'CLCA1', mRNA, '(', p, b, 0.05, ')', and, it, was, reversed, by, 'SnPP-IX,', but, could, not, suppress, 'IL-13-induced', phosphorylation, of, 'STAT6', or, 'SAM', pointed, 'domain-containing', 'ETS', transcription, factor, '(', 'SPDEF)', and, 'Forkhead', box, 'A2', '(', 'FOXA2)', mRNA, expression])].
[sujeto(['In', 'summary,', 'HO-1', overexpression]), verbo([suppressed]), complemento(['IL-13-induced', goblet, cell, hyperplasia, and, 'MUC5AC', 'production,', and, involvement, of, 'CLCA1', in, the, mechanism, was, suggested])].
[sujeto(['To', show, the, efficient, generation, of, 'hepatocyte-like', cells, '(', 'HLCs)', differentiated, from, the]), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'iPSCs)', of, rats])].
[sujeto(['Then', fibroblast, growth, factor, 4, and, bone, morphogenetic, protein, 2, were, added, to, the, culture, medium, and, used, to]), verbo([induce]), complemento([hepatic, differentiation])].
[sujeto(['After', endodermal, 'induction,', the, differentiated, cells]), verbo([expressed]), complemento([endodermal, markers, forkhead, box, protein, 'A2', and, 'SRY-box', containing, gene, 17, at, the, mRNA, and, protein, levels])].
[sujeto(['These', differentiated, cells]), verbo([expressed]), complemento([hepatic, markers, including, 'α-fetoprotein,', albumin, 'CK8,', 'CK18,', 'CK19,', and, transcription, factor, 'HNF-4α'])].
[sujeto(['In', 'addition,', the, cells]), verbo([expressed]), complemento([functional, proteins, such, as, 'α1-antitrypsin,', cytochrome, 'P450', 1, 'A2', and, 'CYP', 3, 'A4'])].
[sujeto(['They']), verbo([acted]), complemento([like, healthy, hepatic, 'cells,', storing, glycogen, and, taking, up, indocyanine, green, and, 'low-density', lipoproteins])].
[sujeto(['Also,', the, rates, of, urea, synthesis, '(', 20, d, 1.202, ±, 0.08, 'mg/dL', vs, 0, d, 0.317, ±, 0.021, 'mg/dL,', 'P', &, 'lt;', 0.01, ')', and, albumin, secretion, '(', 20, d, 1.601, ±, 0.102, 'mg/dL', vs, 0, d, 0.313, ±, 0.015, 'mg/dL,', 'P', &, 'lt;', 0.01, ')']), verbo([increased]), complemento([significantly, as, differentiation, progressed])].
[sujeto(['Hepatocyte-like', cells, differentiated, from, human, pluripotent, stem, cells, '(', such, as, human, embryonic, stem, '(', 'ES)', cells, and]), verbo([induced]), complemento([pluripotent, stem, '(', 'iPS)', 'cells)', are, expected, to, be, utilized, in, drug, screening])].
[sujeto(['To']), verbo([enhance]), complemento([this, hepatocyte, differentiation, 'efficiency,', 'hepatocyte-related', transcription, 'factors,', such, as, forkhead, box, protein, 'A2', '(', 'FOXA2)', and, hepatocyte, nuclear, factor, 1, alpha, '(', 'HNF1α),', were, overexpressed, during, the, hepatocyte, differentiation, process])].
[sujeto(['In', 'addition,', to]), verbo([enhance]), complemento([the, functions, of, 'hepatocyte-like', 'cells,', these, cells, were, cultured, in, three, dimensional, '(', 3, 'D)', conditions, using, a, 'Nanopillar', plate])].
[sujeto(['Various', hepatic, 'functions,', including, albumin, secretion, and, drug, metabolism, 'capacities,', of, the, 'hepatocyte-like', cells, were, significantly]), verbo([enhanced]), complemento([by, performing, 3, 'D', cell, culture])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, method, of, hepatocyte, differentiation, could, be, improved, by, using, gene, transfer, and, 3, 'D', cell, culture, technologies])].
[sujeto(['The', enterohormone, 'glucagon-like', 'peptide-1', '(', 'GLP-1)', is]), verbo([required]), complemento([to, amplify, 'glucose-induced', insulin, secretion, that, facilitates, peripheral, glucose, utilisation])].
[sujeto(['Alteration', in, 'GLP-1', secretion, during, obesity]), verbo([has]), complemento([been, reported, but, is, still, controversial])].
[sujeto(['Due', to, the, high, adaptability, of, intestinal, cells, to, environmental, 'changes,', we, hypothesised, that, the, density, of, 'GLP-1-producing', cells, could, be, modified, by, nutritional, factors, to]), verbo([prevent]), complemento([the, deterioration, of, metabolic, condition, in, obesity])].
[sujeto(['Mice', fed, a, 'HFD', for, 8, weeks, displayed, an]), verbo([increase]), complemento([in, 'GLP-1-positive', cells, in, the, jejunum, and, colon, accordingly, to, 'GLP-1', secretion])].
[sujeto(['Moreover,', genetically, obese, 'ob/ob', mice, did, not, show, alteration, of, 'GLP-1-positive', cell, density, in, the, jejunum, or, 'colon,']), verbo([suggesting]), complemento([that, obesity, per, se, is, not, sufficient, to, trigger, the, mechanism])].
[sujeto(['The', higher, 'L-cell', density, in, 'HFD-fed', mice]), verbo([involved]), complemento([a, rise, in, 'L-cell', terminal, differentiation, as, witnessed, by, the, increased, expression, of, transcription, factors, downstream, of, neurogenin3, '(', 'Ngn3)'])].
[sujeto(['We']), verbo([suggest]), complemento([that, the, observed, increase, in, 'GLP-1-positive', cell, density, triggered, by, high, fat, consumption, in, humans, and, mice, might, favour, insulin, secretion, and, therefore, constitute, an, adaptive, response, of, the, intestine, to, balance, 'diet-induced', insulin, resistance])].
[sujeto(['Despite', the, better, prognosis, of, embryonal, 'RMS,', patients, in, the, 'E2', are, likely, to]), verbo([have]), complemento([a, poor, prognosis])].
[sujeto(['It']), verbo([has]), complemento([been, shown, that, acetylcholine, is, both, a, neurotransmitter, and, acts, as, a, local, 'mediator,', produced, by, airway, cells, including, epithelial, cells])].
[sujeto(['In', vivo, studies]), verbo([have]), complemento([demonstrated, an, indirect, role, for, acetylcholine, in, epithelial, cell, differentiation])].
[sujeto(['Human', airway, epithelial, cells]), verbo([expressed]), complemento([all, components, of, the, 'non-neuronal', cholinergic, 'system,', suggesting, acetylcholine, production])].
[sujeto(['Differentiation', into, goblet, cells, was, barely]), verbo([induced]), complemento([after, air, exposure])].
[sujeto(['Therefore,', 'IL-13', '(', 1, 'ng/mL)', was, used, to]), verbo([induce]), complemento([goblet, cell, metaplasia])].
[sujeto(['IL-13']), verbo([induced]), complemento(['MUC5AC-positive', cells, '(', 5, -, 'fold)', and, goblet, cells, '(', 14, -, 'fold),', as, assessed, by, 'histochemistry,', and, 'MUC5AC', gene, expression, '(', 105, -, 'fold)'])].
[sujeto(['These', effects, were, partly]), verbo([prevented]), complemento([by, tiotropium, '(', 47, -, 92, '%', ')'])].
[sujeto(['Goblet', cell, metaplasia, was]), verbo([induced]), complemento([by, 'IL-13', in, a, 'dose-dependent', 'manner,', which, was, inhibited, by, tiotropium])].
[sujeto(['In', 'addition,', tiotropium, reversed, goblet, cell, metaplasia]), verbo([induced]), complemento([by, 2, weeks, of, 'IL-13', exposure])].
[sujeto(['IL-13']), verbo([decreased]), complemento([forkhead, box, protein, 'A2', '(', 'FoxA2)', expression, '(', 1.6, -, 'fold)', and, increased, 'FoxA3', '(', 3.6, -, 'fold)', and, 'SAM-pointed', 'domain-containing', 'ETS', transcription, factor, '(', 'SPDEF)', '(', 5.2, -, 'fold)', expression])].
[sujeto(['Tiotropium']), verbo([prevented]), complemento([the, effects, on, 'FoxA2', and, 'FoxA3,', but, not, on, 'SPDEF'])].
[sujeto(['We', demonstrate, that, tiotropium]), verbo([has]), complemento([no, effects, on, epithelial, cell, differentiation, after, air, 'exposure,', but, inhibits, and, reverses, 'IL-13-induced', goblet, cell, 'metaplasia,', possibly, via, 'FoxA2', and, 'FoxA3'])].
[sujeto(['Their', importance, in]), verbo([regulating]), complemento([biological, processes, in, the, lung, and, liver, is, extensively, 'characterized,', though, much, less, is, known, about, their, role, in, intestine])].
[sujeto(['FOXA2']), verbo([binding]), complemento([sites, 'genome-wide', were, determined, by, 'ChIP-seq', and, direct, targets, of, the, factor, were, validated, by, 'ChIP-qPCR', and, 'siRNA-mediated', depletion, of, 'FOXA1/2', followed, by, 'RT-qPCR'])].
[sujeto(['Depletion', of, both, 'FOXA1', and, 'FOXA2']), verbo([led]), complemento([to, a, significant, reduction, in, the, expression, of, multiple, transmembrane, proteins, including, ion, channels, and, 'transporters,', which, form, a, network, that, is, essential, for, maintaining, normal, ion, and, solute, transport])].
[sujeto(['One', of, the]), verbo([targets]), complemento([was, the, adenosine, 'A2B', 'receptor,', and, reduced, receptor, mRNA, levels, were, associated, with, a, functional, decrease, in, intracellular, cyclic, 'AMP'])].
[sujeto(['We', also, observed, that, 30, '%', of, 'FOXA2']), verbo([binding]), complemento([sites, contained, a, 'GATA', motif, and, that, 'FOXA1/A2', depletion, reduced, 'GATA-4,', but, not, 'GATA-6', protein, levels])].
[sujeto(['These', data, show, that, 'FOXA2', plays, a, pivotal, role, in]), verbo([regulating]), complemento([intestinal, epithelial, cell, function])].
[sujeto(['Moreover,', that, the, 'FOXA', and, 'GATA', families, of, transcription, factors, may, work, cooperatively, to]), verbo([regulate]), complemento([gene, expression, 'genome-wide', in, the, intestinal, epithelium])].
[sujeto(['While', chronic, elevation, of, 'FBG', is, detrimental, to, 'health,', glucocorticoids]), verbo([induce]), complemento(['G6PC2', expression, suggesting, that, 'G6PC2', evolved, to, transiently, modulate, 'FBG', under, conditions, of, 'glucocorticoid-related', stress])].
[sujeto(['We', show, using, competition, and, mutagenesis, 'experiments,', that, the, synthetic, glucocorticoid, dexamethasone, '(', 'Dex)']), verbo([induces]), complemento(['G6PC2', promoter, activity, through, a, mechanism, involving, displacement, of, the, 'islet-enriched', transcription, factor, 'MafA', by, the, glucocorticoid, receptor])].
[sujeto(['The', induction, of, 'G6PC2', promoter, activity, by, 'Dex', is]), verbo([modulated]), complemento([by, a, single, nucleotide, 'polymorphism,', previously, linked, to, altered, 'FBG', in, 'humans,', that, affects, 'FOXA2', binding])].
[sujeto(['Acute', 'Dex', treatment, only]), verbo([induces]), complemento(['G6pc2', expression, in, 129, 'SvEv', but, not, 'C57BL/6J', mice, but, this, chronic, treatment, induced, 'G6pc2', expression, in, both])].
[sujeto(['In', 6, hr, fasted, 'C57BL/6J', wild, type, '(', 'WT)', 'mice,', 'Dex', treatment, lowered, 'FBG', and, improved, glucose, 'tolerance,', with, 'G6pc2', deletion, exacerbating, the]), verbo([decrease]), complemento([in, 'FBG', and, enhancing, the, improvement, in, glucose, tolerance])].
[sujeto(['In', 'contrast,', in, 24, hr, fasted, 'C57BL/6J', 'WT', 'mice,', 'Dex', treatment, raised, 'FBG', but, still, improved, glucose, 'tolerance,', with, 'G6pc2', deletion, limiting, the]), verbo([increase]), complemento([in, 'FBG', and, enhancing, the, improvement, in, glucose, tolerance])].
[sujeto(['These', observations, demonstrate, that, 'G6pc2']), verbo([modulates]), complemento([the, complex, effects, of, 'Dex', on, both, 'FBG', and, glucose, tolerance])].
[sujeto(['We', show, characteristic, morphological, changes, corresponding, to, 'epithelial-mesenchymal', transition, '(', 'EMT)', program, fulfillment, in, 'PANC1', cell, line]), verbo([stimulated]), complemento([with, 'TGFβ1'])].
[sujeto(['We', show, 5, -, and, 28, -, fold]), verbo([increase]), complemento([in, 'SNAI1', and, 'SNAI2', expression, levels, and, 25, -, and, 15, -, fold, decrease, in, 'CDH1', and, 'KRT8', expression, 'levels,', 'respectively,', which, confirms, the, 'EMT-program', fulfillment])].
[sujeto(['We', demonstrate, downregulation, of, expression, of, pancreatic, master, genes, 'SOX9,', 'FOXA2,', and, 'GATA4', '(', 2, -, ',', 5, -, ',', and, 4, -, 'fold,', 'respectively)', and, absence, of, significant, changes, in, 'HES1,', 'NR5A2,', and, 'GATA6', expression, levels, in, the, cells]), verbo([stimulated]), complemento([with, 'TGFβ1'])].
[sujeto([1, ',', and, 'ONECUT1', 'genes,', which, are, inactive, in, 'PANC1', cell, line, after, the, 'EMT']), verbo([stimulated]), complemento([by, 'TGFβ1'])].
[sujeto(['Consequently,', the, contribution, of, 'intestine-enriched', factors]), verbo([expressed]), complemento([within, 'BO', to, oncogenesis, is, unclear])].
[sujeto(['Herein,', using, transcriptomics, we, define, the, 'intestine-enriched', genes]), verbo([expressed]), complemento([in, 'meta-profiles', of, 'BO', and, 'OAC'])].
[sujeto(['Interestingly,', 77, '%', of, the, genes, differentially]), verbo([expressed]), complemento([in, a, 'meta-profile', of, 'BO', were, similarly, expressed, in, intestinal, tissues])].
[sujeto(['Furthermore,', 85, '%', of, this, 'intestine-like', signature, was]), verbo([maintained]), complemento([upon, transition, to, 'OAC'])].
[sujeto(['Simulated', acid, reflux, was, observed, to]), verbo([induce]), complemento([the, expression, of, both, 'NR5A2', and, 'GATA6'])].
[sujeto(['Abrogation', of, 'NR5A2-GATA6', expression, in, conjunction, with, 'BCL-XL', 'co-silencing', resulted, in, synergistically]), verbo([increased]), complemento([sensitivity, to, chemotherapeutics, and, 'photo-dynamic', therapeutics])].
[sujeto(['These', findings, characterize, the, 'intestine-like', signature]), verbo([associated]), complemento([with, 'IM', which, may, have, important, consequences, to, adenocarcinogenesis])].
[sujeto(['Transcription', factors, that, play, key, roles, in]), verbo([regulating]), complemento([pancreatic, progenitor, state, have, been, 'identified,', but, the, chromatin, regulators, that, help, establishing, and, maintaining, pancreatic, fate, are, less, well, known])].
[sujeto(['We', show, that, 'Setd7', is]), verbo([expressed]), complemento([in, the, prospective, pancreatic, endoderm, of, 'Xenopus', and, mouse, embryos, prior, to, 'Pdx1', induction])].
[sujeto(['Importantly,', we, demonstrate, that, setd7, is, sufficient, and]), verbo([required]), complemento([for, pancreatic, cell, fate, specification, in, 'Xenopus', 'Functional', and, biochemical, approaches, in, 'Xenopus', and, mouse, endoderm, support, that, 'Setd7', modulates, methylation, marks, at, pancreatic, regulatory, 'regions,', possibly, through, interaction, with, the, transcription, factor, 'Foxa2'])].
[sujeto(['Together,', these, results, demonstrate, that, 'Setd7']), verbo([acts]), complemento([as, a, central, component, of, the, transcription, complex, initiating, the, pancreatic, program])].
[sujeto(['Recently,', the, 'US', 'FDA']), verbo([has]), complemento([approved, &, 'quot;vagal', blocking, therapy, or, 'vBLoc®', 'therapy&quot;', as, a, new, treatment, for, obesity])].
[sujeto(['Rats', were, implanted, with, 'VBLOC,', an, 'intra-abdominal', electrical, device, with]), verbo([leads]), complemento([placed, around, gastric, vagal, trunks, through, an, abdominal, incision, and, controlled, by, wireless, device])].
[sujeto(['VBLOC', reduced, body, weight, and, food, 'intake,', which, was]), verbo([associated]), complemento([with, increased, satiety, but, not, with, decreased, hunger])].
[sujeto(['Brain', activities, in, response, to, 'VBLOC', included]), verbo([increased]), complemento([gene, expression, of, leptin, and, 'CCKb', 'receptors,', 'interleukin-1β,', tumor, necrosis, 'factor,', and, transforming, growth, factor, β1, in, the, 'brainstem;', increased, 'CCK,', 'somatostatin,', and, tyrosine, hydroxylase, in, the, 'hippocampus;', increased, 'NPY,', 'AgRP,', and, 'Foxa2', in, the, 'hypothalamus;', and, reduced, 'CCKb', 'receptor,', melanocortin, 4, 'receptor,', and, insulin, receptor, in, the, hypothalamus])].
[sujeto(['Based', on, the, present, 'study,', we, may]), verbo([suggest]), complemento([that, 'VBLOC', induces, satiety, through, vagal, 'signaling,', leading, to, reduced, food, intake, and, loss, of, body, weight])].
[sujeto(['Because', the, original, 'N27', cell, line]), verbo([has]), complemento([been, passaged, many, 'times,', the, line, has, become, a, mixture, of, cell, types, with, highly, variable, expression, of, 'TH'])].
[sujeto(['In', the, current, 'study,', we]), verbo([have]), complemento([performed, multiple, rounds, of, clonal, cultures, and, have, identified, a, dopaminergic, cell, clone, expressing, high, levels, of, 'TH', and, the, dopamine, transporter, '(', 'DAT)'])].
[sujeto(['We']), verbo([have]), complemento([named, this, new, clone, 'N27-A'])].
[sujeto(['Nearly', 100, '%', of, 'N27-A', cells]), verbo([express]), complemento(['TH,', 'DAT', and, 'Tuj1'])].
[sujeto(['Western', blots]), verbo([have]), complemento([confirmed, that, 'N27-A', cells, have, three, to, four, times, the, levels, of, 'TH', and, 'DAT', compared, to, the, previous, mixed, population, in, 'N27'])].
[sujeto(['Further', analysis]), verbo([has]), complemento([shown, that, the, new, clone, expresses, the, dopamine, neuron, transcription, factors, 'Nurr1,', 'En1,', 'FoxA2', and, 'Pitx3'])].
[sujeto(['The', 'N27-A', cells]), verbo([express]), complemento([the, vesicular, monoamine, transporter, '(', 'VMAT2),', but, do, not, express, 'dopamine-beta-hydroxylase', '(', 'DβH),', the, enzyme, responsible, for, converting, dopamine, to, norepinephrine])].
[sujeto(['Functional', analysis]), verbo([has]), complemento([shown, that, 'N27-A', cells, are, more, sensitive, than, 'N27', cells, to, neurotoxins, taken, up, by, the, dopamine, transporter, such, as, 6, -, hydroxydopamine, and, 1, -, 'methyl-4-phenylpyridine', '(', 'MPP+)'])].
[sujeto(['The', 'DAT', inhibitor, nomifensine, can, block, 'MPP+']), verbo([induced]), complemento([toxicity])].
[sujeto(['The', 'N27-A', cells, show, dopamine]), verbo([release]), complemento([under, basal, and, depolarization, conditions])].
[sujeto(['We', conclude, that, the, new, 'N27-A', clone, of, the, immortalized, rat, dopaminergic, cell, line, 'N27', should]), verbo([provide]), complemento([an, improved, in, vitro, model, for, 'Parkinson\'s', disease, research])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF4α),', a, critical, transcription, 'factor,', plays, an, essential, role, in, the, entire, process, of, liver, development])].
[sujeto(['In', hepatocyte, culture, 'medium,', 'HNF4α-transduced', 'MSCs', '(', 'E7-hHNF4α', 'cells)', strongly]), verbo([expressed]), complemento([the, albumin, '(', 'ALB),', 'CYP2B6,', 'alpha-1', antitrypsin, '(', 'AAT),', and, 'FOXA2', mRNA, and, exhibited, morphology, markedly, similar, to, that, of, mature, hepatocytes])].
[sujeto(['Approximately', 28, '%', of, 'E7-hHNF4α', cells]), verbo([expressed]), complemento([both, 'ALB', and, 'AAT'])].
[sujeto(['Furthermore,', these, 'E7-hHNF4α', cells, via, superior, mesenteric, vein, '(', 'SMV)', injection]), verbo([expressed]), complemento([human, 'ALB', in, mouse, chronic, injured, liver])].
[sujeto(['In', 'conclusion,', this, study, represents, a, novel, strategy, by, directly]), verbo([inducing]), complemento(['hepatocyte-like', cells, from, 'MSCs'])].
[sujeto(['The', ultraweb, 'NF']), verbo([caused]), complemento([better, proliferation, and, characterization, of, 'MSCs'])].
[sujeto(['MSCs', transplantation, significantly, improved, liver, 'functions,']), verbo([increased]), complemento([hepatic, 'HGF', and, 'Bcl-2', 'levels,', whereas, decreased, serum, 'fibronectin,', hepatic, 'TNF-α', and, 'TGF-β1', levels])].
[sujeto(['Hepatic', 'HNF4α,', 'FOXa2,', 'CYP7a1', genes, expression, were]), verbo([enhanced]), complemento([while, 'β-5-Tub', and, 'AFP', genes, expression, were, depressed])].
[sujeto(['ELOVL', family, member, 6, ',', elongation, of, very, long, chain, fatty, acids, '(', 'Elovl6)', is, a, microsomal, 'enzyme,', which]), verbo([regulates]), complemento([the, elongation, of, 'C12-16', saturated, and, monounsaturated, fatty, acids])].
[sujeto(['Elovl6']), verbo([has]), complemento([been, shown, to, be, associated, with, various, pathophysiologies, including, insulin, 'resistance,', 'atherosclerosis,', and, 'non-alcoholic', steatohepatitis])].
[sujeto(['Histological', analysis, revealed, a, reduced, length, of, proliferating, and, an, elongated, length, of, hypertrophic, chondrocyte, 'layer,', and]), verbo([decreased]), complemento([trabecular, bone, in, 'Elovl6-/-', mice, compared, with, controls])].
[sujeto(['These', results, were, presumably, due, to, a, modest]), verbo([decrease]), complemento([in, chondrocyte, proliferation, and, accelerated, differentiation, of, cells, of, the, chondrocyte, lineage])].
[sujeto(['Consistent', with, the]), verbo([increased]), complemento([length, of, the, hypertrophic, chondrocyte, layer, in, 'Elovl6-/-', 'mice,', 'Collagen10α1', was, identified, as, one, of, the, most, affected, genes, by, ablation, of, 'Elovl6', in, chondrocytes])].
[sujeto(['Furthermore,', this, elevated, expression, of, 'Collagen10α1', of, 'Elovl6-null', chondrocytes, was, likely]), verbo([associated]), complemento([with, increased, levels, of, 'Foxa2/a3', and, 'Mef2c', mRNA, expression])].
[sujeto(['Relative']), verbo([increases]), complemento([in, protein, levels, of, nuclear, 'Foxa2', and, cytoplasmic, histone, deacethylase, 4, /, 5, /, 7, were, also, observed, in, 'Elovl6', knockdown, cells, of, the, chondrocyte, lineage])].
[sujeto(['Collectively,', our, data]), verbo([suggest]), complemento([that, 'Elovl6', plays, a, critical, role, for, proper, development, of, embryonic, growth, plate])].
[sujeto(['Studies', in, cultured, cell, lines, and, mice]), verbo([have]), complemento([shown, a, loss, of, 'ZIC2', function, is, the, pathogenic, mechanism, but, the, molecular, details, of, this, 'ZIC2', requirement, remain, elusive])].
[sujeto(['An', intact, 'NODAL', signal, transduction, pathway, and, functional, 'ZIC2', are, both]), verbo([required]), complemento([for, 'PrCP', establishment])].
[sujeto(['We', now, show, that, 'ZIC2']), verbo([acts]), complemento([downstream, of, the, 'NODAL', signal, during, 'PrCP', development])].
[sujeto(['ZIC2', physically]), verbo([interacts]), complemento([with, 'SMAD2', and, 'SMAD3,', the, receptor, activated, proteins, that, control, transcription, in, a, 'NODAL', dependent, manner])].
[sujeto(['Together', 'SMAD3', and, 'ZIC2']), verbo([regulate]), complemento(['FOXA2', transcription, in, cultured, cells, and, 'Zic2', also, controls, the, foxA2, expression, during, 'Xenopus', development])].
[sujeto(['Variant', forms, of, the, 'ZIC2', 'protein,']), verbo([associated]), complemento([with, 'HPE', in, man, or, 'mouse,', are, deficient, in, their, ability, to, influence, 'SMAD-dependent', transcription])].
[sujeto(['These', findings]), verbo([reveal]), complemento([a, new, mechanism, of, 'NODAL', signal, transduction, in, the, mammalian, node, and, provide, the, first, molecular, explanation, of, how, 'ZIC2', 'loss-of-function', precipitates, 'HPE'])].
[sujeto(['Although', much, attention]), verbo([has]), complemento([been, given, to, explore, its, clinical, 'application,', research, of, the, basic, mechanisms, of, 'HE4', in, ovarian, cancer, are, still, unclear])].
[sujeto(['In', the, present, 'study,', we]), verbo([provide]), complemento([fundamental, data, to, identify, 'full-scale', differentially, expressed, genes, '(', 'DEGs)', in, response, to, 'HE4', by, use, of, human, 'whole-genome', microarrays, in, human, epithelial, ovarian, cancer, cell, line, 'ES-2', following, overexpression, and, silencing, of, 'HE4'])].
[sujeto(['We']), verbo([found]), complemento([that, a, total, of, 717, &, 'nbsp;genes', were, upregulated, and, 898, &, 'nbsp;genes', were, downregulated, in, the, 'HE4-overexpressing', cells, vs])].
[sujeto(['These', 'DEGs', were]), verbo([involved]), complemento([in, 'MAPK,', steroid, 'biosynthesis,', cell, 'cycle,', the, p53, hypoxia, 'pathway,', and, focal, adhesion, pathways])].
[sujeto(['Interaction', network, analysis, predicted, that, the, genes]), verbo([participated]), complemento([in, the, regulatory, connection])].
[sujeto(['We']), verbo([found]), complemento([that, 'SERPIND1', may, act, as, a, potential, oncogene, in, the, development, of, ovarian, cancer])].
[sujeto(['These', identified, genes, may]), verbo([provide]), complemento([a, theoretical, basis, for, investigations, of, the, underlying, molecular, mechanism, of, 'HE4', in, ovarian, cancer])].
[sujeto(['The', soluble, form, of, activin, 'A', '(', 'Act)']), verbo([has]), complemento([been, widely, used, as, an, in, vitro, inducer, of, definitive, endoderm, '(', 'DE)'])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([developed, a, nanofibrous, poly, '(', 'ɛ-caprolactone)', 'substrate,', biofunctionalized, with, 'Act,', for, directed, differentiation, of, hESCs, into, 'DE'])].
[sujeto(['The', nanofibers, with, covalent, iAct, significantly]), verbo([increased]), complemento([expression, levels, of, the, endodermal, markers, 'SOX17,', 'FOXA2,', and, 'CXCR4,', compared, with, physically, adsorbed, 'Act', '(', 'aAct)', or, without, 'Act', '(', 'noAct)'])].
[sujeto(['In', 'addition,', iAct]), verbo([retained]), complemento([its, bioactivity, after, storage, for, five, days, in, the, absence, of, cell, seeding])].
[sujeto(['Hypoxia']), verbo([has]), complemento([been, demonstrated, to, play, an, important, role, in, embryonic, formation, and, development, and, to, modulate, stem, cell, differentiation])].
[sujeto(['However,', the, influence, of, oxygen, tension, on, thyroid, differentiation]), verbo([has]), complemento([not, been, studied])].
[sujeto(['In', this, 'study,', we, used, murine]), verbo([induced]), complemento([pluripotent, stem, '(', 'iPS)', cells, for, thyroid, cell, differentiation, under, normoxic, and, hypoxic, conditions, and, compared, differentiation, efficiency, in, 'morphology,', 'function,', gene, and, protein, expression, under, both, conditions])].
[sujeto(['We']), verbo([found]), complemento([that, hypoxia, promoted, adhesion, and, outgrowth, of, embryoid, bodies, '(', 'EBs)', derived, from, murine, iPS, cells])].
[sujeto([1, ')', was]), verbo([increased]), complemento([by, hypoxia, at, both, gene, and, protein, levels, during, 'early-mid', differentiation, stages, '(', 'p&lt;0'])].
[sujeto(['In', 'addition,', functional, iodide, uptake, by, differentiated, cells, was, also]), verbo([increased]), complemento([after, hypoxia])].
[sujeto(['Thyroid', differentiation, from, iPS, cells, is]), verbo([enhanced]), complemento([under, hypoxia, and, this, may, involve, hypoxia, inducible, factors, '(', 'HIFs)', and, their, downstream, gene, 'FGF2'])].
[sujeto(['Our', data, offer, a, foundation, for, understanding, thyroid, development, and]), verbo([provide]), complemento([a, potentially, more, efficient, way, to, use, cell, therapy, for, treating, thyroid, deficiency])].
[sujeto([:, 'The', progressive, death, of, dopamine, producing, neurons, in, the, substantia, nigra, pars, compacta, is, the, principal]), verbo([cause]), complemento([of, symptoms, of, 'Parkinson\'s', disease, '(', 'PD)'])].
[sujeto(['Stem', cells]), verbo([have]), complemento([potential, therapeutic, use, in, replacing, these, cells, and, restoring, function])].
[sujeto(['To', this, 'end,', we, differentiated, baboon, 'fibroblast-derived']), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'biPSCs)', into, dopaminergic, neurons, with, the, application, of, specific, morphogens, and, growth, factors])].
[sujeto(['We', confirmed, that, 'biPSC-derived', dopaminergic, neurons, resemble, those]), verbo([found]), complemento([in, the, human, midbrain, based, on, cell, 'type-specific', expression, of, dopamine, markers, 'TH', and, 'GIRK2'])].
[sujeto(['Using', the, reverse, transcriptase, quantitative, polymerase, chain, 'reaction,', we, also, showed, that, 'biPSC-derived', dopaminergic, neurons]), verbo([express]), complemento(['PAX6,', 'FOXA2,', 'LMX1A,', 'NURR1,', and, 'TH', genes, characteristic, of, this, cell, type, in, vivo])].
[sujeto(['Finally,', we, showed, that, 'biPSC-derived', neurons]), verbo([released]), complemento([catecholamines, in, response, to, electrical, stimulation])].
[sujeto(['Functional', dopamine, neurons, were, produced, from, baboon]), verbo([induced]), complemento([pluripotent, stem, 'cells,', and, their, properties, were, compared, to, baboon, midbrain, cells, in, vivo])].
[sujeto(['The', baboon]), verbo([has]), complemento([advantages, as, a, clinically, relevant, model, in, which, to, optimize, the, efficacy, and, safety, of, stem, 'cell-based', therapies, for, neurodegenerative, 'diseases,', such, as, 'Parkinson\'s', disease])].
[sujeto(['However,', it, is, currently, unclear, how, these, embryonic, tissue, interactions, can, be]), verbo([translated]), complemento([into, a, defined, differentiation, protocol, for, human, embryonic, stem, cells])].
[sujeto(['Activin', 'A']), verbo([has]), complemento([been, proposed, to, direct, 'DE', into, a, 'SOX2-positive', 'foregut-like', cell, type])].
[sujeto(['We', show, in, contrast, to, previous, studies, that, the, generation, of, the, foregut, marked, by, 'SOX2/FOXA2', 'double-positive', cells, does, not, depend, on, activin, 'A/TGF-β-signaling', but, is]), verbo([mediated]), complemento([by, the, inhibition, of, 'Wnt-', and, 'BMP-signaling'])].
[sujeto(['Retinoic', acid, can, posteriorize, and, at, the, same, time, dorsalize, the, foregut, toward, a, 'PDX1-positive', pancreatic, duodenal, cell, type, whereas, active, 'Wnt/beta-catenin', signaling, synergistically, with, 'FGF-2,', 'BMP-4,', and, 'RA']), verbo([induces]), complemento([the, formation, of, 'CDX2-positive', posterior, endoderm])].
[sujeto(['Thus,', these, results]), verbo([provide]), complemento([new, insights, into, the, mechanisms, behind, cell, specification, of, human, 'DE', derived, from, pluripotent, stem, cells])].
[sujeto(['While', orthotopic, transplantation, into, the, testis]), verbo([promotes]), complemento([seminomatous, growth, of, the, 'seminoma-like', cell, line, 'TCam-2,', ectopic, xenotransplantation, into, the, flank, initiates, reprogramming, into, an, 'EC-like', fate])].
[sujeto(['During', this, 'reprogramming,', 'BMP', signaling, is, 'inhibited,']), verbo([leading]), complemento([to, induction, of, 'NODAL', 'signaling,', upregulation, of, pluripotency, factors, and, downregulation, of, seminoma, 'markers,', like, 'SOX17'])].
[sujeto(['In', 'contrast,', the, pioneer, factor, 'FOXA2', and, its]), verbo([target]), complemento([genes, were, 'upregulated,', suggesting, that, 'FOXA2', might, play, an, important, role, in, induction, of, 'non-seminomatous', differentiation])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, exposure, to, phenyl, ethyl, alcohol, '(', 'PEA)', causes, an, increase, in, the, expression, of, the, transcription, factor, otx2, in, the, olfactory, epithelium, '(', 'OE)', of, juvenile, 'zebrafish,', and, this, change, is, correlated, with, the, formation, of, an, odor, memory, of, 'PEA'])].
[sujeto(['Subsequent', in, silico, analysis, uncovered, 'Hnf3b']), verbo([binding]), complemento([sites, closely, associated, with, 'Otx2', binding, sites, in, the, regions, flanking, the, 'ORs'])].
[sujeto(['Analysis', by, quantitative, polymerase, chain, reaction, and, 'RNA-seq', of, 'OR', expression, in, developing, zebrafish, exposed, to, different, isoforms, of, 'PEA', showed, that, a, subset, of, 'ORs', containing, both, 'Otx2/Hnf3b']), verbo([binding]), complemento([sites, were, downregulated, only, in, 'βPEA-exposed', juveniles, and, this, change, persisted, through, adult, life])].
[sujeto(['Localization', of, 'OR', expression, by, in, situ, hybridization, indicates, the, downregulation, occurs, at, the, level, of, 'RNA', and, not, the, number, of, cells]), verbo([expressing]), complemento([a, given, receptor])].
[sujeto(['Finally,', analysis, of, immediate, early, gene, expression, in, the, 'OE', did, not]), verbo([reveal]), complemento([changes, in, 'c-fos', expression, in, response, to, either, αPEA, or, βPEA])].
[sujeto(['To', identify, differentially]), verbo([expressed]), complemento([genes, '(', 'DEGs)', and, find, associated, pathways, that, may, function, as, targets, of, lung, cancer])].
[sujeto(['Besides,', novel, genes]), verbo([associated]), complemento([with, lung, cancer, were, identified, by, 'co-expression', analysis])].
[sujeto(['Then,', 'GO', enrichment, and, transcription]), verbo([binding]), complemento([site, analysis, were, performed, on, these, 'DEGs,', and, novel, genes, were, predicted, using, 'DAVID'])].
[sujeto(['Finally,', 'PPI', network, was, constructed, by, 'String', software, in, order, to, get, the, hub, codes]), verbo([involved]), complemento([in, cancer, carcinoma])].
[sujeto(['The', transcription, biding, site, analysis, showed, that, these, genes, were]), verbo([regulated]), complemento([by, 'LHX3,', 'HNF3B,', 'CDP,', 'HFH1,', 'FOXO4,', 'STAT,', 'SOX5,', 'MEF2,', 'FOXO3', and, 'SRY'])].
[sujeto(['Hub', codes, as, 'BUB1B,', 'MAD2L', and, 'TOP2A', may, play, as]), verbo([target]), complemento([genes, in, lung, carcinoma, in, the, result, of, 'PPI', network, analysis])].
[sujeto(['Newly', predicted, genes, and, hub, codes, can, perform, as]), verbo([target]), complemento([genes, for, diagnose, and, clinical, therapy, of, lung, cancer])].
[sujeto(['SSCs', first, changed, into, hepatic, 'stem-like', cells, since, they, resembled, hepatic, oval, cells, in, morphology, and]), verbo([expressed]), complemento(['Ck8,', 'Ck18,', 'Ck7,', 'Ck19,', 'OV6,', and, albumin])].
[sujeto(['Notably,', these, differentiated, cells, acquired, functional, attributes, of, 'hepatocyte-like', cells, because, they, secreted, 'albumin,', synthesized, 'urea,', and, uptake, and]), verbo([released]), complemento([indocyanine, green])].
[sujeto(['Moreover,', phosphorylation, of, 'ERK1/2', and, 'Smad2/3', rather, than, 'Akt', was]), verbo([activated]), complemento([in, hepatic, stem, cells, and, mature, hepatocytes])].
[sujeto(['This', study, thus]), verbo([provides]), complemento([an, invaluable, source, of, mature, hepatocytes, for, treating, 'liver-related', diseases, and, drug, toxicity, screening, and, offers, novel, insights, into, mechanisms, of, liver, development, and, cell, reprogramming])].
[sujeto(['This', gene]), verbo([has]), complemento([a, 'CpG', island, extending, 2500, bp, from, the, translational, start, 'site;', 'however,', studies, characterizing, its, transcriptional, regulation, have, not, been, conducted])].
[sujeto(['Two', transcripts, for, 'DAPK', were, identified, that, code, for, a, single, 'protein,', while, being]), verbo([regulated]), complemento([by, two, promoters])].
[sujeto(['The', previously, identified, 'DAPK', transcript, designated, as, exon, 1, transcript, was]), verbo([expressed]), complemento([at, levels, 3, -, fold, greater, than, the, alternate, exon, 1, b, transcript])].
[sujeto(['Sequencing', the, 'DAPK', 'CpG', island, in, tumor, cell, lines, revealed, 'dense,', but, heterogenous, methylation, of, 'CpGs', that, blocked, access, of, the, 'CP2', and, 'HNF3B', proteins, that, in, 'turn,', was]), verbo([associated]), complemento([with, loss, of, transcription, that, was, restored, by, treatment, with, 5, -, 'aza-2\'-deoxycytidine'])].
[sujeto(['Growing', evidence, indicates, that, microRNAs]), verbo([have]), complemento([a, significant, role, in, tumor, development, and, may, constitute, robust, biomarkers, for, cancer, diagnosis, and, prognosis])].
[sujeto(['We']), verbo([report]), complemento([that, 'miR-122', is, specifically, repressed, in, a, subset, of, primary, tumors, that, are, characterized, by, poor, prognosis])].
[sujeto(['We', further, show, that, the]), verbo([loss]), complemento([of, 'miR-122', expression, in, tumor, cells, segregates, with, specific, gene, expression, profiles, linked, to, cancer, 'progression,', namely, the, suppression, of, hepatic, phenotype, and, the, acquisition, of, invasive, properties])].
[sujeto(['We', identify, 'liver-enriched', transcription, factors, as, central, regulatory, molecules, in, the, gene, networks]), verbo([associated]), complemento([with, loss, of, 'miR-122,', and, provide, evidence, suggesting, that, 'miR-122', is, under, the, transcriptional, control, of, 'HNF1A,', 'HNF3A', and, 'HNF3B'])].
[sujeto(['We', further, show, that]), verbo([loss]), complemento([of, 'miR-122', results, in, an, increase, of, cell, migration, and, invasion, and, that, restoration, of, 'miR-122', reverses, this, phenotype])].
[sujeto(['One', known, genetic, mechanism, for, transient, neonatal, diabetes, is]), verbo([loss]), complemento([of, methylation, at, 6, q24])].
[sujeto(['The', etiology, of, prune, belly, sequence, is, unknown, but, a, genetic, 'defect,', affecting, the, mesoderm, from, which, the, triad, abdominal, muscle, 'hypoplasia,', urinary, tract, 'abnormalities,', and, cryptorchidism, 'develop,']), verbo([has]), complemento([been, suggested])].
[sujeto(['The', proband, had]), verbo([loss]), complemento([of, methylation, at, the, 6, q24, locus, 'TNDM', and, also, at, the, loci, 'IGF2R,', 'DIRAS3,', and, 'PEG1,', while, the, other, family, 'members,', including, the, healthy, monozygotic, 'twin,', had, normal, findings])].
[sujeto(['The']), verbo([loss]), complemento([of, methylation, on, chromosome, 6, q24, and, elsewhere, may, indicate, a, generalized, maternal, hypomethylation, 'syndrome,', which, accounts, for, both, transient, neonatal, diabetes, and, prune, belly, sequence])].
[sujeto(['Mammalian', 'tissue-', 'and/or', 'time-specific', transcription, is, primarily]), verbo([regulated]), complemento([in, a, combinatorial, fashion, through, interactions, between, a, specific, set, of, transcriptional, regulatory, factors, '(', 'TRFs)', and, their, cognate, 'cis-regulatory', elements, located, in, the, regulatory, regions])].
[sujeto(['In', exploring, the, 'DNA', regions, and, 'TRFs']), verbo([involved]), complemento([in, combinatorial, transcriptional, 'regulation,', we, noted, that, individual, knockdown, of, a, set, of, human, 'liver-enriched', 'TRFs', such, as, 'HNF1A,', 'HNF3A,', 'HNF3B,', 'HNF3G', and, 'HNF4A', resulted, in, perturbation, of, the, expression, of, several, single, 'TRF', 'genes,', such, as, 'HNF1A,', 'HNF3G', and, 'CEBPA', genes])].
[sujeto(['We', thus, searched, the, potential]), verbo([binding]), complemento([sites, for, these, five, 'TRFs', in, the, highly, conserved, genomic, regions, around, these, three, 'TRF', genes, and, found, several, putative, combinatorial, regulatory, regions])].
[sujeto(['Chromatin', immunoprecipitation, analysis, revealed, that, almost, all, of, the, putative, regulatory, 'DNA', regions, were]), verbo([bound]), complemento([by, the, 'TRFs', as, well, as, two, coactivators, '(', 'CBP', and, 'p300)'])].
[sujeto(['EMSA', demonstrated, specific, bindings, of, these, 'HNFs', to, the]), verbo([target]), complemento(['DNA', region])].
[sujeto(['The', 'liver-specific', activity, of, 'ENII', is]), verbo([regulated]), complemento([by, multiple, 'liver-enriched', transcription, 'factors,', including, 'LRH-1/hB1F,', 'HNF1,', 'HNF3b,', 'HNF4', and, 'C/EBP'])].
[sujeto(['In', this, 'study,', we, demonstrate, a, functional, synergism, between, the, orphan]), verbo([nuclear]), complemento([receptor, 'LRH-1/hB1F', and, the, homeoprotein, 'HNF1', in, 'up-regulating', the, 'liver-specific', activity, of, 'ENII'])].
[sujeto(['We']), verbo([have]), complemento([defined, the, activation, domains, in, hB1F, and, 'HNF1', that, contribute, to, the, synergism])].
[sujeto(['We', further, show, that, hB1F, and, 'HNF1', can]), verbo([interact]), complemento([directly, in, vitro, and, have, mapped, the, domains, required, for, this, interaction])].
[sujeto(['Angiotensin', 'II']), verbo([has]), complemento([been, shown, to, exert, complex, effects, on, proximal, tubular, cell, function, and, growth])].
[sujeto(['We', used, 'DNA', microarrays, to, analyze, multiple, gene, expression, responses, to]), verbo([increasing]), complemento([angiotensin, 'II', concentrations])].
[sujeto(['Coordinated', changes, were, observed, in, genes, of, the, hepatocyte]), verbo([nuclear]), complemento([factor, 3, family, '(', 'NHF3;', 'HNF3A,', 'HNF3B', and, 'HNF3G),', in, the, 'E2F', genes, '(', 'E2F1,', 'E2F3)', and, the, interferon, regulatory, factors, 'IRF1', and, 'IRF5'])].
[sujeto(['Three', genes]), verbo([involved]), complemento([in, the, dampening, of, oxidative, stress, were, enhanced])].
[sujeto(['Taken', 'together,', brief, exposure, of, human, tubular, epithelial, cells, to, angiotensin, 'II', elicited, a, marked, induction, of]), verbo([nuclear]), complemento(['factors,', antioxidant, genes, and, hormones, and, hormone, receptor, genes])].
[sujeto(['We']), verbo([have]), complemento([discovered, two, 'single-nucleotide', polymorphisms, in, the, 5, '\'', flanking, region, of, the, 'HFE', gene])].
[sujeto(['When', a, 'T', was, present, at, -, 970, ',', a, 'C', was, always]), verbo([found]), complemento([at, -, 467])].
[sujeto(['The', less, common, -, 467, mutation, was]), verbo([found]), complemento([in, almost, 12, chromosomes, that, bore, the, 845, 'G--&gt;A', '(', 'C282Y)', mutation, and, was, significantly, more, prevalent, in, chromosomes, containing, the, 187, 'C--&gt;G', '(', 'H63D)', mutation])].
[sujeto(['The', tighter, association, of, the, -, 467, polymorphism, with, the, 'C282Y', mutation, is, consistent, with, other, data, that]), verbo([suggest]), complemento([that, the, 'C282Y', mutation, has, occurred, relatively, recently, and, that, the, 'H63D', mutation, is, considerably, older])].
[sujeto(['DNase', 'I', footprinting, from, mouse, cells, revealed, that, several, potential, 'cis-elements', were, occupied, by]), verbo([nuclear]), complemento([proteins])].
[sujeto(['Our', data]), verbo([provide]), complemento([insight, into, the, regulatory, mechanisms, that, govern, the, expression, of, the, 'MAP1A', gene])].
[sujeto(['Mutations', in, genes, encoding, hepatocyte]), verbo([nuclear]), complemento([factor, '(', 'HNF)', are, responsible, for, three, of, the, five, subtypes, of, 'maturity-onset', diabetes, of, the, young, '(', 'MODY)'])].
[sujeto(['This', observation, and, molecular, studies, indicate, that, the, 'HNF', network, is]), verbo([required]), complemento([for, normal, function, of, pancreatic, 'beta-cells'])].
[sujeto(['This']), verbo([suggests]), complemento([that, transcription, factors, involved, in, this, complex, network, are, candidates, for, genetic, defects, in, 'MODY'])].
[sujeto(['All', of, the, five, known, 'MODY', 'genes,', 'HNF-4alpha,', 'glucokinase,', 'HNF-1alpha,', 'HNF-1beta,', and, 'IPF1,', were, previously, excluded, as, being, the]), verbo([cause]), complemento([of, diabetes, in, these, families])].
[sujeto(['Familial', segregation, studies, and, linkage, analysis, showed, that, genetic, variation, in, the, 'HNF-3beta', gene, is, unlikely, to, be, the]), verbo([cause]), complemento([of, 'early-onset', type, 2, diabetes, in, these, 'Caucasian', families])].
[sujeto(['Mutations', in, the, transcription, factors, hepatocyte]), verbo([nuclear]), complemento([factor, '(', 'HNF)-4alpha', and, -, 1, 'alpha,', insulin, promoter, 'factor-1,', and, 'HNF-1beta', are, the, causes, of, four, forms, of, 'maturity-onset', diabetes, of, the, young, '(', 'MODY1', and, 3, -, 5, ',', 'respectively)'])].
[sujeto(['The', 'winged-helix', transcription, factor, 'HNF-3beta']), verbo([has]), complemento([been, implicated, in, the, regulation, of, expression, of, each, of, these, 'MODY', 'genes,', suggesting, that, mutations, in, the, 'HNF-3beta', gene, '(', 'HNF3B)', may, also, cause, 'MODY'])].
[sujeto(['We']), verbo([have]), complemento([tested, this, hypothesis, by, screening, a, panel, of, 57, unrelated, 'Japanese', subjects, with, a, clinical, diagnosis, of, 'MODY', for, mutations, in, 'HNF3B'])].
[sujeto(['This', analysis, revealed, four, frequent, polymorphisms, that, were, not]), verbo([associated]), complemento([with, 'MODY,', including, one, in, the, promoter, region, '(', -, 213, 'A/G),', two, silent, mutations, in, the, codons, for, 'Ala', 97, '(', 291, 'C/T)', and, 'Gly', 279, '(', 837, 'A/G),', and, one, in, the, 3, '\'', -, untranslated, region, '(', 1424, 'C/T)'])].
[sujeto(['Two', rare, substitutions, in, the, 5, '\'', -, untranslated, 'region,', -, 156, 'C/T', and, -, 67, 'A/C,', were]), verbo([found]), complemento([in, a, heterozygous, state, in, two, 'subjects,', and, two, subjects, were, heterozygous, for, putative, missense, 'mutations,', 'S109N', '(', 326, 'G', &, 'gt;', 'A)', and, 'A328V', '(', 983, 'C&gt;T)'])].
[sujeto(['The', two, missense, mutations, were, not]), verbo([found]), complemento([in, 106, normal, chromosomes, from, nondiabetic, subjects])].
[sujeto(['It', was, not, possible, to, test, for, 'co-segregation', of, these, mutations, with, diabetes, and, 'thus,', it, is, unclear, whether, or, not, these, mutations, can]), verbo([cause]), complemento(['MODY'])].
[sujeto(['The', results, of, our, study]), verbo([suggest]), complemento([that, mutations, in, 'HNF3B', are, not, a, common, cause, of, 'MODY', in, 'Japanese', subjects])].
[sujeto(['Small', heterodimer, partner, '(', 'SHP;', 'NR0B2)', is, an, atypical, orphan]), verbo([nuclear]), complemento([receptor, and, acts, as, a, coregulator, of, various, nuclear, receptors])].
[sujeto(['Herein,', we, examined, a, novel, cross, talk, between, 'SHP', and, a, forkhead, transcription, factor, 'HNF3', '(', hepatocyte]), verbo([nuclear]), complemento([factor, 3, /, 'Foxa'])].
[sujeto(['Transient', transfection, assay, demonstrated, that, 'SHP']), verbo([inhibited]), complemento([the, transcriptional, activity, of, all, three, isoforms, of, 'HNF3,', 'HNF3alpha,', 'beta,', and, gamma])].
[sujeto(['In', vivo, and, in, vitro, protein, interaction, studies, showed, that, 'SHP', physically]), verbo([interacted]), complemento([with, 'HNF3'])].
[sujeto(['Adenovirus-mediated', overexpression, of, 'SHP', significantly]), verbo([decreased]), complemento([the, mRNA, levels, of, 'glucose-6-phosphase', '(', 'G6Pase),', cholesterol, 7, -, 'alpha-hydroxylase', '(', 'CYP7A1),', and, phosphoenolpyruvate, carboxykinase, '(', 'PEPCK)', in, 'HepG2', cells, and, rat, primary, hepatocytes])].
[sujeto(['Moreover,', the, mRNA, level, of, 'G6Pase', was, notably]), verbo([increased]), complemento([by, 'down-regulation', of, 'SHP', with, small, interfering, 'RNA'])].
[sujeto(['Interestingly,', 'HNF3', transactivity, was, still]), verbo([repressed]), complemento([by, 'SHPDelta128-139', that, fails, to, repress, nuclear, receptors])].
[sujeto(['Mapping', of, interaction, domain, revealed, that, 'SHP']), verbo([interacted]), complemento([with, forkhead, 'DNA', binding, domain, of, 'HNF3alpha'])].
[sujeto(['Gel', mobility, shift, and, chromatin, immunoprecipitation, assays, demonstrated, that, 'SHP']), verbo([inhibits]), complemento(['DNA', binding, of, 'HNF3'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'SHP', is, involved, in, the, regulation, of, 'G6Pase,', 'CYP7A1,', and, 'PEPCK', gene, expression, via, novel, mechanism, of, inhibition, of, 'HNF3', activity, and, expand, the, role, of, 'SHP', as, a, coregulator, of, other, family, of, transcription, factors, in, addition, to, nuclear, receptors])].
[sujeto(['We']), verbo([have]), complemento([developed, a, protocol, of, differentiation, of, human, embryonic, stem, cells, '(', 'ES)', towards, 'hepatocyte-like', cells, '(', 'ES-Hep)'])].
[sujeto(['Using', a, set, of, human, adult, markers, including, 'CAAT/enhancer']), verbo([binding]), complemento([protein, '(', 'C/EBPalpha),', hepatocyte, nuclear, factor, 4, /, 7, ratio, '(', 'HNF4alpha1/HNF4alpha7),', cytochrome, 'P450', 7, 'A1', '(', 'CYP7A1),', 'CYP3A4', and, constitutive, androstane, receptor, '(', 'CAR),', and, fetal, markers, including, 'alpha-fetoprotein,', 'CYP3A7', and, glutathione, 'S-transferase', 'P1,', we, analyzed, the, expression, of, a, panel, of, 41, genes, in, 'ES-Hep', comparatively, with, human, adult, primary, 'hepatocytes,', adult, and, fetal, liver])].
[sujeto(['When', compared, with, 'hepatocyte-like', cells, derived, from, adult, liver, non, parenchymal, epithelial, '(', 'NPE)', cells, '(', 'NPE-Hep),', 'ES-Hep']), verbo([expressed]), complemento([several, adult, and, fetal, liver, makers, at, much, greater, levels, '(', at, least, one, order, of, 'magnitude),', consistent, with, greater, expression, of, 'liver-enriched', transcription, factors, 'Forkhead', box, 'A2,', 'C/EBPalpha,', 'HNF4alpha', and, 'HNF6'])].
[sujeto(['Finally', we, showed, that, 'lentivirus-mediated', expression, of, xenoreceptor, 'CAR', in, 'ES-Hep']), verbo([induced]), complemento([the, expression, of, several, detoxification, genes, including, 'CYP2B6,', 'CYP2C9,', 'CYP3A4,', 'UDP-glycosyltransferase', 1, 'A1,', solute, carriers, 21, 'A6,', as, well, as, biotransformation, of, 'midazolam,', a, 'CYP3A4-specific', substrate])].
[sujeto(['We']), verbo([found]), complemento([that, the, hepatic, differentiation, of, maGSCs, was, induced, by, the, 'OP9', 'co-culture', system, in, comparison, to, the, gelatin, culture])].
[sujeto(['Furthermore,', we, showed, that, the, combination, of, 'OP9', 'co-culture', with, activin, 'A', resulted, in, the]), verbo([increased]), complemento([expression, of, endodermal, and, early, hepatic, markers, 'Gata4,', 'Sox17,', 'Foxa2,', 'Hnf4,', 'Afp,', and, 'Ttr', compared, to, differentiated, cells, on, gelatin, or, on, 'OP9', alone])].
[sujeto(['These', generated, hepatic, cells, successfully, demonstrated, in, vitro, functions]), verbo([associated]), complemento([with, mature, 'hepatocytes,', including, albumin, and, urea, 'secretion,', glycogen, 'storage,', and, uptake, of, 'low-density', lipoprotein])].
[sujeto(['Specification', of, these, progenitors, with, bone, morphogenetic, 'protein-4', in, combination, with, basic, fibroblast, growth, factor, and, activin, 'A', results, in, the, development, of, hepatic, populations, highly, enriched, '(', 45, -, 70, '%', ')', for, cells, that]), verbo([express]), complemento([the, 'alpha-fetoprotein', and, albumin, proteins])].
[sujeto(['These', cells, also]), verbo([express]), complemento([transcripts, of, 'Afp,', 'Alb1,', 'Tat,', 'Cps1,', 'Cyp7a1', and, 'Cyp3a11;', they, secrete, 'albumin,', store, 'glycogen,', show, ultrastructural, characteristics, of, mature, 'hepatocytes,', and, are, able, to, integrate, into, and, proliferate, in, injured, livers, in, vivo, and, mature, into, hepatocytes, expressing, dipeptidyl, peptidase, 'IV', or, fumarylacetoacetate, hydrolase])].
[sujeto(['Together,', these, findings, establish, a, developmental, pathway, in, embryonic, stem, cell, differentiation, cultures, that]), verbo([leads]), complemento([to, efficient, generation, of, cells, with, an, immature, hepatocytic, phenotype])].
[sujeto(['Corneal', epithelium, is]), verbo([maintained]), complemento([by, a, population, of, stem, cells, '(', 'SCs)', that, have, not, been, identified, by, specific, molecular, markers])].
[sujeto(['The', objective, of, this, study, was, to]), verbo([find]), complemento([new, putative, markers, for, these, 'SCs', and, to, identify, associated, molecular, pathways])].
[sujeto(['RT²-PCR-A', results, indicated, an]), verbo([increased]), complemento([or, decreased, expression, in, 21, and, 24, 'genes,', 'respectively,', in, cells, from, the, corneal, 'SC', niche, compared, to, cells, from, the, central, corneal, epithelium])].
[sujeto(['Functional', analysis, by, proprietary, software]), verbo([found]), complemento([4, different, associated, pathways, and, a, novel, network, with, the, highest, upregulated, genes, in, the, corneal, 'SC', niche])].
[sujeto(['This']), verbo([led]), complemento([to, the, identification, of, specific, 'molecules,', chemokine, '(', 'C-X-C', 'motif)', ligand, 12, '(', 'CXCL12),', 'islet-1', transcription, factor, 'LIM/homeodomain', '(', 'ISL1),', 'collagen-type', 'II', alpha, 1, '(', 'COL2A),', neural, cell, adhesion, molecule, 1, '(', 'NCAM1),', aggrecan, '(', 'ACAN),', forkhead, box, 'A2', '(', 'FOXA2),', 'Gap', junction, protein, beta, 1, /, connexin, 32, '(', 'GJB1/Cnx32),', and, 'Msh', homeobox, 1, '(', 'MSX1),', that, could, be, used, to, recognize, putative, corneal, epithelial, 'SCs', grown, in, culture, and, intended, for, transplantation])].
[sujeto(['Knowledge', of, these, gene, and, molecular, pathways]), verbo([has]), complemento([provided, a, better, understanding, of, the, signaling, molecular, pathways, associated, with, 'progenitor-rich', limbal, epithelium])].
[sujeto(['FoxO1']), verbo([binds]), complemento([to, insulin, response, elements, located, in, the, promoters, of, 'insulin-like', growth, 'factor-binding', protein, 1, '(', 'IGFBP1)', and, 'glucose-6-phosphatase', '(', 'G6Pase),', activating, their, expression])].
[sujeto(['Insulin-mediated', phosphorylation, of, 'FoxO1']), verbo([promotes]), complemento([cytoplasmic, 'translocation,', inhibiting, 'FoxO1-mediated', transactivation])].
[sujeto(['We']), verbo([have]), complemento([previously, demonstrated, that, 'FoxO1', opens, and, remodels, chromatin, assembled, from, the, 'IGFBP1', promoter, via, a, highly, conserved, winged, helix, motif])].
[sujeto(['This', 'finding,', which, established, 'FoxO1', as, a, &, 'quot;pioneer&quot;', 'factor,']), verbo([suggested]), complemento([a, model, whereby, 'FoxO1', chromatin, remodeling, at, regulatory, targets, facilitates, binding, and, recruitment, of, additional, regulatory, factors])].
[sujeto(['However,', the, impact, of, 'FoxO1', phosphorylation, on, its, ability, to]), verbo([bind]), complemento([chromatin, and, the, effect, of, 'FoxO1', loss, on, recruitment, of, neighboring, transcription, factors, at, its, regulatory, targets, in, liver, chromatin, is, unknown])].
[sujeto(['In', this, 'study,', we, demonstrate, that, an, amino, acid, substitution, that, mimics, 'insulin-mediated', phosphorylation, of, a, serine, in, the, winged, helix, 'DNA']), verbo([binding]), complemento([motif, curtails, 'FoxO1', nucleosome, binding])].
[sujeto(['We', also, demonstrate, that, 'shRNA-mediated']), verbo([loss]), complemento([of, 'FoxO1', binding, to, the, 'IGFBP1', and, 'G6Pase', promoters, in, 'HepG2', cells, significantly, reduces, binding, of, 'RNA', polymerase, 'II', and, the, pioneer, factors, 'FoxA1/A2'])].
[sujeto(['Knockdown', of, 'FoxA1', similarly, reduced]), verbo([binding]), complemento([of, 'RNA', polymerase, 'II', and, 'FoxO1'])].
[sujeto(['Reduction', in, acetylation, of, histone, 'H3', 'Lys-27', accompanies]), verbo([loss]), complemento([of, 'FoxO1', and, 'FoxA1/A2', binding])].
[sujeto(['Interdependent']), verbo([binding]), complemento([of, 'FoxO1', and, 'FoxA1/A2', possibly, entails, cooperative, binding, because, 'FoxO1', and, 'FoxA1/A2', facilitate, one, 'another\'s', binding, to, 'IGFPB1', promoter, 'DNA'])].
[sujeto(['These', results, illustrate, how, transcription, factors, can, nucleate, transcriptional, events, in, chromatin, in, response, to, signaling, events, and]), verbo([suggest]), complemento([a, model, for, regulation, of, hepatic, glucose, metabolism, through, interdependent, 'FoxO/FoxA', binding])].
[sujeto([5, mouse, 'brain,', we]), verbo([found]), complemento([that, 'Shh', and, its, receptor, 'Ptch1', define, two, adjacent, mutually, exclusive, gene, expression, 'domains:', 'Shh+Ptch1-', and, 'Shh-Ptch1+'])].
[sujeto(['These', two, domains, are]), verbo([associated]), complemento([respectively, with, 'Foxa2', and, 'Gata3,', two, transcription, factors, that, play, key, roles, in, specifying, them])].
[sujeto(['Important', 'Gata3']), verbo([targets]), complemento([include, 'Slit2', and, 'Slit3,', which, are, involved, in, the, process, of, axon, 'guidance,', as, well, as, 'Slc18a1,', 'Th', and, 'Qdpr,', which, are, associated, with, neurotransmitter, synthesis, and, release])].
[sujeto(['By', 'contrast,', 'Foxa2', both, 'up-regulates', the, genes]), verbo([expressed]), complemento([in, the, 'Shh+Ptch1-', domain, and, 'down-regulates', the, genes, characteristic, of, the, 'Shh-Ptch1+', domain])].
[sujeto(['Our', work]), verbo([provides]), complemento([the, first, 'genome-wide', characterization, of, the, gene, regulatory, network, involved, in, the, 'Shh', pathway, that, underlies, pattern, formation, in, the, early, mouse, brain])].
[sujeto(['The', aryl, hydrocarbon, receptor, '(', 'AhR)', is, a, 'ligand-activated', transcription, factor, that]), verbo([mediates]), complemento([diverse, dioxin, toxicities])].
[sujeto(['While', the, acute, effects, of, activation, of, the, 'AhR', pathway, by, 2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD)']), verbo([have]), complemento([been, a, focus, of, past, 'study,', the, role, of, this, pathway, in, normal, physiology, and, ageing, is, unclear])].
[sujeto(['Adult', pregnant, 'Lewis', rat, dams, were, dosed, with, corn, oil, vehicle, or, 'TCDD', '(', 50, 'ng/kg-week', by, 'gavage)', on, days, 14, and, 21, of, gestation, and, 'post-natal', days, 7, and, 14, to]), verbo([provide]), complemento([in, utero, and, lactational, '(', 'IUL)', exposure, to, pups])].
[sujeto(['Data', analysis, revealed, an, accelerated, onset, of, acyclicity, by, 5, months, in, all, groups]), verbo([involving]), complemento(['IUL', exposure, of, the, developing, ovary, to, 'TCDD'])].
[sujeto([17, 'beta-oestradiol', was, significantly]), verbo([decreased]), complemento([in, animals, receiving, 'TCDD', during, 'IUL', exposure, of, the, 'H-H', axis])].
[sujeto(['This', study]), verbo([reveals]), complemento([a, particular, sensitivity, of, the, developing, ovary, to, 'TCDD', leading, to, early, loss, of, reproductive, function, with, age])].
[sujeto(['Xenobiotic', and, drug, metabolism, and, transport, are, managed, by, a, large, number, of, genes, coordinately]), verbo([regulated]), complemento([by, at, least, three, nuclear, receptors, or, 'xenosensors:', aryl, hydrocarbon, receptor, '(', 'AhR),', constitutive, androstane, receptor, '(', 'CAR,', 'NR1I3),', and, pregnane, 'X', receptor, '(', 'PXR,', 'NR1I2)'])].
[sujeto(['Initially', characterized, as, 'xenosensors,', it, is, now, evident, that, 'CAR', and, 'PXR', also]), verbo([trigger]), complemento([pleiotropic, effects, on, liver, function])].
[sujeto(['Recent', studies]), verbo([have]), complemento([shown, the, existence, of, crosstalk, between, xenosensors, and, other, nuclear, receptors, or, transcription, factors, controlling, endogenous, signaling, pathways, which, regulate, physiological, functions])].
[sujeto(['Such', crosstalks, explain, clinical, observations, and]), verbo([provide]), complemento([molecular, mechanisms, allowing, understanding, how, xenobiotics, and, drugs, may, affect, physiological, functions, and, provoke, endocrine, disruptions])].
[sujeto(['Cytochrome', 'P450', 2, 'A2', '(', 'CYP2A2)', is, an, adult, 'male-specific', rat, liver, steroid, hydroxylase, whose, 'sex-dependent', expression, is]), verbo([regulated]), complemento([at, the, transcriptional, level, by, sexually, dimorphic, pituitary, growth, hormone, '(', 'GH)', secretory, patterns])].
[sujeto(['In', contrast, to, 'CYP2C11', and, other, 'male-specific,', plasma, 'GH', 'pulse-inducible', liver, 'genes,', 'CYP2A2', is, highly]), verbo([expressed]), complemento([in, hypophysectomized, rat, 'liver,', despite, the, absence, of, 'GH', stimulation])].
[sujeto(['A', further, approximately, 2.5, -, fold]), verbo([increase]), complemento([in, activity, was, obtained, by, cotransfection, of, hepatocyte, nuclear, factor, '(', 'HNF)', 3, gamma, or, 'HNF4alpha'])].
[sujeto(['CYP2A2', promoter, activity, was]), verbo([inhibited]), complemento([approximately, 85, '%', by, transfection, of, 'HNF3beta', or, 'HNF6,', both, of, which, are, more, highly, expressed, in, female, than, male, liver, and, can, strongly, 'trans-activate', the, 'female-specific', 'CYP2C12', promoter])].
[sujeto(['By', 'contrast,', 'STAT5b', synergistically]), verbo([enhanced]), complemento([the, transcriptional, activity, of, 'HNF4alpha', toward, two, other, 'male-specific', liver, target, 'genes,', 'Cyp2d9', and, 'CYP8B1'])].
[sujeto(['Furthermore,', 'STAT5b', in, combination, with, the, 'HNF4alpha', coactivator, peroxisome, 'proliferator-activated', receptor, gamma, 'coactivator-1alpha', strongly]), verbo([enhanced]), complemento([the, transcriptional, activity, of, 'HNF4alpha', toward, 'CYP8B1', but, not, toward, 'CYP2A2'])].
[sujeto(['These', findings, support, the, hypothesis, that, 'sex-dependent', 'HNFs', contribute, to, the, sexually, dimorphic, expression, of, 'CYP2A2', and, other, liver, 'CYPs', and, highlight, the, ability, of, 'STAT5b', to]), verbo([act]), complemento([in, concert, with, 'HNF4alpha', to, regulate, select, 'male-specific', liver, 'CYP', genes])].
[sujeto(['In', particular, the, parenchymal, liver, cells, or, hepatocytes, are]), verbo([targeted]), complemento([since, they, are, the, major, sites, of, drug, transport, and, of, metabolite, formation, and, thus, also, the, place, where, not, only, 'detoxification,', but, also, activation, of, new, chemical, '(', 'NCE)', and, biological, '(', 'NBE)', entities, may, occur])].
[sujeto(['However,', within, a, few, 'days,', they, undergo, dedifferentiation, with]), verbo([loss]), complemento([of, 'liver-specific', 'functionality,', including, xenobiotic, biotransformation, 'capacity,', making, them, only, suitable, for, 'short-term', applications])].
[sujeto(['A', plausible, alternative, to, primary, hepatocyte, cultures, that, can, be]), verbo([maintained]), complemento([for, longer, periods, of, time, could, be, the, use, of, 'liver-derived', epithelial, cell, lines, and, their, optimized, derivatives])].
[sujeto(['Undifferentiated', rLEC, stably]), verbo([express]), complemento([the, hepatic, progenitor, markers, 'CEBPA,', 'FOXA2,', 'GJA1,', 'ONECUT1,', 'KRT18', and, 'KRT19', for, at, least, 15, consecutive, passages, after, cryopreservation])].
[sujeto(['Upon', sequential, exposure, to, hepatogenic, growth, factors, and, 'cytokines,', rLEC, generate, functional, hepatic, 'progeny,']), verbo([expressing]), complemento([mature, hepatic, markers, including, 'Alb,', 'Ahr,', 'Car,', 'C/ebpα,', 'Cx32,', 'Foxa2,', 'Hnf1α,', 'Hnf1β', and, 'Onecut1'])].
[sujeto(['rLEC-derived', hepatic, cells, also, acquire, the, ability, to, store, 'glycogen,']), verbo([express]), complemento([genes, encoding, for, key, hepatic, enzymes, as, shown, by, 'Affymetrix', microarray, 'data,', and, display, stable, 'CYP1A1/2-', and, 'CYP2B1/2-dependent', activities, for, several, weeks, at, levels, comparable, to, those, observed, in, cultured, primary, rat, hepatocytes])].
[sujeto(['Many', different, markers]), verbo([have]), complemento([been, attributed, to, these, 'cells,', but, their, nature, still, remains, obscure])].
[sujeto(['This', study, is, a, detailed, gene, expression, analysis, aimed, at]), verbo([revealed]), complemento([their, identity, and, repopulating, in, vivo, capacity])].
[sujeto(['Oval', cells, were]), verbo([activated]), complemento([in, 2, -, 'acetylaminofluorene-treated', rats, subjected, to, partial, hepatectomy, or, in, 'D-galactosamine-treated', rats])].
[sujeto(['We']), verbo([found]), complemento([that, 'EpCAM(+)', and, 'Thy-1(+)', cells, represent, two, different, populations, of, cells, in, the, oval, cell, niche])].
[sujeto(['EpCAM(+)', cells]), verbo([express]), complemento([the, classical, oval, cell, markers, '(', 'alpha-fetoprotein,', 'cytokeratin-19,', 'OV-1', 'antigen,', a6, 'integrin,', and, connexin, 43, ')', ',', cell, surface, markers, recently, identified, by, us, '(', 'CD44,', 'CD24,', 'EpCAM,', aquaporin, 5, ',', 'claudin-4,', secretin, 'receptor,', 'claudin-7,', 'V-ros', sarcoma, virus, oncogene, homolog, 1, ',', cadherin, 22, ',', 'mucin-1,', and, 'CD133),', and, 'liver-enriched', transcription, factors, '(', forkhead, box, 'q,', forkhead, box, 'a2,', onecut, 1, ',', and, transcription, factor, 2, ')'])].
[sujeto(['Oval', cells, do, not]), verbo([express]), complemento([previously, reported, hematopoietic, stem, cell, markers, 'Thy-1,', 'c-kit,', and, 'CD34', or, the, neuroepithelial, marker, neural, cell, adhesion, molecule, 1])].
[sujeto(['However,', oval, cells]), verbo([express]), complemento([a, number, of, mesenchymal, markers, including, 'vimentin,', 'mesothelin,', bone, morphogenetic, protein, 7, ',', and, 'Tweak', receptor, '(', tumor, necrosis, factor, receptor, 'superfamily,', member, 12, 'A)'])].
[sujeto(['A', group, of, novel, differentially]), verbo([expressed]), complemento([oval, cell, genes, is, also, presented])].
[sujeto(['Transplantation', experiments]), verbo([reveal]), complemento([that, 'EpCAM(+)', cells, are, true, progenitors, capable, of, repopulating, injured, rat, liver])].
[sujeto(['We']), verbo([have]), complemento([shown, that, 'EpCAM(+)', oval, cells, are, bipotential, adult, hepatic, epithelial, progenitors])].
[sujeto(['These', cells, display, a, mixed, 'epithelial/mesenchymal', phenotype, that]), verbo([has]), complemento([not, been, recognized, previously])].
[sujeto(['Here', we]), verbo([report]), complemento([that, 'BCa', cells, are, dependent, on, a, mechanism, to, supply, precursors, for, intracellular, lipid, production, derived, from, extracellular, sources, and, that, the, endothelial, lipase, '(', 'LIPG)', fulfils, this, function])].
[sujeto(['LIPG', is, ubiquitously, and, highly]), verbo([expressed]), complemento([under, the, control, of, 'FoxA1', or, 'FoxA2', in, all, 'BCa', subtypes])].
[sujeto(['The', downregulation, of, either, 'LIPG', or, 'FoxA', in, transformed, cells, results, in]), verbo([decreased]), complemento([proliferation, and, impaired, synthesis, of, intracellular, lipids])].
[sujeto(['Limited', adult, dopaminergic, neurogenesis]), verbo([has]), complemento([led, to, novel, therapeutic, strategies, such, as, transplantation, of, dopaminergic, precursors, '(', 'DPs)'])].
[sujeto(['Here,', we, demonstrate, the, direct, conversion, of, mouse, fibroblasts, into]), verbo([induced]), complemento(['DPs', '(', 'iDPs)', by, ectopic, expression, of, 'Brn2,', 'Sox2', and, 'Foxa2'])].
[sujeto(['After', transplantation, into, 'MPTP-lesioned', 'mice,', iDPs, differentiated, into, 'DA', 'neurons,', functionally, alleviated, the, motor, 'deficits,', and, reduced, the]), verbo([loss]), complemento([of, striatal, 'DA', neuronal, axonal, termini])].
[sujeto(['We', propose, that, the, iDPs, from, direct, reprogramming]), verbo([provides]), complemento([a, safe, and, efficient, cell, source, for, 'PD', treatment])].
[sujeto(['Farnesol', is, a, 'non-cyclic', sesquiterpene, '(', 'isoprenoid)']), verbo([found]), complemento([in, the, essential, oils, of, many, plants])].
[sujeto(['Therefore,', farnesyltransferase, is, a]), verbo([target]), complemento([for, drug, development, to, inhibit, 'Ras'])].
[sujeto(['Tumors', frequently, develop, resistance, towards, standard, 'chemotherapies,', and, thus, novel, agents, are, urgently]), verbo([required]), complemento([that, bypass, the, 'cross-resistance', evoked, by, established, anticancer, drugs])].
[sujeto(['Remarkably,', none, of, these, genes]), verbo([conferred]), complemento([resistance, to, 'farnesol,', indicating, that, this, compound, may, be, useful, for, the, treatment, of, otherwise, 'drug-resistant', and, refractory, tumors, expressing, these, mechanisms, of, resistance])].
[sujeto(['Among', the, candidates, were, genes]), verbo([involved]), complemento([in, apoptosis, '(', 'STAB2,', 'NUMBL),', regulation, of, transcription, '(', 'CDYL,', 'FOXA2)', and, diverse, other, functional, groups, '(', 'INE1,', 'CTRL,', 'MRS2,', 'NEB,', 'LMO7,', 'C9orf3,', 'EHBP1)'])].
[sujeto(['The', fact, that, these, genes, are, not]), verbo([associated]), complemento([with, resistance, to, traditional, anticancer, drugs, suggests, farnesol, may, possess, a, novel, mechanism, of, 'action,', and, consequently, might, bypass, drug, resistance, to, established, chemotherapeutics])].
[sujeto(['We']), verbo([targeted]), complemento([the, reverse, tetracycline, controlled, transactivator, '(', 'rtTA)', to, the, 'Foxa2', locus, '(', 'Foxa2(ITA))', to, generate, a, system, for, regulating, 'Cre-recombinase', activity, within, 'Foxa2', expression, 'domains,', including, the, 'endoderm,', 'notochord,', and, floor, plate, of, early, mouse, embryos])].
[sujeto(['The', use, of, an, internal, ribosomal, entry, site, to, obtain, rtTA, expression, preserves, 'Foxa2', function, of, the]), verbo([targeted]), complemento([allele])].
[sujeto(['This', system, will]), verbo([provide]), complemento([a, useful, tool, for, manipulating, gene, expression, in, 'endoderm,', 'notochord,', and, floor, 'plate,', all, of, which, are, tissues, with, important, structural, and, patterning, functions, during, embryogenesis])].
[sujeto(['Since', the, lung, is, repeatedly, subjected, to, injury, by, pathogens, and, 'toxicants,', maintenance, of, pulmonary, homeostasis]), verbo([requires]), complemento([rapid, repair, of, its, epithelial, surfaces])].
[sujeto(['Expression', of, transcription, factors, active, in, morphogenesis, and, differentiation, of, the, embryonic, 'lung,', including, 'beta-catenin,', 'Foxa2,', 'Foxj1,', and, 'Sox', family, members, '(', 'Sox17', and, 'Sox2),', was, dynamically]), verbo([regulated]), complemento([during, repair, and, redifferentiation, of, the, bronchiolar, epithelium, after, naphthalene, injury])].
[sujeto(['Squamous', cells, derived, from, ciliated, cells, spread, beneath, injured, 'Clara', cells, within, 6, -, 12, h, after, 'injury,']), verbo([maintaining]), complemento([the, integrity, of, the, epithelium])].
[sujeto(['Agonists', for, the]), verbo([nuclear]), complemento([receptor, peroxisomal, 'proliferator-activated', 'receptor-gamma', '(', 'PPARgamma)', and, its, heterodimeric, 'partner,', retinoid, 'X', receptor, '(', 'RXR),', are, effective, agents, for, the, treatment, of, type, 2, diabetes])].
[sujeto(['To']), verbo([gain]), complemento([insight, into, the, antidiabetic, action, of, these, 'compounds,', we, treated, female, 'Zucker', diabetic, rats, '(', 'ZFF)', with, 'AGN194204,', which, we, show, to, be, a, 'homodimer-specific', 'RXR', 'agonist,', or, the, 'PPARgamma', 'agonist,', troglitazone])].
[sujeto(['AGN194204', had, no, effect, on, peripheral, glucose, 'utilization,', whereas, troglitazone]), verbo([increased]), complemento(['insulin-stimulated', glucose, utilization, by, 50, '%', ',', glucose, uptake, into, skeletal, muscle, by, 85, '%', ',', and, de, novo, skeletal, muscle, glycogen, synthesis, by, 300, '%'])].
[sujeto(['Troglitazone']), verbo([increased]), complemento([skeletal, muscle, 'Irs-1', and, 'phospho-Akt', levels, following, in, vivo, insulin, 'treatment,', whereas, 'AGN194204', increased, hepatic, 'Irs-2', and, insulin, stimulated, 'phospho-Akt', in, liver])].
[sujeto(['Gene', profiles, of, 'AGN194204-treated', mouse, liver, analyzed, by, 'Ingenuity', 'Pathway', 'Analysis', identified]), verbo([increases]), complemento([in, fatty, acid, synthetic, 'genes,', including, 'Srebp-1', and, fatty, acid, 'synthase,', a, pathway, previously, shown, to, be, induced, by, 'RXR', agonists])].
[sujeto(['A', network, of, 'down-regulated', genes, containing, 'Foxa2,', 'Foxa3,', and, 'G-protein', subunits, was, 'identified,', and]), verbo([decreases]), complemento([in, these, mRNA, levels, were, confirmed, by, quantitative, reverse, 'transcription-PCR'])].
[sujeto(['Treatment', of, 'HepG2', cells, with, 'AGN194204', resulted, in, inhibition, of, 'glucagon-stimulated', cAMP, accumulation]), verbo([suggesting]), complemento([the, 'G-protein', 'down-regulation', may, provide, an, additional, mechanism, for, hepatic, insulin, sensitization, by, 'RXR'])].
[sujeto(['These', studies, demonstrate, distinct, molecular, events]), verbo([lead]), complemento([to, insulin, sensitization, by, high, affinity, 'RXR', and, 'PPARgamma', agonists])].
[sujeto(['Although']), verbo([expressed]), complemento([in, all, cells, at, the, early, 'stages,', in, the, adult, it, is, mainly, restricted, to, the, 'beta-cell'])].
[sujeto(['DNase', 'I', footprinting, analysis, revealed, two, protected, 'regions,', one]), verbo([binding]), complemento([the, transcription, factors, 'SP1', and, 'SP3', and, the, other, hepatocyte, nuclear, factor, 3, beta, '(', 'HNF-3beta)', and, 'HNF-1alpha'])].
[sujeto(['Cotransfection', experiments]), verbo([suggest]), complemento([that, 'HNF-3beta,', 'HNF-1alpha,', and, 'SP1', are, positive, regulators, of, the, 'herein-described', human, 'PDX-1', enhancer, element])].
[sujeto(['Furthermore,', mutations, within, each, motif, abolished, the]), verbo([binding]), complemento([of, the, corresponding, 'factor(s)', and, dramatically, impaired, the, enhancer, 'activity,', therefore, suggesting, cooperativity, between, these, factors])].
[sujeto(['To', address, the, question, whether, these, enzymatic, alterations, result, from, specific, changes, in, the, levels, of, 'hepatocyte-enriched']), verbo([nuclear]), complemento([factors, '(', 'HNF),', we, analysed, the, mRNA, levels, of, six, different, 'HNFs', '(', 'HNF-1alpha,', 'beta,', 'HNF-3alpha,', 'beta,', 'gamma,', and, 'HNF-4)', by, 'RNase', protection, assay, in, chemically, induced, liver, tumours, and, corresponding, normal, liver, tissue, from, mice, of, three, different, strains])].
[sujeto(['When', compared, with, the, normal, liver, 'tissue,', 'HNF-1beta,', 'HNF-3alpha', and, 'HNF-3beta', showed, unchanged, expression, levels, in, the, various, liver, 'tumours,', which, 'HNF-1alpha', and, 'HNF-4', mRNAs, were, lowered, by, 20, -, 30, '%', ',', and, 'HNF-3gamma', mRNA, was]), verbo([increased]), complemento([by, 50, '%'])].
[sujeto(['We']), verbo([found]), complemento([a, substantial, reduction, in, cancer, risk, '(', 'OR', 0.39, ;, 95, '%', 'CI', 0.25, -, 0.61, ;, 'Pinteraction', =, 0.029, ')', associated, with, combined, genotypes, for, 'CYP2A13', 'R257C', and, a, functionary, regulatory, variant, in, the, cis, element, of, 'ABCB1', synergistically, targeted, by, 'GATA', binding, protein, 6, and, 'FOXA2'])].
[sujeto(['Genetic', manipulation, of, 'FOXA2', consistently, influenced, its]), verbo([binding]), complemento([to, and, transactivation, of, the, promoters, of, 'CYP2A13,', 'UGT2B17,', and, 'ABCB1,', whose, mRNA, and, protein, expressions, were, all, consistently, correlated, with, those, of, 'FOXA2', in, both, tumorous, and, normal, lung, tissues])].
[sujeto(['We', previously, identified, polymorphisms, in, pregnane, 'X', receptor, '(', 'PXR)', and, 'ATP-binding', cassette, subfamily, 'B', member, 1, '(', 'ABCB1)']), verbo([associated]), complemento([with, 'CYP3A4', mRNA, levels, in, small, cohorts, of, human, livers])].
[sujeto(['We', resequenced, hepatic]), verbo([nuclear]), complemento(['factor-3-beta', '(', 'HNF3beta,', 'FoxA2),', 'HNF4alpha,', 'HNF3gamma', '(', 'FoxA3),', nuclear, receptor, corepressor, 2, '(', 'NCoR2),', and, regions, of, the, 'CYP3A4', promoter, and, genotyped, informative, 'single-nucleotide', polymorphisms, in, 'PXR', and, 'ABCB1', in, the, same, livers])].
[sujeto(['A', common, silent, polymorphism, and, a, polymorphic, trinucleotide, '(', 'CCT)', repeat, in, 'FoxA2', were]), verbo([associated]), complemento([with, 'CYP3A4', expression])].
[sujeto(['The', transcriptional, activity, of, the, 'FoxA2', polymorphic, 'CCT', repeat, alleles, '(', 'wild-type,', n, =, 14, and, 'variant,', n, =, 13, ',', 15, ',', and, 19, ')', when, assayed, by, luciferase, reporter, transactivation, assays, was, greatest, for, the, 'wild-type', 'repeat,', with, deviations, from, this, number, having]), verbo([decreased]), complemento([transcriptional, activity])].
[sujeto(['This', corresponded, with, higher, expression, of, 'FoxA2', mRNA, and, its]), verbo([targets]), complemento(['PXR', and, 'CYP3A4', in, human, livers, with, '(', 'CCT)', n, =, 14, genotypes])].
[sujeto(['Nuclear', receptors, constitutive, 'active/androstane', receptor, '(', 'CAR)', and, pregnane, 'X', receptor, '(', 'PXR)', were, originally, characterized, as, transcription, factors]), verbo([regulating]), complemento([the, hepatic, genes, that, encode, drug, metabolizing, enzymes])].
[sujeto(['Recent', works]), verbo([have]), complemento([now, revealed, that, these, nuclear, receptors, also, play, the, critical, roles, in, modulating, hepatic, energy, metabolism])].
[sujeto(['While', 'CAR', and, 'PXR', directly]), verbo([bind]), complemento([to, their, response, sequences, 'phenobarbital-responsive', enhancer, module, '(', 'PBREM)', and, xenobiotic, responsive, enhancer, module, '(', 'XREM)', in, the, promoter, of, target, genes, to, increase, drug, 'metabolism,', the, receptors, also, cross, talk, with, various, hormone, responsive, transcription, factors, such, as, forkhead, box, 'O1', '(', 'FoxO1),', forkhead, box, 'A2', '(', 'FoxA2),', 'cAMP-response', element, binding, 'protein,', and, peroxisome, proliferator, activated, receptor, gamma, coactivator, 1, alpha, '(', 'PGC', 1, 'alpha)', to, decrease, energy, metabolism, through, 'down-regulating', 'gluconeogenesis,', fatty, acid, oxidation, and, ketogenesis, and, 'up-regulating', lipogenesis])].
[sujeto(['In', 'addition,', 'CAR']), verbo([modulates]), complemento([thyroid, hormone, activity, by, regulating, type, 1, deiodinase, in, the, regenerating, liver])].
[sujeto(['Cytochrome', 'P450', 3, 'A4', '(', 'CYP3A4)', is, the, major, cytochrome, 'P450', present, in, adult, human, liver, and, is]), verbo([involved]), complemento([in, the, metabolism, of, over, 50, '%', of, therapeutic, compounds, currently, in, use])].
[sujeto(['Since', expression, levels, of, 'CYP3A4', are]), verbo([regulated]), complemento([by, many, of, these, 'compounds,', this, raises, the, potential, for, 'drug-drug', interactions, and, subsequent, altered, efficacy, or, toxicity, of, the, individual, compounds, at, the, dose, prescribed])].
[sujeto(['To', examine, this, we]), verbo([have]), complemento([used, 'DNase', 'I', footprinting, and, bioinformatic, analysis, to, identify, putative, transcription, factor, binding, sites, within, the, 250, base, pairs, of, promoter, proximal, to, the, transcription, start, site])].
[sujeto(['We', identified, several, protected, fragments, within, this, region, that, corresponded, to, putative]), verbo([binding]), complemento([sites, for, 'Sp1,', 'AP2,', 'CCAAT/enhancer', binding, protein, '(', 'C/EBPalpha),', and, hepatic, nuclear, 'factor-3', '(', 'HNF3),', as, well, as, confirming, previously, identified, 'C/EBPalpha,', pregnane, 'X', receptor, '(', 'PXR),', and, 'HNF3', binding, sites])].
[sujeto(['Sequential', 'site-directed', mutagenesis, of, 'C/EBPalpha,', 'Sp1,', 'HNF3,', and, 'PXR']), verbo([binding]), complemento([sites, was, next, used, to, examine, the, role, of, these, sites, in, basal, 'CYP3A4', expression])].
[sujeto(['Disruption', of, the, 'C/EBPalpha,', 'HNF3,', and, 'PXR']), verbo([binding]), complemento([sites, all, affected, basal, expression])].
[sujeto(['Disruption', of, any, of, these, sites, either]), verbo([led]), complemento([to, an, altered, pattern, of, activation, by, the, 'xenobiotic,', as, altered, maximal, 'activation,', or, altered, the, 'EC(50)', value, of, activation])].
[sujeto(['Chicken', 'CYP2H1', promoter, constructs]), verbo([express]), complemento([strongly, in, chick, embryo, hepatocytes, at, a, level, comparable, with, that, of, 'Rous', sarcoma, viral, promoter])].
[sujeto(['We']), verbo([have]), complemento([identified, the, transcription, factors, responsible, for, the, active, 'CYP2H1', promoter])].
[sujeto(['Protein']), verbo([binding]), complemento([to, these, sites, was, established, by, gel, mobility, shift, assays])].
[sujeto(['The', promoter, was, also, active, in, mammalian, 'HepG2', and, 'COS-1', cell, lines, where, expression, was, dependent, on, the, identified, transcription, factor]), verbo([binding]), complemento([sites, but, promoter, activity, in, the, 'HeLa', cells, was, low])].
[sujeto(['Transactivation', experiments, revealed, that, promoter, expression, could, be]), verbo([activated]), complemento([through, the, appropriate, binding, sites, by, exogenously, expressed, rat, 'HNF-1alpha', or, 'HNF-1beta,', rat, 'HNF-3alpha', or, 'HNF-3beta', and, chicken, 'C/EBP', alpha])].
[sujeto(['By', 'comparison,', in, vivo, expression, of, this, gene, in, uninduced, chick, embryo, hepatocytes, is, low, but, markedly]), verbo([increased]), complemento([by, phenobarbital])].
[sujeto(['RUNX1']), verbo([loss]), complemento([in, 'ER(+)', mammary, epithelial, cells, increases, 'β-catenin,', deregulates, mitosis, and, stimulates, cell, proliferation, and, expression, of, stem, cell, markers])].
[sujeto(['However,', it, does, not]), verbo([stimulate]), complemento(['LEF/TCF,', 'c-Myc', or, 'CCND1,', and, it, does, not, accelerate, 'G1/S', cell, cycle, phase, transition])].
[sujeto(['Finally,', 'RUNX1', 'loss-mediated', deregulation, of, 'β-catenin', and, mitosis, is, ameliorated, by, 'AXIN1', stabilization, in, 'vitro,', highlighting, 'AXIN1', as, a, potential]), verbo([target]), complemento([for, the, management, of, 'ER(+)', breast, cancer])].
[sujeto(['AML1-ETO', is, the, most, common, fusion, oncoprotein]), verbo([causing]), complemento([acute, myeloid, leukemia, '(', 'AML),', a, disease, with, a, 5, -, year, survival, rate, of, only, 24, '%'])].
[sujeto(['While', known, for, decades, to, be, the, translational, product, of, a, chimeric, gene, created, by, the, stable, chromosome, translocation, 't(8;21)(q22;q22),', it, is, not, known, how, 'AML1-ETO', achieves, its, native, and, functional, conformation, or, whether, this, process, can, be]), verbo([targeted]), complemento([for, therapeutic, benefit])].
[sujeto(['We', demonstrate, that, a, folding, intermediate, of, 'AML1-ETO']), verbo([binds]), complemento([to, 'TRiC', 'directly,', mainly, through, its, 'β-strand', 'rich,', 'DNA-binding', domain, '(', 'AML-(1-175)),', with, the, assistance, of, 'HSP70'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'TRiC', contributes, to, 'AML1-ETO', proteostasis, through, specific, interactions, between, the, 'oncoprotein\'s', 'DNA-binding', 'domain,', which, may, be, targeted, for, therapeutic, benefit])].
[sujeto(['Acute', myeloid, leukemia, '(', 'AML)', 1, -, 'Evi-1', is, a, chimeric, gene, generated, by, the, t, '(', 3, ;, 21, ')', '(', 'q26;', 'q22)', 'translocation,', which]), verbo([leads]), complemento([into, malignant, transformation, of, hematopoietic, stem, cells, by, unclear, mechanisms])].
[sujeto(['This', in, vivo, study, aimed, to, establish, a, stable, line, of, zebrafish]), verbo([expressing]), complemento([the, human, 'RUNX1-Evi-1', fusion, gene, under, the, control, of, a, heat, 'stress-inducible', bidirectional, 'promoter,', and, investigate, its, roles, in, hematopoiesis, and, hematologic, malignancies])].
[sujeto(['Consequently,', primitive, hematopoiesis, was]), verbo([enhanced]), complemento([by, upregulation, of, gata2, and, 'scl,', while, erythropoiesis, was, downregulated, due, to, the, suppression, of, gata1])].
[sujeto([1, ',', but, it, was]), verbo([inhibited]), complemento([along, with, the, low, expression, of, mpo])].
[sujeto(['Microarray', analysis, demonstrated, that, 'RUNX1-Evi-1', not, only, upregulated, 'proteasome,', cell, 'cycle,', 'glycolysis/gluconeogenesis,', tyrosine, 'metabolism,', drug, 'metabolism,', and, 'PPAR', 'pathway,', but, also]), verbo([suppressed]), complemento([transforming, growth, factor, 'β,', 'Jak-STAT,', 'DNA', 'replication,', mismatch, 'repair,', p53, 'pathway,', 'JNK', signaling, 'pathway,', and, nucleotide, excision, repair])].
[sujeto(['Factors', in, cell, proliferation, were, obviously]), verbo([suppressed]), complemento([after, 3, -, day, treatment, with, histone, deacetylase, 'inhibitor,', valproic, acid])].
[sujeto(['Accordingly,', higher, proportion, of, 'G1']), verbo([arrest]), complemento([and, apoptosis, were, manifested, by, the, propidium, iodide, staining])].
[sujeto(['RUNX1-Evi-1', may]), verbo([promote]), complemento([proliferation, and, apoptosis, resistance, of, primitive, hematopoietic, 'cell,', and, inhibit, the, differentiation, of, myeloid, cells, with, the, synergy, of, different, pathways, and, factors])].
[sujeto(['VPA', may, be, a, promising, choice, in, the, molecular]), verbo([targeting]), complemento([therapy, of, 'RUNX1-Evi-1-related', leukemia])].
[sujeto(['Two', distantly, located, promoter, regions]), verbo([regulate]), complemento([the, dynamic, expression, of, 'RUNX', genes, during, 'development:', distal, 'P1', and, proximal, 'P2', promoters])].
[sujeto(['We']), verbo([have]), complemento([recently, described, that, 'β-catenin', increases, total, 'Runx1', mRNA, levels, in, human, 'CD34(+)', hematopoietic, progenitors, and, enhances, spatial, proximity, with, its, translocation, partner, 'ETO'])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, induction, of, 'Wnt/β-catenin', signaling, in, 'HL60', and, 'Jurkat', 'leukemia-derived', cell, lines, and, 'CD34(+)', progenitors, selectively, activate, the, production, of, the, longer, distal, 'P1-Runx1', mRNA, isoform])].
[sujeto(['Gain-', and, 'loss-of-function', experiments, revealed, that, the, differential]), verbo([increase]), complemento([in, 'P1-Runx1', expression, is, accomplished, through, a, minimal, 'β-catenin', responsive, region, that, includes, a, highly, conserved, 'TCF/LEF-binding', 'element,', located, -, 20, /, -, 16, bp, upstream, of, the, canonical, distal, 'P1-Runx1', transcription, start, site])].
[sujeto(['We', conclude, that, the, distal, 'P1-Runx1', promoter, is, a, direct, transcriptional]), verbo([target]), complemento([of, 'Wnt/β-catenin', signaling, that, may, be, important, in, normal, hematopoiesis, or, its, transition, into, malignant, stem, cells, during, the, onset, or, progression, of, leukemia])].
[sujeto(['The', generation, of, diverse, neuronal, subtypes]), verbo([involves]), complemento([specification, of, neural, progenitors, 'and,', 'subsequently,', postmitotic, neuronal, 'differentiation,', a, relatively, poorly, understood, process])].
[sujeto(['NGF', signals, through, the, 'ERK/MAPK', pathway, to]), verbo([promote]), complemento([expression, of, 'Cbfb', but, not, 'Runx1', prior, to, maturation, of, nonpeptidergic, nociceptors])].
[sujeto(['Thus,', an, 'NGF/TrkA-MAPK-CBFβ', pathway, converges, with, 'Islet1-Runx1', signaling, to]), verbo([promote]), complemento(['Runx1/CBFβ', holocomplex, formation, and, nonpeptidergic, nociceptor, maturation])].
[sujeto(['Convergence', of, extrinsic, and, intrinsic, signals, to, control, heterodimeric, transcription, factor, complex, formation]), verbo([provides]), complemento([a, robust, mechanism, for, postmitotic, neuronal, subtype, specification])].
[sujeto(['The', 't(8;21)', and, 'Inv(16)', translocations, disrupt, the, normal, function, of, core]), verbo([binding]), complemento([factors, alpha, '(', 'CBFA)', and, beta, '(', 'CBFB),', respectively])].
[sujeto(['Both', translocations, are]), verbo([associated]), complemento([with, favorable, clinical, outcomes, after, intensive, 'chemotherapy,', and, given, the, perceived, mechanistic, 'similarities,', patients, with, these, translocations, are, frequently, referred, to, as, having, 'CBF-AML'])].
[sujeto(['It', remains, uncertain, as, to, 'whether,', 'collectively,', these, translocations, are, mechanistically, the, same, or, impact, different, pathways, in, subtle, ways, that]), verbo([have]), complemento([both, biological, and, clinical, significance])].
[sujeto(['A', total, of, 1291, genes, in, 't(8;21)', and, 474, genes, in, 'Inv(16)', were, differentially]), verbo([expressed]), complemento([relative, to, the, 'NK', 'controls,', with, 198, genes, differentially, expressed, in, both, subtypes])].
[sujeto(['The', majority, of, these, genes, '(', 175, /, 198, ;, binomial, test, 'p-value', &, 'lt;', 10, '(', -, 30, ')', ')', are, consistent, in, expression, changes, among, the, two, subtypes]), verbo([suggesting]), complemento([the, expression, profiles, are, more, similar, between, the, 'CBF', cohorts, than, in, the, 'NK', cohort])].
[sujeto(['Our', analysis, also, revealed, alternative, splicing, events, '(', 'ASEs)', differentially]), verbo([expressed]), complemento([across, 'subtypes,', with, 337, 't(8;21)-specific', and, 407, 'Inv(16)-specific', 'ASEs', 'detected,', the, majority, of, which, were, acetylated, proteins, '(', p, =, 1.5, x, 10, '(', -, 51, ')', and, p, =, 1.8, x, 10, '(', -, 54, ')', for, the, two, 'subsets)'])].
[sujeto(['In', addition, to, known, 'fusions,', we, identified, and, verified, 16, de, novo, fusions, in, 43, 'patients,', including, three, fusions]), verbo([involving]), complemento(['NUP98', in, six, patients])].
[sujeto(['Clustering', of, differentially]), verbo([expressed]), complemento([genes, indicated, that, the, homeobox, '(', 'HOX)', gene, 'family,', including, two, transcription, factors, '(', 'MEIS1', and, 'NKX2-3)', were, 'down-regulated', in, 'CBF', compared, to, 'NK', samples])].
[sujeto(['This']), verbo([finding]), complemento([supports, existing, data, that, the, dysregulation, of, 'HOX', genes, play, a, central, role, in, biology, 'CBF-AML', hematopoiesis])].
[sujeto(['These', data]), verbo([provide]), complemento([comprehensive, transcriptome, profiling, of, 'CBF-AML', and, delineate, genes, and, pathways, that, are, differentially, 'expressed,', providing, insights, into, the, shared, biology, as, well, as, differences, in, the, two, 'CBF', subsets])].
[sujeto(['Chromosomal', translocations, are, frequently]), verbo([associated]), complemento([with, a, wide, variety, of, 'cancers,', particularly, hematologic, malignancies])].
[sujeto(['We']), verbo([report]), complemento([here, that, 'Wnt/β-catenin', signaling, increases, the, expression, of, 'ETO', and, 'RUNX1', genes, in, human, hematopoietic, progenitors])].
[sujeto(['We']), verbo([found]), complemento([that, 'β-catenin', is, rapidly, recruited, into, 'RNA', polymerase, 'II', transcription, factories, '(', 'RNAPII-Ser5)', and, that, 'ETO', and, 'RUNX1', genes, are, brought, into, close, spatial, proximity, upon, 'Wnt3a', induction])].
[sujeto(['Notably,', 'long-term', treatment, of, cells, with, 'Wnt3a']), verbo([induces]), complemento([the, generation, a, frequent, 'RUNX1-ETO', translocation, event])].
[sujeto(['Thus,', 'Wnt/β-catenin', signaling]), verbo([induces]), complemento([transcription, and, translocation, of, 'RUNX1', and, 'ETO', fusion, gene, 'partners,', opening, a, novel, window, to, understand, the, 'onset/development', of, leukemia])].
[sujeto(['Th-inducing', 'Pox', virus, and, zinc, 'finger/Krüppel-like', factor, '(', 'ThPOK)', is, a, key, commitment, factor, for, 'CD4(+)', lineage, 'T', cells, and, is, essential, for, the, maintenance, of, 'CD4', lineage, 'integrity;', 'thus,', the, expression, of, 'ThPOK']), verbo([has]), complemento([to, be, tightly, controlled])].
[sujeto(['In', this, 'article,', we, demonstrate, that, 'Myc-associated', zinc, 'finger-related', factor, '(', 'MAZR)', and, 'Runt-related', transcription, factor, 1, '(', 'Runx1)', together]), verbo([repressed]), complemento(['ThPOK', in, preselection, 'double-positive', 'thymocytes,', whereas, 'MAZR', acted, in, synergy, with, 'Runx3', in, the, repression, of, 'ThPOK', in, 'CD8(+)', 'T', cells])].
[sujeto(['Furthermore,', 'MAZR-Runx1', and, 'MAZR-Runx3', 'double-mutant', mice, showed]), verbo([enhanced]), complemento([derepression, of, 'Cd4', in, 'double-negative', thymocytes, and, in, 'CD8(+)', 'T', cells, in, comparison, with, 'Runx1', or, 'Runx3', 'single-deficient', 'mice,', 'respectively,', indicating, that, 'MAZR', modulates, 'Cd4', silencing])].
[sujeto(['Finally,', retroviral, 'Cre-mediated', conditional, deletion, of, 'MAZR', in, peripheral, 'CD8(+)', 'T', cells]), verbo([led]), complemento([to, the, derepression, of, 'ThPOK,', thus, showing, that, 'MAZR', is, also, part, of, the, molecular, machinery, that, maintains, a, repressed, state, of, 'ThPOK', in, 'CD8(+)', 'T', cells])].
[sujeto(['However,', the, molecular, mechanisms]), verbo([involved]), complemento([in, regulating, the, differentiation, and, function, of, 'MDSCs', remain, largely, unclear])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, inhibition, of, microRNA, '(', 'miR)-9', promoted, the, differentiation, of, 'MDSCs', with, significantly, reduced, immunosuppressive, function, whereas, overexpression, of, 'miR-9', markedly, enhanced, the, function, of, 'MDSCs'])].
[sujeto(['Notably,', knockdown, of, 'miR-9', significantly, impaired, the, activity, of, 'MDSCs', and]), verbo([inhibited]), complemento([the, tumor, growth, of, 'Lewis', lung, carcinoma, in, mice])].
[sujeto(['Moreover,', 'miR-9']), verbo([regulated]), complemento(['MDSCs', differentiation, by, targeting, the, 'runt-related', transcription, factor, 1, ',', an, essential, transcription, factor, in, regulating, 'MDSC', differentiation, and, function])].
[sujeto(['Furthermore,', the, 'CREB', was]), verbo([found]), complemento([to, regulate, 'miR-9', expression, in, 'MDSCs'])].
[sujeto(['Taken', 'together,', our, findings]), verbo([have]), complemento([identified, a, critical, role, of, 'miR-9', in, regulating, the, differentiation, and, function, of, 'MDSCs'])].
[sujeto(['Acute', stimulation, of, 'nucleotide-binding', oligomerization, domain, 2, '(', 'NOD2),', the, 'Crohn\'s', 'disease-associated', sensor, of, bacterial, 'peptidoglycan,']), verbo([induces]), complemento([cytokines])].
[sujeto(['However,', chronic, 'NOD2', stimulation, in, macrophages]), verbo([decreases]), complemento([cytokines, upon, pattern, recognition, receptor, '(', 'PRR)', 'restimulation;', cytokine, attenuation, to, 'PRR', stimulation, is, similarly, observed, in, intestinal, macrophages])].
[sujeto(['The', role, for, the, transcriptional, repressors, 'Twist1', and, 'Twist2', in]), verbo([regulating]), complemento(['PRR-induced', cytokine, outcomes, is, poorly, understood, and, has, not, been, reported, for, 'NOD2'])].
[sujeto(['We']), verbo([found]), complemento([that, 'Twist1', and, 'Twist2', were, required, for, optimal, cytokine, downregulation, during, acute, 'and,', 'particularly,', chronic, 'NOD2', stimulation, of, human, macrophages])].
[sujeto(['Consistently,', 'Twist1', and, 'Twist2', expression, was]), verbo([increased]), complemento([after, chronic, 'NOD2', 'stimulation;', this, increased, expression, was, 'IL-10', and, 'TGF-β', dependent])].
[sujeto(['Although', 'Twist1', and, 'Twist2', did, not, coregulate, each, 'other\'s', 'expression,', they, cooperated, to]), verbo([enhance]), complemento([binding, to, cytokine, promoters, after, chronic, 'NOD2', stimulation])].
[sujeto(['Moreover,', 'Twist1', and, 'Twist2', contributed, to]), verbo([enhance]), complemento([expression, and, promoter, binding, of, the, proinflammatory, inhibitor, 'c-Maf', and, the, transcriptional, repressor, 'Bmi1'])].
[sujeto(['Furthermore,', with, chronic, 'NOD2', 'stimulation,', 'Twist1', and, 'Twist2', contributed, to, the]), verbo([decreased]), complemento([expression, and, cytokine, promoter, binding, of, the, transcriptional, activators, activating, transcription, factor, 4, ',', 'C/EBPα,', 'Runx1,', and, 'Runx2'])].
[sujeto(['Finally,', 'NOD2', synergized, with, additional, 'PRRs', to]), verbo([increase]), complemento(['Twist1', and, 'Twist2', expression, and, 'Twist-dependent', pathways])].
[sujeto(['Therefore,', after, chronic, 'NOD2', stimulation, 'Twist1', and, 'Twist2', coordinate, the, regulation, of, both, transcriptional, activators, and, 'repressors,', thereby]), verbo([mediating]), complemento([optimal, cytokine, downregulation])].
[sujeto(['A', recent, study]), verbo([has]), complemento([shown, that, transcriptional, regulators, of, core, binding, factor, '(', 'Cbf)', β2, and, 'promotor-1-transcribed', 'Runt-related', transcription, factor, 1, '(', 'P1-Runx1)', are, required, for, the, differentiation, of, 'CD3-CD4+CD45+', lymphoid, tissue, inducer, '(', 'LTi)', 'cells,', which, initiate, and, trigger, the, developmental, program, of, 'PPs,', but, the, involvement, of, this, pathway, in, 'NALT', and, 'TALT', development, remains, to, be, elucidated])].
[sujeto(['Here', we]), verbo([report]), complemento([that, 'Cbfβ2', plays, an, essential, role, in, 'NALT', and, 'TALT', development, by, regulating, 'LTi', cell, trafficking, to, the, 'NALT', and, 'TALT', anlagens])].
[sujeto(['Cbfβ2', was]), verbo([expressed]), complemento([in, 'LTi', cells, in, all, three, types, of, 'MALT', examined])].
[sujeto(['Indeed,', similar, to, the, previous]), verbo([finding]), complemento([for, 'PPs,', we, found, that, 'Cbfβ2-/-', mice, lacked, 'NALT', and, 'TALT', lymphoid, structures])].
[sujeto(['Recent', studies, indicate, that, 'DNA', methylation, can, be, used, to, identify, transcriptional, 'enhancers,', but, no, systematic, approach]), verbo([has]), complemento([been, developed, for, 'genome-wide', identification, and, analysis, of, enhancers, based, on, 'DNA', methylation])].
[sujeto(['We', identified, networks]), verbo([regulated]), complemento([by, known, cancer, drivers, such, as, 'GATA3', and, 'FOXA1', '(', breast, 'cancer),', 'SOX17', and, 'FOXA2', '(', endometrial, 'cancer),', and, 'NFE2L2,', 'SOX2,', and, 'TP63', '(', squamous, cell, lung, 'cancer)'])].
[sujeto(['We', propose, 'ELMER', as, a, powerful, new, paradigm, for, understanding, the, 'cis-regulatory', interface, between, 'cancer-associated', transcription, factors, and, their, functional]), verbo([target]), complemento([genes])].
[sujeto(['We', exploited, a, pluripotent, hematopoietic, 'stem/progenitor', cell, 'line,', 'EML1,', and, generated, a, cell, line, '(', 'EML-TA)', stably]), verbo([expressing]), complemento([the, 'TEL-AML1', fusion, protein])].
[sujeto(['Global', gene, expression, profiling, of, 'EML1', cells, at, different, stages, of, 'B-lymphoid', 'differentiation,', compared, with, 'EML-TA,', identified, the, interferon, '(', 'IFN)α/β', pathway, as, a, primary]), verbo([target]), complemento([of, repression, by, 'TEL-AML1'])].
[sujeto(['In', 'particular,', expression, and, phosphorylation, of, 'interferon-regulatory', factor, 3, '(', 'IRF3)', was]), verbo([decreased]), complemento([in, 'EML-TA', 'cells;', 'strikingly,', stable, expression, of, 'IRF3', restored, the, capacity, of, 'EML-TA', cells, to, differentiate, into, mature, 'B-cells'])].
[sujeto(['The', ability, of, 'TEL-AML1', to, block, 'B-cell', differentiation, and, downregulate, the, 'IRF3-IFNα/β', pathway, was, confirmed, in, mouse, and, human, primary, hematopoietic, precursor, cells, '(', 'Lin-', and, 'CD34+', 'cells,', 'respectively),', and, in, a, 'patient-derived', cell, line]), verbo([expressing]), complemento(['TEL-AML1', '(', 'REH)'])].
[sujeto(['Furthermore,', treatment, of, 'TEL-AML1']), verbo([expressing]), complemento([cells, with, 'IFNα/β', was, sufficient, to, overcome, the, maturation, block])].
[sujeto(['Our', data]), verbo([provide]), complemento([new, insight, on, 'TEL-AML1', function, and, may, offer, a, new, therapeutic, opportunity, for, 'B-ALL'])].
[sujeto(['High', mutation, frequencies, of, 'RUNX1', gene, in, chronic, myelomonocytic, leukemia, '(', 'CMML)', and, myelodysplastic, syndromes, '(', 'MDS)']), verbo([have]), complemento([been, 'described,', whereas, the, biologic, significances, of, the, mutations, were, not, investigated])].
[sujeto(['Then,', we, studied, the, 'DNA', and, 'CBFβ']), verbo([binding]), complemento([abilities, of, all, the, 'RUNX1', mutants, identified, by, using, electrophoretic, mobility, shift, assay, and, 'co-immunoprecipitation', 'assay,', and, also, determined, their, activities, on, target, 'C-FMS', gene, induction, by, 'Western', blotting, and, luciferase, reporter, assay])].
[sujeto(['Previously,', it, was, proposed, that, 'CBFβ-SMMHC']), verbo([acts]), complemento([by, dominantly, repressing, the, transcription, factor, 'RUNX1', '(', 'Runt-related', protein, 1, ')', ',', but, we, recently, showed, that, 'CBFβ-SMMHC', has, activities, that, are, independent, of, 'RUNX1', repression])].
[sujeto(['In', 'addition,', we, showed, that, a, modified, 'CBFβ-SMMHC', with]), verbo([decreased]), complemento(['RUNX1-binding', activity, accelerates, leukemogenesis])].
[sujeto(['To', test, 'this,', we, generated, mice]), verbo([expressing]), complemento(['Cbfb-MYH11', in, a, 'Runx1-deficient', 'background,', resulting, from, either, homozygous, 'Runx1-null', alleles, '(', 'Runx1(-/-))', or, a, single, 'dominant-negative', 'Runx1', allele, '(', 'Runx1(+/lz))'])].
[sujeto(['We']), verbo([found]), complemento([that, loss, of, 'Runx1', activity, rescued, the, differentiation, defects, induced, by, 'Cbfb-MYH11', during, primitive, hematopoiesis])].
[sujeto(['During', definitive, 'hematopoiesis,', 'RUNX1']), verbo([loss]), complemento([also, significantly, reduced, the, proliferation, and, differentiation, defects, induced, by, 'Cbfb-MYH11'])].
[sujeto(['The', transcription, factor, fusion, 'CBFβ-SMMHC', '(', core]), verbo([binding]), complemento([factor, β, and, the, 'smooth-muscle', myosin, heavy, 'chain),', expressed, in, 'AML', with, the, chromosome, inversion, 'inv(16)(p13q22),', outcompetes, 'wild-type', 'CBFβ', for, binding, to, the, transcription, factor, 'RUNX1,', deregulates, 'RUNX1', activity, in, 'hematopoiesis,', and, induces, 'AML'])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, development, of, a, 'protein-protein', interaction, 'inhibitor,', 'AI-10-49,', that, selectively, binds, to, 'CBFβ-SMMHC', and, disrupts, its, binding, to, 'RUNX1'])].
[sujeto(['Treatment', of, primary, 'inv(16)', 'AML', patient, blasts, with, 'AI-10-49']), verbo([triggers]), complemento([selective, cell, death])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, direct, inhibition, of, the, oncogenic, 'CBFβ-SMMHC', fusion, protein, may, be, an, effective, therapeutic, approach, for, 'inv(16)', 'AML,', and, they, provide, support, for, transcription, factor, targeted, therapy, in, other, cancers])].
[sujeto([1, +, ')', 'Th1', cells]), verbo([induced]), complemento([colitis, in, 'Rag(-/-)', mice, after, adoptive, transfer, and, converted, into, 'IL-17(+)', 'Th17,', but, not, 'Foxp3(+)', 'Treg', cells, in, the, inflamed, intestines])].
[sujeto(['TGF-β', and, 'IL-6,', but, not, 'IL-1β', and, 'IL-23,']), verbo([regulated]), complemento(['Th1', conversion, into, 'Th17', cells])].
[sujeto(['TGF-β', induction, of, transcriptional, factor, 'Runx1', is, crucial, for, the, 'conversion,', since, silencing, 'Runx1', by, siRNA]), verbo([inhibited]), complemento(['Th1', conversion, into, 'Th17', cells])].
[sujeto(['Furthermore,', 'TGF-β']), verbo([enhanced]), complemento([histone, 'H3K9', acetylation, but, inhibited, 'H3K9', trimethylation, of, 'Runx1-', and, 'ROR-γt-binding', sites, on, 'il-17', or, rorc, gene, in, 'Th1', cells])].
[sujeto(['We', conclude, that, 'Th1', cells, convert, into, 'Th17', cells, under, inflammatory, conditions, in, 'intestines,', which, is, possibly]), verbo([mediated]), complemento([by, 'TGF-β', induction, of, 'Runx1'])].
[sujeto(['Cooperative', assemblies, of, transcription, factors, '(', 'TFs)', on]), verbo([target]), complemento([gene, enhancers, coordinate, cell, 'proliferation,', fate, 'specification,', and, differentiation, through, precise, and, complicated, transcriptional, mechanisms])].
[sujeto(['Chemical', 'modifications,', such, as, 'phosphorylation,', of, 'TFs']), verbo([induced]), complemento([by, cell, signaling, further, modulate, the, dynamic, cooperativity, of, 'TFs'])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, various, 'Ets1-containing', 'TF-DNA', complexes, respond, differently, to, 'calcium-induced', phosphorylation, of, 'Ets1,', which, is, known, to, inhibit, 'Ets1-DNA', binding])].
[sujeto(['Crystallographic', analysis, of, a, complex, comprising, 'Ets1,', 'Runx1,', and, 'CBFβ', at, the, 'TCRα', enhancer, revealed, that, 'Ets1', acquires, robust]), verbo([binding]), complemento([stability, in, the, 'Runx1', and, 'DNA-complexed', 'state,', via, allosteric, mechanisms])].
[sujeto(['This', allows]), verbo([phosphorylated]), complemento(['Ets1', to, be, retained, at, the, 'TCRα', enhancer, with, 'Runx1,', in, contrast, to, other, 'Ets1', target, gene, enhancers, including, 'mb-1', and, 'stromelysin-1'])].
[sujeto(['This', study]), verbo([provides]), complemento([a, 'structure-based', model, for, 'cell-signaling-dependent', regulation, of, target, 'genes,', mediated, via, chemical, modification, of, 'TFs'])].
[sujeto(['The', 2, genes, 'RUNX1', and, 'SP7', resulted, differently]), verbo([expressed]), complemento([in, cells, cultured, on, metallic, supports, if, compared, with, the, expression, recorded, for, 'OIC'])].
[sujeto(['However,', the, mechanism, by, which, 'Cbfβ']), verbo([regulates]), complemento([cartilage, and, bone, development, remains, unclear])].
[sujeto(['Surprisingly,', the, mutant, mice, had, 'under-developed', larynx, and, tracheal, 'cartilage,']), verbo([causing]), complemento([alveolus, defects, that, led, to, death, shortly, after, birth, from, suffocation])].
[sujeto(['Importantly,', we, showed, that, 'Cbfβ', was]), verbo([expressed]), complemento([throughout, the, skeleton, during, both, embryonic, and, postnatal, 'development,', which, explains, the, 'multiple-skeletal', defects, observed, in, the, mutant, mice])].
[sujeto(['Notably,', 'Cbfβ,', 'Runx1', and, 'Runx2', displayed, different, expression, patterns, in, the, growth, plates, of, the, 'wild-type', 'mice,', indicating, that, 'Cbfβ/Runx1', complex, and, 'Cbfβ/Runx2', complex, may]), verbo([regulate]), complemento([chondrocyte, proliferation, and, 'hypertrophy,', 'respectively,', in, a, spatial, and, temporal, manner])].
[sujeto(['Collectively,', the, results, demonstrate, that, 'Cbfβ']), verbo([mediates]), complemento([cartilage, and, bone, development, by, interacting, with, 'Runx1', and, 'Runx2', to, regulate, the, expressions, of, 'Col', 'X', and, 'Osx', for, chondrocyte, and, osteoblast, development])].
[sujeto(['These', findings, not, only]), verbo([reveal]), complemento([a, critical, role, for, 'Cbfβ', in, cartilage, and, bone, development, but, also, facilitate, the, design, of, novel, therapeutic, approaches, for, skeletal, diseases])].
[sujeto(['Core']), verbo([binding]), complemento([factor, '(', 'CBF)', is, a, heterodimeric, transcription, factor, complex, composed, of, a, 'DNA-binding', 'subunit,', one, of, three, 'runt-related', transcription, factor, '(', 'RUNX)', 'factors,', and, a, 'non-DNA', binding, 'subunit,', 'CBFβ'])].
[sujeto(['CBFβ', is, critical, for, 'DNA']), verbo([binding]), complemento([and, stability, of, the, 'CBF', transcription, factor, complex])].
[sujeto(['In', the, 'ovary,', the, 'LH', surge]), verbo([increases]), complemento([the, expression, of, 'Runx1', and, 'Runx2', in, periovulatory, 'follicles,', implicating, a, role, for, 'CBFs', in, the, periovulatory, process])].
[sujeto(['The', mutant, female, mice, exhibited, significant, reductions, in, 'fertility,', with, smaller, litter, 'sizes,']), verbo([decreased]), complemento([progesterone, during, 'gestation,', and, fewer, cumulus, oocyte, complexes, collected, after, an, induced, superovulation])].
[sujeto(['Cbfβ', knockdown, mice, also, exhibited]), verbo([decreased]), complemento([expression, of, key, genes, within, the, corpora, lutea, and, morphological, changes, in, the, ovarian, 'structure,', including, the, presence, of, large, antral, follicles, well, into, the, luteal, phase])].
[sujeto(['Overall,', these, data]), verbo([suggest]), complemento([a, role, for, 'CBFs', as, significant, regulators, of, gene, 'expression,', ovulatory, 'processes,', and, luteal, development, in, the, ovary])].
[sujeto(['Core']), verbo([binding]), complemento([factor, β, '(', 'Cbfβ)', is, a, partner, protein, of, 'Runx', family, transcription, factors, with, minimally, characterized, function, in, cartilage])].
[sujeto(['Here', we, address, the, role, of, 'Cbfβ', in, cartilage, by, generating, 'chondrocyte-specific', 'Cbfβ-deficient', mice, '(', 'Cbfb(Δch/Δch)', ')', from, 'Cbfb-floxed', mice, crossed, with, mice]), verbo([expressing]), complemento(['Cre', from, the, 'Col2a1', promoter])].
[sujeto(['Cbfb(Δch/Δch)', mice, died, soon, after, birth, and, exhibited, delayed, endochondral, bone, 'formation,', shorter, appendicular, skeleton, length, with]), verbo([increased]), complemento([proliferative, 'chondrocytes,', and, nearly, absent, hypertrophic, chondrocyte, zones])].
[sujeto(['Immunohistochemical', and, quantitative, 'real-time', 'PCR', analyses, showed, that, the, number, and, size, of, proliferative, chondrocytes]), verbo([increased]), complemento([and, the, expression, of, chondrocyte, maturation, markers, at, the, growth, 'plates,', including, 'Runx2,', 'osterix,', and, 'osteopontin,', significantly, diminished, in, 'Cbfb(Δch/Δch)', mice, compared, to, wild, type, mice])].
[sujeto(['Mechanistically,', 'Cbfβ', deficiency, in, chondrocytes]), verbo([caused]), complemento([a, decrease, of, protein, levels, of, 'Runx', transcription, factors, by, accelerating, 'polyubiquitination-mediated', proteosomal, degradation, in, vitro])].
[sujeto(['Indeed,', 'Runx2', and, 'Runx3,', but, not, 'Runx1,']), verbo([decreased]), complemento([in, 'Cbfb(Δch/Δch)', mice])].
[sujeto(['Runx2', is]), verbo([required]), complemento([for, osteoblast, differentiation, and, chondrocyte, 'maturation,', and, haplodeficiency, of, 'RUNX2', causes, cleidocranial, 'dysplasia,', which, is, characterized, by, open, fontanelles, and, sutures, and, hypoplastic, clavicles])].
[sujeto(['Cbfb', forms, a, heterodimer, with, 'Runx', family, proteins, and]), verbo([enhances]), complemento([their, 'DNA-binding', capacity])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, the, partial, rescue, of, hematopoiesis, in, 'Cbfb(-/-)', mice, revealed, the, requirement, of, 'Cbfb', in, skeletal, development])].
[sujeto(['The', differentiation, of, chondrocytes, and, osteoblasts, were, severely]), verbo([inhibited]), complemento([in, 'vitro,', and, the, reporter, activities, of, 'Ihh,', 'Col10a1,', and, 'Bglap2', promoter, constructs, were, reduced, in, 'Cbfb(fl/fl/Cre)', chondrocytes, or, osteoblasts])].
[sujeto(['These', findings, indicate, that, 'Cbfb', is]), verbo([required]), complemento([for, skeletal, development, by, regulating, chondrocyte, differentiation, and, proliferation, and, osteoblast, 'differentiation;', that, 'Cbfb', plays, an, important, role, in, the, stabilization, of, 'Runx', family, 'proteins;', and, that, 'Runx2', protein, stability, is, less, dependent, on, 'Cbfb', in, calvariae, than, in, cartilaginous, limb, skeletons])].
[sujeto(['Cytogenetics']), verbo([provide]), complemento([reliable, risk, stratification, for, 'treatment:', high, hyperdiploidy, and, 'ETV6-RUNX1', are, good, 'risk,', whereas, 'BCR-ABL1,', 'MLL', 'rearrangements,', and, hypodiploidy, are, poor, risk])].
[sujeto(['With', advancing, technologies, in, 'array-based', approaches, '(', single, nucleotide, polymorphism, 'arrays)', and, 'next-generation', sequencing, to, study, the, 'genome,']), verbo([increasing]), complemento([numbers, of, new, genetic, changes, are, being, discovered])].
[sujeto(['Whether', they]), verbo([have]), complemento([a, link, to, outcome, is, the, most, important, factor, for, refinement, of, risk, factors, in, relation, to, clinical, trials])].
[sujeto(['For', several, newly, identified, 'abnormalities,', including, intrachromosomal, amplification, of, chromosome, 21, '(', 'iAMP21),', that, are]), verbo([associated]), complemento([with, a, poor, prognosis, with, standard, 'therapy,', appropriately, modified, treatment, has, significantly, improved, outcome])].
[sujeto(['After', the, successful, use, of, tyrosine, kinase, inhibitors, in, the, treatment, of, 'BCR-ABL1-positive', acute, lymphoblastic, 'leukemia,', patients, with, alternative, 'ABL1', translocations, and, rearrangements]), verbo([involving]), complemento(['PDGFRB', may, benefit, from, treatment, with, tyrosine, kinase, inhibitors])].
[sujeto(['Other', 'aberrations,', for, 'example,', 'CRLF2', overexpression, and, 'JAK2', 'mutations,', are, also]), verbo([providing]), complemento([potential, novel, therapeutic, targets, with, the, prospect, of, reduced, toxicity])].
[sujeto(['Inactivating', 'RUNX1', mutations]), verbo([have]), complemento([frequently, been, found, in, patients, with, myelodysplastic, syndrome, '(', 'MDS)', and, cytogenetically, normal, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['However,', no, somatic, 'RUNX1', alteration, was]), verbo([found]), complemento([in, 'AMLs', with, leukemogenic, fusion, 'proteins,', such, as, 'core-binding', factor, '(', 'CBF)', leukemia, and, 'MLL', fusion, 'leukemia,', raising, the, possibility, that, 'RUNX1', could, actually, promote, the, growth, of, these, leukemia, cells])].
[sujeto(['Using', normal, human, cord, blood, cells, and, those]), verbo([expressing]), complemento([leukemogenic, fusion, 'proteins,', we, discovered, a, dual, role, of, 'RUNX1', in, myeloid, leukemogenesis])].
[sujeto(['RUNX1', overexpression]), verbo([inhibited]), complemento([the, growth, of, normal, cord, blood, cells, by, inducing, myeloid, 'differentiation,', whereas, a, certain, level, of, 'RUNX1', activity, was, required, for, the, growth, of, 'AML1-ETO', and, 'MLL-AF9', cells])].
[sujeto(['Using', a, mouse, genetic, 'model,', we, also, showed, that, the, combined]), verbo([loss]), complemento([of, 'Runx1/Cbfb', inhibited, leukemia, development, induced, by, 'MLL-AF9'])].
[sujeto(['RUNX2', could, compensate, for, the]), verbo([loss]), complemento([of, 'RUNX1'])].
[sujeto(['The', survival, effect, of, 'RUNX1', was]), verbo([mediated]), complemento([by, 'BCL2', in, 'MLL', fusion, leukemia])].
[sujeto(['Inhibiting', 'RUNX1', activity, rather, than]), verbo([enhancing]), complemento([it, could, be, a, promising, therapeutic, strategy, for, 'AMLs', with, leukemogenic, fusion, proteins])].
[sujeto(['This', translocation]), verbo([causes]), complemento([expression, of, the, 'RUNX1-ETO', '(', 'AML1-ETO)', fusion, 'protein,', which, cooperates, with, additional, mutations, in, leukemia, development])].
[sujeto(['We']), verbo([report]), complemento([here, that, interferons, '(', 'IFNs)', and, 'IFN-stimulated', genes, are, a, group, of, genes, consistently, 'up-regulated', by, 'RUNX1-ETO', in, both, human, and, murine, models])].
[sujeto(['Addition', of, exogenous, 'IFN', in, vitro, significantly, reduces, the]), verbo([increase]), complemento([in, 'self-renewal', potential, induced, by, both, 'RUNX1-ETO', and, its, leukemogenic, splicing, isoform, 'RUNX1-ETO9a'])].
[sujeto(['Finally,']), verbo([loss]), complemento([of, type, 'I', 'IFN', signaling, via, knockout, of, 'Ifnar1', significantly, accelerates, leukemogenesis, in, a, 't(8;21)', murine, model])].
[sujeto(['This', demonstrates, the, role, of]), verbo([increased]), complemento(['IFN', signaling, as, an, important, factor, inhibiting, 't(8;21)', fusion, protein, function, and, leukemia, development, and, supports, the, use, of, type, 'I', 'IFNs', in, the, treatment, of, 'AML'])].
[sujeto(['Lymphoid', 'enhancer-binding', factor, 1, '(', 'LEF1)', is, a, downstream, effector, of, the, 'Wnt/β-catenin', signaling, pathway, and, its, dysregulation, is]), verbo([associated]), complemento([with, a, number, of, malignant, diseases, such, as, leukemia])].
[sujeto(['Moreover,', we]), verbo([provide]), complemento([the, first, evidence, that, primary, 'AML', samples, with, 'AML1-ETO', or, 'PML-RARα', have, a, higher, 'LEF1', level, compared, with, those, without, each, fusion, gene])].
[sujeto(['High', 'LEF1', level, was]), verbo([associated]), complemento([with, a, favorable, 'relapse-free', survival, in, patients, with, 'FLT3-ITD', 'wild-type'])].
[sujeto(['No', consecutive, analysis, of, 'BAALC', and, 'WT1', expressions]), verbo([associated]), complemento([with, 'core-binding', factor, 'AML', '(', 'CBF-AML)', from, diagnosis, to, hematopoietic, stem, cell, transplantation, '(', 'HSCT)', has, yet, been, reported])].
[sujeto(['A', subgroup, of, 't(8;21)', showing, higher, 'BAALC', and, 'WT1', expressions, at, 'post-HSCT', were, also]), verbo([associated]), complemento([with, inferior, 'OS', '(', 'P', =, 0.018, ',', 0.015, ')', and, higher, 'CIR', rates, '(', 'P', =, 0.019, ',', 0.011, ')'])].
[sujeto(['Developing', novel, therapies, that]), verbo([suppress]), complemento(['self-renewal', of, leukemia, stem, cells, may, reduce, the, likelihood, of, relapses, and, extend, 'long-term', survival, of, patients, with, acute, myelogenous, leukemia, '(', 'AML)'])].
[sujeto(['AML1-ETO', '(', 'AE)', is, an, oncogene, that, plays, an, important, role, in]), verbo([inducing]), complemento(['self-renewal', of, hematopoietic, 'stem/progenitor', cells, '(', 'HSPCs),', leading, to, the, development, of, leukemia, stem, cells])].
[sujeto(['Previously,', using, a, zebrafish, model, of, 'AE', and, a, 'whole-organism', chemical, suppressor, 'screen,', we]), verbo([have]), complemento([discovered, that, 'AE', induces, specific, hematopoietic, phenotypes, in, embryonic, zebrafish, through, a, cyclooxygenase, '(', 'COX)-2', and, 'β-catenin-dependent', pathway])].
[sujeto(['Here,', we, show, that, 'AE', also]), verbo([induces]), complemento([expression, of, the, 'Cox-2', gene, and, activates, 'β-catenin', in, mouse, bone, marrow, cells])].
[sujeto(['Inhibition', of, 'COX']), verbo([suppresses]), complemento(['β-catenin', activation, and, serial, replating, of, 'AE(+)', mouse, 'HSPCs'])].
[sujeto(['In', 'addition,', treatment, with, 'nimesulide,', a, 'COX-2', selective, 'inhibitor,', dramatically]), verbo([suppresses]), complemento([xenograft, tumor, formation, and, inhibits, in, vivo, progression, of, human, leukemia, cells])].
[sujeto(['In', 'summary,', our, data, indicate, an, important, role, of, a, 'COX/β-catenin-dependent', signaling, pathway, in, tumor, 'initiation,', 'growth,', and, 'self-renewal,', and, in]), verbo([providing]), complemento([the, rationale, for, testing, potential, benefits, from, common, 'COX', inhibitors, as, a, part, of, 'AML', treatments])].
[sujeto(['It', is, known, that, leukemia, patients, with, extramedullary, infiltration, '(', 'EMI)']), verbo([have]), complemento([a, worse, prognosis, than, patients, without, it])].
[sujeto(['Recent', data, indicate, that, the, amyloid, precursor, protein, '(', 'APP)', is]), verbo([involved]), complemento([in, cell, 'adhesion,', 'motility,', and, proliferation])].
[sujeto(['The', expression, of, 'APP', and, its, prognostic, significance, in, acute, myeloid, leukemia, '(', 'AML)']), verbo([have]), complemento([not, been, studied])].
[sujeto(['Transwell', data, show, that, 'siRNA/APP', substantially, impairs, cell, 'migration,', but, it, does, not]), verbo([inhibit]), complemento([cell, proliferation])].
[sujeto(['Furthermore,', by, quantitative, 'real-time', polymerase, chain, reaction, and, 'Western', 'blot,', we]), verbo([found]), complemento([that, 'siRNA/APP', decreases, 'MMP-2', expression, in, vitro])].
[sujeto(['Our', study]), verbo([provides]), complemento([a, novel, clue, that, 'APP', is, involved, in, the, extramedullary, infiltration, of, leukemia, by, 'MMP-2'])].
[sujeto(['Secreted-frizzled', related, proteins, '(', 'SFRPs)', are, modulators, of, the, 'Wnt', signaling, pathway, that, is, closely]), verbo([involved]), complemento([in, normal, and, malignant, hematopoiesis])].
[sujeto(['Epigenetic', deregulation, of, 'Wnt', modulators]), verbo([leading]), complemento([to, aberrant, signaling, has, been, reported, in, adult, patients, with, acute, myeloid, leukemia, '(', 'AML),', but, its, occurrence, in, childhood, patients, with, 'AML', and, the, role, of, individual, modulators, are, unclear])].
[sujeto(['In', this, 'study,', we, examined, 'SFRP1,', 'SFRP2,', 'SFRP4,', and, 'SFRP5', promoter, methylation, in, 83, patients, with, 'AML', '(', 59, children, and, 24, 'adults)', and]), verbo([found]), complemento([preferential, 'SFRP1', methylation, and, mRNA, 'down-regulation', in, the, prognostically, favorable, subgroup, of, 'AML', with, 't(8;21)', translocation])].
[sujeto(['Mechanistically,', we, further, demonstrated, that, 'RUNX1-ETO,', the, 't(8;21)', fusion, 'product,', specifically]), verbo([bound]), complemento([the, 'SFRP1', promoter, and, repressed, its, transcription, via, a, consensus, 'RUNX', binding, site])].
[sujeto(['In', 't(8;21)-leukemia', 'cells,', 'SFRP1', selectively]), verbo([inhibited]), complemento([canonical, 'Wnt', signaling, and, cellular, proliferation, that, were, associated, with, concomitant, 'down-regulation', of, 'Wnt/β-catenin', target, 'genes,', including, 'CCND1', and, 'MYC'])].
[sujeto(['Taken', 'together,', we, identified, 'SFRP1', as, a, transcriptional, repression]), verbo([target]), complemento([of, the, 't(8;21)', fusion, protein, and, demonstrated, a, novel, mechanism, of, 'Wnt', activation, in, a, specific, subtype, of, 'AML'])].
[sujeto(['The', 'mixed-lineage', leukemia, '(', 'MLL)', 'H3K4', methyltransferase, 'protein,', and, the, heterodimeric, 'RUNX1/CBFβ', transcription, factor, 'complex,', are, critical, for, definitive, and, adult, 'hematopoiesis,', and, both, are, frequently]), verbo([targeted]), complemento([in, human, acute, leukemia])].
[sujeto(['We', identified, a, physical, and, functional, interaction, between, 'RUNX1', '(', 'AML1)', and, 'MLL', and, show, that, both, are]), verbo([required]), complemento([to, maintain, the, histone, lysine, 4, trimethyl, mark, '(', 'H3K4me3)', at, 2, critical, regulatory, regions, of, the, 'AML1', target, gene, 'PU'])].
[sujeto(['Similar', to, 'CBFβ,', we, show, that, 'MLL']), verbo([binds]), complemento([to, 'AML1', abrogating, its, 'proteasome-dependent', degradation])].
[sujeto(['Furthermore,', a, subset, of, previously, uncharacterized, 'frame-shift', and, missense, mutations, at, the, 'N', terminus, of, 'AML1,']), verbo([found]), complemento([in, 'MDS', and, 'AML', 'patients,', impairs, its, interaction, with, 'MLL,', resulting, in, loss, of, the, 'H3K4me3', mark, within, 'PU'])].
[sujeto([1, regulatory, 'regions,', and]), verbo([decreased]), complemento(['PU'])].
[sujeto(['The', interaction, between, 'MLL', and, 'AML1']), verbo([provides]), complemento([a, mechanism, for, the, 'sequence-specific', binding, of, 'MLL', to, 'DNA,', and, identifies, 'RUNX1', target, genes, as, potential, effectors, of, 'MLL', function])].
[sujeto(['The', genetic, origins, of, the, development, of, malignant, haematological, disorders]), verbo([have]), complemento([been, established, at, the, beginning, of, the, 80, ies])].
[sujeto(['Systematic', characterization, of, chromosomal, structural, abnormalities, 'and,', more, recently, by, 'DNA', microarray, approaches, and, sequencing, of, tumour, genomes]), verbo([have]), complemento([allowed, the, identification, of, a, large, number, of, genes, that, are, mutated, during, malignant, transformation, in, humans])].
[sujeto(['Functional', studies, of, these, human, oncogenes]), verbo([have]), complemento([shown, that, most, of, them, were, not, able, to, transform, a, haematologic, progenitor, when, acting, alone, and, that, cooperation, with, other, oncogenic, events, was, required])].
[sujeto(['From', these, 'data,', the, development, of, efficient, therapeutic, approaches, will, be, possible, by]), verbo([targeting]), complemento([the, early, oncogenic, events, which, are, at, the, origin, of, the, malignant, transformation])].
[sujeto(['To', identify, genes, and, components]), verbo([associated]), complemento([with, this, oncogene, we, used, 'Drosophila', as, a, genetic, model])].
[sujeto(['Expression', of, 'AML1-ETO']), verbo([caused]), complemento([an, expansion, of, hematopoietic, precursors, in, 'Drosophila,', which, expressed, high, levels, of, reactive, oxygen, species, '(', 'ROS)'])].
[sujeto(['Mutations', in, functional, domains, of, the, fusion, protein]), verbo([suppress]), complemento([the, proliferative, phenotype])].
[sujeto(['In', a, genetic, 'screen,', we]), verbo([found]), complemento([that, inactivation, of, 'EcRB1', or, activation, of, 'Foxo', and, superoxide, 'dismutase-2', '(', 'SOD2)', suppress, the, 'AML1-ETO-induced', phenotype, by, reducing, 'ROS', expression, in, the, precursor, cells])].
[sujeto(['Our', studies, indicate, that, 'ROS', is, a, signaling, factor]), verbo([promoting]), complemento([maintenance, of, normal, as, well, as, the, aberrant, myeloid, precursors, and, suggests, the, importance, of, antioxidant, enzymes, and, their, regulators, as, targets, for, further, study, in, the, context, of, leukemia])].
[sujeto(['Although', 'NF-E2', levels, correlate, with, 'JAK2(V671F)', allele, burden, in, some, 'PV', 'cohorts,', the, molecular, mechanism]), verbo([causing]), complemento([aberrant, 'NF-E2', expression, has, not, been, described])].
[sujeto(['Here', we, show, that, 'NF-E2', expression, is, also]), verbo([increased]), complemento([in, patients, with, essential, thrombocythemia, and, primary, myelofibrosis, independent, of, the, presence, of, the, 'JAK2(V617F)', mutation])].
[sujeto(['Characterization', of, the, 'NF-E2', promoter, revealed, multiple, functional]), verbo([binding]), complemento([sites, for, 'AML1/RUNX-1'])].
[sujeto(['Chromatin', immunoprecipitation, demonstrated, 'AML1']), verbo([binding]), complemento([to, the, 'NF-E2', promoter, in, vivo])].
[sujeto(['Moreover,', 'AML1']), verbo([binding]), complemento([to, the, 'NF-E2', promoter, was, significantly, increased, in, granulocytes, from, 'PV', patients, compared, with, healthy, controls])].
[sujeto(['RNAi-mediated', suppression, of, either, 'AML1', or, of, its]), verbo([binding]), complemento([partner, 'CBF-beta', significantly, decreased, 'NF-E2', expression])].
[sujeto(['Moreover,', expression, of, the, leukemic, fusion, protein, 'AML/ETO', drastically]), verbo([decreased]), complemento(['NF-E2', protein, levels])].
[sujeto(['Our', data, identify, 'NF-E2', as, a, novel, 'AML1']), verbo([target]), complemento([gene, and, delineate, a, role, for, aberrant, 'AML1', expression, in, mediating, elevated, 'NF-E2', expression, in, 'MPN', patients])].
[sujeto(['The', acquisition, of, the, 'critical,', secondary, 'CNAs']), verbo([requires]), complemento([some, 'Darwinian', selective, advantage, to, expand, numbers, of, cells, at, 'risk,', and, the, cytokine, 'TGF', beta, is, able, to, exercise, this, function])].
[sujeto(['The', clonal, architecture, of, 'ALL']), verbo([has]), complemento([been, investigated, by, single, cell, analysis, with, multicolor, probes, to, mutant, genes])].
[sujeto(['The', data]), verbo([reveal]), complemento([not, a, linear, sequence, of, mutation, acquisition, with, clonal, succession, but, rather, considerable, complexity, with, a, 'tree-like', or, branching, structure, of, genetically, distinct, subclones, very, reminiscent, of, 'Darwin\'s', original, 1837, evolutionary, divergence, diagram])].
[sujeto(['This', evolutionary, pattern]), verbo([has]), complemento([important, implications, for, stem, cells, in, 'ALL,', for, the, origins, of, relapse, and, for, therapeutic, targeting])].
[sujeto(['However,', optimal, sampling, intervals]), verbo([have]), complemento([not, been, defined, and, are, likely, to, vary, according, to, the, underlying, molecular, lesion])].
[sujeto(['Combination', of, conventional, chromosome, analysis, '(', 'CCA)', and, 'FISH']), verbo([provides]), complemento([higher, sensitivity, in, detecting, these, genetic, 'abnormalities,', and, it, is, effective, to, apply, several, 'FISH', probes, as, a, profile, test])].
[sujeto(['Naturally', arising, regulatory, 'T', '(', 'Treg)', cells]), verbo([express]), complemento([the, transcription, factor, 'FoxP3,', which, critically, controls, the, development, and, function, of, 'Treg', cells])].
[sujeto(['FoxP3']), verbo([interacts]), complemento([with, another, transcription, factor, 'Runx1', '(', also, known, as, 'AML1)'])].
[sujeto(['Here,', we, showed, that, 'Treg', 'cell-specific', deficiency, of, 'Cbfbeta,', a, cofactor, for, all, 'Runx', 'proteins,', or, that, of, 'Runx1,', but, not, 'Runx3,']), verbo([induced]), complemento(['lymphoproliferation,', autoimmune, 'disease,', and, hyperproduction, of, 'IgE'])].
[sujeto(['The', 'Runx', complex]), verbo([bound]), complemento([to, more, than, 3000, gene, loci, in, 'Treg', 'cells,', including, the, 'Foxp3', regulatory, regions, and, the, 'Il4', silencer])].
[sujeto(['In', 'addition,', knockdown, of, 'RUNX1', showed, that, 'RUNX1', is]), verbo([required]), complemento([for, the, optimal, regulation, of, 'FoxP3', expression, in, human, 'T', cells])].
[sujeto(['Interestingly,', both, 'CBF', leukemia, fusion, proteins, and, 'miR-17,', which]), verbo([targets]), complemento(['RUNX1-3\'UTR,', negatively, affect, a, common, core, 'RUNX1-miRNA', mechanism, that, forces, myeloid, cells, into, an, 'undifferentiated,', 'KIT-induced,', proliferating, state])].
[sujeto(['In', the, second, part, of, this, study, we, took, advantage, of, the, conservation, of, the, core, 'RUNX1-miRNA', mechanism, in, mouse, and, 'human,', to, mechanistically, demonstrate, in, a, mouse, myeloid, cell, model, that]), verbo([increased]), complemento(['KIT-induced', proliferation, is, per, se, a, mechanism, sufficient, to, delay, myeloid, differentiation])].
[sujeto(['In', the, first, part, of, this, study, we]), verbo([found]), complemento([that, stable, 'miR-17', upregulation, 'affects,', like, the, 'CBF-AML', fusion, proteins, '(', 'RUNX1-MTG8', or, 'CBFB-MYH11),', a, core, 'RUNX1-miRNA', mechanism, leading, to, 'KIT-induced', proliferation, of, 'differentiation-arrested', 'U937', myeloid, cells])].
[sujeto(['The', integrated, information, gathered, from, the, two, myeloid, cell, models, shows, that, 'RUNX1']), verbo([regulates]), complemento([myeloid, differentiation, not, only, by, direct, transcriptional, regulation, of, coding, and, 'non-coding', myeloid, differentiation, functions, '(', e])].
[sujeto(['miR-223),', but, also, by]), verbo([modulating]), complemento(['KIT-induced', proliferation, via, 'non-coding', miRNAs, '(', e])].
[sujeto(['On', the, other, 'hand,', the, extent, of, 'KIT-induced', proliferation, itself, can]), verbo([modulate]), complemento([myeloid, differentiation, of, cells, with, wild, type, 'RUNX1', function])].
[sujeto(['CBFβ', and, 'RUNX1', form, a, 'DNA-binding', heterodimer, and, are, both]), verbo([required]), complemento([for, hematopoietic, stem, cell, '(', 'HSC)', generation, in, mice])].
[sujeto(['However,', the, nascent, 'HSCs', were, not]), verbo([released]), complemento([from, the, 'aorta-gonad-mesonephros', '(', 'AGM)', 'region,', as, evidenced, by, the, accumulation, of, 'runx1(+)', cells, in, the, 'AGM', that, could, not, enter, circulation])].
[sujeto(['Finally,', we]), verbo([found]), complemento([that, cbfb, was, downstream, of, the, 'Notch', pathway, during, 'HSC', development])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, runx1, and, cbfb, are, required, at, 2, different, steps, during, early, 'HSC', development])].
[sujeto(['CBFβ', is, not]), verbo([required]), complemento([for, nascent, 'HSC', emergence, but, is, required, for, the, release, of, 'HSCs', from, 'AGM', into, circulation])].
[sujeto(['Despite', the, absolute, requirements, for, these, factors, in, the, development, of, hematopoietic, stem, cells, and, 'lymphocytes,', their, roles, in, the, development, of, bone, marrow, progenitor, subsets]), verbo([have]), complemento([not, been, defined])].
[sujeto(['Besides', the]), verbo([loss]), complemento([of, 'DC', 'progenitors,', 'pan-hematopoietic', 'Cbfb-deficient', mice, also, lack, 'CD105(+)', erythroid, 'progenitors,', leading, to, severe, anemia, at, 3, to, 4, months, of, age])].
[sujeto(['RUNX1/CBFβ', '(', core]), verbo([binding]), complemento([factor, '[', 'CBF])', is, a, heterodimeric, transcription, factor, complex, that, is, frequently, involved, in, chromosomal, 'translocations,', point, 'mutations,', or, deletions, in, acute, leukemia])].
[sujeto(['The', mixed, lineage, leukemia, '(', 'MLL)', gene, is, also, frequently]), verbo([involved]), complemento([in, chromosomal, translocations, or, partial, tandem, duplication, in, acute, leukemia])].
[sujeto(['The', 'MLL', protein]), verbo([interacts]), complemento([with, 'RUNX1', and, prevents, 'RUNX1', from, 'ubiquitin-mediated', degradation])].
[sujeto(['RUNX1/CBFβ']), verbo([recruits]), complemento(['MLL', to, regulate, downstream, target, genes])].
[sujeto(['However,', the, functional, consequence, of, 'MLL', fusions, on, 'RUNX1/CBFβ', activity]), verbo([has]), complemento([not, been, fully, understood])].
[sujeto(['We', confirmed, this]), verbo([finding]), complemento([in, 'Mll-Af9', 'knock-in', mice, and, human, 'M4/M5', acute, myeloid, leukemia, '(', 'AML)', cell, 'lines,', with, or, without, 'MLL', 'translocations,', showing, that, 'MLL', translocations, cause, a, hypomorph, phenotype, of, 'RUNX1/CBFβ'])].
[sujeto(['Overexpression', of, 'RUNX1']), verbo([inhibits]), complemento([the, development, of, 'AML', in, 'Mll-Af9', 'knock-in', 'mice;', 'conversely,', further, reducing, 'Runx1/Cbfβ', levels, accelerates, 'MLL-AF9-mediated', 'AML', in, bone, marrow, transplantation, assays])].
[sujeto(['These', data]), verbo([reveal]), complemento([a, newly, defined, negative, regulation, of, 'RUNX1/CBFβ', by, 'MLL', fusion, proteins, and, suggest, that, targeting, 'RUNX1/CBFβ', levels, may, be, a, potential, therapy, for, 'MLLs'])].
[sujeto(['The', human, immunodeficiency, virus, '(', 'HIV)-1', protein, 'Vif']), verbo([has]), complemento([a, central, role, in, the, neutralization, of, host, innate, defences, by, hijacking, cellular, proteasomal, degradation, pathways, to, subvert, the, antiviral, activity, of, host, restriction, 'factors;', 'however,', the, underlying, mechanism, by, which, 'Vif', achieves, this, remains, unclear])].
[sujeto(['Here', we]), verbo([report]), complemento([a, crystal, structure, of, the, 'Vif-CBF-β-CUL5-ELOB-ELOC', complex])].
[sujeto(['The', structure]), verbo([reveals]), complemento([that, 'Vif,', by, means, of, two, 'domains,', organizes, formation, of, the, pentameric, complex, by, interacting, with, 'CBF-β,', 'CUL5', and, 'ELOC'])].
[sujeto(['The', larger, domain, '(', 'α/β', 'domain)', of, 'Vif']), verbo([binds]), complemento([to, the, same, side, of, 'CBF-β', as, 'RUNX1,', indicating, that, 'Vif', and, 'RUNX1', are, exclusive, for, 'CBF-β', binding])].
[sujeto(['Together,', our, data]), verbo([reveal]), complemento([the, structural, basis, for, 'Vif', hijacking, of, the, 'CBF-β', and, 'CUL5', 'E3', ligase, 'complex,', laying, a, foundation, for, rational, design, of, novel, 'anti-HIV', drugs])].
[sujeto(['Different', mechanisms, for, 'CBFβ-MYH11', function, in, acute, myeloid, leukemia, with, 'inv(16)']), verbo([have]), complemento([been, proposed, such, as, tethering, of, 'RUNX1', outside, the, 'nucleus,', interference, with, transcription, factor, complex, assembly, and, recruitment, of, histone, 'deacetylases,', all, resulting, in, transcriptional, repression, of, 'RUNX1', target, genes])].
[sujeto(['Here,', through, 'genome-wide', 'CBFβ-MYH11-binding', site, analysis, and, quantitative, interaction, 'proteomics,', we]), verbo([found]), complemento([that, 'CBFβ-MYH11', localizes, to, 'RUNX1', occupied, 'promoters,', where, it, interacts, with, 'TAL1,', 'FLI1', and, 'TBP-associated', factors, '(', 'TAFs)', in, the, context, of, the, hematopoietic, transcription, factors, 'ERG,', 'GATA2', and, 'PU'])].
[sujeto(['Transcriptional', analysis, revealed, that, upon, fusion, protein, 'knockdown,', a, small, subset, of, the, 'CBFβ-MYH11']), verbo([target]), complemento([genes, show, increased, 'expression,', confirming, a, role, in, transcriptional, repression])].
[sujeto(['However,', the, majority, of, 'CBFβ-MYH11']), verbo([target]), complemento(['genes,', including, genes, implicated, in, hematopoietic, stem, cell, 'self-renewal', such, as, 'ID1,', 'LMO1', and, 'JAG1,', are, actively, transcribed, and, repressed, upon, fusion, protein, knockdown])].
[sujeto(['Together', these, results]), verbo([suggest]), complemento([an, essential, role, for, 'CBFβ-MYH11', in, regulating, the, expression, of, genes, involved, in, maintaining, a, stem, cell, phenotype])].
[sujeto(['The', rare, but, recurrent, 'RUNX1-USP42', fusion, gene, is, the, result, of, a, 't(7;21)(p22;q22)', chromosomal, translocation, and]), verbo([has]), complemento([been, described, in, 6, cases, of, acute, myeloid, leukemia, '(', 'AML)', and, one, case, of, refractory, anemia, with, excess, of, blast])].
[sujeto(['The', bone, marrow, cells, in, the, present, case, also, had, a, 5, q, 'deletion,', and, it, was, revealed, that, 5, out, of, the, 8]), verbo([reported]), complemento([cases, '(', including, the, present, 'case)', with, 't(7;21)(p22;q22)/RUNX1-USP42', also, had, cytogenetic, abnormalities, of, 5, q])].
[sujeto(['Most', patients, with, acute, myeloid, leukemia, '(', 'AML)', and, genetic, rearrangements]), verbo([involving]), complemento([the, core, binding, factor, '(', 'CBF)', have, favorable, prognosis])].
[sujeto(['In', 'contrast,', a, minority, of, them, still]), verbo([have]), complemento([a, high, risk, of, leukemia, recurrence])].
[sujeto(['In', multivariate, 'analyses,', leukocyte, count, above, 20, &, 'nbsp;×&nbsp;10(9)', /, 'L,', 'BAALC', 'over-expression,', and, high, copy, numbers, of, 'RUNX1-RUNXT1', or, 'CBFB-MYH11', after, induction, chemotherapy, '(', 'CT)']), verbo([led]), complemento([to, increased, relapse, rate])].
[sujeto(['Regarding', 'OS,', age, &, 'gt;50&nbsp;yr,', leukocyte, count, above, 20, &, 'nbsp;×&nbsp;10(9)', /, 'L,', and]), verbo([increased]), complemento(['MN1', expression, were, adverse, features])].
[sujeto(['Core']), verbo([binding]), complemento([factor, '(', 'CBF)-positive', acute, myeloid, leukemia, '(', 'AML)', presents, a, favorable, 'prognosis,', except, for, patients, with, 'KIT', 'mutation,', especially, 'D816', mutation])].
[sujeto(['The', study, patients, consisted, of, 121, patients, with, 'CBF', 'AML', '(', 82, patients, with, 'RUNX1/RUNX1T1', '[', 67.8, &, 'nbsp;%]', and, 39, patients, with, 'CBFB/MYH11', '[', 32.2, &, 'nbsp;%])']), verbo([recruited]), complemento([from, eight, institutions, in, 'Korea'])].
[sujeto(['The', presence, of, 'KIT', 'D816', mutation, was]), verbo([associated]), complemento([with, adverse, outcomes, for, the, 'event-free', survival, '(', p, =, 0.03, ')', and, for, the, overall, survival, '(', p, =, 0.02, ')'])].
[sujeto(['Core']), verbo([binding]), complemento([factor, '(', 'CBF)', 'leukemias,', those, with, translocations, or, inversions, that, affect, transcription, factor, genes, 'RUNX1', or, 'CBFB,', account, for, '~24%', of, adult, acute, myeloid, leukemia, '(', 'AML)', and, 25, '%', of, pediatric, acute, lymphocytic, leukemia, '(', 'ALL)'])].
[sujeto(['Current', treatments, for, 'CBF', leukemias, are]), verbo([associated]), complemento([with, significant, morbidity, and, 'mortality,', with, a, 5, -, y, survival, rate, of, '~50%'])].
[sujeto(['We', hypothesize, that, the, interaction, between, 'RUNX1', and, 'CBFβ', is, critical, for, 'CBF', leukemia, and, can, be]), verbo([targeted]), complemento([for, drug, development])].
[sujeto(['Ro5-3335,', a, benzodiazepine, identified, from, the, 'screen,', was, able, to]), verbo([interact]), complemento([with, 'RUNX1', and, 'CBFβ', 'directly,', repress, 'RUNX1/CBFB-dependent', transactivation, in, reporter, 'assays,', and, repress, 'runx1-dependent', hematopoiesis, in, zebrafish, embryos])].
[sujeto(['Our', data, thus, confirmed, that, 'RUNX1-CBFβ', interaction, can, be]), verbo([targeted]), complemento([for, leukemia, treatment, and, we, have, identified, a, promising, lead, compound, for, this, purpose])].
[sujeto(['The', clinical, value, of, serial, minimal, residual, disease, '(', 'MRD)', monitoring, in, core]), verbo([binding]), complemento([factor, '(', 'CBF)', acute, myeloid, leukemia, '(', 'AML)', by, quantitative, 'RT-PCR', was, prospectively, assessed, in, 278, patients, '[', 163, with, 't(8;21)', and, 115, with, 'inv(16)]', entered, in, the, 'United', 'Kingdom', 'MRC', 'AML', 15, trial])].
[sujeto(['During', 'follow-up,', 'cut-off', 'MRD', thresholds, in, 'BM', and, 'PB']), verbo([associated]), complemento([with, a, 100, '%', relapse, rate, were, 'identified:', for, 't(8;21)', patients, 'BM', &, 'gt;', 500, 'copies,', 'PB', &, 'gt;', 100, 'copies;', for, 'inv(16)', 'patients,', 'BM', &, 'gt;', 50, copies, and, 'PB', &, 'gt;', 10, copies])].
[sujeto(['Breast', carcinoma, is, the]), verbo([leading]), complemento([cause, of, 'cancer-related', mortality, in, women, 'worldwide,', with, an, estimated, 1.38, million, new, cases, and, 458, ',', 0, deaths, in, 2008, alone])].
[sujeto(['Recurrent', somatic, alterations, in, breast, cancer]), verbo([have]), complemento([been, 'described,', including, mutations, and, copy, number, 'alterations,', notably, 'ERBB2', 'amplifications,', the, first, successful, therapy, target, defined, by, a, genomic, aberration])].
[sujeto(['Previous', 'DNA', sequencing, studies, of, breast, cancer, genomes]), verbo([have]), complemento([revealed, additional, candidate, mutations, and, gene, rearrangements])].
[sujeto(['Here', we]), verbo([report]), complemento([the, 'whole-exome', sequences, of, 'DNA', from, 103, human, breast, cancers, of, diverse, subtypes, from, patients, in, 'Mexico', and, 'Vietnam', compared, to, 'matched-normal', 'DNA,', together, with, 'whole-genome', sequences, of, 22, breast, 'cancer/normal', pairs])].
[sujeto(['Furthermore,', we]), verbo([have]), complemento([identified, a, recurrent, 'MAGI3-AKT3', fusion, enriched, in, 'triple-negative', breast, cancer, lacking, oestrogen, and, progesterone, receptors, and, 'ERBB2', expression])].
[sujeto(['The', 'MAGI3-AKT3', fusion]), verbo([leads]), complemento([to, constitutive, activation, of, 'AKT', 'kinase,', which, is, abolished, by, treatment, with, an, 'ATP-competitive', 'AKT', 'small-molecule', inhibitor])].
[sujeto(['Osteoarthritis', '(', 'OA)', is, a, degenerative, joint, disease, that]), verbo([involves]), complemento([the, destruction, of, articular, cartilage, and, eventually, leads, to, disability])].
[sujeto(['Molecules', that]), verbo([promote]), complemento([the, selective, differentiation, of, multipotent, mesenchymal, stem, cells, '(', 'MSCs)', into, chondrocytes, may, stimulate, the, repair, of, damaged, cartilage])].
[sujeto(['Using', an, 'image-based', 'high-throughput', 'screen,', we, identified, the, small, molecule, 'kartogenin,', which]), verbo([promotes]), complemento([chondrocyte, differentiation, '(', median, effective, concentration, =, 100, 'nM),', shows, chondroprotective, effects, in, 'vitro,', and, is, efficacious, in, two, 'OA', animal, models])].
[sujeto(['Kartogenin']), verbo([binds]), complemento([filamin, 'A,', disrupts, its, interaction, with, the, transcription, factor, 'core-binding', factor, β, subunit, '(', 'CBFβ),', and, induces, chondrogenesis, by, regulating, the, 'CBFβ-RUNX1', transcriptional, program])].
[sujeto(['This', work]), verbo([provides]), complemento([new, insights, into, the, control, of, chondrogenesis, that, may, ultimately, lead, to, a, stem, 'cell-based', therapy, for, osteoarthritis])].
[sujeto(['Yet', the, mechanisms, that]), verbo([target]), complemento(['PRCs', to, specific, loci, in, mammalian, cells, remain, incompletely, understood])].
[sujeto(['In', this, study, we, show, that, 'Bmi1,', a, core, component, of, 'Polycomb', 'Repressive', 'Complex', 1, '(', 'PRC1),']), verbo([binds]), complemento([directly, to, the, 'Runx1/CBFβ', transcription, factor, complex])].
[sujeto(['Genome-wide', studies, in, megakaryocytic, cells, demonstrate, significant, chromatin, occupancy, overlap, between, the, 'PRC1', core, component, 'Ring1b', and, 'Runx1/CBFβ', and, functional, regulation, of, a, considerable, fraction, of, commonly]), verbo([bound]), complemento([genes])].
[sujeto(['We', also, show, that, 'Ring1b', occupies, key, 'Runx1']), verbo([binding]), complemento([sites, in, primary, murine, thymocytes, and, that, this, occurs, via, 'PRC2-independent', mechanisms])].
[sujeto(['Genetic', depletion, of, 'Runx1', results, in, reduced, 'Ring1b']), verbo([binding]), complemento([at, these, sites, 'in&nbsp;vivo'])].
[sujeto(['These', findings]), verbo([provide]), complemento([evidence, for, 'site-specific', 'PRC1', chromatin, recruitment, by, core, binding, transcription, factors, in, mammalian, cells])].
[sujeto(['An', active, search, for, them, may]), verbo([provide]), complemento([both, pathogenetic, and, prognostic, novel, information])].
[sujeto(['ETV6/RUNX1', displayed, discordance, between, fusion, transcript, assay, and, 'FISH', results, as, well, as, rare, 'non-specific']), verbo([binding]), complemento([in, 'AL', samples, with, normal, or, complex, cytogenetics])].
[sujeto(['The', identification, of, minimal, residual, disease, '(', 'MRD)']), verbo([has]), complemento([led, to, substantial, improvements, in, early, recognition, of, the, recurrence, of, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['Besides,', more, than, 50, '%', of, all, 'AML', patients, lack, one, of, these, specific, 'sequences,', so, it, is, crucial, to, identify, molecular]), verbo([targets]), complemento([applicable, for, the, majority, of, patients])].
[sujeto(['These', features]), verbo([have]), complemento([led, to, its, adoption, for, 'MRD', detection, using, 'RQ-PCR'])].
[sujeto(['A', 'European', 'LeukemiaNet', 'Study']), verbo([found]), complemento([the, magnitude, of, 'WT1', log, reduction, after, induction, chemotherapy, to, be, an, independent, predictor, of, relapse])].
[sujeto(['Finally,', some, authors]), verbo([translated]), complemento([the, use, of, 'WT1', in, the, clinic, giving, donor, lymphocytes, infusions, to, patients, with, increasing, 'WT1-mRNA', levels, after, allogeneic, stem, cell, transplantation, and, obtaining, an, improvement, of, survival, in, this, subset])].
[sujeto(['Data', collected, on, 'WT1', expression, over, the, past, years]), verbo([provided]), complemento([evidence, for, the, use, of, this, molecular, marker, to, stratify, 'high-risk', 'AML', patients])].
[sujeto(['NanoString', nCounter, system, is, a, novel, 'probe-based', gene, expression, platform, capable, of, measuring, up, to, 800]), verbo([targets]), complemento([with, advantages, of, 'reproducibility,', 'accuracy,', and, sample, type, flexibility])].
[sujeto(['To', examine, the, value, of, minimal, residual, disease, '(', 'MRD)', by, multiparameter, flow, cytometry, '(', 'MFC)', in, core]), verbo([binding]), complemento([factor, '(', 'CBF)', acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto([1, ',', 0.01, to, 0.1, ',', 0.1, to, 1, ',', 1, to, 10, ',', and, &, 'gt;10%,', and]), verbo([reporting]), complemento(['MFC', '(', 'sensitivity,', 0.1, '%', -, 0.01, '%', ')', as, positive, or, 'negative,', κ, coefficient, test, showed, no, agreement, between, 'qRT-PCR', and, 'MFC', in, 'BM', samples, obtained, postinduction, '(', n, =, 44, ',', κ, =, 0.041, ')', ',', and, only, weak, agreement, during, consolidation, '(', n, =, 108, ',', κ, =, 0.083, ')', ',', 'maintenance/follow-up', '(', n, =, 107, ',', κ, =, 0.164, ')', ',', and, salvage, chemotherapy, '(', n, =, 24, ',', 0.376, ')'])].
[sujeto([1, '%', was]), verbo([associated]), complemento([with, lower, and, '≥10%', with, higher, 'AML', relapse, risk, '(', 'P', =])].
[sujeto(['In', the, latter, group, with, intermediate, 'qRT-PCR', 'results,', 'MFC']), verbo([provided]), complemento([prognostic, value, for, relapse, '(', 'P', =, 0.006, ')'])].
[sujeto(['The', most, common, subgroups, were, 'KMT2A', rearrangement, '(', 29, '%', ')', ',', normal, karyotype, '(', 15, '%', ')', ',', 'RUNX1-RUNX1T1', '(', 10, '%', ')', ',', deletions, of, 5, 'q,', 7, q, 'and/or', 17, p, '(', 9, '%', ')', ',', myeloid, leukaemia]), verbo([associated]), complemento([with, 'Down', syndrome, '(', 7, '%', ')', ',', 'PML-RARA', '(', 7, '%', ')', and, 'CBFB-MYH11', '(', 5, '%', ')'])].
[sujeto(['Single', nucleotide, polymorphism, array, '(', 'SNP-A)', analysis, and, exon, sequencing, of, 100, 'genes,', performed, in, 52, and, 40, 'cases,', respectively, '(', 39, 'overlapping),', revealed, '≥1', aberration, in, 89, '%', ;, when, adding, cytogenetic, 'data,', this, frequency]), verbo([increased]), complemento([to, 98, '%'])].
[sujeto(['Twenty-two', genes, were]), verbo([targeted]), complemento([by, focal, 'CNAs,', including, 'AEBP2', and, 'PHF6', deletions, and, genes, involved, in, 'AML-associated', gene, fusions])].
[sujeto(['In', 'total,', 60, mutations, were]), verbo([found]), complemento([in, 30, 'genes,', primarily, those, encoding, signalling, proteins, '(', 47, '%', ')', ',', transcription, factors, '(', 25, '%', ')', ',', or, epigenetic, modifiers, '(', 13, '%', ')'])].
[sujeto(['It', is]), verbo([required]), complemento([for, fetal, liver, hematopoiesis, and, skeletal, development])].
[sujeto(['Cbfb']), verbo([has]), complemento([two, functional, 'isoforms,', 'Cbfb1', and, 'Cbfb2,', which, are, formed, by, alternative, splicing])].
[sujeto(['Intramembranous', and, endochondral, ossification, was, retarded, and, chondrocyte, and, osteoblast, differentiation, was]), verbo([inhibited]), complemento([in, 'Cbfb2(-/-)', embryos, but, not, in, 'Cbfb1(-/-)', embryos])].
[sujeto(['Furthermore,', the, amounts, of, 'Runx', proteins, and, 'Cbfb', in, 'Cbfb2(-/-)', embryos, differed, similarly, among, skeletal, 'tissues,', 'livers,', and, 'thymuses,']), verbo([suggesting]), complemento([that, 'Runx', proteins, and, 'Cbfb', are, mutually, required, for, their, stability])].
[sujeto(['Although', 'Cbfb1(-/-)', embryos, developed, 'normally,', 'Cbfb1']), verbo([induced]), complemento([chondrocyte, and, osteoblast, differentiation, and, enhanced, 'DNA', binding, of, 'Runx2', more, efficiently, than, 'Cbfb2'])].
[sujeto(['Cbfb2', was, more, 'abundant,', but, 'Cbfb1', was, more, potent, for]), verbo([enhancing]), complemento(['Runx2', activity])].
[sujeto(['Although', only, 'Cbfb2']), verbo([loss]), complemento([generated, overt, skeletal, 'phenotypes,', both, may, play, major, roles, in, skeletal, development, with, functional, redundancy])].
[sujeto(['Genetic', alterations, such, as, chromosomal, 'translocations,', copy, number, variations, and, point, mutations]), verbo([have]), complemento([been, widely, reported, to, result, in, the, malfunction, of, 'RUNX', transcription, factors])].
[sujeto(['Leukemias', arising, from, such, alterations, in, 'RUNX', family, genes, are, collectively, termed, core]), verbo([binding]), complemento([factor, '(', 'CBF)', leukemias])].
[sujeto(['Over', the, 'years,', retroviral, 'transduction-transplantation', assays, and, 'transgenic,', knockin, and, knockout, mouse, models, alone, or, in, combination, with, mutagenesis]), verbo([have]), complemento([been, used, to, study, the, roles, of, 'RUNX', alterations, in, leukemogenesis])].
[sujeto(['Although', successful, in]), verbo([inducing]), complemento(['leukemia,', the, existing, assays, and, models, possess, many, inherent, limitations])].
[sujeto(['A', 'CBF', leukemia, model, which]), verbo([induces]), complemento([leukemia, with, complete, penetrance, and, short, latency, would, be, ideal, as, a, platform, for, drug, discovery])].
[sujeto(['Here,', we, summarize, the, currently, available, mouse, models, which]), verbo([have]), complemento([been, utilized, to, study, 'CBF', 'leukemias,', discuss, the, advantages, and, limitations, of, individual, experimental, 'systems,', and, propose, suggestions, for, improvements, of, mouse, models])].
[sujeto(['In', a, patient, with, acute, myeloid, leukemia, '(', 'AML)', following, 'therapy,']), verbo([finding]), complemento(['≥5%', bone, marrow, '(', 'BM)', blasts, is, highly, concerning, for, 'residual/relapsed', disease])].
[sujeto(['The', receptor, tyrosine, kinase, 'KIT', is]), verbo([expressed]), complemento([in, the, vast, majority, of, these, acute, myeloid, leukemias, and, frequent, activating, 'KIT', gene, mutations, have, been, associated, with, a, higher, risk, of, relapse])].
[sujeto(['The', disappearance, of, 'KIT', gene, mutations, at, relapse]), verbo([suggests]), complemento([that, clonal, devolution, may, in, part, explain, the, absence, of, efficacy, observed, with, 'single-agent', dasatinib, in, these, patients, '(', n])].
[sujeto(['In', acute, myeloid, leukaemia, '(', 'AML),', the, presence, of, 't(8;21)(q22;q22)', and, 'inv(16)(p13q22)/t(16;16)(p13;q22)', 'and/or', the, corresponding, molecular, rearrangements, 'RUNX1/RUNX1T1', and, 'CBFB/MYH11', '[', collectively, referred, to, as, core]), verbo([binding]), complemento([factor, '(', 'CBF)', 'AML]', predict, for, a, more, favourable, outcome, in, patients, receiving, 'cytarabine-anthracycline', based, induction, and, upon, achievement, of, complete, 'remission,', 'high-dose', cytarabine, consolidation, chemotherapy])].
[sujeto(['Clinical', studies, with]), verbo([targeting]), complemento([compounds, '(', e])].
[sujeto([gemtuzumab, 'ozogamicin,', 'dasatinib)', added, to, intensive, chemotherapy, appear, beneficial, both, in, younger, and, older, 'patients,', albeit, the, latter, continue, to]), verbo([have]), complemento([a, significantly, worse, outcome, than, the, former])].
[sujeto(['Regularly', molecular, monitoring, of, disease, during, remission, may]), verbo([provide]), complemento([a, strategy, for, early, therapeutic, intervention, before, overt, relapse])].
[sujeto(['Core-binding', factor, acute, myeloid, leukemia, '(', 'CBF-AML)', -, including, 'AML', with, 't(8;21)', and, 'AML', with, 'inv(16)', -, accounts, for, about, 15, '%', of, adult, 'AML', and, is]), verbo([associated]), complemento([with, a, relatively, favorable, prognosis])].
[sujeto(['Due', to, similarities, between, their, molecular, and, prognostic, 'features,', 't(8;21)', and, 'inv(16)-AML', are, usually, grouped, and]), verbo([reported]), complemento([together, in, clinical, studies])].
[sujeto(['However,', considerable, experimental, evidences]), verbo([have]), complemento([highlighted, that, they, represent, two, distinct, entities, and, should, be, considered, separately, for, further, studies])].
[sujeto(['The', diagnostics, of, leukemia, relies, upon, 'multi-parametric', approach]), verbo([involving]), complemento([a, number, of, different, pathology, disciplines, such, as, flow, 'cytometry,', 'histopathology,', cytogenetics, and, molecular, genetics, '[', fluorescent, in, situ, hybridization, '(', 'FISH)', and, polymerase, chain, reaction, '(', 'PCR)]'])].
[sujeto(['In', the, last, two, 'decades,', several, studies]), verbo([have]), complemento([reported, observations, that, 'PFG', are, present, in, healthy, population, and, not, necessarily, result, in, leukemia])].
[sujeto(['The', first, such, study, by, 'Limpens', and, colleagues, on, 't(14/18)/', 'BCL2-JH', '[', 1, ']', and, next, in, line, '[', 2, ',', 3, ']']), verbo([led]), complemento([to, many, questions, regarding, the, significance, of, these, chromosomal, translocations, in, leukemogenesis])].
[sujeto(['Translocation', 't(8;21)/', 'AML1', 'ETO', was]), verbo([found]), complemento([in, 4.4, '%', of, patients, with, a, mean, age, of, 45.4, 'years,', while, none, of, these, patients, was, older, than, 55, years])].
[sujeto(['Translocation', 't(15;17)/', 'PMLRARA', was]), verbo([found]), complemento([in, 5.5, '%', of, patients, with, a, mean, age, of, 52.6, years, and, an, almost, equal, distribution, between, younger, and, older, patients])].
[sujeto(['The', 'MLL', gene, rearrangements, were]), verbo([found]), complemento([in, 6.6, '%', of, 'patients,', the, -, 5, /, 5, 'q-', 'and/', or, -, 7, /, 7, 'q-', aberrations, in, 7.7, '%', of, 'patients,', while, the, most, frequent, genetic, abnormality, in, our, study, was, trisomy, 8, '(', 10, '%', ')'])].
[sujeto(['Moreover,', we]), verbo([found]), complemento([a, favorable, clinical, outcome, in, patients, expressing, fusion, genes, 'AML1-ETO', or, 'PMLRARA', in, contrast, to, an, adverse, clinical, outcome, with, few, remissions, and, death, in, 'AML', patients, with, 'MLL,', -, 5, 'q/', -, 5, and, -, 7, 'q/', 7, -])].
[sujeto(['Finally,', an, intermediate, prognosis, was]), verbo([found]), complemento([in, patients, with, trisomy, 8])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([a, good, congruence, with, published, literature, on, the, incidence, and, prognostic, value, of, several, well, established, 'AML-associated', genetic, aberrations])].
[sujeto(['The', multiplex, 'RT-nPCR', used, in, this, study, can, 'quickly,', effectively, and, accurately, screen, the, fusion, genes, in, 'AML', 'patients,', which, can]), verbo([provide]), complemento([important, evidence, for, assessing, diagnosis, and, 'treatment,', and, also, provide, necessary, information, for, minimal, residual, disease, '(', 'MRD)', and, prognosis])].
[sujeto(['Within', the, past, few, 'years,', the, invention, of, 'next-generation', sequencing]), verbo([has]), complemento([revealed, several, new, genes, associated, with, tumor, formation, and, 'development,', for, example, 'DNMT3a'])].
[sujeto(['PCR', amplification, of, the, entire, coding, region, of, 'DNMT3a', was, performed, using, 23, overlapping]), verbo([primer]), complemento([pairs, in, 57, patients, who, were, diagnosed, in, 'Blood', 'Disease', 'Hospital', of, 'Chinese', 'Academy', of, 'Medical', 'Sciences,', then, the, directly, sequencing, was, underwent])].
[sujeto(['The', results, showed, that, no, 'DNMT3a', mutation, was]), verbo([found]), complemento([in, these, patients, including, the, hotspot, 'R882'])].
[sujeto(['But', 'AML1/ETO', mutation, was]), verbo([found]), complemento([in, 10, 'patients,', 'CBFB/MYH11', mutation, in, 3, 'patients,', 'PML/RARa', mutation, in, 13, 'patients,', 'FLT3/ITD', mutation, in, 5, 'patients,', 'FLT3/TKD', mutation, in, 1, 'patient,', 'PML/RARa', and, 'FLT3/TKD', mutation, coexisted, in, 2, patients])].
[sujeto(['Most', sensitive, methodology, to, detect, 'MRD', is, molecular, polymerase, chain, reaction, '(', 'PCR)', but, its, applicability, is, restricted, to, 'AML', with, 'leukemia-specific', molecular]), verbo([targets]), complemento(['(', e])].
[sujeto(['To', realize, the, methodology, that, better, identify, high, risk, 'patients,', an, analysis, of, 'sensitivity,', 'specificity,', predictive, values, '(', 'PV)', and, likelihood, ratio, '(', 'LR)', was]), verbo([provided]), complemento([and, similar, results, were, showed])].
[sujeto([1, ;, 'q22);', 'CBFB-MYH11', chromosomal, 'rearrangements,', but, whether, the, mutation, is, indicative, of]), verbo([associated]), complemento(['SM', is, unclear])].
[sujeto(['Five', of, the, eight, cases, carried, the, mutation, in, a, cell, fraction, below, 'one-tenth', of, the, blast, cell, 'fraction,', thus]), verbo([suggesting]), complemento([that, 'KIT', mutation, is, often, a, late, event, in, leukemogenesis])].
[sujeto(['The', presence, of, the, 'KIT', 'D816V', mutation, in, the, 'CBF', 'AML', subgroup, can, therefore, not, be, considered, indicative, of]), verbo([associated]), complemento(['SM'])].
[sujeto(['The', rearrangements, 't(8;21)', and, 'inv(16)']), verbo([involve]), complemento([the, 'RUNX1/RUNX1T1', '(', 'AML1-ETO', ')', and, 'CBFB/MYH11', 'genes,', respectively])].
[sujeto(['The', 't(8;21)', and, 'inv(16)', subtypes, of, 'AML']), verbo([have]), complemento([been, usually, grouped, and, reported, together, in, clinical, 'studies;', 'however,', recent, studies, have, demonstrated, 'genetic,', 'clinical,', and, prognostic, 'differences,', supporting, the, notion, that, they, represent, 2, distinct, biologic, and, clinical, entities])].
[sujeto(['No', correlation, was, observed, between, incidence, and, age, except, for, 'BCR-ABL', p210, 'fusion,', the, incidence, of, which, rises, with]), verbo([increasing]), complemento([age])].
[sujeto(['To', our, 'knowledge,', the, presence, of, 'PML-RARA', and, 'CBFB-MYH11', in, healthy, individuals]), verbo([has]), complemento([not, been, previously, described])].
[sujeto(['The', present, study]), verbo([provides]), complemento([further, evidence, for, the, presence, of, 'LLA', genetic, alterations, in, healthy, individuals, and, suggests, that, these, mutations, are, not, themselves, sufficient, for, malignant, transformation])].
[sujeto(['AML1-ETO', fusion, gene, transcript, was]), verbo([found]), complemento([in, 14, patients, '(', 19, '%', ')'])].
[sujeto(['Duplication', of, 'FLT3', gene, was]), verbo([found]), complemento([in, 4, '(', 5.3, '%', ')', cases])].
[sujeto(['Analysis', of, 'MRD', level, in, subsequent, time, points, showed, systematic]), verbo([decrease]), complemento([of, number, of, fusion, gene, transcript, copies, and, gene, 'WT1', expression])].
[sujeto(['To', establish, the, rate, of, molecular, marker, presence, in, 'AML', in, children, and, the, influence, of, the, presence, of, 'MRD', on, the, treatment, results, as, 'well,', the, study]), verbo([has]), complemento([to, be, conducted, on, a, larger, group, of, patients, with, longer, 'follow-up'])].
[sujeto(['Many', oncogenetic, aberrations, in, acute, leukemias, result, in, a, fusion, 'gene,', which, is]), verbo([transcribed]), complemento([into, fusion, transcripts, and, translated, into, fusion, 'proteins,', which, are, assumed, to, play, a, critical, role, in, the, oncogenetic, process])].
[sujeto(['So', 'far,', we]), verbo([have]), complemento([been, able, to, design, such, fusion, protein, immunobead, assays, for, 'BCR-ABL,', 'PML-RARA,', 'TEL-AML1,', 'E2A-PBX1,', 'MLL-AF4,', 'AML1-ETO', and, 'CBFB-MYH11'])].
[sujeto(['The', novel, immunobead, assay, will, enable, fast, and, easy, classification, of, acute, leukemia, patients, that]), verbo([express]), complemento([fusion, proteins])].
[sujeto(['Fluorescence', in, situ, hybridization, '(', 'FISH)', analysis, can]), verbo([provide]), complemento([important, information, in, the, management, of, patients, with, hematologic, malignancies])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, performing, 'FISH', in, addition, to, 'G-banded', karyotype, may, contribute, little, additional, genetic, information, in, 'AML', and, 'MDS,', whereas, routine, 'FISH', analysis, appears, to, be, an, efficient, screening, method, in, 'ALL', and, 'MM'])].
[sujeto(['In', a, 'large-scale', miRNA, expression, profiling, analysis, of, 435, human, miRNAs, in, 52, acute, myeloid, leukemia, '(', 'AML)', 'samples,', we]), verbo([found]), complemento([that, 'miR-126', and, its, minor, counterpart, in, 'biogenesis,', 'namely,', 'miR-126*,', were, specifically, aberrantly, overexpressed, in, core, binding, factor, '(', 'CBF)', 'AMLs', including, both, 't(8;21)/AML1-ETO', and, 'inv(16)/CBFB-MYH11', samples])].
[sujeto(['Our', in, vitro, 'gain-', and, 'loss-of-function', experiments, showed, that, forced, expression, of, 'miR-126']), verbo([inhibited]), complemento([apoptosis, and, increased, the, viability, of, 'AML', 'cells,', whereas, the, opposite, effect, was, observed, when, endogenous, expression, of, 'miR-126', was, knocked, down])].
[sujeto(['In', 'addition,', through, in, vitro, 'colony-forming/replating', 'assays,', we, demonstrated, that, forced, expression, of, 'miR-126']), verbo([enhanced]), complemento([proliferation, and, 'colony-forming/replating', capacity, of, mouse, normal, bone, marrow, progenitor, cells, alone, and, 'particularly,', in, cooperation, with, 'AML1-ETO,', a, fusion, gene, resulting, from, 't(8;21)'])].
[sujeto(['Aberrant', promoter, 'DNA', methylation]), verbo([has]), complemento([been, shown, to, play, a, role, in, acute, myeloid, leukemia, '(', 'AML)', pathophysiology])].
[sujeto(['Methylation', signatures, were]), verbo([associated]), complemento([with, the, presence, of, a, specific, cytogenetic, status])].
[sujeto(['The', presence, of, 'MLL', rearrangements, in, 'HSPC']), verbo([induced]), complemento([the, methylation, profile, observed, in, the, 'MLL-positive', primary, samples])].
[sujeto(['Our', study]), verbo([provides]), complemento([a, comprehensive, epigenetic, profiling, of, 'AML,', identifies, new, clinical, markers, for, cases, with, a, normal, 'karyotype,', and, reveals, relevant, biological, information, related, to, the, role, of, fusion, proteins, on, the, methylation, signature])].
[sujeto(['Inv(16)(p13q22)', is]), verbo([associated]), complemento([with, acute, myeloid, leukemia, subtype, 'M4Eo', that, is, characterized, by, the, presence, of, myelomonocytic, blasts, and, atypical, eosinophils])].
[sujeto(['CBF', beta, normally]), verbo([interacts]), complemento([with, 'RUNX1', to, form, a, transcriptionally, active, nuclear, complex])].
[sujeto(['The', 'CBF', 'beta-SMMHC', fusion, protein, is, capable, of]), verbo([binding]), complemento([to, 'RUNX1', and, form, dimers, and, multimers, through, its, myosin, tail])].
[sujeto(['Previous', results, from, transgenic, mouse, models, show, that, 'Cbfb-MYH11', is, able, to]), verbo([inhibit]), complemento([dominantly, 'Runx1', function, in, 'hematopoiesis,', and, is, a, key, player, in, the, pathogenesis, of, leukemia])].
[sujeto(['In', recent, 'years,', molecular, and, cellular, biological, studies]), verbo([have]), complemento([led, to, the, proposal, of, several, models, to, explain, the, function, of, 'CBF', 'beta-SMMHC'])].
[sujeto(['Core-binding', factor, beta, '(', 'CBFbeta,', also, called, polyomavirus, enhancer]), verbo([binding]), complemento([protein, 2, beta, '(', 'PEBP2B))', is, associated, with, an, inversion, of, chromosome, 16, and, is, associated, with, acute, myeloid, leukemia, in, humans])].
[sujeto(['CBFbeta', forms, a, heterodimer, with, 'RUNX1', '(', 'runt-related', transcription, factor, 1, ')', ',', which]), verbo([has]), complemento([a, 'DNA', binding, domain, homologous, to, the, 'pair-rule', protein, runt, in, 'Drosophila', melanogaster])].
[sujeto(['Haploinsufficiency', of, another, 'runt-related', 'protein,', 'RUNX2', '(', also, called, 'CBFA1),']), verbo([causes]), complemento([cleidocranial, dysplasia, in, humans, and, is, essential, in, skeletal, development, by, regulating, osteoblast, differentiation, and, chondrocyte, maturation])].
[sujeto(['Mice', deficient, in, 'Cbfb', '(', 'Cbfb(-/-))', die, at, 'midgestation,', so, the, function, of, 'Cbfbeta', in, skeletal, development]), verbo([has]), complemento([yet, to, be, ascertained])].
[sujeto(['Electrophoretic', mobility, shift, assays, and, reporter, assays, showed, that, 'Cbfbeta', was, necessary, for, the, efficient, 'DNA']), verbo([binding]), complemento([of, 'Runx2', and, for, 'Runx2-dependent', transcriptional, activation])].
[sujeto(['These', findings, indicate, that, 'Cbfbeta', is]), verbo([required]), complemento([for, the, function, of, 'Runx2', in, skeletal, development])].
[sujeto(['AML1/RUNX1', is, an, essential, transcription, factor]), verbo([involved]), complemento([in, the, differentiation, of, hematopoietic, cells])].
[sujeto(['AML1']), verbo([binds]), complemento([to, the, 'Runt-binding', 'double-stranded', 'DNA', element, '(', 'RDE)', of, target, genes, through, its, 'N-terminal', 'Runt', domain])].
[sujeto(['In', a, previous, 'study,', we, obtained, 'RNA', aptamers, against, the, 'AML1', 'Runt', domain, by, systematic, evolution, of, ligands, by, exponential, enrichment, and, revealed, that, 'RNA', aptamers, exhibit, higher, affinity, for, the, 'Runt', domain, than, that, for, 'RDE', and, possess, the, 5, '\'', -, 'GCGMGNN-3\'', and, 5, '\'', -, 'N\'N\'CCAC-3\'']), verbo([conserved]), complemento([motif, '(', 'M:', 'A', or, 'C;', 'N', and, 'N\'', form, 'Watson-Crick', base, 'pairs)', that, is, important, for, 'Runt', domain, binding])].
[sujeto(['In', this, 'study,', to, understand, the, structural, basis, of, recognition, of, the, 'Runt', domain, by, the, aptamer, 'motif,', the, solution, structure, of, a, 22, -, mer, 'RNA', was, determined, using]), verbo([nuclear]), complemento([magnetic, resonance])].
[sujeto(['Structural', analysis, of, the, aptamer, motif, indicated, that, the, aptamer]), verbo([binds]), complemento([to, the, 'Runt', domain, by, mimicking, the, 'RDE', sequence, and, structure])].
[sujeto(['Our', data, should]), verbo([enhance]), complemento([the, understanding, of, the, structural, basis, of, 'DNA', mimicry, by, 'RNA', molecules])].
[sujeto(['Runt-related', transcription, factor, 2, '(', 'Runx2)', and, muscle, segment, homeobox, homolog, 2, -]), verbo([interacting]), complemento([nuclear, target, '(', 'MINT)', '(', 'Spen', 'homolog)', are, transcriptional, regulators, critical, for, mammalian, development])].
[sujeto(['MINT']), verbo([enhances]), complemento(['Runx2', activation, of, osteocalcin, '(', 'OC)', fibroblast, growth, factor, '(', 'FGF)', response, element, in, an, 'FGF2-dependent', fashion, in, 'C3H10T1/2', cells])].
[sujeto(['Although', the, 'MINT', 'N-terminal', 'RNA', recognition, motif, domain, 'contributes,', the, muscle, segment, homeobox, homolog, 2, -]), verbo([interacting]), complemento([domain, is, sufficient, for, 'Runx2', activation])].
[sujeto(['Conversely,', phosphomimetic, 'Asp', substitution, of, these, 'AD3', 'Ser/Thr', residues]), verbo([enhanced]), complemento([activation, by, 'MINT'])].
[sujeto(['Systematic', screening, with, 'PDPK', inhibitors, identified, that, the, casein, 'kinase-2/homeodomain-interacting', protein, kinase, '(', 'HIPK)/dual', specificity, tyrosine, phosphorylation]), verbo([regulated]), complemento([kinase, inhibitor, 2, -, 'dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole', '(', 'DMAT),', but, not, 'ERK,', 'c-Jun', 'N-terminal', 'kinase,', 'p38MAPK,', or, other, casein, 'kinase-2', 'inhibitors,', abrogated, 'Runx2-,', 'MINT-,', and, 'FGF2-activation'])].
[sujeto(['HIPK3', and, 'Runx2', coprecipitate, after, in, vitro, 'transcription-translation,', and, recombinant, 'HIPK3']), verbo([recognizes]), complemento(['Runx2', 'AD3', as, kinase, substrate])].
[sujeto(['Furthermore,', 'DMAT', treatment, and, 'HIPK3', 'RNAi']), verbo([inhibited]), complemento(['MINT+FGF2', activation, of, 'Runx2', 'AD3,', and, nuclear, 'HIPK3', colocalized, with, 'MINT'])].
[sujeto(['Thus,', 'HIPK3']), verbo([participates]), complemento([in, 'MINT+FGF2', regulation, of, 'Runx2', 'AD3', activity, and, controls, 'Runx2-dependent', 'OC', expression])].
[sujeto(['Expression', of, the, 'IL-7R', 'alpha-chain', '(', 'IL-7Ralpha)', is, strictly]), verbo([regulated]), complemento([during, the, development, and, maturation, of, lymphocytes])].
[sujeto(['Glucocorticoids', '(', 'GC)']), verbo([have]), complemento([pleiotypic, effects, on, the, growth, and, function, of, lymphocytes])].
[sujeto(['Although', 'GC']), verbo([have]), complemento([been, reported, to, induce, the, transcription, of, 'IL-7Ralpha', gene, in, human, 'T', 'cells,', its, molecular, mechanism, is, largely, unknown])].
[sujeto(['This', effect, does, not]), verbo([require]), complemento([protein, synthesis, de, 'novo,', because, protein, synthesis, inhibitors, do, not, block, the, process])].
[sujeto(['Mouse', 'IL-7Ralpha', promoter]), verbo([has]), complemento([striking, homology, with, human, and, 'rat,', containing, consensus, motifs, of, 'Ikaros,', 'PU'])].
[sujeto(['In', 'addition,', a]), verbo([conserved]), complemento([noncoding, sequence, '(', 'CNS)', of, approximately, 270, bp, was, found, 3.6, -, kb, upstream, of, the, 'promoter,', which, was, designated, as, 'CNS-1'])].
[sujeto(['Importantly,', we, show, by, reporter, assay, that, the, 'IL-7Ralpha', promoter]), verbo([has]), complemento([specific, transcription, activity, in, 'T', cells])].
[sujeto(['We', also, demonstrate, that, 'GR']), verbo([binds]), complemento([to, the, 'GR', motif, by, 'EMSA'])].
[sujeto(['In', 'addition,', by, chromatin, immunoprecipitation, 'assay,', we, show, that, 'GR', is, rapidly]), verbo([recruited]), complemento([to, endogenous, 'CNS-1', chromatin, after, 'GC', stimulation])].
[sujeto(['These', results, demonstrate, that, 'GR']), verbo([binds]), complemento([to, the, 'GR', motif, in, the, 'CNS-1', region, after, 'GC', stimulation, and, then, activates, the, transcription, of, the, 'IL-7Ralpha', promoter])].
[sujeto(['The', 'RUNX3', gene, belongs, to, the, runt, domain, family, of, transcription, factors, that]), verbo([act]), complemento([as, master, regulators, of, gene, expression, in, major, developmental, pathways])].
[sujeto(['Two', large]), verbo([conserved]), complemento(['CpG', islands, were, found, within, both, 'genes,', one, around, exon, 2, and, the, other, at, the, beginning, of, exon, 6])].
[sujeto(['RUNX1,', 'RUNX2', and, 'RUNX3', gene, products]), verbo([bind]), complemento([to, the, same, 'DNA', 'motif,', hence, their, temporal, and, spatial, expression, during, development, should, be, tightly, regulated])].
[sujeto(['Structure/function', analysis, showed, that, two, promoter, 'regions,', designated, 'P1', and, 'P2,']), verbo([regulate]), complemento(['RUNX3', expression, in, a, cell, 'type-specific', manner])].
[sujeto(['Transfection', experiments, demonstrated, that, both, promoters, were, highly, active, in, the, 'GM1500', 'B-cell', 'line,', which, endogenously]), verbo([expresses]), complemento(['RUNX3,', but, were, inactive, in, the, 'K562', myeloid, cell, 'line,', which, does, not, express, 'RUNX3'])].
[sujeto(['We', specified, 43, genes, which, are, most, suitable, as, molecular, markers, of, 'PTC,', among, them, some, 'well-known', 'PTC', markers, '(', 'MET,', fibronectin, 1, ',', dipeptidylpeptidase, 4, ',', or, adenosine, 'A1', 'receptor)', and, potential, new, ones, '(', 'UDP-galactose-4-epimerase,', cadherin, 16, ',', gap, junction, protein, 3, ',', 'sushi,', 'nidogen,', and, 'EGF-like', domains, 1, ',', inhibitor, of, 'DNA']), verbo([binding]), complemento([3, ',', 'RUNX1,', leiomodin, 1, ',', 'F-box', protein, 9, ',', and, tripartite, 'motif-containing', 58, ')'])].
[sujeto(['Both', aging, rat, muscle, and, 'Sarco', mouse, muscle, exhibited, marked, 'fiber-type', 'grouping,', consistent, with, repeating, cycles, of, denervation, and, 'reinnervation,', yet, in, 'VO', 'muscle,', rapsyn, at, the, endplate]), verbo([increased]), complemento([and, was, associated, with, only, a, 10, &, 'nbsp;%', decline, in, acetylcholine, receptor, '(', 'AChR)', 'intensity,', whereas, in, 'Sarco', 'mice,', there, was, a, decline, in, rapsyn, and, a, 25, &, 'nbsp;%', decrease, in, 'AChR', intensity])].
[sujeto(['In', the, 'Sarco', 'mice,', there, were, much, smaller]), verbo([increases]), complemento([in, denervation, transcripts, '(', 0, -, 3.5, -, 'fold)', and, accumulation, of, very, small, fibers, '(', 2, -, 6, &, 'nbsp;%)', compared, to, the, 'VO', 'rat,', suggesting, a, reduced, capacity, for, reinnervation, in, aging, muscle])].
[sujeto(['Despite', the, marked, persistent, denervation, in, the, 'VO', rat, 'muscle,', transcripts, of, neurotrophins]), verbo([involved]), complemento([in, promoting, axonal, sprouting, following, denervation, exhibited, no, 'increase,', and, several, miRNAs, predicted, to, suppress, neurotrophins, were, elevated, in, 'VO', rat])].
[sujeto(['Our', results, support, the, hypothesis, that, the, accumulation, of, denervated, fibers, with, aging, is, due, to, failed, reinnervation, and, that, this, may, be, affected, by, a, limited, neurotrophin, response, that]), verbo([mediates]), complemento([axonal, sprouting, following, denervation])].
[sujeto(['An', appropriate, inflammatory, response, plays, critical, roles, in, eliminating, 'pathogens,', whereas, an, excessive, inflammatory, response, can]), verbo([cause]), complemento([tissue, damage])].
[sujeto(['Overexpression', of, 'RUNX1']), verbo([promoted]), complemento(['IL-1β', and, 'IL-6', production, in, response, to, 'LPS', stimulation])].
[sujeto(['Moreover,', 'RUNX1']), verbo([interacted]), complemento([with, the, 'NF-κB', subunit, 'p50,', and, coexpression, of, 'RUNX1', with, p50, further, enhanced, the, 'NF-κB', luciferase, activity])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'RUNX1', may, be, a, new, potential, target, for, resolving, 'TLR4-associated', uncontrolled, inflammation, and, preventing, sepsis])].
[sujeto(['Based', on, this, 'data,', it, was]), verbo([suggested]), complemento([that, the, 'well-recognized', 'phenotype-ameliorating', role, assigned, to, positive, 'XmnI', could, be, associated, with, its, linked, elements, in, the, 'LCR'])].
[sujeto(['To', investigate, the, functional, significance, of, polymorphisms, at, the, 5, '\'', 'HS4-LCR,', we, studied, its, influence, on]), verbo([binding]), complemento([of, transcription, factors])].
[sujeto(['Web-based', predictions, of, transcription, factor]), verbo([binding]), complemento([revealed, a, binding, site, for, 'runt-related', transcription, factor, 1, '(', 'RUNX1),', when, the, allele, at, the, center, of, the, palindrome, '(', 'TGGGG(A/G)CCCCA)', was, 'A', but, not, when, it, was, 'G'])].
[sujeto(['Furthermore,', electromobility, shift, assay, '(', 'EMSA)', presented, evidence, in, support, of, 'allele-specific']), verbo([binding]), complemento([of, 'RUNX1', to, 5, '\'', 'HS4'])].
[sujeto(['Considering', that, 'RUNX1', is, a, 'well-known', regulator, of, 'hematopoiesis,', these, preliminary, data]), verbo([suggest]), complemento([the, importance, of, further, studies, to, confirm, this, interaction, and, consequently, investigate, its, functional, and, phenotypical, relevance])].
[sujeto(['These', studies, could, help, us, to, understand, the, molecular, mechanism, behind, the, phenotype, modifying, role, of, the, 5, '\'', 'HS4-LCR', polymorphic, palindromic, region, '(', 'rs16912979),', which]), verbo([has]), complemento([been, observed, in, previous, studies])].
[sujeto(['Aberrant', expression, of, long, noncoding, 'RNAs']), verbo([has]), complemento([recently, been, reported, in, tumorigenesis, and, plays, a, pivotal, role, in, regulating, malignant, behavior, of, cancers])].
[sujeto(['Knockdown', of, 'HCP5']), verbo([inhibited]), complemento([the, malignant, biological, behavior, of, glioma, cells, by, reducing, 'proliferation,', migration, and, 'invasion,', and, inducing, apoptosis])].
[sujeto(['HCP5']), verbo([regulated]), complemento([the, malignant, behavior, of, glioma, cells, by, binding, to, 'microRNA-139,', which, functions, as, a, tumor, suppressor])].
[sujeto(['Moreover,', knockdown, of, 'HCP5', 'down-regulated', 'Runt-related', transcription, factor, 1, ',', a, direct, and, functional, downstream]), verbo([target]), complemento([of, 'microRNA-139', that, is, involved, in, 'microRNA-139-mediated', 'tumor-suppressive', effects, in, glioma, cells])].
[sujeto(['Runt-related', transcription, factor, 1]), verbo([increased]), complemento([promoter, activities, and, upregulated, expression, of, the, oncogenic, gene, astrocyte, elevated, 'gene-1', '(', 'AEG-1)'])].
[sujeto(['Runt-related', transcription, factor, 1, also]), verbo([increased]), complemento([the, promoter, activities, and, expression, of, 'HCP5,', which, showed, a, positive, feedback, loop, in, regulating, the, malignant, behavior, of, glioma, cells])].
[sujeto(['In', 'conclusion,', this, study, demonstrated, that, the, 'HCP5-microRNA-139-', 'Runt-related', transcription, factor, 1, feedback, loop, plays, a, pivotal, role, in]), verbo([regulating]), complemento([the, malignant, behavior, of, glioma, 'cells,', which, may, provide, a, potential, therapeutic, strategy, for, treating, glioma])].
[sujeto(['Chromosomal', abnormalities]), verbo([lead]), complemento([to, the, development, of, hematologic, malignancies, such, as, 'Myelodysplastic', 'Syndrome', '(', 'MDS)'])].
[sujeto(['Known', chromosomal, changes]), verbo([causing]), complemento(['MDS', include, deletion, of, the, long, arm, of, chromosome, 5, ',', 'runt-related', transcription, factor, 1, '(', 'RUNX1)', also, known, as, acute, myeloid, leukemia, 1, protein, '(', 'AML1),', and, very, rarely, fusion, genes, involving, 'RUNX1', at, 't(5;21)(q15;q22)'])].
[sujeto(['Therapy', was, started, with, 'Lenalidomide']), verbo([leading]), complemento([to, normal, blood, counts])].
[sujeto(['We']), verbo([report]), complemento([a, new, case, of, 't(5;21)(q15;q22)', involving, the, 'RUNX1', gene, and, 'del(5)(q13q33)', in, a, 'MDS', 'patient,', a, combination, of, chromosomal, abnormalities, heretofore, not, reported, in, the, literature])].
[sujeto(['RUNX1', rearrangement, is, usually]), verbo([associated]), complemento([with, an, adverse, prognosis, in, 'AML', and, 'MDS'])].
[sujeto(['Deletions', of, 5, q, are, typically]), verbo([associated]), complemento([with, poor, prognosis, in, 'AML,', however, it, is, usually, associated, with, a, favorable, prognosis, in, 'MDS'])].
[sujeto(['Our', patient]), verbo([responded]), complemento([very, well, to, 'Lenalidomide', therapy, with, achievement, of, 'CR'])].
[sujeto(['Lenalidomide', is, approved, for, treatment, of, anemia, in, low, and, intermediate, risk, 'MDS', with, del, '(', 5, 'q),', however, based, on, a, search, of, literature, it, seems, that, 'RUNX1', mutations, are, also, more, prominent, in, patients, who]), verbo([have]), complemento([responded, to, 'Lenalidomide', therapy])].
[sujeto(['Hence,', it, is, conceivable, that, our, patient, started, with, a, 5, q, minus, syndrome, and, then, acquired, the, second, hit, 'RUNX1', translocation]), verbo([leading]), complemento([to, an, accelerated, phase, of, myeloid, neoplasm, or, refractory, anemia, with, excess, 'blasts,', type, 1])].
[sujeto(['Hence,', the, temporal, relationship, between, acquisition, of, del, 5, q, and, 'RUNX1', rearrangement, may]), verbo([have]), complemento([influenced, the, clinical, outcome, and, possibly, response, to, therapy])].
[sujeto(['AAA', is]), verbo([caused]), complemento([by, segmental, weakening, of, the, aortic, walls, and, progressive, aortic, dilation, leading, to, the, eventual, rupture, of, the, 'aorta,', accompanied, by, intense, inflammation])].
[sujeto(['Additionally,', studies]), verbo([have]), complemento([indicated, a, close, relationship, between, the, pathogenesis, and, progression, of, 'AAA', and, cellular, immune, responses, in, aneurysm, wall, tissue])].
[sujeto(['There', are, no, proven, clinical, management, strategies, or, 'pharmaco-therapeutics', to]), verbo([prevent]), complemento(['AAA', progression, once, an, 'AAA', has, been, detected])].
[sujeto(['Moreover,', so, far, no, biomarkers]), verbo([have]), complemento([been, established, to, indicate, the, disease, status, of, 'AAA'])].
[sujeto(['Hence,', understanding, the, pathogenesis, of, 'AAA']), verbo([has]), complemento([recently, become, an, increasing, priority, in, basic, and, translational, vascular, research])].
[sujeto(['The', results, of, elevated, expression, of, 'RUNX', genes, and, their, relationships, in, the, 'AAA', tissues]), verbo([suggest]), complemento([the, involvement, of, conserved, 'Runt-related', genes, in, the, pathophysiology, of, 'AAA', development])].
[sujeto(['Th17', and]), verbo([associated]), complemento(['IL-17', were, involved, in, the, pathogenesis, of, 'ITP'])].
[sujeto(['Runt-related', transcription, factor, 1, '(', 'RUNX1),', a, member, of, the, runt, 'domain-containing', family, of, transcription, 'factors,', is]), verbo([required]), complemento([for, 'Th17', differentiation])].
[sujeto(['Whether', 'RUNX1', was]), verbo([involved]), complemento([in, the, pathogenesis, of, 'ITP', remains, poorly, understood])].
[sujeto(['Furthermore,', a, significantly, positive, correlation, of, 'RUNX1', with, 'RORγt', was]), verbo([found]), complemento([in, active, 'ITP', patients])].
[sujeto(['In', 'conclusion,', 'RUNX1', was]), verbo([associated]), complemento([with, the, pathogenesis, of, 'ITP', possibly, through, regulation, of, 'Th17', cell, differentiation, and, therapeutically, targeting, it, might, be, a, novel, approach, in, 'ITP', treatment])].
[sujeto(['Runt-related', transcription, factor, 1, '(', 'Runx1),', a, master, regulator, of, 'hematopoiesis,', is]), verbo([expressed]), complemento([in, preosteoclasts])].
[sujeto(['Previously', we, evaluated, the, bone, phenotype, of, 'CD11b-Cre', 'Runx1(fl/fl)', mice, and, demonstrated]), verbo([enhanced]), complemento([osteoclasts, and, decreased, bone, mass, in, males])].
[sujeto(['Both', female, and, male, 'LysM-Cre', 'Runx1(fl/fl)', mice, had]), verbo([decreased]), complemento([trabecular, bone, mass, '(', 72, '%', decrease, in, bone, volume, 'fraction)', and, increased, osteoclast, number, '(', 2, -, 3, 'times)', '(', 'P', &, 'lt;'])].
[sujeto(['We', also, demonstrated, that]), verbo([loss]), complemento([of, 'Runx1', in, pluripotential, myeloid, precursors, with, 'LysM-Cre', did, not, alter, the, number, of, myeloid, precursor, cells, in, bone, marrow, or, their, ability, to, differentiate, into, phagocytizing, or, 'antigen-presenting', cells])].
[sujeto(['This', study, demonstrates, that, abrogation, of, 'Runx1', in, multipotential, myeloid, precursor, cells, significantly, and, specifically]), verbo([enhanced]), complemento([the, ability, of, receptor, activator, of, nuclear, 'factor-κB', ligand, to, stimulate, osteoclast, formation, and, fusion, in, female, and, male, mice, without, affecting, other, myeloid, cell, fates])].
[sujeto(['In', 'turn,']), verbo([increased]), complemento([osteoclast, activity, in, 'LysM-Cre', 'Runx1(fl/fl)', mice, likely, contributed, to, a, decrease, in, bone, mass])].
[sujeto(['These', dramatic, effects, were, not, due, to]), verbo([increased]), complemento([osteoclast, precursors, in, the, deleted, mutants, and, argue, that, inhibition, of, 'Runx1', in, multipotential, myeloid, precursor, cells, is, important, for, osteoclast, formation, and, function])].
[sujeto(['Previously,', we, showed, that, 'SMAD4', and, 'runt-related', transcription, factor, 1, '(', 'RUNX1)', were, independently]), verbo([required]), complemento([for, 'MDE', to, express, 'ΔNp63'])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, vaginal, mesenchyme, directs, vaginal, epithelial, cell, fate, in, 'MDE', through, paracrine, activation, of, fibroblast, growth, factor, '(', 'FGF)', 'receptor-MAPK', pathway])].
[sujeto(['In', the, developing, reproductive, 'tract,', 'FGF7', and, 'FGF10', were, enriched, in, vaginal, 'mesenchyme,', whereas, 'FGF', receptor, 2, 'IIIb', was]), verbo([expressed]), complemento([in, epithelia, of, both, the, uterus, and, vagina])].
[sujeto(['In', 'vitro,', 'FGF10', in, combination, with, bone, morphogenetic, protein, 4, and, activin, 'A', '(', 'ActA)', was, sufficient, to]), verbo([induce]), complemento(['ΔNp63', in, 'MDE,', and, 'ActA', was, essential, for, induction, of, 'RUNX1', through, 'SMAD-independent', pathways])].
[sujeto(['Accordingly,', inhibition, of, type, 1, receptors, for, activin, in, neonatal, mice]), verbo([induced]), complemento([uterine, differentiation, in, vaginal, epithelium, by, 'down-regulating', 'RUNX1,', whereas, conditional, deletion, of, 'Smad2', and, 'Smad3', had, no, effect, on, vaginal, epithelial, differentiation])].
[sujeto(['In', 'conclusion,', vaginal, epithelial, cell, fate, in, 'MDE', is]), verbo([induced]), complemento([by, 'FGF7/10-MAPK,', bone, morphogenetic, protein, 4, -, 'SMAD,', and, 'ActA-RUNX1', pathway, 'activities,', and, the, disruption, in, any, one, of, these, pathways, results, in, conversion, from, vaginal, to, uterine, epithelial, cell, fate])].
[sujeto(['Osseo', genic, lineage, differentiation, was, also, tested, by, means, of, the, 'catenin-β1', 'immunofluorescence,']), verbo([induced]), complemento(['osteoblasts,', which, represented, the, internal, control])].
[sujeto(['The', 'RUNX1', and, 'SP7', expressions, in, the]), verbo([induced]), complemento([osteoblasts, prove, to, be, 'different,', compared, with, cells, cultured, on, metallic, supports])].
[sujeto(['Present', results]), verbo([suggested]), complemento([that, different, titanium, surfaces, might, induce, some, differences, in, terms, of, gene, expression])].
[sujeto(['However,', the, 'TEL-AML1', copies, in, her, blood, still]), verbo([increased]), complemento([and, she, died, with, leukemia, relapse, after, additional, 'CAR-T', cell, infusion])].
[sujeto(['CAR-T', therapy, is, a, novel, therapeutic, approach, that, could, be, useful, for, patients, with, relapsed, and, refractory, 'B-ALL', who]), verbo([have]), complemento([failed, all, other, treatment, options])].
[sujeto(['Homoharringtonine', combined, aclarubicin, and, cytarabine, '(', 'HAA)']), verbo([has]), complemento([been, demonstrated, to, achieve, a, high, remission, rate, and, provide, a, survival, advantage, in, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['The', median, fold]), verbo([decrease]), complemento([of, the, 'RUNX1/RUNX1T1', transcript, level, was, 200, '(', 1, -, 358000, ')', ',', and, 16.7, '%', '(', 5, /, 30, ')', patients, achieved, &, 'gt;3', log, decrease, after, one, cycle, of, the, 'HAA', regimen])].
[sujeto(['A', network, of, 'lineage-specific', transcription, factors, and, microRNAs, tightly]), verbo([regulates]), complemento([differentiation, of, hematopoietic, stem, cells, along, the, distinct, lineages])].
[sujeto(['We']), verbo([found]), complemento([that, the, hematopoietic, master, regulator, 'RUNX1', controls, the, expression, of, certain, 'microRNAs,', of, importance, during, 'erythroid/megakaryocytic', differentiation])].
[sujeto(['In', 'particular,', we, show, that, the, erythorid, 'miR144/451', cluster, is, epigenetically]), verbo([repressed]), complemento([by, 'RUNX1', during, megakaryopoiesis])].
[sujeto(['Furthermore,', the, leukemogenic, 'RUNX1/ETO', fusion, protein, transcriptionally]), verbo([represses]), complemento([the, 'miR144/451', 'pre-microRNA'])].
[sujeto(['Thus', 'RUNX1/ETO', contributes, to]), verbo([increased]), complemento([expression, of, miR451, target, genes, and, interferes, with, normal, gene, expression, during, differentiation])].
[sujeto(['Furthermore,', we, observed, that, inhibition, of, 'RUNX1/ETO', in, 'Kasumi1', cells, and, in, 'RUNX1/ETO', positive, primary, acute, myeloid, leukemia, patient, samples]), verbo([leads]), complemento([to, 'up-regulation', of, 'miR144/451'])].
[sujeto(['RUNX1', '(', 'AML1)', amplification, in, patients, with, 'B-cell', acute, lymphoblastic, leukemia, '(', 'B-ALL)']), verbo([has]), complemento([been, associated, with, poor, survival, for, unclear, reasons])].
[sujeto(['Our', anecdotal, experience]), verbo([suggests]), complemento([that, children, with, 'B-ALL', and, 'RUNX1', amplification, might, be, predisposed, to, thrombosis])].
[sujeto(['The', 'RUNX1', isoforms, derived, from, 'P2', are]), verbo([expressed]), complemento([in, a, variety, of, 'tissues,', but, expression, of, 'P1-derived', isoform, is, restricted, to, cells, of, hematopoietic, lineage])].
[sujeto(['Here', we]), verbo([report]), complemento([regulation, of, 'P1-derived', 'RUNX1', mRNA, by, 'RUNX1', protein])].
[sujeto(['In', silico, analysis, of, 'P1', promoter, revealed, presence, of, two, evolutionary]), verbo([conserved]), complemento(['RUNX', 'motifs,', 0.6, kb, upstream, of, the, transcription, start, 'site,', and, three, 'RUNX', motifs, within, 170, bp, of, the, 5, '\'', 'UTR'])].
[sujeto(['Mutation', or, deletion, of, 'RUNX', motifs, in, the, 'UTR']), verbo([enhances]), complemento([basal, activity, of, the, 'RUNX1', promoter])].
[sujeto(['Chromatin', immunoprecipitation, revealed, that, 'RUNX1', protein, is]), verbo([recruited]), complemento([to, these, sites])].
[sujeto(['We', also, demonstrate, that, 'RUNX1', protein]), verbo([regulates]), complemento([transcription, of, endogenous, 'RUNX1', mRNA, in, 'T-cell'])].
[sujeto(['Finally', we, show, that, 'SCL', transcription, factor, is]), verbo([recruited]), complemento([to, regions, containing, 'RUNX', motifs, in, the, promoter, and, the, 'UTR', and, regulates, activity, of, the, 'RUNX1', 'P1', promoter, in, vitro])].
[sujeto(['Thus,', multiple, lines, of, evidence, show, that, 'RUNX1', protein]), verbo([regulates]), complemento([its, own, gene, transcription])].
[sujeto(['For', acute, myeloid, 'leukemia,', we, identified, a, 'MEGS', with, five, genes, '(', 'FLT3,', 'IDH2,', 'NRAS,', 'KIT,', and, 'TP53)', and, a, 'MEGS', '(', 'NPM1,', 'TP53,', and, 'RUNX1)', whose, mutation, status, was, strongly]), verbo([associated]), complemento([with, survival, '(', p, =, 6.7, ×, 10, '(', -, 4, ')', ')'])].
[sujeto(['For', breast, 'cancer,', we, identified, a, significant, 'MEGS', consisting, of, 'TP53', and, four, infrequently, mutated, genes, '(', 'ARID1A,', 'AKT1,', 'MED23,', and, 'TBL1XR1),']), verbo([providing]), complemento([support, for, their, role, as, cancer, drivers])].
[sujeto(['Transmissible', gastroenteritis, virus, '(', 'TGEV),', belonging, to, the, coronaviridae, 'family,', is, the, key]), verbo([cause]), complemento([of, the, fatal, diarrhea, of, piglets, and, results, in, many, pathological, processes])].
[sujeto(['During', the, process, of, apoptosis]), verbo([induced]), complemento([by, 'TGEV', infection, in, 'PK-15', 'cells,', the, 'miR-27b', is, notably, 'down-regulated'])].
[sujeto(['Thus,', we, speculate, that, 'miR-27b', is]), verbo([involved]), complemento([in, regulating, the, process, of, apoptosis, in, 'PK-15', cells])].
[sujeto(['In', this, study, we, demonstrated, that, the, 'over-expression', of, 'miR-27b']), verbo([led]), complemento([to, the, inhibition, of, 'TGEV-induced', 'apoptosis,', reduction, of, 'Bax', protein, 'level,', and, decrease, of, 'caspase-3', and, -, 9, activities])].
[sujeto(['Conversely,', silencing, of, 'miR-27b', by, 'miR-27b', inhibitors]), verbo([enhanced]), complemento([apoptosis, via, 'up-regulating', 'Bax', expression, and, promoting, the, activities, of, 'caspase-3', and, -, 9, in, 'TGEV-infected', cells])].
[sujeto(['Subsequently,', the, 'runt-related', transcription, factor, 1, '(', 'RUNX1)', is, a, candidate]), verbo([target]), complemento([of, 'miR-27b', predicted, by, bioinformatics, search])].
[sujeto(['We', further, identified, that, the, 'miR-27b', directly]), verbo([bound]), complemento([to, the, 3, '\'', 'UTR', of, 'RUNX1', mRNA, and, suppressed, 'RUNX1', 'expression,', which, indicates, 'RUNX1', is, the, direct, target, gene, of, 'miR-27b'])].
[sujeto(['The', 'over-expression', of, 'RUNX1']), verbo([increased]), complemento([apoptosis, and, knockdown, 'RUNX1blocked', apoptosis, of, 'viral-infected', cells, via, regulating, 'Bax', expression, and, the, activities, of, 'caspase-3', and, -, 9])].
[sujeto(['Our', data]), verbo([reveal]), complemento([that, 'miR-27b', may, repress, the, mitochondrial, pathway, of, apoptosis, by, targeting, 'RUNX1,', indicating, that, 'TGEV', may, induce, apoptosis, via, 'down-regulating', 'miR-27b', and, that, 'miR-27b', may, act, as, a, target, for, therapeutic, intervention])].
[sujeto(['Differentially']), verbo([expressed]), complemento([genes, '(', 'DEGs)', were, then, screened, using, a, paired, 't&#8209;test'])].
[sujeto(['Functional', enrichment, analysis, indicated, that, inhibitor, of, 'DNA', 'binding&nbsp;4', '(', 'ID4)', was]), verbo([involved]), complemento([in, neuronal, differentiation, and, transcriptional, suppression])].
[sujeto(['In', the, 'PPI', 'network,', genes, may, be]), verbo([involved]), complemento([in, 'DS', by, interacting, with, 'others,', including, nuclear, receptor, 'subfamily&nbsp;4', 'group&nbsp;A', 'member&nbsp;2', '(', 'NR4A2)&#8209;early', growth, response, '(', 'EGR)2', and, 'NR4A2&#8209;EGR3'])].
[sujeto(['Therefore,', 'RUNX1,', 'NR4A2,', 'EGR2,', 'EGR3', and, 'ID4', may, be, key, genes]), verbo([associated]), complemento([with, the, pathogenesis, of, 'DS'])].
[sujeto(['The', 't(12;21)(p13;q22)', with, 'ETV6-RUNX1', fusion, occurs, in, 25, '%', of, cases, of, 'B-cell', precursor, acute, lymphoblastic, leukemia, '(', 'BCP-ALL);', and, is, generally]), verbo([associated]), complemento([with, favorable, prognosis])].
[sujeto(['However,', 15, -, 20, '%', of, the, 't(12;21)-positive', cases, are]), verbo([associated]), complemento([with, 'high-risk', disease, due, to, for, example, slow, early, responses, to, therapy])].
[sujeto(['It', is, 'well-known', that, development, of, overt, leukemia, in, 't(12;21)-positive', 'ALL']), verbo([requires]), complemento([secondary, chromosomal, aberrations, although, the, full, spectrum, of, these, cytogenetic, alterations, is, yet, 'unsettled,', and, 'also,', how, they, may, be, associated, with, disease, outcome])].
[sujeto(['This']), verbo([report]), complemento([describes, the, case, of, an, adolescent, male, with, 't(12;21)-positive', 'ALL', who, displayed, a, 'G-banded', karyotype, initially, interpreted, as, 'del(1)(p22p13)', and, 'del(15)(q15)'])].
[sujeto([1, '%']), verbo([he]), complemento([was, then, assigned, as, a, high, risk, patient, and, received, intensified, chemotherapy, accordingly])].
[sujeto(['The', unbalanced, complex, rearrangements]), verbo([have]), complemento([not, been, described, previously])].
[sujeto(['Extended', 'locus-specific', 'FISH', analyses, showed, that, the, three, deletions, were, on, the, same, chromosome, 1, homologue, that, was]), verbo([involved]), complemento([in, the, 't(1;15),', and, that, the, deletion, on, chromosome, 15, also, was, on, the, same, chromosome, 15, homologue, as, involved, in, the, 't(1;15)'])].
[sujeto(['Together', these, findings, show, the, great, importance, of, the, combined, usage, of, molecular, cytogenetic, analyses, and, oaCGH, analysis, to]), verbo([enhance]), complemento([characterization, of, apparently, simple, 'G-banded', 'karyotypes,', and, to, provide, a, more, complete, spectrum, of, secondary, chromosomal, aberrations, in, high, risk, 't(12;21)-positive', 'BCP-ALLs'])].
[sujeto(['Overwhelming', evidence, indicates, that, long, 'non-coding', 'RNAs']), verbo([have]), complemento([essential, roles, in, tumorigenesis])].
[sujeto(['Nevertheless,', their, role, in, the, molecular, pathogenesis, of, pediatric, 'B-cell', precursor, acute, lymphoblastic, leukemia]), verbo([has]), complemento([not, been, extensively, explored])].
[sujeto(['Next,', integration, of, this, lncRNA, signature, with, 'RNA', sequencing, of, 'BCP-ALL', cell, lines, and, lncRNA, profiling, of, an, in, vitro, model, system, of, 'ETV6/RUNX1', 'knockdown,', revealed, that, 'lnc-NKX2-3-1,', 'lnc-TIMM21-5,', 'lnc-ASTN1-1', and, 'lnc-RTN4R-1', are, truly]), verbo([regulated]), complemento([by, the, oncogenic, fusion, protein])].
[sujeto(['Moreover,', sustained, inactivation, of, 'lnc-RTN4R-1', and, 'lnc-NKX2-3-1', in, 'ETV6/RUNX1', positive, cells]), verbo([caused]), complemento([profound, changes, in, gene, expression])].
[sujeto(['All', 'together,', our, study, defined, a, unique, lncRNA, expression, signature]), verbo([associated]), complemento([with, 'ETV6/RUNX1-positive', 'BCP-ALL', and, identified, 'lnc-RTN4R-1', and, 'lnc-NKX2-3-1', as, lncRNAs, that, might, be, functionally, implicated, in, the, biology, of, this, prevalent, subtype, of, human, leukemia])].
[sujeto(['Transcription', factors, of, the]), verbo([nuclear]), complemento([factor, of, activated, 'T', cell, '(', 'NFAT)-family', are, essential, for, 'antigen-specific', 'T', cell, activation, and, differentiation])].
[sujeto(['Their', cooperative, 'DNA']), verbo([binding]), complemento([with, other, transcription, 'factors,', such, as, 'AP1-proteins', '(', 'FOS,', 'JUN,', 'JUNB),', 'FOXP3,', 'IRFs', and, 'EGR1,', dictate, the, gene, regulatory, action, of, 'NFATs'])].
[sujeto(['We', revealed, more, than, 170, 'NFAT']), verbo([associated]), complemento(['proteins,', half, of, which, are, involved, in, transcriptional, regulation])].
[sujeto(['Moreover,', our, computational, analysis, discovered, that]), verbo([binding]), complemento([motifs, for, 'RUNX', and, 'CREB1', are, found, preferentially, in, the, direct, vicinity, of, 'NFAT', binding, motifs, and, in, a, distinct, orientation, to, them])].
[sujeto(['Furthermore,', we]), verbo([provide]), complemento([evidence, that, mTOR, and, 'CHEK1', kinase, activity, influence, 'NFAT\'s', transcriptional, potency])].
[sujeto(['Finally,', our, dataset, of, 'NFAT-associated', proteins]), verbo([provides]), complemento([a, good, basis, to, further, study, 'NFAT\'s', diverse, functions, and, how, these, are, modulated, due, to, the, interplay, of, multiple, interaction, partners])].
[sujeto(['While', decades, of, research]), verbo([have]), complemento([identified, molecular, pathways, inducing, and, promoting, stages, of, prostate, cancer, 'malignancy,', studies, addressing, dynamic, changes, of, 'cancer-related', regulatory, factors, in, a, prostate, tumor, progression, model, are, limited])].
[sujeto(['Our', studies]), verbo([reveal]), complemento([a, 'Runx/miRNA', interaction, axis, centered, on, 'PTEN-PI3K-AKT', signaling])].
[sujeto(['This', regulatory, network]), verbo([translates]), complemento([to, mechanistic, understanding, of, prostate, tumorigenesis, that, can, be, developed, for, diagnosis, and, directed, therapy])].
[sujeto(['Despite', its, 'prevalence,', the, exact, genomic]), verbo([targets]), complemento([of, 'E/R', have, remained, elusive])].
[sujeto(['We', evaluated, gene, loci, and, enhancers]), verbo([targeted]), complemento([by, 'E/R', 'genome-wide', in, precursor, 'B', acute, leukemia, cells, using, global, 'run-on', sequencing, '(', 'GRO-seq)'])].
[sujeto(['We', show, that, expression, of, the, 'E/R', fusion]), verbo([leads]), complemento([to, widespread, repression, of, 'RUNX1-motif', containing, enhancers, at, its, target, gene, loci])].
[sujeto(['Moreover,', multiple, 'super-enhancers', from, 'CD19/CD20-lineage', were]), verbo([repressed]), complemento([implicating, a, role, in, impediment, of, lineage, commitment])].
[sujeto(['In', 'effect,', the, expression, of, several, genes]), verbo([involved]), complemento([in, 'B', cell, signaling, and, adhesion, was, 'downregulated,', and, the, repression, depended, on, the, 'wild-type', 'DNA-binding', 'Runt', domain, of, 'RUNX1'])].
[sujeto(['The', results]), verbo([provide]), complemento([a, comprehensive, 'genome-wide', mapping, between, 'E/R-regulated', key, regulatory, elements, and, genes, in, precursor, 'B', cell, leukemia, that, disrupt, normal, 'B', lymphopoiesis])].
[sujeto(['Down', syndrome, '(', 'DS)', is, the]), verbo([leading]), complemento([genetic, cause, of, mental, retardation, and, is, caused, by, a, third, copy, of, human, chromosome, 21])].
[sujeto(['The', different, pathologies, of, 'DS']), verbo([involve]), complemento([many, tissues, with, a, distinct, array, of, neural, phenotypes])].
[sujeto(['Our', results, show, that, neural, progenitor, cells, '(', 'NPCs)', differentiated, from, five, independent, 'DS-ESC', lines, display]), verbo([increased]), complemento([apoptosis, and, downregulation, of, forehead, developmental, genes])].
[sujeto(['Analysis', of, differentially]), verbo([expressed]), complemento([genes, suggested, 'RUNX1', as, a, key, transcription, regulator, in, 'DS-NPCs'])].
[sujeto(['Using', genome, editing, we, were, able, to, disrupt, all, three, copies, of, 'RUNX1', in, 'DS-ESCs,']), verbo([leading]), complemento([to, downregulation, of, several, 'RUNX1', target, developmental, genes, accompanied, by, reduced, apoptosis, and, neuron, migration])].
[sujeto(['Galectin-3', '(', 'Gal-3)']), verbo([has]), complemento([been, implicated, in, pancreatic, ductal, adenocarcinoma, '(', 'PDAC),', and, its, candidacy, as, a, therapeutic, target, has, been, evaluated])].
[sujeto(['Gal-3', is, widely, upregulated, in, 'tumors,', and, its, expression, is]), verbo([associated]), complemento([with, the, development, and, malignancy, of, 'PDAC'])].
[sujeto(['In', the, present, 'study,', we, demonstrate, that, a, 'polysaccharide,', 'RN1,', purified, from, the, flower, of, 'Panax', notoginseng]), verbo([binds]), complemento([to, 'Gal-3', and, suppresses, its, expression])].
[sujeto(['In', 'addition,', 'RN1', markedly]), verbo([inhibits]), complemento(['PDAC', cells, growth, in, 'vitro,', in, vivo, and, in, 'patient-derived', xenografts])].
[sujeto(['Mechanistically,', 'RN1']), verbo([binds]), complemento([to, epidermal, growth, factor, receptor, '(', 'EGFR)', and, 'Gal-3,', thereby, disrupting, the, interaction, between, 'Gal-3', and, 'EGFR', and, downregulating, 'extracellular-related', kinase, '(', 'ERK)', phosphorylation, and, the, transcription, factor, of, 'Gal-3,', 'Runx1', expression])].
[sujeto(['Inhibiting', the, expression, of, 'Runx1', by, 'RN1,']), verbo([suppresses]), complemento(['Gal-3', expression, and, inactivates, 'Gal-3-associated', signaling, 'pathways,', including, the, 'EGFR/ERK/Runx1,', 'BMP/smad/Id-3', and, 'integrin/FAK/JNK', signaling, pathways])].
[sujeto(['In', 'addition,', 'RN1', can, also]), verbo([bind]), complemento([to, bone, morphogenetic, protein, receptors, '(', 'BMPR1A', and, 'BMPR2)', and, block, the, interaction, between, 'Gal-3', and, the, 'BMPRs'])].
[sujeto(['Thus,', our, results]), verbo([suggest]), complemento([that, a, novel, 'Gal-3', inhibitor, 'RN1', may, be, a, potential, candidate, for, human, 'PDAC', treatment, via, multiple, targets, and, multiple, signaling, pathways])].
[sujeto(['BCP-ALL', are, believed, to, be]), verbo([arrested]), complemento([at, the, 'pre-BCR', checkpoint, independent, of, 'pre-BCR', expression])].
[sujeto(['However,', the, cellular, stage, at, which, 'BCP-ALL', are]), verbo([arrested]), complemento([and, whether, this, relates, to, expression, of, the, 'pre-BCR', components, '(', 'IGHM,', 'IGLL1', and, 'VPREB1)', is, still, unclear])].
[sujeto(['Moreover,', analyzing, six, 'BCP-ALL', data, sets, '(', n, =, 733, ')', ',', we, demonstrate, that, 'TCF3-PBX1', 'ALL']), verbo([express]), complemento([high, levels, of, 'IGHM,', 'IGLL1', and, 'VPREB1,', and, are, arrested, at, the, 'pre-B', stage])].
[sujeto(['By', 'contrast,', 'ETV6-RUNX1', 'ALL']), verbo([express]), complemento([low, levels, of, 'IGHM', or, 'VPREB1,', and, are, arrested, at, the, 'pro-B', stage])].
[sujeto(['Irrespective', of, 'subtype,', 'ALL', with, high, levels, of, 'IGHM,', 'IGLL1', and, 'VPREB1', are]), verbo([arrested]), complemento([at, the, 'pre-B', stage, and, correlate, with, good, prognosis, in, 'high-risk', pediatric, 'BCP-ALL', '(', n, =, 207, ')'])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, 'BCP-ALL', are, arrested, at, different, cellular, 'stages,', which, relates, to, the, expression, pattern, of, the, 'pre-BCR', components, that, could, serve, as, prognostic, markers, for, 'high-risk', pediatric, 'BCP-ALL', patients])].
[sujeto(['The', genetic, basis, of, myelodysplastic, syndromes, '(', 'MDS)', is, 'heterogeneous,', and, various, combinations, of, somatic, mutations, are]), verbo([associated]), complemento([with, different, clinical, phenotypes, and, outcomes])].
[sujeto(['Somatic', mutation, in, 'ASXL1,', 'RUNX1,', or, 'TP53', is, independently]), verbo([associated]), complemento([with, unfavorable, outcomes, and, shorter, survival, after, allogeneic, 'HSCT', for, patients, with, 'MDS', and, 'MDS/AML'])].
[sujeto(['In', 'contrast,', congenital, disorders]), verbo([caused]), complemento([by, a, single, genetic, mutation, are, ideal, candidates, for, deriving, iPSCs])].
[sujeto(['We']), verbo([have]), complemento([been, investigating, the, molecular, mechanisms, underlying, leukemia, and, 'MDS', by, implementing, iPSC, technology])].
[sujeto(['Familial', platelet, disorder, '(', 'FPD)', is, a, rare, autosomal, dominant, disorder, characterized, by, thrombocytopenia, and, a, high, propensity, for, developing, acute, 'leukemia,', which, is]), verbo([caused]), complemento([by, heterozygous, mutation, of, 'RUNX1'])].
[sujeto(['We']), verbo([have]), complemento([successfully, established, iPSCs, from, three, distinct, 'FPD', pedigrees, and, examined, the, responsible, defect, during, hematopoietic, development])].
[sujeto(['A', novel, role, for, phenotypic, transcription, factors, in, very, early, differentiation, was, recently, observed, and, merits, further, study, to, elucidate, what, role, this, precocious, expression, may]), verbo([have]), complemento([in, development])].
[sujeto(['This', early, 'RUNX1', expression, spike]), verbo([provides]), complemento([a, paradigm, for, precocious, expression, of, a, phenotypic, transcription, factor, that, invites, detailed, mechanistic, study, to, fully, understand, its, biological, importance])].
[sujeto(['We']), verbo([found]), complemento([an, overall, greater, mutational, burden, and, more, driver, mutations, in, 'T-cell', 'ALL', '(', 'T-ALL)', patients, compared, to, 'B-cell', precursor, 'ALL', '(', 'BCP-ALL)', patients])].
[sujeto(['Specifically', in, 'BCP-ALL,', we, identified, 'ATRX', as, a, novel, putative, driver, gene, and, uncovered, an, association, between, somatic, mutations, in, the, 'Notch', signaling, pathway, at, 'ALL', diagnosis, and]), verbo([increased]), complemento([risk, of, relapse])].
[sujeto(['The', genes, highlighted, in, our, study, were, frequently]), verbo([involved]), complemento([in, epigenetic, 'regulation,', associated, with, germline, susceptibility, to, 'ALL,', and, present, in, minor, subclones, at, diagnosis, that, became, dominant, at, relapse])].
[sujeto(['We', observed, a, high, degree, of, clonal, heterogeneity, and, evolution, between, diagnosis, and, relapse, in, both, 'BCP-ALL', and, 'T-ALL,', which, could]), verbo([have]), complemento([implications, for, the, treatment, efficiency])].
[sujeto(['Five', clinically, actionable, variants, were]), verbo([reported]), complemento([to, the, pregnant, 'women,', including, haploinsufficiency, of, 'RUNX1,', a, mosaicism, for, segmental, chromosome, 13, 'deletion,', an, unbalanced, 'translocation,', and, two, interstitial, chromosome, 'X', deletions])].
[sujeto(['Shotgun', sequencing, of, cfDNA, not, only, enables, the, detection, of, fetal, aneuploidies, but, also]), verbo([reveals]), complemento([the, presence, of, maternal, 'CNVs'])].
[sujeto(['Interrogating', the, maternal, 'CNV', landscape, can, improve, overall, pregnancy, 'management,', and, we, propose]), verbo([reporting]), complemento([those, variants, if, clinically, relevant])].
[sujeto(['The', identification, and]), verbo([reporting]), complemento([of, such, 'CNVs', pose, novel, counseling, dilemmas, that, warrant, further, discussions, and, development, of, societal, guidelines])].
[sujeto(['To', orchestrate, the, genomic, response, to, cellular, stress, 'signals,', p53]), verbo([recognizes]), complemento([and, binds, to, 'DNA', containing, specific, and, 'well-characterized', 'p53-responsive', elements, '(', 'REs)'])].
[sujeto(['Therefore,', the, identification, and, characterization, of, a, 'species-specific', p53, 'Binding', sistes, '(', 'BS)', consensus, sequence, and, of, the]), verbo([associated]), complemento([target, genes, may, help, to, provide, new, insights, into, the, evolution, of, the, p53, regulatory, networks, across, different, species])].
[sujeto(['Here,', we, designed, and, biochemically, validated, a, computational, approach, to, identify, novel, p53]), verbo([target]), complemento([genes, in, 'Danio', rerio, genome])].
[sujeto(['Screening', all, the, 'Danio', rerio, genome, by, 'pattern-matching-based', 'analysis,', we]), verbo([found]), complemento([p53, 'RE-like', patterns, proximal, to, 979, annotated, 'Danio', rerio, genes])].
[sujeto(['Prioritization', analysis, identified, a, subset, of, 134, candidate, 'pattern-related', 'genes,', 31, of, which]), verbo([have]), complemento([been, investigated, in, further, biochemical, assays])].
[sujeto(['Our', study, identified, 'runx1,', 'axin1,', 'traf4a,', 'hspa8,', 'col4a5,', 'necab2,', and, dnajc9, genes, as, novel, direct, p53]), verbo([targets]), complemento([and, 12, additional, 'p53-controlled', genes, in, 'Danio', rerio, genome])].
[sujeto(['The', proposed, combinatorial, approach, resulted, to, be, highly, sensitive, and, robust, for, identifying, new, p53]), verbo([target]), complemento([genes, also, in, additional, animal, species])].
[sujeto(['Aspirin']), verbo([prevents]), complemento([cardiovascular, disease, and, colon, 'cancer;', however, 'aspirin\'s', inhibition, of, platelet, 'COX-1', only, partially, explains, its, diverse, effects])].
[sujeto(['Here', we]), verbo([report]), complemento([that, 60, '%', of, 'ARS', transcripts, are, regulated, by, 'RUNX1', -, a, hematopoietic, transcription, factor, -, and, 48, '%', of, 'ARS', gene, promoters, contain, a, 'RUNX1', binding, site])].
[sujeto(['Megakaryocytic', cells, exposed, to, aspirin, and, its, metabolite, '(', salicylic, 'acid,', a, weak, 'COX-1', 'inhibitor)', showed, up, regulation, in, the, 'RUNX1', 'P1', isoform, and, 'MYL9,', which, is, transcriptionally]), verbo([regulated]), complemento([by, 'RUNX1'])].
[sujeto(['In', human, 'subjects,', 'RUNX1', 'P1', expression, in, blood, and, 'RUNX1-regulated', platelet, 'proteins,', including, 'MYL9,', were, 'aspirin-responsive', and]), verbo([associated]), complemento([with, platelet, function])].
[sujeto(['In', cardiovascular, disease, patients, 'RUNX1', 'P1', expression, was]), verbo([associated]), complemento([with, death, or, 'MI'])].
[sujeto(['RUNX1']), verbo([acts]), complemento([as, a, tumor, suppressor, gene, in, gastrointestinal, malignancies])].
[sujeto(['We', show, that, 'RUNX1', 'P1', expression, is]), verbo([associated]), complemento([with, colon, cancer, free, survival, suggesting, a, role, for, 'RUNX1', in, 'aspirin\'s', protective, effect, in, colon, cancer])].
[sujeto(['Our', studies]), verbo([reveal]), complemento([an, effect, of, aspirin, on, 'RUNX1', and, gene, expression, that, may, additionally, explain, 'aspirin\'s', effects, in, cardiovascular, disease, and, cancer])].
[sujeto([cCD3, was, not]), verbo([expressed]), complemento([in, both, groups])].
[sujeto(['ASXL2', mutation, may, be, a, new, event, that, can, cooperate, with, 'AML1-ETO', to]), verbo([induce]), complemento([leukemia])].
[sujeto(['ASXL2', gene, mutations, and, 'c-kit', gene, mutations, may, not]), verbo([have]), complemento([a, specific, correlation, between, them])].
[sujeto(['Human', endogenous, retrovirus, '(', 'HERV)', sequences, make, up, '~8%', of, the, human, genome, and]), verbo([increased]), complemento([expression, of, some, 'HERV', proteins, has, been, observed, in, various, pathologies, including, leukaemia, and, multiple, sclerosis])].
[sujeto(['However,', little, is, known, about, the, function, of, these, 'HERV', proteins, or, environmental, factors, which]), verbo([regulate]), complemento([their, expression])].
[sujeto(['Cell', proliferation, and, cell, toxicity, assays, were, carried, out, on, human, acute, 'T', lymphoblastic, leukaemia, '(', 'MOLT-4)', and, 'Fanconi', anaemia]), verbo([associated]), complemento([acute, myeloid, leukaemia, '(', 'FA-AML1)', cells, treated, with, two, different, sizes, of, 'AgNPs', '(', 7, nm, and, 50, nm, 'diameter)'])].
[sujeto(['Syncytin-1', mRNA, and, protein, were]), verbo([induced]), complemento([by, both, 7, and, 50, nm, 'AgNPs', in, both, cell, types, yet, with, different, kinetics])].
[sujeto(['In', 'summary,', the, observation, that, 'AgNPs']), verbo([induce]), complemento([expression, of, 'syncytin-1', in, 'FA-AML1', and, 'MOLT-4', cells, at, doses, as, little, as, 5, 'µg/ml', is, grounds, for, concern, since, this, protein, is, 'up-regulated', in, both, malignant, and, neurodegenerative, diseases])].
[sujeto(['Considering', the, widespread, use, of, 'AgNPs', in, the, environment, it, is, clear, that, their, ability, to]), verbo([induce]), complemento(['syncytin-1', should, be, investigated, further, in, other, cell, types])].
[sujeto(['Histone', deacetylases, '(', 'HDACs)', critically]), verbo([regulate]), complemento([gene, expression, by, determining, the, acetylation, status, of, histones])].
[sujeto(['In', 'addition,', studies]), verbo([have]), complemento([increasingly, focused, on, the, activities, of, 'HDACs,', especially, involving, 'non-histone', 'proteins,', and, their, various, biological, effects])].
[sujeto(['Aberrant', 'HDAC', expression, observed, in, several, kinds, of, human, tumors, makes, 'HDACs', potential]), verbo([targets]), complemento([for, cancer, treatment])].
[sujeto(['Several', preclinical, studies]), verbo([have]), complemento([suggested, that, 'HDAC', inhibitors, exhibit, some, efficacy, in, the, treatment, of, acute, myelogenous, leukemia, '(', 'AML)', with, 'AML1-ETO,', which, mediates, transcriptional, repression, through, its, interaction, with, a, complex, including, 'HDAC1'])].
[sujeto(['Recurrent', mutations, in, epigenetic, regulators, are]), verbo([found]), complemento([in, 'T-cell', lymphomas, '(', 'TCLs),', and, 'HDAC', inhibitors, and, hypomethylating, agents, were, shown, to, act, cooperatively, in, the, treatment, of, 'TCLs'])].
[sujeto(['Preclinical', modeling]), verbo([has]), complemento([suggested, that, persistent, activation, of, the, signal, transducer, and, activator, of, transcription, '(', 'STAT)', signaling, pathway, could, serve, as, a, useful, biomarker, of, resistance, to, 'HDAC', inhibitor, in, patients, with, cutaneous, 'TCL'])].
[sujeto(['Panobinostat,', a, 'pan-HDAC', 'inhibitor,', in, combination, with, bortezomib, and, 'dexamethasone,']), verbo([has]), complemento([achieved, longer, 'progression-free', survival, in, patients, with, 'relapsed/refractory', multiple, myeloma, '(', 'MM)', than, the, placebo, in, combination, with, bortezomib, and, dexamethasone])].
[sujeto(['Panobinostat']), verbo([inhibited]), complemento(['MM', cell, growth, by, degrading, protein, phosphatase, 3, catalytic, subunit, α, '(', 'PPP3CA),', a, catalytic, subunit, of, calcineurin])].
[sujeto(['This', degradation, was]), verbo([suggested]), complemento([to, be, mediated, by, the, blockade, of, the, chaperone, function, of, heat, shock, protein, 90, '(', 'HSP90)', due, to, 'HDAC6', inhibition])].
[sujeto(['Furthermore,', 'PPP3CA', was]), verbo([suggested]), complemento([as, a, common, target, of, panobinostat, and, bortezomib])].
[sujeto(['A', frequent, concomitant, event, is, the]), verbo([loss]), complemento([of, the, residual, 'ETV6', allele, suggesting, a, critical, role, for, the, 'ETV6', transcriptional, repressor, in, the, etiology, of, this, cancer])].
[sujeto(['However,', the, precise, mechanism, through, which]), verbo([loss]), complemento([of, functional, 'ETV6', contributes, to, disease, pathogenesis, is, still, unclear])].
[sujeto(['To', investigate, the, impact, of, 'ETV6']), verbo([loss]), complemento([on, the, transcriptional, network, and, to, identify, new, transcriptional, targets, of, 'ETV6,', we, used, whole, transcriptome, analysis, of, both, 'pre-B', leukemic, cell, lines, and, patients, combined, with, chromatin, immunoprecipitation])].
[sujeto(['Using', this, integrative, 'approach,', we, identified, 4, novel, direct, 'ETV6']), verbo([target]), complemento(['genes:', 'CLIC5,', 'BIRC7,', 'ANGPTL2', and, 'WBP1L'])].
[sujeto(['To', further, evaluate, the, role, of, chloride, intracellular, channel, protein, 'CLIC5', in, 'leukemogenesis,', we, generated, cell, lines, overexpressing, 'CLIC5', and, demonstrated, an]), verbo([increased]), complemento([resistance, to, hydrogen, 'peroxide-induced', apoptosis])].
[sujeto(['We', further, described, the, implications, of, 'CLIC5\'s', ion, channel, activity, in, 'lysosomal-mediated', cell, 'death,', possibly, by]), verbo([modulating]), complemento([the, function, of, transferrin, receptor, with, which, it, 'co-localizes', intracellularly])].
[sujeto(['For', the, first, 'time,', we, showed, that]), verbo([loss]), complemento([of, 'ETV6', leads, to, significant, overexpression, of, 'CLIC5,', which, in, turn, leads, to, decreased, 'lysosome-mediated', apoptosis])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, heightened, 'CLIC5', activity, could, promote, a, permissive, environment, for, 'oxidative-stress', induced, 'DNA', damage, accumulation, and, thereby, contribute, to, leukemogenesis])].
[sujeto(['CD56(+)', 'AML', patients]), verbo([respond]), complemento([poorly, to, 'treatment,', frequently, relapse, after, complete, remission, and, have, a, low, survival, rate])].
[sujeto(['The', interval, of, 'MRD', detection, should, be, shortened, to]), verbo([find]), complemento([out, relapse, earlier])].
[sujeto(['CD19(+)', 'AML', patients]), verbo([have]), complemento([a, good, treatment, outcome, and, often, accompanies, with, 'AML1/ETO', fusion, 'gene,', which, is, known, to, be, a, good, prognostic, marker])].
[sujeto(['Acute', myelogenous, leukemia, '(', 'AML)', carrying, 't(8;21)(q22;q22)', or, 'inv(16)/t(16;16)(p13;q22)', is, classified, as, core]), verbo([binding]), complemento([factor, '(', 'CBF)-AML', and, accounts, for, approximately, 15, '%', of, 'AML'])].
[sujeto(['c-KIT', mutation, can, be, detected, in, 17, '%', '∼46%', of, 'CBF-AML', and, is]), verbo([associated]), complemento([with, poor, prognosis])].
[sujeto(['c-KIT', mutation, is, a, crucial, hit, and, cooperates, with, 'AML1-ETO', resulting, from, 't(8;21)(q22;q22)', to]), verbo([cause]), complemento([overt, 'AML'])].
[sujeto(['Tyrosine', kinase, inhibitors, '(', 'TKI)']), verbo([targeting]), complemento(['c-KIT,', such, as, 'imatinib,', has, been, used, successfully, to, treat, 'c-KIT', driven, gastrointestinal, stromal, tumors])].
[sujeto(['However,', the, effect, of, 'TKI', on, 'c-KIT-driven', 'leukemia,', including, 'CBF-AML', and, systemic, mastocytosis, '(', 'SM),']), verbo([has]), complemento([not, been, satisfactory])].
[sujeto(['BPR1J373', is, a, 5, -, 'phenylthiazol-2-ylamine-pyriminide', derivative]), verbo([targeting]), complemento([multiple, tyrosine, kinases])].
[sujeto(['It', was, shown, to]), verbo([inhibit]), complemento([cell, proliferation, and, induce, apoptosis, in, 'AML', cells, with, constitutively, activated, 'c-KIT', via, inhibiting, 'c-KIT', phosphorylation, and, its, downstream, signals])].
[sujeto(['The', compound]), verbo([induced]), complemento([apoptosis, by, the, mitochondrial, intrinsic, pathway, through, upregulation, of, proapoptotic, proteins, 'Bax', and, 'Bak', and, caspase, 8, and, 9, activation, in, 'c-KIT', mutant, 'Kasumi-1', cells])].
[sujeto(['Furthermore,', it]), verbo([induced]), complemento(['cell-cycle', arrest, via, targeting, aurora, kinase, 'B', in, 'c-KIT', 'wild-type', 'KG-1', cells])].
[sujeto(['BPR1J373', was, shown, to, effectively]), verbo([suppress]), complemento(['c-KIT', phosphorylation, of, 'D816V', mutation, by, treating, 'c-KIT-null', 'COS-1', cells, transfected, with, 'c-KIT', 'D816V', mutant, plasmid])].
[sujeto(['In', 'conclusion,', 'BPR1J373']), verbo([inhibits]), complemento([cell, proliferation, of, 'c-KIT-driven', 'AML', cells, via, induction, of, apoptosis, and, 'cell-cycle', arrest])].
[sujeto(['Human', 'CD34+', hematopoietic, stem, and, progenitor, cells, '(', 'HSPC)']), verbo([expressing]), complemento([fusion, protein, 'AML1-ETO', '(', 'AE),', generated, by, the, 't(8;21)(q22;q22)', 'rearrangement,', manifest, enhanced, 'self-renewal', and, dysregulated, differentiation, without, leukemic, 'transformation,', representing, a, 'pre-leukemia', stage])].
[sujeto(['However,', 'AE', expression, alone, is, not, sufficient, to]), verbo([maintain]), complemento([high, telomerase, activity, to, immortalize, human, 'HSPC', 'cells,', which, may, hamper, transformation])].
[sujeto(['Enforced', expression, of, hTERT, immortalized, human, 'AE', 'pre-leukemia', cells, in, a, 'telomere-lengthening', independent, 'manner,', and, improved, the, 'pre-leukemia', stem, cell, function, by]), verbo([enhancing]), complemento([cell, proliferation, and, survival])].
[sujeto(['AE-hTERT', cells]), verbo([retained]), complemento([cytokine, dependency, and, 'multi-lineage', differentiation, potential, similar, to, parental, 'AE', clones])].
[sujeto(['The', presence, of, 'AML1-ETO', '(', 'RUNX1-CBF2T1),', a, fusion, oncoprotein, resulting, from, a, 't(8;21)', chromosomal, 'translocation,']), verbo([has]), complemento([been, implicated, as, a, necessary, but, insufficient, event, in, the, development, of, a, subset, of, acute, myeloid, leukemias, '(', 'AML)'])].
[sujeto(['While', 'AML1-ETO', prolongs, survival, and]), verbo([inhibits]), complemento([differentiation, of, hematopoietic, stem, cells, '(', 'HSC),', other, contributory, events, are, needed, for, cell, proliferation, and, leukemogenesis])].
[sujeto(['We']), verbo([have]), complemento([postulated, that, specific, tumor, suppressor, genes, keep, the, leukemic, potential, of, 'AML1-ETO', in, check])].
[sujeto(['In', studying, 'del(9q),', one, of, the, most, common, concomitant, chromosomal, abnormalities, with, 't(8;21),', we, identified, the]), verbo([loss]), complemento([of, an, apparent, tumor, 'suppressor,', 'TLE4,', that, appears, to, cooperate, with, 'AML1-ETO', to, confer, a, leukemic, phenotype])].
[sujeto(['We', show, that, the]), verbo([loss]), complemento([of, 'TLE4', confers, proliferative, advantage, to, leukemic, 'cells,', simultaneous, with, an, upregulation, of, a, 'pro-', inflammatory, signature, mediated, through, aberrant, increases, in, 'Wnt', signaling, activity])].
[sujeto(['It']), verbo([has]), complemento([been, reported, that, amyloid, precursor, 'protein&nbsp;(APP)', promotes, cell, proliferation, and, metastasis, in, various, types, of, solid, cancers])].
[sujeto(['In', our, previous, 'study,', we, showed, that, 'APP', is, highly]), verbo([expressed]), complemento([and, regulates, leukemia, cell, migration, in, 'AML1&#8209;ETO-positive&nbsp;(AE)', leukemia])].
[sujeto(['Whether', 'APP', is]), verbo([involved]), complemento([in, the, regulation, of, 'AE', leukemia, cell, proliferation, or, apoptosis, is, unclear])].
[sujeto([1, ')', and]), verbo([increased]), complemento([levels, of, 'c-KIT', expression, '(', 'P=0'])].
[sujeto([1, ')', ',', was, significantly]), verbo([increased]), complemento([when, the, 'APP', gene, was, knocked, 'down,', concomitant, with, reduced, levels, of, 'anti-apoptotic', protein, 'Bcl-2', and, increased, levels, of, 'caspase-3&nbsp;and&nbsp;-9,', 'however,', no, apparent, change, was, observed, in, the, cell, cycle, distribution, '(', 'P&gt;0'])].
[sujeto(['Moreover,', the, knockdown, of, 'APP', markedly]), verbo([decreased]), complemento(['c-KIT', expression, at, both, the, transcription, '(', as, evidenced, by, qPCR, 'analysis)', and, translation, '(', as, confirmed, by, 'CD117', assay, and, western, blot, 'analysis)', 'levels,', as, well, as, 'p-AKT', and, its, downstream, targets, including, 'NF-κB,', p53, and, 'Bcl-2'])].
[sujeto(['Chromosomal', translocation, 8, ;, 21, is]), verbo([found]), complemento([in, 40, '%', of, the, 'FAB', 'M2', subtype, of, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['The', resultant, 'in-frame', fusion, protein, 'AML1-ETO', '(', 'AE)']), verbo([acts]), complemento([as, an, initiating, oncogene, for, leukemia, development])].
[sujeto(['Full', activity, was, realized, only, upon]), verbo([increased]), complemento([fusion, protein, expression])].
[sujeto(['In', the, context, of, 'AE,', 'AE9a', did, not, show, selection, for]), verbo([increased]), complemento(['expression,', affirming, observations, of, human, 't(8;21)', patient, samples, where, 'full-length', 'AE', is, the, dominant, protein, detected])].
[sujeto(['Mechanistically,', 'AE9a', showed, defective, transcriptional, regulation, of, 'AE']), verbo([target]), complemento([genes, that, was, partially, corrected, at, high, expression])].
[sujeto(['MicroRNAs', '(', 'miRNAs)', are, a, class, of, small, endogenous, 'non-coding', 'RNAs', that, play, important, regulatory, roles, by]), verbo([targeting]), complemento([mRNAs, for, cleavage, or, translational, repression])].
[sujeto([miRNAs]), verbo([act]), complemento([in, diverse, biological, processes, including, 'development,', cell, 'growth,', 'apoptosis,', and, hematopoiesis])].
[sujeto(['The', miRNA, expression, is]), verbo([associated]), complemento([with, specific, cytogenetic, changes, and, can, also, be, used, to, discriminate, between, the, different, subtypes, of, leukemia, in, acute, lymphoblastic, leukemia, with, common, 'translocations,', it, is, shown, that, the, miRNAs, have, the, potential, to, be, used, for, clinical, diagnosis, and, prognosis])].
[sujeto(['Although', the, 'TALE', family, homeodomain, factor, 'Meis1']), verbo([has]), complemento([been, linked, to, 'malignancy,', a, role, for, 'MEIS2', is, less, clear])].
[sujeto(['Here,', we, demonstrate, that, 'MEIS2', is]), verbo([expressed]), complemento([at, high, levels, in, patients, with, 'AML1-ETO-positive', acute, myeloid, leukemia, and, that, growth, of, 'AML1-ETO-positive', leukemia, depends, on, 'MEIS2', expression])].
[sujeto(['In', 'mice,', 'MEIS2', collaborates, with, 'AML1-ETO', to]), verbo([induce]), complemento([acute, myeloid, leukemia])].
[sujeto(['MEIS2']), verbo([binds]), complemento([strongly, to, the, 'Runt', domain, of, 'AML1-ETO,', indicating, a, direct, interaction, between, these, transcription, factors])].
[sujeto(['High', expression, of, 'MEIS2', impairs, repressive, 'DNA']), verbo([binding]), complemento([of, 'AML1-ETO,', inducing, increased, expression, of, genes, such, as, the, druggable, 'proto-oncogene', 'YES1'])].
[sujeto(['It']), verbo([causes]), complemento([acute, myeloid, leukemia, '(', 'AML)', by, dysregulating, the, expression, of, genes, critical, for, myeloid, cell, development, and, differentiation, and, recently, has, been, reported, to, bind, multiple, subunits, of, the, mammalian, cytosolic, chaperonin, 'TRiC', '(', or, 'CCT),', primarily, through, its, 'DNA', binding, domain, '(', 'AML1-175)'])].
[sujeto(['Our', structure]), verbo([reveals]), complemento([that, 'AML1-175', associates, directly, with, a, specific, subset, of, 'TRiC', subunits, in, the, open, conformation])].
[sujeto(['Here', we, show, that, salicylate, specifically]), verbo([inhibits]), complemento(['CBP', and, p300, lysine, acetyltransferase, activity, in, vitro, by, direct, competition, with, 'acetyl-Coenzyme', 'A', at, the, catalytic, site])].
[sujeto(['We', used, a, chemical, 'structure-similarity', search, to, identify, another, 'anti-inflammatory', 'drug,', 'diflunisal,', that]), verbo([inhibits]), complemento([p300, more, potently, than, salicylate])].
[sujeto(['Finally,', we]), verbo([found]), complemento([that, diflunisal, suppressed, the, growth, of, 'p300-dependent', leukemia, cell, lines, expressing, 'AML1-ETO', fusion, protein, in, vitro, and, in, vivo])].
[sujeto(['The', 'IGF2', mRNA]), verbo([binding]), complemento([protein, 1, '(', 'IGF2BP1)', belongs, to, a, family, of, regulatory, 'RNA-binding', proteins, and, controls, 'stability,', transport, or, translation, of, its, target, transcripts])].
[sujeto(['Re-expression', of, 'IGF2BP1', is, frequently]), verbo([found]), complemento([in, different, tumors, and, has, been, associated, with, aggressive, disease, phenotypes])].
[sujeto(['IGF2BP1']), verbo([has]), complemento([also, been, identified, to, be, exclusively, specific, for, 't(12;21)(p13;q22)-positive', acute, lymphoblastic, leukemia, '(', 'ALL)', but, biological, significance, of, 'IGF2BP1', overexpression, has, not, been, investigated, to, date])].
[sujeto(['We']), verbo([have]), complemento([recently, reported, that, 'ETV6/RUNX1', transcript, is, a, target, of, 'RNA-binding', protein, 'IGF2BP1', in, 't(12;21)(p13;q22)-positive', 'ALL', suggesting, a, direct, role, of, 'IGF2BP1', in, 'ETV6/RUNX1-mediated', leukemogenesis])].
[sujeto(['To', address, this, question, we]), verbo([have]), complemento([employed, stable, clones, of, 'REH', cells, -, a, model, cell, line, of, 't(12;21)(p13;q22)-positive', 'ALL', -, with, downregulated, 'IGF2BP1', expression])].
[sujeto(['Here', we, show, that, downregulation, of, 'IGF2BP1', impairs, proliferation, by, attenuating, cell, cycle, progression, and]), verbo([increasing]), complemento([the, rate, of, spontaneous, cell, death])].
[sujeto(['We', also]), verbo([provide]), complemento([evidence, that, downregulation, of, 'IGF2BP1', induce, reduction, of, 'STAT3', mRNA, levels, and, augments, sensitivity, to, 'STAT3', selective, inhibitor, 'S3I-201'])].
[sujeto(['Here', we, demonstrate, that, 'Ikaros', also]), verbo([regulates]), complemento(['Th17', differentiation, through, its, ability, to, promote, expression, of, multiple, 'Th17', 'lineage-determining', 'genes,', including, 'Ahr,', 'Runx1,', 'Rorc,', 'Il17a,', and, 'Il22'])].
[sujeto(['In', naive, 'cells,', 'Ikaros', is]), verbo([required]), complemento([to, limit, repressive, chromatin, modifications, at, these, gene, 'loci,', thus, maintaining, the, potential, for, expression, of, the, 'Th17', gene, program])].
[sujeto(['Additionally,', 'Ikaros']), verbo([represses]), complemento([the, expression, of, genes, that, limit, 'Th17', 'development,', including, 'Foxp3', and, 'Tbx21'])].
[sujeto(['These', data, define, new]), verbo([targets]), complemento([of, the, action, of, 'Ikaros', and, indicate, that, 'Ikaros', plays, a, critical, role, in, 'CD4+', 'T', cell, differentiation, by, integrating, specific, cytokine, cues, and, directing, epigenetic, modifications, that, facilitate, activation, or, repression, of, relevant, genes, that, drive, 'T', cell, lineage, choice])].
[sujeto(['Forced', expression, of, the, transcription, factor, 'HoxB4']), verbo([has]), complemento([been, shown, to, enhance, the, 'self-renewal', capacity, of, mouse, bone, marrow, hematopoietic, stem, cells, '(', 'HSCs)', and, confer, a, 'long-term', repopulating, capacity, to, yolk, sac, and, embryonic, stem, '(', 'ES)', 'cell-derived', hematopoietic, precursors])].
[sujeto(['The', results, revealed, many, of, the, genes, essential, for, 'HSC', development, to, be, direct]), verbo([targets]), complemento([of, 'HoxB4,', such, as, 'Runx1,', 'Scl/Tal1,', 'Gata2,', and, 'Gfi1'])].
[sujeto(['HoxB4', tended, to]), verbo([activate]), complemento([the, 'transcription,', but, the, 'down-regulation', of, a, significant, portion, of, direct, targets, suggested, its, function, to, be, 'context-dependent'])].
[sujeto(['Our', list, of, 'HoxB4']), verbo([targets]), complemento([also, provides, novel, candidate, regulators, for, 'HSCs'])].
[sujeto(['AML1-ETO', fusion, protein, is, a, product, of, chromosome, translocation, 't(8;21)', frequently, occurred, in, acute, myeloid, leukemia, '(', 'AML),', but, its, sole, expression, appears, to, fail, to]), verbo([cause]), complemento([overt, leukemia, in, vivo])].
[sujeto(['AML1-ETO', fusion, protein, was, conditionally]), verbo([induced]), complemento([in, engineered, 'U937-A/E', 9, /, 14, /, 18, cells])].
[sujeto(['Our', results, showed, that, 'AML1-ETO', induction, significantly]), verbo([increased]), complemento([the, formation, of, carcinogen, 'benzopyrene-DNA', adducts, in, leukemic, cells])].
[sujeto(['In', line, with, the, 'effect,', we, also]), verbo([found]), complemento([that, 'AML1-ETO', induction, upregulated, 'CYP1A1', 'expression,', which, was, dependent, on, 'AML1-binding', motif, in, the, promotor, of, 'CYP1A1', gene])].
[sujeto(['Additionally,', 'AML1-ETO', protein, also]), verbo([increased]), complemento(['AhR', 'expression,', a, 'ligand-activated', transcription, factor, that, mediates, 'PAHs-induced', 'CYP1A1', gene, expression])].
[sujeto(['These', 'data,', combined, with, its, inhibitory, effect, on, 'DNA', repair, as]), verbo([reported]), complemento(['previously,', propose, that, the, presence, of, 'AML1-ETO', increases, the, susceptibility, of, cells, to, chemical, 'carcinogens,', which, favors, the, development, of, additional, genetic, alterations])].
[sujeto(['Cytogenetically', normal, acute, myeloid, leukemia, '(', 'CN-AML)', patients, harboring, 'RUNX1', mutations]), verbo([have]), complemento([a, dismal, prognosis, with, 'anthracycline/cytarabine-based', chemotherapy])].
[sujeto(['Tail', vein, injection, of, 'CG-SH', into, 'NOD', scid, gamma, mice]), verbo([led]), complemento([to, leukemic, engraftment, in, the, bone, 'marrow,', 'spleen,', and, peripheral, blood, within, 6, weeks])].
[sujeto(['Single', nucleotide, polymorphism, '(', 'SNP)', rs11671784, is, in, the, loop, of, 'pre-miR-27a', and, the, 'G/A', variation, can, significantly]), verbo([decrease]), complemento([mature, 'miR-27a', expression])].
[sujeto(['In-vitro', study, was, performed, to, explore, the, mechanism, of, 'chemo-sensitivity', and, the, downstream]), verbo([target]), complemento([of, 'miR-27a', by, using, bladder, cancer, cell, lines])].
[sujeto(['This', study, identified, a, causative, relationship, between, rs11671784, 'G/A', 'variation,', lowered, 'miR-27a', 'expression,']), verbo([increased]), complemento(['RUNX-1', expression, and, following, weakened, 'chemo-sensitivity'])].
[sujeto([rs11671784, 'G', allele]), verbo([has]), complemento([significantly, stronger, effect, over, 'A', allele, in, promoting, 'chemo-sensitivity', in, bladder, cancer])].
[sujeto(['miR-27a']), verbo([mediates]), complemento([chemotherapy, at, least, partially, through, reducing, 'P-gp', expression, and, increasing, apoptosis])].
[sujeto(['In', 'addition,', 'RUNX-1', is, a, novel, direct]), verbo([target]), complemento([of, 'miR-27a,', which, is, involved, in, its, regulation, of, 'chemo-sensitivity', in, bladder, cancer])].
[sujeto(['The', presence, of, 'FISH(+)CD34(+)CD38(-)', cells, before, consolidation, was, negatively]), verbo([associated]), complemento([with, cumulative, incidence, of, relapse, '(', 64, vs, 18, '%', ',', 'P', =])].
[sujeto([5, ')', ',', and]), verbo([retained]), complemento([prognostic, significance, for, 'RFS', in, multivariate, analysis])].
[sujeto(['EPs', can, revert, to, 'SCs', upon, 'injury,', but, whether, this, dedifferentiation, occurs, in, normal, 'HF', homeostasis, '(', hair, 'cycle)', and, the, mechanisms]), verbo([regulating]), complemento([both, differentiation, and, dedifferentiation, are, unclear])].
[sujeto(['Here,', we, use, lineage, 'tracing,']), verbo([gain]), complemento([of, 'function,', transcriptional, 'profiling,', and, functional, assays, to, examine, the, role, of, observed, endogenous, 'Runx1', level, changes, in, the, hair, cycle])].
[sujeto(['We']), verbo([find]), complemento([that, forced, 'Runx1', expression, induces, hair, degeneration, '(', 'catagen)', and, simultaneously, promotes, changes, in, the, quiescent, bulge, 'SC', transcriptome, toward, a, cell, state, resembling, the, 'EP', 'HG', fate])].
[sujeto(['We', propose, that, 'SC', differentiation, and, dedifferentiation, are, likely, to, occur, during, normal, 'HF', degeneration, and, niche, restructuring, in, response, to, changes, in, endogenous, 'Runx1', levels]), verbo([associated]), complemento([with, 'SC', location, with, respect, to, the, niche])].
[sujeto(['Rearrangements']), verbo([involving]), complemento([the, 'RUNX1', gene, account, for, approximately, 15, '%', of, balanced, translocations, in, 'therapy-related', acute, myeloid, leukemia, '(', 't-AML)', patients, and, are, one, of, the, most, common, genetic, abnormalities, observed, in, 't-AML'])].
[sujeto(['Drugs']), verbo([targeting]), complemento([the, topoisomerase, 'II', '(', 'TOP2)', enzyme, are, implicated, in, 't-AML;', 'however,', the, mechanism, is, not, well, understood, and, to, date, a, single, 'RUNX1-RUNX1T1', 't-AML', breakpoint, junction, sequence, has, been, published])].
[sujeto(['Here', we]), verbo([report]), complemento([an, additional, five, breakpoint, junction, sequences, from, 't-AML', patients, with, the, 'RUNX1-', 'RUNX1T1', translocation])].
[sujeto(['Using', a, leukemia, cell, line, 'model,', we, show, that, 'TOP2', beta, '(', 'TOP2B)', is]), verbo([required]), complemento([for, induction, of, 'RUNX1', chromosomal, breaks, by, the, 'TOP2', poison, etoposide, and, 'that,', while, 'TOP2', alpha, '(', 'TOP2A)', and, 'TOP2B', proteins, are, both, present, on, 'RUNX1', and, 'RUNX1T1', 'chromatin,', only, the, 'TOP2B', enrichment, reached, significance, following, etoposide, exposure, at, a, region, on, 'RUNX1', where, translocations, occur])].
[sujeto(['Specifically,', we, identified, a, 'TOP2B-dependent']), verbo([increase]), complemento([in, the, number, of, nuclei, displaying, juxtaposed, 'RUNX1', and, 'RUNX1T1', loci, following, etoposide, treatment])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([found, for, the, first, time, that, 'Runt-related', transcription, factor, 1, '(', 'RUNX1)', contributes, to, 'p53-dependent', 'DNA', damage, response])].
[sujeto(['Upon', adriamycin, '(', 'ADR)', 'exposure,', p53, as, well, as, 'RUNX1', were, strongly]), verbo([induced]), complemento([in, 'p53-proficient', 'HCT116', and, 'U2OS', 'cells,', which, were, closely, associated, with, significant, transactivation, of, p53, target, 'genes,', such, as, 'p21(WAF)(1),', 'BAX,', 'NOXA,', and, 'PUMA'])].
[sujeto(['RUNX1', was, exclusively]), verbo([expressed]), complemento([in, the, cell, nucleus, and, formed, a, complex, with, p53, in, response, to, 'ADR'])].
[sujeto(['Chromatin', immunoprecipitation, assay, demonstrated, that, p53, together, with, 'RUNX1', are, efficiently]), verbo([recruited]), complemento([onto, p53, target, gene, promoters, following, 'ADR', 'exposure,', indicating, that, 'RUNX1', is, involved, in, 'p53-mediated', transcriptional, regulation])].
[sujeto(['Indeed,', forced, expression, of, 'RUNX1']), verbo([stimulated]), complemento([the, transcriptional, activity, of, p53, in, response, to, 'ADR'])].
[sujeto(['Consistent', with, these, 'observations,', knockdown, of, 'RUNX1', attenuated, 'ADR-mediated', induction, of, p53]), verbo([target]), complemento([genes, and, suppressed, 'ADR-dependent', apoptosis])].
[sujeto(['Furthermore,', 'RUNX1', was]), verbo([associated]), complemento([with, p300, histone, 'acetyltransferase,', and, 'ADR-dependent', acetylation, of, p53, at, 'Lys-373/382', was, markedly, inhibited, in, 'RUNX1', knockdown, cells])].
[sujeto(['In', 'addition,', knockdown, of, 'RUNX1', resulted, in, a, significant]), verbo([decrease]), complemento([in, the, amount, of, 'p53-p300', complex, following, 'ADR', exposure])].
[sujeto(['Taken', 'together,', our, present, results, strongly]), verbo([suggest]), complemento([that, 'RUNX1', is, required, for, the, stimulation, of, p53, in, response, to, 'DNA', damage, and, also, provide, novel, insight, into, understanding, the, molecular, mechanisms, behind, 'p53-dependent', 'DNA', damage, response])].
[sujeto(['The', 5, -, year, cumulative, incidence, of, relapse, was, 19.4, '%', and, testes, were, more, frequently]), verbo([involved]), complemento([in, 'ETV6/RUNX1-positive', relapses, '(', 'P=0'])].
[sujeto(['In', univariate, 'analysis,', female, gender, was]), verbo([associated]), complemento([with, a, poor, 'survival,', whereas, site, of, 'relapse,', age, at, 'diagnosis,', leukocytosis, and, consolidation, strategy, had, no, effect])].
[sujeto(['In', multivariate, 'analysis,', only, the, duration, of, first, remission, remained]), verbo([associated]), complemento([with, outcome])].
[sujeto(['We']), verbo([found]), complemento([an, excellent, outcome, for, patients, with, 'ETV6/RUNX1-positive', leukemia, relapses, that, occurred, more, than, 36, months, after, diagnosis])].
[sujeto(['Here', we]), verbo([report]), complemento([that, triptolide, inhibits, cell, proliferation, and, induces, apoptosis, in, a, 'dose-', and, 'time-dependent', manner, of, 't(8;21)-bearing', 'Kasumi-1,', 'SKNO-1', and, 'CD34+', cells, harvested, from, bone, marrow, samples, of, patients, with, 't(8;21)', leukemia])].
[sujeto(['We', show, that, triptolide]), verbo([triggers]), complemento([cleavage, of, the, resultant, 'AML1-ETO', fusion, protein, of, 't(8;21),', and, causes, downregulation, of, 'C-KIT', followed, by, inhibition, of, 'JAK-STAT', signaling])].
[sujeto(['Triptolide', downregulates, p65, and]), verbo([inhibits]), complemento([the, 'DNA-binding', activity, of, 'NF-κB'])].
[sujeto(['Culture', with, 'BMP-2', or, 'BMP-6+AA']), verbo([increased]), complemento(['ALP', activity, of, 'PDLCs,', suggesting, their, 'osteo-inductive', effects])].
[sujeto(['However,', longer, duration, of, culture, showed, neither, of, the, 'BMPs']), verbo([induced]), complemento([in, vitro, mineralization])].
[sujeto(['In', 'contrast,', 'OS', were, able, to]), verbo([increase]), complemento(['ALP', activity, and, 'OPN', 'expressions,', and, also, induced, in, vitro, mineralization])].
[sujeto(['The', mineralization, ability, was, not]), verbo([enhanced]), complemento([by, the, addition, of, 'BMP-2', or, 'BMP-6'])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, addition, of, 'BMP-2', or, 'BMP-6', to, 'OS', may, not, enhance, an, osteogenic, differentiation, of, hPDLCs])].
[sujeto(['Runx1,', a, 'Runt', domain, transcription, 'factor,', controls, the, differentiation, of, nociceptors, that]), verbo([express]), complemento([the, neurotrophin, receptor, 'Ret,', regulates, the, expression, of, many, ion, channels, and, 'receptors,', and, controls, the, 'lamina-specific', innervation, pattern, of, nociceptive, afferents, in, the, spinal, cord])].
[sujeto(['We']), verbo([activated]), complemento([ectopic, expression, of, 'Runx1a', in, cultured, 'NCSCs', using, the, 'Tet-ON', gene, regulatory, system, during, the, formation, of, neurospheres, and, analyzed, the, proportion, of, neurons, and, glial, cells, originating, from, 'NCSCs'])].
[sujeto(['Offsprings', in, which, 'Runx1a', had, been]), verbo([activated]), complemento([showed, retarded, growth, and, displayed, 'megacolon,', pigment, 'defects,', and, dystrophic, dorsal, root, ganglia])].
[sujeto(['In', the, neuropathic, pain, 'model,', the, threshold, for, mechanical, sensitivity, was, markedly]), verbo([increased]), complemento([following, activation, of, 'Runx1a'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'Runx1a', has, a, specific, role, in, 'NCSC', development, and, that, modulation, of, 'Runx1a', activity, may, reduce, mechanical, hypersensitivity, associated, with, neuropathic, pain])].
[sujeto(['We']), verbo([report]), complemento([a, case, of, a, 31, -, 'year-old', female, with, a, positive, 'RUNX1/CBFA2T1', '(', alias, 'AML1/ETO)', fusion, gene, and, a, karyotype, with, a, 't(2;21;8)(p12;q22;q22)'])].
[sujeto(['Although', variant, translocations]), verbo([involving]), complemento([chromosome, region, 2, p12, have, never, been, reported, 'before,', we, suppose, this, translocation, may, be, responsible, for, the, clinical, manifestation, and, prognosis, of, this, case])].
[sujeto(['The', translocation, 't(16;21)']), verbo([involving]), complemento(['RUNX1', '(', 'AML1)', and, resulting, in, the, 'RUNX1-CBFA2T3', fusion, is, a, rare, but, recurrent, abnormality, mostly, found, in, 'therapy-related', acute, myeloid, leukemia, '(', 't-AML)', associated, with, agents, targeting, topoisomerase, 'II', '(', topo, 'II)'])].
[sujeto(['This', study]), verbo([suggests]), complemento([a, wider, distribution, in, the, human, 'genome,', and, particularly, at, genes, involved, in, chromosome, translocations, observed, in, 't-AML,', of, 'DNA', regions, '(', 'hotspot)', targeted, by, specific, topo, 'II', drugs])].
[sujeto(['The', median, copy, number, of, the, 'RUNX1/MTG8', 'transcript,', measured, after, each, treatment, course]), verbo([decreased]), complemento([over, time])].
[sujeto(['However,', an]), verbo([increase]), complemento([in, the, 'MRD', level, was, documented, in, three, patients, after, the, second, 'consolidation,', and, all, of, them, subsequently, relapsed])].
[sujeto(['But', no, data]), verbo([have]), complemento([been, available, up, to, date, concerning, mutual, positioning, of, these, particular, genes, in, the, nucleus, of, a, living, cell, as, well, as, the, mechanism, of, their, rapprochement, and, realignment])].
[sujeto(['Here', we, show, that, there, is, no, proximity, between, these, two, genes, in, the, primary, nuclei, of, normal, human, male, fibroblasts, and, moreover, that, these, genes, are, located, in, different]), verbo([nuclear]), complemento([layers])].
[sujeto(['But', we, further, show, that, treatment, of, cells, with, 'VP-16', '(', 'etoposide),', an, inhibitor, of, 'DNA', topoisomerase, 'II', widely, used, in, anticancer, 'chemotherapy,']), verbo([causes]), complemento([the, 'ETO', gene, repositioning, which, allows, 'AML1', and, 'ETO', genes, to, be, localized, in, the, same, nuclear, layer])].
[sujeto(['Finally,', inhibition, of, 'ETO', gene, repositioning, by, 2, ',', 3, -, butanedione, monoxime, '(', 'BDM)']), verbo([suggests]), complemento([that, this, process, depends, on, nuclear, myosin])].
[sujeto(['Mesenchymal', stem, cells, '(', 'MSC)']), verbo([have]), complemento([been, derived, from, different, cultured, human, 'tissues,', including, bone, 'marrow,', adipose, 'tissue,', amniotic, fluid, and, umbilical, cord, blood])].
[sujeto(['Only', recently, it, was]), verbo([suggested]), complemento([that, 'MSC', descended, from, perivascular, 'cells,', the, latter, being, defined, as, 'CD146⁺', 'neuro-glial', proteoglycan, '(', 'NG)2⁺', 'platelet-derived', growth, 'factor-Rβ⁺', 'ALP⁺', 'CD34⁻', 'CD45⁻', von, 'Willebrand', factor, '(', 'vWF)⁻', 'CD144⁻'])].
[sujeto(['Moreover,', foetal, 'HUC', perivascular, cells, '(', 'HUCPC)']), verbo([express]), complemento([the, embryonic, cell, markers, specific, embryonic, 'antigen-4,', 'Runx1', and, 'Oct-4', and, can, be, cultured, over, the, long, term])].
[sujeto(['The', secretory, profile, exhibited, by, foetal, 'HUCPC', in, the, migration, assay]), verbo([suggested]), complemento([a, paracrine, effect, that, could, be, exploited, in, various, clinical, conditions, including, lung, disorders])].
[sujeto(['The', 'tick-borne', protozoan, parasite, 'Theileria', annulata]), verbo([causes]), complemento([a, debilitating, disease, of, cattle, called, 'Tropical', 'Theileriosis'])].
[sujeto(['The', parasite, predominantly, invades, bovine, macrophages, '(', m, 'phi)', and]), verbo([induces]), complemento([host, cell, transformation, by, a, mechanism, that, has, not, been, fully, elucidated])].
[sujeto(['Infection', is]), verbo([associated]), complemento([with, loss, of, characteristic, m, phi, functions, and, phenotypic, 'markers,', indicative, of, host, cell, 'de-differentiation'])].
[sujeto(['We']), verbo([have]), complemento([investigated, the, effect, of, 'T'])].
[sujeto(['The', 'up-regulation', of, 'c-maf', mRNA, levels, observed, during, bovine, monocyte, differentiation, to, m, phi, was]), verbo([suppressed]), complemento([by, 'T'])].
[sujeto(['annulata-infected', cells, with, the, theileriacidal, drug, buparvaquone]), verbo([induced]), complemento(['up-regulation', of, 'c-maf', and, 'mafB,', which, correlated, with, altered, expression, of, 'down-stream', target, 'genes,', e])].
[sujeto([annulata, infection, is]), verbo([associated]), complemento([with, the, suppression, of, the, transcription, 'factors,', 'Pu'])].
[sujeto([1, and, 'RUNX1,', and, colony]), verbo([stimulating]), complemento([factor, 1, receptor, '(', 'CSF1R)', which, are, also, involved, in, the, regulation, of, 'monocyte/m', phi, differentiation])].
[sujeto(['We', believe, these, results]), verbo([provide]), complemento([the, first, direct, evidence, that, 'T'])].
[sujeto([annulata]), verbo([modulates]), complemento([the, host, m, phi, differentiation, 'state,', which, may, diminish, the, defence, capabilities, of, the, infected, cell, 'and/or', promote, cell, proliferation])].
[sujeto(['The', 't(8;21)', chromosomal, translocation]), verbo([activates]), complemento([aberrant, expression, of, the, 'AML1-ETO', '(', 'AE)', fusion, protein, and, is, commonly, associated, with, core, binding, factor, acute, myeloid, leukaemia, '(', 'CBF', 'AML)'])].
[sujeto(['Combining', a, conditional, mouse, model, that, closely, resembles, the, slow, evolution, and, the, mosaic, 'AE', expression, pattern, of, human, 't(8;21)', 'CBF', 'AML', with, global, transcriptome, 'sequencing,', we]), verbo([find]), complemento([that, disease, progression, was, characterized, by, two, principal, pathogenic, mechanisms])].
[sujeto(['We', also]), verbo([find]), complemento([that, both, 'HSC', and, 'lineage-restricted', granulocyte, macrophage, progenitors, '(', 'GMPs)', acquired, leukaemic, stem, cell, '(', 'LSC)', potential, being, capable, of, initiating, and, maintaining, the, disease])].
[sujeto(['Finally,', our, data, demonstrate, that, 'long-term', expression, of, 'AE']), verbo([induces]), complemento([an, indolent, myeloproliferative, disease, '(', 'MPD)-like', myeloid, leukaemia, phenotype, with, complete, penetrance, and, that, acute, inactivation, of, 'AE', function, is, a, potential, novel, therapeutic, option])].
[sujeto(['MicroRNA']), verbo([regulate]), complemento([the, activity, of, 'protein-coding', genes, including, those, involved, in, hematopoietic, cancers])].
[sujeto(['T-cell,', 'MLL-rearranged,', 'TEL-AML1-positive,', 'E2A-PBX1-positive', and, hyperdiploid, acute, lymphoblastic, 'leukemia,', with, the, exception, of, 'BCR-ABL-positive', and, '\'', 'B-other\'', acute, lymphoblastic, leukemias, '(', defined, as, precursor, 'B-cell', acute, lymphoblastic, leukemia, not, carrying, the, foregoing, cytogenetic, 'aberrations),', were]), verbo([found]), complemento([to, have, unique, 'microRNA-signatures', that, differed, from, each, other, and, from, those, of, healthy, hematopoietic, cells])].
[sujeto(['Strikingly,', the, microRNA, signature, of, 'TEL-AML1-positive', and, hyperdiploid, cases, partly, 'overlapped,', which, may]), verbo([suggest]), complemento([a, common, underlying, biology])].
[sujeto(['No', discriminative, microRNA, were]), verbo([found]), complemento([for, prednisolone, response, and, only, one, microRNA, was, linked, to, resistance, to, 'L-asparaginase'])].
[sujeto(['A', combined, expression, profile, based, on, 14, microRNA, that, were, individually]), verbo([associated]), complemento([with, 'prognosis,', was, highly, predictive, of, clinical, outcome, in, pediatric, acute, lymphoblastic, leukemia, '(', 5, -, year, 'disease-free', survival, of, 89.4, '%', '±7%', versus, 60.8, '±12%,', 'P=0'])].
[sujeto(['Functional', studies, of, discriminative, and, prognostically, important, microRNA, may]), verbo([provide]), complemento([new, insights, into, the, biology, of, pediatric, acute, lymphoblastic, leukemia])].
[sujeto(['CD20', is]), verbo([expressed]), complemento([in, approximately, 'one-', half, of, pediatric, acute, lymphoblastic, leukemia, '(', 'ALL)', cases, with, 'B-cell', precursor, '(', 'BCP)', origin])].
[sujeto(['CD20-positivity', significantly]), verbo([increased]), complemento([from, 45, '%', in, initial, samples, to, 81, '%', at, 'end-induction', '(', day, 15, ',', 71, '%', ')'])].
[sujeto(['In', 'vitro,', 'CD20', 'up-regulation', significantly]), verbo([enhanced]), complemento([rituximab, cytotoxicity, and, could, be, elicited, on, prednisolone, incubation])].
[sujeto(['In', 'conclusion,', 'CD20', 'up-regulation', is, frequently]), verbo([induced]), complemento([in, 'BCP-ALL', during, 'induction,', and, this, translates, into, an, acquired, state, of, higher, sensitivity, to, rituximab])].
[sujeto(['The', 'Wilms\'', tumour, gene, 1, '(', 'WT1)', protein, is, highly]), verbo([expressed]), complemento([in, most, leukaemias])].
[sujeto(['Co-expression', of, 'WT1', and, the, fusion, protein, 'AML1-ETO', in, mice, rapidly]), verbo([induces]), complemento([acute, myeloid, leukaemia, '(', 'AML)'])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, the, fusion, protein, 'BCR/ABL1', increases, expression, of, 'WT1', mRNA, and, protein, via, the, 'phosphatidylinositol-3', kinase, '(', 'PI3K)-Akt', pathway])].
[sujeto(['Inhibition', of, 'BCR/ABL1', or, 'PI3K', activity, strongly]), verbo([suppressed]), complemento([transcription, from, 'WT1', 'promoter/enhancer', reporters])].
[sujeto(['Forced', expression, of, 'BCR/ABL1', in, normal, human, progenitor, 'CD34+', cells]), verbo([increased]), complemento(['WT1', mRNA, and, 'protein,', further, supporting, the, notion, of, 'BCR/ABL1-driven', expression, of, 'WT1', in, human, haematopoietic, cells])].
[sujeto(['Forced', expression, of, 'WT1', in, 'K562', cells]), verbo([provided]), complemento([protection, against, cytotoxic, effects, of, the, 'ABL1', tyrosine, kinase, inhibitor, 'imatinib,', as, judged, by, effects, on, viability, measured, by, trypan, blue, 'exclusion,', metabolic, 'activity,', annexin, 'V', and, 'DAPI', '(', 4, '\'', ',', 6, -, 'diamidino-2-phenylindole)', staining])].
[sujeto(['None', of, the, isoforms]), verbo([provided]), complemento([any, detectable, protection, against, apoptosis, induced, by, arsenic, trioxide, and, only, very, weak, protection, against, 'etoposide,', indicating, that, 'WT1', interferes, with, specific, apoptotic, signalling, pathways])].
[sujeto(['Our', data, demonstrate, that, 'WT1', expression, is]), verbo([induced]), complemento([by, oncogenic, signalling, from, 'BCR/ABL1', and, that, 'WT1', contributes, to, resistance, against, apoptosis, induced, by, imatinib])].
[sujeto(['c-MET', was]), verbo([found]), complemento([to, be, expressed, in, normal, 'B', cells, and, in, 'B-ALL', patients, with, the, 't(12;21)', 'TEL-AML1', 'translocation,', but, it, is, not, expressed, in, the, most, part, of, 'B-ALL', without, the, 't(12;21)'])].
[sujeto(['We', also]), verbo([found]), complemento([that, 'c-MET,', related, to, proliferation, and, protection, from, 'apoptosis,', is, associated, with, the, 'pro-apoptotic', protein, 'FAS', in, 'TEL-AML1', 'B-ALL', cells, and, in, normal, 'B', lymphocytes])].
[sujeto(['REH', cells]), verbo([stimulated]), complemento([with, 'IL-3', and, treated, with, doxorubicin, did, not, undergo, apoptosis, more, than, nonstimulated, 'cells,', demonstrating, that, increased, proliferation, in, itself, is, not, directly, related, to, the, higher, apoptotic, sensitivity, observed, with, 'HGF', stimulation])].
[sujeto(['These', results, indicate, that, 'c-MET', activation]), verbo([enhances]), complemento([specifically, 'FAS-mediated', apoptosis, in, 'TEL-AML1', 'ALL', cells, 'and,', considering, that, the, 'c-MET/FAS', complex, is, present, only, in, normal, 'B', lymphocytes, and, in, 'TEL-AML1', 'leukemias,', this, implies, that, it, may, have, an, important, contribution, in, cellular, homeostasis, and, in, high, sensitivity, of, 'TEL-AML1', 'ALL', to, chemotherapeutic, regimens])].
[sujeto(['Further', 'follow-up', of, this, patient, and, the, analysis, of, a, larger, number, of, children, are, needed, to, define, whether, the]), verbo([gains]), complemento([of, the, specific, extra, chromosomes, modify, the, good, prognosis, that, 't(8;21)', confers, to, this, subgroup, of, 'AML'])].
[sujeto(['AML1-ETO', fusion, 'protein,', a, product, of, 'leukemia-related', chromosomal, translocation, 't(8;21),', was]), verbo([reported]), complemento([to, upregulate, expression, of, 'connexin-43', '(', 'Cx43),', a, member, of, gap, 'junction-constituted', connexin, family])].
[sujeto(['By', bioinformatic, 'analysis,', here, we, showed, that, there, are, two, putative, 'AML1-binding', consensus, sequences, followed, by, two]), verbo([activated]), complemento([protein, '(', 'AP)1', sites, in, the, 5, '\'', -, flanking, region, upstream, to, 'Cx43', gene])].
[sujeto(['AML1-ETO', could, directly]), verbo([bind]), complemento([to, these, two, 'AML1-binding', sites, in, electrophoretic, mobility, shift, 'assay,', but, luciferase, reporter, assay, revealed, that, the, 'AML1', binding, sites, were, not, indispensable, for, 'Cx43', induction, by, 'AML1-ETO', protein])].
[sujeto(['In', 'agreement,', 'AML1-ETO', overexpression, in, leukemic, 'U937', cells]), verbo([activated]), complemento(['c-Jun', 'N-terminal', kinase, '(', 'JNK),', while, its, specific, inhibitor, 'SP600125', effectively, abrogated, 'AML1-ETO-induced', 'Cx43', 'expression,', indicating, that, 'JNK', signaling, pathway, contributes, to, 'AML1-ETO', induced, 'Cx43', expression])].
[sujeto(['Chromosome', rearrangements, are, believed, to]), verbo([cause]), complemento([the, secondary, leukemias, which, constitute, frequent, complications, of, antitumor, chemotherapy, with, topoisomerase, 'II-specific', drugs])].
[sujeto(['Here', we, show, that, inhibition, of, 'DNA', topoisomerase, 'II', in, cultured, cells]), verbo([stimulates]), complemento([association, of, components, of, the, 'non-homologous', end, joining, system, with, a, known, breakpoint, cluster, region, of, the, human, 'AML1', 'gene,', suggesting, that, errors, of, 'DNA', repair, during, 'NHEJ', may, be, the, cause, of, illegitimate, recombination, in, cells, treated, with, topoisomerase, 'II', poisons])].
[sujeto(['Carcinogens\'', failure, to, be, degraded, by, 'CYP2B6', may]), verbo([cause]), complemento(['DNA', injury, and, cancer])].
[sujeto(['We']), verbo([recruited]), complemento([300, patients, including, 164, cases, of, acute, myeloid, leukemia, '(', 'AML),', 96, cases, of, acute, lymphoblastic, leukemia, '(', 'ALL,', including, 17, cases, of, 'T-ALL', and, 79, cases, of, 'B-ALL),', 40, cases, of, 'MDS,', as, well, as, 348, unrelated, umbilical, cord, blood, as, the, controls])].
[sujeto(['T', allele, of, 'CYP2B6', 516, 'G&gt;T', 'SNP', may, be, one, of, the, risk, factors, predisposing, to, the, pathogenesis, of, a, majority, of, 'ALL', and, 'AML,', but]), verbo([has]), complemento([no, relationship, with, 'B-ALL', and, leukemia, with, or, without, chromosome, abnormalities])].
[sujeto([2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin;', 'TCDD)']), verbo([cause]), complemento([cleft, palate, at, a, high, rate])].
[sujeto(['Runx2', and, osteopontin, immunoreactivity]), verbo([decreased]), complemento([in, the, 'TCDD-treated', palatal, 'bone,', and, 'MyoD', and, desmin, decreased, in, the, 'TCDD-treated', palatal, muscle])].
[sujeto(['TCDD', may]), verbo([suppress]), complemento([palatal, osteogenesis, and, myogenesis, via, 'AhR,', and, cause, cleft, palates, via, a, 'post-fusional', split, 'mechanism,', in, addition, to, a, failure, of, palatal, fusion])].
[sujeto(['Aryl', hydrocarbon, receptor, '(', 'AhR)']), verbo([nuclear]), complemento([translocator, '(', 'Arnt)', gene, has, been, isolated, and, characterized, from, a, mouse, genomic, 'DNA', library])].
[sujeto(['An', unusual, 'exon/intron', junctional, sequence, was]), verbo([found]), complemento([in, the, 11, th, intron, of, the, gene, that, begins, with, 'GC', at, its, 5, '\'', -, end])].
[sujeto(['The', gene, is, 'TATA-less', and]), verbo([has]), complemento([several, transcription, start, sites])].
[sujeto(['Of', 'all,', two, 'GC-boxes', displayed, the, most, dominant]), verbo([enhancing]), complemento([effects])].
[sujeto(['It', was, demonstrated, that, there, exist, specific, factors]), verbo([binding]), complemento([to, these, 'DNA', elements, in, the, nuclear, extracts, of, 'HeLa', cells])].
[sujeto(['Among', 'them,', 'Sp1', and, 'Sp3,', and, 'CAAT-box']), verbo([binding]), complemento(['factor-A', were, identified, to, bind, the, 'GC-boxes', and, 'CAAT-box,', respectively])].
[sujeto(['Expression', of, 'MyoD', in, 'HeLa', cells]), verbo([stimulated]), complemento([the, 'Arnt', promoter, activity, by, binding, to, the, 'E-box'])].
[sujeto(['The', 'AH-receptor', is, a, 'ligand-activated', transcription, factor, that]), verbo([regulates]), complemento([a, number, of, biological, responses, to, planar, aromatic, hydrocarbons])].
[sujeto(['Interest', in, this, receptor, is, related, to, its, role, in, the, toxic, action, of, a, variety, of, environmental, 'chemicals,', the, simplicity, and, elegance, of, the, murine, genetics, that]), verbo([led]), complemento([to, its, characterization, and, the, distinctive, mechanism, by, which, this, receptor, activates, gene, expression])].
[sujeto(['Recent', cloning, experiments]), verbo([have]), complemento([demonstrated, that, the, 'AH-receptor', is, structurally, related, to, the, 'Per,', 'ARNT', and, 'Sim', proteins])].
[sujeto(['In', the, 'AH-receptor,', this, domain, harbours, sequences]), verbo([involved]), complemento([in, the, formation, of, a, hydrophobic, pocket, that, bind, receptor, agonists])].
[sujeto(['Adjacent', to, the, 'PAS', domain, in, the, 'AH-receptor,', 'ARNT', and, 'Sim', proteins, is, a, 'basic/helix-loop-helix', '(', 'bHLH)', domain, that, appears, to]), verbo([mediate]), complemento([heterodimerization, and, sequence, specific, 'DNA', binding, properties])].
[sujeto(['The', observation, that, the, bHLH, domain, is, present, in, the, 'AH-receptor', and, the, 'ARNT', 'protein,', a, factor]), verbo([required]), complemento([for, proper, 'AH-receptor', 'function,', suggests, that, these, proteins, are, heterodimeric, partners, that, activate, gene, expression, in, a, manner, similar, to, 'Myc/Max', and, 'MyoD/E2A'])].
[sujeto(['The', objectives, of, this, review, are, to, describe, recent, experimental, results, in, this, field, and, to, use, this, information, to, develop, a, molecular, model, of, 'AH-receptor']), verbo([mediated]), complemento([signal, transduction])].
[sujeto(['A', cDNA, encoding, the, murine, 'Ah', receptor, '(', 'Ahb-1', allele, for, aromatic, hydrocarbon, 'responsiveness)']), verbo([has]), complemento([been, isolated, and, characterized])].
[sujeto(['Analysis', of, the, deduced, protein, sequence, revealed, a, region, with, similarity, to, the, basic, 'region/helix-loop-helix', '(', 'BR/HLH)', motif]), verbo([found]), complemento([in, many, transcription, factors, that, undergo, dimerization, for, function])].
[sujeto(['In', addition, to, the, 'BR/HLH', 'domain,', the, 'N-terminal', domain, of, the, 'Ah', receptor]), verbo([has]), complemento([extensive, sequence, similarity, to, the, human, 'ARNT', '(', aryl, hydrocarbon, receptor, nuclear, 'translocator)', protein, and, two, regulatory, proteins, of, 'Drosophila,', 'Sim', and, 'Per'])].
[sujeto(['Photoaffinity', labeling, and, peptide, mapping, studies, indicate, that, the, 'Ah', receptor]), verbo([binds]), complemento([agonist, at, a, domain, that, lies, within, this, conserved, 'N-terminal', domain])].
[sujeto(['The', 'Ah', receptor, appears, to, be, a, 'ligand-activated', transcription, factor, with, a, 'helix-loop-helix', motif, similar, to, those]), verbo([found]), complemento([in, a, variety, of, 'DNA-binding', 'proteins,', including, 'Myc', and, 'MyoD'])].
[sujeto(['The', protein, chaperone, heat, shock, protein, 90, '(', 'Hsp90)', is, a, major, regulator, of, different, transcription, factors, such, as, 'MyoD,', a, basic, helix, loop, helix, '(', 'bHLH)', 'protein,', and, the, 'bHLH-Per-aryl', hydrocarbon]), verbo([nuclear]), complemento([translocator, '(', 'ARNT)-Sim', '(', 'PAS)', factors, 'Sim', and, aryl, hydrocarbon, receptor, '(', 'Ahr)'])].
[sujeto(['The', transcription, factor, 'hypoxia-inducible', 'factor-1alpha', '(', 'HIF-1alpha),']), verbo([involved]), complemento([in, the, response, to, 'hypoxia,', also, belongs, to, the, 'bHLH-PAS', family])].
[sujeto(['Using', a, 'EGFP-HIF-1alpha', fusion, 'protein,', 'co-immunoprecipitation', experiments, evidenced, that, the, chimeric, protein]), verbo([expressed]), complemento([in, 'COS-7', cells, interacts, with, 'Hsp90', in, normoxia, but, not, in, hypoxia])].
[sujeto(['We', also, demonstrated, that, 'Hsp90']), verbo([interacts]), complemento([with, the, 'bHLH-PAS', domain, of, 'HIF-1alpha'])].
[sujeto(['At', 'last,', we, showed, that, 'Hsp90', activity, is, essential, for, 'HIF-1', activation, in, hypoxia, since, it, is]), verbo([inhibited]), complemento([in, the, presence, of, geldanamycin])].
[sujeto([1384, 'G&gt;A', 'SNP', was]), verbo([associated]), complemento([with, litter, size, in, the, 'GZ', goats, '(', 'P&lt;0'])].
[sujeto(['Luciferase', assay, analysis]), verbo([suggested]), complemento([that, the, 1384, 'A', allele, increased, luciferase, activity, when, compared, to, the, 1384, 'G', allele])].
[sujeto(['Functional', analysis]), verbo([suggested]), complemento([that, this, g])].
[sujeto([1384, 'G&gt;A', 'SNP', may, be, an, important, genetic, regulator, of, 'KISS1', gene, expression, with, effects, on, downstream, processes, that, are]), verbo([modulated]), complemento([by, 'KISS1', gene, because, of, the, changes, of, methylation, and, transcription, 'factor-binding', sites])].
[sujeto(['Therefore,', the, current, study]), verbo([provides]), complemento([evidence, in, goats, for, genetic, markers, that, might, be, used, in, breeding, programs])].
[sujeto(['Doxorubicin', '(', 'Dox,', 'Adriamicin),', a, potent, broad, spectrum, anthracycline, anticancer, 'drug,', selectively]), verbo([inhibits]), complemento([muscle, specific, gene, expression, in, cardiac, cells, in, vivo, and, prevents, terminal, differentiation, of, skeletal, muscle, cells, in, vitro])].
[sujeto(['By']), verbo([inducing]), complemento([the, expression, of, the, 'helix-loop-helix', '(', 'HLH)', transcriptional, inhibitor, 'ld2,', 'Dox', represses, the, myogenic, function, of, the, 'MyoD', family, of, muscle, regulatory, factors, '(', 'MRFs)'])].
[sujeto(['In', many, cell, 'types,', terminal, differentiation, is, coupled, to, an, irreversible, exit, from, the, cell, cycle, and, 'MyoD', plays, a, critical, role, in, the, permanent, cell, cycle]), verbo([arrest]), complemento([of, differentiating, myocytes, by, upregulating, the, cyclin, dependent, kinase, inhibitor, '(', 'cdki)', p21])].
[sujeto(['In', 'Dox-treated', quiescent, 'myoblasts,', which, fail, to, differentiate, into, myotubes, under, permissive, culture, 'conditions,', serum, 're-stimulation']), verbo([induces]), complemento(['cyclin/cdk', 're-association', on, the, 'E2F/DP', complexes, and, this, correlates, with, an, evident, increase, in, 'E2F/DP', driven, transcription, and, 're-entry', of, myoblasts, into, the, cell, cycle])].
[sujeto(['Despite', 'Dox', ability, to]), verbo([activate]), complemento([the, 'DNA-damage', dependent, 'p53/p21', 'pathway,', when, induced, in, the, absence, of, 'MyoD', or, other, 'MRFs,', p21, fails, to, maintain, the, postmitotic, state, in, 'Dox-treated', myocytes, induced, to, differentiate])].
[sujeto(['Thus,', uncoupling, p21, induction, and, 'MyoD', activity, results, in, a, 'serum-reversible', cell, cycle, 'arrest,', indicating, that, 'MRF', specific, activation, of, 'cdki(s)', is]), verbo([required]), complemento([for, permanent, cell, cycle, arrest, in, differentiating, muscle, cells])].
[sujeto(['Duchenne', muscular, dystrophy, '(', 'DMD)', is, a, progressive, and, fatal, muscle, degenerating, disease]), verbo([caused]), complemento([by, a, dystrophin, deficiency])].
[sujeto(['Patient-derived', human]), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'hiPSCs)', are, a, promising, tool, for, drug, discovery])].
[sujeto(['Here,', we]), verbo([report]), complemento([an, in, vitro, evaluation, system, for, a, 'DMD', therapy, using, hiPSCs, that, recapitulate, the, primary, pathology, and, can, be, used, for, 'DMD', drug, screening])].
[sujeto(['However,', electric, stimulation, of, these, myotubes, for, in, vitro, contraction]), verbo([caused]), complemento([pronounced, calcium, ion, '(', 'Ca(2+))', influx, only, in, 'DMD', myocytes])].
[sujeto(['Restoration', of, dystrophin, by, the, 'exon-skipping', technique]), verbo([suppressed]), complemento([this, 'Ca(2+)', overflow, and, reduced, the, secretion, of, creatine, kinase, '(', 'CK)', in, 'DMD', myotubes])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, early, pathogenesis, of, 'DMD', can, be, effectively, modelled, in, skeletal, myotubes, induced, from, 'patient-derived', 'iPSCs,', thereby, enabling, the, development, and, evaluation, of, novel, drugs])].
[sujeto(['Patient-derived']), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'iPSCs)', have, opened, the, door, to, recreating, pathological, conditions, in, vitro, using, differentiation, into, diseased, cells, corresponding, to, each, target, tissue])].
[sujeto(['Yet', for, muscular, 'diseases,', a, method, for, reproducible, and, efficient, myogenic, differentiation, from, human, iPSCs, is]), verbo([required]), complemento([for, in, vitro, modeling])].
[sujeto(['Here,', we, introduce, a, myogenic, differentiation, protocol]), verbo([mediated]), complemento([by, inducible, transcription, factor, expression, that, reproducibly, and, efficiently, drives, human, iPSCs, into, myocytes])].
[sujeto(['This', differentiation, protocol, can, be, applied, widely, in, various, types, of, 'patient-derived', human, iPSCs, and]), verbo([has]), complemento([great, prospects, in, disease, modeling, particularly, with, inherited, diseases, that, require, studies, of, early, pathogenesis, and, drug, screening])].
[sujeto(['Overexpression', of, 'SIRT1', is, frequently, observed, in, various, types, of, 'cancers,']), verbo([suggesting]), complemento([its, potential, role, in, malignancies])].
[sujeto(['This']), verbo([suggests]), complemento([aberrant, 'CpG', 'DNA', methylation, as, the, mechanistic, background, for, malignant, 'SIRT1', elevation])].
[sujeto(['Our', work, also]), verbo([provides]), complemento([an, example, where, epigenetic, mechanisms, cause, the, 'group-wide', regulation, of, miRNAs, sharing, a, common, key, target])].
[sujeto(['The', 'ZHTc6-MyoD', embryonic, stem, cell, line]), verbo([expresses]), complemento([the, myogenic, transcriptional, factor, 'MyoD', under, the, control, of, a, 'tetracycline-inducible', promoter])].
[sujeto(['However,', a, small, fraction, does, not, 'differentiate,', instead, forming, colonies, that]), verbo([retain]), complemento([the, potential, for, myocyte, differentiation])].
[sujeto(['In', our, current, 'study,', we]), verbo([found]), complemento([that, parathyroid, hormone, type, 1, receptor, '(', 'PTH1R)', expression, in, 'colony-forming', cells, at, 13, days, after, differentiation, was, higher, than, that, in, the, undifferentiated, 'ZHTc6-MyoD', cells])].
[sujeto(['We', also]), verbo([found]), complemento([that, 'PTH1R', expression, was, required, for, myocyte, 'differentiation,', and, that, parathyroid, hormone, accelerated, the, differentiation])].
[sujeto(['Our', analysis, of, human, and, mouse, skeletal, muscle, tissues, showed, that, most, cells]), verbo([expressing]), complemento(['PTH1R', also, expressed, 'Pax7', and, 'CD34,', which, are, biomarkers, of, satellite, cells])].
[sujeto(['Furthermore,', we]), verbo([found]), complemento([that, parathyroid, hormone, treatment, significantly, improved, muscle, weakness, in, 'dystrophin-deficient', mdx, mice])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([indicating, that, 'PTH1R', and, 'PTH', accelerate, myocyte, differentiation])].
[sujeto([3, -, 'Methylcholanthrene', '(', 3, 'MC)']), verbo([induces]), complemento([tumor, formation, at, the, site, of, injection, in, the, hind, leg, of, mice, within, 110, days])].
[sujeto(['Recent']), verbo([reports]), complemento([reveal, that, the, transformation, of, normal, muscle, cells, to, atypical, cells, is, one, of, the, causes, for, tumor, 'formation,', however, the, molecular, mechanism, behind, this, process, is, not, well, understood])].
[sujeto(['Here,', we, show, in, an, in, vitro, study, that, 3, 'MC']), verbo([induces]), complemento([fragmentation, of, multinucleate, myotubes, into, viable, mononucleates])].
[sujeto(['Immunoblot', analysis]), verbo([reveals]), complemento([that, phosphorylation, of, myosin, regulatory, light, chain, '(', 'RLC20)', is, 5.6, '±0'])].
[sujeto(['Interestingly,', addition, of, the, myosin, light, chain, kinase, 'inhibitor,', 'ML-7,']), verbo([enhances]), complemento([the, 'fragmentation,', whereas, phosphatase, inhibitor, perturbs, the, 3, 'MC', induced, fragmentation, of, myotubes])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, decrease, in, 'RLC20', phosphorylation, may, be, associated, with, the, fragmentation, step, of, dedifferentiation])].
[sujeto(['The', establishment, of, human]), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'hiPSCs)', has, enabled, the, production, of, in, 'vitro,', 'patient-specific', cell, models, of, human, disease])].
[sujeto(['However,', myogenic, differentiation, of, hiPSCs]), verbo([has]), complemento([faced, 'obstacles,', 'namely,', low, efficiency, 'and/or', poor, reproducibility])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, 'rapid,', 'efficient,', and, reproducible, differentiation, of, hiPSCs, into, mature, myocytes])].
[sujeto(['Myocytes']), verbo([induced]), complemento([in, this, manner, reach, maturity, within, 2, weeks, of, differentiation, as, assessed, by, marker, gene, expression, and, functional, 'properties,', including, in, vitro, and, in, vivo, cell, fusion, and, twitching, in, response, to, electrical, stimulation])].
[sujeto(['Miyoshi', 'Myopathy', '(', 'MM)', is, a, congenital, distal, myopathy]), verbo([caused]), complemento([by, defective, muscle, membrane, repair, due, to, mutations, in, 'DYSFERLIN'])].
[sujeto(['Using', our]), verbo([induced]), complemento([differentiation, 'technique,', we, successfully, recreated, the, pathological, condition, of, 'MM', in, 'vitro,', demonstrating, defective, membrane, repair, in, 'hiPSC-derived', myotubes, from, an, 'MM', patient, and, phenotypic, rescue, by, expression, of, 'full-length', 'DYSFERLIN', '(', 'DYSF)'])].
[sujeto(['We']), verbo([target]), complemento([this, inducible, cassette, exchange, '(', 'ICE)', allele, to, the, '(', 'HPRT)', locus, and, demonstrate, recombination, in, murine, embryonic, stem, cells, '(', 'ESCs)', and, primary, cells, from, derivative, 'ICE', mice])].
[sujeto(['In', the, present, 'study,', methods, were, developed, to, expand, cultures, of, 'MSCs', and, to]), verbo([promote]), complemento([the, myogenic, differentiation, of, these, 'cells,', which, were, then, used, in, a, new, approach, for, the, treatment, of, 'DMD'])].
[sujeto(['The', transduction, of, 'CD271(+)', 'MSCs', with, 'MyoD']), verbo([caused]), complemento([myogenic, differentiation, in, vitro, and, the, formation, of, myotubes, expressing, late, myogenic, markers])].
[sujeto(['Despite', having, distinct, expression, patterns, and, phenotypes, in, mutant, 'mice,', the, myogenic, regulatory, factors, 'Myf5', and, 'MyoD']), verbo([have]), complemento([been, considered, to, be, functionally, equivalent])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, these, factors, have, a, different, response, to, 'DNA', 'damage,', due, to, the, presence, in, 'MyoD', and, absence, in, 'Myf5', of, a, consensus, site, for, 'Abl-mediated', tyrosine, phosphorylation, that, inhibits, 'MyoD', activity, in, response, to, 'DNA', damage])].
[sujeto(['Genotoxins', failed, to]), verbo([repress]), complemento([skeletal, myogenesis, in, 'MyoD-null', 'embryos;', reintroduction, of, 'wild-type', 'MyoD,', but, not, mutant, 'Abl', 'phosphorylation-resistant', 'MyoD,', restored, the, 'DNA-damage-dependent', inhibition, of, muscle, differentiation])].
[sujeto(['The', presence, of, a, 'DNA-damage-responsive', phosphorylation, motif, in, 'vertebrate,', but, not, in, invertebrate, 'MyoD']), verbo([suggests]), complemento([an, evolved, response, to, environmental, 'stress,', originated, from, basic, 'helix-loop-helix', gene, duplication, in, vertebrate, myogenesis])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, that, the, level, of, 'MyoD', expression, correlates, with, the, level, of, apoptosis, that, occurs, in, a, subpopulation, of, skeletal, myoblasts, induced, to, differentiate, by, serum, withdrawal])].
[sujeto(['Further,', using, a, fibroblast, cell, line]), verbo([expressing]), complemento([an, estrogen, 'receptor:MyoD', fusion, 'protein,', we, have, determined, that, addition, of, estrogen, sensitizes, these, fibroblasts, to, apoptosis, induced, by, serum, 'withdrawal,', or, by, treatment, with, etoposide, or, thapsigargin])].
[sujeto(['RNAi']), verbo([mediated]), complemento([silencing, of, 'MyoD', in, either, 23, 'A2', or, 'C2C12', myoblasts, renders, these, cells, resistant, to, apoptosis, induced, by, serum, 'withdrawal,', or, by, treatment, with, etoposide, or, thapsigargin])].
[sujeto(['Finally,', 'MyoD']), verbo([mediated]), complemento([regulation, of, the, apoptotic, response, to, these, various, 'stimuli,', in, both, myoblasts, and, 'fibroblasts,', correlates, with, the, level, of, induction, of, the, 'pro-apoptotic', 'Bcl2', family, member, 'PUMA'])].
[sujeto(['We', used, external, fixation, '(', 'EF),', as, a, clinically, relevant, 'model,', to]), verbo([gain]), complemento([insights, into, the, relationships, between, muscle, degenerative, and, regenerative, conditions, to, the, myogenic, properties, and, abundance, of, bona, fide, satellite, cells])].
[sujeto(['EF']), verbo([induced]), complemento([muscle, mass, 'loss;', declined, expression, of, the, muscle, specific, regulatory, factors, '(', 'MRFs)', 'Myf5,', 'MyoD,', 'myogenin,', and, also, of, satellite, cell, numbers, and, myogenic, differentiation, aptitude])].
[sujeto(['Tet']), verbo([enhanced]), complemento([the, expression, of, 'MRFs,', but, did, not, prevent, the, decline, of, the, satellite, cell, pool])].
[sujeto(['Together,', our, results, point, to, 'Tet', and, exercise, running, as, promising, and, relevant, approaches, for]), verbo([enhancing]), complemento([muscle, recovery, after, atrophy])].
[sujeto(['In', our, present, proof, of, principle, 'studies,', we]), verbo([have]), complemento([successfully, constructed, a, multilayered, culture, of, skeletal, muscle, 'cells,', derived, from, neonatal, satellite, 'cells,', that, are, distributed, in, a, 3, 'D', pattern, of, organization, that, mimics, many, of, the, features, of, intact, tissue])].
[sujeto(['In', myogenic, 'C(2)C(12)', 'cells,', 5, mM, creatine]), verbo([increased]), complemento([the, incorporation, of, labeled, '[', '(', 35, ')', 'S]methionine', into, sarcoplasmic, '(', +, 20, '%', ',', 'P', &, 'lt;', 0.05, ')', and, myofibrillar, proteins, '(', +, 50, '%', ',', 'P', &, 'lt;', 0.01, ')'])].
[sujeto(['Creatine', also]), verbo([promoted]), complemento([the, fusion, of, myoblasts, assessed, by, an, increased, number, of, nuclei, incorporated, within, myotubes, '(', +, 40, '%', ',', 'P', &, 'lt;', 0.001, ')'])].
[sujeto(['Expression', of, myosin, heavy, chain, type, 'II', '(', +, 1, ',', 300, '%', ',', 'P', &, 'lt;', 0.001, ')', ',', troponin, 'T', '(', +, 65, '%', ',', 'P', &, 'lt;', 0.01, ')', ',', and, titin, '(', +, 40, '%', ',', 'P', &, 'lt;', 0.05, ')', was]), verbo([enhanced]), complemento([by, creatine])].
[sujeto(['The', addition, of, 'rapamycin,', the, inhibitor, of, mammalian]), verbo([target]), complemento([of, 'rapamycin/70-kDa', ribosomal, 'S6', protein, kinase, '(', 'mTOR/p70(s6k))', 'pathway,', and, 'SB', 202190, ',', the, inhibitor, of, 'p38,', completely, blocked, differentiation, in, control, 'cells,', and, creatine, did, not, reverse, this, 'inhibition,', suggesting, that, the, 'mTOR/p70(s6k)', and, p38, pathways, could, be, potentially, involved, in, the, effect, induced, by, creatine, on, differentiation])].
[sujeto(['Creatine', also, affected, the, phosphorylation, state, of, p38, '(', -, 50, '%', at, 24, h, and, +, 70, '%', at, 96, 'h,', 'P', &, 'lt;', 0.05, ')', as, well, as, the]), verbo([nuclear]), complemento([content, of, its, downstream, targets, myocyte, enhancer, 'factor-2', '(', -, 55, '%', at, 48, h, and, +, 170, '%', at, 96, 'h,', 'P', &, 'lt;', 0.05, ')', and, 'MyoD', '(', +, 60, '%', ',', 'P', &, 'lt;', 0.01, ')'])].
[sujeto(['In', 'conclusion,', this, study, points, out, the, involvement, of, the, p38, and, the, 'Akt/PKB-p70(s6k)', pathways, in, the]), verbo([enhanced]), complemento([differentiation, induced, by, creatine, in, 'C(2)C(12)', cells])].
[sujeto(['The', hindlimbs, of, some, animals, in, each, group, were, irradiated, before, injury, to]), verbo([prevent]), complemento([proliferation, of, myogenic, cells, during, recovery])].
[sujeto(['Inhibiting', myogenesis]), verbo([prevented]), complemento([the, recovery, of, contractile, function, after, 'MR,', but, not, after, 1, 'R'])].
[sujeto(['Both', protocols]), verbo([caused]), complemento(['Evans', blue, dye, uptake, immediately, after, 'injury,', but, 'Evans', blue, dye, was, only, retained, in, fibers, for, several, days, after, 1, 'R'])].
[sujeto(['This']), verbo([suggests]), complemento([that, membranes, reseal, after, 1, 'R,', but, not, after, 'MR'])].
[sujeto(['The', mechanisms, that, underlie, recovery, after, injuries]), verbo([caused]), complemento([by, repeated, lengthening, contractions, and, injuries, caused, by, a, single, lengthening, contraction, are, different])].
[sujeto(['The', differences, may, be, important, when, planning]), verbo([targeted]), complemento([rehabilitation, strategies, for, each, type, of, injury])].
[sujeto(['Advanced', gene, 'therapy,', tissue, engineering, and, biopharmaceutical, manufacturing]), verbo([require]), complemento([sophisticated, and, 'well-balanced', multiregulated, multigene, interventions, to, reprogram, desired, mammalian, cell, phenotypes])].
[sujeto(['We']), verbo([have]), complemento([combined, the, streptogramin, '(', 'PIP)-', and, tetracycline, '(', 'TET)-responsive', gene, regulation, systems, for, independent, expression, control, of, the, differentiation, determinants, myoD, and, msx1, in, 'C2C12-derived', cells])].
[sujeto(['Different', 'dual-regulated', expression, scenarios, which]), verbo([induce]), complemento([either, 'both,', only, one, or, none, of, the, lineage, control, genes, triggered, differential, differentiation, and, precise, control, of, 'myogenic,', osteogenic, or, adipogenic, cell, phenotypes])].
[sujeto(['We']), verbo([reported]), complemento([previously, that, transcription, factor, nuclear, factor, '(', 'NF)-kappaB', is, constitutively, activated, in, human, and, murine, squamous, cell, carcinomas, '(', 'SCCs)'])].
[sujeto(['Remarkably,', 'NF-kappaB']), verbo([modulated]), complemento([the, expression, of, &, 'gt;60%', of, the, 308, genes, differentially, expressed, between, normal, keratinocytes, and, metastatic, 'SCCs'])].
[sujeto(['NF-kappaB', directly, or, indirectly]), verbo([modulated]), complemento([expression, of, programs, of, genes, functionally, linked, to, 'proliferation,', 'apoptosis,', 'adhesion,', and, angiogenesis])].
[sujeto(['NF-kappaB', 'DNA']), verbo([binding]), complemento([motifs, were, detected, in, the, promoter, of, approximately, 63, '%', of, genes, showing, increased, expression, and, 33, '%', of, the, genes, showing, decreased, expression])].
[sujeto(['The', 'ACTACAG', motif, implicated, in, the, 'NF-kappaB-dependent', 'down-regulation', of, mRNA, expression, of, 'MyoD', and, 'Sox9', was, detected, in, the, coding, portion, of, about, 15, '%', of, genes, showing]), verbo([increased]), complemento([or, decreased, expression])].
[sujeto(['Inactivation', of, 'NF-kappaB']), verbo([inhibited]), complemento([malignant, phenotypic, features, including, 'proliferation,', cell, 'survival,', 'migration,', 'angiogenesis,', and, tumorigenesis])].
[sujeto(['These', results]), verbo([provide]), complemento([evidence, that, 'NF-kappaB', is, an, important, modulator, of, gene, expression, programs, that, contribute, to, the, malignant, phenotype, of, 'SCC'])].
[sujeto(['In', the, present, study, optimized, 'HIV-1-based', vector, systems, that, display, efficient, doxycycline, '(', 'Dox)-dependent', transgene, expression, in, vitro, and, in, vivo]), verbo([have]), complemento([been, developed, through, the, modification, of, factors, that, contribute, to, basal, activity, levels])].
[sujeto(['Dissection', of, 'HIV-1', vectors, harboring, a, 'tTA-dependent', transgene, expression, cassette, revealed, several, mechanisms, that, account, for, 'Dox-independent', transgene, 'expression,', including, those]), verbo([mediated]), complemento([by, an, internal, 'CMV', 'promoter,', as, well, as, a, potential, contribution, from, fusion, proteins, generated, by, translational, readthrough])].
[sujeto(['Cell-substratum', interactions]), verbo([trigger]), complemento([key, signaling, pathways, that, modulate, growth, control, and, 'tissue-specific', gene, expression])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, abolishing, adhesive, interactions, by, suspension, culture, results, in, 'G(0)', arrest, of, myoblasts])].
[sujeto(['We']), verbo([report]), complemento([that, blocking, intracellular, transmission, of, 'adhesion-dependent', signals, in, adherent, cells, mimics, the, absence, of, adhesive, contacts])].
[sujeto(['Furthermore,', both, 'ML7', and, 'BDM']), verbo([suppressed]), complemento([expression, of, 'MyoD', and, 'myogenin,', induced, 'p27(kip1)', but, not, 'p21(cip1),', and, inhibited, differentiation])].
[sujeto(['Thus,', as, with, 'suspension-arrest,', inhibition, of, 'acto-myosin', contractility, in, adherent, cells]), verbo([led]), complemento([to, arrest, uncoupled, from, differentiation])].
[sujeto(['By', 'contrast,', 'wild-type', 'RhoA']), verbo([induced]), complemento(['arrest,', maintained, 'MyoD', and, activated, myogenin, and, p21, expression])].
[sujeto(['The', 'Rho', effector, kinase, 'ROCK', did, not, appear, to]), verbo([mediate]), complemento(['Rho\'s', effects, on, 'MyoD'])].
[sujeto(['Signals']), verbo([regulated]), complemento([by, 'MLCK', are, 'critical,', since, inhibition, of, 'MLCK', suppressed, 'MyoD', expression, but, inhibition, of, 'ROCK', did, not])].
[sujeto(['Inhibition', of, contractility]), verbo([suppressed]), complemento(['MyoD', but, did, not, reduce, actin, polymer, levels])].
[sujeto(['However,', actin, depolymerization, with, latrunculin, 'B']), verbo([inhibited]), complemento(['MyoD', expression])].
[sujeto(['Taken', 'together,', our, observations, indicate, that, actin, polymer, status, and, contractility]), verbo([regulate]), complemento(['MyoD', expression])].
[sujeto(['We']), verbo([suggest]), complemento([that, in, 'myoblasts,', the, 'Rho', pathway, and, regulation, of, 'acto-myosin', contractility, may, define, a, control, point, for, conditional, uncoupling, of, differentiation, and, the, cell, cycle])].
[sujeto(['Several', studies]), verbo([have]), complemento([already, demonstrated, that, 'micro-', and, 'milli-calpains', '(', 'CAPN', 1, -, 'CAPN', 2, ')', ',', 'calcium-dependent', intracellular, 'cysteine-proteases', are, involved, in, many, biological, phenomenon, including, muscle, growth, and, development])].
[sujeto(['More', 'particularly,', recent, studies]), verbo([have]), complemento([demonstrated, that, 'milli-calpain', is, implicated, in, myoblast, fusion])].
[sujeto(['Because', 'micro-', and, 'milli-calpains', do, not]), verbo([have]), complemento([the, same, intracellular, 'localization,', it, appears, likely, that, these, two, 'calcium-dependent', proteases, have, different, biological, roles, during, muscle, cell, differentiation])].
[sujeto(['We', 'therefore,']), verbo([have]), complemento([developed, a, muscle, cell, line, in, which, 'micro-calpain', is, 'over-expressed,', using, the, inducible, 'Tet', 'Regulated', 'Expression', 'System'])].
[sujeto(['The', present, study, shows, important]), verbo([decreases]), complemento([in, the, expression, level, of, ezrin, '(', 68, '%', ')', ',', vimentin, '(', 64, '%', ')', and, caveolin, 3, '(', 76, '%', ')', whereas, many, other, cytoskeletal, proteins, remain, remarkably, stable])].
[sujeto(['Concerning', the, myogenic, transcription, 'factors,', only, the, level, of, myogenin]), verbo([decreased]), complemento(['(', 59, '%', ')', after, the, 'over-expression', of, 'micro-calpain'])].
[sujeto(['Ultra', structural, studies]), verbo([have]), complemento([shown, that, the, myofibrils, formed, near, the, cell, periphery, are, normally, 'oriented,', lying, along, the, longitudinal, axis])].
[sujeto(['This', regularity, is, lost, progressively, towards, the, cell, center, where, the, cytoskeleton, presented, an]), verbo([increasing]), complemento([disorganization])].
[sujeto(['All', these, results, indicate, that, 'micro-calpain', is]), verbo([involved]), complemento([in, regulation, pathway, of, myogenesis, via, at, least, its, action, on, 'ezrin,', 'vimentin,', caveolin, 3, and, 'myogenin,', a, muscle, transcription, factor])].
[sujeto(['Skeletal', muscle, contractile, activity]), verbo([has]), complemento([been, implicated, in, many, aspects, of, muscle, cell, differentiation, and, maturation])].
[sujeto(['Much', of, the, research, in, this, area]), verbo([has]), complemento([depended, upon, costly, and, 'labor-intensive', cultures, of, isolated, primary, muscle, cells, because, widely, available, immortalized, muscle, cell, lines, often, do, not, display, a, high, level, of, either, spontaneous, or, stimulated, contractile, activity])].
[sujeto(['We', sought, to, develop, 'conditionally-immortalized', skeletal, muscle, cell, lines, that, would]), verbo([provide]), complemento([a, source, of, myofibers, that, exhibit, robust, spontaneous, contractile, activity, similar, to, primary, muscle, cultures])].
[sujeto(['Using', a, 'tetracycline-regulated', retroviral, vector]), verbo([expressing]), complemento([a, 'temperature-sensitive', 'T-antigen', to, infect, primary, 'myoblasts,', we, isolated, individual, clonal, muscle, precursor, cell, lines, that, have, characteristics, of, activated, satellite, cells, during, growth, and, rapidly, differentiate, into, mature, myotubes, with, spontaneous, contractile, activity, after, culture, in, 'non-transformation-permissive', conditions])].
[sujeto([')', 'Kuntze']), verbo([has]), complemento([been, well, known, for, its, antioxidative, properties])].
[sujeto(['Reduction', of, these, two, transcription, factors, resulted, in, a]), verbo([decrease]), complemento([in, melanogenic, enzymes, such, as, 'tyrosinase,', 'tyrosinase-related', protein, 1, ',', and, dopachrome, tautomerase])].
[sujeto(['As', a, 'result,', 1, significantly]), verbo([inhibited]), complemento([the, melanin, synthesis, in, 'melan-a', mouse, melanocytes, and, 'NHEMs'])].
[sujeto(['The', cytokine, interleukin, 12, '(', 'IL-12)']), verbo([has]), complemento([been, implicated, as, a, potent, stimulator, of, tissue, degradation, in, the, pathogenesis, of, several, inflammatory, 'diseases,', including, periodontitis])].
[sujeto(['In', patients, with, 'periodontitis,', an]), verbo([increased]), complemento([level, of, 'IL-12', is, found, in, serum, and, gingival, crevicular, fluid])].
[sujeto(['As', inflammatory, cytokines]), verbo([have]), complemento([been, demonstrated, to, induce, activation, of, the, immunomodulatory, properties, of, mesenchymal, stem, cells, '(', 'MSCs),', this, study, aimed, to, investigate, the, influence, of, 'IL-12', on, these, properties, in, human, periodontal, ligament, '(', 'hPDL)', cells])].
[sujeto(['Moreover,', 'IL-12']), verbo([induced]), complemento([the, expression, of, the, immunomodulatory, proteins, 'IDO', and, 'HLA-G', via, an, 'IFN-γ-dependent', 'pathway,', as, indicated, by, experiments, using, an, 'IFN-γ', neutralizing, antibody])].
[sujeto(['Finally,', 'IL-12']), verbo([inhibited]), complemento([osteogenic, differentiation, of, the, hPDL, cells, and, preserved, the, 'self-clonal', expansion, property, of, these, 'cells,', as, assessed, by, 'Alizarin', 'Red', 'S', staining, and, the, 'colony-forming', unit, assay])].
[sujeto(['MR', hypointensities]), verbo([caused]), complemento([by, 'MPIOs', were, observed, on, 'T2(⁎)-weighted', images, at, all, time, points, after, 'MSCs', injection])].
[sujeto(['Real-time', 'PCR', for, rat, 'SRY', gene, showed, the, number, of, survival, 'MSCs', considerably]), verbo([decreased]), complemento([after, transplantation])].
[sujeto(['MSC-treated', hearts, had, significantly]), verbo([increased]), complemento([capillary, density, in, 'peri-infarct', region, and, lower, cardiomyocytes, apoptosis, and, fibrosis, formation])].
[sujeto(['The', internal, gonad, sexing, method, was]), verbo([found]), complemento([to, be, highly, 'accurate,', while, the, peritoneal, pigmentation, method, was, slightly, less, accurate])].
[sujeto(['In', 'Algeria,', the, data, on, infertility, and, its, various]), verbo([causes]), complemento([are, rare])].
[sujeto(['Recently,', the, introduction, of, assisted, reproduction]), verbo([has]), complemento([allowed, expecting, that, 300000, 'couples,', which, represent, 7, '%', of, couples, of, reproductive, 'age,', face, difficulty, conceiving, a, child])].
[sujeto(['Follicle']), verbo([stimulating]), complemento([hormone, '(', 'FSH)', and, luteinizing, hormone, '(', 'LH)', levels, were, evaluated, by, immunoradiometric, method])].
[sujeto(['Fetuses', with, lissencephaly]), verbo([have]), complemento([an, abnormal, smooth, brain, with, fewer, folds, and, grooves, which, will, be, detected, by, ultrasounds, or, fetal, magnetic, resonance, imaging, '(', 'MRI)', after, 30, weeks, of, gestation])].
[sujeto(['We']), verbo([report]), complemento([a, fetus, with, lissencephaly, diagnosed, as, 'Miller-Dieker', syndrome, postnatally])].
[sujeto(['However,', only, a, few, genetic, studies]), verbo([have]), complemento([explored, the, macaques, in, this, region])].
[sujeto([fascicularis, into, five, subclades, '(', 'Insular', 'Indonesia,', 'Sundaic', 'Thai', 'Gulf,', 'Vietnam,', 'Sundaic', 'Andaman']), verbo([sea]), complemento(['coast,', and, 'Indochina)', and, revealed, genetic, differentiation, between, the, two, sides, of, the, 'Thai', 'peninsula,', which, had, previously, been, reported, as, a, single, group, of, 'Malay', peninsular, macaques])].
[sujeto(['From', the, estimated, divergence, time, of, the, 'Sundaic', 'Andaman']), verbo([sea]), complemento([coast, 'subclade,', it, is, proposed, that, after, 'M'])].
[sujeto(['Then,', some, of, them, migrated, north, and, south, to, colonize, the, 'Thai', 'Andaman']), verbo([sea]), complemento([coast, and, northern, 'Sumatra,', respectively])].
[sujeto(['The', 'SRY-TSPY', phylogenetic, analysis]), verbo([suggested]), complemento([that, 'male-mediated', gene, flow, from, 'M'])].
[sujeto(['The', aim, of, the, present, study, was, to, prove, that, primary, cells, enriched, with, stem, cells, are, more, easily, reprogrammed, to, generate]), verbo([induced]), complemento([pluripotent, stem, '(', 'iPS)', cells, than, those, with, scarce, numbers, of, stem, cells])].
[sujeto(['The', number, of, cells, with, the, stemness, property, of, 'HDDPC', differs, among, 'individuals,', which]), verbo([suggests]), complemento([that, 'HDDPC', showing, an, increased, expression, of, both, 'ALP', and, 'OCT-3/4', can, be, more, easily, reprogrammed, to, generate, iPS, cells, after, the, forced, expression, of, reprogramming, factors])].
[sujeto(['Histone', acetylation]), verbo([regulated]), complemento([by, class, 'I', histone, deacetylases, '(', 'HDACs)', plays, a, pivotal, role, in, 'matrix-specific', gene, transcription, and, cartilage, development])].
[sujeto(['While', we, previously, demonstrated, that, microRNA, '(', 'miR)-455-3p', is, upregulated, during, chondrogenesis, and, can]), verbo([enhance]), complemento([early, 'chondrogenesis,', the, mechanism, underlying, this, process, remains, largely, unclear])].
[sujeto(['We', observed, that, 'miR-455-3p', was, highly]), verbo([expressed]), complemento([in, proliferating, and, 'pre-hypertrophic', 'chondrocytes,', while, 'HDAC2', and, 'HDAC8', were, primarily, expressed, in, hypertrophic, chondrocytes])].
[sujeto(['Meanwhile,', 'miR-455-3p']), verbo([suppressed]), complemento([the, activity, of, reporter, constructs, containing, the, 3, '\'', -, untranslated, regions, of, 'HDAC2/8,', inhibited, 'HDAC2/8', expression, and, promoted, histone, 'H3', acetylation, at, the, collagen, 2, '(', 'COL2A1)', promoter, in, human, 'SW1353', 'chondrocyte-like', cells])].
[sujeto(['Treatment', with, the, 'HDAC', inhibitor, trichostatin, 'A', '(', 'TSA)', resulted, in]), verbo([increased]), complemento([expression, of, 'cartilage-specific', genes, and, promoted, glycosaminoglycan, deposition])].
[sujeto(['Moreover,', 'TSA']), verbo([inhibited]), complemento([matrix, metalloproteinase, 13, '(', 'Mmp13)', expression, and, promoted, nuclear, translocation, of, 'SOX9', in, 'interleukin-1-treated', primary, mouse, chondrocytes])].
[sujeto(['Lastly,', knockdown, of, 'HDAC2/3/8']), verbo([increased]), complemento(['SRY', '(', 'sex-determining', region, 'Y)-box', 9, '(', 'SOX9)', and, decreased, 'Runt-related', transcription, factor, 2, '(', 'RUNX2)', expression])].
[sujeto(['Taken', 'together,', these, findings]), verbo([suggest]), complemento([that, 'miR-455-3p', plays, a, critical, role, during, chondrogenesis, by, directly, targeting, 'HDAC2/8', and, promoting, histone, 'H3', 'acetylation,', which, raises, possibilities, of, using, 'miR-455-3p', to, influence, chondrogenesis, and, cartilage, degeneration])].
[sujeto(['To', investigate, whether, high, 'glucose-induced', oxidative, stress, is, implicated, in, apoptosis, of, rat, nucleus, pulposus, cells, '(', 'NPCs)', and, abnormal, expression, of, critical, genes]), verbo([involved]), complemento([in, the, metabolic, balance, of, extracellular, matrix, '(', 'ECM)'])].
[sujeto(['High', glucose, reduced, viability, of, 'NPCs', and]), verbo([induced]), complemento([apoptosis])].
[sujeto(['High', glucose, resulted, in]), verbo([increased]), complemento(['ROS', generation, and, p38, 'MAPK', activation])].
[sujeto(['In', 'addition,', it, negatively]), verbo([regulated]), complemento([the, expression, of, type, 'II', 'collagen,', 'aggrecan,', 'Sox-9,', and, 'TIMP-1', and, positively, regulated, 'MMP-3', expression])].
[sujeto(['High', glucose, might]), verbo([promote]), complemento([apoptosis, of, 'NPCs,', trigger, 'ECM', catabolic, 'pathways,', and, inhibit, its, anabolic, 'activities,', possibly, through, a, p38, 'MAPK-dependent', oxidative, stress, mechanism])].
[sujeto(['In', this, 'study,', we, identified, the, transcriptional, factor, 'ZNF606', as, an]), verbo([interacting]), complemento([partner, for, 'Sox9', in, cells])].
[sujeto(['We', further, demonstrated, that, overexpression, of, 'ZNF606']), verbo([inhibited]), complemento([the, transcriptional, activity, of, 'Sox9,', while, knockdown, of, 'ZNF606', increased, 'Sox9-mediated', transcription])].
[sujeto(['Chromatin', immunoprecipitation, analysis, revealed, that, 'ZNF606']), verbo([prevents]), complemento(['Sox9', binding, to, the, enhancers, of, its, target, gene, col2a1])].
[sujeto(['Importantly,', the, interaction, between, 'ZNF606', and, 'Sox9', was]), verbo([decreased]), complemento([during, chondrocyte, differentiation])].
[sujeto(['Consistent', with, these, 'findings,', 'ZNF606']), verbo([inhibited]), complemento([chondrocyte, differentiation])].
[sujeto(['Thus,', our, results, demonstrate, that, 'ZNF606']), verbo([acts]), complemento([as, a, novel, 'Sox9', 'co-regulator', that, inhibits, 'Sox9-mediated', chondrocyte, differentiation])].
[sujeto(['To', establish, a, rabbit, model, for, investigating, the, effects, of, intermittent, cyclic, mechanical, tension, '(', 'ICMT)', on]), verbo([promoting]), complemento([degeneration, of, endplate, cartilage])].
[sujeto(['Multiple', strategies, were, employed, to, examine, degeneration, of, endplate, cartilage, and]), verbo([nuclear]), complemento([factor, '(', 'NF)-κB', signaling, pathway, activation])].
[sujeto(['Examination', of, hematoxylin, and, eosin, staining, of, sections, of, endplate, cartilage, showed, significant, damage, as, the, load, duration]), verbo([increased]), complemento([in, the, 'ICMT', loading, group])].
[sujeto(['Additionally,', 'ICMT', loading, can]), verbo([lead]), complemento([to, 'NF-κB', signaling, pathway, activation, as, well, as, degeneration, of, endplate, cartilage])].
[sujeto(['These', experiments, indicate, that, 'ICMT', contributes, to, the, activation, of, 'NF-κB', signaling, pathway, in, vivo, and, that, the, 'NF-κB', signaling, pathway, further, 'up-regulates', 'MMP13,']), verbo([leading]), complemento([to, degeneration, of, endplate, cartilage])].
[sujeto(['Although', oxidative, stress, is, implicated, in, 'SeMet', 'toxicity,', knowledge, gaps, remain, in, how, 'SeMet']), verbo([causes]), complemento([characteristic, spinal, deformities])].
[sujeto(['Gene', expression, studies, for, the, 'UPR']), verbo([suggest]), complemento([a, potential, role, for, 'CHOP', '(', 'c/ebp', homologous, 'protein)', induced, apoptosis, deformed, embryos, after, 5, μM, 'SeMet,', accompanied, by, a, significant, decrease, in, 'PDIA4', '(', protein, disulfide, isomerase, 'A4)', and, no, change, in, 'Dnajb9', '(', 'ER', 'DNA', 'J', 'Domain-Containing', 'Protein', 4, ')'])].
[sujeto(['This', expression, was, distinct, from, the, 'UPR']), verbo([induced]), complemento([by, 'well-studied', 'ER', stress, 'inducer,', 'tunicamycin,', which, robustly, activated, 'CHOP,', 'PDIA4', and, 'Dnajb9'])].
[sujeto(['Finally,', 'SeMet', treatment, significantly]), verbo([decreased]), complemento([transcripts, of, cartilage, 'development,', 'Sox9', '(', 'SRY', box, 9, ')', ',', while, increasing, 'Runx2', in, deformed, 'embryos,', without, altering, 'Twist', or, 'Collagen', 2, a1])].
[sujeto(['Results']), verbo([suggest]), complemento([that, oxidative, 'stress,', the, 'UPR', and, cell, death, play, key, roles, in, 'SeMet', induced, deformities, and, altered, skeletal, development, factors])].
[sujeto(['The', 'sex-determining', gene, 'SRY']), verbo([induces]), complemento(['SOX9', expression, in, the, testes, of, eutherian, mammals, via, two, pathways])].
[sujeto(['SRY']), verbo([binds]), complemento([to, 'testis-specific', enhancer, of, 'Sox9', '(', 'TESCO)', with, 'SF1', to, activate, 'SOX9', transcription])].
[sujeto(['SRY', also, 'up-regulates', 'ER71', 'expression,', and, 'ER71']), verbo([activates]), complemento(['Sox9', transcription])].
[sujeto(['After', the, initiation, of, testis, 'differentiation,', 'SOX9']), verbo([enhances]), complemento(['Amh', expression, by, binding, to, its, promoter, with, 'SF1'])].
[sujeto(['SOX8,', 'SOX9', and, 'SOX10,', members, of, the, 'SOXE', gene, 'family,', also]), verbo([enhance]), complemento([the, activities, of, the, 'Amh', promoter, and, 'TESCO'])].
[sujeto(['The', activity, of, the, 'AMH', promoter, was]), verbo([stimulated]), complemento([by, 'SOXE', genes, and, 'SF1'])].
[sujeto(['Mutant', 'AMH', 'promoters,', with, mutations, in, its, 'SOX', and, 'SF1']), verbo([binding]), complemento(['sites,', did, not, show, significant, activity, by, 'SOX9', and, 'SF1'])].
[sujeto(['These', results, indicate, that, 'AMH', expression, was]), verbo([regulated]), complemento([by, the, binding, of, 'SOX9', and, 'SF1'])].
[sujeto(['By', 'contrast,', 'SOXE', genes, could, not]), verbo([enhance]), complemento(['TESCO', activity])].
[sujeto(['Furthermore,', the, activity, of, the, 'SOX9', promoter, was]), verbo([enhanced]), complemento([by, 'ER71,', indicating, that, 'ER71', may, play, an, important, role, in, the, 'testis-specific', expression, of, 'SOX9'])].
[sujeto(['In', a, 46, ',', 'XY', 'individual,', the, presence, of, the, 'Y', chromosome, harboring, the, 'testis-determining', factor, '(', 'SRY)']), verbo([triggers]), complemento([testis, determination, and, differentiation])].
[sujeto(['In', a, 46, ',', 'XX', 'individual,', the, absence, of, 'SRY', along, with, the, activation, of, genes]), verbo([associated]), complemento([with, the, female, pathway, leads, to, ovarian, development])].
[sujeto(['The', latter, process]), verbo([has]), complemento([long, been, considered, as, a, default, pathway])].
[sujeto(['However,', recent, studies]), verbo([have]), complemento([cast, doubts, on, this, dogma])].
[sujeto(['Especial', attention, is, paid, to, 'FOXL2', whose, mutations, are, responsible, for, the, blepharophimosis, 'syndrome,', often]), verbo([associated]), complemento([with, female, 'infertility,', and, for, cancer])].
[sujeto(['We', highlight, the, cooperation, of, 'WNT4,', 'RSPO1', and, 'FOXL2', within, a, regulatory, network, and, the, need, for, further, research, to, better, understand, their, role, in, defining, and]), verbo([maintaining]), complemento([ovarian, identity])].
[sujeto(['Here,', we]), verbo([report]), complemento([a, rare, congenital, chromosomal, 'aberration,', 46, ',', 'X,dic(X;Y)(p22'])].
[sujeto(['A', cytogenetic, examination, of]), verbo([stimulated]), complemento([peripheral, blood, cells, revealed, the, constitutional, karyotype, 46, ',', 'X,dic(X;Y)(p22'])].
[sujeto(['A', 'CGH/SNP', array, '(', 'Illumina)', revealed, a]), verbo([gain]), complemento([of, 153, ',', 7, 'Mbp', of, the, 'X', chromosome, and, a, 803, -, kbp, microdeletion, '(', including, the, 'SHOX', 'gene),', which, were, also, confirmed, with, 'FISH'])].
[sujeto(['SHOX', encodes, a, transcriptional, factor, that]), verbo([regulates]), complemento([the, growth, of, the, long, bones])].
[sujeto(['The', deletion, of, the, 'SHOX', gene, together, with, the, 'Madelung', deformity, of, the, forearm, and, the, short, stature, of, the, proband]), verbo([led]), complemento([to, a, diagnosis, of, 'Léri-Weill', dyschondrosteosis, '(', 'LWD)'])].
[sujeto(['The']), verbo([gain]), complemento([of, almost, the, whole, 'X', chromosome, '(', 153, ',', 7, 'Mbp)', was, considered, a, variant, of, 'Klinefelter', syndrome, '(', 'KS)'])].
[sujeto(['We']), verbo([have]), complemento([reported, a, structural, aberration, of, the, sex, 'chromosomes,', 'dic(X;Y)(p22'])].
[sujeto(['The', related, genomic, imbalance, is]), verbo([associated]), complemento([with, two, known, hereditary, 'syndromes,', 'LWD', and, a, 'KS', 'variant,', identified, in, our, proband, at, an, advanced, age])].
[sujeto(['Because', the, breakpoints, did, not]), verbo([involve]), complemento([cancer, 'genes,', we, inferred, that, the, two, malignancies, in, the, proband, were, not, caused, by, this, abnormality])].
[sujeto(['The', addition, of, fibrin, protein, was, typically]), verbo([required]), complemento([to, achieve, a, similar, effect, on, 'M-ECM-adherent', monolayered, fibroblasts])].
[sujeto(['The', spheroid, fusion, process, was, followed, by, an]), verbo([increase]), complemento([in, cell, density, and, the, formation, of, tight, clusters])].
[sujeto(['The', fused, spheroids, continued, to]), verbo([maintain]), complemento([their, intracellular, 'ECM', turnover, and, proliferation, capacities])].
[sujeto(['A', model, is]), verbo([provided]), complemento([by, testis, determination, in, therian, mammals])].
[sujeto(['Mutations', in, human, 'SRY']), verbo([cause]), complemento([gonadal, dysgenesis, leading, to, 'XY', female, development, '(', 'Swyer', 'syndrome)'])].
[sujeto(['Here,', we]), verbo([have]), complemento([characterized, an, inherited, mutation, compatible, with, either, male, or, female, somatic, phenotypes, as, respectively, observed, in, an, 'XY', father, and, 'XY', daughter])].
[sujeto(['The', mutation, '(', a, 'crevice-forming', substitution, at, a]), verbo([conserved]), complemento([back, surface, of, the, 'SRY', 'high-mobility-group', 'box)', markedly, destabilizes, the, domain, but, preserves, specific, 'DNA', affinity, and, induced, 'DNA', bend, angle])].
[sujeto(['On', transient, transfection, of, diverse, human, and, rodent, cell, 'lines,', the, variant, 'SRY', exhibited, accelerated, proteasomal, degradation, '(', relative, to, 'wild-type)']), verbo([associated]), complemento([with, increased, 'ubiquitination;', in, vitro, susceptibility, to, 'ubiquitin-independent', '(', '″default″)', cleavage, by, the, 20, 'S', core, proteasome, was, unchanged])].
[sujeto(['Our', findings, define, a, novel, mechanism, of, impaired, 'organogenesis:', accelerated, 'ubiquitin-directed', proteasomal, degradation, of, a, master, transcription, factor]), verbo([leading]), complemento([to, a, developmental, decision, poised, at, the, edge, of, ambiguity])].
[sujeto(['In', this, commentary, we, briefly, summarize, early, work, on, circular, 'RNAs', derived, from, spliceosome]), verbo([mediated]), complemento([circularization])].
[sujeto(['We', highlight, how, this, early, work, inspired, work, on, the, basic, mechanisms, of]), verbo([nuclear]), complemento(['RNA', 'splicing,', the, possible, function, of, circular, 'RNAs', and, the, potential, uses, of, circular, 'RNAs', as, tools, in, biomedicine])].
[sujeto(['Recent', developments, in, the, study, of, circular, 'RNAs,', summarized, in, this, 'volume,']), verbo([have]), complemento([brought, these, questions, back, to, the, foreground])].
[sujeto(['The', 'SRY', gene, '(', 'SRY)']), verbo([provides]), complemento([instructions, for, making, a, transcription, factor, called, the, 'sex-determining', region, 'Y', protein])].
[sujeto(['The', 'sex-determining', region, 'Y', protein]), verbo([causes]), complemento([a, fetus, to, develop, as, a, male])].
[sujeto(['The', multiple, sequence, alignment, results, indicated, that, 'SRY', protein, sequences, from, 'Orcinus', orca, '(', killer, 'whale)', and, 'Tursiopsaduncus', '(', 'dolphin)']), verbo([have]), complemento([least, genetic, distance, of, 0.33, in, these, 15, species, and, are, 99.67, '%', identical, at, the, amino, acid, level])].
[sujeto(['Homosapiens', and, 'Pantroglodytes', '(', 'chimpanzee)']), verbo([have]), complemento([the, next, lowest, genetic, distance, of, 1.35, and, are, 98.65, '%', identical, at, the, amino, acid, level])].
[sujeto(['These', findings, indicate, that, the, 'SRY', proteins, are]), verbo([conserved]), complemento([in, the, 15, 'species,', and, their, evolutionary, relationships, are, similar])].
[sujeto(['No', mutation, was]), verbo([found]), complemento([in, the, 'SRY', gene])].
[sujeto(['The', karyotype, of, patients, carrying, 'idic(Y)(p)', seems, 'unstable,', and, female, patients]), verbo([have]), complemento([the, characteristics, of, short, stature, and, secondary, sexual, hypoplasia])].
[sujeto(['Here,', we, replaced, 'Sry', by, transgenic, activation, of, its, downstream]), verbo([target]), complemento(['Sox9,', and, 'Eif2s3y,', by, transgenic, overexpression, of, its, 'X', 'chromosome-encoded', homolog, 'Eif2s3x'])].
[sujeto(['During', its, final, 'phase,', 'spermiogenesis,', haploid, round, spermatids, undergo, cellular, differentiation, into, 'spermatozoa,', which]), verbo([involves]), complemento([extensive, restructuring, of, cell, 'morphology,', 'DNA,', and, epigenome])].
[sujeto(['Compared', with, the, 'Control', 'group,', 'CD47', +, 'MSC', +, 'BiAb', +, 'MB,', 'CD47', +, 'MSC', +, 'BiAb,', 'CD47', +, 'MSC', and, 'MSC', groups, had]), verbo([decreased]), complemento([levels, of, 'MMP-9,', 'TIMP-1,', 'STAT', 1, and, collagen, 'deposition,', and, increased, levels, of, 'STAT', 3])].
[sujeto(['Up']), verbo([regulated]), complemento(['STAT', 3, and, down, regulated, 'TIMP-1', were, significantly, different, in, 'CD47', +, 'MSC', +, 'BiAb', +, 'MB', compared, with, 'CD47', +, 'MSC', or, 'CD47', +, 'MSC', +, 'BiAb'])].
[sujeto(['CD47', can]), verbo([enhance]), complemento([the, homing, rate, and, repairing, efficacy, of, 'MSC'])].
[sujeto(['An', analytical, evaluation, using, blood, samples, from, patients, with, leukemia, showed, that, the, while, blood, cell, '(', 'WBC)', depletion, and, 'NRBC']), verbo([loss]), complemento([rates, of, the, positive, enrichment, process, were, 93.98, &, 'nbsp;%', and, 6.02, &, 'nbsp;%,', respectively])].
[sujeto(['Gonadoblastoma', '(', 'GB),', a, rare, in, situ, germ, cell, tumor, derived, from, sex, cord, and, germ, 'cells,', is, closely]), verbo([associated]), complemento([with, gonadal, dysgenesis])].
[sujeto(['Increasing', studies, show, that, the, formation, of, 'GB', is, closely, related, to, genes]), verbo([regulating]), complemento([sexual, differentiation, and, determination, '(', e])].
[sujeto(['Here', we, describe, the, clinical, and, pathological, 'features,', diagnosis, and, treatment, of, 'GB,', and, also, summarize, the, molecular, genetic, and, epigenetic, mechanisms, underlying, the, gonadal, abnormalities, that]), verbo([lead]), complemento([to, 'GB'])].
[sujeto(['We', analyze, and, construct, the, common, gene, regulatory, networks, related, to, the, development, of, 'GB,', and, describe, some, obstacles, and, deficiencies, in, current, studies, to]), verbo([provide]), complemento([innovative, perspectives, on, further, studying, the, pathological, and, molecular, mechanisms, of, 'GB'])].
[sujeto(['Sex', determination, in, mammals]), verbo([requires]), complemento([expression, of, the, 'Y-linked', gene, 'Sry', in, the, bipotential, genital, ridges, of, the, 'XY', embryo])].
[sujeto(['Here,', we, analysed, 'Sry', flanking, sequences, across, many, 'species,', using, newly, available, genome, sequences, and, computational, 'tools,', to, better, understand, 'Sry\'s', genomic, context, and, to, identify]), verbo([conserved]), complemento([regions, predictive, of, functional, roles])].
[sujeto(['We', identified, 'position-specific', conservation, of]), verbo([binding]), complemento([motifs, for, multiple, transcription, factor, 'families,', including, 'GATA', binding, factors, and, 'Oct/Sox', dimers])].
[sujeto(['In', contrast, with, the, landscape, of, extremely, low, sequence, conservation, around, the, 'Sry', coding, 'region,', our, analysis, highlighted, a, strongly]), verbo([conserved]), complemento([interval, of, '~106&nbsp;bp', within, the, 'Sry', promoter, '(', which, we, term, the, 'Sry', 'Proximal', 'Conserved', 'Interval,', 'SPCI)'])].
[sujeto(['We', further]), verbo([report]), complemento([that, inverted, repeats, flanking, murine, 'Sry', are, much, larger, than, previously, recognised])].
[sujeto(['The', unusually, fast, pace, of, sequence, drift, on, the, 'Y', chromosome, sharpens, the, likely, functional, significance, of, both, the, 'SPCI', and, the, identified]), verbo([binding]), complemento(['motifs,', providing, a, basis, for, future, studies, of, the, 'role(s)', of, these, elements, in, 'Sry', regulation])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([in, the, scientific, literature, of, an, 'SRY-positive', hermaphrodite, 'Holstein', cattle, with, continuous, ovarian, cycles])].
[sujeto(['In', mouse, 'XY', 'gonads,', 'SRY']), verbo([induces]), complemento(['SOX9', upregulation, and, subsequent, 'FGF9', expression, by, embryonic, day, 11.5, '(', 'E11'])].
[sujeto([5, ')', ',']), verbo([leading]), complemento([to, the, differentiation, of, 'Sertoli', cells])].
[sujeto(['These', 2, ovarian, 'factors,', together, with, retinoic, acid, '(', 'RA)', 'action,']), verbo([promote]), complemento([feminization, partially, through, the, repression, of, the, masculinizing, activities, of, 'SOX9,', 'FGF9', and, 'DMRT1'])].
[sujeto(['At', 'birth,', the, oocyte, nests, break, down, into, single, oocytes, surrounded, by, granulosa, 'cells,']), verbo([leading]), complemento([to, the, assembly, of, primordial, follicles])].
[sujeto(['Animal', researches, and, clinical, studies]), verbo([have]), complemento([supported, the, relevance, between, phthalates, exposure, and, testicular, dysgenesis, syndrome, '(', 'TDS)'])].
[sujeto(['DEHP', exposure, resulted, in, significant, reduction, in, mRNA, of, 'Sry', during, sex, determination, from, gestation, day, '(', 'GD)', 11.0, to, 11.5, in, male, fetal, 'mice,', and, the]), verbo([increasing]), complemento([of, 'Sry', expression, to, threshold, level, on, 'GD', 11.5, was, delayed])].
[sujeto(['Taken', 'together,', the, results]), verbo([suggest]), complemento([that, the, potential, mechanism, of, gonadal, development, disorder, by, 'DEHP', may, origin, from, repression, of, important, male, sex, determination, signaling, 'pathway,', involving, 'Gadd45g', '→', 'Gata4', '→', 'Sry', '→', 'Sox9'])].
[sujeto(['The', results, would]), verbo([promote]), complemento([a, better, understanding, of, the, association, between, phthalate, esters, '(', 'PAEs)', exposure, and, the, reductive, disorder])].
[sujeto(['The', 'SOX9', gene]), verbo([has]), complemento([been, identified, as, a, major, factor, in, testis, development, in, mammals, after, it, is, activated, by, the, 'SRY', gene])].
[sujeto(['However,', duplication, of, the, gene, itself, in, some, mammalian, 'species,', or, of, a, 'well-delimited', upstream, '\'', 'RevSex\'', region, in, 'humans,']), verbo([has]), complemento([been, shown, to, result, in, testis, development, in, the, absence, of, the, 'SRY', gene])].
[sujeto(['Contrary', to, what, is, observed, in, the, current, dog, genome, 'assembly,', we]), verbo([found]), complemento([that, the, genomic, organization, is, quite, similar, to, that, reported, in, humans, and, other, mammalian, 'species,', including, the, position, of, the, 'RevSex', region, in, respect, to, 'SOX9'])].
[sujeto(['The', analysis, of, the]), verbo([conserved]), complemento([sequences, within, this, region, in, 7, mammalian, species, facilitated, the, highlighting, of, a, consensus, sequence, for, 'SRY', binding])].
[sujeto(['This', new, information, could, help, in, the, identification, of, evolutionarily]), verbo([conserved]), complemento([elements, relevant, for, 'SOX9', gene, 'regulation,', and, could, provide, valid, targets, for, mutation, analysis, in, 'XY', 'DSD', patients])].
[sujeto(['Diagnosis', of, fetal, gender, early, in, pregnancy, is, very, useful, as, it, would]), verbo([prevent]), complemento([invasive, fetal, sampling, in, almost, half, the, cases, at, risk, of, inheriting, 'X-linked', disorders, or, those, affecting, sexual, differentiation])].
[sujeto(['Noninvasive', prenatal, diagnosis, '(', 'NIPD)', using, circulating, 'cell-free', fetal, '(', 'cff)', 'DNA', from, maternal, circulation]), verbo([has]), complemento([emerged, as, a, useful, alternative, to, existing, methods, for, prenatal, diagnosis, of, gender])].
[sujeto(['Sex-reversal', cases, in, humans, and, genetic, models, in, mice]), verbo([have]), complemento([revealed, that, the, fate, of, the, bipotential, gonad, hinges, upon, the, balance, between, 'pro-testis', 'SOX9', and, 'pro-ovary', 'beta-catenin', pathways])].
[sujeto(['In', the, absence, of, 'Sox9', and, 'beta-catenin,', both, 'XX', and, 'XY', gonads, progressively, lean, toward, the, testis, 'fate,', indicating, that, expression, of, certain, 'pro-testis', genes]), verbo([requires]), complemento([the, repression, of, the, 'beta-catenin', 'pathway,', rather, than, a, direct, activation, by, 'SOX9'])].
[sujeto(['XY)', affects, this, 'process,', we, compared, the, transcriptomes, of, 'Sox9/beta-catenin', mutant, gonads, and]), verbo([found]), complemento([that, early, molecular, changes, underlying, the, 'XY-specific', masculinization, involve, the, expression, of, 'Sry', and, 21, 'SRY', direct, target, 'genes,', such, as, 'Sox8', and, 'Cyp26b1'])].
[sujeto(['These', results, imply, that, when, both, 'Sox9', and, 'beta-catenin', are, 'absent,', 'Sry', is, capable, of]), verbo([activating]), complemento([other, 'pro-testis', genes, and, drive, testis, differentiation])].
[sujeto(['Our', findings, not, only]), verbo([provide]), complemento([insight, into, the, mechanism, of, sex, 'determination,', but, also, identify, candidate, genes, that, are, potentially, involved, in, disorders, of, sex, development])].
[sujeto(['This']), verbo([report]), complemento([describes, a, disorder, of, the, sexual, development, in, a, beagle, dog, resulting, in, an, intersex, condition])].
[sujeto(['Testosterone', levels, that, were, within, the, male, reference, ranges, before, surgery]), verbo([decreased]), complemento([to, basal, levels, postsurgically])].
[sujeto(['The', stem, cell, marker, 'OCT4', is, frequently]), verbo([expressed]), complemento([in, 'HCCs,', and, its, expression, correlates, with, those, of, putative, cancer, stem, cell, '(', 'CSC)', markers, and, 'CSC', properties])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, 'Sry', is, involved, in, tumor, malignancy, in, rodent, 'HCCs'])].
[sujeto(['Ectopic', expression, of, 'SRY']), verbo([increased]), complemento([multiple, stem, cell, 'factors,', including, 'OCT4', and, 'CD13'])].
[sujeto(['The', 'OCT4', promoter, contained, 'SRY-binding', sites, that, were, directly]), verbo([activated]), complemento([by, 'SRY'])].
[sujeto(['In', 'HCC-derived', 'cells,', 'SRY', knockdown]), verbo([decreased]), complemento(['OCT4', expression, and, cancer, 'stem-like', phenotypes, such, as, 'self-renewal,', 'chemoresistance,', and, tumorigenicity])].
[sujeto(['Conversely,', 'OCT4', and, 'SRY', overexpression]), verbo([promoted]), complemento([cancer, 'stem-like', phenotypes])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'SRY', is, involved, in, the, maintenance, of, cancer, 'stem-like', characteristics, through, 'OCT4'])].
[sujeto(['Noteworthily,', 'SRY', was, highly]), verbo([expressed]), complemento([in, some, hHCC, patients])].
[sujeto(['Gender', role, and, gender, identity, are]), verbo([reported]), complemento([as, male])].
[sujeto(['SRY,', the, gene, that, encodes, the, 'sex-determining', region, 'Y', 'protein,', is, the, principal, gene, known, to, be]), verbo([associated]), complemento([with, 46, ',', 'XX', testicular, 'DSD'])].
[sujeto(['Rearrangements', in, or, around, 'SOX9', and, 'SOX3', detected, by, 'CMA,', or, rarely, 'karyotype,']), verbo([have]), complemento([recently, been, reported, in, a, few, 'cases;', at, least, one, more, 'as-yet-unknown', gene, at, another, locus, is, implicated])].
[sujeto(['Treatment', of, 'manifestations:', 'Similar', to, that, for, other]), verbo([causes]), complemento([of, testosterone, deficiency])].
[sujeto(['After', age, 14, 'years,', 'low-dose', testosterone, therapy, is, initiated, and, gradually]), verbo([increased]), complemento([to, reach, adult, levels])].
[sujeto(['Surveillance:', 'Monitor', for, testosterone, effects, during, testosterone, replacement, 'therapy,', including, prostate, size, and, 'prostate-specific', antigen, '(', 'PSA)', in, 'adults;', routine, monitoring, of, 'hematocrit,', lipid, 'profile,', and, liver, function, 'tests;', bone, mineral, density, determination, by, bone, densitometry, '(', 'DEXA)', 'annually,', if, osteopenia]), verbo([has]), complemento([been, diagnosed])].
[sujeto(['Autosomal', dominant, inheritance]), verbo([has]), complemento([been, documented, for, familial, cases, thought, to, be, caused, by, 'CNV', in, or, around, 'SOX9'])].
[sujeto(['The', mode, of, inheritance, of, other, 'SRY-negative', 46, ',', 'XX', testicular, 'DSD', is, not, 'known,', but, autosomal, recessive, inheritance]), verbo([has]), complemento([been, postulated])].
[sujeto(['Although', the, miRNAs, are]), verbo([involved]), complemento([in, breast, cancer, 'development,', their, axis, with, the, transcription, factors, that, show, therapeutic, potential, in, breast, cancer, is, largely, unknown])].
[sujeto(['Recently,', we, demonstrated, that, 'agonist-activated', 'Ahr']), verbo([induced]), complemento([a, highly, conserved, miRNA, 'cluster,', named, 'miR-212/132,', in, murine, cellular, immune, compartment])].
[sujeto(['Therefore,', current, study, was, performed, to, examine, if, this, miRNA, cluster]), verbo([mediates]), complemento([the, 'anti-metastatic', properties, of, 'Ahr', agonists])].
[sujeto(['The', 2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD)', and, 3, ',', 3, '\'', -, diindolylmethane, '(', 'DIM)', were, used, to]), verbo([activate]), complemento(['Ahr', in, 'MDA-MB-231', and, 'T47D', breast, cancer, cells])].
[sujeto(['Chromatin', immunoprecipitation, '(', 'ChIP)', assay, was, used, to, identify, the]), verbo([binding]), complemento(['site(s)', for, 'Ahr', on, 'miR-212/132', promoter])].
[sujeto(['For', prediction, of, potentially]), verbo([target]), complemento([gene, of, the, miRNA, 'cluster,', bioinformatics, analysis, was, carried, 'out,', and, to, test, 'targeting,', luciferase, activity, was, quantified])].
[sujeto(['The', 'miR-212/132', cluster, was, transcriptionally]), verbo([activated]), complemento([in, 'MDA-MB-231', and, 'T47D', cells, by, 'TCDD', and, 'DIM,', and, this, activation, was, regulated, by, 'Ahr'])].
[sujeto(['A', reciprocal, correlation, was, identified, between, 'Ahr', 'agonists-induced', 'miR-212/132', and, the, 'pro-metastatic', 'SRY-related', 'HMG-box4', '(', 'SOX4),', and, a, new, specific]), verbo([binding]), complemento([sites, for, 'miR-212/132', were, identified, on, the, untranslated, region, '(', 3, '\'', 'UTR)', of, 'SOX4'])].
[sujeto(['Further', in, vivo, studies, demonstrated, that, the, 'Ahr-miR-212/132-SOX4', module, was]), verbo([induced]), complemento([by, 'Ahr', activation])].
[sujeto(['Taken', 'together,', the, findings]), verbo([provide]), complemento([the, first, evidences, of, the, synergistic, 'anti-metastatic', properties, of, 'miR-212/132', cluster, through, suppression, of, 'SOX4'])].
[sujeto(['Also,', current, study]), verbo([suggest]), complemento([a, new, 'miRNA-based', mechanism, elucidating, the, 'anti-metastatic', properties, of, 'Ahr', 'agonists,', suggesting, possibility, of, using, 'miR-212/132', to, control, metastasis, in, breast, cancer, patients])].
[sujeto(['Goldfish', '(', 'Carassius', 'auratus)', and, zebrafish, '(', 'Danio', 'rerio)']), verbo([have]), complemento([utility, as, complementary, models, for, understanding, the, molecular, basis, and, functional, significance, of, exaggerated, neural, estrogen, biosynthesis])].
[sujeto(['Multiple', cytochrome, 'P450', aromatase, '(', 'P450arom)', cDNAs, that, derive, from, separate, gene, loci, '(', cyp19a, and, 'cyp19b)', are, differentially]), verbo([expressed]), complemento([in, brain, '(', 'P450aromB&gt;A)', and, ovary, '(', 'P450aromA&gt;B)', and, have, a, different, developmental, program, '(', 'B&gt;A)', and, response, to, estrogen, upregulation, '(', 'B', 'only)'])].
[sujeto(['As', measured, by]), verbo([increased]), complemento(['P450aromB', 'mRNA,', a, functional, estrogen, response, system, is, first, detected, 24, -, 48, h, 'post-fertilization', '(', 'hpf),', consistent, with, the, onset, of, estrogen, receptor, '(', 'ER)', expression, '(', 'alpha,', 'beta,', and, 'gamma)'])].
[sujeto(['The', 5, '\'', -, flanking, region, of, the, cyp19b, gene]), verbo([has]), complemento([a, 'TATA', 'box,', two, estrogen, response, elements, '(', 'EREs),', an, 'ERE', 'half-site', '(', 'ERE1/2),', a, nerve, growth, factor, 'inducible-B', protein, '(', 'NGFI-B)/Nur77', responsive, element, '(', 'NBRE)', binding, 'site,', and, a, sequence, identical, to, the, zebrafish, 'GATA-2', gene, neural, specific, enhancer])].
[sujeto(['The', cyp19a, promoter, region]), verbo([has]), complemento(['TATA', and, 'CAAT', 'boxes,', a, steroidogenic, 'factor-1', '(', 'SF-1)', binding, 'site,', and, two, aryl, hydrocarbon, receptor, '(', 'AhR)/AhR', nuclear, translocator, factor, '(', 'ARNT)', binding, motifs])].
[sujeto(['Both', genes]), verbo([have]), complemento([multiple, potential, 'SRY/SOX', binding, sites, '(', 16, and, 8, in, cyp19b, and, 'cyp19a,', 'respectively)'])].
[sujeto(['Luciferase', reporters]), verbo([have]), complemento([basal, promoter, activity, in, 'GH3', 'cells,', but, differences, '(', 'a&gt;b)', are, opposite, to, fish, pituitary, '(', 'b&gt;a)'])].
[sujeto(['When', microinjected, into, fertilized, zebrafish, 'eggs,', a, cyp19b, 'promoter-driven', green, fluorescent, protein, '(', 'GFP)', reporter, '(', but, not, 'cyp19a)', is]), verbo([expressed]), complemento([in, neurons, of, 30, -, 48, hpf, 'embryos,', most, prominently, in, retinal, ganglion, cells, '(', 'RGCs)', and, their, projections, to, optic, tectum])].
[sujeto(['Further', studies, are]), verbo([required]), complemento([to, identify, functionally, relevant, 'cis-elements', and, cellular, 'factors,', and, to, determine, the, regulatory, role, of, estrogen, in, neurodevelopment])].
[sujeto(['Diet', and, microbiome, derived, indole, derivatives, are, known, to]), verbo([activate]), complemento([the, ligand, induced, transcription, 'factor,', the, 'Aryl', hydrocarbon, 'Receptor', '(', 'AhR)'])].
[sujeto(['While', the, current, understanding, of, 'AhR', biology]), verbo([has]), complemento([confirmed, its, role, in, mucosal, 'lymphocytes,', its, function, in, intestinal, antigen, presenting, cells, '(', 'APCs)', is, poorly, understood])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, 'Cre-mediated', deletion, of, 'AhR', in, 'CD11c-expressing', cells, in, 'C57/BL6', mice, is, associated, with, altered, intestinal, epithelial, morphogenesis, in, vivo])].
[sujeto(['Moreover,', when, 'co-cultured', with, 'AhR-deficient', 'DCs', ex, 'vivo,', intestinal, organoids, showed, reduced, 'SRY', '(', sex, determining, region, 'Y)-box', 9, and]), verbo([increased]), complemento(['Mucin', 2, 'expression,', which, correlates, with, reduced, 'Paneth', cells, and, increased, goblet, cell, 'differentiation,', similar, to, the, data, obtained, in, vivo])].
[sujeto(['Further,', characterization, of, intestinal, 'APC', 'subsets,', devoid, of, 'AhR,', revealed, an, expression, pattern]), verbo([associated]), complemento([with, aberrant, intrinsic, 'Wnt', pathway, regulation])].
[sujeto(['At', a, functional, 'level,', the]), verbo([loss]), complemento([of, 'AhR', in, 'APCs', resulted, in, a, dysfunctional, epithelial, 'barrier,', associated, with, a, more, aggressive, chemically, induced, colitis, compared, to, wild, type, animals])].
[sujeto(['Our', results, are, consistent, with, a, model, whereby, the, 'AhR', signalling, pathway, may]), verbo([participate]), complemento([in, the, regulation, of, innate, immunity, through, intestinal, epithelium, development, and, mucosal, immunity])].
[sujeto(['In', the, 'male,', testosterone, '(', 'T)', secreted, by, the, developing, testes, defeminizes, 'LH']), verbo([release]), complemento(['mechanisms;', 'conversely,', perinatal, 'AhR', activation, by, 2, ',', 3, ',', 7, ',', 8, ',', -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD)', blocks, defeminization])].
[sujeto(['To', better, understand, developmental, mechanisms, altered, by, 'TCDD', 'exposure,', we, first, verified, that, neonatal, 'TCDD', exposure, in, male, rats]), verbo([prevented]), complemento([the, loss, of, 'AVPV', 'GABA/glutamate', neurons, that, are, critical, for, 'female-typical', 'LH', surge, release])].
[sujeto(['In', 'addition,', upstream, regulatory, analysis]), verbo([suggests]), complemento([that, both, estrogen, receptors, '(', 'ER)', and, androgen, receptors, '(', 'AR)', regulate, genes, targeted, by, 'TCDD'])].
[sujeto(['Of', the, 23, mRNAs]), verbo([found]), complemento([to, be, changed, by, 'TCDD', at, least, 2, -, fold, '(', 'p&lt;0'])].
[sujeto([5, ')', ',', most]), verbo([participate]), complemento([in, the, functions, identified, in, our, bioinformatics, analyses])].
[sujeto(['Several,', including, matrix, metallopeptidase, 9, and, 'SRY-box', 11, '(', 'Sox11),', are, known]), verbo([targets]), complemento([of, 'E2'])].
[sujeto(['CUG', triplet, 'repeat,', 'RNA']), verbo([binding]), complemento([protein, 2, '(', 'cugbp2)', is, particularly, interesting, because, it, is, 'sex-specific,', oppositely, regulated, by, estradiol, '(', 'E2)', and, 'TCDD'])].
[sujeto(['Moreover,', it]), verbo([regulates]), complemento([the, 'post-transcriptional', processing, of, molecules, previously, linked, to, sexual, differentiation, of, the, brain])].
[sujeto(['These', findings]), verbo([provide]), complemento([new, insights, into, how, 'TCDD', may, interfere, with, defeminization, of, 'LH', release, patterns])].
[sujeto(['Two', 'P450arom', mRNAs, which, derive, from, separate, gene, loci, '(', cyp19a, and, 'cyp19b)', are, differentially]), verbo([expressed]), complemento([in, brain, '(', 'b&gt;a)', and, ovary, '(', 'a&gt;b)', and, have, a, different, developmental, program, '(', 'b&gt;a)', and, estrogen, upregulation, '(', b, 'only)'])].
[sujeto(['Sequence', analysis, of, the, cyp19b, gene, approximately, 1.8, kb, upstream, of, the, transcription, start, site, revealed, a, 'TATA', box, at, nucleotide, '(', 'nt)', -, 30, ',', two, estrogen, responsive, elements, '(', 'EREs;', nt, -, 351, and, -, 211, ')', and, a, consensus]), verbo([binding]), complemento([site, '(', 'NBRE)', for, nerve, growth, factor, 'inducible-B', protein, '(', 'NGFI-B/Nur77)', at, -, 286, ',', which, includes, another, 'ERE', 'half-site'])].
[sujeto(['Also', present, were, a, sequence, at, nt, -, 399, '(', 'CCCTCCT)']), verbo([required]), complemento([for, neural, specificity, of, the, zebrafish, 'GATA-2', 'gene,', and, 16, copies, of, an, 'SRY/SOX', binding, motif])].
[sujeto(['The', 5, '\'', -, flanking, region, '(', approximately, 1.0, 'kb)', of, the, cyp19a, gene, had, 'TATA', '(', nt, -, 48, ')', and, 'CAAT', '(', nt, -, 71, ')', 'boxes,', a, steroidogenic, 'factor-1', '(', 'SF-1)']), verbo([binding]), complemento([site, '(', nt, -, 265, ')', ',', eight, copies, of, the, 'SRY/SOX', 'motif,', and, two, copies, of, a, recognition, site, for, binding, the, arylhydrocarbon, receptor, '(', 'AhR)/AhR', nuclear, translocator, factor, '(', 'ARNT)', heterodimer])].
[sujeto(['Tandem', analysis, of, cyp19a, and, cyp19b, promoters, in, living, zebrafish, embryos, can, be, a, useful, approach, for, identifying, 'cis-elements', and, cellular, factors]), verbo([involved]), complemento([in, the, correct, 'tissue-specific,', 'spatial,', temporal, and, estrogen, regulated, expression, of, aromatase, genes, during, 'CNS', and, gonadal, development])].
[sujeto(['ELISA', and, 'RT-PCR', were, used, to, measure, protein, and, mRNA, 'levels,', 'respectively,', of]), verbo([nuclear]), complemento([factor, '(', 'NF)-κB,', 'IL-1β,', 'IL-6', and, 'TNF-α'])].
[sujeto(['Donor', cell, numbers]), verbo([decreased]), complemento([over, time])].
[sujeto(['Pretreatment', with, triptolide, improved, graft, survival, both, 24, '(', 29.3, ±, 0.9, '%', ')', and, 72, h, '(', 17.5, ±, 1.2, '%', ')', after, transplantation, of, 'MSCs', and, resulted, in, a, 2.5, -, fold]), verbo([increase]), complemento([in, the, total, cell, number, 72, h, after, cell, transplantation])].
[sujeto(['The', mechanism, underlying, this, effect]), verbo([involves]), complemento([attenuating, the, inflammatory, response, via, inhibition, of, the, 'NF-κB', signaling, pathway])].
[sujeto(['Many', papers]), verbo([have]), complemento([shown, that, 'SRY', '(', 'sex-determining', region, 'Y)-box', '(', 'SOX)', family, genes, serve, as, either, tumor, suppressor, genes, '(', 'TSGs)', or, oncogenes, by, regulating, the, 'Wnt', signaling, pathway, in, different, cancers])].
[sujeto(['We']), verbo([have]), complemento([demonstrated, recently, that, epigenetic, silencing, of, 'SOX1', gene, occurs, frequently, in, cervical, cancer])].
[sujeto(['Overexpression', of, 'SOX1']), verbo([inhibited]), complemento([cell, 'proliferation,', anchorage, 'independency,', and, invasion, in, vitro])].
[sujeto(['SOX1']), verbo([suppressed]), complemento([tumor, growth, in, nonobese, 'diabetic/severe', combined, immunodeficiency, mice])].
[sujeto(['After', induction, of, 'SOX1', by, doxycycline, '(', 'DOX),', 'SOX1']), verbo([inhibited]), complemento([cell, growth, and, invasion, in, the, inducible, system])].
[sujeto(['SOX1']), verbo([inhibited]), complemento(['TCF-dependent', transcriptional, activity, and, the, 'Wnt', target, genes])].
[sujeto(['SOX1', also]), verbo([repressed]), complemento([the, invasive, phenotype, by, regulating, the, expression, of, 'invasion-related', genes])].
[sujeto(['Taken', 'together,', these, data]), verbo([suggest]), complemento([that, 'SOX1', can, function, as, a, tumor, suppressor, partly, by, interfering, with, 'Wnt/β-catenin', signaling, in, cervical, cancer])].
[sujeto(['BM-derived', 'MSCs', were, detected, by, 'RT-PCR', of, 'CD29', and, were, then, infused, into, the, tail, vein, of, female, rats, that, received, 'CCl4', injection, to]), verbo([induce]), complemento([liver, fibrosis])].
[sujeto(['MSCs', and, 'SIMV']), verbo([decreased]), complemento([liver, procollagens, 'I', and, 'III,', 'TIMP-1', and, endoglin, gene, 'expressions,', 'TGF-β1', 'immunostaining,', and, serum, liver, function, tests, compared, with, the, 'CCl4', group])].
[sujeto(['MMP-1', expression, was]), verbo([increased]), complemento([in, the, 'CCl4/MSCs', group])].
[sujeto(['Our', recent, studies]), verbo([have]), complemento([demonstrated, that, 'SRY', '(', sex, determining, region, 'Y)-box', 1, '(', 'SOX1)', and, secreted, 'frizzled-related', proteins, are, concomitantly, 'promoter-hypermethylated,', and, this, might, lead, to, abnormal, activation, of, the, 'Wnt', signaling, pathway, in, 'HCC'])].
[sujeto(['SOX1', encodes, a, transcription, factor]), verbo([involved]), complemento([in, the, regulation, of, embryonic, development, and, cell, fate, determination])].
[sujeto(['Overexpression', of, 'SOX1', by, a, constitutive, or, inducible, approach, could]), verbo([suppress]), complemento([cell, 'proliferation,', colony, 'formation,', and, invasion, ability, in, 'HCC', cell, 'lines,', as, well, as, tumor, growth, in, nonobese, 'diabetic/severe', combined, immunodeficiency, mice])].
[sujeto(['We', used, a, 'T', cell, factor, '(', 'TCF)-responsive', luciferase, reporter, assay, and, western, blot, analysis, to, prove, that, 'SOX1', could]), verbo([regulate]), complemento(['TCF-responsive', transcriptional, activity, and, inhibit, the, expression, of, 'Wnt', downstream, genes])].
[sujeto(['Furthermore,', we, used, glutathione, 'S-transferase', 'pull-down,', 'co-immunoprecipitation,', and, confocal, microscopy, to, demonstrate, that, 'SOX1', could]), verbo([interact]), complemento([with, 'β-catenin', but, not, with, the, 'β-catenin/TCF', complex])].
[sujeto(['Moreover,', restoration, of, the, expression, of, 'SOX1']), verbo([induces]), complemento([significant, cellular, senescence, in, 'Hep3B', cells])].
[sujeto(['MSCs', were, mainly, distributed, in, the, glomerular, capillaries, at, the, time, points, of, 6, h, and, 48, 'h,', but, the, number, of, 'MSCs', in, glomerular, capillaries]), verbo([decreased]), complemento([and, those, in, renal, mesenchyma, increased, at, the, time, points, from, 10, d, to, 60, d, 'gradually,', then, tended, to, a, steady, 'state,', meanwhile, it, showed, a, stable, increasing, trend, in, renal, tubule])].
[sujeto(['Cell', colony, of, 'MSCs', could, be]), verbo([found]), complemento([in, mesenchyma, with, a, slowed, down, increasing, between, 30, d, to, 60, 'd,', but, the, increasing, in, tubule, was, still, steady])].
[sujeto(['MSCs', transplantation]), verbo([has]), complemento([beneficial, effects, on, 'CAAN,', which, is, possibly, related, with, the, reduction, of, 'PTC'])].
[sujeto(['The', results, indicate, that, 'X-', or, 'Y-linked', genes]), verbo([have]), complemento([direct, 'effects,', not, mediated, by, gonadal, 'secretions,', on, sex, differences, in, two, different, types, of, acute, nociception])].
[sujeto(['Recent', studies]), verbo([have]), complemento([shown, that, hematopoietic, bone, marrow, '(', 'BM)', 'stem/progenitor', cells, can, give, rise, to, hepatocytes, in, 'diseased/damaged', liver])].
[sujeto(['One', study]), verbo([has]), complemento([reported, that, 'BM', cells, can, transdifferentiate, into, liver, 'progenitor/oval', 'cells,', but, it, has, not, been, proven, that, the, latter, can, repopulate, the, liver])].
[sujeto(['To', answer, this, 'question,', we]), verbo([have]), complemento([lethally, irradiated, female, 'DPP4(-)', mutant, 'F344', rats, and, transplanted, them, with, 50, million, 'wild-type', male, 'F344', 'BM', cells])].
[sujeto(['Fetoprotein', transcription, factor, '(', 'FTF)', is, an, orphan]), verbo([nuclear]), complemento([receptor, that, activates, the, 'alpha(1)-fetoprotein', gene, during, early, liver, developmental, growth])].
[sujeto(['Here', we, sought, to, define, better, the, position, of, 'FTF', in, transcriptional, cascades]), verbo([leading]), complemento([to, hepatic, differentiation])].
[sujeto(['The', mFTF, transcription, initiation, site, was, located, in, adult, liver, at, 238, nucleotides, from, the, first, translation, initiator, 'codon,', with, six, canonical, 'GATA,', 'E', 'box,', and, 'Nkx', motifs, clustered, between, -, 50, /, -, 140, base, pairs, '(', 'bp)', from, the, cap, 'site;', 'DNA/protein']), verbo([binding]), complemento([assays, also, pinpointed, an, 'HNF4-binding', element, at, +, 36, bp, and, an, 'FTF-binding', element, at, -, 257, bp])].
[sujeto(['Transfection', assays, and, point, mutations, showed, that, the, mFTF, promoter, is]), verbo([activated]), complemento([by, 'GATA,', 'HNF4alpha,', 'FTF,', 'Nkx,', and, basic, 'helix-loop-helix', 'factors,', with, marked, cooperativity, between, 'GATA', and, 'HNF4alpha'])].
[sujeto(['Three', genes, encoding, transcription, factors, critical, to, early, hepatic, 'differentiation,', 'Hnf3beta,', 'Hnf4alpha,', and, 'Hnf1alpha,', each, contain, dual, 'FTF-binding', elements, in, their, proximal, 'promoters,', and, all, three, promoters, are]), verbo([activated]), complemento([by, 'FTF', in, transfection, assays])].
[sujeto(['Direct', 'DNA']), verbo([binding]), complemento([action, and, cooperativity, was, demonstrated, between, 'FTF', and, 'HNF3beta', on, the, 'Hnf3beta', promoter, and, between, 'FTF', and, 'HNF4alpha', on, the, 'Hnf1alpha', promoter])].
[sujeto(['These', combined, results]), verbo([suggest]), complemento([that, 'FTF', is, an, early, intermediary, between, endodermal, specification, signals, and, downstream, genes, that, establish, and, amplify, the, hepatic, phenotype])].
[sujeto(['The', definitive, endoderm, 'marker,', 'FoxA2', is, the, key, transcriptional, factor, that]), verbo([regulates]), complemento([cell, differentiation, and, tissue, regeneration])].
[sujeto(['We', demonstrated, that, 'FoxA2', was, notably]), verbo([enhanced]), complemento([in, murine, liver, progenitor, cells, and, 'SMCCs,', and, was, silenced, in, human, 'PSC', and, 'PBC', liver, tissues, relative, to, respective, controls, that, are, correlated, with, the, epigenetic, methylation, enzymes, 'DNMT1', and, 'DNMT3B'])].
[sujeto(['Furthermore,', activation, of, fibrosis, signaling, pathways, were, observed, in, 'BDL/MDR2(-/-)', mouse, liver, as, well, as, in, isolated, hepatic, stellate, cells, by, laser, capture, 'microdissection,', and, these, signals, were, recovered, along, with, reduced, hepatic, senescence, and]), verbo([enhanced]), complemento([hepatic, stellate, cellular, senescence, after, 'SMCC', engraft])].
[sujeto(['The', definitive, endoderm, marker, and, the, positive, regulator, of, biliary, 'development,', 'FoxA2,']), verbo([mediates]), complemento([the, therapeutic, effect, of, 'biliary-committed', progenitor, cells, during, cholestatic, liver, injury])].
[sujeto(['The', majority, of, mutations, were, 'novel,']), verbo([loss]), complemento([of, function, '(', 'LOF)', '(', 78.4, '%', ')', 'mutations,', and, most, disrupted, the, 'DNA-binding', domain, '(', 58.8, '%', ')'])].
[sujeto(['Mutation', status, was]), verbo([associated]), complemento([with, tumor, grade, and, not, associated, with, survival, outcomes])].
[sujeto(['Most', tumors]), verbo([expressed]), complemento(['FOXA2', at, both, the, mRNA, and, protein, level])].
[sujeto(['In', those, tumors, with, 'mutations,', the, majority, of, cases]), verbo([expressed]), complemento([both, alleles])].
[sujeto(['The', pattern, of, 'FOXA2', mutations, and, expression, in, tumors]), verbo([suggests]), complemento([complex, regulation, and, a, haploinsufficient, or, 'dominant-negative', tumor, suppressor, function])].
[sujeto(['Insulin', is, a, crucial, mediator, of, the, glucose, and, lipid, metabolism, that]), verbo([has]), complemento([been, implicated, in, atherosclerotic, and, inflammatory, processes])].
[sujeto(['Important', mediators, of, insulin, signaling, such, as, 'Liver', 'X', 'Receptors', '(', 'LXRs)', and, 'Forkhead', 'Box', 'A2', '(', 'FOXA2)', are, known, to]), verbo([regulate]), complemento(['apoA-I', expression, in, liver])].
[sujeto(['Forkhead', 'Box', 'O1', '(', 'FOXO1)', is, a, 'well-known']), verbo([target]), complemento([of, insulin, signaling, and, a, key, mediator, of, oxidative, stress, response])].
[sujeto(['Low', doses, of, insulin, were, shown, to]), verbo([activate]), complemento(['apoA-I', expression, in, human, hepatoma, 'HepG2', cells])].
[sujeto(['Treatment', of, 'HepG2', cells, with, high, doses, of, insulin, '(', 48, 'hours,', 100, 'nM)']), verbo([suppresses]), complemento(['apoA-I', gene, expression])].
[sujeto(['FOXO1', forms, a, complex, with, 'LXRβ', and, insulin, treatment, impairs, 'FOXO1/LXRβ', complex]), verbo([binding]), complemento([to, hepatic, enhancer, and, triggers, its, nuclear, export])].
[sujeto(['Insulin', as, well, as, 'LXR', ligand, 'TO901317']), verbo([enhance]), complemento([the, interaction, between, 'FOXA2,', 'LXRα', and, hepatic, enhancer])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, high, doses, of, insulin, downregulate, 'apoA-I', gene, expression, in, 'HepG2', cells, through, redistribution, of, 'FOXO1/LXRβ', 'complex,', 'FOXA2', and, 'LXRα', on, hepatic, enhancer, of, 'apoA-I', gene])].
[sujeto(['Genes', significantly]), verbo([associated]), complemento([with, baseline, seizure, frequency, on, likelihood, ratio, test, were, identified, based, on, &, 'gt;0'])].
[sujeto(['Expression', levels, of, forty, genes, were, significantly]), verbo([associated]), complemento([with, baseline, seizure, frequency])].
[sujeto(['Of', the, seven, most, 'significant,', four]), verbo([have]), complemento([been, linked, to, other, neurologic, diseases])].
[sujeto(['Expression', levels]), verbo([associated]), complemento([with, high, seizure, frequency, included, low, expression, of, 'Homeobox', 'A10,', 'Forkhead', box, 'A2,', 'Lymphoblastic', leukemia, derived, sequence, 1, ',', 'HGF', 'activator,', 'Kelch', repeat, and, 'BTB', '(', 'POZ)', domain, containing, 11, ',', 'Thanatos-associated', protein, domain, containing, 8, and, 'Heparin', sulfate, '(', 'glucosamine)', 3, -, 'O-sulfotransferase', 3, 'A1'])].
[sujeto(['Four', of, the, seven, discussed]), verbo([have]), complemento([been, previously, related, to, other, neurologic, diseases])].
[sujeto(['Future', investigation, of, these, genes, could, establish, new, biomarkers, for, predicting, 'epileptogenicity,', and, could]), verbo([have]), complemento([significant, implications, for, diagnosis, and, management, of, temporal, lobe, 'epilepsy,', as, well, as, epilepsy, pathogenesis])].
[sujeto(['Pancreatic', cancer, is, the, fourth]), verbo([leading]), complemento([cause, of, cancer, death, in, the, 'United', 'States'])].
[sujeto(['Restoration', of, 'miR-1291', expression]), verbo([inhibited]), complemento([pancreatic, cancer, cell, 'proliferation,', which, was, associated, with, cell, cycle, arrest, and, enhanced, apoptosis])].
[sujeto(['Furthermore,', 'miR-1291', sharply]), verbo([suppressed]), complemento([the, tumorigenicity, of, 'PANC-1', cells, in, mouse, models])].
[sujeto(['Through', computational, and, experimental, studies, we, further, identified, that, forkhead, box, protein, 'A2', '(', 'FOXA2),', a, transcription, factor, governing, 'AGR2', 'expression,', was, a, direct]), verbo([target]), complemento([of, 'miR-1291'])].
[sujeto(['These', results, connect, 'miR-1291', to, the, 'FOXA2-AGR2', regulatory, pathway, in, the, suppression, of, pancreatic, cancer, cell, proliferation, and, 'tumorigenesis,']), verbo([providing]), complemento([new, insight, into, the, development, of, 'miRNA-based', therapy, to, combat, pancreatic, cancer])].
[sujeto(['Since', 'LAL-deficient', '(', 'Lal', '(', -, /, -, ')', ')', mice, suffer, from, progressive]), verbo([loss]), complemento([of, adipose, tissue, and, severe, accumulation, of, lipids, in, hepatic, 'lysosomes,', we, hypothesised, that, 'LAL', deficiency, triggers, alternative, energy, 'pathway(s)'])].
[sujeto(['Despite']), verbo([loss]), complemento([of, adipose, 'tissue,', 'Lal', '(', -, /, -, ')', mice, show, enhanced, glucose, clearance, during, insulin, and, glucose, tolerance, tests, and, have, increased, uptake, of, '[', '(', 3, ')', 'H]2-deoxy-D-glucose', into, skeletal, muscle, compared, with, 'wild-type', mice])].
[sujeto(['We', observed, 84, '%']), verbo([decreased]), complemento([plasma, leptin, levels, and, significantly, reduced, hepatic, 'ATP,', 'glucose,', glycogen, and, glutamine, concentrations, in, fed, 'Lal', '(', -, /, -, ')', mice])].
[sujeto(['Markedly', reduced, hepatic, 'acyl-CoA', concentrations]), verbo([decrease]), complemento([the, expression, of, peroxisome, 'proliferator-activated', receptor, α, '(', 'PPARα)', target, genes])].
[sujeto(['However,', treatment, of, 'Lal', '(', -, /, -, ')', mice, with, the, 'PPARα', agonist, fenofibrate, further]), verbo([decreased]), complemento([plasma, 'TG', '(', and, hepatic, glucose, and, 'glycogen)', concentrations, in, 'Lal', '(', -, /, -, ')', mice])].
[sujeto(['Depletion', of, hepatic]), verbo([nuclear]), complemento([factor, 4, α, and, forkhead, box, protein, a2, in, fasted, 'Lal', '(', -, /, -, ')', mice, might, be, responsible, for, reduced, expression, of, microsomal, 'TG', transfer, 'protein,', defective, 'VLDL', synthesis, and, drastically, reduced, plasma, 'TG', levels])].
[sujeto(['We', conclude, that]), verbo([decreased]), complemento([plasma, 'VLDL', production, enhances, glucose, uptake, into, skeletal, muscle, to, compensate, for, the, lack, of, energy, supply])].
[sujeto(['Genome-wide', association, studies, '(', 'GWAS)', of, type, 2, diabetes, '(', 'T2D)']), verbo([have]), complemento([discovered, a, number, of, loci, that, contribute, to, susceptibility, to, the, disease])].
[sujeto(['Future', challenges, include, elucidation, of, functional, mechanisms, through, which, these, 'GWAS-identified', loci]), verbo([modulate]), complemento(['T2D', disease, risk])].
[sujeto(['The', aim, of, the, present, study, was, to, comprehensively, characterize, 'T2D']), verbo([associated]), complemento([single, nucleotide, polymorphisms, '(', 'SNPs)', and, genes, through, computational, approaches])].
[sujeto(['Computational', biology, approaches, used, in, the, present, study, included, comparative, genomic, analyses, and, functional, annotation, using, 'GWAS3D', and, 'RegulomeDB,', investigation, of, the, effects, of, 'T2D-associated', 'SNPs', on, miRNA]), verbo([binding]), complemento([and, protein, 'phosphorylation,', and, gene, 'ontology,', pathway, 'enrichment,', 'protein-protein', interaction, '(', 'PPI)', networks, and, functional, module, analysis, of, 'T2D-associated', genes, from, previously, published, 'GWAS'])].
[sujeto(['Computational', analysis, identified, a, number, of, 'T2D', 'GWAS-associated', 'SNPs', that, were, located, at, protein]), verbo([binding]), complemento(['sites,', including, 'CCCTC-binding', factor, '(', 'CTCF),', 'E1A', binding, protein, p300, '(', 'EP300),', hepatocyte, nuclear, factor, 4, alpha, '(', 'HNF4A),', transcription, factor, 7, like, 2, '(', 'TCF7L2),', forkhead, box, 'A1', '(', 'FOXA1)', and, 'A2', '(', 'FOXA2),', and, potentially, affected, the, binding, of, miRNAs, and, protein, phosphorylation])].
[sujeto(['The', results]), verbo([provide]), complemento([objectives, and, clues, for, future, experimental, studies, and, further, insights, into, the, molecular, pathogenesis, of, 'T2D'])].
[sujeto(['Mutations', in, hepatocyte]), verbo([nuclear]), complemento([factor, 1, transcription, factors, '(', 'HNF1α/β)', are, associated, with, diabetes])].
[sujeto(['However,', they, also]), verbo([have]), complemento([an, important, role, in, the, biology, of, many, other, 'tissues,', including, the, intestine])].
[sujeto(['We', used, chromatin, immunoprecipitation, followed, by, direct, sequencing, '(', 'ChIP-seq)', to, identify, 'HNF1']), verbo([binding]), complemento([sites, 'genome-wide'])].
[sujeto(['Direct']), verbo([targets]), complemento([of, 'HNF1', were, validated, using, conventional, 'ChIP', assays, and, confirmed, by, 'siRNA-mediated', depletion, of, 'HNF1,', followed, by, 'RT-qPCR'])].
[sujeto(['Gene', ontology, process, enrichment, analysis, of, the, 'HNF1']), verbo([targets]), complemento([identified, multiple, processes, with, a, role, in, intestinal, epithelial, cell, 'function,', including, properties, of, the, cell, 'membrane,', cellular, response, to, 'hormones,', and, regulation, of, biosynthetic, processes])].
[sujeto(['Approximately', 50, '%', of, 'HNF1']), verbo([binding]), complemento([sites, were, also, occupied, by, other, members, of, the, intestinal, transcriptional, 'network,', including, hepatocyte, nuclear, factor, 4, 'A', '(', 'HNF4A),', caudal, type, homeobox, 2, '(', 'CDX2),', and, forkhead, box, 'A2', '(', 'FOXA2)'])].
[sujeto(['Depletion', of, 'HNF1', in, 'Caco2', cells]), verbo([increases]), complemento(['FOXA2', abundance, and, decreases, levels, of, 'CDX2,', illustrating, the, coordinated, activities, of, the, network])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'HNF1', plays, an, important, role, in, regulating, intestinal, epithelial, cell, 'function,', both, directly, and, through, interactions, with, other, intestinal, transcription, factors])].
[sujeto(['The', transcription, factor, forkhead, box, protein, 'A2', '(', 'FOXA2,', also, known, as, hepatocyte]), verbo([nuclear]), complemento([factor, 3, β, or, transcription, factor, 3, 'β),', has, been, found, to, play, pivotal, roles, in, multiple, phases, of, mammalian, 'life,', from, the, early, development, to, the, 'organofaction,', and, subsequently, in, homeostasis, and, metabolism, in, the, adult])].
[sujeto(['In', the, embryonic, development, 'period,', 'FOXA2', is]), verbo([require]), complemento([d, for, the, formation, of, the, primitive, node, and, 'notochord,', and, its, absence, results, in, embryonic, lethality])].
[sujeto(['Leukotriene', pathway, and, signal, transducers, and, activators, of, transcription, 6, pathway, may]), verbo([mediate]), complemento([this, inflammation, through, recruitment, and, activation, of, denditric, cell, during, lung, developments])].
[sujeto(['FOXA2', is, a, potential, treatment]), verbo([target]), complemento([for, lung, diseases, with, 'Th2', inflammation, and, goblet, cell, 'hyperplasia,', such, as, asthma, and, chronic, obstructive, pulmonary, disease])].
[sujeto(['In', this, 'study,', by, using, a, combination, of, chemical, inhibition, and, genetic, approaches, in, zebrafish, and, murine, 'cells,', we, identify, a, mechanism, by, which, cPLA2α]), verbo([promotes]), complemento([cell, proliferation])].
[sujeto(['We', identified, 2, cpla2α, genes, in, 'zebrafish,', cpla2αa, and, 'cpla2αb,', with]), verbo([conserved]), complemento([phospholipase, activity])].
[sujeto(['In', 'zebrafish,']), verbo([loss]), complemento([of, cpla2α, expression, or, inhibition, of, cpla2α, activity, diminished, 'G1', progression, through, the, cell, cycle])].
[sujeto(['We', further, show, that, 'PGE2,', through, 'PI3K/AKT', 'activation,']), verbo([promoted]), complemento(['Forkhead', box, protein, 'O1', '(', 'FOXO1)', phosphorylation, and, 'FOXO1', nuclear, export])].
[sujeto(['This']), verbo([led]), complemento([to, 'up-regulation', of, cyclin, 'D1', and, 'down-regulation', of, 'p27(Kip1),', thus, promoting, 'G1', progression])].
[sujeto(['Finally,', using, pharmacologic, 'inhibitors,', we, show, that, 'cPLA2α,', rapidly, accelerated, fibrosarcoma, '(', 'RAF)/MEK/ERK,', and, 'PI3K/AKT', signaling, pathways, cooperatively]), verbo([regulate]), complemento(['G1', progression, in, response, to, 'platelet-derived', growth, factor, stimulation])].
[sujeto(['In', 'summary,', these, data, indicate, that, 'cPLA2α,', through, its, phospholipase, 'activity,', is, a, critical, effector, of, 'G1', phase, progression, through, the, cell, cycle, and]), verbo([suggest]), complemento([that, pharmacological, targeting, of, this, enzyme, may, have, important, therapeutic, benefits, in, disease, mechanisms, that, involve, excessive, cell, 'proliferation,', in, 'particular,', cancer, and, proliferative, glomerulopathies])].
[sujeto(['The']), verbo([nuclear]), complemento(['receptor,', pregnane, 'X', receptor, '(', 'PXR),', is, a, key, transcription, factor, for, the, 'xenobiotic-induced', expression, of, genes, associated, with, various, liver, functions])].
[sujeto(['Recently,', we]), verbo([reported]), complemento([that, 'PXR', activation, stimulates, 'xenobiotic-induced', hepatocyte, proliferation])].
[sujeto(['In', the, present, 'study,', we, investigated, whether, 'PXR', activation, also]), verbo([stimulates]), complemento([growth, 'factor-mediated', hepatocyte, proliferation])].
[sujeto(['In', 'G0', 'phase-synchronized,', immortalized, mouse, 'hepatocytes,', serum, or, epidermal, growth, factor, treatment]), verbo([increased]), complemento([cell, growth, and, this, growth, was, augmented, by, the, expression, of, mouse, 'PXR', and, 'co-treatment', with, pregnenolone, 16, 'α-carbonitrile', '(', 'PCN),', a, 'PXR', ligand])].
[sujeto(['In', a, liver, regeneration, model, using, carbon, 'tetrachloride,', 'PCN', treatment]), verbo([enhanced]), complemento([the, 'injury-induced', increase, in, the, number, of, 'Ki-67-positive', nuclei, as, well, as, 'Ccna2', and, 'Ccnb1', mRNA, levels, in, 'wild-type', '(', 'WT)', but, not, 'Pxr-null', mice])].
[sujeto(['Chronological', analysis, of, this, model, demonstrated, that, 'PCN', treatment, shifted, the, maximum, cell, proliferation, to, an, earlier, time, point, and]), verbo([increased]), complemento([the, number, of, 'M-phase', cells, at, those, time, points])].
[sujeto(['In', 'WT', but, not, 'Pxr-null', 'mice,', 'PCN', treatment, reduced, hepatic, mRNA, levels, of, genes]), verbo([involved]), complemento([in, the, suppression, of, 'G0/G1-', and, 'G1/S-phase', 'transition,', e])].
[sujeto(['Analysis', of, the, 'Rbl2', promoter, revealed, that, 'PXR', activation]), verbo([inhibited]), complemento([its, 'Forkhead', box, 'O3', '(', 'FOXO3)-mediated', transcription])].
[sujeto(['Finally,', the, 'PXR-mediated', enhancement, of, hepatocyte, proliferation, was]), verbo([inhibited]), complemento([by, the, expression, of, dominant, active, 'FOXO3', 'in&nbsp;vitro'])].
[sujeto(['The', results, of, the, present, study]), verbo([suggest]), complemento([that, 'PXR', activation, stimulates, growth, 'factor-mediated', hepatocyte, proliferation, in, 'mice,', at, least, in, 'part,', through, inhibiting, 'FOXO3', from, accelerating, 'cell-cycle', progression])].
[sujeto(['The']), verbo([binding]), complemento([activity, of, 'H3/H4', histone, on, the, 'Ets-1', 'promoter,', and, that, of, forkhead, box, '(', 'FOX)A2,', 'FOXO1', and, 'Ets-1', on, the, 'Pdx-1', promoter, was, measured, by, chromatin, immunoprecipitation, and, quantitative, 'real-time', 'PCR', assay])].
[sujeto(['High', glucose]), verbo([induced]), complemento([upregulation, of, 'Ets-1', expression, and, hyperacetylation, of, histone, 'H3', and, 'H4', at, the, 'Ets-1', gene, promoter, in, beta, cells])].
[sujeto(['Ets-1', overexpression, dramatically]), verbo([suppressed]), complemento([insulin, secretion, and, biosynthesis, both, in, vivo, and, in, vitro])].
[sujeto(['Besides,', 'Ets-1', overexpression]), verbo([increased]), complemento([the, activity, of, 'FOXO1', but, decreased, that, of, 'FOXA2', binding, to, the, pancreatic, and, duodenal, homeobox, 1, '(', 'PDX-1)', homology, region, 2, '(', 'PH2),', resulting, in, inhibition, of, 'Pdx-1', promoter, activity, and, downregulation, of, 'PDX-1', expression, and, activity])].
[sujeto(['In', 'addition,', high, glucose]), verbo([promoted]), complemento([the, interaction, of, 'Ets-1', and, 'FOXO1,', and, the, activity, of, 'Ets-1', binding, to, the, 'Pdx-1', promoter])].
[sujeto(['Importantly,', 'PDX-1', overexpression, reversed, the, defect, in, pancreatic, beta, cells]), verbo([induced]), complemento([by, 'Ets-1', 'excess,', while, knockdown, of, 'Ets-1', prevented, 'hyperglycaemia-induced', dysfunction, of, pancreatic, beta, cells])].
[sujeto(['Our', observations]), verbo([suggest]), complemento([that, 'Ets-1', links, glucotoxicity, to, pancreatic, beta, cell, dysfunction, through, inhibiting, 'PDX-1', expression, in, type, 2, diabetes])].
[sujeto(['Cellular', metabolism, is, increasingly]), verbo([recognized]), complemento([as, a, controller, of, immune, cell, fate, and, function])].
[sujeto(['MicroRNA-33', '(', 'miR-33)']), verbo([regulates]), complemento([cellular, lipid, metabolism, and, represses, genes, involved, in, cholesterol, 'efflux,', 'HDL', 'biogenesis,', and, fatty, acid, oxidation])].
[sujeto(['Macrophage-specific', 'Mir33', deletion]), verbo([increased]), complemento([oxidative, 'respiration,', enhanced, spare, respiratory, 'capacity,', and, induced, an, 'M2', macrophage, 'polarization-associated', gene, profile])].
[sujeto(['Furthermore,', 'miR-33-mediated', 'M2', polarization]), verbo([required]), complemento(['miR-33', targeting, of, the, energy, sensor, 'AMP-activated', protein, kinase, '(', 'AMPK),', but, not, cholesterol, efflux])].
[sujeto(['Notably,', 'miR-33', inhibition]), verbo([increased]), complemento([macrophage, expression, of, the, retinoic, 'acid-producing', enzyme, aldehyde, dehydrogenase, family, 1, ',', subfamily, 'A2', '(', 'ALDH1A2)', and, retinal, dehydrogenase, activity, both, in, vitro, and, in, a, mouse, model])].
[sujeto(['Consistent', with, the, ability, of, retinoic, acid, to, foster, inducible, 'Tregs,', 'miR-33-depleted', macrophages, had, an]), verbo([enhanced]), complemento([capacity, to, induce, forkhead, box, 'P3', '(', 'FOXP3)', expression, in, naive, 'CD4(+)', 'T', cells])].
[sujeto(['Collectively,', these, results]), verbo([reveal]), complemento([that, 'miR-33', regulates, macrophage, inflammation, and, demonstrate, that, 'miR-33', antagonism, is, 'atheroprotective,', in, 'part,', by, reducing, plaque, inflammation, by, promoting, 'M2', macrophage, polarization, and, 'Treg', induction])].
[sujeto(['IL-13']), verbo([increases]), complemento([mucin, '(', 'MUC)', 5, 'AC,', the, major, component, of, airway, 'mucus,', in, airway, epithelial, cells])].
[sujeto(['According', to, the, 'literature,', 'IL-13', receptor, activation]), verbo([leads]), complemento([to, 'STAT6', activation, and, consequent, induction, of, chloride, channel, accessory, 1, '(', 'CLCA1)', gene, 'expression,', associated, with, the, induction, of, 'MUC5AC'])].
[sujeto(['Heme', 'oxygenase-1', '(', 'HO-1)', is, an, enzyme, that, catalyzes, oxidation, of, heme, to, 'biliverdin,', and]), verbo([has]), complemento(['anti-inflammatory', and, 'anti-oxidant', properties])].
[sujeto(['We', examined, the, effects, of, 'HO-1', on, mucin, production, and, goblet, cell, hyperplasia]), verbo([induced]), complemento([by, 'IL-13'])].
[sujeto(['Hemin', '(', 4, 'μM)', significantly]), verbo([increased]), complemento(['HO-1', protein, expression, '(', p, b, 0.01, ')', and, 'HO-1', mRNA, expression, '(', p, b, 0.001, ')'])].
[sujeto(['IL-13', significantly]), verbo([increased]), complemento([goblet, 'cells,', 'MUC5AC', protein, secretion, '(', p, b, 0.01, ')', and, 'MUC5AC', mRNA, '(', p, b, 0.001, ')', ',', and, these, were, decreased, by, hemin, by, way, of, 'HO-1'])].
[sujeto(['Hemin']), verbo([decreased]), complemento([the, expression, of, 'CLCA1', mRNA, '(', p, b, 0.05, ')', and, it, was, reversed, by, 'SnPP-IX,', but, could, not, suppress, 'IL-13-induced', phosphorylation, of, 'STAT6', or, 'SAM', pointed, 'domain-containing', 'ETS', transcription, factor, '(', 'SPDEF)', and, 'Forkhead', box, 'A2', '(', 'FOXA2)', mRNA, expression])].
[sujeto(['In', 'summary,', 'HO-1', overexpression]), verbo([suppressed]), complemento(['IL-13-induced', goblet, cell, hyperplasia, and, 'MUC5AC', 'production,', and, involvement, of, 'CLCA1', in, the, mechanism, was, suggested])].
[sujeto(['To', show, the, efficient, generation, of, 'hepatocyte-like', cells, '(', 'HLCs)', differentiated, from, the]), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'iPSCs)', of, rats])].
[sujeto(['Then', fibroblast, growth, factor, 4, and, bone, morphogenetic, protein, 2, were, added, to, the, culture, medium, and, used, to]), verbo([induce]), complemento([hepatic, differentiation])].
[sujeto(['After', endodermal, 'induction,', the, differentiated, cells]), verbo([expressed]), complemento([endodermal, markers, forkhead, box, protein, 'A2', and, 'SRY-box', containing, gene, 17, at, the, mRNA, and, protein, levels])].
[sujeto(['These', differentiated, cells]), verbo([expressed]), complemento([hepatic, markers, including, 'α-fetoprotein,', albumin, 'CK8,', 'CK18,', 'CK19,', and, transcription, factor, 'HNF-4α'])].
[sujeto(['In', 'addition,', the, cells]), verbo([expressed]), complemento([functional, proteins, such, as, 'α1-antitrypsin,', cytochrome, 'P450', 1, 'A2', and, 'CYP', 3, 'A4'])].
[sujeto(['They']), verbo([acted]), complemento([like, healthy, hepatic, 'cells,', storing, glycogen, and, taking, up, indocyanine, green, and, 'low-density', lipoproteins])].
[sujeto(['Also,', the, rates, of, urea, synthesis, '(', 20, d, 1.202, ±, 0.08, 'mg/dL', vs, 0, d, 0.317, ±, 0.021, 'mg/dL,', 'P', &, 'lt;', 0.01, ')', and, albumin, secretion, '(', 20, d, 1.601, ±, 0.102, 'mg/dL', vs, 0, d, 0.313, ±, 0.015, 'mg/dL,', 'P', &, 'lt;', 0.01, ')']), verbo([increased]), complemento([significantly, as, differentiation, progressed])].
[sujeto(['Hepatocyte-like', cells, differentiated, from, human, pluripotent, stem, cells, '(', such, as, human, embryonic, stem, '(', 'ES)', cells, and]), verbo([induced]), complemento([pluripotent, stem, '(', 'iPS)', 'cells)', are, expected, to, be, utilized, in, drug, screening])].
[sujeto(['To']), verbo([enhance]), complemento([this, hepatocyte, differentiation, 'efficiency,', 'hepatocyte-related', transcription, 'factors,', such, as, forkhead, box, protein, 'A2', '(', 'FOXA2)', and, hepatocyte, nuclear, factor, 1, alpha, '(', 'HNF1α),', were, overexpressed, during, the, hepatocyte, differentiation, process])].
[sujeto(['In', 'addition,', to]), verbo([enhance]), complemento([the, functions, of, 'hepatocyte-like', 'cells,', these, cells, were, cultured, in, three, dimensional, '(', 3, 'D)', conditions, using, a, 'Nanopillar', plate])].
[sujeto(['Various', hepatic, 'functions,', including, albumin, secretion, and, drug, metabolism, 'capacities,', of, the, 'hepatocyte-like', cells, were, significantly]), verbo([enhanced]), complemento([by, performing, 3, 'D', cell, culture])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, method, of, hepatocyte, differentiation, could, be, improved, by, using, gene, transfer, and, 3, 'D', cell, culture, technologies])].
[sujeto(['The', enterohormone, 'glucagon-like', 'peptide-1', '(', 'GLP-1)', is]), verbo([required]), complemento([to, amplify, 'glucose-induced', insulin, secretion, that, facilitates, peripheral, glucose, utilisation])].
[sujeto(['Alteration', in, 'GLP-1', secretion, during, obesity]), verbo([has]), complemento([been, reported, but, is, still, controversial])].
[sujeto(['Due', to, the, high, adaptability, of, intestinal, cells, to, environmental, 'changes,', we, hypothesised, that, the, density, of, 'GLP-1-producing', cells, could, be, modified, by, nutritional, factors, to]), verbo([prevent]), complemento([the, deterioration, of, metabolic, condition, in, obesity])].
[sujeto(['Mice', fed, a, 'HFD', for, 8, weeks, displayed, an]), verbo([increase]), complemento([in, 'GLP-1-positive', cells, in, the, jejunum, and, colon, accordingly, to, 'GLP-1', secretion])].
[sujeto(['Moreover,', genetically, obese, 'ob/ob', mice, did, not, show, alteration, of, 'GLP-1-positive', cell, density, in, the, jejunum, or, 'colon,']), verbo([suggesting]), complemento([that, obesity, per, se, is, not, sufficient, to, trigger, the, mechanism])].
[sujeto(['The', higher, 'L-cell', density, in, 'HFD-fed', mice]), verbo([involved]), complemento([a, rise, in, 'L-cell', terminal, differentiation, as, witnessed, by, the, increased, expression, of, transcription, factors, downstream, of, neurogenin3, '(', 'Ngn3)'])].
[sujeto(['We']), verbo([suggest]), complemento([that, the, observed, increase, in, 'GLP-1-positive', cell, density, triggered, by, high, fat, consumption, in, humans, and, mice, might, favour, insulin, secretion, and, therefore, constitute, an, adaptive, response, of, the, intestine, to, balance, 'diet-induced', insulin, resistance])].
[sujeto(['Despite', the, better, prognosis, of, embryonal, 'RMS,', patients, in, the, 'E2', are, likely, to]), verbo([have]), complemento([a, poor, prognosis])].
[sujeto(['It']), verbo([has]), complemento([been, shown, that, acetylcholine, is, both, a, neurotransmitter, and, acts, as, a, local, 'mediator,', produced, by, airway, cells, including, epithelial, cells])].
[sujeto(['In', vivo, studies]), verbo([have]), complemento([demonstrated, an, indirect, role, for, acetylcholine, in, epithelial, cell, differentiation])].
[sujeto(['Human', airway, epithelial, cells]), verbo([expressed]), complemento([all, components, of, the, 'non-neuronal', cholinergic, 'system,', suggesting, acetylcholine, production])].
[sujeto(['Differentiation', into, goblet, cells, was, barely]), verbo([induced]), complemento([after, air, exposure])].
[sujeto(['Therefore,', 'IL-13', '(', 1, 'ng/mL)', was, used, to]), verbo([induce]), complemento([goblet, cell, metaplasia])].
[sujeto(['IL-13']), verbo([induced]), complemento(['MUC5AC-positive', cells, '(', 5, -, 'fold)', and, goblet, cells, '(', 14, -, 'fold),', as, assessed, by, 'histochemistry,', and, 'MUC5AC', gene, expression, '(', 105, -, 'fold)'])].
[sujeto(['These', effects, were, partly]), verbo([prevented]), complemento([by, tiotropium, '(', 47, -, 92, '%', ')'])].
[sujeto(['Goblet', cell, metaplasia, was]), verbo([induced]), complemento([by, 'IL-13', in, a, 'dose-dependent', 'manner,', which, was, inhibited, by, tiotropium])].
[sujeto(['In', 'addition,', tiotropium, reversed, goblet, cell, metaplasia]), verbo([induced]), complemento([by, 2, weeks, of, 'IL-13', exposure])].
[sujeto(['IL-13']), verbo([decreased]), complemento([forkhead, box, protein, 'A2', '(', 'FoxA2)', expression, '(', 1.6, -, 'fold)', and, increased, 'FoxA3', '(', 3.6, -, 'fold)', and, 'SAM-pointed', 'domain-containing', 'ETS', transcription, factor, '(', 'SPDEF)', '(', 5.2, -, 'fold)', expression])].
[sujeto(['Tiotropium']), verbo([prevented]), complemento([the, effects, on, 'FoxA2', and, 'FoxA3,', but, not, on, 'SPDEF'])].
[sujeto(['We', demonstrate, that, tiotropium]), verbo([has]), complemento([no, effects, on, epithelial, cell, differentiation, after, air, 'exposure,', but, inhibits, and, reverses, 'IL-13-induced', goblet, cell, 'metaplasia,', possibly, via, 'FoxA2', and, 'FoxA3'])].
[sujeto(['Their', importance, in]), verbo([regulating]), complemento([biological, processes, in, the, lung, and, liver, is, extensively, 'characterized,', though, much, less, is, known, about, their, role, in, intestine])].
[sujeto(['FOXA2']), verbo([binding]), complemento([sites, 'genome-wide', were, determined, by, 'ChIP-seq', and, direct, targets, of, the, factor, were, validated, by, 'ChIP-qPCR', and, 'siRNA-mediated', depletion, of, 'FOXA1/2', followed, by, 'RT-qPCR'])].
[sujeto(['Depletion', of, both, 'FOXA1', and, 'FOXA2']), verbo([led]), complemento([to, a, significant, reduction, in, the, expression, of, multiple, transmembrane, proteins, including, ion, channels, and, 'transporters,', which, form, a, network, that, is, essential, for, maintaining, normal, ion, and, solute, transport])].
[sujeto(['One', of, the]), verbo([targets]), complemento([was, the, adenosine, 'A2B', 'receptor,', and, reduced, receptor, mRNA, levels, were, associated, with, a, functional, decrease, in, intracellular, cyclic, 'AMP'])].
[sujeto(['We', also, observed, that, 30, '%', of, 'FOXA2']), verbo([binding]), complemento([sites, contained, a, 'GATA', motif, and, that, 'FOXA1/A2', depletion, reduced, 'GATA-4,', but, not, 'GATA-6', protein, levels])].
[sujeto(['These', data, show, that, 'FOXA2', plays, a, pivotal, role, in]), verbo([regulating]), complemento([intestinal, epithelial, cell, function])].
[sujeto(['Moreover,', that, the, 'FOXA', and, 'GATA', families, of, transcription, factors, may, work, cooperatively, to]), verbo([regulate]), complemento([gene, expression, 'genome-wide', in, the, intestinal, epithelium])].
[sujeto(['While', chronic, elevation, of, 'FBG', is, detrimental, to, 'health,', glucocorticoids]), verbo([induce]), complemento(['G6PC2', expression, suggesting, that, 'G6PC2', evolved, to, transiently, modulate, 'FBG', under, conditions, of, 'glucocorticoid-related', stress])].
[sujeto(['We', show, using, competition, and, mutagenesis, 'experiments,', that, the, synthetic, glucocorticoid, dexamethasone, '(', 'Dex)']), verbo([induces]), complemento(['G6PC2', promoter, activity, through, a, mechanism, involving, displacement, of, the, 'islet-enriched', transcription, factor, 'MafA', by, the, glucocorticoid, receptor])].
[sujeto(['The', induction, of, 'G6PC2', promoter, activity, by, 'Dex', is]), verbo([modulated]), complemento([by, a, single, nucleotide, 'polymorphism,', previously, linked, to, altered, 'FBG', in, 'humans,', that, affects, 'FOXA2', binding])].
[sujeto(['Acute', 'Dex', treatment, only]), verbo([induces]), complemento(['G6pc2', expression, in, 129, 'SvEv', but, not, 'C57BL/6J', mice, but, this, chronic, treatment, induced, 'G6pc2', expression, in, both])].
[sujeto(['In', 6, hr, fasted, 'C57BL/6J', wild, type, '(', 'WT)', 'mice,', 'Dex', treatment, lowered, 'FBG', and, improved, glucose, 'tolerance,', with, 'G6pc2', deletion, exacerbating, the]), verbo([decrease]), complemento([in, 'FBG', and, enhancing, the, improvement, in, glucose, tolerance])].
[sujeto(['In', 'contrast,', in, 24, hr, fasted, 'C57BL/6J', 'WT', 'mice,', 'Dex', treatment, raised, 'FBG', but, still, improved, glucose, 'tolerance,', with, 'G6pc2', deletion, limiting, the]), verbo([increase]), complemento([in, 'FBG', and, enhancing, the, improvement, in, glucose, tolerance])].
[sujeto(['These', observations, demonstrate, that, 'G6pc2']), verbo([modulates]), complemento([the, complex, effects, of, 'Dex', on, both, 'FBG', and, glucose, tolerance])].
[sujeto(['We', show, characteristic, morphological, changes, corresponding, to, 'epithelial-mesenchymal', transition, '(', 'EMT)', program, fulfillment, in, 'PANC1', cell, line]), verbo([stimulated]), complemento([with, 'TGFβ1'])].
[sujeto(['We', show, 5, -, and, 28, -, fold]), verbo([increase]), complemento([in, 'SNAI1', and, 'SNAI2', expression, levels, and, 25, -, and, 15, -, fold, decrease, in, 'CDH1', and, 'KRT8', expression, 'levels,', 'respectively,', which, confirms, the, 'EMT-program', fulfillment])].
[sujeto(['We', demonstrate, downregulation, of, expression, of, pancreatic, master, genes, 'SOX9,', 'FOXA2,', and, 'GATA4', '(', 2, -, ',', 5, -, ',', and, 4, -, 'fold,', 'respectively)', and, absence, of, significant, changes, in, 'HES1,', 'NR5A2,', and, 'GATA6', expression, levels, in, the, cells]), verbo([stimulated]), complemento([with, 'TGFβ1'])].
[sujeto([1, ',', and, 'ONECUT1', 'genes,', which, are, inactive, in, 'PANC1', cell, line, after, the, 'EMT']), verbo([stimulated]), complemento([by, 'TGFβ1'])].
[sujeto(['Consequently,', the, contribution, of, 'intestine-enriched', factors]), verbo([expressed]), complemento([within, 'BO', to, oncogenesis, is, unclear])].
[sujeto(['Herein,', using, transcriptomics, we, define, the, 'intestine-enriched', genes]), verbo([expressed]), complemento([in, 'meta-profiles', of, 'BO', and, 'OAC'])].
[sujeto(['Interestingly,', 77, '%', of, the, genes, differentially]), verbo([expressed]), complemento([in, a, 'meta-profile', of, 'BO', were, similarly, expressed, in, intestinal, tissues])].
[sujeto(['Furthermore,', 85, '%', of, this, 'intestine-like', signature, was]), verbo([maintained]), complemento([upon, transition, to, 'OAC'])].
[sujeto(['Simulated', acid, reflux, was, observed, to]), verbo([induce]), complemento([the, expression, of, both, 'NR5A2', and, 'GATA6'])].
[sujeto(['Abrogation', of, 'NR5A2-GATA6', expression, in, conjunction, with, 'BCL-XL', 'co-silencing', resulted, in, synergistically]), verbo([increased]), complemento([sensitivity, to, chemotherapeutics, and, 'photo-dynamic', therapeutics])].
[sujeto(['These', findings, characterize, the, 'intestine-like', signature]), verbo([associated]), complemento([with, 'IM', which, may, have, important, consequences, to, adenocarcinogenesis])].
[sujeto(['Transcription', factors, that, play, key, roles, in]), verbo([regulating]), complemento([pancreatic, progenitor, state, have, been, 'identified,', but, the, chromatin, regulators, that, help, establishing, and, maintaining, pancreatic, fate, are, less, well, known])].
[sujeto(['We', show, that, 'Setd7', is]), verbo([expressed]), complemento([in, the, prospective, pancreatic, endoderm, of, 'Xenopus', and, mouse, embryos, prior, to, 'Pdx1', induction])].
[sujeto(['Importantly,', we, demonstrate, that, setd7, is, sufficient, and]), verbo([required]), complemento([for, pancreatic, cell, fate, specification, in, 'Xenopus', 'Functional', and, biochemical, approaches, in, 'Xenopus', and, mouse, endoderm, support, that, 'Setd7', modulates, methylation, marks, at, pancreatic, regulatory, 'regions,', possibly, through, interaction, with, the, transcription, factor, 'Foxa2'])].
[sujeto(['Together,', these, results, demonstrate, that, 'Setd7']), verbo([acts]), complemento([as, a, central, component, of, the, transcription, complex, initiating, the, pancreatic, program])].
[sujeto(['Recently,', the, 'US', 'FDA']), verbo([has]), complemento([approved, &, 'quot;vagal', blocking, therapy, or, 'vBLoc®', 'therapy&quot;', as, a, new, treatment, for, obesity])].
[sujeto(['Rats', were, implanted, with, 'VBLOC,', an, 'intra-abdominal', electrical, device, with]), verbo([leads]), complemento([placed, around, gastric, vagal, trunks, through, an, abdominal, incision, and, controlled, by, wireless, device])].
[sujeto(['VBLOC', reduced, body, weight, and, food, 'intake,', which, was]), verbo([associated]), complemento([with, increased, satiety, but, not, with, decreased, hunger])].
[sujeto(['Brain', activities, in, response, to, 'VBLOC', included]), verbo([increased]), complemento([gene, expression, of, leptin, and, 'CCKb', 'receptors,', 'interleukin-1β,', tumor, necrosis, 'factor,', and, transforming, growth, factor, β1, in, the, 'brainstem;', increased, 'CCK,', 'somatostatin,', and, tyrosine, hydroxylase, in, the, 'hippocampus;', increased, 'NPY,', 'AgRP,', and, 'Foxa2', in, the, 'hypothalamus;', and, reduced, 'CCKb', 'receptor,', melanocortin, 4, 'receptor,', and, insulin, receptor, in, the, hypothalamus])].
[sujeto(['Based', on, the, present, 'study,', we, may]), verbo([suggest]), complemento([that, 'VBLOC', induces, satiety, through, vagal, 'signaling,', leading, to, reduced, food, intake, and, loss, of, body, weight])].
[sujeto(['Because', the, original, 'N27', cell, line]), verbo([has]), complemento([been, passaged, many, 'times,', the, line, has, become, a, mixture, of, cell, types, with, highly, variable, expression, of, 'TH'])].
[sujeto(['In', the, current, 'study,', we]), verbo([have]), complemento([performed, multiple, rounds, of, clonal, cultures, and, have, identified, a, dopaminergic, cell, clone, expressing, high, levels, of, 'TH', and, the, dopamine, transporter, '(', 'DAT)'])].
[sujeto(['We']), verbo([have]), complemento([named, this, new, clone, 'N27-A'])].
[sujeto(['Nearly', 100, '%', of, 'N27-A', cells]), verbo([express]), complemento(['TH,', 'DAT', and, 'Tuj1'])].
[sujeto(['Western', blots]), verbo([have]), complemento([confirmed, that, 'N27-A', cells, have, three, to, four, times, the, levels, of, 'TH', and, 'DAT', compared, to, the, previous, mixed, population, in, 'N27'])].
[sujeto(['Further', analysis]), verbo([has]), complemento([shown, that, the, new, clone, expresses, the, dopamine, neuron, transcription, factors, 'Nurr1,', 'En1,', 'FoxA2', and, 'Pitx3'])].
[sujeto(['The', 'N27-A', cells]), verbo([express]), complemento([the, vesicular, monoamine, transporter, '(', 'VMAT2),', but, do, not, express, 'dopamine-beta-hydroxylase', '(', 'DβH),', the, enzyme, responsible, for, converting, dopamine, to, norepinephrine])].
[sujeto(['Functional', analysis]), verbo([has]), complemento([shown, that, 'N27-A', cells, are, more, sensitive, than, 'N27', cells, to, neurotoxins, taken, up, by, the, dopamine, transporter, such, as, 6, -, hydroxydopamine, and, 1, -, 'methyl-4-phenylpyridine', '(', 'MPP+)'])].
[sujeto(['The', 'DAT', inhibitor, nomifensine, can, block, 'MPP+']), verbo([induced]), complemento([toxicity])].
[sujeto(['The', 'N27-A', cells, show, dopamine]), verbo([release]), complemento([under, basal, and, depolarization, conditions])].
[sujeto(['We', conclude, that, the, new, 'N27-A', clone, of, the, immortalized, rat, dopaminergic, cell, line, 'N27', should]), verbo([provide]), complemento([an, improved, in, vitro, model, for, 'Parkinson\'s', disease, research])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF4α),', a, critical, transcription, 'factor,', plays, an, essential, role, in, the, entire, process, of, liver, development])].
[sujeto(['In', hepatocyte, culture, 'medium,', 'HNF4α-transduced', 'MSCs', '(', 'E7-hHNF4α', 'cells)', strongly]), verbo([expressed]), complemento([the, albumin, '(', 'ALB),', 'CYP2B6,', 'alpha-1', antitrypsin, '(', 'AAT),', and, 'FOXA2', mRNA, and, exhibited, morphology, markedly, similar, to, that, of, mature, hepatocytes])].
[sujeto(['Approximately', 28, '%', of, 'E7-hHNF4α', cells]), verbo([expressed]), complemento([both, 'ALB', and, 'AAT'])].
[sujeto(['Furthermore,', these, 'E7-hHNF4α', cells, via, superior, mesenteric, vein, '(', 'SMV)', injection]), verbo([expressed]), complemento([human, 'ALB', in, mouse, chronic, injured, liver])].
[sujeto(['In', 'conclusion,', this, study, represents, a, novel, strategy, by, directly]), verbo([inducing]), complemento(['hepatocyte-like', cells, from, 'MSCs'])].
[sujeto(['The', ultraweb, 'NF']), verbo([caused]), complemento([better, proliferation, and, characterization, of, 'MSCs'])].
[sujeto(['MSCs', transplantation, significantly, improved, liver, 'functions,']), verbo([increased]), complemento([hepatic, 'HGF', and, 'Bcl-2', 'levels,', whereas, decreased, serum, 'fibronectin,', hepatic, 'TNF-α', and, 'TGF-β1', levels])].
[sujeto(['Hepatic', 'HNF4α,', 'FOXa2,', 'CYP7a1', genes, expression, were]), verbo([enhanced]), complemento([while, 'β-5-Tub', and, 'AFP', genes, expression, were, depressed])].
[sujeto(['ELOVL', family, member, 6, ',', elongation, of, very, long, chain, fatty, acids, '(', 'Elovl6)', is, a, microsomal, 'enzyme,', which]), verbo([regulates]), complemento([the, elongation, of, 'C12-16', saturated, and, monounsaturated, fatty, acids])].
[sujeto(['Elovl6']), verbo([has]), complemento([been, shown, to, be, associated, with, various, pathophysiologies, including, insulin, 'resistance,', 'atherosclerosis,', and, 'non-alcoholic', steatohepatitis])].
[sujeto(['Histological', analysis, revealed, a, reduced, length, of, proliferating, and, an, elongated, length, of, hypertrophic, chondrocyte, 'layer,', and]), verbo([decreased]), complemento([trabecular, bone, in, 'Elovl6-/-', mice, compared, with, controls])].
[sujeto(['These', results, were, presumably, due, to, a, modest]), verbo([decrease]), complemento([in, chondrocyte, proliferation, and, accelerated, differentiation, of, cells, of, the, chondrocyte, lineage])].
[sujeto(['Consistent', with, the]), verbo([increased]), complemento([length, of, the, hypertrophic, chondrocyte, layer, in, 'Elovl6-/-', 'mice,', 'Collagen10α1', was, identified, as, one, of, the, most, affected, genes, by, ablation, of, 'Elovl6', in, chondrocytes])].
[sujeto(['Furthermore,', this, elevated, expression, of, 'Collagen10α1', of, 'Elovl6-null', chondrocytes, was, likely]), verbo([associated]), complemento([with, increased, levels, of, 'Foxa2/a3', and, 'Mef2c', mRNA, expression])].
[sujeto(['Relative']), verbo([increases]), complemento([in, protein, levels, of, nuclear, 'Foxa2', and, cytoplasmic, histone, deacethylase, 4, /, 5, /, 7, were, also, observed, in, 'Elovl6', knockdown, cells, of, the, chondrocyte, lineage])].
[sujeto(['Collectively,', our, data]), verbo([suggest]), complemento([that, 'Elovl6', plays, a, critical, role, for, proper, development, of, embryonic, growth, plate])].
[sujeto(['Studies', in, cultured, cell, lines, and, mice]), verbo([have]), complemento([shown, a, loss, of, 'ZIC2', function, is, the, pathogenic, mechanism, but, the, molecular, details, of, this, 'ZIC2', requirement, remain, elusive])].
[sujeto(['An', intact, 'NODAL', signal, transduction, pathway, and, functional, 'ZIC2', are, both]), verbo([required]), complemento([for, 'PrCP', establishment])].
[sujeto(['We', now, show, that, 'ZIC2']), verbo([acts]), complemento([downstream, of, the, 'NODAL', signal, during, 'PrCP', development])].
[sujeto(['ZIC2', physically]), verbo([interacts]), complemento([with, 'SMAD2', and, 'SMAD3,', the, receptor, activated, proteins, that, control, transcription, in, a, 'NODAL', dependent, manner])].
[sujeto(['Together', 'SMAD3', and, 'ZIC2']), verbo([regulate]), complemento(['FOXA2', transcription, in, cultured, cells, and, 'Zic2', also, controls, the, foxA2, expression, during, 'Xenopus', development])].
[sujeto(['Variant', forms, of, the, 'ZIC2', 'protein,']), verbo([associated]), complemento([with, 'HPE', in, man, or, 'mouse,', are, deficient, in, their, ability, to, influence, 'SMAD-dependent', transcription])].
[sujeto(['These', findings]), verbo([reveal]), complemento([a, new, mechanism, of, 'NODAL', signal, transduction, in, the, mammalian, node, and, provide, the, first, molecular, explanation, of, how, 'ZIC2', 'loss-of-function', precipitates, 'HPE'])].
[sujeto(['Although', much, attention]), verbo([has]), complemento([been, given, to, explore, its, clinical, 'application,', research, of, the, basic, mechanisms, of, 'HE4', in, ovarian, cancer, are, still, unclear])].
[sujeto(['In', the, present, 'study,', we]), verbo([provide]), complemento([fundamental, data, to, identify, 'full-scale', differentially, expressed, genes, '(', 'DEGs)', in, response, to, 'HE4', by, use, of, human, 'whole-genome', microarrays, in, human, epithelial, ovarian, cancer, cell, line, 'ES-2', following, overexpression, and, silencing, of, 'HE4'])].
[sujeto(['We']), verbo([found]), complemento([that, a, total, of, 717, &, 'nbsp;genes', were, upregulated, and, 898, &, 'nbsp;genes', were, downregulated, in, the, 'HE4-overexpressing', cells, vs])].
[sujeto(['These', 'DEGs', were]), verbo([involved]), complemento([in, 'MAPK,', steroid, 'biosynthesis,', cell, 'cycle,', the, p53, hypoxia, 'pathway,', and, focal, adhesion, pathways])].
[sujeto(['Interaction', network, analysis, predicted, that, the, genes]), verbo([participated]), complemento([in, the, regulatory, connection])].
[sujeto(['We']), verbo([found]), complemento([that, 'SERPIND1', may, act, as, a, potential, oncogene, in, the, development, of, ovarian, cancer])].
[sujeto(['These', identified, genes, may]), verbo([provide]), complemento([a, theoretical, basis, for, investigations, of, the, underlying, molecular, mechanism, of, 'HE4', in, ovarian, cancer])].
[sujeto(['The', soluble, form, of, activin, 'A', '(', 'Act)']), verbo([has]), complemento([been, widely, used, as, an, in, vitro, inducer, of, definitive, endoderm, '(', 'DE)'])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([developed, a, nanofibrous, poly, '(', 'ɛ-caprolactone)', 'substrate,', biofunctionalized, with, 'Act,', for, directed, differentiation, of, hESCs, into, 'DE'])].
[sujeto(['The', nanofibers, with, covalent, iAct, significantly]), verbo([increased]), complemento([expression, levels, of, the, endodermal, markers, 'SOX17,', 'FOXA2,', and, 'CXCR4,', compared, with, physically, adsorbed, 'Act', '(', 'aAct)', or, without, 'Act', '(', 'noAct)'])].
[sujeto(['In', 'addition,', iAct]), verbo([retained]), complemento([its, bioactivity, after, storage, for, five, days, in, the, absence, of, cell, seeding])].
[sujeto(['Hypoxia']), verbo([has]), complemento([been, demonstrated, to, play, an, important, role, in, embryonic, formation, and, development, and, to, modulate, stem, cell, differentiation])].
[sujeto(['However,', the, influence, of, oxygen, tension, on, thyroid, differentiation]), verbo([has]), complemento([not, been, studied])].
[sujeto(['In', this, 'study,', we, used, murine]), verbo([induced]), complemento([pluripotent, stem, '(', 'iPS)', cells, for, thyroid, cell, differentiation, under, normoxic, and, hypoxic, conditions, and, compared, differentiation, efficiency, in, 'morphology,', 'function,', gene, and, protein, expression, under, both, conditions])].
[sujeto(['We']), verbo([found]), complemento([that, hypoxia, promoted, adhesion, and, outgrowth, of, embryoid, bodies, '(', 'EBs)', derived, from, murine, iPS, cells])].
[sujeto([1, ')', was]), verbo([increased]), complemento([by, hypoxia, at, both, gene, and, protein, levels, during, 'early-mid', differentiation, stages, '(', 'p&lt;0'])].
[sujeto(['In', 'addition,', functional, iodide, uptake, by, differentiated, cells, was, also]), verbo([increased]), complemento([after, hypoxia])].
[sujeto(['Thyroid', differentiation, from, iPS, cells, is]), verbo([enhanced]), complemento([under, hypoxia, and, this, may, involve, hypoxia, inducible, factors, '(', 'HIFs)', and, their, downstream, gene, 'FGF2'])].
[sujeto(['Our', data, offer, a, foundation, for, understanding, thyroid, development, and]), verbo([provide]), complemento([a, potentially, more, efficient, way, to, use, cell, therapy, for, treating, thyroid, deficiency])].
[sujeto([:, 'The', progressive, death, of, dopamine, producing, neurons, in, the, substantia, nigra, pars, compacta, is, the, principal]), verbo([cause]), complemento([of, symptoms, of, 'Parkinson\'s', disease, '(', 'PD)'])].
[sujeto(['Stem', cells]), verbo([have]), complemento([potential, therapeutic, use, in, replacing, these, cells, and, restoring, function])].
[sujeto(['To', this, 'end,', we, differentiated, baboon, 'fibroblast-derived']), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'biPSCs)', into, dopaminergic, neurons, with, the, application, of, specific, morphogens, and, growth, factors])].
[sujeto(['We', confirmed, that, 'biPSC-derived', dopaminergic, neurons, resemble, those]), verbo([found]), complemento([in, the, human, midbrain, based, on, cell, 'type-specific', expression, of, dopamine, markers, 'TH', and, 'GIRK2'])].
[sujeto(['Using', the, reverse, transcriptase, quantitative, polymerase, chain, 'reaction,', we, also, showed, that, 'biPSC-derived', dopaminergic, neurons]), verbo([express]), complemento(['PAX6,', 'FOXA2,', 'LMX1A,', 'NURR1,', and, 'TH', genes, characteristic, of, this, cell, type, in, vivo])].
[sujeto(['Finally,', we, showed, that, 'biPSC-derived', neurons]), verbo([released]), complemento([catecholamines, in, response, to, electrical, stimulation])].
[sujeto(['Functional', dopamine, neurons, were, produced, from, baboon]), verbo([induced]), complemento([pluripotent, stem, 'cells,', and, their, properties, were, compared, to, baboon, midbrain, cells, in, vivo])].
[sujeto(['The', baboon]), verbo([has]), complemento([advantages, as, a, clinically, relevant, model, in, which, to, optimize, the, efficacy, and, safety, of, stem, 'cell-based', therapies, for, neurodegenerative, 'diseases,', such, as, 'Parkinson\'s', disease])].
[sujeto(['However,', it, is, currently, unclear, how, these, embryonic, tissue, interactions, can, be]), verbo([translated]), complemento([into, a, defined, differentiation, protocol, for, human, embryonic, stem, cells])].
[sujeto(['Activin', 'A']), verbo([has]), complemento([been, proposed, to, direct, 'DE', into, a, 'SOX2-positive', 'foregut-like', cell, type])].
[sujeto(['We', show, in, contrast, to, previous, studies, that, the, generation, of, the, foregut, marked, by, 'SOX2/FOXA2', 'double-positive', cells, does, not, depend, on, activin, 'A/TGF-β-signaling', but, is]), verbo([mediated]), complemento([by, the, inhibition, of, 'Wnt-', and, 'BMP-signaling'])].
[sujeto(['Retinoic', acid, can, posteriorize, and, at, the, same, time, dorsalize, the, foregut, toward, a, 'PDX1-positive', pancreatic, duodenal, cell, type, whereas, active, 'Wnt/beta-catenin', signaling, synergistically, with, 'FGF-2,', 'BMP-4,', and, 'RA']), verbo([induces]), complemento([the, formation, of, 'CDX2-positive', posterior, endoderm])].
[sujeto(['Thus,', these, results]), verbo([provide]), complemento([new, insights, into, the, mechanisms, behind, cell, specification, of, human, 'DE', derived, from, pluripotent, stem, cells])].
[sujeto(['While', orthotopic, transplantation, into, the, testis]), verbo([promotes]), complemento([seminomatous, growth, of, the, 'seminoma-like', cell, line, 'TCam-2,', ectopic, xenotransplantation, into, the, flank, initiates, reprogramming, into, an, 'EC-like', fate])].
[sujeto(['During', this, 'reprogramming,', 'BMP', signaling, is, 'inhibited,']), verbo([leading]), complemento([to, induction, of, 'NODAL', 'signaling,', upregulation, of, pluripotency, factors, and, downregulation, of, seminoma, 'markers,', like, 'SOX17'])].
[sujeto(['In', 'contrast,', the, pioneer, factor, 'FOXA2', and, its]), verbo([target]), complemento([genes, were, 'upregulated,', suggesting, that, 'FOXA2', might, play, an, important, role, in, induction, of, 'non-seminomatous', differentiation])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, exposure, to, phenyl, ethyl, alcohol, '(', 'PEA)', causes, an, increase, in, the, expression, of, the, transcription, factor, otx2, in, the, olfactory, epithelium, '(', 'OE)', of, juvenile, 'zebrafish,', and, this, change, is, correlated, with, the, formation, of, an, odor, memory, of, 'PEA'])].
[sujeto(['Subsequent', in, silico, analysis, uncovered, 'Hnf3b']), verbo([binding]), complemento([sites, closely, associated, with, 'Otx2', binding, sites, in, the, regions, flanking, the, 'ORs'])].
[sujeto(['Analysis', by, quantitative, polymerase, chain, reaction, and, 'RNA-seq', of, 'OR', expression, in, developing, zebrafish, exposed, to, different, isoforms, of, 'PEA', showed, that, a, subset, of, 'ORs', containing, both, 'Otx2/Hnf3b']), verbo([binding]), complemento([sites, were, downregulated, only, in, 'βPEA-exposed', juveniles, and, this, change, persisted, through, adult, life])].
[sujeto(['Localization', of, 'OR', expression, by, in, situ, hybridization, indicates, the, downregulation, occurs, at, the, level, of, 'RNA', and, not, the, number, of, cells]), verbo([expressing]), complemento([a, given, receptor])].
[sujeto(['Finally,', analysis, of, immediate, early, gene, expression, in, the, 'OE', did, not]), verbo([reveal]), complemento([changes, in, 'c-fos', expression, in, response, to, either, αPEA, or, βPEA])].
[sujeto(['To', identify, differentially]), verbo([expressed]), complemento([genes, '(', 'DEGs)', and, find, associated, pathways, that, may, function, as, targets, of, lung, cancer])].
[sujeto(['Besides,', novel, genes]), verbo([associated]), complemento([with, lung, cancer, were, identified, by, 'co-expression', analysis])].
[sujeto(['Then,', 'GO', enrichment, and, transcription]), verbo([binding]), complemento([site, analysis, were, performed, on, these, 'DEGs,', and, novel, genes, were, predicted, using, 'DAVID'])].
[sujeto(['Finally,', 'PPI', network, was, constructed, by, 'String', software, in, order, to, get, the, hub, codes]), verbo([involved]), complemento([in, cancer, carcinoma])].
[sujeto(['The', transcription, biding, site, analysis, showed, that, these, genes, were]), verbo([regulated]), complemento([by, 'LHX3,', 'HNF3B,', 'CDP,', 'HFH1,', 'FOXO4,', 'STAT,', 'SOX5,', 'MEF2,', 'FOXO3', and, 'SRY'])].
[sujeto(['Hub', codes, as, 'BUB1B,', 'MAD2L', and, 'TOP2A', may, play, as]), verbo([target]), complemento([genes, in, lung, carcinoma, in, the, result, of, 'PPI', network, analysis])].
[sujeto(['Newly', predicted, genes, and, hub, codes, can, perform, as]), verbo([target]), complemento([genes, for, diagnose, and, clinical, therapy, of, lung, cancer])].
[sujeto(['SSCs', first, changed, into, hepatic, 'stem-like', cells, since, they, resembled, hepatic, oval, cells, in, morphology, and]), verbo([expressed]), complemento(['Ck8,', 'Ck18,', 'Ck7,', 'Ck19,', 'OV6,', and, albumin])].
[sujeto(['Notably,', these, differentiated, cells, acquired, functional, attributes, of, 'hepatocyte-like', cells, because, they, secreted, 'albumin,', synthesized, 'urea,', and, uptake, and]), verbo([released]), complemento([indocyanine, green])].
[sujeto(['Moreover,', phosphorylation, of, 'ERK1/2', and, 'Smad2/3', rather, than, 'Akt', was]), verbo([activated]), complemento([in, hepatic, stem, cells, and, mature, hepatocytes])].
[sujeto(['This', study, thus]), verbo([provides]), complemento([an, invaluable, source, of, mature, hepatocytes, for, treating, 'liver-related', diseases, and, drug, toxicity, screening, and, offers, novel, insights, into, mechanisms, of, liver, development, and, cell, reprogramming])].
[sujeto(['This', gene]), verbo([has]), complemento([a, 'CpG', island, extending, 2500, bp, from, the, translational, start, 'site;', 'however,', studies, characterizing, its, transcriptional, regulation, have, not, been, conducted])].
[sujeto(['Two', transcripts, for, 'DAPK', were, identified, that, code, for, a, single, 'protein,', while, being]), verbo([regulated]), complemento([by, two, promoters])].
[sujeto(['The', previously, identified, 'DAPK', transcript, designated, as, exon, 1, transcript, was]), verbo([expressed]), complemento([at, levels, 3, -, fold, greater, than, the, alternate, exon, 1, b, transcript])].
[sujeto(['Sequencing', the, 'DAPK', 'CpG', island, in, tumor, cell, lines, revealed, 'dense,', but, heterogenous, methylation, of, 'CpGs', that, blocked, access, of, the, 'CP2', and, 'HNF3B', proteins, that, in, 'turn,', was]), verbo([associated]), complemento([with, loss, of, transcription, that, was, restored, by, treatment, with, 5, -, 'aza-2\'-deoxycytidine'])].
[sujeto(['Growing', evidence, indicates, that, microRNAs]), verbo([have]), complemento([a, significant, role, in, tumor, development, and, may, constitute, robust, biomarkers, for, cancer, diagnosis, and, prognosis])].
[sujeto(['We']), verbo([report]), complemento([that, 'miR-122', is, specifically, repressed, in, a, subset, of, primary, tumors, that, are, characterized, by, poor, prognosis])].
[sujeto(['We', further, show, that, the]), verbo([loss]), complemento([of, 'miR-122', expression, in, tumor, cells, segregates, with, specific, gene, expression, profiles, linked, to, cancer, 'progression,', namely, the, suppression, of, hepatic, phenotype, and, the, acquisition, of, invasive, properties])].
[sujeto(['We', identify, 'liver-enriched', transcription, factors, as, central, regulatory, molecules, in, the, gene, networks]), verbo([associated]), complemento([with, loss, of, 'miR-122,', and, provide, evidence, suggesting, that, 'miR-122', is, under, the, transcriptional, control, of, 'HNF1A,', 'HNF3A', and, 'HNF3B'])].
[sujeto(['We', further, show, that]), verbo([loss]), complemento([of, 'miR-122', results, in, an, increase, of, cell, migration, and, invasion, and, that, restoration, of, 'miR-122', reverses, this, phenotype])].
[sujeto(['One', known, genetic, mechanism, for, transient, neonatal, diabetes, is]), verbo([loss]), complemento([of, methylation, at, 6, q24])].
[sujeto(['The', etiology, of, prune, belly, sequence, is, unknown, but, a, genetic, 'defect,', affecting, the, mesoderm, from, which, the, triad, abdominal, muscle, 'hypoplasia,', urinary, tract, 'abnormalities,', and, cryptorchidism, 'develop,']), verbo([has]), complemento([been, suggested])].
[sujeto(['The', proband, had]), verbo([loss]), complemento([of, methylation, at, the, 6, q24, locus, 'TNDM', and, also, at, the, loci, 'IGF2R,', 'DIRAS3,', and, 'PEG1,', while, the, other, family, 'members,', including, the, healthy, monozygotic, 'twin,', had, normal, findings])].
[sujeto(['The']), verbo([loss]), complemento([of, methylation, on, chromosome, 6, q24, and, elsewhere, may, indicate, a, generalized, maternal, hypomethylation, 'syndrome,', which, accounts, for, both, transient, neonatal, diabetes, and, prune, belly, sequence])].
[sujeto(['Mammalian', 'tissue-', 'and/or', 'time-specific', transcription, is, primarily]), verbo([regulated]), complemento([in, a, combinatorial, fashion, through, interactions, between, a, specific, set, of, transcriptional, regulatory, factors, '(', 'TRFs)', and, their, cognate, 'cis-regulatory', elements, located, in, the, regulatory, regions])].
[sujeto(['In', exploring, the, 'DNA', regions, and, 'TRFs']), verbo([involved]), complemento([in, combinatorial, transcriptional, 'regulation,', we, noted, that, individual, knockdown, of, a, set, of, human, 'liver-enriched', 'TRFs', such, as, 'HNF1A,', 'HNF3A,', 'HNF3B,', 'HNF3G', and, 'HNF4A', resulted, in, perturbation, of, the, expression, of, several, single, 'TRF', 'genes,', such, as, 'HNF1A,', 'HNF3G', and, 'CEBPA', genes])].
[sujeto(['We', thus, searched, the, potential]), verbo([binding]), complemento([sites, for, these, five, 'TRFs', in, the, highly, conserved, genomic, regions, around, these, three, 'TRF', genes, and, found, several, putative, combinatorial, regulatory, regions])].
[sujeto(['Chromatin', immunoprecipitation, analysis, revealed, that, almost, all, of, the, putative, regulatory, 'DNA', regions, were]), verbo([bound]), complemento([by, the, 'TRFs', as, well, as, two, coactivators, '(', 'CBP', and, 'p300)'])].
[sujeto(['EMSA', demonstrated, specific, bindings, of, these, 'HNFs', to, the]), verbo([target]), complemento(['DNA', region])].
[sujeto(['The', 'liver-specific', activity, of, 'ENII', is]), verbo([regulated]), complemento([by, multiple, 'liver-enriched', transcription, 'factors,', including, 'LRH-1/hB1F,', 'HNF1,', 'HNF3b,', 'HNF4', and, 'C/EBP'])].
[sujeto(['In', this, 'study,', we, demonstrate, a, functional, synergism, between, the, orphan]), verbo([nuclear]), complemento([receptor, 'LRH-1/hB1F', and, the, homeoprotein, 'HNF1', in, 'up-regulating', the, 'liver-specific', activity, of, 'ENII'])].
[sujeto(['We']), verbo([have]), complemento([defined, the, activation, domains, in, hB1F, and, 'HNF1', that, contribute, to, the, synergism])].
[sujeto(['We', further, show, that, hB1F, and, 'HNF1', can]), verbo([interact]), complemento([directly, in, vitro, and, have, mapped, the, domains, required, for, this, interaction])].
[sujeto(['Angiotensin', 'II']), verbo([has]), complemento([been, shown, to, exert, complex, effects, on, proximal, tubular, cell, function, and, growth])].
[sujeto(['We', used, 'DNA', microarrays, to, analyze, multiple, gene, expression, responses, to]), verbo([increasing]), complemento([angiotensin, 'II', concentrations])].
[sujeto(['Coordinated', changes, were, observed, in, genes, of, the, hepatocyte]), verbo([nuclear]), complemento([factor, 3, family, '(', 'NHF3;', 'HNF3A,', 'HNF3B', and, 'HNF3G),', in, the, 'E2F', genes, '(', 'E2F1,', 'E2F3)', and, the, interferon, regulatory, factors, 'IRF1', and, 'IRF5'])].
[sujeto(['Three', genes]), verbo([involved]), complemento([in, the, dampening, of, oxidative, stress, were, enhanced])].
[sujeto(['Taken', 'together,', brief, exposure, of, human, tubular, epithelial, cells, to, angiotensin, 'II', elicited, a, marked, induction, of]), verbo([nuclear]), complemento(['factors,', antioxidant, genes, and, hormones, and, hormone, receptor, genes])].
[sujeto(['We']), verbo([have]), complemento([discovered, two, 'single-nucleotide', polymorphisms, in, the, 5, '\'', flanking, region, of, the, 'HFE', gene])].
[sujeto(['When', a, 'T', was, present, at, -, 970, ',', a, 'C', was, always]), verbo([found]), complemento([at, -, 467])].
[sujeto(['The', less, common, -, 467, mutation, was]), verbo([found]), complemento([in, almost, 12, chromosomes, that, bore, the, 845, 'G--&gt;A', '(', 'C282Y)', mutation, and, was, significantly, more, prevalent, in, chromosomes, containing, the, 187, 'C--&gt;G', '(', 'H63D)', mutation])].
[sujeto(['The', tighter, association, of, the, -, 467, polymorphism, with, the, 'C282Y', mutation, is, consistent, with, other, data, that]), verbo([suggest]), complemento([that, the, 'C282Y', mutation, has, occurred, relatively, recently, and, that, the, 'H63D', mutation, is, considerably, older])].
[sujeto(['DNase', 'I', footprinting, from, mouse, cells, revealed, that, several, potential, 'cis-elements', were, occupied, by]), verbo([nuclear]), complemento([proteins])].
[sujeto(['Our', data]), verbo([provide]), complemento([insight, into, the, regulatory, mechanisms, that, govern, the, expression, of, the, 'MAP1A', gene])].
[sujeto(['Mutations', in, genes, encoding, hepatocyte]), verbo([nuclear]), complemento([factor, '(', 'HNF)', are, responsible, for, three, of, the, five, subtypes, of, 'maturity-onset', diabetes, of, the, young, '(', 'MODY)'])].
[sujeto(['This', observation, and, molecular, studies, indicate, that, the, 'HNF', network, is]), verbo([required]), complemento([for, normal, function, of, pancreatic, 'beta-cells'])].
[sujeto(['This']), verbo([suggests]), complemento([that, transcription, factors, involved, in, this, complex, network, are, candidates, for, genetic, defects, in, 'MODY'])].
[sujeto(['All', of, the, five, known, 'MODY', 'genes,', 'HNF-4alpha,', 'glucokinase,', 'HNF-1alpha,', 'HNF-1beta,', and, 'IPF1,', were, previously, excluded, as, being, the]), verbo([cause]), complemento([of, diabetes, in, these, families])].
[sujeto(['Familial', segregation, studies, and, linkage, analysis, showed, that, genetic, variation, in, the, 'HNF-3beta', gene, is, unlikely, to, be, the]), verbo([cause]), complemento([of, 'early-onset', type, 2, diabetes, in, these, 'Caucasian', families])].
[sujeto(['Mutations', in, the, transcription, factors, hepatocyte]), verbo([nuclear]), complemento([factor, '(', 'HNF)-4alpha', and, -, 1, 'alpha,', insulin, promoter, 'factor-1,', and, 'HNF-1beta', are, the, causes, of, four, forms, of, 'maturity-onset', diabetes, of, the, young, '(', 'MODY1', and, 3, -, 5, ',', 'respectively)'])].
[sujeto(['The', 'winged-helix', transcription, factor, 'HNF-3beta']), verbo([has]), complemento([been, implicated, in, the, regulation, of, expression, of, each, of, these, 'MODY', 'genes,', suggesting, that, mutations, in, the, 'HNF-3beta', gene, '(', 'HNF3B)', may, also, cause, 'MODY'])].
[sujeto(['We']), verbo([have]), complemento([tested, this, hypothesis, by, screening, a, panel, of, 57, unrelated, 'Japanese', subjects, with, a, clinical, diagnosis, of, 'MODY', for, mutations, in, 'HNF3B'])].
[sujeto(['This', analysis, revealed, four, frequent, polymorphisms, that, were, not]), verbo([associated]), complemento([with, 'MODY,', including, one, in, the, promoter, region, '(', -, 213, 'A/G),', two, silent, mutations, in, the, codons, for, 'Ala', 97, '(', 291, 'C/T)', and, 'Gly', 279, '(', 837, 'A/G),', and, one, in, the, 3, '\'', -, untranslated, region, '(', 1424, 'C/T)'])].
[sujeto(['Two', rare, substitutions, in, the, 5, '\'', -, untranslated, 'region,', -, 156, 'C/T', and, -, 67, 'A/C,', were]), verbo([found]), complemento([in, a, heterozygous, state, in, two, 'subjects,', and, two, subjects, were, heterozygous, for, putative, missense, 'mutations,', 'S109N', '(', 326, 'G', &, 'gt;', 'A)', and, 'A328V', '(', 983, 'C&gt;T)'])].
[sujeto(['The', two, missense, mutations, were, not]), verbo([found]), complemento([in, 106, normal, chromosomes, from, nondiabetic, subjects])].
[sujeto(['It', was, not, possible, to, test, for, 'co-segregation', of, these, mutations, with, diabetes, and, 'thus,', it, is, unclear, whether, or, not, these, mutations, can]), verbo([cause]), complemento(['MODY'])].
[sujeto(['The', results, of, our, study]), verbo([suggest]), complemento([that, mutations, in, 'HNF3B', are, not, a, common, cause, of, 'MODY', in, 'Japanese', subjects])].
[sujeto(['Small', heterodimer, partner, '(', 'SHP;', 'NR0B2)', is, an, atypical, orphan]), verbo([nuclear]), complemento([receptor, and, acts, as, a, coregulator, of, various, nuclear, receptors])].
[sujeto(['Herein,', we, examined, a, novel, cross, talk, between, 'SHP', and, a, forkhead, transcription, factor, 'HNF3', '(', hepatocyte]), verbo([nuclear]), complemento([factor, 3, /, 'Foxa'])].
[sujeto(['Transient', transfection, assay, demonstrated, that, 'SHP']), verbo([inhibited]), complemento([the, transcriptional, activity, of, all, three, isoforms, of, 'HNF3,', 'HNF3alpha,', 'beta,', and, gamma])].
[sujeto(['In', vivo, and, in, vitro, protein, interaction, studies, showed, that, 'SHP', physically]), verbo([interacted]), complemento([with, 'HNF3'])].
[sujeto(['Adenovirus-mediated', overexpression, of, 'SHP', significantly]), verbo([decreased]), complemento([the, mRNA, levels, of, 'glucose-6-phosphase', '(', 'G6Pase),', cholesterol, 7, -, 'alpha-hydroxylase', '(', 'CYP7A1),', and, phosphoenolpyruvate, carboxykinase, '(', 'PEPCK)', in, 'HepG2', cells, and, rat, primary, hepatocytes])].
[sujeto(['Moreover,', the, mRNA, level, of, 'G6Pase', was, notably]), verbo([increased]), complemento([by, 'down-regulation', of, 'SHP', with, small, interfering, 'RNA'])].
[sujeto(['Interestingly,', 'HNF3', transactivity, was, still]), verbo([repressed]), complemento([by, 'SHPDelta128-139', that, fails, to, repress, nuclear, receptors])].
[sujeto(['Mapping', of, interaction, domain, revealed, that, 'SHP']), verbo([interacted]), complemento([with, forkhead, 'DNA', binding, domain, of, 'HNF3alpha'])].
[sujeto(['Gel', mobility, shift, and, chromatin, immunoprecipitation, assays, demonstrated, that, 'SHP']), verbo([inhibits]), complemento(['DNA', binding, of, 'HNF3'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'SHP', is, involved, in, the, regulation, of, 'G6Pase,', 'CYP7A1,', and, 'PEPCK', gene, expression, via, novel, mechanism, of, inhibition, of, 'HNF3', activity, and, expand, the, role, of, 'SHP', as, a, coregulator, of, other, family, of, transcription, factors, in, addition, to, nuclear, receptors])].
[sujeto(['We']), verbo([have]), complemento([developed, a, protocol, of, differentiation, of, human, embryonic, stem, cells, '(', 'ES)', towards, 'hepatocyte-like', cells, '(', 'ES-Hep)'])].
[sujeto(['Using', a, set, of, human, adult, markers, including, 'CAAT/enhancer']), verbo([binding]), complemento([protein, '(', 'C/EBPalpha),', hepatocyte, nuclear, factor, 4, /, 7, ratio, '(', 'HNF4alpha1/HNF4alpha7),', cytochrome, 'P450', 7, 'A1', '(', 'CYP7A1),', 'CYP3A4', and, constitutive, androstane, receptor, '(', 'CAR),', and, fetal, markers, including, 'alpha-fetoprotein,', 'CYP3A7', and, glutathione, 'S-transferase', 'P1,', we, analyzed, the, expression, of, a, panel, of, 41, genes, in, 'ES-Hep', comparatively, with, human, adult, primary, 'hepatocytes,', adult, and, fetal, liver])].
[sujeto(['When', compared, with, 'hepatocyte-like', cells, derived, from, adult, liver, non, parenchymal, epithelial, '(', 'NPE)', cells, '(', 'NPE-Hep),', 'ES-Hep']), verbo([expressed]), complemento([several, adult, and, fetal, liver, makers, at, much, greater, levels, '(', at, least, one, order, of, 'magnitude),', consistent, with, greater, expression, of, 'liver-enriched', transcription, factors, 'Forkhead', box, 'A2,', 'C/EBPalpha,', 'HNF4alpha', and, 'HNF6'])].
[sujeto(['Finally', we, showed, that, 'lentivirus-mediated', expression, of, xenoreceptor, 'CAR', in, 'ES-Hep']), verbo([induced]), complemento([the, expression, of, several, detoxification, genes, including, 'CYP2B6,', 'CYP2C9,', 'CYP3A4,', 'UDP-glycosyltransferase', 1, 'A1,', solute, carriers, 21, 'A6,', as, well, as, biotransformation, of, 'midazolam,', a, 'CYP3A4-specific', substrate])].
[sujeto(['We']), verbo([found]), complemento([that, the, hepatic, differentiation, of, maGSCs, was, induced, by, the, 'OP9', 'co-culture', system, in, comparison, to, the, gelatin, culture])].
[sujeto(['Furthermore,', we, showed, that, the, combination, of, 'OP9', 'co-culture', with, activin, 'A', resulted, in, the]), verbo([increased]), complemento([expression, of, endodermal, and, early, hepatic, markers, 'Gata4,', 'Sox17,', 'Foxa2,', 'Hnf4,', 'Afp,', and, 'Ttr', compared, to, differentiated, cells, on, gelatin, or, on, 'OP9', alone])].
[sujeto(['These', generated, hepatic, cells, successfully, demonstrated, in, vitro, functions]), verbo([associated]), complemento([with, mature, 'hepatocytes,', including, albumin, and, urea, 'secretion,', glycogen, 'storage,', and, uptake, of, 'low-density', lipoprotein])].
[sujeto(['Specification', of, these, progenitors, with, bone, morphogenetic, 'protein-4', in, combination, with, basic, fibroblast, growth, factor, and, activin, 'A', results, in, the, development, of, hepatic, populations, highly, enriched, '(', 45, -, 70, '%', ')', for, cells, that]), verbo([express]), complemento([the, 'alpha-fetoprotein', and, albumin, proteins])].
[sujeto(['These', cells, also]), verbo([express]), complemento([transcripts, of, 'Afp,', 'Alb1,', 'Tat,', 'Cps1,', 'Cyp7a1', and, 'Cyp3a11;', they, secrete, 'albumin,', store, 'glycogen,', show, ultrastructural, characteristics, of, mature, 'hepatocytes,', and, are, able, to, integrate, into, and, proliferate, in, injured, livers, in, vivo, and, mature, into, hepatocytes, expressing, dipeptidyl, peptidase, 'IV', or, fumarylacetoacetate, hydrolase])].
[sujeto(['Together,', these, findings, establish, a, developmental, pathway, in, embryonic, stem, cell, differentiation, cultures, that]), verbo([leads]), complemento([to, efficient, generation, of, cells, with, an, immature, hepatocytic, phenotype])].
[sujeto(['The', aryl, hydrocarbon, receptor, '(', 'AhR)', is, a, 'ligand-activated', transcription, factor, that]), verbo([mediates]), complemento([diverse, dioxin, toxicities])].
[sujeto(['While', the, acute, effects, of, activation, of, the, 'AhR', pathway, by, 2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD)']), verbo([have]), complemento([been, a, focus, of, past, 'study,', the, role, of, this, pathway, in, normal, physiology, and, ageing, is, unclear])].
[sujeto(['Adult', pregnant, 'Lewis', rat, dams, were, dosed, with, corn, oil, vehicle, or, 'TCDD', '(', 50, 'ng/kg-week', by, 'gavage)', on, days, 14, and, 21, of, gestation, and, 'post-natal', days, 7, and, 14, to]), verbo([provide]), complemento([in, utero, and, lactational, '(', 'IUL)', exposure, to, pups])].
[sujeto(['Data', analysis, revealed, an, accelerated, onset, of, acyclicity, by, 5, months, in, all, groups]), verbo([involving]), complemento(['IUL', exposure, of, the, developing, ovary, to, 'TCDD'])].
[sujeto([17, 'beta-oestradiol', was, significantly]), verbo([decreased]), complemento([in, animals, receiving, 'TCDD', during, 'IUL', exposure, of, the, 'H-H', axis])].
[sujeto(['This', study]), verbo([reveals]), complemento([a, particular, sensitivity, of, the, developing, ovary, to, 'TCDD', leading, to, early, loss, of, reproductive, function, with, age])].
[sujeto(['Xenobiotic', and, drug, metabolism, and, transport, are, managed, by, a, large, number, of, genes, coordinately]), verbo([regulated]), complemento([by, at, least, three, nuclear, receptors, or, 'xenosensors:', aryl, hydrocarbon, receptor, '(', 'AhR),', constitutive, androstane, receptor, '(', 'CAR,', 'NR1I3),', and, pregnane, 'X', receptor, '(', 'PXR,', 'NR1I2)'])].
[sujeto(['Initially', characterized, as, 'xenosensors,', it, is, now, evident, that, 'CAR', and, 'PXR', also]), verbo([trigger]), complemento([pleiotropic, effects, on, liver, function])].
[sujeto(['Recent', studies]), verbo([have]), complemento([shown, the, existence, of, crosstalk, between, xenosensors, and, other, nuclear, receptors, or, transcription, factors, controlling, endogenous, signaling, pathways, which, regulate, physiological, functions])].
[sujeto(['Such', crosstalks, explain, clinical, observations, and]), verbo([provide]), complemento([molecular, mechanisms, allowing, understanding, how, xenobiotics, and, drugs, may, affect, physiological, functions, and, provoke, endocrine, disruptions])].
[sujeto(['Cytochrome', 'P450', 2, 'A2', '(', 'CYP2A2)', is, an, adult, 'male-specific', rat, liver, steroid, hydroxylase, whose, 'sex-dependent', expression, is]), verbo([regulated]), complemento([at, the, transcriptional, level, by, sexually, dimorphic, pituitary, growth, hormone, '(', 'GH)', secretory, patterns])].
[sujeto(['In', contrast, to, 'CYP2C11', and, other, 'male-specific,', plasma, 'GH', 'pulse-inducible', liver, 'genes,', 'CYP2A2', is, highly]), verbo([expressed]), complemento([in, hypophysectomized, rat, 'liver,', despite, the, absence, of, 'GH', stimulation])].
[sujeto(['A', further, approximately, 2.5, -, fold]), verbo([increase]), complemento([in, activity, was, obtained, by, cotransfection, of, hepatocyte, nuclear, factor, '(', 'HNF)', 3, gamma, or, 'HNF4alpha'])].
[sujeto(['CYP2A2', promoter, activity, was]), verbo([inhibited]), complemento([approximately, 85, '%', by, transfection, of, 'HNF3beta', or, 'HNF6,', both, of, which, are, more, highly, expressed, in, female, than, male, liver, and, can, strongly, 'trans-activate', the, 'female-specific', 'CYP2C12', promoter])].
[sujeto(['By', 'contrast,', 'STAT5b', synergistically]), verbo([enhanced]), complemento([the, transcriptional, activity, of, 'HNF4alpha', toward, two, other, 'male-specific', liver, target, 'genes,', 'Cyp2d9', and, 'CYP8B1'])].
[sujeto(['Furthermore,', 'STAT5b', in, combination, with, the, 'HNF4alpha', coactivator, peroxisome, 'proliferator-activated', receptor, gamma, 'coactivator-1alpha', strongly]), verbo([enhanced]), complemento([the, transcriptional, activity, of, 'HNF4alpha', toward, 'CYP8B1', but, not, toward, 'CYP2A2'])].
[sujeto(['These', findings, support, the, hypothesis, that, 'sex-dependent', 'HNFs', contribute, to, the, sexually, dimorphic, expression, of, 'CYP2A2', and, other, liver, 'CYPs', and, highlight, the, ability, of, 'STAT5b', to]), verbo([act]), complemento([in, concert, with, 'HNF4alpha', to, regulate, select, 'male-specific', liver, 'CYP', genes])].
[sujeto(['In', particular, the, parenchymal, liver, cells, or, hepatocytes, are]), verbo([targeted]), complemento([since, they, are, the, major, sites, of, drug, transport, and, of, metabolite, formation, and, thus, also, the, place, where, not, only, 'detoxification,', but, also, activation, of, new, chemical, '(', 'NCE)', and, biological, '(', 'NBE)', entities, may, occur])].
[sujeto(['However,', within, a, few, 'days,', they, undergo, dedifferentiation, with]), verbo([loss]), complemento([of, 'liver-specific', 'functionality,', including, xenobiotic, biotransformation, 'capacity,', making, them, only, suitable, for, 'short-term', applications])].
[sujeto(['A', plausible, alternative, to, primary, hepatocyte, cultures, that, can, be]), verbo([maintained]), complemento([for, longer, periods, of, time, could, be, the, use, of, 'liver-derived', epithelial, cell, lines, and, their, optimized, derivatives])].
[sujeto(['Undifferentiated', rLEC, stably]), verbo([express]), complemento([the, hepatic, progenitor, markers, 'CEBPA,', 'FOXA2,', 'GJA1,', 'ONECUT1,', 'KRT18', and, 'KRT19', for, at, least, 15, consecutive, passages, after, cryopreservation])].
[sujeto(['Upon', sequential, exposure, to, hepatogenic, growth, factors, and, 'cytokines,', rLEC, generate, functional, hepatic, 'progeny,']), verbo([expressing]), complemento([mature, hepatic, markers, including, 'Alb,', 'Ahr,', 'Car,', 'C/ebpα,', 'Cx32,', 'Foxa2,', 'Hnf1α,', 'Hnf1β', and, 'Onecut1'])].
[sujeto(['rLEC-derived', hepatic, cells, also, acquire, the, ability, to, store, 'glycogen,']), verbo([express]), complemento([genes, encoding, for, key, hepatic, enzymes, as, shown, by, 'Affymetrix', microarray, 'data,', and, display, stable, 'CYP1A1/2-', and, 'CYP2B1/2-dependent', activities, for, several, weeks, at, levels, comparable, to, those, observed, in, cultured, primary, rat, hepatocytes])].
[sujeto(['Many', different, markers]), verbo([have]), complemento([been, attributed, to, these, 'cells,', but, their, nature, still, remains, obscure])].
[sujeto(['This', study, is, a, detailed, gene, expression, analysis, aimed, at]), verbo([revealed]), complemento([their, identity, and, repopulating, in, vivo, capacity])].
[sujeto(['Oval', cells, were]), verbo([activated]), complemento([in, 2, -, 'acetylaminofluorene-treated', rats, subjected, to, partial, hepatectomy, or, in, 'D-galactosamine-treated', rats])].
[sujeto(['We']), verbo([found]), complemento([that, 'EpCAM(+)', and, 'Thy-1(+)', cells, represent, two, different, populations, of, cells, in, the, oval, cell, niche])].
[sujeto(['EpCAM(+)', cells]), verbo([express]), complemento([the, classical, oval, cell, markers, '(', 'alpha-fetoprotein,', 'cytokeratin-19,', 'OV-1', 'antigen,', a6, 'integrin,', and, connexin, 43, ')', ',', cell, surface, markers, recently, identified, by, us, '(', 'CD44,', 'CD24,', 'EpCAM,', aquaporin, 5, ',', 'claudin-4,', secretin, 'receptor,', 'claudin-7,', 'V-ros', sarcoma, virus, oncogene, homolog, 1, ',', cadherin, 22, ',', 'mucin-1,', and, 'CD133),', and, 'liver-enriched', transcription, factors, '(', forkhead, box, 'q,', forkhead, box, 'a2,', onecut, 1, ',', and, transcription, factor, 2, ')'])].
[sujeto(['Oval', cells, do, not]), verbo([express]), complemento([previously, reported, hematopoietic, stem, cell, markers, 'Thy-1,', 'c-kit,', and, 'CD34', or, the, neuroepithelial, marker, neural, cell, adhesion, molecule, 1])].
[sujeto(['However,', oval, cells]), verbo([express]), complemento([a, number, of, mesenchymal, markers, including, 'vimentin,', 'mesothelin,', bone, morphogenetic, protein, 7, ',', and, 'Tweak', receptor, '(', tumor, necrosis, factor, receptor, 'superfamily,', member, 12, 'A)'])].
[sujeto(['A', group, of, novel, differentially]), verbo([expressed]), complemento([oval, cell, genes, is, also, presented])].
[sujeto(['Transplantation', experiments]), verbo([reveal]), complemento([that, 'EpCAM(+)', cells, are, true, progenitors, capable, of, repopulating, injured, rat, liver])].
[sujeto(['We']), verbo([have]), complemento([shown, that, 'EpCAM(+)', oval, cells, are, bipotential, adult, hepatic, epithelial, progenitors])].
[sujeto(['These', cells, display, a, mixed, 'epithelial/mesenchymal', phenotype, that]), verbo([has]), complemento([not, been, recognized, previously])].
[sujeto(['Here', we]), verbo([report]), complemento([that, 'BCa', cells, are, dependent, on, a, mechanism, to, supply, precursors, for, intracellular, lipid, production, derived, from, extracellular, sources, and, that, the, endothelial, lipase, '(', 'LIPG)', fulfils, this, function])].
[sujeto(['LIPG', is, ubiquitously, and, highly]), verbo([expressed]), complemento([under, the, control, of, 'FoxA1', or, 'FoxA2', in, all, 'BCa', subtypes])].
[sujeto(['The', downregulation, of, either, 'LIPG', or, 'FoxA', in, transformed, cells, results, in]), verbo([decreased]), complemento([proliferation, and, impaired, synthesis, of, intracellular, lipids])].
[sujeto(['Limited', adult, dopaminergic, neurogenesis]), verbo([has]), complemento([led, to, novel, therapeutic, strategies, such, as, transplantation, of, dopaminergic, precursors, '(', 'DPs)'])].
[sujeto(['Here,', we, demonstrate, the, direct, conversion, of, mouse, fibroblasts, into]), verbo([induced]), complemento(['DPs', '(', 'iDPs)', by, ectopic, expression, of, 'Brn2,', 'Sox2', and, 'Foxa2'])].
[sujeto(['After', transplantation, into, 'MPTP-lesioned', 'mice,', iDPs, differentiated, into, 'DA', 'neurons,', functionally, alleviated, the, motor, 'deficits,', and, reduced, the]), verbo([loss]), complemento([of, striatal, 'DA', neuronal, axonal, termini])].
[sujeto(['We', propose, that, the, iDPs, from, direct, reprogramming]), verbo([provides]), complemento([a, safe, and, efficient, cell, source, for, 'PD', treatment])].
[sujeto(['Farnesol', is, a, 'non-cyclic', sesquiterpene, '(', 'isoprenoid)']), verbo([found]), complemento([in, the, essential, oils, of, many, plants])].
[sujeto(['Therefore,', farnesyltransferase, is, a]), verbo([target]), complemento([for, drug, development, to, inhibit, 'Ras'])].
[sujeto(['Tumors', frequently, develop, resistance, towards, standard, 'chemotherapies,', and, thus, novel, agents, are, urgently]), verbo([required]), complemento([that, bypass, the, 'cross-resistance', evoked, by, established, anticancer, drugs])].
[sujeto(['Remarkably,', none, of, these, genes]), verbo([conferred]), complemento([resistance, to, 'farnesol,', indicating, that, this, compound, may, be, useful, for, the, treatment, of, otherwise, 'drug-resistant', and, refractory, tumors, expressing, these, mechanisms, of, resistance])].
[sujeto(['Among', the, candidates, were, genes]), verbo([involved]), complemento([in, apoptosis, '(', 'STAB2,', 'NUMBL),', regulation, of, transcription, '(', 'CDYL,', 'FOXA2)', and, diverse, other, functional, groups, '(', 'INE1,', 'CTRL,', 'MRS2,', 'NEB,', 'LMO7,', 'C9orf3,', 'EHBP1)'])].
[sujeto(['The', fact, that, these, genes, are, not]), verbo([associated]), complemento([with, resistance, to, traditional, anticancer, drugs, suggests, farnesol, may, possess, a, novel, mechanism, of, 'action,', and, consequently, might, bypass, drug, resistance, to, established, chemotherapeutics])].
[sujeto(['We']), verbo([targeted]), complemento([the, reverse, tetracycline, controlled, transactivator, '(', 'rtTA)', to, the, 'Foxa2', locus, '(', 'Foxa2(ITA))', to, generate, a, system, for, regulating, 'Cre-recombinase', activity, within, 'Foxa2', expression, 'domains,', including, the, 'endoderm,', 'notochord,', and, floor, plate, of, early, mouse, embryos])].
[sujeto(['The', use, of, an, internal, ribosomal, entry, site, to, obtain, rtTA, expression, preserves, 'Foxa2', function, of, the]), verbo([targeted]), complemento([allele])].
[sujeto(['This', system, will]), verbo([provide]), complemento([a, useful, tool, for, manipulating, gene, expression, in, 'endoderm,', 'notochord,', and, floor, 'plate,', all, of, which, are, tissues, with, important, structural, and, patterning, functions, during, embryogenesis])].
[sujeto(['Since', the, lung, is, repeatedly, subjected, to, injury, by, pathogens, and, 'toxicants,', maintenance, of, pulmonary, homeostasis]), verbo([requires]), complemento([rapid, repair, of, its, epithelial, surfaces])].
[sujeto(['Expression', of, transcription, factors, active, in, morphogenesis, and, differentiation, of, the, embryonic, 'lung,', including, 'beta-catenin,', 'Foxa2,', 'Foxj1,', and, 'Sox', family, members, '(', 'Sox17', and, 'Sox2),', was, dynamically]), verbo([regulated]), complemento([during, repair, and, redifferentiation, of, the, bronchiolar, epithelium, after, naphthalene, injury])].
[sujeto(['Squamous', cells, derived, from, ciliated, cells, spread, beneath, injured, 'Clara', cells, within, 6, -, 12, h, after, 'injury,']), verbo([maintaining]), complemento([the, integrity, of, the, epithelium])].
[sujeto(['Agonists', for, the]), verbo([nuclear]), complemento([receptor, peroxisomal, 'proliferator-activated', 'receptor-gamma', '(', 'PPARgamma)', and, its, heterodimeric, 'partner,', retinoid, 'X', receptor, '(', 'RXR),', are, effective, agents, for, the, treatment, of, type, 2, diabetes])].
[sujeto(['To']), verbo([gain]), complemento([insight, into, the, antidiabetic, action, of, these, 'compounds,', we, treated, female, 'Zucker', diabetic, rats, '(', 'ZFF)', with, 'AGN194204,', which, we, show, to, be, a, 'homodimer-specific', 'RXR', 'agonist,', or, the, 'PPARgamma', 'agonist,', troglitazone])].
[sujeto(['AGN194204', had, no, effect, on, peripheral, glucose, 'utilization,', whereas, troglitazone]), verbo([increased]), complemento(['insulin-stimulated', glucose, utilization, by, 50, '%', ',', glucose, uptake, into, skeletal, muscle, by, 85, '%', ',', and, de, novo, skeletal, muscle, glycogen, synthesis, by, 300, '%'])].
[sujeto(['Troglitazone']), verbo([increased]), complemento([skeletal, muscle, 'Irs-1', and, 'phospho-Akt', levels, following, in, vivo, insulin, 'treatment,', whereas, 'AGN194204', increased, hepatic, 'Irs-2', and, insulin, stimulated, 'phospho-Akt', in, liver])].
[sujeto(['Gene', profiles, of, 'AGN194204-treated', mouse, liver, analyzed, by, 'Ingenuity', 'Pathway', 'Analysis', identified]), verbo([increases]), complemento([in, fatty, acid, synthetic, 'genes,', including, 'Srebp-1', and, fatty, acid, 'synthase,', a, pathway, previously, shown, to, be, induced, by, 'RXR', agonists])].
[sujeto(['A', network, of, 'down-regulated', genes, containing, 'Foxa2,', 'Foxa3,', and, 'G-protein', subunits, was, 'identified,', and]), verbo([decreases]), complemento([in, these, mRNA, levels, were, confirmed, by, quantitative, reverse, 'transcription-PCR'])].
[sujeto(['Treatment', of, 'HepG2', cells, with, 'AGN194204', resulted, in, inhibition, of, 'glucagon-stimulated', cAMP, accumulation]), verbo([suggesting]), complemento([the, 'G-protein', 'down-regulation', may, provide, an, additional, mechanism, for, hepatic, insulin, sensitization, by, 'RXR'])].
[sujeto(['These', studies, demonstrate, distinct, molecular, events]), verbo([lead]), complemento([to, insulin, sensitization, by, high, affinity, 'RXR', and, 'PPARgamma', agonists])].
[sujeto(['Although']), verbo([expressed]), complemento([in, all, cells, at, the, early, 'stages,', in, the, adult, it, is, mainly, restricted, to, the, 'beta-cell'])].
[sujeto(['DNase', 'I', footprinting, analysis, revealed, two, protected, 'regions,', one]), verbo([binding]), complemento([the, transcription, factors, 'SP1', and, 'SP3', and, the, other, hepatocyte, nuclear, factor, 3, beta, '(', 'HNF-3beta)', and, 'HNF-1alpha'])].
[sujeto(['Cotransfection', experiments]), verbo([suggest]), complemento([that, 'HNF-3beta,', 'HNF-1alpha,', and, 'SP1', are, positive, regulators, of, the, 'herein-described', human, 'PDX-1', enhancer, element])].
[sujeto(['Furthermore,', mutations, within, each, motif, abolished, the]), verbo([binding]), complemento([of, the, corresponding, 'factor(s)', and, dramatically, impaired, the, enhancer, 'activity,', therefore, suggesting, cooperativity, between, these, factors])].
[sujeto(['To', address, the, question, whether, these, enzymatic, alterations, result, from, specific, changes, in, the, levels, of, 'hepatocyte-enriched']), verbo([nuclear]), complemento([factors, '(', 'HNF),', we, analysed, the, mRNA, levels, of, six, different, 'HNFs', '(', 'HNF-1alpha,', 'beta,', 'HNF-3alpha,', 'beta,', 'gamma,', and, 'HNF-4)', by, 'RNase', protection, assay, in, chemically, induced, liver, tumours, and, corresponding, normal, liver, tissue, from, mice, of, three, different, strains])].
[sujeto(['When', compared, with, the, normal, liver, 'tissue,', 'HNF-1beta,', 'HNF-3alpha', and, 'HNF-3beta', showed, unchanged, expression, levels, in, the, various, liver, 'tumours,', which, 'HNF-1alpha', and, 'HNF-4', mRNAs, were, lowered, by, 20, -, 30, '%', ',', and, 'HNF-3gamma', mRNA, was]), verbo([increased]), complemento([by, 50, '%'])].
[sujeto(['RUNX1']), verbo([loss]), complemento([in, 'ER(+)', mammary, epithelial, cells, increases, 'β-catenin,', deregulates, mitosis, and, stimulates, cell, proliferation, and, expression, of, stem, cell, markers])].
[sujeto(['However,', it, does, not]), verbo([stimulate]), complemento(['LEF/TCF,', 'c-Myc', or, 'CCND1,', and, it, does, not, accelerate, 'G1/S', cell, cycle, phase, transition])].
[sujeto(['Finally,', 'RUNX1', 'loss-mediated', deregulation, of, 'β-catenin', and, mitosis, is, ameliorated, by, 'AXIN1', stabilization, in, 'vitro,', highlighting, 'AXIN1', as, a, potential]), verbo([target]), complemento([for, the, management, of, 'ER(+)', breast, cancer])].
[sujeto(['AML1-ETO', is, the, most, common, fusion, oncoprotein]), verbo([causing]), complemento([acute, myeloid, leukemia, '(', 'AML),', a, disease, with, a, 5, -, year, survival, rate, of, only, 24, '%'])].
[sujeto(['While', known, for, decades, to, be, the, translational, product, of, a, chimeric, gene, created, by, the, stable, chromosome, translocation, 't(8;21)(q22;q22),', it, is, not, known, how, 'AML1-ETO', achieves, its, native, and, functional, conformation, or, whether, this, process, can, be]), verbo([targeted]), complemento([for, therapeutic, benefit])].
[sujeto(['We', demonstrate, that, a, folding, intermediate, of, 'AML1-ETO']), verbo([binds]), complemento([to, 'TRiC', 'directly,', mainly, through, its, 'β-strand', 'rich,', 'DNA-binding', domain, '(', 'AML-(1-175)),', with, the, assistance, of, 'HSP70'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'TRiC', contributes, to, 'AML1-ETO', proteostasis, through, specific, interactions, between, the, 'oncoprotein\'s', 'DNA-binding', 'domain,', which, may, be, targeted, for, therapeutic, benefit])].
[sujeto(['Acute', myeloid, leukemia, '(', 'AML)', 1, -, 'Evi-1', is, a, chimeric, gene, generated, by, the, t, '(', 3, ;, 21, ')', '(', 'q26;', 'q22)', 'translocation,', which]), verbo([leads]), complemento([into, malignant, transformation, of, hematopoietic, stem, cells, by, unclear, mechanisms])].
[sujeto(['This', in, vivo, study, aimed, to, establish, a, stable, line, of, zebrafish]), verbo([expressing]), complemento([the, human, 'RUNX1-Evi-1', fusion, gene, under, the, control, of, a, heat, 'stress-inducible', bidirectional, 'promoter,', and, investigate, its, roles, in, hematopoiesis, and, hematologic, malignancies])].
[sujeto(['Consequently,', primitive, hematopoiesis, was]), verbo([enhanced]), complemento([by, upregulation, of, gata2, and, 'scl,', while, erythropoiesis, was, downregulated, due, to, the, suppression, of, gata1])].
[sujeto([1, ',', but, it, was]), verbo([inhibited]), complemento([along, with, the, low, expression, of, mpo])].
[sujeto(['Microarray', analysis, demonstrated, that, 'RUNX1-Evi-1', not, only, upregulated, 'proteasome,', cell, 'cycle,', 'glycolysis/gluconeogenesis,', tyrosine, 'metabolism,', drug, 'metabolism,', and, 'PPAR', 'pathway,', but, also]), verbo([suppressed]), complemento([transforming, growth, factor, 'β,', 'Jak-STAT,', 'DNA', 'replication,', mismatch, 'repair,', p53, 'pathway,', 'JNK', signaling, 'pathway,', and, nucleotide, excision, repair])].
[sujeto(['Factors', in, cell, proliferation, were, obviously]), verbo([suppressed]), complemento([after, 3, -, day, treatment, with, histone, deacetylase, 'inhibitor,', valproic, acid])].
[sujeto(['Accordingly,', higher, proportion, of, 'G1']), verbo([arrest]), complemento([and, apoptosis, were, manifested, by, the, propidium, iodide, staining])].
[sujeto(['RUNX1-Evi-1', may]), verbo([promote]), complemento([proliferation, and, apoptosis, resistance, of, primitive, hematopoietic, 'cell,', and, inhibit, the, differentiation, of, myeloid, cells, with, the, synergy, of, different, pathways, and, factors])].
[sujeto(['VPA', may, be, a, promising, choice, in, the, molecular]), verbo([targeting]), complemento([therapy, of, 'RUNX1-Evi-1-related', leukemia])].
[sujeto(['Two', distantly, located, promoter, regions]), verbo([regulate]), complemento([the, dynamic, expression, of, 'RUNX', genes, during, 'development:', distal, 'P1', and, proximal, 'P2', promoters])].
[sujeto(['We']), verbo([have]), complemento([recently, described, that, 'β-catenin', increases, total, 'Runx1', mRNA, levels, in, human, 'CD34(+)', hematopoietic, progenitors, and, enhances, spatial, proximity, with, its, translocation, partner, 'ETO'])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, induction, of, 'Wnt/β-catenin', signaling, in, 'HL60', and, 'Jurkat', 'leukemia-derived', cell, lines, and, 'CD34(+)', progenitors, selectively, activate, the, production, of, the, longer, distal, 'P1-Runx1', mRNA, isoform])].
[sujeto(['Gain-', and, 'loss-of-function', experiments, revealed, that, the, differential]), verbo([increase]), complemento([in, 'P1-Runx1', expression, is, accomplished, through, a, minimal, 'β-catenin', responsive, region, that, includes, a, highly, conserved, 'TCF/LEF-binding', 'element,', located, -, 20, /, -, 16, bp, upstream, of, the, canonical, distal, 'P1-Runx1', transcription, start, site])].
[sujeto(['We', conclude, that, the, distal, 'P1-Runx1', promoter, is, a, direct, transcriptional]), verbo([target]), complemento([of, 'Wnt/β-catenin', signaling, that, may, be, important, in, normal, hematopoiesis, or, its, transition, into, malignant, stem, cells, during, the, onset, or, progression, of, leukemia])].
[sujeto(['The', generation, of, diverse, neuronal, subtypes]), verbo([involves]), complemento([specification, of, neural, progenitors, 'and,', 'subsequently,', postmitotic, neuronal, 'differentiation,', a, relatively, poorly, understood, process])].
[sujeto(['NGF', signals, through, the, 'ERK/MAPK', pathway, to]), verbo([promote]), complemento([expression, of, 'Cbfb', but, not, 'Runx1', prior, to, maturation, of, nonpeptidergic, nociceptors])].
[sujeto(['Thus,', an, 'NGF/TrkA-MAPK-CBFβ', pathway, converges, with, 'Islet1-Runx1', signaling, to]), verbo([promote]), complemento(['Runx1/CBFβ', holocomplex, formation, and, nonpeptidergic, nociceptor, maturation])].
[sujeto(['Convergence', of, extrinsic, and, intrinsic, signals, to, control, heterodimeric, transcription, factor, complex, formation]), verbo([provides]), complemento([a, robust, mechanism, for, postmitotic, neuronal, subtype, specification])].
[sujeto(['The', 't(8;21)', and, 'Inv(16)', translocations, disrupt, the, normal, function, of, core]), verbo([binding]), complemento([factors, alpha, '(', 'CBFA)', and, beta, '(', 'CBFB),', respectively])].
[sujeto(['Both', translocations, are]), verbo([associated]), complemento([with, favorable, clinical, outcomes, after, intensive, 'chemotherapy,', and, given, the, perceived, mechanistic, 'similarities,', patients, with, these, translocations, are, frequently, referred, to, as, having, 'CBF-AML'])].
[sujeto(['It', remains, uncertain, as, to, 'whether,', 'collectively,', these, translocations, are, mechanistically, the, same, or, impact, different, pathways, in, subtle, ways, that]), verbo([have]), complemento([both, biological, and, clinical, significance])].
[sujeto(['A', total, of, 1291, genes, in, 't(8;21)', and, 474, genes, in, 'Inv(16)', were, differentially]), verbo([expressed]), complemento([relative, to, the, 'NK', 'controls,', with, 198, genes, differentially, expressed, in, both, subtypes])].
[sujeto(['The', majority, of, these, genes, '(', 175, /, 198, ;, binomial, test, 'p-value', &, 'lt;', 10, '(', -, 30, ')', ')', are, consistent, in, expression, changes, among, the, two, subtypes]), verbo([suggesting]), complemento([the, expression, profiles, are, more, similar, between, the, 'CBF', cohorts, than, in, the, 'NK', cohort])].
[sujeto(['Our', analysis, also, revealed, alternative, splicing, events, '(', 'ASEs)', differentially]), verbo([expressed]), complemento([across, 'subtypes,', with, 337, 't(8;21)-specific', and, 407, 'Inv(16)-specific', 'ASEs', 'detected,', the, majority, of, which, were, acetylated, proteins, '(', p, =, 1.5, x, 10, '(', -, 51, ')', and, p, =, 1.8, x, 10, '(', -, 54, ')', for, the, two, 'subsets)'])].
[sujeto(['In', addition, to, known, 'fusions,', we, identified, and, verified, 16, de, novo, fusions, in, 43, 'patients,', including, three, fusions]), verbo([involving]), complemento(['NUP98', in, six, patients])].
[sujeto(['Clustering', of, differentially]), verbo([expressed]), complemento([genes, indicated, that, the, homeobox, '(', 'HOX)', gene, 'family,', including, two, transcription, factors, '(', 'MEIS1', and, 'NKX2-3)', were, 'down-regulated', in, 'CBF', compared, to, 'NK', samples])].
[sujeto(['This']), verbo([finding]), complemento([supports, existing, data, that, the, dysregulation, of, 'HOX', genes, play, a, central, role, in, biology, 'CBF-AML', hematopoiesis])].
[sujeto(['These', data]), verbo([provide]), complemento([comprehensive, transcriptome, profiling, of, 'CBF-AML', and, delineate, genes, and, pathways, that, are, differentially, 'expressed,', providing, insights, into, the, shared, biology, as, well, as, differences, in, the, two, 'CBF', subsets])].
[sujeto(['Chromosomal', translocations, are, frequently]), verbo([associated]), complemento([with, a, wide, variety, of, 'cancers,', particularly, hematologic, malignancies])].
[sujeto(['We']), verbo([report]), complemento([here, that, 'Wnt/β-catenin', signaling, increases, the, expression, of, 'ETO', and, 'RUNX1', genes, in, human, hematopoietic, progenitors])].
[sujeto(['We']), verbo([found]), complemento([that, 'β-catenin', is, rapidly, recruited, into, 'RNA', polymerase, 'II', transcription, factories, '(', 'RNAPII-Ser5)', and, that, 'ETO', and, 'RUNX1', genes, are, brought, into, close, spatial, proximity, upon, 'Wnt3a', induction])].
[sujeto(['Notably,', 'long-term', treatment, of, cells, with, 'Wnt3a']), verbo([induces]), complemento([the, generation, a, frequent, 'RUNX1-ETO', translocation, event])].
[sujeto(['Thus,', 'Wnt/β-catenin', signaling]), verbo([induces]), complemento([transcription, and, translocation, of, 'RUNX1', and, 'ETO', fusion, gene, 'partners,', opening, a, novel, window, to, understand, the, 'onset/development', of, leukemia])].
[sujeto(['Th-inducing', 'Pox', virus, and, zinc, 'finger/Krüppel-like', factor, '(', 'ThPOK)', is, a, key, commitment, factor, for, 'CD4(+)', lineage, 'T', cells, and, is, essential, for, the, maintenance, of, 'CD4', lineage, 'integrity;', 'thus,', the, expression, of, 'ThPOK']), verbo([has]), complemento([to, be, tightly, controlled])].
[sujeto(['In', this, 'article,', we, demonstrate, that, 'Myc-associated', zinc, 'finger-related', factor, '(', 'MAZR)', and, 'Runt-related', transcription, factor, 1, '(', 'Runx1)', together]), verbo([repressed]), complemento(['ThPOK', in, preselection, 'double-positive', 'thymocytes,', whereas, 'MAZR', acted, in, synergy, with, 'Runx3', in, the, repression, of, 'ThPOK', in, 'CD8(+)', 'T', cells])].
[sujeto(['Furthermore,', 'MAZR-Runx1', and, 'MAZR-Runx3', 'double-mutant', mice, showed]), verbo([enhanced]), complemento([derepression, of, 'Cd4', in, 'double-negative', thymocytes, and, in, 'CD8(+)', 'T', cells, in, comparison, with, 'Runx1', or, 'Runx3', 'single-deficient', 'mice,', 'respectively,', indicating, that, 'MAZR', modulates, 'Cd4', silencing])].
[sujeto(['Finally,', retroviral, 'Cre-mediated', conditional, deletion, of, 'MAZR', in, peripheral, 'CD8(+)', 'T', cells]), verbo([led]), complemento([to, the, derepression, of, 'ThPOK,', thus, showing, that, 'MAZR', is, also, part, of, the, molecular, machinery, that, maintains, a, repressed, state, of, 'ThPOK', in, 'CD8(+)', 'T', cells])].
[sujeto(['However,', the, molecular, mechanisms]), verbo([involved]), complemento([in, regulating, the, differentiation, and, function, of, 'MDSCs', remain, largely, unclear])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, inhibition, of, microRNA, '(', 'miR)-9', promoted, the, differentiation, of, 'MDSCs', with, significantly, reduced, immunosuppressive, function, whereas, overexpression, of, 'miR-9', markedly, enhanced, the, function, of, 'MDSCs'])].
[sujeto(['Notably,', knockdown, of, 'miR-9', significantly, impaired, the, activity, of, 'MDSCs', and]), verbo([inhibited]), complemento([the, tumor, growth, of, 'Lewis', lung, carcinoma, in, mice])].
[sujeto(['Moreover,', 'miR-9']), verbo([regulated]), complemento(['MDSCs', differentiation, by, targeting, the, 'runt-related', transcription, factor, 1, ',', an, essential, transcription, factor, in, regulating, 'MDSC', differentiation, and, function])].
[sujeto(['Furthermore,', the, 'CREB', was]), verbo([found]), complemento([to, regulate, 'miR-9', expression, in, 'MDSCs'])].
[sujeto(['Taken', 'together,', our, findings]), verbo([have]), complemento([identified, a, critical, role, of, 'miR-9', in, regulating, the, differentiation, and, function, of, 'MDSCs'])].
[sujeto(['Acute', stimulation, of, 'nucleotide-binding', oligomerization, domain, 2, '(', 'NOD2),', the, 'Crohn\'s', 'disease-associated', sensor, of, bacterial, 'peptidoglycan,']), verbo([induces]), complemento([cytokines])].
[sujeto(['However,', chronic, 'NOD2', stimulation, in, macrophages]), verbo([decreases]), complemento([cytokines, upon, pattern, recognition, receptor, '(', 'PRR)', 'restimulation;', cytokine, attenuation, to, 'PRR', stimulation, is, similarly, observed, in, intestinal, macrophages])].
[sujeto(['The', role, for, the, transcriptional, repressors, 'Twist1', and, 'Twist2', in]), verbo([regulating]), complemento(['PRR-induced', cytokine, outcomes, is, poorly, understood, and, has, not, been, reported, for, 'NOD2'])].
[sujeto(['We']), verbo([found]), complemento([that, 'Twist1', and, 'Twist2', were, required, for, optimal, cytokine, downregulation, during, acute, 'and,', 'particularly,', chronic, 'NOD2', stimulation, of, human, macrophages])].
[sujeto(['Consistently,', 'Twist1', and, 'Twist2', expression, was]), verbo([increased]), complemento([after, chronic, 'NOD2', 'stimulation;', this, increased, expression, was, 'IL-10', and, 'TGF-β', dependent])].
[sujeto(['Although', 'Twist1', and, 'Twist2', did, not, coregulate, each, 'other\'s', 'expression,', they, cooperated, to]), verbo([enhance]), complemento([binding, to, cytokine, promoters, after, chronic, 'NOD2', stimulation])].
[sujeto(['Moreover,', 'Twist1', and, 'Twist2', contributed, to]), verbo([enhance]), complemento([expression, and, promoter, binding, of, the, proinflammatory, inhibitor, 'c-Maf', and, the, transcriptional, repressor, 'Bmi1'])].
[sujeto(['Furthermore,', with, chronic, 'NOD2', 'stimulation,', 'Twist1', and, 'Twist2', contributed, to, the]), verbo([decreased]), complemento([expression, and, cytokine, promoter, binding, of, the, transcriptional, activators, activating, transcription, factor, 4, ',', 'C/EBPα,', 'Runx1,', and, 'Runx2'])].
[sujeto(['Finally,', 'NOD2', synergized, with, additional, 'PRRs', to]), verbo([increase]), complemento(['Twist1', and, 'Twist2', expression, and, 'Twist-dependent', pathways])].
[sujeto(['Therefore,', after, chronic, 'NOD2', stimulation, 'Twist1', and, 'Twist2', coordinate, the, regulation, of, both, transcriptional, activators, and, 'repressors,', thereby]), verbo([mediating]), complemento([optimal, cytokine, downregulation])].
[sujeto(['A', recent, study]), verbo([has]), complemento([shown, that, transcriptional, regulators, of, core, binding, factor, '(', 'Cbf)', β2, and, 'promotor-1-transcribed', 'Runt-related', transcription, factor, 1, '(', 'P1-Runx1)', are, required, for, the, differentiation, of, 'CD3-CD4+CD45+', lymphoid, tissue, inducer, '(', 'LTi)', 'cells,', which, initiate, and, trigger, the, developmental, program, of, 'PPs,', but, the, involvement, of, this, pathway, in, 'NALT', and, 'TALT', development, remains, to, be, elucidated])].
[sujeto(['Here', we]), verbo([report]), complemento([that, 'Cbfβ2', plays, an, essential, role, in, 'NALT', and, 'TALT', development, by, regulating, 'LTi', cell, trafficking, to, the, 'NALT', and, 'TALT', anlagens])].
[sujeto(['Cbfβ2', was]), verbo([expressed]), complemento([in, 'LTi', cells, in, all, three, types, of, 'MALT', examined])].
[sujeto(['Indeed,', similar, to, the, previous]), verbo([finding]), complemento([for, 'PPs,', we, found, that, 'Cbfβ2-/-', mice, lacked, 'NALT', and, 'TALT', lymphoid, structures])].
[sujeto(['Recent', studies, indicate, that, 'DNA', methylation, can, be, used, to, identify, transcriptional, 'enhancers,', but, no, systematic, approach]), verbo([has]), complemento([been, developed, for, 'genome-wide', identification, and, analysis, of, enhancers, based, on, 'DNA', methylation])].
[sujeto(['We', identified, networks]), verbo([regulated]), complemento([by, known, cancer, drivers, such, as, 'GATA3', and, 'FOXA1', '(', breast, 'cancer),', 'SOX17', and, 'FOXA2', '(', endometrial, 'cancer),', and, 'NFE2L2,', 'SOX2,', and, 'TP63', '(', squamous, cell, lung, 'cancer)'])].
[sujeto(['We', propose, 'ELMER', as, a, powerful, new, paradigm, for, understanding, the, 'cis-regulatory', interface, between, 'cancer-associated', transcription, factors, and, their, functional]), verbo([target]), complemento([genes])].
[sujeto(['We', exploited, a, pluripotent, hematopoietic, 'stem/progenitor', cell, 'line,', 'EML1,', and, generated, a, cell, line, '(', 'EML-TA)', stably]), verbo([expressing]), complemento([the, 'TEL-AML1', fusion, protein])].
[sujeto(['Global', gene, expression, profiling, of, 'EML1', cells, at, different, stages, of, 'B-lymphoid', 'differentiation,', compared, with, 'EML-TA,', identified, the, interferon, '(', 'IFN)α/β', pathway, as, a, primary]), verbo([target]), complemento([of, repression, by, 'TEL-AML1'])].
[sujeto(['In', 'particular,', expression, and, phosphorylation, of, 'interferon-regulatory', factor, 3, '(', 'IRF3)', was]), verbo([decreased]), complemento([in, 'EML-TA', 'cells;', 'strikingly,', stable, expression, of, 'IRF3', restored, the, capacity, of, 'EML-TA', cells, to, differentiate, into, mature, 'B-cells'])].
[sujeto(['The', ability, of, 'TEL-AML1', to, block, 'B-cell', differentiation, and, downregulate, the, 'IRF3-IFNα/β', pathway, was, confirmed, in, mouse, and, human, primary, hematopoietic, precursor, cells, '(', 'Lin-', and, 'CD34+', 'cells,', 'respectively),', and, in, a, 'patient-derived', cell, line]), verbo([expressing]), complemento(['TEL-AML1', '(', 'REH)'])].
[sujeto(['Furthermore,', treatment, of, 'TEL-AML1']), verbo([expressing]), complemento([cells, with, 'IFNα/β', was, sufficient, to, overcome, the, maturation, block])].
[sujeto(['Our', data]), verbo([provide]), complemento([new, insight, on, 'TEL-AML1', function, and, may, offer, a, new, therapeutic, opportunity, for, 'B-ALL'])].
[sujeto(['High', mutation, frequencies, of, 'RUNX1', gene, in, chronic, myelomonocytic, leukemia, '(', 'CMML)', and, myelodysplastic, syndromes, '(', 'MDS)']), verbo([have]), complemento([been, 'described,', whereas, the, biologic, significances, of, the, mutations, were, not, investigated])].
[sujeto(['Then,', we, studied, the, 'DNA', and, 'CBFβ']), verbo([binding]), complemento([abilities, of, all, the, 'RUNX1', mutants, identified, by, using, electrophoretic, mobility, shift, assay, and, 'co-immunoprecipitation', 'assay,', and, also, determined, their, activities, on, target, 'C-FMS', gene, induction, by, 'Western', blotting, and, luciferase, reporter, assay])].
[sujeto(['Previously,', it, was, proposed, that, 'CBFβ-SMMHC']), verbo([acts]), complemento([by, dominantly, repressing, the, transcription, factor, 'RUNX1', '(', 'Runt-related', protein, 1, ')', ',', but, we, recently, showed, that, 'CBFβ-SMMHC', has, activities, that, are, independent, of, 'RUNX1', repression])].
[sujeto(['In', 'addition,', we, showed, that, a, modified, 'CBFβ-SMMHC', with]), verbo([decreased]), complemento(['RUNX1-binding', activity, accelerates, leukemogenesis])].
[sujeto(['To', test, 'this,', we, generated, mice]), verbo([expressing]), complemento(['Cbfb-MYH11', in, a, 'Runx1-deficient', 'background,', resulting, from, either, homozygous, 'Runx1-null', alleles, '(', 'Runx1(-/-))', or, a, single, 'dominant-negative', 'Runx1', allele, '(', 'Runx1(+/lz))'])].
[sujeto(['We']), verbo([found]), complemento([that, loss, of, 'Runx1', activity, rescued, the, differentiation, defects, induced, by, 'Cbfb-MYH11', during, primitive, hematopoiesis])].
[sujeto(['During', definitive, 'hematopoiesis,', 'RUNX1']), verbo([loss]), complemento([also, significantly, reduced, the, proliferation, and, differentiation, defects, induced, by, 'Cbfb-MYH11'])].
[sujeto(['The', transcription, factor, fusion, 'CBFβ-SMMHC', '(', core]), verbo([binding]), complemento([factor, β, and, the, 'smooth-muscle', myosin, heavy, 'chain),', expressed, in, 'AML', with, the, chromosome, inversion, 'inv(16)(p13q22),', outcompetes, 'wild-type', 'CBFβ', for, binding, to, the, transcription, factor, 'RUNX1,', deregulates, 'RUNX1', activity, in, 'hematopoiesis,', and, induces, 'AML'])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, development, of, a, 'protein-protein', interaction, 'inhibitor,', 'AI-10-49,', that, selectively, binds, to, 'CBFβ-SMMHC', and, disrupts, its, binding, to, 'RUNX1'])].
[sujeto(['Treatment', of, primary, 'inv(16)', 'AML', patient, blasts, with, 'AI-10-49']), verbo([triggers]), complemento([selective, cell, death])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, direct, inhibition, of, the, oncogenic, 'CBFβ-SMMHC', fusion, protein, may, be, an, effective, therapeutic, approach, for, 'inv(16)', 'AML,', and, they, provide, support, for, transcription, factor, targeted, therapy, in, other, cancers])].
[sujeto([1, +, ')', 'Th1', cells]), verbo([induced]), complemento([colitis, in, 'Rag(-/-)', mice, after, adoptive, transfer, and, converted, into, 'IL-17(+)', 'Th17,', but, not, 'Foxp3(+)', 'Treg', cells, in, the, inflamed, intestines])].
[sujeto(['TGF-β', and, 'IL-6,', but, not, 'IL-1β', and, 'IL-23,']), verbo([regulated]), complemento(['Th1', conversion, into, 'Th17', cells])].
[sujeto(['TGF-β', induction, of, transcriptional, factor, 'Runx1', is, crucial, for, the, 'conversion,', since, silencing, 'Runx1', by, siRNA]), verbo([inhibited]), complemento(['Th1', conversion, into, 'Th17', cells])].
[sujeto(['Furthermore,', 'TGF-β']), verbo([enhanced]), complemento([histone, 'H3K9', acetylation, but, inhibited, 'H3K9', trimethylation, of, 'Runx1-', and, 'ROR-γt-binding', sites, on, 'il-17', or, rorc, gene, in, 'Th1', cells])].
[sujeto(['We', conclude, that, 'Th1', cells, convert, into, 'Th17', cells, under, inflammatory, conditions, in, 'intestines,', which, is, possibly]), verbo([mediated]), complemento([by, 'TGF-β', induction, of, 'Runx1'])].
[sujeto(['Cooperative', assemblies, of, transcription, factors, '(', 'TFs)', on]), verbo([target]), complemento([gene, enhancers, coordinate, cell, 'proliferation,', fate, 'specification,', and, differentiation, through, precise, and, complicated, transcriptional, mechanisms])].
[sujeto(['Chemical', 'modifications,', such, as, 'phosphorylation,', of, 'TFs']), verbo([induced]), complemento([by, cell, signaling, further, modulate, the, dynamic, cooperativity, of, 'TFs'])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, various, 'Ets1-containing', 'TF-DNA', complexes, respond, differently, to, 'calcium-induced', phosphorylation, of, 'Ets1,', which, is, known, to, inhibit, 'Ets1-DNA', binding])].
[sujeto(['Crystallographic', analysis, of, a, complex, comprising, 'Ets1,', 'Runx1,', and, 'CBFβ', at, the, 'TCRα', enhancer, revealed, that, 'Ets1', acquires, robust]), verbo([binding]), complemento([stability, in, the, 'Runx1', and, 'DNA-complexed', 'state,', via, allosteric, mechanisms])].
[sujeto(['This', allows]), verbo([phosphorylated]), complemento(['Ets1', to, be, retained, at, the, 'TCRα', enhancer, with, 'Runx1,', in, contrast, to, other, 'Ets1', target, gene, enhancers, including, 'mb-1', and, 'stromelysin-1'])].
[sujeto(['This', study]), verbo([provides]), complemento([a, 'structure-based', model, for, 'cell-signaling-dependent', regulation, of, target, 'genes,', mediated, via, chemical, modification, of, 'TFs'])].
[sujeto(['The', 2, genes, 'RUNX1', and, 'SP7', resulted, differently]), verbo([expressed]), complemento([in, cells, cultured, on, metallic, supports, if, compared, with, the, expression, recorded, for, 'OIC'])].
[sujeto(['However,', the, mechanism, by, which, 'Cbfβ']), verbo([regulates]), complemento([cartilage, and, bone, development, remains, unclear])].
[sujeto(['Surprisingly,', the, mutant, mice, had, 'under-developed', larynx, and, tracheal, 'cartilage,']), verbo([causing]), complemento([alveolus, defects, that, led, to, death, shortly, after, birth, from, suffocation])].
[sujeto(['Importantly,', we, showed, that, 'Cbfβ', was]), verbo([expressed]), complemento([throughout, the, skeleton, during, both, embryonic, and, postnatal, 'development,', which, explains, the, 'multiple-skeletal', defects, observed, in, the, mutant, mice])].
[sujeto(['Notably,', 'Cbfβ,', 'Runx1', and, 'Runx2', displayed, different, expression, patterns, in, the, growth, plates, of, the, 'wild-type', 'mice,', indicating, that, 'Cbfβ/Runx1', complex, and, 'Cbfβ/Runx2', complex, may]), verbo([regulate]), complemento([chondrocyte, proliferation, and, 'hypertrophy,', 'respectively,', in, a, spatial, and, temporal, manner])].
[sujeto(['Collectively,', the, results, demonstrate, that, 'Cbfβ']), verbo([mediates]), complemento([cartilage, and, bone, development, by, interacting, with, 'Runx1', and, 'Runx2', to, regulate, the, expressions, of, 'Col', 'X', and, 'Osx', for, chondrocyte, and, osteoblast, development])].
[sujeto(['These', findings, not, only]), verbo([reveal]), complemento([a, critical, role, for, 'Cbfβ', in, cartilage, and, bone, development, but, also, facilitate, the, design, of, novel, therapeutic, approaches, for, skeletal, diseases])].
[sujeto(['Core']), verbo([binding]), complemento([factor, '(', 'CBF)', is, a, heterodimeric, transcription, factor, complex, composed, of, a, 'DNA-binding', 'subunit,', one, of, three, 'runt-related', transcription, factor, '(', 'RUNX)', 'factors,', and, a, 'non-DNA', binding, 'subunit,', 'CBFβ'])].
[sujeto(['CBFβ', is, critical, for, 'DNA']), verbo([binding]), complemento([and, stability, of, the, 'CBF', transcription, factor, complex])].
[sujeto(['In', the, 'ovary,', the, 'LH', surge]), verbo([increases]), complemento([the, expression, of, 'Runx1', and, 'Runx2', in, periovulatory, 'follicles,', implicating, a, role, for, 'CBFs', in, the, periovulatory, process])].
[sujeto(['The', mutant, female, mice, exhibited, significant, reductions, in, 'fertility,', with, smaller, litter, 'sizes,']), verbo([decreased]), complemento([progesterone, during, 'gestation,', and, fewer, cumulus, oocyte, complexes, collected, after, an, induced, superovulation])].
[sujeto(['Cbfβ', knockdown, mice, also, exhibited]), verbo([decreased]), complemento([expression, of, key, genes, within, the, corpora, lutea, and, morphological, changes, in, the, ovarian, 'structure,', including, the, presence, of, large, antral, follicles, well, into, the, luteal, phase])].
[sujeto(['Overall,', these, data]), verbo([suggest]), complemento([a, role, for, 'CBFs', as, significant, regulators, of, gene, 'expression,', ovulatory, 'processes,', and, luteal, development, in, the, ovary])].
[sujeto(['Core']), verbo([binding]), complemento([factor, β, '(', 'Cbfβ)', is, a, partner, protein, of, 'Runx', family, transcription, factors, with, minimally, characterized, function, in, cartilage])].
[sujeto(['Here', we, address, the, role, of, 'Cbfβ', in, cartilage, by, generating, 'chondrocyte-specific', 'Cbfβ-deficient', mice, '(', 'Cbfb(Δch/Δch)', ')', from, 'Cbfb-floxed', mice, crossed, with, mice]), verbo([expressing]), complemento(['Cre', from, the, 'Col2a1', promoter])].
[sujeto(['Cbfb(Δch/Δch)', mice, died, soon, after, birth, and, exhibited, delayed, endochondral, bone, 'formation,', shorter, appendicular, skeleton, length, with]), verbo([increased]), complemento([proliferative, 'chondrocytes,', and, nearly, absent, hypertrophic, chondrocyte, zones])].
[sujeto(['Immunohistochemical', and, quantitative, 'real-time', 'PCR', analyses, showed, that, the, number, and, size, of, proliferative, chondrocytes]), verbo([increased]), complemento([and, the, expression, of, chondrocyte, maturation, markers, at, the, growth, 'plates,', including, 'Runx2,', 'osterix,', and, 'osteopontin,', significantly, diminished, in, 'Cbfb(Δch/Δch)', mice, compared, to, wild, type, mice])].
[sujeto(['Mechanistically,', 'Cbfβ', deficiency, in, chondrocytes]), verbo([caused]), complemento([a, decrease, of, protein, levels, of, 'Runx', transcription, factors, by, accelerating, 'polyubiquitination-mediated', proteosomal, degradation, in, vitro])].
[sujeto(['Indeed,', 'Runx2', and, 'Runx3,', but, not, 'Runx1,']), verbo([decreased]), complemento([in, 'Cbfb(Δch/Δch)', mice])].
[sujeto(['Runx2', is]), verbo([required]), complemento([for, osteoblast, differentiation, and, chondrocyte, 'maturation,', and, haplodeficiency, of, 'RUNX2', causes, cleidocranial, 'dysplasia,', which, is, characterized, by, open, fontanelles, and, sutures, and, hypoplastic, clavicles])].
[sujeto(['Cbfb', forms, a, heterodimer, with, 'Runx', family, proteins, and]), verbo([enhances]), complemento([their, 'DNA-binding', capacity])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, the, partial, rescue, of, hematopoiesis, in, 'Cbfb(-/-)', mice, revealed, the, requirement, of, 'Cbfb', in, skeletal, development])].
[sujeto(['The', differentiation, of, chondrocytes, and, osteoblasts, were, severely]), verbo([inhibited]), complemento([in, 'vitro,', and, the, reporter, activities, of, 'Ihh,', 'Col10a1,', and, 'Bglap2', promoter, constructs, were, reduced, in, 'Cbfb(fl/fl/Cre)', chondrocytes, or, osteoblasts])].
[sujeto(['These', findings, indicate, that, 'Cbfb', is]), verbo([required]), complemento([for, skeletal, development, by, regulating, chondrocyte, differentiation, and, proliferation, and, osteoblast, 'differentiation;', that, 'Cbfb', plays, an, important, role, in, the, stabilization, of, 'Runx', family, 'proteins;', and, that, 'Runx2', protein, stability, is, less, dependent, on, 'Cbfb', in, calvariae, than, in, cartilaginous, limb, skeletons])].
[sujeto(['Cytogenetics']), verbo([provide]), complemento([reliable, risk, stratification, for, 'treatment:', high, hyperdiploidy, and, 'ETV6-RUNX1', are, good, 'risk,', whereas, 'BCR-ABL1,', 'MLL', 'rearrangements,', and, hypodiploidy, are, poor, risk])].
[sujeto(['With', advancing, technologies, in, 'array-based', approaches, '(', single, nucleotide, polymorphism, 'arrays)', and, 'next-generation', sequencing, to, study, the, 'genome,']), verbo([increasing]), complemento([numbers, of, new, genetic, changes, are, being, discovered])].
[sujeto(['Whether', they]), verbo([have]), complemento([a, link, to, outcome, is, the, most, important, factor, for, refinement, of, risk, factors, in, relation, to, clinical, trials])].
[sujeto(['For', several, newly, identified, 'abnormalities,', including, intrachromosomal, amplification, of, chromosome, 21, '(', 'iAMP21),', that, are]), verbo([associated]), complemento([with, a, poor, prognosis, with, standard, 'therapy,', appropriately, modified, treatment, has, significantly, improved, outcome])].
[sujeto(['After', the, successful, use, of, tyrosine, kinase, inhibitors, in, the, treatment, of, 'BCR-ABL1-positive', acute, lymphoblastic, 'leukemia,', patients, with, alternative, 'ABL1', translocations, and, rearrangements]), verbo([involving]), complemento(['PDGFRB', may, benefit, from, treatment, with, tyrosine, kinase, inhibitors])].
[sujeto(['Other', 'aberrations,', for, 'example,', 'CRLF2', overexpression, and, 'JAK2', 'mutations,', are, also]), verbo([providing]), complemento([potential, novel, therapeutic, targets, with, the, prospect, of, reduced, toxicity])].
[sujeto(['Inactivating', 'RUNX1', mutations]), verbo([have]), complemento([frequently, been, found, in, patients, with, myelodysplastic, syndrome, '(', 'MDS)', and, cytogenetically, normal, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['However,', no, somatic, 'RUNX1', alteration, was]), verbo([found]), complemento([in, 'AMLs', with, leukemogenic, fusion, 'proteins,', such, as, 'core-binding', factor, '(', 'CBF)', leukemia, and, 'MLL', fusion, 'leukemia,', raising, the, possibility, that, 'RUNX1', could, actually, promote, the, growth, of, these, leukemia, cells])].
[sujeto(['Using', normal, human, cord, blood, cells, and, those]), verbo([expressing]), complemento([leukemogenic, fusion, 'proteins,', we, discovered, a, dual, role, of, 'RUNX1', in, myeloid, leukemogenesis])].
[sujeto(['RUNX1', overexpression]), verbo([inhibited]), complemento([the, growth, of, normal, cord, blood, cells, by, inducing, myeloid, 'differentiation,', whereas, a, certain, level, of, 'RUNX1', activity, was, required, for, the, growth, of, 'AML1-ETO', and, 'MLL-AF9', cells])].
[sujeto(['Using', a, mouse, genetic, 'model,', we, also, showed, that, the, combined]), verbo([loss]), complemento([of, 'Runx1/Cbfb', inhibited, leukemia, development, induced, by, 'MLL-AF9'])].
[sujeto(['RUNX2', could, compensate, for, the]), verbo([loss]), complemento([of, 'RUNX1'])].
[sujeto(['The', survival, effect, of, 'RUNX1', was]), verbo([mediated]), complemento([by, 'BCL2', in, 'MLL', fusion, leukemia])].
[sujeto(['Inhibiting', 'RUNX1', activity, rather, than]), verbo([enhancing]), complemento([it, could, be, a, promising, therapeutic, strategy, for, 'AMLs', with, leukemogenic, fusion, proteins])].
[sujeto(['This', translocation]), verbo([causes]), complemento([expression, of, the, 'RUNX1-ETO', '(', 'AML1-ETO)', fusion, 'protein,', which, cooperates, with, additional, mutations, in, leukemia, development])].
[sujeto(['We']), verbo([report]), complemento([here, that, interferons, '(', 'IFNs)', and, 'IFN-stimulated', genes, are, a, group, of, genes, consistently, 'up-regulated', by, 'RUNX1-ETO', in, both, human, and, murine, models])].
[sujeto(['Addition', of, exogenous, 'IFN', in, vitro, significantly, reduces, the]), verbo([increase]), complemento([in, 'self-renewal', potential, induced, by, both, 'RUNX1-ETO', and, its, leukemogenic, splicing, isoform, 'RUNX1-ETO9a'])].
[sujeto(['Finally,']), verbo([loss]), complemento([of, type, 'I', 'IFN', signaling, via, knockout, of, 'Ifnar1', significantly, accelerates, leukemogenesis, in, a, 't(8;21)', murine, model])].
[sujeto(['This', demonstrates, the, role, of]), verbo([increased]), complemento(['IFN', signaling, as, an, important, factor, inhibiting, 't(8;21)', fusion, protein, function, and, leukemia, development, and, supports, the, use, of, type, 'I', 'IFNs', in, the, treatment, of, 'AML'])].
[sujeto(['Lymphoid', 'enhancer-binding', factor, 1, '(', 'LEF1)', is, a, downstream, effector, of, the, 'Wnt/β-catenin', signaling, pathway, and, its, dysregulation, is]), verbo([associated]), complemento([with, a, number, of, malignant, diseases, such, as, leukemia])].
[sujeto(['Moreover,', we]), verbo([provide]), complemento([the, first, evidence, that, primary, 'AML', samples, with, 'AML1-ETO', or, 'PML-RARα', have, a, higher, 'LEF1', level, compared, with, those, without, each, fusion, gene])].
[sujeto(['High', 'LEF1', level, was]), verbo([associated]), complemento([with, a, favorable, 'relapse-free', survival, in, patients, with, 'FLT3-ITD', 'wild-type'])].
[sujeto(['No', consecutive, analysis, of, 'BAALC', and, 'WT1', expressions]), verbo([associated]), complemento([with, 'core-binding', factor, 'AML', '(', 'CBF-AML)', from, diagnosis, to, hematopoietic, stem, cell, transplantation, '(', 'HSCT)', has, yet, been, reported])].
[sujeto(['A', subgroup, of, 't(8;21)', showing, higher, 'BAALC', and, 'WT1', expressions, at, 'post-HSCT', were, also]), verbo([associated]), complemento([with, inferior, 'OS', '(', 'P', =, 0.018, ',', 0.015, ')', and, higher, 'CIR', rates, '(', 'P', =, 0.019, ',', 0.011, ')'])].
[sujeto(['Developing', novel, therapies, that]), verbo([suppress]), complemento(['self-renewal', of, leukemia, stem, cells, may, reduce, the, likelihood, of, relapses, and, extend, 'long-term', survival, of, patients, with, acute, myelogenous, leukemia, '(', 'AML)'])].
[sujeto(['AML1-ETO', '(', 'AE)', is, an, oncogene, that, plays, an, important, role, in]), verbo([inducing]), complemento(['self-renewal', of, hematopoietic, 'stem/progenitor', cells, '(', 'HSPCs),', leading, to, the, development, of, leukemia, stem, cells])].
[sujeto(['Previously,', using, a, zebrafish, model, of, 'AE', and, a, 'whole-organism', chemical, suppressor, 'screen,', we]), verbo([have]), complemento([discovered, that, 'AE', induces, specific, hematopoietic, phenotypes, in, embryonic, zebrafish, through, a, cyclooxygenase, '(', 'COX)-2', and, 'β-catenin-dependent', pathway])].
[sujeto(['Here,', we, show, that, 'AE', also]), verbo([induces]), complemento([expression, of, the, 'Cox-2', gene, and, activates, 'β-catenin', in, mouse, bone, marrow, cells])].
[sujeto(['Inhibition', of, 'COX']), verbo([suppresses]), complemento(['β-catenin', activation, and, serial, replating, of, 'AE(+)', mouse, 'HSPCs'])].
[sujeto(['In', 'addition,', treatment, with, 'nimesulide,', a, 'COX-2', selective, 'inhibitor,', dramatically]), verbo([suppresses]), complemento([xenograft, tumor, formation, and, inhibits, in, vivo, progression, of, human, leukemia, cells])].
[sujeto(['In', 'summary,', our, data, indicate, an, important, role, of, a, 'COX/β-catenin-dependent', signaling, pathway, in, tumor, 'initiation,', 'growth,', and, 'self-renewal,', and, in]), verbo([providing]), complemento([the, rationale, for, testing, potential, benefits, from, common, 'COX', inhibitors, as, a, part, of, 'AML', treatments])].
[sujeto(['It', is, known, that, leukemia, patients, with, extramedullary, infiltration, '(', 'EMI)']), verbo([have]), complemento([a, worse, prognosis, than, patients, without, it])].
[sujeto(['Recent', data, indicate, that, the, amyloid, precursor, protein, '(', 'APP)', is]), verbo([involved]), complemento([in, cell, 'adhesion,', 'motility,', and, proliferation])].
[sujeto(['The', expression, of, 'APP', and, its, prognostic, significance, in, acute, myeloid, leukemia, '(', 'AML)']), verbo([have]), complemento([not, been, studied])].
[sujeto(['Transwell', data, show, that, 'siRNA/APP', substantially, impairs, cell, 'migration,', but, it, does, not]), verbo([inhibit]), complemento([cell, proliferation])].
[sujeto(['Furthermore,', by, quantitative, 'real-time', polymerase, chain, reaction, and, 'Western', 'blot,', we]), verbo([found]), complemento([that, 'siRNA/APP', decreases, 'MMP-2', expression, in, vitro])].
[sujeto(['Our', study]), verbo([provides]), complemento([a, novel, clue, that, 'APP', is, involved, in, the, extramedullary, infiltration, of, leukemia, by, 'MMP-2'])].
[sujeto(['Secreted-frizzled', related, proteins, '(', 'SFRPs)', are, modulators, of, the, 'Wnt', signaling, pathway, that, is, closely]), verbo([involved]), complemento([in, normal, and, malignant, hematopoiesis])].
[sujeto(['Epigenetic', deregulation, of, 'Wnt', modulators]), verbo([leading]), complemento([to, aberrant, signaling, has, been, reported, in, adult, patients, with, acute, myeloid, leukemia, '(', 'AML),', but, its, occurrence, in, childhood, patients, with, 'AML', and, the, role, of, individual, modulators, are, unclear])].
[sujeto(['In', this, 'study,', we, examined, 'SFRP1,', 'SFRP2,', 'SFRP4,', and, 'SFRP5', promoter, methylation, in, 83, patients, with, 'AML', '(', 59, children, and, 24, 'adults)', and]), verbo([found]), complemento([preferential, 'SFRP1', methylation, and, mRNA, 'down-regulation', in, the, prognostically, favorable, subgroup, of, 'AML', with, 't(8;21)', translocation])].
[sujeto(['Mechanistically,', we, further, demonstrated, that, 'RUNX1-ETO,', the, 't(8;21)', fusion, 'product,', specifically]), verbo([bound]), complemento([the, 'SFRP1', promoter, and, repressed, its, transcription, via, a, consensus, 'RUNX', binding, site])].
[sujeto(['In', 't(8;21)-leukemia', 'cells,', 'SFRP1', selectively]), verbo([inhibited]), complemento([canonical, 'Wnt', signaling, and, cellular, proliferation, that, were, associated, with, concomitant, 'down-regulation', of, 'Wnt/β-catenin', target, 'genes,', including, 'CCND1', and, 'MYC'])].
[sujeto(['Taken', 'together,', we, identified, 'SFRP1', as, a, transcriptional, repression]), verbo([target]), complemento([of, the, 't(8;21)', fusion, protein, and, demonstrated, a, novel, mechanism, of, 'Wnt', activation, in, a, specific, subtype, of, 'AML'])].
[sujeto(['The', 'mixed-lineage', leukemia, '(', 'MLL)', 'H3K4', methyltransferase, 'protein,', and, the, heterodimeric, 'RUNX1/CBFβ', transcription, factor, 'complex,', are, critical, for, definitive, and, adult, 'hematopoiesis,', and, both, are, frequently]), verbo([targeted]), complemento([in, human, acute, leukemia])].
[sujeto(['We', identified, a, physical, and, functional, interaction, between, 'RUNX1', '(', 'AML1)', and, 'MLL', and, show, that, both, are]), verbo([required]), complemento([to, maintain, the, histone, lysine, 4, trimethyl, mark, '(', 'H3K4me3)', at, 2, critical, regulatory, regions, of, the, 'AML1', target, gene, 'PU'])].
[sujeto(['Similar', to, 'CBFβ,', we, show, that, 'MLL']), verbo([binds]), complemento([to, 'AML1', abrogating, its, 'proteasome-dependent', degradation])].
[sujeto(['Furthermore,', a, subset, of, previously, uncharacterized, 'frame-shift', and, missense, mutations, at, the, 'N', terminus, of, 'AML1,']), verbo([found]), complemento([in, 'MDS', and, 'AML', 'patients,', impairs, its, interaction, with, 'MLL,', resulting, in, loss, of, the, 'H3K4me3', mark, within, 'PU'])].
[sujeto([1, regulatory, 'regions,', and]), verbo([decreased]), complemento(['PU'])].
[sujeto(['The', interaction, between, 'MLL', and, 'AML1']), verbo([provides]), complemento([a, mechanism, for, the, 'sequence-specific', binding, of, 'MLL', to, 'DNA,', and, identifies, 'RUNX1', target, genes, as, potential, effectors, of, 'MLL', function])].
[sujeto(['The', genetic, origins, of, the, development, of, malignant, haematological, disorders]), verbo([have]), complemento([been, established, at, the, beginning, of, the, 80, ies])].
[sujeto(['Systematic', characterization, of, chromosomal, structural, abnormalities, 'and,', more, recently, by, 'DNA', microarray, approaches, and, sequencing, of, tumour, genomes]), verbo([have]), complemento([allowed, the, identification, of, a, large, number, of, genes, that, are, mutated, during, malignant, transformation, in, humans])].
[sujeto(['Functional', studies, of, these, human, oncogenes]), verbo([have]), complemento([shown, that, most, of, them, were, not, able, to, transform, a, haematologic, progenitor, when, acting, alone, and, that, cooperation, with, other, oncogenic, events, was, required])].
[sujeto(['From', these, 'data,', the, development, of, efficient, therapeutic, approaches, will, be, possible, by]), verbo([targeting]), complemento([the, early, oncogenic, events, which, are, at, the, origin, of, the, malignant, transformation])].
[sujeto(['To', identify, genes, and, components]), verbo([associated]), complemento([with, this, oncogene, we, used, 'Drosophila', as, a, genetic, model])].
[sujeto(['Expression', of, 'AML1-ETO']), verbo([caused]), complemento([an, expansion, of, hematopoietic, precursors, in, 'Drosophila,', which, expressed, high, levels, of, reactive, oxygen, species, '(', 'ROS)'])].
[sujeto(['Mutations', in, functional, domains, of, the, fusion, protein]), verbo([suppress]), complemento([the, proliferative, phenotype])].
[sujeto(['In', a, genetic, 'screen,', we]), verbo([found]), complemento([that, inactivation, of, 'EcRB1', or, activation, of, 'Foxo', and, superoxide, 'dismutase-2', '(', 'SOD2)', suppress, the, 'AML1-ETO-induced', phenotype, by, reducing, 'ROS', expression, in, the, precursor, cells])].
[sujeto(['Our', studies, indicate, that, 'ROS', is, a, signaling, factor]), verbo([promoting]), complemento([maintenance, of, normal, as, well, as, the, aberrant, myeloid, precursors, and, suggests, the, importance, of, antioxidant, enzymes, and, their, regulators, as, targets, for, further, study, in, the, context, of, leukemia])].
[sujeto(['Although', 'NF-E2', levels, correlate, with, 'JAK2(V671F)', allele, burden, in, some, 'PV', 'cohorts,', the, molecular, mechanism]), verbo([causing]), complemento([aberrant, 'NF-E2', expression, has, not, been, described])].
[sujeto(['Here', we, show, that, 'NF-E2', expression, is, also]), verbo([increased]), complemento([in, patients, with, essential, thrombocythemia, and, primary, myelofibrosis, independent, of, the, presence, of, the, 'JAK2(V617F)', mutation])].
[sujeto(['Characterization', of, the, 'NF-E2', promoter, revealed, multiple, functional]), verbo([binding]), complemento([sites, for, 'AML1/RUNX-1'])].
[sujeto(['Chromatin', immunoprecipitation, demonstrated, 'AML1']), verbo([binding]), complemento([to, the, 'NF-E2', promoter, in, vivo])].
[sujeto(['Moreover,', 'AML1']), verbo([binding]), complemento([to, the, 'NF-E2', promoter, was, significantly, increased, in, granulocytes, from, 'PV', patients, compared, with, healthy, controls])].
[sujeto(['RNAi-mediated', suppression, of, either, 'AML1', or, of, its]), verbo([binding]), complemento([partner, 'CBF-beta', significantly, decreased, 'NF-E2', expression])].
[sujeto(['Moreover,', expression, of, the, leukemic, fusion, protein, 'AML/ETO', drastically]), verbo([decreased]), complemento(['NF-E2', protein, levels])].
[sujeto(['Our', data, identify, 'NF-E2', as, a, novel, 'AML1']), verbo([target]), complemento([gene, and, delineate, a, role, for, aberrant, 'AML1', expression, in, mediating, elevated, 'NF-E2', expression, in, 'MPN', patients])].
[sujeto(['The', acquisition, of, the, 'critical,', secondary, 'CNAs']), verbo([requires]), complemento([some, 'Darwinian', selective, advantage, to, expand, numbers, of, cells, at, 'risk,', and, the, cytokine, 'TGF', beta, is, able, to, exercise, this, function])].
[sujeto(['The', clonal, architecture, of, 'ALL']), verbo([has]), complemento([been, investigated, by, single, cell, analysis, with, multicolor, probes, to, mutant, genes])].
[sujeto(['The', data]), verbo([reveal]), complemento([not, a, linear, sequence, of, mutation, acquisition, with, clonal, succession, but, rather, considerable, complexity, with, a, 'tree-like', or, branching, structure, of, genetically, distinct, subclones, very, reminiscent, of, 'Darwin\'s', original, 1837, evolutionary, divergence, diagram])].
[sujeto(['This', evolutionary, pattern]), verbo([has]), complemento([important, implications, for, stem, cells, in, 'ALL,', for, the, origins, of, relapse, and, for, therapeutic, targeting])].
[sujeto(['However,', optimal, sampling, intervals]), verbo([have]), complemento([not, been, defined, and, are, likely, to, vary, according, to, the, underlying, molecular, lesion])].
[sujeto(['Combination', of, conventional, chromosome, analysis, '(', 'CCA)', and, 'FISH']), verbo([provides]), complemento([higher, sensitivity, in, detecting, these, genetic, 'abnormalities,', and, it, is, effective, to, apply, several, 'FISH', probes, as, a, profile, test])].
[sujeto(['Naturally', arising, regulatory, 'T', '(', 'Treg)', cells]), verbo([express]), complemento([the, transcription, factor, 'FoxP3,', which, critically, controls, the, development, and, function, of, 'Treg', cells])].
[sujeto(['FoxP3']), verbo([interacts]), complemento([with, another, transcription, factor, 'Runx1', '(', also, known, as, 'AML1)'])].
[sujeto(['Here,', we, showed, that, 'Treg', 'cell-specific', deficiency, of, 'Cbfbeta,', a, cofactor, for, all, 'Runx', 'proteins,', or, that, of, 'Runx1,', but, not, 'Runx3,']), verbo([induced]), complemento(['lymphoproliferation,', autoimmune, 'disease,', and, hyperproduction, of, 'IgE'])].
[sujeto(['The', 'Runx', complex]), verbo([bound]), complemento([to, more, than, 3000, gene, loci, in, 'Treg', 'cells,', including, the, 'Foxp3', regulatory, regions, and, the, 'Il4', silencer])].
[sujeto(['In', 'addition,', knockdown, of, 'RUNX1', showed, that, 'RUNX1', is]), verbo([required]), complemento([for, the, optimal, regulation, of, 'FoxP3', expression, in, human, 'T', cells])].
[sujeto(['Interestingly,', both, 'CBF', leukemia, fusion, proteins, and, 'miR-17,', which]), verbo([targets]), complemento(['RUNX1-3\'UTR,', negatively, affect, a, common, core, 'RUNX1-miRNA', mechanism, that, forces, myeloid, cells, into, an, 'undifferentiated,', 'KIT-induced,', proliferating, state])].
[sujeto(['In', the, second, part, of, this, study, we, took, advantage, of, the, conservation, of, the, core, 'RUNX1-miRNA', mechanism, in, mouse, and, 'human,', to, mechanistically, demonstrate, in, a, mouse, myeloid, cell, model, that]), verbo([increased]), complemento(['KIT-induced', proliferation, is, per, se, a, mechanism, sufficient, to, delay, myeloid, differentiation])].
[sujeto(['In', the, first, part, of, this, study, we]), verbo([found]), complemento([that, stable, 'miR-17', upregulation, 'affects,', like, the, 'CBF-AML', fusion, proteins, '(', 'RUNX1-MTG8', or, 'CBFB-MYH11),', a, core, 'RUNX1-miRNA', mechanism, leading, to, 'KIT-induced', proliferation, of, 'differentiation-arrested', 'U937', myeloid, cells])].
[sujeto(['The', integrated, information, gathered, from, the, two, myeloid, cell, models, shows, that, 'RUNX1']), verbo([regulates]), complemento([myeloid, differentiation, not, only, by, direct, transcriptional, regulation, of, coding, and, 'non-coding', myeloid, differentiation, functions, '(', e])].
[sujeto(['miR-223),', but, also, by]), verbo([modulating]), complemento(['KIT-induced', proliferation, via, 'non-coding', miRNAs, '(', e])].
[sujeto(['On', the, other, 'hand,', the, extent, of, 'KIT-induced', proliferation, itself, can]), verbo([modulate]), complemento([myeloid, differentiation, of, cells, with, wild, type, 'RUNX1', function])].
[sujeto(['CBFβ', and, 'RUNX1', form, a, 'DNA-binding', heterodimer, and, are, both]), verbo([required]), complemento([for, hematopoietic, stem, cell, '(', 'HSC)', generation, in, mice])].
[sujeto(['However,', the, nascent, 'HSCs', were, not]), verbo([released]), complemento([from, the, 'aorta-gonad-mesonephros', '(', 'AGM)', 'region,', as, evidenced, by, the, accumulation, of, 'runx1(+)', cells, in, the, 'AGM', that, could, not, enter, circulation])].
[sujeto(['Finally,', we]), verbo([found]), complemento([that, cbfb, was, downstream, of, the, 'Notch', pathway, during, 'HSC', development])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, runx1, and, cbfb, are, required, at, 2, different, steps, during, early, 'HSC', development])].
[sujeto(['CBFβ', is, not]), verbo([required]), complemento([for, nascent, 'HSC', emergence, but, is, required, for, the, release, of, 'HSCs', from, 'AGM', into, circulation])].
[sujeto(['Despite', the, absolute, requirements, for, these, factors, in, the, development, of, hematopoietic, stem, cells, and, 'lymphocytes,', their, roles, in, the, development, of, bone, marrow, progenitor, subsets]), verbo([have]), complemento([not, been, defined])].
[sujeto(['Besides', the]), verbo([loss]), complemento([of, 'DC', 'progenitors,', 'pan-hematopoietic', 'Cbfb-deficient', mice, also, lack, 'CD105(+)', erythroid, 'progenitors,', leading, to, severe, anemia, at, 3, to, 4, months, of, age])].
[sujeto(['RUNX1/CBFβ', '(', core]), verbo([binding]), complemento([factor, '[', 'CBF])', is, a, heterodimeric, transcription, factor, complex, that, is, frequently, involved, in, chromosomal, 'translocations,', point, 'mutations,', or, deletions, in, acute, leukemia])].
[sujeto(['The', mixed, lineage, leukemia, '(', 'MLL)', gene, is, also, frequently]), verbo([involved]), complemento([in, chromosomal, translocations, or, partial, tandem, duplication, in, acute, leukemia])].
[sujeto(['The', 'MLL', protein]), verbo([interacts]), complemento([with, 'RUNX1', and, prevents, 'RUNX1', from, 'ubiquitin-mediated', degradation])].
[sujeto(['RUNX1/CBFβ']), verbo([recruits]), complemento(['MLL', to, regulate, downstream, target, genes])].
[sujeto(['However,', the, functional, consequence, of, 'MLL', fusions, on, 'RUNX1/CBFβ', activity]), verbo([has]), complemento([not, been, fully, understood])].
[sujeto(['We', confirmed, this]), verbo([finding]), complemento([in, 'Mll-Af9', 'knock-in', mice, and, human, 'M4/M5', acute, myeloid, leukemia, '(', 'AML)', cell, 'lines,', with, or, without, 'MLL', 'translocations,', showing, that, 'MLL', translocations, cause, a, hypomorph, phenotype, of, 'RUNX1/CBFβ'])].
[sujeto(['Overexpression', of, 'RUNX1']), verbo([inhibits]), complemento([the, development, of, 'AML', in, 'Mll-Af9', 'knock-in', 'mice;', 'conversely,', further, reducing, 'Runx1/Cbfβ', levels, accelerates, 'MLL-AF9-mediated', 'AML', in, bone, marrow, transplantation, assays])].
[sujeto(['These', data]), verbo([reveal]), complemento([a, newly, defined, negative, regulation, of, 'RUNX1/CBFβ', by, 'MLL', fusion, proteins, and, suggest, that, targeting, 'RUNX1/CBFβ', levels, may, be, a, potential, therapy, for, 'MLLs'])].
[sujeto(['The', human, immunodeficiency, virus, '(', 'HIV)-1', protein, 'Vif']), verbo([has]), complemento([a, central, role, in, the, neutralization, of, host, innate, defences, by, hijacking, cellular, proteasomal, degradation, pathways, to, subvert, the, antiviral, activity, of, host, restriction, 'factors;', 'however,', the, underlying, mechanism, by, which, 'Vif', achieves, this, remains, unclear])].
[sujeto(['Here', we]), verbo([report]), complemento([a, crystal, structure, of, the, 'Vif-CBF-β-CUL5-ELOB-ELOC', complex])].
[sujeto(['The', structure]), verbo([reveals]), complemento([that, 'Vif,', by, means, of, two, 'domains,', organizes, formation, of, the, pentameric, complex, by, interacting, with, 'CBF-β,', 'CUL5', and, 'ELOC'])].
[sujeto(['The', larger, domain, '(', 'α/β', 'domain)', of, 'Vif']), verbo([binds]), complemento([to, the, same, side, of, 'CBF-β', as, 'RUNX1,', indicating, that, 'Vif', and, 'RUNX1', are, exclusive, for, 'CBF-β', binding])].
[sujeto(['Together,', our, data]), verbo([reveal]), complemento([the, structural, basis, for, 'Vif', hijacking, of, the, 'CBF-β', and, 'CUL5', 'E3', ligase, 'complex,', laying, a, foundation, for, rational, design, of, novel, 'anti-HIV', drugs])].
[sujeto(['Different', mechanisms, for, 'CBFβ-MYH11', function, in, acute, myeloid, leukemia, with, 'inv(16)']), verbo([have]), complemento([been, proposed, such, as, tethering, of, 'RUNX1', outside, the, 'nucleus,', interference, with, transcription, factor, complex, assembly, and, recruitment, of, histone, 'deacetylases,', all, resulting, in, transcriptional, repression, of, 'RUNX1', target, genes])].
[sujeto(['Here,', through, 'genome-wide', 'CBFβ-MYH11-binding', site, analysis, and, quantitative, interaction, 'proteomics,', we]), verbo([found]), complemento([that, 'CBFβ-MYH11', localizes, to, 'RUNX1', occupied, 'promoters,', where, it, interacts, with, 'TAL1,', 'FLI1', and, 'TBP-associated', factors, '(', 'TAFs)', in, the, context, of, the, hematopoietic, transcription, factors, 'ERG,', 'GATA2', and, 'PU'])].
[sujeto(['Transcriptional', analysis, revealed, that, upon, fusion, protein, 'knockdown,', a, small, subset, of, the, 'CBFβ-MYH11']), verbo([target]), complemento([genes, show, increased, 'expression,', confirming, a, role, in, transcriptional, repression])].
[sujeto(['However,', the, majority, of, 'CBFβ-MYH11']), verbo([target]), complemento(['genes,', including, genes, implicated, in, hematopoietic, stem, cell, 'self-renewal', such, as, 'ID1,', 'LMO1', and, 'JAG1,', are, actively, transcribed, and, repressed, upon, fusion, protein, knockdown])].
[sujeto(['Together', these, results]), verbo([suggest]), complemento([an, essential, role, for, 'CBFβ-MYH11', in, regulating, the, expression, of, genes, involved, in, maintaining, a, stem, cell, phenotype])].
[sujeto(['The', rare, but, recurrent, 'RUNX1-USP42', fusion, gene, is, the, result, of, a, 't(7;21)(p22;q22)', chromosomal, translocation, and]), verbo([has]), complemento([been, described, in, 6, cases, of, acute, myeloid, leukemia, '(', 'AML)', and, one, case, of, refractory, anemia, with, excess, of, blast])].
[sujeto(['The', bone, marrow, cells, in, the, present, case, also, had, a, 5, q, 'deletion,', and, it, was, revealed, that, 5, out, of, the, 8]), verbo([reported]), complemento([cases, '(', including, the, present, 'case)', with, 't(7;21)(p22;q22)/RUNX1-USP42', also, had, cytogenetic, abnormalities, of, 5, q])].
[sujeto(['Most', patients, with, acute, myeloid, leukemia, '(', 'AML)', and, genetic, rearrangements]), verbo([involving]), complemento([the, core, binding, factor, '(', 'CBF)', have, favorable, prognosis])].
[sujeto(['In', 'contrast,', a, minority, of, them, still]), verbo([have]), complemento([a, high, risk, of, leukemia, recurrence])].
[sujeto(['In', multivariate, 'analyses,', leukocyte, count, above, 20, &, 'nbsp;×&nbsp;10(9)', /, 'L,', 'BAALC', 'over-expression,', and, high, copy, numbers, of, 'RUNX1-RUNXT1', or, 'CBFB-MYH11', after, induction, chemotherapy, '(', 'CT)']), verbo([led]), complemento([to, increased, relapse, rate])].
[sujeto(['Regarding', 'OS,', age, &, 'gt;50&nbsp;yr,', leukocyte, count, above, 20, &, 'nbsp;×&nbsp;10(9)', /, 'L,', and]), verbo([increased]), complemento(['MN1', expression, were, adverse, features])].
[sujeto(['Core']), verbo([binding]), complemento([factor, '(', 'CBF)-positive', acute, myeloid, leukemia, '(', 'AML)', presents, a, favorable, 'prognosis,', except, for, patients, with, 'KIT', 'mutation,', especially, 'D816', mutation])].
[sujeto(['The', study, patients, consisted, of, 121, patients, with, 'CBF', 'AML', '(', 82, patients, with, 'RUNX1/RUNX1T1', '[', 67.8, &, 'nbsp;%]', and, 39, patients, with, 'CBFB/MYH11', '[', 32.2, &, 'nbsp;%])']), verbo([recruited]), complemento([from, eight, institutions, in, 'Korea'])].
[sujeto(['The', presence, of, 'KIT', 'D816', mutation, was]), verbo([associated]), complemento([with, adverse, outcomes, for, the, 'event-free', survival, '(', p, =, 0.03, ')', and, for, the, overall, survival, '(', p, =, 0.02, ')'])].
[sujeto(['Core']), verbo([binding]), complemento([factor, '(', 'CBF)', 'leukemias,', those, with, translocations, or, inversions, that, affect, transcription, factor, genes, 'RUNX1', or, 'CBFB,', account, for, '~24%', of, adult, acute, myeloid, leukemia, '(', 'AML)', and, 25, '%', of, pediatric, acute, lymphocytic, leukemia, '(', 'ALL)'])].
[sujeto(['Current', treatments, for, 'CBF', leukemias, are]), verbo([associated]), complemento([with, significant, morbidity, and, 'mortality,', with, a, 5, -, y, survival, rate, of, '~50%'])].
[sujeto(['We', hypothesize, that, the, interaction, between, 'RUNX1', and, 'CBFβ', is, critical, for, 'CBF', leukemia, and, can, be]), verbo([targeted]), complemento([for, drug, development])].
[sujeto(['Ro5-3335,', a, benzodiazepine, identified, from, the, 'screen,', was, able, to]), verbo([interact]), complemento([with, 'RUNX1', and, 'CBFβ', 'directly,', repress, 'RUNX1/CBFB-dependent', transactivation, in, reporter, 'assays,', and, repress, 'runx1-dependent', hematopoiesis, in, zebrafish, embryos])].
[sujeto(['Our', data, thus, confirmed, that, 'RUNX1-CBFβ', interaction, can, be]), verbo([targeted]), complemento([for, leukemia, treatment, and, we, have, identified, a, promising, lead, compound, for, this, purpose])].
[sujeto(['The', clinical, value, of, serial, minimal, residual, disease, '(', 'MRD)', monitoring, in, core]), verbo([binding]), complemento([factor, '(', 'CBF)', acute, myeloid, leukemia, '(', 'AML)', by, quantitative, 'RT-PCR', was, prospectively, assessed, in, 278, patients, '[', 163, with, 't(8;21)', and, 115, with, 'inv(16)]', entered, in, the, 'United', 'Kingdom', 'MRC', 'AML', 15, trial])].
[sujeto(['During', 'follow-up,', 'cut-off', 'MRD', thresholds, in, 'BM', and, 'PB']), verbo([associated]), complemento([with, a, 100, '%', relapse, rate, were, 'identified:', for, 't(8;21)', patients, 'BM', &, 'gt;', 500, 'copies,', 'PB', &, 'gt;', 100, 'copies;', for, 'inv(16)', 'patients,', 'BM', &, 'gt;', 50, copies, and, 'PB', &, 'gt;', 10, copies])].
[sujeto(['Breast', carcinoma, is, the]), verbo([leading]), complemento([cause, of, 'cancer-related', mortality, in, women, 'worldwide,', with, an, estimated, 1.38, million, new, cases, and, 458, ',', 0, deaths, in, 2008, alone])].
[sujeto(['Recurrent', somatic, alterations, in, breast, cancer]), verbo([have]), complemento([been, 'described,', including, mutations, and, copy, number, 'alterations,', notably, 'ERBB2', 'amplifications,', the, first, successful, therapy, target, defined, by, a, genomic, aberration])].
[sujeto(['Previous', 'DNA', sequencing, studies, of, breast, cancer, genomes]), verbo([have]), complemento([revealed, additional, candidate, mutations, and, gene, rearrangements])].
[sujeto(['Here', we]), verbo([report]), complemento([the, 'whole-exome', sequences, of, 'DNA', from, 103, human, breast, cancers, of, diverse, subtypes, from, patients, in, 'Mexico', and, 'Vietnam', compared, to, 'matched-normal', 'DNA,', together, with, 'whole-genome', sequences, of, 22, breast, 'cancer/normal', pairs])].
[sujeto(['Furthermore,', we]), verbo([have]), complemento([identified, a, recurrent, 'MAGI3-AKT3', fusion, enriched, in, 'triple-negative', breast, cancer, lacking, oestrogen, and, progesterone, receptors, and, 'ERBB2', expression])].
[sujeto(['The', 'MAGI3-AKT3', fusion]), verbo([leads]), complemento([to, constitutive, activation, of, 'AKT', 'kinase,', which, is, abolished, by, treatment, with, an, 'ATP-competitive', 'AKT', 'small-molecule', inhibitor])].
[sujeto(['Osteoarthritis', '(', 'OA)', is, a, degenerative, joint, disease, that]), verbo([involves]), complemento([the, destruction, of, articular, cartilage, and, eventually, leads, to, disability])].
[sujeto(['Molecules', that]), verbo([promote]), complemento([the, selective, differentiation, of, multipotent, mesenchymal, stem, cells, '(', 'MSCs)', into, chondrocytes, may, stimulate, the, repair, of, damaged, cartilage])].
[sujeto(['Using', an, 'image-based', 'high-throughput', 'screen,', we, identified, the, small, molecule, 'kartogenin,', which]), verbo([promotes]), complemento([chondrocyte, differentiation, '(', median, effective, concentration, =, 100, 'nM),', shows, chondroprotective, effects, in, 'vitro,', and, is, efficacious, in, two, 'OA', animal, models])].
[sujeto(['Kartogenin']), verbo([binds]), complemento([filamin, 'A,', disrupts, its, interaction, with, the, transcription, factor, 'core-binding', factor, β, subunit, '(', 'CBFβ),', and, induces, chondrogenesis, by, regulating, the, 'CBFβ-RUNX1', transcriptional, program])].
[sujeto(['This', work]), verbo([provides]), complemento([new, insights, into, the, control, of, chondrogenesis, that, may, ultimately, lead, to, a, stem, 'cell-based', therapy, for, osteoarthritis])].
[sujeto(['Yet', the, mechanisms, that]), verbo([target]), complemento(['PRCs', to, specific, loci, in, mammalian, cells, remain, incompletely, understood])].
[sujeto(['In', this, study, we, show, that, 'Bmi1,', a, core, component, of, 'Polycomb', 'Repressive', 'Complex', 1, '(', 'PRC1),']), verbo([binds]), complemento([directly, to, the, 'Runx1/CBFβ', transcription, factor, complex])].
[sujeto(['Genome-wide', studies, in, megakaryocytic, cells, demonstrate, significant, chromatin, occupancy, overlap, between, the, 'PRC1', core, component, 'Ring1b', and, 'Runx1/CBFβ', and, functional, regulation, of, a, considerable, fraction, of, commonly]), verbo([bound]), complemento([genes])].
[sujeto(['We', also, show, that, 'Ring1b', occupies, key, 'Runx1']), verbo([binding]), complemento([sites, in, primary, murine, thymocytes, and, that, this, occurs, via, 'PRC2-independent', mechanisms])].
[sujeto(['Genetic', depletion, of, 'Runx1', results, in, reduced, 'Ring1b']), verbo([binding]), complemento([at, these, sites, 'in&nbsp;vivo'])].
[sujeto(['These', findings]), verbo([provide]), complemento([evidence, for, 'site-specific', 'PRC1', chromatin, recruitment, by, core, binding, transcription, factors, in, mammalian, cells])].
[sujeto(['An', active, search, for, them, may]), verbo([provide]), complemento([both, pathogenetic, and, prognostic, novel, information])].
[sujeto(['ETV6/RUNX1', displayed, discordance, between, fusion, transcript, assay, and, 'FISH', results, as, well, as, rare, 'non-specific']), verbo([binding]), complemento([in, 'AL', samples, with, normal, or, complex, cytogenetics])].
[sujeto(['The', identification, of, minimal, residual, disease, '(', 'MRD)']), verbo([has]), complemento([led, to, substantial, improvements, in, early, recognition, of, the, recurrence, of, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['Besides,', more, than, 50, '%', of, all, 'AML', patients, lack, one, of, these, specific, 'sequences,', so, it, is, crucial, to, identify, molecular]), verbo([targets]), complemento([applicable, for, the, majority, of, patients])].
[sujeto(['These', features]), verbo([have]), complemento([led, to, its, adoption, for, 'MRD', detection, using, 'RQ-PCR'])].
[sujeto(['A', 'European', 'LeukemiaNet', 'Study']), verbo([found]), complemento([the, magnitude, of, 'WT1', log, reduction, after, induction, chemotherapy, to, be, an, independent, predictor, of, relapse])].
[sujeto(['Finally,', some, authors]), verbo([translated]), complemento([the, use, of, 'WT1', in, the, clinic, giving, donor, lymphocytes, infusions, to, patients, with, increasing, 'WT1-mRNA', levels, after, allogeneic, stem, cell, transplantation, and, obtaining, an, improvement, of, survival, in, this, subset])].
[sujeto(['Data', collected, on, 'WT1', expression, over, the, past, years]), verbo([provided]), complemento([evidence, for, the, use, of, this, molecular, marker, to, stratify, 'high-risk', 'AML', patients])].
[sujeto(['NanoString', nCounter, system, is, a, novel, 'probe-based', gene, expression, platform, capable, of, measuring, up, to, 800]), verbo([targets]), complemento([with, advantages, of, 'reproducibility,', 'accuracy,', and, sample, type, flexibility])].
[sujeto(['To', examine, the, value, of, minimal, residual, disease, '(', 'MRD)', by, multiparameter, flow, cytometry, '(', 'MFC)', in, core]), verbo([binding]), complemento([factor, '(', 'CBF)', acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto([1, ',', 0.01, to, 0.1, ',', 0.1, to, 1, ',', 1, to, 10, ',', and, &, 'gt;10%,', and]), verbo([reporting]), complemento(['MFC', '(', 'sensitivity,', 0.1, '%', -, 0.01, '%', ')', as, positive, or, 'negative,', κ, coefficient, test, showed, no, agreement, between, 'qRT-PCR', and, 'MFC', in, 'BM', samples, obtained, postinduction, '(', n, =, 44, ',', κ, =, 0.041, ')', ',', and, only, weak, agreement, during, consolidation, '(', n, =, 108, ',', κ, =, 0.083, ')', ',', 'maintenance/follow-up', '(', n, =, 107, ',', κ, =, 0.164, ')', ',', and, salvage, chemotherapy, '(', n, =, 24, ',', 0.376, ')'])].
[sujeto([1, '%', was]), verbo([associated]), complemento([with, lower, and, '≥10%', with, higher, 'AML', relapse, risk, '(', 'P', =])].
[sujeto(['In', the, latter, group, with, intermediate, 'qRT-PCR', 'results,', 'MFC']), verbo([provided]), complemento([prognostic, value, for, relapse, '(', 'P', =, 0.006, ')'])].
[sujeto(['The', most, common, subgroups, were, 'KMT2A', rearrangement, '(', 29, '%', ')', ',', normal, karyotype, '(', 15, '%', ')', ',', 'RUNX1-RUNX1T1', '(', 10, '%', ')', ',', deletions, of, 5, 'q,', 7, q, 'and/or', 17, p, '(', 9, '%', ')', ',', myeloid, leukaemia]), verbo([associated]), complemento([with, 'Down', syndrome, '(', 7, '%', ')', ',', 'PML-RARA', '(', 7, '%', ')', and, 'CBFB-MYH11', '(', 5, '%', ')'])].
[sujeto(['Single', nucleotide, polymorphism, array, '(', 'SNP-A)', analysis, and, exon, sequencing, of, 100, 'genes,', performed, in, 52, and, 40, 'cases,', respectively, '(', 39, 'overlapping),', revealed, '≥1', aberration, in, 89, '%', ;, when, adding, cytogenetic, 'data,', this, frequency]), verbo([increased]), complemento([to, 98, '%'])].
[sujeto(['Twenty-two', genes, were]), verbo([targeted]), complemento([by, focal, 'CNAs,', including, 'AEBP2', and, 'PHF6', deletions, and, genes, involved, in, 'AML-associated', gene, fusions])].
[sujeto(['In', 'total,', 60, mutations, were]), verbo([found]), complemento([in, 30, 'genes,', primarily, those, encoding, signalling, proteins, '(', 47, '%', ')', ',', transcription, factors, '(', 25, '%', ')', ',', or, epigenetic, modifiers, '(', 13, '%', ')'])].
[sujeto(['It', is]), verbo([required]), complemento([for, fetal, liver, hematopoiesis, and, skeletal, development])].
[sujeto(['Cbfb']), verbo([has]), complemento([two, functional, 'isoforms,', 'Cbfb1', and, 'Cbfb2,', which, are, formed, by, alternative, splicing])].
[sujeto(['Intramembranous', and, endochondral, ossification, was, retarded, and, chondrocyte, and, osteoblast, differentiation, was]), verbo([inhibited]), complemento([in, 'Cbfb2(-/-)', embryos, but, not, in, 'Cbfb1(-/-)', embryos])].
[sujeto(['Furthermore,', the, amounts, of, 'Runx', proteins, and, 'Cbfb', in, 'Cbfb2(-/-)', embryos, differed, similarly, among, skeletal, 'tissues,', 'livers,', and, 'thymuses,']), verbo([suggesting]), complemento([that, 'Runx', proteins, and, 'Cbfb', are, mutually, required, for, their, stability])].
[sujeto(['Although', 'Cbfb1(-/-)', embryos, developed, 'normally,', 'Cbfb1']), verbo([induced]), complemento([chondrocyte, and, osteoblast, differentiation, and, enhanced, 'DNA', binding, of, 'Runx2', more, efficiently, than, 'Cbfb2'])].
[sujeto(['Cbfb2', was, more, 'abundant,', but, 'Cbfb1', was, more, potent, for]), verbo([enhancing]), complemento(['Runx2', activity])].
[sujeto(['Although', only, 'Cbfb2']), verbo([loss]), complemento([generated, overt, skeletal, 'phenotypes,', both, may, play, major, roles, in, skeletal, development, with, functional, redundancy])].
[sujeto(['Genetic', alterations, such, as, chromosomal, 'translocations,', copy, number, variations, and, point, mutations]), verbo([have]), complemento([been, widely, reported, to, result, in, the, malfunction, of, 'RUNX', transcription, factors])].
[sujeto(['Leukemias', arising, from, such, alterations, in, 'RUNX', family, genes, are, collectively, termed, core]), verbo([binding]), complemento([factor, '(', 'CBF)', leukemias])].
[sujeto(['Over', the, 'years,', retroviral, 'transduction-transplantation', assays, and, 'transgenic,', knockin, and, knockout, mouse, models, alone, or, in, combination, with, mutagenesis]), verbo([have]), complemento([been, used, to, study, the, roles, of, 'RUNX', alterations, in, leukemogenesis])].
[sujeto(['Although', successful, in]), verbo([inducing]), complemento(['leukemia,', the, existing, assays, and, models, possess, many, inherent, limitations])].
[sujeto(['A', 'CBF', leukemia, model, which]), verbo([induces]), complemento([leukemia, with, complete, penetrance, and, short, latency, would, be, ideal, as, a, platform, for, drug, discovery])].
[sujeto(['Here,', we, summarize, the, currently, available, mouse, models, which]), verbo([have]), complemento([been, utilized, to, study, 'CBF', 'leukemias,', discuss, the, advantages, and, limitations, of, individual, experimental, 'systems,', and, propose, suggestions, for, improvements, of, mouse, models])].
[sujeto(['In', a, patient, with, acute, myeloid, leukemia, '(', 'AML)', following, 'therapy,']), verbo([finding]), complemento(['≥5%', bone, marrow, '(', 'BM)', blasts, is, highly, concerning, for, 'residual/relapsed', disease])].
[sujeto(['The', receptor, tyrosine, kinase, 'KIT', is]), verbo([expressed]), complemento([in, the, vast, majority, of, these, acute, myeloid, leukemias, and, frequent, activating, 'KIT', gene, mutations, have, been, associated, with, a, higher, risk, of, relapse])].
[sujeto(['The', disappearance, of, 'KIT', gene, mutations, at, relapse]), verbo([suggests]), complemento([that, clonal, devolution, may, in, part, explain, the, absence, of, efficacy, observed, with, 'single-agent', dasatinib, in, these, patients, '(', n])].
[sujeto(['In', acute, myeloid, leukaemia, '(', 'AML),', the, presence, of, 't(8;21)(q22;q22)', and, 'inv(16)(p13q22)/t(16;16)(p13;q22)', 'and/or', the, corresponding, molecular, rearrangements, 'RUNX1/RUNX1T1', and, 'CBFB/MYH11', '[', collectively, referred, to, as, core]), verbo([binding]), complemento([factor, '(', 'CBF)', 'AML]', predict, for, a, more, favourable, outcome, in, patients, receiving, 'cytarabine-anthracycline', based, induction, and, upon, achievement, of, complete, 'remission,', 'high-dose', cytarabine, consolidation, chemotherapy])].
[sujeto(['Clinical', studies, with]), verbo([targeting]), complemento([compounds, '(', e])].
[sujeto([gemtuzumab, 'ozogamicin,', 'dasatinib)', added, to, intensive, chemotherapy, appear, beneficial, both, in, younger, and, older, 'patients,', albeit, the, latter, continue, to]), verbo([have]), complemento([a, significantly, worse, outcome, than, the, former])].
[sujeto(['Regularly', molecular, monitoring, of, disease, during, remission, may]), verbo([provide]), complemento([a, strategy, for, early, therapeutic, intervention, before, overt, relapse])].
[sujeto(['Core-binding', factor, acute, myeloid, leukemia, '(', 'CBF-AML)', -, including, 'AML', with, 't(8;21)', and, 'AML', with, 'inv(16)', -, accounts, for, about, 15, '%', of, adult, 'AML', and, is]), verbo([associated]), complemento([with, a, relatively, favorable, prognosis])].
[sujeto(['Due', to, similarities, between, their, molecular, and, prognostic, 'features,', 't(8;21)', and, 'inv(16)-AML', are, usually, grouped, and]), verbo([reported]), complemento([together, in, clinical, studies])].
[sujeto(['However,', considerable, experimental, evidences]), verbo([have]), complemento([highlighted, that, they, represent, two, distinct, entities, and, should, be, considered, separately, for, further, studies])].
[sujeto(['The', diagnostics, of, leukemia, relies, upon, 'multi-parametric', approach]), verbo([involving]), complemento([a, number, of, different, pathology, disciplines, such, as, flow, 'cytometry,', 'histopathology,', cytogenetics, and, molecular, genetics, '[', fluorescent, in, situ, hybridization, '(', 'FISH)', and, polymerase, chain, reaction, '(', 'PCR)]'])].
[sujeto(['In', the, last, two, 'decades,', several, studies]), verbo([have]), complemento([reported, observations, that, 'PFG', are, present, in, healthy, population, and, not, necessarily, result, in, leukemia])].
[sujeto(['The', first, such, study, by, 'Limpens', and, colleagues, on, 't(14/18)/', 'BCL2-JH', '[', 1, ']', and, next, in, line, '[', 2, ',', 3, ']']), verbo([led]), complemento([to, many, questions, regarding, the, significance, of, these, chromosomal, translocations, in, leukemogenesis])].
[sujeto(['Translocation', 't(8;21)/', 'AML1', 'ETO', was]), verbo([found]), complemento([in, 4.4, '%', of, patients, with, a, mean, age, of, 45.4, 'years,', while, none, of, these, patients, was, older, than, 55, years])].
[sujeto(['Translocation', 't(15;17)/', 'PMLRARA', was]), verbo([found]), complemento([in, 5.5, '%', of, patients, with, a, mean, age, of, 52.6, years, and, an, almost, equal, distribution, between, younger, and, older, patients])].
[sujeto(['The', 'MLL', gene, rearrangements, were]), verbo([found]), complemento([in, 6.6, '%', of, 'patients,', the, -, 5, /, 5, 'q-', 'and/', or, -, 7, /, 7, 'q-', aberrations, in, 7.7, '%', of, 'patients,', while, the, most, frequent, genetic, abnormality, in, our, study, was, trisomy, 8, '(', 10, '%', ')'])].
[sujeto(['Moreover,', we]), verbo([found]), complemento([a, favorable, clinical, outcome, in, patients, expressing, fusion, genes, 'AML1-ETO', or, 'PMLRARA', in, contrast, to, an, adverse, clinical, outcome, with, few, remissions, and, death, in, 'AML', patients, with, 'MLL,', -, 5, 'q/', -, 5, and, -, 7, 'q/', 7, -])].
[sujeto(['Finally,', an, intermediate, prognosis, was]), verbo([found]), complemento([in, patients, with, trisomy, 8])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([a, good, congruence, with, published, literature, on, the, incidence, and, prognostic, value, of, several, well, established, 'AML-associated', genetic, aberrations])].
[sujeto(['The', multiplex, 'RT-nPCR', used, in, this, study, can, 'quickly,', effectively, and, accurately, screen, the, fusion, genes, in, 'AML', 'patients,', which, can]), verbo([provide]), complemento([important, evidence, for, assessing, diagnosis, and, 'treatment,', and, also, provide, necessary, information, for, minimal, residual, disease, '(', 'MRD)', and, prognosis])].
[sujeto(['Within', the, past, few, 'years,', the, invention, of, 'next-generation', sequencing]), verbo([has]), complemento([revealed, several, new, genes, associated, with, tumor, formation, and, 'development,', for, example, 'DNMT3a'])].
[sujeto(['PCR', amplification, of, the, entire, coding, region, of, 'DNMT3a', was, performed, using, 23, overlapping]), verbo([primer]), complemento([pairs, in, 57, patients, who, were, diagnosed, in, 'Blood', 'Disease', 'Hospital', of, 'Chinese', 'Academy', of, 'Medical', 'Sciences,', then, the, directly, sequencing, was, underwent])].
[sujeto(['The', results, showed, that, no, 'DNMT3a', mutation, was]), verbo([found]), complemento([in, these, patients, including, the, hotspot, 'R882'])].
[sujeto(['But', 'AML1/ETO', mutation, was]), verbo([found]), complemento([in, 10, 'patients,', 'CBFB/MYH11', mutation, in, 3, 'patients,', 'PML/RARa', mutation, in, 13, 'patients,', 'FLT3/ITD', mutation, in, 5, 'patients,', 'FLT3/TKD', mutation, in, 1, 'patient,', 'PML/RARa', and, 'FLT3/TKD', mutation, coexisted, in, 2, patients])].
[sujeto(['Most', sensitive, methodology, to, detect, 'MRD', is, molecular, polymerase, chain, reaction, '(', 'PCR)', but, its, applicability, is, restricted, to, 'AML', with, 'leukemia-specific', molecular]), verbo([targets]), complemento(['(', e])].
[sujeto(['To', realize, the, methodology, that, better, identify, high, risk, 'patients,', an, analysis, of, 'sensitivity,', 'specificity,', predictive, values, '(', 'PV)', and, likelihood, ratio, '(', 'LR)', was]), verbo([provided]), complemento([and, similar, results, were, showed])].
[sujeto([1, ;, 'q22);', 'CBFB-MYH11', chromosomal, 'rearrangements,', but, whether, the, mutation, is, indicative, of]), verbo([associated]), complemento(['SM', is, unclear])].
[sujeto(['Five', of, the, eight, cases, carried, the, mutation, in, a, cell, fraction, below, 'one-tenth', of, the, blast, cell, 'fraction,', thus]), verbo([suggesting]), complemento([that, 'KIT', mutation, is, often, a, late, event, in, leukemogenesis])].
[sujeto(['The', presence, of, the, 'KIT', 'D816V', mutation, in, the, 'CBF', 'AML', subgroup, can, therefore, not, be, considered, indicative, of]), verbo([associated]), complemento(['SM'])].
[sujeto(['The', rearrangements, 't(8;21)', and, 'inv(16)']), verbo([involve]), complemento([the, 'RUNX1/RUNX1T1', '(', 'AML1-ETO', ')', and, 'CBFB/MYH11', 'genes,', respectively])].
[sujeto(['The', 't(8;21)', and, 'inv(16)', subtypes, of, 'AML']), verbo([have]), complemento([been, usually, grouped, and, reported, together, in, clinical, 'studies;', 'however,', recent, studies, have, demonstrated, 'genetic,', 'clinical,', and, prognostic, 'differences,', supporting, the, notion, that, they, represent, 2, distinct, biologic, and, clinical, entities])].
[sujeto(['No', correlation, was, observed, between, incidence, and, age, except, for, 'BCR-ABL', p210, 'fusion,', the, incidence, of, which, rises, with]), verbo([increasing]), complemento([age])].
[sujeto(['To', our, 'knowledge,', the, presence, of, 'PML-RARA', and, 'CBFB-MYH11', in, healthy, individuals]), verbo([has]), complemento([not, been, previously, described])].
[sujeto(['The', present, study]), verbo([provides]), complemento([further, evidence, for, the, presence, of, 'LLA', genetic, alterations, in, healthy, individuals, and, suggests, that, these, mutations, are, not, themselves, sufficient, for, malignant, transformation])].
[sujeto(['AML1-ETO', fusion, gene, transcript, was]), verbo([found]), complemento([in, 14, patients, '(', 19, '%', ')'])].
[sujeto(['Duplication', of, 'FLT3', gene, was]), verbo([found]), complemento([in, 4, '(', 5.3, '%', ')', cases])].
[sujeto(['Analysis', of, 'MRD', level, in, subsequent, time, points, showed, systematic]), verbo([decrease]), complemento([of, number, of, fusion, gene, transcript, copies, and, gene, 'WT1', expression])].
[sujeto(['To', establish, the, rate, of, molecular, marker, presence, in, 'AML', in, children, and, the, influence, of, the, presence, of, 'MRD', on, the, treatment, results, as, 'well,', the, study]), verbo([has]), complemento([to, be, conducted, on, a, larger, group, of, patients, with, longer, 'follow-up'])].
[sujeto(['Many', oncogenetic, aberrations, in, acute, leukemias, result, in, a, fusion, 'gene,', which, is]), verbo([transcribed]), complemento([into, fusion, transcripts, and, translated, into, fusion, 'proteins,', which, are, assumed, to, play, a, critical, role, in, the, oncogenetic, process])].
[sujeto(['So', 'far,', we]), verbo([have]), complemento([been, able, to, design, such, fusion, protein, immunobead, assays, for, 'BCR-ABL,', 'PML-RARA,', 'TEL-AML1,', 'E2A-PBX1,', 'MLL-AF4,', 'AML1-ETO', and, 'CBFB-MYH11'])].
[sujeto(['The', novel, immunobead, assay, will, enable, fast, and, easy, classification, of, acute, leukemia, patients, that]), verbo([express]), complemento([fusion, proteins])].
[sujeto(['Fluorescence', in, situ, hybridization, '(', 'FISH)', analysis, can]), verbo([provide]), complemento([important, information, in, the, management, of, patients, with, hematologic, malignancies])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, performing, 'FISH', in, addition, to, 'G-banded', karyotype, may, contribute, little, additional, genetic, information, in, 'AML', and, 'MDS,', whereas, routine, 'FISH', analysis, appears, to, be, an, efficient, screening, method, in, 'ALL', and, 'MM'])].
[sujeto(['In', a, 'large-scale', miRNA, expression, profiling, analysis, of, 435, human, miRNAs, in, 52, acute, myeloid, leukemia, '(', 'AML)', 'samples,', we]), verbo([found]), complemento([that, 'miR-126', and, its, minor, counterpart, in, 'biogenesis,', 'namely,', 'miR-126*,', were, specifically, aberrantly, overexpressed, in, core, binding, factor, '(', 'CBF)', 'AMLs', including, both, 't(8;21)/AML1-ETO', and, 'inv(16)/CBFB-MYH11', samples])].
[sujeto(['Our', in, vitro, 'gain-', and, 'loss-of-function', experiments, showed, that, forced, expression, of, 'miR-126']), verbo([inhibited]), complemento([apoptosis, and, increased, the, viability, of, 'AML', 'cells,', whereas, the, opposite, effect, was, observed, when, endogenous, expression, of, 'miR-126', was, knocked, down])].
[sujeto(['In', 'addition,', through, in, vitro, 'colony-forming/replating', 'assays,', we, demonstrated, that, forced, expression, of, 'miR-126']), verbo([enhanced]), complemento([proliferation, and, 'colony-forming/replating', capacity, of, mouse, normal, bone, marrow, progenitor, cells, alone, and, 'particularly,', in, cooperation, with, 'AML1-ETO,', a, fusion, gene, resulting, from, 't(8;21)'])].
[sujeto(['Aberrant', promoter, 'DNA', methylation]), verbo([has]), complemento([been, shown, to, play, a, role, in, acute, myeloid, leukemia, '(', 'AML)', pathophysiology])].
[sujeto(['Methylation', signatures, were]), verbo([associated]), complemento([with, the, presence, of, a, specific, cytogenetic, status])].
[sujeto(['The', presence, of, 'MLL', rearrangements, in, 'HSPC']), verbo([induced]), complemento([the, methylation, profile, observed, in, the, 'MLL-positive', primary, samples])].
[sujeto(['Our', study]), verbo([provides]), complemento([a, comprehensive, epigenetic, profiling, of, 'AML,', identifies, new, clinical, markers, for, cases, with, a, normal, 'karyotype,', and, reveals, relevant, biological, information, related, to, the, role, of, fusion, proteins, on, the, methylation, signature])].
[sujeto(['Inv(16)(p13q22)', is]), verbo([associated]), complemento([with, acute, myeloid, leukemia, subtype, 'M4Eo', that, is, characterized, by, the, presence, of, myelomonocytic, blasts, and, atypical, eosinophils])].
[sujeto(['CBF', beta, normally]), verbo([interacts]), complemento([with, 'RUNX1', to, form, a, transcriptionally, active, nuclear, complex])].
[sujeto(['The', 'CBF', 'beta-SMMHC', fusion, protein, is, capable, of]), verbo([binding]), complemento([to, 'RUNX1', and, form, dimers, and, multimers, through, its, myosin, tail])].
[sujeto(['Previous', results, from, transgenic, mouse, models, show, that, 'Cbfb-MYH11', is, able, to]), verbo([inhibit]), complemento([dominantly, 'Runx1', function, in, 'hematopoiesis,', and, is, a, key, player, in, the, pathogenesis, of, leukemia])].
[sujeto(['In', recent, 'years,', molecular, and, cellular, biological, studies]), verbo([have]), complemento([led, to, the, proposal, of, several, models, to, explain, the, function, of, 'CBF', 'beta-SMMHC'])].
[sujeto(['Core-binding', factor, beta, '(', 'CBFbeta,', also, called, polyomavirus, enhancer]), verbo([binding]), complemento([protein, 2, beta, '(', 'PEBP2B))', is, associated, with, an, inversion, of, chromosome, 16, and, is, associated, with, acute, myeloid, leukemia, in, humans])].
[sujeto(['CBFbeta', forms, a, heterodimer, with, 'RUNX1', '(', 'runt-related', transcription, factor, 1, ')', ',', which]), verbo([has]), complemento([a, 'DNA', binding, domain, homologous, to, the, 'pair-rule', protein, runt, in, 'Drosophila', melanogaster])].
[sujeto(['Haploinsufficiency', of, another, 'runt-related', 'protein,', 'RUNX2', '(', also, called, 'CBFA1),']), verbo([causes]), complemento([cleidocranial, dysplasia, in, humans, and, is, essential, in, skeletal, development, by, regulating, osteoblast, differentiation, and, chondrocyte, maturation])].
[sujeto(['Mice', deficient, in, 'Cbfb', '(', 'Cbfb(-/-))', die, at, 'midgestation,', so, the, function, of, 'Cbfbeta', in, skeletal, development]), verbo([has]), complemento([yet, to, be, ascertained])].
[sujeto(['Electrophoretic', mobility, shift, assays, and, reporter, assays, showed, that, 'Cbfbeta', was, necessary, for, the, efficient, 'DNA']), verbo([binding]), complemento([of, 'Runx2', and, for, 'Runx2-dependent', transcriptional, activation])].
[sujeto(['These', findings, indicate, that, 'Cbfbeta', is]), verbo([required]), complemento([for, the, function, of, 'Runx2', in, skeletal, development])].
[sujeto(['Here', we, demonstrate, that, 'Ikaros', also]), verbo([regulates]), complemento(['Th17', differentiation, through, its, ability, to, promote, expression, of, multiple, 'Th17', 'lineage-determining', 'genes,', including, 'Ahr,', 'Runx1,', 'Rorc,', 'Il17a,', and, 'Il22'])].
[sujeto(['In', naive, 'cells,', 'Ikaros', is]), verbo([required]), complemento([to, limit, repressive, chromatin, modifications, at, these, gene, 'loci,', thus, maintaining, the, potential, for, expression, of, the, 'Th17', gene, program])].
[sujeto(['Additionally,', 'Ikaros']), verbo([represses]), complemento([the, expression, of, genes, that, limit, 'Th17', 'development,', including, 'Foxp3', and, 'Tbx21'])].
[sujeto(['These', data, define, new]), verbo([targets]), complemento([of, the, action, of, 'Ikaros', and, indicate, that, 'Ikaros', plays, a, critical, role, in, 'CD4+', 'T', cell, differentiation, by, integrating, specific, cytokine, cues, and, directing, epigenetic, modifications, that, facilitate, activation, or, repression, of, relevant, genes, that, drive, 'T', cell, lineage, choice])].
[sujeto(['Forced', expression, of, the, transcription, factor, 'HoxB4']), verbo([has]), complemento([been, shown, to, enhance, the, 'self-renewal', capacity, of, mouse, bone, marrow, hematopoietic, stem, cells, '(', 'HSCs)', and, confer, a, 'long-term', repopulating, capacity, to, yolk, sac, and, embryonic, stem, '(', 'ES)', 'cell-derived', hematopoietic, precursors])].
[sujeto(['The', results, revealed, many, of, the, genes, essential, for, 'HSC', development, to, be, direct]), verbo([targets]), complemento([of, 'HoxB4,', such, as, 'Runx1,', 'Scl/Tal1,', 'Gata2,', and, 'Gfi1'])].
[sujeto(['HoxB4', tended, to]), verbo([activate]), complemento([the, 'transcription,', but, the, 'down-regulation', of, a, significant, portion, of, direct, targets, suggested, its, function, to, be, 'context-dependent'])].
[sujeto(['Our', list, of, 'HoxB4']), verbo([targets]), complemento([also, provides, novel, candidate, regulators, for, 'HSCs'])].
[sujeto(['AML1-ETO', fusion, protein, is, a, product, of, chromosome, translocation, 't(8;21)', frequently, occurred, in, acute, myeloid, leukemia, '(', 'AML),', but, its, sole, expression, appears, to, fail, to]), verbo([cause]), complemento([overt, leukemia, in, vivo])].
[sujeto(['AML1-ETO', fusion, protein, was, conditionally]), verbo([induced]), complemento([in, engineered, 'U937-A/E', 9, /, 14, /, 18, cells])].
[sujeto(['Our', results, showed, that, 'AML1-ETO', induction, significantly]), verbo([increased]), complemento([the, formation, of, carcinogen, 'benzopyrene-DNA', adducts, in, leukemic, cells])].
[sujeto(['In', line, with, the, 'effect,', we, also]), verbo([found]), complemento([that, 'AML1-ETO', induction, upregulated, 'CYP1A1', 'expression,', which, was, dependent, on, 'AML1-binding', motif, in, the, promotor, of, 'CYP1A1', gene])].
[sujeto(['Additionally,', 'AML1-ETO', protein, also]), verbo([increased]), complemento(['AhR', 'expression,', a, 'ligand-activated', transcription, factor, that, mediates, 'PAHs-induced', 'CYP1A1', gene, expression])].
[sujeto(['These', 'data,', combined, with, its, inhibitory, effect, on, 'DNA', repair, as]), verbo([reported]), complemento(['previously,', propose, that, the, presence, of, 'AML1-ETO', increases, the, susceptibility, of, cells, to, chemical, 'carcinogens,', which, favors, the, development, of, additional, genetic, alterations])].
[sujeto(['Homoharringtonine', combined, aclarubicin, and, cytarabine, '(', 'HAA)']), verbo([has]), complemento([been, demonstrated, to, achieve, a, high, remission, rate, and, provide, a, survival, advantage, in, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['The', median, fold]), verbo([decrease]), complemento([of, the, 'RUNX1/RUNX1T1', transcript, level, was, 200, '(', 1, -, 358000, ')', ',', and, 16.7, '%', '(', 5, /, 30, ')', patients, achieved, &, 'gt;3', log, decrease, after, one, cycle, of, the, 'HAA', regimen])].
[sujeto(['Cytogenetically', normal, acute, myeloid, leukemia, '(', 'CN-AML)', patients, harboring, 'RUNX1', mutations]), verbo([have]), complemento([a, dismal, prognosis, with, 'anthracycline/cytarabine-based', chemotherapy])].
[sujeto(['Tail', vein, injection, of, 'CG-SH', into, 'NOD', scid, gamma, mice]), verbo([led]), complemento([to, leukemic, engraftment, in, the, bone, 'marrow,', 'spleen,', and, peripheral, blood, within, 6, weeks])].
[sujeto(['Single', nucleotide, polymorphism, '(', 'SNP)', rs11671784, is, in, the, loop, of, 'pre-miR-27a', and, the, 'G/A', variation, can, significantly]), verbo([decrease]), complemento([mature, 'miR-27a', expression])].
[sujeto(['In-vitro', study, was, performed, to, explore, the, mechanism, of, 'chemo-sensitivity', and, the, downstream]), verbo([target]), complemento([of, 'miR-27a', by, using, bladder, cancer, cell, lines])].
[sujeto(['This', study, identified, a, causative, relationship, between, rs11671784, 'G/A', 'variation,', lowered, 'miR-27a', 'expression,']), verbo([increased]), complemento(['RUNX-1', expression, and, following, weakened, 'chemo-sensitivity'])].
[sujeto([rs11671784, 'G', allele]), verbo([has]), complemento([significantly, stronger, effect, over, 'A', allele, in, promoting, 'chemo-sensitivity', in, bladder, cancer])].
[sujeto(['miR-27a']), verbo([mediates]), complemento([chemotherapy, at, least, partially, through, reducing, 'P-gp', expression, and, increasing, apoptosis])].
[sujeto(['In', 'addition,', 'RUNX-1', is, a, novel, direct]), verbo([target]), complemento([of, 'miR-27a,', which, is, involved, in, its, regulation, of, 'chemo-sensitivity', in, bladder, cancer])].
[sujeto(['The', presence, of, 'FISH(+)CD34(+)CD38(-)', cells, before, consolidation, was, negatively]), verbo([associated]), complemento([with, cumulative, incidence, of, relapse, '(', 64, vs, 18, '%', ',', 'P', =])].
[sujeto([5, ')', ',', and]), verbo([retained]), complemento([prognostic, significance, for, 'RFS', in, multivariate, analysis])].
[sujeto(['EPs', can, revert, to, 'SCs', upon, 'injury,', but, whether, this, dedifferentiation, occurs, in, normal, 'HF', homeostasis, '(', hair, 'cycle)', and, the, mechanisms]), verbo([regulating]), complemento([both, differentiation, and, dedifferentiation, are, unclear])].
[sujeto(['Here,', we, use, lineage, 'tracing,']), verbo([gain]), complemento([of, 'function,', transcriptional, 'profiling,', and, functional, assays, to, examine, the, role, of, observed, endogenous, 'Runx1', level, changes, in, the, hair, cycle])].
[sujeto(['We']), verbo([find]), complemento([that, forced, 'Runx1', expression, induces, hair, degeneration, '(', 'catagen)', and, simultaneously, promotes, changes, in, the, quiescent, bulge, 'SC', transcriptome, toward, a, cell, state, resembling, the, 'EP', 'HG', fate])].
[sujeto(['We', propose, that, 'SC', differentiation, and, dedifferentiation, are, likely, to, occur, during, normal, 'HF', degeneration, and, niche, restructuring, in, response, to, changes, in, endogenous, 'Runx1', levels]), verbo([associated]), complemento([with, 'SC', location, with, respect, to, the, niche])].
[sujeto(['Rearrangements']), verbo([involving]), complemento([the, 'RUNX1', gene, account, for, approximately, 15, '%', of, balanced, translocations, in, 'therapy-related', acute, myeloid, leukemia, '(', 't-AML)', patients, and, are, one, of, the, most, common, genetic, abnormalities, observed, in, 't-AML'])].
[sujeto(['Drugs']), verbo([targeting]), complemento([the, topoisomerase, 'II', '(', 'TOP2)', enzyme, are, implicated, in, 't-AML;', 'however,', the, mechanism, is, not, well, understood, and, to, date, a, single, 'RUNX1-RUNX1T1', 't-AML', breakpoint, junction, sequence, has, been, published])].
[sujeto(['Here', we]), verbo([report]), complemento([an, additional, five, breakpoint, junction, sequences, from, 't-AML', patients, with, the, 'RUNX1-', 'RUNX1T1', translocation])].
[sujeto(['Using', a, leukemia, cell, line, 'model,', we, show, that, 'TOP2', beta, '(', 'TOP2B)', is]), verbo([required]), complemento([for, induction, of, 'RUNX1', chromosomal, breaks, by, the, 'TOP2', poison, etoposide, and, 'that,', while, 'TOP2', alpha, '(', 'TOP2A)', and, 'TOP2B', proteins, are, both, present, on, 'RUNX1', and, 'RUNX1T1', 'chromatin,', only, the, 'TOP2B', enrichment, reached, significance, following, etoposide, exposure, at, a, region, on, 'RUNX1', where, translocations, occur])].
[sujeto(['Specifically,', we, identified, a, 'TOP2B-dependent']), verbo([increase]), complemento([in, the, number, of, nuclei, displaying, juxtaposed, 'RUNX1', and, 'RUNX1T1', loci, following, etoposide, treatment])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([found, for, the, first, time, that, 'Runt-related', transcription, factor, 1, '(', 'RUNX1)', contributes, to, 'p53-dependent', 'DNA', damage, response])].
[sujeto(['Upon', adriamycin, '(', 'ADR)', 'exposure,', p53, as, well, as, 'RUNX1', were, strongly]), verbo([induced]), complemento([in, 'p53-proficient', 'HCT116', and, 'U2OS', 'cells,', which, were, closely, associated, with, significant, transactivation, of, p53, target, 'genes,', such, as, 'p21(WAF)(1),', 'BAX,', 'NOXA,', and, 'PUMA'])].
[sujeto(['RUNX1', was, exclusively]), verbo([expressed]), complemento([in, the, cell, nucleus, and, formed, a, complex, with, p53, in, response, to, 'ADR'])].
[sujeto(['Chromatin', immunoprecipitation, assay, demonstrated, that, p53, together, with, 'RUNX1', are, efficiently]), verbo([recruited]), complemento([onto, p53, target, gene, promoters, following, 'ADR', 'exposure,', indicating, that, 'RUNX1', is, involved, in, 'p53-mediated', transcriptional, regulation])].
[sujeto(['Indeed,', forced, expression, of, 'RUNX1']), verbo([stimulated]), complemento([the, transcriptional, activity, of, p53, in, response, to, 'ADR'])].
[sujeto(['Consistent', with, these, 'observations,', knockdown, of, 'RUNX1', attenuated, 'ADR-mediated', induction, of, p53]), verbo([target]), complemento([genes, and, suppressed, 'ADR-dependent', apoptosis])].
[sujeto(['Furthermore,', 'RUNX1', was]), verbo([associated]), complemento([with, p300, histone, 'acetyltransferase,', and, 'ADR-dependent', acetylation, of, p53, at, 'Lys-373/382', was, markedly, inhibited, in, 'RUNX1', knockdown, cells])].
[sujeto(['In', 'addition,', knockdown, of, 'RUNX1', resulted, in, a, significant]), verbo([decrease]), complemento([in, the, amount, of, 'p53-p300', complex, following, 'ADR', exposure])].
[sujeto(['Taken', 'together,', our, present, results, strongly]), verbo([suggest]), complemento([that, 'RUNX1', is, required, for, the, stimulation, of, p53, in, response, to, 'DNA', damage, and, also, provide, novel, insight, into, understanding, the, molecular, mechanisms, behind, 'p53-dependent', 'DNA', damage, response])].
[sujeto(['The', 5, -, year, cumulative, incidence, of, relapse, was, 19.4, '%', and, testes, were, more, frequently]), verbo([involved]), complemento([in, 'ETV6/RUNX1-positive', relapses, '(', 'P=0'])].
[sujeto(['In', univariate, 'analysis,', female, gender, was]), verbo([associated]), complemento([with, a, poor, 'survival,', whereas, site, of, 'relapse,', age, at, 'diagnosis,', leukocytosis, and, consolidation, strategy, had, no, effect])].
[sujeto(['In', multivariate, 'analysis,', only, the, duration, of, first, remission, remained]), verbo([associated]), complemento([with, outcome])].
[sujeto(['We']), verbo([found]), complemento([an, excellent, outcome, for, patients, with, 'ETV6/RUNX1-positive', leukemia, relapses, that, occurred, more, than, 36, months, after, diagnosis])].
[sujeto(['Here', we]), verbo([report]), complemento([that, triptolide, inhibits, cell, proliferation, and, induces, apoptosis, in, a, 'dose-', and, 'time-dependent', manner, of, 't(8;21)-bearing', 'Kasumi-1,', 'SKNO-1', and, 'CD34+', cells, harvested, from, bone, marrow, samples, of, patients, with, 't(8;21)', leukemia])].
[sujeto(['We', show, that, triptolide]), verbo([triggers]), complemento([cleavage, of, the, resultant, 'AML1-ETO', fusion, protein, of, 't(8;21),', and, causes, downregulation, of, 'C-KIT', followed, by, inhibition, of, 'JAK-STAT', signaling])].
[sujeto(['Triptolide', downregulates, p65, and]), verbo([inhibits]), complemento([the, 'DNA-binding', activity, of, 'NF-κB'])].
[sujeto(['Culture', with, 'BMP-2', or, 'BMP-6+AA']), verbo([increased]), complemento(['ALP', activity, of, 'PDLCs,', suggesting, their, 'osteo-inductive', effects])].
[sujeto(['However,', longer, duration, of, culture, showed, neither, of, the, 'BMPs']), verbo([induced]), complemento([in, vitro, mineralization])].
[sujeto(['In', 'contrast,', 'OS', were, able, to]), verbo([increase]), complemento(['ALP', activity, and, 'OPN', 'expressions,', and, also, induced, in, vitro, mineralization])].
[sujeto(['The', mineralization, ability, was, not]), verbo([enhanced]), complemento([by, the, addition, of, 'BMP-2', or, 'BMP-6'])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, addition, of, 'BMP-2', or, 'BMP-6', to, 'OS', may, not, enhance, an, osteogenic, differentiation, of, hPDLCs])].
[sujeto(['Runx1,', a, 'Runt', domain, transcription, 'factor,', controls, the, differentiation, of, nociceptors, that]), verbo([express]), complemento([the, neurotrophin, receptor, 'Ret,', regulates, the, expression, of, many, ion, channels, and, 'receptors,', and, controls, the, 'lamina-specific', innervation, pattern, of, nociceptive, afferents, in, the, spinal, cord])].
[sujeto(['We']), verbo([activated]), complemento([ectopic, expression, of, 'Runx1a', in, cultured, 'NCSCs', using, the, 'Tet-ON', gene, regulatory, system, during, the, formation, of, neurospheres, and, analyzed, the, proportion, of, neurons, and, glial, cells, originating, from, 'NCSCs'])].
[sujeto(['Offsprings', in, which, 'Runx1a', had, been]), verbo([activated]), complemento([showed, retarded, growth, and, displayed, 'megacolon,', pigment, 'defects,', and, dystrophic, dorsal, root, ganglia])].
[sujeto(['In', the, neuropathic, pain, 'model,', the, threshold, for, mechanical, sensitivity, was, markedly]), verbo([increased]), complemento([following, activation, of, 'Runx1a'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'Runx1a', has, a, specific, role, in, 'NCSC', development, and, that, modulation, of, 'Runx1a', activity, may, reduce, mechanical, hypersensitivity, associated, with, neuropathic, pain])].
[sujeto(['We']), verbo([report]), complemento([a, case, of, a, 31, -, 'year-old', female, with, a, positive, 'RUNX1/CBFA2T1', '(', alias, 'AML1/ETO)', fusion, gene, and, a, karyotype, with, a, 't(2;21;8)(p12;q22;q22)'])].
[sujeto(['Although', variant, translocations]), verbo([involving]), complemento([chromosome, region, 2, p12, have, never, been, reported, 'before,', we, suppose, this, translocation, may, be, responsible, for, the, clinical, manifestation, and, prognosis, of, this, case])].
[sujeto(['The', translocation, 't(16;21)']), verbo([involving]), complemento(['RUNX1', '(', 'AML1)', and, resulting, in, the, 'RUNX1-CBFA2T3', fusion, is, a, rare, but, recurrent, abnormality, mostly, found, in, 'therapy-related', acute, myeloid, leukemia, '(', 't-AML)', associated, with, agents, targeting, topoisomerase, 'II', '(', topo, 'II)'])].
[sujeto(['This', study]), verbo([suggests]), complemento([a, wider, distribution, in, the, human, 'genome,', and, particularly, at, genes, involved, in, chromosome, translocations, observed, in, 't-AML,', of, 'DNA', regions, '(', 'hotspot)', targeted, by, specific, topo, 'II', drugs])].
[sujeto(['The', median, copy, number, of, the, 'RUNX1/MTG8', 'transcript,', measured, after, each, treatment, course]), verbo([decreased]), complemento([over, time])].
[sujeto(['However,', an]), verbo([increase]), complemento([in, the, 'MRD', level, was, documented, in, three, patients, after, the, second, 'consolidation,', and, all, of, them, subsequently, relapsed])].
[sujeto(['But', no, data]), verbo([have]), complemento([been, available, up, to, date, concerning, mutual, positioning, of, these, particular, genes, in, the, nucleus, of, a, living, cell, as, well, as, the, mechanism, of, their, rapprochement, and, realignment])].
[sujeto(['Here', we, show, that, there, is, no, proximity, between, these, two, genes, in, the, primary, nuclei, of, normal, human, male, fibroblasts, and, moreover, that, these, genes, are, located, in, different]), verbo([nuclear]), complemento([layers])].
[sujeto(['But', we, further, show, that, treatment, of, cells, with, 'VP-16', '(', 'etoposide),', an, inhibitor, of, 'DNA', topoisomerase, 'II', widely, used, in, anticancer, 'chemotherapy,']), verbo([causes]), complemento([the, 'ETO', gene, repositioning, which, allows, 'AML1', and, 'ETO', genes, to, be, localized, in, the, same, nuclear, layer])].
[sujeto(['Finally,', inhibition, of, 'ETO', gene, repositioning, by, 2, ',', 3, -, butanedione, monoxime, '(', 'BDM)']), verbo([suggests]), complemento([that, this, process, depends, on, nuclear, myosin])].
[sujeto(['Mesenchymal', stem, cells, '(', 'MSC)']), verbo([have]), complemento([been, derived, from, different, cultured, human, 'tissues,', including, bone, 'marrow,', adipose, 'tissue,', amniotic, fluid, and, umbilical, cord, blood])].
[sujeto(['Only', recently, it, was]), verbo([suggested]), complemento([that, 'MSC', descended, from, perivascular, 'cells,', the, latter, being, defined, as, 'CD146⁺', 'neuro-glial', proteoglycan, '(', 'NG)2⁺', 'platelet-derived', growth, 'factor-Rβ⁺', 'ALP⁺', 'CD34⁻', 'CD45⁻', von, 'Willebrand', factor, '(', 'vWF)⁻', 'CD144⁻'])].
[sujeto(['Moreover,', foetal, 'HUC', perivascular, cells, '(', 'HUCPC)']), verbo([express]), complemento([the, embryonic, cell, markers, specific, embryonic, 'antigen-4,', 'Runx1', and, 'Oct-4', and, can, be, cultured, over, the, long, term])].
[sujeto(['The', secretory, profile, exhibited, by, foetal, 'HUCPC', in, the, migration, assay]), verbo([suggested]), complemento([a, paracrine, effect, that, could, be, exploited, in, various, clinical, conditions, including, lung, disorders])].
[sujeto(['The', 'tick-borne', protozoan, parasite, 'Theileria', annulata]), verbo([causes]), complemento([a, debilitating, disease, of, cattle, called, 'Tropical', 'Theileriosis'])].
[sujeto(['The', parasite, predominantly, invades, bovine, macrophages, '(', m, 'phi)', and]), verbo([induces]), complemento([host, cell, transformation, by, a, mechanism, that, has, not, been, fully, elucidated])].
[sujeto(['Infection', is]), verbo([associated]), complemento([with, loss, of, characteristic, m, phi, functions, and, phenotypic, 'markers,', indicative, of, host, cell, 'de-differentiation'])].
[sujeto(['We']), verbo([have]), complemento([investigated, the, effect, of, 'T'])].
[sujeto(['The', 'up-regulation', of, 'c-maf', mRNA, levels, observed, during, bovine, monocyte, differentiation, to, m, phi, was]), verbo([suppressed]), complemento([by, 'T'])].
[sujeto(['annulata-infected', cells, with, the, theileriacidal, drug, buparvaquone]), verbo([induced]), complemento(['up-regulation', of, 'c-maf', and, 'mafB,', which, correlated, with, altered, expression, of, 'down-stream', target, 'genes,', e])].
[sujeto([annulata, infection, is]), verbo([associated]), complemento([with, the, suppression, of, the, transcription, 'factors,', 'Pu'])].
[sujeto([1, and, 'RUNX1,', and, colony]), verbo([stimulating]), complemento([factor, 1, receptor, '(', 'CSF1R)', which, are, also, involved, in, the, regulation, of, 'monocyte/m', phi, differentiation])].
[sujeto(['We', believe, these, results]), verbo([provide]), complemento([the, first, direct, evidence, that, 'T'])].
[sujeto([annulata]), verbo([modulates]), complemento([the, host, m, phi, differentiation, 'state,', which, may, diminish, the, defence, capabilities, of, the, infected, cell, 'and/or', promote, cell, proliferation])].
[sujeto(['The', 't(8;21)', chromosomal, translocation]), verbo([activates]), complemento([aberrant, expression, of, the, 'AML1-ETO', '(', 'AE)', fusion, protein, and, is, commonly, associated, with, core, binding, factor, acute, myeloid, leukaemia, '(', 'CBF', 'AML)'])].
[sujeto(['Combining', a, conditional, mouse, model, that, closely, resembles, the, slow, evolution, and, the, mosaic, 'AE', expression, pattern, of, human, 't(8;21)', 'CBF', 'AML', with, global, transcriptome, 'sequencing,', we]), verbo([find]), complemento([that, disease, progression, was, characterized, by, two, principal, pathogenic, mechanisms])].
[sujeto(['We', also]), verbo([find]), complemento([that, both, 'HSC', and, 'lineage-restricted', granulocyte, macrophage, progenitors, '(', 'GMPs)', acquired, leukaemic, stem, cell, '(', 'LSC)', potential, being, capable, of, initiating, and, maintaining, the, disease])].
[sujeto(['Finally,', our, data, demonstrate, that, 'long-term', expression, of, 'AE']), verbo([induces]), complemento([an, indolent, myeloproliferative, disease, '(', 'MPD)-like', myeloid, leukaemia, phenotype, with, complete, penetrance, and, that, acute, inactivation, of, 'AE', function, is, a, potential, novel, therapeutic, option])].
[sujeto(['MicroRNA']), verbo([regulate]), complemento([the, activity, of, 'protein-coding', genes, including, those, involved, in, hematopoietic, cancers])].
[sujeto(['T-cell,', 'MLL-rearranged,', 'TEL-AML1-positive,', 'E2A-PBX1-positive', and, hyperdiploid, acute, lymphoblastic, 'leukemia,', with, the, exception, of, 'BCR-ABL-positive', and, '\'', 'B-other\'', acute, lymphoblastic, leukemias, '(', defined, as, precursor, 'B-cell', acute, lymphoblastic, leukemia, not, carrying, the, foregoing, cytogenetic, 'aberrations),', were]), verbo([found]), complemento([to, have, unique, 'microRNA-signatures', that, differed, from, each, other, and, from, those, of, healthy, hematopoietic, cells])].
[sujeto(['Strikingly,', the, microRNA, signature, of, 'TEL-AML1-positive', and, hyperdiploid, cases, partly, 'overlapped,', which, may]), verbo([suggest]), complemento([a, common, underlying, biology])].
[sujeto(['No', discriminative, microRNA, were]), verbo([found]), complemento([for, prednisolone, response, and, only, one, microRNA, was, linked, to, resistance, to, 'L-asparaginase'])].
[sujeto(['A', combined, expression, profile, based, on, 14, microRNA, that, were, individually]), verbo([associated]), complemento([with, 'prognosis,', was, highly, predictive, of, clinical, outcome, in, pediatric, acute, lymphoblastic, leukemia, '(', 5, -, year, 'disease-free', survival, of, 89.4, '%', '±7%', versus, 60.8, '±12%,', 'P=0'])].
[sujeto(['Functional', studies, of, discriminative, and, prognostically, important, microRNA, may]), verbo([provide]), complemento([new, insights, into, the, biology, of, pediatric, acute, lymphoblastic, leukemia])].
[sujeto(['CD20', is]), verbo([expressed]), complemento([in, approximately, 'one-', half, of, pediatric, acute, lymphoblastic, leukemia, '(', 'ALL)', cases, with, 'B-cell', precursor, '(', 'BCP)', origin])].
[sujeto(['CD20-positivity', significantly]), verbo([increased]), complemento([from, 45, '%', in, initial, samples, to, 81, '%', at, 'end-induction', '(', day, 15, ',', 71, '%', ')'])].
[sujeto(['In', 'vitro,', 'CD20', 'up-regulation', significantly]), verbo([enhanced]), complemento([rituximab, cytotoxicity, and, could, be, elicited, on, prednisolone, incubation])].
[sujeto(['In', 'conclusion,', 'CD20', 'up-regulation', is, frequently]), verbo([induced]), complemento([in, 'BCP-ALL', during, 'induction,', and, this, translates, into, an, acquired, state, of, higher, sensitivity, to, rituximab])].
[sujeto(['The', 'Wilms\'', tumour, gene, 1, '(', 'WT1)', protein, is, highly]), verbo([expressed]), complemento([in, most, leukaemias])].
[sujeto(['Co-expression', of, 'WT1', and, the, fusion, protein, 'AML1-ETO', in, mice, rapidly]), verbo([induces]), complemento([acute, myeloid, leukaemia, '(', 'AML)'])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, the, fusion, protein, 'BCR/ABL1', increases, expression, of, 'WT1', mRNA, and, protein, via, the, 'phosphatidylinositol-3', kinase, '(', 'PI3K)-Akt', pathway])].
[sujeto(['Inhibition', of, 'BCR/ABL1', or, 'PI3K', activity, strongly]), verbo([suppressed]), complemento([transcription, from, 'WT1', 'promoter/enhancer', reporters])].
[sujeto(['Forced', expression, of, 'BCR/ABL1', in, normal, human, progenitor, 'CD34+', cells]), verbo([increased]), complemento(['WT1', mRNA, and, 'protein,', further, supporting, the, notion, of, 'BCR/ABL1-driven', expression, of, 'WT1', in, human, haematopoietic, cells])].
[sujeto(['Forced', expression, of, 'WT1', in, 'K562', cells]), verbo([provided]), complemento([protection, against, cytotoxic, effects, of, the, 'ABL1', tyrosine, kinase, inhibitor, 'imatinib,', as, judged, by, effects, on, viability, measured, by, trypan, blue, 'exclusion,', metabolic, 'activity,', annexin, 'V', and, 'DAPI', '(', 4, '\'', ',', 6, -, 'diamidino-2-phenylindole)', staining])].
[sujeto(['None', of, the, isoforms]), verbo([provided]), complemento([any, detectable, protection, against, apoptosis, induced, by, arsenic, trioxide, and, only, very, weak, protection, against, 'etoposide,', indicating, that, 'WT1', interferes, with, specific, apoptotic, signalling, pathways])].
[sujeto(['Our', data, demonstrate, that, 'WT1', expression, is]), verbo([induced]), complemento([by, oncogenic, signalling, from, 'BCR/ABL1', and, that, 'WT1', contributes, to, resistance, against, apoptosis, induced, by, imatinib])].
[sujeto(['c-MET', was]), verbo([found]), complemento([to, be, expressed, in, normal, 'B', cells, and, in, 'B-ALL', patients, with, the, 't(12;21)', 'TEL-AML1', 'translocation,', but, it, is, not, expressed, in, the, most, part, of, 'B-ALL', without, the, 't(12;21)'])].
[sujeto(['We', also]), verbo([found]), complemento([that, 'c-MET,', related, to, proliferation, and, protection, from, 'apoptosis,', is, associated, with, the, 'pro-apoptotic', protein, 'FAS', in, 'TEL-AML1', 'B-ALL', cells, and, in, normal, 'B', lymphocytes])].
[sujeto(['REH', cells]), verbo([stimulated]), complemento([with, 'IL-3', and, treated, with, doxorubicin, did, not, undergo, apoptosis, more, than, nonstimulated, 'cells,', demonstrating, that, increased, proliferation, in, itself, is, not, directly, related, to, the, higher, apoptotic, sensitivity, observed, with, 'HGF', stimulation])].
[sujeto(['These', results, indicate, that, 'c-MET', activation]), verbo([enhances]), complemento([specifically, 'FAS-mediated', apoptosis, in, 'TEL-AML1', 'ALL', cells, 'and,', considering, that, the, 'c-MET/FAS', complex, is, present, only, in, normal, 'B', lymphocytes, and, in, 'TEL-AML1', 'leukemias,', this, implies, that, it, may, have, an, important, contribution, in, cellular, homeostasis, and, in, high, sensitivity, of, 'TEL-AML1', 'ALL', to, chemotherapeutic, regimens])].
[sujeto(['Further', 'follow-up', of, this, patient, and, the, analysis, of, a, larger, number, of, children, are, needed, to, define, whether, the]), verbo([gains]), complemento([of, the, specific, extra, chromosomes, modify, the, good, prognosis, that, 't(8;21)', confers, to, this, subgroup, of, 'AML'])].
[sujeto(['AML1-ETO', fusion, 'protein,', a, product, of, 'leukemia-related', chromosomal, translocation, 't(8;21),', was]), verbo([reported]), complemento([to, upregulate, expression, of, 'connexin-43', '(', 'Cx43),', a, member, of, gap, 'junction-constituted', connexin, family])].
[sujeto(['By', bioinformatic, 'analysis,', here, we, showed, that, there, are, two, putative, 'AML1-binding', consensus, sequences, followed, by, two]), verbo([activated]), complemento([protein, '(', 'AP)1', sites, in, the, 5, '\'', -, flanking, region, upstream, to, 'Cx43', gene])].
[sujeto(['AML1-ETO', could, directly]), verbo([bind]), complemento([to, these, two, 'AML1-binding', sites, in, electrophoretic, mobility, shift, 'assay,', but, luciferase, reporter, assay, revealed, that, the, 'AML1', binding, sites, were, not, indispensable, for, 'Cx43', induction, by, 'AML1-ETO', protein])].
[sujeto(['In', 'agreement,', 'AML1-ETO', overexpression, in, leukemic, 'U937', cells]), verbo([activated]), complemento(['c-Jun', 'N-terminal', kinase, '(', 'JNK),', while, its, specific, inhibitor, 'SP600125', effectively, abrogated, 'AML1-ETO-induced', 'Cx43', 'expression,', indicating, that, 'JNK', signaling, pathway, contributes, to, 'AML1-ETO', induced, 'Cx43', expression])].
[sujeto(['Chromosome', rearrangements, are, believed, to]), verbo([cause]), complemento([the, secondary, leukemias, which, constitute, frequent, complications, of, antitumor, chemotherapy, with, topoisomerase, 'II-specific', drugs])].
[sujeto(['Here', we, show, that, inhibition, of, 'DNA', topoisomerase, 'II', in, cultured, cells]), verbo([stimulates]), complemento([association, of, components, of, the, 'non-homologous', end, joining, system, with, a, known, breakpoint, cluster, region, of, the, human, 'AML1', 'gene,', suggesting, that, errors, of, 'DNA', repair, during, 'NHEJ', may, be, the, cause, of, illegitimate, recombination, in, cells, treated, with, topoisomerase, 'II', poisons])].
[sujeto([miRNAs]), verbo([have]), complemento([been, widely, investigated, in, terms, of, cell, proliferation, and, differentiation])].
[sujeto(['Here', we, characterized, the, promoter, of, 'miR-206', in, chicken, and]), verbo([found]), complemento([that, the, preferable, promoter, was, located, in, 1200, bp, upstream, of, 'pri-miR-206'])].
[sujeto(['In', this, 'region,', many, key, transcription, 'factors,', including, 'MyoD,', 'c-Myb,', 'CEBPα/β,', 'AP-4,', 'RAP1,', 'Brn2,', 'GATA-1/2/3,', 'E47,', 'Sn,', upstream, stimulatory, factor, '(', 'USF)', and, 'CdxA,', were, predicted, to]), verbo([bind]), complemento([and, interact, with, 'miR-206', promoter])].
[sujeto(['Overexpression', of, 'MyoD', sharply]), verbo([increased]), complemento(['miR-206', expression, in, both, fibroblast, and, myoblast, 'cells,', and, also, the, regulation, in, the, myoblast, cells, was, much, 'stronger,', indicating, that, 'miR-206', was, regulated, by, 'MyoD', combined, with, other, muscle, specific, transcriptional, factors])].
[sujeto(['Interestingly,', the, motif]), verbo([bound]), complemento([by, 'MyoD', was, individually, destroyed, by, 'G-to-C', mutation, located, at, 419, bp, upstream, of, 'miR-206', precursor])].
[sujeto(['Thus,', this, mutation]), verbo([caused]), complemento([low, expression, of, 'miR-206'])].
[sujeto(['Additionally,', the, regulation, of, 'miR-206', on, embryo, muscle, mass, mainly, by]), verbo([increasing]), complemento(['MyoG', and, muscle, creatine, kinase, '(', 'MCK)', expression, '(', p, &, 'lt;', 0.05, ')', with, little, change, in, 'MyoD,', 'TMEM8C', and, myosin, heavy, chain, '(', 'MHC)'])].
[sujeto(['In', 'conclusion,', our, findings]), verbo([provide]), complemento([a, novel, mutation, destroying, the, promoter, activity, of, 'miR-206', in, birds, and, shed, new, light, to, understand, the, regulation, mechanism, of, 'miR-206', on, the, embryonic, muscle, growth])].
[sujeto(['Previously,', we, identified, five, 'POs,', designated, 'As-pro-PO', 'I-V,', from, the, mosquito, 'Armigeres', subalbatus, and, demonstrated, that, the, functions, of, 'As-pro-PO', 'I,', 'II', and, 'III,', were]), verbo([associated]), complemento([with, filarial, parasite, 'melanization,', blood, feeding, and, cuticle, 'formation,', respectively])].
[sujeto(['We']), verbo([found]), complemento([that, the, level, of, 'As-pro-PO', 'V', mRNA, in, mosquitoes, was, significantly, increased, after, microfilaria, challenge, or, blood, 'feeding,', and, decreased, to, normal, level, after, oviposition])].
[sujeto(['Knockdown', of, 'As-pro-PO', 'V', by, dsRNA, resulted, in, significant]), verbo([decreases]), complemento([in, the, degree, of, microfilaria, 'melanization,', egg, chronic, melanization, rates, and, egg, hatching, rates, in, 'Ar'])].
[sujeto(['Further', transfection, and, electrophoretic, 'mobility-shift', assays, verified, the, 'As-pro-PO', 'V', gene, might]), verbo([regulated]), complemento([by, both, 'AP-1,', a, putative, 'immune-related', regulatory, element, and, 'CdxA,', a, developmental, regulatory, element])].
[sujeto(['The']), verbo([binding]), complemento([of, 'AP-1', and, 'CdxA', motif, with, mosquito, nuclear, extracts, was, significantly, enhanced, after, microfilaria, challenge, and, 'blood-feeding', in, 'Ar'])].
[sujeto(['These', results, indicate, that, 'As-pro-PO', 'V', is, a, critical, enzyme, that, is]), verbo([required]), complemento([for, both, an, effective, melanization, immune, response, and, egg, chorion, melanization, in, this, mosquito])].
[sujeto(['Our', recent, 'genome-wide', association, study, '(', 'GWAS)', had, discovered, a, new, locus, at, 8, p23, '(', 'rs2738048)']), verbo([associated]), complemento([with, 'IgA', nephropathy, '(', 'IgAN)', in, 'Chinese', 'Han', 'patients,', implicating, the, 'DEFA', gene, family, within, this, locus, as, susceptibility, genes])].
[sujeto(['However,', it, is, still, unknown, whether, there, are, additional, variations, within, these, genes]), verbo([associated]), complemento([with, the, disease, susceptibility])].
[sujeto(['We']), verbo([found]), complemento([seven, 'SNPs', within, 'DEFA', genes, that, were, significantly, associated, with, 'IgAN,', including, rs2738048, discovered, in, our, previous, 'GWAS', '(', 'p&nbsp;=&nbsp;0'])].
[sujeto(['Electrophoretic', mobility, shift, assays, and, luciferase, assays, demonstrated, that, fragments, containing, 'rs2738048,', rs2738081, and, rs6984215, were, transcription, factor]), verbo([binding]), complemento([sites, for, 'CTF,', 'SP1', and, 'CdxA,', 'respectively,', and, the, allele, status, of, rs2738048, and, rs6984215, could, significantly, change, the, luciferase, activity])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, polymorphisms, within, 'DEFA', genes, are, involved, in, gene, transcriptional, 'regulation,', and, this, may, have, some, effect, in, mediating, susceptibility, to, 'IgAN', in, southern, 'Chinese'])].
[sujeto(['Children', '(', 'n=488;', age, 'range:', 1.8, -, 6.0, 'y)', were, randomly]), verbo([recruited]), complemento([from, 'Montreal'])].
[sujeto([1, ')', were, positively]), verbo([associated]), complemento([with, 'BMC', and, aBMD, in, all, regression, 'models,', whereas, male, sex, contributed, positively, to, forearm, 'BMC', and, aBMD])].
[sujeto(['Having', a, 25, '(', 'OH)D', concentration, of, &, 'gt;75', 'nmol/L', positively]), verbo([associated]), complemento([with, forearm, and, whole, body, 'BMC', and, aBMD, '(', 'p&lt;0'])].
[sujeto(['Helicobacter', pylori, encoded, 'CagA', is, presently, the, only, known, virulence, factor, that, is, injected, into, gastric, epithelial, cells, where, it, destroys, apical, junctional, complexes, and]), verbo([induces]), complemento([dedifferentiation, of, gastric, epithelial, 'cells,', leading, to, 'H'])].
[sujeto(['However,', little, is, known, about, the, molecular, mechanisms, by, which, 'CagA']), verbo([mediates]), complemento([these, changes])].
[sujeto(['Caudal-related', homeobox, 2, '(', 'Cdx2)', is, an, 'intestine-specific', transcription, factor, highly]), verbo([expressed]), complemento([in, multistage, tissues, of, dysplasia, and, cancer])].
[sujeto(['One', specific]), verbo([target]), complemento([of, 'Cdx2,', 'Claudin-2,', is, involved, in, the, regulation, of, tight, junction, '(', 'TJ)', permeability])].
[sujeto(['In', this, 'study,', our, findings, showed, that, the, activity, of, 'Cdx2']), verbo([binding]), complemento([to, 'Cdx', binding, sites, of, 'CdxA', '(', 'GTTTATG)', and, 'CdxB', '(', 'TTTTAGG)', of, probes, corresponding, to, 'claudin-2', flanking, region, increased, in, 'AGS', 'cells,', infected, with, 'CagA', positive, 'wild-type', strain, of, 'H'])].
[sujeto(['In', the, 'meantime,', we]), verbo([found]), complemento([that, 'TJs', of, 'AGS', 'cells,', infected, with, 'CagA', positive, 'wild-type', strain, of, 'H'])].
[sujeto(['pylori,', compared, to, 'CagA', negative, isogenic, 'mutant-type', 'strain,', were, more, severely, 'destroyed,']), verbo([leading]), complemento([to, wider, cell, 'gap,', interference, of, 'contact,', scattering, and, highly, elevated, migration, of, cells])].
[sujeto(['pylori-encoded', 'CagA', disrupts, 'TJs', and]), verbo([induces]), complemento([invasiveness, of, 'AGS', gastric, carcinoma, cells, via, 'Cdx2-dependent', targeting, of, 'Claudin-2'])].
[sujeto(['This']), verbo([provides]), complemento([a, new, mechanism, whereby, 'CagA', induced, dedifferentiation, of, 'AGS', 'cells,', leading, to, malignant, behavior, of, biology])].
[sujeto(['In', this, 'study,', 'real-time', polymerase, chain, reactions, and, 'Western', blot, assays, indicated, that, 'HMGB1', transcriptional, activity, and, protein, level, are]), verbo([increased]), complemento([in, 'Tax+-T', cells, '(', 'TaxP)'])].
[sujeto(['We']), verbo([found]), complemento([that, promoter, activity, in, 'Tax+-T', cells, to, be, higher, than, that, in, 'Tax--T', 'cells,', indicating, a, significant, increase, in, pHLuc6])].
[sujeto(['Bay11-7082', '(', 'NF-κB', 'inhibitor)', treatment, did, not, block, the]), verbo([enhancing]), complemento([effect])].
[sujeto(['Chromatin', immunoprecipitation, assays, revealed, that, 'Tax', was]), verbo([retained]), complemento([on, a, 'HMGB1', promoter, fragment, encompassing, -, 1163, to, -, 975])].
[sujeto(['Mutation', of, 'cis-', elements, for, 'C/EBP', reduced, significant, 'HMGB1', promoter, activity]), verbo([induced]), complemento([by, 'Tax'])].
[sujeto(['These', findings, indicate, that, 'Tax']), verbo([enhances]), complemento([the, expression, of, 'HMGB1', gene, at, the, transcriptional, 'level,', possibly, by, interacting, with, 'C/EBP'])].
[sujeto(['Interferon', regulatory, factor, 2, '(', 'IRF-2)', is, a, 'multi-functional', transcription, factor, in, the, 'IRF', family, exhibiting, both, transcriptional]), verbo([activating]), complemento([and, repressing, activities])].
[sujeto(['The', amino, acid, sequence, had, a, highly]), verbo([conserved]), complemento(['N-terminal', 'DBD', 'structure,', containing, characteristic, repeats, of, six, tryptophan, residues])].
[sujeto(['Only&nbsp;+2365T/C', 'SNP', was, significantly]), verbo([associated]), complemento([with, 'resistance/susceptibility', of, 'H'])].
[sujeto(['Among', 'them,', three, 'SNPs', including, 'A-99G,', 'A-86C,', and, 'A-49C', in, 'GPX', promoter, and, five, 'SNPs', including, 'A2841T,', 'C2847T,', 'G3146C,', 'A3150G,', and, 'G4645T', in, 'GPX', introns, were]), verbo([associated]), complemento([with, 'resistance/susceptibility', of, 'H'])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, the, polymorphic, loci, in, the, 'GPX', gene, could, be, potential, genetic, markers, for, future, molecular, selection, of, strains, resistant, to, diseases])].
[sujeto(['However,', these, approaches]), verbo([require]), complemento([the, use, of, sophisticated, and, expensive, 'serum-free', medium, supplemented, with, epithelial, growth, factor, '(', 'EGF),', 'Wnt', agonist, '(', 'R-spondin', 1, ')', ',', and, bone, morphogenetic, protein, inhibitor, '(', 'Noggin)', in, high, concentrations])].
[sujeto(['They']), verbo([have]), complemento([the, appearance, of, empty, spheres, and, comprise, cells, expressing, cytokeratin, '(', an, epithelial, cell, 'marker),', villin, '(', a, marker, of, 'enterocytes),', and, 'Sox-9', '(', a, transcription, factor, characteristic, of, progenitors, and, stem, cells, of, intestinal, 'crypts)'])].
[sujeto(['With', chicken, embryonic, tissue, as, a, source, of, 'organoids,', prostaglandin, 'E2', is, as, effective, as, 'R-spondin', 1, and, 'Noggin', in]), verbo([promoting]), complemento([sustained, growth, and, survival, of, epithelial, spheroids])].
[sujeto(['Specifically,', 'β-casein', is, a, major, component, of, 'cow,', goat, and, sheep, 'milk,', and, its, promoter]), verbo([has]), complemento([been, used, to, regulate, the, expression, of, transgenic, genes, in, the, mammary, gland, of, transgenic, animals])].
[sujeto(['We', estimated, the, transcriptional, activity, for, the, 5, '\'', -, proximal, region, with, or, without, intron, 1, of, the, porcine, 'β-casein', gene, in, 'HC11', cells]), verbo([stimulated]), complemento([with, lactogenic, hormones])].
[sujeto(['Taken', 'together,', these, findings]), verbo([suggest]), complemento([that, the, transcription, of, porcine, 'β-casein', gene, is, regulated, by, lactogenic, hormone, via, intron, 1, and, promoter, containing, a, mutant, 'TATA', box, '(', 'CATAAAA)', has, poor, porcine, 'β-casein', gene, activity])].
[sujeto(['To', examine, whether, 'PARK16,', which, was, recently, identified, as, a, protective, locus, for, 'Parkinson', disease, '(', 'PD)', in, 'Asian,', 'white,', and, 'South', 'American', 'populations,', is, also]), verbo([associated]), complemento([with, 'PD', in, the, genetically, homogeneous, 'Ashkenazi', 'Jewish', population])].
[sujeto(['Bioinformatic', analysis, defined, the, putative, promoter, region, of, 'RAB7L1', and, the, transcription, factor]), verbo([binding]), complemento([sites, that, are, potentially, affected, by, 2, of, the, tested, 'SNPs'])].
[sujeto(['All', tested, 'SNPs', were, significantly]), verbo([associated]), complemento([with, 'PD', '(', odds, 'ratios&nbsp;=&nbsp;0'])].
[sujeto(['Two', of, 'them,', rs1572931, and, 'rs823144,', were, localized, to, the, putative, promoter, region, of, 'RAB7L1', and, their, sequence, variations, altered, the, predicted, transcription, factor]), verbo([binding]), complemento([sites, of, 'CdxA,', 'p300,', 'GATA-1,', 'Sp1,', and, 'c-Ets-1'])].
[sujeto(['Our', data, demonstrate, that, specific, 'SNP', variations, and, haplotypes, in, the, 'PARK16', locus, are]), verbo([associated]), complemento([with, reduced, risk, for, 'PD', in, 'Ashkenazim'])].
[sujeto(['Although', it, is, possible, that, alterations, in, the, putative, promoter, of, 'RAB7L1', are]), verbo([associated]), complemento([with, this, 'effect,', the, role, of, other, genes, in, this, locus, cannot, be, ruled, out])].
[sujeto(['It', is]), verbo([involved]), complemento([in, the, regulation, of, the, 'G1-phase', of, the, cell, cycle, and, is, considered, to, be, an, important, candidate, gene, for, selection, of, body, measurement, traits, through, 'marker-assisted', selection])].
[sujeto(['We', cloned, the, promoter, sequence, of, this, gene, in, bovines, and]), verbo([found]), complemento([it, to, share, high, similarity, with, that, of, the, human, 'CDK6', promoter])].
[sujeto(['A', 2271, -, bp, sequence, upstream, of, the, start, codon, in, the, bovine, 'CDK6', 5, '\'', -, flanking, sequence, is, rich, in, 'GC;', it, lacks, consensus, 'TATA', or, 'CAAT', 'box,', but, it, contains, several, 'MZF1']), verbo([binding]), complemento([sites])].
[sujeto(['Other', potential, 'cis-regulatory', elements, were]), verbo([found]), complemento([in, the, 5, '\'', -, flanking, 'region,', including, 'CdxA,', 'SRY,', 'p300,', 'GATA-1,', and, deltaE])].
[sujeto(['The', 'T-1075C', 'SNP', in, the, promoter, was]), verbo([found]), complemento([to, be, significantly, associated, with, body, length, and, heart, girth])].
[sujeto(['This', 'SNP', marker, was]), verbo([found]), complemento([to, be, significantly, associated, with, body, length, and, the, heart, girth, in, 737, individuals])].
[sujeto(['We', conclude, that, this, 'SNP', of, the, 'CDK6', gene]), verbo([has]), complemento([potential, as, a, genetic, marker, for, important, body, traits, in, bovine, reproduction, and, breeding])].
[sujeto(['The', aim, of, this, study]), verbo([has]), complemento([been, to, analyze, whether, 33, '%', radius, should, be, considered, the, recommended, area, to, assess, 'BMD', in, prostate, cancer, patients])].
[sujeto(['Normal', 'BMD', was]), verbo([found]), complemento([in, 17.7, '%', at, 33, '%', radius, and, 34.8, '%', at, cDXA])].
[sujeto(['The', 33, '%', radius, was, the, only, site, where, a, significant]), verbo([increase]), complemento([in, the, osteoporosis, rate, was, detected, in, patients, subjected, to, 'AS', compared, to, those, hormone, naïve, '(', 33, and, 13.8, '%', ')'])].
[sujeto(['The', 33, '%', radius, seems, more, sensible, than, the, central, skeleton, areas, to, detect, bone, mass]), verbo([loss]), complemento([in, patients, with, prostate, cancer])].
[sujeto(['Alkaline', phosphatases, are, ubiquitous, enzymes]), verbo([involved]), complemento([in, many, important, biological, processes])].
[sujeto(['Mammalian', 'tissue-nonspecific', alkaline, phosphatase]), verbo([has]), complemento([long, been, thought, to, feature, in, embryonic, development, and, bone, formation])].
[sujeto(['An', analysis, of, its, secondary, and, tertiary, structure, revealed, that, the, 'POALP', was]), verbo([conserved]), complemento([in, different, 'species,', but, one, disulfide, linkage, made, it, possible, to, adapt, to, 'low-temperature', environment])].
[sujeto(['The', 'ALP', activity, was]), verbo([found]), complemento([to, be, first, detectable, in, the, embryo, before, hatching])].
[sujeto(['These', findings]), verbo([suggest]), complemento([the, potential, role, of, 'POALP', in, nutrient, absorption, and, transportation])].
[sujeto(['To', evaluate, whether, these, genes, encode, enzymes, with, redundant, biological, 'functions,', each, gene, was, cloned, and]), verbo([expressed]), complemento([in, 'Escherichia', coli])].
[sujeto(['To', identify, the, amino, acid, residues, that, contribute, to, catalysis, and, substrate, specificity, within, this, family, of, 'enzymes,', the, roles, of]), verbo([conserved]), complemento([residues, '(', 'R177,', 'K214,', 'H215,', 'M251,', and, 'D286)', in, 'Xyl3B', were, probed, by, 'site-directed', mutagenesis])].
[sujeto(['Each', mutation]), verbo([led]), complemento([to, a, severely, decreased, catalytic, efficiency, without, a, change, in, the, overall, structure, of, the, mutant, enzymes])].
[sujeto(['Through', amino, acid, sequence, 'alignments,', an, amino, acid, residue, '(', 'E115)', 'that,', when, mutated, to, aspartic, 'acid,', resulted, in, a, 14, -, fold]), verbo([decrease]), complemento([in, the, 'k(cat)/K(m)', for, 'pNP-beta-d-xylopyranoside', '(', 'pNPX)', with, a, concurrent, 1.1, -, fold, increase, in, the, 'k(cat)/K(m)', for, 'pNP-beta-d-glucopyranoside', '(', 'pNPG)', was, identified])].
[sujeto(['Our', results, demonstrate, that, each, of, the, four, 'GH3', enzymes]), verbo([has]), complemento([evolved, to, perform, a, specific, role, in, lignopolysaccharide, hydrolysis, and, provide, insight, into, the, role, of, 'active-site', residues, in, catalysis, and, substrate, specificity, for, 'GH3', enzymes])].
[sujeto(['More', than, ten, 'bradykinin-related', peptides, and, their, cDNAs]), verbo([have]), complemento([been, identified, from, 'amphibians,', but, their, genes, are, unknown])].
[sujeto(['The', promoter, region, of, the, bradykinin, gene, contains, several, putative, recognition, sites, for]), verbo([nuclear]), complemento(['factors,', such, as, 'SRY,', 'GATA-1,', 'LYF-1,', 'DeltaE,', 'CDXA,', 'NKX-2'])].
[sujeto(['Interferon', regulatory, factor, 3, '(', 'IRF-3),', an, essential, transcriptional, regulator, of, the, interferon, 'genes,']), verbo([has]), complemento([been, implicated, in, virus, and, 'double-stranded', 'RNA', mediated, induction, of, 'IFN-α,', 'IFN-β', and, 'RANTES,', in, 'virus-induced', apoptosis, and, in, tumor, suppression])].
[sujeto(['Promoter', plays, an, important, role, in, the, regulation, of, gene, 'expression,', but, the, characterization, of, the, human, 'IRF-3', promoter]), verbo([has]), complemento([not, been, systematically, analyzed, in, 'HEK', 293, cells])].
[sujeto(['To', characterize, the, human, 'IRF-3', 'promoter,', we]), verbo([have]), complemento([isolated, a, genomic, clone, of, the, human, 'IRF-3', gene, promoter, region, containing, 1, ',', 0, nucleotides, of, the, 5, '\'', -, flanking, region])].
[sujeto(['This', region, contains, 'HSF,', 'E2F,', 'CdxA', and, 'c-Myb', transcription, factor]), verbo([binding]), complemento([sites])].
[sujeto(['The', 'E2F', sites, are, highly]), verbo([conserved]), complemento([among, 'IRF-3', promoter, regions, of, 'mouse,', rat, and, human])].
[sujeto(['Therefore,', it, was]), verbo([suggested]), complemento([that, this, 'E2F', site, may, be, essential, for, basal, promoter, activity])].
[sujeto(['Surprisingly,', mutation, of, this, 'E2F', site]), verbo([increased]), complemento([the, promoter, activity, by, 2, -, fold])].
[sujeto(['E2F1', transcription, factor, negatively]), verbo([regulates]), complemento([human, 'IRF-3', gene, promoter])].
[sujeto(['Although', the, requirement, for, 'RA', signaling, for, the, development, of, a, few, individual, endoderm, organs]), verbo([has]), complemento([been, established, a, systematic, assessment, of, its, activity, along, the, entire, 'antero-posterior', axis, has, not, been, performed, in, this, germ, layer])].
[sujeto(['These', results, imply, that, 'RA']), verbo([acts]), complemento([as, a, caudalizing, factor, in, a, graded, manner, in, pharyngeal, endoderm])].
[sujeto(['Posterior', foregut, and, midgut, organ, primordia, also]), verbo([require]), complemento(['RA,', but, exposing, endoderm, to, additional, 'RA', is, not, sufficient, to, expand, these, primordia, anteriorly])].
[sujeto(['Our', results, show, that, the, induction, of, 'CdxA,', a, midgut, 'marker,', and, pancreas, induction]), verbo([require]), complemento([direct, 'RA', signaling, in, endoderm])].
[sujeto(['Moreover,', communication, between, 'CdxA(+)', cells, is, necessary, to]), verbo([maintain]), complemento(['CdxA', 'expression,', therefore, synchronizing, the, cells, of, the, midgut, primordium])].
[sujeto(['We', further, show, that, the, 'RA', pathway]), verbo([acts]), complemento([synergistically, with, 'FGF4', in, endoderm, patterning, rather, than, mediating, 'FGF4', activity])].
[sujeto(['Gene', regulation, during, development, is, an, important, biological, activity, that]), verbo([leads]), complemento([to, synthesis, of, biomolecules, at, specific, locations, and, specific, times])].
[sujeto(['We', investigated, the, internal, promoter, of, tropomyosin, to, identify, sequences, that]), verbo([regulate]), complemento([expression, of, 'tmy-1', in, the, pharynx, and, intestine])].
[sujeto(['By', promoter, deletion, of, 'tmy-1', reporters, as, well, as, by, database, 'analyses,', a, 100, -, bp, fragment, that, contained]), verbo([binding]), complemento([sequences, for, a, 'GATA', 'factor,', for, a, chicken, 'CdxA', 'homolog,', and, for, a, forkhead, factor, was, identified])].
[sujeto(['Both', the, forkhead, and, 'CdxA']), verbo([binding]), complemento([sequences, contributed, to, pharyngeal, and, intestinal, expression])].
[sujeto(['We', showed, that, 'ELT-2', and, 'PHA-4', proteins]), verbo([interact]), complemento([directly, with, the, 'GATA', and, forkhead, binding, 'sequences,', 'respectively,', in, gel, mobility, shift, assays])].
[sujeto(['We']), verbo([found]), complemento([no, indication, of, a, synergistic, relation, between, 'ELT-2', and, 'PHA-4'])].
[sujeto(['The', expression, of, mRNA, for, a, brush, border, 'enzyme,', 'sucrase-isomaltase', '(', 'SI),', which, is, critical, in, disaccharide, 'digestion,', was, 'determined,', together, with, that, of, the, 'Na-glucose', transporter, '(', 'SGLT)-1,', which, is, the, major, apical, glucose, 'transporter,', 'In', 'addition,', the, homeobox, gene, 'cdx,', which, is]), verbo([involved]), complemento([in, inducing, 'SI', expression, in, mammals, was, examined])].
[sujeto(['It', was]), verbo([found]), complemento([that, the, expression, of, cdxA, mRNA, and, cdxA, protein, increased, from, day, 15, of, incubation, until, 'hatch,', after, which, further, changes, were, small])].
[sujeto(['CdxA', protein, was, shown, to]), verbo([bind]), complemento([to, the, promoter, region, of, 'SI', in, the, chick, indicating, that, cdxA, is, similar, to, the, mammalian, cdx2])].
[sujeto(['The', mRNA, of, 'SI', was, observed, at, 15, d, 'incubation,']), verbo([increased]), complemento([from, 17, d, of, incubation, to, a, peak, on, day, 19, ',', decreased, at, hatch, and, had, a, further, peak, of, expression, 2, d, 'post-hatch'])].
[sujeto(['In', 'contrast,', the, mRNA, of, 'SGLT-1', was, not, detected, until, 19, d, of, incubation, when, a, major, peak, of, expression, was, observed, followed, by, a]), verbo([decrease]), complemento([to, low, levels, at, hatch, and, small, increases, 'post-hatch'])].
[sujeto(['It', appears, that, both, 'SI', and, 'SGLT-1', mRNA, are]), verbo([expressed]), complemento([before, hatch, in, the, 'chick,', but, the, ontogeny, of, expression, is, controlled, by, different, mechanisms])].
[sujeto(['Determination', of, the, developmental, fate, in, the, small, intestinal, epithelium, of, the, chicken, embryo]), verbo([has]), complemento([not, been, fully, analyzed, up, to, the, present])].
[sujeto(['The', small, intestinal, epithelium, reassociated, and, cultivated, with, the, proventricular, or, gizzard, mesenchyme, or, the, dermis]), verbo([expressed]), complemento([chicken, intestinal, fatty, acid, binding, 'protein,', sucrase, and, 'CdxA', as, occurs, during, the, normal, development, of, the, small, intestinal, epithelium])].
[sujeto(['The', presumptive, intestinal, endoderm, taken, from, an, earlier, stage, embryo, and]), verbo([associated]), complemento([and, cultivated, with, the, proventricular, or, gizzard, 'mesenchyme,', showed, gene, expression, patterns, which, were, the, same, as, those, found, in, normal, development])].
[sujeto(['However,', when, the, dermis, was, 'associated,', the, epithelium]), verbo([expressed]), complemento([sonic, 'hedgehog,', but, never, expressed, intestinal, 'epithelial-', or, stomach, 'epithelial-markers'])].
[sujeto(['ACS3', is, an, 'arachidonate-preferring', enzyme]), verbo([expressed]), complemento([in, a, wide, range, of, human, tissues, including, 'brain,', 'heart,', 'placenta,', 'prostate,', skeletal, 'muscle,', testis, and, thymus])].
[sujeto(['A', minimal, promoter, region]), verbo([required]), complemento([for, the, expression, of, the, human, 'ACS3', gene, in, melanoma, 'G361', cells, was, determined])].
[sujeto(['This', analysis, revealed, that, the, most, common, transcription, factor]), verbo([binding]), complemento([site, in, the, examined, collection, of, core, promoters, appears, to, be, initiator, '(', characterized, by, 'GEN_INI),', which, is, expected])].
[sujeto(['The', other, less, obvious, sites]), verbo([found]), complemento([were, 'Spz1,', 'E2F-1,', 'ZF5,', and, 'C/EBP'])].
[sujeto(['Interestingly,', the, 'TATA-box']), verbo([has]), complemento([been, found, in, only, 11.63, '%', of, all, examined, promoters])].
[sujeto(['These', additional, analyses, revealed, that, the, most, common, promoter, elements]), verbo([found]), complemento([also, include, 'AP-2,', 'CdxA,', 'Pax-2,', 'SRY,', 'STAT1', and, 'STAT5A'])].
[sujeto(['Spindle-checkpoint', genes]), verbo([have]), complemento([been, reported, to, be, mutated, in, several, human, 'cancers,', but, these, mutations, are, infrequent])].
[sujeto(['Recent']), verbo([reports]), complemento([suggest, that, the, hBUBR1, gene, may, play, an, important, role, in, mitotic, checkpoint, control, and, in, mitotic, checkpoint, impairment, in, human, cancers])].
[sujeto(['The', expression, of, 'BUBR1', was]), verbo([found]), complemento([to, be, 'up-regulated', in, all, of, these, cell, lines])].
[sujeto(['The', promoter, region, '(', 424, bp, upstream, from, exon, 1, ')', showed, promoter, activity, and, includes, multiple, transcription, factor, consensus]), verbo([binding]), complemento(['motifs,', including, those, for, 'Sp1,', 'Nkx-2,', 'CdxA,', 'SRY,', 'MyoD,', 'Ik-2,', 'HNF-3b,', 'Staf,', 'Oct-1,', 'Nkx-2,', 'v-Myb,', and, 'AML', 1, a])].
[sujeto(['Multiple', pathways]), verbo([leading]), complemento([to, activation, of, those, binding, factors, may, contribute, to, hBUBR1, gene, transcription])].
[sujeto(['Initiation', of, 'Hox', genes]), verbo([requires]), complemento([interactions, between, numerous, factors, and, signaling, pathways, in, order, to, establish, their, precise, domain, boundaries, in, the, developing, nervous, system])].
[sujeto(['There', are, distinct, differences, in, the, expression, and, regulation, of, members, of, 'Hox', genes, within, a, complex]), verbo([suggesting]), complemento([that, multiple, competing, mechanisms, are, used, to, initiate, their, expression, domains, in, early, embryogenesis])].
[sujeto(['In', this, 'study,', by, analyzing, the, response, of, 'HoxB', genes, to, both, 'RA', and, 'FGF', signaling, in, neural, tissue, during, early, chick, embryogenesis, '(', 'HH', stages, 7, -, 15, ')', ',', we]), verbo([have]), complemento([defined, two, distinct, groups, of, 'Hox', genes, based, on, their, reciprocal, sensitivity, to, 'RA', or, 'FGF', during, this, developmental, period])].
[sujeto(['We']), verbo([found]), complemento([that, the, expression, domain, of, 5, '\'', members, from, the, 'HoxB', complex, '(', 'Hoxb6-Hoxb9)', can, be, expanded, anteriorly, in, the, chick, neural, tube, up, to, the, level, of, the, otic, vesicle, following, 'FGF', treatment, and, that, these, same, genes, are, refractory, to, 'RA', treatment, at, these, stages])].
[sujeto(['Using', a, dominant, negative, form, of, a, 'Xenopus', 'Cdx', gene, '(', 'XcadEnR)', we]), verbo([found]), complemento([that, the, effect, of, 'FGF', treatment, on, 5, '\'', 'HoxB', genes, is, mediated, in, part, through, the, activation, and, function, of, 'CDX', activity])].
[sujeto(['We', demonstrated, by, in, ovo, electroporation, of, a, dominant, negative, retinoid, receptor, construct, '(', 'dnRAR)', that, retinoid, signaling, is]), verbo([required]), complemento([to, initiate, expression])].
[sujeto(['Elevating', 'CDX', activity, by, ectopic, expression, of, an]), verbo([activated]), complemento([form, of, a, 'Xenopus', 'Cdx', gene, '(', 'XcadVP16)', in, the, hindbrain, ectopically, activates, and, anteriorly, expands, 'Hoxb4', expression])].
[sujeto(['In', a, similar, 'manner,', when, ectopic, expression, of, 'XcadVP16', is, combined, with, 'FGF', 'treatment,', we]), verbo([found]), complemento([that, 'Hoxb9', expression, expands, anteriorly, into, the, hindbrain, region])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([a, model, 'whereby,', over, the, window, of, early, development, we, 'examined,', all, 'HoxB', genes, are, actually, competent, to, interpret, an, 'FGF', signal, via, a, 'CDX-dependent', pathway])].
[sujeto(['However,', mechanisms, that, axially, restrict, the, 'Cdx', domains, of, 'expression,', serve, to]), verbo([prevent]), complemento([3, '\'', genes, from, responding, to, 'FGF', signaling, in, the, hindbrain])].
[sujeto(['FGF', may]), verbo([have]), complemento([a, dual, role, in, both, modulating, the, accessibility, of, the, 'HoxB', complex, along, the, axis, and, in, activating, the, expression, of, 'Cdx', genes])].
[sujeto(['These', results, highlight, the, key, role, of, 'Cdx', genes, in, integrating, the, input, of, multiple, signaling, 'pathways,', such, as, 'FGFs', and, 'RA,', in, controlling, initiation, of, 'Hox', expression, during, development, and, the, importance, of, understanding, regulatory, 'events/mechanisms', that]), verbo([modulate]), complemento(['Cdx', expression])].
[sujeto(['Mouse', 'GLUT5', cDNA, and, a, 7.7, -, kb, genomic, fragment]), verbo([have]), complemento([been, isolated, and, characterized])].
[sujeto(['The', cDNA, sequence]), verbo([suggests]), complemento([mouse, 'GLUT5', is, composed, of, 501, amino, 'acids,', and, has, 69, -, 88, '%', amino, acid, identity, with, 'human,', 'rat,', and, rabbit, 'GLUT5'])].
[sujeto(['Expression', of, mouse, 'GLUT5', cRNA, in, 'Xenopus', laevis, oocytes, showed, that, 'GLUT5']), verbo([mediated]), complemento([fructose, 'transport,', with, a, 'K(t)', of, 13, mM])].
[sujeto(['In', agreement, with, studies, in, rats, and, 'rabbits,', mouse, small, intestinal, 'GLUT5', mRNA, expression, levels, were]), verbo([increased]), complemento([following, exposure, to, a, 65, '%', 'fructose-enriched', diet])].
[sujeto(['In', 'addition,', developmental, studies, showed, a, significant]), verbo([increase]), complemento([in, 'GLUT5', mRNA, expression, levels, in, adult, mouse, testis, when, compared, to, prepubertal, mouse, testis])].
[sujeto(['Moreover,', caudal, homeobox, gene, '(', 'CdxA),', upstream, stimulatory, factor, '(', 'USF),', and, 'sex-determining', region, of, 'Y', '(', 'SRY)']), verbo([binding]), complemento([sites, were, identified, in, the, 5, '\'', flanking, region, that, may, be, responsible, for, 'GLUT5\'s', expression, 'characteristics:', tissue, 'distribution,', sensitivity, to, dietary, fructose, in, the, small, 'intestine,', and, developmental, expression, in, the, testis])].
[sujeto(['To', investigate, the, mechanisms]), verbo([involved]), complemento([in, regulation, of, 'NHE3', gene, 'expression,', the, human, 'NHE3', promoter, region, was, cloned, and, characterized])].
[sujeto(['Deletion', of, a, fragment, containing, the, 'AP-2', and, 'Sp1', motifs, resulted, in, a, drastic]), verbo([decrease]), complemento([in, promoter, activity])].
[sujeto(['In', gel, mobility, shift, 'assays,', an, oligonucleotide, spanning, from, -, 78, to, -, 56, bp]), verbo([bound]), complemento([a, recombinant, 'AP-2,', and, the, corresponding, binding, activity, in, nuclear, extracts, was, supershifted, with, 'anti-AP2alpha', antibody])].
[sujeto(['Our', studies]), verbo([suggest]), complemento([that, the, 'NHE3', expression, is, regulated, by, a, combination, of, cis, elements, and, their, cognate, transcription, factors, that, include, the, 'AP-2', and, 'Sp1', family, members])].
[sujeto(['The', human, gene]), verbo([has]), complemento([now, been, isolated, and, characterized])].
[sujeto(['The', immunoglobulin, 'enhancer-binding', 'proteins,', 'E12', and, 'E47,', encoded, by, the, 'E2A', gene, belong, to, the, basic, 'helix-loop-helix', '(', 'bHLH)', family, of, regulatory, proteins, and]), verbo([act]), complemento([as, transcriptional, activators])].
[sujeto(['In', addition, to, their, critical, role, in, 'B-lymphocyte', 'development,', the, 'E12', and, 'E47', proteins]), verbo([have]), complemento([been, implicated, in, the, induction, of, myogenesis, as, heterodimeric, partners, of, myogenic, bHLH, 'proteins,', 'MyoD', and, myogenin])].
[sujeto(['Here', we, demonstrate, that, the, 'E2A', proteins, form, heterodimers, with, the, bHLH, oncoprotein, 'tal-1', in, myeloid, and, erythroid, cells, and, that, these, heterodimers, specifically]), verbo([bind]), complemento([to, the, 'CANNTG', 'DNA', motif])].
[sujeto(['Heterodimerization', with, 'tal-1']), verbo([represses]), complemento([transactivation, by, 'E47', and, could, function, to, prevent, the, expression, of, immunoglobulin, genes, in, cells, other, than, 'B', lymphocytes])].
[sujeto(['DNA']), verbo([binding]), complemento([by, 'E2A-tal-1', heterodimers, in, the, 'M1', mouse, myeloid, cell, line, is, abrogated, upon, terminal, macrophage, differentiation, induced, by, the, cytokine, interleukin, 6])].
[sujeto(['The']), verbo([loss]), complemento([of, 'E2A-tal-1', 'DNA', binding, is, correlated, with, elevated, expression, of, mRNA, encoding, the, dominant, negative, 'HLH', 'proteins,', 'Id1', and, particularly, 'Id2'])].
[sujeto(['Moreover,', recombinant, 'Id', proteins]), verbo([inhibit]), complemento([the, 'E2A-tal-1-specific', 'DNA', binding, activity, from, undifferentiated, 'M1', cells])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'E2A-tal-1', heterodimers, may, play, a, role, in, preventing, terminal, differentiation, in, the, myeloid, lineage, and, provide, a, possible, explanation, for, oncogenic, transformation, induced, by, ectopic, 'tal-1', expression, in, acute, 'T-cell', lymphoblastic, leukemias])].
[sujeto(['In', the, present, study, four, 'genes,', 'H-FABP', '(', heart, fatty, 'acid-binding', 'protein),', 'MASTR', '(', 'MEF2']), verbo([activating]), complemento([motif, and, 'SAP', domain, containing, transcriptional, 'regulator),', 'UCP3', '(', uncoupling, protein, 3, ')', and, 'MYOD1', '(', myogenic, differentiation, 1, ')', were, researched, in, 'Large', 'White', pigs])].
[sujeto([187, 'C&gt;T']), verbo([have]), complemento([been, reported, to, be, associated, with, meat, quality, traits, in, pigs])].
[sujeto(['The', single, marker, association, analysis, showed, that, the, 'H-FABP', and, 'MASTR', genes, were]), verbo([associated]), complemento([with, 'IMF', '(', intramuscular, fat, 'content)', '(', 'P', &, 'lt;', 0.05, ')', ',', and, that, the, g])].
[sujeto(['Thus,', our, study, results]), verbo([suggested]), complemento([that, 'H-FABP', and, 'MASTR', polymorphisms, could, be, used, as, genetic, markers, in, the, 'marker-assisted', selection, towards, the, improvement, of, 'IMF', in, 'Large', 'White', pigs])].
[sujeto(['It', dorsalized, 'Xenopus', embryos, and, was]), verbo([expressed]), complemento([in, the, 'Spemann', organizer, during, early, gastrulation])].
[sujeto(['Frzb', was, secretable, and, could]), verbo([act]), complemento([across, cell, boundaries])].
[sujeto(['Furthermore,', 'Frzb', blocked, induction, of, 'MyoD,', an, action]), verbo([reported]), complemento([recently, for, a, 'dominant-negative', 'Xwnt-8'])].
[sujeto(['Frzb', coimmunoprecipitated, with, 'Wnt', 'proteins,']), verbo([providing]), complemento([direct, biochemical, evidence, for, 'Frzb-Wnt', interactions])].
[sujeto(['These', observations, implicate, 'Frzb', in, axial, patterning, and, support, the, concept, that, 'Frzb']), verbo([binds]), complemento([and, inactivates, 'Xwnt-8', during, 'gastrulation,', preventing, inappropriate, ventral, signaling, in, developing, dorsal, tissues])].
[sujeto(['Transcription', factors, containing, a, basic, 'helix-loop-helix', '(', 'bHLH)', motif]), verbo([regulate]), complemento([the, expression, of, 'tissue-specific', genes, in, a, number, of, mammalian, and, insect, systems])].
[sujeto(['Consequently,', 'Id', proteins]), verbo([inhibit]), complemento([binding, to, 'DNA', and, transcriptional, transactivation, by, heterodimerization, with, bHLH, proteins])].
[sujeto(['We']), verbo([report]), complemento([here, the, cDNA, sequence, of, a, novel, human, 'HLH', gene, '(', 'HGMW-approved', symbol, 'ID4)', that, lacks, the, basic, domain])].
[sujeto(['ID4', is, differentially]), verbo([expressed]), complemento([in, adult, organs, in, four, mRNA, 'molecules,', which, are, presumably, a, result, of, differential, splicing, 'and/or', alternative, usage, of, the, polyadenylation, sites])].
[sujeto(['Transfection', experiments, indicated, that, enforced, expression, of, 'Id-4H', protein]), verbo([inhibits]), complemento([the, 'trans-activation', of, the, muscle, creatine, kinase, 'E-box', enhancer, by, 'MyoD'])].
[sujeto(['The', three, ternary, complex, factors, '(', 'TCFs),', 'Net', '(', 'ERP/', 'SAP-2),', 'ELK-1', and, 'SAP-1,', are, highly, related, ets, oncogene, family, members, that]), verbo([participate]), complemento([in, the, response, of, the, cell, to, 'Ras', and, growth, signals])].
[sujeto(['Understanding', the, different, roles, of, these, factors, will]), verbo([provide]), complemento([insights, into, how, the, signals, result, in, coordinate, regulation, of, the, cell])].
[sujeto(['We', show, that, 'Net']), verbo([inhibits]), complemento([transcription, under, basal, 'conditions,', in, which, 'SAP-1a', is, inactive, and, 'ELK-1', stimulates])].
[sujeto(['Repression', is]), verbo([mediated]), complemento([by, the, 'NID,', the, 'Net', 'Inhibitory', 'Domain', of, about, 50, amino, 'acids,', which, autoregulates, the, 'Net', protein, and, also, inhibits, when, it, is, isolated, in, a, heterologous, fusion, protein])].
[sujeto(['Ras']), verbo([activates]), complemento(['Net', through, the, 'C-domain,', which, is, conserved, between, the, three, 'TCFs,', and, the, 'NID', is, an, efficient, inhibitor, of, 'Ras', activation])].
[sujeto(['The', 'NID,', as, well, as, more, 'C-terminal', 'sequences,']), verbo([inhibit]), complemento(['DNA', binding])].
[sujeto(['Net', is, more, refractory, to, 'DNA']), verbo([binding]), complemento([than, the, other, 'TCFs,', possibly, due, to, the, presence, of, multiple, inhibitory, elements])].
[sujeto(['The', sequence, resemblance, with, myogenic, factors]), verbo([suggested]), complemento([that, 'Net', may, form, complexes, with, the, same, partners])].
[sujeto(['Indeed,', we]), verbo([found]), complemento([that, 'Net', can, interact, in, vivo, with, the, basic, 'HLH', 'factor,', 'E47'])].
[sujeto(['We', propose, that, 'Net', is]), verbo([regulated]), complemento([at, the, level, of, its, latent, 'DNA-binding', activity, by, protein, interactions, 'and/or', phosphorylation])].
[sujeto(['The', identification, of, the, novel, inhibitory, domain]), verbo([provides]), complemento([a, new, inroad, into, exploring, the, different, roles, of, the, ternary, complex, factors, in, growth, control, and, transformation])].
[sujeto(['I-mfa', '(', inhibitor, of, the, 'MyoD', family, 'a)', is, a, transcription, modulator, that]), verbo([binds]), complemento([to, 'MyoD', family, members, and, inhibits, their, transcriptional, activities])].
[sujeto(['It', is, highly]), verbo([expressed]), complemento([in, the, sclerotome, and, plays, an, important, role, in, the, patterning, of, the, somite, early, in, development])].
[sujeto(['The', statistical, analyses, indicated, that, the, three, 'SNPs,', are]), verbo([associated]), complemento([with, the, phenotypic, traits, in, 'Luxi', '(', 'LX),', 'Qinchuan', '(', 'QC),', and, 'Jiaxian', '(', 'JX)', cattle, population, '(', 'P&nbsp;&lt;&nbsp;0'])].
[sujeto(['The', 'mutant-type', variants, were, superior, for, growth, 'traits;', the, heterozygote, diplotype, was]), verbo([associated]), complemento([with, higher, growth, traits, compared, to, 'wild-type', homozygote])].
[sujeto(['Our', results]), verbo([provide]), complemento([evidence, that, polymorphisms, in, the, 'I-mfa', gene, are, associated, with, growth, traits, and, may, be, used, for, 'marker-assisted', selection, in, beef, cattle, breeding, program])].
[sujeto(['Accumulating', evidence]), verbo([suggests]), complemento([that, 'Sirtuin', '(', 'Sirt)1', serves, a, significant, role, in, proliferation, and, differentiation, of, myoblast, 'cells;', however, the, signaling, mechanisms, involved, remain, to, be, established])].
[sujeto(['To', determine, if, 'MSTN', is]), verbo([involved]), complemento([in, the, regulation, of, myoblast, cell, proliferation, by, 'Sirt1,', the, present, study, administrated, the, 'Sirt1&nbsp;activator', 'resveratrol,', inhibitor, nicotinamide, '(', 'NAM)', and, 'MSTN', inhibitor, 'SB431542&nbsp;to', 'C2C12&nbsp;myoblast', cells])].
[sujeto(['It', was, demonstrated, that, the, 'Sirt1&nbsp;activator,', 'resveratrol,', 'repressed,', whereas, the, 'Sirt1&nbsp;inhibitor,', 'NAM,']), verbo([enhanced]), complemento(['C2C12&nbsp;myoblast', cells, proliferation, in, a, 'Sirt1&#8209;dependent', manner])].
[sujeto(['Additionally,', resveratrol, upregulated, the, mRNA, expression, of, 'MyoD,', but]), verbo([inhibited]), complemento([the, expression, of, 'MSTN'])].
[sujeto(['Additionally,', 'NAM', significantly]), verbo([repressed]), complemento([the, expression, of, 'MyoD', and, the, phosphorylation, of, 'P107', '(', 'p&#8209;P107),', but, enhanced, the, expression, of, 'MSTN', and, the, protein, expression, of, 'P107'])].
[sujeto(['Marek\'s', disease, '(', 'MD)', is, an, infectious, disease, of, chickens]), verbo([caused]), complemento([by, 'MD', virus, '(', 'MDV),', which, is, a, herpesvirus, that, initiates, tumor, formation])].
[sujeto(['Studies']), verbo([have]), complemento([indicated, that, microRNAs, '(', 'miRNAs)', are, linked, with, the, development, of, cancers, or, tumors])].
[sujeto(['The']), verbo([target]), complemento([genes, of, 'gga-miR-130a', were, predicted, using, 'TargetScan', and, miRDB, and, clustered, through, 'Gene', 'Ontology', analysis])].
[sujeto(['The']), verbo([target]), complemento([genes, were, validated, by, western, 'blot,', 'qRT-PCR,', and, a, dual, luciferase, reporter, assay])].
[sujeto(['Two']), verbo([target]), complemento(['genes,', homeobox, 'A3', '(', 'HOXA3)', and, 'MyoD', family, inhibitor, domain, containing, '(', 'MDFIC),', were, predicted, and, clustered, to, cell, proliferation])].
[sujeto(['Results', indicate, that, 'gga-miR-130a']), verbo([regulates]), complemento(['HOXA3', and, 'MDFIC', at, the, protein, level, but, not, at, the, mRNA, level])].
[sujeto(['Moreover,', the, 'gga-miR-130a']), verbo([binding]), complemento([sites, of, two, target, genes, have, been, confirmed])].
[sujeto(['We', conclude, that, 'gga-miR-130a', can]), verbo([arrest]), complemento(['MSB1', cell, proliferation, and, 'migration,', and, target, 'HOXA3', and, 'MDFIC,', which, are, both, involved, in, the, regulation, of, cell, proliferation])].
[sujeto(['Collectively,', 'gga-miR-130a', plays, a, critical, role, in, the, tumorigenesis]), verbo([associated]), complemento([with, chicken, 'MD'])].
[sujeto(['Extracellular', stimuli]), verbo([induce]), complemento([gene, expression, responses, through, intracellular, signaling, mediators])].
[sujeto(['To', investigate, the, global, gene, transcription, program]), verbo([regulated]), complemento([by, p38α, during, satellite, cell, differentiation, '(', 'myogenesis),', and, to, specifically, address, whether, this, regulation, occurs, through, direct, action, of, p38α, on, gene, 'promoters,', we, performed, a, combination, of, microarray, gene, expression, and, 'genome-wide', binding, analyses])].
[sujeto(['For', experimental, 'robustness,', two, myogenic, cellular, systems, with, genetic, and, chemical]), verbo([loss]), complemento([of, p38α, function, were, 'used:', '(', 1, ')', satellite, cells, derived, from, mice, with, 'muscle-specific', deletion, of, 'p38α,', and, '(', 2, ')', the, 'C2C12', murine, myoblast, cell, line, cultured, in, the, absence, or, presence, of, the, 'p38α/β', inhibitor, 'SB203580'])].
[sujeto(['We', show, that, p38α]), verbo([binds]), complemento([to, a, large, set, of, active, promoters, during, the, transition, of, myoblasts, from, proliferation, to, differentiation, stages])].
[sujeto(['p38α-bound', promoters, are, enriched, with]), verbo([binding]), complemento([motifs, for, several, transcription, 'factors,', with, 'Sp1,', 'Tcf3/E47,', 'Lef1,', 'FoxO4,', 'MyoD,', and, 'NFATc', standing, out, in, all, experimental, conditions])].
[sujeto(['Interestingly,', p38α, also]), verbo([associates]), complemento([with, genes, repressed, at, the, onset, of, 'differentiation,', thus, highlighting, the, relevance, of, 'p38-dependent', chromatin, regulation, for, transcriptional, activation, and, repression, during, myogenesis])].
[sujeto(['These', results, uncover, p38α, association, and, function, on, chromatin, at, novel, classes, of]), verbo([target]), complemento([genes, during, skeletal, muscle, cell, differentiation])].
[sujeto(['Acute', muscle, injury, and, physiological, stress, from, chronic, muscle, diseases, and, aging]), verbo([lead]), complemento([to, impairment, of, skeletal, muscle, function])].
[sujeto(['This', raises, the, question, of, whether, 'p53,', a, cellular, stress, 'sensor,']), verbo([regulates]), complemento([muscle, tissue, repair, under, stress, conditions])].
[sujeto(['By', investigating, muscle, differentiation, in, the, presence, of, genotoxic, 'stress,', we, discovered, that, p53]), verbo([binds]), complemento([directly, to, the, myogenin, promoter, and, represses, transcription, of, 'myogenin,', a, member, of, the, 'MyoD', family, of, transcription, factors, that, plays, a, critical, role, in, driving, terminal, muscle, differentiation])].
[sujeto(['This', reduction, of, myogenin, protein, is, observed, in, 'G1-arrested', cells, and]), verbo([leads]), complemento([to, decreased, expression, of, late, but, not, early, differentiation, markers])].
[sujeto(['In', response, to, acute, genotoxic, 'stress,', 'p53-mediated', repression, of, myogenin, reduces, 'post-mitotic']), verbo([nuclear]), complemento([abnormalities, in, terminally, differentiated, cells])].
[sujeto(['This', study]), verbo([reveals]), complemento([a, mechanistic, link, previously, unknown, between, p53, and, muscle, 'differentiation,', and, suggests, new, avenues, for, managing, 'p53-mediated', stress, responses, in, chronic, muscle, diseases, or, during, muscle, aging])].
[sujeto(['In', the, present, 'study,', we, performed, a, genome, wide, survey, of, candidate, genes, and, pathways]), verbo([associated]), complemento([with, individual, birth, weight, '(', 'IBW)', using, the, 'Illumina', 'PorcineSNP60', 'BeadChip', on, 24, high, '(', 'HEBV)', and, 24, low, estimated, breeding, value, '(', 'LEBV)', animals])].
[sujeto(['A', 'DSR', with, the, most, number, of, significant, 'SNPs', '(', including, 7, top, 0.1, '%', and, 31, top, 5, '%', 'SNPs)', was, located, on, 'SSC6,', while, another, 'DSR', with, the, largest, genetic, differences, in, 'F', 'ST', was]), verbo([found]), complemento([on, 'SSC18'])].
[sujeto(['These', regions, harbor, known, functionally, important, genes]), verbo([involved]), complemento([in, growth, and, 'development,', such, as, 'TNFRSF9', '(', tumor, necrosis, factor, receptor, superfamily, member, 9, ')', ',', 'CA6', '(', carbonic, anhydrase, 'VI)', and, 'MDFIC', '(', 'MyoD', family, inhibitor, domain, 'containing)'])].
[sujeto(['A', 'DSR', rich, in, imprinting, genes, appeared, on, 'SSC9,', which, included, 'PEG10', '(', paternally]), verbo([expressed]), complemento([10, ')', ',', 'SGCE', '(', 'sarcoglycan,', 'epsilon),', 'PPP1R9A', '(', protein, phosphatase, 1, ',', regulatory, subunit, 9, 'A)', and, 'ASB4', '(', ankyrin, repeat, and, 'SOCS', box, containing, 4, ')'])].
[sujeto(['More', 'importantly,', our, present, study]), verbo([provided]), complemento([evidence, to, support, six, quantitative, trait, loci, '(', 'QTL)', regions, for, pig, birth, 'weight,', six, 'QTL', regions, for, average, birth, weight, '(', 'ABW)', and, three, 'QTL', regions, for, litter, birth, weight, '(', 'LBW)', reported, previously, by, other, groups])].
[sujeto(['Furthermore,', gene, ontology, analysis, with, 183, genes, harbored, in, these, 27, 'DSRs']), verbo([suggested]), complemento([that, 'protein,', 'metal,', ion, and, 'ATP', 'binding,', viral, process, and, innate, immune, response, present, important, pathways, for, deciphering, their, roles, in, fetal, growth, or, development])].
[sujeto(['Overall,', our, study]), verbo([provides]), complemento([useful, information, on, candidate, genes, and, pathways, for, regulating, birth, weight, in, 'piglets,', thus, improving, our, understanding, of, the, genetic, mechanisms, involved, in, porcine, embryonic, or, fetal, development])].
[sujeto(['We']), verbo([have]), complemento([discovered, that, a, 'T-box', family, 'member,', 'TBX2,', is, highly, upregulated, in, tumor, cells, of, both, major, 'RMS', subtypes])].
[sujeto(['The', cell, cycle, regulator, p21, is]), verbo([required]), complemento([for, the, terminal, differentiation, of, skeletal, muscle, cells, and, is, silenced, in, 'RMS', cells])].
[sujeto(['We']), verbo([have]), complemento([found, that, 'TBX2', interacts, with, the, myogenic, regulatory, factors, 'MyoD', and, myogenin, and, inhibits, the, activity, of, these, factors])].
[sujeto(['TBX2', is]), verbo([expressed]), complemento([in, primary, myoblasts, and, 'C2C12', 'cells,', but, is, strongly, downregulated, upon, differentiation])].
[sujeto(['TBX2']), verbo([recruits]), complemento([the, histone, deacetylase, 'HDAC1', and, is, a, potent, inhibitor, of, the, expression, of, 'muscle-specific', genes, and, the, cell, cycle, 'regulators,', p21, and, p14])].
[sujeto(['TBX2']), verbo([promotes]), complemento([the, proliferation, of, 'RMS', cells, and, either, depletions, of, 'TBX2', or, dominant, negative, 'TBX2', upregulate, 'p21-', and, 'muscle-specific', genes])].
[sujeto(['Significantly,', depletion, or, interference, with, 'TBX2', completely]), verbo([inhibits]), complemento([tumor, growth, in, a, xenograft, 'assay,', highlighting, the, oncogenic, role, of, 'TBX2', in, 'RMS', cells])].
[sujeto(['Thus,', the, data, demonstrate, that, elevated, expression, of, 'TBX2', contributes, to, the, pathology, of, 'RMS', cells, by]), verbo([promoting]), complemento([proliferation, and, repressing, 'differentiation-specific', gene, expression])].
[sujeto(['These', results, show, that, deregulated, 'TBX2', serves, as, an, oncogene, in, 'RMS,']), verbo([suggesting]), complemento([that, 'TBX2', may, serve, as, a, new, diagnostic, marker, or, therapeutic, target, for, 'RMS', tumors])].
[sujeto(['I-mfa', null, mice]), verbo([have]), complemento([an, osteopenic, phenotype, characterized, by, increased, osteoclast, numbers, and, 'surface,', which, are, normalized, in, mice, lacking, both, 'Trpc1', and, 'I-mfa'])].
[sujeto(['In', vitro, differentiation, of, 'pre-osteoclasts', derived, from, 'I-mfa-deficient', mice]), verbo([leads]), complemento([to, an, increased, number, of, mature, osteoclasts, and, higher, bone, resorption, per, osteoclast])].
[sujeto(['Consistently,', whole, cell, currents]), verbo([activated]), complemento([in, response, to, the, depletion, of, intracellular, 'Ca(2+)', stores, are, larger, in, 'pre-osteoclasts', derived, from, 'I-mfa', 'knock-out', mice, compared, with, currents, in, wild, type, mice, and, normalized, in, cells, derived, from, double, mutant, 'mice,', suggesting, a, 'cell-autonomous', effect, of, 'I-mfa', on, 'TRPC1', in, these, cells])].
[sujeto(['Heterologous', expression, of, 'TRPC1ε', in, 'HEK293', cells, revealed, that, it, is, unique, among, all, known, 'TRPC1', isoforms, in, its, ability, to, amplify, the, activity, of, the, 'Ca(2+)', 'release-activated', 'Ca(2+)', '(', 'CRAC)', 'channel,']), verbo([mediating]), complemento(['store-operated', currents])].
[sujeto(['TRPC1ε', physically]), verbo([interacts]), complemento([with, 'Orai1,', the, 'pore-forming', subunit, of, the, 'CRAC', 'channel,', and, 'I-mfa', is, recruited, to, the, 'TRPC1ε-Orai1', complex, through, 'TRPC1ε', suppressing, 'CRAC', channel, activity])].
[sujeto(['We', propose, that, the, positive, and, negative, modulation, of, the, 'CRAC', channel, by, 'TRPC1ε', and, 'I-mfa,', 'respectively,', 'fine-tunes', the, dynamic, range, of, the, 'CRAC', channel]), verbo([regulating]), complemento([osteoclastogenesis])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, a, natural, compound, of, the, hydroxybenzoquinone, 'class,', 'embelin,', specifically, inhibits, 'H3Lys9', acetylation, in, mice, and, inhibits, recombinant, 'PCAF-mediated', acetylation, with, near, complete, specificity, in, vitro])].
[sujeto(['Furthermore,', using, 'embelin,', we]), verbo([have]), complemento([identified, the, gene, networks, that, are, regulated, by, 'PCAF', during, muscle, 'differentiation,', further, highlighting, the, broader, regulatory, functions, of, 'PCAF', in, muscle, differentiation, in, addition, to, the, regulation, via, 'MyoD', acetylation])].
[sujeto(['Ephrin-A5', is, a, chemotactic, molecule, that]), verbo([participates]), complemento([in, the, correct, positioning, and, formation, of, the, 'NMJ'])].
[sujeto(['Treatment', of, the, 'BSC', with, 'ephrin-A5']), verbo([causes]), complemento([a, reduction, '(', 'P', &, 'lt;', 0.05, ')', in, velocity, with, a, concomitant, increase, '(', 'P', &, 'lt;', 0.05, ')', in, directed, migration])].
[sujeto(['Ephrin-A5']), verbo([induced]), complemento([migration, appears, to, require, components, of, the, 'Ras', homolog, gene, family, member, 'A', '(', 'RhoA)', and, 'Rho-associated', protein, kinase, '(', 'ROCK)', signaling, machinery])].
[sujeto(['Supplementation', of, culture, media, with, a, chemical, 'ROCK', inhibitor]), verbo([suppressed]), complemento(['(', 'P', &, 'lt;', 0.05, ')', 'ephrin-A5', initiated, 'BSC', migration])].
[sujeto(['Twenty-four', hours, after, culture, 'establishment,', 'BSC', demonstrated, an]), verbo([increase]), complemento(['(', 'P', &, 'lt;', 0.05, ')', in, transwell, migration, toward, 'HGF'])].
[sujeto(['These', results, document, that, temporal, and, spatial, gradients, of, chemokines, and, growth, factors]), verbo([participate]), complemento([in, the, localization, of, 'BSC', within, the, niche])].
[sujeto(['The', class, 'IIa', histone, deacetylases, '(', 'HDACs)']), verbo([act]), complemento([as, transcriptional, repressors, by, altering, chromatin, structure, through, histone, deacetylation])].
[sujeto(['This', family, of, enzymes]), verbo([regulates]), complemento([muscle, development, and, 'phenotype,', through, regulation, of, 'muscle-specific', genes, including, myogenin, and, 'MyoD', '(', 'MYOD1)'])].
[sujeto(['More', 'recently,', class, 'IIa', 'HDACs']), verbo([have]), complemento([been, implicated, in, regulation, of, genes, involved, in, glucose, metabolism])].
[sujeto(['However,', the, effects, of, 'HDAC5', on, glucose, metabolism, and, insulin, action]), verbo([have]), complemento([not, been, directly, assessed])].
[sujeto(['Knockdown', of, 'HDAC5', in, human, primary, muscle, cells]), verbo([increased]), complemento([glucose, uptake, and, was, associated, with, increased, 'GLUT4', '(', 'SLC2A4)', expression, and, promoter, activity, but, was, associated, with, reduced, 'GLUT1', '(', 'SLC2A1)', expression])].
[sujeto(['The', effects, of, 'HDAC5', knockdown, on, glucose, metabolism, were, not, due, to, alterations, in, the, initiation, of, 'differentiation,', as, knockdown, of, 'HDAC5', after, the, onset, of, differentiation, also, resulted, in]), verbo([increased]), complemento([glucose, uptake, and, 'insulin-stimulated', glycogen, synthesis])].
[sujeto(['These', data, show, that, inhibition, of, 'HDAC5']), verbo([enhances]), complemento([metabolism, and, insulin, action, in, muscle, cells])].
[sujeto(['In', 'myotubes,', 'Scriptaid']), verbo([increased]), complemento([histone, 3, 'acetylation,', 'GLUT4', 'expression,', glucose, uptake, and, both, oxidative, and, 'non-oxidative', metabolic, flux])].
[sujeto(['Together,', these, data]), verbo([suggest]), complemento([that, 'HDAC5', regulates, muscle, glucose, metabolism, and, insulin, action, and, that, 'HDAC', inhibitors, can, be, used, to, modulate, these, parameters, in, muscle, cells])].
[sujeto(['Skeletal', muscle, differentiation, is]), verbo([regulated]), complemento([by, transcription, 'factors,', including, members, of, the, myogenic, regulatory, factor, '(', 'MRF)', family, and, many, signaling, pathways])].
[sujeto(['The', 'JAK1', and, 'JAK2', pathways, are, known, to, each]), verbo([have]), complemento([different, effects, on, myoblast, proliferation, and, 'differentiation;', 'however,', the, role, of, 'JAK3', in, myoblast, differentiation, remains, unclear])].
[sujeto(['During', myogenic, 'differentiation,', treatment, with, the, 'JAK3', inhibitor, 'WHIp154', significantly]), verbo([increased]), complemento([the, number, of, 'MHC-positive', multinucleated, myotubes, and, the, expressions, of, myosin, heavy, chain, '(', 'MHC),', myogenin, '(', 'MGN),', 'MyoD,', and, myogenic, enhancer, factor, 2, '(', 'MEF2)'])].
[sujeto(['Knockdown', of, the, 'JAK3', gene, using, siJAK3, also, significantly]), verbo([increased]), complemento(['MHC,', 'MGN', and, 'MyoD', mRNA, expressions, as, well, as, 'insulin-like', growth, 'factor-II', '(', 'IGF-II)', gene, expression])].
[sujeto(['During', 'differentiation,', 'JAK3', was, initially]), verbo([activated]), complemento([and, later, decreased])].
[sujeto(['Differentiation']), verbo([decreased]), complemento(['STAT1,', which, was, further, decreased, by, 'WHIp154'])].
[sujeto(['In', 'contrast,', 'STAT3', gradually, was, elevated, during, 'differentiation,', and, was]), verbo([increased]), complemento([by, 'JAK3', inhibition])].
[sujeto(['Moreover,', we]), verbo([found]), complemento([that, 'up-regulation', of, 'AKT', activity, and, 'down-regulation', of, 'ERK', activity, cooperated, to, accelerate, myogenic, differentiation])].
[sujeto(['Additionally,', 'JAK3', inhibition]), verbo([induced]), complemento([precocious, differentiation, and, played, important, roles, for, terminal, 'differentiation,', including, 'fusion,', which, is, involved, with, regulation, of, 'AKT', and, 'ERK', pathways])].
[sujeto(['Expression', of]), verbo([phosphorylated]), complemento(['Smad1/5/8,', which, is, an, indicator, of, 'BMP', 'activity,', was, higher, before, 'differentiation,', and, rapidly, decreased, after, differentiation, stimulation])].
[sujeto(['Treatment', with, inhibitors, of, 'BMP', type, 'I', receptors, or, noggin, in, 'C2C12', myoblasts, 'down-regulated', the, expression, of, myogenic, regulatory, 'factors,', such, as, 'Myf5', and, 'MyoD,']), verbo([leading]), complemento([to, impaired, myotube, formation])].
[sujeto(['Addition', of, 'BMP-2', during, the, myoblast, phase, also]), verbo([inhibited]), complemento([myotube, differentiation, through, the, 'down-regulation', of, 'Myf5', and, 'MyoD'])].
[sujeto(['A-83-01,', an, inhibitor, of, 'TGF-β', type, 'I', 'receptor,']), verbo([increased]), complemento([the, expression, of, 'Myf5', and, 'MyoD,', and, enhanced, myotube, formation])].
[sujeto(['The', present, results]), verbo([reveal]), complemento([that, endogenous, activities, of, the, 'TGF-β', family, are, changed, during, myogenesis, in, a, 'pathway-specific', 'manner,', and, that, the, activities, are, required, for, myogenesis])].
[sujeto(['Differentiation', often]), verbo([requires]), complemento([conversion, of, analogue, signals, to, a, stable, binary, output, through, positive, feedback])].
[sujeto(['Hedgehog', '(', 'Hh)', signalling]), verbo([promotes]), complemento([myogenesis, in, the, vertebrate, 'somite,', in, part, by, raising, the, activity, of, muscle, regulatory, factors, '(', 'MRFs)', of, the, 'Myod', family, above, a, threshold])].
[sujeto(['Hh', is, known, to]), verbo([enhance]), complemento(['MRF', expression])].
[sujeto(['Here', we, show, that, 'Hh', is, also, essential, at, a, second, step, that]), verbo([increases]), complemento(['Myod', protein, 'activity,', permitting, it, to, promote, 'Myogenin', expression])].
[sujeto(['Hh']), verbo([acts]), complemento([by, inducing, expression, of, cdkn1c, '(', 'p57(Kip2))', in, slow, muscle, precursor, 'cells,', but, neither, 'Hh', nor, 'Cdkn1c', is, required, for, their, cell, cycle, exit])].
[sujeto(['Myod', in, turn, 'up-regulates', 'cdkn1c,', thereby]), verbo([providing]), complemento([a, positive, feedback, loop, that, switches, myogenic, cells, to, terminal, differentiation])].
[sujeto(['We', show, here, that, 'OSM', potently]), verbo([inhibited]), complemento([myoblast, differentiation, mainly, by, activating, the, 'JAK1/STAT1/STAT3', pathway])].
[sujeto(['OSM', downregulated, myocyte, 'enhancer-binding', factor, 2, 'A', '(', 'MEF2A),', upregulated, the, expression, of, 'Id1', and, 'Id2,', and]), verbo([inhibited]), complemento([the, transcriptional, activity, of, 'MyoD', and, 'MEF2'])].
[sujeto(['In', 'addition,', 'OSM', also]), verbo([enhanced]), complemento([the, expression, of, 'STAT3', and, 'OSM', 'receptor,', which, constituted, a, positive, feedback, loop, to, further, amplify, 'OSM-induced', signaling])].
[sujeto(['Moreover,', we]), verbo([found]), complemento([that, 'STAT1', physically, associated, with, 'MEF2', and, repressed, its, transcriptional, 'activity,', which, could, account, for, the, 'OSM-mediated', repression, of, 'MEF2'])].
[sujeto(['Although', undetectable, in, normal, muscles, in, 'vivo,', 'OSM', was, rapidly]), verbo([induced]), complemento([on, muscle, injury, and, then, promptly, downregulated, just, before, the, majority, of, myoblasts, differentiate])].
[sujeto(['Prolonged', expression, of, 'OSM', in, muscles, compromised, the, regeneration, process, without, affecting, myoblast, 'proliferation,']), verbo([suggesting]), complemento([that, 'OSM', functions, to, prevent, proliferating, myoblasts, from, premature, differentiation, during, the, early, phase, of, muscle, regeneration])].
[sujeto(['Splitting', 'Fluc', into, 'N-', and, 'C-terminal', fragments, destroys, its, enzymatic, 'activity,', resulting, in, a, complete]), verbo([loss]), complemento([of, bioluminescence])].
[sujeto(['This']), verbo([led]), complemento([to, the, development, of, a, novel, labeling, strategy, for, imaging, 'protein–protein', interactions, in, 'vivo,', the, split, reporter, '(', 4, ')'])].
[sujeto(['In', this, 'method,', reporters, like, 'Fluc', are, dissected, into, two, fragments, and, fused, to, a, pair, of, proteins, '(', 'A', and, 'B)', that, strongly]), verbo([interact]), complemento([with, each, other])].
[sujeto(['The', interaction, between, protein, 'A', and, 'B', brings, the, 'N-', and, 'C-inteins', 'together,', resulting, in, the, joining, of, 'N-', and, 'C-terminal', fragments, of, 'Fluc', by, a, peptide, bond, and, a]), verbo([release]), complemento([of, a, fully, reconstituted, protein, 'Fluc'])].
[sujeto(['MyoD']), verbo([activates]), complemento([myogenesis, by, binding, directly, to, the, control, region, of, 'muscle-specific', 'genes,', and, it, converts, fibroblasts, into, skeletal, muscle])].
[sujeto(['The', helices, in, 'MyoD']), verbo([bind]), complemento([tightly, with, other, 'HLH', factors, such, as, 'Id', to, form, a, heterodimer])].
[sujeto(['Id,', also, known, as, an, inhibitor, of, differentiation, or, inhibitor, of, 'DNA', 'binding,', lacks, the, basic, domain, for, 'DNA']), verbo([binding]), complemento([and, acts, as, dominant, negative, regulator, in, myogenesis, or, other, cell, proliferations, '(', 6, ')'])].
[sujeto(['Id', 'protein-firefly', luciferase, 'N-fragment', &, 'amp;', firefly, luciferase, 'C-fragment-MyoD', protein, '(', 'Id-NFluc', &, 'amp;', 'CFluc-MyoD)', make, up, a, pair, of]), verbo([interacting]), complemento([proteins, attached, to, the, split, 'Fluc', fragments, '(', 7, ')'])].
[sujeto(['Kaposi\'s', 'sarcoma-associated', herpes, virus, '(', 'KSHV)-encoded', 'latency-associated']), verbo([nuclear]), complemento([antigen, '(', 'LANA)', protein, has, been, reported, to, interact, with, glycogen, synthase, kinase, 3, beta, '(', 'GSK-3beta)', and, to, negatively, regulate, its, 'activity,', leading, to, stimulation, of, 'GSK-3beta-dependent', 'beta-catenin', degradation])].
[sujeto(['We', show, here, that, the, 'I-mfa', domain, 'proteins,', 'HIC', '(', human, 'I-mfa', 'domain-containing', 'protein)', and, 'I-mfa', '(', inhibitor, of, 'MyoD', family, 'a),']), verbo([interacted]), complemento([in, vivo, with, 'LANA', through, their, 'C-terminal', 'I-mfa', domains])].
[sujeto(['This', interaction, affected, the, intracellular, localization, of, 'HIC,']), verbo([inhibited]), complemento([the, 'LANA-dependent', transactivation, of, a, 'beta-catenin-regulated', reporter, 'construct,', and, decreased, the, level, of, the, 'LANA'])].
[sujeto(['These', data]), verbo([reveal]), complemento([for, the, first, time, that, 'I-mfa', domain, proteins, interact, with, 'LANA', and, negatively, regulate, 'LANA-mediated', activation, of, 'Wnt', 'signaling-dependent', transcription, by, inhibiting, the, formation, of, the, 'LANA'])].
[sujeto(['MyoD', is, a, 'DNA-binding', protein, capable, of, specific, interactions, that]), verbo([involve]), complemento([the, 'helix-loop-helix', '(', 'HLH)', domain])].
[sujeto(['The', 'Id', family, consists, of, four, related, proteins, that, contain, a, highly]), verbo([conserved]), complemento([dimerization, motif, known, as, the, 'HLH', domain])].
[sujeto(['In', signaling, 'pathways,', 'Id', proteins]), verbo([act]), complemento([as, dominant, negative, antagonists, of, the, basic, 'helix-loop-helix', '(', 'bHLH)', family, of, transcription, factors, which, play, important, roles, in, cellular, 'development,', 'proliferation,', and, differentiation])].
[sujeto(['The', mechanism, of, 'Id', proteins, is, to, antagonize, bHLH, proteins, by]), verbo([binding]), complemento([as, dominant, negative, 'HLH', proteins, to, form, 'high-affinity', heterodimers, with, other, bHLH, 'proteins,', thereby, preventing, them, from, binding, to, 'DNA', and, inhibiting, transcription, of, 'differentiation-associated', genes])].
[sujeto(['The', goal, of, this, study, is, to, design, and, synthesize, peptide, fragments, of, 'MyoD', with, high, affinity, for, 'Id1', to, interrupt, the, interactions, among, 'Id1,', 'MyoD,', and, other, bHLH, 'DNA-binding', proteins, and, to]), verbo([inhibit]), complemento([the, proliferation, of, cancer, cells])].
[sujeto(['The', percentage, of, 'sub-G1', in, the, cell, cycle, of, the, cancer, cells, treated, with, 5, microM, of, 3, 'C', was, 'increased,', indicating, the]), verbo([induced]), complemento([apoptosis, of, cancer, cells, by, 3, 'C'])].
[sujeto(['Taken', 'together,', the, peptide, 3, 'C', is, a, promising]), verbo([lead]), complemento([compound, for, the, development, of, antiproliferative, agents])].
[sujeto(['Most', growth, factors]), verbo([stimulate]), complemento([myoblast, proliferation, and, prevent, 'differentiation,', whereas, 'insulin-like', growth, factors, '(', 'IGFs)', promote, myoblast, differentiation, through, the, phosphatidylinositol, 3, -, kinase, '(', 'PI3K)', pathway])].
[sujeto(['Subtilisin-like', proprotein, convertases, '(', 'SPCs)', are]), verbo([involved]), complemento([in, cell, growth, and, differentiation, via, activation, of, 'pro-growth', factors])].
[sujeto(['PACE4', mRNA, levels]), verbo([increased]), complemento([markedly, during, 'myogenesis,', whereas, the, expression, of, other, member, of, 'SPC', 'family,', furin, and, 'PC6,', remained, unchanged])].
[sujeto(['The', expression, of, shRNA]), verbo([targeting]), complemento(['PACE4,', but, not, 'furin,', suppressed, the, expression, of, the, 'muscle-specific', myosin, light, chain, '(', 'MLC)'])].
[sujeto(['Finally,', we, demonstrated, that, the, 'PI3K', inhibitor, 'LY294002', blocked, the, induction, of, 'PACE4', 'mRNA,', a, result, not, observed, when, another, myogenic, differentiation, 'inhibitor,', 'SB203580', '(', p38, 'MAP', kinase, 'inhibitor),', was, 'employed,', indicating, the, presence, of, a, positive, feedback, loop]), verbo([regulating]), complemento(['PACE4', expression])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'PACE4', plays, an, important, role, in, myogenic, differentiation, through, its, association, with, the, 'IGF-II', pathway])].
[sujeto(['Nuclear', localization, of, 'N', is, 'non-essential', for, 'PRRSV', replication, in, cultured, cells, but]), verbo([has]), complemento([been, shown, to, modulate, the, pathogenesis, of, virus, in, 'pigs,', suggesting, that, 'N', plays, an, accessory, role, in, the, nucleus, during, infection])].
[sujeto(['The', porcine, homolog, of, 'HIC', is, universally]), verbo([expressed]), complemento([in, pig, tissues, including, alveolar, macrophages])].
[sujeto(['The', 'I-mfa', domain, proteins, 'HIC', '(', also, known, as, 'MDFIC)', and, 'I-mfa', '(', also, known, as, 'MDFI)', are, candidate, tumor, suppressor, genes, that, are]), verbo([involved]), complemento([in, cellular, and, viral, transcriptional, regulation])].
[sujeto(['Here,', we, show, that, 'HIC', and, 'I-mfa', directly]), verbo([interact]), complemento([with, human, 'T-cell', leukemia, virus, 'type-1', '(', 'HTLV-1)', 'Tax', protein, in, vitro])].
[sujeto(['In', 'addition,', 'HIC', and, 'I-mfa']), verbo([repress]), complemento(['Tax-dependent', transactivation, of, an, 'HTLV-1', long, terminal, repeat, '(', 'LTR)', reporter, construct, in, 'COS-1,', 'Jurkat', and, 'high-Tax-producing', 'HTLV-1-infected', 'T', cells])].
[sujeto(['HIC', also]), verbo([interacts]), complemento([with, 'Tax', through, its, 'I-mfa', domain, in, vivo, and, represses, 'Tax-dependent', transactivation, of, 'HTLV-1', 'LTR', and, 'NF-κB', reporter, constructs, in, an, 'interaction-dependent', manner])].
[sujeto(['Furthermore,', we, show, that, 'HIC']), verbo([decreases]), complemento([the, nuclear, distribution, and, stimulates, the, proteasomal, degradation, of, 'Tax'])].
[sujeto(['These', data]), verbo([reveal]), complemento([that, 'HIC', specifically, interacts, with, 'HTLV-1', 'Tax', and, negatively, regulates, 'Tax', transactivational, activity, by, altering, its, subcellular, distribution, and, stability])].
[sujeto(['Furthermore,', 'genome-wide', 'DNA']), verbo([binding]), complemento([of, p53, was, analyzed, by, 'chromatin-immunoprecipitation', '(', 'ChIP-Seq)'])].
[sujeto(['Thereby,', we, identified, differentially]), verbo([regulated]), complemento([proteins, '(', 542, 'up,', 569, 'down),', mRNAs, '(', 1258, 'up,', 415, 'down),', miRNAs, '(', 111, 'up,', 95, 'down)', and, lncRNAs, '(', 270, 'up,', 123, 'down)'])].
[sujeto(['In', 'total,', we, detected, 133, direct, p53]), verbo([target]), complemento([genes, that, were, differentially, expressed, and, displayed, p53, occupancy, in, the, vicinity, of, their, promoter])].
[sujeto(['More', transcriptionally]), verbo([induced]), complemento([genes, displayed, occupied, p53, binding, sites, '(', 4.3, '%', 'mRNAs,', 7.2, '%', 'miRNAs,', 6.3, '%', 'lncRNAs,', 5.9, '%', 'proteins)', than, repressed, genes, '(', 2.4, '%', 'mRNAs,', 3.2, '%', 'miRNAs,', 0.8, '%', 'lncRNAs,', 1.9, '%', 'proteins),', suggesting, indirect, mechanisms, of, repression])].
[sujeto(['Moreover,', proteins]), verbo([repressed]), complemento([by, p53, significantly, overlapped, with, those, previously, shown, to, be, repressed, by, 'miR-34a'])].
[sujeto(['We', confirmed, 'up-regulation', of, the, novel, direct, p53]), verbo([target]), complemento([genes, 'LINC01021,', 'MDFI,', 'ST14', and, 'miR-486', and, showed, that, ectopic, 'LINC01021', expression, inhibits, proliferation, in, 'SW480', cells])].
[sujeto(['Furthermore,', 'KLF12,', 'HMGB1', and, 'CIT', mRNAs, were, confirmed, as, direct]), verbo([targets]), complemento([of, the, 'p53-induced', 'miR-34a,', 'miR-205', and, 'miR-486-5p,', respectively])].
[sujeto(['In', line, with, the]), verbo([loss]), complemento([of, p53, function, during, tumor, 'progression,', elevated, expression, of, 'KLF12,', 'HMGB1', and, 'CIT', was, detected, in, advanced, stages, of, cancer])].
[sujeto(['In', 'conclusion,', the, integration, of, multiple, omics, methods, allowed, the, comprehensive, identification, of, direct, and, indirect, effectors, of, p53, that]), verbo([provide]), complemento([new, insights, and, leads, into, the, mechanisms, of, 'p53-mediated', tumor, suppression])].
[sujeto(['However,', certain, patients, develop, drug, resistance, following, 'chemotherapy,', which, can]), verbo([lead]), complemento([to, disease, relapse, and, death])].
[sujeto(['Subgroups,', personalized, 'biomarkers,', and, therapy]), verbo([targets]), complemento([were, identified, using, cluster, analysis, of, differentially, expressed, genes])].
[sujeto(['We']), verbo([found]), complemento([that, 'basal-like', breast, cancer, could, be, further, divided, into, at, least, four, distinct, 'subgroups,', including, two, groups, at, risk, for, drug, resistance, and, two, groups, characterized, by, sensitivity, to, pharmacotherapy])].
[sujeto(['Therefore,', these, nine, differentially]), verbo([expressed]), complemento([genes, and, their, associated, functional, pathways, should, provide, the, basis, for, novel, personalized, clinical, treatments, of, 'basal-like', breast, cancer])].
[sujeto(['The', identified, hypermethylation, markers, in, 'CRC', patients, may]), verbo([have]), complemento([good, sensitivity, in, different, 'CRC', stages])].
[sujeto(['Whole', human, genome, oligo, microarray, was, applied, to, detect, the, differentially]), verbo([expressed]), complemento([genes, in, invasive, cells])].
[sujeto(['For', primary, cultured, invasive, 'cells,', differential, expressions, of, several, groups, of, common, genes, are, known, to]), verbo([have]), complemento([capacities, to, promote, proliferation, '(', 'CAV1,', 'IL6,', 'PLAT,', 'RRAD,', 'SRPX),', remodeling, of, extracellular, matrix, '(', 'COL1A1,', 'COL1A2,', 'NID2,', 'TNC,', 'RELN,', 'SPARC),', migration, '(', 'ACTG2,', 'CAV1,', 'CCL2,', 'CCL26,', 'CDC42EP3,', 'CNN1,', 'PHLDB2,', 'PLAT,', 'RRAD,', 'SRPX),', implantation, '(', 'IL6),', immune, escape, '(', 'CD70)', and, angiogenesis, '(', 'CCL2,', 'IL6,', 'IL18,', 'PLAT,', 'SLIT3)'])].
[sujeto(['In', 'conclusion,', the, characteristics, of, invasive, phenotype, 'HCC', cells, are, originated, from, differential, expressions, of, several, groups, of, genes, rather, than, few]), verbo([target]), complemento([genes])].
[sujeto(['Analysis', of, the, results, from, a, purchased, cell, line, may]), verbo([have]), complemento([bias, due, to, 'long-term', repeated, in, vitro, cultures])].
[sujeto(['Many', 'QTLs', for, fatness, traits]), verbo([have]), complemento([been, mapped, on, pig, chromosome, 7, q1])].
[sujeto(['Eight', novel, 'markers,', including, seven, 'SNPs', and, one, insertion, or, deletion, within, 'BTNL1,', 'COL21A1,', 'PPARD,', 'GLP1R,', 'MDFI,', 'GNMT,', 'ABCC10,', and, 'PLA2G7', 'genes,', as, well, as, two, previously]), verbo([reported]), complemento(['SNPs', in, 'SLC39A7', and, 'HMGA1', 'genes,', were, genotyped, in, 'Large', 'White', and, 'Meishan', pig, breeds])].
[sujeto(['Nine']), verbo([target]), complemento([genes, were, assayed, by, 'real-time', 'methylation-specific', polymerase, chain, reaction, '(', 'MSP)', in, 'bisulfite-treated', 'DNA', from, microdissected, frozen, specimens, of, 24, 'PanC', cases, and, 30, normal, colon, controls])].
[sujeto(['Combining', methylated, 'BMP3', and, mutant, 'KRAS']), verbo([increased]), complemento([stool, detection, over, either, marker, alone])].
[sujeto(['In', an, alkaline, 'medium,', the, chemiluminescence, '(', 'CL)', reaction, of, imidazole, derivatives, with, 'H(2)O(2)']), verbo([has]), complemento([been, investigated])].
[sujeto(['It', was, also]), verbo([found]), complemento([that, 'MDFI/H(2)O(2)', and, 't-BDFI/H(2)O(2)', systems, gave, strong, 'CL'])].
[sujeto(['Migraine', is]), verbo([associated]), complemento([with, an, increased, risk, for, cardiovascular, disease, '(', 'CVD)'])].
[sujeto(['We', performed, a, 'genome-wide', association, study, for, incident, 'CVD', events, during, 12, years, of, 'follow-up', among, 5, ',', 122, migraineurs]), verbo([participating]), complemento([in, the, 'population-based', 'Women\'s', 'Genome', 'Health', 'Study'])].
[sujeto(['No', 'SNP', was]), verbo([associated]), complemento([with, major, 'CVD,', ischemic, 'stroke,', myocardial, 'infarction,', or, 'CVD', death, at, the, 'genome-wide', 'level;', 'however,', five, 'SNPs', showed, association, with, 'p&lt;5×10(-6)'])].
[sujeto(['Among', migraineurs, with, aura, rs7698623, in, 'MEPE', '(', 'OR', =, 6.37, ;, 95, '%', 'CI', 3.15, -, 12.9, ;, p, =, 2.7, '×10(-7))', and, rs4975709, in, 'IRX4', '(', 'OR', =, 5.06, ;, 95, '%', 'CI', 2.66, -, 9.62, ;, p, =, 7.7, '×10(-7))', appeared, to, be]), verbo([associated]), complemento([with, ischemic, 'stroke,', rs2143678, located, close, to, 'MDF1', with, major, 'CVD', '(', 'OR', =, 3.05, ;, 95, '%', 'CI', 1.98, -, 4.69, ;, p, =, 4.3, '×10(-7)),', and, the, intergenic, rs1406961, with, 'CVD', death, '(', 'OR', =, 12.33, ;, 95, '%', 'CI', 4.62, -, 32.87, ;, p, =, 5.2, '×10(-7))'])].
[sujeto(['Further,', rs1047964, in, 'BACE1', appeared, to, be]), verbo([associated]), complemento([with, 'CVD', death, among, women, with, any, migraine, '(', 'OR', =, 4.67, ;, 95, '%', 'CI', 2.53, -, 8.62, ;, p, =, 8.0, '×10(-7))'])].
[sujeto(['Our', results]), verbo([provide]), complemento([some, suggestion, for, an, association, of, five, 'SNPs', with, 'CVD', events, among, women, with, 'migraine;', none, of, the, results, was, 'genome-wide', significant])].
[sujeto(['The', 'I-mfa', domain, proteins, 'I-mfa', and, 'HIC', are, considered, to, be, candidate, tumor, suppressor, genes, and]), verbo([have]), complemento([been, shown, to, be, involved, in, transcriptional, regulation])].
[sujeto(['We', show, here, that, 'I-mfa', and, 'HIC', specifically]), verbo([interact]), complemento([with, 'SEI-1', through, their, 'C-terminal', 'I-mfa', domains, 'in&nbsp;vivo'])].
[sujeto(['This', interaction, affects, the, intracellular, localization, of, 'I-mfa', and]), verbo([requires]), complemento([the, region, of, 'SEI-1', between, 30, and, 90, amino, 'acids,', which, includes, its, 'SERTA', 'domain,', and, results, in, repression, of, its, intrinsic, transcriptional, activity])].
[sujeto(['I-mfa', also]), verbo([decreases]), complemento([the, levels, of, the, 'SEI-1·DP-1', complex, and, endogenous, 'Fbxw7', 'mRNA,', the, expression, of, which, is, coregulated, by, 'E2F·DP-1', and, 'SEI-1', in, an, 'interaction-dependent', manner, 'in&nbsp;vitro'])].
[sujeto(['In', 'addition,', 'I-mfa', also, specifically]), verbo([interacts]), complemento([with, other, 'SERTA', 'domain-containing', 'proteins,', including, 'SEI-2,', 'SEI-3,', 'SERTAD3', and, 'SERTAD4,', through, its, 'I-mfa', domain, 'in&nbsp;vivo'])].
[sujeto(['This', interaction, also, affects, the, intracellular, localization, of, 'I-mfa', and]), verbo([represses]), complemento([the, intrinsic, transcriptional, activities, of, 'SEI-2', and, 'SERTAD3,', which, are, also, involved, in, the, 'E2F-dependent', transcription])].
[sujeto(['These', data]), verbo([reveal]), complemento([for, the, first, time, that, 'I-mfa', domain, proteins, interact, with, 'SERTA', domain, proteins, and, negatively, regulate, their, transcriptional, activity])].
[sujeto(['Because', 'SEI-1,', 'SEI-2', and, 'SERTAD3,', whose, intrinsic, transcriptional, activities, are]), verbo([repressed]), complemento([by, 'I-mfa,', are, suggested, to, be, 'oncogenes,', 'I-mfa', domain, proteins, may, be, involved, in, their, oncogenic, functions, by, negatively, regulating, their, transcriptional, activities])].
[sujeto(['The', phenotypes, of, the, 'Scnm1Delta3-5', mutant, confirm, the, role, of, this, splice, factor, in, processing, the, 'Scn8a(medJ)', transcript, and]), verbo([provide]), complemento([a, new, allele, of, greater, severity, for, future, studies])].
[sujeto(['More', than, 1, /, 2, of, the, genes, aberrantly, hypermethylated, in, 'Panc-1', were, not]), verbo([expressed]), complemento([in, the, pancreatic, duct, '(', 'HPDE)', by, expression, array, analysis])].
[sujeto(['Promoter', and, 'CpG', island, array, analysis]), verbo([finds]), complemento([aberrant, methylation, of, hundreds, of, promoters, and, 'CpG', islands, in, pancreatic, cancer, cells])].
[sujeto(['A', commercial, chromogenic, agar, medium, '(', 'DFI)', was, supplemented, with, glucose, '(', 'mDFI)', to]), verbo([enhance]), complemento([the, specificity, of, 'Enterobacter', sakazakii, '(', 'E'])].
[sujeto(['In', these, patients, the, discriminatory, function, index, '(', 'DFI)', &, 'gt;', 32, ',']), verbo([has]), complemento([been, associated, with, a, mortality, rate, of, up, to, 50, '%'])].
[sujeto(['MELD', is, a, scale, that]), verbo([has]), complemento([been, recently, validated, as, independent, risk, factors, for, death, in, patients, who, are, candidates, for, liver, transplantation])].
[sujeto(['Wnt', regulation, of, muscle, development, is, thought, to, be]), verbo([mediated]), complemento([by, the, 'beta-catenin-TCF/LEF-dependent', canonical, pathway])].
[sujeto(['Here', we, demonstrate, that, 'beta-catenin,', not, 'TCF/LEF,', is]), verbo([required]), complemento([for, muscle, differentiation])].
[sujeto(['We', showed, that, 'beta-catenin']), verbo([interacts]), complemento([directly, with, 'MyoD,', a, basic, 'helix-loop-helix', transcription, factor, essential, for, muscle, differentiation, and, enhances, its, binding, to, 'E', box, elements, and, transcriptional, activity])].
[sujeto(['MyoD-mediated', transactivation, is]), verbo([inhibited]), complemento([in, muscle, cells, when, 'beta-catenin', is, deficient, or, the, interaction, between, 'MyoD', and, 'beta-catenin', is, disrupted])].
[sujeto(['We', identify, a, novel, interaction, of, 'Hand1', with, a, protein, that, contains, an, 'I-mfa', '(', inhibitor, of, myogenic, 'factor)', domain, that, anchors, 'Hand1', in, the, nucleolus, where, it, negatively]), verbo([regulates]), complemento(['Hand1', activity])].
[sujeto(['In', the, trophoblast, 'stem-cell', line, 'Rcho-1,', nucleolar, sequestration, of, 'Hand1', accompanies, sustained, cell, proliferation, and, 'renewal,', whereas]), verbo([release]), complemento([of, 'Hand1', into, the, nucleus, leads, to, its, 'activation,', thus, committing, cells, to, a, differentiated, 'giant-cell', fate])].
[sujeto(['Site-specific', phosphorylation, is]), verbo([required]), complemento([for, nucleolar, release, of, 'Hand1,', for, its, dimerization, and, biological, 'function,', and, this, is, mediated, by, the, 'non-canonical', 'polo-like', kinase, 'Plk4', '(', 'Sak)'])].
[sujeto(['Sak', is, 'co-expressed', in, 'Rcho-1', 'cells,', localizes, to, the, nucleolus, during, 'G2', and]), verbo([phosphorylates]), complemento(['Hand1', as, a, requirement, for, trophoblast, 'stem-cell', commitment, to, a, 'giant-cell', fate])].
[sujeto(['This', study, defines, a, novel, cellular, mechanism, for]), verbo([regulating]), complemento(['Hand1', that, is, a, crucial, step, in, the, 'stem-cell', differentiation, pathway])].
[sujeto(['Positive', transcription, elongation, factor, b, '(', 'P-TEFb)', 'complexes,', composed, of, 'cyclin-dependent', kinase, 9, '(', 'CDK9)', and, cyclin, 'T1', or, 'T2,', are, engaged, by, many, cellular, transcription, regulators, that]), verbo([activate]), complemento([or, inhibit, transcription, from, specific, promoters])].
[sujeto(['The', related, 'I-mfa', '(', inhibitor, of, 'MyoD', family, 'a)', and, 'HIC', '(', human, 'I-mfa-domain-containing)', proteins, function, in, myogenic, differentiation, and, embryonic, development, by]), verbo([participating]), complemento([in, the, 'Wnt', signaling, pathway])].
[sujeto(['We']), verbo([report]), complemento([that, 'I-mfa', is, a, novel, regulator, of, 'P-TEFb'])].
[sujeto(['Both', 'HIC', and, 'I-mfa']), verbo([interact]), complemento([through, their, homologous, 'I-mfa', domains, with, cyclin, 'T1', and, 'T2', at, two, binding, sites])].
[sujeto(['One', site, is, the, regulatory, 'histidine-rich', domain, that]), verbo([interacts]), complemento([with, 'CDK9', substrates, including, 'RNA', polymerase, 'II'])].
[sujeto(['The', second, site, contains, a, lysine, and, 'arginine-rich', motif, that, is, highly]), verbo([conserved]), complemento([between, the, two, 'T', cyclins])].
[sujeto(['This', site, overlaps, and, includes, the, previously, identified, 'Tat/TAR', recognition, motif, of, cyclin, 'T1']), verbo([required]), complemento([for, activation, of, human, immunodeficiency, virus, type, 1, '(', 'HIV-1)', transcription])].
[sujeto(['Their', 'I-mfa', domains, also]), verbo([bind]), complemento([the, activation, domain, of, 'HIV-1', 'Tat', and, inhibit, 'Tat-', and, 'P-TEFb-dependent', transcription, from, the, 'HIV-1', promoter])].
[sujeto(['Our', findings, link, 'I-mfa', and, 'HIC', to, viral, 'replication,', and]), verbo([suggest]), complemento([that, 'P-TEFb', is, modulated, in, the, 'Wnt', signaling, pathway])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, 'beta-catenin', interacts, with, a, transcription, suppressor, 'I-mfa', 'and,', through, this, 'interaction,', canonical, 'Wnt', signaling, could, relieve, 'I-mfa-mediated', suppression, of, myogenic, regulatory, factors, '(', 'MRFs)'])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento(['that,', based, on, this, 'interaction,', 'I-mfa-mediated', suppression, of, the, 'Wnt', transcription, factor, 'T-cell', 'factor/lymphoid', enhancing, 'factor-1', '(', 'TCF/LEF-1)', can, also, be, relieved])].
[sujeto(['Our', work, showed, that, knocking, down, endogenous, 'I-mfa', expression, mimics, canonical, 'Wnt', treatment, by]), verbo([inducing]), complemento([myogenesis, and, increasing, 'Wnt', reporter, gene, 'activity,', endogenous, 'Wnt', target, gene, expression, and, expression, of, 'MRFs', in, 'P19', cells])].
[sujeto(['In', 'addition,', we]), verbo([found]), complemento([that, 'beta-catenin', could, compete, with, 'I-mfa', for, binding, to, 'LEF-1', and, relieve, the, inhibitory, effects, of, 'I-mfa', in, overexpression, systems])].
[sujeto(['Furthermore,', canonical, 'Wnt', was, able, to, reduce, the, levels, of, endogenous, 'I-mfa']), verbo([associated]), complemento([with, 'LEF-1,', while, increasing, that, of, 'I-mfa', associated, with, 'beta-catenin'])].
[sujeto(['All', of, the, evidence, supports, a, conclusion, that, 'I-mfa', can]), verbo([suppress]), complemento([myogenesis, by, inhibiting, 'TCF/LEF-1', and, that, canonical, 'Wnt', signaling, may, relieve, the, suppression, through, elevating, 'beta-catenin', 'levels,', which, in, turn, relieve, 'I-mfa-mediated', suppression])].
[sujeto(['Moreover,', we]), verbo([suggest]), complemento([that, the, modified, gene, expression, in, fetal, skeletal, muscle, can, be, viewed, as, the, origin, of, developmental, muscular, plasticity, involved, in, the, concept, of, fetal, programming])].
[sujeto(['Here,', we, demonstrate, that, fusion, of, 'Tet1', or, 'Dnmt3a', with, a, catalytically, inactive, 'Cas9', '(', 'dCas9)', enables]), verbo([targeted]), complemento(['DNA', methylation, editing])].
[sujeto(['Targeting', of, the, 'dCas9-Tet1', or, -, 'Dnmt3a', fusion, protein, to, methylated, or, unmethylated, promoter, sequences]), verbo([caused]), complemento([activation, or, 'silencing,', 'respectively,', of, an, endogenous, reporter])].
[sujeto(['Targeted', demethylation, of, the, 'BDNF', promoter, 'IV', or, the, 'MyoD', distal, enhancer, by, 'dCas9-Tet1']), verbo([induced]), complemento(['BDNF', expression, in, 'post-mitotic', neurons, or, activated, 'MyoD', facilitating, reprogramming, of, fibroblasts, into, 'myoblasts,', respectively])].
[sujeto(['Targeted', de, novo, methylation, of, a, 'CTCF', loop, anchor, site, by, 'dCas9-Dnmt3a', blocked, 'CTCF']), verbo([binding]), complemento([and, interfered, with, 'DNA', 'looping,', causing, altered, gene, expression, in, the, neighboring, loop])].
[sujeto(['PAS', domain, containing, protein, kinase, '(', 'Pask)', is, an, evolutionarily]), verbo([conserved]), complemento([protein, kinase, implicated, in, energy, homeostasis, and, metabolic, regulation, across, eukaryotic, species])].
[sujeto(['We', now, describe, an, unexpected, role, of, 'Pask', in]), verbo([promoting]), complemento([the, differentiation, of, myogenic, progenitor, 'cells,', embryonic, stem, cells, and, adipogenic, progenitor, cells])].
[sujeto(['This', function, of, 'Pask', is, dependent, upon, its, ability, to]), verbo([phosphorylate]), complemento(['Wdr5,', a, member, of, several, protein, complexes, including, those, that, catalyze, histone, 'H3', 'Lysine', 4, trimethylation, '(', 'H3K4me3)', during, transcriptional, activation])].
[sujeto(['Our', findings]), verbo([suggest]), complemento(['that,', during, myoblast, 'differentiation,', 'Pask', stimulates, the, conversion, of, repressive, 'H3K4me1', to, activating, 'H3K4me3', marks, on, the, promoter, of, the, differentiation, gene, myogenin, '(', 'Myog)', via, 'Wdr5', phosphorylation])].
[sujeto(['This']), verbo([enhances]), complemento([accessibility, of, the, 'MyoD', transcription, factor, and, enables, transcriptional, activation, of, the, 'Myog', promoter, to, initiate, muscle, differentiation])].
[sujeto(['Thus,', as, an, upstream, kinase, of, 'Wdr5,', 'Pask', integrates, signaling, cues, with, the, transcriptional, network, to]), verbo([regulate]), complemento([the, differentiation, of, progenitor, cells])].
[sujeto(['A', subset, of, microRNAs, '(', 'miRNAs)']), verbo([have]), complemento([been, identified, as, critical, regulators, of, myogenesis])].
[sujeto(['Recently,', 'miR-378a', was]), verbo([found]), complemento([to, be, involved, in, 'myogenesis,', but, the, mechanism, of, how, 'miR-378a', regulates, the, proliferation, and, differentiation, of, myoblasts, has, not, been, determined])].
[sujeto(['We']), verbo([found]), complemento([that, 'miR-378a-3p', expression, in, muscle, was, significantly, higher, than, in, other, 'tissues,', suggesting, an, important, effect, on, muscle, development])].
[sujeto(['Overexpression', of, 'miR-378a-3p']), verbo([increased]), complemento([the, expression, of, 'MyoD', and, 'MHC', in, 'C2C12', myoblasts, both, at, the, level, of, mRNA, and, 'protein,', confirming, that, 'miR-378a-3p', promoted, muscle, cell, differentiation])].
[sujeto(['The', forced, expression, of, 'miR-378a-3p']), verbo([promoted]), complemento([apoptosis, of, 'C2C12', cells, as, evidenced, by, 'CCK-8', assay, and, 'Annexin', 'V-FITC/PI', staining, results])].
[sujeto(['Through', 'TargetScan,', histone, acetylation, enzyme, 4, '(', 'HDAC4)', was, identified, as, a, potential]), verbo([target]), complemento([of, 'miR-378a-3p'])].
[sujeto(['We', confirmed]), verbo([targeting]), complemento([of, 'HDAC4', by, 'miR-378a-3p', using, a, dual, luciferase, assay, and, western, blotting])].
[sujeto(['Our', 'RNAi', analysis, results, also, showed, that, 'HDAC4', significantly]), verbo([promoted]), complemento([differentiation, of, 'C2C12', cells, and, inhibited, cell, survival, through, 'Bcl-2'])].
[sujeto(['Therefore,', we, conclude, that, 'miR-378a-3p']), verbo([regulates]), complemento([skeletal, muscle, growth, and, promotes, the, differentiation, of, myoblasts, through, the, 'post-transcriptional', 'down-regulation', of, 'HDAC4'])].
[sujeto(['Cellular', models, of, muscle, disease, are, taking, on]), verbo([increasing]), complemento([importance, with, the, large, number, of, genes, and, mutations, implicated, in, causing, myopathies, and, the, concomitant, need, to, test, personalized, therapies])].
[sujeto(['Fibroblasts', are, a, human, cell, source, that, works, well, for, the, generation, of]), verbo([induced]), complemento([pluripotent, stem, 'cells,', which, can, then, be, differentiated, into, cardiomyocyte, 'lineages,', and, with, less, 'efficiency,', skeletal, 'muscle-like', lineages])].
[sujeto(['Alternatively,', direct, reprogramming, with, the, transcription, factor, 'MyoD']), verbo([has]), complemento([been, used, to, generate, myotubes, from, cultured, human, fibroblasts])].
[sujeto(['Although', 'useful,', fibroblasts]), verbo([require]), complemento([a, skin, biopsy, to, obtain, and, this, can, limit, their, 'access,', especially, from, pediatric, populations])].
[sujeto(['Recent', evidence]), verbo([suggests]), complemento([that, autophagy, and, bone, morphogenetic, protein, signaling, pathway, regulate, skeletal, muscle, growth, and, bone, formation, in, aged, rats])].
[sujeto(['Downhill', and, uphill, training]), verbo([increased]), complemento([the, 'autophagy-related', proteins, 5, '(', 'ATG5),', 'microtubule-associated', protein, light, chain, '(', 'LC3-Ⅱ),', 'Beclin-1,', and, p62, proteins, in, aged, rats])].
[sujeto(['Phosphorylation', of, mammalian]), verbo([target]), complemento([of, rapamycin, '(', 'p-mTOR)', and, myogenic, differentiation, '(', 'MyoD)', were, increased, significantly, in, 'LMD', and, 'LMU', groups])].
[sujeto(['Consequently', in, the, 'femur,', 'BMP-2,', -, 7, and, autophagy, molecules, were]), verbo([expressed]), complemento([highly, in, 'LMD', and, 'LMU', groups])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, both, of, the, downhill, and, uphill, training, appeared, to, positively, affect, autophagy, molecules, and, 'BMPs', 'expression,', respectively])].
[sujeto(['Particularly,', these, physiological, adaptations, from, gradual, downhill, training]), verbo([have]), complemento([an, effect, on, bone, morphological, changes, and, muscle, quality, similar, to, gradual, uphill, training, interventions, in, aging])].
[sujeto(['Biomedical', scaffolds, must, be, used, in, tissue, engineering, to]), verbo([provide]), complemento([physical, stability, and, 'topological/biochemical', properties, that, directly, affect, tissue, regeneration])].
[sujeto(['In', this, 'study,', a, new, 'cell-laden', scaffold, was, developed, that, supplies, 'micro/nano-topological', cues, and]), verbo([promotes]), complemento([efficient, release, of, cells])].
[sujeto(['Importantly,', the, printed, myoblasts, were, fully, safe, and, were, efficiently]), verbo([released]), complemento([from, the, 'cell-laden', struts, to, neighboring, nanofiber, networks])].
[sujeto(['Postnatal', skeletal, muscle, growth, results, from, the, activation, of, satellite, cells, 'and/or', an]), verbo([increase]), complemento([in, protein, synthesis])].
[sujeto(['The', 'Notch', signalling, pathway]), verbo([maintains]), complemento([satellite, cells, in, a, quiescent, 'state,', and, once, 'activated,', sustains, their, proliferation, and, commitment, towards, differentiation])].
[sujeto(['In', 'mammals,', 'POFUT1-mediated', 'O-fucosylation']), verbo([regulates]), complemento([the, interactions, between, 'NOTCH', receptors, and, ligands, of, the, 'DELTA/JAGGED', 'family,', thus, initiating, the, activation, of, canonical, 'Notch', signalling])].
[sujeto(['Pofut1(cax/cax)', mice, exhibited, muscle, 'hypertrophy,', no, hyperplasia, and, a]), verbo([decrease]), complemento([in, satellite, cell, numbers, compared, with, 'wild-type', 'C3H', mice])].
[sujeto(['In', agreement, with, these, 'observations,', 'Pofut1(cax/cax)', 'SCDMs', differentiated, earlier, concomitant, with, reduced, 'Pax7', expression, and]), verbo([decrease]), complemento([in, 'PAX7(+)/MYOD(-)', progenitor, cells])].
[sujeto(['In', vitro]), verbo([binding]), complemento([assays, showed, a, reduced, interaction, of, 'DELTA-LIKE', 1, ligand, '(', 'DLL1)', with, 'NOTCH', receptors, expressed, at, the, cell, surface, of, 'SCDMs,', leading, to, a, decreased, 'Notch', signalling, as, seen, by, the, quantification, of, cleaved, 'NICD', and, 'Notch', target, genes])].
[sujeto(['These', results, demonstrated, that, 'POFUT1-mediated', 'O-fucosylation', of, 'NOTCH', receptors]), verbo([regulates]), complemento([myogenic, cell, differentiation, and, affects, postnatal, muscle, growth, in, mice])].
[sujeto(['Cdkn1c', protein, levels, are, carefully]), verbo([regulated]), complemento([via, imprinting, and, other, epigenetic, mechanisms, affecting, both, the, promoter, and, distant, regulatory, 'elements,', which, restrict, its, expression, to, particular, developmental, phases, or, specific, cell, types])].
[sujeto(['Inappropriate', activation, of, these, regulatory, mechanisms]), verbo([leads]), complemento([to, 'Cdkn1c', 'silencing,', causing, growth, disorders, and, cancer])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, 'that,', in, skeletal, muscle, 'cells,', induction, of, 'Cdkn1c', expression, requires, the, binding, of, the, bHLH, myogenic, factor, 'MyoD', to, a, 'long-distance', regulatory, element, within, the, imprinting, control, region, 'KvDMR1'])].
[sujeto(['Interestingly,', 'MyoD']), verbo([binding]), complemento([to, 'KvDMR1', is, prevented, in, myogenic, cell, types, refractory, to, the, induction, of, 'Cdkn1c'])].
[sujeto(['We', show, that, treatment, with, the, 'DNA', demethylating, agent, 5, -, azacytidine, restores, the]), verbo([binding]), complemento([of, 'MyoD', to, 'KvDMR1', in, cells, refractory, to, 'Cdkn1c', induction])].
[sujeto(['This,', in, 'turn,']), verbo([promotes]), complemento([the, release, of, a, repressive, chromatin, loop, between, 'KvDMR1', and, 'Cdkn1c', promoter, 'and,', 'thus,', the, upregulation, of, the, gene])].
[sujeto(['Analysis', of, the, chromatin, status, of, 'Cdkn1c', promoter, and, 'KvDMR1', in, two, cell, types, showed, that, their, differential, responsiveness, to, the, 'MyoD-dependent', induction, of, the, gene, does, not]), verbo([involve]), complemento([just, their, methylation, status, 'but,', 'rather,', the, differential, 'H3', lysine, 9, dimethylation, at, 'KvDMR1'])].
[sujeto(['Finally,', we]), verbo([report]), complemento([that, the, same, histone, modification, also, marks, the, 'KvDMR1', region, of, human, cancer, cells, in, which, 'Cdkn1c', is, silenced])].
[sujeto(['On', the, basis, of, these, 'results,', we]), verbo([suggest]), complemento([that, the, epigenetic, status, of, 'KvDMR1', represents, a, critical, determinant, of, the, cell, 'type-restricted', expression, of, 'Cdkn1c', 'and,', 'possibly,', of, its, aberrant, silencing, in, some, pathological, conditions])].
[sujeto(['The', purpose, of, this, paper, was, to, study, the, effect, of, transforming, growth, factor, beta, '(', 'TGFβ)', signaling, pathway, on, 'reloading-mediated', restoration, of, disuse, muscle]), verbo([loss]), complemento([induced, by, hind, limb, suspension, in, rats])].
[sujeto(['Reloading']), verbo([increased]), complemento(['MyoD', mRNA, and, restored, the, decreased, gastrocnemius, 'weight/body', weight, 'ratio,', protein, concentration, of, 'gastrocnemius,', 'phospho-ERK2,', 'Pax7', and, the, increased, 'TGFβ1,', 'MSTN,', 'phospho-smad2/3,', 'phospho-p38,', 'phospho-JNK1/2,', and, p21, induced, by, hind, limb, suspension])].
[sujeto(['Disuse', muscle]), verbo([loss]), complemento([can, be, recovered, by, reloading, in, an, 'intensity-dependent', manner, through, canonical, and, noncanonical, 'TGFβ', signaling, pathways])].
[sujeto(['Pax7', and, 'MyoD', might, be, the, effectors, of, 'TGFβ', pathway, in]), verbo([mediating]), complemento([the, recovery, effect, of, reloading])].
[sujeto(['Transfection', with, 'in&nbsp;vitro']), verbo([transcribed]), complemento([mRNAs, is, a, safe, and, effective, tool, to, convert, somatic, cells, to, any, cell, type, of, interest])].
[sujeto(['One', caveat, of, mRNA, transfection, is, that, mRNAs, are]), verbo([recognized]), complemento([by, multiple, 'RNA-sensing', toll, like, receptors, '(', 'TLRs)'])].
[sujeto(['These', 'TLRs', can, both]), verbo([promote]), complemento([and, inhibit, cellular, reprogramming])].
[sujeto(['We', demonstrated, that, mRNA, transfection]), verbo([stimulated]), complemento(['TLR3', and, 'TLR7', and, induced, cytotoxicity, and, 'IFN-β', expression, in, human, and, mouse, fibroblasts])].
[sujeto(['Furthermore,', mRNA, transfection]), verbo([induced]), complemento([paracrine, inhibition, of, repeated, mRNA, transfection, through, type, 'I', 'IFNs'])].
[sujeto(['Repeated', liposomal, transfection, with, 'MyoD', mmRNAs, significantly]), verbo([enhanced]), complemento([myogenic, conversion, of, human, and, mouse, fibroblasts, compared, with, repeated, transfection, with, 'MyoD', mRNAs])].
[sujeto(['At', a, low, 'concentration,', 'TLR7/8', agonist, 'R848']), verbo([enhanced]), complemento(['MyoD', 'mmRNA-driven', conversion, of, human, fibroblasts, into, skeletal, muscle, 'cells,', whereas, high, concentrations, of, 'R848', inhibited, myogenic, conversion, of, fibroblasts])].
[sujeto(['Our', study]), verbo([suggests]), complemento([that, deliberate, control, of, 'TLR', signaling, is, a, key, factor, in, the, success, of, 'mRNA-driven', cellular, reprogramming])].
[sujeto(['Quercetin']), verbo([inhibited]), complemento([myeloperoxidase, '(', 'MPO)', and, 'N-acetyl-β-D-', glucosaminidase, '(', 'NAG)', 'activities,', cytokine, 'production,', oxidative, 'stress,', 'cyclooxygenase-2', '(', 'COX-2)', and, gp91phox, mRNA, expression, and, muscle, injury, '(', creatinine, kinase, '[', 'CK]', blood, levels, and, myoblast, determination, protein, '[', 'MyoD]', mRNA, 'expression)', as, well, as, inhibited, 'NFκB', activation, and, induced, 'Nrf2', and, 'HO-1', mRNA, expression, in, the, soleus, muscle])].
[sujeto(['Beyond']), verbo([inhibiting]), complemento([those, peripheral, 'effects,', quercetin, also, inhibited, spinal, cord, cytokine, 'production,', oxidative, stress, and, glial, cells, activation, '(', glial, fibrillary, acidic, protein, '[', 'GFAP]', and, ionized, 'calcium-binding', adapter, molecule, 1, '[', 'Iba-1]', mRNA, 'expression)'])].
[sujeto(['Muscle', regeneration, is, a, coordinated, process, that]), verbo([involves]), complemento([proliferation, and, differentiation, of, muscle, progenitor, cells])].
[sujeto(['Activation', of, 'MyoD', is, a, key, event, in, myogenic, 'differentiation,', which, is]), verbo([regulated]), complemento([by, 'p38&nbsp;mitogen&#8209;activated', protein, kinases, '(', 'MAPK)'])].
[sujeto(['Treatment', of, 'C2C12', myoblasts, with, 'DHC']), verbo([increased]), complemento([the, expression, levels, of, 'muscle&#8209;specific', 'proteins,', including, 'MyoD,', myogenin, and, myosin, heavy, chain])].
[sujeto(['In', 'addition,', 'C2C12', myoblasts, exhibited]), verbo([enhanced]), complemento([multinucleated, myotube, formation, without, any, cytotoxicity])].
[sujeto(['Furthermore,', defects, in, 'differentiation&#8209;induced', 'p38&nbsp;MAPK', activation, and, myoblast, differentiation]), verbo([induced]), complemento([by, depletion, of, the, promyogenic, receptor, protein, 'Cdo', in, 'C2C12', myoblasts, were, restored, by, 'DHC', treatment])].
[sujeto(['In', 'conclusion,', these, results, indicated, that, 'DHC']), verbo([stimulates]), complemento(['p38&nbsp;MAPK', 'activation,', which, can, enhance, heterodimerization, of, 'MyoD', and, 'E&nbsp;proteins,', thus, resulting, in, 'MyoD', activation, and, myoblast, differentiation])].
[sujeto(['These', findings]), verbo([suggested]), complemento([that, 'DHC', may, be, considered, a, potential, therapeutic, compound, for, the, improvement, of, muscle, stem, cell, regenerative, capacity, in, injured, muscle])].
[sujeto(['Skeletal', muscle, is, capable, of, robust, 'self-repair', following, mild, 'trauma,', yet, in, cases, of, traumatic, volumetric, muscle]), verbo([loss]), complemento(['(', 'VML),', where, more, than, 20, '%', of, a, 'muscle\'s', mass, is, 'lost,', this, capacity, is, overwhelmed])].
[sujeto(['Current', autogenic, whole, muscle, transfer, techniques, are, 'imperfect,', which]), verbo([has]), complemento([motivated, the, exploration, of, implantable, scaffolding, strategies])].
[sujeto(['We']), verbo([found]), complemento([that, the, repair, of, 'VML', injuries, using, 'DSM', +, 'MM', scaffolds, significantly, increased, recovery, of, peak, contractile, force, '(', 81, ±, 3, '%', of, normal, contralateral, 'muscle)', compared, to, unrepaired, 'VML', controls, '(', 62, ±, 4, '%', ')'])].
[sujeto(['Histological', findings, revealed, a, marked]), verbo([decrease]), complemento([in, collagen, dense, repair, tissue, formation, both, at, and, away, from, the, implant, site, for, 'DSM', +, 'MM', repaired, muscles])].
[sujeto(['The', addition, of, 'MM', to, 'DSM', significantly]), verbo([increased]), complemento(['MyoD', 'expression,', compared, to, isolated, 'DSM', treatment, '(', 21, -, fold, 'increase)', and, unrepaired, 'VML', '(', 37, -, 'fold)', controls])].
[sujeto(['Current', therapeutic, options, for, the, pediatric, cancer, rhabdomyosarcoma, '(', 'RMS)']), verbo([have]), complemento([not, improved, 'significantly,', especially, for, metastatic, 'RMS'])].
[sujeto(['The', signature, we, determined, could, discriminate, 'RMS', from, 'muscle,']), verbo([revealed]), complemento([a, subset, of, 'muscle-enriched', microRNA, '(', 'myomiR),', including, 'miR-22', which, was, strongly, underexpressed, in, tumors])].
[sujeto(['miR-22', was, physiologically]), verbo([induced]), complemento([during, normal, myogenic, differentiation, and, was, transcriptionally, regulated, by, 'MyoD,', confirming, its, identity, as, a, myomiR])].
[sujeto(['Once', introduced, into, 'RMS', 'cells,', 'miR-22']), verbo([decreased]), complemento([cell, 'proliferation,', 'anchorage-independent', 'growth,', invasiveness, and, promoted, apoptosis])].
[sujeto(['Moreover,', restoring, 'miR-22', expression, blocked, tumor, growth, and]), verbo([prevented]), complemento([tumor, dissemination, in, vivo])].
[sujeto(['Gene', expression, profiling, analysis, of, 'miR-22-expressing', cells]), verbo([suggested]), complemento(['TACC1', and, 'RAB5B', as, possible, direct, 'miR-22', targets])].
[sujeto(['Accordingly,']), verbo([loss]), complemento([and, gain, of, function, experiments, defined, the, biological, relevance, of, these, genes, in, 'RMS', pathogenesis])].
[sujeto(['In', previous, 'studies,', we]), verbo([have]), complemento([reported, that, phospholipase, 'C', '(', 'PLC)-β1', plays, a, crucial, role, in, myogenic, differentiation, and, we, determined, the, importance, of, its, catalytic, activity, for, the, initiation, of, this, process])].
[sujeto(['We', show, that, the, 'Inositol', 'Polyphosphate', 'Multikinase', '(', 'IPMK)', is, able, to]), verbo([promote]), complemento([myogenic, differentiation, since, its, overexpression, determines, the, 'up-regulation', of, several, myogenic, markers])].
[sujeto(['Moreover,', we, demonstrate, that, 'IPMK']), verbo([activates]), complemento([the, same, cyclin, 'D3', promoter, region, targeted, by, 'PLC-β1', and, that, 'IPMK-induced', promoter, activation, relies, upon, 'c-jun', binding, to, the, 'promoter,', as, we, have, shown, previously, for, 'PLC-β1'])].
[sujeto(['Furthermore,', our, data, shows, that, 'IPMK', overexpression]), verbo([causes]), complemento([an, increase, in, 'β-catenin', translocation, and, accumulation, to, the, nuclei, of, differentiating, myoblasts, resulting, in, higher, 'MyoD', activation])].
[sujeto(['Finally,', we, describe, that, 'PLC-β1', overexpression, determines, too, an]), verbo([increase]), complemento([in, 'β-catenin', translocation, and, that, 'PLC-β1,', 'IPMK', and, 'β-catenin', are, mediators, of, the, same, signaling, pathway, since, their, overexpression, results, in, cyclin, 'D3', and, myosin, heavy, chain, '(', 'MYH)', induction])].
[sujeto(['Pompe', disease, '(', 'PD)', is, a, lysosomal, disorder]), verbo([caused]), complemento([by, acid, 'α-glucosidase', '(', 'GAA)', deficiency])].
[sujeto(['We', previously, used, lentiviral, 'vector-mediated', 'GAA', gene, transfer, in, 'PD', 'patient-specific']), verbo([induced]), complemento([pluripotent, stem, cells])].
[sujeto(['Transcription', factor, 'EB', is, a, master, regulator, of, lysosomal, biogenesis, and, autophagy, that]), verbo([has]), complemento([recently, been, associated, with, muscular, 'pathology,', and, is, now, a, potential, therapeutic, target, in, 'PD', model, mice])].
[sujeto(['Here,', we, differentiated, skeletal, muscle, from, 'PD', 'patient-specific']), verbo([induced]), complemento([pluripotent, stem, cells, by, forced, 'MyoD', expression])].
[sujeto(['Thus,', our, findings, show, that, abnormal, lysosomal, biogenesis, is]), verbo([associated]), complemento([with, the, muscular, pathology, of, 'PD,', and, transcription, factor, 'EB', gene, transfer, is, effective, as, an, 'add-on', strategy, to, 'GAA', gene, transfer])].
[sujeto(['We', previously, demonstrated, that, histone, methyltransferase, 'KMT1A']), verbo([associates]), complemento([with, and, inhibits, 'MyoD', in, proliferating, 'myoblasts,', and, must, be, removed, to, allow, differentiation, to, proceed])].
[sujeto(['Conversely,', forced, activation, of, p38α, was, sufficient, to]), verbo([activate]), complemento(['MyoD', and, overcome, the, differentiation, blockade, in, 'KMT1A-overexpressing', 'C2C12', cells])].
[sujeto(['This', phosphorylation, was]), verbo([prevented]), complemento([by, the, inhibition, of, p38α])].
[sujeto(['A', ready, source, of, autologous, myogenic, cells, is, of, vital, importance, for, drug, screening, and, functional, genetic, studies, in, 'Duchenne', 'Muscular', 'Dystrophy', '(', 'DMD),', a, rare, disease]), verbo([caused]), complemento([by, a, variety, of, dystrophin, gene, mutations])].
[sujeto(['We', demonstrated, that, native, 'urine-derived', stem, cells]), verbo([express]), complemento([the, 'full-length', dystrophin, 'transcript,', and, that, the, dystrophin, mutation, was, retained, in, 'DMD', patient, 'cells,', although, the, dystrophin, protein, was, detected, solely, in, control, cells, following, myogenic, transformation, according, to, the, phenotype])].
[sujeto(['Notably,', we, also, showed, that, treatment, with, antisense, oligoribonucleotide, against, dystrophin, exon, 44]), verbo([induced]), complemento([skipping, in, both, native, and, 'MyoD-transformed', 'urine-derived', stem, cells, in, 'DMD,', with, a, therapeutic, 'transcript-reframing', 'effect,', as, well, as, visible, protein, restoration, in, the, latter])].
[sujeto(['Helix-loop-helix', '(', 'HLH)', and, 'helix-loop-helix-leucine', zipper, '(', 'HLHZip)', are, dimerization, domains, that]), verbo([mediate]), complemento([selective, pairing, among, members, of, a, large, transcription, factor, family, involved, in, cell, fate, determination])].
[sujeto(['To', investigate, the, molecular, rules, underlying, recognition, specificity, and, to, isolate, molecules, interfering, with, cell, proliferation, and, differentiation, 'control,', we, assembled, two, molecular, repertoires, obtained, by, directed, randomization, of, the]), verbo([binding]), complemento([surface, in, these, two, domains])].
[sujeto(['By', affinity, 'selection,', many, domains, were, isolated, that]), verbo([bound]), complemento([to, the, proteins, 'Mad,', 'Rox,', 'MyoD,', and, 'Id2', with, different, levels, of, affinity])].
[sujeto(['Although', several, residues, along, an, extended, surface, within, each, domain, appeared, to, contribute, to, 'dimerization,', some, key, residues, critically]), verbo([involved]), complemento([in, molecular, recognition, could, be, identified])].
[sujeto(['Furthermore,', a, number, of, charged, residues, appeared, to]), verbo([act]), complemento([as, switch, points, facilitating, partner, exchange])].
[sujeto(['By', successfully, selecting, ligands, for, four, of, four, 'HLH', or, 'HLHZip', 'proteins,', we]), verbo([have]), complemento([shown, that, the, repertoires, assembled, are, rather, general, and, possibly, contain, elements, that, bind, with, sufficient, affinity, to, any, natural, 'HLH', or, 'HLHZip', molecule])].
[sujeto(['Under', physiological, 'conditions,', satellite, cells, are, 'quiescent,', but, they]), verbo([maintain]), complemento([a, strong, proliferative, potential, and, propensity, to, 'differentiate,', which, underlies, their, critical, role, in, muscle, preservation, and, growth])].
[sujeto(['Here,', we, study, bovine, satellite, cells, '(', 'BoSCs)', undergoing, a, differentiation, process, and]), verbo([report]), complemento([the, expression, pattern, of, selected, genes, and, miRNAs, involved])].
[sujeto(['To', characterize, the, dynamics, of, several, transcription, factors]), verbo([expressed]), complemento([in, 'BoSCs,', we, performed, 'real-time', 'PCR', on, complementary, 'DNA', generated, from, the, total, 'RNA', extracted, from, 'BoSCs', cultivated, in, growth, medium, '(', 'GM)', or, in, differentiation, medium, '(', 'DM)', for, 4, days])].
[sujeto(['In', the, 'GM', 'condition,', 'BoSCs']), verbo([expressed]), complemento([the, satellite, cell, lineage, markers, as, well, as, transcripts, for, the, myogenic, regulatory, factors])].
[sujeto(['At', the, time, of, isolation, from, 'muscle,', 'PAX7', was]), verbo([expressed]), complemento([in, nearly, 100, '%', of, 'BoSCs;', 'however,', its, messenger, 'RNA', '(', 'mRNA)', levels, dramatically, decreased, between, 3, and, 6, days, post, isolation, '(', 'P&lt;0'])].
[sujeto(['MyoD', mRNA, levels]), verbo([increased]), complemento([during, the, 1, st, day, of, cultivation, in, 'DM', '(', day, 7, ;, 'P&lt;0'])].
[sujeto(['During', the, subsequent, 4, days, of, culture, in, 'DM,', several, tested, 'genes,', including, 'MRF4,', 'MYOG,', 'MEF2C,', 'TMEM8C,', 'DES', and, 'MYH1,', showed]), verbo([increased]), complemento([expression, '(', 'P&lt;0'])].
[sujeto(['Meanwhile,', the, expression, of, genes]), verbo([involved]), complemento([in, the, differentiation, process, also, 'miRNA-1,', 'miRNA-133a', and, 'miRNA-206', were, strongly, 'up-regulated', on, the, 1, st, day, in, 'DM', '(', day, 7, ;, 'P&lt;0'])].
[sujeto(['We', previously, showed, that, 'Semaphorin', 3, 'A', '(', 'Sema3A)', expression, was]), verbo([induced]), complemento([when, quiescent, muscle, satellite, cells, were, stimulated, by, hepatocyte, growth, factor, and, became, activated, satellite, cells, '(', 'ASCs)'])].
[sujeto(['However,', how, 'Sema3A']), verbo([regulates]), complemento([genes, in, the, early, phase, of, 'ASCs', remains, unclear])].
[sujeto(['In', this, 'study,', we, investigated, whether, 'Sema3A', signaling, can]), verbo([regulate]), complemento([the, early, phase, of, 'ASCs,', an, important, satellite, cell, stage, for, postnatal, 'growth,', 'repair,', and, maintenance, of, skeletal, muscle])].
[sujeto(['We', showed, that, expression, of, the, myogenic, proliferation, regulatory, factors, 'Pax7', and, 'Myf5', was]), verbo([decreased]), complemento([in, myoblasts, transfected, with, 'Sema3A', siRNA])].
[sujeto(['These', cells, failed, to]), verbo([activate]), complemento([expression, 'MyoD,', another, myogenic, proliferation, regulatory, 'factor,', during, differentiation])].
[sujeto(['Interestingly,', some, of, the, 'Sema3A-depleted', cells, did, not]), verbo([express]), complemento(['Pax7', and, 'MyoD', and, had, enlarged, nuclei, and, very, large, cytoplasmic, areas])].
[sujeto(['We', also, observed, that, 'Pax7', and, 'Myf5', expression, was]), verbo([increased]), complemento([in, 'Myc-Sema3A', overexpressing, myoblasts])].
[sujeto(['BrdU', analysis, indicated, that, 'Sema3A']), verbo([regulated]), complemento([proliferation, of, 'ASCs'])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'Sema3A', signaling, can, modulate, expression, of, 'Pax7,', 'Myf5,', and, 'MyoD'])].
[sujeto(['Moreover,', we]), verbo([found]), complemento([that, expression, of, 'emerin,', an, inner, nuclear, membrane, 'protein,', was, regulated, by, 'Sema3A', signaling])].
[sujeto(['In', 'conclusion,', our, results, support, a, role, for, 'Sema3A', in]), verbo([maintaining]), complemento(['ASCs', through, 'regulation,', via, 'emerin,', of, 'Pax7,', 'Myf5,', and, 'MyoD', expression])].
[sujeto(['The', 'Peg3', '(', 'Paternally', 'Expressed', 'Gene', 3, ')', imprinted, domain, is, predicted, to, be]), verbo([regulated]), complemento([through, a, large, number, of, evolutionarily, conserved, regions, '(', 'ECRs)', that, are, localized, within, its, middle, 200, -, kb, region])].
[sujeto(['Phylogenetic', and, bioinformatic, analyses, further, revealed, that, several, 'cis-regulatory', motifs, are, frequently]), verbo([associated]), complemento([with, the, 'ECRs,', such, as, the, 'E', 'box,', 'PITX2,', 'NF-κB', and, 'RFX1', motifs])].
[sujeto(['A', series, of, subsequent, 'ChIP', experiments, demonstrated, that, the, trans, factor, 'MYOD', indeed]), verbo([binds]), complemento([to, the, 'E', box, of, several, 'ECRs,', further, suggesting, that, 'MYOD', may, play, significant, roles, in, the, transcriptional, control, of, the, 'Peg3', domain])].
[sujeto(['MicroRNAs', are, a, class, of, 18, -, 22, nucleotide, 'non-coding', 'RNAs', that]), verbo([modulate]), complemento([gene, expression, by, associating, with, the, 3, '\'', untranslated, regions, of, mRNAs])].
[sujeto(['A', large, number, of, microRNAs, are]), verbo([involved]), complemento([in, the, regulation, of, myoblast, 'differentiation,', many, of, which, remain, undiscovered])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, 'miR-143-3p', was, upregulated, during, 'C2C12', myoblast, differentiation, and, 'over-expression', of, 'miR-143-3p', significantly, inhibited, the, relative, expression, levels, of, 'MyoD,', 'MyoG,', 'myf5,', and, 'MyHC', 'genes,', especially, in, the, later, stages, of, differentiation])].
[sujeto(['In', 'addition,', 'miR-143-3p']), verbo([inhibited]), complemento([expression, of, genes, involved, in, the, endogenous, 'Wnt', signaling, pathway, during, 'C2C12', myoblast, 'differentiation,', including, 'Wnt5a,', 'LRP5,', 'Axin2,', and, 'β-catenin'])].
[sujeto(['These', results, indicate, that, 'miR-143-3p', represents, a, new, myogenic, 'differentiation-associated', microRNA, that, can]), verbo([inhibit]), complemento(['C2C12', myoblast, 'differentiation,', especially, in, the, later, stages, of, differentiation])].
[sujeto(['We', aimed, to, identify, the, underlying, genetic]), verbo([cause]), complemento([of, this, disorder, in, a, family, in, which, there, were, three, affected, individuals, from, two, sibships])].
[sujeto(['Autosomal-recessive', inheritance, was]), verbo([suggested]), complemento([by, a, family, history, of, consanguinity, and, by, recurrence, of, the, phenotype, between, the, two, sibships])].
[sujeto(['This', gene, encodes, an, extensively, studied, transcription, factor]), verbo([involved]), complemento([in, muscle, 'development,', which, has, nonetheless, not, hitherto, been, associated, with, a, hereditary, human, disease, phenotype])].
[sujeto(['We']), verbo([provide]), complemento([the, first, description, of, a, human, phenotype, that, appears, to, result, from, 'MYOD1', mutation])].
[sujeto(['Sclerosing', rhabdomyosarcoma, '(', 'ScRMS)', and, spindle, cell, rhabdomyosarcoma, '(', 'SRMS)']), verbo([have]), complemento([been, recently, reclassified, as, a, 'stand-alone', pathologic, 'entity,', separate, from, embryonal, 'RMS'])].
[sujeto(['In', this, study, we, sought, to, investigate, a, large, group, of, pediatric, 'SRMS/ScRMS,', spanning, a, diverse, clinical, and, pathologic, 'spectrum,', by, using, a, combined, fluorescence, in, situ, 'hybridization,']), verbo([targeted]), complemento(['DNA,', and, 'whole-transcriptome', sequencing, methodology, for, a, more, definitive, molecular, classification])].
[sujeto(['A', total, of, 26, 'SRMS', and, 'ScRMS', cases, were, selected, from, the, 2]), verbo([participating]), complemento([institutions, for, the, molecular, analysis])].
[sujeto(['In', polyglutamine, '(', 'polyQ)', 'diseases,', large, polyQ, repeats]), verbo([cause]), complemento([juvenile, cases, with, different, symptoms, than, those, of, 'adult-onset', 'patients,', who, carry, smaller, expanded, polyQ, repeats])].
[sujeto(['The', mechanisms, behind, the, differential, pathology]), verbo([mediated]), complemento([by, different, polyQ, repeat, lengths, remain, unknown])].
[sujeto(['By', studying, knockin, mouse, models, of, spinal, cerebellar, 'ataxia-17', '(', 'SCA17),', we]), verbo([found]), complemento([that, a, large, polyQ, '(', 105, 'glutamines)', in, the, 'TATA-box-binding', protein, '(', 'TBP)', preferentially, causes, muscle, degeneration, and, reduces, the, expression, of, 'muscle-specific', genes])].
[sujeto(['Direct', expression, of, 'TBP', with, different, polyQ, repeats, in, mouse, muscle, revealed, that, muscle, degeneration, is]), verbo([mediated]), complemento([only, by, the, large, polyQ, repeats])].
[sujeto(['As', a, 'result,', the, large, polyQ, repeat]), verbo([decreases]), complemento([the, association, of, 'MyoD', with, 'TBP', and, 'DNA', promoters])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, specific, alterations, in, protein, interactions, by, large, polyQ, repeats, may, account, for, the, unique, pathology, in, juvenile, polyQ, diseases])].
[sujeto(['Human', pluripotent, stem, cells, '(', 'hPSCs)', possess, unlimited, proliferative, potential, while]), verbo([maintaining]), complemento([the, ability, to, differentiate, into, any, cell, type, including, skeletal, muscle, cells, '(', 'SMCs)'])].
[sujeto(['There', are, unresolved, challenges, however]), verbo([associated]), complemento([with, the, derivation, and, 'scale-up', of, hPSCs, and, generation, of, differentiated, cells, in, large, quantity, and, high, purity])].
[sujeto(['Reported', myogenic, differentiation, protocols, are, 'long,']), verbo([require]), complemento([cell, sorting, 'and/or', rely, on, ectopic, expression, of, myogenic, master, regulators])].
[sujeto(['More', recent, advances]), verbo([have]), complemento([been, made, with, the, application, of, small, molecules, to, enhance, the, myogenic, differentiation, efficiency, and, the, identification, of, more, selective, markers, for, the, enrichment, of, myogenic, progenitors, with, enhanced, regenerative, potential])].
[sujeto(['Here', we, review, the, field, of, myogenic, differentiation, and, highlight, areas]), verbo([requiring]), complemento([further, research])].
[sujeto(['Electrically', conductive, materials]), verbo([provide]), complemento([a, suitable, platform, for, the, in, vitro, study, of, excitable, 'cells,', such, as, skeletal, muscle, 'cells,', due, to, their, inherent, conductivity, and, electroactivity])].
[sujeto(['Here', it, is, demonstrated, that, bioinspired, electroconductive, nanopatterned, substrates]), verbo([enhance]), complemento([myogenic, differentiation, and, maturation])].
[sujeto(['It', is]), verbo([found]), complemento([that, biomimetic, nanotopography, enhances, the, formation, of, aligned, myotubes, and, the, addition, of, an, electroconductive, coating, promotes, myogenic, differentiation, and, 'maturation,', as, indicated, by, the, upregulation, of, myogenic, regulatory, factors, 'Myf5,', 'MyoD,', and, myogenin, '(', 'MyoG)'])].
[sujeto(['These', results]), verbo([suggest]), complemento([the, suitability, of, electroconductive, nanopatterned, substrates, as, a, biomimetic, platform, for, the, in, vitro, engineering, of, skeletal, muscle, tissue])].
[sujeto(['There', is]), verbo([increasing]), complemento([evidence, that, 'WT1', protein, expression, is, found, not, only, at, 'nuclear,', but, also, at, 'cytoplasmic,', level, in, several, developing, and, neoplastic, tissues])].
[sujeto(['The', present, study, shows, that, 'WT1', protein, is, developmentally]), verbo([expressed]), complemento([in, the, cytoplasm, of, human, myoblasts, from, the, 6, weeks, of, gestational, age])].
[sujeto(['This', expression, was]), verbo([maintained]), complemento([in, the, myotubes, of, developing, muscles, of, the, 'trunk,', 'head,', 'neck,', and, 'extremities,', while, it, was, 'down-regulated', in, fetal, skeletal, fibers, from, 20, weeks, of, gestational, age, as, well, as, in, adult, normal, skeletal, muscle])].
[sujeto(['The', comparative, evaluation, of, the, immunohistochemical, findings, revealed, that, 'WT1', cytoplasmic, expression, in, rhabdomyosarcoma, may, represent, an, ontogenetic, 'reversal,', and, this]), verbo([nuclear]), complemento([transcription, factor, can, also, be, considered, an, oncofetal, protein, which, can, be, exploitable, as, an, 'additional,', highly, sensitive, 'immunomarker,', together, with, 'desmin,', myogenin, and, 'MyoD1,', of, this, tumor])].
[sujeto(['Moreover,', our, observations, support, the, rationale, for, the, use, of, 'WT1', 'protein-based']), verbo([target]), complemento([therapy, in, high, risk, rhabdomyosarcomas, in, children, and, adolescents])].
[sujeto(['SIRT3', deacetylases, and]), verbo([activates]), complemento([a, large, number, of, mitochondrial, enzymes, involved, in, the, respiratory, 'chain,', in, 'ATP', 'production,', and, in, both, the, citric, acid, and, urea, cycles])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, the, regulation, of, myoblast, differentiation, is, tightly, linked, to, mitochondrial, activity])].
[sujeto(['Since', 'SIRT3']), verbo([modulates]), complemento([mitochondrial, 'activity,', we, decide, to, address, its, role, during, myoblast, differentiation])].
[sujeto(['The', inhibition, of, 'SIRT3', expression]), verbo([mediated]), complemento([by, the, stable, integration, of, 'SIRT3', short, inhibitory, 'RNA', '(', 'SIRT3shRNA)', in, 'C2C12', 'myoblasts,', resulted, 'in:', 1, ')', abrogation, of, terminal, differentiation, -, as, evidenced, by, a, marked, decrease, in, the, myoblast, fusion, index, and, a, significant, reduction, of, 'Myogenin,', 'MyoD,', 'Sirtuin', 1, and, 'Troponin', 'T', protein, expression, -, restored, upon, 'MyoD', 'overexpression;', 2, ')', a, decrease, in, peroxisome, 'proliferator-activated', receptor, gamma, coactivator, 1, -, alpha, '(', 'PGC-1α)', and, citrate, synthase, protein, expression, reflecting, an, alteration, of, mitochondrial, 'density;', and, 3, ')', an, increased, production, of, reactive, oxygen, species, '(', 'ROS)', mirrored, by, the, decreased, activity, of, manganese, superoxide, dismutase, '(', 'MnSOD)'])].
[sujeto(['Altogether', our, data, demonstrate, that, 'SIRT3', mainly]), verbo([regulates]), complemento([myoblast, differentiation, via, its, influence, on, mitochondrial, activity])].
[sujeto(['A', large, majority, of, these, 'Pax7(+)MyoD(-)', cells, are, not, 'self-renewed', satellite, 'cells,', but]), verbo([have]), complemento([different, potentials, for, both, proliferation, and, differentiation, from, 'Pax7(+)MyoD(+)', myoblasts, '(', classical, daughter, 'cells),', and, are, specifically, marked, by, expression, of, the, doublecortin, '(', 'Dcx)', gene])].
[sujeto(['Transplantation', and, 'lineage-tracing', experiments, demonstrated, that, 'Dcx-expressing', cells, originate, from, quiescent, satellite, cells, and, that, the, microenvironment]), verbo([induces]), complemento(['Dcx', in, myoblasts])].
[sujeto(['Expression', of, 'Dcx', seems, to, be, necessary, for, myofiber, maturation, because, 'Dcx-deficient', mice, exhibited, impaired, myofiber, maturation, resulting, from, a]), verbo([decrease]), complemento([in, the, number, of, myonuclei])].
[sujeto(['Furthermore,', in, vitro, and, in, vivo, studies]), verbo([suggest]), complemento([that, one, function, of, 'Dcx', in, myogenic, cells, is, acceleration, of, cell, motility])].
[sujeto(['Therefore,', an, improved, pork, production, strongly, depends, on, identifying, and, studying, how, genetic, variations, contribute, to]), verbo([modulate]), complemento([gene, expression])].
[sujeto(['Promoters', are, key, regions, in, gene, modulation, as, they, harbour, several]), verbo([binding]), complemento([motifs, to, transcription, regulatory, factors])].
[sujeto(['In', this, 'study,', we]), verbo([report]), complemento([the, identification, of, single, nucleotide, polymorphisms, '(', 'SNPs)', in, promoter, regions, of, candidate, genes, involved, in, 'development,', cellular, differentiation, and, muscle, growth, in, 'Sus', scrofa])].
[sujeto(['The', luciferase, expression, driven, by, the, 'MYOD1-A', allelic, variant, displayed, a, 3.8, -, fold]), verbo([increased]), complemento([transcriptional, activity])].
[sujeto(['Additionally,', we, could, assess, a, different, response, of, in, vitro, gene, expression, according, to, cell, type, used, to, transfect, 'constructs,']), verbo([suggesting]), complemento([that, 'MyoD', activation, is, regulated, by, mechanisms, that, are, specific, of, myoblasts])].
[sujeto(['Currently,', accumulating, evidence]), verbo([has]), complemento([revealed, the, essential, roles, of, satellite, cells, in, muscle, regeneration, and, the, regulatory, 'mechanisms,', while, it, still, remains, to, be, elucidated, how, satellite, cell, 'self-renewal', is, molecularly, regulated, and, how, satellite, cells, are, important, in, aging, and, diseased, muscle])].
[sujeto(['The', number, of, satellite, cells, is]), verbo([decreased]), complemento([due, to, the, changing, niche, during, 'ageing,', resulting, in, attenuation, of, muscle, regeneration, capacity])].
[sujeto(['Additionally,', in, 'Duchenne', muscular, dystrophy, '(', 'DMD)', 'patients,', the]), verbo([loss]), complemento([of, satellite, cell, regenerative, capacity, and, decreased, satellite, cell, number, due, to, continuous, needs, for, satellite, cells, lead, to, progressive, muscle, weakness, with, chronic, degeneration])].
[sujeto(['Recently,', this, developing, mode]), verbo([has]), complemento([been, referred, to, as, the, &, 'quot;In-Out&quot;', mechanism])].
[sujeto(['Moreover,', we, analyzed, the, 'MyoD', expression, in, 'CXCR4-mutant', mouse, embryos, and, observed, a, considerable]), verbo([decrease]), complemento([in, pectoral, girdle, musculature])].
[sujeto(['Muscular', dystrophies, comprise, a, large, group, of, inherited, disorders, that]), verbo([lead]), complemento([to, progressive, muscle, wasting])].
[sujeto(['We', wanted, to, investigate, if]), verbo([targeting]), complemento([satellite, cells, can, enhance, muscle, regeneration, and, thus, increase, muscle, mass])].
[sujeto(['We']), verbo([found]), complemento([that, hepatocyte, growth, factor, treatment, led, to, activation, of, the, 'Akt/mTOR/p70S6K', protein, synthesis, 'pathway,', 'up-regulation', of, the, myognic, transcription, factors, 'MyoD', and, 'myogenin,', and, subsequently, the, negative, growth, control, 'factor,', myostatin, and, atrophy, markers, 'MAFbx', and, 'MuRF1'])].
[sujeto(['Dividing', satellite, cells, were, 'three-fold']), verbo([increased]), complemento([in, the, treatment, group, compared, to, control])].
[sujeto(['Finally,', we, demonstrated, that, myostatin]), verbo([regulates]), complemento([satellite, cell, activation, and, myogenesis, in, vivo, following, 'treatment,', consistent, with, previous, findings, in, vitro])].
[sujeto(['Our', results, 'suggest,', not, only, a, novel, in, vivo, pharmacological, treatment, directed, specifically, at]), verbo([activating]), complemento([the, satellite, 'cells,', but, also, a, myostatin, dependent, mechanism, that, may, contribute, to, the, progressive, muscle, wasting, seen, in, severely, affected, patients, with, muscular, dystrophy, and, significant, 'on-going', regeneration])].
[sujeto(['This', treatment, could, potentially, be, applied, to, many, conditions, that, feature, muscle, wasting, to]), verbo([increase]), complemento([muscle, bulk, and, strength])].
[sujeto(['As', the, understanding, of, the, nutritional, regulation, of, muscle, growth, mechanisms, in, fish, is, 'fragmentary,', the, present, study, aimed, to, '(', 1, ')', characterise, ontogenetic, changes, in, muscle, 'growth-related', genes, in, parallel, to, changes, in, muscle, 'cellularity;', '(', 2, ')', determine, whether, an, early]), verbo([decrease]), complemento([in, dietary, 'protein:energy', ratio, by, fat, addition, affects, the, muscle, growth, mechanisms, of, rainbow, trout, '(', 'Oncorhynchus', 'mykiss)', 'alevins;', and, '(', 3, ')', determine, whether, this, early, feeding, of, a, 'high-fat', '(', 'HF)', diet, to, alevins, had, a, 'long-term', effect, on, muscle, growth, processes, in, juveniles, fed, a, commercial, diet])].
[sujeto(['Developmental', regulation, of, hyperplasia, and, hypertrophy, was, evidenced, at, the, molecular, '(', expression, of, myogenic, regulatory, 'factors,', proliferating, cell]), verbo([nuclear]), complemento([antigen, and, myosin, heavy, chains, '(', 'MHC))', and, cellular, '(', number, and, diameter, of, white, muscle, 'fibres)', levels])].
[sujeto(['An', early]), verbo([decrease]), complemento([in, dietary, 'protein:energy', ratio, by, fat, addition, stimulated, the, body, growth, of, alevins, but, led, to, a, fatty, 'phenotype,', with, accumulation, of, lipids, in, the, anterior, 'part,', and, less, caudal, muscle, when, compared, at, similar, body, 'weights,', due, to, a, decrease, in, both, the, white, muscle, hyperplasia, and, maximum, hypertrophy, of, white, muscle, fibres])].
[sujeto(['TCAP', '(', also, known, as, 'titin-cap', or, 'telethonin)', is, one, of, the, titin]), verbo([interacting]), complemento(['Z-disk', proteins, involved, in, the, regulation, and, development, of, normal, sarcomeric, structure])].
[sujeto(['Quantitative', 'real-time', 'PCR', '(', 'qRT-PCR)', analyses, showed, that, porcine, 'TCAP', was, highly]), verbo([expressed]), complemento([in, the, skeletal, 'muscle,', 'heart,', and, kidney])].
[sujeto(['In', 'addition,', we]), verbo([found]), complemento([that, the, porcine, 'TCAP', promoter, can, be, activated, by, 'MyoD,', 'MyoG', and, 'MEF2', in, 'myotubes,', which, indicated, that, 'TCAP', may, play, a, role, in, the, regulation, of, porcine, skeletal, muscle, development])].
[sujeto(['These', findings]), verbo([provide]), complemento([useful, information, for, the, further, investigation, of, the, function, of, 'TCAP', in, porcine, skeletal, muscle])].
[sujeto(['Botulinum', toxin]), verbo([has]), complemento([been, widely, used, therapeutically, to, reduce, contraction, force, of, spastic, muscle])].
[sujeto(['Upregulation', of, 'GAP-43,', 'IGF-1,', 'Myo-D,', 'Myf-5,', 'myogenin,', and, 'AChR', subunits, α, and, β, were]), verbo([found]), complemento([following, treadmill, running])].
[sujeto(['The', expression, of, genes]), verbo([associated]), complemento([with, neurite, and, 'AChR', regeneration, following, treadmill, exercise, was, 'upregulated,', which, may, have, contributed, to, enhanced, recovery, of, gastrocnemius, strength])].
[sujeto([',', vagal, and, 'enteric)', and, the, skeletal, 'muscle-secreted', neurotrophins]), verbo([have]), complemento([a, role, in, 'smooth-to-skeletal', muscle, transdifferentiation, and, in, the, 'muscarinic-to-nicotinic', acetylcholine, receptor, type, transition])].
[sujeto(['We']), verbo([found]), complemento(['that,', in, the, absence, of, 'Myf5', and, 'MyoD,', the, esophageal, muscle, cells, failed, to, develop, the, striated, phenotype, of, acetylcholine, receptors])].
[sujeto(['The', smooth, muscle, cells, in, the, esophagus, appeared, to, be, a, distinct, subpopulation, of, cells, and, their, ability, to, transdifferentiate, was, based, on, their, competence, to]), verbo([express]), complemento([neurotrophins, and, their, receptors])].
[sujeto(['Finally,', our, data]), verbo([suggest]), complemento([a, role, for, 'NT-3', in, the, esophageal, muscle, transdifferentiation])].
[sujeto(['Previous', studies, had, shown, that, 'MyoD']), verbo([promoted]), complemento([nicotinic, acetylcholine, subunit, gene, 'expression;', the, present, experiments, were, done, to, determine, whether, this, subsequently, led, to, the, development, of, functional, nicotinic, acetylcholine, receptors])].
[sujeto(['Transfection', of, 'C3H', 10, 'T1/2', cells, with, 'MyoD', cDNA, resulted, in, the, appearance, of, '[', 125, 'I]alpha-bungarotoxin']), verbo([binding]), complemento(['sites;', radiolabelled, 'alpha-toxin', binding, was, not, observed, in, cells, transfected, with, a, plasmid, that, lacked, 'MyoD', cDNA])].
[sujeto(['Receptor', development, plateaued, over, a, time, course, of, several, days, with, maximal]), verbo([binding]), complemento([seven, and, 11, days, after, exposure, to, fusion, medium])].
[sujeto(['[', 125, 'I]alpha-bungarotoxin']), verbo([binding]), complemento([was, of, high, affinity, '(', 'Kd', =, 1, 'nM),', saturable, and, was, inhibited, by, nicotinic, but, not, muscarinic, receptor, 'ligands,', with, 'IC50s', of, 1, -, 3, nM, for, 'alpha-bungarotoxin,', 1, -, 3, microM, for, 'd-tubocurarine', and, 3, -, 10, microM, for, nicotine])].
[sujeto(['Not', only, did, the, cells, exhibit, a, cell, surface, nicotinic, receptor, but, they, also]), verbo([expressed]), complemento([a, nicotinic, receptor, mediated, functional, response])].
[sujeto(['Carbachol', resulted, in, uptake, of, 22, 'Na', into, the, cells, at, concentrations, similar, to, those]), verbo([required]), complemento([for, receptor, activation, at, a, muscle, type, nicotinic, 'receptor;', 'furthermore,', the, functional, response, was, effectively, blocked, by, nicotinic, receptor, 'ligands,', including, 'alpha-bungarotoxin', '(', 'IC50', =, 2, to, 6, 'nM)', and, 'd-tubocurarine', '(', 'IC50', =, 0.1, to, 0.4, 'microM);', muscarinic, receptor, ligands, had, no, effect])].
[sujeto(['A', time, course, study, showed, that, 'alpha-bungarotoxin']), verbo([binding]), complemento([and, carbachol, stimulated, 22, 'Na', uptake, developed, in, 'parallel,', suggesting, that, the, observed, functional, response, was, mediated, through, an, interaction, at, the, 'alpha-bungarotoxin', recognition, site])].
[sujeto(['(', 'ABSTRACT', 'TRUNCATED', 'AT', 250, 'WORDS)', 'The', 'chemokine-like', 'receptor-1', '(', 'CMKLR1)', is, a, 'G', 'protein-coupled', receptor, that, is]), verbo([activated]), complemento([by, 'chemerin,', a, secreted, plasma, leukocyte, attractant, and, adipokine])].
[sujeto(['Previous', studies, identified, that, 'CMKLR1', is]), verbo([expressed]), complemento([in, skeletal, muscle, in, a, 'stage-specific', fashion, during, embryogenesis, and, in, adult, 'mice;', 'however,', its, function, in, skeletal, muscle, remains, unclear])].
[sujeto(['Based', on, the, established, function, of, 'CMKLR1', in, cell, migration, and, 'differentiation,', we, investigated, the, hypothesis, that, 'CMKLR1']), verbo([regulates]), complemento([the, differentiation, of, myoblasts, into, myotubes])].
[sujeto(['In', 'C(2)C(12)', mouse, 'myoblasts,', 'CMKLR1', expression]), verbo([increased]), complemento([threefold, with, differentiation, into, multinucleated, myotubes])].
[sujeto(['Decreasing', 'CMKLR1', expression, by, 'adenoviral-delivered', 'small-hairpin', 'RNA', '(', 'shRNA)', impaired, the, differentiation, of, 'C(2)C(12)', myoblasts, into, mature, myotubes, and, reduced, the, mRNA, expression, of, myogenic, regulatory, factors, myogenin, and, 'MyoD', while]), verbo([increasing]), complemento(['Myf5', and, 'Mrf4'])].
[sujeto(['These', changes, were]), verbo([associated]), complemento([with, increased, 'Myf5', and, decreased, 'MyoD', protein, expression, in, the, somites, of, 'E12'])].
[sujeto(['We', conclude, that, 'CMKLR1', is, essential, for, myogenic, differentiation, of, 'C(2)C(12)', cells, in, 'vitro,', and, the, 'CMKLR1', null, mice]), verbo([have]), complemento([a, subtle, skeletal, muscle, deficit, beginning, from, embryonic, life, that, persists, during, postnatal, life])].
[sujeto(['Leukaemia', inhibitory, factor, '(', 'LIF)']), verbo([has]), complemento([been, shown, to, have, an, important, role, during, muscle, regeneration])].
[sujeto(['To', clarify, whether, 'LIF']), verbo([modulates]), complemento([muscle, regeneration, by, regulating, myogenic, precursor, cell, 'activity,', we, studied, 'LIF', expression, and, myogenic, precursor, cell, activity, in, gastrocnemius, muscles, from, 'Wistar', rats, at, various, times, after, contusion, injury, using, immunohistochemistry, and, the, direct, effect, of, 'LIF', on, a, rat, myoblast, cell, line, '(', 'L6)'])].
[sujeto(['After', contusion, 'injury,', transient, upregulation, of, the, mRNA, expression, of, 'LIF,', 'LIF', receptors, and, signal, transducer, and, activator, of, transcription, '(', 'STAT)', 3, ',', downstream, of, 'LIF', and]), verbo([involved]), complemento([in, enhanced, cell, 'proliferation,', was, observed])].
[sujeto(['A', marked]), verbo([increase]), complemento([in, 'LIF', protein, in, the, cytosol, of, damaged, myofibres, was, strongly, correlated, with, a, significant, increase, in, the, number, of, myogenic, precursor, cells, '(', 'MyoD-positive', 'cells)', by, 12, h, after, contusion])].
[sujeto(['Treatment', of, 'L6', cells, with, 'LIF', '(', 1, 'ng/mL)', in, 'serum-free', medium]), verbo([enhanced]), complemento([proliferation, '(', bromodeoxyuridine, 'incorporation)', by, 24, h])].
[sujeto(['This', was, accompanied, by]), verbo([increased]), complemento([expression, of, 'c-Myc', protein, within, 12, h, and, was, abolished, by, short, interference, 'RNA', against, 'c-Myc', mRNA])].
[sujeto(['Together,', the, results, of, the, present, study]), verbo([suggest]), complemento([that, 'LIF', acts, via, paracrine, and, autocrine, actions, to, regulate, myogenic, precursor, cell, activity, during, muscle, regeneration, after, contusion, injury, and, that, the, proliferative, effect, of, 'LIF', on, 'L6', cells, occurs, via, 'c-Myc', signalling])].
[sujeto(['Reduced', muscle, mass, and]), verbo([increased]), complemento([susceptibility, to, 'TNF-induced', degradation, accompany, inflamed, ageing, and, chronic, diseases])].
[sujeto(['Furthermore,', 'C(2)', myoblasts, display, diminished, differentiation, and]), verbo([increased]), complemento([susceptibility, to, 'TNF-alpha-induced', cell, death, versus, subcloned, 'C(2)C(12)', 'cells,', providing, relevant, models, to, 'assess:', differentiation, '(', creatine, 'kinase),', growth, '(', 'protein),', death, '(', 'trypan-blue)', and, 'anabolic/catabolic', parameters, '(', 'RT-PCR)', over, 72, h, +, /, -, 'TNF-alpha', '(', 20, ng, 'ml(-1))'])].
[sujeto([39.4, +, /, -, 3.37, mU, mg, 'ml(-1),', 'P', &, 'lt;', 0.05, ')', ',', fold]), verbo([increases]), complemento([in, myoD, '(', 21.45, +, /, -, 3.12, vs])].
[sujeto(['C(2)C(12)', showed, significant]), verbo([increases]), complemento([in, 'IGF-I', mRNA, '(', 243.05, +, /, -, 3.87, vs])].
[sujeto(['Significant', temporal, reductions, in, 'C(2)C(12)', 'IGFBP2', mRNA, '(', 28.02, +, /, -, 15.44, ',', 13.82, +, /, -, 8.07, ',', 6.92, +, /, -, 4.37, ',', 'P', &, 'lt;', 0.05, ')', contrasted]), verbo([increases]), complemento([in, 'C(2)s', '(', 4.31, +, /, -, 3.31, ',', 13.02, +, /, -, 9.92, ',', 82.9, +, /, -, 58.9, ',', 'P', &, 'lt;', 0.05, ')', at, 0, ',', 48, and, 72, 'h,', respectively])].
[sujeto(['TNF-alpha']), verbo([increased]), complemento([cell, death, in, 'C(2)s', '(', 2.67, +, /, -, 1.54, '%', ',', 34.42, +, /, -, 5.39, '%', ',', 29.71, +, /, -, 5.79, '%', '(', 0, ',', 48, ',', 72, 'h),', 'P', &, 'lt;', 0.05, ')', ',', yet, was, without, effect, in, 'C(2)C(12)s', at, 48, h, but, caused, a, small, significant, increase, at, 72, h, '(', 9.88, +, /, -, 4.02, '%', '(', 'TNF-alpha)', vs])].
[sujeto(['This', investigation]), verbo([provides]), complemento([insight, into, regulators, of, altered, basal, hypertrophy, and, 'TNF-induced', 'atrophy,', providing, a, model, for, future, investigation, into, therapeutic, initiatives, for, 'ageing/wasting', disorders])].
[sujeto(['Contrary', to, general, 'expectation,', in, 'humans,', we]), verbo([have]), complemento([recently, shown, that, after, complete, conus, cauda, 'lesion,', the, lower, motoneuron, denervated, myofibers, may, survive, several, years])].
[sujeto(['In', adult, 'rats,', the, sciatectomized, muscle, progresses, in, 4, -, 6, months, from, severe, atrophy, to, a, dystrophic, stage, and, undergoes, a, dramatic, weight, 'loss;', during, this, 'process,', myofiber, 'death/regeneration', processes]), verbo([maintain]), complemento([a, decreasing, population, of, very, 'small,', but, vital, myofibers])].
[sujeto(['At', the, same, 'time,', in, vitro, electrophysiologic, recordings, show, that, denervated, fibers, can]), verbo([maintain]), complemento([membrane, excitability, longer, than, they, can, retain, contractile, properties])].
[sujeto(['A', certain, level, of, myofiber, regeneration, seems, to]), verbo([have]), complemento([a, role, in, the, 'process,', with, the, early, 're-expression', of, embryonic, subunits, of, integrins, and, acetylcholine, receptor, subunits])].
[sujeto(['In', 'fact,', we, show, here, that, in, sciatectomized, 'muscle,', the, expression, of, 12, selected, genes, was, differentially]), verbo([regulated]), complemento([after, 3, and, 9, month, denervation])].
[sujeto(['Xin', is, a, 'muscle-specific', actin]), verbo([binding]), complemento([protein, of, which, its, role, and, regulation, within, skeletal, muscle, is, not, well, understood])].
[sujeto(['Reducing', endogenous, 'Xin', expression, resulted, in, a, 26, '%']), verbo([increase]), complemento(['(', 'P', &, 'lt;', 0.05, ')', in, cell, proliferation, and, a, 20, '%', increase, '(', 'P', &, 'lt;', 0.05, ')', in, myoblast, migratory, capacity])].
[sujeto(['Skeletal', muscle, myosin, heavy, chain, protein, levels, were]), verbo([increased]), complemento(['(', 'P', &, 'lt;', 0.05, ')', with, 'Xin', shRNA, 'administration;', 'however,', this, was, not, accompanied, by, changes, in, myoglobin, protein, '(', another, marker, of, 'differentiation)', nor, overt, morphological, differences, relative, to, differentiating, control, cells])].
[sujeto(['Taken', 'together,', the, present, findings, support, the, hypothesis, that, 'Xin', is]), verbo([expressed]), complemento([within, muscle, satellite, cells, during, skeletal, muscle, regeneration, and, is, involved, in, the, regulation, of, myoblast, function])].
[sujeto(['The', 'Na(+)/H(+)', exchanger, '(', 'NHE)', 2, belongs, to, a, family, of, plasma, membrane, transporters]), verbo([involved]), complemento([in, intracellular, pH, and, cell, volume, regulation])].
[sujeto(['We', recently]), verbo([reported]), complemento([cloning, of, human, 'NHE2', '(', 'hNHE2)', from, a, colonic, cDNA, library])].
[sujeto(['Northern', blot, analysis]), verbo([has]), complemento([identified, 'NHE2', mRNA, only, in, small, 'intestine,', 'prostate,', 'kidney,', 'colon,', and, skeletal, muscle])].
[sujeto(['All', introns, contain, the]), verbo([conserved]), complemento(['GT', and, 'AG', dinucleotides, at, the, donor, and, acceptor, 'sites,', respectively])].
[sujeto(['However,', the, promoter, region, contains, several, potential, 'cis-regulatory', elements, such, as, 'Sp1,', early, growth, 'response-1,', activator, 'protein-2,', 'MyoD,', 'p300,']), verbo([nuclear]), complemento(['factor-kappaB,', myeloid, zinc, finger, 'protein-1,', 'caudal-related', homeobox, '(', 'Cdx)', gene, 'A,', and, 'Cdx', 'protein-2', binding, sites])].
[sujeto(['However,', after, deletion, upstream, of, -, 664, ',', its, activity]), verbo([increased]), complemento([approximately, threefold])].
[sujeto(['Thus', our, data]), verbo([suggest]), complemento([that, an, inhibitory, element, may, exist, in, the, 'NHE2', promoter, 5, '\'', -, upstream, region])].
[sujeto([2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin;', 'TCDD)']), verbo([cause]), complemento([cleft, palate, at, a, high, rate])].
[sujeto(['Runx2', and, osteopontin, immunoreactivity]), verbo([decreased]), complemento([in, the, 'TCDD-treated', palatal, 'bone,', and, 'MyoD', and, desmin, decreased, in, the, 'TCDD-treated', palatal, muscle])].
[sujeto(['TCDD', may]), verbo([suppress]), complemento([palatal, osteogenesis, and, myogenesis, via, 'AhR,', and, cause, cleft, palates, via, a, 'post-fusional', split, 'mechanism,', in, addition, to, a, failure, of, palatal, fusion])].
[sujeto(['Aryl', hydrocarbon, receptor, '(', 'AhR)']), verbo([nuclear]), complemento([translocator, '(', 'Arnt)', gene, has, been, isolated, and, characterized, from, a, mouse, genomic, 'DNA', library])].
[sujeto(['An', unusual, 'exon/intron', junctional, sequence, was]), verbo([found]), complemento([in, the, 11, th, intron, of, the, gene, that, begins, with, 'GC', at, its, 5, '\'', -, end])].
[sujeto(['The', gene, is, 'TATA-less', and]), verbo([has]), complemento([several, transcription, start, sites])].
[sujeto(['Of', 'all,', two, 'GC-boxes', displayed, the, most, dominant]), verbo([enhancing]), complemento([effects])].
[sujeto(['It', was, demonstrated, that, there, exist, specific, factors]), verbo([binding]), complemento([to, these, 'DNA', elements, in, the, nuclear, extracts, of, 'HeLa', cells])].
[sujeto(['Among', 'them,', 'Sp1', and, 'Sp3,', and, 'CAAT-box']), verbo([binding]), complemento(['factor-A', were, identified, to, bind, the, 'GC-boxes', and, 'CAAT-box,', respectively])].
[sujeto(['Expression', of, 'MyoD', in, 'HeLa', cells]), verbo([stimulated]), complemento([the, 'Arnt', promoter, activity, by, binding, to, the, 'E-box'])].
[sujeto(['The', 'AH-receptor', is, a, 'ligand-activated', transcription, factor, that]), verbo([regulates]), complemento([a, number, of, biological, responses, to, planar, aromatic, hydrocarbons])].
[sujeto(['Interest', in, this, receptor, is, related, to, its, role, in, the, toxic, action, of, a, variety, of, environmental, 'chemicals,', the, simplicity, and, elegance, of, the, murine, genetics, that]), verbo([led]), complemento([to, its, characterization, and, the, distinctive, mechanism, by, which, this, receptor, activates, gene, expression])].
[sujeto(['Recent', cloning, experiments]), verbo([have]), complemento([demonstrated, that, the, 'AH-receptor', is, structurally, related, to, the, 'Per,', 'ARNT', and, 'Sim', proteins])].
[sujeto(['In', the, 'AH-receptor,', this, domain, harbours, sequences]), verbo([involved]), complemento([in, the, formation, of, a, hydrophobic, pocket, that, bind, receptor, agonists])].
[sujeto(['Adjacent', to, the, 'PAS', domain, in, the, 'AH-receptor,', 'ARNT', and, 'Sim', proteins, is, a, 'basic/helix-loop-helix', '(', 'bHLH)', domain, that, appears, to]), verbo([mediate]), complemento([heterodimerization, and, sequence, specific, 'DNA', binding, properties])].
[sujeto(['The', observation, that, the, bHLH, domain, is, present, in, the, 'AH-receptor', and, the, 'ARNT', 'protein,', a, factor]), verbo([required]), complemento([for, proper, 'AH-receptor', 'function,', suggests, that, these, proteins, are, heterodimeric, partners, that, activate, gene, expression, in, a, manner, similar, to, 'Myc/Max', and, 'MyoD/E2A'])].
[sujeto(['The', objectives, of, this, review, are, to, describe, recent, experimental, results, in, this, field, and, to, use, this, information, to, develop, a, molecular, model, of, 'AH-receptor']), verbo([mediated]), complemento([signal, transduction])].
[sujeto(['A', cDNA, encoding, the, murine, 'Ah', receptor, '(', 'Ahb-1', allele, for, aromatic, hydrocarbon, 'responsiveness)']), verbo([has]), complemento([been, isolated, and, characterized])].
[sujeto(['Analysis', of, the, deduced, protein, sequence, revealed, a, region, with, similarity, to, the, basic, 'region/helix-loop-helix', '(', 'BR/HLH)', motif]), verbo([found]), complemento([in, many, transcription, factors, that, undergo, dimerization, for, function])].
[sujeto(['In', addition, to, the, 'BR/HLH', 'domain,', the, 'N-terminal', domain, of, the, 'Ah', receptor]), verbo([has]), complemento([extensive, sequence, similarity, to, the, human, 'ARNT', '(', aryl, hydrocarbon, receptor, nuclear, 'translocator)', protein, and, two, regulatory, proteins, of, 'Drosophila,', 'Sim', and, 'Per'])].
[sujeto(['Photoaffinity', labeling, and, peptide, mapping, studies, indicate, that, the, 'Ah', receptor]), verbo([binds]), complemento([agonist, at, a, domain, that, lies, within, this, conserved, 'N-terminal', domain])].
[sujeto(['The', 'Ah', receptor, appears, to, be, a, 'ligand-activated', transcription, factor, with, a, 'helix-loop-helix', motif, similar, to, those]), verbo([found]), complemento([in, a, variety, of, 'DNA-binding', 'proteins,', including, 'Myc', and, 'MyoD'])].
[sujeto(['The', protein, chaperone, heat, shock, protein, 90, '(', 'Hsp90)', is, a, major, regulator, of, different, transcription, factors, such, as, 'MyoD,', a, basic, helix, loop, helix, '(', 'bHLH)', 'protein,', and, the, 'bHLH-Per-aryl', hydrocarbon]), verbo([nuclear]), complemento([translocator, '(', 'ARNT)-Sim', '(', 'PAS)', factors, 'Sim', and, aryl, hydrocarbon, receptor, '(', 'Ahr)'])].
[sujeto(['The', transcription, factor, 'hypoxia-inducible', 'factor-1alpha', '(', 'HIF-1alpha),']), verbo([involved]), complemento([in, the, response, to, 'hypoxia,', also, belongs, to, the, 'bHLH-PAS', family])].
[sujeto(['Using', a, 'EGFP-HIF-1alpha', fusion, 'protein,', 'co-immunoprecipitation', experiments, evidenced, that, the, chimeric, protein]), verbo([expressed]), complemento([in, 'COS-7', cells, interacts, with, 'Hsp90', in, normoxia, but, not, in, hypoxia])].
[sujeto(['We', also, demonstrated, that, 'Hsp90']), verbo([interacts]), complemento([with, the, 'bHLH-PAS', domain, of, 'HIF-1alpha'])].
[sujeto(['At', 'last,', we, showed, that, 'Hsp90', activity, is, essential, for, 'HIF-1', activation, in, hypoxia, since, it, is]), verbo([inhibited]), complemento([in, the, presence, of, geldanamycin])].
[sujeto([1384, 'G&gt;A', 'SNP', was]), verbo([associated]), complemento([with, litter, size, in, the, 'GZ', goats, '(', 'P&lt;0'])].
[sujeto(['Luciferase', assay, analysis]), verbo([suggested]), complemento([that, the, 1384, 'A', allele, increased, luciferase, activity, when, compared, to, the, 1384, 'G', allele])].
[sujeto(['Functional', analysis]), verbo([suggested]), complemento([that, this, g])].
[sujeto([1384, 'G&gt;A', 'SNP', may, be, an, important, genetic, regulator, of, 'KISS1', gene, expression, with, effects, on, downstream, processes, that, are]), verbo([modulated]), complemento([by, 'KISS1', gene, because, of, the, changes, of, methylation, and, transcription, 'factor-binding', sites])].
[sujeto(['Therefore,', the, current, study]), verbo([provides]), complemento([evidence, in, goats, for, genetic, markers, that, might, be, used, in, breeding, programs])].
[sujeto(['Doxorubicin', '(', 'Dox,', 'Adriamicin),', a, potent, broad, spectrum, anthracycline, anticancer, 'drug,', selectively]), verbo([inhibits]), complemento([muscle, specific, gene, expression, in, cardiac, cells, in, vivo, and, prevents, terminal, differentiation, of, skeletal, muscle, cells, in, vitro])].
[sujeto(['By']), verbo([inducing]), complemento([the, expression, of, the, 'helix-loop-helix', '(', 'HLH)', transcriptional, inhibitor, 'ld2,', 'Dox', represses, the, myogenic, function, of, the, 'MyoD', family, of, muscle, regulatory, factors, '(', 'MRFs)'])].
[sujeto(['In', many, cell, 'types,', terminal, differentiation, is, coupled, to, an, irreversible, exit, from, the, cell, cycle, and, 'MyoD', plays, a, critical, role, in, the, permanent, cell, cycle]), verbo([arrest]), complemento([of, differentiating, myocytes, by, upregulating, the, cyclin, dependent, kinase, inhibitor, '(', 'cdki)', p21])].
[sujeto(['In', 'Dox-treated', quiescent, 'myoblasts,', which, fail, to, differentiate, into, myotubes, under, permissive, culture, 'conditions,', serum, 're-stimulation']), verbo([induces]), complemento(['cyclin/cdk', 're-association', on, the, 'E2F/DP', complexes, and, this, correlates, with, an, evident, increase, in, 'E2F/DP', driven, transcription, and, 're-entry', of, myoblasts, into, the, cell, cycle])].
[sujeto(['Despite', 'Dox', ability, to]), verbo([activate]), complemento([the, 'DNA-damage', dependent, 'p53/p21', 'pathway,', when, induced, in, the, absence, of, 'MyoD', or, other, 'MRFs,', p21, fails, to, maintain, the, postmitotic, state, in, 'Dox-treated', myocytes, induced, to, differentiate])].
[sujeto(['Thus,', uncoupling, p21, induction, and, 'MyoD', activity, results, in, a, 'serum-reversible', cell, cycle, 'arrest,', indicating, that, 'MRF', specific, activation, of, 'cdki(s)', is]), verbo([required]), complemento([for, permanent, cell, cycle, arrest, in, differentiating, muscle, cells])].
[sujeto(['Duchenne', muscular, dystrophy, '(', 'DMD)', is, a, progressive, and, fatal, muscle, degenerating, disease]), verbo([caused]), complemento([by, a, dystrophin, deficiency])].
[sujeto(['Patient-derived', human]), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'hiPSCs)', are, a, promising, tool, for, drug, discovery])].
[sujeto(['Here,', we]), verbo([report]), complemento([an, in, vitro, evaluation, system, for, a, 'DMD', therapy, using, hiPSCs, that, recapitulate, the, primary, pathology, and, can, be, used, for, 'DMD', drug, screening])].
[sujeto(['However,', electric, stimulation, of, these, myotubes, for, in, vitro, contraction]), verbo([caused]), complemento([pronounced, calcium, ion, '(', 'Ca(2+))', influx, only, in, 'DMD', myocytes])].
[sujeto(['Restoration', of, dystrophin, by, the, 'exon-skipping', technique]), verbo([suppressed]), complemento([this, 'Ca(2+)', overflow, and, reduced, the, secretion, of, creatine, kinase, '(', 'CK)', in, 'DMD', myotubes])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, early, pathogenesis, of, 'DMD', can, be, effectively, modelled, in, skeletal, myotubes, induced, from, 'patient-derived', 'iPSCs,', thereby, enabling, the, development, and, evaluation, of, novel, drugs])].
[sujeto(['Patient-derived']), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'iPSCs)', have, opened, the, door, to, recreating, pathological, conditions, in, vitro, using, differentiation, into, diseased, cells, corresponding, to, each, target, tissue])].
[sujeto(['Yet', for, muscular, 'diseases,', a, method, for, reproducible, and, efficient, myogenic, differentiation, from, human, iPSCs, is]), verbo([required]), complemento([for, in, vitro, modeling])].
[sujeto(['Here,', we, introduce, a, myogenic, differentiation, protocol]), verbo([mediated]), complemento([by, inducible, transcription, factor, expression, that, reproducibly, and, efficiently, drives, human, iPSCs, into, myocytes])].
[sujeto(['This', differentiation, protocol, can, be, applied, widely, in, various, types, of, 'patient-derived', human, iPSCs, and]), verbo([has]), complemento([great, prospects, in, disease, modeling, particularly, with, inherited, diseases, that, require, studies, of, early, pathogenesis, and, drug, screening])].
[sujeto(['Overexpression', of, 'SIRT1', is, frequently, observed, in, various, types, of, 'cancers,']), verbo([suggesting]), complemento([its, potential, role, in, malignancies])].
[sujeto(['This']), verbo([suggests]), complemento([aberrant, 'CpG', 'DNA', methylation, as, the, mechanistic, background, for, malignant, 'SIRT1', elevation])].
[sujeto(['Our', work, also]), verbo([provides]), complemento([an, example, where, epigenetic, mechanisms, cause, the, 'group-wide', regulation, of, miRNAs, sharing, a, common, key, target])].
[sujeto(['The', 'ZHTc6-MyoD', embryonic, stem, cell, line]), verbo([expresses]), complemento([the, myogenic, transcriptional, factor, 'MyoD', under, the, control, of, a, 'tetracycline-inducible', promoter])].
[sujeto(['However,', a, small, fraction, does, not, 'differentiate,', instead, forming, colonies, that]), verbo([retain]), complemento([the, potential, for, myocyte, differentiation])].
[sujeto(['In', our, current, 'study,', we]), verbo([found]), complemento([that, parathyroid, hormone, type, 1, receptor, '(', 'PTH1R)', expression, in, 'colony-forming', cells, at, 13, days, after, differentiation, was, higher, than, that, in, the, undifferentiated, 'ZHTc6-MyoD', cells])].
[sujeto(['We', also]), verbo([found]), complemento([that, 'PTH1R', expression, was, required, for, myocyte, 'differentiation,', and, that, parathyroid, hormone, accelerated, the, differentiation])].
[sujeto(['Our', analysis, of, human, and, mouse, skeletal, muscle, tissues, showed, that, most, cells]), verbo([expressing]), complemento(['PTH1R', also, expressed, 'Pax7', and, 'CD34,', which, are, biomarkers, of, satellite, cells])].
[sujeto(['Furthermore,', we]), verbo([found]), complemento([that, parathyroid, hormone, treatment, significantly, improved, muscle, weakness, in, 'dystrophin-deficient', mdx, mice])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([indicating, that, 'PTH1R', and, 'PTH', accelerate, myocyte, differentiation])].
[sujeto([3, -, 'Methylcholanthrene', '(', 3, 'MC)']), verbo([induces]), complemento([tumor, formation, at, the, site, of, injection, in, the, hind, leg, of, mice, within, 110, days])].
[sujeto(['Recent']), verbo([reports]), complemento([reveal, that, the, transformation, of, normal, muscle, cells, to, atypical, cells, is, one, of, the, causes, for, tumor, 'formation,', however, the, molecular, mechanism, behind, this, process, is, not, well, understood])].
[sujeto(['Here,', we, show, in, an, in, vitro, study, that, 3, 'MC']), verbo([induces]), complemento([fragmentation, of, multinucleate, myotubes, into, viable, mononucleates])].
[sujeto(['Immunoblot', analysis]), verbo([reveals]), complemento([that, phosphorylation, of, myosin, regulatory, light, chain, '(', 'RLC20)', is, 5.6, '±0'])].
[sujeto(['Interestingly,', addition, of, the, myosin, light, chain, kinase, 'inhibitor,', 'ML-7,']), verbo([enhances]), complemento([the, 'fragmentation,', whereas, phosphatase, inhibitor, perturbs, the, 3, 'MC', induced, fragmentation, of, myotubes])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, decrease, in, 'RLC20', phosphorylation, may, be, associated, with, the, fragmentation, step, of, dedifferentiation])].
[sujeto(['The', establishment, of, human]), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'hiPSCs)', has, enabled, the, production, of, in, 'vitro,', 'patient-specific', cell, models, of, human, disease])].
[sujeto(['However,', myogenic, differentiation, of, hiPSCs]), verbo([has]), complemento([faced, 'obstacles,', 'namely,', low, efficiency, 'and/or', poor, reproducibility])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, 'rapid,', 'efficient,', and, reproducible, differentiation, of, hiPSCs, into, mature, myocytes])].
[sujeto(['Myocytes']), verbo([induced]), complemento([in, this, manner, reach, maturity, within, 2, weeks, of, differentiation, as, assessed, by, marker, gene, expression, and, functional, 'properties,', including, in, vitro, and, in, vivo, cell, fusion, and, twitching, in, response, to, electrical, stimulation])].
[sujeto(['Miyoshi', 'Myopathy', '(', 'MM)', is, a, congenital, distal, myopathy]), verbo([caused]), complemento([by, defective, muscle, membrane, repair, due, to, mutations, in, 'DYSFERLIN'])].
[sujeto(['Using', our]), verbo([induced]), complemento([differentiation, 'technique,', we, successfully, recreated, the, pathological, condition, of, 'MM', in, 'vitro,', demonstrating, defective, membrane, repair, in, 'hiPSC-derived', myotubes, from, an, 'MM', patient, and, phenotypic, rescue, by, expression, of, 'full-length', 'DYSFERLIN', '(', 'DYSF)'])].
[sujeto(['We']), verbo([target]), complemento([this, inducible, cassette, exchange, '(', 'ICE)', allele, to, the, '(', 'HPRT)', locus, and, demonstrate, recombination, in, murine, embryonic, stem, cells, '(', 'ESCs)', and, primary, cells, from, derivative, 'ICE', mice])].
[sujeto(['In', the, present, 'study,', methods, were, developed, to, expand, cultures, of, 'MSCs', and, to]), verbo([promote]), complemento([the, myogenic, differentiation, of, these, 'cells,', which, were, then, used, in, a, new, approach, for, the, treatment, of, 'DMD'])].
[sujeto(['The', transduction, of, 'CD271(+)', 'MSCs', with, 'MyoD']), verbo([caused]), complemento([myogenic, differentiation, in, vitro, and, the, formation, of, myotubes, expressing, late, myogenic, markers])].
[sujeto(['Despite', having, distinct, expression, patterns, and, phenotypes, in, mutant, 'mice,', the, myogenic, regulatory, factors, 'Myf5', and, 'MyoD']), verbo([have]), complemento([been, considered, to, be, functionally, equivalent])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, these, factors, have, a, different, response, to, 'DNA', 'damage,', due, to, the, presence, in, 'MyoD', and, absence, in, 'Myf5', of, a, consensus, site, for, 'Abl-mediated', tyrosine, phosphorylation, that, inhibits, 'MyoD', activity, in, response, to, 'DNA', damage])].
[sujeto(['Genotoxins', failed, to]), verbo([repress]), complemento([skeletal, myogenesis, in, 'MyoD-null', 'embryos;', reintroduction, of, 'wild-type', 'MyoD,', but, not, mutant, 'Abl', 'phosphorylation-resistant', 'MyoD,', restored, the, 'DNA-damage-dependent', inhibition, of, muscle, differentiation])].
[sujeto(['The', presence, of, a, 'DNA-damage-responsive', phosphorylation, motif, in, 'vertebrate,', but, not, in, invertebrate, 'MyoD']), verbo([suggests]), complemento([an, evolved, response, to, environmental, 'stress,', originated, from, basic, 'helix-loop-helix', gene, duplication, in, vertebrate, myogenesis])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, that, the, level, of, 'MyoD', expression, correlates, with, the, level, of, apoptosis, that, occurs, in, a, subpopulation, of, skeletal, myoblasts, induced, to, differentiate, by, serum, withdrawal])].
[sujeto(['Further,', using, a, fibroblast, cell, line]), verbo([expressing]), complemento([an, estrogen, 'receptor:MyoD', fusion, 'protein,', we, have, determined, that, addition, of, estrogen, sensitizes, these, fibroblasts, to, apoptosis, induced, by, serum, 'withdrawal,', or, by, treatment, with, etoposide, or, thapsigargin])].
[sujeto(['RNAi']), verbo([mediated]), complemento([silencing, of, 'MyoD', in, either, 23, 'A2', or, 'C2C12', myoblasts, renders, these, cells, resistant, to, apoptosis, induced, by, serum, 'withdrawal,', or, by, treatment, with, etoposide, or, thapsigargin])].
[sujeto(['Finally,', 'MyoD']), verbo([mediated]), complemento([regulation, of, the, apoptotic, response, to, these, various, 'stimuli,', in, both, myoblasts, and, 'fibroblasts,', correlates, with, the, level, of, induction, of, the, 'pro-apoptotic', 'Bcl2', family, member, 'PUMA'])].
[sujeto(['We', used, external, fixation, '(', 'EF),', as, a, clinically, relevant, 'model,', to]), verbo([gain]), complemento([insights, into, the, relationships, between, muscle, degenerative, and, regenerative, conditions, to, the, myogenic, properties, and, abundance, of, bona, fide, satellite, cells])].
[sujeto(['EF']), verbo([induced]), complemento([muscle, mass, 'loss;', declined, expression, of, the, muscle, specific, regulatory, factors, '(', 'MRFs)', 'Myf5,', 'MyoD,', 'myogenin,', and, also, of, satellite, cell, numbers, and, myogenic, differentiation, aptitude])].
[sujeto(['Tet']), verbo([enhanced]), complemento([the, expression, of, 'MRFs,', but, did, not, prevent, the, decline, of, the, satellite, cell, pool])].
[sujeto(['Together,', our, results, point, to, 'Tet', and, exercise, running, as, promising, and, relevant, approaches, for]), verbo([enhancing]), complemento([muscle, recovery, after, atrophy])].
[sujeto(['In', our, present, proof, of, principle, 'studies,', we]), verbo([have]), complemento([successfully, constructed, a, multilayered, culture, of, skeletal, muscle, 'cells,', derived, from, neonatal, satellite, 'cells,', that, are, distributed, in, a, 3, 'D', pattern, of, organization, that, mimics, many, of, the, features, of, intact, tissue])].
[sujeto(['In', myogenic, 'C(2)C(12)', 'cells,', 5, mM, creatine]), verbo([increased]), complemento([the, incorporation, of, labeled, '[', '(', 35, ')', 'S]methionine', into, sarcoplasmic, '(', +, 20, '%', ',', 'P', &, 'lt;', 0.05, ')', and, myofibrillar, proteins, '(', +, 50, '%', ',', 'P', &, 'lt;', 0.01, ')'])].
[sujeto(['Creatine', also]), verbo([promoted]), complemento([the, fusion, of, myoblasts, assessed, by, an, increased, number, of, nuclei, incorporated, within, myotubes, '(', +, 40, '%', ',', 'P', &, 'lt;', 0.001, ')'])].
[sujeto(['Expression', of, myosin, heavy, chain, type, 'II', '(', +, 1, ',', 300, '%', ',', 'P', &, 'lt;', 0.001, ')', ',', troponin, 'T', '(', +, 65, '%', ',', 'P', &, 'lt;', 0.01, ')', ',', and, titin, '(', +, 40, '%', ',', 'P', &, 'lt;', 0.05, ')', was]), verbo([enhanced]), complemento([by, creatine])].
[sujeto(['The', addition, of, 'rapamycin,', the, inhibitor, of, mammalian]), verbo([target]), complemento([of, 'rapamycin/70-kDa', ribosomal, 'S6', protein, kinase, '(', 'mTOR/p70(s6k))', 'pathway,', and, 'SB', 202190, ',', the, inhibitor, of, 'p38,', completely, blocked, differentiation, in, control, 'cells,', and, creatine, did, not, reverse, this, 'inhibition,', suggesting, that, the, 'mTOR/p70(s6k)', and, p38, pathways, could, be, potentially, involved, in, the, effect, induced, by, creatine, on, differentiation])].
[sujeto(['Creatine', also, affected, the, phosphorylation, state, of, p38, '(', -, 50, '%', at, 24, h, and, +, 70, '%', at, 96, 'h,', 'P', &, 'lt;', 0.05, ')', as, well, as, the]), verbo([nuclear]), complemento([content, of, its, downstream, targets, myocyte, enhancer, 'factor-2', '(', -, 55, '%', at, 48, h, and, +, 170, '%', at, 96, 'h,', 'P', &, 'lt;', 0.05, ')', and, 'MyoD', '(', +, 60, '%', ',', 'P', &, 'lt;', 0.01, ')'])].
[sujeto(['In', 'conclusion,', this, study, points, out, the, involvement, of, the, p38, and, the, 'Akt/PKB-p70(s6k)', pathways, in, the]), verbo([enhanced]), complemento([differentiation, induced, by, creatine, in, 'C(2)C(12)', cells])].
[sujeto(['The', hindlimbs, of, some, animals, in, each, group, were, irradiated, before, injury, to]), verbo([prevent]), complemento([proliferation, of, myogenic, cells, during, recovery])].
[sujeto(['Inhibiting', myogenesis]), verbo([prevented]), complemento([the, recovery, of, contractile, function, after, 'MR,', but, not, after, 1, 'R'])].
[sujeto(['Both', protocols]), verbo([caused]), complemento(['Evans', blue, dye, uptake, immediately, after, 'injury,', but, 'Evans', blue, dye, was, only, retained, in, fibers, for, several, days, after, 1, 'R'])].
[sujeto(['This']), verbo([suggests]), complemento([that, membranes, reseal, after, 1, 'R,', but, not, after, 'MR'])].
[sujeto(['The', mechanisms, that, underlie, recovery, after, injuries]), verbo([caused]), complemento([by, repeated, lengthening, contractions, and, injuries, caused, by, a, single, lengthening, contraction, are, different])].
[sujeto(['The', differences, may, be, important, when, planning]), verbo([targeted]), complemento([rehabilitation, strategies, for, each, type, of, injury])].
[sujeto(['Advanced', gene, 'therapy,', tissue, engineering, and, biopharmaceutical, manufacturing]), verbo([require]), complemento([sophisticated, and, 'well-balanced', multiregulated, multigene, interventions, to, reprogram, desired, mammalian, cell, phenotypes])].
[sujeto(['We']), verbo([have]), complemento([combined, the, streptogramin, '(', 'PIP)-', and, tetracycline, '(', 'TET)-responsive', gene, regulation, systems, for, independent, expression, control, of, the, differentiation, determinants, myoD, and, msx1, in, 'C2C12-derived', cells])].
[sujeto(['Different', 'dual-regulated', expression, scenarios, which]), verbo([induce]), complemento([either, 'both,', only, one, or, none, of, the, lineage, control, genes, triggered, differential, differentiation, and, precise, control, of, 'myogenic,', osteogenic, or, adipogenic, cell, phenotypes])].
[sujeto(['We']), verbo([reported]), complemento([previously, that, transcription, factor, nuclear, factor, '(', 'NF)-kappaB', is, constitutively, activated, in, human, and, murine, squamous, cell, carcinomas, '(', 'SCCs)'])].
[sujeto(['Remarkably,', 'NF-kappaB']), verbo([modulated]), complemento([the, expression, of, &, 'gt;60%', of, the, 308, genes, differentially, expressed, between, normal, keratinocytes, and, metastatic, 'SCCs'])].
[sujeto(['NF-kappaB', directly, or, indirectly]), verbo([modulated]), complemento([expression, of, programs, of, genes, functionally, linked, to, 'proliferation,', 'apoptosis,', 'adhesion,', and, angiogenesis])].
[sujeto(['NF-kappaB', 'DNA']), verbo([binding]), complemento([motifs, were, detected, in, the, promoter, of, approximately, 63, '%', of, genes, showing, increased, expression, and, 33, '%', of, the, genes, showing, decreased, expression])].
[sujeto(['The', 'ACTACAG', motif, implicated, in, the, 'NF-kappaB-dependent', 'down-regulation', of, mRNA, expression, of, 'MyoD', and, 'Sox9', was, detected, in, the, coding, portion, of, about, 15, '%', of, genes, showing]), verbo([increased]), complemento([or, decreased, expression])].
[sujeto(['Inactivation', of, 'NF-kappaB']), verbo([inhibited]), complemento([malignant, phenotypic, features, including, 'proliferation,', cell, 'survival,', 'migration,', 'angiogenesis,', and, tumorigenesis])].
[sujeto(['These', results]), verbo([provide]), complemento([evidence, that, 'NF-kappaB', is, an, important, modulator, of, gene, expression, programs, that, contribute, to, the, malignant, phenotype, of, 'SCC'])].
[sujeto(['In', the, present, study, optimized, 'HIV-1-based', vector, systems, that, display, efficient, doxycycline, '(', 'Dox)-dependent', transgene, expression, in, vitro, and, in, vivo]), verbo([have]), complemento([been, developed, through, the, modification, of, factors, that, contribute, to, basal, activity, levels])].
[sujeto(['Dissection', of, 'HIV-1', vectors, harboring, a, 'tTA-dependent', transgene, expression, cassette, revealed, several, mechanisms, that, account, for, 'Dox-independent', transgene, 'expression,', including, those]), verbo([mediated]), complemento([by, an, internal, 'CMV', 'promoter,', as, well, as, a, potential, contribution, from, fusion, proteins, generated, by, translational, readthrough])].
[sujeto(['Cell-substratum', interactions]), verbo([trigger]), complemento([key, signaling, pathways, that, modulate, growth, control, and, 'tissue-specific', gene, expression])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, abolishing, adhesive, interactions, by, suspension, culture, results, in, 'G(0)', arrest, of, myoblasts])].
[sujeto(['We']), verbo([report]), complemento([that, blocking, intracellular, transmission, of, 'adhesion-dependent', signals, in, adherent, cells, mimics, the, absence, of, adhesive, contacts])].
[sujeto(['Furthermore,', both, 'ML7', and, 'BDM']), verbo([suppressed]), complemento([expression, of, 'MyoD', and, 'myogenin,', induced, 'p27(kip1)', but, not, 'p21(cip1),', and, inhibited, differentiation])].
[sujeto(['Thus,', as, with, 'suspension-arrest,', inhibition, of, 'acto-myosin', contractility, in, adherent, cells]), verbo([led]), complemento([to, arrest, uncoupled, from, differentiation])].
[sujeto(['By', 'contrast,', 'wild-type', 'RhoA']), verbo([induced]), complemento(['arrest,', maintained, 'MyoD', and, activated, myogenin, and, p21, expression])].
[sujeto(['The', 'Rho', effector, kinase, 'ROCK', did, not, appear, to]), verbo([mediate]), complemento(['Rho\'s', effects, on, 'MyoD'])].
[sujeto(['Signals']), verbo([regulated]), complemento([by, 'MLCK', are, 'critical,', since, inhibition, of, 'MLCK', suppressed, 'MyoD', expression, but, inhibition, of, 'ROCK', did, not])].
[sujeto(['Inhibition', of, contractility]), verbo([suppressed]), complemento(['MyoD', but, did, not, reduce, actin, polymer, levels])].
[sujeto(['However,', actin, depolymerization, with, latrunculin, 'B']), verbo([inhibited]), complemento(['MyoD', expression])].
[sujeto(['Taken', 'together,', our, observations, indicate, that, actin, polymer, status, and, contractility]), verbo([regulate]), complemento(['MyoD', expression])].
[sujeto(['We']), verbo([suggest]), complemento([that, in, 'myoblasts,', the, 'Rho', pathway, and, regulation, of, 'acto-myosin', contractility, may, define, a, control, point, for, conditional, uncoupling, of, differentiation, and, the, cell, cycle])].
[sujeto(['Several', studies]), verbo([have]), complemento([already, demonstrated, that, 'micro-', and, 'milli-calpains', '(', 'CAPN', 1, -, 'CAPN', 2, ')', ',', 'calcium-dependent', intracellular, 'cysteine-proteases', are, involved, in, many, biological, phenomenon, including, muscle, growth, and, development])].
[sujeto(['More', 'particularly,', recent, studies]), verbo([have]), complemento([demonstrated, that, 'milli-calpain', is, implicated, in, myoblast, fusion])].
[sujeto(['Because', 'micro-', and, 'milli-calpains', do, not]), verbo([have]), complemento([the, same, intracellular, 'localization,', it, appears, likely, that, these, two, 'calcium-dependent', proteases, have, different, biological, roles, during, muscle, cell, differentiation])].
[sujeto(['We', 'therefore,']), verbo([have]), complemento([developed, a, muscle, cell, line, in, which, 'micro-calpain', is, 'over-expressed,', using, the, inducible, 'Tet', 'Regulated', 'Expression', 'System'])].
[sujeto(['The', present, study, shows, important]), verbo([decreases]), complemento([in, the, expression, level, of, ezrin, '(', 68, '%', ')', ',', vimentin, '(', 64, '%', ')', and, caveolin, 3, '(', 76, '%', ')', whereas, many, other, cytoskeletal, proteins, remain, remarkably, stable])].
[sujeto(['Concerning', the, myogenic, transcription, 'factors,', only, the, level, of, myogenin]), verbo([decreased]), complemento(['(', 59, '%', ')', after, the, 'over-expression', of, 'micro-calpain'])].
[sujeto(['Ultra', structural, studies]), verbo([have]), complemento([shown, that, the, myofibrils, formed, near, the, cell, periphery, are, normally, 'oriented,', lying, along, the, longitudinal, axis])].
[sujeto(['This', regularity, is, lost, progressively, towards, the, cell, center, where, the, cytoskeleton, presented, an]), verbo([increasing]), complemento([disorganization])].
[sujeto(['All', these, results, indicate, that, 'micro-calpain', is]), verbo([involved]), complemento([in, regulation, pathway, of, myogenesis, via, at, least, its, action, on, 'ezrin,', 'vimentin,', caveolin, 3, and, 'myogenin,', a, muscle, transcription, factor])].
[sujeto(['Skeletal', muscle, contractile, activity]), verbo([has]), complemento([been, implicated, in, many, aspects, of, muscle, cell, differentiation, and, maturation])].
[sujeto(['Much', of, the, research, in, this, area]), verbo([has]), complemento([depended, upon, costly, and, 'labor-intensive', cultures, of, isolated, primary, muscle, cells, because, widely, available, immortalized, muscle, cell, lines, often, do, not, display, a, high, level, of, either, spontaneous, or, stimulated, contractile, activity])].
[sujeto(['We', sought, to, develop, 'conditionally-immortalized', skeletal, muscle, cell, lines, that, would]), verbo([provide]), complemento([a, source, of, myofibers, that, exhibit, robust, spontaneous, contractile, activity, similar, to, primary, muscle, cultures])].
[sujeto(['Using', a, 'tetracycline-regulated', retroviral, vector]), verbo([expressing]), complemento([a, 'temperature-sensitive', 'T-antigen', to, infect, primary, 'myoblasts,', we, isolated, individual, clonal, muscle, precursor, cell, lines, that, have, characteristics, of, activated, satellite, cells, during, growth, and, rapidly, differentiate, into, mature, myotubes, with, spontaneous, contractile, activity, after, culture, in, 'non-transformation-permissive', conditions])].
[sujeto(['Nutrition', plays, a, key, role, in, the, maintenance, of, muscle, and, bone, 'mass,', and, dietary, protein, deficiency]), verbo([has]), complemento([in, particular, been, associated, with, catabolism, of, both, muscle, and, bone, tissue])].
[sujeto(['One', mechanism, thought, to, link, protein, deficiency, with]), verbo([loss]), complemento([of, muscle, mass, is, deficiency, in, specific, amino, acids, that, play, a, role, in, muscle, metabolism])].
[sujeto(['Adult', mice, '(', 12, 'mo)', were, fed, a, normal, diet, '(', 18, '%', 'protein),', as, well, as, diets, with, low, protein, '(', 8, '%', ')', supplemented, with]), verbo([increasing]), complemento([concentrations, '(', 50, ',', 100, ',', and, 200, 'uM)', of, kynurenine, '(', 'Kyn)', or, with, tryptophan, '(', 'Trp;', 1.5, 'mM)', for, 8, weeks])].
[sujeto(['Enzyme-linked', immunosorbent, assays, showed, significant]), verbo([increases]), complemento([in, skeletal, muscle, 'insulin-like', growth, 'factor-1,', 'leptin,', and, the, myostatin, antagonist, follistatin, with, 'Trp', supplementation])].
[sujeto(['In', 'vitro,', neither, amino, acid, affected, proliferation, of, 'myoprogenitors,', but, 'Trp']), verbo([increased]), complemento([the, expression, of, the, myogenic, markers, 'MyoD,', 'myogenin,', and, myosin, heavy, chain])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, dietary, amino, acids, can, directly, affect, molecular, signaling, in, skeletal, 'muscle,', further, indicating, that, dietary, manipulation, with, specific, amino, acids, could, potentially, attenuate, muscle, loss, with, dietary, protein, deficiency])].
[sujeto(['Brown', fat, or, brown, adipose, tissue, '(', 'BAT),']), verbo([found]), complemento([in, newborn, mammals, as, small, depots, localized, in, the, interscapular, 'region,', plays, a, prominent, role, in, regulating, thermogenesis, perinatally])].
[sujeto(['The', physiological, importance, of, functional, 'BAT']), verbo([has]), complemento([been, recently, reasserted, in, human, adults])].
[sujeto(['The']), verbo([increased]), complemento([adipocyte, proliferation, in, 'BAT', of, 'double-mutant', newborns, was, associated, with, overexpression, of, the, brown, 'fat-specific', marker, 'Ucp1'])].
[sujeto(['More', 'strikingly,', expression, of, the, master, key, gene, 'Prdm16']), verbo([involved]), complemento([in, the, switch, between, myogenic, and, brown, adipogenic, lineages, was, drastically, enhanced])].
[sujeto(['We', further, demonstrate, that, concomitant, 'Myod', and, 'Igf2', inactivation, accelerates, differentiation, of, a, brown, preadipocyte, cell, line, and]), verbo([induces]), complemento([lipid, accumulation, and, increased, 'Ucp1', and, 'Prdm16', expression])].
[sujeto(['These', results]), verbo([provide]), complemento([the, first, in, vivo, evidence, that, a, myogenic, regulator, together, with, a, growth, factor, act, simultaneously, but, through, independent, pathways, to, repress, 'Prdm16,', which, opens, potential, therapeutic, perspectives, for, human, metabolic, disorders])].
[sujeto(['Such', quadruplexes, were, implicated, in, the, regulation, of, gene, 'expression,', plausibly, by]), verbo([interacting]), complemento([with, transcription, factors])].
[sujeto(['We', showed, previously, that, homodimers, of, the, myogenic, transcription, factor, 'MyoD']), verbo([bound]), complemento([in, vitro, most, tightly, bimolecular, quadruplexes, of, promoter, sequences, of, 'muscle-specific', genes])].
[sujeto(['Here,', we, show, that, 'DNA', quadruplexes]), verbo([enhance]), complemento([in, vivo, 'MyoD', and, 'E-box-driven', expression, of, a, firefly, luciferase, '(', 'FL)', reporter, gene])].
[sujeto(['HEK293', cells, were, transfected, with, 'FL']), verbo([expressing]), complemento(['p4RTK-FL', vector, alone, or, together, with, 'MyoD', expressing, 'pEMSV-MyoD', 'plasmid,', with, quadruplexes, of, alpha7, integrin, or, sarcomeric, mitochondrial, creatine, kinase, '(', 'sMtCK)', muscle, gene, promoters, or, with, a, combination, thereof])].
[sujeto(['However,', together, with, 'MyoD,', quadruplex, 'DNA']), verbo([increased]), complemento([by, approximately, 35, -, fold, the, amounts, of, 'FL', mRNA, and, protein])].
[sujeto(['Without', affecting, its, 'expression,', 'DNA', quadruplexes]), verbo([bound]), complemento(['MyoD', in, the, cells])].
[sujeto(['Heterodimers', of, 'MRFs', with, 'E-proteins']), verbo([activate]), complemento(['muscle-specific', gene, expression, by, binding, to, 'E-box', motifs, 'd(CANNTG)', in, their, promoters, or, enhancers])].
[sujeto(['We', showed, previously, that, in, contrast, to, the, favored]), verbo([binding]), complemento([of, 'E-box', by, 'MyoD-E47', 'heterodimers,', homodimeric, 'MyoD', associated, preferentially, with, quadruplex, structures, of, regulatory, sequences, of, 'muscle-specific', genes])].
[sujeto(['To', inquire, whether, other, 'MRFs', shared, the, 'DNA']), verbo([binding]), complemento([preferences, of, 'MyoD,', the, 'DNA', affinities, of, 'hetero-', and, 'homo-dimeric', 'MyoD,', 'MRF4', and, 'Myogenin', were, compared])].
[sujeto(['Similarly', to, 'MyoD,', heterodimers, with, 'E47', of, 'MRF4', or, 'Myogenin']), verbo([bound]), complemento(['E-box', more, tightly, than, quadruplex, 'DNA'])].
[sujeto(['However,', unlike, homodimeric, 'MyoD', or, 'MRF4,', 'Myogenin', homodimers]), verbo([associated]), complemento([weakly, and, nonpreferentially, with, quadruplex, 'DNA'])].
[sujeto(['Thus,', 'Myogenin', with, an, implanted, 'MyoD', basic, region]), verbo([bound]), complemento([quadruplex, 'DNA', nearly, as, tightly, as, 'MyoD'])].
[sujeto(['We', speculate, that, the, dissimilar, interaction, of, 'MyoD', and, 'Myogenin', with, tetrahelical, domains, in, muscle, gene, promoters, may, differently]), verbo([regulate]), complemento([their, myogenic, activities])].
[sujeto(['Muscle', differentiation, and, expression, of, 'muscle-specific', proteins, are, initiated, by, the]), verbo([binding]), complemento([of, heterodimers, of, the, transcription, factor, 'MyoD', with, 'E2A', proteins, to, 'E-box', motif, 'd(CANNTG)', in, promoters, or, enhancers, of, 'muscle-specific', genes])].
[sujeto(['In', this, 'work,', we, identified, elements, in, 'MyoD', that]), verbo([bind]), complemento(['E-box', or, tetraplex, structures, of, promoter, sequences, of, the, 'muscle-specific', genes, alpha7, integrin, and, sarcomeric, 'Mitochondrial', 'Creatine', 'Kinase', '(', 'sMtCK)'])].
[sujeto(['Deletions', of, large, domains, of, the, 315, amino, acids, long, recombinant, 'MyoD', indicated, that, the]), verbo([binding]), complemento([site, for, both, 'E-box', and, tetraplex, 'DNA', is, its, basic, region, 'KRKTTNADRRKAATMRERRR', that, encompasses, the, three, underlined, clusters, of, basic, residues, designated, 'R(1),', 'R(2)', and, 'R(3)'])].
[sujeto(['By', 'contrast,', the, 'MyoD', deletion, mutants, 'Delta102-114,', 'DeltaR(3),', 'DeltaR(1)R(3)', or, 'DeltaR(2)R(3)']), verbo([maintained]), complemento([comparable, tetraplex, 'DNA-binding', capacity, as, reflected, by, the, similar, dissociation, constants, of, their, 'protein-DNA', complexes])].
[sujeto(['Only', deletion, of, all, three, basic, clusters, abolished, the]), verbo([binding]), complemento([of, tetraplex, 'DNA'])].
[sujeto(['Implications', of, the]), verbo([binding]), complemento([of, 'E-box', and, tetraplex, 'DNA', by, 'non-identical', 'MyoD', elements, are, considered])].
[sujeto(['We', therefore, perturbed, vascular, assembly, in, chick, limbs, by, overexpressing, 'VEGFA', and, demonstrated, that, ectopic, blood, vessels]), verbo([inhibit]), complemento([muscle, 'formation,', while, promoting, connective, tissue])].
[sujeto(['Conversely,', local, inhibition, of, vessel, formation, using, a, soluble, form, of, 'VEGFR1']), verbo([leads]), complemento([to, muscle, fusion])].
[sujeto(['The', endogenous, location, of, endothelial, cells, in, the, future, muscle, cleavage, zones, and, the, inverse, correlation, between, blood, vessels, and, muscle]), verbo([suggests]), complemento([that, vessels, are, involved, in, the, muscle, splitting, process])].
[sujeto(['We', also, identify, the, secreted, factor, 'PDGFB', '(']), verbo([expressed]), complemento([in, endothelial, 'cells)', as, a, putative, molecular, candidate, mediating, the, 'muscle-inhibiting', and, connective, 'tissue-promoting', functions, of, blood, vessels])].
[sujeto(['Finally,', we, propose, that, 'PDGFB']), verbo([promotes]), complemento([the, production, of, extracellular, matrix, and, attracts, connective, tissue, cells, to, the, future, splitting, 'site,', allowing, separation, of, the, muscle, masses, during, the, splitting, process])].
[sujeto(['Myogenic', transcription, is]), verbo([activated]), complemento([by, the, binding, of, heterodimers, of, the, basic, 'helix-loop-helix', proteins, 'MyoD', and, 'E12', or, 'E47', to, a, consensus, 'E-box', 'sequence,', 'd(CANNTG),', in, promoter, or, enhancer, regions, of, 'muscle-specific', genes])].
[sujeto(['Homodimers', of, 'MyoD']), verbo([bind]), complemento(['E-box', less, tightly, and, are, less, efficient, activators, of, transcription])].
[sujeto(['Here', we]), verbo([have]), complemento([shown, that, homodimers, of, 'full-length', recombinant, 'MyoD', formed, complexes, with, bimolecular, tetraplex, structures, of, 'muscle-specific', regulatory, sequences, but, not, with, their, 'double-stranded,', 'hairpin,', or, unimolecular, tetraplex, forms])].
[sujeto(['Preferential']), verbo([binding]), complemento([of, homodimeric, 'MyoD', to, bimolecular, tetraplex, 'DNA', structures, over, 'E-box', 'DNA', was, reflected, by, the, 18.7, -, 39.9, -, fold, lower, dissociation, 'constants,', 'Kd,', of, the, 'MyoD-tetraplex', 'DNA', complexes])].
[sujeto(['Similarly,', homodimers, of, the, 60, -, amino, acid, basic, 'helix-loop-helix', domain, of, 'MyoD']), verbo([bound]), complemento(['E-box', more, efficiently, and, tetraplex, 'DNA', less, efficiently, than, homodimers, of, 'full-length', 'MyoD'])].
[sujeto(['It', might, be, that, the, favored]), verbo([binding]), complemento([of, 'MyoD', homodimers, to, tetraplex, 'DNA', structures, lowers, their, ability, to, activate, 'muscle-specific', gene, 'transcription,', whereas, the, formation, of, 'MyoD-E47', heterodimers, and, their, preferential, binding, to, 'E-box', 'DNA', enhance, transcription])].
[sujeto(['The', myogenic, determination, protein, 'MyoD', was]), verbo([reported]), complemento([to, bind, to, a, tetrahelical, structure, of, 'guanine-rich', enhancer, sequence, of, muscle, creatine, kinase, '(', 'MCK)', more, tightly, than, to, its, target, 'E-box', motif, '[', 'K'])].
[sujeto([',', 267, ',', 13714, -, 13718, ']', ',']), verbo([suggesting]), complemento([that, tetraplex, structures, of, regulatory, sequences, of, 'muscle-specific', genes, could, contribute, to, transcriptional, regulation])].
[sujeto(['The', sMtCK, sequence, folded, into, a, hairpin, 'structure;', the, alpha7, integrin, oligonucleotide, generated, a, unimolecular, 'tetraplex;', and, sequences, from, all, three, genes]), verbo([associated]), complemento([to, generate, bimolecular, tetraplexes])].
[sujeto(['We', also, show, that, homodimeric, 'MyoD']), verbo([bound]), complemento([bimolecular, tetraplex, structures, of, 'muscle-specific', regulatory, sequences, more, efficiently, than, its, target, 'E-box', motif])].
[sujeto(['Forced', expression, of, the, bHLH, myogenic, 'factors,', 'Myf5', and, 'MyoD,', in, various, mammalian, cell, lines]), verbo([induces]), complemento([the, full, program, of, myogenic, differentiation])].
[sujeto(['However,', this, property]), verbo([has]), complemento([not, been, extensively, explored, in, vivo])].
[sujeto(['We']), verbo([have]), complemento([taken, advantage, of, the, chick, model, to, investigate, the, effect, of, electroporation, of, the, mouse, 'Myf5', and, 'MyoD', genes, in, the, embryonic, neural, tube])].
[sujeto(['We']), verbo([found]), complemento([that, misexpression, of, either, mouse, 'Myf5', or, 'MyoD', in, the, chick, neural, tube, leads, to, ectopic, skeletal, muscle, 'differentiation,', assayed, by, the, expression, of, the, myosin, heavy, chains, in, the, neural, tube, and, neural, crest, derivatives])].
[sujeto(['We', also, showed, that, the, endogenous, neuronal, differentiation, program, is]), verbo([inhibited]), complemento([under, the, influence, of, either, ectopic, mouse, 'Myf5', or, 'MyoD'])].
[sujeto(['We']), verbo([found]), complemento([that, 'MyoD', and, 'Myogenin', expression, can, be, activated, by, ectopic, mouse, 'Myf5', or, 'MyoD,', while, 'Myf5', expression, cannot, be, activated, either, by, mouse, 'MyoD', or, by, itself])].
[sujeto(['We', also, analysed, the, transcriptional, regulation, between, the, myogenic, factors, and, the, different, genes]), verbo([involved]), complemento([in, 'myogenesis,', such, as, 'Mef2c,', 'Pax3,', 'Paraxis,', 'Six1,', 'Mox1,', 'Mox2', and, 'FgfR4'])].
[sujeto(['Here,', we, investigated, the, effect, of]), verbo([increased]), complemento(['NDRG2', levels, on, the, 'proliferation,', differentiation, and, apoptosis, in, skeletal, muscle, cells, under, basal, and, stress, conditions])].
[sujeto(['NDRG2', overexpression]), verbo([increased]), complemento(['C2C12', myoblast, proliferation, and, the, expression, of, positive, cell, cycle, 'regulators,', 'cdk2,', cyclin, 'B', and, cyclin, 'D,', and, phosphorylation, of, 'Rb,', while, the, 'serine/threonine-deficient', 'NDRG2,', 3, 'A-NDRG2,', had, less, effect])].
[sujeto(['The', onset, of, differentiation, was]), verbo([enhanced]), complemento([by, 'NDRG2', as, determined, through, the, myogenic, regulatory, factor, expression, profiles, and, myocyte, fusion, index])].
[sujeto(['While', 'NDRG2', 'up-regulated', caspase, 3, /, 7, activities, during, 'differentiation,', no]), verbo([increase]), complemento([in, apoptosis, was, measured, by, 'TUNEL', assay, or, through, cleavage, of, caspase, 3, and, 'PARP', proteins])].
[sujeto(['During', 'H2O2', treatment, to]), verbo([induce]), complemento([oxidative, 'stress,', 'NDRG2', helped, protect, against, the, loss, of, proliferation, and, 'ER', stress, as, measured, by, 'GRP78', expression, with, 3, 'A-NDRG2', displaying, less, protection])].
[sujeto(['NDRG2', also, attenuated, apoptosis, by, reducing, cleavage, of, 'PARP', and, caspase, 3, and, expression, of, 'pro-apoptotic', 'Bax', while]), verbo([enhancing]), complemento([the, 'pro-survival', 'Bcl-2', and, 'Bcl-xL', levels])].
[sujeto(['Our', findings, show, that, 'NDRG2', overexpression]), verbo([increases]), complemento([myoblast, proliferation, and, caspase, 3, /, 7, activities, without, increasing, overall, differentiation])].
[sujeto(['Glucocorticoids']), verbo([cause]), complemento([secondary, osteoporosis, and, 'myopathy,', characterized, by, type, 'II', muscle, fiber, atrophy])].
[sujeto(['We', examined, whether, a, new, vitamin, 'D3', 'analogue,', 'eldecalcitol,', could]), verbo([inhibit]), complemento(['glucocorticoid-induced', osteopenia, or, myopathy, in, 'rats,', and, also, determined, the, effects, of, prednisolone, '(', 'PSL)', 'and/or', eldecalcitol, on, 'muscle-related', gene, expression])].
[sujeto(['Eldecalcitol', treatment, for, 4, &, 'nbsp;weeks']), verbo([maintained]), complemento([the, same, 'BMD', as, the, 'PSL&nbsp;+&nbsp;E', group])].
[sujeto(['After', 2, &, 'nbsp;weeks,', but, not, 4, &, 'nbsp;weeks,', eldecalcitol, treatment, significantly]), verbo([increased]), complemento(['Pax7', and, myogenin, mRNA, expression, in, gastrocnemius, 'muscle,', and, 'PSL', also, stimulated, myogenin, expression])].
[sujeto(['Eldecalcitol', appears, to]), verbo([increase]), complemento([muscle, volume, and, to, protect, against, femur, 'BMD', loss, in, 'PSL-administered', 'rats,', and, it, may, also, stimulate, myoblast, differentiation, into, early, myotubes])].
[sujeto(['Corticosteroids']), verbo([cause]), complemento([muscle, atrophy, by, acting, on, proteasomal, and, lysosomal, systems, and, by, affecting, pathways, related, to, muscular, 'trophysm,', such, as, the, 'IGF-1/PI-3k/Akt/mTOR'])].
[sujeto(['Omega-3', fatty, acid, '(', 'n-3)']), verbo([has]), complemento([been, used, beneficially, to, attenuate, muscle, atrophy, linked, to, sepsis, and, 'cachexia;', 'however,', its, effect, on, 'dexamethasone-induced', muscle, atrophy, has, not, been, evaluated])].
[sujeto(['Dexamethasone']), verbo([induced]), complemento([a, significant, loss, in, body, and, muscle, 'weight,', atrophy, in, type, 2, 'B', 'fibers,', and, decreased, expression, of, 'P-Akt,', 'P-GSK3β,', and, 'P-FOXO3a'])].
[sujeto(['N-3', supplementation, did, not, attenuate, the, negative, effects, of, dexamethasone, on, skeletal, 'muscle;', 'instead,', it]), verbo([caused]), complemento([atrophy, in, type, 1, ',', 2, 'A,', reduced, the, expression, of, 'Myogenin,', and, increased, the, expression, of, 'Atrogin-1'])].
[sujeto(['Myostatin', '(', 'MSTN)', is, primarily]), verbo([expressed]), complemento([in, muscle, and, plays, an, important, role, in, muscle, and, fat, development, in, pigs])].
[sujeto(['In', order, to, elucidate, whether, pig, 'MSTN', could, be]), verbo([regulated]), complemento([by, 'muscle-', and, 'fat-related', 'factors,', the, porcine, 'MSTN', promoter, was, amplified, and, cloned, into, 'pGL3-basic', 'vector,', and, transfected, into, cells, to, analyze, the, transcriptional, activity, of, promoter, with, 'muscle-', and, 'fat-related', factors, through, 'dual-luciferase', reporter, assays])].
[sujeto(['We']), verbo([found]), complemento([that, 'MSTN', promoter, transcriptional, activity, can, be, regulated, by, 'IBMX,', but, not, by, 'DIM'])].
[sujeto(['CCAAT/enhancer']), verbo([binding]), complemento([protein, '(', 'C/EBP)', α, and, 'C/EBPβ,', two, proteins, which, are, induced, by, 'DIM', during, adipogenesis, were, cotransfected, with, the, 1.7, -, kb, 'fragment,', 'respectively,', resulting, in, promoter, transcriptional, activity, downregulation])].
[sujeto(['Treating', the, fragment, with, rosiglitazone, which]), verbo([induce]), complemento([the, expression, of, peroxisome, 'proliferator-activated', receptor, γ, '(', 'PPARγ),', resulting, in, promoter, transcriptional, activity, upregulation])].
[sujeto(['The', purpose, of, this, review, is, to, discuss, novel, insight, into, mechanisms, of, 'glucocorticoid-regulated', muscle, 'wasting,', in, particular, the, role, of, transcription, factors, and]), verbo([nuclear]), complemento([cofactors])].
[sujeto(['Studies']), verbo([suggest]), complemento([that, 'glucocorticoid-induced', upregulation, of, the, transcription, factors, 'Forkhead', box, 'O', 1, and, 'CCAAT/enhancer-binding', protein, beta, and, downregulation, of, 'MyoD', and, myogenin, are, involved, in, 'glucocorticoid-induced', muscle, wasting])].
[sujeto(['In', 'addition,', 'glucocorticoid-induced', hyperacetylation]), verbo([caused]), complemento([by, increased, expression, of, the, nuclear, cofactor, p300, and, its, histone, acetyl, transferase, activity, and, decreased, expression, and, activity, of, histone, deacetylases, plays, an, important, role, in, 'glucocorticoid-induced', muscle, proteolysis, and, wasting])].
[sujeto(['Other', mechanisms, may, also, be]), verbo([involved]), complemento([in, 'glucocorticoid-induced', muscle, 'wasting,', including, insulin, resistance, and, 'store-operated', calcium, entry])].
[sujeto(['Novel', potential, strategies, to]), verbo([prevent]), complemento([or, treat, 'glucocorticoid-induced', muscle, wasting, include, the, use, of, small, molecule, histone, deacetylase, 'activators,', dissociated, glucocorticoid, receptor, 'agonists,', and, 11, 'beta-hydroxysteroid', dehydrogenase, type, 1, inhibitors])].
[sujeto(['An']), verbo([increased]), complemento([understanding, of, molecular, mechanisms, regulating, 'glucocorticoid-induced', muscle, wasting, will, help, develop, new, strategies, to, prevent, and, treat, this, debilitating, condition])].
[sujeto(['Long-term', corticosteroid, therapy]), verbo([causes]), complemento([myopathy, and, can, inhibit, regeneration, of, skeletal, muscle])].
[sujeto(['Single', myofibers, were, isolated, from, the, 'gastrocnemius,', centrifuged, to, mechanically]), verbo([activate]), complemento([satellite, 'cells,', and, maintained, in, culture, for, 48, h])].
[sujeto(['Supplementation', of, culture, media, with, the, nitric, oxide, 'donor,', diethylenetriamine, 'NONOate', '(', 'DETA-NO;', 5, -, 50, 'microM),']), verbo([caused]), complemento([a, 'dose-dependent', increase, in, the, number, of, 'myoD+', cells, arising, from, both, control, and, 'GC', myofibers, '(', 'P', &, 'lt;', 0.05, ')', ',', and, 10, and, 50, microM, 'DETA-NO', eliminated, the, 'GC-induced', deficit, in, myogenic, cells, '(', 'P', &, 'gt;', 0.05, ')'])].
[sujeto(['Nitric', oxide, production, could, be, an, important, therapeutic]), verbo([target]), complemento([for, the, prevention, of, corticosteroid, myopathy])].
[sujeto(['Glucocorticoid-induced', 'gene-1', '(', 'Gig1)', was, identified, in, a, yeast, 'one-hybrid', screen, for, factors, that]), verbo([interact]), complemento([with, the, 'MyoD', core, enhancer])].
[sujeto(['The', 'Gig1', gene, encodes, a, novel, 'C2H2', zinc, finger, protein, that, shares, a, high, degree, of, sequence, similarity, with, two, known, 'DNA']), verbo([binding]), complemento([proteins, in, 'humans,', 'Glut4', enhancer, factor, and, papillomavirus, binding, factor, '(', 'PBF)'])].
[sujeto(['The', 'DNA']), verbo([binding]), complemento([domain, of, 'Gig1,', which, contains, 'TCF-E-tail', 'CR1', and, 'CR2', motifs, shown, to, mediate, promoter, specificity, of, 'TCF-E-tail', 'isoforms,', was, mapped, to, a, 'C-terminal', domain, that, is, highly, conserved, in, 'Glut4', enhancer, factor, and, 'PBF'])].
[sujeto(['Gig1', was, also]), verbo([expressed]), complemento([in, a, subset, of, 'Scleraxis-positive', tendon, 'precursors/rudiments', of, the, 'limbs,', but, not, in, the, earliest, tendon, precursors, of, the, somite, '(', 'syndetome)', defined, by, 'Scleraxis', expression])].
[sujeto(['Skeletal', muscle, homoeostasis, is]), verbo([maintained]), complemento([by, a, variety, of, cytoprotective, mechanisms])].
[sujeto(['Since', ablation, of, the, 'TauT', '(', taurine, 'transporter)', gene, results, in, susceptibility, to, 'exercise-induced', muscle, weakness, in, 'vivo,', it]), verbo([has]), complemento([been, suggested, that, 'TauT', is, essential, for, skeletal, muscle, function])].
[sujeto(['Treatment', with, bFGF, '(', basic, fibroblast, growth, 'factor),', which]), verbo([inhibited]), complemento([muscle, 'differentiation,', abrogated, myogenic, induction, of, 'TauT'])].
[sujeto(['Database', analyses, identified, an, 'MEF2', '(', myocyte, enhancer]), verbo([binding]), complemento([factor, 2, ')', consensus, sequence, at, -, 844, in, the, rat, 'TauT', gene])].
[sujeto(['Electrophoretic', 'mobility-shift', assays, confirmed, that, 'MEF2']), verbo([bound]), complemento([to, the, 'MEF2', consensus, sequence, and, that, 'DNA-protein', complex, levels, were, increased, during, differentiation])].
[sujeto(['Importantly,', transfection, with, a, 'MyoD', expression, vector, markedly]), verbo([enhanced]), complemento(['TauT', promoter, activity, in, the, '(', 'non-myogenic)', 10, 'T1/2', cells])].
[sujeto(['Moreover,', 'co-transfection', with, an, 'MEF2', expression, vector, augmented, 'MyoD-induced', 'TauT', promoter, 'activity,']), verbo([suggesting]), complemento([that, 'MEF2', is, required, for, full, activation, of, 'TauT', expression])].
[sujeto(['Finally,', we, examined, the, effects, of, taurine, on, myotube, atrophy, to, clarify, the, biological, significance, of, the, 'up-regulation', of, 'TauT,', and, demonstrated, that, taurine, attenuated, muscle, atrophy]), verbo([induced]), complemento([by, dexamethasone])].
[sujeto(['TauT', expression, is]), verbo([regulated]), complemento([under, the, control, of, the, myogenic, 'programme,', and, we, propose, that, this, is, the, mechanism, for, 'taurine-mediated', resistance, to, muscle, atrophy])].
[sujeto(['Glucocorticoids']), verbo([have]), complemento([also, been, characterized, as, muscle, atrophying, agents])].
[sujeto(['However,', glucocorticoids, are, also, the, only, drugs]), verbo([reported]), complemento([to, have, a, beneficial, effect, on, the, treatment, of, muscle, degenerative, disorders])].
[sujeto(['Since', muscle, mass, relates, to, 'gender,', this, may, be, partially]), verbo([caused]), complemento([by, gender])].
[sujeto(['Male', rats, treated, with, dexamethasone, for, 14, days, '(', 1, mg, per, kg, body, 'weight)', showed]), verbo([increased]), complemento([levels, of, 'MyoD1,', myogenin, and, 'myf-5', compared, to, control, male, rats])].
[sujeto(['Female', rats, treated, with, dexamethasone, showed]), verbo([decreased]), complemento([expression, of, 'myf-6', compared, to, control, female, rats])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, dexamethasone, increase, satellite, 'cell-specific', 'MRF', activity, in, male, muscle, 'tissue,', which, is, suggested, to, be, associated, with, muscle, 'hypertrophy,', while, maintenance, of, muscle, tissue, is, affected, in, female, muscle, tissue])].
[sujeto(['Therefore,', we, conclude, that, both, basal, and, 'dexamethasone-induced', 'MRF', gene, mRNA, levels, are]), verbo([regulated]), complemento(['gender-specific'])].
[sujeto(['The', manner, in, which, growth, factors]), verbo([acting]), complemento([at, the, cell, surface, regulate, activity, of, myogenic, 'basic-helix-loop-helix', proteins, in, the, nucleus, and, thus, control, the, fate, of, committed, skeletal, myoblasts, remains, poorly, understood])].
[sujeto(['In', this, 'study,', we]), verbo([report]), complemento([that, immunoreactive, 'Gs', protein, 'alpha-subunits', '(', 'Gs', 'alpha)', localize, to, nuclei, of, proliferating, 'C2C12', myoblasts, but, not, to, nuclei, of, differentiated, postmitotic, 'C2C12', myotubes])].
[sujeto(['Dexamethasone-induced', expression, of]), verbo([activated]), complemento(['Gs', alpha, markedly, delayed, differentiation, in, comparison, with, uninduced, stably, transfected, 'cells,', which, differentiated, normally, in, 'mitogen-depleted', media])].
[sujeto(['Northern', blot, analysis, showed, that, impaired, differentiation, was]), verbo([associated]), complemento([with, delayed, 'up-regulation', of, 'MyoD', and, myogenin, and, delayed, 'down-regulation', of, 'Id,', a, dominant, negative, inhibitor, of, differentiation])].
[sujeto(['Similar', impairment, of, differentiation, could, not, be, reproduced, in, 'wild-type', 'C2C12', cells, by]), verbo([increasing]), complemento([intracellular, cAMP, either, with, forskolin, or, treatment, with, a, 'cell-permeable', cAMP, analog])].
[sujeto(['However,', treatment, of, myoblasts, with, cholera, toxin, markedly]), verbo([inhibited]), complemento([myogenic, differentiation])].
[sujeto(['Taken', 'together,', these, findings]), verbo([suggest]), complemento([a, novel, role, for, 'Gs', alpha, in, modulating, myogenic, differentiation])].
[sujeto(['After', treating, proliferating, cells, with, 'dexamethasone,', bmyf, transcripts, were]), verbo([induced]), complemento([approximately, fivefold, within, 1.5, -, 2.5, h])].
[sujeto(['Induction', of, bmyf, was, followed, 4, h, later, by, a, similar]), verbo([increase]), complemento([in, myogenin, transcripts, which, was, dependent, on, protein, synthesis])].
[sujeto(['The', 4, -, h, lag, before, the, myogenin, response]), verbo([suggested]), complemento([involvement, of, an, intermediate, factor])].
[sujeto(['However,', one, possible, 'factor,', 'myocyte-specific', enhancer]), verbo([binding]), complemento([factor, '(', 'MEF-2)', '(', a, known, enhancer, of, myogenin, promoter, 'activity)', was, neither, detectable, nor, inducible, by, dexamethasone, in, proliferating, cells])].
[sujeto(['There', was, also, a, transient, twofold]), verbo([increase]), complemento([in, mrf4, transcripts, by, dexamethasone, treatment, in, dividing, 'cells,', while, no, changes, were, detected, in, the, levels, of, 'Id,', 'E12,', or, 'TnC', messages])].
[sujeto(['We', conclude, that, ectopic, expression, of, 'MMTV-bmyf']), verbo([led]), complemento([to, activation, of, three, of, the, endogenous, myogenic, factor, genes, of, which, only, myogenin, showed, a, rapid, and, sustained, response, to, 'dexamethasone-mediated', induction, of, bmyf, in, dividing, cells])].
[sujeto(['Tissue', engineered, skeletal, muscle]), verbo([has]), complemento([potential, for, application, as, a, graft, source, for, repairing, soft, tissue, 'injuries,', a, model, for, testing, 'pharmaceuticals,', and, a, biomechanical, actuator, system, for, soft, robots])].
[sujeto(['However,', engineered, muscle, to, date]), verbo([has]), complemento([not, produced, forces, comparable, to, native, 'muscle,', limiting, its, potential, for, repair, and, for, use, as, an, in, vitro, model, for, pharmaceutical, testing])].
[sujeto(['In', this, 'study,', we, examined, the, trophic, effects, of, dexamethasone, '(', 'DEX),', a, glucocorticoid, that]), verbo([stimulates]), complemento([myoblast, differentiation, and, fusion, into, 'myotubes,', on, our, tissue, engineered, 'three-dimensional', skeletal, muscle, units, '(', 'SMUs)'])].
[sujeto(['These', optimized, 'SMUs', exhibited, formation, of, advanced, sarcomeric, structure, and, significant]), verbo([increases]), complemento([in, myotube, diameter, and, myotube, fusion, 'index,', compared, with, untreated, controls])].
[sujeto(['In', 'conclusion,', we]), verbo([have]), complemento([demonstrated, that, the, addition, of, 'DEX', to, our, process, of, engineering, skeletal, muscle, tissue, improves, 'myogenesis,', advances, muscle, 'structure,', and, increases, force, production, in, the, resulting, 'SMUs'])].
[sujeto(['Androgens,', known, mediators, of, overall, body, composition, and, specifically, skeletal, muscle, 'mass,']), verbo([have]), complemento([been, shown, to, regulate, 'MSCs'])].
[sujeto(['The', possible, overlapping, function, of, androgen, regulation, of, muscle, growth, and, 'MSC', activation]), verbo([has]), complemento([not, been, carefully, investigated, with, regards, to, muscle, regeneration])].
[sujeto(['In', an, in, vivo, muscle, atrophy, 'model,', androgen, 're-supplementation', significantly]), verbo([increased]), complemento([muscle, size, and, expression, of, 'IGF-1,', 'FST,', and, 'HGF,', while, significantly, decreasing, expression, of, 'GR'])].
[sujeto(['Biphasic', gene, expression, profiles, over, the, 7, -, day, 're-supplementation', period, identified, temporal, androgen, regulation, of, molecular]), verbo([targets]), complemento([involved, in, satellite, cell, engagement, into, myogenesis])].
[sujeto(['Modifications', in, the, androgen, signaling, gene, 'signature,', along, with, reduced, 'Pax7', and, 'MyoD', 'expression,']), verbo([suggested]), complemento([that, limited, 'MSC', activation, and, increased, inflammation, contributed, to, the, delayed, regeneration])].
[sujeto(['However,']), verbo([enhanced]), complemento(['MSC', activation, in, the, 'androgen-deplete', mouse, injury, model, was, driven, by, an, androgen, receptor, '(', 'AR)', agonist])].
[sujeto(['These', results]), verbo([provide]), complemento([novel, in, vitro, and, in, vivo, evidence, describing, molecular, targets, of, androgen, 'signaling,', while, also, increasing, support, for, translational, use, of, 'AR', agonists, in, skeletal, muscle, recovery, and, regeneration])].
[sujeto(['Recent', studies]), verbo([have]), complemento([demonstrated, that, 'HMB', inhibits, 'dexamethasone-induced', atrophy, in, cultured, 'myotubes,', but, its, effect, on, 'dexamethasone-induced', muscle, atrophy, has, not, been, determined, in, vivo])].
[sujeto(['Treatment', with, dexamethasone, weakened, grip, strengths, and]), verbo([increased]), complemento([muscle, damage, as, determined, by, increased, serum, creatine, kinase, levels, and, by, histological, analysis])].
[sujeto(['However,', 'HMB', supplementation, significantly]), verbo([prevented]), complemento([reductions, in, grip, 'strengths,', reduced, muscle, 'damage,', and, prevented, muscle, mass, and, protein, concentration, decrease, in, soleus, muscle])].
[sujeto(['Biochemical', analysis, demonstrated, that, dexamethasone, markedly]), verbo([increased]), complemento([levels, of, 'MuRF1', 'protein,', which, causes, the, ubiquitination, and, degradation, of, 'MyHC'])].
[sujeto(['Indeed,', dexamethasone, treatment]), verbo([decreased]), complemento(['MyHC', protein, expression, and, increased, the, 'ubiquitinated-MyHC', to, 'MyHC', ratio])].
[sujeto(['However,', 'HMB', supplementation]), verbo([caused]), complemento([the, 'down-regulations', of, 'MuRF1', protein, and, of, 'ubiquitinated-MyHC'])].
[sujeto(['Furthermore,', additional, experiments]), verbo([provided]), complemento([evidence, that, 'HMB', supplementation, inhibited, the, nuclear, translocation, of, 'FOXO1', induced, by, 'dexamethasone,', and, showed, increased, 'MyoD', expression, in, the, nuclear, fractions, of, soleus, muscles])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'HMB', supplementation, attenuates, 'dexamethasone-induced', muscle, wasting, by, regulating, 'FOXO1', transcription, factor, and, subsequent, 'MuRF1', expression])].
[sujeto(['Accordingly,', our, results]), verbo([suggest]), complemento([that, 'HMB', supplementation, could, be, used, to, prevent, steroid, myopathy])].
[sujeto(['Glucocorticoids', production, is]), verbo([increased]), complemento([in, many, pathological, conditions, that, are, associated, with, muscle, 'loss,', but, their, role, in, causing, muscle, wasting, is, not, fully, understood])].
[sujeto(['We']), verbo([have]), complemento([demonstrated, a, new, mechanism, of, 'glucocorticoid-induced', muscle, 'atrophy:', 'Dexamethasone', '(', 'Dex)', suppresses, satellite, cell, function, contributing, to, the, development, of, muscle, atrophy])].
[sujeto(['Specifically,', we]), verbo([found]), complemento([that, 'Dex', decreases, satellite, cell, proliferation, and, differentiation, in, vitro, and, in, vivo])].
[sujeto(['The', mechanism]), verbo([involved]), complemento(['Dex-induced', upregulation, of, myostatin, and, suppression, of, 'Akirin1,', a, promyogenic, gene])].
[sujeto(['When', myostatin, was]), verbo([inhibited]), complemento([in, 'Dex-treated', 'mice,', 'Akirin1', expression, increased, as, did, satellite, cell, 'activity,', muscle, regeneration, and, muscle, growth])].
[sujeto(['In', 'addition,', silencing, myostatin, in, myoblasts, or, satellite, cells]), verbo([prevented]), complemento(['Dex', from, suppressing, 'Akirin1', expression, and, cellular, proliferation, and, differentiation])].
[sujeto(['Finally,', overexpression, of, 'Akirin1', in, myoblasts]), verbo([increased]), complemento([their, expression, of, 'MyoD', and, myogenin, and, improved, cellular, proliferation, and, 'differentiation,', theses, improvements, were, no, longer, suppressed, by, 'Dex'])].
[sujeto(['We', conclude, that, glucocorticoids]), verbo([stimulate]), complemento([myostatin, which, inhibits, 'Akirin1', expression, and, the, reparative, functions, of, satellite, cells])].
[sujeto(['Thus,', inhibition, of, myostatin, or]), verbo([increasing]), complemento(['Akirin1', expression, could, lead, to, therapeutic, strategies, for, improving, satellite, cell, activation, and, enhancing, muscle, growth, in, diseases, associated, with, increased, glucocorticoid, production])].
[sujeto(['Annexin', 'A1', '(', 'ANXA1,', 'lipocortin-1)', is, a, 'glucocorticoid-regulated', 37, -, kDa, 'protein,', so, called, since, its, main, property, is, to]), verbo([bind]), complemento(['(', i])].
[sujeto(['Although', 'ANXA1']), verbo([has]), complemento([predominantly, been, studied, in, the, context, of, immune, responses, and, 'cancer,', the, protein, can, affect, a, larger, variety, of, biological, 'phenomena,', including, cell, proliferation, and, migration])].
[sujeto(['Our', previous, results, show, that, endogenous, 'ANXA1', positively]), verbo([modulates]), complemento([myoblast, cell, differentiation, by, promoting, migration, of, satellite, cells, 'and,', 'consequently,', skeletal, muscle, differentiation])].
[sujeto(['In', this, 'work,', we]), verbo([have]), complemento([evaluated, the, hypothesis, that, 'ANXA1', is, able, to, exert, effects, on, myoblast, cell, migration, acting, through, formyl, peptide, receptors, '(', 'FPRs)', following, changes, in, its, subcellular, localization, as, in, other, cell, types, and, tissues])].
[sujeto(['The', analysis, of, the, subcellular, localization, of, 'ANXA1', in, 'C2C12', myoblasts, during, myogenic, differentiation, showed, an, interesting]), verbo([increase]), complemento([of, extracellular, 'ANXA1', starting, from, the, initial, phases, of, skeletal, muscle, cell, differentiation])].
[sujeto(['Wound', healing, assay, experiments, showed, that, 'Ac2-26', peptide, is, able, to]), verbo([increase]), complemento([migration, of, 'C2C12', skeletal, muscle, cells, and, to, induce, cell, surface, translocation, and, secretion, of, 'ANXA1'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([a, role, for, 'ANXA1', as, a, highly, versatile, component, in, the, signaling, chains, triggered, by, the, proper, calcium, perturbation, that, takes, place, during, active, migration, and, differentiation, or, membrane, repair, since, the, protein, is, strongly, redistributed, onto, the, plasma, membranes, after, an, rapid, increase, of, intracellular, levels, of, 'Ca(2+)'])].
[sujeto(['These', properties, indicate, that, 'ANXA1', may, be]), verbo([involved]), complemento([in, a, novel, repair, mechanism, for, skeletal, muscle, and, may, have, therapeutic, implications, with, respect, to, the, development, of, 'ANXA1', mimetics])].
[sujeto(['Glucocorticoids', '(', 'GCs)', are]), verbo([involved]), complemento([in, the, muscle, wasting, caused, by, 'trauma,', 'inactivity,', and, stress])].
[sujeto(['The', results, showed, that, 'BM']), verbo([gain]), complemento([was, significantly, suppressed, by, 'DEX', treatment])].
[sujeto(['The', plasma, level, of, insulin, was]), verbo([increased]), complemento(['(', 'P&lt;0'])].
[sujeto([5, ')', by, 'DEX', treatment, at, 'feeding,', whereas, 'IGF1', was]), verbo([decreased]), complemento(['(', 'P&lt;0'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'GCs', suppress, 'IGF1', and, upregulate, myostatin, 'and/or', activated, myostatin, and, the, 'UBP', 'pathway,', which, might, be, the, source, of, the, effect, of, 'GCs', on, muscle, development])].
[sujeto(['We', investigated, the, expression, of, hepatocyte, growth, factor, '(', 'HGF),', which]), verbo([has]), complemento([mitogenic, and, 'anti-fibrotic', 'activities,', in, muscle, tissue, of, 'polymyositis/dermatomyositis', '(', 'PM/DM)', 'patients,', as, well, as, its, functional, roles, in, cultured, myoblasts])].
[sujeto(['Immunohistochemistry', in, muscle, from, 'PM/DM', patients, revealed, that, 'HGF', was]), verbo([expressed]), complemento([predominantly, on, infiltrating, mononuclear, cells, and, that, muscle, cells, expressed, the, receptor, 'c-met'])].
[sujeto(['Cultured', myoblasts, produced, 'HGF;', which, was]), verbo([increased]), complemento([by, 'IL-1alpha', but, suppressed, by, 'TGF-beta', and, dexamethasone])].
[sujeto(['Exogenous', 'HGF']), verbo([induced]), complemento([myoblast, proliferation, and, reduced, procollagen, type, 'I', production])].
[sujeto(['Furthermore,', 'HGF']), verbo([enhanced]), complemento([the, gene, expression, of, muscle, regulatory, factors, 'MyoD', and, 'Myf5,', while, suppressing, expression, of, 'fibrosis-related', 'genes,', connective, tissue, growth, factor, and, 'alpha-smooth', muscle, actin])].
[sujeto(['Various', signals, and, factors]), verbo([modulate]), complemento([this, 'process,', and, glucocorticoids, '(', 'GCs)', are, important, regulators, of, skeletal, muscle, metabolism])].
[sujeto(['We', show, that, 'glucocorticoid-induced', leucine, zipper, '(', 'GILZ),', a, 'GC-induced', 'gene,', and, the, newly, identified, isoform, long, 'GILZ', '(', 'L-GILZ)', are]), verbo([expressed]), complemento([in, skeletal, muscle, tissue, and, in, 'C2C12', myoblasts, where, 'GILZ/L-GILZ', maximum, expression, occurs, during, the, first, few, days, in, differentiation, medium])].
[sujeto(['Moreover,', we, observed, that, 'GC', treatment, of, 'myoblasts,', which]), verbo([increased]), complemento(['GILZ/L-GILZ', 'expression,', resulted, in, reduced, myotube, 'formation,', whereas, 'GILZ', and, 'L-GILZ', silencing, dampened, 'GC', effects])].
[sujeto(['Inhibition', of, differentiation]), verbo([caused]), complemento([by, 'GILZ/L-GILZ', overexpression, correlated, with, inhibition, of, 'MyoD', function, and, reduced, expression, of, myogenin])].
[sujeto(['Notably,', results, indicate, that, 'GILZ', and, 'L-GILZ']), verbo([bind]), complemento([and, regulate, 'MyoD/HDAC1', transcriptional, 'activity,', thus, mediating, the, 'anti-myogenic', effect, of, 'GCs'])].
[sujeto(['Atrophy', may, be, the, result, of]), verbo([increased]), complemento([catabolic, 'factors,', e])].
[sujeto(['Restraint', resulted, in, a, significant]), verbo([increase]), complemento([in, myostatin, which, was, significantly, reduced, with, 'Sutherlandia', treatment])].
[sujeto(['Restraint', also, resulted, in, a, significant, attenuation, of, the, 'PI3-Kinase/Akt', signaling, pathway, and]), verbo([increased]), complemento([apoptosis, which, was, reversed, with, 'Sutherlandia', treatment])].
[sujeto(['This', study, demonstrates, for, the, first, time, that, psychological, stress, elevates, markers, of, muscle, atrophy, and, 'apoptosis,', whilst, a, herbal, 'remedy,', 'Sutherlandia,']), verbo([inhibits]), complemento(['apoptosis,', and, signaling, pathways, associated, with, muscle, atrophy])].
[sujeto(['Myogenin', is, known, to, be, polyubiquitinated, by, 'SCF', '(', 'Skp1/Cullin', 1, /, 'F-box', 'protein)', followed, by, proteasomal, 'degradation,', though, the]), verbo([participating]), complemento(['F-box', protein, is, remaining, unidentified])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, myogenin, in, differentiated, myoblasts, is, destabilized, by, muscle, 'atrophy-inducing', dexamethasone, and, that, 'MAFbx', '(', muscle, atrophy, 'F-box', 'protein)', is, increased, in, atrophying, myotubes])].
[sujeto(['Myogenin', had, a, 'MAFbx-recognition', motif, and]), verbo([interacted]), complemento([with, 'MAFbx'])].
[sujeto(['MAFbx']), verbo([activated]), complemento([polyubiquitination, of, myogenin])].
[sujeto(['The', results, of, this, study]), verbo([suggest]), complemento([that, 'MAFbx', functions, as, an, 'F-box', protein, for, ubiquitination, of, myogenin])].
[sujeto(['Mechanical', ventilation, is, known, to]), verbo([induce]), complemento(['ventilator-induced', diaphragm, dysfunction])].
[sujeto(['Patients', submitted, to, mechanical, ventilation, often, receive, massive, doses, of, corticosteroids, that, may]), verbo([cause]), complemento([further, deterioration, of, diaphragm, function])].
[sujeto(['The', diaphragm, 'force-frequency', curve, was, shifted, downward, in, the, mechanical, ventilation, 'group,', but, this, deleterious, effect, was]), verbo([prevented]), complemento([when, corticosteroids, were, administered])].
[sujeto(['Diaphragm', 'cross-sectional', area, of, type, 'I', fibers, was, similarly]), verbo([decreased]), complemento([in, both, mechanical, ventilation, groups, while, atrophy, of, type, 'IIx/b', fibers, was, attenuated, after, corticosteroid, administration])].
[sujeto(['Plasma', cytokine, levels, were, unchanged, while, diaphragm, lipid, hydroperoxides, were, similarly]), verbo([increased]), complemento([in, both, mechanical, ventilation, groups])].
[sujeto(['Diaphragmatic', calpain, activity, was, significantly]), verbo([increased]), complemento([in, the, mechanical, ventilation, 'group,', but, calpain, activation, was, abated, with, corticosteroid, administration])].
[sujeto(['Inverse', correlations, were]), verbo([found]), complemento([between, calpain, activity, and, diaphragm, force])].
[sujeto(['Inhibition', of, the, calpain, system, is, most, likely, the, mechanism, by, which, corticosteroids]), verbo([induce]), complemento([this, protective, effect])].
[sujeto(['Accelerated', protein, degradation, via, the, 'ubiquitin-proteasome', pathway, is, the, principal]), verbo([cause]), complemento([of, skeletal, muscle, wasting, associated, with, common, human, disease, states, and, pharmacological, treatment, with, glucocorticoids])].
[sujeto(['Although', many, protein, regulatory, factors, essential, for, muscle, development, and, regeneration, are, degraded, via, the, ubiquitin, 'system,', little, is, known, about, the, mechanisms, and, regulation, of, this, pathway, that]), verbo([promote]), complemento([wasting, muscle])].
[sujeto(['Here,', we, demonstrate, 'that,', in, differentiated, 'myotubes,', 'glucocorticoid,', via, the, glucocorticoid, 'receptor,', selectively]), verbo([induces]), complemento([a, decrease, in, protein, abundance, of, 'MyoD,', a, master, switch, for, muscle, development, and, 'regeneration,', but, not, that, of, its, negative, regulator, 'Id1'])].
[sujeto(['This']), verbo([decrease]), complemento([in, 'MyoD', protein, results, from, accelerated, degradation, after, glucocorticoid, exposure])].
[sujeto(['Using', 'MyoD', and, 'Id1', mutants, deficient, in, either, 'N', 'terminus-dependent', or, internal, 'lysine-dependent', 'ubiquitination,', we, further, show, that, these, ubiquitination, pathways, of, 'MyoD', degradation, are]), verbo([regulated]), complemento([differently, from, those, of, 'Id1', degradation])].
[sujeto(['Specifically,', glucocorticoid]), verbo([activates]), complemento([the, 'N-terminal', ubiquitination, pathway, in, 'MyoD', degradation, in, 'myotubes,', without, concomitant, effects, on, 'Id1', degradation])].
[sujeto(['This', effect, of, glucocorticoid, on, 'MyoD', and, 'Id1', protein, degradation, is]), verbo([associated]), complemento([with, the, distinct, cellular, compartments, in, which, their, degradation, occurs])].
[sujeto(['UCP3', '(', uncoupling, 'protein-3)', is, a, mitochondrial, membrane, transporter]), verbo([expressed]), complemento([preferentially, in, skeletal, muscle])].
[sujeto(['Glucocorticoids']), verbo([activate]), complemento([the, transcription, of, the, ucp3, gene, through, a, glucocorticoid, 'receptor-binding', site, in, the, promoter, region])].
[sujeto(['Glucocorticoids', are, capable, of]), verbo([inducing]), complemento([ucp3, gene, transcription, independently, from, the, myogenic, regulatory, factor, 'MyoD,', in, contrast, with, the, transcriptional, activation, of, the, ucp3, gene, through, other, nuclear, hormone, receptors])].
[sujeto(['An', interplay, of, regulatory, factors]), verbo([modulates]), complemento([positively, '(', 'p300)', or, negatively, '(', histone, 'deacetylases)', the, action, of, glucocorticoids, on, ucp3, gene, transcription, via, histone, acetylation, or, deacetylation, 'processes,', respectively])].
[sujeto(['Among', 'them,', 'SIRT1']), verbo([acts]), complemento([as, a, major, repressor, of, ucp3, gene, expression, in, response, to, glucocorticoids])].
[sujeto(['The', action, of, 'SIRT1']), verbo([requires]), complemento([its, deacetylase, activity, and, results, in, histone, deacetylation, in, the, ucp3, promoter])].
[sujeto(['Moreover,', it]), verbo([involves]), complemento([a, specific, impairment, of, association, of, p300, with, the, glucocorticoid, receptor])].
[sujeto(['Agents']), verbo([activating]), complemento(['SIRT1,', such, as, 'resveratrol,', repress, ucp3, gene, expression])].
[sujeto(['Despite', a, demonstrated, role, for, 'TNF-α', in]), verbo([promoting]), complemento([muscle, wasting, and, 'cachexia,', the, associated, molecular, mechanisms, and, signaling, pathways, of, myoblast, differentiation, dysregulated, by, 'TNF-α', remain, poorly, understood])].
[sujeto(['Primary', human, muscle, precursor, cells, '(', 'MPCs)', cultured, in, growth, medium, '(', 'GM),', differentiation, medium, '(', 'DM)', to]), verbo([induce]), complemento([myogenic, 'differentiation,', and, 'DM', with, 20, 'ng/mL', of, 'TNF-α', '(', n, =, 5, /, 'group)', were, comparatively, analyzed, by, an, ion, 'current-based', quantitative, platform, consisting, of, reproducible, sample, 'preparation/on-pellet', 'digestion,', a, 'long-column', 'nano-LC', 'separation,', and, ion, 'current-based', differential, analysis])].
[sujeto(['Functional', analysis, and, validation, by, immunoassay, analysis]), verbo([suggested]), complemento([that, the, cooperation, of, 'NF-κB', and, 'STAT', proteins, is, responsible, for, dysregulated, differentiation, in, 'MPCs', by, 'TNF-α', treatment])].
[sujeto(['Interestingly,', inhibition, of, the, cholesterol, biosynthesis, pathway, during, myogenic, differentiation]), verbo([induced]), complemento([by, serum, starvation, was, not, recovered, by, 'TNF-α', 'treatment,', which, combined, with, previous, 'reports,', implies, that, this, process, may, be, an, early, event, of, myogenesis])].
[sujeto(['This']), verbo([finding]), complemento([could, lay, the, foundation, for, the, potential, use, of, statins, in, modulating, myogenesis, through, 'cholesterol,', for, 'example,', in, stem, 'cell-based', myocardial, infarction, 'treatment,', where, differentiation, of, myoblasts, and, stem, cells, into, 'force-generating', mature, muscle, cells, is, a, key, step, to, the, therapeutic, capacity])].
[sujeto(['Recently,', we, showed, that, cholesterol, depletion, by, 'methyl-β-cyclodextrin', '(', 'MCD)']), verbo([enhances]), complemento([the, differentiation, step, in, 'chick-cultured', myogenic, 'cells,', involving, the, activation, of, the, 'Wnt/β-catenin', signaling, pathway])].
[sujeto(['However,', the, effects, of, cholesterol, depletion, on, myoblast, replication]), verbo([have]), complemento([not, been, carefully, studied])].
[sujeto(['Here', we, show, that, 'MCD', treatment]), verbo([increases]), complemento([cell, proliferation, in, primary, chick, myogenic, cell, cultures])].
[sujeto(['Cholesterol', depletion]), verbo([induced]), complemento([an, increase, in, the, number, of, 'desmin-positive', mononucleated, 'cells,', and, an, increase, in, desmin, expression])].
[sujeto(['MCD']), verbo([induces]), complemento([an, increase, in, the, expression, of, the, cell, cycle, regulator, p53, and, the, master, switch, gene, 'MyoD1'])].
[sujeto(['Treatment', with, 'BIO,', a, specific, inhibitor, of, 'GSK3β,']), verbo([induced]), complemento([effects, similar, to, 'MCD', on, cell, 'proliferation;', while, treatment, with, 'Dkk1,', a, specific, inhibitor, of, the, 'Wnt/β-catenin', 'pathway,', neutralized, the, effects, of, 'MCD'])].
[sujeto(['These', findings, indicate, that, rapid, changes, in, the, cholesterol, content, in, cell, membranes, of, myoblasts, can]), verbo([induce]), complemento([cell, 'proliferation,', possibly, by, the, activation, of, the, 'Wnt/β-catenin', signaling, pathway])].
[sujeto(['Positive', feedback, is, a, common, mechanism, enabling, biological, systems, to]), verbo([respond]), complemento([to, stimuli, in, a, 'switch-like', manner])].
[sujeto(['To', understand, why, this, motif, is, so, 'prevalent,', we, examined, its, properties, in, an, evolutionarily]), verbo([conserved]), complemento([transcriptional, regulatory, network, in, yeast, '(', 'Oaf1p/Pip2p)'])].
[sujeto(['We', demonstrate, that, the, asymmetry, in, positive, feedback]), verbo([confers]), complemento([a, competitive, advantage, and, allows, the, system, to, robustly, increase, its, responsiveness, while, precisely, tuning, the, response, to, a, consistent, level, in, the, presence, of, varying, stimuli])].
[sujeto(['This', study]), verbo([reveals]), complemento([evolutionary, advantages, for, the, 'ASSURE', 'motif,', and, mechanisms, for, 'control,', that, are, relevant, to, pharmacologic, intervention, and, synthetic, biology, applications])].
[sujeto(['Classic', studies, of, limb, 'ischemia-reperfusion', injury]), verbo([have]), complemento([been, performed, using, young, healthy, mice])].
[sujeto(['Mice', with, genetic, deletion, of, apolipoprotein, 'E', '(', 'ApoE(-/-))']), verbo([have]), complemento([been, used, as, a, model, in, various, experimental, scenarios, of, hypercholesterolemia])].
[sujeto(['This', lag, in, muscle, regeneration, was]), verbo([associated]), complemento([with, lower, levels, of, myogenin, at, 7, 'DR', and, an, increased, level, of, 'MCP-1', at, 14, 'DR', in, the, 'ApoE(-/-)', mice])].
[sujeto(['The', delay, in, skeletal, muscle, healing, in, the, 'ApoE(-/-)', mice, may]), verbo([have]), complemento([broader, implications, for, poor, tissue, healing, and, functional, recovery, in, elderly, patients, who, have, vascular, risk, factors, such, as, hypercholesterolemia])].
[sujeto(['Previous', studies, of, 'Delta', 4, -, 'androstene-3,17-dione', '(', 4, -, 'androstenedione)', administration, in, men]), verbo([have]), complemento([not, demonstrated, sustained, increments, in, testosterone, 'levels,', 'fat-free', mass, '(', 'FFM),', and, muscle, 'strength,', and, failure, to, demonstrate, 'androstenedione\'s', 'androgenic/anabolic', effects, has, stifled, efforts, to, regulate, its, sales])].
[sujeto(['To', determine, whether, 4, -, androstenedione]), verbo([has]), complemento(['androgenic/anabolic', 'properties,', we, evaluated, its, association, with, androgen, receptor, '(', 'AR)', and, its, effects, on, myogenesis, in, vitro])].
[sujeto(['AR']), verbo([nuclear]), complemento([translocation, and, myogenic, activity, of, androstenedione, were, evaluated, in, 'mesenchymal,', pluripotent, 'C3H10T1/2', 'cells,', in, which, androgens, stimulate, myogenesis, through, an, 'AR', pathway])].
[sujeto(['In', 'C3H10T1/2', 'cells,', 4, -, androstenedione]), verbo([caused]), complemento([nuclear, translocation, of, 'AR', and, stimulated, 'myogenesis,', as, indicated, by, a, 'dose-dependent', increase, in, myosin, heavy, chain, 'II+', myotube, area, and, 'up-regulation', of, 'MyoD', protein])].
[sujeto(['Administration', of, 1500, mg, 4, -, androstenedione, daily, to, hypogonadal, men, significantly]), verbo([increased]), complemento([serum, 'androstenedione,', total, and, free, 'testosterone,', 'estradiol,', and, estrone, levels, and, suppressed, 'SHBG', and, 'high-density', lipoprotein, cholesterol, levels])].
[sujeto([4, -, androstenedione, administration, was]), verbo([associated]), complemento([with, significant, gains, in, 'FFM', '(', +, 1.7, +, /, -, 0.5, 'kg;', 'P', =, 0.012, ')', and, muscle, strength, in, bench, press, '(', +, 4.3, +, /, -, 3.1, 'kg;', 'P', =, 0.006, ')', and, leg, press, exercises, '(', +, 18.8, +, /, -, 17.3, 'kg;', 'P', =, 0.045, ')'])].
[sujeto([4, -, androstenedione, is, an, androgen, that]), verbo([binds]), complemento(['AR,', induces, 'AR', nuclear, 'translocation,', and, promotes, myogenesis, in, 'vitro,', with, substantially, lower, potency, than, dihydrotestosterone])].
[sujeto([4, -, androstenedione, administration, in, high, doses, to, hypogonadal, men]), verbo([increases]), complemento([testosterone, 'levels,', 'FFM,', and, muscle, 'strength,', although, at, the, dose, 'tested,', the, anabolic, effects, in, hypogonadal, men, are, likely, because, of, its, conversion, to, testosterone])].
[sujeto(['Viral', oncoproteins, that, inactivate, the, retinoblastoma, tumor, suppressor, protein, '(', 'pRb)', family, both, block, skeletal, muscle, differentiation, and]), verbo([promote]), complemento([cell, cycle, progression])].
[sujeto(['To', clarify, the, dependence, of, terminal, differentiation, on, the, presence, of, the, different, 'pRb-related', 'proteins,', we]), verbo([have]), complemento([studied, myogenesis, using, isogenic, primary, fibroblasts, derived, from, mouse, embryos, individually, deficient, for, 'pRb,', 'p107,', or, p130])].
[sujeto(['When', ectopically]), verbo([expressed]), complemento([in, fibroblasts, lacking, 'pRb,', 'MyoD', induces, an, aberrant, skeletal, muscle, differentiation, program, characterized, by, normal, expression, of, early, differentiation, markers, such, as, myogenin, and, 'p21,', but, attenuated, expression, of, late, differentiation, markers, such, as, myosin, heavy, chain, '(', 'MHC)'])].
[sujeto(['Similar', defects, in, 'MHC', expression, were, not, observed, in, cells, lacking, either, p107, or, 'p130,', indicating, that, the, defect, is, specific, to, the]), verbo([loss]), complemento([of, pRb])].
[sujeto(['In', contrast, to, 'wild-type,', 'p107-deficient,', or, 'p130-deficient', differentiated, myocytes, that, are, permanently, withdrawn, from, the, cell, 'cycle,', differentiated, myocytes, lacking, pRb, accumulate, in, 'S', and, 'G2', phases, and]), verbo([express]), complemento([extremely, high, levels, of, cyclins, 'A', and, 'B,', 'cyclin-dependent', kinase, '(', 'Cdk2),', and, 'Cdc2,', but, fail, to, readily, proceed, to, mitosis])].
[sujeto(['Administration', of, 'caffeine,', an, agent, that, removes, inhibitory, phosphorylations, on, inactive, 'Cdc2/cyclin', 'B', 'complexes,', specifically]), verbo([induced]), complemento([mitotic, catastrophe, in, 'pRb-deficient', 'myocytes,', consistent, with, the, observation, that, the, majority, of, 'pRb-deficient', myocytes, arrest, in, 'S', and, 'G2'])].
[sujeto(['Together,', these, findings, indicate, that, pRb, is]), verbo([required]), complemento([for, the, expression, of, late, skeletal, muscle, differentiation, markers, and, for, the, inhibition, of, 'DNA', 'synthesis,', but, that, a, 'pRb-independent', mechanism, restricts, entry, of, differentiated, myocytes, into, mitosis])].
[sujeto(['PCAF', is, a, histone, acetyltransferase, that]), verbo([associates]), complemento([with, 'p300/CBP', and, competes, with, 'E1A', for, access, to, them])].
[sujeto(['While', exogenous, expression, of, 'PCAF', potentiates, both, 'MyoD-directed', transcription, and, myogenic, 'differentiation,', 'PCAF', inactivation, by, 'anti-PCAF', antibody, microinjection]), verbo([prevents]), complemento([differentiation])].
[sujeto(['MyoD']), verbo([interacts]), complemento([directly, with, both, 'p300/CBP', and, 'PCAF,', forming, a, multimeric, protein, complex, on, the, promoter, elements])].
[sujeto(['Exogenous', expression, of, 'PCAF', or, p300]), verbo([promotes]), complemento([p21, expression, and, terminal, 'cell-cycle', arrest])].
[sujeto(['PPARalpha', is, a]), verbo([nuclear]), complemento([receptor, important, for, lipid, and, glucose, metabolism])].
[sujeto(['It']), verbo([has]), complemento([been, suggested, that, in, brown, adipose, 'tissue,', 'PPARalpha', represses, the, expression, of, 'muscle-associated', 'genes,', in, this, way, potentially, acting, to, determine, cell, fate, in, brown, adipocytes])].
[sujeto(['Thus,', it, would, not, seem, that, 'PPARalpha']), verbo([represses]), complemento(['muscle-associated', 'genes,', but, 'PPARalpha', may, still, play, a, role, in, the, regulation, of, the, bifurcation, of, the, adipomyocyte, precursor, into, a, brown, adipocyte, or, myocyte, phenotype])].
[sujeto(['The', present, study]), verbo([has]), complemento([been, aimed, at, evaluating, comparatively, the, involvement, of, oxidative, stress, in, the, pathogenesis, of, skeletal, muscle, wasting, in, two, different, experimental, 'models:', rats, rendered, hyperglycemic, by, treatment, with, streptozotocin, and, rats, bearing, the, 'Yoshida', 'AH-130', ascites, hepatoma])].
[sujeto(['For', this, 'purpose,', both, tumor, bearers, and, diabetic, animals]), verbo([have]), complemento([been, treated, with, dehydroepiandrosterone, '(', 'DHEA),', a, multifunctional, steroid, endowed, with, multitargeted, antioxidant, properties])].
[sujeto(['The', 'hypercatabolism,', evaluated, in, terms, of, proteasome, activity, and, expression, of, 'atrogin-1', and, 'MuRF1,', is]), verbo([activated]), complemento([in, 'AH-130', 'rats,', whereas, it, is, lacking, in, 'streptozotocin-treated', rats])].
[sujeto(['Moreover,', we, demonstrate, that, the, role, of, oxidative, stress, can, interfere, with, muscle, wasting, through, different, 'mechanisms,', not, necessarily]), verbo([involving]), complemento(['NF-kappaB', activation])].
[sujeto(['SREBP-1', are, ubiquitously]), verbo([expressed]), complemento([transcription, 'factors,', strongly, expressed, in, lipogenic, tissues, where, they, regulate, several, metabolic, processes, like, fatty, acid, synthesis])].
[sujeto(['In', skeletal, 'muscle,', 'SREBP-1', proteins]), verbo([regulate]), complemento([the, expression, of, hundreds, of, 'genes,', and, we, previously, showed, that, their, overexpression, induced, muscle, atrophy, together, with, a, combined, lack, of, expression, of, myogenic, regulatory, factors])].
[sujeto(['Here', we, present, evidences, that, 'SREBP-1']), verbo([regulate]), complemento([muscle, protein, synthesis, through, the, downregulation, of, the, expression, of, 'MYOD1,', 'MYOG', and, 'MEF2C', factors])].
[sujeto(['In', myotubes, overexpressing, 'SREBP-1,', restoring, the, expression, of, myogenic, factors]), verbo([prevented]), complemento([atrophy, and, rescued, protein, 'synthesis,', without, affecting, 'SREBP-1', action, on, atrogenes, and, proteolysis])].
[sujeto(['Our', results, point, out, the, roles, of, 'MRFs', in, the, maintenance, of, the, protein, content, and, cell, size, in, adult, muscle, 'fibre,', and, contribute, to, decipher, the, mechanisms, by, which, 'SREBP-1']), verbo([regulate]), complemento([muscle, mass])].
[sujeto(['Interleukin-11', '(', 'IL-11)', is, a, pleiotropic, cytokine, that, supports, various, types, of, hematopoietic, cell, growth, and, is]), verbo([involved]), complemento([in, bone, resorption])].
[sujeto(['We']), verbo([report]), complemento([here, the, involvement, of, recombinant, human, 'IL-11', '(', 'rHuIL-11)', in, osteoblast, differentiation, in, mouse, mesenchymal, progenitor, 'cells,', 'C3H10T1/2'])].
[sujeto(['rHuIL-11', alone]), verbo([increased]), complemento([alkaline, phosphatase, '(', 'ALP)', activity, and, upregulated, expression, levels, of, osteocalcin, '(', 'OC),', bone, sialo, protein, '(', 'BSP),', and, parathyroid, hormone, receptor, '(', 'PTHR)', mRNA])].
[sujeto(['Recombinant', human, bone, morphogenetic, protein, '(', 'rHuBMP)-2']), verbo([increased]), complemento(['ALP', activity, and, mRNA, expression, of, these, genes, except, for, 'MyoD'])].
[sujeto(['The', expression, patterns, of, 'ALP', activity, and, 'osteoblast-specific', or, 'chondrocyte-specific', genes]), verbo([suggest]), complemento([that, 'rHuIL-11', may, be, involved, in, early, differentiation, of, osteoblasts, at, a, step, earlier, than, that, which, is, affected, by, 'rHuBMP-2'])].
[sujeto(['In', support, of, this, 'hypothesis,', combined, treatment, with, 'rHuIL-11', and, 'rHuBMP-2', synergistically]), verbo([increased]), complemento(['ALP', activity, and, mRNA, expression, of, 'OC', and, type, 'II', 'collagen,', 'rHuIL-11', also, abrogated, the, increased, levels, of, 'PPAR-gamma2,', aP2, mRNA, caused, by, 'rHuBMP-2'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'rHuIL-11', alone, and, in, combination, with, 'rHuBMP-2', can, induce, osteoblastic, differentiation, of, progenitor, cells, and, plays, an, important, role, in, osteogenesis])].
[sujeto(['Coumaric', acid, '(', 'CA)', is, a, phenolic, acid, of, the, hydroxycinnamic, acid, 'family,', and, it]), verbo([has]), complemento([many, biological, functions, such, as, 'anti-oxidant,', 'anti-inflammatory,', 'antidiabetic,', 'anti-ulcer,', 'anti-platelet,', 'anti-cancer', 'activities,', etc])].
[sujeto(['It', revealed, that, 'CA', treatment]), verbo([inhibited]), complemento([horse, 'serum-induced', skeletal, muscle, differentiation, as, evidenced, by, the, decreased, expression, of, early, myogenic, differentiation, markers, such, as, 'Myogenin', and, myoD, via, the, 'AMP', activated, protein, 'kinase-', alpha, 'AMPK-α', mediated, pathway])].
[sujeto(['Furthermore,', the, level, of, lipid, accumulation, and, changes, in, genes, and, protein, expressions, that, are]), verbo([associated]), complemento([with, lipogenesis, and, lipolysis, were, analyzed, in, 3, 'T3-L1', cells])].
[sujeto(['The', 'Oil', 'Red', 'O', staining, evidenced, that, 'CA', treatment]), verbo([inhibited]), complemento([lipid, accumulation, at, the, concentration, of, 0.1, and, 0.2, mM])].
[sujeto(['Furthermore,', coumaric, acid, treatment]), verbo([decreased]), complemento([the, expression, of, main, transcriptional, factors, such, as, 'CCAAT/enhancer', binding, 'protein-alpha', '(', 'C/EBP-α)', and, peroxisome, 'proliferator-activated', receptor, 'gamma-2', '(', 'PPAR-γ2)'])].
[sujeto(['Subsequently,', 'CA', treatment]), verbo([decreased]), complemento([the, expression, of, sterol, regulatory, element, binding, 'protein-1', '(', 'SREBP-1),', fatty, acid, synthase, '(', 'FAS),', acetyl, 'CoA', carboxylase, '(', 'ACC)', and, adiponectin])].
[sujeto(['Finally,', we, identified, conformational, changes]), verbo([induced]), complemento([by, 'CA', in, 'PPAR-γ2', using, computational, biology, tools])].
[sujeto(['It', revealed, that, 'CA', might, downregulate, the, 'PPAR-γ2', expression, by, directly]), verbo([binding]), complemento([with, amino, acids, of, 'PPAR-γ2', by, hydrogen, at, 3.26, distance, and, hydrophobic, interactions, at, 3.9, contact, distances])].
[sujeto(['These', data, indicated, that, 'CA']), verbo([suppressed]), complemento([skeletal, muscle, and, preadipocytes, differentiation, through, downregulation, of, the, main, transcriptional, factors, and, their, downstream, targets])].
[sujeto(['Both', cell, types, attached, and, were]), verbo([found]), complemento([evenly, distributed, within, the, material])].
[sujeto([1, ')', were]), verbo([increased]), complemento([compared, with, the, control, 'C2C12', cells])].
[sujeto(['Only', one, donor, showed, an]), verbo([increase]), complemento([in, the, osteogenic, markers, osteocalcin, '(', 'p=0'])].
[sujeto([1, ')', was]), verbo([found]), complemento([in, 'C2C12', cells])].
[sujeto([4, ')', ',', fatty, acid]), verbo([binding]), complemento([protein, 4, '(', 'FABP4)', '(', 'p=0'])].
[sujeto(['In', 'conclusion,', the, thermoresponsive, scaffold, was]), verbo([found]), complemento([suitable, for, 3, 'D', in, vitro, differentiation, toward, soft, tissue])].
[sujeto(['Ucp3', is, an, integral, protein, of, the, inner, mitochondrial, membrane, with, a, role, in, lipid, metabolism]), verbo([preventing]), complemento([deleterious, effects, of, fatty, acids, in, states, of, high, lipid, oxidation])].
[sujeto(['Ucp3', is]), verbo([expressed]), complemento([in, brown, adipose, tissue, and, skeletal, muscle, and, controlled, by, a, transcription, factor, complex, including, 'PPARalpha,', 'MyoD', and, the, histone, acetyltransferase, p300])].
[sujeto(['Several', studies]), verbo([have]), complemento([demonstrated, interaction, of, these, factors, with, chicken, ovalbumin, upstream, promoter, transcription, factor, 'II', '(', 'Coup-TFII)'])].
[sujeto(['This']), verbo([nuclear]), complemento([receptor, is, involved, in, organogenesis, and, other, developmental, processes, including, skeletal, muscle, 'development,', but, also, 'co-regulates', a, number, of, metabolic, genes])].
[sujeto(['In', reporter, gene, assays, 'Coup-TFII']), verbo([enhanced]), complemento([transactivation, of, the, 'Ucp3', promoter, conveyed, by, 'MyoD,', 'PPARalpha,', 'RXRalpha', 'and/or', p300])].
[sujeto(['Given', the, substantial, evidence, for, a, function, of, 'Ucp3', in, lipid, 'metabolism,', 'Coup-TFII', may, not, only, be, a, negative, regulator, of, glucose, responsive, genes, but, also, transactivate, genes]), verbo([involved]), complemento([in, lipid, metabolism])].
[sujeto(['Coping', with, reduced, energy, sources, entails, drastic, morphological, and, functional, changes, in, skeletal, 'muscle,', but, the, sequence, of, events]), verbo([required]), complemento([classification])].
[sujeto(['We']), verbo([found]), complemento([that, gastrocnemius, muscle, from, 'food-deprived', rats, shows, acute, rises, in, peroxisome, proliferator, activated, receptor, '(', 'PPAR)', gamma, coactivator, '(', 'PGC)', -, 1, 'alpha/PPAR', delta, nuclear, protein, and, myosin, heavy, chain, '(', 'MHC)', 'Ib', 'protein,', while, type, 'I', fibers, accumulate, and, the, muscle, tissue, appears, redder])].
[sujeto(['AMP', 'levels,', phosphorylation, of, both, 'AMP-activated', protein, kinase, '(', 'AMPK)', and, its, downstream]), verbo([target]), complemento([acetyl, coenzyme, 'A', carboxylase, '(', 'ACC)', are, induced, within, 6, h])].
[sujeto(['Rapidly']), verbo([increased]), complemento(['MyoD', mRNA, levels, are, followed, by, an, increase, in, uncoupling, protein, '(', 'UCP)', 3, '(', 'UCP3)', transcription])].
[sujeto(['Increased', serum, fatty, acid, levels, coincide, with]), verbo([increases]), complemento([in, mitochondrial, 'UCP3', protein, levels, and, fatty, acid, oxidation])].
[sujeto(['Accompanying', this, is, a]), verbo([decrease]), complemento([in, 'AMPK', 'phosphorylation,', reversible, upon, nicotinic, acid, 'treatment,', indicating, that, fatty, acids, may, modulate, this, 'kinase\'s', activity, after, the, metabolic, challenges, posed, by, food, deprivation])].
[sujeto(['The', transcription, factors, myogenin, and, 'MyoD']), verbo([have]), complemento([been, suggested, to, be, involved, in, maintaining, slow, and, fast, 'muscle-fiber', 'phenotypes,', 'respectively,', in, rodents])].
[sujeto(['The', training, evoked, the, expected, mRNA]), verbo([increase]), complemento([for, slow, 'fiber-specific', markers, myosin, heavy, chain, 'I', and, 3, -, 'hydroxyacyl-CoA', dehydrogenase, 'A,', whereas, an, mRNA, decrease, was, seen, for, fast, 'fiber-specific', markers, myosin, heavy, chain, 'IIx', and, glycerol, phosphate, dehydrogenase])].
[sujeto(['Although', the, slow, 'fiber-specific', markers, citrate, synthase, and, muscle, fatty, acid]), verbo([binding]), complemento([protein, did, not, display, a, significant, increase, in, 'mRNA,', they, did, tend, to, increase])].
[sujeto(['The', results, indicate, that, myogenin, is, indeed]), verbo([involved]), complemento([in, the, regulation, of, the, slow, oxidative, phenotype, in, human, skeletal, muscle, 'fibers,', whereas, 'MyoD', appears, to, have, a, more, complex, regulatory, function])].
[sujeto(['The', transcription, of, the, human, 'UCP3', '(', uncoupling, 'protein-3)', gene, in, skeletal, muscle, is, tightly]), verbo([regulated]), complemento([by, metabolic, signals, related, to, fatty, acid, availability])].
[sujeto(['However,', changes, in, thyroid, status, also]), verbo([modulate]), complemento(['UCP3', gene, 'expression,', albeit, by, unknown, mechanisms])].
[sujeto(['Treatment', of, human, 'UCP3', transgenic, mice, with, thyroid, hormones]), verbo([induced]), complemento([the, expression, of, the, human, gene, in, skeletal, muscle])].
[sujeto(['In', 'addition,', transient, transfection, experiments, demonstrate, that, thyroid, hormones]), verbo([activate]), complemento([the, transcription, of, the, human, 'UCP3', gene, promoter, when, 'MyoD', and, the, 'TR', '(', thyroid, hormone, 'receptor)', were, 'co-transfected'])].
[sujeto(['The', action, of, thyroid, hormones, on, 'UCP3', gene, transcription, is]), verbo([mediated]), complemento([by, the, binding, of, the, 'TR', to, a, proximal, region, in, the, 'UCP3', gene, promoter, that, contains, a, direct, repeat, structure])].
[sujeto(['An', intact, 'DNA', sequence, of, this, site, is]), verbo([required]), complemento([for, thyroid, hormone, responsiveness, and, 'TR', binding])].
[sujeto(['Chromatin', immunoprecipitation, assays, revealed, that, the, 'TR']), verbo([binds]), complemento([this, element, in, vivo])].
[sujeto(['In', 'summary,', 'UCP3', gene, transcription, is]), verbo([activated]), complemento([by, thyroid, hormone, treatment, in, 'vivo,', and, this, activation, is, mediated, by, a, 'TRE', '(', thyroid, hormone, response, 'element)', in, the, proximal, promoter, region])].
[sujeto(['Such', regulation]), verbo([suggests]), complemento([a, link, between, 'UCP3', gene, expression, and, the, effects, of, thyroid, hormone, on, mitochondrial, function, in, skeletal, muscle])].
[sujeto(['This', study, determined, whether, estradiol, '(', 'E2)', or, the, phytoestrogens, genistein, and, daidzein]), verbo([regulate]), complemento([expression, of, 'growth-related', and, lipogenic, genes, in, rainbow, trout])].
[sujeto(['In', 'liver,', expression, of, vitellogenin, '(', 'vtg)', and, estrogen, receptor, alpha, '(', 'era1)']), verbo([increased]), complemento([in, all, treatments, and, reflected, treatment, estrogenicity, '(', 'E2&gt;genistein', '(', 50, 'μg/g)&gt;genistein', '(', 5, 'μg/g)=daidzein', '(', 5, 'μg/g))'])].
[sujeto(['Estradiol', and, genistein, '(', 50, 'μg/g)', reduced, components, of, the, growth, hormone, '(', 'GH)/insulin-like', growth, factor, '(', 'IGF)', axis, in, 'liver,', including]), verbo([increased]), complemento([expression, of, 'IGF', binding, 'protein-2b1', '(', 'igfbp2b1)', and, reduced, igfbp5b1])].
[sujeto(['In', liver, 'E2', and, genistein, '(', 50, 'μg/g)', affected, expression, of, components, of, the, transforming, growth, factor, beta, signaling, 'mechanism,', reduced, expression, of, ppar, and, rxr, transcription, 'factors,', and]), verbo([increased]), complemento([expression, of, fatty, acid, synthesis, genes, 'srebp1,', 'acly,', 'fas,', 'scd1,', and, gpat, and, lipid, binding, proteins, fabp3, and, lpl])].
[sujeto(['In', muscle, 'E2', and, genistein, '(', 50, 'μg/g)']), verbo([increased]), complemento([era1, and, erb1, expression, and, decreased, erb2, expression])].
[sujeto(['Other', genes]), verbo([responded]), complemento([to, phytoestrogens, in, a, manner, that, suggested, regulation, by, estrogen, 'receptor-independent', 'mechanisms,', including, increased, 'ghr2,', 'igfbp2a,', 'igfbp4,', and, igfbp5b1])].
[sujeto(['Expression', of, muscle, regulatory, factors, pax7, and, myod, was]), verbo([increased]), complemento([by, 'E2', and, genistein])].
[sujeto(['These', data, indicate, that, genistein, and, daidzein, affect, expression, of, genes, in, rainbow, trout, that]), verbo([regulate]), complemento([physiological, mechanisms, central, to, growth, and, nutrient, retention])].
[sujeto(['p204,', an, 'interferon-inducible', p200, family, 'protein,']), verbo([inhibits]), complemento([rRNA, synthesis, in, fibroblasts, by, blocking, the, binding, of, the, upstream, binding, factor, transcription, factor, to, 'DNA'])].
[sujeto(['Here', we]), verbo([report]), complemento([that, among, 10, adult, mouse, tissues, 'tested,', the, level, of, p204, was, highest, in, heart, and, skeletal, muscles])].
[sujeto(['Leptomycin', 'B,', an, inhibitor, of]), verbo([nuclear]), complemento([export, that, blocked, myoblast, 'fusion,', inhibited, the, nuclear, export, 'signal-dependent', translocation, of, p204, to, the, cytoplasm])].
[sujeto(['The']), verbo([increase]), complemento([in, the, p204, level, during, myoblast, fusion, was, a, consequence, of, 'MyoD', transcription, factor, binding, to, several, 'MyoD-specific', sequences, in, the, gene, encoding, 'p204,', followed, by, transcription])].
[sujeto(['Overexpression', of, p204, '(', in, 'C2C12', myoblasts, carrying, an, inducible, p204, expression, 'plasmid)', accelerated, the, fusion, of, myoblasts, to, myotubes, in, differentiation, medium, and]), verbo([induced]), complemento([the, fusion, even, in, growth, medium])].
[sujeto(['The', level, of, p204, in, mouse, heart, muscle, strongly]), verbo([increased]), complemento([during, 'differentiation;', it, was, barely, detectable, in, 10])].
[sujeto([p204, is, the, second, p200, family, protein, '(', after, 'p202a)']), verbo([found]), complemento([to, be, involved, in, muscle, differentiation])].
[sujeto([')', 'These', results]), verbo([reveal]), complemento([that, p204, and, p202a, function, in, both, muscle, differentiation, and, interferon, action])].
[sujeto(['In', 'Duchenne', muscle, dystrophy, '(', 'DMD)', and, in, the, mdx, mouse, model, of, 'DMD,', a, lack, of, dystrophin]), verbo([leads]), complemento([to, myonecrosis, and, cardiorespiratory, failure])].
[sujeto(['Several', lines, of, evidence]), verbo([suggest]), complemento([a, detrimental, role, of, the, inflammatory, process, in, the, dystrophic, process])].
[sujeto(['Long-term', therapy, with, 'omega-3']), verbo([increased]), complemento([the, regulatory, protein, 'MyoD', and, muscle, regeneration, and, reduced, markers, of, inflammation, '(', 'TNF-α', and, 'NF-kB)', in, both, muscles, studied])].
[sujeto(['Assessments', included, bone, mineral, 'density/content', by, 'dual-energy', 'X-ray', 'absorptiometry,', muscle, wet, weight, '(', 'quadriceps)', and, expression, of, selected, genes]), verbo([regulating]), complemento([muscle, mass, and, protein, turnover])].
[sujeto(['Bone', mineral, content]), verbo([increased]), complemento([in, the, 'ALT', group, '(', +, 16, '%', ')', and, decreased, in, the, 'C', group, '(', -, 32, '%', ')'])].
[sujeto(['Mammalian']), verbo([target]), complemento([of, rapamycin, expression, was, higher, in, 'CH', than, 'ALT', and, 'ALTH'])].
[sujeto(['We']), verbo([have]), complemento([previously, 'shown,', that, the, leucine, 'metabolite,', 'β-hydroxy-β-methylbutyrate', '(', 'HMB)', suppresses, apoptotic, signaling, and, the, apoptotic, index, '(', the, ratio, of, apoptotic, positive, to, apoptotic, negative, 'myonuclei)', during, muscle, disuse, and, during, reloading, periods, after, disuse, in, aged, rats])].
[sujeto(['However,', it, was, not, clear, if, the, apoptotic, signaling, indexes, were, due, only, to, preservation, of, myonuclei, or, if, perhaps, the, total, myogenic, pool]), verbo([increased]), complemento([as, a, result, of, 'HMB-mediated', satellite, cell, proliferation, as, this, would, have, also, reduced, the, apoptotic, index])].
[sujeto(['HMB']), verbo([prevented]), complemento([the, functional, decline, in, maximal, plantar, flexion, isometric, force, production, during, the, reloading, 'period,', but, not, during, 'HLS'])].
[sujeto(['HMB-treatment']), verbo([enhanced]), complemento([the, proliferation, of, muscle, stem, cells, as, shown, by, a, greater, percentage, of, satellite, cells, that, had, proliferated, '(', more, 'BrdU', 'positive,', 'Pax-7', 'positive,', and, more, 'Pax7/Ki67', positive, 'nuclei)', and, as, a, 'result,', more, differentiated, stem, cells, were, present, '(', more, 'MyoD/myogenin', positive, 'myonuclei),', relative, to, total, 'myonuclei,', in, reloaded, plantaris, muscles, as, compared, to, reloaded, muscles, from, 'vehicle-treated', animals])].
[sujeto(['Furthermore', 'HMB']), verbo([increased]), complemento([the, nuclear, protein, abundance, of, proliferation, 'markers,', inhibitor, of, 'differentiation-2', and, cyclin, 'A,', as, compared, to, vehicle, treatment, in, reloaded, muscles])].
[sujeto(['Although', 'HMB']), verbo([increased]), complemento([phosphorylated, 'Akt', during, 'reloading,', other, mTOR, related, proteins, were, not, altered, by, 'HMB', treatment])].
[sujeto(['Enhanced', satellite, cell, proliferation]), verbo([leading]), complemento([to, increased, differentiated, myonuclei, should, increase, the, transcriptional, potential, to, support, muscle, hypertrophic, changes, and, functional, changes, in, sarcopenic, 'muscles,', and, this, could, partly, explain, the, reduced, apoptotic, index, in, 'HMB', treated, muscles])].
[sujeto(['Chronic', inflammation]), verbo([induces]), complemento([skeletal, muscle, wasting, and, cachexia])].
[sujeto(['In', arthritic, 'rats,', 'fenofibrate,', a, peroxisome, 'proliferator-activated', receptor, α, '(', 'PPARα', '(', 'PPARA))', 'agonist,', reduces, wasting, of, 'gastrocnemius,', a, predominantly, glycolytic, 'muscle,', by]), verbo([decreasing]), complemento([atrogenes, and, myostatin])].
[sujeto(['Considering', that, fenofibrate]), verbo([increases]), complemento([fatty, acid, 'oxidation,', the, aim, of, this, study, was, to, elucidate, whether, fenofibrate, is, able, to, prevent, the, effect, of, arthritis, on, serum, adipokines, and, on, 'soleus,', a, type, 'I', muscle, in, which, oxidative, metabolism, is, the, dominant, source, of, energy])].
[sujeto(['Arthritis', was]), verbo([induced]), complemento([by, injection, of, 'Freund\'s', adjuvant])].
[sujeto(['Arthritis']), verbo([decreased]), complemento([serum, 'leptin,', 'adiponectin,', and, insulin, '(', 'P&lt;0'])].
[sujeto(['In', arthritic, 'rats,', fenofibrate, administration]), verbo([increased]), complemento([serum, concentrations, of, leptin, and, adiponectin])].
[sujeto(['Arthritis']), verbo([decreased]), complemento([soleus, 'weight,', 'cross-sectional', 'area,', fiber, 'size,', and, its, 'Ppar', α, mRNA, expression])].
[sujeto(['In', arthritic, 'rats,', fenofibrate]), verbo([increased]), complemento([soleus, 'weight,', fiber, 'size,', and, 'Ppar', α, expression, and, prevented, the, increase, in, 'Murf1', mRNA])].
[sujeto(['Fenofibrate']), verbo([decreased]), complemento(['myostatin,', whereas, it, increased, 'MyoD', '(', 'Myod1)', and, myogenin, expressions, in, the, soleus, of, control, and, arthritic, rats])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, in, oxidative, 'muscle,', fenofibrate, treatment, is, able, to, prevent, 'arthritis-induced', muscle, wasting, by, decreasing, 'Murf1', and, myostatin, expression, and, also, by, increasing, the, myogenic, regulatory, 'factors,', 'MyoD', and, myogenin])].
[sujeto(['Taking', into, account, the, beneficial, action, of, adiponectin, on, muscle, wasting, and, the, correlation, between, adiponectin, and, soleus, 'mass,', part, of, the, anticachectic, action, of, fenofibrate, may, be]), verbo([mediated]), complemento([through, stimulation, of, adiponectin, secretion])].
[sujeto(['Suboptimal', fetal, environments, due, to, inadequate, maternal, 'nutrition,', 'obesity,', inflammation, or, gestational, diabetes, expose, the, fetus, to, humoral, cues, that, alter, metabolism, and, growth, parameters]), verbo([leading]), complemento([to, metabolic, disturbances, later, in, life])].
[sujeto(['Maternal', obesity]), verbo([induces]), complemento([inflammation, in, the, fetus, causing, modifications, in, the, development, of, fetal, skeletal, muscle])].
[sujeto(['Changes', in, the, normal, course, of, myogenesis, may, arise, through, several, 'mechanisms:', changes, in, 'WNT/β-catenin', signaling, 'pathway,']), verbo([decreased]), complemento(['AMPK', activity, evoked, by, 'TNF-α,', increased, activity, of, 'NF-κB', in, response, to, 'inflammation,', which, leads, to, a, decrease, in, myogenic, factor, 'MyoD,', and, increased, expression, of, 'TGF', β1])].
[sujeto(['Modification', in, fetal, development]), verbo([associated]), complemento([with, maternal, obesity, is, attributed, to, epigenetic, changes])].
[sujeto(['These', adipocytes, stained, with, 'Oil-Red-O', and]), verbo([expressed]), complemento([the, terminal, differentiation, 'markers,', adipsin, and, fatty, acid, binding, protein, 4, ',', but, did, not, express, 'EYFP', and, were, therefore, not, of, satellite, cell, origin])].
[sujeto(['Satellite', cells, mutant, for, either, 'MyoD', or, 'Myf-5', also]), verbo([maintained]), complemento([myogenic, programming, in, culture, and, did, not, adopt, an, adipogenic, fate])].
[sujeto(['Under', 'adipogenesis-inducing', 'conditions,', satellite, cells, accumulated, cytoplasmic, lipid, but]), verbo([maintained]), complemento([myogenic, protein, expression, and, did, not, fully, execute, the, adipogenic, differentiation, 'program,', distinguishing, them, from, adipocytes, observed, in, muscle, fiber, cultures])].
[sujeto(['Although', iPS, cells, are, similar, to, embryonic, stem, '(', 'ES)', cells, in, their, 'pluripotency,', their, inherited, 'defects,', such, as, insertion, 'mutagenesis,', employment, of, 'oncogenes,', and, low, 'efficiency,']), verbo([associated]), complemento([with, the, reprogramming, procedure, have, hindered, their, clinical, application])].
[sujeto(['A', study]), verbo([has]), complemento([shown, that, valproic, acid, '(', 'VPA)', treatment, can, significantly, enhance, the, reprogramming, efficiency, and, avoid, the, usage, of, oncogenes])].
[sujeto(['To', understand, how, 'VPA', can]), verbo([enhance]), complemento(['pluripotency,', we, stably, transfected, an, 'Oct4', promoter, driven, luciferase, reporter, '(', 'Oct4-1'])].
[sujeto(['We']), verbo([found]), complemento([that, 'VPA', could, both, activate, 'Oct4', promoter, and, rescue, its, inhibition, by, retinoic, acid, '(', 'RA)'])].
[sujeto(['In', 'C2C12', 'myoblasts,', 'VPA', treatment, also]), verbo([enhanced]), complemento([endogenous, 'Oct4', expression, but, repressed, that, of, 'MyoD'])].
[sujeto(['Furthermore,', both, 'RARalpha', 'over-expression', and, mutation, of, a, proximal, hormone, response, element, '(', 'HRE)', blocked, the, activation, effect, of, 'VPA', on, 'Oct4', 'promoter,', implying, that, 'VPA', may, exert, its, activation, effect, through, factors]), verbo([targeting]), complemento([this, 'HRE'])].
[sujeto(['Taken', 'together,', these, observations, identify, a, molecular, mechanism, by, which, 'VPA', directly]), verbo([regulate]), complemento(['Oct4', expression, to, ensure, the, acquirement, and, maintenance, of, pluripotency])].
[sujeto(['We', demonstrate, that, 'PGD(2)', strongly]), verbo([inhibits]), complemento(['C2C12', myogenesis, as, measured, by, cell, 'fusion,', creatine, kinase, activity, and, 'MyoD,', myogenin, and, 'alpha-actin', expression])].
[sujeto(['Inhibition', of, myogenesis]), verbo([required]), complemento([micromolar, 'PGD(2)', concentrations, and, was, independent, of, the, known, 'PGD(2)', receptors, 'DP1', and, 'DP2'])].
[sujeto(['Unlike', its, cyclopentenone, derivative, 15, -, 'deoxy-Delta(12,14)-PGJ(2)', '(', 15, 'd-PGJ(2)),', 'PGD(2)', did, not, generate, toxic, mitochondrial, superoxide, indicating, that, the, inhibition, of, myogenesis, is, not]), verbo([mediated]), complemento([by, generation, of, high, concentrations, of, 'PGD(2)-derived', 15, 'd-PGJ(2)'])].
[sujeto(['Thus', our, observations]), verbo([provide]), complemento([evidence, for, a, novel, 'PGD(2)', signalling, mechanism, during, muscle, repair, exclusively, mediated, by, high, inflammatory, associated, 'PGD(2)', concentrations])].
[sujeto(['These', findings, indicate, a, complex, interplay, between, myoblasts, and, inflammatory, cells, during, the, repair, process, and]), verbo([have]), complemento([implications, for, the, use, of, 'non-steroidal', 'anti-inflammatory', drugs, in, the, treatment, of, muscle, injuries])].
[sujeto(['The', 't10,c12', 'CLA', 'isomer,', but, not, the, 'c9,t11', 'isomer,', significantly]), verbo([decreased]), complemento(['MIA', 'PaCa-2', proliferation, by, between, 15, '%', and, 19, '%'])].
[sujeto(['There', was, a, marked]), verbo([decrease]), complemento([in, muscle, 'MyoD', and, myogenin, expression, '(', 78, '%', and, 62, '%', ',', 'respectively),', but, no, change, in, either, 'Myf5', or, 'myostatin,', in, myotubes, grown, in, coculture, with, 'MIA', 'PaCa-2', cells])].
[sujeto(['Several-fold', significant]), verbo([increases]), complemento([in, 'CCL-2,', 'COX-2,', 'IL-8,', and, 'TNF-alpha', expression, in, myotubes, were, observed, with, 'MIA', 'PaCa-2', coculture])].
[sujeto(['The', 'c9,t11', 'CLA', isomer, significantly]), verbo([decreased]), complemento([basal, expression, of, 'TNF-alpha', in, myotubes, and, could, ameliorate, its, 'tumor-induced', rise])].
[sujeto(['The', study]), verbo([provides]), complemento([insight, into, the, 'anti-inflammatory', and, antiproliferative, actions, of, 'CLA', and, its, application, as, a, therapeutic, agent, in, inflammatory, disease, states])].
[sujeto(['Eicosapentaenoic', acid, '(', 'EPA)', is, an, 'omega-3', polyunsaturated, fatty, acid, that]), verbo([has]), complemento(['anti-inflammatory', and, anticachectic, actions])].
[sujeto(['The', aim, of, this, work, was, to, elucidate, whether, 'EPA', administration, is, able, to]), verbo([prevent]), complemento([an, 'arthritis-induced', decrease, in, body, weight, and, muscle, wasting, in, rats])].
[sujeto(['Arthritis', was]), verbo([induced]), complemento([by, intradermal, injection, of, 'Freund\'s', 'adjuvant;', 3, days, 'later,', nine, rats, received, 1, 'g/kg', 'EPA', or, coconut, oil, daily])].
[sujeto(['EPA', administration]), verbo([decreased]), complemento([the, external, signs, of, arthritis, and, paw, volume, as, well, as, liver, 'TNF-alpha', mRNA])].
[sujeto(['EPA', did, not, modify, 'arthritis-induced']), verbo([decrease]), complemento([in, food, intake, or, body, weight, gain])].
[sujeto(['However,', 'EPA', treatment]), verbo([prevented]), complemento(['arthritis-induced', increase, in, muscle, 'TNF-alpha', and, 'atrogin-1,', whereas, it, attenuated, the, decrease, in, gastrocnemius, weight, and, the, increase, in, 'MuRF1', mRNA])].
[sujeto(['Arthritis', not, only]), verbo([decreased]), complemento([myogenic, regulatory, factors, but, also, increased, 'PCNA,', 'MyoD,', and, myogenin, mRNA, in, the, gastrocnemius])].
[sujeto(['In', the, control, 'rats,', 'EPA', administration]), verbo([increased]), complemento(['PCNA', and, 'MyoD', mRNA, and, protein])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, in, experimental, 'arthritis,', in, addition, to, its, 'anti-inflammatory', 'effect,', 'EPA', treatment, attenuates, muscle, wasting, by, decreasing, 'atrogin-1', and, 'MuRF1', gene, expression, and, increasing, the, transcription, factors, that, regulate, myogenesis])].
[sujeto(['As', muscle, regeneration, comes, with, an, inflammatory, 'process,', it]), verbo([has]), complemento([been, proposed, that, the, inflammatory, cells, can, play, an, important, role, in, the, induction, of, muscle, fibres, regeneration])].
[sujeto(['The', data, obtained, showed, a, very, large]), verbo([decrease]), complemento([in, the, number, of, 'MyoD', 'positive/m-cadherin', positive, cells, in, the, ketoprofen, injected, group, compared, to, the, control, group])].
[sujeto(['Although', further, studies, are, needed, to, elucidate, the, sequence, of, biochemical, events, that]), verbo([induce]), complemento([a, reduction, of, 'MyoD', expression, due, to, 'ketoprofen,', the, results, demonstrate, that, prostaglandin, synthesis, is, required, for, the, induction, of, 'MyoD', expression, and, that, ketoprofen, can, affect, this, 'expression,', with, possible, adverse, effects, on, muscle, regeneration])].
[sujeto(['RT-PCR', showed, that, myoblasts]), verbo([expressed]), complemento([mRNA, for, 'LTB(4)', receptors, 'BLT1', and, 'BLT2,', and, 'LTB4', promoted, myoblast, proliferation, and, fusion])].
[sujeto(['U-75302,', a, specific, 'BLT1', 'inhibitor,', but, not, 'LY2552833,', a, specific, 'BLT2', 'inhibitor,', blocked, proliferation, and, differentiation, of, myoblasts]), verbo([induced]), complemento([by, 'LTB(4),', which, implies, the, involvement, of, the, 'BLT1', pathway])].
[sujeto(['Overall,', the, data]), verbo([suggest]), complemento([that, 'LTB(4)', contributes, to, muscle, regeneration, by, accelerating, proliferation, and, differentiation, of, satellite, cells])].
[sujeto(['Primary', alveolar, type, of, rhabdomyosarcoma, '(', 'RMS)', tumor, tissue, was, collected, from, the, tongue, of, a, 17, -, 'year-old', 'Japanese', woman, and, used, to, successfully, establish, a, rhabdomyosarcoma, cell, 'line,', which]), verbo([has]), complemento([been, designated, 'NUTOS'])].
[sujeto(['Side', effects, from, 'long-term', 'HAART', therapy, include]), verbo([loss]), complemento([of, muscle, mass])].
[sujeto(['Myoblasts', when, cultured, in, media, low, in, growth, factors, withdraw, from, the, cell, 'cycle,']), verbo([express]), complemento(['muscle-specific', differentiation, inducers, and, 'proteins,', and, fuse, to, form, myotubes])].
[sujeto(['The', neutral, 'protease,', 'calpain,', is]), verbo([required]), complemento([for, myotube, formation, and, 'RTV', decreased, calpain, activity, in, vitro])].
[sujeto(['We']), verbo([found]), complemento([lower, calpain, 'activity,', but, not, 'protein,', in, homogenates, of, 'RTV-treated', 'L6', cells, than, in, control, cultures])].
[sujeto(['Control', and, 'drug-related', 'L6', myoblasts, showed, identical]), verbo([decreases]), complemento([in, proliferating, cell, nuclear, antigens, expression, indicating, proliferation, arrest])].
[sujeto(['Similarly,', muscle, differentiation, inducers, 'MyoD', and, myogenin, and, their, downstream, 'target,', myosin, heavy, 'chain,', were]), verbo([expressed]), complemento([at, similar, levels, in, control, and, 'drug-treated', cells])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, protease, inhibitors, included, in, 'HAART', might, be, directly, involved, in, muscle, wasting, by, reducing, muscle, remodeling])].
[sujeto(['MyoD', and, 'Myf5', genes, are, selectively]), verbo([activated]), complemento([during, development, in, a, time, and, 'region-specific', manner, and, in, response, to, different, stimuli])].
[sujeto(['However,', molecules, that, specifically]), verbo([regulate]), complemento([the, expression, of, these, two, genes, and, the, pathways, involved, remain, to, be, determined])].
[sujeto(['We']), verbo([have]), complemento([recently, shown, that, the, serum, response, factor, '(', 'SRF),', a, transcription, factor, involved, in, activation, of, both, mitogenic, response, and, muscle, 'differentiation,', is, required, for, 'MyoD', gene, expression])].
[sujeto(['We']), verbo([have]), complemento([investigated, here, whether, 'SRF', is, also, involved, in, the, control, of, 'Myf5', gene, 'expression,', and, the, potential, role, of, upstream, regulators, of, 'SRF', 'activity,', the, 'Rho', family, 'G-proteins', including, 'Rho,', 'Rac,', and, 'CDC42,', in, the, regulation, of, 'MyoD', and, 'Myf5'])].
[sujeto(['We', show, that, inactivation, of, 'SRF', does, not, alter, 'Myf5', gene, 'expression,', whereas, it]), verbo([causes]), complemento([a, rapid, extinction, of, 'MyoD', gene, expression])].
[sujeto(['Furthermore,', we, show, that, 'RhoA,', but, not, 'Rac', or, 'CDC42,', is, also]), verbo([required]), complemento([for, the, expression, of, 'MyoD'])].
[sujeto(['Indeed,', blocking, the, activity, of, 'G-proteins', using, the, general, inhibitor, 'lovastatin,', or, more, specific, antagonists, of, 'Rho', proteins, such, as, 'C3-transferase', or, dominant, negative, 'RhoA', 'protein,', resulted, in, a, dramatic]), verbo([decrease]), complemento([of, 'MyoD', protein, levels, and, promoter, activity, without, any, effects, on, 'Myf5', expression])].
[sujeto(['We', further, show, that, 'RhoA-dependent', transcriptional, activation]), verbo([required]), complemento([functional, 'SRF', in, 'C2', muscle, cells])].
[sujeto(['These', data, illustrate, that, 'MyoD', and, 'Myf5', are]), verbo([regulated]), complemento([by, different, upstream, activation, pathways, in, which, 'MyoD', expression, is, specifically, modulated, by, a, 'RhoA/SRF', signaling, cascade])].
[sujeto(['Our', current, understanding, of, muscle, and, adipose, tissue, development]), verbo([has]), complemento([been, largely, restricted, to, the, study, of, murine, myogenic, and, adipogenic, cell, 'lines,', since, attempts, to, establish, these, cell, lines, from, other, species, have, met, with, only, limited, success])].
[sujeto(['Here', we]), verbo([report]), complemento([that, a, spontaneously, immortalized, bovine, embryonic, fibroblast, cell, line, '(', 'BEFS)', undergoes, differentiation, into, adipogenic, or, myogenic, lineages, when, ectopically, transduced, with, 'PPARgamma2', '(', an, adipogenic, lineage, 'determinant)', or, 'MyoD', '(', a, myogenic, lineage, 'determinant)', and, grown, in, adipogenic, and, myogenic, differentiation, culture, media, '(', 'ADCM', and, 'MDCM,', 'respectively)'])].
[sujeto(['We', also]), verbo([found]), complemento([that, 'PPARgamma2-overexpressing', 'BEFS', cells, '(', 'BEFS-PPARgamma2)', grown, in, 'ADCM', with, or, without, the, 'PPARgamma2', 'ligand,', 'troglitazone,', preferentially, differentiate, into, adipogenic, cells, in, the, presence, of, ectopic, 'MyoD', expression])].
[sujeto(['Ectopic', expression, of, 'PPARgamma2', in, the, inducible, 'MyoD-overepxressing', 'BEFS', cells, '(', 'BEFS-TetOn-MyoD)', completely]), verbo([suppresses]), complemento([myogenic, differentiation, and, leads, to, a, significant, increase, in, adipogenic, 'differentiation,', suggesting, that, the, adipogenic, differentiation, program, might, be, dominant])].
[sujeto(['Plasminogen', activators, 'urokinase-type', plasminogen, activator, '(', 'uPA)', and, 'tissue-type', plasminogen, activator, '(', 'tPA)', are, extracellular, proteases]), verbo([involved]), complemento([in, various, tissue, remodeling, processes])].
[sujeto(['In', 'contrast,', 'uPA-/-', mice, had, a, severe, regeneration, 'defect,', with]), verbo([decreased]), complemento([recruitment, of, 'blood-derived', monocytes, to, the, site, of, injury, and, with, persistent, myotube, degeneration])].
[sujeto(['A', similar, severe, regeneration, deficit, with, persistent, fibrin, deposition, was, also, reproducible, in, 'plasminogen-deficient', mice, after, 'injury,']), verbo([suggesting]), complemento([that, fibrinolysis, by, 'uPA-mediated', plasminogen, activation, plays, a, fundamental, role, in, skeletal, muscle, regeneration])].
[sujeto(['In', 'conclusion,', the, 'uPA-plasmin', system, is, identified, as, a, critical, component, of, the, mammalian, skeletal, muscle, regeneration, 'process,', possibly, because, it]), verbo([prevents]), complemento([intramuscular, fibrin, accumulation, and, contributes, to, the, adequate, inflammatory, response, after, injury])].
[sujeto(['To', identify, transcriptional, 'gene-networks']), verbo([involved]), complemento([in, the, early, in, vivo, response, of, liver, cells, to, radiation, exposure, and, improve, our, understanding, of, the, molecular, processes, responsible, for, tissue, radiosensitivity])].
[sujeto(['Other', genes]), verbo([regulated]), complemento([by, the, 'transformation-related', protein, 53, '(', 'Trp53/p53)', such, as, 'Bcl2-associated', 'X', protein, '(', 'Bax)', or, 'etoposide-induced-2'])].
[sujeto(['Grouping', differentially]), verbo([expressed]), complemento([genes, into, functional, categories, revealed, that, the, primary, response, of, liver, cells, to, radiation, exposure, was, the, enhancement, of, oxidoreductase, activity, and, inhibition, of, cell, 'proliferation,', involving, cell, cycle, progression, and, 'apoptosis-related', genes])].
[sujeto(['The', data]), verbo([provides]), complemento([evidence, of, gene, expression, modifications, associated, with, the, hepatic, response, to, radiation, exposure])].
[sujeto(['Overall,', our, expression, data, revealed, genes, and, cellular, pathways, that, might, help, to, improve, our, understanding, of, the, molecular, basis, underlying, tissue, radiosensitivity, and, to, identify, possible]), verbo([targets]), complemento([for, novel, therapeutic, strategies])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, 'PUMA', plays, a, pivotal, role, in, the, apoptosis, associated, with, skeletal, myoblast, differentiation, and, that, a, 'MyoD-dependent', mechanism, is, responsible, for, the, increased, expression, of, 'PUMA', in, these, cells])].
[sujeto(['Herein,', we]), verbo([report]), complemento([that, the, increased, expression, of, 'PUMA', under, these, conditions, involves, regulation, at, the, level, of, translation])].
[sujeto(['Specifically,', we]), verbo([have]), complemento([found, that, the, increase, in, 'PUMA', protein, levels, occurs, under, conditions, of, decreased, total, protein, 'synthesis,', 'eIF2-alpha', phosphorylation, and, hypophosphorylation, of, 'eIF4E-BP,', suggesting, that, 'PUMA', translation, is, proceeding, via, an, alternative, initiation, mechanism])].
[sujeto(['A', combination, of, in, vitro, and, ex, vivo, '(', 'cellular)', approaches]), verbo([has]), complemento([provided, evidence, suggesting, that, 'PUMA', mRNA, 5, '\'', 'UTR', harbors, an, 'Internal', 'Ribosome', 'Entry', 'Site', '(', 'IRES)', element])].
[sujeto(['Using', 'mono-', and, 'bi-cistronic', reporter, 'constructs,', we]), verbo([have]), complemento([delineated, an, mRNA, fragment, that, allows, for, 'cap-independent', translation, in, vitro, and, ex, vivo, '(', in, skeletal, 'myoblasts)', in, response, to, culture, in, differentiation, media, '(', 'DM),', or, in, response, to, treatment, with, the, 'DNA-damaging', 'agent,', etoposide])].
[sujeto(['Thus,', our, data]), verbo([has]), complemento([revealed, a, novel, 'IRES-mediated', regulation, of, 'PUMA', expression, in, several, cell, types, and, in, response, to, several, stimuli])].
[sujeto(['These', findings, contribute, to, our, understanding, and, potential, manipulation, of, any, developmental, or, therapeutic, scenario]), verbo([involving]), complemento(['PUMA'])].
[sujeto(['To']), verbo([prevent]), complemento([the, formation, of, differentiated, cells, with, genetic, 'instability,', we, hypothesized, that, genotoxic, stress, may, trigger, a, differentiation, checkpoint])].
[sujeto(['Here', we, show, that, exposure, to, genotoxic, agents]), verbo([causes]), complemento([a, reversible, inhibition, of, myogenic, differentiation])].
[sujeto(['Muscle-specific', gene, expression, is]), verbo([suppressed]), complemento([by, 'DNA-damaging', agents, if, applied, prior, to, differentiation, induction, but, not, after, the, differentiation, program, is, established])].
[sujeto(['The', myogenic, determination, 'factor,', 'MyoD', '(', encoded, by, 'Myod1),', is, a]), verbo([target]), complemento([of, the, differentiation, checkpoint, in, myoblasts])].
[sujeto(['The', inhibition, of, 'MyoD', by, 'DNA', damage]), verbo([requires]), complemento([a, functional, 'c-Abl', tyrosine, kinase, '(', encoded, by, 'Abl1),', but, occurs, in, cells, deficient, for, p53, '(', 'transformation-related', protein, 53, ',', encoded, by, 'Trp53)', or, 'c-Jun', '(', encoded, by, the, oncogene, 'Jun)'])].
[sujeto(['These', results, support, the, idea, that, genotoxic, stress, can]), verbo([regulate]), complemento(['differentiation,', and, identify, a, new, biological, function, for, 'DNA', 'damage-activated', signaling, network])].
[sujeto(['However,']), verbo([phosphorylated]), complemento(['IRS1(Ser636/639),', which, impedes, binding, of, downstream, effectors, and, the, negative, regulator, '(', 'PTEN)', of, 'PIP3,', was, increased, in, 'DEHP-exposed', groups])].
[sujeto(['Down-regulation', of, glucose, transporter, 4, '(', 'Glut4', '(', 'Slc2a4))', gene, expression, and]), verbo([increased]), complemento(['GLUT4(Ser488)', 'phosphorylation,', which, decreases, its, intrinsic, activity, and, translocation, towards, the, plasma, 'membrane,', were, recorded])].
[sujeto(['Chromatin', immunoprecipitation, assays, detected]), verbo([decreased]), complemento(['MYOD', binding, and, increased, histone, deacetylase, 2, interaction, towards, 'Glut4,', indicative, of, the, tight, chromatin, structure, at, the, 'Glut4', promoter])].
[sujeto(['Furthermore,', methylation, of, 'Glut4', at, the, 'MYOD-binding', site, was]), verbo([increased]), complemento([in, 'DEHP-exposed', groups])].
[sujeto(['These', findings, indicate, 'that,', gestational, 'DEHP', exposure, predisposes, 'F1', offspring, to, glucometabolic, dysfunction, at, adulthood, by, 'down-regulating', the, expression, of, critical, genes]), verbo([involved]), complemento([in, the, insulin, signalling, pathway])].
[sujeto(['Myogenic', differentiation, is, principally]), verbo([regulated]), complemento([by, activities, of, myogenic, regulatory, 'factors,', such, as, 'MyoD', and, 'myogenin,', leading, the, elongation, and, fusion, of, mononucleated, myoblasts, into, multinucleated, myotubes])].
[sujeto(['In', the, present, 'study,', myogenic, differentiation, of, 'C2C12', cells, was]), verbo([induced]), complemento([by, serum, deprivation, with, medium, containing, vehicle, or, 'DEHP', '(', 10, ',', 100, ',', 1, ',', 0, 'μg/ml)', for, 5, days])].
[sujeto(['This', in, vitro, study]), verbo([suggests]), complemento([that, 'DEHP', may, be, an, environmental, risk, factor, for, myogenesis])].
[sujeto(['For', reconstruction, or, repair, of, damaged, 'tissues,', an, artificially]), verbo([regulated]), complemento([switch, from, proliferation, to, differentiation, would, be, of, great, advantage])].
[sujeto(['To', achieve, conditional, 'myogenesis,', we]), verbo([expressed]), complemento(['MyoD', in, mouse, 'C3H', 10, 'T1/2', fibroblastic, 'cells,', using, a, gene, regulation, system, based, on, the, synthetic, steroid, 'RU', 486])].
[sujeto(['The', leucine, zipper, transcription, factors, cAMP, response, element]), verbo([binding]), complemento([protein, '(', 'CREB),', cAMP, response, element, modulatory, protein, '(', 'CREM)', and, activating, transcription, factor, 1, '(', 'ATF1)', bind, to, the, cAMP, response, element, '(', 'CRE)', with, the, palindromic, consensus, sequence, 'TGACGTCA'])].
[sujeto(['Their', transcriptional, activities, are, dependent, on, serine, phosphorylation]), verbo([induced]), complemento([by, various, extracellular, signals, such, as, 'hormones,', growth, factors, and, neurotransmitters])].
[sujeto(['The', importance, of, 'CREB', for, morphogenetic, processes, was, assessed, by, injection, of, 'RNA', encoding, a, 'dominant-negative', form, of, 'CREB', that, is, fused, to, a, truncated, progesterone, receptor, ligand]), verbo([binding]), complemento([domain])].
[sujeto(['In', this, fusion, 'protein,', a, 'dominant-negative', function, can, be]), verbo([induced]), complemento([by, application, of, the, synthetic, steroid, 'RU486', at, given, developmental, stages])].
[sujeto(['The', inhibition, of, 'CREB', at, blastula, and, early, gastrula, stages]), verbo([leads]), complemento([to, severe, posterior, defects, of, the, embryos, reflected, by, strong, spina, 'bifida,', whereas, the, inhibition, of, 'CREB', at, the, beginning, of, neurulation, resulted, in, stunted, embryos, with, microcephaly])].
[sujeto(['In', these, 'embryos,', initial, induction, of, neural, and, mesodermal, tissues, is, not, dependent, on, 'CREB', 'function,', as, genes, such, as, 'Otx2,', 'Krox20,', 'Shh', and, 'MyoD', are, still]), verbo([expressed]), complemento([in, injected, embryos])].
[sujeto(['But', the, expression, domains, of, 'Otx2', and, 'MyoD', were]), verbo([found]), complemento([to, be, distorted, reflecting, the, abnormal, development, in, both, neural, and, somitic, derivatives])].
[sujeto(['Testosterone', is, a, key, hormone]), verbo([regulating]), complemento([animal, growth, and, 'development,', which, promotes, skeletal, muscle, growth, and, inhibits, fat, 'deposition;', 'however,', the, underlying, mechanisms, remain, poorly, defined])].
[sujeto(['Because', canonical, 'Wingless', and, 'Int/β-catenin', signaling]), verbo([promotes]), complemento(['myogenesis,', we, hypothesized, that, testosterone, regulates, myogenesis, through, enhancing, the, 'β-catenin', signaling, pathway, and, the, expression, of, its, targeted, genes])].
[sujeto(['Trenbolone', treatment]), verbo([increased]), complemento([the, protein, levels, of, 'MyoD', and, myosin, heavy, 'chain,', as, well, as, the, androgen, receptor, content])].
[sujeto(['The', myogenic, effect, of, trenbolone, was, blocked, by, cyproterone, 'acetate,', a, specific, inhibitor, of, androgen, 'receptor,', showing, that, the, myogenic, effect, of, trenbolone, was]), verbo([mediated]), complemento([by, the, androgen, receptor])].
[sujeto(['Immunoprecipitation', showed, that, androgen, receptor, and, 'β-catenin', formed, a, 'complex,', which, was]), verbo([increased]), complemento([by, trenbolone, treatment])].
[sujeto(['Trenbolone']), verbo([activated]), complemento([adenosine, 'monophosphate-activated', protein, 'kinase,', which, might, phosphorylate, 'β-catenin', at, 'Ser552,', stabilizing, 'β-catenin'])].
[sujeto(['Indeed,', both, cytoplasmic, and]), verbo([nuclear]), complemento(['β-catenin', levels, were, increased, after, trenbolone, treatment])].
[sujeto(['As', a, 'result,', 'β-catenin-mediated', transcriptional, activity, was]), verbo([enhanced]), complemento([by, trenbolone, treatment])].
[sujeto(['In', 'conclusion,', these, data]), verbo([provide]), complemento([evidence, that, testosterone, increases, cellular, 'β-catenin', content, which, promotes, the, expression, of, 'β-catenin-targeted', genes, and, myogenesis, in, the, 'muscle-derived', stem, cells, of, cattle])].
[sujeto(['Two', kinds, of, proliferation, and, differentiation, patterns]), verbo([have]), complemento([been, obtained, in, the, resulting, clones])].
[sujeto(['When', 'SRF', antisense, 'RNA', expression, is]), verbo([induced]), complemento([in, proliferating, myoblasts, by, dexamethasone, 'treatment,', cell, growth, is, blocked, and, cyclin, 'A', concentration, drops])].
[sujeto(['When', 'SRF', antisense, 'RNA', synthesis, is]), verbo([induced]), complemento([in, arrested, confluent, myoblasts, cultured, in, a, differentiation, 'medium,', cell, fusion, is, blocked, and, synthesis, of, not, only, 'SRF', but, also, 'MyoD,', 'myogenin,', and, myosin, heavy, chain, is, inhibited])].
[sujeto(['Obesity', is, documented, to, be, a, state, of, chronic, mild, inflammation]), verbo([associated]), complemento([with, increased, macrophage, infiltration, into, adipose, tissue, and, liver, and, skeletal, muscle])].
[sujeto(['As', a, pleiotropic, inflammatory, 'mediator,', macrophage, migration, inhibitory, factor, '(', 'MIF)', is]), verbo([associated]), complemento([with, metabolic, 'disease,', so, 'MIF', may, signal, molecular, links, between, adipocytes, and, myocytes])].
[sujeto(['It', did, not, change, 'proliferation,', but, downregulated, cyclin, 'D1', and, 'CDK4,']), verbo([causing]), complemento([cell, accumulation, in, the, 'G1', phase])].
[sujeto([p21, protein, was]), verbo([increased]), complemento([significantly, and, 'MyoD,', 'MyoG,', and, p21, mRNA, also, increased, significantly, in, the, 'C2C12', cells, treated, with, 'ISO-1,', suggesting, that, inhibition, of, 'MIF', promotes, differentiation])].
[sujeto(['MIF']), verbo([inhibits]), complemento([the, myoblast, differentiation, by, affecting, the, cell, cycle, 'progression,', but, does, not, affect, proliferation])].
[sujeto(['Sequence', analysis, showed, that, the, 'full-length', 'FOXO3', 'CDS', is, 1467, &, 'nbsp;bp,', encoding, 488, amino, acids, and, is, highly]), verbo([conserved]), complemento([across, many, bird, species])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'FOXO3', plays, a, critical, role, in, the, proliferation, and, differentiation, of, duck, myoblasts])].
[sujeto(['Peroxiredoxin6', '(', 'Prdx6)', is, one, of, the, peroxiredoxin, '(', 'Prdxs)', family, members, that, play, an, important, role, in]), verbo([maintaining]), complemento([cell, homeostasis])].
[sujeto(['Our', previous, studies, demonstrated, that, 'Prdx6', was, significantly]), verbo([associated]), complemento([with, pig, meat, 'quality,', especially, meat, tenderness])].
[sujeto(['Several', regulatory, elements, including, 'CCAAT/enhancer-binding', proteinβ, '(', 'C/EBPβ),', 'Myogenic', 'Differentiation', '(', 'MyoD),', cAMP, response, element]), verbo([binding]), complemento([protein, '(', 'CREB),', stimulating, protein1, '(', 'Sp1)', and, heat, shock, factor, '(', 'HSF)', binding, sites, were, found, by, computational, analyses, together, with, luciferase, reporter, system])].
[sujeto(['Electrophoretic', mobility, shift, assays, '(', 'EMSA)', and, chromatin, immunoprecipitation, assays, '(', 'ChIP)', confirmed, that, 'C/EBPβ', and, 'CREB', could]), verbo([interact]), complemento([with, 'Prdx6', promoter])].
[sujeto(['Immuoprecipitation', results, also, showed, that, 'C/EBPβ', could]), verbo([interact]), complemento([with, 'Prdx6', in, vivo])].
[sujeto(['MyoD', and, 'MyoG', are, transcription, factors, that]), verbo([have]), complemento([essential, roles, in, myogenic, lineage, determination, and, muscle, differentiation])].
[sujeto(['These', analyses]), verbo([suggest]), complemento([that, the, evolution, of, 'MyoD', and, 'MyoG', was, driven, by, different, pathways])].
[sujeto(['Four', and, a, half, 'LIM', domain, protein, 3, '(', 'FHL3)']), verbo([regulates]), complemento([myoblasts, differentiation, and, gene, expression, by, acting, as, a, transcriptional, 'co-activator', or, 'co-repressor'])].
[sujeto(['However,', how, 'FHL3']), verbo([regulates]), complemento(['MyHC', expression, is, currently, not, clear])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, 'FHL3', 'down-regulated', the, expression, of, 'MyHC', 1, /, slow, and, 'up-regulated', the, expression, of, 'MyHC', 2, a, and, 'MyHC', 2, 'b,', whereas, no, significant, effect, was, found, on, 'MyHC', 2, x, expression])].
[sujeto(['MyoD', and]), verbo([phosphorylated]), complemento([cAMP, response, element, binding, protein, '(', 'pCREB)', played, important, roles, in, the, regulation, of, 'MyHC', 1, /, slow, and, 'MyHC', 2, a, expression, by, 'FHL3,', respectively])].
[sujeto(['FHL3', could]), verbo([interact]), complemento([with, 'MyoD,', 'CREB', and, pCREB, in, vivo])].
[sujeto([pCREB, had, stronger, interaction, with, the, cyclic, 'AMP-responsive', elements, '(', 'CRE)', of, the, 'MyHC', 2, a, promoter, compared, with, 'CREB,', and, 'FHL3', significantly, affected, the]), verbo([binding]), complemento([capacity, of, pCREB, to, 'CRE'])].
[sujeto(['We', established, a, model, in, which, 'FHL3']), verbo([promotes]), complemento([the, expression, of, 'MyHC', 2, a, through, 'CREB-mediated', transcription, and, inhibits, the, expression, of, 'MyHC', 1, /, slow, by, inhibiting, 'MyoD', transcription, activity, during, myogenesis])].
[sujeto(['Many', 'SET', domain, containing, proteins, and, several, 'PRDM', members]), verbo([have]), complemento([been, found, to, possess, histone, methyltransferase, 'activity,', yet, the, role, of, 'PRDM16', and, its, 'PR', domain, in, the, epigenetic, regulation, of, myogenic, and, adipogenic, genes, during, 'myoblasts/adipocytes', transdifferentiation, remains, unexplored])].
[sujeto(['In', this, 'study,', we, transfected, 'C2C12', myoblasts, to, stably]), verbo([express]), complemento(['PRDM16', and, observed, the, repression, of, myogenic, genes, and, activation, of, adipogenic, genes, at, both, proliferation, and, differentiation, stages])].
[sujeto(['Ectopic', 'PRDM16-induced', reprogramming, of, myogenic, and, adipogenic, genes, was]), verbo([associated]), complemento([with, the, hypermethylation, on, some, 'CpG', sites, in, the, enhancer, or, promoter, of, 'MyoD', and, 'myogenin,', but, the, methylation, status, of, 'PPARγ', promoter, was, not, affected])].
[sujeto(['C2C12', cells]), verbo([expressing]), complemento([truncated, 'PRDM16', lacking, 'PR', domain, '(', 'ΔPR-PRDM16)', demonstrated, attenuation, of, both, adipogenic, and, myogenic, 'potentials,', indicated, by, 'PPARγ', inactivation, and, decreased, triglyceride, 'deposition,', as, well, as, a, downregulation, of, 'MyoD,', 'MyHC', and, 'MCK', 'genes,', as, compared, with, 'C2C12', cells, expressing, intact, 'PRDM16'])].
[sujeto(['Furthermore,', 'C2C12', cells]), verbo([expressing]), complemento(['ΔPR-PRDM16', exhibited, significant, differences, in, histone, modifications, on, the, promoters, of, 'MyoD', and, 'PPARγ', genes])].
[sujeto(['Taken', 'together,', 'PRDM16-induced', 'C2C12', transdifferentiation, is]), verbo([associated]), complemento([with, alterations, in, 'CpG', methylation, of, myogenic, 'factors,', and, 'PR', domain, affects, both, myogenesis, and, adipogenesis, with, modified, histone, methylation, marks, on, 'MyoD', and, 'PPARγ', promoters])].
[sujeto(['Myostatin', '(', 'MSTN)', is, a, secreted, protein, belonging, to, the, transforming, growth, 'factor-β', '(', 'TGF-β)', family, that, is, primarily]), verbo([expressed]), complemento([in, skeletal, muscle, and, also, functions, in, adipocyte, maturation])].
[sujeto(['Studies']), verbo([have]), complemento([shown, that, 'MSTN', can, inhibit, adipogenesis, in, muscle, satellite, cells, '(', 'MSCs)', but, not, in, 'adipose-derived', stem, cells, '(', 'ADSCs)'])].
[sujeto(['However,', the, mechanism, by, which, 'MSTN', differently]), verbo([regulates]), complemento([adipogenesis, in, these, two, cell, types, remains, unknown])].
[sujeto(['To', investigate, whether, 'MSTN', differentially]), verbo([regulates]), complemento(['PPARγ', and, 'MyoD,', we, analyzed, 'PPARγ', and, 'MyoD', expression, by, assessing, 'mRNA,', protein, and, methylation, levels, in, 'ADSCs', and, 'MSCs', after, treatment, with, 100, 'ng/mL', 'MSTN', for, 0, ',', 24, ',', and, 48, h])].
[sujeto(['MyoD', expression, was, significantly]), verbo([increased]), complemento([in, 'ADSCs', and, decreased, in, 'MSCs'])].
[sujeto(['The', 'CpG', methylation, levels, of, the, 'PPARγ', and, 'MyoD', promoters, were]), verbo([decreased]), complemento([in, 'ADSCs', and, increased, in, 'MSCs'])].
[sujeto(['Therefore,', this, study, demonstrated, that, the, different, regulatory, adipogenic, roles, of, 'MSTN', in, 'ADSCs', and, 'MSCs']), verbo([act]), complemento([by, differentially, regulating, 'PPARγ', and, 'MyoD', expression])].
[sujeto(['Hyperplasia', and, hypertrophy, are, two, distinct, processes, of, skeletal, muscle, growth]), verbo([regulated]), complemento([by, four, myogenic, regulatory, factors, '(', 'MRFs,', contains, 'MyoD,', 'Myf5,', 'Mrf4', and, myogenin, '(', 'MyoG))', and, myostatin, '(', 'MSTN)'])].
[sujeto(['amblycephala,', the, diameter, scope, of, 'epaxial,', horizontal, septum, and, hypaxial, muscle, fibers, including, red, and, white, muscle, in, 2, -, 'year-old', fish, exhibited, broader, with, dramatic, reduction, in, frequency, distribution, of, &, 'lt;20', μm, 'diameter,', nevertheless, observable]), verbo([increase]), complemento([in, frequency, distribution, of, &, 'gt;50', μm, diameter])].
[sujeto(['Intermyofibrillar', '(', 'IM)', nuclei, were, also]), verbo([found]), complemento([except, numerous, subsarcolemmal, '(', 'SS)', nuclei, in, 2, -, 'year-old', 'fish,', whereas, only, 'SS', nuclei, were, observed, in, 1, -, 'year-old', fish])].
[sujeto(['Moreover,', we, observed, predominant]), verbo([increase]), complemento([in, the, mRNA, levels, of, 'MyoD,', 'Myf5,', 'Mrf4,', and, 'MSTN', during, muscle, development, of, fish, in, 2, -, 'year-old', fish, except, 'MyoG'])].
[sujeto(['Electrical', stimulation, is, often, used, to]), verbo([prevent]), complemento([muscle, atrophy, and, preserve, contractile, 'function,', but, its, effects, on, the, satellite, cell, population, after, nerve, injury, are, not, well, understood])].
[sujeto(['More', 'Pax7+/MyoD+', nuclei, in]), verbo([stimulated]), complemento([muscles, were, observed, than, in, 'non-stimulated', muscles])].
[sujeto([eMyHC, expression, was, elevated, in]), verbo([stimulated]), complemento([muscles, and, correlated, positively, with, enhanced, force, production])].
[sujeto(['Four', of, the, five, 'SNVs', were, significantly]), verbo([associated]), complemento([with, growth, performance, and, carcass, traits, of, the, cattle])].
[sujeto(['Statistical', analyses, of, combined, genotypes, indicated, that, some, combined, genotypes, were, significantly, or, highly, significantly]), verbo([associated]), complemento([with, growth, and, carcass, traits, in, the, 'Qinchuan', cattle, population])].
[sujeto([qPCR, analyses, also, showed, that, bovine, 'CSRP3', gene, was, exclusively]), verbo([expressed]), complemento([in, longissimus, dorsi, muscle, and, heart, tissues])].
[sujeto(['We']), verbo([found]), complemento([that, the, expression, levels, of, 'Tmod4', were, higher, in, skeletal, muscle, and, adipose, tissues])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, the, expression, of, 'Tmod4', was, decreased, in, myogenesis, while, increased, in, adipogenesis])].
[sujeto(['Then,', the, transcriptional, regulation, analysis, of, 'Tmod4', promoter, showed, that, 'Tmod4', could, be]), verbo([regulated]), complemento([directly, by, myogenic, factors, and, adipogenic, factors])].
[sujeto(['Furthermore,', the, roles, of, 'Tmod4', in, the, myogenesis, and, adipogenesis, were, confirmed, by, its, 'over-expression', in, 'C2C12', cells, and, 3, 'T3', 'cells,', which]), verbo([suggested]), complemento([that, 'Tmod4', could, promote, adipogenesis, by, 'up-regulating', the, adipogenic, factors, but, moderately, delay, the, myogenesis])].
[sujeto(['It', is, showed, that, the, expression, of, 'Tmod4', was]), verbo([activated]), complemento([in, adipogenesis, by, adipogenic, factors, while, inhibited, in, myogenesis, by, myogenic, factors])].
[sujeto(['Moreover,', 'Tmod4', could]), verbo([promote]), complemento([adipogenesis, by, 'up-regulating', the, expression, of, adipogenic, factors, while, moderately, delaying, the, myogenesis])].
[sujeto(['Our', study]), verbo([provides]), complemento([an, important, basis, for, further, understanding, the, regulation, and, function, of, porcine, 'Tmod4', in, muscle, and, fat, development])].
[sujeto(['Nectin-like', 'molecule-2', '(', 'Necl-2),', a, junction, 'molecule,', is, exclusively]), verbo([expressed]), complemento([by, spermatogenic, cells])].
[sujeto(['It']), verbo([mediates]), complemento([homophilic, interaction, between, germ, cells, and, heterophilic, interaction, between, 'Sertoli', and, germ, cells])].
[sujeto(['Knockout', studies]), verbo([have]), complemento([shown, that, loss, of, 'Necl-2', causes, male, 'infertility,', suggesting, 'Necl-2-based', cell, adhesion, is, crucial, for, spermatogenesis])].
[sujeto(['Transforming', growth, 'factor-βs', '(', 'TGF-βs)', are, crucial, for]), verbo([regulating]), complemento([cell, junction, restructuring, that, are, required, for, spermatogenesis])].
[sujeto(['In', the, present, 'study,', we, aim, to, investigate, the, mechanism, on, how, 'TGF-β1']), verbo([regulates]), complemento(['Necl-2', expression, to, achieve, timely, junction, restructuring, in, the, seminiferous, epithelium, during, spermatogenesis])].
[sujeto(['We']), verbo([have]), complemento([demonstrated, that, 'TGF-β1', reduces, 'Necl-2', mRNA, and, protein, levels, at, both, transcriptional, and, 'post-translational', levels])].
[sujeto(['Using', inhibitor, and, clathrin, 'shRNA,', we]), verbo([have]), complemento([revealed, that, 'TGF-β1', induces, 'Necl-2', protein, degradation, via, 'clathrin-dependent', endocytosis])].
[sujeto(['Mutational', studies, coupled, with, knockdown, experiments]), verbo([have]), complemento([shown, that, 'TGF-β1-induced', 'Necl-2', repression, requires, activation, of, 'Smad', proteins])].
[sujeto(['EMSA', and, 'ChIP', assays, further, confirmed, that, 'TGF-β1']), verbo([promotes]), complemento([the, binding, of, 'Smad', proteins, onto, 'MyoD', and, 'CCAATa', motifs, in, vitro, and, in, vivo])].
[sujeto(['Taken', 'together,', 'TGF-β1', is, a, potent, cytokine, that]), verbo([provides]), complemento([an, effective, mechanism, in, controlling, 'Necl-2', expression, in, the, testis, via, 'Smad-dependent', gene, repression, and, 'clathrin-mediated', endocytosis])].
[sujeto(['Semaphorin4d', '(', 'SEMA4D),', also, known, as, 'CD100,', an, oligodendrocyte, secreted, 'R-Ras', 'GTPase-activating', protein, '(', 'GAP),', affecting, axonal, growth, is]), verbo([involved]), complemento([in, a, range, of, processes, including, cell, 'adhesion,', 'motility,', 'angiogenesis,', immune, responses, and, tumour, progression])].
[sujeto(['This', study]), verbo([has]), complemento([focused, on, the, role, of, sema4d, in, the, development, and, expression, patterns, in, zebrafish, embryos, and, the, effect, of, its, suppression, on, development, using, 'sema4d-specific', antisense, 'morpholino-oligonucleotides'])].
[sujeto(['In', this, study, the, knockdown, of, 'sema4d,']), verbo([expressed]), complemento([at, all, developmental, 'stages,', lead, to, defects, in, the, hindbrain, and, trunk, structure, of, zebrafish, embryos])].
[sujeto(['In', 'addition,', these, phenotypes, appeared, to, be]), verbo([associated]), complemento([with, the, abnormal, expression, of, three, hindbrain, rhombomere, boundary, 'markers,', 'wnt1,', epha4a, and, foxb1])].
[sujeto(['Further,', a, notable]), verbo([increase]), complemento([of, cell, apoptosis, appeared, in, the, sema4d, knockdown, 'embryos,', while, no, obvious, reduction, in, cell, proliferation, was, observed])].
[sujeto(['Collectively,', these, data]), verbo([suggest]), complemento([that, sema4d, plays, an, important, role, in, the, development, of, the, hindbrain, and, skeletal, muscle])].
[sujeto(['Both', skeletal, muscle, and, tendon, are, closely]), verbo([associated]), complemento([during, their, development, and, both, can, bear, strong, mechanical, loading, dynamically])].
[sujeto(['Quantitatively,', 'MDCs']), verbo([expressed]), complemento([higher, levels, of, 'GDF-8,', collagens, 'III', and, 'VI', '(', p, &, 'lt;', 0.05, ')', ',', whereas, tenocytes, expressed, higher, levels, of, collagen, 'I,', scleraxis, and, tenomodulin, '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['Furthermore,', with, the]), verbo([increase]), complemento([of, implantation, 'time,', 'MDCs', gradually, lost, their, expression, of, myogenic, molecules, of, 'MyoD', and, desmin, and, gained, the, expression, of, 'tenomodulin,', a, marker, for, tenocytes])].
[sujeto(['It']), verbo([has]), complemento([been, suggested, that, mouse, lbx1, is, essential, for, directing, hypaxial, myogenic, precursor, cell, migration])].
[sujeto(['In', 'zebrafish,', the, expression, of, 'lbx1a,', 'lbx1b,', and, lbx2]), verbo([has]), complemento([been, observed, in, pectoral, fin, buds])].
[sujeto(['It']), verbo([has]), complemento([also, been, shown, that, knocking, down, endogenous, lbx2, in, zebrafish, embryos, diminishes, myoD, expression, in, the, pectoral, fin, bud])].
[sujeto(['Our', transplantation, studies, further, demonstrated, that, the, overexpression, of, lbx2, autonomously]), verbo([promotes]), complemento(['CE', movements])].
[sujeto(['We']), verbo([have]), complemento([demonstrated, that, application, of, the, wnt5b, 'MO,', a, 'dominant-negative', form, of, disheveled, '(', 'Dvl)', and, a, chemical, inhibitor, of, 'Rho-associated', kinase, 'Y27632', in, zebrafish, embryos, have, effects, reminiscent, that, are, of, the, 'CE', and, hypaxial, myogenesis, defects, observed, in, lbx2, morphants])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, the, key, noncanonical, 'Wnt', signaling, components, 'Wnt5,', 'Dvl,', and, 'RhoA', are, downstream, effectors, involved, in, the, regulative, roles, of, lbx2, in, 'CE', movement, and, hypaxial, myogenesis, during, zebrafish, embryogenesis])].
[sujeto(['It', encodes, for, skeletal, 'muscle-specific', transcription, factors, containing, highly]), verbo([conserved]), complemento([basic, 'helix-loop-helix', regions, that, perform, important, roles, in, the, 'initiation,', 'maintenance,', and, regulation, of, phenotypic, traits])].
[sujeto(['A', 'C→G', transversion, at, position, 624, was, detected, in, exon, 1, of, the, 'MyoD1', 'gene;', it]), verbo([causes]), complemento([an, amino, acid, substitution, '(', '(', 624, ')', 'serine/(624)cysteine)'])].
[sujeto(['Least', squares, analysis, showed, that, this, 'SNP', is, not, significantly]), verbo([associated]), complemento([with, back, fat, 'thickness,', eye, muscle, 'area,', intramuscular, 'fat,', or, marbling])].
[sujeto(['The', 'MyoD', mRNA]), verbo([expressed]), complemento([in, both, kinds, of, muscle, tissues, and, the, expression, profile, had, a, similar, 'trend,', although, the, expression, level, of, 'MyoD', in, the, breast, muscle, was, significantly, higher, than, that, in, the, leg, muscle, at, each, developmental, stages, '(', 'p&lt;0'])].
[sujeto(['Results']), verbo([suggested]), complemento([that, 'MyoD', might, have, potential, functions, in, controlling, muscle, fiber, phenotype, during, the, secondary, myogenesis, of, muscle, development])].
[sujeto(['These', fundamental, works, may]), verbo([provide]), complemento([some, valuable, clues, for, knowing, the, roles, of, 'MyoD', in, the, myogenesis, and, the, muscle, fiber, type, differentiation, in, birds])].
[sujeto(['Mesenchymal', stromal, cells, '(', 'MSC)']), verbo([have]), complemento([been, thought, to, be, attractive, candidates, for, the, treatment, of, 'Duchenne', muscular, dystrophy, '(', 'DMD),', but, the, rate, of, 'MSC', myogenesis, is, very, low])].
[sujeto(['Adipogenic', differentiation, of, rMSC]), verbo([inhibited]), complemento([by, 'anti-Mstn', 'Ab', was, evaluated, by, 'Oil', 'Red', 'O', staining])].
[sujeto(['Five-azacytidine-mediated', myogenic, differentiation]), verbo([induced]), complemento([significant, endogenous, 'Mstn', expression])].
[sujeto(['Anti-Mstn', 'Ab', improved, the, expression, of, 'MyoD,', myogenin, and, 'MHC-alpha', and]), verbo([inhibited]), complemento([adipocyte, formation])].
[sujeto(['In', accordance, with, the]), verbo([increased]), complemento([motor, function, and, muscle, 'mass,', dystrophin, expression, had, increased])].
[sujeto(['Furthermore,', serum, 'CK', and, centrally, nucleated, fiber, '(', 'CNF)', levels]), verbo([decreased]), complemento(['slightly,', suggesting, specific, pathologic, features, of, the, dystrophic, muscle, were, partially, restored])].
[sujeto(['Using', 'anti-Mstn', 'Ab,', we]), verbo([found]), complemento([that, inhibition, of, 'Mstn', improved, myogenic, differentiation, of, rMSC, in, vitro, and, in, vivo])].
[sujeto(['A', combination, of, 'Mstn', blockade, and, 'MSC', transplantation, may]), verbo([provide]), complemento([a, pharmacologic, and, 'cell-based', strategy, for, the, treatment, of, 'DMD'])].
[sujeto(['To', explore, the, in, vitro, differentiation, of, the, rat, mesenchymal, stem, cells, '(', 'MSCs)', into, the, skeletal, muscle, cells]), verbo([induced]), complemento([by, the, myoblast, differentiation, factor, '(', 'MyoD)', and, 5, -, azacytidine])].
[sujeto(['The', differentiation, of, the, 3, rd, passage, of, 'MSCs', was]), verbo([induced]), complemento([by, the, combination, of, 5, -, 'azacytidine,', 'MyoD,', transforming, growth, factor, 'beta1,', and, the, 'insulin-like', growth, factor, 1])].
[sujeto(['Nine', days, after, the, 'induction,', the]), verbo([induced]), complemento(['MSCs', were, 'collected,', which, were, analyzed, with, the, 'MTT', 'chromatometry,', the, flow, 'cytometry,', and, the, immunohistochemistry])].
[sujeto(['The', primarily, cultured, 'MSCs', grew, as, a, colony, on, the, walls, of, the, culture, 'bottle;', after, the, culture, for, 5, -, 7, 'days,', the, cells, were, shaped, like, the, 'fibroblasts,', the, big, flat, polygonal, 'cells,', the, 'medium-sized', polygonal, 'cells,', and, the, small, triangle, 'cells;', after, the, culture, for, 12, 'days,', the, cells, were]), verbo([found]), complemento([to, be, 'fused,', spreading, all, over, the, bottle, 'bottom,', but, 'MSCs', were, unchanged, too, much, in, shape])].
[sujeto(['However,', after, the, culture, for, 7, 'days,', the, cells, grew, 'remarkably,', the, cell, volume]), verbo([increased]), complemento([gradually, in, a, form, of, 'ellipse,', fusiform, or, irregularity])].
[sujeto(['After', the, culture, for, 14, 'days,', the, proliferated, fusiform, cells, began, to]), verbo([increase]), complemento([in, a, great, amount])].
[sujeto(['After', the, culture, for, 18, -, 22, 'days,', the, myotubes]), verbo([increased]), complemento([in, number, and, 'volume,', with, the, nucleus, increased, in, 'number,', and, the, 'newly-formed', myotubes, and, the, fusiform, myoblst, grew, parallelly, and, separately])].
[sujeto(['The']), verbo([induced]), complemento(['MSCs', were, found, to, be, positive, for, desmin, and, specific, myoglobulin, of, the, skeletal, muscle])].
[sujeto(['The', flow, cytometry, showed, that, most, of, the, 'MSCs', and, the]), verbo([induced]), complemento(['MSCs', were, in, the, stages, of, 'G0/G1,', accounting, for, 79.4, '%', and, 62.9, '%', ',', 'respectively;', 'however,', the, cells, in, the, stages, of, 'G2/S', accounted, for, 20.6, '%', and, 36.1, '%'])].
[sujeto(['The', growth, curve, was, drawn, based, on, 'MTT,which', showed, that, 'MSCs', were, greater, in, the, growth, speed, than, the]), verbo([induced]), complemento(['MSCs'])].
[sujeto(['Heart', failure, was]), verbo([associated]), complemento([with, marked, effects, on, the, expression, of, 'Bmal1,', 'Clock', and, 'Rora', in, addition, to, several, 'non-circadian', genes, important, in, regulating, skeletal, muscle, phenotype, including, 'Mck,', 'Ttn', and, 'Mef2c'])].
[sujeto(['We']), verbo([found]), complemento([that, 'hypertensive/hypertrophic', 'SHR', showed, a, dampening, of, peak, 'Bmal1', and, 'Rev-erb', expression, in, the, 'liver,', and, the, 'clock-controlled', gene, 'Pgc1α', in, the, gastrocnemius])].
[sujeto(['In', 'addition,', the, 'core-clock', gene, 'Clock', and, the, 'muscle-specific,', 'clock-controlled', gene, 'Myod1,', no, longer]), verbo([maintained]), complemento([a, circadian, pattern, of, expression, in, gastrocnemius, from, the, hypertensive, 'SHR'])].
[sujeto(['These', findings]), verbo([provide]), complemento([a, framework, to, suggest, a, mechanism, whereby, chronic, heart, failure, leads, to, skeletal, muscle, 'pathologies;', prolonged, dysregulation, of, the, molecular, clock, in, skeletal, muscle, results, in, altered, 'Clock,', 'Pgc1α', and, 'Myod1', expression, which, in, turn, leads, to, the, 'mis-regulation', of, target, genes, important, for, mechanical, and, metabolic, function, of, skeletal, muscle])].
[sujeto(['In', 'vertebrates,', transcriptional, control, of, skeletal, muscle, genes, during, differentiation, is]), verbo([regulated]), complemento([by, enhancers, that, direct, the, combinatorial, binding, 'and/or', interaction, of, 'MEF2', and, the, bHLH, 'MyoD', family, of, myogenic, factors])].
[sujeto(['We']), verbo([have]), complemento([shown, that, 'Drosophila', 'MEF2', plays, a, role, similar, to, its, vertebrate, counterpart, in, the, regulation, of, the, 'Tropomyosin', 'I', gene, in, the, development, of, 'Drosophila', somatic, 'muscles,', 'however,', unlike, 'vertebrates,', 'Drosophila', 'MEF2', interacts, with, a, muscle, activator, region, that, does, not, have, binding, sites, for, myogenic, 'bHLH-like', factors, or, any, other, known, 'Drosophila', transcription, factors])].
[sujeto(['We', describe, here, the, isolation, and, characterization, of, a, component, of, the, muscle, activator, region, that, we]), verbo([have]), complemento([named, 'PDP1', '(', 'PAR', domain, protein, 1, ')'])].
[sujeto(['We', show, that, 'PDP1', is]), verbo([involved]), complemento([in, regulating, expression, of, the, 'Tropomyosin', 'I', gene, in, somatic, 'body-wall', and, pharyngeal, muscles, by, binding, to, 'DNA', sequences, within, the, muscle, activator, that, are, required, for, activator, function])].
[sujeto(['Mutations', that, eliminate, 'PDP1']), verbo([binding]), complemento([eliminate, muscle, activator, function, and, severely, reduce, expression, of, a, muscle, activator, plus, 'MEF2', 'mini-enhancer'])].
[sujeto(['These', and, previous, results]), verbo([suggest]), complemento([that, 'PDP1', may, function, as, part, of, a, larger, 'protein/DNA', complex, that, interacts, with, 'MEF2', to, regulate, transcription, of, 'Drosophila', muscle, genes])].
[sujeto(['Furthermore,', in, addition, to, being]), verbo([expressed]), complemento([in, the, mesoderm, that, gives, rise, to, the, somatic, 'muscles,', 'PDP1', is, also, expressed, in, the, mesodermal, fat, 'body,', the, developing, midgut, 'endoderm,', the, hindgut, and, 'Malpighian', 'tubules,', and, the, epidermis, and, central, nervous, 'system,', suggesting, that, 'PDP1', is, also, involved, in, the, terminal, differentiation, of, these, tissues])].
[sujeto(['Cellular', retinoic, acid]), verbo([binding]), complemento([protein, 2, '(', 'CRABP2),', a, member, of, a, family, of, specific, carrier, proteins, for, 'Vitamin', 'A,', belongs, to, a, family, of, small, cytosolic, lipid, binding, proteins])].
[sujeto(['Our', previous, study]), verbo([suggested]), complemento([that, 'CRABP2', was, involved, in, skeletal, muscle, 'development;', 'however,', the, molecular, function, and, regulatory, mechanism, of, 'CRABP2', in, myogenesis, remained, unclear])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, the, expression, of, the, 'CRABP2', gene, was, upregulated, during, 'C2C12', differentiation])].
[sujeto(['An', 'over-expression', assay, revealed, that, 'CRABP2']), verbo([promotes]), complemento([myogenic, transformation, by, regulating, the, cell, cycle, during, 'C2C12', differentiation])].
[sujeto(['The', region, from, -, 459, to, -, 4, bp, was, identified, as, the, core, promoter, and, contains, a, 'TATA', 'box,', a, 'GC', box, and]), verbo([binding]), complemento([sites, for, the, transcription, factors, 'MyoD', and, 'Sp1'])].
[sujeto(['Over-expression,', 'site-directed', mutagenesis, and, 'EMSA', assays, indicated, that, the, transcription, factors, 'MyoD', and, 'Sp1']), verbo([regulate]), complemento(['CRABP2', expression, and, promote, myoblast, differentiation, in, 'C2C12', cells])].
[sujeto(['The', myocyte, enhancer, factor, 2, 'C', '(', 'MEF2C)', is, a, member, of, the, 'MEF2', family, of, transcription, 'factors,']), verbo([involved]), complemento([in, skeletal, muscle, development])].
[sujeto(['In', this, study, we]), verbo([report]), complemento([the, cDNA, sequence, and, isolate, the, 5, '\'', upstream, region, of, the, mef2c, gene, from, porcine, genomic, 'DNA', using, 'PCR-based', 'GenomeWalker'])].
[sujeto(['No', typical, 'TATA,', 'GC', box, or, 'CAAT', box]), verbo([binding]), complemento([site, was, found, in, porcine, mef2c, 5, '\'', upstream, 'region,', whereas, some, potential, binding, sites, for, 'MyoD', '(', 'E-box),', 'MEF2', and, 'MBF1', were, present, in, the, proximal, upstream, region])].
[sujeto(['Co-transfection', assays, demonstrated, that, 'MBF1']), verbo([bound]), complemento([the, mef2c, promoter, and, inhibited, mef2c, expression])].
[sujeto(['These', results, may, be, useful, for, elucidating, the, regulation, mechanisms, of, 'mef2c,', which]), verbo([interacts]), complemento([with, other, factors, to, regulate, target, genes])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'SNPs', analysed, in, this, study, are, not, causative, 'mutations,', but, can, be, considered, as, markers, of, some, 'other,', still, unrevealed, genetic, polymorphism, that, influences, the, physiological, processes, and, phenotypic, traits, considered, in, this, study])].
[sujeto(['Tissue', factor, pathway, 'Inhibitor-2', '(', 'TFPI-2)', is]), verbo([associated]), complemento([with, extracellular, matrices, and, plays, a, major, role, in, cell, migration, and, tumor, invasion])].
[sujeto(['Moreover,', several, putative]), verbo([binding]), complemento([sites, for, transcription, factors, were, identified, '(', 'MyoD,', 'LYF1,', 'NF-Y,', 'GATA,', 'oct-1,', 'AP-1,', 'Sp1,', 'NF1,', 'NF-kappa', 'B', and, 'egr-1)'])].
[sujeto(['Luciferase', activity, consistently]), verbo([increased]), complemento([after, stimulation, of, 'JEG-3', cells, by, phorbol, 12, -, myristate, 13, -, acetate, indicating, that, 'NF1,', 'NF-kappa', 'B', and, 'egr-1/Sp1', binding, sites, are, crucial, in, inducible, 'TFPI-2', expression])].
[sujeto(['Moreover,', negative, regulatory, regions, included, 'AP-1']), verbo([binding]), complemento([sites, were, identified])].
[sujeto(['In', 'addition,', cotransfection, analysis, indicated, that, the, 'MyoD']), verbo([activates]), complemento([the, mouse, mafB, promoter, and, the, gene, is, positively, 'auto-regulated', by, its, own, product])].
[sujeto(['The', author]), verbo([reports]), complemento([the, isolation, and, analysis, of, genomic, clone, of, the, mouse, mafB, gene])].
[sujeto(['A', 'TATA-like', sequence, '(', 5, '\'', -, 'GATAAAA-3\')', and, an, inverted, 'CCAAT-box', '(', 5, '\'', -, 'ATTGG-3\')', were]), verbo([found]), complemento([to, be, located, at, nucleotide, -, 31, and, -, 86, ',', referring, to, the, transcription, initiation, 'site,', respectively])].
[sujeto(['Promoter', activity, of, the, 5, '\'', -, flanking, region, was, analyzed, by, reporter, transfection, 'assay,', which]), verbo([suggested]), complemento([that, these, segments, were, an, important, transcriptional, activator])].
[sujeto(['It', was, also]), verbo([suggested]), complemento([that, 'MyoD', transactivated, the, mouse, mafB, promoter, and, this, gene, was, positively, autoregulated, by, its, 'product,', 'MafB'])].
[sujeto(['For', the, mouse, 'UCP2,', the, region, near, the, 'transcription-initiation', site, lacked, the, typical, 'TATA', 'box,', but, was, 'GC-rich,', resulting, in, presence, of, several, potential, specificity, protein, 1, '(', 'Sp-1),', activator, protein, '(', 'AP)-1', and, 'AP-2']), verbo([binding]), complemento([sites])].
[sujeto(['The', putative, regulatory, motifs, for, 'muscle-regulatory', protein, '(', 'MyoD),', 'brown-fat', regulatory, 'element,', 'CCAAT', 'box,', 'cAMP-response', element, and, 'Y', box, were, also]), verbo([found]), complemento([in, the, mouse, 'UCP2', promoter, region, by, 'computer-assisted', analysis])].
[sujeto(['From', the, results, of, 'Northern-blot', analysis, and, transient, expression, 'assay,', we]), verbo([found]), complemento([that, the, mouse, 'UCP2', gene, responded, to, the, 'cAMP-dependent', protein, kinase, 'alpha-catalytic', subunit, signal, activation, at, the, transcription, level])].
[sujeto(['In', 'particular,', the, region, from, nt, -, 233, to, -, 34, significantly]), verbo([induced]), complemento(['PLAP', activity, in, the, cell, lines, derived, from, various, tissues, and, in, the, primary, culture, cells, of, rat, brown, adipose, 'tissue,', suggesting, that, this, region, is, most, important, for, the, ubiquitous, expression, of, mouse, 'UCP2', mRNA])].
[sujeto(['Furthermore,', it, was, shown, that, two, silencer, elements, were]), verbo([involved]), complemento([in, the, mouse, 'UCP2', 'gene;', one, was, located, between, nt, -, 2746, and, -, 602, ',', and, the, other, was, identified, in, intron, 1])].
[sujeto(['These', regions, deprived, the, enhancer, of, the, ability, to]), verbo([induce]), complemento(['PLAP', activity])].
[sujeto(['This', study, shows, a, fundamental, role, for, positive, and, negative, 'cis-acting', 'DNA', elements, in]), verbo([regulating]), complemento([the, basal, and, 'cAMP-induced', transcription, activity, of, the, mouse, 'UCP2', gene])].
[sujeto(['Uncoupling', protein, 3, '(', 'UCP3),', a, member, of, the, 'UCP', 'family,', mainly]), verbo([expressed]), complemento([in, skeletal, muscle, could, be, responsible, for, thermogenesis, in, humans])].
[sujeto(['We']), verbo([report]), complemento([the, hUCP3, transcription, initiation, on, a, 'G', located, 764, nucleotides, upstream, the, 'A', contained, in, the, first, translated, codon])].
[sujeto(['Therefore,', hUCP3, first, exon]), verbo([has]), complemento([669, bases, of, untranslated, sequence])].
[sujeto(['We', also]), verbo([report]), complemento([the, cloning, and, sequencing, of, seven, kilobases, from, the, gene, 5, '\'', end, and, analyze, the, features, of, the, potential, proximal, promoter])].
[sujeto(['The', 'MyoD', family]), verbo([binding]), complemento(['motif,', called, 'E-box,', is, the, most, abundant, on, this, region])].
[sujeto(['Other', 'muscle-specific', motives, present, in, the, potential, proximal, promoter, include, a, 'MEF2', site, as, well, as]), verbo([binding]), complemento([sequences, for, ubiquitous, factors, such, as, 'GC', box, and, two, 'CAAT', boxes])].
[sujeto(['Additionally,', three, putative, peroxisome, proliferator, and, one, thyroid, hormone, response, elements, '(', 'PPRE', and, 'TRE,', 'respectively)', are, 'found,', which]), verbo([suggest]), complemento([a, potential, role, for, the, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)', and, thyroid, hormone, in, human, 'UCP3', gene, expression])].
[sujeto(['The', aim, of, our, study, was, to, isolate, novel, 'gene(s)']), verbo([involved]), complemento([in, cell, differentiation, and, embryonic, liver, development])].
[sujeto(['Analysis', of, the, 'cded/lior', promoter, region, revealed, a, high, 'GC-content,', high, ratio, of, 'CpG/GpC,', multiple, 'GC-boxes,', the, lack, of, a, 'TATA', 'box,', 'CTF/NFI', 'element,', and, two, 'MyoD-MCK']), verbo([binding]), complemento([sites])].
[sujeto(['These', characteristics, are, also]), verbo([found]), complemento([in, several, genes, important, in, the, regulation, of, cell, growth, or, 'DNA', 'synthesis,', such, as, transforming, growth, 'factor-beta1,', 'c-Ha-ras,', nerve, growth, 'factor,', epidermal, growth, factor, 'receptor,', and, 'DNA', polymerase, beta])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'cded/lior', is, a, 'mesoderm/muscle-specific', transcript, that, may, be, involved, in, the, mesodermal, inductive, and, regulatory, interactions, required, for, liver, formation, and, embryonic, development])].
[sujeto(['We']), verbo([have]), complemento([mapped, two, transcriptional, start, sites, by, primer, extension])].
[sujeto(['This', sequence, contains, a]), verbo([conserved]), complemento(['GC', box, to, which, the, transcription, factor, 'Sp1', binds])].
[sujeto(['Reporter', gene, constructs, containing, a, 2, -, kilobase, pair, first, intron, fragment, of, the, myotonic, dystrophy, protein, kinase, gene]), verbo([enhances]), complemento([reporter, activity, up, to, 6, -, fold, in, the, human, rhabdomyosarcoma, myoblast, cell, line, 'TE32', but, not, in, 'NIH', 3, 'T3', fibroblasts])].
[sujeto(['Deletion', analysis, of, four, 'E-box', elements, within, the, first, intron]), verbo([reveal]), complemento([that, these, elements, contribute, to, enhancer, activity, similarly, in, 'TE32', myoblasts, and, 10, 'T1/2', fibroblasts])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'E-boxes', within, the, myotonic, dystrophy, protein, kinase, first, intron, mediate, interactions, with, upstream, promoter, elements, to, 'up-regulate', transcription, of, this, gene, in, myoblasts])].
[sujeto(['Glypicans', are, a, member, of, a, family, of, glycosylphosphatidylinositol, anchored, heparan, sulfate, proteoglycans, that, are]), verbo([expressed]), complemento([in, cell, and, development, specific, patterns])].
[sujeto(['One', of, the, genomic, clones, extended, approximately, 2.8, kb, 5, '\'', of, the, exon, 1, coding, 'sequence,', and, is, thus, likely, to, contain, sequences, that]), verbo([regulate]), complemento(['GPC1', gene, expression])].
[sujeto(['A', search, for, potential, transcription, factor]), verbo([binding]), complemento([sites, revealed, a, number, of, such, 'motifs,', including, 'Sp1', '(', 'GC', 'box),', 'NF-kappaB,', and, 'MyoD', '(', 'E-box)'])].
[sujeto(['Muscle', glycogen, phosphorylase, '(', 'MGP)', transcript, and, protein, levels]), verbo([increase]), complemento([during, skeletal, muscle, development, in, tandem, with, the, products, of, other, muscle, genes, responsible, for, glucose, and, glycogen, metabolism])].
[sujeto(['Three', of, the, 'E', box, motifs, in, the, 'MGP', proximal, promoter]), verbo([interacted]), complemento([with, 'C2C12', nuclear, proteins])].
[sujeto(['Mutational', analyses, of, the, 'MGP', promoter, demonstrated, that]), verbo([increased]), complemento([expression, in, 'C2C12', myotubes, did, not, require, any, of, the, 'E', box, motifs, or, the, 'CArG-like', element])].
[sujeto(['The', functional, studies]), verbo([suggest]), complemento([that, 'MGP', is, developmentally, regulated, during, myogenesis, by, alternative, pathways, that, utilize, unidentified, regulatory, elements, or, ancillary, factors])].
[sujeto(['One', alternately, spliced, exon, encodes, part, of, the, 'MYC-binding', 'domain,']), verbo([suggesting]), complemento([that, splicing, controls, the, 'MYC-binding', capacity, of, 'BIN1', polypeptides])].
[sujeto(['The', 'full-length', cDNA, encoding, the, murine, ryudocan, core, protein]), verbo([has]), complemento([now, been, cloned, and, sequenced])].
[sujeto(['The', promoter, region, of, the, mouse, gene, contains, various, 'cis-acting', 'elements,', including, a, 'TATA-like', box, and, a, 'GC', box, as, well, as, potential]), verbo([binding]), complemento([sites, for, the, transcription, factors, 'NF-IL6,', 'MyoD,', 'GATA,', 'C/EBP,', 'AP-2,', 'NF-kappaB,', 'AP-1,', and, 'Sp1'])].
[sujeto(['Deletion', analysis]), verbo([suggested]), complemento([that, the, proximal, promoter, region, including, the, 'TATA-like', 'box,', the, 'GC', 'box,', and, other, 'Sp1', binding, sites, was, required, for, full, transcriptional, activity])].
[sujeto(['These', findings, will, be, useful, for, the, study, of, ryudocan, gene, regulation, and, the, generation, of, mice, with]), verbo([targeted]), complemento([disruption, of, the, gene])].
[sujeto(['Mitogen-activated', protein, kinase, '(', 'MAPK)', or, extracellular, 'signal-regulated', kinase, are, ubiquitous, kinases]), verbo([conserved]), complemento([from, fungi, to, mammals])].
[sujeto(['Their', activity, is]), verbo([regulated]), complemento([by, phosphorylation, on, both, threonine, and, 'tyrosine,', and, they, play, a, crucial, role, in, the, regulation, of, proliferation, and, differentiation])].
[sujeto(['We']), verbo([report]), complemento([here, the, cloning, of, the, murine, p44, 'MAP', kinase, '(', extracellular, 'signal-regulated', kinase, 1, ')', 'gene,', the, determination, of, its, 'intron/exon', 'boundaries,', and, the, characterization, of, its, promoter])].
[sujeto(['The', gene, spans, approximately, eight, kilobases, '(', 'kb)', and, can, be, divided, into, nine, exons, and, eight, 'introns,', each, coding, region, exon, containing, from, one, to, three, of, the, highly]), verbo([conserved]), complemento([protein, kinase, domains])].
[sujeto(['Primer', extension, analysis]), verbo([reveals]), complemento([the, existence, of, two, major, start, sites, of, transcription, located, at, -, 183, and, -, 186, base, pairs, '(', 'bp)', as, well, as, four, discrete, start, sites, for, transcription, located, at, -, 178, ',', -, 192, ',', -, 273, ',', and, -, 292, bp, of, the, initiation, of, translation])].
[sujeto(['However,', the, start, site, region, lacks, 'TATA-like', sequences, but, does, contain, 'initiator-like', sequences, proximal, to, the, major, start, sites, obtained, by]), verbo([primer]), complemento([extension])].
[sujeto([1, kb, of, the, promoter, region]), verbo([has]), complemento([been, sequenced])].
[sujeto(['It', contains, three, putative, 'TATA', boxes, far, upstream, of, the, main, start, sites, 'region,', one, 'AP-1', 'box,', one, 'AP-2', 'box,', one, 'Malt', 'box,', one, 'GAGA', 'box,', one, half, 'serum-responsive', 'element,', and, putative]), verbo([binding]), complemento([sites, for, 'Sp1', '(', 'five),', 'GC-rich', binding, factor, '(', 'five),', 'CTF-NF1', '(', 'one),', 'Myb', '(', 'one),', p53, '(', 'two),', 'Ets-1', '(', 'one),', 'NF-IL6', '(', 'two),', 'MyoD', '(', 'two),', 'Zeste', '(', 'one),', and, hepatocyte, nuclear, 'factor-5', '(', 'one)'])].
[sujeto(['Progressive', deletions, of, the, approximately, 1, kb, '(', -, 1200, /, -, 78, ')', promoter, region, allowed, us, to, define, a, minimal, region, of, 186, bp, '(', -, 284, /, -, 78, ')', that]), verbo([has]), complemento([maximal, promoter, activity])].
[sujeto(['Within', this, 'context,', deletion, of, the, 'AP-2']), verbo([binding]), complemento([site, reduces, by, 30, -, 40, '%', the, activity, of, the, promoter])].
[sujeto(['(', 'ABSTRACT', 'TRUNCATED', 'AT', 400, 'WORDS)', rSkM2, is, a, 'tetrodotoxin-resistant', rat, skeletal, muscle, 'voltage-sensitive', sodium, channel, that, is]), verbo([expressed]), complemento([in, immature, and, denervated, skeletal, muscle, and, in, adult, heart])].
[sujeto(['We']), verbo([have]), complemento([isolated, a, 3.7, -, kb, gene, segment, that, contains, the, first, 'exon,', multiple, transcription, initiation, 'sites,', the, core, promoter, '(', nt, -, 102, to, +, 1, ')', ',', 'GC-rich', elements, '(', 'Sp1', recognition, 'sites),', three, overlapping, 'C-rich', motifs, '(', important, for, 'muscle-specific', expression, of, some, muscle, 'genes),', and, multiple, 'CANNTG', '(', 'E-box)', motifs, '(', 'MyoD', binding, 'sites)'])].
[sujeto(['A', deletion, analysis, of, the, 5, '\'', upstream, 2.8, -, kb, 'segment,', driving, the, rSkM2, core, 'promoter,']), verbo([has]), complemento([localized, a, 'muscle-restrictive', enhancer, element, '(', 'MRSE)', at, least, 2, kb, upstream, from, the, core, promoter])].
[sujeto(['Gel-shift', assays]), verbo([have]), complemento([identified, 'sequence-', and, 'cell-type-specific', proteins, that, bind, to, a, 16, -, bp, region, '(', -, 44, /, -, 29, ')', containing, 'C-rich', motifs])].
[sujeto(['Muscle-specific', complexes, formed, from, muscle, cell]), verbo([nuclear]), complemento([extracts, and, a, 16, -, bp, element, '(', -, 44, /, -, 29, ')', are, competed, by, unlabeled, -, 44, /, -, 29, oligonucleotide, but, not, by, several, mutant, oligonucleotides, that, implicate, nucleotides, -, 40, to, -, 38, and, -, 34, to, -, 32, in, the, binding, of, a, nuclear, protein, '(', designated, 'SkM2', transcription, factor, 1, ',', 'SkM2-TF1)'])].
[sujeto(['Vitamin', 'D', deficiency, and, advanced, glycation, end, products, '(', 'AGEs)', are]), verbo([suggested]), complemento([to, be, involved, in, the, pathogenesis, of, osteoporosis, and, sarcopenia])].
[sujeto(['We', previously, showed, that, osteoglycin, '(', 'OGN)', is, secreted, from, myoblasts, and]), verbo([stimulates]), complemento([osteoblastic, 'differentiation,', suggesting, that, it, plays, important, roles, in, the, interaction, between, muscle, and, bone])].
[sujeto([1, 'α,25-dihydroxyvitamin', 'D3', '(', 1, ',', 25, 'D)', and, 'eldecalcitol,', an, active, vitamin, 'D', 'analog,']), verbo([induced]), complemento([the, expression, of, 'MyoD,', myogenin, and, 'OGN,', and, these, effects, were, abolished, by, vitamin, 'D', receptor, '(', 'VDR)', suppression, by, siRNA, in, 'C2C12', cells])].
[sujeto(['Moreover,', conditioned, medium, from, 1, ',', 25, 'D-pretreated', 'C2C12', cells]), verbo([stimulated]), complemento([the, expression, of, type, 1, collagen, and, alkaline, phosphatase, in, 'MC3T3-E1', 'cells,', compared, to, control, medium, from, 1, ',', 25, 'D-untreated', 'C2C12', cells])].
[sujeto(['AGE2', and, 'AGE3']), verbo([suppressed]), complemento([the, expression, of, 'MyoD,', myogenin, and, 'OGN', in, 'C2C12', cells])].
[sujeto(['Active', vitamin, 'D', treatment, may, rescue, the, 'AGEs-induced', sarcopenia, as, well, as, -]), verbo([suppressed]), complemento([osteoblastic, differentiation, via, 'OGN', expression, in, myoblasts])].
[sujeto(['The', regulation, of, gene, expression, by, thyroid, hormone, '(', 'T3)']), verbo([involves]), complemento([binding, of, the, hormone, to, nuclear, receptors, '[', thyroid, hormone, receptor, '(', 'TR)]', acting, as, 'T3-dependent', transcription, factors, encoded, by, 'TRalpha', '(', 'NR1A1)', and, 'TRbeta', '(', 'NR1A2)', genes])].
[sujeto(['Several', 'TRalpha', variants]), verbo([have]), complemento([already, been, 'characterized,', but, only, some, of, them, display, 'T3', binding, activity])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([identified, another, 'transcript,', 'TRalpha-DeltaE6,', produced, by, alternative, splicing, with, microexon, 6, b, instead, of, exon, 6])].
[sujeto(['This', splicing]), verbo([leads]), complemento([to, the, synthesis, of, a, protein, devoid, of, a, hinge, domain])].
[sujeto(['Although', 'TRalpha-DeltaE6', did, not]), verbo([bind]), complemento(['DNA,', its, expression, induced, a, 'TRalpha1', sequestration, in, the, cytoplasm])].
[sujeto(['Functional', studies, demonstrated, that, 'TRalpha-DeltaE6']), verbo([inhibits]), complemento([the, transcriptional, activity, of, 'TRalpha1', and, retinoic, 'X', 'receptor-alpha,', but, not, of, retinoic, acid, 'receptor-alpha'])].
[sujeto(['We', also]), verbo([found]), complemento([that, 'TRalpha-DeltaE6', efficiently, decreased, the, ability, of, 'TRalpha', to, inhibit, 'MyoD', transcriptional, activity, during, myoblast, proliferation])].
[sujeto(['Consequently,', when, overexpressed, in, 'myoblasts,', it]), verbo([stimulated]), complemento([terminal, differentiation])].
[sujeto(['We']), verbo([suggest]), complemento([that, this, novel, 'TRalpha', variant, may, act, as, down, regulator, of, overall, 'T3', receptor, 'activity,', including, its, ability, to, repress, 'MyoD', transcriptional, activity, during, myoblast, proliferation])].
[sujeto(['Classical', 'ligand-activated']), verbo([nuclear]), complemento([receptors, '(', e])].
[sujeto([thyroid, hormone, 'receptor,', retinoic, acid, 'receptor),', orphan]), verbo([nuclear]), complemento([receptors, '(', e])].
[sujeto(['Rev-erbAalpha/beta),', 'Mad/Max', bHLH, '(', basic, helix, loop, 'helix)-LZ', 'proteins,', and, 'oncoproteins,', 'PLZF', and, 'LAZ3/BCL6,']), verbo([bind]), complemento(['DNA', and, silence, transcription, by, recruiting, a, repressor, complex, that, contains, 'N-CoR', '(', nuclear, receptor, 'corepressor)/SMRT', '(', silencing, mediator, of, retinoic, acid, and, thyroid, hormone, 'receptor),', 'Sin3A/B,', and, 'HDAc-1/-2', proteins])].
[sujeto(['The', function, of, the, 'corepressor,', 'N-CoR,', in, the, process, of, cellular, differentiation, and, coupled, phenotypic, 'acquisition,']), verbo([has]), complemento([not, been, investigated])].
[sujeto(['We', observed, that, the, mRNA, encoding, 'N-CoR', was]), verbo([suppressed]), complemento([as, proliferating, myoblasts, exited, the, cell, 'cycle,', and, formed, morphologically, and, biochemically, differentiated, myotubes])].
[sujeto(['Furthermore,', 'N-CoR', expression, efficiently]), verbo([inhibits]), complemento([the, 'myoD-mediated', myogenic, conversion, of, pluripotential, 'C3H10T1/2', cells])].
[sujeto(['We', demonstrate, that, 'MyoD-mediated', transactivation, and, activity, are]), verbo([repressed]), complemento([by, 'N-CoR'])].
[sujeto(['The', mechanism]), verbo([involves]), complemento([direct, interactions, between, 'MyoD', and, 'N-CoR;', 'moreover,', the, interaction, was, dependent, on, the, 'amino-terminal', repression, domain, '(', 'RD1)', of, 'N-CoR', and, the, bHLH, region, of, 'MyoD'])].
[sujeto(['Trichostatin', 'A', treatment, significantly]), verbo([stimulated]), complemento([the, activity, of, 'MyoD', by, approximately, 10, -, fold, and, inhibited, the, ability, of, 'N-CoR', to, repress, 'MyoD-mediated', 'transactivation,', consistent, with, the, involvement, of, the, corepressor, and, the, recruitment, of, a, histone, deacteylase, activity, in, the, process])].
[sujeto(['This', work, demonstrates, that, the, corepressor, 'N-CoR', is, a, key, regulator, of, 'MyoD', activity, and, mammalian, 'differentiation,', and, that, 'N-CoR']), verbo([has]), complemento([a, multifaceted, role, in, myogenesis])].
[sujeto(['Syndecan-1', is, an, integral, membrane, proteoglycan]), verbo([involved]), complemento([in, the, interaction, of, cells, with, extracellular, matrix, proteins, and, growth, factors])].
[sujeto(['It', is, transiently]), verbo([expressed]), complemento([in, several, condensing, mesenchymal, tissues, after, epithelial, induction])].
[sujeto(['The']), verbo([decrease]), complemento([in, 'syndecan-1', gene, expression, is, not, dependent, on, the, presence, of, 'E-boxes,', binding, sites, for, the, 'MyoD', family, of, transcription, factors, in, the, promoter, 'region,', or, myogenin, expression])].
[sujeto(['When', added, 'together,', 'however,', they]), verbo([induced]), complemento(['syndecan-1', expression])].
[sujeto(['Retinoic', 'acid,', an, inducer, of, 'myogenesis,']), verbo([inhibited]), complemento(['syndecan-1', expression, and, abolished, the, effect, of, the, growth, factors])].
[sujeto(['These', results, indicate, that, 'syndecan-1', expression, is, 'down-regulated', during, myogenesis, and, that, growth, factors, and, retinoic, acid]), verbo([modulate]), complemento(['syndecan-1', expression, by, a, mechanism, that, is, independent, of, myogenin])].
[sujeto(['Two', clonal, rat, rhabdomyosarcoma, cell, lines, 'BA-Han-1B', and, 'BA-Han-1C', with, different, capacities, for, myogenic, differentiation]), verbo([have]), complemento([been, examined, for, the, expression, of, muscle, regulatory, basic, 'helix-loop-helix', '(', 'bHLH)', proteins, of, the, 'MyoD', family])].
[sujeto(['Whereas', cells, of, the, 'BA-Han-1C', subpopulation, constitutively]), verbo([expressed]), complemento(['MyoD1', and, could, be, induced, to, differentiate, with, retinoic, acid, '(', 'RA),', 'BA-Han-1B', cells, did, not, express, any, of, the, myogenic, control, factors, and, appeared, to, be, largely, 'differentiation-defective'])].
[sujeto(['Upon', induction, with, 'RA,', 'BA-Han-1C', cells]), verbo([expressed]), complemento([also, 'myogenin,', in, contrast, to, 'BA-Han-1B', cells, which, never, activated, any, of, the, genes, encoding, muscle, bHLH, factors])].
[sujeto(['The', onset, of, myogenin, transcription, in, 'BA-Han-1C', cells]), verbo([required]), complemento([de, novo, protein, synthesis, and, 'DNA', replication, suggesting, that, 'RA', probably, did, not, act, directly, on, the, myogenin, gene])].
[sujeto(['Although', 'MyoD1', was]), verbo([expressed]), complemento([in, proliferating, 'BA-Han-1C', 'myoblasts,', 'muscle-specific', reporter, genes, were, not, activated, indicating, that, 'MyoD', was, biologically, inactive])].
[sujeto(['However,', transfections, with, plasmid]), verbo([expressing]), complemento([additional, 'MyoD1', protein, resulted, in, the, transactivation, of, muscle, genes, even, in, the, absence, of, 'RA'])].
[sujeto([mRNA, encoding, the, negative, regulatory, 'HLH', protein, 'Id', was]), verbo([expressed]), complemento([in, proliferating, 'BA-Han-1C', cells, and, disappeared, later, after, 'RA', induction, which, suggested, that, it, may, be, involved, in, the, regulation, of, 'MyoD1', activity])].
[sujeto(['In', 'fact,', stable, transfections, of, 'BA-Han-1C', cells, with, myogenin]), verbo([expressing]), complemento([plasmids, resulted, in, spontaneous, differentiation])].
[sujeto(['Together,', our, results]), verbo([suggest]), complemento([that, the, transformed, and, undifferentiated, phenotype, of, 'BA-Han-1C', rhabdomyosarcoma, cells, is, associated, with, the, inactivation, of, the, myogenic, factor, 'MyoD1', as, well, as, lack, of, myogenin, expression])].
[sujeto(['RA', alleviates, the, inhibition, of, myogenic, 'differentiation,', probably, by]), verbo([activating]), complemento(['MyoD', protein, and, myogenin, gene, transcription])].
[sujeto(['BA-Han-1B', cells, did, not]), verbo([respond]), complemento([to, 'RA', and, the, differentiated, phenotype, could, not, be, restored, by, overexpression, of, 'MyoD1', or, myogenin])].
[sujeto(['Sarcopenic', 'obesity,', 'age-related', muscle, 'loss,', which, is, compensated, by, an]), verbo([increase]), complemento([in, fat, 'mass,', impairs, quality, of, life, in, elderly, people])].
[sujeto(['Although', the]), verbo([increase]), complemento([in, intramuscular, fat, is, associated, with, decreased, insulin, sensitivity, and, increased, metabolic, risk, 'factors,', the, origin, of, 'diabetes-associated', intramuscular, fat, has, not, been, elucidated])].
[sujeto(['Expression', of, a, myogenic, 'marker,', 'myoD,', was, lower, and, that, of, 'PDGF', receptor, alpha, and, 'CCAAT/enhancer']), verbo([binding]), complemento([protein, '(', 'CEBP)', alpha, was, higher, in, 'Ctx-injured', 'TA', of, 'KKAy', compared, with, that, of, 'C57BL/6'])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, γ, '(', 'PPARγ)', was, highly]), verbo([expressed]), complemento([in, 'fat-forming', lesions, in, older, 'KKAy'])].
[sujeto(['Treatment', with, 'all-trans', retinoic, acid]), verbo([prevented]), complemento([the, formation, of, intramuscular, 'fat;', 'however,', treatment, with, 'GW9662,', a, 'PPARγ', 'antagonist,', increased, the, fibrotic, change, in, muscle])].
[sujeto(['Diabetic', mice, showed, impaired, muscle, regeneration, with, fat, 'deposition,']), verbo([suggesting]), complemento([that, diabetes, may, enhance, sarcopenic, obesity, through, a, mechanism, involving, anomalous, 'fibro-adipocyte', progenitor, cell, differentiation])].
[sujeto(['This', shows, that, 'FGF18']), verbo([induces]), complemento([expression, of, 'MyoD', and, 'ERK', phosphorylation, and, both, endogenous, and, 'FGF18', induced, 'MyoD', expression, is, inhibited, by, 'U0126'])].
[sujeto(['To', uncover, how, foxc1a]), verbo([regulates]), complemento([zebrafish, 'somitogenesis,', we, generated, foxc1a, 'knock-out', zebrafish, using, 'TALEN', '(', transcription, 'activator-like', effector, 'nuclease)', technology])].
[sujeto(['Analyses', on, the, expressions, of, the, key, genes, that, control, processes, of, somitogenesis, revealed, that, foxc1a, controlled, early, somitogenesis, by]), verbo([regulating]), complemento([the, expression, of, myod1])].
[sujeto(['In', the, somites, of, foxc1a, 'knock-out', 'embryos,', expressions, of, fgf8a, and, deltaC, were, 'abolished,', whereas, the, expression, of, aldh1a2, '(', responsible, for]), verbo([providing]), complemento([retinoic, acid, 'signaling)', was, significantly, increased])].
[sujeto(['Once', the]), verbo([increased]), complemento([retinoic, acid, level, in, the, foxc1a, null, embryos, was, reduced, by, knocking, down, 'aldh1a2,', the, reduced, expression, of, myod1, was, partially, rescued, by, resuming, expressions, of, fgf8a, and, deltaC, in, the, somites, of, the, mutant, embryos])].
[sujeto(['Moreover,', a, chromatin, immunoprecipitation, assay, on, zebrafish, embryos, revealed, that, 'Foxc1a']), verbo([bound]), complemento([aldh1a2, promoter, directly])].
[sujeto(['On', the, other, 'hand,', neither, knocking, down, fgf8a, nor]), verbo([inhibiting]), complemento(['Notch', signaling, affected, the, expression, of, 'aldh1a2,', although, knocking, down, fgf8a, reduced, expression, of, deltaC, in, the, somites, of, zebrafish, embryos, at, early, somitogenesis, and, vice, versa])].
[sujeto(['Only', then, do, they, begin, to, differentiate, and]), verbo([express]), complemento([markers, of, myogenic, commitment, and, determination, such, as, 'Myf5', and, 'MyoD'])].
[sujeto(['However', the, signals]), verbo([regulating]), complemento([this, process, remain, poorly, characterised])].
[sujeto(['We', show, that, 'FGF18,', which, is]), verbo([expressed]), complemento([in, the, distal, mesenchyme, of, the, limb, 'bud,', induces, premature, expression, of, both, 'Myf5', and, 'MyoD', and, that, blocking, 'FGF', signalling, also, inhibits, endogenous, 'MyoD', expression])].
[sujeto(['This', expression, is]), verbo([mediated]), complemento([by, 'ERK', 'MAP', kinase, but, not, 'PI3K', signalling])].
[sujeto(['We', also, show, that, retinoic, acid, '(', 'RA)', can]), verbo([inhibit]), complemento([the, myogenic, activity, of, 'FGF18', and, that, blocking, 'RA', signalling, allows, premature, induction, of, 'MyoD', by, 'FGF18', at, 'HH19'])].
[sujeto(['We', propose, a, model, where, interactions, between, 'FGF18', in, the, distal, limb, and, retinoic, acid, in, the, proximal, limb]), verbo([regulate]), complemento([the, timing, of, myogenic, gene, expression, during, limb, bud, development])].
[sujeto(['We']), verbo([have]), complemento([used, 'wild-type', and, transgenic, zebrafish, to, examine, the, role, of, 'RARγ'])].
[sujeto(['Treatment', of, zebrafish, embryos, with, an, 'RARγ-specific', agonist, reduced, somite, formation, and, axial, 'length,', which, was]), verbo([associated]), complemento([with, a, loss, of, hoxb13a, expression, and, 'less-clear', alterations, in, hoxc11a, or, myoD, expression])].
[sujeto(['There', was, a]), verbo([loss]), complemento([of, 'Sox', 9, -, immunopositive, neural, crest, 'stem/progenitor', cells, in, the, same, anterior, regions])].
[sujeto(['However,', there, was, no]), verbo([loss]), complemento([of, 'Tbx-5-immunopositive', lateral, plate, mesodermal, 'stem/progenitor', cells, and, the, block, was, reversed, by, agonist, washout, or, by, cotreatment, with, an, 'RARγ', antagonist])].
[sujeto(['Regeneration', of, the, caudal, fin, was, also, blocked, by, 'RARγ', agonist, 'treatment,', which, was]), verbo([associated]), complemento([with, a, loss, of, canonical, 'Wnt', signaling])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'RARγ', plays, an, essential, role, in, maintaining, 'stem/progenitor', cells, during, embryonic, development, and, tissue, regeneration, when, the, receptor, is, in, its, nonligated, state])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, pregnant, mice, treated, with, retinoic, acid, '(', +, 'RA)', produce, embryos, with, tongue, malformation, and, a, cleft, palate])].
[sujeto(['In', 'mock-', and, 'Wnt5a-transfected', 'C2C12', '(', 'Wnt5a-C2C12)', 'cells,', 'Wnt5a', overexpression, impaired, 'proliferation,', and]), verbo([maintained]), complemento(['Myf5', at, a, relative, high, level, after, 'RA', treatment])].
[sujeto(['These', data, support, the, hypothesis, that, the, 'Wnt5a/CaMKII', pathway, is, directly]), verbo([involved]), complemento([in, 'RA-induced', hypoplasia, and, disorder, of, tongue, muscles])].
[sujeto(['In', the, current, 'study,', we]), verbo([found]), complemento([that, α7, 'integrin-positive', human, skeletal, muscle, stem, cells, '(', 'α7(+)hSMSCs)', could, differentiate, into, the, odontoblast, lineage, under, specific, inductive, conditions, in, response, to, bone, morphogenetic, 'protein-4', '(', 'BMP-4)'])].
[sujeto(['Following', this, 'protocol,', 'α7(+)hSMSCs', were]), verbo([induced]), complemento([to, 'down-regulate', myogenic, genes, '(', 'MYOD', and, α7, 'integrin)', and, 'up-regulate', odontogenic, markers, including, dentin, 'sialophosphoprotein,', matrix, 'metalloproteinase-20', '(', 'enamelysin),', dentin, 'sialoprotein,', and, alkaline, phosphatase, but, not, osteoblastic, genes, '(', osteopontin, and, 'osteocalcin)'])].
[sujeto(['Interestingly,', using, siRNA, knockdown, strategies, revealed, that, the, 'differentiation-related', expression, of, the, α1, integrin, receptor, positively]), verbo([regulates]), complemento([the, expression, of, the, odontoblastic, markers, dentin, sialophosphoprotein, and, matrix, 'metalloproteinase-20'])].
[sujeto(['These', results, strongly]), verbo([suggest]), complemento([that, the, differentiation, of, 'α7(+)hSMSCs', along, the, odontogenic, lineage, is, dependent, on, the, concurrent, expression, of, α1, integrin])].
[sujeto(['When', buffalo, embryonic, stem, '(', 'ES)', 'cell-like', cells, that]), verbo([expressed]), complemento([surface, markers, 'SSEA-4,', 'TRA-1-60,', 'TRA-1-81,', 'CD9', and, 'CD90', and, intracellular, markers, 'OCT4,', 'SOX2', and, 'FOXD3,', as, shown, by, 'immunofluorescence,', and, that, expressed, 'REX-1', and, 'NUCLEOSTEMIN', as, confirmed, by, 'RT-PCR,', were, subjected, to, suspension, culture, in, hanging, drops, in, absence, of, 'LIF', and, buffalo, foetal, fibroblast, feeder, layer, 'support,', they, differentiated, to, form, 'three-dimensional', embryoid, bodies, '(', 'EBs)'])].
[sujeto(['The', cells, obtained, from, 'EBs', were]), verbo([found]), complemento([to, express, 'NF-68', and, 'NESTIN', '(', ectodermal, 'lineage),', 'BMP-4', and, 'α-skeletal', actin, '(', mesodermal, 'lineage),', and, 'α-fetoprotein,', 'GATA-4', and, 'HNF-4', '(', endodermal, 'lineage)'])].
[sujeto(['To', 'date,', it]), verbo([has]), complemento([proven, difficult, to, generate, skeletal, muscle, from, hESCs, in, high, yields, and, within, a, reasonable, timeframe])].
[sujeto(['Further,', a, 'hESC-derived', 'Pax3/7-positive', skeletal, muscle, progenitor, population]), verbo([has]), complemento([not, yet, been, described])].
[sujeto(['Previous', studies]), verbo([have]), complemento([shown, that, 'Pax3/7-positive', progenitor, cells, can, repopulate, the, satellite, cell, 'niche,', indicating, the, importance, of, this, population, for, therapy])].
[sujeto(['We', treated, hESCs, with, retinoic, acid, '(', 'RA)', and]), verbo([found]), complemento([an, enhancement, of, skeletal, 'myogenesis,', and, the, expression, of, the, myogenic, regulatory, factors, '(', 'MRFs)', 'MyoD', and, myogenin, by, day, 25])].
[sujeto(['Furthermore,', we]), verbo([found]), complemento([that, 'RA', treatment, expanded, the, muscle, progenitor, 'pool,', which, occurred, as, a, distinct, 'Pax3(+ve)', population, prior, to, 'MRF', expression])].
[sujeto(['Therefore,', we]), verbo([have]), complemento([identified, a, differentiation, pathway, in, hESCs, that, provides, a, skeletal, muscle, progenitor, population, which, can, undergo, myogenesis, more, efficiently])].
[sujeto(['The', contribution, of, 'PcG', proteins, to, cell, commitment, and, differentiation, relates, to, their, ability, to]), verbo([repress]), complemento([transcription, of, developmental, regulators, in, embryonic, stem, '(', 'ES)', cells, and, in, committed, cell, 'lineages,', including, skeletal, muscle, cells, '(', 'SMC)'])].
[sujeto(['PcG', proteins, are, preferentially, removed, from]), verbo([transcribed]), complemento(['regions,', but, the, underlying, mechanisms, remain, unclear])].
[sujeto(['Here,', 'PcG', proteins, are]), verbo([found]), complemento([to, occupy, and, repress, transcription, from, an, intronic, region, containing, the, microRNA, 'miR-214', in, undifferentiated, 'SMC'])].
[sujeto(['Once', 'transcribed,', 'miR-214', negatively, feeds, back, on, 'PcG', by]), verbo([targeting]), complemento([the, 'Ezh2', 3, '\'', 'UTR,', the, catalytic, subunit, of, the, 'PRC2', complex])].
[sujeto(['miR-214-mediated', 'Ezh2', protein, reduction, accelerates, 'SMC', differentiation, and]), verbo([promotes]), complemento([unscheduled, transcription, of, developmental, regulators, in, 'ES', cells])].
[sujeto(['While', retinoic, acid, '(', 'RA)', is, the, most, potent, small, molecule, enhancer, of, skeletal, myogenesis, in, stem, 'cells,', the, stage, and, mechanism, of, its, function]), verbo([has]), complemento([not, yet, been, elucidated])].
[sujeto(['Further,', the, intersection, of, 'RA', with, other, signalling, pathways, that]), verbo([stimulate]), complemento([or, inhibit, myogenesis, '(', such, as, 'Wnt', and, 'BMP4,', 'respectively)', is, unknown])].
[sujeto(['Thus,', the, purpose, of, this, study, is, to, examine, the, molecular, mechanisms, by, which, 'RA']), verbo([enhances]), complemento([skeletal, myogenesis, and, interacts, with, 'Wnt', and, 'BMP4', signalling, during, 'P19', or, mouse, embryonic, stem, '(', 'ES)', cell, differentiation])].
[sujeto(['Treatment', of, 'P19', or, mouse, 'ES', cells, with, low, levels, of, 'RA']), verbo([led]), complemento([to, an, enhancement, of, skeletal, myogenesis, by, upregulating, the, expression, of, the, mesodermal, 'marker,', 'Wnt3a,', the, skeletal, muscle, progenitor, factors, 'Pax3', and, 'Meox1,', and, the, myogenic, regulatory, factors, '(', 'MRFs)', 'MyoD', and, myogenin])].
[sujeto(['By', chromatin, 'immunoprecipitation,', 'RA', receptors, '(', 'RARs)']), verbo([bound]), complemento([directly, to, regulatory, regions, in, the, 'Wnt3a,', 'Pax3,', and, 'Meox1', genes, and, 'RA', activated, a, 'beta-catenin-responsive', promoter, in, aggregated, 'P19', cells])].
[sujeto(['Finally,', 'RA']), verbo([inhibited]), complemento([cardiomyogenesis, but, not, in, the, presence, of, 'BMP4'])].
[sujeto(['RA', can]), verbo([enhance]), complemento([skeletal, myogenesis, in, stem, cells, at, the, muscle, 'specification/progenitor', stage, by, activating, 'RARs', bound, directly, to, mesoderm, and, skeletal, muscle, progenitor, 'genes,', activating, 'beta-catenin', function, and, inhibiting, bone, morphogenetic, protein, '(', 'BMP)', signalling])].
[sujeto(['Thus,', a, signalling, pathway, can, function, at, multiple, levels, to, positively]), verbo([regulate]), complemento([a, developmental, program, and, can, function, by, abrogating, inhibitory, pathways])].
[sujeto(['Finally,', since, 'RA']), verbo([enhances]), complemento([skeletal, muscle, progenitor, 'formation,', it, will, be, a, valuable, tool, for, designing, future, stem, cell, therapies])].
[sujeto(['At', early, stages, of, limb, 'development,', 'RA', levels, are, highest, proximally, and]), verbo([regulate]), complemento([the, migration, of, myoblasts, into, the, limb])].
[sujeto(['As', the, premyogenic, progenitor, cells, migrate, into, the, limb, and, accumulate, in, premuscle, 'masses,', they]), verbo([express]), complemento(['Pax3', and, 'Meox2'])].
[sujeto(['Myogenic', differentiation, is, initiated, by, expression, of, 'Myf5', and, 'MyoD,', and, both, 'Pax3', and, 'Meox2', are]), verbo([required]), complemento([for, normal, 'Myf5', expression])].
[sujeto(['We', show, by]), verbo([loss]), complemento([of, function, using, the, inhibitor, 'citral,', that, 'RA', signalling, within, the, limb, bud, is, required, to, maintain, 'Pax3', and, 'Meox2', in, the, progenitor, and, 'Myf5', and, 'MyoD', in, the, differentiating, myoblasts])].
[sujeto(['RA', treatment, followed, by, exposure, to, triiodothyronine, '(', 'T3)', and, insulin]), verbo([induces]), complemento(['ES', cells, differentiation, into, adipocytes, and, skeletomyocytes])].
[sujeto(['On', the, other, 'hand,', 'OT', '(', 10, '(', -, 7, ')', 'M)', was]), verbo([reported]), complemento([to, inhibit, 3, 'T3', preadipocyte, maturation])].
[sujeto(['The', present, work, was, undertaken, to, determine, whether, 'P19', cells]), verbo([have]), complemento([an, adipogenic, potential, that, could, be, affected, by, 'OT'])].
[sujeto(['Levels', of, cTpnI, and, of, the, skeletal, marker, 'MyoD', were, almost, similar, in, both, 'protocols,', whereas, no, 'Oil-Red-O', staining, was]), verbo([associated]), complemento([with, the, cardiomyogenic, protocol])].
[sujeto(['Interestingly,', 'Oct3/4', pluripotency, marker, disappeared, in, the, adipogenic, protocol, but, remained]), verbo([expressed]), complemento([in, the, cardiomyogenic, one])].
[sujeto(['P19', cells, thus]), verbo([have]), complemento([an, adipogenic, potential, non, affected, by, 10, '(', -, 7, ')', 'M', 'OT'])].
[sujeto(['Retinoic', acid, '(', 'RA)']), verbo([has]), complemento([been, shown, to, regulate, muscle, differentiation, in, vitro])].
[sujeto(['Here,', we]), verbo([have]), complemento([investigated, the, role, of, 'RA', signalling, during, embryonic, myogenesis, in, zebrafish])].
[sujeto(['We']), verbo([have]), complemento([altered, 'RA', signalling, from, gastrulation, stages, onwards, by, either, inhibiting, endogenous, 'RA', synthesis, using, an, inhibitor, of, retinaldehyde, dehydrogenases, '(', 'DEAB)', or, by, addition, of, exogenous, 'RA'])].
[sujeto(['DEAB', reduces, expression, of, the, myogenic, markers, myoD, and, myogenin, in, 'somites,', whereas, 'RA']), verbo([induces]), complemento([increased, expression, of, these, genes, and, strongly, induces, premature, myoD, expression, in, the, presomitic, mesoderm, '(', 'psm)'])].
[sujeto(['The', expression, dynamics, of, myf5, in, presomitic, and, somitic, mesoderm]), verbo([suggest]), complemento([that, 'RA', promotes, muscle, 'differentiation,', a, role, supported, by, the, fact, that, 'RA', activates, expression, of, fast, 'myosin,', while, 'DEAB', represses, it])].
[sujeto(['We', show, that, fgf8, expression, in, somites, and, anterior, psm, is]), verbo([regulated]), complemento([by, 'RA,', and, find, that, in, the, absence, of, 'Fgf8', signalling, in, the, acerebellar, mutant, 'RA', fails, to, promote, myoD, expression])].
[sujeto(['We', propose, 'that,', in, the, developing, 'embryo,', localised, synthesis, of, 'RA', by, 'Raldh2', in, the, anterior, psm, and, in, somites]), verbo([activates]), complemento([fgf8, expression, which, in, turn, induces, the, expression, of, myogenic, genes, and, fast, muscle, differentiation])].
[sujeto(['We']), verbo([have]), complemento([already, shown, that, 'BTG1,', considered, as, an, antiproliferative, 'protein,', strongly, stimulates, myoblast, differentiation])].
[sujeto(['However,', the, mechanisms]), verbo([involved]), complemento([in, this, influence, remained, unknown])].
[sujeto(['In', cultured, 'myoblasts,', we]), verbo([found]), complemento([that, 'BTG1', stimulates, the, transcriptional, activity, of, nuclear, receptors, '(', 'T3', and, 'all-trans', retinoic, acid, receptors, but, not, 'RXRalpha', and, 'PPARgamma),', 'c-Jun', and, myogenic, factors, '(', 'CMD1,', 'Myf5,', 'myogenin)'])].
[sujeto(['Immunoprecipitation', experiments, performed, in, cells, or, using, in, 'vitro-synthesized', proteins, and, 'GST', 'pull-down', assays, established, that, 'BTG1', directly]), verbo([interacts]), complemento([with, 'T3', and, 'all-trans', retinoic, acid, receptors, and, with, avian, 'MyoD', '(', 'CMD1)'])].
[sujeto(['These', interactions, are]), verbo([mediated]), complemento([by, the, transactivation, domain, of, each, transcription, factor, and, the, 'A', box, and, 'C-terminal', part, of, 'BTG1'])].
[sujeto(['NCoR', presence]), verbo([induces]), complemento([the, ligand, dependency, of, the, interaction, with, nuclear, receptors])].
[sujeto(['Lastly,', deletion, of, 'BTG1']), verbo([interacting]), complemento([domains, abrogates, its, ability, to, stimulate, nuclear, receptors, and, 'CMD1', 'activity,', and, its, myogenic, influence])].
[sujeto(['In', 'conclusion,', 'BTG1', is, a, novel, important, coactivator]), verbo([involved]), complemento([in, the, regulation, of, myoblast, differentiation])].
[sujeto(['It', not, only]), verbo([stimulates]), complemento([the, activity, of, myogenic, 'factors,', but, also, of, nuclear, receptors, already, known, as, positive, myogenic, regulators])].
[sujeto(['On', the, basis, of, our, analysis, of, genes, on, the, cDNA, array, plus, the, data, from, our, 'RT-PCR', 'assays,', the, metabolic, adaptations, shown, by, rat, gastrocnemius, muscle, during, fasting, are, reflected, by, 'i)']), verbo([increased]), complemento([transcription, both, of, myosin, heavy, chain, '(', 'MHC)', 'Ib', '(', associated, with, type, 'I', 'fibers)', and, of, at, least, three, factors, involved, in, the, shift, toward, type, 'I', fibers, '[', 'p27kip1,', muscle, 'LIM', protein, '(', 'MLP),', cystein, rich, 'protein-2],', of, which, one, '(', 'MLP)', has, been, shown, to, enhance, the, activity, of, 'MyoD,', which, would, explain, the, known, increase, in, the, expression, of, skeletal, muscle, uncoupling, 'protein-3', '(', 'UCP3);', 'ii)', increased, lipoprotein, lipase, '(', 'LPL)', 'expression,', known, to, trigger, 'UCP3', 'transcription,', which, 'tends,', together, with, the, first, 'point,', to, underline, the, suggested, role, of, 'UCP3', in, mitochondrial, lipid, handling, '(', the, variations, under, the, first, point, and, this, one, have, not, been, observed, in, 'mice,', indicating, a, 'species-specific', regulation, of, these, 'mechanisms);', 'iii)', reduced, expression, of, the, 'muscle-specific', coenzyme, 'Q', '(', 'CoQ)7', 'gene,', which, is, necessary, for, mitochondrial, 'CoQ', 'synthesis,', together, with, an, increased, expression, of, mitochondrial, adenylate, kinase, 3, ',', which, inactivates, the, resident, key, enzyme, for, 'CoQ', 'synthesis,', 3, -, 'hydroxy-3-methylglutaryl', 'CoA', reductase, '(', 'HMGR),', the, mRNA, level, for, which, fell, during, 'fasting;', and, 'iv)', increased, transcription, of, components, of, the, proteasomal, pathways, involved, in, protein, 'degradation/turnover'])].
[sujeto(['Here,', we]), verbo([find]), complemento([that, correct, patterning, of, 'Hgf', expression, in, forelimb, buds, is, dependent, on, retinoic, acid, '(', 'RA)', synthesized, by, retinaldehyde, dehydrogenase, 2, '(', 'Raldh2)', expressed, proximally])].
[sujeto(['Met', and, 'MyoD', are]), verbo([expressed]), complemento([in, this, abnormal, 'domain,', indicating, that, myogenic, cell, migration, and, differentiation, are, occurring, in, the, absence, of, 'RA,', but, in, an, abnormal, location])].
[sujeto(['Expression', of, 'Bmp4,', an, inhibitor, of, 'Hgf', 'expression,', is]), verbo([increased]), complemento([and, shifted, anteroproximally, in, 'Raldh2(-/-)', limb, 'buds,', thus, encroaching, into, the, normal, expression, domain, of, 'Hgf'])].
[sujeto(['Our', studies]), verbo([suggest]), complemento([that, 'RA', signaling, provides, proximodistal, information, for, limb, buds, that, counterbalances, 'Bmp', 'signaling,', which, in, turn, helps, mediate, proximodistal, and, anteroposterior, patterning, of, 'Hgf', expression, to, correctly, direct, migration, of, 'Met-expressing', myogenic, precursor, cells])].
[sujeto(['Retinoids', '(', all, trans, and, 9, -, cis, retinoic, 'acid)', are, pleiotropic, regulators, of, cell, 'fate,', and]), verbo([have]), complemento([been, shown, to, regulate, the, expression, of, helix, loop, helix, transcription, factors, '(', e])].
[sujeto(['The', effects, of, retinoids, are]), verbo([mediated]), complemento([through, the, ligand, dependent, retinoic, acid, receptors, '(', 'RARs)', and, retinoid, 'X', receptors, '(', 'RXRs)'])].
[sujeto(['We']), verbo([have]), complemento([found, that, the, messenger, 'RNA', transcripts, encoding, 'RAR', are, repressed, during, differentiation, of, 'C2C12', myoblasts, 'while,', 'conversely,', 'RXR', mRNA, transcripts, are, induced, in, 'C2C12', myotubes])].
[sujeto(['The', 'Myf5', gene]), verbo([has]), complemento([both, in, vivo, and, in, vitro, expression, patterns, consistent, with, an, involvement, in, the, first, events, of, 'myogenesis,', such, as, acquisition, 'and/or', maintenance, of, myogenic, &, 'quot;determined&quot;', phenotype])].
[sujeto(['We']), verbo([report]), complemento([here, that, retinoic, acid, '(', 'RA)', reduces, the, level, of, 'Myf5', message, in, both, mouse, 'C2', and, rat, 'L6', cell, 'lines,', probably, at, the, transcriptional, 'level,', because, 'Myf5', mRNA, stability, is, not, affected, by, 'RA'])].
[sujeto(['This', repression, is, dose, 'dependent,', starting, at, 0.1, microM, of, 'all-trans', 'RA,', and, is, not, abrogated, by, 'cycloheximide,']), verbo([suggesting]), complemento([a, direct, involvement, of, 'RA', receptors, in, the, control, of, 'Myf5', expression])].
[sujeto(['Furthermore,', we, compared, the, efficiency, of, natural, '(', 'all-trans', 'RA', and, 9, -, cis, 'RA)', or, synthetic, '(', 'TTNPB)', retinoids, that, differentially]), verbo([activate]), complemento([the, two, families, of, 'RA', 'receptors,', 'RA', receptors, and, retinoid, 'X-receptors', '(', 9, -, cis, 'RA)'])].
[sujeto(['As', 9, -, cis, 'RA', is, about, 10, times, more, efficient, than, 'all-trans', 'RA', in]), verbo([repressing]), complemento(['Myf5,', whereas, 'TTNPB,', which, preferentially, activates, 'RA', 'receptors,', is, far, less, 'potent,', our, data, provide, evidence, for, an, important, role, of, 'ligand-bound', retinoid, 'X-receptors', in, the, mediation, of, this, inhibition])].
[sujeto(['There', is]), verbo([increasing]), complemento([evidence, that, the, biological, activity, of, myostatin, '(', 'MSTN),', a, negative, regulator, of, muscle, 'growth,', is, affected, by, training, but, also, anabolic, steroids])].
[sujeto(['Md', treatment, resulted, in, a, significant, stimulation, of, anabolic, activity, of, the, levator, ani, 'muscle,', which, was, further]), verbo([increased]), complemento([by, 'training,', while, prostate, and, seminal, vesicle, weights, decreased, in, conformance, with, hormone, concentrations, of, 'LH', and, testosterone])].
[sujeto(['In', 'summary,', our, data, demonstrate, that, 'Md', treatment, of, intact, rats, results, in, anabolic, effects, which, are]), verbo([enhanced]), complemento([in, combination, with, physical, activity])].
[sujeto(['Interestingly,', the, anabolic, activity, on, the, levator, ani, was]), verbo([increased]), complemento([in, combination, with, 'training,', although, the, levator, ani, muscle, was, not, specifically, stimulated, by, our, training, protocol])].
[sujeto([gastrocnemius, and, 'soleus,', the, anabolic, effects, correlate, with, changes, in, the, expression, patterns, of, genes]), verbo([involved]), complemento([in, 'MSTN', signaling])].
[sujeto(['Our', data]), verbo([provide]), complemento([evidence, that, the, decrease, in, the, weight, of, 'androgen-sensitive', sexual, 'glands,', observed, after, 'Md', 'treatment,', is, caused, by, a, suppression, of, endogenous, testosterone, synthesis])].
[sujeto(['These', observations]), verbo([provide]), complemento([new, insights, into, the, molecular, mechanisms, of, the, interaction, between, anabolic, 'steroids,', training, and, 'MSTN', signaling, during, skeletal, muscle, adaptation])].
[sujeto(['We', recently]), verbo([reported]), complemento([increased, leg, lean, mass, and, strength, in, men, with, chronic, obstructive, pulmonary, disease, '(', 'COPD)', receiving, 10, wk, of, testosterone, '(', 'T)', and, leg, resistance, training, '(', 'R)', '(', 'Casaburi', 'R,', 'Bhasin', 'S,', 'Cosentino', 'L,', 'Porszasz', 'J,', 'Somfay', 'A,', 'Lewis', 'M,', 'Fournier', 'M,', 'Storer', 'T'])].
[sujeto(['While', no, significant, changes, in, fiber, 'CSAs', were, noted, across, 'groups,']), verbo([increased]), complemento([trends, were, observed, after, 10, 'wk,', and, significant, decrements, in, muscle, fiber, density, were, noted, in, all, treated, groups])].
[sujeto(['A', global]), verbo([increase]), complemento([in, all, myosin, heavy, chain, '(', 'MyHC)', mRNA, isoforms, was, observed, in, 'TR', patients])].
[sujeto(['Muscle', 'IGF-IEa', and, 'IGF-IEc', mRNAs, were, significantly]), verbo([increased]), complemento([with, 'TR', group])].
[sujeto(['Muscle', 'IGF-I', protein, was]), verbo([increased]), complemento([in, all, intervention, groups, '(', greatest, in, 'TR)'])].
[sujeto(['IGF']), verbo([binding]), complemento(['protein-4', mRNA, was, increased, with, 'TR'])].
[sujeto(['Myogenin', mRNA, was]), verbo([increased]), complemento([in, both, 'T', 'groups,', while, 'MyoD', and, myostatin, were, unchanged])].
[sujeto(['Muscle', atrophy, 'F-box', mRNA, tended, to]), verbo([increase]), complemento([with, 'TR'])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, the, combined, interventions, produced, an, enhanced, local, anabolic, milieu, driven, in, large, part, by, the, muscle, 'IGF', 'system,', despite, potentially, negative, biochemical, influences, present, in, 'COPD', patients])].
[sujeto(['Resting', serum, testosterone]), verbo([decreased]), complemento([significantly, '(', 'P', &, 'lt;', 0.01, ')', in, the, goserelin, group, from, 22.6, +, /, -, 1.6, '(', mean, +, /, -, s])].
[sujeto(['An', acute]), verbo([increase]), complemento([of, serum, testosterone, was, observed, during, the, final, 'ST', session, in, the, placebo, group, '(', 'P', &, 'lt;', 0.05, ')', ',', whereas, a, decreased, response, was, observed, in, the, goserelin, group, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto([mRNA, expression, of, 'IGF-IE(bc)', and, myogenin, 'increased,', while, expression, of, myostatin]), verbo([decreased]), complemento(['(', 'P', &, 'lt;', 0.01, ')', ;, 'however,', no, differences, were, observed, between, the, groups])].
[sujeto(['Muscle', strength, and, muscle, mass, showed, a, tendency, to]), verbo([increase]), complemento([more, in, the, placebo, group, than, in, the, goserelin, group, '(', 'P', =, 0.05, ')'])].
[sujeto(['Testosterone', supplementation]), verbo([increases]), complemento([skeletal, muscle, mass, and, decreases, fat, 'mass;', 'however,', the, underlying, mechanisms, are, unknown])].
[sujeto(['We', hypothesized, that, testosterone]), verbo([regulates]), complemento([body, composition, by, promoting, the, commitment, of, mesenchymal, pluripotent, cells, into, myogenic, lineage, and, inhibiting, their, differentiation, into, adipogenic, lineage])].
[sujeto(['Adipogenic', differentiation, was, assessed, by, adipocyte, counting, and, by, measurements, of, peroxisomal, 'proliferator-activated', receptor, gamma, 2, '(', 'PPAR', gamma, 2, ')', mRNA, and, 'PPAR', gamma, 2, protein, and, 'CCAAT/enhancer']), verbo([binding]), complemento([protein, alpha])].
[sujeto(['The', number, of, 'MyoD+', myogenic, cells, and, 'MHC+', myotubes, and, 'MyoD', and, 'MHC', mRNA, and, protein, levels]), verbo([increased]), complemento([dose, dependently, in, response, to, testosterone, and, 'DHT', treatment])].
[sujeto(['Both', testosterone, and, 'DHT']), verbo([decreased]), complemento([the, number, of, adipocytes, and, 'down-regulated', the, expression, of, 'PPAR', gamma, 2, mRNA, and, 'PPAR', gamma, 2, protein, and, 'CCAAT/enhancer', binding, protein, alpha])].
[sujeto(['Androgen', receptor, mRNA, and, protein, levels, were, low, at, baseline, but]), verbo([increased]), complemento([after, testosterone, or, 'DHT', treatment])].
[sujeto(['Therefore,', testosterone, and, 'DHT']), verbo([regulate]), complemento([lineage, determination, in, mesenchymal, pluripotent, cells, by, promoting, their, commitment, to, the, myogenic, lineage, and, inhibiting, their, differentiation, into, the, adipogenic, lineage, through, an, androgen, 'receptor-mediated', pathway])].
[sujeto(['The', observation, that, differentiation, of, pluripotent, cells, is, androgen, dependent]), verbo([provides]), complemento([a, unifying, explanation, for, the, reciprocal, effects, of, androgens, on, muscle, and, fat, mass, in, men])].
[sujeto(['Evidence']), verbo([has]), complemento([accumulated, that, suggests, that, 'insulin-like', growth, factors, '(', 'IGFs)', exert, a, positive, influence, on, myoblast, differentiation])].
[sujeto(['We']), verbo([have]), complemento([undertaken, to, study, the, signalling, events, required, for, differentiation, resulting, from, 'type-1', 'IGF', receptor, stimulation, in, 'C2', 'myoblasts,', where, autocrine, production, of, 'IGF-II', was, abolished, by, means, of, antisense, 'RNA'])].
[sujeto(['Exposure', of, the, cells, to, 'IGFs']), verbo([leads]), complemento([to, a, rapid, and, sustained, activation, of, 'phosphatidyl-inositol', 3, -, kinase, followed, by, the, expression, of, 'Myod,', myogenin, and, differentiation])].
[sujeto(['The', fungal, 'metabolite,', 'wortmannin,']), verbo([inhibits]), complemento([both, 'PI', 3, -, kinase, and, muscle, differentiation, with, an, 'IC', 50, in, the, nanomolar, range])].
[sujeto(['IGFs', are, also, known, to]), verbo([cause]), complemento([a, rapid, activation, of, 'MAP', kinase])].
[sujeto(['However,', the, synthetic, inhibitor, of, 'MEK,', 'PD098059,', which]), verbo([prevents]), complemento(['MAP', kinase, 'activation,', does, not, affect, myoblast, differentiation])].
[sujeto(['These', results]), verbo([provide]), complemento([evidence, that, 'PI', 3, -, 'kinase,', but, not, 'MAP', 'kinase,', is, required, for, 'insulin-like', growth, factor, 'receptor-dependent', differentiation, of, muscle, cells])].
[sujeto(['Skeletal', muscle, differentiation]), verbo([involves]), complemento([myoblast, 'alignment,', 'elongation,', and, fusion, into, multinucleate, 'myotubes,', together, with, the, induction, of, regulatory, and, structural, 'muscle-specific', genes])].
[sujeto(['Upon', serum, 'withdrawal,', 10, 'T1/2-MyoD', cells, formed, myotubes, and, showed]), verbo([increased]), complemento([levels, of, myogenin, and, p21])].
[sujeto(['In', 'contrast,', 'LY294002-treated', cells, exhibited, none, of, these, myogenic, characteristics, and]), verbo([maintained]), complemento([high, levels, of, 'Id,', a, negative, regulator, of, myogenesis])].
[sujeto(['The', 'cyclin-dependent-kinase', inhibitors, p21, and, p57, are, highly]), verbo([expressed]), complemento([in, skeletal, muscle, where, they, redundantly, control, cell, cycle, arrest, during, differentiation])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, p57, is, a, target, of, the, myogenic, factor, 'MyoD', in, cells, lacking, p21])].
[sujeto(['Here', we, show, that, 'MyoD']), verbo([induces]), complemento([p57, at, the, transcriptional, level, through, a, mechanism, different, from, that, involved, in, p21, 'regulation,', since, it, is, 'E-box-independent', and, requires, new, synthesized, 'protein(s)'])].
[sujeto(['We']), verbo([have]), complemento([identified, p73, family, members, as, the, factors, that, mediate, the, activation, of, p57, through, a, 165, bp, promoter, region])].
[sujeto(['The', levels, of, p73, 'alpha,', beta, and, delta, isoforms]), verbo([increase]), complemento([during, muscle, differentiation, both, in, 'MyoD-expressing', fibroblasts, and, in, spontaneously, differentiating, 'C2', myoblasts])].
[sujeto(['Finally,', each, of, the, isoforms, 'up-regulated', by, 'MyoD,', even, when, 'over-expressed', 'alone,', is, capable, of]), verbo([inducing]), complemento([p57, in, 'p21-lacking', fibroblasts])].
[sujeto(['In', 'contrast,', the, same, p73, 'isoforms,', either]), verbo([induced]), complemento([by, 'MyoD', or, exogenously, 'over-expressed,', are, unable, to, activate, the, expression, of, p57, in, 'p21-expressing', fibroblasts])].
[sujeto(['Our']), verbo([finding]), complemento([that, a, transfected, p57, 'promoter-reporter', 'construct,', unlike, the, endogenous, 'gene,', is, responsive, to, both, 'MyoD', and, p73, even, in, these, 'cells,', suggests, that, a, 'cis-acting', 'mechanism,', probably, involving, a, repressive, chromatin, 'structure,', prevents, the, induction, of, p57, in, 'p21-expressing', fibroblasts])].
[sujeto(['Myogenic', regulatory, factors, of, the, 'MyoD', family]), verbo([have]), complemento([the, ability, to, reprogram, differentiated, cells, toward, a, myogenic, fate])].
[sujeto(['In', this, 'study,', we, demonstrate, that, 'Six1', or, 'Six4', are]), verbo([required]), complemento([for, the, reprogramming, by, 'MyoD', of, mouse, embryonic, fibroblasts, '(', 'MEFs)'])].
[sujeto(['Using', microarray, 'experiments,', we]), verbo([found]), complemento([761, genes, under, the, control, of, both, 'Six', and, 'MyoD'])].
[sujeto(['Using', 'MyoD', 'ChIPseq', data, and, a, 'genome-wide', search, for, 'Six1/4', 'MEF3']), verbo([binding]), complemento(['sites,', we, found, significant, 'co-localization', of, binding, sites, for, 'MyoD', and, 'Six', proteins, on, over, a, thousand, mouse, genomic, 'DNA', regions])].
[sujeto(['The', combination, of, both, datasets, yielded, 82, genes, which, are, synergistically]), verbo([activated]), complemento([by, 'Six', and, 'MyoD,', with, 96, associated, 'MyoD+MEF3', putative, 'cis-regulatory', modules, '(', 'CRMs)'])].
[sujeto(['We', searched, putative]), verbo([binding]), complemento([sites, on, these, 'CRMs', using, available, databases, and, de, novo, search, of, conserved, motifs, and, demonstrated, that, the, 'Six/MyoD', synergistic, activation, takes, place, in, a, feedforward, way])].
[sujeto(['It']), verbo([involves]), complemento([the, recruitment, of, these, two, families, of, transcription, factors, to, their, 'targets,', together, with, partner, transcription, 'factors,', encoded, by, genes, that, are, themselves, activated, by, 'Six', and, 'MyoD,', including, 'Mef2,', 'Pbx-Meis', and, 'EBF'])].
[sujeto(['DNA', is, organized, into, complex, 'three-dimensional', chromatin, 'structures,', but, how, this, spatial, organization]), verbo([regulates]), complemento([gene, expression, remains, a, central, question])].
[sujeto(['Recently,', the, influence, of, telomere, length, on, chromatin, organization, prior, to, senescence]), verbo([has]), complemento([revealed, the, existence, of, 'long-distance', chromatin, loops, that, dictate, the, expression, of, genes, located, up, to, 10, 'Mb', from, the, telomeres, '(', 'Telomere', 'Position', 'Effect-Over', 'Long', 'Distances', '[', 'TPE-OLD])'])].
[sujeto(['Here,', we, demonstrate, the, existence, of, a, telomere, loop, at, the, 4, q35, locus]), verbo([involving]), complemento([the, sorbin, and, 'SH3', 'domain-containing', protein, 2, 'gene,', 'SORBS2,', a, skeletal, muscle, protein, using, a, modification, of, the, chromosome, conformation, capture, method])].
[sujeto(['The', loop]), verbo([reveals]), complemento([a, 'cis-acting', mechanism, modifying, 'SORBS2', transcription])].
[sujeto(['SORBS2', is]), verbo([expressed]), complemento([in, 'FSHD', myoblasts, with, short, 'telomeres,', while, not, detectable, in, 'FSHD', myoblasts, with, long, telomeres, or, in, healthy, myoblasts, regardless, of, telomere, length])].
[sujeto(['Upon', 'differentiation,', both, 'FSHD', and, healthy, myotubes]), verbo([express]), complemento(['SORBS2,', suggesting, that, 'SORBS2', is, normally, 'up-regulated', by, 'maturation/differentiation', of, skeletal, muscle, and, is, misregulated, by, 'TPE-OLD-dependent', variegation, in, 'FSHD', myoblasts])].
[sujeto(['These', findings]), verbo([provide]), complemento([additional, insights, for, the, complexity, and, 'age-related', symptoms, of, 'FSHD'])].
[sujeto(['Emerging', studies, document, the, roles, of, long, 'non-coding', 'RNAs', '(', 'LncRNAs)', in]), verbo([regulating]), complemento([gene, expression, at, chromatin, level, but, relatively, less, is, known, how, they, regulate, 'DNA', methylation])].
[sujeto(['Here', we, identify, an, 'lncRNA,', 'Dum', '(', developmental, 'pluripotency-associated', 2, '(', 'Dppa2)', 'Upstream']), verbo([binding]), complemento(['Muscle', 'lncRNA)', in, skeletal, myoblast, cells])].
[sujeto(['The', expression, of, 'Dum', is, dynamically]), verbo([regulated]), complemento([during, myogenesis, in, vitro, and, in, vivo])].
[sujeto(['It', is, also, transcriptionally]), verbo([induced]), complemento([by, 'MyoD', binding, upon, myoblast, differentiation])].
[sujeto(['Functional', analyses, show, that, it]), verbo([promotes]), complemento([myoblast, differentiation, and, 'damage-induced', muscle, regeneration])].
[sujeto(['Mechanistically,', 'Dum', was]), verbo([found]), complemento([to, silence, its, neighboring, 'gene,', 'Dppa2,', in, cis, through, recruiting, 'Dnmt1,', 'Dnmt3a', and, 'Dnmt3b'])].
[sujeto(['Collectively,', we]), verbo([have]), complemento([identified, a, novel, lncRNA, that, interacts, with, 'Dnmts', to, regulate, myogenesis])].
[sujeto(['Wnt', proteins, are, secreted, cytokines, and, several, 'Wnts', are]), verbo([expressed]), complemento([in, the, developing, somites, and, surrounding, tissues])].
[sujeto(['These', 'Wnt', signals, received, by, somitic, cells, can]), verbo([lead]), complemento([to, activation, of, 'Pax3/Pax7', and, myogenic, regulatory, factors, '(', 'MRFs),', especially, 'Myf5', and, 'MyoD'])].
[sujeto(['However,', it, is, currently, unknown, whether, 'Wnts']), verbo([activate]), complemento(['Myf5', and, 'MyoD', through, direct, targeting, of, their, 'cis-regulatory', elements, or, via, indirect, pathways])].
[sujeto(['We']), verbo([found]), complemento([that, 'Wnt3a', activated, the, 'MyoD', proximal, 6.0, k, promoter, '(', 'P6P)', only, 'marginally,', but, highly, enhanced, the, activity, of, the, composite, 'P6P', plus, distal, enhancer, '(', 'DE)', reporter, through, canonical, and, 'non-canonical', pathways])].
[sujeto(['Further', screening, of, the, intervening, fragments, between, the, 'DE', and, the, 'P6P', identified, a, strong, 'Wnt-response', element, '(', 'WRE)', in, the, upstream, -, 8, to, -, 9, k, region, '(', 'L', 'fragment)', that]), verbo([acted]), complemento([independently, of, the, 'DE,', but, was, dependent, on, the, 'P6P'])].
[sujeto(['Deletion', of, a, 'Pax3/Pax7-targeted', site, in, the, 'L', fragment, significantly, reduced, its, response, to, 'Wnt3a,', implying, that, 'Wnt3a']), verbo([activates]), complemento([the, 'L', fragment, partially, through, 'Pax3/Pax7', action])].
[sujeto(['Binding', of, 'β-catenin', and, 'Pax7', to, their]), verbo([target]), complemento([sites, in, the, 'DE', and, the, 'L', fragment, respectively, was, also, demonstrated, by, 'ChIP'])].
[sujeto(['These', observations, demonstrated, the, first, time, that, 'Wnt3a', can, directly]), verbo([activate]), complemento(['MyoD', expression, through, targeting, 'cis-elements', in, the, 'DE', and, the, 'L', fragment])].
[sujeto(['MUNC', is, specifically]), verbo([expressed]), complemento([in, skeletal, muscle, and, exists, as, in, unspliced, and, spliced, 'isoforms,', and, its, 5, '\'', end, overlaps, with, the, 'cis-acting', distal, regulatory, region, '(', 'DRR)', of, 'MyoD'])].
[sujeto(['Stable', overexpression, of, 'MUNC', from, a, heterologous, promoter]), verbo([increased]), complemento([endogenous, 'MyoD,', 'Myogenin,', and, 'Myh3', '(', myosin, heavy, 'chain,', '[', 'MHC]', 'gene)', mRNAs, but, not, the, cognate, 'proteins,', suggesting, that, 'MUNC', can, act, in, trans, to, promote, gene, expression, but, that, this, activity, does, not, require, an, induction, of, 'MyoD', protein])].
[sujeto(['MUNC', also]), verbo([stimulates]), complemento([the, transcription, of, other, genes, that, are, not, recognized, as, 'MyoD-inducible', genes])].
[sujeto(['We', also, discovered, a, human, 'MUNC', that, is]), verbo([induced]), complemento([during, differentiation, of, myoblasts, and, whose, knockdown, decreases, 'differentiation,', suggesting, an, evolutionarily, conserved, role, of, 'MUNC', lncRNA, in, myogenesis])].
[sujeto(['Although', 'MUNC', overlaps, with, the, 'DRR', 'enhancer,', our, results]), verbo([suggest]), complemento([that, 'MUNC', is, not, a, classic, 'cis-acting', enhancer, 'RNA', '(', 'e-RNA)', acting, exclusively, by, stimulating, the, neighboring, 'MyoD', gene, but, more, like, a, promyogenic, lncRNA, that, acts, directly, or, indirectly, on, multiple, promoters, to, increase, myogenic, gene, expression])].
[sujeto(['However,', only, with, the, emergence, of, 'genome-wide', techniques]), verbo([has]), complemento([the, genuine, biological, scope, of, enhancers, begun, to, be, fully, uncovered])].
[sujeto(['Massive', scientific, efforts, of, multiple, laboratories, rapidly, advanced, the, overall, perception, that, enhancers, are, typified, by, common, epigenetic, characteristics, that, distinguish, their]), verbo([activating]), complemento([potential])].
[sujeto(['Broadly,', chromatin, modifiers, and, transcriptional, regulators, lay, down, the, essential, foundations, necessary, for, constituting, enhancers, in, their]), verbo([activated]), complemento([form])].
[sujeto(['Basing', on, 'genome-wide', 'ChIP-sequencing', of, 'enhancer-related', marks, we, identified, myogenic, enhancers, before, and, after, muscle, differentiation, and, discovered, that, 'MyoD', was]), verbo([bound]), complemento([to, nearly, a, third, of, 'condition-specific', enhancers])].
[sujeto(['Experimental', studies, that, tested, the, deposition, patterns, of, 'enhancer-related', epigenetic, marks, in, 'MyoD-null', myoblasts, revealed, the, high, dependency, that, a, specific, set, of, muscle, enhancers]), verbo([have]), complemento([towards, this, transcriptional, regulator])].
[sujeto(['Our', proposed, mechanistic, model]), verbo([suggests]), complemento([that, 'MyoD', is, involved, in, recruitment, of, methyltransferase, 'Set7,', acetyltransferase, p300, and, deposition, of, 'H3K4me1', and, 'H3K27ac', at, myogenic, enhancers])].
[sujeto(['In', 'addition,', 'MyoD']), verbo([binding]), complemento([at, enhancers, is, associated, with, 'PolII', occupancy, and, with, local, noncoding, transcription])].
[sujeto(['Modulation', of, muscle, enhancers, is]), verbo([suggested]), complemento([to, be, coordinated, via, transcription, factors, 'docking,', including, 'c-Jun', and, 'Jdp2', that, bind, to, muscle, enhancers, in, a, 'MyoD-dependent', manner])].
[sujeto(['We', hypothesize, that, distinct, transcription, factors, may]), verbo([act]), complemento([as, placeholders, and, mediate, the, assembly, of, newly, formed, myogenic, enhancers])].
[sujeto(['TBX1', encodes, a, transcription, factor, protein, that, contains, an, evolutionarily]), verbo([conserved]), complemento(['DNA', binding, domain, termed, the, 'T-box', that, is, shared, with, other, family, members])].
[sujeto(['All', 'T-box', 'proteins,', examined, so, 'far,']), verbo([bind]), complemento([to, similar, but, not, identical, consensus, 'DNA', 'sequences,', indicating, that, they, have, specific, binding, preferences])].
[sujeto(['In', contrast, to, other, 'TBX', family, members]), verbo([recognizing]), complemento([palindrome, 'sequences,', we, found, that, 'TBX1', preferentially, binds, to, a, tandem, repeat, of, 5, '\'', -, 'AGGTGTGAAGGTGTGA-3\''])].
[sujeto(['We', show, that, three, known, human, 'disease-causing', 'TBX1', missense, mutations, '(', 'F148Y,', 'H194Q', and, 'G310S)', do, not, alter]), verbo([nuclear]), complemento(['localization,', or, disrupt, binding, to, the, tandem, repeat, consensus, 'sequences,', but, they, reduce, transcriptional, activity, in, cell, culture, reporter, assays])].
[sujeto(['To', identify, 'Tbx1-downstream', 'genes,', we, performed, an, in, silico, genome, wide, analysis, of, potential, 'cis-acting', elements, in, 'DNA', and]), verbo([found]), complemento([strong, enrichment, of, genes, required, for, developmental, processes, and, transcriptional, regulation])].
[sujeto(['We']), verbo([found]), complemento([that, 'TBX1', binds, to, 19, different, loci, in, 'vitro,', which, may, correspond, to, putative, 'cis-acting', binding, sites])].
[sujeto(['In', situ, hybridization, coupled, with, luciferase, gene, reporter, assays, on, three, gene, 'loci,', 'Fgf8,', 'Bmper,', 'Otog-MyoD,', show, that, these, motifs, are, directly]), verbo([regulated]), complemento([by, 'TBX1', in, vitro])].
[sujeto(['Collectively,', the, present, studies, establish, new, insights, into, molecular, aspects, of, 'TBX1']), verbo([binding]), complemento([to, 'DNA'])].
[sujeto(['Its', transcription, is, mainly]), verbo([regulated]), complemento([by, peroxisome, 'proliferator-activated', receptors, '(', 'PPAR),', a, family, of, nuclear, hormone, receptors])].
[sujeto(['We', demonstrate]), verbo([binding]), complemento([of, 'SP1', and, 'SP3', to, this, element, which, is, adjacent, to, a, direct, repeat, 1, element, mediating, activation, of, 'UCP3', expression, by, 'PPARγ', agonists])].
[sujeto(['Transactivation']), verbo([mediated]), complemento([by, these, elements, is, interdependent, and, indispensable, for, 'UCP3', expression])].
[sujeto(['Systematic', deletion, uncovered, a, third]), verbo([binding]), complemento(['element,', a, putative, 'NF1', 'site,', in, close, proximity, to, the, 'SP1/3', and, 'PPARγ', binding, elements])].
[sujeto(['Data', mining, demonstrated]), verbo([binding]), complemento([of, 'MyoD', and, 'Myogenin', to, this, third, element, in, 'C2C12', 'cells,', 'and,', 'furthermore,', revealed, recruitment, of, p300])].
[sujeto(['Taken', 'together,', this, intronic, region, is, the, main, enhancer, driving, 'UCP3', expression, with, 'SP1/3', and, 'PPARγ', as, the, core, factors]), verbo([required]), complemento([for, expression])].
[sujeto(['Although', numerous, attempts]), verbo([have]), complemento([been, made, to, identify, these, 'combinations,', important, 'details,', such, as, mutual, positioning, of, the, factors, that, have, an, important, role, in, the, 'TF', 'interplay,', are, still, missing])].
[sujeto(['The', goal, of, the, present, work, is, in, silico, mapping, of, some, of, such]), verbo([associating]), complemento([factors, based, on, their, mutual, 'positioning,', using, computational, screening])].
[sujeto(['We']), verbo([have]), complemento([selected, the, process, of, myogenesis, as, a, study, 'case,', and, we, focused, on, 'TF', combinations, involving, master, myogenic, 'TF', 'Myogenic', differentiation, '(', 'MyoD)', with, other, factors, situated, at, specific, distances, from, it])].
[sujeto(['However,', we]), verbo([have]), complemento([also, found, novel, relationships, of, 'MyoD', with, other, factors, not, specific, for, muscle])].
[sujeto(['Additionally,', we]), verbo([have]), complemento([observed, that, 'MyoD', tends, to, associate, with, different, factors, in, proximal, and, distal, promoter, areas])].
[sujeto(['The', major, outcome, of, our, study, is, establishing, the, 'genome-wide', connection, between, biological, interactions, of, 'TFs', and, close, 'co-occurrence', of, their]), verbo([binding]), complemento([sites])].
[sujeto(['Identifying', gene, regulatory, elements, and, their]), verbo([target]), complemento([genes, in, vertebrates, remains, a, significant, challenge])].
[sujeto(['It', is, now]), verbo([recognized]), complemento([that, transcriptional, regulatory, sequences, are, critical, in, orchestrating, dynamic, controls, of, 'tissue-specific', gene, expression, during, vertebrate, development, and, in, adult, 'tissues,', and, that, these, elements, can, be, positioned, at, great, distances, in, relation, to, the, promoters, of, the, genes, they, control])].
[sujeto(['While', significant, progress]), verbo([has]), complemento([been, made, in, mapping, 'DNA', binding, regions, by, combining, chromatin, immunoprecipitation, and, next, generation, 'sequencing,', functional, validation, remains, a, limiting, step, in, improving, our, ability, to, correlate, in, silico, predictions, with, biological, function])].
[sujeto(['We', applied, this, method, to, 270, genes, highly]), verbo([expressed]), complemento([in, skeletal, muscle, and, predicted, 190, putative, 'cis-regulatory', modules])].
[sujeto(['We']), verbo([found]), complemento([45, '%', of, these, elements, expressed, only, in, the, fast, muscle, fibers, that, are, oriented, in, highly, organized, chevrons, in, the, 'Xenopus', laevis, tadpole])].
[sujeto(['Transcription', factor]), verbo([binding]), complemento([site, analysis, identified, &, 'gt;2', 'Mef2/MyoD', sites, within, '~200', bp, regions, in, 6, of, the, validated, 'enhancers,', and, systematic, mutagenesis, of, these, sites, revealed, that, they, are, critical, for, the, enhancer, function])].
[sujeto(['Skeletal', muscle, development, is, orchestrated, by, the, myogenic, regulatory, factor, 'MyoD,', whose, activity, is, blocked, in, myoblasts, by, proteins]), verbo([preventing]), complemento([its, nuclear, translocation, 'and/or', binding, to, 'G/C-centered', 'E-boxes', in, target, genes])].
[sujeto(['Recent', evidence, indicates, that, muscle, gene, expression, is, also]), verbo([regulated]), complemento([at, the, cis, level, by, differential, affinity, for, 'DNA', between, 'MyoD', and, other, 'E-box', binding, proteins, during, myogenesis])].
[sujeto(['MyoD']), verbo([binds]), complemento([to, 'G/C-centered', 'E-boxes,', enriched, in, muscle, differentiation, 'genes,', in, myotubes, but, not, in, myoblasts])].
[sujeto(['Here,', we, used, 'cell-based', and, in, vivo, 'Drosophila,', 'Xenopus', 'laevis,', and, mouse, models, to, show, that, 'ZEB1,', a, 'G/C-centered', 'E-box']), verbo([binding]), complemento([transcriptional, 'repressor,', imposes, a, temporary, 'stage-dependent', inhibition, of, muscle, gene, expression, and, differentiation, via, 'CtBP-mediated', transcriptional, repression])].
[sujeto(['We']), verbo([found]), complemento(['that,', contrary, to, 'MyoD,', 'ZEB1', binds, to, 'G/C-centered', 'E-boxes', in, muscle, differentiation, genes, at, the, myoblast, stage, but, not, in, myotubes])].
[sujeto(['Inhibition', of, muscle, genes, by, 'ZEB1', occurs, via, transcriptional, repression, and]), verbo([involves]), complemento([recruitment, of, the, 'CtBP', corepressor])].
[sujeto(['Lastly,', we, show, that, the, pattern, of, gene, expression]), verbo([associated]), complemento([with, muscle, differentiation, is, accelerated, in, 'ZEB1(-/-)', mouse, embryos])].
[sujeto(['The', 'up-regulation', of, the, cdk, inhibitor, p57kip2, plays, a, critical, role, in, coordinating, differentiation, and, growth]), verbo([arrest]), complemento([during, muscle, 'development,', as, well, as, in, other, tissues])].
[sujeto(['We']), verbo([have]), complemento([identified, an, unexpected, mechanism, by, which, 'MyoD', regulates, p57kip2, transcription, in, differentiating, muscle, cells])].
[sujeto(['We', show, that, the, induction, of, p57kip2]), verbo([requires]), complemento(['MyoD', binding, to, a, 'long-distance', element, located, within, the, imprinting, control, region, 'KvDMR1', and, the, consequent, release, of, a, chromatin, loop, involving, p57kip2, promoter])].
[sujeto(['We', also, show, that, 'differentiation-dependent', regulation, of, 'p57kip2,', while]), verbo([involving]), complemento([a, region, implicated, in, the, imprinting, 'process,', is, distinct, and, hierarchically, subordinated, to, the, imprinting, control])].
[sujeto(['These', findings, highlight, a, novel, 'mechanism,']), verbo([involving]), complemento([the, modification, of, higher, order, chromatin, 'structures,', by, which, 'MyoD', regulates, gene, expression])].
[sujeto(['Our', results, also]), verbo([suggest]), complemento([that, chromatin, folding, mediated, by, 'KvDMR1', could, account, for, the, highly, restricted, expression, of, p57kip2, during, development, 'and,', 'possibly,', for, its, aberrant, silencing, in, some, pathologies])].
[sujeto(['The', rate, of, predictive, success]), verbo([reveals]), complemento([striking, limitations, of, computational, regulatory, sequence, analysis, methods, for, 'CRM', discovery])].
[sujeto(['The', myosin, heavy, chain, 'gene,', 'MYH(M743-2),', is, highly]), verbo([expressed]), complemento([in, fast, muscle, fibers, of, torafugu, embryos, and, 'larvae,', suggesting, its, functional, roles, for, embryonic, and, larval, muscle, development])].
[sujeto(['However,', the, transcriptional, regulatory, mechanism]), verbo([involved]), complemento([in, its, expression, remained, unknown])].
[sujeto(['The', immunohistochemical, observation, revealed, that, the, zebrafish, larvae, from, the, stable, transgenic, line, consistently]), verbo([expressed]), complemento([enhanced, green, fluorescent, protein, '(', 'EGFP)', in, fast, muscle, fibers])].
[sujeto(['We', discovered, that, the, serum, response, factor, '(', 'SRF)-like']), verbo([binding]), complemento([sites, are, required, for, promoting, 'MYH(M743-2)', expression, and, myoblast, determining, factor, '(', 'MyoD)', and, myocyte, enhancer, 'factor-2', '(', 'MEF2)', binding, sites, participate, in, the, transcriptional, control, of, 'MYH(M743-2)', expression, in, fast, skeletal, muscles])].
[sujeto(['We', further, discovered, that, 'MyoD']), verbo([binding]), complemento(['sites,', but, not, 'MEF2,', participate, in, the, transcriptional, regulation, of, 'MYH(M743-2)', expression, in, pectoral, fin, and, craniofacial, muscles])].
[sujeto(['Skeletal', muscle, and, kidney, enriched, inositol, phosphatase, '(', 'SKIP)', was, identified, as, a, 5, '\'', -, inositol, phosphatase, that, hydrolyzes, 'PI(3,4,5)P3', to, 'PI(3,4)P2', that, negatively]), verbo([regulates]), complemento(['insulin-induced', phosphatidylinositol, 3, -, kinase, signaling, in, skeletal, muscle])].
[sujeto([5, ')', ',', and, allele, 'G', seemed, to, be]), verbo([associated]), complemento([with, an, increase, in, the, growth, trait])].
[sujeto(['Porcine', 'SKIP', was]), verbo([expressed]), complemento([abundantly, in, skeletal, muscle, tissue, and, was, transcriptionally, upregulated, during, skeletal, muscle, differentiation])].
[sujeto(['Analysis', of, the, porcine, 'SKIP', promoter, sequence, demonstrated, that, 'MyoD', was]), verbo([involved]), complemento([in, regulating, 'SKIP', mRNA, expression, in, 'myotubes,', partly, via, the, 'cis-acting', elements, in, 'SKIP', promoter])].
[sujeto(['In', 'summary,', we]), verbo([suggested]), complemento([that, 'SKIP', might, play, a, role, in, the, regulation, of, skeletal, muscle, development, in, pigs])].
[sujeto(['Diet-induced', weight]), verbo([loss]), complemento([is, affected, by, a, wide, range, of, 'factors,', including, genetic, variation])].
[sujeto(['Previously,', we]), verbo([reported]), complemento([a, strong, association, between, a, common, single, nucleotide, polymorphism, '(', 'SNP)', rs2419621, '(', 'C&gt;T)', in, the, promoter, of, 'acyl-CoA', synthetase, long, chain, 5, '(', 'ACSL5),', rapid, weight, loss, in, obese, 'Caucasian', 'females,', and, elevated, 'ACSL5', mRNA, levels, in, skeletal, muscle, biopsies])].
[sujeto(['Here,', we, showed, by, electrophoretic, mobility, shift, assay, '(', 'EMSA)', that, the, 'T', allele, creates, a, functional, 'cis-regulatory', 'E-box', element, '(', 'CANNTG)', that, is]), verbo([recognized]), complemento([by, the, myogenic, regulatory, factor, 'MyoD'])].
[sujeto(['The', 'T', allele]), verbo([promoted]), complemento(['MyoD-dependent', activation, of, a, 1089, -, base, pair, 'ACSL5', promoter, fragment, in, nonmuscle, 'CV1', cells])].
[sujeto(['These', results]), verbo([reveal]), complemento([a, mechanism, for, elevated, transcription, of, 'ACSL5', in, skeletal, muscle, of, carriers, of, the, 'rs2419621(T)', 'allele,', associated, with, more, rapid, 'diet-induced', weight, loss])].
[sujeto(['In', the, current, 'study,', treatment, of, the, rat, osteogenic, cell, line, 'ROB-C26', cells, with, fibroblast, growth, factor, 8, '(', 'FGF8)']), verbo([stimulated]), complemento([alkaline, phosphatase, '(', 'ALP)', 'activity,', and, also, induced, the, expression, of, the, 'Runx2', transcription, 'factor,', and, increased, the, activity, of, a, luciferase, reporter, gene, containing, the, osteocalcin, '(', 'OCN)', promoter, and, six, copies, of, the, osteoblast, specific, 'cis-acting', element, 2, '(', 'OSE2)', response, element])].
[sujeto(['In', 'contrast,', 'FGF8', treatment, of, the, mouse, myoblast, cell, line, 'C2C12']), verbo([inhibited]), complemento([the, expression, of, desmin, and, the, synthesis, of, myotubes])].
[sujeto(['The', expression, of, 'MyoD,', 'Myogenin,', 'Foxc2,', and, 'Hand1', was, also]), verbo([decreased]), complemento([by, 'FGF8'])].
[sujeto(['Transient', expression, of, 'Foxc2', in, 'C2C12', cells]), verbo([induced]), complemento([the, expression, of, 'Hand1,', and, chromatin, immunoprecipitation, '(', 'ChIP)', analysis, indicated, that, 'Foxc2', binds, to, the, promoter, region, of, the, 'Hand1', gene])].
[sujeto(['These', results, indicated, that, 'Foxc2', is, directly]), verbo([involved]), complemento([in, the, regulation, of, 'Hand1', expression])].
[sujeto(['The', results, of, the, current, study, indicate, that, 'FGF8']), verbo([regulates]), complemento([myoblast, differentiation, through, the, regulation, of, 'MyoD', 'expression,', and, that, this, regulation, is, independent, of, 'Hand1', in, cultured, cells])].
[sujeto(['Facioscapulohumeral', muscular, dystrophy, '(', 'FSHD)', is]), verbo([caused]), complemento([by, an, unusual, deletion, with, neomorphic, activity])].
[sujeto(['This', deletion, derepresses, genes, in, 'cis;', however, which, candidate, gene]), verbo([causes]), complemento([the, 'FSHD', 'phenotype,', and, through, what, 'mechanism,', is, unknown])].
[sujeto(['We', compare, the, effects, of]), verbo([expressing]), complemento([variable, levels, of, each, 'FSHD', candidate, gene, on, myoblasts])].
[sujeto(['DUX4', expression, recapitulates, key, features, of, the, 'FSHD', molecular, 'phenotype,', including, repression, of, 'MyoD', and, its]), verbo([target]), complemento(['genes,', diminished, myogenic, 'differentiation,', repression, of, glutathione, redox, pathway, 'components,', and, sensitivity, to, oxidative, stress])].
[sujeto(['We', further, demonstrate, competition, between, 'DUX4', and, 'Pax3/Pax7:', when, either, 'Pax3', or, 'Pax7', is]), verbo([expressed]), complemento([at, high, 'levels,', 'DUX4', is, no, longer, toxic])].
[sujeto(['We', propose, a, hypothesis, for, 'FSHD', in, which, 'DUX4', expression, interferes, with, 'Pax7', in, satellite, 'cells,', and, inappropriately]), verbo([regulates]), complemento(['Pax', 'targets,', including, myogenic, regulatory, 'factors,', during, regeneration])].
[sujeto(['Cells', were, cultured, in, 'low-mitogen', differentiation, medium, to]), verbo([induce]), complemento([cell, 'differentiation,', with, or, without, the, addition, of, lactoferrin])].
[sujeto(['ALPase', activity]), verbo([increased]), complemento([after, the, addition, of, lactoferrin])].
[sujeto(['The', mRNA, expression, of, 'Runx2,', 'osteocalcin,', and, 'Sox9']), verbo([increased]), complemento([markedly, as, a, result, of, lactoferrin, 'treatment,', whereas, the, expression, of, 'MyoD,', 'desmin,', and, 'PPARgamma', decreased, significantly])].
[sujeto(['Western', blots, showed, that, lactoferrin, stimulation]), verbo([increased]), complemento(['Runx2', and, 'Sox9', 'proteins,', whereas, it, decreased, 'MyoD', and, 'PPARgamma', synthesis])].
[sujeto(['C2C12', cells]), verbo([expressed]), complemento([the, 'LRP1', lactoferrin, receptor])].
[sujeto(['De', novo, methylation, of, 'CpG', islands, within, the, promoters, of, eukaryotic, genes, is, often]), verbo([associated]), complemento([with, their, transcriptional, 'repression,', yet, the, methylation, of, 'CpG', islands, located, downstream, of, promoters, does, not, block, transcription])].
[sujeto(['The', rates, of, remethylation, of, both, 'CpG', islands, were]), verbo([associated]), complemento([with, time, but, not, with, the, rate, of, cell, 'division,', and, remethylation, of, the, p16, exon, 2, 'CpG', island, occurred, at, a, higher, rate, than, that, of, the, p16, promoter])].
[sujeto(['Remethylation', occurred, most, rapidly, in, the, 'p16,', 'PAX-6,', and, 'c-ABL', 'genes,', shown, to, be]), verbo([transcribed]), complemento([prior, to, drug, treatment])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, de, novo, methylation, is, not, restricted, to, the, 'S', phase, of, the, cell, cycle, and, that, transcription, through, 'CpG', islands, does, not, inhibit, their, remethylation])].
[sujeto([5, -, 'Azacytidine', '(', 5, -, 'aza-CR)', and, 5, -, 'aza-2\'-deoxycytidine', '(', 5, -, 'aza-CdR),', analogs, of, cytidine, modified, in, position, 5, ',', were, originally, developed, as, antitumor, 'agents,', and]), verbo([have]), complemento([been, useful, in, the, treatment, of, both, childhood, and, adult, leukemias])].
[sujeto(['These', agents, are, cytotoxic, per, 'se,', but, also]), verbo([induce]), complemento([differentiation, in, several, experimental, 'systems,', most, notably, the, induction, of, 'muscle,', 'adipocytes,', and, chondrocytes, in, cultures, of, 'drug-treated', mouse, embryo, fibroblasts])].
[sujeto(['The', mechanisms, underlying, this, 'drug-induced', differentiation]), verbo([have]), complemento([been, difficult, to, 'unravel,', a, fact, which, limits, the, rational, design, of, differentiation, therapy, as, a, modulator, of, cancer, using, these, agents])].
[sujeto(['Induction', of, new, developmental, pathways, in, cultured, cells]), verbo([involves]), complemento(['stable,', heritable, 'changes,', presumably, of, an, epigenetic, nature])].
[sujeto(['Since', 'DNA', methylation, is, believed, to, be]), verbo([involved]), complemento([at, some, level, in, the, regulation, of, gene, 'expression,', the, hypothesis, was, developed, that, changes, in, methylation, allowed, the, expression, of, new, genes, whose, activity, initiated, new, pathways, of, differentiation])].
[sujeto(['The', characterization, of, this, 'drug-induced', system, of, differentiation]), verbo([has]), complemento([therefore, opened, the, way, to, identifying, genes, directly, involved, in, the, initiation, or, modification, of, pathways, of, differentiation])].
[sujeto(['Expression', of, 'MyoD', in, myogenic, cell, lines]), verbo([has]), complemento([been, correlated, with, loss, of, methylation, at, specific, sites, in, the, 'genome,', but, the, critical, events, leading, to, expression, of, 'MyoD', and, muscle, differentiation, are, poorly, understood])].
[sujeto(['MyoD1', transfection]), verbo([induced]), complemento([the, synthesis, of, 'myosin,', 'desmin,', and, vimentin, without, substantially, altering, the, epidermal, differentiation, properties, '(', 'morphology,', keratin, 'profile)', in, vitro, nor, epidermal, morphogenesis, '(', formation, of, a, complex, stratified, squamous, 'epithelium)', in, surface, 'transplants,', demonstrating, the, stability, of, the, keratinocyte, phenotype])].
[sujeto(['The', present, study, evaluated, 'low-level', laser, therapy, '(', 'LLLT)', effects, on, some, physiological, pathways, that, may]), verbo([lead]), complemento([to, muscle, damage, or, regeneration, capacity, in, 'dystrophin-deficient', muscle, cells, of, mdx, 'mice,', the, experimental, model, of, 'Duchenne', muscular, dystrophy, '(', 'DMD)'])].
[sujeto(['The', mdx, 'LA', 24, and, mdx, 'LA', 48, groups, showed, significant]), verbo([increase]), complemento([in, cell, 'proliferation,', higher, diameter, in, muscle, cells, and, decreased, 'MyoD', levels, compared, to, the, mdx, group])].
[sujeto(['The', mdx, 'LA', 48, group, showed, significant]), verbo([increase]), complemento([in, 'Myosin', 'Heavy', 'Chain', levels, compared, to, the, untreated, mdx, and, mdx, 'LA', 24, groups])].
[sujeto(['The', mdx, 'LA', 24, and, mdx, 'LA', 48, groups, showed, significant]), verbo([increase]), complemento([in, '[', 'Ca2+]i'])].
[sujeto(['The', mdx, group, showed, significant]), verbo([increase]), complemento([in, 'H2O2', production, and, 4, -, 'HNE', levels, compared, to, the, 'Ctrl', group, and, 'LLLT', treatment, reduced, this, increase])].
[sujeto(['GSH', levels, and, 'GPx,', 'GR', and, 'SOD', activities]), verbo([increased]), complemento([in, the, mdx, group])].
[sujeto(['The', mdx, group, showed, significant]), verbo([increase]), complemento([in, the, 'TNF-α', and, 'NF-κB', 'levels,', which, in, turn, was, reduced, by, the, 'LLLT', treatment])].
[sujeto(['Together,', these, results]), verbo([suggest]), complemento([that, the, laser, treatment, improved, regenerative, capacity, and, decreased, inflammatory, response, and, oxidative, stress, in, dystrophic, muscle, 'cells,', indicating, that, 'LLLT', could, be, a, helpful, alternative, therapy, to, be, associated, with, other, treatment, for, dystrophinopathies])].
[sujeto(['It', is, known, that, 'non-cachectic', patients, with, chronic, obstructive, pulmonary, disease, '(', 'COPD)']), verbo([respond]), complemento([well, to, pulmonary, 'rehabilitation,', but, whether, cachectic, 'COPD', patients, are, capable, of, adaptive, responses, is, both, important, and, unknown])].
[sujeto(['Before', and, after, rehabilitation, vastus, lateralis, muscle, biopsies, were, analysed, morphologically, and, for, the, expression, of, muscle, remodelling, factors, '(', 'insulin-like', growth, factor, '(', 'IGF)-I,', myogenic, differentiation, factor, 'D', '(', 'MyoD),', tumour, necrosis, factor, '(', 'TNF)-alpha,']), verbo([nuclear]), complemento([factor, '(', 'NF)-kappaB', and, 'myostatin)', and, key, components, of, 'ubiquitin-mediated', proteolytic, systems, '(', muscle, ring, finger, protein, '(', 'MURF)-1', and, 'Atrogin-1)'])].
[sujeto(['Mean', muscle, fibre, 'cross-sectional', area]), verbo([increased]), complemento([in, both, 'groups,', but, significantly, less, in, cachectic, '(', 7, +, /, -, 2, '%', ')', than, in, 'non-cachectic', '(', 11, +, /, -, 2, '%', ')', patients])].
[sujeto(['Both', groups, equally]), verbo([decreased]), complemento([the, proportion, of, type, 'IIb', fibres, and, increased, muscle, 'capillary/fibre', ratio])].
[sujeto(['IGF-I', mRNA, expression]), verbo([increased]), complemento([in, both, 'groups,', but, 'IGF-I', protein, levels, increased, more, in, 'non-cachectic', 'COPD'])].
[sujeto(['Whilst', rehabilitation, had, no, effect, on, 'TNF-alpha', 'expression,', it]), verbo([decreased]), complemento([the, activation, of, the, transcription, factor, 'NF-kappaB', in, both, groups, by, the, same, amount])].
[sujeto(['Atrogin-1', and, 'MURF-1', expression, were]), verbo([increased]), complemento([in, cachectic, 'COPD,', but, it, was, decreased, in, 'non-cachectic', patients])].
[sujeto(['Cachectic', 'COPD', patients, partially]), verbo([retain]), complemento([the, capacity, for, peripheral, muscle, remodelling, in, response, to, rehabilitation, and, are, able, to, increase, exercise, capacity, as, much, as, those, without, 'cachexia,', even, if, they, exhibit, both, quantitative, and, qualitative, differences, in, the, type, of, muscle, fibre, remodelling, in, response, to, exercise, training])].
[sujeto(['Skeletal', muscle, wasting, commonly, occurs, in, patients, with, chronic, obstructive, pulmonary, disease, '(', 'COPD)', and]), verbo([has]), complemento([been, associated, with, the, presence, of, systemic, inflammation])].
[sujeto(['This', study, investigated, whether, rehabilitative, exercise, training]), verbo([decreases]), complemento([the, levels, of, systemic, or, local, muscle, inflammation, or, reverses, the, abnormalities, associated, with, muscle, deconditioning])].
[sujeto(['In', 'contrast,', there, was, a, significant]), verbo([increase]), complemento([in, mRNA, expression, of, 'IGF-I', '(', by, 67, '(', 22, ')', '%', ;, p, =, 0.044, ')', ',', 'MGF', '(', by, 67, '(', 15, ')', '%', ;, p, =, 0.002, ')', and, 'MyoD', '(', by, 116, '(', 30, ')', '%', ;, p, =, 0.001, ')'])].
[sujeto(['The']), verbo([increase]), complemento([observed, at, the, mRNA, level, was, also, seen, at, the, protein, level, for, 'IGF-I', '(', by, 72, '(', 36, ')', '%', ;, p, =, 0.046, ')', and, 'MyoD', '(', by, 67, '(', 21, ')', '%', ;, p, =, 0.012, ')'])].
[sujeto(['Pulmonary', rehabilitation, can]), verbo([induce]), complemento([peripheral, muscle, adaptations, and, modifications, in, factors, regulating, skeletal, muscle, hypertrophy, and, regeneration, without, decreasing, the, levels, of, systemic, or, local, muscle, inflammation])].
[sujeto(['This', pharmacological, treatment]), verbo([has]), complemento([been, demonstrated, to, induce, specific, apoptotic, death, in, monocytes, and, phagocytic, macrophages])].
[sujeto([',', 'MyoD', and, 'myogenin)', directly]), verbo([involved]), complemento([in, the, 'activation/proliferation', and, differentiation, of, muscle, precursor, cells, was, not, altered, by, the, clodronate, liposome, treatment])].
[sujeto(['The', repair, process, in, the, injured, muscle, of, clodronate, 'liposome-treated', mice, was, characterized, by, prolonged, clearance, of, necrotic, myofibers, and, a, tendency, for]), verbo([increased]), complemento([muscle, fat, accumulation, at, day, 9, and, 14, 'postinjury,', respectively])].
[sujeto(['In', 'conclusion,', a, significant, reduction, of, the, initial, 'monocyte/macrophage', influx, into, the, injured, muscle, is]), verbo([associated]), complemento([with, not, 'improved,', but, moderately, 'impaired,', repair, processes, after, skeletal, muscle, injury])].
[sujeto(['T(3)']), verbo([regulates]), complemento([energy, metabolism, by, stimulating, metabolic, rate, and, decreasing, metabolic, efficiency])].
[sujeto(['Within', 8, h, of, 'single-dose', 'T(3)', 'administration,', hypothyroid, rats, showed, a, rise, in, serum, fatty, acid, levels, concomitant, with, a, rapid]), verbo([increase]), complemento([in, 'UCP3', expression, in, gastrocnemius, 'muscle,', followed, by, inductions, of, peroxisome, proliferator, activated, receptor, delta, '(', 'PPARdelta)', '(', within, 24, 'h)', and, 'PPAR', target, gene, expression, '(', after, 24, 'h)'])].
[sujeto(['In', transfected, rat, 'L6', 'myoblasts,', only, the, rat, 'UCP3', promoter, positively]), verbo([responded]), complemento([to, 'T(3)', and, 'L165,041', together, in, the, presence, of, 'MyoD,', thyroid, hormone, receptor, beta1, '(', 'TRbeta1),', 'PPARdelta,', or, 'PPARdelta', plus, the, 'TR', dimerization, partner, retinoid, 'X', receptor, alpha])].
[sujeto(['Although', physical, interactions, with, other, receptors]), verbo([have]), complemento([been, 'reported,', heterodimeric, complexes, of, 'T(3)', nuclear, receptors, '(', 'TR)', with, retinoid, 'X', receptors, '(', 'RXRs)', are, considered, as, major, regulators, of, 'T(3)', target, gene, expression])].
[sujeto(['However,', despite, the, potent, 'T(3)', influence, in, proliferating, 'myoblasts,', 'RXR', isoforms, are, not]), verbo([expressed]), complemento([during, 'proliferation,', raising, the, question, of, the, nature, of, the, complex, involved, in, 'TRalpha', transcriptional, activity])].
[sujeto(['We']), verbo([have]), complemento([previously, established, that, 'c-Jun', induces, 'TRalpha1', transcriptional, activity, in, proliferating, myoblasts, not, expressing, 'RXR'])].
[sujeto(['This', regulation, is, specific, to, the, muscle, 'lineage,']), verbo([suggesting]), complemento([the, involvement, of, a, 'muscle-specific', factor])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, 'MyoD', expression, in, 'HeLa', cells, stimulates, 'TRalpha1', 'activity,', an, influence, potentiated, by, 'c-Jun', coexpression])].
[sujeto(['Similarly,', in, the, absence, of, 'RXR,', 'MyoD', or, 'c-Jun', overexpression, in, myoblasts]), verbo([induces]), complemento(['TRalpha1', transcriptional, activity, through, a, direct, repeat, 4, or, an, inverted, palindrome, 6, thyroid, hormone, response, element])].
[sujeto(['Furthermore,', we, demonstrated, that, 'TRalpha1', and, 'MyoD', physically]), verbo([interact]), complemento([in, the, hinge, region, of, the, receptor, and, the, transactivation, and, basic, helix, loop, helix, domains, of, 'MyoD'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, in, the, absence, of, 'RXR,', 'TRalpha1', transcriptional, activity, in, myoblasts, is, mediated, through, a, complex, including, 'MyoD', and, 'c-Jun'])].
[sujeto(['Mammals']), verbo([have]), complemento([two, major, isoforms, of, 'acetyl-CoA', carboxyase, '(', 'ACC)'])].
[sujeto(['ACCbeta', is, thought, to, control, fatty, acid, oxidation, by, means, of, the, ability, of, 'malonyl-CoA', to]), verbo([inhibit]), complemento([carnitine, 'palmitoyl-CoA', 'transferase-1', '(', 'CPT-1),', which, is, a, 'rate-limiting', enzyme, of, fatty, acid, oxidation, in, mitochondria])].
[sujeto(['Previously,', it, was]), verbo([reported]), complemento([that, 'MyoD', and, other, muscle, regulating, factors, '(', 'MRFs)', 'up-regulate', the, expression, of, 'ACCbeta', by, interactions, between, these, factors, and, several, 'cis-elements', of, 'ACCbeta', promoter])].
[sujeto(['We', described, here, that, 'ACCbeta', expression]), verbo([mediated]), complemento([by, 'MRFs', is, regulated, by, retinoic, acids])].
[sujeto(['Endogenous', expression, of, 'ACCbeta', in, differentiated, 'H9C2', myotube, was, significantly]), verbo([increased]), complemento([by, retinoic, acid, treatment])].
[sujeto(['However,', on, transient, transfection, assay, in, 'H9C2', 'myoblast,', 'ACCbeta', promoter, activity, was]), verbo([suppressed]), complemento([by, 'RXRalpha', and, more, severely, by, 'RARalpha'])].
[sujeto(['These', effects, on, 'ACCbeta', expression, in, myoblasts, and, myotubes, by, 'RXRalpha', and, 'RARalpha', seem, to, be]), verbo([mediated]), complemento([by, their, interactions, with, 'MRFs', because, no, consensus, sequence, for, 'RXRalpha', and, 'RARalpha', has, been, found, in, 'ACCbeta', promoter, and, retinoic, acid, receptors, did, not, affect, this, promoter, activities, by, itself])].
[sujeto(['In', transient, transfection, in, 'NIH3T3', 'fibroblast,', the, activation, of, 'ACCbeta', promoter, by, 'MyoD,', main, 'MRF', in, 'myoblast,', was, significantly]), verbo([suppressed]), complemento([by, 'RARalpha', and, to, a, less, extent, by, 'RXRalpha', while, the, 'RXRalpha', drastically, augmented, the, activation, by, 'MRF4,', major, 'MRF', in, myotube])].
[sujeto(['These', results, explained, that, retinoic, acids, differentially, affected, the, action, of, 'MRFs', according, to, their, types, and, 'RXRalpha', specially, elevates, the, expression, of, muscle, specific, genes, by]), verbo([stimulating]), complemento([the, action, of, 'MRF4'])].
[sujeto(['Rev-erbA', alpha, is, an, orphan, steroid, receptor, that, is]), verbo([expressed]), complemento([in, skeletal, muscle])].
[sujeto(['Rev-erbA', alpha]), verbo([binds]), complemento([to, 'single/tandem', copies, of, an, 'AGGTCA', 'motif,', is, transcribed, on, the, noncoding, strand, of, the, 'c-erbA-', alpha, gene, 'locus,', and, is, postulated, to, modulate, the, thyroid, hormone, '(', 'T3)', response])].
[sujeto(['T3']), verbo([induces]), complemento([terminal, muscle, differentiation, and, regulates, fiber, type, composition, via, direct, activation, of, the, 'muscle-specific', myoD, gene, family, '(', e])].
[sujeto(['The', myoD, gene, family, can, direct, the, fate, of, mesodermal, cell, lineages, and]), verbo([activate]), complemento([muscle, differentiation])].
[sujeto(['We', observed, abundant, levels, of, 'Rev-erbA', alpha, mRNA, in, dividing, 'C2C12', 'myoblasts,', which, were]), verbo([suppressed]), complemento([when, the, cells, differentiated, into, postmitotic, multinucleated, myotubes])].
[sujeto(['This']), verbo([decrease]), complemento([in, 'Rev-erbA', alpha, mRNA, correlated, with, the, appearance, of, 'muscle-specific', mRNAs, '(', e])].
[sujeto(['Constitutive', overexpression, of, full, length, 'Rev-erbA', alpha, cDNA, in, the, myogenic, cells, completely, abolished, 'differentiation,']), verbo([suppressed]), complemento([myoD, mRNA, 'levels,', and, abrogated, the, induction, of, myogenin, mRNA])].
[sujeto(['We', then, demonstrated, that, 1, ')', 'GAL4-REV-erbA', alpha, chimeras, that, contain, the, '\'', 'AB\'', region, and, lack, the, '\'', 'E\'', region]), verbo([activated]), complemento([transcription, of, 'GAL4', response, elements, in, the, presence, of, 8, -, 'Br-cAMP', and, 2, ')', the, 'ligand-binding', domain, '(', 'LBD)', contains, an, active, transcriptional, silencer])].
[sujeto(['Furthermore,', this, orphan, receptor, 1, ')', 'down-regulated', thyroid, hormone, receptor, '(', 'TR)/T3']), verbo([mediated]), complemento([transcriptional, activity, from, the, myogenin, promoter, and, thyroid, hormone, response, element, '(', 'TRE)', an, 2, ')', disrupted, 'TR', homodimer, and, 'TR/retinoid', 'X', receptor, '(', 'RXR)', heterodimer, formation, on, a, number, of, 'TREs', found, in, the, myoD, gene, family])].
[sujeto(['In', 'conclusion,', 'Rev-erbA', alpha, functions, as, a, negative, regulator, of, myogenesis, by]), verbo([targeting]), complemento([the, expression, of, the, myoD, gene, family])].
[sujeto(['The', mechanism, of, action, may]), verbo([involve]), complemento([inhibition, of, functional, 'TR/RXR', heterodimer, formation, on, critical, 'TREs', and, dominant, 'trans-repression', of, gene, expression])].
[sujeto(['COUP-TF', 'II', is, an, '\'', orphan, steroid, 'receptor\'', that]), verbo([binds]), complemento([a, wide, variety, of, 'AGGTCA', repeats, and, represses, thyroid, hormone, '(', 'T3)', and, retinoid, dependent, 'trans-activation;', 'however,', very, little, is, known, of, its, functional, 'and/or', developmental, role, during, mammalian, cell, differentiation])].
[sujeto(['T3', and, retinoids]), verbo([have]), complemento([been, demonstrated, to, promote, terminal, muscle, differentiation, via, activation, of, the, muscle, specific, myoD, gene, family, '(', 'myoD,', 'myogenin,', 'myf-5', and, 'MRF-4)'])].
[sujeto(['The', myoD, gene, family, can, direct, the, fate, of, mesodermal, cell, 'lineages,']), verbo([repress]), complemento(['proliferation,', activate, differentiation, and, the, contractile, phenotype])].
[sujeto(['Proliferating', 'C2C12', myoblasts]), verbo([expressed]), complemento(['COUP-TF', 'II', mRNA, which, was, repressed, when, cells, were, induced, to, differentiate, into, 'post-mitotic', multinucleated, myotubes, by, serum, withdrawal])].
[sujeto(['Concomitant', with, the]), verbo([decrease]), complemento([of, 'COUP-TF', 'II', mRNA, was, the, appearance, of, muscle, specific, mRNAs, '(', e])].
[sujeto(['We', show, that, 'Escherichia', coli]), verbo([expressed]), complemento([full, length, and, truncated, 'COUP-TF', 'II', bound, in, a, sequence, specific, manner, to, the, 'T3', response, elements, '(', 'TREs)', in, the, myoD, and, myogenin, regulatory, 'HLH', genes, '[', 'Olson', '(', 1992, ')', 'Dev'])].
[sujeto(['COUP-TF', 'II', diminished, the, homodimeric]), verbo([binding]), complemento([of, the, thyroid, hormone, receptor, and, the, heterodimeric, binding, of, thyroid, hormone, and, retinoid, 'X', receptor, complexes, to, these, 'TREs'])].
[sujeto(['Constitutive', 'over-expression', of, 'COUP-TF', 'II', cDNA, in, mouse, 'C2C12', myogenic, cells]), verbo([suppressed]), complemento([the, levels, of, myoD, mRNA, and, blocked, the, induction, of, myogenin, 'mRNA,', whereas, constitutive, expression, of, 'anti-sense', 'COUP-TF', 'II', cDNA, significantly, increased, the, steady, state, levels, of, myoD, mRNA, and, 'hyper-induced', myogenin, mRNA])].
[sujeto(['Triiodo-L-thyronine', treatment]), verbo([promotes]), complemento([terminal, muscle, differentiation, and, results, in, increased, 'MyoD', gene, transcription, in, myogenic, cell, 'lines;', furthermore, myoD, and, fast, myosin, heavy, chain, gene, expression, are, activated, in, rodent, slow, twitch, muscle, fibers, '(', 'Molecular', 'Endocrinology', 6, :, 1185, -, 1194, ',', 1992, ;, 'Development', 118, :, 1137, -, 1147, ',', 1993, ')'])].
[sujeto(['We']), verbo([have]), complemento([identified, a, 'T3', response, element, '(', 'TRE)', in, the, mouse, 'MyoD', promoter, between, nucleotide, positions, -, 337, and, -, 309, '(', 5, '\'', 'CTGAGGTCAGTACAGGCTGGAGGAGTAGA', 3, '\'', ')'])].
[sujeto(['This', sequence]), verbo([conferred]), complemento([an, appropriate, 'T3', response, to, an, enhancerless, 'SV40', promoter])].
[sujeto(['In', vitro]), verbo([binding]), complemento([studies, showed, that, the, thyroid, hormone, receptor, alpha, '(', 'TR', 'alpha)', formed, a, heterodimeric, 'complex,', with, either, the, retinoid, 'X', receptor, alpha, or, gamma, 1, isoforms, '(', 'RXR', 'alpha,', 'RXR', 'gamm),', on, the, 'MyoD', 'TRE', that, was, specifically, competed, by, other, well, characterised, 'TREs', and, not, by, other, response, elements])].
[sujeto(['EMSA', experiments, demonstrated, that, the]), verbo([nuclear]), complemento(['factor(s)', present, in, muscle, cells, that, bound, to, the, myoD, 'TRE', were, constitutively, expressed, during, 'myogenesis;', this, complex, was, competed, by, the, myosin, heavy, 'chain,', 'DR-4', and, 'PAL-0', 'TREs', in, a, sequence, specific, fashion])].
[sujeto(['Western', blot, analysis, indicated, that, 'TR', alpha, 1, was, constitutively]), verbo([expressed]), complemento([during, 'C2C12', differentiation])].
[sujeto(['Mutagenesis', of, the, myoD, 'TRE', indicated, that, the, sequence, of, the, direct, repeats, '(', 'AGGTCA)', and, the, 4, nucleotide, gap, were, necessary, for, efficient]), verbo([binding]), complemento([to, the, 'TR', 'alpha/RXR', alpha, heterodimeric, complex])].
[sujeto(['In', conclusion, our, data]), verbo([suggest]), complemento([that, the, 'TRE', in, the, helix, loop, helix, 'gene,', 'myoD,', is, a, target, for, the, direct, heterodimeric, binding, of, 'TR', alpha, and, 'RXR', 'alpha/gamma'])].
[sujeto(['These', results]), verbo([provide]), complemento([a, molecular, 'mechanism/model', for, the, effects, of, 'triiodo-L-thyronine', on, in, vitro, 'myogenesis;', the, activation, of, myoD, gene, expression, in, the, slow, twitch, fibres, and, the, cascade, of, myogenic, events, regulated, by, thyroid, hormone])].
[sujeto(['However,', whether, vitamin, 'D', directly, reduces, muscle, fiber, atrophy, or]), verbo([stimulates]), complemento([muscle, fiber, hypertrophy, remains, subject, of, debate])].
[sujeto(['We', show, that, myoblasts, not, only]), verbo([responded]), complemento([to, 1, ',', 25, '(', 'OH)2', 'D3', ',', but, also, to, the, precursor, 25, '(', 'OH)D3', by, increasing, their, 'VDR', mRNA, expression, and, reducing, their, proliferation])].
[sujeto(['In', differentiating, myoblasts, and, myotubes, 1, ',', 25, '(', 'OH)2', 'D3', as, well, as, 25, '(', 'OH)D3']), verbo([stimulated]), complemento(['VDR', mRNA, expression, and, in, myotubes, 1, ',', 25, '(', 'OH)2', 'D3', also, stimulated, 'MHC', mRNA, expression])].
[sujeto(['Interestingly,', both, myoblasts, and, myotubes]), verbo([expressed]), complemento(['CYP27B1', and, 'CYP24', mRNA, which, are, required, for, vitamin, 'D3', metabolism])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, skeletal, muscle, is, not, only, a, direct, target, for, vitamin, 'D3', 'metabolites,', but, is, also, able, to, metabolize, 25, '(', 'OH)D3', and, 1, ',', 25, '(', 'OH)2', 'D3'])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, the, expression, of, 'MyoD', mRNA, oscillates, over, 24, h, in, skeletal, muscle, and, that, the, circadian, clock, transcription, 'factors,', 'BMAL1', '(', brain, and, muscle, 'ARNT-like', 1, ')', and, 'CLOCK', '(', circadian, locomotor, output, cycles, 'kaput),', were, bound, to, the, core, enhancer, '(', 'CE)', of, the, 'MyoD', gene, in, vivo])].
[sujeto(['In', this, 'study,', we]), verbo([provide]), complemento([in, vivo, and, in, vitro, evidence, that, the, 'CE', is, necessary, for, circadian, expression, of, 'MyoD', in, adult, muscle])].
[sujeto(['Gel', shift, assays, identified, a]), verbo([conserved]), complemento(['non-canonical', 'E-box', within, the, 'CE', that, is, bound, by, 'CLOCK', and, 'BMAL1'])].
[sujeto(['Functional', analysis, revealed, that, this, 'E-box', was]), verbo([required]), complemento([for, full, activation, by, 'BMAL1/CLOCK', and, for, in, vitro, circadian, oscillation])].
[sujeto(['Expression', profiling, of, muscle, of, 'CE(loxP/loxP)', mice]), verbo([found]), complemento([approximately, 1300, genes, 'mis-expressed', relative, to, 'wild-type'])].
[sujeto(['The', results, of, this, work, identify, a, novel, element, in, the, 'MyoD', enhancer, that]), verbo([confers]), complemento([circadian, regulation, to, 'MyoD', in, skeletal, muscle, and, suggest, that, loss, of, circadian, regulation, leads, to, changes, in, myogenic, expression, and, downstream, mitochondrial, function])].
[sujeto(['Machado-Joseph', disease, '(', 'MJD)', is, a, neurodegenerative, 'disorder,']), verbo([caused]), complemento([by, the, expansion, of, the, '(', 'CAG)n', tract, in, the, 'MJD', gene])].
[sujeto(['The', mouse, 'Mjd', gene]), verbo([has]), complemento([a, structure, similar, to, that, of, its, human, counterpart, and, it, also, contains, a, 'TATA-less', promoter])].
[sujeto(['Its', 5, '\'', flanking, region, contains]), verbo([conserved]), complemento([putative, binding, regions, for, transcription, factors, 'Sp1,', 'USF,', 'Arnt,', 'Max,', 'E47,', and, 'MyoD'])].
[sujeto(['Upon', differentiation, of, 'P19', 'cells,', the, 'Mjd', gene, promoter, is, preferentially]), verbo([activated]), complemento([in, endodermal, and, mesodermal, 'derivatives,', including, cardiac, and, skeletal, 'myocytes;', and, less, so, in, neuronal, precursors])].
[sujeto(['Mouse', 'ataxin-3', is, ubiquitously]), verbo([expressed]), complemento([during, embryonic, development, and, in, the, 'adult,', with, strong, expression, in, regions, of, the, 'CNS', affected, in, 'MJD'])].
[sujeto(['It', is, particularly, abundant, in, all, types, of, muscle, and, in, ciliated, epithelial, 'cells,']), verbo([suggesting]), complemento([that, it, may, be, associated, with, the, cytoskeleton, and, may, have, an, important, function, in, cell, structure, 'and/or', motility])].
[sujeto(['Lysosomal', sialidase, is]), verbo([required]), complemento([for, the, catabolism, of, sialoglycoconjugates, such, as, gangliosides, and, deficiency, in, this, enzyme, results, in, the, autosomal, recessive, disease, sialidosis])].
[sujeto(['Furthermore,', we]), verbo([have]), complemento([shown, that, overexpression, of, human, sialidase, is, sufficient, to, clear, accumulated, ganglioside, in, 'Tay-Sachs', neuroglia, '[', 'Hum'])].
[sujeto(['In', this, 'paper,', we]), verbo([have]), complemento([characterized, the, 5, '\'', regulatory, region, of, the, mouse, lysosomal, sialidase, gene, in, order, to, understand, the, molecular, mechanisms, regulating, its, expression])].
[sujeto(['Expression', by, the, promoter, was]), verbo([found]), complemento([to, be, 'cell-type', restricted, and, required, at, least, 750, bp, upstream, of, the, 'ATG', for, 'high-level', expression])].
[sujeto(['Taken', 'together,', these, results, identify, 'cis-', and, 'trans-acting', factors]), verbo([involved]), complemento([in, the, regulation, of, sialidase, and, point, to, mechanisms, of, gene, upregulation])].
[sujeto(['Glycerol', kinase, '(', 'GK)', is, at, the, interface, of, fat, and, carbohydrate, metabolism, and]), verbo([has]), complemento([been, linked, to, obesity, and, type, 2, diabetes, mellitus, '(', 'T2DM)'])].
[sujeto(['Microarray', analysis, determined, that, there, were, 525, genes, that, were, differentially]), verbo([expressed]), complemento(['(', 1.2, -, 'fold,', p, 'value&lt;0'])].
[sujeto(['Quantitative', 'PCR', '(', 'qPCR)', confirmed, the, differential, expression, of, genes, including, glycerol, kinase, '(', 'Gyk),', phosphatidylinositol, 3, -, kinase, regulatory, 'subunit,', polypeptide, 1, '(', p85, 'alpha)', '(', 'Pik3r1),', 'insulin-like', growth, factor, 1, '(', 'Igf1),', and, growth, factor, receptor]), verbo([bound]), complemento([protein, 2, -, associated, protein, 1, '(', 'Gab1)'])].
[sujeto(['Network', component, analysis, demonstrated, that, transcription, factor, activities, of, myogenic, differentiation, 1, '(', 'MYOD),', myogenic, regulatory, factor, 5, '(', 'MYF5),', myogenin, '(', 'MYOG),']), verbo([nuclear]), complemento([receptor, subfamily, 4, ',', group, 'A,', member, 1, '(', 'NUR77)', are, decreased, in, the, 'Gyk', 'KO', whereas, the, activity, of, paired, box, 3, '(', 'PAX3)', is, increased])].
[sujeto(['The', activity, of, 'MYOD', was, confirmed, using, a, 'DNA']), verbo([binding]), complemento([assay])].
[sujeto(['T3', treatment, '(', 'T1,', 1, 'mg;', 'T3,', 3, 'mg;', 'T10,', 10, 'mg/kg/day)', of, 'KK', mice, for, 4, days]), verbo([caused]), complemento([a, decrease, in, blood, glucose, level, by, 11, '%', ',', 25, '%', ',', and, 24, '%', ',', 'respectively,', without, affecting, body, weight])].
[sujeto(['Skeletal', muscle, of, mice, treated, with, 'T3', '(', 'T10)', showed, a, 98, '%']), verbo([increase]), complemento([in, the, mRNA, level, of, the, glucose, transporter, isotype, 4, '(', 'Glut4)'])].
[sujeto(['The', mRNA, level, of, a, muscle, cell, specific, differentiation, 'marker,', 'MyoD,', showed, a, significant]), verbo([increase]), complemento([in, the, 'T3', treatment, group, with, an, accompanying, enhancement, of, 'glyceraldehyde-3-phosphate', dehydrogenase, '(', 'GAPDH)', mRNA, level])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'T3', stimulates, muscle, cell, differentiation, in, 'vivo,', concomitant, with, a, stimulation, of, cellular, glucose, 'metabolism,', thus, decreasing, the, blood, glucose, level, in, hyperglycemic, 'KK', mice])].
[sujeto(['It', is, unclear, whether, insulin, resistance, is, a, primary, defect]), verbo([leading]), complemento([to, 'NIDDM', or, the, result, of, hyperinsulinemia, and, hyperglycemia])].
[sujeto(['These', cell, cultures]), verbo([expressed]), complemento([a, variety, of, 'muscle-specific', phenotypes, including, the, proteins, 'alpha-actinin', and, 'myosin,', 'muscle-specific', creatine, kinase, 'activity,', and, 'RNA', encoding, 'GLUT4,', 'MYF5,', 'MYOD1,', and, 'MYOGENIN'])].
[sujeto(['This', defect, in, insulin, action, is, stable, in, a, uniform, culture, environment, and, is]), verbo([retained]), complemento([over, time])].
[sujeto(['Class', 'II', 'HLH', 'proteins,', such, as, 'MyoD,', are]), verbo([expressed]), complemento([in, a, 'tissue-specific', manner])].
[sujeto(['Class', 'I', and, 'II', heterodimers, can]), verbo([bind]), complemento([to, 'E-boxes', '(', 'CANNTG)', and, regulate, lineage, commitments, of, embryonic, cells])].
[sujeto(['HHM', is, structurally, related, to, the, 'Id', family, and, was, highly]), verbo([expressed]), complemento([in, 'brain,', pituitary, 'gland,', 'lung,', 'heart,', 'placenta,', fetal, 'liver,', and, bone, marrow])].
[sujeto(['HHM', physically]), verbo([interacted]), complemento([with, 'E12', in, vitro, and, in, mammalian, cells])].
[sujeto(['Comparison', of, the, dominant, inhibitory, effects, of, 'HHM', and, 'Id2', on, the]), verbo([binding]), complemento([of, 'E12/MyoD', dimer, to, an, 'E-box', element, revealed, a, weaker, inhibition, by, 'HHM'])].
[sujeto(['However,', 'HHM', but, not, 'Id2', specifically]), verbo([inhibited]), complemento([the, luciferase, gene, activation, induced, by, hepatic, nuclear, factor, 4, '(', 'HNF4)', promoter])].
[sujeto(['The', 'HHM', was, transiently]), verbo([expressed]), complemento([during, 'stem-cell-driven', regeneration, of, the, liver, at, the, stage, in, which, the, early, basophilic, foci, of, hepatocytes, started, to, appear])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'HHM', is, a, novel, type, of, dominant, inhibitory, 'HLH', protein, that, might, modulate, 'liver-specific', gene, expression])].
[sujeto(['The', zebrafish, fushi, tarazu, 'factor-1a', '(', 'ff1a)', is, a, transcription, factor, belonging, to, the, 'NR5A', subgroup, of]), verbo([nuclear]), complemento([receptors])].
[sujeto(['The', 'NR5A', receptors]), verbo([bind]), complemento(['DNA', as, monomers, and, are, considered, to, be, orphans, due, to, their, ability, to, promote, transcription, of, downstream, genes, without, ligands])].
[sujeto(['In', 'zebrafish,', four, ff1, homologues, '(', 'Ff1a,', 'Ff1b,', 'Ff1c,', and, 'Ff1d)']), verbo([have]), complemento([been, identified, so, far])].
[sujeto(['Ff1a', is]), verbo([expressed]), complemento([in, the, somites, and, pronephric, ducts, during, somitogenesis, and, in, the, 'brain,', 'liver,', and, mandibular, arch, during, later, embryonic, stages])].
[sujeto(['In', adults, the, gene, is, highly]), verbo([expressed]), complemento([in, 'gonads,', 'liver,', and, 'intestine,', but, can, be, detected, in, most, tissues])].
[sujeto(['The', zebrafish, ff1a, dual, promoter, contains, several, 'GATA']), verbo([binding]), complemento([sites, and, 'E-boxes,', a, site, for, 'DR4,', 'XFD2,', 'MyoD,', 'Snail,', 'HNF3,', 'S8,', and, an, 'HMG-box', recognition, site, for, 'Sox9'])].
[sujeto(['In', a, first, attempt, to, dissect, the, ff1a, promoter, in, vivo, we]), verbo([have]), complemento([produced, first, generation, transgenes, in, order, to, determine, the, correlation, between, the, expression, of, the, endogenous, ff1a, gene, and, the, microinjected, ff1a, dual, promoter, coupled, to, the, pEGFP, reporter, vector])].
[sujeto(['Our', results, show, that, the, microinjected, constructs, are]), verbo([expressed]), complemento([in, the, correct, tissues])].
[sujeto(['MRF4', was, the, only, member, of, the, 'MyoD', family, that, was, concentrated, at, the, mature, 'NMJ,']), verbo([suggesting]), complemento([that, it, may, have, a, unique, role, in, the, maintenance, of, 'post-synaptic', specialization])].
[sujeto(['Three', potential, regulators, of, the, 'NMJ', were, identified, and, confirmed, by, 'real-time', 'PCR:', glia, maturation, factor, gamma, was, concentrated, at, the, 'NMJ', whereas, 'Unr', protein, and, protein, tyrosine, phosphatase, were]), verbo([repressed]), complemento([synaptically])].
[sujeto(['The', expression, of, transcription, factors, for, muscle, regeneration, '(', 'Pax3,', 'Pax7', and, 'MyoD)', was]), verbo([increased]), complemento([in, 'CWS', and, 'HE', compared, with, 'HMA', '(', 'p≤0'])].
[sujeto(['In', 'contrast,', the, expression, of, the, late, myogenic, differentiation, marker, 'MyoG', was, reduced, in, 'CWS', and, 'CWL', but]), verbo([increased]), complemento([in, 'HE', '(', 'p≤0'])].
[sujeto(['Bax', was, significantly]), verbo([increased]), complemento([in, 'CWS,', 'CWL', and, 'HE', '(', 'p≤0'])].
[sujeto(['Expression', of, the, oxidative, defense, genes, 'SOD2,', 'GCLM,', and, 'Nrf2', was]), verbo([decreased]), complemento([in, 'CWS', and, 'CWL', but, increased, in, 'HE', '(', 'p≤0'])].
[sujeto(['After', 'trauma,', 'SCs', leave, their, quiescent, state, to, enter, the, cell, cycle, and, undergo, multiple, rounds, of, 'proliferation,', a, process]), verbo([regulated]), complemento([by, 'MyoD'])].
[sujeto(['In', both, promoter, studies, with, myoblasts, and, a, mouse, model, of, muscle, injury, in, 'Nrf2-deficient', 'mice,', we, show, that, 'Nrf2', prolongs, 'SC', proliferation, by, 'up-regulating', 'MyoD', and]), verbo([suppresses]), complemento(['SC', differentiation, by, 'down-regulating', myogenin])].
[sujeto(['Moreover,', we, show, that, 'IL-6', and, 'HGF,', both, factors, that, facilitate, 'SC', 'activation,']), verbo([induce]), complemento(['Nrf2', activity, in, myoblasts])].
[sujeto(['Thus,', 'Nrf2', activity]), verbo([promotes]), complemento([muscle, regeneration, by, modulating, 'SC', proliferation, and, differentiation, and, thereby, provides, implications, for, tissue, regeneration])].
[sujeto(['Skeletal', muscle, redox, homeostasis, is, transcriptionally]), verbo([regulated]), complemento([by, nuclear, 'erythroid-2-p45-related', 'factor-2', '(', 'Nrf2)'])].
[sujeto(['Here,', we, hypothesize, that, 'age-dependent', decline, or, genetic, ablation, of, 'Nrf2']), verbo([leads]), complemento([to, accelerated, apoptosis, and, skeletal, muscle, degeneration])].
[sujeto(['Under', 'basal-physiological', 'conditions,', disruption, of, 'Nrf2', significantly, downregulates, antioxidants, and]), verbo([causes]), complemento([oxidative, stress])].
[sujeto(['Surprisingly,', 'Nrf2-null', mice, had]), verbo([enhanced]), complemento([antioxidant, capacity, identical, to, 'wild-type', '(', 'WT)', upon, acute, endurance, exercise, stress, '(', 'AEES),', suggesting, activation, of, 'Nrf2-independent', mechanisms, '(', i])].
[sujeto(['Analysis', of, prosurvival, pathways, in, the, basal, state]), verbo([reveals]), complemento([decreased, 'AKT', 'levels,', whereas, 'p-p53,', a, repressor, of, 'AKT,', was, increased, in, 'Nrf2-null', vs, 'WT', mice])].
[sujeto(['Upon', 'AEES,', 'AKT', and, 'p-AKT', levels, were, significantly, '(', p, &, 'lt;', 0.001, ')']), verbo([increased]), complemento(['(', &, 'gt;10-fold)', along, with, profound, downregulation, of, 'p-p53', '(', p, &, 'lt;', 0.01, ')', in, 'Nrf2-null', vs, 'WT', skeletal, 'muscle,', indicating, the, onset, of, prosurvival, mechanisms, to, compensate, for, the, loss, of, 'Nrf2', signaling])].
[sujeto(['However,', we]), verbo([found]), complemento([a, decreased, stem, cell, population, '(', 'PAX7)', and, 'MyoD', expression, '(', 'differentiation)', along, with, profound, activation, of, ubiquitin, and, apoptotic, pathways, in, 'Nrf2-null', vs, 'WT', mice, upon, 'AEES,', suggesting, that, compensatory, prosurvival, mechanisms, failed, to, overcome, the, programmed, cell, death, and, degeneration, in, skeletal, muscle])].
[sujeto(['The', 'Rho', family, 'GTPase', 'RhoA', is, known, to]), verbo([promote]), complemento(['myogenesis,', 'however,', the, mechanisms, controlling, its, regulation, in, myoblasts, have, yet, to, be, fully, elucidated])].
[sujeto(['We', show, here, that, the, 'SH2-containing', protein, tyrosine, 'phosphatase,', 'SHP-2,', functions, as, an, early, modulator, of, myogenesis, by]), verbo([regulating]), complemento(['RhoA'])].
[sujeto(['When', 'MyoD', was]), verbo([expressed]), complemento([in, fibroblasts, lacking, functional, 'SHP-2,', 'muscle-specific', gene, activity, was, impaired, and, abolition, of, 'SHP-2', expression, by, 'RNA', interference, inhibited, muscle, differentiation])].
[sujeto(['When', 'dephosphorylated,', 'p190-B', 'RhoGAP']), verbo([has]), complemento([been, shown, to, stimulate, the, activation, of, 'RhoA'])].
[sujeto(['Moreover,', overexpression, of, a, catalytically, inactive, mutant, of, 'SHP-2']), verbo([inhibited]), complemento(['p190-B', 'RhoGAP', tyrosyl, 'dephosphorylation,', 'RhoA', 'activity,', and, myogenesis])].
[sujeto(['These', observations, strongly]), verbo([suggest]), complemento([that, 'SHP-2', dephosphorylates, 'p190-B', 'RhoGAP,', leading, to, the, activation, of, 'RhoA'])].
[sujeto(['Collectively,', these, data]), verbo([provide]), complemento([a, mechanistic, basis, for, 'RhoA', activation, in, myoblasts, and, demonstrate, that, myogenesis, is, critically, regulated, by, the, actions, of, 'SHP-2', on, the, 'p190-B', 'Rho', 'GAP/RhoA', pathway])].
[sujeto(['Myogenesis', is, a, highly, ordered, process, that]), verbo([involves]), complemento([the, expression, of, 'muscle-specific', 'genes,', 'cell-cell', recognition, and, multinucleated, myotube, formation])].
[sujeto(['Although', protein, tyrosine, kinases]), verbo([have]), complemento([figured, prominently, in, 'myogenesis,', the, involvement, of, tyrosine, phosphatases, in, this, process, is, unknown])].
[sujeto(['SHP-2', is, an, 'SH2', 'domain-containing', tyrosine, 'phosphatase,', which, positively]), verbo([regulates]), complemento([growth, and, differentiation])].
[sujeto(['We', show, that, in, 'C2C12', 'myoblasts,', 'SHP-2', becomes, upregulated, early, on, during, myogenesis, and]), verbo([associates]), complemento([with, a, 120, kDa, 'tyrosyl-phosphorylated', complex])].
[sujeto(['We']), verbo([have]), complemento([identified, that, the, 120, kDa, complex, consists, of, the, 'SHP-2', 'substrate-1', '(', 'SHPS-1)', and, the, 'Grb2-associated', 'binder-1', '(', 'Gab-1)'])].
[sujeto(['Either', constitutive, expression, or, inducible, activation, of, 'MyoD', in, 10, 'T(1/2)', fibroblasts]), verbo([promotes]), complemento(['SHPS-1', tyrosyl, phosphorylation, and, its, association, with, 'SHP-2'])].
[sujeto(['It']), verbo([has]), complemento([been, shown, that, p38, 'mitogen-activated', protein, kinase, '(', 'MAPK)', activity, is, required, for, the, 'expression/activation', of, 'MyoD', and, 'MyoD-responsive', genes])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'SHPS-1/SHP-2', complex, formation, is, an, integral, signaling, component, of, skeletal, muscle, differentiation])].
[sujeto(['Shp-2', is, a, ubiquitously]), verbo([expressed]), complemento([tyrosine, phosphatase, with, two, 'SH2', domains])].
[sujeto(['Homozygous', mutant, mice, with, a]), verbo([targeted]), complemento([deletion, of, 65, amino, acid, residues, in, the, 'N-terminal', 'SH2', domain, of, 'Shp-2', die, in, utero, at, 'mid-gestation,', with, multiple, defects, in, mesodermal, patterning])].
[sujeto(['Further,', mutant, 'ES', cells, were, more, sensitive, than, 'wild-type', cells, to, the, differentiation]), verbo([suppressing]), complemento([effect, of, leukemia, inhibitory, factor, '(', 'LIF)'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, 'Shp-2', tyrosine, phosphatase, is, a, positive, regulator, for, both, cell, differentiation, and, 'proliferation,', in, contrast, to, the, 'Src-family', kinases, which, promote, cell, growth, but, block, differentiation])].
[sujeto(['Triiodothyronine', '(', 'T3)', positively]), verbo([regulates]), complemento([both, the, expression, of, the, 'MyoD', 'gene,', a, key, myogenic, 'regulator,', and, 'C2', muscle, cell, differentiation])].
[sujeto(['To', directly, examine, the, role, of, its]), verbo([nuclear]), complemento([receptors, in, the, control, of, 'myogenesis,', we, introduced, a, 'c-erbA', expression, vector, into, 'C2', muscle, cells, by, transient, or, stable, transfection])].
[sujeto(['Our', results, show, that, 'c-erbA', can, play, a, potent, role, in, the]), verbo([triggering]), complemento([of, muscle, terminal, differentiation, since, its, overexpression, leads, 'to:', '(', 1, ')', a, complete, abrogation, of, the, activity, of, the, myogenesis, inhibitor, 'AP-1', '(', 'fos/jun)', transcription, 'factor;', '(', 2, ')', an, enhanced, induction, of, 'MyoD', expression, upon, 'T3', 'treatment;', '(', 3, ')', the, acquisition, by, 'T3', of, the, ability, to, trigger, both, growth, arrest, and, terminal, differentiation, in, the, presence, of, large, amounts, of, serum, 'mitogens,', a, property, that, is, otherwise, specific, to, retinoic, acid, '(', 'RA)'])].
[sujeto(['Thus,', 'c-erbA', is, one, of, the, two, protooncogenes, '(', with, 'c-ski)', that]), verbo([acts]), complemento([as, positive, regulator, of, muscle, differentiation])].
[sujeto(['Furthermore,', the, fact, that, 'c-erbA', overexpression, allows, 'T3', to, largely, mimic, the, 'RA', effects, indicates, that, their, biological, differences, in, the, modulation, of, myogenic, program, primarily, rely, on, the, differential, expression, of, their, receptors, in, 'C2', muscle, cells, rather, than, on, an, intrinsic, specificity, of, their]), verbo([target]), complemento([genes])].
[sujeto(['RVR/Rev-erb', 'beta/BD73', is, an, orphan, steroid, receptor, that]), verbo([has]), complemento([no, known, ligand, in, the, &, 'quot;classical\'', sense])].
[sujeto(['RVR']), verbo([binds]), complemento([as, a, monomer, to, an, element, which, consists, of, an, 'A/T-rich', sequence, upstream, of, the, consensus, hexameric, 'half-site'])].
[sujeto(['However,', 'RVR', does, not]), verbo([activate]), complemento([transcription, and, blocks, transactivation, of, this, element, by, 'ROR/RZR'])].
[sujeto(['The', mechanism, of, 'RVR', action, remains, 'obscure,', hence, we, used, the, 'GAL4', hybrid, system, to, identify, and, characterize, an, active, transcriptional, silencer, in, the, ligand]), verbo([binding]), complemento([domain, '(', 'LBD)', of, 'RVR'])].
[sujeto(['Although', 'RVR', is]), verbo([expressed]), complemento([in, many, adult, 'tissues,', including, skeletal, 'muscle,', and, during, 'embryogenesis,', its, physiological, function, in, differentiation, and, mammalian, development, remains, unknown])].
[sujeto(['COUP-TF', 'II', and, 'Rev-erbA', 'alpha,']), verbo([have]), complemento([been, demonstrated, to, regulate, muscle, and, adipocyte, 'differentiation,', we, investigated, the, expression, and, functional, role, of, 'RVR', during, mouse, myogenesis])].
[sujeto(['In', 'C2C12', myogenic, 'cells,', 'RVR', mRNA, was, detected, in, proliferating, myoblasts, and, was]), verbo([suppressed]), complemento([when, the, cells, were, induced, to, differentiate, into, 'post-mitotic,', multinucleated, myotubes, by, serum, withdrawal])].
[sujeto(['This']), verbo([decrease]), complemento([in, 'RVR', mRNA, correlated, with, the, appearance, of, 'muscle-specific', markers, '(', e])].
[sujeto(['RVR', '\'']), verbo([loss]), complemento([of, 'function\'', studies, by, constitutive, 'over-expression', of, a, dominant, negative, 'RVR', delta, 'E', resulted, in, increased, levels, of, 'p21Cip1/Waf1', and, myogenin, mRNAs, after, serum, withdrawal])].
[sujeto(['In', 'conclusion,', our, studies, identified, a, potent, transcriptional, repression, domain, in, 'RVR,', characterized, critical, amino, acids, within, the, silencing, region, and]), verbo([provide]), complemento([evidence, for, the, physiological, role, of, 'RVR', during, myogenesis])].
[sujeto(['ER-alpha', mRNA, expression]), verbo([increased]), complemento([with, all, three, drug, treatments, '(', 'P', &, 'lt;', 0.05, ')', while, there, was, no, change, in, mRNA, expression, of, 'ER-beta', in, hSkM, cells])].
[sujeto([mRNA, expression, of, 'SRC']), verbo([increased]), complemento([and, 'SMRT', decreased, with, 'oestradiol,', 'TAM', and, 'RAL', in, hSkM, cells, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['Importantly,', mRNA, expression, of, 'MyoD']), verbo([increased]), complemento([with, oestradiol, and, decreased, with, 'TAM', and, 'RAL', in, hSkM, cells, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto([mRNA, expression, of, 'GLUT4']), verbo([increased]), complemento([with, oestradiol, and, 'RAL', and, decreased, with, 'TAM', in, hSkM, cells, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['These', findings, are, novel, in, that, they]), verbo([provide]), complemento([the, first, evidence, that, oestradiol, and, selective, 'ER', modulators, influence, 'ER-alpha', function, in, hSkM, cells])].
[sujeto(['This', demonstrates, the, importance, of, the, 'ER', and, alterations, in, its, 'coregulators,', to, potentially]), verbo([prevent]), complemento([sarcopenia, and, promote, muscle, growth, in, postmenopausal, women, using, these, forms, of, hormone, replacement, therapy])].
[sujeto(['Thyroid', hormone]), verbo([stimulates]), complemento([myoblast, 'differentiation,', through, an, inhibition, of, 'AP-1', activity, occurring, at, the, onset, of, differentiation])].
[sujeto(['In', this, study, we]), verbo([found]), complemento([that, the, 'T3', nuclear, receptor, 'c-ErbAalpha1', '(', 'T3Ralpha1)', is, involved, in, a, mechanism, preserving, the, duration, of, myoblast, proliferation])].
[sujeto(['Independently', of, the, hormone, 'presence,', 'T3Ralpha1']), verbo([represses]), complemento([avian, 'MyoD', transcriptional, activity])].
[sujeto(['Using', several, mutants, of, 'T3Ralpha1,', we]), verbo([found]), complemento([that, the, hinge, region, plays, a, crucial, role, in, the, inhibition, of, 'MyoD', activity])].
[sujeto(['Similarly,', the, 'T3', receptor, also]), verbo([represses]), complemento([myogenin, transcriptional, activity])].
[sujeto(['Therefore,', despite]), verbo([stimulating]), complemento([avian, myoblast, differentiation, by, a, 'T3-dependent', pathway, not, involving, myogenic, 'factors,', 'T3Ralpha1', contributes, to, maintain, an, optimal, myoblast, proliferation, period, by, inhibiting, 'MyoD', and, myogenin, activity])].
[sujeto(['When', the, gene, for, this, chimeric, protein, was]), verbo([expressed]), complemento([in, 'NIH', 3, 'T3', or, 10, 'T1/2', 'fibroblasts,', these, cells, displayed, 'hormone-dependent', induction, of, myogenesis])].
[sujeto(['Our', experiments, focused, on, cell, lines]), verbo([expressing]), complemento([estrogen, 'receptor-MyoD', chimeras])].
[sujeto(['Induction', of, these, lines, in, the, presence, of, estradiol, and, an, inhibitor, of, protein, 'synthesis,', 'cycloheximide,', resulted, in, the, activation, of, the, endogenous, myogenin, gene, but, did, not]), verbo([activate]), complemento([the, 'muscle-specific', creatine, kinase, or, cardiac, 'alpha-actin', gene])].
[sujeto(['This', result]), verbo([suggests]), complemento([that, 'MyoD', is, not, a, &, 'quot;direct&quot;', activator, of, these, downstream, myogenic, genes, but, must, first, activate, myogenin, as, an, intermediary])].
[sujeto(['Once', muscle, is]), verbo([induced]), complemento([by, estrogen, 'receptor-MyoD', the, muscle, phenotype, is, very, stable, and, does, not, need, the, continued, presence, of, estradiol, for, its, maintenance])].
[sujeto(['The', leukocyte, adhesion, receptors, 'M290', '(', alpha, 'M290/beta', 7, ')', and, 'LPAM-1', '(', alpha, 4, beta, 7, ')', comprise, the, beta, 7, -, subfamily, of, 'integrins,', which, are, constitutively]), verbo([expressed]), complemento([on, subsets, of, lymphocytes, populating, the, mouse, small, intestine])].
[sujeto(['They', are]), verbo([induced]), complemento([de, novo, after, in, vitro, activation, of, lymphocytes, and, hence, may, serve, a, more, general, role, in, inflammation])].
[sujeto(['In', order, to, understand, how, beta, 7, integrins, are]), verbo([regulated]), complemento([during, an, immune, 'response,', we, isolated, and, characterized, the, promoter, region, of, the, beta, 7, gene])].
[sujeto(['Transfection', assays, with, a, luciferase, reporter, gene, revealed, that, 'cell-specific', expression, in, vitro, was]), verbo([retained]), complemento([in, a, 292, bp, 'sequence,', which, contained, several, consensus, binding, motifs, for, transcriptional, factors, preferentially, expressed, in, cells, of, the, lymphoid, lineages])].
[sujeto(['The', beta, 7, 'promoter,', like, its, alpha, 4, chain, 'partner,', contains, the, 'E', box, core, sequence, 'CACCTG']), verbo([found]), complemento([within, the, muscle, creatine, kinase, enhancer, which, binds, 'MyoD', in, vitro])].
[sujeto(['The', number, of, potential, 'DNA']), verbo([binding]), complemento([sites, for, transcriptional, factors, in, the, beta, 7, promoter, parallels, the, complex, regulation, of, expression, of, 'M290', and, 'LPAM-1', in, inflammation, and, gut, mucosal, immunity])].
[sujeto(['The', metamorphosis, of, anuran, amphibians, is]), verbo([induced]), complemento([by, thyroid, hormone, '(', 'TH)'])].
[sujeto(['The', cells]), verbo([expressed]), complemento([myoblast, markers, and, differentiated, into, myotubes, in, differentiation, medium])].
[sujeto(['XL-B4', cells]), verbo([expressing]), complemento([fluorescent, proteins, were, transplanted, into, tadpole, tails])].
[sujeto(['Exposure', of, 'XL-B4', cells, to, the, 'TH', triiodothyronine, '(', 'T3)', for, several, days, significantly]), verbo([induced]), complemento([apoptotic, cell, death])].
[sujeto(['We', then, examined, an, early, response, of, expression, of, genes]), verbo([involved]), complemento([in, apoptosis, or, myogenesis, to, 'T3'])].
[sujeto(['Treatment', of, the, cells, with, 'T3']), verbo([increased]), complemento([transcription, of, genes, for, matrix, 'metalloproteinase-9', '(', 'MMP-9)', and, thyroid, hormone, receptor, beta])].
[sujeto(['Interestingly,', the, 'T3-treatment', also]), verbo([increased]), complemento([myoD, 'transcripts,', but, decreased, the, amounts, of, myogenin, mRNA, and, myosin, heavy, chain])].
[sujeto(['These', results, indicated, that, 'T3', could, not, only]), verbo([induce]), complemento(['apoptosis,', but, also, attenuate, myogenesis, in, tadpole, tails, during, metamorphosis])].
[sujeto(['This', complex]), verbo([interacts]), complemento([physically, with, several, nuclear, receptors, through, the, 'TRAP220', 'subunit,', and, with, diverse, activators, through, other, subunits])].
[sujeto(['TRAP220']), verbo([has]), complemento([been, reported, to, show, 'ligand-enhanced', interaction, with, peroxisome, 'proliferator-activated', receptor, 'gamma(2)', '(', 'PPAR', 'gamma(2)),', a, nuclear, receptor, essential, for, adipogenesis])].
[sujeto(['Here', we, show, that, 'Trap220(-/-)', fibroblasts, are, refractory, to, 'PPAR', 'gamma(2)-stimulated', 'adipogenesis,', but, not, to, 'MyoD-stimulated', 'myogenesis,', and, do, not]), verbo([express]), complemento([adipogenesis, markers, or, 'PPAR', 'gamma(2)', target, genes])].
[sujeto(['Further', indicative, of, a, direct, role, for, 'TRAP220', in, 'PPAR', 'gamma(2)', function, via, the, 'TRAP', 'complex,', 'TRAP', functions, directly, as, a, transcriptional, coactivator, for, 'PPAR', 'gamma(2)', in, a, purified, in, vitro, system, and]), verbo([interacts]), complemento([with, 'PPAR', 'gamma(2)', in, a, 'ligand-', and, 'TRAP220-dependent', manner])].
[sujeto(['One', aspect, of, this, control, is, 'unquestioned:', circulating, 'GH']), verbo([acts]), complemento([on, the, liver, to, stimulate, expression, of, the, 'IGF-I', and, 'IGFBP3', 'genes,', substantially, increasing, the, levels, of, these, proteins, in, the, circulation])].
[sujeto(['It', also, seems, that, 'GH']), verbo([stimulates]), complemento([expression, of, 'IGF-I', genes, in, skeletal, 'muscle,', although, there, are, a, number, of, cases, in, which, skeletal, muscle, 'IGF-I', expression, is, elevated, in, the, absence, of, 'GH'])].
[sujeto(['It', is, substantially, less, clear, that, 'GH']), verbo([acts]), complemento([directly, on, skeletal, muscle, to, stimulate, its, 'growth;', the, presence, of, 'GH', receptor, mRNA, in, skeletal, muscle, is, well, 'established,', but, most, investigators, have, been, unsuccessful, in, demonstrating, any, specific, binding, of, 'GH', to, skeletal, muscle, or, to, myoblasts, in, culture])].
[sujeto(['It']), verbo([has]), complemento([been, equally, difficult, to, show, direct, actions, of, 'GH', on, cultured, muscle, 'cells;', the, only, positive, report, concludes, that, the, early, 'insulin-like', effects, of, 'GH', can, result, from, direct, interactions, between, 'GH', and, isolated, muscle, cells])].
[sujeto(['It', is, well, established, by, studies, in, a, number, of, laboratories, on, a, variety, of, systems, that, 'IGFs']), verbo([stimulate]), complemento([many, anabolic, responses, in, 'myoblasts,', as, they, do, in, other, cell, types])].
[sujeto(['IGFs']), verbo([have]), complemento([the, unusual, property, of, stimulating, both, proliferation, and, differentiation, of, 'myoblasts,', responses, that, are, generally, believed, to, be, mutually, 'exclusive;', in, 'myoblasts,', they, are, in, fact, temporally, separated])].
[sujeto(['The', stimulation, of, differentiation, by, 'IGF-I', is, '(', at, least, in, 'part)', a, result, of, substantially]), verbo([increased]), complemento([levels, of, the, mRNA, for, 'myogenin,', the, member, of, the, 'MyoD', family, most, directly, associated, with, terminal, myogenesis])].
[sujeto(['As', levels, of, myogenin, mRNA, 'rise,', those, of, 'myf-5', mRNA, '(', the, only, other, member, of, the, 'MyoD', family]), verbo([expressed]), complemento([significantly, in, 'L6', 'myoblasts)', fall, 'dramatically,', although, 'myf-5', expression, is, required, for, the, initial, elevation, of, myogenin])].
[sujeto(['The', effects, of, 'IGFs', are, significantly]), verbo([modulated]), complemento([by, 'IGFBPs', secreted, by, myoblasts, in, 'serum-free', 'medium,', inhibitory, 'IG-FBPs-4', and, -, 6, are, expressed, and, secreted, by, 'L6A1', 'myoblasts,', while, expression, of, 'IGFBP-5', rises, dramatically, as, differentiation, proceeds])].
[sujeto(['Even', if, exogenous, 'IGFs', are, not, added, to, the, 'low-serum', &, 'quot;differentiation&quot;', 'medium,', myoblasts]), verbo([express]), complemento([sufficient, amounts, of, autocrine, 'IGF-II', to, stimulate, myogenesis, after, a, period, of, 'time;', some, myogenic, cell, 'lines,', '(', such, as, 'Sol', 8, ')', are, so, active, in, expressing, the, 'IGF-II', gene, that, it, is, not, possible, to, demonstrate, effects, of, exogenous, 'IGFs'])].
[sujeto(['This', autocrine, expression, of, 'IGFs', is, by, no, means, unique, to, skeletal, muscle, 'cells;', 'indeed,', it, is, so, widely, seen, in, cells]), verbo([responding]), complemento([to, mitogenic, stimuli, that, we, suggest, that, 'IGFs', can, be, viewed, as, extracellular, second, messengers, that, mediate, 'most,', if, not, 'all,', such, actions, of, agents, that, stimulate, cell, proliferation])].
[sujeto(['The', component, of, serum, that]), verbo([suppresses]), complemento(['IGF-II', gene, expression, under, &, 'quot;growth&quot;', conditions, appears, to, be, the, 'IGFs', 'themselves,', which, exhibit, a, very, high, potency, in, the, feedback, inhibition, of, 'IGF-II', expression])].
[sujeto(['In', 'addition,', 'IGFs']), verbo([have]), complemento([effects, on, the, expression, of, other, genes, related, to, differentiation])].
[sujeto(['Treatment', of, 'L6A1', cell, with, 'IGFs']), verbo([suppresses]), complemento([their, expression, of, the, 'myogenesis-inhibiting', 'TGF', beta, s, with, a, time, course, consistent, with, an, initial, proliferative, step, followed, by, 'differentiation,', i])].
[sujeto([expression, is, first]), verbo([increased]), complemento([and, then, very, substantially, decreased])].
[sujeto(['It', is, not, established, that, this, plays, a, role, in, control, of, 'differentiation,', but, experiments, with, 'FGF', antisense, constructs]), verbo([suggests]), complemento([that, this, may, well, be, the, case])].
[sujeto(['Until', 'recently,', 'IGFs', were, the, only, circulating, agents, known, to]), verbo([stimulate]), complemento([myoblast, 'differentiation,', in, contrast, to, the, relatively, large, number, of, growth, factors, that, inhibit, the, process])].
[sujeto(['It', is, now, clear, that, thyroid, hormones, and, 'RA', also]), verbo([stimulate]), complemento(['myogenesis,', and, that, 'IL-15', enhances, the, stimulatory, eff, 'Mouse', embryonic, stem, '(', 'ES)', cells, grown, in, aggregates, give, rise, to, several, different, cell, 'types,', including, cardiac, muscle])].
[sujeto(['We', confirm, that, alpha, 6, 'B', is, constitutively]), verbo([expressed]), complemento([by, 'ES', cells])].
[sujeto(['Culturing', the, aggregates, under, conditions, that]), verbo([stimulate]), complemento(['(', transforming, growth, factor, beta, 1, 'supplement)', or, inhibit, '(', 'TGF', beta, 1, plus, 10, '(', -, 9, ')', 'M', retinoic, acid, 'supplement)', cardiac, muscle, differentiation, does, not, lead, to, any, qualitative, differences, in, the, timing, of, expression, of, these, 'genes,', but, quantitative, changes, cannot, be, excluded])].
[sujeto(['The', 'TGF', beta, 1, supplement, 'does,', 'however,']), verbo([lead]), complemento([to, a, relatively, greater, expression, of, alpha, 6, 'A', compared, to, alpha, 6, 'B', than, the, 'TGF', beta, 1, plus, 10, '(', -, 9, ')', 'M', 'RA', supplement, after, 6, days, in, 'culture,', suggesting, that, alpha, 6, 'A', expression, is, favoured, under, conditions, that, stimulate, cardiac, muscle, differentiation])].
[sujeto(['The', switch, towards, alpha, 6, 'A', expression, in, 'ES', cell, aggregates, is, paralleled, by, expression, of, the]), verbo([binding]), complemento([receptor, for, 'TGF', beta, '(', 'T', beta, 'RII)'])].
[sujeto(['The', initial, characterisation, of, differentiating, 'ES', cell, aggregates, in, terms, of, alpha, 6, 'A', integrin, subunit, expression]), verbo([suggests]), complemento([that, this, model, system, could, be, a, valuable, tool, in, the, study, of, the, role, of, the, alpha, 6, 'A', beta, 1, integrin, in, cardiac, muscle, differentiation])].
[sujeto(['By', using, the, reverse, 'transcriptase-polymerase', chain, 'reaction,', we]), verbo([have]), complemento([detected, expression, of, various, genes, before, and, after, differentiation, induction, with, four, different, agents, in, four, established, 'MRT', cell, lines, '(', 'TM87-16,', 'STM91-01,', 'TTC642,', and, 'TTC549)'])].
[sujeto(['Before', and, after, 'induction,', 'c-myc,', 'IGF-II,', 'IGF-I', 'receptor,', and, 'IGF-II', receptor, were, constitutively]), verbo([expressed]), complemento([by, all, four, cell, lines])].
[sujeto(['The', neurofilament, 'medium-size', '(', 'NF-M)', was, constitutively]), verbo([expressed]), complemento([by, the, 'TM87-16', and, 'TTC642,', and, the, 'S100', protein, alpha, subunit, was, expressed, by, 'TM87-16,', 'TTC642,', and, 'TTC549'])].
[sujeto(['Chromogranin', 'A', was]), verbo([expressed]), complemento([by, 'TM87-16', only, after, treatment, with, either, 'TPA', or, 'RA'])].
[sujeto(['MyoD,', 'N-myc,', tyrosine, 'hydroxylase,', 'N-CAM,', 'trkA,', and, the, 'S100', protein, beta, subunit, were, not]), verbo([expressed]), complemento([by, any, cell, line, before, or, after, induction, with, these, agents])].
[sujeto(['The', proliferating, cells, in, 'TM87-16', and, 'TTC642']), verbo([expressed]), complemento([mRNA, profiles, characteristic, of, neuroectoderm])].
[sujeto(['The', uncoupling, 'protein-3', '(', 'UCP-3)', gene, encodes, for, a, mitochondrial, protein]), verbo([expressed]), complemento([preferentially, in, skeletal, muscle])].
[sujeto(['UCP-3', mRNA, is]), verbo([expressed]), complemento([in, cultured, muscle, cells, '(', 'C2C12', or, 'L6E9)', only, when, 'differentiated,', at, which, stage, 'UCP-3', is, highly, induced, by, 'all-trans', retinoic, acid, '(', 'RA)'])].
[sujeto(['Here', we]), verbo([report]), complemento([that, human, 'UCP-3', promoter, activity, is, dependent, on, 'MyoD', and, inducible, by, all, 'trans-RA'])].
[sujeto(['The', action, of, all, 'trans-RA', is]), verbo([increased]), complemento([by, 'co-transfection', with, 'RA', receptor, '(', 'RAR)'])].
[sujeto(['We']), verbo([have]), complemento([characterized, the, 'RA', response, element, that, controls, the, induction, by, 'RA', in, the, 5, '\'', noncoding, region, of, the, 'UCP-3', gene])].
[sujeto(['Deletion', and, 'point-mutation', analysis, of, the, 'hUCP-3', promoter]), verbo([led]), complemento([us, to, identify, a, 'direct-repeat', element, with, one, 'base-pair', spacing, '(', 'DR1)', at, position, -, 71, /, -, 59, responsible, for, the, induction, by, 'RA', of, the, activity, of, the, promoter])].
[sujeto(['This', 'DR1', element]), verbo([bound]), complemento([a, nuclear, protein, complex, from, muscle, cells, that, contain, 'RAR', and, retinoid, 'X', receptor, '(', 'RXR)'])].
[sujeto(['In', 'conclusion,', it]), verbo([has]), complemento([been, established, that, 'UCP-3', gene, promoter, activity, is, dependent, on, 'MyoD,', and, the, first, regulatory, pathway, for, 'UCP-3', gene, promoter, regulation, has, been, recognized, by, identifying, 'RA', as, a, transcriptional, activator, of, the, gene])].
[sujeto(['In', 'C2', 'myoblasts,', retinoic, acid, '(', 'RA)', is, an, efficient, inducer, of, both, growth]), verbo([arrest]), complemento([and, differentiation])].
[sujeto(['These', 'RA', effects, are]), verbo([mediated]), complemento([through, at, least, two, classes, of, retinoic, acid, receptors, '(', 'RARs', and, 'RXRs),', which, belong, to, the, nuclear, receptor, superfamily])].
[sujeto(['To', determine, the, role, played, by, each, 'RAR', or, 'RXR', family, in, this, model, 'system,', we]), verbo([have]), complemento([analysed, the, effects, of, 'RA', in, 'C2', myoblasts, expressing, a, dominant, negative, 'RAR', '(', 'dnRAR)', or, a, dominant, negative, 'RXR', '(', 'dnRXR)'])].
[sujeto(['The', stable, expression, of, dnRAR, or, dnRXR, in, 'C2', cells, delays, the, 'RA-induced', growth]), verbo([arrest]), complemento([and, 'differentiation,', an, effect, which, is, more, pronounced, in, 'C2-dnRXR', myoblasts])].
[sujeto(['Furthermore,', the, 'RA-inducible', expression, of, 'MyoD', gene, is, lost, in, 'C2-dnRXR', but, not, in, 'C2-dnRAR', 'cells,', indicating, that, each, family, of, retinoid, receptors, 'RAR', and, 'RXR', may]), verbo([regulate]), complemento([distinct, subsets, of, 'RA-responsive', genes])].
[sujeto(['Finally,', using, 'C2', cell, lines, with, different, retinoid, 'responsiveness,', we]), verbo([provided]), complemento([evidence, for, a, link, between, the, 'RXR', and, 'MyoD', families, in, the, process, of, myogenic, differentiation])].
[sujeto(['These', results, illustrate, a, critical, role, for, 'RA-receptors', in, 'RA-control', of, 'C2', myogenesis, and]), verbo([provide]), complemento([tools, for, studying, the, function, of, 'RA', and, its, receptors, during, vertebrate, development])].
[sujeto(['Betaglycan', is, a, 'membrane-anchored', proteoglycan, 'co-receptor', that]), verbo([binds]), complemento([transforming, growth, factor, beta, '(', 'TGF-beta)', via, its, core, protein, and, basic, fibroblast, growth, factor, through, its, glycosaminoglycan, chains])].
[sujeto(['The', mouse, betaglycan, gene, promoter, was, 'cloned,', and, its, sequence, showed, putative]), verbo([binding]), complemento([sites, for, 'SP1,', 'Smad3,', 'Smad4,', muscle, regulatory, factor, elements, such, as, 'MyoD', and, 'MEF2,', and, retinoic, acid, receptor])].
[sujeto(['We']), verbo([found]), complemento([that, 'MyoD,', but, not, 'myogenin,', stimulated, this, transcriptional, activity, even, in, the, presence, of, high, serum])].
[sujeto(['Betaglycan', promoter, activity, was]), verbo([increased]), complemento([by, 'RA', and, inhibited, by, the, three, isoforms, of, 'TGF-beta'])].
[sujeto(['Forced', expression, of, betaglycan, in, 'C(2)C(12)', myoblasts]), verbo([increases]), complemento([their, responsiveness, to, 'TGF-beta2,', suggesting, that, it, performs, a, 'TGF-beta', presentation, function, in, this, cell, lineage])].
[sujeto(['These', results, indicate, that, betaglycan, expression, is, 'up-regulated', during, myogenesis, and, that, 'MyoD', and, 'RA']), verbo([modulate]), complemento([its, expression, by, a, mechanism, that, is, independent, of, myogenin])].
[sujeto(['Based', on, the, findings, that, 'AT2', receptor, stimulation]), verbo([causes]), complemento([inhibition, of, 'proliferation,', and, that, other, antiproliferative, agents, such, as, transforming, growth, 'factor-beta,', retinoic, 'acid,', and, 'MyoD', act, via, repression, of, immediate, early, gene, '(', 'IEG)', 'expression,', this, study, was, aimed, at, elucidating, whether, downregulation, of, 'IEG', expression, is, also, part, of, the, 'AT2', receptor, coupled, signaling, mechanism])].
[sujeto(['Stimulation', of, angiotensin, 'AT2', receptors, in, the, rat, pheochromocytoma, cell, line, 'PC12', 'W', following, pretreatment, with, growth, factors, was, able, to, counteract, growth, factor]), verbo([induced]), complemento([proliferation, but, not, to, repress, growth, factor, induced, 'c-fos', and, 'c-jun', 'expression;', neither, did, 'AT2', receptor, stimulation, cause, an, induction, of, 'c-fos', expression])].
[sujeto(['We', conclude, 'that,', in, contrast, to, other, 'growth-inhibiting', 'agents,', the, antiproliferative, effect, of, angiotensin, 'II', via, the, 'AT2', receptor, is, not]), verbo([mediated]), complemento([by, repression, of, the, immediate, early, genes, 'c-fos', and, 'c-jun'])].
[sujeto(['Muscle', is]), verbo([found]), complemento([in, close, association, with, orthopaedic, 'injury,', however, its, capacity, to, make, a, cellular, contribution, to, bone, repair, remains, ambiguous])].
[sujeto(['To', exclude, the, prospect, that, osteoprogenitors, spontaneously]), verbo([express]), complemento(['MyoD', during, bone, 'repair,', we, created, a, metaphyseal, drill, hole, defect, in, the, tibia])].
[sujeto(['No', 'hAP+', staining, was, observed, in, this, model]), verbo([suggesting]), complemento([that, the, expression, of, 'MyoD', is, not, a, normal, event, for, endogenous, osteoprogenitors])].
[sujeto(['These', data, document, for, the, first, time, that, muscle, cells, can, play, a, significant, secondary, role, in, bone, repair, and, this, knowledge, may]), verbo([lead]), complemento([to, important, translational, applications, in, orthopaedic, surgery])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, 'β/δ', '(', 'PPARβ/δ)']), verbo([regulates]), complemento([postnatal, myogenesis, by, alleviating, myostatin, 'activity,', but, the, molecular, mechanisms, by, which, it, regulates, myogenesis, are, not, fully, understood])].
[sujeto(['C2C12', myoblasts, treated, with, a, 'PPARβ/δ', 'agonist,', 'GW0742', exhibit]), verbo([enhanced]), complemento([myotube, formation, and, 'muscle-specific', gene, expression])].
[sujeto(['GW0742', treatment, dramatically]), verbo([activates]), complemento([promyogenic, 'kinases,', p38MAPK, and, 'Akt,', in, a, 'dose-dependent', manner])].
[sujeto(['GW0742-stimulated', myoblast, differentiation, is]), verbo([mediated]), complemento([by, p38MAPK, and, 'Akt,', since, it, failed, to, restore, myoblast, differentiation, repressed, by, inhibition, of, p38MAPK, and, 'Akt'])].
[sujeto(['In', 'addition,', 'GW0742', treatment]), verbo([enhances]), complemento(['MyoD-reporter', activities])].
[sujeto(['Consistently,', overexpression, of, 'PPARβ/δ']), verbo([enhances]), complemento([myoblast, differentiation, accompanied, by, elevated, activation, of, p38MAPK, and, 'Akt'])].
[sujeto(['Collectively,', these, results]), verbo([suggest]), complemento([that, 'PPARβ/δ', enhances, myoblast, differentiation, through, activation, of, promyogenic, signaling, pathways])].
[sujeto(['To']), verbo([enhance]), complemento([the, 'PPARγ', 'signaling,', 'M3,', the, transactivation, domain, of, 'MyoD,', was, fused, to, 'PPARγ'])].
[sujeto(['Although', the, transduction, of, either, 'PPARγ', or, 'M3-PPARγ']), verbo([induced]), complemento([adipogenesis, in, 'myoblasts,', 'M3-PPARγ', drastically, induced, the, brown, adipocyte, markers, of, 'UCP1,', 'CIDEA,', and, 'PRDM16', by, 1, ',', 50, ',', 2.4, ',', and, 5.0, 'fold,', respectively, and, increased, mitochondria, contents, by, 4, 'fold,', compared, to, 'PPARγ'])].
[sujeto(['The', mRNA, expression, of, 'MyoD', tended, to]), verbo([increase]), complemento([with, days, of, gestation, '(', 'P', =, 0.06, ')'])].
[sujeto(['The', mRNA, expression, of, zinc, finger, protein, 423, '(', 'Zfp423;', 'P', &, 'lt;', 0.0001, ')', ',', 'C/EBPα', '(', 'P', =, 0.01, ')', ',', and, 'PPARγ', '(', 'P', &, 'lt;', 0.0001, ')', were]), verbo([enhanced]), complemento([in, 'ON', fetuses])].
[sujeto(['The', mRNA, expression, of, transforming, growth, factor, β, '(', 'TGF-β;', 'P', &, 'lt;', 0.0001, ')', ',', collagen, type, 'III,', α, 'I', '(', 'COL3A1;', 'P', &, 'lt;', 0.0001, ')', ',', and, collagen, content, '(', 'P', =, 0.01, ')', were]), verbo([increased]), complemento([in, 'ON', fetuses])].
[sujeto(['These', data, shows, that, maternal, overnutrition]), verbo([enhances]), complemento([fibrogenesis, and, likely, adipogenesis, without, compromising, myogenesis, in, fetal, skeletal, muscle, of, cattle])].
[sujeto(['Here', we, show, that, 'cross-antagonistic', mechanisms, of, actions, of, 'MyoD', and, 'PPARγ,', which, are, the, master, regulators, of, muscle, and, adipose, 'differentiation,', 'respectively,']), verbo([confer]), complemento([robustness, to, the, integrity, 'of&nbsp;cell', differentiation])].
[sujeto(['Simultaneous', expression, of, 'MyoD', and, 'PPARγ', in, mesenchymal, 'stem/stromal', cells]), verbo([led]), complemento([to, the, generation, of, a, mixture, of, multinucleated, myotubes, and, 'lipid-filled', adipocytes])].
[sujeto([',', 'lipid-filled', 'myotubes)', were, not, 'generated,']), verbo([suggesting]), complemento([that, these, differentiation, programs, are, mutually, exclusive])].
[sujeto(['Mechanistically,', although, exogenously]), verbo([expressed]), complemento(['MyoD', was, rapidly, degraded, in, adipocytes, through, 'ubiquitin-proteasome', 'pathways,', exogenously, expressed, 'PPARγ', was, not, downregulated, in, myotubes])].
[sujeto(['In', 'PPARγ-expressing', 'myotubes,', 'PPARγ-dependent', histone, hyperacetylation, was]), verbo([inhibited]), complemento([in, a, subset, of, adipogenic, gene, 'loci,', including, that, of, 'C/EBPα,', an, essential, effector, of, 'PPARγ'])].
[sujeto(['Thus,', the, 'cross-repressive', interactions, between, 'MyoD-', and, 'PPARγ-induced', differentiation, programs]), verbo([ensure]), complemento([discrete, 'cell-fate', decisions])].
[sujeto(['Real-time', polymerase, chain, reaction, '(', 'PCR)', analyses, revealed, significant, upregulation, of, the, myogenic, regulatory, factors, 'MyoD', and, myogenin, and, significant, downregulation, of, the, adipogenic, transcription, factors, peroxisome, 'proliferator-activated', 'receptor-γ', '(', 'PPARγ)', and, 'CCAAT/enhancer']), verbo([binding]), complemento(['protein-α', '(', 'CEBPα)', in, masseter, muscles, treated, with, 'Mst-siRNA-lipoplexes'])].
[sujeto(['The', duty, times, of, masseter, muscle, activity, exceeding, 5, '%', showed, a, slight, tendency, to]), verbo([increase]), complemento([in, both, wild, type, and, mdx, mice])].
[sujeto(['Therefore,', cationic, 'liposome-mediated', local, administration, of, 'Mst-siRNA', could]), verbo([increase]), complemento([muscular, size, and, improve, muscle, activity])].
[sujeto(['Administration', of, 'β2-agonists']), verbo([triggers]), complemento([skeletal, muscle, anabolism, and, hypertrophy])].
[sujeto(['Phosphorylation', of, 'Akt,', ribosomal, protein, 'S6,', '4E-BP1', and, 'ERK1/2', was]), verbo([increased]), complemento([at, day, 3, ',', but, returned, to, control, level, at, day, 10])].
[sujeto(['This', could]), verbo([lead]), complemento([to, a, transient, increase, in, protein, translation, and, could, explain, previous, studies, that, reported, increase, in, protein, synthesis, following, 'β2-agonist', administration])].
[sujeto(['Formoterol', administration, was, also]), verbo([associated]), complemento([with, a, significant, reduction, in, 'MAFbx/atrogin-1', mRNA, level, '(', day, 3, ')', ',', suggesting, that, formoterol, can, also, affect, protein, degradation, of, 'MAFbx/atrogin1', targeted, 'substrates,', including, 'MyoD', and, eukaryotic, initiation, 'factor-3f', '(', 'eIF3-f)'])].
[sujeto(['Surprisingly,', mRNA, level, of, 'autophagy-related', 'genes,', light, chain, 3, beta, '(', 'LC3b)', and, 'gamma-aminobutyric', acid, 'receptor-associated', 'protein-like', 1, '(', 'Gabarapl1),', as, well, as, lysosomal, 'hydrolases,', cathepsin, 'B', and, cathepsin, 'L,', was, significantly, and, transiently]), verbo([increased]), complemento([after, 1, 'and/or', 3, 'days,', suggesting, that, autophagosome, formation, would, be, increased, in, response, to, formoterol, administration])].
[sujeto(['However,', this]), verbo([has]), complemento([to, be, relativized, since, the, mRNA, level, of, 'Unc-51-like', kinase1, '(', 'Ulk1),', 'BCL2/adenovirus', 'E1B', interacting, protein3, '(', 'Bnip3),', and, transcription, factor, 'EB', '(', 'TFEB),', as, well, as, the, protein, content, of, 'Ulk1,', 'Atg13,', 'Atg5-Atg12', complex, and, 'p62/Sqstm1', remained, unchanged, or, was, even, decreased, in, response, to, formoterol, administration])].
[sujeto(['Human', 'Adipose', stem, cells, '(', 'ASCs)']), verbo([have]), complemento([been, reported, to, regenerate, muscle, fibers, and, reconstitute, the, pericytic, cell, pool, after, myogenic, differentiation, in, vitro])].
[sujeto(['Thirty', days, after, engraftment, in, 'mice,', we]), verbo([found]), complemento([that, 'NG2(+)', 'ASCs', underwent, a, complete, myogenic, 'differentiation,', fabricating, a, human, skeletal, muscle, 'tissue,', while, 'NG2(-)', 'ASCs', merely, formed, a, human, adipose, tissue])].
[sujeto(['Both', tissues, formed]), verbo([expressed]), complemento(['Class', 'I', 'HLA,', confirming, their, human, origin, and, excluding, any, contamination, by, murine, cells])].
[sujeto(['In', 'conclusion,', our, study]), verbo([provides]), complemento([novel, evidence, that, 'NG2(+)', 'ASCs', loaded, on, 'XHA', scaffolds, are, able, to, fabricate, a, human, skeletal, muscle, tissue, in, vivo, without, the, need, of, a, myogenic, 'pre-differentiation', step, in, vitro])].
[sujeto(['The', 'self-healing', potential, of, each, tissue, belongs, to, endogenous, stem, cells, residing, in, the, 'tissue;', 'however,', there, are, currently, no]), verbo([reports]), complemento([mentioned, for, the, isolation, of, human, rotator, 'cuff-derived', mesenchymal, stem, cells, '(', 'RC-MSCs)', since])].
[sujeto(['Similar', to, 'BM-MSCs,', 'RC-MSCs', were, demonstrated, to]), verbo([have]), complemento([the, potential, to, undergo, 'osteogenic,', 'adipogenic,', and, chondrogenic, differentiation])].
[sujeto(['Upon', induction, in, the, defined, 'media,', 'RC-MSCs', also]), verbo([expressed]), complemento(['lineage-specific', 'genes,', such, as, 'Runx', 2, and, osteocalcin, in, osteogenic, 'induction,', 'PPAR-γ', and, 'LPL', in, adipogenic, 'differentiation,', and, aggrecan, and, 'Col2a1', in, chondrogenic, differentiation])].
[sujeto(['The', multipotent, feature, of, 'RC-MSCs', in, the, myogenic, injury, model, was, further, strengthened, by, the]), verbo([increase]), complemento([in, myogenic, potential, both, in, vitro, and, in, vivo, when, compared, with, 'BM-MSCs'])].
[sujeto(['We', hypothesized, that, key, genes]), verbo([involved]), complemento([in, muscle, development, and, mitochondrial, biogenesis, would, be, altered, following, uteroplacental, insufficiency, in, rat, 'pups,', and, improving, postnatal, nutrition, by, 'cross-fostering', would, ameliorate, these, deficits])].
[sujeto(['In', both, 'sexes,', peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)-γ', 'coactivator-1α', '(', 'PGC-1α),', cytochrome, c, oxidase, subunits, 3, and, 4, '(', 'COX', 'III', and, 'IV)', and, myogenic, regulatory, factor, 4, expression]), verbo([increased]), complemento([from, late, gestation, to, postnatal, 'life,', whereas, mitochondrial, transcription, factor, 'A,', myogenic, differentiation, 1, '(', 'MyoD),', myogenin, and, 'insulin-like', growth, factor, 'I', '(', 'IGF-I)', decreased])].
[sujeto(['Foetal', growth, restriction]), verbo([increased]), complemento(['MyoD', mRNA, in, females, at, 'PN7,', whereas, in, males, 'IGF-I', mRNA, was, higher, at, 'E20', and, 'PN1'])].
[sujeto(['Cross-fostering', 'Restricted', pups, onto, a, 'Control', mother, significantly]), verbo([increased]), complemento(['COX', 'III', mRNA, in, males, and, 'COX', 'IV', mRNA, in, both, sexes, above, controls, with, little, effect, on, other, genes])].
[sujeto(['Developmental', age, appears, to, be, a, major, factor]), verbo([regulating]), complemento([skeletal, muscle, mitochondrial, and, developmental, 'genes,', with, growth, restriction, and, 'cross-fostering', having, only, subtle, effects])].
[sujeto(['Arthritis', is, a, chronic, inflammatory, illness, that]), verbo([induces]), complemento(['cachexia,', which, has, a, direct, impact, on, morbidity, and, mortality])].
[sujeto(['Fenofibrate,', a, selective, 'PPARα', activator, prescribed, to, treat, human, 'dyslipidemia,']), verbo([has]), complemento([been, reported, to, decrease, inflammation, in, rheumatoid, arthritis, patients])].
[sujeto(['Fenofibrate']), verbo([decreased]), complemento([external, signs, of, arthritis, and, liver, 'TNFα', and, blocked, 'arthritis-induced', decreased, in, 'PPARα', expression, in, the, gastrocnemius, muscle])].
[sujeto(['Arthritis']), verbo([decreased]), complemento([gastrocnemius, 'weight,', which, results, from, a, decrease, in, 'cross-section', area, and, myofiber, 'size,', whereas, fenofibrate, administration, to, arthritic, rats, attenuated, the, decrease, in, both, gastrocnemius, weight, and, fast, myofiber, size])].
[sujeto(['Fenofibrate', treatment]), verbo([prevented]), complemento(['arthritis-induced', increase, in, 'atrogin-1', and, 'MuRF1', expression, in, the, gastrocnemius])].
[sujeto(['Myostatin', expression, was, not, modified, by, 'arthritis,', but, fenofibrate]), verbo([decreased]), complemento([myostatin, expression, in, the, gastrocnemius, of, arthritic, rats])].
[sujeto(['Arthritis']), verbo([increased]), complemento([muscle, expression, of, 'MyoD,', 'PCNA,', and, myogenin, in, the, rats, treated, with, vehicle, but, not, in, those, treated, with, fenofibrate])].
[sujeto(['The', results, indicate, 'that,', in, experimental, 'arthritis,', fenofibrate]), verbo([decreases]), complemento([skeletal, muscle, atrophy, through, inhibition, of, the, 'ubiquitin-proteasome', system, and, myostatin])].
[sujeto(['About', 30, '%', of, the, total, single, 'cell-derived', colonies]), verbo([expressed]), complemento([adipogenic, potential, '(', defined, 'cytochemically)', when, 'BRL', was, present])].
[sujeto(['Notably,', 'however,', some, cells, exhibited, both, 'PPARgamma', and, 'Runx2']), verbo([nuclear]), complemento([labeling, with, concomitant, upregulation, of, expression, of, their, target, genes, with, 'BRL', treatment])].
[sujeto(['The', fact, that, some, 'ObL', cells]), verbo([maintain]), complemento([capacity, for, adipogenic, fate, selection, even, at, relatively, mature, developmental, stages, implies, an, unexpected, plasticity, with, important, implications, in, normal, and, pathological, bone, development])].
[sujeto(['Menopause,', the, 'age-related']), verbo([loss]), complemento([of, ovarian, hormone, 'production,', promotes, increased, adiposity, and, associated, metabolic, 'pathology,', but, molecular, mechanisms, remain, unclear])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, estrogen, increases, skeletal, muscle, 'PPARdelta', expression, in, 'vivo,', and, transgenic, mice, overexpressing, 'muscle-specific', 'PPARdelta', are, reportedly, protected, from, 'diet-induced', obesity])].
[sujeto(['Compared', to, 'SHM,', muscle, from, 'OVX', mice, displayed, significantly]), verbo([decreased]), complemento([expression, of, 'PPARdelta', '(', 3.4, -, 'fold),', 'FoxO1', '(', 4.5, -, 'fold),', 'PDK-4', '(', 2.3, -, 'fold),', and, 'UCP-2', '(', 1.8, -, 'fold)'])].
[sujeto(['Consistent', with, studies, indicating, 'PPARdelta', and, 'FoxO1']), verbo([regulate]), complemento([muscle, fiber, 'type,', we, observed, dramatic, 'OVX-specific', decreases, in, slow, isoforms, of, the, contractile, proteins, myosin, light, chain, '(', 11.1, -, 'fold)', and, troponin, 'C', '(', 11.8, -, 'fold)'])].
[sujeto(['In', 'addition,', muscles, from, 'OVX', mice]), verbo([expressed]), complemento([57, '%', less, myogenin, '(', drives, type, 'I', fiber, 'formation),', 2, -, fold, more, 'MyoD', '(', drives, type, 'II', fiber, 'formation),', and, 1.6, -, fold, less, musclin, '(', produced, exclusively, by, type, 'II', 'fibers)', than, 'SHM,', collectively, suggesting, a, shift, towards, less, type, 'I', oxidative, fibers])].
[sujeto(['Finally,', and, consistent, with, changes, in, 'PPARdelta', and, 'FoxO1', 'activity,', we, observed]), verbo([decreased]), complemento([expression, of, 'atrogin-1', '(', 2.3, -, 'fold)', and, 'MuRF-1', '(', 1.9, -, 'fold)', in, 'OVX', mice])].
[sujeto(['In', 'conclusion,', muscles, from, ovariectomized, mice, display]), verbo([decreased]), complemento(['PPARdelta', and, 'FoxO1', 'expression,', abrogated, expression, of, downstream, targets, involved, in, lipid, and, protein, 'metabolism,', and, gene, expression, profiles, indicating, less, type, 'I', oxidative, fibers])].
[sujeto(['Initial', force, production, '(', 1.6, +, /, -, 0.1, 'g/g', body, 'wt)', declined, 45, '%', within, 10, min, and, was]), verbo([maintained]), complemento([for, the, remainder, of, the, experiment])].
[sujeto(['An', 'immediate-early', growth, response, was, present, in, the, extensor, digitorum, longus, '(', 'EDL)', muscle, '(', 'FOS,', 'JUN,']), verbo([activating]), complemento([transcription, factor, 3, ',', and, musculoaponeurotic, fibrosarcoma, 'oncogene)', with, a, similar, but, attenuated, pattern, in, the, soleus, muscle])].
[sujeto(['Transcript', profiles, showed]), verbo([decreased]), complemento([fast, 'fiber-specific', mRNA, '(', myosin, heavy, chains, 2, 'A', and, 2, 'B,', fast, troponins, 'T(3)', and, 'I,', 'alpha-tropomyosin,', muscle, creatine, 'kinase,', and, 'parvalbumin)', and, increased, slow, transcripts, '(', myosin, heavy, 'chain-1beta/slow,', troponin, 'C', 'slow,', and, tropomyosin, 3, 'y)', in, the, 'EDL', versus, soleus, muscles])].
[sujeto(['Histological', analysis, of, the, 'EDL', revealed, glycogen, depletion, without, inflammatory, cell, infiltration, in]), verbo([stimulated]), complemento([versus, control, 'muscles,', whereas, ultrastructural, analysis, showed, no, evidence, of, myofiber, damage, after, stimulation])].
[sujeto(['Multiple', fiber, 'type-specific', transcription, factors, '(', tea, domain, family, member, 1, ',']), verbo([nuclear]), complemento([factor, of, activated, 'T', cells, 1, ',', peroxisome, 'proliferator-activated', 'receptor-gamma', 'coactivator-1alpha', and, -, 'beta,', circadian, locomotor, output, cycles, 'kaput,', and, 'hypoxia-inducible', 'factor-1alpha)', increased, in, the, 'EDL', along, with, transcription, factors, characteristic, of, embryogenesis, '(', 'Kruppel-like', factor, 4, ;, 'SRY', box, containing, 17, ;, transcription, factor, 15, ;, 'PBX/knotted', 1, homeobox, 1, ;, and, embryonic, 'lethal,', abnormal, 'vision)'])].
[sujeto(['No', established, in, vivo, satellite, cell, markers, or, genes]), verbo([activated]), complemento([in, our, parallel, experiments, of, satellite, cell, proliferation, in, vitro, '(', cyclins, 'A(2),', 'B(2),', 'C,', and, 'E(1)', and, 'MyoD)', were, differentially, increased, in, the, stimulated, muscles])].
[sujeto(['This', conversion, was]), verbo([associated]), complemento([with, the, expression, of, 'phenotype-specific', transcription, factors, from, resident, fiber, 'myonuclei,', including, the, activation, of, nascent, developmental, transcriptional, programs])].
[sujeto(['Ucp3', is, predominantly]), verbo([expressed]), complemento([in, skeletal, muscle, and, brown, adipose, tissue, and, is, regulated, by, a, transcription, factor, complex, involving, peroxisome, 'proliferator-activated', 'receptor-alpha,', 'MyoD,', and, 'COUP', transcription, factor, 'II'])].
[sujeto(['By', analysis, of, a, mutant, 'Djungarian', hamster, model, lacking, 'Ucp3', transcription, specifically, in, brown, adipose, 'tissue,', we, identified, a, putative, transcription, 'factor-binding', site, that]), verbo([confers]), complemento([tissue, specificity])].
[sujeto(['A', naturally, occurring, intronic, point, mutation, disrupting, this, site]), verbo([leads]), complemento([to, brown, adipose, 'tissue-specific', loss, of, 'Ucp3', expression, and, an, altered, body, weight, trajectory])].
[sujeto(['Our', findings]), verbo([provide]), complemento([insight, into, 'tissue-specific', 'Ucp3', regulation, 'and,', for, the, first, 'time,', unambiguously, demonstrate, that, changes, in, 'Ucp3', expression, can, interfere, with, body, weight, regulation])].
[sujeto(['Several', signaling, pathways]), verbo([have]), complemento([been, shown, to, regulate, the, lineage, commitment, and, terminal, differentiation, of, 'MSCs'])].
[sujeto(['Here,', we, conducted, a, comprehensive, analysis, of, the, 14, types, of, bone, morphogenetic, protein, '(', 'BMPs)', for, their, abilities, to]), verbo([regulate]), complemento([multilineage, specific, differentiation, of, 'MSCs'])].
[sujeto(['We']), verbo([found]), complemento([that, most, 'BMPs', exhibited, distinct, abilities, to, regulate, the, expression, of, 'Runx2,', 'Sox9,', 'MyoD,', and, 'PPARgamma2'])].
[sujeto(['Further', analysis, indicated, that, 'BMP-2,', 'BMP-4,', 'BMP-6,', 'BMP-7,', and, 'BMP-9', effectively]), verbo([induced]), complemento([both, adipogenic, and, osteogenic, differentiation, in, vitro, and, in, vivo])].
[sujeto(['Overexpression', of, 'Runx2']), verbo([enhanced]), complemento(['BMP-induced', osteogenic, 'differentiation,', whereas, knockdown, of, 'Runx2', expression, diminished, 'BMP-induced', bone, formation, with, a, decrease, in, adipocyte, accumulation, in, vivo])].
[sujeto(['Interestingly,', overexpression, of, 'PPARgamma2', not, only]), verbo([promoted]), complemento([adipogenic, 'differentiation,', but, also, enhanced, osteogenic, differentiation, upon, 'BMP-2,', 'BMP-6,', and, 'BMP-9', stimulation])].
[sujeto(['Conversely,', 'MSCs', with, 'PPARgamma2', knockdown, or, mouse, embryonic, fibroblasts, derived, from, 'PPARgamma2(-/-)', mice, exhibited, a, marked]), verbo([decrease]), complemento([in, adipogenic, 'differentiation,', coupled, with, reduced, osteogenic, differentiation, and, diminished, mineralization, upon, 'BMP-9', 'stimulation,', suggesting, that, 'PPARgamma2', may, play, a, role, in, 'BMP-induced', osteogenic, and, adipogenic, differentiation])].
[sujeto(['Thus,', it, is, important, to, understand, the, molecular, mechanism, behind, 'BMP-regulated', lineage, divergence, during, 'MSC', 'differentiation,', as, this, knowledge, could, help, us, to, understand, the, pathogenesis, of, skeletal, diseases, and, may]), verbo([lead]), complemento([to, the, development, of, strategies, for, regenerative, medicine])].
[sujeto(['Women', exhibit, an]), verbo([enhanced]), complemento([capability, for, lipid, metabolism, during, endurance, exercise, compared, with, men])].
[sujeto(['Nuclear', 'AMP-activated', protein, 'kinase-alpha', '(', 'alphaAMPK)', 'Thr(172)', '(', 'P', &, 'lt;', 0.001, ')', ',', histone, deacetylase, 5, '(', 'HDAC5)', 'Ser(498)', '(', 'P', &, 'lt;', 0.001, ')', ',', and, 'MEF2', 'Thr', '(', 'P', &, 'lt;', 0.01, ')', phosphorylation]), verbo([increased]), complemento([with, exercise])].
[sujeto(['Of', 'these,', 'MEF2A', mRNA]), verbo([increased]), complemento([25, '%', specifically, in, women, '(', 'P', &, 'lt;', 0.05, ')', ',', whereas, 'MEF2D', mRNA, tended, to, increase, in, men, '(', 'P', =, 0.11, ')'])].
[sujeto(['Although', minor, sex, differences, in, mRNA, expression, were, 'observed,', the, main]), verbo([finding]), complemento([of, the, present, study, was, the, implication, of, a, joint, signaling, action, of, 'AMPK,', 'HDAC5,', and, 'PGC1alpha', on, 'MEF2', in, the, immediate, regulatory, response, to, endurance, exercise])].
[sujeto(['In', skeletal, muscle, 'cells,', connexin43, '(', 'Cx43)']), verbo([has]), complemento([been, identified, as, the, major, 'connexin,', and, 'gap-junctional', communication, mediated, by, connexins, has, been, shown, to, be, required, for, their, myogenic, differentiation])].
[sujeto(['In', 'addition,', inhibition, of, connexin, function]), verbo([has]), complemento([been, shown, to, induce, transdifferentiation, of, osteoblasts, to, an, adipocytic, phenotype])].
[sujeto(['In', the, present, 'study,', we, examined, whether, the, inhibition, of, connexin, function, could]), verbo([induce]), complemento([phenotypic, changes, in, skeletal, muscle, cells])].
[sujeto(['Treatment', of, skeletal, muscle, cells, with, an, inhibitor, of, connexin, 'function,', 18, 'alpha-glycyrrhetinic', acid, '(', 'AGRA),', resulted, in, a, reduction, in, the, number, of, 'MyoD-positive', cells, and, complete, inhibition, of, myotube, 'formation,', concomitantly, with, an]), verbo([increase]), complemento([in, the, number, of, 'C/EBPalpha-positive', cells])].
[sujeto(['AGRA-treated', cells, cultured, in, adipogenic, differentiation, medium, could, give, rise, to, mature, adipocytes, that]), verbo([express]), complemento([both, 'PPARgamma', and, 'C/EBPalpha'])].
[sujeto(['The', presence, of, 'AGRA', during, adipogenic, differentiation, did, not]), verbo([inhibit]), complemento([adipogenesis, of, skeletal, muscle, cells])].
[sujeto(['These', results, indicate, that, inhibition, of, connexin, function]), verbo([induces]), complemento([phenotypic, changes, of, skeletal, muscle, cells, to, enter, adipogenesis])].
[sujeto(['Wnt3a', signaling]), verbo([induced]), complemento(['beta-catenin', nuclear, translocation, and, activated, the, 'Wnt', pathway, in, rMSC])].
[sujeto(['Moreover,', 'Wnt3a', signaling]), verbo([induced]), complemento([2.62, '%', and, 3.76, '%', of, 'rMSC-expressed', desmin, and, myosin, heavy, chain, after, being, cultured, in, myogenic, medium])].
[sujeto(['The', myogenic, differentiation, 'genes,', including, 'Pax7,', 'MyoD,', 'Myf5,', 'Myf4,', and, 'myogenin,', were]), verbo([activated]), complemento([after, 'Wnt3a', treatment])].
[sujeto(['On', the, other, 'hand,', 'Wnt3a']), verbo([inhibited]), complemento([the, adipogenic, differentiation, in, rMSC, through, the, downregulated, expression, of, 'CCAAT/enhancer-binding', protein, alpha, '(', 'C/EBPalpha)', and, peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPARgamma)'])].
[sujeto(['Furthermore,', 'Wnt3a']), verbo([promoted]), complemento([the, migration, capacity, of, rMSC])].
[sujeto(['The', results, indicate, that, 'Wnt3a', signaling, can]), verbo([induce]), complemento([myogenic, differentiation, in, rMSC])].
[sujeto(['Wnt3a', signaling, is, also]), verbo([involved]), complemento([in, the, regulation, of, the, proliferation, and, migration, of, rMSC])].
[sujeto(['These', results, could]), verbo([provide]), complemento([a, rational, foundation, for, 'cell-based', tissue, repair, in, humans])].
[sujeto(['Muscle', fibres]), verbo([have]), complemento([different, properties, with, respect, to, 'force,', contraction, 'speed,', 'endurance,', 'oxidative/glycolytic', capacity, etc])].
[sujeto(['It', is]), verbo([suggested]), complemento([that, changes, in, 'nerve-evoked', muscle, activity, lead, to, a, variety, of, activity, correlates, such, as, increases, in, free, intracellular, 'Ca(2+)', levels, caused, by, influx, across, the, cell, membrane, 'and/or', release, from, the, sarcoplasmatic, 'reticulum,', concentrations, of, metabolites, such, as, lipids, and, 'ADP,', hypoxia, and, mechanical, stress])].
[sujeto(['Such', correlates, are, detected, by, sensors, such, as, protein, kinase, 'C', '(', 'PKC),', 'calmodulin,', 'AMP-activated', kinase, '(', 'AMPK),', peroxisome, 'proliferator-activated', receptor, δ, '(', 'PPARδ),', and, oxygen, dependent, prolyl, hydroxylases, that]), verbo([trigger]), complemento([intracellular, signaling, cascades])].
[sujeto(['These', complex, cascades]), verbo([involve]), complemento([several, transcription, factors, such, as, nuclear, factor, of, activated, 'T-cells', '(', 'NFAT),', myocyte, enhancer, factor, 2, '(', 'MEF2),', myogenic, differentiation, factor, '(', 'myoD),', 'myogenin,', 'PPARδ,', and, sine, oculis, homeobox, 1, /, eyes, absent, 1, '(', 'Six1/Eya1)'])].
[sujeto(['These', factors, might]), verbo([act]), complemento([indirectly, by, inducing, gene, products, that, act, back, on, the, 'cascade,', or, as, ultimate, transcription, factors, binding, to, and, 'transactivating/repressing', genes, for, the, fast, and, slow, isoforms, of, various, contractile, proteins, and, of, metabolic, enzymes])].
[sujeto(['The', determination, of, size, and, force, is, even, more, complex, as, this]), verbo([involves]), complemento([not, only, intracellular, signaling, within, the, muscle, 'fibres,', but, also, muscle, stem, cells, called, satellite, cells])].
[sujeto(['Intercellular', signaling, substances, such, as, myostatin, and, 'insulin-like', growth, factor, 1, '(', 'IGF-1)', seem, to]), verbo([act]), complemento([in, a, paracrine, fashion])].
[sujeto(['Induction', of, hypertrophy, is, accompanied, by, the, satellite, cells, fusing, to, myofibres, and, thereby]), verbo([increasing]), complemento([the, capacity, for, protein, synthesis])].
[sujeto(['In', addition, to, changes, in, myonuclear, number, during, 'hypertrophy,', changes, in, muscle, fibre, size, seem, to, be]), verbo([caused]), complemento([by, alterations, in, 'transcription,', translation, '(', per, 'nucleus)', and, protein, degradation])].
[sujeto(['Treatment', of, 'C2C12', cells, with, the, 'PPARgamma', 'ligand,', 15, -, 'deoxy-Delta12,14-prostaglandin', 'J2', '(', 15, 'd-PGJ2),']), verbo([repressed]), complemento([morphologically, defined, myogenesis, and, reduced, endogenous, mRNA, levels, of, the, myogenic, differentiation, markers, 'MyoD,', 'myogenin,', and, 'alpha-actin'])].
[sujeto(['In', transient, transfection, 'assays,', 15, 'd-PGJ2', specifically]), verbo([inhibited]), complemento([the, expression, of, a, 'MyoD', 'promoter-luciferase', reporter, gene, '(', 'MyoDLuc)', in, a, cell, 'type-', and, 'promoter-specific', 'manner,', indicating, that, 15, 'd-PGJ2', functions, in, part, by, repressing, 'MyoD', gene, transcription])].
[sujeto(['The', inhibition, of, 'MyoD', gene, expression, by, 15, 'd-PGJ2', is]), verbo([mediated]), complemento([by, the, distal, region, of, the, 'MyoD', gene, promoter])].
[sujeto(['PPARgamma', on, its, own, also]), verbo([inhibited]), complemento(['MyoDLuc', expression, and, further, augmented, the, 15, 'd-PGJ2', response])].
[sujeto(['In', 'contrast,', 'L-805645', and, ciglitazone, did, not]), verbo([inhibit]), complemento(['MyoDLuc', expression, on, their, own, but, did, so, in, the, presence, of, ectopically, expressed, 'PPARgamma'])].
[sujeto(['Thus,', distinct, 'PPARgamma', ligands, may]), verbo([repress]), complemento(['MyoD', gene, expression, through, 'PPARgamma-dependent', and, -, independent, 'pathways,', and, 15, 'd-PGJ2', can, inhibit, the, myogenic, program, independent, of, its, cognate, 'receptor,', 'PPARgamma'])].
[sujeto(['Peroxisome', 'proliferator-activated', receptor, γ, '(', 'PPARγ)', is, a, key, transcription, factor, in, adipogenesis, and, can, be]), verbo([regulated]), complemento([by, 'adipogenesis-related', factors])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, 'over-expression', of, 'MyoD', enhanced, porcine, adipocyte, differentiation, and, 'up-regulated', 'PPARγ', 'expression,', whereas, small, interfering, 'RNA', against, 'MyoD', significantly, attenuated, porcine, adipocyte, differentiation, and, inhibited, 'PPARγ', expression])].
[sujeto(['Electrophoretic', mobility, shift, assays, and, chromatin, immunoprecipitation, further, showed, that, these, two, regions, are, 'MyoD-binding', 'sites,', both, in, vitro, and, in, 'vivo,', indicating, that, 'MyoD', directly]), verbo([interacts]), complemento([with, the, porcine, 'PPARγ', promoter])].
[sujeto(['Thus,', our, results, demonstrate, that, an, 'Enhancer', box, and, a]), verbo([binding]), complemento([site, for, a, cooperative, 'co-activator', of, 'MyoD', are, present, in, the, promoter, region, of, porcine, 'PPARγ;', 'furthermore,', 'MyoD', 'up-regulates', 'PPARγ', expression, and, promotes, porcine, adipocyte, differentiation])].
[sujeto(['Adenosine', monophosphate, '(', 'AMP)-activated', protein, kinase, '(', 'AMPK)', is]), verbo([inhibited]), complemento([in, 'SM', of, fetuses, born, to, obese, mothers])].
[sujeto(['Metformin', administration]), verbo([prevented]), complemento([these, changes, in, 'OB', offspring, 'SM'])].
[sujeto(['Mitochondrial', content, 'decreased,', and, activities, of, citrate, synthase, and, 'β-hydroxyacyl-CoA', dehydrogenase, also]), verbo([decreased]), complemento([in, 'OB', offspring, 'SM,', whereas, they, were, recovered, in, 'MET', offspring, 'SM'])].
[sujeto(['Efficacy', of, differentiated, 'MSCs', to, regenerate, cells, in, the, injured, tissues]), verbo([requires]), complemento([the, ability, to, maintain, the, differentiation, toward, the, desired, cell, fate])].
[sujeto(['Since', 'MSCs', represent, an, attractive, source, for, autologous, 'transplantation,', cellular, and, molecular, signaling, pathways, and, 'micro-environmental', changes]), verbo([have]), complemento([been, studied, in, order, to, understand, the, role, of, 'cytokines,', 'chemokines,', and, transcription, factors, on, the, differentiation, of, 'MSCs'])].
[sujeto(['The', differentiation, of, 'MSC', into, a, mesenchymal, lineage, is, genetically, manipulated, and]), verbo([promoted]), complemento([by, specific, transcription, factors, associated, with, a, particular, cell, lineage])].
[sujeto(['Recent', studies]), verbo([have]), complemento([explored, the, integration, of, transcription, 'factors,', including, 'Runx2,', 'Sox9,', 'PPARγ,', 'MyoD,', 'GATA4,', and, 'GATA6', in, the, differentiation, of, 'MSCs'])].
[sujeto(['Therefore,', the, overexpression, of, a, single, transcription, factor, in, 'MSCs', may]), verbo([promote]), complemento(['trans-differentiation', into, specific, cell, 'lineage,', which, can, be, used, for, treatment, of, some, diseases])].
[sujeto(['Recently,', understanding, the, underlying, genetic, bases, of, 'IMF']), verbo([has]), complemento([been, a, focus, particularly, in, the, beef, industry])].
[sujeto(['In', this, 'study,', with, the, deep, insights, of, ameliorating, the, beef, quality, by, genetic, 'means,', the, role, of, the, 'CCAAT/enhancer']), verbo([binding]), complemento([protein, alpha, '(', 'C/EBPα)', gene, was, investigated, by, 'over-expressing', 'C/EBPα', in, bovine, muscle, stem, cells, '(', 'MSCs)', to, initiate, the, adipogenic, program])].
[sujeto(['Prior', to, 'this,', bovine, 'MSCs', were, isolated, and]), verbo([induced]), complemento([to, differentiate, into, adipocytes, from, cells, that, were, exposed, to, dexamethasone, isobutylmethylxanthine, and, 'indomethacin;', the, presence, of, insulin, and, fetal, bovine, serum, was, examined])].
[sujeto(['Either', ectopic, expression, of, 'C/EBPα', or, treatment, with, dexamethasone, and, insulin]), verbo([induced]), complemento([the, accumulation, of, fat, droplets, and, the, expression, of, adipogenic, induction, genes, '(', 'LPL,', 'PPARγ,', 'C/EBPβ,', and, 'C/EBPδ)'])].
[sujeto(['This', study]), verbo([provides]), complemento([evidence, that, the, 'C/EBPα', gene, is, essential, for, cattle, adipose, tissue, growth, and, development])].
[sujeto(['Hence,', this]), verbo([finding]), complemento([can, contribute, to, improving, beef, carcass, quality])].
[sujeto(['Chemerin', is, an, 'adipocyte-secreted', adipokine, that]), verbo([regulates]), complemento([the, differentiation, and, metabolism, of, adipose, through, 'auto-/paracrine', signaling])].
[sujeto(['Its', function, in, the, differentiation, of, multipotent, myoblast, cells]), verbo([has]), complemento([thus, far, received, little, attention])].
[sujeto(['The', results, showed, that, 'Chemerin']), verbo([increased]), complemento(['ROS', levels, and, 'TG', content, of, 'C2C12', cells])].
[sujeto(['At', the, same, 'time,', the, mRNA, expressions, and, protein, concentrations, of, the, adipogenic, factors, 'PPARγ,', 'C/EBPα', and, 'UCP1', were, 'up-regulated,', while, the, muscle, specific, transcription, factors, 'MyoD,', 'Myogenin', and, 'MyHC', were]), verbo([decreased]), complemento([in, cultured, 'C2C12', cells])].
[sujeto(['In', 'conclusion,', the, adipokine, 'Chemerin']), verbo([promoted]), complemento([the, adipogenic, differentiation, potential, and, altered, the, fate, of, myoblast, cells, from, myogenesis, to, 'adipogenesis,', which, contributed, in, part, to, the, 'up-regulated', adipocyte, genes])].
[sujeto(['Our', study]), verbo([reveals]), complemento([the, importance, of, functional, 'Chemerin', signaling, in, adipogenesis, and, in, directing, the, differentiation, of, multipotent, myoblast, cells])].
[sujeto(['It']), verbo([has]), complemento([been, reported, that, the, 'lineage-specific', transcriptional, factors, including, 'Runt', related, transcription, factor, 2, '(', 'RUNX2),', 'Peroxisome', 'proliferator-activator', receptor, gamma, '(', 'PPARgamma)', and, 'Myogenic', differentiation, 1, '(', 'MyoD)', may, play, key, regulatory, roles, among, the, differentiation, of, 'MSCs'])].
[sujeto(['Recently,', researches]), verbo([have]), complemento([confirmed, that, the, 'Hippo', pathway, impacts, the, differentiation, fates, of, 'MSCs', through, regulating, the, activity, of, 'line-', 'age-specific', transcription, factors, by, the, 'Hippo', pathway, effectors, 'Tafazzin', '(', 'TAZ)', 'and/or', 'Yes-associated', protein, '(', 'YAP)'])].
[sujeto(['The', interaction, between, 'TAZ', and, 'RUNX2', boosts, the, osteogenic, processes, and]), verbo([promotes]), complemento(['MSCs', differentiating, into, osteoblast, lineage])].
[sujeto(['However,', 'PPARgamma']), verbo([binding]), complemento([to, 'TAZ', may, inhibit, the, adipocytes, 'differentiation,', and, thus, overexpression, of, 'TAZ', in, mesenchymal, stem, 'cell-like', cells, increases, the, expression, of, myogenic, genes, and, hastens, myofiber, formation, through, a, 'MyoD-dependent', manner])].
[sujeto([')', ',', and, mechanistic, stimuli, can, also, affect, the, fate, by]), verbo([regulating]), complemento([the, activity, of, 'TAZ/YAP'])].
[sujeto(['Compared', with, 'Chenghua', 'pigs,', development, and, maturation, of, fetal, skeletal, muscles, may, occur, earlier, in, 'Yorkshire', 'pigs,', but, the, negative, regulatory, effects, of, myostatin, may]), verbo([suppress]), complemento([muscle, development, at, the, later, stage])].
[sujeto(['The', following, parameters, were, 'measured:', cell, number, and, viability, by, laser, scanning, confocal, 'microscopy;', cell, proliferation, with, the, 'MTS', 'assay;', the, expression, of, a, panel, of, 18, genes, using, 'real-time', 'RT-PCR;', matrix, metalloproteinases, '(', 'MMPs)', 1, -, 3, ',', 'TIMP-1,', 'CTGF', and, 'FGF-2', protein, levels, in, supernatants, from, mechanically]), verbo([activated]), complemento([cultures, with, 'Enzyme-linked', immunosorbent, assays])].
[sujeto(['CTGF/FGF-2']), verbo([stimulated]), complemento([cell, proliferation, in, stationary, 'cultures,', but, relative, quantity, values, suggested, modest, effects, on, gene, expression])].
[sujeto(['Three-dimensional', tissue, constructs]), verbo([provide]), complemento([additional, complexity, to, monolayer, culture, 'systems,', and, suggest, some, of, the, assumptions, regarding, cell, 'growth,', differentiation, and, matrix, turnover, based, on, 'two-dimensional', cultures, may, not, apply, to, cells, in, 'three-dimensional', matrices])].
[sujeto(['The', five, cell, lines, were, transfected, with]), verbo([enhanced]), complemento([green, fluorescence, protein, gene, respectively, using, lipofection])].
[sujeto(['NS', and, 'AFS', cells, were]), verbo([induced]), complemento([to, differentiate, in, vitro])].
[sujeto(['The', five, cell, lines, were, used, for]), verbo([nuclear]), complemento([transfer])].
[sujeto(['The', results, showed, that, both, 'NS', and, 'AFS', cells]), verbo([expressed]), complemento(['POU5F1,', 'THY1', and, 'SOX2,', and, they, were, both, induced, to, differentiate, into, astrocyte, '(', 'GFAP+),', oligodendrocyte, '(', 'GalC+),', neuron, '(', 'NF+,', 'ENO2+,', and, 'MAP2+),', adipocyte, '(', 'LPL+', and, 'PPARG-D+),', osteoblast, '(', 'osteonectin+', and, 'osteocalcin+),', myocyte, '(', 'MYF6+', and, 'MYOD+),', and, endothelium, '(', 'PECAM1+,', 'CD34+,', 'CDH5+,', and, 'NOS3+)', respectively])].
[sujeto([5, ')', than, that, of, the, embryos, cloned, from, somatic, cells, '(', 'morula-blastocyst', rate, was, 16.27, -, 19.28, '%', and, pregnancy, rate, was, 0.0, '%', ')', ',', which]), verbo([suggests]), complemento([that, the, undifferentiated, state, of, the, donor, cells, increases, cloning, efficiency])].
[sujeto(['Skeletal', muscle, wasting, is, an, important, public, health, problem]), verbo([associated]), complemento([with, 'aging,', chronic, 'disease,', 'cancer,', kidney, 'dialysis,', and, 'HIV/AIDS'])].
[sujeto([1, ',', 25, -, 'Dihydroxyvitamin', 'D', '(', 1, ',', 25, -, 'D3),', the, active, form, of, vitamin, 'D,', is, widely]), verbo([recognized]), complemento([for, its, regulation, of, calcium, and, phosphate, homeostasis, in, relation, to, bone, development, and, maintenance, and, for, its, calcemic, effects, on, target, 'organs,', such, as, 'intestine,', 'kidney,', and, parathyroid, glands])].
[sujeto(['Emerging', evidence]), verbo([has]), complemento([shown, that, vitamin, 'D', administration, improves, muscle, performance, and, reduces, falls, in, vitamin, 'D-deficient', older, adults])].
[sujeto(['However,', little, is, known, of, the, underlying, mechanism, or, the, role, 1, ',', 25, -, 'D3', plays, in]), verbo([promoting]), complemento([myogenic, differentiation, at, the, cellular, 'and/or', molecular, level])].
[sujeto(['Addition', of, 1, ',', 25, -, 'D3', to, 'C(2)C(12)', myoblasts, 1, ')']), verbo([increased]), complemento([expression, and, nuclear, translocation, of, the, vitamin, 'D', 'receptor,', 2, ')', decreased, cell, 'proliferation,', 3, ')', decreased, 'IGF-I', 'expression,', and, 4, ')', promoted, myogenic, differentiation, by, increasing, 'IGF-II', and, follistatin, expression, and, decreasing, the, expression, of, 'myostatin,', the, only, known, negative, regulator, of, muscle, 'mass,', without, changing, growth, differentiation, factor, 11, expression])].
[sujeto(['Recent', studies, on, 'VDR', gene, knockout, mice, revealed, that, 'VDR', also]), verbo([regulates]), complemento([expression, of, the, 'MyoD', family, of, transcription, factors, in, skeletal, muscle])].
[sujeto(['Thus,', vitamin, 'D', and, 'Ca', appear, to]), verbo([regulate]), complemento(['proliferation,', maturation, and, function, of, skeletal, muscle, through, these, complex, actions])].
[sujeto(['In', an, earlier, 'study,', we]), verbo([reported]), complemento([on, the, linkage, relationships, of, 16, loci, on, mouse, chromosome, 7, and, the, homologous, relationship, between, this, chromosome, and, the, myotonic, dystrophy, gene, region, on, human, chromosome, 19])].
[sujeto(['Overexpression', of, multidrug, resistance, 1, '(', 'MDR1)', in, cancer, remains, one, of, the, major]), verbo([causes]), complemento([for, the, failure, of, chemotherapy])].
[sujeto(['In', the, present, 'study,', we]), verbo([found]), complemento([that, 'MyoD', and, 'PEA3', could, activate, 'P-glycoprotein', '(', 'P-gp)', expression, in, 'SGC7901', cells])].
[sujeto(['Knockdown', of, 'MyoD', and, 'PEA3', attenuated, 'MDR1', expression, and]), verbo([increased]), complemento([the, sensitivity, of, multidrug, resistant, cancer, cells, to, cytotoxic, drugs, that, were, transported, by, 'P-gp', in, 'SGC7901/VCR', cells])].
[sujeto(['MyoD', or, 'PEA3', could]), verbo([bind]), complemento([to, the, 'E-box', and, 'PEA3', sites, on, the, 'MDR1', promoter, and, activate, its, transcription])].
[sujeto(['The', regulation, of, 'MDR1', expression, by, 'MyoD', and, 'PEA3', may]), verbo([provide]), complemento([potential, ways, to, overcome, 'MDR', in, cancer, treatment])].
[sujeto(['We']), verbo([have]), complemento([characterized, the, promoter, methylation, profile, of, 82, genes, in, three, prostate, cancer, cell, lines, '(', 'LNCaP,', 'PC3,', and, 'DU145)', and, two, normal, prostate, cell, lines, '(', 'RWPE1', and, 'RWPE2)'])].
[sujeto(['Methylation']), verbo([binding]), complemento(['protein-purified', methylated, 'DNA', was, hybridized, on, the, membrane, and, detected, by, the, chemiluminescence, method])].
[sujeto(['In', 'addition,', promoter, methylation, was, detected, for, the, first, time, in]), verbo([target]), complemento([genes, such, as, 'RIOK3,', 'STAT5,', 'CASP8,', 'SRBC,', 'GAGE1,', and, 'NPAT'])].
[sujeto(['Overexpression', of, 'MDR1', in, breast, cancer, remains, a, major]), verbo([cause]), complemento([for, the, failure, of, chemotherapy])].
[sujeto(['In', the, present, 'report,', we]), verbo([find]), complemento(['UHRF1', plays, an, important, role, in, inhibiting, 'MDR1', promoter, activity, by, directly, binding, to, the, 'MDR1', promoter])].
[sujeto(['Knockdown', of, 'UHRF1']), verbo([activates]), complemento(['MDR1', promoter, activity, and, 'expression,', attenuates, the, binding, of, 'UHRF1', and, 'HDAC1', to, the, 'MDR1', promoter])].
[sujeto(['Overexpression', of, 'UHRF1', in, 'NCI/ADR-RES', cells, can]), verbo([induce]), complemento([deacetylation, of, histones, 'H3', and, 'H4', on, the, 'MDR1', 'promoter,', which, is, facilitated, by, recruitment, of, 'HDAC1', to, the, 'MDR1', promoter])].
[sujeto(['Loss', of, histone, acetylation, is, accompanied, by]), verbo([loss]), complemento([of, binding, of, the, key, transcription, 'factor,', 'MyoD,', 'CBP', and, 'p300,', locking, in, marked, suppression, of, 'MDR1,', increasing, sensitivity, of, 'MDR', cancer, cells, to, cytotoxic, drugs, that, are, transported, by, 'P-glycoprotein(P-gp)'])].
[sujeto(['The', inhibition, of, 'MDR1', expression, by, 'UHRF1', may]), verbo([provide]), complemento([potential, ways, to, overcome, multidrug, resistance, '(', 'MDR)', in, breast, cancer, treatment])].
[sujeto(['Fibroblast', growth, factor, 6, '(', 'FGF6)', is, selectively]), verbo([expressed]), complemento([during, muscle, development, and, regeneration])].
[sujeto(['FGF6', produced, in, genetically, engineered, mpc, was, 'active,']), verbo([inducing]), complemento([strong, morphological, 'changes,', altering, cell, adhesion, and, compromising, their, ability, to, differentiate, into, myotubes])].
[sujeto(['We', also]), verbo([report]), complemento([that, in, the, presence, of, 'FGF6,', the, minor, '(', 0.5, -, 2, '%', ')', subpopulation, of, cells, actively, excluding, 'Hoechst', 33342, in, a, 'verapamil-dependent', manner, '(', 'SP', 'phenotype)', was, increased, to, 15, -, 20, '%', and, the, expression, of, the, mdr1a, gene, '(', but, not, 'mdr1b)', was, upregulated, by, 400, -, fold])].
[sujeto(['Our', data, establish, a, previously, undescribed, link, between, 'FGF6--a', muscle, specific, growth, 'factor--and', a, multidrug, resistance, gene]), verbo([expressed]), complemento([in, stem, 'cells,', and, suggest, a, role, for, 'FGF6', in, the, maintenance, of, a, reserve, pool, of, progenitor, cells, in, the, skeletal, muscle])].
[sujeto([')', 'Kuntze']), verbo([has]), complemento([been, well, known, for, its, antioxidative, properties])].
[sujeto(['Reduction', of, these, two, transcription, factors, resulted, in, a]), verbo([decrease]), complemento([in, melanogenic, enzymes, such, as, 'tyrosinase,', 'tyrosinase-related', protein, 1, ',', and, dopachrome, tautomerase])].
[sujeto(['As', a, 'result,', 1, significantly]), verbo([inhibited]), complemento([the, melanin, synthesis, in, 'melan-a', mouse, melanocytes, and, 'NHEMs'])].
[sujeto(['The', cytokine, interleukin, 12, '(', 'IL-12)']), verbo([has]), complemento([been, implicated, as, a, potent, stimulator, of, tissue, degradation, in, the, pathogenesis, of, several, inflammatory, 'diseases,', including, periodontitis])].
[sujeto(['In', patients, with, 'periodontitis,', an]), verbo([increased]), complemento([level, of, 'IL-12', is, found, in, serum, and, gingival, crevicular, fluid])].
[sujeto(['As', inflammatory, cytokines]), verbo([have]), complemento([been, demonstrated, to, induce, activation, of, the, immunomodulatory, properties, of, mesenchymal, stem, cells, '(', 'MSCs),', this, study, aimed, to, investigate, the, influence, of, 'IL-12', on, these, properties, in, human, periodontal, ligament, '(', 'hPDL)', cells])].
[sujeto(['Moreover,', 'IL-12']), verbo([induced]), complemento([the, expression, of, the, immunomodulatory, proteins, 'IDO', and, 'HLA-G', via, an, 'IFN-γ-dependent', 'pathway,', as, indicated, by, experiments, using, an, 'IFN-γ', neutralizing, antibody])].
[sujeto(['Finally,', 'IL-12']), verbo([inhibited]), complemento([osteogenic, differentiation, of, the, hPDL, cells, and, preserved, the, 'self-clonal', expansion, property, of, these, 'cells,', as, assessed, by, 'Alizarin', 'Red', 'S', staining, and, the, 'colony-forming', unit, assay])].
[sujeto(['MR', hypointensities]), verbo([caused]), complemento([by, 'MPIOs', were, observed, on, 'T2(⁎)-weighted', images, at, all, time, points, after, 'MSCs', injection])].
[sujeto(['Real-time', 'PCR', for, rat, 'SRY', gene, showed, the, number, of, survival, 'MSCs', considerably]), verbo([decreased]), complemento([after, transplantation])].
[sujeto(['MSC-treated', hearts, had, significantly]), verbo([increased]), complemento([capillary, density, in, 'peri-infarct', region, and, lower, cardiomyocytes, apoptosis, and, fibrosis, formation])].
[sujeto(['The', internal, gonad, sexing, method, was]), verbo([found]), complemento([to, be, highly, 'accurate,', while, the, peritoneal, pigmentation, method, was, slightly, less, accurate])].
[sujeto(['In', 'Algeria,', the, data, on, infertility, and, its, various]), verbo([causes]), complemento([are, rare])].
[sujeto(['Recently,', the, introduction, of, assisted, reproduction]), verbo([has]), complemento([allowed, expecting, that, 300000, 'couples,', which, represent, 7, '%', of, couples, of, reproductive, 'age,', face, difficulty, conceiving, a, child])].
[sujeto(['Follicle']), verbo([stimulating]), complemento([hormone, '(', 'FSH)', and, luteinizing, hormone, '(', 'LH)', levels, were, evaluated, by, immunoradiometric, method])].
[sujeto(['Fetuses', with, lissencephaly]), verbo([have]), complemento([an, abnormal, smooth, brain, with, fewer, folds, and, grooves, which, will, be, detected, by, ultrasounds, or, fetal, magnetic, resonance, imaging, '(', 'MRI)', after, 30, weeks, of, gestation])].
[sujeto(['We']), verbo([report]), complemento([a, fetus, with, lissencephaly, diagnosed, as, 'Miller-Dieker', syndrome, postnatally])].
[sujeto(['However,', only, a, few, genetic, studies]), verbo([have]), complemento([explored, the, macaques, in, this, region])].
[sujeto([fascicularis, into, five, subclades, '(', 'Insular', 'Indonesia,', 'Sundaic', 'Thai', 'Gulf,', 'Vietnam,', 'Sundaic', 'Andaman']), verbo([sea]), complemento(['coast,', and, 'Indochina)', and, revealed, genetic, differentiation, between, the, two, sides, of, the, 'Thai', 'peninsula,', which, had, previously, been, reported, as, a, single, group, of, 'Malay', peninsular, macaques])].
[sujeto(['From', the, estimated, divergence, time, of, the, 'Sundaic', 'Andaman']), verbo([sea]), complemento([coast, 'subclade,', it, is, proposed, that, after, 'M'])].
[sujeto(['Then,', some, of, them, migrated, north, and, south, to, colonize, the, 'Thai', 'Andaman']), verbo([sea]), complemento([coast, and, northern, 'Sumatra,', respectively])].
[sujeto(['The', 'SRY-TSPY', phylogenetic, analysis]), verbo([suggested]), complemento([that, 'male-mediated', gene, flow, from, 'M'])].
[sujeto(['The', aim, of, the, present, study, was, to, prove, that, primary, cells, enriched, with, stem, cells, are, more, easily, reprogrammed, to, generate]), verbo([induced]), complemento([pluripotent, stem, '(', 'iPS)', cells, than, those, with, scarce, numbers, of, stem, cells])].
[sujeto(['The', number, of, cells, with, the, stemness, property, of, 'HDDPC', differs, among, 'individuals,', which]), verbo([suggests]), complemento([that, 'HDDPC', showing, an, increased, expression, of, both, 'ALP', and, 'OCT-3/4', can, be, more, easily, reprogrammed, to, generate, iPS, cells, after, the, forced, expression, of, reprogramming, factors])].
[sujeto(['Histone', acetylation]), verbo([regulated]), complemento([by, class, 'I', histone, deacetylases, '(', 'HDACs)', plays, a, pivotal, role, in, 'matrix-specific', gene, transcription, and, cartilage, development])].
[sujeto(['While', we, previously, demonstrated, that, microRNA, '(', 'miR)-455-3p', is, upregulated, during, chondrogenesis, and, can]), verbo([enhance]), complemento([early, 'chondrogenesis,', the, mechanism, underlying, this, process, remains, largely, unclear])].
[sujeto(['We', observed, that, 'miR-455-3p', was, highly]), verbo([expressed]), complemento([in, proliferating, and, 'pre-hypertrophic', 'chondrocytes,', while, 'HDAC2', and, 'HDAC8', were, primarily, expressed, in, hypertrophic, chondrocytes])].
[sujeto(['Meanwhile,', 'miR-455-3p']), verbo([suppressed]), complemento([the, activity, of, reporter, constructs, containing, the, 3, '\'', -, untranslated, regions, of, 'HDAC2/8,', inhibited, 'HDAC2/8', expression, and, promoted, histone, 'H3', acetylation, at, the, collagen, 2, '(', 'COL2A1)', promoter, in, human, 'SW1353', 'chondrocyte-like', cells])].
[sujeto(['Treatment', with, the, 'HDAC', inhibitor, trichostatin, 'A', '(', 'TSA)', resulted, in]), verbo([increased]), complemento([expression, of, 'cartilage-specific', genes, and, promoted, glycosaminoglycan, deposition])].
[sujeto(['Moreover,', 'TSA']), verbo([inhibited]), complemento([matrix, metalloproteinase, 13, '(', 'Mmp13)', expression, and, promoted, nuclear, translocation, of, 'SOX9', in, 'interleukin-1-treated', primary, mouse, chondrocytes])].
[sujeto(['Lastly,', knockdown, of, 'HDAC2/3/8']), verbo([increased]), complemento(['SRY', '(', 'sex-determining', region, 'Y)-box', 9, '(', 'SOX9)', and, decreased, 'Runt-related', transcription, factor, 2, '(', 'RUNX2)', expression])].
[sujeto(['Taken', 'together,', these, findings]), verbo([suggest]), complemento([that, 'miR-455-3p', plays, a, critical, role, during, chondrogenesis, by, directly, targeting, 'HDAC2/8', and, promoting, histone, 'H3', 'acetylation,', which, raises, possibilities, of, using, 'miR-455-3p', to, influence, chondrogenesis, and, cartilage, degeneration])].
[sujeto(['To', investigate, whether, high, 'glucose-induced', oxidative, stress, is, implicated, in, apoptosis, of, rat, nucleus, pulposus, cells, '(', 'NPCs)', and, abnormal, expression, of, critical, genes]), verbo([involved]), complemento([in, the, metabolic, balance, of, extracellular, matrix, '(', 'ECM)'])].
[sujeto(['High', glucose, reduced, viability, of, 'NPCs', and]), verbo([induced]), complemento([apoptosis])].
[sujeto(['High', glucose, resulted, in]), verbo([increased]), complemento(['ROS', generation, and, p38, 'MAPK', activation])].
[sujeto(['In', 'addition,', it, negatively]), verbo([regulated]), complemento([the, expression, of, type, 'II', 'collagen,', 'aggrecan,', 'Sox-9,', and, 'TIMP-1', and, positively, regulated, 'MMP-3', expression])].
[sujeto(['High', glucose, might]), verbo([promote]), complemento([apoptosis, of, 'NPCs,', trigger, 'ECM', catabolic, 'pathways,', and, inhibit, its, anabolic, 'activities,', possibly, through, a, p38, 'MAPK-dependent', oxidative, stress, mechanism])].
[sujeto(['In', this, 'study,', we, identified, the, transcriptional, factor, 'ZNF606', as, an]), verbo([interacting]), complemento([partner, for, 'Sox9', in, cells])].
[sujeto(['We', further, demonstrated, that, overexpression, of, 'ZNF606']), verbo([inhibited]), complemento([the, transcriptional, activity, of, 'Sox9,', while, knockdown, of, 'ZNF606', increased, 'Sox9-mediated', transcription])].
[sujeto(['Chromatin', immunoprecipitation, analysis, revealed, that, 'ZNF606']), verbo([prevents]), complemento(['Sox9', binding, to, the, enhancers, of, its, target, gene, col2a1])].
[sujeto(['Importantly,', the, interaction, between, 'ZNF606', and, 'Sox9', was]), verbo([decreased]), complemento([during, chondrocyte, differentiation])].
[sujeto(['Consistent', with, these, 'findings,', 'ZNF606']), verbo([inhibited]), complemento([chondrocyte, differentiation])].
[sujeto(['Thus,', our, results, demonstrate, that, 'ZNF606']), verbo([acts]), complemento([as, a, novel, 'Sox9', 'co-regulator', that, inhibits, 'Sox9-mediated', chondrocyte, differentiation])].
[sujeto(['To', establish, a, rabbit, model, for, investigating, the, effects, of, intermittent, cyclic, mechanical, tension, '(', 'ICMT)', on]), verbo([promoting]), complemento([degeneration, of, endplate, cartilage])].
[sujeto(['Multiple', strategies, were, employed, to, examine, degeneration, of, endplate, cartilage, and]), verbo([nuclear]), complemento([factor, '(', 'NF)-κB', signaling, pathway, activation])].
[sujeto(['Examination', of, hematoxylin, and, eosin, staining, of, sections, of, endplate, cartilage, showed, significant, damage, as, the, load, duration]), verbo([increased]), complemento([in, the, 'ICMT', loading, group])].
[sujeto(['Additionally,', 'ICMT', loading, can]), verbo([lead]), complemento([to, 'NF-κB', signaling, pathway, activation, as, well, as, degeneration, of, endplate, cartilage])].
[sujeto(['These', experiments, indicate, that, 'ICMT', contributes, to, the, activation, of, 'NF-κB', signaling, pathway, in, vivo, and, that, the, 'NF-κB', signaling, pathway, further, 'up-regulates', 'MMP13,']), verbo([leading]), complemento([to, degeneration, of, endplate, cartilage])].
[sujeto(['Although', oxidative, stress, is, implicated, in, 'SeMet', 'toxicity,', knowledge, gaps, remain, in, how, 'SeMet']), verbo([causes]), complemento([characteristic, spinal, deformities])].
[sujeto(['Gene', expression, studies, for, the, 'UPR']), verbo([suggest]), complemento([a, potential, role, for, 'CHOP', '(', 'c/ebp', homologous, 'protein)', induced, apoptosis, deformed, embryos, after, 5, μM, 'SeMet,', accompanied, by, a, significant, decrease, in, 'PDIA4', '(', protein, disulfide, isomerase, 'A4)', and, no, change, in, 'Dnajb9', '(', 'ER', 'DNA', 'J', 'Domain-Containing', 'Protein', 4, ')'])].
[sujeto(['This', expression, was, distinct, from, the, 'UPR']), verbo([induced]), complemento([by, 'well-studied', 'ER', stress, 'inducer,', 'tunicamycin,', which, robustly, activated, 'CHOP,', 'PDIA4', and, 'Dnajb9'])].
[sujeto(['Finally,', 'SeMet', treatment, significantly]), verbo([decreased]), complemento([transcripts, of, cartilage, 'development,', 'Sox9', '(', 'SRY', box, 9, ')', ',', while, increasing, 'Runx2', in, deformed, 'embryos,', without, altering, 'Twist', or, 'Collagen', 2, a1])].
[sujeto(['Results']), verbo([suggest]), complemento([that, oxidative, 'stress,', the, 'UPR', and, cell, death, play, key, roles, in, 'SeMet', induced, deformities, and, altered, skeletal, development, factors])].
[sujeto(['The', 'sex-determining', gene, 'SRY']), verbo([induces]), complemento(['SOX9', expression, in, the, testes, of, eutherian, mammals, via, two, pathways])].
[sujeto(['SRY']), verbo([binds]), complemento([to, 'testis-specific', enhancer, of, 'Sox9', '(', 'TESCO)', with, 'SF1', to, activate, 'SOX9', transcription])].
[sujeto(['SRY', also, 'up-regulates', 'ER71', 'expression,', and, 'ER71']), verbo([activates]), complemento(['Sox9', transcription])].
[sujeto(['After', the, initiation, of, testis, 'differentiation,', 'SOX9']), verbo([enhances]), complemento(['Amh', expression, by, binding, to, its, promoter, with, 'SF1'])].
[sujeto(['SOX8,', 'SOX9', and, 'SOX10,', members, of, the, 'SOXE', gene, 'family,', also]), verbo([enhance]), complemento([the, activities, of, the, 'Amh', promoter, and, 'TESCO'])].
[sujeto(['The', activity, of, the, 'AMH', promoter, was]), verbo([stimulated]), complemento([by, 'SOXE', genes, and, 'SF1'])].
[sujeto(['Mutant', 'AMH', 'promoters,', with, mutations, in, its, 'SOX', and, 'SF1']), verbo([binding]), complemento(['sites,', did, not, show, significant, activity, by, 'SOX9', and, 'SF1'])].
[sujeto(['These', results, indicate, that, 'AMH', expression, was]), verbo([regulated]), complemento([by, the, binding, of, 'SOX9', and, 'SF1'])].
[sujeto(['By', 'contrast,', 'SOXE', genes, could, not]), verbo([enhance]), complemento(['TESCO', activity])].
[sujeto(['Furthermore,', the, activity, of, the, 'SOX9', promoter, was]), verbo([enhanced]), complemento([by, 'ER71,', indicating, that, 'ER71', may, play, an, important, role, in, the, 'testis-specific', expression, of, 'SOX9'])].
[sujeto(['In', a, 46, ',', 'XY', 'individual,', the, presence, of, the, 'Y', chromosome, harboring, the, 'testis-determining', factor, '(', 'SRY)']), verbo([triggers]), complemento([testis, determination, and, differentiation])].
[sujeto(['In', a, 46, ',', 'XX', 'individual,', the, absence, of, 'SRY', along, with, the, activation, of, genes]), verbo([associated]), complemento([with, the, female, pathway, leads, to, ovarian, development])].
[sujeto(['The', latter, process]), verbo([has]), complemento([long, been, considered, as, a, default, pathway])].
[sujeto(['However,', recent, studies]), verbo([have]), complemento([cast, doubts, on, this, dogma])].
[sujeto(['Especial', attention, is, paid, to, 'FOXL2', whose, mutations, are, responsible, for, the, blepharophimosis, 'syndrome,', often]), verbo([associated]), complemento([with, female, 'infertility,', and, for, cancer])].
[sujeto(['We', highlight, the, cooperation, of, 'WNT4,', 'RSPO1', and, 'FOXL2', within, a, regulatory, network, and, the, need, for, further, research, to, better, understand, their, role, in, defining, and]), verbo([maintaining]), complemento([ovarian, identity])].
[sujeto(['Here,', we]), verbo([report]), complemento([a, rare, congenital, chromosomal, 'aberration,', 46, ',', 'X,dic(X;Y)(p22'])].
[sujeto(['A', cytogenetic, examination, of]), verbo([stimulated]), complemento([peripheral, blood, cells, revealed, the, constitutional, karyotype, 46, ',', 'X,dic(X;Y)(p22'])].
[sujeto(['A', 'CGH/SNP', array, '(', 'Illumina)', revealed, a]), verbo([gain]), complemento([of, 153, ',', 7, 'Mbp', of, the, 'X', chromosome, and, a, 803, -, kbp, microdeletion, '(', including, the, 'SHOX', 'gene),', which, were, also, confirmed, with, 'FISH'])].
[sujeto(['SHOX', encodes, a, transcriptional, factor, that]), verbo([regulates]), complemento([the, growth, of, the, long, bones])].
[sujeto(['The', deletion, of, the, 'SHOX', gene, together, with, the, 'Madelung', deformity, of, the, forearm, and, the, short, stature, of, the, proband]), verbo([led]), complemento([to, a, diagnosis, of, 'Léri-Weill', dyschondrosteosis, '(', 'LWD)'])].
[sujeto(['The']), verbo([gain]), complemento([of, almost, the, whole, 'X', chromosome, '(', 153, ',', 7, 'Mbp)', was, considered, a, variant, of, 'Klinefelter', syndrome, '(', 'KS)'])].
[sujeto(['We']), verbo([have]), complemento([reported, a, structural, aberration, of, the, sex, 'chromosomes,', 'dic(X;Y)(p22'])].
[sujeto(['The', related, genomic, imbalance, is]), verbo([associated]), complemento([with, two, known, hereditary, 'syndromes,', 'LWD', and, a, 'KS', 'variant,', identified, in, our, proband, at, an, advanced, age])].
[sujeto(['Because', the, breakpoints, did, not]), verbo([involve]), complemento([cancer, 'genes,', we, inferred, that, the, two, malignancies, in, the, proband, were, not, caused, by, this, abnormality])].
[sujeto(['The', addition, of, fibrin, protein, was, typically]), verbo([required]), complemento([to, achieve, a, similar, effect, on, 'M-ECM-adherent', monolayered, fibroblasts])].
[sujeto(['The', spheroid, fusion, process, was, followed, by, an]), verbo([increase]), complemento([in, cell, density, and, the, formation, of, tight, clusters])].
[sujeto(['The', fused, spheroids, continued, to]), verbo([maintain]), complemento([their, intracellular, 'ECM', turnover, and, proliferation, capacities])].
[sujeto(['A', model, is]), verbo([provided]), complemento([by, testis, determination, in, therian, mammals])].
[sujeto(['Mutations', in, human, 'SRY']), verbo([cause]), complemento([gonadal, dysgenesis, leading, to, 'XY', female, development, '(', 'Swyer', 'syndrome)'])].
[sujeto(['Here,', we]), verbo([have]), complemento([characterized, an, inherited, mutation, compatible, with, either, male, or, female, somatic, phenotypes, as, respectively, observed, in, an, 'XY', father, and, 'XY', daughter])].
[sujeto(['The', mutation, '(', a, 'crevice-forming', substitution, at, a]), verbo([conserved]), complemento([back, surface, of, the, 'SRY', 'high-mobility-group', 'box)', markedly, destabilizes, the, domain, but, preserves, specific, 'DNA', affinity, and, induced, 'DNA', bend, angle])].
[sujeto(['On', transient, transfection, of, diverse, human, and, rodent, cell, 'lines,', the, variant, 'SRY', exhibited, accelerated, proteasomal, degradation, '(', relative, to, 'wild-type)']), verbo([associated]), complemento([with, increased, 'ubiquitination;', in, vitro, susceptibility, to, 'ubiquitin-independent', '(', '″default″)', cleavage, by, the, 20, 'S', core, proteasome, was, unchanged])].
[sujeto(['Our', findings, define, a, novel, mechanism, of, impaired, 'organogenesis:', accelerated, 'ubiquitin-directed', proteasomal, degradation, of, a, master, transcription, factor]), verbo([leading]), complemento([to, a, developmental, decision, poised, at, the, edge, of, ambiguity])].
[sujeto(['In', this, commentary, we, briefly, summarize, early, work, on, circular, 'RNAs', derived, from, spliceosome]), verbo([mediated]), complemento([circularization])].
[sujeto(['We', highlight, how, this, early, work, inspired, work, on, the, basic, mechanisms, of]), verbo([nuclear]), complemento(['RNA', 'splicing,', the, possible, function, of, circular, 'RNAs', and, the, potential, uses, of, circular, 'RNAs', as, tools, in, biomedicine])].
[sujeto(['Recent', developments, in, the, study, of, circular, 'RNAs,', summarized, in, this, 'volume,']), verbo([have]), complemento([brought, these, questions, back, to, the, foreground])].
[sujeto(['The', 'SRY', gene, '(', 'SRY)']), verbo([provides]), complemento([instructions, for, making, a, transcription, factor, called, the, 'sex-determining', region, 'Y', protein])].
[sujeto(['The', 'sex-determining', region, 'Y', protein]), verbo([causes]), complemento([a, fetus, to, develop, as, a, male])].
[sujeto(['The', multiple, sequence, alignment, results, indicated, that, 'SRY', protein, sequences, from, 'Orcinus', orca, '(', killer, 'whale)', and, 'Tursiopsaduncus', '(', 'dolphin)']), verbo([have]), complemento([least, genetic, distance, of, 0.33, in, these, 15, species, and, are, 99.67, '%', identical, at, the, amino, acid, level])].
[sujeto(['Homosapiens', and, 'Pantroglodytes', '(', 'chimpanzee)']), verbo([have]), complemento([the, next, lowest, genetic, distance, of, 1.35, and, are, 98.65, '%', identical, at, the, amino, acid, level])].
[sujeto(['These', findings, indicate, that, the, 'SRY', proteins, are]), verbo([conserved]), complemento([in, the, 15, 'species,', and, their, evolutionary, relationships, are, similar])].
[sujeto(['No', mutation, was]), verbo([found]), complemento([in, the, 'SRY', gene])].
[sujeto(['The', karyotype, of, patients, carrying, 'idic(Y)(p)', seems, 'unstable,', and, female, patients]), verbo([have]), complemento([the, characteristics, of, short, stature, and, secondary, sexual, hypoplasia])].
[sujeto(['Here,', we, replaced, 'Sry', by, transgenic, activation, of, its, downstream]), verbo([target]), complemento(['Sox9,', and, 'Eif2s3y,', by, transgenic, overexpression, of, its, 'X', 'chromosome-encoded', homolog, 'Eif2s3x'])].
[sujeto(['During', its, final, 'phase,', 'spermiogenesis,', haploid, round, spermatids, undergo, cellular, differentiation, into, 'spermatozoa,', which]), verbo([involves]), complemento([extensive, restructuring, of, cell, 'morphology,', 'DNA,', and, epigenome])].
[sujeto(['Compared', with, the, 'Control', 'group,', 'CD47', +, 'MSC', +, 'BiAb', +, 'MB,', 'CD47', +, 'MSC', +, 'BiAb,', 'CD47', +, 'MSC', and, 'MSC', groups, had]), verbo([decreased]), complemento([levels, of, 'MMP-9,', 'TIMP-1,', 'STAT', 1, and, collagen, 'deposition,', and, increased, levels, of, 'STAT', 3])].
[sujeto(['Up']), verbo([regulated]), complemento(['STAT', 3, and, down, regulated, 'TIMP-1', were, significantly, different, in, 'CD47', +, 'MSC', +, 'BiAb', +, 'MB', compared, with, 'CD47', +, 'MSC', or, 'CD47', +, 'MSC', +, 'BiAb'])].
[sujeto(['CD47', can]), verbo([enhance]), complemento([the, homing, rate, and, repairing, efficacy, of, 'MSC'])].
[sujeto(['An', analytical, evaluation, using, blood, samples, from, patients, with, leukemia, showed, that, the, while, blood, cell, '(', 'WBC)', depletion, and, 'NRBC']), verbo([loss]), complemento([rates, of, the, positive, enrichment, process, were, 93.98, &, 'nbsp;%', and, 6.02, &, 'nbsp;%,', respectively])].
[sujeto(['Gonadoblastoma', '(', 'GB),', a, rare, in, situ, germ, cell, tumor, derived, from, sex, cord, and, germ, 'cells,', is, closely]), verbo([associated]), complemento([with, gonadal, dysgenesis])].
[sujeto(['Increasing', studies, show, that, the, formation, of, 'GB', is, closely, related, to, genes]), verbo([regulating]), complemento([sexual, differentiation, and, determination, '(', e])].
[sujeto(['Here', we, describe, the, clinical, and, pathological, 'features,', diagnosis, and, treatment, of, 'GB,', and, also, summarize, the, molecular, genetic, and, epigenetic, mechanisms, underlying, the, gonadal, abnormalities, that]), verbo([lead]), complemento([to, 'GB'])].
[sujeto(['We', analyze, and, construct, the, common, gene, regulatory, networks, related, to, the, development, of, 'GB,', and, describe, some, obstacles, and, deficiencies, in, current, studies, to]), verbo([provide]), complemento([innovative, perspectives, on, further, studying, the, pathological, and, molecular, mechanisms, of, 'GB'])].
[sujeto(['Sex', determination, in, mammals]), verbo([requires]), complemento([expression, of, the, 'Y-linked', gene, 'Sry', in, the, bipotential, genital, ridges, of, the, 'XY', embryo])].
[sujeto(['Here,', we, analysed, 'Sry', flanking, sequences, across, many, 'species,', using, newly, available, genome, sequences, and, computational, 'tools,', to, better, understand, 'Sry\'s', genomic, context, and, to, identify]), verbo([conserved]), complemento([regions, predictive, of, functional, roles])].
[sujeto(['We', identified, 'position-specific', conservation, of]), verbo([binding]), complemento([motifs, for, multiple, transcription, factor, 'families,', including, 'GATA', binding, factors, and, 'Oct/Sox', dimers])].
[sujeto(['In', contrast, with, the, landscape, of, extremely, low, sequence, conservation, around, the, 'Sry', coding, 'region,', our, analysis, highlighted, a, strongly]), verbo([conserved]), complemento([interval, of, '~106&nbsp;bp', within, the, 'Sry', promoter, '(', which, we, term, the, 'Sry', 'Proximal', 'Conserved', 'Interval,', 'SPCI)'])].
[sujeto(['We', further]), verbo([report]), complemento([that, inverted, repeats, flanking, murine, 'Sry', are, much, larger, than, previously, recognised])].
[sujeto(['The', unusually, fast, pace, of, sequence, drift, on, the, 'Y', chromosome, sharpens, the, likely, functional, significance, of, both, the, 'SPCI', and, the, identified]), verbo([binding]), complemento(['motifs,', providing, a, basis, for, future, studies, of, the, 'role(s)', of, these, elements, in, 'Sry', regulation])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([in, the, scientific, literature, of, an, 'SRY-positive', hermaphrodite, 'Holstein', cattle, with, continuous, ovarian, cycles])].
[sujeto(['In', mouse, 'XY', 'gonads,', 'SRY']), verbo([induces]), complemento(['SOX9', upregulation, and, subsequent, 'FGF9', expression, by, embryonic, day, 11.5, '(', 'E11'])].
[sujeto([5, ')', ',']), verbo([leading]), complemento([to, the, differentiation, of, 'Sertoli', cells])].
[sujeto(['These', 2, ovarian, 'factors,', together, with, retinoic, acid, '(', 'RA)', 'action,']), verbo([promote]), complemento([feminization, partially, through, the, repression, of, the, masculinizing, activities, of, 'SOX9,', 'FGF9', and, 'DMRT1'])].
[sujeto(['At', 'birth,', the, oocyte, nests, break, down, into, single, oocytes, surrounded, by, granulosa, 'cells,']), verbo([leading]), complemento([to, the, assembly, of, primordial, follicles])].
[sujeto(['Animal', researches, and, clinical, studies]), verbo([have]), complemento([supported, the, relevance, between, phthalates, exposure, and, testicular, dysgenesis, syndrome, '(', 'TDS)'])].
[sujeto(['DEHP', exposure, resulted, in, significant, reduction, in, mRNA, of, 'Sry', during, sex, determination, from, gestation, day, '(', 'GD)', 11.0, to, 11.5, in, male, fetal, 'mice,', and, the]), verbo([increasing]), complemento([of, 'Sry', expression, to, threshold, level, on, 'GD', 11.5, was, delayed])].
[sujeto(['Taken', 'together,', the, results]), verbo([suggest]), complemento([that, the, potential, mechanism, of, gonadal, development, disorder, by, 'DEHP', may, origin, from, repression, of, important, male, sex, determination, signaling, 'pathway,', involving, 'Gadd45g', '→', 'Gata4', '→', 'Sry', '→', 'Sox9'])].
[sujeto(['The', results, would]), verbo([promote]), complemento([a, better, understanding, of, the, association, between, phthalate, esters, '(', 'PAEs)', exposure, and, the, reductive, disorder])].
[sujeto(['The', 'SOX9', gene]), verbo([has]), complemento([been, identified, as, a, major, factor, in, testis, development, in, mammals, after, it, is, activated, by, the, 'SRY', gene])].
[sujeto(['However,', duplication, of, the, gene, itself, in, some, mammalian, 'species,', or, of, a, 'well-delimited', upstream, '\'', 'RevSex\'', region, in, 'humans,']), verbo([has]), complemento([been, shown, to, result, in, testis, development, in, the, absence, of, the, 'SRY', gene])].
[sujeto(['Contrary', to, what, is, observed, in, the, current, dog, genome, 'assembly,', we]), verbo([found]), complemento([that, the, genomic, organization, is, quite, similar, to, that, reported, in, humans, and, other, mammalian, 'species,', including, the, position, of, the, 'RevSex', region, in, respect, to, 'SOX9'])].
[sujeto(['The', analysis, of, the]), verbo([conserved]), complemento([sequences, within, this, region, in, 7, mammalian, species, facilitated, the, highlighting, of, a, consensus, sequence, for, 'SRY', binding])].
[sujeto(['This', new, information, could, help, in, the, identification, of, evolutionarily]), verbo([conserved]), complemento([elements, relevant, for, 'SOX9', gene, 'regulation,', and, could, provide, valid, targets, for, mutation, analysis, in, 'XY', 'DSD', patients])].
[sujeto(['Diagnosis', of, fetal, gender, early, in, pregnancy, is, very, useful, as, it, would]), verbo([prevent]), complemento([invasive, fetal, sampling, in, almost, half, the, cases, at, risk, of, inheriting, 'X-linked', disorders, or, those, affecting, sexual, differentiation])].
[sujeto(['Noninvasive', prenatal, diagnosis, '(', 'NIPD)', using, circulating, 'cell-free', fetal, '(', 'cff)', 'DNA', from, maternal, circulation]), verbo([has]), complemento([emerged, as, a, useful, alternative, to, existing, methods, for, prenatal, diagnosis, of, gender])].
[sujeto(['Sex-reversal', cases, in, humans, and, genetic, models, in, mice]), verbo([have]), complemento([revealed, that, the, fate, of, the, bipotential, gonad, hinges, upon, the, balance, between, 'pro-testis', 'SOX9', and, 'pro-ovary', 'beta-catenin', pathways])].
[sujeto(['In', the, absence, of, 'Sox9', and, 'beta-catenin,', both, 'XX', and, 'XY', gonads, progressively, lean, toward, the, testis, 'fate,', indicating, that, expression, of, certain, 'pro-testis', genes]), verbo([requires]), complemento([the, repression, of, the, 'beta-catenin', 'pathway,', rather, than, a, direct, activation, by, 'SOX9'])].
[sujeto(['XY)', affects, this, 'process,', we, compared, the, transcriptomes, of, 'Sox9/beta-catenin', mutant, gonads, and]), verbo([found]), complemento([that, early, molecular, changes, underlying, the, 'XY-specific', masculinization, involve, the, expression, of, 'Sry', and, 21, 'SRY', direct, target, 'genes,', such, as, 'Sox8', and, 'Cyp26b1'])].
[sujeto(['These', results, imply, that, when, both, 'Sox9', and, 'beta-catenin', are, 'absent,', 'Sry', is, capable, of]), verbo([activating]), complemento([other, 'pro-testis', genes, and, drive, testis, differentiation])].
[sujeto(['Our', findings, not, only]), verbo([provide]), complemento([insight, into, the, mechanism, of, sex, 'determination,', but, also, identify, candidate, genes, that, are, potentially, involved, in, disorders, of, sex, development])].
[sujeto(['This']), verbo([report]), complemento([describes, a, disorder, of, the, sexual, development, in, a, beagle, dog, resulting, in, an, intersex, condition])].
[sujeto(['Testosterone', levels, that, were, within, the, male, reference, ranges, before, surgery]), verbo([decreased]), complemento([to, basal, levels, postsurgically])].
[sujeto(['The', stem, cell, marker, 'OCT4', is, frequently]), verbo([expressed]), complemento([in, 'HCCs,', and, its, expression, correlates, with, those, of, putative, cancer, stem, cell, '(', 'CSC)', markers, and, 'CSC', properties])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, 'Sry', is, involved, in, tumor, malignancy, in, rodent, 'HCCs'])].
[sujeto(['Ectopic', expression, of, 'SRY']), verbo([increased]), complemento([multiple, stem, cell, 'factors,', including, 'OCT4', and, 'CD13'])].
[sujeto(['The', 'OCT4', promoter, contained, 'SRY-binding', sites, that, were, directly]), verbo([activated]), complemento([by, 'SRY'])].
[sujeto(['In', 'HCC-derived', 'cells,', 'SRY', knockdown]), verbo([decreased]), complemento(['OCT4', expression, and, cancer, 'stem-like', phenotypes, such, as, 'self-renewal,', 'chemoresistance,', and, tumorigenicity])].
[sujeto(['Conversely,', 'OCT4', and, 'SRY', overexpression]), verbo([promoted]), complemento([cancer, 'stem-like', phenotypes])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'SRY', is, involved, in, the, maintenance, of, cancer, 'stem-like', characteristics, through, 'OCT4'])].
[sujeto(['Noteworthily,', 'SRY', was, highly]), verbo([expressed]), complemento([in, some, hHCC, patients])].
[sujeto(['Gender', role, and, gender, identity, are]), verbo([reported]), complemento([as, male])].
[sujeto(['SRY,', the, gene, that, encodes, the, 'sex-determining', region, 'Y', 'protein,', is, the, principal, gene, known, to, be]), verbo([associated]), complemento([with, 46, ',', 'XX', testicular, 'DSD'])].
[sujeto(['Rearrangements', in, or, around, 'SOX9', and, 'SOX3', detected, by, 'CMA,', or, rarely, 'karyotype,']), verbo([have]), complemento([recently, been, reported, in, a, few, 'cases;', at, least, one, more, 'as-yet-unknown', gene, at, another, locus, is, implicated])].
[sujeto(['Treatment', of, 'manifestations:', 'Similar', to, that, for, other]), verbo([causes]), complemento([of, testosterone, deficiency])].
[sujeto(['After', age, 14, 'years,', 'low-dose', testosterone, therapy, is, initiated, and, gradually]), verbo([increased]), complemento([to, reach, adult, levels])].
[sujeto(['Surveillance:', 'Monitor', for, testosterone, effects, during, testosterone, replacement, 'therapy,', including, prostate, size, and, 'prostate-specific', antigen, '(', 'PSA)', in, 'adults;', routine, monitoring, of, 'hematocrit,', lipid, 'profile,', and, liver, function, 'tests;', bone, mineral, density, determination, by, bone, densitometry, '(', 'DEXA)', 'annually,', if, osteopenia]), verbo([has]), complemento([been, diagnosed])].
[sujeto(['Autosomal', dominant, inheritance]), verbo([has]), complemento([been, documented, for, familial, cases, thought, to, be, caused, by, 'CNV', in, or, around, 'SOX9'])].
[sujeto(['The', mode, of, inheritance, of, other, 'SRY-negative', 46, ',', 'XX', testicular, 'DSD', is, not, 'known,', but, autosomal, recessive, inheritance]), verbo([has]), complemento([been, postulated])].
[sujeto(['The', 'RNA']), verbo([binding]), complemento([motif, protein, 38, '(', 'RBM38,', also, known, as, 'RNPC1)', plays, a, pivotal, role, in, regulating, a, wide, range, of, biological, 'processes,', from, cell, proliferation, and, cell, cycle, arrest, to, cell, myogenic, differentiation])].
[sujeto(['It', was, originally]), verbo([recognized]), complemento([as, an, 'oncogene,', and, was, frequently, found, to, be, amplified, in, 'prostate,', ovarian, and, colorectal, 'cancer,', chronic, lymphocytic, 'leukemia,', colon, 'carcinoma,', esophageal, 'cancer,', dog, lymphomas, and, breast, cancer])].
[sujeto(['In', the, present, 'study,', the, complete, 'RNPC1', gene, was, identified, in, a, number, of, vertebrate, 'genomes,']), verbo([suggesting]), complemento([that, 'RNPC1', exists, in, all, types, of, 'vertebrates,', including, 'fish,', 'amphibians,', birds, and, mammals])].
[sujeto(['A', total, of, 34, functionally, relevant, single, nucleotide, polymorphisms, '(', 'SNPs),', including, 14, 'SNPs']), verbo([causing]), complemento([missense, 'mutations,', 8, exonic, splicing, enhancer, 'SNPs', and, 12, 'SNPs', causing, nonsense, 'mutations,', were, identified, in, the, human, 'RNPC1', gene])].
[sujeto(['RNPC1', was]), verbo([found]), complemento([to, be, expressed, in, 'bladder,', 'blood,', 'brain,', 'breast,', 'colorectal,', 'eye,', head, and, 'neck,', 'lung,', 'ovarian,', skin, and, soft, tissue, cancer])].
[sujeto(['We']), verbo([found]), complemento([that, the, association, between, the, expression, of, 'RNPC1', and, prognosis, varied, in, different, types, of, 'cancer,', and, even, in, the, same, type, of, cancer, from, the, different, databases, used])].
[sujeto(['This']), verbo([suggests]), complemento([that, the, function, of, 'RNPC1', in, these, tumors, may, be, multidimensional])].
[sujeto(['The', sex, determining, region, 'Y', '(', 'SRY)-box', 5, '(', 'Sox5),', 'runt-related', transcription, factor, 3, '(', 'RUNX3),', 'CCAAT', displacement, protein, 1, '(', 'CUTL1),', 'v-rel', avian, reticuloendotheliosis, viral, oncogene, homolog, '(', 'Rel)A,', peroxisome, 'proliferator-activated', receptor, γ, isoform, 2, '(', 'PPARγ2)', and]), verbo([activating]), complemento([transcription, factor, 6, '(', 'ATF6)', regulatory, transcription, factor, binding, sites, were, identified, in, the, upstream, '(', 'promoter)', region, of, the, 'RNPC1', 'gene,', and, may, thus, be, involved, in, the, effects, of, 'RNPC1', in, tumors])].
[sujeto(['The', upstream, region, of, the, 'XFGF8', gene, contains, two, putative]), verbo([binding]), complemento([sites, for, the, 'SRY', '(', 'sex-determining', region, 'Y)-box', 2, '(', 'SOX2)', transcription, factor])].
[sujeto(['Furthermore,', 'Xenopus', 'SOX2', '(', 'XSOX2)', physically]), verbo([interacted]), complemento([with, the, 'SOX2-binding', motif, within, the, upstream, region, of, the, 'XFGF8', gene, in, vitro, and, in, vivo])].
[sujeto(['Depletion', of, endogenous, 'XSOX2', resulted, in]), verbo([loss]), complemento([of, 'XFGF8', gene, expression, in, 'midbrain-hindbrain', 'junction,', auditory, 'placode,', lens, placode, and, forebrain, in, developing, 'Xenopus', embryos])].
[sujeto(['Collectively,', our, results]), verbo([suggest]), complemento([that, 'XSOX2', directly, upregulates, 'XFGF8', gene, expression, in, the, early, embryonic, development, of, 'Xenopus'])].
[sujeto(['Nuclear', receptor, subfamily, 5, ',', group, 'A,', member, 1, '(', 'NR5A1', previously, known, as, 'SF-1/AD4BP)', is, a, transcription, factor]), verbo([involved]), complemento([in, the, development, of, 'adrenal/gonadal', tissues, and, steroidogenic, lineage, cell, differentiation, in, adult, somatic, stem, cells])].
[sujeto(['To', understand, the, cellular, signaling, network, that]), verbo([regulates]), complemento(['NR5A1', gene, 'expression,', loss, of, function, screening, with, an, siRNA, kinome, 'library,', and, gain, of, function, screening, with, an, addressable, 'full-length', cDNA, library, representing, one, quarter, of, the, human, genome, was, carried, out])].
[sujeto(['The', 'NR5A1', gene, expression, was]), verbo([activated]), complemento([in, mesenchymal, stem, cells, by, siRNA, directed, against, protein, kinase, 'C', '(', 'PKC)-delta,', 'erb-B3,', 'RhoGAP', '(', 'ARHGAP26),', and, hexokinase, 2, ',', none, of, which, were, previously, known, to, be, involved, in, the, 'NR5A1', gene, expression])].
[sujeto(['In', 'addition,', the]), verbo([gain]), complemento([of, function, studies, indicated, that, 'sex-determining', region, 'Y', '(', 'SRY)-box', 15, '(', 'SOX15),', 'TEA', domain, family, member, 4, ',', 'KIAA1257', '(', a, gene, of, unknown, 'function),', 'ADAM', metallopeptidase, with, thrombospondin, type, 1, motif, 6, ',', 'Josephin', domain, containing, 1, ',', centromere, 'protein,', 'TATA', 'box-binding', 'protein-associated', factor, 5, -, like, 'RNA', 'polymerase,', and, inducible, 'T-cell', 'co-stimulator', activate, 'NR5A1', gene, expression])].
[sujeto(['These', results]), verbo([provide]), complemento([new, insights, into, the, molecular, mechanisms, of, 'NR5A1', gene, expression])].
[sujeto(['Seven', different, sets, of, oligonucleotide, 'primers,', sex, determining, region, 'Y', '(', 'SRY),', zinc, finger, gene, on, the, 'Y', chromosome, '(', 'ZFY),', testis, specific, protein, 'Y', '(', 'TSPY),', 'DYZ3,', 'DYF49S1,', 'RNA']), verbo([binding]), complemento([motif, protein, '(', 'RBM),', and, 'DYZ1,', spanning, on, centromeres, and, short, and, long, arms, of, the, 'Y', chromosome, were, used, for, 'PCR'])].
[sujeto(['The', 'leucine-zipper', and, 'HMG-box', motif, were, almost, completely]), verbo([conserved]), complemento([between, these, homologues])].
[sujeto([rSox6, '(', rat, 'Sox6)', was, specifically]), verbo([expressed]), complemento([in, the, neonatal, brain, and, adult, testis, with, 'Northern', blotting])].
[sujeto(['The', rSox6, was]), verbo([expressed]), complemento([in, the, neonatal, brain, and, adult, testis, as, well, as, by, 'Northern', blotting, and, also, expressed, in, the, adult, eyeball, and, slightly, in, the, ovary])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([identified, a, new, human, 'SOX', 'gene,', 'SOX13,', as, encoding, the, type, 1, diabetes, 'autoantigen,', islet, cell, antigen, 12, '(', 'ICA12)'])].
[sujeto(['Deletion', mapping, of, the, antibody, epitopes, showed, that, the, autoantibodies, were, primarily, directed, against, an, epitope]), verbo([requiring]), complemento([the, majority, of, the, protein])].
[sujeto(['Recombinant', 'SOX13', protein]), verbo([bound]), complemento([to, the, 'SOX', consensus, 'DNA', motif, 'AACAAT,', and, binding, was, inhibited, by, homodimer, formation])].
[sujeto(['These', 'observations-along', with, the, known, molecular, interactions, of, the, closely, related, 'protein,', rainbow, trout, 'Sox23-suggest', that, 'SOX13', may, be]), verbo([activated]), complemento([for, nuclear, import, and, 'DNA', binding, through, heterodimer, formation])].
[sujeto(['In', 'conclusion,', we]), verbo([have]), complemento([identified, 'ICA12', as, the, putative, transcription, factor, 'SOX13', and, demonstrated, an, increased, frequency, of, autoantibody, reactivity, in, sera, from, type, 1, diabetic, subjects, compared, with, type, 2, diabetic, and, healthy, control, subjects])].
[sujeto(['Leydig', cells, and, 'Sertoli', cells, of, the, testes, produce, hormones, that]), verbo([cause]), complemento([male, 'differentiation,', if, receptors, are, present])].
[sujeto(['The', 'Y', chromosomal, 'SRY', gene, '(', sex, determining, 'Region', 'Y', 'gene)']), verbo([acts]), complemento([as, 'TDF', and, is, required, for, regular, male, sex, determination])].
[sujeto(['SRY', represents, a, transcription, factor, belonging, to, the, superfamily, of, genes, sharing, the, 'HMG-box', 'motif(high-mobility', 'group-box),', which]), verbo([acts]), complemento([as, 'DNA', binding, region])].
[sujeto(['The', glycine, at, codon, 95, is, highly]), verbo([conserved]), complemento([between, the, family, of, 'HMG-box', proteins, and, between, species])].
[sujeto(['This', point, mutation]), verbo([has]), complemento([not, been, described, earlier, and, brings, the, total, number, of, 'SRY', mutations, described, so, far, to, 36, ',', each, mutation, being, unique])].
[sujeto(['The', present, data]), verbo([provide]), complemento([further, evidence, to, support, the, functional, importance, of, the, putative, 'DNA', binding, activity, of, the, 'SRY', 'HMG-box', domain])].
[sujeto(['In', vertebrates, several, proteins, containing, a, covalently]), verbo([bound]), complemento([selenocysteine, residue, have, been, identified])].
[sujeto(['The', protein, was, traced, in, rat, 'plasma,', but, its, role]), verbo([has]), complemento([not, been, worked, out, so, far])].
[sujeto(['Selenoprotein', 'P', was, also]), verbo([found]), complemento([to, be, expressed, in, 'testis,', 'brain,', 'gut,', and, hematopoietic, cells])].
[sujeto(['One', 'TATA', motif, 38, bp, upstream, to, exon, 1]), verbo([suggests]), complemento([transcription, of, selp, by, 'RNA', polymerase, 'II'])].
[sujeto(['Within', the, 1116, bp, upstream, of, exon, 1, four, hepatic]), verbo([nuclear]), complemento([factor, 3, beta, '(', 'HNF3beta)', binding, motifs, were, 'found,', which, is, in, line, with, 'liver-specific', expression, of, selenoprotein, 'P'])].
[sujeto(['Two', 'BRN-2', motifs, suitable, for, the]), verbo([binding]), complemento([of, 'brain-specific', regulatory, factors, correlated, to, the, selenoprotein, 'P', expression, in, the, cerebellum])].
[sujeto(['Selenoprotein', 'P', was, also]), verbo([expressed]), complemento([in, 'Leydig', cells, which, could, be, regulated, by, binding, proteins, docking, to, the, 'SRY', motifs, present, in, the, promoter, region])].
[sujeto(['The', methodology]), verbo([involved]), complemento([a, combination, of, polymerase, chain, reaction, '(', 'PCR)', and, nested, 'PCR', followed, by, 'Southern', blot, analysis, of, three, genes, the, sex, determining, region, 'Y', '(', 'SRY),', testis, specific, protein, 'Y', encoded, '(', 'TSPY)', and, 'RNA', binding, motif, protein, '(', 'RBM)', '(', previously, designated, as, 'YRRM)', and, nine, additional, 'STSs', spanning, all, seven, intervals, of, the, 'Y', chromosome])].
[sujeto(['The', methodology]), verbo([has]), complemento([a, high, sensitivity, as, it, detects, one, 46, ',', 'XY', cell, among, 10, '(', 5, ')', 46, ',', 'XX', cells])].
[sujeto(['Reliability', was]), verbo([ensured]), complemento([by, taking, several, precautions, to, avoid, false, positive, results])].
[sujeto(['We']), verbo([report]), complemento([the, results, of, screening, 50, 'TS', patients, and, the, identification, of, cryptic, 'Y', chromosome, material, in, 12, '(', 24, '%', ')', of, them])].
[sujeto(['Karyotypes', were, divided, in, four, 'groups:', 5, '(', 23.8, '%', ')', patients, out, of, the, 21, 'TS', patients, which]), verbo([have]), complemento([the, 45, ',', 'X', karyotype, '(', group, 'A)', also, have, cryptic, 'Y', 'sequences;', none, '(', 0, '%', ')', of, the, 7, patients, who, have, karyotypes, with, anomalies, on, one, of, the, 'X', chromosomes, have, 'Y', mosaicism, '(', group, 'B);', 1, '(', 6.3, '%', ')', of, the, 16, patients, with, a, mosaic, karyotype, have, 'Y', material, '(', group, 'C);', and, 6, '(', 100, '%', ')', out, of, 6, patients, with, a, supernumerary, marker, chromosome, '(', 'SMC)', have, 'Y', chromosome, sequences, '(', group, 'D)'])].
[sujeto(['This', study, used, a, reliable, and, sensitive, methodology, to, identify, the, presence, of, 'Y', chromosome, material, in, 'TS', patients, thus]), verbo([providing]), complemento([not, only, a, better, estimate, of, a, 'patient\'s', risk, in, developing, either, gonadoblastoma, or, another, form, of, gonadal, tumor, but, also, the, overall, incidence, of, cryptic, 'Y', mosaicism])].
[sujeto(['Regrowing', neurites, grew, atop, this, 'layer,', forming, 'non-uniform', patterns, that, were, similar, to, those, formed, by, endogenously]), verbo([expressed]), complemento(['laminin-1,', entactin, and, integrin, 'beta4,', but, not, fibronectin, or, tenascin])].
[sujeto(['In', cultures, grown, for, 42, h, and]), verbo([maintained]), complemento([in, three, different, growth, 'media,', all, regrowing, neurites, were, preferentially, associated, with, 'spindle-shaped', nonneural, cells])].
[sujeto(['The', spontaneous, and, preferential, association, of, neurites, in, culture, with, mitotic, 'Schwann', cells, highlights, the, potential, contribution, 'neurite-Schwann', cell, interactions, may]), verbo([have]), complemento([in, promoting, the, growth, and, regrowth, of, damaged, spiral, ganglion, neurons, in, the, cochlea])].
[sujeto(['The', other, 'X', male, patient, had, not]), verbo([found]), complemento(['SRY', gene, in, its, 'whole-genome', 'DNA'])].
[sujeto(['At', the, same, 'time,', it]), verbo([suggested]), complemento([that, male, infertility, might, be, related, to, meiotic, disturbances, with, spermatogenetic, arrest, in, 'Y-autosome', 'translocations,', which, could, result, in, infertility, by, reduction, of, sperm, production])].
[sujeto(['Testicular', or, ovotesticular, disorder, of, sex, development, '(', 'DSD)', in, genetic, females, '(', 78, ',', 'XX;', 'SRY-negative)']), verbo([has]), complemento([been, reported, quite, frequently, in, numerous, dog, breeds, and, is, usually, diagnosed, due, to, the, presence, of, female, external, genitalia, with, an, enlarged, clitoris])].
[sujeto(['However,', it]), verbo([has]), complemento([recently, been, proposed, that, a, copy, number, variation, '(', 'CNV)', in, the, region, upstream, of, the, 'SOX9', gene, is, associated, with, it])].
[sujeto(['FISH', studies, showed, a, female, 'karyotype,', lack, of, a, translocation]), verbo([involving]), complemento([the, 'Y', 'chromosome,', and, a, distinct, size, variation, in, the, 'CNV', region, '(', 'CNVR)', upstream, of, the, 'SOX9', 'gene,', located, on, chromosome, 9, '(', 'CFA9)'])].
[sujeto(['Our', observations, are, in, agreement, with, earlier, suggestions, that, a, high, number, of, copies, at, the, 'CNVR', upstream, of, 'SOX9', may, be]), verbo([associated]), complemento([with, this, type, of, 'DSD'])].
[sujeto(['Somatic', mutations, in, isocitrate, dehydrogenase, '(', 'IDH)', genes]), verbo([have]), complemento([recently, been, identified, in, a, large, proportion, of, glial, tumors, of, the, 'CNS', and, reported, to, be, a, strong, prognostic, factor, in, gliomas, whatever, the, tumor, grade])].
[sujeto([p53, 'expression,', 1, p19q, deletion, and, 'IDH', mutation, status, were]), verbo([provided]), complemento([for, all, tumors])].
[sujeto(['Also', 'HIF', '(', hypoxia, inducible, 'factor)-1α,', 'HIF-2α,', 'HAF,', 'Sox2', '(', 'SRY(Sex', determining, region, 'Y)-box2)', and, 'OCT', '(', octamer]), verbo([binding]), complemento(['factor)', 3, /, 4, expressions, were, analyzed])].
[sujeto(['We']), verbo([found]), complemento([positive, 'HIF-2α', staining, in, 38.7, '%', of, cases, which, was, uncorrelated, to, 'HIF-1α', expression, or, 'IDH1/2', mutation, status])].
[sujeto(['However,', 'HIF-2α', staining, was, significantly]), verbo([associated]), complemento([with, 'HAF', 'expression,', a, 'stem-like', cell, 'marker,', in, the, whole, population])].
[sujeto(['Furthermore,', 'HAF', expression, was, significantly]), verbo([associated]), complemento([with, the, &, 'quot;triple', 'negative&quot;', glioma, phenotype])].
[sujeto(['We']), verbo([provide]), complemento([here, first, evidence, that, 'HAF,', a, 'stem-like', cell, 'marker,', expression, is, highly, correlated, to, the, triple, negative, aggressive, 'LGG/AG', molecular, phenotype, suggesting, that, these, tumours, might, arise, from, cells, of, different, origin])].
[sujeto(['Chromosomal', defects, are, relatively, frequent, in, infertile, men, 'however,', translocations, between, the, 'Y', chromosome, and, autosomes, are, rare, and, less, than, 40, cases, of, 'Y-autosome', translocation]), verbo([have]), complemento([been, reported])].
[sujeto(['In', 'particular,', only, three, individuals]), verbo([has]), complemento([been, described, with, a, 'Y;21', 'translocation,', up, to, now])].
[sujeto(['We']), verbo([report]), complemento([on, an, additional, case, of, an, infertile, man, in, whom, a, 'Y;21', translocation, was, associated, with, the, deletion, of, a, large, part, of, the, 'Y', chromosome, long, arm])].
[sujeto(['The', 'Y', chromosome, structural, rearrangement, resulted, in, the, intactness, of, the, entire, short, 'arm,', including, the, 'sex-determining', region, 'Y', '(', 'SRY)', and, the, short, stature, homeobox, '(', 'SHOX)', 'loci,', although, translocated, on, the, 21, 'chromosome,', and, the]), verbo([loss]), complemento([of, a, large, part, of, the, long, arm, of, the, 'Y', 'chromosome,', including, azoospermia, 'factor-a', '(', 'AZFa),', 'AZFb,', 'AZFc', and, 'Yq', heterochromatin, regions])].
[sujeto(['This', is, the, first, case, in, which, a, '(', 'Yp;21p)', translocation]), verbo([has]), complemento([been, ascertained, using, an, 'array-CGH', 'approach,', thus, reporting, details, of, such, a, rearrangement, at, higher, resolution])].
[sujeto(['Research', into, prenatal, programming, in, the, pig]), verbo([has]), complemento([shown, that, the, sex, of, the, developing, embryo, or, fetus, can, influence, the, developmental, outcome])].
[sujeto(['The', preparation, of, the, whole, embryo, for, this, 'PCR', based, sexing, technique, simply]), verbo([involves]), complemento([grinding, the, frozen, embryo, to, a, fine, powder, using, a, 'pre-chilled', mortar, and, pestle])].
[sujeto(['PCR-quality', 'DNA', is]), verbo([released]), complemento([from, a, small, amount, of, embryo, powder, by, applying, a, hot, incubation, in, an, alkaline, lysis, reagent])].
[sujeto(['Two']), verbo([primer]), complemento([pairs, are, generated, to, detect, specific, sex, determining, region, of, the, 'Y-', chromosome, '(', 'SRY)', and, 'ZFX', region, of, the, 'X-', chromosome, with, high, accuracy, and, specificity])].
[sujeto(['RNA', from, these, specimens, was, subjected, to, expression, profiling, with, 'RNA', 'sequencing,', and, results, were, analyzed, to, identify, transcripts, in, 'epithelial-dominant', 'ACC', '(', 'E-ACC),', 'myoepithelial-dominant', 'ACC', '(', 'M-ACC),', and, all, 'ACC', that, were]), verbo([expressed]), complemento([differentially, compared, with, the, transcripts, in, normal, salivary, tissue])].
[sujeto(['In', 'total,', the, authors, identified, 430, differentially]), verbo([expressed]), complemento([transcripts, that, were, unique, to, 'E-ACC,', 392, that, were, unique, to, 'M-ACC,', and, 424, that, were, common, to, both, 'M-ACC', and, 'E-ACC'])].
[sujeto(['Three', sets, of, highly]), verbo([expressed]), complemento([candidate, 'genes-distal-less', homeobox, 6, '(', 'DLX6)', for, 'E-ACC;', protein, keratin, 16, '(', 'KRT16),', 'SRY', box, 11, '(', 'SOX11),', and, 'v-myb', avian, myeloblastosis, viral, oncogene, homolog, '(', 'MYB)', for, 'M-ACC;', and, engrailed, 1, '(', 'EN1)', and, statherin, '(', 'STATH),', which, are, common, to, both, 'E-ACC', and, 'M-ACC)-were', further, validated, at, the, protein, level])].
[sujeto(['The', current, results, enabled, the, authors, to, identify, novel, potential, therapeutic]), verbo([targets]), complemento([and, biomarkers, in, 'E-ACC', and, 'M-ACC', 'individually,', with, the, implication, that, 'EN1,', 'DLX6,', and, 'OTX1', '(', orthodenticle, homeobox, 1, ')', are, potential, drivers, of, these, cancers])].
[sujeto(['The', 'male-specific', region, of, 'chromosome-Y', '(', 'MSY)', contributes, to, phenotypes, outside, of, testis, development, and]), verbo([has]), complemento([a, high, rate, of, evolution, between, mammalian, species])].
[sujeto(['With', a, lack, of, genomic, 'crossover,', 'MSY', is, one, of, the, few, genomic, areas, under, similar, variation, and, evolutionary, selection, in, inbred, and, outbred, animal, 'populations,', allowing, for, an, assessment, of, evolutionary, mechanisms, to]), verbo([translate]), complemento([between, the, populations])].
[sujeto(['We']), verbo([have]), complemento([shown, that, '(', 1, ')', 'MSY', of, rat, has, nine, autosomal, gene, transposition, events, with, 'strain-specific', 'selection;', '(', 2, ')', sequence, variants, in, 'MSY', occur, with, a, 1.98, -, fold, higher, number, of, variants, than, other, chromosomes, in, seven, sequenced, rat, 'strains;', '(', 3, ')', 'Sry,', the, most, studied, 'MSY', 'gene,', has, undergone, extensive, gene, 'duplications,', driving, ubiquitous, expression, not, seen, in, human, or, 'mouse;', '(', 4, ')', the, expression, profile, of, 'Sry', in, the, rat, is, driven, by, the, insertion, of, the, 'Sry2', copy, into, an, intron, of, the, ubiquitously, expressed, 'Kdm5d', gene, in, antisense, 'orientation,', but, due, to, several, loss, of, function, mutations, in, the, 'Sry2', 'protein,', nuclear, localization, and, transcriptional, control, are, 'decreased;', '(', 5, ')', expression, of, 'Sry', copies, other, than, 'Sry2', in, the, rat, overlaps, with, the, expression, profile, for, human, 'SRY;', '(', 6, ')', gene, duplications, and, sequence, variants, '(', 'P76T)', of, 'Sry', can, be, selected, for, phenotypes, such, as, high, blood, pressure, and, androgen, receptor, signaling, within, inbred, 'mating;', and, most, 'importantly,', '(', 7, ')', per, chromosome, 'size,', 'MSY', contributes, to, higher, 'strain-specific', phenotypic, variation, relative, to, all, other, 'chromosomes,', with, 53, phenotypes, showing, both, a, male, to, female, and, consomic, cross, significance])].
[sujeto(['The', swamp, type, of, the, 'Asian', water, buffalo, is, assumed, to]), verbo([have]), complemento([been, domesticated, by, about, 4000, years, 'BP,', following, the, introduction, of, rice, cultivation])].
[sujeto(['Swamp', buffalo]), verbo([has]), complemento([a, higher, diversity, of, both, maternal, and, paternal, lineages, than, river, 'buffalo,', with, also, a, remarkable, contrast, between, a, weak, phylogeographic, structure, of, river, buffalo, and, a, strong, geographic, differentiation, of, swamp, buffalo])].
[sujeto(['The', highest, diversity, of, the, swamp, buffalo, maternal, lineages, was]), verbo([found]), complemento([in, south, 'China', and, north, 'Indochina', on, both, banks, of, the, 'Mekong', 'River,', while, the, highest, diversity, in, paternal, lineages, was, in, the, 'China/Indochina', border, region])].
[sujeto(['Migration', to, the, north, followed, the, 'Yangtze', valley, as, well, as, a, more, eastern, 'route,', but, also]), verbo([involved]), complemento([translocations, of, both, cows, and, bulls, over, large, distances, with, a, minor, influence, of, river, buffaloes, in, recent, decades])].
[sujeto(['In', 'mice,', circulating, estradiol]), verbo([increases]), complemento(['Gh', mRNA, in, female, but, not, in, male, medial, preoptic, area, '(', 'mPOA);', 'therefore,', additional, factors, regulate, sexually, dimorphic, 'Gh', expression, in, the, brain])].
[sujeto(['Thus,', we, hypothesized, that, sex, chromosomes]), verbo([interact]), complemento([with, estradiol, to, promote, sex, differences, in, 'GH'])].
[sujeto(['The', 'FCG', model]), verbo([has]), complemento([a, deletion, of, the, 'sex-determining', region, on, the, 'Y', chromosome, '(', 'Sry)', and, transgenic, insertion, of, 'Sry', on, an, autosome])].
[sujeto(['Estradiol']), verbo([increased]), complemento(['Gh', mRNA, in, the, cerebellum, and, 'hippocampus,', regardless, of, sex, chromosome, complement, or, gonadal, sex])].
[sujeto(['Sex', chromosome, complement]), verbo([regulates]), complemento(['GH', in, some, but, not, all, brain, 'areas,', and, within, the, 'hypothalamus,', sex, chromosomes, have, 'cell-specific', actions, on, 'GH'])].
[sujeto(['Minor', histocompatibility, antigen, '(', 'miHA)', vaccines]), verbo([have]), complemento([the, potential, to, augment, 'graft-versus-tumor', effects, without, 'graft-versus-host', disease, '(', 'GVHD)'])].
[sujeto(['Priming', with, 'replication-deficient', human, adenovirus, type, 5, constructs, and, boosting, with, ex, vivo, 'plasmid-transfected', dendritic, cells, and, cutaneous, delivery, of, plasmids, with, a, 'particle-mediated', epidermal, delivery, device, '(', 'PMED)', in, 2, female, dogs]), verbo([induced]), complemento(['antigen-specific', 'T-cell', responses])].
[sujeto(['This', model]), verbo([provides]), complemento([a, platform, for, ongoing, experiments, designed, to, define, optimal, miHA, targets, and, develop, protocols, to, directly, vaccinate, the, recipient])].
[sujeto(['Indeed,', groups, of, large, rounded, cells, laying, on, smaller, and, more, compacted, ones]), verbo([expressing]), complemento(['osteocalcin,', vascular, endothelial, growth, factor, '(', 'VEGF)', and, nerve, growth, factor, '(', 'NGF)', were, identified, exclusively, in, fetal, 'mid-stage', 'tissues,', and, not, in, late, fetal, or, adult, tendons])].
[sujeto(['VEGF,', 'NGF', as, well, as, blood, vessels, and, nerve, fibers, showed]), verbo([decreased]), complemento([expression, during, tendon, development])].
[sujeto(['Moreover,', the, endotenon, of, 'mid-', and, late, fetuses, contained, identifiable, cells, that]), verbo([expressed]), complemento([several, pluripotent, stem, cell, markers, '[', 'Telomerase', 'Reverse', 'Transcriptase', '(', 'TERT),', 'SRY', 'Determining', 'Region', 'Y', 'Box-2', '(', 'SOX2),', 'Nanog', 'Homeobox', '(', 'NANOG)', and, 'Octamer', 'Binding', 'Transcription', 'Factor-4A', '(', 'OCT-4A)]'])].
[sujeto(['Ovine', tendon, development, was, also, accompanied, by, morphological, modifications, to, cell, 'nuclei,', and, a, progressive]), verbo([decrease]), complemento([in, 'cellularity,', proliferation, index, and, expression, of, connexins, 43, and, 32])].
[sujeto(['Transforming', growth, 'factor-β~1', expression, '(']), verbo([involved]), complemento([in, collagen, 'synthesis)', underwent, a, similar, decrease])].
[sujeto(['Conventional', 'time-consuming', hormonal, and, genetic, 'work-up']), verbo([provides]), complemento([a, genetic, diagnosis, in, around, 20, -, 40, '%', of, 46, ',', 'XY', cases, with, ambiguous, genitalia])].
[sujeto(['The', investigation, of, milder, 'cases,', as]), verbo([suggested]), complemento([by, recent, reports, remains, controversial])].
[sujeto(['In', 'addition,', three, novel, 'NR5A1', mutations, were]), verbo([found]), complemento([in, 'non-syndromic', patients])].
[sujeto(['There', is, no, difference, in, diagnostic, yield, between, patients, with, more, or, less, pronounced, 'phenotypes,', as]), verbo([expressed]), complemento([by, the, external, masculinisation, score, '(', 'EMS)'])].
[sujeto(['Interestingly', this, chromosomal, abnormality]), verbo([has]), complemento([been, previously, reported, less, than, twenty, 'times,', and, never, in, the, 'PRE', or, 'MEN', horses])].
[sujeto(['SRY', upregulates, the, expression, of, 'SOX9', that, sets, into, motion, a, cascade, of, complex, genetic, interactions, for, the, formation, of, male, internal, and, external, genitalia, whilst]), verbo([repressing]), complemento([the, formation, of, female, genitalia])].
[sujeto(['However,', at, least, in, 'mice,', the, primary, 'sex-determining', decision, is, not, final, but, is]), verbo([maintained]), complemento([in, adulthood, by, a, mutually, antagonistic, 'double-repressive', pathway])].
[sujeto(['In', the, 'human,', any, imbalance, between, these, two, antagonistic, genetic, and, physiological, pathways, results, in, inappropriate, gonad, differentiation, and, function]), verbo([leading]), complemento([to, disorders, of, sex, development, '(', 'DSD)'])].
[sujeto(['Genetic', analysis, of, individuals, presenting, with, 'DSD', and, 'sex-reversed', mice]), verbo([has]), complemento([revealed, a, number, of, sexually, dimorphic, genes, that, are, involved, in, the, formation, of, mammalian, 'gonads,', which, are, discussed, in, this, chapter])].
[sujeto(['Despite', an]), verbo([increase]), complemento([in, the, knowledge, of, genes, involved, in, mammalian, sex, 'determination,', the, molecular, mechanisms, remain, by, and, large, undetermined])].
[sujeto(['The', use, of, novel, '\'', 'omics\'', technologies, for, analyzing, a, large, number, of, patients, with, 'DSD,', and, careful, assessment, of, the, resulting, datasets, may, result, in, the, identification, of, novel, genetic, factors, in, human, sex, determination, and]), verbo([lead]), complemento([to, the, development, of, novel, ex, vivo, cellular, models])].
[sujeto(['This', arvicoline]), verbo([has]), complemento([unique, derived, features, in, the, 'cranium,', mandible, and, dentition])].
[sujeto(['In', this, 'study,', we, propose, a, phylogenetic, lineage, that, includes, 'Cabrera\'s', vole, in, what, until, now]), verbo([has]), complemento([been, the, 'Microtus', subgenus, 'Iberomys'])].
[sujeto(['Genus', 'Iberomys', comprises, species, that]), verbo([have]), complemento([appeared, in, succession, during, the, 'Quaternary:', in, the, 'Early', 'Pleistocene,', the, extinct, 'I'])].
[sujeto(['This', study, also]), verbo([suggests]), complemento([a, modification, of, 'nomenclature:', 'Microtus', '(', 'Iberomys)', brecciensis, is, replaced, with, 'I'])].
[sujeto(['We']), verbo([report]), complemento([on, a, patient, with, a, 47, ',', 'XXY', karyotype, who, presents, a, normal, female, 'phenotype,', which, is, an, extremely, rare, observation, worldwide])].
[sujeto(['Type', 'B', ultrasound, scans, and, other, tests]), verbo([suggested]), complemento([that, her, ovaries, had, completely, failed])].
[sujeto(['Microsatellite', 'DNA', marker, analysis, revealed, that, the, 2, 'X', chromosomes, were, derived, from, her, mother, and, that, this, abnormality, was]), verbo([caused]), complemento([by, 'non-disjunction', of, the, maternal, 'X', chromosomes, during, meiosis, 'II'])].
[sujeto(['This', paper, is, the, first]), verbo([report]), complemento([of, a, 47, ',', 'XXY', female, with, ovarian, failure])].
[sujeto(['We', were, able, to, identify, two, predominant, clonal, 'NP', subtypes, based, on, their, morphological, characteristics, and, their, ability, to]), verbo([induce]), complemento(['SOX9', and, 'COL2A1', under, conventional, differentiation, conditions])].
[sujeto(['In', 'addition,', cluster, of, differentiation, 24, '(', 'CD24)-negative', 'NP']), verbo([responder]), complemento([clones, formed, spheroid, structures, in, various, culture, 'systems,', suggesting, the, preservation, of, a, more, immature, phenotype, compared, to, 'CD24-positive', nonresponder, clones])].
[sujeto(['Here', we]), verbo([report]), complemento([the, generation, of, clonal, 'NP', cell, lines, from, nondegenerate, human, 'IVD', tissue, and, present, a, detailed, characterization, of, 'NP', cellular, subpopulations])].
[sujeto(['Differential', cell, surface, marker, expression, and, divergent, responses, to, differentiation, conditions]), verbo([suggest]), complemento([that, the, 'NP', subtypes, may, correspond, to, distinct, maturation, stages, and, represent, distinct, 'NP', cell, subpopulations])].
[sujeto(['Hence,', we]), verbo([provide]), complemento([evidence, that, the, immortalization, strategy, that, we, applied, is, capable, of, detecting, cell, heterogeneity, in, the, 'NP'])].
[sujeto(['Our', cell, lines, yield, novel, insights, into, 'NP', biology, and]), verbo([provide]), complemento([promising, new, tools, for, studies, of, 'IVD', 'development,', cell, function, and, disease])].
[sujeto(['In', order, to]), verbo([promote]), complemento([research, on, its, 'genome,', a, 'high-redundancy', 'BAC', library, of, the, 'Siberian', tiger, was, constructed, and, characterized])].
[sujeto(['The', conditions, were]), verbo([found]), complemento([from, the, preliminary, experiment, and, literature, review])].
[sujeto(['The', 'L60', '(', 212, ')', orthogonal, experiment, was, designed, using, the, 'SPSS', 18.0, with, 2, level, conditions, and, the, cells, were]), verbo([induced]), complemento([to, differentiate, on, the, small, intestinal, submucosa, '(', 'SIS)-3D', scaffold])].
[sujeto(['The', conditions, of, 'DEX,', 'ASA,', 'ITS,', 'transferrin,', bFGF, showed]), verbo([decreasing]), complemento([promotional, function, by, 'degrees,', and, the, model, showed, the, perfect, relevance])].
[sujeto(['RIG1', is]), verbo([expressed]), complemento([in, high, levels, in, 'well-differentiated', 'tissues,', but, its, expression, is, decreased, in, cancer, tissues, and, cancer, cell, lines])].
[sujeto(['We']), verbo([found]), complemento(['RIG1', to, be, highly, expressed, in, testicular, cells])].
[sujeto(['When', 'RIG1', was]), verbo([expressed]), complemento([in, 'NT2/D1', testicular, cancer, 'cells,', neither, cell, death, nor, cell, viability, was, affected])].
[sujeto(['However,', 'RIG1', significantly]), verbo([inhibited]), complemento([cell, migration, and, invasion, in, 'NT2/D1', cells])].
[sujeto(['We']), verbo([found]), complemento([that, prostaglandin, 'D2', synthase, '(', 'PTGDS)', interacted, with, 'RIG1', using, yeast, 'two-hybrid', screens])].
[sujeto(['Further,', we]), verbo([found]), complemento(['PTGDS', to, be, 'co-localized', with, 'RIG1', in, 'NT2/D1', testis, cells])].
[sujeto(['This', indicated, that, 'RIG1', can]), verbo([enhance]), complemento(['PTGDS', activity])].
[sujeto(['Silencing', of, 'PTGDS', expression, significantly]), verbo([decreased]), complemento(['RIG1-mediated', cAMP, and, 'PGD2', production])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'RIG1', will, suppress, cell, 'migration/invasion', through, the, 'PGD2', signaling, pathway])].
[sujeto(['In', 'conclusion,', 'RIG1', can]), verbo([interact]), complemento([with, 'PTGDS', to, enhance, its, function, and, to, further, suppress, 'NT2/D1', cell, migration, and, invasion])].
[sujeto(['Our', study]), verbo([suggests]), complemento([that, 'RIG1-PGD2', signaling, might, play, an, important, role, in, cancer, cell, suppression, in, the, testis])].
[sujeto(['Although', the, miRNAs, are]), verbo([involved]), complemento([in, breast, cancer, 'development,', their, axis, with, the, transcription, factors, that, show, therapeutic, potential, in, breast, cancer, is, largely, unknown])].
[sujeto(['Recently,', we, demonstrated, that, 'agonist-activated', 'Ahr']), verbo([induced]), complemento([a, highly, conserved, miRNA, 'cluster,', named, 'miR-212/132,', in, murine, cellular, immune, compartment])].
[sujeto(['Therefore,', current, study, was, performed, to, examine, if, this, miRNA, cluster]), verbo([mediates]), complemento([the, 'anti-metastatic', properties, of, 'Ahr', agonists])].
[sujeto(['The', 2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD)', and, 3, ',', 3, '\'', -, diindolylmethane, '(', 'DIM)', were, used, to]), verbo([activate]), complemento(['Ahr', in, 'MDA-MB-231', and, 'T47D', breast, cancer, cells])].
[sujeto(['Chromatin', immunoprecipitation, '(', 'ChIP)', assay, was, used, to, identify, the]), verbo([binding]), complemento(['site(s)', for, 'Ahr', on, 'miR-212/132', promoter])].
[sujeto(['For', prediction, of, potentially]), verbo([target]), complemento([gene, of, the, miRNA, 'cluster,', bioinformatics, analysis, was, carried, 'out,', and, to, test, 'targeting,', luciferase, activity, was, quantified])].
[sujeto(['The', 'miR-212/132', cluster, was, transcriptionally]), verbo([activated]), complemento([in, 'MDA-MB-231', and, 'T47D', cells, by, 'TCDD', and, 'DIM,', and, this, activation, was, regulated, by, 'Ahr'])].
[sujeto(['A', reciprocal, correlation, was, identified, between, 'Ahr', 'agonists-induced', 'miR-212/132', and, the, 'pro-metastatic', 'SRY-related', 'HMG-box4', '(', 'SOX4),', and, a, new, specific]), verbo([binding]), complemento([sites, for, 'miR-212/132', were, identified, on, the, untranslated, region, '(', 3, '\'', 'UTR)', of, 'SOX4'])].
[sujeto(['Further', in, vivo, studies, demonstrated, that, the, 'Ahr-miR-212/132-SOX4', module, was]), verbo([induced]), complemento([by, 'Ahr', activation])].
[sujeto(['Taken', 'together,', the, findings]), verbo([provide]), complemento([the, first, evidences, of, the, synergistic, 'anti-metastatic', properties, of, 'miR-212/132', cluster, through, suppression, of, 'SOX4'])].
[sujeto(['Also,', current, study]), verbo([suggest]), complemento([a, new, 'miRNA-based', mechanism, elucidating, the, 'anti-metastatic', properties, of, 'Ahr', 'agonists,', suggesting, possibility, of, using, 'miR-212/132', to, control, metastasis, in, breast, cancer, patients])].
[sujeto(['Goldfish', '(', 'Carassius', 'auratus)', and, zebrafish, '(', 'Danio', 'rerio)']), verbo([have]), complemento([utility, as, complementary, models, for, understanding, the, molecular, basis, and, functional, significance, of, exaggerated, neural, estrogen, biosynthesis])].
[sujeto(['Multiple', cytochrome, 'P450', aromatase, '(', 'P450arom)', cDNAs, that, derive, from, separate, gene, loci, '(', cyp19a, and, 'cyp19b)', are, differentially]), verbo([expressed]), complemento([in, brain, '(', 'P450aromB&gt;A)', and, ovary, '(', 'P450aromA&gt;B)', and, have, a, different, developmental, program, '(', 'B&gt;A)', and, response, to, estrogen, upregulation, '(', 'B', 'only)'])].
[sujeto(['As', measured, by]), verbo([increased]), complemento(['P450aromB', 'mRNA,', a, functional, estrogen, response, system, is, first, detected, 24, -, 48, h, 'post-fertilization', '(', 'hpf),', consistent, with, the, onset, of, estrogen, receptor, '(', 'ER)', expression, '(', 'alpha,', 'beta,', and, 'gamma)'])].
[sujeto(['The', 5, '\'', -, flanking, region, of, the, cyp19b, gene]), verbo([has]), complemento([a, 'TATA', 'box,', two, estrogen, response, elements, '(', 'EREs),', an, 'ERE', 'half-site', '(', 'ERE1/2),', a, nerve, growth, factor, 'inducible-B', protein, '(', 'NGFI-B)/Nur77', responsive, element, '(', 'NBRE)', binding, 'site,', and, a, sequence, identical, to, the, zebrafish, 'GATA-2', gene, neural, specific, enhancer])].
[sujeto(['The', cyp19a, promoter, region]), verbo([has]), complemento(['TATA', and, 'CAAT', 'boxes,', a, steroidogenic, 'factor-1', '(', 'SF-1)', binding, 'site,', and, two, aryl, hydrocarbon, receptor, '(', 'AhR)/AhR', nuclear, translocator, factor, '(', 'ARNT)', binding, motifs])].
[sujeto(['Both', genes]), verbo([have]), complemento([multiple, potential, 'SRY/SOX', binding, sites, '(', 16, and, 8, in, cyp19b, and, 'cyp19a,', 'respectively)'])].
[sujeto(['Luciferase', reporters]), verbo([have]), complemento([basal, promoter, activity, in, 'GH3', 'cells,', but, differences, '(', 'a&gt;b)', are, opposite, to, fish, pituitary, '(', 'b&gt;a)'])].
[sujeto(['When', microinjected, into, fertilized, zebrafish, 'eggs,', a, cyp19b, 'promoter-driven', green, fluorescent, protein, '(', 'GFP)', reporter, '(', but, not, 'cyp19a)', is]), verbo([expressed]), complemento([in, neurons, of, 30, -, 48, hpf, 'embryos,', most, prominently, in, retinal, ganglion, cells, '(', 'RGCs)', and, their, projections, to, optic, tectum])].
[sujeto(['Further', studies, are]), verbo([required]), complemento([to, identify, functionally, relevant, 'cis-elements', and, cellular, 'factors,', and, to, determine, the, regulatory, role, of, estrogen, in, neurodevelopment])].
[sujeto(['Diet', and, microbiome, derived, indole, derivatives, are, known, to]), verbo([activate]), complemento([the, ligand, induced, transcription, 'factor,', the, 'Aryl', hydrocarbon, 'Receptor', '(', 'AhR)'])].
[sujeto(['While', the, current, understanding, of, 'AhR', biology]), verbo([has]), complemento([confirmed, its, role, in, mucosal, 'lymphocytes,', its, function, in, intestinal, antigen, presenting, cells, '(', 'APCs)', is, poorly, understood])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, 'Cre-mediated', deletion, of, 'AhR', in, 'CD11c-expressing', cells, in, 'C57/BL6', mice, is, associated, with, altered, intestinal, epithelial, morphogenesis, in, vivo])].
[sujeto(['Moreover,', when, 'co-cultured', with, 'AhR-deficient', 'DCs', ex, 'vivo,', intestinal, organoids, showed, reduced, 'SRY', '(', sex, determining, region, 'Y)-box', 9, and]), verbo([increased]), complemento(['Mucin', 2, 'expression,', which, correlates, with, reduced, 'Paneth', cells, and, increased, goblet, cell, 'differentiation,', similar, to, the, data, obtained, in, vivo])].
[sujeto(['Further,', characterization, of, intestinal, 'APC', 'subsets,', devoid, of, 'AhR,', revealed, an, expression, pattern]), verbo([associated]), complemento([with, aberrant, intrinsic, 'Wnt', pathway, regulation])].
[sujeto(['At', a, functional, 'level,', the]), verbo([loss]), complemento([of, 'AhR', in, 'APCs', resulted, in, a, dysfunctional, epithelial, 'barrier,', associated, with, a, more, aggressive, chemically, induced, colitis, compared, to, wild, type, animals])].
[sujeto(['Our', results, are, consistent, with, a, model, whereby, the, 'AhR', signalling, pathway, may]), verbo([participate]), complemento([in, the, regulation, of, innate, immunity, through, intestinal, epithelium, development, and, mucosal, immunity])].
[sujeto(['In', the, 'male,', testosterone, '(', 'T)', secreted, by, the, developing, testes, defeminizes, 'LH']), verbo([release]), complemento(['mechanisms;', 'conversely,', perinatal, 'AhR', activation, by, 2, ',', 3, ',', 7, ',', 8, ',', -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD)', blocks, defeminization])].
[sujeto(['To', better, understand, developmental, mechanisms, altered, by, 'TCDD', 'exposure,', we, first, verified, that, neonatal, 'TCDD', exposure, in, male, rats]), verbo([prevented]), complemento([the, loss, of, 'AVPV', 'GABA/glutamate', neurons, that, are, critical, for, 'female-typical', 'LH', surge, release])].
[sujeto(['In', 'addition,', upstream, regulatory, analysis]), verbo([suggests]), complemento([that, both, estrogen, receptors, '(', 'ER)', and, androgen, receptors, '(', 'AR)', regulate, genes, targeted, by, 'TCDD'])].
[sujeto(['Of', the, 23, mRNAs]), verbo([found]), complemento([to, be, changed, by, 'TCDD', at, least, 2, -, fold, '(', 'p&lt;0'])].
[sujeto([5, ')', ',', most]), verbo([participate]), complemento([in, the, functions, identified, in, our, bioinformatics, analyses])].
[sujeto(['Several,', including, matrix, metallopeptidase, 9, and, 'SRY-box', 11, '(', 'Sox11),', are, known]), verbo([targets]), complemento([of, 'E2'])].
[sujeto(['CUG', triplet, 'repeat,', 'RNA']), verbo([binding]), complemento([protein, 2, '(', 'cugbp2)', is, particularly, interesting, because, it, is, 'sex-specific,', oppositely, regulated, by, estradiol, '(', 'E2)', and, 'TCDD'])].
[sujeto(['Moreover,', it]), verbo([regulates]), complemento([the, 'post-transcriptional', processing, of, molecules, previously, linked, to, sexual, differentiation, of, the, brain])].
[sujeto(['These', findings]), verbo([provide]), complemento([new, insights, into, how, 'TCDD', may, interfere, with, defeminization, of, 'LH', release, patterns])].
[sujeto(['Two', 'P450arom', mRNAs, which, derive, from, separate, gene, loci, '(', cyp19a, and, 'cyp19b)', are, differentially]), verbo([expressed]), complemento([in, brain, '(', 'b&gt;a)', and, ovary, '(', 'a&gt;b)', and, have, a, different, developmental, program, '(', 'b&gt;a)', and, estrogen, upregulation, '(', b, 'only)'])].
[sujeto(['Sequence', analysis, of, the, cyp19b, gene, approximately, 1.8, kb, upstream, of, the, transcription, start, site, revealed, a, 'TATA', box, at, nucleotide, '(', 'nt)', -, 30, ',', two, estrogen, responsive, elements, '(', 'EREs;', nt, -, 351, and, -, 211, ')', and, a, consensus]), verbo([binding]), complemento([site, '(', 'NBRE)', for, nerve, growth, factor, 'inducible-B', protein, '(', 'NGFI-B/Nur77)', at, -, 286, ',', which, includes, another, 'ERE', 'half-site'])].
[sujeto(['Also', present, were, a, sequence, at, nt, -, 399, '(', 'CCCTCCT)']), verbo([required]), complemento([for, neural, specificity, of, the, zebrafish, 'GATA-2', 'gene,', and, 16, copies, of, an, 'SRY/SOX', binding, motif])].
[sujeto(['The', 5, '\'', -, flanking, region, '(', approximately, 1.0, 'kb)', of, the, cyp19a, gene, had, 'TATA', '(', nt, -, 48, ')', and, 'CAAT', '(', nt, -, 71, ')', 'boxes,', a, steroidogenic, 'factor-1', '(', 'SF-1)']), verbo([binding]), complemento([site, '(', nt, -, 265, ')', ',', eight, copies, of, the, 'SRY/SOX', 'motif,', and, two, copies, of, a, recognition, site, for, binding, the, arylhydrocarbon, receptor, '(', 'AhR)/AhR', nuclear, translocator, factor, '(', 'ARNT)', heterodimer])].
[sujeto(['Tandem', analysis, of, cyp19a, and, cyp19b, promoters, in, living, zebrafish, embryos, can, be, a, useful, approach, for, identifying, 'cis-elements', and, cellular, factors]), verbo([involved]), complemento([in, the, correct, 'tissue-specific,', 'spatial,', temporal, and, estrogen, regulated, expression, of, aromatase, genes, during, 'CNS', and, gonadal, development])].
[sujeto(['ELISA', and, 'RT-PCR', were, used, to, measure, protein, and, mRNA, 'levels,', 'respectively,', of]), verbo([nuclear]), complemento([factor, '(', 'NF)-κB,', 'IL-1β,', 'IL-6', and, 'TNF-α'])].
[sujeto(['Donor', cell, numbers]), verbo([decreased]), complemento([over, time])].
[sujeto(['Pretreatment', with, triptolide, improved, graft, survival, both, 24, '(', 29.3, ±, 0.9, '%', ')', and, 72, h, '(', 17.5, ±, 1.2, '%', ')', after, transplantation, of, 'MSCs', and, resulted, in, a, 2.5, -, fold]), verbo([increase]), complemento([in, the, total, cell, number, 72, h, after, cell, transplantation])].
[sujeto(['The', mechanism, underlying, this, effect]), verbo([involves]), complemento([attenuating, the, inflammatory, response, via, inhibition, of, the, 'NF-κB', signaling, pathway])].
[sujeto(['Many', papers]), verbo([have]), complemento([shown, that, 'SRY', '(', 'sex-determining', region, 'Y)-box', '(', 'SOX)', family, genes, serve, as, either, tumor, suppressor, genes, '(', 'TSGs)', or, oncogenes, by, regulating, the, 'Wnt', signaling, pathway, in, different, cancers])].
[sujeto(['We']), verbo([have]), complemento([demonstrated, recently, that, epigenetic, silencing, of, 'SOX1', gene, occurs, frequently, in, cervical, cancer])].
[sujeto(['Overexpression', of, 'SOX1']), verbo([inhibited]), complemento([cell, 'proliferation,', anchorage, 'independency,', and, invasion, in, vitro])].
[sujeto(['SOX1']), verbo([suppressed]), complemento([tumor, growth, in, nonobese, 'diabetic/severe', combined, immunodeficiency, mice])].
[sujeto(['After', induction, of, 'SOX1', by, doxycycline, '(', 'DOX),', 'SOX1']), verbo([inhibited]), complemento([cell, growth, and, invasion, in, the, inducible, system])].
[sujeto(['SOX1']), verbo([inhibited]), complemento(['TCF-dependent', transcriptional, activity, and, the, 'Wnt', target, genes])].
[sujeto(['SOX1', also]), verbo([repressed]), complemento([the, invasive, phenotype, by, regulating, the, expression, of, 'invasion-related', genes])].
[sujeto(['Taken', 'together,', these, data]), verbo([suggest]), complemento([that, 'SOX1', can, function, as, a, tumor, suppressor, partly, by, interfering, with, 'Wnt/β-catenin', signaling, in, cervical, cancer])].
[sujeto(['BM-derived', 'MSCs', were, detected, by, 'RT-PCR', of, 'CD29', and, were, then, infused, into, the, tail, vein, of, female, rats, that, received, 'CCl4', injection, to]), verbo([induce]), complemento([liver, fibrosis])].
[sujeto(['MSCs', and, 'SIMV']), verbo([decreased]), complemento([liver, procollagens, 'I', and, 'III,', 'TIMP-1', and, endoglin, gene, 'expressions,', 'TGF-β1', 'immunostaining,', and, serum, liver, function, tests, compared, with, the, 'CCl4', group])].
[sujeto(['MMP-1', expression, was]), verbo([increased]), complemento([in, the, 'CCl4/MSCs', group])].
[sujeto(['Our', recent, studies]), verbo([have]), complemento([demonstrated, that, 'SRY', '(', sex, determining, region, 'Y)-box', 1, '(', 'SOX1)', and, secreted, 'frizzled-related', proteins, are, concomitantly, 'promoter-hypermethylated,', and, this, might, lead, to, abnormal, activation, of, the, 'Wnt', signaling, pathway, in, 'HCC'])].
[sujeto(['SOX1', encodes, a, transcription, factor]), verbo([involved]), complemento([in, the, regulation, of, embryonic, development, and, cell, fate, determination])].
[sujeto(['Overexpression', of, 'SOX1', by, a, constitutive, or, inducible, approach, could]), verbo([suppress]), complemento([cell, 'proliferation,', colony, 'formation,', and, invasion, ability, in, 'HCC', cell, 'lines,', as, well, as, tumor, growth, in, nonobese, 'diabetic/severe', combined, immunodeficiency, mice])].
[sujeto(['We', used, a, 'T', cell, factor, '(', 'TCF)-responsive', luciferase, reporter, assay, and, western, blot, analysis, to, prove, that, 'SOX1', could]), verbo([regulate]), complemento(['TCF-responsive', transcriptional, activity, and, inhibit, the, expression, of, 'Wnt', downstream, genes])].
[sujeto(['Furthermore,', we, used, glutathione, 'S-transferase', 'pull-down,', 'co-immunoprecipitation,', and, confocal, microscopy, to, demonstrate, that, 'SOX1', could]), verbo([interact]), complemento([with, 'β-catenin', but, not, with, the, 'β-catenin/TCF', complex])].
[sujeto(['Moreover,', restoration, of, the, expression, of, 'SOX1']), verbo([induces]), complemento([significant, cellular, senescence, in, 'Hep3B', cells])].
[sujeto(['MSCs', were, mainly, distributed, in, the, glomerular, capillaries, at, the, time, points, of, 6, h, and, 48, 'h,', but, the, number, of, 'MSCs', in, glomerular, capillaries]), verbo([decreased]), complemento([and, those, in, renal, mesenchyma, increased, at, the, time, points, from, 10, d, to, 60, d, 'gradually,', then, tended, to, a, steady, 'state,', meanwhile, it, showed, a, stable, increasing, trend, in, renal, tubule])].
[sujeto(['Cell', colony, of, 'MSCs', could, be]), verbo([found]), complemento([in, mesenchyma, with, a, slowed, down, increasing, between, 30, d, to, 60, 'd,', but, the, increasing, in, tubule, was, still, steady])].
[sujeto(['MSCs', transplantation]), verbo([has]), complemento([beneficial, effects, on, 'CAAN,', which, is, possibly, related, with, the, reduction, of, 'PTC'])].
[sujeto(['The', results, indicate, that, 'X-', or, 'Y-linked', genes]), verbo([have]), complemento([direct, 'effects,', not, mediated, by, gonadal, 'secretions,', on, sex, differences, in, two, different, types, of, acute, nociception])].
[sujeto(['Recent', studies]), verbo([have]), complemento([shown, that, hematopoietic, bone, marrow, '(', 'BM)', 'stem/progenitor', cells, can, give, rise, to, hepatocytes, in, 'diseased/damaged', liver])].
[sujeto(['One', study]), verbo([has]), complemento([reported, that, 'BM', cells, can, transdifferentiate, into, liver, 'progenitor/oval', 'cells,', but, it, has, not, been, proven, that, the, latter, can, repopulate, the, liver])].
[sujeto(['To', answer, this, 'question,', we]), verbo([have]), complemento([lethally, irradiated, female, 'DPP4(-)', mutant, 'F344', rats, and, transplanted, them, with, 50, million, 'wild-type', male, 'F344', 'BM', cells])].
[sujeto(['A', 'real-time', 'PCR-based', gene, expression, survey, was, performed, on, isolated, 'European']), verbo([sea]), complemento([bass, follicles, from, primary, growth, to, late, vitellogenesis])].
[sujeto([',', the, beginning, of, the, secondary, growth, 'phase)', showed, elevated, mRNA, amounts, of, follicle]), verbo([stimulating]), complemento([hormone, receptor, '(', 'fshr)', and, 'anti-Mullerian', hormone])].
[sujeto(['Early-to-mid', vitellogenic, follicles, showed, high, mRNA, levels, of, fshr, and, cytochrome, 'P450,', family, 19, ',', subfamily, 'A,', polypeptide, 1, a, while, 'mid-to-late', vitellogenic, follicles]), verbo([expressed]), complemento([increasing, transcript, amounts, of, luteinizing, 'hormone/choriogonadotropin', 'receptor,', steroidogenic, acute, regulatory, 'protein,', and, estrogen, receptors, 1, and, 2, a])].
[sujeto(['The', expression, of, 'biliary/progenitor', markers, by, hepatocellular, carcinoma, '(', 'HCC)', is, often]), verbo([associated]), complemento([with, poor, prognosis, and, stem, 'cell-like', behaviors, of, tumor, cells])].
[sujeto(['Hepatocellular', adenomas, '(', 'HCAs)', also, often]), verbo([express]), complemento(['biliary/progenitor', markers, and, frequently, act, as, precursor, lesions, for, 'HCC'])].
[sujeto(['However,', the, cell, of, origin, of, 'HCA', and, 'HCC', that]), verbo([expresses]), complemento([these, markers, remains, unclear])].
[sujeto(['Therefore,', to, evaluate, if, mature, hepatocytes, give, rise, to, 'HCA', and, 'HCC', tumors, and, to, understand, the, molecular, pathways]), verbo([involved]), complemento([in, 'tumorigenesis,', we, 'lineage-labeled', hepatocytes, by, injecting, 'adeno-associated', virus, containing, 'thyroxine-binding', globulin, 'promoter-driven', causes, recombination, '(', 'AAV-TBG-Cre)', into, 'Rosa(YFP)', mice])].
[sujeto(['We', treated, 'AAV-TBG-Cre;', 'Rosa(YFP)', mice, with, diethylnitrosamine, '(', 'DEN),', followed, by, multiple, injections, of, carbon, tetrachloride, to]), verbo([induce]), complemento([carcinogenesis, and, fibrosis, and, found, that, 'HCA', and, 'HCC', nodules, were, 'YFP(+)', 'lineage-labeled;', positive, for, 'osteopontin,', 'SRY', '(', sex, determining, region, 'Y)-box', 9, ',', and, epithelial, cell, adhesion, 'molecule;', and, enriched, for, transcripts, of, 'biliary/progenitor', markers, such, as, prominin, 1, ',', 'Cd44,', and, 'delta-like', 1, homolog])].
[sujeto(['None', of, the, tumor, nodules]), verbo([expressed]), complemento(['YFP,', indicating, that, 'Foxl1-expressing', cells, are, not, the, origin, for, 'hepatotoxin-induced', liver, tumors])].
[sujeto(['Hepatocytes', are, the, cell, of, origin, of, 'HCA', and, 'HCC', in, 'DEN/carbon', tetrachloride, and, 'DEN/TCPOBOP']), verbo([induced]), complemento([liver, tumors])].
[sujeto(['By', contrast, with, the, 'mouse,', 'SRY', is, primarily]), verbo([expressed]), complemento([in, most, cells, of, 'XY', 'genital-ridges', and, not, solely, in, 'pre-Sertoli', cells])].
[sujeto(['Between', cord, formation, and, 'prepuberty,', 'SRY', remains]), verbo([expressed]), complemento([in, both, 'Sertoli', and, germinal, cells])].
[sujeto(['Unlike', the, germinal, 'lineage,', 'SRY', continues, to, be, highly]), verbo([expressed]), complemento([in, adult, 'Sertoli', cells, with, a, typical, nuclear, staining])].
[sujeto(['Our', data, indicate, that, in, 'goat,', the, role, of, 'SRY', may, not, be, limited, to, testis, determination, and, could]), verbo([have]), complemento([other, functions, in, testicular, maintenance, and, hence, male, fertility])].
[sujeto(['To', evaluate, 'SRY', phylogenic, conservation, in, regards, to, its, 'function,', we]), verbo([expressed]), complemento([the, goat, gene, '(', 'gSRY)', in, 'XX', transgenic, mouse, gonads])].
[sujeto(['Here,', we, show, that, gSRY]), verbo([induces]), complemento([testis, 'formation,', despite, a, goat, expression, profile])].
[sujeto(['Our', results, demonstrate, that, 'sex-reversal', can, be]), verbo([induced]), complemento([in, 'XX-mice', by, a, 'non-mouse', 'SRY', thus, suggesting, a, conserved, molecular, mechanism, of, action, of, this, 'testis-determining', gene, across, mammalian, species])].
[sujeto(['In', 'mammals,', the, 'Y-located', 'SRY', gene, is, known, to]), verbo([induce]), complemento([testis, formation, from, the, indifferent, gonad])].
[sujeto(['It', is, now, assumed, that, 'SRY']), verbo([acts]), complemento([upstream, of, 'SOX9', in, the, sex, determination, 'cascade,', but, the, regulatory, link, which, should, exist, between, these, two, genes, remains, unknown])].
[sujeto(['Studies', on, 'XX', sex, reversal, in, polled, goats, '(', 'PIS', 'mutation:', 'Polled', 'Intersex', 'Syndrome)']), verbo([have]), complemento([led, to, the, discovery, of, a, 'female-specific', locus, crucial, for, ovarian, differentiation])].
[sujeto(['The', 'FOXL2', expression, profile, of, mice, is, similar, to, that, described, in, goats, in, accordance, with, a]), verbo([conserved]), complemento([role, of, this, ovarian, differentiating, gene, in, mammals])].
[sujeto(['On', the, 'contrary,', the, 'PISRT1', expression, profile, is, different, between, mice, and, 'goats,']), verbo([suggesting]), complemento([different, mechanisms, of, the, primary, switch, in, the, testis, determination, process, within, mammals])].
[sujeto(['By', 'definition,', the, 'DNA']), verbo([binding]), complemento([domain, of, 'SOX', genes, is, at, least, 50, '%', identical, to, the, 79, amino, acid, 'HMG', domain, of, the, 'SRY', gene])].
[sujeto(['We']), verbo([report]), complemento([here, two, 'HMG-box', sequences, from, two, microbat, species, '(', 'R'])].
[sujeto(['Pipistrellus)', which, were, 'PCR', amplified, using, a]), verbo([primer]), complemento([pair, specific, to, the, mouse, 'Sry', 'HMG-box'])].
[sujeto(['The', high, percentage, of, identity, of, this, sequences, with, the, human, and, mouse, 'SOX30', 'HMG-box']), verbo([suggests]), complemento([that, they, are, the, 'SOX30', 'HMG-box', for, these, two, bat, species])].
[sujeto(['This', fragment, contains, two]), verbo([binding]), complemento([sites, for, the, 'Serendipity', '(', 'Sry)', d, zinc, finger, 'activator,', that, mediate, its, cooperative, binding])].
[sujeto(['Further', analysis, showed, that, the, bcd, promoter, configuration, is, decisive, for, 'Sry', d]), verbo([activating]), complemento([function])].
[sujeto(['Replacement', of, sdbs, by]), verbo([binding]), complemento([sites, for, 'Sry', 'b,', the, 'Sry', d, 'paralog,', restores, bcd, transcription, in, sry, d, mutant, 'ovaries,', demonstrating, that, the, functional, divergence, between, these, two, proteins, during, evolution, was, mainly, driven, by, changes, in, their, 'DNA-specific', recognition, 'properties,', resulting, in, the, control, of, separate, developmental, pathways])].
[sujeto(['The', drug, discovery, research, for, cholestatic, liver, diseases]), verbo([has]), complemento([been, hampered, by, the, lack, of, a, 'well-established', human, cholangiocyte, model])].
[sujeto(['Functional', 'cholangiocyte-like', cells, differentiated, from, human]), verbo([induced]), complemento([pluripotent, stem, '(', 'iPS)', cells, are, expected, to, be, a, promising, candidate, for, such, 'research,', but, there, remains, no, 'well-established', method, for, differentiating, cholangiocytes, from, human, iPS, cells])].
[sujeto(['In', this, 'study,', we, searched, for, a, suitable, extracellular, matrix, to]), verbo([promote]), complemento([cholangiocyte, differentiation, from, human, iPS, 'cells,', and, found, that, both, laminin, 411, and, laminin, 511, were, suitable, for, this, purpose])].
[sujeto(['The', gene, expression, levels, of, the, cholangiocyte, 'markers,', aquaporin, 1, '(', 'AQP1),', 'SRY-box', 9, '(', 'SOX9),', cystic, fibrosis, transmembrane, conductance, regulator, '(', 'CFTR),', 'G', 'protein-coupled', bile, acid, receptor, 1, '(', 'GPBAR1),', 'Jagged', 1, '(', 'JAG1),', secretin, receptor, '(', 'SCTR),', and, 'γ-glutamyl', transferase, '(', 'GGT1)', were]), verbo([increased]), complemento([by, using, laminin, 411, or, laminin, 511, as, a, matrix])].
[sujeto(['In', 'addition,', the, percentage, of, 'AQP1-positive', cells, was]), verbo([increased]), complemento([from, 61.8, '%', to, 92.5, '%', by, using, laminin, 411, or, laminin, 511])].
[sujeto(['Furthermore,', the, diameter, and, number, of, cysts, consisted, of, 'cholangiocyte-like', cells, were]), verbo([increased]), complemento([when, using, either, matrix])].
[sujeto(['After', partial, hepatectomy, '(', 'PH),', diethylnitrosamine, '(', 'DEN)', was, administered, to]), verbo([induce]), complemento([liver, fibrosis])].
[sujeto(['Transplanted', cells, proliferated, and, differentiated, into, hepatocytes, and, bile, duct, epithelial, cells, with, 30, '%', -, 50, '%', repopulation, in, the, liver, fibrosis]), verbo([induced]), complemento([by, 'DEN', after, 3, mo])].
[sujeto(['Transplanted', 'FLEP', cells, proliferate, and, differentiate, into, hepatocytes, and, bile, duct, epithelial, cells, with, high, repopulation, capacity, in, the, fiberized, liver]), verbo([induced]), complemento([by, 'DEN,', which, restores, liver, function, and, reduces, liver, fibrosis])].
[sujeto(['Both', patients, and, controls, had, to]), verbo([have]), complemento([male, 'offspring,', and, no, history, of, miscarriages, or, blood, 'transfusions;', they, could, not, be, twins])].
[sujeto(['Y-chromosome', sequences, were]), verbo([found]), complemento([in, three, of, the, four, 'PBC', women, with, associated, systemic, sclerosis])].
[sujeto(['This', discrepancy, may]), verbo([suggest]), complemento([that, not, only, fetal, cells, but, also, fragments, of, fetal, 'DNA', are, present, in, maternal, circulation])].
[sujeto(['This', study, aimed, to, evaluate, whether, female, adult, offspring, born, with, intrauterine, growth, retardation]), verbo([induced]), complemento([by, prenatal, nicotine, exposure, '(', 'PNE)', are, susceptible, to, osteoarthritis, '(', 'OA)', and, to, explore, the, underlying, programming, mechanisms])].
[sujeto(['The', female, adult, offspring, with, or, without, 'PNE', were, forced, with, a, strenuous, treadmill, running, for, 6, wk, to]), verbo([induce]), complemento(['OA'])].
[sujeto(['For', adult, 'offspring,']), verbo([increased]), complemento([cartilage, destruction, and, accelerated, 'OA', progression, were, observed, in, the, 'PNE', group, with, 'running;', the, expression, of, α1, chain, of, type, 'II', collagen, '(', 'Col2A1),', 'aggrecan,', 'SRY-type', high, mobility, group, box, 9, '(', 'Sox9),', and, 'IGF1', signaling, molecules, in, the, cartilage, of, 'PNE', offspring, were, decreased])].
[sujeto(['For', 'fetuses,', elevated, serum, corticosteroid, and, nicotine, levels, and]), verbo([suppressed]), complemento(['IGF1', levels, were, 'observed;', expression, of, 'Col2A1,', 'aggrecan,', 'Sox9,', and, 'IGF1', were, reduced])].
[sujeto(['In', 'conclusion,', 'PNE']), verbo([increases]), complemento([the, susceptibility, of, adult, offspring, to, 'OA;', the, potential, mechanism, involves, 'IGF1', 'low-functional', programming, in, articular, cartilage, caused, directly, by, the, action, of, nicotine, on, 'α4β2-nAChR'])].
[sujeto(['Prenatal', stress, is, known, to]), verbo([cause]), complemento([intrauterine, fetal, growth, 'retardation,', and, is, also, associated, with, various, 'long-term', effects, in, the, form, of, metabolic, and, neurodevelopmental, diseases, in, adults])].
[sujeto(['Many', of, the, diseases]), verbo([associated]), complemento([with, prenatal, stress, exhibit, a, sex, bias])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, administration, of, the, synthetic, 'glucocorticoid,', dexamethasone, '(', 'Dex),', at, embryonic, days, 7.5, ',', 8.5, ',', and, 9.5, ',', induces, embryonic, growth, restriction, in, a, 'sex-dependent', manner, in, a, mouse, model])].
[sujeto(['During', male, gonadal, 'development,', 'sex-determining', 'genes,', such, as, 'Sry,', 'Sox9,', and, other, downstream, 'genes,', were]), verbo([found]), complemento([to, be, dysregulated, in, response, to, prenatal, 'Dex,', whereas, the, genes, for, the, ovarian, pathway, were, affected, to, a, lesser, degree, in, females])].
[sujeto(['In', 'addition,', fetal, testosterone, concentrations, were]), verbo([decreased]), complemento([by, prenatal, exposure, to, 'Dex,', in, parallel, with, reduced, numbers, of, 3, 'β-hydroxysteroid', dehydrogenase, '(', 3, 'β-HSD)-positive', cells, in, the, embryonic, testis])].
[sujeto(['We', believe, these, studies]), verbo([provide]), complemento([valuable, insights, into, possible, mechanisms, responsible, for, 'sex-specific', responses, to, prenatal, stress])].
[sujeto(['The', knowledge, that, diverse, populations, of, dopaminergic, neurons, within, the, ventral, tegmental, area, '(', 'VTA)', can, be, distinguished, in, terms, of, their, 'molecular,', electrophysiological, and, functional, 'properties,', as, well, as, their, differential, projections, to, cortical, and, subcortical, regions]), verbo([has]), complemento([significance, for, key, brain, 'functions,', such, as, the, regulation, of, 'motivation,', working, memory, and, sensorimotor, control])].
[sujeto(['Almost', without, 'exception,', this, understanding]), verbo([has]), complemento([evolved, from, landmark, studies, performed, in, the, male, sex])].
[sujeto(['This', may, be, driven, by, sex, differences, in, the, hormonal, environment, during, adulthood, '(', '\'', 'activational\'', 'effects)', and, development, '(', perinatal, 'and/or', pubertal, '\'', 'organizational\'', 'effects),', as, well, as, genetic, 'factors,', especially, the, 'SRY', gene, on, the, 'Y', chromosome, in, 'males,', which, is]), verbo([expressed]), complemento([in, a, 'sub-population', of, adult, midbrain, dopaminergic, neurons])].
[sujeto(['Stress', and, stress, 'hormones,', especially, 'glucocorticoids,', are, important, factors, which]), verbo([interact]), complemento([with, the, 'VTA', dopaminergic, systems, in, order, to, achieve, behavioral, adaptation, and, enable, the, individual, to, cope, with, environmental, change])].
[sujeto(['This', may]), verbo([have]), complemento([enduring, consequences, for, individual, resilience, or, susceptibility, to, pathophysiological, change, induced, by, stressors, in, later, 'life,', with, potential, translational, significance, for, sex, bias, commonly, found, in, disorders, involving, dysfunction, of, the, mesocorticolimbic, dopaminergic, systems])].
[sujeto(['Prenatal', dexamethasone, '(', 'DEX)', treatment]), verbo([has]), complemento([been, proposed, since, 1984, to, prevent, genital, virilization, in, girls, with, congenital, adrenal, hyperplasia, '(', 'CAH)'])].
[sujeto(['It', avoided, prenatal, 'DEX', in, 68, '%', of, 'males,', and, this, percentage]), verbo([increased]), complemento([over, the, years])].
[sujeto(['DEX', was]), verbo([maintained]), complemento([until, prenatal, diagnosis, in, 'non-CAH', females])].
[sujeto(['Virilization', was]), verbo([prevented]), complemento([in, 12, 'CAH', girls, treated, at, the, latest, at, 6, weeks, gestation, and, minimized, in, 3, girls, treated, between, 6, and, 7, weeks, gestation])].
[sujeto(['Prenatal', 'DEX', should, be]), verbo([maintained]), complemento([to, prevent, virilization, and, traumatic, surgery, in, 'CAH', girls, after, informed, consent, and, information, provided, to, families, about, the, benefit, to, risk, ratio, in, limiting, hyperandrogenism, during, fetal, life])].
[sujeto(['Our', large, multicentric, 'French', cohort]), verbo([has]), complemento([helped, to, better, assess, the, risks, previously, reported])].
[sujeto(['Normal', male, sex, development]), verbo([requires]), complemento([the, 'SRY', gene, on, the, 'Y', 'chromosome,', the, regression, of, 'Müllerian', structures, via, 'anti-Müllerian', hormone, '(', 'AMH)', 'signalling,', the, development, of, the, 'Wolffian', duct, system, into, normal, male, internal, genital, structures, consequent, to, testosterone, secretion, by, the, testicular, 'Leydig', 'cells,', and, 'finally,', sufficient, activation, of, testosterone, to, dihydrotestosterone, by, 5, 'alpha-reductase'])].
[sujeto(['Recent', studies, in, human, fetal, development]), verbo([have]), complemento([demonstrated, the, early, fetal, expression, of, the, adrenocorticotrophic, hormone, '(', 'ACTH)', receptor, and, all, steroidogenic, components, necessary, for, the, biosynthesis, of, cortisol])].
[sujeto(['These', findings]), verbo([provide]), complemento([compelling, evidence, for, the, assumed, pathogenesis, of, congenital, adrenal, hyperplasia, '(', 'CAH)', due, to, 21, -, hydroxylase, 'deficiency,', diminished, feedback, to, the, pituitary, due, to, glucocorticoid, 'deficiency,', subsequent, 'ACTH', 'excess,', and, 'up-regulation', of, adrenal, androgen, production, with, subsequent, virilization])].
[sujeto(['Thus', 'CAH', teaches, important, lessons, from, 'nature,']), verbo([providing]), complemento([privileged, insights, into, the, window, of, human, sexual, 'differentiation,', and, particularly, highlighting, the, importance, of, steroidogenesis, in, the, process, of, human, sexual, differentiation])].
[sujeto(['Mutations', in, the, gene, encoding, 110, -, hydroxylase, '(', 'CYPI]BJ)', are, the, second, most, common]), verbo([cause]), complemento([of, congenital, adrenal, hyperplasia, '(', 'CAH),', a, disorder, characterized, by, adrenal, insufficiency, and, virilization, of, female, external, genitalia])].
[sujeto(['We', describe, a, new, case, of, 1113, -, hydroxylase, 'CAH']), verbo([caused]), complemento([by, donor, splice, site, mutation, in, the, 'CYPllB1', gene])].
[sujeto(['In', a, previous]), verbo([reported]), complemento([case, a, donor, splice, mutation, was, identified, for, the, first, time, at, the, same, position, codon, 318, of, the, 'CYPIIB1', gene])].
[sujeto(['To', clarify, the, complexity, of, possible, interactions, between, two, distinct, 'ligands,', 'PTH', and, 'PTHrP,', and, their, common, receptor, in, the, intact, 'organism,', and, to, identify, as, yet, unrecognized, roles, for, 'PTH', in, normal, 'physiology,', we]), verbo([have]), complemento([cloned, and, characterized, the, structural, 'organization,', nucleotide, sequence, and, transcriptional, regulation, of, the, murine, gene, encoding, 'PTH'])].
[sujeto(['Comparison', of, the, murine, preproPTH, sequence, with, other, mammalian, forms, of, the, protein, shows, it, to, be, highly]), verbo([conserved]), complemento([and, to, share, limited, structural, similarity, to, 'PTHrP', at, the, 'amino-terminal', 'region,', a, domain, critical, for, binding, and, activation, of, their, common, receptor])].
[sujeto(['Putative']), verbo([binding]), complemento([motifs, for, the, transcription, factors, 'sex-determining', region, 'Y', gene, 'product,', transcriptional, repressor, 'CDP,', hepatic, nuclear, factor, 3, 'beta,', 'GATA-binding', factor, 1, ',', glucocorticoid, 'receptor,', 'SRY-related', high, mobility, group, box, protein, 5, and, cAMP, response, element, binding, protein, were, identified, in, the, 5, '\'', flanking, region, of, the, 'Pth', gene])].
[sujeto(['When', placed, upstream, of, a, reporter, 'gene,', these, sequences, failed, to]), verbo([confer]), complemento([transcriptional, regulation, in, response, to, 1, ',', 25, '(', 'OH)(2)', vitamin, 'D(3),', but, responded, positively, to, the, addition, of, isoproterenol, and, forskolin])].
[sujeto(['Acutely', rejecting, allografts, showed, a, dense, mononuclear, infiltrate, consisting, of]), verbo([activated]), complemento(['CD4(+)', and, 'CD8(+)', 'T', cells, with, some, macrophages])].
[sujeto(['SOX9', is, a, transcription, factor, that]), verbo([activates]), complemento([type, 'II', procollagen, '(', 'Col2a1)', gene, expression, during, chondrocyte, differentiation])].
[sujeto(['Glucocorticoids', are, also, known, to]), verbo([promote]), complemento([chondrocyte, differentiation, via, unknown, molecular, mechanisms])].
[sujeto(['Sox9', mRNA, was]), verbo([expressed]), complemento([at, high, levels, in, these, chondrocytes])].
[sujeto(['Treatment', with, 'DEX']), verbo([enhanced]), complemento(['Sox9', mRNA, expression, within, 24, h, and, this, effect, was, observed, at, least, up, to, 48, h])].
[sujeto(['Western', blot, analysis, revealed, that, 'DEX', also]), verbo([enhanced]), complemento([the, levels, of, 'SOX9', protein, expression])].
[sujeto(['Treatment', with, 'DEX']), verbo([enhanced]), complemento(['Col2a1', mRNA, expression, in, these, chondrocytes, and, 'furthermore,', 'DEX', enhanced, the, activity, of, 'Col2-CAT', '(', chloramphenicol, 'acetyltransferase)', construct, containing, a, 1.6, kb, intron, fragment, where, 'chondrocyte-specific', 'Sry/Sox-', consensus, sequence, is, located])].
[sujeto(['The']), verbo([enhancing]), complemento([effect, of, 'DEX', was, specific, to, 'SOX9,', as, 'DEX', did, not, alter, the, levels, of, 'Sox6', mRNA, expression])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'DEX', promotes, chondrocyte, differentiation, through, enhancement, of, 'SOX9'])].
[sujeto(['Consequently,', each, invertebrate, gene]), verbo([has]), complemento([been, amplified, to, the, maximum, of, four, paralogous, genes, in, 'vertebrates:', the, 'one-to-four', rule])].
[sujeto(['When', this, rule, is, applied, to, genes, pertinent, to, gonadal, development, and, 'differentiation,', the, following, 'emerged:', '(', 'i)', 'Two', closely, related, 'zinc-finger', transcription, factor, genes, in, invertebrates]), verbo([have]), complemento([been, amplified, to, two, paralogous, groups, in, vertebrates])].
[sujeto(['Interestingly,', 'EGR1', and, 'WT1']), verbo([act]), complemento([as, antagonists, of, each, other, in, nephroblastic, cells])].
[sujeto(['Its', ancient, origin]), verbo([suggests]), complemento([that, 'SRY', once, became, extinct, in, earlier, 'vertebrates,', only, to, revive, itself, in, the, mammalian, ancestor])].
[sujeto(['(', 'iv)', 'Inasmuch', as, four, paralogues, of, one, invertebrate]), verbo([nuclear]), complemento([receptor, gene, have, differentiated, to, receptors, of, 'androgen,', 'mineralocorticoid,', glucocorticoid, and, 'progesterone,', there, should, at, most, be, four, paralogous, 'estrogen-receptor', genes, in, the, vertebrate, genome])].
[sujeto(['It', is, likely, that, one, of, them, plays, a, pivotal, role, in, the, 'estrogen-dependent', 'sex-determining', mechanism, so, commonly]), verbo([found]), complemento([among, 'reptiles,', amphibians, and, fish])].
[sujeto(['Alleles', of, the, 'sex-determining', genes, and, the, genes, of, the, other, genetic, systems, which]), verbo([participate]), complemento([in, regulation, of, reproduction, may, be, responsible, for, this, variability])].
[sujeto(['We']), verbo([have]), complemento([found, nearly, twofold, interstrain, differences, in, testosterone, levels, in, the, blood, of, male, rat, fetuses, of, 2, strains])].
[sujeto(['The', rats, with, higher, testosterone, levels, during, intrauterine, development]), verbo([have]), complemento([higher, rates, of, sexual, maturation, and, sexual, activity, in, future, life])].
[sujeto(['Genetic', differences, were, also]), verbo([found]), complemento([in, sensitivity, of, fetal, testosterone, to, disruptive, influences])].
[sujeto(['Consequently,', each, invertebrate, gene]), verbo([has]), complemento([been, amplified, to, the, maximum, of, four, paralogous, genes, in, 'vertebrates:', the, 'one-to-four', rule])].
[sujeto(['When', this, rule, is, applied, to, genes, pertinent, to, gonadal, development, and, 'differentiation,', the, following, 'emerged:', '(', 'i)', 'Two', closely, related, 'zinc-finger', transcription, factor, genes, in, invertebrates]), verbo([have]), complemento([been, amplified, to, two, paralogous, groups, in, vertebrates])].
[sujeto(['Interestingly,', 'EGR1', and, 'WT1']), verbo([act]), complemento([as, antagonists, of, each, other, in, nephroblastic, cells])].
[sujeto(['Its', ancient, origin]), verbo([suggests]), complemento([that, 'SRY', once, became, extinct, in, earlier, 'vertebrates,', only, to, revive, itself, in, the, mammalian, ancestor])].
[sujeto(['(', 'iv)', 'Inasmuch', as, four, paralogues, of, one, invertebrate]), verbo([nuclear]), complemento([receptor, gene, have, differentiated, to, receptors, of, 'androgen,', 'mineralocoticoid,', glucocorticoid, and, 'progesterone,', there, should, at, most, be, four, paralogous, 'estrogen-receptor', genes, in, the, vertebrate, genome])].
[sujeto(['It', is, likely, that, one, of, them, plays, a, pivotal, role, in, the, 'estrogen-dependent', 'sex-determining', mechanism, so, commonly]), verbo([found]), complemento([among, 'reptiles,', amphibians, and, fish])].
[sujeto(['A', de, novo, apparently, balanced, translocation]), verbo([involving]), complemento([chromosomes, 8, and, 20, was, found, in, a, 14, -, 'year-old', boy, with, minor, 'anomalies,', mild, skeletal, abnormalities, and, ambiguous, external, genitalia, including, perineoscrotal, 'hypospadias,', rudimentary, fused, labioscrotal, 'folds,', bilateral, 'cryptorchidism,', and, small, penis])].
[sujeto(['No', signs, of, other, conditions, known, to, be]), verbo([associated]), complemento([with, structural, anomalies, of, either, chromosome, 8, or, 20, were, present, and, incomplete, masculinisation, of, the, external, genitalia, appears, to, be, the, main, component, of, the, phenotype])].
[sujeto(['Coding', sequences, of, the, 'sex-determining', gene, '(', 'SRY)', and, androgen, receptor, gene, '(', 'AR)', were]), verbo([found]), complemento([to, be, identical, to, those, of, a, normal, male, excluding, their, role, in, the, cause, of, the, present, condition])].
[sujeto(['Since', several, other]), verbo([reports]), complemento([describe, the, association, of, hypospadias, and, hypertelorism, with, deletions, or, translocations, involving, 8, 'q,', we, suggest, that, a, locus, necessary, for, male, sex, differentiation, is, located, at, distal, 8, q])].
[sujeto(['Although', the, etiologies, of, true, hermaphroditism, and, mixed, gonadal, dysgenesis, remain, 'elusive,', most, gene, defects, in, female, pseudohermaphroditism, or, 'CAH']), verbo([have]), complemento([been, pinpointed, to, the, 21, -, hydroxylase, gene])].
[sujeto(['Incomplete', masculinization]), verbo([has]), complemento([been, found, to, be, due, to, defects, in, the, androgen, 'receptor,', 5, 'alpha-reductase,', or, enzymes, in, the, pathway, from, cholesterol, to, testosterone])].
[sujeto(['SRY', point, mutations]), verbo([have]), complemento([been, implicated, in, 46, 'XY', pure, gonadal, dysgenesis])].
[sujeto(['Retained', müllerian, ducts]), verbo([have]), complemento([been, attributed, to, point, mutations, in, the, 'MIS', 'gene;', those, with, normal, 'MIS', levels, should, be, expected, to, have, receptor, deficits])].
[sujeto(['The', proper, care, of, these, complex, patients]), verbo([requires]), complemento([that, the, physician, be, a, scientist, as, well, as, a, clinician, and, a, skilled, technician])].
[sujeto(['Several', genes, or, loci]), verbo([associated]), complemento([with, plasma, 'HDL-cholesterol', levels, have, been, identified, on, autosomes, and, the, 'X', chromosome])].
[sujeto(['In', 'contrast,', genes, or, loci, on, the, 'Y', chromosome]), verbo([have]), complemento([not, attracted, significant, attention, hitherto])].
[sujeto(['We', obtained, the, following, results, from, the, genotype, data, on, 30, single, nucleotide, polymorphisms, '(', 'SNPs),', including, nonsynonymous, and, synonymous, 'SNPs', and, 9, polymorphisms, in, 'Sry:', '(', 1, ')', 'Variation', in, rs46947134, of, 'Uty', was, significantly]), verbo([associated]), complemento([with, plasma, 'HDL-cholesterol', levels])].
[sujeto(['(', 2, ')', 'A', 'CAG', repeat, number, polymorphism, in, 'Sry', was, significantly]), verbo([associated]), complemento([with, plasma, 'HDL-cholesterol', levels])].
[sujeto(['We', identified, several, variants]), verbo([associated]), complemento([with, plasma, 'HDL-cholesterol', levels])].
[sujeto(['Because', the, physiological, significance, of, various, 'Y-linked', genes, remains, 'unclear,', the, results, of, this, study, will]), verbo([provide]), complemento([further, insights, into, the, functions, of, 'Y-linked', genes, in, lipid, metabolism])].
[sujeto(['Genome', analysis, of, patients, with, disorders, of, sex, 'development,', and, 'gain-', and, 'loss-of-function', studies, in, mice, indicate, that, gonadal, development, is]), verbo([regulated]), complemento([by, opposing, signals])].
[sujeto(['In', 'females,', the, 'Wnt/β-catenin', canonical, pathway, blocks, testicular, differentiation, by]), verbo([repressing]), complemento([the, expression, of, the, 'Sertoli', 'cell-specific', gene, 'Sox9', by, an, unknown, mechanism])].
[sujeto(['Using', cell, and, embryonic, gonad, culture, 'models,', we, show, that, activation, of, the, 'Wnt/β-catenin', pathway]), verbo([inhibits]), complemento([the, expression, of, 'Sox9', and, 'Amh,', whereas, mRNA, and, protein, levels, of, 'Sry', and, steroidogenic, factor, 1, '(', 'Sf1),', two, key, transcriptional, regulators, of, 'Sox9,', are, not, altered])].
[sujeto(['Ectopic', activation, of, 'Wnt/β-catenin', signaling, in, male, gonads]), verbo([led]), complemento([to, a, loss, of, 'Sf1', binding, to, the, 'Tesco', enhancer, and, absent, 'Sox9', expression, that, we, also, observed, in, 'wild-type', ovaries])].
[sujeto(['Moreover,', ectopic, 'Wnt/β-catenin', signaling]), verbo([induced]), complemento([the, expression, of, the, female, somatic, cell, 'markers,', 'Bmp2', and, 'Rspo1,', as, a, likely, consequence, of, 'Sox9', loss])].
[sujeto(['Wnt/β-catenin', signaling, in, 'XY', gonads, did, 'not,', 'however,', affect, gene, expression, of, the, steroidogenic, 'Leydig', cell, 'Sf1']), verbo([target]), complemento(['gene,', 'Cyp11a1,', or, 'Sf1', binding, to, the, 'Cyp11a1', promoter])].
[sujeto(['Our', data, support, a, model, in, ovary, development, whereby, activation, of, 'β-catenin']), verbo([prevents]), complemento(['Sf1', binding, to, the, 'Sox9', 'enhancer,', thereby, inhibiting, 'Sox9', expression, and, 'Sertoli', cell, differentiation])].
[sujeto(['Since']), verbo([loss]), complemento([of, myelin, is, considered, as, a, main, pathogenetic, 'factor,', the, precise, mechanism, inducing, dysmylination, in, 'NPC1', disease, is, still, unclear])].
[sujeto(['The', results, showed, that, 'NPC1', protein, was]), verbo([expressed]), complemento([in, oligodendrocytes, and, the, amount, of, myelin, protein, was, generally, decreased, in, all, parts, of, the, brain, and, spinal, cord, in, 'NPC1-mutant', mice])].
[sujeto(['Compared', to, wild, 'type,', the, amount, of, 'Sox10', and, 'YY1', was, not, different, in, 'NPC1-mutant', 'mice,', but, 'MRF', was, significantly, 'decreased,']), verbo([suggesting]), complemento([a, possible, mechanism, perturbing, differentiation, of, oligodendrocytes, and, the, myelination, process, in, the, 'NPC1-mutant', mouse])].
[sujeto(['Excess', cardiovascular, risk, in, men, compared, with, women]), verbo([has]), complemento([been, suggested, to, be, partly, explained, by, effects, of, the, 'Y', chromosome])].
[sujeto(['However,', inconsistent, results]), verbo([have]), complemento([been, reported, on, the, 'Y', 'chromosome\'s', genetic, influence, on, blood, pressure, and, lipid, levels])].
[sujeto(['The', prevalence, of, hypertension, tended, to, be, higher, in, 'YAP(+)', than, in, 'YAP(-)', 'men,', and, this, tendency, was]), verbo([found]), complemento([to, be, stronger, among, men, aged, 65, years, or, older])].
[sujeto(['In', 'conclusion,', 'Y', chromosome, polymorphisms, '(', 'YAP,', 'M175', and, 'SRY+465)', do, not, appear, to, be]), verbo([associated]), complemento([with, cardiovascular, risk, factors, in, 'Japanese', men])].
[sujeto(['Studies', using, much, larger, sample, sizes, 'and/or', additional, independent, samples, will, be]), verbo([required]), complemento([for, definitive, conclusions])].
[sujeto(['Previous', work]), verbo([suggested]), complemento([that, there, were, 'X-linked', 'parent-of-origin', effects, on, the, phenotype])].
[sujeto(['Eighty-three', percent, of, 45, ',', 'X']), verbo([retained]), complemento([their, maternal, 'X', '(', 'X(m)),', whereas, 64, '%', 46, 'Xi(Xq)', retained, their, paternal, 'X', '(', 'X(p),', 'P', &, 'lt;', 0.001, ')'])].
[sujeto(['Kidney', malformations, were, exclusively]), verbo([found]), complemento([in, 'X(m)', patients, '(', 'P', =, 0.03, ')'])].
[sujeto(['The', 'X(m)', group, had, lower, total, and, 'low-density', lipoprotein, cholesterol, '(', 'P', &, 'lt;', 0.003, ')', ',', and, higher, body, mass, index, sd, score, '(', 'P', =, 0.03, ')', that, was, not]), verbo([maintained]), complemento([after, 'GH', treatment])].
[sujeto(['The', parental, origin, of, the, missing, short, arm, of, the, 'X', chromosome]), verbo([has]), complemento([an, impact, on, 'overweight,', 'kidney,', 'eye,', and, 'lipids,', which, suggests, a, potential, effect, of, an, 'as-yet-undetermined', 'X', chromosome, gene, imprinting])].
[sujeto(['Genes', previously, implicated, in, mammalian, sexual, development]), verbo([have]), complemento([either, a, 'male-', or, 'female-specific', role])].
[sujeto(['The', signaling, molecule, 'WNT4']), verbo([has]), complemento([been, shown, to, be, important, in, female, sexual, development])].
[sujeto(['Lack', of, 'Wnt4', gives, rise, to, masculinization, of, the, 'XX', gonad, and, we, showed, previously, that, the, role, of, 'WNT4', was, to]), verbo([inhibit]), complemento([endothelial, and, steroidogenic, cell, migration, into, the, developing, ovary])].
[sujeto(['Here', we, show, that, 'Wnt4', also]), verbo([has]), complemento([a, function, in, the, male, gonad])].
[sujeto(['We']), verbo([find]), complemento([that, 'Sertoli', cell, differentiation, is, compromised, in, 'Wnt4', mutant, testes, and, that, this, defect, occurs, downstream, of, the, 'testis-determining', gene, 'Sry', but, upstream, of, 'Sox9', and, 'Dhh,', two, early, 'Sertoli', cell, markers])].
[sujeto(['Analysis', of, different, markers, identifies, the, most, striking, difference, in, the, genital, ridge, at, early, stages, of, its, development, between, 'wild-type', and, 'Wnt4', mutant, embryos, to, be, a, significant]), verbo([increase]), complemento([of, steroidogenic, cells, in, the, 'Wnt4', -, /, -, gonad])].
[sujeto(['These', results, identify, 'WNT4', as, a, new, factor]), verbo([involved]), complemento([in, the, mammalian, testis, determination, pathway, and, show, that, genes, can, have, a, specific, but, distinct, role, in, both, male, and, female, gonad, development])].
[sujeto(['In', 'addition,', their, effects, on, the, inflammatory, changes]), verbo([induced]), complemento([in, 'LDL-receptor', mice, fed, a, 'Western', diet, following, influenza, 'A', infection, were, studied])].
[sujeto(['When', apolipoprotein, 'AI', mimetic, peptides, synthesized, from, either, 'D-', or, 'L-amino', acids, were, administered, to, 'LDL-receptor', null, 'mice,', only, peptides, synthesized, from, 'D-amino', acids, were, stable, in, the, circulation, and]), verbo([enhanced]), complemento([the, ability, of, 'high-density', lipoprotein, '(', 'HDL)', to, protect, 'LDL', against, oxidation])].
[sujeto(['Administration', of, the, peptide, 'D-4F', to, 'LDL-receptor', null, mice, and, apoE, null, mice]), verbo([decreased]), complemento([lesion, size])].
[sujeto(['Additionally,', in, 'LDL', receptor, null, mice, after, influenza, 'infection,', 'D-4F', treatment]), verbo([increased]), complemento([plasma, 'HDL', levels, and, paraoxonase, 'activity,', and, inhibited, increased, in, 'LDL-cholesterol', and, peak, levels, of, 'interleukin-6', 'post-infection'])].
[sujeto(['Injection', of, female, mice, with, male, 'macrophages,', and, subsequent, measurement, of, the, male, '\'', 'sry\'', 'gene,', revealed, a, marked]), verbo([increase]), complemento([in, macrophage, traffic, into, the, aortic, arch, after, infection, that, was, prevented, by, administration, of, 'D-4F'])].
[sujeto(['This', indicates, 'that:', '(', 'i)', oral, 'D-4F']), verbo([has]), complemento([powerful, 'anti-atherosclerotic', 'properties,', and, '(', 'ii)', the, loss, of, the, 'anti-inflammatory', properties, of, 'HDL', after, influenza, infection, in, mice, is, associated, with, increased, arterial, macrophage, traffic, that, can, be, prevented, by, administration, of, 'D-4F'])].
[sujeto(['In', the, absence, of, 'Sry,', or, if, 'Sry', is]), verbo([expressed]), complemento([at, insufficient, 'levels,', the, support, cell, precursors, differentiate, as, granulosa, 'cells,', thus, initiating, the, ovarian, pathway])].
[sujeto(['We', demonstrate, that, the, transcription, factor, 'GATA4', and, its, 'co-factor', 'FOG2', are]), verbo([required]), complemento([for, gonadal, differentiation])].
[sujeto(['Mouse', fetuses, homozygous, for, a, null, allele, of, 'Fog2', or, homozygous, for, a]), verbo([targeted]), complemento([mutation, in, 'Gata4', '(', 'Gata4(ki))', that, abrogates, the, interaction, of, 'GATA4', with, 'FOG', 'co-factors', exhibit, abnormalities, in, gonadogenesis])].
[sujeto(['We']), verbo([found]), complemento([that, 'Sry', transcript, levels, were, significantly, reduced, in, 'XY', 'Fog2(-/-)', gonads, at, 'E11'])].
[sujeto(['In', 'addition,', three, genes, crucial, for, normal, 'Sertoli', cell, function, '(', 'Sox9,', 'Mis', and, 'Dhh)', and, three, 'Leydig', cell, steroid, biosynthetic, enzymes, '(', 'p450scc,', 3, betaHSD, and, 'p450c17)', were, not]), verbo([expressed]), complemento([in, 'XY', 'Fog2(-/-)', and, 'Gata(ki/ki)', 'gonads,', whereas, 'Wnt4,', a, gene, required, for, normal, ovarian, 'development,', was, expressed, ectopically])].
[sujeto(['By', 'contrast,', 'Wt1', and, 'Sf1,', which, are]), verbo([expressed]), complemento([prior, to, 'Sry', and, necessary, for, gonad, development, in, both, 'sexes,', were, expressed, normally, in, both, types, of, mutant, 'XY', gonads])].
[sujeto(['These', results, indicate, that, 'GATA4', and, 'FOG2', and, their, physical, interaction, are]), verbo([required]), complemento([for, normal, gonadal, development])].
[sujeto(['We']), verbo([reported]), complemento([that, 'HDL', loses, its, antiinflammatory, properties, during, acute, influenza, 'A', infection, in, 'mice,', and, we, hypothesized, that, these, changes, might, be, associated, with, increased, trafficking, of, macrophages, into, the, artery, wall])].
[sujeto(['D-4F', treatment]), verbo([increased]), complemento([plasma, 'HDL', cholesterol, and, paraoxonase, activity, compared, with, 'PBS', and, inhibited, increases, in, 'LDL', cholesterol, and, peak, levels, of, 'interleukin-6', after, infection])].
[sujeto(['Injection', of, female, mice, with, male, 'macrophages,', which, were, detected, with, 'real-time', polymerase, chain, reaction, to, measure, the, male, 'Sry', 'gene,', revealed, a, marked]), verbo([increase]), complemento([in, macrophage, traffic, into, the, aortic, arch, and, innominate, arteries, after, infection, that, was, prevented, by, administration, of, 'D-4F'])].
[sujeto(['We', conclude, that]), verbo([loss]), complemento([of, antiinflammatory, properties, of, 'HDL', after, influenza, infection, in, mice, is, associated, with, increased, arterial, macrophage, traffic, that, can, be, prevented, by, administration, of, 'D-4F'])].
[sujeto(['A', testicular, form, of, 'hormone-sensitive', lipase, '(', 'HSL(tes)),', a, triacylglycerol, 'lipase,', and, cholesterol, 'esterase,', is]), verbo([expressed]), complemento([in, male, germ, cells])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, 0.5, kilobase, pairs, of, the, human, 'HSL(tes)', promoter, directs, 'testis-specific', expression, of, a, chloramphenicol, acetyltransferase, reporter, gene, in, transgenic, mice, and, determined, regions, binding, nuclear, proteins, expressed, in, testis, but, not, in, liver, '(', 'Blaise,', 'R'])].
[sujeto(['In', gel, retardation, assays, using, early, spermatid]), verbo([nuclear]), complemento(['extracts,', a, germ, 'cell-specific', 'DNA-protein', interaction, was, mapped, between, -, 46, and, -, 29, base, pairs])].
[sujeto(['The', 'DNA']), verbo([binding]), complemento([nuclear, protein, showed, properties, of, zinc, finger, transcription, factors])].
[sujeto(['It', is, well, known, that, fetal, androgens, are]), verbo([required]), complemento([for, male, sexual, 'differentiation,', and, it, is, thought, that, fetal, ovaries, are, not, steroidogenically, active])].
[sujeto(['However,', molecular, 'details,', such, as, which, steroidogenic, enzymes, are, present, in, fetal, testes, and, which, enzymes, are, absent, in, fetal, 'ovaries,']), verbo([have]), complemento([not, been, established])].
[sujeto(['P450scc,', 3, beta, 'HSD,', and, 'P450c17', transcripts, were, detected, at, all, ages, in, fetal, 'testes,', indicating, that, mRNAs, for, the, steroidogenic, enzymes, that, are]), verbo([required]), complemento([to, convert, cholesterol, to, androgens, are, present, in, the, male, gonad, even, before, sexual, differentiation])].
[sujeto(['The', expression, of, 'P450arom']), verbo([suggests]), complemento([the, potential, of, fetal, and, neonatal, testes, to, convert, androgens, to, estrogens])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, the, absence, of, fetal, ovarian, steroid, hormone, production, is, the, result, of, lack, of, expression, of, at, least, three, of, the, steroidogenic, 'enzymes,', 'P450scc,', 'P450c17,', and, 'P450arom'])].
[sujeto(['Di-(2-ethylhexyl)', phthalate, '(', 'DEHP)', is, a, plasticizer, with, endocrine, disrupting, properties, that, is]), verbo([found]), complemento([ubiquitously, in, the, environment, as, well, as, in, human, amniotic, 'fluid,', umbilical, cord, 'blood,', human, 'milk,', 'semen,', and, saliva])].
[sujeto(['It', is, used, in, the, industry, to, add, flexibility, to, polyvinyl, 'chloride-derived', plastics, and, its, wide, spread, use, and, presence]), verbo([has]), complemento([resulted, in, constant, human, exposure, through, fetal, development, and, postnatal, life])].
[sujeto(['Epidemiological', studies]), verbo([have]), complemento([suggested, an, association, between, phthalate, exposures, and, human, reproductive, effects, in, infant, and, adult, populations])].
[sujeto(['The', present, review, focuses, on, these, novel, 'findings,', which]), verbo([suggest]), complemento([that, 'DEHP', exerts, more, complex, and, broader, disruptive, effects, on, the, endocrine, system, and, metabolism, than, previously, thought])].
[sujeto(['To']), verbo([report]), complemento([a, translocation, between, chromosomes, 3, and, 4, :, 46, ',', 'XY,t(3;4)(p25;q31'])].
[sujeto(['G-banding', of, his, chromosomes, showed, that, the, patient, had, a, balanced, translocation]), verbo([involving]), complemento([chromosomes, 3, and, 4, :, 46, ',', 'XY,t(3;4)(p25;q31'])].
[sujeto(['This', karyotype]), verbo([finding]), complemento([was, confirmed, by, 'FISH'])].
[sujeto(['Although', no, such, association]), verbo([has]), complemento([been, reported, to, 'date,', we, think, that, the, severe, hypospadias, in, our, case, might, be, associated, with, this, translocation])].
[sujeto(['Polymorphisms', 'C-824T', and, 'A-581G', were, located, in, highly]), verbo([conserved]), complemento([regions, and, were, predicted, to, disrupt, known, transcriptional, control, motifs, myocyte, enhancer, 'factor-2', '(', 'MEF2),', 'sex-determining', region, 'Y', '(', 'SRY),', and, forkhead, box, 'D1', '(', 'FOXD1)', at, 'C-824T', and, 'G/C-rich', binding, factors, specificity, protein, 1, '(', 'SP1),', activating, 'enhancer-binding', protein, 2, '(', 'AP2)],', early, growth, response, protein, 1, '(', 'EGR1)', at, 'A-581G'])].
[sujeto(['We', further, probed, the, functional, significance, of, 'C-824T', and, 'A-581G', by, cotransfection, of, 'trans-activating', factors, in, 'cella;', 'MEF2,', 'SRY,', and, 'FOXD1', differentially]), verbo([activated]), complemento(['C-824T,', whereas, the, 'G/C-rich', binding, factors, 'SP1,', 'AP2,', and, 'EGR1', differentially, activated, 'A-581G'])].
[sujeto(['At', 'C-824T,', factor, 'MEF2']), verbo([acted]), complemento([in, a, directionally, coordinate, fashion, '(', at, 'T&gt;C)', to, explain, the, in, vivo, trait, 'associations,', whereas, at, 'A-581G,', factors, 'SP1,', 'AP2,', and, 'EGR1', displayed, similar, differential, actions, '(', at, 'G&gt;A)'])].
[sujeto(['Finally,', chromatin, immunoprecipitation, demonstrated, that, the, endogenous, factors]), verbo([bound]), complemento([to, the, motifs, in, cella])].
[sujeto(['MEF2,', 'FOXD1,', and, 'SRY', contribute, to, functional, differences, in, 'C-824T', 'expression,', whereas, 'SP1,', 'AP2,', and, 'EGR1']), verbo([mediate]), complemento([those, of, 'A-581G'])].
[sujeto(['The', 'SRY', effect, on, 'TH', transcription]), verbo([suggests]), complemento([a, mechanism, whereby, male, and, female, sex, may, differ, in, sympathetic, activity, and, hence, blood, pressure])].
[sujeto(['This', fatty, acid]), verbo([has]), complemento([profound, and, diverse, effects, on, liver, metabolism])].
[sujeto(['The', levels, of, 'AST,', 'ALT', and, 'ALP', in, the, serum, of, rats, with, 'APAP-induced', liver, injury, were, significantly]), verbo([increased]), complemento([and, returned, to, the, levels, in, control, group, by, day, six])].
[sujeto(['The', 'APAP-induced']), verbo([decrease]), complemento([in, albumin, was, significantly, improved, in, rats, through, cell, 'therapy,', when, compared, with, that, in, the, 'APAP-alone', treated, rats])].
[sujeto(['Depending', on, multiple, signaling, 'cues,', in, about, half, of, the, 'individuals,', the, juvenile, ovaries, degenerate, or, undergo, apoptosis, to, initiate, testes, development, while, the, other, half]), verbo([maintains]), complemento([the, oogenic, pathway])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, activation, of, 'NFκB', and, prostaglandin, synthase, 2, '(', 'ptgs2)', results, in, 'female-biased', sex, ratios])].
[sujeto(['Prostaglandin', synthase, and, prostaglandins, are]), verbo([involved]), complemento([in, multiple, physiological, 'functions,', including, cell, survival, and, apoptosis])].
[sujeto(['On', further, 'evaluation,', we, observed, that, exposure, with, the, prostaglandin, 'D2', '(', 'PGD2)', analogue, 'BW-245C']), verbo([induced]), complemento(['SRY-box', containing, gene, 9, a, '(', 'sox9a)', and, resulted, in, 'male-biased', sex, ratios])].
[sujeto(['On', the, other, 'hand,', prostaglandin, 'E2', '(', 'PGE2)', treatment, resulted, in, 'female-biased', sex, ratios, and]), verbo([involved]), complemento([activation, of, 'NFκB', and, the, 'β-catenin', pathway, as, well, as, inhibition, of, sox9])].
[sujeto(['In', this, 'study,', we, show, that, 'PGD2', and, 'PGE2', can, program, the, gonads, to, either, the, testis, or, the, ovary, differentiation, 'pathways,', indicating, that, prostaglandins, are]), verbo([involved]), complemento([in, the, regulation, of, zebrafish, gonadal, differentiation])].
[sujeto(['Valproic', acid, also]), verbo([inhibits]), complemento([histone, deacetylase, 'activity,', which, is, associated, with, histone, hyperacetylation, and, changes, in, gene, expression])].
[sujeto(['Reverse', 'transcription-polymerase', chain, reaction, analysis, revealed, a, significant]), verbo([increase]), complemento([in, conserved, dopamine, neurotrophic, factor, '(', 'CDNF)', and, glial, cell, 'line-derived', neurotrophic, factor, mRNA, 'expression,', after, treatment, with, clinically, relevant, concentrations, of, 'VPA', '(', 0.5, or, 1.0, 'mM)', for, 24, hr])].
[sujeto(['In', 'addition,', significant]), verbo([increases]), complemento([in, the, mRNA, levels, of, the, early, dopaminergic, neuron, 'marker,', nuclear, 'receptor-related', protein, 1, '(', 'Nurr1),', and, the, transcriptional, 'regulator,', early, growth, response, protein, 1, '(', 'Egr1),', were, observed, after, treatment, with, 'VPA', for, 24, hr])].
[sujeto([2, cells, after, 'VPA', treatment, for, 24, hr, or, 48, 'hr,']), verbo([suggesting]), complemento([involvement, of, an, epigenetic, mechanism, in, the, observed, gene, induction, by, this, drug])].
[sujeto(['These', findings, support, a, role, for, 'VPA', in]), verbo([modulating]), complemento([neurotrophic, and, differentiation, factor, 'expression,', in, keeping, with, its, reported, neuroprotective, and, neurodevelopmental, effects])].
[sujeto(['The', potential, of, 'MSC', for, mesenchymal, differentiation]), verbo([has]), complemento([been, well, documented, in, different, animal, models, predominantly, on, rodents])].
[sujeto(['Plastic-adherent', bMSC, isolated, from, fetal, 'BM']), verbo([maintained]), complemento([a, 'fibroblast-like', morphology, under, monolayer, culture, conditions])].
[sujeto(['These', cells]), verbo([expressed]), complemento([high, levels, of, 'MSC', surface, markers, '(', 'CD73,', 'CD90,', and, 'CD105)', and, low, levels, of, hematopoietic, surface, markers, '(', 'CD34', and, 'CD45)'])].
[sujeto(['Culture', of, bMSC, under, osteogenic, conditions, during, a, 27, -, day, period]), verbo([induced]), complemento(['up-regulation', of, the, osteocalcin, '(', 'OC)', gene, expression, and, alkaline, phosphatase, '(', 'ALPL)', 'activity,', and, promoted, mineralization, of, the, matrix])].
[sujeto(['Increasing', supplementation, levels, of, ascorbic, acid, to, culture, media]), verbo([enhanced]), complemento([osteogenic, differentiation, of, 'bMSC;', 'whereas,', reduction, of, 'FBS', supplementation, compromised, osteogenesis])].
[sujeto([bMSC]), verbo([increased]), complemento([expression, of, 'cartilage-specific', genes, aggrecan, '(', 'ACAN),', collagen, 2, 'A1', '(', 'COL2A1)', and, 'SRY', '(', 'sex-determining', region, 'Y)', box, 9, '(', 'SOX9)', at, 'Day', 21, of, chondrogenic, differentiation])].
[sujeto(['Treatment', of, bMSC, with, adipogenic, factors]), verbo([increased]), complemento([levels, of, fatty, 'acid-binding', protein, 2, '(', 'AP2)', mRNA, and, accumulation, of, lipid, vacuoles, after, 18, &, 'nbsp;days', of, culture])].
[sujeto(['NANOG', mRNA, levels, in, differentiating, bMSC, were, not, affected, during, adipogenic, 'culture;', 'however,', osteogenic, and, chondrogenic, conditions]), verbo([induced]), complemento([higher, and, lower, 'levels,', respectively])].
[sujeto(['The', simplicity, of, isolation, and, the, differentiation, potential]), verbo([suggest]), complemento([that, bMSC, from, 'abattoir-derived', fetal, 'BM', are, appropriate, candidate, for, investigating, 'MSC', biology, and, for, eventual, applications, for, regenerative, therapy])].
[sujeto(['H-REV107']), verbo([has]), complemento([been, shown, to, express, at, high, levels, in, differentiated, tissues, of, 'post-meiotic', testicular, germ, cells])].
[sujeto(['Prostaglandin', 'D2', '(', 'PGD2)', is, conjectured, to]), verbo([induce]), complemento(['SRY-related', 'high-mobility', group, box, 9, '(', 'SOX9)', expression, and, subsequent, 'Sertoli', cell, differentiation])].
[sujeto(['To', 'date,', the, function, of, 'H-rev107', in, differentiated, testicular, cells]), verbo([has]), complemento([not, been, well, defined])].
[sujeto(['In', the, 'study,', we]), verbo([found]), complemento([that, 'H-rev107', was, 'co-localized', with, prostaglandin, 'D2', synthase, '(', 'PTGDS)', and, enhanced, the, activity, of, 'PTGDS,', resulting, in, increase, of, 'PGD2', production, in, testis, cells])].
[sujeto(['Furthermore,', when, 'H-rev107', was]), verbo([expressed]), complemento([in, human, 'NT2/D1', testicular, cancer, 'cells,', cell, migration, and, invasion, were, inhibited])].
[sujeto(['Also,', silencing, of, 'PTGDS', would, reduce, 'H-rev107-mediated']), verbo([increase]), complemento([in, 'PGD2,', 'cAMP,', and, 'SOX9'])].
[sujeto(['These', results, revealed, that, 'H-rev107,', through, 'PTGDS,']), verbo([suppressed]), complemento([cell, migration, and, invasion])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, the, 'PGD2-cAMP-SOX9', signal, pathway, might, play, an, important, role, in, 'H-rev107-mediated', cancer, cell, invasion, in, testes])].
[sujeto(['Afterwards', the, expression, of, 'Sox9', is]), verbo([maintained]), complemento([by, a, positive, feedback, loop, with, 'Fgf9', and, prostaglandin, 'D2', as, well, as, by, autoregulative, ability, of, 'Sox9'])].
[sujeto(['If', these, factors, reach, high, 'concentrations,', then, 'Sox9', 'and/or', 'Fgf9', may]), verbo([inhibit]), complemento([the, female, pathway])].
[sujeto(['Surprisingly,', 'splicing,']), verbo([nuclear]), complemento(['transport,', and, extramatrix, proteins, may, be, involved, in, sex, determination])].
[sujeto(['In', the, mouse, 'XY', 'gonad,', 'SOX9', upregulates, 'Fgf9,', which, initiates, a, 'Sox9/Fgf9', feedforward, 'loop,', and, 'Sox9', expression, is]), verbo([stimulated]), complemento([by, the, prostaglandin, 'D2', '(', 'PGD2)', producing, lipocalin, prostaglandin, 'D', synthase, '(', 'L-PGDS,', or, 'PTDGS)', 'enzyme,', which, accelerates, commitment, to, the, male, pathway])].
[sujeto(['In', an, attempt, to, decipher, the, genetic, relationships, between, 'Sox9', and, the, 'L-Pgds/PGD2', pathway, during, mouse, testicular, 'organogenesis,', we]), verbo([found]), complemento([that, ablation, of, 'Sox9', at, the, onset, or, during, the, time, window, of, expression, in, embryonic, 'Sertoli', cells, abolished, 'L-Pgds', transcription])].
[sujeto(['In', this, 'study,', we, demonstrated, genetically, that, the, 'L-Pgds/PGD2', pathway]), verbo([acts]), complemento([as, a, second, amplification, loop, of, 'Sox9', expression])].
[sujeto(['These', data]), verbo([suggest]), complemento(['that,', once, activated, and, maintained, by, 'SOX9,', production, of, testicular, 'L-PGDS', leads, to, the, accumulation, of, 'PGD2,', which, in, turn, activates, 'Sox9', transcription, and, nuclear, translocation, of, 'SOX9'])].
[sujeto(['This', mechanism]), verbo([participates]), complemento([together, with, 'FGF9', as, an, amplification, system, of, 'Sox9', gene, expression, and, activity, during, mammalian, testicular, organogenesis])].
[sujeto(['However,', expression, of, the, transcription, factor, 'SRY', initiates, male, development, and]), verbo([induces]), complemento(['patterning,', 'proliferation,', and, epithelialization, specific, to, the, testis])].
[sujeto(['These', mechanisms]), verbo([have]), complemento([recently, been, shown, to, both, promote, the, male, fate, and, simultaneously, repress, ovarian, development])].
[sujeto(['After', their, 'specification,', 'Sertoli', cells, epithelialize, and, surround, the, male, germ, line, to, form, large, looping, structures]), verbo([bound]), complemento([by, extracellular, matrix])].
[sujeto(['To']), verbo([ensure]), complemento([that, 'Sertoli', cells, differentiate, in, sufficient, numbers, to, induce, normal, testis, 'development,', the, early, testis, produces, prostaglandin, 'D(2)', '(', 'PGD(2)),', which, recruits, cells, of, the, supporting, cell, lineage, to, a, 'Sertoli', cell, fate])].
[sujeto(['Here', we, show, that, the, gene, encoding, prostaglandin, 'D', synthase, '(', 'Pgds),', the, enzyme, that, produces, 'PGD(2),', is]), verbo([expressed]), complemento([in, 'Sertoli', cells, immediately, after, the, onset, of, 'Sox9', expression])].
[sujeto(['Promoter', analysis, in, silico, and, in, vitro, identified, a, paired, 'SOX/SRY']), verbo([binding]), complemento([site])].
[sujeto(['Interestingly,', only, 'SOX9,', and, not, 'SRY,', was, able, to]), verbo([bind]), complemento([as, a, dimer, to, this, site, and, transactivate, the, 'Pgds', promoter])].
[sujeto(['Finally,', chromatin, immunoprecipitation, proved, that, 'SOX9', but, not, 'SRY']), verbo([binds]), complemento([to, the, 'Pgds', promoter, in, vivo])].
[sujeto(['We']), verbo([have]), complemento([raised, an, antibody, specifically, recognizing, endogenous, mouse, 'SRY', protein, and, used, it, to, investigate, the, molecular, and, cellular, mode, of, action, of, 'SRY', in, testis, determination])].
[sujeto(['We']), verbo([find]), complemento([that, expression, of, 'SRY', protein, closely, mirrors, the, expression, of, 'Sry', mRNA, in, mouse, genital, ridges, and, is, detectable, for, 6, to, 8, h, after, the, mRNA, ceases, to, be, detectable])].
[sujeto(['The', subset, of, somatic, cells, that]), verbo([expresses]), complemento(['SRY', begins, to, express, 'SOX9', almost, immediately])].
[sujeto(['Since', these, 'SOX9-positive', cells, go, on, to, develop, as, 'Sertoli', 'cells,', it, appears, that, 'SRY', expression, marks, the, 'pre-Sertoli', cell, lineage, and]), verbo([leads]), complemento([to, 'up-regulation', of, 'Sox9', expression, 'cell-autonomously'])].
[sujeto(['However,', a, small, proportion, of, 'SOX9-positive', cells, did, not, appear, to]), verbo([express]), complemento(['SRY,', possibly, reflecting, the, additional, involvement, of, paracrine, signaling, in, activating, 'Sox9', transcription, in, these, cells])].
[sujeto(['Finally,', we, showed, by, employing, specific, inhibitors, that, the, causative, signaling, molecule, is, prostaglandin, 'D2', '(', 'PGD2)', and, that, 'PGD2', can]), verbo([induce]), complemento(['Sox9', transcription, in, cultured, 'XX', gonads])].
[sujeto(['Our', data, indicate, a, mechanism, whereby, 'Sry', uses, both, a, 'cell-autonomous', mechanism, and, a, 'PGD2-mediated', signaling, mechanism, to]), verbo([stimulate]), complemento([expression, of, 'Sox9', and, induce, the, differentiation, of, 'Sertoli', cells, in, vivo])].
[sujeto(['During', mammalian, gonadal, 'development,']), verbo([nuclear]), complemento(['import/export', of, the, transcription, factor, 'SOX9', is, a, critical, step, of, the, 'Sry-initiated', 'testis-determining', cascade])].
[sujeto(['In', this, 'study,', we, identify, a, molecular, mechanism, contributing, to, the, 'SOX9']), verbo([nuclear]), complemento([translocation, in, 'NT2/D1', 'cells,', which, is, mediated, by, the, prostaglandin, 'D2', '(', 'PGD2)', signalling, pathway, via, stimulation, of, its, 'adenylcyclase-coupled', 'DP1', receptor])].
[sujeto(['We']), verbo([find]), complemento([that, activation, of, 'cAMP-dependent', protein, kinase, 'A', '(', 'PKA)', induces, phosphorylation, of, 'SOX9', on, its, two, 'S64', and, 'S181', 'PKA', 'sites,', and, its, nuclear, localization, by, enhancing, 'SOX9', binding, to, the, nucleocytoplasmic, transport, protein, importin, beta])].
[sujeto(['We', thus, propose, a, new, step, in, the, 'sex-determining', cascade, where, 'PGD2']), verbo([acts]), complemento([as, an, autocrine, factor, inducing, 'SOX9', nuclear, translocation, and, subsequent, 'Sertoli', cell, differentiation])].
[sujeto(['We']), verbo([have]), complemento([examined, specific, genes, whose, expression, is, altered, during, apoptosis, induced, by, prostaglandin, '(', 'PG)A2', and, 'Delta12-PGJ2', in, human, hepatocellular, carcinoma, 'Hep3B', cells])].
[sujeto(['Using', mRNA, differential, 'display,', we]), verbo([have]), complemento([identified, two, 'genes:', one, is, specifically, 'up-regulated', and, encodes, for, human, 'Sox-4', '(', 'Sry-HMG', box, 'gene)', and, the, other, is, significantly, 'down-regulated', and, is, the, human, homolog, of, yeast, 'Ssf-1,', a, novel, splicing, factor])].
[sujeto(['Interestingly,', 'Sox-4', was, highly]), verbo([expressed]), complemento([in, subcutaneous, tumors, grown, in, nude, mice, as, a, xenograft, from, 'Hep3B', cells])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, expression, of, 'Sox-4', may, be, related, to, the, apoptosis, pathway, leading, to, cell, death, as, well, as, to, 'tumorigenesis,', and, that, 'Ssf-1', gene, may, serve, as, a, negative, regulator, of, 'PGA2/Delta12-PGJ2-mediated', 'Hep3B', cell, apoptosis])].
[sujeto(['We', describe, a, method, for, rapid, and, efficient, polymerase, chain, reaction, '(', 'PCR)', amplification, of, specific]), verbo([target]), complemento(['DNA', sequences, directly, from, cells, fixed, in, 3, :, 1, 'methanol-acetic', acid, '(', 'Carnoy\'s', 'fixative)', for, routine, cytogenetic, analysis])].
[sujeto(['No', differences, in, quality, of, amplification, products, were]), verbo([found]), complemento([between, 'PCR', templates, obtained, from, fresh, tissues, or, from, cells, fixed, for, varying, lengths, of, time, in, 'Carnoy\'s', fixative])].
[sujeto(['This', technique]), verbo([has]), complemento([the, following, 'advantages:', '(', 1, ')', it, allows, retrospective, studies, of, genetic, disorders, from, archived, 'specimens;', '(', 2, ')', it, requires, only, a, limited, number, of, 'cells;', '(', 3, ')', it, is, rapid, and, 'simple;', and, '(', 4, ')', it, avoids, multistep, procedures, required, in, extraction, of, the, 'DNA'])].
[sujeto(['Transforming', growth, factor, β, 1, '(', 'Tgfβ1)', is]), verbo([involved]), complemento([in, the, progression, of, renal, fibrosis])].
[sujeto(['According', to, recent, 'observations,', ammonium, chloride, '(', 'NH4Cl)']), verbo([prevented]), complemento(['phosphate-induced', vascular, 'remodeling,', effects, involving, decrease, of, 'Tgfβ1', expression, and, inhibition, of, 'Tgfβ1-dependent', signaling])].
[sujeto(['The', present, 'study,', 'thus,', explored, whether, 'NH4Cl', influences, renal, 'Tgfβ1-induced', 'pro-fibrotic', signaling, in, obstructive, nephropathy]), verbo([induced]), complemento([by, unilateral, ureteral, obstruction, '(', 'UUO)'])].
[sujeto(['UUO', was]), verbo([induced]), complemento([for, seven, days, in, 'C57Bl6', mice, with, or, without, additional, treatment, with, 'NH4Cl', '(', 0.28, 'M', in, drinking, 'water)'])].
[sujeto(['UUO']), verbo([increased]), complemento([renal, mRNA, expression, of, 'Tgfb1,', 'Tgfβ-activated', kinase, 1, '(', 'Tak1)', protein, abundance, and, 'Smad2', phosphorylation, in, the, nuclear, fraction, of, the, obstructed, kidney, 'tissues,', effects, blunted, in, 'NH4Cl', treated, mice, as, compared, to, control, treated, mice])].
[sujeto(['The', mRNA, levels, of, the, transcription, factors]), verbo([nuclear]), complemento([factor, of, activated, 'T', cells, 5, '(', 'Nfat5)', and, 'SRY', '(', sex, determining, region, 'Y)-box', 9, '(', 'Sox9)', as, well, as, of, tumor, necrosis, factor, α, '(', 'Tnfα),', interleukin, 6, '(', 'Il6),', plasminogen, activator, inhibitor, 1, '(', 'Pai1)', and, 'Snai1', were, 'up-regulated', in, the, obstructed, kidney, tissues, following, 'UUO,', effects, again, significantly, ameliorated, following, 'NH4Cl', treatment])].
[sujeto(['Furthermore,', the]), verbo([increased]), complemento([protein, and, mRNA, expression, of, 'α-smooth', muscle, actin, '(', 'α-Sma),', fibronectin, and, collagen, type, 'I', in, the, obstructed, kidney, tissues, following, 'UUO', were, significantly, attenuated, following, 'NH4Cl', treatment])].
[sujeto(['Sixty-five', percent, of, fibroblast, colonies, '(', 55, of, 85, ')', isolated, from, female, heart, allografts]), verbo([expressed]), complemento([the, male, sry, gene])].
[sujeto(['Cardiac', fibroblasts, are]), verbo([activated]), complemento([and, exist, in, a, profibrogenic, microenvironment, in, allografts, undergoing, chronic, rejection])].
[sujeto(['A', substantial, proportion, of, intragraft, fibroblasts, are]), verbo([recruited]), complemento([from, allograft, recipients, in, this, experimental, model, of, chronic, cardiac, allograft, rejection])].
[sujeto(['To']), verbo([gain]), complemento([more, insights, into, the, function, of, specific, genes, in, these, complex, 'processes,', the, expression, of, multiple, candidates, needs, to, be, 'assessed,', preferably, on, the, protein, level])].
[sujeto(['Here,', we, developed, a]), verbo([targeted]), complemento([proteomics, method, based, on, selected, reaction, monitoring, '(', 'SRM)', to, study, the, candidate, 'sex-related', proteins, in, zebrafish, which, were, selected, based, on, a, global, proteomics, analysis, of, adult, gonads, and, representational, difference, analysis, of, male, and, female, 'DNA,', as, well, as, on, published, information, on, zebrafish, and, other, vertebrates])].
[sujeto(['Evidence', on, protein, expression, was, obtained, for, the, first, time, for, several, candidate, genes, previously, studied, only, on, the, mRNA, level, or]), verbo([suggested]), complemento([by, bioinformatic, predictions])].
[sujeto(['Tuba1b', '(', tubulin, alpha, 1, 'b),', initially, included, in, the, study, as, one, of, the, potential, housekeeping, 'proteins,', was]), verbo([found]), complemento([to, be, preferentially, expressed, in, the, adult, testis, with, nearly, absent, expression, in, the, ovary])].
[sujeto(['The', revealed, changes, in, protein, expression, patterns]), verbo([associated]), complemento([with, gonad, differentiation, suggest, that, several, of, the, examined, 'proteins,', especially, 'Ilf2', and, 'Ilf3', '(', interleukin, 'enhancer-binding', factors, 2, and, 3, ')', ',', 'Raldh3', '(', retinaldehyde, dehydrogenase, type, 3, ')', ',', 'Zgc:195027', '(', low, density, 'lipoprotein-related', receptor, protein, 3, ')', and, 'Sept5a', '(', septin, 5, 'a),', may, play, a, specific, role, in, the, sexual, differentiation, in, zebrafish])].
[sujeto(['We']), verbo([report]), complemento([that, mMSC, 'Feeder', 'Layer', and, the, combination, of, 'VEGF,', 'SCF', and, 'TPO', strongly, promote, hematopoietic, differentiation])].
[sujeto(['The', results, showed, that, the, cells]), verbo([induced]), complemento([from, 'ES-D3', expressed, hematopoietic, progenitor, antigens, '(', 'CD34', and, 'CD117),', myelocyte, cell, antigen, '(', 'CD11b),', erythrocyte, cell, antigen, '(', 'Ter119),', and, transcription, factors, '(', 'Flk-1,', 'GATA-2,', 'SCL,', 'beta-H1', and, 'beta-major)'])].
[sujeto(['Furthermore,', those]), verbo([induced]), complemento([differentiated, cells, were, injected, into, female, 'C57BL/6', mice, which, were, treated, with, high, dose, topotecan, chemotherapy, to, restore, part, of, their, blood, system, function])].
[sujeto(['We', observed, rapid, white, blood, cell, 'recovery,', which]), verbo([suggested]), complemento([that, the, infusion, of, differentiated, cells, has, a, positive, impact, on, hematopoiesis])].
[sujeto(['Emerging', data]), verbo([suggest]), complemento([that, cancer, stem, cells, '(', 'CSCs)', exist, in, equilibrium, with, differentiated, cells, and, that, stochastic, transitions, between, these, states, can, account, for, tumor, heterogeneity, and, drug, resistance])].
[sujeto(['These', tumor, spheres, were]), verbo([found]), complemento([to, have, higher, aldehyde, dehydrogenase, '(', 'ALD)', cell, fractions, and, increased, expression, of, 'Kruppel-like', factor, 4, ',', 'SRY', '(', sex, determining, region, 'Y)-box', 2, ',', and, 'Nanog', and, were, resistant, to, 'γ-radiation,', 5, -, 'fluorouracil,', 'cisplatin,', and, etoposide, treatment, compared, with, monolayer, culture, cells])].
[sujeto(['ALDHigh', clones, showed]), verbo([increased]), complemento(['EGF', receptor, '(', 'EGFR)', and, 'insulin-like', growth, 'factor-1', receptor, '(', 'IGF-1R)', 'phosphorylation,', with, increased, activation, of, downstream, pathways, compared, with, 'ALDLow', clones])].
[sujeto(['Taken', 'together,', these, results, show, that, 'HNSCC', 'CSCs', exhibit, 'plasticity,', with, the, maintenance, of, the, stem, cell, fraction, dependent, on, the, 'EGFR', and, 'IGF-1R', pathways, and, potentially, amenable, to]), verbo([targeted]), complemento([therapeutics])].
[sujeto(['True', hermaphrodite, '(', 'TH)', is, genetically, a, heterogenous, condition]), verbo([causing]), complemento([ovarian, and, testicular, tissue, development, in, the, same, individual])].
[sujeto(['We']), verbo([report]), complemento([here, the, first, case, of, pure, 'NGCO', in, the, right, ovotestis, of, a, 23, -, 'year-old', 45, ',', 'XO/46X,X', 'sex-determining', region, 'Y', chromosome, '(', 'SRY)-negative', 'TH'])].
[sujeto(['The', patient]), verbo([responded]), complemento([well, to, radical, surgery, with, 'bleomycin,', 'etoposide,', cisplatin, '(', 'BEP)', regimen])].
[sujeto(['We', also, hypothesize, that, some, mutations, of, an, 'X-linked', or, autosomal, gene]), verbo([lead]), complemento([to, testicular, determination, in, 'SRY-negative', 'TH', patients])].
[sujeto(['In', the, past, 15, 'years,', anomalies, of, male, sexual, differentiation]), verbo([have]), complemento([greatly, increased, in, both, wildlife, and, humans, in, different, parts, of, the, world])].
[sujeto(['Environmental', endocrine, disruptors]), verbo([have]), complemento([been, implicated, in, the, dramatic, rise, in, neonatal, ambiguous, genitalia, with, variable, rates, of, 'severity,', such, as, 'micropenis,', 'cryptorchidism,', and, isolated, or, associated, hypospadias])].
[sujeto(['Because', most, environmental, 'pollutants,', such, as, organochlorine, 'pesticides,', polychlorinated, 'biphenyls,', dioxins, and, 'furans,', alkylphenol, 'polyetholyethoxylates,', and, phytoestrogens, and, 'phtalates,']), verbo([have]), complemento([estrogenic, and, antiandrogenic, 'activity,', they, are, able, to, interfere, with, normal, fetal, male, sexual, differentiation])].
[sujeto(['All', had, normal, testosterone, production, after, human, chorionic, gonadotrophin, stimulation, 'testing,']), verbo([suggesting]), complemento([androgen, resistance, or, 'so-called', idiopathic, 'MPH'])].
[sujeto(['Since', environmental, pollutants, are, known, for, their, estrogenic, activity, and, can, be]), verbo([released]), complemento([progressively, from, the, adipose, tissue, where, they, 'accumulate,', we, detected, their, presence, by, measuring, the, estrogenic, bioactivity, of, the, 'newborns\'', serum, with, a, recently, developed, ultrasensitive, bioassay])].
[sujeto(['We']), verbo([found]), complemento([higher, estrogenic, bioactivity, in, these, newborns, than, in, controls])].
[sujeto(['In', 'conclusion,', the, maternal, exposure, to, environmental, pollutants, during, pregnancy, and, high, estrogenic, bioactivity, in, the, 'newborns\'', serum, highly]), verbo([suggest]), complemento([that, ambiguous, genitalia, are, related, to, fetal, exposure, to, endocrine, disruptors])].
[sujeto(['Mice', may, share, similar, mechanism, with, human, underlying, reproductive, toxicity]), verbo([induced]), complemento([by, 'di(2-ethylhexyl)', phthalate, '(', 'DEHP),', which, is, not, supposed, to, be, associated, with, decreased, testicular, testosterone])].
[sujeto(['After', in, utero, 'DEHP', 'exposure,']), verbo([loss]), complemento([of, 'Sertoli', cells, and, germ, cells, were, observed, in, the, male, pups, at, postnatal, days, 21])].
[sujeto(['And', 'SRY-related', 'HMG', box, 9, '(', 'SOX9),', 'Fibroblast', growth, 'factor-9', '(', 'FGF9),', and, 'Double-sex', and, 'Mab-3', related, transcripttion, factor, 1, '(', 'DMRT1)', proteins, were, significantly, downregulated, by, 'DEHP', at, 2, 'mg/kg/d', and, 'above,']), verbo([suggesting]), complemento([the, depression, of, 'Sertoli', cell, differentiation])].
[sujeto(['Furthermore,', the, 'testosterone-independent', pathway]), verbo([regulating]), complemento(['Sertoli', cells, differentiation, was, disturbed, in, fetus, by, 'DEHP', at, 2, 'mg/kg/d', and, above, during, the, critical, time, window, of, sex, 'determination,', involving, 'Gadd45g', '→', 'Gata4/Fog2', '→', 'Sry', '→', 'Sox9', '→', 'Fgf9', 'The', results, suggest, that, in, utero, 'DEHP', exposure, damaged, 'Sertoli', cells, in, the, postnatal, life, of, mice, offspring, via, disturbance, of, the, differentiation, regulating, 'pathway,', potentially, inducing, declines, in, spermatogenesis])].
[sujeto(['Insulin-like', androgenic, gland, hormone, gene, '(', 'IAG)', is, a, sex, regulator, specifically]), verbo([expressed]), complemento([in, male, 'crustaceans,', controlling, the, male, sexual, 'differentiation,', spermatogenesis, and, reproductive, strategy])].
[sujeto(['Our', previous, study]), verbo([reported]), complemento([the, cloning, and, characterization, of, the, prawn, 'Macrobrachium', nipponense, 'IAG', '(', 'MnIAG)'])].
[sujeto(['In', this, 'study,', we, further, identified, a, 2214, -, bp, 'MnIAG', 5, '\'', -, flanking, 'region,', and, analyzed, its, transcription, factor]), verbo([binding]), complemento([sites, and, transcriptional, activity])].
[sujeto(['The', results, showed, that, there, were, two, potential, promoter, core, 'sequences,', three, 'TATA', boxes, and, one, 'CAAT', box, existing, in, the, 'MnIAG', 5, '\'', -, flanking, region, as, well, as, many, potential, transcription, factor]), verbo([binding]), complemento(['sites,', such, as, 'SRY,', 'Sox-5,', 'GATA-1,', etc])].
[sujeto(['Notably,', the, transcriptional, activity, was, weak, in, this, 'region,', and, a, negative, regulatory, region, was]), verbo([found]), complemento([in, -, 604, to, -, 231, bp])].
[sujeto([nipponense, yeast, libraries, and, identified, proteins]), verbo([interacting]), complemento([with, the, 'MnIAG', protein, by, yeast, two, hybridization, assay])].
[sujeto(['The', identification, of, 'MnIAG', putative, regulatory, region, and, proteins, that]), verbo([interact]), complemento([with, 'IAG', will, facilitate, our, understanding, of, the, regulatory, role, of, 'MnIAG', and, provide, a, foundation, for, deep, insight, into, the, prawn, sex, differentiation, mechanism, and, signaling, transduction, pathways])].
[sujeto(['To', identify, differentially]), verbo([expressed]), complemento([genes, '(', 'DEGs)', and, find, associated, pathways, that, may, function, as, targets, of, lung, cancer])].
[sujeto(['Besides,', novel, genes]), verbo([associated]), complemento([with, lung, cancer, were, identified, by, 'co-expression', analysis])].
[sujeto(['Then,', 'GO', enrichment, and, transcription]), verbo([binding]), complemento([site, analysis, were, performed, on, these, 'DEGs,', and, novel, genes, were, predicted, using, 'DAVID'])].
[sujeto(['Finally,', 'PPI', network, was, constructed, by, 'String', software, in, order, to, get, the, hub, codes]), verbo([involved]), complemento([in, cancer, carcinoma])].
[sujeto(['The', transcription, biding, site, analysis, showed, that, these, genes, were]), verbo([regulated]), complemento([by, 'LHX3,', 'HNF3B,', 'CDP,', 'HFH1,', 'FOXO4,', 'STAT,', 'SOX5,', 'MEF2,', 'FOXO3', and, 'SRY'])].
[sujeto(['Hub', codes, as, 'BUB1B,', 'MAD2L', and, 'TOP2A', may, play, as]), verbo([target]), complemento([genes, in, lung, carcinoma, in, the, result, of, 'PPI', network, analysis])].
[sujeto(['Newly', predicted, genes, and, hub, codes, can, perform, as]), verbo([target]), complemento([genes, for, diagnose, and, clinical, therapy, of, lung, cancer])].
[sujeto(['Single', nucleotide, polymorphisms, '(', 'SNPs)', are, an, important]), verbo([cause]), complemento([of, functional, variation, in, proteins, leading, to, tumorigenesis])].
[sujeto(['After', preprocessing, of, raw, 'data,', 'GC-associated', 'SNPs', were, identified, using, the, 'Cochran-Armitage', trend, 'test,', and, differentially]), verbo([expressed]), complemento([genes, '(', 'DEGs)', were, screened, out, using, the, limma, package, in, 'R'])].
[sujeto(['Significant', 'DEGs', with, risk]), verbo([associated]), complemento(['SNP', loci, were, screened, using, the, 'Fisher', combination, test])].
[sujeto(['Gene', ontology, function, and, pathway, enrichment, analyses, were, performed, for, 'DEGs', with, risk]), verbo([associated]), complemento(['SNP', loci, by, 'GenCLip', online, tool])].
[sujeto(['Transcriptional', regulatory, analysis, was, also, conducted, for, transcription, factor, and]), verbo([target]), complemento(['DEGs'])].
[sujeto(['A', total, of, 79, 'DEGs', with, risk]), verbo([associated]), complemento(['SNP', loci, were, identified, from, 'GC', samples, compared, with, normal, controls])].
[sujeto(['Additionally,', 'DEGs', were, significantly]), verbo([involved]), complemento([in, the, 'NO1', 'pathway,', including, 'actin,', alpha, 1, ',', skeletal, muscle, '(', 'ACTA1)'])].
[sujeto(['In', the, regulatory, 'network,', transcription, factor, forkhead, box, 'L1', '(', 'FOXL1)']), verbo([regulated]), complemento([26, 'DEGs', with, risk, associated, 'SNP', 'loci,', including, 'Iroquois', homeobox, 1, '(', 'IRX1)', 'rs11134044,', sex, determining, region, 'Y', '(', 'SRY)-box1', '(', 'SOX1)', rs9549447, and, msh, homeobox, 1, '(', 'MSX1)', rs41451149])].
[sujeto(['IRX1,', 'SOX1', and, 'MSX1', with, risk]), verbo([associated]), complemento(['SNP', loci, may, serve, as, candidate, biomarkers, for, diagnosis, and, prognosis, of, 'GC'])].
[sujeto(['We']), verbo([report]), complemento([a, case, of, a, 14, -, 'year-old', male, with, microorchidism, and, mild, bilateral, gynecomastia, who, referred, to, our, hospital, because, of, abnormal, gender, characteristics])].
[sujeto(['This', study, adds, a, new, case, of, 'SRY-negative', 46, ',', 'XX', testicular, disorder, of, sex, development, and, further, verifies, the, view, that, the, absence, of, major, regions, from, the, 'Y', chromosome]), verbo([leads]), complemento([to, an, incomplete, masculine, 'phenotype,', abnormal, hormone, levels, and, infertility])].
[sujeto(['Although', members, of, 'SOX', family]), verbo([have]), complemento([been, well, documented, for, their, essential, roles, in, embryonic, 'development,', cell, proliferation, and, 'disease,', the, functional, role, and, molecular, mechanism, of, 'SOX30', in, cancer, are, largely, unexplored])].
[sujeto(['SOX30', was]), verbo([expressed]), complemento([in, normal, and, 'peri-tumoral', lung, tissues, in, which, 'SOX30', was, 'unmethylated,', but, was, silenced, or, downregulated, in, lung, cancer, cell, lines, and, primary, lung, tumor, tissues, harboring, a, hypermethylated, 'SOX30'])].
[sujeto(['De-methylation', experiments, further, confirmed, that, silence, of, 'SOX30', was]), verbo([regulated]), complemento([by, its, hypermethylation])].
[sujeto(['Ectopic', expression, of, 'SOX30']), verbo([induces]), complemento([cancer, cell, apoptosis, with, inhibiting, proliferation, in, vitro, and, represses, tumor, formation, in, 'vivo,', whereas, knockdown, of, 'SOX30', demonstrates, a, reversed, effect, both, in, vitro, and, in, vivo])].
[sujeto(['At', the, molecular, 'level,', the, antitumorigenic, effect, of, 'SOX30', is]), verbo([mediated]), complemento([by, directly, binding, to, 'CACTTTG', '(', +, 115, to, +, 121, ')', of, p53, promoter, region, and, activating, p53, 'transcription,', suggesting, that, 'SOX30', is, a, novel, transcriptional, activating, factor, of, p53])].
[sujeto(['Overall,', these, findings, demonstrate, that, 'SOX30', is, a, novel, epigenetic, silenced, tumor, suppressor]), verbo([acting]), complemento([through, direct, regulation, of, p53, transcription, and, expression])].
[sujeto(['This', study]), verbo([provides]), complemento([novel, insights, on, the, mechanism, of, tumorigenesis, in, lung, cancer])].
[sujeto(['This', study, adds, cases, on, the, five, new, 46, ',', 'XX', male, individuals, with, 'SRY-positive', and, further, verifies, the, view, that, the, presence, of, 'SRY', gene, and, the, absence, of, major, regions, in, 'Y', chromosome, should]), verbo([lead]), complemento([to, the, expectance, of, a, completely, masculinised, 'phenotype,', abnormal, hormone, levels, and, infertility])].
[sujeto(['In', recent, 'years,', 'up-regulation', of, 'SOX11']), verbo([has]), complemento([been, detected, in, various, types, of, solid, tumors])].
[sujeto(['In', this, 'study,methylation-specific', 'PCR', and, real, time, quantitative, 'PCR']), verbo([have]), complemento([been, applied, to, investigate, the, effect, of, promoter, methylation, of, the, 'SOX11', gene, on, 'SOX11', expression, in, the, nasopharyngeal, carcinoma, and, chronic, inflammation, tissues])].
[sujeto(['SOX11', mRNA, and, protein, were, 're-expressed,', 'SOX11', gene, was, 'demethylated,', and, growth, and, invasion, of, cells, were]), verbo([inhibited]), complemento([in, 'CNE2', cell, line, after, 5, -, 'aza-2\'-deoxycytidine', treatment])].
[sujeto(['MiR-375', is, an, important, small, 'non-coding', 'RNA', that, is, specifically]), verbo([expressed]), complemento([in, islet, cells, of, the, pancreas])].
[sujeto(['miR-375', is]), verbo([required]), complemento([for, normal, pancreatic, genesis, and, influences, not, only, 'β-cell', mass, but, also, 'α-cell', mass])].
[sujeto(['When', human, embryonic, stem, cells, '(', 'hESCs)', differentiate, into, endodermal, 'lineages,', 'miR-375', is, highly]), verbo([expressed]), complemento([in, the, definitive, 'endoderm,', which, suggests, that, 'miR-375', may, have, a, distinct, role, in, early, development])].
[sujeto(['miR-375', plays, an, important, role, in, the, complex, regulatory, network, of, pancreatic, 'development,', which, could, be]), verbo([regulated]), complemento([by, pancreatic, 'genes,', such, as, 'NeuroD1,', 'Ngn3,', 'Pdx1', and, 'Hnf6;', 'additionally,', 'miR-375', regulates, genes, related, to, pancreas, 'development,', cell, growth, and, proliferation, and, insulin, secretion, genes, to, exert, its, function])].
[sujeto(['Because', of, the, special, role, of, 'miR-375,', it, may, be, a, potential]), verbo([target]), complemento([to, treat, diabetes])].
[sujeto(['Antagonising', 'miR-375', may]), verbo([enhance]), complemento([the, effects, of, 'exendin-4', in, 'patients,', and, controlling, the, expression, of, 'miR-375', could, assist, mature, 'hESCs-derived', 'β-cells'])].
[sujeto(['Ovarian-specific', promoter, '(', 'OSP)', is, a, 'tissue-specific', promoter, only]), verbo([expressed]), complemento([in, the, ovary, to, regulate, its, development])].
[sujeto(['Bioinformatics', analysis, indicated, that, the, fragment, contained, multiple, transcription, factor]), verbo([binding]), complemento(['sites,', such, as, 'SRY,', 'HSF,', 'AP-1,', 'C/EBP,', 'CAAT,', 'TATA,', and, so, 'on,', and, the, nucleotide, sequence, of, 'OSP', shared, 99, '%', and, 97, '%', similarity, with, those, of, 'OSP-1', and, 'OSP-2', in, rat])].
[sujeto(['In', 'summary,', we, successfully, extracted, dairy, goat, 'OSP', and, identified, its, transcriptional, 'activity,', which, in, part, shed, light, on, the, study, of, 'ovarian-specific', transcription, and]), verbo([provided]), complemento([further, insights, into, the, development, and, regulation, of, dairy, 'goat\'s', ovary, as, well])].
[sujeto(['Long', noncoding, 'RNAs', '(', 'lncRNAs)']), verbo([have]), complemento([been, attracting, immense, research, 'interest,', while, only, a, handful, of, lncRNAs, have, been, characterized, thoroughly])].
[sujeto(['Their', involvement, in, the, fundamental, cellular, processes, including]), verbo([regulate]), complemento([gene, expression, at, 'epigenetics,', 'transcription,', and, 'post-transcription', highlighted, a, central, role, in, cell, homeostasis])].
[sujeto(['Here,', we, give, a, systematic, and, comprehensive, summary, of, the, existing, knowledge, of, lncRNAs, in, order, to]), verbo([provide]), complemento([a, better, understanding, of, this, new, studying, field])].
[sujeto(['In', this, 'review,', we, also, highlighted, recent, studies, related, lncRNAs, in, central, nervous, system, '(', 'CNS)', development, and, neurodegenerative, 'diseases,', including, 'Alzheimer\'s', disease, '(', 'AD),', 'Parkinson\'s', disease, '(', 'PD),', 'Huntington\'s', disease, '(', 'HD)', and, amyotrophic, lateral, sclerosis, '(', 'ALS),', and, elucidated, some, specific, lncRNAs, which, may, be, important, for, understanding, the, pathophysiology, of, neurodegenerative, 'diseases,', also]), verbo([have]), complemento([the, potential, as, therapeutic, targets])].
[sujeto(['Recently,', 'genome-wide', association, studies]), verbo([have]), complemento([implicated, 'SOX5', as, a, candidate, gene, for, susceptibility, to, four, 'cardiac-related', 'endophenotypes:', higher, resting, heart, rate, '(', 'HR),', the, electrocardiographic, 'PR', 'interval,', atrial, fibrillation, and, left, ventricular, mass])].
[sujeto(['We']), verbo([have]), complemento([determined, that, human, 'SOX5', has, a, highly, conserved, 'Drosophila', 'ortholog,', 'Sox102F,', and, have, employed, transgenic, 'Drosophila', models, to, quantitatively, measure, cardiac, function, in, adult, flies])].
[sujeto(['For', this, 'purpose,', we]), verbo([have]), complemento([developed, a, 'high-speed', and, 'ultrahigh-resolution', optical, coherence, tomography, imaging, 'system,', which, enables, rapid, 'cross-sectional', imaging, of, the, heart, tube, over, various, cardiac, cycles, for, the, measurement, of, cardiac, structural, and, dynamical, parameters, such, as, 'HR,', dimensions, and, areas, of, heart, 'chambers,', cardiac, wall, thickness, and, wall, velocities])].
[sujeto(['We']), verbo([have]), complemento([found, that, the, silencing, of, 'Sox102F', resulted, in, a, significant, decrease, in, 'HR,', heart, chamber, size, and, cardiac, wall, 'velocities,', and, a, significant, increase, in, cardiac, wall, thickness, that, was, accompanied, by, disrupted, myofibril, structure, in, adult, flies])].
[sujeto(['In', 'addition,', the, silencing, of, 'Sox102F', in, the, wing]), verbo([led]), complemento([to, increased, 'L2,', 'L3', and, wing, marginal, veins, and, increased, and, disorganized, expression, of, 'wingless,', the, central, component, of, the, 'Wnt', signaling, pathway])].
[sujeto(['This', implicates, an, important, functional, role, for, 'SOX5', in, heart, and]), verbo([suggests]), complemento([that, the, alterations, in, 'SOX5', levels, may, contribute, to, the, pathogenesis, of, multiple, cardiac, diseases, or, traits])].
[sujeto(['The', aim]), verbo([has]), complemento([been, to, set, up, a, rapid, and, accurate, microarray, assay, using, sandwich, mode, for, sex, determination, of, bovine, preimplantation, embryos])].
[sujeto(['This']), verbo([suggests]), complemento([that, the, oligonucleotide, microarray, method, of, 'SRY', gene, analysis, can, be, used, in, early, sex, prediction, of, bovine, embryos, in, breeding, programs])].
[sujeto(['The', 'Sry-containing', protein, 'Sox2', initially, was, known, to]), verbo([regulate]), complemento([the, 'self-renewal', of, the, mouse, and, human, embryonic, stem, cells, '(', 'ESCs)'])].
[sujeto(['It', is, also, important, for, the, maintenance, of, stem, cells, in, multiple, adult, tissues, including, the, brain, and, 'trachea,', and, it, is, one, of, the, key, transcription, factors, for, establishing]), verbo([induced]), complemento([pluripotent, stem, cells])].
[sujeto(['Recently,', overexpression, and, gene, amplification, of, 'Sox2']), verbo([have]), complemento([been, associated, with, the, development, of, squamous, cell, carcinoma, in, multiple, tissues, such, as, the, lung, and, esophagus])].
[sujeto(['These', different, roles, for, 'Sox2']), verbo([involve]), complemento([a, complicated, regulatory, networks, consisting, of, 'microRNAs,', kinases, and, signaling, molecules])].
[sujeto(['While', the, levels, of, 'Sox2', are]), verbo([modulated]), complemento([transcriptionally, and, 'translationally,', 'post-translational', modification, is, also, important, for, the, various, functions, of, 'Sox2'])].
[sujeto(['In', 'clinics,', high, levels, of, 'Sox2', are, correlated, with, poor, prognosis, and]), verbo([increased]), complemento([proliferation, of, cancer, stem, cells])].
[sujeto(['Therefore']), verbo([targeting]), complemento(['Sox2', can, be, potentially, explored, for, a, new, therapeutic, avenue, to, treat, cancers])].
[sujeto(['We', will, also, review, the, main, upstream, and, downstream]), verbo([targets]), complemento([of, 'Sox2,', which, can, be, potentially, used, as, therapeutic, measures, to, treat, cancer, with, abnormal, levels, of, 'Sox2'])].
[sujeto(['In', the, present, 'study,']), verbo([increased]), complemento([expression, levels, of, 'COL9A1', were, identified, in, the, abductor, hallucis, muscle, of, 'ICTEV', patients, compared, with, those, in, control, samples])].
[sujeto(['The', 'COL9A1', gene, is]), verbo([regulated]), complemento([by, 'SRY', '(', 'sex&#8209;determining', region, 'Y)&#8209;box', 9, '(', 'SOX9)'])].
[sujeto([mRNA, and, protein, expression, levels, of, 'SOX9', were, detected, by, 'real&#8209;time', polymerase, chain, reaction, and, western, blot, 'analysis,', respectively, and, were]), verbo([found]), complemento([to, be, significantly, higher, in, 'ICTEV', muscle, samples, compared, with, those, in, control, samples])].
[sujeto(['Intestinal', metaplasia, began, to]), verbo([express]), complemento(['CEACAM1', and, showed, more, membranous, staining, of, 'CEACAM1', than, normal, mucosa, and, hyperplastic, polyps, '(', 'P', =])].
[sujeto(['SOX9', expression, significantly]), verbo([increased]), complemento([from, nonneoplastic, lesions, to, neoplastic, 'lesions,', and, 'CEACAM1', expression, patterns, markedly, 'changed;', their, coexpression, also, showed, signally, elevated, suggesting, that, 'SOX9,', as, a, transcriptional, 'regulator,', play, important, roles, in, the, changing, of, 'CEACAM1', expression, 'patterns,', which, might, promote, the, tumor, progression])].
[sujeto(['Stem', cell, transplantation]), verbo([has]), complemento([become, a, promising, therapeutic, approach, for, the, treatment, of, myocardial, infarction, '(', 'MI)'])].
[sujeto(['However,', the, poor, survival, of, the, donor, cells, after, transplantation]), verbo([has]), complemento([restricted, its, therapeutic, efficacy])].
[sujeto(['Hydrogen', sulfide, '(', 'H(2)S),', one, gaseous, signaling, 'molecule,']), verbo([has]), complemento([been, applied, to, inhibit, cell, apoptosis, and, promote, cell, survival])].
[sujeto(['Preconditioning', 'MSCs', with, 200, 'µmol/L', 'NaHS', '(', as, the, donor, of, 'H(2)S)', for, 30, min]), verbo([decreased]), complemento([the, 'hypoxia-induced', cell, apoptosis, in, vitro])].
[sujeto(['The', mechanisms, contributing, to, the, beneficial, effects, of, 'H(2)S', on, 'MSCs', were]), verbo([associated]), complemento([with, increased, levels, of, phosphorylated, 'Akt', '(', 'pAkt),', phosphorylated, 'Erk1/2', '(', 'pErk1/2)', and, phosphorylated, glycogen, synthase, 'kinase-3β', '(', 'pGSK-3β)', in, 'MSCs'])].
[sujeto(['Furthermore,', transplantation, of, the, 'H(2)S-pretreated', 'MSCs', reduced, the, infarct, size, and]), verbo([increased]), complemento([left, ventricular, '(', 'LV)', 'function,', as, judged, by, transthoracic, echocardiography])].
[sujeto(['In', 'conclusion,', 'H(2)S', preconditioning, effectively]), verbo([promotes]), complemento(['MSCs', survival, under, ischemic, injury, and, helps, cardiac, repair, after, 'MI,', which, has, great, clinical, significance])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, the, observed, complex, 'DSD', phenotype, is, the, result, of, somatic, gonosomal, mosaicism, and, 'UPD', despite, a, normal, blood, karyotype])].
[sujeto(['The', discovery, of, the, role, of, a, 'teleost-specific', aquaporin, '(', 'Aqp1ab)', during, the, process, of, oocyte, hydration, in, marine, fish, producing, pelagic, '(', 'floating)', 'eggs,', recently, confirmed, by, molecular, 'approaches,']), verbo([has]), complemento([revealed, that, this, mechanism, is, more, sophisticated, than, initially, thought])].
[sujeto(['Recent', phylogenetic, and, genomic, studies]), verbo([suggest]), complemento([that, 'Aqp1ab', likely, evolved, by, tandem, duplication, from, a, common, ancestor, and, further, neofunctionalized, in, oocytes, for, water, transport])].
[sujeto(['Investigations', into, the, regulation, of, 'Aqp1ab', during, oogenesis, indicate, that, the, mRNA, and, protein, product, are, highly, accumulated, during, early, oocyte, 'growth,', possibly, through, the, transcriptional, activation, of, the, aqp1ab, promoter, by, the, classical]), verbo([nuclear]), complemento([progesterone, receptor, and, perhaps, by, 'Sry-related', high, mobility, group, '[', 'HMG]-box', '(', 'Sox)', transcription, factors])].
[sujeto(['During', oocyte, growth, and, 'maturation,', 'Aqp1ab', intracellular, trafficking, may, be]), verbo([regulated]), complemento([by, phosphorylation, 'and/or', dephosphorylation, of, specific, 'C-terminal', residues, in, 'Aqp1ab,', as, well, as, by, 'signal-mediated', sorting, processes])].
[sujeto(['These', mechanisms, possibly]), verbo([regulate]), complemento([the, temporal, insertion, of, 'Aqp1ab', into, the, oocyte, plasma, membrane, during, oocyte, 'hydration,', although, the, intracellular, signaling, pathways, involved, are, yet, unknown])].
[sujeto(['Interestingly,', in, some, freshwater, species, that, spawn, partially, hydrated, 'eggs,', high, accumulation, of, transcripts, encoding, functional, 'Aqp1ab', channels]), verbo([have]), complemento([also, been, found, in, the, ovary])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, 'Aqp1ab-mediated', mechanism, for, oocyte, hydration, is, likely, conserved, in, teleosts])].
[sujeto(['One', of, the, most, dramatic, differences]), verbo([involves]), complemento([estrogen, positive, 'feedback,', which, leads, to, ovulation])].
[sujeto(['Estradiol']), verbo([stimulated]), complemento([both, '[', 'Ca2+]i', release, and, progesterone, synthesis, in, hypothalamic, astrocytes, from, adult, female, mice])].
[sujeto(['Surface', biotinylation, demonstrated, mERα, in, both, female, and, male, 'astrocytes,', but, only, in, female, astrocytes, did, estradiol, treatment]), verbo([increase]), complemento([insertion, of, the, receptor, into, the, 'membrane,', a, necessary, step, for, maximal, '[', 'Ca2+]i', release])].
[sujeto(['The', trafficking, of, mERα, in, 'female,', but, not, 'male,', astrocytes, further]), verbo([suggests]), complemento([that, cell, signaling, mechanisms, are, sexually, differentiated])].
[sujeto(['SOX-9,', an, essential, factor, for, male, sexual, 'development,', can, be]), verbo([induced]), complemento([by, prostaglandin, 'D2', in, a, 'Sry-independent', mechanism])].
[sujeto(['Recent', data]), verbo([suggest]), complemento([that, the, hedgehog, pathway, is, involved, in, the, differentiation, of, normal, 'Sertoli', and, 'Leydig', cells])].
[sujeto(['The', purpose, of, our, study, was, to, investigate, the, mechanisms]), verbo([involved]), complemento([in, the, differentiation, of, ovarian, sex, 'cord-stromal', tumour, '(', 'SCST)', cells])].
[sujeto(['Sertoli', cells]), verbo([expressed]), complemento(['anti-Mullerian', hormone, '(', 'AMH),', 'SOX-9,', prostaglandin, 'D', synthase, '(', 'Pgds)', and, 'bcl-2', '(', in, four, of, four, 'cases);', sonic, hedgehog, '(', 'Shh)', and, p53, '(', in, three, of, four, 'cases)', and, androgen, receptors, '(', 'AR;', in, one, of, four, 'cases)'])].
[sujeto(['Leydig', cells]), verbo([expressed]), complemento(['Shh', and, 'AR', '(', two, of, two, 'cases),', while, they, showed, no, expression, of, 'p53,', 'bcl-2', and, 0, '%', 'Ki-67', index])].
[sujeto(['Granulosa', cells]), verbo([expressed]), complemento(['AMH,', 'Pgds,', 'Shh,', estrogen, 'receptors,', progesterone, 'receptors,', 'AR', and, 'bcl-2', '(', in, two, of, two, 'cases)', and, p53, '(', in, one, of, two, 'cases)'])].
[sujeto(['Further', investigation, is]), verbo([required]), complemento([to, clarify, the, role, of, the, molecules, outlined, above, in, the, histogenesis, of, ovarian, 'SCST,', as, 'Pgds-mediated', 'SOX-9', upregulation, could, provide, a, reasonable, explanation, for, the, presence, of, testicular, differentiation, in, ovarian, 'SCST'])].
[sujeto(['This', result]), verbo([suggests]), complemento([that, sexual, differentiation, of, 'PR', expression, in, these, regions, is, likely, controlled, mainly, by, gonadal, 'hormones,', not, by, the, genetic, sex, of, the, brain, cells])].
[sujeto(['No', differences, in, 'PRir', were, detected, between, 'wild-type', 'XY', mice, with, the, 'Sry', gene, on, the, 'Y-chromosome', and, 'XY', mice, with, the, 'Sry', 'transgene,']), verbo([suggesting]), complemento([that, testicular, hormones, produced, in, these, two, genotypes, have, comparable, effects, on, neural, tissue])].
[sujeto(['Here,', we]), verbo([report]), complemento([a, 'SLCT', with, intermediate, differentiation, in, a, 23, -, 'year-old', woman, investigated, by, light, 'microscopy,', immunohistochemistry, for, intermediate, 'filaments,', and, sex, steroid, hormone, receptors, '(', 'SSHR),', as, well, as, by, polymerase, chain, reaction, '(', 'PCR)', for, the, presence, of, the, 'sex-determining', region, 'Y', gene, '(', 'SRY)'])].
[sujeto(['Our', investigation, shows, that, the, 'SCs', of, 'SLCT']), verbo([express]), complemento([progesterone, and, androgen, receptors, as, well, as, cytokeratins, and, vimentin])].
[sujeto(['Thus,', our, results]), verbo([provide]), complemento([strong, evidence, for, a, close, histogenetic, relationship, between, the, 'SLCT', and, the, female, 'gonocyte-supporting', 'cell,', the, granulosa, cell, '(', 'GC)'])].
[sujeto(['To', study, the, process, of, mammalian, sex, determination, and, in, particular, to, further, understand, the, mechanisms, of, transcriptional, regulation, of, the, 'SRY', 'gene,', we]), verbo([have]), complemento([isolated, a, 4.5, -, kilobase, '(', 'kb)', pig, 'SRY', 5, '\'', flanking, sequence])].
[sujeto(['To', facilitate, the, in, vitro, analysis, of, these, 'sequences,', we]), verbo([have]), complemento([generated, a, porcine, genital, ridge, '(', 'PGR)', cell, line, '(', 900000000000.0, ')', that, expresses, 'SRY', as, well, as, 'SOX9,', steroidogenic, 'factor-1', '(', 'SF-1),', and, 'DAX1'])].
[sujeto(['Via']), verbo([primer]), complemento([extension, analysis, on, 'RNA', from, this, cell, 'line,', a, transcription, start, site, for, porcine, 'SRY', was, identified, at, -, 661, base, pairs, '(', 'bps)', 5, '\'', from, the, translation, initiation, site])].
[sujeto(['Deletion', studies, of, the, 'SRY', 5, '\'', flanking, sequences, in, 'PGR', 900000000000.0, cells, demonstrated, that, -, 1.4, kb, of, 5, '\'', flanking, sequences]), verbo([retained]), complemento([full, transcriptional, activity, compared, with, the, -, 4.5, kb, 'fragment,', but, that, transcriptional, activity, fell, when, further, deletions, were, made])].
[sujeto(['Sequences', downstream, of, the, transcriptional, start, site, are, important, for, promoter, 'activity,', because, deleting]), verbo([transcribed]), complemento([but, not, translated, sequences, eliminated, promoter, activity])].
[sujeto(['Sequence', analysis, of, the, -, 1.4, kb, fragment, identified, two, potential]), verbo([binding]), complemento([sites, for, 'SF-1,', at, -, 1369, and, at, -, 290, from, the, 'ATG'])].
[sujeto(['To', address, the, role, of, 'SF-1', transactivation, in, 'SRY', promoter, 'activity,', mutagenesis, studies, of, the, potential, 'SF-1']), verbo([binding]), complemento([sites, were, performed, and, revealed, that, these, sites, were, indeed, important, for, 'SRY', promoter, activity])].
[sujeto(['Gel', shift, assays, confirmed, that, the, upstream, site, was]), verbo([recognized]), complemento([by, mouse, 'SF-1', protein])].
[sujeto(['The', purpose, of, this, study, is, to, understand, whether, naturally, occurring, genetic, variation, in, the, promoter, of, chromogranin, 'B', '(', 'CHGB),', a, major, constituent, of, catecholamine, storage, 'vesicles,', is, functional, and]), verbo([confers]), complemento([risk, for, cardiovascular, disease])].
[sujeto(['Previously,', we]), verbo([found]), complemento([that, genetic, variation, at, 'CHGB', influenced, autonomic, 'function,', with, association, maximal, toward, the, 5, '\'', region])].
[sujeto(['The', 'A-296C', disrupted, a, 'c-FOS', 'motif,', exhibiting, differential, mobility, shifting, to, chromaffin, cell]), verbo([nuclear]), complemento([proteins, during, 'EMSA,', binding, of, endogenous, 'c-FOS', on, 'ChIP,', and, differential, response, to, exogenous, 'c-FOS'])].
[sujeto(['The', common, 'CHGB', promoter, variants, 'A-296C', and, 'A-261T,', and, their, consequent, 'haplotypes,', alter]), verbo([binding]), complemento([of, specific, transcription, factors, to, influence, gene, expression, in, cella, as, well, as, 'BP', in, vivo])].
[sujeto(['Involvement', of, the, 'sex-specific', factor, 'SRY']), verbo([suggests]), complemento([a, novel, mechanism, for, development, of, sexual, dimorphism, in, 'BP'])].
[sujeto(['Trophoblast', migration, into, the, maternal, circulation, is]), verbo([increased]), complemento([in, preeclampsia, and, can, trigger, the, endothelial, dysfunction, that, characterizes, the, clinical, disease])].
[sujeto(['We', hypothesised, that, '\'', fetal, 'trafficking\'', is]), verbo([increased]), complemento([in, women, with, severe, preeclampsia, and, that, the, quantity, of, trafficking, is, greater, in, women, with, more, severe, disease])].
[sujeto(['No', correlation, was]), verbo([found]), complemento([between, the, quantity, of, fetal, 'DNA', and, disease, severity])].
[sujeto(['Catsper', genes, are, exclusively]), verbo([expressed]), complemento([in, the, testis, during, 'spermatogenesis,', but, the, function, and, regulation, of, the, corresponding, promoter, regions, are, unknown])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, cloning, and, characterization, of, the, promoter, regions, in, the, human, and, murine, 'Catsper1', genes])].
[sujeto(['We', also]), verbo([found]), complemento([that, the, immediate, upstream, region, and, the, first, exon, in, the, human, 'CATSPER1', gene, negatively, regulate, transcriptional, activity])].
[sujeto(['In', the, murine, 'Catsper1', 'promoter,']), verbo([binding]), complemento([sites, for, transcription, factors, 'SRY,', 'SOX9', and, 'CREB', were, protected, by, the, presence, of, nuclear, testis, proteins, in, 'DNAse', degradation, assays])].
[sujeto(['SOX9', is, a, member, of, the, 'SOX', '[', 'Sry-related', 'high-mobility', group, '(', 'HMG)', 'box]', family, and, is]), verbo([required]), complemento([for, the, development, and, differentiation, of, multiple, cell, lineages])].
[sujeto(['The', 'SOX9', expression]), verbo([increased]), complemento([from, 'non-neoplastic', mucosa, to, early, cancer])].
[sujeto(['Three', of, six, cell, lines, had]), verbo([increased]), complemento([methylation, through, 'EBV', infection, and, decreased, 'SOX9', expression])].
[sujeto(['In', the, adult, 'testis,', 'Sertoli', cells, '(', 'SCs)', are, the, epithelial, supporting, cells, of, the, seminiferous, tubules, that]), verbo([provide]), complemento([germ, cells, '(', 'GCs)', with, the, required, nutrients, and, structural, and, regulatory, support, to, complete, spermatogenesis])].
[sujeto(['SCs', also, form, the, 'blood-testis', 'barrier,', phagocytose, apoptotic, spermatocytes, and, cell, debris, derived, from, 'spermiogenesis,', and, produce, and, secrete, numerous, paracrine, and, endocrine, signals]), verbo([involved]), complemento([in, different, regulatory, processes])].
[sujeto(['They', are, the, first, cells, to, differentiate, in, the, embryonic, 'XY', gonadal, primordium, and, are]), verbo([involved]), complemento([in, the, regulation, of, 'testis-specific', differentiation, 'processes,', such, as, prevention, of, 'GC', entry, into, 'meiosis,', 'Leydig', and, peritubular, myoid, cell, 'differentiation,', and, regression, of, the, 'Müllerian', 'duct,', the, anlagen, of, the, 'uterus,', 'oviducts,', and, the, upper, part, of, the, vagina])].
[sujeto(['Expression', of, the, 'Y-linked', gene, 'SRY', in, 'pre-SCs', initiates, a, genetic, cascade, that]), verbo([leads]), complemento([to, 'SC', differentiation, and, subsequently, to, testis, development])].
[sujeto(['Since', the, identification, of, the, 'SRY', 'gene,', many, 'Sertoli-specific', transcription, factors, and, signals, underlying, the, molecular, mechanisms, of, early, testis, differentiation]), verbo([have]), complemento([been, identified])].
[sujeto(['Here,', we, review, the, state, of, the, art, of, the, molecular, interactions, that, commit, the, supporting, cell, lineage, of, the, gonadal, primordium, to, differentiate, as, 'SCs', and, the, subsequent, 'Sertoli-specific', signaling, pathways]), verbo([involved]), complemento([in, early, testis, differentiation])].
[sujeto(['Epithelial-mesenchymal', transition, '(', 'EMT)', changes, polarized, epithelial, cells, into, migratory, phenotypes]), verbo([associated]), complemento([with, loss, of, 'cell-cell', adhesion, molecules, and, cytoskeletal, rearrangements])].
[sujeto(['In', 'particular,', the, promoter, sequences, of, differentially]), verbo([expressed]), complemento([genes, and, their, transcription, factors, were, analyzed, to, identify, potential, binding, sites, and, partners])].
[sujeto(['The', four, most, frequent, 'cis-regulatory', elements, '(', 'CREs)', in, 'up-regulated', genes, were, 'SRY,', 'FTS-1,', 'Evi-1,', and, 'GC-Box,', and, 'RNA', inhibition, of, the, four, transcription, 'factors,', 'Atf2,', 'Klf10,', 'Sox11,', and, 'SP1,', most, frequently]), verbo([binding]), complemento([these, 'CREs,', establish, their, importance, in, the, initiation, and, propagation, of, 'EMT'])].
[sujeto(['Our', results, identify, new, transcriptional, interactions, with, high, frequency, 'CREs', that]), verbo([modulate]), complemento([the, stability, of, cellular, 'plasticity,', and, may, serve, as, targets, for, modulating, these, transitional, states, in, fibroblasts])].
[sujeto(['The', past, few, years]), verbo([have]), complemento([seen, an, enormous, increase, in, the, knowledge, of, the, signaling, pathways, and, the, transcription, factors, that, control, endochondral, bone, development])].
[sujeto(['Recent', studies, of, rare, chondrodysplasias, that, exhibit, disproportionate, dwarfism, due, to, the, impairment, of, endochondral, ossification]), verbo([have]), complemento([identified, many, responsible, genes, and, have, clarified, pathogenic, mechanisms, of, these, diseases, by, using, molecular, genetics, and, biology])].
[sujeto(['Waardenburg', syndrome, '(', 'WS)', is, an, 'auditory-pigmentary', disorder, that, exhibits, varying, combinations, of, sensorineural, hearing]), verbo([loss]), complemento([and, abnormal, pigmentation, of, the, hair, and, skin])].
[sujeto(['WS', type, 4, '(', 'WS4),', a, subtype, of, 'WS,', is, characterized, by, the, presence, of, the, aganglionic, megacolon, and, is]), verbo([associated]), complemento([with, mutations, in, the, gene, encoding, either, endothelin, 3, ',', endothelin, receptor, type, 'B', '(', 'EDNRB),', or, 'Sry-box', 10, '(', 'SOX10)'])].
[sujeto(['Here,', we]), verbo([provide]), complemento([evidence, that, 'SOX10', regulates, the, expression, of, 'EDNRB', gene, in, human, 'melanocyte-lineage', 'cells,', as, judged, by, 'RNA', interference, and, chromatin, immunoprecipitation, analyses])].
[sujeto(['Human', melanocytes, preferentially]), verbo([express]), complemento([the, 'EDNRB', transcripts, derived, from, the, conventional, 'EDNRB', promoter])].
[sujeto(['Moreover,', a, transcription, factor, 'Sp1']), verbo([enhances]), complemento([the, degree, of, the, 'SOX10-mediated', transactivation, of, the, 'EDNRB', promoter, through, these, 'cis-acting', elements])].
[sujeto(['Furthermore,', we]), verbo([have]), complemento([shown, that, the, 'EDNRB', promoter, is, heavily, methylated, in, 'HeLa', human, cervical, cancer, 'cells,', lacking, 'EDNRB', 'expression,', but, not, in, melanocytes, and, 'HMV-II', melanoma, cells])].
[sujeto(['The', expression, of, 'EDNRB', became, detectable, in, 'HeLa', cells, after, treatment, with, a, demethylating, 'reagent,', 5, '\'', -, 'aza-2\'-deoxycytidine,', which, was, further]), verbo([enhanced]), complemento([in, the, transformed, cells, 'over-expressing', 'SOX10'])].
[sujeto(['We', therefore]), verbo([suggest]), complemento([that, 'SOX10,', alone, or, in, combination, with, 'Sp1,', regulates, transcription, of, the, 'EDNRB', 'gene,', thereby, ensuring, appropriate, expression, level, of, 'EDNRB', in, human, melanocytes])].
[sujeto(['The', 'Wilms', tumor, 1, '(', 'WT1)', gene, product, may]), verbo([regulate]), complemento([the, 'mullerian-inhibiting', substance, '(', 'MIS)', 'gene,', because, mutations, in, 'WT1', can, cause, persistence, of, the, mullerian, duct, in, men])].
[sujeto(['In', the, present, 'study,', we, show, by, gel, shift, and, chromatin, immunoprecipitation, assays, that, 'WT1']), verbo([bound]), complemento([to, a, 'GC-rich', sequence, in, the, murine, 'Mis', promoter])].
[sujeto(['The', 'WT1,', 'SRY', box, protein, 9, ',', and, steroidogenic, factor, 1, could, synergistically]), verbo([activate]), complemento([the, 'Mis', 'promoter,', and, at, least, two, factors, were, necessary, for, minimal, activation])].
[sujeto(['The', deficiency, of, this, hydrolase]), verbo([causes]), complemento([a, disorder, known, as, mucopolysaccharidosis, type, 'IIIA,', characterized, by, a, profound, neurological, deterioration])].
[sujeto(['Human', and, mouse, 'exon-intron', structures, were]), verbo([reported]), complemento([without, any, characterization, of, their, promoter, regions, '[', 'DNA', 'Res'])].
[sujeto(['The', 5, '\'', -, flanking, region, was, shown, to, contain, a, 'GC-rich', region, and, putative]), verbo([binding]), complemento([sites, for, the, transcription, factors, 'SRY,', 'MZF1', and, 'Nkx-2'])].
[sujeto(['Finally,', the, 3, '\'', -, untranslated, region, of, the, mouse, sulphamidase, gene, was, isolated, and]), verbo([found]), complemento([to, be, longer, than, the, region, identified, in, the, human, gene])].
[sujeto(['Genetic', analysis]), verbo([has]), complemento([implicated, a, number, of, gene, products, essential, for, this, 'process,', which, include, 'Sry,', 'WT1,', 'SF-1,', and, 'DAX-1'])].
[sujeto(['We']), verbo([have]), complemento([sought, to, better, define, the, role, of, 'WT1', in, this, process, by, identifying, downstream, targets, of, 'WT1', during, normal, gonadal, development])].
[sujeto(['We']), verbo([have]), complemento([noticed, that, in, the, developing, murine, gonadal, 'ridge,', wt1, expression, precedes, expression, of, 'Dax-1,', a, nuclear, receptor, gene])].
[sujeto(['We', also, demonstrate, that, 'WT1', can]), verbo([activate]), complemento([the, 'Dax-1', promoter])].
[sujeto(['Footprinting', 'analysis,', transient, 'transfections,', promoter, 'mutagenesis,', and, mobility, shift, assays]), verbo([suggest]), complemento([that, 'WT1', regulates, 'Dax-1', via, 'GC-rich', binding, sites, found, upstream, of, the, 'Dax-1', 'TATA', box])].
[sujeto(['We', show, that, two, 'WT1-interacting', 'proteins,', the, product, of, a, 'Denys-Drash', syndrome, allele, of, wt1, and, prostate, apoptosis, 'response-4', 'protein,']), verbo([inhibit]), complemento(['WT1-mediated', transactivation, of, 'Dax-1'])].
[sujeto(['In', 'addition,', we, demonstrate, that, 'WT1', can]), verbo([activate]), complemento([the, endogenous, 'Dax-1', promoter])].
[sujeto(['Determination', of, 41.2, kb, of, 'Y', chromosome, genomic, sequence]), verbo([has]), complemento([been, made, from, a, cosmid, that, spans, the, 'Yp', pseudoautosomal, boundary, and, includes, 18.5, kb, of, sequence, from, the, 'patient-defined', 'sex-determining', region, of, the, 'Y', chromosome])].
[sujeto(['An', 'AceDB', database, of, the, sequence, and, the, analysis, data]), verbo([have]), complemento([been, produced, as, a, resource, for, studies, of, the, evolution, and, population, genetics, of, the, 'Y', chromosome])].
[sujeto(['Indeed,', no, coding, regions, other, than, those, previously]), verbo([reported]), complemento([can, be, detected, anywhere, in, the, 41, kb])].
[sujeto(['The', 'Y-specific', and, pseudoautosomal, portions, of, this, sequence]), verbo([have]), complemento([different, repeat, sequence, and, 'GC', 'contents:', this, may, have, relevance, both, to, the, events, defining, the, pseudoautosomal, boundary, and, to, the, course, of, sequence, evolution, in, the, absence, of, recombination])].
[sujeto(['In', 'contrast,', meiotic, entry, is, actively]), verbo([prevented]), complemento([in, the, fetal, testis, at, this, developmental, 'time-point'])].
[sujeto(['It']), verbo([has]), complemento([previously, been, shown, that, 'RA-treatment', mediates, initiation, of, meiosis, in, human, fetal, ovary, ex, vivo])].
[sujeto(['Continued', proliferation, of, cells, without, signs, of]), verbo([increased]), complemento([apoptosis, was, observed, after, 2, weeks, of, culture])].
[sujeto(['In', cultured, fetal, ovaries, treated, with, 'RA,', an]), verbo([increased]), complemento([number, of, meiotic, germ, cells, '(', 'P', &, 'lt;', 0.05, ')', and, 'DMRT1-positive', oogonia, initiating, meiosis, '(', 'P', &, 'lt;', 0.05, ')', was, 'observed,', which, is, in, agreement, with, a, previous, study])].
[sujeto(['In', fetal, 'testes,', 'RA-treatment', resulted, in, a]), verbo([decreased]), complemento([number, of, gonocytes, '(', 'P', &, 'lt;', 0.05, ')', ',', a, reduced, percentage, of, proliferating, gonocytes, '(', 'P', &, 'lt;', 0.05, ')', ',', altered, expression, pattern, of, the, somatic, cell, markers, 'AMH', and, 'COUP-TFII,', as, well, as, disrupted, seminiferous, cord, structure, and, testis, morphology])].
[sujeto(['Our', novel]), verbo([finding]), complemento([of, disrupted, fetal, testis, development, after, treatment, with, 'RA', indicates, that, abnormal, meiosis, regulation, can, potentially, cause, gonadal, dysgenesis])].
[sujeto(['The', authors]), verbo([have]), complemento([no, conflicts, of, interest])].
[sujeto(['Elastic', 'net-Cox\'s', proportional, regression, hazards, model, '(', 'EN-COX)', was, used, to, identify, the, prognostic]), verbo([associated]), complemento([factors])].
[sujeto(['Then,', the]), verbo([target]), complemento([genes, of, the, obtained, miRNAs, were, predicted, followed, by, function, prediction])].
[sujeto(['The']), verbo([target]), complemento([genes, of, 'miRNA-342', such, as, 'B-cell', 'CLL/lymphoma', 2, '(', 'BCL2)', were, mainly, enriched, in, the, biological, process, related, to, cellular, metabolic, process, and, 'Disease', 'Ontology', terms, of, lymphoma])].
[sujeto(['The']), verbo([target]), complemento([genes, of, 'miRNA-93', were, mainly, enriched, in, the, pathway, of, 'G1', phase])].
[sujeto(['These', prognostic, markers, such, as, 'miRNA-93,', 'miRNA-342,', 'RARA,', 'MAFF,', 'SOX4,', and, 'BCL2', may, be, used, as]), verbo([targets]), complemento([for, 'TPC', chemoprevention])].
[sujeto(['In', 'XY', 'gonads,', 'sex-determining', region, 'Y', '(', 'SRY)']), verbo([triggers]), complemento([fibroblast, growth, factor, 9, '(', 'FGF9)', expression, in, somatic, cells])].
[sujeto(['FGF', 'signaling,', together, with, downstream, 'nodal/activin', 'signaling,']), verbo([promotes]), complemento([male, differentiation, in, 'XY', germ, cells, by, suppressing, retinoic, acid, '(', 'RA)-dependent', meiotic, entry, and, inducing, 'male-specific', genes])].
[sujeto(['However,', the, mechanism, by, which, 'nodal/activin', signaling]), verbo([regulates]), complemento(['XY', 'PGC', fate, is, unknown])].
[sujeto(['We']), verbo([found]), complemento([that, conditional, deletion, of, 'Smad2,', but, not, 'Smad3,', from, 'XY', 'PGCs', led, to, a, loss, of, 'male-specific', gene, expression])].
[sujeto(['Moreover,', suppression, of, 'RA', signaling, did, not, rescue, 'male-specific', gene, expression, in, 'Smad2-mutant', 'testes,', indicating, that, 'SMAD2', signaling]), verbo([promotes]), complemento([male, differentiation, in, a, 'RA-independent', manner])].
[sujeto(['By', 'contrast,', we]), verbo([found]), complemento([that, p38, signaling, has, an, important, role, in, the, suppression, of, 'RA', signaling])].
[sujeto(['The', 'Smad2', deletion, did, not, disrupt, the, p38, signaling, pathway, even, though, 'Nodal', expression, was, significantly, 'reduced,']), verbo([suggesting]), complemento([that, p38, was, not, regulated, by, nodal, signaling, in, 'XY', 'PGCs'])].
[sujeto(['Additionally,', the, inhibition, of, p38, signaling, in, the, 'Smad2-mutant', testes, severely, impeded, 'XY', 'PGC', differentiation, and]), verbo([induced]), complemento([meiosis])].
[sujeto(['Firstly,', the, peak, of, 'SRY', gene, expression, that, is, observed, in, early, differentiated, 'XY', gonads, in, numerous, mammals, was, also, seen, in, the, 'rabbit,', but, this, expression, was]), verbo([maintained]), complemento([at, a, high, level, until, the, end, of, puberty])].
[sujeto(['Thirdly,', the, expression, of, 'STRA8', and, 'DMC1', genes, '(', which, are, known, to, be, specifically]), verbo([expressed]), complemento([in, germ, cells, during, 'meiosis)', was, enhanced, in, 'XX', gonads, around, birth, but, also, slightly, and, significantly, in, 'XY', gonads, at, the, same, 'time,', even, though, no, meiosis, occurs, in, 'XY', gonad, at, this, stage])].
[sujeto(['SRY,', as, a, founder, member, of, 'SOX', 'family,']), verbo([has]), complemento([been, long, believed, to, be, involved, in, the, development, of, sexual, gonads, by, triggering, signaling, cascades, which, lead, to, the, formation, of, testis, or, ovary, from, bipotential, gonads])].
[sujeto(['In', order, to]), verbo([gain]), complemento([further, insight, into, the, possible, roles, of, 'SRY', during, 'development,', we, looked, into, possible, 'SRY-regulated', genes, and, their, levels, of, expression, in, a, human, embryonic, carcinoma, cell, 'line,', named, 'NTera2,', before, and, after, induction, of, differentiation])].
[sujeto(['The', results, showed, that, incorporation, of, 'SRY', in, both, groups, of, genes, was]), verbo([increased]), complemento([after, induction, of, differentiation])].
[sujeto(['Besides,', lower, expression, of, 'OCT4,', 'SOX2,', and, 'NANOG', and, higher, expression, of, 'PAX6', and, 'NESTIN', genes, in, differentiated, cells]), verbo([suggest]), complemento([that, 'SRY', may, act, as, a, transcription, repressor, for, 'pluripotency-associated', genes, and, as, a, transcription, activator, for, 'differentiation-related', genes])].
[sujeto(['We', show, that, mice, fed, excess, vitamin, 'A', develop, aortic, valve, stenosis, and, leaflet, calcification]), verbo([associated]), complemento([with, increased, expression, of, osteogenic, genes, and, decreased, expression, of, cartilaginous, markers])].
[sujeto(['Using', a, pharmacological, 'approach,', we, show, that, 'RA-mediated', 'Sox9', repression, and, calcification, is]), verbo([regulated]), complemento([by, classical, 'RA', signaling, and, requires, both, 'RA', and, retinoid, 'X', receptors])].
[sujeto(['Our', studies, demonstrate, that, excess, vitamin, 'A', dietary, intake]), verbo([promotes]), complemento([heart, valve, calcification, in, vivo])].
[sujeto(['Therefore']), verbo([suggesting]), complemento([that, hypervitaminosis, 'A', could, serve, as, a, new, risk, factor, of, calcific, aortic, valve, disease, in, the, human, population])].
[sujeto(['Y(Tir)', '(', mice, with, 'Y', chromosome, from, a, strain, in, 'Tirano,', 'Italy,', and, autosomes, and, 'X-chromosomes', from, the, 'B6', 'strain)', mice]), verbo([provide]), complemento([an, excellent, model, for, analysing, sex, development, that, occurs, during, gonadal, 'differentiation;', 'however,', the, molecular, mechanisms, that, contribute, to, sex, reversal, are, unclear])].
[sujeto(['Our', aim]), verbo([has]), complemento([been, to, establish, which, molecular, events, participate, in, this, sex, reversal])].
[sujeto(['The', pattern, of, gene, expression, related, to, testicular, '[', 'Sry', '(', 'sex-determining', region, of, the, 'Y', 'chromosome),', 'Sox9', '(', 'Sry-related', 'high-mobility', group, box, gene, 9, ')', and, 'Mis', '(', 'Müllerian-inhibiting', 'substance)]', and, ovarian, '[', 'Wnt4', '(', 'Wingless-type', 'MMTV', '(', 'murine-mammary-tumour', 'virus)', integration, site, 'family,', member, 4, ')', ',', 'Rspo1', '(', 'cysteine-rich', secretory, protein, containing, a, thrombospondin, type, 1, 'repeat)', and, 'Stra8', '(']), verbo([stimulated]), complemento([by, retinoic, acid, gene, 8, ')', ']', differentiation, was, analysed, by, applying, immunofluorescence, and, 'real-time', 'RT-PCR', '(', reverse, 'transcription-PCR),', focusing, on, 'XY', gonads, from, the, 'B6'])].
[sujeto(['Y(Tir)', 'strain,', both, at, the, transcript, and, protein, 'level,']), verbo([inducing]), complemento([differentiation, of, ovaries, and, 'ovotestes,', but, not, the, formation, of, the, 'testes,', which, were, normal])].
[sujeto(['Our', results, indicate, that, the, expression, of, testicular, genes, is]), verbo([inhibited]), complemento([at, various, 'levels,', permitting, the, expression, of, ovarian, genes, such, as, 'Wnt4,', 'Stra8', and, 'Rspo1'])].
[sujeto(['Correlation', analysis, indicated, that, an, ovary, differentiation, pathway, is]), verbo([activated]), complemento([when, the, testicular, differentiation, pathway, is, inhibited])].
[sujeto(['The', unexpected, action, of, 'SRY', in, the, control, of, voluntary, movement, in, male, rodents]), verbo([suggests]), complemento([a, role, in, the, regulation, of, dopamine, transmission, and, 'dopamine-related', disorders, with, gender, 'bias,', such, as, 'Parkinson\'s', disease])].
[sujeto(['Retinoic', 'acid-induced', differentiation, of, human, precursor, 'NT2', cells, into, dopaminergic, cells]), verbo([increased]), complemento([expression, of, 'TH,', 'NURR1,', 'D2', 'R', and, 'SRY'])].
[sujeto(['Conversely,', 'SRY', 'over-expression']), verbo([increased]), complemento(['TH,', 'DDC,', 'DBH,', 'D2', 'R', and, 'MAO-A', 'levels,', accompanied, by, increased, extracellular, dopamine, levels])].
[sujeto(['A', luciferase, assay, demonstrated, that, 'SRY']), verbo([activated]), complemento([a, 4.6, kb, 5, '\'', upstream, regulatory, region, of, the, human, 'TH', 'promoter/nigral', enhancer])].
[sujeto(['Combined,', these, results]), verbo([suggest]), complemento([that, 'SRY', plays, a, role, as, a, positive, regulator, of, catecholamine, synthesis, and, metabolism, in, the, human, male, midbrain])].
[sujeto(['This', ancillary, genetic, mechanism, might, contribute, to, gender, bias, in, 'fight-flight', behaviours, in, men, or, their]), verbo([increased]), complemento([susceptibility, to, dopamine, 'disorders,', such, as, 'Parkinson\'s', disease, and, schizophrenia])].
[sujeto(['Therefore,', identification, of, factors]), verbo([regulating]), complemento([the, expression, of, the, 'Cyp26b1', gene, is, an, important, goal, in, reproductive, biology])].
[sujeto(['In', the, mouse, gonadal, somatic, cell, line, 'TM3,', transfection, of, constructs]), verbo([expressing]), complemento(['SOX9', and, 'SF1', activated, 'Cyp26b1', 'expression,', independently, of, the, positive, regulator, 'RA'])].
[sujeto(['In', embryonic, gonads, deficient, in, 'SOX9', or, 'SF1,', 'Cyp26b1', expression, was]), verbo([decreased]), complemento([relative, to, 'wild-type', '(', 'WT)', 'controls,', as, measured, by, quantitative, 'RT-PCR', '(', 'qRT-PCR)'])].
[sujeto(['Furthermore,', 'qRT-PCR', showed, that, 'Cyp26b1', 'up-regulation', by, 'SOX9/SF1', was, attenuated, by, the, ovarian, transcription, factor, 'Forkhead', box, 'L2', '(', 'FOXL2)', in, 'TM3', 'cells,', whereas, in, 'Foxl2-null', 'mice,', 'Cyp26b1', expression, in, 'XX', gonads, was]), verbo([increased]), complemento(['∼20-fold', relative, to, 'WT', controls])].
[sujeto(['These', data, support, the, hypothesis, that, 'SOX9', and, 'SF1']), verbo([ensure]), complemento([the, male, fate, of, germ, cells, by, 'up-regulating', 'Cyp26b1', and, that, 'FOXL2', acts, to, antagonize, 'Cyp26b1', expression, in, ovaries])].
[sujeto(['The', 'SRY-related', transcription, factor, 'Sox9', is]), verbo([expressed]), complemento([in, developing, and, mature, heart, 'valves,', and, its, function, is, required, for, expression, of, 'cartilage-associated', 'proteins,', similar, to, its, role, in, chondrogenesis])].
[sujeto(['In', addition, to, 'cartilage-associated', 'defects,', mice, with, reduced, sox9, function, develop, skeletal, bone, 'prematurely;', 'however,', the, ability, of, sox9, deficiency, to]), verbo([promote]), complemento([ectopic, osteogenic, phenotypes, in, heart, valves, has, not, been, examined])].
[sujeto(['This', study, aims, to, determine, the, role, of, 'Sox9', in]), verbo([maintaining]), complemento([connective, tissue, homeostasis, in, mature, heart, valves, using, in, vivo, and, in, vitro, approaches])].
[sujeto(['Using', histological, and, molecular, 'analyses,', we]), verbo([report]), complemento(['that,', from, 3, months, of, 'age,', 'Sox9(fl/+);Col2a1-cre', mice, develop, calcific, lesions, in, heart, valve, leaflets, associated, with, increased, expression, of, 'bone-related', genes, and, activation, of, inflammation, and, matrix, remodeling, processes])].
[sujeto(['Furthermore,', we, show, that, retinoic, acid, treatment, in, mature, heart, valves, is, sufficient, to]), verbo([promote]), complemento([calcific, processes, in, 'vitro,', which, can, be, attenuated, by, 'Sox9', overexpression])].
[sujeto(['This', study]), verbo([provides]), complemento([insight, into, the, molecular, mechanisms, of, heart, valve, calcification, and, identifies, reduced, 'Sox9', function, as, a, potential, genetic, basis, for, calcific, valvular, disease])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, characterization, of, the, 'SOX3', promoter, and, demonstrated, that, the, general, transcription, factors, 'NF-Y', '(', nuclear, 'factor-Y),', 'Sp1', '(', specificity, protein, 1, ')', and, 'USF', '(', upstream, stimulatory, 'factor)', are, involved, in, transcriptional, regulation, of, 'SOX3', promoter, activity])].
[sujeto(['In', the, present, study, we]), verbo([provide]), complemento([the, first, evidence, that, the, 'TALE', '(', 'three-amino-acid', loop, 'extension)', transcription, factors, 'PBX1', '(', 'pre-B-cell', leukaemia, homeobox, 1, ')', and, 'MEIS1', '(', myeloid, ecotropic, viral, integration, site, 1, 'homologue)', participate, in, regulating, human, 'SOX3', gene, expression, in, 'NT2/D1', cells, by, direct, interaction, with, the, consensus, 'PBX/MEIS-binding', 'site,', which, is, conserved, in, all, mammalian, orthologue, promoters, analysed])].
[sujeto(['PBX1', is, present, in, the, protein, complex, formed, at, this, site, with]), verbo([nuclear]), complemento([proteins, from, uninduced, 'cells,', whereas, both, 'PBX1', and, 'MEIS1', proteins, were, detected, in, the, complex, created, with, extract, from, 'RA', '(', retinoic, 'acid)-induced', 'NT2/D1', cells])].
[sujeto(['Finally,', we, demonstrated, that, overexpressed, 'PBX1', and, 'MEIS1']), verbo([increased]), complemento([endogenous, 'SOX3', protein, expression, in, both, uninduced, and, 'RA-induced', 'NT2/D1', cells])].
[sujeto(['With', the, results, of, the, present, 'study,', for, the, first, 'time,', we]), verbo([have]), complemento([established, a, functional, link, between, the, 'TALE', 'proteins,', 'PBX1', and, 'MEIS1,', and, expression, of, the, human, 'SOX3', gene])].
[sujeto(['This', link, is, of, particular, interest, since, both, 'TALE', family, members, and, members, of, the, 'SOX', superfamily, are]), verbo([recognized]), complemento([as, important, developmental, regulators])].
[sujeto(['Balanced', production, and, degradation, of, retinoids, is, important, in]), verbo([regulating]), complemento([development, of, several, organ, systems, in, the, vertebrate, embryo])].
[sujeto(['Among', 'these,', it, is, known, that, retinoic, acid, '(', 'RA),', and, the, 'retinoid-catabolyzing', enzyme, 'CYP26B1', together]), verbo([regulate]), complemento([the, 'sex-specific', behavior, of, germ, cells, in, developing, mouse, gonads])].
[sujeto(['We']), verbo([report]), complemento([here, that, the, gene, encoding, a, cytosolic, 'class-1', aldehyde, 'dehydrogenase,', 'ALDH1A1,', a, weak, catalyst, of, 'RA', 'production,', is, strongly, expressed, in, a, 'male-specific', manner, in, somatic, cells, of, the, developing, mouse, 'testis,', beginning, shortly, after, 'Sry', expression, is, first, detectable])].
[sujeto(['This', expression, pattern, is]), verbo([conserved]), complemento([in, the, developing, male, gonad, of, the, chicken, and, is, dependent, on, the, 'testis-specific', transcription, factor, 'SOX9'])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, low, levels, of, 'RA', may, be, required, for, early, developmental, events, in, the, 'testis,', or, that, 'Aldh1a1', expression, in, the, fetus, may, prefigure, a, later, requirement, for, 'ALDH1A1', in, regulating, spermatogenesis, postnatally])].
[sujeto(['DAX-1', '(', 'DSS-AHC', 'Critical', 'Region', on, the, 'X', 'Chromosome-1)', is, a, member, of, the]), verbo([nuclear]), complemento([hormone, receptor, superfamily, that, has, an, important, role, in, steroidogenesis, and, gonadogenesis])].
[sujeto(['We', show, here, that, 'DAX-1', is, able, to]), verbo([inhibit]), complemento([splicing, in, in, vivo, and, in, vitro, splicing, 'assays,', and, this, inhibition, is, relieved, by, the, addition, of, 'SOX6'])].
[sujeto(['SOX6', appears, to]), verbo([inhibit]), complemento([the, interaction, between, 'DAX-1', and, the, splicing, 'machinery,', thus, providing, a, likely, mechanism, for, functional, interference])].
[sujeto(['We', conclude, that, 'DAX-1', and, 'SOX6', proteins, 'interact,']), verbo([have]), complemento([overlapped, expression, in, the, 'testis,', and, act, antagonistically, during, 'pre-mRNA', splicing])].
[sujeto(['Mammalian', gonad, differentiation]), verbo([involves]), complemento([sexually, dimorphic, 'cell-fate', decisions, within, the, bipotential, gonadal, primordia])].
[sujeto(['Testis', differentiation, is, initiated, by, a, 'center-to-poles', wave, of, 'Sry', expression, that]), verbo([induces]), complemento([supporting, cell, precursors, '(', 'SCPs)', to, become, 'Sertoli', rather, than, granulosa, cells])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, 1700106, 'J16Rik', and, 'Sprr2d', may, have, important, roles, in, early, gonad, 'development,', and, are, consistent, with, the, hypothesis, that, ovarian, 'SCP', differentiation, occurs, in, a, 'center-to-poles', wave, with, similar, timing, to, that, of, testicular, 'SCP', differentiation])].
[sujeto(['Different', genes]), verbo([express]), complemento([in, different, phases, and, tend, to, change, with, the, time])].
[sujeto(['The', functions, of, some, 'genes,', such, as, 'SRY,', 'SOX9,', 'SOX8,', 'DAX1,', and, 'FGF9,']), verbo([have]), complemento([already, been, defined, in, male, gonadal, morphogenesis])].
[sujeto(['This', paper, presents, a, review, of, the, genes]), verbo([involved]), complemento([in, the, formation, of, the, male, gonad, in, mammals])].
[sujeto(['This', highly]), verbo([conserved]), complemento([function, is, retained, in, birds, and, is, supported, by, the, high, levels, of, 'AMH', expression, in, developing, testes])].
[sujeto(['Mammalian', 'AMH', expression, is]), verbo([regulated]), complemento([by, a, combination, of, transcription, 'factors,', the, most, important, being, 'Sry-type', 'high-mobility-group', box, transcription, 'factor-9', '(', 'SOX9)'])].
[sujeto(['In', the, chicken, 'embryo,', 'however,', 'AMH', mRNA, expression, precedes, that, of, 'SOX9,']), verbo([leading]), complemento([to, the, view, that, 'AMH', may, play, a, more, central, role, in, avian, testicular, development])].
[sujeto(['AMH']), verbo([caused]), complemento([the, gonads, of, both, sexes, to, develop, as, small, and, undeveloped, structures, at, both, embryonic, and, adult, stages])].
[sujeto(['A', similar, gonadal, phenotype, was, also, observed, in, 'males,', with, a, complete]), verbo([loss]), complemento([of, both, 'Sertoli', 'cells,', disrupted, 'SOX9', expression, and, gonadal, steroidogenesis])].
[sujeto(['At', sexual, maturity, both, sexes, showed, a, female, external, phenotype, but]), verbo([retained]), complemento([sexually, dimorphic, body, weights, that, matched, their, genetic, sexes])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'AMH', does, not, operate, as, an, early, testis, activator, in, the, chicken, but, can, affect, downstream, 'events,', such, as, sex, steroid, hormone, production])].
[sujeto(['In', 'addition,', this, study]), verbo([provides]), complemento([a, unique, opportunity, to, assess, chicken, sexual, development, in, an, environment, of, sex, hormone, 'deficiency,', demonstrating, the, importance, of, both, hormonal, signaling, and, direct, cell, autonomous, factors, for, somatic, sex, identity, in, birds])].
[sujeto(['The', 'phenotype,', ultrasonographic, 'examination,', hormone, 'status,', cytogenetic, evaluation, and, molecular, diagnostics]), verbo([lead]), complemento([to, the, diagnosis, of, an, 'XY', testicular, disorder, of, sexual, development, '(', 'DSD)', due, to, a, complete, androgen, insensitivity, syndrome])].
[sujeto(['To', our, knowledge, this, is, the, first]), verbo([report]), complemento([about, a, thoroughbred, in, racing, sports, with, an, 'XY', testicular, disorder, of, sexual, development])].
[sujeto(['To', 'date,', intersex, racing, horses]), verbo([have]), complemento([never, been, described, in, thoroughbreds, or, a, regulation, for, intersexes, in, regard, to, horse, races, has, been, issued])].
[sujeto(['The', establishment, of, social, hierarchies, is, a, naturally, 'occurring,', evolutionarily]), verbo([conserved]), complemento([phenomenon, with, a, 'well-established', impact, on, fitness, and, health])].
[sujeto(['Together,', our, results, demonstrate, a, 'sex-specific', mechanism, underlying, social, 'hierarchy,', in, which, both, males, and, females]), verbo([retain]), complemento([the, functional, capacity, to, adapt, their, social, strategy])].
[sujeto(['More', 'generally,', we, expect, the, automated, tube, test, to]), verbo([provide]), complemento([an, important, complementary, approach, for, both, fundamental, and, translational, studies, of, social, behavior])].
[sujeto(['In', 'teleosts,', the, expression, of, steroidogenic, enzymes, and, related, transcription, factor, genes, occurs, in, a, 'stage-', and, 'tissue-specific', manner]), verbo([causing]), complemento([sexual, development])].
[sujeto(['The', role, of, 'sox3,', an, evolutionary, ancestor, of, 'SRY,']), verbo([has]), complemento([not, been, studied, in, detail])].
[sujeto(['Developing', and, mature, testis, showed, higher, sox3, expression, than, ovary, of, corresponding, 'stages,', and, more, sox3, transcripts, were]), verbo([found]), complemento([during, the, spawning, phase, of, the, seasonal, reproductive, cycle])].
[sujeto(['Expression', of, sox3, was, upregulated, by, hCG, after, in, vivo, and, in, vitro, 'induction,']), verbo([suggesting]), complemento([that, gonadotropins, might, stimulate, it])].
[sujeto(['Sox3', could, also, be]), verbo([found]), complemento([in, the, zona, radiata, of, developing, and, mature, oocytes])].
[sujeto(['These', results]), verbo([suggest]), complemento([a, possible, role, for, 'Sox3', in, the, regulation, of, testicular, development, and, function])].
[sujeto(['Criteria']), verbo([suggested]), complemento(['XY', 'DSD', include, overt, genital, 'ambiguity,', apparent, 'female/male', genitalia, with, 'inguinal/labial', 'mass,', apparent, male, genitalia, with, unilateral, or, bilateral, 'non-palpable', 'testes,', micropenis, and, isolated, hypospadias, or, with, undescended, testis])].
[sujeto(['Numerous', spermatogenic, cells, were, observed, in, the, 'semen,', and, approximately, 60, '%', of, the, cells, examined, in, semen, were, primary, 'spermatocytes,', showing, spermatogenic]), verbo([arrest]), complemento([at, the, primary, spermatocyte, level])].
[sujeto(['This', is, the, first, case]), verbo([reported]), complemento([with, a, nonmosaic, 46, ',', 'X,', i, '(', 'Y)', '(', p11])].
[sujeto(['Aberrations', in, pseudoautosomal, region, 1, on, the, rearranged, 'Y', chromosome, may, result, in, the, deficiency, of, 'X-Y', pairing, or, 'recombination,', ultimately]), verbo([lead]), complemento([to, the, spermatogenic, failure])].
[sujeto(['Whilst', gonadal, hormones, can, substantially, influence, sexual, differentiation, of, the, 'brain,', recent, findings]), verbo([have]), complemento([suggested, that, 'sex-linked', genes, may, also, directly, influence, neurodevelopment])].
[sujeto(['Over', a, 24, hour, 'period,', 'XX', and, 'XY', gonadally, female, mice, '(', lacking, 'Sry)', exhibited, greater, horizontal, locomotor, activity, and, reduced, food, consumption, per, unit, bodyweight, than, 'XX', and, 'XY', gonadally, male, mice, '(', possessing, 'Sry);', in, two, behavioural, tests, '(', the, elevated, plus, and, zero, 'mazes)', 'XX', and, 'XY', gonadally, female, mice, showed, evidence, for]), verbo([increased]), complemento(['anxiety-related', behaviours, relative, to, 'XX', and, 'XY', gonadally, male, mice])].
[sujeto(['The', present, data]), verbo([suggest]), complemento(['that:', 'i)', the, 'male-specific', factor, 'Sry', may, influence, activity, and, feeding, behaviours, in, 'mice,', and, 'ii)', dissociable, feeding, and, 'anxiety-related', murine, phenotypes, may, be, differentially, modulated, by, 'Sry', and, by, other, 'sex-linked', genes])].
[sujeto(['Our', results, may]), verbo([have]), complemento([relevance, for, understanding, the, molecular, underpinnings, of, sexually, dimorphic, behavioural, phenotypes, in, healthy, men, and, 'women,', and, in, individuals, with, abnormal, sex, chromosome, constitutions])].
[sujeto(['Here,', we]), verbo([report]), complemento([about, a, 30, years, old, male, subject, with, vanishing, testis, 'syndrome,', feminization, and, gynecomastia])].
[sujeto(['Follicle']), verbo([stimulating]), complemento([hormone, '(', 'FSH)', and, 'Leutinizing', hormone, '(', 'LH)', levels, were, elevated, whereas, testosterone, was, below, normal, and, 'anti-mullerian-hormone', level, was, undetectable, in, the, patient])].
[sujeto(['The', chromosomal, analysis, and, 'DNA', analysis, of, 'SRY', and, 'ZFY,', 'DAX-I,', 'AZFa,', 'AZFb,', 'AZFc', and, heterochromatic, region, of, 'Y', chromosome, with, 'STS']), verbo([primer]), complemento(['(', 'sY160)', were, done, to, detect, any, genetic, changes, at, specified, sites, '(', both, at, chromosomal, and, molecular, 'level)'])].
[sujeto(['PCR', amplification, of, 'SRY,', 'ZFY,', 'DAX-I,', 'AZFa,', 'AZFb,', 'AZFc', gene, and, 'Y', chromosome, heterochromatic, region, using, 'STS']), verbo([primer]), complemento(['sY(160)', did, not, reveal, any, microdeletions])].
[sujeto(['The', 'anti-mullerian-hormone', level, was, undetectable, indicating, that, the, patient, 'didn\'t']), verbo([have]), complemento([any, testicular, tissue, in, scrotum])].
[sujeto(['Increased', levels, of, 'FSH,', 'LH', and, reversed, 'androgen:', estrogen, ratio, might]), verbo([have]), complemento([given, rise, to, gynecomastia, in, the, patient])].
[sujeto(['The', torsion, of, testis, might]), verbo([have]), complemento([caused, vascular, occlusion, and, thereby, regression, of, testicular, tissue, 'occurred,', but, the, exact, genetic, condition, yet, to, understand])].
[sujeto(['Post-surgery', subjects, showed, reduced, 'androgens,', a, marked]), verbo([increase]), complemento([in, 'LH', and, 'FSH', and, normal, 'PRL'])].
[sujeto(['There', was, a, marked]), verbo([increase]), complemento([in, the, baseline, and, 'post-stimulation', 'GH', values, in, 6, of, the, 13, 'pre-surgery', 'patients,', peaking, at, 'T15'])].
[sujeto(['Qualitative', analysis, of, the, 'AZFa,', 'AZFb,', and, 'AZFc', regions, did, not]), verbo([reveal]), complemento([any, microdeletions, in, any, subject])].
[sujeto(['This', gender, disorder, does, not, seem, to, be]), verbo([associated]), complemento([with, any, molecular, mutations, of, some, of, the, main, genes, involved, in, sexual, differentiation])].
[sujeto(['With', 'aging,', this, cardiovascular, protection, in, women, is, lost, and, this, may, be, related, to]), verbo([loss]), complemento([of, estrogen, postmenopause, but, the, possible, contribution, of, other, sex, hormones, needs, to, be, further, examined])].
[sujeto(['Restoration', of, these, 'RAS', depressor, pathways, in, older, 'women,', or, 'up-regulation', of, these, in, 'males,', represents, a, therapeutic]), verbo([target]), complemento([that, is, worth, pursuing])].
[sujeto(['An', irregularity, in, any, of, these, three, steps, can]), verbo([lead]), complemento([to, a, disorder, in, sexual, development, '(', 'DSD)'])].
[sujeto(['All', seven, 'XX', 'sex-reversed', dogs, were]), verbo([found]), complemento([to, be, negative, for, the, 'SRY', gene, by, polymerase, chain, reaction])].
[sujeto(['The', basal, plasma, 'LH', concentration]), verbo([increased]), complemento([significantly, after, 'GnRH', administration, in, all, dogs, with, 'DSD'])].
[sujeto(['An', early, investigation, and, management, op, cryptorchidism, are, essential, for, the, diagnosis, of]), verbo([associated]), complemento(['pathologies,', because, 'intra-abdominal', testis, are, associated, with, infertility, and, neoplasic, risk])].
[sujeto(['The', authors, describe, a, case, of, late, presentation, of, cryptorchidism]), verbo([associated]), complemento([with, genetic, disorder])].
[sujeto(['With', this, case]), verbo([report]), complemento([the, authors, intend, to, enhance, the, need, of, early, management, of, cryptorchidism, and, short, 'stature,', in, order, to, improve, the, prognosis])].
[sujeto(['The', measurements, of, luteinizing, 'hormone,', follicle]), verbo([stimulating]), complemento(['hormone,', testosterone, and, 'ir-inhibin', showed, a, tendency, to, increase, gradually, from, 'April'])].
[sujeto(['In', 'autopsy,', immature, symmetrical, subcutaneous, testes, were]), verbo([found]), complemento([in, the, inguinal, regions])].
[sujeto(['The', authors]), verbo([report]), complemento([a, case, of, a, dysgenetic, male, pseudohermaphroditism, with, a, 45, ',', 'X/46,XY', karyotype, in, a, mosaic, 'form,', which, was, diagnosed, in, an, infant])].
[sujeto(['Surgical', removal, of, the, dysgenetic, testicular, tissue, located, in, the, abdominal, cavity, and, its, histological, evaluation]), verbo([provides]), complemento([separation, of, mixed, gonadal, 'dysgenesis,', dysgenetic, male, 'pseudohermaphroditism,', bilateral, gonadal, dysgenesis, and, ovotestis, in, the, 45, ',', 'X/46,XY', mosaic, cases])].
[sujeto(['An', accurate, evaluation, is, necessary, for, a, correct, sex, assignment, and, for, surgical, intervention, to]), verbo([prevent]), complemento([neoplastic, degeneration, of, the, dysgenetic, gonad])].
[sujeto(['To', describe, a, rare, case, of, 45, ',', 'X', 'Turner\'s', syndrome, with, elevated, 'T', and, clitoromegaly]), verbo([caused]), complemento([by, ovarian, hilus, cell, hyperplasia])].
[sujeto(['An', 11, -, 'and-a-half-year-old', girl, with, 45, ',', 'X', karyotype, showed, signs, of, accelerated, growth, and, clitoromegaly, and, was]), verbo([found]), complemento([to, have, elevated, serum, 'T'])].
[sujeto(['Ovarian', hilus, cell, hyperplasia, is, an, extremely, rare]), verbo([cause]), complemento([of, virilization, in, 'Turner\'s', syndrome])].
[sujeto(['Data', in, the, rat]), verbo([have]), complemento([suggested, the, 'male-specific', 'Y-chromosome', gene, 'Sry', to, contribute, to, balance, between, these, two, 'axes,', but, why, the, 'testis-determining', gene, has, these, functions, remains, unknown])].
[sujeto(['A', combination, of, in, silico, 'genetic/protein', 'comparisons,', functional, luciferase, assays, for, promoters, of, the, human, 'RAS,', and, 'RNA-Seq', profiling, in, rat, were, used, to, address, if, regulation, of, 'Sry', on, the, 'RAS', is]), verbo([conserved]), complemento([in, the, homologous, 'X-chromosome', 'gene,', 'Sox3'])].
[sujeto(['The', regulation, by, both, 'SRY', and, 'SOX3', on, the, 'MAS', promoter, indicates, a, cis, regulation, through, multiple, 'SOX']), verbo([binding]), complemento([sites])].
[sujeto(['Sry', transcripts, are]), verbo([found]), complemento([in, all, analyzed, male, rat, tissues, including, the, 'kidney,', while, 'Sox3', transcripts, are, found, only, in, the, brain, and, 'testis,', suggesting, that, the, primary, tissue, for, renin, production, '(', 'kidney)', can, only, be, regulated, by, 'SRY', and, not, 'SOX3'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'SRY', regulation, of, the, 'RAS', is, partially, shared, with, its, 'X-chromosome', homolog, 'SOX3,', but, 'SRY', gained, a, 'sex-specific', control, in, the, kidney, for, the, 'rate-limiting', step, of, the, 'RAS,', potentially, resulting, in, 'male-specific', blood, pressure, regulation])].
[sujeto(['Mammalian', sex, determination, hinges, on, the, development, of, ovaries, or, 'testes,', with, testis, fate, being]), verbo([triggered]), complemento([by, the, expression, of, the, transcription, factor, 'sex-determining', region, 'Y', '(', 'Sry)'])].
[sujeto(['Several', epigenetic, 'modifiers,', transcription, factors, and, kinases, are, implicated, in]), verbo([regulating]), complemento(['Sry', 'transcription,', but, it, remains, unclear, whether, or, how, this, farrago, of, factors, acts, 'co-ordinately'])].
[sujeto(['Here', we, review, our, current, understanding, of, 'Sry', regulation, and]), verbo([provide]), complemento([a, model, that, assembles, all, known, regulators, into, three, 'modules,', each, converging, on, a, single, transcription, factor, that, binds, to, the, 'Sry', promoter])].
[sujeto(['We', also, discuss, potential, future, avenues, for, discovering, the, 'cis-elements', and, 'trans-factors']), verbo([required]), complemento([for, 'Sry', regulation])].
[sujeto(['The', 'Y-chromosomal', gene, 'SRY']), verbo([acts]), complemento([as, the, primary, trigger, for, male, sex, determination, in, mammalian, embryos])].
[sujeto(['However,', the, 'cis-sequences']), verbo([involved]), complemento([in, regulation, of, 'Sry', have, not, been, 'identified,', precluding, a, test, of, this, hypothesis])].
[sujeto(['To', avoid, problems]), verbo([associated]), complemento([with, conventional, pronuclear, injection, of, 'transgenes,', we, used, a, published, strategy, designed, to, yield, 'single-copy', transgene, integration, at, a, 'defined,', transcriptionally, 'open,', autosomal, 'locus,', 'Col1a1'])].
[sujeto(['None', of, the, 'Sry', transgenes, tested, was]), verbo([expressed]), complemento([at, levels, compatible, with, activation, of, 'Sox9', or, 'XX', sex, reversal])].
[sujeto(['Our', findings, indicate, either, that, the, 'Col1a1', locus, does, not]), verbo([provide]), complemento([an, appropriate, context, for, the, correct, expression, of, 'Sry', 'transgenes,', or, that, the, 'cis-sequences', required, for, 'Sry', expression, in, the, developing, gonads, lie, beyond, 8, kb, 5, '\'', of, the, 'TSS'])].
[sujeto(['The', full, length, of, 'ZP3', cDNA, was, firstly, characterized, and, its, tissue, distribution, revealed, that, 'ZP3', mRNA, was, predominantly]), verbo([expressed]), complemento([in, ovary, of, 'G'])].
[sujeto(['The', 5, '\'', flanking, regions, of, 'ZP2', and, 'ZP3', were, isolated, and, the, comparison, of, transcription, factors, in, the, regions, of, 'ZP2', and, 'ZP3']), verbo([suggested]), complemento([that, the, disparity, for, the, responsiveness, of, 'ZP2', and, 'ZP3', to, 'EE2', could, partly, be, a, result, of, differential, 'cis-elements', such, as, 'oocyte-specific', protein, '(', 'Osp1)', binding, sites, 'or/and', 'sex-determining', region, 'Y', '(', 'SRY)', binding, site])].
[sujeto(['To']), verbo([provide]), complemento([a, summary, of, the, recent, major, advances, in, the, field, of, molecular, genetics, and, understanding, of, psychosexual, 'development,', as, these, developments, have, resulted, in, changes, in, terminology, and, classification, of, disorders, of, sexual, differentiation, '(', 'DSD)/intersex;', and, to, provide, a, quick, and, simplified, review, of, the, basic, information])].
[sujeto(['The', newly, proposed, terminology, and, classification]), verbo([has]), complemento([eliminated, some, confusion, for, both, patient, and, 'family,', as, well, as, among, health, professionals])].
[sujeto(['The', new, advances]), verbo([have]), complemento([facilitated, the, categorisation, of, gonadal, malignancy, in, patients, with, 'DSD', into, 'high-,', 'intermediate-', and, 'low-risk', groups])].
[sujeto(['More', molecular, genetics, studies, will, allow, a, better, understanding, of, the]), verbo([causes]), complemento([of, each, condition, of, 'DSD'])].
[sujeto([',', 'Swyer', 'syndrome),', 'SRY', 'mutations,', residing, in, the, 'HMG', '(', 'High', 'Mobility', 'Group)', 'domain,', are]), verbo([found]), complemento([to, affect, nuclear, transport, or, binding, to, and, bending, of, 'DNA'])].
[sujeto(['Mutations', in, 'SRY', as, well, as, 'WT1', can]), verbo([lead]), complemento([to, diminished, expression, and, function, of, 'SRY,', resulting, in, 'sub-optimal', 'SOX9', 'expression,', 'Sertoli', cell, formation, and, subsequent, lack, of, proper, testicular, development])].
[sujeto(['Embryonic', germ, cells, residing, in, this, unfavourable, 'micro-environment']), verbo([have]), complemento([an, increased, risk, for, malignant, transformation])].
[sujeto(['Occurrence', of, a, delayed, progressive, kidney, failure, '(', focal, segmental, glomerular, 'sclerosis)']), verbo([triggered]), complemento([analysis, of, 'WT1,', revealing, a, pathogenic, 'splice-site', mutation, in, intron, 9])].
[sujeto(['Analysis', of, the, 'SRY', gene, in, an, additional, five, 'FS', cases, did, not]), verbo([reveal]), complemento([any, mutations])].
[sujeto(['The', case, presented, shows, the, importance, of, 'multi-gene', based, diagnosis, of, 'DSD', 'patients,', allowing, early, diagnosis, and, 'treatment,', thus]), verbo([preventing]), complemento([putative, development, of, an, invasive, cancer])].
[sujeto(['SRY', is, a, transcription, factor, and, together, with, 'SF1', it, directly, 'up-regulates', the, expression, of, the, pivotal, 'sex-determining', gene, 'Sox9', via, a, 1.3, -, kb, 'cis-regulatory', element, '(', 'TESCO)', which, contains, an, evolutionarily]), verbo([conserved]), complemento([region, '(', 'ECR)', of, 180, &, 'nbsp;bp'])].
[sujeto(['Remarkably,', several, rodent, species, appear, to, determine, sex, in, the, absence, of, 'Sry', and, a, 'Y', 'chromosome,', including, the, mole, voles, 'Ellobius', lutescens, and, 'Ellobius', 'tancrei,', whereas, 'Ellobius', fuscocapillus, of, the, same, genus]), verbo([retained]), complemento(['Sry'])].
[sujeto(['We']), verbo([have]), complemento([cloned, and, sequenced, 1.1, &, 'nbsp;kb', of, 'E'])].
[sujeto([lutescens, might, still, be]), verbo([regulated]), complemento([via, 'TESCO'])].
[sujeto(['We']), verbo([have]), complemento([also, cloned, and, sequenced, the, 'ECRs', of, 'E'])].
[sujeto(['While', the, three, 'Ellobius', 'ECRs', are, highly, similar, '(', 94, -, 97, '%', sequence, 'identity),', they, all, display, a, 14, -, bp, deletion, '(', 'Δ14)', removing, a, highly]), verbo([conserved]), complemento(['SOX/TCF', site])].
[sujeto(['Introducing', 'Δ14', into, mouse, 'TESCO']), verbo([increased]), complemento([both, basal, activity, and, 'SF1-mediated', activation, of, 'TESCO', in, 'HEK293T', cells])].
[sujeto(['We', propose, a, model, whereby, 'Δ14', may]), verbo([have]), complemento([triggered, 'up-regulation', of, 'Sox9', in, 'XX', gonads, leading, to, destabilization, of, the, 'XY/XX', 'sex-determining', mechanism, in, 'Ellobius'])].
[sujeto([fuscocapillus, could]), verbo([have]), complemento([independently, stabilized, their, sex, determination, mechanisms, by, 'Sry-independent', and, 'Sry-dependent', 'approaches,', respectively])].
[sujeto(['The', mechanism, of, donor, choice]), verbo([ensuring]), complemento([that, switching, occurs, primarily, and, productively, to, the, opposite, 'type,', called, 'directionality,', is, largely, unknown])].
[sujeto(['A', previously, 'unrecognized,', shorter, swi2, 'mRNA,', a, truncated, form, of, the, 'swi2,', was, 'identified,', and, its, expression]), verbo([requires]), complemento([the, 'mat1-Mc', function])].
[sujeto(['We', also]), verbo([found]), complemento([that, the, abp1, gene, '(', human, 'CENPB', 'homolog)', controls, directionality, through, swi2, regulation])].
[sujeto(['Sex', determining, region, 'Y', '(', 'SRY)-box', 2, '(', 'SOX2)', anophthalmia, syndrome, is, an, autosomal, dominant, disorder, manifesting, as, severe, developmental, eye, malformations]), verbo([associated]), complemento([with, 'brain,', 'esophageal,', 'genital,', and, kidney, abnormalities])].
[sujeto(['The', syndrome, is, usually]), verbo([caused]), complemento([by, de, novo, mutations, or, deletions, in, the, transcription, factor, 'SOX2'])].
[sujeto(['In', keeping, with, several, genetic, 'disorders,', we]), verbo([found]), complemento([that, 'SOX2', mutations, were, associated, with, older, parental, age, and, the, difference, was, statistically, significant, for, mothers, '(', 'p=0'])].
[sujeto(['With', the, current, sample, 'size,', there, was, no, evidence, that, sequence, variants, in, cis, surrounding, 'SOX2']), verbo([confer]), complemento([susceptibility, to, either, mutations, or, deletions])].
[sujeto(['CD133']), verbo([has]), complemento([been, recognized, as, a, specific, cell, surface, marker, for, cancer, stem, cells, in, various, 'tumors,', although, its, biological, functions, and, transcriptional, regulation, remain, unclear])].
[sujeto(['We']), verbo([found]), complemento([that, the, 'CD133', expression, level, was, 'up-regulated', in, the, lung, cancer, cell, lines, 'N417,', 'H358,', and, 'A549,', when, these, cell, lines, were, cultured, under, hypoxic, conditions])].
[sujeto(['Among', the, five, promoters, '(', 'P1-P5)', of, human, 'CD133', gene, 'loci,', 'P1', promoter, was, most, strongly]), verbo([associated]), complemento([with, 'hypoxia-induced', promoter, activity, of, 'CD133', gene, expression])].
[sujeto(['The', chromatin, immunoprecipitation, assay, further, confirmed, the, direct]), verbo([binding]), complemento([of, 'Octamer', biding, 'trans-cription', factor, 3, /, 4, '(', 'OCT4)', 'and/or', 'SRY-box', containing, 'gene&nbsp;2', '(', 'SOX2)', to, the, 'P1', promoter, region, of, 'CD133', gene, loci])].
[sujeto(['In', 'addition,', the, enhancement, of, both, 'OCT4', and, 'SOX2', expression, by, the, α, subunit, of, 'hypoxia-inducible', factors, '(', 'HIF1α', and, 'HIF2α)', was]), verbo([required]), complemento([for, 'hypoxia-induced', 'CD133', expression])].
[sujeto(['Knockdown', of, 'OCT4', or, 'SOX2', expression, in, 'N417', cells, with, stabilized, 'HIF1α', 'and/or', 'HIF2α', abolished, 'CD133P1', 'activity,', while, ectopic, 'OCT4', or, 'SOX2', expression]), verbo([triggers]), complemento(['CD133P1', activity, in, the, absence, of, 'HIF1α', or, 'HIF2α'])].
[sujeto(['Thus,', in, the, hypoxic, 'conditions,', 'OCT4', and, 'SOX2,', both, of, which, are]), verbo([induced]), complemento([by, 'HIF1α/HIF2α'])].
[sujeto([',', sets, of]), verbo([expressed]), complemento([transcription, 'factors,', define, the, gene, expression, capabilities, of, cells, in, animal, development])].
[sujeto(['Here', we, explore, the, functional, significance, of, an, unprecedented, example, of, regulatory, state, conservation, from, the, cnidarian, 'Nematostella', to, 'Drosophila,']), verbo([sea]), complemento(['urchin,', 'fish,', and, mammals])].
[sujeto(['Our', probe, is, a, deeply]), verbo([conserved]), complemento(['cis-regulatory', 'DNA', module, of, the, 'SRY-box', 'B2', '(', 'soxB2),', recognizable, at, the, sequence, level, across, many, phyla])].
[sujeto(['Transphyletic', 'cis-regulatory', 'DNA', transfer, experiments]), verbo([reveal]), complemento([that, the, plesiomorphic, control, function, of, this, module, may, have, been, to, respond, to, a, regulatory, state, associated, with, neuronal, differentiation])].
[sujeto(['By', introducing, expression, constructs, driven, by, this, module, from, any, phyletic, source, into, the, genomes, of, diverse, developing, 'animals,', we, discover, that, the, regulatory, state, to, which, it]), verbo([responds]), complemento([is, used, at, different, levels, of, the, neurogenic, developmental, 'process,', including, patterning, and, development, of, the, vertebrate, forebrain, and, neurogenesis, in, the, 'Drosophila', optic, lobe, and, brain])].
[sujeto(['The', regulatory, state]), verbo([recognized]), complemento([by, the, conserved, 'DNA', sequence, may, have, been, redeployed, to, different, levels, of, the, developmental, regulatory, program, during, evolution, of, complex, central, nervous, systems])].
[sujeto(['Since', on, the, canine, chromosome, 23, '(', 'CFA23)', 3, genes, '(', 'FOXL2,PISRT1', and, 'CTNNB1)']), verbo([involved]), complemento([in, the, sex, determination, process, are, 'present,', further, cytogenetic, 'FISH', studies, were, carried, out, with, the, use, of, 'BAC', probes, specific, for, this, chromosome])].
[sujeto(['It', was]), verbo([found]), complemento([that, a, pericentromeric, fragment, of, 'CFA23', was, deleted, as, a, result, of, the, centric, fusion])].
[sujeto(['Acquired', during, early, 'development,', the, cell, 'type-specific', epigenotype, is]), verbo([maintained]), complemento([by, cellular, memory, mechanisms, that, involve, epigenetic, modifications])].
[sujeto(['Here', we, present, the, epigenetic, status, of, the, euchromatic, region, of, the, human, 'Y', chromosome, that]), verbo([has]), complemento([mostly, been, ignored, in, earlier, whole, genome, epigenetic, mapping, studies])].
[sujeto(['Using', 'ChIP-on-chip', 'approach,', we, mapped, 'H3K9ac,', 'H3K9me3,', 'H3K27me3', modifications, and, 'CTCF']), verbo([binding]), complemento([sites, while, 'DNA', methylation, analysis, of, selected, 'CpG', islands, was, done, using, bisulfite, sequencing])].
[sujeto(['The', combination, of, histone, and, 'DNA', 'modifications,', along, with, 'CTCF', association, in, some, 'cases,']), verbo([reveals]), complemento([the, transcriptional, potential, of, all, protein, coding, genes, including, the, 'sex-determining', gene, 'SRY', and, the, oncogene, 'TSPY'])].
[sujeto(['We', also, observe, preferential, association, of, histone, marks, with, different, tandem, 'repeats,']), verbo([suggesting]), complemento([their, importance, in, genome, organization, and, gene, regulation])].
[sujeto(['Individuals', with, rare, cytogenetic, variants]), verbo([have]), complemento([contributed, to, our, understanding, of, the, genetics, of, sex, development, and, its, disorders])].
[sujeto(['Here,', we]), verbo([report]), complemento([on, a, child, with, a, de, novo, 12, ;, 17, 'translocation,', 46, ',', 'XX,t(12;17)(q14'])].
[sujeto(['Thus,', the, 12, ;, 17, translocation, removed, part, of, the, 'SOX9', 'cis-regulatory', region, and, replaced, it, with, a, regulatory, element, from, pseudogene, 'LOC204010', or, the, next, 'gene,', 'Deynar,', of, chromosome, 12, ',', potentially]), verbo([causing]), complemento(['up-regulation', of, the, 'testis-determining', 'SOX9', gene, during, gonadal, development, and, the, phenotype, of, 46, ',', 'XX', testicular, 'DSD'])].
[sujeto(['To']), verbo([gain]), complemento([further, insights, on, the, genetic, divergence, and, the, 'species-specific', characteristics, of, the, 'follicle-stimulating', hormone, receptor, '(', 'FSHR),', we, cloned, 946, bp, of, the, 5, '\'', -, flanking, region, of, the, 'FSHR', gene, from, the, volcano, mouse, '(', 'Neotomodon', alstoni, 'alstoni),', and, compared, its, features, with, those, from, other, mammalian, species])].
[sujeto(['The', low, transcription, levels, detected, in, 'MSC-1', cells, probably, reflect, the, recruitment, of, 'Sertoli', 'cells-specific']), verbo([nuclear]), complemento([factors, that, repress, transcription, of, the, 'FSHR', gene])].
[sujeto(['Functional', analysis, of, a, series, of, progressive, 5, '\'', -, deletion, mutants, identified, regions]), verbo([involved]), complemento([in, positive, and, negative, transcriptional, regulation, as, well, as, the, strongest, minimal, promoter, spanning, 260, bp, upstream, the, translation, initiation, site])].
[sujeto(['The', identification, of, inhibitory]), verbo([nuclear]), complemento([transcription, 'factors,', which, are, apparently, expressed, in, 'MSC-1', 'cells,', may, contribute, to, a, better, understanding, of, the, transcriptional, regulation, of, the, 'FSHR', gene])].
[sujeto(['Thus', 'far,', only, a, handful, of, direct]), verbo([target]), complemento([genes, are, known, for, this, transcription, factor, limiting, our, understanding, of, the, biological, network, it, governs])].
[sujeto(['We', describe, identification, of, multiple, direct, regulatory]), verbo([target]), complemento([genes, of, 'Sox10', through, a, procedure, based, on, function, and, conservation])].
[sujeto(['By', combining, 'RNA', interference, technique, and, 'DNA', microarray, 'technology,', we]), verbo([have]), complemento([identified, a, set, of, genes, that, show, significant, 'down-regulation', upon, introduction, of, 'Sox10', specific, siRNA, into, 'Schwannoma', cells])].
[sujeto(['Subsequent', comparative, genomics, analyses]), verbo([led]), complemento([to, potential, binding, sites, for, 'Sox10', protein, conserved, across, several, mammalian, species, within, the, genomic, region, proximal, to, these, genes])].
[sujeto(['Multiple', sites, belonging, to, 4, different, genes, '(', proteolipid, 'protein,', 'Sox10,', extracellular, superoxide, 'dismutase,', and, 'pleiotrophin)', were, shown, to, directly]), verbo([interact]), complemento([with, 'Sox10', by, chromatin, immunoprecipitation, assay])].
[sujeto(['In', 'sum,', the, process, of, combining, differential, expression, profiling, and, comparative, genomics, successfully]), verbo([led]), complemento([to, further, defining, the, role, of, 'Sox10,', a, critical, transcription, factor, for, the, development, of, peripheral, glia])].
[sujeto(['The', 'Sry-related', 'high-mobility-group', box, transcription, factor, 'Sox9']), verbo([recruits]), complemento([the, redundant, 'L-Sox5', and, 'Sox6', proteins, to, effect, 'chondrogenesis,', but, the, mode, of, action, of, the, trio, remains, unclear])].
[sujeto(['We', identify, here, a, highly]), verbo([conserved]), complemento([359, -, bp, sequence, 10, kb, upstream, of, the, 'Agc1', gene, for, 'aggrecan,', a, most, essential, cartilage, proteoglycan, and, key, marker, of, chondrocyte, differentiation])].
[sujeto(['The', chondrogenic, trio, is]), verbo([required]), complemento([and, sufficient, to, mediate, the, activity, of, this, enhancer])].
[sujeto(['It']), verbo([acts]), complemento(['directly,', 'Sox9', binding, to, a, critical, 'cis-acting', element, and, 'L-Sox5/Sox6', binding, to, three, additional, 'elements,', which, are, cooperatively, needed])].
[sujeto(['Upon']), verbo([binding]), complemento([to, their, specific, 'sites,', 'L-Sox5/Sox6', increases, the, efficiency, of, 'Sox9', binding, to, its, own, recognition, site, and, thereby, robustly, potentiates, the, ability, of, 'Sox9', to, activate, the, enhancer])].
[sujeto(['L-Sox5/Sox6', similarly, secures, 'Sox9']), verbo([binding]), complemento([to, 'Col2a1', '(', encoding, 'collagen-2)', and, other, 'cartilage-specific', enhancers])].
[sujeto(['This', study, thus, uncovers, critical, 'cis-acting', elements, and, transcription, factors, driving, 'Agc1', expression, in, cartilage, and]), verbo([increases]), complemento([understanding, of, the, mode, of, action, of, the, chondrogenic, 'Sox', trio])].
[sujeto(['Endothelial', progenitor, cells, '(', 'EPCs)']), verbo([provide]), complemento([paracrine, support, to, the, vascular, endothelium, and, may, also, replace, damaged, or, senescent, endothelial, cells])].
[sujeto(['We', hypothesized, that, the, number, of, 'CFU-ECs', derived, from, maternal, blood, are]), verbo([decreased]), complemento([in, women, with, preeclampsia, compared, to, normal, pregnancy])].
[sujeto(['The', critical, role, of, monocyte, recruitment, in, atherogenesis]), verbo([has]), complemento([been, appreciated, for, some, time])].
[sujeto(['However,', until, 'recently,', there]), verbo([have]), complemento([been, no, sufficiently, sensitive, methods, for, measuring, rates, of, monocyte, recruitment, to, the, arterial, wall, in, vivo])].
[sujeto(['We']), verbo([have]), complemento([developed, a, novel, highly, sensitive, 'method,', based, on, the, polymerase, chain, 'reaction,', for, quantitatively, tracking, 'DNA-marked', monocytes, and, have, adapted, it, for, use, in, mice])].
[sujeto(['In', control, low, density, lipoprotein, 'receptor-negative', 'mice,', monocyte, recruitment]), verbo([decreased]), complemento([slightly, but, significantly, as, lesions, progressed])].
[sujeto(['Intrauterine', exposure, to, 5, -, 'AZA-2\'-deoxycytidine', '(', 5, -, 'AZA-CdR)', alters, gene, expression]), verbo([causing]), complemento(['malformations,', abnormal, 'post-natal', growth, and, altered, reproductive, capacity])].
[sujeto(['While', normal, presence, of, 'Sry', gene, was, 'observed,', mating, behavior, was, altered, in, exposed, males]), verbo([suggesting]), complemento([that, the, reproductive, alteration, could, be, attributed, to, a, behavioral, phenomenon])].
[sujeto(['The', tissues, from, the, tumor, and, its, periphery, carry, a, significantly]), verbo([increased]), complemento([number, of, 'SRY', copies, compared, to, its, neighboring, common, breast, tissue, '(', p, =, 0.005, ')'])].
[sujeto(['We']), verbo([found]), complemento([a, heterogeneous, distribution, of, fetal, microchimerism, in, breast, cancer, environment])].
[sujeto(['Are', 'Y-chromosome', microdeletions]), verbo([associated]), complemento([with, 'SHOX', 'haploinsufficiency,', thus, representing, a, risk, of, skeletal, anomalies, for, the, carriers, and, their, male, 'descendents?', 'The', present, study, shows, that, 'SHOX', haploinsufficiency, is, unlikely, to, be, associated, with, 'Y-chromosome', microdeletions])].
[sujeto(['Y-chromosome', microdeletions, are, not, commonly, known, as, a, major, molecular, genetic]), verbo([cause]), complemento([of, any, pathological, condition, except, spermatogenic, failure])].
[sujeto(['However,', it]), verbo([has]), complemento([been, recently, proposed, that, they, are, associated, not, only, with, infertility, but, also, with, anomalies, in, the, pseudoautosomal, regions, '(', 'PAR),', among, which, 'SHOX', haploinsufficiency, stands, out, with, a, frequency, of, 5.4, '%', in, microdeletion, carriers, bearing, a, normal, karyotype])].
[sujeto(['This']), verbo([finding]), complemento([implies, that, sons, fathered, by, men, with, 'Y-chromosome', defects, will, not, only, exhibit, fertility, 'problems,', but, might, also, suffer, from, 'SHOX-related', conditions])].
[sujeto(['No', 'SHOX', deletions, were]), verbo([found]), complemento([in, any, of, the, examined, subjects, '(', patients, as, well, as, 'controls),', thus, excluding, an, association, with, 'SHOX', haploinsufficiency])].
[sujeto(['This', might]), verbo([suggest]), complemento([that, 'Y-chromosome', microdeletions, have, a, higher, incidence, for, 'SHOX', 'duplications,', irrespective, of, the, 'patient\'s', karyotype])].
[sujeto(['The', number, of, controls, analyzed, is, rather, low, to, assess, whether, the, 'SHOX', duplications]), verbo([found]), complemento([in, the, two, men, with, 'Y-chromosome', microdeletions, and, a, normal, karyotype, represent, a, neutral, polymorphism, or, are, actually, associated, with, the, presence, of, the, microdeletion])].
[sujeto(['Our', results, imply, that, deletion, carriers]), verbo([have]), complemento([no, augmented, risk, of, 'SHOX-related', pathologies, '(', short, stature, and, skeletal, 'anomalies)', and, indicate, that, there, is, no, need, for, radical, changes, in, genetic, counseling, of, 'Yq', microdeletion, carriers, attempting, 'ART,', since, the, only, risk, established, so, far, for, their, male, offspring, remains, impaired, spermatogenesis])].
[sujeto(['The', specifics, of, the, interstrain, variation, in, spermatogenetic, parameters, indicated, that, a, physiological, compensatory, mechanism]), verbo([increases]), complemento([certain, spermatogenetic, parameters, when, other, ones, are, low, to, maintain, male, fertility, at, a, level, sufficient, for, successful, reproduction])].
[sujeto(['The']), verbo([decreases]), complemento([in, proportion, of, motile, sperms, and, in, their, velocity, were, attributed, to, mutations, '(', 'I63T', and, 'W133L)', of, the, 'Sry', gene, in, the, 'DD/He', strain])].
[sujeto(['Clinical', indications, for, fetal, sex, determination, include, risk, of, 'X-linked', 'disorders,', a, family, history, of, conditions]), verbo([associated]), complemento([with, ambiguous, development, of, the, external, 'genitalia,', and, some, fetal, ultrasound, findings])].
[sujeto(['It', is, usually, performed, in, the, first, trimester, from, fetal, material, obtained, through, 'CVS', and, is]), verbo([associated]), complemento([with, an, approximately, 1, '%', risk, of, miscarriage])].
[sujeto(['A', multiplex, 'PCR', was, performed, for, the, simultaneous, amplification, of]), verbo([target]), complemento([sequences, of, 'SRY', and, 'DYS14', from, chromosome, 'Y,', along, with, 'RASSF1A', and, 'ACTB', sequences])].
[sujeto(['In', the, clinical, 'studies,', fetal, sex, was, correctly, diagnosed, in, 16, 'pregnancies,', and, one, case, was]), verbo([reported]), complemento([as, inconclusive])].
[sujeto(['SNV', analysis, showed, 'DAZ1/DAZ2', deletion, in, all, those, with, 'gr/gr', and, those, with, 'b1/b3', 'deletion,', 'DAZ3/DAZ4', deletion, in, those, with, 'b2/b3', 'deletion,', and, 'DAZ-SNV', sY587, deletion, in, 1, case, of, 'sY1291,', sY1197, 'deletion,', but, no, 'DAZ', deletion, was]), verbo([found]), complemento([in, 1, case, of, 'b1/b2', deletion])].
[sujeto(['The', most, common, genetic]), verbo([causes]), complemento([of, spermatogenic, failure, are, sex, chromosomal, abnormalities, '(', most, frequently, 'Klinefelter\'s', 'syndrome)', and, deletions, of, the, azoospermia, factor, '(', 'AZF)', regions, '(', 'AZFa,', 'AZFb,', and, 'AZFc)', of, the, 'Y', chromosome])].
[sujeto(['Several', studies]), verbo([have]), complemento([proposed, that, partial, 'AZFc', 'deletions/duplications', may, be, a, risk, factor, for, spermatogenic, impairment])].
[sujeto(['We', describe, a, multiplex, quantitative, 'fluorescent-polymerase', chain, reaction, '(', 'QF-PCR)', method, that, allows, simultaneous, detection, of, these, genetic]), verbo([causes]), complemento([and, risk, factors, of, male, infertility])].
[sujeto(['The', consequences, of, such, rearrangements, are, not, only]), verbo([loss]), complemento([but, also, gain, of, specific, genes])].
[sujeto(['One', hundred, and, fifty, three, haplotypes]), verbo([have]), complemento([been, discovered, in, the, human, 'Y', chromosome])].
[sujeto(['Among', 'them,', 16, gene, products]), verbo([have]), complemento([been, discovered, in, the, azoospermia, factor, region, '(', 'AZF)', and, are, related, to, spermatogenesis])].
[sujeto(['It']), verbo([has]), complemento([been, discovered, that, one, subset, of, gene, rearrangements, on, the, 'Y', 'chromosome,', &, 'quot;micro-deletions&quot;,', is, a, major, cause, of, male, infertility, in, some, populations])].
[sujeto(['Six', 'AZFs', of, the, 'Y', chromosome]), verbo([have]), complemento([been, discovered, including, 'AZFa,', 'AZFb,', 'AZFc,', and, their, combinations, 'AZFbc,', 'AZFabc,', and, partial, 'AZFc', called, 'AZFc/gr/gr'])].
[sujeto(['Different', deletions, in, 'AZF']), verbo([lead]), complemento([to, different, content, spermatogenesis, loss, from, teratozoospermia, to, infertility, in, different, populations, depending, on, their, 'Y', haplotypes])].
[sujeto(['This', article, describes, the, structure, of, the, human, 'Y', chromosome, and, investigates, the]), verbo([causes]), complemento([of, 'micro-deletions', and, their, relationship, with, male, infertility, from, the, view, of, chromosome, evolution])].
[sujeto(['Regardless', of, the, exact, 'mechanism,', 'however,', all, these, animals, would, exhibit, a, 'sex-specific', gene, expression, 'inequality,', due, to, the, different, number, of, 'X', 'chromosomes,', a, phenomenon]), verbo([inhibited]), complemento([by, a, series, of, genetic, and, epigenetic, regulatory, events, described, as, &, 'quot;dosage', 'compensation&quot;'])].
[sujeto(['Since', adequate, available, data, is, currently, restricted, to, 'worms,', flies, and, 'mammals,', while, for, other, groups, of, 'animals,', such, as, 'reptiles,', fish, and, birds, it, is, very, 'limited,', it, is, not, yet, clear, whether, this, is, an, evolutionary]), verbo([conserved]), complemento([mechanism])].
[sujeto(['However', certain, striking, similarities]), verbo([have]), complemento([already, been, observed, among, evolutionary, distant, 'species,', such, as, 'Drosophila', melanogaster, and, 'Mus', musculus])].
[sujeto([the, ratio, of, autosomes, to, gonosomes, '(', a, process, well, understood, in, 'flies,', but, still, hypothesized, in, 'mammals),', 'b)', the, implication, of, 'non-translated,', 'sex-specific,', regulatory, 'RNAs', '(', roX, and, 'Xist,', 'respectively)', as, key, elements, in, this, process, and, the, location, of, similar, mediators, in, the, 'Z', chromosome, of, chicken, 'c)', the, inclusion, of, a, chromatin, modification, epigenetic, final, 'step,', which]), verbo([ensures]), complemento([that, gene, expression, remains, stably, regulated, throughout, the, affected, area, of, the, gonosome])].
[sujeto(['This', review, summarizes, these, points, and, proposes, a, possible, role, for, comparative, 'genetics,', as, they, seem, to, constitute, proof, of]), verbo([maintained]), complemento([cell, economy, '(', by, using, the, same, basic, regulatory, elements, in, various, different, 'scenarios)', throughout, numerous, centuries, of, evolutionary, history])].
[sujeto(['We']), verbo([found]), complemento([significantly, more, 'LH', but, not, 'FSH', peaks, per, 24, 'h,', as, estimated, by, the, 'Weibull', lambda, analysis])].
[sujeto(['In', this, group, of, patients, with, severe, hypergonadotropic, hypogonadism, due, to, a, supernumerary, 'X', 'chromosome,', higher, 'basal,', 'pulsatile,', and, total, 'LH', and, 'FSH', secretion, were]), verbo([associated]), complemento([with, significantly, more, 'LH', peaks, per, 24, h, in, comparison, with, healthy, controls])].
[sujeto(['Thus,', our, data, indicate, that, in, patients, with, 'Klinefelter', syndrome, and, 'XX', male, karyotypes, the, entire, 'hypothalamic-pituitary-gonadal', axis]), verbo([has]), complemento([undergone, functional, changes])].
[sujeto(['We']), verbo([report]), complemento([on, a, 13, -, 'year-old', boy, presenting, with, left, scrotal, hemorrhage])].
[sujeto(['A', variety, of, such, regulatory, mechanisms]), verbo([have]), complemento([been, described, so, far, and, some, of, the, more, extensively, studied, ones, are, being, discussed])].
[sujeto(['Another', model, organism, whose, sex, depends, on, the, 'X:A', 'ratio,', 'Caenorhabditis', 'elegans,']), verbo([has]), complemento([furthermore, to, provide, for, the, brief, period, of, spermatogenesis, in, hermaphrodites, '(', 'XX)', without, the, benefit, of, the, &, 'quot;male&quot;', genes, of, the, sex, determination, pathway])].
[sujeto(['Many', reptiles]), verbo([have]), complemento([no, discernible, sex, determining, genes])].
[sujeto(['Their', sexual, fate, is, determined, by, the, temperature, of, the, environment, during, the, thermosensitive, period, '(', 'TSP)', of, 'incubation,', which]), verbo([regulates]), complemento([aromatase, activity])].
[sujeto(['However,', we]), verbo([have]), complemento([yet, to, decipher, which, of, the, two, '(', 'Z', or, 'W)', is, responsible, for, the, choice, between, males, and, females])].
[sujeto(['Similar', observations]), verbo([have]), complemento([been, described, not, only, in, 'mammals,', but, also, in, other, 'vertebrates,', emphasizing, the, need, for, further, study, of, both, normal, hormonal, regulators, of, sexual, phenotype, and, patterns, of, 'epigenetic/environmental', disruption])].
[sujeto(['This', is, due, to, the, distinct, content, of, the, 'X', and, 'Y-chromosomes', in, both, genes, and, regulatory, 'sequences,', 'SRY', being, the, key, regulator, 'Hormones', '(', 'AMH,', 'testosterone,', 'Insl3)', secreted, by, the, foetal, testis, '(', gonadal, sexual, 'dimorphism),', impede, 'Müller', duct, 'development,', masculinize, 'Wolff', duct, derivatives, and, are]), verbo([involved]), complemento([in, testicular, descent, '(', hormonal, sexual, 'dimorphism)'])].
[sujeto(['Intervertebral', disc, degeneration, is, the]), verbo([leading]), complemento([cause, of, chronic, back, pain])].
[sujeto(['Hypoxia']), verbo([induced]), complemento(['SDC4', mRNA, and, protein, expression, by, '~2'])].
[sujeto(['While', the, activity, of, the, 'SDC4', promoter, containing, hypoxia, response, element, '(', 'HRE)', was]), verbo([induced]), complemento([2, -, fold, '(', 'P&lt;0'])].
[sujeto([5, ')', ',', the, 'HRE', mutation]), verbo([decreased]), complemento([the, activity, by, 40, '%', in, hypoxia])].
[sujeto(['Transfections', with, plasmids, coding, 'prolyl-4-hydroxylase', domain, protein, 2, '(', 'PHD2)', and, 'ShPHD2', show, that, hypoxic, expression, of, 'SDC4', mRNA, and, protein, is]), verbo([regulated]), complemento([by, 'PHD2', through, controlling, 'hypoxia-inducible', factor, 1, α, '(', 'HIF-1α)', levels])].
[sujeto(['Although', overexpression, of, 'HIF-1α', significantly]), verbo([increased]), complemento(['SDC4', protein, 'levels,', stable, suppression, of, 'HIF-1α', and, 'HIF-1β', decreased, 'SDC4', expression, by, 50, '%', in, human, 'NP', cells])].
[sujeto(['Finally,', suppression, of, 'SDC4', 'expression,', as, well, as, 'HS', 'function,', resulted, in, an, '~2-fold']), verbo([increase]), complemento([in, 'sex-determining', region, 'Y', '(', 'SRY)-box', 9, '(', 'Sox9)', 'mRNA,', and, protein, '(', 'P&lt;0'])].
[sujeto([5, ')', and, simultaneous]), verbo([increase]), complemento([in, 'Sox9', transcriptional, activity, and, target, gene, expression])].
[sujeto(['Taken', 'together,', our, findings]), verbo([suggest]), complemento([that, in, healthy, 'discs,', 'SDC4,', through, its, 'HS', side, 'chains,', contributes, to, maintenance, of, the, hypoxic, tissue, niche, by, controlling, baseline, expression, of, 'Sox9'])].
[sujeto(['We']), verbo([report]), complemento([isolation, of, novel, splice, variants, of, chicken, 'Neuronal', 'Per-Arnt-Sim', domain, protein, 3, '(', 'cNPAS3)', gene, distinct, from, the, previously, predicted, cNPAS3, at, the, 5, '\'', end])].
[sujeto(['We', also, show, that, the, alternative, splicing, pattern, of, 'NPAS3', is]), verbo([conserved]), complemento([between, chicken, and, human])].
[sujeto(['RNA', in, situ, hybridization, indicated, that, the, expression, of, cNPAS3, in, the, developing, central, nervous, system, '(', 'CNS)', is, limited, to, the, ventricular, zone, and, only, partially, overlaps, with, that, of, chicken, 'Reelin', '(', 'cReelin),', the, only, known, regulatory]), verbo([target]), complemento([gene, of, 'NPAS3', in, the, adult, brain])].
[sujeto(['Epidermal', keratinocytes]), verbo([respond]), complemento([to, extracellular, influences, by, activating, cytoplasmic, signal, transduction, pathways, that, change, gene, expression])].
[sujeto(['Using', 'pathway-specific', transcriptional, 'profiling,', we, identified, the, genes]), verbo([regulated]), complemento([by, two, such, 'pathways,', p38, and, 'ERK'])].
[sujeto(['We', used, 'SB203580', and, 'PD98059', as, specific, inhibitors, and, 'Affymetrix', 'Hu133Av2', 'microarrays,', to, identify, the, genes]), verbo([regulated]), complemento([after, 1, ',', 4, ',', 24, ',', and, 48, h, and, compared, them, to, genes, regulated, by, 'JNK'])].
[sujeto(['Both', pathways]), verbo([promote]), complemento([epidermal, 'differentiation;', 'however,', there, is, a, surprising, disconnect, between, the, expression, of, steroid, synthesis, enzymes, and, differentiation, markers])].
[sujeto(['The', p38, pathway]), verbo([induces]), complemento([the, expression, of, extracellular, matrix, and, 'proliferation-associated', 'genes,', while, suppressing, 'microtubule-associated', genes])].
[sujeto(['The', 'ERK', pathway]), verbo([induces]), complemento([nuclear, envelope, and, mRNA, splicing, 'proteins,', while, suppressing, steroid, synthesis, and, mitochondrial, energy, production, enzymes])].
[sujeto(['Transcription', factors, 'SRY,', 'c-FOS,', and, 'N-Myc', are, the, principal]), verbo([targets]), complemento([of, the, p38, 'pathway,', 'Elk-1', 'SAP1', and, 'HLH2', of, 'ERK,', while, 'FREAC-4,', 'ARNT', and, 'USF', are, shared])].
[sujeto(['The', results]), verbo([suggest]), complemento([a, list, of, targets, potentially, useful, in, therapeutic, interventions, in, cutaneous, diseases, and, wound, healing])].
[sujeto(['Here', we, describe, how, the, interaction, between, 'Hhex', '(', hematopoietically]), verbo([expressed]), complemento(['homeobox)', and, 'SOX13', '(', 'SRY-related', high, mobility, group, box, transcription, factor, 13, ')', ',', modulates, 'Wnt/TCF', pathway, activity])].
[sujeto(['Hhex', is, a, homeodomain, factor]), verbo([expressed]), complemento([in, multiple, 'endoderm-derived', 'tissues,', like, the, 'liver,', where, it, is, essential, for, proper, development])].
[sujeto(['The', pleiotropic, expression, of, 'Hhex', during, embryonic, development, and, its, dual, role, as, a, transcriptional, repressor, and, activator]), verbo([suggest]), complemento([the, presence, of, different, 'tissue-specific', partners, capable, of, modulating, its, activity, and, function])].
[sujeto(['While', searching, for, developmentally]), verbo([regulated]), complemento(['Hhex', 'partners,', we, set, up, a, yeast, 'two-hybrid', screening, using, an, 'E9'])].
[sujeto(['We']), verbo([found]), complemento([that, 'SOX13', interacts, directly, with, 'full-length', 'Hhex,', and, we, delineated, the, interaction, domains, within, the, two, proteins])].
[sujeto(['SOX13', is, known, to]), verbo([repress]), complemento(['Wnt/TCF', signaling, by, interacting, with, 'TCF1'])].
[sujeto(['That', it, arises, from, embryonic, epiblast, cells, prior, to, gastrulation]), verbo([suggests]), complemento([that, it, may, retain, a, reservoir, of, stem, cells, throughout, pregnancy])].
[sujeto(['We']), verbo([found]), complemento([that, human, amniotic, epithelial, cells, '(', 'hAECs)', harvested, from, 'term-delivered', fetal, membranes, express, mRNA, and, proteins, present, in, human, embryonic, stem, cells, '(', 'hESCs),', including, 'POU', 'domain,', class, 5, ',', transcription, factor, 1, ;, 'Nanog', 'homeobox;', 'SRY-box', 2, ;, and, 'stage-specific', embryonic, 'antigen-4'])].
[sujeto(['In', keeping, with, possible, stem, 'cell-like', 'activity,', hAECs, were, also, 'clonogenic,', and, primary, hAEC, cultures, could, be]), verbo([induced]), complemento([to, differentiate, into, 'cardiomyocytic,', 'myocytic,', 'osteocytic,', adipocytic, '(', 'mesodermal),', 'pancreatic,', hepatic, '(', 'endodermal),', 'neural,', and, astrocytic, '(', 'neuroectodermal)', cells, in, 'vitro,', as, defined, by, 'phenotypic,', mRNA, 'expression,', 'immunocytochemical,', 'and/or', ultrastructural, characteristics])].
[sujeto(['Last,', using, flow, cytometry, we]), verbo([have]), complemento([shown, that, only, a, very, small, proportion, of, primary, hAECs, contain, class, 'IA', and, class, 'II', human, leukocyte, antigens, '(', 'HLAs),', consistent, with, a, low, risk, of, tissue, rejection])].
[sujeto(['These', observations]), verbo([suggest]), complemento([that, the, term, 'amnion,', an, abundant, and, easily, accessible, 'tissue,', may, be, a, useful, source, of, multipotent, stem, cells, that, possess, a, degree, of, immune, privilege])].
[sujeto(['Cells', showed]), verbo([increased]), complemento([hepatic, associated, gene, expression, of, 'alpha-fetoprotein', '(', 'AFP),', 'Albumin', '(', 'Alb),', 'Glucose-6-phosphatase', '(', 'G6Pc),', 'SRY', '(', sex, determining, region, 'Y)-box', 9, '(', 'Sox9),', hepatic, nuclear, factors, '(', 'HNF1a,', 'HNF1β,', 'HNF3β,', 'HNF4α,', 'HNF6,', 'Epithelial', cell, adhesion, molecule, '(', 'EpCAM),', 'Leucine-rich', 'repeated-containing', 'G-protein', coupled, receptor, 5, -, positive, '(', 'Lgr5)', and, 'Tyrosine', aminotransferase, '(', 'TAT)'])].
[sujeto(['Cells', showed]), verbo([decreased]), complemento(['fibrogenesis,', hepatic, stellate, cell, 'infiltration,', 'Kupffer', cells, and, inflammatory, cytokines])].
[sujeto(['In', 'addition,', grafted, 'MLpvNG2(+)', cells, could, mobilize, endogenous, 'stem/progenitors', to]), verbo([participate]), complemento([in, liver, repair])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'MLpvNG2(+)', cells, may, be, novel, adult, liver, progenitors, that, participate, in, liver, regeneration])].
[sujeto(['In', a, logistic, regression, model]), verbo([involving]), complemento(['demographic,', anthropometric, and, metabolic, 'variables,', only, diabetes, duration, was, significantly, associated, with, 'anti-SOX-13', 'positivity,', especially, for, duration, &, 'gt;', 5, years, '(', 'P', &, 'lt;', 0.002, ')'])].
[sujeto(['Whilst', the, frequency, of, 'anti-SOX-13', may, be]), verbo([increased]), complemento([in, some, populations, of, diabetic, 'patients,', this, reactivity, does, not, usefully, distinguish, 'Type', 1, from, 'Type', 2, diabetes])].
[sujeto(['However,', the, association, with, diabetes, duration]), verbo([suggests]), complemento([that, 'anti-SOX-13', may, be, a, 'non-specific', marker, of, tissue, damage, associated, with, chronic, hyperglycaemia])].
[sujeto(['Despite', its, essential, function, during, endoderm, formation, and, 'differentiation,', few, direct]), verbo([targets]), complemento([of, 'SOX17', are, known])].
[sujeto(['To', identify]), verbo([targets]), complemento([of, 'SOX17,', we, isolated, 'SOX17', binding, sites, with, a, chromatin, immunoprecipitation, '(', 'ChIP)-cloning', screen])].
[sujeto(['SOX17-ChIP', identified, zinc, finger, protein, 202, '(', 'Zfp202)', as, a, direct]), verbo([target]), complemento([of, 'SOX17', during, endoderm, differentiation, of, 'F9', embryonal, carcinoma, cells])].
[sujeto(['A', sequence, in, the, first, intron, of, 'Zfp202']), verbo([activated]), complemento([transcription, in, differentiated, 'F9', 'cells,', and, overexpression, of, 'Sox17', increased, the, transcriptional, activity, of, this, sequence])].
[sujeto(['SOX17']), verbo([binds]), complemento([to, a, site, within, this, sequence, in, electrophoretic, mobility, shift, 'assays,', and, mutation, of, this, site, decreases, the, transcriptional, activation])].
[sujeto(['Zfp202', is]), verbo([induced]), complemento([concomitantly, with, 'Sox17', during, endoderm, differentiation, of, 'F9', cells])].
[sujeto(['We', also, show, that, 'ZFP202']), verbo([represses]), complemento(['Hnf4a,', which, has, been, reported, for, the, human, ortholog, 'ZNF202'])].
[sujeto(['Identifying']), verbo([targets]), complemento([of, 'SOX17', will, help, to, elucidate, the, molecular, basis, of, endoderm, differentiation, and, may, provide, a, better, understanding, of, the, role, of, endoderm, in, patterning, the, other, germ, layers])].
[sujeto(['We', hypothesized, that, 'estrogen,', directly, or, 'indirectly,']), verbo([regulates]), complemento([genes, responsible, for, somatic, cell, differentiation, and, steroidogenesis])].
[sujeto(['ArKO', ovaries]), verbo([expressed]), complemento([estrogen, receptors, alpha, and, 'beta,', and, 'LH', 'receptor,', indices, of, estrogen, responsiveness, in, the, ovary])].
[sujeto(['E2']), verbo([decreased]), complemento([serum, 'FSH', and, 'LH', and, increased, uterine, weights, of, 10, -, 'wk-old', 'ArKO', mice])].
[sujeto(['Placebo-treated', 'ArKO', ovaries]), verbo([have]), complemento([increased, 'Sox9', '(', 15, -, 'fold;', 'P', &, 'lt;', 0.001, ')', ',', 'Müllerian-inhibiting', substance, '(', 2.9, -, 'fold),', 'Lrh-1', '(', 7.7, -, 'fold),', and, 'dosage-sensitive', sex, reversal, adrenal, hypoplasia, congenital, critical, region, on, the, 'X', chromosome, gene, 1, '(', 12, -, 'fold)', expression, compared, with, 'Wt', at, 10, wk])].
[sujeto(['Consistent', with]), verbo([increased]), complemento([serum, 'T', levels, and, 'Leydig', cells, in, their, 'ovaries,', 'placebo-treated', 'ArKO', ovaries, had, increased, 17, 'alpha-hydroxylase,', 17, 'beta-hydroxysteroid', dehydrogenase, 'type-3,', and, 17, 'beta-hydroxysteroid', dehydrogenase, 'type-1', expression, compared, with, 'Wt', at, 10, wk])].
[sujeto(['E2', treatment, for, 3, wk, improved, the, ovarian, 'phenotype,']), verbo([decreased]), complemento([development, of, 'Sertoli', 'cells,', decreased, the, expression, of, 'Sox9,', 'Lrh-1,', and, the, steroidogenic, enzymes, in, 'ArKO', 'ovaries,', and, induced, ovulation, in, some, cases])].
[sujeto(['In', 'conclusion,', the, expression, of, the, genes]), verbo([regulating]), complemento([somatic, cell, differentiation, is, directly, or, indirectly, responsive, to, estrogen])].
[sujeto(['We', aimed, to, identify, the, genetic]), verbo([cause]), complemento([in, a, cohort, of, 11, unrelated, cases, and, two, sisters, with, 46, ',', 'XX', 'SRY-negative', '(', 'ovo)testicular', disorders, of, sex, development, '(', 'DSD)'])].
[sujeto(['Whole-exome', sequencing, '(', n, =, 9, ')', ',']), verbo([targeted]), complemento([resequencing, '(', n, =, 4, ')', ',', and, haplotyping, were, performed])].
[sujeto(['The', 'Arg92', residue, is, highly]), verbo([conserved]), complemento([and, located, in, the, 'Ftz-F1', 'region,', probably, involved, in, 'DNA-binding', specificity, and, stability])].
[sujeto(['Transcriptomics', in, 'patient-derived', lymphocytes, showed, upregulation, of, 'MAMLD1,', a, direct, 'NR5A1']), verbo([target]), complemento([previously, associated, with, 46, ',', 'XY', 'DSD'])].
[sujeto(['We', propose, 'NR5A1,', previously]), verbo([associated]), complemento([with, 46, ',', 'XY', 'DSD', and, 46, ',', 'XX', primary, ovarian, 'insufficiency,', as, a, novel, gene, for, 46, ',', 'XX', '(', 'ovo)testicular', 'DSD'])].
[sujeto(['(', 'Arg92Trp)', results, in]), verbo([decreased]), complemento([inhibition, of, the, male, developmental, pathway, through, downregulation, of, female, antitestis, 'genes,', thereby, tipping, the, balance, toward, testicular, differentiation, in, 46, ',', 'XX', individuals])].
[sujeto([ff1d, is, a, novel, zebrafish, 'FTZ-F1', gene, with, sequence, characteristics, indicating, similar, basic, regulatory, mechanisms, as, the, previously, characterized, ff1, based, on, the, presence, of, an, 'FTZ-F1', box, in, the, 'DNA']), verbo([binding]), complemento([domain, and, an, interactive, domain, '(', 'I-Box)', and, an, 'AF-2', in, the, ligand, binding, domain])].
[sujeto(['The', highest, sequence, similarity, was]), verbo([found]), complemento([between, ff1d, and, ff1b, '(', 'NR5A4),', a, gene, previously, shown, to, be, a, functional, homolog, to, the, steroidogenic, factor, 1, '(', 'SF-1)'])].
[sujeto(['SF-1', is, crucial, in, mammalian, steroidogenesis, and, in, sex, determination, by]), verbo([regulating]), complemento([the, 'anti-Mullerian', hormone, '(', 'AMH)'])].
[sujeto(['In', 'fish,', 'AMH']), verbo([has]), complemento([not, been, described, previously])].
[sujeto(['AMH', was, detected, in, growing, 'oocytes,', the, ovarian, follicular, layer, and, testicular, 'Sertoli', 'cells,', similar, to, the, mammalian, 'pattern,']), verbo([suggesting]), complemento([a, conserved, role, between, zebrafish, and, mammalian, 'AMH'])].
[sujeto(['Comparison', of, sequences, and, expression, patterns, indicate, that, ff1d, is, a, new, candidate, for, sex, determination, and, differentiation, in, a, way, similar, to, 'SF-1,', possibly]), verbo([involving]), complemento(['AMH'])].
[sujeto(['The', study, of, naturally, occurring, mutations, in, humans, and]), verbo([induced]), complemento([mutations, in, mice, that, cause, sex, reversal, has, been, instrumental, in, the, cloning, and, functional, analysis, of, genes, involved, in, gonadal, differentiation])].
[sujeto(['Several', genes]), verbo([required]), complemento([for, this, complex, developmental, process, have, now, been, identified])].
[sujeto(['The', genes, 'LIM1,', 'WT1', and, 'FTZ-F1']), verbo([have]), complemento([been, demonstrated, to, be, involved, in, the, formation, of, the, gonads, prior, to, their, differentiation, as, testes, or, ovaries])].
[sujeto(['Subsequent', 'sex-specific', gonadal, differentiation, appears, to, be]), verbo([mediated]), complemento([by, the, 'SRY', and, 'SOX9', genes, in, the, 'testis,', and, the, 'DAX-1', gene, in, the, ovary])].
[sujeto(['Mammals']), verbo([have]), complemento([two, genes, '(', 'SRY', and, 'DMT1)', for, testis, 'formation-androgenesis,', an, 'anti-testis', 'gene,', 'DAX1,', an, 'anti-Müllerian', duct, 'hormone,', and, steroid, sex, hormones])].
[sujeto(['However,', the, statement, that, insects, do, not]), verbo([have]), complemento([sex, hormones, loses, much, of, its, credibility, if, one, considers, '(', 1, ')', the, classical, endocrinological, work, on, sexual, differentiation, in, the, firefly, 'Lampyris', and, in, the, hevea, tussock, moth, 'Orgyia;', '(', 2, ')', the, recent, identification, of, an, androgenic, hormone, and, its, role, in, sex, determination, in, the, isopod, 'Armadillidium;', '(', 3, ')', the, similarity, between, steroidogenic, factor, 1, '(', 'SF-1)', of, mammals, and, fushi, tarazu, factor, 1, '(', 'FTZ-F1)', of, 'Drosophila;', and, '(', 4, ')', the, steroidogenic, effect, of, gonadotropins, secreted, by, the, brain, of, female, locusts, and, mosquitoes, and, of, male, gypsy, moth])].
[sujeto(['In', 'mammals,', the, presence, of, 'SRY,', the, 'sex-determining', gene, located, on, the, 'Y', chromosome, is]), verbo([required]), complemento([to, induce, the, gonadal, anlage, to, differentiate, as, a, 'testis,', whereas, its, absence, leads, to, the, development, of, an, ovary])].
[sujeto(['We']), verbo([report]), complemento([here, the, characterization, by, 5, '\'', and, 3, '\'', 'RACE', analysis, of, several, 'SRY', transcripts, which, are, expressed, in, the, ovine, male, developing, gonads])].
[sujeto(['These', transcripts, were, not, detected, in, any, other, fetal, tissues, and, were]), verbo([expressed]), complemento([only, in, the, genital, portion, of, the, urogenital, ridge])].
[sujeto(['The', temporal, profile, of, 'SRY', expression, analyzed, by, 'RT-PCR']), verbo([suggests]), complemento([that, in, the, sheep, fetus, the, role, of, 'SRY', is, not, limited, to, initiating, 'Sertoli', cell, differentiation, as, in, mice])].
[sujeto(['In', addition, to, 'SRY,', other, genes, are, known, to, be]), verbo([involved]), complemento([in, mammalian, sex, 'determination:', 'Wilms\'', tumor, gene, 'WT-1,', steroidogenic, factor, gene, 'Ftz-F1', '(', 'SF-1)', and, 'anti-Müllerian', hormone, '(', 'AMH)'])].
[sujeto(['In', 'female,', we]), verbo([have]), complemento([observed, the, presence, of, 'SF-1', transcripts, from, the, undifferentiated, stage, until, birth])].
[sujeto(['These', data]), verbo([reveal]), complemento([significant, differences, between, rodent, and, ruminant, models, concerning, the, 'sex-determining', pathway])].
[sujeto(['However,', the, indifferent, gonad]), verbo([has]), complemento([two, 'options,', to, form, either, a, testis, or, an, 'ovary,', and, mutations, of, this, tissue, usually, produce, sex, reversal, or, sterility, which, is, not, lethal, for, the, individual])].
[sujeto(['The', studies, of, human, patients, showing, different, types, of, sex, 'reversal,', in, combination, with, the, use, of, transgenic, mice, 'and/or', gene]), verbo([targeting]), complemento(['disruption,', have, led, to, the, isolation, of, several, genes, important, for, sex, development])].
[sujeto(['However,', the, mammalian, sex, differentiation, pathway]), verbo([requires]), complemento([the, function, of, a, number, of, additional, genes, which, we, are, now, trying, to, identify, with, the, help, of, mRNA, differential, display, technique])].
[sujeto(['In', 'particular,', chondrogenic, differentiation]), verbo([has]), complemento([never, been, deeply, investigated])].
[sujeto(['Both', populations]), verbo([expressed]), complemento([mesenchymal, but, not, endothelial, and, hematopoietic, 'markers,', even, though, we, observed, a, lower, expression, of, human, leukocyte, antigen, '(', 'HLA)', 'I', in, 'CB-MSCs'])].
[sujeto(['Adipose', 'tissue-derived', stem, cells, '(', 'ADSCs)']), verbo([have]), complemento([shown, potential, for, the, treatment, of, nerve, injuries])].
[sujeto(['Most', previous, efforts]), verbo([have]), complemento([aimed, at, stimulating, regeneration, by, using, 'neural-differentiation', 'protocols,', but, the, potential, of, undifferentiated, 'ADSCs', to, enhance, axonal, growth, as, well, as, their, ability, to, transdifferentiate, in, situ, have, been, poorly, investigated])].
[sujeto(['In', this, 'study,', using, a, rat, sciatic, nerve, model, we, show, that, 'ADSCs,', transplanted, in, an, artificial, nerve, 'conduit,']), verbo([stimulate]), complemento([axonal, outgrowth, from, the, proximal, nerve, stump, and, evoke, greater, 'Schwann', cell, '(', 'SC)', 'proliferation/intrusion', in, the, distal, stump])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, any, regenerative, effect, of, transplanted, 'ADSCs', is, more, likely, to, be, mediated, by, an, initial, boost, of, released, growth, factors, 'and/or', by, an, indirect, effect, on, endogenous, 'SCs', activity])].
[sujeto(['Using', a, 'cell-free', degradation, assay, and, 'site-directed', 'mutagenesis,', we]), verbo([report]), complemento([here, that, the, three, 'PEST', motifs, of, 'c-fos', are, not, required, for, rapid, cleavage, by, calpains])].
[sujeto(['Here', we]), verbo([report]), complemento([the, analysis, of, an, unexplored, sequence, inside, the, 'bone-specific', distal, promoter, 'F', '(', 'PF)', with, respect, to, the, regulation, of, 'ERalpha', gene, expression, in, bone])].
[sujeto(['It', contains, a, 'TA', reach, 'box,', a, conventional, 'CAAT', box, and, potential, regulatory, elements, for, many, transcription, 'factors,', including, 'Cbfa1', '[', 'OSE2', '(', 'osteoblast-specific', 'element)', core]), verbo([binding]), complemento(['factor],', 'GATA-1', '[', '(', 'A/T)GATA(A/G)', binding, 'protein],', 'Sox5', '[', 'sex-determining', region, 'Y', '(', 'SRY)-type', 'HMG', bOX, 'protein,', belonging, to, a, subfamily, of, 'DNA-binding', proteins, with, an, 'HMG', 'domain],', 'Sry,', 'AP1', '(', activator, protein, 1, ')', and, 'CP2', '(', activator, of, 'gamma-globin)'])].
[sujeto(['It', is, able, to, strongly]), verbo([activate]), complemento([the, luciferase, reporter, gene, in, 'MG-63', 'osteoblastic-like', 'cells,', but, not, in, 'MCF7', 'breast-cancer', cells])].
[sujeto(['This', is, in, agreement, with, different, transcripts, that, we]), verbo([found]), complemento([in, the, two, cell, types])].
[sujeto(['The', footprinting, and, electrophoretic, 'mobility-shift', assays, '(', 'EMSAs)', showed, 'that,', inside, the, region, 'analysed,', there, were, some, sequences, that, specifically, reacted, to]), verbo([nuclear]), complemento([proteins, isolated, from, 'MG-63', cells])].
[sujeto(['In', 'particular,', we, identified, two, 'regions,', named, 'PF', a, and, 'PF', 'b,', that, do, not, present]), verbo([binding]), complemento([sites, for, known, transcription, factors, and, that, are, involved, in, a, strong, 'DNA-protein', interaction, in, 'MG-63,', but, not, in, 'MCF7,', cells])].
[sujeto(['The', analysis, of, three, transcription, factors, '(', 'GATA-1,', 'Sry', and, 'Sox)', that, might]), verbo([bind]), complemento([the, identified, footprinted, areas, suggested, a, possible, indirect, role, of, these, proteins, in, the, regulation, of, 'ERalpha', gene, expression, in, bone])].
[sujeto(['These', data]), verbo([provide]), complemento([evidence, for, different, promoter, usage, of, the, 'ERalpha', gene, through, the, recruitment, of, 'tissue-specific', transcription, activators, and, 'co-regulators'])].
[sujeto(['Formation', of, a, testis]), verbo([requires]), complemento([the, interaction, of, 'gene-products', and, hormones, '(', 'androgens)', on, pluripotent, tissue])].
[sujeto(['Sertoli', cells, make, a, number, of, substances, that, affect, testicular, development, and, 'function,', particularly, 'anti-Müllerian', 'hormone,', which]), verbo([inhibits]), complemento([female, oviduct, formation, from, the, 'Müllerian', 'anlage,', inhibits, aromatase, activity, to, stop, estrogen, 'production,', and, possibly, stimulates, androgen, production, by, 'Leydig', cells])].
[sujeto(['Although', information, concerning, paracrine, and, autocrine, regulation, of, the, avian, testis, by, these, substances, is, 'sparse,', much, can, be, learned, from, mammalian, 'studies,', in, which, putative, roles, of, each, of, these, substances]), verbo([have]), complemento([been, established])].
[sujeto(['How', 'Sertoli', cells]), verbo([cause]), complemento([directed, apoptosis, of, spermatogonia, using, the, 'Fas-ligand,', 'Fas-receptor', pathway, is, 'reviewed,', as, well, as, ways, to, circumvent, this, process])].
[sujeto(['Sex', differentiation, in, organisms, is, correlated, to, sex, steroid, production, and, receptor, signaling, pathways]), verbo([involving]), complemento([androgens, and, estrogens])].
[sujeto(['The', objectives, of, this, study, were, to, determine, whether, genes, related, to, steroid, 'biosynthesis,', steroid, receptor, 'signaling,', and, those, related, to, sex, differentiation, were]), verbo([expressed]), complemento([in, 'pre-differentiated', fathead, minnow, '(', 'FHM)', 'embryos,', an, ecotoxicological, model])].
[sujeto(['The', majority, of, transcripts, 'investigated,', for, example, 'estrogen,', 'androgen,', and, thyroid, receptors, as, well, as, steroid, biosynthesis, 'transcripts,', were]), verbo([expressed]), complemento([within, the, first, 72, hours, of, 'development;', exceptions, were, star, '(', steroidogenic, acute, regulatory, 'protein)', and, 'cyp19a,', which, did, not, have, detectable, expression, until, 5, dpf, '(', 'pre-hatch)'])].
[sujeto(['Transcripts', that]), verbo([increased]), complemento([in, relative, mRNA, abundance, over, the, first, two, weeks, of, development, included, 'ar,', 'dax1,', 'hsd11b2,', 'hsd17b,', cyp19a, and, thra])].
[sujeto(['Additional', studies, are]), verbo([required]), complemento([to, determine, their, relative, roles, in, male, and, female, differentiation, during, these, early, developmental, periods])].
[sujeto(['One', set, of, 'sense/antisense', primers, is, used, to, amplify, the, experimental, transgene, '(', androgen, receptor, gene, in, this, 'case),', the, second, set, for, the, mouse, 'Y-chromosome-specific', 'SRY', 'gene,', and, the, third, set, for, the, beta, subunit, of, the, thyroid]), verbo([stimulating]), complemento([hormone, '(', 'TSH', 'beta),', an, internal, control])].
[sujeto(['Dax-1', '[', 'dosage-sensitive', sex, 'reversal-adrenal', hypoplasia, congenita, critical, region, on, the, 'X', 'chromosome,', gene, 1, '(', 'NR0B1)]', is, an, orphan]), verbo([nuclear]), complemento([receptor, acting, as, a, suppressor, of, 'Ad4', binding, 'protein/steroidogenic', factor, 1, '[', 'Ad4BP/SF-1', '(', 'NR5A1)]', and, as, an, 'anti-Sry', factor, in, the, process, of, gonadal, sex, differentiation])].
[sujeto(['The', roles, of, these]), verbo([nuclear]), complemento([receptors, in, the, differentiation, of, the, gonads, and, the, adrenal, cortex, have, been, established, through, studies, of, the, mutant, phenotype, in, both, mice, and, humans])].
[sujeto(['Reporter', gene, analysis, revealed, that, 'Dax-1', gene, transcription, was]), verbo([activated]), complemento([by, 'beta-catenin,', a, key, 'signal-transducing', protein, in, the, 'Wnt', 'pathway,', acting, in, synergy, with, 'Ad4BP/SF-1'])].
[sujeto(['These', results, were, supported, by, in, vivo, observations, using, 'Wnt4', 'gene-disrupted', 'mice,', in, which, 'Dax-1', gene, expression, was]), verbo([decreased]), complemento([significantly, in, sexually, differentiating, female, gonads])].
[sujeto(['We', thus, conclude, that, 'Wnt4', signaling]), verbo([mediates]), complemento([the, increased, expression, of, 'Dax-1', as, the, ovary, becomes, sexually, differentiated])].
[sujeto(['Here,', we, explored, the, role, of, the, neuropeptide, 'orexin,', a, respiratory, homeostasis, 'modulator,', in, growth, retardation]), verbo([induced]), complemento([in, an, upper, airway, obstructed, '(', 'AO)', rat, model])].
[sujeto(['The', 'AO', group, gained, 46, '%', less, body, weight, compared, to, the, control, 'group,', despite, elevated, food, 'intake;', plasma, ghrelin]), verbo([increased]), complemento([by, 275, '%', and, leptin, level, decreased, by, 44, '%'])].
[sujeto(['The', impediment, of, bone, elongation, and, bone, mass, was, followed, by, a, 200, '%']), verbo([increase]), complemento([in, 'OX1R', and, 38, '%', reduction, of, local, 'GP', ghrelin, proteins, and, growth, hormone, secretagogue, receptor, 1, a])].
[sujeto(['Sry-related', transcription, factor, nine, '(', 'Sox9),', a, molecule]), verbo([mediating]), complemento([cartilage, 'ossification,', was, downregulated, and, the, level, of, transcription, factor, peroxisome, 'proliferator-activated', receptor, gamma, was, 'upregulated,', explaining, the, bone, architecture, abnormalities])].
[sujeto(['In', 'AO', 'animals,']), verbo([enhanced]), complemento([expression, of, orexin, and, 'OX1R', plays, a, role, in, respiratory, induced, sleep, and, growth, abnormalities])].
[sujeto(['The', purpose, of, this, study, was, to, investigate, whether, suppression, of, 'Wnt', signaling, pathway, by, 'PPARγ', gene, affects]), verbo([target]), complemento(['SOX9', gene, expression])].
[sujeto(['High', expression, of, 'PPARγ', '(', p, &, 'lt;', 0.05, ')', for, transfection, recombinant, plasmid, group]), verbo([induced]), complemento([obviously, decreased, expression, of, 'β-catenin', '(', p, &, 'lt;', 0.05, ')', ',', whereas, 'SOX9', expression, decreased, significantly, '(', p, &, 'lt;', 0.05, ')', compared, with, the, transfection, empty, vector, group, and, normal, comparison, group])].
[sujeto(['PPARγ', can]), verbo([suppress]), complemento(['β-catenin', expression, in, 'Wnt', signaling, pathway, and, its, downstream, effector, 'SOX9', expression, in, gastric, cancer, cells])].
[sujeto(['We']), verbo([have]), complemento([shown, earlier, that, peroxisome, 'proliferator-activated', receptor, gamma, '(', 'PPARγ)', agonists, inhibit, the, expansion, of, 'BTSCs', in, 'T98G', and, 'U87MG', glioma])].
[sujeto(['We']), verbo([found]), complemento([that, 'PPARγ', 'agonists,', ciglitazone, and, 15, -, 'deoxy-Δ(12,14)-ProstaglandinJ(2),', inhibited, cell, viability, and, proliferation, of, 'T98G-', and, 'DB29-BTSCs'])].
[sujeto(['They', also]), verbo([inhibited]), complemento(['Sox2', while, enhancing, 'Nanog', expression, in, 'BTSCs'])].
[sujeto(['These', findings, highlight, that, 'PPARγ', agonists]), verbo([inhibit]), complemento(['BTSC', proliferation, in, association, with, altered, expression, of, 'Sox2,', 'Nanog,', and, other, stemness, genes])].
[sujeto(['Therefore,']), verbo([targeting]), complemento([stemness, genes, in, 'BTSCs', could, be, a, novel, strategy, in, the, treatment, of, glioblastoma])].
[sujeto(['We', established, a, mammary, epithelial, cell, line, with, a, genotype, of, 'PBPLoxP/LoxP', by]), verbo([expressing]), complemento([an, active, form, of, 'Notch4'])].
[sujeto(['Null', mutation, of, 'PBP']), verbo([caused]), complemento([severe, growth, inhibition, of, the, 'Notch4-immortalized', mammary, cells])].
[sujeto(['We']), verbo([found]), complemento([that, truncated, 'PBP', without, the, two, 'LXXLL', motifs, could, reverse, the, growth, inhibition, due, to, the, deficiency, of, endogenous, 'PBP,', indicating, that, signalling, through, nuclear, receptors, is, unlikely, to, be, responsible, for, the, growth, inhibition, as, the, result, of, 'PBP', deficiency])].
[sujeto(['The', 're-expression', of, 'SOX10', was, capable, of, reversing, the, growth, inhibition, due, to, 'PBP', 'deficiency,', whereas]), verbo([suppressed]), complemento([expression, of, 'SOX10', inhibited, the, growth, of, 'Notch4-immortalized', mammary, cells])].
[sujeto(['Further', studies, revealed, 'PBP', is, directly]), verbo([recruited]), complemento([to, the, enhancer, of, the, 'SOX10', 'gene,', indicating, that, 'SOX10', is, a, direct, target, gene, of, 'PBP'])].
[sujeto(['We', conclude, that, 'PBP', is, essential, for, the, growth, of, 'Notch4-immortalized', mammary, cells, by]), verbo([activating]), complemento(['SOX10', 'expression,', providing, a, potential, molecular, mechanism, through, which, 'PBP', regulates, the, growth, of, mammary, 'stem/progenitor', cells])].
[sujeto(['MicroRNA-124', contributes, to, neurogenesis, through]), verbo([regulating]), complemento([its, 'targets,', but, its, expression, both, in, the, brain, of, 'Huntington\'s', disease, mouse, models, and, patients, is, decreased])].
[sujeto(['However,', the, effects, of, 'microRNA-124', on, the, progression, of, 'Huntington\'s', disease]), verbo([have]), complemento([not, been, reported])].
[sujeto(['Results', from, this, study, showed, that, 'microRNA-124']), verbo([increased]), complemento([the, latency, to, fall, for, each, 'R6/2', 'Huntington\'s', disease, transgenic, mouse, in, the, rotarod, test])].
[sujeto([5, -, 'Bromo-2\'-deoxyuridine', '(', 'BrdU)', staining, of, the, striatum, shows, an]), verbo([increase]), complemento([in, neurogenesis])].
[sujeto(['In', 'addition,', 'brain-derived', neurotrophic, factor, and, peroxisome, 'proliferator-activated', receptor, gamma, coactivator, 1, -, alpha, protein, levels, in, the, striatum, were]), verbo([increased]), complemento([and, 'SRY-related', 'HMG', box, transcription, factor, 9, protein, level, was, decreased])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'microRNA-124', slows, down, the, progression, of, 'Huntington\'s', disease, possibly, through, its, important, role, in, neuronal, differentiation, and, survival])].
[sujeto(['A', total, of, 6, 'SNPs', and, one, 4, bp, insertion, variation, in, the, promoter, region, of, the, bovine, 'PPARGC1A', gene, were, 'identified:', 'SNP', -, 259, 'T&gt;A,', -, 301, '_-298insCTTT,', -, 915, 'A&gt;G,', -, 1175, 'T&gt;G,', -, 1590, 'C&gt;T,', -, 1665, 'C&gt;T', and, -, 1690, 'G&gt;A,', which, are, in, the]), verbo([binding]), complemento([sites, of, some, important, transcription, 'factors:', 'sex-determining', region, 'Y', '(', 'SRY),', 'myeloid-specific', zinc, 'finger-1', '(', 'MZF-1)', and, octamer, factor, 1, '(', 'Oct-1)'])].
[sujeto(['It', is, expected, that, these, polymorphisms, may]), verbo([regulate]), complemento(['PPARGC1A', gene, transcription, and, might, have, consequences, at, a, regulatory, level])].
[sujeto(['The', transcription, factor, 'Sox9', '(', 'SRY-related', high, mobility, 'group-Box', gene, 9, ')']), verbo([regulates]), complemento([chondrocyte, differentiation, and, 'cartilage-specific', expression, of, 'genes,', such, as, 'Col2a1', '(', collagen, type, 'II', 'alpha1)'])].
[sujeto(['However,', 'Sox9', expression, is, detected, not, only, in, chondrogenic, tissue, but, also, in, nonchondrogenic, 'tissues,']), verbo([suggesting]), complemento([the, existence, of, a, molecular, 'partner(s)', required, for, 'Sox9', to, control, chondrogenesis, and, chondrogenic, gene, expression])].
[sujeto(['Here,', we]), verbo([report]), complemento([identification, of, peroxisome, 'proliferator-activated', receptor, gamma, 'co-activator', 1, alpha, '(', 'PGC-1alpha)', as, a, coactivator, for, 'Sox9', during, chondrogenesis])].
[sujeto(['Expression', of, 'PGC-1alpha', is]), verbo([induced]), complemento([at, chondrogenesis, sites, during, mouse, embryonic, limb, development, and, during, chondrogenesis, in, human, 'MSC', cultures])].
[sujeto(['PGC-1alpha', directly]), verbo([interacts]), complemento([with, 'Sox9', and, promotes, 'Sox9-dependent', transcriptional, 'activity,', suggesting, that, 'PGC-1alpha', acts, as, a, transcriptional, coactivator, for, 'Sox9'])].
[sujeto(['Consistent', with, this, 'finding,', 'PGC-1alpha', disruption, in, 'MSC', by, small, interfering, 'RNA']), verbo([inhibits]), complemento(['Col2a1', expression, during, chondrogenesis])].
[sujeto(['Furthermore,', overexpression, of, both, 'PGC-1alpha', and, 'Sox9']), verbo([induced]), complemento([expression, of, chondrogenic, 'genes,', including, 'Col2a1,', followed, by, chondrogenesis, in, the, 'MSC', and, developing, chick, limb])].
[sujeto(['Together,', our, results]), verbo([suggest]), complemento([a, transcriptional, mechanism, for, chondrogenesis, that, is, coordinated, by, 'PGC-1alpha'])].
[sujeto(['A', recent, paper, demonstrated, that, decellularized, extracellular, matrix, '(', 'DECM)', deposited, by, 'synovium-derived', stem, cells, '(', 'SDSCs),', especially, from, fetal, 'donors,', could, rejuvenate, human, adult, 'SDSCs', in, both, proliferation, and, chondrogenic, 'potential,', in, which, expanded, cells, and, corresponding, culture, substrate, '(', such, as, 'DECM)', were]), verbo([found]), complemento([to, share, a, mutual, reaction, in, both, elasticity, and, protein, profiles, '(', see, ref])].
[sujeto(['It', seems, that, young, 'DECM', may, assist, in, the, development, of, culture, strategies, that, optimize, proliferation, and]), verbo([maintain]), complemento([&, 'quot;stemness&quot;', of, mesenchymal, stem, cells, '(', 'MSCs),', helping, to, overcome, one, of, the, primary, difficulties, in, 'MSC-based', regenerative, therapies])].
[sujeto(['The', three, mouse, models, were, 'i)', 'XSxr(a)O', in, which, the, 'Yp-derived', 'Tp(Y)1Ct(Sxr-a)', sex, reversal, factor]), verbo([provides]), complemento([an, almost, complete, 'Yp', gene, 'complement,', 'ii)', 'XSxr(b)O,Eif2s3y', males, in, which, 'Tp(Y)1Ct(Sxr-b)', has, a, deletion, completely, or, partially, removing, eight, 'Yp', genes, -, the, 'Yp', gene, 'Eif2s3y', has, been, added, as, a, transgene, to, support, spermatogonial, 'proliferation,', and, 'iii)', 'XOSry,Eif2s3y', males, in, which, the, 'Sry', transgene, directs, gonad, development, along, the, male, pathway])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([used, the, same, mouse, models, analysed, at, 6, weeks, of, age, to, investigate, potential, 'Yp', gene, involvement, in, spermiogenesis])].
[sujeto(['We']), verbo([found]), complemento([that, all, three, mouse, models, produce, haploid, and, diploid, spermatids, and, that, the, diploid, spermatids, showed, frequent, duplication, of, the, developing, acrosomal, cap, during, the, early, stages])].
[sujeto(['Most', 'strikingly,', in, 'XOSry,Eif2s3y', 'males,', spermatid, development]), verbo([arrested]), complemento([at, round, spermatid, step, 7, so, that, no, sperm, head, restructuring, or, tail, development, was, observed])].
[sujeto(['We', conclude, that, 'Sxr(a)', '(', and, therefore, 'Yp)', includes, genetic, information, essential, for, sperm, morphogenesis, and, that, this, is, partially]), verbo([retained]), complemento([in, 'Sxr(b)'])].
[sujeto(['Most', of, our, current, knowledge, on, mammalian, sex, 'determination,', the, genetic, process, by, which, the, gonadal, primordia, are, committed, to, differentiate, as, either, testes, or, 'ovaries,']), verbo([has]), complemento([derived, mainly, from, the, study, of, 'sex-reversed', mice, obtained, by, direct, genetic, manipulation])].
[sujeto(['However,', there, are, also, numerous, cases, of, natural, exceptions, to, normal, gonad, development, which]), verbo([have]), complemento([been, described, in, a, variety, of, 'mammals,', including, both, domestic, and, wild, species])].
[sujeto(['These', studies, are, necessary, to, elucidate, particular, aspects, of, mammalian, gonad, development, in, some, instances, and, to, understand, how, the, genetic, mechanisms, controlling, gonad, development]), verbo([have]), complemento([evolved])].
[sujeto(['Sxr(b)', is, an, 'Sxr(a)-derived', variant, in, which, a, deletion]), verbo([has]), complemento([removed, six, 'Y', 'short-arm', genes, and, created, a, 'Zfy2/Zfy1', fusion, gene, spanning, the, deletion, breakpoint, '[', 4, ',', 5, ']'])].
[sujeto(['XSxr(b)O', males]), verbo([have]), complemento([spermatogonial, arrest, that, can, be, overcome, by, the, 're-addition', of, 'Eif2s3y', from, the, deletion, as, a, 'transgene;', 'however,', 'XSxr(b)OEif2s3y', transgenic, males, do, not, show, the, expected, elimination, of, 'MI', spermatocytes, in, response, to, the, univalent, '[', 6, ']'])].
[sujeto(['Here', we, show, that, these, 'XSxr(b)OEif2s3y', males]), verbo([have]), complemento([an, impaired, apoptotic, response, with, completion, of, the, first, meiotic, 'division,', but, there, is, no, second, meiotic, division])].
[sujeto(['These', findings]), verbo([provide]), complemento([further, insight, into, the, basis, for, the, much, lower, transmission, of, chromosomal, errors, originating, at, the, first, meiotic, division, in, men, than, in, women, '[', 7, ']'])].
[sujeto(['Investigations', in, mice]), verbo([suggest]), complemento([that, the, 'Y-chromosomal', genes, affect, certain, behaviors])].
[sujeto(['Here,', we, studied, whether, a, part, of, the, 'Y', 'chromosome,', the, 'Sxr', 'locus,']), verbo([has]), complemento([an, effect, on, induction, of, motivation, for, parental, care, '(', pup, 'retrieval)', or, of, parental, aggression, towards, pups, '(', 'infanticide)'])].
[sujeto(['The']), verbo([induced]), complemento([pup, retrieval, or, infanticide, behaviors, were, 'genotype-dependent'])].
[sujeto(['Further,', it]), verbo([induces]), complemento([infanticide, to, a, level, higher, than, that, of, 'XX', females, but, significantly, lower, than, that, of, normal, males, '(', 'XY)'])].
[sujeto(['Hence,', we]), verbo([suggest]), complemento([that, genes, outside, the, 'sex-determining', region, of, the, 'Y', chromosome, 'and/or', genes, on, autosomes, are, necessary, for, manifestation, of, full, 'male-type', parental, behavior])].
[sujeto(['In', the, absence, of, any, other, 'mutations,', testis, differentiation, in, 'XXSxr', fetuses, is, essentially, normal, and, only, one]), verbo([report]), complemento([of, an, 'XXSxr', fetus, with, ovotestes, is, in, the, literature])].
[sujeto(['We']), verbo([report]), complemento([that, 84, '%', '(', 21, /, 25, ')', of, 13, days, postcoitum, 'XXSxr', fetuses, on, the, 'B6', inbred, genomic, background, have, ovotestes])].
[sujeto(['Ovotestes', were]), verbo([found]), complemento([in, fetuses, from, both, 'Sxra', and, 'Sxrb', variants])].
[sujeto(['Examination', of, fetuses, older, than, 13, dpc]), verbo([suggests]), complemento([that, the, presence, of, ovotestes, is, transient, in, most, fetuses])].
[sujeto(['The', development, of, ovotestes, is]), verbo([associated]), complemento([with, the, inbred, background, and, is, exacerbated, by, the, dominant, spotting, oncogene, allele, 'KitW-42J'])].
[sujeto(['We', propose, that, spreading, of, 'X-inactivation', into, the, 'Sxr', region, resulting, in]), verbo([loss]), complemento([of, 'Sry', expression, is, more, extensive, in, 'B6-Sxr', strains])].
[sujeto(['Earlier', cytogenetic, observations, had]), verbo([suggested]), complemento([that, the, deletions, resulted, from, asymmetrical, meiotic, recombination, between, the, 'Y', and, the, homologous, 'Sxr', 'region,', but, no, direct, evidence, for, this, hypothesis, was, available])].
[sujeto(['We']), verbo([have]), complemento([now, analyzed, the, offspring, of, 'XSxr/Y', males, carrying, an, evolutionarily, divergent, 'Mus', musculus, domesticus, 'Y', 'chromosome,', which, permits, detection, and, characterization, of, such, recombination, events])].
[sujeto(['This', analysis]), verbo([has]), complemento([enabled, the, derivation, of, a, recombination, map, of, 'Yp', and, 'Sxr,', also, demonstrating, the, orientation, of, 'Yp', with, respect, to, the, 'Y', centromere])].
[sujeto(['The', mapping, data]), verbo([have]), complemento([established, that, 'Rbm,', the, murine, homologue, of, a, gene, family, cloned, from, the, human, 'Y', 'chromosome,', lies, between, 'Sry', and, the, centromere])].
[sujeto(['Analysis', of, two, additional, 'XY', female, lines, shows, that, asymmetrical, 'Yp-Sxr', recombination]), verbo([leading]), complemento([to, 'XY', female, sex, reversal, results, in, deletion, of, 'Rbm', sequences])].
[sujeto(['This']), verbo([suggests]), complemento([that, the, rearrangement, arose, from, a, recombination, event, involving, the, distal, 'Y', telomere, 'sequences,', i])].
[sujeto([',', within, the, 'telomere,', a, structure, historically, assumed, to, be, incapable, of]), verbo([participating]), complemento([in, chromosome, rearrangements])].
[sujeto(['The', 'Sxr', '(', 'sex-reversed)', 'region,', a, fragment, of, the, 'Y', chromosome, short, 'arm,', can]), verbo([cause]), complemento([chromosomally, female, 'XXSxr', or, 'XSxrO', mice, to, develop, as, sterile, males])].
[sujeto(['The', original, 'Sxr', 'region,', termed, 'Sxra,', 'encodes:', 'Tdy,', the, primary, 'sex-determining', 'gene;', 'Hya,', the, controlling, or, structural, locus, for, the, minor, transplantation, antigen, 'H-Y;', 'gene(s)', controlling, the, expression, of, the, serologically, detected, male, antigen, '(', 'SDMA);', 'Spy,', a, 'gene(s)']), verbo([required]), complemento([for, the, survival, and, proliferation, of, 'A', spermatogonia, during, 'spermatogenesis;', 'Zfy-1/Zfy-2,', 'zinc-finger-containing', genes, of, unknown, 'function;', and, 'Sry,', which, is, probably, identical, to, 'Tdy'])].
[sujeto(['We']), verbo([report]), complemento([here, the, isolation, of, a, new, 'testis-specific', 'gene,', 'Sby,', mapping, to, the, 'DNA', deleted, from, the, 'Sxrb', region, '(', the, delta, 'Sxrb', 'interval)'])].
[sujeto(['Sby']), verbo([has]), complemento([extensive, homology, to, the, 'X-linked', human, 'ubiquitin-activating', enzyme, 'E1'])].
[sujeto(['The', critical, role, of, this, enzyme, in]), verbo([nuclear]), complemento(['DNA', replication, together, with, the, 'testis-specific', expression, of, 'Sby', suggests, 'Sby', as, a, candidate, for, the, spermatogenic, gene, 'Spy'])].
[sujeto(['According', to, our, 'results,', the, most, useful, markers, for, these, chromosomal, variants, were, the, genes]), verbo([found]), complemento([in, the, pseudoautosomic, regions, 1, and, 2, '(', 'PAR1', and, 'PAR2),', because, differences, in, gene, dosage, '(', relative, 'quantification)', between, groups, were, more, evident, in, 'SHOX', and, 'VAMP7', gene, expression])].
[sujeto(['Therefore,', we, conclude, that, these, markers, are, useful, for, early, detection, in, aneuploidies]), verbo([involving]), complemento([sex, chromosomes])].
[sujeto(['This', calcification, shares, features, with, osteogenesis, and, may]), verbo([involve]), complemento([osteogenic, factors])].
[sujeto(['Compared', with, 'DCC-resistant', 'C57BL/6', 'mice,', a, significant]), verbo([increase]), complemento([in, 'Opn', transcription, was, demonstrated, in, necrotic, lesions, of, both, 'DCC-susceptible', 'C3H/He', and, 'B6'])].
[sujeto(['Significant']), verbo([increases]), complemento([in, gene, expression, were, also, demonstrated, for, the, transcription, factors, runt, 'domain-containing', transcription, factor, 2, '(', 'Runx2),', vitamin, 'D', receptor, '(', 'Vdr),', 'SRY', '(', 'sex-determining', region, 'Y)-box', 9, 'protein,', and, 'Nfkb1', in, 'C3H/He', mice, versus, 'C57BL/6', controls])].
[sujeto(['However,', only, 'Runx2', remained, significantly]), verbo([increased]), complemento([in, the, 'B6'])].
[sujeto(['Luciferase', assay, use]), verbo([increased]), complemento(['Opn', promoter, 'activity,', which, was, demonstrated, after, overexpression, of, 'Runx2'])].
[sujeto(['A', 'poly-T', stretch, insertion, was, identified, to, stabilize, the]), verbo([binding]), complemento([of, 'Runx2,', thus, significantly, enhancing, 'Opn', promoter, activity])].
[sujeto(['This', 'Runx2-mediated', activation, was, further]), verbo([enhanced]), complemento([by, cotransfection, with, 'Vdr'])].
[sujeto(['Our', data]), verbo([suggest]), complemento([a, key, role, of, 'Runx2', in, the, regulation, of, 'Opn', in, a, model, of, cardiovascular, calcification, and, demonstrate, a, synergistic, cooperation, of, 'Runx2', and, 'Vdr'])].
[sujeto(['The', order, of, the, 'Y-linked', type, 'I', markers, was, 'STS-Y,', 'SRY', and, 'ZFY', 'These', orders, are, the, same, arrangements, as]), verbo([reported]), complemento([for, the, human, 'X-', and, 'Y-chromosomes,', supporting, the, conservation, of, genomic, organization, between, the, human, and, the, horse, sex, chromosomes])].
[sujeto(['Regional', ordering, of, 'X-linked', type, 'I', and, microsatellite, markers]), verbo([provides]), complemento([the, first, integration, of, type, 'I', and, type, 'II', markers, in, the, horse, 'X', chromosome])].
[sujeto(['Rainbow', darter, '(', 'Etheostoma', 'caeruleum)', is, a, small, benthic, fish, species]), verbo([found]), complemento([in, 'North', 'America', that, are, abundant, and, distributed, throughout, the, 'Grand', 'River', 'watershed,', 'ON,', 'Canada'])].
[sujeto(['There', were, no, changes, in, condition, 'factor;', 'however,', there, was, a, significant]), verbo([increase]), complemento([in, 'LSI', and, a, decrease, in, 'GSI', in, fish, inhabiting, downstream, environments, when, compared, with, fish, collected, from, the, reference, site])].
[sujeto(['In', the, 'gonad,', there, were, sex, specific, differences, for, genes, related, to, sexual, 'differentiation;', dmrt1, was, only]), verbo([expressed]), complemento([in, males, whereas, foxl2, and, sox9, were, highly, expressed, in, females, compared, to, males])].
[sujeto(['Conversely,', esrb, was, not, differentially]), verbo([expressed]), complemento([between, sexes, or, among, sites])].
[sujeto(['This', study, is, the, first, to]), verbo([report]), complemento([on, gene, expression, changes, in, the, rainbow, 'darter,', with, emphasis, on, the, differences, in, transcript, abundance, between, sexes, and, how, these, changes, relate, to, exposures, to, 'MWWEs'])].
[sujeto(['Molecular', approaches, are, being, investigated, for, their, potential, application, to, field, 'ecotoxicology,', and, molecular, bioassays, for, 'relevant,', sentinel, species, in, environmental, monitoring, programs, are]), verbo([required]), complemento([to, better, understand, the, impact, of, anthropogenic, impacts, on, species, at, risk, in, river, systems])].
[sujeto(['The']), verbo([increasing]), complemento([relevance, of, the, cancer, stem, cell, '(', 'CSC)', hypothesis, and, the, impact, of, 'CSC-associated', markers, in, the, carcinogenesis, of, solid, tumours, may, provide, potential, prognostic, implications, in, lung, cancer])].
[sujeto(['We', observed, that, 'ALDH', and, 'OCT4A', were]), verbo([associated]), complemento([with, nodal, status, '(', 'ALDH,', 'P', =, 0.05, ;, 'OCT4A,', 'P', =, 0.03, ')', having, lower, mRNA, levels, in, tumours, with, lymph, node, 'metastasis,', 'N+,', compared, with, that, in, 'N0'])].
[sujeto(['High', 'OCT4A', levels, were, significantly, correlated, with, tumour, size, of, &, 'lt;3', 'cm,']), verbo([decrease]), complemento([in, tumours, &, 'gt;3', cm, '(', 'P', =, 0.03, ')'])].
[sujeto(['Our', study]), verbo([reveals]), complemento([that, 'CSC-associated', 'markers:', 'OCT4A,', 'CD133', and, 'ALDH', are, involved, in, the, initial, phase, of, carcinogenesis, of, 'LAC,', and, can, be, used, as, predictors, of, early, stage, 'LAC', and, poor, 'disease-free', intervals])].
[sujeto(['Allopatric', diversification, driven, by, geological, or, climatic, processes]), verbo([has]), complemento([been, identified, as, the, main, mechanism, shaping, present, faunal, distribution, on, the, island])].
[sujeto(['Tarsiers,', small, nocturnal, primates, with, possible, evidence, of, an, 'Eocene', fossil, record, on, the, 'Asian', 'mainland,', are, at, present, exclusively]), verbo([found]), complemento([in, insular, 'Southeast', 'Asia'])].
[sujeto(['We']), verbo([found]), complemento([that, their, arrival, at, the, 'Proto-Sulawesi', archipelago, coincided, with, initial, 'Miocene', tectonic, uplift, and, hypothesize, that, tarsiers, dispersed, over, the, region, in, distinct, waves])].
[sujeto(['This', 'congruence,', 'however,']), verbo([has]), complemento([partially, been, superimposed, by, 'taxon-specific', dispersal, patterns])].
[sujeto(['Whereas', similar, disorders, and, 'similar-looking', coat, colour, phenotypes, sometimes]), verbo([have]), complemento([a, different, genetic, background, '(', e])].
[sujeto(['The', human, predilection, for, fancy, phenotypes, that, ignore, disorders, and, genetic, defects, is, a, major, driving, force, for, the]), verbo([increase]), complemento([of, pleiotropic, effects, in, domestic, species, and, laboratory, subjects, since, domestication, has, commenced, approximately, 18, ',', 0, years, ago])].
[sujeto(['We', hypothesized, that, bone, marrow, derived, 'Sca-1+', stem, cells, '(', 'BM', 'Sca-1+)', transduced, with, multiple, therapeutic, cytokines, with, diverse, effects, will]), verbo([induce]), complemento([faster, angiomyogenic, differentiation, in, the, infarcted, myocardium])].
[sujeto(['BM', 'Sca-1+', were, purified, from, transgenic, male, mice]), verbo([expressing]), complemento(['GFP'])].
[sujeto(['LDH', and, 'TUNEL', assays, showed]), verbo([enhanced]), complemento([survival, of, 'GFSca-1+', under, lethal, anoxia, '(', 'p&lt;0'])].
[sujeto(['MTS', assay, showed, significant]), verbo([increased]), complemento([cell, proliferation, in, 'GFSca-1+', '(', 'p&lt;0'])].
[sujeto(['Immunostaining', for, vWF, showed]), verbo([increased]), complemento([blood, vessel, density, in, both, 'peri-infarct', and, infarct, regions, in, 'group-3'])].
[sujeto(['This', study, used, genomewide, 'array-CGH', in, microdissected, specimens, to, map, genetic, alterations]), verbo([found]), complemento([in, primary, 'OSCC', and, neck, lymph, node, metastases])].
[sujeto(['The', highest, frequencies, of]), verbo([gains]), complemento([were, detected, in, 'LMYC,', 'REL,', 'TERC,', 'PIK3CA,', 'MYB,', 'MDR1,', 'HRAS,', 'GARP,', 'CCND2,', 'FES,', 'HER2,', 'SIS,', and, 'SRY'])].
[sujeto(['The', highest, frequencies, of]), verbo([losses]), complemento([were, detected, in, 'p44S10,', 'TIF1,', 'LPL,', 'MTAP,', 'BMI1,', 'EGR2,', and, 'MAP2K5'])].
[sujeto(['Higher', 'FGF4', immunoreactivity, in, primary, 'OSCC', is]), verbo([associated]), complemento([with, a, worse, prognosis])].
[sujeto(['Our', study]), verbo([suggests]), complemento([that, precise, genomic, profiling, can, be, useful, in, determining, gene, number, changes, in, 'OSCC'])].
[sujeto(['ABCC4', gene, on, chromosome, 13, ',', 'TYMS', gene, on, chromosome, 18, ',', 'DSCR3', gene, on, chromosome, 21, ',', 'HPRT2', gene, on, chromosome, 'X,', and, 'SRY', gene, on, 'Y', chromosome, were, used, as, the]), verbo([target]), complemento(['genes,', with, 'GAPDH', gene, on, chromosome, 12, as, the, control, gene])].
[sujeto(['The', ratio, of, the]), verbo([target]), complemento([gene, on, chromosome, 13, to, the, control, gene, showed, a, significant, difference, between, the, normal, karyotype, group, '(', 0.9, -, or, +, 0.31, ')', and, trisome, group, '(', 1.39, -, or, +, 0.12, ',', 'P=0'])].
[sujeto(['The', expression, of, the]), verbo([target]), complemento([gene, on, the, 'Y', chromosome, was, not, detected, in, normal, females, '(', 46, ',', 'XX),', and, a, significant, difference, in, the, expression, was, found, between, normal, male, group, '(', 46, ',', 'XY)', and, 47, ',', 'XYY', group, '(', 1.57, -, or, +, 0.54, vs, 3.08, -, or, +, 0.15, ',', 'P=0'])].
[sujeto(['Fetoprotein', transcription, factor, '(', 'FTF)', is, an, orphan]), verbo([nuclear]), complemento([receptor, that, activates, the, 'alpha(1)-fetoprotein', gene, during, early, liver, developmental, growth])].
[sujeto(['Here', we, sought, to, define, better, the, position, of, 'FTF', in, transcriptional, cascades]), verbo([leading]), complemento([to, hepatic, differentiation])].
[sujeto(['The', mFTF, transcription, initiation, site, was, located, in, adult, liver, at, 238, nucleotides, from, the, first, translation, initiator, 'codon,', with, six, canonical, 'GATA,', 'E', 'box,', and, 'Nkx', motifs, clustered, between, -, 50, /, -, 140, base, pairs, '(', 'bp)', from, the, cap, 'site;', 'DNA/protein']), verbo([binding]), complemento([assays, also, pinpointed, an, 'HNF4-binding', element, at, +, 36, bp, and, an, 'FTF-binding', element, at, -, 257, bp])].
[sujeto(['Transfection', assays, and, point, mutations, showed, that, the, mFTF, promoter, is]), verbo([activated]), complemento([by, 'GATA,', 'HNF4alpha,', 'FTF,', 'Nkx,', and, basic, 'helix-loop-helix', 'factors,', with, marked, cooperativity, between, 'GATA', and, 'HNF4alpha'])].
[sujeto(['Three', genes, encoding, transcription, factors, critical, to, early, hepatic, 'differentiation,', 'Hnf3beta,', 'Hnf4alpha,', and, 'Hnf1alpha,', each, contain, dual, 'FTF-binding', elements, in, their, proximal, 'promoters,', and, all, three, promoters, are]), verbo([activated]), complemento([by, 'FTF', in, transfection, assays])].
[sujeto(['Direct', 'DNA']), verbo([binding]), complemento([action, and, cooperativity, was, demonstrated, between, 'FTF', and, 'HNF3beta', on, the, 'Hnf3beta', promoter, and, between, 'FTF', and, 'HNF4alpha', on, the, 'Hnf1alpha', promoter])].
[sujeto(['These', combined, results]), verbo([suggest]), complemento([that, 'FTF', is, an, early, intermediary, between, endodermal, specification, signals, and, downstream, genes, that, establish, and, amplify, the, hepatic, phenotype])].
[sujeto(['The', definitive, endoderm, 'marker,', 'FoxA2', is, the, key, transcriptional, factor, that]), verbo([regulates]), complemento([cell, differentiation, and, tissue, regeneration])].
[sujeto(['We', demonstrated, that, 'FoxA2', was, notably]), verbo([enhanced]), complemento([in, murine, liver, progenitor, cells, and, 'SMCCs,', and, was, silenced, in, human, 'PSC', and, 'PBC', liver, tissues, relative, to, respective, controls, that, are, correlated, with, the, epigenetic, methylation, enzymes, 'DNMT1', and, 'DNMT3B'])].
[sujeto(['Furthermore,', activation, of, fibrosis, signaling, pathways, were, observed, in, 'BDL/MDR2(-/-)', mouse, liver, as, well, as, in, isolated, hepatic, stellate, cells, by, laser, capture, 'microdissection,', and, these, signals, were, recovered, along, with, reduced, hepatic, senescence, and]), verbo([enhanced]), complemento([hepatic, stellate, cellular, senescence, after, 'SMCC', engraft])].
[sujeto(['The', definitive, endoderm, marker, and, the, positive, regulator, of, biliary, 'development,', 'FoxA2,']), verbo([mediates]), complemento([the, therapeutic, effect, of, 'biliary-committed', progenitor, cells, during, cholestatic, liver, injury])].
[sujeto(['The', majority, of, mutations, were, 'novel,']), verbo([loss]), complemento([of, function, '(', 'LOF)', '(', 78.4, '%', ')', 'mutations,', and, most, disrupted, the, 'DNA-binding', domain, '(', 58.8, '%', ')'])].
[sujeto(['Mutation', status, was]), verbo([associated]), complemento([with, tumor, grade, and, not, associated, with, survival, outcomes])].
[sujeto(['Most', tumors]), verbo([expressed]), complemento(['FOXA2', at, both, the, mRNA, and, protein, level])].
[sujeto(['In', those, tumors, with, 'mutations,', the, majority, of, cases]), verbo([expressed]), complemento([both, alleles])].
[sujeto(['The', pattern, of, 'FOXA2', mutations, and, expression, in, tumors]), verbo([suggests]), complemento([complex, regulation, and, a, haploinsufficient, or, 'dominant-negative', tumor, suppressor, function])].
[sujeto(['Insulin', is, a, crucial, mediator, of, the, glucose, and, lipid, metabolism, that]), verbo([has]), complemento([been, implicated, in, atherosclerotic, and, inflammatory, processes])].
[sujeto(['Important', mediators, of, insulin, signaling, such, as, 'Liver', 'X', 'Receptors', '(', 'LXRs)', and, 'Forkhead', 'Box', 'A2', '(', 'FOXA2)', are, known, to]), verbo([regulate]), complemento(['apoA-I', expression, in, liver])].
[sujeto(['Forkhead', 'Box', 'O1', '(', 'FOXO1)', is, a, 'well-known']), verbo([target]), complemento([of, insulin, signaling, and, a, key, mediator, of, oxidative, stress, response])].
[sujeto(['Low', doses, of, insulin, were, shown, to]), verbo([activate]), complemento(['apoA-I', expression, in, human, hepatoma, 'HepG2', cells])].
[sujeto(['Treatment', of, 'HepG2', cells, with, high, doses, of, insulin, '(', 48, 'hours,', 100, 'nM)']), verbo([suppresses]), complemento(['apoA-I', gene, expression])].
[sujeto(['FOXO1', forms, a, complex, with, 'LXRβ', and, insulin, treatment, impairs, 'FOXO1/LXRβ', complex]), verbo([binding]), complemento([to, hepatic, enhancer, and, triggers, its, nuclear, export])].
[sujeto(['Insulin', as, well, as, 'LXR', ligand, 'TO901317']), verbo([enhance]), complemento([the, interaction, between, 'FOXA2,', 'LXRα', and, hepatic, enhancer])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, high, doses, of, insulin, downregulate, 'apoA-I', gene, expression, in, 'HepG2', cells, through, redistribution, of, 'FOXO1/LXRβ', 'complex,', 'FOXA2', and, 'LXRα', on, hepatic, enhancer, of, 'apoA-I', gene])].
[sujeto(['Genes', significantly]), verbo([associated]), complemento([with, baseline, seizure, frequency, on, likelihood, ratio, test, were, identified, based, on, &, 'gt;0'])].
[sujeto(['Expression', levels, of, forty, genes, were, significantly]), verbo([associated]), complemento([with, baseline, seizure, frequency])].
[sujeto(['Of', the, seven, most, 'significant,', four]), verbo([have]), complemento([been, linked, to, other, neurologic, diseases])].
[sujeto(['Expression', levels]), verbo([associated]), complemento([with, high, seizure, frequency, included, low, expression, of, 'Homeobox', 'A10,', 'Forkhead', box, 'A2,', 'Lymphoblastic', leukemia, derived, sequence, 1, ',', 'HGF', 'activator,', 'Kelch', repeat, and, 'BTB', '(', 'POZ)', domain, containing, 11, ',', 'Thanatos-associated', protein, domain, containing, 8, and, 'Heparin', sulfate, '(', 'glucosamine)', 3, -, 'O-sulfotransferase', 3, 'A1'])].
[sujeto(['Four', of, the, seven, discussed]), verbo([have]), complemento([been, previously, related, to, other, neurologic, diseases])].
[sujeto(['Future', investigation, of, these, genes, could, establish, new, biomarkers, for, predicting, 'epileptogenicity,', and, could]), verbo([have]), complemento([significant, implications, for, diagnosis, and, management, of, temporal, lobe, 'epilepsy,', as, well, as, epilepsy, pathogenesis])].
[sujeto(['Pancreatic', cancer, is, the, fourth]), verbo([leading]), complemento([cause, of, cancer, death, in, the, 'United', 'States'])].
[sujeto(['Restoration', of, 'miR-1291', expression]), verbo([inhibited]), complemento([pancreatic, cancer, cell, 'proliferation,', which, was, associated, with, cell, cycle, arrest, and, enhanced, apoptosis])].
[sujeto(['Furthermore,', 'miR-1291', sharply]), verbo([suppressed]), complemento([the, tumorigenicity, of, 'PANC-1', cells, in, mouse, models])].
[sujeto(['Through', computational, and, experimental, studies, we, further, identified, that, forkhead, box, protein, 'A2', '(', 'FOXA2),', a, transcription, factor, governing, 'AGR2', 'expression,', was, a, direct]), verbo([target]), complemento([of, 'miR-1291'])].
[sujeto(['These', results, connect, 'miR-1291', to, the, 'FOXA2-AGR2', regulatory, pathway, in, the, suppression, of, pancreatic, cancer, cell, proliferation, and, 'tumorigenesis,']), verbo([providing]), complemento([new, insight, into, the, development, of, 'miRNA-based', therapy, to, combat, pancreatic, cancer])].
[sujeto(['Since', 'LAL-deficient', '(', 'Lal', '(', -, /, -, ')', ')', mice, suffer, from, progressive]), verbo([loss]), complemento([of, adipose, tissue, and, severe, accumulation, of, lipids, in, hepatic, 'lysosomes,', we, hypothesised, that, 'LAL', deficiency, triggers, alternative, energy, 'pathway(s)'])].
[sujeto(['Despite']), verbo([loss]), complemento([of, adipose, 'tissue,', 'Lal', '(', -, /, -, ')', mice, show, enhanced, glucose, clearance, during, insulin, and, glucose, tolerance, tests, and, have, increased, uptake, of, '[', '(', 3, ')', 'H]2-deoxy-D-glucose', into, skeletal, muscle, compared, with, 'wild-type', mice])].
[sujeto(['We', observed, 84, '%']), verbo([decreased]), complemento([plasma, leptin, levels, and, significantly, reduced, hepatic, 'ATP,', 'glucose,', glycogen, and, glutamine, concentrations, in, fed, 'Lal', '(', -, /, -, ')', mice])].
[sujeto(['Markedly', reduced, hepatic, 'acyl-CoA', concentrations]), verbo([decrease]), complemento([the, expression, of, peroxisome, 'proliferator-activated', receptor, α, '(', 'PPARα)', target, genes])].
[sujeto(['However,', treatment, of, 'Lal', '(', -, /, -, ')', mice, with, the, 'PPARα', agonist, fenofibrate, further]), verbo([decreased]), complemento([plasma, 'TG', '(', and, hepatic, glucose, and, 'glycogen)', concentrations, in, 'Lal', '(', -, /, -, ')', mice])].
[sujeto(['Depletion', of, hepatic]), verbo([nuclear]), complemento([factor, 4, α, and, forkhead, box, protein, a2, in, fasted, 'Lal', '(', -, /, -, ')', mice, might, be, responsible, for, reduced, expression, of, microsomal, 'TG', transfer, 'protein,', defective, 'VLDL', synthesis, and, drastically, reduced, plasma, 'TG', levels])].
[sujeto(['We', conclude, that]), verbo([decreased]), complemento([plasma, 'VLDL', production, enhances, glucose, uptake, into, skeletal, muscle, to, compensate, for, the, lack, of, energy, supply])].
[sujeto(['Genome-wide', association, studies, '(', 'GWAS)', of, type, 2, diabetes, '(', 'T2D)']), verbo([have]), complemento([discovered, a, number, of, loci, that, contribute, to, susceptibility, to, the, disease])].
[sujeto(['Future', challenges, include, elucidation, of, functional, mechanisms, through, which, these, 'GWAS-identified', loci]), verbo([modulate]), complemento(['T2D', disease, risk])].
[sujeto(['The', aim, of, the, present, study, was, to, comprehensively, characterize, 'T2D']), verbo([associated]), complemento([single, nucleotide, polymorphisms, '(', 'SNPs)', and, genes, through, computational, approaches])].
[sujeto(['Computational', biology, approaches, used, in, the, present, study, included, comparative, genomic, analyses, and, functional, annotation, using, 'GWAS3D', and, 'RegulomeDB,', investigation, of, the, effects, of, 'T2D-associated', 'SNPs', on, miRNA]), verbo([binding]), complemento([and, protein, 'phosphorylation,', and, gene, 'ontology,', pathway, 'enrichment,', 'protein-protein', interaction, '(', 'PPI)', networks, and, functional, module, analysis, of, 'T2D-associated', genes, from, previously, published, 'GWAS'])].
[sujeto(['Computational', analysis, identified, a, number, of, 'T2D', 'GWAS-associated', 'SNPs', that, were, located, at, protein]), verbo([binding]), complemento(['sites,', including, 'CCCTC-binding', factor, '(', 'CTCF),', 'E1A', binding, protein, p300, '(', 'EP300),', hepatocyte, nuclear, factor, 4, alpha, '(', 'HNF4A),', transcription, factor, 7, like, 2, '(', 'TCF7L2),', forkhead, box, 'A1', '(', 'FOXA1)', and, 'A2', '(', 'FOXA2),', and, potentially, affected, the, binding, of, miRNAs, and, protein, phosphorylation])].
[sujeto(['The', results]), verbo([provide]), complemento([objectives, and, clues, for, future, experimental, studies, and, further, insights, into, the, molecular, pathogenesis, of, 'T2D'])].
[sujeto(['Mutations', in, hepatocyte]), verbo([nuclear]), complemento([factor, 1, transcription, factors, '(', 'HNF1α/β)', are, associated, with, diabetes])].
[sujeto(['However,', they, also]), verbo([have]), complemento([an, important, role, in, the, biology, of, many, other, 'tissues,', including, the, intestine])].
[sujeto(['We', used, chromatin, immunoprecipitation, followed, by, direct, sequencing, '(', 'ChIP-seq)', to, identify, 'HNF1']), verbo([binding]), complemento([sites, 'genome-wide'])].
[sujeto(['Direct']), verbo([targets]), complemento([of, 'HNF1', were, validated, using, conventional, 'ChIP', assays, and, confirmed, by, 'siRNA-mediated', depletion, of, 'HNF1,', followed, by, 'RT-qPCR'])].
[sujeto(['Gene', ontology, process, enrichment, analysis, of, the, 'HNF1']), verbo([targets]), complemento([identified, multiple, processes, with, a, role, in, intestinal, epithelial, cell, 'function,', including, properties, of, the, cell, 'membrane,', cellular, response, to, 'hormones,', and, regulation, of, biosynthetic, processes])].
[sujeto(['Approximately', 50, '%', of, 'HNF1']), verbo([binding]), complemento([sites, were, also, occupied, by, other, members, of, the, intestinal, transcriptional, 'network,', including, hepatocyte, nuclear, factor, 4, 'A', '(', 'HNF4A),', caudal, type, homeobox, 2, '(', 'CDX2),', and, forkhead, box, 'A2', '(', 'FOXA2)'])].
[sujeto(['Depletion', of, 'HNF1', in, 'Caco2', cells]), verbo([increases]), complemento(['FOXA2', abundance, and, decreases, levels, of, 'CDX2,', illustrating, the, coordinated, activities, of, the, network])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'HNF1', plays, an, important, role, in, regulating, intestinal, epithelial, cell, 'function,', both, directly, and, through, interactions, with, other, intestinal, transcription, factors])].
[sujeto(['The', transcription, factor, forkhead, box, protein, 'A2', '(', 'FOXA2,', also, known, as, hepatocyte]), verbo([nuclear]), complemento([factor, 3, β, or, transcription, factor, 3, 'β),', has, been, found, to, play, pivotal, roles, in, multiple, phases, of, mammalian, 'life,', from, the, early, development, to, the, 'organofaction,', and, subsequently, in, homeostasis, and, metabolism, in, the, adult])].
[sujeto(['In', the, embryonic, development, 'period,', 'FOXA2', is]), verbo([require]), complemento([d, for, the, formation, of, the, primitive, node, and, 'notochord,', and, its, absence, results, in, embryonic, lethality])].
[sujeto(['Leukotriene', pathway, and, signal, transducers, and, activators, of, transcription, 6, pathway, may]), verbo([mediate]), complemento([this, inflammation, through, recruitment, and, activation, of, denditric, cell, during, lung, developments])].
[sujeto(['FOXA2', is, a, potential, treatment]), verbo([target]), complemento([for, lung, diseases, with, 'Th2', inflammation, and, goblet, cell, 'hyperplasia,', such, as, asthma, and, chronic, obstructive, pulmonary, disease])].
[sujeto(['In', this, 'study,', by, using, a, combination, of, chemical, inhibition, and, genetic, approaches, in, zebrafish, and, murine, 'cells,', we, identify, a, mechanism, by, which, cPLA2α]), verbo([promotes]), complemento([cell, proliferation])].
[sujeto(['We', identified, 2, cpla2α, genes, in, 'zebrafish,', cpla2αa, and, 'cpla2αb,', with]), verbo([conserved]), complemento([phospholipase, activity])].
[sujeto(['In', 'zebrafish,']), verbo([loss]), complemento([of, cpla2α, expression, or, inhibition, of, cpla2α, activity, diminished, 'G1', progression, through, the, cell, cycle])].
[sujeto(['We', further, show, that, 'PGE2,', through, 'PI3K/AKT', 'activation,']), verbo([promoted]), complemento(['Forkhead', box, protein, 'O1', '(', 'FOXO1)', phosphorylation, and, 'FOXO1', nuclear, export])].
[sujeto(['This']), verbo([led]), complemento([to, 'up-regulation', of, cyclin, 'D1', and, 'down-regulation', of, 'p27(Kip1),', thus, promoting, 'G1', progression])].
[sujeto(['Finally,', using, pharmacologic, 'inhibitors,', we, show, that, 'cPLA2α,', rapidly, accelerated, fibrosarcoma, '(', 'RAF)/MEK/ERK,', and, 'PI3K/AKT', signaling, pathways, cooperatively]), verbo([regulate]), complemento(['G1', progression, in, response, to, 'platelet-derived', growth, factor, stimulation])].
[sujeto(['In', 'summary,', these, data, indicate, that, 'cPLA2α,', through, its, phospholipase, 'activity,', is, a, critical, effector, of, 'G1', phase, progression, through, the, cell, cycle, and]), verbo([suggest]), complemento([that, pharmacological, targeting, of, this, enzyme, may, have, important, therapeutic, benefits, in, disease, mechanisms, that, involve, excessive, cell, 'proliferation,', in, 'particular,', cancer, and, proliferative, glomerulopathies])].
[sujeto(['The']), verbo([nuclear]), complemento(['receptor,', pregnane, 'X', receptor, '(', 'PXR),', is, a, key, transcription, factor, for, the, 'xenobiotic-induced', expression, of, genes, associated, with, various, liver, functions])].
[sujeto(['Recently,', we]), verbo([reported]), complemento([that, 'PXR', activation, stimulates, 'xenobiotic-induced', hepatocyte, proliferation])].
[sujeto(['In', the, present, 'study,', we, investigated, whether, 'PXR', activation, also]), verbo([stimulates]), complemento([growth, 'factor-mediated', hepatocyte, proliferation])].
[sujeto(['In', 'G0', 'phase-synchronized,', immortalized, mouse, 'hepatocytes,', serum, or, epidermal, growth, factor, treatment]), verbo([increased]), complemento([cell, growth, and, this, growth, was, augmented, by, the, expression, of, mouse, 'PXR', and, 'co-treatment', with, pregnenolone, 16, 'α-carbonitrile', '(', 'PCN),', a, 'PXR', ligand])].
[sujeto(['In', a, liver, regeneration, model, using, carbon, 'tetrachloride,', 'PCN', treatment]), verbo([enhanced]), complemento([the, 'injury-induced', increase, in, the, number, of, 'Ki-67-positive', nuclei, as, well, as, 'Ccna2', and, 'Ccnb1', mRNA, levels, in, 'wild-type', '(', 'WT)', but, not, 'Pxr-null', mice])].
[sujeto(['Chronological', analysis, of, this, model, demonstrated, that, 'PCN', treatment, shifted, the, maximum, cell, proliferation, to, an, earlier, time, point, and]), verbo([increased]), complemento([the, number, of, 'M-phase', cells, at, those, time, points])].
[sujeto(['In', 'WT', but, not, 'Pxr-null', 'mice,', 'PCN', treatment, reduced, hepatic, mRNA, levels, of, genes]), verbo([involved]), complemento([in, the, suppression, of, 'G0/G1-', and, 'G1/S-phase', 'transition,', e])].
[sujeto(['Analysis', of, the, 'Rbl2', promoter, revealed, that, 'PXR', activation]), verbo([inhibited]), complemento([its, 'Forkhead', box, 'O3', '(', 'FOXO3)-mediated', transcription])].
[sujeto(['Finally,', the, 'PXR-mediated', enhancement, of, hepatocyte, proliferation, was]), verbo([inhibited]), complemento([by, the, expression, of, dominant, active, 'FOXO3', 'in&nbsp;vitro'])].
[sujeto(['The', results, of, the, present, study]), verbo([suggest]), complemento([that, 'PXR', activation, stimulates, growth, 'factor-mediated', hepatocyte, proliferation, in, 'mice,', at, least, in, 'part,', through, inhibiting, 'FOXO3', from, accelerating, 'cell-cycle', progression])].
[sujeto(['The']), verbo([binding]), complemento([activity, of, 'H3/H4', histone, on, the, 'Ets-1', 'promoter,', and, that, of, forkhead, box, '(', 'FOX)A2,', 'FOXO1', and, 'Ets-1', on, the, 'Pdx-1', promoter, was, measured, by, chromatin, immunoprecipitation, and, quantitative, 'real-time', 'PCR', assay])].
[sujeto(['High', glucose]), verbo([induced]), complemento([upregulation, of, 'Ets-1', expression, and, hyperacetylation, of, histone, 'H3', and, 'H4', at, the, 'Ets-1', gene, promoter, in, beta, cells])].
[sujeto(['Ets-1', overexpression, dramatically]), verbo([suppressed]), complemento([insulin, secretion, and, biosynthesis, both, in, vivo, and, in, vitro])].
[sujeto(['Besides,', 'Ets-1', overexpression]), verbo([increased]), complemento([the, activity, of, 'FOXO1', but, decreased, that, of, 'FOXA2', binding, to, the, pancreatic, and, duodenal, homeobox, 1, '(', 'PDX-1)', homology, region, 2, '(', 'PH2),', resulting, in, inhibition, of, 'Pdx-1', promoter, activity, and, downregulation, of, 'PDX-1', expression, and, activity])].
[sujeto(['In', 'addition,', high, glucose]), verbo([promoted]), complemento([the, interaction, of, 'Ets-1', and, 'FOXO1,', and, the, activity, of, 'Ets-1', binding, to, the, 'Pdx-1', promoter])].
[sujeto(['Importantly,', 'PDX-1', overexpression, reversed, the, defect, in, pancreatic, beta, cells]), verbo([induced]), complemento([by, 'Ets-1', 'excess,', while, knockdown, of, 'Ets-1', prevented, 'hyperglycaemia-induced', dysfunction, of, pancreatic, beta, cells])].
[sujeto(['Our', observations]), verbo([suggest]), complemento([that, 'Ets-1', links, glucotoxicity, to, pancreatic, beta, cell, dysfunction, through, inhibiting, 'PDX-1', expression, in, type, 2, diabetes])].
[sujeto(['Cellular', metabolism, is, increasingly]), verbo([recognized]), complemento([as, a, controller, of, immune, cell, fate, and, function])].
[sujeto(['MicroRNA-33', '(', 'miR-33)']), verbo([regulates]), complemento([cellular, lipid, metabolism, and, represses, genes, involved, in, cholesterol, 'efflux,', 'HDL', 'biogenesis,', and, fatty, acid, oxidation])].
[sujeto(['Macrophage-specific', 'Mir33', deletion]), verbo([increased]), complemento([oxidative, 'respiration,', enhanced, spare, respiratory, 'capacity,', and, induced, an, 'M2', macrophage, 'polarization-associated', gene, profile])].
[sujeto(['Furthermore,', 'miR-33-mediated', 'M2', polarization]), verbo([required]), complemento(['miR-33', targeting, of, the, energy, sensor, 'AMP-activated', protein, kinase, '(', 'AMPK),', but, not, cholesterol, efflux])].
[sujeto(['Notably,', 'miR-33', inhibition]), verbo([increased]), complemento([macrophage, expression, of, the, retinoic, 'acid-producing', enzyme, aldehyde, dehydrogenase, family, 1, ',', subfamily, 'A2', '(', 'ALDH1A2)', and, retinal, dehydrogenase, activity, both, in, vitro, and, in, a, mouse, model])].
[sujeto(['Consistent', with, the, ability, of, retinoic, acid, to, foster, inducible, 'Tregs,', 'miR-33-depleted', macrophages, had, an]), verbo([enhanced]), complemento([capacity, to, induce, forkhead, box, 'P3', '(', 'FOXP3)', expression, in, naive, 'CD4(+)', 'T', cells])].
[sujeto(['Collectively,', these, results]), verbo([reveal]), complemento([that, 'miR-33', regulates, macrophage, inflammation, and, demonstrate, that, 'miR-33', antagonism, is, 'atheroprotective,', in, 'part,', by, reducing, plaque, inflammation, by, promoting, 'M2', macrophage, polarization, and, 'Treg', induction])].
[sujeto(['IL-13']), verbo([increases]), complemento([mucin, '(', 'MUC)', 5, 'AC,', the, major, component, of, airway, 'mucus,', in, airway, epithelial, cells])].
[sujeto(['According', to, the, 'literature,', 'IL-13', receptor, activation]), verbo([leads]), complemento([to, 'STAT6', activation, and, consequent, induction, of, chloride, channel, accessory, 1, '(', 'CLCA1)', gene, 'expression,', associated, with, the, induction, of, 'MUC5AC'])].
[sujeto(['Heme', 'oxygenase-1', '(', 'HO-1)', is, an, enzyme, that, catalyzes, oxidation, of, heme, to, 'biliverdin,', and]), verbo([has]), complemento(['anti-inflammatory', and, 'anti-oxidant', properties])].
[sujeto(['We', examined, the, effects, of, 'HO-1', on, mucin, production, and, goblet, cell, hyperplasia]), verbo([induced]), complemento([by, 'IL-13'])].
[sujeto(['Hemin', '(', 4, 'μM)', significantly]), verbo([increased]), complemento(['HO-1', protein, expression, '(', p, b, 0.01, ')', and, 'HO-1', mRNA, expression, '(', p, b, 0.001, ')'])].
[sujeto(['IL-13', significantly]), verbo([increased]), complemento([goblet, 'cells,', 'MUC5AC', protein, secretion, '(', p, b, 0.01, ')', and, 'MUC5AC', mRNA, '(', p, b, 0.001, ')', ',', and, these, were, decreased, by, hemin, by, way, of, 'HO-1'])].
[sujeto(['Hemin']), verbo([decreased]), complemento([the, expression, of, 'CLCA1', mRNA, '(', p, b, 0.05, ')', and, it, was, reversed, by, 'SnPP-IX,', but, could, not, suppress, 'IL-13-induced', phosphorylation, of, 'STAT6', or, 'SAM', pointed, 'domain-containing', 'ETS', transcription, factor, '(', 'SPDEF)', and, 'Forkhead', box, 'A2', '(', 'FOXA2)', mRNA, expression])].
[sujeto(['In', 'summary,', 'HO-1', overexpression]), verbo([suppressed]), complemento(['IL-13-induced', goblet, cell, hyperplasia, and, 'MUC5AC', 'production,', and, involvement, of, 'CLCA1', in, the, mechanism, was, suggested])].
[sujeto(['To', show, the, efficient, generation, of, 'hepatocyte-like', cells, '(', 'HLCs)', differentiated, from, the]), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'iPSCs)', of, rats])].
[sujeto(['Then', fibroblast, growth, factor, 4, and, bone, morphogenetic, protein, 2, were, added, to, the, culture, medium, and, used, to]), verbo([induce]), complemento([hepatic, differentiation])].
[sujeto(['After', endodermal, 'induction,', the, differentiated, cells]), verbo([expressed]), complemento([endodermal, markers, forkhead, box, protein, 'A2', and, 'SRY-box', containing, gene, 17, at, the, mRNA, and, protein, levels])].
[sujeto(['These', differentiated, cells]), verbo([expressed]), complemento([hepatic, markers, including, 'α-fetoprotein,', albumin, 'CK8,', 'CK18,', 'CK19,', and, transcription, factor, 'HNF-4α'])].
[sujeto(['In', 'addition,', the, cells]), verbo([expressed]), complemento([functional, proteins, such, as, 'α1-antitrypsin,', cytochrome, 'P450', 1, 'A2', and, 'CYP', 3, 'A4'])].
[sujeto(['They']), verbo([acted]), complemento([like, healthy, hepatic, 'cells,', storing, glycogen, and, taking, up, indocyanine, green, and, 'low-density', lipoproteins])].
[sujeto(['Also,', the, rates, of, urea, synthesis, '(', 20, d, 1.202, ±, 0.08, 'mg/dL', vs, 0, d, 0.317, ±, 0.021, 'mg/dL,', 'P', &, 'lt;', 0.01, ')', and, albumin, secretion, '(', 20, d, 1.601, ±, 0.102, 'mg/dL', vs, 0, d, 0.313, ±, 0.015, 'mg/dL,', 'P', &, 'lt;', 0.01, ')']), verbo([increased]), complemento([significantly, as, differentiation, progressed])].
[sujeto(['Hepatocyte-like', cells, differentiated, from, human, pluripotent, stem, cells, '(', such, as, human, embryonic, stem, '(', 'ES)', cells, and]), verbo([induced]), complemento([pluripotent, stem, '(', 'iPS)', 'cells)', are, expected, to, be, utilized, in, drug, screening])].
[sujeto(['To']), verbo([enhance]), complemento([this, hepatocyte, differentiation, 'efficiency,', 'hepatocyte-related', transcription, 'factors,', such, as, forkhead, box, protein, 'A2', '(', 'FOXA2)', and, hepatocyte, nuclear, factor, 1, alpha, '(', 'HNF1α),', were, overexpressed, during, the, hepatocyte, differentiation, process])].
[sujeto(['In', 'addition,', to]), verbo([enhance]), complemento([the, functions, of, 'hepatocyte-like', 'cells,', these, cells, were, cultured, in, three, dimensional, '(', 3, 'D)', conditions, using, a, 'Nanopillar', plate])].
[sujeto(['Various', hepatic, 'functions,', including, albumin, secretion, and, drug, metabolism, 'capacities,', of, the, 'hepatocyte-like', cells, were, significantly]), verbo([enhanced]), complemento([by, performing, 3, 'D', cell, culture])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, method, of, hepatocyte, differentiation, could, be, improved, by, using, gene, transfer, and, 3, 'D', cell, culture, technologies])].
[sujeto(['The', enterohormone, 'glucagon-like', 'peptide-1', '(', 'GLP-1)', is]), verbo([required]), complemento([to, amplify, 'glucose-induced', insulin, secretion, that, facilitates, peripheral, glucose, utilisation])].
[sujeto(['Alteration', in, 'GLP-1', secretion, during, obesity]), verbo([has]), complemento([been, reported, but, is, still, controversial])].
[sujeto(['Due', to, the, high, adaptability, of, intestinal, cells, to, environmental, 'changes,', we, hypothesised, that, the, density, of, 'GLP-1-producing', cells, could, be, modified, by, nutritional, factors, to]), verbo([prevent]), complemento([the, deterioration, of, metabolic, condition, in, obesity])].
[sujeto(['Mice', fed, a, 'HFD', for, 8, weeks, displayed, an]), verbo([increase]), complemento([in, 'GLP-1-positive', cells, in, the, jejunum, and, colon, accordingly, to, 'GLP-1', secretion])].
[sujeto(['Moreover,', genetically, obese, 'ob/ob', mice, did, not, show, alteration, of, 'GLP-1-positive', cell, density, in, the, jejunum, or, 'colon,']), verbo([suggesting]), complemento([that, obesity, per, se, is, not, sufficient, to, trigger, the, mechanism])].
[sujeto(['The', higher, 'L-cell', density, in, 'HFD-fed', mice]), verbo([involved]), complemento([a, rise, in, 'L-cell', terminal, differentiation, as, witnessed, by, the, increased, expression, of, transcription, factors, downstream, of, neurogenin3, '(', 'Ngn3)'])].
[sujeto(['We']), verbo([suggest]), complemento([that, the, observed, increase, in, 'GLP-1-positive', cell, density, triggered, by, high, fat, consumption, in, humans, and, mice, might, favour, insulin, secretion, and, therefore, constitute, an, adaptive, response, of, the, intestine, to, balance, 'diet-induced', insulin, resistance])].
[sujeto(['Despite', the, better, prognosis, of, embryonal, 'RMS,', patients, in, the, 'E2', are, likely, to]), verbo([have]), complemento([a, poor, prognosis])].
[sujeto(['It']), verbo([has]), complemento([been, shown, that, acetylcholine, is, both, a, neurotransmitter, and, acts, as, a, local, 'mediator,', produced, by, airway, cells, including, epithelial, cells])].
[sujeto(['In', vivo, studies]), verbo([have]), complemento([demonstrated, an, indirect, role, for, acetylcholine, in, epithelial, cell, differentiation])].
[sujeto(['Human', airway, epithelial, cells]), verbo([expressed]), complemento([all, components, of, the, 'non-neuronal', cholinergic, 'system,', suggesting, acetylcholine, production])].
[sujeto(['Differentiation', into, goblet, cells, was, barely]), verbo([induced]), complemento([after, air, exposure])].
[sujeto(['Therefore,', 'IL-13', '(', 1, 'ng/mL)', was, used, to]), verbo([induce]), complemento([goblet, cell, metaplasia])].
[sujeto(['IL-13']), verbo([induced]), complemento(['MUC5AC-positive', cells, '(', 5, -, 'fold)', and, goblet, cells, '(', 14, -, 'fold),', as, assessed, by, 'histochemistry,', and, 'MUC5AC', gene, expression, '(', 105, -, 'fold)'])].
[sujeto(['These', effects, were, partly]), verbo([prevented]), complemento([by, tiotropium, '(', 47, -, 92, '%', ')'])].
[sujeto(['Goblet', cell, metaplasia, was]), verbo([induced]), complemento([by, 'IL-13', in, a, 'dose-dependent', 'manner,', which, was, inhibited, by, tiotropium])].
[sujeto(['In', 'addition,', tiotropium, reversed, goblet, cell, metaplasia]), verbo([induced]), complemento([by, 2, weeks, of, 'IL-13', exposure])].
[sujeto(['IL-13']), verbo([decreased]), complemento([forkhead, box, protein, 'A2', '(', 'FoxA2)', expression, '(', 1.6, -, 'fold)', and, increased, 'FoxA3', '(', 3.6, -, 'fold)', and, 'SAM-pointed', 'domain-containing', 'ETS', transcription, factor, '(', 'SPDEF)', '(', 5.2, -, 'fold)', expression])].
[sujeto(['Tiotropium']), verbo([prevented]), complemento([the, effects, on, 'FoxA2', and, 'FoxA3,', but, not, on, 'SPDEF'])].
[sujeto(['We', demonstrate, that, tiotropium]), verbo([has]), complemento([no, effects, on, epithelial, cell, differentiation, after, air, 'exposure,', but, inhibits, and, reverses, 'IL-13-induced', goblet, cell, 'metaplasia,', possibly, via, 'FoxA2', and, 'FoxA3'])].
[sujeto(['Their', importance, in]), verbo([regulating]), complemento([biological, processes, in, the, lung, and, liver, is, extensively, 'characterized,', though, much, less, is, known, about, their, role, in, intestine])].
[sujeto(['FOXA2']), verbo([binding]), complemento([sites, 'genome-wide', were, determined, by, 'ChIP-seq', and, direct, targets, of, the, factor, were, validated, by, 'ChIP-qPCR', and, 'siRNA-mediated', depletion, of, 'FOXA1/2', followed, by, 'RT-qPCR'])].
[sujeto(['Depletion', of, both, 'FOXA1', and, 'FOXA2']), verbo([led]), complemento([to, a, significant, reduction, in, the, expression, of, multiple, transmembrane, proteins, including, ion, channels, and, 'transporters,', which, form, a, network, that, is, essential, for, maintaining, normal, ion, and, solute, transport])].
[sujeto(['One', of, the]), verbo([targets]), complemento([was, the, adenosine, 'A2B', 'receptor,', and, reduced, receptor, mRNA, levels, were, associated, with, a, functional, decrease, in, intracellular, cyclic, 'AMP'])].
[sujeto(['We', also, observed, that, 30, '%', of, 'FOXA2']), verbo([binding]), complemento([sites, contained, a, 'GATA', motif, and, that, 'FOXA1/A2', depletion, reduced, 'GATA-4,', but, not, 'GATA-6', protein, levels])].
[sujeto(['These', data, show, that, 'FOXA2', plays, a, pivotal, role, in]), verbo([regulating]), complemento([intestinal, epithelial, cell, function])].
[sujeto(['Moreover,', that, the, 'FOXA', and, 'GATA', families, of, transcription, factors, may, work, cooperatively, to]), verbo([regulate]), complemento([gene, expression, 'genome-wide', in, the, intestinal, epithelium])].
[sujeto(['While', chronic, elevation, of, 'FBG', is, detrimental, to, 'health,', glucocorticoids]), verbo([induce]), complemento(['G6PC2', expression, suggesting, that, 'G6PC2', evolved, to, transiently, modulate, 'FBG', under, conditions, of, 'glucocorticoid-related', stress])].
[sujeto(['We', show, using, competition, and, mutagenesis, 'experiments,', that, the, synthetic, glucocorticoid, dexamethasone, '(', 'Dex)']), verbo([induces]), complemento(['G6PC2', promoter, activity, through, a, mechanism, involving, displacement, of, the, 'islet-enriched', transcription, factor, 'MafA', by, the, glucocorticoid, receptor])].
[sujeto(['The', induction, of, 'G6PC2', promoter, activity, by, 'Dex', is]), verbo([modulated]), complemento([by, a, single, nucleotide, 'polymorphism,', previously, linked, to, altered, 'FBG', in, 'humans,', that, affects, 'FOXA2', binding])].
[sujeto(['Acute', 'Dex', treatment, only]), verbo([induces]), complemento(['G6pc2', expression, in, 129, 'SvEv', but, not, 'C57BL/6J', mice, but, this, chronic, treatment, induced, 'G6pc2', expression, in, both])].
[sujeto(['In', 6, hr, fasted, 'C57BL/6J', wild, type, '(', 'WT)', 'mice,', 'Dex', treatment, lowered, 'FBG', and, improved, glucose, 'tolerance,', with, 'G6pc2', deletion, exacerbating, the]), verbo([decrease]), complemento([in, 'FBG', and, enhancing, the, improvement, in, glucose, tolerance])].
[sujeto(['In', 'contrast,', in, 24, hr, fasted, 'C57BL/6J', 'WT', 'mice,', 'Dex', treatment, raised, 'FBG', but, still, improved, glucose, 'tolerance,', with, 'G6pc2', deletion, limiting, the]), verbo([increase]), complemento([in, 'FBG', and, enhancing, the, improvement, in, glucose, tolerance])].
[sujeto(['These', observations, demonstrate, that, 'G6pc2']), verbo([modulates]), complemento([the, complex, effects, of, 'Dex', on, both, 'FBG', and, glucose, tolerance])].
[sujeto(['We', show, characteristic, morphological, changes, corresponding, to, 'epithelial-mesenchymal', transition, '(', 'EMT)', program, fulfillment, in, 'PANC1', cell, line]), verbo([stimulated]), complemento([with, 'TGFβ1'])].
[sujeto(['We', show, 5, -, and, 28, -, fold]), verbo([increase]), complemento([in, 'SNAI1', and, 'SNAI2', expression, levels, and, 25, -, and, 15, -, fold, decrease, in, 'CDH1', and, 'KRT8', expression, 'levels,', 'respectively,', which, confirms, the, 'EMT-program', fulfillment])].
[sujeto(['We', demonstrate, downregulation, of, expression, of, pancreatic, master, genes, 'SOX9,', 'FOXA2,', and, 'GATA4', '(', 2, -, ',', 5, -, ',', and, 4, -, 'fold,', 'respectively)', and, absence, of, significant, changes, in, 'HES1,', 'NR5A2,', and, 'GATA6', expression, levels, in, the, cells]), verbo([stimulated]), complemento([with, 'TGFβ1'])].
[sujeto([1, ',', and, 'ONECUT1', 'genes,', which, are, inactive, in, 'PANC1', cell, line, after, the, 'EMT']), verbo([stimulated]), complemento([by, 'TGFβ1'])].
[sujeto(['Consequently,', the, contribution, of, 'intestine-enriched', factors]), verbo([expressed]), complemento([within, 'BO', to, oncogenesis, is, unclear])].
[sujeto(['Herein,', using, transcriptomics, we, define, the, 'intestine-enriched', genes]), verbo([expressed]), complemento([in, 'meta-profiles', of, 'BO', and, 'OAC'])].
[sujeto(['Interestingly,', 77, '%', of, the, genes, differentially]), verbo([expressed]), complemento([in, a, 'meta-profile', of, 'BO', were, similarly, expressed, in, intestinal, tissues])].
[sujeto(['Furthermore,', 85, '%', of, this, 'intestine-like', signature, was]), verbo([maintained]), complemento([upon, transition, to, 'OAC'])].
[sujeto(['Simulated', acid, reflux, was, observed, to]), verbo([induce]), complemento([the, expression, of, both, 'NR5A2', and, 'GATA6'])].
[sujeto(['Abrogation', of, 'NR5A2-GATA6', expression, in, conjunction, with, 'BCL-XL', 'co-silencing', resulted, in, synergistically]), verbo([increased]), complemento([sensitivity, to, chemotherapeutics, and, 'photo-dynamic', therapeutics])].
[sujeto(['These', findings, characterize, the, 'intestine-like', signature]), verbo([associated]), complemento([with, 'IM', which, may, have, important, consequences, to, adenocarcinogenesis])].
[sujeto(['Transcription', factors, that, play, key, roles, in]), verbo([regulating]), complemento([pancreatic, progenitor, state, have, been, 'identified,', but, the, chromatin, regulators, that, help, establishing, and, maintaining, pancreatic, fate, are, less, well, known])].
[sujeto(['We', show, that, 'Setd7', is]), verbo([expressed]), complemento([in, the, prospective, pancreatic, endoderm, of, 'Xenopus', and, mouse, embryos, prior, to, 'Pdx1', induction])].
[sujeto(['Importantly,', we, demonstrate, that, setd7, is, sufficient, and]), verbo([required]), complemento([for, pancreatic, cell, fate, specification, in, 'Xenopus', 'Functional', and, biochemical, approaches, in, 'Xenopus', and, mouse, endoderm, support, that, 'Setd7', modulates, methylation, marks, at, pancreatic, regulatory, 'regions,', possibly, through, interaction, with, the, transcription, factor, 'Foxa2'])].
[sujeto(['Together,', these, results, demonstrate, that, 'Setd7']), verbo([acts]), complemento([as, a, central, component, of, the, transcription, complex, initiating, the, pancreatic, program])].
[sujeto(['Recently,', the, 'US', 'FDA']), verbo([has]), complemento([approved, &, 'quot;vagal', blocking, therapy, or, 'vBLoc®', 'therapy&quot;', as, a, new, treatment, for, obesity])].
[sujeto(['Rats', were, implanted, with, 'VBLOC,', an, 'intra-abdominal', electrical, device, with]), verbo([leads]), complemento([placed, around, gastric, vagal, trunks, through, an, abdominal, incision, and, controlled, by, wireless, device])].
[sujeto(['VBLOC', reduced, body, weight, and, food, 'intake,', which, was]), verbo([associated]), complemento([with, increased, satiety, but, not, with, decreased, hunger])].
[sujeto(['Brain', activities, in, response, to, 'VBLOC', included]), verbo([increased]), complemento([gene, expression, of, leptin, and, 'CCKb', 'receptors,', 'interleukin-1β,', tumor, necrosis, 'factor,', and, transforming, growth, factor, β1, in, the, 'brainstem;', increased, 'CCK,', 'somatostatin,', and, tyrosine, hydroxylase, in, the, 'hippocampus;', increased, 'NPY,', 'AgRP,', and, 'Foxa2', in, the, 'hypothalamus;', and, reduced, 'CCKb', 'receptor,', melanocortin, 4, 'receptor,', and, insulin, receptor, in, the, hypothalamus])].
[sujeto(['Based', on, the, present, 'study,', we, may]), verbo([suggest]), complemento([that, 'VBLOC', induces, satiety, through, vagal, 'signaling,', leading, to, reduced, food, intake, and, loss, of, body, weight])].
[sujeto(['Because', the, original, 'N27', cell, line]), verbo([has]), complemento([been, passaged, many, 'times,', the, line, has, become, a, mixture, of, cell, types, with, highly, variable, expression, of, 'TH'])].
[sujeto(['In', the, current, 'study,', we]), verbo([have]), complemento([performed, multiple, rounds, of, clonal, cultures, and, have, identified, a, dopaminergic, cell, clone, expressing, high, levels, of, 'TH', and, the, dopamine, transporter, '(', 'DAT)'])].
[sujeto(['We']), verbo([have]), complemento([named, this, new, clone, 'N27-A'])].
[sujeto(['Nearly', 100, '%', of, 'N27-A', cells]), verbo([express]), complemento(['TH,', 'DAT', and, 'Tuj1'])].
[sujeto(['Western', blots]), verbo([have]), complemento([confirmed, that, 'N27-A', cells, have, three, to, four, times, the, levels, of, 'TH', and, 'DAT', compared, to, the, previous, mixed, population, in, 'N27'])].
[sujeto(['Further', analysis]), verbo([has]), complemento([shown, that, the, new, clone, expresses, the, dopamine, neuron, transcription, factors, 'Nurr1,', 'En1,', 'FoxA2', and, 'Pitx3'])].
[sujeto(['The', 'N27-A', cells]), verbo([express]), complemento([the, vesicular, monoamine, transporter, '(', 'VMAT2),', but, do, not, express, 'dopamine-beta-hydroxylase', '(', 'DβH),', the, enzyme, responsible, for, converting, dopamine, to, norepinephrine])].
[sujeto(['Functional', analysis]), verbo([has]), complemento([shown, that, 'N27-A', cells, are, more, sensitive, than, 'N27', cells, to, neurotoxins, taken, up, by, the, dopamine, transporter, such, as, 6, -, hydroxydopamine, and, 1, -, 'methyl-4-phenylpyridine', '(', 'MPP+)'])].
[sujeto(['The', 'DAT', inhibitor, nomifensine, can, block, 'MPP+']), verbo([induced]), complemento([toxicity])].
[sujeto(['The', 'N27-A', cells, show, dopamine]), verbo([release]), complemento([under, basal, and, depolarization, conditions])].
[sujeto(['We', conclude, that, the, new, 'N27-A', clone, of, the, immortalized, rat, dopaminergic, cell, line, 'N27', should]), verbo([provide]), complemento([an, improved, in, vitro, model, for, 'Parkinson\'s', disease, research])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'HNF4α),', a, critical, transcription, 'factor,', plays, an, essential, role, in, the, entire, process, of, liver, development])].
[sujeto(['In', hepatocyte, culture, 'medium,', 'HNF4α-transduced', 'MSCs', '(', 'E7-hHNF4α', 'cells)', strongly]), verbo([expressed]), complemento([the, albumin, '(', 'ALB),', 'CYP2B6,', 'alpha-1', antitrypsin, '(', 'AAT),', and, 'FOXA2', mRNA, and, exhibited, morphology, markedly, similar, to, that, of, mature, hepatocytes])].
[sujeto(['Approximately', 28, '%', of, 'E7-hHNF4α', cells]), verbo([expressed]), complemento([both, 'ALB', and, 'AAT'])].
[sujeto(['Furthermore,', these, 'E7-hHNF4α', cells, via, superior, mesenteric, vein, '(', 'SMV)', injection]), verbo([expressed]), complemento([human, 'ALB', in, mouse, chronic, injured, liver])].
[sujeto(['In', 'conclusion,', this, study, represents, a, novel, strategy, by, directly]), verbo([inducing]), complemento(['hepatocyte-like', cells, from, 'MSCs'])].
[sujeto(['The', ultraweb, 'NF']), verbo([caused]), complemento([better, proliferation, and, characterization, of, 'MSCs'])].
[sujeto(['MSCs', transplantation, significantly, improved, liver, 'functions,']), verbo([increased]), complemento([hepatic, 'HGF', and, 'Bcl-2', 'levels,', whereas, decreased, serum, 'fibronectin,', hepatic, 'TNF-α', and, 'TGF-β1', levels])].
[sujeto(['Hepatic', 'HNF4α,', 'FOXa2,', 'CYP7a1', genes, expression, were]), verbo([enhanced]), complemento([while, 'β-5-Tub', and, 'AFP', genes, expression, were, depressed])].
[sujeto(['ELOVL', family, member, 6, ',', elongation, of, very, long, chain, fatty, acids, '(', 'Elovl6)', is, a, microsomal, 'enzyme,', which]), verbo([regulates]), complemento([the, elongation, of, 'C12-16', saturated, and, monounsaturated, fatty, acids])].
[sujeto(['Elovl6']), verbo([has]), complemento([been, shown, to, be, associated, with, various, pathophysiologies, including, insulin, 'resistance,', 'atherosclerosis,', and, 'non-alcoholic', steatohepatitis])].
[sujeto(['Histological', analysis, revealed, a, reduced, length, of, proliferating, and, an, elongated, length, of, hypertrophic, chondrocyte, 'layer,', and]), verbo([decreased]), complemento([trabecular, bone, in, 'Elovl6-/-', mice, compared, with, controls])].
[sujeto(['These', results, were, presumably, due, to, a, modest]), verbo([decrease]), complemento([in, chondrocyte, proliferation, and, accelerated, differentiation, of, cells, of, the, chondrocyte, lineage])].
[sujeto(['Consistent', with, the]), verbo([increased]), complemento([length, of, the, hypertrophic, chondrocyte, layer, in, 'Elovl6-/-', 'mice,', 'Collagen10α1', was, identified, as, one, of, the, most, affected, genes, by, ablation, of, 'Elovl6', in, chondrocytes])].
[sujeto(['Furthermore,', this, elevated, expression, of, 'Collagen10α1', of, 'Elovl6-null', chondrocytes, was, likely]), verbo([associated]), complemento([with, increased, levels, of, 'Foxa2/a3', and, 'Mef2c', mRNA, expression])].
[sujeto(['Relative']), verbo([increases]), complemento([in, protein, levels, of, nuclear, 'Foxa2', and, cytoplasmic, histone, deacethylase, 4, /, 5, /, 7, were, also, observed, in, 'Elovl6', knockdown, cells, of, the, chondrocyte, lineage])].
[sujeto(['Collectively,', our, data]), verbo([suggest]), complemento([that, 'Elovl6', plays, a, critical, role, for, proper, development, of, embryonic, growth, plate])].
[sujeto(['Studies', in, cultured, cell, lines, and, mice]), verbo([have]), complemento([shown, a, loss, of, 'ZIC2', function, is, the, pathogenic, mechanism, but, the, molecular, details, of, this, 'ZIC2', requirement, remain, elusive])].
[sujeto(['An', intact, 'NODAL', signal, transduction, pathway, and, functional, 'ZIC2', are, both]), verbo([required]), complemento([for, 'PrCP', establishment])].
[sujeto(['We', now, show, that, 'ZIC2']), verbo([acts]), complemento([downstream, of, the, 'NODAL', signal, during, 'PrCP', development])].
[sujeto(['ZIC2', physically]), verbo([interacts]), complemento([with, 'SMAD2', and, 'SMAD3,', the, receptor, activated, proteins, that, control, transcription, in, a, 'NODAL', dependent, manner])].
[sujeto(['Together', 'SMAD3', and, 'ZIC2']), verbo([regulate]), complemento(['FOXA2', transcription, in, cultured, cells, and, 'Zic2', also, controls, the, foxA2, expression, during, 'Xenopus', development])].
[sujeto(['Variant', forms, of, the, 'ZIC2', 'protein,']), verbo([associated]), complemento([with, 'HPE', in, man, or, 'mouse,', are, deficient, in, their, ability, to, influence, 'SMAD-dependent', transcription])].
[sujeto(['These', findings]), verbo([reveal]), complemento([a, new, mechanism, of, 'NODAL', signal, transduction, in, the, mammalian, node, and, provide, the, first, molecular, explanation, of, how, 'ZIC2', 'loss-of-function', precipitates, 'HPE'])].
[sujeto(['Although', much, attention]), verbo([has]), complemento([been, given, to, explore, its, clinical, 'application,', research, of, the, basic, mechanisms, of, 'HE4', in, ovarian, cancer, are, still, unclear])].
[sujeto(['In', the, present, 'study,', we]), verbo([provide]), complemento([fundamental, data, to, identify, 'full-scale', differentially, expressed, genes, '(', 'DEGs)', in, response, to, 'HE4', by, use, of, human, 'whole-genome', microarrays, in, human, epithelial, ovarian, cancer, cell, line, 'ES-2', following, overexpression, and, silencing, of, 'HE4'])].
[sujeto(['We']), verbo([found]), complemento([that, a, total, of, 717, &, 'nbsp;genes', were, upregulated, and, 898, &, 'nbsp;genes', were, downregulated, in, the, 'HE4-overexpressing', cells, vs])].
[sujeto(['These', 'DEGs', were]), verbo([involved]), complemento([in, 'MAPK,', steroid, 'biosynthesis,', cell, 'cycle,', the, p53, hypoxia, 'pathway,', and, focal, adhesion, pathways])].
[sujeto(['Interaction', network, analysis, predicted, that, the, genes]), verbo([participated]), complemento([in, the, regulatory, connection])].
[sujeto(['We']), verbo([found]), complemento([that, 'SERPIND1', may, act, as, a, potential, oncogene, in, the, development, of, ovarian, cancer])].
[sujeto(['These', identified, genes, may]), verbo([provide]), complemento([a, theoretical, basis, for, investigations, of, the, underlying, molecular, mechanism, of, 'HE4', in, ovarian, cancer])].
[sujeto(['The', soluble, form, of, activin, 'A', '(', 'Act)']), verbo([has]), complemento([been, widely, used, as, an, in, vitro, inducer, of, definitive, endoderm, '(', 'DE)'])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([developed, a, nanofibrous, poly, '(', 'ɛ-caprolactone)', 'substrate,', biofunctionalized, with, 'Act,', for, directed, differentiation, of, hESCs, into, 'DE'])].
[sujeto(['The', nanofibers, with, covalent, iAct, significantly]), verbo([increased]), complemento([expression, levels, of, the, endodermal, markers, 'SOX17,', 'FOXA2,', and, 'CXCR4,', compared, with, physically, adsorbed, 'Act', '(', 'aAct)', or, without, 'Act', '(', 'noAct)'])].
[sujeto(['In', 'addition,', iAct]), verbo([retained]), complemento([its, bioactivity, after, storage, for, five, days, in, the, absence, of, cell, seeding])].
[sujeto(['Hypoxia']), verbo([has]), complemento([been, demonstrated, to, play, an, important, role, in, embryonic, formation, and, development, and, to, modulate, stem, cell, differentiation])].
[sujeto(['However,', the, influence, of, oxygen, tension, on, thyroid, differentiation]), verbo([has]), complemento([not, been, studied])].
[sujeto(['In', this, 'study,', we, used, murine]), verbo([induced]), complemento([pluripotent, stem, '(', 'iPS)', cells, for, thyroid, cell, differentiation, under, normoxic, and, hypoxic, conditions, and, compared, differentiation, efficiency, in, 'morphology,', 'function,', gene, and, protein, expression, under, both, conditions])].
[sujeto(['We']), verbo([found]), complemento([that, hypoxia, promoted, adhesion, and, outgrowth, of, embryoid, bodies, '(', 'EBs)', derived, from, murine, iPS, cells])].
[sujeto([1, ')', was]), verbo([increased]), complemento([by, hypoxia, at, both, gene, and, protein, levels, during, 'early-mid', differentiation, stages, '(', 'p&lt;0'])].
[sujeto(['In', 'addition,', functional, iodide, uptake, by, differentiated, cells, was, also]), verbo([increased]), complemento([after, hypoxia])].
[sujeto(['Thyroid', differentiation, from, iPS, cells, is]), verbo([enhanced]), complemento([under, hypoxia, and, this, may, involve, hypoxia, inducible, factors, '(', 'HIFs)', and, their, downstream, gene, 'FGF2'])].
[sujeto(['Our', data, offer, a, foundation, for, understanding, thyroid, development, and]), verbo([provide]), complemento([a, potentially, more, efficient, way, to, use, cell, therapy, for, treating, thyroid, deficiency])].
[sujeto([:, 'The', progressive, death, of, dopamine, producing, neurons, in, the, substantia, nigra, pars, compacta, is, the, principal]), verbo([cause]), complemento([of, symptoms, of, 'Parkinson\'s', disease, '(', 'PD)'])].
[sujeto(['Stem', cells]), verbo([have]), complemento([potential, therapeutic, use, in, replacing, these, cells, and, restoring, function])].
[sujeto(['To', this, 'end,', we, differentiated, baboon, 'fibroblast-derived']), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'biPSCs)', into, dopaminergic, neurons, with, the, application, of, specific, morphogens, and, growth, factors])].
[sujeto(['We', confirmed, that, 'biPSC-derived', dopaminergic, neurons, resemble, those]), verbo([found]), complemento([in, the, human, midbrain, based, on, cell, 'type-specific', expression, of, dopamine, markers, 'TH', and, 'GIRK2'])].
[sujeto(['Using', the, reverse, transcriptase, quantitative, polymerase, chain, 'reaction,', we, also, showed, that, 'biPSC-derived', dopaminergic, neurons]), verbo([express]), complemento(['PAX6,', 'FOXA2,', 'LMX1A,', 'NURR1,', and, 'TH', genes, characteristic, of, this, cell, type, in, vivo])].
[sujeto(['Finally,', we, showed, that, 'biPSC-derived', neurons]), verbo([released]), complemento([catecholamines, in, response, to, electrical, stimulation])].
[sujeto(['Functional', dopamine, neurons, were, produced, from, baboon]), verbo([induced]), complemento([pluripotent, stem, 'cells,', and, their, properties, were, compared, to, baboon, midbrain, cells, in, vivo])].
[sujeto(['The', baboon]), verbo([has]), complemento([advantages, as, a, clinically, relevant, model, in, which, to, optimize, the, efficacy, and, safety, of, stem, 'cell-based', therapies, for, neurodegenerative, 'diseases,', such, as, 'Parkinson\'s', disease])].
[sujeto(['However,', it, is, currently, unclear, how, these, embryonic, tissue, interactions, can, be]), verbo([translated]), complemento([into, a, defined, differentiation, protocol, for, human, embryonic, stem, cells])].
[sujeto(['Activin', 'A']), verbo([has]), complemento([been, proposed, to, direct, 'DE', into, a, 'SOX2-positive', 'foregut-like', cell, type])].
[sujeto(['We', show, in, contrast, to, previous, studies, that, the, generation, of, the, foregut, marked, by, 'SOX2/FOXA2', 'double-positive', cells, does, not, depend, on, activin, 'A/TGF-β-signaling', but, is]), verbo([mediated]), complemento([by, the, inhibition, of, 'Wnt-', and, 'BMP-signaling'])].
[sujeto(['Retinoic', acid, can, posteriorize, and, at, the, same, time, dorsalize, the, foregut, toward, a, 'PDX1-positive', pancreatic, duodenal, cell, type, whereas, active, 'Wnt/beta-catenin', signaling, synergistically, with, 'FGF-2,', 'BMP-4,', and, 'RA']), verbo([induces]), complemento([the, formation, of, 'CDX2-positive', posterior, endoderm])].
[sujeto(['Thus,', these, results]), verbo([provide]), complemento([new, insights, into, the, mechanisms, behind, cell, specification, of, human, 'DE', derived, from, pluripotent, stem, cells])].
[sujeto(['While', orthotopic, transplantation, into, the, testis]), verbo([promotes]), complemento([seminomatous, growth, of, the, 'seminoma-like', cell, line, 'TCam-2,', ectopic, xenotransplantation, into, the, flank, initiates, reprogramming, into, an, 'EC-like', fate])].
[sujeto(['During', this, 'reprogramming,', 'BMP', signaling, is, 'inhibited,']), verbo([leading]), complemento([to, induction, of, 'NODAL', 'signaling,', upregulation, of, pluripotency, factors, and, downregulation, of, seminoma, 'markers,', like, 'SOX17'])].
[sujeto(['In', 'contrast,', the, pioneer, factor, 'FOXA2', and, its]), verbo([target]), complemento([genes, were, 'upregulated,', suggesting, that, 'FOXA2', might, play, an, important, role, in, induction, of, 'non-seminomatous', differentiation])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, exposure, to, phenyl, ethyl, alcohol, '(', 'PEA)', causes, an, increase, in, the, expression, of, the, transcription, factor, otx2, in, the, olfactory, epithelium, '(', 'OE)', of, juvenile, 'zebrafish,', and, this, change, is, correlated, with, the, formation, of, an, odor, memory, of, 'PEA'])].
[sujeto(['Subsequent', in, silico, analysis, uncovered, 'Hnf3b']), verbo([binding]), complemento([sites, closely, associated, with, 'Otx2', binding, sites, in, the, regions, flanking, the, 'ORs'])].
[sujeto(['Analysis', by, quantitative, polymerase, chain, reaction, and, 'RNA-seq', of, 'OR', expression, in, developing, zebrafish, exposed, to, different, isoforms, of, 'PEA', showed, that, a, subset, of, 'ORs', containing, both, 'Otx2/Hnf3b']), verbo([binding]), complemento([sites, were, downregulated, only, in, 'βPEA-exposed', juveniles, and, this, change, persisted, through, adult, life])].
[sujeto(['Localization', of, 'OR', expression, by, in, situ, hybridization, indicates, the, downregulation, occurs, at, the, level, of, 'RNA', and, not, the, number, of, cells]), verbo([expressing]), complemento([a, given, receptor])].
[sujeto(['Finally,', analysis, of, immediate, early, gene, expression, in, the, 'OE', did, not]), verbo([reveal]), complemento([changes, in, 'c-fos', expression, in, response, to, either, αPEA, or, βPEA])].
[sujeto(['SSCs', first, changed, into, hepatic, 'stem-like', cells, since, they, resembled, hepatic, oval, cells, in, morphology, and]), verbo([expressed]), complemento(['Ck8,', 'Ck18,', 'Ck7,', 'Ck19,', 'OV6,', and, albumin])].
[sujeto(['Notably,', these, differentiated, cells, acquired, functional, attributes, of, 'hepatocyte-like', cells, because, they, secreted, 'albumin,', synthesized, 'urea,', and, uptake, and]), verbo([released]), complemento([indocyanine, green])].
[sujeto(['Moreover,', phosphorylation, of, 'ERK1/2', and, 'Smad2/3', rather, than, 'Akt', was]), verbo([activated]), complemento([in, hepatic, stem, cells, and, mature, hepatocytes])].
[sujeto(['This', study, thus]), verbo([provides]), complemento([an, invaluable, source, of, mature, hepatocytes, for, treating, 'liver-related', diseases, and, drug, toxicity, screening, and, offers, novel, insights, into, mechanisms, of, liver, development, and, cell, reprogramming])].
[sujeto(['This', gene]), verbo([has]), complemento([a, 'CpG', island, extending, 2500, bp, from, the, translational, start, 'site;', 'however,', studies, characterizing, its, transcriptional, regulation, have, not, been, conducted])].
[sujeto(['Two', transcripts, for, 'DAPK', were, identified, that, code, for, a, single, 'protein,', while, being]), verbo([regulated]), complemento([by, two, promoters])].
[sujeto(['The', previously, identified, 'DAPK', transcript, designated, as, exon, 1, transcript, was]), verbo([expressed]), complemento([at, levels, 3, -, fold, greater, than, the, alternate, exon, 1, b, transcript])].
[sujeto(['Sequencing', the, 'DAPK', 'CpG', island, in, tumor, cell, lines, revealed, 'dense,', but, heterogenous, methylation, of, 'CpGs', that, blocked, access, of, the, 'CP2', and, 'HNF3B', proteins, that, in, 'turn,', was]), verbo([associated]), complemento([with, loss, of, transcription, that, was, restored, by, treatment, with, 5, -, 'aza-2\'-deoxycytidine'])].
[sujeto(['Growing', evidence, indicates, that, microRNAs]), verbo([have]), complemento([a, significant, role, in, tumor, development, and, may, constitute, robust, biomarkers, for, cancer, diagnosis, and, prognosis])].
[sujeto(['We']), verbo([report]), complemento([that, 'miR-122', is, specifically, repressed, in, a, subset, of, primary, tumors, that, are, characterized, by, poor, prognosis])].
[sujeto(['We', further, show, that, the]), verbo([loss]), complemento([of, 'miR-122', expression, in, tumor, cells, segregates, with, specific, gene, expression, profiles, linked, to, cancer, 'progression,', namely, the, suppression, of, hepatic, phenotype, and, the, acquisition, of, invasive, properties])].
[sujeto(['We', identify, 'liver-enriched', transcription, factors, as, central, regulatory, molecules, in, the, gene, networks]), verbo([associated]), complemento([with, loss, of, 'miR-122,', and, provide, evidence, suggesting, that, 'miR-122', is, under, the, transcriptional, control, of, 'HNF1A,', 'HNF3A', and, 'HNF3B'])].
[sujeto(['We', further, show, that]), verbo([loss]), complemento([of, 'miR-122', results, in, an, increase, of, cell, migration, and, invasion, and, that, restoration, of, 'miR-122', reverses, this, phenotype])].
[sujeto(['One', known, genetic, mechanism, for, transient, neonatal, diabetes, is]), verbo([loss]), complemento([of, methylation, at, 6, q24])].
[sujeto(['The', etiology, of, prune, belly, sequence, is, unknown, but, a, genetic, 'defect,', affecting, the, mesoderm, from, which, the, triad, abdominal, muscle, 'hypoplasia,', urinary, tract, 'abnormalities,', and, cryptorchidism, 'develop,']), verbo([has]), complemento([been, suggested])].
[sujeto(['The', proband, had]), verbo([loss]), complemento([of, methylation, at, the, 6, q24, locus, 'TNDM', and, also, at, the, loci, 'IGF2R,', 'DIRAS3,', and, 'PEG1,', while, the, other, family, 'members,', including, the, healthy, monozygotic, 'twin,', had, normal, findings])].
[sujeto(['The']), verbo([loss]), complemento([of, methylation, on, chromosome, 6, q24, and, elsewhere, may, indicate, a, generalized, maternal, hypomethylation, 'syndrome,', which, accounts, for, both, transient, neonatal, diabetes, and, prune, belly, sequence])].
[sujeto(['Mammalian', 'tissue-', 'and/or', 'time-specific', transcription, is, primarily]), verbo([regulated]), complemento([in, a, combinatorial, fashion, through, interactions, between, a, specific, set, of, transcriptional, regulatory, factors, '(', 'TRFs)', and, their, cognate, 'cis-regulatory', elements, located, in, the, regulatory, regions])].
[sujeto(['In', exploring, the, 'DNA', regions, and, 'TRFs']), verbo([involved]), complemento([in, combinatorial, transcriptional, 'regulation,', we, noted, that, individual, knockdown, of, a, set, of, human, 'liver-enriched', 'TRFs', such, as, 'HNF1A,', 'HNF3A,', 'HNF3B,', 'HNF3G', and, 'HNF4A', resulted, in, perturbation, of, the, expression, of, several, single, 'TRF', 'genes,', such, as, 'HNF1A,', 'HNF3G', and, 'CEBPA', genes])].
[sujeto(['We', thus, searched, the, potential]), verbo([binding]), complemento([sites, for, these, five, 'TRFs', in, the, highly, conserved, genomic, regions, around, these, three, 'TRF', genes, and, found, several, putative, combinatorial, regulatory, regions])].
[sujeto(['Chromatin', immunoprecipitation, analysis, revealed, that, almost, all, of, the, putative, regulatory, 'DNA', regions, were]), verbo([bound]), complemento([by, the, 'TRFs', as, well, as, two, coactivators, '(', 'CBP', and, 'p300)'])].
[sujeto(['EMSA', demonstrated, specific, bindings, of, these, 'HNFs', to, the]), verbo([target]), complemento(['DNA', region])].
[sujeto(['The', 'liver-specific', activity, of, 'ENII', is]), verbo([regulated]), complemento([by, multiple, 'liver-enriched', transcription, 'factors,', including, 'LRH-1/hB1F,', 'HNF1,', 'HNF3b,', 'HNF4', and, 'C/EBP'])].
[sujeto(['In', this, 'study,', we, demonstrate, a, functional, synergism, between, the, orphan]), verbo([nuclear]), complemento([receptor, 'LRH-1/hB1F', and, the, homeoprotein, 'HNF1', in, 'up-regulating', the, 'liver-specific', activity, of, 'ENII'])].
[sujeto(['We']), verbo([have]), complemento([defined, the, activation, domains, in, hB1F, and, 'HNF1', that, contribute, to, the, synergism])].
[sujeto(['We', further, show, that, hB1F, and, 'HNF1', can]), verbo([interact]), complemento([directly, in, vitro, and, have, mapped, the, domains, required, for, this, interaction])].
[sujeto(['Angiotensin', 'II']), verbo([has]), complemento([been, shown, to, exert, complex, effects, on, proximal, tubular, cell, function, and, growth])].
[sujeto(['We', used, 'DNA', microarrays, to, analyze, multiple, gene, expression, responses, to]), verbo([increasing]), complemento([angiotensin, 'II', concentrations])].
[sujeto(['Coordinated', changes, were, observed, in, genes, of, the, hepatocyte]), verbo([nuclear]), complemento([factor, 3, family, '(', 'NHF3;', 'HNF3A,', 'HNF3B', and, 'HNF3G),', in, the, 'E2F', genes, '(', 'E2F1,', 'E2F3)', and, the, interferon, regulatory, factors, 'IRF1', and, 'IRF5'])].
[sujeto(['Three', genes]), verbo([involved]), complemento([in, the, dampening, of, oxidative, stress, were, enhanced])].
[sujeto(['Taken', 'together,', brief, exposure, of, human, tubular, epithelial, cells, to, angiotensin, 'II', elicited, a, marked, induction, of]), verbo([nuclear]), complemento(['factors,', antioxidant, genes, and, hormones, and, hormone, receptor, genes])].
[sujeto(['We']), verbo([have]), complemento([discovered, two, 'single-nucleotide', polymorphisms, in, the, 5, '\'', flanking, region, of, the, 'HFE', gene])].
[sujeto(['When', a, 'T', was, present, at, -, 970, ',', a, 'C', was, always]), verbo([found]), complemento([at, -, 467])].
[sujeto(['The', less, common, -, 467, mutation, was]), verbo([found]), complemento([in, almost, 12, chromosomes, that, bore, the, 845, 'G--&gt;A', '(', 'C282Y)', mutation, and, was, significantly, more, prevalent, in, chromosomes, containing, the, 187, 'C--&gt;G', '(', 'H63D)', mutation])].
[sujeto(['The', tighter, association, of, the, -, 467, polymorphism, with, the, 'C282Y', mutation, is, consistent, with, other, data, that]), verbo([suggest]), complemento([that, the, 'C282Y', mutation, has, occurred, relatively, recently, and, that, the, 'H63D', mutation, is, considerably, older])].
[sujeto(['DNase', 'I', footprinting, from, mouse, cells, revealed, that, several, potential, 'cis-elements', were, occupied, by]), verbo([nuclear]), complemento([proteins])].
[sujeto(['Our', data]), verbo([provide]), complemento([insight, into, the, regulatory, mechanisms, that, govern, the, expression, of, the, 'MAP1A', gene])].
[sujeto(['Mutations', in, genes, encoding, hepatocyte]), verbo([nuclear]), complemento([factor, '(', 'HNF)', are, responsible, for, three, of, the, five, subtypes, of, 'maturity-onset', diabetes, of, the, young, '(', 'MODY)'])].
[sujeto(['This', observation, and, molecular, studies, indicate, that, the, 'HNF', network, is]), verbo([required]), complemento([for, normal, function, of, pancreatic, 'beta-cells'])].
[sujeto(['This']), verbo([suggests]), complemento([that, transcription, factors, involved, in, this, complex, network, are, candidates, for, genetic, defects, in, 'MODY'])].
[sujeto(['All', of, the, five, known, 'MODY', 'genes,', 'HNF-4alpha,', 'glucokinase,', 'HNF-1alpha,', 'HNF-1beta,', and, 'IPF1,', were, previously, excluded, as, being, the]), verbo([cause]), complemento([of, diabetes, in, these, families])].
[sujeto(['Familial', segregation, studies, and, linkage, analysis, showed, that, genetic, variation, in, the, 'HNF-3beta', gene, is, unlikely, to, be, the]), verbo([cause]), complemento([of, 'early-onset', type, 2, diabetes, in, these, 'Caucasian', families])].
[sujeto(['Mutations', in, the, transcription, factors, hepatocyte]), verbo([nuclear]), complemento([factor, '(', 'HNF)-4alpha', and, -, 1, 'alpha,', insulin, promoter, 'factor-1,', and, 'HNF-1beta', are, the, causes, of, four, forms, of, 'maturity-onset', diabetes, of, the, young, '(', 'MODY1', and, 3, -, 5, ',', 'respectively)'])].
[sujeto(['The', 'winged-helix', transcription, factor, 'HNF-3beta']), verbo([has]), complemento([been, implicated, in, the, regulation, of, expression, of, each, of, these, 'MODY', 'genes,', suggesting, that, mutations, in, the, 'HNF-3beta', gene, '(', 'HNF3B)', may, also, cause, 'MODY'])].
[sujeto(['We']), verbo([have]), complemento([tested, this, hypothesis, by, screening, a, panel, of, 57, unrelated, 'Japanese', subjects, with, a, clinical, diagnosis, of, 'MODY', for, mutations, in, 'HNF3B'])].
[sujeto(['This', analysis, revealed, four, frequent, polymorphisms, that, were, not]), verbo([associated]), complemento([with, 'MODY,', including, one, in, the, promoter, region, '(', -, 213, 'A/G),', two, silent, mutations, in, the, codons, for, 'Ala', 97, '(', 291, 'C/T)', and, 'Gly', 279, '(', 837, 'A/G),', and, one, in, the, 3, '\'', -, untranslated, region, '(', 1424, 'C/T)'])].
[sujeto(['Two', rare, substitutions, in, the, 5, '\'', -, untranslated, 'region,', -, 156, 'C/T', and, -, 67, 'A/C,', were]), verbo([found]), complemento([in, a, heterozygous, state, in, two, 'subjects,', and, two, subjects, were, heterozygous, for, putative, missense, 'mutations,', 'S109N', '(', 326, 'G', &, 'gt;', 'A)', and, 'A328V', '(', 983, 'C&gt;T)'])].
[sujeto(['The', two, missense, mutations, were, not]), verbo([found]), complemento([in, 106, normal, chromosomes, from, nondiabetic, subjects])].
[sujeto(['It', was, not, possible, to, test, for, 'co-segregation', of, these, mutations, with, diabetes, and, 'thus,', it, is, unclear, whether, or, not, these, mutations, can]), verbo([cause]), complemento(['MODY'])].
[sujeto(['The', results, of, our, study]), verbo([suggest]), complemento([that, mutations, in, 'HNF3B', are, not, a, common, cause, of, 'MODY', in, 'Japanese', subjects])].
[sujeto(['Small', heterodimer, partner, '(', 'SHP;', 'NR0B2)', is, an, atypical, orphan]), verbo([nuclear]), complemento([receptor, and, acts, as, a, coregulator, of, various, nuclear, receptors])].
[sujeto(['Herein,', we, examined, a, novel, cross, talk, between, 'SHP', and, a, forkhead, transcription, factor, 'HNF3', '(', hepatocyte]), verbo([nuclear]), complemento([factor, 3, /, 'Foxa'])].
[sujeto(['Transient', transfection, assay, demonstrated, that, 'SHP']), verbo([inhibited]), complemento([the, transcriptional, activity, of, all, three, isoforms, of, 'HNF3,', 'HNF3alpha,', 'beta,', and, gamma])].
[sujeto(['In', vivo, and, in, vitro, protein, interaction, studies, showed, that, 'SHP', physically]), verbo([interacted]), complemento([with, 'HNF3'])].
[sujeto(['Adenovirus-mediated', overexpression, of, 'SHP', significantly]), verbo([decreased]), complemento([the, mRNA, levels, of, 'glucose-6-phosphase', '(', 'G6Pase),', cholesterol, 7, -, 'alpha-hydroxylase', '(', 'CYP7A1),', and, phosphoenolpyruvate, carboxykinase, '(', 'PEPCK)', in, 'HepG2', cells, and, rat, primary, hepatocytes])].
[sujeto(['Moreover,', the, mRNA, level, of, 'G6Pase', was, notably]), verbo([increased]), complemento([by, 'down-regulation', of, 'SHP', with, small, interfering, 'RNA'])].
[sujeto(['Interestingly,', 'HNF3', transactivity, was, still]), verbo([repressed]), complemento([by, 'SHPDelta128-139', that, fails, to, repress, nuclear, receptors])].
[sujeto(['Mapping', of, interaction, domain, revealed, that, 'SHP']), verbo([interacted]), complemento([with, forkhead, 'DNA', binding, domain, of, 'HNF3alpha'])].
[sujeto(['Gel', mobility, shift, and, chromatin, immunoprecipitation, assays, demonstrated, that, 'SHP']), verbo([inhibits]), complemento(['DNA', binding, of, 'HNF3'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'SHP', is, involved, in, the, regulation, of, 'G6Pase,', 'CYP7A1,', and, 'PEPCK', gene, expression, via, novel, mechanism, of, inhibition, of, 'HNF3', activity, and, expand, the, role, of, 'SHP', as, a, coregulator, of, other, family, of, transcription, factors, in, addition, to, nuclear, receptors])].
[sujeto(['We']), verbo([have]), complemento([developed, a, protocol, of, differentiation, of, human, embryonic, stem, cells, '(', 'ES)', towards, 'hepatocyte-like', cells, '(', 'ES-Hep)'])].
[sujeto(['Using', a, set, of, human, adult, markers, including, 'CAAT/enhancer']), verbo([binding]), complemento([protein, '(', 'C/EBPalpha),', hepatocyte, nuclear, factor, 4, /, 7, ratio, '(', 'HNF4alpha1/HNF4alpha7),', cytochrome, 'P450', 7, 'A1', '(', 'CYP7A1),', 'CYP3A4', and, constitutive, androstane, receptor, '(', 'CAR),', and, fetal, markers, including, 'alpha-fetoprotein,', 'CYP3A7', and, glutathione, 'S-transferase', 'P1,', we, analyzed, the, expression, of, a, panel, of, 41, genes, in, 'ES-Hep', comparatively, with, human, adult, primary, 'hepatocytes,', adult, and, fetal, liver])].
[sujeto(['When', compared, with, 'hepatocyte-like', cells, derived, from, adult, liver, non, parenchymal, epithelial, '(', 'NPE)', cells, '(', 'NPE-Hep),', 'ES-Hep']), verbo([expressed]), complemento([several, adult, and, fetal, liver, makers, at, much, greater, levels, '(', at, least, one, order, of, 'magnitude),', consistent, with, greater, expression, of, 'liver-enriched', transcription, factors, 'Forkhead', box, 'A2,', 'C/EBPalpha,', 'HNF4alpha', and, 'HNF6'])].
[sujeto(['Finally', we, showed, that, 'lentivirus-mediated', expression, of, xenoreceptor, 'CAR', in, 'ES-Hep']), verbo([induced]), complemento([the, expression, of, several, detoxification, genes, including, 'CYP2B6,', 'CYP2C9,', 'CYP3A4,', 'UDP-glycosyltransferase', 1, 'A1,', solute, carriers, 21, 'A6,', as, well, as, biotransformation, of, 'midazolam,', a, 'CYP3A4-specific', substrate])].
[sujeto(['We']), verbo([found]), complemento([that, the, hepatic, differentiation, of, maGSCs, was, induced, by, the, 'OP9', 'co-culture', system, in, comparison, to, the, gelatin, culture])].
[sujeto(['Furthermore,', we, showed, that, the, combination, of, 'OP9', 'co-culture', with, activin, 'A', resulted, in, the]), verbo([increased]), complemento([expression, of, endodermal, and, early, hepatic, markers, 'Gata4,', 'Sox17,', 'Foxa2,', 'Hnf4,', 'Afp,', and, 'Ttr', compared, to, differentiated, cells, on, gelatin, or, on, 'OP9', alone])].
[sujeto(['These', generated, hepatic, cells, successfully, demonstrated, in, vitro, functions]), verbo([associated]), complemento([with, mature, 'hepatocytes,', including, albumin, and, urea, 'secretion,', glycogen, 'storage,', and, uptake, of, 'low-density', lipoprotein])].
[sujeto(['Specification', of, these, progenitors, with, bone, morphogenetic, 'protein-4', in, combination, with, basic, fibroblast, growth, factor, and, activin, 'A', results, in, the, development, of, hepatic, populations, highly, enriched, '(', 45, -, 70, '%', ')', for, cells, that]), verbo([express]), complemento([the, 'alpha-fetoprotein', and, albumin, proteins])].
[sujeto(['These', cells, also]), verbo([express]), complemento([transcripts, of, 'Afp,', 'Alb1,', 'Tat,', 'Cps1,', 'Cyp7a1', and, 'Cyp3a11;', they, secrete, 'albumin,', store, 'glycogen,', show, ultrastructural, characteristics, of, mature, 'hepatocytes,', and, are, able, to, integrate, into, and, proliferate, in, injured, livers, in, vivo, and, mature, into, hepatocytes, expressing, dipeptidyl, peptidase, 'IV', or, fumarylacetoacetate, hydrolase])].
[sujeto(['Together,', these, findings, establish, a, developmental, pathway, in, embryonic, stem, cell, differentiation, cultures, that]), verbo([leads]), complemento([to, efficient, generation, of, cells, with, an, immature, hepatocytic, phenotype])].
[sujeto(['Corneal', epithelium, is]), verbo([maintained]), complemento([by, a, population, of, stem, cells, '(', 'SCs)', that, have, not, been, identified, by, specific, molecular, markers])].
[sujeto(['The', objective, of, this, study, was, to]), verbo([find]), complemento([new, putative, markers, for, these, 'SCs', and, to, identify, associated, molecular, pathways])].
[sujeto(['RT²-PCR-A', results, indicated, an]), verbo([increased]), complemento([or, decreased, expression, in, 21, and, 24, 'genes,', 'respectively,', in, cells, from, the, corneal, 'SC', niche, compared, to, cells, from, the, central, corneal, epithelium])].
[sujeto(['Functional', analysis, by, proprietary, software]), verbo([found]), complemento([4, different, associated, pathways, and, a, novel, network, with, the, highest, upregulated, genes, in, the, corneal, 'SC', niche])].
[sujeto(['This']), verbo([led]), complemento([to, the, identification, of, specific, 'molecules,', chemokine, '(', 'C-X-C', 'motif)', ligand, 12, '(', 'CXCL12),', 'islet-1', transcription, factor, 'LIM/homeodomain', '(', 'ISL1),', 'collagen-type', 'II', alpha, 1, '(', 'COL2A),', neural, cell, adhesion, molecule, 1, '(', 'NCAM1),', aggrecan, '(', 'ACAN),', forkhead, box, 'A2', '(', 'FOXA2),', 'Gap', junction, protein, beta, 1, /, connexin, 32, '(', 'GJB1/Cnx32),', and, 'Msh', homeobox, 1, '(', 'MSX1),', that, could, be, used, to, recognize, putative, corneal, epithelial, 'SCs', grown, in, culture, and, intended, for, transplantation])].
[sujeto(['Knowledge', of, these, gene, and, molecular, pathways]), verbo([has]), complemento([provided, a, better, understanding, of, the, signaling, molecular, pathways, associated, with, 'progenitor-rich', limbal, epithelium])].
[sujeto(['FoxO1']), verbo([binds]), complemento([to, insulin, response, elements, located, in, the, promoters, of, 'insulin-like', growth, 'factor-binding', protein, 1, '(', 'IGFBP1)', and, 'glucose-6-phosphatase', '(', 'G6Pase),', activating, their, expression])].
[sujeto(['Insulin-mediated', phosphorylation, of, 'FoxO1']), verbo([promotes]), complemento([cytoplasmic, 'translocation,', inhibiting, 'FoxO1-mediated', transactivation])].
[sujeto(['We']), verbo([have]), complemento([previously, demonstrated, that, 'FoxO1', opens, and, remodels, chromatin, assembled, from, the, 'IGFBP1', promoter, via, a, highly, conserved, winged, helix, motif])].
[sujeto(['This', 'finding,', which, established, 'FoxO1', as, a, &, 'quot;pioneer&quot;', 'factor,']), verbo([suggested]), complemento([a, model, whereby, 'FoxO1', chromatin, remodeling, at, regulatory, targets, facilitates, binding, and, recruitment, of, additional, regulatory, factors])].
[sujeto(['However,', the, impact, of, 'FoxO1', phosphorylation, on, its, ability, to]), verbo([bind]), complemento([chromatin, and, the, effect, of, 'FoxO1', loss, on, recruitment, of, neighboring, transcription, factors, at, its, regulatory, targets, in, liver, chromatin, is, unknown])].
[sujeto(['In', this, 'study,', we, demonstrate, that, an, amino, acid, substitution, that, mimics, 'insulin-mediated', phosphorylation, of, a, serine, in, the, winged, helix, 'DNA']), verbo([binding]), complemento([motif, curtails, 'FoxO1', nucleosome, binding])].
[sujeto(['We', also, demonstrate, that, 'shRNA-mediated']), verbo([loss]), complemento([of, 'FoxO1', binding, to, the, 'IGFBP1', and, 'G6Pase', promoters, in, 'HepG2', cells, significantly, reduces, binding, of, 'RNA', polymerase, 'II', and, the, pioneer, factors, 'FoxA1/A2'])].
[sujeto(['Knockdown', of, 'FoxA1', similarly, reduced]), verbo([binding]), complemento([of, 'RNA', polymerase, 'II', and, 'FoxO1'])].
[sujeto(['Reduction', in, acetylation, of, histone, 'H3', 'Lys-27', accompanies]), verbo([loss]), complemento([of, 'FoxO1', and, 'FoxA1/A2', binding])].
[sujeto(['Interdependent']), verbo([binding]), complemento([of, 'FoxO1', and, 'FoxA1/A2', possibly, entails, cooperative, binding, because, 'FoxO1', and, 'FoxA1/A2', facilitate, one, 'another\'s', binding, to, 'IGFPB1', promoter, 'DNA'])].
[sujeto(['These', results, illustrate, how, transcription, factors, can, nucleate, transcriptional, events, in, chromatin, in, response, to, signaling, events, and]), verbo([suggest]), complemento([a, model, for, regulation, of, hepatic, glucose, metabolism, through, interdependent, 'FoxO/FoxA', binding])].
[sujeto([5, mouse, 'brain,', we]), verbo([found]), complemento([that, 'Shh', and, its, receptor, 'Ptch1', define, two, adjacent, mutually, exclusive, gene, expression, 'domains:', 'Shh+Ptch1-', and, 'Shh-Ptch1+'])].
[sujeto(['These', two, domains, are]), verbo([associated]), complemento([respectively, with, 'Foxa2', and, 'Gata3,', two, transcription, factors, that, play, key, roles, in, specifying, them])].
[sujeto(['Important', 'Gata3']), verbo([targets]), complemento([include, 'Slit2', and, 'Slit3,', which, are, involved, in, the, process, of, axon, 'guidance,', as, well, as, 'Slc18a1,', 'Th', and, 'Qdpr,', which, are, associated, with, neurotransmitter, synthesis, and, release])].
[sujeto(['By', 'contrast,', 'Foxa2', both, 'up-regulates', the, genes]), verbo([expressed]), complemento([in, the, 'Shh+Ptch1-', domain, and, 'down-regulates', the, genes, characteristic, of, the, 'Shh-Ptch1+', domain])].
[sujeto(['Our', work]), verbo([provides]), complemento([the, first, 'genome-wide', characterization, of, the, gene, regulatory, network, involved, in, the, 'Shh', pathway, that, underlies, pattern, formation, in, the, early, mouse, brain])].
[sujeto(['The', results, of, 'DNA', microarray, analysis, showed, that, 9, genes]), verbo([associated]), complemento([with, apoptosis, '(', murine, double, minute, 2, ',', 'heat-labile', enterotoxin, 'B', 'subunit,', lymphotoxin, 'B', 'receptor,', tumor, necrosis, factor, ligand, superfamily, 7, ',', tumor, necrosis, factor, receptor, superfamily, 21, ',', tumor, necrosis, factor, receptor, superfamily, 1, 'A,', myeloid, cell, 'leukemia-1,', 'caspase3),', 13, genes, associated, with, cell, proliferation, and, cell, cycle, '(', cell, division, 'cycle27,', cell, division, 'cycle37,', 'CDC28', protein, kinase, 1, 'B,', cycling, 'B1,', cullin, 2, ',', cullin, 3, ',', cullin, 4, 'A,', growth, arrest, and, 'DNA', 'damage-inducible', 45, 'A,', meiotic, recombination, 11, homolog, 'B,', forkhead, box, 'M1,', minichromosome, maintenance, 7, ',', antigen, identified, by, monoclonal, antibody, ki, 67, ',', proliferating, cell, nuclear, 'antigen),', and, 11, genes, associated, with, cellular, stress, and, toxic, reaction, '(', glutathione, peroxidase, 1, ',', 'metallothioneins,', superoxide, 'dismutase-1,', heat, shock, protein, 'A1A,', heat, shock, protein, 'A2,', heat, shock, protein, 'A4,', heat, shock, protein, 'A5,', heat, shock, protein, 9, 'B,', heat, shock, protein, 'CA,', macrophage, migration, inhibitory, 'factor,', plasminogen, activator, 'inhibitor)were', up, or, down, regulated, more, than, 2, folds, in, tumors, treated, with, 'Bleomycin', 'A5', compared, with, controls])].
[sujeto(['Bleomycin', 'A5', could, not, only]), verbo([induce]), complemento([apoptosis, and, inhibit, cell, 'proliferation,', but, also, depressed, the, ability, of, cell, stress, and, toxic, reaction])].
[sujeto(['Receptors', for, advanced, glycation, 'end-products', '(', 'RAGE)', are, 'cell-surface', receptors]), verbo([expressed]), complemento([by, pulmonary, tissue, that, influence, alveolar, type, '(', 'AT)', 'II-ATI', transition, required, for, normal, alveolar, formation])].
[sujeto(['These', results]), verbo([reveal]), complemento([that, precise, regulation, of, 'RAGE', expression, is, required, during, lung, formation])].
[sujeto(['Thyroid', carcinoma, cells, often, do, not]), verbo([express]), complemento(['thyroid-specific', genes, including, sodium, iodide, symporter, '(', 'NIS),', thyroperoxidase, '(', 'TPO),', thyroglobulin, '(', 'TG),', and, 'thyrotropin-stimulating', hormone, receptor, '(', 'TSHR)'])].
[sujeto(['Treatment', of, thyroid, carcinoma, cells, '(', four, papillary, and, two, anaplastic, cell, 'lines)', with, histone, deacetylase, inhibitors, '(', 'SAHA', or, 'VPA)', modestly]), verbo([induced]), complemento([the, expression, of, the, 'NIS', gene])].
[sujeto(['The', promoter, regions, of, the, 'thyroid-specific', genes, contained]), verbo([binding]), complemento([sites, for, hepatocyte, nuclear, factor, 3, beta, '(', 'HNF3', 'beta)/forkhead', box, 'A2', '(', 'FoxA2),', thyroid, transcription, factor, 1, '(', 'TTF-1),', and, 'CCAAT/enhancer', binding, protein, '(', 'C/EBP', 'beta)'])].
[sujeto(['Quantitative', reverse, 'transcription-polymerase', chain, reaction, '(', 'RT-PCR)', showed]), verbo([decreased]), complemento([expression, of, 'HNF3', 'beta/FoxA2', and, 'TTF-1', mRNA, in, papillary, thyroid, carcinoma, cell, 'lines,', when, compared, with, normal, thyroid, cells])].
[sujeto(['Forced', expression, of, these, genes, in, papillary, thyroid, carcinoma, cells]), verbo([inhibited]), complemento([their, growth])].
[sujeto(['Furthermore,', the, 'CpG', island, in, the, promoter, region, of, 'HNF3', 'beta/FoxA2', was, aberrantly, 'methylated;', and, treatment, with, 5, -, 'aza-2-deoxycytidine', '(', 5, -, 'Az)']), verbo([induced]), complemento([its, expression])].
[sujeto(['Subcellular', fractionation, of, papillary, thyroid, carcinoma, cell, lines, also, demonstrated, high, levels, of, expression, of, 'C/EBP', beta, in, the, 'cytoplasm,']), verbo([suggesting]), complemento([that, a, large, proportion, of, 'C/EBP', beta, protein, is, inappropriately, localised, in, the, cytoplasm])].
[sujeto(['In', 'summary,', these, findings]), verbo([reveal]), complemento([novel, abnormalities, in, thyroid, carcinoma, cells])].
[sujeto(['The', human, gene, 'MUC4', encodes, a, large, transmembrane, mucin, that, is, developmentally]), verbo([regulated]), complemento([and, expressed, along, the, undifferentiated, pseudostratified, 'epithelium,', as, early, as, 6.5, weeks, during, fetal, development])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factors, '(', 'HNF),', forkhead, box, 'A', '(', 'FOXA),', 'GATA,', and, 'caudal-related', homeobox, transcription, factors, '(', 'TFs)', are, known, to, control, cell, differentiation, of, gut, endoderm, 'derived-tissues', during, embryonic, development])].
[sujeto(['Experiments', using, small, interfering, 'RNA,', cell, 'co-transfection,', and, 'site-directed', mutagenesis, indicated, that, 'MUC4', is]), verbo([regulated]), complemento([at, the, transcriptional, level, by, 'CDX-1', and, -, 2, ',', 'HNF-1', alpha, and, -, 1, 'beta,', 'FOXA1/A2,', 'HNF-4', alpha, and, -, 4, 'gamma,', and, 'GATA-4,', -, 5, ',', and, -, 6, factors, in, a, 'cell-specific', manner])].
[sujeto(['Altogether,', these, results, demonstrate, that, 'MUC4', is, a]), verbo([target]), complemento([gene, of, endodermal, 'TFs', and, thus, point, out, an, important, role, for, these, 'TFs', in, regulating, 'MUC4', expression, during, epithelial, differentiation, during, 'development,', 'cancer,', and, repair])].
[sujeto(['Forkhead', box, 'A2', '(', 'Foxa2)', is, a, winged, helix]), verbo([nuclear]), complemento([transcription, protein, that, regulates, the, expression, of, genes, that, are, critical, to, lung, 'morphogenesis,', 'differentiation,', and, 'function,', including, thyroid, transcription, 'factor-1,', surfactant, 'proteins,', and, 'Clara', cell, secretory, protein])].
[sujeto(['CTCs', are, assumed, to]), verbo([have]), complemento([characteristics, of, cancer, stem, cells, '(', 'CSCs)', and, an, 'epithelial-mesenchymal', transition, '(', 'EMT)', 'phenotype,', but, extravasation, of, tumors, at, distal, sites, is, marked, by, epithelial, features])].
[sujeto(['Stem', 'cell-associated', markers, 'SOX17,', 'α-fetoprotein,', 'OCT-3/4,', 'KDR,', 'Otx2,', 'GATA-4,', 'Nanog,', 'HCG,', 'TP63', and, 'Goosecoid', were, not]), verbo([expressed]), complemento([in, the, 2, 'CTC', lines])].
[sujeto(['In', 'contrast,', high, expression, was]), verbo([found]), complemento([for, 'HNF-3β/FOXA2,', 'SOX2,', 'PDX-1/IPF1', and, 'E-cadherin'])].
[sujeto(['Thus,', these, 'SCLC', 'CTCs', established, from, extended, disease, 'SCLC', patients, lack, expression, of, stem, cell, markers, which]), verbo([suppress]), complemento([the, epithelial, phenotype])].
[sujeto(['Instead', they]), verbo([express]), complemento([high, levels, of, 'E-cadherin', consistent, with, a, 'mesenchymal-epithelial', transition, '(', 'MET', or, 'EMrT)', and, form, large, tumorospheres, possibly, in, response, to, the, selection, pressure, of, 'first-line', chemotherapy])].
[sujeto(['Mouse', 'ESCs', were, encapsulated, into, heparin, microgels, with, a, single, dose, of, 'Nodal', and, 'FGF-2,', and]), verbo([expressed]), complemento([high, levels, of, endoderm, markers, 'Sox17', and, 'FoxA2', after, 5, days])].
[sujeto(['These', results, highlight, the, use, of, microencapsulation, for, tailoring, the, stem, cell, microenvironment, to]), verbo([promote]), complemento([directed, 'differentiation,', and, may, provide, a, straightforward, path, to, large, scale, bioprocessing, in, the, future])].
[sujeto(['Here', we, describe, the, microfluidic, fabrication, of, 'bioactive,', 'heparin-based', 'microgels,', and, demonstrate, the, adsorption, of, 'heparin-binding', growth, factors, for]), verbo([enhancing]), complemento([directed, differentiation, of, embryonic, stem, cells, toward, endoderm])].
[sujeto(['This', approach, also, facilitated, a, '∼90-fold']), verbo([decrease]), complemento([in, consumption, of, exogenous, growth, factors, compared, to, conventional, differentiation, protocols])].
[sujeto(['Higher', identities, of, amino, acid, sequences, and]), verbo([conserved]), complemento(['exon-intron', organizations, were, found, between, 'LcGnRH3', and, other, 'GnRH3', genes])].
[sujeto(['For', 'example,', two, specific, residues, '(', 'V', and, 'A)', were]), verbo([found]), complemento([in, the, family, 'Sciaenidae,', and, the, unique, 75, -, 72, bp, type, of, the, open, reading, frame, 2, and, 3, existed, in, the, family, 'Cyprinidae'])].
[sujeto(['Analysis', of, the, 2576, bp, promoter, fragment, of, 'LcGnRH3', showed, a, number, of, transcription, factor]), verbo([binding]), complemento(['sites,', such, as, 'AP1,', 'CREB,', 'GATA-1,', 'HSF,', 'FOXA2,', and, 'FOXL1'])].
[sujeto(['Dlx5', and, 'Dlx6', are, two, closely]), verbo([associated]), complemento([homeobox, genes, which, code, for, transcription, factors, involved, in, the, control, of, steroidogenesis, and, reproduction])].
[sujeto(['DLX5/6', are, also, strongly]), verbo([expressed]), complemento([by, the, human, endometrium, but, their, function, in, the, uterus, is, unknown])].
[sujeto(['The', involvement, of, 'DLX5/6', in, human, uterine, pathology, is]), verbo([suggested]), complemento([by, their, strong, downregulation, in, endometriotic, lesions, and, upregulation, in, endometrioïd, adenocarcinomas])].
[sujeto(['In', 'Dlx5/6', mutant, 'uteri,', the, expression, of, genes]), verbo([involved]), complemento([in, gland, formation, '(', 'Foxa2)', and, in, epithelial, remodelling, during, implantation, '(', 'Msx1)', is, significantly, reduced])].
[sujeto(['Furthermore,', we, show, that, 'DLX5', is, highly]), verbo([expressed]), complemento([in, human, endometrial, glandular, epithelium, and, that, its, expression, is, affected, in, endometriosis])].
[sujeto(['Given', their, importance, for, female, 'reproduction,', 'DLX5', and, 'DLX6', must, be, regarded, as, interesting]), verbo([targets]), complemento([for, future, clinical, research])].
[sujeto(['Here,', we, present, evidence, that]), verbo([loss]), complemento([of, 'Foxa2', and, 'Cdx2', synergizes, with, loss, of, 'Nkx2-1', to, fully, activate, the, metastatic, program])].
[sujeto(['Knockdown', of, these, three, factors]), verbo([acts]), complemento([synergistically, and, is, sufficient, to, promote, the, metastatic, potential, of, nonmetastatic, cells, to, that, of, naturally, arising, metastatic, cells, in, vivo])].
[sujeto(['Our', findings]), verbo([reveal]), complemento([that, a, large, part, of, the, complex, transcriptional, network, in, metastasis, can, be, controlled, by, a, small, number, of, regulatory, nodes, that, function, 'redundantly,', and, loss, of, multiple, nodes, is, required, to, fully, activate, the, metastatic, program])].
[sujeto(['Our', recent, efforts]), verbo([led]), complemento([to, a, successful, production, of, chimeric, 'pre-miR-27b', in, bacteria, using, a, transfer, 'RNA', '(', 'tRNA)-based', recombinant, 'RNA', 'technology,', but, at, very, low, expression, levels])].
[sujeto(['Consequently,', recombinant, 'tRNA/mir-1291', reduced, the, protein, levels, of, 'miR-1291']), verbo([target]), complemento(['genes,', including, 'ABCC1,', 'FOXA2,', and, 'MeCP2,', as, compared, with, cells, transfected, with, the, same, doses, of, control, 'methionyl-tRNA', scaffold, with, a, sephadex, aptamer, '(', 'tRNA/MSA)'])].
[sujeto(['In', 'addition,', 'tRNA-carried', 'pre-miR-1291']), verbo([suppressed]), complemento([the, growth, of, 'MCF-7', and, 'PANC-1', cells, in, a, 'dose-dependent', 'manner,', and, significantly, enhanced, the, sensitivity, of, 'ABCC1-overexpressing', 'PANC-1', cells, to, doxorubicin])].
[sujeto(['These', results, indicate, that, recombinant, 'miR-1291', agent, is, effective, in, the, modulation, of]), verbo([target]), complemento([gene, expression, and, 'chemosensitivity,', which, may, provide, insights, into, 'high-yield', bioengineering, of, new, ncRNA, agents, for, pharmacoepigenetics, research])].
[sujeto(['Long', 'non-coding', 'RNAs', '(', 'lncRNAs)']), verbo([regulate]), complemento([diverse, biological, 'processes,', including, cell, lineage, specification])].
[sujeto(['Here,', we]), verbo([report]), complemento([transcriptome, profiling, of, human, endoderm, and, pancreatic, cell, lineages, using, purified, cell, populations])].
[sujeto(['DEANR1', contributes, to, endoderm, differentiation, by, positively]), verbo([regulating]), complemento([expression, of, the, endoderm, factor, 'FOXA2'])].
[sujeto(['Importantly,', overexpression, of, 'FOXA2', is, able, to, rescue, endoderm, differentiation, defects]), verbo([caused]), complemento(['by&nbsp;DEANR1', depletion])].
[sujeto(['Thus,', our, 'study&nbsp;not', only]), verbo([reveals]), complemento([a, large, set, of, 'differentiation-stage-specific', lncRNAs, but, also, characterizes, a, functional, lncRNA, that, is, important, for, endoderm, differentiation])].
[sujeto(['We', recently, demonstrated, that, 'β-cells', become, hypoxic, under, high, glucose, conditions, due, to]), verbo([increased]), complemento([oxygen, consumption, and, that, the, pancreatic, islets, of, diabetic, mice, but, not, those, of, control, mice, are, moderately, hypoxic])].
[sujeto(['In', the, present, 'study,', moderate, hypoxia]), verbo([induced]), complemento([a, hypoxic, response, in, 'MIN6', 'cells,', as, evidenced, by, increased, levels, of, 'HIF-1α', protein, and, target, genes])].
[sujeto(['Most', of, the, 'hypoxia-induced', gene, downregulation, in, 'MIN6', cells, was, not, affected, by, the, suppression, of, 'HIF-1α,']), verbo([suggesting]), complemento([a, 'HIF-1-independent', mechanism])].
[sujeto(['Moderate', hypoxia, also]), verbo([induced]), complemento([apoptosis, in, 'MIN6', cells])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, hypoxia, is, a, novel, stressor, of, 'β-cells', and, that, hypoxic, stress, may, play, a, role, in, the, deterioration, of, 'β-cell', function])].
[sujeto(['The', applications, of, human, pluripotent, stem, cell, '(', 'hPSC)-derived', cells, in, regenerative, medicine]), verbo([has]), complemento([encountered, a, 'long-standing', 'challenge:', how, can, we, efficiently, obtain, mature, cell, types, from, 'hPSCs?', 'Attempts', to, address, this, problem, are, hindered, by, the, complexity, of, controlling, cell, fate, commitment, and, the, lack, of, sufficient, developmental, knowledge, for, guiding, hPSC, differentiation])].
[sujeto(['To', identify, the, transcriptional, regulators, of, 'MafA,', we, examined, various, transcription, 'factors,', which, are, potentially]), verbo([involved]), complemento([in, β, cell, differentiation])].
[sujeto(['An', 'adenovirus-mediated', overexpression, study, clearly, demonstrated, that, 'Onecut1']), verbo([suppresses]), complemento([the, promoter, activity, of, 'MafA', through, the, 'Foxa2-binding', 'cis-element', on, the, 'MafA', enhancer, region, '(', named, area, 'A)'])].
[sujeto(['However,', 'ChIP', analysis, showed, that, 'Foxa2', but, not, 'Onecut1', could, directly]), verbo([bind]), complemento([to, area, 'A'])].
[sujeto(['Furthermore,', overexpression, of, 'Onecut1']), verbo([inhibited]), complemento([the, binding, of, 'Foxa2', onto, area, 'A', upon, 'ChIP', analysis])].
[sujeto(['Importantly,', insertion, of, a, mutation, in, the, 'Foxa2-binding', site, of, area, 'A', significantly]), verbo([decreased]), complemento([the, promoter, activity, of, 'MafA'])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'Onecut1', suppresses, 'MafA', gene, expression, through, the, 'Foxa2-binding', site])].
[sujeto(['In', 'addition,', 'Onecut1', expression, was, significantly]), verbo([increased]), complemento([in, the, islets, of, diabetic, 'db/db', 'mice,', whereas, 'MafA', expression, was, markedly, decreased])].
[sujeto(['These', in, vivo, experiments, also]), verbo([suggest]), complemento([that, 'Onecut1', is, a, negative, regulator, of, 'MafA', gene, expression])].
[sujeto(['This', study, implicates, the, novel, role, of, 'Onecut1', in, the, control, of, normal, β, cell, differentiation, and, its, involvement, in, β, cell, dysfunction, under, diabetic, conditions, by]), verbo([suppressing]), complemento(['MafA', gene, expression])].
[sujeto(['In', human, embryonic, stem, cells, '(', 'hESCs),', thousands, of, genes, are]), verbo([targets]), complemento([for, histone, modifications, leading, to, activation, or, suppression, of, transcription])].
[sujeto(['These', discoveries]), verbo([provide]), complemento([better, understanding, of, the, natural, program, of, differentiation, and, also, open, up, new, opportunities, for, large, scale, production, of, endothelial, progenitors])].
[sujeto(['MafA', and, 'Pdx1', represent, critical, transcriptional, regulators]), verbo([required]), complemento([for, the, maintenance, of, pancreatic, islet, 'β-cell', function])].
[sujeto(['The', in, vivo, 'β-cell-enriched', expression, pattern, of, these, genes, is, principally, directed, by, islet, transcription, factors]), verbo([binding]), complemento([within, conserved, 'Region', 3, '(', base, pairs, '(', 'bp)', -, 8118, /, -, 7750, ')', of, 'MafA', and, 'Area', 'II', '(', bp, -, 2153, /, -, 1923, ')', of, the, 'Pdx1', gene])].
[sujeto(['Comprehensive', mutational, analysis, of]), verbo([conserved]), complemento(['MafA', 'Region', 3, revealed, two, new, 'β-cell', 'line-specific', 'cis-activation', 'elements,', termed, 'Site', 4, '(', bp, -, 7997, to, -, 7988, ')', and, 'Site', 12, '(', bp, -, 7835, to, -, 7826, ')'])].
[sujeto(['Gel', mobility, and, antibody, 'super-shift', analysis, identified, 'Pdx1', as, the, 'Site', 4]), verbo([binding]), complemento(['factor,', while, an, 80, -, 88, kilodalton, '(', 'kDa)', 'β-cell', 'line-enriched', protein, complex, bound, 'Site', 12, and, similar, aligned, nucleotides, within, 'Pdx1', 'Area', 'II'])].
[sujeto(['The', 80, -, 88, kDa, activator, was, also]), verbo([found]), complemento([in, adult, mouse, islet, extract])].
[sujeto(['Neuroendocrine', '(', 'NE)', prostate, tumors, and, neuroendocrine, differentiation, '(', 'NED)', in, prostatic, adenocarcinomas]), verbo([have]), complemento([been, associated, with, poor, prognosis])].
[sujeto(['In', this, 'study,', we, used, the, 'TRAMP', mouse, model, that, develops, 'NE', prostate, tumors, to, identify, key, factors, that, can]), verbo([lead]), complemento([to, 'NED'])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, that, 'NE', tumors, express, the, forkhead, transcription, 'factor,', 'Foxa2,', 'Mash1', '(', mouse, achaete, scute, 'homolog-1),', as, well, as, 'Synaptophysin'])].
[sujeto(['In', 'TRAMP,', the, prostatic, intraepithelial, neoplasia, '(', 'PIN)', first]), verbo([expresses]), complemento(['Foxa2', and, 'Synaptophysin,', which, then, progresses, to, 'NE', cancer])].
[sujeto([1, -, 'Cre/Foxa2(loxP/loxP)', mice, showed]), verbo([loss]), complemento([of, 'Foxa2', expression, in, embryonic, prostatic, buds])].
[sujeto(['Foxa2', is, universally]), verbo([expressed]), complemento([in, all, wild, type, 'TRAMP', 'NE', 'tumors,', but, 'Mash1', expression, is, seen, only, in, a, few, samples, in, a, few, cells])].
[sujeto(['With', the]), verbo([loss]), complemento([of, 'Foxa2', in, the, 'NE', tumors, of, the, 'TRAMP/Nkx3'])].
[sujeto(['NE', tumors, from, both, the, 'TRAMP', control, and, 'Foxa2-deficient', 'TRAMP', prostate]), verbo([express]), complemento(['Synaptophysin', and, 'SV40', 'Large', 'T-antigen,', and, both, show, a, loss, of, androgen, receptor, expression, in, 'NE', cells])].
[sujeto(['These', studies]), verbo([suggest]), complemento([that, the, 'TRAMP', 'NE', tumors, can, form, in, the, absence, of, 'Foxa2', by, an, up, regulation, of, 'Mash1'])].
[sujeto(['A', potential, path, to, functional, relevance, is, mutation, of, the, coding, sequence]), verbo([leading]), complemento([to, the, acquisition, of, novel, biochemical, 'properties,', as, analyzed, here, for, the, highly, homologous, paralogs, 'Foxa1', and, 'Foxa2', transcriptional, regulators])].
[sujeto(['We', determine, by, 'genome-wide', location, analysis, '(', 'ChIP-Seq)', 'that,', although, 'Foxa1', and, 'Foxa2', share, a, large, fraction, of]), verbo([binding]), complemento([sites, in, the, 'liver,', each, protein, also, occupies, distinct, regulatory, elements, in, vivo])].
[sujeto(['Foxa1-only', sites, are, enriched, for, p53]), verbo([binding]), complemento([sites, and, are, frequently, found, near, genes, important, to, cell, cycle, 'regulation,', while, 'Foxa2-restricted', sites, show, only, a, limited, match, to, the, forkhead, consensus, and, are, found, in, genes, involved, in, steroid, and, lipid, metabolism])].
[sujeto(['Thus,', 'Foxa1', and, 'Foxa2,', while, redundant, during, 'development,']), verbo([have]), complemento([evolved, divergent, roles, in, the, adult, 'liver,', ensuring, the, maintenance, of, both, genes, during, evolution])].
[sujeto(['LIM', homeobox, transcription, factor, 1, alpha, '(', 'Lmx1a)', is]), verbo([required]), complemento([for, the, development, of, midbrain, dopaminergic, 'neurons,', roof, plate, 'formation,', and, cortical, hem, development])].
[sujeto(['Under', neutral, 'conditions,', 'Lmx1a(+)', cells]), verbo([express]), complemento([genes, known, to, be, downstream, of, 'Lmx1a', and, cortical, hem, markers, 'Wnt3a', and, p73])].
[sujeto(['The', majority, of, these, cells, did, not]), verbo([express]), complemento([the, ventral, midbrain, dopaminergic, marker, 'Foxa2', or, dorsal, roof, plate, marker, 'BMP-2'])].
[sujeto(['PA6', coculture, produced, a, substantial, population, of, 'Lmx1a(+)', progenitors, that, also]), verbo([expressed]), complemento(['Foxa2', and, on, further, differentiation, gave, rise, to, dopaminergic, neurons, at, high, frequency])].
[sujeto(['We']), verbo([have]), complemento([demonstrated, large, differences, in, the, gene, expression, profile, of, human, embryonic, 'NSC,', and, adult, human, 'OBNSCs,', but, less, variability, between, parallel, cultures])].
[sujeto(['Transcripts', of, genes]), verbo([involved]), complemento([in, neural, tube, development, and, patterning, '(', 'ALDH1A2,', 'FOXA2),', progenitor, marker, genes, '(', 'LMX1a,', 'ALDH1A1,', 'SOX10),', proliferation, of, neural, progenitors, '(', 'WNT1', and, 'WNT3a),', neuroplastin, '(', 'NPTN),', 'POU3F1', '(', 'OCT6),', neuroligin, '(', 'NLGN4X),', 'MEIS2,', and, 'NPAS1', were, 'up-regulated', in, both, cell, populations])].
[sujeto(['Levels', of, gene, expression, were, explored, in, three, signaling, 'pathways,', 'Notch,', 'Wnt,', and, mTOR, that, are, known, to, be]), verbo([involved]), complemento([in, 'NS', cell, fates, determination])].
[sujeto(['The', transcriptional, signature, also, deciphers, the, role, of, genes]), verbo([involved]), complemento([in, epigenetic, modifications])].
[sujeto(['SWI/SNF', 'DNA', chromatin, remodeling, complex, 'family,', including, 'SMARCC1', and, 'SMARCE1,', were]), verbo([found]), complemento([specifically, 'up-regulated', in, our, 'OBNSC', but, not, in, hENSC])].
[sujeto(['The', coexpression, of, 'Mafa,', 'Neurod1', and, 'Ipf1']), verbo([induced]), complemento(['Ins1', and, 'Ins2', expression, in, 'PLT-PPPD', cells])].
[sujeto(['The', forced, expression, of, 'Pax6', alone]), verbo([induced]), complemento([the, expression, of, glucagon])].
[sujeto(['The', coexpression, of, 'Neurod1', and, 'Isl1']), verbo([induced]), complemento(['Ins2', and, 'Sst', expression])].
[sujeto(['In', 'contrast,', the, expression, of, 'Ptf1a', and, 'Foxa2']), verbo([induced]), complemento([the, expression, of, exocrine, markers, 'Cpa1', and, 'Amy2'])].
[sujeto(['Transfections', with, multiple, transcription, factors, showed, that, 'Isl1', is]), verbo([required]), complemento([for, the, differentiation, of, both, 'insulin-positive', cells, and, 'somatostatin-positive', cells])].
[sujeto(['In', 'addition,', 'Foxa2']), verbo([induced]), complemento([the, differentiation, of, 'glucagon-positive', cells, and, inhibited, the, differentiation, of, 'insulin-positive', and, 'somatostatin-positive', cells])].
[sujeto(['PLT-PPPD', cells, allow, episomal, 'vector-based', gene, expression, and, should, be, useful, for, studying, the, transcription, factor, cascades]), verbo([involved]), complemento([in, the, differentiation, of, pancreatic, cell, types, in, vitro])].
[sujeto(['PROCR', haplotype, 3, '(', 'H3)', and, 'FOXA2', rs1055080, were]), verbo([associated]), complemento([with, 'PC', levels, in, the, family, but, only, 'PROCR', 'H3', was, also, associated, with, plasma, levels, in, the, healthy, individuals])].
[sujeto(['Carriers', of, both, variants, had, higher, 'PC', levels, than, carriers, of, only, 'PROCR', 'H3', in, the, family, but, not, in, healthy, 'individuals,']), verbo([suggesting]), complemento([that, a, second, determinant, is, present])].
[sujeto(['EDEM2', 'SNPs', were]), verbo([associated]), complemento([with, 'PC', 'levels,', but, their, effect, was, small])].
[sujeto(['PC', and, sEPCR, levels, were]), verbo([associated]), complemento([in, both, studies])].
[sujeto([sTM, was, not]), verbo([associated]), complemento([with, variations, of, 'THBD', or, 'PC', levels])].
[sujeto(['Chromosome', 20, harbors, genetic, determinants, of, 'PC', and, sEPCR, levels, and, the, analysis, of, candidate, genes]), verbo([suggests]), complemento([that, the, 'PROCR', locus, is, responsible])].
[sujeto(['The', aryl, hydrocarbon, receptor, '(', 'AhR)', is, a, 'ligand-activated', transcription, factor, that]), verbo([mediates]), complemento([diverse, dioxin, toxicities])].
[sujeto(['While', the, acute, effects, of, activation, of, the, 'AhR', pathway, by, 2, ',', 3, ',', 7, ',', 8, -, 'tetrachlorodibenzo-p-dioxin', '(', 'TCDD)']), verbo([have]), complemento([been, a, focus, of, past, 'study,', the, role, of, this, pathway, in, normal, physiology, and, ageing, is, unclear])].
[sujeto(['Adult', pregnant, 'Lewis', rat, dams, were, dosed, with, corn, oil, vehicle, or, 'TCDD', '(', 50, 'ng/kg-week', by, 'gavage)', on, days, 14, and, 21, of, gestation, and, 'post-natal', days, 7, and, 14, to]), verbo([provide]), complemento([in, utero, and, lactational, '(', 'IUL)', exposure, to, pups])].
[sujeto(['Data', analysis, revealed, an, accelerated, onset, of, acyclicity, by, 5, months, in, all, groups]), verbo([involving]), complemento(['IUL', exposure, of, the, developing, ovary, to, 'TCDD'])].
[sujeto([17, 'beta-oestradiol', was, significantly]), verbo([decreased]), complemento([in, animals, receiving, 'TCDD', during, 'IUL', exposure, of, the, 'H-H', axis])].
[sujeto(['This', study]), verbo([reveals]), complemento([a, particular, sensitivity, of, the, developing, ovary, to, 'TCDD', leading, to, early, loss, of, reproductive, function, with, age])].
[sujeto(['Xenobiotic', and, drug, metabolism, and, transport, are, managed, by, a, large, number, of, genes, coordinately]), verbo([regulated]), complemento([by, at, least, three, nuclear, receptors, or, 'xenosensors:', aryl, hydrocarbon, receptor, '(', 'AhR),', constitutive, androstane, receptor, '(', 'CAR,', 'NR1I3),', and, pregnane, 'X', receptor, '(', 'PXR,', 'NR1I2)'])].
[sujeto(['Initially', characterized, as, 'xenosensors,', it, is, now, evident, that, 'CAR', and, 'PXR', also]), verbo([trigger]), complemento([pleiotropic, effects, on, liver, function])].
[sujeto(['Recent', studies]), verbo([have]), complemento([shown, the, existence, of, crosstalk, between, xenosensors, and, other, nuclear, receptors, or, transcription, factors, controlling, endogenous, signaling, pathways, which, regulate, physiological, functions])].
[sujeto(['Such', crosstalks, explain, clinical, observations, and]), verbo([provide]), complemento([molecular, mechanisms, allowing, understanding, how, xenobiotics, and, drugs, may, affect, physiological, functions, and, provoke, endocrine, disruptions])].
[sujeto(['Cytochrome', 'P450', 2, 'A2', '(', 'CYP2A2)', is, an, adult, 'male-specific', rat, liver, steroid, hydroxylase, whose, 'sex-dependent', expression, is]), verbo([regulated]), complemento([at, the, transcriptional, level, by, sexually, dimorphic, pituitary, growth, hormone, '(', 'GH)', secretory, patterns])].
[sujeto(['In', contrast, to, 'CYP2C11', and, other, 'male-specific,', plasma, 'GH', 'pulse-inducible', liver, 'genes,', 'CYP2A2', is, highly]), verbo([expressed]), complemento([in, hypophysectomized, rat, 'liver,', despite, the, absence, of, 'GH', stimulation])].
[sujeto(['A', further, approximately, 2.5, -, fold]), verbo([increase]), complemento([in, activity, was, obtained, by, cotransfection, of, hepatocyte, nuclear, factor, '(', 'HNF)', 3, gamma, or, 'HNF4alpha'])].
[sujeto(['CYP2A2', promoter, activity, was]), verbo([inhibited]), complemento([approximately, 85, '%', by, transfection, of, 'HNF3beta', or, 'HNF6,', both, of, which, are, more, highly, expressed, in, female, than, male, liver, and, can, strongly, 'trans-activate', the, 'female-specific', 'CYP2C12', promoter])].
[sujeto(['By', 'contrast,', 'STAT5b', synergistically]), verbo([enhanced]), complemento([the, transcriptional, activity, of, 'HNF4alpha', toward, two, other, 'male-specific', liver, target, 'genes,', 'Cyp2d9', and, 'CYP8B1'])].
[sujeto(['Furthermore,', 'STAT5b', in, combination, with, the, 'HNF4alpha', coactivator, peroxisome, 'proliferator-activated', receptor, gamma, 'coactivator-1alpha', strongly]), verbo([enhanced]), complemento([the, transcriptional, activity, of, 'HNF4alpha', toward, 'CYP8B1', but, not, toward, 'CYP2A2'])].
[sujeto(['These', findings, support, the, hypothesis, that, 'sex-dependent', 'HNFs', contribute, to, the, sexually, dimorphic, expression, of, 'CYP2A2', and, other, liver, 'CYPs', and, highlight, the, ability, of, 'STAT5b', to]), verbo([act]), complemento([in, concert, with, 'HNF4alpha', to, regulate, select, 'male-specific', liver, 'CYP', genes])].
[sujeto(['In', particular, the, parenchymal, liver, cells, or, hepatocytes, are]), verbo([targeted]), complemento([since, they, are, the, major, sites, of, drug, transport, and, of, metabolite, formation, and, thus, also, the, place, where, not, only, 'detoxification,', but, also, activation, of, new, chemical, '(', 'NCE)', and, biological, '(', 'NBE)', entities, may, occur])].
[sujeto(['However,', within, a, few, 'days,', they, undergo, dedifferentiation, with]), verbo([loss]), complemento([of, 'liver-specific', 'functionality,', including, xenobiotic, biotransformation, 'capacity,', making, them, only, suitable, for, 'short-term', applications])].
[sujeto(['A', plausible, alternative, to, primary, hepatocyte, cultures, that, can, be]), verbo([maintained]), complemento([for, longer, periods, of, time, could, be, the, use, of, 'liver-derived', epithelial, cell, lines, and, their, optimized, derivatives])].
[sujeto(['Undifferentiated', rLEC, stably]), verbo([express]), complemento([the, hepatic, progenitor, markers, 'CEBPA,', 'FOXA2,', 'GJA1,', 'ONECUT1,', 'KRT18', and, 'KRT19', for, at, least, 15, consecutive, passages, after, cryopreservation])].
[sujeto(['Upon', sequential, exposure, to, hepatogenic, growth, factors, and, 'cytokines,', rLEC, generate, functional, hepatic, 'progeny,']), verbo([expressing]), complemento([mature, hepatic, markers, including, 'Alb,', 'Ahr,', 'Car,', 'C/ebpα,', 'Cx32,', 'Foxa2,', 'Hnf1α,', 'Hnf1β', and, 'Onecut1'])].
[sujeto(['rLEC-derived', hepatic, cells, also, acquire, the, ability, to, store, 'glycogen,']), verbo([express]), complemento([genes, encoding, for, key, hepatic, enzymes, as, shown, by, 'Affymetrix', microarray, 'data,', and, display, stable, 'CYP1A1/2-', and, 'CYP2B1/2-dependent', activities, for, several, weeks, at, levels, comparable, to, those, observed, in, cultured, primary, rat, hepatocytes])].
[sujeto(['Many', different, markers]), verbo([have]), complemento([been, attributed, to, these, 'cells,', but, their, nature, still, remains, obscure])].
[sujeto(['This', study, is, a, detailed, gene, expression, analysis, aimed, at]), verbo([revealed]), complemento([their, identity, and, repopulating, in, vivo, capacity])].
[sujeto(['Oval', cells, were]), verbo([activated]), complemento([in, 2, -, 'acetylaminofluorene-treated', rats, subjected, to, partial, hepatectomy, or, in, 'D-galactosamine-treated', rats])].
[sujeto(['We']), verbo([found]), complemento([that, 'EpCAM(+)', and, 'Thy-1(+)', cells, represent, two, different, populations, of, cells, in, the, oval, cell, niche])].
[sujeto(['EpCAM(+)', cells]), verbo([express]), complemento([the, classical, oval, cell, markers, '(', 'alpha-fetoprotein,', 'cytokeratin-19,', 'OV-1', 'antigen,', a6, 'integrin,', and, connexin, 43, ')', ',', cell, surface, markers, recently, identified, by, us, '(', 'CD44,', 'CD24,', 'EpCAM,', aquaporin, 5, ',', 'claudin-4,', secretin, 'receptor,', 'claudin-7,', 'V-ros', sarcoma, virus, oncogene, homolog, 1, ',', cadherin, 22, ',', 'mucin-1,', and, 'CD133),', and, 'liver-enriched', transcription, factors, '(', forkhead, box, 'q,', forkhead, box, 'a2,', onecut, 1, ',', and, transcription, factor, 2, ')'])].
[sujeto(['Oval', cells, do, not]), verbo([express]), complemento([previously, reported, hematopoietic, stem, cell, markers, 'Thy-1,', 'c-kit,', and, 'CD34', or, the, neuroepithelial, marker, neural, cell, adhesion, molecule, 1])].
[sujeto(['However,', oval, cells]), verbo([express]), complemento([a, number, of, mesenchymal, markers, including, 'vimentin,', 'mesothelin,', bone, morphogenetic, protein, 7, ',', and, 'Tweak', receptor, '(', tumor, necrosis, factor, receptor, 'superfamily,', member, 12, 'A)'])].
[sujeto(['A', group, of, novel, differentially]), verbo([expressed]), complemento([oval, cell, genes, is, also, presented])].
[sujeto(['Transplantation', experiments]), verbo([reveal]), complemento([that, 'EpCAM(+)', cells, are, true, progenitors, capable, of, repopulating, injured, rat, liver])].
[sujeto(['We']), verbo([have]), complemento([shown, that, 'EpCAM(+)', oval, cells, are, bipotential, adult, hepatic, epithelial, progenitors])].
[sujeto(['These', cells, display, a, mixed, 'epithelial/mesenchymal', phenotype, that]), verbo([has]), complemento([not, been, recognized, previously])].
[sujeto(['Here', we]), verbo([report]), complemento([that, 'BCa', cells, are, dependent, on, a, mechanism, to, supply, precursors, for, intracellular, lipid, production, derived, from, extracellular, sources, and, that, the, endothelial, lipase, '(', 'LIPG)', fulfils, this, function])].
[sujeto(['LIPG', is, ubiquitously, and, highly]), verbo([expressed]), complemento([under, the, control, of, 'FoxA1', or, 'FoxA2', in, all, 'BCa', subtypes])].
[sujeto(['The', downregulation, of, either, 'LIPG', or, 'FoxA', in, transformed, cells, results, in]), verbo([decreased]), complemento([proliferation, and, impaired, synthesis, of, intracellular, lipids])].
[sujeto(['Limited', adult, dopaminergic, neurogenesis]), verbo([has]), complemento([led, to, novel, therapeutic, strategies, such, as, transplantation, of, dopaminergic, precursors, '(', 'DPs)'])].
[sujeto(['Here,', we, demonstrate, the, direct, conversion, of, mouse, fibroblasts, into]), verbo([induced]), complemento(['DPs', '(', 'iDPs)', by, ectopic, expression, of, 'Brn2,', 'Sox2', and, 'Foxa2'])].
[sujeto(['After', transplantation, into, 'MPTP-lesioned', 'mice,', iDPs, differentiated, into, 'DA', 'neurons,', functionally, alleviated, the, motor, 'deficits,', and, reduced, the]), verbo([loss]), complemento([of, striatal, 'DA', neuronal, axonal, termini])].
[sujeto(['We', propose, that, the, iDPs, from, direct, reprogramming]), verbo([provides]), complemento([a, safe, and, efficient, cell, source, for, 'PD', treatment])].
[sujeto(['Farnesol', is, a, 'non-cyclic', sesquiterpene, '(', 'isoprenoid)']), verbo([found]), complemento([in, the, essential, oils, of, many, plants])].
[sujeto(['Therefore,', farnesyltransferase, is, a]), verbo([target]), complemento([for, drug, development, to, inhibit, 'Ras'])].
[sujeto(['Tumors', frequently, develop, resistance, towards, standard, 'chemotherapies,', and, thus, novel, agents, are, urgently]), verbo([required]), complemento([that, bypass, the, 'cross-resistance', evoked, by, established, anticancer, drugs])].
[sujeto(['Remarkably,', none, of, these, genes]), verbo([conferred]), complemento([resistance, to, 'farnesol,', indicating, that, this, compound, may, be, useful, for, the, treatment, of, otherwise, 'drug-resistant', and, refractory, tumors, expressing, these, mechanisms, of, resistance])].
[sujeto(['Among', the, candidates, were, genes]), verbo([involved]), complemento([in, apoptosis, '(', 'STAB2,', 'NUMBL),', regulation, of, transcription, '(', 'CDYL,', 'FOXA2)', and, diverse, other, functional, groups, '(', 'INE1,', 'CTRL,', 'MRS2,', 'NEB,', 'LMO7,', 'C9orf3,', 'EHBP1)'])].
[sujeto(['The', fact, that, these, genes, are, not]), verbo([associated]), complemento([with, resistance, to, traditional, anticancer, drugs, suggests, farnesol, may, possess, a, novel, mechanism, of, 'action,', and, consequently, might, bypass, drug, resistance, to, established, chemotherapeutics])].
[sujeto(['We']), verbo([targeted]), complemento([the, reverse, tetracycline, controlled, transactivator, '(', 'rtTA)', to, the, 'Foxa2', locus, '(', 'Foxa2(ITA))', to, generate, a, system, for, regulating, 'Cre-recombinase', activity, within, 'Foxa2', expression, 'domains,', including, the, 'endoderm,', 'notochord,', and, floor, plate, of, early, mouse, embryos])].
[sujeto(['The', use, of, an, internal, ribosomal, entry, site, to, obtain, rtTA, expression, preserves, 'Foxa2', function, of, the]), verbo([targeted]), complemento([allele])].
[sujeto(['This', system, will]), verbo([provide]), complemento([a, useful, tool, for, manipulating, gene, expression, in, 'endoderm,', 'notochord,', and, floor, 'plate,', all, of, which, are, tissues, with, important, structural, and, patterning, functions, during, embryogenesis])].
[sujeto(['Since', the, lung, is, repeatedly, subjected, to, injury, by, pathogens, and, 'toxicants,', maintenance, of, pulmonary, homeostasis]), verbo([requires]), complemento([rapid, repair, of, its, epithelial, surfaces])].
[sujeto(['Expression', of, transcription, factors, active, in, morphogenesis, and, differentiation, of, the, embryonic, 'lung,', including, 'beta-catenin,', 'Foxa2,', 'Foxj1,', and, 'Sox', family, members, '(', 'Sox17', and, 'Sox2),', was, dynamically]), verbo([regulated]), complemento([during, repair, and, redifferentiation, of, the, bronchiolar, epithelium, after, naphthalene, injury])].
[sujeto(['Squamous', cells, derived, from, ciliated, cells, spread, beneath, injured, 'Clara', cells, within, 6, -, 12, h, after, 'injury,']), verbo([maintaining]), complemento([the, integrity, of, the, epithelium])].
[sujeto(['Agonists', for, the]), verbo([nuclear]), complemento([receptor, peroxisomal, 'proliferator-activated', 'receptor-gamma', '(', 'PPARgamma)', and, its, heterodimeric, 'partner,', retinoid, 'X', receptor, '(', 'RXR),', are, effective, agents, for, the, treatment, of, type, 2, diabetes])].
[sujeto(['To']), verbo([gain]), complemento([insight, into, the, antidiabetic, action, of, these, 'compounds,', we, treated, female, 'Zucker', diabetic, rats, '(', 'ZFF)', with, 'AGN194204,', which, we, show, to, be, a, 'homodimer-specific', 'RXR', 'agonist,', or, the, 'PPARgamma', 'agonist,', troglitazone])].
[sujeto(['AGN194204', had, no, effect, on, peripheral, glucose, 'utilization,', whereas, troglitazone]), verbo([increased]), complemento(['insulin-stimulated', glucose, utilization, by, 50, '%', ',', glucose, uptake, into, skeletal, muscle, by, 85, '%', ',', and, de, novo, skeletal, muscle, glycogen, synthesis, by, 300, '%'])].
[sujeto(['Troglitazone']), verbo([increased]), complemento([skeletal, muscle, 'Irs-1', and, 'phospho-Akt', levels, following, in, vivo, insulin, 'treatment,', whereas, 'AGN194204', increased, hepatic, 'Irs-2', and, insulin, stimulated, 'phospho-Akt', in, liver])].
[sujeto(['Gene', profiles, of, 'AGN194204-treated', mouse, liver, analyzed, by, 'Ingenuity', 'Pathway', 'Analysis', identified]), verbo([increases]), complemento([in, fatty, acid, synthetic, 'genes,', including, 'Srebp-1', and, fatty, acid, 'synthase,', a, pathway, previously, shown, to, be, induced, by, 'RXR', agonists])].
[sujeto(['A', network, of, 'down-regulated', genes, containing, 'Foxa2,', 'Foxa3,', and, 'G-protein', subunits, was, 'identified,', and]), verbo([decreases]), complemento([in, these, mRNA, levels, were, confirmed, by, quantitative, reverse, 'transcription-PCR'])].
[sujeto(['Treatment', of, 'HepG2', cells, with, 'AGN194204', resulted, in, inhibition, of, 'glucagon-stimulated', cAMP, accumulation]), verbo([suggesting]), complemento([the, 'G-protein', 'down-regulation', may, provide, an, additional, mechanism, for, hepatic, insulin, sensitization, by, 'RXR'])].
[sujeto(['These', studies, demonstrate, distinct, molecular, events]), verbo([lead]), complemento([to, insulin, sensitization, by, high, affinity, 'RXR', and, 'PPARgamma', agonists])].
[sujeto(['Although']), verbo([expressed]), complemento([in, all, cells, at, the, early, 'stages,', in, the, adult, it, is, mainly, restricted, to, the, 'beta-cell'])].
[sujeto(['DNase', 'I', footprinting, analysis, revealed, two, protected, 'regions,', one]), verbo([binding]), complemento([the, transcription, factors, 'SP1', and, 'SP3', and, the, other, hepatocyte, nuclear, factor, 3, beta, '(', 'HNF-3beta)', and, 'HNF-1alpha'])].
[sujeto(['Cotransfection', experiments]), verbo([suggest]), complemento([that, 'HNF-3beta,', 'HNF-1alpha,', and, 'SP1', are, positive, regulators, of, the, 'herein-described', human, 'PDX-1', enhancer, element])].
[sujeto(['Furthermore,', mutations, within, each, motif, abolished, the]), verbo([binding]), complemento([of, the, corresponding, 'factor(s)', and, dramatically, impaired, the, enhancer, 'activity,', therefore, suggesting, cooperativity, between, these, factors])].
[sujeto(['To', address, the, question, whether, these, enzymatic, alterations, result, from, specific, changes, in, the, levels, of, 'hepatocyte-enriched']), verbo([nuclear]), complemento([factors, '(', 'HNF),', we, analysed, the, mRNA, levels, of, six, different, 'HNFs', '(', 'HNF-1alpha,', 'beta,', 'HNF-3alpha,', 'beta,', 'gamma,', and, 'HNF-4)', by, 'RNase', protection, assay, in, chemically, induced, liver, tumours, and, corresponding, normal, liver, tissue, from, mice, of, three, different, strains])].
[sujeto(['When', compared, with, the, normal, liver, 'tissue,', 'HNF-1beta,', 'HNF-3alpha', and, 'HNF-3beta', showed, unchanged, expression, levels, in, the, various, liver, 'tumours,', which, 'HNF-1alpha', and, 'HNF-4', mRNAs, were, lowered, by, 20, -, 30, '%', ',', and, 'HNF-3gamma', mRNA, was]), verbo([increased]), complemento([by, 50, '%'])].
[sujeto(['We']), verbo([found]), complemento([a, substantial, reduction, in, cancer, risk, '(', 'OR', 0.39, ;, 95, '%', 'CI', 0.25, -, 0.61, ;, 'Pinteraction', =, 0.029, ')', associated, with, combined, genotypes, for, 'CYP2A13', 'R257C', and, a, functionary, regulatory, variant, in, the, cis, element, of, 'ABCB1', synergistically, targeted, by, 'GATA', binding, protein, 6, and, 'FOXA2'])].
[sujeto(['Genetic', manipulation, of, 'FOXA2', consistently, influenced, its]), verbo([binding]), complemento([to, and, transactivation, of, the, promoters, of, 'CYP2A13,', 'UGT2B17,', and, 'ABCB1,', whose, mRNA, and, protein, expressions, were, all, consistently, correlated, with, those, of, 'FOXA2', in, both, tumorous, and, normal, lung, tissues])].
[sujeto(['We', previously, identified, polymorphisms, in, pregnane, 'X', receptor, '(', 'PXR)', and, 'ATP-binding', cassette, subfamily, 'B', member, 1, '(', 'ABCB1)']), verbo([associated]), complemento([with, 'CYP3A4', mRNA, levels, in, small, cohorts, of, human, livers])].
[sujeto(['We', resequenced, hepatic]), verbo([nuclear]), complemento(['factor-3-beta', '(', 'HNF3beta,', 'FoxA2),', 'HNF4alpha,', 'HNF3gamma', '(', 'FoxA3),', nuclear, receptor, corepressor, 2, '(', 'NCoR2),', and, regions, of, the, 'CYP3A4', promoter, and, genotyped, informative, 'single-nucleotide', polymorphisms, in, 'PXR', and, 'ABCB1', in, the, same, livers])].
[sujeto(['A', common, silent, polymorphism, and, a, polymorphic, trinucleotide, '(', 'CCT)', repeat, in, 'FoxA2', were]), verbo([associated]), complemento([with, 'CYP3A4', expression])].
[sujeto(['The', transcriptional, activity, of, the, 'FoxA2', polymorphic, 'CCT', repeat, alleles, '(', 'wild-type,', n, =, 14, and, 'variant,', n, =, 13, ',', 15, ',', and, 19, ')', when, assayed, by, luciferase, reporter, transactivation, assays, was, greatest, for, the, 'wild-type', 'repeat,', with, deviations, from, this, number, having]), verbo([decreased]), complemento([transcriptional, activity])].
[sujeto(['This', corresponded, with, higher, expression, of, 'FoxA2', mRNA, and, its]), verbo([targets]), complemento(['PXR', and, 'CYP3A4', in, human, livers, with, '(', 'CCT)', n, =, 14, genotypes])].
[sujeto(['Nuclear', receptors, constitutive, 'active/androstane', receptor, '(', 'CAR)', and, pregnane, 'X', receptor, '(', 'PXR)', were, originally, characterized, as, transcription, factors]), verbo([regulating]), complemento([the, hepatic, genes, that, encode, drug, metabolizing, enzymes])].
[sujeto(['Recent', works]), verbo([have]), complemento([now, revealed, that, these, nuclear, receptors, also, play, the, critical, roles, in, modulating, hepatic, energy, metabolism])].
[sujeto(['While', 'CAR', and, 'PXR', directly]), verbo([bind]), complemento([to, their, response, sequences, 'phenobarbital-responsive', enhancer, module, '(', 'PBREM)', and, xenobiotic, responsive, enhancer, module, '(', 'XREM)', in, the, promoter, of, target, genes, to, increase, drug, 'metabolism,', the, receptors, also, cross, talk, with, various, hormone, responsive, transcription, factors, such, as, forkhead, box, 'O1', '(', 'FoxO1),', forkhead, box, 'A2', '(', 'FoxA2),', 'cAMP-response', element, binding, 'protein,', and, peroxisome, proliferator, activated, receptor, gamma, coactivator, 1, alpha, '(', 'PGC', 1, 'alpha)', to, decrease, energy, metabolism, through, 'down-regulating', 'gluconeogenesis,', fatty, acid, oxidation, and, ketogenesis, and, 'up-regulating', lipogenesis])].
[sujeto(['In', 'addition,', 'CAR']), verbo([modulates]), complemento([thyroid, hormone, activity, by, regulating, type, 1, deiodinase, in, the, regenerating, liver])].
[sujeto(['Cytochrome', 'P450', 3, 'A4', '(', 'CYP3A4)', is, the, major, cytochrome, 'P450', present, in, adult, human, liver, and, is]), verbo([involved]), complemento([in, the, metabolism, of, over, 50, '%', of, therapeutic, compounds, currently, in, use])].
[sujeto(['Since', expression, levels, of, 'CYP3A4', are]), verbo([regulated]), complemento([by, many, of, these, 'compounds,', this, raises, the, potential, for, 'drug-drug', interactions, and, subsequent, altered, efficacy, or, toxicity, of, the, individual, compounds, at, the, dose, prescribed])].
[sujeto(['To', examine, this, we]), verbo([have]), complemento([used, 'DNase', 'I', footprinting, and, bioinformatic, analysis, to, identify, putative, transcription, factor, binding, sites, within, the, 250, base, pairs, of, promoter, proximal, to, the, transcription, start, site])].
[sujeto(['We', identified, several, protected, fragments, within, this, region, that, corresponded, to, putative]), verbo([binding]), complemento([sites, for, 'Sp1,', 'AP2,', 'CCAAT/enhancer', binding, protein, '(', 'C/EBPalpha),', and, hepatic, nuclear, 'factor-3', '(', 'HNF3),', as, well, as, confirming, previously, identified, 'C/EBPalpha,', pregnane, 'X', receptor, '(', 'PXR),', and, 'HNF3', binding, sites])].
[sujeto(['Sequential', 'site-directed', mutagenesis, of, 'C/EBPalpha,', 'Sp1,', 'HNF3,', and, 'PXR']), verbo([binding]), complemento([sites, was, next, used, to, examine, the, role, of, these, sites, in, basal, 'CYP3A4', expression])].
[sujeto(['Disruption', of, the, 'C/EBPalpha,', 'HNF3,', and, 'PXR']), verbo([binding]), complemento([sites, all, affected, basal, expression])].
[sujeto(['Disruption', of, any, of, these, sites, either]), verbo([led]), complemento([to, an, altered, pattern, of, activation, by, the, 'xenobiotic,', as, altered, maximal, 'activation,', or, altered, the, 'EC(50)', value, of, activation])].
[sujeto(['Chicken', 'CYP2H1', promoter, constructs]), verbo([express]), complemento([strongly, in, chick, embryo, hepatocytes, at, a, level, comparable, with, that, of, 'Rous', sarcoma, viral, promoter])].
[sujeto(['We']), verbo([have]), complemento([identified, the, transcription, factors, responsible, for, the, active, 'CYP2H1', promoter])].
[sujeto(['Protein']), verbo([binding]), complemento([to, these, sites, was, established, by, gel, mobility, shift, assays])].
[sujeto(['The', promoter, was, also, active, in, mammalian, 'HepG2', and, 'COS-1', cell, lines, where, expression, was, dependent, on, the, identified, transcription, factor]), verbo([binding]), complemento([sites, but, promoter, activity, in, the, 'HeLa', cells, was, low])].
[sujeto(['Transactivation', experiments, revealed, that, promoter, expression, could, be]), verbo([activated]), complemento([through, the, appropriate, binding, sites, by, exogenously, expressed, rat, 'HNF-1alpha', or, 'HNF-1beta,', rat, 'HNF-3alpha', or, 'HNF-3beta', and, chicken, 'C/EBP', alpha])].
[sujeto(['By', 'comparison,', in, vivo, expression, of, this, gene, in, uninduced, chick, embryo, hepatocytes, is, low, but, markedly]), verbo([increased]), complemento([by, phenobarbital])].
[sujeto(['BMP4', is, preferentially]), verbo([expressed]), complemento([in, 'diffuse-type', gastric, cancer, cells])].
[sujeto(['Human', 'BMP4', gene, was]), verbo([found]), complemento([consisting, of, six, 'exons,', including, novel, exon, 1, 'C,', and, known, exons, 1, '(', 1, 'A', or, 'I),', 1, 'B', '(', 'II),', 2, '(', 'III),', 3, '(', 'IV)', and, 4, '(', 'V)'])].
[sujeto(['The', 5, '\'', -, flanking, region, of, exon, 1, and, exon, 1, 'itself,', but, not, exons, 1, 'C', and, 1, 'B,', were, well]), verbo([conserved]), complemento([between, human, 'BMP4', and, rodent, 'Bmp4', genes])].
[sujeto(['FOXA2,', 'OLF1,', and, 'MYC-binding', sites, were]), verbo([conserved]), complemento([among, the, major, promoter, region, of, 'human,', 'baboon,', 'cow,', 'bat,', mouse, and, rat, 'BMP4', orthologs])].
[sujeto(['Capicua', '(', 'CIC)']), verbo([has]), complemento([been, implicated, in, pathogenesis, of, spinocerebellar, ataxia, type, 1, and, cancer, in, 'mammals;', 'however,', the, in, vivo, physiological, functions, of, 'CIC', remain, largely, unknown])].
[sujeto(['Here', we, show, that, 'Cic', hypomorphic, '(', 'Cic-L(-/-))', mice]), verbo([have]), complemento([impaired, bile, acid, '(', 'BA)', homeostasis, associated, with, induction, of, proinflammatory, cytokines])].
[sujeto(['We', discovered, that, several, drug, metabolism, and, 'BA', transporter, genes, were, 'down-regulated', in, 'Cic-L(-/-)', 'liver,', and, that, 'BA', was]), verbo([increased]), complemento([in, the, liver, and, serum, whereas, bile, was, decreased, within, the, gallbladder, of, 'Cic-L(-/-)', mice])].
[sujeto(['We', also]), verbo([found]), complemento([that, levels, of, proinflammatory, cytokine, genes, were, 'up-regulated', in, 'Cic-L(-/-)', liver])].
[sujeto(['Consistent', with, this, 'finding,', levels, of, hepatic, transcriptional, 'regulators,', such, as, hepatic]), verbo([nuclear]), complemento([factor, 1, alpha, '(', 'HNF1α),', 'CCAAT/enhancer-binding', protein, beta, '(', 'C/EBPβ),', forkhead, box, protein, 'A2', '(', 'FOXA2),', and, retinoid, 'X', receptor, alpha, '(', 'RXRα),', were, markedly, decreased, in, 'Cic-L(-/-)', mice])].
[sujeto(['Moreover,', induction, of, tumor, necrosis, factor, alpha, '(', 'Tnfα)', expression, and]), verbo([decrease]), complemento([in, the, levels, of, 'FOXA2,', 'C/EBPβ,', and, 'RXRα', were, found, in, 'Cic-L(-/-)', liver, before, 'BA', was, 'accumulated,', suggesting, that, inflammation, might, be, the, cause, for, the, cholestasis, in, 'Cic-L(-/-)', mice])].
[sujeto(['Our', findings, indicate, that, 'CIC', is, a, critical, regulator, of, 'BA', 'homeostasis,', and, that, its, dysfunction, might, be]), verbo([associated]), complemento([with, chronic, liver, disease, and, metabolic, disorders])].
[sujeto(['ATP']), verbo([binding]), complemento([cassette, transporter, 'A1', '(', 'ABCA1)', plays, a, key, role, in, the, biogenesis, of, 'HDL', by, promoting, the, efflux, of, cellular, cholesterol, and, phospholipids, to, lipid, free, 'apoA-I'])].
[sujeto(['Mutations', in, the, 'ABCA1', gene]), verbo([cause]), complemento(['Tangier', disease, which, is, characterized, by, near, or, complete, absence, of, circulating, plasma, 'HDL'])].
[sujeto(['We', show, that, the, 'ABCA1', promoter, contains, three, 'FOXA2']), verbo([binding]), complemento([elements, in, the, proximal, region])].
[sujeto(['Two', of, the, sites, are, localized, in, a, region, of, the, 'ABCA1', promoter, enriched, in]), verbo([binding]), complemento([elements, for, transcriptional, repressor, proteins, whereas, the, third, site, is, the, core, of, the, 'TATA', element, of, the, 'ABCA1', promoter])].
[sujeto(['Inhibition', of, 'FOXA2']), verbo([binding]), complemento([to, the, 'ABCA1', promoter, by, 'site-directed', mutagenesis, or, 'FOXA2', gene, expression, by, siRNA, was, associated, with, increased, 'ABCA1', promoter, activity, and, protein, levels])].
[sujeto(['Overexpression', of, 'FOXA2']), verbo([inhibited]), complemento([both, the, constitutive, 'ABCA1', gene, expression, as, well, as, 'ABCA1', gene, induction, by, oxysterols, and, retinoids, via, nuclear, receptors, 'LXRα/RXRα'])].
[sujeto(['In', 'summary,', the, present, study, identifies, transcription, factor, 'FOXA2', as, a, negative, modulator, of, 'ABCA1', gene, expression, in, hepatic, cells, and]), verbo([reveals]), complemento([a, novel, mechanism, of, transcriptional, repression, by, 'FOXA2', which, involves, the, 'TATA', element, of, the, 'ABCA1', gene])].
[sujeto(['Cytokine', signaling]), verbo([has]), complemento([been, connected, to, regulation, of, metabolism, and, energy, balance])].
[sujeto(['Numerous', cytokine, gene, expression, changes, are]), verbo([stimulated]), complemento([by, accumulation, of, bile, acids, in, livers, of, young, 'Foxa2', 'liver-conditional', null, mice])].
[sujeto(['We']), verbo([found]), complemento([that, loss, of, 'Foxa2', in, the, liver, results, in, a, premature, aging, 'phenotype,', including, significant, weight, 'gain,', reduced, food, 'intake,', and, decreased, energy, expenditure])].
[sujeto(['We', show, that, 'Foxa2', antagonizes, the, mammalian]), verbo([target]), complemento([of, rapamycin, '(', 'mTOR)', 'pathway,', resulting, in, increased, hepatic, lipogenesis, and, adiposity])].
[sujeto(['While', much, prior, work]), verbo([has]), complemento([focused, on, adipose, tissue, in, 'obesity,', we, discovered, a, novel, 'age-onset', obesity, phenotype, in, a, model, where, gene, deletion, occurs, only, in, the, 'liver,', underscoring, the, importance, of, the, role, hepatic, lipogenesis, plays, in, the, development, of, obesity])].
[sujeto(['We', recently]), verbo([reported]), complemento([a, novel, role, for, 'Foxa2', in, bile, acid, metabolism])].
[sujeto(['The', winged, helix, transcription, factor, 'Foxa2', is]), verbo([required]), complemento([to, prevent, intrahepatic, cholestasis, and, liver, injury, in, mice, fed, a, cholic, 'acid-enriched', diet])].
[sujeto(['Here,', we, use, functional, genomics, to, study, how, 'Foxa2']), verbo([regulates]), complemento([its, targets, in, a, cholic, 'acid-dependent', manner])].
[sujeto(['We']), verbo([found]), complemento([that, multiple, signaling, pathways, essential, for, the, hepatic, response, to, acute, liver, injury, are, impaired, in, livers, of, 'Foxa2-deficient', 'mice,', suggesting, that, the, deletion, of, 'Foxa2', in, the, hepatocyte, affects, the, liver, on, a, large, scale])].
[sujeto(['We', also, discovered, distinct, 'feed-forward', regulatory, loops, controlling, 'Foxa2-dependent']), verbo([targets]), complemento([in, a, cholic, 'acid-dependent', or, -, independent, manner])].
[sujeto(['We', show, that, 'Foxa2']), verbo([interacts]), complemento([with, different, transcription, factors, to, achieve, gene, expression, responses, appropriate, for, each, physiologic, state])].
[sujeto(['Homeostatic', regulation, of, bile, acid, metabolism, and, biliary, lipid, secretion, is, critical, to]), verbo([prevent]), complemento([enterohepatic, diseases])].
[sujeto([',', 2008, ')', show, that]), verbo([loss]), complemento([of, forkhead, box, transcription, factor, 'Foxa2', in, the, liver, leads, to, hepatic, injury, due, to, downregulation, in, the, expression, levels, of, bile, acid, transporters, and, detoxification, enzymes])].
[sujeto(['Dysregulation', of, bile, acid, homeostasis, can]), verbo([lead]), complemento([to, cholestatic, liver, disease, and, endoplasmic, reticulum, '(', 'ER)', stress])].
[sujeto(['We', show, by, global, location, analysis, '(', '\'', 'ChIP-on-chip\')', and, cell, 'type-specific', gene, ablation, that, the, winged, helix, transcription, factor, 'Foxa2', is]), verbo([required]), complemento([for, normal, bile, acid, homeostasis])].
[sujeto(['As']), verbo([suggested]), complemento([by, the, location, 'analysis,', deletion, of, 'Foxa2', in, hepatocytes, in, mice, using, the, 'Cre-lox', system, leads, to, decreased, transcription, of, genes, encoding, bile, acid, transporters, on, both, the, basolateral, and, canalicular, 'membranes,', resulting, in, intrahepatic, cholestasis])].
[sujeto(['In', 'addition,', we, show, that, expression, of, 'FOXA2', is, markedly]), verbo([decreased]), complemento([in, liver, samples, from, individuals, with, different, cholestatic, 'syndromes,', suggesting, that, reduced, 'FOXA2', abundance, could, exacerbate, the, injury])].
[sujeto(['Microsomal', epoxide, hydrolase, '(', 'mEH)', is, a, bifunctional, protein, that, plays, a, central, role, in, carcinogen, metabolism, and, is, also, able, to]), verbo([mediate]), complemento([the, 'sodium-dependent', uptake, of, bile, acids, into, hepatocytes])].
[sujeto(['Studies']), verbo([have]), complemento([identified, a, subject, '(', 'S-1)', with, extremely, elevated, serum, bile, salt, levels, in, the, absence, of, observable, hepatocellular, 'injury,', suggesting, a, defect, in, bile, acid, uptake])].
[sujeto(['Sequence', analysis, of, the, mEH, gene, '(', 'EPHX1)', revealed, a, point, mutation, at, an, upstream, 'HNF-3', site, '(', allele, 'I)', and, in, intron, 1, '(', allele, 'II),', which, resulted, in, a, significant]), verbo([decrease]), complemento([in, 'EPHX1', promoter, activity, in, transient, transfection, assays])].
[sujeto(['Gel', shift, assays, using, a, radiolabeled, oligonucleotide, from, each, region, resulted, in, specific, transcription, factor]), verbo([binding]), complemento(['patterns,', which, were, altered, in, the, presence, of, the, mutation])].
[sujeto(['These', studies, demonstrate, that, the, expression, of, mEH, is, greatly, reduced, in, a, patient, with, 'hypercholanemia,']), verbo([suggesting]), complemento([that, mEH, participates, in, 'sodium-dependent', bile, acid, uptake, in, human, liver, where, its, absence, may, contribute, to, the, etiology, of, this, disease])].
[sujeto(['We', previously, generated, a, transgenic, mouse, line, '(', 'T-77)', in, which]), verbo([increased]), complemento([hepatic, expression, of, the, hepatocyte, nuclear, 'factor-3beta', '(', 'HNF-3beta)', protein, was, used, to, assess, its, role, in, 'hepatocyte-specific', gene, transcription])].
[sujeto(['These', postnatal, liver, defects, were]), verbo([associated]), complemento([with, diminished, expression, of, hepatocyte, genes, involved, in, gluconeogenesis, and, bile, acid, transport, as, well, as, reduced, levels, of, hepatocyte, transcription, factors])].
[sujeto(['In', this, 'study,', we, show, that, mouse, tail, vein, injections, of, adenovirus]), verbo([expressing]), complemento([the, rat, 'HNF-3beta', '(', 'AdHNF3beta)', cDNA, efficiently, increased, its, levels, throughout, the, liver, lobule, and, recapitulated, the, 'T-77', transgenic, liver, phenotype, within, several, days, postinfection])].
[sujeto(['Likewise,', the, 'AdHNF3beta-infected', liver, phenotype, was]), verbo([associated]), complemento([with, reduced, hepatic, expression, of, genes, involved, in, glucose, 'homeostasis,', bile, acid, 'transport,', and, bilirubin, 'conjugation,', which, were, not, found, with, control, adenovirus, infections])].
[sujeto(['These', studies, show, that, 'adenovirus-mediated', gene, transfer, is, an, effective, method, for, rapid, hepatic]), verbo([increases]), complemento([in, transcription, factor, levels, to, determine, in, vivo, target, genes])].
[sujeto(['In', 'contrast,', 'AdHNF3alpha-infected', liver, displayed, only, a, transient, reduction, in, hepatic, glycogen, levels, and, was]), verbo([associated]), complemento([with, less, severe, decreases, in, hepatic, expression, of, gluconeogenic, and, bilirubin, metabolism, genes])].
[sujeto(['Consistent', with, these, 'findings,', only, 'T-77', transgenic, and, 'AdHNF3beta-infected', liver, exhibited, diminished, hepatic, expression, of, the, 'HNF-6', transcription, 'factor,']), verbo([suggesting]), complemento([that, reduced, 'HNF-6', levels, contribute, to, diminished, 'HNF-3beta-specific', transcriptional, activity])].
[sujeto(['The', winged, helix, transcription, 'factor,', hepatocyte]), verbo([nuclear]), complemento(['factor-3beta', '(', 'HNF-3beta),', mediates, the, 'hepatocyte-specific', transcription, of, numerous, genes, important, for, liver, function])].
[sujeto(['However,', the, in, vivo, role, of, 'HNF-3beta', in]), verbo([regulating]), complemento([these, genes, remains, unknown, because, homozygous, null, 'HNF3beta', mouse, embryos, die, in, utero, prior, to, liver, formation])].
[sujeto(['In', order, to, examine, the, regulatory, function, of, 'HNF-3beta,', we, created, transgenic, mice, in, which, the, -, 3, -, kb, transthyretin, promoter, functions, to]), verbo([increase]), complemento([hepatocyte, expression, of, the, rat, 'HNF-3beta', protein])].
[sujeto(['The', retarded, growth, phenotype, is, likely, due, to, a, 20, -, fold]), verbo([increase]), complemento([in, hepatic, expression, of, 'insulin-like', growth, factor, binding, protein, 1, '(', 'IGFBP-1),', which, results, in, elevated, levels, in, serum, of, 'IGFBP-1', and, limits, the, biological, availability, of, 'IGFs', required, for, postnatal, growth])].
[sujeto(['The', defects, in, glycogen, storage, and, serum, bile, acids, coincide, with, diminished, postnatal, expression, of, hepatocyte, genes]), verbo([involved]), complemento([in, gluconeogenesis, '(', phosphoenolpyruvate, carboxykinase, and, glycogen, 'synthase)', and, sinusoidal, bile, acid, uptake, '(', 'Ntcp),', respectively])].
[sujeto(['These', transgenic, studies, represent, the, first, in, vivo, demonstration, that, the, 'HNF-3beta', transcriptional, network]), verbo([regulates]), complemento([expression, of, 'hepatocyte-specific', genes, required, for, bile, acid, and, glucose, 'homeostasis,', as, well, as, postnatal, growth])].
[sujeto(['Transcription', factors, forkhead, box, '(', 'Fox)O1', and, pancreatic, and, duodenal, 'homeobox-1', '(', 'PDX-1)', are]), verbo([involved]), complemento([in, dexamethasone, '(', 'DEX)-induced', dysfunction, in, pancreatic, 'β-cells'])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, 'DEX', markedly, increased, 'FoxO1', mRNA, and, protein, 'expression,', whereas, it, decreased, 'PDX-1', mRNA, and, protein, expression, in, a, 'dose-', and, 'time-dependent', manner])].
[sujeto(['Further', study, showed, that, 'FoxA2', was]), verbo([involved]), complemento([in, regulation, of, 'FoxO1', and, 'PDX-1', expression, in, 'DEX-induced', pancreatic, 'β-cells', dysfunction])].
[sujeto(['Interestingly,', we, demonstrated, for, the, first, time, that, 'FoxA2', could]), verbo([bind]), complemento([to, the, 'FoxO1', gene, promoter, and, positively, regulate, 'FoxO1', expression])].
[sujeto(['Moreover,', we]), verbo([found]), complemento([that, 'DEX', increased, the, activity, of, 'FoxA2', binding, to, the, 'FoxO1', promoter, but, decreased, the, activity, of, 'FoxA2', binding, to, the, 'PDX-1', promoter, of, 'RINm5F', cells])].
[sujeto(['Knockdown', of, 'FoxA2', by, 'RNA', interference]), verbo([inhibited]), complemento(['FoxO1', expression, and, restored, 'PDX-1', expression, in, pancreatic, 'β-cells', treated, with, 'DEX'])].
[sujeto(['Together,', the, results, of, the, present, study, demonstrated, that, 'FoxA2', could, dynamically]), verbo([regulate]), complemento(['FoxO1', and, 'PDX-1', expression, in, pancreatic, 'β-cells', treated, with, 'DEX,', which, provides, new, important, information, on, the, transcriptional, regulation, of, 'FoxO1', and, 'PDX-1', in, 'DEX-induced', pancreatic, 'β-cells'])].
[sujeto(['Insulin', can]), verbo([inhibit]), complemento([the, stimulatory, effect, of, glucocorticoid, hormones, on, the, transcription, of, genes, coding, for, enzymes, involved, in, glucose, metabolism])].
[sujeto(['We']), verbo([reported]), complemento([earlier, that, insulin, inhibits, the, 'glucocorticoid-stimulated', transcription, of, the, gene, coding, for, liver, 6, -, 'phosphofructo-2-kinase', '(', 'PFK-2)'])].
[sujeto(['To', elucidate, the, mechanism, of, these, hormonal, 'effects,', we]), verbo([have]), complemento([studied, the, regulatory, regions, of, the, 'PFK-2', gene, in, transfection, experiments])].
[sujeto(['We']), verbo([found]), complemento([that, both, glucocorticoids, and, insulin, act, via, the, glucocorticoid, response, unit, '(', 'GRU)', located, in, the, first, intron])].
[sujeto(['Footprinting', experiments, showed, that, the, 'GRU']), verbo([binds]), complemento([not, only, the, glucocorticoid, receptor, '(', 'GR),', but, also, ubiquitous, '[', nuclear, factor, 'I', '(', 'NF-I)]', and, 'liver-enriched', '[', hepatocyte, nuclear, factor, '(', 'HNF)-3,', 'HNF-6,', 'CAAT/enhancer', binding, protein, '(', 'C/EBP)]', transcription, factors])].
[sujeto(['Site-directed', mutational, analysis, of, the, 'GRU', revealed, that, these, factors]), verbo([modulate]), complemento([glucocorticoid, action, but, that, none, of, them, seems, to, be, individually, involved, in, the, inhibitory, effect, of, insulin])].
[sujeto(['We', did, not]), verbo([find]), complemento([an, insulin, response, element, in, the, 'GRU,', but, we, showed, that, insulin, targets, the, 'GR'])].
[sujeto(['Insulin-induced', inhibition, of, the, glucocorticoid, stimulation]), verbo([required]), complemento([the, 'ligand-binding', domain, of, the, 'GR'])].
[sujeto(['Finally,', the, 'insulin-signaling', cascade]), verbo([involved]), complemento([was, independent, of, the, 'phosphatidylinositol-3-kinase', and, 'mitogen-activated', protein, kinase, pathways])].
[sujeto(['Together,', these, results]), verbo([suggest]), complemento([that, insulin, acts, on, the, 'PFK-2', gene, via, another, pathway, and, targets, either, the, 'GR', in, its, 'ligand-binding', domain, or, a, cofactor, interacting, with, this, domain])].
[sujeto(['The', rate, of, transcription, of, the, hepatic, phosphoenolpyruvate, carboxykinase, '(', 'PEPCK)', and, 'insulin-like', growth, 'factor-binding', protein, 1, '(', 'IGFBP-1)', genes, is]), verbo([stimulated]), complemento([by, glucocorticoids, and, inhibited, by, insulin])].
[sujeto(['In', both, 'cases,', the, effect, of, insulin, is, 'dominant,', since, it]), verbo([suppresses]), complemento([both, basal, and, 'glucocorticoid-stimulated', 'PEPCK', or, 'IGFBP-1', gene, transcription])].
[sujeto(['Analyses', of, both, promoters, by, transfection, of, 'PEPCK', or, 'IGFBP-1-chloramphenicol', acetyltransferase, fusion, genes, into, rat, hepatoma, cells]), verbo([has]), complemento([led, to, the, identification, of, insulin, response, sequences, '(', 'IRSs)', in, both, genes])].
[sujeto(['The', core, 'IRS,', 'T(G/A)TTTTG,', is, the, same, in, both, 'genes,', but, the, 'PEPCK', promoter]), verbo([has]), complemento([a, single, copy, of, this, element, whereas, the, 'IGFBP-1', promoter, has, two, copies, arranged, as, an, inverted, palindrome])].
[sujeto(['The', 'IGFBP-1', 'IRS', and, 'PEPCK', 'IRS', both]), verbo([bind]), complemento([the, alpha, and, beta, forms, of, hepatic, nuclear, factor, 3, '(', 'HNF-3),', although, the, latter, does, so, with, a, 'sixfold-lower', relative, affinity])].
[sujeto(['Both', the, 'PEPCK', and, the, 'IGFBP-1', 'IRSs', also, function, as, accessory, factor]), verbo([binding]), complemento([sites, required, for, the, full, induction, of, gene, transcription, by, glucocorticoids])].
[sujeto(['A', combination, of, transient, transfection, and, 'DNA']), verbo([binding]), complemento([studies, suggests, that, 'HNF-3', is, the, accessory, factor, that, supports, 'glucocorticoid-induced', gene, transcription])].
[sujeto(['In', both, 'genes,', the, 'HNF-3']), verbo([binding]), complemento([site, overlaps, the, 'IRS', core, 'motif(s)'])].
[sujeto(['A', model, in, which, insulin, is, postulated, to]), verbo([mediate]), complemento([its, negative, effect, on, 'glucocorticoid-induced', 'PEPCK', and, 'IGFBP-1', gene, transcription, indirectly, by, inhibiting, 'HNF-3', action, is, proposed])].
[sujeto(['Using', conditional, gene, ablation, during, a, later, phase, of, liver, 'development,', we, show, here, that, deletion, of, both, 'Foxa1', and, 'Foxa2', '(', 'Foxa1/2)', in, the, embryonic, liver]), verbo([caused]), complemento([hyperplasia, of, the, biliary, tree])].
[sujeto(['The', glucocorticoid, receptor, is, a, negative, regulator, of, 'IL-6', 'transcription;', in, the, absence, of, 'Foxa1/2,', the, glucocorticoid, receptor, failed, to]), verbo([bind]), complemento([to, the, 'IL-6', 'promoter,', causing, enhanced, 'IL-6', expression])].
[sujeto(['Thus,', after, liver, 'specification,', 'Foxa1/2', are]), verbo([required]), complemento([for, normal, bile, duct, development, through, prevention, of, excess, cholangiocyte, proliferation])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, 'Foxa1/2', function, as, terminators, of, bile, duct, expansion, in, the, adult, liver, through, inhibition, of, 'IL-6', expression])].
[sujeto(['We', show, here, 'that,', in, 'HepG2', hepatoma, 'cells,', 'EGF', '(', epidermal, growth, 'factor)']), verbo([inhibits]), complemento([basal, mouse, 'G6Pase', fusion, gene, transcription])].
[sujeto(['Several', studies]), verbo([have]), complemento([shown, that, insulin, represses, basal, mouse, 'G6Pase', fusion, gene, transcription, through, 'FOXO1', '(', forkhead, box, 'O1),', but, 'Stoffel', and, colleagues, have, recently, suggested, that, insulin, can, also, regulate, gene, transcription, through, 'FOXA2', '(', forkhead, box, 'A2)', '[', 'Wolfrum,', 'Asilmaz,', 'Luca,', 'Friedman', and, 'Stoffel', '(', 2003, ')', 'Proc'])].
[sujeto(['A', combined, 'GR', '(', glucocorticoid, 'receptor)-FOXA2']), verbo([binding]), complemento([site, is, located, between, -, 185, and, -, 174, in, the, mouse, 'G6Pase', promoter, overlapping, two, 'FOXO1', binding, sites, located, between, '(', -, 188, and, -, 182, ')', and, '(', -, 174, and, -, 168, ')'])].
[sujeto(['Selective', mutation, of, the, 'FOXO1']), verbo([binding]), complemento([sites, reduced, the, effect, of, 'insulin,', whereas, mutation, of, the, 'GR/FOXA2', binding, site, had, no, effect, on, the, insulin, response])].
[sujeto(['In', 'contrast,', selective, mutation, of, the, 'FOXO1', and, 'GR/FOXA2']), verbo([binding]), complemento([sites, both, reduced, the, effect, of, 'EGF'])].
[sujeto(['The', effect, of, these, mutations, was, 'additive,', since, the, combined, mutation, of, both, 'FOXO1', and, 'GR/FOXA2']), verbo([binding]), complemento([sites, reduced, the, effect, of, 'EGF', to, a, greater, extent, than, the, individual, mutations])].
[sujeto(['These', results]), verbo([suggest]), complemento(['that,', in, 'HepG2', 'cells,', 'GR', 'and/or', 'FOXA2', are, required, for, the, inhibition, of, basal, 'G6Pase', gene, transcription, by, 'EGF', but, not, insulin])].
[sujeto(['EGF', also]), verbo([inhibits]), complemento([hepatic, 'G6Pase', gene, expression, in, 'vivo,', but, in, cultured, hepatocytes, 'EGF', has, the, opposite, effect, of, stimulating, 'expression,', an, observation, that, may, be, explained, by, a, switch, in, 'ErbB', receptor, 'sub-type', expression, following, hepatocyte, isolation])].
[sujeto(['At', the, transcriptional, 'level,', maturation, is, controlled, by, the, actions, of, a, group, of, transcription, factors]), verbo([mediating]), complemento([gene, expression, in, the, lung])].
[sujeto(['A', network, of, transcription, factors]), verbo([regulates]), complemento([gene, expression, in, the, respiratory, 'epithelium,', which, then, influences, cell, maturation, throughout, the, lung])].
[sujeto(['Glucocorticoids', '(', via, the, glucocorticoid, 'receptor),']), verbo([acting]), complemento([primarily, in, the, pulmonary, 'mesenchyme,', influence, maturation, in, the, respiratory, epithelium])].
[sujeto(['Elucidation', of, the, intersecting, pathways, controlling, perinatal, lung, function, may]), verbo([provide]), complemento([opportunities, to, induce, pulmonary, maturation, in, preterm, infants, at, risk, for, respiratory, distress, syndrome, before, 'birth,', and, will, help, identify, genes, and, processes, important, for, various, aspects, of, lung, function])].
[sujeto(['Activation', of, the, genes, encoding, gluconeogenic, enzymes, is]), verbo([mediated]), complemento([by, 'hormone-responsive', transcription, factors, such, as, the, cyclic, 'AMP', response, element, binding, protein, '(', 'CREB)', and, the, glucocorticoid, receptor, '(', 'GR)'])].
[sujeto(['Here', we, show, using, 'cell-type-specific', gene, ablation, that, the, winged, helix, transcription, factor, 'Foxa2', is]), verbo([required]), complemento([for, activation, of, the, hepatic, gluconeogenic, program, during, fasting])].
[sujeto(['Specifically,', 'Foxa2']), verbo([promotes]), complemento([gene, activation, both, by, cyclic, 'AMP,', the, second, messenger, for, 'glucagon,', and, glucocorticoids])].
[sujeto(['Foxa2']), verbo([mediates]), complemento([these, effects, by, enabling, recruitment, of, 'CREB', and, 'GR', to, their, respective, target, sites, in, chromatin])].
[sujeto(['We', conclude, that, 'Foxa2', is]), verbo([required]), complemento([for, execution, of, the, hepatic, gluconeogenic, program, by, integrating, the, transcriptional, response, of, the, hepatocyte, to, hormonal, stimulation])].
[sujeto(['They', significantly]), verbo([suppress]), complemento([glucocorticoid, induction, of, tyrosine, aminotransferase, '(', 'TAT)', in, the, liver, of, sensitive, animals, and, have, minor, effect, on, the, induction, of, this, enzyme, in, the, liver, of, resistant, animals, '(', 3, '\'', -, 'MeDAB-treated', mice, and, 'OAT-treated', 'rats)'])].
[sujeto(['The', inhibitory, effect, of, these, carcinogens, is, realized, at, the, level, of, gene, transcription, '(']), verbo([decreased]), complemento([accumulation, of, 'TAT', 'mRNA)'])].
[sujeto(['This', effect, is]), verbo([mediated]), complemento([via, reduction, of, 'DNA-binding', activity, of, transcription, factor, 'HNF3', '(', without, decrease, of, its, 'content)', without, any, involvement, of, the, glucocorticoid, receptor])].
[sujeto(['It', was, shown, that, carcinogens, influence, 'DNA-binding', activity, of, 'HNF3', via, an, unknown]), verbo([nuclear]), complemento([factor])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento(['factor-3', '(', 'HNF-3)', belongs, to, a, large, family, of, forkhead, transcription, factors, and, is, made, up, of, three, members, '(', 'HNF-3alpha,', -, 3, beta, and, -, 3, 'gamma)'])].
[sujeto(['It']), verbo([has]), complemento([been, shown, that, 'HNF-3', regulates, a, number, of, metabolically, important, genes])].
[sujeto(['However,', the, mechanisms, underlying, this, regulation, of, 'HNF-3', activity, by, hormones, and, nutrition]), verbo([have]), complemento([not, yet, been, well, elucidated])].
[sujeto(['The', 'protein-free', diet, and, gluten, diet]), verbo([caused]), complemento([a, 3])].
[sujeto([7, -, fold]), verbo([increase]), complemento([in, 'HNF-3g', mRNA, in, the, liver, and, did, not, affect, the, mRNA, level, of, either, 'HNF-3alpha', or, 'HNF-3beta'])].
[sujeto(['Daily', administration, of, dexamethasone]), verbo([caused]), complemento([the, mRNA, levels, of, 'HNF-3alpha', and, 'HNF-3beta', to, increase, '(', 2.3, -, and, 1.4, -, 'fold,', 'respectively),', but, had, no, effect, on, the, 'HNF-3gamma', mRNA, level])].
[sujeto(['Insulin', replacement, in, the, diabetic, rats]), verbo([decreased]), complemento([both, mRNA, levels, in, a, 'dose-dependent', manner])].
[sujeto(['These', results, show, that, the, genes, of, the, three, members, of, the, 'HNF-3', family]), verbo([respond]), complemento([differently, to, hormonal, and, nutritional, factors, suggesting, that, the, activities, of, 'HNF-3', members, are, 'regulated,', at, least, in, 'part,', by, the, levels, of, their, gene, expression])].
[sujeto(['Hypersensitivity', to, acetylcholinesterase, inhibitors, '(', 'anti-AChEs)']), verbo([causes]), complemento([severe, nervous, system, symptoms, under, low, dose, exposure])].
[sujeto(['Two', contiguous, 'mutations,', a, 'T--&gt;A', 'substitution,', disrupting, a, putative, glucocorticoid, response, 'element,', and, a, 4, -, bp, 'deletion,', abolishing, one, of, two, adjacent, 'HNF3']), verbo([binding]), complemento(['sites,', were, identified, 17, kb, upstream, of, the, transcription, start, site])].
[sujeto(['Electromobility', shift, 'assays,', transfection, studies, and, measurements, of, 'AChE', levels, in, immortalized, lymphocytes, as, well, as, in, peripheral, blood, from, both, carriers, and, 'non-carriers,', revealed, functional, relevance, for, this, mutation, both, in, vitro, and, in, vivo, and, showed, it, to]), verbo([increase]), complemento(['AChE', 'expression,', probably, by, alleviating, competition, between, the, two, hepatocyte, nuclear, factor, 3, binding, sites])].
[sujeto(['Moreover,', 'AChE-overexpressing', transgenic, 'mice,', unlike, normal, 'FVB/N', 'mice,', displayed, 'anti-AChE', hypersensitivity, and, failed, to, transcriptionally]), verbo([induce]), complemento(['AChE', production, following, exposure, to, 'anti-AChEs'])].
[sujeto(['Glucocorticoids']), verbo([stimulate]), complemento([gluconeogenesis, by, increasing, the, rate, of, transcription, of, genes, that, encode, gluconeogenic, enzymes, such, as, phosphoenolpyruvate, carboxykinase, '(', 'PEPCK)', and, 'glucose-6-phosphatase'])].
[sujeto(['Previous', studies]), verbo([have]), complemento([shown, that, hepatic, nuclear, factor, 3, '(', 'HNF3)', is, required, as, an, accessory, factor, for, several, 'glucocorticoid-stimulated', 'genes,', including, 'PEPCK'])].
[sujeto(['These', results]), verbo([provide]), complemento([direct, evidence, that, members, of, the, 'HNF3', family, are, required, for, proper, regulation, of, hepatic, gluconeogenesis])].
[sujeto(['Expression', of, the, rat, cytosolic, aspartate, aminotransferase, gene, is]), verbo([stimulated]), complemento([by, glucocorticoids, and, repressed, by, insulin, in, the, liver])].
[sujeto(['The', regulation, by, insulin, and, part, of, the, glucocorticoid, effect, are]), verbo([mediated]), complemento([by, a, distal, region, in, the, promoter])].
[sujeto(['A', 142, bp, fragment, '(', -, 1844, to, -, 1702, ')']), verbo([confers]), complemento([hormonal, sensitivity, to, the, heterologous, thymidine, kinase, promoter, in, 'transient-transfection', assays, in, 'H4IIEC3', hepatoma, cells])].
[sujeto(['Footprinting', and, 'gel-shift', assays, showed, that, several]), verbo([nuclear]), complemento([proteins, bind, to, this, region, at, conserved, 'CCAAT-enhancer', binding, protein, '(', 'C/EBP),', activator, protein, '(', 'AP-1)', and, 'E-box', sequences])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento(['factor-3alpha', '(', 'HNF-3)alpha', and, beta, bind, to, sequences, upstream, of, a, 'glucocorticoid-responsive', element, '(', 'GRE)', 'half-site', as, demonstrated, by, supershift, experiments])].
[sujeto(['Nuclear', factor, 'I', '(', 'NFI)-like', proteins]), verbo([bind]), complemento([downstream, of, the, 'GRE', 'half-site'])].
[sujeto(['The', effect, of, insulin, was, not]), verbo([prevented]), complemento([by, any, single, mutation, in, the, 'IRE-like', sites])].
[sujeto(['However,', mutation, of, two, 'IRE', sites, '(', namely, 'IREc', and, 'd)']), verbo([prevented]), complemento([the, insulin, effect, although, only, marginally, affecting, the, glucocorticoid, effect])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, the, effect, of, insulin, is, due, to, a, complex, interplay, of, factors, requiring, the, synergistic, contribution, of, at, least, two, sites, and, underline, the, contribution, of, 'HNF-3', and, 'NFI-like', proteins])].
[sujeto(['Complete', induction, of, hepatic, phosphoenolpyruvate, carboxykinase, '(', 'PEPCK)', gene, transcription, by, glucocorticoids]), verbo([requires]), complemento([a, complex, glucocorticoid, response, unit, '(', 'GRU)'])].
[sujeto(['The', 'GRU', is, comprised, of, two, glucocorticoid, receptor, '(', 'GR)-binding', sites, '(', 'GR1', and, 'GR2)', and, four, accessory, 'factor-binding', sites, '[', 'AF1,', 'AF2,', 'AF3,', and, cAMP, response, element, '(', 'CRE)]', that]), verbo([bind]), complemento([distinct, transcription, factors])].
[sujeto(['Hepatic']), verbo([nuclear]), complemento([factor, 4, '(', 'HNF4)', and, chicken, ovalbumin, upstream, promoter, transcription, factor, '(', 'COUP-TF)', bind, to, the, 'AF1', element, and, account, for, 'AF1', activity])].
[sujeto(['Members', of, the, hepatic]), verbo([nuclear]), complemento([factor, 3, '(', 'HNF3)', family, bind, to, the, 'AF2', element, and, provide, 'AF2', activity])].
[sujeto(['We', also, identified, the, domains, of, 'HNF4', and, 'HNF3', beta, that, are]), verbo([required]), complemento([for, the, 'AF1', and, 'AF2', 'activities,', respectively])].
[sujeto(['The', 'carboxy-terminal', transactivation, domain, of, 'HNF4', '(', amino, acids, 128, -, 374, ')']), verbo([confers]), complemento([most, of, the, 'AF1', 'activity,', while, the, carboxyterminal, transactivation, domain, of, 'HNF3', beta, '(', amino, acids, 361, -, 458, ')', mediates, 'AF2', activity])].
[sujeto(['These', domains, of, 'HNF4', and, 'HNF3', beta, appear, to]), verbo([have]), complemento([distinct, roles, in, the, response, to, 'glucocorticoids,', as, there, are, unique, structural, requirements, for, 'each,', as, judged, by, the, failure, of, most, other, classes, of, transactivation, domains, to, serve, as, accessory, factors])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, regulation, of, the, 'PEPCK', gene, by, glucocorticoids, requires, specific, interactions, between, 'GR,', accessory, 'factors,', and, 'coactivators,', and, that, the, transactivation, domains, of, 'AF1', and, 'AF2', are, of, fundamental, importance, in, the, assembly, of, this, multiprotein, complex])].
[sujeto(['A', single, 'far-upstream', enhancer, is, sufficient, to]), verbo([confer]), complemento(['hepatocyte-specific,', 'glucocorticoid-', and, cyclic, 'AMP-inducible', periportal, expression, to, the, carbamoylphosphate, synthetase, 'I', '(', 'CPS)', gene])].
[sujeto(['To', identify, the, mechanism, of, 'hormone-dependent', 'activation,', the, composition, and, function, of, the, enhancer]), verbo([have]), complemento([been, analyzed])].
[sujeto(['The', in, vivo, relevance, of, the, transcription, factors]), verbo([interacting]), complemento([with, the, enhancer, in, the, regulation, of, 'CPS', expression, in, the, liver, was, assessed, by, the, analysis, of, knockout, mice])].
[sujeto(['A', strong, reduction, of, 'CPS', mRNA, levels, was, observed, in, glucocorticoid, 'receptor-', and, 'C/EBPalpha-deficient', 'mice,', whereas, the, 'CPS', mRNA, was, normally]), verbo([expressed]), complemento([in, 'C/EBPbeta', knockout, mice, and, in, 'HNF3alpha', and, -, gamma, 'double-knockout', mice])].
[sujeto(['Here', we, characterize, a, composite, enhancer, which, directs, 'STF-1', expression, to, pancreatic, islet, cells, via, two, functional, elements, that]), verbo([recognize]), complemento([the, nuclear, factors, 'HNF-3beta', and, 'BETA-2'])].
[sujeto(['In', keeping, with, their, inhibitory, effects, on, islet, cell, 'maturation,', glucocorticoids, were]), verbo([found]), complemento([to, repress, 'STF-1', gene, expression, by, interfering, with, 'HNF-3beta', activity, on, the, 'islet-specific', enhancer])].
[sujeto(['Overexpression', of, 'HNF-3beta']), verbo([suppressed]), complemento([glucocorticoid, 'receptor-mediated', inhibition, of, the, 'STF-1', 'gene,', and, our, results, suggest, that, the, expansion, of, pancreatic, islet, precursor, cells, during, development, may, be, restricted, by, hormonal, cues, which, regulate, 'STF-1', gene, expression])].
[sujeto(['Transcription', of, the, hepatic, phosphoenolpyruvate, carboxykinase, gene, is]), verbo([stimulated]), complemento([by, glucocorticoids, and, inhibited, by, insulin])].
[sujeto(['The', glucocorticoid, response, is]), verbo([mediated]), complemento([by, a, complex, glucocorticoid, response, unit, that, consists, of, two, glucocorticoid, receptor, '(', 'GR)-binding', sites, '(', 'GR1', and, 'GR2)', and, two, accessory, 'factor-binding', sites, '(', 'AF1', and, 'AF2)'])].
[sujeto(['The', complete, unit, is]), verbo([required]), complemento([for, the, full, glucocorticoid, response])].
[sujeto(['The', dominant, insulin, effect, is]), verbo([mediated]), complemento([in, part, through, an, insulin, response, sequence, that, is, coincident, with, the, 'AF2', element])].
[sujeto(['Members', of, the, hepatic]), verbo([nuclear]), complemento([factor, 3, '(', 'HNF3)', and, 'CCAAT', enhancer, binding, protein, '(', 'C/EBP)', families, bind, to, the, 'AF2', 'element;', 'however,', there, is, no, correlation, between, binding, of, these, factors, and, the, ability, of, the, 'AF2', element, to, mediate, an, insulin, response])].
[sujeto(['We', show, here, that]), verbo([binding]), complemento([of, 'HNF3', does, correlate, with, the, stimulation, of, the, glucocorticoid, response, by, the, 'AF2', element, and, that, 'C/EBP', is, apparently, not, involved, in, this, effect])].
[sujeto(['This', requirement, for, 'HNF3', is, quite, specific, since, the, substitution, of, elements, known, to]), verbo([enhance]), complemento([the, action, of, the, 'GR', in, other, promoters, fails, to, recapitulate, 'AF2', accessory, factor, activity])].
[sujeto(['Based', on, current, and, previous, 'observations,', the, glucocorticoid, response, unit, consists, of, four, 'DNA', elements, that]), verbo([bind]), complemento([four, different, proteins])].
[sujeto(['These', 'are:', 'AF1', '(', hepatic]), verbo([nuclear]), complemento([factor, 4, /, chicken, ovalbumin, upstream, promoter, transcription, 'factor),', 'AF2', '(', 'HNF3),', 'GR1', '(', 'GR),', and, 'GR2', '(', 'GR)'])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 3, '(', 'HNF3)', recognizes, two, apparently, distinct, classes, of, sequence])].
[sujeto(['However,', a, detailed, mutational, analysis, of, a, representative]), verbo([binding]), complemento([site, of, each, class, reveals, that, these, sequences, display, common, features])].
[sujeto(['Particularly,', our, study]), verbo([reveals]), complemento([that, the, 'DNA', site, used, for, this, structural, analysis, is, too, short, to, account, for, all, 'HNF3-DNA', interactions])].
[sujeto(['The', better, knowledge, of, the, sequence, determinant]), verbo([recognized]), complemento([by, 'HNF3', has, allowed, us, to, analyze, its, function, in, the, glucocorticoid, response, of, the, rat, tyrosine, aminotransferase, '(', 'TAT)', gene])].
[sujeto(['This', response, is]), verbo([mediated]), complemento([through, a, complex, array, of, neighboring, and, overlapping, transcription, factor, binding, sites])].
[sujeto(['Furthermore,', 'HNF3', beta, overexpression, results, in, a, stimulation, of, the, glucocorticoid, response, that, is, dependent, on, the, integrity, of, its]), verbo([binding]), complemento([sites])].
[sujeto(['We', also, show, that, the, relative, level, of, 'HNF3', determines, the, extent, of, the, contribution, of, one, of, the, glucocorticoid, receptor]), verbo([binding]), complemento([sites])].
[sujeto(['Glucocorticoids']), verbo([stimulate]), complemento([and, insulin, inhibits, hepatic, production, of, 'IGFBP-1', at, the, level, of, gene, transcription])].
[sujeto(['We']), verbo([have]), complemento([reported, that, both, the, 'IGFBP-1', and, 'PEPCK', 'IRSs', bind, hepatocyte, nuclear, 'factor-3', '(', 'HNF-3)', proteins, '[', 1, ']'])].
[sujeto(['We', now]), verbo([report]), complemento([that, 'IRSs', from, the, 'IGFBP-1', and, 'PEPCK,', as, well, as, an, 'IRS', which, also, binds, 'HNF-3', in, the, rat, tyrosine, aminotransferase, '(', 'TAT)', 'gene,', also, interact, with, another, 'DNA/protein', complex, in, gel, shift, studies])].
[sujeto(['Of', 'note,', a, 250, -, fold, excess, of, an, oligo, containing, a, 'C/EBP']), verbo([binding]), complemento([site, '(', but, not, other, 'AT-rich', 'sequences)', inhibits, the, formation, of, this, complex, in, gel, shift, assays])].
[sujeto(['Similarly,', preincubation, with, 'CHOP,', a, truncated, member, of, the, 'C/EBP', family, which, contains, a, 'beta-leucine', zipper, 'domain,', does, not]), verbo([prevent]), complemento([or, alter, the, mobility, of, this, novel, 'DNA/protein', 'complex,', indicating, that, components, of, this, complex, do, not, form, heterodimers, with, 'beta-ZIP', proteins])].
[sujeto(['We', conclude, that, 'HNF-3', proteins, and, this, novel, 'C/EBP-related', 'DNA/protein', complex, may, play, an, important, role, in]), verbo([mediating]), complemento([interactions, between, glucocorticoids, and, insulin, in, the, regulation, of, 'IGFBP-1', and, perhaps, multiple, hepatic, genes])].
[sujeto(['An', insulin, response, element, '(', 'IRE)']), verbo([has]), complemento([been, identified, approximately, 100, base, pairs, '(', 'bp)', 5, '\'', to, the, transcription, start, site, of, the, human, 'insulin-like', growth, factor, binding, 'protein-1', '(', 'hIGFBP-1)', gene])].
[sujeto(['This', cis, element, appears, crucial, to, the, multihormonal, regulation, of, 'hIGFBP-1', expression, in, 'liver,', since, '(', 'i)', an, intact, 'IRE', is]), verbo([required]), complemento([for, maximal, stimulation, of, 'hIGFBP-1', promoter, activity, by, 'dexamethasone,', and, '(', 'ii)', the, 'IRE', confers, insulin, inhibition, of, both, basal, and, 'dexamethasone-stimulated', 'hIGFBP-1', promoter, activity])].
[sujeto(['Further', progress, in, understanding, how, the, 'IRE']), verbo([confers]), complemento([insulin, and, glucocorticoid, effects, requires, identification, of, transcription, factors, confering, effects, of, these, hormones])].
[sujeto(['D-site']), verbo([binding]), complemento([protein, '(', 'DBP),', and, members, of, the, hepatic, nuclear, factor, 3, '(', 'HNF', 3, ')', and, high, mobility, group, 'I/Y', '(', 'HMG', 'I/Y)', protein, 'families,', each, known, to, bind, 'DNA', elements, similar, in, sequence, to, the, 'IRE,', were, tested, for, 'IRE', binding])].
[sujeto(['Additional', studies, are]), verbo([required]), complemento([to, establish, whether, binding, of, any, of, these, proteins, to, the, 'IRE', is, important, to, the, regulation, of, 'hIGFBP-1', expression, by, insulin, 'and/or', glucocorticoids])].
[sujeto(['We', aimed, to, investigate, whether, vascular, endothelial, growth, factor, '(', 'VEGF)', influences, apolipoprotein, 'M', '(', 'ApoM)', expression, and, 'pre-β-high-density', lipoprotin, '(', 'HDL)', 'formation,', and, whether, forkhead, box, 'A2', '(', 'Foxa2)', and, 'Nur77', are]), verbo([involved]), complemento([in, this, process])].
[sujeto(['We', analyzed, the, serum, 'VEGF', concentrations, of, 264, adults, who, underwent, a, medical, checkup, and]), verbo([found]), complemento([that, 'VEGF', concentration, was, positively, correlated, with, serum, 'triglyceride,', total, 'cholesterol,', 'LDL', cholesterol, '(', 'LDL-C),', 'very-low-density', lipoprotein, cholesterol, '(', 'VLDL-C),', and, 'ApoB', 'concentrations,', but, was, negatively, correlated, with, serum, 'high-density', lipoprotein, cholesterol, '(', 'HDL-C)', and, 'ApoM', concentrations])].
[sujeto(['At', the, same, 'time,', expression, of, 'Foxa2', was, also, 'inhibited,', whereas, expression, of, 'Nur77', was]), verbo([increased]), complemento([by, treatment, with, 'VEGF'])].
[sujeto(['In', 'addition,', siRNA, knockdown, of, 'Nur77', significantly, compensated, for, the, inhibitory, effect, of, 'VEGF', on, 'Foxa2', 'expression,', whereas, the, 'Nur77', agonist, cytosporone, 'B']), verbo([led]), complemento([to, the, downregulation, of, 'Foxa2', expression, more, significantly, than, 'VEGF'])].
[sujeto(['Moreover,', overexpression, of, a, 'Nur77', transgene, in, 'C57BL/6', mice, resulted, in]), verbo([decreased]), complemento([serum, 'ApoM', and, 'pre-β-HDL', 'levels,', whereas, 'si-Nur77-treated', mice, displayed, upregulated, serum, 'ApoM', and, 'pre-β-HDL', levels])].
[sujeto(['These', results]), verbo([provide]), complemento([evidence, that, 'VEGF', may, first, downregulate, expression, of, 'Foxa2', by, enhancing, 'Nur77', activity, and, then, decrease, expression, of, 'ApoM', and, 'pre-β-HDL', formation])].
[sujeto(['Nonalcoholic', steatohepatitis, '(', 'NASH)', is, one, of, the, most, frequent]), verbo([causes]), complemento([of, abnormal, liver, dysfunction, associated, with, synthesis, and, oxidation, of, fatty, acids])].
[sujeto(['As', a, result, of, the]), verbo([decrease]), complemento([of, 'AdipoR1/R2', 'expression,', the, messenger, 'RNA', expression, levels, of, genes, located, downstream, of, 'AdipoR1/R2,', adenosine, 'monophosphate-activated', protein, kinase, 'α1/α2,', which, inhibits, fatty, acid, 'synthesis,', and, peroxisome, 'proliferator-activated', receptor, 'α,', which, activates, fatty, acid, 'oxidation,', also, decreased])].
[sujeto(['Expression', level, of, sterol, regulatory, element]), verbo([binding]), complemento(['protein-1c', was, found, to, be, 'elevated,', suggesting, the, 'up-regulation', of, 'IRS-1,', and, resulted, in, increased, fatty, acid, synthesis])].
[sujeto(['Furthermore,']), verbo([increase]), complemento([of, forkhead, box, protein, 'A2', expression, was, 'observed,', which, might, be, associated, with, the, 'down-regulation', of, 'IRS-2,', facilitating, fatty, acid, oxidation])].
[sujeto(['Taken', 'together,']), verbo([increased]), complemento([synthesis, and, oxidation, of, fatty, acids, by, 'up-', or, 'down-regulation', of, 'AdipoR', or, 'IRS', may, contribute, to, the, progression, of, 'NASH'])].
[sujeto(['The', lipophilic, statin, lovastatin]), verbo([decreases]), complemento([cholesterol, synthesis, and, is, a, safe, and, effective, treatment, for, the, prevention, of, cardiovascular, diseases])].
[sujeto(['We']), verbo([found]), complemento([that, lovastatin, treatment, delayed, 'NANOG', downregulation, during, ectodermal, and, endodermal, differentiation])].
[sujeto(['Exposure', of, hES, cells, to, lovastatin]), verbo([led]), complemento([to, a, minor, decrease, in, the, expression, of, 'SSEA-3', and, a, significant, reduction, in, 'CD133', expression])].
[sujeto(['By', analyzing, hES, with, and, without, 'CD133,', we, discovered, that, 'CD133', expression, is]), verbo([required]), complemento([for, proper, formation, of, embryoid, bodies])].
[sujeto(['Here,', we, develop, two, novel, strategies, to, combine, epigenomic, data, with, transcriptomic, profiles, in, humans, or, mice, to, prioritize, potential, candidate, 'SNPs']), verbo([associated]), complemento([with, lipid, levels, by, 'genome-wide', association, study, '(', 'GWAS)'])].
[sujeto(['This', method]), verbo([recognized]), complemento([the, known, 'SORT1', rs12740374, regulatory, 'SNP', associated, with, 'LDL-cholesterol,', and, highlighted, candidate, functional, 'SNPs', at, 15, additional, lipid, loci])].
[sujeto(['This', approach, identified, 'SNPs', in, specific, transcription, factor]), verbo([binding]), complemento([sites, that, are, located, near, target, genes, of, these, transcription, factors])].
[sujeto(['We', show, that, 'FOXA2', transcription, factor]), verbo([binding]), complemento([sites, are, enriched, at, 'lipid-associated', loci, and, experimentally, validate, that, alleles, of, one, such, proxy, 'SNP', located, near, the, 'FOXA2', target, gene, 'BIRC5', show, allelic, differences, in, 'FOXA2-DNA', binding, and, enhancer, activity])].
[sujeto(['These', methods, can, be, used, to, generate, testable, hypotheses, for, many, 'non-coding', 'SNPs']), verbo([associated]), complemento([with, complex, diseases, or, traits])].
[sujeto(['Forkhead', transcription, factor, 'Foxa2']), verbo([activates]), complemento([genes, involved, in, hepatic, lipid, metabolism, and, is, regulated, by, insulin])].
[sujeto(['Activation', of, 'Foxa2', in, the, liver]), verbo([leads]), complemento([to, increased, oxidation, and, secretion, of, fatty, acids, in, the, form, of, triacylglycerols, '(', 'TAGs),', a, process, impaired, in, type, 2, diabetes])].
[sujeto(['Adenoviral', expression, of, 'Foxa2', and, 'Pgc-1beta', in, livers, of, 'ob/ob', mice, results, in]), verbo([decreased]), complemento([hepatic, 'TAG', content, and, increased, plasma, 'TAG', concentrations])].
[sujeto(['In', 'addition,', the, concerted, action, of, 'Foxa2/Pgc-1beta']), verbo([activates]), complemento([genes, in, mitochondrial, beta, oxidation, and, enhances, fatty, acid, metabolism])].
[sujeto(['Furthermore,', 'Foxa2/Pgc-1beta']), verbo([induce]), complemento([the, expression, of, microsomal, transfer, 'protein,', thereby, increasing, 'apoB-containing', 'VLDL', secretion])].
[sujeto(['This', process, is]), verbo([inhibited]), complemento([by, insulin, through, a, 'Foxa2-dependent', mechanism])].
[sujeto(['These', data, demonstrate, that, 'Foxa2/Pgc-1beta']), verbo([regulate]), complemento([hepatic, lipid, homeostasis, by, affecting, the, clearance, rate, of, fatty, acids, through, oxidation, 'and/or', secretion, of, lipids, in, response, to, insulin])].
[sujeto(['Studies']), verbo([have]), complemento([shown, 'over-expression', of, 'GLUT2', in, diabetic, conditions])].
[sujeto(['Ferulic', acid, '(', 'FA)', is, an, antidiabetic, phenolic, phytocompound, which, is]), verbo([reported]), complemento([to, regulate, 'GLUT4', in, vitro])].
[sujeto(['Male', 'Wistar', rats, were, divided, into, 5, 'groups:', 'control,', diabetic, '(', diabetes, was]), verbo([induced]), complemento([by, giving, high, fat, diet, and, high, fructose, water, for, 60, 'days),', diabetic, rats, treated, with, 'FA', '(', 50, 'mg/kg', body, 'weight/day,', orally, for, 30, 'days),', diabetic, rats, treated, with, metformin, '(', 50, 'mg/kg', body, 'weight/day,', orally, for, 30, 'days)', and, control, rats, treated, with, 'FA', '(', 50, 'mg/kg', body, 'weight/day', orally, for, 30, 'days)'])].
[sujeto(['Glucose', uptake, and, 'oxidation,', expression, of, 'GLUT2', and]), verbo([binding]), complemento([of, transcription, factors, -, 'SREBP1c,', 'HNF1α', and, 'HNF3β', with, 'GLUT2', gene, promoter, were, studied])].
[sujeto(['Over-expression', of, 'GLUT2', in, hepatic, tissue, was]), verbo([found]), complemento([in, high, fat, and, 'fructose-', induced, 'type-2', diabetic, animals])].
[sujeto(['Foxa2', '(', 'Hnf3beta)', is, a, 'winged-helix/forkhead', transcription, factor, that]), verbo([regulates]), complemento([gene, expression, in, the, 'liver,', pancreatic, islets, and, adipocytes])].
[sujeto(['It', is]), verbo([required]), complemento([for, the, maintenance, of, glucose, and, lipid, homeostasis])].
[sujeto(['Hyperinsulinemia-mediated', inactivation, of, 'Foxa2', by]), verbo([nuclear]), complemento([exclusion, has, recently, been, implicated, in, the, development, of, liver, steatosis, and, insulin, resistance, in, three, animal, models, of, diabetes])].
[sujeto(['These', abnormalities, were, cured, by, 'adenovirus-mediated', expression, of, a, constitutively, active, form, of, 'Foxa2', containing, a, mutated, 'T156', phosphorylation, 'site,', which]), verbo([increases]), complemento([fatty, acid, oxidation, and, reduces, its, biosynthesis])].
[sujeto(['Accordingly,', the, prevention, of, phosphorylation, of, 'Foxa2', was]), verbo([suggested]), complemento([as, a, pharmacological, target, for, the, treatment, of, obesity, and, diabetes])].
[sujeto(['In', 'particular,', 'growth-restricted', infants, or, infants, born, prematurely, may, develop, a, severe, form, of, intestinal, inflammation, known, as, necrotizing, enterocolitis, '(', 'NEC),', which]), verbo([has]), complemento([a, high, mortality])].
[sujeto(['Milk']), verbo([provides]), complemento([a, multitude, of, proteins, with, 'anti-inflammatory', properties, and, in, this, review, we, gather, together, some, recent, significant, advances, regarding, the, isolation, and, proteomic, identification, of, these, minor, constituents, of, both, human, and, bovine, milk])].
[sujeto(['We', introduce, the, process, of, 'inflammation,', with, a, focus, on, the, immature, 'gut,', and, describe, how, a, multitude, of, milk, proteins]), verbo([act]), complemento([against, the, inflammatory, process, according, to, both, in, vitro, and, in, vivo, studies])].
[sujeto(['Nonalcoholic', fatty, liver, disease, '(', 'NAFLD)', is, a, common, liver, disease, whose, prevalence]), verbo([has]), complemento([increased, markedly])].
[sujeto(['We']), verbo([reported]), complemento([previously, that, fatty, acid, synthesis, was, enhanced, in, 'NAFLD', with, the, accumulation, of, fatty, acids])].
[sujeto(['To', clarify, the, 'disorder,', we, evaluated, the, expression, of, genes]), verbo([regulating]), complemento([fatty, acid, synthesis, by, 'real-time', 'PCR', using, samples, from, 'NAFLD', '(', 'n=22)', and, normal, liver, '(', 'control;', 'n=10)'])].
[sujeto(['SREBP-1c', is, positively]), verbo([regulated]), complemento([by, insulin, signaling, 'pathways,', including, insulin, receptor, substrate, '(', 'IRS)-1', and, -, 2])].
[sujeto(['In', 'NAFLD,', 'IRS-1', expression, was]), verbo([enhanced]), complemento([and, correlated, positively, with, 'SREBP-1c', expression])].
[sujeto(['In', 'contrast,', 'IRS-2', expression]), verbo([decreased]), complemento([by, 50, '%', and, was, not, correlated, with, 'SREBP-1c'])].
[sujeto(['Forkhead', box, protein, 'A2', '(', 'Foxa2)', is, a, positive, regulator, of, fatty, acid, oxidation, and, is, itself, negatively]), verbo([regulated]), complemento([by, 'IRSs'])].
[sujeto(['Foxa2', expression]), verbo([increased]), complemento([in, 'NAFLD', and, showed, a, negative, correlation, with, 'IRS-2,', but, not, with, 'IRS-1,', expression])].
[sujeto(['It', is, known, that, 'SREBP-1c', is, negatively]), verbo([regulated]), complemento([by, 'AMP-activated', protein, kinase, '(', 'AMPK)', but, expression, levels, of, 'AMPK', in, 'NAFLD', were, almost, equal, to, those, of, the, controls])].
[sujeto(['These', data, indicate, 'that,', in, 'NAFLD,', insulin, signaling, via, 'IRS-1']), verbo([causes]), complemento([the, 'up-regulation', of, 'SREBP1-c,', leading, to, the, increased, synthesis, of, fatty, acids, by, the, 'hepatocytes;', negative, feedback, regulation, via, 'AMPK', does, not, occur, and, the, activation, of, 'Foxa2,', following, a, decrease, of, 'IRS-2,', 'up-regulates', fatty, acid, oxidation])].
[sujeto(['The', 'Forkhead', box, '(', 'Fox)', transcription, factor, 'Foxa2', '(', 'HNF-3beta)', and, related, family, members, 'Foxa1', '(', 'HNF-3alpha)', and, 'Foxa3', '(', 'HNF-3gamma)']), verbo([act]), complemento([in, concert, with, other, hepatocyte, nuclear, factors, '(', 'HNF)', to, coordinately, regulate, 'liver-specific', gene, expression])].
[sujeto(['To', circumvent, the, hepatic, functional, redundancy, of, the, 'Foxa', 'proteins,', we, used, the, 'T-77', transgenic, '(', 'TG)', mouse, line, in, which, the, -, 3, -, kb, transthyretin, '(', 'TTR)', promoter, functioned, to]), verbo([increase]), complemento([hepatocyte, expression, of, the, 'Foxa2', cDNA])].
[sujeto(['Adult', 'TG', mice, exhibited, reduced, hepatic, glycogen, and, progressive, liver, 'injury,', but]), verbo([maintained]), complemento([normal, serum, levels, of, 'glucose,', 'insulin,', and, glucagon])].
[sujeto(['The', postnatal, 'TG', mice, displayed, significant, reduction, in, serum, glucose, levels, and, in, hepatocyte, glycogen, storage, without]), verbo([increased]), complemento([serum, levels, of, ketone, bodies, and, free, fatty, acid, suggesting, that, they, are, not, undergoing, a, starvation, response])].
[sujeto(['We', show, that, 'TG', liver, developed, a, substantial, transient, 'steatosis,', which, reached, a, maximum, at, postnatal, day, 5, and, is]), verbo([associated]), complemento([with, increased, expression, of, hepatic, genes, involved, in, fatty, acid, and, triglyceride, 'synthesis,', lipid, 'beta-oxidation,', and, amino, acid, biosynthesis])].
[sujeto(['In', 'conclusion,', our, model, proposes, that, in, response, to, reduction, in, hepatocyte, glycogen, 'storage,', the, 'TTR-Foxa2', 'TG', mice, survive, by]), verbo([maintaining]), complemento([sufficient, serum, levels, of, glucose, through, gluconeogenesis, using, deaminated, amino, acids, with, dicarboxylate, products, of, peroxisomal, lipid, 'beta-oxidation', shuttled, through, the, tricarboxylic, acid, cycle])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, hepatitis, 'C', virus, '(', 'HCV)', infection, modulates, the, expression, of, forkhead, box, transcription, 'factors,', including, 'FoxO1', and, 'FoxA2,', which, play, key, roles, in, gluconeogenesis, and, 'β-oxidation', of, fatty, 'acid,', respectively])].
[sujeto(['The', aim, of, the, present, study, was, to, determine, the, role, of, forkhead, box, transcription, factors, in]), verbo([modulating]), complemento([lipid, metabolism])].
[sujeto([5, cells]), verbo([increased]), complemento([expression, of, sterol, regulatory, element, binding, protein, 1, c, '(', 'SREBP-1c)', and, its, downstream, 'target,', fatty, acid, synthase, '(', 'FASN),', which, are, key, proteins, involved, in, lipid, synthesis])].
[sujeto(['Knockdown', of, 'FoxO1', by, small, interfering, 'RNA', in, 'HCV-infected', cells, significantly]), verbo([decreased]), complemento(['SREBP-1c', and, 'FASN', expression])].
[sujeto([5, cells, significantly]), verbo([decreased]), complemento([the, expression, of, 'medium-chain', acyl, coenzyme, 'A', dehydrogenase, '(', 'MCAD)', and, 'short-chain', acyl, coenzyme, 'A', dehydrogenase, '(', 'SCAD),', involved, in, the, regulation, of, 'β-oxidation', of, fatty, acids])].
[sujeto(['Oil', red, 'O', and, neutral, lipid, staining, indicated, that, 'HCV', infection, significantly]), verbo([increases]), complemento([lipid, accumulation, compared, to, that, in, the, 'mock-infected', control])].
[sujeto(['This', was, further, verified, by, the]), verbo([increased]), complemento([expression, of, 'perilipin-2', and, decreased, activity, of, 'hormone-sensitive', lipase, '(', 'HSL)', in, 'HCV-infected', 'hepatocytes,', implying, increased, accumulation, of, neutral, lipids])].
[sujeto(['Knockdown', of, 'FoxO1', and, ectopic, expression, of, 'FoxA2', significantly]), verbo([decreased]), complemento(['HCV', replication])].
[sujeto(['Taken', 'together,', these, results]), verbo([suggest]), complemento([that, 'HCV', modulates, forkhead, box, transcription, factors, which, together, increase, lipid, accumulation, and, promote, viral, replication])].
[sujeto(['Hepatic', steatosis, is, a, frequent, complication]), verbo([associated]), complemento([with, chronic, 'HCV', infection])].
[sujeto(['Its', presence, is, a, key, prognostic, indicator]), verbo([associated]), complemento([with, the, progression, to, hepatic, fibrosis, and, hepatocellular, carcinoma])].
[sujeto(['Several', mechanisms]), verbo([have]), complemento([been, proposed, to, account, for, the, development, of, steatosis, and, fatty, liver, during, 'HCV', infection])].
[sujeto(['We', observed, that, 'HCV', infection]), verbo([increases]), complemento([expression, of, both, 'SREBP-1c', and, 'FASN'])].
[sujeto(['Further', investigation]), verbo([suggested]), complemento([that, the, expression, of, 'SREBP-1c', and, 'FASN', is, controlled, by, the, transcription, factor, 'FoxO1', during, 'HCV', infection])].
[sujeto(['In', 'addition,', 'HCV', infection, significantly]), verbo([decreased]), complemento([both, 'MCAD', and, 'SCAD', 'expression,', which, is, controlled, by, 'FoxA2'])].
[sujeto(['HCV', infection, also]), verbo([increased]), complemento([lipid, droplet, 'accumulation,', increased, 'perilipin-2', 'expression,', and, decreased, 'HSL', activity])].
[sujeto(['Thus,', knockdown, of, 'FoxO1', '(']), verbo([decreased]), complemento(['lipogenesis)', and, overexpression, of, 'FoxA2', '(', increased, 'β-oxidation)', resulted, in, a, significant, disruption, of, the, platform, 'and,', 'hence,', a, decrease, in, 'HCV', genome, replication])].
[sujeto(['Thus,']), verbo([targeting]), complemento([of, 'FoxO1', and, 'FoxA2', might, be, useful, in, developing, a, therapeutic, approach, against, 'HCV', infection])].
[sujeto(['Dietary', 'n-3', polyunsaturated, fatty, acid, '(', 'n-3', 'PUFA)', supplementation, is, postulated, to]), verbo([have]), complemento([positive, effects, on, fertility])].
[sujeto(['The', impact, of, dietary, 'n-3', 'PUFA', supplementation, on, physiological, and, biochemical, processes]), verbo([involved]), complemento([in, reproduction, is, likely, to, be, associated, with, significant, alterations, in, gene, expression, in, key, reproductive, tissues, which, is, in, turn, regulated, by, transcription, factors])].
[sujeto(['Furthermore,', oPOSSUM, was, employed, to, identify, transcription, factors]), verbo([involved]), complemento([in, gene, expression, changes, due, to, supplementary, 'PUFA'])].
[sujeto(['The', human, liver, fatty, acid]), verbo([binding]), complemento([protein, '(', 'hFABP1)', participates, in, cellular, 'long-chain', fatty, acid, trafficking, and, regulation, of, lipid, metabolism, and, changes, in, hFABP1, are, associated, with, an, increased, risk, for, type, 2, 'diabetes,', cardiovascular, disease, '(', 'CVD),', and, metabolic, syndromes])].
[sujeto(['TFSEARCH', and, 'TESS', programs, were, used, to, predict, potential, transcription, factor]), verbo([binding]), complemento([sites])].
[sujeto(['Two', putative]), verbo([binding]), complemento([sites, for, the, 'liver-enriched', transcription, factors, hepatocyte, nuclear, factor, 3, β, '(', 'HNF3β)', and, 'CCAAT/enhancer', binding, protein, α, '(', 'C/EBPα)', were, identified, in, 'the&nbsp;-255&nbsp;nt', 'to&nbsp;-155&nbsp;nt', hFABP1, promoter, region])].
[sujeto(['In', 'addition,', the, electrophoretic, mobility, shift, assay, '(', 'EMSA)', and, chromatin, immunoprecipitation, assay, '(', 'ChIP)', revealed, that, these]), verbo([binding]), complemento([sites, were, recognized, by, 'HNF3β', and, 'C/EBPα', respectively])].
[sujeto(['Overexpression', of, 'HNF3β', and, 'C/EBPα']), verbo([enhanced]), complemento([the, transcription, of, hFABP1, and, consequently, improved, the, protein, level, of, hFABP1, 'in&nbsp;HepG2', 'cells,', while, knockdown, of, 'HNF3β', and, 'C/EBPα', showed, the, inverse, effects])].
[sujeto(['Taken', 'together,', the, hFABP1, gene, is, highly]), verbo([transcribed]), complemento([in, 'liver-derived', 'cells,', and, regulated, predominantly, by, 'liver-enriched', transcription, factors, 'HNF3β', and, 'C/EBPα'])].
[sujeto(['Glucose', disposal]), verbo([induces]), complemento([a, signal, that, modulates, the, transcriptional, regulation, of, genes, involved, in, the, glycolysis, and, lipogenesis, pathways])].
[sujeto(['By', microarray, 'analysis,', we, observed, that, critical, genes, such, as, 'liver-type', pyruvate, 'kinase,', malic, 'enzyme,', fatty, acid, 'synthase,', and, 'stearoyl-CoA', desaturase, 1, were]), verbo([enhanced]), complemento(['multiple-fold,', whereas, genes, involved, in, mitochondrial, fatty, acid, oxidation, and, the, 'Krebs', cycle, were, downregulated])].
[sujeto(['Despite', the]), verbo([increase]), complemento([in, expression, of, fatty, acid, synthesis, genes, and, the, presence, of, 'steatosis,', no, major, alterations, to, the, levels, of, genes, involved, in, 'VLDL', assembly, and, 'secretion,', such, as, diacylglycerol, acyltransferases, 1, and, 2, and, microsomal, triglyceride, transfer, 'protein,', were, observed])].
[sujeto(['Overall,', our, data]), verbo([suggest]), complemento([that, the, gene, expression, pattern, induced, by, glucose, metabolism, favors, fatty, acid, storage, in, the, liver, rather, than, secretion, into, the, circulation])].
[sujeto(['Lack', of, surfactant, lipids, and, proteins, in, the, lungs]), verbo([causes]), complemento([respiratory, distress, 'syndrome,', a, common, cause, of, morbidity, and, mortality, in, preterm, infants])].
[sujeto(['We', show, that, 'C/EBPalpha', plays, a, crucial, role, in, the, maturation, of, the, respiratory, epithelium, in, late, 'gestation,', being]), verbo([required]), complemento([for, the, production, of, surfactant, lipids, and, proteins, necessary, for, lung, function])].
[sujeto(['Deletion', of, the, 'Cebpa', gene, in, respiratory, epithelial, cells, in, fetal, mice]), verbo([caused]), complemento([respiratory, failure, at, birth])].
[sujeto(['Normal', synthesis, of, surfactant, lipids, and, 'proteins,', including, 'SP-A,', 'SP-B,', 'SP-C,', 'SP-D,', 'ABCA3', '(', a, lamellar, body]), verbo([associated]), complemento(['protein)', and, 'FAS', '(', precursor, of, fatty, acid, 'synthesis)', were, dependent, upon, expression, of, the, 'C/EBPalpha', in, respiratory, epithelial, cells])].
[sujeto(['Deletion', of, the, 'Cebpa', gene]), verbo([caused]), complemento([increased, expression, of, 'Tgfb2,', a, growth, factor, that, inhibits, lung, epithelial, cell, proliferation, and, differentiation])].
[sujeto(['Normal', expression, of, 'C/EBPalpha']), verbo([required]), complemento(['Titf1', and, 'Foxa2,', transcription, factors, that, also, play, an, important, role, in, perinatal, lung, differentiation])].
[sujeto(['C/EBPalpha']), verbo([participates]), complemento([in, a, transcriptional, network, that, is, required, for, the, regulation, of, genes, mediating, perinatal, lung, maturation, and, surfactant, homeostasis, that, is, necessary, for, adaptation, to, air, breathing, at, birth])].
[sujeto(['Changes', in, the, circulating, concentrations, of, these, hormones, signal, fed, or, starvation, states, and, elicit, 'counter-regulatory', responses, that]), verbo([maintain]), complemento([normoglycaemia])].
[sujeto(['Here', we, show, that, in, normal, 'mice,', plasma, insulin]), verbo([inhibits]), complemento([the, forkhead, transcription, factor, 'Foxa2', by, nuclear, exclusion, and, that, in, the, fasted, '(', low, 'insulin)', state, 'Foxa2', activates, transcriptional, programmes, of, lipid, metabolism, and, ketogenesis])].
[sujeto(['In', these, 'mice,', adenoviral, expression, of, 'Foxa2T156A,', a, 'nuclear,', constitutively, active, 'Foxa2', that, cannot, be]), verbo([inhibited]), complemento([by, 'insulin,', decreases, hepatic, triglyceride, 'content,', increases, hepatic, insulin, 'sensitivity,', reduces, glucose, 'production,', normalizes, plasma, glucose, and, significantly, lowers, plasma, insulin])].
[sujeto(['These', changes, are]), verbo([associated]), complemento([with, increased, expression, of, genes, encoding, enzymes, of, fatty, acid, 'oxidation,', ketogenesis, and, glycolysis])].
[sujeto(['Chronic', hyperinsulinaemia, in, 'insulin-resistant', syndromes, results, in, the, cytoplasmic, localization, and, inactivation, of, 'Foxa2,', thereby]), verbo([promoting]), complemento([lipid, accumulation, and, insulin, resistance, in, the, liver])].
[sujeto(['Pharmacological', intervention, to]), verbo([inhibit]), complemento([phosphorylation, of, 'Foxa2', may, be, an, effective, treatment, for, type, 2, diabetes])].
[sujeto(['Liver', fatty, acid]), verbo([binding]), complemento([protein, '(', 'L-FABP)', is, a, small, protein, that, is, thought, to, play, an, important, role, in, the, intracellular, binding, and, trafficking, of, long, chain, fatty, acids, in, the, liver])].
[sujeto(['Expression', of, the, gene, encoding, the, zebrafish, liver, fatty, acid]), verbo([binding]), complemento([protein, is, regulated, by, a, 435, -, bp, distal, region, '(', -, 1944, to, -, 1510, ')', of, the, 'L-FABP', promoter])].
[sujeto(['The', 435, -, bp, sequence, region]), verbo([has]), complemento([two, distinct, liver, regulatory, 'elements,', 'A', '(', -, 1944, to, -, 1623, ')', and, 'B', '(', -, 1622, to, -, 1510, ')', ',', and, contains, multiple, putative, consensus, binding, sites])].
[sujeto(['The', importance, of, the, 'HNF-1alpha', consensus]), verbo([binding]), complemento([site, in, the, 'A', element, and, the, 'HNF-3beta', consensus, binding, site, in, the, 'B', element, within, the, 435, -, bp, distal, region, of, the, 'L-FABP', promoter, region, suggests, that, combinatorial, interactions, between, multiple, regulatory, factors, are, responsible, for, the, gene, expression, of, 'L-FABP', in, the, liver])].
[sujeto(['The', prevalence, of, diabetes]), verbo([has]), complemento([exponentially, increased, in, recent, decades, due, to, environmental, factors, such, as, nocturnal, lifestyle, and, 'aging,', both, of, which, influence, the, amount, of, melatonin, produced, in, the, pineal, gland])].
[sujeto(['Intriguingly,', treatment, of, 'C2C12', cells, with, melatonin, '(', 1, 'nm)']), verbo([stimulated]), complemento([glucose, uptake, twofold, increase])].
[sujeto(['Melatonin-stimulated', glucose, transport, was]), verbo([inhibited]), complemento([with, 'co-treatment', with, the, melatonin, receptor, antagonist, luzindole])].
[sujeto(['Melatonin', also]), verbo([increased]), complemento([the, phosphorylation, level, of, insulin, receptor, 'substrate-1', '(', 'IRS-1)', and, the, activity, of, phosphoinositide, 3, -, kinase, '(', 'PI-3-kinase)'])].
[sujeto(['In', 'addition,', melatonin]), verbo([increased]), complemento([the, expression, level, of, forkhead, box, 'A2,', which, was, recently, discovered, to, regulate, fatty, acid, oxidation, and, to, be, inhibited, by, insulin])].
[sujeto(['In', 'summary,', melatonin]), verbo([stimulates]), complemento([glucose, transport, to, skeletal, muscle, cells, via, 'IRS-1/PI-3-kinase', 'pathway,', which, 'implies,', at, the, molecular, 'level,', its, role, in, glucose, homeostasis, and, possibly, in, diabetes])].
[sujeto(['Apolipoprotein', 'M', '(', 'apoM),', as, a, novel, apolipoprotein, which, is, mainly]), verbo([expressed]), complemento([in, liver, and, kidney, 'tissues,', is, associated, with, development, and, progression, of, atherosclerosis, and, diabetes])].
[sujeto(['Our', group]), verbo([have]), complemento([recently, shown, that, 'Dihydrocapsaicin(DHC)can', significantly, decrease, atherosclerotic, plaque, formation, in, 'apoE-/-', mice])].
[sujeto(['We']), verbo([found]), complemento([that, 'DHC', markedly, decreased, expression, of, apoM, at, both, mRNA, and, protein, level, in, 'HepG2', cells, in, a, 'dose-dependent', and, 'time-dependent', manner])].
[sujeto(['Expression', of, 'Foxa2', was]), verbo([decreased]), complemento([while, expression, of, 'LXRα', was, increased, by, 'DHC', treatment, in, 'HepG2', cells])].
[sujeto(['In', 'addittion,', overexpression, of, 'Foxa2', markedly, compensated, the, inhibition, effect]), verbo([induced]), complemento([by, 'DHC', on, apoM, expression])].
[sujeto(['LXRα', small, interfering, 'RNA', significantly, abolished, the, inhibition, effect, which]), verbo([induced]), complemento([by, 'DHC', on, apoM, expression])].
[sujeto(['DHC', could, 'down-regulate', apoM, expression, through]), verbo([inhibiting]), complemento(['Foxa2', expression, and, enhancing, 'LXRα', expression, in, 'HepG2', cells])].
[sujeto(['Previous', studies]), verbo([have]), complemento([reported, the, differentiation, of, mesodermal, 'MSCs', into, endodermal, and, ectodermal, cell, types, beyond, their, embryonic, 'lineages,', including, hepatocytes, and, neurons])].
[sujeto(['In', the, present, 'study,', we, demonstrated, that, valproic, acid, '(', 'VPA),', which, is, a, histone, deacetylase, 'inhibitor,']), verbo([induced]), complemento([an, increase, in, the, expression, of, endodermal, genes, including, 'CXCR4,', 'SOX17,', 'FOXA1,', 'FOXA2,', 'GSC,', 'c-MET,', 'EOMES,', and, 'HNF-1β', in, human, umbilical, cord, derived, 'MSCs', '(', 'hUCMSCs)'])].
[sujeto(['In', 'addition,', we]), verbo([found]), complemento([that, 'VPA', is, able, to, increase, these, endodermal, genes, in, hUCMSCs, by, activating, signal, transduction, of, 'AKT', and, 'ERK'])].
[sujeto(['VPA', pretreatment]), verbo([increased]), complemento([hepatic, differentiation, at, the, expense, of, adipogenic, differentiation])].
[sujeto(['The', effects, of, 'VPA', on]), verbo([modulating]), complemento([hUCMSCs, fate, were, diminished, by, blocking, 'AKT', and, 'ERK', activation, using, specific, signaling, inhibitors])].
[sujeto(['Together,', our, results]), verbo([suggest]), complemento([that, 'VPA', contributes, to, the, lineage, conversion, of, hUCMSCs, to, hepatic, cell, fate, by, upregulating, the, expression, of, endodermal, genes, through, 'AKT', and, 'ERK', activation])].
[sujeto(['Foxa2', is, a, member, of, the, 'Forkhead', family, of]), verbo([nuclear]), complemento([transcription, factors, that, is, highly, expressed, in, respiratory, epithelial, cells, of, the, developing, and, mature, lung])].
[sujeto(['Foxa2', is]), verbo([required]), complemento([for, normal, airway, epithelial, 'differentiation,', and, its, deletion, causes, 'goblet-cell', metaplasia, and, 'Th2-mediated', pulmonary, inflammation, during, postnatal, development])].
[sujeto(['Foxa2', expression, is]), verbo([inhibited]), complemento([during, aeroallergen, sensitization, and, after, stimulation, with, 'Th2', 'cytokines,', when, its, loss, is, associated, with, 'goblet-cell', metaplasia])].
[sujeto(['During', the, first, 2, weeks, after, 'birth,', the]), verbo([loss]), complemento([of, 'Foxa2', increases, the, production, of, leukotrienes, '(', 'LTs)', and, 'Th2', cytokines, in, the, lungs, of, 'Foxa2', 'gene-targeted', mice])].
[sujeto(['Foxa2', expression]), verbo([inhibited]), complemento([15, -, lipoxygenase, '(', 'Alox15)', and, increased, 'Alox5', 'transcription,', each, encoding, key, lipoxygenases, associated, with, asthma])].
[sujeto(['The', inhibition, of, the, cysteinyl, 'LT', '(', 'CysLT)', signaling, pathway, by, montelukast]), verbo([inhibited]), complemento(['IL-4,', 'IL-5,', 'eotaxin-2,', and, regulated, upon, activation, normal, 'T', cell, expressed, and, presumably, secreted, expression, in, the, developing, lungs, of, 'Foxa2', 'gene-targeted', mice])].
[sujeto(['Montelukast']), verbo([inhibited]), complemento([the, expression, of, genes, regulating, mucus, 'metaplasia,', including, 'Spdef,', 'Muc5ac,', 'Foxa3,', and, 'Arg2'])].
[sujeto(['Foxa2', plays, a, 'cell-autonomous', role, in, the, respiratory, 'epithelium,', and, is]), verbo([required]), complemento([for, the, suppression, of, 'Th2', immunity, and, mucus, metaplasia, in, the, developing, lung, in, a, process, determined, in, part, by, its, regulation, of, the, 'CysLT', pathway])].
[sujeto(['Circulating', levels, of, insulin, and, glucagon, reflect, the, nutritional, state, of, animals, and, elicit, regulatory, responses, in, the, liver, that]), verbo([maintain]), complemento([glucose, and, lipid, homeostasis])].
[sujeto(['The', transcription, factor, 'Foxa2']), verbo([activates]), complemento([lipid, metabolism, and, ketogenesis, during, fasting, and, is, inhibited, via, 'insulin-PI3K-Akt', 'signaling-mediated', phosphorylation, at, 'Thr156', and, nuclear, exclusion])].
[sujeto(['Here', we, show, 'that,', in, 'addition,', 'Foxa2', is, acetylated, at, the]), verbo([conserved]), complemento([residue, 'Lys259', following, inhibition, of, histone, deacetylases, '(', 'HDACs)', class, 'I-III', and, the, cofactors, p300, and, 'SirT1', are, involved, in, 'Foxa2', acetylation, and, 'deacetylation,', respectively])].
[sujeto(['Physiologically,', fasting, states, and, glucagon, stimulation, are, sufficient, to]), verbo([induce]), complemento(['Foxa2', acetylation])].
[sujeto(['Introduction', of, the, 'acetylation-mimicking', '(', 'K259Q)', or, -, deficient, '(', 'K259R)', mutations]), verbo([promotes]), complemento([or, inhibits, 'Foxa2', 'activity,', 'respectively,', and, adenoviral, expression, of, 'Foxa2-K259Q', augments, expression, of, genes, involved, in, fatty, acid, oxidation, and, ketogenesis])].
[sujeto(['Our', study]), verbo([reveals]), complemento([a, molecular, mechanism, by, which, glucagon, signaling, activates, a, fasting, response, through, acetylation, of, 'Foxa2'])].
[sujeto(['It']), verbo([has]), complemento([been, reported, that, peroxisome, 'proliferator-activated', receptor, '(', 'PPAR)-γ', and, their, synthetic, ligands, have, direct, effects, on, pancreatic, 'β-cells'])].
[sujeto(['We', investigated, whether, 'PPAR-γ', activation]), verbo([stimulates]), complemento([insulin, secretion, through, the, 'up-regulation', of, 'GPR40', in, pancreatic, 'β-cells'])].
[sujeto(['PPAR-γ', activation, with, 'RGZ', 'and/or', adenoviral, 'PPAR-γ', overexpression]), verbo([increased]), complemento([free, fatty, acid, '(', 'FFA)', receptor, 'GPR40', 'expression,', and, increased, insulin, secretion, and, intracellular, calcium, 'mobilization,', and, was, blocked, by, the, 'PLC', 'inhibitors,', 'GPR40', 'RNA', 'interference,', and, 'GLUT2', 'RNA', interference])].
[sujeto(['As', a, downstream, signaling, pathway, of, intracellular, calcium, 'mobilization,', the]), verbo([phosphorylated]), complemento([levels, of, 'CaMKII', and, 'CREB,', and, the, downstream, 'IRS-2', and, 'phospho-Akt', were, significantly, increased])].
[sujeto(['Despite', of, insulin, receptor, 'RNA', 'interference,', the, levels, of, 'IRS-2', and, 'phospho-Akt', was, still]), verbo([maintained]), complemento([with, 'PPAR-γ', activation])].
[sujeto(['In', 'addition,', the, 'β-cell', specific, gene, 'expression,', including, 'Pdx-1', and, 'FoxA2,']), verbo([increased]), complemento([in, a, 'GPR40-', and, 'GLUT2-dependent', manner])].
[sujeto(['The', levels, of, 'GPR40,']), verbo([phosphorylated]), complemento(['CaMKII', and, 'CREB,', and, 'β-cell', specific, genes, induced, by, 'RGZ', were, blocked, by, 'GW9662,', a, 'PPAR-γ', antagonist])].
[sujeto(['Finally,', 'PPAR-γ', activation, 'up-regulated', 'β-cell', gene, expressions, through, 'FoxO1']), verbo([nuclear]), complemento(['exclusion,', independent, of, the, insulin, signaling, pathway])].
[sujeto(['Based', on, immunohistochemical, 'staining,', the, 'GLUT2,', 'IRS-2,', 'Pdx-1,', and, 'GPR40', were, more, strongly]), verbo([expressed]), complemento([in, islets, from, 'RGZ-treated', 'OLETF', rats, compared, to, control, islets])].
[sujeto(['These', observations]), verbo([suggest]), complemento([that, 'PPAR-γ', activation, with, 'RGZ', 'and/or', adenoviral, overexpression, increased, intracellular, calcium, 'mobilization,', insulin, 'secretion,', and, 'β-cell', gene, expression, through, 'GPR40', and, 'GLUT2', gene, 'up-regulation'])].
[sujeto(['The', 'Foxa', subfamily, of, winged, 'helix/forkhead', box, '(', 'Fox)', transcription, factors, comprises, three, members, which, play, important, roles, in, controlling, both, metabolism, and, homeostasis, through, the, regulation, of, multiple]), verbo([target]), complemento([genes, in, the, 'liver,', pancreas, and, adipose, tissue])].
[sujeto(['In', the, mouse, 'liver,', 'Foxa2', is]), verbo([repressed]), complemento([by, insulin, and, mediates, fasting, responses])].
[sujeto(['Unlike', 'Foxa2', 'however,', the, role, of, 'Foxa1', in, the, liver]), verbo([has]), complemento([not, yet, been, investigated, in, detail])].
[sujeto(['Results', demonstrate, that, 'Foxa1', is, a, potent, inhibitor, of, hepatic, triglyceride, 'synthesis,', accumulation, and, secretion, by]), verbo([repressing]), complemento([the, expression, of, multiple, target, genes, of, these, pathways, '(', e])].
[sujeto(['Moreover,', 'Foxa1']), verbo([represses]), complemento([the, fatty, acid, transporter, protein, 'FATP2', and, lowers, fatty, acid, uptake])].
[sujeto(['Foxa1', also]), verbo([increases]), complemento([the, breakdown, of, fatty, acids, by, inducing, peroxisomal, fatty, acid, 'β-oxidation', and, ketone, body, synthesis])].
[sujeto(['Finally,', 'Foxa1', is, able, to, largely, 'up-regulate', 'UCP1,', thereby, dissipating, energy, and, consistently]), verbo([decreasing]), complemento([the, mitochondria, membrane, potential])].
[sujeto(['We', also]), verbo([report]), complemento([that, human, and, rat, 'NAFL', have, a, reduced, 'Foxa1', 'expression,', possibly, through, a, protein, kinase, 'C-dependent', pathway])].
[sujeto(['However,', 'Foxa1', is, 'down-regulated', in, human, and, rat, 'NAFL', 'and,', 'therefore,']), verbo([increasing]), complemento(['Foxa1', levels, could, protect, from, steatosis])].
[sujeto(['Altogether,', we]), verbo([suggest]), complemento([that, 'Foxa1', could, be, a, novel, therapeutic, target, for, 'NAFL', disease, and, insulin, resistance])].
[sujeto(['The', factors, responsible]), verbo([provoke]), complemento([both, insulin, resistance, and, pancreatic, beta, cell, dysfunction, but, remain, to, be, fully, identified])].
[sujeto(['We']), verbo([report]), complemento([a, combination, of, molecular, events, in, human, and, mouse, pancreatic, beta, 'cells,', induced, by, elevated, levels, of, free, fatty, acids, or, by, administration, of, a, 'high-fat', diet, with, associated, 'obesity,', that, comprise, a, pathogenic, pathway, to, diabetes])].
[sujeto(['Elevated', concentrations, of, free, fatty, acids]), verbo([caused]), complemento([nuclear, exclusion, and, reduced, expression, of, the, transcription, factors, 'FOXA2', and, 'HNF1A', in, beta, cells])].
[sujeto(['Protection', from, disease, was]), verbo([conferred]), complemento([by, enforced, beta, 'cell-specific', 'GnT-4a', protein, glycosylation, and, involved, the, maintenance, of, glucose, transporter, expression, and, the, preservation, of, glucose, transport])].
[sujeto(['Recent', success, in, pancreatic, islet, transplantation]), verbo([has]), complemento([energized, the, field, to, discover, an, alternative, source, of, stem, cells, with, differentiation, potential, to, beta, cells])].
[sujeto(['Generation', of, 'glucose-responsive,', 'insulin-producing', beta, cells, from, 'self-renewing,', pluripotent, human, 'ESCs', '(', 'hESCs)']), verbo([has]), complemento([immense, potential, for, diabetes, treatment])].
[sujeto(['We']), verbo([report]), complemento([here, the, development, of, a, novel, 'serum-free', protocol, to, generate, 'insulin-producing', 'islet-like', clusters, '(', 'ILCs)', from, hESCs, grown, under, 'feeder-free', conditions])].
[sujeto(['Disclosure', of, potential, conflicts, of, interest, is]), verbo([found]), complemento([at, the, end, of, this, article])].
[sujeto(['A', study, by, 'Wolfrum', and, 'Stoffel', '(', 2006, ')', shows, that, the, forkhead, protein, 'Foxa2']), verbo([stimulates]), complemento([hepatic, 'VLDL', production, in, concert, with, the, coactivator, 'PGC-1beta', and, that, insulin, inhibits, this, process, by, inactivating, 'Foxa2'])].
[sujeto(['The', 'SNPs', most, consistently]), verbo([associated]), complemento([with, 'CYP3A4', phenotypic, measures, were, a, 44477, 'T&gt;C(-1359)', promoter, 'SNP', '(', in, linkage, disequilibrium, with, 'SNP', 463970, ',', a, 6, -, base, pair, deletion, in, intron, 1, 'a,', and, 'SNP', 46551, ',', a, 'C', nucleotide, insertion, in, intron, 1, 'b);', 'SNP', 63396, 'C&gt;T', in, intron, 1, '(', in, linkage, disequilibrium, with, 'SNP', 63704, 'A&gt;G,', a, 63813, '(', 'CAAA)(CA)', variable, 'repeat,', and, 'SNP', 65104, 'T&gt;C);', and, 'SNP', 56348, 'C&gt;A,', 'SNP', 69789, 'A&gt;G,', and, 'SNP', 66034, 'T&gt;C'])].
[sujeto(['Donor', livers, with, the, variant, 'PXR', alleles, had, altered, hepatic, expression, of, 'PXR']), verbo([targets]), complemento([compared, with, livers, with, 'PXR', 'wild-type', alleles])].
[sujeto(['These', results, identified, 'PXR', promoter, and, intron, 1, 'SNPs']), verbo([associated]), complemento([with, 'PXR', target, gene, expression, '(', 'CYP3A4)', in, donor, livers, and, cultured, hepatocytes, and, that, a, striking, number, of, the, linked, intron, 1, 'SNPs', will, affect, putative, binding, sites, for, hepatic, nuclear, factor, 3, beta, '(', 'FOXA2),', a, transcription, factor, linked, with, 'PXR', expression])].
[sujeto(['In', this, 'study,', a, subpopulation, of, 'CSCs', of, ovarian, carcinoma, was, isolated, and, the, genes, differentially]), verbo([expressed]), complemento([in, these, cells, were, identified, to, characterize, 'CSCs', and, to, find, candidate, biomarkers])].
[sujeto(['Overexpression', of, 'LEF1,', 'VAV3,', and, 'NKX3-2', was, significantly]), verbo([associated]), complemento([with, distant, metastasis, by, immunohistochemistry])].
[sujeto(['The', further, functional, assay, revealed, that, 'VAV3', knockdown]), verbo([regulated]), complemento(['CSC', activation, and, ovarian, cancer, cell, proliferation, and, sensitized, paclitaxel, '(', 'PTX)-resistant', cancer, cells, to, 'PTX', treatment])].
[sujeto(['Hepatocyte-like', cells, differentiated, from, human, embryonic, stem, cells, '(', 'hESCs)', and]), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'hiPSCs)', can, be, utilized, as, a, tool, for, screening, for, hepatotoxicity, in, the, early, phase, of, pharmaceutical, development])].
[sujeto(['We']), verbo([have]), complemento([recently, reported, that, hepatic, differentiation, is, promoted, by, sequential, transduction, of, 'SOX17,', 'HEX,', and, 'HNF4α', into, 'hESC-', or, 'hiPSC-derived', 'cells,', but, further, maturation, of, 'hepatocyte-like', cells, is, required, for, widespread, use, of, drug, screening])].
[sujeto(['The', combination, of, two, transcription, 'factors,', 'FOXA2', and, 'HNF1α,']), verbo([promoted]), complemento([efficient, hepatic, differentiation, from, hESCs, and, hiPSCs])].
[sujeto(['The', expression, profile, of, 'hepatocyte-related', genes, '(', such, as, genes, encoding, cytochrome, 'P450', 'enzymes,', conjugating, 'enzymes,', hepatic, 'transporters,', and, hepatic]), verbo([nuclear]), complemento(['receptors)', achieved, with, 'FOXA2', and, 'HNF1α', transduction, was, comparable, to, that, obtained, in, primary, human, hepatocytes])].
[sujeto(['The', objectives, of, this, study, were, to, examine, the, effects, of, 'P4', on, androgen, production, in, the, mature, teleost, testis, and, to, identify, molecular, signaling, cascades]), verbo([regulated]), complemento([by, 'P4', to, improve, understanding, of, its, role, in, male, reproduction])].
[sujeto(['P4', significantly]), verbo([increased]), complemento([testosterone, '(', 'T)', production, in, the, 'FHM', testis, but, did, not, affect, 11, -, ketotestosterone])].
[sujeto(['There', was, also, a, 20, '%']), verbo([increase]), complemento([in, a, gene, network, for, 'follicle-stimulating', hormone, secretion, and, an, 18, '%', decrease, in, genes, involved, in, vasopressin, signaling])].
[sujeto(['star,', 'cyp19a,', 11, 'bhsd)', were, not, significantly, affected, by, 'P4', treatments, in, this, 'study,', and, it, is, hypothesized, that, 'pre-existing', molecular, machinery, may, be, more]), verbo([involved]), complemento([in, the, increased, production, of, 'T', rather, than, the, de, novo, expression, of, 'steroid-related', transcripts, and, receptors])].
[sujeto(['There', was, a, significant]), verbo([decrease]), complemento([in, prostaglandin, 'E', synthase, 3, b, '(', 'cytosolic)', '(', 'ptges3b)', after, treatment, with, 'P4,', suggesting, that, there, is, cross, talk, between, 'P4', and, prostaglandin, pathways, in, the, reproductive, testis])].
[sujeto(['P4']), verbo([has]), complemento([a, role, in, regulating, steroid, production, in, the, male, testis, and, may, do, so, by, modulating, gene, networks, related, to, endocrine, 'pathways,', such, as, 'Igf1,', 'Tnfr,', and, vasopressin])].
[sujeto(['Three', distinct, hepatocyte]), verbo([nuclear]), complemento(['factor-3', '(', 'HNF-3)', proteins, '(', 'alpha,', 'beta,', and, 'gamma)', regulate, the, transcription, of, numerous, 'liver-enriched', genes])].
[sujeto(['The', 'HNF-3', proteins]), verbo([bind]), complemento(['DNA', via, a, homologous, winged, helix, motif, common, to, a, number, of, proteins, known, to, be, critical, for, determination, events, in, embryogenesis])].
[sujeto(['We']), verbo([have]), complemento([demonstrated, previously, that, two, binding, sites, in, the, -, 184, 'HNF-3', beta, promoter, are, recognized, by, widely, distributed, factors, and, that, there, is, also, a, critical, autoregulatory, 'site,', we, identified, a, binding, site, for, a, 'cell-specific', 'factor,', 'LF-H3', 'beta,', that, may, function, in, restricting, 'HNF-3', beta, gene, expression, to, hepatocytes])].
[sujeto(['Our', present, study, demonstrates, that, members, of, the, 'C/EBP', and, proline, and, acidic, amino, 'acid-rich', subfamilies, of, basic, region, leucine, zipper, transcription, factors]), verbo([bind]), complemento([the, 'LF-H3', beta, 'site,', and, cotransfection, of, 'HepG2', cells, shows, that, these, factors, are, able, to, activate, an, 'HNF-3', beta, promoter, reporter, construct])].
[sujeto(['The', 'LF-H3', 'beta-C/EBP']), verbo([binding]), complemento([sequence, also, confers, 'HNF-3', beta, promoter, stimulation, in, response, to, interleukin, '(', 'IL)-1', and, 'IL-6'])].
[sujeto(['Upstream', of, this, 'HNF-3', beta, proximal, promoter, 'region,', an, 'IFN-stimulated', response, element, core, sequence, '(', -, 231, to, -, 210, ')', was]), verbo([found]), complemento([that, mediates, transcriptional, induction, by, 'IFN-gamma', but, not, 'IFN-alpha'])].
[sujeto(['Consistent', with, this, 'finding,', we, observed, that, 'IFN-gamma', induction]), verbo([requires]), complemento([ongoing, protein, synthesis])].
[sujeto(['HNF-3beta', joins, the, 'C/EBP', family, on, the, list, of, 'liver-enriched', transcription, 'factors,', the, expression, of, which, is]), verbo([modulated]), complemento([by, cytokines])].
[sujeto(['FOXH1', and, 'FOXO1', mRNAs, are]), verbo([expressed]), complemento([in, human, embryonic, stem, '(', 'ES)', cells])].
[sujeto(['Deregulation', of, 'FOX', family, genes]), verbo([leads]), complemento([to, congenital, 'disorders,', diabetes, 'mellitus,', or, carcinogenesis])].
[sujeto(['Expression', 'profiles,', genetic, alterations, and, epigenetic, changes, of, 'FOX', family, genes, as, well, as]), verbo([binding]), complemento([proteins, and, target, genes, of, 'FOX', family, transcription, factors, should, be, comprehensively, investigated, to, develop, novel, therapeutics, and, preventives, for, human, diseases])].
[sujeto(['Embryonic', heart, development, is, a, very, complicated, process]), verbo([regulated]), complemento([precisely, by, a, network, composed, of, many, genes, and, signaling, pathways, in, time, and, space])].
[sujeto(['Forkhead', box, '(', 'Fox,', 'FOX)', proteins, are, a, family, of, transcription, factors, characterized, by, the, presence, of, an, evolutionary]), verbo([conserved]), complemento([&, 'quot;forkhead&quot;or', &, 'quot;winged-helix&quot;', 'DNA-binding', domain, and, able, to, organize, temporal, and, spatial, gene, expression, during, development])].
[sujeto(['They', are]), verbo([involved]), complemento([in, a, wide, variety, of, cellular, 'processes,', such, as, cell, cycle, 'progression,', 'proliferation,', 'differentiation,', 'migration,', metabolism, and, 'DNA', damage, response])].
[sujeto(['An', abundance, of, studies, in, model, organisms, and, systems]), verbo([has]), complemento([established, that, 'Foxa2,', 'Foxc1/c2,', 'Foxh1', and, 'Foxm1,', 'Foxos', and, 'Foxps', are, important, components, of, the, signaling, pathways, that, instruct, cardiogenesis, and, embryonic, heart, 'development,', playing, paramount, roles, in, heart, development])].
[sujeto(['The', previous, studies, also]), verbo([have]), complemento([demonstrated, that, mutations, in, some, of, the, forkhead, box, genes, and, the, aberrant, expression, of, forkhead, box, gene, are, heavily, implicated, in, the, congenital, heart, disease, '(', 'CHD)', of, humans])].
[sujeto(['This', review, primarily, focuses, on, the, current, understanding, of, heart, development]), verbo([regulated]), complemento([by, forkhead, box, transcription, factors, and, molecular, genetic, mechanisms, by, which, forkhead, box, factors, modulate, heart, development, during, embryogenesis, and, organogenesis])].
[sujeto(['The', 'aspartate-histidine-histidine-cysteine', '(', 'DHHC)', protein, family, shares, a, 50, -, amino, acid, 'cysteine-rich', domain, with, a]), verbo([conserved]), complemento(['DHHC', signature, motif])].
[sujeto(['Several', 'DHHC', family, members]), verbo([have]), complemento([been, implicated, in, neuronal, differentiation, and, synaptic, plasticity])].
[sujeto(['And', disruptions, to, their, function, can]), verbo([lead]), complemento([to, disease, in, the, nervous, system])].
[sujeto(['In', the, 'meanshile,', mutant, zdhhc15b, zebrafish, was]), verbo([associated]), complemento([with, poor, learning, behavior, as, detected, by, 'T-maze', testing])].
[sujeto(['Consistent', with, the]), verbo([decreased]), complemento([number, of, 'DA', neurons, following, 'knock-down', of, 'zdhhc15b,', the, expression, of, fate, 'determination-related', transcription, factors, such, as, 'nurr1,', 'foxA2,', and, lmx1a, were, also, reduced, in, morphant, zebrafish])].
[sujeto(['Our', results]), verbo([reveal]), complemento([that, zdhhc15b, controls, 'DA', neuronal, fate, decisions, by, regulating, differentiation, but, not, progenitor, cell, proliferation, or, 'DA', neuronal, survival])].
[sujeto(['Laminin', 411, is, a, key, component, of, the, basement, membrane, and, is]), verbo([involved]), complemento([in, the, regulation, of, cell, 'differentiation;', 'however,', little, is, known, about, a, role, of, laminin, 411, in, the, regulation, of, 'IPC', differentiation, from, human, 'MSCs'])].
[sujeto(['To', evaluate, potential, therapeutic, efficacy, of, 'IPCs']), verbo([induced]), complemento([from, 'UC-MSCs,', a, 'type-1', diabetes, '(', 'T1DM)', rat, model, was, generated, using, streptozotocin])].
[sujeto(['Laminin', 411, markedly]), verbo([induced]), complemento([the, expression, of, the, genes, 'Foxa2', and, 'Sox17,', markers, for, pancreatic, precursor, 'cells,', efficiently, induced, 'IPC', differentiation, from, 'MSCs,', and, 'up-regulated', insulin, expression, at, both, mRNA, and, protein, levels])].
[sujeto(['Furthermore,', the, expression, of, the, genes, known, to, govern, insulin, expression, including, 'Pdx1', and, 'Ngn3', was, markedly]), verbo([induced]), complemento([by, laminin, 411, ',', which, suggests, that, 'Pdx1', and, 'Ngn3', signaling, pathways, are, involved, in, laminin, 411, 'induced-insulin', expression, machinery])].
[sujeto(['More', 'importantly,', administration, of, laminin, 411, -]), verbo([induced]), complemento(['IPCs', rapidly, and, significantly, 'down-regulated', fasting, blood, glucose, 'levels,', significantly, reduced, the, 'HbA1c', concentration, and, markedly, improved, the, symptoms, and, survival, of, 'T1DM', rats])].
[sujeto(['Our', results, demonstrate, that, laminin, 411]), verbo([acts]), complemento([as, a, potent, differentiation, inducer, of, 'IPCs', from, 'UC-MSCs', via, the, 'Pdx1', and, 'Ngn3', signaling, pathways])].
[sujeto(['These', novel]), verbo([finding]), complemento([highlights, a, potential, clinical, application, of, laminin, 411, 'induced-IPCs', in, the, treatment, of, 'T1DM,', which, calls, for, further, studies])].
[sujeto(['The', results, showed, that, most, frequent]), verbo([gains]), complemento([included, 8, q24])].
[sujeto([33, and]), verbo([losses]), complemento([in, 8, p23])].
[sujeto([1, -, p12, and]), verbo([gains]), complemento([of, 7, p12])].
[sujeto([1, -, q34, were]), verbo([associated]), complemento([with, positive, lymph, node, status, and, advanced, clinical, stage, '(', 'stages&nbsp;III&nbsp;and&nbsp;IV)'])].
[sujeto([2, -, 25.3]), verbo([gain]), complemento([was, more, frequent, in, patients, with, distant, metastasis])].
[sujeto(['Integrated', analysis, indicated, that, overexpression, of, 'PDP1,', 'TRIB1,', 'C13orf27,', 'FOXA2,', 'PMEPA1', and, 'PHACTR3', was]), verbo([associated]), complemento([with, 'gains,', and, underexpression, of, 'FHOD,', 'SMAD4', and, 'BCL2', was, associated, with, losses])].
[sujeto(['The', definitive, role, of, 'Wnt7a', in, postnatal, uterine, development, and, adult, function]), verbo([requires]), complemento([a, conditional, 'knockout,', because, global, deletion, disrupts, müllerian, duct, 'patterning,', 'specification,', and, cell, fate, in, the, fetus])].
[sujeto(['The', 'Wnt7a-null', uterus, appears, to, be, posteriorized, because, of, developmental, defects, in, the, 'embryo,', as, evidenced, by, the, stratified, luminal, epithelium, that, is, normally]), verbo([found]), complemento([in, the, vagina, and, the, presence, of, short, and, uncoiled, oviducts])].
[sujeto(['During', embryonic, 'development,', 'Foxa2', is]), verbo([required]), complemento([for, the, formation, of, the, node, and, 'notochord,', and, ablation, of, this, gene, results, in, defects, in, 'gastrulation,', neural, tube, 'patterning,', and, gut, morphogenesis])].
[sujeto(['Foxa2']), verbo([has]), complemento([been, shown, to, be, expressed, specifically, in, the, glandular, epithelium, of, the, murine, uterus])].
[sujeto(['Pgr(cre/+)', 'Foxa2(loxP/loxP)', mice, also, showed, a, severe, impairment, of, the, uterus, to]), verbo([respond]), complemento([to, the, artificial, induction, of, the, decidual, response])].
[sujeto(['The']), verbo([loss]), complemento([of, endometrial, glands, resulted, in, the, reduction, of, leukemia, inhibitory, factor, '(', 'Lif)', expression])].
[sujeto(['This', analysis, demonstrates, that, 'Foxa2']), verbo([regulates]), complemento([endometrial, gland, development, and, that, mice, with, a, loss, of, endometrial, glands, cannot, support, implantation, in, part, due, to, the, loss, of, 'LIF,', which, is, a, requisite, for, fertility, in, the, mouse])].
[sujeto(['The', oval, cells, are, thought, to, be, the, progeny, of, a, liver, stem, cell, compartment, and, strong, evidence, now, exists, indicating, that, these, cells, can]), verbo([participate]), complemento([in, liver, regeneration, by, differentiating, into, different, hepatic, lineages])].
[sujeto(['To', better, understand, the, regulation, of, this, process, we]), verbo([have]), complemento([studied, the, expression, of, 'liver-enriched', transcriptional, factors, '(', 'HNF1', alpha, and, 'HNF1', 'beta,', 'HNF3', 'alpha,', 'HNF3', 'beta,', and, 'HNF3', 'gamma,', 'HNF4,', 'C/EBP,', 'C/EBP', 'beta,', and, 'DBP)', in, an, experimental, model, of, oval, cell, proliferation, and, differentiation, and, compared, the, expression, of, these, factors, to, that, observed, during, late, stages, of, hepatic, ontogenesis])].
[sujeto(['The', 'steady-state', mRNA, levels, of, four, '(', 'HNF1', 'alpha,', 'HNF3', 'alpha,', 'HNF4,', and, 'C/EBP', 'beta)', &, 'quot;liver-enriched&quot;', transcriptional, factors, gradually]), verbo([decrease]), complemento([during, the, late, period, of, embryonic, liver, development, while, three, factors, '(', 'HNF1', 'beta,', 'HNF3', 'beta,', and, 'DBP)', increase])].
[sujeto(['However,', during, early, stages, of, oval, cell, proliferation, both, small, and, large, bile, ducts, start, to]), verbo([express]), complemento(['HNF1', alpha, and, 'HNF1', 'beta,', 'HNF3', 'gamma,', 'C/EBP,', and, 'DBP', but, not, 'HNF4'])].
[sujeto(['At', the, later, stages, all, of, these, factors, are, also, highly]), verbo([expressed]), complemento([in, the, proliferating, oval, cells])].
[sujeto(['Based', on, these, data, we]), verbo([suggest]), complemento([that, the, upregulation, of, the, &, 'quot;establishment&quot;', factors, '(', 'HNF1', and, -, 3, ')', may, be, an, important, step, in, oval, cell, activation])].
[sujeto(['Furthermore,', the, data]), verbo([suggest]), complemento([that, 'HNF4', may, be, responsible, for, the, final, commitment, of, a, small, portion, of, the, oval, cells, to, differentiate, into, hepatocytes, which, form, the, basophilic, foci, and, eventually, regenerate, the, liver, parenchyma])].
[sujeto(['However,', the, underlying, genetic, mechanism]), verbo([associated]), complemento([with, vitamin, 25, '(', 'OH)D', concentrations, is, poorly, understood])].
[sujeto(['We', earlier]), verbo([reported]), complemento([a, very, high, prevalence, of, vitamin, 'D', deficiency, associated, with, an, increased, risk, for, type, 2, diabetes, and, obesity, in, a, 'Punjabi', 'Sikh', diabetic, cohort, as, part, of, the, 'Asian', 'Indian', diabetic, heart, study, '(', 'AIDHS)'])].
[sujeto(['Here', we]), verbo([have]), complemento([performed, the, first, 'genome-wide', association, study, '(', 'GWAS)', of, serum, 25, '(', 'OH)D', on, 3538, individuals, from, this, 'Punjabi', 'Sikh', population])].
[sujeto([47, '×10(-9)]', between, 'FOXA2', and, 'SSTR4', was, identified, to, be]), verbo([associated]), complemento([with, 25, '(', 'OH)D', levels])].
[sujeto([36, '×10(-6)]', was]), verbo([found]), complemento([within, the, regulatory, region, of, the, 'IVL', gene, on, chromosome, 1, q21])].
[sujeto(['Additionally,', our, study, replicated, 3, of, 5, known, 'GWAS', genes]), verbo([associated]), complemento([with, 25, '(', 'OH)D', concentrations, including, 'GC', '(', 'p=0'])].
[sujeto([19, ')']), verbo([reported]), complemento([in, 'Europeans', and, the, 'DAB1', '(', 'p=0'])].
[sujeto([3, ')', ',']), verbo([reported]), complemento([in, 'Hispanics'])].
[sujeto(['Identification', of, novel, association, signals, in, biologically, plausible, regions, with, 25, '(', 'OH)D', metabolism, will]), verbo([provide]), complemento([new, molecular, insights, on, genetic, drivers, of, vitamin, 'D', status, and, its, implications, in, health, disparities])].
[sujeto(['Evidence']), verbo([suggests]), complemento([that, the, cytokine, interferon, '(', 'IFN)-γ', released, by, natural, killer, and, 'CD4(+)', 'T', cells, contributes, to, the, conjunctival, goblet, cell, '(', 'GC)', loss, in, dry, eye])].
[sujeto(['The', purpose, of, this, study, was, to, investigate, if, topical, neutralization, of, 'IFN-γ']), verbo([prevents]), complemento([or, alleviates, 'GC', loss, in, an, experimental, desiccating, stress, '(', 'DS)', model, of, dry, eye])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, topical, 'IFN-γ', neutralization, significantly, decreased, 'DS-induced', conjunctival, 'GC', loss])].
[sujeto(['This', was, accompanied, by]), verbo([decreased]), complemento([epithelial, 'apoptosis,', and, increased, 'IL-13', and, decreased, 'FoxA2', expression, in, the, forniceal, conjunctiva])].
[sujeto(['Similar', to, the, donor, 'mice,', topical, 'IFN-γ', neutralization]), verbo([decreased]), complemento([conjunctival, 'GC', 'loss,', suppressed, apoptosis, and, increased, 'IL-13', expression, in, adoptive, transfer, recipients])].
[sujeto(['In', 'summary,', this, study, demonstrated, that, topical, neutralization, of, 'IFN-γ']), verbo([prevents]), complemento(['GC', loss, via, modulating, apoptosis, and, maintaining, 'IL-13', signaling])].
[sujeto(['Activation', of, sonic, hedgehog, '(', 'HH)', signaling, pathway]), verbo([has]), complemento([been, implicated, in, aggressiveness, and, progression, of, gastrointestinal, tumors])].
[sujeto(['We', planned, this, study, to, identify, a, subgroup, of, gastric, cancer, '(', 'GC)', patients, with, 'HH', activation, and, to, assess, the, effect, of, a, 'HH', inhibitor, in, 'HH']), verbo([activated]), complemento(['GC', in, vitro])].
[sujeto(['We', surveyed, 'HH', pathway, activation, among, 512, 'GC', specimens, for, protein, expression, of, various]), verbo([target]), complemento([genes, involved, in, 'HH', 'pathway:', 'Indian', hedgehog, '(', 'IHH),', 'patched-1', '(', 'PTCH1),', smoothened, '(', 'SMO),', 'GLI2,', and, 'FOXA2'])].
[sujeto(['This', is, the, largest]), verbo([report]), complemento([to, analyze, the, hedgehog, pathway, in, 'GC'])].
[sujeto(['PTCH1', overexpression, was, an, independent, prognostic, factor, for, survival, and, 'SMO', overexpression, which, was]), verbo([found]), complemento([in, 12.0, '%', of, 'GC', patients, might, be, the, potential, predictive, marker, of, 'HH', inhibitor])].
[sujeto(['Intestinal', cell, kinase, '(', 'ICK;', 'GeneID', 22858, ')', is, a]), verbo([conserved]), complemento(['MAPK', and, 'CDK-like', kinase, that, is, widely, expressed, in, human, tissues])].
[sujeto(['Data', from, the, 'Cancer', 'Genome', 'Anatomy', 'Project', indicated, 'ICK', mRNA, is]), verbo([increased]), complemento([in, 'cancer,', and, that, its, expression, correlated, with, expression, of, mRNA, for, an, uncharacterized, 'F-box', 'protein,', 'FBX9', '(', 'GeneID:', 26268, ')'])].
[sujeto(['Results', from, deletions, and, truncations, defined, a, minimal, promoter, for, 'ICK,', and, revealed, that, repressors, and, enhancers, differentially]), verbo([regulate]), complemento(['ICK', versus, 'FBX9', promoter, activity])].
[sujeto(['FOXA1', and, 'FOXA2']), verbo([increase]), complemento([luciferase, activity, of, a, minimal, promoter, 10, -, 20, fold, in, 'HEK293T', cells])].
[sujeto(['The', expression, of, 'beta-catenin']), verbo([increased]), complemento([activity, of, the, minimal, promoter, approximately, 10, fold])].
[sujeto([3, ',', 'NM_016513)', are]), verbo([expressed]), complemento([in, low, copy, number, and, increased, in, some, breast, 'cancers,', using, a, ten, base, tag, 5, '\'', -, 'TCAACCTTAT-3\'', specific, for, both, 'ICK', transcripts])].
[sujeto(['ICK', and, 'FBX9', are, divergently]), verbo([transcribed]), complemento([from, a, bidirectional, promoter, that, is, 'GC-rich', and, contains, a, 'CpG', island])].
[sujeto(['These', data, are, consistent, with, functions, that]), verbo([have]), complemento([been, proposed, for, 'ICK', in, development, and, in, proliferation, or, survival, of, some, breast, and, colon, cancers])].
[sujeto(['WNT5A', is, a, 'cancer-associated', gene]), verbo([involved]), complemento([in, invasion, and, metastasis, of, 'melanoma,', breast, 'cancer,', pancreatic, 'cancer,', and, gastric, cancer])].
[sujeto(['SNAI1', '(', 'Snail),', 'CD44,', 'G3BP2,', and, 'YAP1', are, 'WNT5A']), verbo([target]), complemento([genes])].
[sujeto(['We', and, other, groups, previously]), verbo([reported]), complemento([that, 'IL6-', or, 'LIF-induced', signaling, through, 'JAK-STAT3', signaling, cascade, is, involved, in, 'WNT5A', upregulation, '(', 'STAT3-WNT5A', signaling, 'loop)'])].
[sujeto(['The', 'WNT5A', gene, was]), verbo([found]), complemento([to, encode, two, isoforms, by, using, alternative, first, exons, 1, 'A', and, 1, 'B'])].
[sujeto(['Quadruple', 'Smad-binding', elements, '(', 'SBEs),', single, 'Sp1-binding', site, '(', 'GC-box),', 'PPARgamma-binding', 'site,', 'C/EBP-binding', site, and, 'bHLH-binding', site, within, the, promoter, 'A', 'region,', 5, '\'', -, adjacent, to, exon, 1, 'A,', were]), verbo([conserved]), complemento([in, human, 'WNT5A,', chimpanzee, 'WNT5A,', mouse, 'Wnt5a,', and, rat, 'Wnt5a'])].
[sujeto(['NF-kappaB-binding', 'site,', 'CUX1-binding', 'site,', double, 'SBEs', and, double, 'GC-boxes', within, the, promoter, 'B', 'region,', 5, '\'', -, adjacent, to, exon, 1, 'B,', were]), verbo([conserved]), complemento([in, mammalian, 'WNT5A', orthologs])].
[sujeto(['Quadruple', 'FOX-binding', sites, and, double, 'SBEs', within, 'ultra-conserved', intron, 1, were, also]), verbo([conserved]), complemento([in, mammalian, 'WNT5A', orthologs])].
[sujeto(['Quadruple', 'FOX-binding', sites, rather, than, 'GLI-binding', site, revealed, that, 'Hedgehog', signals]), verbo([induce]), complemento(['WNT5A', upregulation, indirectly, via, 'FOX', family, 'members,', such, as, 'FOXA2,', 'FOXC2,', 'FOXE1,', 'FOXF1', and, 'FOXL1'])].
[sujeto(['TGFbeta', signals, were]), verbo([found]), complemento([to, upregulate, 'WNT5A', expression, directly, through, the, 'Smad', 'complex,', and, also, indirectly, through, 'Smad-induced', 'CUX1', and, 'MAP3K7-mediated', 'NF-kappaB'])].
[sujeto(['Together', these, facts, indicate, that, 'WNT5A', is]), verbo([transcribed]), complemento([based, on, multiple, 'mechanisms,', such, as, 'NF-kappaB,', 'Hedgehog,', 'TGFbeta,', and, 'Notch', signaling, cascades])].
[sujeto(['The', endostatin, precursor, collagen, 'XVIII', is]), verbo([expressed]), complemento([at, high, levels, in, human, 'livers,', the, main, source, being, hepatocytes])].
[sujeto(['We']), verbo([have]), complemento([studied, the, regulatory, elements, in, the, promoter, 2, of, the, 'Col18a1', gene, that, directs, the, transcription, of, the, 'NC1-517', variant, of, collagen, 'alpha1(XVIII),', which, is, the, main, form, expressed, in, the, liver])].
[sujeto(['Gel-shift', analyses, showed, that, 'HNF3,', 'NF1/CTF,', and, 'Sp1-like', sites, specifically]), verbo([recognized]), complemento([nuclear, factors])].
[sujeto(['Super-shift', experiments, indicated, that, 'HNF3beta', was, the, major, form, of, 'HNF3']), verbo([interacting]), complemento([with, the, 'HNF3/NF1', site])].
[sujeto(['The', 'well-differentiated', hepatoma, cell, line, mhATFS315, transfected, with, a, truncated, form, of, 'HNF3beta,', which, competitively, blocks, 'HNF3', transactivating, 'activity,']), verbo([expressed]), complemento([the, 'Col18a1gene', at, a, very, low, level])].
[sujeto(['Taken', 'together,', these, data, strongly]), verbo([suggest]), complemento([that, 'Col18a1', is, a, 'liver-specific', gene])].
[sujeto(['Furthermore,', 'gel-shift', analyses, performed, with]), verbo([nuclear]), complemento([factors, prepared, from, 'well-differentiated', hepatocellular, carcinomas, showed, increased, 'HNF3/NF1', binding, activity, compared, with, normal, livers])].
[sujeto(['Consequently,', the, precursor, of, endostatin, might, be, differently]), verbo([expressed]), complemento([according, to, the, differentiated, 'and/or', transformed, state, of, hepatocytes])].
[sujeto(['Long', noncoding, 'RNAs', '(', 'lncRNAs)', are, thought, to, play, important, roles, in]), verbo([regulating]), complemento([gene, 'transcription,', but, few, have, 'well-defined', expression, patterns, or, known, biological, functions, during, mammalian, development])].
[sujeto(['Using', a, conservative, pipeline, to, identify, lncRNAs, that]), verbo([have]), complemento([important, biological, 'functions,', we, identified, 363, lncRNAs, in, the, lung, and, foregut, endoderm])].
[sujeto([1, -]), verbo([associated]), complemento([noncoding, intergenic, 'RNA)', and, 'LL34,', play, distinct, roles, in, endoderm, development, by, controlling, expression, of, critical, developmental, transcription, factors, and, 'pathways,', including, retinoic, acid, signaling])].
[sujeto(['In', 'particular,', we, show, that, 'LL18/NANCI']), verbo([acts]), complemento([upstream, of, 'Nkx2'])].
[sujeto([1, and, downstream, from, 'Wnt', signaling, to]), verbo([regulate]), complemento([lung, endoderm, gene, expression])].
[sujeto(['These', studies]), verbo([reveal]), complemento([that, lncRNAs, play, an, important, role, in, foregut, and, lung, endoderm, development, by, regulating, multiple, aspects, of, gene, 'transcription,', often, through, regulation, of, transcription, factor, expression])].
[sujeto(['Our', goal, is, to, decipher, which, 'DNA', sequences, are]), verbo([required]), complemento([for, 'tissue-specific', expression, of, epididymal, genes])].
[sujeto(['These', are, differently]), verbo([regulated]), complemento([and, regionalized, in, the, epididymis])].
[sujeto(['To', define, further, the, fragments]), verbo([regulating]), complemento([gene, 'expression,', the, 'Lcn5', promoter, was, examined, in, transgenic, mice, and, immortalized, epididymal, cell, lines])].
[sujeto(['Transient', transfection, analysis, revealed, that, a, transcription, factor, forkhead, box, 'A2', '(', 'Foxa2)']), verbo([interacts]), complemento([with, androgen, receptor, and, binds, to, the, 100, bp, fragment, of, the, 'Lcn5', promoter, between, 1.2, kb, and, 1.3, kb, and, that, 'Foxa2', expression, inhibits, 'androgen-dependent', induction, of, the, 'Lcn5', promoter, activity])].
[sujeto(['Immunohistochemistry', indicated, a, restricted, expression, of, 'Foxa2', in, the, epididymis, where, endogenous, 'Lcn5', gene, expression, is]), verbo([suppressed]), complemento([and, that, the, 'Foxa2', inhibition, of, the, 'Lcn5', promoter, is, consistent, with, the, lack, of, expression, of, 'Lcn5', in, the, corpus, and, cauda])].
[sujeto(['Our', approach]), verbo([provides]), complemento([a, basic, strategy, for, further, analysis, of, the, epididymal, lipocalin, gene, regulation, and, flexible, control, of, epididymal, function])].
[sujeto(['The', relative, lack, of, successful, pancreatic, differentiation, of, human, embryonic, stem, cells, '(', 'hESCs)', may]), verbo([suggest]), complemento([that, directed, differentiation, of, hESCs, into, definitive, endoderm, and, subsequent, commitment, towards, a, pancreatic, fate, are, not, readily, achieved])].
[sujeto(['The', patterns, of, gene, expression, and, protein, production]), verbo([associated]), complemento([with, embryonic, germ, layers, and, pancreatic, endoderm, were, analysed, by, 'RT-PCR', and, immunostaining])].
[sujeto(['The', population, of, pancreatic, endodermal, cells, that, produced, 'PDX1', was, significantly]), verbo([increased]), complemento([at, the, expense, of, ectodermal, 'differentiation,', and, a, subset, of, the, 'PDX1-positive', cells, also, produced, 'FOXA2,', 'caudal-type', homeobox, transcription, factor, 2, '(', 'CDX2),', and, nestin, '(', 'NES)'])].
[sujeto(['After', 'transplantation,', the, 'PDX1-positive', cells, further, differentiated, into, mature, cell, types, producing, insulin, and, 'glucagon,', resulting, in, amelioration, of, hyperglycaemia, and, weight]), verbo([loss]), complemento([in, 'streptozotocin-treated', diabetic, mice])].
[sujeto(['Here,', we]), verbo([reported]), complemento([that, the, 1.8, -, kb, 'Lcn5', promoter, confers, epididymis, 'region-specific', gene, expression, in, transgenic, mice])].
[sujeto(['Between', the, 1.2, -, kb, to, 1.3, -, kb, 'region,', two, androgen, receptor, '(', 'AR)']), verbo([binding]), complemento([sites, were, identified])].
[sujeto(['Adjacent', to, 'AR']), verbo([binding]), complemento(['sites,', a, 'Foxa2', '[', 'Fox', '(', 'Forkhead', 'box)', subclass, 'A]', binding, site, was, confirmed, by, gel, shift, assay])].
[sujeto(['Similar', 'Foxa']), verbo([binding]), complemento([sites, were, also, found, on, the, promoters, of, human, and, rat, 'Lcn5,', indicating, the, 'Foxa', binding, site, is, conserved, among, species])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, among, the, three, members, of, 'Foxa', 'family,', 'Foxa1', and, 'Foxa3', were, absent, in, the, epididymis, whereas, 'Foxa2', was, detected, in, epididymal, principal, cells])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, 'Foxa2', displays, a, 'region-specific', expression, pattern, along, the, 'epididymis:', no, staining, observed, in, initial, 'segment,', light, staining, in, proximal, 'caput,', gradiently, heavier, staining, in, middle, and, distal, 'caput,', and, strongest, staining, in, corpus, and, 'cauda,', regions, with, little, or, no, expression, of, 'Lcn5'])].
[sujeto(['In', transient, transfection, 'experiments,', 'Foxa2', expression]), verbo([inhibits]), complemento(['AR', induction, of, the, 'Lcn5', 'promoter,', which, is, consistent, with, the, lack, of, expression, of, 'Lcn5', in, the, corpus, and, cauda])].
[sujeto(['One', would, hypothesize, that, disrupting, this, process]), verbo([provides]), complemento([an, ideal, approach, to, male, 'contraception,', since, it, would, not, interfere, with, testicular, endocrine, output, or, sperm, production])].
[sujeto(['To', achieve, this, 'purpose,', we, studied, a, cluster, of, 'epididymis-specific', lipocalin, genes, for, understanding, the, specific, mechanisms]), verbo([involved]), complemento([in, the, control, of, gene, expression, in, the, epididymis])].
[sujeto(['We']), verbo([have]), complemento([identified, six, 'epididymis-specific', lipocalin, genes, that, are, differently, regulated, and, regionalized, in, the, epididymis])].
[sujeto(['Lipocalin', 5, '[', 'Lcn5', or, epididymal, retinoic, 'acid-binding', protein, '(', 'E-RABP)]', is, a, member, of, this, 'epididymis-specific', lipocalin, gene, 'cluster,', which]), verbo([binds]), complemento([hydrophobic, molecules, such, as, retinoic, acid])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, the, 5, kb, promoter, fragment, of, the, 'Lcn5', gene, confers, both, 'androgen-dependent', regulation, and, 'epididymis-specific', gene, expression, in, transgenic, mice, whereas, 0.6, kb, promoter, fragment, does, not])].
[sujeto(['To', further, narrow, down, the, important, 'cis-regulatory', elements, that]), verbo([regulate]), complemento([gene, expression, in, the, 'epididymis,', we, studied, the, 'Lcn5', promoter, in, both, transgenic, mice, and, immortalized, epididymal, cells])].
[sujeto(['We']), verbo([have]), complemento([found, that, 1.8, kb, promoter, fragment, of, the, 'Lcn5', gene, was, sufficient, for, 'tissue-', and, 'region-specific', expression, in, transgenic, 'mice,', and, that, a, transcription, factor, 'Forkhead', box, 'A2', '(', 'Foxa2)', interacts, with, the, androgen, receptor, and, binds, to, the, 100, bp, fragment, of, the, 'Lcn5', promoter, between, 1.2, and, 1.3, kb])].
[sujeto(['Our']), verbo([finding]), complemento([provides, a, framework, for, further, analysis, of, the, epididymal, lipocalin, gene, regulation, and, modulated, control, of, 'epididymis-specific', expression])].
[sujeto(['Human', embryonic, stem, cells, '(', 'hESCs)']), verbo([retain]), complemento([the, extraordinary, capacity, to, differentiate, into, different, cell, types, of, an, adult, 'organism,', including, pancreatic, 'β-cells'])].
[sujeto(['For', this, particular, 'lineage,', although, a, lot, of, effort]), verbo([has]), complemento([been, made, in, the, last, ten, years, to, achieve, an, efficient, and, reproducible, differentiation, 'protocol,', it, was, not, until, recently, that, this, aim, was, roughly, accomplished])].
[sujeto(['Our', results, indicate, that, treatment, of, hESCs, '(', 'HS-181)', with, 'activin-A']), verbo([induced]), complemento([definitive, endoderm, differentiation, as, detected, by, the, expression, of, 'SOX17', and, 'FOXA2'])].
[sujeto(['Addition', of, retinoic, acid, '(', 'RA),', 'Noggin', and, 'Cyclopamine']), verbo([promoted]), complemento([pancreatic, differentiation, as, indicated, by, the, expression, of, the, early, pancreatic, progenitor, markers, 'ISL1,', 'NGN3', and, 'PDX1'])].
[sujeto(['Moreover,', during, maturation, in, suspension, 'culture,', differentiating, cells, assembled, in, 'islet-like', 'clusters,', which]), verbo([expressed]), complemento([specific, endocrine, markers, such, as, 'PDX1,', 'SST,', 'GCG', and, 'INS'])].
[sujeto(['Similar', results, were, confirmed, with, the, human]), verbo([induced]), complemento(['Pluripotent', 'Stem', 'Cell', '(', 'hiPSC)', line, 'MSUH-001'])].
[sujeto(['Finally,', differentiation, protocols, incorporating, 'RSV', treatment, yielded, numerous, 'insulin-positive', 'cells,']), verbo([induced]), complemento([significantly, higher, 'PDX1', expression, and, were, able, to, transiently, normalize, glycaemia, when, transplanted, in, streptozotocin, '(', 'STZ)', induced, diabetic, mice, thus, promoting, its, survival])].
[sujeto(['It', was, recently]), verbo([reported]), complemento([that, human, periapical, cysts, '(', 'hPCys),', a, commonly, occurring, odontogenic, cystic, lesion, of, inflammatory, 'origin,', contain, mesenchymal, stem, cells, '(', 'MSCs)', with, the, capacity, for, 'self-renewal', and, multilineage, differentiation])].
[sujeto(['In', this, 'study,', periapical, inflammatory, cysts, were, compared, with, dental, pulp, to, determine, whether, this, tissue, may, be, an, alternative, accessible, tissue, source, of, 'MSCs', that]), verbo([retain]), complemento([the, potential, for, neurogenic, differentiation])].
[sujeto(['Flow', cytometry, and, immunofluorescence, analysis, indicated, that, 'hPCy-MSCs', and, dental, pulp, stem, cells, spontaneously]), verbo([expressed]), complemento([the, 'neuron-specific', protein, 'β-III', tubulin, and, the, neural, 'stem-/astrocyte-specific', protein, glial, fibrillary, acidic, protein, '(', 'GFAP)', in, their, basal, state, before, differentiation, occurs])].
[sujeto(['After', exposure, to, neurogenic, differentiation, conditions, '(', neural, media, containing, epidermal, growth, factor, '[', 'EGF],', basic, fibroblast, growth, factor, '[', 'bFGF],', and, retinoic, 'acid),', the, 'hPCy-MSCs', showed]), verbo([enhanced]), complemento([expression, of, 'β-III', tubulin, and, 'GFAP', 'proteins,', as, well, as, increased, expression, of, neurofilaments, 'medium,', neurofilaments, 'heavy,', and, 'neuron-specific', enolase, at, the, transcript, level])].
[sujeto(['The', present, study, demonstrated, for, the, first, time, that, 'hPCy-MSCs']), verbo([have]), complemento([a, predisposition, toward, the, neural, phenotype, that, is, increased, when, exposed, to, neural, differentiation, 'cues,', based, on, upregulation, of, a, comprehensive, set, of, proteins, and, genes, that, define, neuronal, cells])].
[sujeto(['In', 'conclusion,', these, results]), verbo([provide]), complemento([evidence, that, 'hPCy-MSCs', might, be, another, optimal, source, of, 'neural/glial', cells, for, 'cell-based', therapies, to, treat, neurologic, diseases])].
[sujeto(['We', previously]), verbo([reported]), complemento([the, in, vitro, differentiation, of, human, embryonic, stem, cells, '(', 'hESCs)', into, pancreatic, endoderm])].
[sujeto(['Sequential', treatment, with, 'Wnt3a,', activin, 'A,', and, noggin]), verbo([induced]), complemento([a, transient, upregulation, of, 'T', and, 'MixL1,', followed, by, increased, expression, of, endodermal, 'genes,', including, 'FOXA2,', 'SOX17,', and, 'CXCR4'])].
[sujeto(['We', also, show, that, inhibition, of, sonic, hedgehog, signaling, by, 'bFGF/activin', βB, and, cotreatment, with, 'VEGF', and, 'FGF7', produced, many, 3, 'D', cellular, clusters, that]), verbo([express]), complemento([both, 'SOX17', and, 'PDX1'])].
[sujeto(['We']), verbo([found]), complemento([for, the, first, time, that, proteoglycans, and, 'vimentin(+)', mesenchymal, cells, were, mainly, localized, in, 'hESC-derived', 'PDX1(+)', clusters])].
[sujeto(['Importantly,', treatment, with, 'chlorate,', an, inhibitor, of, proteoglycan, 'sulfation,', together, with, inhibition, of, 'Notch', signaling, significantly]), verbo([increased]), complemento([the, expression, of, 'Neurog3', and, 'NeuroD1,', promoting, a, transition, from, 'PDX1(+)', progenitor, cells, toward, mature, pancreatic, endocrine, cells])].
[sujeto(['Purified', 'dithizone(+)', 3, 'D', aggregates, generated, by, our, refined, protocol, produced, pancreatic, hormones, and]), verbo([released]), complemento([insulin, in, response, to, both, glucose, and, pharmacological, drugs, in, vitro])].
[sujeto(['Furthermore,', the, 'islet-like', 3, 'D', aggregates]), verbo([decreased]), complemento([blood, glucose, levels, and, continued, to, exhibit, pancreatic, features, after, transplantation, into, diabetic, mice])].
[sujeto(['Retinoic', acid, '(', 'RA)']), verbo([has]), complemento([diverse, biological, effects])].
[sujeto(['The', liver, stores, vitamin, 'A,', generates, 'RA,', and]), verbo([expresses]), complemento([receptors, for, 'RA'])].
[sujeto(['The', current, study, examines, the, hepatic]), verbo([binding]), complemento([profile, of, two, 'RA', receptor, 'isoforms,', 'RARA', '(', 'RARα)', and, 'RARB', '(', 'RARβ),', in, response, to, 'RA', treatment, in, mouse, livers])].
[sujeto(['Each']), verbo([expressed]), complemento([unique, and, common, 'bindings,', implying, their, redundant, and, specific, roles])].
[sujeto(['RARB']), verbo([has]), complemento([higher, 'RA', responsiveness, than, 'RARB'])].
[sujeto(['RAR', frequently]), verbo([bound]), complemento([the, consensus, hormone, response, element, '[', 'HRE;', '(', 'A/G)G(G/T)TCA],', which, often, contained, the, motifs, assigned, to, 'SP1,', 'GABPA,', and, 'FOXA2,', suggesting, potential, interactions, between, those, transcriptional, factors])].
[sujeto(['Functional', annotation, coupled, with, principle, component, analysis, revealed, that, the, function, of, 'RAR']), verbo([target]), complemento([genes, were, motif, dependent])].
[sujeto(['RAR']), verbo([target]), complemento([genes, are, enriched, in, various, biological, processes])].
[sujeto(['The', hepatic, 'RAR', 'genome-wide']), verbo([binding]), complemento([data, can, help, us, understand, the, global, molecular, mechanisms, underlying, 'RAR', and, 'RA-mediated', gene, and, pathway, regulation])].
[sujeto(['Moreover,', in, 'Step', 'III,', the]), verbo([induced]), complemento([cells, expressed, pancreatic, markers, such, as, 'amylase,', carboxypeptidase, 'A', and, chymotrypsinogen, 'B,', which, were, similar, to, those, in, normal, human, pancreas])].
[sujeto(['From', day, 8, in, 'Step', 'III,', cells, immunohistochemically, positive, for, amylase, and, for, carboxypeptidase, 'A,', a, pancreatic, exocrine, cell, 'product,', were]), verbo([induced]), complemento([by, 'FGF7'])].
[sujeto(['Thus,', our, 'three-step', culture, protocol, for, human, 'ES', cells, effectively]), verbo([induces]), complemento([the, differentiation, of, 'amylase-', and, 'carboxypeptidase-A-containing', pancreatic, exocrine, cells])].
[sujeto(['Sox17,', 'GATA4,', 'GATA6,', 'FoxA2,', 'HEX,', 'HNF4α', and, 'C/EBPα', were]), verbo([expressed]), complemento([in, fetal, and, adult, liver, 'cells,', but, not, in, iPS, cells])].
[sujeto(['Sox17,', 'GATA6', and, 'HNF4α', were]), verbo([expressed]), complemento([after, exposure, a, combination, of, oncostatin, 'M,', epidermal, growth, 'factor,', retinoic, 'acid,', dexamethasone, and, 'ITS', '(', 'OERDITS)'])].
[sujeto(['When', iPS, cells, were, introduced, with, 'FoxA2,', 'GATA4,', 'HEX', and, 'C/EBPα', and, cultured, with, 'OERDITS', for, 8, 'days,', the, cells]), verbo([expressed]), complemento(['α-fetoprotein,', 'δ-like', '(', 'Dlk)-1', and, 'γ-glutamyl', transpeptidase, '(', 'GTP),', and, 'ICG', uptake, was, observed])].
[sujeto(['Generation', of, 'PP', cells, from, adipose, 'tissue-derived', mesenchymal, stem, cells, '(', 'AD-MSCs)', would]), verbo([provide]), complemento([an, unlimited, source, of, 'PP', cells])].
[sujeto(['Here', we, developed, a, 2, -, step, stepwise, 'protocol,', which]), verbo([induced]), complemento(['AD-MSCs', to, generate, 'FOXA2-', or, 'SOX17-positive', definitive, endoderm, '(', 'DE)', '(', 5, 'days)', and, pancreatic, and, duodenal, homeobox, gene, 1, '(', 'PDX1)-positive', 'PP', cells, '(', 4, -, 6, 'days)'])].
[sujeto(['By', mimicking, the, developmental, progress, in, embryonic, 'development,', we, optimized, the, timing, and, combination, of, cytokines, to]), verbo([activate]), complemento([the, key, signaling, pathways, during, pancreatic, development])].
[sujeto(['We']), verbo([found]), complemento([that, activating, the, 'Nodal/Activin', signal, with, 'Activin', 'A', could, induce, differentiation, of, 'AD-MSCs', toward, 'DE,', which, could, be, further, promoted, by, the, 'Wnt', signaling, pathway, activator, 'Wnt3a'])].
[sujeto(['Subsequently,', the, 'Wnt', signaling, pathway, inhibitor, 'Dkk1', along, with, retinoic, 'acid/FGF2', '(', 60, 'ng/mL)', further]), verbo([induced]), complemento(['AD-MSC-derived', 'DE', cells, to, differentiate, into, 'PDX1-positive', 'PP', cells])].
[sujeto(['It', might]), verbo([provide]), complemento([an, unlimited, source, of, autologous, 'PP', cells, for, pancreatic, diseases])].
[sujeto(['One', of, the, earliest, 'epithelial-to-mesenchymal', transitions, in, mouse, embryogenesis]), verbo([involves]), complemento([the, differentiation, of, inner, cell, mass, cells, into, primitive, and, then, into, parietal, endoderm])].
[sujeto(['Our', previous, work, on, how, primitive, endoderm, develops, revealed, that, the, 'Wnt6', gene, is, upregulated, by, 'RA,']), verbo([leading]), complemento([to, the, activation, of, the, canonical, 'WNT-β-catenin', pathway])].
[sujeto(['The', mechanism, by, which, 'Wnt6', is]), verbo([regulated]), complemento([was, not, 'determined,', but, in, silico, analysis, of, the, human, 'WNT6', promoter, region, had, suggested, that, the, 'GATA6', and, 'FOXA2', transcription, factors, might, be, involved, '[', 1, ']'])].
[sujeto(['More', 'specifically,', overexpression, of, 'Gata6', or, 'Foxa2', alone]), verbo([induced]), complemento([molecular, and, morphological, markers, of, primitive, 'endoderm,', which, occurred, concomitantly, with, the, upregulation, of, the, 'Wnt6', gene])].
[sujeto(['Gata6-', or, 'Foxa2-overexpressing', cells, were, also]), verbo([found]), complemento([to, have, increased, levels, in, 'T-cell', factor, '(', 'TCF)-dependent', 'transcription,', and, when, these, cells, were, treated, with, 'db-cAMP,', they, developed, into, parietal, endoderm])].
[sujeto(['Chromatin', immunoprecipitation, analysis, revealed, that, 'GATA6', and, 'FOXA2', were]), verbo([bound]), complemento([to, the, 'Wnt6', 'promoter,', and, overexpression, studies, showed, that, these, transcription, factors, were, sufficient, to, switch, on, the, gene, expression, of, a, 'Wnt6', reporter, construct])].
[sujeto(['Together,', these, results]), verbo([provide]), complemento([evidence, for, the, direct, regulation, of, 'Wnt6', that, leads, to, the, activation, of, the, canonical, 'WNT-β-catenin', pathway, and, subsequent, induction, of, primitive, extraembryonic, endoderm])].
[sujeto(['The', results, obtained, demonstrated, that, neural, rosette, forming, cells]), verbo([respond]), complemento([to, 'RA', with, clear, 'concentration-dependent', 'morphological,', and, gene, expression, changes, remarkably, similar, to, those, induced, in, 'vivo,', in, the, developing, neural, 'tube,', by, 'RA', exposure])].
[sujeto(['This', strict, correspondence, indicates, that, the, neural, rosette, protocol, described, is, capable, of, detecting, specific, teratogenic, mechanisms]), verbo([causing]), complemento([perturbations, of, early, neural, development, and, therefore, represents, a, promising, alternative, test, for, human, prenatal, developmental, toxicity])].
[sujeto(['Mouse', embryonic, stem, cells, '(', 'ESCs)', can, be]), verbo([induced]), complemento([to, form, pancreatic, exocrine, 'enzyme-producing', cells, in, vitro, in, a, stepwise, fashion, that, recapitulates, the, development, in, vivo])].
[sujeto(['Based', upon, the, mouse, 'ESC', 'model,', we]), verbo([have]), complemento([induced, the, in, vitro, formation, of, pancreatic, exocrine, 'enzyme-producing', cells, from, hESCs])].
[sujeto(['In', 'Stage', 1, ',', embryoid, bodies, '(', 'EBs)', were, formed, from, dissociated, hESCs, and, then, treated, with, the, growth, factor, activin, 'A,', which]), verbo([promoted]), complemento([the, expression, of, 'Foxa2', and, 'Sox17', 'mRNAs,', markers, of, definitive, endoderm])].
[sujeto(['In', 'Stage', 2, ',', the, cells, were, treated, with, 'all-trans', retinoic, acid, which]), verbo([promoted]), complemento([the, transition, to, cells, that, expressed, gut, tube, endoderm, mRNA, marker, 'HNF1b'])].
[sujeto(['In', 'Stage', 3, ',', the, cells, were, treated, with, fibroblast, growth, factor, 7, '(', 'FGF7),', which]), verbo([induced]), complemento([expression, of, 'Pdx1', typical, of, pancreatic, progenitor, cells])].
[sujeto(['In', 'Stage', 4, ',', treatment, with, 'FGF7,', 'glucagon-like', peptide, 1, ',', and, nicotinamide]), verbo([induced]), complemento([the, expression, amylase, '(', 'AMY)', 'mRNA,', a, marker, for, mature, pancreatic, exocrine, cells])].
[sujeto(['These', cells, also]), verbo([expressed]), complemento([other, exocrine, secretory, proteins, including, 'elastase,', carboxypeptidase, 'A,', 'chymotrypsin,', and, pancreatic, lipase, in, culture])].
[sujeto(['The', homeobox, gene, 'Noto', is]), verbo([expressed]), complemento([in, the, node, and, its, derivative, the, notochord])].
[sujeto(['Here', we, use, a]), verbo([targeted]), complemento(['Noto-GFP', reporter, to, isolate, and, characterize, 'node/notochord-like', cells, derived, from, mouse, embryonic, stem, cells])].
[sujeto(['We']), verbo([find]), complemento([very, few, 'Noto-expressing', cells, after, spontaneous, differentiation])].
[sujeto(['However,', the, number, of, 'Noto-expressing', cells, was]), verbo([increased]), complemento([when, using, 'Activin', 'A', to, induce, a, 'Foxa2-', and, 'Brachyury-expressing', progenitor, 'population,', whose, further, differentiation, into, 'Noto-expressing', cells, was, improved, by, simultaneous, inhibition, of, 'BMP,', 'Wnt,', and, retinoic, acid, signaling])].
[sujeto(['Noto-GFP(+)', cells]), verbo([expressed]), complemento([the, 'node/notochord', markers, 'Noto,', 'Foxa2,', 'Shh,', 'Noggin,', 'Chordin,', 'Foxj1,', and, 'Brachyury;', showed, a, vacuolarization, characteristic, of, notochord, 'cells;', and, can, integrate, into, midline, structures, when, grafted, into, 'Hensen\'s', node, of, gastrulating, chicken, embryos])].
[sujeto(['The', produced, cells, were, analyzed, by, quantitative, 'PCR,', immunohistochemistry, and, static, insulin]), verbo([release]), complemento([assay, for, markers, of, trilaminar, 'embryo,', and, pancreas])].
[sujeto(['Differentiated', cells, displayed]), verbo([increased]), complemento(['Sox17', and, 'Foxa2', expression, consistent, with, definitive, endoderm, production])].
[sujeto(['Various', assays, revealed, that, the, cell, clusters, generated, by, this, protocol]), verbo([express]), complemento([markers, of, the, pancreatic, lineage, including, insulin, 'I,', insulin, 'II,', 'C-peptide,', 'PDX-1,', carboxypeptidase, 'E,', 'pan-cytokeratin,', 'amylase,', 'glucagon,', 'PAX6,', 'Ngn3', and, 'Nkx6'])].
[sujeto(['This', protocol, using, 'all-trans-retinoic', 'acid,', 'DBcAMP,', in, the, absence, of, embryoid, 'bodies,', generated, cells, that]), verbo([have]), complemento([features, of, definitive, endoderm, that, may, serve, as, pancreatic, endocrine, precursors])].
[sujeto(['We', developed, a, differentiation, protocol, that, gradually]), verbo([induced]), complemento([the, formation, of, mouse, pancreatic, exocrine, cells, from, embryonic, stem, cells, '(', 'ESCs)'])].
[sujeto(['This', process, mimicked, in, vivo, pancreatic, development, by, directing, cells, through, definitive, endoderm, '(', 'DE),', gut, tube, 'endoderm,', and, pancreatic, progenitor, cells, to, differentiated, cells, that]), verbo([expressed]), complemento([pancreatic, exocrine, enzymes])].
[sujeto(['Treatment', of, embryoid, bodies, with, activin, 'A']), verbo([induced]), complemento([the, formation, of, 'DE', cells, that, expressed, marker, mRNAs, 'Goosecoid', and, 'Mixl1', and, that, were, 'double-positive', with, 'Foxa2', and, 'Sox17', proteins])].
[sujeto(['Subsequent', treatment, of, the, 'DE', cells, by, retinoic, acid]), verbo([induced]), complemento([the, formation, of, gut, tube, endoderm, cells, that, expressed, the, specific, marker, 'Hnf1b'])].
[sujeto(['Fibroblast', growth, factor, 7, '(', 'FGF7)']), verbo([promoted]), complemento([differentiation, of, 'PDX1-expressing', pancreatic, progenitor, cells, that, also, expressed, 'Foxa2', 'mRNA,', an, endodermal, 'marker,', suggesting, derivation, from, the, 'DE', cells])].
[sujeto(['Exocrine', cell, differentiation, was]), verbo([induced]), complemento([with, 'FGF7,', 'glucagon-like', 'peptide-1,', and, nicotinamide])].
[sujeto(['The', differentiated, cells]), verbo([expressed]), complemento([mature, pancreatic, exocrine, cell, 'mRNAs,', such, as, 'Amylase,', 'Elastase,', and, 'Carboxypeptidase', 'A'])].
[sujeto(['Active', amylase, was]), verbo([released]), complemento([into, the, medium])].
[sujeto(['Moreover,', 'FGF7', was]), verbo([associated]), complemento([with, differentiation, of, pancreatic, exocrine, cells])].
[sujeto(['The', findings]), verbo([reported]), complemento([here, offer, a, novel, and, effective, process, to, develop, pancreatic, exocrine, cells, from, 'ESCs'])].
[sujeto(['The', cardinal, motor, symptoms, of, 'Parkinson\'s', disease, '(', 'PD)', are]), verbo([caused]), complemento([by, the, vulnerability, to, dysfunction, and, degeneration, of, ventral, midbrain, '(', 'VM)', dopaminergic, '(', 'DA)', neurons])].
[sujeto(['Here', we, demonstrate, a, combination, of, three, modifications, that, were]), verbo([required]), complemento([to, produce, 'VM', 'DA', neurons])].
[sujeto(['Thirdly,', early, exposure, to, 'FGF8a,', rather, than, 'Fgf8b,', and, 'WNT1', was]), verbo([required]), complemento([for, robust, differentiation, of, the, 'FOXA2(+)', floor, 'plate-like', human, neural, progenitor, cells, into, 'FOXA2(+)', 'DA', neurons])].
[sujeto(['In', 'summary,', this, new, human, 'ES', and, iPS, cell, differentiation, protocol, using, 'FGF8a,', 'WNT1,', low, dose, retinoic, acid, and, a, high, activity, form, of, 'SHH', can, generate, human, 'VM', 'DA', neurons, that, are]), verbo([required]), complemento([for, relevant, new, 'bioassays,', drug, discovery, and, cell, based, therapies, for, 'PD'])].
[sujeto(['Hepatic', 'pre-induction', was, performed, by, activinA, and, 'FGF4', resulting, in]), verbo([enhanced]), complemento(['SOX17', and, 'FOXA2', expression])].
[sujeto(['By', tracing, the, fate, of, the, 'molecule\'s', label, via, isotopomer, analysis, using, '(', 13, ')', 'C', 'NMR', 'spectroscopy,', formation, of, both, glycogen, and, some, gluconeogenetic, activity, could, be, observed]), verbo([providing]), complemento([evidence, of, a, 'hepatocyte-like', glucose, metabolism, in, differentiated, 'USSC'])].
[sujeto(['Similarly,', pluripotent, embryonic, stem, cells, can, be]), verbo([induced]), complemento([to, differentiate, in, vitro, into, specific, phenotypes, in, response, to, morphogen, treatment])].
[sujeto(['Degradable', 'PLGA', microspheres]), verbo([releasing]), complemento([retinoic, acid, were, incorporated, directly, within, 'EBs', and, induced, the, formation, of, cystic, spheroids, uniquely, resembling, the, phenotype, and, structure, of, early, streak, mouse, embryos, '(', 'E6'])].
[sujeto(['Higher', order, chromatin, structures, across, the, genome, are]), verbo([maintained]), complemento([in, part, by, the, architectural, proteins, 'CCCTC', binding, factor, '(', 'CTCF)', and, the, cohesin, 'complex,', which, 'co-localize', at, many, sites, across, the, genome])].
[sujeto(['Here,', we, examine, the, role, of, these, proteins, in]), verbo([mediating]), complemento([chromatin, structure, at, the, cystic, fibrosis, transmembrane, conductance, regulator, '(', 'CFTR)', gene])].
[sujeto(['CFTR', encompasses, nearly, 200, kb, flanked, by, 'CTCF-binding', 'enhancer-blocking', insulator, elements, and, is]), verbo([regulated]), complemento([by, 'cell-type-specific', intronic, 'enhancers,', which, loop, to, the, promoter, in, the, active, locus])].
[sujeto(['SiRNA-mediated', depletion, of, 'CTCF', or, the, cohesin, 'component,', 'RAD21,', showed, that, these, two, factors]), verbo([have]), complemento([distinct, roles, in, regulating, the, higher, order, organization, of, 'CFTR'])].
[sujeto(['CTCF']), verbo([mediates]), complemento([the, interactions, between, 'CTCF/cohesin', binding, 'sites,', some, of, which, have, 'enhancer-blocking', insulator, activity])].
[sujeto(['Disruption', of, the, 'three-dimensional', structure, of, the, 'CFTR', gene, by, depletion, of, 'CTCF', or, 'RAD21']), verbo([increases]), complemento([gene, 'expression,', which, is, accompanied, by, alterations, in, histone, modifications, and, 'TF', occupancy, across, the, 'locus,', and, causes, internalization, of, the, gene, from, the, nuclear, periphery])].
[sujeto(['The', forkhead, box, 'A', transcription, 'factors,', 'FOXA1', and, 'FOXA2,', function, as, pioneer, factors, to, open, condensed, chromatin, and, facilitate]), verbo([binding]), complemento([of, other, proteins])].
[sujeto(['Here', we, show, that, concurrent, depletion, of, 'FOXA1', and, 'FOXA2']), verbo([represses]), complemento(['CFTR', expression, and, alters, the, 'three-dimensional', architecture, of, the, active, locus, by, diminishing, interactions, between, the, promoter, and, intronic, 'cis-acting', elements])].
[sujeto(['Moreover,']), verbo([loss]), complemento([of, 'FOXA1/A2', suppresses, the, recruitment, of, other, members, of, the, transcriptional, network, including, 'HNF1', and, 'CDX2,', to, multiple, 'cis-elements'])].
[sujeto(['These', data]), verbo([reveal]), complemento([a, complex, molecular, mechanism, underlying, the, role, of, 'FOXA1/A2', in, achieving, high, levels, of, 'CFTR', expression, in, intestinal, epithelial, cells])].
[sujeto(['This', sequence, contains, an, 'intestine-selective', enhancer, and]), verbo([associates]), complemento([with, enhancer, signature, 'proteins,', such, as, 'p300,', in, addition, to, 'tissue-specific', 'TFs', '(', transcription, 'factors)'])].
[sujeto(['In', the, present, study, we, identify, critical, 'TFs', that, are]), verbo([recruited]), complemento([to, this, element, and, demonstrate, their, importance, in, regulating, 'CFTR', expression])].
[sujeto(['In', vitro, 'DNase', 'I', footprinting, and, 'EMSAs', '(', electrophoretic, 'mobility-shift', 'assays)', identified, four, 'cell-type-selective', regions, that]), verbo([bound]), complemento(['TFs', in, vitro])].
[sujeto(['ChIP', '(', chromatin, 'immunoprecipitation)', identified, 'FOXA1/A2', '(', forkhead, box, 'A1/A2),', 'HNF1', '(', hepatocyte]), verbo([nuclear]), complemento([factor, 1, ')', and, 'CDX2', '(', 'caudal-type', homeobox, 2, ')', as, in, vivo, 'trans-interacting', factors])].
[sujeto(['Mutation', of, their]), verbo([binding]), complemento([sites, in, the, intron, 11, core, compromised, its, enhancer, activity, when, measured, by, reporter, gene, assay])].
[sujeto(['Moreover,', siRNA, '(', small, interfering, 'RNA)-mediated', knockdown, of, 'CDX2']), verbo([caused]), complemento([a, significant, reduction, in, endogenous, 'CFTR', transcription, in, intestinal, 'cells,', suggesting, that, this, factor, is, critical, for, the, maintenance, of, high, levels, of, 'CFTR', expression, in, these, cells])].
[sujeto(['The', 'ChIP', data, also, demonstrate, that, these, 'TFs']), verbo([interact]), complemento([with, multiple, 'cis-regulatory', elements, across, the, 'CFTR', 'locus,', implicating, a, more, global, role, in, intestinal, expression, of, the, gene])].
[sujeto(['A', main, challenge, of, modern, biology, is, to, understand, how, specific, constellations, of, genes, are]), verbo([activated]), complemento([to, differentiate, cells, and, give, rise, to, distinct, tissues])].
[sujeto(['This', study, focuses, on, elucidating, how, gene, expression, is, initiated, in, the, 'notochord,', an, axial, structure, that]), verbo([provides]), complemento([support, and, patterning, signals, to, embryos, of, humans, and, all, other, chordates])].
[sujeto(['Although', numerous, notochord, genes]), verbo([have]), complemento([been, 'identified,', the, regulatory, 'DNAs', that, orchestrate, development, and, propel, evolution, of, this, structure, by, eliciting, notochord, gene, expression, remain, mostly, 'uncharted,', and, the, information, on, their, configuration, and, recurrence, is, still, quite, fragmentary])].
[sujeto(['We']), verbo([found]), complemento([that, most, 'Ciona', notochord, 'CRMs', relied, upon, variable, combinations, of, binding, sites, for, the, transcription, factors, 'Brachyury', 'and/or', 'Foxa2,', which, can, act, either, synergistically, or, independently, from, one, another])].
[sujeto(['Notably,', one, of, these, 'CRMs', contains, a, 'Brachyury']), verbo([binding]), complemento([site, juxtaposed, to, an, '(', 'AC)', 'microsatellite,', an, unusual, arrangement, also, found, in, 'Brachyury-bound', regulatory, regions, in, mouse])].
[sujeto(['In', 'contrast,', different, subsets, of, 'CRMs', relied, upon]), verbo([binding]), complemento([sites, for, transcription, factors, of, widely, diverse, families])].
[sujeto(['Surprisingly,', we]), verbo([found]), complemento([that, neither, 'intra-genomic', nor, interspecific, conservation, of, binding, sites, were, reliably, predictive, hallmarks, of, notochord, 'CRMs'])].
[sujeto(['Both', caloric, restriction, '(', 'CR)', and, resveratrol, '(', 'RSV)']), verbo([have]), complemento([beneficial, effects, on, obesity])].
[sujeto(['However,', the, biochemical, pathways, that]), verbo([mediate]), complemento([these, beneficial, effects, might, be, complex, and, interconnected, and, have, not, been, fully, elucidated])].
[sujeto(['To']), verbo([reveal]), complemento([the, common, therapeutic, mechanism, of, 'CR', and, 'RSV,', we, performed, a, comparative, transcriptome, analysis, of, adipose, tissues, from, 'diet-induced', obese, '(', 'DIO)', zebrafish, and, obese, humans])].
[sujeto(['We', identified, nine, genes, in, 'DIO', zebrafish, and, seven, genes, in, obese, humans, whose, expressions, were]), verbo([regulated]), complemento([by, 'CR', and, 'RSV'])].
[sujeto(['Although', the, gene, lists, did, not, overlap, except, for, one, 'gene,', the, gene, ontologies, enriched, in, the, gene, lists, were, highly, 'overlapped,', and, included, genes]), verbo([involved]), complemento([in, adipocyte, 'differentiation,', lipid, storage, and, lipid, metabolism])].
[sujeto(['EP300', is, a, histone, and, lysyl, acetyltransferase, that]), verbo([modulates]), complemento([the, function, of, histone, and, various, proteins, including, 'CEBPB,', 'CEBPD,', 'FOXA1,', and, 'FOXA2'])].
[sujeto(['The', reduction, of, adiposity, by, 'C646', was, not, significantly, different, from, that]), verbo([induced]), complemento([by, 'RSV', or, 'co-treatment', of, 'C646', and, 'RSV'])].
[sujeto(['Recent', studies, indicate, that, 'DNA', methylation, can, be, used, to, identify, transcriptional, 'enhancers,', but, no, systematic, approach]), verbo([has]), complemento([been, developed, for, 'genome-wide', identification, and, analysis, of, enhancers, based, on, 'DNA', methylation])].
[sujeto(['We', identified, networks]), verbo([regulated]), complemento([by, known, cancer, drivers, such, as, 'GATA3', and, 'FOXA1', '(', breast, 'cancer),', 'SOX17', and, 'FOXA2', '(', endometrial, 'cancer),', and, 'NFE2L2,', 'SOX2,', and, 'TP63', '(', squamous, cell, lung, 'cancer)'])].
[sujeto(['We', propose, 'ELMER', as, a, powerful, new, paradigm, for, understanding, the, 'cis-regulatory', interface, between, 'cancer-associated', transcription, factors, and, their, functional]), verbo([target]), complemento([genes])].
[sujeto(['Midbrain', dopamine, neuronal, progenitors, develop, into, heterogeneous, subgroups, of, 'neurons,', such, as, substantia, nigra, pars, 'compacta,', ventral, tegmental, area, and, retrorubal, 'field,', that]), verbo([regulate]), complemento([motor, 'control,', motivated, and, addictive, behaviours])].
[sujeto(['The', development, of, midbrain, dopamine, neurons]), verbo([has]), complemento([been, extensively, 'studied,', and, these, studies, indicate, that, complex, 'cross-regulatory', interactions, between, extrinsic, and, intrinsic, molecules, regulate, a, precise, temporal, and, spatial, programme, of, neurogenesis, in, midbrain, dopamine, progenitors])].
[sujeto(['To', elucidate, direct, molecular, interactions, between, multiple, regulatory, factors, during, neuronal, differentiation, in, 'mice,', we, characterised, 'genome-wide']), verbo([binding]), complemento([sites, of, the, 'forkhead/winged', helix, transcription, factor, 'Foxa1,', which, functions, redundantly, with, 'Foxa2', to, regulate, the, differentiation, of, mDA, neurons])].
[sujeto(['Interestingly,', our, studies, identified, a, rostral, brain, floor, plate, 'Neurog2', enhancer, that]), verbo([requires]), complemento([direct, input, from, 'Otx2,', 'Foxa1,', 'Foxa2', and, an, 'E-box', transcription, factor, for, its, transcriptional, activity])].
[sujeto(['Furthermore,', the, chromatin, remodelling, factor, 'Smarca1', was, shown, to, function, downstream, of, 'Foxa1', and, 'Foxa2', to]), verbo([regulate]), complemento([differentiation, from, immature, to, mature, midbrain, dopaminergic, neurons])].
[sujeto(['Our', 'genome-wide', 'Foxa1-bound', 'cis-regulatory', sequences, from, 'ChIP-Seq', and, 'Foxa1/2', candidate]), verbo([target]), complemento([genes, from, 'RNA-Seq', analyses, of, embryonic, midbrain, dopamine, cells, also, provide, an, excellent, resource, for, probing, mechanistic, insights, into, gene, regulatory, networks, involved, in, the, differentiation, of, midbrain, dopamine, neurons])].
[sujeto(['We']), verbo([have]), complemento([shown, previously, that, 'Clock,', microsomal, triglyceride, transfer, protein, '(', 'MTP),', and, nocturnin, are, involved, in, the, circadian, regulation, of, intestinal, lipid, absorption])].
[sujeto(['Plasma', triglyceride, in, 'apoAIV(-/-)', mice, showed, diurnal, variations, similar, to, 'apoAIV(+/+)', 'mice;', 'however,', the]), verbo([increases]), complemento([in, plasma, triglyceride, at, night, were, significantly, lower, in, these, mice])].
[sujeto(['Conversely,', apoAIV, overexpression]), verbo([increased]), complemento(['MTP', mRNA, in, hepatoma, 'cells,', indicating, transcriptional, regulation])].
[sujeto(['Mechanistic', studies, revealed, that, sequences, between, -, 204, /, -, 775, bp, in, the, 'MTP', promoter]), verbo([respond]), complemento([to, apoAIV, and, that, apoAIV, enhances, expression, of, 'FoxA2', and, 'FoxO1', transcription, factors, and, their, binding, to, the, identified, cis, elements, in, the, 'MTP', promoter, at, night])].
[sujeto(['These', data, indicate, that, apoAIV]), verbo([modulates]), complemento([diurnal, changes, in, lipid, absorption, by, regulating, forkhead, transcription, factors, and, 'MTP', and, that, inhibition, of, apoAIV, expression, might, reduce, plasma, lipids])].
[sujeto(['It', is, not, clear, to, what, extent, 'cell-specific', features, determine, the]), verbo([binding]), complemento([capacity, of, seven, 'STAT', members, and, to, what, degree, they, share, genetic, targets])].
[sujeto(['We', determined, that, the, genomic]), verbo([binding]), complemento([capacity, of, 'STATs', is, primarily, defined, by, the, cell, type, and, to, a, lesser, extent, by, individual, family, members])].
[sujeto(['For', 'example,', the, overlap, of, shared]), verbo([binding]), complemento([sites, between, 'STATs', 3, and, 5, in, 'T', cells, is, greater, than, that, between, 'STAT5', in, 'T', cells, and, 'non-T', cells])].
[sujeto(['Even', for, the, top, 1, ',', 0, highly, enriched, 'STAT']), verbo([binding]), complemento(['sites,', '~15%', of, 'STAT5', binding, sites, in, mouse, female, liver, are, shared, by, other, 'STATs', in, different, cell, types, while, in, 'T', cells, '~90%', of, 'STAT5', binding, sites, are, 'co-occupied', by, 'STAT3,', 'STAT4', and, 'STAT6'])].
[sujeto(['In', 'addition,', we, identified, 116, 'cis-regulatory', modules, '(', 'CRM),', which, are]), verbo([recognized]), complemento([by, all, 'STAT', members, across, cell, types, defining, a, common, 'JAK-STAT', signature])].
[sujeto(['Lastly,', in, liver, 'STAT5']), verbo([binding]), complemento([significantly, coincides, with, binding, of, the, 'cell-specific', transcription, factors, 'HNF4A,', 'FOXA1', and, 'FOXA2', and, is, associated, with, 'cell-type', specific, gene, transcription])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, genomic, binding, of, 'STATs', is, primarily, determined, by, the, cell, type, and, further, specificity, is, achieved, in, part, by, juxtaposed, binding, of, 'cell-specific', transcription, factors])].
[sujeto(['The', vertebrate, organizer, and, notochord]), verbo([have]), complemento(['conserved,', essential, functions, for, embryonic, development, and, patterning])].
[sujeto(['Some', 'CRMs']), verbo([have]), complemento([been, conserved, throughout, vertebrates, and, likely, represent, ancestral, regulatory, 'networks,', while, others, have, diverged, beyond, recognition, but, still, function, over, a, wide, evolutionary, range])].
[sujeto(['Here', we, identify, and, characterize, a, 'mammalian-specific', 'CRM']), verbo([required]), complemento([for, node, and, notochord, specific, '(', 'NNC)', expression, of, 'NOTO,', a, transcription, factor, essential, for, node, 'morphogenesis,', nodal, cilia, movement, and, establishment, of, laterality, in, mouse])].
[sujeto(['Three', subregions, in, 'NOCE', together]), verbo([mediated]), complemento([full, activity, in, vivo])].
[sujeto(['NOCE', represents, a, 'novel,', 'mammal-specific', 'CRM']), verbo([required]), complemento([for, the, highly, restricted, 'Noto', expression, in, the, node, and, nascent, notochord, and, thus, regulates, normal, node, development, and, function])].
[sujeto(['The', transcription, factors, 'Foxa1', and, 'Foxa2']), verbo([promote]), complemento([the, specification, of, midbrain, dopaminergic, '(', 'mDA)', neurons, and, the, floor, plate])].
[sujeto(['Whether', their, role, is, direct]), verbo([has]), complemento([remained, unclear, as, they, also, regulate, the, expression, of, 'Shh,', which, has, similar, roles])].
[sujeto(['This', identified, 9160, 'high-quality', 'Foxa2']), verbo([binding]), complemento([sites, associated, with, 5409, 'genes,', providing, mechanistic, insights, into, 'Foxa2-mediated', positive, and, negative, regulatory, events])].
[sujeto(['Foxa2']), verbo([regulates]), complemento([directly, and, positively, key, determinants, of, mDA, 'neurons,', including, 'Lmx1a,', 'Lmx1b,', 'Msx1', and, 'Ferd3l,', while, negatively, inhibiting, transcription, factors, expressed, in, ventrolateral, midbrain, such, as, 'Helt,', 'Tle4,', 'Otx1,', 'Sox1', and, 'Tal2'])].
[sujeto(['Furthermore,', 'Foxa2', negatively]), verbo([regulates]), complemento([extrinsic, and, intrinsic, components, of, the, 'Shh', signaling, 'pathway,', possibly, by, binding, to, the, same, enhancer, regions, of, 'co-regulated', genes, as, 'Gli1'])].
[sujeto(['Foxa2', also]), verbo([regulates]), complemento([the, expression, of, floor, plate, factors, that, control, axon, trajectories, around, the, midline, of, the, 'embryo,', thereby, contributing, to, the, axon, guidance, function, of, the, floor, plate])].
[sujeto(['This', work, represents, the, first, comprehensive, characterization, of, 'Foxa2']), verbo([targets]), complemento([in, mDA, progenitors, and, provides, a, framework, for, elaborating, gene, regulatory, networks, in, a, functionally, important, progenitor, population])].
[sujeto(['The', 'G6PC2', gene, encoding, 'islet-specific', 'glucose-6-phosphatase', related, protein, '(', 'IGRP)']), verbo([has]), complemento([a, common, promoter, 'variant,', rs573225, '(', -, 231, 'G/A),', located, within, a, 'Foxa', binding, site])].
[sujeto(['In', 'vitro,', the, 'G', allele, showed, a, higher, affinity, for]), verbo([binding]), complemento(['Foxa2', transcription, factor, and, increased, 'G6PC2', promoter, activity])].
[sujeto(['Foxa2']), verbo([binding]), complemento([is, modified, if, the, 'C', adjacent, to, the, 'G', allele, is, methylated])].
[sujeto(['IGI', was]), verbo([associated]), complemento([with, rs573225, by, linear, regression, analysis, and, was, 30, '%', greater, in, 'AA', or, 'AG', than, in, 'GG', obese, children])].
[sujeto([rs573225, was, also]), verbo([associated]), complemento([with, fasting, glucose])].
[sujeto([rs573225, is, a, functional, 'cis-regulatory', '(', 'epi)-single-nucleotide', polymorphism, '(', 'SNP)', of, 'G6PC2']), verbo([associated]), complemento([with, 'glucose-insulin', homeostasis, in, obese, 'children,', likely, to, explain, the, results, of, recent, 'genome-wide', association, studies, in, nondiabetic, adults])].
[sujeto(['Here,', we, use, 'genome-wide', location, analysis, for, 'Foxa2', to, identify, its]), verbo([targets]), complemento([in, the, adult, liver])].
[sujeto(['We', then, show, by, computational, analyses, that, 'Foxa2', containing, 'cis-regulatory', modules, are, not, constructed, from, a, random, assortment, of]), verbo([binding]), complemento([sites, for, other, transcription, factors, expressed, in, the, 'liver,', but, rather, that, their, composition, depends, on, the, strength, of, the, 'Foxa2', consensus, site, present])].
[sujeto(['We', not, only]), verbo([provide]), complemento([a, better, understanding, of, the, mechanisms, of, 'Foxa2', regulation, but, also, introduce, a, novel, method, for, identification, of, different, 'cis-regulatory', modules, involving, a, single, factor])].
[sujeto(['The', 'cis-regulatory', regions, of, many, developmental, regulators, and, transcription, factors, are, believed, to, be, highly]), verbo([conserved]), complemento([in, the, genomes, of, vertebrate, 'species,', suggesting, specific, regulatory, mechanisms, for, these, gene, classes])].
[sujeto(['Synthetic', enhancers, containing, the, two, essential, regions, in, front, of, a, 'TATA-box', drive, expression, in, the, notochord, while, concatemerization, of, the, subregions, alone, is, not, 'sufficient,', indicating, that, the, combination, of, the, two, sequence, elements, is]), verbo([required]), complemento([for, notochord, expression])].
[sujeto(['This']), verbo([suggests]), complemento([that, the, regulatory, grammar, itself, does, not, dictate, the, high, evolutionary, conservation, between, these, orthologous, 'cis-regulatory', sequences])].
[sujeto(['Foxa1', and, 'Foxa2', forkhead, box, transcription, factors, '(', 'TFs)']), verbo([participate]), complemento([in, transcriptional, programs, governing, intestinal, cell, differentiation])].
[sujeto(['Down-regulation', of, 'Foxa1', and, 'Foxa2', by, 'RNA', interference, in, cultured, intestinal, cells]), verbo([decreased]), complemento(['Muc2', mRNA, level, by, 'half,', and, abolished, 'Muc2', protein, expression])].
[sujeto(['Chromatin', immunoprecipitation, and, gel, shift, assays, showed, that, these, two, 'TFs', directly]), verbo([bind]), complemento([to, the, 'Muc2', promoter])].
[sujeto(['Co-transfection', experiments, indicated, that, both, 'TFs']), verbo([activate]), complemento([the, 'Muc2', promoter, and, that, mutations, of, three, 'Foxa', 'cis-elements', inhibit, 'Muc2', transactivation])].
[sujeto(['To', identify, transcription, factors, that]), verbo([regulate]), complemento(['ABCA3', expression, in, the, 'lung,', we, identified, by, bioinformatic, and, functional, analyses, two, positive, regulatory, 'regions,', located, between, bp, -, 2591, and, -, 1102, and, bp, -, 1102, and, +, 11, ',', relative, to, the, exon, 1, of, the, 'Abca3', gene, promoter])].
[sujeto(['The', distal, cassette, contains, consensus, sequences, predicting]), verbo([binding]), complemento([to, lung, transcription, factors, including, 'FOXA2,', 'CCAAT/enhancer', binding, 'protein-alpha', '(', 'C/EBPalpha),', 'GATA-6,', thyroid, transcription, 'factor-1', '(', 'TTF-1', or, 'Nkx2'])].
[sujeto([1, ')', ',', and]), verbo([nuclear]), complemento([factor, of, activated, 'T', 'cells-c3', '(', 'NFATc3)'])].
[sujeto(['FOXA2,', 'C/EBPalpha,', 'GATA-6,', 'TTF-1,', and, 'NFATc3']), verbo([increased]), complemento([the, activity, of, the, 'Abca3', luciferase, construct, in, a, 'dose-dependent', manner])].
[sujeto(['The', distal, cassette]), verbo([conferred]), complemento([activation, by, 'FOXA2,', 'C/EBPalpha,', 'GATA-6,', 'TTF-1,', and, 'NFATc3', in, a, 'position-', and, 'orientation-independent', 'manner,', serving, as, an, 'enhancer-like', regulatory, element])].
[sujeto(['The', proximal, 'Abca3', promoter, region, contained, multiple, sterol, responsive, element, '(', 'SRE)']), verbo([binding]), complemento([sites])].
[sujeto(['SRE']), verbo([binding]), complemento([protein, '(', 'SREBP)-1c', significantly, increased, the, activity, of, the, 'Abca3', luciferase, construct, in, a, 'dose-dependent', 'manner,', whereas, 'SREBP-1a', and, 'SREBP-2', did, not, influence, the, 'Abca3', promoter, activity])].
[sujeto(['Chromatin', immunoprecipitation, '(', 'ChIP)', analyses, demonstrated, the]), verbo([binding]), complemento([of, 'SREBP-1c,', 'C/EBPalpha,', and, 'TTF-1', to, their, respective, regulatory, elements])].
[sujeto(['Conditional', deletion, of, 'SREBP', 'cleavage-activating', protein, '(', 'Scap)', in, respiratory, epithelial, cells, in, the, mouse, lung, in, vivo]), verbo([inhibited]), complemento([the, expression, of, 'SREBPs', in, concert, with, 'Abca3'])].
[sujeto(['Abca3', gene, expression, is]), verbo([mediated]), complemento([by, discrete, 'cis-acting', cassettes, that, mediate, pulmonary, 'cell-', and, 'lipid-sensitive', pathways, regulating, surfactant, homeostasis])].
[sujeto(['However,', disruption, of, either, the, -, 803, /, -, 795, or, the, -, 408, /, -, 403, site, did, not, affect, reporter, gene, activity, in, 'NIH', 3, 'T3', 'cells,']), verbo([suggesting]), complemento([that, this, promoter, fragment, is, subjected, to, 'cell-specific', regulation])].
[sujeto(['The']), verbo([nuclear]), complemento([proteins, that, bound, to, these, -, 803, /, -, 795, and, -, 408, /, -, 403, sites, were, identified, by, gel, retardation, assays, as, 'HNF3beta', '(', hepatocyte, nuclear, factor, 3, 'beta)/Foxa2', '(', 'forkhead/winged', helix, transcription, factor, 'box2)', and, 'USFs', '(', upstream, stimulatory, 'factors),', 'USF1', and, 'USF2,', respectively])].
[sujeto(['Chromatin', immunoprecipitation, assays, using, antisera, against, 'HNF3beta/Foxa2,', 'USF1', and, 'USF2', demonstrated, that, endogenous, 'HNF3beta/Foxa2']), verbo([binds]), complemento([to, the, -, 803, /, -, 795, 'Foxa2', 'site,', and, 'USF1', and, 'USF2', bind, to, the, -, 408, /, -, 403, 'E-box', respectively, in, 'vivo,', consistent, with, the, gel, retardation, assay, results])].
[sujeto(['Although', there, are, weak]), verbo([binding]), complemento([sites, located, at, regions, -, 904, and, -, 572, for, 'PDX1', '(', pancreatic, duodenal, 'homeobox-1),', a, transcription, factor, that, controls, expression, of, 'beta-cell-specific', 'genes,', it, did, not, appear, to, regulate, 'PC', expression, in, 'INS-1', cells, in, the, context, of, the, 1.2, kb, promoter, fragment])].
[sujeto(['The', results, presented, here, show, that, 'Foxa2', and, 'USFs']), verbo([regulate]), complemento([the, distal, promoter, of, the, rat, 'PC', gene, in, a, 'cell-specific', manner])].
[sujeto(['Apolipoprotein', 'M', '(', 'ApoM)', is, a, novel, apolipoprotein, that, was, discovered, in, 1999, and, is]), verbo([bound]), complemento([primarily, to, 'high-density', lipoproteins, '(', 'HDLs)', in, the, plasma])].
[sujeto(['Multiple', factors, may, influence, its, expression, at, both, the, 'post-transcriptional', and, the, transcriptional, levels, both, in, vivo, and, ex, vivo, as, 'follows:', hepatocyte]), verbo([nuclear]), complemento(['factor-1α,', 4, α, '(', 'HNF-1α,', 4, 'α),', liver, receptor, 'homolog-1', '(', 'LRH-1),', forkhead, box, 'A2', '(', 'Foxa2)', and, platelet, activating, factor, '(', 'PAF)', upregulate, its, 'expression;', liver, 'X', receptor, '(', 'LXR),', retinoid, 'X', receptor, '(', 'RXR),', farnesoid, 'X', receptor, '(', 'FXR),', small, heterodimer, partner, '(', 'SHP)', and, the, majority, of, cytokines, downregulate, its, expression])].
[sujeto(['Structurally,', there, exists, a, characterized, hydrophobic]), verbo([binding]), complemento([pocket, within, the, apoM, 'protein,', which, enables, it, to, bind, functional, lipids, such, as, 'Sphingosine-1-Phosphate', '(', 'S1P)'])].
[sujeto(['Functionally,', it, facilitates, the, formation, of, 'preβ-HDL', and]), verbo([enhances]), complemento([an, avalanche, of, atheroprotective, effects, exerted, by, 'HDL'])].
[sujeto(['Moreover,', in, patients, with, 'diabetes,', the, levels, of, plasma, apoM, may, 'decrease,', whereas, the, augmentation, of, apoM]), verbo([decreases]), complemento([plasma, glucose, levels, and, magnifies, the, secretion, of, insulin])].
[sujeto(['More', 'precisely,', we, 'observe,', in, patients, with, type, 2, 'diabetes,', an]), verbo([increased]), complemento([production, of, 'VLDL(1)', particles, that, is, potentially, detrimental, by, generating, atherogenic, 'remnants,', small, dense, 'LDL', particles, and, 'triglyceride-rich', 'HDL', particles])].
[sujeto(['Several', pathophysiological, factors, are, responsible, for]), verbo([increased]), complemento(['VLDL', 'production,', in, type, 2, diabetes])].
[sujeto(['Indeed,', defective, activation, of, 'PI3-kinase,', secondary, to, insulin, 'resistance,', is]), verbo([associated]), complemento([with, a, reduction, of, apoB, degradation, in, the, 'hepatocytes,', a, rise, in, 'MTP', expression, '(', by, increasing, nuclear, transcription, factors, 'Fox01', and, 'Foxa2)', and, an, increased, activity, of, phospholipase, 'D1', and, 'ARF-1,', which, are, involved, in, 'VLDL(1)', formation])].
[sujeto(['Moreover,', peripheral, insulin, resistance, is, responsible, for]), verbo([increased]), complemento([lipolysis, of, adipose, tissue, leading, to, augmented, portal, flux, of, 'FFA', to, the, liver, 'and,', as, a, 'consequence,', activation, of, 'VLDL', production])].
[sujeto(['In', 'addition,']), verbo([increased]), complemento([de, novo, lipogenesis, is, observed, in, type, 2, diabetes])].
[sujeto(['This', is, secondary, to]), verbo([increased]), complemento([activation, of, 'SREBP-1c', '(', 'Sterol', 'Regulatory', 'Element-Binding', 'Protein-1c),', mainly, by, 'Endoplasmic', 'Reticulum', 'stress,', and, of, 'ChREBP', '(', 'Carbohydrate', 'Responsive', 'Element', 'Binding', 'Protein),', mainly, by, hyperglycemia])].
[sujeto(['Furthermore,']), verbo([decreased]), complemento([plasma, adiponectin, observed, in, type, 2, 'diabetes,', may, also, play, a, role, in, increased, 'VLDL', production, by, decreasing, liver, 'AMP-kinase', activation, and, by, increasing, plasma, 'FFA', levels, as, a, consequence, of, reduced, muscle, 'FFA', oxidation])].
[sujeto(['They', are, among, the, earliest, to]), verbo([bind]), complemento([quiescent, 'genes,', which, they, activate, in, conjunction, with, other, transcription, factors])].
[sujeto(['Here', we, confirmed, by, chromatin, immunoprecipitation, that, 'FoxA2', is, one, of, the, factors]), verbo([bound]), complemento([to, the, 'promoter-proximal', enhancer, of, the, gene, encoding, apolipoprotein, 'AI', '(', a, component, of, high, density, 'lipoprotein)', and, that, it, functions, in, synergy, with, the, nuclear, receptor, hepatocyte, nuclear, 'factor-4alpha'])].
[sujeto(['Furthermore,', toward, identifying, additional, cofactors, that, could, potentially]), verbo([regulate]), complemento(['FoxA2', 'activity,', we, identified, 'DNA-dependent', protein, kinase, '(', 'DNA-PK)', as, a, 'FoxA2-associated', factor, upon, affinity, purification, of, 'epitope-tagged', 'FoxA2'])].
[sujeto(['We', show, that, 'FoxA2,']), verbo([found]), complemento([to, be, a, phosphoprotein, in, 'vivo,', is, also, an, efficient, substrate, for, 'DNA-PK,', which, targets, serine, 283])].
[sujeto(['This', residue, is, contained, within, a]), verbo([conserved]), complemento(['serine-glutamine', phosphorylation, signal, for, 'DNA-PK,', located, within, the, 'C-terminal', third, of, the, 'polypeptide,', just, distal, to, its, 'winged-helix', 'DNA', binding, domain])].
[sujeto(['We', establish, that, this, residue, is, critical, for, 'FoxA2', function, because, 'FoxA2', bearing, a, mutation, at, this, site, is, severely, compromised, in, its, ability, to]), verbo([activate]), complemento([a, reporter, gene, under, the, control, of, its, cognate, 'DNA-binding', site, '(', apoAI, site, 'B)'])].
[sujeto(['Complementary', experiments, rule, out, that, this, mutation, compromises, the, ability, of, 'FoxA2', to, either, translocate, to, the, nucleus, or, to]), verbo([bind]), complemento([site, 'B'])].
[sujeto(['Obesity,', 'diabetes,', insulin, 'resistance,', and, hyperinsulinemia, are, frequently]), verbo([associated]), complemento([with, a, cluster, of, closely, related, lipid, abnormalities, such, as, low, plasma, levels, of, high, density, lipoprotein, '(', 'HDL)', and, elevated, levels, of, 'triglyceride,', both, known, to, increase, the, risk, of, developing, atherosclerotic, disease])].
[sujeto(['Here', we, demonstrate, that, 'insulin,', through, a, 'Foxa2-mediated', 'mechanism,']), verbo([inhibited]), complemento([the, expression, of, apolipoprotein, 'M', '(', 'apoM),', an, important, determinant, of, plasma, 'pre-beta-HDL', and, 'alpha-HDL', concentrations])].
[sujeto(['Obese', mice, had]), verbo([decreased]), complemento([apoM, expression, and, plasma, 'pre-beta-HDL', levels, due, to, inactivation, of, 'Foxa2', in, hyperinsulinemic, states])].
[sujeto(['Nuclear', reexpression, of, 'Foxa2', with, a, 'phosphorylation-deficient', mutant, 'Foxa2T156A', '(', 'Ad-T156A)']), verbo([activated]), complemento([apoM, expression, and, increased, plasma, 'pre-beta-HDL', and, 'alpha-HDL', levels])].
[sujeto(['In', 'contrast,', haploinsufficient, 'Foxa2(+/-)', mice, exhibited]), verbo([decreased]), complemento([hepatic, apoM, expression, and, plasma, 'pre-beta-HDL', and, 'HDL', levels])].
[sujeto(['The']), verbo([increase]), complemento([in, plasma, 'HDL', levels, and, 'pre-beta-HDL', formation, by, 'Foxa2', was, mediated, exclusively, by, 'apoM,', as, constitutive, active, expression, of, 'Foxa2', in, 'apoM(-/-)', mice, had, no, effect, on, plasma, 'HDL', levels])].
[sujeto(['Our', results, identify, a, fundamental, mechanism, by, which, insulin]), verbo([regulates]), complemento([plasma, 'HDL', levels, in, physiological, and, 'insulin-resistant', states, and, thus, have, important, implications, for, novel, therapeutic, approaches, to, prevent, atherosclerosis])].
[sujeto(['Apolipoprotein', '(', 'apo)A-I', alone, or, as, a, component, of, high, density, lipoprotein, particles]), verbo([has]), complemento([antiatherogenic, properties])].
[sujeto(['Results', in, rats, showed, that, levels, of, serum, 'apoA-I', 'protein,', hepatic, 'mRNA,', and, transcription, of, the, gene, were]), verbo([decreased]), complemento([to, 39, '%', ',', 18, '%', ',', and, 38, '%', ',', 'respectively,', in, 180, -, 'day-old', animals, compared, to, those, of, newborn, rats])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, a, nuclear, 'mechanism(s)', may, account, for, the, decline, in, 'apoA-I', expression])].
[sujeto(['Accordingly,', we, examined, hepatic]), verbo([nuclear]), complemento([binding, activity, to, four, specific, 'cis-acting', elements, of, the, rat, 'apoA-I', promoter])].
[sujeto(['There', were, 'age-dependent', changes, of]), verbo([binding]), complemento([activity, to, two, proximal, 'sites,', 'B', and, 'C,', but, not, to, the, more, distal, 'elements,', 'IRCE', and, 'A'])].
[sujeto(['Decreased', 'B-site']), verbo([binding]), complemento([activity, correlated, with, lower, mRNA, levels, encoding, the, 'activator,', 'HNF-3beta'])].
[sujeto(['The', 'age-dependent', change, in, the, pattern, of]), verbo([binding]), complemento([to, site, 'C', was, due, to, a, switch, from, the, 'activator,', 'HNF-4,', to, the, 'repressor,', 'ARP-1'])].
[sujeto(['Estrogen', replacement, therapy]), verbo([increases]), complemento([plasma, concentrations, of, high, density, lipoprotein, and, its, major, protein, 'constituent,', apolipoprotein, 'AI', '(', 'apoAI)'])].
[sujeto(['Studies', with, animal, model, 'systems,', 'however,']), verbo([suggest]), complemento([opposite, effects])].
[sujeto(['In', 'HepG2', cells, stably]), verbo([expressing]), complemento([estrogen, receptor, alpha, '(', 'ERalpha),', 17, 'beta-estradiol', '(', 'E2)', potently, inhibited, apoAI, mRNA, steady, state, levels])].
[sujeto(['ApoAI', promoter, deletion, mapping, experiments, indicated, that, 'ERalpha', plus, 'E2']), verbo([inhibited]), complemento([apoAI, activity, through, the, 'liver-specific', enhancer])].
[sujeto(['Although', the, 'ERalpha', 'DNA']), verbo([binding]), complemento([domain, was, essential, but, not, sufficient, for, apoAI, enhancer, 'inhibition,', 'ERalpha', binding, to, the, apoAI, enhancer, could, not, be, detected, by, electrophoretic, mobility, shift, assays])].
[sujeto(['Expression', of, the, 'ERalpha', coactivator, 'RIP140', dramatically]), verbo([repressed]), complemento([apoAI, enhancer, function, in, cotransfection, 'experiments,', suggesting, that, 'RIP140', may, also, function, as, a, coactivator, on, the, apoAI, enhancer])].
[sujeto(['At', low, ratios, of, 'RIP140', to, 'ERalpha,', 'E2']), verbo([repressed]), complemento([apoAI, enhancer, 'activity,', whereas, at, high, ratios, this, repression, was, reversed])].
[sujeto(['Recently,']), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'iPSCs)', derived, from, the, reprogramming, of, somatic, 'fibroblasts,', have, been, shown, to, resemble, embryonic, stem, '(', 'ES)', cells, in, that, they, have, pluripotent, properties, and, the, potential, to, differentiate, into, all, cell, lineages, in, 'vitro,', including, hepatocytes])].
[sujeto(['We']), verbo([have]), complemento([established, a, rapid, and, efficient, differentiation, protocol, that, is, able, to, generate, functional, 'hepatocyte-like', cells, from, human, iPSCs])].
[sujeto(['Human', embryonic, stem, cells, '(', 'hESCs)']), verbo([provide]), complemento([a, new, source, for, hepatocyte, production, in, translational, medicine, and, cell, replacement, therapy])].
[sujeto(['The']), verbo([reported]), complemento(['hESC-derived', 'hepatocyte-like', cells, '(', 'HLCs)', were, commonly, generated, on, 'Matrigel,', a, mouse, cell, 'line-derived', extracellular, matrix, '(', 'ECM)'])].
[sujeto(['In', comparison, with, 'Matrigel,', the, differentiated, 'HLCs', on, both, 'ECMs']), verbo([expressed]), complemento([similar, levels, of, 'hepatocyte-specific', 'genes,', secreted, 'α-fetoprotein,', and, metabolized, 'ammonia,', showed, glycogen, storage, activity, as, well, as, 'low-density', lipoprotein, and, indocyanine, green, uptake])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, the, 'xeno-free', and, 'cost-benefit', matrix, may, be, applicable, in, bioartificial, livers, and, also, may, facilitating, a, clinical, application, of, human, pluripotent, stem, 'cell-derived', hepatocytes, in, the, future])].
[sujeto(['The', generation, of]), verbo([induced]), complemento([pluripotent, stem, cells, '(', 'iPSCs)', is, an, innovative, 'personalized-regenerative', 'technology,', which, can, transform, 'own-self', somatic, cells, into, embryonic, stem, '(', 'ES)-like', 'cells,', which, have, the, potential, to, differentiate, into, all, cell, types, of, three, dermal, lineages])].
[sujeto(['We', showed, that, 'FMSNs', of, various, surface, charges, could, be, efficiently, internalized, by, iPSCs, without]), verbo([causing]), complemento([cytotoxicity])].
[sujeto(['Notably,', 'positive-charged', 'FMSN']), verbo([enhanced]), complemento([cellular, uptake, efficiency, and, retention, time])].
[sujeto(['Moreover,', when, using, 'positive-charged', 'FMSN', to, deliver, hepatocyte]), verbo([nuclear]), complemento([factor, 3, β, '(', 'HNF3β)', plasmid, 'DNA', '(', 'pDNA),', the, treated, iPSCs, exhibited, significantly, improved, definitive, endoderm, formation, and, further, quickly, differentiated, into, 'hepatocyte-like', cells, with, mature, functions, '(', 'low-density', lipoprotein, uptake, and, glycogen, 'storage)', within, 2, weeks, in, vitro])].
[sujeto(['These', findings]), verbo([reveal]), complemento([the, multiple, advantages, of, 'FMSNs', to, serve, as, ideal, vectors, not, only, for, stem, cell, labeling, but, also, for, safe, gene, delivery, to, promote, the, production, of, 'hepatocyte-like', cells, from, iPSCs])].
[sujeto(['The', nature, of, extranuclear, estrogen, elements]), verbo([has]), complemento([not, been, elucidated, so, 'far;', classical, or, alternatively, transcribed, 'ER', isoforms, '(', 'ERα36,', 'ERα46)', anchored, to, the, plasma, membrane, and, 'GPR30', '(', 'GPER1)', have, been, reported, to, exert, early, estrogen, actions])].
[sujeto(['Two', different, clusters, of, transcripts, could, be, 'identified:', '(', 1, ')', the, majority, of, transcripts, were]), verbo([inhibited]), complemento([by, both, 'ICI182,780', and, 'G15,', suggesting, an, interaction, of, 'E2-BSA', with, a, common, 'ER-related', 'element,', or, a, direct, 'ER-GPER1', 'interaction;', '(', 2, ')', a, small, number, of, 'G15-only', modified, 'transcripts,', in, two, cell, lines, '(', 'T47D', and, 'SKBR3', 'cells),', indicative, of, specific, 'GPER1-related', effects])].
[sujeto(['The', latter, transcripts, were, significantly, related, to, pathways, including, 'FOXA2/FOXA3', transcription, factor, 'networks,', 'RNA-Polymerases', 'Transcription', 'Regulation', and, lipid, 'metabolism,', while, 'ICI/G15']), verbo([inhibited]), complemento([transcripts, affected, pathways, related, to, 'apoptosis,', erythropoietin, 'signaling,', metabolic, effects, through, the, citric, acid, 'cycle,', 'IL-4', and, 'IL-5', mediated, events, and, homologous, 'DNA', recombination])].
[sujeto(['Here,', we, show, that, the]), verbo([nuclear]), complemento([hormone, 'receptors,', hepatocyte, nuclear, factor, 4, and, retinoid, 'X', receptor, alpha, plus, peroxisome, 'proliferator-activated', receptor, 'alpha,', support, 'HBV', replication, in, nonhepatic, cells, by, controlling, pregenomic, 'RNA', 'synthesis,', indicating, these, 'liver-enriched', transcription, factors, control, a, unique, molecular, switch, restricting, viral, tropism])].
[sujeto(['In', 'contrast,', hepatocyte]), verbo([nuclear]), complemento([factor, 3, antagonizes, nuclear, hormone, 'receptor-mediated', viral, 'replication,', demonstrating, distinct, regulatory, roles, for, these, 'liver-enriched', transcription, factors])].
[sujeto(['The', signalling, molecule, 'Sonic', hedgehog, is]), verbo([involved]), complemento([in, a, multitude, of, distinct, patterning, processes, during, vertebrate, embryogenesis])].
[sujeto(['We', show, here, that, misexpression, of, axial]), verbo([leads]), complemento([to, ectopic, activation, of, sonic, hedgehog, expression, in, the, 'zebrafish,', suggesting, that, axial, is, a, regulator, of, sonic, hedgehog, transcription])].
[sujeto(['This', effect, is]), verbo([mediated]), complemento([by, two, 'Axial', '(', 'HNF3beta)', recognition, sequences])].
[sujeto(['We', furthermore, identified, a, retinoic, acid, response, element, '(', 'RARE)', in, the, sonic, hedgehog, upstream, region, which, can, be]), verbo([bound]), complemento([by, retinoic, acid, receptor, '(', 'RAR)', and, retinoid, 'X', receptor, '(', 'RXR)', heterodimers, in, vitro, and, confers, retinoic, acid, inducibility, to, the, sonic, hedgehog, promoter, in, the, 'HeLa', cell, system])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, both, 'Axial', '(', 'HNF3beta)', and, retinoic, acid, receptors, are, direct, regulators, of, the, sonic, hedgehog, gene])].
[sujeto(['Human', 'CYP3A7', and, 'CYP3A4', are]), verbo([expressed]), complemento([in, fetal, and, adult, 'livers,', 'respectively,', although, the, 5, '\'', -, flanking, regions, of, the, two, genes, show, 90, '%', homology])].
[sujeto(['Transfection', studies, using, a, series, of, the, 'CYP3A7', or, 'CYP3A4', 'promoter-luciferase', chimeric, genes, identified, a]), verbo([nuclear]), complemento([factor, kappaB, '(', 'NF-kappaB)-like', element, between, nucleotides, -, 2326, and, -, 2297, that, conferred, the, transcriptional, activation, of, the, 'CYP3A7', gene])].
[sujeto(['A', gel, shift, assay, using]), verbo([nuclear]), complemento([extracts, from, 'HepG2', cells, showed, that, 'Sp1', and, 'Sp3', bound, to, the, 'NF-kappaB-like', element, of, the, 'CYP3A7', but, not, 'CYP3A4', gene])].
[sujeto(['Additionally,', introduction, of, mutations, into]), verbo([binding]), complemento([sites, for, hepatocyte, nuclear, factor, 3, 'beta,', upstream, stimulatory, factor, 1, ',', and, a, basic, transcription, element, in, the, proximal, promoter, attenuated, luciferase, activity, to, 20, '%', of, the, level, seen, with, the, intact, 'CYP3A7', promoter])].
[sujeto(['Thus,', we, conclude, that, the, expression, of, the, 'CYP3A7', gene, in, 'HepG2', cells, is, cooperatively]), verbo([regulated]), complemento([by, 'Sp1,', 'Sp3,', hepatocyte, nuclear, factor, 3, 'beta,', and, upstream, stimulatory, factor, 1])].
[sujeto(['In', the, present, 'study,', we]), verbo([have]), complemento([used, reporter, gene, analysis, and, 'semi-quantitative', 'RT-PCR', to, establish, that, 'insulin,', 'glucagon,', 'glucagon-like', 'peptide-1', '(', 'GLP-1)', and, the, 'GLP-1', derivatives, 'GLP(7-36)Amide', and, 'Exendin-4', all, stimulate, 'IAPP', promoter, 'activity,', as, well, as, endogenous, 'IAPP', mRNA, levels, in, isolated, islets, of, 'Langerhans'])].
[sujeto(['In', 'contrast,', somatostatin, had, no, 'effect,', and, whilst, the, inflammatory, cytokines, 'TNF-alpha,', 'IL-1alpha', and, 'IL-1beta', had, no, effect, on, promoter, 'activity,', they, all]), verbo([decreased]), complemento(['IAPP', mRNA, levels, in, isolated, islets])].
[sujeto(['Finally,', utilising, a, series, of, deletion, reporter, gene, constructs, of, the, human, 'IAPP', gene, 'promoter,', we, used, overexpression, studies, to, establish, that, 'HNF-3beta', '(', 'FoxA2)', negatively]), verbo([regulates]), complemento([the, 'IAPP', 'promoter,', whilst, the, 'MODY3', transcription, factor, 'HNF-1alpha', positively, regulates, promoter, activity])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, '(', 'HNF)-1alpha', plays, a, central, role, in, intestinal, and, hepatic, gene, regulation, and, is, required, for, hepatic, expression, of, the, liver, fatty, acid, binding, protein, gene, '(', 'Fabpl)'])].
[sujeto(['An', 'Fabpl', transgene, was, directly]), verbo([activated]), complemento([through, cognate, sites, by, 'HNF-1alpha', and, 'HNF-1beta,', as, well, as, five, other, endodermal, 'factors:', 'CDX-1,', 'C/EBPbeta,', 'GATA-4,', 'FoxA2,', and, 'HNF-4alpha'])].
[sujeto(['HNF-1alpha']), verbo([activated]), complemento([the, 'Fabpl', transgene, by, as, much, as, 60, -, fold, greater, in, the, presence, of, the, other, five, endodermal, factors, than, in, their, 'absence,', accounting, for, up, to, 'one-half', the, total, transgene, activation, by, the, group, of, six, factors])].
[sujeto(['This', degree, of, synergistic, interaction]), verbo([suggests]), complemento([that, multifactor, cooperativity, is, a, critical, determinant, of, endodermal, gene, activation, by, 'HNF-1alpha'])].
[sujeto(['Mutations', in, 'HNF-1alpha', that, result, in, maturity, onset, diabetes, of, the, young, '(', 'MODY3)']), verbo([provide]), complemento([evidence, for, the, in, vivo, significance, of, these, synergistic, interactions])].
[sujeto(['An', 'R131Q', 'HNF-1alpha', 'MODY3', mutant, exhibits, complete]), verbo([loss]), complemento([of, synergistic, activation, in, concert, with, the, other, endodermal, transcription, factors, despite, 'wild-type', transactivation, ability, in, their, absence])].
[sujeto(['Selective']), verbo([loss]), complemento([of, synergy, with, other, endodermal, transcription, factors, accompanied, by, retention, of, native, transactivation, ability, in, an, 'HNF-1alpha', 'MODY', mutant, suggests, in, vivo, significance, for, cooperative, synergy])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, '(', 'HNF)-3beta,', a, transcription, factor, expressed, in, pancreatic, beta, 'cells,', is, an, upstream, regulator, of, 'HNF-1alpha/MODY3,', 'HNF-4alpha/MODY1', and, 'IPF1/MODY5', genes])].
[sujeto(['Our', previous, screening, of, 'MODY', subjects, showed, that, mutations, in, the, 'HNF-3beta', gene, are, not, a, common]), verbo([cause]), complemento([of, this, form, of, diabetes, in, the, 'Japanese'])].
[sujeto(['We', tested, the, hypothesis, that, mutations, in, the, 'HNF-3beta', gene]), verbo([cause]), complemento(['late-onset', 'Type', 'II', '(', 'non-insulin-dependent)', diabetes, mellitus, in, this, population])].
[sujeto(['The', 'A86T', mutation, in, the, 'HNF-3beta', gene, might, be]), verbo([involved]), complemento([in, the, development, of, 'late-onset', 'Type', 'II', diabetes, in, a, small, group, of, 'Japanese', people])].
[sujeto(['The', genes, encoding, the, functionally, related, hepatocyte]), verbo([nuclear]), complemento([factors, 'HNF-1alpha', and, 'HNF-4alpha', play, a, critical, role, in, normal, pancreatic, 'beta-cell', function])].
[sujeto(['The', transcriptional, hierarchy, of, 'HNFs']), verbo([suggests]), complemento([that, other, proteins, of, the, regulatory, cascade, might, be, responsible, for, other, forms, of, 'MODY', 'and/or', 'late-onset', type, 2, diabetes])].
[sujeto(['In', this, 'study,', we, show, that, 'HNF-3alpha,', -, 3, 'beta,', -, 3, 'gamma,', -, 4, 'gamma,', and, -, 6, are]), verbo([expressed]), complemento([in, pancreatic, 'beta-cells'])].
[sujeto(['We']), verbo([report]), complemento([the, identification, and, characterization, of, simple, tandem, repeat, 'DNA', polymorphisms, in, the, genes, encoding, 'HNF-3alpha,', -, 3, 'beta,', -, 3, 'gamma,', -, 4, 'gamma,', and, -, 6, and, the, mapping, of, 'HNF-6', to, chromosome, bands, 15, q21])].
[sujeto(['In', diabetes, 'mellitus,', hepatic, and, tubular, glucose, output]), verbo([has]), complemento([been, related, to, 'Slc2a2/GLUT2', 'overexpression;', and, controlling, the, expression, of, this, gene, may, be, an, important, adjuvant, way, to, improve, glycemic, homeostasis])].
[sujeto(['Thus,', the, present, study, investigated, transcriptional, mechanisms]), verbo([involved]), complemento([in, the, 'diabetes-induced', overexpression, of, the, 'Slc2a2', gene])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factors, 1, α, and, 4, α, '(', 'HNF-1α', and, 'HNF-4α),', forkhead, box, 'A2', '(', 'FOXA2),', sterol, regulatory, element, binding, 'protein-1c', '(', 'SREBP-1c)', and, the, 'CCAAT-enhancer-binding', protein, '(', 'C/EBPβ)', mRNA, expression, '(', 'RT-PCR)', and, binding, activity, into, the, 'Slc2a2', promoter, '(', electrophoretic, mobility, 'assay)', were, analyzed, in, the, liver, and, kidney, of, diabetic, and, 6, -, day, 'insulin-treated', diabetic, rats])].
[sujeto(['Slc2a2/GLUT2', expression]), verbo([increased]), complemento([by, more, than, 50, '%', '(', 'P&lt;0'])].
[sujeto(['Similarly,', the, mRNA, expression, and, the]), verbo([binding]), complemento([activity, of, 'HNF-1α,', 'HNF-4α', and, 'FOXA2', increased, by, 50, to, 100, '%', '(', 'P&lt;0'])].
[sujeto(['Neither', the, 'Srebf1', and, 'Cebpb', mRNA, 'expression,', nor, the, 'SREBP-1c', and, 'C/EBP-β']), verbo([binding]), complemento([activity, was, altered, in, diabetic, rats])].
[sujeto(['HNF-1α,', 'HNF-4α', and, 'FOXA2', transcriptional, factors, are]), verbo([involved]), complemento([in, 'diabetes-induced', overexpression, of, 'Slc2a2', gene, in, the, liver, and, kidney])].
[sujeto(['These', data, point, out, that, these, transcriptional, factors, are, important]), verbo([targets]), complemento([to, control, 'GLUT2', expression, in, these, 'tissues,', which, can, contribute, to, glycemic, homeostasis, in, diabetes])].
[sujeto(['The']), verbo([cause]), complemento([of, organ, failure, is, enigmatic, for, many, degenerative, 'diseases,', including, 'end-stage', liver, disease])].
[sujeto(['Here,', using, a, 'CCl4-induced', rat, model, of, irreversible, and, fatal, hepatic, 'failure,', which, also, exhibits, terminal, changes, in, the, extracellular, 'matrix,', we, demonstrated, that, chronic, injury, stably, reprograms, the, critical, balance, of, transcription, factors, and, that, diseased, and, dedifferentiated, cells, can, be, returned, to, normal, function, by, 're-expression', of, critical, transcription, 'factors,', a, process, similar, to, the, type, of, reprogramming, that]), verbo([induces]), complemento([somatic, cells, to, become, pluripotent, or, to, change, their, cell, lineage])].
[sujeto(['Forced', 're-expression', of, the, transcription, factor, 'HNF4α']), verbo([induced]), complemento([expression, of, the, other, 'hepatocyte-expressed', transcription, 'factors;', restored, functionality, in, terminally, diseased, hepatocytes, isolated, from, 'CCl4-treated', 'rats;', and, rapidly, reversed, fatal, liver, failure, in, 'CCl4-treated', animals, by, restoring, diseased, hepatocytes, rather, than, replacing, them, with, new, hepatocytes, or, stem, cells])].
[sujeto(['Together,', the, results, of, our, study, indicate, that, disruption, of, the, transcription, factor, network, and, cellular, dedifferentiation, likely]), verbo([mediate]), complemento([terminal, liver, failure, and, suggest, reinstatement, of, this, network, has, therapeutic, potential, for, correcting, organ, failure, without, cell, replacement])].
[sujeto(['Siah2-dependent', expression, and, activity, of, 'HIF-1α']), verbo([regulate]), complemento([its, availability, to, form, a, transcriptional, complex, with, 'FoxA2,', resulting, in, expression, of, specific, target, 'genes,', including, 'Hes6,', 'Sox9', and, 'Jmjd1a,', whose, 'co-expression', is, sufficient, for, formation, of, 'NE', tumors, and, 'NE', lesions, in, 'PCa'])].
[sujeto(['These', studies]), verbo([provide]), complemento([novel, markers, to, diagnose, and, monitor, formation, of, 'NE', lesions, and, 'NE', tumors])].
[sujeto(['Furthermore,', defining, the, regulatory, axis, consisting, of, 'Siah2', and, 'HIF-1α/FoxA2', cooperation]), verbo([suggests]), complemento([novel, therapeutic, modalities, to, treat, these, most, aggressive, forms, of, prostate, cancer])].
[sujeto(['Here', we, review, current, understanding, of, 'Siah', role, in, control, of, hypoxia, and, prostate, tumor, development, and, highlight, potential, approaches, for]), verbo([targeting]), complemento([components, along, 'Siah-regulated', pathways])].
[sujeto(['Formation', of, 'NE', prostate, tumors, in, the, 'TRAMP', mouse, model, was]), verbo([suppressed]), complemento([in, mice, lacking, the, ubiquitin, ligase, 'Siah2,', which, regulates, 'HIF-1alpha', availability])].
[sujeto(['Cooperation', between, 'HIF-1alpha', and, 'FoxA2,', a, transcription, factor]), verbo([expressed]), complemento([in, 'NE', 'tissue,', promotes, recruitment, of, p300, to, transactivate, select, 'HIF-regulated', 'genes,', 'Hes6,', 'Sox9,', and, 'Jmjd1a'])].
[sujeto(['These', 'HIF-regulated', genes, are, highly]), verbo([expressed]), complemento([in, metastatic, 'PCa', and, required, for, 'hypoxia-mediated', 'NE', 'phenotype,', metastasis, in, 'PCa,', and, the, formation, of, 'NE', tumors])].
[sujeto(['Tissue-specific', expression, of, 'FoxA2', combined, with, 'Siah2-dependent', 'HIF-1alpha', availability, enables, a, transcriptional, program]), verbo([required]), complemento([for, 'NE', prostate, tumor, development, and, 'NE', phenotype, in, 'PCa'])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, 'PGC-1alpha-mediated', upregulation, of, 'beta-cell', sterol, element, binding, protein, '(', 'SREBP)', gene, expression, impairs, insulin, secretion, via, increased, transcription, of, uncoupling, protein, 2, '(', 'UCP2)'])].
[sujeto(['PGC-1beta,', in, contrast, to, 'PGC-1alpha,', directly]), verbo([binds]), complemento([to, and, acts, as, a, 'co-activator', of, 'SREBPs', and, the, forkhead, transcription, factor, 2, 'A', '(', 'FOXA2)', involved, in, pancreas, development, and, function])].
[sujeto(['In', comparison, to, 'controls,', mRNA, levels, of, all, genes, studied, except, for, 'FOXA2', and, 'FOXO1', were]), verbo([increased]), complemento([in, islets, of, 'obese,', 'fa/fa', 'ZDF', rats])].
[sujeto(['PGC-1beta', as, well, as, 'SREBP-1c', and, -, 2]), verbo([increased]), complemento([transcription, from, the, 'UCP2', promoter, in, 'INS-1E', cells])].
[sujeto(['Transient', transfection, of, 'PGC-1beta-specific', siRNAs, significantly]), verbo([decreased]), complemento(['SREBP-2-mediated', transcriptional, activation, of, the, 'UCP2', gene])].
[sujeto(['Furthermore', 'PGC-1beta,', 'SREBP-1c,', and, 'FOXA2', overexpression, augmented, granuphilin, promoter, 'activity,', whereas, 'siRNA-mediated', gene, knockdown, of, 'PGC-1beta', reduced, the, effects, of, 'SREBP-1c', and, 'FOXA2', on, granuphilin, gene, transcription, and, significantly]), verbo([increased]), complemento(['glucose-stimulated', insulin, release, from, 'INS-1E', cells])].
[sujeto(['Morphological', changes, that, occur, during, pancreatic, endocrine, cell, differentiation]), verbo([have]), complemento([been, shown, in, rodent, systems, to, be, dependent, on, sequential, alterations, in, transcription, factor, expression])].
[sujeto(['However,', similar, data, for, humans]), verbo([have]), complemento([been, limited])].
[sujeto(['The', aim, of, the, present, study, was, to]), verbo([provide]), complemento([a, connection, between, pancreatic, 'morphology,', transcription, factor, gene, expression, and, protein, localisation, during, human, fetal, development])].
[sujeto(['We', observed, a, significant]), verbo([decrease]), complemento([in, pancreatic, duodenal, homeobox, 1, '(', 'PDX-1)(+)/cytokeratin', 19, '(', +, ')', cells, '(', p, &, 'lt;', 0.001, ')', ',', with, a, simultaneous, increase, in, 'PDX-1(+)/insulin(+)', cells, from, 8, to, 21, weeks, '(', p, &, 'lt;', 0.05, ')'])].
[sujeto(['Increased', 'PDX-1/insulin', 'co-localisation', within, islet, clusters, was, 'noted,', while, no, 'co-expression', of, 'PDX-1', with, glucagon, was, 'found,']), verbo([suggesting]), complemento([that, loss, of, 'PDX-1', is, essential, for, alpha, cell, formation])].
[sujeto(['Co-localisation', of, 'NGN3', with, 'PDX-1,', insulin, and, glucagon, was, noted, during, early, 'development,', with, significant]), verbo([decreases]), complemento([in, middle, and, late, stages, '(', p, &, 'lt;', 0.001, ')'])].
[sujeto(['Our', microarray, and, 'co-localisation', analyses, of, transcription, factors, linked, to, 'NGN3', demonstrated, that, 'ISL1', transcription, factor, '(', 'ISL1),', neurogenic, differentiation, 1, '(', 'NEUROD1),', 'NK2', related, transcription, factor, 'related,', locus, 2, '(', 'NKX2-2)', and, paired, box, gene, 6, '(', 'PAX6)', were, upregulated, during, development, and, present, in, all, four, endocrine, cell, 'types,', while, 'NK6', related, transcription, factor, 'related,', locus, 1, '(', 'NKX6-1)', was]), verbo([expressed]), complemento([exclusively, in, beta, cells])].
[sujeto(['This', study, is, an, important, step, towards, identifying, key, molecular, factors]), verbo([involved]), complemento([in, development, of, the, human, fetal, endocrine, pancreas])].
[sujeto(['We', demonstrate, that, the]), verbo([binding]), complemento([sites, for, highly, conserved, transcription, factors, vary, extensively, between, human, and, mouse])].
[sujeto(['We', mapped, the]), verbo([binding]), complemento([of, four, 'tissue-specific', transcription, factors, '(', 'FOXA2,', 'HNF1A,', 'HNF4A', and, 'HNF6)', to, 4, ',', 0, orthologous, gene, pairs, in, hepatocytes, purified, from, human, and, mouse, livers])].
[sujeto(['Despite', the]), verbo([conserved]), complemento([function, of, these, 'factors,', from, 41, '%', to, 89, '%', of, their, binding, events, seem, to, be, species, specific])].
[sujeto(['When', the, same, protein]), verbo([binds]), complemento([the, promoters, of, orthologous, 'genes,', approximately, 'two-thirds', of, the, binding, sites, do, not, align])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factors, '(', 'HNF)', play, a, critical, role, in, development, of, the, liver])].
[sujeto(['This', in, vivo, model]), verbo([has]), complemento([allowed, us, to, investigate, the, fundamental, mechanisms, underlying, 'HCC', progression])].
[sujeto(['A', complete]), verbo([loss]), complemento([of, cell, 'polarity,', a, decrease, in, 'cell-cell', and, 'cell-extracellular', matrix, '(', 'ECM)', 'adhesion,', elevation, of, telomerase, 'activity,', and, extinction, of, 'liver-specific', gene, expression, accompanies, tumor, progression])].
[sujeto(['Forced', 're-expression', of, 'HNF4alpha1', in, cultured, fgHCC, cells, reversed, the, progressive, phenotype, and]), verbo([induced]), complemento([fgHCC, cells, to, 're-establish', an, epithelium, and, reform, 'cell-ECM', contacts])].
[sujeto(['Moreover,', fgHCC, cells, that]), verbo([expressed]), complemento(['HNF4alpha1', also, 're-established', expression, of, the, profile, of, liver, transcription, factors, and, hepatic, genes, that, are, associated, with, a, differentiated, hepatocyte, phenotype])].
[sujeto(['In', 'conclusion,']), verbo([loss]), complemento([of, 'HNF4', expression, is, an, important, determinant, of, 'HCC', progression])].
[sujeto(['Forced', expression, of, this, factor, can]), verbo([promote]), complemento([reversion, of, tumors, toward, a, less, invasive, highly, differentiated, 'slow-growing', phenotype])].
[sujeto(['Down-regulation', of, constitutive, hepatic, cytochrome, 'P450', '(', 'P450)', mRNAs, by, bacterial, endotoxin, '(', 'lipopolysaccharide,', 'LPS)', or, other, inflammatory, stimuli]), verbo([has]), complemento([been, documented, 'extensively,', but, the, contribution, of, transcriptional, suppression, to, this, effect, is, poorly, understood])].
[sujeto(['Injection', of, curcumin, significantly]), verbo([inhibited]), complemento([the, rapid, transcriptional, suppression, of, 'CYP2E1,', and, blocked, that, of, 'CYP3A2'])].
[sujeto(['These', effects, seemed, to, be, independent, of, inhibition, of]), verbo([nuclear]), complemento(['factor-kappaB', '(', 'NF-kappaB)', activation, by, 'curcumin,', because, induction, of, known, 'NF-kappaB-regulated', genes, was, not, attenuated])].
[sujeto(['One', hour, after, 'LPS', 'injection,', the, 'DNA-binding', activities, of, hepatocyte]), verbo([nuclear]), complemento([factor, '(', 'HNF)1alpha,', 'HNF3beta,', and, 'HNF4alpha', were, reduced, to, 73, ',', 72, ',', and, 53, '%', ',', 'respectively,', of, control, values])].
[sujeto(['The']), verbo([nuclear]), complemento([abundances, of, 'Sp1,', 'liver-enriched', transcriptional, inhibitory, protein, '(', 'LIP),', 'HNF1alpha,', and, 'HNF3beta', were, 'unchanged,', whereas, the, abundance, of, 'HNF4alpha', was, reduced, to, 87, '%', of, control, levels])].
[sujeto(['Differentiation', of, hepatocytes, is, reflected, by, their, expression, of, hepatic, functional, proteins, in, the, mouse, 'embryo,', and, 'liver-enriched', transcription, factors, '(', 'LETFs)']), verbo([have]), complemento([been, shown, to, regulate, hepatic, functional, genes, strictly])].
[sujeto(['Previous']), verbo([reports]), complemento([demonstrated, that, the, level, of, 'LETF', expression, is, altered, in, 'HCC', or, preneoplastic, nodules, compared, with, noncancerous, tissues])].
[sujeto(['These', findings]), verbo([suggested]), complemento([that, 'HNF-4', alpha, and, 'HNF-1', alpha, are, useful, markers, to, assess, the, degree, of, 'HCC', 'differentiation,', which, we, suggest, could, be, evaluated, objectively, by, the, quantitative, analysis, of, 'HNFs', and, 'C/EBP', alpha, in, 'HCCs'])].
[sujeto(['Overexpression', of, prothrombin]), verbo([leads]), complemento([to, an, increased, risk, of, venous, thrombosis])].
[sujeto(['The', aim, of, our, study, was, to, localize, the, regions, within, the, prothrombin, enhancer, responsible, for, its, 'activity,', to, identify, the, proteins]), verbo([binding]), complemento([to, these, 'regions,', and, to, establish, their, functional, importance])].
[sujeto(['Putative', transcription, factor, '(', 'TF)']), verbo([binding]), complemento([sites, were, evaluated, by, electrophoretic, mobility, shift, assays])].
[sujeto(['The', functional, importance, of, each, 'TF']), verbo([binding]), complemento([site, was, evaluated, by, site, directed, mutagenesis, and, transient, transfection, of, the, mutant, constructs])].
[sujeto(['Analysis', of, this, region, revealed, putative]), verbo([binding]), complemento([sites, for, hepatocyte, nuclear, factor, 'HNF4,', 'HNF3-beta', and, specificity, 'protein(Sp)1'])].
[sujeto(['We', identified, six, different, 'TFs']), verbo([binding]), complemento([to, three, evolutionary, conserved, sites, in, the, 'enhancer:', 'HNF4-alpha', '(', site, 1, ')', ',', 'HNF1-alpha,', 'HNF3-beta', and, an, as, yet, unidentified, 'TF', '(', site, 2, ')', and, the, ubiquitously, expressed, 'TFs', 'Sp1', and, 'Sp3', '(', site, 3, ')'])].
[sujeto(['Mutagenesis', studies, showed, that]), verbo([loss]), complemento([of, binding, of, 'HNF3-beta', resulted, in, a, considerable, decrease, of, enhancer, 'activity,', whereas, loss, of, 'HNF4-alpha', or, 'Sp1/Sp3', resulted, in, milder, reductions])].
[sujeto(['Six', different, 'TFs', are, able, to]), verbo([bind]), complemento([to, this, region])].
[sujeto(['A', possible, role, of, hepatocyte]), verbo([nuclear]), complemento([factor, 1, '(', 'HNF1)', or, 'HNF3,', a, predominant, 'trans-acting', factors, of, hepatic, or, pancreatic, 'beta-cells,', was, examined, on, the, tissue, specific, interdependent, expression, of, glucokinase, '(', 'GK)', in, 'liver,', 'H4IIE,', 'HepG2,', 'HIT-T15', and, 'MIN6', cell, line])].
[sujeto(['The', tissues, or, cell, lines, known, to]), verbo([express]), complemento(['GK', showed, abundant, levels, of, 'HNF1', and, 'HNF3', mRNA, as, observed, in, 'liver,', 'H4IIE,', 'HepG2,', 'HIT-T15', and, 'MIN6', 'cells,', whereas, they, were, not, detected, in, 'brain,', 'heart,', 'NIH', 3, 'T3,', 'HeLa', cells])].
[sujeto(['The', promoter, of, glucokinase, contains, several, 'HNF3', consensus, sequences, and, are, well]), verbo([conserved]), complemento([in, 'human,', mouse, and, rat])].
[sujeto(['Transfection', of, the, glucokinase, promotor, linked, with, luciferase, reporter, to, liver, or, pancreatic, beta, cell, lines, showed, high]), verbo([interacting]), complemento([activities, with, 'HNF1', and, 'HNF3,', whereas, minimal, activities, were, detected, in, the, cells, expressing, very, low, levels, of, 'HNFs'])].
[sujeto(['The']), verbo([binding]), complemento([of, 'HNF1', or, 'HNF3', to, the, 'GK', promoter, genes, was, confirmed, by, electrophoretic, mobility, shift, assay, '(', 'EMSA)'])].
[sujeto(['During', hepatic, 'proliferation,', expression, of, hepatocyte]), verbo([nuclear]), complemento([factors, '(', 'HNF)1alpha,', 'HNF4,', 'C/EBP', 'alpha,', and, 'C/EBP', beta, mRNAs, was, 'depressed,', whereas, that, of, 'HNF3alpha', and, 'HNF3beta', transcripts, was, enhanced])].
[sujeto(['The', mitoinhibitory, 'agents,', 'IL-1beta,', 'IL-6,', 'TGF-beta,', and, activin, 'A,', were, examined, to, determine, whether, they, could]), verbo([induce]), complemento([differentiation, of, proliferating, hepatocytes, as, shown, in, cells, treated, with, 'DMSO'])].
[sujeto(['Although', these, factors]), verbo([inhibited]), complemento([cell, 'growth,', the, cells, did, not, differentiate])].
[sujeto(['Therefore,', hepatic, differentiation]), verbo([requires]), complemento([not, only, inhibition, of, 'DNA', synthesis, but, also, induction, of, appropriate, transcription, factors])].
[sujeto(['Liver-specific', gene, expression, in, adult, hepatocytes, relies, on, four, families, of, evolutionary]), verbo([conserved]), complemento([transcription, factors, that, are, 'liver-enriched', but, not, restricted, to, this, tissue])].
[sujeto(['These', factors, function, in, unique, 'combinations,', often, 'synergistically,', to]), verbo([stimulate]), complemento(['cell-specific', transcription])].
[sujeto(['Each', family, is, composed, of, several, members, displaying, 'similar,', if, not, 'identical,', 'DNA', recognition, properties, and, sharing, structural, homology, in, their, 'DNA']), verbo([binding]), complemento([domains])].
[sujeto(['The', consequences, of, inactivating, different, family, members, in, the, mouse, by, homologous, 'recombination,', together, with, recent, studies, of, their, 'regulation,']), verbo([suggest]), complemento([a, model, for, liver, differentiation, involving, a, regulatory, network, rather, than, a, completely, hierarchical, genetic, circuitry])].
[sujeto(['We', investigated, transacting, factors]), verbo([binding]), complemento([to, the, 'cis-element', important, in, 'tissue-specific', expression, of, the, human, glucose, transporter, type, 2, isoform, '(', 'GLUT2)', gene])].
[sujeto(['DNase', 'I', footprinting, and, electrophoretic, mobility, shift, assay, indicated, that, site, 'C', contained, one]), verbo([binding]), complemento([site, for, hepatocyte, nuclear, factor, 1, '(', 'HNF1)', and, two, binding, sites, for, 'HNF3'])].
[sujeto(['The', mutations, at, positions, +, 101, and, +, 103, ',', which, are, considered, to, be, critical, in]), verbo([binding]), complemento(['HNF1', and, 'HNF3,', resulted, in, a, 53, '%', decrease, in, promoter, 'activity,', whereas, the, mutation, of, the, proximal, 'HNF3', binding, site, '(', +, 115, and, +, 117, ')', reduced, promoter, activity, by, 28, '%'])].
[sujeto(['The', mutations, of, these, four, sites, resulted, in, marked]), verbo([decrease]), complemento(['(', 70, '%', ')', in, promoter, activity, as, well, as, diminished, bindings, of, 'HNF1', and, 'HNF3'])].
[sujeto(['A', to, 'G', 'mutation,', which]), verbo([causes]), complemento([conversion, of, the, 'HNF1', and, 'HNF3', binding, sequence, to, the, 'NF-Y', binding, 'site,', resulted, in, a, 22, '%', decrease, in, promoter, activity])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'HNF1alpha', and, 'HNF3beta', may, be, the, most, important, players, in, the, 'tissue-specific', expression, of, the, human, 'GLUT2', gene])].
[sujeto(['Within', the, liver, acinus, the, majority, of, genes, are]), verbo([expressed]), complemento([in, an, ascending, or, descending, gradient, from, the, portal, to, the, central, vein])].
[sujeto(['The', regulatory, factors]), verbo([involved]), complemento([in, this, spatial, pattern, of, gene, expression, are, still, poorly, understood])].
[sujeto(['Many', liver, genes, are]), verbo([regulated]), complemento([by, 'liver-enriched', transcription, factors])].
[sujeto(['Here', we]), verbo([report]), complemento([on, mRNA, distribution, of, four, transcription, factors, in, cell, lysates, obtained, from, either, the, periportal, or, the, perivenous, region, after, 'zone-specific', digitonin, infusion, and, by, 'in-situ', hybridization])].
[sujeto(['The', moderate, acinar, zonation, of, the, mRNAs, of, these, transcription, factors]), verbo([suggests]), complemento([that, at, best, they, could, modulate, but, not, govern, the, zonated, expression, of, liver, genes, in, the, mature, liver])].
[sujeto(['alpha-Fetoprotein', '(', 'AFP)', and, transthyretin, '(', 'TTR)', transcripts]), verbo([increased]), complemento([at, the, stage, when, embryoid, bodies, began, to, form, 'yolk-sac-like', structures, and, were, expressed, strongly, thereafter])].
[sujeto(['Expression', of, hepatocyte]), verbo([nuclear]), complemento([factor, '(', 'HNF)', 4, ',', a, variant, form, of, 'HNF1', '(', also, called, 'HNF1beta),', and, 'HNF3beta', started, before, the, onset, of, 'AFP', and, 'TTR', expression])].
[sujeto(['Serum', albumin, '(', 'ALB)', transcript, was, only]), verbo([found]), complemento([in, late, large, cystic, 'EBs'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, patterns, of, endoderm, gene, expression, during, 'EB', development, reflect, the, order, found, during, mouse, development, in, 'vivo,', and, 'EB', formation, may, serve, as, an, in, vitro, system, to, study, the, differentiation, process])].
[sujeto(['Transcription', of, 'hepatocyte-specific', genes]), verbo([requires]), complemento([the, interaction, of, their, regulatory, regions, with, several, nuclear, factors])].
[sujeto(['Among', them, is, the, hepatocyte]), verbo([nuclear]), complemento([factor, 3, '(', 'HNF3)', 'family,', composed, of, the, 'HNF3', 'alpha,', 'HNF3', 'beta,', and, 'HNF3', gamma, 'proteins,', which, are, expressed, in, the, liver, and, have, very, similar, fork, head, 'DNA', binding, domains])].
[sujeto(['The', regulatory, regions, of, numerous, 'hepatocyte-specific', genes, contain, 'HNF3']), verbo([binding]), complemento([sites])].
[sujeto(['Cells', were, stably, transfected, with, a, vector, allowing, the, synthesis, of, an, 'HNF3', beta, fragment, consisting, of, the, fork, head, 'DNA']), verbo([binding]), complemento([domain, without, the, transactivating, 'amino-', and, 'carboxy-terminal', domains])].
[sujeto(['The', truncated, protein, was, located, in, the, nuclei, of, cultured, hepatoma, cells, and, competed, with, endogenous, 'HNF3', proteins, for]), verbo([binding]), complemento([to, cognate, 'DNA', sites])].
[sujeto(['Overproduction', of, this, truncated, 'protein,', lacking, any, transactivating, 'activity,']), verbo([induced]), complemento([a, dramatic, decrease, in, the, expression, of, 'liver-specific', 'genes,', including, those, for, 'albumin,', 'transthyretin,', 'transferrin,', phosphoenolpyruvate, 'carboxykinase,', and, aldolase, 'B,', whereas, the, expression, of, the, 'L-type', pyruvate, kinase, 'gene,', containing, no, 'HNF3', binding, 'sites,', was, unaltered])].
[sujeto(['Thus,', the, transactivating, domains, of, 'HNF3', proteins, are, needed, for, the, proper, expression, of, a, set, of, 'liver-specific', genes, but, not, for, expression, of, the, genes, encoding, transcription, factors]), verbo([found]), complemento([in, differentiated, hepatocytes])].
[sujeto(['The', influence, of, hepatocyte]), verbo([nuclear]), complemento([factor, 3, '(', 'HNF3)', on, the, level, of, transcriptional, activity, from, the, four, hepatitis, 'B', virus, promoters, was, investigated, by, 'transient-transfection', analysis, in, the, dedifferentiated, hepatoma, cell, 'line,', 'HepG2'])].
[sujeto(['It', was]), verbo([found]), complemento([that, the, large, surface, antigen, promoter, 'and,', to, a, much, lesser, 'extent,', the, nucleocapsid, promoter, were, transactivated, in, the, presence, of, 'HNF3'])].
[sujeto(['The', complex, formed, with, 'Huh7', cell, extract, comigrated, with, exogenously]), verbo([expressed]), complemento(['HNF3', beta, in, 'HeLa', 'S3', extracts, and, was, specifically, inhibited, from, forming, by, the, addition, of, 'HNF3', beta, antiserum])].
[sujeto(['The', promoter, element, which, appears, to]), verbo([mediate]), complemento([the, 'HNF3', transactivation, was, functionally, mapped, by, mutational, analysis, to, a, region, between, nucleotides, -, 65, and, -, 54, relative, to, the, transcriptional, start, site])].
[sujeto(['A', synthetic, promoter, construct, containing, this, 'HNF3-binding', site, was, able, to]), verbo([mediate]), complemento([transactivation, by, 'HNF3', beta])].
[sujeto(['These', and, previous, results]), verbo([suggest]), complemento([that, the, hepatitis, 'B', virus, large, surface, antigen, promoter, is, regulated, by, at, least, two, 'liver-enriched', transcription, 'factors,', 'HNF1', and, 'HNF3,', which, together, may, contribute, to, the, differentiated, liver, cell, type, specificity, of, this, promoter])].
[sujeto(['The', transthyretin, '(', 'TTR)', gene, is]), verbo([regulated]), complemento([by, two, 'DNA', regions, which, elicit, 'hepatocyte-specific', 'expression:', a, proximal, promoter, and, distal, enhancer])].
[sujeto(['The', 'TTR', promoter, and, enhancer, are, composed, of, at, least, eight, 'DNA']), verbo([binding]), complemento([sites, for, three, different, hepatocyte, nuclear, factors, '(', 'HNF),', 'CCAAT/enhancer', binding, protein, '(', 'C/EBP),', and, 'AP-1/cJun'])].
[sujeto(['Site', directed, mutations, within, each, of, the, 'HNF']), verbo([binding]), complemento([sites, in, the, 'TTR', promoter, were, introduced, to, evaluate, their, contribution, to, transcriptional, activity, in, hepatoma, cells])].
[sujeto(['The', data, indicate, that, the, strong, affinity, 'HNF-3-S']), verbo([binding]), complemento([site, '(', -, 106, to, -, 94, ')', is, absolutely, required, for, 'TTR', promoter, activity, since, several, mutations, in, this, site, eliminate, 'TTR', expression, in, the, context, of, its, enhancer])].
[sujeto(['In', 'contrast,', when, we, deleted, the, 'TTR', enhancer, from, these, 'HNF', mutant, 'constructs,', 'TTR', expression]), verbo([decreased]), complemento([to, undetectable, levels])].
[sujeto(['This', result]), verbo([suggests]), complemento([cooperation, between, the, factors, binding, to, the, 'TTR', promoter, and, enhancer, regions])].
[sujeto(['These', results, also, demonstrate, that, the, 'HNF3-S', site, alone, is, not, sufficient, to]), verbo([activate]), complemento(['TTR', 'transcription,', but, rather, requires, the, participation, of, three, 'cell-specific', factors, to, elicit, minimal, promoter, activity])].
[sujeto(['To', investigate, the, regulation, of, genes, whose, expression, is, enriched, in, liver, we, studied, expression, of, the, albumin, and, transthyretin, '(', 'TTR)', genes, in, a, series, of, rat, hepatoma, cell, lines, '(', 'FaO,', 'C2,', 'C2rev7,', and, 'H5)', that]), verbo([express]), complemento([these, genes, at, different, rates])].
[sujeto(['The', level, of, expression, of, albumin, and, 'TTR', was, compared, to, the, expression, and, 'DNA-binding', activity, of, four, transcription, 'factors,', 'HNF1/LFB1,', 'C/EBP,', 'HNF3,', and, 'HNF4,', that, are]), verbo([found]), complemento([at, high, concentrations, in, liver])].
[sujeto(['The', hepatocyte]), verbo([nuclear]), complemento(['factors,', 'Hnf1a', and, 'Hnf4a,', in, addition, to, playing, key, roles, in, determining, hepatocyte, 'fate,', have, been, implicated, as, candidate, 'lineage-determining', transcription, factors, in, the, kidney, proximal, tubule, '(', 'PT)', '[', 'Martovetsky', et])].
[sujeto(['Mouse', embryonic, fibroblasts, '(', 'MEFs)', transduced, with, 'Hnf1a', and, 'Hnf4a', form, tight, junctions, and]), verbo([express]), complemento([multiple, 'PT', drug, transporters, '(', e])].
[sujeto(['In', 'contrast,', the, coexpression, '(', with, 'Hnf1a', and, 'Hnf4a)', of, 'GATA']), verbo([binding]), complemento([protein, 4, '(', 'Gata4),', as, well, as, the, forkhead, box, transcription, 'factors,', 'Foxa2', and, 'Foxa3,', in, 'MEFs', not, only, downregulates, 'PT', markers, but, also, leads, to, upregulation, of, several, hepatocyte, 'markers,', including, 'albumin,', 'apolipoprotein,', and, transferrin])].
[sujeto(['Thus,', the, presence, of, 'Gata4', and, 'Foxa2/Foxa3', appears, to, alter, the, effect, of, 'Hnf1a', and, 'Hnf4a', by, an, 'as-yet', unidentified, 'mechanism,']), verbo([leading]), complemento([toward, the, generation, of, more, 'hepatocyte-like', cells, as, opposed, to, cells, exhibiting, 'PT', characteristics])].
[sujeto(['These', findings]), verbo([provide]), complemento([valuable, 'insight,', not, only, into, the, 'developmental,', and, perhaps, 'organotypic,', regulation, of, drug, 'transporters,', 'drug-metabolizing', 'enzymes,', and, tight, 'junctions,', but, also, for, regenerative, medicine, strategies, aimed, at, restoring, the, function, of, the, liver, 'and/or', kidney, '(', acute, kidney, 'injury,', 'AKI;', chronic, kidney, 'disease,', 'CKD)'])].
[sujeto(['To', investigate, the, molecular, mechanism, for, their, 'diversities,', we, test, the, hypothesis, that, large, and, small, 'BEC']), verbo([have]), complemento([disparity, in, their, target, gene, response, to, their, transcriptional, 'regulator,', the, biliary, 'cell-enriched', hepatocyte, nuclear, factor, 'HNF6'])].
[sujeto(['The', expression, of, the, major, 'HNF', '(', 'HNF6,', 'OC2,', 'HNF1b,', 'HNF1a,', 'HNF4a,', 'C/EBPb,', and, 'Foxa2)', and, representative, biliary, transport]), verbo([target]), complemento([genes, that, are, 'HNF', dependent, were, compared, between, 'SV40-transformed', 'BEC', derived, from, large, '(', 'SV40LG)', and, small, '(', 'SV40SM)', 'ducts,', before, and, after, treatment, with, recombinant, adenoviral, vectors, expressing, 'HNF6', '(', 'AdHNF6)', or, control, 'LacZ', cDNA, '(', 'AdLacZ)'])].
[sujeto(['Large', and, small, 'BEC', were, isolated, from, mouse, liver, treated, with, growth, 'hormone,', a, known, transcriptional, activator, of, 'HNF6,', and, the, effects, on, selected]), verbo([target]), complemento([genes, were, examined])].
[sujeto(['This', was]), verbo([associated]), complemento([with, 2.7, -, and, 4, -, fold, higher, baseline, expression, of, 'HNF1a-', and, 'HNF4a-regulated', ntcp, and, oatp1, 'genes,', respectively])].
[sujeto(['The', net, effects, were, upregulation, of, 'HNF6']), verbo([target]), complemento([gene, glucokinase, and, of, 'Foxa2,', 'HNF1a,', and, 'HNF4a', target, genes, 'oatp1,', 'ntcp,', and, mrp2, over, 'AdLacZ', control, in, both, 'cells,', but, with, higher, levels, in, 'AdH6-SV40SM', over, 'AdH6-SV40LG', of, 'glucokinase,', 'oatp1,', 'ntcp,', and, mrp2, '(', by, 1.8, -, ',', 3.4, -, ',', 2.4, -, ',', and, 2.5, -, 'fold,', 'respectively)'])].
[sujeto(['In', 'vivo,', growth, 'hormone-mediated']), verbo([increase]), complemento([in, 'HNF6', expression, was, associated, with, similar, higher, upregulation, of, glucokinase, and, mrp2, in, cholangiocytes, from, small, vs])].
[sujeto(['Small', and, large, 'BEC']), verbo([have]), complemento([a, distinct, profile, of, hepatocyte, transcription, factor, and, cognate, target, gene, 'expression,', as, well, as, differential, strength, of, response, to, transcriptional, 'regulation,', thus, providing, a, potential, molecular, basis, for, their, divergent, function])].
[sujeto(['We', developed, a, method, for, estimating, the, positional, distribution, of, transcription, factor, '(', 'TF)']), verbo([binding]), complemento([sites, using, 'ChIP-chip', 'data,', and, applied, it, to, recently, published, experiments, on, binding, sites, of, nine, 'TFs:', 'OCT4,', 'SOX2,', 'NANOG,', 'HNF1A,', 'HNF4A,', 'HNF6,', 'FOXA2,', 'USF1', and, 'CREB1'])].
[sujeto(['The', number, of]), verbo([target]), complemento([genes, of, each, 'TF', ranges, from, few, hundred, to, several, thousand])].
[sujeto(['We']), verbo([found]), complemento([that, for, each, of, the, nine, 'TFs', the, estimated, binding, site, distribution, is, closely, approximated, by, a, mixture, of, two, 'components:', a, narrow, 'peak,', localized, within, 300, -, bp, upstream, of, the, 'TSS,', and, a, distribution, of, almost, uniform, density, within, the, tested, region])].
[sujeto(['Using', 'Gene', 'Ontology', '(', 'GO)', and, 'Enrichment', 'analysis,', we, were, able, to]), verbo([associate]), complemento(['(', for, each, of, the, 'TFs', 'studied)', the, target, genes, of, both, types, of, binding, with, known, biological, processes])].
[sujeto(['Most', 'GO', terms, were, enriched, either, among, the, proximal]), verbo([targets]), complemento([or, among, those, with, a, uniform, distribution, of, binding, sites])].
[sujeto(['For', 'example,', the, three, 'stemness-related', 'TFs']), verbo([have]), complemento([several, hundred, target, genes, that, belong, to, '\'', 'development\'', and, '\'', 'morphogenesis\'', whose, binding, sites, belong, to, the, uniform, distribution])].
[sujeto(['\'', 'Credible', 'sets\'', of, the, variants, most, likely, to, drive, each, distinct, signal, mapped, predominantly, to, noncoding, 'sequence,', implying, that, association, with, 'T2D', is]), verbo([mediated]), complemento([through, gene, regulation])].
[sujeto(['Credible', set, variants, were, enriched, for, overlap, with, 'FOXA2', chromatin, immunoprecipitation]), verbo([binding]), complemento([sites, in, human, islet, and, liver, 'cells,', including, at, 'MTNR1B,', where, fine, mapping, implicated, rs10830963, as, driving, 'T2D', association])].
[sujeto(['We', confirmed, that, the, 'T2D', risk, allele, for, this, 'SNP']), verbo([increases]), complemento(['FOXA2-bound', enhancer, activity, in, 'islet-', and, 'liver-derived', cells])].
[sujeto(['We', observed, 'allele-specific', differences, in, 'NEUROD1']), verbo([binding]), complemento([in, 'islet-derived', 'cells,', consistent, with, evidence, that, the, 'T2D', risk, allele, increases, islet, 'MTNR1B', expression])].
[sujeto(['MicroRNAs', are, a, class, of, negative, regulators, of, gene, 'expression,', which]), verbo([have]), complemento([been, shown, to, be, involved, in, the, development, of, endocrine, pancreas, and, in, the, regulation, of, insulin, secretion])].
[sujeto(['Since', type, 2, diabetes, '(', 'T2D)', is, characterized, by, beta, cell, 'dysfunction,', we, aimed, at, evaluating, expression, levels, of, 'miR-124a', and, 'miR-375,', both]), verbo([involved]), complemento([in, the, control, of, beta, cell, 'function,', in, human, pancreatic, islets, obtained, from, 'T2D', and, from, 'age-matched', 'non-diabetic', organ, donors])].
[sujeto(['In', 'addition,', 'miR-124a', silencing, in, 'MIN6', pseudoislets, resulted, in]), verbo([increased]), complemento([expression, of, predicted, target, genes, '(', 'Mtpn,', 'Foxa2,', 'Flot2,', 'Akt3,', 'Sirt1', and, 'NeuroD1)', involved, in, beta, cell, function])].
[sujeto(['For', 'Mtpn', and, 'Foxa2,', we, further, demonstrated, the, actual]), verbo([binding]), complemento([of, 'miR-124a', to, their, 3, 'UTR', sequences, by, luciferase, assay])].
[sujeto(['We', uncovered, a, major, hyperexpression, of, 'miR-124a', in, 'T2D', 'islets,', whose, silencing, resulted, in]), verbo([increased]), complemento([expression, of, target, genes, of, major, importance, for, beta, cell, function, and, whose, overexpression, impaired, 'glucose-stimulated', insulin, 'secretion,', leading, to, the, hypothesis, that, an, altered, 'miR-124a', expression, may, contribute, to, beta, cell, dysfunction, in, type, 2, diabetes])].
[sujeto(['Many', of, the, type, 2, diabetes, loci, identified, through, 'genome-wide', association, studies, localize, to, 'non-protein-coding', intronic, and, intergenic, regions, and, likely, contain, variants, that]), verbo([regulate]), complemento([gene, transcription])].
[sujeto(['To']), verbo([gain]), complemento([insight, into, the, molecular, mechanisms, underlying, the, association, 'signal,', we, used, open, 'chromatin,', histone, modifications, and, transcription, factor, 'ChIP-seq', data, sets, from, type, 2, 'diabetes-relevant', cell, types, to, identify, 'SNPs', overlapping, predicted, regulatory, regions])].
[sujeto(['Using', electromobility, shift, and, supershift, assays, we, demonstrated, that, the, rs11257655, risk, allele, showed, 'allele-specific']), verbo([binding]), complemento([to, 'FOXA1', and, 'FOXA2'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, rs11257655, affects, transcriptional, activity, through, altered, binding, of, a, protein, complex, that, includes, 'FOXA1', and, 'FOXA2,', providing, a, potential, molecular, mechanism, at, this, 'GWAS', locus])].
[sujeto(['MicroRNAs', '(', 'miRNAs)']), verbo([have]), complemento([emerged, as, biomarkers, of, metabolic, 'status,', etiological, factors, in, complex, 'disease,', and, promising, drug, targets])].
[sujeto(['Recent']), verbo([reports]), complemento([suggest, that, miRNAs, are, critical, regulators, of, pathways, underlying, the, pathophysiology, of, type, 2, diabetes])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'miR-29', is, an, important, regulatory, factor, in, normal, metabolism, and, may, represent, a, novel, therapeutic, target, in, type, 2, diabetes, and, related, metabolic, syndromes])].
[sujeto(['In', order, to, explore, how, common, genetic, variants]), verbo([associated]), complemento([with, 'T2D', correlate, with, body, mass, index, '(', 'BMI),', we, examined, the, influence, of, 25, 'T2D', associated, loci, on, obesity, risk])].
[sujeto(['We', used, 5056, individuals, '(', 2528, 'sib-pairs)']), verbo([recruited]), complemento([in, 'Indian', 'Migration', 'Study', and, conducted, within, 'sib-pair', analysis, for, six, obesity, phenotypes])].
[sujeto(['We']), verbo([found]), complemento([associations, of, variants, in, 'CXCR4', '(', 'rs932206)', and, 'HHEX', '(', 'rs5015480)', with, higher, body, mass, index, '(', 'BMI)', '(', 'β=0'])].
[sujeto(['CXCR4', variant, was, also, strongly]), verbo([associated]), complemento([with, body, fat, '(', 'β=0'])].
[sujeto(['In', 'summary,', we, establish, the, role, of, 'T2D']), verbo([associated]), complemento([loci, in, influencing, the, measures, of, obesity, in, 'Indian', 'population,', suggesting, common, underlying, pathophysiology, across, populations])].
[sujeto(['Dietary', 'Se', deficiency]), verbo([decreased]), complemento(['(', 'P', &, 'lt;', 0.05, ')', 'OE', islet, mRNA, levels, of, 2, key, transcriptional, activators, '(', 'Beta2', and, 'Foxa2)', and, removed, genotype, differences, in, islet, mRNA, levels, of, 7, genes, '(', 'Beta2,', 'Cfos,', 'Foxa2,', 'Pregluc,', 'Ins1,', 'p53,', and, 'Sur1)', related, to, insulin, synthesis, and, secretion])].
[sujeto(['Dietary', 'Se', deficiency, also]), verbo([decreased]), complemento(['(', 'P', &, 'lt;', 0.05, ')', blood, glucose, and, hepatic, lipid, concentrations, in, the, 'WT', mice])].
[sujeto(['This', alleviation, resulted, from]), verbo([modulating]), complemento([the, expression, 'and/or', function, of, proinsulin, 'genes,', lipogenesis, 'rate-limiting', enzyme, 'genes,', and, key, glycolysis, and, gluconeogenesis, enzymes, in, 'islets,', 'liver,', and, muscle])].
[sujeto(['Variations', within, the, 'FOXA', family]), verbo([have]), complemento([been, studied, for, a, putative, contribution, to, the, risk, of, type, 2, diabetes, '(', 'T2D),', and, recently, the, minor, 'T-allele', of, 'FOXA2', rs1209523, was, reported, to, associate, with, decreased, fasting, plasma, glucose, levels, in, a, study, using, a, weighted, false, discovery, rate, control, procedure, to, enhance, the, statistical, power, of, genome, wide, association, studies, in, detecting, associations, between, 'low-frequency', variants, and, a, given, trait])].
[sujeto(['Thus,', the, primary, aim, of, this, study, was, to, investigate, whether, the, minor, 'T-allele', of, rs1205923, in, 'FOXA2']), verbo([associated]), complemento([with, 1, ')', decreased, fasting, plasma, glucose, and, 2, ')', a, lower, risk, of, developing, 'T2D'])].
[sujeto(['Secondly,', we, investigated, whether, rs1205923, in, 'FOXA2']), verbo([associated]), complemento([with, other, 'glucose-related', phenotypes])].
[sujeto(['We', examined, for, associations, of, the, 'FOXA2', genotype, with, fasting, plasma, glucose, and, estimates, of, insulin]), verbo([release]), complemento([and, insulin, sensitivity, following, an, oral, glucose, tolerance, test, in, 6, ',', 162, 'Danish', individuals, from, the, 'population-based', 'Inter99', study, while, association, with, 'T2D', risk, was, assessed, in, 10, ',', 196, 'Danish', individuals, including, four, different, study, populations])].
[sujeto(['The', 'FOXA2', rs1209523, was, not]), verbo([associated]), complemento([with, fasting, plasma, glucose, '(', effect, size, '(', 'β)', =, -, 0.03, 'mmol/l', '(', 95, '%', 'CI:', -, 0.07, ;, 0.01, ')', ',', p, =, 0.2, ')', in, 'glucose-tolerant', individuals, from, the, general, 'Danish', population])].
[sujeto(['Also,', several, indices, of, insulin]), verbo([release]), complemento([and, 'β-cell', function, were, associated, with, the, minor, 'T-allele', of, 'FOXA2', rs1209523, in, 'non-obese', individuals])].
[sujeto(['Insulin', secretion, by, the, pancreatic, beta, cell, is, critical, to]), verbo([maintain]), complemento([glucose, homeostasis])].
[sujeto(['During', the, last, few, 'years,', several, beta, 'cell-specific', transcription, factors, that]), verbo([regulate]), complemento([insulin, synthesis, and, secretion, in, response, to, glucose, have, been, discovered])].
[sujeto(['These', factors, are]), verbo([regulated]), complemento([not, only, in, their, expression, by, other, 'genes,', but, also, in, their, activity, by, other, proteins, and, by, 'post-translational', 'modifications,', therefore, participating, in, physiologically, important, signaling, pathways, of, the, beta, cell])].
[sujeto(['We']), verbo([found]), complemento([a, strong, association, of, '(', 'TCC)(', n, ')', common, allele, 'A5', with, type, 2, diabetes, '[', 'OR', =, 1.66, '(', 95, '%', 'CI', 1.36, -, 2.04, ',', p, =, 5.9, x, 10, '(', -, 7, ')', ')', for, 'A5', 'homozygotes]'])].
[sujeto(['Obese', individuals, with, 'A5A5', genotype, had]), verbo([enhanced]), complemento([risk, when, segregated, from, 'normal-weight', subjects, '[', 'OR', =, 1.92, '(', 95, '%', 'CI', 1.47, -, 2.51, ')', ',', p, =, 1.6, x, 10, '(', -, 6, ')', ']'])].
[sujeto(['A5', was, also, nominally]), verbo([associated]), complemento([with, higher, fasting, glucose, '(', p, =, 0.02, ')', and, lower, fasting, insulin, '(', p, =, 0.0028, ')', and, 'C-peptide', '(', p, =, 0.036, ')', levels, among, controls])].
[sujeto(['At', the, rs1055080, 'locus,', 'GG', was]), verbo([found]), complemento([to, provide, reduced, risk, among, 'normal-weight', subjects, '[', 'OR', =, 0.59, '(', 95, '%', 'CI', 0.4, -, 0.88, ')', ',', p, =, 0.011, ']'])].
[sujeto(['For', the, first, time, we, demonstrated, that, 'FOXA2', variants, may, affect, risk, of, type, 2, diabetes, and, metabolic, traits, in, 'North', 'India,', however, replication, analyses, in, other, cohorts, are]), verbo([required]), complemento([to, confirm, the, findings])].
[sujeto(['We', demonstrated, that, 'long-term', treatment, with, 'ISV', improves, glucose, 'homeostasis,']), verbo([increases]), complemento([insulin, 'sensitivity,', lowers, plasma, triglycerides, and, lowers, weight, in, the, diabetic, 'KKAy', mice])].
[sujeto(['We']), verbo([have]), complemento([now, generated, mice, that, lack, the, lambda, isoform, of, 'PKC', in, pancreatic, beta, cells, '(', 'betaPKClambda(-/-)', 'mice)', and, show, that, these, animals, manifest, impaired, glucose, tolerance, and, hypoinsulinemia])].
[sujeto(['Furthermore,', insulin, secretion, in, response, to, high, concentrations, of, glucose, was, 'impaired,', whereas, the, basal, rate, of, insulin]), verbo([release]), complemento([was, 'increased,', in, islets, isolated, from, 'betaPKClambda(-/-)', mice])].
[sujeto(['The', abundance, of, mRNAs, for, 'Glut2', and, 'HNF3beta', was, reduced, in, islets, of, 'betaPKClambda(-/-)', 'mice,', and, the, expression, of, genes]), verbo([regulated]), complemento([by, 'HNF3beta', was, also, affected, '(', that, of, 'Sur1', and, 'Kir6'])].
[sujeto(['These', results, indicate, that, 'PKClambda', plays, a, prominent, role, in, regulation, of, 'glucose-induced', insulin, secretion, by]), verbo([modulating]), complemento([the, expression, of, genes, important, for, beta, cell, function])].
[sujeto(['Liver', is, a, vital, organ, and]), verbo([retains]), complemento([its, regeneration, capability, throughout, 'adulthood,', which, requires, contributions, from, different, cell, 'populations,', including, liver, precursors, and, intrahepatic, stem, cells])].
[sujeto(['Using', retroviral, system, to, stably]), verbo([express]), complemento(['SV40', 'T', antigen, flanked, with, 'Cre/LoxP', 'sites,', we, establish, a, repertoire, of, iHP, clones, with, varied, differentiation, potential])].
[sujeto(['The', iHP, cells]), verbo([maintain]), complemento(['long-term', proliferative, activity, and, express, varied, levels, of, progenitor, markers, '(', 'Pou5f1/Oct4', and, 'Dlk)', and, hepatocyte, markers, '(', 'AFP,', 'Alb', and, 'ApoB)'])].
[sujeto(['Five', representative, iHP, clones]), verbo([express]), complemento(['hepatic/pancreatic', transcription, factors, 'HNF3α/Foxa1,', 'HNF3β/Foxa2,', and, 'HNF4α/MODY1'])].
[sujeto(['Dexamethasone', is, shown, to]), verbo([promote]), complemento([the, expression, of, hepatocyte, markers, 'AFP', and, 'TAT,', along, with, 'ICG-uptake', and, glycogen, storage, functions, in, the, iHP, clones])].
[sujeto(['Molecular', defects, of, the, genes, for, transcription, 'factors,', hepatocyte]), verbo([nuclear]), complemento([factor, '(', 'HNF)-4', 'alpha,', 'HNF-1', 'alpha,', 'HNF-1', beta, and, insulin, promoter, 'factor-1', cause, 'maturity-onset', diabetes, of, the, young, '(', 'MODY1,', 3, ',', 5, ',', and, 4, ',', 'respectively)'])].
[sujeto(['This']), verbo([suggests]), complemento([the, 'HNF-related', transcription, cascade, is, important, in, insulin, secretion, which, is, induced, by, glucose])].
[sujeto(['When', these, 'EBs', are, treated, with, 'tamoxifen,', the, 'Oct4']), verbo([expressing]), complemento([cells, switch, from, a, red, to, a, green, fluorescence, 'color,', and, this, is, maintained, thereafter, by, all, their, progeny])].
[sujeto(['Markers', of, the, early, body, 'axis,', 'Brachyury', '(', 'BRA)', and, 'FOXA2,', usually, showed, a, concentration, of, positive, cells, in, one, region, of, the, 'EB,', but, the, morphology, is, not, predictable, and, there, are, also, scattered, cells]), verbo([expressing]), complemento([these, markers])].
[sujeto(['BRA,', which, marks, the, early, 'mesoderm,', node, and, 'notochord,', arises, in, 'Oct4']), verbo([expressing]), complemento([cells, on, days, 3, -, 4])].
[sujeto(['FOXA2,', which, marks, the, floor, plate, of, the, neural, tube, and, definitive, 'endoderm,', as, well, as, the, node, and, 'notochord,', arises, at, the, same, time, but, mostly, in, cells, that]), verbo([have]), complemento([already, lost, 'Oct4', expression])].
[sujeto(['The']), verbo([nuclear]), complemento([hormone, receptors, hepatocyte, nuclear, factor, 4, '(', 'HNF4)', and, the, retinoid, 'X', alpha, '(', 'RXRalpha)', plus, the, peroxisome, 'proliferator-activated', receptor, alpha, '(', 'PPARalpha)', heterodimer, support, hepatitis, 'B', virus, '(', 'HBV)', replication, in, nonhepatoma, cells])].
[sujeto(['Hepatocyte']), verbo([nuclear]), complemento([factor, 3, '(', 'HNF3)', inhibits, nuclear, hormone, 'receptor-mediated', viral, replication])].
[sujeto(['Inhibition', of, 'HBV', replication, by, 'HNF3beta', is]), verbo([associated]), complemento([with, the, preferential, reduction, in, the, level, of, the, pregenomic, 'RNA', compared, with, that, of, precore, 'RNA'])].
[sujeto(['Hepatitis', 'B', e, antigen, '(', 'HBeAg),', encoded, by, the, precore, 'RNA,']), verbo([mediates]), complemento([part, of, the, inhibition, of, viral, replication, by, 'HNF3beta'])].
[sujeto(['Therefore,', transcriptional, interference]), verbo([mediated]), complemento([by, 'HNF3', may, also, regulate, 'HBV', 'RNA', synthesis, and, viral, replication])].
[sujeto(['The', transcription, factors, of, the, hepatocyte]), verbo([nuclear]), complemento([factor, 3, '(', 'HNF3)', 'family,', which, are, active, in, the, 'liver,', are, expressed, early, during, endoderm, differentiation])].
[sujeto(['Overexpression', of, 'HNF3beta', '(', and, to, a, lesser, extent, of, 'HNF3alpha)']), verbo([induced]), complemento([the, expression, of, genes, associated, with, endodermal, 'lineage,', 'namely,', the, genes, for, 'CFTR', and, 'albumin,', but, did, not, induce, the, expression, of, genes, involved, in, late, endoderm, 'differentiation,', such, as, the, genes, for, 'PEPCK', and, 'alpha1-antitrypsin'])].
[sujeto(['Moreover,', expression, of, 'HNF1beta', was, highly]), verbo([induced]), complemento([in, 'HNF3-overexpressing', 'cells,', while, expression, of, 'HNF1alpha', and, 'HNF4', was, only, mildly, induced, in, these, cells])].
[sujeto(['Therefore,', 'HNF3alpha', and, -, beta, seem, to, be]), verbo([involved]), complemento([in, early, endoderm, differentiation, of, 'ES', cells, and, together, with, other, developmental, factors, are, apparently, needed, for, the, induction, of, the, endodermal, lineage, in, vivo])].
[sujeto(['The', 'tissue-specific', transcription, factors, of, the, hepatocyte]), verbo([nuclear]), complemento(['factor-4', '(', 'HNF4),', hepatocyte, nuclear, 'factor-3', '(', 'HNF3),', and, liver, factor, 'B1', '(', 'LFB1)', families, are, thought, to, play, a, role, in, the, development, of, internal, organs, and, in, the, 'tissue-specific', expression, of, many, distinct, genes])].
[sujeto(['We']), verbo([have]), complemento([now, constructed, derivatives, of, these, proteins, by, introducing, the, 'hormone-binding', domain, of, the, estrogen, receptor, and, show, that, in, transient, transfections, these, chimeric, proteins, act, as, 'estrogen-inducible', transcription, factors, with, the, 'DNA', sequence, specificity, of, the, original, factors])].
[sujeto(['These', chimeric, transcription, factors, are, differently, affected, by, the, partial, estrogen, antagonist, 4, -, hydroxytamoxifen, and, the, pure, antiestrogen, 'N-n-butyl-11-(3,17-dihydroxy-estra-1,3,5(10)-trien-', 7, 'alpha-yl)N-methyl-undecamide', '(', 'ICI', 164384, ')', ;, 4, -, hydroxytamoxifen, 'activates,', at, least, 'partially,', all, the, chimeric, factors, and, the, estrogen, 'receptor,', while, 'ICI', 164384, surprisingly]), verbo([activates]), complemento([the, transcription, factors, derived, from, 'HNF3', and, 'LFB1', and, inhibits, only, the, estrogen, receptor, and, the, 'HNF4', derivative])].
[sujeto(['Recent', work]), verbo([has]), complemento([shown, that, overexpression, of, 'lineage-specific', transcription, factors, can, directly, cause, cells, phenotypic, 'changes,', including, 'differentiation,', 'trans-differentiation,', and, 'de-differentiation'])].
[sujeto(['We', hypothesized, that, 'lentivirus-mediated', constitutive, expression, of, forkhead, box, 'A2', '(', 'Foxa2)', and, hepatocyte]), verbo([nuclear]), complemento([factor, 4, alpha, '(', 'Hnf4a)', could, promote, inducing, mouse, 'ESCs', to, 'hepatocyte-likes', cells])].
[sujeto(['First,', 'ESC', lines, that, stably]), verbo([expressed]), complemento(['Foxa2,', 'Hnf4a,', or, 'Foxa2/Hnf4a', were, constructed, via, lentiviral, expression, vectors])].
[sujeto(['However,', with, some, assistance, from]), verbo([inducing]), complemento(['factors,', 'Foxa2', significantly, increased, the, hepatic, differentiation, of, 'ESCs,', whereas, the, expression, of, 'Hnf4a', alone, or, 'Foxa2/Hnf4a', could, not])].
[sujeto(['Differentiated', 'CCE-Foxa2', cells, were, more, superior, in]), verbo([expressing]), complemento([several, 'liver-specific', markers, and, 'protein,', storing, glycogen, than, differentiated, 'CCE', cells])].
[sujeto(['Here,', we]), verbo([found]), complemento([that, 'FOXA', members, are, directly, and, indirectly, involved, in, 'HBV', replication, in, human, hepatic, cells])].
[sujeto(['In', 'addition,', 'FOXA1', and, 'FOXA2']), verbo([suppressed]), complemento([nuclear, hormone, 'receptors,', such, as, 'HNF4α,', that, are, related, to, 'HBV', replication])].
[sujeto(['However,', it, remains, unclear, how, 'lineage-specifying', transcription, 'factors,', which, are, often]), verbo([expressed]), complemento([in, both, progenitor, and, mature, cell, 'populations,', influence, cell, differentiation])].
[sujeto(['Using', in, vivo, mouse, liver, development, as, a, 'model,', we, identified, thousands, of, enhancers, that, are]), verbo([bound]), complemento([by, the, master, regulators, 'HNF4A', and, 'FOXA2', in, a, 'differentiation-dependent', 'manner,', subject, to, chromatin, 'remodeling,', and, associated, with, differentially, expressed, target, genes])].
[sujeto(['Enhancers', exclusively, occupied, in, the, embryo, were]), verbo([found]), complemento([to, be, responsive, to, developmentally, regulated, 'TEAD2', and, coactivator, 'YAP1'])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, 'Hippo', signaling, may, affect, hepatocyte, differentiation, by, influencing, 'HNF4A', and, 'FOXA2', interactions, with, temporal, enhancers])].
[sujeto(['Here', we, use, conditional, murine, genetics, to, determine, how, the, identity, of, lung, epithelial, cells, changes, upon]), verbo([loss]), complemento([of, their, master, 'cell-fate', regulator])].
[sujeto(['Nkx2-1', deletion, in, normal, and, neoplastic, lungs]), verbo([causes]), complemento([not, only, loss, of, pulmonary, identity, but, also, conversion, to, a, gastric, lineage])].
[sujeto(['Nkx2-1', is, likely, to]), verbo([maintain]), complemento([pulmonary, identity, by, recruiting, transcription, factors, 'Foxa1', and, 'Foxa2', to, 'lung-specific', 'loci,', thus, preventing, them, from, binding, gastrointestinal, targets])].
[sujeto(['Nkx2-1-negative', murine, lung, tumors, mimic, mucinous, human, lung, 'adenocarcinomas,', which]), verbo([express]), complemento([gastric, markers])].
[sujeto(['Loss', of, the, gastrointestinal, transcription, factor, 'Hnf4α']), verbo([leads]), complemento([to, derepression, of, the, embryonal, 'proto-oncogene', 'Hmga2', in, 'Nkx2-1-negative', tumors])].
[sujeto(['These', observations]), verbo([suggest]), complemento([that, loss, of, both, active, and, latent, differentiation, programs, is, required, for, tumors, to, reach, a, 'primitive,', poorly, differentiated, state])].
[sujeto(['One', mechanism, by, which, 'TCF7L2', could, influence, expression, of, genes]), verbo([involved]), complemento([in, diverse, diseases, is, by, binding, to, distinct, regulatory, regions, in, different, tissues])].
[sujeto(['We', identified, 116, ',', 0, 'non-redundant', 'TCF7L2']), verbo([binding]), complemento(['sites,', with, only, 1, ',', 864, sites, common, to, the, six, cell, lines])].
[sujeto(['Using', 'ChIP-seq,', we, showed, that, many, genomic, regions, that, are, marked, by, both, 'H3K4me1', and, 'H3K27Ac', are, also]), verbo([bound]), complemento([by, 'TCF7L2,', suggesting, that, 'TCF7L2', plays, a, critical, role, in, enhancer, activity])].
[sujeto(['Bioinformatic', analysis, of, the, cell, 'type-specific', 'TCF7L2']), verbo([binding]), complemento([sites, revealed, enrichment, for, multiple, transcription, 'factors,', including, 'HNF4alpha', and, 'FOXA2', motifs, in, 'HepG2', cells, and, the, 'GATA3', motif, in, 'MCF7', cells])].
[sujeto(['Interestingly,', in, 'MCF7', cells, the, 'TCF7L2', motif, is, enriched, in, most, 'TCF7L2', sites, but, is, not, enriched, in, the, sites]), verbo([bound]), complemento([by, both, 'GATA3', and, 'TCF7L2'])].
[sujeto(['This', analysis]), verbo([suggested]), complemento([that, 'GATA3', might, tether, 'TCF7L2', to, the, genome, at, these, sites])].
[sujeto(['To', test, this, 'hypothesis,', we, depleted, 'GATA3', in, 'MCF7', cells, and, showed, that, 'TCF7L2']), verbo([binding]), complemento([was, lost, at, a, subset, of, sites])].
[sujeto(['RNA-seq', analysis]), verbo([suggested]), complemento([that, 'TCF7L2', represses, transcription, when, tethered, to, the, genome, via, 'GATA3'])].
[sujeto(['Our', studies, demonstrate, a, novel, relationship, between, 'GATA3', and, 'TCF7L2,', and]), verbo([reveal]), complemento([important, insights, into, 'TCF7L2-mediated', gene, regulation])].
[sujeto(['However,', previous, studies]), verbo([have]), complemento([shown, that, the, hepatic, program, can, also, be, activated, in, 'non-hepatic', lineage, cells, after, exposure, to, particular, stimuli, or, fusion, with, hepatocytes])].
[sujeto(['These', unexpected, findings]), verbo([suggest]), complemento([that, factors, critical, to, hepatocyte, differentiation, exist, and, become, activated, to, induce, 'hepatocyte-specific', properties, in, different, cell, types])].
[sujeto(['The']), verbo([induced]), complemento(['hepatocyte-like', '(', 'iHep)', cells, have, multiple, 'hepatocyte-specific', features, and, reconstitute, damaged, hepatic, tissues, after, transplantation])].
[sujeto(['The', generation, of, iHep, cells, may]), verbo([provide]), complemento([insights, into, the, molecular, nature, of, hepatocyte, differentiation, and, potential, therapies, for, liver, diseases])].
[sujeto(['To', investigate, the, gene, expression, pattern, of, hepatocyte]), verbo([nuclear]), complemento([factor, 6, '(', 'HNF6)', and, other, 'liver-enriched', transcription, factors, in, various, segments, of, the, human, intestine, to, better, understand, the, differentiation, of, the, gut, epithelium])].
[sujeto(['Protein', expression, of, major, 'liver-enriched', transcription, factors, was, determined, by, 'Western', blotting, while, the, 'DNA']), verbo([binding]), complemento([of, 'HNF6', was, investigated, by, electromobility, shift, assays])].
[sujeto(['The', gene, expression, patterning, of, 'liver-enriched', transcription, factors, differed, in, the, various, segments, of, the, human, intestine, with, 'HNF6', gene, expression, being, most, abundant, in, the, duodenum, '(', 'P', &, 'lt;', 0.05, ')', whereas, expression, of, the, zinc, finger, protein, 'GATA4', and, of, the, 'HNF6']), verbo([target]), complemento([gene, 'ALDH3A1', was, most, abundant, in, the, jejunum, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['Likewise,', expression, of, 'FOXA2', and, the, splice, variants, 2, and, 4, of, 'HNF4alpha', were, most, abundantly]), verbo([expressed]), complemento([in, the, jejunum, '(', 'P', &, 'lt;', 0.05, ')'])].
[sujeto(['The', expression, of, 'HNF6', and, of, genes]), verbo([targeted]), complemento([by, this, 'factor,', i])].
[sujeto([neurogenin, 3, '(', 'NGN3)', was, most, abundant, in, the, jejunum, followed, by, the, ileum, and, the, colon, while, 'DNA']), verbo([binding]), complemento([activity, of, 'HNF4alpha', and, of, 'NGN3', was, confirmed, by, electromobility, shift, assays, to, an, optimized, probe])].
[sujeto(['Furthermore,', 'Western', blotting]), verbo([provided]), complemento([evidence, of, the, expression, of, several, 'liver-enriched', transcription, factors, in, cultures, of, colon, epithelial, 'cells,', albeit, at, different, levels])].
[sujeto(['To']), verbo([gain]), complemento([insight, into, the, transcriptional, networks, regulating, the, function, of, these, 'tissues,', we, globally, identify, binding, sites, for, 'FOXA2', in, adult, mouse, islets, and, 'liver,', 'PDX1', in, 'islets,', and, 'HNF4A', in, liver])].
[sujeto(['Because', most, eukaryotic, transcription, factors]), verbo([bind]), complemento([thousands, of, 'loci,', many, of, which, are, thought, to, be, 'inactive,', methods, that, can, discriminate, functionally, active, binding, events, are, essential, for, the, interpretation, of, 'genome-wide', transcription, factor, binding, data])].
[sujeto(['By', analyzing, our]), verbo([binding]), complemento([and, histone, methylation, data, in, combination, with, comprehensive, gene, expression, 'data,', we, show, that, 'H3K4me1', enrichment, profiles, discriminate, transcription, factor, occupied, loci, into, three, 'classes:', those, that, are, functionally, 'active,', those, that, are, poised, for, 'activation,', and, those, that, reflect, 'pioneer-like', transcription, factor, activity])].
[sujeto(['Furthermore,', we, demonstrate, that, the]), verbo([regulated]), complemento([presence, of, 'H3K4me1-marked', nucleosomes, at, transcription, factor, occupied, promoters, and, enhancers, controls, their, 'activity,', implicating, both, 'tissue-specific', transcription, factor, binding, and, nucleosome, remodeling, complex, recruitment, in, determining, 'tissue-specific', gene, expression])].
[sujeto(['Gene', expression, is]), verbo([regulated]), complemento([by, combinations, of, transcription, 'factors,', which, can, be, mapped, to, regulatory, elements, on, a, 'genome-wide', scale, using, 'ChIP', experiments])].
[sujeto(['In', a, previous, 'ChIP-chip', study, of, 'USF1', and, 'USF2', we]), verbo([found]), complemento([evidence, also, of, binding, of, 'GABP,', 'FOXA2', and, 'HNF4a', within, the, enriched, regions])].
[sujeto(['Here,', we]), verbo([have]), complemento([applied, 'ChIP-seq', for, these, transcription, factors, and, identified, 3064, peaks, of, enrichment, for, 'GABP,', 7266, for, 'FOXA2', and, 18783, for, 'HNF4a'])].
[sujeto(['Distal', elements, with, 'USF2', signal, was, frequently]), verbo([bound]), complemento([also, by, 'HNF4a', and, 'FOXA2'])].
[sujeto(['GABP', peaks, were]), verbo([found]), complemento([at, transcription, start, 'sites,', whereas, 94, '%', of, 'FOXA2', and, 90, '%', of, 'HNF4a', peaks, were, located, at, other, positions])].
[sujeto(['We', developed, a, method, to, accurately, define, 'TFBS', within, 'peaks,', and]), verbo([found]), complemento([the, predicted, sites, to, have, an, elevated, conservation, level, compared, to, peak, 'centers;', however, the, majority, of, bindings, were, not, evolutionary, conserved])].
[sujeto(['An', interaction, between, 'HNF4a', and, 'GABP', was, seen, at, 'TSS,', with, 'one-third', of, the, 'HNF4a', positive, promoters, being]), verbo([bound]), complemento([also, by, 'GABP,', and, this, interaction, was, verified, by, 'co-immunoprecipitations'])].
[sujeto(['ChIP-seq', data, are, enriched, in]), verbo([binding]), complemento([sites, for, the, protein, immunoprecipitated])].
[sujeto(['Some', sequences, may, also, contain]), verbo([binding]), complemento([sites, for, a, coregulator])].
[sujeto(['Biologists', are, interested, in, knowing, which, coregulatory, factor, motifs, may, be, present, in, the, sequences]), verbo([bound]), complemento([by, the, protein, 'ChIP\'ed'])].
[sujeto(['When', applied, to, a, mouse, liver, 'Foxa2', 'ChIP-seq', dataset]), verbo([involving]), complemento([~, 12, 0, 400, -, bp, 'sequences,', coMOTIF, identified, 'co-occurrence', of, 'Foxa2', with, 'Hnf4a,', 'Cebpa,', 'E-box,', 'Ap1/Maf', or, 'Sp1', motifs, in, '~6-33%', of, these, sequences])].
[sujeto(['These', motifs, are, either, known, as, 'liver-specific', transcription, factors, or]), verbo([have]), complemento([an, important, role, in, liver, function])].
[sujeto(['It', was, established, that, genes, 'Gata6,', 'Foxa2', and, 'Hnf4a', were, specifically]), verbo([expressed]), complemento([in, vole, extraembryonic, endoderm, 'cells,', while, 'Cdx2', and, 'Handl', 'genes,', in, trophoblast, stem, cells])].
[sujeto(['During', 'organogenesis,', the, winged, helix, hepatocyte]), verbo([nuclear]), complemento([factor, 3, beta, '(', 'HNF-3beta)', protein, participates, in, regulating, gene, transcription, in, the, developing, 'esophagus,', 'trachea,', 'liver,', 'lung,', 'pancreas,', and, intestine])].
[sujeto(['Squamous', tumours, are, enriched, for, 'TP53', and, 'KDM6A', 'mutations,', upregulation, of, the, 'TP63∆N', transcriptional, 'network,', hypermethylation, of, pancreatic, endodermal, 'cell-fate', determining, genes, and]), verbo([have]), complemento([a, poor, prognosis])].
[sujeto(['Pancreatic', progenitor, tumours, preferentially]), verbo([express]), complemento([genes, involved, in, early, pancreatic, development, '(', 'FOXA2/3,', 'PDX1', and, 'MNX1)'])].
[sujeto(['ADEX', tumours, displayed, upregulation, of, genes, that]), verbo([regulate]), complemento([networks, involved, in, 'KRAS', 'activation,', exocrine, '(', 'NR5A2', and, 'RBPJL),', and, endocrine, differentiation, '(', 'NEUROD1', and, 'NKX2-2)'])].
[sujeto(['Immunogenic', tumours, contained, upregulated, immune, networks, including, pathways]), verbo([involved]), complemento([in, acquired, immune, suppression])].
[sujeto(['The', orphan]), verbo([nuclear]), complemento([receptor, 'NR5A2', is, necessary, for, the, 'stem-like', properties, of, the, epiblast, of, the, 'pre-gastrulation', embryo, and, for, cellular, and, physiological, homeostasis, of, 'endoderm-derived', organs, postnatally])].
[sujeto(['At', 'birth,', the, 'NR5A2-deficient', pancreas]), verbo([has]), complemento([defects, in, all, three, epithelial, 'tissues:', a, partial, loss, of, endocrine, 'cells,', a, disrupted, ductal, tree, and, a, &, 'gt;90%', deficit, of, acini])].
[sujeto(['In', 'particular,', 'Nr5a2', and, 'Ptf1a', establish, mutually, reinforcing, regulatory, interactions, and, collaborate, to, control, developmentally]), verbo([regulated]), complemento([pancreatic, genes, by, binding, to, shared, transcriptional, regulatory, regions])].
[sujeto(['Nr5a2', controls, several, temporally, distinct, stages, of, pancreatic, development, that]), verbo([involve]), complemento([regulatory, mechanisms, relevant, to, pancreatic, oncogenesis, and, the, maintenance, of, the, exocrine, phenotype])].
[sujeto(['Curcumin', '(', 'diferuloylmethane),', a, golden, pigment, from, 'turmeric,']), verbo([has]), complemento([been, linked, with, 'antioxidant,', 'anti-inflammatory,', 'anticancer,', 'antiviral,', 'antibacterial,', and, antidiabetic, properties])].
[sujeto(['Most', of, the, these, activities]), verbo([have]), complemento([been, assigned, to, 'methoxy,', 'hydroxyl,', 'α,β-unsaturated', carbonyl, moiety, or, to, diketone, groups, present, in, curcumin])].
[sujeto(['Various', studies]), verbo([suggest]), complemento([that, curcumin, is, a, more, potent, antioxidant, than, 'THC;', curcumin, '(', but, not, 'THC)', can, bind, and, inhibit, numerous, targets, including, 'DNA', '(', 'cytosine-5)-methyltransferase-1,', heme, 'oxygenase-1,', 'Nrf2,', 'β-catenin,', 'cyclooxygenase-2,', 'NF-kappaB,', inducible, nitric, oxide, 'synthase,', nitric, 'oxide,', amyloid, 'plaques,', reactive, oxygen, 'species,', vascular, endothelial, growth, 'factor,', cyclin, 'D1,', 'glutathione,', 'P300/CBP,', 5, -, 'lipoxygenase,', cytosolic, phospholipase, 'A2,', prostaglandin, 'E2,', inhibitor, of, 'NF-kappaB', 'kinase-1,', -, 2, ',', 'P38MAPK,', 'p-Tau,', tumor, necrosis, 'factor-α,', forkhead, box, 'O3a,', 'CRAC;', curcumin, can, inhibit, tumor, cell, growth, and, suppress, cellular, entry, of, viruses, such, as, influenza, 'A', virus, and, hepatitis, 'C', virus, much, more, effectively, than, 'THC;', curcumin, affects, membrane, 'mobility;', and, curcumin, is, also, more, effective, than, 'THC', in, suppressing, 'phorbol-ester-induced', tumor, promotion])].
[sujeto(['Other', 'studies,', 'however,']), verbo([suggest]), complemento([that, 'THC', is, superior, to, curcumin, for, induction, of, 'GSH', 'peroxidase,', 'glutathione-S-transferase,', 'NADPH:', quinone, 'reductase,', and, quenching, of, free, radicals])].
[sujeto(['Most', studies]), verbo([have]), complemento([indicated, that, 'THC', exhibits, higher, antioxidant, 'activity,', but, curcumin, exhibits, both, 'pro-oxidant', and, antioxidant, properties])].
[sujeto(['The', aim, of, the, study, was, to, determine, whether, metformin]), verbo([regulates]), complemento([hepatic, gluconeogenesis, through, the, orphan, nuclear, receptor, small, heterodimer, partner, '(', 'SHP;', 'NR0B2)'])].
[sujeto(['Hepatic', 'SHP', gene, expression, was]), verbo([induced]), complemento([by, 'metformin,', 5, -, 'aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside', '(', 'AICAR),', and, 'Ad-AMPK'])].
[sujeto(['Metformin']), verbo([inhibited]), complemento([hepatocyte, nuclear, 'factor-4alpha-or', 'FoxA2-mediated', promoter, activity, of, 'PEPCK', and, 'G6Pase,', and, the, inhibition, was, blocked, with, siRNA, 'SHP'])].
[sujeto(['Additionally,', 'SHP', knockdown, by, adenovirus, containing, siRNA, 'SHP']), verbo([inhibited]), complemento(['metformin-mediated', repression, of, 'cAMP/dexamethasone-induced', hepatic, gluconeogenic, gene, expression])].
[sujeto(['Furthermore,', oral, administration, of, metformin]), verbo([increased]), complemento(['SHP', mRNA, levels, in, 'B6-Lep(ob/ob)', mice])].
[sujeto(['Overexpression', of, 'SHP', by, 'Ad-SHP']), verbo([decreased]), complemento([blood, glucose, levels, and, hepatic, gluconeogenic, gene, expression, in, 'B6-Lep(ob/ob)', mice])].
[sujeto(['We']), verbo([have]), complemento([concluded, that, metformin, inhibits, hepatic, gluconeogenesis, through, 'AMPK-dependent', regulation, of, 'SHP'])].
[sujeto(['Transdifferentiattion', potential, of, mesenchymal, stem, cells, '(', 'MSCs)', into, 'insulin-producing', cells, '(', 'IPCs)']), verbo([has]), complemento([been, suggested, recently])].
[sujeto(['In', order, to, 'differentiate,', 'MSCs', were]), verbo([induced]), complemento([by, selection, of, 'nestin-expressing', cells, and, treatment, with, 100, 'μg/mL', 'MPE'])].
[sujeto(['In', 'contrast,', a, crosstalk, between, 'FOXA2', and, 'TCF7L2', transcription, 'factors,', 'DNA-PK', 'complex,', 'KAT2B', protein, positively]), verbo([interacting]), complemento([with, 'PDX-1,', 'CREB1,', 'EP300', resulted, in, the, induction, of, 'IPC', and, following, insulin, production])].
[sujeto(['In', 'conclusion,', we]), verbo([report]), complemento([an, 'efficient,', 'simple,', and, easy, method, for, production, of, functional, 'IPCs', from, 'MSCs', by, 'MPE', treatment])].
[sujeto(['Lung', cancer, is, the]), verbo([leading]), complemento([cause, of, 'cancer-mediated', death])].
[sujeto(['Although', various, therapeutic, approaches, are, used, for, lung, cancer, 'treatment,', these, mainly]), verbo([target]), complemento([the, tumor, suppressor, p53, transcription, 'factor,', which, is, involved, in, apoptosis, and, cell, cycle, arrest])].
[sujeto(['However,', 'p53-targeted', therapies]), verbo([have]), complemento([limited, application, in, lung, 'cancer,', since, p53, is, found, to, be, mutated, in, more, than, half, of, lung, cancers])].
[sujeto(['In', this, 'study,', we, propose, tumor, suppressor, 'FOXA2', as, an, alternative]), verbo([target]), complemento([protein, for, therapies, against, lung, cancer, and, reveal, a, possible, 'FOXA2-centered', transcriptional, regulation, network, by, identifying, new, target, genes, and, binding, partners, of, 'FOXA2', by, using, various, screening, techniques])].
[sujeto(['The', genes, encoding, 'Glu/Asp-rich', 'carboxy-terminal', domain, 2, '(', 'CITED2),']), verbo([nuclear]), complemento([receptor, subfamily, 0, ',', group, 'B,', member, 2, '(', 'NR0B2),', cell, adhesion, molecule, 1, '(', 'CADM1)', and, 'BCL2-associated', 'X', protein, '(', 'BAX)', were, identified, as, putative, target, genes, of, 'FOXA2'])].
[sujeto(['Additionally,', the, proteins, including, highly, similar, to, heat, shock, protein, 'HSP', 90, -, beta, '(', 'HSP90A),', heat, shock, 70, &, 'nbsp;kDa', protein, 1, 'A', variant, '(', 'HSPA1A),', histone, deacetylase, 1, '(', 'HDAC1)', and, 'HDAC3', were, identified, as, novel]), verbo([interacting]), complemento([partners, of, 'FOXA2'])].
[sujeto(['Moreover,', we, showed, that, 'FOXA2-dependent', promoter, activation, of, 'BAX', and, p21, genes, is, significantly, reduced, via, physical, interactions, between, the, identified]), verbo([binding]), complemento([partners, and, 'FOXA2'])].
[sujeto(['These', results]), verbo([provide]), complemento([opportunities, to, understand, the, 'FOXA2-centered', transcriptional, regulation, network, and, novel, therapeutic, targets, to, modulate, this, network, in, 'p53-deficient', lung, cancer])].
[sujeto(['Enterocytes', of, the, jejunum]), verbo([express]), complemento([several, genes, related, to, 'digestion/absorption', of, nutrients, and, ions, when, these, cells, rapidly, differentiate, from, crypt, to, villus, cells])].
[sujeto(['Several', transcriptional, factors, such, as, 'Pdx1,', 'Foxa2', and, 'Thra', were]), verbo([expressed]), complemento([in, the, 'crypt,', whereas, 'Klf15', was, highly, expressed, during, the, 'crypt-villus', transition])].
[sujeto(['Subsets', of, genes, related, to, the, digestion, and, absorption, of, 'starch/sucrose', and, dietary, fat, as, well, as, their, transcriptional, 'factors/co-factors', are]), verbo([expressed]), complemento([in, the, specific, locations, along, the, 'crypt-villus', axis])].
[sujeto(['The', jejunum, may, absorb, nutrients, effectively, by, simultaneously]), verbo([expressing]), complemento([subsets, of, genes, along, the, 'villus-crypt', axis])].
[sujeto(['The', mechanisms, controlling, thyrocyte, development, during, embryonic, stem, '(', 'ES)', cell, differentiation]), verbo([have]), complemento([only, been, partially, 'elucidated,', although, previous, studies, have, suggested, the, participation, of, thyroid, stimulating, hormone, '(', 'TSH)', in, these, processes])].
[sujeto(['To', further, define, the, role, of, 'TSH', in, this, 'context,', we]), verbo([have]), complemento([studied, a, murine, 'ES', cell, line, in, which, green, fluorescent, protein, '(', 'GFP)', cDNA, is, targeted, to, the, 'TSH', receptor, '(', 'TSHR)', 'gene,', linking, the, expression, of, 'GFP', to, the, transcription, of, the, endogenous, 'TSHR', gene])].
[sujeto(['We', demonstrate, 'that,', in, the, initial, stages, of, embryoid, body, 'formation,', activin, 'A', and, 'TSH']), verbo([induce]), complemento([the, differentiation, of, definitive, endoderm, and, thyrocyte, progenitors, expressing, 'Sox17,', 'Foxa2,', and, 'TSHR'])].
[sujeto(['Our', data]), verbo([suggest]), complemento(['that,', despite, the, fact, that, 'TSH', is, important, for, the, induction, and, specification, of, thyrocytes, from, 'ES', 'cells,', insulin, and, 'IGF-1', are, crucial, for, thyrocyte, maturation])].
[sujeto(['Our', method]), verbo([provides]), complemento([a, powerful, in, vitro, differentiation, model, for, studying, the, mechanisms, of, early, thyrocyte, lineage, development])].
[sujeto(['Previous', studies, from, our, group]), verbo([have]), complemento([shown, that, 'Foxa1', is, expressed, in, the, prostate, and, interacts, with, the, androgen, receptor, '(', 'AR)', to, regulate, 'prostate-specific', genes, such, as, 'prostate-specific', antigen, '(', 'PSA)', and, probasin, '(', 'PB)'])].
[sujeto(['We']), verbo([report]), complemento([here, that, 'Foxa2', but, not, 'Foxa1', is, expressed, in, the, epididymis])].
[sujeto(['Further,', 'Foxa2']), verbo([interacts]), complemento([with, the, 'AR', to, regulate, the, mouse, epididymal, retinoic, acid, binding, protein, '(', 'mE-RABP)', 'gene,', an, 'epididymis-specific', gene])].
[sujeto(['Overexpression', of, 'Foxa2']), verbo([suppresses]), complemento([androgen, activation, of, the, 'mE-RABP', promoter, while, overexpression, of, 'Foxa2', with, 'prostate-specific', promoters, activates, gene, expression, in, an, 'androgen-independent', manner])].
[sujeto(['GST', 'pull-down', assays, determined, that, both, 'Foxa1', and, 'Foxa2', physically]), verbo([interact]), complemento([with, the, 'DNA', binding, domain, of, the, 'AR'])].
[sujeto(['The', interaction, between, 'Foxa', proteins, and, 'AR', was, further, confirmed, by, 'gel-shift', assays, where, 'Foxa', protein, was]), verbo([recruited]), complemento([to, 'AR', binding, oligomers, even, when, 'Foxa', binding, sites, were, not, 'present,', and, 'AR', was, recruited, to, 'Foxa', binding, oligomers, even, in, the, absence, of, an, 'AR', binding, site])].
[sujeto(['Given', that, 'Foxa1', and, 'Foxa2', proteins, are]), verbo([expressed]), complemento([differentially, in, the, prostate, and, 'epididymis,', these, data, suggest, that, the, 'Foxa', proteins, have, distinct, effects, on, 'AR-regulated', genes, in, different, male, reproductive, accessory, organs])].
[sujeto(['Secondary', neurulation, and, axis, formation]), verbo([involve]), complemento([differentiation, of, the, tail, bud, mesenchyme])].
[sujeto(['We']), verbo([report]), complemento([a, detailed, analysis, of, gene, expression, in, the, caudal, region, of, day, 10, mouse, embryos, during, primary, neuropore, closure])].
[sujeto(['Genes', selected, for, study, include, those]), verbo([involved]), complemento([in, the, key, events, of, gastrulation, and, neurulation, at, earlier, stages, and, more, cranial, levels])].
[sujeto(['Specifically,', we]), verbo([report]), complemento([continuity, of, expression, of, the, genes, 'Wnt5a,', 'Wnt5b,', 'Evx1,', 'Fgf8,', 'RARgamma,', 'Brachyury,', and, 'Hoxb1', from, primitive, streak, and, node, into, subpopulations, of, the, tail, bud, and, caudal, axial, structures])].
[sujeto(['The', patterns, of, expression, of, 'Wnt5a,', 'Hoxb1,', 'Brachyury,', 'RARgamma,', and, 'Evx1,', together, with, observations, on, 'proliferation,']), verbo([reveal]), complemento([that, the, caudal, mesoderm, is, organised, at, a, molecular, level, into, distinct, domains, delineated, by, longitudinal, and, transverse, borders, before, histological, differentiation])].
[sujeto(['Expression', of, 'Wnt5a', in, the, ventral, ectodermal, ridge, supports, previous, evidence, that, this, structure, is]), verbo([involved]), complemento([in, 'epithelial-mesenchymal', interaction])].
[sujeto(['These', results]), verbo([provide]), complemento([a, foundation, for, understanding, the, mechanisms, facilitating, transition, from, primary, to, secondary, body, axis, 'formation,', as, well, as, the, factors, involved, in, defective, spinal, neurulation])].
[sujeto(['Treatment', of, pseudoglandular, stage, fetal, lungs, in, vitro, with, the, 'pan-retinoic', acid, receptor, '(', 'pan-RAR)', 'antagonist,', 'BMS493,', reduces, retinoic, acid, receptor, beta, '(', 'Rarb)', gene, expression, within, the, proximal, bronchial, tubules, and]), verbo([increases]), complemento([explant, bud, formation])].
[sujeto(['Treatment', with, retinoic, acid, '(', 'RA)']), verbo([increases]), complemento(['Rarb', expression, and, reduces, explant, bud, formation, through, a, signaling, mechanism, involving, 'RARbeta'])].
[sujeto(['Together', these, data]), verbo([suggest]), complemento([that, 'RA', through, 'RARbeta', provides, morphogenetic, stabilizing, activity, to, the, proximal, tubules, during, lung, branching, morphogenesis])].
[sujeto(['We', demonstrate, that, 'Rarb', isoform, transcripts, are, the, only, known, 'Rar', transcripts, to, specifically, localize, to, the, proximal, tubules, and, that, 'RAREhsp68lacZ', reporter, transgene, activity]), verbo([reveals]), complemento([endogenous, 'RA', signaling, activity, within, these, same, proximal, tubules])].
[sujeto(['We', therefore, discuss, an, 'interbud/proximal', tubule, signaling, niche]), verbo([involving]), complemento([feedback, between, 'Rarb', expression, and, 'Raldh1-mediated', synthesis, of, 'RA'])].
[sujeto(['We']), verbo([suggest]), complemento([that, this, feedback, favors, interbud, morphogenetic, stability, by, increasing, expression, of, morphoregulatory, molecules, such, as, 'TGFbeta3', and, 'Foxa2,', thus, promoting, bronchial, tubule, formation, rather, than, continual, budding, and, branching])].
[sujeto(['Transcriptional', changes]), verbo([suggest]), complemento([that, derepression, of, the, nuclear, receptors, 'PPARα,', 'PPARγ,', and, 'LXRα', in, aged, mouse, liver, leads, to, activation, of, targets, regulating, lipid, synthesis, and, 'storage,', whereas, 'age-dependent', changes, in, nucleosome, occupancy, are, associated, with, binding, sites, for, both, known, regulators, '(', forkhead, factors, and, nuclear, 'receptors)', and, candidates, associated, with, nuclear, lamina, '(', 'Hdac3', and, 'Srf)', implicated, to, govern, metabolic, function, of, aging, liver])].
[sujeto(['Winged-helix', transcription, factor, 'Foxa2', and]), verbo([nuclear]), complemento([receptor, corepressor, 'Hdac3', exhibit, a, reciprocal, binding, pattern, at, 'PPARα', targets, contributing, to, gene, expression, changes, that, lead, to, steatosis, in, aged, liver])].
[sujeto(['The', winged, helix, protein, 'FOXA2', and, the]), verbo([nuclear]), complemento([receptor, peroxisome, 'proliferator-activated', 'receptor-γ', '(', 'PPARγ)', are, highly, 'conserved,', regionally, expressed, transcription, factors, '(', 'TFs)', that, regulate, networks, of, genes, controlling, complex, metabolic, functions])].
[sujeto(['Cistrome', analysis, for, 'Foxa2', in, mouse, liver, and, 'PPARγ', in, mouse, adipocytes]), verbo([has]), complemento([previously, produced, 'consensus-binding', sites, that, are, nearly, identical, to, those, used, by, the, corresponding, 'TFs', in, human, cells])].
[sujeto(['We']), verbo([report]), complemento([here, 'that,', despite, the, conservation, of, the, canonical, binding, 'motif,', the, great, majority, of, binding, regions, for, 'FOXA2', in, human, liver, and, for, 'PPARγ', in, human, adipocytes, are, not, in, the, orthologous, locations, corresponding, to, the, mouse, 'genome,', and, vice, versa])].
[sujeto(['Of', 'note,', 'TF']), verbo([binding]), complemento([can, be, absent, in, one, species, despite, sequence, 'conservation,', including, motifs, that, do, support, binding, in, the, other, 'species,', demonstrating, a, major, limitation, of, in, silico, binding, site, prediction])].
[sujeto(['Whereas', only, approximately, 10, '%', of]), verbo([binding]), complemento([sites, are, 'conserved,', 'gene-centric', analysis, reveals, that, about, 50, '%', of, genes, with, nearby, 'TF', occupancy, are, shared, across, species, for, both, hepatic, 'FOXA2', and, adipocyte, 'PPARγ'])].
[sujeto(['Thus,', 'species-specific', strategies, underlie, the, biological, functions, of, metabolic, 'TFs', that, are, highly]), verbo([conserved]), complemento([across, mammalian, species])].
[sujeto(['Analysis', of, factor]), verbo([binding]), complemento([in, multiple, species, may, be, necessary, to, distinguish, apparent, 'species-unique', noise, and, reveal, functionally, relevant, information])].
[sujeto(['Regular', use, of, 'beta(2)-adrenoceptor', agonists, may]), verbo([enhance]), complemento(['non-specific', airway, responsiveness, and, inflammation])].
[sujeto(['In', earlier, experimental, 'studies,', we, showed, that, prolonged, in, vitro, fenoterol, exposure]), verbo([induced]), complemento([airway, sensitization, via, perturbed, epithelial, regulation, of, bronchoconstriction])].
[sujeto(['Fenoterol', exposure, significantly]), verbo([enhanced]), complemento(['CD8(+)-T', and, differentiated, 'CD138(+)-B-cells', infiltration, into, the, 'bronchi,', especially, the, subepithelial, area])].
[sujeto(['Increase', in, 'CD8', or, 'CD138', 'labeling-intensity', strongly, correlated, with, rise, in, maximal, contraction, to, 'endothelin-1']), verbo([induced]), complemento([by, fenoterol, exposure])].
[sujeto(['In', 'summary,', our, results, show, that, fenoterol]), verbo([modulates]), complemento([the, 'T', and, 'B', cells, chemotaxis, possibly, via, the, epithelial, chemokine, secretion, in, isolated, bronchi, from, 'ex-smokers'])].
[sujeto(['They', also]), verbo([suggest]), complemento([that, the, infiltration, of, resident, 'T', and, 'B', cells, into, the, subepithelial, area, is, associated, with, an, increase, in, airway, responsiveness, due, to, fenoterol, exposure])].
[sujeto(['While', both, drugs]), verbo([have]), complemento([been, shown, to, improve, 'insulin-sensitive', glucose, 'uptake,', the, direct, effects, of, these, drugs, on, pancreatic, beta, cells, is, only, now, beginning, to, be, clarified])].
[sujeto(['Western', blot, and, gel, retardation, analyses, were, used, to, examine, the, effects, of, both, drugs, on, the, regulation, of, 'IPF1', protein, 'production,']), verbo([nuclear]), complemento([accumulation, and, 'DNA', binding, activity, in, both, 'Min6', cells, and, isolated, rat, islets, of, 'Langerhans'])].
[sujeto(['Over', 24, 'h,', rosiglitazone]), verbo([promoted]), complemento([the, nuclear, accumulation, of, 'IPF1', and, forkhead, homeobox, 'A2', '(', 'FOXA2),', independently, of, glucose, 'concentration,', and, stimulated, a, 'two-fold', increase, in, the, activity, of, the, 'Ipf1', gene, promoter, '(', 'p&lt;0'])].
[sujeto(['Stimulation', of, the, 'Ipf1', promoter, by, rosiglitazone, was, unaffected, by, the, presence, of, the, peroxisome, proliferator]), verbo([activated]), complemento([receptor, gamma, antagonist, 'GW9662'])].
[sujeto(['Metformin']), verbo([stimulated]), complemento(['IPF1', nuclear, accumulation, and, 'DNA', binding, activity, in, a, 'time-dependent', 'manner,', with, maximal, effects, observed, after, 2, h])].
[sujeto(['Metformin', and, rosiglitazone]), verbo([have]), complemento([direct, effects, on, beta, cell, gene, 'expression,', suggesting, that, these, agents, may, play, a, previously, unrecognised, role, in, the, direct, regulation, of, pancreatic, beta, cell, function])].
[sujeto(['Upon', drug, 'activation,', the]), verbo([nuclear]), complemento([pregnane, 'X', receptor, '(', 'PXR)', regulates, not, only, hepatic, drug, but, also, energy, metabolism])].
[sujeto(['Using', 'Pxr(-/-)', 'mice,', we]), verbo([have]), complemento([now, investigated, the, 'PXR-mediated', repression, of, lipid, metabolism, in, the, fasting, livers])].
[sujeto(['Reflecting', these, 'up-', and, 'down-regulations', and, consistent, with]), verbo([decreased]), complemento([energy, 'metabolism,', the, levels, of, hepatic, triglycerides, and, of, serum, 3, -, hydroxybutylate, were, increased, and, 'decreased,', 'respectively,', in, the, 'PCN-treated', 'Pxr(+/+)', mice])].
[sujeto(['Using', gel, 'shift,', glutathione, 'S-transferase', 'pull-down', and, 'cell-based', reporter, 'assays,', we, then, examined, whether, 'PXR', could, 'cross-talk', with, the, insulin, response, forkhead, factor, 'FoxA2', to]), verbo([repress]), complemento([the, transcription, of, the, 'Cpt1a', and, 'Hmgcs2', 'genes,', because, 'FoxA2', activates, these, genes, in, fasting, liver])].
[sujeto(['PXR', directly]), verbo([bound]), complemento([to, 'FoxA2', and, repressed, its, activation, of, the, 'Cpt1a', and, 'Hmgcs2', promoters])].
[sujeto(['Moreover,', 'ChIP', assays, showed, that, 'PCN', treatment, attenuated, the]), verbo([binding]), complemento([of, 'FoxA2', to, these, promoters, in, fasting, 'Pxr(+/+)', but, not, 'Pxr(-/-)', mice])].
[sujeto(['These', results, are, consistent, with, the, conclusion, that, 'PCN-activated', 'PXR']), verbo([represses]), complemento(['FoxA2-mediated', transcription, of, 'Ctp1a', and, 'Hmgcs2', genes, in, fasting, liver])].
[sujeto(['Streptozotocin', '(', 'STZ),', a, 'glucosamine-nitrosourea', 'compound,']), verbo([has]), complemento([potent, genotoxic, effects, on, pancreatic, 'β-cells', and, is, frequently, used, to, induce, diabetes, in, experimental, animals])].
[sujeto(['Glucagon-like', 'peptide-1', '(', 'GLP-1)']), verbo([has]), complemento(['β-cell', protective, effects, and, is, known, to, preserve, 'β-cells', from, 'STZ', treatment])].
[sujeto(['At', 1, week, after, multiple, 'low-dose', 'STZ', 'administrations,', pancreatic, 'β-cells', showed, impaired, insulin, 'expression,', while]), verbo([maintaining]), complemento([expression, of, nuclear, 'Nkx6'])].
[sujeto(['STZ', treatment, also]), verbo([suppressed]), complemento([expression, of, a, wide, range, of, genes, linked, with, key, 'β-cell', functions, or, diabetes, 'development,', such, as, 'G6pc2,', 'Slc2a2', '(', 'Glut2),', 'Slc30a8,', 'Neurod1,', 'Ucn3,', 'Gad1,', 'Isl1,', 'Foxa2,', 'Vdr,', 'Pdx1,', 'Fkbp1b', and, 'Abcc8,', suggesting, global, 'β-cell', defects, in, 'STZ-treated', islets])].
[sujeto(['The', 'Tmem229B,', 'Prss53', and, 'Ttc28', genes, were, highly]), verbo([expressed]), complemento([in, untreated, islets, and, strongly, suppressed, by, 'STZ,', suggesting, their, potential, roles, in, 'β-cell', function])].
[sujeto(['Given', the, 'pro-β-cell-survival', effects, of, 'Cxcl12', '(', 'Sdf-1)', in]), verbo([inducing]), complemento(['GLP-1', production, in, 'α-cells,', pancreatic, 'GLP-1-mediated', 'Cxcl13', induction, might, also, play, a, crucial, role, in, maintaining, the, integrity, of, 'β-cells', in, damaged, islets])].
[sujeto(['Although', the, negative, regulation, of, gene, expression, by, insulin]), verbo([has]), complemento([been, widely, 'studied,', the, transcription, factors, responsible, for, the, insulin, effect, are, still, unknown])].
[sujeto(['The', purpose, of, this, work, was, to, explore, the, molecular, mechanisms]), verbo([involved]), complemento([in, the, insulin, repression, of, the, 5, -, aminolevulinate, synthase, '(', 'ALAS)', gene])].
[sujeto(['By', transient, transfection, 'assays,', we, determined, that, hepatic]), verbo([nuclear]), complemento([factor, 3, '(', 'HNF3)', and, nuclear, factor, 1, '(', 'NF1)', are, necessary, for, an, appropriate, expression, of, the, 'ALAS', gene])].
[sujeto(['Electrophoretic', mobility, shift, assay, and, 'Southwestern', blotting, indicate, that, 'HNF3']), verbo([binds]), complemento([to, the, 'ALAS', promoter])].
[sujeto(['Mutational', analysis, of, this, region, revealed, that, 'IRE', disruption, abrogates, insulin, 'action,', whereas, mutation, of, the, 'HNF3', element]), verbo([maintains]), complemento([hormone, responsiveness])].
[sujeto(['This', dissociation, between, 'HNF3']), verbo([binding]), complemento([and, insulin, action, suggests, that, 'HNF3beta', is, not, the, sole, physiologic, mediator, of, 'insulin-induced', transcriptional, repression])].
[sujeto(['Furthermore,', 'Southwestern', blotting, assay, shows, that, at, least, two, polypeptides, other, than, 'HNF3beta', can]), verbo([bind]), complemento([to, 'ALAS', promoter, and, that, this, binding, is, dependent, on, the, integrity, of, the, 'IRE'])].
[sujeto(['We', propose, a, model, in, which, insulin, exerts, its, negative, effect, through, the, disturbance, of, 'HNF3beta']), verbo([binding]), complemento([or, transactivation, 'potential,', probably, due, to, specific, phosphorylation, of, this, transcription, factor, by, 'Akt'])].
[sujeto(['The', posttranslational, modification, of, 'HNF3', would, allow, the]), verbo([binding]), complemento([of, a, protein, complex, that, recognizes, the, core, 'IRE'])].
[sujeto(['These', results]), verbo([provide]), complemento([a, potential, mechanism, for, the, 'insulin-mediated', repression, of, 'IRE-containing', promoters])].
[sujeto(['The', first, mouse, model, for, 'PHHI']), verbo([has]), complemento([a, conditional, deletion, of, the, gene, encoding, the, 'winged-helix', transcription, factor, 'Foxa2', '(', 'Forkhead', box, 'a2,', formerly, 'Hepatocyte', nuclear, factor, 3, 'beta)', in, pancreatic, beta, cells])].
[sujeto(['Using', isolated, 'islets,', we]), verbo([found]), complemento([that, 'Foxa2', deficiency, resulted, in, excessive, insulin, release, in, response, to, amino, acids, and, complete, loss, of, 'glucose-stimulated', insulin, secretion])].
[sujeto(['Most', 'PHHI', cases, are]), verbo([associated]), complemento([with, mutations, in, 'SUR1', '(', 'Sulfonylurea', receptor, 1, ')', or, 'KIR6'])].
[sujeto(['We', utilized, expression, profiling, to, identify, additional]), verbo([targets]), complemento([of, 'Foxa2'])].
[sujeto(['Strikingly,', one, of, these, 'genes,', 'Hadhsc,', encodes, 'short-chain', 'L-3-hydroxyacyl-coenzyme', 'A', 'dehydrogenase,', deficiency, of, which]), verbo([has]), complemento([been, shown, to, cause, 'PHHI', in, humans])].
[sujeto(['Hadhsc', is, a, direct]), verbo([target]), complemento([of, 'Foxa2,', as, demonstrated, by, cotransfection, as, well, as, in, vivo, chromatin, immunoprecipitation, experiments, using, isolated, islets])].
[sujeto(['Thus,', we]), verbo([have]), complemento([established, 'Foxa2', as, an, essential, activator, of, genes, that, function, in, multiple, pathways, governing, insulin, secretion])].
[sujeto(['The', organic, anion, transporting, polypeptides, '(', 'OATPs)']), verbo([mediate]), complemento([the, uptake, of, numerous, amphipathic, compounds, into, hepatocytes])].
[sujeto(['The', expression, of, 'OATP8', was]), verbo([decreased]), complemento([in, 60, '%', of, 'HCC', compared, to, surrounding, 'non-tumor', liver, 'tissue,', on, both, the, mRNA, and, protein, levels])].
[sujeto(['Expression', of, the, 'liver-enriched', transcription, factor, hepatocyte]), verbo([nuclear]), complemento([factor, 3, beta, '(', 'HNF3beta)', was, increased, in, 70, '%', of, 'HCC', and, correlated, inversely, with, 'OATP8', mRNA, '(', 'r=-0'])].
[sujeto(['In', contrast, to, 'OATP8,', expression, of, 'OATP-C', was, not, significantly]), verbo([decreased]), complemento([in, 'HCC'])].
[sujeto(['In', transfected, 'Huh7', 'cells,', 'OATP8', promoter, activity, was]), verbo([inhibited]), complemento([by, 70, '%', when, 'HNF3beta', was, cotransfected])].
[sujeto(['An', 'HNF3beta']), verbo([binding]), complemento([site, was, located, at, nt, -, 39, /, -, 23, by, 'EMSA'])].
[sujeto(['The', 'OATP-C', promoter, was, not]), verbo([inhibited]), complemento([by, 'HNF3beta'])].
[sujeto(['HNF3beta']), verbo([represses]), complemento([transcription, of, the, 'OATP8', but, not, the, 'OATP-C', 'gene,', providing, a, mechanism, for, reduced, expression, of, 'OATP8', in, 'HCC'])].
[sujeto(['Mouse', embryonic, stem, '(', 'ES)', cells, are, clonal, cell, lines, derived, from, the, inner, cell, mass, of, developing, blastocysts, and]), verbo([have]), complemento(['multi-lineage', differentiation, ability])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, 'ES', cells, can, be, made, to, differentiate, into, hepatocytes, possessing, high, metabolic, activities, by, transfection, of, hepatocyte, nuclear, 'factor-3beta', '(', 'HNF-3beta)'])].
[sujeto(['The', expression, of, organic, anion, transporting, polypeptide, 1, '(', 'oatp1),', multidrug, 'resistance-associated', protein, 1, '(', 'mrp1),', 'mrp2,', 'mrp3,', and, ugt1a1, was, not, seen, in, the, undifferentiated, 'HNF-3beta-ES', cells, by, 'RT-PCR,', whereas, all, were]), verbo([expressed]), complemento([in, differentiating, 'HNF-3beta-ES', cells])].
[sujeto(['An', immunofluorescence, examination, revealed, that, oatp1, was, 'co-located', with, 'desmoplakin,', a, marker, for, the, basolateral, '(', 'sinusoidal)', 'membrane,', and, mrp2, was, 'co-localized', with, 'CD26,', a, marker, for, the, apical, '(', 'canalicular)', 'membrane,', though, they, were, both]), verbo([expressed]), complemento([throughout, most, of, the, cell, membranes])].
[sujeto(['They']), verbo([express]), complemento([endodermal, transcription, factors, '(', e])].
[sujeto(['Transfer', into, distinct, culture, 'conditions,', each, comprised, of, a, specific, mix, of, hormones, and, matrix, 'components,', yields, either, cords, of, hepatocytes, '(']), verbo([express]), complemento(['albumin,', 'CYP3A4,', and, 'transferrin),', branching, ducts, of, cholangiocytes, '(', expressing, anion, 'exchanger-2-AE2', and, 'CFTR),', or, regulatable, 'C-peptide', secreting, 'neoislet-like', clusters, '(', expressing, 'glucagon,', 'insulin)', and, accompanied, by, changes, in, gene, expression, correlating, with, the, adult, fate])].
[sujeto(['The', phenotypes, and, availability, from, all, age, donors]), verbo([suggest]), complemento([that, these, 'stem/progenitors', have, considerable, potential, for, regenerative, therapies, of, 'liver,', bile, 'duct,', and, pancreatic, diseases, including, diabetes])].
[sujeto(['RUNX1']), verbo([loss]), complemento([in, 'ER(+)', mammary, epithelial, cells, increases, 'β-catenin,', deregulates, mitosis, and, stimulates, cell, proliferation, and, expression, of, stem, cell, markers])].
[sujeto(['However,', it, does, not]), verbo([stimulate]), complemento(['LEF/TCF,', 'c-Myc', or, 'CCND1,', and, it, does, not, accelerate, 'G1/S', cell, cycle, phase, transition])].
[sujeto(['Finally,', 'RUNX1', 'loss-mediated', deregulation, of, 'β-catenin', and, mitosis, is, ameliorated, by, 'AXIN1', stabilization, in, 'vitro,', highlighting, 'AXIN1', as, a, potential]), verbo([target]), complemento([for, the, management, of, 'ER(+)', breast, cancer])].
[sujeto(['AML1-ETO', is, the, most, common, fusion, oncoprotein]), verbo([causing]), complemento([acute, myeloid, leukemia, '(', 'AML),', a, disease, with, a, 5, -, year, survival, rate, of, only, 24, '%'])].
[sujeto(['While', known, for, decades, to, be, the, translational, product, of, a, chimeric, gene, created, by, the, stable, chromosome, translocation, 't(8;21)(q22;q22),', it, is, not, known, how, 'AML1-ETO', achieves, its, native, and, functional, conformation, or, whether, this, process, can, be]), verbo([targeted]), complemento([for, therapeutic, benefit])].
[sujeto(['We', demonstrate, that, a, folding, intermediate, of, 'AML1-ETO']), verbo([binds]), complemento([to, 'TRiC', 'directly,', mainly, through, its, 'β-strand', 'rich,', 'DNA-binding', domain, '(', 'AML-(1-175)),', with, the, assistance, of, 'HSP70'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'TRiC', contributes, to, 'AML1-ETO', proteostasis, through, specific, interactions, between, the, 'oncoprotein\'s', 'DNA-binding', 'domain,', which, may, be, targeted, for, therapeutic, benefit])].
[sujeto(['Acute', myeloid, leukemia, '(', 'AML)', 1, -, 'Evi-1', is, a, chimeric, gene, generated, by, the, t, '(', 3, ;, 21, ')', '(', 'q26;', 'q22)', 'translocation,', which]), verbo([leads]), complemento([into, malignant, transformation, of, hematopoietic, stem, cells, by, unclear, mechanisms])].
[sujeto(['This', in, vivo, study, aimed, to, establish, a, stable, line, of, zebrafish]), verbo([expressing]), complemento([the, human, 'RUNX1-Evi-1', fusion, gene, under, the, control, of, a, heat, 'stress-inducible', bidirectional, 'promoter,', and, investigate, its, roles, in, hematopoiesis, and, hematologic, malignancies])].
[sujeto(['Consequently,', primitive, hematopoiesis, was]), verbo([enhanced]), complemento([by, upregulation, of, gata2, and, 'scl,', while, erythropoiesis, was, downregulated, due, to, the, suppression, of, gata1])].
[sujeto([1, ',', but, it, was]), verbo([inhibited]), complemento([along, with, the, low, expression, of, mpo])].
[sujeto(['Microarray', analysis, demonstrated, that, 'RUNX1-Evi-1', not, only, upregulated, 'proteasome,', cell, 'cycle,', 'glycolysis/gluconeogenesis,', tyrosine, 'metabolism,', drug, 'metabolism,', and, 'PPAR', 'pathway,', but, also]), verbo([suppressed]), complemento([transforming, growth, factor, 'β,', 'Jak-STAT,', 'DNA', 'replication,', mismatch, 'repair,', p53, 'pathway,', 'JNK', signaling, 'pathway,', and, nucleotide, excision, repair])].
[sujeto(['Factors', in, cell, proliferation, were, obviously]), verbo([suppressed]), complemento([after, 3, -, day, treatment, with, histone, deacetylase, 'inhibitor,', valproic, acid])].
[sujeto(['Accordingly,', higher, proportion, of, 'G1']), verbo([arrest]), complemento([and, apoptosis, were, manifested, by, the, propidium, iodide, staining])].
[sujeto(['RUNX1-Evi-1', may]), verbo([promote]), complemento([proliferation, and, apoptosis, resistance, of, primitive, hematopoietic, 'cell,', and, inhibit, the, differentiation, of, myeloid, cells, with, the, synergy, of, different, pathways, and, factors])].
[sujeto(['VPA', may, be, a, promising, choice, in, the, molecular]), verbo([targeting]), complemento([therapy, of, 'RUNX1-Evi-1-related', leukemia])].
[sujeto(['Two', distantly, located, promoter, regions]), verbo([regulate]), complemento([the, dynamic, expression, of, 'RUNX', genes, during, 'development:', distal, 'P1', and, proximal, 'P2', promoters])].
[sujeto(['We']), verbo([have]), complemento([recently, described, that, 'β-catenin', increases, total, 'Runx1', mRNA, levels, in, human, 'CD34(+)', hematopoietic, progenitors, and, enhances, spatial, proximity, with, its, translocation, partner, 'ETO'])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, induction, of, 'Wnt/β-catenin', signaling, in, 'HL60', and, 'Jurkat', 'leukemia-derived', cell, lines, and, 'CD34(+)', progenitors, selectively, activate, the, production, of, the, longer, distal, 'P1-Runx1', mRNA, isoform])].
[sujeto(['Gain-', and, 'loss-of-function', experiments, revealed, that, the, differential]), verbo([increase]), complemento([in, 'P1-Runx1', expression, is, accomplished, through, a, minimal, 'β-catenin', responsive, region, that, includes, a, highly, conserved, 'TCF/LEF-binding', 'element,', located, -, 20, /, -, 16, bp, upstream, of, the, canonical, distal, 'P1-Runx1', transcription, start, site])].
[sujeto(['We', conclude, that, the, distal, 'P1-Runx1', promoter, is, a, direct, transcriptional]), verbo([target]), complemento([of, 'Wnt/β-catenin', signaling, that, may, be, important, in, normal, hematopoiesis, or, its, transition, into, malignant, stem, cells, during, the, onset, or, progression, of, leukemia])].
[sujeto(['The', generation, of, diverse, neuronal, subtypes]), verbo([involves]), complemento([specification, of, neural, progenitors, 'and,', 'subsequently,', postmitotic, neuronal, 'differentiation,', a, relatively, poorly, understood, process])].
[sujeto(['NGF', signals, through, the, 'ERK/MAPK', pathway, to]), verbo([promote]), complemento([expression, of, 'Cbfb', but, not, 'Runx1', prior, to, maturation, of, nonpeptidergic, nociceptors])].
[sujeto(['Thus,', an, 'NGF/TrkA-MAPK-CBFβ', pathway, converges, with, 'Islet1-Runx1', signaling, to]), verbo([promote]), complemento(['Runx1/CBFβ', holocomplex, formation, and, nonpeptidergic, nociceptor, maturation])].
[sujeto(['Convergence', of, extrinsic, and, intrinsic, signals, to, control, heterodimeric, transcription, factor, complex, formation]), verbo([provides]), complemento([a, robust, mechanism, for, postmitotic, neuronal, subtype, specification])].
[sujeto(['The', 't(8;21)', and, 'Inv(16)', translocations, disrupt, the, normal, function, of, core]), verbo([binding]), complemento([factors, alpha, '(', 'CBFA)', and, beta, '(', 'CBFB),', respectively])].
[sujeto(['Both', translocations, are]), verbo([associated]), complemento([with, favorable, clinical, outcomes, after, intensive, 'chemotherapy,', and, given, the, perceived, mechanistic, 'similarities,', patients, with, these, translocations, are, frequently, referred, to, as, having, 'CBF-AML'])].
[sujeto(['It', remains, uncertain, as, to, 'whether,', 'collectively,', these, translocations, are, mechanistically, the, same, or, impact, different, pathways, in, subtle, ways, that]), verbo([have]), complemento([both, biological, and, clinical, significance])].
[sujeto(['A', total, of, 1291, genes, in, 't(8;21)', and, 474, genes, in, 'Inv(16)', were, differentially]), verbo([expressed]), complemento([relative, to, the, 'NK', 'controls,', with, 198, genes, differentially, expressed, in, both, subtypes])].
[sujeto(['The', majority, of, these, genes, '(', 175, /, 198, ;, binomial, test, 'p-value', &, 'lt;', 10, '(', -, 30, ')', ')', are, consistent, in, expression, changes, among, the, two, subtypes]), verbo([suggesting]), complemento([the, expression, profiles, are, more, similar, between, the, 'CBF', cohorts, than, in, the, 'NK', cohort])].
[sujeto(['Our', analysis, also, revealed, alternative, splicing, events, '(', 'ASEs)', differentially]), verbo([expressed]), complemento([across, 'subtypes,', with, 337, 't(8;21)-specific', and, 407, 'Inv(16)-specific', 'ASEs', 'detected,', the, majority, of, which, were, acetylated, proteins, '(', p, =, 1.5, x, 10, '(', -, 51, ')', and, p, =, 1.8, x, 10, '(', -, 54, ')', for, the, two, 'subsets)'])].
[sujeto(['In', addition, to, known, 'fusions,', we, identified, and, verified, 16, de, novo, fusions, in, 43, 'patients,', including, three, fusions]), verbo([involving]), complemento(['NUP98', in, six, patients])].
[sujeto(['Clustering', of, differentially]), verbo([expressed]), complemento([genes, indicated, that, the, homeobox, '(', 'HOX)', gene, 'family,', including, two, transcription, factors, '(', 'MEIS1', and, 'NKX2-3)', were, 'down-regulated', in, 'CBF', compared, to, 'NK', samples])].
[sujeto(['This']), verbo([finding]), complemento([supports, existing, data, that, the, dysregulation, of, 'HOX', genes, play, a, central, role, in, biology, 'CBF-AML', hematopoiesis])].
[sujeto(['These', data]), verbo([provide]), complemento([comprehensive, transcriptome, profiling, of, 'CBF-AML', and, delineate, genes, and, pathways, that, are, differentially, 'expressed,', providing, insights, into, the, shared, biology, as, well, as, differences, in, the, two, 'CBF', subsets])].
[sujeto(['Chromosomal', translocations, are, frequently]), verbo([associated]), complemento([with, a, wide, variety, of, 'cancers,', particularly, hematologic, malignancies])].
[sujeto(['We']), verbo([report]), complemento([here, that, 'Wnt/β-catenin', signaling, increases, the, expression, of, 'ETO', and, 'RUNX1', genes, in, human, hematopoietic, progenitors])].
[sujeto(['We']), verbo([found]), complemento([that, 'β-catenin', is, rapidly, recruited, into, 'RNA', polymerase, 'II', transcription, factories, '(', 'RNAPII-Ser5)', and, that, 'ETO', and, 'RUNX1', genes, are, brought, into, close, spatial, proximity, upon, 'Wnt3a', induction])].
[sujeto(['Notably,', 'long-term', treatment, of, cells, with, 'Wnt3a']), verbo([induces]), complemento([the, generation, a, frequent, 'RUNX1-ETO', translocation, event])].
[sujeto(['Thus,', 'Wnt/β-catenin', signaling]), verbo([induces]), complemento([transcription, and, translocation, of, 'RUNX1', and, 'ETO', fusion, gene, 'partners,', opening, a, novel, window, to, understand, the, 'onset/development', of, leukemia])].
[sujeto(['Th-inducing', 'Pox', virus, and, zinc, 'finger/Krüppel-like', factor, '(', 'ThPOK)', is, a, key, commitment, factor, for, 'CD4(+)', lineage, 'T', cells, and, is, essential, for, the, maintenance, of, 'CD4', lineage, 'integrity;', 'thus,', the, expression, of, 'ThPOK']), verbo([has]), complemento([to, be, tightly, controlled])].
[sujeto(['In', this, 'article,', we, demonstrate, that, 'Myc-associated', zinc, 'finger-related', factor, '(', 'MAZR)', and, 'Runt-related', transcription, factor, 1, '(', 'Runx1)', together]), verbo([repressed]), complemento(['ThPOK', in, preselection, 'double-positive', 'thymocytes,', whereas, 'MAZR', acted, in, synergy, with, 'Runx3', in, the, repression, of, 'ThPOK', in, 'CD8(+)', 'T', cells])].
[sujeto(['Furthermore,', 'MAZR-Runx1', and, 'MAZR-Runx3', 'double-mutant', mice, showed]), verbo([enhanced]), complemento([derepression, of, 'Cd4', in, 'double-negative', thymocytes, and, in, 'CD8(+)', 'T', cells, in, comparison, with, 'Runx1', or, 'Runx3', 'single-deficient', 'mice,', 'respectively,', indicating, that, 'MAZR', modulates, 'Cd4', silencing])].
[sujeto(['Finally,', retroviral, 'Cre-mediated', conditional, deletion, of, 'MAZR', in, peripheral, 'CD8(+)', 'T', cells]), verbo([led]), complemento([to, the, derepression, of, 'ThPOK,', thus, showing, that, 'MAZR', is, also, part, of, the, molecular, machinery, that, maintains, a, repressed, state, of, 'ThPOK', in, 'CD8(+)', 'T', cells])].
[sujeto(['However,', the, molecular, mechanisms]), verbo([involved]), complemento([in, regulating, the, differentiation, and, function, of, 'MDSCs', remain, largely, unclear])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, inhibition, of, microRNA, '(', 'miR)-9', promoted, the, differentiation, of, 'MDSCs', with, significantly, reduced, immunosuppressive, function, whereas, overexpression, of, 'miR-9', markedly, enhanced, the, function, of, 'MDSCs'])].
[sujeto(['Notably,', knockdown, of, 'miR-9', significantly, impaired, the, activity, of, 'MDSCs', and]), verbo([inhibited]), complemento([the, tumor, growth, of, 'Lewis', lung, carcinoma, in, mice])].
[sujeto(['Moreover,', 'miR-9']), verbo([regulated]), complemento(['MDSCs', differentiation, by, targeting, the, 'runt-related', transcription, factor, 1, ',', an, essential, transcription, factor, in, regulating, 'MDSC', differentiation, and, function])].
[sujeto(['Furthermore,', the, 'CREB', was]), verbo([found]), complemento([to, regulate, 'miR-9', expression, in, 'MDSCs'])].
[sujeto(['Taken', 'together,', our, findings]), verbo([have]), complemento([identified, a, critical, role, of, 'miR-9', in, regulating, the, differentiation, and, function, of, 'MDSCs'])].
[sujeto(['Acute', stimulation, of, 'nucleotide-binding', oligomerization, domain, 2, '(', 'NOD2),', the, 'Crohn\'s', 'disease-associated', sensor, of, bacterial, 'peptidoglycan,']), verbo([induces]), complemento([cytokines])].
[sujeto(['However,', chronic, 'NOD2', stimulation, in, macrophages]), verbo([decreases]), complemento([cytokines, upon, pattern, recognition, receptor, '(', 'PRR)', 'restimulation;', cytokine, attenuation, to, 'PRR', stimulation, is, similarly, observed, in, intestinal, macrophages])].
[sujeto(['The', role, for, the, transcriptional, repressors, 'Twist1', and, 'Twist2', in]), verbo([regulating]), complemento(['PRR-induced', cytokine, outcomes, is, poorly, understood, and, has, not, been, reported, for, 'NOD2'])].
[sujeto(['We']), verbo([found]), complemento([that, 'Twist1', and, 'Twist2', were, required, for, optimal, cytokine, downregulation, during, acute, 'and,', 'particularly,', chronic, 'NOD2', stimulation, of, human, macrophages])].
[sujeto(['Consistently,', 'Twist1', and, 'Twist2', expression, was]), verbo([increased]), complemento([after, chronic, 'NOD2', 'stimulation;', this, increased, expression, was, 'IL-10', and, 'TGF-β', dependent])].
[sujeto(['Although', 'Twist1', and, 'Twist2', did, not, coregulate, each, 'other\'s', 'expression,', they, cooperated, to]), verbo([enhance]), complemento([binding, to, cytokine, promoters, after, chronic, 'NOD2', stimulation])].
[sujeto(['Moreover,', 'Twist1', and, 'Twist2', contributed, to]), verbo([enhance]), complemento([expression, and, promoter, binding, of, the, proinflammatory, inhibitor, 'c-Maf', and, the, transcriptional, repressor, 'Bmi1'])].
[sujeto(['Furthermore,', with, chronic, 'NOD2', 'stimulation,', 'Twist1', and, 'Twist2', contributed, to, the]), verbo([decreased]), complemento([expression, and, cytokine, promoter, binding, of, the, transcriptional, activators, activating, transcription, factor, 4, ',', 'C/EBPα,', 'Runx1,', and, 'Runx2'])].
[sujeto(['Finally,', 'NOD2', synergized, with, additional, 'PRRs', to]), verbo([increase]), complemento(['Twist1', and, 'Twist2', expression, and, 'Twist-dependent', pathways])].
[sujeto(['Therefore,', after, chronic, 'NOD2', stimulation, 'Twist1', and, 'Twist2', coordinate, the, regulation, of, both, transcriptional, activators, and, 'repressors,', thereby]), verbo([mediating]), complemento([optimal, cytokine, downregulation])].
[sujeto(['A', recent, study]), verbo([has]), complemento([shown, that, transcriptional, regulators, of, core, binding, factor, '(', 'Cbf)', β2, and, 'promotor-1-transcribed', 'Runt-related', transcription, factor, 1, '(', 'P1-Runx1)', are, required, for, the, differentiation, of, 'CD3-CD4+CD45+', lymphoid, tissue, inducer, '(', 'LTi)', 'cells,', which, initiate, and, trigger, the, developmental, program, of, 'PPs,', but, the, involvement, of, this, pathway, in, 'NALT', and, 'TALT', development, remains, to, be, elucidated])].
[sujeto(['Here', we]), verbo([report]), complemento([that, 'Cbfβ2', plays, an, essential, role, in, 'NALT', and, 'TALT', development, by, regulating, 'LTi', cell, trafficking, to, the, 'NALT', and, 'TALT', anlagens])].
[sujeto(['Cbfβ2', was]), verbo([expressed]), complemento([in, 'LTi', cells, in, all, three, types, of, 'MALT', examined])].
[sujeto(['Indeed,', similar, to, the, previous]), verbo([finding]), complemento([for, 'PPs,', we, found, that, 'Cbfβ2-/-', mice, lacked, 'NALT', and, 'TALT', lymphoid, structures])].
[sujeto(['We', exploited, a, pluripotent, hematopoietic, 'stem/progenitor', cell, 'line,', 'EML1,', and, generated, a, cell, line, '(', 'EML-TA)', stably]), verbo([expressing]), complemento([the, 'TEL-AML1', fusion, protein])].
[sujeto(['Global', gene, expression, profiling, of, 'EML1', cells, at, different, stages, of, 'B-lymphoid', 'differentiation,', compared, with, 'EML-TA,', identified, the, interferon, '(', 'IFN)α/β', pathway, as, a, primary]), verbo([target]), complemento([of, repression, by, 'TEL-AML1'])].
[sujeto(['In', 'particular,', expression, and, phosphorylation, of, 'interferon-regulatory', factor, 3, '(', 'IRF3)', was]), verbo([decreased]), complemento([in, 'EML-TA', 'cells;', 'strikingly,', stable, expression, of, 'IRF3', restored, the, capacity, of, 'EML-TA', cells, to, differentiate, into, mature, 'B-cells'])].
[sujeto(['The', ability, of, 'TEL-AML1', to, block, 'B-cell', differentiation, and, downregulate, the, 'IRF3-IFNα/β', pathway, was, confirmed, in, mouse, and, human, primary, hematopoietic, precursor, cells, '(', 'Lin-', and, 'CD34+', 'cells,', 'respectively),', and, in, a, 'patient-derived', cell, line]), verbo([expressing]), complemento(['TEL-AML1', '(', 'REH)'])].
[sujeto(['Furthermore,', treatment, of, 'TEL-AML1']), verbo([expressing]), complemento([cells, with, 'IFNα/β', was, sufficient, to, overcome, the, maturation, block])].
[sujeto(['Our', data]), verbo([provide]), complemento([new, insight, on, 'TEL-AML1', function, and, may, offer, a, new, therapeutic, opportunity, for, 'B-ALL'])].
[sujeto(['High', mutation, frequencies, of, 'RUNX1', gene, in, chronic, myelomonocytic, leukemia, '(', 'CMML)', and, myelodysplastic, syndromes, '(', 'MDS)']), verbo([have]), complemento([been, 'described,', whereas, the, biologic, significances, of, the, mutations, were, not, investigated])].
[sujeto(['Then,', we, studied, the, 'DNA', and, 'CBFβ']), verbo([binding]), complemento([abilities, of, all, the, 'RUNX1', mutants, identified, by, using, electrophoretic, mobility, shift, assay, and, 'co-immunoprecipitation', 'assay,', and, also, determined, their, activities, on, target, 'C-FMS', gene, induction, by, 'Western', blotting, and, luciferase, reporter, assay])].
[sujeto(['Previously,', it, was, proposed, that, 'CBFβ-SMMHC']), verbo([acts]), complemento([by, dominantly, repressing, the, transcription, factor, 'RUNX1', '(', 'Runt-related', protein, 1, ')', ',', but, we, recently, showed, that, 'CBFβ-SMMHC', has, activities, that, are, independent, of, 'RUNX1', repression])].
[sujeto(['In', 'addition,', we, showed, that, a, modified, 'CBFβ-SMMHC', with]), verbo([decreased]), complemento(['RUNX1-binding', activity, accelerates, leukemogenesis])].
[sujeto(['To', test, 'this,', we, generated, mice]), verbo([expressing]), complemento(['Cbfb-MYH11', in, a, 'Runx1-deficient', 'background,', resulting, from, either, homozygous, 'Runx1-null', alleles, '(', 'Runx1(-/-))', or, a, single, 'dominant-negative', 'Runx1', allele, '(', 'Runx1(+/lz))'])].
[sujeto(['We']), verbo([found]), complemento([that, loss, of, 'Runx1', activity, rescued, the, differentiation, defects, induced, by, 'Cbfb-MYH11', during, primitive, hematopoiesis])].
[sujeto(['During', definitive, 'hematopoiesis,', 'RUNX1']), verbo([loss]), complemento([also, significantly, reduced, the, proliferation, and, differentiation, defects, induced, by, 'Cbfb-MYH11'])].
[sujeto(['The', transcription, factor, fusion, 'CBFβ-SMMHC', '(', core]), verbo([binding]), complemento([factor, β, and, the, 'smooth-muscle', myosin, heavy, 'chain),', expressed, in, 'AML', with, the, chromosome, inversion, 'inv(16)(p13q22),', outcompetes, 'wild-type', 'CBFβ', for, binding, to, the, transcription, factor, 'RUNX1,', deregulates, 'RUNX1', activity, in, 'hematopoiesis,', and, induces, 'AML'])].
[sujeto(['Here,', we]), verbo([report]), complemento([the, development, of, a, 'protein-protein', interaction, 'inhibitor,', 'AI-10-49,', that, selectively, binds, to, 'CBFβ-SMMHC', and, disrupts, its, binding, to, 'RUNX1'])].
[sujeto(['Treatment', of, primary, 'inv(16)', 'AML', patient, blasts, with, 'AI-10-49']), verbo([triggers]), complemento([selective, cell, death])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, direct, inhibition, of, the, oncogenic, 'CBFβ-SMMHC', fusion, protein, may, be, an, effective, therapeutic, approach, for, 'inv(16)', 'AML,', and, they, provide, support, for, transcription, factor, targeted, therapy, in, other, cancers])].
[sujeto([1, +, ')', 'Th1', cells]), verbo([induced]), complemento([colitis, in, 'Rag(-/-)', mice, after, adoptive, transfer, and, converted, into, 'IL-17(+)', 'Th17,', but, not, 'Foxp3(+)', 'Treg', cells, in, the, inflamed, intestines])].
[sujeto(['TGF-β', and, 'IL-6,', but, not, 'IL-1β', and, 'IL-23,']), verbo([regulated]), complemento(['Th1', conversion, into, 'Th17', cells])].
[sujeto(['TGF-β', induction, of, transcriptional, factor, 'Runx1', is, crucial, for, the, 'conversion,', since, silencing, 'Runx1', by, siRNA]), verbo([inhibited]), complemento(['Th1', conversion, into, 'Th17', cells])].
[sujeto(['Furthermore,', 'TGF-β']), verbo([enhanced]), complemento([histone, 'H3K9', acetylation, but, inhibited, 'H3K9', trimethylation, of, 'Runx1-', and, 'ROR-γt-binding', sites, on, 'il-17', or, rorc, gene, in, 'Th1', cells])].
[sujeto(['We', conclude, that, 'Th1', cells, convert, into, 'Th17', cells, under, inflammatory, conditions, in, 'intestines,', which, is, possibly]), verbo([mediated]), complemento([by, 'TGF-β', induction, of, 'Runx1'])].
[sujeto(['Cooperative', assemblies, of, transcription, factors, '(', 'TFs)', on]), verbo([target]), complemento([gene, enhancers, coordinate, cell, 'proliferation,', fate, 'specification,', and, differentiation, through, precise, and, complicated, transcriptional, mechanisms])].
[sujeto(['Chemical', 'modifications,', such, as, 'phosphorylation,', of, 'TFs']), verbo([induced]), complemento([by, cell, signaling, further, modulate, the, dynamic, cooperativity, of, 'TFs'])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, various, 'Ets1-containing', 'TF-DNA', complexes, respond, differently, to, 'calcium-induced', phosphorylation, of, 'Ets1,', which, is, known, to, inhibit, 'Ets1-DNA', binding])].
[sujeto(['Crystallographic', analysis, of, a, complex, comprising, 'Ets1,', 'Runx1,', and, 'CBFβ', at, the, 'TCRα', enhancer, revealed, that, 'Ets1', acquires, robust]), verbo([binding]), complemento([stability, in, the, 'Runx1', and, 'DNA-complexed', 'state,', via, allosteric, mechanisms])].
[sujeto(['This', allows]), verbo([phosphorylated]), complemento(['Ets1', to, be, retained, at, the, 'TCRα', enhancer, with, 'Runx1,', in, contrast, to, other, 'Ets1', target, gene, enhancers, including, 'mb-1', and, 'stromelysin-1'])].
[sujeto(['This', study]), verbo([provides]), complemento([a, 'structure-based', model, for, 'cell-signaling-dependent', regulation, of, target, 'genes,', mediated, via, chemical, modification, of, 'TFs'])].
[sujeto(['The', 2, genes, 'RUNX1', and, 'SP7', resulted, differently]), verbo([expressed]), complemento([in, cells, cultured, on, metallic, supports, if, compared, with, the, expression, recorded, for, 'OIC'])].
[sujeto(['However,', the, mechanism, by, which, 'Cbfβ']), verbo([regulates]), complemento([cartilage, and, bone, development, remains, unclear])].
[sujeto(['Surprisingly,', the, mutant, mice, had, 'under-developed', larynx, and, tracheal, 'cartilage,']), verbo([causing]), complemento([alveolus, defects, that, led, to, death, shortly, after, birth, from, suffocation])].
[sujeto(['Importantly,', we, showed, that, 'Cbfβ', was]), verbo([expressed]), complemento([throughout, the, skeleton, during, both, embryonic, and, postnatal, 'development,', which, explains, the, 'multiple-skeletal', defects, observed, in, the, mutant, mice])].
[sujeto(['Notably,', 'Cbfβ,', 'Runx1', and, 'Runx2', displayed, different, expression, patterns, in, the, growth, plates, of, the, 'wild-type', 'mice,', indicating, that, 'Cbfβ/Runx1', complex, and, 'Cbfβ/Runx2', complex, may]), verbo([regulate]), complemento([chondrocyte, proliferation, and, 'hypertrophy,', 'respectively,', in, a, spatial, and, temporal, manner])].
[sujeto(['Collectively,', the, results, demonstrate, that, 'Cbfβ']), verbo([mediates]), complemento([cartilage, and, bone, development, by, interacting, with, 'Runx1', and, 'Runx2', to, regulate, the, expressions, of, 'Col', 'X', and, 'Osx', for, chondrocyte, and, osteoblast, development])].
[sujeto(['These', findings, not, only]), verbo([reveal]), complemento([a, critical, role, for, 'Cbfβ', in, cartilage, and, bone, development, but, also, facilitate, the, design, of, novel, therapeutic, approaches, for, skeletal, diseases])].
[sujeto(['Core']), verbo([binding]), complemento([factor, '(', 'CBF)', is, a, heterodimeric, transcription, factor, complex, composed, of, a, 'DNA-binding', 'subunit,', one, of, three, 'runt-related', transcription, factor, '(', 'RUNX)', 'factors,', and, a, 'non-DNA', binding, 'subunit,', 'CBFβ'])].
[sujeto(['CBFβ', is, critical, for, 'DNA']), verbo([binding]), complemento([and, stability, of, the, 'CBF', transcription, factor, complex])].
[sujeto(['In', the, 'ovary,', the, 'LH', surge]), verbo([increases]), complemento([the, expression, of, 'Runx1', and, 'Runx2', in, periovulatory, 'follicles,', implicating, a, role, for, 'CBFs', in, the, periovulatory, process])].
[sujeto(['The', mutant, female, mice, exhibited, significant, reductions, in, 'fertility,', with, smaller, litter, 'sizes,']), verbo([decreased]), complemento([progesterone, during, 'gestation,', and, fewer, cumulus, oocyte, complexes, collected, after, an, induced, superovulation])].
[sujeto(['Cbfβ', knockdown, mice, also, exhibited]), verbo([decreased]), complemento([expression, of, key, genes, within, the, corpora, lutea, and, morphological, changes, in, the, ovarian, 'structure,', including, the, presence, of, large, antral, follicles, well, into, the, luteal, phase])].
[sujeto(['Overall,', these, data]), verbo([suggest]), complemento([a, role, for, 'CBFs', as, significant, regulators, of, gene, 'expression,', ovulatory, 'processes,', and, luteal, development, in, the, ovary])].
[sujeto(['Core']), verbo([binding]), complemento([factor, β, '(', 'Cbfβ)', is, a, partner, protein, of, 'Runx', family, transcription, factors, with, minimally, characterized, function, in, cartilage])].
[sujeto(['Here', we, address, the, role, of, 'Cbfβ', in, cartilage, by, generating, 'chondrocyte-specific', 'Cbfβ-deficient', mice, '(', 'Cbfb(Δch/Δch)', ')', from, 'Cbfb-floxed', mice, crossed, with, mice]), verbo([expressing]), complemento(['Cre', from, the, 'Col2a1', promoter])].
[sujeto(['Cbfb(Δch/Δch)', mice, died, soon, after, birth, and, exhibited, delayed, endochondral, bone, 'formation,', shorter, appendicular, skeleton, length, with]), verbo([increased]), complemento([proliferative, 'chondrocytes,', and, nearly, absent, hypertrophic, chondrocyte, zones])].
[sujeto(['Immunohistochemical', and, quantitative, 'real-time', 'PCR', analyses, showed, that, the, number, and, size, of, proliferative, chondrocytes]), verbo([increased]), complemento([and, the, expression, of, chondrocyte, maturation, markers, at, the, growth, 'plates,', including, 'Runx2,', 'osterix,', and, 'osteopontin,', significantly, diminished, in, 'Cbfb(Δch/Δch)', mice, compared, to, wild, type, mice])].
[sujeto(['Mechanistically,', 'Cbfβ', deficiency, in, chondrocytes]), verbo([caused]), complemento([a, decrease, of, protein, levels, of, 'Runx', transcription, factors, by, accelerating, 'polyubiquitination-mediated', proteosomal, degradation, in, vitro])].
[sujeto(['Indeed,', 'Runx2', and, 'Runx3,', but, not, 'Runx1,']), verbo([decreased]), complemento([in, 'Cbfb(Δch/Δch)', mice])].
[sujeto(['Runx2', is]), verbo([required]), complemento([for, osteoblast, differentiation, and, chondrocyte, 'maturation,', and, haplodeficiency, of, 'RUNX2', causes, cleidocranial, 'dysplasia,', which, is, characterized, by, open, fontanelles, and, sutures, and, hypoplastic, clavicles])].
[sujeto(['Cbfb', forms, a, heterodimer, with, 'Runx', family, proteins, and]), verbo([enhances]), complemento([their, 'DNA-binding', capacity])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, the, partial, rescue, of, hematopoiesis, in, 'Cbfb(-/-)', mice, revealed, the, requirement, of, 'Cbfb', in, skeletal, development])].
[sujeto(['The', differentiation, of, chondrocytes, and, osteoblasts, were, severely]), verbo([inhibited]), complemento([in, 'vitro,', and, the, reporter, activities, of, 'Ihh,', 'Col10a1,', and, 'Bglap2', promoter, constructs, were, reduced, in, 'Cbfb(fl/fl/Cre)', chondrocytes, or, osteoblasts])].
[sujeto(['These', findings, indicate, that, 'Cbfb', is]), verbo([required]), complemento([for, skeletal, development, by, regulating, chondrocyte, differentiation, and, proliferation, and, osteoblast, 'differentiation;', that, 'Cbfb', plays, an, important, role, in, the, stabilization, of, 'Runx', family, 'proteins;', and, that, 'Runx2', protein, stability, is, less, dependent, on, 'Cbfb', in, calvariae, than, in, cartilaginous, limb, skeletons])].
[sujeto(['Cytogenetics']), verbo([provide]), complemento([reliable, risk, stratification, for, 'treatment:', high, hyperdiploidy, and, 'ETV6-RUNX1', are, good, 'risk,', whereas, 'BCR-ABL1,', 'MLL', 'rearrangements,', and, hypodiploidy, are, poor, risk])].
[sujeto(['With', advancing, technologies, in, 'array-based', approaches, '(', single, nucleotide, polymorphism, 'arrays)', and, 'next-generation', sequencing, to, study, the, 'genome,']), verbo([increasing]), complemento([numbers, of, new, genetic, changes, are, being, discovered])].
[sujeto(['Whether', they]), verbo([have]), complemento([a, link, to, outcome, is, the, most, important, factor, for, refinement, of, risk, factors, in, relation, to, clinical, trials])].
[sujeto(['For', several, newly, identified, 'abnormalities,', including, intrachromosomal, amplification, of, chromosome, 21, '(', 'iAMP21),', that, are]), verbo([associated]), complemento([with, a, poor, prognosis, with, standard, 'therapy,', appropriately, modified, treatment, has, significantly, improved, outcome])].
[sujeto(['After', the, successful, use, of, tyrosine, kinase, inhibitors, in, the, treatment, of, 'BCR-ABL1-positive', acute, lymphoblastic, 'leukemia,', patients, with, alternative, 'ABL1', translocations, and, rearrangements]), verbo([involving]), complemento(['PDGFRB', may, benefit, from, treatment, with, tyrosine, kinase, inhibitors])].
[sujeto(['Other', 'aberrations,', for, 'example,', 'CRLF2', overexpression, and, 'JAK2', 'mutations,', are, also]), verbo([providing]), complemento([potential, novel, therapeutic, targets, with, the, prospect, of, reduced, toxicity])].
[sujeto(['Inactivating', 'RUNX1', mutations]), verbo([have]), complemento([frequently, been, found, in, patients, with, myelodysplastic, syndrome, '(', 'MDS)', and, cytogenetically, normal, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['However,', no, somatic, 'RUNX1', alteration, was]), verbo([found]), complemento([in, 'AMLs', with, leukemogenic, fusion, 'proteins,', such, as, 'core-binding', factor, '(', 'CBF)', leukemia, and, 'MLL', fusion, 'leukemia,', raising, the, possibility, that, 'RUNX1', could, actually, promote, the, growth, of, these, leukemia, cells])].
[sujeto(['Using', normal, human, cord, blood, cells, and, those]), verbo([expressing]), complemento([leukemogenic, fusion, 'proteins,', we, discovered, a, dual, role, of, 'RUNX1', in, myeloid, leukemogenesis])].
[sujeto(['RUNX1', overexpression]), verbo([inhibited]), complemento([the, growth, of, normal, cord, blood, cells, by, inducing, myeloid, 'differentiation,', whereas, a, certain, level, of, 'RUNX1', activity, was, required, for, the, growth, of, 'AML1-ETO', and, 'MLL-AF9', cells])].
[sujeto(['Using', a, mouse, genetic, 'model,', we, also, showed, that, the, combined]), verbo([loss]), complemento([of, 'Runx1/Cbfb', inhibited, leukemia, development, induced, by, 'MLL-AF9'])].
[sujeto(['RUNX2', could, compensate, for, the]), verbo([loss]), complemento([of, 'RUNX1'])].
[sujeto(['The', survival, effect, of, 'RUNX1', was]), verbo([mediated]), complemento([by, 'BCL2', in, 'MLL', fusion, leukemia])].
[sujeto(['Inhibiting', 'RUNX1', activity, rather, than]), verbo([enhancing]), complemento([it, could, be, a, promising, therapeutic, strategy, for, 'AMLs', with, leukemogenic, fusion, proteins])].
[sujeto(['This', translocation]), verbo([causes]), complemento([expression, of, the, 'RUNX1-ETO', '(', 'AML1-ETO)', fusion, 'protein,', which, cooperates, with, additional, mutations, in, leukemia, development])].
[sujeto(['We']), verbo([report]), complemento([here, that, interferons, '(', 'IFNs)', and, 'IFN-stimulated', genes, are, a, group, of, genes, consistently, 'up-regulated', by, 'RUNX1-ETO', in, both, human, and, murine, models])].
[sujeto(['Addition', of, exogenous, 'IFN', in, vitro, significantly, reduces, the]), verbo([increase]), complemento([in, 'self-renewal', potential, induced, by, both, 'RUNX1-ETO', and, its, leukemogenic, splicing, isoform, 'RUNX1-ETO9a'])].
[sujeto(['Finally,']), verbo([loss]), complemento([of, type, 'I', 'IFN', signaling, via, knockout, of, 'Ifnar1', significantly, accelerates, leukemogenesis, in, a, 't(8;21)', murine, model])].
[sujeto(['This', demonstrates, the, role, of]), verbo([increased]), complemento(['IFN', signaling, as, an, important, factor, inhibiting, 't(8;21)', fusion, protein, function, and, leukemia, development, and, supports, the, use, of, type, 'I', 'IFNs', in, the, treatment, of, 'AML'])].
[sujeto(['Lymphoid', 'enhancer-binding', factor, 1, '(', 'LEF1)', is, a, downstream, effector, of, the, 'Wnt/β-catenin', signaling, pathway, and, its, dysregulation, is]), verbo([associated]), complemento([with, a, number, of, malignant, diseases, such, as, leukemia])].
[sujeto(['Moreover,', we]), verbo([provide]), complemento([the, first, evidence, that, primary, 'AML', samples, with, 'AML1-ETO', or, 'PML-RARα', have, a, higher, 'LEF1', level, compared, with, those, without, each, fusion, gene])].
[sujeto(['High', 'LEF1', level, was]), verbo([associated]), complemento([with, a, favorable, 'relapse-free', survival, in, patients, with, 'FLT3-ITD', 'wild-type'])].
[sujeto(['No', consecutive, analysis, of, 'BAALC', and, 'WT1', expressions]), verbo([associated]), complemento([with, 'core-binding', factor, 'AML', '(', 'CBF-AML)', from, diagnosis, to, hematopoietic, stem, cell, transplantation, '(', 'HSCT)', has, yet, been, reported])].
[sujeto(['A', subgroup, of, 't(8;21)', showing, higher, 'BAALC', and, 'WT1', expressions, at, 'post-HSCT', were, also]), verbo([associated]), complemento([with, inferior, 'OS', '(', 'P', =, 0.018, ',', 0.015, ')', and, higher, 'CIR', rates, '(', 'P', =, 0.019, ',', 0.011, ')'])].
[sujeto(['Developing', novel, therapies, that]), verbo([suppress]), complemento(['self-renewal', of, leukemia, stem, cells, may, reduce, the, likelihood, of, relapses, and, extend, 'long-term', survival, of, patients, with, acute, myelogenous, leukemia, '(', 'AML)'])].
[sujeto(['AML1-ETO', '(', 'AE)', is, an, oncogene, that, plays, an, important, role, in]), verbo([inducing]), complemento(['self-renewal', of, hematopoietic, 'stem/progenitor', cells, '(', 'HSPCs),', leading, to, the, development, of, leukemia, stem, cells])].
[sujeto(['Previously,', using, a, zebrafish, model, of, 'AE', and, a, 'whole-organism', chemical, suppressor, 'screen,', we]), verbo([have]), complemento([discovered, that, 'AE', induces, specific, hematopoietic, phenotypes, in, embryonic, zebrafish, through, a, cyclooxygenase, '(', 'COX)-2', and, 'β-catenin-dependent', pathway])].
[sujeto(['Here,', we, show, that, 'AE', also]), verbo([induces]), complemento([expression, of, the, 'Cox-2', gene, and, activates, 'β-catenin', in, mouse, bone, marrow, cells])].
[sujeto(['Inhibition', of, 'COX']), verbo([suppresses]), complemento(['β-catenin', activation, and, serial, replating, of, 'AE(+)', mouse, 'HSPCs'])].
[sujeto(['In', 'addition,', treatment, with, 'nimesulide,', a, 'COX-2', selective, 'inhibitor,', dramatically]), verbo([suppresses]), complemento([xenograft, tumor, formation, and, inhibits, in, vivo, progression, of, human, leukemia, cells])].
[sujeto(['In', 'summary,', our, data, indicate, an, important, role, of, a, 'COX/β-catenin-dependent', signaling, pathway, in, tumor, 'initiation,', 'growth,', and, 'self-renewal,', and, in]), verbo([providing]), complemento([the, rationale, for, testing, potential, benefits, from, common, 'COX', inhibitors, as, a, part, of, 'AML', treatments])].
[sujeto(['It', is, known, that, leukemia, patients, with, extramedullary, infiltration, '(', 'EMI)']), verbo([have]), complemento([a, worse, prognosis, than, patients, without, it])].
[sujeto(['Recent', data, indicate, that, the, amyloid, precursor, protein, '(', 'APP)', is]), verbo([involved]), complemento([in, cell, 'adhesion,', 'motility,', and, proliferation])].
[sujeto(['The', expression, of, 'APP', and, its, prognostic, significance, in, acute, myeloid, leukemia, '(', 'AML)']), verbo([have]), complemento([not, been, studied])].
[sujeto(['Transwell', data, show, that, 'siRNA/APP', substantially, impairs, cell, 'migration,', but, it, does, not]), verbo([inhibit]), complemento([cell, proliferation])].
[sujeto(['Furthermore,', by, quantitative, 'real-time', polymerase, chain, reaction, and, 'Western', 'blot,', we]), verbo([found]), complemento([that, 'siRNA/APP', decreases, 'MMP-2', expression, in, vitro])].
[sujeto(['Our', study]), verbo([provides]), complemento([a, novel, clue, that, 'APP', is, involved, in, the, extramedullary, infiltration, of, leukemia, by, 'MMP-2'])].
[sujeto(['Secreted-frizzled', related, proteins, '(', 'SFRPs)', are, modulators, of, the, 'Wnt', signaling, pathway, that, is, closely]), verbo([involved]), complemento([in, normal, and, malignant, hematopoiesis])].
[sujeto(['Epigenetic', deregulation, of, 'Wnt', modulators]), verbo([leading]), complemento([to, aberrant, signaling, has, been, reported, in, adult, patients, with, acute, myeloid, leukemia, '(', 'AML),', but, its, occurrence, in, childhood, patients, with, 'AML', and, the, role, of, individual, modulators, are, unclear])].
[sujeto(['In', this, 'study,', we, examined, 'SFRP1,', 'SFRP2,', 'SFRP4,', and, 'SFRP5', promoter, methylation, in, 83, patients, with, 'AML', '(', 59, children, and, 24, 'adults)', and]), verbo([found]), complemento([preferential, 'SFRP1', methylation, and, mRNA, 'down-regulation', in, the, prognostically, favorable, subgroup, of, 'AML', with, 't(8;21)', translocation])].
[sujeto(['Mechanistically,', we, further, demonstrated, that, 'RUNX1-ETO,', the, 't(8;21)', fusion, 'product,', specifically]), verbo([bound]), complemento([the, 'SFRP1', promoter, and, repressed, its, transcription, via, a, consensus, 'RUNX', binding, site])].
[sujeto(['In', 't(8;21)-leukemia', 'cells,', 'SFRP1', selectively]), verbo([inhibited]), complemento([canonical, 'Wnt', signaling, and, cellular, proliferation, that, were, associated, with, concomitant, 'down-regulation', of, 'Wnt/β-catenin', target, 'genes,', including, 'CCND1', and, 'MYC'])].
[sujeto(['Taken', 'together,', we, identified, 'SFRP1', as, a, transcriptional, repression]), verbo([target]), complemento([of, the, 't(8;21)', fusion, protein, and, demonstrated, a, novel, mechanism, of, 'Wnt', activation, in, a, specific, subtype, of, 'AML'])].
[sujeto(['The', 'mixed-lineage', leukemia, '(', 'MLL)', 'H3K4', methyltransferase, 'protein,', and, the, heterodimeric, 'RUNX1/CBFβ', transcription, factor, 'complex,', are, critical, for, definitive, and, adult, 'hematopoiesis,', and, both, are, frequently]), verbo([targeted]), complemento([in, human, acute, leukemia])].
[sujeto(['We', identified, a, physical, and, functional, interaction, between, 'RUNX1', '(', 'AML1)', and, 'MLL', and, show, that, both, are]), verbo([required]), complemento([to, maintain, the, histone, lysine, 4, trimethyl, mark, '(', 'H3K4me3)', at, 2, critical, regulatory, regions, of, the, 'AML1', target, gene, 'PU'])].
[sujeto(['Similar', to, 'CBFβ,', we, show, that, 'MLL']), verbo([binds]), complemento([to, 'AML1', abrogating, its, 'proteasome-dependent', degradation])].
[sujeto(['Furthermore,', a, subset, of, previously, uncharacterized, 'frame-shift', and, missense, mutations, at, the, 'N', terminus, of, 'AML1,']), verbo([found]), complemento([in, 'MDS', and, 'AML', 'patients,', impairs, its, interaction, with, 'MLL,', resulting, in, loss, of, the, 'H3K4me3', mark, within, 'PU'])].
[sujeto([1, regulatory, 'regions,', and]), verbo([decreased]), complemento(['PU'])].
[sujeto(['The', interaction, between, 'MLL', and, 'AML1']), verbo([provides]), complemento([a, mechanism, for, the, 'sequence-specific', binding, of, 'MLL', to, 'DNA,', and, identifies, 'RUNX1', target, genes, as, potential, effectors, of, 'MLL', function])].
[sujeto(['The', genetic, origins, of, the, development, of, malignant, haematological, disorders]), verbo([have]), complemento([been, established, at, the, beginning, of, the, 80, ies])].
[sujeto(['Systematic', characterization, of, chromosomal, structural, abnormalities, 'and,', more, recently, by, 'DNA', microarray, approaches, and, sequencing, of, tumour, genomes]), verbo([have]), complemento([allowed, the, identification, of, a, large, number, of, genes, that, are, mutated, during, malignant, transformation, in, humans])].
[sujeto(['Functional', studies, of, these, human, oncogenes]), verbo([have]), complemento([shown, that, most, of, them, were, not, able, to, transform, a, haematologic, progenitor, when, acting, alone, and, that, cooperation, with, other, oncogenic, events, was, required])].
[sujeto(['From', these, 'data,', the, development, of, efficient, therapeutic, approaches, will, be, possible, by]), verbo([targeting]), complemento([the, early, oncogenic, events, which, are, at, the, origin, of, the, malignant, transformation])].
[sujeto(['To', identify, genes, and, components]), verbo([associated]), complemento([with, this, oncogene, we, used, 'Drosophila', as, a, genetic, model])].
[sujeto(['Expression', of, 'AML1-ETO']), verbo([caused]), complemento([an, expansion, of, hematopoietic, precursors, in, 'Drosophila,', which, expressed, high, levels, of, reactive, oxygen, species, '(', 'ROS)'])].
[sujeto(['Mutations', in, functional, domains, of, the, fusion, protein]), verbo([suppress]), complemento([the, proliferative, phenotype])].
[sujeto(['In', a, genetic, 'screen,', we]), verbo([found]), complemento([that, inactivation, of, 'EcRB1', or, activation, of, 'Foxo', and, superoxide, 'dismutase-2', '(', 'SOD2)', suppress, the, 'AML1-ETO-induced', phenotype, by, reducing, 'ROS', expression, in, the, precursor, cells])].
[sujeto(['Our', studies, indicate, that, 'ROS', is, a, signaling, factor]), verbo([promoting]), complemento([maintenance, of, normal, as, well, as, the, aberrant, myeloid, precursors, and, suggests, the, importance, of, antioxidant, enzymes, and, their, regulators, as, targets, for, further, study, in, the, context, of, leukemia])].
[sujeto(['Although', 'NF-E2', levels, correlate, with, 'JAK2(V671F)', allele, burden, in, some, 'PV', 'cohorts,', the, molecular, mechanism]), verbo([causing]), complemento([aberrant, 'NF-E2', expression, has, not, been, described])].
[sujeto(['Here', we, show, that, 'NF-E2', expression, is, also]), verbo([increased]), complemento([in, patients, with, essential, thrombocythemia, and, primary, myelofibrosis, independent, of, the, presence, of, the, 'JAK2(V617F)', mutation])].
[sujeto(['Characterization', of, the, 'NF-E2', promoter, revealed, multiple, functional]), verbo([binding]), complemento([sites, for, 'AML1/RUNX-1'])].
[sujeto(['Chromatin', immunoprecipitation, demonstrated, 'AML1']), verbo([binding]), complemento([to, the, 'NF-E2', promoter, in, vivo])].
[sujeto(['Moreover,', 'AML1']), verbo([binding]), complemento([to, the, 'NF-E2', promoter, was, significantly, increased, in, granulocytes, from, 'PV', patients, compared, with, healthy, controls])].
[sujeto(['RNAi-mediated', suppression, of, either, 'AML1', or, of, its]), verbo([binding]), complemento([partner, 'CBF-beta', significantly, decreased, 'NF-E2', expression])].
[sujeto(['Moreover,', expression, of, the, leukemic, fusion, protein, 'AML/ETO', drastically]), verbo([decreased]), complemento(['NF-E2', protein, levels])].
[sujeto(['Our', data, identify, 'NF-E2', as, a, novel, 'AML1']), verbo([target]), complemento([gene, and, delineate, a, role, for, aberrant, 'AML1', expression, in, mediating, elevated, 'NF-E2', expression, in, 'MPN', patients])].
[sujeto(['The', acquisition, of, the, 'critical,', secondary, 'CNAs']), verbo([requires]), complemento([some, 'Darwinian', selective, advantage, to, expand, numbers, of, cells, at, 'risk,', and, the, cytokine, 'TGF', beta, is, able, to, exercise, this, function])].
[sujeto(['The', clonal, architecture, of, 'ALL']), verbo([has]), complemento([been, investigated, by, single, cell, analysis, with, multicolor, probes, to, mutant, genes])].
[sujeto(['The', data]), verbo([reveal]), complemento([not, a, linear, sequence, of, mutation, acquisition, with, clonal, succession, but, rather, considerable, complexity, with, a, 'tree-like', or, branching, structure, of, genetically, distinct, subclones, very, reminiscent, of, 'Darwin\'s', original, 1837, evolutionary, divergence, diagram])].
[sujeto(['This', evolutionary, pattern]), verbo([has]), complemento([important, implications, for, stem, cells, in, 'ALL,', for, the, origins, of, relapse, and, for, therapeutic, targeting])].
[sujeto(['However,', optimal, sampling, intervals]), verbo([have]), complemento([not, been, defined, and, are, likely, to, vary, according, to, the, underlying, molecular, lesion])].
[sujeto(['Combination', of, conventional, chromosome, analysis, '(', 'CCA)', and, 'FISH']), verbo([provides]), complemento([higher, sensitivity, in, detecting, these, genetic, 'abnormalities,', and, it, is, effective, to, apply, several, 'FISH', probes, as, a, profile, test])].
[sujeto(['Naturally', arising, regulatory, 'T', '(', 'Treg)', cells]), verbo([express]), complemento([the, transcription, factor, 'FoxP3,', which, critically, controls, the, development, and, function, of, 'Treg', cells])].
[sujeto(['FoxP3']), verbo([interacts]), complemento([with, another, transcription, factor, 'Runx1', '(', also, known, as, 'AML1)'])].
[sujeto(['Here,', we, showed, that, 'Treg', 'cell-specific', deficiency, of, 'Cbfbeta,', a, cofactor, for, all, 'Runx', 'proteins,', or, that, of, 'Runx1,', but, not, 'Runx3,']), verbo([induced]), complemento(['lymphoproliferation,', autoimmune, 'disease,', and, hyperproduction, of, 'IgE'])].
[sujeto(['The', 'Runx', complex]), verbo([bound]), complemento([to, more, than, 3000, gene, loci, in, 'Treg', 'cells,', including, the, 'Foxp3', regulatory, regions, and, the, 'Il4', silencer])].
[sujeto(['In', 'addition,', knockdown, of, 'RUNX1', showed, that, 'RUNX1', is]), verbo([required]), complemento([for, the, optimal, regulation, of, 'FoxP3', expression, in, human, 'T', cells])].
[sujeto(['Interestingly,', both, 'CBF', leukemia, fusion, proteins, and, 'miR-17,', which]), verbo([targets]), complemento(['RUNX1-3\'UTR,', negatively, affect, a, common, core, 'RUNX1-miRNA', mechanism, that, forces, myeloid, cells, into, an, 'undifferentiated,', 'KIT-induced,', proliferating, state])].
[sujeto(['In', the, second, part, of, this, study, we, took, advantage, of, the, conservation, of, the, core, 'RUNX1-miRNA', mechanism, in, mouse, and, 'human,', to, mechanistically, demonstrate, in, a, mouse, myeloid, cell, model, that]), verbo([increased]), complemento(['KIT-induced', proliferation, is, per, se, a, mechanism, sufficient, to, delay, myeloid, differentiation])].
[sujeto(['In', the, first, part, of, this, study, we]), verbo([found]), complemento([that, stable, 'miR-17', upregulation, 'affects,', like, the, 'CBF-AML', fusion, proteins, '(', 'RUNX1-MTG8', or, 'CBFB-MYH11),', a, core, 'RUNX1-miRNA', mechanism, leading, to, 'KIT-induced', proliferation, of, 'differentiation-arrested', 'U937', myeloid, cells])].
[sujeto(['The', integrated, information, gathered, from, the, two, myeloid, cell, models, shows, that, 'RUNX1']), verbo([regulates]), complemento([myeloid, differentiation, not, only, by, direct, transcriptional, regulation, of, coding, and, 'non-coding', myeloid, differentiation, functions, '(', e])].
[sujeto(['miR-223),', but, also, by]), verbo([modulating]), complemento(['KIT-induced', proliferation, via, 'non-coding', miRNAs, '(', e])].
[sujeto(['On', the, other, 'hand,', the, extent, of, 'KIT-induced', proliferation, itself, can]), verbo([modulate]), complemento([myeloid, differentiation, of, cells, with, wild, type, 'RUNX1', function])].
[sujeto(['CBFβ', and, 'RUNX1', form, a, 'DNA-binding', heterodimer, and, are, both]), verbo([required]), complemento([for, hematopoietic, stem, cell, '(', 'HSC)', generation, in, mice])].
[sujeto(['However,', the, nascent, 'HSCs', were, not]), verbo([released]), complemento([from, the, 'aorta-gonad-mesonephros', '(', 'AGM)', 'region,', as, evidenced, by, the, accumulation, of, 'runx1(+)', cells, in, the, 'AGM', that, could, not, enter, circulation])].
[sujeto(['Finally,', we]), verbo([found]), complemento([that, cbfb, was, downstream, of, the, 'Notch', pathway, during, 'HSC', development])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, runx1, and, cbfb, are, required, at, 2, different, steps, during, early, 'HSC', development])].
[sujeto(['CBFβ', is, not]), verbo([required]), complemento([for, nascent, 'HSC', emergence, but, is, required, for, the, release, of, 'HSCs', from, 'AGM', into, circulation])].
[sujeto(['Despite', the, absolute, requirements, for, these, factors, in, the, development, of, hematopoietic, stem, cells, and, 'lymphocytes,', their, roles, in, the, development, of, bone, marrow, progenitor, subsets]), verbo([have]), complemento([not, been, defined])].
[sujeto(['Besides', the]), verbo([loss]), complemento([of, 'DC', 'progenitors,', 'pan-hematopoietic', 'Cbfb-deficient', mice, also, lack, 'CD105(+)', erythroid, 'progenitors,', leading, to, severe, anemia, at, 3, to, 4, months, of, age])].
[sujeto(['RUNX1/CBFβ', '(', core]), verbo([binding]), complemento([factor, '[', 'CBF])', is, a, heterodimeric, transcription, factor, complex, that, is, frequently, involved, in, chromosomal, 'translocations,', point, 'mutations,', or, deletions, in, acute, leukemia])].
[sujeto(['The', mixed, lineage, leukemia, '(', 'MLL)', gene, is, also, frequently]), verbo([involved]), complemento([in, chromosomal, translocations, or, partial, tandem, duplication, in, acute, leukemia])].
[sujeto(['The', 'MLL', protein]), verbo([interacts]), complemento([with, 'RUNX1', and, prevents, 'RUNX1', from, 'ubiquitin-mediated', degradation])].
[sujeto(['RUNX1/CBFβ']), verbo([recruits]), complemento(['MLL', to, regulate, downstream, target, genes])].
[sujeto(['However,', the, functional, consequence, of, 'MLL', fusions, on, 'RUNX1/CBFβ', activity]), verbo([has]), complemento([not, been, fully, understood])].
[sujeto(['We', confirmed, this]), verbo([finding]), complemento([in, 'Mll-Af9', 'knock-in', mice, and, human, 'M4/M5', acute, myeloid, leukemia, '(', 'AML)', cell, 'lines,', with, or, without, 'MLL', 'translocations,', showing, that, 'MLL', translocations, cause, a, hypomorph, phenotype, of, 'RUNX1/CBFβ'])].
[sujeto(['Overexpression', of, 'RUNX1']), verbo([inhibits]), complemento([the, development, of, 'AML', in, 'Mll-Af9', 'knock-in', 'mice;', 'conversely,', further, reducing, 'Runx1/Cbfβ', levels, accelerates, 'MLL-AF9-mediated', 'AML', in, bone, marrow, transplantation, assays])].
[sujeto(['These', data]), verbo([reveal]), complemento([a, newly, defined, negative, regulation, of, 'RUNX1/CBFβ', by, 'MLL', fusion, proteins, and, suggest, that, targeting, 'RUNX1/CBFβ', levels, may, be, a, potential, therapy, for, 'MLLs'])].
[sujeto(['The', human, immunodeficiency, virus, '(', 'HIV)-1', protein, 'Vif']), verbo([has]), complemento([a, central, role, in, the, neutralization, of, host, innate, defences, by, hijacking, cellular, proteasomal, degradation, pathways, to, subvert, the, antiviral, activity, of, host, restriction, 'factors;', 'however,', the, underlying, mechanism, by, which, 'Vif', achieves, this, remains, unclear])].
[sujeto(['Here', we]), verbo([report]), complemento([a, crystal, structure, of, the, 'Vif-CBF-β-CUL5-ELOB-ELOC', complex])].
[sujeto(['The', structure]), verbo([reveals]), complemento([that, 'Vif,', by, means, of, two, 'domains,', organizes, formation, of, the, pentameric, complex, by, interacting, with, 'CBF-β,', 'CUL5', and, 'ELOC'])].
[sujeto(['The', larger, domain, '(', 'α/β', 'domain)', of, 'Vif']), verbo([binds]), complemento([to, the, same, side, of, 'CBF-β', as, 'RUNX1,', indicating, that, 'Vif', and, 'RUNX1', are, exclusive, for, 'CBF-β', binding])].
[sujeto(['Together,', our, data]), verbo([reveal]), complemento([the, structural, basis, for, 'Vif', hijacking, of, the, 'CBF-β', and, 'CUL5', 'E3', ligase, 'complex,', laying, a, foundation, for, rational, design, of, novel, 'anti-HIV', drugs])].
[sujeto(['Different', mechanisms, for, 'CBFβ-MYH11', function, in, acute, myeloid, leukemia, with, 'inv(16)']), verbo([have]), complemento([been, proposed, such, as, tethering, of, 'RUNX1', outside, the, 'nucleus,', interference, with, transcription, factor, complex, assembly, and, recruitment, of, histone, 'deacetylases,', all, resulting, in, transcriptional, repression, of, 'RUNX1', target, genes])].
[sujeto(['Here,', through, 'genome-wide', 'CBFβ-MYH11-binding', site, analysis, and, quantitative, interaction, 'proteomics,', we]), verbo([found]), complemento([that, 'CBFβ-MYH11', localizes, to, 'RUNX1', occupied, 'promoters,', where, it, interacts, with, 'TAL1,', 'FLI1', and, 'TBP-associated', factors, '(', 'TAFs)', in, the, context, of, the, hematopoietic, transcription, factors, 'ERG,', 'GATA2', and, 'PU'])].
[sujeto(['Transcriptional', analysis, revealed, that, upon, fusion, protein, 'knockdown,', a, small, subset, of, the, 'CBFβ-MYH11']), verbo([target]), complemento([genes, show, increased, 'expression,', confirming, a, role, in, transcriptional, repression])].
[sujeto(['However,', the, majority, of, 'CBFβ-MYH11']), verbo([target]), complemento(['genes,', including, genes, implicated, in, hematopoietic, stem, cell, 'self-renewal', such, as, 'ID1,', 'LMO1', and, 'JAG1,', are, actively, transcribed, and, repressed, upon, fusion, protein, knockdown])].
[sujeto(['Together', these, results]), verbo([suggest]), complemento([an, essential, role, for, 'CBFβ-MYH11', in, regulating, the, expression, of, genes, involved, in, maintaining, a, stem, cell, phenotype])].
[sujeto(['The', rare, but, recurrent, 'RUNX1-USP42', fusion, gene, is, the, result, of, a, 't(7;21)(p22;q22)', chromosomal, translocation, and]), verbo([has]), complemento([been, described, in, 6, cases, of, acute, myeloid, leukemia, '(', 'AML)', and, one, case, of, refractory, anemia, with, excess, of, blast])].
[sujeto(['The', bone, marrow, cells, in, the, present, case, also, had, a, 5, q, 'deletion,', and, it, was, revealed, that, 5, out, of, the, 8]), verbo([reported]), complemento([cases, '(', including, the, present, 'case)', with, 't(7;21)(p22;q22)/RUNX1-USP42', also, had, cytogenetic, abnormalities, of, 5, q])].
[sujeto(['Most', patients, with, acute, myeloid, leukemia, '(', 'AML)', and, genetic, rearrangements]), verbo([involving]), complemento([the, core, binding, factor, '(', 'CBF)', have, favorable, prognosis])].
[sujeto(['In', 'contrast,', a, minority, of, them, still]), verbo([have]), complemento([a, high, risk, of, leukemia, recurrence])].
[sujeto(['In', multivariate, 'analyses,', leukocyte, count, above, 20, &, 'nbsp;×&nbsp;10(9)', /, 'L,', 'BAALC', 'over-expression,', and, high, copy, numbers, of, 'RUNX1-RUNXT1', or, 'CBFB-MYH11', after, induction, chemotherapy, '(', 'CT)']), verbo([led]), complemento([to, increased, relapse, rate])].
[sujeto(['Regarding', 'OS,', age, &, 'gt;50&nbsp;yr,', leukocyte, count, above, 20, &, 'nbsp;×&nbsp;10(9)', /, 'L,', and]), verbo([increased]), complemento(['MN1', expression, were, adverse, features])].
[sujeto(['Core']), verbo([binding]), complemento([factor, '(', 'CBF)-positive', acute, myeloid, leukemia, '(', 'AML)', presents, a, favorable, 'prognosis,', except, for, patients, with, 'KIT', 'mutation,', especially, 'D816', mutation])].
[sujeto(['The', study, patients, consisted, of, 121, patients, with, 'CBF', 'AML', '(', 82, patients, with, 'RUNX1/RUNX1T1', '[', 67.8, &, 'nbsp;%]', and, 39, patients, with, 'CBFB/MYH11', '[', 32.2, &, 'nbsp;%])']), verbo([recruited]), complemento([from, eight, institutions, in, 'Korea'])].
[sujeto(['The', presence, of, 'KIT', 'D816', mutation, was]), verbo([associated]), complemento([with, adverse, outcomes, for, the, 'event-free', survival, '(', p, =, 0.03, ')', and, for, the, overall, survival, '(', p, =, 0.02, ')'])].
[sujeto(['Core']), verbo([binding]), complemento([factor, '(', 'CBF)', 'leukemias,', those, with, translocations, or, inversions, that, affect, transcription, factor, genes, 'RUNX1', or, 'CBFB,', account, for, '~24%', of, adult, acute, myeloid, leukemia, '(', 'AML)', and, 25, '%', of, pediatric, acute, lymphocytic, leukemia, '(', 'ALL)'])].
[sujeto(['Current', treatments, for, 'CBF', leukemias, are]), verbo([associated]), complemento([with, significant, morbidity, and, 'mortality,', with, a, 5, -, y, survival, rate, of, '~50%'])].
[sujeto(['We', hypothesize, that, the, interaction, between, 'RUNX1', and, 'CBFβ', is, critical, for, 'CBF', leukemia, and, can, be]), verbo([targeted]), complemento([for, drug, development])].
[sujeto(['Ro5-3335,', a, benzodiazepine, identified, from, the, 'screen,', was, able, to]), verbo([interact]), complemento([with, 'RUNX1', and, 'CBFβ', 'directly,', repress, 'RUNX1/CBFB-dependent', transactivation, in, reporter, 'assays,', and, repress, 'runx1-dependent', hematopoiesis, in, zebrafish, embryos])].
[sujeto(['Our', data, thus, confirmed, that, 'RUNX1-CBFβ', interaction, can, be]), verbo([targeted]), complemento([for, leukemia, treatment, and, we, have, identified, a, promising, lead, compound, for, this, purpose])].
[sujeto(['The', clinical, value, of, serial, minimal, residual, disease, '(', 'MRD)', monitoring, in, core]), verbo([binding]), complemento([factor, '(', 'CBF)', acute, myeloid, leukemia, '(', 'AML)', by, quantitative, 'RT-PCR', was, prospectively, assessed, in, 278, patients, '[', 163, with, 't(8;21)', and, 115, with, 'inv(16)]', entered, in, the, 'United', 'Kingdom', 'MRC', 'AML', 15, trial])].
[sujeto(['During', 'follow-up,', 'cut-off', 'MRD', thresholds, in, 'BM', and, 'PB']), verbo([associated]), complemento([with, a, 100, '%', relapse, rate, were, 'identified:', for, 't(8;21)', patients, 'BM', &, 'gt;', 500, 'copies,', 'PB', &, 'gt;', 100, 'copies;', for, 'inv(16)', 'patients,', 'BM', &, 'gt;', 50, copies, and, 'PB', &, 'gt;', 10, copies])].
[sujeto(['Breast', carcinoma, is, the]), verbo([leading]), complemento([cause, of, 'cancer-related', mortality, in, women, 'worldwide,', with, an, estimated, 1.38, million, new, cases, and, 458, ',', 0, deaths, in, 2008, alone])].
[sujeto(['Recurrent', somatic, alterations, in, breast, cancer]), verbo([have]), complemento([been, 'described,', including, mutations, and, copy, number, 'alterations,', notably, 'ERBB2', 'amplifications,', the, first, successful, therapy, target, defined, by, a, genomic, aberration])].
[sujeto(['Previous', 'DNA', sequencing, studies, of, breast, cancer, genomes]), verbo([have]), complemento([revealed, additional, candidate, mutations, and, gene, rearrangements])].
[sujeto(['Here', we]), verbo([report]), complemento([the, 'whole-exome', sequences, of, 'DNA', from, 103, human, breast, cancers, of, diverse, subtypes, from, patients, in, 'Mexico', and, 'Vietnam', compared, to, 'matched-normal', 'DNA,', together, with, 'whole-genome', sequences, of, 22, breast, 'cancer/normal', pairs])].
[sujeto(['Furthermore,', we]), verbo([have]), complemento([identified, a, recurrent, 'MAGI3-AKT3', fusion, enriched, in, 'triple-negative', breast, cancer, lacking, oestrogen, and, progesterone, receptors, and, 'ERBB2', expression])].
[sujeto(['The', 'MAGI3-AKT3', fusion]), verbo([leads]), complemento([to, constitutive, activation, of, 'AKT', 'kinase,', which, is, abolished, by, treatment, with, an, 'ATP-competitive', 'AKT', 'small-molecule', inhibitor])].
[sujeto(['Osteoarthritis', '(', 'OA)', is, a, degenerative, joint, disease, that]), verbo([involves]), complemento([the, destruction, of, articular, cartilage, and, eventually, leads, to, disability])].
[sujeto(['Molecules', that]), verbo([promote]), complemento([the, selective, differentiation, of, multipotent, mesenchymal, stem, cells, '(', 'MSCs)', into, chondrocytes, may, stimulate, the, repair, of, damaged, cartilage])].
[sujeto(['Using', an, 'image-based', 'high-throughput', 'screen,', we, identified, the, small, molecule, 'kartogenin,', which]), verbo([promotes]), complemento([chondrocyte, differentiation, '(', median, effective, concentration, =, 100, 'nM),', shows, chondroprotective, effects, in, 'vitro,', and, is, efficacious, in, two, 'OA', animal, models])].
[sujeto(['Kartogenin']), verbo([binds]), complemento([filamin, 'A,', disrupts, its, interaction, with, the, transcription, factor, 'core-binding', factor, β, subunit, '(', 'CBFβ),', and, induces, chondrogenesis, by, regulating, the, 'CBFβ-RUNX1', transcriptional, program])].
[sujeto(['This', work]), verbo([provides]), complemento([new, insights, into, the, control, of, chondrogenesis, that, may, ultimately, lead, to, a, stem, 'cell-based', therapy, for, osteoarthritis])].
[sujeto(['Yet', the, mechanisms, that]), verbo([target]), complemento(['PRCs', to, specific, loci, in, mammalian, cells, remain, incompletely, understood])].
[sujeto(['In', this, study, we, show, that, 'Bmi1,', a, core, component, of, 'Polycomb', 'Repressive', 'Complex', 1, '(', 'PRC1),']), verbo([binds]), complemento([directly, to, the, 'Runx1/CBFβ', transcription, factor, complex])].
[sujeto(['Genome-wide', studies, in, megakaryocytic, cells, demonstrate, significant, chromatin, occupancy, overlap, between, the, 'PRC1', core, component, 'Ring1b', and, 'Runx1/CBFβ', and, functional, regulation, of, a, considerable, fraction, of, commonly]), verbo([bound]), complemento([genes])].
[sujeto(['We', also, show, that, 'Ring1b', occupies, key, 'Runx1']), verbo([binding]), complemento([sites, in, primary, murine, thymocytes, and, that, this, occurs, via, 'PRC2-independent', mechanisms])].
[sujeto(['Genetic', depletion, of, 'Runx1', results, in, reduced, 'Ring1b']), verbo([binding]), complemento([at, these, sites, 'in&nbsp;vivo'])].
[sujeto(['These', findings]), verbo([provide]), complemento([evidence, for, 'site-specific', 'PRC1', chromatin, recruitment, by, core, binding, transcription, factors, in, mammalian, cells])].
[sujeto(['An', active, search, for, them, may]), verbo([provide]), complemento([both, pathogenetic, and, prognostic, novel, information])].
[sujeto(['ETV6/RUNX1', displayed, discordance, between, fusion, transcript, assay, and, 'FISH', results, as, well, as, rare, 'non-specific']), verbo([binding]), complemento([in, 'AL', samples, with, normal, or, complex, cytogenetics])].
[sujeto(['The', identification, of, minimal, residual, disease, '(', 'MRD)']), verbo([has]), complemento([led, to, substantial, improvements, in, early, recognition, of, the, recurrence, of, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['Besides,', more, than, 50, '%', of, all, 'AML', patients, lack, one, of, these, specific, 'sequences,', so, it, is, crucial, to, identify, molecular]), verbo([targets]), complemento([applicable, for, the, majority, of, patients])].
[sujeto(['These', features]), verbo([have]), complemento([led, to, its, adoption, for, 'MRD', detection, using, 'RQ-PCR'])].
[sujeto(['A', 'European', 'LeukemiaNet', 'Study']), verbo([found]), complemento([the, magnitude, of, 'WT1', log, reduction, after, induction, chemotherapy, to, be, an, independent, predictor, of, relapse])].
[sujeto(['Finally,', some, authors]), verbo([translated]), complemento([the, use, of, 'WT1', in, the, clinic, giving, donor, lymphocytes, infusions, to, patients, with, increasing, 'WT1-mRNA', levels, after, allogeneic, stem, cell, transplantation, and, obtaining, an, improvement, of, survival, in, this, subset])].
[sujeto(['Data', collected, on, 'WT1', expression, over, the, past, years]), verbo([provided]), complemento([evidence, for, the, use, of, this, molecular, marker, to, stratify, 'high-risk', 'AML', patients])].
[sujeto(['NanoString', nCounter, system, is, a, novel, 'probe-based', gene, expression, platform, capable, of, measuring, up, to, 800]), verbo([targets]), complemento([with, advantages, of, 'reproducibility,', 'accuracy,', and, sample, type, flexibility])].
[sujeto(['To', examine, the, value, of, minimal, residual, disease, '(', 'MRD)', by, multiparameter, flow, cytometry, '(', 'MFC)', in, core]), verbo([binding]), complemento([factor, '(', 'CBF)', acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto([1, ',', 0.01, to, 0.1, ',', 0.1, to, 1, ',', 1, to, 10, ',', and, &, 'gt;10%,', and]), verbo([reporting]), complemento(['MFC', '(', 'sensitivity,', 0.1, '%', -, 0.01, '%', ')', as, positive, or, 'negative,', κ, coefficient, test, showed, no, agreement, between, 'qRT-PCR', and, 'MFC', in, 'BM', samples, obtained, postinduction, '(', n, =, 44, ',', κ, =, 0.041, ')', ',', and, only, weak, agreement, during, consolidation, '(', n, =, 108, ',', κ, =, 0.083, ')', ',', 'maintenance/follow-up', '(', n, =, 107, ',', κ, =, 0.164, ')', ',', and, salvage, chemotherapy, '(', n, =, 24, ',', 0.376, ')'])].
[sujeto([1, '%', was]), verbo([associated]), complemento([with, lower, and, '≥10%', with, higher, 'AML', relapse, risk, '(', 'P', =])].
[sujeto(['In', the, latter, group, with, intermediate, 'qRT-PCR', 'results,', 'MFC']), verbo([provided]), complemento([prognostic, value, for, relapse, '(', 'P', =, 0.006, ')'])].
[sujeto(['The', most, common, subgroups, were, 'KMT2A', rearrangement, '(', 29, '%', ')', ',', normal, karyotype, '(', 15, '%', ')', ',', 'RUNX1-RUNX1T1', '(', 10, '%', ')', ',', deletions, of, 5, 'q,', 7, q, 'and/or', 17, p, '(', 9, '%', ')', ',', myeloid, leukaemia]), verbo([associated]), complemento([with, 'Down', syndrome, '(', 7, '%', ')', ',', 'PML-RARA', '(', 7, '%', ')', and, 'CBFB-MYH11', '(', 5, '%', ')'])].
[sujeto(['Single', nucleotide, polymorphism, array, '(', 'SNP-A)', analysis, and, exon, sequencing, of, 100, 'genes,', performed, in, 52, and, 40, 'cases,', respectively, '(', 39, 'overlapping),', revealed, '≥1', aberration, in, 89, '%', ;, when, adding, cytogenetic, 'data,', this, frequency]), verbo([increased]), complemento([to, 98, '%'])].
[sujeto(['Twenty-two', genes, were]), verbo([targeted]), complemento([by, focal, 'CNAs,', including, 'AEBP2', and, 'PHF6', deletions, and, genes, involved, in, 'AML-associated', gene, fusions])].
[sujeto(['In', 'total,', 60, mutations, were]), verbo([found]), complemento([in, 30, 'genes,', primarily, those, encoding, signalling, proteins, '(', 47, '%', ')', ',', transcription, factors, '(', 25, '%', ')', ',', or, epigenetic, modifiers, '(', 13, '%', ')'])].
[sujeto(['It', is]), verbo([required]), complemento([for, fetal, liver, hematopoiesis, and, skeletal, development])].
[sujeto(['Cbfb']), verbo([has]), complemento([two, functional, 'isoforms,', 'Cbfb1', and, 'Cbfb2,', which, are, formed, by, alternative, splicing])].
[sujeto(['Intramembranous', and, endochondral, ossification, was, retarded, and, chondrocyte, and, osteoblast, differentiation, was]), verbo([inhibited]), complemento([in, 'Cbfb2(-/-)', embryos, but, not, in, 'Cbfb1(-/-)', embryos])].
[sujeto(['Furthermore,', the, amounts, of, 'Runx', proteins, and, 'Cbfb', in, 'Cbfb2(-/-)', embryos, differed, similarly, among, skeletal, 'tissues,', 'livers,', and, 'thymuses,']), verbo([suggesting]), complemento([that, 'Runx', proteins, and, 'Cbfb', are, mutually, required, for, their, stability])].
[sujeto(['Although', 'Cbfb1(-/-)', embryos, developed, 'normally,', 'Cbfb1']), verbo([induced]), complemento([chondrocyte, and, osteoblast, differentiation, and, enhanced, 'DNA', binding, of, 'Runx2', more, efficiently, than, 'Cbfb2'])].
[sujeto(['Cbfb2', was, more, 'abundant,', but, 'Cbfb1', was, more, potent, for]), verbo([enhancing]), complemento(['Runx2', activity])].
[sujeto(['Although', only, 'Cbfb2']), verbo([loss]), complemento([generated, overt, skeletal, 'phenotypes,', both, may, play, major, roles, in, skeletal, development, with, functional, redundancy])].
[sujeto(['Genetic', alterations, such, as, chromosomal, 'translocations,', copy, number, variations, and, point, mutations]), verbo([have]), complemento([been, widely, reported, to, result, in, the, malfunction, of, 'RUNX', transcription, factors])].
[sujeto(['Leukemias', arising, from, such, alterations, in, 'RUNX', family, genes, are, collectively, termed, core]), verbo([binding]), complemento([factor, '(', 'CBF)', leukemias])].
[sujeto(['Over', the, 'years,', retroviral, 'transduction-transplantation', assays, and, 'transgenic,', knockin, and, knockout, mouse, models, alone, or, in, combination, with, mutagenesis]), verbo([have]), complemento([been, used, to, study, the, roles, of, 'RUNX', alterations, in, leukemogenesis])].
[sujeto(['Although', successful, in]), verbo([inducing]), complemento(['leukemia,', the, existing, assays, and, models, possess, many, inherent, limitations])].
[sujeto(['A', 'CBF', leukemia, model, which]), verbo([induces]), complemento([leukemia, with, complete, penetrance, and, short, latency, would, be, ideal, as, a, platform, for, drug, discovery])].
[sujeto(['Here,', we, summarize, the, currently, available, mouse, models, which]), verbo([have]), complemento([been, utilized, to, study, 'CBF', 'leukemias,', discuss, the, advantages, and, limitations, of, individual, experimental, 'systems,', and, propose, suggestions, for, improvements, of, mouse, models])].
[sujeto(['In', a, patient, with, acute, myeloid, leukemia, '(', 'AML)', following, 'therapy,']), verbo([finding]), complemento(['≥5%', bone, marrow, '(', 'BM)', blasts, is, highly, concerning, for, 'residual/relapsed', disease])].
[sujeto(['The', receptor, tyrosine, kinase, 'KIT', is]), verbo([expressed]), complemento([in, the, vast, majority, of, these, acute, myeloid, leukemias, and, frequent, activating, 'KIT', gene, mutations, have, been, associated, with, a, higher, risk, of, relapse])].
[sujeto(['The', disappearance, of, 'KIT', gene, mutations, at, relapse]), verbo([suggests]), complemento([that, clonal, devolution, may, in, part, explain, the, absence, of, efficacy, observed, with, 'single-agent', dasatinib, in, these, patients, '(', n])].
[sujeto(['In', acute, myeloid, leukaemia, '(', 'AML),', the, presence, of, 't(8;21)(q22;q22)', and, 'inv(16)(p13q22)/t(16;16)(p13;q22)', 'and/or', the, corresponding, molecular, rearrangements, 'RUNX1/RUNX1T1', and, 'CBFB/MYH11', '[', collectively, referred, to, as, core]), verbo([binding]), complemento([factor, '(', 'CBF)', 'AML]', predict, for, a, more, favourable, outcome, in, patients, receiving, 'cytarabine-anthracycline', based, induction, and, upon, achievement, of, complete, 'remission,', 'high-dose', cytarabine, consolidation, chemotherapy])].
[sujeto(['Clinical', studies, with]), verbo([targeting]), complemento([compounds, '(', e])].
[sujeto([gemtuzumab, 'ozogamicin,', 'dasatinib)', added, to, intensive, chemotherapy, appear, beneficial, both, in, younger, and, older, 'patients,', albeit, the, latter, continue, to]), verbo([have]), complemento([a, significantly, worse, outcome, than, the, former])].
[sujeto(['Regularly', molecular, monitoring, of, disease, during, remission, may]), verbo([provide]), complemento([a, strategy, for, early, therapeutic, intervention, before, overt, relapse])].
[sujeto(['Core-binding', factor, acute, myeloid, leukemia, '(', 'CBF-AML)', -, including, 'AML', with, 't(8;21)', and, 'AML', with, 'inv(16)', -, accounts, for, about, 15, '%', of, adult, 'AML', and, is]), verbo([associated]), complemento([with, a, relatively, favorable, prognosis])].
[sujeto(['Due', to, similarities, between, their, molecular, and, prognostic, 'features,', 't(8;21)', and, 'inv(16)-AML', are, usually, grouped, and]), verbo([reported]), complemento([together, in, clinical, studies])].
[sujeto(['However,', considerable, experimental, evidences]), verbo([have]), complemento([highlighted, that, they, represent, two, distinct, entities, and, should, be, considered, separately, for, further, studies])].
[sujeto(['The', diagnostics, of, leukemia, relies, upon, 'multi-parametric', approach]), verbo([involving]), complemento([a, number, of, different, pathology, disciplines, such, as, flow, 'cytometry,', 'histopathology,', cytogenetics, and, molecular, genetics, '[', fluorescent, in, situ, hybridization, '(', 'FISH)', and, polymerase, chain, reaction, '(', 'PCR)]'])].
[sujeto(['In', the, last, two, 'decades,', several, studies]), verbo([have]), complemento([reported, observations, that, 'PFG', are, present, in, healthy, population, and, not, necessarily, result, in, leukemia])].
[sujeto(['The', first, such, study, by, 'Limpens', and, colleagues, on, 't(14/18)/', 'BCL2-JH', '[', 1, ']', and, next, in, line, '[', 2, ',', 3, ']']), verbo([led]), complemento([to, many, questions, regarding, the, significance, of, these, chromosomal, translocations, in, leukemogenesis])].
[sujeto(['Translocation', 't(8;21)/', 'AML1', 'ETO', was]), verbo([found]), complemento([in, 4.4, '%', of, patients, with, a, mean, age, of, 45.4, 'years,', while, none, of, these, patients, was, older, than, 55, years])].
[sujeto(['Translocation', 't(15;17)/', 'PMLRARA', was]), verbo([found]), complemento([in, 5.5, '%', of, patients, with, a, mean, age, of, 52.6, years, and, an, almost, equal, distribution, between, younger, and, older, patients])].
[sujeto(['The', 'MLL', gene, rearrangements, were]), verbo([found]), complemento([in, 6.6, '%', of, 'patients,', the, -, 5, /, 5, 'q-', 'and/', or, -, 7, /, 7, 'q-', aberrations, in, 7.7, '%', of, 'patients,', while, the, most, frequent, genetic, abnormality, in, our, study, was, trisomy, 8, '(', 10, '%', ')'])].
[sujeto(['Moreover,', we]), verbo([found]), complemento([a, favorable, clinical, outcome, in, patients, expressing, fusion, genes, 'AML1-ETO', or, 'PMLRARA', in, contrast, to, an, adverse, clinical, outcome, with, few, remissions, and, death, in, 'AML', patients, with, 'MLL,', -, 5, 'q/', -, 5, and, -, 7, 'q/', 7, -])].
[sujeto(['Finally,', an, intermediate, prognosis, was]), verbo([found]), complemento([in, patients, with, trisomy, 8])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([a, good, congruence, with, published, literature, on, the, incidence, and, prognostic, value, of, several, well, established, 'AML-associated', genetic, aberrations])].
[sujeto(['The', multiplex, 'RT-nPCR', used, in, this, study, can, 'quickly,', effectively, and, accurately, screen, the, fusion, genes, in, 'AML', 'patients,', which, can]), verbo([provide]), complemento([important, evidence, for, assessing, diagnosis, and, 'treatment,', and, also, provide, necessary, information, for, minimal, residual, disease, '(', 'MRD)', and, prognosis])].
[sujeto(['Within', the, past, few, 'years,', the, invention, of, 'next-generation', sequencing]), verbo([has]), complemento([revealed, several, new, genes, associated, with, tumor, formation, and, 'development,', for, example, 'DNMT3a'])].
[sujeto(['PCR', amplification, of, the, entire, coding, region, of, 'DNMT3a', was, performed, using, 23, overlapping]), verbo([primer]), complemento([pairs, in, 57, patients, who, were, diagnosed, in, 'Blood', 'Disease', 'Hospital', of, 'Chinese', 'Academy', of, 'Medical', 'Sciences,', then, the, directly, sequencing, was, underwent])].
[sujeto(['The', results, showed, that, no, 'DNMT3a', mutation, was]), verbo([found]), complemento([in, these, patients, including, the, hotspot, 'R882'])].
[sujeto(['But', 'AML1/ETO', mutation, was]), verbo([found]), complemento([in, 10, 'patients,', 'CBFB/MYH11', mutation, in, 3, 'patients,', 'PML/RARa', mutation, in, 13, 'patients,', 'FLT3/ITD', mutation, in, 5, 'patients,', 'FLT3/TKD', mutation, in, 1, 'patient,', 'PML/RARa', and, 'FLT3/TKD', mutation, coexisted, in, 2, patients])].
[sujeto(['Most', sensitive, methodology, to, detect, 'MRD', is, molecular, polymerase, chain, reaction, '(', 'PCR)', but, its, applicability, is, restricted, to, 'AML', with, 'leukemia-specific', molecular]), verbo([targets]), complemento(['(', e])].
[sujeto(['To', realize, the, methodology, that, better, identify, high, risk, 'patients,', an, analysis, of, 'sensitivity,', 'specificity,', predictive, values, '(', 'PV)', and, likelihood, ratio, '(', 'LR)', was]), verbo([provided]), complemento([and, similar, results, were, showed])].
[sujeto([1, ;, 'q22);', 'CBFB-MYH11', chromosomal, 'rearrangements,', but, whether, the, mutation, is, indicative, of]), verbo([associated]), complemento(['SM', is, unclear])].
[sujeto(['Five', of, the, eight, cases, carried, the, mutation, in, a, cell, fraction, below, 'one-tenth', of, the, blast, cell, 'fraction,', thus]), verbo([suggesting]), complemento([that, 'KIT', mutation, is, often, a, late, event, in, leukemogenesis])].
[sujeto(['The', presence, of, the, 'KIT', 'D816V', mutation, in, the, 'CBF', 'AML', subgroup, can, therefore, not, be, considered, indicative, of]), verbo([associated]), complemento(['SM'])].
[sujeto(['The', rearrangements, 't(8;21)', and, 'inv(16)']), verbo([involve]), complemento([the, 'RUNX1/RUNX1T1', '(', 'AML1-ETO', ')', and, 'CBFB/MYH11', 'genes,', respectively])].
[sujeto(['The', 't(8;21)', and, 'inv(16)', subtypes, of, 'AML']), verbo([have]), complemento([been, usually, grouped, and, reported, together, in, clinical, 'studies;', 'however,', recent, studies, have, demonstrated, 'genetic,', 'clinical,', and, prognostic, 'differences,', supporting, the, notion, that, they, represent, 2, distinct, biologic, and, clinical, entities])].
[sujeto(['No', correlation, was, observed, between, incidence, and, age, except, for, 'BCR-ABL', p210, 'fusion,', the, incidence, of, which, rises, with]), verbo([increasing]), complemento([age])].
[sujeto(['To', our, 'knowledge,', the, presence, of, 'PML-RARA', and, 'CBFB-MYH11', in, healthy, individuals]), verbo([has]), complemento([not, been, previously, described])].
[sujeto(['The', present, study]), verbo([provides]), complemento([further, evidence, for, the, presence, of, 'LLA', genetic, alterations, in, healthy, individuals, and, suggests, that, these, mutations, are, not, themselves, sufficient, for, malignant, transformation])].
[sujeto(['AML1-ETO', fusion, gene, transcript, was]), verbo([found]), complemento([in, 14, patients, '(', 19, '%', ')'])].
[sujeto(['Duplication', of, 'FLT3', gene, was]), verbo([found]), complemento([in, 4, '(', 5.3, '%', ')', cases])].
[sujeto(['Analysis', of, 'MRD', level, in, subsequent, time, points, showed, systematic]), verbo([decrease]), complemento([of, number, of, fusion, gene, transcript, copies, and, gene, 'WT1', expression])].
[sujeto(['To', establish, the, rate, of, molecular, marker, presence, in, 'AML', in, children, and, the, influence, of, the, presence, of, 'MRD', on, the, treatment, results, as, 'well,', the, study]), verbo([has]), complemento([to, be, conducted, on, a, larger, group, of, patients, with, longer, 'follow-up'])].
[sujeto(['Many', oncogenetic, aberrations, in, acute, leukemias, result, in, a, fusion, 'gene,', which, is]), verbo([transcribed]), complemento([into, fusion, transcripts, and, translated, into, fusion, 'proteins,', which, are, assumed, to, play, a, critical, role, in, the, oncogenetic, process])].
[sujeto(['So', 'far,', we]), verbo([have]), complemento([been, able, to, design, such, fusion, protein, immunobead, assays, for, 'BCR-ABL,', 'PML-RARA,', 'TEL-AML1,', 'E2A-PBX1,', 'MLL-AF4,', 'AML1-ETO', and, 'CBFB-MYH11'])].
[sujeto(['The', novel, immunobead, assay, will, enable, fast, and, easy, classification, of, acute, leukemia, patients, that]), verbo([express]), complemento([fusion, proteins])].
[sujeto(['Fluorescence', in, situ, hybridization, '(', 'FISH)', analysis, can]), verbo([provide]), complemento([important, information, in, the, management, of, patients, with, hematologic, malignancies])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, performing, 'FISH', in, addition, to, 'G-banded', karyotype, may, contribute, little, additional, genetic, information, in, 'AML', and, 'MDS,', whereas, routine, 'FISH', analysis, appears, to, be, an, efficient, screening, method, in, 'ALL', and, 'MM'])].
[sujeto(['In', a, 'large-scale', miRNA, expression, profiling, analysis, of, 435, human, miRNAs, in, 52, acute, myeloid, leukemia, '(', 'AML)', 'samples,', we]), verbo([found]), complemento([that, 'miR-126', and, its, minor, counterpart, in, 'biogenesis,', 'namely,', 'miR-126*,', were, specifically, aberrantly, overexpressed, in, core, binding, factor, '(', 'CBF)', 'AMLs', including, both, 't(8;21)/AML1-ETO', and, 'inv(16)/CBFB-MYH11', samples])].
[sujeto(['Our', in, vitro, 'gain-', and, 'loss-of-function', experiments, showed, that, forced, expression, of, 'miR-126']), verbo([inhibited]), complemento([apoptosis, and, increased, the, viability, of, 'AML', 'cells,', whereas, the, opposite, effect, was, observed, when, endogenous, expression, of, 'miR-126', was, knocked, down])].
[sujeto(['In', 'addition,', through, in, vitro, 'colony-forming/replating', 'assays,', we, demonstrated, that, forced, expression, of, 'miR-126']), verbo([enhanced]), complemento([proliferation, and, 'colony-forming/replating', capacity, of, mouse, normal, bone, marrow, progenitor, cells, alone, and, 'particularly,', in, cooperation, with, 'AML1-ETO,', a, fusion, gene, resulting, from, 't(8;21)'])].
[sujeto(['Aberrant', promoter, 'DNA', methylation]), verbo([has]), complemento([been, shown, to, play, a, role, in, acute, myeloid, leukemia, '(', 'AML)', pathophysiology])].
[sujeto(['Methylation', signatures, were]), verbo([associated]), complemento([with, the, presence, of, a, specific, cytogenetic, status])].
[sujeto(['The', presence, of, 'MLL', rearrangements, in, 'HSPC']), verbo([induced]), complemento([the, methylation, profile, observed, in, the, 'MLL-positive', primary, samples])].
[sujeto(['Our', study]), verbo([provides]), complemento([a, comprehensive, epigenetic, profiling, of, 'AML,', identifies, new, clinical, markers, for, cases, with, a, normal, 'karyotype,', and, reveals, relevant, biological, information, related, to, the, role, of, fusion, proteins, on, the, methylation, signature])].
[sujeto(['Inv(16)(p13q22)', is]), verbo([associated]), complemento([with, acute, myeloid, leukemia, subtype, 'M4Eo', that, is, characterized, by, the, presence, of, myelomonocytic, blasts, and, atypical, eosinophils])].
[sujeto(['CBF', beta, normally]), verbo([interacts]), complemento([with, 'RUNX1', to, form, a, transcriptionally, active, nuclear, complex])].
[sujeto(['The', 'CBF', 'beta-SMMHC', fusion, protein, is, capable, of]), verbo([binding]), complemento([to, 'RUNX1', and, form, dimers, and, multimers, through, its, myosin, tail])].
[sujeto(['Previous', results, from, transgenic, mouse, models, show, that, 'Cbfb-MYH11', is, able, to]), verbo([inhibit]), complemento([dominantly, 'Runx1', function, in, 'hematopoiesis,', and, is, a, key, player, in, the, pathogenesis, of, leukemia])].
[sujeto(['In', recent, 'years,', molecular, and, cellular, biological, studies]), verbo([have]), complemento([led, to, the, proposal, of, several, models, to, explain, the, function, of, 'CBF', 'beta-SMMHC'])].
[sujeto(['Core-binding', factor, beta, '(', 'CBFbeta,', also, called, polyomavirus, enhancer]), verbo([binding]), complemento([protein, 2, beta, '(', 'PEBP2B))', is, associated, with, an, inversion, of, chromosome, 16, and, is, associated, with, acute, myeloid, leukemia, in, humans])].
[sujeto(['CBFbeta', forms, a, heterodimer, with, 'RUNX1', '(', 'runt-related', transcription, factor, 1, ')', ',', which]), verbo([has]), complemento([a, 'DNA', binding, domain, homologous, to, the, 'pair-rule', protein, runt, in, 'Drosophila', melanogaster])].
[sujeto(['Haploinsufficiency', of, another, 'runt-related', 'protein,', 'RUNX2', '(', also, called, 'CBFA1),']), verbo([causes]), complemento([cleidocranial, dysplasia, in, humans, and, is, essential, in, skeletal, development, by, regulating, osteoblast, differentiation, and, chondrocyte, maturation])].
[sujeto(['Mice', deficient, in, 'Cbfb', '(', 'Cbfb(-/-))', die, at, 'midgestation,', so, the, function, of, 'Cbfbeta', in, skeletal, development]), verbo([has]), complemento([yet, to, be, ascertained])].
[sujeto(['Electrophoretic', mobility, shift, assays, and, reporter, assays, showed, that, 'Cbfbeta', was, necessary, for, the, efficient, 'DNA']), verbo([binding]), complemento([of, 'Runx2', and, for, 'Runx2-dependent', transcriptional, activation])].
[sujeto(['These', findings, indicate, that, 'Cbfbeta', is]), verbo([required]), complemento([for, the, function, of, 'Runx2', in, skeletal, development])].
[sujeto(['AML1/RUNX1', is, an, essential, transcription, factor]), verbo([involved]), complemento([in, the, differentiation, of, hematopoietic, cells])].
[sujeto(['AML1']), verbo([binds]), complemento([to, the, 'Runt-binding', 'double-stranded', 'DNA', element, '(', 'RDE)', of, target, genes, through, its, 'N-terminal', 'Runt', domain])].
[sujeto(['In', a, previous, 'study,', we, obtained, 'RNA', aptamers, against, the, 'AML1', 'Runt', domain, by, systematic, evolution, of, ligands, by, exponential, enrichment, and, revealed, that, 'RNA', aptamers, exhibit, higher, affinity, for, the, 'Runt', domain, than, that, for, 'RDE', and, possess, the, 5, '\'', -, 'GCGMGNN-3\'', and, 5, '\'', -, 'N\'N\'CCAC-3\'']), verbo([conserved]), complemento([motif, '(', 'M:', 'A', or, 'C;', 'N', and, 'N\'', form, 'Watson-Crick', base, 'pairs)', that, is, important, for, 'Runt', domain, binding])].
[sujeto(['In', this, 'study,', to, understand, the, structural, basis, of, recognition, of, the, 'Runt', domain, by, the, aptamer, 'motif,', the, solution, structure, of, a, 22, -, mer, 'RNA', was, determined, using]), verbo([nuclear]), complemento([magnetic, resonance])].
[sujeto(['Structural', analysis, of, the, aptamer, motif, indicated, that, the, aptamer]), verbo([binds]), complemento([to, the, 'Runt', domain, by, mimicking, the, 'RDE', sequence, and, structure])].
[sujeto(['Our', data, should]), verbo([enhance]), complemento([the, understanding, of, the, structural, basis, of, 'DNA', mimicry, by, 'RNA', molecules])].
[sujeto(['Runt-related', transcription, factor, 2, '(', 'Runx2)', and, muscle, segment, homeobox, homolog, 2, -]), verbo([interacting]), complemento([nuclear, target, '(', 'MINT)', '(', 'Spen', 'homolog)', are, transcriptional, regulators, critical, for, mammalian, development])].
[sujeto(['MINT']), verbo([enhances]), complemento(['Runx2', activation, of, osteocalcin, '(', 'OC)', fibroblast, growth, factor, '(', 'FGF)', response, element, in, an, 'FGF2-dependent', fashion, in, 'C3H10T1/2', cells])].
[sujeto(['Although', the, 'MINT', 'N-terminal', 'RNA', recognition, motif, domain, 'contributes,', the, muscle, segment, homeobox, homolog, 2, -]), verbo([interacting]), complemento([domain, is, sufficient, for, 'Runx2', activation])].
[sujeto(['Conversely,', phosphomimetic, 'Asp', substitution, of, these, 'AD3', 'Ser/Thr', residues]), verbo([enhanced]), complemento([activation, by, 'MINT'])].
[sujeto(['Systematic', screening, with, 'PDPK', inhibitors, identified, that, the, casein, 'kinase-2/homeodomain-interacting', protein, kinase, '(', 'HIPK)/dual', specificity, tyrosine, phosphorylation]), verbo([regulated]), complemento([kinase, inhibitor, 2, -, 'dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole', '(', 'DMAT),', but, not, 'ERK,', 'c-Jun', 'N-terminal', 'kinase,', 'p38MAPK,', or, other, casein, 'kinase-2', 'inhibitors,', abrogated, 'Runx2-,', 'MINT-,', and, 'FGF2-activation'])].
[sujeto(['HIPK3', and, 'Runx2', coprecipitate, after, in, vitro, 'transcription-translation,', and, recombinant, 'HIPK3']), verbo([recognizes]), complemento(['Runx2', 'AD3', as, kinase, substrate])].
[sujeto(['Furthermore,', 'DMAT', treatment, and, 'HIPK3', 'RNAi']), verbo([inhibited]), complemento(['MINT+FGF2', activation, of, 'Runx2', 'AD3,', and, nuclear, 'HIPK3', colocalized, with, 'MINT'])].
[sujeto(['Thus,', 'HIPK3']), verbo([participates]), complemento([in, 'MINT+FGF2', regulation, of, 'Runx2', 'AD3', activity, and, controls, 'Runx2-dependent', 'OC', expression])].
[sujeto(['Expression', of, the, 'IL-7R', 'alpha-chain', '(', 'IL-7Ralpha)', is, strictly]), verbo([regulated]), complemento([during, the, development, and, maturation, of, lymphocytes])].
[sujeto(['Glucocorticoids', '(', 'GC)']), verbo([have]), complemento([pleiotypic, effects, on, the, growth, and, function, of, lymphocytes])].
[sujeto(['Although', 'GC']), verbo([have]), complemento([been, reported, to, induce, the, transcription, of, 'IL-7Ralpha', gene, in, human, 'T', 'cells,', its, molecular, mechanism, is, largely, unknown])].
[sujeto(['This', effect, does, not]), verbo([require]), complemento([protein, synthesis, de, 'novo,', because, protein, synthesis, inhibitors, do, not, block, the, process])].
[sujeto(['Mouse', 'IL-7Ralpha', promoter]), verbo([has]), complemento([striking, homology, with, human, and, 'rat,', containing, consensus, motifs, of, 'Ikaros,', 'PU'])].
[sujeto(['In', 'addition,', a]), verbo([conserved]), complemento([noncoding, sequence, '(', 'CNS)', of, approximately, 270, bp, was, found, 3.6, -, kb, upstream, of, the, 'promoter,', which, was, designated, as, 'CNS-1'])].
[sujeto(['Importantly,', we, show, by, reporter, assay, that, the, 'IL-7Ralpha', promoter]), verbo([has]), complemento([specific, transcription, activity, in, 'T', cells])].
[sujeto(['We', also, demonstrate, that, 'GR']), verbo([binds]), complemento([to, the, 'GR', motif, by, 'EMSA'])].
[sujeto(['In', 'addition,', by, chromatin, immunoprecipitation, 'assay,', we, show, that, 'GR', is, rapidly]), verbo([recruited]), complemento([to, endogenous, 'CNS-1', chromatin, after, 'GC', stimulation])].
[sujeto(['These', results, demonstrate, that, 'GR']), verbo([binds]), complemento([to, the, 'GR', motif, in, the, 'CNS-1', region, after, 'GC', stimulation, and, then, activates, the, transcription, of, the, 'IL-7Ralpha', promoter])].
[sujeto(['The', 'RUNX3', gene, belongs, to, the, runt, domain, family, of, transcription, factors, that]), verbo([act]), complemento([as, master, regulators, of, gene, expression, in, major, developmental, pathways])].
[sujeto(['Two', large]), verbo([conserved]), complemento(['CpG', islands, were, found, within, both, 'genes,', one, around, exon, 2, and, the, other, at, the, beginning, of, exon, 6])].
[sujeto(['RUNX1,', 'RUNX2', and, 'RUNX3', gene, products]), verbo([bind]), complemento([to, the, same, 'DNA', 'motif,', hence, their, temporal, and, spatial, expression, during, development, should, be, tightly, regulated])].
[sujeto(['Structure/function', analysis, showed, that, two, promoter, 'regions,', designated, 'P1', and, 'P2,']), verbo([regulate]), complemento(['RUNX3', expression, in, a, cell, 'type-specific', manner])].
[sujeto(['Transfection', experiments, demonstrated, that, both, promoters, were, highly, active, in, the, 'GM1500', 'B-cell', 'line,', which, endogenously]), verbo([expresses]), complemento(['RUNX3,', but, were, inactive, in, the, 'K562', myeloid, cell, 'line,', which, does, not, express, 'RUNX3'])].
[sujeto(['We', specified, 43, genes, which, are, most, suitable, as, molecular, markers, of, 'PTC,', among, them, some, 'well-known', 'PTC', markers, '(', 'MET,', fibronectin, 1, ',', dipeptidylpeptidase, 4, ',', or, adenosine, 'A1', 'receptor)', and, potential, new, ones, '(', 'UDP-galactose-4-epimerase,', cadherin, 16, ',', gap, junction, protein, 3, ',', 'sushi,', 'nidogen,', and, 'EGF-like', domains, 1, ',', inhibitor, of, 'DNA']), verbo([binding]), complemento([3, ',', 'RUNX1,', leiomodin, 1, ',', 'F-box', protein, 9, ',', and, tripartite, 'motif-containing', 58, ')'])].
[sujeto(['Both', aging, rat, muscle, and, 'Sarco', mouse, muscle, exhibited, marked, 'fiber-type', 'grouping,', consistent, with, repeating, cycles, of, denervation, and, 'reinnervation,', yet, in, 'VO', 'muscle,', rapsyn, at, the, endplate]), verbo([increased]), complemento([and, was, associated, with, only, a, 10, &, 'nbsp;%', decline, in, acetylcholine, receptor, '(', 'AChR)', 'intensity,', whereas, in, 'Sarco', 'mice,', there, was, a, decline, in, rapsyn, and, a, 25, &, 'nbsp;%', decrease, in, 'AChR', intensity])].
[sujeto(['In', the, 'Sarco', 'mice,', there, were, much, smaller]), verbo([increases]), complemento([in, denervation, transcripts, '(', 0, -, 3.5, -, 'fold)', and, accumulation, of, very, small, fibers, '(', 2, -, 6, &, 'nbsp;%)', compared, to, the, 'VO', 'rat,', suggesting, a, reduced, capacity, for, reinnervation, in, aging, muscle])].
[sujeto(['Despite', the, marked, persistent, denervation, in, the, 'VO', rat, 'muscle,', transcripts, of, neurotrophins]), verbo([involved]), complemento([in, promoting, axonal, sprouting, following, denervation, exhibited, no, 'increase,', and, several, miRNAs, predicted, to, suppress, neurotrophins, were, elevated, in, 'VO', rat])].
[sujeto(['Our', results, support, the, hypothesis, that, the, accumulation, of, denervated, fibers, with, aging, is, due, to, failed, reinnervation, and, that, this, may, be, affected, by, a, limited, neurotrophin, response, that]), verbo([mediates]), complemento([axonal, sprouting, following, denervation])].
[sujeto(['An', appropriate, inflammatory, response, plays, critical, roles, in, eliminating, 'pathogens,', whereas, an, excessive, inflammatory, response, can]), verbo([cause]), complemento([tissue, damage])].
[sujeto(['Overexpression', of, 'RUNX1']), verbo([promoted]), complemento(['IL-1β', and, 'IL-6', production, in, response, to, 'LPS', stimulation])].
[sujeto(['Moreover,', 'RUNX1']), verbo([interacted]), complemento([with, the, 'NF-κB', subunit, 'p50,', and, coexpression, of, 'RUNX1', with, p50, further, enhanced, the, 'NF-κB', luciferase, activity])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, 'RUNX1', may, be, a, new, potential, target, for, resolving, 'TLR4-associated', uncontrolled, inflammation, and, preventing, sepsis])].
[sujeto(['Based', on, this, 'data,', it, was]), verbo([suggested]), complemento([that, the, 'well-recognized', 'phenotype-ameliorating', role, assigned, to, positive, 'XmnI', could, be, associated, with, its, linked, elements, in, the, 'LCR'])].
[sujeto(['To', investigate, the, functional, significance, of, polymorphisms, at, the, 5, '\'', 'HS4-LCR,', we, studied, its, influence, on]), verbo([binding]), complemento([of, transcription, factors])].
[sujeto(['Web-based', predictions, of, transcription, factor]), verbo([binding]), complemento([revealed, a, binding, site, for, 'runt-related', transcription, factor, 1, '(', 'RUNX1),', when, the, allele, at, the, center, of, the, palindrome, '(', 'TGGGG(A/G)CCCCA)', was, 'A', but, not, when, it, was, 'G'])].
[sujeto(['Furthermore,', electromobility, shift, assay, '(', 'EMSA)', presented, evidence, in, support, of, 'allele-specific']), verbo([binding]), complemento([of, 'RUNX1', to, 5, '\'', 'HS4'])].
[sujeto(['Considering', that, 'RUNX1', is, a, 'well-known', regulator, of, 'hematopoiesis,', these, preliminary, data]), verbo([suggest]), complemento([the, importance, of, further, studies, to, confirm, this, interaction, and, consequently, investigate, its, functional, and, phenotypical, relevance])].
[sujeto(['These', studies, could, help, us, to, understand, the, molecular, mechanism, behind, the, phenotype, modifying, role, of, the, 5, '\'', 'HS4-LCR', polymorphic, palindromic, region, '(', 'rs16912979),', which]), verbo([has]), complemento([been, observed, in, previous, studies])].
[sujeto(['Aberrant', expression, of, long, noncoding, 'RNAs']), verbo([has]), complemento([recently, been, reported, in, tumorigenesis, and, plays, a, pivotal, role, in, regulating, malignant, behavior, of, cancers])].
[sujeto(['Knockdown', of, 'HCP5']), verbo([inhibited]), complemento([the, malignant, biological, behavior, of, glioma, cells, by, reducing, 'proliferation,', migration, and, 'invasion,', and, inducing, apoptosis])].
[sujeto(['HCP5']), verbo([regulated]), complemento([the, malignant, behavior, of, glioma, cells, by, binding, to, 'microRNA-139,', which, functions, as, a, tumor, suppressor])].
[sujeto(['Moreover,', knockdown, of, 'HCP5', 'down-regulated', 'Runt-related', transcription, factor, 1, ',', a, direct, and, functional, downstream]), verbo([target]), complemento([of, 'microRNA-139', that, is, involved, in, 'microRNA-139-mediated', 'tumor-suppressive', effects, in, glioma, cells])].
[sujeto(['Runt-related', transcription, factor, 1]), verbo([increased]), complemento([promoter, activities, and, upregulated, expression, of, the, oncogenic, gene, astrocyte, elevated, 'gene-1', '(', 'AEG-1)'])].
[sujeto(['Runt-related', transcription, factor, 1, also]), verbo([increased]), complemento([the, promoter, activities, and, expression, of, 'HCP5,', which, showed, a, positive, feedback, loop, in, regulating, the, malignant, behavior, of, glioma, cells])].
[sujeto(['In', 'conclusion,', this, study, demonstrated, that, the, 'HCP5-microRNA-139-', 'Runt-related', transcription, factor, 1, feedback, loop, plays, a, pivotal, role, in]), verbo([regulating]), complemento([the, malignant, behavior, of, glioma, 'cells,', which, may, provide, a, potential, therapeutic, strategy, for, treating, glioma])].
[sujeto(['Chromosomal', abnormalities]), verbo([lead]), complemento([to, the, development, of, hematologic, malignancies, such, as, 'Myelodysplastic', 'Syndrome', '(', 'MDS)'])].
[sujeto(['Known', chromosomal, changes]), verbo([causing]), complemento(['MDS', include, deletion, of, the, long, arm, of, chromosome, 5, ',', 'runt-related', transcription, factor, 1, '(', 'RUNX1)', also, known, as, acute, myeloid, leukemia, 1, protein, '(', 'AML1),', and, very, rarely, fusion, genes, involving, 'RUNX1', at, 't(5;21)(q15;q22)'])].
[sujeto(['Therapy', was, started, with, 'Lenalidomide']), verbo([leading]), complemento([to, normal, blood, counts])].
[sujeto(['We']), verbo([report]), complemento([a, new, case, of, 't(5;21)(q15;q22)', involving, the, 'RUNX1', gene, and, 'del(5)(q13q33)', in, a, 'MDS', 'patient,', a, combination, of, chromosomal, abnormalities, heretofore, not, reported, in, the, literature])].
[sujeto(['RUNX1', rearrangement, is, usually]), verbo([associated]), complemento([with, an, adverse, prognosis, in, 'AML', and, 'MDS'])].
[sujeto(['Deletions', of, 5, q, are, typically]), verbo([associated]), complemento([with, poor, prognosis, in, 'AML,', however, it, is, usually, associated, with, a, favorable, prognosis, in, 'MDS'])].
[sujeto(['Our', patient]), verbo([responded]), complemento([very, well, to, 'Lenalidomide', therapy, with, achievement, of, 'CR'])].
[sujeto(['Lenalidomide', is, approved, for, treatment, of, anemia, in, low, and, intermediate, risk, 'MDS', with, del, '(', 5, 'q),', however, based, on, a, search, of, literature, it, seems, that, 'RUNX1', mutations, are, also, more, prominent, in, patients, who]), verbo([have]), complemento([responded, to, 'Lenalidomide', therapy])].
[sujeto(['Hence,', it, is, conceivable, that, our, patient, started, with, a, 5, q, minus, syndrome, and, then, acquired, the, second, hit, 'RUNX1', translocation]), verbo([leading]), complemento([to, an, accelerated, phase, of, myeloid, neoplasm, or, refractory, anemia, with, excess, 'blasts,', type, 1])].
[sujeto(['Hence,', the, temporal, relationship, between, acquisition, of, del, 5, q, and, 'RUNX1', rearrangement, may]), verbo([have]), complemento([influenced, the, clinical, outcome, and, possibly, response, to, therapy])].
[sujeto(['AAA', is]), verbo([caused]), complemento([by, segmental, weakening, of, the, aortic, walls, and, progressive, aortic, dilation, leading, to, the, eventual, rupture, of, the, 'aorta,', accompanied, by, intense, inflammation])].
[sujeto(['Additionally,', studies]), verbo([have]), complemento([indicated, a, close, relationship, between, the, pathogenesis, and, progression, of, 'AAA', and, cellular, immune, responses, in, aneurysm, wall, tissue])].
[sujeto(['There', are, no, proven, clinical, management, strategies, or, 'pharmaco-therapeutics', to]), verbo([prevent]), complemento(['AAA', progression, once, an, 'AAA', has, been, detected])].
[sujeto(['Moreover,', so, far, no, biomarkers]), verbo([have]), complemento([been, established, to, indicate, the, disease, status, of, 'AAA'])].
[sujeto(['Hence,', understanding, the, pathogenesis, of, 'AAA']), verbo([has]), complemento([recently, become, an, increasing, priority, in, basic, and, translational, vascular, research])].
[sujeto(['The', results, of, elevated, expression, of, 'RUNX', genes, and, their, relationships, in, the, 'AAA', tissues]), verbo([suggest]), complemento([the, involvement, of, conserved, 'Runt-related', genes, in, the, pathophysiology, of, 'AAA', development])].
[sujeto(['Th17', and]), verbo([associated]), complemento(['IL-17', were, involved, in, the, pathogenesis, of, 'ITP'])].
[sujeto(['Runt-related', transcription, factor, 1, '(', 'RUNX1),', a, member, of, the, runt, 'domain-containing', family, of, transcription, 'factors,', is]), verbo([required]), complemento([for, 'Th17', differentiation])].
[sujeto(['Whether', 'RUNX1', was]), verbo([involved]), complemento([in, the, pathogenesis, of, 'ITP', remains, poorly, understood])].
[sujeto(['Furthermore,', a, significantly, positive, correlation, of, 'RUNX1', with, 'RORγt', was]), verbo([found]), complemento([in, active, 'ITP', patients])].
[sujeto(['In', 'conclusion,', 'RUNX1', was]), verbo([associated]), complemento([with, the, pathogenesis, of, 'ITP', possibly, through, regulation, of, 'Th17', cell, differentiation, and, therapeutically, targeting, it, might, be, a, novel, approach, in, 'ITP', treatment])].
[sujeto(['Runt-related', transcription, factor, 1, '(', 'Runx1),', a, master, regulator, of, 'hematopoiesis,', is]), verbo([expressed]), complemento([in, preosteoclasts])].
[sujeto(['Previously', we, evaluated, the, bone, phenotype, of, 'CD11b-Cre', 'Runx1(fl/fl)', mice, and, demonstrated]), verbo([enhanced]), complemento([osteoclasts, and, decreased, bone, mass, in, males])].
[sujeto(['Both', female, and, male, 'LysM-Cre', 'Runx1(fl/fl)', mice, had]), verbo([decreased]), complemento([trabecular, bone, mass, '(', 72, '%', decrease, in, bone, volume, 'fraction)', and, increased, osteoclast, number, '(', 2, -, 3, 'times)', '(', 'P', &, 'lt;'])].
[sujeto(['We', also, demonstrated, that]), verbo([loss]), complemento([of, 'Runx1', in, pluripotential, myeloid, precursors, with, 'LysM-Cre', did, not, alter, the, number, of, myeloid, precursor, cells, in, bone, marrow, or, their, ability, to, differentiate, into, phagocytizing, or, 'antigen-presenting', cells])].
[sujeto(['This', study, demonstrates, that, abrogation, of, 'Runx1', in, multipotential, myeloid, precursor, cells, significantly, and, specifically]), verbo([enhanced]), complemento([the, ability, of, receptor, activator, of, nuclear, 'factor-κB', ligand, to, stimulate, osteoclast, formation, and, fusion, in, female, and, male, mice, without, affecting, other, myeloid, cell, fates])].
[sujeto(['In', 'turn,']), verbo([increased]), complemento([osteoclast, activity, in, 'LysM-Cre', 'Runx1(fl/fl)', mice, likely, contributed, to, a, decrease, in, bone, mass])].
[sujeto(['These', dramatic, effects, were, not, due, to]), verbo([increased]), complemento([osteoclast, precursors, in, the, deleted, mutants, and, argue, that, inhibition, of, 'Runx1', in, multipotential, myeloid, precursor, cells, is, important, for, osteoclast, formation, and, function])].
[sujeto(['Previously,', we, showed, that, 'SMAD4', and, 'runt-related', transcription, factor, 1, '(', 'RUNX1)', were, independently]), verbo([required]), complemento([for, 'MDE', to, express, 'ΔNp63'])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, vaginal, mesenchyme, directs, vaginal, epithelial, cell, fate, in, 'MDE', through, paracrine, activation, of, fibroblast, growth, factor, '(', 'FGF)', 'receptor-MAPK', pathway])].
[sujeto(['In', the, developing, reproductive, 'tract,', 'FGF7', and, 'FGF10', were, enriched, in, vaginal, 'mesenchyme,', whereas, 'FGF', receptor, 2, 'IIIb', was]), verbo([expressed]), complemento([in, epithelia, of, both, the, uterus, and, vagina])].
[sujeto(['In', 'vitro,', 'FGF10', in, combination, with, bone, morphogenetic, protein, 4, and, activin, 'A', '(', 'ActA)', was, sufficient, to]), verbo([induce]), complemento(['ΔNp63', in, 'MDE,', and, 'ActA', was, essential, for, induction, of, 'RUNX1', through, 'SMAD-independent', pathways])].
[sujeto(['Accordingly,', inhibition, of, type, 1, receptors, for, activin, in, neonatal, mice]), verbo([induced]), complemento([uterine, differentiation, in, vaginal, epithelium, by, 'down-regulating', 'RUNX1,', whereas, conditional, deletion, of, 'Smad2', and, 'Smad3', had, no, effect, on, vaginal, epithelial, differentiation])].
[sujeto(['In', 'conclusion,', vaginal, epithelial, cell, fate, in, 'MDE', is]), verbo([induced]), complemento([by, 'FGF7/10-MAPK,', bone, morphogenetic, protein, 4, -, 'SMAD,', and, 'ActA-RUNX1', pathway, 'activities,', and, the, disruption, in, any, one, of, these, pathways, results, in, conversion, from, vaginal, to, uterine, epithelial, cell, fate])].
[sujeto(['Osseo', genic, lineage, differentiation, was, also, tested, by, means, of, the, 'catenin-β1', 'immunofluorescence,']), verbo([induced]), complemento(['osteoblasts,', which, represented, the, internal, control])].
[sujeto(['The', 'RUNX1', and, 'SP7', expressions, in, the]), verbo([induced]), complemento([osteoblasts, prove, to, be, 'different,', compared, with, cells, cultured, on, metallic, supports])].
[sujeto(['Present', results]), verbo([suggested]), complemento([that, different, titanium, surfaces, might, induce, some, differences, in, terms, of, gene, expression])].
[sujeto(['However,', the, 'TEL-AML1', copies, in, her, blood, still]), verbo([increased]), complemento([and, she, died, with, leukemia, relapse, after, additional, 'CAR-T', cell, infusion])].
[sujeto(['CAR-T', therapy, is, a, novel, therapeutic, approach, that, could, be, useful, for, patients, with, relapsed, and, refractory, 'B-ALL', who]), verbo([have]), complemento([failed, all, other, treatment, options])].
[sujeto(['Homoharringtonine', combined, aclarubicin, and, cytarabine, '(', 'HAA)']), verbo([has]), complemento([been, demonstrated, to, achieve, a, high, remission, rate, and, provide, a, survival, advantage, in, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['The', median, fold]), verbo([decrease]), complemento([of, the, 'RUNX1/RUNX1T1', transcript, level, was, 200, '(', 1, -, 358000, ')', ',', and, 16.7, '%', '(', 5, /, 30, ')', patients, achieved, &, 'gt;3', log, decrease, after, one, cycle, of, the, 'HAA', regimen])].
[sujeto(['A', network, of, 'lineage-specific', transcription, factors, and, microRNAs, tightly]), verbo([regulates]), complemento([differentiation, of, hematopoietic, stem, cells, along, the, distinct, lineages])].
[sujeto(['We']), verbo([found]), complemento([that, the, hematopoietic, master, regulator, 'RUNX1', controls, the, expression, of, certain, 'microRNAs,', of, importance, during, 'erythroid/megakaryocytic', differentiation])].
[sujeto(['In', 'particular,', we, show, that, the, erythorid, 'miR144/451', cluster, is, epigenetically]), verbo([repressed]), complemento([by, 'RUNX1', during, megakaryopoiesis])].
[sujeto(['Furthermore,', the, leukemogenic, 'RUNX1/ETO', fusion, protein, transcriptionally]), verbo([represses]), complemento([the, 'miR144/451', 'pre-microRNA'])].
[sujeto(['Thus', 'RUNX1/ETO', contributes, to]), verbo([increased]), complemento([expression, of, miR451, target, genes, and, interferes, with, normal, gene, expression, during, differentiation])].
[sujeto(['Furthermore,', we, observed, that, inhibition, of, 'RUNX1/ETO', in, 'Kasumi1', cells, and, in, 'RUNX1/ETO', positive, primary, acute, myeloid, leukemia, patient, samples]), verbo([leads]), complemento([to, 'up-regulation', of, 'miR144/451'])].
[sujeto(['RUNX1', '(', 'AML1)', amplification, in, patients, with, 'B-cell', acute, lymphoblastic, leukemia, '(', 'B-ALL)']), verbo([has]), complemento([been, associated, with, poor, survival, for, unclear, reasons])].
[sujeto(['Our', anecdotal, experience]), verbo([suggests]), complemento([that, children, with, 'B-ALL', and, 'RUNX1', amplification, might, be, predisposed, to, thrombosis])].
[sujeto(['The', 'RUNX1', isoforms, derived, from, 'P2', are]), verbo([expressed]), complemento([in, a, variety, of, 'tissues,', but, expression, of, 'P1-derived', isoform, is, restricted, to, cells, of, hematopoietic, lineage])].
[sujeto(['Here', we]), verbo([report]), complemento([regulation, of, 'P1-derived', 'RUNX1', mRNA, by, 'RUNX1', protein])].
[sujeto(['In', silico, analysis, of, 'P1', promoter, revealed, presence, of, two, evolutionary]), verbo([conserved]), complemento(['RUNX', 'motifs,', 0.6, kb, upstream, of, the, transcription, start, 'site,', and, three, 'RUNX', motifs, within, 170, bp, of, the, 5, '\'', 'UTR'])].
[sujeto(['Mutation', or, deletion, of, 'RUNX', motifs, in, the, 'UTR']), verbo([enhances]), complemento([basal, activity, of, the, 'RUNX1', promoter])].
[sujeto(['Chromatin', immunoprecipitation, revealed, that, 'RUNX1', protein, is]), verbo([recruited]), complemento([to, these, sites])].
[sujeto(['We', also, demonstrate, that, 'RUNX1', protein]), verbo([regulates]), complemento([transcription, of, endogenous, 'RUNX1', mRNA, in, 'T-cell'])].
[sujeto(['Finally', we, show, that, 'SCL', transcription, factor, is]), verbo([recruited]), complemento([to, regions, containing, 'RUNX', motifs, in, the, promoter, and, the, 'UTR', and, regulates, activity, of, the, 'RUNX1', 'P1', promoter, in, vitro])].
[sujeto(['Thus,', multiple, lines, of, evidence, show, that, 'RUNX1', protein]), verbo([regulates]), complemento([its, own, gene, transcription])].
[sujeto(['For', acute, myeloid, 'leukemia,', we, identified, a, 'MEGS', with, five, genes, '(', 'FLT3,', 'IDH2,', 'NRAS,', 'KIT,', and, 'TP53)', and, a, 'MEGS', '(', 'NPM1,', 'TP53,', and, 'RUNX1)', whose, mutation, status, was, strongly]), verbo([associated]), complemento([with, survival, '(', p, =, 6.7, ×, 10, '(', -, 4, ')', ')'])].
[sujeto(['For', breast, 'cancer,', we, identified, a, significant, 'MEGS', consisting, of, 'TP53', and, four, infrequently, mutated, genes, '(', 'ARID1A,', 'AKT1,', 'MED23,', and, 'TBL1XR1),']), verbo([providing]), complemento([support, for, their, role, as, cancer, drivers])].
[sujeto(['Transmissible', gastroenteritis, virus, '(', 'TGEV),', belonging, to, the, coronaviridae, 'family,', is, the, key]), verbo([cause]), complemento([of, the, fatal, diarrhea, of, piglets, and, results, in, many, pathological, processes])].
[sujeto(['During', the, process, of, apoptosis]), verbo([induced]), complemento([by, 'TGEV', infection, in, 'PK-15', 'cells,', the, 'miR-27b', is, notably, 'down-regulated'])].
[sujeto(['Thus,', we, speculate, that, 'miR-27b', is]), verbo([involved]), complemento([in, regulating, the, process, of, apoptosis, in, 'PK-15', cells])].
[sujeto(['In', this, study, we, demonstrated, that, the, 'over-expression', of, 'miR-27b']), verbo([led]), complemento([to, the, inhibition, of, 'TGEV-induced', 'apoptosis,', reduction, of, 'Bax', protein, 'level,', and, decrease, of, 'caspase-3', and, -, 9, activities])].
[sujeto(['Conversely,', silencing, of, 'miR-27b', by, 'miR-27b', inhibitors]), verbo([enhanced]), complemento([apoptosis, via, 'up-regulating', 'Bax', expression, and, promoting, the, activities, of, 'caspase-3', and, -, 9, in, 'TGEV-infected', cells])].
[sujeto(['Subsequently,', the, 'runt-related', transcription, factor, 1, '(', 'RUNX1)', is, a, candidate]), verbo([target]), complemento([of, 'miR-27b', predicted, by, bioinformatics, search])].
[sujeto(['We', further, identified, that, the, 'miR-27b', directly]), verbo([bound]), complemento([to, the, 3, '\'', 'UTR', of, 'RUNX1', mRNA, and, suppressed, 'RUNX1', 'expression,', which, indicates, 'RUNX1', is, the, direct, target, gene, of, 'miR-27b'])].
[sujeto(['The', 'over-expression', of, 'RUNX1']), verbo([increased]), complemento([apoptosis, and, knockdown, 'RUNX1blocked', apoptosis, of, 'viral-infected', cells, via, regulating, 'Bax', expression, and, the, activities, of, 'caspase-3', and, -, 9])].
[sujeto(['Our', data]), verbo([reveal]), complemento([that, 'miR-27b', may, repress, the, mitochondrial, pathway, of, apoptosis, by, targeting, 'RUNX1,', indicating, that, 'TGEV', may, induce, apoptosis, via, 'down-regulating', 'miR-27b', and, that, 'miR-27b', may, act, as, a, target, for, therapeutic, intervention])].
[sujeto(['Acute', myeloid, leukemia, '(', 'AML)', patients, with, 't(8;21)', aberration, often]), verbo([have]), complemento([favorable, 'outcomes,', 'however,', relapse, still, occurs, in, 30, '%', -, 40, '%', 'patients,', with, only, 50, '%', -, 60, '%', of, patients, with, 't(8;21)', 'AML', cured, with, regimens, containing, 'high-dose', cytarabine, '(', 'HD-Ara-C)'])].
[sujeto(['We', also]), verbo([found]), complemento(['RFS', for, patients, without, 'c-kit', mutations, was, 100, '%', in, 'FA', 'arm,', and, 57.8, '%', in, 'HD-Ara-C', arm, at, 36, months, '(', 'P=0'])].
[sujeto([4, ')', ',']), verbo([suggesting]), complemento([a, benefit, of, consolidation, therapy, with, 'FA', for, 't(8;21)', 'AML', 'patients,', 'especially,', those, without, 'c-kit', mutations, '(', 'Clinicaltrials'])].
[sujeto(['Little', is, known, about, mechanisms, of, gastric, 'carcinogenesis,', partly, because, it]), verbo([has]), complemento([been, a, challenge, to, identify, characterize, gastric, stem, cells])].
[sujeto(['Runx', genes]), verbo([regulate]), complemento([development, and, their, products, are, transcription, factors, associated, with, cancer, development])].
[sujeto(['We', then, created, mice, that]), verbo([expressed]), complemento([enhanced, green, fluorescent, protein, '(', 'EGFP)', or, 'CreERT2', under, the, control, of, eR1, '(', 'eR1-CreERT2;Rosa-LSL-tdTomato,', 'eR1-CreERT2;Rosa-LSL-EYFP', 'mice)'])].
[sujeto(['We', investigated, the, effects, of]), verbo([expressing]), complemento([oncogenic, mutations, in, stem, cells, under, control, of, eR1, using, 'eR1-CreERT2;LSL-KrasG12D/+', 'mice;', gastric, tissues, were, collected, and, analyzed, by, histology, and, immunofluorescence])].
[sujeto(['We']), verbo([found]), complemento([that, eR1, marked, undifferentiated, stem, cells, in, the, isthmus, and, a, smaller, number, of, terminally, differentiated, chief, cells, at, the, base])].
[sujeto(['Lineage', tracing, experiments, demonstrated, that, stem, cells, in, the, isthmus, and, antrum, continuously, gave, rise, to, mature, cells, to]), verbo([maintain]), complemento([the, gastric, unit])].
[sujeto(['Using', lineage, tracing, experiments, in, 'mice,', we]), verbo([found]), complemento([that, a, 'Runx1', enhancer, 'element,', 'eR1,', promotes, its, expression, in, the, isthmus, stem, cells, of, stomach, corpus, as, 'well;', as, pyloric, gland, in, the, antrum])].
[sujeto(['We', were, able, to, use, eR1, to]), verbo([express]), complemento([oncogenic, 'mutations;', in, gastric, stem, 'cells,', proving, a, new, model, for, studies, of, gastric, carcinogenesis])].
[sujeto(['Differentially']), verbo([expressed]), complemento([genes, '(', 'DEGs)', were, then, screened, using, a, paired, 't&#8209;test'])].
[sujeto(['Functional', enrichment, analysis, indicated, that, inhibitor, of, 'DNA', 'binding&nbsp;4', '(', 'ID4)', was]), verbo([involved]), complemento([in, neuronal, differentiation, and, transcriptional, suppression])].
[sujeto(['In', the, 'PPI', 'network,', genes, may, be]), verbo([involved]), complemento([in, 'DS', by, interacting, with, 'others,', including, nuclear, receptor, 'subfamily&nbsp;4', 'group&nbsp;A', 'member&nbsp;2', '(', 'NR4A2)&#8209;early', growth, response, '(', 'EGR)2', and, 'NR4A2&#8209;EGR3'])].
[sujeto(['Therefore,', 'RUNX1,', 'NR4A2,', 'EGR2,', 'EGR3', and, 'ID4', may, be, key, genes]), verbo([associated]), complemento([with, the, pathogenesis, of, 'DS'])].
[sujeto(['The', 't(12;21)(p13;q22)', with, 'ETV6-RUNX1', fusion, occurs, in, 25, '%', of, cases, of, 'B-cell', precursor, acute, lymphoblastic, leukemia, '(', 'BCP-ALL);', and, is, generally]), verbo([associated]), complemento([with, favorable, prognosis])].
[sujeto(['However,', 15, -, 20, '%', of, the, 't(12;21)-positive', cases, are]), verbo([associated]), complemento([with, 'high-risk', disease, due, to, for, example, slow, early, responses, to, therapy])].
[sujeto(['It', is, 'well-known', that, development, of, overt, leukemia, in, 't(12;21)-positive', 'ALL']), verbo([requires]), complemento([secondary, chromosomal, aberrations, although, the, full, spectrum, of, these, cytogenetic, alterations, is, yet, 'unsettled,', and, 'also,', how, they, may, be, associated, with, disease, outcome])].
[sujeto(['This']), verbo([report]), complemento([describes, the, case, of, an, adolescent, male, with, 't(12;21)-positive', 'ALL', who, displayed, a, 'G-banded', karyotype, initially, interpreted, as, 'del(1)(p22p13)', and, 'del(15)(q15)'])].
[sujeto([1, '%']), verbo([he]), complemento([was, then, assigned, as, a, high, risk, patient, and, received, intensified, chemotherapy, accordingly])].
[sujeto(['The', unbalanced, complex, rearrangements]), verbo([have]), complemento([not, been, described, previously])].
[sujeto(['Extended', 'locus-specific', 'FISH', analyses, showed, that, the, three, deletions, were, on, the, same, chromosome, 1, homologue, that, was]), verbo([involved]), complemento([in, the, 't(1;15),', and, that, the, deletion, on, chromosome, 15, also, was, on, the, same, chromosome, 15, homologue, as, involved, in, the, 't(1;15)'])].
[sujeto(['Together', these, findings, show, the, great, importance, of, the, combined, usage, of, molecular, cytogenetic, analyses, and, oaCGH, analysis, to]), verbo([enhance]), complemento([characterization, of, apparently, simple, 'G-banded', 'karyotypes,', and, to, provide, a, more, complete, spectrum, of, secondary, chromosomal, aberrations, in, high, risk, 't(12;21)-positive', 'BCP-ALLs'])].
[sujeto(['Overwhelming', evidence, indicates, that, long, 'non-coding', 'RNAs']), verbo([have]), complemento([essential, roles, in, tumorigenesis])].
[sujeto(['Nevertheless,', their, role, in, the, molecular, pathogenesis, of, pediatric, 'B-cell', precursor, acute, lymphoblastic, leukemia]), verbo([has]), complemento([not, been, extensively, explored])].
[sujeto(['Next,', integration, of, this, lncRNA, signature, with, 'RNA', sequencing, of, 'BCP-ALL', cell, lines, and, lncRNA, profiling, of, an, in, vitro, model, system, of, 'ETV6/RUNX1', 'knockdown,', revealed, that, 'lnc-NKX2-3-1,', 'lnc-TIMM21-5,', 'lnc-ASTN1-1', and, 'lnc-RTN4R-1', are, truly]), verbo([regulated]), complemento([by, the, oncogenic, fusion, protein])].
[sujeto(['Moreover,', sustained, inactivation, of, 'lnc-RTN4R-1', and, 'lnc-NKX2-3-1', in, 'ETV6/RUNX1', positive, cells]), verbo([caused]), complemento([profound, changes, in, gene, expression])].
[sujeto(['All', 'together,', our, study, defined, a, unique, lncRNA, expression, signature]), verbo([associated]), complemento([with, 'ETV6/RUNX1-positive', 'BCP-ALL', and, identified, 'lnc-RTN4R-1', and, 'lnc-NKX2-3-1', as, lncRNAs, that, might, be, functionally, implicated, in, the, biology, of, this, prevalent, subtype, of, human, leukemia])].
[sujeto(['Transcription', factors, of, the]), verbo([nuclear]), complemento([factor, of, activated, 'T', cell, '(', 'NFAT)-family', are, essential, for, 'antigen-specific', 'T', cell, activation, and, differentiation])].
[sujeto(['Their', cooperative, 'DNA']), verbo([binding]), complemento([with, other, transcription, 'factors,', such, as, 'AP1-proteins', '(', 'FOS,', 'JUN,', 'JUNB),', 'FOXP3,', 'IRFs', and, 'EGR1,', dictate, the, gene, regulatory, action, of, 'NFATs'])].
[sujeto(['We', revealed, more, than, 170, 'NFAT']), verbo([associated]), complemento(['proteins,', half, of, which, are, involved, in, transcriptional, regulation])].
[sujeto(['Moreover,', our, computational, analysis, discovered, that]), verbo([binding]), complemento([motifs, for, 'RUNX', and, 'CREB1', are, found, preferentially, in, the, direct, vicinity, of, 'NFAT', binding, motifs, and, in, a, distinct, orientation, to, them])].
[sujeto(['Furthermore,', we]), verbo([provide]), complemento([evidence, that, mTOR, and, 'CHEK1', kinase, activity, influence, 'NFAT\'s', transcriptional, potency])].
[sujeto(['Finally,', our, dataset, of, 'NFAT-associated', proteins]), verbo([provides]), complemento([a, good, basis, to, further, study, 'NFAT\'s', diverse, functions, and, how, these, are, modulated, due, to, the, interplay, of, multiple, interaction, partners])].
[sujeto(['While', decades, of, research]), verbo([have]), complemento([identified, molecular, pathways, inducing, and, promoting, stages, of, prostate, cancer, 'malignancy,', studies, addressing, dynamic, changes, of, 'cancer-related', regulatory, factors, in, a, prostate, tumor, progression, model, are, limited])].
[sujeto(['Our', studies]), verbo([reveal]), complemento([a, 'Runx/miRNA', interaction, axis, centered, on, 'PTEN-PI3K-AKT', signaling])].
[sujeto(['This', regulatory, network]), verbo([translates]), complemento([to, mechanistic, understanding, of, prostate, tumorigenesis, that, can, be, developed, for, diagnosis, and, directed, therapy])].
[sujeto(['Despite', its, 'prevalence,', the, exact, genomic]), verbo([targets]), complemento([of, 'E/R', have, remained, elusive])].
[sujeto(['We', evaluated, gene, loci, and, enhancers]), verbo([targeted]), complemento([by, 'E/R', 'genome-wide', in, precursor, 'B', acute, leukemia, cells, using, global, 'run-on', sequencing, '(', 'GRO-seq)'])].
[sujeto(['We', show, that, expression, of, the, 'E/R', fusion]), verbo([leads]), complemento([to, widespread, repression, of, 'RUNX1-motif', containing, enhancers, at, its, target, gene, loci])].
[sujeto(['Moreover,', multiple, 'super-enhancers', from, 'CD19/CD20-lineage', were]), verbo([repressed]), complemento([implicating, a, role, in, impediment, of, lineage, commitment])].
[sujeto(['In', 'effect,', the, expression, of, several, genes]), verbo([involved]), complemento([in, 'B', cell, signaling, and, adhesion, was, 'downregulated,', and, the, repression, depended, on, the, 'wild-type', 'DNA-binding', 'Runt', domain, of, 'RUNX1'])].
[sujeto(['The', results]), verbo([provide]), complemento([a, comprehensive, 'genome-wide', mapping, between, 'E/R-regulated', key, regulatory, elements, and, genes, in, precursor, 'B', cell, leukemia, that, disrupt, normal, 'B', lymphopoiesis])].
[sujeto(['Down', syndrome, '(', 'DS)', is, the]), verbo([leading]), complemento([genetic, cause, of, mental, retardation, and, is, caused, by, a, third, copy, of, human, chromosome, 21])].
[sujeto(['The', different, pathologies, of, 'DS']), verbo([involve]), complemento([many, tissues, with, a, distinct, array, of, neural, phenotypes])].
[sujeto(['Our', results, show, that, neural, progenitor, cells, '(', 'NPCs)', differentiated, from, five, independent, 'DS-ESC', lines, display]), verbo([increased]), complemento([apoptosis, and, downregulation, of, forehead, developmental, genes])].
[sujeto(['Analysis', of, differentially]), verbo([expressed]), complemento([genes, suggested, 'RUNX1', as, a, key, transcription, regulator, in, 'DS-NPCs'])].
[sujeto(['Using', genome, editing, we, were, able, to, disrupt, all, three, copies, of, 'RUNX1', in, 'DS-ESCs,']), verbo([leading]), complemento([to, downregulation, of, several, 'RUNX1', target, developmental, genes, accompanied, by, reduced, apoptosis, and, neuron, migration])].
[sujeto(['Galectin-3', '(', 'Gal-3)']), verbo([has]), complemento([been, implicated, in, pancreatic, ductal, adenocarcinoma, '(', 'PDAC),', and, its, candidacy, as, a, therapeutic, target, has, been, evaluated])].
[sujeto(['Gal-3', is, widely, upregulated, in, 'tumors,', and, its, expression, is]), verbo([associated]), complemento([with, the, development, and, malignancy, of, 'PDAC'])].
[sujeto(['In', the, present, 'study,', we, demonstrate, that, a, 'polysaccharide,', 'RN1,', purified, from, the, flower, of, 'Panax', notoginseng]), verbo([binds]), complemento([to, 'Gal-3', and, suppresses, its, expression])].
[sujeto(['In', 'addition,', 'RN1', markedly]), verbo([inhibits]), complemento(['PDAC', cells, growth, in, 'vitro,', in, vivo, and, in, 'patient-derived', xenografts])].
[sujeto(['Mechanistically,', 'RN1']), verbo([binds]), complemento([to, epidermal, growth, factor, receptor, '(', 'EGFR)', and, 'Gal-3,', thereby, disrupting, the, interaction, between, 'Gal-3', and, 'EGFR', and, downregulating, 'extracellular-related', kinase, '(', 'ERK)', phosphorylation, and, the, transcription, factor, of, 'Gal-3,', 'Runx1', expression])].
[sujeto(['Inhibiting', the, expression, of, 'Runx1', by, 'RN1,']), verbo([suppresses]), complemento(['Gal-3', expression, and, inactivates, 'Gal-3-associated', signaling, 'pathways,', including, the, 'EGFR/ERK/Runx1,', 'BMP/smad/Id-3', and, 'integrin/FAK/JNK', signaling, pathways])].
[sujeto(['In', 'addition,', 'RN1', can, also]), verbo([bind]), complemento([to, bone, morphogenetic, protein, receptors, '(', 'BMPR1A', and, 'BMPR2)', and, block, the, interaction, between, 'Gal-3', and, the, 'BMPRs'])].
[sujeto(['Thus,', our, results]), verbo([suggest]), complemento([that, a, novel, 'Gal-3', inhibitor, 'RN1', may, be, a, potential, candidate, for, human, 'PDAC', treatment, via, multiple, targets, and, multiple, signaling, pathways])].
[sujeto(['BCP-ALL', are, believed, to, be]), verbo([arrested]), complemento([at, the, 'pre-BCR', checkpoint, independent, of, 'pre-BCR', expression])].
[sujeto(['However,', the, cellular, stage, at, which, 'BCP-ALL', are]), verbo([arrested]), complemento([and, whether, this, relates, to, expression, of, the, 'pre-BCR', components, '(', 'IGHM,', 'IGLL1', and, 'VPREB1)', is, still, unclear])].
[sujeto(['Moreover,', analyzing, six, 'BCP-ALL', data, sets, '(', n, =, 733, ')', ',', we, demonstrate, that, 'TCF3-PBX1', 'ALL']), verbo([express]), complemento([high, levels, of, 'IGHM,', 'IGLL1', and, 'VPREB1,', and, are, arrested, at, the, 'pre-B', stage])].
[sujeto(['By', 'contrast,', 'ETV6-RUNX1', 'ALL']), verbo([express]), complemento([low, levels, of, 'IGHM', or, 'VPREB1,', and, are, arrested, at, the, 'pro-B', stage])].
[sujeto(['Irrespective', of, 'subtype,', 'ALL', with, high, levels, of, 'IGHM,', 'IGLL1', and, 'VPREB1', are]), verbo([arrested]), complemento([at, the, 'pre-B', stage, and, correlate, with, good, prognosis, in, 'high-risk', pediatric, 'BCP-ALL', '(', n, =, 207, ')'])].
[sujeto(['Our', findings]), verbo([suggest]), complemento([that, 'BCP-ALL', are, arrested, at, different, cellular, 'stages,', which, relates, to, the, expression, pattern, of, the, 'pre-BCR', components, that, could, serve, as, prognostic, markers, for, 'high-risk', pediatric, 'BCP-ALL', patients])].
[sujeto(['The', genetic, basis, of, myelodysplastic, syndromes, '(', 'MDS)', is, 'heterogeneous,', and, various, combinations, of, somatic, mutations, are]), verbo([associated]), complemento([with, different, clinical, phenotypes, and, outcomes])].
[sujeto(['Somatic', mutation, in, 'ASXL1,', 'RUNX1,', or, 'TP53', is, independently]), verbo([associated]), complemento([with, unfavorable, outcomes, and, shorter, survival, after, allogeneic, 'HSCT', for, patients, with, 'MDS', and, 'MDS/AML'])].
[sujeto(['In', 'contrast,', congenital, disorders]), verbo([caused]), complemento([by, a, single, genetic, mutation, are, ideal, candidates, for, deriving, iPSCs])].
[sujeto(['We']), verbo([have]), complemento([been, investigating, the, molecular, mechanisms, underlying, leukemia, and, 'MDS', by, implementing, iPSC, technology])].
[sujeto(['Familial', platelet, disorder, '(', 'FPD)', is, a, rare, autosomal, dominant, disorder, characterized, by, thrombocytopenia, and, a, high, propensity, for, developing, acute, 'leukemia,', which, is]), verbo([caused]), complemento([by, heterozygous, mutation, of, 'RUNX1'])].
[sujeto(['We']), verbo([have]), complemento([successfully, established, iPSCs, from, three, distinct, 'FPD', pedigrees, and, examined, the, responsible, defect, during, hematopoietic, development])].
[sujeto(['A', novel, role, for, phenotypic, transcription, factors, in, very, early, differentiation, was, recently, observed, and, merits, further, study, to, elucidate, what, role, this, precocious, expression, may]), verbo([have]), complemento([in, development])].
[sujeto(['This', early, 'RUNX1', expression, spike]), verbo([provides]), complemento([a, paradigm, for, precocious, expression, of, a, phenotypic, transcription, factor, that, invites, detailed, mechanistic, study, to, fully, understand, its, biological, importance])].
[sujeto(['We']), verbo([found]), complemento([an, overall, greater, mutational, burden, and, more, driver, mutations, in, 'T-cell', 'ALL', '(', 'T-ALL)', patients, compared, to, 'B-cell', precursor, 'ALL', '(', 'BCP-ALL)', patients])].
[sujeto(['Specifically', in, 'BCP-ALL,', we, identified, 'ATRX', as, a, novel, putative, driver, gene, and, uncovered, an, association, between, somatic, mutations, in, the, 'Notch', signaling, pathway, at, 'ALL', diagnosis, and]), verbo([increased]), complemento([risk, of, relapse])].
[sujeto(['The', genes, highlighted, in, our, study, were, frequently]), verbo([involved]), complemento([in, epigenetic, 'regulation,', associated, with, germline, susceptibility, to, 'ALL,', and, present, in, minor, subclones, at, diagnosis, that, became, dominant, at, relapse])].
[sujeto(['We', observed, a, high, degree, of, clonal, heterogeneity, and, evolution, between, diagnosis, and, relapse, in, both, 'BCP-ALL', and, 'T-ALL,', which, could]), verbo([have]), complemento([implications, for, the, treatment, efficiency])].
[sujeto(['Five', clinically, actionable, variants, were]), verbo([reported]), complemento([to, the, pregnant, 'women,', including, haploinsufficiency, of, 'RUNX1,', a, mosaicism, for, segmental, chromosome, 13, 'deletion,', an, unbalanced, 'translocation,', and, two, interstitial, chromosome, 'X', deletions])].
[sujeto(['Shotgun', sequencing, of, cfDNA, not, only, enables, the, detection, of, fetal, aneuploidies, but, also]), verbo([reveals]), complemento([the, presence, of, maternal, 'CNVs'])].
[sujeto(['Interrogating', the, maternal, 'CNV', landscape, can, improve, overall, pregnancy, 'management,', and, we, propose]), verbo([reporting]), complemento([those, variants, if, clinically, relevant])].
[sujeto(['The', identification, and]), verbo([reporting]), complemento([of, such, 'CNVs', pose, novel, counseling, dilemmas, that, warrant, further, discussions, and, development, of, societal, guidelines])].
[sujeto(['To', orchestrate, the, genomic, response, to, cellular, stress, 'signals,', p53]), verbo([recognizes]), complemento([and, binds, to, 'DNA', containing, specific, and, 'well-characterized', 'p53-responsive', elements, '(', 'REs)'])].
[sujeto(['Therefore,', the, identification, and, characterization, of, a, 'species-specific', p53, 'Binding', sistes, '(', 'BS)', consensus, sequence, and, of, the]), verbo([associated]), complemento([target, genes, may, help, to, provide, new, insights, into, the, evolution, of, the, p53, regulatory, networks, across, different, species])].
[sujeto(['Here,', we, designed, and, biochemically, validated, a, computational, approach, to, identify, novel, p53]), verbo([target]), complemento([genes, in, 'Danio', rerio, genome])].
[sujeto(['Screening', all, the, 'Danio', rerio, genome, by, 'pattern-matching-based', 'analysis,', we]), verbo([found]), complemento([p53, 'RE-like', patterns, proximal, to, 979, annotated, 'Danio', rerio, genes])].
[sujeto(['Prioritization', analysis, identified, a, subset, of, 134, candidate, 'pattern-related', 'genes,', 31, of, which]), verbo([have]), complemento([been, investigated, in, further, biochemical, assays])].
[sujeto(['Our', study, identified, 'runx1,', 'axin1,', 'traf4a,', 'hspa8,', 'col4a5,', 'necab2,', and, dnajc9, genes, as, novel, direct, p53]), verbo([targets]), complemento([and, 12, additional, 'p53-controlled', genes, in, 'Danio', rerio, genome])].
[sujeto(['The', proposed, combinatorial, approach, resulted, to, be, highly, sensitive, and, robust, for, identifying, new, p53]), verbo([target]), complemento([genes, also, in, additional, animal, species])].
[sujeto([cCD3, was, not]), verbo([expressed]), complemento([in, both, groups])].
[sujeto(['ASXL2', mutation, may, be, a, new, event, that, can, cooperate, with, 'AML1-ETO', to]), verbo([induce]), complemento([leukemia])].
[sujeto(['ASXL2', gene, mutations, and, 'c-kit', gene, mutations, may, not]), verbo([have]), complemento([a, specific, correlation, between, them])].
[sujeto(['Human', endogenous, retrovirus, '(', 'HERV)', sequences, make, up, '~8%', of, the, human, genome, and]), verbo([increased]), complemento([expression, of, some, 'HERV', proteins, has, been, observed, in, various, pathologies, including, leukaemia, and, multiple, sclerosis])].
[sujeto(['However,', little, is, known, about, the, function, of, these, 'HERV', proteins, or, environmental, factors, which]), verbo([regulate]), complemento([their, expression])].
[sujeto(['Cell', proliferation, and, cell, toxicity, assays, were, carried, out, on, human, acute, 'T', lymphoblastic, leukaemia, '(', 'MOLT-4)', and, 'Fanconi', anaemia]), verbo([associated]), complemento([acute, myeloid, leukaemia, '(', 'FA-AML1)', cells, treated, with, two, different, sizes, of, 'AgNPs', '(', 7, nm, and, 50, nm, 'diameter)'])].
[sujeto(['Syncytin-1', mRNA, and, protein, were]), verbo([induced]), complemento([by, both, 7, and, 50, nm, 'AgNPs', in, both, cell, types, yet, with, different, kinetics])].
[sujeto(['In', 'summary,', the, observation, that, 'AgNPs']), verbo([induce]), complemento([expression, of, 'syncytin-1', in, 'FA-AML1', and, 'MOLT-4', cells, at, doses, as, little, as, 5, 'µg/ml', is, grounds, for, concern, since, this, protein, is, 'up-regulated', in, both, malignant, and, neurodegenerative, diseases])].
[sujeto(['Considering', the, widespread, use, of, 'AgNPs', in, the, environment, it, is, clear, that, their, ability, to]), verbo([induce]), complemento(['syncytin-1', should, be, investigated, further, in, other, cell, types])].
[sujeto(['Histone', deacetylases, '(', 'HDACs)', critically]), verbo([regulate]), complemento([gene, expression, by, determining, the, acetylation, status, of, histones])].
[sujeto(['In', 'addition,', studies]), verbo([have]), complemento([increasingly, focused, on, the, activities, of, 'HDACs,', especially, involving, 'non-histone', 'proteins,', and, their, various, biological, effects])].
[sujeto(['Aberrant', 'HDAC', expression, observed, in, several, kinds, of, human, tumors, makes, 'HDACs', potential]), verbo([targets]), complemento([for, cancer, treatment])].
[sujeto(['Several', preclinical, studies]), verbo([have]), complemento([suggested, that, 'HDAC', inhibitors, exhibit, some, efficacy, in, the, treatment, of, acute, myelogenous, leukemia, '(', 'AML)', with, 'AML1-ETO,', which, mediates, transcriptional, repression, through, its, interaction, with, a, complex, including, 'HDAC1'])].
[sujeto(['Recurrent', mutations, in, epigenetic, regulators, are]), verbo([found]), complemento([in, 'T-cell', lymphomas, '(', 'TCLs),', and, 'HDAC', inhibitors, and, hypomethylating, agents, were, shown, to, act, cooperatively, in, the, treatment, of, 'TCLs'])].
[sujeto(['Preclinical', modeling]), verbo([has]), complemento([suggested, that, persistent, activation, of, the, signal, transducer, and, activator, of, transcription, '(', 'STAT)', signaling, pathway, could, serve, as, a, useful, biomarker, of, resistance, to, 'HDAC', inhibitor, in, patients, with, cutaneous, 'TCL'])].
[sujeto(['Panobinostat,', a, 'pan-HDAC', 'inhibitor,', in, combination, with, bortezomib, and, 'dexamethasone,']), verbo([has]), complemento([achieved, longer, 'progression-free', survival, in, patients, with, 'relapsed/refractory', multiple, myeloma, '(', 'MM)', than, the, placebo, in, combination, with, bortezomib, and, dexamethasone])].
[sujeto(['Panobinostat']), verbo([inhibited]), complemento(['MM', cell, growth, by, degrading, protein, phosphatase, 3, catalytic, subunit, α, '(', 'PPP3CA),', a, catalytic, subunit, of, calcineurin])].
[sujeto(['This', degradation, was]), verbo([suggested]), complemento([to, be, mediated, by, the, blockade, of, the, chaperone, function, of, heat, shock, protein, 90, '(', 'HSP90)', due, to, 'HDAC6', inhibition])].
[sujeto(['Furthermore,', 'PPP3CA', was]), verbo([suggested]), complemento([as, a, common, target, of, panobinostat, and, bortezomib])].
[sujeto(['A', frequent, concomitant, event, is, the]), verbo([loss]), complemento([of, the, residual, 'ETV6', allele, suggesting, a, critical, role, for, the, 'ETV6', transcriptional, repressor, in, the, etiology, of, this, cancer])].
[sujeto(['However,', the, precise, mechanism, through, which]), verbo([loss]), complemento([of, functional, 'ETV6', contributes, to, disease, pathogenesis, is, still, unclear])].
[sujeto(['To', investigate, the, impact, of, 'ETV6']), verbo([loss]), complemento([on, the, transcriptional, network, and, to, identify, new, transcriptional, targets, of, 'ETV6,', we, used, whole, transcriptome, analysis, of, both, 'pre-B', leukemic, cell, lines, and, patients, combined, with, chromatin, immunoprecipitation])].
[sujeto(['Using', this, integrative, 'approach,', we, identified, 4, novel, direct, 'ETV6']), verbo([target]), complemento(['genes:', 'CLIC5,', 'BIRC7,', 'ANGPTL2', and, 'WBP1L'])].
[sujeto(['To', further, evaluate, the, role, of, chloride, intracellular, channel, protein, 'CLIC5', in, 'leukemogenesis,', we, generated, cell, lines, overexpressing, 'CLIC5', and, demonstrated, an]), verbo([increased]), complemento([resistance, to, hydrogen, 'peroxide-induced', apoptosis])].
[sujeto(['We', further, described, the, implications, of, 'CLIC5\'s', ion, channel, activity, in, 'lysosomal-mediated', cell, 'death,', possibly, by]), verbo([modulating]), complemento([the, function, of, transferrin, receptor, with, which, it, 'co-localizes', intracellularly])].
[sujeto(['For', the, first, 'time,', we, showed, that]), verbo([loss]), complemento([of, 'ETV6', leads, to, significant, overexpression, of, 'CLIC5,', which, in, turn, leads, to, decreased, 'lysosome-mediated', apoptosis])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, heightened, 'CLIC5', activity, could, promote, a, permissive, environment, for, 'oxidative-stress', induced, 'DNA', damage, accumulation, and, thereby, contribute, to, leukemogenesis])].
[sujeto(['CD56(+)', 'AML', patients]), verbo([respond]), complemento([poorly, to, 'treatment,', frequently, relapse, after, complete, remission, and, have, a, low, survival, rate])].
[sujeto(['The', interval, of, 'MRD', detection, should, be, shortened, to]), verbo([find]), complemento([out, relapse, earlier])].
[sujeto(['CD19(+)', 'AML', patients]), verbo([have]), complemento([a, good, treatment, outcome, and, often, accompanies, with, 'AML1/ETO', fusion, 'gene,', which, is, known, to, be, a, good, prognostic, marker])].
[sujeto(['Acute', myelogenous, leukemia, '(', 'AML)', carrying, 't(8;21)(q22;q22)', or, 'inv(16)/t(16;16)(p13;q22)', is, classified, as, core]), verbo([binding]), complemento([factor, '(', 'CBF)-AML', and, accounts, for, approximately, 15, '%', of, 'AML'])].
[sujeto(['c-KIT', mutation, can, be, detected, in, 17, '%', '∼46%', of, 'CBF-AML', and, is]), verbo([associated]), complemento([with, poor, prognosis])].
[sujeto(['c-KIT', mutation, is, a, crucial, hit, and, cooperates, with, 'AML1-ETO', resulting, from, 't(8;21)(q22;q22)', to]), verbo([cause]), complemento([overt, 'AML'])].
[sujeto(['Tyrosine', kinase, inhibitors, '(', 'TKI)']), verbo([targeting]), complemento(['c-KIT,', such, as, 'imatinib,', has, been, used, successfully, to, treat, 'c-KIT', driven, gastrointestinal, stromal, tumors])].
[sujeto(['However,', the, effect, of, 'TKI', on, 'c-KIT-driven', 'leukemia,', including, 'CBF-AML', and, systemic, mastocytosis, '(', 'SM),']), verbo([has]), complemento([not, been, satisfactory])].
[sujeto(['BPR1J373', is, a, 5, -, 'phenylthiazol-2-ylamine-pyriminide', derivative]), verbo([targeting]), complemento([multiple, tyrosine, kinases])].
[sujeto(['It', was, shown, to]), verbo([inhibit]), complemento([cell, proliferation, and, induce, apoptosis, in, 'AML', cells, with, constitutively, activated, 'c-KIT', via, inhibiting, 'c-KIT', phosphorylation, and, its, downstream, signals])].
[sujeto(['The', compound]), verbo([induced]), complemento([apoptosis, by, the, mitochondrial, intrinsic, pathway, through, upregulation, of, proapoptotic, proteins, 'Bax', and, 'Bak', and, caspase, 8, and, 9, activation, in, 'c-KIT', mutant, 'Kasumi-1', cells])].
[sujeto(['Furthermore,', it]), verbo([induced]), complemento(['cell-cycle', arrest, via, targeting, aurora, kinase, 'B', in, 'c-KIT', 'wild-type', 'KG-1', cells])].
[sujeto(['BPR1J373', was, shown, to, effectively]), verbo([suppress]), complemento(['c-KIT', phosphorylation, of, 'D816V', mutation, by, treating, 'c-KIT-null', 'COS-1', cells, transfected, with, 'c-KIT', 'D816V', mutant, plasmid])].
[sujeto(['In', 'conclusion,', 'BPR1J373']), verbo([inhibits]), complemento([cell, proliferation, of, 'c-KIT-driven', 'AML', cells, via, induction, of, apoptosis, and, 'cell-cycle', arrest])].
[sujeto(['Human', 'CD34+', hematopoietic, stem, and, progenitor, cells, '(', 'HSPC)']), verbo([expressing]), complemento([fusion, protein, 'AML1-ETO', '(', 'AE),', generated, by, the, 't(8;21)(q22;q22)', 'rearrangement,', manifest, enhanced, 'self-renewal', and, dysregulated, differentiation, without, leukemic, 'transformation,', representing, a, 'pre-leukemia', stage])].
[sujeto(['However,', 'AE', expression, alone, is, not, sufficient, to]), verbo([maintain]), complemento([high, telomerase, activity, to, immortalize, human, 'HSPC', 'cells,', which, may, hamper, transformation])].
[sujeto(['Enforced', expression, of, hTERT, immortalized, human, 'AE', 'pre-leukemia', cells, in, a, 'telomere-lengthening', independent, 'manner,', and, improved, the, 'pre-leukemia', stem, cell, function, by]), verbo([enhancing]), complemento([cell, proliferation, and, survival])].
[sujeto(['AE-hTERT', cells]), verbo([retained]), complemento([cytokine, dependency, and, 'multi-lineage', differentiation, potential, similar, to, parental, 'AE', clones])].
[sujeto(['The', presence, of, 'AML1-ETO', '(', 'RUNX1-CBF2T1),', a, fusion, oncoprotein, resulting, from, a, 't(8;21)', chromosomal, 'translocation,']), verbo([has]), complemento([been, implicated, as, a, necessary, but, insufficient, event, in, the, development, of, a, subset, of, acute, myeloid, leukemias, '(', 'AML)'])].
[sujeto(['While', 'AML1-ETO', prolongs, survival, and]), verbo([inhibits]), complemento([differentiation, of, hematopoietic, stem, cells, '(', 'HSC),', other, contributory, events, are, needed, for, cell, proliferation, and, leukemogenesis])].
[sujeto(['We']), verbo([have]), complemento([postulated, that, specific, tumor, suppressor, genes, keep, the, leukemic, potential, of, 'AML1-ETO', in, check])].
[sujeto(['In', studying, 'del(9q),', one, of, the, most, common, concomitant, chromosomal, abnormalities, with, 't(8;21),', we, identified, the]), verbo([loss]), complemento([of, an, apparent, tumor, 'suppressor,', 'TLE4,', that, appears, to, cooperate, with, 'AML1-ETO', to, confer, a, leukemic, phenotype])].
[sujeto(['We', show, that, the]), verbo([loss]), complemento([of, 'TLE4', confers, proliferative, advantage, to, leukemic, 'cells,', simultaneous, with, an, upregulation, of, a, 'pro-', inflammatory, signature, mediated, through, aberrant, increases, in, 'Wnt', signaling, activity])].
[sujeto(['It']), verbo([has]), complemento([been, reported, that, amyloid, precursor, 'protein&nbsp;(APP)', promotes, cell, proliferation, and, metastasis, in, various, types, of, solid, cancers])].
[sujeto(['In', our, previous, 'study,', we, showed, that, 'APP', is, highly]), verbo([expressed]), complemento([and, regulates, leukemia, cell, migration, in, 'AML1&#8209;ETO-positive&nbsp;(AE)', leukemia])].
[sujeto(['Whether', 'APP', is]), verbo([involved]), complemento([in, the, regulation, of, 'AE', leukemia, cell, proliferation, or, apoptosis, is, unclear])].
[sujeto([1, ')', and]), verbo([increased]), complemento([levels, of, 'c-KIT', expression, '(', 'P=0'])].
[sujeto([1, ')', ',', was, significantly]), verbo([increased]), complemento([when, the, 'APP', gene, was, knocked, 'down,', concomitant, with, reduced, levels, of, 'anti-apoptotic', protein, 'Bcl-2', and, increased, levels, of, 'caspase-3&nbsp;and&nbsp;-9,', 'however,', no, apparent, change, was, observed, in, the, cell, cycle, distribution, '(', 'P&gt;0'])].
[sujeto(['Moreover,', the, knockdown, of, 'APP', markedly]), verbo([decreased]), complemento(['c-KIT', expression, at, both, the, transcription, '(', as, evidenced, by, qPCR, 'analysis)', and, translation, '(', as, confirmed, by, 'CD117', assay, and, western, blot, 'analysis)', 'levels,', as, well, as, 'p-AKT', and, its, downstream, targets, including, 'NF-κB,', p53, and, 'Bcl-2'])].
[sujeto(['Chromosomal', translocation, 8, ;, 21, is]), verbo([found]), complemento([in, 40, '%', of, the, 'FAB', 'M2', subtype, of, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['The', resultant, 'in-frame', fusion, protein, 'AML1-ETO', '(', 'AE)']), verbo([acts]), complemento([as, an, initiating, oncogene, for, leukemia, development])].
[sujeto(['Full', activity, was, realized, only, upon]), verbo([increased]), complemento([fusion, protein, expression])].
[sujeto(['In', the, context, of, 'AE,', 'AE9a', did, not, show, selection, for]), verbo([increased]), complemento(['expression,', affirming, observations, of, human, 't(8;21)', patient, samples, where, 'full-length', 'AE', is, the, dominant, protein, detected])].
[sujeto(['Mechanistically,', 'AE9a', showed, defective, transcriptional, regulation, of, 'AE']), verbo([target]), complemento([genes, that, was, partially, corrected, at, high, expression])].
[sujeto(['MicroRNAs', '(', 'miRNAs)', are, a, class, of, small, endogenous, 'non-coding', 'RNAs', that, play, important, regulatory, roles, by]), verbo([targeting]), complemento([mRNAs, for, cleavage, or, translational, repression])].
[sujeto([miRNAs]), verbo([act]), complemento([in, diverse, biological, processes, including, 'development,', cell, 'growth,', 'apoptosis,', and, hematopoiesis])].
[sujeto(['The', miRNA, expression, is]), verbo([associated]), complemento([with, specific, cytogenetic, changes, and, can, also, be, used, to, discriminate, between, the, different, subtypes, of, leukemia, in, acute, lymphoblastic, leukemia, with, common, 'translocations,', it, is, shown, that, the, miRNAs, have, the, potential, to, be, used, for, clinical, diagnosis, and, prognosis])].
[sujeto(['Although', the, 'TALE', family, homeodomain, factor, 'Meis1']), verbo([has]), complemento([been, linked, to, 'malignancy,', a, role, for, 'MEIS2', is, less, clear])].
[sujeto(['Here,', we, demonstrate, that, 'MEIS2', is]), verbo([expressed]), complemento([at, high, levels, in, patients, with, 'AML1-ETO-positive', acute, myeloid, leukemia, and, that, growth, of, 'AML1-ETO-positive', leukemia, depends, on, 'MEIS2', expression])].
[sujeto(['In', 'mice,', 'MEIS2', collaborates, with, 'AML1-ETO', to]), verbo([induce]), complemento([acute, myeloid, leukemia])].
[sujeto(['MEIS2']), verbo([binds]), complemento([strongly, to, the, 'Runt', domain, of, 'AML1-ETO,', indicating, a, direct, interaction, between, these, transcription, factors])].
[sujeto(['High', expression, of, 'MEIS2', impairs, repressive, 'DNA']), verbo([binding]), complemento([of, 'AML1-ETO,', inducing, increased, expression, of, genes, such, as, the, druggable, 'proto-oncogene', 'YES1'])].
[sujeto(['It']), verbo([causes]), complemento([acute, myeloid, leukemia, '(', 'AML)', by, dysregulating, the, expression, of, genes, critical, for, myeloid, cell, development, and, differentiation, and, recently, has, been, reported, to, bind, multiple, subunits, of, the, mammalian, cytosolic, chaperonin, 'TRiC', '(', or, 'CCT),', primarily, through, its, 'DNA', binding, domain, '(', 'AML1-175)'])].
[sujeto(['Our', structure]), verbo([reveals]), complemento([that, 'AML1-175', associates, directly, with, a, specific, subset, of, 'TRiC', subunits, in, the, open, conformation])].
[sujeto(['Here', we, show, that, salicylate, specifically]), verbo([inhibits]), complemento(['CBP', and, p300, lysine, acetyltransferase, activity, in, vitro, by, direct, competition, with, 'acetyl-Coenzyme', 'A', at, the, catalytic, site])].
[sujeto(['We', used, a, chemical, 'structure-similarity', search, to, identify, another, 'anti-inflammatory', 'drug,', 'diflunisal,', that]), verbo([inhibits]), complemento([p300, more, potently, than, salicylate])].
[sujeto(['Finally,', we]), verbo([found]), complemento([that, diflunisal, suppressed, the, growth, of, 'p300-dependent', leukemia, cell, lines, expressing, 'AML1-ETO', fusion, protein, in, vitro, and, in, vivo])].
[sujeto(['The', 'IGF2', mRNA]), verbo([binding]), complemento([protein, 1, '(', 'IGF2BP1)', belongs, to, a, family, of, regulatory, 'RNA-binding', proteins, and, controls, 'stability,', transport, or, translation, of, its, target, transcripts])].
[sujeto(['Re-expression', of, 'IGF2BP1', is, frequently]), verbo([found]), complemento([in, different, tumors, and, has, been, associated, with, aggressive, disease, phenotypes])].
[sujeto(['IGF2BP1']), verbo([has]), complemento([also, been, identified, to, be, exclusively, specific, for, 't(12;21)(p13;q22)-positive', acute, lymphoblastic, leukemia, '(', 'ALL)', but, biological, significance, of, 'IGF2BP1', overexpression, has, not, been, investigated, to, date])].
[sujeto(['We']), verbo([have]), complemento([recently, reported, that, 'ETV6/RUNX1', transcript, is, a, target, of, 'RNA-binding', protein, 'IGF2BP1', in, 't(12;21)(p13;q22)-positive', 'ALL', suggesting, a, direct, role, of, 'IGF2BP1', in, 'ETV6/RUNX1-mediated', leukemogenesis])].
[sujeto(['To', address, this, question, we]), verbo([have]), complemento([employed, stable, clones, of, 'REH', cells, -, a, model, cell, line, of, 't(12;21)(p13;q22)-positive', 'ALL', -, with, downregulated, 'IGF2BP1', expression])].
[sujeto(['Here', we, show, that, downregulation, of, 'IGF2BP1', impairs, proliferation, by, attenuating, cell, cycle, progression, and]), verbo([increasing]), complemento([the, rate, of, spontaneous, cell, death])].
[sujeto(['We', also]), verbo([provide]), complemento([evidence, that, downregulation, of, 'IGF2BP1', induce, reduction, of, 'STAT3', mRNA, levels, and, augments, sensitivity, to, 'STAT3', selective, inhibitor, 'S3I-201'])].
[sujeto(['Prioritization', of, candidate, genes, emanating, from, 'large-scale', screens]), verbo([requires]), complemento([integrated, analyses, at, the, 'genomics,', 'molecular,', network, and, structural, biology, levels])].
[sujeto(['We']), verbo([have]), complemento([extended, the, 'Integrated', 'Genome', 'Browser', '(', 'IGB)', to, facilitate, these, tasks])].
[sujeto(['The', source, code, is]), verbo([released]), complemento([under, the, 'Apache', 'License,', 'Version', 2])].
[sujeto(['We', also, identified, three, cases, with]), verbo([increased]), complemento(['RUNX1', signals, scattered, on, multiple, marker, chromosomes, that, did, not, meet, the, 'COG', definition, of, iAMP21, but, showed, similar, 21, q, instability, and, older, age, at, presentation])].
[sujeto(['Our', findings, not, only, demonstrate, that, 'B-ALL', with, iAMP21, is, truly, a, distinct, clinicopathologic, entity, but, also]), verbo([suggest]), complemento([that, a, subset, of, cases, of, 'B-ALL', with, iAMP21, can, show, variable, cytogenetic, features])].
[sujeto(['Tongue', squamous, cell, carcinoma, '(', 'TSCC)', is, a, rare, and, aggressive, type, of, 'cancer,', which, is]), verbo([associated]), complemento([with, a, poor, prognosis])].
[sujeto(['Identification', of, patients, at, high, risk, of, 'TSCC', tumorigenesis, may]), verbo([provide]), complemento([information, for, the, early, detection, of, 'metastases,', and, for, potential, treatment, strategies])].
[sujeto(['Bioinformatics', 'analyses,', including, the, 'Gene', 'Ontology', '(', 'GO)', and, 'Kyoto', 'Encyclopedia', of, 'Genes', and, 'Genomes', were, used, to, identify, genes, and, pathways, specifically]), verbo([associated]), complemento([with, 'miRNA-associated', 'TSCC', oncology])].
[sujeto(['A', total, of, 25, miRNAs, and, 769, mRNAs, were, differentially]), verbo([expressed]), complemento([in, the, two, groups, 'assessed,', and, all, the, differentially, expressed, miRNA, and, mRNA, target, interactions, were, analyzed])].
[sujeto(['The', miRNA]), verbo([target]), complemento([genes, were, predominantly, associated, with, 38, 'GO', terms, and, 13, pathways])].
[sujeto(['Of', the, genes, differentially]), verbo([expressed]), complemento([between, the, two, 'groups,', and, confirmed, in, another, 'GEO', 'series,', 'miRNA-494,', 'miRNA-96,', 'miRNA-183,', 'runt-related', transcription, factor, 1, ',', programmed, cell, death, protein, 4, and, 'membrane-associated', guanylate, kinase, were, the, most, significantly, 'altered,', and, may, be, central, in, the, regulation, of, 'TSCC'])].
[sujeto(['In', the, present, 'study,', a, novel, differential, 'miRNA-mRNA', expression, network, was, 'constructed,', and, further, investigation, may]), verbo([provide]), complemento([novel, targets, for, the, diagnosis, of, 'TSCC'])].
[sujeto(['The', differentiation, from, multipotent, hematopoietic, stem, cells, '(', 'HSC)', to, mature, and, functional, blood, cells]), verbo([requires]), complemento([the, finely, tuned, regulation, of, gene, expression, at, each, stage, of, development])].
[sujeto(['Specific', transcription, factors, play, a, key, role, in, this, process, as, they]), verbo([modulate]), complemento([the, expression, of, their, target, genes, in, an, exquisitely, 'lineage-specific', manner])].
[sujeto(['A', large, number, of, important, transcriptional, regulators]), verbo([have]), complemento([been, identified, which, establish, and, maintain, specific, gene, expression, patterns, during, hematopoietic, development])].
[sujeto(['In', this, 'review,', we, focus, on, the, current, knowledge, of, the, biological, and, functional, properties, of, the, hematopoietic, master, regulator, 'RUNX1', '(', also, known, as, 'AML1,', 'CBFA2,', 'PEBP2aB)', transcription, factor, and, its, main, downstream]), verbo([target]), complemento(['PU'])].
[sujeto(['Recently,', a, number, of, novel, genetic, loci, were]), verbo([reported]), complemento([to, be, associated, with, 'JIA', at, '(', or, 'near)', 'genome-wide', significance, in, a, large, 'case-control', discovery, sample, using, the, 'Immunochip', genotyping, array])].
[sujeto(['However,', independent, replication, of, findings]), verbo([has]), complemento([yet, to, be, performed])].
[sujeto(['Genotyping', was, successfully, performed, on, a, total, of, 404, 'JIA', cases, '(', mean, age, 6.4, 'years,', 68, '%', 'female)', and, 676, healthy, child, controls, '(', mean, age, 7.1, 'years,', 42, '%', 'female)', across, 19, 'SNPs', previously]), verbo([associated]), complemento([with, 'JIA'])].
[sujeto(['We']), verbo([have]), complemento([carried, out, the, first, independent, replication, of, association, for, six, genes, implicated, in, 'JIA', susceptibility])].
[sujeto(['Our', data, significantly, strengthens, the, evidence, that, these, loci, harbor, true, disease]), verbo([associated]), complemento([variants])].
[sujeto(['Thus,', this, study, makes, an, important, contribution, to, the, growing, body, of, international, data, that, is]), verbo([revealed]), complemento([the, genetic, risk, landscape, of, 'JIA'])].
[sujeto(['To', clarify, the, prevalence, and, prognostic, significance, of, 'c-KIT', mutations, in, patients, with, core]), verbo([binding]), complemento([factor, acute, myeloid, leukemia, '(', 'CBF-AML),', a, total, of, 351, patients, who, were, categorized, as, pediatric, 't(8;21),', adult, 't(8;21),', pediatric, 'inv(16),', or, adult, 'inv(16)', were, screened, at, diagnosis, for, 'c-KIT', mutations, in, exons, 17, and, 8, using, direct, sequencing])].
[sujeto(['Higher', 'White', blood, cell, '(', 'WBC)', 'count,', 'WBC', 'index,', and, 'AML1-ETO', transcript, levels, in, adult, 't(8;21)', patients, were, significantly]), verbo([associated]), complemento([with, 'c-KIT', mutations, and, mutations, in, exon, 17, '(', 'P≤0'])].
[sujeto(['c-KIT', mutations]), verbo([have]), complemento([a, strong, adverse, effect, on, the, relapse, and, survival, of, adult, 't(8;21)', 'AML', patients])].
[sujeto(['Thousands', of, unique, mutations, in, transcription, factors, '(', 'TFs)', arise, in, 'cancers,', and, the, functional, and, biological, roles, of, relatively, few, of, these]), verbo([have]), complemento([been, characterized])].
[sujeto(['Biophysical', predictions, also, indicated, that, the, relative, prevalence, of, 'TP53', missense, mutations, in, cancer, is, proportional, to, their, thermodynamic, impacts, on, protein, stability, and, 'DNA', 'binding,', which, is, consistent, with, the, selection, for, the]), verbo([loss]), complemento([of, p53, transcriptional, function, in, cancers])].
[sujeto(['Haematopoiesis', in, adult, animals, is]), verbo([maintained]), complemento([by, haematopoietic, stem, cells, '(', 'HSCs),', which, 'self-renew', and, can, give, rise, to, all, blood, cell, lineages])].
[sujeto(['Here,', we]), verbo([have]), complemento([investigated, requirements, for, 'Runx1', using, a, conditional, reversible, knockout, strategy])].
[sujeto(['We']), verbo([report]), complemento([that, 'Runx1', deficiency, does, not, preclude, formation, of, 'VE-cad+CD45-CD41+', 'cells,', which, are, phenotypically, equivalent, to, precursors, of, definitive, 'HSCs', '(', 'pre-HSC', 'Type', 'I)', but, blocks, transition, to, the, subsequent, 'CD45+', stage, '(', 'pre-HSC', 'Type', 'II)'])].
[sujeto(['These', data, emphasise, that, developmental, progression, of, 'HSCs', during, a, very, short, period, of, time, is]), verbo([regulated]), complemento([by, precise, 'stage-specific', molecular, mechanisms])].
[sujeto(['Previously,', we]), verbo([reported]), complemento([that, 'Runx1(+)', cells, in, embryonic, day, 7.5, '(', 'E7'])].
[sujeto(['This']), verbo([suggests]), complemento([a, developmental, trajectory, from, 'Runx1(+)', cells, in, the, 'E7'])].
[sujeto(['Recent', genomic, studies]), verbo([have]), complemento([provided, a, refined, genetic, map, of, acute, lymphoblastic, leukemia, '(', 'ALL)', and, increased, the, number, of, potential, prognostic, markers])].
[sujeto(['This', study, was, undertaken, by, 'MECCA', as, initial, efforts, in, collaborative, data, collection, to]), verbo([provide]), complemento([clinical, and, demographic, information, on, children, with, 'ALL', in, the, 'Middle', 'East'])].
[sujeto(['The', distribution, of, common, genetic, abnormalities, reflected, a, similar, percentage, of, hyperdiploidy, '(', 25.6, '%', ')', ',', but, a, lower, percentage, of, 'ETV6-RUNX1', translocation, '(', 14.7, '%', ')', compared, to, large, series]), verbo([reported]), complemento([from, 'Western', populations])].
[sujeto(['This', first, collaborative, study]), verbo([has]), complemento([established, a, process, for, prospective, data, collection, and, future, multinational, collaborative, research, in, the, 'Middle', 'East'])].
[sujeto(['Despite', the, limitations, of, an, incomplete, 'population-based', 'study,', it]), verbo([provides]), complemento([the, first, comprehensive, baseline, data, on, clinical, 'characteristics,', laboratory, 'evaluation,', induction, 'outcome,', and, toxicity])].
[sujeto(['TLS/FUS-ERG', chimeric, fusion, transcript, resulting, from, translocation, changes]), verbo([involving]), complemento([chromosomes, 16, and, 21, is, a, rare, genetic, event, associated, with, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['The', distinct, 't(16;21)', 'AML', subtype, exhibits, unique, clinical, and, morphological, features, and, is]), verbo([associated]), complemento([with, poor, prognosis, and, a, high, relapse, 'rate;', 'however,', the, underlying, mechanism, remains, to, be, clarified])].
[sujeto(['Here,', we]), verbo([report]), complemento([three, pediatric, 'AML', patients, with, 't(16;21)', '(', 'p11;', 'q22)'])].
[sujeto(['Interestingly,', we]), verbo([found]), complemento(['RUNX1', mutation, in, relapsed, sample, of, one, patient, in, whom, cytogenetic, analysis, showed, the, emergence, of, a, new, additional, clone])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, precedent, genetic, alterations, may, be, essential, to, drive, the, progression, and, relapse, of, 't(16;21)-AML', patients])].
[sujeto(['These', neurons, project, to, peripheral]), verbo([targets]), complemento([throughout, the, 'body,', which, can, be, divided, into, superficial, and, deep, tissues])].
[sujeto(['Here,', we]), verbo([find]), complemento([that, the, transcription, factor, 'Runx1', is, required, for, the, development, of, many, 'epidermis-projecting', 'TrkA', lineage, neurons])].
[sujeto(['Accordingly,', knockout, of, 'Runx1']), verbo([leads]), complemento([to, the, selective, loss, of, sensory, innervation, to, the, 'epidermis,', whereas, deep, tissue, innervation, and, two, types, of, deep, tissue, pain, are, unaffected])].
[sujeto(['Within', these, cutaneous, 'neurons,', 'Runx1']), verbo([suppresses]), complemento([a, large, molecular, program, normally, associated, with, sensory, neurons, that, innervate, deep, 'tissues,', such, as, muscle, and, visceral, organs])].
[sujeto(['Ectopic', expression, of, 'Runx1', in, these, deep, sensory, neurons]), verbo([causes]), complemento([a, loss, of, this, molecular, program, and, marked, deficits, in, deep, tissue, pain])].
[sujeto(['Thus,', this, study]), verbo([provides]), complemento([insight, into, a, genetic, program, controlling, the, segregation, of, cutaneous, versus, deep, tissue, pain, pathways])].
[sujeto(['Myeloproliferative', neoplasms, '(', 'MPNs)', such, as, chronic, myelogenous, '(', 'CML)', and, chronic, myelomonocytic, leukemias, '(', 'CMML)', are, frequently]), verbo([induced]), complemento([by, tyrosine, kinase, oncogenes])].
[sujeto(['We', used, a, model, of, 'MPN,', which, is]), verbo([induced]), complemento([by, 'co-expression', of, the, oncoproteins, 'HIP1/PDGFβR', '(', 'H/P)', and, 'AML1/ETO', from, their, endogenous, 'loci,', to, examine, the, mechanisms, of, disease, development, and, recurrence, following, imatinib, withdrawal])].
[sujeto(['Within', 1, week, of, imatinib, 'treatment,', more, than, 98, '%', of, gene, expression, changes]), verbo([induced]), complemento([by, the, oncogenes, in, isolated, hematopoietic, stem, and, progenitor, cells, '(', 'lineage(-)Sca-1(+)c-Kit(+)', 'immunophenotype)', normalized])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, treatment, with, a, combination, of, arsenic, trioxide, and, imatinib, can, eliminate, refractory, 'MPN-initiating', cells, and, reduce, disease, relapse])].
[sujeto(['Hematopoiesis', -, the, process, by, which, blood, cells, are, formed, -]), verbo([has]), complemento([been, studied, intensely, for, over, a, century, using, a, variety, of, model, systems])].
[sujeto(['Over', the, last, 'decade,', the, zebrafish]), verbo([has]), complemento([come, to, the, forefront, as, a, new, model, in, hematopoiesis, 'research,', as, it, allows, the, use, of, 'large-scale', 'genetics,', chemical, screens, and, transgenics])].
[sujeto(['This', comparative, approach, to, understanding, hematopoiesis]), verbo([has]), complemento([led, to, fundamental, knowledge, about, the, process, and, to, the, development, of, new, therapies, for, disease])].
[sujeto(['Here,', we]), verbo([provide]), complemento([a, broad, overview, of, vertebrate, hematopoiesis])].
[sujeto(['Interferon-induced', transmembrane, protein, 3, '(', 'IFITM3;', 'FRAGILIS;', 'MIL-1)', is, part, of, a, larger, family, of, important, small, 'interferon-induced', transmembrane, genes, and, proteins]), verbo([involved]), complemento([in, early, 'development,', cell, 'adhesion,', and, cell, 'proliferation,', and, which, also, play, a, major, role, in, response, to, bacterial, and, viral, infections, 'and,', more, 'recently,', in, pronounced, malignancies])].
[sujeto(['IFITM3,', together, with, 'tissue-nonspecific', alkaline, phosphatase, '(', 'TNAP),', 'PRDM1,', and, 'STELLA,']), verbo([has]), complemento([been, claimed, to, be, a, hallmark, of, segregated, primordial, germ, cells, '(', 'PGCs)', '(', 'Saitou', et, al])].
[sujeto(['IFITM3,', like, 'STELLA,', was, also]), verbo([found]), complemento([in, the, ventral, ectodermal, ridge, '(', 'VER),', a, posterior, progenitor, pool, that, builds, the, tailbud])].
[sujeto(['That', relatively, high, levels, of, 'IFITM3', were]), verbo([found]), complemento([throughout, the, posterior, primitive, streak, and, its, derivatives, is, consistent, with, evidence, that, 'IFITM3,', like, 'STELLA,', is, part, of, a, larger, 'stem/progenitor', cell, pool, at, the, posterior, end, of, the, primitive, streak, that, forms, the, base, of, the, allantois, and, builds, the, 'fetal-umbilical', 'connection,', thus, further, obfuscating, practical, phenotypic, distinctions, between, 'so-called', 'PGCs', and, surrounding, soma])].
[sujeto(['VGLUT3-expressing', unmyelinated, 'low-threshold', mechanoreceptors, '(', 'C-LTMRs)', are, proposed, to]), verbo([mediate]), complemento([pleasant, touch, 'and/or', 'pain,', but, the, molecular, programs, controlling, 'C-LTMR', development, are, unknown])].
[sujeto(['We', then]), verbo([found]), complemento([that, 'VGLUT3-persistent', neurons, express, the, runt, domain, transcription, factor, 'Runx1'])].
[sujeto(['Furthermore,', 'Runx1', is]), verbo([required]), complemento([to, establish, mechanosensitivity, in, 'C-LTMRs,', by, controlling, the, expression, of, the, mechanically, gated, ion, channel, 'Piezo2'])].
[sujeto(['These', findings, appear, to, argue, against, the, recently, proposed, role, of, 'VGLUT3', in, 'C-LTMRs', in]), verbo([mediating]), complemento([mechanical, hypersensitivity, induced, by, nerve, injury, or, inflammation])].
[sujeto(['Thus,', our, studies]), verbo([provide]), complemento([new, insight, into, the, genetic, program, controlling, 'C-LTMR', development, and, call, for, a, revisit, for, the, physiological, functions, of, 'C-LTMRs'])].
[sujeto(['RUNX1']), verbo([has]), complemento([been, shown, to, be, part, of, a, large, transcription, factor, 'complex,', together, with, 'LDB1,', 'GATA1,', 'TAL1,', and, 'ETO2', '(', 'N'])].
[sujeto(['We', used, a, tagging, strategy, to, show, that, 'RUNX1']), verbo([interacts]), complemento([with, two, novel, protein, 'partners,', 'LSD1', and, 'MYEF2,', in, erythroid, cells])].
[sujeto(['MYEF2', is]), verbo([bound]), complemento([in, undifferentiated, cells, and, is, lost, upon, 'differentiation,', whereas, 'LSD1', is, bound, in, differentiated, cells])].
[sujeto(['Chromatin', immunoprecipitation, followed, by, sequencing, '(', 'ChIP-seq)', and, microarray, expression, analysis, were, used, to, show, that, 'RUNX1']), verbo([binds]), complemento([approximately, 9, ',', 0, target, sites, in, erythroid, cells, and, is, primarily, active, in, the, undifferentiated, state])].
[sujeto(['Functional', analysis, shows, that, a, subset, of, the]), verbo([target]), complemento([genes, is, suppressed, by, 'RUNX1', via, the, newly, identified, partner, 'MYEF2'])].
[sujeto(['We']), verbo([found]), complemento([patterns, of, significantly, comutated, driver, genes, suggesting, functional, synergism])].
[sujeto(['Furthermore,', we]), verbo([provide]), complemento([detailed, information, on, associations, between, gene, 'mutations,', clinical, patient, 'characteristics,', and, therapeutic, outcomes, in, this, large, cohort, of, uniformly, treated, 'AML', patients])].
[sujeto(['In', 'summary,', our, study]), verbo([provides]), complemento([a, comprehensive, overview, of, the, 'spectrum,', clinical, 'associations,', and, prognostic, relevance, of, recurrent, driver, gene, mutations, in, a, large, cohort, representing, a, broad, spectrum, and, age, range, of, intensively, treated, 'AML', patients])].
[sujeto(['Although', recent, 'large-scale', genomic, analysis]), verbo([has]), complemento([improved, the, description, of, the, genetic, abnormalities, of, 'OSCC,', few, targetable, genomic, lesions, have, been, 'identified,', and, no, molecular, therapy, is, available])].
[sujeto(['The', unbiased, 'high-throughput', 'small-molecule', inhibitor, screening]), verbo([led]), complemento([us, to, discover, a, highly, potent, 'anti-OSCC', 'compound,', 'THZ1,', a, specific, 'CDK7', inhibitor])].
[sujeto(['RNA-Seq', revealed, that, 'low-dose', 'THZ1', treatment]), verbo([caused]), complemento([selective, inhibition, of, a, number, of, oncogenic, transcripts])].
[sujeto(['Notably,', further, characterisation, of, the, genomic, features, of, these, 'THZ1-sensitive', transcripts, demonstrated, that, they, were, frequently]), verbo([associated]), complemento([with, 'super-enhancer', '(', 'SE)'])].
[sujeto(['Our', integrative, approaches]), verbo([led]), complemento([to, a, catalogue, of, 'SE-associated', master, regulators, and, oncogenic, 'transcripts,', which, may, significantly, promote, both, the, understanding, of, 'OSCC', biology, and, the, development, of, more, innovative, therapies])].
[sujeto(['Less', than, 50, patients, with, 'FPD/AML', '(', 'OMIM', 601309, ')']), verbo([have]), complemento([been, reported, as, of, today, and, there, may, an, underestimation])].
[sujeto(['We']), verbo([have]), complemento([investigated, 41, carriers, of, 'RUNX1', alteration, belonging, to, nine, unrelated, 'French', families, with, 'FPD/AML', and, two, syndromic, 'patients,', registered, in, the, 'French', network, on, rare, platelet, disorders, from, 2005, to, 2015])].
[sujeto(['Five', 'missense,', one, 'non-sense,', three, frameshift, mutations, and, two, large, deletions]), verbo([involving]), complemento([several, genes, including, 'RUNX1', were, evidenced])].
[sujeto(['A', functional, platelet, defect, consistent, with, a, 'δ-granule']), verbo([release]), complemento([defect, was, found, in, ten, patients, regardless, of, the, type, of, 'RUNX1', alteration])].
[sujeto(['The', incidence, of, haematological, malignancies, was, higher, when, the, mutated, 'RUNX1', allele, was, likely, to]), verbo([cause]), complemento([a, dominant, negative, effect, '(', 19, /, 34, ')', in, comparison, with, loss, of, function, alleles, '(', 3, /, 9, ')'])].
[sujeto(['A', normal, platelet, count, does, not, rule, out, the, diagnosis, of, 'FPD/AML,', since, the, platelet, count, was]), verbo([found]), complemento([normal, for, three, mutated, 'subjects,', a, feature, that, has, a, direct, impact, in, the, search, for, a, related, donor, in, case, of, allogeneic, haematopoietic, stem, cell, transplantation])].
[sujeto(['Platelet', dysfunction, suggestive, of, defective, 'δ-granule']), verbo([release]), complemento([could, be, of, values, for, the, diagnosis, of, 'FPD/AML', particularly, when, the, clinical, presentation, is, an, autosomal, dominant, thrombocytopenia, with, normal, platelet, size, in, the, absence, of, familial, malignancies])].
[sujeto(['The', results]), verbo([suggested]), complemento([that, the, stem, cells, in, the, hematopoietic, tissue, of, 'Chinese', mitten, crab, 'E'])].
[sujeto([&, 'nbsp;sinensis', were]), verbo([regulated]), complemento([by, transcriptional, and, humoral, factors, to, generate, hemocytes])].
[sujeto(['Familial', acute, myeloid, leukemia, is, rare, and, linked, to, germline, mutations, in, 'RUNX1,', 'GATA2', or, 'CCAAT/enhancer']), verbo([binding]), complemento(['protein-α', '(', 'CEBPA)'])].
[sujeto(['Protein', structural, modeling]), verbo([suggested]), complemento([that, the, 'Q311P', mutation, alters, the, ability, of, the, 'CEBPA', dimer, to, bind, 'DNA'])].
[sujeto(['Electrophoretic', mobility, shift, assays, showed, that, the, 'Q311P', 'mu-tant', had, attenuated]), verbo([binding]), complemento([to, 'DNA,', as, predicted, by, the, protein, modeling])].
[sujeto(['Consistent', with, these, 'findings,', we]), verbo([found]), complemento([that, the, 'Q311P', mutation, has, reduced, 'transactivation,', consistent, with, a, 'loss-of-function', mutation])].
[sujeto(['This', study, of, a, large, 'multi-generational', pedigree]), verbo([reveals]), complemento([that, a, germline, mutation, in, the, 'C-terminal', bZip, domain, can, alter, the, ability, of, 'C/EBP-α', to, bind, 'DNA', and, reduces, 'transactivation,', leading, to, acute, myeloid, leukemia])].
[sujeto(['In', the, last, 'decade,', a, number, of, genes]), verbo([have]), complemento([been, reported, to, be, recurrently, associated, with, myeloid, malignancies])].
[sujeto(['However,', newly, developed, approaches, for, 'next-generation', sequencing]), verbo([provide]), complemento([an, affordable, solution, for, targeted, multiplex, resequencing, of, up, to, several, hundreds, of, amplicons])].
[sujeto(['Here,', we, aimed, to, develop, and, validate, a, novel, custom, panel, for]), verbo([targeted]), complemento([resequencing, of, myeloid, malignancy, samples, using, the, 'Ion', 'PGM(™)', 'System', '(', 'Ion', 'Torrent,', 'Paisley,', 'UK)'])].
[sujeto(['The', inherited, platelet, disorders]), verbo([have]), complemento([witnessed, a, surge, in, our, understanding, of, molecular, mechanisms, of, disease, in, the, past, few, years, due, in, large, to, part, to, the, introduction, of, 'next-generation', sequencing, for, discovery, of, novel, genes])].
[sujeto(['The', implications, for, clinical, practice, of, the, continually, growing, list, of, genes, described, in, small, numbers, of, families, makes, whole, 'exome/genome', tempting, as, an, option, for, evaluation, of, 'patients,', but, use, outside, of, the, research, setting, still, needs, to, be, done, with, extreme, caution, as, interpretation, of, variants, is, likely, to]), verbo([require]), complemento([additional, studies])].
[sujeto(['The', 'NFE2', protein, forms, heterodimers, with, small, 'MAF', 'proteins,', and, the, resulting, complex]), verbo([binds]), complemento([to, regulatory, elements, in, a, large, number, of, target, genes])].
[sujeto(['In', contrast, to, other, 'CNC', transcription, family, members, including, 'NFE2L1', '(', 'NRF1),', 'NFE2L2', '(', 'NRF2)', and, 'NFE2L3', '(', 'NRF3),', which, are, widely, 'expressed,', earlier, studies, had]), verbo([suggested]), complemento([that, the, major, sites, of, 'NFE2', expression, are, hematopoietic, cells])].
[sujeto(['Based', on, cell, culture, studies, it, was, proposed, that, this, protein]), verbo([acts]), complemento([as, a, critical, regulator, of, globin, gene, expression])].
[sujeto(['Indeed,', absence, of, 'NFE2']), verbo([led]), complemento([to, severely, impaired, platelet, production])].
[sujeto(['Surprisingly,', it, was, recently]), verbo([found]), complemento([that, 'NFE2', also, has, a, role, in, 'non-hematopoietic', 'tissues,', such, as, the, 'trophoblast,', in, which, it, is, also, 'expressed,', as, well, as, the, 'bone,', opening, the, door, to, new, research, areas, for, this, transcription, factor])].
[sujeto(['Important', strides]), verbo([have]), complemento([been, made, with, respect, to, the, clinical, significance, of, 'NFE2,', linking, this, transcription, factor, to, hematological, disorders, such, as, polycythemias])].
[sujeto(['In', certain, human, 'cancers,', the, expression, of, critical, oncogenes, is, driven, from, large, regulatory, 'elements,', called, 'super-enhancers,', that]), verbo([recruit]), complemento([much, of, the, 'cell\'s', transcriptional, apparatus, and, are, defined, by, extensive, acetylation, of, histone, 'H3', lysine, 27, '(', 'H3K27ac)'])].
[sujeto(['In', a, subset, of, 'T-cell', acute, lymphoblastic, leukemia, '(', 'T-ALL)', 'cases,', we]), verbo([found]), complemento([that, heterozygous, somatic, mutations, are, acquired, that, introduce, binding, motifs, for, the, 'MYB', transcription, factor, in, a, precise, noncoding, 'site,', which, creates, a, 'super-enhancer', upstream, of, the, 'TAL1', oncogene])].
[sujeto(['MYB']), verbo([binds]), complemento([to, this, new, site, and, recruits, its, 'H3K27', 'acetylase-binding', partner, 'CBP,', as, well, as, core, components, of, a, major, leukemogenic, transcriptional, complex, that, contains, 'RUNX1,', 'GATA-3,', and, 'TAL1', itself])].
[sujeto(['Additionally,', most, endogenous, 'super-enhancers']), verbo([found]), complemento([in, 'T-ALL', cells, are, occupied, by, 'MYB', and, 'CBP,', which, suggests, a, general, role, for, 'MYB', in, 'super-enhancer', initiation])].
[sujeto(['Communities', of, arbuscular, mycorrhizal, fungi, '(', 'AMF)', colonizing, roots]), verbo([have]), complemento([been, increasingly, investigated, by, molecular, approaches, with, 'AMF-specific', 'PCR', primers])].
[sujeto(['We', chose, four, commonly, used, 'AMF-specific']), verbo([primer]), complemento([combinations, '(', 'NS31-AM1,', 'AMLl-AML2,', 'NS31-AML2', and, 'SSUmCf-LSUmBr),', and, used, 18, 'S', rDNA, clone, libraries, to, describe, the, 'AMF', diversity, and, community])].
[sujeto(['Our', results, showed, that, the, specificity, and, coverage, varied, among, the, tested, 'primers,', different]), verbo([primer]), complemento([combinations, would, yield, distinct, patterns, of, species, diversity, and, composition, of, 'AMF', community])].
[sujeto(['SSUmCf-LSUmBr', is, not, the, optimal]), verbo([primer]), complemento([pair, for, 'AMF', community, study, in, current, stage, due, to, limited, reference, sequences, and, large, 'DNA', size])].
[sujeto(['As', an, 'alternative,', 'NS31-AML2', is, more, suitable, in, 'AMF', community, 'study,', because, its]), verbo([target]), complemento([rDNA, region, could, well, match, the, increasingly, used, virtual, taxonomy, database, '(', 'http://maarjam'])].
[sujeto(['DNA', methylation, is, tightly]), verbo([regulated]), complemento([throughout, mammalian, 'development,', and, altered, 'DNA', methylation, patterns, are, a, general, hallmark, of, cancer])].
[sujeto(['The', methylcytosine, dioxygenase, 'TET2', is, frequently, mutated, in, hematological, 'disorders,', including, acute, myeloid, leukemia, '(', 'AML),', and]), verbo([has]), complemento([been, suggested, to, protect, 'CG', dinucleotide, '(', 'CpG)', islands, and, promoters, from, aberrant, 'DNA', methylation])].
[sujeto(['Using', this, 'model,', we, show, that, the, primary, effect, of, 'Tet2']), verbo([loss]), complemento([in, preleukemic, hematopoietic, cells, is, progressive, and, widespread, 'DNA', hypermethylation, affecting, up, to, 25, '%', of, active, enhancer, elements])].
[sujeto(['In', 'contrast,', 'CpG', island, and, promoter, methylation, does, not, change, in, a, 'Tet2-dependent', manner, but]), verbo([increases]), complemento([relative, to, population, doublings])].
[sujeto(['Analysis', of, immediate, gene, expression, changes]), verbo([reveals]), complemento([rapid, deregulation, of, a, large, number, of, genes, implicated, in, 'tumorigenesis,', including, many, 'down-regulated', tumor, suppressor, genes])].
[sujeto(['Hence,', we, propose, that, 'TET2']), verbo([prevents]), complemento([leukemic, transformation, by, protecting, enhancers, from, aberrant, 'DNA', methylation, and, that, it, is, the, combined, silencing, of, several, tumor, suppressor, genes, in, 'TET2', mutated, hematopoietic, cells, that, contributes, to, increased, stem, cell, proliferation, and, leukemogenesis])].
[sujeto(['The', 'AML1-ETO', fusion, 'protein,', which, is, present, in, 10, -, 15, '%', of, cases, of, acute, myeloid, 'leukemia,', is, known, to]), verbo([repress]), complemento([myeloid, differentiation, genes, through, 'DNA', binding, and, recruitment, of, 'chromatin-modifying', proteins, and, transcription, factors, in, target, genes])].
[sujeto(['ChIP-chip', analysis, of, human, hematopoietic, 'stem/progenitor', cells, transduced, with, the, 'AML1-ETO', fusion, gene, enabled, us, to, identify, 1168, 'AML1-ETO']), verbo([target]), complemento(['genes,', 103, of, which, were, 'co-occupied', by, histone, deacetylase, 1, '(', 'HDAC1)', and, had, lost, the, hyperacetylation, mark, at, histone, 'H4,', and, 264, showed, a, 'K9', trimethylation, at, histone, 'H3'])].
[sujeto(['Enrichment', of, genes]), verbo([involved]), complemento([in, hematopoietic, differentiation, and, in, specific, signaling, pathways, was, observed, in, the, presence, of, these, epigenetic, modifications, associated, with, an, '\'', 'inactive\'', chromatin, status])].
[sujeto(['Furthermore,', 'AML1-ETO']), verbo([target]), complemento([genes, had, a, significant, correlation, between, the, chromatin, marks, studied, and, transcriptional, silencing])].
[sujeto(['Interestingly,', 'AML1']), verbo([binding]), complemento([sites, were, absent, on, a, large, number, of, selected, 'AML1-ETO', promoters, and, an, 'Sp1', binding, site, was, found, in, over, 50, '%', of, them])].
[sujeto(['Reversible', silencing]), verbo([induced]), complemento([by, the, fusion, protein, in, the, presence, of, 'AML1', 'and/or', 'Sp1', transcription, factor, binding, site, was, confirmed])].
[sujeto(['Therefore,', this, study]), verbo([provides]), complemento([a, global, analysis, of, 'AML1-ETO', functional, chromatin, modifications, and, identifies, the, important, role, of, 'Sp1', in, the, 'DNA', binding, pattern, of, 'AML1-ETO,', suggesting, a, role, for, 'Sp1-targeted', therapy, in, this, leukemia, subtype])].
[sujeto(['Several', large, biobanks, comprising, umbilical, cord, blood, samples]), verbo([have]), complemento([been, established, allowing, efforts, to, characterize, the, prevalence, and, risk, factors, for, preleukemic, cell, clones, in, healthy, newborns])].
[sujeto(['Fusion', oncogenes, in, acute, myeloid, leukemia, '(', 'AML)']), verbo([promote]), complemento(['self-renewal', from, committed, 'progenitors,', thereby, linking, transformation, and, 'self-renewal', pathways])].
[sujeto(['Like', most, 'cancers,', 'AML', is, a, genetically, and, biologically, heterogeneous, 'disease,', but, it, is, unclear, whether, transformation, results, from, common, or, overlapping, genetic, programs]), verbo([acting]), complemento([downstream, of, multiple, mutations, or, by, the, engagement, of, unique, genetic, programs, acting, cooperatively, downstream, of, individual, mutations])].
[sujeto(['This', distinction, is, 'important,', because, the, involvement, of, common, programs, would, imply, the, existence, of, common, molecular]), verbo([targets]), complemento([to, treat, 'AML,', no, matter, which, oncogenes, are, involved])].
[sujeto(['Here', we, show, that, the, ability, to]), verbo([promote]), complemento(['self-renewal', is, a, generalized, property, of, 'leukemia-associated', oncogenes])].
[sujeto(['Notably,', individual, genes, commonly]), verbo([activated]), complemento([in, these, programs, could, partially, phenocopy, the, 'self-renewal', function, of, 'leukemia-associated', oncogenes, in, committed, murine, progenitors])].
[sujeto(['In', 'summary,', our, findings]), verbo([reveal]), complemento([the, operation, of, common, programs, of, 'self-renewal', and, transformation, downstream, of, 'leukemia-associated', 'oncogenes,', suggesting, that, mechanistically, common, therapeutic, approaches, to, 'AML', are, likely, to, be, 'possible,', regardless, of, the, identity, of, the, driver, oncogene, involved])].
[sujeto(['LMO2', is, highly]), verbo([expressed]), complemento([at, the, most, immature, stages, of, lymphopoiesis])].
[sujeto(['In', 'T-lymphocytes,', aberrant, 'LMO2', expression, beyond, those, stages]), verbo([leads]), complemento([to, 'T-cell', acute, lymphoblastic, 'leukemia,', while, in, 'B', cells, 'LMO2', is, also, expressed, in, germinal, center, lymphocytes, and, diffuse, large, 'B-cell', 'lymphomas,', where, it, predicts, better, clinical, outcome])].
[sujeto(['B-cell', acute, lymphoblastic, leukemia, cases]), verbo([expressed]), complemento([variable, levels, of, 'LMO2', depending, on, immunophenotypical, and, cytogenetic, features])].
[sujeto(['Transcriptional', activation, of, the, 'VEGFA', 'promoter,', a, core, mechanism, for, 'VEGFA', 'regulation,']), verbo([has]), complemento([not, been, fully, elucidated])].
[sujeto(['We']), verbo([found]), complemento([a, significant, '(', 'P', &, 'lt;', 0.0001, ')', inverse, correlation, between, expression, of, 'VEGFA', and, 'AML1/RUNX1', in, a, large, set, of, gene, expression, array, data])].
[sujeto(['Strikingly,', highest, 'VEGFA', levels, were, demonstrated, in, 'AML', blasts, containing, a, 't(8;21)', 'translocation,', which]), verbo([involves]), complemento([the, 'AML1/RUNX1', protein, '(', 'AML1/ETO)'])].
[sujeto(['Overexpression', of, 'AML1/RUNX1']), verbo([led]), complemento([to, downregulation, of, 'VEGFA', 'expression,', whereas, blocking, of, 'AML1/RUNX1', with, siRNAs, resulted, in, increased, 'VEGFA', expression])].
[sujeto(['Cotransfection', of, 'AML1/RUNX1', and, 'VEGFA', promoter, luciferase, promoter, constructs, resulted, in, a]), verbo([decrease]), complemento([in, 'VEGFA', promoter, activity])].
[sujeto(['ChIP', analysis, shows, a, direct]), verbo([binding]), complemento([of, 'AML1/RUNX1', to, the, promoter, of, 'VEGFA', on, three, 'AML1/RUNX1', binding, sites])].
[sujeto(['Silencing', of, 'AML1/ETO']), verbo([caused]), complemento([a, decrease, in, 'VEGFA', mRNA, expression, and, a, decrease, in, secreted, 'VEGFA', protein, levels, in, 'AML1/ETO-positive', 'Kasumi-1', cells])].
[sujeto(['Taken', 'together,', these, data, pinpoint, to, a, model, whereby, in, normal, cells, 'AML1/RUNX1']), verbo([acts]), complemento([as, a, repressor, for, 'VEGFA,', while, in, 'AML', cells, 'VEGFA', expression, is, upregulated, due, to, 'AML1/RUNX1', 'aberrations,', for, 'example,', 'AML1/ETO'])].
[sujeto(['The', 'TGF-beta1/SMAD', signaling, pathway, usually]), verbo([participates]), complemento([in, a, wide, range, of, cellular, processes, such, as, 'growth,', 'proliferation,', differentiation, and, apoptosis])].
[sujeto(['Upon']), verbo([binding]), complemento([on, 'TGF-beta1,', the, dimerized, 'TGF-beta', type, 'II', receptors, recruit, and, phosphorylate, the, 'TGF-beta', type, 'I', 'receptors,', which, phosphorylate, the, 'receptor-regulated', 'SMAD', '(', 'SMAD2', and, 'SMAD3)', presented, by, the, 'SMAD', anchor, for, receptor, activation])].
[sujeto(['The']), verbo([phosphorylated]), complemento(['receptor-regulated', 'SMAD', form, heterologous, complexes, with, the, 'common-mediator', 'SMAD', '(', 'SMAD4)', and, subsequently, translocate, into, the, 'nucleus,', where, they, interact, with, other, transcription, factors, to, regulate, the, expression, of, target, genes])].
[sujeto(['This', 'multi-functional', signaling, pathway]), verbo([modulated]), complemento([by, various, elements, with, complex, mechanisms, at, different, levels, is, also, inevitably, involved, in, cancer])].
[sujeto(['The', constitutively, active, tyrosine, kinase, produced, by, the, specific, 'Bcr-Abl', fusion, gene, on, the, 'Philadelphia', chromosome, can]), verbo([enhance]), complemento([the, resistance, of, malignant, cells, to, 'TGF-beta1-induced', growth, inhibition, and, 'apoptosis,', which, contributes, to, enhancement, of, proteasomal, degradation, of, p27])].
[sujeto(['However,', overexpression, of, the, 'EVI1', 'gene,', which, is, also]), verbo([caused]), complemento([by, 'Bcr-Abl,', can, recruit, the, 'C-terminal', binding, protein, and, histone, deacetylase, to, prevent, the, 'MH2', domain, on, 'SMAD3'])].
[sujeto(['The', later, is, essential, for, transcription, activation, on]), verbo([target]), complemento([genes, and, leads, to, blockage, of, the, 'TGF-beta1/SMAD', signaling, pathway])].
[sujeto(['Some', studies]), verbo([have]), complemento([indicated, that, certain, therapeutic, agents, applied, in, clinical, treatment, can, inhibit, proliferation, and, promote, differentiation, of, leukemia, cells, by, way, of, modulation, of, the, 'TGF-beta1/SMAD', signal, pathway])].
[sujeto(['For', 'example,', arsenic, trioxide, can]), verbo([promote]), complemento([specific, degradation, of, the, 'AML1/MDS1/EVI1', oncoprotein, and, inhibit, the, proliferation, of, leukemia, cells])].
[sujeto(['The', tyrosine, kinase, inhibitor, in, the]), verbo([target]), complemento([therapy, of, chronic, myeloid, leukemia, can, effectively, inhibit, the, tyrosine, kinase, activity, of, 'Bcr-Abl', and, induce, suppression, on, the, 'TGF-beta1/SMAD', signaling, pathway])].
[sujeto(['The', 'TGF-beta1/SMAD', signaling, pathway, plays, an, important, role, in, chronic, myeloid, leukemia, cells, and]), verbo([leads]), complemento([the, leukemia, cells, to, growth, 'inhibition,', differentiation, and, apoptosis])].
[sujeto(['Since', it, is, a, complex, signaling, pathway, widely]), verbo([involved]), complemento([in, many, aspects, of, cellular, 'activities,', further, study, and, comprehensive, analysis, of, the, 'TGF-beta1/SMAD', signaling, pathway, are, imperative, and, will, have, a, guiding, significance, in, research, and, clinical, applications])].
[sujeto(['The', 'Graffi', murine, leukemia, virus]), verbo([induces]), complemento([a, large, spectrum, of, leukemias, in, mice, and, thus, provides, a, good, model, to, compare, the, transcriptome, of, all, types, of, leukemias])].
[sujeto(['We', analyzed, the, gene, expression, profiles, of, both, 'T', and, 'B', leukemias]), verbo([induced]), complemento([by, the, virus, with, 'DNA', microarrays])].
[sujeto(['Given', that, we, considered, that, a, 4, -, fold, change, in, expression, level, was, 'significant,', 388, probe, sets, were]), verbo([associated]), complemento([to, 'B,', to, 'T,', or, common, to, both, leukemias])].
[sujeto(['Several', of, them, were, not, yet]), verbo([associated]), complemento([with, lymphoid, leukemia])].
[sujeto(['More', 'importantly,', we, show, that, the, mouse, 'Fmn2']), verbo([induced]), complemento([an, 'anchorage-independent', 'growth,', a, drastic, modification, in, cell, shape, with, a, concomitant, disruption, of, the, actin, cytoskeleton])].
[sujeto(['Interestingly,', we]), verbo([found]), complemento([that, human, 'FMN2', is, overexpressed, in, approximately, 95, '%', of, 'pre-B', acute, lymphoblastic, leukemia, with, the, highest, expression, levels, in, patients, with, a, 'TEL/AML1', rearrangement])].
[sujeto(['These', 'results,', surely, related, to, the, role, of, 'FMN2', in, meiotic, spindle, 'maintenance,']), verbo([suggest]), complemento([its, important, role, in, leukemogenesis])].
[sujeto(['Finally,', we, propose, a, new, panel, of, genes, potentially]), verbo([involved]), complemento([in, 'T', 'and/or', 'B', leukemias])].
[sujeto(['The', 'ETV6/RUNX1', fusion, 'gene,', present, in, 25, '%', of, 'B-lineage', childhood, acute, lymphoblastic, leukemia, '(', 'ALL),', is, thought, to, represent, an, initiating, 'event,', which]), verbo([requires]), complemento([additional, genetic, changes, for, leukemia, development])].
[sujeto(['As', previously, 'demonstrated,', alterations]), verbo([targeting]), complemento([genes, involved, in, 'B-cell', development, were, common, '(', present, in, 28, '%', of, 'cases)'])].
[sujeto(['However,', the, combined, analysis, also, identified, alterations, affecting]), verbo([nuclear]), complemento([hormone, response, '(', 24, '%', ')', to, be, a, characteristic, feature, of, 'ETV6/RUNX1-positive', 'ALL'])].
[sujeto(['Transforming', growth, factor, beta, '(', 'TGFbeta)']), verbo([regulates]), complemento([essential, cellular, functions, such, as, cellular, 'proliferation,', 'differentiation,', and, apoptosis])].
[sujeto(['The', 'Bcl-2', family, of, proteins]), verbo([has]), complemento([been, implicated, as, mediators, of, 'TGFbeta-induced', apoptosis])].
[sujeto(['We', demonstrated, previously, that, 'TGFbeta']), verbo([induces]), complemento([the, expression, of, 'Bim', '(', 'Bcl-2-interacting', mediator, of, cell, 'death),', a, member, of, the, 'BH3-only', family, of, 'pro-apoptotic', 'Bcl-2', 'proteins,', to, induce, cell, death, in, 'B-lymphocytes'])].
[sujeto(['We', show, that, 'TGFbeta']), verbo([induces]), complemento(['Bim', protein, and, mRNA, 'levels,', and, its, expression, is, sufficient, to, induce, cell, death])].
[sujeto(['Gene', array, results, revealed, that, 'Runx1,', a, member, of, the, 'Runx', family, of, transcription, 'factors,', was]), verbo([induced]), complemento([by, 'TGFbeta,', and, this, induction, was, confirmed, at, the, mRNA, and, protein, levels])].
[sujeto(['Interestingly,', 'TGFbeta', specifically]), verbo([induced]), complemento([the, expression, of, 'Runx1', protein, from, an, internal, ribosome, entry, site, '(', 'IRES)-dependent,', 'cap-independent,', mRNA, 'transcript,', and, its, overexpression, was, sufficient, to, induce, hepatocyte, apo, pto, sis])].
[sujeto(['Deletion', and, mutation, analyses, of, the, murine, 'Bim', promoter, identified, a, putative, forkhead]), verbo([binding]), complemento(['element,', at, position, -, 174, to, -, 168, from, the, transcription, start, 'site,', as, the, mediator, of, 'Runx1', induction])].
[sujeto(['Co-immunoprecipitation,', electrophoretic, mobility, shift, 'assays,', and, chromatin, immunoprecipitation, assays, demonstrated, that, 'Runx1', does, not]), verbo([bind]), complemento([directly, to, the, identified, forkhead, binding, element, but, rather, binds, the, transcriptional, regulator, 'FOXO3,', which, occupies, this, site])].
[sujeto(['Finally,', small, interfering, 'RNA', knockdown, of, 'Runx1', or, 'FOXO3']), verbo([decreased]), complemento(['TGFbeta-induced', 'Bim', expression])].
[sujeto(['Our', results, support, a, mechanism, in, which, 'TGFbeta']), verbo([stimulates]), complemento(['Bim', transcription, by, 'up-regulating', 'Runx1', 'expression,', which, binds, 'FOXO3,', and, the, two, cooperate, in, the, transcriptional, induction, of, 'Bim'])].
[sujeto(['Although', most, skeletal, muscle, genes, are]), verbo([expressed]), complemento([at, similar, levels, in, electrically, 'active,', innervated, muscle, and, in, electrically, 'inactive,', denervated, 'muscle,', a, small, number, of, 'genes,', including, those, encoding, the, acetylcholine, 'receptor,', 'N-CAM,', and, 'myogenin,', are, expressed, at, significantly, higher, levels, in, denervated, than, in, innervated, muscle])].
[sujeto(['The', mechanisms, that]), verbo([mediate]), complemento([electrical, 'activity-dependent', gene, regulation, are, not, 'understood,', but, these, mechanisms, are, likely, to, be, 'responsible,', at, least, in, 'part,', for, the, changes, in, muscle, structure, and, function, that, accompany, a, decrease, in, myofiber, electrical, activity])].
[sujeto(['To', understand, how, muscle, activity]), verbo([regulates]), complemento([muscle, structure, and, 'function,', we, used, a, 'subtractive-hybridization', and, cloning, strategy, to, identify, and, isolate, genes, that, are, expressed, preferentially, in, innervated, or, denervated, muscle])].
[sujeto(['One', of, the, genes, which, we]), verbo([found]), complemento([to, be, regulated, by, electrical, activity, is, the, recently, discovered, acute, myeloid, leukemia, 1, '(', 'AML1)', gene])].
[sujeto(['We', show, that, 'AML1', is]), verbo([expressed]), complemento([at, low, levels, in, innervated, skeletal, muscle, and, at, 50, -, to, 100, -, 'fold-higher', levels, in, denervated, muscle])].
[sujeto(['Four', 'AML1', transcripts, are]), verbo([expressed]), complemento([in, denervated, 'muscle,', and, the, abundance, of, each, transcript, increases, after, denervation])].
[sujeto(['We', transfected, 'C2', muscle, cells, with, an, expression, vector, encoding, 'AML1,', tagged, with, an, epitope, from, 'hemagglutinin,', and, we, show, that, 'AML1', is, a]), verbo([nuclear]), complemento([protein, in, muscle])].
[sujeto(['AML1']), verbo([dimerizes]), complemento([with, 'core-binding', factor, beta, '(', 'CBF', 'beta),', and, we, show, that, 'CGF', beta, is, expressed, at, high, levels, in, both, innervated, and, denervated, skeletal, muscle])].
[sujeto(['PEBP2', 'alpha,', which, is, structurally, related, to, 'AML1', and, which, also]), verbo([dimerizes]), complemento([with, 'CBF', 'beta,', is, expressed, at, low, levels, in, skeletal, muscle, and, is, 'up-regulated', only, weakly, by, denervation])].
[sujeto(['These', results, are, consistent, with, the, idea, that, 'AML1', may]), verbo([have]), complemento([a, role, in, regulating, gene, expression, in, skeletal, muscle])].
[sujeto(['Here', we, demonstrate, that, 'Ikaros', also]), verbo([regulates]), complemento(['Th17', differentiation, through, its, ability, to, promote, expression, of, multiple, 'Th17', 'lineage-determining', 'genes,', including, 'Ahr,', 'Runx1,', 'Rorc,', 'Il17a,', and, 'Il22'])].
[sujeto(['In', naive, 'cells,', 'Ikaros', is]), verbo([required]), complemento([to, limit, repressive, chromatin, modifications, at, these, gene, 'loci,', thus, maintaining, the, potential, for, expression, of, the, 'Th17', gene, program])].
[sujeto(['Additionally,', 'Ikaros']), verbo([represses]), complemento([the, expression, of, genes, that, limit, 'Th17', 'development,', including, 'Foxp3', and, 'Tbx21'])].
[sujeto(['These', data, define, new]), verbo([targets]), complemento([of, the, action, of, 'Ikaros', and, indicate, that, 'Ikaros', plays, a, critical, role, in, 'CD4+', 'T', cell, differentiation, by, integrating, specific, cytokine, cues, and, directing, epigenetic, modifications, that, facilitate, activation, or, repression, of, relevant, genes, that, drive, 'T', cell, lineage, choice])].
[sujeto(['Forced', expression, of, the, transcription, factor, 'HoxB4']), verbo([has]), complemento([been, shown, to, enhance, the, 'self-renewal', capacity, of, mouse, bone, marrow, hematopoietic, stem, cells, '(', 'HSCs)', and, confer, a, 'long-term', repopulating, capacity, to, yolk, sac, and, embryonic, stem, '(', 'ES)', 'cell-derived', hematopoietic, precursors])].
[sujeto(['The', results, revealed, many, of, the, genes, essential, for, 'HSC', development, to, be, direct]), verbo([targets]), complemento([of, 'HoxB4,', such, as, 'Runx1,', 'Scl/Tal1,', 'Gata2,', and, 'Gfi1'])].
[sujeto(['HoxB4', tended, to]), verbo([activate]), complemento([the, 'transcription,', but, the, 'down-regulation', of, a, significant, portion, of, direct, targets, suggested, its, function, to, be, 'context-dependent'])].
[sujeto(['Our', list, of, 'HoxB4']), verbo([targets]), complemento([also, provides, novel, candidate, regulators, for, 'HSCs'])].
[sujeto(['AML1-ETO', fusion, protein, is, a, product, of, chromosome, translocation, 't(8;21)', frequently, occurred, in, acute, myeloid, leukemia, '(', 'AML),', but, its, sole, expression, appears, to, fail, to]), verbo([cause]), complemento([overt, leukemia, in, vivo])].
[sujeto(['AML1-ETO', fusion, protein, was, conditionally]), verbo([induced]), complemento([in, engineered, 'U937-A/E', 9, /, 14, /, 18, cells])].
[sujeto(['Our', results, showed, that, 'AML1-ETO', induction, significantly]), verbo([increased]), complemento([the, formation, of, carcinogen, 'benzopyrene-DNA', adducts, in, leukemic, cells])].
[sujeto(['In', line, with, the, 'effect,', we, also]), verbo([found]), complemento([that, 'AML1-ETO', induction, upregulated, 'CYP1A1', 'expression,', which, was, dependent, on, 'AML1-binding', motif, in, the, promotor, of, 'CYP1A1', gene])].
[sujeto(['Additionally,', 'AML1-ETO', protein, also]), verbo([increased]), complemento(['AhR', 'expression,', a, 'ligand-activated', transcription, factor, that, mediates, 'PAHs-induced', 'CYP1A1', gene, expression])].
[sujeto(['These', 'data,', combined, with, its, inhibitory, effect, on, 'DNA', repair, as]), verbo([reported]), complemento(['previously,', propose, that, the, presence, of, 'AML1-ETO', increases, the, susceptibility, of, cells, to, chemical, 'carcinogens,', which, favors, the, development, of, additional, genetic, alterations])].
[sujeto(['Cytogenetically', normal, acute, myeloid, leukemia, '(', 'CN-AML)', patients, harboring, 'RUNX1', mutations]), verbo([have]), complemento([a, dismal, prognosis, with, 'anthracycline/cytarabine-based', chemotherapy])].
[sujeto(['Tail', vein, injection, of, 'CG-SH', into, 'NOD', scid, gamma, mice]), verbo([led]), complemento([to, leukemic, engraftment, in, the, bone, 'marrow,', 'spleen,', and, peripheral, blood, within, 6, weeks])].
[sujeto(['Single', nucleotide, polymorphism, '(', 'SNP)', rs11671784, is, in, the, loop, of, 'pre-miR-27a', and, the, 'G/A', variation, can, significantly]), verbo([decrease]), complemento([mature, 'miR-27a', expression])].
[sujeto(['In-vitro', study, was, performed, to, explore, the, mechanism, of, 'chemo-sensitivity', and, the, downstream]), verbo([target]), complemento([of, 'miR-27a', by, using, bladder, cancer, cell, lines])].
[sujeto(['This', study, identified, a, causative, relationship, between, rs11671784, 'G/A', 'variation,', lowered, 'miR-27a', 'expression,']), verbo([increased]), complemento(['RUNX-1', expression, and, following, weakened, 'chemo-sensitivity'])].
[sujeto([rs11671784, 'G', allele]), verbo([has]), complemento([significantly, stronger, effect, over, 'A', allele, in, promoting, 'chemo-sensitivity', in, bladder, cancer])].
[sujeto(['miR-27a']), verbo([mediates]), complemento([chemotherapy, at, least, partially, through, reducing, 'P-gp', expression, and, increasing, apoptosis])].
[sujeto(['In', 'addition,', 'RUNX-1', is, a, novel, direct]), verbo([target]), complemento([of, 'miR-27a,', which, is, involved, in, its, regulation, of, 'chemo-sensitivity', in, bladder, cancer])].
[sujeto(['The', presence, of, 'FISH(+)CD34(+)CD38(-)', cells, before, consolidation, was, negatively]), verbo([associated]), complemento([with, cumulative, incidence, of, relapse, '(', 64, vs, 18, '%', ',', 'P', =])].
[sujeto([5, ')', ',', and]), verbo([retained]), complemento([prognostic, significance, for, 'RFS', in, multivariate, analysis])].
[sujeto(['EPs', can, revert, to, 'SCs', upon, 'injury,', but, whether, this, dedifferentiation, occurs, in, normal, 'HF', homeostasis, '(', hair, 'cycle)', and, the, mechanisms]), verbo([regulating]), complemento([both, differentiation, and, dedifferentiation, are, unclear])].
[sujeto(['Here,', we, use, lineage, 'tracing,']), verbo([gain]), complemento([of, 'function,', transcriptional, 'profiling,', and, functional, assays, to, examine, the, role, of, observed, endogenous, 'Runx1', level, changes, in, the, hair, cycle])].
[sujeto(['We']), verbo([find]), complemento([that, forced, 'Runx1', expression, induces, hair, degeneration, '(', 'catagen)', and, simultaneously, promotes, changes, in, the, quiescent, bulge, 'SC', transcriptome, toward, a, cell, state, resembling, the, 'EP', 'HG', fate])].
[sujeto(['We', propose, that, 'SC', differentiation, and, dedifferentiation, are, likely, to, occur, during, normal, 'HF', degeneration, and, niche, restructuring, in, response, to, changes, in, endogenous, 'Runx1', levels]), verbo([associated]), complemento([with, 'SC', location, with, respect, to, the, niche])].
[sujeto(['Rearrangements']), verbo([involving]), complemento([the, 'RUNX1', gene, account, for, approximately, 15, '%', of, balanced, translocations, in, 'therapy-related', acute, myeloid, leukemia, '(', 't-AML)', patients, and, are, one, of, the, most, common, genetic, abnormalities, observed, in, 't-AML'])].
[sujeto(['Drugs']), verbo([targeting]), complemento([the, topoisomerase, 'II', '(', 'TOP2)', enzyme, are, implicated, in, 't-AML;', 'however,', the, mechanism, is, not, well, understood, and, to, date, a, single, 'RUNX1-RUNX1T1', 't-AML', breakpoint, junction, sequence, has, been, published])].
[sujeto(['Here', we]), verbo([report]), complemento([an, additional, five, breakpoint, junction, sequences, from, 't-AML', patients, with, the, 'RUNX1-', 'RUNX1T1', translocation])].
[sujeto(['Using', a, leukemia, cell, line, 'model,', we, show, that, 'TOP2', beta, '(', 'TOP2B)', is]), verbo([required]), complemento([for, induction, of, 'RUNX1', chromosomal, breaks, by, the, 'TOP2', poison, etoposide, and, 'that,', while, 'TOP2', alpha, '(', 'TOP2A)', and, 'TOP2B', proteins, are, both, present, on, 'RUNX1', and, 'RUNX1T1', 'chromatin,', only, the, 'TOP2B', enrichment, reached, significance, following, etoposide, exposure, at, a, region, on, 'RUNX1', where, translocations, occur])].
[sujeto(['Specifically,', we, identified, a, 'TOP2B-dependent']), verbo([increase]), complemento([in, the, number, of, nuclei, displaying, juxtaposed, 'RUNX1', and, 'RUNX1T1', loci, following, etoposide, treatment])].
[sujeto(['In', this, 'study,', we]), verbo([have]), complemento([found, for, the, first, time, that, 'Runt-related', transcription, factor, 1, '(', 'RUNX1)', contributes, to, 'p53-dependent', 'DNA', damage, response])].
[sujeto(['Upon', adriamycin, '(', 'ADR)', 'exposure,', p53, as, well, as, 'RUNX1', were, strongly]), verbo([induced]), complemento([in, 'p53-proficient', 'HCT116', and, 'U2OS', 'cells,', which, were, closely, associated, with, significant, transactivation, of, p53, target, 'genes,', such, as, 'p21(WAF)(1),', 'BAX,', 'NOXA,', and, 'PUMA'])].
[sujeto(['RUNX1', was, exclusively]), verbo([expressed]), complemento([in, the, cell, nucleus, and, formed, a, complex, with, p53, in, response, to, 'ADR'])].
[sujeto(['Chromatin', immunoprecipitation, assay, demonstrated, that, p53, together, with, 'RUNX1', are, efficiently]), verbo([recruited]), complemento([onto, p53, target, gene, promoters, following, 'ADR', 'exposure,', indicating, that, 'RUNX1', is, involved, in, 'p53-mediated', transcriptional, regulation])].
[sujeto(['Indeed,', forced, expression, of, 'RUNX1']), verbo([stimulated]), complemento([the, transcriptional, activity, of, p53, in, response, to, 'ADR'])].
[sujeto(['Consistent', with, these, 'observations,', knockdown, of, 'RUNX1', attenuated, 'ADR-mediated', induction, of, p53]), verbo([target]), complemento([genes, and, suppressed, 'ADR-dependent', apoptosis])].
[sujeto(['Furthermore,', 'RUNX1', was]), verbo([associated]), complemento([with, p300, histone, 'acetyltransferase,', and, 'ADR-dependent', acetylation, of, p53, at, 'Lys-373/382', was, markedly, inhibited, in, 'RUNX1', knockdown, cells])].
[sujeto(['In', 'addition,', knockdown, of, 'RUNX1', resulted, in, a, significant]), verbo([decrease]), complemento([in, the, amount, of, 'p53-p300', complex, following, 'ADR', exposure])].
[sujeto(['Taken', 'together,', our, present, results, strongly]), verbo([suggest]), complemento([that, 'RUNX1', is, required, for, the, stimulation, of, p53, in, response, to, 'DNA', damage, and, also, provide, novel, insight, into, understanding, the, molecular, mechanisms, behind, 'p53-dependent', 'DNA', damage, response])].
[sujeto(['The', 5, -, year, cumulative, incidence, of, relapse, was, 19.4, '%', and, testes, were, more, frequently]), verbo([involved]), complemento([in, 'ETV6/RUNX1-positive', relapses, '(', 'P=0'])].
[sujeto(['In', univariate, 'analysis,', female, gender, was]), verbo([associated]), complemento([with, a, poor, 'survival,', whereas, site, of, 'relapse,', age, at, 'diagnosis,', leukocytosis, and, consolidation, strategy, had, no, effect])].
[sujeto(['In', multivariate, 'analysis,', only, the, duration, of, first, remission, remained]), verbo([associated]), complemento([with, outcome])].
[sujeto(['We']), verbo([found]), complemento([an, excellent, outcome, for, patients, with, 'ETV6/RUNX1-positive', leukemia, relapses, that, occurred, more, than, 36, months, after, diagnosis])].
[sujeto(['Here', we]), verbo([report]), complemento([that, triptolide, inhibits, cell, proliferation, and, induces, apoptosis, in, a, 'dose-', and, 'time-dependent', manner, of, 't(8;21)-bearing', 'Kasumi-1,', 'SKNO-1', and, 'CD34+', cells, harvested, from, bone, marrow, samples, of, patients, with, 't(8;21)', leukemia])].
[sujeto(['We', show, that, triptolide]), verbo([triggers]), complemento([cleavage, of, the, resultant, 'AML1-ETO', fusion, protein, of, 't(8;21),', and, causes, downregulation, of, 'C-KIT', followed, by, inhibition, of, 'JAK-STAT', signaling])].
[sujeto(['Triptolide', downregulates, p65, and]), verbo([inhibits]), complemento([the, 'DNA-binding', activity, of, 'NF-κB'])].
[sujeto(['Culture', with, 'BMP-2', or, 'BMP-6+AA']), verbo([increased]), complemento(['ALP', activity, of, 'PDLCs,', suggesting, their, 'osteo-inductive', effects])].
[sujeto(['However,', longer, duration, of, culture, showed, neither, of, the, 'BMPs']), verbo([induced]), complemento([in, vitro, mineralization])].
[sujeto(['In', 'contrast,', 'OS', were, able, to]), verbo([increase]), complemento(['ALP', activity, and, 'OPN', 'expressions,', and, also, induced, in, vitro, mineralization])].
[sujeto(['The', mineralization, ability, was, not]), verbo([enhanced]), complemento([by, the, addition, of, 'BMP-2', or, 'BMP-6'])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, addition, of, 'BMP-2', or, 'BMP-6', to, 'OS', may, not, enhance, an, osteogenic, differentiation, of, hPDLCs])].
[sujeto(['Runx1,', a, 'Runt', domain, transcription, 'factor,', controls, the, differentiation, of, nociceptors, that]), verbo([express]), complemento([the, neurotrophin, receptor, 'Ret,', regulates, the, expression, of, many, ion, channels, and, 'receptors,', and, controls, the, 'lamina-specific', innervation, pattern, of, nociceptive, afferents, in, the, spinal, cord])].
[sujeto(['We']), verbo([activated]), complemento([ectopic, expression, of, 'Runx1a', in, cultured, 'NCSCs', using, the, 'Tet-ON', gene, regulatory, system, during, the, formation, of, neurospheres, and, analyzed, the, proportion, of, neurons, and, glial, cells, originating, from, 'NCSCs'])].
[sujeto(['Offsprings', in, which, 'Runx1a', had, been]), verbo([activated]), complemento([showed, retarded, growth, and, displayed, 'megacolon,', pigment, 'defects,', and, dystrophic, dorsal, root, ganglia])].
[sujeto(['In', the, neuropathic, pain, 'model,', the, threshold, for, mechanical, sensitivity, was, markedly]), verbo([increased]), complemento([following, activation, of, 'Runx1a'])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, 'Runx1a', has, a, specific, role, in, 'NCSC', development, and, that, modulation, of, 'Runx1a', activity, may, reduce, mechanical, hypersensitivity, associated, with, neuropathic, pain])].
[sujeto(['We']), verbo([report]), complemento([a, case, of, a, 31, -, 'year-old', female, with, a, positive, 'RUNX1/CBFA2T1', '(', alias, 'AML1/ETO)', fusion, gene, and, a, karyotype, with, a, 't(2;21;8)(p12;q22;q22)'])].
[sujeto(['Although', variant, translocations]), verbo([involving]), complemento([chromosome, region, 2, p12, have, never, been, reported, 'before,', we, suppose, this, translocation, may, be, responsible, for, the, clinical, manifestation, and, prognosis, of, this, case])].
[sujeto(['The', translocation, 't(16;21)']), verbo([involving]), complemento(['RUNX1', '(', 'AML1)', and, resulting, in, the, 'RUNX1-CBFA2T3', fusion, is, a, rare, but, recurrent, abnormality, mostly, found, in, 'therapy-related', acute, myeloid, leukemia, '(', 't-AML)', associated, with, agents, targeting, topoisomerase, 'II', '(', topo, 'II)'])].
[sujeto(['This', study]), verbo([suggests]), complemento([a, wider, distribution, in, the, human, 'genome,', and, particularly, at, genes, involved, in, chromosome, translocations, observed, in, 't-AML,', of, 'DNA', regions, '(', 'hotspot)', targeted, by, specific, topo, 'II', drugs])].
[sujeto(['The', median, copy, number, of, the, 'RUNX1/MTG8', 'transcript,', measured, after, each, treatment, course]), verbo([decreased]), complemento([over, time])].
[sujeto(['However,', an]), verbo([increase]), complemento([in, the, 'MRD', level, was, documented, in, three, patients, after, the, second, 'consolidation,', and, all, of, them, subsequently, relapsed])].
[sujeto(['But', no, data]), verbo([have]), complemento([been, available, up, to, date, concerning, mutual, positioning, of, these, particular, genes, in, the, nucleus, of, a, living, cell, as, well, as, the, mechanism, of, their, rapprochement, and, realignment])].
[sujeto(['Here', we, show, that, there, is, no, proximity, between, these, two, genes, in, the, primary, nuclei, of, normal, human, male, fibroblasts, and, moreover, that, these, genes, are, located, in, different]), verbo([nuclear]), complemento([layers])].
[sujeto(['But', we, further, show, that, treatment, of, cells, with, 'VP-16', '(', 'etoposide),', an, inhibitor, of, 'DNA', topoisomerase, 'II', widely, used, in, anticancer, 'chemotherapy,']), verbo([causes]), complemento([the, 'ETO', gene, repositioning, which, allows, 'AML1', and, 'ETO', genes, to, be, localized, in, the, same, nuclear, layer])].
[sujeto(['Finally,', inhibition, of, 'ETO', gene, repositioning, by, 2, ',', 3, -, butanedione, monoxime, '(', 'BDM)']), verbo([suggests]), complemento([that, this, process, depends, on, nuclear, myosin])].
[sujeto(['Mesenchymal', stem, cells, '(', 'MSC)']), verbo([have]), complemento([been, derived, from, different, cultured, human, 'tissues,', including, bone, 'marrow,', adipose, 'tissue,', amniotic, fluid, and, umbilical, cord, blood])].
[sujeto(['Only', recently, it, was]), verbo([suggested]), complemento([that, 'MSC', descended, from, perivascular, 'cells,', the, latter, being, defined, as, 'CD146⁺', 'neuro-glial', proteoglycan, '(', 'NG)2⁺', 'platelet-derived', growth, 'factor-Rβ⁺', 'ALP⁺', 'CD34⁻', 'CD45⁻', von, 'Willebrand', factor, '(', 'vWF)⁻', 'CD144⁻'])].
[sujeto(['Moreover,', foetal, 'HUC', perivascular, cells, '(', 'HUCPC)']), verbo([express]), complemento([the, embryonic, cell, markers, specific, embryonic, 'antigen-4,', 'Runx1', and, 'Oct-4', and, can, be, cultured, over, the, long, term])].
[sujeto(['The', secretory, profile, exhibited, by, foetal, 'HUCPC', in, the, migration, assay]), verbo([suggested]), complemento([a, paracrine, effect, that, could, be, exploited, in, various, clinical, conditions, including, lung, disorders])].
[sujeto(['The', 'tick-borne', protozoan, parasite, 'Theileria', annulata]), verbo([causes]), complemento([a, debilitating, disease, of, cattle, called, 'Tropical', 'Theileriosis'])].
[sujeto(['The', parasite, predominantly, invades, bovine, macrophages, '(', m, 'phi)', and]), verbo([induces]), complemento([host, cell, transformation, by, a, mechanism, that, has, not, been, fully, elucidated])].
[sujeto(['Infection', is]), verbo([associated]), complemento([with, loss, of, characteristic, m, phi, functions, and, phenotypic, 'markers,', indicative, of, host, cell, 'de-differentiation'])].
[sujeto(['We']), verbo([have]), complemento([investigated, the, effect, of, 'T'])].
[sujeto(['The', 'up-regulation', of, 'c-maf', mRNA, levels, observed, during, bovine, monocyte, differentiation, to, m, phi, was]), verbo([suppressed]), complemento([by, 'T'])].
[sujeto(['annulata-infected', cells, with, the, theileriacidal, drug, buparvaquone]), verbo([induced]), complemento(['up-regulation', of, 'c-maf', and, 'mafB,', which, correlated, with, altered, expression, of, 'down-stream', target, 'genes,', e])].
[sujeto([annulata, infection, is]), verbo([associated]), complemento([with, the, suppression, of, the, transcription, 'factors,', 'Pu'])].
[sujeto([1, and, 'RUNX1,', and, colony]), verbo([stimulating]), complemento([factor, 1, receptor, '(', 'CSF1R)', which, are, also, involved, in, the, regulation, of, 'monocyte/m', phi, differentiation])].
[sujeto(['We', believe, these, results]), verbo([provide]), complemento([the, first, direct, evidence, that, 'T'])].
[sujeto([annulata]), verbo([modulates]), complemento([the, host, m, phi, differentiation, 'state,', which, may, diminish, the, defence, capabilities, of, the, infected, cell, 'and/or', promote, cell, proliferation])].
[sujeto(['The', 't(8;21)', chromosomal, translocation]), verbo([activates]), complemento([aberrant, expression, of, the, 'AML1-ETO', '(', 'AE)', fusion, protein, and, is, commonly, associated, with, core, binding, factor, acute, myeloid, leukaemia, '(', 'CBF', 'AML)'])].
[sujeto(['Combining', a, conditional, mouse, model, that, closely, resembles, the, slow, evolution, and, the, mosaic, 'AE', expression, pattern, of, human, 't(8;21)', 'CBF', 'AML', with, global, transcriptome, 'sequencing,', we]), verbo([find]), complemento([that, disease, progression, was, characterized, by, two, principal, pathogenic, mechanisms])].
[sujeto(['We', also]), verbo([find]), complemento([that, both, 'HSC', and, 'lineage-restricted', granulocyte, macrophage, progenitors, '(', 'GMPs)', acquired, leukaemic, stem, cell, '(', 'LSC)', potential, being, capable, of, initiating, and, maintaining, the, disease])].
[sujeto(['Finally,', our, data, demonstrate, that, 'long-term', expression, of, 'AE']), verbo([induces]), complemento([an, indolent, myeloproliferative, disease, '(', 'MPD)-like', myeloid, leukaemia, phenotype, with, complete, penetrance, and, that, acute, inactivation, of, 'AE', function, is, a, potential, novel, therapeutic, option])].
[sujeto(['MicroRNA']), verbo([regulate]), complemento([the, activity, of, 'protein-coding', genes, including, those, involved, in, hematopoietic, cancers])].
[sujeto(['T-cell,', 'MLL-rearranged,', 'TEL-AML1-positive,', 'E2A-PBX1-positive', and, hyperdiploid, acute, lymphoblastic, 'leukemia,', with, the, exception, of, 'BCR-ABL-positive', and, '\'', 'B-other\'', acute, lymphoblastic, leukemias, '(', defined, as, precursor, 'B-cell', acute, lymphoblastic, leukemia, not, carrying, the, foregoing, cytogenetic, 'aberrations),', were]), verbo([found]), complemento([to, have, unique, 'microRNA-signatures', that, differed, from, each, other, and, from, those, of, healthy, hematopoietic, cells])].
[sujeto(['Strikingly,', the, microRNA, signature, of, 'TEL-AML1-positive', and, hyperdiploid, cases, partly, 'overlapped,', which, may]), verbo([suggest]), complemento([a, common, underlying, biology])].
[sujeto(['No', discriminative, microRNA, were]), verbo([found]), complemento([for, prednisolone, response, and, only, one, microRNA, was, linked, to, resistance, to, 'L-asparaginase'])].
[sujeto(['A', combined, expression, profile, based, on, 14, microRNA, that, were, individually]), verbo([associated]), complemento([with, 'prognosis,', was, highly, predictive, of, clinical, outcome, in, pediatric, acute, lymphoblastic, leukemia, '(', 5, -, year, 'disease-free', survival, of, 89.4, '%', '±7%', versus, 60.8, '±12%,', 'P=0'])].
[sujeto(['Functional', studies, of, discriminative, and, prognostically, important, microRNA, may]), verbo([provide]), complemento([new, insights, into, the, biology, of, pediatric, acute, lymphoblastic, leukemia])].
[sujeto(['CD20', is]), verbo([expressed]), complemento([in, approximately, 'one-', half, of, pediatric, acute, lymphoblastic, leukemia, '(', 'ALL)', cases, with, 'B-cell', precursor, '(', 'BCP)', origin])].
[sujeto(['CD20-positivity', significantly]), verbo([increased]), complemento([from, 45, '%', in, initial, samples, to, 81, '%', at, 'end-induction', '(', day, 15, ',', 71, '%', ')'])].
[sujeto(['In', 'vitro,', 'CD20', 'up-regulation', significantly]), verbo([enhanced]), complemento([rituximab, cytotoxicity, and, could, be, elicited, on, prednisolone, incubation])].
[sujeto(['In', 'conclusion,', 'CD20', 'up-regulation', is, frequently]), verbo([induced]), complemento([in, 'BCP-ALL', during, 'induction,', and, this, translates, into, an, acquired, state, of, higher, sensitivity, to, rituximab])].
[sujeto(['The', 'Wilms\'', tumour, gene, 1, '(', 'WT1)', protein, is, highly]), verbo([expressed]), complemento([in, most, leukaemias])].
[sujeto(['Co-expression', of, 'WT1', and, the, fusion, protein, 'AML1-ETO', in, mice, rapidly]), verbo([induces]), complemento([acute, myeloid, leukaemia, '(', 'AML)'])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, the, fusion, protein, 'BCR/ABL1', increases, expression, of, 'WT1', mRNA, and, protein, via, the, 'phosphatidylinositol-3', kinase, '(', 'PI3K)-Akt', pathway])].
[sujeto(['Inhibition', of, 'BCR/ABL1', or, 'PI3K', activity, strongly]), verbo([suppressed]), complemento([transcription, from, 'WT1', 'promoter/enhancer', reporters])].
[sujeto(['Forced', expression, of, 'BCR/ABL1', in, normal, human, progenitor, 'CD34+', cells]), verbo([increased]), complemento(['WT1', mRNA, and, 'protein,', further, supporting, the, notion, of, 'BCR/ABL1-driven', expression, of, 'WT1', in, human, haematopoietic, cells])].
[sujeto(['Forced', expression, of, 'WT1', in, 'K562', cells]), verbo([provided]), complemento([protection, against, cytotoxic, effects, of, the, 'ABL1', tyrosine, kinase, inhibitor, 'imatinib,', as, judged, by, effects, on, viability, measured, by, trypan, blue, 'exclusion,', metabolic, 'activity,', annexin, 'V', and, 'DAPI', '(', 4, '\'', ',', 6, -, 'diamidino-2-phenylindole)', staining])].
[sujeto(['None', of, the, isoforms]), verbo([provided]), complemento([any, detectable, protection, against, apoptosis, induced, by, arsenic, trioxide, and, only, very, weak, protection, against, 'etoposide,', indicating, that, 'WT1', interferes, with, specific, apoptotic, signalling, pathways])].
[sujeto(['Our', data, demonstrate, that, 'WT1', expression, is]), verbo([induced]), complemento([by, oncogenic, signalling, from, 'BCR/ABL1', and, that, 'WT1', contributes, to, resistance, against, apoptosis, induced, by, imatinib])].
[sujeto(['c-MET', was]), verbo([found]), complemento([to, be, expressed, in, normal, 'B', cells, and, in, 'B-ALL', patients, with, the, 't(12;21)', 'TEL-AML1', 'translocation,', but, it, is, not, expressed, in, the, most, part, of, 'B-ALL', without, the, 't(12;21)'])].
[sujeto(['We', also]), verbo([found]), complemento([that, 'c-MET,', related, to, proliferation, and, protection, from, 'apoptosis,', is, associated, with, the, 'pro-apoptotic', protein, 'FAS', in, 'TEL-AML1', 'B-ALL', cells, and, in, normal, 'B', lymphocytes])].
[sujeto(['REH', cells]), verbo([stimulated]), complemento([with, 'IL-3', and, treated, with, doxorubicin, did, not, undergo, apoptosis, more, than, nonstimulated, 'cells,', demonstrating, that, increased, proliferation, in, itself, is, not, directly, related, to, the, higher, apoptotic, sensitivity, observed, with, 'HGF', stimulation])].
[sujeto(['These', results, indicate, that, 'c-MET', activation]), verbo([enhances]), complemento([specifically, 'FAS-mediated', apoptosis, in, 'TEL-AML1', 'ALL', cells, 'and,', considering, that, the, 'c-MET/FAS', complex, is, present, only, in, normal, 'B', lymphocytes, and, in, 'TEL-AML1', 'leukemias,', this, implies, that, it, may, have, an, important, contribution, in, cellular, homeostasis, and, in, high, sensitivity, of, 'TEL-AML1', 'ALL', to, chemotherapeutic, regimens])].
[sujeto(['Further', 'follow-up', of, this, patient, and, the, analysis, of, a, larger, number, of, children, are, needed, to, define, whether, the]), verbo([gains]), complemento([of, the, specific, extra, chromosomes, modify, the, good, prognosis, that, 't(8;21)', confers, to, this, subgroup, of, 'AML'])].
[sujeto(['AML1-ETO', fusion, 'protein,', a, product, of, 'leukemia-related', chromosomal, translocation, 't(8;21),', was]), verbo([reported]), complemento([to, upregulate, expression, of, 'connexin-43', '(', 'Cx43),', a, member, of, gap, 'junction-constituted', connexin, family])].
[sujeto(['By', bioinformatic, 'analysis,', here, we, showed, that, there, are, two, putative, 'AML1-binding', consensus, sequences, followed, by, two]), verbo([activated]), complemento([protein, '(', 'AP)1', sites, in, the, 5, '\'', -, flanking, region, upstream, to, 'Cx43', gene])].
[sujeto(['AML1-ETO', could, directly]), verbo([bind]), complemento([to, these, two, 'AML1-binding', sites, in, electrophoretic, mobility, shift, 'assay,', but, luciferase, reporter, assay, revealed, that, the, 'AML1', binding, sites, were, not, indispensable, for, 'Cx43', induction, by, 'AML1-ETO', protein])].
[sujeto(['In', 'agreement,', 'AML1-ETO', overexpression, in, leukemic, 'U937', cells]), verbo([activated]), complemento(['c-Jun', 'N-terminal', kinase, '(', 'JNK),', while, its, specific, inhibitor, 'SP600125', effectively, abrogated, 'AML1-ETO-induced', 'Cx43', 'expression,', indicating, that, 'JNK', signaling, pathway, contributes, to, 'AML1-ETO', induced, 'Cx43', expression])].
[sujeto(['Chromosome', rearrangements, are, believed, to]), verbo([cause]), complemento([the, secondary, leukemias, which, constitute, frequent, complications, of, antitumor, chemotherapy, with, topoisomerase, 'II-specific', drugs])].
[sujeto(['Here', we, show, that, inhibition, of, 'DNA', topoisomerase, 'II', in, cultured, cells]), verbo([stimulates]), complemento([association, of, components, of, the, 'non-homologous', end, joining, system, with, a, known, breakpoint, cluster, region, of, the, human, 'AML1', 'gene,', suggesting, that, errors, of, 'DNA', repair, during, 'NHEJ', may, be, the, cause, of, illegitimate, recombination, in, cells, treated, with, topoisomerase, 'II', poisons])].
[sujeto(['Carcinogens\'', failure, to, be, degraded, by, 'CYP2B6', may]), verbo([cause]), complemento(['DNA', injury, and, cancer])].
[sujeto(['We']), verbo([recruited]), complemento([300, patients, including, 164, cases, of, acute, myeloid, leukemia, '(', 'AML),', 96, cases, of, acute, lymphoblastic, leukemia, '(', 'ALL,', including, 17, cases, of, 'T-ALL', and, 79, cases, of, 'B-ALL),', 40, cases, of, 'MDS,', as, well, as, 348, unrelated, umbilical, cord, blood, as, the, controls])].
[sujeto(['T', allele, of, 'CYP2B6', 516, 'G&gt;T', 'SNP', may, be, one, of, the, risk, factors, predisposing, to, the, pathogenesis, of, a, majority, of, 'ALL', and, 'AML,', but]), verbo([has]), complemento([no, relationship, with, 'B-ALL', and, leukemia, with, or, without, chromosome, abnormalities])].
[sujeto(['Runx1', and, 'Notch', signaling, are]), verbo([involved]), complemento([in, this, 'process,', with, 'Notch', signaling, decreasing, with, time, in, 'HCs'])].
[sujeto(['Inhibiting', 'Notch', signaling, readily]), verbo([increases]), complemento(['HC', production, in, mouse, and, chicken, embryos])].
[sujeto(['In', the, 'mouse,', 'however,&nbsp;this']), verbo([increase]), complemento([is, transient])].
[sujeto(['Collectively,', we, show, complementary, roles, of, hemogenic, 'ECs', and, mesenchymal, compartments, in]), verbo([triggering]), complemento([aortic, hematopoiesis])].
[sujeto(['The', subaortic, mesenchyme]), verbo([induces]), complemento(['Runx1', expression, in, 'hemogenic-primed', 'ECs', and, collaborates, with, 'Notch', dynamics, to, control, aortic, hematopoiesis])].
[sujeto(['On', the, other, 'hand,', dexamethasone, can]), verbo([induce]), complemento([apoptosis, in, these, cells, at, low, 'concentrations,', whereas, other, myelomonocytic, leukemia, cell, lines, tested, were, resistant, to, 'glucocorticoid-induced', apoptosis])].
[sujeto(['Glucocorticoids', might]), verbo([induce]), complemento([the, apoptosis, of, some, types, of, 'AML', 'cells,', just, like, that, of, some, lymphoid, leukemia, cells])].
[sujeto(['Naturally', arising, 'CD25+CD4+', regulatory, 'T', cells, '(', 'T(R)', 'cells)', are, engaged, in, the, maintenance, of, immunological, 'self-tolerance', and, immune, homeostasis, by]), verbo([suppressing]), complemento([aberrant, or, excessive, immune, 'responses,', such, as, autoimmune, disease, and, allergy])].
[sujeto(['T(R)', cells, specifically]), verbo([express]), complemento([the, transcription, factor, 'Foxp3,', a, key, regulator, of, 'T(R)-cell', development, and, function])].
[sujeto(['Ectopic', expression, of, 'Foxp3', in, conventional, 'T', cells, is, indeed, sufficient, to]), verbo([confer]), complemento([suppressive, 'activity,', repress, the, production, of, cytokines, such, as, 'interleukin-2', '(', 'IL-2)', and, 'interferon-gamma', '(', 'IFN-gamma),', and, upregulate, 'T(R)-cell-associated', molecules, such, as, 'CD25,', cytotoxic, 'T-lymphocyte-associated', 'antigen-4,', and, 'glucocorticoid-induced', 'TNF-receptor-family-related', protein])].
[sujeto(['However,', the, method, by, which, 'Foxp3', controls, these, molecular, events]), verbo([has]), complemento([yet, to, be, explained])].
[sujeto(['Here', we, show, that, the, transcription, factor, 'AML1', '(', acute, myeloid, leukaemia, 1, ')', /, 'Runx1', '(', 'Runt-related', transcription, factor, 1, ')', ',', which, is, crucially]), verbo([required]), complemento([for, normal, haematopoiesis, including, thymic, 'T-cell', 'development,', activates, 'IL-2', and, 'IFN-gamma', gene, expression, in, conventional, 'CD4+', 'T', cells, through, binding, to, their, respective, promoters])].
[sujeto(['In', natural, 'T(R)', 'cells,', 'Foxp3']), verbo([interacts]), complemento([physically, with, 'AML1'])].
[sujeto(['Several', lines, of, evidence, support, a, model, in, which, the, interaction]), verbo([suppresses]), complemento(['IL-2', and, 'IFN-gamma', 'production,', upregulates, 'T(R)-cell-associated', 'molecules,', and, exerts, suppressive, activity])].
[sujeto(['Infection', of, newborn, inbred, 'NMRI', mice, with, 'Akv']), verbo([induced]), complemento([35, '%', plasma, cell, proliferations, '(', 'PCPs)', '(', consistent, with, 'plasmacytoma),', 33, '%', diffuse, large, 'B-cell', 'lymphomas,', 25, '%', follicular, 'B-cell', lymphomas, and, few, splenic, marginal, zone, and, small, 'B-cell', lymphomas])].
[sujeto(['Additional', mutation, of]), verbo([binding]), complemento([sites, for, the, glucocorticoid, 'receptor,', 'Ets,', 'Runx,', or, basic, 'helix-loop-helix', transcription, factors, in, the, proviral, 'U3', 'region,', 'however,', shifted, disease, induction, to, almost, exclusively, 'PCPs,', but, had, no, major, influence, on, tumor, latency, periods])].
[sujeto(['Southern', analysis, of, immunoglobulin, rearrangements, and, ecotropic, provirus, integration, patterns, showed, that, many, of, the, 'tumors/cell', proliferations]), verbo([induced]), complemento([by, each, virus, were, polyclonal])].
[sujeto(['Our', results, indicate, that, enhancer, mutations, weaken, the, ability, of, 'Akv', to]), verbo([induce]), complemento([mature, 'B-cell', lymphomas, prior, to, the, plasma, cell, 'stage,', whereas, development, of, plasma, cell, proliferations, is, less, dependent, of, viral, enhancer, strength])].
[sujeto(['Myeloblasts', in, the, peripheral, blood]), verbo([increased]), complemento([43, months, after, the, onset, of, 'NHL'])].
[sujeto(['Translocation', '(', 2, ;, 21, ')', '(', 'q21;q22)']), verbo([has]), complemento([not, been, described, previously, to, our, knowledge])].
[sujeto(['The', disrupted, 'AML1', gene, resulting, from, two, 21, q22, rearrangements, may, be]), verbo([involved]), complemento([in, the, pathogenesis, of, 'AML', in, the, present, case])].
[sujeto(['In', this, 'study,', we, present, a, remarkable, clonal, cell, 'line,', 32080, ',', derived, from, a, 'CD2-Lmo2-', transgenic, 'T-cell', leukemia, with, differentiation]), verbo([arrest]), complemento([at, the, transition, from, the, intermediate, single, positive, to, double, positive, stages, of, 'T-cell', development])].
[sujeto(['There', was, 'cell-to-cell', 'variability,', with, some, cells]), verbo([expressing]), complemento([no, 'CD4', and, others, expressing, high, 'CD4'])].
[sujeto(['Lmo2', knockdown]), verbo([decreased]), complemento(['CD4', 'expression,', while, inhibition, of, intracellular, 'NOTCH1', or, histone, deacetylase, activity, induced, 'CD4', expression])].
[sujeto(['Enforced', expression, of, 'RUNX1']), verbo([repressed]), complemento(['CD4', expression])].
[sujeto(['We', analyzed, the, 'CD4', locus, by, 'Histone', 3, chromatin, immunoprecipitation, and]), verbo([found]), complemento([silencing, marks, in, the, 'CD4(-)', cells, and, activating, marks, in, the, 'CD4(+)', population])].
[sujeto(['Retrospective', findings, indicated, that, 't-AML/MDS']), verbo([associated]), complemento([genetic, aberrations, can, be, observed, directly, after, exposure, to, chemotherapy, and, can, precede, 't-AML', by, several, months])].
[sujeto(['Clonal', aberrations, were]), verbo([found]), complemento([in, three, patients])].
[sujeto(['Sustained', high, expression, of, 'TEL-AML1']), verbo([participated]), complemento([in, and, maintained, the, occurrence, of, 'GC', resistance])].
[sujeto(['Inhibition', of, 'TEL-AML1', may]), verbo([provide]), complemento([a, new, therapeutic, approach, to, reverse, 'GC', resistance])].
[sujeto(['Recurrent']), verbo([losses]), complemento([affected, chromosomal, regions, 12, 'p13,', 6, 'q21,', 15, q15])].
[sujeto([2, ',', whereas]), verbo([gains]), complemento([occurred, in, regions, 21, q22, and, 12, p])].
[sujeto(['Loss', of, 12, p13, including, 'CDKN1B', was]), verbo([associated]), complemento([with, a, shorter, remission, duration, '(', 'P=0'])].
[sujeto(['Distribution', of, 'X-chromosomal', copy, number, alterations, was, 'gender-specific:', whole, 'X-chromosome']), verbo([loss]), complemento([occurred, exclusively, in, 'females,', gain, of, 'Xq', only, in, males])].
[sujeto([3, ')', was]), verbo([associated]), complemento([with, a, poor, response, to, induction, treatment, '(', 'P=0'])].
[sujeto(['To', probe, the, effects, of, dexamethasone, '(', 'DEX)', combined, with, histone, deacetylase, '(', 'HDAC)', inhibitor, vorinostat, on]), verbo([inhibiting]), complemento([proliferation, and, inducing, differentiation, and, apoptosis, in, 'Kasumi-1', leukemia, 'cells,', and, its, possible, mechanisms, in, order, to, provide, a, theoretical, basis, for, the, treatment, of, 'AML1-ETO', positive, 'AML'])].
[sujeto(['Treatment', with, the, combination, of, 'DEX', and, vorinostat, for, 48, h]), verbo([led]), complemento([to, statistically, significant, differences, of, inhibited, proliferation, '[', '(', 42.06, '±8'])].
[sujeto([20, ')', '%', ']', ',']), verbo([increased]), complemento([differentiation, '[', '(', 52.83, '±8'])].
[sujeto(['Also', significant, ubiquitination, and]), verbo([decreased]), complemento(['AML1-ETO', protein, in, 'Kasumi-1', cells, after, the, combination, treatment, over, single, agent, or, control, were, observed])].
[sujeto(['The', results, indicated, that, 'DEX', and, vorinostat, could, synergistically]), verbo([inhibit]), complemento([the, 'Kasumi-1', cells, 'proliferation,', induce, 'Kasumi-1', cells, differentiation, and, apoptosis, through, ubiquitination, and, degradation, of, 'AML1-ETO'])].
[sujeto(['The', 'ETV6/RUNX1', '(', 'E/R)', gene, fusion, is, generated, by, the, 't(12;21)', and]), verbo([found]), complemento([in, approximately, 25, '%', of, childhood, 'B-cell', precursor, acute, lymphoblastic, leukemia])].
[sujeto(['To', investigate, this, 'issue,', we]), verbo([suppressed]), complemento([the, endogenous, 'E/R', fusion, protein, with, lentivirally, transduced, short, hairpin, 'RNA', in, the, leukemia, cell, lines, 'REH', and, 'AT-2,', and, found, a, distinct, reduction, of, proliferation, and, cell, survival])].
[sujeto(['In', line, with, the, observed, concurrent, inactivation, of, the, phosphoinositide, 3, -, kinase, '(', 'PI3K)/AKT/mammalian']), verbo([target]), complemento([of, rapamycin, '(', 'mTOR)', 'pathway,', pharmacological, inhibition, diminished, the, phosphorylation, of, 'AKT', and, ribosomal, protein, 'S6,', and, significantly, increased, the, apoptosis, rate, in, 'E/R-positive', leukemias])].
[sujeto(['Collectively,', these, data, demonstrate, that, the, 'E/R', fusion, protein]), verbo([activates]), complemento([the, 'PI3K/AKT/mTOR', pathway, and, is, indispensible, for, disease, maintenance])].
[sujeto(['Importantly,', these, results]), verbo([provide]), complemento([a, first, rationale, and, justification, for, targeting, the, fusion, gene, and, the, 'PI3K/AKT/mTOR', pathway, therapeutically])].
[sujeto(['To']), verbo([gain]), complemento([insight, into, the, relapse, 'mechanisms,', we, analyzed, single, nucleotide, polymorphism, arrays, for, 'DNA', copy, number, aberrations, '(', 'CNAs)', in, 18, matched, diagnosis, and, relapse, leukemias])].
[sujeto(['Moreover,', we, identified, 'recurrent,', mainly, nonoverlapping, deletions]), verbo([associated]), complemento([with, 'glucocorticoid-mediated', apoptosis, targeting, the, 'Bcl2', modifying, factor, '(', 'BMF)', '(', 'n=3),', glucocorticoid, receptor, 'NR3C1', '(', 'n=4),', and, components, of, the, mismatch, repair, pathways, '(', 'n=3)'])].
[sujeto(['They', were, all]), verbo([associated]), complemento([with, 'leukemias,', which, poorly, responded, to, treatment])].
[sujeto(['With', rare, 'exception,', 'however,', the, resultant, protein, products]), verbo([have]), complemento([remained, largely, intractable, as, pharmacologic, targets])].
[sujeto(['One', example, is, 'AML1-ETO,', the, most, common, translocation]), verbo([reported]), complemento([in, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['Gene', expression, signatures, were, used, as, surrogates, for, the, expression, versus]), verbo([loss]), complemento([of, the, translocation, in, 'AML1-ETO-expressing', cells])].
[sujeto(['In', addition, to]), verbo([modulating]), complemento([the, 'AML1-ETO', 'signature,', both, classes, induced, evidence, of, 'differentiation,', dramatically, inhibited, cell, 'viability,', and, ultimately, induced, apoptosis, via, 'on-target', activity])].
[sujeto(['This', work]), verbo([suggests]), complemento([a, role, for, 'DHFR', inhibitors, and, corticosteroids, in, treating, patients, with, 'AML1-ETO-positive', disease])].
[sujeto(['We', explored, the, mechanisms]), verbo([leading]), complemento([to, the, distinct, overexpression, of, 'EPOR', as, well, as, the, effects, of, 'EPO', signaling, on, 'ETV6/RUNX1-positive', acute, lymphoblastic, leukemias])].
[sujeto(['We', show, here, that, ectopic, expression, of, 'ETV6/RUNX1']), verbo([induced]), complemento(['EPOR', 'up-regulation'])].
[sujeto(['Exposure', to, 'EPO']), verbo([increased]), complemento([proliferation, and, survival, of, 'ETV6/RUNX1-positive', leukemias, in, 'vitro,', whereas, blocking, its, binding, site, did, not, alter, cell, survival])].
[sujeto(['The', latter, was, not]), verbo([caused]), complemento([by, activating, mutations, in, the, 'EPOR', but, might, be, triggered, by, constitutive, activation, of, phosphatidylinositol, 3, -, 'kinase/Akt,', the, major, signaling, pathway, of, 'EPOR', in, these, cells])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, 'ETV6/RUNX1', leads, to, 'EPOR', 'up-regulation', and, that, activation, by, 'EPO', might, be, of, relevance, to, the, biology, of, this, leukemia, subtype])].
[sujeto([20, ']', ',', while, no, differences, were]), verbo([found]), complemento([between, two, groups, in, 'age,', gender, 'ratio,', initial, platelet, 'count,', percentage, of, blast, in, bone, 'marrow,', immunophenotypes, and, the, expression, of, myeloid, antigen, 'CD13,', 'CD33', and, 'CD34'])].
[sujeto(['The', load, of, leukemia, cells, in, 'TEL-AML1', positive, patients, is, significantly, smaller, than, its, 'counterparts,', and, the, blast, cells, in, 'TEL-AML1', positive, patients, are, more, sensitive, to, 'prednisone,', indicating, childhood, 'ALL', with, 'TEL-AML1', fusion, gene]), verbo([has]), complemento([a, favorable, prognosis])].
[sujeto(['This']), verbo([report]), complemento([suggests, that, a, subset, of, 'CD7+', 'T-cell', leukemias, without, mature, 'T-cell', antigens, '(', 'CD4-,', 'CD8-)', are, minimally, differentiated, and, can, relapse, as, 'AML'])].
[sujeto(['This', study, analyzes, the, relationship, between, the, mRNA, expression, of, the, genes, and, fusion, products]), verbo([involved]), complemento([in, 't(12;21),', in, vitro, sensitivity, to, 'prednisolone,', 'vincristine,', and, 'L-asparaginase,', and, 'long-term', clinical, outcome, in, 't(12;21)+', acute, lymphoblastic, leukemia, '(', 'ALL)', patients])].
[sujeto(['The', 'TEL-AML1', fusion, product, was]), verbo([expressed]), complemento([in, all, 't(12;21)+', 'cases,', whereas, the, reciprocal, fusion, product, 'AML1-TEL', was, expressed, in, only, 76, '%'])].
[sujeto(['High', expression, levels, of, 'TEL-AML1', '[', hazard, ratio, '(', 'HR),', 1.3, ;, 95, '%', confidence, interval, '(', 95, '%', 'CI),', 1.1, -, 1.57, ;, 'P', =, 0.003, ']', ',', 'AML1-TEL', '(', 'HR,', 4.9, ;, 95, '%', 'CI,', 1.99, -, 12.4, ;, 'P', =, 0.001, ')', and, 'AML1', '(', 'HR,', 1.1, ;, 95, '%', 'CI,', 1.03, -, 1.22, ;, 'P', =, 0.006, ')', were]), verbo([associated]), complemento([with, a, poor, 'long-term', clinical, outcome, within, 't(12;21)+', 'ALL'])].
[sujeto(['Acute', lymphoblastic, leukemia, '(', 'ALL)', can, be, cured, with, combination, chemotherapy, in, over, 75, '%', of, 'children,', but, the]), verbo([cause]), complemento([of, treatment, failure, in, the, remaining, patients, is, unknown])].
[sujeto(['We', determined, the, sensitivity, of, 'ALL', cells, to, individual, antileukemic, agents, in, 441, patients, and, used, a, 'genome-wide', approach, to, identify, 45, genes, differentially]), verbo([expressed]), complemento([in, 'ALL', exhibiting, crossresistance, to, 'prednisolone,', 'vincristine,', 'asparaginase,', and, daunorubicin])].
[sujeto(['We', also, identified, a, distinct, phenotype, of, discordant, resistance, to, asparaginase, and, vincristine, and, 139, genes, whose, expression, was]), verbo([associated]), complemento([with, this, novel, phenotype])].
[sujeto(['We']), verbo([report]), complemento([a, case, of, de, novo, acute, lymphoblastic, leukemia, with, tandem, amplification, of, the, 'AML1', gene, located, in, a, chromosome, marker, that, originated, from, chromosome, 21, and, a, long, 'event-free', survival])].
[sujeto(['t(12;21)(p1', 3, ;, 'q22),', the, most, frequent, chromosomal, translocation]), verbo([found]), complemento([in, childhood, acute, lymphoblastic, leukemia, '(', 'ALL),', occurs, in, approximately, 25, '%', of, 'B-lineage', 'ALL', cases, and, has, been, claimed, to, carry, a, good, prognosis])].
[sujeto(['Al', though, patients, with, 't(12;21)-positive', 'ALL']), verbo([have]), complemento([been, claimed, to, have, a, good, 'outcome,', these, data, indicate, that, this, does, not, reflect, a, high, sensitivity, to, 'prednisolone,', 'vincristine,', and, doxorubicin, given, during, induction, therapy])].
[sujeto(['The', 'TEL-AML1', fusion, which, results, from, a, cryptic, 't(12;21)', translocation, is, the, most, frequently, occurring, genetic, abnormality, in, childhood, acute, lymphoblastic, leukemia, '(', 'ALL)', and]), verbo([has]), complemento([been, associated, with, an, excellent, treatment, outcome])].
[sujeto(['TEL-AML1(+)', 'ALL', cells]), verbo([expressed]), complemento([higher, levels, of, the, 'pro-apoptotic', protein, 'Fas', and, lower, levels, of, the, 'anti-apoptotic', protein, 'Bcl2', than, 'TEL-AML1(-)', 'ALL', 'cells,', as, determined, by, confocal, laser, scanning, microscopy])].
[sujeto(['This', study]), verbo([provides]), complemento([novel, mechanistic, insights, regarding, the, chemosensitivity, of, 'TEL-AML1(+)', 'ALL', cells, and, provides, a, cogent, explanation, for, the, excellent, 'leukemia-free', survival, outcome, of, children, with, 'TEL-AML1(+)', 'ALL', treated, on, contemporary, chemotherapy, programs])].
[sujeto(['The', polyomavirus, enhancer]), verbo([binding]), complemento([protein, 2, '(', 'PEBP2)/core', binding, factor, '(', 'CBF)', is, a, transcription, factor, composed, of, two, 'subunits,', alpha, and, beta])].
[sujeto(['The', gene, encoding, the, beta, subunit, is, disrupted, by, 'inv(16),', resulting, in, the, formation, of, a, chimeric, 'protein,', 'beta-SMMHC,', which, is]), verbo([associated]), complemento([with, acute, myelogenous, leukemia])].
[sujeto(['To', understand, the, effect, of, 'beta-SMMHC', on, 'PEBP2-mediated', 'transactivation,', we, used, a, luciferase, assay, system, in, which, contribution, of, both, the, alpha, and, beta, subunits, was, absolutely]), verbo([required]), complemento([to, activate, transcription])].
[sujeto(['Using', this, 'system,', we]), verbo([found]), complemento([that, the, minimal, region, of, the, beta, subunit, required, for, transactivation, resides, between, amino, acid, 1, and, 135, ',', which, is, known, to, dimerize, with, the, alpha, subunit])].
[sujeto(['Furthermore', 'beta-SMMHC', blocked, the, synergistic, transcription, achieved, by, 'PEBP2', and, 'CCAAT/enhancer']), verbo([binding]), complemento([protein, alpha])].
[sujeto(['By', using, a, construct, in, which, the, 'PEBP2', alpha, subunit, was, fused, to, the, glucocorticoid, receptor, ligand]), verbo([binding]), complemento(['domain,', we, demonstrated, that, coexpressed, 'beta-SMMHC', tightly, sequestered, the, alpha, subunit, in, the, cytoplasm, and, blocked, 'dexamethasone-dependent', nuclear, translocation, of, the, alpha, subunit])].
[sujeto(['Thus,', the, result, suggess, that, 'beta-SMMHC']), verbo([inhibits]), complemento(['PEBP2-mediated', transcription, via, cytoplasmic, sequestration, of, the, alpha, subunit])].
[sujeto(['Lastly', proliferation, of, 'ME-1', cells, that, harbor, 'inv(16)', was, blocked, by, an, antisense, oligonucleotide, complementary, to, the, junction, of, the, chimeric, 'mRNA,']), verbo([suggesting]), complemento([that, 'beta-SMMHC', contributes, to, leukemogenesis, by, blocking, the, differentiation, of, myeloid, cells])].
[sujeto(['We', previously, showed, 'that,', among, patients, treated, on, 'St', 'Jude', 'protocols,', 'TEL', rearrangement, independently]), verbo([conferred]), complemento([an, excellent, prognosis])].
[sujeto(['Thus,', the, presence, of, a, rearranged, 'TEL', gene, is, also]), verbo([associated]), complemento([with, an, improved, survival, among, patients, treated, with, 'antimetabolite-based', therapy])].
[sujeto(['Our', results, indicate, that, all, newly, diagnosed, 'ALL', patients, should, be, screened, for, 'TEL', gene, rearrangements, and]), verbo([suggest]), complemento([that, these, patients, are, candidates, for, less, intensive, therapy])].
[sujeto(['Hematopoietic', stem, and, progenitor, cell, '(', 'HSPC)', specification, is]), verbo([regulated]), complemento([by, numerous, defined, factors, acting, locally, within, the, hemogenic, 'niche;', 'however,', it, is, unclear, whether, production, can, 'adapt&nbsp;to', fluctuating, systemic, needs])].
[sujeto(['Exposure', to, serotonin, or, the, reuptake, inhibitor, fluoxetine]), verbo([increased]), complemento([runx1, expression, and, 'Flk1(+)/cMyb(+)', 'HSPCs', independent, of, peripheral, innervation])].
[sujeto(['Significantly,', developmental, 'hypoxia,', as, indicated, by, 'Hif1α', 'function,']), verbo([induced]), complemento([the, 'HPA/I', axis, and, cortisol, production])].
[sujeto(['Our', data, establish, that, embryonic, 'HSC', production]), verbo([responds]), complemento([to, physiologic, stress, via, 'CNS-derived', serotonin, synthesis, and, central, feedback, regulation, to, control, 'HSC', numbers])].
[sujeto(['In', 58, '%', of, 'samples,', we]), verbo([found]), complemento([deletions, in, various, glucocorticoid, signaling, 'pathway-associated', 'genes,', but, only, 'NR3C1', and, 'ETV6', deletions, prevailed, in, minimal, residual, disease, poor, responding, and, subsequently, relapsing, cases, '(', 'p&lt;0'])].
[sujeto(['The', leukemic, cells, from, these, five, patients, demonstrated]), verbo([increased]), complemento([in, vitro, resistance, to, asparaginase, compared, to, those, from, the, other, 11, patients, '(', p, =, 0.009, ')'])].
[sujeto(['From', the, present, case, 'series,', the, demonstrated, in, vitro, resistance, to, chemotherapeutic, agents, may]), verbo([have]), complemento([a, prognostic, value, in, children, with, 'ALL', before, comprehensive, minimal, residual, disease, measurement, is, available])].
[sujeto(['The', prognosis, for, older, adolescents, and, young, adults, with, acute, lymphoblastic, leukemia, '(', 'ALL)']), verbo([has]), complemento([been, historically, much, worse, than, that, for, younger, patients])].
[sujeto(['The', 89, older, adolescents, were, significantly, more, likely, to]), verbo([have]), complemento(['T-cell', 'ALL,', the, 't(4;11)(MLL-AF4),', and, detectable, minimal, residual, disease, during, or, at, the, end, of, remission, 'induction;', they, were, less, likely, to, have, the, 't(12;21)(ETV6-RUNX1)', compared, with, younger, patients])].
[sujeto(['The', 'Runx', genes, are, important, in, development, and, 'cancer,', where, they, can]), verbo([act]), complemento([either, as, oncogenes, or, tumour, suppressors])].
[sujeto(['We', compared, the, effects, of, ectopic, 'Runx', expression, in, established, 'fibroblasts,', where, all, three, genes, produce, an, indistinguishable, phenotype, entailing, epithelioid, morphology, and]), verbo([increased]), complemento([cell, survival, under, stress, conditions])].
[sujeto(['Gene', array, analysis, revealed, a, strongly, overlapping, transcriptional, 'signature,', with, no, examples, of, opposing, regulation, of, the, same]), verbo([target]), complemento([gene])].
[sujeto(['A', common, set, of, 50, highly]), verbo([regulated]), complemento([genes, was, identified, after, further, filtering, on, regulation, by, inducible, 'RUNX1-ER'])].
[sujeto(['This', set, revealed, a, strong, bias, toward, genes, with, annotated, roles, in, cancer, and, 'development,', and, a, preponderance, of]), verbo([targets]), complemento([encoding, extracellular, or, surface, 'proteins,', reflecting, the, marked, effects, of, 'Runx', on, cell, adhesion])].
[sujeto(['Furthermore,', in, silico, prediction, of, resistance, to, glucocorticoid, growth, inhibition, was, confirmed, in, fibroblasts, and, lymphoid, cells]), verbo([expressing]), complemento([ectopic, 'Runx'])].
[sujeto(['Although', two, direct, 'Runx', activation]), verbo([target]), complemento([genes, were, repressed, '(', 'Ncam1', and, 'Rgc32),', the, fusion, proteins, appeared, to, disrupt, the, regulation, of, downregulated, targets, '(', 'Cebpd,', 'Id2', and, 'Rgs2)', rather, than, impose, constitutive, repression])].
[sujeto(['These', results, elucidate, the, oncogenic, potential, of, the, 'Runx', family, and]), verbo([reveal]), complemento([novel, targets, for, therapeutic, inhibition])].
[sujeto(['The', study]), verbo([recruited]), complemento([309, hospitalized, patients, '(', 187, male, and, 122, 'female)', with, childhood, 'ALL,', the, 'sex,', 'age,', initial, 'WBC', 'count,', 'immunophenotype,', chromosome, and, gene, expression, were, recorded])].
[sujeto(['Acute', lymphoblastic, leukemia, '(', 'ALL)', with, distinct, fusion, transcripts]), verbo([has]), complemento([unique, clinical, features])].
[sujeto(['T-ALL', was]), verbo([associated]), complemento([with, a, high, 'WBC,', increased, 'age,', more, central, nervous, system, 'involvement,', a, poor, prednisone, 'response,', and, high, 'MRD,', with, a, 5, -, year, 'EFS', of, 68.4, ±, 5.2, '%'])].
[sujeto(['Therefore,', this, study]), verbo([suggests]), complemento([that, a, fusion, 'gene-specific', chemotherapy, regimen, 'and/or', targeted, therapy, should, be, developed, to, improve, further, the, cure, rate, of, pediatric, 'ALL'])].
[sujeto(['Early', 'B', cell, factor, '(', 'EBF)', family, members, are, transcription, factors, known, to]), verbo([have]), complemento([important, roles, in, several, aspects, of, vertebrate, 'neurogenesis,', including, 'commitment,', migration, and, differentiation])].
[sujeto(['Knowledge', of, how, 'EBF', family, members, contribute, to, neurogenesis, is, limited, by, a, lack, of, detailed, understanding, of, genes, that, are, transcriptionally]), verbo([regulated]), complemento([by, these, factors])].
[sujeto(['We', performed, a, microarray, screen, in, 'Xenopus', animal, caps, to, search, for]), verbo([targets]), complemento([of, 'EBF', transcriptional, 'activity,', and, identified, candidate, targets, with, multiple, 'roles,', including, transcription, factors, of, several, classes])].
[sujeto(['We', determined, 'that,', among, the, most, upregulated, candidate, genes, with, expected, neuronal, 'functions,', most]), verbo([require]), complemento(['EBF', activity, for, some, or, all, of, their, 'expression,', and, most, have, overlapping, expression, with, ebf, genes])].
[sujeto(['We', also]), verbo([found]), complemento([that, the, candidate, target, genes, that, had, the, most, strongly, overlapping, expression, patterns, with, ebf, genes, were, predicted, to, be, direct, transcriptional, targets, of, 'EBF', transcriptional, activity])].
[sujeto(['The', identification, of, candidate]), verbo([targets]), complemento([that, are, transcription, factor, 'genes,', including, 'nscl-1,', emx1, and, 'aml1,', improves, our, understanding, of, how, 'EBF', proteins, participate, in, the, hierarchy, of, transcription, control, during, neuronal, 'development,', and, suggests, novel, mechanisms, by, which, 'EBF', activity, promotes, migration, and, differentiation])].
[sujeto(['Large', progress]), verbo([has]), complemento([been, made, in, the, treatment, of, acute, lymphoblastic, leukemia, '(', 'ALL)', of, childhood, and, adolescence, over, the, past, 30, years])].
[sujeto(['Event-free', survival, '(', 'pEFS)', of, the, total, group, was, significantly]), verbo([associated]), complemento([with, age])].
[sujeto(['The', most, unfavorable, outcome, was]), verbo([found]), complemento([in, infancy, and, the, best, results, were, achieved, at, toddler, and, 'pre-school', age])].
[sujeto(['Beyond', 5, y, of, 'age,', survival, probability]), verbo([decreased]), complemento(['(', pEFS, at, 8, 'y:', &, 'lt;', 1, y, =, 0.45, ;, 1, -, 5, y, =, 0.82, ;, 6, -, 9, y, =, 0.75, ;, 10, -, 14, y, =, 0.63, ;, &, 'gt;', or, =, 15, y, =, 0.59, ')'])].
[sujeto(['The', incidence, was, constant, after, a, peak, in, the, first, year, of, 'life,', yet, the, percentage, of, 'CD10', negativity]), verbo([increased]), complemento([with, rising, age, in, this, subgroup])].
[sujeto(['We']), verbo([report]), complemento([a, case, of, acute, myeloblastic, leukemia, '(', 'AML)-M2', '(', by, 'French-American-British', 'classification)', with, 't(8;21)', '(', 'q22:q22)', that, was, complicated, with, severe, pneumonia])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, patient, acquired, 'morphological,', cytogenetic])].
[sujeto(['Vascular', calcification, is, an, active, deposition, process, of, calcium, phosphate, which, resembles, bone, formation, and, is, highly]), verbo([regulated]), complemento([by, 'osteoblast-like', cells])].
[sujeto(['In', study, 'III,', we, investigated, whether, 'A7r5', aortic, smooth, muscle, cells, were]), verbo([induced]), complemento([into, 'osteoblast-like', phenotypes, by, incubation, with, or, without, 80, 'μg/mL', of, 'RAW264'])].
[sujeto(['Both', animal, and, cell, studies, consistently, demonstrated, that, the, 'CML/RAGE', axis, may, first, initiate, the, apoptosis, of, macrophages, in, atherosclerotic, lesions, and, then]), verbo([induce]), complemento(['BMP-2-cbfα1-ALP-calcification', cascade, in, a, 'high-lipid,', 'apoptosis-coexisting', environment])].
[sujeto(['The', 'CML/RAGE', axis, may, play, an, important, role, in, atherosclerotic, calcification, of, diabetes, through, the, mechanism, that]), verbo([induces]), complemento([the, apoptosis, of, macrophages, followed, by, the, osteogenic, differentiation, of, aortic, smooth, muscle, cells])].
[sujeto(['L-ergothioneine', '(', 'ET),', a, putative, antioxidant, compound, acquired, by, animals, through, dietary, 'sources,']), verbo([has]), complemento([been, suggested, to, accumulate, in, certain, cells, and, tissues, in, the, body, that, are, predisposed, to, high, oxidative, stress])].
[sujeto(['In', the, present, 'study,', we, identified, an, elevation, of, 'ET', in, the, liver, of, a, guinea, pig, model, of, 'non-alcoholic', fatty, liver, disease, '(', 'NAFLD),', elucidated, a, possible, mechanism, for, the]), verbo([increased]), complemento([uptake, and, investigated, the, possible, role, for, this, accumulation])].
[sujeto(['This']), verbo([increase]), complemento([in, liver, 'ET', levels, correlated, with, cholesterol, accumulation, and, disease, severity])].
[sujeto(['We', identified, an]), verbo([increase]), complemento([in, the, transcriptional, 'factor,', 'RUNX1,', which, has, been, shown, to, upregulate, the, expression, of, the, 'ET-specific', transporter, 'OCTN1,', and, could, consequently, lead, to, the, observable, elevation, in, 'ET'])].
[sujeto(['An']), verbo([increase]), complemento([was, also, seen, in, heat, shock, protein, 70, '(', 'HSP70)', which, seemingly, corresponds, to, 'ET', elevation])].
[sujeto(['No', significant]), verbo([increase]), complemento([was, observed, in, oxidative, damage, 'markers,', 'F2-isoprostanes,', and, protein, 'carbonyls,', which, could, possibly, be, attributed, to, the, increase, in, liver, 'ET', through, direct, antioxidant, 'action,', induction, of, 'HSP70,', or, by, chelation, of, 'Fe(2+),', preventing, redox, chemistry])].
[sujeto(['The', data]), verbo([suggest]), complemento([a, novel, mechanism, by, which, the, guinea, pig, fatty, liver, accumulates, 'ET', via, upregulation, of, its, 'transporter,', as, a, possible, stress, response, by, the, damaged, liver, to, further, suppress, oxidative, damage, and, delay, tissue, injury])].
[sujeto(['Genes', upregulated, in, 'G', +, 'E', +, 'H(trt)', encode, 'for:', proteins, that, are]), verbo([involved]), complemento([in, prostaglandin, synthesis, '(', 'Ptgs2,', 'Pla2g4a,', and, 'Runx1)', and, cholesterol, biosynthesis, '(', 'Hmgcr,', 'Sc4mol,', and, 'Dhcr24);', receptors, that, allow, cholesterol, uptake, '(', 'Ldlr', and, 'Scarb1),', regulate, progesterone, synthesis, '(', 'Star),', and, inactivate, estrogen, '(', 'Sult1e1);', and, downstream, effectors, of, 'LH', signal, '(', 'Pgr,', 'Cebpb,', 'Creb3l1,', 'Areg,', 'Ereg,', and, 'Adamts1)'])].
[sujeto(['Conversely,', 'G', +, 'E', +, 'H(trt)', downregulated, genes, encoding, proteins]), verbo([involved]), complemento(['in:', 'DNA', replication, and, cell, cycle, progression, '(', 'Ccne2,', 'Orc5l,', 'Rad50,', and, 'Mcm6);', reproductive, developmental, 'process;', and, granulosa, cell, expansion, '(', 'Gdf9,', 'Bmp15,', 'Amh,', 'Amhr2,', 'Bmpr1b,', 'Tgfb2,', 'Foxl2,', 'Pde3a,', 'Esr2,', 'Fshr,', 'Ybx2,', 'Ccnd2,', 'Ccnb1ip1,', and, 'Zp3);', maternal, effect, genes, required, for, embryo, development, '(', 'Zar1,', 'Npm2,', 'Nlrp5,', 'Dnmt1,', 'H1foo,', and, 'Zfp57);', amino, acid, 'degradation;', and, ketogenesis, '(', 'Hmgcs2,', and, 'Cpt1b)'])].
[sujeto(['These', results, from, the, rat, show, that, hormones, used, for, estrus, synchronization, '(', 'G(trt))', and, ovarian, hyper, stimulation, '(', 'G', +, 'E(trt))', had, minimal, effects, on, gene, 'expression,', whereas, induction, of, ovulation, '(', 'G', +, 'E', +, 'H(trt))']), verbo([caused]), complemento([major, changes, in, gene, expression, of, rat, 'COCs'])].
[sujeto(['This', study]), verbo([provides]), complemento([comprehensive, information, about, regulated, genes, during, late, follicle, development, and, ovulation, induction])].
[sujeto(['Haematopoietic', stem, and, progenitor, cell, '(', 'HSPC)', transplant, is, a, widely, used, treatment, for, 'life-threatening', conditions, such, as, 'leukaemia;', 'however,', the, molecular, mechanisms]), verbo([regulating]), complemento(['HSPC', engraftment, of, the, recipient, niche, remain, incompletely, understood])].
[sujeto(['We', use, this, system, to, conduct, a, chemical, 'screen,', and, identify, epoxyeicosatrienoic, acids, '(', 'EETs)', as, a, family, of, lipids, that]), verbo([enhance]), complemento(['HSPC', engraftment])].
[sujeto(['The', 'pro-haematopoietic', effects, of, 'EETs', were]), verbo([conserved]), complemento([in, the, developing, zebrafish, 'embryo,', where, 11, ',', 12, -, 'EET', promoted, 'HSPC', specification, by, activating, a, unique, activator, protein, 1, '(', 'AP-1)', and, runx1, transcription, program, autonomous, to, the, haemogenic, endothelium])].
[sujeto(['This', effect]), verbo([required]), complemento([the, activation, of, the, 'phosphatidylinositol-3-OH', kinase, '(', 'PI(3)K)', 'pathway,', specifically, 'PI(3)Kγ'])].
[sujeto(['In', adult, 'HSPCs,', 11, ',', 12, -, 'EET']), verbo([induced]), complemento([transcriptional, 'programs,', including, 'AP-1', 'activation,', which, modulate, several, cellular, 'processes,', such, as, 'migration,', to, promote, engraftment])].
[sujeto(['Furthermore,', we, demonstrate, that, the, 'EET', effects, on]), verbo([enhancing]), complemento(['HSPC', homing, and, engraftment, are, conserved, in, mammals])].
[sujeto(['Our', study, establishes, a, new, method, to, explore, the, molecular, mechanisms, of, 'HSPC', 'engraftment,', and, discovers, a, previously, 'unrecognized,', evolutionarily]), verbo([conserved]), complemento([pathway, regulating, multiple, haematopoietic, generation, and, regeneration, processes])].
[sujeto(['EETs', may]), verbo([have]), complemento([clinical, application, in, marrow, or, cord, blood, transplantation])].
[sujeto(['On', the, one, 'hand,', autophagy, might, be]), verbo([induced]), complemento([as, a, prosurvival, response, to, 'therapy,', thereby, reducing, treatment, efficiency])].
[sujeto(['Here,', we, investigated, these, opposing, roles, of, autophagy, in, 't(8;21)', acute, myeloid, leukemia, '(', 'AML)', 'cells,', which]), verbo([express]), complemento([the, most, frequently, occurring, 'AML', fusion, 'oncoprotein,', 'AML1-eight-twenty-one', '(', 'ETO)'])].
[sujeto(['We', demonstrate, that, autophagy, is]), verbo([induced]), complemento([by, 'AML1-ETO-targeting', 'drugs,', such, as, the, histone, deacetylase, inhibitors, '(', 'HDACis)', valproic, acid, '(', 'VPA)', and, vorinostat])].
[sujeto(['Furthermore,', we, show, that, autophagy, does, not]), verbo([mediate]), complemento([degradation, of, 'AML1-ETO', but, rather, has, a, prosurvival, role, in, 'AML', 'cells,', as, inhibition, of, autophagy, significantly, reduced, the, viability, and, 'colony-forming', ability, of, 'HDACi-treated', 'AML', cells])].
[sujeto(['Combined', treatment, with, 'HDACis', and, autophagy, inhibitors, such, as, chloroquine, '(', 'CQ)']), verbo([led]), complemento([to, a, massive, accumulation, of, ubiquitinated, proteins, that, correlated, with, increased, cell, death])].
[sujeto(['Finally,', we, show, that, 'VPA']), verbo([induced]), complemento([autophagy, in, 't(8;21)', 'AML', patient, 'cells,', and, combined, treatment, with, 'CQ', enhanced, cell, death])].
[sujeto(['Peroxisome', 'proliferator-activated', 'receptor-gamma', '(', 'PPARγ)']), verbo([regulates]), complemento([both, glucose, metabolism, and, bone, mass])].
[sujeto(['Evidence']), verbo([suggests]), complemento([that, the, therapeutic, modulation, of, 'PPARγ', with, synthetic, agonists, activity, may, elicit, undesirable, effects, on, bone])].
[sujeto(['In', the, presence, of, 15, 'd-PGJ2', it, was, possible, to, visualize, mineralized, nodules, in, the, extracellular, matrix, confirmed, with, the]), verbo([increased]), complemento(['RUNX', mRNA, expression])].
[sujeto([15, 'd-PGJ2', at, small, doses]), verbo([increased]), complemento([the, osteoblast, activity, and, the, 'bone-related', proteins, expression])].
[sujeto(['We', analyzed, the, activity, of, the, histone, deacetylase, inhibitor, '(', 'HDACi)', 'suberoyl-anilide', hydroxamic, acid, '(', 'SAHA)', on, 'Kasumi-1', acute, myeloid, leukemia, '(', 'AML)', cells]), verbo([expressing]), complemento(['AML1/ETO'])].
[sujeto(['SAHA', and, 'VPA']), verbo([induced]), complemento([histone, 'H3', and, 'H4', 'acetylation,', myeloid, differentiation, and, massive, early, apoptosis])].
[sujeto(['The', latter, effects, were, not, determined, by, either, drug, in, 'AML', cell, 'lines,', such, as, 'NB4', or, 'THP-1,', not]), verbo([expressing]), complemento(['AML1/ETO'])].
[sujeto(['SAHA', was, more, rapid, and, effective, than, 'VPA', in]), verbo([increasing]), complemento(['H3', and, 'H4', acetylation, in, total, 'Kasumi-1', cell, lysates, and, more, effective, than, 'VPA', in, inducing, acetylation, of, 'H4K8,', 'H4K12,', 'H4K16', residues])].
[sujeto(['At', the, promoter, of, 'IL3,', a, 'transcriptionally-silenced']), verbo([target]), complemento([of, 'AML1/ETO,', 'SAHA', was, also, more, rapid, than, 'VPA', in, inducing, total, 'H4,', 'H4K5,', 'H4K8', and, 'H3K27', 'acetylation,', while, 'VPA', was, more, effective, than, 'SAHA', at, later, times, in, inducing, acetylation, of, total, 'H4,', 'H4K12,', 'H4K16,', as, well, as, total, 'H3'])].
[sujeto(['Consistent', with, these, 'differences,', 'SAHA']), verbo([induced]), complemento([the, expression, of, 'IL3', mRNA, more, rapidly, than, 'VPA,', while, the, effect, of, 'VPA', was, delayed])].
[sujeto(['Our', results]), verbo([led]), complemento([to, include, 'SAHA,', an, 'FDA-approved', 'drug,', among, the, 'HDACi', active, in, the, 'AML1/ETO-expressing', 'AML', cells])].
[sujeto(['We']), verbo([have]), complemento([examined, the, effect, of, 'all-trans', retinoic, acid, '(', 'ATRA)', on, growth, and, differentiation, of, 'preadipocytes,', and, on, adipokine, gene, expression, in, mature, adipocytes, using, human, preadipocyte, cell, 'model,', 'AML-I'])].
[sujeto(['Both', 'ATRA', and, 9, -, cis, 'RA']), verbo([induced]), complemento([growth, arrest, in, 'AML-I', preadipocyte, at, between, 50, and, 100, 'µM,', which, was, accompanied, by, apoptosis])].
[sujeto(['Western', blotting, showed, a]), verbo([loss]), complemento([of, 'NF-κB,', 'Bcl-2', and, 'p-Akt,', and, the, accumulation, of, 'Bad', and, 'Akt', in, cytoplasm, of, 'ATRA-treated', 'AML-I', preadipocytes])].
[sujeto(['Exposure', of, 'AML-I', to, 'ATRA', or, 9, -, cis, 'RA']), verbo([increased]), complemento([intracellular, lipid, accumulation, in, a, 'time-dependent', manner, compared, to, 'vehicle-treated', cells])].
[sujeto(['Expression', of, fatty, acid, synthase, '(', 'FAS)', and, peroxisome, 'proliferator-activated', 'receptor-γ', '(', 'PPAR-γ)', proteins, was]), verbo([increased]), complemento([in, 'ATRA-treated', cells])].
[sujeto(['Thus,', both, 'ATRA', and, 9, -, cis, 'RA']), verbo([promoted]), complemento(['differentiation,', inhibited, proliferation, and, induced, apoptosis, in, 'AML-I', preadipocytes])].
[sujeto(['ATRA', also]), verbo([modulated]), complemento([adipokine, expression, by, increasing, the, mRNA, level, of, adipocytokines, '(', 'adiponectin,', leptin, and, 'LPL),', and, by, inhibiting, 'PAI-1', mRNA, expression, in, mature, 'AML-I', adipocytes])].
[sujeto(['The', data]), verbo([suggest]), complemento([that, 'ATRA', exerts, a, wide, range, of, 'effects--growth', 'arrest,', 'apoptosis,', lipogenesis, and, modulation, of, adipokine, gene, 'expression--during', the, maturation, of, preadipocytes, into, adipocytes])].
[sujeto(['Valproic', acid, '(', 'VPA)']), verbo([has]), complemento([extensive, effects, on, leukemic, blasts, through, its, inhibition, of, histone, deacetylases])].
[sujeto(['In', 't(8;21)', 'AML,', leukemogenesis, is, supposed, to, be]), verbo([induced]), complemento([via, aberrant, recruitment, of, histone, deacetylases])].
[sujeto(['VPA']), verbo([induced]), complemento([apoptosis, in, 'AML1/ETO-positive', and, 'MLL-AF4-positive', cells, in, a, 'dose-dependent', manner])].
[sujeto(['VPA']), verbo([increased]), complemento([the, expression, of, 'AML1', target, genes, -, 'PU'])].
[sujeto(['AML1/ETO-positive', leukemia, shows, specific, mechanism, of, 'VPA', residing, from, differentiation, followed, by, apoptosis, that, is, accompanied, by, an]), verbo([increase]), complemento([in, the, expression, of, repressed, 'AML1', target, genes])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, 'AML1/ETO-positive', patients, might, derive, the, greatest, benefit, from, 'VPA', treatment])].
[sujeto(['Haploinsufficiency', of, 'RUNX1', '(', also, known, as, 'CBFA2/AML1)', is]), verbo([associated]), complemento([with, familial, 'thrombocytopenia,', platelet, 'dysfunction,', and, predisposition, to, acute, leukemia])].
[sujeto(['We']), verbo([have]), complemento([reported, on, a, patient, with, thrombocytopenia, and, impaired, 'agonist-induced', 'aggregation,', 'secretion,', and, protein, phosphorylation, associated, with, a, 'RUNX1', mutation])].
[sujeto(['Expression', profiling, of, platelets, revealed, approximately, 5, -, fold]), verbo([decreased]), complemento([expression, of, 12, -, lipoxygenase, '(', 12, -, 'LO,', gene, 'ALOX12),', which, catalyzes, 12, -, hydroxyeicosatetraenoic, acid, production, from, arachidonic, acid])].
[sujeto(['We', hypothesized, that, 'ALOX12', is, a, direct, transcriptional]), verbo([target]), complemento([gene, of, 'RUNX1'])].
[sujeto(['In', present, 'studies,', 'agonist-induced', platelet, 12, -, 'HETE', production, was]), verbo([decreased]), complemento([in, the, patient])].
[sujeto(['In', luciferase, reporter, studies, in, human, erythroleukemia, 'cells,', mutation, of, each, site]), verbo([decreased]), complemento(['activity;', overexpression, of, 'RUNX1', 'up-regulated', promoter, 'activity,', which, was, abolished, by, mutation, of, 'RUNX1', sites])].
[sujeto(['Gel', shift, 'studies,', including, with, recombinant, 'protein,', revealed, 'RUNX1']), verbo([binding]), complemento([to, each, site])].
[sujeto(['Chromatin', immunoprecipitation, revealed, in, vivo, 'RUNX1']), verbo([binding]), complemento([in, the, region, of, interest])].
[sujeto([siRNA, knockdown, of, 'RUNX1']), verbo([decreased]), complemento(['RUNX1', and, 12, -, 'LO', proteins])].
[sujeto(['ALOX12', is, a, direct, transcriptional]), verbo([target]), complemento([of, 'RUNX1'])].
[sujeto(['Our', studies]), verbo([provide]), complemento([further, proof, of, principle, that, platelet, expression, profiling, can, elucidate, novel, alterations, in, platelets, with, inherited, dysfunction])].
[sujeto(['Compared', with, control, 'group,', the, expression, level, of, 'AML1', mRNA, significantly]), verbo([increased]), complemento([in, a, 'dose-dependent', manner])].
[sujeto(['Compared', with, control, 'group,', the, expression, level, of, cyclin, 'D2', mRNA, significantly]), verbo([decreased]), complemento([when, 'kasumi-1', cells, had, been, treated, with, 3, 'mmol/L', 'VPA', as, well, as, 'kasumi-1', cells, were, treated, with, different, concentrations, of, 'VPA', for, 3, days])].
[sujeto(['In', 'conclusion,', 'VPA', could, remove, transcription, inhibition, of, 'AML1-ETO', fusion, 'protein,']), verbo([increase]), complemento([transcription, of, 'AML1', and, 'down-regulate', mRNA, expression, of, 'AML1', target, gene, cyclin, 'D2', through, 'HDAC', inhibiting, activity])].
[sujeto(['RUNX1-related', chimeras, generated, by, the, chromosomal, translocations]), verbo([repress]), complemento([transcriptional, activity, of, 'wild-type', 'RUNX1', by, recruiting, the, 'co-repressor/histone', deacetylase, complex])].
[sujeto(['Thus,', histone, deacetylase, inhibitors, are, expected, to, restore, normal, functions, of, 'wild-type', 'RUNX1', and, thereby, affect, the, growth, and, differentiation, ability, of, leukemic, cells]), verbo([expressing]), complemento([the, chimera])].
[sujeto(['We', investigated, the, in, vitro, effects, of, histone, deacetylase, 'inhibitors,', trichostatin, 'A', and, valproic, 'acid,', on, human, leukemic, cell, lines, such, as, 'SKNO-1', and, 'Kasumi-1']), verbo([expressing]), complemento(['RUNX1/ETO,', 'Reh', expressing, 'TEL/RUNX1', and, 'SKH-1', 'co-expressing', 'RUNX1/EVI1', and, 'BCR/ABL'])].
[sujeto(['We', also, employed, 'K562', cells]), verbo([expressing]), complemento(['BCR/ABL', without, such, a, chimera, as, a, control])].
[sujeto(['Treatment', with, each, inhibitor]), verbo([increased]), complemento([acetylated, histone, 4, in, all, of, these, cell, lines])].
[sujeto(['Interestingly,', proliferation, of, 'SKNO-1,', 'Kasumi-1,', 'SKH-1', and, 'Reh', cells, was, significantly]), verbo([suppressed]), complemento([after, 3, -, day, culture, with, trichostatin, 'A', or, valproic, 'acid,', when, compared, to, that, of, 'K562', cells])].
[sujeto(['We', observed, cell, cycle]), verbo([arrest]), complemento([and, apoptotic, induction, in, the, 'RUNX1', 'chimera-expressing', cells, by, the, propidium, iodide, staining])].
[sujeto(['We', propose, histone, deacetylase, inhibitors, to, be, an, attractive, choice, in, the, molecular]), verbo([targeting]), complemento([therapy, of, 'RUNX1-related', leukemia])].
[sujeto(['Contrary', to, its, role, in, 'HDAC2', 'degradation,', the, 'E3-ligase', 'RLIM', does, not]), verbo([target]), complemento(['AML1-ETO', and, 'PML-RARalpha', for, 'ubiquitin-dependent', elimination])].
[sujeto(['The', former]), verbo([requires]), complemento([the, induction, of, 'UbcH8', expression, and, each, of, these, processes, might, be, beneficial, for, leukemia, treatment])].
[sujeto(['Our', observations, shed, light, on, the, mechanism, determining, the, interplay, between, 'E2-conjugases,', 'E3-ligases,', and, their, substrates, and]), verbo([suggest]), complemento([a, strategy, for, utilizing, the, ubiquitylation, machinery, in, a, therapeutic, setting])].
[sujeto(['Here,', we, show, that, chemicals, that]), verbo([enhance]), complemento([prostaglandin, '(', 'PG)', 'E2', synthesis, increased, 'HSC', 'numbers,', and, those, that, block, prostaglandin, synthesis, decreased, stem, cell, numbers])].
[sujeto(['The', cyclooxygenases, responsible, for, 'PGE2', synthesis, were]), verbo([required]), complemento([for, 'HSC', formation])].
[sujeto(['In', murine, embryonic, stem, cell, differentiation, 'assays,', 'PGE2']), verbo([caused]), complemento([amplification, of, multipotent, progenitors])].
[sujeto(['Furthermore,', ex, vivo, exposure, to, stabilized, 'PGE2']), verbo([enhanced]), complemento([spleen, colony, forming, units, at, day, 12, post, transplant, and, increased, the, frequency, of, 'long-term', repopulating, 'HSCs', present, in, murine, bone, marrow, after, limiting, dilution, competitive, transplantation])].
[sujeto(['The']), verbo([conserved]), complemento([role, for, 'PGE2', in, the, regulation, of, vertebrate, 'HSC', homeostasis, indicates, that, modulation, of, the, prostaglandin, pathway, may, facilitate, expansion, of, 'HSC', number, for, therapeutic, purposes])].
[sujeto(['Histone', deacetylase, inhibitor, valproic, acid, '(', 'VPA)', was, recently, shown, to]), verbo([enhance]), complemento([proliferation, and, 'self-renewal', of, normal, hematopoietic, stem, 'cells,', raising, the, possibility, that, 'VPA', may, also, support, growth, of, leukemic, progenitor, cells, '(', 'LPC)'])].
[sujeto(['Here,', 'VPA']), verbo([maintains]), complemento([a, significantly, higher, proportion, of, 'CD34+', 'LPC', and, colony, forming, units, compared, to, control, cultures, in, six, 'AML', 'samples,', but, selectively, reduces, leukemic, cell, numbers, in, another, 'AML', sample, with, expression, of, 'AML1/ETO'])].
[sujeto(['Our', data]), verbo([suggest]), complemento([a, differential, effect, of, 'VPA', on, the, small, population, of, 'AML', progenitor, cells, and, the, bulk, of, aberrantly, differentiated, blasts, in, the, majority, of, 'AML', samples, tested])].
[sujeto(['In', 't(8;21)', acute, myeloid, leukemia, '(', 'AML),', the, 'AML1/ETO', fusion, protein]), verbo([promotes]), complemento([leukemogenesis, by, recruiting, class, 'I', histone, deacetylase, '(', 'HDAC)-containing', repressor, complex, to, the, promoter, of, 'AML1', target, genes])].
[sujeto(['Valproic', acid, '(', 'VPA),', a, commonly, used, antiseizure, and, mood, stabilizer, 'drug,']), verbo([has]), complemento([been, shown, to, cause, growth, arrest, and, induce, differentiation, of, malignant, cells, via, 'HDAC', inhibition])].
[sujeto(['VPA']), verbo([causes]), complemento([selective, proteasomal, degradation, of, 'HDAC2', but, not, other, class, 'I', 'HDACs', '(', i])].
[sujeto(['Therefore,', we, raised, the, question, of, whether, this, drug, can, effectively]), verbo([target]), complemento([the, leukemogenic, activity, of, the, 'AML1/ETO', fusion, protein, that, also, recruits, 'HDAC1,', a, key, regulator, of, normal, and, aberrant, histone, acetylation])].
[sujeto(['We']), verbo([report]), complemento([here, that, 'VPA', treatment, disrupts, the, 'AML1/ETO-HDAC1', physical, 'interaction,', stimulates, the, global, dissociation, of, 'AML1/ETO-HDAC1', complex, from, the, promoter, of, 'AML1/ETO', target, 'genes,', and, induces, relocation, of, both, 'AML1/ETO', and, 'HDAC1', protein, from, nuclear, to, perinuclear, region])].
[sujeto(['Furthermore,', we, show, that, mechanistically, these, effects]), verbo([associate]), complemento([with, a, significant, inhibition, of, 'HDAC', 'activity,', histone, 'H3', and, 'H4', 'hyperacetylation,', and, recruitment, of, 'RNA', polymerase, 'II,', leading, to, transcriptional, reactivation, of, target, genes, '(', i])].
[sujeto(['Ultimately,', these, pharmacological, effects, resulted, in, significant, antileukemic, activity]), verbo([mediated]), complemento([by, partial, cell, differentiation, and, 'caspase-dependent', apoptosis])].
[sujeto(['Taken', 'together,', these, data, support, the, notion, that, 'VPA', might, effectively]), verbo([target]), complemento(['AML1/ETO-driven', leukemogenesis, through, disruption, of, aberrant, 'HDAC1', function, and, that, 'VPA', should, be, integrated, in, novel, therapeutic, approaches, for, 'AML1/ETO-positive', 'AML'])].
[sujeto(['The', fusion, protein, 'TEL-AML1', in, 't(12;21)+', acute, lymphoblastic, leukemia, '(', 'ALL)']), verbo([recruits]), complemento(['co-repressors', and, histone, deacetylases, '(', 'HDAC),', which, transrepress, 'AML1', target, genes])].
[sujeto(['Normal', bone, marrow, cells, were, more, resistant, to, 'HDAC', inhibitor, 'FK228']), verbo([induced]), complemento([cell, killing, than, were, cells, from, 'ALL', patients, with, or, without, 't(12;21)'])].
[sujeto(['FK228']), verbo([induced]), complemento([differentiation, in, 'ALL,', irrespective, of, the, presence, of, 't(12;21)'])].
[sujeto(['Acute', myeloid, leukemia, 1, '(', 'AML1),', also, denoted, 'Runx1,', is, a, transcription, factor, essential, for, 'hematopoiesis,', and, the, 'AML1', gene, is, the, most, common]), verbo([target]), complemento([of, chromosomal, translocations, in, human, leukemias])].
[sujeto(['AML1']), verbo([binds]), complemento([to, sequences, present, in, the, regulatory, regions, of, a, number, of, 'hematopoiesis-specific', 'genes,', including, certain, cytokines, such, as, granulocyte, macrophage, 'colony-stimulating', factor, '(', 'GM-CSF)', 'up-regulated', after, 'T', cell, receptor, stimulation])].
[sujeto(['Here', we, show, that, both, subunits, of, the, 'Ca(2+)/calmodulin-dependent', protein, phosphatase, calcineurin, '(', 'CN),', which, is]), verbo([activated]), complemento([upon, 'T', cell, receptor, 'stimulation,', interact, directly, with, the, 'N-terminal', runt, homology, 'domain-containing', part, of, 'AML1'])].
[sujeto(['The', regulatory, 'CN', subunit]), verbo([binds]), complemento(['AML1', with, a, higher, affinity, and, in, addition, also, interacts, with, the, isolated, runt, homology, domain])].
[sujeto(['The', related, 'Runx2', transcription, 'factor,', which, is, essential, for, bone, 'formation,', also]), verbo([interacts]), complemento([with, 'CN'])].
[sujeto(['A', constitutively, active, derivative, of, 'CN', is, shown, to]), verbo([activate]), complemento([synergistically, the, 'GM-CSF', 'promoter/enhancer', together, with, 'AML1', or, 'Runx2'])].
[sujeto(['We', also]), verbo([provide]), complemento([evidence, that, relief, of, the, negative, effect, of, the, 'AML1', sites, is, important, for, 'Ca(2+)', activation, of, the, 'GM-CSF', 'promoter/enhancer', and, that, 'AML1', overexpression, increases, this, 'Ca(2+)', activation])].
[sujeto(['Both', subunits, of, 'CN']), verbo([interact]), complemento([with, 'AML1', in, coimmunoprecipitation, 'analyses,', and, confocal, microscopy, analysis, of, cells, expressing, 'fluorescence-tagged', protein, derivatives, shows, that, 'CN', can, be, recruited, to, the, nucleus, by, 'AML1', in, vivo])].
[sujeto(['Mutant', analysis, of, the, 'GM-CSF', promoter, shows, that, the, 'Ets1']), verbo([binding]), complemento([site, of, the, promoter, is, essential, for, the, synergy, between, 'AML1', and, 'CN', in, 'Jurkat', 'T', cells])].
[sujeto(['Analysis', of, the, effects, of, inhibitors, of, the, protein, kinase, glycogen, synthase, 'kinase-3beta', and, in, vitro, 'phosphorylation/dephosphorylation', analysis, of, 'Ets1']), verbo([suggest]), complemento([that, glycogen, synthase, 'kinase-3beta-phosphorylated', 'Ets1', is, a, target, of, 'AML1-recruited', 'CN', phosphatase, at, the, 'GM-CSF', promoter])].
[sujeto(['Posttranslational', modification, by, small, 'ubiquitin-like', modifier, '(', 'SUMO)', conjugation]), verbo([regulates]), complemento([the, subnuclear, localization, of, several, 'proteins;', 'however,', 'SUMO', modification, has, not, been, directly, linked, to, nuclear, export])].
[sujeto(['The', 'ETS', '(', 'E-Twenty-Six)', family, member, 'TEL', '(', 'ETV6)', is, a, transcriptional, repressor, that, can]), verbo([inhibit]), complemento(['Ras-dependent', colony, growth, in, soft, agar, and, induce, cellular, aggregation, of, 'Ras-transformed', cells])].
[sujeto(['TEL', is, frequently, disrupted, by, chromosomal, translocations, such, as, the, 't(12;21),', which, is]), verbo([associated]), complemento([with, nearly, 'one-fourth', of, pediatric, 'B', cell, acute, lymphoblastic, leukemia])].
[sujeto(['In', the, vast, majority, of, 't(12;21)-containing', 'cases,', the, second, allele, of, 'TEL', is, 'deleted,']), verbo([suggesting]), complemento([that, inactivation, of, 'TEL', contributes, to, the, disease])].
[sujeto(['Although', 'TEL', functions, in, the, nucleus, as, a, 'DNA-binding', transcriptional, 'repressor,', it]), verbo([has]), complemento([also, been, detected, in, the, cytoplasm])].
[sujeto(['TEL', is, posttranslationally, modified, by, sumoylation, at, lysine, 99, within, a, highly]), verbo([conserved]), complemento([domain, '(', the, &, 'quot;pointed&quot;', 'domain)'])].
[sujeto(['Mutation', of, the, 'sumo-acceptor', lysine, or, mutations, within, the, pointed, domain, that, affect, sumoylation, impair]), verbo([nuclear]), complemento([export, of, 'TEL'])].
[sujeto(['Mutation', of, lysine, 99, also, results, in, an]), verbo([increase]), complemento([in, 'TEL', transcriptional, 'repression,', presumably, because, of, decreased, nuclear, export])].
[sujeto(['We', propose, that, the, ability, of, 'TEL', to]), verbo([repress]), complemento([transcription, and, suppress, growth, is, regulated, by, sumoylation, and, nuclear, export])].
[sujeto(['AML1', may, play, a, role, in, growth, and, differentiation, of, cells, along, erythroid, 'and/or', megakaryocytic, 'lineages,', because, a, significant, level, of, the, 'AML1', gene, is]), verbo([expressed]), complemento([in, these, cells])].
[sujeto(['We', overexpressed, 'AML1a', '(', without, the, 'transcription-activating', 'domain)', and, 'AML1b', '(', with, the, 'domain)', proteins, in, 'K562', leukemia, 'cells,', which, can, be]), verbo([induced]), complemento([to, differentiate, into, 'hemoglobin-producing', cells, and, megakaryocytes])].
[sujeto(['On', the, other, 'hand,', 'AML1b']), verbo([conferred]), complemento([a, similar, 'differentiation-inducing', capacity, upon, 'K562', cells, transfected, with, vector, alone])].
[sujeto(['AML1a', expression, was]), verbo([associated]), complemento([with, enhanced, sensitivity, to, megakaryocytic, differentiation, induced, by, phorbol, ester])].
[sujeto(['These', results]), verbo([provide]), complemento([evidence, that, 'AML1', proteins, play, a, role, in, erythroid, and, megakaryocytic, differentiation])].
[sujeto(['Cannabinoids', '(', 'CB)']), verbo([modulate]), complemento([adult, hematopoietic, stem, and, progenitor, cell, '(', 'HSPCs)', 'function,', 'however,', impact, on, the, 'production,', 'expansion,', or, migration, of, embryonic, 'HSCs', is, currently, uncharacterized])].
[sujeto(['Here,', using, chemical, and, genetic, approaches]), verbo([targeting]), complemento(['CB-signaling', in, 'zebrafish,', we, show, that, 'CB', receptor, '(', 'CNR)', 2, ',', but, not, 'CNR1,', regulates, embryonic, 'HSC', development])].
[sujeto(['During', 'HSC', specification, in, the, 'aorta-gonad-mesonephros', '(', 'AGM)', 'region,', 'CNR2', stimulation, by, 'AM1241']), verbo([increased]), complemento(['runx1;cmyb(+)', 'HSPCs,', through, heightened, 'proliferation,', whereas, 'CNR2', antagonism, decreased, 'HSPC', 'number;', 'FACS', analysis, and, absolute, 'HSC', counts, confirmed, and, quantified, these, effects])].
[sujeto(['Epistatic', investigations, showed, 'AM1241', significantly, upregulated, 'PGE2', synthesis, in, a, 'Ptgs2-dependent', manner, to]), verbo([increase]), complemento(['AGM', 'HSCs'])].
[sujeto(['Using', a, candidate, approach, for, 'HSC', migration, and, retention, 'factors,', 'P-selectin', was, identified, as, the, functional]), verbo([target]), complemento([of, 'CNR2', regulation])].
[sujeto(['Together,', these, data]), verbo([suggest]), complemento(['CNR2-signaling', optimizes, the, 'production,', 'expansion,', and, migration, of, embryonic, 'HSCs', by, modulating, multiple, downstream, signaling, pathways])].
[sujeto(['Valproic', acid, '(', 'VPA)', exhibits, important, pharmacological, properties, but]), verbo([has]), complemento([been, reported, to, trigger, side, 'effects,', notably, on, the, hematological, system])].
[sujeto(['We', previously]), verbo([reported]), complemento([that, 'VPA', affects, hematopoietic, homeostasis, by, inhibiting, erythroid, differentiation, and, promoting, myeloid, and, megakaryocyte, differentiation])].
[sujeto(['Here,', we, analyzed, the, effect, of, 'VPA', on, regulatory, factors]), verbo([involved]), complemento([in, 'erythro-megakaryocytic', differentiation, 'pathways,', including, transcription, factors, and, microRNAs, '(', 'miRs)'])].
[sujeto(['We', demonstrate, that, 'VPA']), verbo([inhibited]), complemento([erythroid, differentiation, in, erythropoietin, '(', 'Epo)-stimulated', 'TF1', leukemia, cells, and, 'CD34(+)/hematopoietic', stem, cells, '(', 'HSCs)', and, in, 'aclacinomycin-(Acla)-treated', 'K562', cells])].
[sujeto(['Mir-144/451', gene, expression, was]), verbo([decreased]), complemento([in, all, erythroid, and, megakaryocyte, models, in, correlation, with, 'GATA-1', inhibition])].
[sujeto(['In', 'Epo-stimulated', 'CD34(+)/HSCs,', 'VPA']), verbo([induced]), complemento([the, expression, of, the, 'ETS', family, transcription, factors, 'PU'])].
[sujeto([1, ',', 'ETS-1,', 'GABP-α,', 'Fli-1', and, 'GATA-2,', which, are, all, known, to, be, negative, regulators, of, 'erythropoiesis,', while, it]), verbo([promoted]), complemento([the, megakaryocytic, pathway])].
[sujeto([1, and, 'ETS-1', expression, were]), verbo([induced]), complemento([in, correlation, with, 'miR-155', 'inhibition;', 'however,', the, 'GATA-1/PU'])].
[sujeto(['Using', megakaryoblastic, 'Meg-01', 'cells,', we, demonstrated, that, 'VPA']), verbo([induced]), complemento([megakaryocyte, morphological, features, and, 'CD61', expression])].
[sujeto(['GATA-2', and, 'miR-27a', expression, were]), verbo([increased]), complemento([in, correlation, with, a, decrease, in, 'RUNX1', mRNA, 'expression,', suggesting, megakaryocyte, differentiation])].
[sujeto(['Finally,', by, using, valpromide, and, the, 'Class', 'I', 'HDACi', 'MS-275,', we, validated, that, the, 'well-described', 'HDACi', activity, of, 'VPA', is, not]), verbo([required]), complemento([in, the, inhibitory, effect, on, erythropoiesis])].
[sujeto(['Overall,', this]), verbo([report]), complemento([shows, that, 'VPA', modulates, the, 'erythro-megakaryocytic', differentiation, program, through, regulatory, 'micro-networks', involving, 'GATA', and, 'ETS', transcription, factors, and, 'miRNAs,', notably, the, 'GATA-1/miR-144/451', axis])].
[sujeto(['Molecular', mechanisms, that, are]), verbo([associated]), complemento([with, 'age-related', denervation, and, loss, of, skeletal, muscle, mass, and, function, '(', 'sarcopenia)', are, described, for, female, 'C57Bl/6J', mice, aged, 3, ',', 15, ',', 24, ',', 27, and, 29, months, '(', 'm)'])].
[sujeto(['Changes', in, mRNAs, and, proteins]), verbo([associated]), complemento([with, myofibre, denervation, and, protein, metabolism, in, ageing, muscles, are, 'reported,', across, the, transition, from, healthy, adult, myofibres, to, sarcopenia, that, occurs, between, 15, and, 24, m])].
[sujeto(['This', onset, of, sarcopenia, at, 24, 'm,', corresponded, with]), verbo([increased]), complemento([expression, of, genes, associated, with, neuromuscular, junction, denervation, including, 'Chnrg,', 'Chrnd,', 'Ncam1,', 'Runx1,', 'Gadd45a', and, 'Myog'])].
[sujeto(['Sarcopenia', in, quadriceps, muscles, also, coincided, with]), verbo([increased]), complemento([protein, levels, for, 'Igf1', 'receptor,', 'Akt', and, ribosomal, protein, 'S6', '(', 'Rps6)', with, increased, phosphorylation, of, 'Rps6', '(', 'Ser235/236)', and, elevated, 'Murf1', mRNA, and, 'protein,', but, not, 'Fbxo32:', many, of, these, changes, are, also, linked, to, denervation])].
[sujeto(['Global', transcription, profiling, via, microarray, analysis, confirmed, these, functional, themes, and, highlighted, additional, themes, that, may, be, a, consequence, of, pathology]), verbo([associated]), complemento([with, 'sarcopenia,', including, changes, in, fatty, acid, 'metabolism,', extracellular, matrix, structure, and, protein, catabolism])].
[sujeto(['Ageing', was, also]), verbo([associated]), complemento([with, increased, global, gene, expression, 'variance,', consistent, with, decreased, control, of, gene, regulation])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, the, patients, of, both, myelodysplastic, syndromes, and, chronic, myeloid, leukaemia, with, 'BMI1', overexpression, had, a, higher, risk, in, malignant, myeloid, progression])].
[sujeto(['In', vitro, gene, transfection, studies, showed, that, 'BMI1']), verbo([inhibited]), complemento([cell, myeloid, and, erythroid, differentiation, induced, by, 12, -, 'O-tetradecanoyl', 'phorbol-13-acetate', '(', 'TPA)', and, histone, deacetylase, inhibitor, sodium, butyrate, respectively])].
[sujeto(['BMI1', also, resisted, apoptosis]), verbo([induced]), complemento([by, arsenic, trioxide])].
[sujeto(['By', using, chromatin, immunoprecipitation, '(', 'ChIP)', collaborated, with, secondary, generation, sequencing, and, verified, by, 'ChIP-PCR,', we]), verbo([found]), complemento([that, 'BMI1', directly, bound, to, the, promoter, region, of, 'Zmym3,', which, encodes, a, component, of, histone, 'deacetylase-containing', complexes])].
[sujeto(['In', 'addition,', as, one, of, the, downstream]), verbo([target]), complemento([genes, of, this, 'complex,', 'c-fos', was, activated, with, increasing, histone, acetylation, when, 'ZMYM3', was, suppressed, in, the, 'Bmi1-transfected', cells])].
[sujeto(['These', results]), verbo([suggested]), complemento([that, 'BMI1', may, reprogramme, the, histone, acetylation, profile, in, multiple, genes, through, either, indirect, or, direct, binding, effects, which, probably, contributes, to, the, malignant, progression, of, myeloid, progenitor, cells])].
[sujeto(['Nickel', '(', 'Ⅱ)', is, a, toxic, and, carcinogenic, metal, which]), verbo([induces]), complemento([a, redox, imbalance, following, oxidative, stress])].
[sujeto(['Nuclear', factor, 'erythroid-2', related, factor, 2, '(', 'Nrf2)', is, a, redox, factor, that]), verbo([regulates]), complemento(['oxidation/reduction', status, and, consequently, mediates, cytoprotective, responses, against, exposure, to, environmental, toxicants])].
[sujeto(['In', this, 'study,', we, investigated, the, protective, roles, of, the, 'Nrf2', gene, against, oxidative, stress, and, 'DNA', damage]), verbo([induced]), complemento([by, nickel, at, 'sub-lethal', doses])].
[sujeto(['Under', nickel, exposure, 'conditions,', we, detected, significantly]), verbo([increased]), complemento([intracellular, 'ROS', 'generation,', in, addition, to, higher, amounts, of, 'DNA', damage, using, comet, assay, and, 'γ-H2AX', immunofluorescence, staining, in, 'Nrf2', lacking, 'cells,', as, compared, to, 'Nrf2', 'wild-type', cells])].
[sujeto(['In', 'addition,', we, attempted, to, identify, potential, nickel, and, 'Nrf2-responsive']), verbo([targets]), complemento([and, the, relevant, pathway])].
[sujeto(['Additionally,', using, bioinformatics, 'tool,', we]), verbo([found]), complemento([that, these, genes, functioned, principally, in, a, variety, of, molecular, 'processes,', including, oxidative, stress, 'response,', 'necrosis,', 'DNA', repair, and, cell, survival])].
[sujeto(['Although', exposure, to, 'SPs', is]), verbo([associated]), complemento([with, reproductive, toxicity, in, 'mammals,', limited, information, is, available, regarding, the, effects, of, 'SPs', on, female, ovulatory, function])].
[sujeto(['Bifenthrin', '(', 'BF),', a, 'broad-spectrum', type, 'I', 'SP,']), verbo([has]), complemento([been, widely, used, for, pest, control, for, two, decades])].
[sujeto(['Our', in, vivo, studies, demonstrated, that, 'short-term', administration, of, 'BF', to, 'gonadotropin-primed', rats, disrupted, the, expression, of, 'LH-responsible', ovulatory, 'genes,']), verbo([suggesting]), complemento([that, 'BF', has, similar, disrupting, effects, on, in, vitro, and, in, vivo, 'LH', signaling])].
[sujeto(['Importantly,', we]), verbo([found]), complemento([that, 'BF', blocked, 'LH-inducible', prostaglandin, 'E2', '(', 'PGE2)', accumulation, in, cultured, medium, of, granulosa, cells])].
[sujeto(['Forskolin']), verbo([stimulated]), complemento(['PTGS2', expression, was, decreased, by, treatment, with, 'BF,', indicating, that, 'BF', may, inhibit, 'LH-induced', 'PTGS2', expression, through, the, protein, kinase, 'A', '(', 'PKA)-mediated', signaling, pathway])].
[sujeto(['Taken', 'together,', our, present, study, firstly, shows, the, systemic, disrupting, effects, of, 'BF', on, the, network, of, ovulatory, gene, expression, patterns, as, well, as, prostaglandin, 'synthesis,', and]), verbo([suggest]), complemento([that, exposure, to, 'BF', may, increase, the, risk, of, ovulatory, dysfunction, in, females])].
[sujeto(['Most', of, the, recurrent, karyotypic, rearrangements, in, 'AML']), verbo([have]), complemento([been, defined, as, distinct, disease, entities, in, the, 2008, 'World', 'Health', 'Organization', '(', 'WHO)', classification])].
[sujeto(['In', this, paper, we]), verbo([report]), complemento([an, 'AML', case, showing, a, novel, 't(4;16)(q25;q23'])].
[sujeto([1, ')', rearrangement]), verbo([causing]), complemento([the, activation, of, epidermal, growth, factor, '(', 'EGF)', and, elongation, of, 'long-chain', fatty, acids, family, member, 6, '(', 'ELOVL6)', 'genes,', rather, than, the, generation, of, a, novel, fusion, gene])].
[sujeto(['It']), verbo([has]), complemento([been, proposed, that, inhibitors, of, an, 'oncogene\'s', effects, on, multipotent, hematopoietic, progenitor, cell, differentiation, may, change, the, properties, of, the, leukemic, stem, cells, and, complement, the, clinical, use, of, cytotoxic, drugs])].
[sujeto(['This', approach, may, open, doors, for, developing, therapeutics]), verbo([targeting]), complemento([oncogene, function, within, leukemic, stem, cells])].
[sujeto(['A', thorough, investigation, of, these, mechanisms, and, the, response, to, pharmacologic, modifiers, will]), verbo([provide]), complemento([a, better, understanding, of, the, role, of, histone, acetylation, in, leukemogenesis])].
[sujeto(['The', combined, approach, was, used, to, follow, the, dynamics, of, 'H4', acetylation, in, 'Kasumi-1', cells, harboring, the, fusion, gene, 'AML1/ETO', shown, to, aberrantly]), verbo([recruit]), complemento([histone, deacetylases, '(', 'HDACs)'])].
[sujeto(['Gene', transcription, is]), verbo([regulated]), complemento([by, a, complex, series, of, epigenetic, 'modifications,', i])].
[sujeto(['On', the, other, 'hand,', methylation, of, the, promoter, regions, of, some, genes, by, 'DNA', methyltransferases, '(', 'DNMT)']), verbo([leads]), complemento([to, transcriptional, silencing, and, is, a, common, mechanism, to, regulate, gene, expression])].
[sujeto(['In', normal, eukaryotic, 'cells,', 'DNA', methylation, and, histone, acetylation, are, interdependent, and]), verbo([maintain]), complemento(['equilibrium,', allowing, temporal, expression, of, genes])].
[sujeto(['In', leukemic, 'cells,', hypermethylation, of, 'CpG', islands, in, the, promoter, region, of, genes, critical, for, cell, cycle, and, maturation, is, 'frequent,', and, 'DNMTs', were]), verbo([found]), complemento([to, be, 'overexpressed,', findings, paralleled, by, evidence, of, transcriptional, repression, of, downstream, genes])].
[sujeto(['Therefore,', the, combination, of, 'HDAC', and, 'DNMT', inhibitors]), verbo([has]), complemento([been, considered, to, be, a, possible, therapeutic, approach, to, restore, normal, gene, expression, in, acute, myeloid, leukemia, '(', 'AML)', and, other, diseases])].
[sujeto(['Histone', acetylation, as, measured, by, flow, cytometry, was]), verbo([increased]), complemento([following, treatment, with, 'D1', and, the, combination, of, 'D1', and, decitabine])].
[sujeto(['Addition', of, 'D1', alone, or, in, combination, with, decitabine, also]), verbo([led]), complemento([to, inhibition, of, cell, proliferation, and, induction, of, apoptosis])].
[sujeto(['Thus,', treatment, of, 'AML', with, 'HDAC', inhibitors, such, as, 'D1', and, 'DNMT', inhibitors, such, as, decitabine, might]), verbo([have]), complemento([clinical, benefit, for, 'patients,', especially, these, presenting, subtypes, of, 'AML,', like, 'AML1/ETO,', in, which, the, leukemogenic, mechanism, involves, corepressor, protein, complexes, containing, 'HDAC', and, 'DNMT'])].
[sujeto(['RUNX/AML', transcription, factors, are, critical, regulators, of, cell, growth, and, differentiation, in, multiple, lineages, and]), verbo([have]), complemento([been, linked, to, human, cancers, including, acute, myelogenous, leukemia, '(', 'RUNX1),', as, well, as, breast, '(', 'RUNX2)', and, gastric, cancers, '(', 'RUNX3)'])].
[sujeto(['RUNX', proteins, are]), verbo([targeted]), complemento([to, gene, regulatory, 'micro-environments', within, the, nucleus, via, a, specific, subnuclear, targeting, signal])].
[sujeto(['The', 'taxol-dependent', cytoplasmic, accumulation, of, 'RUNX2', is]), verbo([inhibited]), complemento([by, leptomycin, 'B,', which, blocks, 'CRM-1', dependent, nuclear, 'export,', and, is, not, affected, by, the, protein, synthesis, inhibitor, cycloheximide])].
[sujeto(['Using', biochemical, 'assays,', we, show, that, endogenous, 'RUNX2']), verbo([associates]), complemento([with, stabilized, microtubules, in, a, 'concentration-dependent', manner, and, that, the, 'RUNX2', amino, terminus, mediates, the, microtubule, association])].
[sujeto(['In', soluble, fractions, of, 'cells,', 'RUNX2', 'co-immunoprecipitates', alpha, tubulin]), verbo([suggesting]), complemento([that, microtubule, binding, involves, the, 'alpha/beta', tubulin, subunits])].
[sujeto(['We', conclude, that, 'RUNX2']), verbo([associates]), complemento([with, microtubules, and, shuttles, between, the, nucleus, and, the, cytoplasm])].
[sujeto(['We', propose, that, 'nuclear-cytoplasmic', shuttling, of, 'RUNX2', may]), verbo([modulate]), complemento([its, transcriptional, 'activity,', as, well, as, its, ability, to, interface, with, signal, transduction, pathways, that, are, integrated, at, 'RUNX2', containing, subnuclear, sites])].
[sujeto(['It', is, possible, that, 'taxol-induced', acute, depletion, of, the]), verbo([nuclear]), complemento([levels, of, 'RUNX2', 'and/or', other, cell, growth, regulatory, factors, may, represent, an, alternative, pathway, by, which, taxol, exerts, its, biological, effects, during, cancer, chemotherapies])].
[sujeto(['Additionally,', electrophoretic, mobility, shift, assays]), verbo([have]), complemento([shown, that, the, palindrome, could, bind, the, 'RUNX1', component, in, nuclear, extracts, of, myeloid, cell, lines, exclusively, through, its, 'RUNX', motif])].
[sujeto(['The', palindrome, was]), verbo([found]), complemento([in, five, additional, human, 'genes,', two, of, which, '(', 'MYH11', and, 'MLLT1)', have, been, linked, to, chromosomal, rearrangements, leading, to, leukemia])].
[sujeto(['The', data, presented, here]), verbo([have]), complemento(['implicated,', for, the, first, 'time,', 'RUNX/AML', in, the, regulation, of, the, uPA, gene])].
[sujeto(['To', assess, whether, dopamine, receptor, 2, agonists, reduced, the, size, of, peritoneal, lesions, in, women, with, endometriosis, and, elucidate, whether, affectation, of, vascular, endothelial, growth, factor, '(', 'VEGF)/VEGF', receptor, 2, '(', 'VEGFR2)-dependent', angiogenesis, was]), verbo([mediating]), complemento([the, observed, effects])].
[sujeto(['Hyperprolactinemic', patients, '(', n, =, 9, ')', with, endometriosis]), verbo([requiring]), complemento([a, first, surgical, intervention, '(', 'L1)', and, benefiting, from, a, 'second-look', laparoscopy, '(', 'L2)', were, evaluated])].
[sujeto(['Quinagolide']), verbo([induced]), complemento([a, 69.5, '%', reduction, in, the, size, of, the, 'lesions,', with, 35, '%', vanishing, completely])].
[sujeto(['By', interfering, with, 'angiogenesis,']), verbo([enhancing]), complemento(['fibrinolysis,', and, reducing, 'inflammation,', quinagolide, reduces, or, eliminates, peritoneal, endometriotic, lesions, in, women, with, endometriosis])].
[sujeto(['The', 't(12;21)', chromosomal, 'translocation,']), verbo([targeting]), complemento([the, gene, encoding, the, 'RUNX1', transcription, 'factor,', is, observed, in, 25, '%', of, pediatric, acute, lymphoblastic, leukemia, '(', 'ALL)', and, is, an, initiating, event, in, the, disease])].
[sujeto(['This', study, revealed, 2, critical, functions, of, 'Runx1:', '(', 1, ')', to]), verbo([promote]), complemento([survival, and, development, of, progenitors, specified, to, the, 'B-cell', 'lineage,', a, function, that, can, be, substituted, by, ectopic, 'Bcl2', 'expression,', and, '(', 2, ')', to, enable, the, developmental, transition, through, the, 'pre-B', stage, triggered, by, the, 'pre-B-cell', antigen, receptor, '(', 'pre-BCR)'])].
[sujeto(['Gene', expression, analysis, and, genomewide, 'Runx1', occupancy, studies, support, the, hypothesis, that, 'Runx1', reinforces, the, transcription, factor, network, governing, early, 'B-cell', survival, and, development, and, specifically]), verbo([regulates]), complemento([genes, encoding, members, of, the, 'Lyn', kinase, subfamily, '(', key, integrators, of, 'interleukin-7', and, 'pre-BCR', 'signaling)', and, the, 'stage-specific', transcription, factors, 'SpiB', and, 'Aiolos', '(', critical, downstream, effectors, of, 'pre-BCR', 'signaling)'])].
[sujeto(['Interrogation', of, expression, databases, of, 257, 'ALL', samples, demonstrated, the, specific, 'down-regulation', of, the, 'SPIB', and, 'IKZF3', genes, '(', the, latter, encoding, 'AIOLOS)', in, 't(12;21)', 'ALL,']), verbo([providing]), complemento([novel, insight, into, the, mechanism, by, which, the, translocation, blocks, 'B-cell', development, and, promotes, leukemia])].
[sujeto(['A', causative, role, for, single, nucleotide, polymorphisms, '(', 'SNPs)', in, many, genetic, disorders]), verbo([has]), complemento([become, evident, through, numerous, 'genome-wide', association, studies])].
[sujeto(['Differential', transcription, factor]), verbo([binding]), complemento([at, a, 'SNP', resulting, in, altered, gene, expression, is, one, possible, mechanism])].
[sujeto(['Here', we, apply, 'PWAS', '(', &, 'quot;proteome-wide', analysis, of, 'SNPs&quot;),', a, methodology, based, on, quantitative, mass, spectrometry, that, enables, rapid, screening, of, 'SNPs', for, differential, transcription, factor, 'binding,', to, 12, 'SNPs', that, are, highly]), verbo([associated]), complemento([with, type, 1, diabetes, at, the, 'IL2RA', 'locus,', encoding, the, 'interleukin-2', receptor, 'CD25'])].
[sujeto(['We']), verbo([report]), complemento(['differential,', 'allele-specific', binding, of, the, transcription, factors, 'RUNX1,', 'LEF1,', 'CREB,', and, 'TFAP4', to, 'IL2RA', 'SNPs', 'rs12722508*A,', 'rs12722522*C,', 'rs41295061*A,', and, 'rs2104286*A', and, demonstrate, the, functional, influence, of, 'RUNX1', at, rs12722508, by, reporter, gene, assay])].
[sujeto(['The', cytokines, 'TGFβ', and, 'IL-6']), verbo([promote]), complemento([the, development, of, 'Th17', cells, that, produce, 'IL-17,', an, inflammatory, cytokine, not, expressed, by, other, 'T', helper, lineages])].
[sujeto(['We', show, that, the, +, 28, -, kb, noncoding, sequence, cooperates, with, 'STAT3,', 'RORγt,', and, 'Runx1', to]), verbo([enhance]), complemento([transcription, from, both, il17a, and, il17f, promoters])].
[sujeto(['This', enhancer, and, both, promoters, exhibited, 'Th17', 'lineage-specific', 'DNA', 'demethylation,', accompanied, by, demethylation, of, lysine, 27, of, histone, 'H3', '(', 'H3K27)', and]), verbo([increased]), complemento(['H3K4', methylation])].
[sujeto(['Loss', of, 'DNA', methylation, tended, to, occur, at, 'STAT3', consensus, 'elements,', and, we, show, that, methylation, of, one, of, these, elements, in, the, il17a, promoter, directly]), verbo([inhibits]), complemento(['STAT3', binding, and, transcriptional, activity])].
[sujeto(['These', results, demonstrate, that, 'TGFβ', and, 'IL-6', synergize, to, epigenetically, poise, the, il17, loci, for, expression, in, 'Th17', 'cells,', and]), verbo([suggest]), complemento([a, general, mechanism, by, which, active, 'STAT3', may, be, epigenetically, excluded, from, 'STAT3-responsive', genes, in, 'non-Th17', lineages])].
[sujeto(['Here', we, show, that, optimal, transcription, of, the, gene, encoding, interleukin, 17, '(', 'Il17)']), verbo([required]), complemento([a, 2, -, kilobase, promoter, and, at, least, one, conserved, noncoding, '(', 'enhancer)', 'sequence,', 'CNS-5'])].
[sujeto(['Both', 'cis-regulatory', elements, contained, regions, that]), verbo([bound]), complemento([the, transcription, factors, 'RORgammat', and, 'Runx1'])].
[sujeto(['Runx1', influenced, 'T(H)-17', differentiation, by]), verbo([inducing]), complemento(['RORgammat', expression, and, by, binding, to, and, acting, together, with, 'RORgammat', during, 'Il17', transcription])].
[sujeto(['However,', 'Runx1', also]), verbo([interacts]), complemento([with, the, transcription, factor, 'Foxp3,', and, this, interaction, was, necessary, for, the, negative, effect, of, 'Foxp3', on, 'T(H)-17', differentiation])].
[sujeto(['Thus,', our, data, support, a, model, in, which, the, differential, association, of, 'Runx1', with, 'Foxp3', and, with, 'RORgammat']), verbo([regulates]), complemento(['T(H)-17', differentiation])].
[sujeto(['Although', previous, studies]), verbo([have]), complemento([revealed, the, roles, of, cytokine, signaling, and, of, transcription, factors, during, differentiation, of, 'Th1', or, 'Th2', 'cells,', it, is, unclear, how, the, exclusive, expression, pattern, of, each, hallmark, cytokine, is, established])].
[sujeto(['The', 'DNaseI', hypersensitivity, site, 'IV', within, the, mouse, 'Il4', locus, plays, an, important, role, in, the, repression, of, 'Il4', expression, in, 'Th1', 'cells,', and, it]), verbo([has]), complemento([been, named, the, 'Il4', silencer])].
[sujeto(['Using', 'Cbf', 'beta-', or, 'Runx3-deficient', 'T', 'cells,', we, show, that]), verbo([loss]), complemento([of, 'Runx', complex, function, results, in, derepression, of, 'IL-4', in, 'Th1', cells])].
[sujeto(['Furthermore,', enforced, expression, of, 'GATA-3', in, 'Th1', cells]), verbo([inhibited]), complemento([binding, of, 'Runx', complexes, to, the, 'Il4', silencer])].
[sujeto(['Interestingly,', 'T', 'cell-specific', inactivation, of, the, 'Cbf', beta, gene, in, mice]), verbo([led]), complemento([to, elevated, serum, immunoglobulin, 'E', and, airway, infiltration])].
[sujeto(['These', results, demonstrate, critical, roles, of, 'Runx', complexes, in]), verbo([regulating]), complemento([immune, 'responses,', at, least, in, 'part,', through, the, repression, of, the, 'Il4', gene])].
[sujeto(['T-cell', acute, lymphoblastic, leukemia, '(', 'T-ALL)', is, characterized, as, a, 'high-risk', stratified, disease]), verbo([associated]), complemento([with, frequent, 'relapse,', chemotherapy, 'resistance,', and, a, poorer, prognostic, outlook, than, 'B-precursor', 'ALL'])].
[sujeto(['Many', of, the, challenges, in, treating, 'T-ALL', reflect, the, lack, of, prognostic, cytogenetic, or, molecular, abnormalities, on, which, to, base, 'therapy,', including]), verbo([targeted]), complemento([therapy])].
[sujeto(['Notch1']), verbo([activating]), complemento([mutations, were, identified, in, more, than, 50, '%', of, 'T-ALL', cases, and, can, be, therapeutically, targeted, with, 'γ-secretase', inhibitors, '(', 'GSIs)'])].
[sujeto(['Mutant', 'Notch1', can]), verbo([activate]), complemento([cMyc, and, 'PI3K-AKT-mTOR1', signaling, in, 'T-ALL'])].
[sujeto(['In', 'T-ALLs', with, 'wild-type', phosphatase, and, tensin, homolog, deleted, on, chromosome, ten, '(', 'PTEN),', 'Notch1', transcriptionally]), verbo([represses]), complemento(['PTEN,', an, effect, reversible, by, 'GSIs'])].
[sujeto(['Notch1', also]), verbo([promotes]), complemento([growth, factor, receptor, '(', 'IGF1R', and, 'IL7Rα)', signaling, to, 'PI3K-AKT'])].
[sujeto(['Notch1', itself, might]), verbo([regulate]), complemento([posttranslational, inactivation, of, 'PTEN'])].
[sujeto(['PP2A', is]), verbo([activated]), complemento([by, 'Notch1', in, 'PTEN-null', 'T-ALL', 'cells,', and, 'GSIs', reduce, 'PP2A', activity, and, increase, phosphorylation, of, 'AKT,', 'AMPK,', and, p70S6K])].
[sujeto(['Myeloid', and, lymphoid, neoplasms, with, abnormalities, of, fibroblast, growth, factor, receptor, 1, gene, '(', 'FGFR1)', are, a, rare, and, aggressive, disease, group, that, harbors, translocations, of, 'FGFR1', with, at, least, 14]), verbo([recognized]), complemento([partner, genes])].
[sujeto(['We']), verbo([report]), complemento([a, case, of, a, patient, with, a, novel, 't(17;21)(p13;q22)', with, 'RUNX1', rearrangement, and, trilineage, blasts])].
[sujeto(['To', our, 'knowledge,', this, is, the, first]), verbo([reported]), complemento([case, of, a, myeloid, and, lymphoid, neoplasm, with, abnormalities, of, 'FGFR1', with, 't(17;21)(p13;q22)', and, trilineage, blasts])].
[sujeto(['Four', years, 'before,']), verbo([he]), complemento([had, received, combination, chemotherapy, including, etoposide, for, seminoma])].
[sujeto(['Thus,', acute, leukemia, with, 't(1;21)', and, 'RUNX1', rearrangement, could, be]), verbo([associated]), complemento([with, 'B/myeloid', mixed, phenotype, as, well, as, previous, topoisomerase, 'II', inhibitor, therapy, and, poor, prognoses])].
[sujeto(['Using', 'semi-quantitative', 'PCR-based', 'approach,', we]), verbo([have]), complemento([shown, that, the, breakpoint, cluster, region, of, the, 'AML1', gene, was, associated, with, the, nuclear, matrix])].
[sujeto(['We']), verbo([have]), complemento([demonstrated, that, inhibition, of, topoisomerase, 'II', by, etoposide, stimulates, the, appearance, of, histone, gammaH2AX, 'foci,', an, indicator, for, the, presence, of, 'DNA', 'double-strand', breaks])].
[sujeto(['Furthermore,', the, major, part, of, these, foci, was]), verbo([associated]), complemento([with, the, nuclear, matrix])].
[sujeto(['We', also, visualized]), verbo([nuclear]), complemento(['matrix--associated', multiprotein, complexes, involved, in, topoisomerase, 'II--induced', 'DNA', 'double-strand', break, repair])].
[sujeto(['Colocalization', studies]), verbo([have]), complemento([demonstrated, that, these, complexes, included, the, principal, components, of, the, 'non-homologous', end, joining, repair, system, '(', 'Ku80,', 'DNA-PKcs', and, 'DNA', ligase, 'IV)'])].
[sujeto(['Thus,', it, is, reasonable, to]), verbo([suggest]), complemento([that, the, 'non-homologous', 'DNA', end, joining, is, a, possible, mechanism, of, topoisomerase, 'II--induced', chromosomal, rearrangements])].
[sujeto(['The', 't(3;21)(q26;q22)', translocation, is]), verbo([associated]), complemento([with, myeloid, leukemias, and, results, in, a, chimeric, oncoprotein, containing, 'AML1/RUNX1', variably, fused, to, 'EAP,', 'MDS1,', 'and/or', 'EVI1'])].
[sujeto(['The', current, study, describes, what, to, the, 'authors\'', knowledge, is, the, first, large, case, series]), verbo([reported]), complemento([to, date, of, 26, 't(3;21)(q26;q22)-associated', 'leukemias,', in, which, 24, cases, arose, after, chemotherapy])].
[sujeto(['Eight', patients, with, chronic, myeloproliferative, disorders, '(', 'CMPD)', were]), verbo([found]), complemento([to, have, 't(3;21)', with, 't(9;22)', as, the, sole, cytogenetic, 'abnormality;', in, 5, other, patients, this, was, accompanied, by, trisomy, 8])].
[sujeto(['The', ability, of, topoisomerase, 2, inhibitors, to]), verbo([induce]), complemento(['DNA', breakage, is, well, recognized])].
[sujeto(['Previous', 'studies,', 'however,']), verbo([have]), complemento([concentrated, on, the, effects, on, individual, genes])].
[sujeto(['We']), verbo([found]), complemento(['MLL', to, be, more, susceptible, to, 'etoposide-induced', cleavage, than, 'RUNX1', and, 'MLLT3,', with, maximum, cleavage, at, a, lower, drug, concentration])].
[sujeto(['In', 'conclusion,', we]), verbo([found]), complemento([that, the, presence, of, the, 't(12;21)', translocation, in, childhood, precursor, 'B-ALL', is, associated, with, a, high, tumor, cell, sensitivity, to, doxorubicin, and, etoposide])].
[sujeto(['High', throughput, techniques, should, now, be, used, to, elucidate, the, cellular, mechanisms, by, which, 'ETV6/RUNX1', gene, fusion, is, linked, to]), verbo([increased]), complemento([sensitivity, to, these, drugs])].
[sujeto(['Recent', findings, that, 'site-specific', cleavage, of, the, 'MLL', gene, can, be]), verbo([induced]), complemento([by, chemotherapeutic, agents, such, as, 'topoisomerase-II', inhibitors, suggest, that, apoptogenic, agents, can, cause, chromosomal, translocations, in, hematopoietic, cells])].
[sujeto(['Short-term', culture, of, immature, 'B', cell, lines, in, the, presence, of, apoptogenic, stimuli, such, as, serum, 'starvation,', 'etoposide,', or, salicylic, acid]), verbo([induced]), complemento(['double-strand', breaks, '(', 'DSBs)', in, intron, 5, of, the, 'TEL', gene, and, intron, 1, of, the, 'AML1', gene])].
[sujeto(['DSBs', within, the, 'TEL', gene, were, also]), verbo([associated]), complemento([with, fusion, to, other, unknown, 'genes,', presumably, as, a, result, of, chromosomal, translocation])].
[sujeto(['These', data]), verbo([suggest]), complemento([that, breakage, and, fusion, of, 'TEL', and, 'AML1', may, be, relatively, common, events, and, that, sublethal, apoptotic, signals, could, play, a, role, in, initiating, leukemogenesis, via, the, promotion, of, 'DNA', damage])].
[sujeto(['A', distinct, population, of, 'therapy-related', acute, myeloid, leukemia, '(', 't-AML)', is, strongly]), verbo([associated]), complemento([with, prior, administration, of, topoisomerase, 'II', '(', topo, 'II)', inhibitors])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, 'site-specific', cleavage, within, the, 'MLL', bcr, can, be, induced, by, either, catalytic, topo, 'II', 'inhibitors,', genotoxic, chemotherapeutic, agents, which, do, not, target, topo, 'II,', or, nongenotoxic, stimuli, of, apoptotic, cell, 'death,', suggesting, that, this, 'site-specific', cleavage, is, part, of, a, generalized, cellular, response, to, an, apoptotic, stimulus])].
[sujeto(['We', also, show, that, 'site-specific', cleavage, within, the, 'MLL', bcr, can, be, linked, to, the, 'higher-order', chromatin, fragmentation, that, occurs, during, the, initial, stages, of, 'apoptosis,', possibly, through, cleavage, of, 'DNA', loops, at, their, anchorage, sites, to, the]), verbo([nuclear]), complemento([matrix])].
[sujeto(['In', 'addition,', we, show, that, 'site-specific', cleavage, is]), verbo([conserved]), complemento([between, 'species,', as, specific, 'DNA', cleavage, can, also, be, demonstrated, within, the, murine, 'MLL', locus])].
[sujeto(['Lastly,', 'site-specific', cleavage, during, apoptosis, can, also, be, identified, at, the, 'AML1', 'locus,', a, locus, which, is, also, frequently]), verbo([involved]), complemento([in, chromosomal, rearrangements, present, in, 't-AML', patients])].
[sujeto(['In', 'conclusion,', these, results]), verbo([suggest]), complemento([the, potential, involvement, of, 'higher-order', chromatin, fragmentation, which, occurs, as, a, part, of, a, generalized, apoptotic, response, in, a, mechanism, leading, to, chromosomal, translocation, of, the, 'MLL', and, 'AML1', genes, and, subsequent, 't-AML'])].
[sujeto(['Altered', regulation, of, many, transcription, factors]), verbo([has]), complemento([been, shown, to, be, important, in, the, development, of, leukemia])].
[sujeto(['TWIST2']), verbo([modulates]), complemento([the, activity, of, a, number, of, important, transcription, factors, and, is, known, to, be, a, regulator, of, hematopoietic, differentiation])].
[sujeto(['We']), verbo([found]), complemento([that, 'TWIST2', was, inactivated, in, more, than, 50, '%', of, cases, of, childhood, and, adult, acute, lymphoblastic, leukemia, through, promoter, hypermethylation, and, that, this, epigenetic, regulation, was, especially, prevalent, in, 'RUNX1-ETV6-driven', cases])].
[sujeto(['Furthermore,', 're-expression', of, 'TWIST2', resulted, in]), verbo([increased]), complemento([sensitivity, to, the, chemotherapeutic, agents, 'etoposide,', daunorubicin, and, dexamethasone, and, 'TWIST2', hypermethylation, was, almost, invariably, found, in, relapsed, adult, acute, lymphoblastic, leukemia, '(', 91, '%', of, samples, 'hypermethylated)'])].
[sujeto(['This', study]), verbo([suggests]), complemento([a, dual, role, for, epigenetic, inactivation, of, 'TWIST2', in, acute, lymphoblastic, 'leukemia,', initially, through, altering, cell, growth, and, survival, properties, and, subsequently, by, increasing, resistance, to, chemotherapy])].
[sujeto(['Decreasing', use, of, prophylactic, cranial, irradiation, in, the, period, 1997, -, 2008, was, not]), verbo([associated]), complemento([with, increased, rates, of, 'CNS', 'relapse,', prompting, complete, omission, of, prophylactic, cranial, irradiation, from, 'TPOG', 'protocols,', beginning, in, 2009])].
[sujeto(['Higher', leukocyte, count, and, 't(9;22)']), verbo([retained]), complemento([prognostic, significance, in, both, 'TPOG-97', and, 'TPOG-2002', by, multivariate, analysis])].
[sujeto(['Although', 'long-term', outcome, in, 'TPOG', clinical, trials, is, comparable, with, results, being]), verbo([reported]), complemento(['worldwide,', the, persistent, strength, of, certain, prognostic, variables, and, the, lower, frequencies, of, favorable, outcome, 'predictors,', such, as, 'ETV6-RUNX1', and, hyperdiploidy, &, 'gt;50,', in, 'Taiwanese', children, warrant, renewed, effort, to, cure, a, higher, proportion, of, patients, while, preserving, their, quality, of, life])].
[sujeto(['MLL', gene, fusions, are, the, hallmark, of, more, than, 70, '%', of, 'therapy-related', leukemias, '(', 't-ML)']), verbo([associated]), complemento([with, topoisomerase, 'II', inhibitors, '(', e])].
[sujeto([',', 'etoposide)', and]), verbo([cause]), complemento([leukemia, in, murine, transgenic, models])].
[sujeto(['The', fusion, points, in, 'Mll', chimeric, products]), verbo([induced]), complemento([by, etoposide, were, localized, to, a, 1.5, kb, region, between, exons, 9, and, 11, ',', analogous, to, the, 'MLL', breakpoint, cluster, region, in, human, leukemia])].
[sujeto(['One', partner, was, 'Runx1,', the, murine, homologue, of, the, transcription, factor, 'AML-1,', a]), verbo([target]), complemento([of, human, translocations, in, 'therapy-related', leukemia])].
[sujeto(['These', findings, indicate, that, etoposide]), verbo([triggers]), complemento([the, formation, of, 'Mll', gene, 'fusions,', a, critical, step, for, the, development, of, 'treatment-induced', leukemic, transformation])].
[sujeto(['The', effect, of, intensified, therapy, on, the, importance, of, currently]), verbo([recognized]), complemento([phenotypic, and, genotypic, determinants, of, outcome, was, assessed, in, 2090, children, enrolled, on, the, 'Medical', 'Research', 'Council', 'United', 'Kingdom', acute, lymphoblastic, leukaemia, 'XI', '(', 'MRC', 'UKALL', 'XI)', protocol])].
[sujeto(['Reverse', 'transcriptase-polymerase', chain, reaction, '(', 'RT-PCR)', methods, often, detect, the, 'AML1/MTG8', fusion, transcript, even, in, acute, myelogenous, leukemia, '(', 'AML)', patients, with, 't(8;21)', who]), verbo([have]), complemento([been, in, 'long-term', remission])].
[sujeto(['Southern', blot, analysis, of, bone, marrow, cells, did, not, detect, rearrangement, of, the, 'AML1', 'gene,', 'however,', fluorescence, in, situ, hybridization, '(', 'FISH)', analysis, of, bone, marrow, cells, at, interphase, and, metaphase, revealed, a, translocational, splitting, between, chromosome, 21]), verbo([involving]), complemento(['AML1', gene, and, chromosome, 16])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, the, breakpoint, is, not, located, in, the, breakpoint, cluster, region, for, 't(8;21)'])].
[sujeto(['Treatment-related', acute, myeloid, leukemia, '(', 't-AML)', following, successful, therapy, of, a, primary, malignancy]), verbo([has]), complemento([been, recognized, with, increasing, frequency, among, cancer, survivors, over, the, past, several, years])].
[sujeto(['Many', of, these, 't-AML', cases, are]), verbo([associated]), complemento([with, the, use, of, intensive, chemotherapy, regimens, that, employ, one, or, more, agents, which, target, eukaryotic, topoisomerase, 'II', '(', topo, 'II),', and, demonstrate, 'non-random', chromosomal, translocations, involving, either, the, 'MLL', '(', 'ALL-1,', 'HRX)', gene, at, 11, q23, or, the, 'AML1', gene, at, 21, q22])].
[sujeto(['Although', many, investigators]), verbo([have]), complemento([speculated, that, these, translocations, are, induced, by, the, therapeutic, use, of, topo, 'II', 'inhibitors,', the, molecular, sequence, of, events, by, which, topo, 'II', inhibitors, might, induce, a, chromosomal, translocation, are, not, well, understood])].
[sujeto(['This', 'DNA', 'cleavage,', which, maps, to, a, region, of, the, 'AML1', locus, frequently, disrupted, by, chromosomal, 'translocations,', can, be]), verbo([induced]), complemento([in, several, cell, 'lines,', with, multiple, different, topo, 'II', 'inhibitors,', indicating, that, this, phenomenon, is, not, restricted, to, a, specific, cell, type, or, specific, topo, 'II', inhibitor])].
[sujeto(['It', is, conceivable, that, 'site-specific', 'double-strand', 'DNA', cleavage, within, the, 'AML1', locus]), verbo([induced]), complemento([by, topo, 'II', inhibitors, represents, the, initial, molecular, event, leading, to, a, chromosomal, translocation, and, 't-AML'])].
[sujeto(['The', purposes, of, this, study, were, to, investigate, the, possible, molecular, mechanisms, of, 'miR-18a']), verbo([regulating]), complemento([the, permeability, of, 'blood-tumor', barrier, '(', 'BTB)', via, 'down-regulated', expression, and, distribution, of, 'runt-related', transcription, factor, 1, '(', 'RUNX1)'])].
[sujeto(['The', overexpression, of, 'miR-18a', significantly, impaired, the, integrity, and]), verbo([increased]), complemento([the, permeability, of, 'BTB,', which, respectively, were, detected, by, 'TEER', and, 'HRP', flux, 'assays,', accompanied, by, 'down-regulated', mRNA, and, protein, expressions, and, distributions, of, 'ZO-1,', occludin, and, 'claudin-5', in, 'GECs'])].
[sujeto(['Dual-luciferase', reporter, assay, was, carried, out, and, revealed, 'RUNX1', is, a]), verbo([target]), complemento([gene, of, 'miR-18a'])].
[sujeto(['Most', 'important,', 'miR-18a', and, 'RUNX1', could, reversely]), verbo([regulate]), complemento([the, permeability, of, 'BTB', as, well, as, the, expressions, and, distributions, of, 'ZO-1,', occludin, and, 'claudin-5'])].
[sujeto(['Finally,', chromatin, immunoprecipitation, verified, that, 'RUNX1']), verbo([interacted]), complemento([with, &, 'quot;TGGGGT&quot;', 'DNA', sequence, in, promoter, region, of, 'ZO-1,', occludin, and, 'claudin-5', respectively])].
[sujeto(['Taken', 'together,', our, present, study, indicated, that, 'miR-18a']), verbo([increased]), complemento([the, permeability, of, 'BTB', via, 'RUNX1', mediated, 'down-regulation', of, tight, junction, related, proteins, 'ZO-1,', occludin, and, 'claudin-5,', which, would, attract, more, attention, to, 'miR-18a', and, 'RUNX1', as, potential, targets, of, drug, delivery, across, 'BTB', and, provide, novel, strategies, for, glioma, treatment])].
[sujeto(['Recently', a, putative, link, to, breast, cancer]), verbo([has]), complemento([started, to, 'emerge,', however, the, function, of, 'RUNX1', in, breast, cancer, is, still, unknown])].
[sujeto(['RUNX1', was]), verbo([associated]), complemento([with, progesterone, receptor, '(', 'PR)-positive', tumours, '(', 'P&lt;0'])].
[sujeto([1, ')', 'T-lymphocytic', 'infiltrate,']), verbo([increased]), complemento([tumour, 'CD138+plasma', cell, '(', 'P&lt;0'])].
[sujeto(['RUNX1', expression, did, not, influence, outcome, of, oestrogen, receptor, '(', 'ER)-positive', or, 'HER2-positive', 'disease,', however, on, univariate, analysis, a, high, 'RUNX1', protein, was, significantly]), verbo([associated]), complemento([with, poorer, 'cancer-specific', survival, in, patients, with, 'ER-negative', '(', 'P&lt;0'])].
[sujeto(['Of', 'relevance,', triple, negative, breast, cancer, currently, lacks, good, biomarkers, and, patients, with, this, subtype, do, not, benefit, from, the, option, of]), verbo([targeted]), complemento([therapy, unlike, patients, with, 'ER-positive', or, 'HER2-positive', disease])].
[sujeto(['Studies']), verbo([have]), complemento([suggested, that, myeloid, fate, choice, is, primarily, regulated, by, transcription, 'factors;', 'however,', new, intrinsic, regulators, and, their, underlying, mechanisms, remain, to, be, elucidated])].
[sujeto(['Runx1', is]), verbo([induced]), complemento([by, high, 'Pu'])].
[sujeto([1, level]), verbo([required]), complemento([for, balanced, fate, commitment, to, neutrophils, versus, macrophages])].
[sujeto(['Mammals']), verbo([have]), complemento([two, principal, types, of, fat])].
[sujeto(['Recent', studies]), verbo([have]), complemento([demonstrated, that, brown, adipocytes, arise, in, vivo, from, a, 'Myf5-positive,', myoblastic, progenitor, by, the, action, of, 'Prdm16', '(', 'PR', domain, containing, 16, ')'])].
[sujeto(['Blocking', 'miR-193b', 'and/or', 'miR-365', in, primary, brown, preadipocytes, markedly, impaired, brown, adipocyte, adipogenesis, by]), verbo([enhancing]), complemento(['Runx1t1', '(', 'runt-related', transcription, factor, 1, ;, translocated, 'to,', 1, ')', 'expression,', whereas, myogenic, markers, were, significantly, induced])].
[sujeto(['Forced', expression, of, 'Mir193b', 'and/or', 'Mir365', in, 'C2C12', myoblasts, blocked, the, entire, programme, of, 'myogenesis,', 'and,', in, adipogenic, 'conditions,', 'miR-193b']), verbo([induced]), complemento([myoblasts, to, differentiate, into, brown, adipocytes])].
[sujeto(['Our', results, demonstrate, that, 'Mir193b-365', serves, as, an, essential, regulator, for, brown, fat, 'differentiation,', in, part, by]), verbo([repressing]), complemento([myogenesis])].
[sujeto(['Mutations', of, isocitrate, dehydrogenase, 1, '(', 'IDH1)']), verbo([have]), complemento([recently, been, reported, in, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['We', analyzed, 416, 'Chinese', 'AML', patients, and]), verbo([found]), complemento([28, patients, '(', 6.7, '%', ')', carried, this, mutation])].
[sujeto(['The', 'IDH1', mutations, were]), verbo([associated]), complemento([with, 'NPM1', mutations, '(', 'P=0'])].
[sujeto(['For', 'AML', with, 'AML1-ETO', fusion, 'gene,', 'IDH1(mut)', patients, may]), verbo([have]), complemento([worse, 'disease-free', survival, '(', 'DFS)', than, 'IDH1(wild-type)', patients])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([a, higher, expression, level, of, 'AML1a', in, acute, lymphoblastic, leukemia, and, acute, myeloid, leukemia, '(', 'AML)-M2', patients, in, comparison, to, the, controls])].
[sujeto(['Additionally,', 'AML1a']), verbo([represses]), complemento([transcription, of, promoter, of, macrophage, 'colony-stimulating', factor, receptor, mediated, by, 'AML1b,', indicating, that, 'AML1a', antagonized, the, effect, of, 'AML1b'])].
[sujeto(['Untreated,', the, disease, progresses, to, accelerate, phase, and, blast, crisis, in, which, hematopoietic, differentiation]), verbo([has]), complemento([become, arrested])].
[sujeto(['CML', progression, is, frequently]), verbo([associated]), complemento([with, cytogenetic, evidence, of, clonal, 'evolution,', defined, as, additional, chromosomal, aberrations])].
[sujeto(['We', here]), verbo([report]), complemento([a, 'CML', resistant, to, tyrosine, kinase, inhibitors, that, rapidly, progressed, to, blastic, phase])].
[sujeto(['These', genomic, rearrangements, were, confirmed, by, 'FISH', with, probes]), verbo([targeting]), complemento([the, deletion, on, chromosome, 21, '(', 24, 'kb),', and, with, 'BAC', probes, flanking, the, deletion, on, 1, p36, '(', 220, 'kb)'])].
[sujeto(['However,', no, cryptic, 't(1;21)(p36;q22)', 'and/or', 'RUNX1-PRDM16', were, 'detected,']), verbo([suggesting]), complemento([that, these, deletions, are, the, residual, hallmarks, of, a, more, complex, mechanism, of, chromosomal, 'rearrangement,', as, indicated, by, the, additional, inversion, of, the, region, bounded, by, 1, p36])].
[sujeto(['At', the, molecular, 'level,', these, abnormalities]), verbo([lead]), complemento([to, the, overexpression, of, the, 'PR-domain', negative, oncogenic, isoform, of, 'PRDM16,', associated, with, two, deleted, copies, within, the, runt, domain, of, 'C-teminal', aberrant, 'RUNX1'])].
[sujeto(['In', the, present, 'research,', we]), verbo([found]), complemento([that, 'AML1-ETO', is, able, to, inhibit, 'Sp1', transactivity])].
[sujeto(['We', also]), verbo([found]), complemento([that, this, inhibition, of, 'Sp1', transactivity, by, 'AML1-ETO', is, achieved, by, interaction, between, 'Sp1', and, 'RUNT', domain, of, 'AML1'])].
[sujeto(['Since', 'Sp1', is]), verbo([involved]), complemento([in, hematopoietic, cell, 'differentiation,', we, proposed, that, 'AML1-ETO', promotes, leukemogenesis, by, blocking, cell, differentiation, through, inhibition, of, 'Sp1', transactivity])].
[sujeto(['We', previously, discovered, a, novel, 'trans-tail', histone, code]), verbo([involving]), complemento([monomethylated, histone, 'H4', lysine, 20, '(', 'H4K20)', and, 'H3', lysine, 9, '(', 'H3K9);', 'however,', the, mechanisms, that, establish, this, code, and, its, function, in, transcription, were, unknown])].
[sujeto(['In', this, 'report,', we, demonstrate, that, 'H3K9', monomethylation, is, dependent, upon, the, 'PR-Set7', 'H4K20', monomethyltransferase, but, independent, of, its, catalytic, 'function,', indicating, that, 'PR-Set7']), verbo([recruits]), complemento([an, 'H3K9', monomethyltransferase, to, establish, the, 'trans-tail', histone, code])].
[sujeto(['We', determined, that, this, histone, code, is]), verbo([involved]), complemento([in, a, transcriptional, regulatory, pathway, in, vivo, whereby, monomethylated, 'H4K20', binds, the, 'L3MBTL1', repressor, protein, to, repress, specific, 'genes,', including, 'RUNX1,', a, critical, regulator, of, hematopoietic, differentiation])].
[sujeto(['The', selective]), verbo([loss]), complemento([of, monomethylated, 'H4K20', at, the, 'RUNX1', promoter, resulted, in, the, displacement, of, 'L3MBTL1', and, a, concomitant, increase, in, 'RUNX1', transcription])].
[sujeto(['Importantly,', the, lack, of, monomethylated, 'H4K20', in, the, human, 'K562', multipotent, cell, line, was, specifically]), verbo([associated]), complemento([with, spontaneous, megakaryocytic, 'differentiation,', in, 'part,', by, activating, 'RUNX1'])].
[sujeto(['Our', findings, demonstrate, that, this, newly, described, repression, pathway, is]), verbo([required]), complemento([for, regulating, proper, megakaryopoiesis, and, suggests, that, it, is, likely, to, function, similarly, in, other, multipotent, cell, types, to, regulate, specific, differentiation, pathways])].
[sujeto(['The', 't(12;21)(p13;q22)', translocation, is]), verbo([found]), complemento([in, 20, to, 25, '%', of, cases, of, childhood, 'B-lineage', acute, lymphoblastic, leukemia, '(', 'B-ALL)'])].
[sujeto(['We']), verbo([report]), complemento([an, analysis, of, gene, expression, in, 60, children, with, 'B-lineage', 'ALL', using, 'Agilent', whole, genome, 'oligo-chips', '(', 44, 'K-G4112A)', 'and/or', real, time, 'RT-PCR'])].
[sujeto(['Microarray', analyses, of, 26, samples, allowed, the, identification, of, genes, differentially]), verbo([expressed]), complemento([between, the, 'TEL/AML1-positive', and, negative, 'ALL', groups])].
[sujeto(['Gene', enrichment, analysis, defined, five, enriched, 'GO', 'categories:', cell, 'differentiation,', cell, 'proliferation,', 'apoptosis,', cell, motility, and, response, to, 'wounding,']), verbo([associated]), complemento([with, 14, genes, -, 'RUNX1,', 'TCFL5,', 'TNFRSF7,', 'CBFA2T3,', 'CD9,', 'SCARB1,', 'TP53INP1,', 'ACVR1C,', 'PIK3C3,', 'EGFL7,', 'SEMA6A,', 'CTGF,', 'LSP1,', 'TFPI', -, highlighting, the, biology, of, the, 'TEL/AML1', 'sub-group'])].
[sujeto(['Gene', expression, analyses, of, leukemia, cells, from, 60, children, with, 'TEL/AML1-positive', and, -, negative, 'B-lineage', 'ALL']), verbo([led]), complemento([to, the, identification, of, five, biological, 'processes,', associated, with, 14, validated, genes, characterizing, and, highlighting, the, biology, of, the, 'TEL/AML1-positive', 'ALL', 'sub-group'])].
[sujeto(['Of', the, 62, 'patients,', 23, '(', 37.1, '%', ')', were]), verbo([found]), complemento([to, carry, 13, different, fusion, genes])].
[sujeto(['The', patients, with, immunophenotype, of, 'Pre-B-ALL', were]), verbo([found]), complemento([to, 'carry:', 'TEL/AML1(3', 'cases);', 'E2A/PBX1,', 'E2A/HLF,', 'TLS/ERG,', 'MLL/AF4,', 'MLL/AF9,', 'MLL/AF10,', 'MLL/AFX-MLL/AF6-MLL/ELL,', 'MLL/AF6-MLL/ELL,', dupMLL, '(', one, case, for, 'each);', and, 'HOX11', '(', 6, 'cases)'])].
[sujeto(['The', patients, with, immunophenotype, of, 'Pre-T-ALL', were]), verbo([found]), complemento([to, 'carry:', 'TAL1D', '(', 4, 'cases,', one, is, also, found, to, have, 'HOX11', 'expression);', and, 'HOX11', '(', 2, 'cases)'])].
[sujeto(['Multiplex', 'RT-PCR', combined, with, chromosome, analysis, and, immunophenotyping, can]), verbo([provide]), complemento([reliable, and, helpful, information, for, the, 'diagnosis,', therapy, evaluation, and, prognosis, prediction, in, childhood, 'ALL,', which, may, also, serve, as, a, basis, on, which, to, implement, the, criteria, of, 'WHO', classification])].
[sujeto(['It', is, useful, for]), verbo([revealed]), complemento([whole, gene, expression, profile, and, has, a, great, potentiality, in, the, era, of, functional, genomics])].
[sujeto(['It']), verbo([provides]), complemento([an, alternative, method, of, studies, on, gene, expression, which, is, at, least, as, good, as, 'LacZ', staining, and, immunohistochemistry])].
[sujeto(['EVI1', is, also]), verbo([expressed]), complemento([as, part, of, a, fusion, transcript, with, the, transcription, factor, 'AML1', in, the, 't(3;21)(q26;q22),', associated, with, myeloid, leukemia])].
[sujeto(['MDS1', is, located, at, 3, q26, 170, -, 400, kb, upstream, '(', 'telomeric)', of, 'EVI1', in, the, chromosomal, region, in, which, some, of, the, breakpoints, 5, '\'', of, 'EVI1']), verbo([have]), complemento([been, mapped])].
[sujeto(['MDS1']), verbo([has]), complemento([been, identified, as, a, single, gene, as, well, as, a, previously, unreported, 'exon(s)', of, 'EVI1', 'We', have, analyzed, the, relationship, between, 'MDS1', and, 'EVI1', to, determine, whether, they, are, two, separate, genes])].
[sujeto(['In', this, 'report,', we, present, evidence, indicating, that, 'MDS1', exists, in, normal, tissues, both, as, a, unique, transcript, and, as, a, normal, fusion, transcript, with, 'EVI1,', with, an, additional, 188, codons, at, the, 5, '\'', end, of, the, previously]), verbo([reported]), complemento(['EVI1', open, reading, frame])].
[sujeto(['This', additional, region]), verbo([has]), complemento([about, 40, '%', homology, at, the, amino, acid, level, with, the, 'PR', domain, of, the, 'retinoblastoma-interacting', 'zinc-finger', protein, 'RIZ'])].
[sujeto(['These', results, are, important, in, view, of, the, fact, that, 'EVI1', and, 'MDS1', are]), verbo([involved]), complemento([in, leukemia, associated, with, chromosomal, translocation, breakpoints, in, the, region, between, these, genes])].
[sujeto(['We', aim, to, search, 'non-protein', coding, regions, of, key, hematopoiesis, transcription, factors, for, genetic, variations]), verbo([associated]), complemento([with, acute, myeloid, leukemia, susceptibility])].
[sujeto(['Rs2249650', and, rs2268276, at, 'RUNX1', intron, 5.2, enhancer, were]), verbo([found]), complemento([to, be, associated, with, acute, myeloid, leukemia, susceptibility])].
[sujeto(['Supershift', assay, indicated, that, one, potential]), verbo([binding]), complemento([protein, was, 'PU'])].
[sujeto(['It', is, a, process, tightly]), verbo([regulated]), complemento([by, many, intrinsic, and, extrinsic, 'factors,', including, transcriptional, factors, and, signaling, molecules])].
[sujeto(['Here', we, show, that, 'miR-144']), verbo([regulates]), complemento([hematopoiesis, and, vascular, development, in, zebrafish])].
[sujeto(['Overexpression', of, 'miR-144']), verbo([inhibited]), complemento([primitive, hematopoiesis, as, demonstrated, by, a, reduced, number, of, circulating, blood, 'cells,', reduced, 'o-dianisidine', staining, of, 'hemoglobin,', and, reduced, expression, of, 'hbαe1,', 'hbβe1,', gata1, and, pu])].
[sujeto(['Overexpression', of, 'miR-144', also]), verbo([inhibited]), complemento([definitive, hematopoiesis, as, shown, by, reduced, expression, of, runx1, and, 'c-myb'])].
[sujeto(['Mechanistically,', 'miR-144']), verbo([regulates]), complemento([hematopoiesis, by, repressing, expression, of, meis1, involved, in, hematopoiesis])].
[sujeto(['Both', 'real-time', 'RT-PCR', and, 'Western', blot, analyses, showed, that, overexpression, of, 'miR-144']), verbo([repressed]), complemento([expression, of, meis1])].
[sujeto(['Bioinformatic', analysis, predicts, a]), verbo([target]), complemento([binding, sequence, for, 'miR-144', at, the, 3, '\'', -, 'UTR', of, meis1])].
[sujeto(['Deletion', of, the, 'miR-144']), verbo([target]), complemento([sequence, eliminated, the, repression, of, meis1, expression, mediated, by, 'miR-144'])].
[sujeto(['Finally,', because, meis1, is]), verbo([involved]), complemento([in, vascular, 'development,', we, tested, the, effect, of, 'miR-144', on, vascular, development])].
[sujeto(['These', findings, establish, 'miR-144', as, a, novel, miRNA, that]), verbo([regulates]), complemento([hematopoiesis, and, vascular, development, by, repressing, expression, of, meis1])].
[sujeto(['Studies', implicate, a, potential, role, for, 'EAF1', in, 'MLL-ELL']), verbo([induced]), complemento(['leukemogenesis;', however, the, biological, function, of, 'EAF1', in, this, process, remains, unknown])].
[sujeto(['In', this, 'study,', we, show, that, knockdown, of, zebrafish, eaf1, by, morpholinos]), verbo([caused]), complemento([serious, defects, in, both, primitive, and, definitive, hematopoiesis])].
[sujeto(['Using', microarray, 'analysis,', we, identified, foxo3b, as, a]), verbo([target]), complemento([gene, suppressed, by, eaf1])].
[sujeto(['Ectopic', expression, of, foxo3b, in, embryos, mimicked, the, phenotypes, exhibited, in, eaf1, 'morphants,', except, that, foxo3b, had, no, effect, on, runx1, and, 'c-myb', expression, while, eaf1, morphants, did, not]), verbo([express]), complemento([these, markers, in, the, ventral, wall, of, dorsal, aorta])].
[sujeto(['Subsequent', experiments, showed, that, a, dominant, negative, form, of, 'Foxo3b', '(', 'dn-foxo3b)', partially, restored, primitive, hematopoietic, defects, in, eaf1, 'morphants,']), verbo([suggesting]), complemento([that, foxo3b, might, serve, as, a, key, factor, for, mediating, eaf1, function, in, primitive, hematopoiesis])].
[sujeto(['Furthermore,', we, observed, that, foxo3b]), verbo([inhibited]), complemento([the, transcriptional, activity, of, gata1, and, spi1, through, 'protein-protein', interaction])].
[sujeto(['Our', findings, not, only]), verbo([suggest]), complemento([a, function, of, eaf1, on, hematopoiesis, in, 'vivo,', but, also, reveal, a, novel, regulatory, 'pathway,', 'eaf1-foxo3b-gata1/spi1,', that, may, shed, light, on, the, role, of, 'EAF1', in, 'MLL-ELL', induced, leukemogenesis])].
[sujeto(['After', investigating, common, acute, 'leukemia-related', mutations, in, 17, 'genes,', 12, of, 31, '(', 39, '%', ')', patients, were]), verbo([found]), complemento([to, have, at, least, one, 'mutation,', classified, 'with:', 'IKZF1', deletion, '(', 4, of, 31, ')', ',', and, 'EZH2', '(', 3, of, 31, ')', ',', 'ASXL1', '(', 3, of, 31, ')', ',', 'ETV6', '(', 2, of, 31, ')', ',', 'NOTCH1', '(', 1, of, 31, ')', ',', and, 'TET2', '(', 1, of, 31, ')', mutations])].
[sujeto(['Benzidine', 'staining,', 'semi-quantitative', 'RT-PCR,', 'Western', blot, and, microarray, methods, were, used, to, survey, the, effects, of, 'APS', on]), verbo([inducing]), complemento([erythroid, differentiation, and, the, changes, of, gene, expression, profile, in, 'K562', cells])].
[sujeto(['These', differential, expression, genes, generally]), verbo([regulate]), complemento([protein, 'binding,', cellular, metabolic, 'process,', the, cell, 'proliferation,', and, transcriptional, activator, activity])].
[sujeto(['Our', studies, indicate, that, 'APS', indicate, potent, activities, on, the, erythroid, differentiation, by]), verbo([modulating]), complemento([genes, of, 'LMO2,', 'Klf1,', 'Klf3,', 'Runx1,', 'EphB4', and, 'Sp1,', increasing, 'gamma-globin', mRNA, expression, and, fetal, hemoglobin, synthesis, in, 'K562', cells])].
[sujeto(['Recent', advances]), verbo([have]), complemento([demonstrated, that, the, differentiated, somatic, cells, could, be, reprogrammed, into, pluripotent, state])].
[sujeto(['Consequently,', the, reprogrammed, somatic, cells, recapitulate, the, capacity, to, differentiate, into, specific, cell, lineages, under, appropriate, culture, 'conditions,', which]), verbo([provides]), complemento([unlimited, cell, sources, for, cell, 'transplantation-based', therapy])].
[sujeto(['In', the, present, 'study,', testicular, 'Sertoli', cells, were, successfully, reprogrammed, into, pluripotent, stem, cells, through, somatic, cell]), verbo([nuclear]), complemento([transfer, '(', 'SCNT)'])].
[sujeto([were, dynamically]), verbo([expressed]), complemento([during, the, differentiation, of, the, reprogrammed, somatic, cells, in, vitro])].
[sujeto(['KIT', mutations, may, be]), verbo([associated]), complemento([with, a, poor, prognosis, in, 't(8;21)', 'AML'])].
[sujeto(['AML1-ETO', fusion, gene, and, mutated, 'KIT']), verbo([act]), complemento([as, &, 'quot;two-hit&quot;', factors, in, 'Kasumi-1', cells])].
[sujeto(['Our', results, confirmed, that, 'Hsp90', and, mutated, 'KIT', were, valid, molecular]), verbo([targets]), complemento([in, the, therapy, of, 'AML'])].
[sujeto(['Acute', myeloid, leukemia, '(', 'AML)', arises, from, genetic, changes, at, the, level, of, stem, 'cell,', various, mutations]), verbo([have]), complemento([been, 'elucidated,', including, 'AML1-ETO', fusion, gene, has, been, shown, as, the, representative, target, of, cellular, transformation, for, 'LSCs', originating, from, hematopoietic, stem, cells, '(', 'HSCs)', compartment])].
[sujeto(['And', the, interaction]), verbo([mediated]), complemento([by, adhesion, molecules, between, 'LSCs', and, niche, played, a, role, in, chemoresistance, of, 'LSCs'])].
[sujeto(['Therefore,', study, on, the, 'LSCs', surface, makers, related, to, niche, is, helpful, for, the, potential]), verbo([target]), complemento([therapy, in, the, future])].
[sujeto(['Furthermore,', 'AML1/ETO', fusion, signals, and, 'MDR1', expression, were, detected, on, the, 'CD34(+)/CD38(-)/CD123(+)', 'LSCs', populations]), verbo([expressing]), complemento(['N-Cadherin', and, 'Tie2'])].
[sujeto(['The', detection, rate, of, clonal, chromosomal, aberrations, was]), verbo([enhanced]), complemento([to, 59.5, '%', by, combined, application, of, multiplex, 'RT-PCR', and, karyotype, analysis])].
[sujeto(['Whereas', 'Evi-1a', is, widely]), verbo([recognized]), complemento([as, an, 'oncoprotein,', a, role, for, 'Evi-1c,', which, has, an, additional, 'PR', domain, in, the, 'amino-terminus', of, 'Evi-1a,', in, 'leukemogenesis,', has, not, been, elucidated, thus, far])].
[sujeto(['Aberrant', oligomerization, of, transcription, factors]), verbo([has]), complemento([recently, emerged, as, a, prevalent, mechanism, for, activating, their, oncogenic, potential, in, hematopoietic, malignancies])].
[sujeto(['Remarkably,', 'Evi-1c']), verbo([has]), complemento([lost, the, ability, to, interact, with, 'CtBP,', a, transcriptional, corepressor, that, associates, with, 'Evi-1a'])].
[sujeto(['As', a, 'consequence,', the, ability, of, 'Evi-1c', to]), verbo([repress]), complemento([transforming, growth, 'factor-beta', '(', 'TGF-beta)', signaling, is, significantly, abrogated])].
[sujeto(['These', results, identify, a, novel, function, of, a, 'PR', domain, to]), verbo([regulate]), complemento([oligomerization, of, transcription, factors, and, suggest, that, 'homo-oligomerization', may, play, a, critical, role, in, corepressor, recruitment, by, the, 'Evi-1', proteins])].
[sujeto(['In', 'addition,', we]), verbo([found]), complemento([that, the, chimeric, oncoprotein, acute, myelocytic, leukemia, '(', 'AML)1-Evi-1,', generated, in, 't(3;21)', 'leukemia,', also, forms, 'homo-oligomers', and, 'hetero-oligomers', with, 'Evi-1a,', while, it, did, not, interact, with, 'Evi-1c'])].
[sujeto(['Consistent', with, the, 'results,', repression, of, 'TGF-beta', by, 'AML1-Evi-1', was, significantly]), verbo([enhanced]), complemento([by, 'Evi-1a,', whereas, it, was, hardly, affected, by, the, presence, of, 'Evi-1c'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, oligomerization, may, contribute, to, the, oncogenic, potential, of, 'Evi-1-containing', proteins])].
[sujeto(['The', '(', 8, ;, 21, ')', translocation, between, the, 'AML1', and, 'ETO', genes, is, seen, in, approximately, 12, -, 15, '%', of, all, acute, myeloid, leukemia, '(', 'AML)', and, is, a, frequently, observed, nonrandom, genetic, alteration]), verbo([associated]), complemento([with, 'AML'])].
[sujeto(['The', 'ETO', moiety, was, shown, to]), verbo([interact]), complemento([with, the, nuclear, receptor, 'co-repressor', '(', 'N-CoR)', 'complex,', which, includes, mSin3A, and, the, histone, 'deacetylase,', 'HDAC1'])].
[sujeto(['In', order, to, characterize, the, interaction, between, 'ETO', and, 'N-CoR,', mutants, of, either, protein, were, constructed, and, tested, for]), verbo([binding]), complemento([in, both, yeast, 'two-hybrid', and, immunoprecipitation, assays])].
[sujeto(['We']), verbo([found]), complemento([that, two, domains, of, human, 'N-CoR,', amino, acid, residues, 988, -, 1126, and, 1551, -, 1803, ',', were, necessary, for, interaction, with, 'ETO'])].
[sujeto(['Previously,', we, and, other, investigators, had]), verbo([reported]), complemento([that, two, unusual, zinc, finger, motifs, at, the, 'C-terminus', of, 'ETO', mediated, binding, to, 'N-CoR'])].
[sujeto(['Here,', using, mammalian, 'two-hybrid', 'assays,', we]), verbo([found]), complemento([that, transcription, repression, by, 'ETO', was, substantially, decreased, when, either, zinc, finger, motif, of, 'ETO', is, deleted, or, mutated])].
[sujeto(['Characterization', of, the, 'ETO', interaction, domains, within, human, 'N-CoR', and, of, the, transcription, domains, of, 'ETO', is, a, first, step, in, designing]), verbo([targeted]), complemento([molecular, therapy, for, 't(8;21)', 'AML'])].
[sujeto(['The', complex, variants, of, 't(8;21)']), verbo([involving]), complemento([chromosomes, 8, and, 21, as, well, as, a, variable, chromosome, account, for, 1.1, -, 5, '%', of, acute, myeloid, leukemia, '(', 'AML)', patients])].
[sujeto(['This', paper]), verbo([reports]), complemento([a, case, of, 'AML-M2', with, 't(8;21;8)', translocation, for, the, first, time])].
[sujeto(['A', novel, variant, translocation, 't(8;20)(q22;p13)', detected, by, karyotype, analysis, of, bone, marrow, cells, using, 'R-', and, 'G-banding', 'techniques,', is]), verbo([reported]), complemento([in, a, case, of, 'M2-acute', myeloid, leukaemia, '(', 'AML)'])].
[sujeto(['RT-PCR', revealed, no, 'AML1/ETO', fusion, 'transcript,', but, the, 'wild-type', 'ETO-3\'', was]), verbo([expressed]), complemento([in, the, bone, marrow, cells, suggesting, that, 't(8;20)', is, a, true, simple, variant, translocation, of, 't(8;21),', and, that, a, fusion, gene, consisting, of, 'ETO', and, an, unidentified, gene, located, in, band, 20, p13, may, exist, in, our, case])].
[sujeto(['Further', study, is]), verbo([required]), complemento([to, clarify, the, entity, of, the, assumed, fusion, gene])].
[sujeto(['As', a, single, biopsy, might, not, represent, the, full, biologic, complexity, of, the, 'tumor,', we]), verbo([have]), complemento([analyzed, immunohistochemically, four, different, cores, obtained, from, each, primary, tumor, within, the, cohort, of, 364, patients, with, endometrial, cancer, '(', 'EC)'])].
[sujeto(['The', following, proteins, were, 'examined:', estrogen, receptor, 1, '(', 'ESR1),', progesterone, 'receptor,', epidermal, growth, factor, 'receptor,', 'v-erb-b2', erythroblastic, leukemia, viral, oncogene, homolog, 2, ',', receptor, 'tyrosine-protein', kinase, 'erbB-3,', 'v-erb-b2', avian, erythroblastic, leukemia, viral, oncogene, homolog, 4, ',', 'phosphatidylinositol-4,5-bisphosphate', 3, -, 'kinase,']), verbo([phosphorylated]), complemento(['v-akt', murine, thymoma, viral, oncogene, homolog, 1, ',', 'v-myc', avian, myelocytomatosis, viral, oncogene, 'homolog,', 'DNA', topoisomerase, 'II', alpha, 170, kDa, '(', 'TOP2A),', 'cyclin-dependent', kinase, inhibitor, 2, 'A', '(', 'CDKN2A),', tumor, protein, 'p53,', 'RAD21', 'homolog,', 'S'])].
[sujeto(['Particularly', strong, correlation, was]), verbo([found]), complemento([between, 'TOP2A', and, 'CDKN2A', heterogeneity, and, higher, stage, of, the, disease, '(', 'P', =])].
[sujeto(['A', widely, accepted, dualistic, 'model,', which]), verbo([has]), complemento([been, established, on, a, morphological, 'basis,', differentiates, 'EC', into, two, broad, 'categories:', 'Type', 'I', 'oestrogen-dependent', adenocarcinoma, with, an, endometrioid, morphology, and, 'Type', 'II', 'non-oestrogen-dependent', 'EC', with, a, serous, papillary, or, clear, cell, morphology])].
[sujeto(['Molecular', genetic, evidence, indicates, that, endometrial, 'carcinoma,', as, described, in, other, 'malignancies,', likely, develops, as, the, result, of, a, stepwise, accumulation, of, alterations, in, cellular, regulatory, 'pathways,', such, as, oncogene, activation, and, tumor, suppressor, gene, 'inactivation,', which]), verbo([lead]), complemento([to, dysfunctional, cell, growth])].
[sujeto(['In', type, 'I', endometrioid, endometrial, 'cancer,', 'PTEN', gene, silencing, in, conjunction, with, defects, in, 'DNA', mismatch, repair, 'genes,', as, evidenced, by, the, microsatellite, instability, 'phenotype,', or, mutations, in, the, 'K-ras', 'and/or', 'beta-catenin', 'genes,', are]), verbo([recognized]), complemento([major, 'alterations,', which, define, the, progression, of, the, normal, endometrium, to, 'hyperplasia,', to, endometrial, intraepithelial, 'neoplasia,', and, then, on, to, carcinoma])].
[sujeto(['Nevertheless,', despite, the, great, effort, made, to, establish, a, 'molecularly-based', histological, 'classification,', the, following, issues, must, still, be, 'clarified:', what]), verbo([triggers]), complemento([the, tumor, cells, to, invade, the, myometrium, and, what, causes, vascular, or, lymphatic, 'dissemination,', finally, culminating, in, 'metastasis?', 'RUNX1,', a, transcription, 'factor,', was, recently, identified, as, one, of, the, most, highly, 'over-expressed', genes, in, a, microarray, study, of, invasive, endometrial, carcinoma])].
[sujeto(['Another', candidate, 'gene,', which, may, be]), verbo([associated]), complemento([with, an, initial, switch, to, myometrial, 'infiltration,', is, the, transcription, factor, 'ETV5/ERM'])].
[sujeto(['These', 'studies,', as, well, as, those, conducted, for, other, genes, possibly]), verbo([involved]), complemento([in, the, mitotic, checkpoint, as, a, major, mechanism, of, carcinogenesis, in, 'non-endometrioid', endometrial, 'cancer,', could, help, in, understanding, the, differences, in, the, biology, and, the, clinical, outcome, among, histological, types])].
[sujeto(['The', 'LH', surge]), verbo([induces]), complemento([specific, transcription, factors, that, regulate, the, expression, of, a, myriad, of, genes, in, periovulatory, follicles, to, bring, about, ovulation, and, luteinization])].
[sujeto(['The', present, study, determined, 1, ')', the, localization, of, 'RUNX1,', a]), verbo([nuclear]), complemento([transcription, 'factor,', 2, ')', regulation, of, 'Runx1', mRNA, 'expression,', and, 3, ')', its, potential, function, in, rat, ovaries])].
[sujeto(['Treatments', with, 'hCG,', 'forskolin,', or, phorbol, 12, myristate, 13, -, acetate]), verbo([stimulated]), complemento(['Runx1', mRNA, expression])].
[sujeto(['The', effects, of, hCG, were, reduced, by, inhibitors, of, protein, kinase, 'A,', 'MAPK', 'kinase,', or, p38, 'kinase,', indicating, that, 'Runx1', expression, is]), verbo([regulated]), complemento([by, the, 'LH-initiated', activation, of, these, signaling, mediators])].
[sujeto(['In', 'addition,', 'hCG-induced', 'Runx1', mRNA, expression, was]), verbo([inhibited]), complemento([by, a, progesterone, receptor, antagonist, and, an, epidermal, growth, factor, receptor, tyrosine, kinase, 'inhibitor,', whereas, amphiregulin, stimulated, 'Runx1', mRNA, 'expression,', demonstrating, that, the, expression, is, mediated, by, the, activation, of, the, progesterone, receptor, and, epidermal, growth, factor, receptor])].
[sujeto(['Finally,', knockdown, of, 'Runx1', mRNA, by, small, interfering, 'RNA']), verbo([decreased]), complemento([progesterone, secretion, and, reduced, levels, of, mRNA, for, 'Cyp11a1,', 'Hapln1,', 'Mt1a,', and, 'Rgc32'])].
[sujeto(['The', hormonally]), verbo([regulated]), complemento([expression, of, 'Runx1', in, periovulatory, 'follicles,', its, involvement, in, progesterone, 'production,', and, regulation, of, preovulatory, gene, expression, suggest, important, roles, of, 'RUNX1', in, the, periovulatory, process])].
[sujeto(['RNA', expression, of, 42, 'genes,', including, 24, putative, genes]), verbo([associated]), complemento([with, plasma, 'E2', 'levels,', seven, proliferation, genes, and, 'RANKL', was, measured])].
[sujeto(['Expression', of, 'PGR,', 'TFF1,', 'GREB1', and, 'PDZK1', followed, the, previously]), verbo([reported]), complemento(['pattern:', a, higher, level, in, 'W2', compared, to, 'W1', while, 'W3', had, an, intermediate, 'value,', mirroring, changes, in, plasma, estradiol])].
[sujeto(['The', 'TGF-β', signaling, pathway]), verbo([has]), complemento([a, significant, role, in, breast, cancer, initiation, and, promotion, by, regulating, various, cellular, processes])].
[sujeto(['We', evaluated, whether, genetic, variation, in, eight, genes, '(', 'TGF-β1,', 'TGF-β2,', 'TGF-βR1,', 'TGF-βR2,', 'TGF-βR3,', 'RUNX1,', 'RUNX2,', and, 'RUNX3)', is]), verbo([associated]), complemento([with, breast, cancer, risk, in, women, from, the, 'Breast', 'Cancer', 'Health', 'Disparities', 'Study'])].
[sujeto(['After', adjustment, for, multiple, 'comparisons,', two, 'SNPs', were, significantly]), verbo([associated]), complemento([with, breast, cancer, 'risk:', 'RUNX3', '(', rs906296, 'ORCG/GG', =, 1.15, 95, '%', 'CI', 1.04, -, 1.26, ')', and, 'TGF-β1', '(', rs4803455, 'ORCA/AA', =, 0.89, 95, '%', 'CI', 0.81, -, 0.98, ')'])].
[sujeto(['RUNX3', '(', 'rs906296)', and, 'TGF-βR2', '(', 'rs3773644)', were]), verbo([associated]), complemento([with, risk, in, 'pre-menopausal', women, '(', p, adj, =, 0.002, and, 0.02, ',', 'respectively)', and, in, those, with, intermediate, to, high, 'NA', ancestry, '(', p, adj, =, 0.04, and, 0.01, ',', 'respectively)'])].
[sujeto(['Four', 'RUNX', 'SNPs', were]), verbo([associated]), complemento([with, increased, risk, of, 'ER-', tumors])].
[sujeto(['Results']), verbo([provide]), complemento([evidence, that, genetic, variation, in, 'TGF-β', and, 'RUNX', genes, are, associated, with, breast, cancer, risk])].
[sujeto(['This', is, the, first]), verbo([report]), complemento([of, significant, associations, between, genetic, variants, in, 'TGF-β', and, 'RUNX', genes, and, breast, cancer, risk, among, women, of, 'NA', ancestry])].
[sujeto(['Response', gene, to, complement, 32, '(', 'Rgc32)']), verbo([has]), complemento([recently, been, suggested, to, be, expressed, in, the, ovary, and, regulated, by, 'RUNX1,', a, transcription, factor, in, periovulatory, follicles])].
[sujeto(['In', the, present, 'study,', we, determined, the, expression, profile, of, the, 'Rgc32', gene, in, the, rodent, ovary, throughout, the, reproductive, cycle, and, the, regulatory, 'mechanism(s)']), verbo([involved]), complemento([in, 'Rgc32', expression, during, the, periovulatory, period])].
[sujeto(['Further', studies, using, hormonally]), verbo([induced]), complemento([luteal, and, luteolysis, models, revealed, a, transient, increase, in, levels, of, 'Rgc32', mRNA, at, the, time, of, functional, regression, of, the, 'CL'])].
[sujeto(['The', effect, of, human, chorionic, gonadotropin, on, 'Rgc32', expression, was, mimicked, by, 'forskolin,', but, not, phorbol, 12, -, myristate, 13, -, 'acetate,', and, was]), verbo([mediated]), complemento([by, the, activation, of, progesterone, receptors, and, the, epidermal, growth, 'factor-signaling', pathway])].
[sujeto(['The', mechanism, by, which, 'RUNX1']), verbo([regulates]), complemento(['Rgc32', expression, was, investigated, using, chromatin, immunoprecipitation, and, 'Rgc32', 'promoter-luciferase', reporter, assays])].
[sujeto(['Data', from, these, assays, revealed, direct]), verbo([binding]), complemento([of, 'RUNX1', in, the, 'Rgc32', promoter, region, in, vivo, as, well, as, the, involvement, of, 'RUNX', binding, sites, in, the, transactivation, of, the, 'Rgc32', promoter, in, vitro])].
[sujeto(['In', 'summary,', the, present, study, demonstrated, the, 'spatial/temporal-specific', expression, of, 'Rgc32', in, the, 'ovary,', and]), verbo([provided]), complemento([evidence, of, 'LH-initiated', and, 'RUNX1-mediated', expression, of, 'Rgc32', gene, in, luteinizing, granulosa, cells])].
[sujeto(['Herein', we, document, that, epidermal, growth, factor, '(', 'EGF)-like', factors, amphiregulin, '(', 'Areg),', epiregulin, '(', 'Ereg),', and, betacellulin, '(', 'Btc)', are]), verbo([induced]), complemento([in, cumulus, oocyte, complexes, '(', 'COCs)', by, autocrine, and, paracrine, mechanisms, that, involve, the, actions, of, prostaglandins, '(', 'PGs)', and, progesterone, receptor, '(', 'PGR)'])].
[sujeto(['In', cultured, 'COCs,', 'FSH/forskolin']), verbo([induced]), complemento(['Areg', mRNA, within, 0.5, h, that, peaked, at, 4, 'h,', a, process, blocked, by, inhibitors, of, p38MAPK, '(', 'SB203580),', 'MAPK', kinase, '(', 'MEK)', 1, '(', 'PD98059),', and, 'PTGS2', '(', 'NS398)', but, not, protein, kinase, 'A', '(', 'PKA)', '(', 'KT5720)'])].
[sujeto(['Conversely,', 'AREG', but, not, 'FSH']), verbo([induced]), complemento(['Ptsg2', mRNA, at, 0.5, h, with, peak, expression, of, 'Ptgs2', and, 'Areg', mRNAs, at, 4, 'h,', processes, blocked, by, the, 'EGF', receptor, tyrosine, kinase, inhibitor, 'AG1478', '(', 'AG),', 'PD98059,', and, 'NS398'])].
[sujeto(['Phorbol', 12, -, myristate, 13, -, acetate, '(', 'PMA)', and, adenovirally]), verbo([expressed]), complemento(['PGRA', synergistically, induced, 'Areg', mRNA, in, granulosa, cells])].
[sujeto(['In', 'COCs,', 'AREG', not, only]), verbo([induced]), complemento([genes, that, impact, matrix, formation, but, also, genes, involved, in, steroidogenesis, '(', 'StAR,', 'Cyp11a1)', and, immune, 'cell-like', functions, '(', 'Pdcd1,', 'Runx1,', 'Cd52)'])].
[sujeto(['PGs']), verbo([acting]), complemento([via, 'PTGER2', in, cumulus, cells, provide, a, 'secondary,', autocrine, pathway, to, regulate, expression, of, 'Areg', in, 'COCs', showing, critical, functional, links, between, 'G', 'protein-coupled', receptor, and, growth, factor, receptor, pathways, in, ovulating, follicles])].
[sujeto(['High', and, low, molecular, weight, '(', 'LMW)', tropomyosin, 'isoforms,', by, regulation, of, actin, 'filaments,']), verbo([have]), complemento([a, major, role, in, the, regulation, of, cell, behaviour])].
[sujeto(['Expression', of, 'LMW', isoforms, from, the, 'TPM1', and, 'TPM3', genes]), verbo([have]), complemento([an, important, role, in, these, effects, but, the, regulation, of, their, expression, is, unknown])].
[sujeto(['The', effect, of, mutating, candidate, transcription, factor]), verbo([binding]), complemento([sites, identified, an, 'AML1-like', transcription, factor, binding, site, in, 'TPM1', and, a, cAMP, response, element, in, 'TPM3'])].
[sujeto(['Downstream', from, the, primary, activation, sequence, in, 'TPM1', was, a, repressor, region, corresponding, to, two, 'Sp/KLF', family]), verbo([binding]), complemento(['GC', boxes])].
[sujeto(['Band', shift, assays, confirmed, that, deletion, of, these, sites, altered, transcription, factor]), verbo([binding]), complemento([and, 'ChIP', assays, confirmed, the, presence, of, 'AML1', and, 'CREB', at, the, 'TPM1', and, 'TPM3', activation, sequences, in, the, respective, promoters])].
[sujeto(['Expression', of, 'LMW', isoforms, from, 'TPM1', and, 'TPM3', genes, is]), verbo([regulated]), complemento([very, differently])].
[sujeto(['This', facilitates, regulation, of, the, many, cell, processes]), verbo([involving]), complemento([these, proteins])].
[sujeto(['In', situations, where, these, proteins]), verbo([have]), complemento([a, critical, 'role,', such, as, cancer, 'metastasis,', it, also, facilitates, specific, intervention])].
[sujeto(['MTG16,', 'MTGR1', and, 'ETO', are]), verbo([nuclear]), complemento([transcriptional, corepressors, of, the, human, 'ETO', protein, family])].
[sujeto(['We', tried, to, identify, structural, and, functional, promoter, elements, of, 'MTG16', and, 'MTGR1', genes, in, order, to]), verbo([find]), complemento([associations, between, their, regulation, and, hematopoiesis])].
[sujeto(['Mutation', of, an, evolutionary]), verbo([conserved]), complemento(['GATA', -, 301, consensus, binding, site, repressed, promoter, function])].
[sujeto(['Furthermore,', results, from, in, vitro, 'antibody-enhanced', electrophoretic, mobility, shift, assay, and, in, vivo, chromatin, immunoprecipitation, indicated]), verbo([binding]), complemento([of, 'GATA-1', to, the, 'GATA', -, 301, site])].
[sujeto(['Furthermore,', expression, of, the, transcription, factor, 'HERP2,', which]), verbo([represses]), complemento(['GATA-1,', produced, strong, inhibition, of, the, 'MTG16', promoter, reporter, consistent, with, a, role, of, 'GATA-1', in, transcriptional, activation])].
[sujeto(['The', 'TATA-less', and, 'CCAAT-less', 'MTGR1', promoter]), verbo([retained]), complemento([most, of, the, transcriptional, activity, within, a, -, 308, to, -, 207, bp, region, with, a, 'GC-box-rich', sequence, containing, multiple, 'SP1', binding, sites, reminiscent, of, a, housekeeping, gene, with, constitutive, expression])].
[sujeto(['However,', mutations, of, individual, 'SP1']), verbo([binding]), complemento([sites, did, not, repress, promoter, 'function;', multiple, active, 'SP1', binding, sites, may, be, required, to, safeguard, constitutive, 'MTGR1', transcriptional, activity])].
[sujeto(['The', observed, repression, of, 'MTG16/MTGR1', promoters, by, the, leukemia]), verbo([associated]), complemento(['AML1-ETO', fusion, gene, may, have, a, role, in, hematopoietic, dysfunction, of, leukemia])].
[sujeto(['An', evolutionary]), verbo([conserved]), complemento(['GATA', binding, site, is, critical, in, transcriptional, regulation, of, the, 'MTG16', promoter])].
[sujeto(['Our', results, demonstrate, that, the, 'ETO', homologue, promoters, are]), verbo([regulated]), complemento([differently, consistent, with, hematopoietic, 'cell-type-', specific, expression, and, function])].
[sujeto(['We']), verbo([found]), complemento([that, 'Sp1', could, bind, to, the, 'guanine-cytosine', '(', 'GC)-stretch', of, the, 'EEN', promoter, and, was, critical, for, the, normal, 'EEN', 'expression,', whereas, the, 'leukemia-associated', fusion, protein, 'AML1-ETO', could, aberrantly, transactivate, the, 'EEN', gene, through, an, 'AML1', binding, site])].
[sujeto(['Of', 'note,', overexpressed, 'EEN', showed, oncogenic, 'properties,', such, as, transforming, potential, in, 'NIH3T3', 'cells,']), verbo([stimulating]), complemento([cell, 'proliferation,', and, increasing, the, activity, of, transcriptional, factor, 'AP-1'])].
[sujeto(['Retroviral', transduction, of, 'EEN']), verbo([increased]), complemento(['self-renewal', and, proliferation, of, murine, hematopoietic, progenitor, cells])].
[sujeto(['Moreover,', 'Kasumi-1', and, 'HL60-cell', growth, was]), verbo([inhibited]), complemento([with, 'down-regulation', of, 'EEN', by, 'RNAi'])].
[sujeto(['These', findings, demonstrate, that, 'EEN', might, be, a, common]), verbo([target]), complemento([in, 2, major, types, of, 'AML', associated, with, 'MLL', or, 'AML1', 'translocations,', and, overexpression, of, 'EEN', may, play, an, essential, role, in, leukemogenesis])].
[sujeto(['The', objective, of, this, study, was, to, identify, elements]), verbo([regulating]), complemento([specific, expression, of, 'Mona/Gads', in, human, 'T', cell, and, myelomonocytic, cell, lines])].
[sujeto(['Deletion', analysis, and, electrophoresis, mobility, shift, assay, identified, several, cis, regulatory, 'elements:', overlapping, initiator, 'sequences,', one, interferon, response, 'factor-2', '(', 'IRF-2)-binding', site, at, position, -, 154, ',', one, 'GC', box]), verbo([recognized]), complemento([by, 'Sp1', and, 'Sp3', at, position, -, 52, ',', and, two, acute, myeloid, leukemia, '(', 'AML)-1', binding, sites, at, positions, -, 70, and, -, 13])].
[sujeto(['Site-directed', mutagenesis, experiments, indicated, a, key, role, of, 'AML-1', for, driving, 'Mona', expression, in, 'T', cells, and, myeloid, 'cells,', and, involvement, of, 'Sp1/Sp3', and, 'IRF-2', transcription, factors, to]), verbo([modulate]), complemento(['Mona', expression, in, a, 'cell-specific', manner])].
[sujeto(['miR-215', was]), verbo([reported]), complemento([to, be, downregulated, and, functioned, as, a, tumor, suppressor, in, several, cancers])].
[sujeto(['Ectopic', expression, of, 'miR-215', in, 'GES-1', and, 'HGC-27', cells, '(', low, 'miR-215', 'expression)']), verbo([promoted]), complemento([cell, 'growth,', 'migration,', 'invasion,', and, 'metastasis,', and, these, were, reversed, in, 'NCI-N87', cells, '(', high, 'miR-215', 'expression)', after, 'miR-215', downregulation])].
[sujeto(['Potential']), verbo([target]), complemento([genes, of, 'miR-215', were, predicted, and, 'RUNX1,', a, transcription, factor, and, a, tumor, 'suppressor,', was, confirmed, to, be, potential, target, according, to, luciferase, studies])].
[sujeto(['miR-215']), verbo([promotes]), complemento([malignant, progression, of, 'GC', by, targeting, 'RUNX1,', and, 'RUNX1', can, partially, reverse, 'miR-215', effects])].
[sujeto(['Latent', 'TGF-beta']), verbo([binding]), complemento([proteins, '(', 'LTBPs)', are, extracellular, matrix, 'glycoproteins,', which, are, essential, for, the, targeting, and, activation, of, 'TGF-betas'])].
[sujeto(['LTBP-3']), verbo([regulates]), complemento([the, bioavailability, of, 'TGF-beta', especially, in, the, bone])].
[sujeto(['To', understand, the, regulation, of, 'LTBP-3', 'expression,', we]), verbo([have]), complemento([isolated, and, characterized, the, promoter, region, of, human, 'LTBP-3', gene])].
[sujeto(['The', 'GC-rich', 'TATA-less', promoter, contained, several, transcription, initiation, sites, and, putative]), verbo([binding]), complemento([sites, for, multiple, sequence, specific, transcription, factors, including, 'Sp1,', 'AP-1,', 'c-Ets,', 'MZF-1,', 'Runx1', and, members, of, the, 'GATA-family'])].
[sujeto(['Reporter', gene, analyses, of, the, promoter, indicated, that, it, was, more, active, in, 'MG-63', than, in, 'Saos-2', osteosarcoma, 'cells,']), verbo([suggesting]), complemento([that, it, is, regulated, as, the, endogenous, gene])].
[sujeto(['TGF-beta1']), verbo([stimulated]), complemento([the, transcriptional, activity, of, 'LTBP-3', promoter, in, 'MG-63', 'cells,', while, certain, other, 'bone-derived', growth, factors, and, hormones, were, ineffective])].
[sujeto(['TGF-beta1']), verbo([increased]), complemento(['LTBP-3', mRNA, levels, accordingly])].
[sujeto(['Analyses', of, deletion, constructs, of, the, promoter, and, mutational, deletion, of, specific, transcription, factor]), verbo([binding]), complemento([sites, indicated, that, 'Smad3/4', and, 'AP-1', binding, sites, mediated, the, 'TGF-beta1', response])].
[sujeto(['The', involvement, of, 'AP-1', activity, was, further, indicated, by]), verbo([decreased]), complemento(['TGF-beta', responsiveness, of, the, 'LTBP-3', promoter, in, the, presence, of, a, 'MEK/Erk', signaling, pathway, inhibitor])].
[sujeto(['Our', results]), verbo([suggest]), complemento([an, important, new, role, for, 'TGF-beta1', in, the, regulation, of, its, binding, 'protein,', 'LTBP-3'])].
[sujeto([4, ',', designated, the, human, leukocyte, receptor, 'complex,', and, are, predominantly]), verbo([expressed]), complemento([on, myeloid, lineage, cells])].
[sujeto(['Inhibitory', 'ILT2', and, 'ILT4', both]), verbo([have]), complemento([a, similar, genomic, 'structure,', in, which, the, approximately, 160, -, bp, 5, '\'', -, flanking, regions, function, as, core, promoters, with, critically, important, 'PU'])].
[sujeto([1]), verbo([binding]), complemento([sites])].
[sujeto(['Additionally,', 'ILT4', transcription, is, tightly]), verbo([regulated]), complemento([by, chromatin, modifications, accompanied, by, histone, 'acetylation,', which, strictly, controls, expression, within, myeloid, lineage, cells])].
[sujeto([1, and, 'Runx1']), verbo([binding]), complemento([sites, are, 'essential,', but, a, downstream, heat, shock, element, also, augments, promoter, activity])].
[sujeto(['Thus,', each, 'ILT', is]), verbo([regulated]), complemento([by, a, distinct, transcriptional, 'mechanism,', although, 'PU'])].
[sujeto([1]), verbo([acts]), complemento([as, a, common, 'trans-acting', factor])].
[sujeto(['We', also]), verbo([found]), complemento([that, human, 'CMV', infection, strongly, 'trans-activates', inhibitory, 'ILT2', and, 'ILT4', genes, through, the, expression, of, 'immediate-early', proteins])].
[sujeto(['Tnk1/Kos1', is, a, 'non-receptor', protein, tyrosine, kinase]), verbo([found]), complemento([to, be, a, tumor, suppressor])].
[sujeto(['It', negatively]), verbo([regulates]), complemento([cell, growth, by, indirectly, suppressing, 'Ras', activity])].
[sujeto(['We', identified, and, characterized, the, critical, 'cis-elements']), verbo([required]), complemento([for, 'Tnk1/Kos1\'s', promoter, activity])].
[sujeto(['Deletion', analysis, of, the, 'm-Tnk1', promoter]), verbo([reveals]), complemento([the, presence, of, both, positive, '(', -, 25, to, -, 151, ')', and, negative, '(', -, 151, to, -, 1201, ')', regulatory, regions])].
[sujeto(['The', three, 'GC', boxes, which]), verbo([bind]), complemento(['Sp1', and, 'Sp3', with, high, 'affinity,', an, 'AP2', site, '(', that, overlaps, with, an, 'AML1', 'site)', and, a, 'MED1', site, comprise, the, necessary, 'cis-elements', of, the, proximal, promoter, required, for, both, constitutive, and, inducible, 'Tnk1/Kos1', expression])].
[sujeto(['Importantly,', results]), verbo([reveal]), complemento([that, cellular, stress, reverses, the, repression, of, 'Tnk1/Kos1', and, induces, its, expression, through, increased, high, affinity, interactions, between, nuclear, proteins, 'Sp1,', 'Sp3,', 'AP2', and, 'MED1', for, the, 'm-Tnk1', promoter])].
[sujeto(['These', findings]), verbo([provide]), complemento([a, mechanism, by, which, the, 'm-Tnk1', promoter, can, be, dynamically, regulated, during, normal, growth])].
[sujeto(['They']), verbo([suggest]), complemento([that, prenatal, pesticide, exposures, may, be, causal, factors, for, the, generation, of, 'leukemia-associated', chromosomal, translocations])].
[sujeto(['The', main, start, sites, were]), verbo([found]), complemento([at, -, 591, ',', -, 577, ',', -, 560, and, -, 541, nucleotides, 5, '\'', of, the, 'AUG'])].
[sujeto(['Comparison', of, the, rat, sequences, with, the, human, sequences, from, the, 'Human', 'Genome', 'Data', 'Bank', revealed, that, the, 5, '\'', 'UTR', exon, 2, was, extremely]), verbo([conserved]), complemento([with, 95.8, '%', sequence, 'identity,', as, were, the, initial, 640, bp, of, 5, '\'', flanking, 'sequences,', with, 78, '%', sequence, identity])].
[sujeto(['Chromosomal', rearrangements, of, trkC]), verbo([have]), complemento([been, recently, reported, in, congenital, fibrosarcoma, and, it, has, been, proposed, that, abnormal, activation, of, this, gene, might, be, involved, in, tumor, development])].
[sujeto(['To', facilitate, the, search, for, new, mutations, and, rearrangements, in, the, human, trkC, locus, we]), verbo([have]), complemento([partially, characterized, its, genomic, organization, by, restriction, mapping, and, have, obtained, the, complete, 'intron-exon', structure])].
[sujeto(['Analysis', of, the, 5, '\'', flanking, region, revealed, the, absence, of, 'TATA', 'box,', a, very, high, content, in, 'C/G', compatible, with, a, 'CpG', island, and, the, presence, of, putative]), verbo([binding]), complemento([sites, for, the, 'AP1,', 'AP2,', 'GC,', 'ATF,', 'BRN2,', 'AML1', and, 'Nkx2'])].
[sujeto(['Upon', recognition, of, viral, components, by, pattern, recognition, 'receptors,', including, 'TLRs', and, retinoic, 'acid-inducible', gene, 'I-like', 'helicases,', cells, are]), verbo([activated]), complemento([to, produce, type, 'I', 'IFN,', which, plays, key, roles, in, host, antiviral, innate, immune, response])].
[sujeto(['However,', excessive, 'IFN', production, may]), verbo([induce]), complemento([immune, 'disorders,', and, the, mechanisms, responsible, for, the, regulation, of, type, 'I', 'IFN', production, have, attracted, much, attention])].
[sujeto(['Furthermore,', type, 'I', 'IFN']), verbo([activates]), complemento([the, downstream, 'IFN/JAK/STAT', pathway, to, modulate, expression, of, a, set, of, genes, against, viral, 'infection,', but, whether, these, genes, can, feedback, regulate, type, 'I', 'IFN', production, is, poorly, understood])].
[sujeto(['In', this, 'study,', by, screening, the, microRNAs]), verbo([modulated]), complemento([by, viral, infection, in, 'macrophages,', we, identified, that, microRNA, '(', 'miR)-27a', was, significantly, downregulated, via, the, 'IFN/JAK/STAT1/runt-related', transcription, factor, 1, pathway])].
[sujeto(['Inducible', downregulation, of, 'miR-27a,', in, 'turn,', negatively]), verbo([regulated]), complemento([vesicular, stomatitis, 'virus-triggered', type, 'I', 'IFN', 'production,', thus, promoting, vesicular, stomatitis, virus, replication, in, macrophages])].
[sujeto(['Mechanistically,', we]), verbo([found]), complemento([that, 'miR-27a', directly, targeted, sialic, 'acid-binding', 'Ig-like', lectin, '(', 'Siglec)1', and, 'E3', ubiquitin, ligase, tripartite, 'motif-containing', protein, 27, '(', 'TRIM27),', both, of, which, were, previously, verified, as, negative, regulators, of, type, 'I', 'IFN', production])].
[sujeto(['Furthermore,', we, constructed, &, 'quot;Sponge&quot;', transgenic, mice, against, 'miR-27a', expression, and]), verbo([found]), complemento([that, 'Siglec1', and, 'TRIM27', expression, were, elevated, whereas, type, 'I', 'IFN', production, was, inhibited, and, viral, replication, was, aggregated, in, vivo])].
[sujeto(['Therefore,', type, 'I', 'IFN-induced', downregulation, of, 'miR-27a', can, upregulate, 'Siglec1', and, 'TRIM27', 'expression,', feedback]), verbo([inhibiting]), complemento([type, 'I', 'IFN', production, in, antiviral, innate, response])].
[sujeto(['Our', study, outlines, a, new, negative, way, to, feedback]), verbo([regulate]), complemento([type, 'I', 'IFN', production])].
[sujeto(['Advances', in, molecular, research]), verbo([have]), complemento([greatly, improved, our, understanding, of, the, leukemogenesis, in, 'AML'])].
[sujeto(['While', 'loss-of-function', mutations, in, 'DNMT3A', are, highly, recurrent, in, acute, myeloid, leukemia, '(', 'AML),', 'DNMT3A', mutations, are, almost, never]), verbo([found]), complemento([in, 'AML', patients, with, translocations, that, create, oncogenic, fusion, genes, such, as, 'PML-RARA,', 'RUNX1-RUNX1T1,', and, 'MLL-AF9'])].
[sujeto(['Here,', we, explored, how, 'DNMT3A', is]), verbo([involved]), complemento([in, the, function, of, these, fusion, genes])].
[sujeto(['We', used, retroviral, vectors, to]), verbo([express]), complemento(['PML-RARA,', 'RUNX1-RUNX1T1,', or, 'MLL-AF9', in, bone, marrow, cells, derived, from, 'WT', or, 'DNMT3A-deficient', mice])].
[sujeto(['Additionally,', we, examined, the, phenotypes, of, hematopoietic, cells, from, 'Ctsg-PML-RARA', 'mice,', which]), verbo([express]), complemento(['PML-RARA', in, early, hematopoietic, progenitors, and, myeloid, 'precursors,', with, or, without, 'DNMT3A'])].
[sujeto(['We', determined, that, the, methyltransferase, activity, of, 'DNMT3A,', but, not, 'DNMT3B,', is]), verbo([required]), complemento([for, aberrant, 'PML-RARA-driven', 'self-renewal', ex, vivo, and, that, 'DNMT3A', is, dispensable, for, 'RUNX1-RUNX1T1-', and, 'MLL-AF9-driven', 'self-renewal'])].
[sujeto(['Furthermore,', both, the, 'PML-RARA-driven', competitive, transplantation, advantage, and, development, of, acute, promyelocytic, leukemia, '(', 'APL)']), verbo([required]), complemento(['DNMT3A'])].
[sujeto(['Together,', these, findings]), verbo([suggest]), complemento([that, 'PML-RARA', requires, 'DNMT3A', to, initiate, 'APL', in, mice])].
[sujeto(['Acute', myeloid, leukemia, '(', 'AML)', is, mostly, driven, by, oncogenic, transcription, 'factors,', which]), verbo([have]), complemento([been, classically, viewed, as, intractable, targets, using, 'small-molecule', inhibitor, approaches])].
[sujeto(['Here', we, demonstrate, that, 'AML', driven, by, repressive, transcription, 'factors,', including, 'AML1-ETO', '(', encoded, by, the, fusion, oncogene, 'RUNX1-RUNX1T1)', and, 'PML-RARα', fusion, oncoproteins, '(', encoded, by, 'PML-RARA)', are, extremely, sensitive, to, poly, '(', 'ADP-ribose)', polymerase, '(', 'PARP)', 'inhibition,', in, part, owing, to, their]), verbo([suppressed]), complemento([expression, of, key, homologous, recombination, '(', 'HR)-associated', genes, and, their, compromised, 'DNA-damage', response, '(', 'DDR)'])].
[sujeto(['Intriguingly,', genetic, or, pharmacological, inhibition, of, an, 'MLL', downstream, 'target,', 'HOXA9,', which]), verbo([activates]), complemento([expression, of, various, 'HR-associated', 'genes,', impairs, 'DDR', and, sensitizes, 'MLL', leukemia, to, 'PARP', inhibitors, '(', 'PARPis)'])].
[sujeto(['Conversely,', 'HOXA9', overexpression]), verbo([confers]), complemento(['PARPi', resistance, to, 'AML1-ETO', and, 'PML-RARα', transformed, cells])].
[sujeto(['Together,', these, studies, describe, a, potential, utility, of, 'PARPi-induced', synthetic, lethality, for, leukemia, treatment, and]), verbo([reveal]), complemento([a, novel, molecular, mechanism, governing, 'PARPi', sensitivity, in, 'AML'])].
[sujeto(['Here,', we, identified, 'Mtss1', expression, to, be]), verbo([increased]), complemento([in, 'AML', subsets, with, favorable, 'outcome,', while, suppressed, in, high, risk, 'AML', patients])].
[sujeto(['Mechanistically,', 'MTSS1', expression, was, negatively]), verbo([regulated]), complemento([by, 'FLT3-ITD', signaling, but, enhanced, by, the, 'AML1-ETO', fusion, protein])].
[sujeto(['DNMT3B,', a, negative, regulator, of, 'MTSS1,', showed, strong]), verbo([binding]), complemento([to, the, 'MTSS1', promoter, in, 'PML-RARA', positive, but, not, 'AML1-ETO', positive, 'cells,', suggesting, that, 'AML1-ETO', leads, to, derepression, of, 'MTSS1'])].
[sujeto(['Pharmacological', treatment, of, 'AML', cell, lines, carrying, the, 'FLT3-ITD', mutation, with, the, specific, 'FLT3', inhibitor, 'PKC-412']), verbo([caused]), complemento([upregulation, of, 'MTSS1'])].
[sujeto(['Moreover,', treatment, of, acute, promyelocytic, cells, '(', 'APL)', with, 'all-trans', retinoic, acid, '(', 'ATRA)']), verbo([increased]), complemento(['MTSS1', mRNA, levels])].
[sujeto(['Taken', 'together,', our, findings]), verbo([suggest]), complemento([that, 'MTSS1', might, have, a, 'context-dependent', function, and, could, act, as, a, tumor, 'suppressor,', which, is, pharmacologically, targetable, in, 'AML', patients])].
[sujeto(['Here', we, show, that, both, oncogenic, proteins, specifically, downregulate, the, expression, of, 'CD48,', a, ligand, of, the, natural, killer, '(', 'NK)', cell]), verbo([activating]), complemento([receptor, 2, 'B4,', thereby, leading, to, decreased, killing, by, 'NK', cells])].
[sujeto(['We', demonstrate, that, this, process, is, histone, deacetylase, '(', 'HDAC)-dependent,', that, it, is]), verbo([mediated]), complemento([through, the, downregulation, of, 'CD48', messenger, 'RNA,', and, that, treatment, with, 'HDAC', inhibitors, '(', 'HDACi)', restores, the, expression, of, 'CD48'])].
[sujeto(['Furthermore,', by, using, chromatin, immunoprecepitation, '(', 'ChIP)', 'experiments,', we, show, that, 'AML1-ETO', directly]), verbo([interacts]), complemento([with, 'CD48'])].
[sujeto(['Finally,', we, show, that, 'AML', patients, who, are, carrying, these, specific, translocations]), verbo([have]), complemento([low, expression, of, 'CD48'])].
[sujeto(['Delineating', the, mechanism, or, mechanisms, that]), verbo([regulate]), complemento([the, specification, of, hemogenic, endothelial, cells, from, primordial, endothelium, is, critical, for, optimizing, their, derivation, from, human, stem, cells, for, clinical, therapies])].
[sujeto(['We', previously, determined, that, retinoic, acid, '(', 'RA)', is]), verbo([required]), complemento([for, hemogenic, 'specification,', as, well, as, 'cell-cycle', 'control,', of, endothelium, during, embryogenesis])].
[sujeto(['Herein,', we, define, the, molecular, signals, downstream, of, 'RA', that]), verbo([regulate]), complemento([hemogenic, endothelial, cell, development, and, demonstrate, that, 'cell-cycle', control, is, required, for, this, process])].
[sujeto(['We']), verbo([found]), complemento([that, 're-expression', of, 'c-Kit', in, 'RA-deficient', '(', 'Raldh2(-/-))', primordial, endothelium, induced, 'Notch', signaling, and, p27, 'expression,', which, restored, 'cell-cycle', control, and, rescued, hemogenic, endothelial, cell, specification, and, function])].
[sujeto(['Thus,', 'RA', regulation, of, hemogenic, endothelial, cell, specification]), verbo([requires]), complemento(['c-Kit,', notch, 'signaling,', and, 'p27-mediated', 'cell-cycle', control])].
[sujeto(['Both', radiation, and, chemotherapeutic, drugs]), verbo([induce]), complemento([autophagy, in, tumor, 'cells,', and, whether, this, contributes, to, cell, death, or, survival, is, debated])].
[sujeto(['Although', a, prodeath, role]), verbo([has]), complemento([been, reported, in, certain, 'contexts,', 'treatment-induced', autophagy, often, exerts, a, prosurvival, function, by, preventing, apoptosis, and, delaying, necrosis])].
[sujeto(['Interestingly,', a, more, specific, role, of, autophagy]), verbo([has]), complemento([been, demonstrated, in, certain, subtypes, of, leukemia])].
[sujeto(['The', fusion, oncoproteins, 'PML-RARA', and, 'BCR-ABL,', the, main, oncogenic, drivers, of, acute, promyelocytic, leukemia, and, chronic, myeloid, leukemia, '(', 'CML),', 'respectively,']), verbo([have]), complemento([recently, been, identified, as, autophagy, substrates, and, their, degradation, by, autophagy, shown, to, contribute, to, treatment])].
[sujeto(['However,', this, does, not, seem, to, be, a, general, feature, of, leukemic, fusion, 'oncoproteins,', as, we, recently]), verbo([found]), complemento([that, 'AML1-ETO,', the, most, frequently, occurring, acute, myeloid, leukemia, '(', 'AML)', fusion, 'protein,', is, not, an, autophagy, substrate])].
[sujeto(['ATRA']), verbo([enhances]), complemento([hematopoietic, stem, cell, 'self-renewal', through, retinoic, acid, receptor, '(', 'RAR)γ', activation, while, promoting, differentiation, of, committed, myeloid, progenitors, through, 'RARα', activation])].
[sujeto(['Its', lack, of, success, in, the, treatment, of, 'non-APL', acute, myeloid, leukemia, '(', 'AML)', may, be, related, to, 'ATRA\'s', 'non-selectivity', for, the, 'RARα', and, 'RARγ', 'isotypes,', and, specific, 'RARα', activation, may, be, more, beneficial, in]), verbo([promoting]), complemento([myeloid, differentiation])].
[sujeto(['Morphological', and, flow, cytometric, analysis, confirmed, a, predominantly, immature, myeloid, population, in, the, 'ATRA-treated', 'AE', cells, while, the, 'NRX195183-treated', cells, demonstrated, an]), verbo([increase]), complemento([in, the, mature, myeloid, population])].
[sujeto(['Similarly,', 'NRX195183', treatment]), verbo([promoted]), complemento([myeloid, differentiation, in, an, 'AE9a', in, vivo, murine, model])].
[sujeto(['In', the, 'ATRA-treated', 'AE', 'cells,', gene, expression, analyses, revealed, functional, networks]), verbo([involving]), complemento(['SERPINE1', and, bone, morphogenetic, protein, 2, ;, 'AKT', phosphorylation, was, upregulated])].
[sujeto(['Chromatin', accessibility, plays, a, key, role, in]), verbo([regulating]), complemento([cell, type, specific, gene, expression, during, hematopoiesis, but, has, also, been, suggested, to, be, aberrantly, regulated, during, leukemogenesis])].
[sujeto(['Z', as, a, histone, modification, generally]), verbo([associated]), complemento([with, these, accessible, 'regions,', whereas, unsupervised, clustering, analysis, of, other, chromatin, 'features,', including, 'DNA', 'methylation,', 'H2A'])].
[sujeto(['Of', 'these,', 'PML-RARα']), verbo([binding]), complemento([was, found, specifically, at, accessible, chromatin, regions, characterized, by, p300, binding, and, hypoacetylated, histones])].
[sujeto(['Together,', our, results]), verbo([suggest]), complemento([that, oncofusion, proteins, localize, to, accessible, regions, and, that, chromatin, accessibility, together, with, p300, binding, and, histone, acetylation, characterize, 'AML1-ETO', and, 'PML-RARα', binding, sites])].
[sujeto(['Leukemia,', a, group, of, hematological, malignancies, characterized, by, abnormal, 'proliferation,']), verbo([decreased]), complemento(['apoptosis,', and, blocked, differentiation, of, hematopoietic, 'stem/progenitor', 'cells,', is, a, disease, involving, dynamic, change, in, the, genome])].
[sujeto(['Chromosomal', translocation, and, point, mutation, are, the, major, mechanisms, in, 'leukemia,', which]), verbo([lead]), complemento([to, production, of, oncogenes, with, dominant, gain, of, function, and, tumor, suppressor, genes, with, recessive, loss, of, function])].
[sujeto(['The', past, two, to, three, decades]), verbo([have]), complemento([witnessed, tremendous, success, in, development, of, targeted, therapies, for, acute, and, chronic, myeloid, leukemia, caused, by, the, three, fusion, proteins])].
[sujeto(['Here,', we, review, the, therapeutic, efficacies, and, the, mechanisms, of, action, of]), verbo([targeted]), complemento([therapies, for, myeloid, leukemia, and, show, how, this, strategy, significantly, improve, the, clinical, outcome, of, patients, and, even, turn, acute, promyelocytic, leukemia, from, highly, fatal, to, highly, curable])].
[sujeto(['Our', previous, study, showed, that, the, differentiation, and, apoptosis, of, 'Kasumi-1']), verbo([induced]), complemento([by, sodium, phenylbutyrate, '(', 'PB),', were, accompanied, by, significant, upregulation, of, 'PIG7', and, 'AML1b', '(', one, of, the, 'AML1', 'isoforms)'])].
[sujeto(['The', specific, 'AML1-binding', site]), verbo([required]), complemento([for, 'p53-induced', gene, 7, '(', 'PIG7)', transactivation, was, located, between, nucleotides, -, 1511, and, -, 1503, in, the, 'PIG7', promoter])].
[sujeto(['Overexpression', of, 'PIG7', could]), verbo([induce]), complemento([the, apoptosis, and, differentiation, of, 'Kasumi-1', and, 'SKNO-1', 'cells,', but, showed, less, effect, on, 'NB4', cells, directly])].
[sujeto(['In', 'conclusion,', 'PIG7', could, be, transactivated, by, 'AML1,', which, subsequently]), verbo([induces]), complemento([differentiation, and, apoptosis, of, leukemia, 'cells,', especially, those, with, 'AML1-ETO', fusion, gene])].
[sujeto([22, of, the, 40, 'AML', cases, were]), verbo([found]), complemento([to, carry, 7, types, of, cytogenetic, abnormalities, by, multiprobe, 'FISH', panel, including, 'AML1/ETO', transfusion, 'gene,', 'PML-RARa', transfusion, 'gene,', 'MLL', 'breakapart,', 'P53', 'deletion,', 'Del', '(', 5, 'q),', 'Del7q', and, trisomy, 8])].
[sujeto(['The', 'leukaemia-specific', fusion, oncoprotein, 'RUNX1/RUNX1T1', '(', 'AML1/ETO),', resulting, from, the, chromosomal, translocation, '(', 8, ;, 21, ')', in, acute, myeloid, leukaemia, '(', 'AML),', imposes, a, striking, 'genotype-phenotype', relationship, upon, this, distinct, subtype, of, 'AML,', which, is]), verbo([mediated]), complemento([by, 'multiple,', 'co-ordinate', downstream, effects, induced, by, this, chimeric, transcription, factor])].
[sujeto(['We', previously, identified, the, 'LAT2', 'gene,', encoding, the, adaptor, molecule, 'LAT2', '(', 'NTAL,', 'LAB),', which, is]), verbo([phosphorylated]), complemento([by, 'KIT', and, has, a, role, in, mast, cell, and, 'B-cell', 'activation,', as, a, target, of, the, repressor, activity, of, 'RUNX1/RUNX1T1'])].
[sujeto(['In', 'contrast,', in, a, cohort, of, 43, 'AML', 'patients,', higher, levels, of, 'LAT2', were]), verbo([associated]), complemento([with, myelomonocytic, features])].
[sujeto(['In', previous, 'studies,', we]), verbo([found]), complemento([that, the, deficiency, of, sensory, and, motor, neurons, was, a, primary, defect, associated, with, the, spinal, malformation])].
[sujeto(['Upon', prenatal, treatment, of, spina, bifida, through, in, utero, stem, cell, transplantation, in, a, retinoic, 'acid-induced', spina, bifida, rat, 'model,', we]), verbo([found]), complemento([that, the, mesenchymal, stem, cell, '(', 'MSCs)', 'survived,', 'migrated,', and, differentiated, into, cells, of, a, neural, lineage])].
[sujeto(['Some', of, the, transplanted, 'MSCs']), verbo([expressed]), complemento([sensory, neuron, cell, specific, phenotypes])].
[sujeto(['The', percentage, of, 'Brn3a-positive', neurons, in, 'DRG', was, also]), verbo([increased]), complemento([after, transplantation])].
[sujeto(['Our', results, indicate, that, the, transplantation, of, 'MSCs', into, the, spinal, cord, could]), verbo([promote]), complemento([the, transplanted, 'MSCs', and, the, surrounding, cells, to, differentiate, toward, a, sensory, neuron, cell, fate, and, to, play, an, important, role, in, protecting, sensory, neurons, in, 'DRG'])].
[sujeto(['The', 'ETS', transcription, factor, 'ERG']), verbo([has]), complemento([been, implicated, as, a, major, regulator, of, both, normal, and, aberrant, hematopoiesis])].
[sujeto(['Here,', we, show, that, 'FUS-ERG']), verbo([acts]), complemento([in, the, context, of, a, heptad, of, proteins, '(', 'ERG,', 'FLI1,', 'GATA2,', 'LYL1,', 'LMO2,', 'RUNX1', and, 'TAL1)', central, to, proper, expression, of, genes, involved, in, maintaining, a, stem, cell, hematopoietic, phenotype])].
[sujeto(['Moreover,', in, 't(16;21)', 'FUS-ERG', 'co-occupies', genomic, regions]), verbo([bound]), complemento([by, the, nuclear, receptor, heterodimer, 'RXR:RARA', inhibiting, target, gene, expression, and, interfering, with, hematopoietic, differentiation])].
[sujeto(['Together,', the, results]), verbo([suggest]), complemento([that, 'FUS-ERG', acts, as, a, transcriptional, repressor, of, the, retinoic, acid, signaling, pathway])].
[sujeto(['All-trans', retinoic, acid, '(', 'ATRA)', is, well, established, as, differentiation, therapy, for, acute, promyelocytic, leukemia, '(', 'APL)', in, which, the, 'PML-RARα', '(', promyelocytic, 'leukemia-retinoic', acid, receptor, 'α)', fusion, protein]), verbo([causes]), complemento([blockade, of, the, retinoic, acid, '(', 'RA)', 'pathway;', 'however,', in, types, of, acute, myeloid, leukemia, '(', 'AML)', other, than, 'APL,', the, mechanism, of, 'RA', pathway, inactivation, is, not, fully, understood])].
[sujeto(['Treatment', with, 'ATRA']), verbo([induced]), complemento([significant, myeloid, differentiation, accompanied, by, upregulation, of, 'RARα,', 'C/EBPα,', 'C/EBPɛ', and, 'PU'])].
[sujeto([1, upstream, regulatory, region, '(', 'URE)', and, 'RUNX1+24/+25', intronic, enhancer, was, higher, in, 'MLL-AF9-positive', cells, than, in, 'MLL-AF4-positive', 'cells,', and]), verbo([inhibiting]), complemento(['lysine-specific', demethylase, 1, ',', which, acts, as, a, histone, demethylase, 'inhibitor,', reactivated, 'ATRA', sensitivity, in, 'MLL-AF4-positive', cells])].
[sujeto(['These', findings]), verbo([suggest]), complemento([that, the, level, of, 'H3K4me2', in, the, 'RARα', 'gene-promoter', 'region,', 'PU'])].
[sujeto(['Our', findings]), verbo([provide]), complemento([insight, into, the, mechanisms, of, 'ATRA', sensitivity, in, 'AML', and, novel, treatment, strategies, for, 'ATRA-resistant', 'AML'])].
[sujeto(['The', genetic, diagnostics]), verbo([have]), complemento([become, an, essential, component, in, the, initial, 'work-up', for, disease, 'classification,', prognostication, and, prediction])].
[sujeto(['More', and, more, promising, molecular]), verbo([targeted]), complemento([therapeutics, are, becoming, available])].
[sujeto(['With', the, advent, of, the, next, generation, sequencing, technologies, it, is, expected, that, new, therapeutic]), verbo([targets]), complemento([will, be, identified])].
[sujeto(['These', insights, will]), verbo([lead]), complemento([to, a, further, individualization, of, 'AML', therapy])].
[sujeto(['It', is, concluded, that, the, 'CD200', antigen, expression, in, 'AML', may]), verbo([associate]), complemento([with, a, poor, prognosis, of, patients])].
[sujeto(['Although', 'all-trans', retinoic, acid, '(', 'ATRA)']), verbo([has]), complemento([been, successfully, introduced, to, treat, acute, promyelocytic, leukemia, '(', 'APL),', it, is, rather, ineffective, in, 'non-APL', 'AML'])].
[sujeto(['In', our, present, 'study,', 1200, 'off-patent', marketed, drugs, and, natural, compounds, that]), verbo([have]), complemento([been, approved, by, the, 'Food', and, 'Drug', 'Administration', '(', 'FDA)', were, screened, for, 'anti-leukemia', activity, using, the, retrovirus, 'transduction/transformation', assay, '(', 'RTTA)'])].
[sujeto(['Furazolidone', '(', 'FZD)', was, shown, to]), verbo([inhibit]), complemento([bone, marrow, transformation, mediated, by, several, leukemia, fusion, 'proteins,', including, 'AML1-ETO'])].
[sujeto(['Furazolidone']), verbo([has]), complemento([been, used, in, the, treatment, of, certain, bacterial, and, protozoan, infections, in, human, and, animals, for, more, than, sixty, years])].
[sujeto(['FZD', displayed, potent, antiproliferative, properties, at, submicromolar, concentrations, and]), verbo([induced]), complemento([apoptosis, in, 'AML', cell, lines])].
[sujeto(['Importantly,', 'FZD', treatment, of, certain, 'AML', cells]), verbo([induced]), complemento([myeloid, cell, differentiation, by, morphology, and, flow, cytometry, for, 'CD11b', expression])].
[sujeto(['Furthermore,', 'FZD', treatment, resulted, in]), verbo([increased]), complemento([stability, of, tumor, suppressor, p53, protein, in, 'AML', cells])].
[sujeto(['Our', in, vitro, results]), verbo([suggest]), complemento([furazolidone, as, a, novel, therapeutic, strategy, in, 'AML', patients])].
[sujeto(['CMTM5']), verbo([has]), complemento([been, shown, to, exhibit, tumor, suppressor, 'activities,', 'however,', its, role, in, leukemia, is, unclear])].
[sujeto(['Herein', we, firstly]), verbo([reported]), complemento([the, expression, and, function, of, 'CMTM5', in, myeloid, leukemia])].
[sujeto(['Ectopic', expression, of, 'CMTM5-v1', strongly]), verbo([inhibited]), complemento([the, proliferation, of, 'K562', and, 'MEG-01', cells])].
[sujeto(['Therefore,', 'CMTM5', may, be]), verbo([involved]), complemento([in, the, pathomechanism, of, myeloid, leukemias])].
[sujeto(['The', biologic, functions, of, 'AML1', and, 'AML3']), verbo([have]), complemento([been, well, 'characterized;', 'however,', the, functional, role, of, 'AML2', remains, unknown])].
[sujeto(['In', this, 'study,', we]), verbo([found]), complemento([that, 'AML2', protein, expressed, predominantly, in, cells, of, hematopoietic, origin, is, a, nuclear, serine, phosphoprotein, associated, with, the, nuclear, 'matrix,', and, its, expression, is, not, cell, 'cycle-related'])].
[sujeto(['In', 'HL-60', cells, 'AML2', expression, can, be]), verbo([induced]), complemento([by, all, three, natural, 'retinoids,', 'all-trans-retinoic', acid, '(', 'RA),', 13, -, 'cis-RA,', and, 9, -, 'cis-RA', in, a, 'dose-dependent', manner])].
[sujeto(['A', synthetic, retinoic, acid, 'derivative,', 4, 'HPR,', which, neither]), verbo([activates]), complemento(['RA', receptor, '(', 'RAR)', alpha, nor, retinoic, 'X', receptor, alpha, was, unable, to, induce, the, expression, of, 'AML2'])].
[sujeto(['A', 'RAR-selective', 'activator,', 'TTNPB,']), verbo([induced]), complemento(['AML2', expression, similar, to, 'RA'])].
[sujeto(['Our', study, further, showed, that, 'AGN193109,', a, potent, 'RARalpha', 'antagonist,']), verbo([suppressed]), complemento(['AML2', expression, induced, by, 'RA', and, that, a, retinoic, 'X', receptor, pan, agonist, 'AGN194204', had, no, effect, on, its, expression])].
[sujeto(['Taken', 'together,', these, studies, conclusively, demonstrated, that, the, expression, of, 'AML2', in, 'HL-60', cells, is]), verbo([regulated]), complemento([through, the, 'RARalpha-specific', signaling, pathway])].
[sujeto(['Based', on, these, studies, we, hypothesize, that, 'AML2', expression, is, normally]), verbo([regulated]), complemento([by, 'retinoid/vitamin', 'D', nuclear, receptors, mainly, through, the, 'RARalpha-dependent', signaling, pathway, and, that, it, may, play, a, role, in, hematopoietic, cell, differentiation])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, 'runt-related', transcription, factor, '(', 'RUNX1)', could, be, a, key, molecule, for, the, 'androgen-dependence', of, prostate, cancer])].
[sujeto(['We']), verbo([found]), complemento(['RUNX1', is, a, target, of, 'AR', and, regulated, positively, by, androgen])].
[sujeto(['Our', 'RUNX1', 'ChIP-seq', analysis, indicated, that, 'RUNX1', is]), verbo([recruited]), complemento([to, 'AR', binding, sites, by, interacting, with, 'AR'])].
[sujeto(['In', 'androgen-dependent', 'cancer,']), verbo([loss]), complemento([of, 'RUNX1', impairs, 'AR-dependent', transcription, and, cell, growth])].
[sujeto(['The', 'RUNX1', promoter, is]), verbo([bound]), complemento([by, enhancer, of, zeste, homolog, 2, '(', 'EZH2)', and, is, negatively, regulated, by, histone, 'H3', lysine, 27, '(', 'K27)', trimethylation])].
[sujeto(['In', clinical, prostate, cancer, 'samples,', the, 'RUNX1', expression, level, is, negatively]), verbo([associated]), complemento([with, 'EZH2', and, that, 'RUNX1', loss, correlated, with, poor, prognosis])].
[sujeto(['These', results, indicated, the, significance, of, 'RUNX1', for, 'androgen-dependency', and, that]), verbo([loss]), complemento([of, 'RUNX1', could, be, a, key, step, for, the, progression, of, prostate, cancer])].
[sujeto(['Mutant', 'MAP3K1', was]), verbo([associated]), complemento([with, luminal, 'A', 'status,', 'low-grade', histology, and, low, proliferation, 'rates,', whereas, mutant, 'TP53', was, associated, with, the, opposite, pattern])].
[sujeto(['Distinct', phenotypes, in, 'oestrogen-receptor-positive', breast, cancer, are]), verbo([associated]), complemento([with, specific, patterns, of, somatic, mutations, that, map, into, cellular, pathways, linked, to, tumour, 'biology,', but, most, recurrent, mutations, are, relatively, infrequent])].
[sujeto(['Prospective', clinical, trials, based, on, these, findings, will]), verbo([require]), complemento([comprehensive, genome, sequencing])].
[sujeto(['In', this, 'report,', we]), verbo([have]), complemento([investigated, the, relationship, between, androgen, levels, and, prostate, tumorigenesis, in, 'Nkx3'])].
[sujeto([',', 7, 'months),', we]), verbo([have]), complemento([found, that, prolonged, exposure, of, 'Nkx3'])].
[sujeto(['We']), verbo([found]), complemento([that, prostate, tumors, from, the, 'Low-T', mutant, mice, share, a, similar, gene, expression, profile, as, 'androgen-independent', prostate, tumors, from, these, mutant, 'mice,', which, includes, the, deregulated, expression, of, several, genes, that, are, 'up-regulated', in, human, 'hormone-refractory', prostate, 'cancer,', such, as, 'Vav3', and, 'Runx1'])].
[sujeto(['We', propose, that, exposure, to, reduced, androgens, may]), verbo([promote]), complemento([prostate, tumorigenesis, by, selecting, for, molecular, events, that, promote, more, 'aggressive,', 'hormone-refractory', tumors])].
[sujeto(['The', 't(8;21)', translocation, is, the, most, widespread, genetic, defect]), verbo([found]), complemento([in, human, acute, myeloid, leukemia])].
[sujeto(['Here', we, show, that, the, local, exon, combinatorics, of, the, 'RUNX1-RUNX1T1', gene, follows, a, 'power-law', behavior, and, '(', 'i)', the, vast, majority, of, exons]), verbo([has]), complemento([a, low, 'ECI,', '(', 'ii)', only, a, small, part, is, represented, by, &, 'quot;exons-hubs&quot;', of, splicing, with, very, high, 'ECI', 'values,', and, '(', 'iii)', it, is, 'scale-free', and, very, sensitive, to, targeted, skipping, of, &, 'quot;exons-hubs&quot;'])].
[sujeto(['Half-life', of, these, transcripts, is]), verbo([increased]), complemento([due, to, the, deregulation, of, some, key, genes, of, the, 'nonsense-mediated', decay, system, in, leukemia, cells])].
[sujeto(['Altogether,', our, results, show, that, alternative, splicing, of, the, 'RUNX1-RUNX1T1', transcripts, follows, strict, rules, and, that, the, 'power-law', component, of, the, fusion, gene, organization]), verbo([confers]), complemento([a, high, flexibility, to, this, process])].
[sujeto(['There']), verbo([has]), complemento([been, considerable, interest, in, identifying, a, 'cis-regulatory', element, that, targets, gene, expression, to, stem, cells])].
[sujeto(['Such', an, 'element,', termed, stem, cell, 'enhancer,', holds, the, promise, of]), verbo([providing]), complemento([important, insights, into, the, transcriptional, programs, responsible, for, inherent, stem, 'cell-specific', properties, such, as, 'self-renewal', capacity])].
[sujeto(['A', series, of, candidate, enhancers]), verbo([have]), complemento([been, identified, for, hematopoietic, stem, cells, '(', 'HSCs)'])].
[sujeto(['Human', 'RUNX1', gene, is, one, of, the, most, frequent]), verbo([target]), complemento([for, chromosomal, translocations, associated, with, acute, myeloid, leukemia, '(', 'AML)', and, acute, lymphoid, leukemia, '(', 'ALL)'])].
[sujeto(['No', homologous, sequences]), verbo([have]), complemento([been, found, at, the, recombination, 'regions;', but, 'DNase', 'I', hypersensitive, sites, '(', 'DHS)', have, been, mapped, to, the, areas, of, the, genes, involved, in, 't(8;21)'])].
[sujeto(['Presence', of, 'DHS', sites, is, commonly]), verbo([associated]), complemento([with, regulatory, elements, such, as, 'promoters,', enhancers, and, 'silencers,', among, others])].
[sujeto(['Our', genomic, analysis, identified, nine]), verbo([conserved]), complemento(['non-coding', sequences, that, are, evolutionarily, conserved, among, 'rat,', mouse, and, human])].
[sujeto(['Our', results, demonstrate, that, the, identified, regions, can, indeed]), verbo([regulate]), complemento([transcription, of, a, reporter, gene, in, a, distance, and, position, independent, 'manner;', 'moreover,', their, transcriptional, effect, is, cell, type, specific])].
[sujeto(['We']), verbo([have]), complemento([identified, nine, conserved, non, coding, sequence, that, are, harbored, in, intron, 5, of, the, 'RUNX1', gene])].
[sujeto(['We']), verbo([have]), complemento([also, demonstrated, that, two, of, these, regions, can, regulate, transcriptional, activity, in, vitro])].
[sujeto(['Taken', together, our, results]), verbo([suggest]), complemento([that, intron, 5, of, the, 'RUNX1', gene, contains, multiple, potential, 'cis-regulatory', elements])].
[sujeto(['In', all, 'vertebrates,', the, 'Runx1', gene, is]), verbo([transcribed]), complemento([from, two, 'promoters:', a, proximal, promoter, '(', 'P2),', and, a, distal, promoter, '(', 'P1)'])].
[sujeto(['We', previously]), verbo([found]), complemento([that, runx1, expression, in, a, specific, hematopoietic, cell, population, in, zebrafish, embryos, depends, on, cohesin])].
[sujeto(['Here', we, show, that, zebrafish, runx1, is, directly]), verbo([bound]), complemento([by, cohesin, and, 'CCCTC', binding, factor, '(', 'CTCF)', at, the, 'P1', and, 'P2', 'promoters,', and, within, the, intron, between, 'P1', and, 'P2'])].
[sujeto(['Cohesin', initiates, expression, of, runx1, in, the, posterior, lateral, mesoderm, and, influences, promoter, 'use,', while, 'CTCF']), verbo([represses]), complemento([its, expression, in, the, newly, emerging, cells, of, the, tail, bud])].
[sujeto(['The', intronic]), verbo([binding]), complemento([sites, for, cohesin, and, 'CTCF', coincide, with, histone, modifications, that, confer, 'enhancer-like', 'properties,', and, two, of, the, 'cohesin/CTCF', sites, behaved, as, insulators, in, an, in, vivo, assay])].
[sujeto(['The', identified, cohesin, and, 'CTCF']), verbo([binding]), complemento([sites, are, likely, to, be, 'cis-regulatory', elements, '(', 'CREs)', for, runx1, since, they, also, recruit, 'RNA', polymerase, 'II', '(', 'RNAPII)'])].
[sujeto(['We', propose, that, cohesin, and, 'CTCF']), verbo([have]), complemento([distinct, functions, in, the, regulation, of, runx1, during, zebrafish, 'embryogenesis,', and, that, these, regulatory, functions, are, likely, to, involve, runx1, intronic, 'CREs'])].
[sujeto(['Cohesin', '(', but, not, 'CTCF)', depletion]), verbo([enhanced]), complemento(['RUNX1', expression, in, a, human, leukemia, cell, 'line,', suggesting, conservation, of, 'RUNX1', regulation, through, evolution])].
[sujeto([1]), verbo([has]), complemento([been, shown, to, cause, a, shift, in, myelomonocytic, progenitor, fate])].
[sujeto(['Such', activity]), verbo([has]), complemento([been, demonstrated, to, be, a, tightly, controlled, mechanism, regulating, a, wide, variety, of, protein, functions, under, both, normal, physiological, and, pathological, conditions])].
[sujeto(['We']), verbo([have]), complemento([previously, reported, that, a, conformational, change, in, 'Runx2', induced, by, 'Pin1', is, essential, for, its, function, in, osteogenesis, in, vitro, and, in, vivo])].
[sujeto(['In', this, 'study,', we, show, that, the, 'Pin1-mediated', conformational, change, in, 'Runx1']), verbo([enhances]), complemento([its, acetylation, and, stabilization, 'and,', 'consequently,', enhances, its, transacting, activity])].
[sujeto(['The']), verbo([increased]), complemento([acetylation, of, 'Runx1', represses, 'PU'])].
[sujeto(['Conversely,', the, lack, of, '(', or, the, inhibition, 'of)', 'Pin1']), verbo([increases]), complemento(['PU'])].
[sujeto(['Pin1', 'KO', mice]), verbo([have]), complemento([an, increased, 'CD11b(+)', /, 'F4/80(+)', cell, population, and, 'F4/80', protein, expression, in, spleen])].
[sujeto(['From', our, 'data,', we, can, conclude, that, the, conformational, change, in, 'Runx1']), verbo([induced]), complemento([by, 'Pin1', represses, 'PU'])].
[sujeto([1, is, a, crucial, factor, in, acute, myeloid, leukemia, '(', 'AML),', and, 'Pin1', may, thus, be, a, useful]), verbo([target]), complemento([for, controlling, 'PU'])].
[sujeto(['The', transcription, factor, 'Runx1', '(', 'AML1)', is, a, central, regulator, of, hematopoiesis, and, is]), verbo([required]), complemento([for, the, formation, of, definitive, hematopoietic, stem, cells, '(', 'HSCs)'])].
[sujeto(['Runx1', is, alternatively]), verbo([expressed]), complemento([from, two, 'promoters:', the, proximal, '(', 'P2)', prevails, during, primitive, 'hematopoiesis,', while, the, distal, '(', 'P1)', dominates, in, definitive, 'HSCs'])].
[sujeto(['Although', some, transcription, factor]), verbo([binding]), complemento([sites, and, 'cis-regulatory', elements, have, been, 'identified,', a, mechanistic, explanation, for, the, alternative, promoter, usage, remains, elusive])].
[sujeto(['In', 'vivo,', we]), verbo([find]), complemento([loss, of, methylation, correlated, with, the, primitive, to, definitive, transition, at, the, 'P1', promoter])].
[sujeto(['In', 'vitro,', 'hypomethylation,', acquisition, of, active, chromatin, 'modifications,', and]), verbo([increased]), complemento([transcriptional, activity, at, 'P1', are, promoted, by, direct, interaction, with, 'HOXB4,', a, transcription, factor, that, confers, definitive, repopulation, status, on, primitive, hematopoietic, progenitors])].
[sujeto(['Despite', such, widespread, 'involvements,', the, relationship, between, 'RUNX1', and, 'MLL']), verbo([has]), complemento([never, been, appreciated])].
[sujeto(['Recently,', we, showed, that, 'RUNX1', physically, and, functionally]), verbo([interacts]), complemento([with, 'MLL,', thereby, regulating, the, epigenetic, status, of, critical, 'cis-regulatory', elements, for, hematopoietic, genes])].
[sujeto(['This', newly, unveiled, interaction, between, the, two, most, prevalent, leukemia, genes]), verbo([has]), complemento([solved, a, 'long-standing', 'conundrum:', 'leukemia-associated', 'RUNX1', 'N-terminal', point, mutants, that, exhibit, no, obvious, functional, abnormalities, in, classical, assays, for, the, assessment, of, transcriptional, activities])].
[sujeto(['These', mutants, turned, out, to, be, defective, in, 'MLL', interaction, and, subsequent, epigenetic, modifications, that, can, be, examined, by, the, 'histone-modification', status, of, 'cis-regulatory', elements, in, the]), verbo([target]), complemento([genes])].
[sujeto(['RUNX1/MLL']), verbo([binding]), complemento([confirms, the, importance, of, 'RUNX1', function, as, an, epigenetic, regulator])].
[sujeto(['These', new, findings, would]), verbo([enhance]), complemento([our, understanding, on, the, mechanistic, basis, for, leukemia, development, and, may, provide, a, novel, direction, for, therapeutic, applications])].
[sujeto(['Overexpression', of, the, brain, and, acute, 'leukemia,', cytoplasmic, '(', 'BAALC)', gene, is, implicated, in, myeloid, leukemogenesis, and]), verbo([associated]), complemento([with, poor, outcome, in, both, acute, myeloid, leukemia, '(', 'AML)', and, acute, lymphoblastic, leukemia, patients])].
[sujeto(['Additionally,', high, 'BAALC', expression, occurs, in, 'glioblastoma,', 'melanoma,', and, childhood, gastrointestinal, stroma, 'tumors,']), verbo([suggesting]), complemento([an, oncogenic, role, for, 'BAALC'])].
[sujeto(['We', show, that, 'BAALC', overexpression, occurs, in, the, presence, of, the, 'T', allele, of, 'SNP', 'rs62527607[GT],', which, creates, a]), verbo([binding]), complemento([site, for, the, activating, 'RUNX1', transcription, factor, in, the, 'BAALC', promoter, region])].
[sujeto(['Thus,', we, identify, a, heritable, genomic, feature, predisposing, to, overexpression, of, an, 'oncogene,', thereby, possibly]), verbo([leading]), complemento([to, enhanced, 'AML', leukemogenesis])].
[sujeto(['Our', findings, further]), verbo([suggest]), complemento([that, genomic, variants, might, become, useful, tools, in, the, practice, of, personalized, medicine])].
[sujeto(['However,', the, 'cis-regulatory', mechanisms]), verbo([modulating]), complemento([the, 'Runx1', gene, expression, remain, to, be, elucidated])].
[sujeto(['Herewith,', we]), verbo([report]), complemento([the, identification, of, an, intronic, 'Runx1', 'enhancer,', 'Runx1', +, 24, mouse, conserved, noncoding, element, '(', 'mCNE),', using, a, combinatorial, in, silico, approach, involving, comparative, genomics, and, retroviral, integration, sites, mapping])].
[sujeto(['The', 'Runx1', +, 24, mCNE, was]), verbo([found]), complemento([to, possess, 'hematopoietic-specific', enhancer, activity, in, both, zebrafish, and, mouse, models])].
[sujeto([1, is, critical, for, multiple, hematopoietic, 'lineages,', but, different, leukocyte, types]), verbo([require]), complemento([strictly, distinct, patterns, of, 'PU'])].
[sujeto([1, is]), verbo([required]), complemento([early, for, 'T-cell', lineage, development, but, then, must, be, repressed, by, a, 'stage-specific', mechanism, correlated, with, commitment])].
[sujeto(['Other', lineages]), verbo([require]), complemento(['steady,', low, expression, or, upregulation])].
[sujeto(['However,', the, 'URE', is, dispensable, for, most, 'Sfpi1', downregulation, in, early, 'T', 'cells,', and, we, show, that, it]), verbo([retains]), complemento([enhancer, activity, in, immature, 'T-lineage', cells, even, where, endogenous, 'Sfpi1', is, repressed])].
[sujeto(['We', now, present, evidence, for, another, complex, of]), verbo([conserved]), complemento([noncoding, elements, that, mediate, 'discrete,', 'cell-type-specific', regulatory, features, of, 'Sfpi1,', including, a, myeloid, 'cell-specific', activating, element, and, a, 'separate,', 'pro-T-cell-specific', silencer, element])].
[sujeto(['T-cell-specific', repression]), verbo([requires]), complemento(['Runx1', acting, through, multiple, nonconsensus, sites, in, the, silencer, core])].
[sujeto(['These', newly, characterized, sites]), verbo([recruit]), complemento(['Runx1', binding, in, early, 'T', cells, in, vivo, and, define, a, functionally, specific, scaffold, for, 'dose-dependent,', 'Runx-mediated', repression])].
[sujeto(['The', 'Eight-Twenty-One', '(', 'ETO)']), verbo([nuclear]), complemento(['co-repressor', gene, belongs, to, the, 'ETO', homologue, family, also, containing, 'Myeloid', 'Translocation', 'Gene', on, chromosome, 16, '(', 'MTG16)', and, myeloid, translocation, 'Gene-Related', protein, 1, '(', 'MTGR1)'])].
[sujeto(['Normal', functions, of, 'ETO', homologues]), verbo([have]), complemento([as, yet, not, been, examined])].
[sujeto(['Strong', 'ETO', promoter, activity, was, specifically, observed, upon, transfection, of, a, promoter, reporter, construct, into, 'erythroid/megakaryocytic', 'cells,', which]), verbo([have]), complemento([endogeneous, 'ETO', gene, activity])].
[sujeto(['An', evolutionary]), verbo([conserved]), complemento([region, of, 228, bp, revealed, potential, 'cis-elements', involved, in, transcription, of, 'ETO'])].
[sujeto(['Disruption', of, the, evolutionary]), verbo([conserved]), complemento(['GATA', -, 636, consensus, binding, site, repressed, transactivation, and, disruption, of, the, 'ETS1', -, 705, consensus, binding, site, enhanced, activity, of, the, 'ETO', promoter])].
[sujeto(['The', promoter, was]), verbo([stimulated]), complemento([by, overexpression, of, 'GATA-1', into, 'erythroid/megakaryocytic', cells])].
[sujeto(['Electrophoretic', mobility, shift, assay, with, 'erythroid/megakaryocytic', cells, showed, specific]), verbo([binding]), complemento([of, 'GATA-1', to, the, 'GATA', -, 636, site])].
[sujeto(['Furthermore,', results, from, chromatin, immunoprecipitation, showed, 'GATA-1']), verbo([binding]), complemento([in, vivo, to, the, conserved, region, of, the, 'ETO', promoter, containing, the, -, 636, site])].
[sujeto(['The', results]), verbo([suggest]), complemento([that, the, 'GATA', -, 636, site, may, have, a, role, in, activation, of, the, 'ETO', gene, activity, in, cells, with, 'erythroid/megakaryocytic', potential])].
[sujeto(['Leukemia']), verbo([associated]), complemento(['AML1-ETO', strongly, suppressed, an, 'ETO', promoter, reporter, in, 'erythroid/megakaryocytic', cells])].
[sujeto(['We', demonstrate, that, the, 'GATA-1', transcription, factor]), verbo([binds]), complemento([and, transactivates, the, 'ETO', proximal, promoter, in, an, 'erythroid/megakaryocytic-specific', manner])].
[sujeto(['G2', accumulation, '(', 'G2A)', is, a, 'G-protein', coupled, 'receptor,']), verbo([activated]), complemento([by, several, ligands, and, 'stimuli,', such, as, lysophosphatidylcholine, '(', 'LPC),', extracellular, low, pH, and, oxidized, phospholipids, including, 9, -, and, 13, -, hydroxyoctadecadienoic, 'acid,', and, has, been, implicated, in, mediating, inflammatory, process, under, oxidative, conditions])].
[sujeto(['In', the, course, of, the, 'analysis,', we]), verbo([found]), complemento([that, two, transcriptional, 'variants,', 'hG2A-a', and, -, 'b,', are, produced, by, alternative, 'splicing,', resulting, in, the, production, of, 'N-terminal', different, hG2A, proteins, with, similar, sensitivity, to, low, pH, and, 'LPC'])].
[sujeto(['Using', a, monocytic, cell, line, 'THP-1', as, a, 'model,', transcription, of, hG2A, was, precisely, 'examined,', and, we, demonstrated, that, it, is, dependent, both, on, the, chromatin, structure, around, 'TSS,', and, on, the]), verbo([binding]), complemento([of, the, transcription, factors, '(', 'c/EBPalpha', and, 'beta,', 'Runx1', and, 'Pu'])].
[sujeto(['However,', the, molecular, mechanisms]), verbo([regulating]), complemento([first, the, priming, and, then, maintenance, of, gene, expression, within, one, developmental, pathway, are, essentially, unknown])].
[sujeto(['The', hematopoietic, system, represents, a, powerful, experimental, model, to, address, these, questions, and, here, we]), verbo([have]), complemento([focused, on, a, regulatory, circuit, playing, a, central, role, in, 'myelopoiesis:', the, transcription, factor, 'PU'])].
[sujeto([1, ',', its]), verbo([target]), complemento([gene, 'colony-stimulating-factor', 1, receptor, '(', 'Csf1r),', and, key, upstream, regulators, such, as, 'RUNX1'])].
[sujeto(['We']), verbo([find]), complemento([that, during, 'ontogeny,', chromatin, unfolding, precedes, the, establishment, of, active, histone, marks, and, the, formation, of, stable, transcription, factor, complexes, at, the, 'Pu'])].
[sujeto([1, locus, and, we, show, that, chromatin, remodeling, is]), verbo([mediated]), complemento([by, the, transient, binding, of, 'RUNX1', to, 'Pu'])].
[sujeto(['By', 'contrast,', chromatin, reorganization, of, 'Csf1r']), verbo([requires]), complemento([prior, expression, of, 'PU'])].
[sujeto(['Once', the, full, hematopoietic, program, is, 'established,', stable, transcription, factor, complexes, and, active, chromatin, can, be]), verbo([maintained]), complemento([without, 'RUNX1'])].
[sujeto(['Recently,', we, identified, the, 'Runx1', +, 23, enhancer, that]), verbo([targets]), complemento([reporter, gene, expression, to, the, first, emerging, 'HSCs', of, the, mouse, embryo, when, linked, to, the, heterologous, hsp68, promoter])].
[sujeto(['Endogenous', 'Runx1', is]), verbo([transcribed]), complemento([from, 2, alternative, 'promoters,', 'P1', and, 'P2'])].
[sujeto(['Here,', we, examined, the, in, vivo, 'cis-regulatory', potential, of, these, alternative, promoters, and, asked, whether, they]), verbo([act]), complemento([with, and, contribute, to, the, spatiotemporal, specific, expression, of, the, 'Runx1', +, 23, enhancer])].
[sujeto(['Our', results, firmly, establish, 'that,', in, contrast, to, zebrafish, 'runx1,', mouse, 'Runx1', promoter, sequences, do, not]), verbo([confer]), complemento([any, hematopoietic, specificity, in, transgenic, embryos])].
[sujeto(['Yet,', both, mouse, promoters]), verbo([act]), complemento([with, the, +, 23, enhancer, to, drive, reporter, gene, expression, to, sites, of, 'HSC', emergence, and, 'colonization,', in, a, +, 23, -, specific, pattern])].
[sujeto(['The', 'Runt', homology, domain, '(', 'Runx)', defines, a, metazoan, family, of, 'sequence-specific', transcriptional, regulatory, proteins, that, are, critical, for, animal, development, and, causally]), verbo([associated]), complemento([with, a, variety, of, mammalian, cancers])].
[sujeto(['The']), verbo([sea]), complemento([urchin, 'Runx', gene, 'SpRunt-1', is, expressed, throughout, the, blastula, stage, 'embryo,', and, is, required, globally, during, embryogenesis, for, cell, survival, and, differentiation])].
[sujeto(['Depletion', of, 'SpRunt-1', by, morpholino, 'antisense-mediated', knockdown]), verbo([causes]), complemento([a, blastula, stage, deficit, in, cell, 'proliferation,', as, shown, by, bromodeoxyuridine, '(', 'BrdU)', incorporation, and, direct, cell, counts])].
[sujeto(['Chromatin', immunoprecipitation, '(', 'ChIP)', indicates, that, 'Runx']), verbo([target]), complemento([sites, within, 5, '\'', sequences, flanking, 'cyclinD,', wnt6, and, wnt8, are, directly, bound, by, 'SpRunt-1', protein, at, late, blastula, stage])].
[sujeto(['Furthermore,', experiments, using, a, green, fluorescent, protein, '(', 'GFP)', reporter, transgene, show, that, the, 'blastula-stage', operation, of, a, 'cis-regulatory', module, previously, shown, to, be]), verbo([required]), complemento([for, wnt8, expression, '(', 'Minokawa', et, al])].
[sujeto(['Finally,', inhibitor, studies, and, immunoblot, analysis, show, that, 'SpRunt-1', protein, levels, are, negatively]), verbo([regulated]), complemento([by, glycogen, synthase, kinase, '(', 'GSK)-3'])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'Runx', expression, and, 'Wnt', signaling, are, mutually, linked, in, a, feedback, circuit, that, controls, cell, proliferation, during, development])].
[sujeto(['The', transcription, factor, 'Runx1/AML1', is, an, important, regulator, of, hematopoiesis, and, is, critically]), verbo([required]), complemento([for, the, generation, of, the, first, definitive, hematopoietic, stem, cells, '(', 'HSCs)', in, the, major, vasculature, of, the, mouse, embryo])].
[sujeto(['In', this, 'study,', we, used, a, combination, of, comparative, genomics, and, chromatin, analysis, to, identify, a, highly]), verbo([conserved]), complemento([531, -, bp, enhancer, located, at, position, +, 23.5, in, the, first, intron, of, the, 224, -, kb, mouse, 'Runx1', gene])].
[sujeto(['Transcription', factor]), verbo([binding]), complemento([in, vivo, and, analysis, of, the, mutated, enhancer, in, transient, transgenic, mouse, embryos, implicate, 'Gata2', and, 'Ets', proteins, as, critical, factors, for, its, function])].
[sujeto(['We', also, show, that, the, 'SCL/Lmo2/Ldb-1', complex, is]), verbo([recruited]), complemento([to, the, enhancer, in, vivo])].
[sujeto(['Importantly,', transplantation, experiments, demonstrate, that, the, intronic, 'Runx1', enhancer]), verbo([targets]), complemento([all, definitive, 'HSCs', in, the, mouse, 'embryo,', suggesting, that, it, functions, as, a, crucial, 'cis-regulatory', element, that, integrates, the, 'Gata,', 'Ets,', and, 'SCL', transcriptional, networks, to, initiate, 'HSC', generation])].
[sujeto([1, is]), verbo([activated]), complemento([in, hematopoietic, stem, cells, and, is, expressed, in, mast, 'cells,', 'B', 'cells,', 'granulocytes,', and, macrophages, but, is, switched, off, in, 'T', cells])].
[sujeto(['Many', of, the, transcription, factors]), verbo([regulating]), complemento(['Pu'])].
[sujeto([1]), verbo([have]), complemento([been, 'identified,', but, little, is, known, about, how, they, organize, 'Pu'])].
[sujeto([1, was]), verbo([bound]), complemento([by, a, set, of, transcription, factors, different, from, that, in, myeloid, cells, and, adopted, alternative, chromatin, architectures])].
[sujeto([1, chromatin, at, the, 'URE', was, open, and, the, same, transcription, factor]), verbo([binding]), complemento([sites, were, occupied, as, in, 'B', cells])].
[sujeto(['The', transcription, factor, 'RUNX1', was]), verbo([bound]), complemento([to, the, 'URE', in, precursor, 'cells,', but, binding, was, 'down-regulated', in, maturing, cells])].
[sujeto([1, -]), verbo([expressing]), complemento([cells])].
[sujeto(['Our', results]), verbo([provide]), complemento([important, insights, into, how, 'overlapping,', but, 'different,', sets, of, transcription, factors, program, 'tissue-specific', chromatin, structures, in, the, hematopoietic, system])].
[sujeto(['Mutations', in, mouse, and, human, 'Nfe2,', 'Fli1', and, 'Runx1']), verbo([cause]), complemento([thrombocytopenia])].
[sujeto(['Enhancers', with, 'H3K4me2-marked', nucleosome, pairs, were, most, enriched, for, 'NF-E2,', 'FLI', and, 'RUNX', sequence, 'motifs,']), verbo([suggesting]), complemento([that, this, 'TF', triad, controls, much, of, the, late, 'MK', program])].
[sujeto(['ChIP-seq', revealed, 'NF-E2', occupancy, near, previously, implicated]), verbo([target]), complemento(['genes,', whose, expression, is, compromised, in, 'Nfe2-null', 'cells,', and, many, other, genes, that, become, active, late, in, 'MK', differentiation])].
[sujeto(['FLI', and, 'RUNX', were, also, the, motifs, most, enriched, near, 'NF-E2']), verbo([binding]), complemento([sites, and, 'ChIP-seq', implicated, 'FLI1', and, 'RUNX1', in, activation, of, late, 'MK,', including, 'NF-E2-dependent,', genes])].
[sujeto(['Histones', showed, limited, activation, in, regions, of, single, 'TF', 'binding,', while, enhancers, that]), verbo([bind]), complemento(['NF-E2', and, either, 'RUNX1,', 'FLI1', or, both, 'TFs', gave, the, highest, signals, for, 'TF', occupancy, and, 'H3K4me2;', these, enhancers, associated, best, with, genes, activated, late, in, 'MK', maturation])].
[sujeto(['These', findings]), verbo([provide]), complemento([a, rich, dataset, of, 'TF', and, chromatin, dynamics, in, primary, 'MK', and, explain, why, individual, 'TF', losses, cause, thrombopocytopenia])].
[sujeto(['CCR3', is, a, chemokine, receptor, that]), verbo([mediates]), complemento([the, accumulation, of, allergic, inflammatory, 'cells,', including, eosinophils, and, 'Th2', 'cells,', at, inflamed, sites])].
[sujeto([1, on, transcription, of, the, gene, in, 'EoL-1', eosinophilic, cells, and, 'Jurkat', 'T', 'cells,', both, of, which]), verbo([expressed]), complemento([functional, surface, 'CCR3', and, these, two, transcription, factors])].
[sujeto([1, siRNA, resulted, in, a, modest]), verbo([decrease]), complemento([in, 'CCR3', reporter, activity, in, both, cell, 'types,', compared, with, transfection, of, 'GATA-1', siRNA])].
[sujeto(['Cotransfection', of, the, two, siRNAs]), verbo([led]), complemento([to, inhibition, in, an, additive, manner])].
[sujeto(['EMSA', analysis, showed, that, 'RUNX1,', in, 'particular,']), verbo([bound]), complemento([to, its, binding, motifs])].
[sujeto([1, -]), verbo([binding]), complemento([sites, exhibited, reduced, reporter, activities])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'RUNX1', and, 'PU'])].
[sujeto([1]), verbo([participate]), complemento([in, transcriptional, regulation, of, the, 'CCR3', gene])].
[sujeto(['Although', at, a, terminal, differentiation, 'stage,', hypertrophic, chondrocytes]), verbo([have]), complemento([been, implicated, as, the, principal, engine, of, bone, growth])].
[sujeto(['Abnormal', chondrocyte, hypertrophy]), verbo([has]), complemento([been, seen, in, many, skeletal, dysplasia, and, osteoarthritis])].
[sujeto(['However,', how, the, type, 'X', collagen, gene, is]), verbo([regulated]), complemento([during, chondrocyte, hypertrophy, has, not, been, fully, elucidated])].
[sujeto(['We']), verbo([have]), complemento([recently, demonstrated, that, 'Runx2', interaction, with, a, 150, -, bp, mouse, 'Col10a1', 'cis-enhancer', is, required, but, not, sufficient, for, its, hypertrophic, 'chondrocyte-specific', reporter, expression, in, transgenic, 'mice,', suggesting, requirement, of, additional, 'Col10a1', regulators])].
[sujeto(['In', this, 'study,', we]), verbo([report]), complemento([in, silico, sequence, analysis, of, this, 150, -, bp, enhancer, and, identification, of, its, multiple, binding, 'factors,', including, 'AP1,', 'MEF2,', 'NFAT,', 'Runx1', and, 'TBX5'])].
[sujeto(['We']), verbo([have]), complemento([also, performed, mass, spectrometry, analysis, and, detected, 'EF1-alpha,', 'Fus,', 'GdF7', and, 'Runx3', as, components, of, the, specific, complex, formed, by, the, 'cis-enhancer', and, nuclear, extracts, from, hypertrophic, 'MCT', '(', mouse, chondrocytes, immortalized, with, large, 'T', 'antigen)', cells, that, express, 'Col10a1', abundantly])].
[sujeto(['Notably,', some, of, the, candidate, genes, are, differentially]), verbo([expressed]), complemento([in, hypertrophic, 'MCT', cells, and, have, been, associated, with, chondrocyte, hypertrophy, and, 'Runx2,', an, indispensible, 'Col10a1', regulator])].
[sujeto(['We', identified, a, 'robust,', 'genome-wide', mechanism, of, 'MEG-specific', lineage, priming, by, a, previously, described, 'stem/progenitor', 'cell-expressed', transcription, factor, heptad, '(', 'GATA2,', 'LYL1,', 'TAL1,', 'FLI1,', 'ERG,', 'RUNX1,', 'LMO2)']), verbo([binding]), complemento([to, 'MEG-associated', 'cis-regulatory', modules, '(', 'CRMs)', in, multipotential, progenitors])].
[sujeto(['This', is, followed, by, 'genome-wide', 'GATA', factor, switching, that]), verbo([mediates]), complemento([further, induction, of, 'MEG-specific', genes, following, lineage, commitment])].
[sujeto(['Our', findings]), verbo([reveal]), complemento([important, new, insights, into, how, 'ERY', and, 'MEG', lineages, arise, from, a, common, bipotential, progenitor, via, overlapping, and, divergent, functions, of, shared, hematopoietic, transcription, factors])].
[sujeto(['During', the, last, 'decades,', many, studies]), verbo([have]), complemento([investigated, the, transcriptional, and, epigenetic, regulation, of, lineage, decision, in, the, hematopoietic, system])].
[sujeto(['These', efforts]), verbo([led]), complemento([to, a, model, in, which, extrinsic, signals, and, intrinsic, cues, establish, a, permissive, chromatin, context, upon, which, a, regulatory, network, of, transcription, factors, and, epigenetic, modifiers, act, to, guide, the, differentiation, of, hematopoietic, lineages])].
[sujeto(['These', networks, include, 'lineage-specific', factors, that, further, modify, the, epigenetic, landscape, and]), verbo([promote]), complemento([the, generation, of, specific, cell, types])].
[sujeto(['The', process, of, 'B', lymphopoiesis]), verbo([requires]), complemento([a, set, of, transcription, 'factors,', including, 'Ikaros,', 'PU'])].
[sujeto(['The', expression, of, 'EBF1', is, initiated, by, the, combined, action, of, 'E2A', and, 'FoxO1,', and, it, is, further]), verbo([enhanced]), complemento([and, maintained, by, several, positive, feedback, loops, that, include, 'Pax-5', and, 'IL-7', signaling])].
[sujeto(['EBF1']), verbo([acts]), complemento([in, concert, with, 'Ikaros,', 'PU'])].
[sujeto(['EBF1', and, 'Pax-5', also, collaborate, to]), verbo([repress]), complemento([alternative, cell, fates, and, lock, cells, into, the, 'B-lineage', fate])].
[sujeto(['In', addition, to, the, functions, of, 'EBF1', in, establishing, and]), verbo([maintaining]), complemento(['B-cell', 'identity,', 'EBF1', is, required, to, coordinate, differentiation, with, cell, proliferation, and, survival])].
[sujeto(['Through', the, use, of, alternative, promoters, 'and/or', alternative, 'splicing,', each, of, the, elephant, shark, 'Runx', genes]), verbo([expresses]), complemento([multiple, isoforms, similar, to, their, orthologs, in, human, and, other, bony, vertebrates])].
[sujeto(['The', syntenic, blocks, of, genes, at, the, elephant, shark, 'Runx', gene, loci, are, highly]), verbo([conserved]), complemento([in, 'human,', but, represented, by, shorter, conserved, blocks, in, zebrafish, indicating, a, higher, degree, of, rearrangements, in, this, teleost, fish])].
[sujeto(['Analysis', of, promoter, regions, revealed, conservation, of]), verbo([binding]), complemento([sites, for, transcription, 'factors,', including, two, tandem, binding, sites, for, 'Runx', that, are, totally, conserved, in, the, distal, promoter, regions, of, elephant, shark, 'Runx1-3'])].
[sujeto(['Several']), verbo([conserved]), complemento([noncoding, elements, '(', 'CNEs),', which, are, putative, 'cis-regulatory', 'elements,', and, miRNA, binding, sites, were, identified, in, the, elephant, shark, and, human, 'Runx', gene, loci])].
[sujeto(['Some', of, these, 'CNEs', and, miRNA]), verbo([binding]), complemento([sites, are, absent, in, teleost, fishes, such, as, zebrafish, and, fugu])].
[sujeto(['In', 'summary,', our, analysis]), verbo([reveals]), complemento([that, the, genomic, organization, and, expression, profiles, of, 'Runx', genes, were, already, complex, in, the, common, ancestor, of, jawed, vertebrates])].
[sujeto(['MicroRNAs', '(', 'miRs)']), verbo([have]), complemento([emerged, as, critical, modulators, of, immune, 'responses,', but, little, is, known, about, their, transcriptional, regulation, and, tissue, specificity])].
[sujeto(['miR-142', is, specifically]), verbo([expressed]), complemento([in, hematopoietic, tissues, and, plays, an, important, role, in, regulating, immunity])].
[sujeto([1, ',', 'C/EBPβ,', and, 'Runx1', transcription, factor]), verbo([binding]), complemento([sites, are, conserved, and, constitutively, occupied, by, the, respective, transcription, factors, in, the, 'miR-142', gene, promoter, only, in, the, hematopoietic, cells])].
[sujeto(['Furthermore,', 'TLR4', stimulation]), verbo([enhanced]), complemento(['miR-155', whereas, experiments, with, knockdown, and, mimic, expression, of, 'miR-155', demonstrated, that, 'miR-155', negatively, regulates, 'miR-142-3p', expression, by, targeting, 'PU'])].
[sujeto(['Thus,', 'TLR4', stimulation]), verbo([represses]), complemento(['PU'])].
[sujeto([1, ',', resulting, in, downregulation, of, 'miR-142', and]), verbo([increased]), complemento([expression, of, 'IL-6'])].
[sujeto(['These', results, collectively]), verbo([reveal]), complemento([the, direct, 'cis-acting', sequences, of, 'miR-142', specific, promoter, and, that, transcription, factor, 'PU'])].
[sujeto(['The', gene, encoding, the, receptor, for, macrophage, 'colony-stimulating', factor, '(', 'CSF-1R)', is]), verbo([expressed]), complemento([exclusively, in, cells, of, the, myeloid, lineages, as, well, as, trophoblasts])].
[sujeto(['A']), verbo([conserved]), complemento([element, in, the, second, 'intron,', 'Fms-Intronic', 'Regulatory', 'Element', '(', 'FIRE),', is, essential, for, 'macrophage-specific', transcription, of, the, gene])].
[sujeto(['However,', the, molecular, details, of, how, 'FIRE', activity, is]), verbo([regulated]), complemento([and, how, it, impacts, the, 'Csf1r', promoter, have, not, been, characterised])].
[sujeto(['Here', we, show, that, agents, that, 'down-modulate', 'Csf1r', mRNA, transcription]), verbo([regulated]), complemento([promoter, activity, altered, the, occupancy, of, key, 'FIRE', 'cis-acting', elements, including, 'RUNX1,', 'AP1,', and, 'Sp1', binding, sites])].
[sujeto(['We', demonstrate, that, 'FIRE']), verbo([acts]), complemento([as, an, 'anti-sense', promoter, in, macrophages, and, reversal, of, 'FIRE', orientation, within, its, native, context, greatly, reduced, enhancer, activity, in, macrophages])].
[sujeto(['These', results, demonstrate, that, 'FIRE', is, an, 'orientation-specific']), verbo([transcribed]), complemento([enhancer, element])].
[sujeto(['Chromosome', anomalies, were]), verbo([found]), complemento([in, the, 'BM', of, three, 'patients,', without, any, morphological, evidence, of, 'MDS:', 1, ')', an, acquired, complex, rearrangement, of, chromosome, 21, in, a, boy, with, severe, aplastic, anaemia, '(', 'SAA);', the, rearrangement, caused, the, loss, of, exons, 2, -, 8, of, the, 'RUNX1', gene, with, subsequent, hypoexpression])].
[sujeto([2, ')', a, constitutional, complex, rearrangement, of, chromosome, 21, in, a, girl, with, congenital, 'thrombocytopenia;', the, rearrangement]), verbo([led]), complemento([to, 'RUNX1', disruption, and, hypoexpression])].
[sujeto([3, ')', an, acquired, paracentric, inversion, of, chromosome, 1, ',', in, which, two, regions, at, the, breakpoints, were, shown, to, be, 'lost,', in, a, boy, with, aplastic, 'anaemia;', the, 'MPL', 'gene,', localized, in, chromosome, 1, short, arms, was, not, mutated, neither, 'disrupted,', but, its, expression, was, severely, 'reduced:', we, postulate, that, the, aplastic, anaemia, was, due, to, position, effects]), verbo([acting]), complemento([both, in, cis, and, in, 'trans,', and, causing, 'Congenital', 'Amegakaryocytic', 'Thrombocytopenia', '(', 'CAMT)'])].
[sujeto(['The', anomaly, may, be, either, acquired, or, 'constitutional,', and, it, may]), verbo([act]), complemento([by, 'deletion/disruption', of, the, 'gene,', or, by, position, effects])].
[sujeto(['Expression', of, 'AML1', is]), verbo([regulated]), complemento([at, the, level, of, transcription, by, two, 'promoters,', distal, '(', 'D)', and, proximal, '(', 'P),', that, give, rise, to, mRNAs, bearing, two, distinct, 5, '\'', untranslated, regions, '(', 5, '\'', 'UTRs)', '(', 'D-UTR', and, 'P-UTR)'])].
[sujeto(['Here', we, show, that, these, 5, '\'', 'UTRs']), verbo([act]), complemento([as, translation, regulators, in, vivo])].
[sujeto(['Transfections', and, in, vitro, assays, with, bicistronic, constructs, demonstrate, that, the, 'D-UTR']), verbo([mediates]), complemento(['cap-dependent', translation, whereas, the, 'P-UTR', mediates, 'cap-independent', translation, and, contains, a, functional, internal, ribosome, entry, site, '(', 'IRES)'])].
[sujeto(['The', 'IRES-containing', bicistronic, constructs, are, more, active, in, hematopoietic, cell, lines, that, normally]), verbo([express]), complemento([the, 'P-UTR-containing', mRNAs])].
[sujeto(['Furthermore,', we, show, that, the, 'IRES-dependent', translation]), verbo([increases]), complemento([during, megakaryocytic, differentiation, but, not, during, erythroid, 'differentiation,', of, 'K562', cells])].
[sujeto(['These', results, strongly]), verbo([suggest]), complemento([that, the, function, of, the, 'P-UTR', 'IRES-dependent', translation, in, vivo, is, to, tightly, regulate, the, translation, of, 'AML1', mRNAs])].
[sujeto(['The', data, show, that, 'AML1', expression, is]), verbo([regulated]), complemento([through, usage, of, alternative, promoters, coupled, with, 'IRES-mediated', translation, control])].
[sujeto(['Myeloperoxidase', '(', 'MPO)', is, an, important, antibacterial, enzyme]), verbo([found]), complemento([only, in, granulocytes, and, monocytes])].
[sujeto(['The', human, 'MPO', gene, is]), verbo([transcribed]), complemento([early, during, myelogenesis, but, 'MPO', 'RNA', synthesis, ceases, at, the, end, of, the, promyelocyte, stage, of, myeloid, maturation])].
[sujeto([the, enhancer]), verbo([confers]), complemento(['TPA-', or, 'DMSO-responsiveness', upon, either, endogenous, or, exogenous, promoters])].
[sujeto(['Gelshift', competition, and, supershift, experiments, demonstrated, the]), verbo([binding]), complemento([of, the, alpha, subunit, of, the, transcription, factor, 'AML1', to, this, site, in, 'HL-60', cells])].
[sujeto(['ETV6-RUNX1', fusion, '[', 't(12;21)(p13;q22)]', occurs, in, 25, '%', of, childhood, 'B-cell', precursor, acute, lymphoblastic, leukemia, '(', 'BCP-ALL)', and, is]), verbo([associated]), complemento([with, a, favorable, outcome])].
[sujeto(['Additional', abnormalities]), verbo([involving]), complemento(['der(21)t(12;21)', and, nonrearranged, chromosome, 12, are, well, characterized, but, aberrations, involving, the, 'der(12)t(12;21)', have, rarely, been, described])].
[sujeto(['This']), verbo([led]), complemento([to, the, formation, of, the, following, 'chromosome:', 'der(12)(21qter→21q22'])].
[sujeto(['In', 'conclusion,', this, study]), verbo([has]), complemento([defined, novel, abnormalities, in, 'ETV6-RUNX1', 'BCP-ALL,', which, implicate, new, genes, involved, in, leukemogenesis])].
[sujeto(['We', further, demonstrated, that, four, of, these, 'genes,', 'CXCR3,', 'PGDS,', 'GPR98', and, 'CBS,', consistently]), verbo([responded]), complemento([to, cycloleucine, treatment, in, additional, experiments, over, a, range, of, concentrations])].
[sujeto(['We', carried, out, 'gene-specific', 'DNA', methylation, analysis, on, five, 'genes,', including, 'CBS,', and]), verbo([found]), complemento([no, evidence, that, 'DNA', methylation, changes, were, mediating, the, gene, expression, changes, observed])].
[sujeto(['This', indicates, that, apart, from, their, role, in, the, immune, 'response,', it, is, likely, that, these, gene, products, may, also]), verbo([have]), complemento([a, role, to, play, in, the, cellular, response, to, folate, status])].
[sujeto(['The', 'Wnt/β-catenin', signaling, pathway]), verbo([has]), complemento([a, crucial, role, in, embryonic, 'development,', stem, cell, maintenance, and, human, disease])].
[sujeto(['By', screening, a, synthetic, chemical, library, of, lycorine, 'derivatives,', we, identified, 4, -, 'ethyl-5-methyl-5,6-dihydro-[1,3]dioxolo[4,5-j]phenanthridine', '(', 'HLY78)', as, an, activator, of, the, 'Wnt/β-catenin', signaling, 'pathway,', which]), verbo([acts]), complemento([in, a, 'Wnt', 'ligand-dependent', manner])].
[sujeto(['HLY78']), verbo([targets]), complemento([the, 'DIX', domain, of, 'Axin', and, potentiates, the, 'Axin-LRP6', 'association,', thus, promoting, 'LRP6', phosphorylation, and, 'Wnt', signaling, transduction])].
[sujeto(['Moreover,', we, identified, the, critical, residues, on, 'Axin', for, 'HLY78']), verbo([binding]), complemento([and, showed, that, 'HLY78', may, weaken, the, autoinhibition, of, 'Axin'])].
[sujeto(['In', 'addition,', 'HLY78']), verbo([acts]), complemento([synergistically, with, 'Wnt', in, the, embryonic, development, of, zebrafish, and, increases, the, expression, of, the, conserved, hematopoietic, stem, cell, '(', 'HSC)', 'markers,', runx1, and, 'cmyb,', in, zebrafish, embryos])].
[sujeto(['Collectively,', our, study, not, only]), verbo([provides]), complemento([new, insights, into, the, regulation, of, the, 'Wnt/β-catenin', signaling, pathway, by, a, 'Wnt-specific', small, molecule, but, also, will, facilitate, therapeutic, 'applications,', such, as, 'HSC', expansion])].
[sujeto(['Although', 'Hoxa9', and, 'Meis1', can]), verbo([bind]), complemento(['DNA', as, 'heterodimers,', both, can, also, heterodimerize, with, 'Pbx', proteins])].
[sujeto(['Thus,', while, their, coactivation, may, result, from, the, necessity, to]), verbo([bind]), complemento([promoters, as, 'heterodimers,', it, may, also, result, from, the, necessity, of, altering, independent, biochemical, pathways, that, cooperate, to, generate, 'AML,', either, as, monomers, or, as, heterodimers, with, 'Pbx', proteins])].
[sujeto(['Here', we, demonstrate, that, constitutive, expression, of, 'Hoxa9', in, primary, murine, marrow, immortalizes, a, late, myelomonocytic, 'progenitor,']), verbo([preventing]), complemento([it, from, executing, terminal, differentiation, to, granulocytes, or, monocytes, in, the, presence, of, 'granulocyte-macrophage', 'colony-stimulating', factor, '(', 'GM-CSF)', or, 'interleukin-3'])].
[sujeto(['The', 'Hoxa9-immortalized', progenitor, exhibited, a, promyelocytic, transcriptional, 'profile,']), verbo([expressing]), complemento(['PU'])].
[sujeto([1, ',', 'AML1,', 'c-Myb,', 'C/EBP', 'alpha,', and, 'C/EBP', epsilon, as, well, as, their]), verbo([target]), complemento(['genes,', the, receptors, for, 'GM-CSF,', 'G-CSF,', and, 'M-CSF', and, the, primary, granule, proteins, myeloperoxidase, and, neutrophil, elastase])].
[sujeto(['G-CSF', obviated, the, differentiation, block, of, 'Hoxa9,']), verbo([inducing]), complemento([neutrophilic, differentiation, with, accompanying, expression, of, neutrophil, gelatinase, 'B', and, upregulation, of, gp91phox])].
[sujeto(['M-CSF', also, obviated, the, differentiation, 'block,']), verbo([inducing]), complemento([monocytic, differentiation, with, accompanying, expression, of, the, macrophage, 'acetyl-low-density', lipoprotein, scavenger, receptor, and, 'F4/80', antigen])].
[sujeto(['Therefore,', 'Hoxa9', evokes, a, 'cytokine-selective', block, in, differentiation, by, a, mechanism, that, does, not]), verbo([require]), complemento(['Meis', gene, expression, or, interaction, with, 'Pbx', through, the, 'PIM'])].
[sujeto(['The', 't(16;21)(q24;q22)', translocation, is, a, rare, but, recurrent, chromosomal, abnormality]), verbo([associated]), complemento([with, 'therapy-related', myeloid, malignancies, and, a, variant, of, the, 't(8;21)', translocation, in, which, the, 'AML1', gene, on, chromosome, 21, is, rearranged])].
[sujeto(['Here', we]), verbo([report]), complemento([the, molecular, definition, of, this, chromosomal, aberration, in, four, patients])].
[sujeto(['The', 'AML1-CBFbeta', transcription, factor, complex, is, essential, for, the, definitive, hematopoiesis, of, all, lineages, and, is, the, most, frequent]), verbo([target]), complemento([of, chromosomal, rearrangements, in, human, leukemia])].
[sujeto(['In', the, 't(8;21)', translocation]), verbo([associated]), complemento([with, acute, myeloid, leukemia, '(', 'AML),', the, 'AML1(CBFA2/PEBP2alphaB)', gene, is, juxtaposed, to, the, 'MTG8(ETO/CDR)', gene])].
[sujeto(['We', show, here, that, the, resultant, 'AML1-MTG8', gene, product, specifically, and, strongly]), verbo([interacts]), complemento([with, an, 85, -, kDa, phosphoprotein])].
[sujeto(['Comparison', of, amino, acid, sequences, among, 'MTGR1,', 'MTG8,', and, 'Nervy', revealed, four, evolutionarily]), verbo([conserved]), complemento([regions, '(', 'NHR1', to, 'NHR4)'])].
[sujeto(['Ectopic', expression, of, 'AML1-MTG8', in, 'L-G', murine, myeloid, progenitor, cells]), verbo([inhibits]), complemento([differentiation, to, mature, neutrophils, and, induces, cell, proliferation, in, response, to, granulocyte, 'colony-stimulating', factor, '(', 'G-CSF)'])].
[sujeto(['Immunoprecipitation', analysis, indicates, that, this, region, is]), verbo([required]), complemento([for, 'AML1-MTG8', to, form, a, stable, complex, with, 'MTGR1'])].
[sujeto(['Overexpression', of, 'MTGR1']), verbo([stimulates]), complemento(['AML1-MTG8', to, induce, 'G-CSF-dependent', proliferation, of, 'L-G', cells, and, to, interfere, with, 'AML1-dependent', transcription])].
[sujeto(['These', results]), verbo([suggest]), complemento([that, 'AML1-MTG8', could, function, as, a, complex, with, 'MTGR1', and, that, the, complex, might, be, important, in, promoting, leukemogenesis])].
[sujeto(['The', translocation, '(', 8, ;, 21, ')', is, a, chromosome, abnormality]), verbo([associated]), complemento([with, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['In', this]), verbo([report]), complemento([we, demonstrate, the, use, of, a, highly, specific, 'dual-colour', 'FISH', method, for, the, detection, of, 't(8;21)', on, interphase, cells])].
[sujeto(['AML1,', a, gene, encoding, a, protein, of, the, 'PEBP2/CBF', family, of, transcription, factors, is, disrupted, by, translocations]), verbo([associated]), complemento([with, human, leukemia])].
[sujeto(['In', the, 't(8;21)', acute, myelogenous, leukemia, '(', 'AML),', 'AML1', was]), verbo([found]), complemento([fused, to, a, gene, on, chromosome, 8, that, we, designated, 'CDR', '(', also, known, as, 'ETO', and, 'MTG8)'])].
[sujeto(['Signals', were]), verbo([found]), complemento([in, group, 1, on, chromosomes, 21, and, 21, 'q+,', in, group, 2, on, chromosomes, 21, ',', 21, 'q+', and, 8, 'q-', and, in, group, 3, on, chromosomes, 21, and, 8, 'q-'])].
[sujeto(['Thus', regardless, of, the, heterogeneity]), verbo([suggested]), complemento([by, 'FISH,', all, the, breakpoints, in, the, 'AML1', gene, were, clustered, in, the, same, intro, between, exons, 5, and, 6])].
[sujeto(['AML1', contains, a, region, of, sequence, homology, to, the, 'Drosophila', runt, gene, and, the, mouse, polyomavirus, enhancer]), verbo([binding]), complemento([protein, 'PEBP2', alpha, gene])].
[sujeto(['Deletion', of, the, long, arm, of, chromosome, 9, ',', 'del(9q),', is, a, recurring, chromosomal, aberration, in, acute, myeloid, leukemia, '(', 'AML)', that, is, frequently]), verbo([associated]), complemento([with, 't(8;21)'])].
[sujeto(['We']), verbo([found]), complemento([no, homozygous, loss, at, any, locus, tested])].
[sujeto(['The', results, of, our, studies, are, consistent, with, a, model, of, tumor, suppression]), verbo([mediated]), complemento([by, haploinsufficiency, of, critical, genes, in, 'del(9q)', 'AML'])].
[sujeto(['Tumor', cells, xenografted, could, not, be]), verbo([found]), complemento([in, other, tissues, than, in, inoculation, 'area,', and, still, harbored, the, specific, 't(8;21)', and, 'AML1-ETO', fusion, gene])].
[sujeto(['The', expression, of, 'CD11b', and, 'CD13', antigen, of, the, tumor, cells, was]), verbo([increased]), complemento([in, xenografted, mice, model, treated, with, 'PB', when, compared, with, the, control, \, '[', '(', 12.08, +, /, -, 1.02, ')', '%', and, '(', 54.91, +, /, -, 2.72, ')', '%', \, ']', ',', respectively, '(', 'P', &, 'lt;', 0.01, ')', ',', and, tumor, cells, showed, a, cell, cycle, arrest, with, increased, 'G(0)/G(1)-phase', cells, and, decreased, 'S-phase', cells])].
[sujeto(['PB']), verbo([inhibited]), complemento([the, growth, of, 'Kasumi-1', xenograft, tumor, by, inducing, tumor, cell, apoptosis, and, 'differentiation,', and, suppressing, its, angiogenesis, in, vivo])].
[sujeto([5, -, 'Aza-CdR', could, significantly]), verbo([enhance]), complemento([the, antitumor, activity, of, 'PB'])].
[sujeto(['A', 'proto-oncogene,', 'MTG8', '(', 'ETO/CDR),', is, disrupted, in, the, 't(8;21)', translocation]), verbo([associated]), complemento([with, acute, myeloid, 'leukemia,', and, the, gene, 'product,', 'MTG8,', is, a, phosphoprotein, capable, of, cell, transformation, in, concert, with, 'v-H-ras'])].
[sujeto(['To', obtain, insight, into, functional, regulation, of, 'MTG8', by, 'phosphorylation,', we, studied, protein, kinases, that]), verbo([interact]), complemento(['with,', and, 'phosphorylate,', 'MTG8', in, vitro])].
[sujeto(['Recombinant', 'MTG8', protein, was, first]), verbo([found]), complemento([to, be, associated, with, two, 'serine/threonine', protein, kinases, in, cell, extracts, from, both, 'HEL', cells, and, a, leukemic, cell, line, carrying, 't(8;21)'])].
[sujeto(['A', cytoplasmic, protein, kinase, of, 61, kDa, '(', 'MTG8N-kinase)']), verbo([phosphorylated]), complemento([the, 'amino-terminal', of, 'MTG8,', and, another, of, 52, kDa, '(', 'MTG8C-kinase)', phosphorylated, the, 'carboxyl-terminal', domain])].
[sujeto(['In', 'addition,', we, demonstrated, that, heat, shock, protein, 90, '(', 'HSP90)', specifically]), verbo([binds]), complemento([to, the, 'amino-terminal', domain, of, 'MTG8', in, vitro, and, in, vivo])].
[sujeto(['The', 't(8;21)', translocation]), verbo([associated]), complemento([with, acute, myeloid, leukemia, '(', 'AML)', disrupts, two, 'genes,', the, 'AML1', gene, also, known, as, the, core, binding, factor, 'A2', '(', 'CBFA2)', on, chromosome, 21, ',', and, a, gene, on, chromosome, 8, ',', hereafter, referred, to, as, 'MTG8,', but, also, known, as, 'CDR', and, 'ETO'])].
[sujeto(['Extensive', information, is, available, on, 'AML1,', a, member, of, the, 'CBF', family, of, transcription, 'factors,', containing, a, highly]), verbo([conserved]), complemento(['domain,', the, runt, 'box,', of, the, 'Drosophila', segmentation, gene, runt])].
[sujeto(['This', gene, is, essential, for, the, hematopoietic, development, and, is]), verbo([found]), complemento([disrupted, in, several, leukemias])].
[sujeto(['In', 'addition,', we]), verbo([found]), complemento([a, region, encompassing, aa, 443, -, 514, predicted, to, have, a, significant, propensity, to, form, coiled, coil, structures])].
[sujeto(['MTG8', displays, a, high, degree, of, similarity, with, 'nervy,', a, homeotic]), verbo([target]), complemento([gene, of, 'Drosophila,', expressed, in, the, nervous, system])].
[sujeto(['Human', and, mouse, 'wild-type', 'MTG8', are, also, highly]), verbo([expressed]), complemento([in, brain, relative, to, other, tissues])].
[sujeto(['Immunohistochemical', experiments, in, a, 12.5, -, 'day-old', mouse, embryo, clearly, showed, that, the, protein, was]), verbo([expressed]), complemento([in, the, neural, cells, of, the, developing, brain, and, the, spinal, cord])].
[sujeto(['In', primary, cultures, of, hippocampal, neurons, of, 2, -, 3, 'day-old', 'mice,', 'MTG8', was]), verbo([found]), complemento([in, the, 'nucleus,', in, the, cytoplasm, and, as, fine, granules, in, the, neurites])].
[sujeto(['The', evidence, of, 'MTG8', in, the, nucleus, and, cytoplasm, of, neural, cells]), verbo([suggests]), complemento([a, specific, mechanism, regulating, the, subcellular, localization, of, the, protein])].
[sujeto(['In', the, translocation, '(', 8, ;, 21, ')', '(', 'q22;q22)']), verbo([associated]), complemento([with, acute, myelogenous, leukemia, '(', 'AML),', part, of, the, long, arm, of, chromosome, 8, is, reciprocally, translocated, onto, chromosome, 21])].
[sujeto(['To', isolate, fusion, transcripts, of, 'AML1,', and, an, as, yet, unidentified, gene, on, chromosome, 8]), verbo([involved]), complemento([in, the, 'rearrangement,', we, used, rapid, amplification, of, cDNA, ends, '(', 'RACE)', and, primers, for, 'AML1', exons, 5, and, 6])].
[sujeto(['A', fusion, transcript, was, identified, by, 3, '\'', 'RACE', in, the, 'RNA', of, 't(8;21)', leukemic, cells, that, also]), verbo([express]), complemento([multiple, normal, 'AML1', transcripts])].
[sujeto(['This']), verbo([finding]), complemento([makes, it, possible, to, detect, the, translocation, at, the, molecular, 'level,', thus, improving, the, diagnosis, and, monitoring, of, the, disease, in, leukemic, patients])].
[sujeto(['It']), verbo([has]), complemento([been, demonstrated, that, 'KRAS', mutations, represent, about, 90, '%', of, 'cancer-associated', 'mutations,', and, that, 'KRAS', mutations, play, an, essential, role, in, neoplastic, transformation])].
[sujeto(['Cancer-associated', 'RAS', mutations, occur, frequently, in, acute, myeloid, leukemia, '(', 'AML),']), verbo([suggesting]), complemento([a, functional, role, for, 'Ras', in, leukemogenesis])].
[sujeto(['The', phosphorylation, of, 'MEK/ERK', was, significantly]), verbo([enhanced]), complemento([in, the, 'AML1/ETO', +, 'Kras', group])].
[sujeto(['The', similar, results, of, the, 'AML1/ETO', +, 'Nras', group, were, consistent, with, those]), verbo([reported]), complemento([previously])].
[sujeto(['Co-transduction', of, 'Kras(G12D)', and, 'AML1/ETO']), verbo([induces]), complemento([acute, monoblastic, leukemia])].
[sujeto(['Since', expression, of, mutant, 'K-ras', alone, was, insufficient, to]), verbo([induce]), complemento(['leukemia,', this, model, may, be, useful, for, investigating, the, 'multi-step', leukemogenesis, model, of, human, leukemia])].
[sujeto(['Acute', leukemia, is, the, most, common, malignancy, in, 'children,', being, mostly, produced, by, such, chromosomal, abnormalities, as, translocations, or, inversions]), verbo([causing]), complemento([gene, fusion])].
[sujeto(['To', detect, three, fusion, genes, that]), verbo([have]), complemento([been, proven, very, important, in, patient, 'classification:', 't(9:22)p190,', 't(4:11)', and, 't(12:21)'])].
[sujeto(['We']), verbo([found]), complemento(['t(9:22)p190', in, two, 'patients,', 't(4:11)', in, two, patients, and, 't(12:21)', in, one, patient])].
[sujeto(['Day', 33, can, still, be, considered, the, reference, time, in, the, evaluation, of, treatment, 'response;', patients, with, 'BCR-ABL', seem, to]), verbo([have]), complemento([a, worse, prognosis, than, those, who, do, not, have, this, translocation])].
[sujeto(['A', complex, 120, -, base, pair, 'enhancer,', derived, from, the, mouse, 'sex-limited', protein, '(', 'Slp)', 'gene,', is]), verbo([activated]), complemento([solely, by, the, androgen, receptor, '(', 'AR)', in, specific, 'tissues,', although, it, contains, a, hormone, response, element, recognized, by, several, steroid, receptors])].
[sujeto(['The', generation, of, this, transcriptional, specificity]), verbo([has]), complemento([been, ascribed, to, the, interactions, of, the, receptor, with, 'tissue-specific', nonreceptor, factors, bound, to, accessory, sites, within, the, enhancer])].
[sujeto(['Protein-DNA', interaction, assays, revealed, two, factors]), verbo([binding]), complemento([the, 5, '\'', part, of, the, enhancer, that, differ, widely, in, abundance, between, cells, showing, 'AR-specific', activation, of, the, 'Slp', element, compared, with, those, that, also, permit, activation, by, glucocorticoid, receptor, '(', 'GR)'])].
[sujeto(['The', factor, designated, 'B', formed, a, complex, centered, on, the, sequence, 'TGTGGT,', a, core, motif]), verbo([recognized]), complemento([by, members, of, the, 'AML/CBFalpha', transcription, factor, family])].
[sujeto(['This', complex, was, competed, by, a, high, affinity]), verbo([binding]), complemento([site, specific, for, 'AML/CBFalpha', and, was, specifically, supershifted, by, an, antibody, to, 'AML3/CBFalpha1,', placing, factor, 'B', within, the, 'AML3/CBFalpha1', subclass])].
[sujeto(['Interestingly,', this, factor, was, shown, to]), verbo([bind]), complemento([to, a, second, site, in, the, 3, '\'', part, of, the, 'enhancer,', positioned, between, the, two, critical, 'AR', binding, sites])].
[sujeto(['These', data, demonstrate, that, 'AML3/CBFalpha1', is, functionally]), verbo([required]), complemento([for, hormonal, induction, of, the, 'Slp', enhancer, and, that, 'direct,', preferential, 'protein-protein', interactions, may, contribute, to, 'AR-specific', activation])].
[sujeto(['These', results, demonstrate, an, intriguing, role, of, 'AML3/CBFalpha1', in, 'steroid-', as, well, as, 'tissue-specific', activation, of]), verbo([target]), complemento([genes])].
[sujeto(['Overexpression', of, vegf, and, notch, is, sufficient, to]), verbo([induce]), complemento(['HSCs', in, the, tbx16, 'mutant,', despite, a, lack, of, axial, vascular, organization])].
[sujeto(['The', most, proximal, 'HSC', 'mutants,', such, as, 'hdac1,', were]), verbo([found]), complemento([to, have, no, defect, in, vessel, or, artery, formation])].
[sujeto(['Further', analysis, demonstrated, that, hdac1]), verbo([acts]), complemento([downstream, of, 'Notch', signaling, but, upstream, or, in, parallel, to, runx1, to, promote, 'AGM', hematopoiesis])].
[sujeto(['Together,', our, results, establish, a, hierarchy, of, signaling, programs]), verbo([required]), complemento([and, sufficient, for, 'HSC', emergence, in, the, 'AGM'])].
[sujeto(['The', interaction, of]), verbo([nuclear]), complemento([and, mitochondrial, genes, is, an, essential, feature, in, maintenance, of, normal, cellular, function])].
[sujeto(['Of', 82, structural, subunits, that, make, up, the, oxidative, phosphorylation, system, in, the, 'mitochondria,', mitochondrial, 'DNA', '(', 'mtDNA)', encodes, 13, subunits, and, rest, of, the, subunits, are, encoded, by]), verbo([nuclear]), complemento(['DNA'])].
[sujeto(['Mutations', in, mitochondrial, genes, encoding, the, 13, subunits]), verbo([have]), complemento([been, reported, in, a, variety, of, cancers])].
[sujeto(['However,', little, is, known, about, the]), verbo([nuclear]), complemento([response, to, impairment, of, mitochondrial, function, in, human, cells])].
[sujeto(['Our', study]), verbo([suggests]), complemento([that, depletion, of, mtDNA, results, in, oxidative, 'stress,', causing, increased, lipid, peroxidation, in, breast, cancer, cells])].
[sujeto(['Using', a, cDNA, microarray, we, compared, differences, in, the]), verbo([nuclear]), complemento([gene, expression, profile, between, a, breast, cancer, cell, line, '(', parental, 'Rho+)', and, its, 'Rho0', derivative, impaired, in, mitochondrial, function])].
[sujeto(['Expression', of, several]), verbo([nuclear]), complemento([genes, involved, in, cell, 'signaling,', cell, 'architecture,', energy, 'metabolism,', cell, 'growth,', apoptosis, including, general, transcription, factor, 'TFIIH,', 'v-maf,', 'AML1,', was, induced, in, 'Rho0', cells])].
[sujeto(['Mitochondrial', impairment, in, breast, cancer, cells, results, in, altered, expression, of]), verbo([nuclear]), complemento([genes, involved, in, 'signaling,', cellular, 'architecture,', 'metabolism,', cell, growth, and, 'differentiation,', and, apoptosis])].
[sujeto(['These', genes, may]), verbo([mediate]), complemento([the, cross, talk, between, mitochondria, and, the, nucleus])].
[sujeto(['Breast', tissue, is, among, the, most, sensitive, tissues, to, the, carcinogenic, actions, of, ionizing, radiation, and, epidemiological, studies]), verbo([have]), complemento([linked, radiation, exposure, to, breast, cancer])].
[sujeto(['Functional', analysis, of, the, upregulated, genes, mapped, to, cell, proliferation, and, cancer, related, canonical, pathways, such, as, '\'', 'ERK/MAPK', 'signaling\',', '\'', 'CDK5', 'signaling\',', and, '\'', 14, -, 3, -, 3, -]), verbo([mediated]), complemento(['signaling\''])].
[sujeto(['Interestingly,', the, downregulated, genes, mapped, to, fewer, canonical, pathways]), verbo([involved]), complemento([in, cell, proliferation])].
[sujeto(['Results', from, 'qRT-PCR', on, five, selected, differentially]), verbo([expressed]), complemento([genes, confirmed, microarray, data])].
[sujeto(['The', 'PCR', data, on, 'PPP4c,', 'ELF1,', 'MAPK12,', 'PLCG1,', and, 'E2F6', showed, similar, trend, in, up, and, downregulation, as]), verbo([has]), complemento([been, observed, with, the, microarray])].
[sujeto(['Exposure', to, a, clinically, relevant, radiation, dose]), verbo([led]), complemento([to, 'long-term', activation, of, mammary, gland, genes, involved, in, proliferative, and, metabolic, 'pathways,', which, are, known, to, have, roles, in, carcinogenesis])].
[sujeto(['When', considered, along, with, downregulation, of, a, number, of, tumor, suppressor, 'genes,', our, study]), verbo([has]), complemento([implications, for, breast, cancer, initiation, and, progression, after, therapeutic, radiation, exposure])].
[sujeto(['Alteration', of, 'lineage-specific', transcriptional, programs, for, hematopoiesis]), verbo([causes]), complemento([differentiation, block, and, promotes, leukemia, development])].
[sujeto(['AML1/ETO']), verbo([participates]), complemento([in, a, protein, complex, with, the, 'RA', receptor, alpha, '(', 'RARalpha)', at, 'RA', regulatory, regions, on, 'RARbeta2,', which, is, a, key, 'RA', target, gene, mediating, 'RA', 'activity/resistance', in, cells])].
[sujeto(['At', these, 'sites,', 'AML1/ETO']), verbo([recruits]), complemento([histone, 'deacetylase,', 'DNA', 'methyltransferase,', and, 'DNA-methyl-CpG', binding, activities, that, promote, a, repressed, chromatin, conformation])].
[sujeto(['Finally,', 'RARbeta2', is, commonly, silenced, by, hypermethylation, in, primary, 'AML', blasts, but, not, in, normal, hematopoietic, 'precursors,', thus]), verbo([suggesting]), complemento([a, role, for, the, epigenetic, repression, of, the, 'RA', signaling, pathway, in, myeloid, leukemogenesis])].
[sujeto(['Acute', myeloid, leukemia, '(', 'AML)-associated', chromosomal, translocations, result, in, formation, of, chimeric, transcription, 'factors,', such, as, 'PML/RARalpha,', 'PLZF/RARalpha,', and, 'AML-1/ETO,', of, which, the, components, are]), verbo([involved]), complemento([in, regulation, of, transcription, by, chromatin, modeling, through, histone, 'acetylation/deacetylation'])].
[sujeto(['The', leukemic, differentiation, block, is, attributed, to, deregulated, transcription]), verbo([caused]), complemento([by, these, chimeric, fusion, 'proteins,', which, aberrantly, recruit, 'histone-deacetylase', '(', 'HDAC)', activity])].
[sujeto(['In', the, absence, of, 'ligand,', the, transcriptional, activity, of, 'TR', and, 'RAR', is, silenced, by, recruitment, of, 'HDAC', activity, through]), verbo([binding]), complemento([to, corepressors])].
[sujeto(['In', the, presence, of, 'ligand,', 'TR', and, 'RAR']), verbo([activate]), complemento([transcription, by, releasing, 'HDAC', activity, and, by, recruiting, 'histone-acetyltransferase', activity])].
[sujeto(['Here', we]), verbo([report]), complemento([that, 'VDR', binds, corepressors, in, a, 'ligand-dependent', manner, and, that, inhibition, of, 'HDAC', activity, increases, 'VitD(3)', sensitivity, of, 'HL-60', cells])].
[sujeto(['Nevertheless,', the, inhibition, of, 'HDAC', activity, is, unable, to, overcome, the, block, of, 'VitD(3)-induced', differentiation]), verbo([caused]), complemento([by, 'PLZF/RARalpha', expression])].
[sujeto(['Here', we, demonstrate, that, the, expression, of, the, translocation, products, 'PML/RARalpha', and, 'PLZF/RARalpha', impairs, the, localization, of, 'VDR', in, the, nucleus, by]), verbo([binding]), complemento([to, 'VDR'])].
[sujeto(['Furthermore,', the, overexpression, of, 'VDR', in, 'U937', cells]), verbo([expressing]), complemento(['AML-related', translocation, products, completely, abolishes, the, block, of, 'VitD(3)-induced', differentiation])].
[sujeto(['Taken', together, these, data, indicate, that, the, 'AML-associated', translocation, products, block, differentiation, not, only, by, interfering, with, 'chromatin-modeling', but, also, by, sequestering, factors]), verbo([involved]), complemento([in, the, differentiation, signaling, 'pathways,', such, as, 'VDR', in, the, 'VitD(3)-induced', differentiation])].
[sujeto(['The', retinoic, acid, receptors, '(', 'RARs)', 'alpha,', 'beta2,', and, gamma]), verbo([regulate]), complemento([specific, subsets, of, target, genes, during, 'all-trans', retinoic, acid, '(', 'RA)', induced, differentiation, of, 'F9', teratocarcinoma, stem, cells])].
[sujeto(['Our', goal, was, to, analyze, the, 'Tie1', 'gene,', which, encodes, a, surface, receptor, tyrosine, kinase]), verbo([expressed]), complemento([in, the, hematovascular, system])].
[sujeto(['We', showed, that, 'RARgamma,', but, not, 'RARalpha', or, 'RARbeta2,', is]), verbo([required]), complemento([for, 'Tie1', promoter, activation, by, 'RA'])].
[sujeto(['Treatment', with, a, 'RARgamma', selective, agonist, plus, a, retinoid, 'X', receptor, agonist, '(', 'LGD1069)']), verbo([increased]), complemento(['Tie1', mRNA, levels, by, 11, -, +, /, -, 2.5, -, fold, 48, hours, after, 'RA', addition, in, 'F9', 'WT,', but, not, in, 'F9', 'RARgamma-/-', 'cells,', by, quantitative, reverse, transcription, polymerase, chain, reaction])].
[sujeto(['RA']), verbo([increased]), complemento(['GATA4', transcripts, by, 12, -, +, /, -, 1, -, fold, in, 'F9', 'WT', at, 48, 'hours,', but, not, in, 'F9', 'RARgamma-/-', cells])].
[sujeto(['In', 'addition,', transfection, of, a, 'GATA4', expression, vector]), verbo([increased]), complemento(['Tie1', 'promoter/luciferase', activity, in, both, 'RA-treated', 'F9', 'WT', and, 'RARgamma-/-', cells])].
[sujeto(['Tie1', promoter, deletion, analyses, indicated, that, a, region, of, the, promoter, that, possessed, multiple, 'GATA', sites]), verbo([mediated]), complemento([the, 'RA-associated', 'Tie1', transcriptional, increase])].
[sujeto(['The', biological, effects, of, 'all-trans-retinoic', acid, '(', 'RA),', a, major, active, metabolite, of, 'retinol,', are, mainly]), verbo([mediated]), complemento([through, its, interactions, with, retinoic, acid, receptor, '(', 'RARs', 'alpha,', 'beta,', 'gamma)', and, retinoid, 'X', receptor, '(', 'RXRs', 'alpha,', 'beta,', 'gamma)', heterodimers])].
[sujeto(['RAR/RXR', heterodimers]), verbo([activate]), complemento([transcription, by, binding, to, 'RA-response', elements, '(', 'RAREs', or, 'RXREs)', in, the, promoters, of, primary, target, genes])].
[sujeto(['Murine', 'F9', teratocarcinoma, stem, cells]), verbo([have]), complemento([been, widely, used, as, a, model, for, cellular, differentiation, and, 'RA', signaling, during, embryonic, development])].
[sujeto(['We', identified, and, characterized, genes, that, are, differentially]), verbo([expressed]), complemento([in, 'F9', wild, type, '(', 'Wt)', and, 'F9', 'RARgamma-/-', 'cells,', with, and, without, 'RA', 'treatment,', through, the, use, of, 'oligonucleotide-based', microarrays])].
[sujeto(['Our', data, indicate, that, 'RARgamma,', in, the, absence, of, exogenous, 'RA,']), verbo([modulates]), complemento([gene, expression])].
[sujeto(['Other', 'genes,', such, as, 'Runx1,', were]), verbo([expressed]), complemento([at, lower, levels, in, both, 'F9', 'RARbeta2-/-', and, 'RARgamma-/-', cell, lines, than, in, 'F9', 'Wt', and, 'RARalpha-/-'])].
[sujeto(['Genes', specifically]), verbo([induced]), complemento([by, 'RA', at, 6, h, with, the, protein, synthesis, inhibitor, cycloheximide, in, 'F9', 'Wt,', but, not, in, 'RARgamma-/-', 'cells,', included, 'Hoxa3,', 'Hoxa5,', 'Gas1,', 'Cyp26a1,', 'Sfrp2,', 'Fbp2,', and, 'Emp1'])].
[sujeto(['These', genes, represent, specific, primary, 'RARgamma']), verbo([targets]), complemento([in, 'F9', cells])].
[sujeto(['Several', genes, in, the, 'Wnt', signaling, pathway, were]), verbo([regulated]), complemento([by, 'RARgamma'])].
[sujeto(['The', study, revealed, nine, transcription, factors, presenting, enriched, motifs, for, these, gene, 'promoters,', five, of, which, are, implicated, in, cellular, growth, '(', 'ELK1,', 'ELK4,', 'RUNX1,', 'HOX11-CTF1,', 'TAL1-ternary', complex, factor, 3, ')', and, four, in, mitochondrial, biogenesis, '(']), verbo([nuclear]), complemento([respiratory, 'factor-1', '(', 'NRF-1),', 'GABPA,', 'PPARG-RXRA', and, 'estrogen-related', receptor, alpha, '(', 'ESRRA))'])].
[sujeto(['Exploring', the, thyroid, 'tumours,', we]), verbo([found]), complemento([that, 'DAP3', mRNA, and, protein, expression, is, upregulated, in, tumours, presenting, a, mitochondrial, biogenesis, compared, with, the, normal, tissue])].
[sujeto(['DAP3', may]), verbo([participate]), complemento([in, mitochondrial, maintenance, and, play, a, role, in, the, balance, between, mitochondrial, homoeostasis, and, tumourigenesis])].
[sujeto(['Acute', myeloid, leukemia, '(', 'AML),', a, class, of, prevalent, hematopoietic, 'malignancies,', is]), verbo([caused]), complemento([by, the, acquisition, of, gene, mutations, that, confer, deregulated, 'proliferation,', impaired, differentiation, and, a, survival, advantage, of, hematopoietic, progenitors])].
[sujeto(['More', 'recently,', we]), verbo([reported]), complemento([that, cobalt, chloride, '(', 'CoCl(2))/iron', chelator, desferrioxamine, '(', 'DFO)-mimicked', hypoxia, or, moderate, hypoxia, '(', 2, '%', and, 3, '%', 'O(2))', can, directly, trigger, differentiation, of, many, subtypes, of, 'AML', cells])].
[sujeto(['Additionally,', these, 'hypoxia-simulating', agents, selectively]), verbo([stimulate]), complemento([differentiation, in, acute, promyelocytic, leukemic, cells, induced, by, arsenic, 'trioxide,', an, effective, 'second-line', drug, for, this, unique, type, of, leukemia])].
[sujeto(['Furthermore,', 'HIF-1alpha', and, two, hematopoietic, transcription, factors, 'CCAAT/enhancer']), verbo([binding]), complemento([protein, alpha, '(', 'C/EBPalpha)', and, 'Runx1/AML1', interact, directly, with, each, other])].
[sujeto(['Such', interactions]), verbo([increase]), complemento([the, transcriptional, activities, of, 'C/EBPalpha', and, 'Runx1/AML1,', while, 'C/EBPalpha', competes, with, 'HIF-1beta', for, direct, binding, to, 'HIF-1alpha', 'protein,', and, significantly, inhibits, the, 'DNA-binding', ability, of, 'HIF-1'])].
[sujeto(['We']), verbo([found]), complemento([that, 'Tcf7', is, the, most, 'down-regulated', transcription, factor, when, 'CD34+', cells, switch, into, 'CD34-', 'cells,', using, 'RNA-Seq'])].
[sujeto(['We', subsequently, identified, the]), verbo([target]), complemento([genes, bound, by, 'TCF7,', using, 'ChIP-Seq'])].
[sujeto(['We', show, that, 'TCF7', and, 'RUNX1', '(', 'AML1)']), verbo([bind]), complemento([to, each, 'other\'s', promoter, regions, and, that, 'TCF7', is, necessary, for, the, production, of, the, short, 'isoforms,', but, not, the, long, isoforms, of, 'RUNX1,', suggesting, that, 'TCF7', and, the, short, isoforms, of, 'RUNX1', function, coordinately, in, regulation])].
[sujeto(['Tcf7', 'knock-down', experiments, and, 'Gene', 'Set', 'Enrichment', 'Analyses']), verbo([suggest]), complemento([that, 'TCF7', plays, a, dual, role, in, promoting, the, expression, of, genes, characteristic, of, 'self-renewing', 'CD34+', cells, while, repressing, genes, activated, in, partially, differentiated, 'CD34-', state])].
[sujeto(['Using', 'genome-wide', and, functional, 'approaches,', we, investigated, the]), verbo([binding]), complemento(['properties,', transcriptional, role, and, chromatin, environment, of, 'Ets1', during, this, transition])].
[sujeto(['We']), verbo([found]), complemento([that, while, 'Ets1', binding, at, distal, sites, was, associated, with, active, genes, at, both, 'DN', and, 'DP', 'stages,', its, enhancer, activity, was, attained, at, the, 'DP', 'stage,', as, reflected, by, levels, of, the, core, transcriptional, hallmarks, 'H3K4me1/3,', 'RNA', 'Polymerase', 'II', and, eRNA])].
[sujeto(['Coincidentally,', 'Ets1']), verbo([associates]), complemento([more, specifically, with, 'Runx1', in, 'DN', and, with, 'TCF1', in, 'DP', cells])].
[sujeto(['We', also]), verbo([provide]), complemento([evidence, that, 'Ets1', predominantly, binds, distal, 'nucleosome-occupied', regions, in, 'DN', and, 'nucleosome-depleted', regions, in, 'DP'])].
[sujeto(['Finally', and, 'importantly,', we, demonstrate, that, 'Ets1']), verbo([induces]), complemento([chromatin, remodeling, by, displacing, 'H3K4me1-marked', nucleosomes])].
[sujeto(['Our', results, thus]), verbo([provide]), complemento([an, original, model, whereby, the, ability, of, a, transcription, factor, to, bind, nucleosomal, 'DNA', changes, during, differentiation, with, consequences, on, its, cognate, enhancer, activity])].
[sujeto(['LEF/TCFs']), verbo([have]), complemento([a, 'DNA', 'sequence-specific', 'high-mobility', group, '(', 'HMG)', box, that, binds, 'Wnt', response, elements, '(', 'WREs)'])].
[sujeto(['The', &, 'quot;E', 'tail&quot;', isoforms, of, 'TCFs', are, alternatively, spliced, to, include, a, second, 'DNA']), verbo([binding]), complemento([domain, called, the, 'C-clamp'])].
[sujeto(['We', show, that, induction, of, a, dominant, negative, 'C-clamp', version, of, 'TCF1', '(', 'dnTCF1E)']), verbo([induces]), complemento([p21, expression, and, a, stall, in, the, growth, of, 'DLD1', colon, cancer, cells])].
[sujeto(['Induction', of, a, 'C-clamp', mutant, did, not, efficiently]), verbo([induce]), complemento(['p21,', nor, did, it, stall, cell, growth])].
[sujeto(['Microarray', analysis, revealed, that, induction, of, p21, by, 'wild-type', dnTCF1E, '(', 'dnTCF1E(WT))', correlated, with, a]), verbo([decrease]), complemento([in, expression, of, multiple, p21, suppressors, that, act, at, multiple, levels, from, transcription, '(', 'SP5,', 'YAP1,', and, 'RUNX1),', 'RNA', stability, '(', 'MSI2),', and, protein, stability, '(', 'CUL4A)'])].
[sujeto(['We', show, that, the, 'C-clamp', is, a, 'sequence-specific', 'DNA']), verbo([binding]), complemento([domain, that, can, make, contacts, with, 5, '\'', -, 'RCCG-3\'', elements, upstream, or, downstream, of, 'WREs'])].
[sujeto(['The', 'C-clamp-RCCG', interaction, was, critical, for, 'TCF1E-mediated', transcriptional, control, of, 'p21-connected']), verbo([target]), complemento([gene, promoters])].
[sujeto(['Our', results, indicate, that, a, 'rapid-response', 'WNT/p21', circuit, is, driven, by, 'C-clamp']), verbo([target]), complemento([gene, selection])].
[sujeto(['CBFbeta', is, the, 'non-DNA']), verbo([binding]), complemento([subunit, of, the, core, binding, factors, '(', 'CBFs)'])].
[sujeto(['Here', we, show, that, 'CBFbeta', is, also]), verbo([required]), complemento([at, very, early, stages, of, natural, killer, '(', 'NK)-cell', development])].
[sujeto(['Therefore,', the, ability, of, the, prethymic, cell, to]), verbo([respond]), complemento([appropriately, to, 'Notch', is, dependent, on, 'CBFbeta,', and, both, signals, converge, to, activate, the, 'T-cell', developmental, program])].
[sujeto(['Although', a, number, of, transcription, factors, '(', 'TFs)']), verbo([have]), complemento([been, identified, that, play, a, pivotal, role, in, the, development, of, hematopoietic, 'lineages,', only, little, is, known, about, factors, that, may, influence, development, and, lineage, commitment, of, natural, killer, '(', 'NK)', or, 'NK-like', 'T', '(', 'NKT)-cells'])].
[sujeto(['AML1,', 'E2A,', 'ETS1,', 'IKAROS', and, 'IRF1', were]), verbo([found]), complemento([to, be, positive, for, all, cell, lines, tested, whereas, 'GATA1', turned, out, to, be, universally, negative])].
[sujeto(['Although', 'genome-wide', association, studies, '(', 'GWAS)']), verbo([have]), complemento([identified, a, significant, number, of, 'single-nucleotide', polymorphisms, '(', 'SNPs)', associated, with, many, complex, human, 'traits,', the, susceptibility, loci, identified, so, far, can, explain, only, a, small, fraction, of, the, genetic, risk])].
[sujeto(['Previously,', we]), verbo([reported]), complemento([a, 'model-free', 'Generalized', 'Multifactor', 'Dimensionality', 'Reduction', '(', 'GMDR)', approach, for, detecting, 'G×G', in, both, dichotomous, and, quantitative, phenotypes])].
[sujeto(['Of', these, core, 'SNPs,', 11, in, 'FTO,', 'TSPAN8,', and, 'TCF7L2']), verbo([have]), complemento([been, reported, to, be, associated, with, 'T2D,', 'obesity,', or, 'both,', providing, an, independent, replication, of, previously, reported, 'SNPs'])].
[sujeto([',', 'L3MBTL3,', 'CELF4,', and, 'RUNX1,', for, 'T2D,', a]), verbo([finding]), complemento([that, warrants, further, investigation, with, independent, samples])].
[sujeto(['We']), verbo([found]), complemento([differential, 'DNA', methylation, of, genes, in, biological, pathways, including, 'mitogen-activated', protein, kinase, '(', 'MAPK),', 'insulin,', and, calcium, signaling, '(', 'P', '≤', 0.007, ')', and, of, individual, genes, with, known, function, in, 'muscle,', including, 'MAPK1,', 'MYO18B,', 'HOXC6,', and, the, 'AMP-activated', protein, kinase, subunit, 'PRKAB1', in, skeletal, muscle, of, 'FH(+)', compared, with, 'FH(-)', men])].
[sujeto(['DNA', methylation, of, genes, in, retinol, metabolism, and, calcium, signaling, pathways, '(', 'P', &, 'lt;', 3, ×, 10, '(', -, 6, ')', ')', and, with, known, functions, in, muscle, and, 'T2D', including, 'MEF2A,', 'RUNX1,', 'NDUFC2,', and, 'THADA']), verbo([decreased]), complemento([after, exercise])].
[sujeto(['Methylation', of, these, human, promoter, regions]), verbo([suppressed]), complemento([reporter, gene, expression, in, vitro])].
[sujeto(['These', findings]), verbo([provide]), complemento([new, insights, into, how, genetic, background, and, environment, can, alter, the, human, epigenome])].
[sujeto(['LCRs']), verbo([have]), complemento([been, identified, in, many, immunologically, important, gene, 'loci,', including, one, between, the, 'TCRdelta/TCRalpha', gene, segments, and, the, ubiquitously, expressed, 'Dad1', gene])].
[sujeto(['How', a, ubiquitously, active, element, can]), verbo([participate]), complemento([in, 'tissue-restricted', 'LCR', activity, is, not, clear])].
[sujeto(['In', 'isolation,', the, activity, in, this, region]), verbo([suppresses]), complemento([position, effect, transgene, silencing, in, many, tissues])].
[sujeto(['A', combination, of, in, vivo, footprint, examination, of, this, element, in, widely, active, transgene, and, 'EMSAs', revealed, 'tissue-unrestricted', factor, occupancy, patterns, and]), verbo([binding]), complemento([of, several, ubiquitously, expressed, transcription, factors])].
[sujeto(['We', identified, 'tissue-restricted', 'AML-1', and, 'Elf-1', as, proteins, that, potentially]), verbo([act]), complemento([via, this, element])].
[sujeto(['These', data, demonstrate, that, a, widely, active, 'LCR', module, can, synergize, with, other, 'LCR', components, to, produce, 'tissue-specific', 'LCR', activity, through, differential, protein, occupancy, and, function, and]), verbo([provide]), complemento([evidence, to, support, a, role, for, this, 'LCR', module, in, the, regulation, of, both, 'TCR', and, 'Dad1', genes])].
[sujeto(['Cannabinoid', receptor, type, 2, '(', 'CB2)', activation, is, recently]), verbo([reported]), complemento([to, promote, proliferation, of, some, types, of, resident, stem, cells, '(', e])].
[sujeto(['This', study, aims, to, explore, the, role, and, possible, mechanisms, of, 'CB2', receptor, activation, in]), verbo([enhancing]), complemento([myocardial, repair])].
[sujeto(['Our', results, revealed, that, 'CB2', receptor, agonist, 'AM1241', can, significantly]), verbo([increase]), complemento(['CPCs', by, 'c-kit', and, 'Runx1', staining, in, ischemic, myocardium, as, well, as, improve, cardiomyocyte, proliferation])].
[sujeto(['AM1241', also]), verbo([decreased]), complemento([serum, levels, of, 'MDA,', 'TNF-α', and, 'IL-6', after, 'MI'])].
[sujeto(['Moreover,', 'AM1241', treatment, markedly]), verbo([increased]), complemento(['p-Akt', and, 'HO-1', 'expression,', and, promoted, 'Nrf-2', nuclear, translocation])].
[sujeto(['In', 'conclusion,', 'AM1241', could]), verbo([induce]), complemento([myocardial, regeneration, and, improve, cardiac, 'function,', which, might, be, associated, with, 'PI3K/Akt/Nrf2', signaling, pathway, activation])].
[sujeto(['Our', findings, may]), verbo([provide]), complemento([a, promising, strategy, for, cardiac, endogenous, regeneration, after, 'MI'])].
[sujeto(['Abstract', 'Endothelial', progenitor, cells, '(', 'EPCs)']), verbo([have]), complemento([been, demonstrated, to, be, effective, for, the, treatment, of, cardiovascular, diseases])].
[sujeto(['However,', the, differentiation, process, from, circulation, to, adhesion]), verbo([has]), complemento([not, been, clarified, because, circulating, 'EPCs', rarely, attached, to, dishes, in, 'EPC', cultures, previously])].
[sujeto(['The', bioactivities, of, 'adhesion,', 'proliferation,', 'migration,', tube, 'formation,', and, differentiated, type, of, 'EPC', colony, formation]), verbo([increased]), complemento([in, 'EPCs', exposed, to, dextran])].
[sujeto(['The', surface, protein, expression, rate, of, the, endothelial, markers, vascular, endothelial, growth, factor, '(', 'VEGF)-R1/2,', 'VE-cadherin,', 'Tie2,', 'ICAM1,', 'VCAM1,', and, integrin, 'αv/β3']), verbo([increased]), complemento([in, 'EPCs', exposed, to, dextran])].
[sujeto(['The', mRNA, levels, of, 'VEGF-R1/2,', 'VE-cadherin,', 'Tie2,', endothelial, nitric, oxide, 'synthase,', 'MMP9,', and, 'VEGF']), verbo([increased]), complemento([in, 'EPCs', treated, with, dextran])].
[sujeto(['Those', of, 'endothelium-related', transcription, factors, 'ID1/2,', 'FOXM1,', 'HEY1,', 'SMAD1,', 'FOSL1,', 'NFkB1,', 'NRF2,', 'HIF1A,', 'EPAS1']), verbo([increased]), complemento([in, 'dextran-treated', 'EPCs;', 'however,', those, of, 'hematopoietic-', and, 'antiangiogenic-related', transcription, factors, 'TAL1,', 'RUNX1,', 'c-MYB,', 'GATA1/2,', 'ERG,', 'FOXH1,', 'HHEX,', 'SMAD2/3', decreased, in, 'dextran-exposed', 'EPCs'])].
[sujeto(['Inhibitor', analysis, showed, that, 'PI3K/Akt,', 'ERK1/2,', 'JNK,', and, p38, signal, transduction, pathways, are]), verbo([involved]), complemento([in, the, differentiation, in, response, to, dextran])].
[sujeto(['In', 'conclusion,', dextran]), verbo([induces]), complemento([differentiation, of, circulating, 'EPCs', in, terms, of, 'adhesion,', 'migration,', 'proliferation,', and, vasculogenesis])].
[sujeto(['The', differentiation, mechanism, in, response, to, dextran, is]), verbo([regulated]), complemento([by, multiple, signal, transductions, including, 'PI3K/Akt,', 'ERK1/2,', 'JNK,', and, p38])].
[sujeto(['To', understand, the, role, of, 'ETO', and, 'AML1-ETO', in, the, pathogenesis, of, 'AML,', the, full, length, cDNAs, of, 'ETO', and, 'AML1-ETO', were, cloned, and, antibodies, against, 'AML1', and, 'ETO', proteins]), verbo([have]), complemento([been, developed, in, our, laboratory])].
[sujeto(['Western', blot, analysis, showed, that, 'ETO', and, 'AML1-ETO', were, identified, as, 70, kDa, and, 94, kDa, 'proteins,', 'respectively,', and, that, both, 'proteins,', like, 'AML1,', were]), verbo([associated]), complemento([with, the, nuclear, matrix])].
[sujeto(['To', examine, whether, the, 't(8;21)-positive', 'AMLs']), verbo([expressed]), complemento([a, 94, -, kDa, 'AML1-ETO,', protein, fractions, isolated, from, leukemia, blasts, of, 10, patients, with, 't(8;21)-positive', 'AML', and, the, 'Kasumi-1', cells, were, analyzed, by, 'Western', blotting])].
[sujeto(['We']), verbo([found]), complemento([that, 'AML1-ETO', blocked, the, erythroid, differentiation, of, 'K562', cells, induced, by, low, doses, of, 'Ara-C'])].
[sujeto(['The', 't(8;21)', is]), verbo([associated]), complemento([with, 12, -, 15, '%', of, acute, myelogenous, leukemias, of, the, 'M2', subtype])].
[sujeto(['AML1', encodes, a, 'DNA']), verbo([binding]), complemento(['factor;', the, 'ETO', protein, product, is, less, well, 'characterized,', but, is, thought, to, be, a, transcription, factor])].
[sujeto(['ETO-2', is, also]), verbo([expressed]), complemento([in, myeloid, and, erythroid, cell, lines])].
[sujeto(['We', confirmed, the]), verbo([nuclear]), complemento([localization, of, 'ETO-2', and, demonstrated, that, domain, 'III', and, the, 'zinc-finger', region, are, not, required, for, nuclear, localization])].
[sujeto(['We', further, showed, that, a, region, within, 'ETO,', containing, domain, 'II,']), verbo([mediates]), complemento([dimerization, among, family, members])].
[sujeto(['This', region, is]), verbo([conserved]), complemento([in, the, oncoprotein, 'AML-1/ETO'])].
[sujeto(['Macrophages', are, immune, cells]), verbo([involved]), complemento([in, various, biological, processes, including, host, 'defence,', 'homeostasis,', 'differentiation,', and, organogenesis])].
[sujeto(['Disruption', of, macrophage, biology]), verbo([has]), complemento([been, linked, to, increased, pathogen, 'infection,', inflammation, and, malignant, diseases])].
[sujeto(['Differential', gene, expression, observed, in, monocytic, differentiation, is, primarily]), verbo([regulated]), complemento([by, interacting, transcription, factors, '(', 'TFs)'])].
[sujeto(['Current', research]), verbo([suggests]), complemento([that, microRNAs, '(', 'miRNAs)', degrade, and, repress, translation, of, 'mRNA,', but, also, may, target, genes, involved, in, differentiation])].
[sujeto(['We', focus, on, getting, insights, into, the, transcriptional, circuitry]), verbo([regulating]), complemento([miRNA, genes, expressed, during, monocytic, differentiation])].
[sujeto(['A', set, of, 'TF--&gt;miRNA', associations, was, derived, from, predicted, 'TF']), verbo([binding]), complemento([sites, in, promoter, regions, of, miRNA, genes])].
[sujeto(['Our', analysis, identified, 12, 'TFs', that, potentially, play, a, central, role, in]), verbo([regulating]), complemento([miRNAs, throughout, the, differentiation, process])].
[sujeto(['Six', of, these, 12, 'TFs', '(', 'ATF2,', 'E2F3,', 'HOXA4,', 'NFE2L1,', 'SP3,', and, 'YY1)']), verbo([have]), complemento([not, previously, been, described, to, be, important, for, monocytic, differentiation])].
[sujeto(['Subsequently,', we]), verbo([have]), complemento([identified, 12, candidate, key, controllers, of, miRNAs, during, this, differentiation, process])].
[sujeto(['AML1/RUNX1', mutations]), verbo([have]), complemento([been, reported, frequently, in, myelodysplastic, syndrome, '(', 'MDS)', 'patients,', especially, those, diagnosed, with, refractory, anemia, with, excess, blast, '(', 'RAEB),', 'RAEB', in, transformation, '(', 'RAEBt),', or, 'AML', following, 'MDS', '(', these, categories, are, defined, as, 'MDS/AML)'])].
[sujeto(['AML1', mutations, were, significantly]), verbo([associated]), complemento([with, -, 7, /, 7, 'q-,', whereas, 'MDS/AML', patients, without, 'AML1', mutations, showed, a, high, frequency, of, -, 5, /, 5, 'q-', and, a, complex, karyotype])].
[sujeto(['Furthermore,', blast, cells, of, the, 'AML1-mutated', patients]), verbo([expressing]), complemento([surface, 'c-KIT,', and, 'SHP-2', mutants, contributed, to, prolonged, and, enhanced, extracellular, 'signal-regulated', kinase, activation, following, stem, cell, factor, stimulation])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'MDS/AML', arising, from, 'AML1/RUNX1', mutations, has, a, significant, association, with, -, 7, /, 7, 'q-', 'alteration,', and, frequently, involves, 'RTK-RAS', signaling, pathway, activation])].
[sujeto(['SHP-2', is]), verbo([required]), complemento([during, 'development,', and, germline, mutations, in, 'PTPN11,', the, gene, encoding, 'SHP-2,', cause, 'Noonan', syndrome])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, 'PTPN11', lesions, occur, in, childhood, acute, lymphoblastic, leukemia, '(', 'ALL)'])].
[sujeto(['Our', findings]), verbo([provide]), complemento([evidence, for, a, wider, role, of, 'PTPN11', lesions, in, 'leukemogenesis,', but, also, suggest, a, 'lineage-related', and, differentiation, 'stage-related', contribution, of, these, lesions, to, clonal, expansion])].
[sujeto(['Dysfunction', of, 'FOXP3', in, human, is]), verbo([associated]), complemento([with, fatal, autoimmune, disease, known, as, 'immunodysregulation,', 'polyendocrinopathy,', 'enteropathy,', 'X-linked', syndrome, '(', 'IPEX)', or, 'X-linked', 'autoimmunity-allergic', disregulation, syndrome, '(', 'XLAAD)'])].
[sujeto(['FOXP3', also, can]), verbo([act]), complemento([as, a, breast, tumor, suppressor, of, the, 'v-erb-b2', erythroblastic, leukemia, viral, oncogene, homolog, 2, '(', 'neuro/glioblastoma', derived, oncogene, homolog, '(', 'avian))', '(', 'Her2/neu)', gene])].
[sujeto(['While', the, suppressive, functions, of, 'FOXP3', in]), verbo([maintaining]), complemento([the, immune, balance, between, tolerance, and, autoimmunity, are, 'obvious,', the, underlying, molecular, mechanism, remains, almost, entirely, undefined])].
[sujeto(['Recent', studies, indicate, that, 'FOXP3', may, form, a, dynamic, superamolecular, complex, with, a, variety, of, molecular, partners, including, transcription, factors, and, enzymatic, proteins, to]), verbo([regulate]), complemento([transcription])].
[sujeto(['How', the, 'FOXP3', ensemble, changes, in, response, to, 'T-cell', receptor, signals, 'and/or', proinflammatory, signal, remains, unclear, although, work, from, this, laboratory]), verbo([has]), complemento([revealed, its, complexity])].
[sujeto(['Structural', information, on, 'FOXP3', complex, may, offer, novel, functional, 'insights,', as, well, as, facilitate, the, development, of, rational, means, to]), verbo([modulate]), complemento([regulatory, 'T-cell', function, in, various, human, diseases])].
[sujeto(['The', silencing, mediator, of, retinoic, and, thyroid, hormone, receptors, '(', 'SMRT)', 'co-repressor']), verbo([recruits]), complemento([histone, deacetylases, '(', 'HDAC)', and, mediates, transcriptional, repression, by, interacting, with, various, transcription, factors])].
[sujeto(['We', recently]), verbo([reported]), complemento([that, 'Flt3-ITD', interferes, with, the, transcriptional, and, biological, action, of, promyelocytic, leukaemia, zinc, finger, transcriptional, repressor, by, dissociating, it, from, 'SMRT'])].
[sujeto(['Mammalian', 'two-hybrid', assays, demonstrated, that, this, protein]), verbo([interacts]), complemento([with, 'SMRT'])].
[sujeto(['Furthermore,', this, 'AML1B-SMRT', interaction, was, disrupted, by, the, overexpression, of, 'Flt3-ITD,']), verbo([leading]), complemento([to, the, reduction, of, 'AML1B', repression, activity])].
[sujeto(['Additionally,', we, showed, 'AML1B', repression, 'target,', p21, '(', 'WAF1/CIP1),', was, aberrantly]), verbo([expressed]), complemento([in, 'Flt3-ITD', stably, expressed, 'BaF3', cells])].
[sujeto(['They', differentiate, through, interaction, of, their, 'Valpha14-Jalpha18', invariant, 'TCRalpha', chains, with, 'CD1d']), verbo([expressed]), complemento([on, 'double-positive', '(', 'DP)', thymocytes])].
[sujeto(['Although', their, development]), verbo([has]), complemento([been, shown, to, be, thymus, 'dependent,', their, developmental, pathway, has, not, been, definitively, established])].
[sujeto(['Their', development, is, absolutely, dependent, on, 'Runx1', and, 'ROR(gamma)t,', transcription, factors, that, 'influence,', but, are, not]), verbo([required]), complemento(['for,', development, of, conventional, 'T', cells])].
[sujeto(['Our', results, indicate, that, even, though, 'CD1d']), verbo([binding]), complemento(['DP', thymocytes, have, yet, to, be, 'observed,', 'Valpha14-Jalpha18', rearrangement, in, these, cells, is, required, for, development, of, iNKT, cells])].
[sujeto(['Primary', aggressive, bone, tumors, had, copy, number]), verbo([gains]), complemento([of, 17.8, '±12'])].
[sujeto([7, '%', in, the, 'genome,', and]), verbo([losses]), complemento([of, 17.3, '±11'])].
[sujeto([4, '%', in, 287]), verbo([target]), complemento([clones, '(', threshold, for, each, 'DCNA:', '≦085,', 1.15, '≦)'])].
[sujeto(['Metastatic', lesion, showed]), verbo([increased]), complemento([9, 'DCNAs', of, remarkable, change, '(', 'm/p', ratio, '≧1'])].
[sujeto(['Our', results, may]), verbo([provide]), complemento([several, entry, points, for, the, identification, of, candidate, genes, associated, with, aggressive, change, of, bone, tumors])].
[sujeto(['Little', is, known, about, the, genetic, variants]), verbo([associated]), complemento([with, trabecular, and, cortical, vBMD, in, 'humans,', although, both, may, be, important, for, determining, bone, strength, and, osteoporotic, risk])].
[sujeto(['In', the, current, 'analysis,', we, tested, the, hypothesis, that, there, are, genetic, variants]), verbo([associated]), complemento([with, trabecular, and, cortical, vBMD, at, the, femoral, neck, by, genotyping, 4608, tagging, and, potentially, functional, 'single-nucleotide', polymorphisms, '(', 'SNPs)', in, 383, bone, metabolism, candidate, genes, in, 822, 'Caucasian', men, aged, 65, years, or, older, from, the, 'Osteoporotic', 'Fractures', in, 'Men', 'Study', '(', 'MrOS)'])].
[sujeto(['We', identified, 'SNPs', in, five, genes, '(', 'IFNAR2,', 'NFATC1,', 'SMAD1,', 'HOXA,', and, 'KLF10)', that, were, robustly]), verbo([associated]), complemento([with, cortical, vBMD, and, 'SNPs', in, nine, genes, '(', 'APC,', 'ATF2,', 'BMP3,', 'BMP7,', 'FGF18,', 'FLT1,', 'TGFB3,', 'THRB,', and, 'RUNX1)', that, were, robustly, associated, with, trabecular, vBMD])].
[sujeto(['There', was, no, overlap, between, genes]), verbo([associated]), complemento([with, cortical, vBMD, and, trabecular, vBMD])].
[sujeto(['Two', transcription, 'factors,', the, 'helix-loop-helix', inhibitor, 'Id2', and, the, retinoic, 'acid-related', orphan, receptor, γt, '(', 'Rorγt),']), verbo([have]), complemento([been, shown, to, be, crucial, for, 'LTi', cell, development])].
[sujeto(['In', this, 'study,', we]), verbo([report]), complemento([impaired, lymphoid, tissue, organogenesis, in, mice, in, which, the, function, of, 'Runx1/Cbfβ', transcription, factor, complexes, was, attenuated, by, the, loss, of, either, the, distal, 'promoter-derived', 'Runx1', or, 'Cbfβ2', variant, protein])].
[sujeto(['We']), verbo([found]), complemento([that, 'LTi', progenitors, in, fetal, 'liver,', defined, previously, as, a, lineage, 'marker-negative', α4β7, integrin, '(', 'α4β7)(+)', 'IL-7R', 'α-chain', '(', 'IL-7Rα)(+)', 'population,', can, be, subdivided, into, 'Rorγt-expressing', 'IL-7Rα(high)', cells, and, nonexpressing, 'IL-7Rα(mid)', cells])].
[sujeto(['Whereas', 'Id2', and, 'Rorγt', are]), verbo([required]), complemento([to, direct, 'α4β7(+)IL-7Rα(mid)', cells, to, become, 'α4β7(+)IL-7Rα(high)', 'cells,', 'Runx1/Cbfβ2', complexes, are, necessary, for, the, emergence, of, 'α4β7(+)IL-7Rα(mid)', cells])].
[sujeto(['In', 'addition,', the]), verbo([loss]), complemento([of, 'Cbfβ2,', but, not, 'P1-Runx1,', resulted, in, an, inefficient, upregulation, of, 'Rorγt', in, residual, 'α4β7(+)IL-7Rα(+)', 'LTi', cells, at, anlagen])].
[sujeto(['Our', results, thus, revealed, that, 'Runx1/Cbfβ2', complexes]), verbo([regulate]), complemento([the, differentiation, of, 'LTi', cells, at, two, 'stages:', an, early, specification, of, hematopoietic, progenitors, toward, the, 'LTi', lineage, and, a, subsequent, activation, of, 'Rorγt', expression, at, anlagen])].
[sujeto(['Chemical', 'biology,', using, small, molecules, as, probes, to, study, the, cellular, signaling, 'network,']), verbo([has]), complemento([developed, rapidly, in, recent, years])].
[sujeto(['The', interaction, between, chemistry, and, biology, not, only]), verbo([provides]), complemento([new, insight, into, the, understanding, of, cellular, 'activities,', but, also, generates, new, lead, compounds, for, the, treatment, of, diseases])].
[sujeto(['Abnormalities', in, these, proteins, may]), verbo([cause]), complemento([the, dysregulation, of, hematopoiesis, and, even, the, occurrence, of, leukemia])].
[sujeto(['Ubiquitin-mediated', protein, degradation, represents, a, critical, mechanism, in]), verbo([regulating]), complemento([the, cellular, levels, and, functions, of, these, proteins])].
[sujeto(['Thus,']), verbo([targeting]), complemento([protein, degradation, has, been, emerging, as, an, important, strategy, to, conquer, malignant, diseases])].
[sujeto(['Leukotriene', 'B(4)', 'type-1', receptor, '(', 'BLT1),', which, plays, a, role, in, various, inflammatory, 'diseases,', is, exclusively]), verbo([expressed]), complemento([in, peripheral, 'leukocytes,', which, suggests, that, its, expression, is, stringently, regulated])].
[sujeto(['Here', we]), verbo([report]), complemento([that, acute, myeloid, leukemia, 1, '(', 'AML1/Runx1)', is, involved, in, the, enhancement, of, 'BLT1', expression, in, leukocytes])].
[sujeto(['In', retinoic, acid, '(', 'RA)-stimulated', human, promyelocytic, leukemia, '(', 'HL-60)', 'cells,', the, transcription, of, the, 'BLT1', gene, was]), verbo([found]), complemento([to, be, significantly, activated])].
[sujeto(['RA', did, not, directly]), verbo([modulate]), complemento([the, 'BLT1', 'promoter,', suggesting, enhancers, in, other, loci])].
[sujeto(['DNase', 'I-hypersensitivity', analyses, revealed, an]), verbo([activated]), complemento(['region,', termed, 'AE-BLex,', at, the, 'intron-I:exon-II', boundary])].
[sujeto(['AE-BLex']), verbo([acts]), complemento([as, an, enhancer, for, the, 'BLT1', promoter, and, possesses, 2, 'AML1', recognition, sites])].
[sujeto(['We', demonstrated, that, the, enhancement, of, 'BLT1', expression, during, the, 'RA-induced', differentiation, of, 'HL-60', cells, is, due, to, a, loosening, of, the, chromatin, structure, around, 'AE-BLex,', which]), verbo([leads]), complemento([to, the, incremental, binding, of, 'AML1'])].
[sujeto(['The', 'AML1/AE-BLex', complex, was, confirmed, in, other, 'BLT1-']), verbo([expressing]), complemento([leukemia, cell, lines, and, human, peripheral, leukocytes])].
[sujeto(['Thus,', 'AML1']), verbo([enhances]), complemento(['BLT1', expression, by, binding, to, 'AE-BLex,', which, is, accessible, in, leukocytes])].
[sujeto(['Acute', myeloid, leukemia, '(', 'AML)']), verbo([associated]), complemento([translocations, often, cause, gene, fusions, that, encode, oncofusion, proteins])].
[sujeto(['Although', many, of, the, breakpoints]), verbo([involved]), complemento([in, chromosomal, translocations, have, been, 'cloned,', in, most, cases, the, role, of, the, chimeric, proteins, in, tumorigenesis, is, not, elucidated])].
[sujeto(['Here', we, will, discuss, the, fusion, proteins, of, the, 4, most, common, translocations]), verbo([associated]), complemento([with, 'AML', as, well, as, the, common, molecular, mechanisms, that, these, four, and, other, fusion, proteins, utilize, to, transform, progenitor, cells])].
[sujeto(['Recurrent', balanced, translocations, are, generally]), verbo([recognized]), complemento([to, be, a, major, parameter, for, prognostication, in, acute, myeloid, leukaemia, '(', 'AML)'])].
[sujeto(['Patients', with, these, mutations]), verbo([have]), complemento([a, good, prognosis, unlike, abnormalities, in, chromosome, 5, or, 7, or, 'FLT3', genes])].
[sujeto(['Therefore,', we, screened, the, 'AmL', patients, for, known, specific, genetic, abnormalities, that, could]), verbo([lead]), complemento([to, more, definitive, prognoses])].
[sujeto(['The', prevalence, of, bcr3, '(', short, 'isoform)', was, higher, '(', 62, '%', ')', than, that, of, bcr1, '(', long, 'isoform)', '(', 38, '%', ')', and, no, correlation, was]), verbo([found]), complemento([with, 'age,', sex, or, white, blood, cell, count])].
[sujeto(['Thus,', patients, with, 'APL', who]), verbo([have]), complemento(['FLT3', mutation, appear, to, have, a, poorer, prognosis])].
[sujeto(['ERG', and, 'FLI1', are, closely, related, members, of, the, 'ETS', family, of, transcription, factors, and]), verbo([have]), complemento([been, identified, as, essential, factors, for, the, function, and, maintenance, of, normal, hematopoietic, stem, cells])].
[sujeto(['Here', 'genome-wide', analysis, revealed, that, both, 'ERG', and, 'FLI1', occupy, similar, genomic, regions, as, 'AML1-ETO', in, 't(8;21)', 'AMLs', and, identified, 'ERG/FLI1', as, proteins, that, facilitate]), verbo([binding]), complemento([of, oncofusion, protein, complexes])].
[sujeto(['In', 'addition,', we, demonstrate, that, 'ERG', and, 'FLI1']), verbo([bind]), complemento([the, 'RUNX1', promoter, and, that, 'shRNA-mediated', silencing, of, 'ERG', leads, to, reduced, expression, of, 'RUNX1', and, 'AML1-ETO,', consistent, with, a, role, of, 'ERG', in, transcriptional, activation, of, these, proteins])].
[sujeto(['Finally,', we, identify, 'H3', acetylation, as, the, epigenetic, mark, preferentially]), verbo([associated]), complemento([with, 'ETS', factor, binding])].
[sujeto(['This', intimate, connection, between, 'ERG/FLI1']), verbo([binding]), complemento([and, 'H3', acetylation, implies, that, one, of, the, molecular, strategies, of, oncofusion, 'proteins,', such, as, 'AML1-ETO', and, 'PML-RAR-α,', involves, the, targeting, of, histone, deacetylase, activities, to, 'ERG/FLI1', bound, hematopoietic, regulatory, sites])].
[sujeto(['To', establish, a, 'real-time', quantitative, reverse, transcriptase, polymerase, chain, reaction, '(', 'RQ-RT-PCR)', for, quantitative, detection, of, the, common, molecular, markers, that]), verbo([have]), complemento([affirmative, clinical, significance, in, the, acute, and, chronic, leukemia, 'patients,', and, evaluate, its, significance, in, diagnosing, leukemias, and, monitoring, minimal, residual, disease, '(', 'MRD)'])].
[sujeto(['Different', levels, of, transcription, of, corresponding, fusion, genes, are]), verbo([found]), complemento([in, various, subtypes, of, leukemias, at, 'diagnosis,', among, which, the, level, of, 'AML1-ETO', was, higher, and, 'PML-RAR', alpha, lower])].
[sujeto(['Detection', of, fusion, transcript, levels, in, untreated, leukemia, patients, not, only]), verbo([provides]), complemento([baseline, for, minimal, residual, disease, monitoring, and, treatment, evaluation, but, also, enable, the, comparison, in, 'inter-laboratory', data])].
[sujeto(['The', acute, promyelocytic, 'leukemia-specific', 'PML-RARalpha', fusion, protein, is, a, 'dominant-negative', transcriptional, repressor, of, retinoic, acid, receptor, '(', 'RAR)']), verbo([target]), complemento(['genes,', which, recruits, 'HDAC', and, corepressor, proteins, and, inhibits, coactivators])].
[sujeto(['Another', oncogenic, transcription, 'factor,', 'AML1-ETO,', was, proposed, to]), verbo([cause]), complemento([an, 'HDAC-dependent', repression, of, 'RAR', target, genes])].
[sujeto(['The', 'RAR']), verbo([target]), complemento(['RARbeta2', gene, has, been, reported, to, be, frequently, silenced, by, hypermethylation, in, many, types, of, cancer, cells])].
[sujeto(['PML-RARalpha', positive, 'NB4', and, its, 'ATRA-resistant', subvariant, 'MR2', and, 'AML1-ETO']), verbo([expressing]), complemento(['Kasumi-1', cells, had, heterozygous, methylation, of, 'RARbeta2'])].
[sujeto(['Although', 'DNA', methyltransferase, inhibitor, 5, -, 'aza-2\'-deoxycytidine', partially, reversed, 'RARbeta2', 'CpG', methylation, in, these, 'cells,', it, did, not, significantly]), verbo([enhance]), complemento(['ATRA-induced', 'RARbeta2', mRNA, expression, and, induction, of, maturation])].
[sujeto(['However,', the, histone, acetylase, inhibitor, 'SAHA', combined, with, 'ATRA', significantly]), verbo([reactivated]), complemento(['RARbeta2', mRNA, both, in, 'NB4', and, 'MR2', cells, with, degradation, of, 'PML-RARalpha,', which, was, associated, with, maturation])].
[sujeto(['In', 'contrast,', 'SAHA', did, not, affect, 'AML1-ETO', levels, and, failed, to]), verbo([induce]), complemento(['RARbeta2', expression, and, maturation, in, 'Kasumi-1', cells])].
[sujeto(['These', results, demonstrate, that, oncogenic, 'PML-RARalpha', and, 'AML1-ETO', translocations, are, rarely]), verbo([associated]), complemento([with, 'RARbeta2', promoter, methylation, in, primary, 'AML', samples])].
[sujeto(['Bone', marrow, samples, from, 161, cases, of, leukemia, and, 8, cases, of, myelodysplastic, syndrome, '(', 'MDS)', were]), verbo([involved]), complemento([in, the, study])].
[sujeto(['Ten', fusion, genes, were, detected, in, 115, cases, of, 'leukemia,', including, 'AML1/ETO,', 'PML/RAR', 'alpha,', 'PLZF/RAR', 'alpha,', 'dupMLL,', 'MLL/AF6,', 'MLL/AF10,', 'CBFbeta/MYH11,', 'BCR/ABL,', 'Hox11,', and, 'EVI1', 'BCR/ABL', was, positive, in, all, the, 52, cases, of, chronic, myeloid, 'leukemia;', 'PML/RAR', alpha, was]), verbo([found]), complemento([in, 21, of, 25, acute, promyelocytic, leukemia, '(', 'APL),', and, 'PLZF/RAR', alpha, was, detected, in, one, case, of, 'APL'])].
[sujeto(['MLL', aberrations, were]), verbo([found]), complemento([in, 16, 'AL,', in, which, all, 'MLL/AF6', translocation, existed, in, 'M5', subtype, with, classic, monoblastic, characters])].
[sujeto(['Fusion', genes, were, also]), verbo([found]), complemento([in, 2, 'MDS', 'cases,', of, which, 'AML1/ETO', 'positive-MDS-RAEB', progressed, to, 'AML', rapidly])].
[sujeto(['Screening', of, common, fusion, genes, by, multiplex, 'RT-PCR', is, an, important, tool, which, could]), verbo([provide]), complemento([useful, and, reliable, molecular, genetic, information, for, the, diagnosis, and, treatment, of, leukemia])].
[sujeto(['Many', studies]), verbo([have]), complemento([assessed, the, clinical, significance, of, the, detection, of, minimal, residual, disease, '(', 'MRD)', in, acute, leukemia])].
[sujeto(['Thus', 'far,', many, studies]), verbo([have]), complemento([suggested, that, 'MRD', detection, to, evaluate, the, response, to, chemotherapy, is, useful, for, predicting, the, prognosis, of, childhood, acute, lymphoblastic, leukemia, '(', 'ALL)'])].
[sujeto(['However,', few, studies]), verbo([have]), complemento([reported, on, the, significance, of, 'MRD', in, childhood, acute, myeloid, leukemia, '(', 'AML),', because, of, small, numbers, of, patients, and, limited, availability, of, 'MRD', markers])].
[sujeto(['The', 'AML1/MTG8', fusion, gene, was]), verbo([expressed]), complemento([in, 8, 'patients,', 'PML/RAR', alpha, was, expressed, in, 3, 'patients,', and, 'MYH11/CBF', beta, was, expressed, in, 1, patient])].
[sujeto(['On', the, other, 'hand,', 1, of, the, 2, patients, who, continued, on, chemotherapy, continued, to, be, 'MRD', 'positive,']), verbo([suggesting]), complemento([a, 'graft-versus-leukemia', effect, in, allogeneic, 'SCT'])].
[sujeto(['The', 3, -, year, 'event-free', survival, in, de, novo, 'AML', was, 69.4, '%', +, /, -, 9.8, '%', '(', n, =, 26, ')', ',', a, result, that, is, encouraging, and, superior, to, other]), verbo([reported]), complemento([outcomes])].
[sujeto(['Thus,', an, 'MRD-based', treatment, strategy, together, with, conventional, risk, factors, appears, to, be]), verbo([required]), complemento([for, further, improving, the, outcomes, of, 'AML'])].
[sujeto(['Expression', of, 'AML', fusion, proteins, in, transgenic, mice]), verbo([increases]), complemento([the, risk, of, myeloid, 'leukemias,', suggesting, that, they, induce, a, preleukemic, state])].
[sujeto(['We']), verbo([expressed]), complemento(['AML1/ETO,', 'PML/RAR,', and, 'PLZF/RAR', in, 'U937', hemopoietic, precursor, cells, and, measured, global, gene, expression, using, oligonucleotide, chips])].
[sujeto(['We', identified, 1, ',', 555, genes]), verbo([regulated]), complemento([concordantly, by, at, least, two, fusion, proteins, that, were, further, validated, in, patient, samples, and, finally, classified, according, to, available, functional, information])].
[sujeto(['Strikingly,', we]), verbo([found]), complemento([that, 'AML', fusion, proteins, induce, genes, involved, in, the, maintenance, of, the, stem, cell, phenotype, and, repress, 'DNA', repair, 'genes,', mainly, of, the, base, excision, repair, pathway])].
[sujeto(['Functional', studies, confirmed, that, ectopic, expression, of, fusion, proteins, constitutively]), verbo([activates]), complemento([pathways, leading, to, increased, stem, cell, renewal, '(', e])].
[sujeto([',', the, 'Jagged1/Notch', 'pathway)', and]), verbo([provokes]), complemento([accumulation, of, 'DNA', damage])].
[sujeto(['Mutations', in, signal, transduction, 'molecules,', which]), verbo([regulate]), complemento([cell, differentiation, and, 'proliferation,', are, involved, in, the, development, of, leukemia])].
[sujeto(['BCR/ABL']), verbo([found]), complemento([in, chronic, myelogenous, leukemia, '(', 'CML)', is, a, hallmark, of, the, constitutively, active, forms, of, cytoplasmic, tyrosine, kinases])].
[sujeto(['Downstream', of, the, tyrosine, kinase, is, the, 'RAS', 'GTP-binding', 'protein,', and, genetic, mutations, related, to, this, protein]), verbo([have]), complemento([been, found, in, a, wide, variety, of, malignant, tumors, including, hematopoietic, tumors])].
[sujeto(['In', the, 'nucleus,', transcription, 'factor-encoding', genes, are, frequently, detected, as, the]), verbo([targets]), complemento([of, chromosomal, translocations, found, in, specific, types, of, leukemias])].
[sujeto(['Another', example, of, abnormal, transcription, factors, is, 'PML/RAR', alpha, generated, by, t, '(', 15, ;, 17, ')', translocation]), verbo([found]), complemento([in, acute, promyelocytic, leukemia])].
[sujeto(['Mutations', or, deletions, of, tumor, suppressor, genes, are, frequently]), verbo([found]), complemento([in, cell, cycle, regulators, such, as, 'p53,', 'RB', and, p16, genes])].
[sujeto(['Therefore,', mutations, of, any, molecules]), verbo([involved]), complemento([in, the, signal, transduction, pathways, from, growth, factor, receptors, to, inside, the, nucleus, are, thought, to, contribute, to, neoplastic, transformation, of, hematopoietic, cells])].
[sujeto(['To', present, a, special, case, with, the, karyotype, and, molecular, marker, of, acute, myeloid, leukemia, '(', 'AML)-M2', who, was]), verbo([induced]), complemento([to, complete, remission, by, 'all-trans', retinoic, acid, '(', 'ATRA)', alone])].
[sujeto(['After', primarily, cultured, bone, marrow, cells, from, the, iliac, aspiration, were, tested, for, in, vitro]), verbo([induced]), complemento(['differentiation,', the, patient, was, treated, with, oral, 'all-trans', retinoic, acid, 'alone,', 60, mg, per, day, until, complete, remission, was, achieved])].
[sujeto(['The', characteristic, chromosomal, aberration, for, 'M3,', the, 't(15;17)', reciprocal, 'translocation,', was, not]), verbo([found]), complemento([while, a, 't(8;21)', translocation, was, verified])].
[sujeto(['Primary', cultured, bone, marrow, cells, can, be, fully]), verbo([induced]), complemento([to, terminal, differentiation, after, 4, days, exposure, to, 'ATRA'])].
[sujeto(['A', hematological, complete, remission, was, achieved, after, 40, days, treatment, with, 'ATRA', as, a, single, therapeutic, 'agent,']), verbo([suggesting]), complemento([an, alternative, pathway, mediating, 'ATRA-induced', myeloid, differentiation])].
[sujeto(['A', leukemia, patient, with, a, subtype, other, than, 'M3,', such, as, 'M2', in, this, 'case,', may, also, be]), verbo([induced]), complemento([to, complete, remission, by, the, mechanism, of, 'ATRA-induced', terminal, differentiation])].
[sujeto(['This', implies, that, there, may, be, a, pathway, other, than, 'PML/RAR', alpha, fusion, gene, product, which]), verbo([mediates]), complemento(['ATRA-induced', myeloid, maturation, in, leukemia, cells])].
[sujeto(['This', effect, is, due, to, the, ability, of, the, 'ETO', portion, of, the, protein, to]), verbo([recruit]), complemento(['co-repressors', to, promoters, of, 'AML-1', target, genes])].
[sujeto(['The', 't(11;17)(q21;q23)-associated', acute, promyelocytic, leukemia, creates, the, promyelocytic, leukemia, zinc, finger, 'PLZFt/RAR', alpha, fusion, protein, 'and,', in, a, similar, 'manner,']), verbo([inhibits]), complemento(['RAR', alpha, target, gene, expression, and, myeloid, differentiation])].
[sujeto(['PLZF', is]), verbo([expressed]), complemento([in, hematopoietic, progenitors, and, functions, as, a, growth, suppressor, by, repressing, cyclin, 'A2', and, other, targets])].
[sujeto(['This', effect, was, dependent, on, the, presence, of, the, 'ETO', zinc, finger, 'domain,', which]), verbo([recruits]), complemento(['corepressors,', and, could, not, be, rescued, by, overexpression, of, 'co-repressors', that, normally, enhance, 'PLZF', repression])].
[sujeto(['AML-1/ETO', also, excluded, 'PLZF', from, the]), verbo([nuclear]), complemento([matrix, and, reduced, its, ability, to, bind, to, its, cognate, 'DNA-binding', site])].
[sujeto(['Finally,', 'ETO']), verbo([interacted]), complemento([with, 'PLZF/RAR', alpha, and, enhanced, its, ability, to, repress, through, the, 'RARE'])].
[sujeto([2000, ;, 96, :, 3939, -, 3947, ')', 'RAR', and, 'AML1', transcription, factors, are]), verbo([found]), complemento([in, leukemias, as, fusion, proteins, with, 'PML', and, 'ETO,', respectively])].
[sujeto(['Association', of, 'PML-RAR', and, 'AML1-ETO', with, the]), verbo([nuclear]), complemento([corepressor, '(', 'N-CoR)/histone', deacetylase, '(', 'HDAC)', complex, is, required, to, block, hematopoietic, differentiation])].
[sujeto(['We', show, that, 'PML-RAR', and, 'AML1-ETO', exist, in, vivo, within, high, molecular, weight, '(', 'HMW)']), verbo([nuclear]), complemento(['complexes,', reflecting, their, oligomeric, state])].
[sujeto(['Oligomerization']), verbo([requires]), complemento(['PML', or, 'ETO', 'coiled-coil', regions, and, is, responsible, for, abnormal, recruitment, of, 'N-CoR,', transcriptional, 'repression,', and, impaired, differentiation, of, primary, hematopoietic, precursors])].
[sujeto(['The', 'Wilms', tumor, gene, '(', 'WT1)']), verbo([has]), complemento([been, reported, to, be, a, prognostic, factor, and, a, marker, for, the, detection, of, minimal, residual, disease, '(', 'MRD)', in, acute, leukemia])].
[sujeto(['Here', we, studied, minimal, residual, disease, '(', 'MRD)', of, patients, with, acute, myeloid, leukemia, '(', 'AML)', who]), verbo([have]), complemento(['PML/RAR', alpha, or, 'AML1/ETO', as, well, as, the, phenotypic, analysis, of, lymphocyte, subsets, involved, in, antitumor, immunity])].
[sujeto(['Basically,', the, total, percentage, of, the, 'CD4+,', 'CD8+', and, 'CD56+', cell, populations, in, the, 'BM', was]), verbo([increased]), complemento([and, in, the, following, 'order:', 'MRD-/LT', 'patients,', normal, 'volunteers,', 'MRD+/LT', patients, and, 'MRD+', or, -, /, 'ST', patients])].
[sujeto(['Sequence', analysis, revealed, that, the, promoter, of, gcfoxp3, contains, 'AP-1,', 'AML-1/Runx1,', 'NF-κb', and, 'GATA-3']), verbo([binding]), complemento(['sites,', which, positively, or, negatively, regulate, mammalian, foxp3, expression])].
[sujeto(['In', 'addition,', the, intron, 'II', of, gcfoxp3, contains, some, putative]), verbo([binding]), complemento([sites, including, 'AP-1,', 'NFAT,', 'Smad3,', 'RAR,', 'CREB/ATF', and, 'FOXO1,', which, are, corresponding, to, their, locations, in, the, proximal, intronic, enhancers, of, human, foxp3])].
[sujeto(['In', an, in, vivo, model, of, grass, 'carp,', an, immunosuppressive, agent, rapamycin, was, showed, to]), verbo([stimulate]), complemento([gcfoxp3, mRNA, expression, in, 'thymus,', 'gill,', head, kidney, and, spleen, after, bacterial, challenge])].
[sujeto(['Moreover,', rapamycin]), verbo([increased]), complemento([gcFoxp3, protein, levels, with, an, additive, manner, in, the, infected, fish])].
[sujeto(['These', findings, support, the, involvement, of, fish, 'Foxp3', in, immune, response, and, highlight, a, possible, signaling, pathway, that]), verbo([regulates]), complemento([teleost, 'Foxp3', expression])].
[sujeto(['Terminal', differentiation, of, blood, cells]), verbo([requires]), complemento([the, concerted, action, of, a, series, of, transcription, factors, that, are, expressed, at, specific, stages, of, maturation, and, function, in, a, 'cell-type', and, 'dosage-dependent', manner])].
[sujeto(['A', role, for, 'PIR', in, myeloid, differentiation]), verbo([has]), complemento([not, to, date, been, reported])].
[sujeto(['In', this, study, we, show, that, 'PIR', expression, is, significantly]), verbo([repressed]), complemento([in, a, large, proportion, of, acute, myeloid, leukemias, '(', 'AMLs),', regardless, of, subtype, or, underlying, karyotypic, abnormalities])].
[sujeto(['We', show, that, 'PIR', expression]), verbo([increases]), complemento([during, in, vitro, myeloid, differentiation, of, primary, hematopoietic, precursor, 'cells,', and, that, ablation, of, 'PIR', in, the, 'U937', myelomonocytic, cell, line, or, in, murine, primary, hematopoietic, precursor, cells, results, in, impairment, of, terminal, myeloid, differentiation])].
[sujeto(['Gene', expression, profiling, of, 'U937', cells, after, knockdown, of, 'PIR', revealed]), verbo([increased]), complemento([expression, of, genes, associated, with, the, early, phases, of, 'hematopoiesis,', in, 'particular,', homeobox, 'A', '(', 'HOXA)', genes])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, 'PIR', is, required, for, terminal, myeloid, 'maturation,', and, its, downregulation, may, contribute, to, the, differentiation, arrest, associated, with, 'AML'])].
[sujeto(['A', number, of, molecular]), verbo([targets]), complemento([have, been, identified, in, 'leukemia,', based, on, the, understanding, of, signaling, pathways, controlling, cell, 'differentiation,', 'proliferation,', 'apoptosis,', and, malignant, transformation])].
[sujeto(['Growth', factors, and, integrins]), verbo([interact]), complemento([with, their, receptors, and, activate, signaling, cascades, with, intimate, interconnections])].
[sujeto(['The', specific, niches, within, the, bone, marrow, microenvironment, may]), verbo([provide]), complemento([a, sanctuary, for, subpopulations, of, leukemic, cells, to, escape, 'chemotherapy-induced', death, and, acquire, drug, resistance])].
[sujeto(['Investigations', into, bone, marrow, 'stroma-leukemia', crosstalk, may, result, in, the, development, of, strategies, against, the, acquisition, of, a, 'chemo-resistant', phenotype, and]), verbo([enhance]), complemento([the, efficacy, of, therapies, in, leukemia])].
[sujeto(['In', recent, 'studies,', we, proposed, novel, therapeutic, interventions]), verbo([targeting]), complemento([the, 'microenvironment/leukemia', interaction, focusing, on, 'SDF1/CXCR4,', 'ILK/PI3K/Akt,', 'TGF-beta,', and, 'Notch', signaling])].
[sujeto(['Gene', transcriptional, activity, is]), verbo([regulated]), complemento([by, chromatin, modification, and, 'DNA', methylation])].
[sujeto(['The', transcription, of]), verbo([target]), complemento([genes, is, initiated, following, the, ligation, of, these, 'receptors,', recruitment, of, 'co-activators,', and, replacement, of, repressors])].
[sujeto(['We', demonstrated, that, histone, acetylation, by, the, 'PPARgamma', agonist, 'CDDO,', 'RAR/RXR', agonist, 'ATRA,', 'and/or', histone, deacetylase, inhibitors, '(', 'HDACIs)', reversed, the, silenced, 'RARbeta', and, 'MDR1', genes, in, acute, promyelocytic, 'leukemia,', and, that, 'HDACI']), verbo([induced]), complemento([apoptosis, with, phagocytosis, through, the, induction, of, 'Annexin', 'A1', in, 'AML1/ETO-positive', acute, myelocytic, leukemia, '(', 'AML)', cells])].
[sujeto(['Finally,', we, emphasize, the, potential, applications, of, research, findings, and, methods, in, the, fields, of, clinical, 'medicine,', molecular, 'diagnosis,', and]), verbo([targeting]), complemento([therapy])].
[sujeto(['To', investigate, the, expression, level, of, preferentially]), verbo([expressed]), complemento([antigen, of, melanoma, '(', 'PRAME)', mRNA, in, newly, diagnosed, acute, myeloid, leukemia, '(', 'AML)', patients, and, evaluate, its, usefulness, for, detecting, minimal, residual, disease, '(', 'MRD)'])].
[sujeto(['PRAME', mRNA, levels, were, detected, in, bone, marrow, samples, from, 142, newly, diagnosed, 'AML', patients, '(', 72, of, them, 'didn\'t']), verbo([express]), complemento([any, specific, fusion, 'gene)', by, 'TaqMan', based, 'real-time', quantitative, 'PCR', 'methods,', and, were, serially, monitored, in, 60, bone, marrow, samples, from, 9, 'follow-up', patients, '(', 2, of, them, without, specific, fusion, 'gene),', including, 3, in, continuous, complete, 'remission,', 6, in, hematological, relapse])].
[sujeto([abl, was, selected, as, control, 'gene,', 'PRAME', and, 'AML1-ETO', mRNA, levels, were]), verbo([expressed]), complemento([by, their, 'copies/abl', copies, in, percentage])].
[sujeto(['All', 'NBM', samples]), verbo([expressed]), complemento(['PRAME', mRNA, and, the, upper, limit, was, 0.28, '%'])].
[sujeto(['For', all, newly, diagnosed, 'AML', 'patients,', median, 'PRAME', mRNA, level, was, 3.97, '%', '(', 0.0, '%', -, 714.97, '%', ')', ',', 76.8, '%', of, them, was, higher, than, 0.28, '%', ',', 54.9, '%', had, over, 1, -, log]), verbo([increasing]), complemento([and, 26.1, '%', had, over, 2, -, log, increasing])].
[sujeto(['AML1-ETO', '(', +, ')', 'M2', patients]), verbo([expressed]), complemento([the, highest, levels, '(', all, 'P&lt;0'])].
[sujeto(['PRAME', mRNA, levels, in, 3, hematological, relapsed, patients]), verbo([increased]), complemento([above, 0.28, '%', 1, -, 4, months, ahead, 'relapse,', and, in, other, 3, relapsed, patients, the, levels, never, decreased, to, normal, range, even, in, remission])].
[sujeto(['PRAME', mRNA, could, be, used, to, monitor, 'MRD', for, 'AML', patients, with, higher, than, normal, 'levels,', and, it]), verbo([increases]), complemento([over, or, persistently, higher, than, normal, range, predicts, hematological, relapse])].
[sujeto(['Basophilic', crisis, and, eosinophilia, are, well]), verbo([recognized]), complemento([features, of, advanced, chronic, myeloid, leukaemia])].
[sujeto(['In', this, 'patient,', who, initially, suffered, from, chronic, myelomonocytic, 'leukaemia,', basophils]), verbo([increased]), complemento([to, 48, '%', and, eosinophils, up, to, 31, '%', at, the, time, of, progression])].
[sujeto(['Mixed', lineage, crisis, was, not, accompanied, by, an]), verbo([increase]), complemento([in, blast, cells, or, organomegaly])].
[sujeto(['Basophils', were, thus]), verbo([found]), complemento([to, be, 'CD123+,', 'CD203c+,', 'BB1+,', 'KIT-', 'cells,', and, to, express, a, functional, 'IgE-receptor'])].
[sujeto(['Among', the, other, patients, with, 'MDS', 'examined,', 4, '(', 1.2, '%', ')', were]), verbo([found]), complemento([to, have, marked, basophilia, '(', &, 'gt;or=', 20, '%', ')', and, 7, '(', 2.1, '%', ')', were, found, to, have, massive, eosinophilia, '(', &, 'gt;or=', 20, '%', ')', ',', whereas, 'mixed-lineage', crisis, was, detected, in, none, of, them])].
[sujeto(['Histone', deacetylases, '(', 'HDACs)']), verbo([regulate]), complemento([transcription, and, specific, 'functions,', such, as, tumor, suppression, by, 'p53,', and, are, frequently, altered, in, cancer])].
[sujeto(['Inhibitors', of, 'HDACs', '(', 'HDACI)', possess, 'anti-tumor', activity, and, are, well, 'tolerated,']), verbo([suggesting]), complemento([that, they, might, develop, into, a, specific, strategy, for, cancer, treatment])].
[sujeto(['Indeed,', 'HDACIs']), verbo([have]), complemento([successfully, entered, clinical, 'trials,', but, the, molecular, basis, for, their, selective, 'anti-tumor', activities, is, not, clear])].
[sujeto(['Recent', work, on, leukemias]), verbo([expressing]), complemento([the, 'PML-RAR', or, 'AML1-ETO', 'oncogenes,', known, to, initiate, leukemogenesis, through, deregulation, of, 'HDACs,', shows, that, 'HDACIs', induce, massive, 'blast-cell', apoptosis])].
[sujeto(['Significantly,', normal, myeloid, progenitors, are, not, sensitive, to, 'HDACI-induced', apoptosis, and, oncogene, expression, is, not, sufficient, to]), verbo([confer]), complemento(['HDACI-sensitivity', to, normal, 'cells,', demonstrating, that, sensitivity, to, 'HDACI', is, a, property, of, the, fully, transformed, phenotype])].
[sujeto(['In', the, last, twenty, 'years,', using, 'all-trans', retinoic, acid, '(', 'ATRA)', as, a, differentiation, 'inducer,', 'Shanghai', 'Institute', of, 'Hematology']), verbo([has]), complemento([achieved, an, important, breakthrough, in, the, treatment, of, acute, promyelocytic, leukemia, '(', 'APL),', which, realized, the, theory, of, reversing, phenotype, of, cells, and, provided, a, successful, model, of, differentiation, therapy, in, cancers])].
[sujeto(['The', ability, of, 'ATRA', to, modify, the, recruitment, of]), verbo([nuclear]), complemento([receptor, 'co-repressor', with, 'PML-RAR', alpha, but, not, 'PLZF-RAR', alpha, caused, by, the, variant, chromosome, translocation, elucidated, the, therapeutic, mechanism, of, 'ATRA', from, the, molecular, level, and, provides, new, insight, into, 'transcription-modulating', therapy])].
[sujeto(['Since', 1994, ',', our, group]), verbo([has]), complemento([successfully, applied, arsenic, trioxide, '(', 'As(2)O(3))', in, treating, relapsed, 'APL', 'patients,', with, the, complete, remission, rate, of, 70, '%', -, 80, '%'])].
[sujeto(['Low-dose', 'As(2)O(3)']), verbo([induced]), complemento([partial, differentiation, of, 'APL', 'cells,', while, the, higher, dose, induced, apoptosis])].
[sujeto(['As(2)O(3)']), verbo([binds]), complemento([ubiquitin, like, 'SUMO-1', through, the, lysine, 160, of, 'PML,', resulting, in, the, degradation, of, 'PML-RAR', alpha])].
[sujeto(['Taken', 'together,', 'ATRA', and, 'As(2)O(3)']), verbo([target]), complemento([the, transcription, factor, 'PML-RAR', 'alpha,', the, former, by, retinoic, acid, receptor, and, the, latter, by, 'PML', 'sumolization,', both, induce, 'PML-RAR', alpha, degradation, and, 'APL', cells, differentiation, and, apoptosis])].
[sujeto(['Because', of, the, different]), verbo([acting]), complemento(['pathways,', 'ATRA', and, 'As(2)O(3)', have, no, 'cross-resistance', and, can, be, used, as, combination, therapy])].
[sujeto(['Based', on, the, great, success, of, the, pathogenetic, gene]), verbo([target]), complemento([therapy, in, 'APL,', this, strategy, may, extend, to, other, leukemias])].
[sujeto(['Combination', of, 'Gleevec', and, arsenic, agents, in, treating, chronic, myeloid, leukemia]), verbo([has]), complemento([already, make, a, figure, both, in, clinical, and, laboratory, 'research,', aiming, at, counteracting, the, abnormal, tyrosine, kinase, activity, of, 'ABL', and, the, degradating, 'BCR-ABL', fusion, protein])].
[sujeto(['In', acute, myeloid, leukemia, 'M(2b),', using, new]), verbo([target]), complemento([therapy, degradating, 'AML1-ETO', fusion, protein, and, reducing, the, abnormal, tyrosine, kinase, activity, of, 'c-kit', will, also, lead, to, new, therapeutic, management, in, acute, leukemias])].
[sujeto(['Histone', deacetylases, '(', 'HDACs)']), verbo([regulate]), complemento([transcription, and, specific, cellular, 'functions,', such, as, tumor, suppression, by, 'p53,', and, are, frequently, altered, in, cancer])].
[sujeto(['We', investigated, the, effects, of, 'HDACIs', on, leukemias]), verbo([expressing]), complemento([the, 'PML-RAR', or, 'AML1-ETO', 'oncoproteins,', known, to, initiate, leukemogenesis, through, deregulation, of, 'HDACs'])].
[sujeto(['Here', we]), verbo([report]), complemento(['that:', '(', 'i)', 'HDACIs', induce, apoptosis, of, leukemic, 'blasts,', although, oncogene, expression, is, not, sufficient, to, confer, 'HDACI', sensitivity, to, normal, 'cells;', '(', 'ii)', apoptosis, is, p53, independent, and, 'depends,', both, in, vitro, and, in, 'vivo,', upon, activation, of, the, death, receptor, pathway, '(', 'TRAIL', and, 'Fas', signaling, 'pathways);', '(', 'iii)', 'TRAIL,', 'DR5,', 'FasL', and, 'Fas', are, upregulated, by, 'HDACIs', in, the, leukemic, 'cells,', but, not, in, normal, hematopoietic, progenitors])].
[sujeto(['The', speed, of, 'FISH', is, very, valuable, in, 'AML-M3/M3v', because, 'PML/RAR+', patients]), verbo([require]), complemento([specific, therapy])].
[sujeto(['Furthermore,', we]), verbo([suggest]), complemento(['FISH', screening, in, 'failed,', complex, or, suboptimal, quality, chromosome, and, specific, 'FISH', analysis, for, 5, 'q,', 7, 'q,', 12, 'p,', 17, 'p,', 'inv(16),', 't(11q23)', in, order, to, implement, 'CBA', accuracy])].
[sujeto(['Genes,', such, as, those, of, 'mixed-lineage', 'leukaemia,', 'AML1', and, retinoic, acid, receptor, 'alpha,']), verbo([have]), complemento([been, found, to, be, aberrantly, fused, to, different, 'partners,', which, often, encode, transcription, factors, or, other, chromatin, modifying, 'enzymes,', in, numerous, types, of, acute, lymphoid, and, myeloid, leukaemias])].
[sujeto(['These', chimeric, fusion, 'oncoproteins,', generated, by, reciprocal, chromosomal, 'translocations,', are, responsible, for, chromatin, alterations, on]), verbo([target]), complemento([genes, whose, expression, is, critical, to, stem, cell, development, or, lineage, specification, in, haematopoiesis])].
[sujeto(['Alterations', in, the, '\'', histone, 'code\'', or, in, the, 'DNA', methylation, content, occur, as, consequence, of, aberrant]), verbo([targeting]), complemento([of, the, corresponding, enzymatic, activities])].
[sujeto(['Several', lines, of, evidence]), verbo([suggest]), complemento([similar, pathogenetic, mechanisms, for, these, fusion, proteins])].
[sujeto(['We', used, 'high-density', oligonucleotide, arrays, to, identify, shared]), verbo([target]), complemento([genes, in, inducibly, transfected, 'U937', cells, expressing, 'AML1-ETO,', 'PML-RARalpha,', or, 'PLZF-RARalpha'])].
[sujeto(['All', three, fusion, proteins, significantly]), verbo([repressed]), complemento([the, expression, of, 38, genes, and, induced, the, expression, of, 14, genes])].
[sujeto(['Several', of, the]), verbo([regulated]), complemento([genes, were, associated, with, 'Wnt', signaling])].
[sujeto(['One', of, 'these,', plakoglobin, '(', 'gamma-catenin),', was]), verbo([induced]), complemento([on, the, mRNA, and, protein, level, by, all, three, fusion, proteins])].
[sujeto(['The', plakoglobin, promoter, was, cloned, and, shown, to, be]), verbo([induced]), complemento([by, 'AML1-ETO,', with, promoter, activation, depending, on, the, corepressor, and, histone, deacetylase, binding, domains])].
[sujeto(['The', induction, of, plakoglobin, by, 'AML', fusion, proteins]), verbo([led]), complemento([to, downstream, signaling, and, transactivation, of, 'TCF-', and, 'LEF-dependent', 'promoters,', including, the, 'c-myc', 'promoter,', which, was, found, to, be, bound, by, plakoglobin, in, vivo, after, 'AML1-ETO', expression])].
[sujeto(['beta-Catenin', protein, levels, and, 'TCF', and, 'LEF']), verbo([target]), complemento([genes, such, as, 'c-myc', and, cyclin, 'D1', were, found, to, be, induced, by, the, fusion, proteins])].
[sujeto(['On', the, functional, 'level,', a, dominant, negative, 'TCF']), verbo([inhibited]), complemento([colony, growth, of, 'AML1-ETO-positive', 'Kasumi', 'cells,', whereas, plakoglobin, transfection, into, myeloid, 32, 'D', cells, enhanced, proliferation, and, clonal, growth])].
[sujeto(['Transduction', of, plakoglobin, into, primitive, murine, hematopoietic, progenitor, cells, preserved, the, immature, phenotype, during, colony, 'growth,']), verbo([suggesting]), complemento([enhanced, 'self-renewal'])].
[sujeto(['These', data]), verbo([provide]), complemento([evidence, that, activation, of, 'Wnt', signaling, is, a, common, feature, of, several, balanced, translocations, in, 'AML'])].
[sujeto(['We']), verbo([report]), complemento([a, case, of, acute, myeloid, leukemia, 'FAB-type', 2, with, a, translocation, 't(15;17)(q22;q12)', 'On', the, basis, of, the, cytological, 'findings,', a, translocation, 't(8;21)(q22;q22)', was, suspected])].
[sujeto(['Oncogene', amplification, resulting, in, aberrant, 'expression,', although, common, in, solid, 'tumors,', is, rare, in, acute, myeloid, leukemia, '(', 'AML)', and, is, mostly]), verbo([associated]), complemento([with, amplification, of, 'MYC,', 'RUNX1,', and, 'MLL', genes])].
[sujeto(['Retinoic', acid, receptor, alpha, '(', 'RARA)', and, other]), verbo([target]), complemento([sequences, at, 17, p11])].
[sujeto([2, often, represent, the, amplicons]), verbo([expressed]), complemento([in, breast, 'cancer,', not, in, 'AML'])].
[sujeto(['Fluorescence', in, situ, hybridization, '(', 'FISH)', analysis, showed, amplification, of, 'RARA,']), verbo([loss]), complemento([of, 7, 'q,', monosomy, 7, ',', loss, of, 'DEK', '(', 6, 'p23),', and, additional, copies, of, 'NUP214', '(', 9, 'q34)', and, 'MLL', '(', 11, 'q23)'])].
[sujeto(['Additional', case]), verbo([reports]), complemento([are, necessary, to, assess, whether, 'RARA', amplification, in, hematologic, malignancies, serves, as, an, independent, prognostic, factor])].
[sujeto(['The', use, of, genetically, engineered, mice, '(', 'GEM)']), verbo([have]), complemento([been, critical, in, understanding, disease, states, such, as, 'cancer,', and, none, more, so, than, acute, myelogenous, leukaemia, '(', 'AML),', a, disease, characterized, by, over, 100, distinct, chromosomal, translocations])].
[sujeto(['A', substantial, proportion, of, cases, exhibiting, recurrent, reciprocal, translocations, at, 'diagnosis,', such, as, 't(8;21)', or, 't(15;17)']), verbo([have]), complemento([been, exhaustively, studied, and, are, currently, employed, in, clinical, diagnosis])].
[sujeto(['Furthermore,', little, emphasis]), verbo([has]), complemento([been, paid, to, the, effect, of, chromosomal, translocations, other, than, recurrent, genetic, 'abnormalities,', with, no, models, reflecting, the, multiple, abnormalities, observed, in, 'high-risk', cases, of, 'AML', accounting, for, 8, -, 10, '%', of, adult, 'AML'])].
[sujeto(['The', latter]), verbo([have]), complemento([been, used, to, great, effect, in, defining, the, transforming, properties, of, chromosomal, translocation, products, such, as, 'MLL', '(', found, in, 5, -, 6, '%', of, all, 'AML', 'cases)', and, 'NUP98', '(', denoting, poor, prognosis, in, 'therapy-related', 'disease)', and, particularly, when, 'co-transduced', with, bad, prognostic, factors, such, as, 'Flt3', mutations])].
[sujeto(['Finally,', we, comment, on, the, emergence, of, newer, transduction, 'technologies,', which, can]), verbo([regulate]), complemento([the, level, of, expression, to, defined, cell, lineages, in, both, primary, murine, and, human, 'xenografts,', and, discuss, how, combining, multiple, genetic, 'modalities,', more, relevant, models, of, this, complex, disease, are, being, generated])].
[sujeto([1, gene, mutations, were, identified, in, some, patients, with, acute, myeloid, leukemia, '(', 'AML)', and, as, several, oncogenic, products, '(', 'AML1-ETO,', promyelocytic, 'leukemia-retinoic', acid, receptor, 'alpha,', 'FMS-like', receptor, tyrosine, kinase, 3, internal, tandem, 'duplication)', are]), verbo([associated]), complemento([with, 'PU'])].
[sujeto(['In', 'NB4', cells, we, obtained]), verbo([increases]), complemento([in, 'PU'])].
[sujeto([1, mRNA, and, 'protein,', comparable, to]), verbo([increases]), complemento([obtained, with, 'all-trans', retinoic, 'acid-stimulation'])].
[sujeto(['Transduced', cells, showed]), verbo([increased]), complemento([myelomonocytic, surface, antigen, 'expression,', decreased, proliferation, rates, and, increased, apoptosis])].
[sujeto([1, should, therefore, constitute, an, interesting]), verbo([target]), complemento([for, therapeutic, intervention, in, 'AML'])].
[sujeto(['MEF', is, an, 'ETS-related', transcription, factor, with, strong, transcriptional]), verbo([activating]), complemento([activity, that, affects, hematopoietic, stem, cell, behavior, and, is, required, for, normal, 'NK', cell, and, 'NK', 'T-cell', development])].
[sujeto(['The', 'MEF', '(', also, known, as, 'ELF4)', gene, is]), verbo([repressed]), complemento([by, several, 'leukemia-associated', fusion, transcription, factor, proteins, '(', 'PML-retinoic', acid, receptor, alpha, and, 'AML1-ETO),', but, it, is, also, activated, by, retroviral, insertion, in, several, cancer, models])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, cyclin, 'A-dependent', phosphorylation, of, 'MEF', largely, restricts, its, activity, to, the, 'G(1)', phase, of, the, cell, 'cycle;', we, now, show, that, 'MEF', is, a, 'short-lived', protein, whose, expression, level, also, peaks, during, late, 'G(1)', phase])].
[sujeto(['Mutagenesis', studies, show, that, the, rapid, turnover, of, 'MEF', in, 'S', phase, is, dependent, on, the, specific, phosphorylation, of, threonine, 643, and, serine, 648, at, the, 'C', terminus, of, 'MEF', by, cdk2, and, on, the, 'Skp1/Cul1/F-box', '(', 'SCF)', 'E3', ubiquitin, ligase, complex, 'SCF(Skp2),', which]), verbo([targets]), complemento(['MEF', for, ubiquitination, and, proteolysis])].
[sujeto(['Overexpression', of, 'MEF', drives, cells, through, the, 'G(1)/S', 'transition,', thereby]), verbo([promoting]), complemento([cell, proliferation])].
[sujeto(['The', tight, regulation, of, 'MEF', levels, during, the, cell, cycle, contributes, to, its, effects, on]), verbo([regulating]), complemento([cell, cycle, entry, and, cell, proliferation])].
[sujeto(['Cellular', and, systemic, 'O(2)', concentrations, are, tightly]), verbo([regulated]), complemento([to, maintain, delicate, oxygen, homeostasis])].
[sujeto(['Although', the, roles, of, hypoxia, in, solid, tumors]), verbo([have]), complemento([been, widely, 'studied,', few, studies, were, reported, regarding, the, possible, effects, of, hypoxia, on, leukemic, cells])].
[sujeto(['Here,', we, showed, for, the, first, time, that, low, concentrations, of, cobalt, chloride, '(', 'CoCl(2)),', a, 'hypoxia-mimicking', 'agent,', and, 2, -, 3, '%', 'O(2)']), verbo([triggered]), complemento([differentiation, of, various, subtypes, of, human, acute, myeloid, leukemic, '(', 'AML)', cell, 'lines,', including, 'NB4,', 'U937', and, 'Kasumi-1', 'cells,', 'respectively,', from, 'M3,', 'M5', and, 'M2b-type', 'AML,', but, 'CoCl(2)', did, not, modulate, 'AML', 'subtype-specific', fusion, proteins, promyelocytic, 'leukemia-retinoic', acid, receptor, alpha, '(', 'PML-RARalpha)', and, 'AML1-ETO'])].
[sujeto(['Treatment', with, 'CoCl(2)', also]), verbo([induced]), complemento([primary, leukemic, cells, from, some, 'AML', patients, to, undergo, differentiation])].
[sujeto(['Similar', to, what, occurs, in, solid, tumor, 'cells,', 'CoCl(2)-mimicked', hypoxia, also]), verbo([increased]), complemento([the, level, of, 'hypoxia-inducible', factor, '(', 'HIF)-1alpha', protein, and, its, 'DNA-binding', activity, in, leukemic, cells])].
[sujeto(['The', 'CoCl(2)', induction, of, 'HIF-1alpha', protein, and, its, 'DNA-binding', activity, were]), verbo([inhibited]), complemento([by, 3, -, 'morpholinosydnonimine,', which, also, blocked, 'CoCl(2)-induced', cell, differentiation, in, leukemic, cells])].
[sujeto(['These', results]), verbo([provide]), complemento([an, insight, into, a, possible, link, of, hypoxia, or, 'HIF-1alpha', and, leukemic, cell, 'differentiation,', and, are, possibly, of, significance, to, explore, clinical, potentials, of, hypoxia, or, 'hypoxia-mimicking', agents, and, novel, 'target-based', drugs, for, differentiation, therapy, of, leukemia])].
[sujeto(['Significant', levels, of, 'WT1', gene, were]), verbo([expressed]), complemento([in, all, leukemia, patients, and, for, 'CML', the, levels, increased, as, the, clinical, phase, progressed])].
[sujeto(['Patients', with, less, than, 0.6, levels, had, significantly, higher, rates, of, complete, remission, '(', 'CR),', 'disease-free', 'survival,', and, overall, survival, than, those, with, &, 'gt;', or, =, 0.6, 'levels,', whereas, 'CR', could, not, be]), verbo([induced]), complemento([in, any, of, the, 7, patients, with, acute, leukemia, having, greater, than, 1.0, levels, of, 'WT1', gene, expression])].
[sujeto(['In', 2, other, 'patients,', the, 'WT1', mRNA, gradually]), verbo([increased]), complemento([after, discontinuation, of, chemotherapy])].
[sujeto(['However,', the, development, of, 'therapy-related', myeloid, neoplasms, '(', 't-MN)', is, being]), verbo([reported]), complemento([with, increasing, frequency, in, patients, successfully, treated, for, 'APL'])].
[sujeto(['We', attempted, to, clarify, the, different, clinical, features, and, hematologic, findings, between, 't-MN', and, relapse, 'cases,', and, to, identify, gene, alterations]), verbo([involved]), complemento([in, 't-MN'])].
[sujeto(['Cytogenetic', abnormalities, or, point, mutations, of, the, 'hematopoiesis-specific', genes, are, frequently]), verbo([found]), complemento([in, patients, with, 'AML,', and, these, genetic, aberrations, are, closely, associated, with, the, pathophysiology, of, the, disease])].
[sujeto(['Molecular', pathogenesis, of, 'AML']), verbo([has]), complemento([been, disclosed, through, analyses, of, such, gene, 'aberrations,', including, 'AML1', and, 'MLL', 'abnormalities,', 'PML-RARA', chimeric, 'gene,', activating, mutations, of, 'FLT3,', and, 'EVI-1', abnormalities])].
[sujeto(['Through', prediction, of, prognosis, and]), verbo([targeted]), complemento(['therapy,', this, knowledge, on, pathogenesis, of, 'AML', has, been, applied, to, the, clinical, 'practice,', and, further, investigation, should, improve, the, outcome, of, therapy, for, 'AML', in, the, future])].
[sujeto(['A', reciprocal, translocation]), verbo([involving]), complemento([chromosomes, 15, and, 17, ',', 't(15;17)(q22;q21),', is, a, characteristic, feature, of, 'APL', that, represents, approximately, 5, -, 8, '%', of, 'AML'])].
[sujeto(['Nonetheless,', 'therapy-related', myelodysplastic, 'syndrome-acute', myelogenous, leukemia, '(', 't-MDS/AML)']), verbo([has]), complemento([been, reported, as, a, rare, complication, of, chemotherapy, in, 'APL'])].
[sujeto(['Submicroscopic', deletions, of, genes, in, recurrent, chromosomal, rearrangements, occur, frequently, in, hematologic, 'malignancies,', but, their, incidences]), verbo([have]), complemento([not, been, reported, clearly])].
[sujeto(['We']), verbo([report]), complemento([the, first, 'dry-reagent,', 'disposable,', dipstick, test, for, molecular, screening, of, seven, chromosomal, translocations, associated, with, acute, and, chronic, leukemia])].
[sujeto(['The', dipstick, assay, with, appropriate, probes, can, be, used, for, identification, of, the, fusion, transcripts]), verbo([involved]), complemento([in, the, translocation])].
[sujeto(['This', chromosomal, translocation, is]), verbo([associated]), complemento([with, de, novo, and, 'therapy-related', acute, myeloid, leukemia, and, with, the, blast, crisis, of, chronic, myelogenous, leukemia])].
[sujeto(['The', mechanisms, by, which, 'AME']), verbo([induces]), complemento([a, neoplastic, transformation, in, bone, marrow, cells, are, unknown])].
[sujeto(['AME']), verbo([interacts]), complemento([with, the, corepressors, 'CtBP', and, 'HDAC1,', and, it, was, shown, that, 'AME', is, a, repressor, in, contrast, to, the, parent, transcription, factors, 'AML1', and, 'ME,', which, are, transcription, activators])].
[sujeto(['Studies', with, murine, bone, marrow, progenitors, indicated, that, the, introduction, of, a, point, mutation, that, destroys, the, 'CtBP-binding', consensus, impairs, but, does, not, abolish, the, disruption, of, cell, differentiation, and, replication]), verbo([associated]), complemento([with, 'AME', 'expression,', suggesting, that, additional, events, are, required])].
[sujeto(['We']), verbo([report]), complemento([that, 'AME', is, also, able, to, oligomerize, and, displays, a, complex, pattern, of, 'self-interaction', that, involves, at, least, three, oligomerization, 'regions,', one, of, which, is, the, distal, zinc, finger, domain])].
[sujeto(['Although', the, deletion, of, this, short, domain, does, not, preclude, the, 'self-interaction', of, 'AME,', it, significantly, reduces, the, differentiation, defects]), verbo([caused]), complemento([in, vitro, by, 'AME', in, primary, murine, bone, marrow, progenitors])].
[sujeto(['The', addition, of, a, point, mutation, that]), verbo([inhibits]), complemento(['CtBP', binding, completely, abrogates, the, effects, of, 'AME', on, 'differentiation,', suggesting, that, 'AME', induces, hematopoietic, differentiation, defects, through, at, least, two, separate, but, cooperating, pathways])].
[sujeto(['Fluorescence', in, situ, hybridization, '(', 'FISH)', can, detect, minor, genetic, changes, that, cytogenetic, analysis, may, 'miss;', 'however,', there, are, few]), verbo([reports]), complemento([on, the, kinds, of, genetic, changes, that, show, large, discrepancies, between, results, obtained, with, 'FISH', versus, 'G-banding', techniques])].
[sujeto(['Given', these, 'results,', all, patients, with, known, genetic, changes, should]), verbo([have]), complemento(['FISH', analysis, in, 'follow-up,', for, an, accurate, assessment, of, the, likelihood, of, complete, remission, or, recurrence])].
[sujeto(['Eight', patients, showed]), verbo([increasing]), complemento([levels, of, expression, during, 'follow-up', and, all, had, relapse])].
[sujeto(['By', combining, the, transcription, ratios, at, these, 2, 'checkpoints,', a, new, powerful, prognostic, score]), verbo([has]), complemento([been, established])].
[sujeto(['This', was, due, to, the, apparent]), verbo([loss]), complemento([of, the, 3, '\'', part, of, 'RUNX1'])].
[sujeto(['Since', chromosome, number, abnormalities, may, be]), verbo([associated]), complemento([with, submicroscopic, gene, 'rearrangements,', it, should, be, important, to, search, for, them, for, a, better, understanding, of, mechanisms, of, 'leukemogenesis,', and, to, understand, the, prognostic, heterogeneity, in, leukemic, patients, with, aneusomies, without, apparent, chromosome, structure, rearrangements])].
[sujeto(['We', sought, to, understand, the, structure, and]), verbo([gain]), complemento([insight, into, the, fusion, process, between, 'AML1', and, 'ETO', by, sequencing, genomic, fusions, in, 17, primary, childhood, 'AMLs', and, two, cell, lines, with, 't(8;21)'])].
[sujeto(['All', patients, with, available, 'RNA']), verbo([expressed]), complemento([an, 'AML1-ETO', mRNA, fusion, between, exon, 5, of, 'AML1', and, exon, 2, of, 'ETO'])].
[sujeto(['Breakpoints', in, general, displayed, similar, complexity, of, 'duplications,', 'deletions,', and, insertions, to, other, common, pediatric, leukemia, translocations, '(', 'TEL-AML1,', 'MLL-AF4,', 'PML-RARA,', 'CBFB-MYH11)', that, we, and, others]), verbo([have]), complemento([analyzed])].
[sujeto(['Genetic', features, and, clinical, implications, due, to, the, encoded, chimeric, neoproteins]), verbo([causing]), complemento([malignant, haematopoietic, disorders, are, reviewed])].
[sujeto(['A', pivotal, regulatory, network, of, 18, miRNA, and, 16]), verbo([targets]), complemento([was, identified])].
[sujeto(['The', combination, of, inversely]), verbo([expressed]), complemento([miRNAs, and, targets, improved, diagnostic, accuracy])].
[sujeto(['In', a, clinical, feature, 'analysis,', several, miRNAs, '(', 'miR-34a,', 'miR-424,', 'miR-20b,', and, 'miR-152)', and, genes, '(', 'CCNE2,', 'COL4A1,', 'TRAF6,', and, 'HSP90B1)', were]), verbo([associated]), complemento([with, aggressive, clinical, 'features,', which, have, not, previously, been, reported])].
[sujeto(['Our', study, not, only, identified, a, pivotal, miRNA, regulatory, network]), verbo([associated]), complemento([with, 'PTC', but, also, provided, evidence, that, miRNAs, and, target, genes, can, be, used, as, biomarkers, in, 'PTC', diagnosis, and, clinical, risk, evaluation])].
[sujeto(['Transcriptional', dysregulation, is]), verbo([associated]), complemento([with, haematological, malignancy])].
[sujeto([1, downregulation, 'and/or', dysfunction]), verbo([has]), complemento([been, described, in, human, 'AML', patients, carrying, the, fusion, oncogenes, 'RUNX1-ETO', and, 'PML-RARA'])].
[sujeto(['To', study, the, transcriptional, programmes]), verbo([associated]), complemento([with, compromised, 'PU'])].
[sujeto([1, induction]), verbo([caused]), complemento([transition, from, leukaemia, phenotype, to, monocytic, differentiation])].
[sujeto(['Global']), verbo([binding]), complemento([maps, for, 'PU'])].
[sujeto([1]), verbo([retains]), complemento(['DNA-binding', 'ability,', but, the, induction, of, 'wild-type', protein, dramatically, increases, both, the, number, and, the, height, of, 'PU'])].
[sujeto([1, -]), verbo([binding]), complemento([peaks])].
[sujeto(['Correlating', chromatin, immunoprecipitation, '(', 'ChIP)', 'Seq', with, gene, expression, 'data,', we]), verbo([found]), complemento([that, 'PU'])].
[sujeto([1, recruitment, coupled, with]), verbo([increased]), complemento([histone, acetylation, induces, gene, expression, and, activates, a, 'monocyte/macrophage', transcriptional, programme])].
[sujeto([1, induction, also]), verbo([caused]), complemento([the, reorganisation, of, a, subgroup, of, 'CEBPA', binding, peaks])].
[sujeto([1]), verbo([target]), complemento([gene, set, defined, in, our, model, allows, the, stratification, of, primary, human, 'AML', 'samples,', shedding, light, on, both, known, and, novel, 'AML', subtypes, that, may, be, driven, by, 'PU'])].
[sujeto(['The', lack, of, molecular, diagnosis, in, the, field, of, cancer, in, 'Iraq']), verbo([has]), complemento([motivated, us, to, perform, a, genetic, analysis, of, pediatric, acute, myelogenous, leukemia, '(', 'AML),', including, class, 'I', and, 'II', aberrations])].
[sujeto(['The', recent, 'World', 'Health', 'Organization', classification]), verbo([recognizes]), complemento([different, subtypes, of, acute, myeloid, leukemia, '(', 'AML)', according, to, the, presence, of, several, recurrent, genetic, abnormalities])].
[sujeto(['Detection', of, these, abnormalities, and, other, molecular, changes, is, of]), verbo([increasing]), complemento([interest, because, it, contributes, to, a, refined, diagnosis, and, prognostic, assessment, in, 'AML', and, enables, monitoring, of, minimal, residual, disease])].
[sujeto(['We']), verbo([have]), complemento([developed, a, novel, 'real-time', 'RT-PCR', assay, to, simultaneously, detect, 15, 'AML-associated', rearrangements, that, is, a, simple, and, easily, applicable, method, for, use, in, clinical, diagnostic, laboratories])].
[sujeto(['Accordingly,', 'del(20q)', as, an, isolated, abnormality, must, be, distinguished, from, cases, in, which, it, is]), verbo([associated]), complemento([with, other, chromosomal, rearrangements, for, a, better, stratification, of, prognosis])].
[sujeto(['We']), verbo([report]), complemento([a, case, of, an, isolated, 'del(20q)', abnormality, with, additional, genomic, aberrations, identified, using, 'whole-genome', single, nucleotide, polymorphism, array, '(', 'SNP-A)-based', karyotyping])].
[sujeto(['Using', 'FISH,', other, rearrangements, such, as, 'BCR/ABL1,', 'RUNX1/RUNX1T1,', 'PML/RARA,', 'CBFB/MYH11,', and, 'MLL', were]), verbo([found]), complemento([to, be, negative])].
[sujeto(['SNP-A', identified, an, additional, copy, neutral]), verbo([loss]), complemento([of, heterozygosity, '(', 'CN-LOH)', in, the, 11, q13])].
[sujeto(['Unexpectedly,', the, terminal, regions, showed]), verbo([gain]), complemento([on, chromosome, 20, q])].
[sujeto(['The', patient, did, not, achieve, complete, 'remission;', 8, months, 'later,']), verbo([he]), complemento([died, from, complications, of, leukemic, cell, infiltrations, into, the, central, nervous, system])].
[sujeto(['This', study]), verbo([suggests]), complemento([that, a, presumably, isolated, chromosomal, abnormality, by, 'MC', may, have, additional, genomic, 'aberrations,', including, 'CN-LOH,', which, could, be, associated, with, a, poor, prognosis])].
[sujeto(['Multiplex', reverse, transcription, polymerase, chain, reaction, '(', 'mRT-PCR)']), verbo([has]), complemento([recently, emerged, as, an, alternative, to, cytogenetics])].
[sujeto(['However,', false, negative, results, were]), verbo([found]), complemento([in, three, cases, who, have, 'inv(16),', 't(4;11)', or, 't(11;19)(q23;p13'])].
[sujeto(['This', 'mRT-PCR', assay, is, a, useful, screening, tool, in, acute, leukemia, because, it]), verbo([provides]), complemento([rapid, and, reliable, detection, of, clinically, important, chimeric, transcripts])].
[sujeto(['In', 'addition,', cryptic, translocations]), verbo([provide]), complemento([additional, genetic, information, that, could, be, clinically, useful])].
[sujeto(['Molecular', mutations]), verbo([have]), complemento([been, analyzed, to, subdivide, 'AML', with, normal, karyotype, into, prognostic, subsets])].
[sujeto(['Based', on, 'Cox', regression, and, 'Kaplan-Meier', 'analyses,', 5, distinct, prognostic, subgroups, were, 'identified:', '(', 1, ')', very, 'favorable:', 'PML-RARA', rearrangement, '(', n, =, 29, ')', or, 'CEPBA', double, mutations, '(', n, =, 42, ;, overall, survival, '[', 'OS]', at, 3, 'years:', 82.9, '%', ')', ;, '(', 2, ')', 'favorable:', 'RUNX1-RUNX1T1', '(', n, =, 35, ')', ',', 'CBFB-MYH11', '(', n, =, 31, ')', ',', or, 'NPM1', mutation, without, 'FLT3-ITD', '(', n, =, 186, ;, 'OS', at, 3, 'years:', 62.6, '%', ')', ;, '(', 3, ')', 'intermediate:', none, of, the, mutations]), verbo([leading]), complemento([to, assignment, into, groups, 1, ',', 2, ',', 4, ',', or, 5, '(', n, =, 235, ;, 'OS', at, 3, 'years:', 44.2, '%', ')', ;, '(', 4, ')', 'unfavorable:', 'MLL-PTD', 'and/or', 'RUNX1', mutation, 'and/or', 'ASXL1', mutation, '(', n, =, 203, ;, 'OS', at, 3, 'years:', 21.9, '%', ')', ;, and, '(', 5, ')', very, 'unfavorable:', 'TP53', mutation, '(', n, =, 80, ;, 'OS', at, 3, 'years:', 0, '%', ;, 'P', &, 'lt;'])].
[sujeto(['This', comprehensive, molecular, characterization]), verbo([provides]), complemento([a, more, powerful, model, for, prognostication, than, cytogenetics])].
[sujeto(['From', the, authors, review, it, is, evident, that, this, phenomenon]), verbo([has]), complemento([both, theoretical, and, practical, '(', 'diagnostic,', 'prognostic,', and, 'therapeutic)', significance])].
[sujeto(['Murine', studies, directly, link, primary, acute, myeloid, leukaemia, '(', 'AML)', and]), verbo([decreased]), complemento(['PU'])].
[sujeto(['Similarly,', a, 'radiation-induced', chromosome, 2, deletion, and, subsequent, 'Sfpi1', point, mutation, in, the, remaining, allele]), verbo([lead]), complemento([to, murine, 'radiation-induced', 'AML'])].
[sujeto(['This', review]), verbo([provides]), complemento([an, 'up-to-date', overview, on, our, current, understanding, of, the, involvement, of, 'PU'])].
[sujeto(['It', is, concluded, that, the, 'Msi2', mRNA]), verbo([expresses]), complemento([in, leukamia, stem, 'cells,', the, high, expression, of, 'Msi2', mRNA, has, been, found, in, newly, diagnosed, 'AML', 'patients,', especially, in, 'M1,', 'M4', and, 'M5', 'patients,', the, high, expression, also, has, been, observed, in, patients, with, 'CD34(+)'])].
[sujeto(['The', results, showed, that, the, 'NPM1', mutation, was]), verbo([found]), complemento([in, 14.1, '%', samples, '(', 55, /, 389, ')'])].
[sujeto(['It', is, concluded, that, 'AML', with, 'NPM1', mutation]), verbo([has]), complemento([distinct, clinical, features])].
[sujeto(['It', is, important, to, identify, these, transcripts, as, they]), verbo([provide]), complemento([useful, prognostic, information, to, the, treating, clinician])].
[sujeto(['Acquired', somatic, mutations, of, 'IDH1', and, 'IDH2']), verbo([have]), complemento([recently, been, reported, in, some, types, of, brain, tumors, and, a, small, proportion, of, acute, myeloid, leukemia, '(', 'AML)', cases])].
[sujeto(['Two', missense, mutations, were]), verbo([found]), complemento([in, 'IDH2-mutated', 'cases;', p])].
[sujeto(['Older', age, and, higher, median, platelet, counts, were, significantly]), verbo([associated]), complemento([with, 'IDH2', mutations, although, the, clinical, impact, of, either, 'IDH1', or, 'IDH2', mutations, on, 'patients\'', overall, survival, could, not, be, observed])].
[sujeto(['No', patients, concurrently, carried, both, 'IDH1', and, 'IDH2', mutations]), verbo([suggesting]), complemento([that, these, mutations, were, mutually, exclusive])].
[sujeto(['Our', present, data, failed, to, support, the, prognostic, relevance, of, 'IDH', mutations, although, alterations, of, these, metabolic, genes, potentially]), verbo([have]), complemento([an, important, role, in, leukemia, development])].
[sujeto(['Chromatin', modifications, at, both, histones, and, 'DNA', are, critical, for]), verbo([regulating]), complemento([gene, expression])].
[sujeto(['Mis-regulation', of, such, epigenetic, marks, can]), verbo([lead]), complemento([to, pathological, 'states;', 'indeed,', cancer, affecting, the, hematopoietic, system, is, frequently, linked, to, epigenetic, abnormalities])].
[sujeto(['Further,', we, discuss, how, chromosomal, translocations]), verbo([leading]), complemento([to, fusion, proteins, can, aberrantly, regulate, gene, transcription, through, chromatin, modifications, within, the, hematopoietic, system])].
[sujeto(['PML-RARa,', 'AML1-ETO', and, 'MLL-fusions', are, examples, of, fusion, proteins, that, 'mis-regulate', epigenetic, modifications, '(', either, directly, or, 'indirectly),', which, can]), verbo([lead]), complemento([to, acute, myeloblastic, leukemia, '(', 'AML)'])].
[sujeto(['An', 'in-depth', understanding, of, the, mechanisms, behind, the, 'mis-regulation', of, epigenetic, modifications, that]), verbo([lead]), complemento([to, the, development, and, progression, of, 'AMLs', could, be, critical, for, designing, effective, treatments])].
[sujeto(['Seven', genes, '(', 'RARB,', 'BVES,', 'CDKN2A,', 'KCNH5,', 'RASSF1,', 'CDH13,', and, 'RUNX)', were]), verbo([found]), complemento([to, be, methylated, significantly, more, frequently, in, tumor, tissues, than, in, noncancerous, tissues])].
[sujeto(['Only', methylation, of, 'CCND2', and, 'APC', was, frequently, detected, in, both, cancerous, and, noncancerous, 'tissues,', supporting, the, hypothesis, that, the, methylation, of, these, two, genes, is, a, preneoplastic, change, and, may, be]), verbo([associated]), complemento([with, tobacco, smoking, exposure])].
[sujeto(['Detection', of, methylation, of, these, genes, in, blood, might]), verbo([have]), complemento([utility, in, monitoring, and, detecting, tumor, recurrence, in, 'early-stage', 'NSCLC', after, curative, surgical, resection])].
[sujeto(['MOZ-TIF2', and, 'MOZ-CBP', are, leukemogenic, fusion, proteins]), verbo([associated]), complemento([with, 'therapy-induced', acute, myeloid, leukemia])].
[sujeto(['We']), verbo([have]), complemento([previously, shown, that, 'MOZ-TIF2', inhibits, transcription, by, 'CREB-binding', protein, '(', 'CBP)/p300-dependent', activators, such, as, nuclear, receptors, and, p53])].
[sujeto(['Here', we]), verbo([have]), complemento([shown, that, 'MOZ-TIF2', associates, with, the, 'RARbeta2', promoter, in, 'vivo,', resulting, in, altered, recruitment, of, 'CBP/p300,', aberrant, histone, 'modification,', and, 'down-regulation', of, the, 'RARbeta2', gene])].
[sujeto(['In', 'contrast,', 'MOZ-TIF2', 'up-regulated', transcription]), verbo([mediated]), complemento([by, the, 'MOZ/MYST3-dependent', activator, 'AML1/RUNX1'])].
[sujeto(['Both', wild, type, 'MOZ', and, 'MOZ-TIF2', were]), verbo([found]), complemento([to, colocalize, with, 'AML1,', and, 'MOZ-TIF2', was, recruited, to, an, 'AML1', target, promoter])].
[sujeto(['A', 'MOZ-CBP', fusion, protein, showed, similar, functions, to, 'MOZ-TIF2', in, that, it]), verbo([inhibited]), complemento([retinoic, acid, 'receptor-mediated', transcription, but, enhanced, 'AML1', reporter, activation])].
[sujeto(['Although', it, contains, almost, the, entire, 'CBP', 'sequence,', 'MOZ-CBP', does, not, appear, to]), verbo([associate]), complemento([with, 'PML', bodies])].
[sujeto(['In', 'summary,', our, results, indicate, that, leukemogenic, 'MOZ', fusion, proteins]), verbo([have]), complemento([differential, effects, on, the, activities, of, 'CBP-dependent', and, 'MOZ-dependent', activators, because, of, their, ability, to, alter, cofactor, recruitment, and, chromatin, modification, at, target, promoters])].
[sujeto(['Studies']), verbo([have]), complemento([shown, that, the, fusion, alone, is, insufficient, for, the, initiation, of, 'leukemia;', additional, genetic, changes, are, required])].
[sujeto(['TBL1XR1', is, a, key, component, of, the, 'SMRT', and, 'N-CoR', compressor, 'complexes,', which, control, 'hormone-receptor']), verbo([mediated]), complemento([gene, expression])].
[sujeto(['Differential', expression, of, the, retinoic, acid]), verbo([target]), complemento(['genes,', 'RARB,', 'CRABP1,', and, 'CRABP2,', indicated, that, deletion, of, 'TBL1XR1', compromised, the, function, of, 'SMRT/N-CoR', in, the, appropriate, control, of, gene, expression])].
[sujeto(['We']), verbo([provide]), complemento([evidence, that, implicates, this, deletion, in, the, inappropriate, control, of, gene, expression, in, these, patients])].
[sujeto(['The']), verbo([target]), complemento([of, the, interaction, between, 'TBL1XR1', and, the, signaling, pathways, described, here, may, be, exploited, in, cancer, therapy])].
[sujeto(['IL-13', is, a, central, mediator, of, airway, responsiveness, and, mucus, expression, in, patients, with, allergic, airway, 'inflammation,', and, 'IL-13', is, currently, a, therapeutic]), verbo([target]), complemento([for, asthma])].
[sujeto(['However,', little, is, known, about, how, 'IL-13']), verbo([regulates]), complemento([human, 'CD4(+)', 'T-cell', lineages, because, 'IL-13', receptor, '(', 'IL-13R)', 'α1,', a, subunit, of, 'IL-13R,', has, not, previously, been, reported, to, exist, on, human, 'T', cells])].
[sujeto(['We', sought, to, determine, whether, human, 'CD4(+)', 'T(H)17', cells]), verbo([express]), complemento(['IL-13Rα1', and, whether, 'IL-13', regulates, 'T(H)17', cytokine, production])].
[sujeto(['Naive', human, 'CD4(+)', cells, were, isolated, from, whole, 'blood,']), verbo([activated]), complemento([with, 'anti-CD3', and, 'anti-CD28,', and, polarized, to, 'T(H)1,', 'T(H)2,', 'T(H)17,', or, induced, regulatory, 'T', cells, in, the, presence, of, 'IL-13', '(', 0, -, 10, 'ng/mL)'])].
[sujeto(['T(H)17', 'cells,', but, not, 'T(H)0,', 'T(H)1,', 'T(H)2,', or]), verbo([induced]), complemento([regulatory, 'T', 'cells,', expressed, 'IL-13Rα1'])].
[sujeto(['IL-13', neither]), verbo([inhibited]), complemento(['IFN-γ', production, from, 'T(H)1', cells, nor, inhibited, 'IL-4', production, from, 'T(H)2', cells])].
[sujeto(['IL-13Rα1', is]), verbo([expressed]), complemento([on, human, 'CD4(+)', 'T(H)17', 'cells,', and, 'IL-13', attenuates, 'IL-17A', production, at, polarization, and, restimulation])].
[sujeto(['Although', 'IL-13', is, an, attractive, therapeutic]), verbo([target]), complemento([for, decreasing, symptoms, associated, with, 'asthma,', these, results, suggest, that, therapies, inhibiting, 'IL-13', production, could, have, adverse, side, effects, by, increasing, 'IL-17A', production])].
[sujeto(['Gene', methylation, and, other, epigenetic, modifications, of, gene, regulation]), verbo([have]), complemento([been, implicated, in, the, growth, of, ovarian, 'cancer,', but, the, clinical, significance, of, such, modifications, in, the, 'Notch', pathway, in, 'high-grade', serous, ovarian, cancer, '(', 'HGS-OvCa)', is, not, well, understood])].
[sujeto(['We', also]), verbo([found]), complemento([a, significant, inverse, relationship, between, miRNAs, and, mRNA, expression, for, 'CCND1,', 'PPARG,', and, 'RUNX1'])].
[sujeto(['By', further, analyzing, the, effect, of, miRNAs, on, gene, expression, and, 'OS,', we]), verbo([found]), complemento([that, patients, with, higher, levels, of, 'CCND1,', 'PPARG,', and, 'RUNX1', expression, and, lower, expression, levels, of, their, respective, miRNAs, '(', 502, -, 5, 'p,', 128, ',', and, 215, /, 625, ')', had, significantly, poorer, 'OS'])].
[sujeto(['Epigenetic', alterations, of, multiple, 'Notch']), verbo([target]), complemento([genes, and, pathway, interacting, genes, '(', 'PPARG,', 'CCND1,', and, 'RUNX1)', may, relate, to, activation, of, this, pathway, and, poor, survival, of, patients, with, 'HGS-OvCa'])].
[sujeto([microRNAs, '(', 'miRNAs)', play, key, roles, in]), verbo([modulating]), complemento([a, variety, of, cellular, processes, through, repression, of, their, mRNA, targets])].
[sujeto(['In', skeletal, 'muscle,', miRNAs, are, known, to, be]), verbo([involved]), complemento([in, myoblast, proliferation, and, differentiation])].
[sujeto(['We', identified, a, set, of, miRNAs, that, was, highly]), verbo([expressed]), complemento([in, 'SP', cells, as, compared, with, 'MP', cells])].
[sujeto(['One', 'miRNA,', 'miR-128a,', was, elevated, in, expression, in, 'SP', 'cells,', but]), verbo([decreased]), complemento([in, expression, during, continued, culture, in, vitro])].
[sujeto(['Overexpression', of, 'miR-128a', in, 'SP', cells, resulted, in]), verbo([inhibited]), complemento([cell, proliferation])].
[sujeto(['The', differentiation, potential, of, 'SP', cells, was, also]), verbo([decreased]), complemento([when, 'miR-128a', was, overexpressed])].
[sujeto(['MiR-128a', was]), verbo([found]), complemento([to, regulate, the, target, genes, involved, in, the, regulation, of, 'adipogenic-,', 'osteogenic-', and, myogenic, genes, that, 'include:', 'PPARγ,', 'Runx1,', and, 'Pax3'])].
[sujeto(['Overexpression', of, 'miR-128a']), verbo([suppressed]), complemento([the, activity, of, a, luciferase, reporter, fused, to, the, 3, '\'', -, untranslated, region, of, each, gene])].
[sujeto(['These', results, demonstrate, that, 'miR-128a', contributes, to, the, maintenance, of, the, quiescent, 'state,', and, it]), verbo([regulates]), complemento([cellular, differentiation, by, repressing, individual, genes, in, 'SP', cells])].
[sujeto(['Secreted', 'frizzled-related', protein, 1, '(', 'Sfrp1)', is, highly]), verbo([expressed]), complemento([by, stromal, cells, maintaining, hematopoietic, stem, cells, '(', 'HSCs)'])].
[sujeto(['Sfrp1']), verbo([loss]), complemento([in, stromal, cells, increases, production, of, hematopoietic, 'progenitors,', and, in, knockout, 'mice,', dysregulates, hemostasis, and, increases, 'Flk2-', 'Cd34-', 'Lin-', 'Sca1+', 'Kit+', '(', 'LSK)', cell, numbers, in, bone, marrow])].
[sujeto(['Also,', 'LSK', and, multipotent, progenitors, '(', 'MPPs)', resided, mainly, in, the, 'G0/G1', phase, of, cell, 'cycle,', with, an, accompanying]), verbo([decrease]), complemento([in, intracellular, 'beta-catenin', levels])].
[sujeto(['Gene-expression', studies, showed, a, concomitant]), verbo([decrease]), complemento(['Ccnd1', and, 'Dkk1', in, 'Cd34-', 'LSK', cells, and, increased, expression, of, 'Pparg,', 'Hes1,', and, 'Runx1', in, 'MPP'])].
[sujeto(['Transplantation', experiments, showed, no, intrinsic, effect, of, 'Sfrp1']), verbo([loss]), complemento([on, the, number, of, 'HSCs', or, their, ability, to, engraft, irradiated, recipients])].
[sujeto(['In', 'contrast,', serial, transplantations, of, 'wild-type', 'HSCs', into, 'Sfrp1(-/-)', mice, show, a, progressive]), verbo([decrease]), complemento([of, 'wild-type', 'LSK', and, 'MPP', numbers])].
[sujeto(['Our', results, demonstrate, that, 'Sfrp1', is]), verbo([required]), complemento([to, maintain, 'HSC', homeostasis, through, extrinsic, regulation, of, 'beta-catenin'])].
[sujeto(['The', aim, of, this, study, was, to, characterize, differentially]), verbo([expressed]), complemento([genes, in, the, normal, and, 'adriamycin-induced', 'CGN', rats, by, microarray, 'analysis,', and, to, determine, the, potential, molecular, mechanisms, of, 'CGN', pathogenesis])].
[sujeto(['KEGG,', 'Gene', 'Ontology', '(', 'GO)', 'analyze,', 'LIMMA,', 'String', and, 'Cytoscape', software, were, applied, to, screen, and, analyze, differentially]), verbo([regulated]), complemento([genes])].
[sujeto([2334, differentially]), verbo([regulated]), complemento([genes, were, identified, including, 1294, 'up-regulated', genes, and, 1040, 'down-regulated', genes])].
[sujeto(['Exposure', to, replication, competent, and, 'single-round', 'VSV-G', pseudotyped, 'HIV', strains]), verbo([provide]), complemento([evidence, that, superior, 'HIV', replication, in, 'Th1Th17', vs])].
[sujeto(['Th1', cells, was]), verbo([regulated]), complemento([by, mechanisms, located, at, entry, and, 'post-entry', levels])].
[sujeto(['Gene', 'Set', 'Enrichment', 'Analysis', revealed, pathways, enriched, in, 'Th1Th17', '(']), verbo([nuclear]), complemento(['receptors,', 'trafficking,', 'p38/MAPK,', 'NF-κB,', 'p53/Ras,', 'IL-23)', vs])].
[sujeto(['Differentially']), verbo([expressed]), complemento([genes, were, classified, into, biological, categories, using, 'Gene', 'Ontology'])].
[sujeto(['Th1Th17', cells]), verbo([expressed]), complemento([typical, 'Th17', markers, '(', 'IL-17A/F,', 'IL-22,', 'CCL20,', 'RORC,', 'IL-26,', 'IL-23R,', 'CCR6)', and, transcripts, functionally, linked, to, regulating, cell, trafficking, '(', 'CEACAM1,', 'MCAM),', activation, '(', 'CD28,', 'CD40LG,', 'TNFSF13B,', 'TNFSF25,', 'PTPN13,', 'MAP3K4,', 'LTB,', 'CTSH),', transcription, '(', 'PPARγ,', 'RUNX1,', 'ATF5,', 'ARNTL),', apoptosis, '(', 'FASLG),', and, 'HIV', infection, '(', 'CXCR6,', 'FURIN)'])].
[sujeto(['The']), verbo([nuclear]), complemento([receptor, 'PPARγ', was, preferentially, expressed, by, 'Th1Th17', cells])].
[sujeto(['PPARγ', 'RNA', interference, significantly]), verbo([increased]), complemento(['HIV', replication, at, levels, 'post-entry', and, prior, 'HIV-DNA', integration])].
[sujeto(['Finally,', the, activation, of, 'PPARγ', pathway, via, the, agonist, 'Rosiglitazone']), verbo([induced]), complemento([the, nuclear, translocation, of, 'PPARγ', and, a, robust, inhibition, of, viral, replication])].
[sujeto(['Th1', cells, demonstrated, that, 'HIV', permissiveness, is]), verbo([associated]), complemento([with, a, superior, state, of, cellular, activation, and, limited, antiviral, properties, and, identified, 'PPARγ', as, an, intrinsic, negative, regulator, of, viral, replication])].
[sujeto(['Therefore,']), verbo([triggering]), complemento(['PPARγ', pathway, via, 'non-toxic', agonists, may, contribute, to, limiting, covert, 'HIV', replication, and, disease, progression, during, antiretroviral, treatment])].
[sujeto(['The', 'wingless-Int', '(', 'WNT)', pathway]), verbo([has]), complemento([an, essential, role, in, cell, regulation, of, hematopoietic, stem, cells, '(', 'HSC)'])].
[sujeto(['For', 'Acute', 'Myeloid', 'Leukemia', '(', 'AML),', the, malignant, counterpart, of, 'HSC,', currently, only, a, selective, number, of, genes, of, the, 'WNT', pathway, are, analyzed, by, using, either, gene, expression, or, 'DNA-methylation', profiles, for, the, identification, of, prognostic, markers, and, potential, candidate]), verbo([targets]), complemento([for, drug, therapy])].
[sujeto(['It', is, known, that, mRNA, expression, is, controlled, by, 'DNA-methylation', and, that, specific, patterns, can, infer, the, ability, to, differentiate, biological, 'differences,', thus, a, combined, analysis, using, all, 'WNT', annotated, genes, could]), verbo([provide]), complemento([more, insight, in, the, 'WNT', signaling])].
[sujeto(['Our', results]), verbo([provide]), complemento([novel, insights, in, 'WNT', signaling, in, 'AML,', we, discovered, new, and, previously, identified, prognostic, markers, and, a, refinement, of, the, patient, groups])].
[sujeto(['Limited', evidence, is, available, about, the, specific, miRNA, networks, that]), verbo([regulate]), complemento([differentiation, of, specific, immune, cells])].
[sujeto(['In', this, 'study,', we, characterized, miRNA, expression, and]), verbo([associated]), complemento([alterations, in, expression, with, putative, mRNA, targets, that, are, critical, during, differentiation, of, macrophages])].
[sujeto(['We', identified, 112, miRNAs, with, expression, patterns, that, were, differentially]), verbo([regulated]), complemento([5, -, fold, or, more, during, 'BMDM', development])].
[sujeto(['With', 'TargetScan', and, 'MeSH', 'databases,', we, identified, 1267, transcripts]), verbo([involved]), complemento([in, 30, canonical, pathways, linked, to, macrophage, biology, as, potentially, regulated, by, these, specific, 112, miRNAs])].
[sujeto([1, ',', and, 14, miRNAs]), verbo([target]), complemento([the, nuclear, receptor, 'PPARα', and, 'PPARγ'])].
[sujeto(['This', novel, information]), verbo([provides]), complemento([an, important, reference, resource, for, further, study, of, the, functional, links, between, miRNAs, and, their, target, mRNAs, for, the, regulation, of, differentiation, and, function, of, macrophages])].
[sujeto([',', aerobic, and, 'resistance)', into, one, training, 'protocol,']), verbo([providing]), complemento([stimuli, meant, to, increase, muscle, 'strength,', aerobic, capacity, and, mass])].
[sujeto(['As', disuse, is]), verbo([associated]), complemento([with, decrements, in, 'strength,', aerobic, capacity, and, muscle, size, concurrent, training, is, an, attractive, modality, for, rehabilitation])].
[sujeto(['We']), verbo([recruited]), complemento([18, young, adults, '(', 10, '♂,', 8, '♀)', to, determine, if, order, of, exercise, mode, during, concurrent, training, would, differentially, affect, gene, 'expression,', protein, content, and, measures, of, strength, and, aerobic, capacity, after, 2, weeks, of, 'knee-brace', induced, disuse])].
[sujeto(['Concurrent', exercise, sessions, were, performed, 3, 'x/week', for, 6, weeks, at, gradually]), verbo([increasing]), complemento([intensities, either, with, endurance, exercise, preceding, '(', 'END&gt;RES)', or, following, '(', 'RES&gt;END)', resistance, exercise])].
[sujeto(['Concurrent', exercise, altered, the, expression, of, genes]), verbo([involved]), complemento([in, mitochondrial, biogenesis, '(', 'PGC-1α,', 'PRC,', 'PPARγ),', hypertrophy, '(', 'PGC-1α4,', 'REDD2,', 'Rheb)', and, atrophy, '(', 'MuRF-1,', 'Runx1),', increased, electron, transport, chain, complex, protein, 'content,', citrate, synthase, and, mitochondrial, cytochrome, c, oxidase, enzyme, 'activity,', muscle, 'mass,', maximum, isometric, strength, and, 'VO', 2, peak])].
[sujeto(['In', 'conclusion,', concurrent, exercise, training, is, an, effective, modality, for, the, rehabilitation, of, the]), verbo([loss]), complemento([of, skeletal, muscle, 'mass,', maximum, 'strength,', and, peak, aerobic, capacity, resulting, from, 'disuse,', regardless, of, the, order, in, which, the, modes, of, exercise, are, performed])].
[sujeto(['A', new, class, of, inflammatory, 'CD4(+)', 'T', cells, that, produce, 'interleukin-17', '(', 'IL-17)', '(', termed, 'Th17)']), verbo([has]), complemento([been, 'identified,', which, plays, a, critical, role, in, numerous, inflammatory, conditions, and, autoimmune, diseases])].
[sujeto(['The', active, form, of, vitamin, 'D,', 1, ',', 25, -, dihydroxyvitamin, 'D(3)', '[', 1, ',', 25, '(', 'OH)(2)D(3)],']), verbo([has]), complemento([a, direct, repressive, effect, on, the, expression, of, 'IL-17A', in, both, human, and, mouse, 'T', cells])].
[sujeto(['The', mechanism, of, 1, ',', 25, '(', 'OH)(2)D(3)', repression, of, 'IL-17A', expression, was]), verbo([found]), complemento([to, be, transcriptional, 'repression,', mediated, by, the, vitamin, 'D', receptor, '(', 'VDR)'])].
[sujeto(['Transcription', 'assays,', gel, 'shifting,', and, chromatin, immunoprecipitation, '(', 'ChIP)', assays, indicate, that, the, negative, effect, of, 1, ',', 25, '(', 'OH)(2)D(3)', on, 'IL-17A']), verbo([involves]), complemento([blocking, of, nuclear, factor, for, activated, 'T', cells, '(', 'NFAT),', recruitment, of, histone, deacetylase, '(', 'HDAC),', sequestration, of, 'Runt-related', transcription, factor, 1, '(', 'Runx1)', by, 1, ',', 25, '(', 'OH)(2)D(3)/VDR,', and, a, direct, effect, of, 1, ',', 25, '(', 'OH)(2)D(3)', on, induction, of, 'Foxp3'])].
[sujeto(['Our', results, describe, novel, mechanisms, and, new, concepts, with, regard, to, vitamin, 'D', and, the, immune, system, and]), verbo([suggest]), complemento([therapeutic, targets, for, the, control, of, autoimmune, diseases])].
[sujeto(['Osteopontin', '(', 'OPN),', a, glycosylated, phosphoprotein, that]), verbo([binds]), complemento(['calcium,', is, present, in, bone, extracellular, matrix, and, has, been, reported, to, modulate, both, mineralization, and, bone, resorption])].
[sujeto(['In', this, 'study,', we, addressed, possible, 'cross-talk', between, 'VDR', and, 'Runx2', in]), verbo([regulating]), complemento(['OPN', transcription])].
[sujeto([1, ',', 25, -, 'Dihydroxyvitamin', 'D(3)', '(', 1, ',', 25, '(', 'OH)(2)D(3))', or, 'Runx2']), verbo([stimulated]), complemento(['OPN', transcription, '(', mouse, 'OPN', promoter, -, 777, /, +, 79, ')', 2, -, 3, -, fold])].
[sujeto(['In', 'ROS', 17, /, 2.8, and, 'MC3T3-E1', cells, that, contain, endogenous, 'Runx2,', 'AML-1/ETO,', which]), verbo([acts]), complemento([as, a, repressor, of, 'Runx2,', significantly, inhibited, 1, ',', 25, '(', 'OH)(2)D(3)', induction, of, 'OPN', 'transcription,', 'OPN', 'mRNA,', and, protein, expression])].
[sujeto(['Chromatin', immunoprecipitation, analyses, showed, that, 1, ',', 25, '(', 'OH)(2)D(3)', can]), verbo([enhance]), complemento(['VDR', and, 'Runx2', recruitment, on, the, 'OPN', 'promoter,', further, indicating, cooperation, between, these, two, factors, in, the, regulation, of, 'OPN'])].
[sujeto(['In', osteoblastic, 'cells,', 'Hes-1,', a, downstream, factor, of, the, 'Notch', signaling, 'pathway,', was]), verbo([found]), complemento([to, enhance, basal, and, 1, ',', 25, '(', 'OH)(2)D(3)-induced', 'OPN', transcription])].
[sujeto(['This', enhancement, was]), verbo([inhibited]), complemento([by, 'AML-1/ETO,', an, inhibitor, of, 'Runx2'])].
[sujeto(['Immunoprecipitation', assays, indicated, that, 'Hes-1', and, 'Runx2']), verbo([interact]), complemento([and, that, 1, ',', 25, '(', 'OH)(2)D(3)', can, enhance, this, interaction])].
[sujeto(['Taken', 'together,', these, findings, define, novel, mechanisms]), verbo([involving]), complemento([the, intersection, of, three, 'pathways,', 'Runx2,', 1, ',', 25, '(', 'OH)(2)D(3),', and, 'Notch', 'signaling,', that, play, a, major, role, in, the, regulation, of, 'OPN', in, osteoblastic, cells, and, therefore, in, the, process, of, bone, remodeling])].
[sujeto(['The', mineralized, skeleton, is, a, major, evolutionary, novelty, that]), verbo([has]), complemento([contributed, to, the, impressive, morphological, diversifications, of, the, vertebrates])].
[sujeto(['We', now]), verbo([have]), complemento([a, rather, complete, view, of, the, events, underlying, 'osteogenesis,', from, a, 'cellular,', 'molecular,', 'genetic,', and, epigenetic, perspective])].
[sujeto(['Because', this, knowledge, is, still, largely, restricted, to, 'mammals,', it, is, 'difficult,', if, not, 'impossible,', to, deduce, the, evolutionary, history, of, the, regulatory, network]), verbo([involved]), complemento([in, osteoblasts, specification, and, differentiation])].
[sujeto(['In', this, 'study,', we, focused, on, the, transcriptional, regulators, 'Runx2', and, 'VDR', '(', the, 'Vitamin', 'D', 'Receptor)', 'that,', in, 'mammals,', directly]), verbo([interact]), complemento([together, and, stabilize, complexes, of, 'co-activators', and, chromatin, 'remodellers,', thereby, allowing, the, transcriptional, activation, of, target, genes, involved, in, extracellular, matrix, mineralization])].
[sujeto(['Using', a, combination, of, 'functional,', 'biochemical,', and, histological, 'approaches,', we]), verbo([have]), complemento([asked, if, the, interaction, observed, between, 'Runx2', and, 'VDR', represents, a, recent, mammalian, 'innovation,', or, if, it, results, from, more, ancient, changes, that, have, occurred, deep, in, the, vertebrate, lineage])].
[sujeto(['Using', immunohistochemistry, and, in, situ, hybridization, in, developing, embryos, of, 'chick,', frog, and, teleost, 'fishes,', we]), verbo([have]), complemento([revealed, that, the, 'co-expression', of, 'Runx2', and, 'VDR', in, skeletal, elements, has, been, particularly, strengthened, in, the, lineage, leading, to, amniotes])].
[sujeto(['We', show, that, the, teleost, 'Runx2', orthologue, as, well, as, the, three, mammalian, 'Runx1,', 'Runx2', and, 'Runx3', paralogues, are, able, to, 'co-immunoprecipitate', with, the, 'VDR', protein, present, in]), verbo([nuclear]), complemento([extracts, of, rat, osteoblasts, stimulated, with, 1, 'alpha,25-dihydroxyvitamin', 'D3'])].
[sujeto(['In', 'addition,', the, teleost, 'Runx2', can]), verbo([activate]), complemento([the, transcription, of, the, mammalian, osteocalcin, promoter, in, transfection, 'experiments,', and, this, response, can, be, further, enhanced, by, 1, 'alpha,25-dihydroxyvitamin', 'D3'])].
[sujeto(['Finally,', using, 'pull-down', experiments, between, recombinant, 'proteins,', we, show, that, the, 'VDR', homologue, from, 'teleosts,', but, not, from, 'ascidians,', is, able, to, directly]), verbo([interact]), complemento([with, the, mammalian, 'Runx2', homologue])].
[sujeto(['We', propose, an, evolutionary, scenario, for, the, assembly, of, the, molecular, machinery]), verbo([involving]), complemento(['Runx2', and, 'VDR', in, vertebrates])].
[sujeto(['In', the, last, common, ancestor, of, actinopterygians, and, 'sacropterygians,', the, three, 'Runx', paralogues, possessed, the, potential, to, physically, and, functionally]), verbo([interact]), complemento([with, the, 'VDR', protein])].
[sujeto(['Therefore,', 1, 'alpha,25-dihydroxyvitamin', 'D3', might]), verbo([have]), complemento([been, able, to, modulate, the, transcriptional, activity, of, 'Runx1,', 'Runx2', or, 'Runx3', in, the, tissues, expressing, 'VDR'])].
[sujeto(['After', the, split, from, 'amphibians,', in, the, lineage]), verbo([leading]), complemento([to, 'amniotes,', 'Runx2', and, 'VDR', became, robustly, 'co-expressed', in, developing, skeletal, 'elements,', and, their, regulatory, interaction, was, incorporated, in, the, genetic, program, involved, in, the, specification, and, differentiation, of, osteoblasts])].
[sujeto(['These', small, 'RNAs', exert, their, function, assembled, in, the, 'RNA-induced', silencing, complexes, '(', 'RISCs),', where, members, of, 'Argonaute', '(', 'Ago)', family, of, proteins]), verbo([provide]), complemento([a, unique, platform, for, target, recognition, and, gene, silencing])].
[sujeto(['Here,', by, using, myeloid, cell, lines, and, primary, 'blasts,', we, show, that, 'Ago2']), verbo([has]), complemento([a, key, role, in, human, monocytic, cell, fate, determination, and, in, 'LPS-induced', inflammatory, response, of, 1, ',', 25, -, dihydroxyvitamin, 'D3', '(', 'D3)-treated', myeloid, cells])].
[sujeto(['The', silencing, of, 'Ago2', impairs, the, 'D3-dependent', 'miR-17-5p/20a/106a,', 'miR-125b', and, 'miR-155', 'downregulation,', the, accumulation, of, their, translational]), verbo([targets]), complemento(['AML1,', 'VDR', and, 'C/EBPβ', and, monocytic, cell, differentiation])].
[sujeto(['Moreover,', we, show, that, 'Ago2', is]), verbo([recruited]), complemento([on, 'miR-155', host, gene, promoter, and, on, the, upstream, region, of, an, overlapping, antisense, 'lncRNA,', determining, their, epigenetic, 'silencing,', and, 'miR-155', downregulation])].
[sujeto(['Our', data]), verbo([suggest]), complemento([that, 'RUNX1', haploinsufficiency, collaborates, with, the, 'BCR-ABL1', oncogene, in, this, leukemia])].
[sujeto(['The', description, of, this, atypical, gene, fusion, is, an, important, addition, to, the, characterization, of, the, pathogenomic, mechanisms]), verbo([leading]), complemento([to, 'RUNX1', structural, and, functional, alterations])].
[sujeto(['Furthermore,', our, data, strongly]), verbo([suggests]), complemento([that, inadequate, dosage, of, this, gene, plays, an, essential, role, in, leukemogenesis])].
[sujeto(['AML1-ETO', is, a, 'DNA']), verbo([binding]), complemento([transcription, factor, and, has, been, demonstrated, to, play, a, critical, role, in, promoting, leukemogenesis])].
[sujeto(['Here,', we]), verbo([report]), complemento([that, the, effect, of, 'AML1-ETO', on, the, promoter, of, multidrug, 'resistance-1', '(', 'MDR1)', 'gene,', a, known, 'AML1-ETO', 'target,', is, highly, cell, type, specific])].
[sujeto(['Besides', observing, repression, of, the, 'MDR1', promoter, in, 'C33A', and, 'CV-1', cells, as]), verbo([reported]), complemento(['previously,', 'AML1-ETO', strongly, activated, the, promoter, in, 'K562', and, 'B210', cells])].
[sujeto(['More', 'importantly,', this, activation]), verbo([required]), complemento([both, the, 'AML1', and, 'ETO', portions, of, the, fusion, 'protein,', but, did, not, depend, on, the, 'AML1', binding, site, in, 'MDR1', promoter])].
[sujeto(['Furthermore,', results, from, promoter, deletion, analysis, and, chromatin, immunoprecipitation, assays]), verbo([suggested]), complemento([that, this, activation, effect, was, likely, through, the, influence, of, the, general, transcription, machinery, rather, than, 'promoter-specific', factors])].
[sujeto(['Based', on, these, 'data,', we, propose, that, 'AML1-ETO', may]), verbo([have]), complemento([opposing, effects, on, gene, expression, depending, on, the, various, conditions, of, the, cellular, environment])].
[sujeto(['TEL/AML1-positive', 'ALL']), verbo([has]), complemento([a, favorable, 'prognosis,', and, one, possible, reason, is, that, this, subtype, of, 'ALL', rarely, shows, drug, resistance])].
[sujeto(['AML1/ETO,', another, 'AML1-containing', chimeric, 'protein,']), verbo([has]), complemento([been, shown, to, transcriptionally, repress, the, activity, of, the, multidrug, 'resistance-1', '(', 'MDR-1)', gene, 'promoter;', 'thus,', we, examined, whether, 'TEL/AML1', also, represses, 'MDR-1', gene, 'expression,', possibly, preventing, the, emergence, of, multidrug, resistance])].
[sujeto(['In', this, 'study,', we, show, that, the, 'TEL/AML1', protein]), verbo([binds]), complemento([to, the, consensus, 'AML1', binding, site, in, the, 'MDR-1', promoter, and, transcriptionally, represses, its, activity])].
[sujeto(['Furthermore,', we]), verbo([report]), complemento([that, 'MDR-1', mRNA, levels, in, leukemic, cells, obtained, from, 'TEL/AML1-positive', 'ALL', patients, are, lower, than, those, from, 'TEL/AML1-negative', 'ALL', patients])].
[sujeto(['Thus,', 'TEL/AML1', protein]), verbo([acts]), complemento([as, a, transcriptional, repressor, of, 'MDR-1', gene, 'expression,', and, although, 'TEL/AML1', has, been, implicated, in, 'leukemogenesis,', its, effects, on, the, 'MDR-1', gene, may, contribute, to, the, excellent, prognosis, of, 'TEL/AML1-positive', 'ALL', with, current, therapy])].
[sujeto(['Here', we]), verbo([report]), complemento([that, there, is, significant, association, between, rheumatoid, arthritis, and, the, organic, cation, transporter, gene, 'SLC22A4', '(', 'P', =, 3.4e-5, ')'])].
[sujeto(['We', show, that, expression, of, 'SLC22A4', is, specific, to, hematological, and, immunological, tissues, and, that, 'SLC22A4', is, also, highly]), verbo([expressed]), complemento([in, the, inflammatory, joints, of, mice, with, 'collagen-induced', arthritis])].
[sujeto(['A', 'SNP', in, 'RUNX1', is, also, strongly]), verbo([associated]), complemento([with, rheumatoid, arthritis, '(', 'P', =, 0.00035, ')'])].
[sujeto(['Our', data, indicate, that, the, regulation, of, 'SLC22A4', expression, by, 'RUNX1', is]), verbo([associated]), complemento([with, susceptibility, to, rheumatoid, 'arthritis,', which, may, represent, an, example, of, an, epistatic, effect, of, two, genes, on, this, disorder])].
[sujeto(['However,', the, mechanisms, by, which, these, proteins]), verbo([act]), complemento([remain, obscure])].
[sujeto(['Here', we, demonstrate, that, the, multidrug, resistance, 1, '(', 'MDR-1)', promoter, is, a]), verbo([target]), complemento([for, 'AML/ETO', transcriptional, repression])].
[sujeto(['We']), verbo([have]), complemento([defined, two, domains, in, 'AML/ETO', that, are, required, for, repression, of, basal, transcription, from, the, 'MDR-1', 'promoter:', a, hydrophobic, heptad, repeat, '(', 'HHR)', motif, and, a, conserved, zinc, finger, '(', 'ZnF)', domain, termed, the, 'MYND', domain])].
[sujeto(['The', 'HHR']), verbo([mediates]), complemento([formation, of, 'AML/ETO', homodimers, and, 'AML/ETO-ETO', heterodimers])].
[sujeto(['Single', serine, substitutions, at]), verbo([conserved]), complemento([cysteine, residues, within, the, predicted, 'ZnFs', also, abrogate, transcriptional, repression])].
[sujeto(['Finally,', we, observe, that, 'AML/ETO', can, also]), verbo([inhibit]), complemento(['Ets-1', activation, of, the, 'MDR-1', 'promoter,', indicating, that, 'AML/ETO', can, disrupt, both, basal, and, 'Ets-1-dependent', transcription])].
[sujeto(['The', most, extensively, studied, protein]), verbo([involved]), complemento([in, multidrug, resistance, '(', 'MDR)', is, the, transmembrane, glycoprotein, 'P', '(', 'P-gp),', the, product, of, the, multidrug, resistance, gene, 1, '(', 'MDR1)'])].
[sujeto(['MDR1/P-gp', overexpression, is, frequently, observed, in, hematological, 'malignancies,', especially, in, acute, 'leukemia,', and]), verbo([has]), complemento([been, reported, to, correlate, with, poor, prognosis, in, acute, myeloid, leukemia, '(', 'AML)'])].
[sujeto(['No', such, difference, was]), verbo([found]), complemento([when, analyzing, peripheral, blood, samples])].
[sujeto(['In', 'Caucasians,', the, most, prominent, association, was]), verbo([found]), complemento([with, promoter, 'SNP', rs10489759, in, the, 'LOC647132', pseudogene, on, chromosome, 1, '(', 'p=7'])].
[sujeto(['In', 'addition,', 'SNP', rs4748153, in, the, immune, response, gene, 'PRKCQ', '(', protein, kinase, 'C,', 'theta)', was, significantly]), verbo([associated]), complemento([with, neutralizing, antibody, levels, '(', 'p=2'])].
[sujeto(['This', study]), verbo([has]), complemento([identified, candidate, 'SNPs', that, may, be, important, in, regulating, humoral, immunity, to, smallpox, vaccination])].
[sujeto(['Heterozygous', individuals, '(', 'C/T)']), verbo([have]), complemento([intermediate, activity, and, homozygotes, for, the, variant, allele, '(', 'T/T)', are, deficient, in, 'NQO1', activity])].
[sujeto(['In', previous, 'studies,', genotypes]), verbo([conferring]), complemento([lower, 'NQO1', activity, have, been, associated, with, an, increased, risk, of, acute, 'leukemia,', particularly, infant, leukemia, carrying, 'MLL/AF4', fusion, genes])].
[sujeto(['When', compared, to, the, healthy, control, 'group,', only, children, with, 'Burkitt\'s', lymphoma, significantly, more, often, had, 'NQO1', genotypes]), verbo([associated]), complemento([with, lower, 'NQO1', activity, '(', odds, 'ratio,', 1.81, ;, 'p=0'])].
[sujeto(['Our', results]), verbo([suggest]), complemento([that, in, our, population, the, 'NQO1', 'C609T', polymorphism, does, not, confer, an, increased, risk, of, the, investigated, entities, of, childhood, 'ALL'])].
[sujeto(['However,', there, may, be, a]), verbo([modulating]), complemento([role, for, 'NQO1', in, the, pathogenesis, of, pediatric, sporadic, 'Burkitt\'s', lymphoma])].
[sujeto(['The', risk, of, developing, childhood, leukemia]), verbo([has]), complemento([been, associated, with, gene, polymorphisms, that, decrease, the, activity, of, detoxifying, metabolic, enzymes, and, enzymes, involved, in, systemic, oxidative, stress])].
[sujeto(['PON1', rs854560, '(', 'L55M)', was]), verbo([associated]), complemento([with, an, increased, risk, of, developing, childhood, leukemia, '(', 'LM', +, 'MM,', 'OR', 1.93, ',', 95, '%', 'CI', 1.32, -, 2.81, ')'])].
[sujeto(['The', 'PON1', rs662, 'R192R', genotype, had, a, statistically, significant]), verbo([decreased]), complemento([frequency, in, 'ALL', '(', 'OR', 0.64, ',', 95, '%', 'CI', 0.43, -, 0.93, ')'])].
[sujeto(['Infant', 'ALL', cases, were, more, likely, to, harbor, homozygous, 'PON1', rs854560, alleles, than, controls, '(', 'OR', 1.72, ',', 95, '%', 'CI', 1.03, -, 2.89, ')', ;, at, least, one, 'M', allele, was]), verbo([associated]), complemento([with, an, increased, risk, of, 'ALL', in, children, older, than, 1, year, '(', 'OR', 1.99, ',', 95, '%', 'CI', 1.17, -, 3.3, ')'])].
[sujeto(['The', 'NQO1', rs1800566, '(', 'C609T),', 'PON1', rs854560, '(', 'L55M),', and, 'PON1', rs662, '(', 'Q192R)', polymorphisms, modified, risk, depending, on, leukemia, subtype, '(']), verbo([decreased]), complemento([in, 'AML,', increased, and, decreased, in, 'ALL,', 'respectively),', age, 'strata,', and, variant, genotype, combinations])].
[sujeto(['Analyses', of, chromosomal, translocation, and, inversion, breakpoints, in, sporadic, acute, myeloid, leukemias]), verbo([have]), complemento([identified, many, transcription, factors, as, playing, a, role, in, leukemogenesis])].
[sujeto(['Studies', of, families, with, a, 'Mendelian', predisposition, to, hematological, malignancies]), verbo([have]), complemento([identified, the, gene, coding, for, the, transcription, factor, 'RUNX1', as, a, 'leukemia-predisposing', gene, involved, in, the, first, steps, of, leukemogenesis])].
[sujeto(['Although', 'CBFB', forms, a, 'core-binding', factor, transcriptional, complex, with, 'RUNX1,', previous, analyses]), verbo([have]), complemento([excluded, the, 'CBFB', gene, as, the, 'leukemia-predisposing', gene, in, these, families])].
[sujeto(['The', presence, of, 'NQO1', polymorphisms, may]), verbo([suggest]), complemento([a, role, for, this, gene, in, disease, risk, modification, in, these, families])].
[sujeto(['Despite', the, fact, that, 'BCP-ALL', with, 'ETV6-RUNX1', usually, results, in, a, very, good, 'prognosis,', the, sibs, experienced, divergent, 'outcomes;', a, remarkable, difference, in, one, child, that, presented, a, more, aggressive, disease, was, higher, leukocytosis]), verbo([associated]), complemento([with, 'IKZF1', deletion])].
[sujeto(['The', familial, pattern, of, 'ETV6', was, tested, by, the, 12, p, microsatellite, analysis, and, demonstrated, that, deletions, occurred, in, one, child, but, not, the, 'other,', while, heterozygous, patterns, were]), verbo([found]), complemento([in, the, parents])].
[sujeto(['Altogether,', our, data]), verbo([suggest]), complemento([that, genetic, predisposition, aligned, with, chance, haa, an, additive, effect, in, 'BCP-ALL', outcome])].
[sujeto(['These', data]), verbo([have]), complemento([led, to, the, suggestion, that, some, infant, leukemia, may, arise, via, transplacental, fetal, exposures, during, pregnancy, to, substances, that, form, cleavable, complexes, with, topoisomerase, 'II', and, induce, illegitimate, recombination, of, the, 'MLL', gene])].
[sujeto(['MLL-rearranged', leukemias, were, more, likely, to]), verbo([have]), complemento([genotypes, with, low, 'NQO1', function, '(', heterozygous, 'CT', or, homozygous, 'TT', at, nucleotide, 609, ')', than, controls, '(', odds, 'ratio,', 2.5, ;, 'P', =, 0.015, ')'])].
[sujeto(['In', the, subset, of, infant, leukemias, that, had, 'MLL-AF4', fusion, genes, '(', n, =, 21, ')', ',', the, bias]), verbo([increase]), complemento([in, low, or, null, function, 'NQO1', genotypes, was, more, pronounced, '(', odds, 'ratio,', 8.12, ;, 'P', =, 0.00013, ')'])].
[sujeto(['These', data, support, the, idea, of, a, novel, causal, mechanism, in, infant, leukemia]), verbo([involving]), complemento([genotoxic, exposure, in, utero, and, modulation, of, impact, on, a, selective, target, gene, by, an, inherited, allele, encoding, a, 'rate-limiting', step, in, a, carcinogen, detoxification, pathway])].
[sujeto(['Transcripts', significantly, enriched, in, 'Th17', versus, 'Th1', were, previously]), verbo([associated]), complemento([with, the, regulation, of, 'TCR', signaling, '(', 'ZAP-70,', 'Lck,', and, 'CD96)', and, 'Th17', polarization, '(', 'RORγt,', 'ARNTL,', 'PTPN13,', and, 'RUNX1)'])].
[sujeto(['Functional', studies, demonstrated, an]), verbo([increased]), complemento([ability, of, 'Th17', versus, 'Th1', cells, to, respond, to, 'TCR', triggering, in, terms, of, 'NF-κB', nuclear, 'translocation/DNA-binding', activity, and, proliferation])].
[sujeto(['The', transcriptional, program, of, 'Th17', cells, includes, molecules]), verbo([regulating]), complemento(['HIV', replication, at, multiple, 'post-entry', steps, that, may, represent, potential, targets, for, novel, therapies, aimed, at, protecting, 'Th17', cells, from, infection, and, subsequent, depletion, in, 'HIV-infected', subjects])].
[sujeto(['BACKGROUND:', 'Polymorphisms', in, several, genes, '(', 'NOD2,', 'MDR1,', 'SLC22A4)']), verbo([have]), complemento([been, associated, with, susceptibility, to, 'Crohn\'s', disease])].
[sujeto(['Identification', of, the, remaining, 'Crohn\'s', susceptibility, genes, is, essential, for, the, development, of, 'disease-specific']), verbo([targets]), complemento([for, immunotherapy])].
[sujeto(['Using', gene, expression, 'analysis,', we, identified, a, differentially]), verbo([expressed]), complemento([gene, on, 5, 'q33,', the, colony, stimulating, factor, 1, receptor, '(', 'CSF1R)', 'gene,', and, hypothesized, that, it, is, a, 'Crohn\'s', susceptibility, gene])].
[sujeto(['The', 'CSF1R', gene, is]), verbo([involved]), complemento([in, monocyte, to, macrophage, differentiation, and, in, innate, immunity])].
[sujeto(['METHODS:', 'Patients']), verbo([provided]), complemento([informed, consent, prior, to, entry, into, the, study, as, approved, by, the, 'Institutional', 'Review', 'Board', at, 'LSU', 'Health', 'Sciences', 'Center'])].
[sujeto(['RESULTS:', 'A', single, nucleotide, polymorphism, '(', 'A2033T)', near, a, 'Runx1']), verbo([binding]), complemento([site, in, the, eleventh, intron, of, the, colony, stimulating, factor, 1, receptor, was, identified])].
[sujeto(['CONCLUSIONS:', 'We', conclude, that, the, colony]), verbo([stimulating]), complemento([factor, receptor, 1, gene, may, be, a, susceptibility, gene, for, 'Crohn\'s', disease])].
[sujeto(['To', investigate, retinoblastoma, '(', 'Rb)']), verbo([associated]), complemento([protein, 46, '(', 'RbAp46)', gene, expression, levels, in, bone, marrow, '(', 'BM)', cells, of, leukemia, patients])].
[sujeto(['No', statistic, difference, was]), verbo([found]), complemento([between, the, 'CR', group, and, control, 'group,', or, between, the, newly, diagnosed, group, and, relapsed, group])].
[sujeto(['RbAp46', expression, levels, in, 'ALs', and, 'CML-BC', were, strikingly, higher, than, that, in, 'non-leukemias', and, 'CML-CP,', and, might]), verbo([participate]), complemento([in, leukemogenesis])].